Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:20])[C:3]([C:5]1[N:14]([CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[C:8]2[N:9]=[C:10](Cl)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].C(OC(=O)[NH:27][CH2:28][CH2:29][N:30]([C:32]1[CH:33]=[N:34][C:35]([NH2:38])=[CH:36][CH:37]=1)[CH3:31])(C)(C)C>>[CH3:1][N:2]([CH3:20])[C:3]([C:5]1[N:14]([CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[C:8]2[N:9]=[C:10]([NH:38][C:35]3[CH:36]=[CH:37][C:32]([N:30]([CH2:29][CH2:28][NH2:27])[CH3:31])=[CH:33][N:34]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4]
Reactant: CN(C)C(=O)c1cc2cnc(Cl)nc2n1C1CCCC1
Reactant: CN(CCNC(=O)OC(C)(C)C)c1ccc(N)nc1
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(N(C)CCN)cn3)nc2n1C1CCCC1
Yield: 34.8 %

Procedure:
Following Buchwald Method B, 2-chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (200 mg, 0.68 mmol) and {2-[(6-amino-pyridin-3-yl)-methyl-amino]-ethyl}-carbamic acid tert-butyl ester (200 mg, 0.75 mmol), followed by deprotection using General Procedure A to give 2-{5-[(2-amino-ethyl)-methyl-amino]-pyridin-2-ylamino}-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (100 mg, 34%). MS (ESI) m/z 423.4 (M+H)+
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH:17]=[O:18])=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>C(O)C>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH2:17][OH:18])=[CH:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)n1cc(C=O)c2ccccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)OC(=O)n1cc(CO)c2ccccc21
Reaction time: 6 h

Procedure:
To a 100mL two-necked round-bottom flask equipped with a thermometer 1-(tert-butyloxycarbonyl)-3-formylindole (13.7 g, 60 mmol) was suspended in ethanol (36 mL). Sodium borohydride (4.40 g, 115 mmol) was added in four portions, during which the temperature did not rise about 20° C., and the mixture was stirred for 6 hours. Then the solvent was evaporated in vacuo. The residual oil was shaken with 1.0N sodium hydroxide (150 mL), and the alkaline solution was extracted with ether (3×180 mL), dried with MgSO4, filtered and evaporated to give a colorless oil which solidified on refrigeration (3.95 g, ca. 100%).
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]([C:18](=[O:20])[CH3:19])=[CH:9][C:10]([Cl:17])=[C:11]2[C:16]=1[N:15]=[CH:14][CH:13]=[CH:12]2)(=O)=O.[N:23]1([CH2:29][CH2:30][OH:31])[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCCC1.ClCCl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:17][C:10]1[CH:9]=[C:8]([C:18](=[O:20])[CH3:19])[C:7]([N:26]2[CH2:27][CH2:28][N:23]([CH2:29][CH2:30][OH:31])[CH2:24][CH2:25]2)=[C:16]2[C:11]=1[CH:12]=[CH:13][CH:14]=[N:15]2
Reactant: CC(=O)c1cc(Cl)c2cccnc2c1OS(=O)(=O)C(F)(F)F
Reactant: OCCN1CCNCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(=O)c1cc(Cl)c2cccnc2c1N1CCN(CCO)CC1
Temperature: 65 °C
Yield: 14.1 %

Procedure:
A stirred mixture of 7-acetyl-5-chloroquinolin-8-yl trifluoromethanesulfonate (0.12 g, 0.34 mmol, from Example 47, Step 2), 1-piperazineethanol (0.053 g, 0.41 mmol), palladium acetate (1.5 mg, 0.0068 mmol), (S)-(−)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (6.3 mg, 0.010 mmol), and cesium carbonate (0.31 g, 0.95 mmol) in tetrahydrofuran (3 mL) was heated at 65° C. overnight. The mixture was cooled, diluted with dichloromethane and filtered. The filtrate was washed with water, dried over MgSO4, evaporated to dryness. The resulting residue was purified on silica gel (eluting with 0 to 10% MeOH in dichloromethane) to give the desired product (16 mg, 14%). LCMS calculated for C17H21ClN3O2 (M+H)+: m/z=334.1; Found: 334.0.
Reaction SMILES: [Cl:1][CH2:2][C:3]([N:5]1[C@@H:12]([C:13]#[CH:14])[CH2:11][CH2:10][C@H:6]1[C:7]([NH2:9])=O)=[O:4].N1C=CN=C1.O=P(Cl)(Cl)Cl>N1C=CC=CC=1>[Cl:1][CH2:2][C:3]([N:5]1[C@@H:12]([C:13]#[CH:14])[CH2:11][CH2:10][C@H:6]1[C:7]#[N:9])=[O:4]
Reactant: C#C[C@H]1CC[C@@H](C(N)=O)N1C(=O)CCl
Agent: c1c[nH]cn1
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: C#C[C@H]1CC[C@@H](C#N)N1C(=O)CCl
Reaction time: 1 h

