Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[CH:18]=[CH:17][C:5]2[NH:6][C:7](=[O:16])[CH2:8][C:9](=[CH:12]N(C)C)[C:10](=O)[C:4]=2[CH:3]=1.[NH2:19][C:20]([NH2:22])=[NH:21]>>[NH2:21][C:20]1[N:22]=[CH:12][C:9]2[CH2:8][C:7](=[O:16])[NH:6][C:5]3[CH:17]=[CH:18][C:2]([I:1])=[CH:3][C:4]=3[C:10]=2[N:19]=1
Reactant: N=C(N)N
Reactant: CN(C)C=C1CC(=O)Nc2ccc(I)cc2C1=O
Product: Nc1ncc2c(n1)-c1cc(I)ccc1NC(=O)C2

Procedure:
In a manner similar to that described in method H, 7-iodo-4-dimethylaminomethylene-3,4-dihydro-1H-benzo[b]azepine-2,5-dione (v-a) and guanidine were converted to I-51 (79%): HRMS Calcd. for C12H9N4O: 352.9899, Found 352.9900.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)[NH:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[CH3:26][O:27][C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1.[OH-].[Na+]>C(O)C.C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([C:10]2[NH:11][C:12]([C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([C:31]4[CH:32]=[CH:33][C:28]([O:27][CH3:26])=[CH:29][CH:30]=4)=[CH:3][CH:4]=3)[N:9]=2)=[CH:20][CH:21]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: Clc1ccc(-c2nc(-c3ccc(Br)cc3)c(-c3ccncc3)[nH]2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1ccc(-c2ccc(-c3nc(-c4ccc(Cl)cc4)[nH]c3-c3ccncc3)cc2)cc1
Temperature: 90 °C
Reaction time: 8 h
Yield: 25 %

Procedure:
To a solution of 60 mg (0.146 mmol) of 4-(4-bromophenyl)-2-(4-chlorophenyl)-5-(4-pyridyl)imidazole (from Step C) in 1 mL of ethanol and 1.5 mL of toluene was added 56 mg (0.365 mmol) of 4-methoxybenzeneboronic acid, followed by 0.73 mmol (584 μL of a 1.25 N solution) of aqueous NaOH, and 17 mg (0.146 mmol) of tetrakis(triphenylphosphine)palladium(0). The resulting reaction mixture was stirred at 90° C. overnight. After being cooled to room temperature, the reaction was quenched by addition of water and extracted with ethyl acetate twice. The organic layers were combined, washed with water and brine, and dried over sodium sulfate. After filtration and removal of volatiles, the crude product was flash chromatographed over silica gel (gradient elution using 20-50% EtOAc in hexane). This material appeared to be homogeneous by TLC but contained some uncoupled material as shown by HPLC trace. Therefore, it was further purified via a chromatotron, eluting slowly using a 5:95:0.5 mixture of methanol/DCM/HOAc to provide 16 mg of the desired product as a pale yellow solid, homogeneous by TLC, mass spectrum (CI) m/e 438 (M+1)+.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[N:19]=[C:9]2[N:10]=[C:11]([C:15]([O:17][CH3:18])=[O:16])[CH:12]=[C:13](Cl)[N:8]2[N:7]=1)(=[O:3])[CH3:2].O.[SH2:21].[Na]>CO>[C:1]([O:4][CH2:5][C:6]1[N:19]=[C:9]2[N:10]=[C:11]([C:15]([O:17][CH3:18])=[O:16])[CH:12]=[C:13]([SH:21])[N:8]2[N:7]=1)(=[O:3])[CH3:2]
Reactant: S
Reactant: COC(=O)c1cc(Cl)n2nc(COC(C)=O)nc2n1
Agent: [Na]
Solvent: CO
Solvent: O
Product: COC(=O)c1cc(S)n2nc(COC(C)=O)nc2n1
Temperature: 60 °C
Reaction time: 4 h
Yield: 98.1 %

