Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([SH:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH2:12]Br.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[Br:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH2:12][S:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: SC1CCCCC1
Reactant: BrCc1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Brc1cccc(CSC2CCCCC2)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of cyclohexylmercaptan (1.09 mL, 8.89 mmol), 3-bromobenzyl bromide (2.22 g, 8.882 mmol) and K2CO3 (2.54 g, 18.38 mmol) in acetone was stirred under argon at room temperature for 4 hrs then filtered. The filtrate was concentrated under reduced pressure. Purification by flash chromatography (0% to 20% EtOAc-hexanes gradient) gave (3-bromobenzyl)(cyclohexyl)sulfane as a colorless oil. Yield (2.02 g, 80%); 1H NMR (400 MHz, CDCl3) δ 7.48 (t, J=1.8 Hz, 1H), 7.33-7.37 (m, 1H), 7.22-7.26 (m, 1H), 7.16 (t, J=7.8 Hz, 1H), 3.68 (s, 2H), tt, J=3.33, 10.0 Hz, 1H), 1.87-1.96 (m, 2H), 1.69-1.77 (m, 2H), 1.53-1.61 (m, 1H), 1.18-1.38 (m, 5H).
Reaction SMILES: [CH2:1]([C@@H:4]1[C:9](=[O:10])[NH:8][C:7]2[N:11]=[CH:12][CH:13]=[CH:14][C:6]=2[N:5]1[S:15]([C:18]1[CH:24]=[CH:23][C:21]([CH3:22])=[CH:20][CH:19]=1)(=[O:17])=[O:16])[C:2]#[CH:3].[N:25]([C@@H:28]1[CH2:37][CH2:36][CH2:35][C:34]2[CH:33]=[C:32]([CH2:38][N:39]3[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]3)[CH:31]=[CH:30][C:29]1=2)=[N+:26]=[N-:27]>O1CCOCC1.CC(O)(C)C.O.CCOC(C)=O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Cu+2]>[N:39]1([CH2:38][C:32]2[CH:33]=[C:34]3[C:29](=[CH:30][CH:31]=2)[C@H:28]([N:25]2[CH:3]=[C:2]([CH2:1][C@@H:4]4[C:9](=[O:10])[NH:8][C:7]5[N:11]=[CH:12][CH:13]=[CH:14][C:6]=5[N:5]4[S:15]([C:18]4[CH:19]=[CH:20][C:21]([CH3:22])=[CH:23][CH:24]=4)(=[O:16])=[O:17])[N:27]=[N:26]2)[CH2:37][CH2:36][CH2:35]3)[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1
Reactant: C#CC[C@@H]1C(=O)Nc2ncccc2N1S(=O)(=O)c1ccc(C)cc1
Reactant: [N-]=[N+]=N[C@@H]1CCCc2cc(CN3CCCCC3)ccc21
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: Cc1ccc(S(=O)(=O)N2c3cccnc3NC(=O)[C@H]2Cc2cn([C@@H]3CCCc4cc(CN5CCCCC5)ccc43)nn2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (R)-2-(prop-2-ynyl)-1-tosyl-1,2-dihydropyrido[2,3-b]pyrazin-3(4H)-one (210 mg, 0.615 mmol) and (R)-1-((5-azido-5,6,7,8-tetrahydronaphthalen-2-yl)methyl)piperidine (183 mg, 0.677 mmol) in dioxane (3 mL) and t-BuOH (4 mL) was added a solution of copper(2+) sulfate, pentahydrate (43.0 μl, 0.615 mmol) in water (1 mL), followed by a solution of (+)-sodium 1-ascorbate (122 mg, 615 μmol). The resulting solution was stirred at room temperature overnight. The reaction was diluted with EtOAc, washed with brine, dried over Na2SO4, and evaporated to dryness. Flash chromatography (SiO2, EtOAc to EtOAc/2M NH3 in MeOH=100:5 to 100:10 to 100:15) of the residue afforded the title compound as a white solid.
