Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]2[CH2:17][CH2:16][CH:15]3[CH2:18][CH:13]2[C:14]3([CH3:20])[CH3:19])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH2:21]([OH:25])[CH2:22][C:23]#[CH:24]>CN(C=O)C.CCN(C(C)C)C(C)C>[CH3:19][C:14]1([CH3:20])[CH:13]2[CH2:18][CH:15]1[CH2:16][CH2:17][CH:12]2[NH:11][S:8]([C:5]1[CH:6]=[CH:7][C:2]([C:24]#[C:23][CH2:22][CH2:21][OH:25])=[CH:3][CH:4]=1)(=[O:10])=[O:9]
Reactant: CC1(C)C2CCC(NS(=O)(=O)c3ccc(Br)cc3)C1C2
Reactant: C#CCCO
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)C2CCC(NS(=O)(=O)c3ccc(C#CCCO)cc3)C1C2
Temperature: 25 °C
Reaction time: 16 h
Yield: 60 %

Procedure:
A solution of the product of Step A (0.37 g, 0.5 mmol) and but-3-yn-1-ol (0.12 ml, excess) in a mixture of DMF (5 ml) and DIPEA (0.5 ml) was degassed with N2 and Cl2Pd(PPh3)2 (0.07 g) was added, followed by catalytic amount of CuI and the mixture was stirred for 16 h at room temperature. The reaction was quenched with saturated NH4Cl solution and diluted with H2O followed by the extraction with EtOAc (100 ml). The organic layer was separated, dried over MgSO4, filtered and the filtrate was evaporated to dryness and the residue was purified by FCC (SiO2, hexane/EtOAc) to give the product (0.11 g, 60%), as creamy paste. 1H-NMR (CDCl3) 7.66 (d, 2H, J=8.43 Hz); 7.51 (d, 2H, J=8.43 Hz); 3.81 (b, 2H); 3.01-2.86 (m, 2H); 2.71-2.67 (m, 4H); 2.50-2.10 (m, 2H); 1.94-1.82 (m, 5H); 1.52-1.48 (m, 1H); 1.18 (s, 3H); 1.02 (s, 3H).
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.[F:6][C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[C@:14]1([C@H:17]([N:19]2[CH:27]=[N:26][C:25]3[C:20]2=[N:21][CH:22]=[N:23][C:24]=3[CH3:28])[CH3:18])[CH2:16][O:15]1>>[F:6][C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[C@:14]([OH:15])([C@H:17]([N:19]1[CH:27]=[N:26][C:25]2[C:20]1=[N:21][CH:22]=[N:23][C:24]=2[CH3:28])[CH3:18])[CH2:16][N:1]1[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: Cc1ncnc2c1ncn2[C@H](C)[C@@]1(c2ccc(F)cc2F)CO1
Reactant: c1nc[nH]n1
Product: Cc1ncnc2c1ncn2[C@H](C)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Yield: 16.7 %

Procedure:
Using 1H-1,2,4-triazole (167 mg) and (2S)-2-(2,4-difluorophenyl)-2-[(1R)-1-[6-methyl-9(9H)-purinyl]ethyl]oxirane (388 mg), Compound 48 (79 mg) was obtained as colorless prisms by the same way as in Exmaple 1.
Reaction SMILES: [OH:1][C@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C@@H:4]([CH2:5][CH2:6][C@:7]3([CH3:35])[C@@H:16]2[CH2:15][CH2:14][C@H:13]2[C@@:8]3([CH3:34])[CH2:9][CH2:10][C@@:11]3(/[CH:28]=[C:29](\[CH3:33])/[C:30](O)=[O:31])[CH2:23][C:22](=[O:24])[C:21]([CH:25]([CH3:27])[CH3:26])=[C:12]32)[C:3]1([CH3:37])[CH3:36].Cl.[Cl:39][C:40]1[CH:45]=[CH:44][C:43]([C:46]2([NH2:49])[CH2:48][CH2:47]2)=[CH:42][CH:41]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl>CN(C=O)C>[Cl:39][C:40]1[CH:41]=[CH:42][C:43]([C:46]2([NH:49][C:30](=[O:31])/[C:29](/[CH3:33])=[CH:28]/[C@:11]34[CH2:23][C:22](=[O:24])[C:21]([CH:25]([CH3:26])[CH3:27])=[C:12]3[C@@H:13]3[C@@:8]([CH3:34])([CH2:9][CH2:10]4)[C@@:7]4([CH3:35])[C@@H:16]([C@:17]5([CH3:20])[C@@H:4]([CH2:5][CH2:6]4)[C:3]([CH3:37])([CH3:36])[C@@H:2]([OH:1])[CH2:19][CH2:18]5)[CH2:15][CH2:14]3)[CH2:47][CH2:48]2)=[CH:44][CH:45]=1
Reactant: C/C(=C\[C@@]12CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](O)C(C)(C)[C@@H]5CC[C@]43C)C1=C(C(C)C)C(=O)C2)C(=O)O
Reactant: NC1(c2ccc(Cl)cc2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C/C(=C\[C@@]12CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](O)C(C)(C)[C@@H]5CC[C@]43C)C1=C(C(C)C)C(=O)C2)C(=O)NC1(c2ccc(Cl)cc2)CC1
Temperature: 20 °C
Reaction time: 1 h
Yield: 99.3 %

