Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([C@H:13]([O:15][C@@H:16]2[C@@H:20]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)[CH2:19][N:18]([C:28]3[CH2:32][CH2:31][C:30](=[O:33])[CH:29]=3)[CH2:17]2)[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[Li+].[CH3:37][Si]([N-][Si](C)(C)C)(C)C.IC>O1CCCC1>[F:10][C:9]([F:11])([F:12])[C:7]1[CH:6]=[C:5]([C@H:13]([O:15][C@@H:16]2[C@@H:20]([C:21]3[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=3)[CH2:19][N:18]([C:28]3[CH:32]([CH3:37])[CH2:31][C:30](=[O:33])[CH:29]=3)[CH2:17]2)[CH3:14])[CH:4]=[C:3]([C:2]([F:1])([F:34])[F:35])[CH:8]=1
Reactant: C[C@@H](O[C@H]1CN(C2=CC(=O)CC2)C[C@@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: CC1CC(=O)C=C1N1C[C@H](O[C@H](C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H](c2ccc(F)cc2)C1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
In a round bottomed flask, 50 mg (0.0997 mmol) 3-[(3R,4S)-3-({(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}oxy)-4-(4-fluorophenyl)pyrrolidin-1-yl]cyclopent-2-en-1-one (Example 3, step F) was dissolved in tetrahydrofuran (5 mL) under nitrogen atmosphere and cooled to −78° C. To this solution was added by syringe, 0.090 mL (0.9 equiv, 0.0897 mmol) of a 1M solution of LiHMDS in THF. The resulting faint yellow solution was stirred for 1 hr at −78° C. then 0.0155 mL (0.249 mmol) iodomethane was added by syringe. The resulting yellow solution was stirred for 5 min at −78° C. then warmed to RT over 30 min. The reaction was quenched by the addition of 2 mL sat. aq. NH4Cl stirred 5 min then 2 mL water was added. The resulting mixture was extracted with ether (3×10 mL). The combined organic extracts were dried over anhydrous sodium sulfate, filtered and the solvent removed under vacuum to provide a yellow oil. The resulting oil was purified by prep TLC on silica gel eluting with methylene chloride/methanol (9/1). The UV active band with Rf˜0.85 was isolated. The resulting yellow oil (48 mg) was purified by prep HPLC on Chiralcel OD eluting with heptanes/absolute alcohol (94/6) to afford the title compound as a mixture of stereoisomers. 1H-NMR (CD3OD) rotamers: δ: 1.2-1.45 (m, 6H), 2.04 (m, 1H), 2.78 (m, 1H), 3.18 (m, 1H), 3.30-4.35 (m, 6H), 4.7-4.9 (m, 2H), 4.95, 5.0 (2d, 1H), 6.95-7.02 (m, 2H), 7.10-7.22 (m, 2H), 7.62 (s, 1H), 7.80 (s, 1H), 7.83 (s, 1H)ppm. MS: 516.2 (MH+) observed.
Reaction SMILES: [Mg].I[CH2:3][CH2:4][C:5]([CH3:8])([CH3:7])[CH3:6].[CH3:9][C:10]1[C:11](=[O:22])[O:12][CH2:13][C@H:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:15]=1>O1CCCC1.C(OCC)C>[CH3:6][C:5]([CH3:8])([CH3:7])[CH2:4][CH2:3][C@@:10]1([CH3:9])[C:11](=[O:22])[O:12][CH2:13][C@H:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[NH:15]1
Reactant: CC(C)(C)CCI
Reactant: CC1=N[C@@H](c2ccccc2)COC1=O
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)CC[C@]1(C)N[C@@H](c2ccccc2)COC1=O
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
A suspension of Rieke Magnesium (343 mg, 14.1 mmol) in tetrahydrofuran (13.7 ml) was added to a solution of 1-iodo-3,3-dimethylbutane in diethylether (50 ml) over a period of twenty minutes and the reaction was stirred for 40 minutes at room temperature. The Grignard reagent solution and (5S)-3-methyl-5-phenyl-5,6-dihydro-2H-1,4-oxazin-2-one (1 g, 5.28 mmol, see WO-A-02/051983) were used according to the method of Preparation 1 to generate the title compound. The total amount of compound synthesised was 0.394 g.
Reaction SMILES: [OH:1][N:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][C:11]([OH:13])=[O:12].IC.[C:16](=O)([O-])[O-].[K+].[K+].C([N+](CC)(CC)CC1C=CC=CC=1)C>C(#N)C>[CH3:16][O:1]/[N:2]=[CH:3]/[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][C:11]([OH:13])=[O:12]
Reactant: O=C(O)Cc1ccccc1C=NO
Reactant: O=C([O-])[O-]
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [K+]
Solvent: CC#N
Solvent: CI
Product: CO/N=C/c1ccccc1CC(=O)O
Reaction time: 8 h

Procedure:
1.8 g (10 mmoles) of 2-hydroxyiminomethyl-phenylacetic acid are reacted with 1.50 ml of iodomethane, 5 g of potassium carbonate and 10 mg of triethylbenzylammonium (TEBA) chloride in 20 ml of anhydrous acetonitrile. The system is left for 6 hours at +80° C. and overnight at ambient temperature.
Reaction SMILES: [CH3:1][O:2][C:3]1C=[CH:18][CH:17]=[CH:16][C:4]=1[C:5]([NH:7][C@H:8]1[CH:13]2[CH2:14][CH2:15][N:10]([CH2:11][CH2:12]2)[CH2:9]1)=[O:6].COC1[N:30]=CC=CC=1C(O)=O>>[CH3:1][O:2][C:3]1[C:4]([C:5]([NH:7][C@H:8]2[CH:13]3[CH2:12][CH2:11][N:10]([CH2:15][CH2:14]3)[CH2:9]2)=[O:6])=[CH:16][CH:17]=[CH:18][N:30]=1
Reactant: COc1ncccc1C(=O)O
Reactant: COc1ccccc1C(=O)N[C@@H]1CN2CCC1CC2
Product: COc1ncccc1C(=O)N[C@@H]1CN2CCC1CC2

Procedure:
Title compound was synthesized according to the procedure used in the synthesis of Compound 19S, using 2-methoxynicotinic acid in place of o-methoxybenzoic acid. 1H NMR (400 MHz, CDCl3) δ (ppm): 8.51 (dd, J=8 Hz 1H), 8.28 (dd, J=6 Hz 1H), 7.07 (dd, J=8 Hz 1H), 4.16 (s, 3H, m, 1H), 3.44 (dd, J=12 Hz, 1H), 2.92 (t, J=8 Hz 2H), 2.85 (m, 2H), 2.61 (ddd, J=16, 12 Hz, 1H), 2.03 (m, 1H), 1.75 (m, 3H), 1.59 (m, 1H). C14H19N3O2=261.15 LCMS (M+H): m/z 262
Reaction SMILES: [CH:1]1([C:6]([CH2:21][CH3:22])=[C:7]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[CH2:24][CH:25]([OH:28])[CH2:26][OH:27].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH:1]1([C:6]([CH2:21][CH3:22])=[C:7]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:24][CH:25]([OH:28])[CH2:26][OH:27])=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OCC(O)CCl
Reactant: CCC(=C(c1ccccc1)c1ccc(O)cc1)C1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCC(=C(c1ccccc1)c1ccc(OCC(O)CO)cc1)C1CCCC1

Procedure:
2-cyclopentyl-1-[p-(2,3-dihydroxypropoxy)phenyl]-1-phenyl-1-butene was prepared from pure E- or Z-isomer of 2-cyclopentyl-1-(p-hydroxyphenyl)-1-phenyl-1-butene and 3-chloro-1,2-propandiol in 2-butanone using potassium carbonate as a base (see example 16). In the case of the E-isomer the semisolid product was purified by chromatography over silica gel using methylene chloride as eluent.
Reaction SMILES: C(N(CC)CC)C.[C:8]1([S:14](Cl)(=[O:16])=[O:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[NH2:18][C:19]1[N:24]=[C:23]([C:25]2[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[C:27]([F:33])[CH:26]=2)[CH:22]=[C:21]([N:34]2[C@H:39]([CH3:40])[CH2:38][O:37][C@H:36]([CH2:41][NH2:42])[CH2:35]2)[N:20]=1>C1COCC1>[NH2:18][C:19]1[N:20]=[C:21]([N:34]2[C@H:39]([CH3:40])[CH2:38][O:37][C@H:36]([CH2:41][NH:42][S:14]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)(=[O:16])=[O:15])[CH2:35]2)[CH:22]=[C:23]([C:25]2[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[C:27]([F:33])[CH:26]=2)[N:24]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: C[C@@H]1CO[C@H](CN)CN1c1cc(-c2ccc(C#N)c(F)c2)nc(N)n1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[C@@H]1CO[C@H](CNS(=O)(=O)c2ccccc2)CN1c1cc(-c2ccc(C#N)c(F)c2)nc(N)n1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
Triethylamine (0.05 mL, 0.36 mmol) and benzenesulfonyl chloride (0.04 mL, 0.31 mmol) were added to a solution of 4-{2-amino-6-[(2R,5R)-2-(aminomethyl)-5-methyl-4-morpholinyl]-4-pyrimidinyl}-2-fluorobenzonitrile (99 mg, 0.29 mmol) in THF (3 mL), and the mixture was stirred at room temperature under nitrogen for 45 minutes. The mixture was quenched with saturated aqueous NaHCO3 (10 mL) and extracted with EtOAc (2×10 mL). The extracts were washed with brine (15 mL), dried (Na2SO4), filtered, and concentrated in vacuo to give the title compound as a yellow oil. LC-MS (ES) m/z=483 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][C:14]([NH:16][CH2:17][CH2:18][CH2:19][CH3:20])=[O:15])(=[O:12])=[O:11])=[CH:6][CH:5]=1.[OH-].[Na+].[O:23]=[C:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26][N:25]1[C:33](Cl)=[O:34].Cl>O.CC(C)=O>[O:23]=[C:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26][N:25]1[C:33]([NH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][C:14]([NH:16][CH2:17][CH2:18][CH2:19][CH3:20])=[O:15])(=[O:12])=[O:11])=[CH:6][CH:5]=1)=[O:34]
Reactant: O=C(Cl)N1Cc2ccccc2C1=O
Reactant: CCCCNC(=O)NS(=O)(=O)c1ccc(CCN)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: CCCCNC(=O)NS(=O)(=O)c1ccc(CCNC(=O)N2Cc3ccccc3C2=O)cc1
Reaction time: 2 h

Procedure:
3 g of N-(4-[2-amino-ethyl]-benzenesulfonyl)-N'-butyl-urea (melting point 210°-212° C., prepared by saponification of N-(4-[2-acetylamino-ethyl]-benzenesulfonyl)-N'-butyl-urea with sodium hydroxide solution) are dissolved with 0.4 g of sodium hydroxide in 50 ml of water and 50 ml of acetone and, while stirring, a solution of 2 g of 1-oxo-isoindoline-2-carboxylic acid chloride (melting point 119°-121° C., prepared from 1-oxo-isoindoline sodium and phosgene) in about 50 ml of acetone is added. The temperature of the mixture increases slightly. Stirring is continued for 2 hours at room temperature, whereupon the residue is acidified with dilute hydrochloric acid. The precipitate is reprecipitated from dilute ammonia and recrystallized from dilute acetone. The N-(4-[2-(1-oxo-isoindoline-2-carboxamido)-ethyl]-benzenesulfonyl)-N'-butyl-urea melts at 188°-190° C.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[CH:9][C:10]([N:19]([CH2:23][CH2:24][CH2:25][CH2:26][O:27][CH2:28][C:29](O)=[O:30])[CH:20]([CH3:22])[CH3:21])=[N:11][C:12]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:44][S:45]([NH2:48])(=[O:47])=[O:46].CCCCCCC=CCCC>O1CCCC1.O>[C:1]1([C:7]2[N:8]=[CH:9][C:10]([N:19]([CH2:23][CH2:24][CH2:25][CH2:26][O:27][CH2:28][C:29]([NH:48][S:45]([CH3:44])(=[O:47])=[O:46])=[O:30])[CH:20]([CH3:22])[CH3:21])=[N:11][C:12]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CS(N)(=O)=O
Reactant: CC(C)N(CCCCOCC(=O)O)c1cnc(-c2ccccc2)c(-c2ccccc2)n1
Agent: CCCC=CCCCCCC
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)N(CCCCOCC(=O)NS(C)(=O)=O)c1cnc(-c2ccccc2)c(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.6 %

Procedure:
Under an argon atmosphere, to a solution of 300 mg of 2-{4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butyloxy}acetic acid obtained in Example 42 in 5 ml of anhydrous tetrahydrofuran, 128 mg of 1,1′-carbonyl diimidazole was added and, after stirring at room temperature for 30 minutes, the mixture was heated at reflux for 30 minutes. After air-cooling to room temperature, 69 mg of methanesulfonamide was added. After stirring for 10 minutes, 0.11 ml of 1,8-diazabicyclo[5.4.0.]-7-undecene was added dropwise. After stirring at room temperature overnight, the reaction solution was diluted with water and then extracted with diethyl ether. The extract was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure, and then the residue was purified by silica gel column chromatography to obtain 272 mg of the desired compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9](=[O:16])[N:10]2[CH2:13][CH:14]=O)=[N:5][CH:4]=1.[OH:17][C@@H:18]1[CH2:22][NH:21][CH2:20][C@@H:19]1[CH2:23][NH:24][C:25](=[O:34])[O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.[O-]S([O-])(=O)=O.[Na+].[Na+].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>CO.C(Cl)(Cl)Cl>[OH:17][C@@H:18]1[CH2:22][N:21]([CH2:14][CH2:13][N:10]2[C:11]3[C:6](=[N:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=3)[CH:7]=[CH:8][C:9]2=[O:16])[CH2:20][C@@H:19]1[CH2:23][NH:24][C:25](=[O:34])[O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: COc1cnc2ccc(=O)n(CC=O)c2c1
Reactant: O=C(NC[C@H]1CNC[C@H]1O)OCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COc1cnc2ccc(=O)n(CCN3C[C@H](CNC(=O)OCc4ccccc4)[C@H](O)C3)c2c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of [7-(methoxy)-2-oxo-1,5-naphthyridin-1(2H)-yl]acetaldehyde (as the methyl hemiacetal) (0.654 g, 3.0 mmol) in 1:1 (MeOH/CHCl3) (50 mL) were added phenylmethyl {[(3R,4S)-4-hydroxy-3-pyrrolidinyl]methyl}carbamate (0.750 g, 3.0 mmol) and Na2SO4 (0.100 g) and the resulting solution stirred at ambient temperature for 18 hours. Na(OAc)3BH (1.91 g, 9.0 mmol) was added and the solution stirred an additional 2 hours. The reaction mixture was concentrated onto silica gel and chromatographed on a silica gel column [0-100% CHCl3/(90:10:1) CHCl3/MeOH/NH4OH)] to yield a colorless oil. (0.897 g, 66%).
Reaction SMILES: [N:1]1[CH:6]=[C:5]([CH2:7][C:8]2[C:9](=[O:15])[NH:10][C:11](=[S:14])[NH:12][CH:13]=2)[CH:4]=[N:3][CH:2]=1.CCN(C(C)C)C(C)C.[Cl:25][C:26]1[CH:42]=[CH:41][C:29]([O:30][C:31]2[CH:38]=[CH:37][C:36]([CH2:39]Cl)=[CH:35][C:32]=2[C:33]#[N:34])=[CH:28][C:27]=1[C:43]([F:46])([F:45])[F:44]>C(Cl)Cl>[Cl:25][C:26]1[CH:42]=[CH:41][C:29]([O:30][C:31]2[CH:38]=[CH:37][C:36]([CH2:39][S:14][C:11]3[NH:12][CH:13]=[C:8]([CH2:7][C:5]4[CH:6]=[N:1][CH:2]=[N:3][CH:4]=4)[C:9](=[O:15])[N:10]=3)=[CH:35][C:32]=2[C:33]#[N:34])=[CH:28][C:27]=1[C:43]([F:44])([F:45])[F:46]
Reactant: O=c1[nH]c(=S)[nH]cc1Cc1cncnc1
Reactant: N#Cc1cc(CCl)ccc1Oc1ccc(Cl)c(C(F)(F)F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: N#Cc1cc(CSc2nc(=O)c(Cc3cncnc3)c[nH]2)ccc1Oc1ccc(Cl)c(C(F)(F)F)c1
Temperature: 60 °C
Yield: 43.2 %

Procedure:
To a suspension of 5-(5-pyrimidinylmethyl)-2-thioxo-2,3-dihydro-4(1H)-pyrimidinone (35.0 mg, 0.159 mmol) and DIPEA (0.08 mL, 0.458 mmol) in DCM (1 mL) was added 2-(4-chloro-3-(trifluoromethyl)phenoxy)-5-(chloromethyl)benzonitrile (50 mg, 0.144 mmol). The solution was heated at 60° C. overnight. Purification via MDAP then afforded the title compound (33 mg, 43.1% yield). LCMS: rt=3.28 min, [M+H+]=531
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][NH2:9])=O)=[CH:4][CH:3]=1.I.CS[C:15](=[NH:28])[NH:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=1>N1C=CC=CC=1>[F:25][C:24]([F:26])([F:27])[O:23][C:20]1[CH:19]=[CH:18][C:17]([NH:16][C:15]2[NH:28][C:6]([C:5]3[CH:10]=[CH:11][C:2]([OH:1])=[CH:3][CH:4]=3)=[N:8][N:9]=2)=[CH:22][CH:21]=1
Reactant: NNC(=O)c1ccc(O)cc1
Reactant: CSC(=N)Nc1ccc(OC(F)(F)F)cc1
Agent: I
Solvent: c1ccncc1
Product: Oc1ccc(-c2nnc(Nc3ccc(OC(F)(F)F)cc3)[nH]2)cc1
Temperature: 25 °C
Yield: 40.4 %

Procedure:
4-hydroxybenzoic acid hydrazide (0.643 g, 4.23 mmol) and S-methyl N-[4-(trifluoromethoxy)phenyl]isothiourea hydroiodide (1.6 g, 4.23 mmol) were suspended in 10 mL of anhydrous pyridine. The reaction mixture was refluxed for 24 hours, during which time it changed color from yellow into orange-red. Then it was cooled down to ambient temperature and poured with stirring into 150 mL of ice-water. The formed white solid was collected, washed thoroughly with water and dried in air. The resulting residue was purified by silica gel chromatography using Isco column with 10% to 100% gradient of ethyl acetate in hexane. Solvent was removed in vacuo to give the title product as a pinkish solid (575.2 mg). Yield 40.4
Reaction SMILES: O.[NH2:2][NH2:3].[N:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][NH:13][C:14]([C:16]2[S:20][C:19]([C:21]([O:23]C)=O)=[CH:18][CH:17]=2)=[O:15])=[CH:6][CH:5]=1>CO>[N:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][NH:13][C:14]([C:16]2[S:20][C:19]([C:21]([NH:2][NH2:3])=[O:23])=[CH:18][CH:17]=2)=[O:15])=[CH:6][CH:5]=1
Reactant: NN
Reactant: COC(=O)c1ccc(C(=O)NCCCc2ccncc2)s1
Solvent: CO
Solvent: O
Product: NNC(=O)c1ccc(C(=O)NCCCc2ccncc2)s1
Reaction time: 95 h
Yield: 61 %

Procedure:
80% Hydrazine monohydrate (0.17 mL, 2.8 mmol) was added to methyl 5-[3-(pyridin-4-yl)propylcarbamoyl]thiophene-2-carboxylate (0.28 g, 0.92 mmol) in methanol (10 mL), and the reaction solution was left at 50° C. for 95 hours. After addition of 80% hydrazine monohydrate (0.17 mL, 2.8 mmol), it was left at 55° C. for another 14 hours and concentrated to dryness by evaporating the solvent under reduced pressure. Methanol (2 mL) was added to the residue, and the resulting solution was put on a sonicator. The precipitated solid was recovered by filtration and dried to give the desired product, 5-hydrazinocarbonylthiophene-2-carboxylic acid 3-(pyridin-4-yl)propylamide (yield 61%).
Reaction SMILES: [NH:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH2:5][N:4]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:26][C:27]([CH3:32])=[CH:28][C:29](Cl)=[O:30]>ClCCl>[CH3:26][C:27]([CH3:32])=[CH:28][C:29]([N:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH2:5][N:4]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:3][CH2:2]1)=[O:30]
Reactant: CC(C)(C)OC(=O)N1CCNc2ccccc2C1
Reactant: CC(C)=CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)=CC(=O)N1CCN(C(=O)OC(C)(C)C)Cc2ccccc21
Temperature: 25 °C
Yield: 95.1 %

Procedure:
1 g (4.04 mmol) of tert-butyl 2,3-dihydro-1H-benzo[e][1,4]diazepine-4(5H)-carboxylate was dissolved in 20 mL of dichloromethane and treated with 1.54 mL (8.86 mL) of triethylamine followed by 0.53 mL (4.83 mmol) of 3-methylbut-2-enoyl chloride. The reaction mixture was stirred over night at room temperature, poured onto water (50 mL) and extracted three times with 50 mL of dichloromethane each. The organic phases were combined, washed with a saturated solution of sodium chloride, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica (eluent: 5-10% methanol in dichloromethane) to yield 1.27 g of the title compound as a white solid.
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH2:5][CH2:6][O:7][CH:8]([C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1)[CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)C.C(=O)([O-])[O-].[K+].[K+].Cl[C:32]([O:34][CH2:35][CH3:36])=[O:33].C1(C)C=CC=CC=1>O>[CH3:1][N:2]([CH2:4][CH2:5][CH2:6][O:7][CH:8]([C:18]1[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=1)[CH2:9][CH2:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[C:32]([O:34][CH2:35][CH3:36])=[O:33]
Reactant: CCOC(=O)Cl
Reactant: CN(C)CCCOC(CCCc1ccccc1)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)N(C)CCCOC(CCCc1ccccc1)c1ccc(F)cc1

Procedure:
A mixture of 1.0 g of 1-[3-(N,N-dimethylamino)propoxy]-1-(p-fluorophenyl)-4-phenylbutane, 2.75 g of potassium carbonate, 11 ml of ethyl chloroformate and 20 ml of toluene was heated under refluxing for 2 hours. After cooling, the reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 1-[3-(N-methyl-N-ethoxycarbonylamino)propoxy]-1-(p-fluorophenyl)-4-phenylbutane.
Reaction SMILES: C(O[C:6](=O)[NH:7][N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2([CH3:26])[O:19][C:18]3=[N:20][C:21]([N+:23]([O-:25])=[O:24])=[CH:22][N:17]3[CH2:16]2)[CH2:10][CH2:9]1)(C)(C)C.[F:28][C:29]([F:40])([F:39])[O:30][C:31]1[CH:38]=[CH:37][C:34](C=O)=[CH:33][CH:32]=1.FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+]>C(Cl)Cl>[CH3:26][C:15]1([CH2:14][N:11]2[CH2:12][CH2:13][N:8]([N:7]=[CH:6][C:34]3[CH:33]=[CH:32][C:31]([O:30][C:29]([F:28])([F:39])[F:40])=[CH:38][CH:37]=3)[CH2:9][CH2:10]2)[O:19][C:18]2=[N:20][C:21]([N+:23]([O-:25])=[O:24])=[CH:22][N:17]2[CH2:16]1
Reactant: CC(C)(C)OC(=O)NN1CCN(CC2(C)Cn3cc([N+](=O)[O-])nc3O2)CC1
Reactant: O=Cc1ccc(OC(F)(F)F)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1(CN2CCN(N=Cc3ccc(OC(F)(F)F)cc3)CC2)Cn2cc([N+](=O)[O-])nc2O1
Temperature: 25 °C
Reaction time: 3 h
Yield: 38 %

Procedure:
A mixture of tert-butyl[4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)piperazin-1-yl]carbamate prepared in Example 493 (40 mg, 0.11 mmol), 4-trifluoromethoxybenzaldehyde (24 mg, 0.13 mmol), trifluoroacetic acid (0.08 ml) and methylene chloride (1 ml) was stirred at room temperature for 3 hours. The mixture was added a saturated sodium hydrogencarbonate solution for neutralization followed by extraction with methylene chloride. The solution was washed with water and a saturated saline solution, dried over sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride/ethyl acetate=3/1) to afford N-[4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)piperazin-1-yl]-N-(4-trifluoromethoxybenzylidene)amine (19 mg, yield 40%) as a white powder.
Reaction SMILES: [CH3:1][CH:2]([C:5]#[N:6])[C:3]#[N:4].Br[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10].C(=O)([O-])[O-].[K+].[K+].Cl>CS(C)=O>[CH2:12]([O:11][C:9]([CH2:8][C:2]([CH3:1])([C:5]#[N:6])[C:3]#[N:4])=[O:10])[CH3:13]
Reactant: CCOC(=O)CBr
Reactant: CC(C#N)C#N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCOC(=O)CC(C)(C#N)C#N
Temperature: 25 °C
Reaction time: 4 h
Yield: 24.1 %

Procedure:
2.0 g of 2-methylmalononitrile and 4.2 g of ethyl bromoacetate were dissolved in 10 ml of dimethyl sulfoxide. 3.4 g of potassium carbonate was added thereto and stirred for 4 hours at room temperature. Then, to the reaction mixture was added dilute hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue obtained was subjected to silica gel column chromatography to give 1.0 g of 2-(ethoxycarbonylmethyl)-2-methylmalononitrile (hereinafter referred to as the present invention compound (74)).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:8])[NH:4][CH2:5][C:6]#[CH:7].I[C:10]1[C:18]([N+]([O-])=O)=[CH:17][CH:16]=[C:15]2[C:11]=1/[C:12](=[CH:23]/[C:24]1[NH:25][CH:26]=[CH:27][C:28]=1[O:29][CH3:30])/[C:13](=[O:22])[NH:14]2>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.CN(C=O)C.CCN(CC)CC>[CH3:1][O:2][C:3](=[O:8])[NH:4][CH2:5][C:6]#[C:7][C:10]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:11]=1/[C:12](=[CH:23]/[C:24]1[NH:25][CH:26]=[CH:27][C:28]=1[O:29][CH3:30])/[C:13](=[O:22])[NH:14]2
Reactant: C#CCNC(=O)OC
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc([N+](=O)[O-])c(I)c21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)NCC#Cc1cccc2c1/C(=C/c1[nH]ccc1OC)C(=O)N2

Procedure:
Using Method C above, 2-propynyl carbamic acid methyl ester (71.3 mg, 0.63 mmol) (see below) was coupled with (Z)-1,3-dihydro-4-iodo-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (110 mg, 0.3 mmol) (Starting Material 2 supra) using (Ph3P)2PdCl2 (11 mg) and CuI (3 mg) as catalyst in DMF (3 mL) and Et3N (3 mL) as solvent at 80° C. for 6 h to give (Z)-[3-[2,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2-oxo-1H-indol-4-yl]-2-propynyl]carbamic acid methyl ester. (Yield 25 mg, 23%).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]3[C:13](=[CH:14][CH:15]=2)[CH2:12][NH:11][CH2:10][CH:9]3[F:16])[CH2:3][CH2:2]1.C(OC(=O)[NH:23][C@H:24]([C:26]1[CH:31]=[CH:30][C:29]([CH:32]=O)=[CH:28][CH:27]=1)[CH3:25])(C)(C)C.CC(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1>[CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]3[C:13](=[CH:14][CH:15]=2)[CH2:12][N:11]([CH2:32][C:29]2[CH:30]=[CH:31][C:26]([C@@H:24]([NH2:23])[CH3:25])=[CH:27][CH:28]=2)[CH2:10][CH:9]3[F:16])[CH2:2][CH2:3]1
Reactant: FC1CNCc2ccc(OCC3CC3)cc21
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1ccc(C=O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: C[C@H](N)c1ccc(CN2Cc3ccc(OCC4CC4)cc3C(F)C2)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To 170 mg (0.660 mmol) 6-cyclopropylmethoxy-4-fluoro-1,2,3,4-tetrahydro-isoquinoline (example XLVII.5) and 164 mg (0.660 mmol) [(S)-1-(4-formyl-phenyl)-ethyl]-carbamic acid tert-butyl ester (example II) in 2 mL THF are added 113 μL (1.98 mmol) AcOH and the mixture is stirred at r.t. for 10 min. The resulting mixture is cooled to 0° C., 210 mg (0.989 mmol) sodium triacetoxyborohydride are added and the reaction mixture is stirred at r.t. for 2 h. The reaction is quenched by the addition of 200 μL water and purified by HPLC (ACN/H2O/NH3).