Reaction SMILES: [N:1]1[N:5]2[C:6]([CH:10]([OH:12])[CH3:11])=[CH:7][CH:8]=[N:9][C:4]2=[N:3][CH:2]=1.CCOC(/N=N/C(OCC)=O)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:44][C:45]1[CH:50]=[CH:49][C:48](O)=[CH:47][CH:46]=1>O1CCCC1>[Cl:44][C:45]1[CH:50]=[CH:49][C:48]([O:12][CH:10]([C:6]2[N:5]3[N:1]=[CH:2][N:3]=[C:4]3[N:9]=[CH:8][CH:7]=2)[CH3:11])=[CH:47][CH:46]=1
Reactant: CC(O)c1ccnc2ncnn12
Reactant: Oc1ccc(Cl)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(Oc1ccc(Cl)cc1)c1ccnc2ncnn12
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of (+)-1-(1,2,4-triazolo[1,5-a]pyrimidin-7-yl)ethanol (0.27 g), diethylazodicarboxylate (0.29 g), triphenylphosphine (0.44 g) and 4-chlorophenol (0.22 g) in dry tetrahydrofuran (40 ml) was stirred at ambient temperature for 2 days. Further diethylazodicarboxylate (0.15 g) and triphenylphosphine (0.22 g) was added to the solution, which was stirred overnight until the reaction was complete. The solvent was removed under reduced pressure and the residue was dissolved in ethyl acetate (100 ml). This solution was washed with 1M sodium hydroxide (40 ml) followed by brine (20 ml) and the solvent was evaporated. The residue was purified by flash chromatography on silica gel using as eluent a mixture of triethylamine and ethyl acetate (in the ratio 1:100 respectively) to give (+)-7-[1-(4-chlorophenoxy)ethyl]-1,2,4-triazolo[1,5-a]pyrimidine. Yield 0.33 g.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][C:23]([O:34][CH3:35])=[C:24]([C:27]4[O:31][C:30]([CH:32]=O)=[CH:29][CH:28]=4)[CH:25]=3)[N:20]=[CH:19][N:18]=2)=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:36][S:37]([CH2:40][CH2:41][NH2:42])(=[O:39])=[O:38].C(O)(=O)C.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][C:23]([O:34][CH3:35])=[C:24]([C:27]4[O:31][C:30]([CH2:32][NH:42][CH2:41][CH2:40][S:37]([CH3:36])(=[O:39])=[O:38])=[CH:29][CH:28]=4)[CH:25]=3)[N:20]=[CH:19][N:18]=2)=[CH:12][CH:11]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: COc1cc2ncnc(Nc3ccc(OCc4ccccc4)cc3)c2cc1-c1ccc(C=O)o1
Reactant: CS(=O)(=O)CCN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Product: COc1cc2ncnc(Nc3ccc(OCc4ccccc4)cc3)c2cc1-c1ccc(CNCCS(C)(=O)=O)o1
Reaction time: 96 h
Yield: 48.1 %

Procedure:
Prepared in a similar manner to Procedure D from 5-(4-(4-benzyloxy-phenylamino)-7-methoxy-quinazolin-6-yl)-furan-2-carbaldehyde hydrochloride(78 mg, 0.16 mmol), 2-methanesulphonylethylamine(33 mg, 0.27 mmol), acetic acid(15 mg, 0.25 mmol) and triethylamine(18 mg, 0.18 mmol) in 3 ml of 1,2-dichloroethane added to sodium triacetoxyborohydride(102 mg, 0.48 mmol) portionwise over a two day period. The reaction mixture was stirred four days and then partitioned between 10 ml of 0.5M NaHCO3 solution and 50 ml of ethyl acetate. The organic solution was dried with Na2SO4 and concentrated in vacuo. The residue was chromatographed on silica gel with methanol/methylene chloride(1:49 to 2:48). The resulting solid was crystallized from a small volume of ethyl acetate, suspended in ether and filtered to give 43 mg of product as a pale yellow solid. δ1H NMR (400 MHz, DMSO-d6) 9.78(s, 1H), 8.73(s, 1H), 8.42(s, 1H), 6.64(d, 2H), 7.47(m, 2H), 7.40(m, 2H), 7.33(m, 1H), 7.25(s, 1H), 7.04(d, 2H), 6.98(d, 1H), 6.46(d, 1H), 5.12(s, 2H), 4.04(s, 3H), 3.86(s, 2H), 3.28(t, 2H), 3.01 (s, 3H), 2.99(t, 2H). ESI-MS m/z 559(M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]2[C:9]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=3)=[N:10][N:11]([C:13]3[CH:18]=[CH:17][C:16](=[O:19])[NH:15][N:14]=3)[CH:12]=2)[CH:5]=[CH:4][N:3]=1.NC1C=C(C2C(C3C=CC=CC=3)=NN(C3C=CC(=O)NN=3)C=2)C=CN=1>>[NH2:1][C:2]1[CH:7]=[C:6]([C:8]2[C:9]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=3)=[N:10][N:11]([C:13]3[CH2:18][CH2:17][C:16](=[O:19])[NH:15][N:14]=3)[CH:12]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Nc1cc(-c2cn(-c3ccc(=O)[nH]n3)nc2-c2cccc(F)c2)ccn1