Procedure:
To a solution of (E)-3-((3aS,5aR,5bR,7aR,9S,11aR,11bR,13aS)-9-hydroxy-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-3a-yl)-2-methylacrylic acid (350 mg, 0.685 mmol), 1-(4-chlorophenyl)cyclopropanamine hydrochloride (154 mg, 0.754 mmol) and HATU (521 mg, 1.371 mmol) in DMF (2 mL) stirred at 0° C. was added DIPEA (0.479 mL, 2.74 mmol). The reaction mixture was stirred at 20° C. for 1 h. The reaction mixture was pH adjusted to 3-4 with 2 M HCl and filtered. The solid was washed with water (50 mL), dissolved into DCM, dried over sodium sulfate and evaporated in vacuo to give the crude (E)-N-(1-(4-chlorophenyl)cyclopropyl)-3-((3aS,5aR,5bR,7aR,9S,11aR,11bR,13aS)-9-hydroxy-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-3a-yl)-2-methylacrylamide (650 mg, 0.680 mmol, 99%) as a yellow solid.
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]=[C:5]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=1)[C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2([OH:33])[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C=O)C.C(OCC)(=O)C.O>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2([OH:33])[CH2:28][CH2:29][N:30]([CH2:2][CH2:3][CH:4]=[C:5]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=3)[C:6]3[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=3)[CH2:31][CH2:32]2)=[CH:23][CH:22]=1
Reactant: OC1(c2ccc(Cl)cc2)CCNCC1
Reactant: COc1cccc(C(=CCCBr)c2cccnc2)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: COc1cccc(C(=CCCN2CCC(O)(c3ccc(Cl)cc3)CC2)c2cccnc2)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution the product of step 2 (500 mg) in DMF (20 ml) were added 4-(4-chlorophenyl)-4-hydroxypiperidine (500 mg), potassium carbonate (430 mg), potassium iodide (130 mg) and the mixture was stirred at room temperature for 12 hours. Water and ethyl acetate were added to the reaction mixture, the organic layer was separated and washed with saturated aqueous sodium chloride, and dried with magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography eluting with methylene chloride-methanol (10:1) to give the titled compound as major regioisomer (225 mg) and minor one (140 mg)
Reaction SMILES: CO[C:3]([C:5]1[CH:10]=[CH:9][C:8](=[O:11])[N:7]([CH3:12])[C:6]=1[NH:13][C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:15]=1[F:21])=[O:4].[CH:22]([O:24][CH2:25][CH2:26][O:27][NH2:28])=[CH2:23].C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1>[CH:22]([O:24][CH2:25][CH2:26][O:27][NH:28][C:3]([C:5]1[CH:10]=[CH:9][C:8](=[O:11])[N:7]([CH3:12])[C:6]=1[NH:13][C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:15]=1[F:21])=[O:4])=[CH2:23]
Reactant: C=COCCON
Reactant: COC(=O)c1ccc(=O)n(C)c1Nc1ccc(C)cc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=COCCONC(=O)c1ccc(=O)n(C)c1Nc1ccc(C)cc1F
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 78.1 %

