Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH2:10](Br)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O>[CH2:10]([O:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: BrCc1ccccc1
Reactant: O=Cc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1ccccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Hydroxybenzaldehyde (19.3 g) and benzyl bromide (25.9 g) were dissolved in N,N-dimethylformamide (50 mL). Cesium carbonate (59.0 g) was added to the solution at 0° C., and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with diethyl ether. The organic layer was washed with 1 mol/L aqueous sodium hydroxide solution, water and brine successively, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give 2-benzyloxybenzaldehyde. This compound was dissolved in methanol (100 mL). Sodium borohydride (5.73 g) was added to the solution at 0° C., and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and water was added to the residue. The mixture was extracted with diethyl ether, and the organic layer was washed with 1 mol/L aqueous sodium hydroxide solution, water and brine successively, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give the title compound (32.4 g).
Reaction SMILES: Br[CH2:2][C:3]1[C:4]2[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:5]=2[S:6][C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].[CH3:18][O:19][CH:20]([O:24][CH3:25])[CH2:21][NH:22][CH3:23].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:17][C:15]1[CH:14]=[CH:13][C:5]2[S:6][C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:3]([CH2:2][N:22]([CH2:21][CH:20]([O:24][CH3:25])[O:19][CH3:18])[CH3:23])[C:4]=2[CH:16]=1
Reactant: CNCC(OC)OC
Reactant: CCOC(=O)c1sc2ccc(Cl)cc2c1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)c1sc2ccc(Cl)cc2c1CN(C)CC(OC)OC
Reaction time: 48 h
Yield: 96.2 %

Procedure:
A mixture of ethyl 3-bromomethyl-5-chlorobenzo[b]thiophene-2-carboxylate (11.0 g, 0.033 mol), methylaminoacetaldehyde dimethyl acetal (4.76 g, 0.04 mol) and potassium carbonate (11.4 g, 0.8 mol) in dry acetone (200 ml) was stirred for 48 hours, filtered and the filtrate concentrated to give 11.8 g (96%) of ethyl 5-chloro-3-[N-(2,2-dimethoxyethyl)-N-methyl-(aminomethyl)]benzo[b]thiophene-2-carboxylate.
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4](=[O:8])[CH:3]=1.C1(C)C(S(O)(=O)=O)=CC=CC=1.[CH2:20](O)[CH2:21][OH:22].O>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH2:3][C:4]2([CH2:5][CH2:6][CH:7]=1)[O:22][CH2:21][CH2:20][O:8]2
Reactant: CC1=CC(=O)CCC1
Reactant: OCCO
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: O
Solvent: Cc1ccccc1
Product: CC1=CCCC2(C1)OCCO2
Yield: 62 %

Procedure:
A mixture of 3-methyl-2-cyclohexenone (4 g, 36.36 mmol), toluenesulfonic acid (100 mg) and ethylene glycol (7 mL) in 100 mL of toluene is refluxed overnight and water formed is removed by Dean- Stark trap. The residue after concentration is chromatographed on silica gel (10% ethyl acetate/hexane) to give 3.36 g (62%) of 7-methyl-1,4-dioxa-spiro[4.5]dec-7-ene.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)=[N:4][O:5][C:6]=1[C:7]([F:10])([F:9])[F:8].[C:16](Cl)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH3:1][C:2]1[C:3]([C:11]2[S:12][C:13]([C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:23])=[CH:14][CH:15]=2)=[N:4][O:5][C:6]=1[C:7]([F:8])([F:10])[F:9]
Reactant: Cc1c(-c2cccs2)noc1C(F)(F)F
Reactant: O=C(Cl)c1ccccc1
Product: Cc1c(-c2ccc(C(=O)c3ccccc3)s2)noc1C(F)(F)F
Yield: 70 %