Procedure:
Methyl 2-(acetoxymethyl)-7-chloro-s-triazolo[1,5-a]pyrimidine-5-carboxylate (370 mg) (1.3 mmol) are dissolved in 10 ml of methanol. After the addition of 289 mg (3.9 mmol) of sodium hydrogen sulphide hydrate the mixture is stirred at 60° C. for 4 hours. The yellow solution is concentrated in a vacuum. The residue is dissolved in water and the product is precipitated at pH 3 with 3N aqueous hydrochloric acid. The precipitate is filtered off under suction and crystallized from methanol. There are obtained 360 mg of methyl 2-(acetoxymethyl)-7-mercapto-s-triazolo[1,5-a]pyrimidine-5-carboxylate.
Reaction SMILES: C([O:3][C:4](=O)[C@H:5]([N:7]1[C:12]2[CH:13]=[CH:14][C:15]([Br:17])=[CH:16][C:11]=2[O:10][CH2:9][C:8]1=S)[CH3:6])C.O.[NH2:21][NH2:22]>CCO>[Br:17][C:15]1[CH:16]=[C:11]2[C:12]([N:7]3[C:8]([CH2:9][O:10]2)=[N:22][NH:21][C:4](=[O:3])[C@H:5]3[CH3:6])=[CH:13][CH:14]=1
Reactant: NN
Reactant: CCOC(=O)[C@@H](C)N1C(=S)COc2cc(Br)ccc21
Solvent: O
Solvent: CCO
Product: C[C@@H]1C(=O)NN=C2COc3cc(Br)ccc3N21
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.1 %

Procedure:
To a mixture of (R)-2-(7-bromo-3-thioxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-propionic acid ethyl ester (60 g, 174 mmol) in EtOH (800 mL) was added hydrazine hydrate (98%, 17.4 g, 349 mmol) and the reaction mixture was stirred at ambient temperature overnight. The precipitate was collected by filtration and washed with cold EtOH (3×80 mL) to give (R)-7-bromo-4-methyl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one (32.5 g, 59%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.82 (s, 1H), 7.23 (s, 1H), 7.21 (s, 2H), 4.78 (q, J=6.8 Hz, 1H), 4.68-4.60 (m, 2H), 1.29 (d, J=6.8 Hz, 3H). SFC (Table 1, Method 31) Rt=6.114 min.; [α]D20=−342.08 (C=0.002 g/mL in methanol).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:22][C:21]2[C@:16]([CH3:24])([CH2:17][CH2:18][C:19](=[O:23])[CH:20]=2)[C@@H:15]2[C@@H:3]1[C@H:4]1[C@:12]([CH3:25])([CH2:13][CH2:14]2)[C@@H:7]([C@@H:8]([CH:10]=[O:11])[CH3:9])[CH2:6][CH2:5]1.[BH4-].[Na+].Cl>C(O)C>[OH:1][C@@H:2]1[CH2:22][C:21]2[C@:16]([CH3:24])([CH2:17][CH2:18][C:19](=[O:23])[CH:20]=2)[C@@H:15]2[C@@H:3]1[C@H:4]1[C@:12]([CH3:25])([CH2:13][CH2:14]2)[C@@H:7]([C@H:8]([CH3:9])[CH2:10][OH:11])[CH2:6][CH2:5]1
Reactant: C[C@H](C=O)[C@H]1CC[C@H]2[C@@H]3[C@H](O)CC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: C[C@H](CO)[C@H]1CC[C@H]2[C@@H]3[C@H](O)CC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Yield: 87.9 %

Procedure:
Ethanol (20 ml) was added to (20S)-7α-hydroxy-pregn-4-en-3-one-20-carbaldehyde (2.00 g, 5.81 mmol) obtained in the same manner as in Example 1 and the mixture was ice-cooled with stirring. Sodium borohydride (0.11 g, 2.91 mmol) was added to the obtained solution and the mixture was stirred under ice-cooling for 1 hr. 3% Hydrochloric acid was added to the obtained reaction mixture for neutralization, and ethanol was evaporated under reduced pressure. Ethyl acetate (100 ml) and water (20 ml) were added to wash the residue, and the aqueous layer was separated. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give (20S)-7α,21-dihydroxy-20-methyl-pregn-4-en-3-one (1.77 g, yield 88%) having the following property.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:27](=[CH:28][C:29]=1[O:30][CH3:31])[C:7]1[N:8](COCC[Si](C)(C)C)[N:9]=[C:10]([C:11]3[CH:12]=[CH:13][C:14]([C:17]#[N:18])=[N:15][CH:16]=3)[C:6]=1[C:5]2([CH3:33])[CH3:32]>Cl.CCO>[OH:1][C:2]1[CH:3]=[C:4]2[C:27](=[CH:28][C:29]=1[O:30][CH3:31])[C:7]1[NH:8][N:9]=[C:10]([C:11]3[CH:12]=[CH:13][C:14]([C:17]#[N:18])=[N:15][CH:16]=3)[C:6]=1[C:5]2([CH3:33])[CH3:32]
Reactant: COc1cc2c(cc1O)C(C)(C)c1c(-c3ccc(C#N)nc3)nn(COCC[Si](C)(C)C)c1-2
Agent: Cl
Solvent: CCO
Product: COc1cc2c(cc1O)C(C)(C)c1c(-c3ccc(C#N)nc3)n[nH]c1-2
Yield: 24.2 %

