Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)(=O)C.C(OC([NH:12][NH:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][C:18]([F:21])=[C:17]([CH3:22])[CH:16]=1)=O)(C)(C)C>ClCCl>[F:21][C:18]1[CH:19]=[CH:20][C:15]([C:14]([NH:13][NH2:12])=[O:23])=[CH:16][C:17]=1[CH3:22]
Reactant: Cc1cc(C(=O)NNC(=O)OC(C)(C)C)ccc1F
Solvent: CC(=O)O
Solvent: ClCCl
Product: Cc1cc(C(=O)NN)ccc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.4 %

Procedure:
50 mL trifluor acetic acid was added to 13 g N′-(4-fluoro-3-methyl-benzoyl)-hydrazinecarboxylic acid tert-butyl ester in 150 mL dichlormethane. The reaction was stirred for 1 h at RT and the solvent was evaporated. The residue was basicfied with 1 N sodium hydroxide and extracted with saturated sodium chloride solution and tetrahydrofuran. The organic layer was evaporated and the residue crystallized from ethyl acetate to yield 6.8 g of the desired product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:21]=[C:20]2[C:11]([N:12]3[C:17]([CH2:18][O:19]2)=[N:16][NH:15][C:14](=[O:22])[C@H:13]3[CH3:23])=[CH:10][CH:9]=1.C1C(=O)N([Br:31])C(=O)C1>C(O)(C(F)(F)F)=O>[Br:31][C:9]1[CH:10]=[C:11]2[C:20](=[CH:21][C:8]=1[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[F:1])[O:19][CH2:18][C:17]1[N:12]2[C@H:13]([CH3:23])[C:14](=[O:22])[NH:15][N:16]=1
Reactant: C[C@@H]1C(=O)NN=C2COc3cc(-c4ccccc4F)ccc3N21
Reactant: O=C1CCC(=O)N1Br
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H]1C(=O)NN=C2COc3cc(-c4ccccc4F)c(Br)cc3N21
Temperature: 25 °C
Reaction time: 3 h
Yield: 73.1 %

Procedure:
To a solution of (R)-7-(2-fluoro-phenyl)-4-methyl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one (2.4 g, 7.71 mmol) in TFA (20 mL) was added NBS (1.37 g, 7.71 mmol) in portions. The reaction mixture was stirred at ambient temperature for 3 h then concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluting with 10-50% EtOAc in petroleum ether) to give (R)-6-bromo-7-(2-fluoro-phenyl)-4-methyl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one (2.2 g, 73%) as a colorless solid. 1H NMR (400 MHz, CDCl3) δ 8.23 (brs, 1H), 7.45-7.36 (m, 1H), 7.30-7.11 (m, 5H), 6.99 (s, 1H), 4.74-4.69 (m, 1H), 4.69-4.55 (m, 2H), 1.58 (d, J=6.8 Hz, 3H).
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH2:6][S:7][C@@H:8]2[CH:15]([NH:16][C:17](=[O:56])/[C:18](/[C:31]3[N:32]=[C:33]([NH:36]C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[S:34][CH:35]=3)=[N:19]\[O:20][C:21]([C:24]([O:26]C(C)(C)C)=[O:25])([CH3:23])[CH3:22])[C:14](=[O:57])[N:9]2[C:10]=1[C:11]([OH:13])=[O:12])=[N+]=[N-].O>[Ni].CO.C(O)(C(F)(F)F)=O>[NH2:1][CH2:4][C:5]1[CH2:6][S:7][C@@H:8]2[CH:15]([NH:16][C:17](=[O:56])/[C:18](/[C:31]3[N:32]=[C:33]([NH2:36])[S:34][CH:35]=3)=[N:19]\[O:20][C:21]([C:24]([OH:26])=[O:25])([CH3:23])[CH3:22])[C:14](=[O:57])[N:9]2[C:10]=1[C:11]([OH:13])=[O:12]
Reactant: CC(C)(C)OC(=O)C(C)(C)O/N=C(\C(=O)NC1C(=O)N2C(C(=O)O)=C(CN=[N+]=[N-])CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: [Ni]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: CO
Product: CC(C)(O/N=C(\C(=O)NC1C(=O)N2C(C(=O)O)=C(CN)CS[C@H]12)c1csc(N)n1)C(=O)O
Reaction time: 1 h
Yield: 35.1 %