Procedure:
To a stirred solution of (5R)-1-(chloroacetyl)-5-ethynyl-L-prolinamide (0.16 g, 0.745 mmol) and imidazole (0.05 g, 0.745 mmol) in dry pyridine (4 mL) at −35° C. under nitrogen was added POCl3 (0.15 mL, 1.49 mmol) dropwise. The reaction mixture was stirred between −35° C. to −15° C. for 1 hour and evaporated. The residue was diluted with dichloromethane and washed with H2O (2×), dried (Na2SO4), filtered and concentrated under reduced pressure. Purification by flash chromatography (10% ethyl acetate/hexane) provided the titled compound. MS (CI) m/z 197 (M+1)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[CH3:11])[CH:6]=O.[C:12]([CH:16]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:14][CH3:15])=[O:13]>C1(C)C=CC=CC=1>[CH3:15][O:14][C:12](=[O:13])[CH:16]=[CH:6][C:5]1[CH:8]=[CH:9][C:10]([CH3:11])=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: COc1cc(C=O)ccc1C
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: COC(=O)C=Cc1ccc(C)c(OC)c1
Yield: 97.7 %

Procedure:
A mixture of 3-methoxy-4-methylbenzaldehyde (19.3 g, 0.129 mol), carbomethoxy methylene triphenylphosphorane (51 g) in toluene (250 ml) was refluxed for 24 h. The mixture was quenched with aqueous ammonium chloride and extracted with ethyl acetate and concentrated in vacuo to give a residue. The residue was purified by flash chromatography using ethyl acetate-heptane (1:1) to give 3-(3-methoxy-4-methyl-phenyl)acrylic acid methyl ester (27 g, 0.126 mol). A mixture of 3-(3-methoxy-4-methylphenyl)acrylic acid methyl ester (27 g), sodium hydroxide (14 g), water (70 ml), methanol (140 ml) and tetrahydrofuran (70 ml) was refluxed at 50° C. for 1 h. The mixture was concentrated in vacuo and then water added. The mixture was filtered and 5 M HCl was added until precipitation occurred. The mixture was filtered and the solid precipitate washed with water and dried in-vacuo to give 3-(3-methoxy-4-methylphenyl)acrylic acid (23.5 g, 0.122 mol).
Reaction SMILES: [CH:1]1([CH:7]([NH:18][C:19]2[CH:28]=[CH:27][C:22]([C:23]([O:25]C)=[O:24])=[CH:21][CH:20]=2)[C:8]2[O:16][C:15]3[C:10](=[N:11][CH:12]=[CH:13][CH:14]=3)[C:9]=2[CH3:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O1CCCC1.[OH-].[Na+]>C(O)C>[CH:1]1([CH:7]([NH:18][C:19]2[CH:20]=[CH:21][C:22]([C:23]([OH:25])=[O:24])=[CH:27][CH:28]=2)[C:8]2[O:16][C:15]3[C:10](=[N:11][CH:12]=[CH:13][CH:14]=3)[C:9]=2[CH3:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc(NC(c2oc3cccnc3c2C)C2CCCCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1c(C(Nc2ccc(C(=O)O)cc2)C2CCCCC2)oc2cccnc12
Reaction time: 8 h
Yield: 94.5 %

