Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:8](=[O:9])/[C:7](=[CH:10]/[C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[N:16]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[C:28]([F:31])([F:30])[F:29])[N:15]=[CH:14]3)/[S:6][C:5]1=[O:32].[N:33]1([S:38](Cl)(=[O:40])=[O:39])[CH2:37][CH2:36][CH2:35][CH2:34]1>>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([CH2:20][N:16]2[C:17]3[C:13](=[CH:12][C:11](/[CH:10]=[C:7]4/[C:8](=[O:9])[N:4]([CH2:3][CH2:2][NH:1][S:38]([N:33]5[CH2:37][CH2:36][CH2:35][CH2:34]5)(=[O:40])=[O:39])[C:5](=[O:32])[S:6]/4)=[CH:19][CH:18]=3)[CH:14]=[N:15]2)=[C:22]([C:28]([F:30])([F:29])[F:31])[CH:23]=1
Reactant: O=S(=O)(Cl)N1CCCC1
Reactant: NCCN1C(=O)S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C1=O
Product: O=C1S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C(=O)N1CCNS(=O)(=O)N1CCCC1

Procedure:
N-{2-[(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidin-3-yl]ethyl}pyrrolidine-1-sulfonamide was prepared from 3-(2-aminoethyl)-(5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-1,3-thiazolidine-2,4-dione (from Example 49) and pyrrolidine-1-sulfonyl chloride following
Reaction SMILES: Cl.[NH2:2][CH:3]([CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12](=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:4](=O)[CH3:5].[S-:20][C:21]#[N:22].[K+]>O>[C:12]([NH:11][CH2:10][CH2:9][CH2:8][CH2:7][C:3]1[C:4]([CH3:5])=[N:22][C:21](=[S:20])[N:2]=1)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: N#C[S-]
Reactant: CC(=O)C(N)CCCCNC(=O)c1ccccc1
Agent: Cl
Agent: [K+]
Solvent: O
Product: CC1=NC(=S)N=C1CCCCNC(=O)c1ccccc1
Yield: 25.3 %

Procedure:
A solution of 3-amino-7-benzamidoheptan-2-one hydrochloride (16.39 g, 0.0576 mol) and potassium thiocyanate (7.30 g, 0.0755 mol, excess) in water was heated under reflux for 20 hours. The aquesus phase was decanted off and the organic phase was washed with water, and recrystallised from acetonitrile to give 4-(4-benzamidobutyl)-5-methylimidazole-2-thione (4.18 g, 25%) m.p. 180°-184°.
Reaction SMILES: [C:1]([CH2:6][CH:7]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:3][CH2:4][CH3:5])=[O:2].[CH:27](O)(O)[C:28]([F:31])([F:30])[F:29]>O1CCCC1>[CH3:7]/[C:6](=[CH:27]\[C:28]([F:31])([F:30])[F:29])/[C:1]([O:3][CH2:4][CH3:5])=[O:2]
Reactant: OC(O)C(F)(F)F
Reactant: CCOC(=O)CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)/C(C)=C/C(F)(F)F
Reaction time: 15 h

Procedure:
A suspension of (carbethoxyethylidene)triphenylphosphorane (400 g, 1.10 mole) in tetrahydrofuran (600 mL) was treated with aqueous fluoral hydrate (71.5% w/w, 180 g, 1.10 mole) over a period of 4 hours. During the addition the reaction temperature rose to 45° C. and all of the solid dissolved to give a clear brown solution. The mixture was allowed to stand for 15 hours and was then heated under reflux for 3.5 hours. The solution was distilled at 2,700 Pa until the temperature in the distillation flask reached 140° C., giving ethyl (E)-2-methyl-4,4,4-trifluorobut-2-enoate as a solution in tetrahydrofuran (Solution A, 0.75 L, containing a maximum of 201 g of alkene); NMR (270 MHz, CDCl3): 1.3 (t, 3H, J=7Hz), 2.1 (br, s, 3H), 4.3 (q, 2H, J=7Hz) and 6.7 (m, 1H), (plus signals due to tetrahydrofuran).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=2)[C:3]=1[C:23]([NH2:25])=O.[Cl-].[Na+].P(Cl)(Cl)(Cl)=O>ClCCCl>[CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=2)[C:3]=1[C:23]#[N:25]
Reactant: Cc1nc(-c2ccccc2)nc(-c2cccc([N+](=O)[O-])c2)c1C(N)=O
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCCl
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1nc(-c2ccccc2)nc(-c2cccc([N+](=O)[O-])c2)c1C#N
Yield: 66.6 %