Procedure:
An aqueous slurry of Raney nickel (10.2 g.) was added in one portion to a stirred solution of the azide (20.0 g.) in a mixture of MeOH (60 ml.) and TFA (60 ml.) at room temperature. A vigorous effervescence was observed. Stirring was continued for 1 hour and the Raney nickel was removed by filtration through diatomaceous earth. The filter pad was washed well with MeOH and the washings were combined with the filtrate. The solvents were evaporated under reduced pressure to give a pale green solid residue which was then stirred for 2 hours with a mixture of TFA (60 ml.) and water (15ml.). This mixture was evaporated to dryness and the residue was stirred vigorously with water (400 ml.) for 30 minutes. The resulting solution was filtered through diatomaceous earth to remove the undissolved triphenylmethanol and the filtrate was applied to a column of Diaion HP 20 resin (1 1.). The column was eluted with water (500 ml.) to remove inorganic material and then with aqueous MeOH 1:1 v/v. The fractions which were shown by HPLC to contain the product were evaporated under reduced pressure to yield 3-aminomethyl-7-[2-(2-aminothiazol-4-yl)-2-((Z)-1-carboxy-1-methylethoxyimino)acetamido]ceph-3-em-4-carboxylic acid (4.2 g.) as a pale yellow foam having the following n.m.r. in solvent A: 1.4 (s,6H); 3.1-3.8 (complex, 4H); 4.95 (d,1H); 5.7(d,1H); 6.72 (s,1H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][OH:5].C(N(CC)CC)C.[C:13](Cl)([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14]>C(Cl)Cl.C(OCC)C.O>[OH:5][CH2:4][CH2:3][CH2:2][NH:1][C:13](=[O:14])[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NCCCO
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCCCO)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 107.3 %

Procedure:
3-Aminopropan-1-ol (10 g, 133 mmol) was dissolved in methylene chloride (100 ml) at 0° C. Triethylamine (9 ml, 65 mmol) and CbzCl (10 ml, 66.8 mmol) were added slowly to the resulting solution at 0° C. and warmed to room temperature. The reaction mixture thus obtained was stirred for 1 hour at room temperature, and then diethyl ether (100 ml) and water (50 ml) were poured into the resulting solution. With diethyl ether normal work-up was taken, dried with magnesium sulfate. After evaporation the volatile material, the residue was purified with normal phase preparative column to produce the title compound (15 g, 95%) as colorless oil.
Reaction SMILES: [C:1]([Br:5])(Br)(Br)[Br:2].[F:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:16]=[C:15]([CH:25]([CH3:27])[CH3:26])[C:14]=2[CH:28]=O)=[CH:9][CH:8]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCl.C(Cl)Cl>[Br:2][C:1]([Br:5])=[CH:28][C:14]1[C:15]([CH:25]([CH3:27])[CH3:26])=[N:16][C:17]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:18][C:13]=1[C:10]1[CH:9]=[CH:8][C:7]([F:6])=[CH:12][CH:11]=1
Reactant: BrC(Br)(Br)Br
Reactant: CC(C)c1nc(-c2ccccc2)cc(-c2ccc(F)cc2)c1C=O
Agent: ClCl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)c1nc(-c2ccccc2)cc(-c2ccc(F)cc2)c1C=C(Br)Br
Reaction time: 0.33 h
Yield: 102.2 %