Procedure:
To a solution of 2-(2-fluoro-4-methylphenylamino)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid methyl ester (0.050 g, 0.17 mmol) in THF (1.5 mL) under N2 was added O-(2-vinyloxy-ethyl)-hydroxylamine (0.044 g, 0.43 mmol). The solution was cooled to 0° C. and lithium bis(trimethylsilyl)amide (0.86 mL, 0.86 mmol, 1 M solution in hexanes) was added dropwise. The reaction mixture was warmed to room temperature. After stirring for 40 minutes, the reaction mixture was quenched by the addition of NaHCO3 and partitioned between EtOAc and saturated NaCl. The layers were separated and the aqueous layer was reextracted with EtOAc. The combined organic extracts were dried (Na2SO4) and concentrated under reduced pressure. Purification by flash column chromatography (methylene chloride/methanol, 20:1) gave 0.048 g (77%) pure desired product as an off-white foamy solid.
Reaction SMILES: Cl[C:2]1C=C(SC2C3C(=CC(C)=CC=3)NC=2CCC(N)=O)C=C(Cl)[CH:7]=1.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([S:32][C:33]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][C:40]=3[CH3:42])[NH:35][C:34]=2[C:43]([OH:45])=[O:44])=[CH:28][CH:27]=1.C(Cl)(=O)C(Cl)=O.CCO>C1COCC1>[Cl:25][C:26]1[CH:27]=[CH:28][C:29]([S:32][C:33]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][C:40]=3[CH3:42])[NH:35][C:34]=2[C:43]([O:45][CH2:2][CH3:7])=[O:44])=[CH:30][CH:31]=1
Reactant: Cc1cccc2[nH]c(C(=O)O)c(Sc3ccc(Cl)cc3)c12
Reactant: Cc1ccc2c(Sc3cc(Cl)cc(Cl)c3)c(CCC(N)=O)[nH]c2c1
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)c1[nH]c2cccc(C)c2c1Sc1ccc(Cl)cc1
Yield: 62 %

Procedure:
Following the method used to prepare 24a, the use of 1a (0.19 mmol) and oxalyl chloride in THF followed by allowing the intermediate acid chloride to react with EtOH (3 mL) provided 41 mg (62%) of product 11 as a white solid, mp 186-188° C. 1H NMR (300 MHz, DMSO-d6) δ 1.25 (t, J=7 Hz, 3H), 2.59 (s, 3H), 4.31 (q, J=7 Hz, 2H), 6.88 (d, J=7 Hz, 1H), 6.94-6.98 (m, 2H), 7.23 (t, J=8 Hz, 1H), 7.25-7.30 (m, 2H), 7.42 (d, J=8 Hz, 1H), 12.48 (s, 1H). LC-MS (CI): m/z 346.1 [(M+H)+ C18H16ClNO2S requires 345.06]. Purity (100%). Calcd for C18H16ClNO2S: C, 62.51; H, 4.66; N, 4.05; S, 9.27; Cl, 10.25. Found: C, 62.53; H, 4.59; N, 4.08; S, 9.27; Cl, 10.35.
Reaction SMILES: [Cl:1][C:2]1[C:9]([CH2:10][CH:11]=C)=[CH:8][CH:7]=[C:6]([F:13])[C:3]=1[C:4]#[N:5].N1C=CC=CC=1.[O:20]=[O+][O-]>C(Cl)Cl.CO>[Cl:1][C:2]1[C:9]([CH2:10][CH:11]=[O:20])=[CH:8][CH:7]=[C:6]([F:13])[C:3]=1[C:4]#[N:5]
Reactant: O=[O+][O-]
Reactant: C=CCc1ccc(F)c(C#N)c1Cl
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CO
Product: N#Cc1c(F)ccc(CC=O)c1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-chloro-6-fluoro-3-(prop-2-en-1-yl)benzonitrile (450 mg, 2.296 mmol) in 0.37 mL pyridine (363 mg, 4.592 mmol) and 40 mL DCM/MeOH (V/V=1:1) was bubbled O3 at −78° C. for 15 min. Then N2 was bubbled for another 15 min. at −78° C. and 5 mL of Me2S were added. The mixture was stirred at r.t. overnight and then concentrated to dryness. The residue was dissolve in EtOAc (50 mL) and washed with 1 N HCl (aq.) and brine, dried over anhydrous Na2SO4 and concentrated to dryness to give 2-chloro-6-fluoro-3-(2-oxoethyl)benzonitrile.
Reaction SMILES: C([O:3][C:4]([C:6]1[O:10][C:9]([CH2:11][N:12]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[N:14]=[C:13]2[NH:21][CH:22]2[CH2:27][CH2:26][N:25]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:24][CH2:23]2)=[CH:8][CH:7]=1)=O)C.O1CCCC1.[H-].[Al+3].[Li+].[H-].[H-].[H-].CC(C)=O.ClCCl>ClCCl>[OH:3][CH2:4][C:6]1[O:10][C:9]([CH2:11][N:12]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[N:14]=[C:13]2[NH:21][CH:22]2[CH2:27][CH2:26][N:25]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:24][CH2:23]2)=[CH:8][CH:7]=1
Reactant: CCOC(=O)c1ccc(Cn2c(NC3CCN(C(=O)OCC)CC3)nc3ccccc32)o1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CC(C)=O
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCOC(=O)N1CCC(Nc2nc3ccccc3n2Cc2ccc(CO)o2)CC1
Reaction time: 5.5 h