Procedure:
A mixture of Example 134D (23.0 mg, 0.0497 mmol) and HCl (concentrated, 2 drops) in EtOH (2 mL) was stirred at 75° C. for 1.5 hours. The solvent was evaporated and the residue was purified using reversed-phase HPLC to give the desired product (4.0 mg) as TFA salt. MS (ESI) m/z: 333.0 (M+H)+; 1H NMR (300 MHz, CD3OD) δ ppm 1.56 (s, 6H) 3.93 (s, 3H) 6.94 (s, 1H) 7.20 (s, 1H) 7.99 (d, J=8.14 Hz, 1H) 8.32 (dd, J=8.14, 2.37 Hz, 1H) 9.11 (d, J=2.37 Hz, 1H).
Reaction SMILES: C(=O)(OC(C)(C)C)[NH2:2].C([O-])([O-])=O.[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.Cl[C:58]1[CH:59]=[N:60][CH:61]=[C:62]([F:71])[C:63]=1[N:64]1[CH2:69][CH2:68][N:67]([CH3:70])[CH2:66][CH2:65]1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:71][C:62]1[C:63]([N:64]2[CH2:69][CH2:68][N:67]([CH3:70])[CH2:66][CH2:65]2)=[C:58]([NH2:2])[CH:59]=[N:60][CH:61]=1
Reactant: CC(C)(C)OC(N)=O
Reactant: CN1CCN(c2c(F)cncc2Cl)CC1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CN1CCN(c2c(N)cncc2F)CC1
Temperature: 110 °C

Procedure:
A mixture of tert-butyl carbamate (709.9 mg, 6.060 mmol), Cs2CO3 (3.291 g, 10.10 mmol), xantphos (146.1 mg, 0.2525 mmol), Pd2(dba)3 (231.2 mg, 0.2525 mmol) and 1-(3-chloro-5-fluoro-4-pyridyl)-4-methyl-piperazine (1.16 g, 5.050 mmol) in dioxane (11.60 mL) was heated at 110° C. for 1 h. At room temperature, tert-butyl carbamate (709.9 mg, 6.060 mmol), xantphos (146.1 mg, 0.2525 mmol) and Pd2(dba)3 (231.2 mg, 0.2525 mmol) was added and the mixture was further heated at 120° C. in the microwave for 1 h. The reaction mixture was then filtered through a celite pad and washed with methanol and the filtrate concentrated in vacuo. The residue was purified by column chromatography on silica, using the ISCO column companion system eluting with 0-10% MeOH/DCM. Product fractions were combined and concentrated in vacuo to yield 5-fluoro-4-(4-methylpiperazin-1-yl)pyridin-3-amine as a light brown viscous oil. (642 mg, 60%). MS (ES+) 211.1.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]([C:8]([N:10]2[CH2:15][CH2:14][C:13]3[NH:16][C:17]([C:19]4[C:27]5[C:22](=[CH:23][C:24]([C:28]6[CH:33]=[C:32]([F:34])[C:31]([OH:35])=[CH:30][C:29]=6[CH2:36][CH3:37])=[CH:25][CH:26]=5)[NH:21][N:20]=4)=[N:18][C:12]=3[CH2:11]2)=[O:9])=[N:6][CH:7]=1.[CH3:38][N:39]([CH3:45])[C@@H:40]1[CH2:44][CH2:43][NH:42][CH2:41]1>>[CH3:38][N:39]([CH3:45])[C@@H:40]1[CH2:44][CH2:43][N:42]([C:2]2[N:3]=[CH:4][C:5]([C:8]([N:10]3[CH2:15][CH2:14][C:13]4[NH:16][C:17]([C:19]5[C:27]6[C:22](=[CH:23][C:24]([C:28]7[CH:33]=[C:32]([F:34])[C:31]([OH:35])=[CH:30][C:29]=7[CH2:36][CH3:37])=[CH:25][CH:26]=6)[NH:21][N:20]=5)=[N:18][C:12]=4[CH2:11]3)=[O:9])=[N:6][CH:7]=2)[CH2:41]1
Reactant: CN(C)[C@@H]1CCNC1
Reactant: CCc1cc(O)c(F)cc1-c1ccc2c(-c3nc4c([nH]3)CCN(C(=O)c3cnc(Cl)cn3)C4)n[nH]c2c1
Product: CCc1cc(O)c(F)cc1-c1ccc2c(-c3nc4c([nH]3)CCN(C(=O)c3cnc(N5CC[C@@H](N(C)C)C5)cn3)C4)n[nH]c2c1
Yield: 38.2 %