Procedure:
A solution of carbon tetrabromide (2.204 gm, 6.65 mmol) in CH2 Cl2 (8 ml) was added over a 12 minute period to a cold (-12° C.) solution of 4-(4-fluorophenyl)-2-(1-methylethyl)-6-phenyl-3-pyridinecarboxaldehyde (1.415 gm, 4.43 mmol) (the preparation of which is described in Example 1) and triphenylphosphine (3.488 gm, 13.3 mmol) in CH2Cl2 (25 ml). After the addition was complete, the cooling bath was removed and the mixture was stirred for 20 minutes. The solution was quenched with saturated NaHCO3 and extracted 3× with CH2Cl2. The combined organic layers were washed with saturated NaHCO3, dried (Na2SO4), filtered and stripped to give a yellow oil. The oil was chromatographed (flash, Merck SiO2, 40% CH2Cl2 in hexane) to give 3-(2,2-dibromoethenyl)-4-(4-fluorophenyl)-2-(1-methylethyl)-6-phenylpyridine as a colorless foam (2.152 gm, 100%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[C:8]([C:10]#[C:11][Si](C)(C)C)[CH:7]=[CH:6][C:5]=1[Cl:16].C(O)=[O:19]>>[CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[C:8]([C:10](=[O:19])[CH3:11])[CH:7]=[CH:6][C:5]=1[Cl:16]
Reactant: O=CO
Reactant: COC(=O)c1cc(C#C[Si](C)(C)C)ccc1Cl
Product: COC(=O)c1cc(C(C)=O)ccc1Cl
Temperature: 25 °C

Procedure:
A mixture of 2-chloro-5-trimethylsilanylethynyl-benzoic acid methyl ester (3.2 g, 12 mmol) in formic acid (50 mL) was heated at reflux for 16 h. The mixture was cooled to room temperature and concentrated in vacuo. The residue was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate, water and brine. The organic layer was dried, filtered and concentrated in vacuo to afford the title compound (1.4 g).
Reaction SMILES: C(Cl)CCl.Cl.[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([N:13]2[CH2:18][CH2:17][CH:16]([C:19]([OH:21])=O)[CH2:15][CH2:14]2)=[N:11][CH:12]=1.C1C=CC2N(O)N=NC=2C=1.Cl.[CH3:33][NH:34][O:35][CH3:36].C(N(CC)CC)C>CN(C1C=CN=CC=1)C.ClCCl.O>[CH3:36][O:35][N:34]([CH3:33])[C:19]([CH:16]1[CH2:15][CH2:14][N:13]([C:10]2[CH:9]=[CH:8][C:7]([Cl:6])=[CH:12][N:11]=2)[CH2:18][CH2:17]1)=[O:21]
Reactant: O=C(O)C1CCN(c2ccc(Cl)cn2)CC1
Reactant: CNOC
Agent: CN(C)c1ccncc1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Solvent: O
Product: CON(C)C(=O)C1CCN(c2ccc(Cl)cn2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
EDC (1.61 g, 8.4 mmol) was added portionwise to a stirred solution of 5′-chloro-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylic acid hydrochloride (1.16 g, 4.19 mmol), DMAP (5 mg), HOBt (5 mg) and N,O-dimethylhydroxylamine hydrochloride (818 mg, 8.4 mmol) in dichloromethane (20 mL). Triethylamine (1.69 g, 2.33 mL, 16.8 mmol) was added dropwise, and the reaction mixture was stirred at room temperature overnight. The resulting solution was poured into water and extracted with ethyl acetate (3×). The combined organic phase was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give 5′-chloro-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylic acid, methoxy-methyl-amide as a white solid (1.05 g. 86%); 1H NMR (CDCl3, 300 MHz) δ 8.05 (d, J=2.5 Hz, 1H), 7.36 (dd, J1=9.0 Hz, J2=2.5 Hz, 1H), 6.57 (d, J=9.0 Hz, 1H), 4.25 (dt, J1=13.0 Hz, J2=3.0 Hz, 1H), 3.69 (s, 3H), 3.16 (s, 3H), 2.88 (m, 3H), and 1.78 (m, 4H); MS (+CI): m/z for C13H18ClN3O2: expected 283.1. found 284.2 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][N:10]([CH2:13][C:14]([C:16]3[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][C:24]([O:26]C)=[O:25])=[CH:18][CH:17]=3)=[O:15])[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.[OH-].[Na+]>CO>[N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:8][CH2:9][N:10]([CH2:13][C:14]([C:16]3[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][C:24]([OH:26])=[O:25])=[CH:18][CH:17]=3)=[O:15])[CH2:11][CH2:12]2)=[CH:3][CH:2]=1
Reactant: COC(=O)CCc1ccc(C(=O)CN2CCN(c3ccncc3)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CCc1ccc(C(=O)CN2CCN(c3ccncc3)CC2)cc1
Temperature: 4 °C
Reaction time: 3 h