Procedure:
To a mixture of methyl 4-{[cyclohexyl(3-methylfuro[3,2-b]pyridin-2-yl)methyl]amino}benzoate (789 mg) synthesized above, tetrahydrofuran (10 mL) and ethanol (10 mL) was added 1N aqueous sodium hydroxide solution (10.0 mL), and the mixture was stirred overnight with heating under reflux, and concentrated under reduced pressure. The residue was dissolved in water (20 mL), and 1N hydrochloric acid (10.0 mL) was added at 0° C. The resulting precipitate was collected by filtration to give the title object compound (718 mg, 94%) as a white solid.
Reaction SMILES: C1(O)C=CC=CC=1.[C:8]1([CH:14]([CH3:16])[CH3:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(=O)([O-])[O-].[Na+].[Na+].[O:23]=[O:24]>>[O-:23][OH:24].[C:8]1([CH:14]([CH3:16])[CH3:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)c1ccccc1
Solvent: Oc1ccccc1
Product: [O-]O

Procedure:
Manufacture of phenol is a two-step process, first reacting cumene and sodium carbonate with oxygen in air to produce a cumene hydroperoxide. The crude hydroperoxide and a dilute acid are fed to a cleavage reactor, which produces phenol and an acetone by-product. The phenol is distilled and purified. Cumene from the first reactor is recycled back to the process.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([Cl:20])=[C:18]([Cl:21])[N:17]=[C:16]([NH:22][CH3:23])[N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:24]>C(OC(=O)C)C>[ClH:20].[ClH:24].[Cl:21][C:18]1[C:19]([Cl:20])=[C:14]([N:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[N:15]=[C:16]([NH:22][CH3:23])[N:17]=1
Reactant: CNc1nc(Cl)c(Cl)c(N2CCN(C(=O)OC(C)(C)C)CC2)n1
Agent: Cl
Solvent: CCOC(C)=O
Product: CNc1nc(Cl)c(Cl)c(N2CCNCC2)n1
Yield: 100 %

Procedure:
2.6 g (7.2 mmol) 4-(5,6-dichloro-2-methylamino-pyrimidin-4-yl)-piperazine-1-carboxylic acid tert-butyl ester was deprotected at 10° C. using 100 ml ethylacetate saturated with gaseous hydrochloric acid. After 4 hours the precipitate was filtered giving the title compound (2.4 g, 100%), melting at 204-209° C.
Reaction SMILES: [OH:1][C:2]([C:5]1[O:6][CH:7]=[C:8]([C:10]([OH:12])=O)[N:9]=1)([CH3:4])[CH3:3].[NH2:13][C@@H:14]([CH3:30])[CH2:15][N:16]1[CH:20]=[CH:19][C:18]([C:21]2[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[C:23]([Cl:29])[CH:22]=2)=[N:17]1>>[Cl:29][C:23]1[CH:22]=[C:21]([C:18]2[CH:19]=[CH:20][N:16]([CH2:15][C@@H:14]([NH:13][C:10]([C:8]3[N:9]=[C:5]([C:2]([OH:1])([CH3:3])[CH3:4])[O:6][CH:7]=3)=[O:12])[CH3:30])[N:17]=2)[CH:28]=[CH:27][C:24]=1[C:25]#[N:26]
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Reactant: CC(C)(O)c1nc(C(=O)O)co1
Product: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1coc(C(C)(C)O)n1
Yield: 57.7 %

Procedure:
The title compound was prepared using the method of Example 34(d) starting from 2-(2-hydroxypropan-2-yl)oxazole-4-carboxylic acid (197 mg, 1.151 mmol) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (250 mg, 0.959 mmol). The product was purified by flash chromatography. Yield 57.7%. 1H-NMR (400 MHz; DMSO-d6): δ 1.12 (d, 3H), 1.53 (s, 6H), 4.31 (dd, 1H), 4.40 (dd, 1H), 4.43-4.52 (m, 1H), 5.66 (s, 1H), 6.97 (d, 1H), 7.84 (d, 1H), 7.94-8.00 (m, 2H), 8.08-8.10 (m, 1H), 8.17 (d, 1H), 8.48 (s, 1H).
Reaction SMILES: [CH2:1]([C:4]1[C:5](=[O:18])[C:6]2[CH:17]=[CH:16][CH:15]=[CH:14][C:7]=2[NH:8][C:9](=[O:13])[C:10]=1[O:11]C)[CH:2]=[CH2:3].B(Br)(Br)Br>ClCCl.O>[CH2:1]([C:4]1[C:5](=[O:18])[C:6]2[CH:17]=[CH:16][CH:15]=[CH:14][C:7]=2[NH:8][C:9](=[O:13])[C:10]=1[OH:11])[CH:2]=[CH2:3]
Reactant: C=CCc1c(OC)c(=O)[nH]c2ccccc2c1=O
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: C=CCc1c(O)c(=O)[nH]c2ccccc2c1=O
Yield: 74.3 %