Procedure:
Prepared from 4-Methyl-3-thiophen-2-yl-5-trifluoromethyl-isoxazole and benzoyl chloride by the method described in Example 3. Crude product was chromatographed on silica gel with EtOAc/hexanes (10 then 20%) as eluant to afford product as a colorless solid (118 mg, 70%). 1H NMR (CDCl3) 2.33 (d, J=1.3, 3 H), 7.43-7.59 (m, 4 H), 7.62 (d, J=4.0, 1 H), 7.80-7.83 (m, 2 H). 13C NMR 7.9, 118.7 (q, J =271), 128.8, 128.9, 129.4, 133.0, 134.8, 136.3, 137.7, 145.8, 155.5 (q, J=40), 157.9, 188.0. 19F NMR −63.1. LC/MS 7.29 min, [M+1]+ 338.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[C:7](=[O:22])[C:8]4[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][C:9]=4[C:10]([CH3:16])([CH3:15])[C:11]=3[NH:12]2)=[CH:4][CH:3]=1.Cl[CH2:24][CH2:25][N:26]([CH2:29][CH3:30])[CH2:27][CH3:28].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[Cl:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[C:7](=[O:22])[C:8]4[CH:20]=[CH:19][C:18]([O:21][CH2:24][CH2:25][N:26]([CH2:29][CH3:30])[CH2:27][CH3:28])=[CH:17][C:9]=4[C:10]([CH3:16])([CH3:15])[C:11]=3[NH:12]2)=[CH:4][CH:3]=1
Reactant: CC1(C)c2cc(O)ccc2C(=O)c2c1[nH]c1cc(Cl)ccc21
Reactant: CCN(CC)CCCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN(CC)CCOc1ccc2c(c1)C(C)(C)c1[nH]c3cc(Cl)ccc3c1C2=O
Temperature: 80 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
3-Chloro-8-hydroxy-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one (Compound S2-1, 10 mg, 0.03207 mmol) was dissolved in DMF (0.1 mL), added with (2-chloroethyl)diethylamine (5.5 mg, 0.03207 mmol) and cesium carbonate (20.9 mg, 0.06414 mmol), and stirred at 80° C. for 2 hr. The reaction solution was added to water and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate. The residues obtained after concentration under reduced pressure were purified by NH silica gel column chromatography (ethyl acetate/hexane) to obtain the title compound (11.6 mg, 76%).
Reaction SMILES: [CH3:1][N:2]([CH2:46][CH:47]([OH:56])[CH:48]([OH:55])[CH:49]([OH:54])[CH:50]([OH:53])[CH2:51][OH:52])[C:3](=[O:45])[CH2:4][CH2:5][CH2:6][CH:7]=[CH:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[CH:18]([CH2:19][CH2:20][CH:21]([O:29][Si](C(C)(C)C)(C)C)[C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[C:17](=[O:37])[N:16]2[C:38]2[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=2)=[CH:11][CH:10]=1.Cl.[OH-].[Na+]>CO>[CH3:1][N:2]([CH2:46][CH:47]([OH:56])[CH:48]([OH:55])[CH:49]([OH:54])[CH:50]([OH:53])[CH2:51][OH:52])[C:3](=[O:45])[CH2:4][CH2:5][CH2:6][CH:7]=[CH:8][C:9]1[CH:10]=[CH:11][C:12]([CH:15]2[CH:18]([CH2:19][CH2:20][CH:21]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[OH:29])[C:17](=[O:37])[N:16]2[C:38]2[CH:39]=[CH:40][C:41]([F:44])=[CH:42][CH:43]=2)=[CH:13][CH:14]=1
Reactant: CN(CC(O)C(O)C(O)C(O)CO)C(=O)CCCC=Cc1ccc(C2C(CCC(O[Si](C)(C)C(C)(C)C)c3ccc(F)cc3)C(=O)N2c2ccc(F)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CN(CC(O)C(O)C(O)C(O)CO)C(=O)CCCC=Cc1ccc(C2C(CCC(O)c3ccc(F)cc3)C(=O)N2c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
70 mg of N-methyl-N-(2,3,4,5,6-pentahydroxyhexyl)-6-{4-[3-[3-(tert-butyldimethylsilanyloxy)-3-(4-fluorophenyl)propyl]-1-(4-fluorophenyl)-4-oxoazetidin-2-yl]phenyl}hex-5-enamide are dissolved in 6 ml of methanol. 0.1 N HCl(aq) is then added, and the mixture is stirred at room temperature overnight. The mixture is then neutralized with 1 N aqueous sodium hydroxide solution and concentrated using a rotary evaporator. The residue is stirred with dichloromethane and filtered and the mother liquor is concentrated using a rotary evaporator. The product is obtained following purification by preparative HPLC: C31H44F2N2O8 (682) MS (ESI): M+−18
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[N+:12]([O-])([OH:14])=[O:13]>S(=O)(=O)(O)O>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]([N+:12]([O-:14])=[O:13])[CH:6]=1)(=[O:3])=[O:4]
Reactant: O=[N+]([O-])O
Reactant: Cc1ccc(S(C)(=O)=O)cc1
Agent: O=S(=O)(O)O
Product: Cc1ccc(S(C)(=O)=O)cc1[N+](=O)[O-]
Temperature: 10 °C
Reaction time: 2 h