Procedure:
The title compound was prepared from (5-chloropyrazin-2-yl)(2-(6-(2-ethyl-5-fluoro-4-hydroxyphenyl)-1H-indazol-3-yl)-6,7-dihydro-1H-imidazo[4,5-c]pyridin-5(4H)-yl)methanone (80 mg, 154 μmol) and (R)-3-dimethylaminopyrrolidine, (35 mg, 308 μmol) using the method of Example 32. The crude material was purified by HPLC Method C to afford (35 mg, 38%) of the title compound as white solid.
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]([O:9][CH2:10][CH2:11][N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[C:6]([OH:8])[CH:7]=1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:25]=[CH:26][C:27]([C:30]#[CH:31])=[N:28][CH:29]=2)=[CH:20][CH:19]=1>>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([C:24]2[CH:25]=[CH:26][C:27]([C:30]#[C:31][C:2]3[CH:3]=[CH:4][C:5]([O:9][CH2:10][CH2:11][N:12]4[CH2:16][CH2:15][CH2:14][CH2:13]4)=[C:6]([OH:8])[CH:7]=3)=[N:28][CH:29]=2)=[CH:22][CH:23]=1
Reactant: Oc1cc(I)ccc1OCCN1CCCC1
Reactant: C#Cc1ccc(-c2ccc(Cl)cc2)cn1
Product: Oc1cc(C#Cc2ccc(-c3ccc(Cl)cc3)cn2)ccc1OCCN1CCCC1

Procedure:
The product was obtained analogously to Example 7.1e starting from 5-iodo-2-(2-pyrrolidin-1-ylethoxy)phenol and 5-(4-chlorophenyl)-2-ethynylpyridine. Yield: 0.75 g (48% of theoretical); C25H23ClN2O2 (M=418.915); calc.: molpeak (M+H)+: 419/421 (Cl); found: molpeak (M+H)+: 419/421 (Cl); HPLC-MS: 7.33 minutes (method A).
Reaction SMILES: [CH3:1][C:2]1[CH2:11][S:10][C@@H:5]2[C@H:6]([NH2:9])[C:7](=[O:8])[N:4]2[C:3]=1[C:12]([OH:14])=[O:13].[F:15][C:16]([F:26])([F:25])[CH2:17][S:18]([CH2:21][C:22](O)=[O:23])(=[O:20])=[O:19]>>[F:26][C:16]([F:15])([F:25])[CH2:17][S:18]([CH2:21][C:22]([NH:9][CH:6]1[C:7](=[O:8])[N:4]2[C:3]([C:12]([OH:14])=[O:13])=[C:2]([CH3:1])[CH2:11][S:10][C@H:5]12)=[O:23])(=[O:20])=[O:19]
Reactant: CC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: O=C(O)CS(=O)(=O)CC(F)(F)F
Product: CC1=C(C(=O)O)N2C(=O)C(NC(=O)CS(=O)(=O)CC(F)(F)F)[C@H]2SC1