Agent: Nc1cc(-c2cn(-c3ccc(=O)[nH]n3)nc2-c2ccccc2)ccn1
Product: Nc1cc(-c2cn(C3=NNC(=O)CC3)nc2-c2cccc(F)c2)ccn1
Yield: 68.7 %

Procedure:
The reaction was carried out in the same manner as in Example 49 except for using 300 mg (0.86 mmol) of 4-(2-aminopyridin-4-yl)-3-(3-fluorophenyl)-1-(1,6-dihydro-6-oxopyridazin-3-yl)-1H-pyrazole obtained in Example 22-4) in place of 4-(2-aminopyridin-4-yl)-1-(1,6-dihydro-6-oxopyridazin-3-yl)-3-phenyl-1H-pyrazole to obtain 207 mg of the title compound as a white powder. (Yield: 69%)
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH:13]([C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)/[C:21](=[N:25]/[OH:26])/[CH2:20][CH2:19][CH2:18]2)=[CH2:14].[C:27]1([N:33]2[C:37]([C:38]([F:41])([F:40])[F:39])=[C:36]([C:42](OCC)=O)[CH:35]=[N:34]2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(=O)=O.S(Cl)(Cl)=O.N1C=CC=CC=1>C1COCC1.CCCCCCC.C(OCC)(=O)C.C1(C)C=CC=CC=1>[C:27]1([N:33]2[C:37]([C:38]([F:41])([F:40])[F:39])=[C:36]([C:42]3[O:26][N:25]=[C:21]4[C:22]5[C:17]([CH2:18][CH2:19][C:20]=34)=[CH:16][C:15]([CH:13]=[CH2:14])=[CH:24][CH:23]=5)[CH:35]=[N:34]2)[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: C=Cc1ccc2c(c1)CCC/C2=N\O
Reactant: CCOC(=O)c1cnn(-c2ccccc2)c1C(F)(F)F
Agent: O=C=O
Agent: [Li]CCCC
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: C=Cc1ccc2c(c1)CCc1c-2noc1-c1cnn(-c2ccccc2)c1C(F)(F)F
Temperature: 0 °C
Reaction time: 1 h
Yield: 39.1 %

Procedure:
To stirred solution of diisopropylamine (1.103 mL, 7.74 mmol) in anhydrous THF (8 mL) was added n-butyllithium (3.10 mL, 7.74 mmol) (2.5 M in hexanes) dropwise at 0° C. under nitrogen. The pale yellow solution was stirred at the same temperature for 20 min before a solution of 6-vinyl-3,4-dihydronaphthalen-1(2H)-one oxime (intermediate 1, 0.659 g, 3.52 mmol) in anhydrous THF (4 mL) was added dropwise at 0° C. under nitrogen. The mixture was stirred at 0° C. for 1 hour and then transferred to a dry-ice bath. A solution of ethyl 1-phenyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate (1 g, 3.52 mmol) in anhydrous THF (3 mL) was added dropwise over 4 min. The solution was stirred with dry-ice cooling for 40 min and at 0° C. for 45 min. The reaction mixture was quenched with saturated aqueous ammonium chloride solution (5 mL) and water (3 mL) extracted with ethyl acetate (2×20 mL), washed with brine (10 mL), dried over sodium sulfate, and concentrated to yield a yellow foamy solid. The solid was mixed with anhydrous toluene (20 mL), thionyl chloride (0.514 mL, 7.04 mmol), and pyridine (0.057 mL, 0.704 mmol) was added at room temperature under nitrogen. The reaction mixture was stirred at room temperature for 5 min and at 100° C. for 25 min., concentrated and quenched with saturated aqueous sodium bicarbonate solution (20 mL) and water (10 mL). The reaction mixture was extracted with dichloromethane (20 mL, then 2×10 mL), dried over sodium sulfate, concentrated and chromatographed (40 g silica gel column, 20→100% dichloromethane in n-heptane and then 20%→50% ethyl acetate in n-heptane) to yield 3-(1-phenyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)-7-vinyl-4,5-dihydronaphtho[1,2-c]isoxazole (560 mg, 1.375 mmol, 39.1% yield) as a green solid. The compound had an HPLC retention time=3.98 min (condition C); LC/MS M+1=407.8.