Procedure:
Combine (1-(5-(ethoxycarbonyl)fur-2-ylmethyl)-1H-benzimidazol-2-yl)(1-ethoxycarbonylpiperidin-4-yl)amine (1.0 g, 2.27 mmol) and tetrahydrofuran (10 mL). Add dropwise a solution of lithium aluminum hydride (2.3 mL, 1 M in THF, 2.3 mmol). After 5.5 hours, dilute the reaction mixture with dichloromethane and quench by slow portionwise addition of Glauber's salt (Na2SO4.10 H2O) until gas evolution ceases. Add dichloromethane and celite and stir. Filter, rinse the solids with dichloromethane, and evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting with 40% acetone/dichloromethane to give a residue. Recrystallization from ethyl acetate/hexane to give (1-(5-hydroxymethylfur-2-ylmethyl)-1H-benzimidazol-2-yl)(1-ethoxycarbonylpiperidin-4-yl)amine: mp; 138-140° C. Elemental Analysis calculated for C21H26N4O4: C 63,30; H 6.58; N 14.06; Found: C 63.29; H 6.50; N 14.06.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH:4]([C:12]1([C:26]([CH3:28])=[CH2:27])[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]1=[O:25])[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].C(N(C(C)C)CC)(C)C.[F:38][C:39]1[CH:40]=[C:41]([CH:45]=[CH:46][C:47]=1[F:48])[C:42](Cl)=[O:43]>C(Cl)Cl.CCOC(C)=O>[F:38][C:39]1[CH:40]=[C:41]([CH:45]=[CH:46][C:47]=1[F:48])[C:42]([NH:1][CH2:2][CH2:3][CH:4]([C:12]1([C:26]([CH3:28])=[CH2:27])[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:13]1=[O:25])[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6])=[O:43]
Reactant: O=C(Cl)c1ccc(F)c(F)c1
Reactant: C=C(C)C1(C(CCN)C(=O)OC(C)(C)C)CCN(CCc2ccccc2)C1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: C=C(C)C1(C(CCNC(=O)c2ccc(F)c(F)c2)C(=O)OC(C)(C)C)CCN(CCc2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 137 %