Procedure:
When the t-butyl ester of 7-ADCA is acylated with trifluoroethylsulfonylacetic acid by the procedure of Example 8, 7-trifluoroethylsulfonylacetamido-3-methyl-3-cephem-4-carboxylic acid is obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:32]=[CH:31][C:12]([NH:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([C:24]4[O:28][CH:27]=[C:26]([CH:29]=O)[CH:25]=4)[CH:22]=3)[N:17]=[CH:16][N:15]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:33][S:34]([CH2:37][CH2:38][NH2:39])(=[O:36])=[O:35]>>[CH2:1]([O:8][C:9]1[CH:32]=[CH:31][C:12]([NH:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([C:24]4[O:28][CH:27]=[C:26]([CH2:29][NH:39][CH2:38][CH2:37][S:34]([CH3:33])(=[O:36])=[O:35])[CH:25]=4)[CH:22]=3)[N:17]=[CH:16][N:15]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1coc(-c2ccc3ncnc(Nc4ccc(OCc5ccccc5)cc4)c3c2)c1
Reactant: CS(=O)(=O)CCN
Product: CS(=O)(=O)CCNCc1coc(-c2ccc3ncnc(Nc4ccc(OCc5ccccc5)cc4)c3c2)c1

Procedure:
Prepared according to Procedure D from 5-(4-{4-benzyloxyanilino}-6-quinazolinyl)-furan-3-carbaldehyde (0.6 equiv) and 2-methanesulphonyl-ethylamine (1 equiv). 1HNMR 400 MHz, d6DMSO 9.51 (bs, 2H), 9.11 (s, 1H), 8.79 (s, 1H), 8.29 (d, 1H), 8.06 (s, 1H), 7.90 (d, 1H), 7.60 (d, 2H), 7.5-7.3 (m, 5H), 7.11 (d, 2H), 5.14 (s, 2H), 4.14 (bs, 2H), 3.6-3.5 (m, 3H), 3.12 (s, 3H); MS m/z 529 (M+1).
Reaction SMILES: [OH:1][C@H:2]([CH3:6])[C:3](N)=O.F[B-](F)(F)F.C([O+](CC)CC)C.[CH3:19][S:20]([CH2:23][CH2:24][C@H:25]1[CH2:30][CH2:29][C@H:28]([NH:31][C:32]2[C:37]([NH2:38])=[CH:36][N:35]=[C:34]3[CH:39]=[CH:40][S:41][C:33]=23)[CH2:27][CH2:26]1)(=[O:22])=[O:21]>O1CCCC1.C(O)C>[CH3:19][S:20]([CH2:23][CH2:24][C@H:25]1[CH2:30][CH2:29][C@H:28]([N:31]2[C:32]3=[C:33]4[S:41][CH:40]=[CH:39][C:34]4=[N:35][CH:36]=[C:37]3[N:38]=[C:3]2[C@H:2]([OH:1])[CH3:6])[CH2:27][CH2:26]1)(=[O:21])=[O:22]
Reactant: C[C@@H](O)C(N)=O
Reactant: CS(=O)(=O)CC[C@H]1CC[C@H](Nc2c(N)cnc3ccsc23)CC1
Agent: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: CCO
Solvent: C1CCOC1
Product: C[C@@H](O)c1nc2cnc3ccsc3c2n1[C@H]1CC[C@H](CCS(C)(=O)=O)CC1
Reaction time: 0.25 h

Procedure:
A mixture of (2R)-2-hydroxypropanamide (52 mg, 0.59 mmol) and triethyloxonium tetrafluoroborate (0.11 g, 0.59 mmol) in tetrahydrofuran (1 mL) became a solution after stirring for 15 min. After another 45 min, this solution was added to a mixture of N7-{trans-4-[2-(methylsulfonyl)ethyl]cyclohexyl}thieno[3,2-b]pyridine-6,7-diamine (83 mg, 0.23 mmol) in ethanol (2 mL) and heated at reflux overnight. The resulting mixture was purified on RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 30 mL/min) to give the desired product (1.1 mg, 1.1%). LCMS calculated for C19H26N3O3S2 (M±H)+: m/z=408.1. Found: 408.1.
Reaction SMILES: [CH-:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[CH-:6]1[CH:10]=[CH:9][CH:8]=[CH:7]1.[Fe+2:11].[Cl:12][CH2:13][CH2:14][C:15](Cl)=[O:16].[Cl-].[Al+3].[Cl-].[Cl-]>ClCCl>[Cl:12][CH2:13][CH2:14][C:15]([C-:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1)=[O:16].[CH-:6]1[CH:10]=[CH:9][CH:8]=[CH:7]1.[Fe+2:11]
Reactant: O=C(Cl)CCCl
Agent: [Fe+2]
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(CCCl)[c-]1cccc1
Reaction time: 2 h
Yield: 89.1 %