Procedure:
68 g of 4-methylsulfonyltoluene in 400 ml of concentrated sulfuric acid were admixed at 0°-10° C. with a mixture of 80 ml of concentrated sulfuric acid and 31 ml of 65% strength by weight nitric acid. The reaction mixture was stirred at 10° C. for 2 hours and at room temperature for a further 2 hours. It was then poured onto about 1 kg of ice, and the solids were filtered off with suction, washed with water and dried at 50° C. under reduced pressure, to leave 85 g of 4-methylsulfonyl-2-nitrotoluene (melting point 112°-115° C.).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([S:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)[N:4]=1.C[O:16][C:17](=[O:30])[CH2:18][CH:19]1[CH2:21][CH:20]1[C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[C:24]([F:29])[CH:23]=1>>[CH:10]1([S:9][C:5]2[N:4]=[C:3]([CH2:2][O:28][C:25]3[CH:26]=[CH:27][C:22]([CH:20]4[CH2:21][CH:19]4[CH2:18][C:17]([OH:30])=[O:16])=[CH:23][C:24]=3[F:29])[CH:8]=[CH:7][CH:6]=2)[CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: ClCc1cccc(SC2CCCC2)n1
Reactant: COC(=O)CC1CC1c1ccc(O)c(F)c1
Product: O=C(O)CC1CC1c1ccc(OCc2cccc(SC3CCCC3)n2)c(F)c1
Yield: 90.6 %

Procedure:
2-Chloromethyl-6-cyclopentylsulfanyl-pyridine (0.026 g, 0.11 mmol) obtained in Step C of Preparation Example 27 and [2-(3-fluoro-4-hydroxy-phenyl)-cyclopropyl]-acetic acid methyl ester (0.026 g, 0.11 mmol) obtained in Step F of Preparation Example 53 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (0.040 g, 87%).
Reaction SMILES: S(=O)(=O)(O)O.[CH3:6][NH:7][C:8](=[O:18])[C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[C:11]([NH2:16])[C:10]=1[Cl:17].O[CH2:20][S:21]([C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=1)(=[O:23])=[O:22]>O>[CH3:6][NH:7][C:8](=[O:18])[C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[C:11]([NH:16][CH2:20][S:21]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)(=[O:23])=[O:22])[C:10]=1[Cl:17]
Reactant: O=S(=O)(CO)c1ccc(Cl)cc1
Reactant: CNC(=O)c1cc(Cl)cc(N)c1Cl
Agent: O=S(=O)(O)O
Solvent: O
Product: CNC(=O)c1cc(Cl)cc(NCS(=O)(=O)c2ccc(Cl)cc2)c1Cl
Temperature: 25 °C
Yield: 83.8 %

Procedure:
0.8 g of concentrated sulfuric acid was added to 1.8 g (8.2 mmoles) of 2,5-dichloro-3-aminobenzoic acid N-methylamide, 1.87 g (9 mmoles) of hydroxymethyl-(4-chlorophenyl)-sulfone and 50 ml of water whilst stirring at room temperature. The mixture was stirred for a further 2 hours at room temperature and the solid was then filtered off, washed with water and recrystallized from acetonitrile. 2.8 g (83% of theory) of 2,5-dichloro-3-[(4-chlorophenyl)-sulfonylmethylamino]-benzoic acid N-methylamide were obtained in the form of a colorless solid of melting point 175°-182° C (with decomposition).
Reaction SMILES: [I:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([O:12][CH:13]([S:17][CH3:18])[C:14]([OH:16])=O)=[CH:7][CH:6]=2.[C:19]([NH2:23])([CH3:22])([CH3:21])[CH3:20]>>[C:19]([NH:23][C:14](=[O:16])[CH:13]([O:12][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[N:4]=[CH:3][C:2]([I:1])=[CH:11]2)[S:17][CH3:18])([CH3:22])([CH3:21])[CH3:20]
Reactant: CSC(Oc1ccc2ncc(I)cc2c1)C(=O)O
Reactant: CC(C)(C)N
Product: CSC(Oc1ccc2ncc(I)cc2c1)C(=O)NC(C)(C)C

Procedure:
In a similar procedure to Stage 2 of Example 1, (3-iodo-quinolin-6-yloxy)-methylsulfanyl-acetic acid was condensed with t-butylamine to give N-tert-butyl-2-(3-iodo-quinolin-6-yloxy)-2-methylsulfanyl-acetamide as a white solid (MH+ 431).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[O:11][C:10](=[O:13])[C:9]([C:14]([OH:16])=O)=[CH:8]2.S(Cl)([Cl:19])=O>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[O:11][C:10](=[O:13])[C:9]([C:14]([Cl:19])=[O:16])=[CH:8]2
Reactant: O=S(Cl)Cl
Reactant: COc1cccc2cc(C(=O)O)c(=O)oc12
Product: COc1cccc2cc(C(=O)Cl)c(=O)oc12

Procedure:
A mixture of 8-methoxycoumarin-3-carboxylic acid (0.66 g) and thionyl chloride (2.5 ml) was heated under reflux for one and half hours. Distilling off the excess thionyl chloride in vacuo gave 8-methoxycoumarin-3-carboxylic acid chloride. Reaction of this product with amoxycillin, 1.257 g, in the same manner as in example 16, yielded D(-)-α-(8-methoxycoumarin-3-carbonamido)-p-hydroxybenzylpenicillin (0.95 g), melting at 187°-9° C. (dec.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])=[CH:10][CH3:11])[CH:6]=[CH:7][CH:8]=1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[Br:37]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:37][CH2:11][CH:10]=[C:9]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:18]
Reactant: CC=C(c1cccc(OC)c1)c1ccccc1C
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COc1cccc(C(=CCBr)c2ccccc2C)c1
Reaction time: 8 h

Procedure:
A mixture of 1-(3-methoxyphenyl)-1-(2-methylphenyl)-1-propene (18.3 g, 0.077 mol), carbon tetrachloride (80 ml), benzoylperoxide (0.15 g) and N-bromosuccinimide (14.2 g, 0.080 mol) was heated at reflux temperature for 5 h. The reaction mixture was left overnight at room temperature, filtered and the filtrate was evaporated in vacuo to give 3-bromo-1-(3-methoxyphenyl)-1-(2-methylphenyl)-1-propene in a quantitative yield.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:30])([CH3:29])[CH2:13][C:14]([NH:16][C@@H:17]1[CH2:23][CH2:22][C:21]2[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=2[NH:19][C:18]1=[O:28])=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:34][C:35]1[CH:40]=[CH:39][C:38]([C:41]2[C:42]([C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])=[CH:43][CH:44]=[CH:45][CH:46]=2)=[CH:37][CH:36]=1.[Br-]>CN(C)C=O>[CH3:53][C:50]([O:49][C:47]([C:42]1[C:41]([C:38]2[CH:37]=[CH:36][C:35]([CH2:34][N:19]3[C:20]4[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=4[CH2:22][CH2:23][C@@H:17]([NH:16][C:14](=[O:15])[CH2:13][C:12]([CH3:30])([NH:11][C:9]([O:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[O:10])[CH3:29])[C:18]3=[O:28])=[CH:40][CH:39]=2)=[CH:46][CH:45]=[CH:44][CH:43]=1)=[O:48])([CH3:51])[CH3:52]
Reactant: CC(C)(C)OC(=O)c1ccccc1-c1ccc(CBr)cc1
Reactant: CC(C)(CC(=O)N[C@@H]1CCc2ccccc2NC1=O)NC(=O)OCc1ccccc1
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(CC(=O)N[C@@H]1CCc2ccccc2N(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)C1=O)NC(=O)OCc1ccccc1
Reaction time: 0.33 h
Yield: 85.8 %

Procedure:
To a solution of 1.22 g (3.0 mmol) of 3-benzyloxycarbonylamino-3-methyl-N-[2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl]-butanamide (Example 1, Step F) in 10 mL of dry dimethylformamide under nitrogen was added 131.6 mg (3.92 mmol) of 60% sodium hydride in oil. After stirring for 20 minutes, a solution of 1.14 g (3.29 mmol) of t-butyl 4'-bromomethyl-1,1'-biphenyl-2-carboxylate (prepared according to the procedure of D. J. Carini, et. al. EPO publication 324.377) in 2.5 mL of dimethylformamide was added by cannula. The flask which originally contained the bromide was rinsed with 2.5 mL dimethylformamide which was added to the reaction mixture. After stirring at room temperature for 2 hours, the reaction has diluted with 400 mL of ethyl acetate, washed with 100 mL of water and 100 mL of brine. The organic layer was dried over magnesium sulfate, filtered and the solvent removed under vacuum. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate/hexane (55:45) to afford 1.74 g (96%) of the product as a white foam. 1H NMR (200MHz,CDCl3): 1.15 (s,9H), 1.45 (s,3H), 1.48 (s,3H), 1.76 (m,1H), 2.35-2.62 (m,5H), 4.48 (m,1H), 4.79 (d,14Hz,1H), 5.04 (t,12Hz,2H), 5.35 (d, 14Hz,1H), 6.70 (d,6Hz,1H), 7.10-7.45 (m,17H), 7.72 (m,1H). FAB-MS: calculated for C41H45N3O6 675; found 683 (M+Li).
Reaction SMILES: [CH:1]1([C:5]2[C:14]([C:15](=O)[CH2:16][C:17](=O)[CH2:18][CH3:19])=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([CH3:22])[CH:6]=2)[CH2:4][CH2:3][CH2:2]1.[NH2:23][NH2:24].O>CO>[CH:1]1([C:5]2[C:14]([C:15]3[CH:16]=[C:17]([CH2:18][CH3:19])[NH:24][N:23]=3)=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([CH3:22])[CH:6]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: NN
Reactant: CCC(=O)CC(=O)c1cc(C(=O)OC)c(C)cc1C1CCC1
Solvent: O
Solvent: CO
Product: CCc1cc(-c2cc(C(=O)OC)c(C)cc2C2CCC2)n[nH]1
Reaction time: 1.5 h
Yield: 64 %