Procedure:
A stirred solution of the product of Example 11 (70 mg) in methanol (0.5 ml) was treated with a M sodium hydroxide solution (0.19 ml) and stirring continued for 3 hours. The methanol was removed in vacuo and the residue diluted with water (1 ml), then a M hydrochloric acid solution (0.19 ml) added. On cooling to 4° C. a solid precipitated which was collected, washed with ice-water, then dried to give the title compound, 36.5 mg: m.p. 245°-247° C.; NMR (d6DMSO) δ 8.05(2H,d), 7.91(2H,d), 7.36(2H,d), 6.86(2Hd), 3.89(2H,s), 3.34(4H,t), 2.87(2H,t), 2.62(4H,t), 2.58(2H,t); m/e 354 (M+H)+ : calculated for C20H23N3O3.0.2H2O: C, 67.2; H, 6.6; N, 11.8. found: C, 67.6; H, 6.6; N, 11.4%.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C@:8]2([CH3:17])[C:13]([F:15])([F:14])[CH2:12][O:11][C:10]([NH2:16])=[N:9]2)[CH:7]=1.[Cl:19][C:20]1[C:21]([C:28](O)=[O:29])=[N:22][CH:23]=[C:24]([C:26]#[N:27])[CH:25]=1>>[NH2:16][C:10]1[O:11][CH2:12][C:13]([F:14])([F:15])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:28]([C:21]3[C:20]([Cl:19])=[CH:25][C:24]([C:26]#[N:27])=[CH:23][N:22]=3)=[O:29])[CH:3]=[CH:4][C:5]=2[F:18])([CH3:17])[N:9]=1
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)OCC1(F)F
Reactant: N#Cc1cnc(C(=O)O)c(Cl)c1
Product: C[C@]1(c2cc(NC(=O)c3ncc(C#N)cc3Cl)ccc2F)N=C(N)OCC1(F)F

Procedure:
The condensation of (R)-4-(5-amino-2-fluoro-phenyl)-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate XI-1) and 3-chloro-5-cyano-pyridine-2-carboxylic acid following procedure I yielded the title compound as a white solid. MS (ISP): m/z=424.1 [M+H]+.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[NH2:7][CH2:8][CH2:9][CH2:10][OH:11].[C:12]([C:14]1[N:19]=[CH:18][C:17]([C:20]2[C:32]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[N:25]([C:33]4[CH:45]=[CH:44][C:36]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])=[C:35](F)[CH:34]=4)[C:24]=3[CH:23]=[CH:22][CH:21]=2)=[CH:16][CH:15]=1)#[N:13]>CS(C)=O.O>[C:12]([C:14]1[N:19]=[CH:18][C:17]([C:20]2[C:32]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[N:25]([C:33]4[CH:45]=[CH:44][C:36]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])=[C:35]([NH:7][CH2:8][CH2:9][CH2:10][OH:11])[CH:34]=4)[C:24]=3[CH:23]=[CH:22][CH:21]=2)=[CH:16][CH:15]=1)#[N:13]
Reactant: NCCCO
Reactant: CC(C)(C)OC(=O)c1ccc(-n2c3ccccc3c3c(-c4ccc(C#N)nc4)cccc32)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)c1ccc(-n2c3ccccc3c3c(-c4ccc(C#N)nc4)cccc32)cc1NCCCO
Temperature: 90 °C