Procedure:
To a solution of 4-allyl-3-methoxy-2,5-dioxo-2,5-dihydro-1H-benz[b]azepine (0.2 g) in dichloromethane was added boron tribromide (1M in dichloromethane, 3 mL). The precipitate that formed was diluted with water and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried and evaporated using toluene to azeotrope the water. The solid was recrystallized from hot toluene to give the title compound (0.14 g); mp 174°-175 ° C.; NMR: 5.80 (m,1); 5.03 (s,1); 4.98 (d,1); 3.38 (d,2); MS: m/z=229(M+1). Analysis for C13H11NO3.0.1 H2O: Calculated: C, 67.58; H, 4.89; N, 6.06; Found: C, 67.63; H, 4.88; N, 5.95.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([F:37])=[C:8]([CH:10]2[CH2:15][CH2:14][N:13]([C:16]([C:18]3[C:26]4[C:21](=[C:22]([F:32])[CH:23]=[CH:24][C:25]=4[O:27][C:28]([F:31])([F:30])[F:29])[N:20]([CH2:33][CH2:34][O:35][CH3:36])[CH:19]=3)=[O:17])[CH2:12][CH2:11]2)[CH:9]=1.[NH:38]([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[C@H:39]([C:43](O)=[O:44])[CH:40]([CH3:42])[CH3:41].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC>C(Cl)Cl.CCOC(C)=O>[C:49]([O:48][C:46](=[O:47])[NH:38][C@H:39]([C:43](=[O:44])[NH:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([F:37])=[C:8]([CH:10]2[CH2:15][CH2:14][N:13]([C:16]([C:18]3[C:26]4[C:21](=[C:22]([F:32])[CH:23]=[CH:24][C:25]=4[O:27][C:28]([F:31])([F:29])[F:30])[N:20]([CH2:33][CH2:34][O:35][CH3:36])[CH:19]=3)=[O:17])[CH2:12][CH2:11]2)[CH:9]=1)[CH:40]([CH3:41])[CH3:42])([CH3:50])([CH3:52])[CH3:51]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: COCCn1cc(C(=O)N2CCC(c3cc(CN)ccc3F)CC2)c2c(OC(F)(F)F)ccc(F)c21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COCCn1cc(C(=O)N2CCC(c3cc(CNC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C)ccc3F)CC2)c2c(OC(F)(F)F)ccc(F)c21
Yield: 99.8 %