Procedure:
A mixture of 6-methyl-4-(3-nitrophenyl)-2-phenyl-5-pyrimidinecarboxamide (10 g), sodium chloride (8 g) and phosphorous oxychloride (3.3 g) in 1,2-dichloroethane (50 ml) was refluxed for 10 hours. After removal of the sodium chloride, the reaction mixture was poured into a mixture of dichloromethane (200 ml) and aqueous saturated hydrogen carbonate solution (100 ml). The separated organic layer was dried over magnesium sulfate and evaporated in vacuo. The residue was crystallized from diethyl ether, collected, washed with diethyl ether and dried to give 6-methyl-4-(3-nitrophenyl)-2-phenyl-5-pyrimidinecarbonitrile (6.3 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C@@H:4]([NH2:18])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.[I:20][C:21]1[CH:22]=[CH:23][C:24]([NH2:30])=[C:25]([CH:29]=1)[C:26](O)=[O:27]>>[CH3:1][O:2][C:3](=[O:19])[C@@H:4]([NH:18][C:26](=[O:27])[C:25]1[CH:29]=[C:21]([I:20])[CH:22]=[CH:23][C:24]=1[NH2:30])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:8][CH:7]=1
Reactant: Nc1ccc(I)cc1C(=O)O
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2ccccc2)cc1
Product: COC(=O)[C@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1cc(I)ccc1N
Yield: 74.6 %

Procedure:
(2S)-(2-Amino-5-iodo-benzoyl-amino)-3-biphenyl-4-yl-propionic acid methyl ester (1.53 g, 80%) was prepared from (2S)-amino-3-biphenyl-4-yl-propionic acid methyl ester (1.0 g, 4.1 mmol), 5-iodo-2-amino-benzoic acid (1.23 g, 4.9 mmol) as described in general procedure A.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH3:10])[CH2:5][NH2:6].C(N(C(C)C)C(C)C)C.[Br:20][CH:21]([CH2:25][CH2:26][Br:27])[C:22](Cl)=[O:23]>ClCCl>[Br:20][CH:21]([CH2:25][CH2:26][Br:27])[C:22]([NH:6][CH2:5][C:4]1[CH:7]=[CH:8][C:9]([CH3:10])=[C:2]([F:1])[CH:3]=1)=[O:23]
Reactant: Cc1ccc(CN)cc1F
Reactant: O=C(Cl)C(Br)CCBr
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(CNC(=O)C(Br)CCBr)cc1F
Temperature: 0 °C
Yield: 87.6 %