Procedure:
0.9 g of potassium carbonate and 3.3 ml of 3-amino-1-propanol are successively added to a solution of 1 g of 2-methylpropan-2-yl 4-[4-(6-cyanopyridin-3-yl)-9H-carbazol-9-yl]-2-fluorobenzoate, obtained in stage 1 of Example 49, in 8 ml of dimethyl sulphoxide. The reaction mixture is heated at 90° C. for 1 and a half hours in a microwave, and then diluted with distilled water. The aqueous phase is washed twice with ethyl acetate and the combined organic phases are washed with water and a saturated solution of sodium chloride, dried over magnesium sulphate and filtered. The residue is purified by silica gel chromatography, elution being carried out with a mixture of cyclohexane and ethyl acetate (70/30 by volume), so as to give 0.7 g of 2-methylpropan-2-yl 4-[4-(6-cyanopyridin-3-yl)-9H-carbazol-9-yl]-2-[(3-hydroxypropyl)-amino]benzoate in the form of a yellow oil, the characteristics of which are the following:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([CH3:22])=[C:14]([CH:23]=[O:24])[CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+].C(=O)(O)[O-].[Na+]>CO>[C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([CH3:22])=[C:14]([CH2:23][OH:24])[CH:13]=3)[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1nc2c(cc1C=O)C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@@H](C)N21
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1nc2c(cc1CO)C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@@H](C)N21

Procedure:
To a solution of 90.0 mg (0.27 mmol) (4R,9aR)-7-formyl-4,6-dimethyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester in 1 mL methanol was added 6.2 mg (0.16 mmol) sodium borohydride. After 2 h the reaction mixture was poured into saturated aqueous sodium bicarbonate solution and extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate and filtered. The solvent was removed at a rotary evaporator and the residue was dried under high vacuum to give the compound as a light brown foam which was used without further purification (99.4%).
Reaction SMILES: [C:1]([O:4][C:5]([C:8](Cl)=[O:9])([CH3:7])[CH3:6])(=[O:3])[CH3:2].[CH3:11][O:12][C:13]1[CH:57]=[C:56]([O:58][CH3:59])[CH:55]=[C:54]([O:60][CH3:61])[C:14]=1/[CH:15]=[CH:16]/[CH:17]([S:27]([CH:30](/[CH:40]=[CH:41]/[C:42]1[C:47]([O:48][CH3:49])=[CH:46][C:45]([O:50][CH3:51])=[CH:44][C:43]=1[O:52][CH3:53])[C:31]1[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[C:33]([NH2:39])[CH:32]=1)(=[O:29])=[O:28])[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([NH2:26])[CH:19]=1>>[CH3:61][O:60][C:54]1[CH:55]=[C:56]([O:58][CH3:59])[CH:57]=[C:13]([O:12][CH3:11])[C:14]=1/[CH:15]=[CH:16]/[CH:17]([S:27]([CH:30](/[CH:40]=[CH:41]/[C:42]1[C:43]([O:52][CH3:53])=[CH:44][C:45]([O:50][CH3:51])=[CH:46][C:47]=1[O:48][CH3:49])[C:31]1[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[C:33]([NH:39][C:8](=[O:9])[C:5]([O:4][C:1](=[O:3])[CH3:2])([CH3:7])[CH3:6])[CH:32]=1)(=[O:29])=[O:28])[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([NH:26][C:8](=[O:9])[C:5]([CH3:7])([O:4][C:1](=[O:3])[CH3:2])[CH3:6])[CH:19]=1
Reactant: COc1cc(OC)c(/C=C/C(c2ccc(OC)c(N)c2)S(=O)(=O)C(/C=C/c2c(OC)cc(OC)cc2OC)c2ccc(OC)c(N)c2)c(OC)c1
Reactant: CC(=O)OC(C)(C)C(=O)Cl
Product: COc1cc(OC)c(/C=C/C(c2ccc(OC)c(NC(=O)C(C)(C)OC(C)=O)c2)S(=O)(=O)C(/C=C/c2c(OC)cc(OC)cc2OC)c2ccc(OC)c(NC(=O)C(C)(C)OC(C)=O)c2)c(OC)c1
Yield: 98 %