Procedure:
A solution of [4-(5-aminomethyl-2-fluoro-phenyl)-piperidin-1-yl]-[7-fluoro-1-(2-methoxy-ethyl)-4-trifluoromethoxy-1H-indol-3-yl]-methanone hydrochloride (0.3 g, 0.55 mmol), BOC-Val-OH (0.143 g, 0.66 mmol), EDCI (0.126 g, 0.66 mmol), HOBT (0.224 g, 1.65 mmol), and Et3N (0.23 ml, 1.65 mmol) in CH2Cl2 (30 mL) was stirred at rt overnight. The reaction mixture was poured into EtOAc and the organic layer washed with 10% citric acid and brine. The organic layer was dried over MgSO4, filtered and concentrated in vacuo to give the crude product. Purification by flash chromatography on SiO2 eluting with 3% MeOH/CH2Cl2 afforded the desired product (0.39 g, 99%). 1H NMR (300 MHz, CDCl3) δ 7.4 (s, 1H), 7.1 (m, 2H), 7.0-6.8 (m, 3H), 6.3 (bs, 1H), 5.0 (bs, 1H), 4.5-4.3 (m, 4H), 3.9 (m, 1H), 3.8 (m, 2H), 3.35 (s, 3H), 3.1 (m, 2H), 2.2 (m, 2H), 2.0-1.6 (m, 6H), 1.4 (s, 9H), 0.9 (m, 6H). MS m/z: [M+H]+=711.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C:11]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:12]=1[CH2:13][N:14]=[N+]=[N-])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C:11]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:12]=1[CH2:13][NH2:14])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCc1ccc(Cl)cc1CN=[N+]=[N-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCc1ccc(Cl)cc1CN
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 629 mg (2.02 mmol) 2-(2-(tert-butoxycarbonylamino)ethyl)-5-chlorobenzyl azide from the previous step in 30.0 mL THF containing 3.1 mL water was added 1.06 g (4.05 mmol) triphenylphosphine and the reaction was stirred at room temperature overnight. The THF was removed in vacuo and the residual aqueous phase extracted with methylene chloride (3×). The organics were combined, washed with brine, dried over sodium sulfate, filtered and concentrated to dryness in vacuo. Flash chromatography on silica gel (linear gradient from 266/10/1 to 200/10/1 of methylene chloride/methanol/concentrated ammonium hydroxide) gave 2-(2-(tert-butoxycarbonylamino)ethyl)-5-chlorobenzyl amine as a colorless oil: 1H NMR (DMSO-d6, 400 MHz): δ 7.45 (d, 1H, J=1.7 Hz), 7.18 (dd, 1H, J=2.1 and 8.2 Hz), 7.12 (d, 1H, J=8.2 Hz), 7.01 (br t, 1H, J=5.2 Hz), 3.73 (s, 2H), 3.07 (dt, 2H, J=6.5 and 7.3 Hz), 2.68 (t, 2H, J=7.4 Hz), 1.36 (s, 9H); MS (Electrospray): M+H=285.1; TLC Rf=0.33 (160/10/1 of methylene chloride/methanol/concentrated ammonium hydroxide).
Reaction SMILES: C([O:4][C@@H:5]1[C@H:11]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[S:10][C:9]2[C:20]3[C:25]([CH:26]=[CH:27][C:8]=2[N:7]([CH2:28][CH2:29][NH:30][CH3:31])[C:6]1=[O:32])=[CH:24][CH:23]=[CH:22][CH:21]=3)(=O)C.[C:33]([OH:40])(=[O:39])/[CH:34]=[CH:35]/[C:36]([OH:38])=[O:37]>C(O)C.C([O-])([O-])=O.[K+].[K+].C(#N)C>[C:33]([OH:40])(=[O:39])/[CH:34]=[CH:35]/[C:36]([OH:38])=[O:37].[OH:4][C@@H:5]1[C@H:11]([C:12]2[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=2)[S:10][C:9]2[C:20]3[C:25]([CH:26]=[CH:27][C:8]=2[N:7]([CH2:28][CH2:29][NH:30][CH3:31])[C:6]1=[O:32])=[CH:24][CH:23]=[CH:22][CH:21]=3
Reactant: CNCCN1C(=O)[C@H](OC(C)=O)[C@H](c2ccc(OC)cc2)Sc2c1ccc1ccccc21
Agent: O=C(O)/C=C/C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCO
Product: CNCCN1C(=O)[C@H](O)[C@H](c2ccc(OC)cc2)Sc2c1ccc1ccccc21
Yield: 53.5 %

Procedure:
A solution of 0.4 g (0.00089 mol) of (+)-cis-3-(acetyloxy)-2,3-dihydro-2-(4-methoxyphenyl)-5-[2-(methylamino)ethyl]naphtho[1,2-b][1,4]thiazepin-4(5H)-one in a mixture of 10 ml of ethanol and 10 ml of 0.5M K2CO3 was heated at 70°-80° for one hour. The mixture was concentrated to a low volume under reduced pressure, diluted with water (saturated with NaCl) and extracted with ethyl acetate. The combined ethyl acetate solutions were washed with brine, dried (MgSO4) and the solvent was removed. The residue, 0.25 g in acetonitrile, was treated with 0.08 g (0.0069 mol) of fumaric acid and the crystals were collected to afford 0.25 g (53%) of (+)-cis-2,3-dihydro-3-hydroxy-5-[2-(methylamino)ethyl]-2-(4-methoxyphenyl)naphtho[1,2-b][1,4]thiazepin-4(5H)-one (E)-2-butenedioate as the semihydrate, mp 178°-180° [α]D 25 +7.97° (C. 0.966, MeOH).
Reaction SMILES: [C:1]1([CH:7]=[CH:8][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(OCC)(=O)C.[Pd]>[C:11]1([C:9](=[O:10])[CH2:8][CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(C=Cc1ccccc1)c1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: O=C(CCc1ccccc1)c1ccccc1

Procedure:
(42) Chalcone (2.00 g, 9.60 mmol) dissolved in 24 ml of ethyl acetate was hydrogenated with 100 mg of 10% Pd/C at 55 psi for 2 hours at room temperature. The catalyst was filtered through celite, and the solvent evaporated to give the crude product, which was chromatographed on silica gel using 4:1 hexanes:ethyl acetate yielding 1.20 g (60.0%) of a white, flaky powder. 1H NMR (250 MHz) δ 8.00-7.97 (m, 2 H), 7.61-7.21 (m, 8 H), 3.36-3.30 (t, 2 H), 3.13-3.07 (t, 2 H); 13C NMR (62.7 MHz) 199.4, 141.5, 137.0, 133.3, 128.8, 128.6, 128.2, 126.3, 40.6 ppm.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[N:12]=[CH:11][C:10]([CH:13]=O)=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[N+:17]([CH3:20])([O-:19])=[O:18].C([O-])(=O)C.[NH4+].[BH4-].[Na+]>O.C(O)(=O)C>[F:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]([CH2:13][CH2:20][N+:17]([O-:19])=[O:18])=[CH:11][N:12]=2)=[CH:4][CH:3]=1
Reactant: C[N+](=O)[O-]
Reactant: O=Cc1ccc(Oc2ccc(F)cc2)nc1
Agent: CC(=O)[O-]
Agent: [BH4-]
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: O
Product: O=[N+]([O-])CCc1ccc(Oc2ccc(F)cc2)nc1
Temperature: 100 °C
Reaction time: 3 h
Yield: 71.8 %

Procedure:
To a mixture of 6-(4-fluoro-phenoxy)-pyridine-3-carbaldehyde (150 mg, 0.69 mmol) described in Manufacturing Example 75-1-2 and acetic acid (2 mL) were added nitromethane (0.28 mL, 5.2 mmol) and ammonium acetate (160 mg, 2.1 mmol), which was stirred for 3 hours at 100° C. The reaction mixture was cooled to room temperature and water was added thereto, followed by extraction with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and was concentrated under a reduced pressure. A mixture of dimethyl sulfoxide (3 mL) and acetic acid (0.2 mL) was added to the resulting residue, and sodium borohydride (42 mg, 1.1 mmol) was added at room temperature while cooling appropriately. The reaction mixture was stirred for 10 minutes at that temperature. Water was added at room temperature to the reaction solution at room temperature, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, and was concentrated under a reduced pressure. The residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=1:1) to obtain the title compound (130 mg, 70%).
Reaction SMILES: C([S:4][CH:5]1[CH2:8][N:7]([C:9]2[O:10][CH:11]=[C:12]([C:14]([N:16]3[CH2:19][CH:18]([O:20][Si:21]([C:34]([CH3:37])([CH3:36])[CH3:35])([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH2:17]3)=[O:15])[N:13]=2)[CH2:6]1)(=O)C.C(O)(=O)C.NN.C1(P(O[C:59]2[C@H:60]([CH3:83])[C@H:61]3[C@@H:78]([C@H:79]([OH:81])[CH3:80])[C:77](=[O:82])[N:62]3[C:63]=2[C:64]([O:66][CH2:67][C:68]2[CH:73]=[CH:72][C:71]([N+:74]([O-:76])=[O:75])=[CH:70][CH:69]=2)=[O:65])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(C(C)C)CC)(C)C.C(=O)([O-])O.[Na+]>CN(C)C=O.C(#N)C.C(OCC)(=O)C>[Si:21]([O:20][CH:18]1[CH2:17][N:16]([C:14]([C:12]2[N:13]=[C:9]([N:7]3[CH2:8][CH:5]([S:4][C:59]4[C@H:60]([CH3:83])[C@@H:61]5[C@@H:78]([C@H:79]([OH:81])[CH3:80])[C:77](=[O:82])[N:62]5[C:63]=4[C:64]([O:66][CH2:67][C:68]4[CH:69]=[CH:70][C:71]([N+:74]([O-:76])=[O:75])=[CH:72][CH:73]=4)=[O:65])[CH2:6]3)[O:10][CH:11]=2)=[O:15])[CH2:19]1)([C:34]([CH3:37])([CH3:35])[CH3:36])([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CC(=O)SC1CN(c2nc(C(=O)N3CC(O[Si](c4ccccc4)(c4ccccc4)C(C)(C)C)C3)co2)C1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(OP(=O)(c3ccccc3)c3ccccc3)[C@H](C)[C@@H]12
Agent: NN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(SC3CN(c4nc(C(=O)N5CC(O[Si](c6ccccc6)(c6ccccc6)C(C)(C)C)C5)co4)C3)[C@H](C)[C@H]12
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.9 %