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][CH:18]=3)=[CH:13][C:11]=2[CH:12]=1)(=O)=O.[NH:25]1[CH2:31][CH2:30][CH2:29][C@@H:26]1[CH2:27][OH:28]>>[OH:28][CH2:27][C@H:26]1[CH2:29][CH2:30][CH2:31][N:25]1[CH2:6][CH2:7][C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][CH:18]=3)=[CH:13][C:11]=2[CH:12]=1
Reactant: CS(=O)(=O)OCCc1cc2cc(-c3ccc(C#N)cc3)ccc2o1
Reactant: OC[C@H]1CCCN1
Product: N#Cc1ccc(-c2ccc3oc(CCN4CCC[C@@H]4CO)cc3c2)cc1

Procedure:
The product from Example 1C and (D)-prolinol were processed as described in Example 1D to provide the titled compound. 1H NMR (300 MHz, CD3OD) δ 7.87 (m, 1H), 7.82 (m, 4H), 7.58 (m, 2H), 6.80 (s, 1H), 3.95 (m, 2H), 3.72 (m, 2H), 3.58 (m, 1H), 3.35-3.4 (m, 4H), 1.95-2.3 (m, 4H); MS (DCI) m/z 347 (M+H)+;
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:15]3[C:14]([CH3:16])=[N:13][N:12]([CH:17]4[CH2:19][CH2:18]4)[C:11]=3[C:10](=[O:20])[NH:9]2)=[CH:4][CH:3]=1.I[C:22]1[CH:23]=[C:24]([CH3:30])[C:25](=[O:29])[N:26]([CH3:28])[CH:27]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].CNCCNC>[Cu]I.O1CCOCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:15]3[C:14]([CH3:16])=[N:13][N:12]([CH:17]4[CH2:19][CH2:18]4)[C:11]=3[C:10](=[O:20])[N:9]2[C:22]2[CH:23]=[C:24]([CH3:30])[C:25](=[O:29])[N:26]([CH3:28])[CH:27]=2)=[CH:4][CH:3]=1
Reactant: Cc1nn(C2CC2)c2c1C(c1ccc(Cl)cc1)NC2=O
Reactant: Cc1cc(I)cn(C)c1=O
Agent: [Cu]I
Agent: CNCCNC
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: Cc1nn(C2CC2)c2c1C(c1ccc(Cl)cc1)N(c1cc(C)c(=O)n(C)c1)C2=O
Temperature: 120 °C
Reaction time: 6 h
Yield: 59.8 %

Procedure:
In a 2-mL screw cap vial was introduced 4-(4-chlorophenyl)-1-cyclopropyl-3-methyl-4,5-dihydropyrrolo[3,4-c]pyrazol-6(1H)-one (Step 23.9) (100 mg, 0.348 mmol), 5-iodo-1,3-dimethylpyridin-2(1H)-one (Step 23.2) (104 mg, 0.417 mmol), tripotassium phosphate (148 mg, 0.695 mmol), copper(I) iodide (6.62 mg, 0.035 mmol), N,N′-dimethylethylenediamine (7.48 μL, 0.070 mmol) and dioxane (2 mL). The reaction mixture was stirred for 6 hr at 120° C., concentrated, diluted with water, and extracted with EtOAc. The combined organic layers were washed once with water, dried over Na2SO4 and evaporated. The crude material was purified by silica gel column chromatography (CH2Cl2/MeOH 1-3%) followed by crystallization of the resulting residue in Et2O to provide the title product (85 mg, 0.208 mmol, 69% yield) as a white solid. tR: 4.22 min (HPLC 1); tR: 0.96 min (LC-MS 2); ESI-MS: 409 [M+H]+ (LC-MS 2); Rf=0.42 (CH2Cl2/MeOH 9:1); 1H NMR (400 MHz, DMSO-d6) δ ppm 0.92-1.15 (m, 2H) 1.18-1.33 (m, 2H) 1.86-2.01 (m, 6H) 3.39 (br. s., 3H) 3.75-3.90 (m, 1H) 6.08 (br. s., 1H) 7.30 (d, J=8.2 Hz, 2H) 7.36-7.47 (m, 3H) 7.75 (br. s., 1H).
Reaction SMILES: C([NH:8][C:9]1[C:10]([CH3:23])=[C:11]([CH3:22])[C:12]2[O:16][C:15]([CH3:18])([CH3:17])[C:14](=[O:19])[C:13]=2[C:20]=1[CH3:21])C1C=CC=CC=1>C(OCC)(=O)C.CCCCCC>[NH2:8][C:9]1[C:10]([CH3:23])=[C:11]([CH3:22])[C:12]2[O:16][C:15]([CH3:17])([CH3:18])[C:14](=[O:19])[C:13]=2[C:20]=1[CH3:21]
Reactant: Cc1c(C)c2c(c(C)c1NCc1ccccc1)C(=O)C(C)(C)O2
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Cc1c(C)c2c(c(C)c1N)C(=O)C(C)(C)O2
Yield: 88 %

Procedure:
Using 5-(benzylamino)-2,2,4,6,7-pentamethyl-1-benzofuran-3 (2H)-one obtained in Reference Example 52, the title compound was synthesized in the same manner as in Reference Example 30. Yield 88%. Melting point: 92-93° C. (ethyl acetate-hexane).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.CO[CH:17](OC)[N:18]([CH3:20])[CH3:19]>>[CH3:17][N:18]([CH3:20])[CH:19]=[N:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:4][CH2:3]1
Reactant: COC(OC)N(C)C
Reactant: NC1CCN(Cc2ccccc2)CC1
Product: CN(C)C=NC1CCN(Cc2ccccc2)CC1
Yield: 83.2 %

Procedure:
The starting 4-amino-1-benzylpiperidine from Part B above (15.0 g, 78.8 mmol) is treated with dimethylformamide dimethylacetal (18.78 g, 157.6 mmol) and refluxed for 2 hours. The solution is permitted to cool overnight, then concentrated in vacuo to the product (15.5 g of oil, 83.2% yield), which solidifies on standing. A small portion crystallizes from hexane to afford colorless needles with a melting point of 61°-65° C.: NMR (CDCl3 δ) 7.28, 3.49, 2.80, and 1.75-3.0; mass spectral molecular ion peak at m/e 245, with abundant fragment ions at m/e 200, 173, 172, 154, and 91.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]([C:9]1[CH:14]=[CH:13][C:12]([NH:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[CH:11][CH:10]=1)([OH:8])[C:4]([F:7])([F:6])[F:5].[Cl:23][C:24]1[CH:34]=[CH:33][C:27]2[S:28][C:29]([CH2:31]Cl)=[CH:30][C:26]=2[CH:25]=1>CC(O)(C)C>[Cl:23][C:24]1[CH:34]=[CH:33][C:27]2[S:28][C:29]([CH2:31][N:15]([CH2:16][C:17]([F:19])([F:18])[F:20])[C:12]3[CH:11]=[CH:10][C:9]([C:3]([OH:8])([C:4]([F:7])([F:6])[F:5])[C:2]([F:21])([F:22])[F:1])=[CH:14][CH:13]=3)=[CH:30][C:26]=2[CH:25]=1
Reactant: ClCc1cc2cc(Cl)ccc2s1
Reactant: OC(c1ccc(NCC(F)(F)F)cc1)(C(F)(F)F)C(F)(F)F
Solvent: CC(C)(C)O
Product: OC(c1ccc(N(Cc2cc3cc(Cl)ccc3s2)CC(F)(F)F)cc1)(C(F)(F)F)C(F)(F)F
Temperature: 120 °C
Reaction time: 10 h
Yield: 19.8 %

Procedure:
A solution of 100 mg (0.29 mmol) of 1,1,1,3,3,3-hexafluoro-2-[4-(2,2,2-trifluoro-ethylamino)-phenyl]-propan-2-ol (example 11.2) in 0.5 mL tBuOH was treated with 115 mg (0.44 mmol) of 5-chloro-2-chloromethyl-benzo[b]thiophene and stirred at 120° C. for 10 hours in a sealed tube. Evaporation of the solvent and column chromatography on silicagel with n-heptane/EtOAc 8:1 yielded 30 mg (19%) of 2-{4-[(5-chloro-benzo[b]thiophen-2-ylmethyl)-(2,2,2-trifluoro-ethyl)-amino]-phenyl}-1,1,1,3,3,3-hexafluoro-propan-2-ol, light yellow oil, MS: 520 ((M-H)−, 1Cl).
Reaction SMILES: [C:1]([O-])(=O)[CH3:2].[Na+].[Br:6][CH2:7][CH2:8][NH:9][C:10]([CH2:16][C:17]([O:19][CH3:20])=[O:18])=[CH:11][C:12]([O:14][CH3:15])=[O:13]>C(O)(C)C>[Br:6][CH2:7][CH2:8][N:9]1[CH:2]=[CH:1][C:11]([C:12]([O:14][CH3:15])=[O:13])=[C:10]1[CH2:16][C:17]([O:19][CH3:20])=[O:18]
Reactant: CC(=O)[O-]
Reactant: COC(=O)C=C(CC(=O)OC)NCCBr
Agent: [Na+]
Solvent: CC(C)O
Product: COC(=O)Cc1c(C(=O)OC)ccn1CCBr
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 72.7 %

Procedure:
Sodium acetate (41.0 g, 500 mmol) was added to the 2-bromoacetaaldehyde solution, and stirred for 5 minutes, at which point the solution had a pH of 6. The flask was placed in a cool tap water bath and dimethyl 3-(2-bromoethylamino)-2-pentenedioate (20.0 g, 71 mmol) was added, followed by isopropanol (40 mL), and the solution was stirred at room temperature (25° C.). Within about 35 minutes, all the solids had dissolved, and a precipitate started forming within 90 minutes. Stirring was continued at room temperature for 20 hours, and the solution then cooled to 0° C. and stirred at that temperature for 1 hour, then filtered through a coarse frit. The precipitate was washed with ice-cold water (400 mL) and ice-cold isopropanol (150 mL) and dried, to give 15.7 g (72% yield) of crude methyl N-(2-bromoethyl)-3-methoxycarbonyl-2-pyrroleacetate as a light tan solid, m.p. 129°-130.5° C.,
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:21])=[N:8][CH:9]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][CH:13]=2)[CH:11]=1)=[O:5])[CH3:2].O.Cl>C(O)C.[Fe]>[NH2:18][C:15]1[CH:16]=[CH:17][C:12]([C:10]2[CH:11]=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[C:7]([CH3:21])=[N:8][CH:9]=2)=[CH:13][CH:14]=1
Reactant: CCOC(=O)c1cc(-c2ccc([N+](=O)[O-])cc2)cnc1C
Agent: [Fe]
Agent: Cl
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1cc(-c2ccc(N)cc2)cnc1C
Yield: 68.7 %

Procedure:
3-Ethoxycarbonyl-2-methyl-5-(p-nitrophenyl)pyridine (2 g) was dissolved in warm ethanol (70 ml). Iron powder (4 g) was added to the solution followed by water (7 ml) containing 2 drops of 11.5 N-hydrochloric acid. The mixture was refluxed for 1.5 hours, cooled and filtered. The filtrate was concentrated and the residue dissolved in methylene dichloride. The solution was washed with water, dried and concentrated. The crude product was recrystallised from methylene dichloride-petroleum ether (b.p. 30°-40°) to give the title compound (1.23 g), m.p. 137°-8°.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:9]([OH:11])=O)=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1.Cl.[CH3:13][NH:14][O:15][CH3:16].N1C=CC=CC=1.Cl.C(N=C=NCCCN(C)C)C.[Cl-].[NH4+]>C(Cl)Cl>[Br:1][C:2]1[C:3]([C:9]([N:14]([O:15][CH3:16])[CH3:13])=[O:11])=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1
Reactant: CNOC
Reactant: O=C(O)c1nc(Cl)ccc1Br
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Cl-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CON(C)C(=O)c1nc(Cl)ccc1Br
Reaction time: 1 h

Procedure:
To a solution of 3-bromo-6-chloropicolinic acid (4.516 g, 19.10 mmol), N,O-dimethylhydroxylamine hydrochloride (3.73 g, 38.2 mmol), pyridine (4.63 mL, 57.3 mmol) in CH2Cl2 (40 mL) at 0° C. was added —N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (4.39 g, 22.92 mmol). After 1 h at 0° C., a saturated aqueous solution of ammonium chloride was added and the product was extracted with MTBE/EtOAc (4:1) (repeated 4 times). The organic layers were combined, dried over Na2SO4 and concentrated to dryness. The product was carried out without purification in the next step. LC/MS m/z 281 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:12])[CH:11]=1)[O:8][CH2:7][C:6]([CH:13]1[O:18][CH2:17][CH:16]([C:19]3[CH:28]=[C:27]4[C:22]([CH2:23][CH:24]([CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH2:25][O:26]4)=[CH:21][C:20]=3[F:34])[CH2:15][O:14]1)=[CH:5]2>C1COCC1.[Pd]>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:12])[CH:11]=1)[O:8][CH2:7][C@H:6]([CH:13]1[O:18][CH2:17][CH:16]([C:19]3[CH:28]=[C:27]4[C:22]([CH2:23][C@@H:24]([CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH2:25][O:26]4)=[CH:21][C:20]=3[F:34])[CH2:15][O:14]1)[CH2:5]2
Reactant: CCCCCC1COc2cc(C3COC(C4=Cc5cc(F)cc(F)c5OC4)OC3)c(F)cc2C1
Agent: [Pd]
Solvent: C1CCOC1
Product: CCCCC[C@H]1COc2cc(C3COC([C@H]4COc5c(F)cc(F)cc5C4)OC3)c(F)cc2C1

Procedure:
6,8-Difluoro-3-[5-(6-fluoro-3-pentylchroman-7-yl)-1,3-dioxan-2-yl]-2H-chromene is hydrogenated to completion in THF on a palladium/active carbon catalyst. The solution is filtered and evaporated, and the residue is recrystallised from heptane, giving isomerically pure (R)-6,8-difluoro-3-[5-((R)-6-fluoro-3-pentylchroman-7-yl)-1,3-dioxan-2-yl]chroman as a colourless solid.
Reaction SMILES: C[O:2][CH:3](OC)[C:4]1[C:9]([C:10](=[O:18])[C:11]2[CH:16]=[CH:15][N:14]=[C:13]([Br:17])[CH:12]=2)=[CH:8][C:7]([O:19][CH3:20])=[C:6]([O:21][CH3:22])[CH:5]=1.Cl.CC(C)=O>O>[CH3:22][O:21][C:6]1[CH:5]=[C:4]([C:9]([C:10](=[O:18])[C:11]2[CH:16]=[CH:15][N:14]=[C:13]([Br:17])[CH:12]=2)=[CH:8][C:7]=1[O:19][CH3:20])[CH:3]=[O:2]
Reactant: COc1cc(C(=O)c2ccnc(Br)c2)c(C(OC)OC)cc1OC
Agent: Cl
Solvent: CC(C)=O
Solvent: O
Product: COc1cc(C=O)c(C(=O)c2ccnc(Br)c2)cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.4 %

Procedure:
3,4-Dimethoxy-6-(2-bromoisonicotinoyl)benzaldehyde dimethyl acetal (13.9 g) and 2 M hydrochloric acid (1 ml) are added to a mixture of acetone (30 ml) and water (5 ml), and the mixture is stirred at room temperature for two hours. The mixture is evaporated to remove the acetone, and the remaining aqueous layer is extracted with chloroform. The extract is washed, dried, and concentrated. The residue is purified by silica gel column chromatography (solvent; chloroform:ethyl acetate=4:1) to give 3,4-dimethoxy-6-(2-bromoisonicotinoyl)benzaldehyde (8.65 g).
Reaction SMILES: [CH2:1]([C@:3]12[CH2:11][CH2:10][C:9]3[C:12]4[CH:13]=[CH:14][C:15]([OH:20])=[CH:16][C:17]=4[CH2:18][CH2:19][C:8]=3[C:7]1=[CH:6][CH2:5][C:4]2=[O:21])[CH3:2]>C1C=CC=CC=1.C>[CH2:1]([C@:3]12[CH2:11][CH2:10][C:9]3[C:12]4[CH:13]=[CH:14][C:15]([OH:20])=[CH:16][C:17]=4[CH2:18][CH2:19][C:8]=3[C@@H:7]1[CH2:6][CH2:5][C:4]2=[O:21])[CH3:2]
Reactant: CC[C@]12CCC3=C(CCc4cc(O)ccc43)C1=CCC2=O
Solvent: c1ccccc1
Product: CC[C@]12CCC3=C(CCc4cc(O)ccc43)[C@@H]1CCC2=O

Procedure:
Hydrogenate 13β-ethyl-3-hydroxygona-1,3,5(10),8,14-pentaen-17-one (0.5 g.) in benzene (25 cc.) at atmospheric pressure using a 10% palladized charcoal catalyst (0.025 g.). After the absorption of 1.1 molar equivalents of hydrogen, hydrogenation becomes very slow; remove the catalyst by filtration and evaporate the filtrate to obtain the title product which crystallizes from methanol in colorless plates (0.35 g.), m.p. 235°-9°; ultra-violet absorption peak at 280.5 mμ (ε 15,500).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][N:9]([CH3:21])[CH2:10][CH2:11][CH2:12][NH:13][C:14]1[C:15]([NH2:20])=[CH:16][CH:17]=[CH:18][CH:19]=1.[C:22](Cl)(=O)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]>C(Cl)(Cl)Cl>[CH3:21][N:9]([CH3:8])[CH2:10][CH2:11][CH2:12][N:13]1[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N:20]=[C:37]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH3:22]
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Reactant: CN(C)CCCNc1ccccc1N
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCc1nc2ccccc2n1CCCN(C)C
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
Triethylamine (0.80 ml) was added to a solution containing N-[3-(dimethylamino)propyl]-1,2-benzenediamine (1.00 g) in chloroform (10 ml) and then palmitoyl chloride (1.58 ml) was added thereto while being cooled with ice. After being stirred for 2.5 hours at room temperature, the reaction mixture was diluted with chloroform, washed with saturated sodium bydrogencarbonate aqueous solution and water successively, dried over sodium sulfate anhydride, and concentrated. Concentrated hydrochloric acid (4.3 ml) was added to a solution containing the residue (2.25 g) in ethanol (23 ml). After being stirred for 1.5 hours at 90° C., the reaction mixture was concentrated. The residue, with ethyl acetate added thereto, was washed with 1N sodium hydroxide aqueous solution and saturated brine successively, dried over sodium sulfate anhydride, and concentrated. The residue (2.21 g) was purified by silica gel column chromatography (silica gel 50 g, chloroform:methanol=30:1), thereby yielding the entitled compound (1.44 g) as yellow syrup.