Procedure:
A solution of 1-chlorocarbonyl-1-methylethyl acetate (10 mmol) and (E)-2,4,6-trimethoxystyryl-3-amino-4-methoxybenzylsulfone (10 mmol) was reacted according to General Method A. The crude product obtained was purified by column chromatography to yield the desired product in 98% yield. (m.p. 148-150° C.)
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([CH3:28])[C:14]2[C:9](=[CH:10][C:11]([NH:18][C:19]([C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)=[O:20])=[C:12]([N+:15]([O-])=O)[CH:13]=2)[NH:8][C:7]1=[O:27])=[O:5])[CH3:2]>[Pd].CO>[NH2:15][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][C:11]=1[NH:18][C:19]([C:21]1[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=1)=[O:20])[NH:8][C:7](=[O:27])[C:6]2([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH3:28]
Reactant: CCOC(=O)C1(C)C(=O)Nc2cc(NC(=O)c3ccncc3)c([N+](=O)[O-])cc21
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)C1(C)C(=O)Nc2cc(NC(=O)c3ccncc3)c(N)cc21

Procedure:
A solution of 12.4 g. (32.2 mmol) 3-ethoxycarbonyl-3-methyl-5-nitro-6-(4-pyridinoylamino)-indolin -2-one in 500 ml. methanol is hydrogenated at ambient temperature in the presence of 1 g. 10% Pd/C. The catalyst is filtered off with suction, the filtrate is evaporated and the substance obtained is immediately further worked up.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:29])[C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:28])[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[CH3:27])=[N:15][CH:14]=3)[CH2:10][CH2:9][CH2:8][CH:7]([O:30][CH2:31][C:32](OC)=[O:33])[C:6]=2[CH:36]=1.[BH4-].[Li+].O>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:29])[C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:28])[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[CH3:27])=[N:15][CH:14]=3)[CH2:10][CH2:9][CH2:8][CH:7]([O:30][CH2:31][CH2:32][OH:33])[C:6]=2[CH:36]=1
Reactant: COC(=O)COC1CCCN(C(=O)c2ccc(NC(=O)c3ccccc3C)nc2)c2ccc(Cl)cc21
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(OCCO)c3cc(Cl)ccc32)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.4 %

Procedure:
To a solution of 7-chloro-5-methoxycarbonylmethoxy-1-[6-(2-methylbenzoylamino)nicotinoyl]-2,3,4,5-tetrahydro-1H-benzazepine (1.2 g) in tetrahydrofuran (15 ml) is added with stirring lithium borohydride (0.1 g) under ice-cooling, and the mixture is stirred at room temperature overnight. Water is added to the reaction solution, and the mixture is extracted with ethyl acetate. The extract is washed with water, dried over magnesium sulfate, and evaporated under reduced pressure to remove the solvent. The residue is purified by silica gel column chromatography to give 7-chloro-5-(2-hydroxyethoxy)-1-[6-(2-methylbenzoylamino)nicotinoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.73 g) as colorless amorphous.
Reaction SMILES: Cl[CH2:2][C:3](=O)[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH:11]([NH2:13])=[O:12].C([O-])([O-])=O.[K+].[K+].[Na+].[Cl-]>C1C=CC=CC=1.CCOCC>[CH3:2][C:3]1[N:13]=[CH:11][O:12][C:4]=1[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)CC(=O)CCl
Reactant: NC=O
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CCOCC
Solvent: c1ccccc1
Product: CCOC(=O)c1ocnc1C
Reaction time: 18 h
Yield: 28.3 %