Procedure:
To a solution of 3-acetylthio-1-{4-[3-(t-butyldiphenylsilyloxy)-azetidin-1-ylcarbonyl]-1,3-oxazol-2-yl}azetidine (860 mg, 1.61 mmol) (obtained as described in Reference Example 74) in dimethylformamide (43 ml) was added hydrazine acetate (178 mg, 1.93 mmol) at room temperature under an atmosphere of nitrogen and the mixture was stirred for 1 hour. After checking the completion of the reaction, a solution of p-nitrobenzyl (1R,5S,6S)-2-(diphenylphosphoryloxy)-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate (957 mg, 1.61 mmol) in acetonitrile (48 ml) was added dropwise into the resulting mixture in an ice bath under an atmosphere of nitrogen, followed by the addition of diisopropylethylamine (1.12 ml, 6.44 mmol). The mixture was stirred overnight while gradually raising the temperature to room temperature. After checking the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogencarbonate solution were added to the reaction mixture. The resulting mixture was shaken in a separatory funnel and the ethyl acetate layer was separated, washed with 10% sodium chloride solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column (eluant: ethyl acetate→ethyl acetate:methanol (95:5)) to afford p-nitrobenzyl (1R,5S,6S)-2-(1-{4-[3-(t-butyldiphenylsilyloxy)-azetidin-1-ylcarbonyl]-1,3-oxazol-2-yl}azetidin-3-yl)thio-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate (1.20 g, yield 89%) as a pale yellow solid.
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH2:18][CH2:17][CH:16]([CH:19]=O)[CH2:15][CH2:14]3)=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:21]([NH:23][CH2:24][CH3:25])[CH3:22]>>[CH2:21]([N:23]([CH2:24][CH3:25])[CH2:19][CH:16]1[CH2:17][CH2:18][N:13]([C:10]2[CH:11]=[CH:12][C:7]([CH2:6][N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[CH:8][CH:9]=2)[CH2:14][CH2:15]1)[CH3:22]
Reactant: O=CC1CCN(c2ccc(CN3CCCC3)cc2)CC1
Reactant: CCNCC
Product: CCN(CC)CC1CCN(c2ccc(CN3CCCC3)cc2)CC1

Procedure:
Prepared from the product of Example 16 and diethylamine.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:18][C:19]([C:21]2[CH:26]=[N:25][C:24]([N:27]3[CH2:33][CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)=[CH:23][N:22]=2)=[O:20])=[C:6]([CH:17]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][N:11]=1)=[O:8].C(N(CC)C(C)C)(C)C.Br[CH2:44][C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46]>C(Cl)Cl.[Cl-].C[N+](CCCC)(CCCC)CCCC>[C:48]([O:47][C:45]([CH2:44][N:30]1[CH2:31][CH2:32][CH2:33][N:27]([C:24]2[N:25]=[CH:26][C:21]([C:19]([NH:18][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:17][C:6]=3[C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][N:11]=3)=[O:8])=[O:20])=[N:22][CH:23]=2)[CH2:28][CH2:29]1)=[O:46])([CH3:51])([CH3:50])[CH3:49]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O=C(Nc1ccc(F)cc1C(=O)Nc1ccc(Cl)cn1)c1cnc(N2CCCNCC2)cn1
Agent: CCCC[N+](C)(CCCC)CCCC
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CN1CCCN(c2cnc(C(=O)Nc3ccc(F)cc3C(=O)Nc3ccc(Cl)cn3)cn2)CC1
Temperature: 25 °C

Procedure:
To a solution of 5-fluoro-2-[5-(hexahydro-1,4-diazepin-1-yl)pyrazin-2-ylcarbonylamino]-N-(5-chloropyridin-2-yl)-benzamide (Example 1, 0.3 g, 0.64 mmol) in methylene chloride was added methyltributylammonium chloride (1 mL), N,N-diisopropylethylamine (2.2 mL) and tert-butyl bromoacetate (2.496 g). The mixture was stirred at room temperature until a clear solution was obtained (24–48 h), diluted with methylene chloride (50 mL), washed with water (2×10 mL) and brine, dried over sodium sulfate, evaporated, and dried. Yield=0.079 g.