Procedure:
A cold (0° C.) solution of tert-butyl α-(2-aminoethyl)-2-oxo-1-(2-phenylethyl)-3-(propen-2-yl)-3-pyrrolidineacetate (1.93 g, 4.99 mmol) in dry CH2Cl2 (20 mL) is treated with diisopropylethylamine (1.04 mL, 5.99 mmol) and 3,4-difluorobenzoyl chloride (691 μL, 5.49 mmol). The solution is allowed to warm to room temperature, stirring under N2 overnight. The solution is diluted with EtOAc (100 mL) and washed with 1N HCl (25 mL), 1N NaOH (25 mL), and brine (25 mL). The organic layer is dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure to give 3.60 g of a brown oil. The oil is purified by silica gel chromatography (50 g SG; 25% EtOAc/hexane) to provide 2.10 g (80%) of the title compound as a yellow, amorphous solid:
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N+:12]([O-:14])=[O:13].[C:15]1([CH:21]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(CC)CC)C>CN(C)C(=O)C>[ClH:1].[C:28]1([CH:21]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:22]2[CH2:23][CH2:24][N:25]([CH2:2][CH2:3][CH2:4][NH:5][C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[N+:12]([O-:14])=[O:13])[CH2:26][CH2:27]2)[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Reactant: O=[N+]([O-])c1ccccc1NCCCCl
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Product: Cl
Product: O=[N+]([O-])c1ccccc1NCCCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Temperature: 100 °C

Procedure:
A mixture of 21.5 parts of N-(3-chloropropyl)-2-nitrobenzenamine, 22.68 parts of 1-(diphenylmethyl)piperazine, 20 parts of N,N-diethylethanamine and 180 parts of N,N-dimethylacetamide is stirred and heated for 6 hours at 100° C. The reaction mixture is evaporated and the residue is taken up in water. The oily product is extracted with trichloromethane. The extract is dried, filtered and evaporated. The residue is crystallized from a mixture of 2-propanol, ethanol and 2,2'-oxybispropane. The product is filtered off and dried, yielding 4-(diphenylmethyl)-N-(2-nitrophenyl)-1-piperazinepropanamine hydrochloride; mp. 228° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:11]([CH2:12][O:13][C:14]2[N:15]=[CH:16][C:17]([C:20]([OH:22])=O)=[N:18][CH:19]=2)=[CH:10][O:9][N:8]=1.[CH:23]([NH2:26])([CH3:25])[CH3:24]>>[CH:23]([NH:26][C:20]([C:17]1[CH:16]=[N:15][C:14]([O:13][CH2:12][C:11]2[C:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)=[N:8][O:9][CH:10]=2)=[CH:19][N:18]=1)=[O:22])([CH3:25])[CH3:24]
Reactant: O=C(O)c1cnc(OCc2conc2-c2ccccn2)cn1
Reactant: CC(C)N
Product: CC(C)NC(=O)c1cnc(OCc2conc2-c2ccccn2)cn1
Yield: 68 %

Procedure:
As described for example 19f, 5-(3-pyridin-2-yl-isoxazol-4-ylmethoxy)-pyrazine-2-carboxylic acid (83.6 mg, 2.8 mmol) was converted, using isopropylamine instead of 4-aminotetrahydropyran, to the title compound (SiO2, heptane:ethyl acetate 4:1 to 3:7, 65 mg, 68%) which was obtained as a white solid. MS: m/e=340.2 [M+H]+.
Reaction SMILES: O.[NH2:2][NH2:3].[NH2:4][NH:5][C:6]([NH:8][NH2:9])=[S:7].[CH2:10](O)C>>[NH:2]([C:10]1[N:8]([NH2:9])[C:6]([SH:7])=[N:5][N:4]=1)[NH2:3]
Reactant: NNC(=S)NN
Reactant: NN
Reactant: CCO
Solvent: O
Product: NNc1nnc(S)n1N

Procedure:
Methyl dithiocarbazinate (24.4 g, 0.2 mole) was dissolved in 200 ml. of absolute ethanol and 18 ml. (0.3 mole of hydrazine) of 85% hydrazine hydrate was added. The resulting solution was refluxed until no more solid thiocarbohydrazide precipitated (about 45 minutes). A small amount of 3-hydrazino-4-amino-5-mercapto-1,2,4-triazole that had formed was removed as follows: The reaction mixture was chilled, and the resulting solid product was collected and recrystallized from water acidified with a few drops of hydrochloric acid.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[C@H:9]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([F:17])[CH:11]=2)[O:8][CH2:7][CH2:6][N:5](C(OC(C)(C)C)=O)[CH2:4]1.Cl[CH2:26][CH2:27][CH2:28][C:29](Cl)=[O:30]>>[ClH:16].[Cl:16][C:13]1[CH:14]=[CH:15][C:10]([C@@H:9]2[O:8][CH2:7][CH2:6][NH:5][CH2:4][C@H:3]2[CH2:2][N:1]2[CH2:26][CH2:27][CH2:28][C:29]2=[O:30])=[CH:11][C:12]=1[F:17]
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(F)c2)[C@H](CN)C1
Reactant: O=C(Cl)CCCCl
Product: Cl
Product: O=C1CCCN1C[C@@H]1CNCCO[C@H]1c1ccc(Cl)c(F)c1