Procedure:
This compound was prepared according to the procedure described in French Pat. No. 1,543,853. A mixture of 50.0 g (0.337 moles) of ethyl chloroacetoacetate and 42.0 g (0.933 moles) of formamide was stirred at 120°-135° for 18 hr. Thereafter, the mixture was cooled using an ice bath to 10° C. 300 ml of 1 N K2CO3 was added dropwise with gas evolution noted. After complete addition of K2CO3 solution, the reaction mixture was stirred with 200 ml of benzene/ether (2:1) and saturated with NaCl. The insoluble material was filtered and the benzene/ether layer was separated and washed with water, dried (MgSO4) and concentrated under reduced pressure. The brown residue was distilled on a Kugelrohr to give 14.8 g of white solid, mp 31°-33° C.; yield 31%; nmr (CDCl3) 8.0 (s,1H,C2H), 44 (q, J=7 Hz, 2H,CH2), 2.5 (s,3H,CH3), 1.4 (t,3H,CH3).
Reaction SMILES: Br.Br.[NH2:3][CH:4]1[C:10](=[O:11])[N:9]([CH2:12][C:13]([N:15]([CH:24]([CH3:26])[CH3:25])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)=[O:14])[C:8]2[CH:27]=[CH:28][CH:29]=[CH:30][C:7]=2[C:6]([C:31]2[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=2)=[N:5]1.C(N(CC)CC)C.[C:44]1([N:50]=[C:51]=[O:52])[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>C(Cl)Cl>[CH:24]([N:15]([C:16]1[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=1)[C:13](=[O:14])[CH2:12][N:9]1[C:8]2[CH:27]=[CH:28][CH:29]=[CH:30][C:7]=2[C:6]([C:31]2[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=2)=[N:5][CH:4]([NH:3][C:51]([NH:50][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)=[O:52])[C:10]1=[O:11])([CH3:26])[CH3:25]
Reactant: O=C=Nc1ccccc1
Reactant: COc1ccc(N(C(=O)CN2C(=O)C(N)N=C(c3cccnc3)c3ccccc32)C(C)C)cc1
Agent: Br
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(N(C(=O)CN2C(=O)C(NC(=O)Nc3ccccc3)N=C(c3cccnc3)c3ccccc32)C(C)C)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 58.2 %

Procedure:
According to process A, a solution of 175 mg of 2-(3-amino-2-oxo-5-pyridin-3-yl-2,3-dihydro-benzo[e][1,4]diazepin-1-yl)-N-isopropyl-N-(4-methoxy-phenyl)-acetamide dihydrobromide (0.283 mmol), prepared as in Intermediate 31, in 3 mL of methylene chloride was treated with 98.5 μL of triethylamine (0.706 mmol) and 33.8 μL of phenyl isocyanate (0.311 mmol). After stirring under nitrogen for 20 min., the reaction mixture was diluted with methylene chloride and washed with aqueous potassium carbonate (5% w/v). The phases were separated and the organic layer was dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to a residue. The residue was triturated with 5 mL of acetonitrile and the resulting slurry was heated to reflux under nitrogen. After stirring for 20 min., the slurry was cooled to ambient temperature, filtered and washed with cold acetonitrile. The product was combined again with 3 mL of acetonitrile and brought to reflux. After stirring for 30 min., the slurry was cooled to ambient temperature, filtered and washed with cold acetonitrile. The product was dried under high vacuum to provide 95 mg of the title compound as a white crystalline solid. 1H NMR (300 MHz, d6-DMSO) -- =9.06 (b, 1H), 8.68 (m, 2H), 7.93 (d, 1H, J=8.0), 7.72 (m, 1H), 7.53 (m, 3H), 7.37 (m, 4H), 7.26 (m, 4H), 7.07 (m, 2H), 6.94 (m, 1H), 5.31 (d, 1H, J=8.3), 4.72 (m, 1H), 4.29 (d, 1H, J=16.4), 4.16 (d, 1H, J=16.4), 3.81 (s, 3H), 0.96 (d, 6H, J=6.1); MS (ESI) [M+H]+ =577.
Reaction SMILES: C1C(=O)N([Cl:8])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[Cl:27][C:28]1[C:33]([C:34]#[N:35])=[CH:32][CH:31]=[C:30]([CH3:36])[N:29]=1>C1C=CC=CC=1>[Cl:27][C:28]1[C:33]([C:34]#[N:35])=[CH:32][CH:31]=[C:30]([CH2:36][Cl:8])[N:29]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cc1ccc(C#N)c(Cl)n1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Product: N#Cc1ccc(CCl)nc1Cl
Reaction time: 4 h

Procedure:
NCS (1.44 g, 10.8 mmol) and benzoyl peroxide (238 mg, 0.98 mmol) were added to a stirred solution of 2-chloro-3-cyano-6-methyl-pyridine (750 mg, 4.92 mmol) in benzene (35 mL) and the mixture was heated to reflux. After 4 h, the mixture was cooled and filtered. The filtrate was diluted with ethyl acetate and was washed with sodium metabisulfite solution, water and brine, dried (Na2SO4) and evaporated in vacuo. The residue was purified by chromatography on silica (chloroform) to give the title compound: