Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCN(C(C)C)C(C)C.[NH:10]1[CH2:13][CH2:12][CH2:11]1.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1.[NH2:38][C:39]1[N:40]=[CH:41][C:42]([C:51]2[CH:61]=[CH:60][C:54]([C:55]([N:57]([CH3:59])[CH3:58])=[O:56])=[CH:53][CH:52]=2)=[N:43][C:44]=1[C:45]1[O:46][C:47](=O)[NH:48][N:49]=1>CN(C=O)C>[NH2:38][C:39]1[N:40]=[CH:41][C:42]([C:51]2[CH:52]=[CH:53][C:54]([C:55]([N:57]([CH3:59])[CH3:58])=[O:56])=[CH:60][CH:61]=2)=[N:43][C:44]=1[C:45]1[O:46][C:47]([N:10]2[CH2:13][CH2:12][CH2:11]2)=[N:48][N:49]=1
Reactant: C1CNC1
Reactant: CN(C)C(=O)c1ccc(-c2cnc(N)c(-c3n[nH]c(=O)o3)n2)cc1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(C)C(=O)c1ccc(-c2cnc(N)c(-c3nnc(N4CCC4)o3)n2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 15.8 %

Procedure:
DIPEA (38.44 mg, 51.81 μL, 0.2974 mmol), azetidine (8.490 mg, 0.1487 mmol) and bromo(tripyrrolidin-1-yl)phosphonium hexafluorophosphate (76.27 mg, 0.1636 mmol) were added to a solution of 4-(5-amino-6-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)pyrazin-2-yl)-N,N-dimethylbenzamide (50 mg, 0.1487 mmol) in DMF (485.1 μL) and the resulting solution stirred at room temperature for 2 h. The reaction mixture was filtered and purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 mM, 100 Å column, gradient 10%-95% B (solvent A: 0.05% TFA in water; solvent B: CH3CN) over 16 minutes at 25 mL/min]. Product fractions were concentrated in vacuo and triturated with dichloromethane/diethyl ether to give the product (8.6 mg, 15% yield); 1H NMR (400.0 MHz, DMSO) d 2.96 (s, 3H), 3.00 (s, 6H), 4.25 (t, 4H), 7.52 (dd, 2H), 7.65 (br s, 1H), 8.04-8.06 (m, 2H) and 8.83 (s, 1H) ppm; MS (ES+) 366.21
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]([CH3:13])[CH:7]=1.[N:15]([O-])=O.[Na+]>C(O)(=O)C.O.[Zn]>[F:12][C:9]1[CH:10]=[CH:11][C:6]([N:5]([CH2:4][C:3]([O:2][CH3:1])=[O:14])[NH2:15])=[CH:7][C:8]=1[CH3:13]
Reactant: O=N[O-]
Reactant: COC(=O)CNc1ccc(F)c(C)c1
Agent: [Na+]
Agent: [Zn]
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)CN(N)c1ccc(F)c(C)c1
Reaction time: 1 h
Yield: 17.4 %

Procedure:
N-(4-Fluoro-3-methylphenyl)glycine methyl ester (Intermediate 63, 7.5 g, 0.038 mol) was dissolved in a mixture of glacial acetic acid (60 ml) and water (8 ml) and the solution was cooled to ~5° C. To this was added a solution of sodium nitrite (4.3 g, 0.063 mol) in water (15 ml) at the same low temperature over 20 minutes. Stirring was continued for 1 hour and the temperature was then lowered to between -10° and 0° C. Zinc dust (15.3 g, 0.234 mol) was added at the maintained low temperature and the resulting suspension was stirred at ~0° C. for 4 hours. It was then poured into water (250 ml) and extracted with ethyl acetate (2×200 ml). The extract was washed with 8% sodium bicarbonate solution until all effervescence had ceased. It was then dried (MgSO4) and evaporated to give a brown semi-solid. This was triturated with ether/hexane (1:2, ~15 ml) to give a white solid which was filtered and washed with ice-cold ether. The liquors were evaporated to give a brown oil and this was purified by flash column chromatography on silica (Merck 9385; 225 g) eluting with ether/hexane (1:1) to give the title compound (Intermediate 64) as an orange oil (1.4 g, 17%).
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH3:10])=[C:6]([OH:11])[CH:5]=[CH:4][C:3]=1[C:12](=[O:14])[CH3:13].[CH3:15][O:16][C:17](=[O:37])[CH2:18][O:19][C:20]1[C:25]([C:26](=[O:28])[CH3:27])=[CH:24][CH:23]=[C:22]([O:29][CH2:30][CH2:31][CH2:32]Br)[C:21]=1[CH2:34][CH2:35][CH3:36].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.CN(C)C=O>[CH3:15][O:16][C:17](=[O:37])[CH2:18][O:19][C:20]1[C:25]([C:26](=[O:28])[CH3:27])=[CH:24][CH:23]=[C:22]([O:29][CH2:30][CH2:31][CH2:32][O:11][C:6]2[CH:5]=[CH:4][C:3]([C:12](=[O:14])[CH3:13])=[C:2]([OH:1])[C:7]=2[CH2:8][CH2:9][CH3:10])[C:21]=1[CH2:34][CH2:35][CH3:36]
Reactant: CCCc1c(OCCCBr)ccc(C(C)=O)c1OCC(=O)OC
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: CCCc1c(OCCCOc2ccc(C(C)=O)c(OCC(=O)OC)c2CCC)ccc(C(C)=O)c1O
Yield: 32.7 %

Procedure:
A mixture of 1.72 g of 1-(2,4-dihydroxy-3-propylphenyl)ethanone, 3.43 g of [6-acetyl-3-(3-bromopropoxy)-2-propylphenoxy]acetic acid methyl ester, 2.44 g of anhydrous potassium carbonate in 50 ml of anhydrous acetone and 25 ml of anhydrous dimethylformamide was stirred at reflux for 18 hours. The reaction mixture was concentrated in vacuo and the residue was purified by high pressure liquid chromatography to give 1.45 g (33%) of [6-acetyl-3-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]-2-propylphenoxy]acetic acid methyl ester as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[C:19]([O:21][CH2:22][CH:23]=[C:24]([Cl:26])[Cl:25])[CH:18]=[C:17]([Cl:27])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH:12]=O.Cl.[CH2:29]([O:31][NH2:32])[CH3:30].Cl>N1C=CC=CC=1>[CH2:29]([O:31][N:32]=[CH:12][C:11]1[CH:14]=[CH:15][CH:16]=[C:9]([O:8][CH2:7][CH2:6][CH2:5][O:4][C:3]2[C:2]([Cl:1])=[CH:20][C:19]([O:21][CH2:22][CH:23]=[C:24]([Cl:26])[Cl:25])=[CH:18][C:17]=2[Cl:27])[CH:10]=1)[CH3:30]
Reactant: CCON
Reactant: O=Cc1cccc(OCCCOc2c(Cl)cc(OCC=C(Cl)Cl)cc2Cl)c1
Agent: Cl
Solvent: c1ccncc1
Product: CCON=Cc1cccc(OCCCOc2c(Cl)cc(OCC=C(Cl)Cl)cc2Cl)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 91.3 %

Procedure:
To a mixture of 0.21 g of 3-(3-(2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenoxy)propyloxy)benzaldehyde and 10 ml of pyridine was added 0.09 g of O-ethylhydroxylamine hydrochloride. After stirring at room temperature for 24 hours, the reaction mixture was poured into diluted hydrochloric acid, and extracted twice with diethyl ether. The diethyl ether layers were combined, washed with water, dried over anhydrous magnesium sulfate, and concentrated to give a crude product. This crude product was subjected to silica gel chromatography, which afforded 0.21 g (yield, 92%) of 3-(3-(2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenoxy)propyloxy)benzaldehyde O-ethyloxime, m.p., 42.6° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.[CH3:12][C:13]1[CH:18]=[CH:17][N:16]2[N:19]=[C:20]([NH2:33])[C:21]([C:22]3[CH:27]=[CH:26][C:25]([O:28][C:29]([F:32])([F:31])[F:30])=[CH:24][CH:23]=3)=[C:15]2[N:14]=1.Cl.CN(C)CCCN=C=NCC>CN(C=O)C.N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([NH:33][C:20]2[C:21]([C:22]3[CH:23]=[CH:24][C:25]([O:28][C:29]([F:32])([F:30])[F:31])=[CH:26][CH:27]=3)=[C:15]3[N:14]=[C:13]([CH3:12])[CH:18]=[CH:17][N:16]3[N:19]=2)=[O:11])=[CH:6][CH:7]=1
Reactant: Cc1ccn2nc(N)c(-c3ccc(OC(F)(F)F)cc3)c2n1
Reactant: O=C(O)Cc1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: Cc1ccn2nc(NC(=O)Cc3ccc(F)cc3)c(-c3ccc(OC(F)(F)F)cc3)c2n1
Reaction time: 40 h

Procedure:
4-Fluorophenylacetic acid (32 mg, 0.21 mmol) was added to a stirring solution of the product from Example 168A (20 mg, 0.065 mmol) in DMF (0.5 mL) and pyridine (0.5 mL). 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (43 mg, 0.22 mmol) was added and stirring was continued at room temperature for 40 h. The reaction mixture was quenched by addition of MeOH (1 mL) and HOAc (0.1 mL) and stirred for 40 minutes. The solution was concentrated under vacuum, and the residue was purified by HPLC (30×100 mm XBridge column eluted with aqueous 0.1 M (NH4)2CO3-MeOH, 60:40-0:100 over 15 min) to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 2.56 (s, 3H), 3.65 (s, 2H), 7.03 (d, J=7.1 Hz, 1H), 7.15 (t, J=8.8 Hz, 2H), 7.25 (d, J=8.5 Hz, 2H), 7.29-7.40 (m, 2H), 7.76 (d, J=8.8 Hz, 2H), 8.94 (d, J=7.1 Hz, 1H), 10.42 (s, 1H); MS (DCI/NH3) m/z 445 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[N:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=2)[N:4]([C:15]2[CH:20]=[CH:19][C:18]([S:21]([NH2:24])(=[O:23])=[O:22])=[CH:17][CH:16]=2)[N:3]=1.[H-].[Na+].I[CH3:28].O>CN(C=O)C>[CH3:28][O:1][C:2]1[N:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=2)[N:4]([C:15]2[CH:20]=[CH:19][C:18]([S:21]([NH2:24])(=[O:23])=[O:22])=[CH:17][CH:16]=2)[N:3]=1
Reactant: COc1ccc(-c2nc(O)nn2-c2ccc(S(N)(=O)=O)cc2)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(-c2nc(OC)nn2-c2ccc(S(N)(=O)=O)cc2)cc1
Reaction time: 3 h
Yield: 75 %

Procedure:
500 mg of 4-[3-hydroxy-5-(4-methoxyphenyl)-1,2,4-triazole-1-yl]-benzenesulfonamide prepared in the above Example 16, was dissolved in 10 ml of DMF and then 1.05 eq of NaH was slowly added thereto. Afterwards 1.5 eq of iodomethane was added to the mixture and then stirred for 3 hours at the same temperature. When the reaction was completed, the resultant was poured into 100 ml of cold water to form precipitate. The precipitate was filtered and then washed with 100 ml of cold ether and 100 ml of cold water (1× each) to give 385 mg (yield 75%) of the titled compound as a white solid.
Reaction SMILES: [NH2:1][C:2]1[N:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[C:10]([CH2:12][C:13](OCC)=[O:14])#[N:11].N1CCCCC1>C(O)C>[OH:14][C:13]1[C:12]([C:10]#[N:11])=[CH:4][C:3]2[C:2](=[N:9][CH:8]=[CH:7][CH:6]=2)[N:1]=1
Reactant: CCOC(=O)CC#N
Reactant: Nc1ncccc1C=O
Solvent: C1CCNCC1
Solvent: CCO
Product: N#Cc1cc2cccnc2nc1O
Reaction time: 1 h