Procedure:
Using tert-butyl (6R,7R)-6-(aminomethyl)-7-(4-chloro-3-fluorophenyl)-1,4-oxazepane-4-carboxylate and 4-chlorobutanoyl chloride, and by a method similar to that of Example 363, steps A and B and Example 39, step B, the title compound was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1OS(C(F)(F)F)(=O)=O.[CH3:27][C:28]1([CH2:34][O:35][C:36]2[CH:43]=[CH:42][C:39]([CH2:40][NH2:41])=[CH:38][CH:37]=2)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>O1CCOCC1>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1[NH:41][CH2:40][C:39]1[CH:42]=[CH:43][C:36]([O:35][CH2:34][C:28]2([CH3:27])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)=[CH:37][CH:38]=1
Reactant: O=C(N1CCc2ccc(Cl)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Reactant: CC1(COc2ccc(CN)cc2)CCCCC1
Solvent: C1COCCO1
Product: CC1(COc2ccc(CNc3c(Cl)ccc4c3CCN(C(=O)C(F)(F)F)CC4)cc2)CCCCC1
Yield: 42.2 %

Procedure:
Use a method similar to the General Procedure 5-2 to couple 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (200 mg, 0.47 mmol) with 4-(1-methyl-cyclohexylmethoxy)-benzylamine (120 mg, 0.51 mmol) in anhydrous 1,4-dioxane (7 mL). Purify the crude mixture by chromatography on silica gel eluting with isohexane/EtOAc (19:1 to 4:1 gradient) to obtain 7-chloro-6-[4-(1-methyl-cyclohexylmethoxy)-benzylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (101 mg, 39%).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH2:11]([N:18]1[CH2:23][CH2:22][CH:21]([CH2:24][CH2:25][CH2:26][OH:27])[CH2:20][CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH2:11]([N:18]1[CH2:23][CH2:22][CH:21]([CH2:24][CH2:25][CH:26]=[O:27])[CH2:20][CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: OCCCC1CCN(Cc2ccccc2)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=CCCC1CCN(Cc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a solution of 0.93 mL of oxalyl chloride in 20 mL of CH2Cl2 at −78° C. was added 1.13 mL of DMSO in 0.1 mL of CH2Cl2 dropwise. After stirring 5 min, a solution of 3-(1-benzyl-piperidin)yl)propan-1-ol (form Step C) in 8 mL of CH2Cl2 was added dropwise. After stirring 15 minutes, 0.75 mL of diisopropylethylamine was added. The reaction was warmed to 0° C. and stirred for 20 min. After quenching with H2O, the reaction was diluted with 50 mL of CH2Cl2. The aqueous layer was extracted with 2×50 mL Of CH2Cl2. The combined organic phases were dried over MgSO4 and concentrated to give 612 mg the title compound, which was used for the next step without further purification
Reaction SMILES: N1(C2C=CC(C(C3C=CC=CC=3)=O)=CC=2)CCNCC1.CO[C:23]1[C:42]([O:43][CH3:44])=[CH:41][C:26]2[C:27]([OH:40])=[CH:28][C:29]3[C:30]([CH3:39])([CH3:38])[C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][C:36]=4[C:37]=3[C:25]=2[CH:24]=1.[NH:45]1[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]1.C([Li])CCC.Cl>CCCCCC.O1CCCC1>[N:45]1([C:23]2[C:42]([O:43][CH3:44])=[CH:41][C:26]3[C:27]([OH:40])=[CH:28][C:29]4[C:30]([CH3:38])([CH3:39])[C:31]5[CH:32]=[CH:33][CH:34]=[CH:35][C:36]=5[C:37]=4[C:25]=3[CH:24]=2)[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]1