Procedure:
To a stirring 0° C. solution of 3-fluoro-4-methylbenzyl amine (2.0 g, 14 mmol) and N-ethyl-N-isopropylpropan-2-amine (3.5 mL, 20 mmol) in dichloromethane (30 mL) was added dropwise a solution of 2,4-dibromobutanoyl chloride (3.98 g, 15 mmol) in dichloromethane (5 mL). After completion of the addition, the reaction was stirred in the ice bath until all of the ice had melted, then it was partitioned between ethyl acetate and water. The layers were separated, the organic layer was washed with brine, and it was then dried over magnesium sulfate. The drying agent was filtered off, the solvent was evaporated, and the residue was dissolved in ethyl acetate and subjected to silica gel chromatography in 10→25→100% ethyl acetate/hexane, collecting the main component to yield 4.5 g (85%) 2,4-dibromo-N-(3-fluoro-4-methylbenzyl)butanamide. LCMS (method CZ-1): RT 1.21 min, m/z 367.9 (MH+); 1H NMR (500 MHz, chloroform-d) δ 7.17 (t, J=7.7 Hz, 1H), 7.01-6.91 (m, 2H), 6.70 (br. s., 1H), 4.59 (dd, J=9.0, 4.9 Hz, 1H), 4.51-4.37 (m, 2H), 3.64-3.51 (m, 2H), 2.71 (dddd, J=15.0, 8.5, 6.1, 4.9 Hz, 1H), 2.51 (ddt, J=15.0, 9.2, 5.5 Hz, 1H), 2.27 (d, J=1.4 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:25](=[CH:26][CH:27]=1)[O:24][C:11]1([CH2:16][CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12]1)[CH2:10][C:9]2=[O:28].[ClH:30]>C(Cl)Cl.O1CCOCC1>[ClH:30].[CH3:1][O:2][C:3](=[O:29])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:25](=[CH:26][CH:27]=1)[O:24][C:11]1([CH2:16][CH2:15][CH2:14][NH:13][CH2:12]1)[CH2:10][C:9]2=[O:28]
Reactant: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCCN(C(=O)OC(C)(C)C)C1)O2
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCCNC1)O2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
(+)-(E)-3-[1′-Tert-butoxycarbonyl-4-oxo-spiro(chromane-2,3′-piperidine)-6-yl]-acrylic acid methyl ester (710 mg, 1.77 mmol) was dissolved in DCM (50 ml). 4 M HCl in dioxane (2 ml) was added and the mixture was stirred at RT for 3 h. The precipitate was filtered, washed with DCM and dried to give (−)-(E)-3-[4-oxo-spiro(chromane-2,3′-piperidine)-6-yl]-acrylic acid methyl ester hydrochloride (516 mg)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](Cl)[N:3]=1.[O:9]1[CH:13]=[CH:12][C:11](B(O)O)=[CH:10]1>>[O:9]1[CH:13]=[CH:12][C:11]([C:4]2[N:3]=[C:2]([NH2:1])[CH:7]=[CH:6][CH:5]=2)=[CH:10]1
Reactant: Nc1cccc(Cl)n1
Reactant: OB(O)c1ccoc1
Product: Nc1cccc(-c2ccoc2)n1
Yield: 54.3 %

Procedure:
The title compound was prepared following procedure described for intermediate A1 step a), but starting from 2-amino-6-chloropyridine (25.0 g; 194.5 mmol; 1.0 eq.) and furan-3-boronic acid (26.11 g; 233.4 mmol; 1.2 eq.). The crude was purified by flash chromatography (EtOAc/c-Hex, 50:50) to give the title compound as a brown oil (16.91 g; 54%). 1H NMR (DMSO-d6) δ 7.96 (s, 1H), 7.42 (m, 2H), 6.82 (m, 2H), 6.37 (d, J=7.2 Hz, 1H), 4.54 (m, 2H). HPLC, Rt: 1.30 min. (purity 84.9%). LC/MS, M+(ESI): 161.4.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:6]2[N:5]=[CH:4][C:3]=1[C:16]([N:18]1[CH2:23][CH2:22][CH:21]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[CH2:20][CH2:19]1)=[O:17].[CH3:31][C:32]1[CH:33]=[C:34]([CH:36]=[CH:37][CH:38]=1)[NH2:35]>>[CH2:14]([O:13][C:11]([C:10]1[CH:9]=[N:8][N:7]2[C:2]([NH:35][C:34]3[CH:36]=[CH:37][CH:38]=[C:32]([CH3:31])[CH:33]=3)=[C:3]([C:16]([N:18]3[CH2:23][CH2:22][CH:21]([C:24]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=4)[CH2:20][CH2:19]3)=[O:17])[CH:4]=[N:5][C:6]=12)=[O:12])[CH3:15]
Reactant: Cc1cccc(N)c1
Reactant: CCOC(=O)c1cnn2c(Cl)c(C(=O)N3CCC(c4ccc(F)cc4)CC3)cnc12
Product: CCOC(=O)c1cnn2c(Nc3cccc(C)c3)c(C(=O)N3CCC(c4ccc(F)cc4)CC3)cnc12
Yield: 98 %