Procedure:
A mixture of 2-aminonicotinaldehyde (2.44 g., 0.02 m), ethyl α-cyanoacetate (4.52 g., 0.04 m.), absolute ethanol (50 ml.) and piperidine (0.5 ml) is stirred under reflux. After 1 hour, the solution is cooled to 0°-4° C. The yellow solid is filtered and dried to yield 2.5 g. (73%) of 2-hydroxy-3-cyano-1,8-naphthyridines, m.p. 300° C.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([S:8]([C:11]2[CH:20]=[C:19]3[C:14]([CH2:15][CH2:16][C@H:17]([CH2:21]OS(C)(=O)=O)[O:18]3)=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[OH:27][C@@H:28]1[CH2:32][CH2:31][NH:30][CH2:29]1>CN1C(=O)CCC1>[C:4]1([S:8]([C:11]2[CH:20]=[C:19]3[C:14]([CH2:15][CH2:16][CH:17]([CH2:21][N:30]4[CH2:31][CH2:32][C@@H:28]([OH:27])[CH2:29]4)[O:18]3)=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH:3]=[CH:2][CH:7]=[CH:6][CH:5]=1
Reactant: CS(=O)(=O)OC[C@H]1CCc2ccc(S(=O)(=O)c3cccc(F)c3)cc2O1
Reactant: O[C@@H]1CCNC1
Solvent: CN1CCCC1=O
Product: O=S(=O)(c1ccccc1)c1ccc2c(c1)OC(CN1CC[C@@H](O)C1)CC2
Temperature: 110 °C
Yield: 83.6 %

Procedure:
Methanesulfonic acid (R)-7-(3-fluoro-benzenesulfonyl)-chroman-2-ylmethyl ester (0.052 g, 0.13 mmol), (R)-3-hydroxypyrrolidine (0.035 g) and NMP (0.5 mL were sealed in a tube and heated to 110° C. for 18 hours. The reaction mixture was cooled and partitioned between water and diethyl ether. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography to give 40.6 mg of (R)-1-(7-benzenesulfonyl-chroman-2-ylmethyl)-pyrrolidin-3-ol, MS (M+H)=374.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:20][CH2:19][CH:18]([N:21]([CH2:23][C:24]2[CH:33]=[CH:32][C:27]3[O:28][CH2:29][CH2:30][O:31][C:26]=3[CH:25]=2)[CH3:22])[CH2:17][CH2:16]1)=O)(C)(C)C>ClCCl>[O:28]1[C:27]2[CH:32]=[CH:33][C:24]([CH2:23][N:21]([CH3:22])[CH:18]3[CH2:17][CH2:16][NH:15][CH2:20][CH2:19]3)=[CH:25][C:26]=2[O:31][CH2:30][CH2:29]1
Reactant: CN(Cc1ccc2c(c1)OCCO2)C1CCN(C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(Cc1ccc2c(c1)OCCO2)C1CCNCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 110.6 %

Procedure:
Trifluoroacetic acid (591 μL, 7.67 mmol, 15.0 eq) is added at 0° C. to a stirred solution of 4-[(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-methyl-amino]-piperidine-1-carboxylic acid tert-butyl ester (195 mg, 0.51 mmol, 1.0 eq) in dichloromethane (10 mL). After 3 hours stirring at room temperature, the reaction mixture is extracted with dichloromethane (3×10 mL) and water (10 mL) and the pH is adjusted to 12 by the addition of a 1N sodium hydroxide aqueous solution. The combined organic layers are dried over sodium sulfate, filtered and concentrated to afford (2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-methyl-piperidin-4-yl-amine as a light yellow solid (148 mg, 99% yield).
Reaction SMILES: C(O[C:6]([C:8]1[N:9]=[C:10]([Cl:23])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][C:14]([O:19][CH:20]([CH3:22])[CH3:21])=[CH:13][CH:12]=2)=[O:7])CCC.[NH2:24][CH2:25][CH2:26][OH:27]>>[OH:27][CH2:26][CH2:25][NH:24][C:6]([C:8]1[N:9]=[C:10]([Cl:23])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][C:14]([O:19][CH:20]([CH3:21])[CH3:22])=[CH:13][CH:12]=2)=[O:7]
Reactant: CCCCOC(=O)c1nc(Cl)c2ccc(OC(C)C)cc2c1O
Reactant: NCCO
Product: CC(C)Oc1ccc2c(Cl)nc(C(=O)NCCO)c(O)c2c1

Procedure:
Synthesized from 1-chloro-4-hydroxy-6-isopropoxy-isoquinoline-3-carboxylic acid butyl ester (can be obtained according to U.S. Pat. No. 6,093,730, October 1998, Weidmann et al.) and 2-amino-ethanol in analogy to example B-5; MS-(+)-ion: M+1=325.1.
Reaction SMILES: [CH3:1][C@H:2]1[C@@H:12]2[CH2:13][CH2:14][C@:15]3([CH3:19])[O:17][O:18][C@:11]42[C@H:5]([C@@H:6]([CH3:20])[C:7]([O:9][C@@H:10]4[O:16]3)=[O:8])[CH2:4][CH2:3]1.[BH4-].[Na+].CC(O)=O.CO>CO>[CH3:1][C@H:2]1[C@@H:12]2[CH2:13][CH2:14][C:15]3([CH3:19])[O:17][O:18][C@:11]42[C@H:5]([C@@H:6]([CH3:20])[C@@H:7]([OH:8])[O:9][C@@H:10]4[O:16]3)[CH2:4][CH2:3]1
Reactant: C[C@@H]1CC[C@H]2[C@@H](C)C(=O)O[C@@H]3O[C@]4(C)CC[C@@H]1[C@]32OO4
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: C[C@H]1[C@@H](O)O[C@@H]2OC3(C)CC[C@H]4[C@H](C)CC[C@@H]1[C@@]24OO3
Reaction time: 2 h
Yield: 74.2 %

Procedure:
Artemisinin (compound 3) (0.5 g, 1.8 mmole) in 40 mL of MeOH was cooled in an ice-bath to 0°-5° C. To the solution was added in small portions 0.25 g (6.6 mmole) of NaBH4 over a period of 30 minutes. The solution was stirred at 0°-5° C. for 2 hours after the addition of NaBH4 was complete. The solution was neutralized with 30% AcOH/MeOH and evaporated to dryness under reduced pressure. The white residue was extracted 3 times with 50 mL of EtOAc. The EtOAc extracts were combined, filtered, and evaporated to dryness to give 0.38 g (75%) of white needles mp 152°-154° C. (dec). Recrystallization from EtOAc-hexane raised the melting point to 153°-155° C. (lit. mp 153°-154° C.).
Reaction SMILES: [F:1][CH:2]([F:27])[C:3]1[NH:4][C:5]([CH:24]([F:26])[F:25])=[C:6]([C:22]#[N:23])[CH:7]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][C:19]=2[F:20])[NH:16][N:15]=[C:14]3[CH3:21])[C:8]=1[C:9]#[N:10].[OH-].[Na+:29]>C(O)C>[C:9]([C:8]1[CH:7]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][C:19]=2[F:20])[NH:16][N:15]=[C:14]3[CH3:21])[C:6]([C:22]#[N:23])=[C:5]([CH:24]([F:25])[F:26])[N-:4][C:3]=1[CH:2]([F:1])[F:27])#[N:10].[Na+:29]
Reactant: Cc1n[nH]c2cc(F)c(C3C(C#N)=C(C(F)F)NC(C(F)F)=C3C#N)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1n[nH]c2cc(F)c(C3C(C#N)=C(C(F)F)[N-]C(C(F)F)=C3C#N)cc12
Temperature: 25 °C
Reaction time: 96 h

Procedure:
To a suspension of 100 mg (0.28 mmol) 2,6-bis(difluoromethyl)-4-(6-fluoro-3-methyl-1H-indazol-5-yl)-1,4-dihydropyridine-3,5-dicarbonitrile (Example 14) in ethanol (0.25 ml) under argon atmosphere was added 290 μl (0.29 mmol) 1 N aqueous sodium hydroxide solution, and the mixture was stirred under a weak argon stream for 4 days at room temperature. The resulting precipitate was dried in vacuo to yield 110 mg (100% of th.) of the title compound as a solid.
Reaction SMILES: [O:1]=[S:2]1(=[O:55])[CH2:7][CH2:6][N:5]([CH2:8][CH2:9]CNC[C@]23CC[C@@H](C(C)=C)[C@@H]2[C@@H]2[C@@](C)(CC3)[C@@]3(C)[C@@H]([C@]4(C)[C@@H](CC3)C(C)(C)C(C3CC5(CC(C(O)=O)(C(O)=O)C5)C=3)=CC4)CC2)[CH2:4][CH2:3]1.[NH2:56][C@:57]12[CH2:94][CH2:93][C@@H:92]([C:95]([CH3:97])=[CH2:96])[C@@H:58]1[C@@H:59]1[C@@:72]([CH3:75])([CH2:73][CH2:74]2)[C@@:71]2([CH3:76])[C@@H:62]([C@:63]3([CH3:91])[C@@H:68]([CH2:69][CH2:70]2)[C:67]([CH3:78])([CH3:77])[C:66]([C:79]2[CH2:84][CH2:83][C:82]([C:85]([O:87][CH2:88][CH3:89])=[O:86])=[C:81]([CH3:90])[CH:80]=2)=[CH:65][CH2:64]3)[CH2:61][CH2:60]1>>[O:1]=[S:2]1(=[O:55])[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][NH:56][C@:57]23[CH2:94][CH2:93][C@@H:92]([C:95]([CH3:97])=[CH2:96])[C@@H:58]2[C@@H:59]2[C@@:72]([CH3:75])([CH2:73][CH2:74]3)[C@@:71]3([CH3:76])[C@@H:62]([C@:63]4([CH3:91])[C@@H:68]([CH2:69][CH2:70]3)[C:67]([CH3:77])([CH3:78])[C:66]([C:79]3[CH2:84][CH2:83][C:82]([C:85]([O:87][CH2:88][CH3:89])=[O:86])=[C:81]([CH3:90])[CH:80]=3)=[CH:65][CH2:64]4)[CH2:61][CH2:60]2)[CH2:4][CH2:3]1
Reactant: C=C(C)[C@@H]1CC[C@]2(N)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(C6=CC(C)=C(C(=O)OCC)CC6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: C=C(C)[C@@H]1CC[C@]2(CNCCCN3CCS(=O)(=O)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(C6=CC7(C6)CC(C(=O)O)(C(=O)O)C7)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Product: C=C(C)[C@@H]1CC[C@]2(NCCN3CCS(=O)(=O)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(C6=CC(C)=C(C(=O)OCC)CC6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12

Procedure:
The title compound was prepared following the method described above in Step 2 for the preparation of 6-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(((3-(1,1-dioxidothiomorpholino)propyl)amino)methyl)-5a,5b,8,8,11a-pentamethyl-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)spiro[3.3]hept-5-ene-2,2-dicarboxylic acid (example A14), using ethyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-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)-2-methylcyclohexa-1,3-dienecarboxylate as the reactant. (quantitative yield). MS: m/e 735.8 (M+H)+, 3.41 min (method 3). 1H NMR (400 MHz, CHLOROFORM-d) δ 5.65 (s, 1H), 5.28 (dd, J=6.0, 1.5 Hz, 1H), 4.71 (s, 1H), 4.59 (s, 1H), 4.19 (q, J=7.1 Hz, 2H), 3.15-2.97 (m, 8H), 2.73-2.51 (m, 4H), 2.50-2.38 (m, 3H), 2.22 (q, J=8.3 Hz, 2H), 2.15 (s, 3H), 2.06-1.18 (m, 25H), 1.11-1.04 (m, 6H), 1.00 (s, 3H), 0.98-0.95 (m, 6H), 0.88 (s, 3H).
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([O:13][CH3:14])(=[O:12])[CH2:8][C:9]([CH3:11])=[O:10].C(O)(C)(C)C.[F:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Br)=[CH:23][CH:22]=1>O1CCCC1>[F:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25][CH:8]([C:9](=[O:10])[CH3:11])[C:7]([O:13][CH3:14])=[O:12])=[CH:23][CH:22]=1
Reactant: COC(=O)CC(C)=O
Reactant: Fc1ccc(CBr)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: C1CCOC1
Product: COC(=O)C(Cc1ccc(F)cc1)C(C)=O
Reaction time: 1 h
Yield: 75.2 %

Procedure:
To a suspension of potassium tert-butoxide (10.6 g, 95.0 mmol) in tetrahydrofuran (100 mL) were added methyl acetoacetate (10.0 g, 86.0 mmol) and tert-butanol (0.83 mL, 8.6 mmol) at room temperature. The resulting solution was stirred for 1 h, and then 4-fluorobenzylbromide (11.2 mL, 90 mmol) was added. The reaction mixture was stirred at room temperature for 18 h, and then partitioned between water and ethyl acetate. The aqueous layer was extracted with ethyl acetate (3×), the combined organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated. Column chromatography of the residue on silica (5-20% ethyl acetate in hexanes) gave methyl 2-(4-fluorobenzyl)-3-oxobutanoate (14.5 g, 75% yield) as a colorless oil which was used in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[N:10]2[C:11](=[O:18])[CH:12]([NH2:17])[CH2:13][CH:14]=[CH:15][CH2:16][CH:9]2[CH2:8][CH2:7][CH2:6]1)=[O:4].CCN(CC)CC.[C:26](Cl)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C1COCC1>[CH3:1][O:2][C:3]([C@H:5]1[N:10]2[C:11](=[O:18])[C@@H:12]([NH:17][C:26](=[O:33])[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:13][CH:14]=[CH:15][CH2:16][C@H:9]2[CH2:8][CH2:7][CH2:6]1)=[O:4]
Reactant: COC(=O)C1CCCC2CC=CCC(N)C(=O)N21
Reactant: O=C(Cl)c1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H]1CCC[C@@H]2CC=CC[C@H](NC(=O)c3ccccc3)C(=O)N21
Reaction time: 0.08 h

Procedure:
A solution containing crude 7-amino-6-oxo-1,3,4,6,7,8,11,11a-octahydro-2H-pyrido[1,2-a]azocine-4-carboxylic acid methyl ester, 42, (50 mg, 0.2 mmol) and Et3N (0.56 mL, 4.0 mmol) in 5 mL THF is treated with excess benzoyl chloride (0.23 mL, 2.0 mmol) and stirred for 5 minutes. The reaction is quenched with MeOH and concentrated. The crude residue obtained is purified by preparative reverse phase HPLC (CH3CN/H2O) to yield 45 mg of desired product. 1H NMR (CDCl3) δ 7.92 (d, J=5.9 Hz, 1H), 7.87 (d, J=7.7 Hz, 2H), 7.57–7.42 (m, 3H), 5.70 (m, 2H), 5.30 (m, 1H), 5.18 (m, 1H), 4.63 (m, 1H), 3.74 (s, 3H), 3.12 (m, 1H), 2.67 (m, 1H), 2.52 (m, 1H), 2.29 (m, 2H), 1.90–1.60 (m, 5H); 13C NMR δ 172.8, 172.3, 166.4, 134.4, 131.8, 129.9, 128.8(2C), 127.3(2C), 125.0, 52.3, 51.8, 51.4, 50.8, 35.4, 34.2, 29.7, 26.4, 15.7.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:21]I>>[Cl:1][C:2]1[N:11]=[C:10]([N:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=2)[CH3:21])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: COc1cccc(Nc2nc(Cl)nc3ccccc23)c1
Reactant: CI
Product: COc1cccc(N(C)c2nc(Cl)nc3ccccc23)c1

Procedure:
The title compound was prepared from (2-chloro-quinazolin-4-yl)-(3-methoxy-phenyl)-amine and methyl iodide by a procedure similar to Example 36 (60% yield). 1H NMR (CDCl3): 7.74-7.76 (m, 1H), 7.57 (ddd, J=8.4, 6.0 and 1.8 Hz, 1H), 7.32 (t, J=7.8 Hz, 1H), 6.98-7.03 (m, 2H), 6.89 (dd, J=8.1 and 2.4 Hz, 1H), 6.75-6.81 (m, 2H), 3.65 (s, 3H), 3.37 (s, 3H).
Reaction SMILES: Cl[C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[C:5]2[N:17]=[CH:18][CH:19]=[CH:20][C:4]=2[N:3]=1.[CH2:21]([N:23]([CH2:27][CH3:28])[CH2:24][CH2:25][NH2:26])[CH3:22]>>[CH2:21]([N:23]([CH2:24][CH2:25][NH:26][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[C:5]2[N:17]=[CH:18][CH:19]=[CH:20][C:4]=2[N:3]=1)[CH2:27][CH3:28])[CH3:22]
Reactant: COc1ccc(-n2c(=O)c(Cl)nc3cccnc32)cc1
Reactant: CCN(CC)CCN
Product: CCN(CC)CCNc1nc2cccnc2n(-c2ccc(OC)cc2)c1=O

Procedure:
Preparation as in Example 39 but using 2-chloro-3,4-dihydro-4-(4-methoxyphenyl)-3-oxopyrido[2,3-b]pyrazine and N,N-diethylethylene diamine gave the title compound mp 167°-168° C.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[C:21]([CH:23]=[CH2:24])[CH:20]=[CH:19][C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[CH:9][C:10]2[C:14]([CH3:16])([CH3:15])[O:13][B:12]([OH:17])[C:11]=2[CH:18]=1)=[O:5].[CH2:25]([Sn](CCCC)(CCCC)CCCC)C=C>>[CH2:23]([C:21]1[CH:20]=[CH:19][C:3]([C:4]([NH:6][C:7]2[CH:8]=[CH:9][C:10]3[C:14]([CH3:16])([CH3:15])[O:13][B:12]([OH:17])[C:11]=3[CH:18]=2)=[O:5])=[C:2]([Cl:1])[CH:22]=1)[CH:24]=[CH2:25]
Reactant: C=Cc1ccc(C(=O)Nc2ccc3c(c2)B(O)OC3(C)C)c(Cl)c1
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Product: C=CCc1ccc(C(=O)Nc2ccc3c(c2)B(O)OC3(C)C)c(Cl)c1

Procedure:
The title compound was prepared using a procedure similar to that of 2-chloro-N-(1-hydroxy-3,3-dimethyl-1,3-dihydro-benzo[c][1,2]oxaborol-6-yl)-4-vinyl-benzamide with allyltributyltin replacing tributyl(vinyl)tin. Data: LCMS (M/Z): 356 (M+H); 1H NMR (DMSO-d6) δ: 1.44 (s, 6 H) 3.44 (d, J=6.8 Hz, 2 H) 5.04-5.22 (m, 2 H) 5.87-6.06 (m, 1 H) 7.28 (d, J=9.0 Hz, 1 H) 7.35-7.41 (m, 2 H) 7.50 (s, 1 H) 7.68 (dd, J=8.3, 2.0 Hz, 1 H) 8.05 (d, J=1.8 Hz, 1 H) 9.09 (br. s., 1 H) 10.45 (s, 1 H).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][O:4][C:3]=1[C:7]([NH:9][C:10]1[CH:11]=[C:12]([C:16]#[C:17][C:18]2[CH:19]=[C:20]([C:24]([N:26]=[S@:27]([CH2:35][C:36](OCC)=[O:37])([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[O:28])=[O:25])[CH:21]=[N:22][CH:23]=2)[CH:13]=[CH:14][CH:15]=1)=[O:8].[NH:41]1[CH2:51][CH2:50][CH2:49][CH:43]([C:44]([O:46][CH2:47][CH3:48])=[O:45])[CH2:42]1>>[CH3:1][C:2]1[CH:6]=[CH:5][O:4][C:3]=1[C:7]([NH:9][C:10]1[CH:11]=[C:12]([C:16]#[C:17][C:18]2[CH:19]=[C:20]([C:24]([N:26]=[S:27]([CH2:35][C:36]([N:41]3[CH2:51][CH2:50][CH2:49][C@H:43]([C:44]([O:46][CH2:47][CH3:48])=[O:45])[CH2:42]3)=[O:37])([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)=[O:28])=[O:25])[CH:21]=[N:22][CH:23]=2)[CH:13]=[CH:14][CH:15]=1)=[O:8]
Reactant: CCOC(=O)C[S@@](=O)(=NC(=O)c1cncc(C#Cc2cccc(NC(=O)c3occc3C)c2)c1)c1ccccc1
Reactant: CCOC(=O)C1CCCNC1
Product: CCOC(=O)[C@H]1CCCN(C(=O)CS(=O)(=NC(=O)c2cncc(C#Cc3cccc(NC(=O)c4occc4C)c3)c2)c2ccccc2)C1

Procedure:
In a manner similar to that described in Example 534, (S)-Ethyl (N-{[5-({3-[(3-methyl-2-furoyl)amino]phenyl}ethynyl)pyridin-3-yl]carbonyl}-S-phenylsulfonimidoyl)acetate and ethyl nipecotate were reacted to give the title compound