Procedure:
A solution of ferrocene (2.63 kg, 14.2 mole) and 3-chloropropionyl chloride (1.8 kg, 15.6 moles) in dry dichloromethane (23.5 l) was cooled to -3° and treated over 1 hour with aluminium chloride (2.08 kg, 15.6 mole). The reaction mixture was left to stir for 2 hours. To this was then added ice water (30 kg) and the two layers separated. The aqueous layer was washed with dichloromethane and the combined organic liquors were washed with water (30 l), 2% aqueous sodium bicarbonate solution (20 l) and water again (60 l). The organic liquors were then dried and concentrated affording black/brown semi-solid chloropropionyl ferrocene (3.5 kg).
Reaction SMILES: C[C:2]1[C:11]2[C:6](=[C:7]([C:13]#[C:14]CO)[CH:8]=[CH:9][C:10]=2[F:12])[N:5]=[C:4](C)[C:3]=1[CH3:18].[OH-].[Na+].C1(C)C=CC=CC=1>C(OCC)C>[F:12][C:10]1[CH:9]=[CH:8][C:7]([C:13]#[CH:14])=[C:6]2[C:11]=1[CH:2]=[C:3]([CH3:18])[CH:4]=[N:5]2
Reactant: Cc1nc2c(C#CCO)ccc(F)c2c(C)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: C#Cc1ccc(F)c2cc(C)cnc12
Temperature: 120 °C
Yield: 50.9 %

Procedure:
Dimethylhydroxymethyl-5-fluoro-3-methyl-8-quinolylacetylene (336 mg, 1.38 mmol) and NaOH (55.2 mg, KISHIDA CHEMICAL CO., Ltd., 0.7 mm granular, 98 mass %, 1.38 mmol) were placed in a 300 mL two-neck flask equipped with a reflux condenser and the air inside the flask was replaced with Ar. 3.0 mL of toluene was added thereto and the mixture was refluxed at 120° C. for 30 minutes. Diethyl ether was added to the reaction mixture and the mixture was washed with a saturated aqueous ammonium chloride solution and dried over magnesium sulfate, followed by distilling off of the solvent under reduced pressure by an evaporator. The crude reaction product was purified by column chromatography (Hexane/AcOEt=100/0→1/10) using silica gel to give 130 mg of the desired compound as a brownish brown solid (yield: 50.7%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[C:11]([C:16](=O)[CH3:17])[C:12]([O:14][CH3:15])=[O:13])=[CH:6][CH:5]=1)([O-:3])=[O:2].S(O)(O)(=O)=O.[CH3:24][O:25][C:26](=[NH:28])[NH2:27].CC([O-])=O.[Na+]>CN(C=O)C>[CH3:15][O:14][C:12]([C:11]1[CH:10]([C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[NH:28][C:26]([O:25][CH3:24])=[N:27][C:16]=1[CH3:17])=[O:13]
Reactant: COC(=N)N
Reactant: COC(=O)C(=Cc1ccc([N+](=O)[O-])cc1)C(C)=O
Agent: CC(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C1=C(C)N=C(OC)NC1c1ccc([N+](=O)[O-])cc1
Temperature: 72.5 °C

Procedure:
A mixture of methyl 2-{(4-nitrophen-yl)methylene}-3-oxobutyrate (12.46 g, 0.05 mol), O-methylisourea hydrogen sulfate (10.32 g, 0.06 mol), and NaOAc (9.84 g, 0.06 mol) in DMF (50 mL) was stirred and heated at 70-75° C. for 4 hours. The mixture was cooled and poured into ice-water (300 mL). The precipitate formed was filtered, washed with water, and dried. The crude product was purified by flash column chromatography on silica gel using 10% through 30% EtOAc in hexane as the gradient eluent (9.8 g, 64%). The 1H-NMR analysis of the product showed it to be a 19:1 mixture of the amine/imine tautomers which was used as such in the next step. 1H-NMR (CDCl3): δ 2.32, 2.38 (2 s, 3H), 3.59, 3.70 (2 s, 3H), 3.70, 3.85 (2 s, 3H), 5.40, 5.66 (s, d, J=3 Hz, 1H), 5.50, 6.08 (s, d, J=3 Hz, 1H), 7.43, 7.45 (2 d, J=9 Hz, 2H), 8.10, 8.11 (2 d, J=9 Hz, 2H).
Reaction SMILES: [C:1]([C:4]1[C:5](=[O:26])[NH:6][C:7]2[C:12]([C:13]=1C)=[C:11](OS(O)(=O)=O)[CH:10]=[CH:9][C:8]=2[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)(=[O:3])[CH3:2].[CH3:27][CH:28]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH2:29][NH2:30]>>[C:1]([C:4]1[C:5](=[O:26])[NH:6][C:7]2[C:12]([C:13]=1[NH:30][CH2:29][CH:28]([CH3:27])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[CH:11][CH:10]=[CH:9][C:8]=2[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1c(C)c2c(OS(=O)(=O)O)ccc(-c3ccccc3)c2[nH]c1=O
Reactant: CC(CN)c1ccccc1
Product: CC(=O)c1c(NCC(C)c2ccccc2)c2cccc(-c3ccccc3)c2[nH]c1=O
Yield: 83 %

Procedure:
3-Acetyl-4-methylsulfoxy-8-phenyl-2-quinolinone (3.25g, 0.01 mol) and β-methylphenethylamine (1.35g, 0.01 mol) were used, but the reaction was carried out as the above process of example 37 to obtain the desired product (3.29g, yield: 83%).
Reaction SMILES: FC1(C(O)=O)CCC(=CC2C(C)(C)[C@H]3[C@](C)(CC=2)[C@@H]2[C@](C)([C@@]4(C)[C@H](CC2)[C@H]2[C@H](C(C)=C)CC[C@]2(NCCN2CCC(S(C)(=O)=O)CC2)CC4)CC3)CC1.[CH3:54][C@:55]12[C@@:72]3([CH3:73])[C@@H:63]([C@:64]4([CH3:84])[C@@H:69]([CH2:70][CH2:71]3)[C:68]([CH3:75])([CH3:74])[C:67]([CH:76]=[CH:77][CH:78]=[CH:79][C:80]([O:82]C)=[O:81])=[CH:66][CH2:65]4)[CH2:62][CH2:61][C@@H:60]1[C@H:59]1[C@H:85]([C:88]([CH3:90])=[CH2:89])[CH2:86][CH2:87][C@:58]1([NH:91][CH2:92][CH2:93][N:94]1[CH2:99][CH2:98][CH:97]([S:100]([CH3:103])(=[O:102])=[O:101])[CH2:96][CH2:95]1)[CH2:57][CH2:56]2>>[CH3:54][C@:55]12[C@@:72]3([CH3:73])[C@@H:63]([C@:64]4([CH3:84])[C@@H:69]([CH2:70][CH2:71]3)[C:68]([CH3:74])([CH3:75])[C:67]([CH:76]=[CH:77][CH:78]=[CH:79][C:80]([OH:82])=[O:81])=[CH:66][CH2:65]4)[CH2:62][CH2:61][C@@H:60]1[C@H:59]1[C@H:85]([C:88]([CH3:90])=[CH2:89])[CH2:86][CH2:87][C@:58]1([NH:91][CH2:92][CH2:93][N:94]1[CH2:95][CH2:96][CH:97]([S:100]([CH3:103])(=[O:101])=[O:102])[CH2:98][CH2:99]1)[CH2:57][CH2:56]2
Reactant: C=C(C)[C@@H]1CC[C@]2(NCCN3CCC(S(C)(=O)=O)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(C=CC=CC(=O)OC)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: C=C(C)[C@@H]1CC[C@]2(NCCN3CCC(S(C)(=O)=O)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(C=C6CCC(F)(C(=O)O)CC6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Product: C=C(C)[C@@H]1CC[C@]2(NCCN3CCC(S(C)(=O)=O)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(C=CC=CC(=O)O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12

Procedure:
5-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((2-(4-(methylsulfonyl)piperidin-1-yl)ethyl)amino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)penta-2,4-dienoic acid was prepared was prepared following the procedure described in step 2 of the preparation of 1-fluoro-4-(((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((2-(4-(methylsulfonyl)piperidin-1-yl)ethyl)amino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)methylene)cyclohexanecarboxylic acid using the corresponding crude product from step 1 as the reactant. The title compound was obtained as a mixture of 2E,4E- and 2E,4Z-2,4-dienoic acid isomers (solid, 39%). MS: m/e 695.5 (M+H)+, 2.38 min (method 5). For 2E,4E isomer, 1H NMR (400 MHz, CHLOROFORM-d) δ 7.35-7.24 (m, 1H), 6.50 (d, J=15.3 Hz, 1H), 6.16 (dd, J=15.2, 11.2 Hz, 1H), 5.89 (d, J=15.1 Hz, 1H), 5.60 (s, 1H), 4.82 (s, 1H), 4.66 (s, 1H), 3.38-2.52 (m, 12H), 2.87 (s, 3H), 2.33-0.83 (m, 24H), 1.71 (s, 3H), 1.13 (s, 3H), 0.99 (s, 3H), 0.97 (s, 3H), 0.89 (s, 3H), 0.68 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]=[C:9]([N+]([O-])=O)[CH2:10][CH3:11].FC1C=CC=CC=1C=[O:19].[N+](CCC)([O-])=O.C([O-])(=O)C.[NH4+].C(=O)([O-])O.[Na+]>C(O)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9](=[O:19])[CH2:10][CH3:11]
Reactant: CCC(=Cc1ccccc1F)[N+](=O)[O-]
Reactant: O=Cc1ccccc1F
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [NH4+]
Solvent: CCC[N+](=O)[O-]
Solvent: CC(=O)O
Product: CCC(=O)Cc1ccccc1F
Temperature: 25 °C
Reaction time: 4 h

Procedure:
1-(2-Fluorophenyl)-2-nitro-1-butene 30 ml of acetic acid were added to 4.73 g (38.11 mmole) of 2-fluorobenzaldehyde, 4.41 g (49.49 mmole) of nitropropane and 3.23 g (41.90 mmole) of ammonium acetate, and the resulting mixture was heated under reflux, whilst stirring, for 4 hours. At the end of this time, the reaction mixture was cooled to room temperature, neutralized with an aqueous solution of sodium hydrogencarbonate and extracted with diethyl ether. The extract was dried over anhydrous magnesium sulfate, and then xylene was added to the solution. The mixture was concentrated by evaporation under reduced pressure, to give 7.4 g of the title compound as a pale yellow oil.
Reaction SMILES: [C:1]([OH:7])(=O)[CH2:2][CH2:3][C:4]#[CH:5].Cl.[NH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1.ON1C2C=CC=CC=2N=N1.CCN=C=NCCCN(C)C.Cl.C(N(CC)CC)C>CN(C=O)C.O>[O:12]1[CH2:13][CH2:14][N:9]([C:1]([C:2]#[C:3][CH2:4][CH3:5])=[O:7])[CH2:10][CH2:11]1
Reactant: C#CCCC(=O)O
Reactant: C1COCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCC#CC(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.8 %

Procedure:
A mixture of 4-pentynoic acid (210 mg, 2.14 mmol), morpholine hydrochloride (265 mg, 2.14 mmol), 1-hydroxybenzotriazol (338 mg, 2.50 mmol), WSC HCl (484 mg, 2.52 mmol), and triethylamine (0.37 ml, 2.65 mmol) in DMF (7 mL) was stirred for 1 h at room temperature. Water was added. The mixture was extracted with ethyl acetate-toluene, and the extracts were washed with water, dried over MgSO4, and concentrated. The residue was purified by silica gel column chromatography with 1:1 to 1:5 hexane/ethyl acetate to give the title compound (325 mg, 91%).