Procedure:
In the same manner as in Example 19, step 5 and using 7-chloro-3-ethoxycarbonyl-6-[4-(4-fluorophenyl)piperidine-1-carbonyl]pyrazolo[1,5-a]pyrimidine (0.10 g, 0.23 mmol) obtained in Example 81, step 2 and 3-methylaniline (0.038 g, 0.35 mmol), the title compound (0.113 g, 98%) was obtained.
Reaction SMILES: C([N:8]1[CH2:12][C@@H:11]2[C@@H:13]([NH:16][C:17](=[O:33])[CH:18]([C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)[C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[CH2:14][CH2:15][C@@H:10]2[CH2:9]1)C1C=CC=CC=1.[H][H]>[OH-].[OH-].[Pd+2].C(O)C>[F:32][C:29]1[CH:30]=[CH:31][C:26]([CH:18]([C:19]2[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=2)[C:17]([NH:16][C@@H:13]2[C@@H:11]3[C@@H:10]([CH2:9][NH:8][CH2:12]3)[CH2:15][CH2:14]2)=[O:33])=[CH:27][CH:28]=1
Reactant: O=C(N[C@H]1CC[C@@H]2CN(Cc3ccccc3)C[C@@H]21)C(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: O=C(N[C@H]1CC[C@@H]2CNC[C@@H]21)C(c1ccc(F)cc1)c1ccc(F)cc1

Procedure:
N-((3aR,4S,6aS)-2-benzyloctahydrocyclopenta[c]pyrrol-4-yl)-2,2-bis(4-fluorophenyl)acetamide (150 mg, 0.336 mmol) from Example 228 and ethanol (20 ml) were added to 20% Pd(OH)2 on carbon, wet (30.0 mg, 0.214 mmol) in a 50 mL pressure bottle and stirred for 2 hours at under 30 psi hydrogen at 50° C. The mixture was filtered and the solvent removed in vacuo to give 2,2-bis(4-fluorophenyl)-N-[(3aR,4S,6aS)-octahydrocyclopenta[c]pyrrol-4-yl]acetamide: 1H NMR (500 MHz, pyridine-d5) δ ppm 9.09 (d, J=7.1, 1H), 7.60-7.55 (m, 4H), 7.13 (q, J=8.2, 4H), 5.26 (s, 1H), 4.36-4.27 (m, 1H), 3.06 (dd, J=10.9, 2.7, 1H), 2.92 (dd, J=10.9, 7.0, 1H), 2.81 (dd, J=10.7, 7.0, 1H), 2.59 (dd, J=10.8, 2.8, 1H), 2.52-2.41 (m, 2H), 2.33-2.25 (m, 1H), 2.06-1.96 (m, 1H), 1.83 (td, J=12.7, 6.9, 1H), 1.65-1.52 (m, 1H), 1.26 (ddt, J=12.3, 8.7, 6.1, 1H); MS (ESI+) m/z 357 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]2[CH2:11][CH2:12][CH2:13][C:3]=12.[CH3:14][C:15]1([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:20][CH2:19][CH2:18][NH:17][CH2:16]1.C(N(CC)CC)C>C(O)(C)C>[CH3:14][C:15]1([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:20][CH2:19][CH2:18][N:17]([C:2]2[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]3[CH2:11][CH2:12][CH2:13][C:3]=23)[CH2:16]1
Reactant: CC1(NC(=O)OC(C)(C)C)CCCNC1
Reactant: O=[N+]([O-])c1cnc2c(c1Cl)CCC2
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: CC1(NC(=O)OC(C)(C)C)CCCN(c2c([N+](=O)[O-])cnc3c2CCC3)C1
Temperature: 100 °C
Reaction time: 0.33 h

Procedure:
A mixture of 4-chloro-3-nitro-6,7-dihydro-5H-cyclopenta[b]pyridine (200 mg, 1.01 mmol), tert-butyl (3-methylpiperidin-3-yl)carbamate (227 mg, 1.06 mmol) and triethylamine (281 μL, 2.01 mmol) in isopropyl alcohol (1.2 mL) was stirred at 100° C. for 20 min. After cooling, the sub-title compound precipitated out and was collected by vacuum filtration, followed by washing with cold ether to give the sub-title compound as light yellow powder. LCMS calc. for C19H29N4O4 (M+H)+: m/z=377.2. Found: 377.2.
Reaction SMILES: [CH2:1]([O:3][C:4]1[NH:8][C:7]2[CH:9]=[C:10]([C:14]3[C:15]([CH3:20])=[N:16][O:17][C:18]=3[CH3:19])[CH:11]=[C:12](I)[C:6]=2[N:5]=1)[CH3:2].[CH3:21][N:22]1[C:26](B2OC(C)(C)C(C)(C)O2)=[C:25]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:24]=[N:23]1.COCCOC>O>[CH2:1]([O:3][C:4]1[NH:8][C:7]2[CH:9]=[C:10]([C:14]3[C:15]([CH3:20])=[N:16][O:17][C:18]=3[CH3:19])[CH:11]=[C:12]([C:26]3[N:22]([CH3:21])[N:23]=[CH:24][C:25]=3[C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)[C:6]=2[N:5]=1)[CH3:2]
Reactant: Cn1ncc(-c2ccccc2)c1B1OC(C)(C)C(C)(C)O1
Reactant: CCOc1nc2c(I)cc(-c3c(C)noc3C)cc2[nH]1
Solvent: COCCOC
Solvent: O
Product: CCOc1nc2c(-c3c(-c4ccccc4)cnn3C)cc(-c3c(C)noc3C)cc2[nH]1
Temperature: 130 °C
Yield: 14.9 %

Procedure:
4-(2-ethoxy-4-iodo-1H-benzo[d]imidazol-6-yl)-3,5-dimethylisoxazole (100 mg, 0.26 mmol) and 1-methyl-4-phenyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (37 mg, 0.13 mmol) was added to a solvent mixture of 1,2-dimethoxyethane (2 ml) and water (1 ml). To the above mixture were added PEPPSI-Ipr (18 mg, 0.026 mmol) and CsCO3 (127 mg, 0.39 mmol). The reaction mixture was heated at 130° C. in microwave reactor for 30 mins. The reaction mixture was then filtered and organic solvent was evaporated and the residue was purified with Prep HPLC (0-100% CH3CN/H2O) to afford 8 mg product 4-(2-ethoxy-4-(1-methyl-4-phenyl-1H-pyrazol-5-yl)-1H-benzo[d]imidazol-6-yl)-3,5-dimethylisoxazole.
Reaction SMILES: [CH2:1]([O:3][CH:4]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][C:9]=1[F:16])[C:5]([OH:7])=O)[CH3:2].[NH2:17][CH2:18][C:19]1[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][C:20]=1[Cl:27]>>[Cl:27][C:20]1[CH:21]=[C:22]([C:23]#[N:24])[CH:25]=[CH:26][C:19]=1[CH2:18][NH:17][C:5](=[O:7])[CH:4]([O:3][CH2:1][CH3:2])[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][C:9]=1[F:16]
Reactant: N#Cc1ccc(CN)c(Cl)c1
Reactant: CCOC(C(=O)O)c1ccc(OC)cc1F
Product: CCOC(C(=O)NCc1ccc(C#N)cc1Cl)c1ccc(OC)cc1F

Procedure:
(RS)-Ethoxy-(2-fluoro-4-methoxy-phenyl)-acetic acid, described in example 63.1 was coupled with 4-aminomethyl-3-chlorobenzonitrile (CAS 202521-97-9) according to general procedure C to give (RS)-N-(2-chloro-4-cyano-benzyl)-2-ethoxy-2-(2-fluoro-4-methoxy-phenyl)-acetamide. Yellow oil. MS 377.2 ([M+H]+)
Reaction SMILES: [CH2:1]([O:6][CH:7]1[NH:11][C:10](=[O:12])[CH2:9][CH2:8]1)[C:2]([CH3:5])([CH3:4])[CH3:3].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[C:23](Cl)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(OCC)C>[C:23]([N:11]1[CH:7]([O:6][CH2:1][C:2]([CH3:5])([CH3:4])[CH3:3])[CH2:8][CH2:9][C:10]1=[O:12])(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CC(C)(C)COC1CCC(=O)N1
Reactant: O=C(Cl)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CCOCC
Product: CC(C)(C)COC1CCC(=O)N1C(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 41 %

Procedure:
2.2 g of 5-neopentyloxy pyrrolidin-2-one in 30 cm3 of ethyl ether is added at ambient temperature to a solution of 2.6 g of sodium bis trimethylsilylamide in 160 cm3 of ethyl ether. After 30 minutes, the solution is cooled to 0° C. and 1.89 g of benzoyl chloride diluted with 20 cm3 of ethyl ether is added. After leaving the solution for 30 minutes at 0° C. then allowing to return to ambient temperature, and concentrating to dryness under reduced pressure, the residue is chromatographed on silica (eluent: hexane-ethyl acetate 7-3). After crystallization from ethanol, 1.45 g of expected product is obtained. m.p.=83°-85° C.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]([F:12])([F:11])[F:10].[C:13](Cl)(=[O:17])[CH:14]([CH3:16])[CH3:15]>N1C=CC=CC=1>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:13](=[O:17])[CH:14]([CH3:16])[CH3:15])=[CH:4][C:3]=1[C:9]([F:10])([F:11])[F:12]
Reactant: Nc1ccc(Br)c(C(F)(F)F)c1
Reactant: CC(C)C(=O)Cl
Solvent: c1ccncc1
Product: CC(C)C(=O)Nc1ccc(Br)c(C(F)(F)F)c1
Temperature: 25 °C

Procedure:
To a stirred, cooled solution of 15.0 g. of 4-bromo-3-trifluoromethylaniline in 75 ml. of dry pyridine add 6.8 g. of isobutyrylchloride and heat the resulting mixture at 70° C for 2 hours. Allow the reaction mixture to cool to room temperature and then pour the mixture into 600 ml. of ice-water, filter and dry the precipitate which is recrystallized from 1:1 petroleum etherdichloromethane to yield 4'-bromo-3'-trifluoromethylisobutyranilide, m.p. 126.5°-128° C.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[N:10]([CH3:12])[O:9][C@H:8]3[NH:13][C@H:14]([C:16]([O:18][C@@H:19]4[C@:28]5([OH:29])[C@H:23]([C@@H:24]([C:31]([CH3:33])=[CH2:32])[CH2:25][CH2:26][C@H:27]5[CH3:30])[CH:22]=[C:21]([CH3:34])[C@H:20]4[O:35][C:36]([NH:38][C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)=[O:37])=[O:17])[CH2:15][C@@:7]3([OH:45])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[H][H]>C(OCC)(=O)C.[Pt](=O)=O>[Cl:1][C:2]1[C:11]2[N:10]([CH3:12])[O:9][C@H:8]3[NH:13][C@H:14]([C:16]([O:18][C@@H:19]4[C@:28]5([OH:29])[C@@H:23]([C@H:24]([CH:31]([CH3:33])[CH3:32])[CH2:25][CH2:26][C@H:27]5[CH3:30])[CH:22]=[C:21]([CH3:34])[C@H:20]4[O:35][C:36]([NH:38][C:39]4[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=4)=[O:37])=[O:17])[CH2:15][C@@:7]3([OH:45])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: [H][H]
Reactant: C=C(C)[C@H]1CC[C@@H](C)[C@@]2(O)[C@H]1C=C(C)[C@@H](OC(=O)Nc1ccccc1)[C@@H]2OC(=O)[C@@H]1C[C@@]2(O)c3cccc(Cl)c3N(C)O[C@H]2N1
Agent: O=[Pt]=O
Solvent: CCOC(C)=O
Product: CC1=C[C@@H]2[C@H](C(C)C)CC[C@@H](C)[C@]2(O)[C@@H](OC(=O)[C@@H]2C[C@@]3(O)c4cccc(Cl)c4N(C)O[C@H]3N2)[C@@H]1OC(=O)Nc1ccccc1
Yield: 18.9 %

Procedure:
To (1S,2R,4aR,8R,8aR)-8a-hydroxy-2-[(1H-imidazol-1-ylcarbonyl)oxy]-3,8-dimethyl-5-(1-methylethenyl)-1,2,4a,5,6,7,8,8a-octahydronaphthalen-1-yl (2S,3aR,9bR)-6-chloro-9b-hydroxy-5-methyl-1,2,3,3a,5,9b-hexahydropyrrolo[2,3-c][2,1]benzoxazine-2-carboxylate (Preparation 142, 510 mg, 0.83 mmol) in anhydrous pyridine (10 ml) was added aniline hydrochloride (500 mg, 3.8 mmol) and 4-dimethylaminopyridine (240 mg, 2.0 mmol). The reaction mixture was stirred at room temperature under nitrogen for 4 days before pouring into dichloromethane (100 ml) and washing with saturated aqueous citric acid solution (2×50 ml). The organic fraction was dried (Na2SO4) and concentrated in vacuo to give a yellowish solid (490 mg, 93%). The crude product was purified by flash column chromatography on silica gel eluting with a hexane:ethyl acetate gradient (1:1 to 1:5). The pure fractions were collected and concentrated in vacuo to give (1S,2R,4aS,5S,8R,8aR)-8a-hydroxy-3,8-dimethyl-5-(1-methylethenyl)-2-{[(phenylamino)carbonyl]oxy}-1,2,4a,5,6,7,8,8a-octahydronaphthalen-1-yl (2S,3aR,9bR)-6-chloro-9b-hydroxy-5-methyl-1,2,3,3a,5,9b-hexahydropyrrolo[2,3-c][2,1]benzoxazine-2-carboxylate (440 mg, 83%). To a solution of the (1S,2R,4aS,5S,8R,8aR)-8a-hydroxy-3,8-dimethyl-5-(1-methylethenyl)-2-{[(phenylamino)carbonyl]oxy}-1,2,4a,5,6,7,8,8a-octahydronaphthalen-1-yl (2S,3aR,9bR)-6-chloro-9b-hydroxy-5-methyl-1,2,3,3a,5,9b-hexahydropyrrolo[2,3-c][2,1]benzoxazine-2-carboxylate (100 mg, 0.157 mmol) in ethyl acetate (30 ml) was added platinum(IV) oxide (10 mg, 0.044 mmol) and the resulting mixture was hydrogenated at room temperature under 60 psi hydrogen for 10 hours. The reaction mixture was filtered and the filtrate concentrated in vacuo. The crude product, was purified by flash column chromatography on silica gel eluting with hexane ethyl acetate (1:1). The product was further purified to give the title product (19 mg, 19%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH2:4][C:5]([N:8]1[CH:12]=[C:11]([NH:13][C:14](=[O:20])[CH:15]([NH2:19])[CH2:16][CH2:17][CH3:18])[N:10]=[CH:9]1)([CH3:7])[CH3:6].[F:22][C:23]1[CH:24]=[C:25]2[C:30](=[C:31]([F:33])[CH:32]=1)[CH2:29][C:28](=O)[CH2:27][CH2:26]2>>[CH3:1][O:2][C:3](=[O:21])[CH2:4][C:5]([N:8]1[CH:12]=[C:11]([NH:13][C:14](=[O:20])[CH:15]([NH:19][CH:28]2[CH2:27][CH2:26][C:25]3[C:30](=[C:31]([F:33])[CH:32]=[C:23]([F:22])[CH:24]=3)[CH2:29]2)[CH2:16][CH2:17][CH3:18])[N:10]=[CH:9]1)([CH3:6])[CH3:7]
Reactant: O=C1CCc2cc(F)cc(F)c2C1
Reactant: CCCC(N)C(=O)Nc1cn(C(C)(C)CC(=O)OC)cn1
Product: CCCC(NC1CCc2cc(F)cc(F)c2C1)C(=O)Nc1cn(C(C)(C)CC(=O)OC)cn1

Procedure:
3-[4-(2-Amino-pentanoylamino)-imidazol-1-yl]-3-methyl-butyric acid methyl ester was reacted with 6,8-Difluoro-3,4-dihydro-1H-naphthalen-2-one to provide the title compound: C13 NMR (100 MHz, CDCl3) 14.1, 16.7, 19.5, 19.6, 28.2, 28.7, 29.6, 29.8, 36.5, 47.2, 51.9, 52.1, 52.7, 56.3, 60.2, 60.9, 101.1, 104.4, 110.6, 130.5, 137.7, 170.0; MS 463.3 m/z (M+1).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[CH:5][C:6]2[N:12]3[C:13]([CH2:16]Cl)=[N:14][N:15]=[C:11]3[CH2:10][N:9]=[C:8]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:7]=2[CH:24]=1.[CH3:25][N:26]([CH3:28])O.[H-].[Na+]>CN(C)C=O>[CH3:1][S:2][C:3]1[CH:4]=[CH:5][C:6]2[N:12]3[C:13]([CH2:16][N:26]([CH3:28])[CH3:25])=[N:14][N:15]=[C:11]3[CH2:10][N:9]=[C:8]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:7]=2[CH:24]=1
Reactant: CSc1ccc2c(c1)C(c1ccccc1)=NCc1nnc(CCl)n1-2
Reactant: CN(C)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1ccc2c(c1)C(c1ccccc1)=NCc1nnc(CN(C)C)n1-2

Procedure:
In the manner given in Example 15, 8-methylthio-1-(chloromethyl)-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine is treated with a cold mixture of N,N-dimethylhydroxylamine and sodium hydride in dimethylformamide to give 8-methylthio-1-[(dimethylamino)methyl]-6-phenyl-4H-s-triazolo [4,3-a][1,4]benzodiazepine, N1 -oxide.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:21])[NH:10][CH:11]1[CH2:18][CH2:17][CH:16]2[CH2:19][CH:12]1[CH2:13][CH2:14][C:15]2=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].O.Cl>C1COCC1>[CH2:1]([O:8][C:9](=[O:21])[NH:10][CH:11]1[CH2:18][CH2:17][CH:16]2[CH2:19][CH:12]1[CH2:13][CH2:14][CH:15]2[OH:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(NC1CCC2CC1CCC2=O)OCc1ccccc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(NC1CCC2CC1CCC2O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 91.7 %

Procedure:
780 mg of (6-Oxo-bicyclo[3.3.1]non-2-yl)-carbamic acid benzyl ester (100) were dissolved in 14 mL of THF under argon, cooled to 0° C. and 113 mg of sodium borohydride were added. The mixture was stirred for 2 h at 0° C., water was added and the pH of solution was adjusted to 2 by addition of 2M HCl. The aqueous layer was extracted with ethyl acetate three times. The combined organic layer was dried over sodium sulfate and evaporated to dryness to give 0.72 g of the desired product. Rt=1.23 min (Method C). Detected mass: 290.3 (M+H+).