Reactant: C1CCNCC1
Reactant: COc1cc2c(O)cc3c(c2cc1OC)-c1ccccc1C3(C)C
Agent: Cl
Agent: O=C(c1ccccc1)c1ccc(N2CCNCC2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1cc2c(O)cc3c(c2cc1N1CCCCC1)-c1ccccc1C3(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To an oven-dried 500 mL one-neck flask was added the product of Step 3, Example 1, of U.S. Pat. No. 6,296,785B1, 2,3-dimethoxy-7,7-dimethyl-7H-benzo[C]fluoren-5-ol (10 g) which is included herein as reference, piperidine (5.2 mL) and anhydrous tetrahydrofuran (150 mL). n-Butyl lithium in hexane solution (2.5M, 35 mL) was dropped to the mixture slowly. The reaction mixture was stirred at room temperature for 3 hours. The mixture was poured into cold aqueous hydrochloric acid (10%, 60 mL). The mixture was extracted with ethyl acetate (200 mL) and the recovered top layer was filtered through a silica gel plug. The desired product 2-piperidino-3-methoxy-7,7-dimethyl-7H-benzo[C]fluoren-5-ol (10 g) was obtained by recrystallization from solution in ethyl acetate/hexanes.
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]([CH:13]=[CH:14][CH:15]=1)[C:8]([O:10][CH2:11][CH3:12])=[O:9])(=[O:4])=[O:3].[F:16][C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][CH:23]=1)[NH2:20]>CN(C)C(=O)C.C(OCC)(=O)C>[F:16][C:17]1[CH:18]=[C:19]([NH:20][S:2]([C:5]2[CH:6]=[C:7]([CH:13]=[CH:14][CH:15]=2)[C:8]([O:10][CH2:11][CH3:12])=[O:9])(=[O:4])=[O:3])[CH:21]=[CH:22][CH:23]=1
Reactant: Nc1cccc(F)c1
Reactant: CCOC(=O)c1cccc(S(=O)(=O)Cl)c1
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: CCOC(=O)c1cccc(S(=O)(=O)Nc2cccc(F)c2)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To ethyl 3-(chlorosulfonyl)benzoate (1.0 g, 4.02 mmol) in N,N-dimethylacetamide (5 mL) was added 3-fluoroaniline (1.79 g, 16.08 mmol) dropwise over 30 seconds at room temperature. The mixture was stirred at room temperature for 4 hours, and then it was diluted with ethyl acetate (33 mL). The organic solution was washed with 1 N HCl (2×13 mL) and saturated NaCl (13 mL). The organic layer was concentrated, ethanol (8 mL) was added, and the mixture concentrated to give ethyl 3-{[(3-fluorophenyl)amino]sulfonyl}benzoate.
Reaction SMILES: [C:1](/[C:3](=[C:7](\OCC)/[CH3:8])/[C:4](=[S:6])[NH2:5])#[N:2].[NH3:12]>CO>[NH2:12]/[C:7](/[CH3:8])=[C:3](\[C:1]#[N:2])/[C:4](=[S:6])[NH2:5]
Reactant: N
Reactant: CCO/C(C)=C(\C#N)C(N)=S
Solvent: CO
Product: C/C(N)=C(/C#N)C(N)=S
Temperature: 25 °C
Reaction time: 8 h
Yield: 63 %

Procedure:
(2E)-2-Cyano-3-ethoxybut-2-enethioamide (method 2) (19.2 g, 0.136 mol) was dissolved in a saturated solution of ammonia in methanol (500 mL) and stirred at r.t. overnight. The reaction mixture was concentrated and the residue was dissolved in hot water (600 mL) and the undissoved solid was filtered and dried to recover 6 g of the starting thiocrotonamide. The aqueous solution on standing overnight provided the pure (2E)-3-amino-2-cyanobut-2-enethioamide (6.85 g, 63%) as off-white crystals. 1H NMR (300 MHz, DMSO-d6) δ 2.22 (s, 3H), 7.73 (bs, 1H), 8.53 (bs, 1H), 9.01 (bs, 1H), 11.60 (bs, 1H).