Procedure:
To a solution of methyl 4-cyclobutyl-2-methyl-5-(3-oxopentanoyl)benzoate (compound 445.1, 300 mg, 0.990 mmol, 1.00 equiv) in methanol (15 mL) was added NH2NH2.H2O. The resulting solution was stiffed for 1.5 h at 80° C. in an oil bath, and then concentrated under reduced pressure. The residue was diluted with 100 mL of ethyl acetate, then washed with 3×100 mL of brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified using silica gel column chromatography with ethyl acetate/petroleum ether (1:5) as eluent to yield 188 mg (64%) of the title compound as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:30]=[C:29]([N+:31]([O-])=O)[CH:28]=[CH:27][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[CH:26]=[CH:25][C:17]([CH2:18][N:19]4[CH2:23][CH2:22][CH2:21][C:20]4=[O:24])=[CH:16][CH:15]=3)[S:13][C:6]=12.[Cl-].[NH4+]>CCO.O.[Fe]>[NH2:31][C:29]1[CH:28]=[CH:27][C:3]([O:4][C:5]2[CH:10]=[CH:9][N:8]=[C:7]3[CH:11]=[C:12]([C:14]4[CH:26]=[CH:25][C:17]([CH2:18][N:19]5[CH2:23][CH2:22][CH2:21][C:20]5=[O:24])=[CH:16][CH:15]=4)[S:13][C:6]=23)=[C:2]([F:1])[CH:30]=1
Reactant: O=C1CCCN1Cc1ccc(-c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Nc1ccc(Oc2ccnc3cc(-c4ccc(CN5CCCC5=O)cc4)sc23)c(F)c1
Temperature: 80 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
The reaction mixture consisting of the nitro compound 203 (580 mg, 1.25 mmol), iron powder (594 mg, 10.64 mmol), and ammonium chloride (57.6 mg, 1.076 mmol) in EtOH/water mixture (16 mL/8 mL) was stirred for 2 hr at 80° C. The reaction mixture was filtered while hot. The filtrate was concentrated to give title compound 204 (542 mg, 100% yield) as a brown solid. MS: 434 (MH)+.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.CC1C=CC(S(O[CH2:21][CH2:22][CH2:23][NH:24][C:25]2[C:26](=[O:42])[N:27]([C:38]([CH3:41])([CH3:40])[CH3:39])[S:28](=[O:37])(=[O:36])[C:29]=2[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)(=O)=O)=CC=1>>[C:38]([N:27]1[C:26](=[O:42])[C:25]([NH:24][CH2:23][CH2:22][CH2:21][O:9][C:6]2[CH:7]=[CH:8][C:3]([CH2:2][OH:1])=[CH:4][CH:5]=2)=[C:29]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[S:28]1(=[O:36])=[O:37])([CH3:39])([CH3:40])[CH3:41]
Reactant: OCc1ccc(O)cc1
Reactant: Cc1ccc(S(=O)(=O)OCCCNC2=C(c3ccccc3)S(=O)(=O)N(C(C)(C)C)C2=O)cc1
Product: CC(C)(C)N1C(=O)C(NCCCOc2ccc(CO)cc2)=C(c2ccccc2)S1(=O)=O
Yield: 34 %

Procedure:
The title compound was prepared as described for Example 12 from 4-(hydroxymethyl)phenol and 3-[(2-tert-butyl-1,1-dioxido-3-oxo-5-phenyl-2,3-dihydroisothiazol-4-yl)amino]propyl 4-methylbenzenesulfonate. Purified by silica gel column chromatography (Horizons Biotage) using 0-10% EtOAc in DCM as eluent to give the title compound (0.037 mg, 34%) as a solid. 1H NMR (500 MHz CDCl3): δ 7.54-7.48 (m, 2H), 7.46-7.40 (m, 3H), 7.29 (d, 2H), 6.85 (d, 2H), 5.74 (t, 1H), 4.64 (s, 2H), 3.90 (t, 2H), 3.11-3.00 (m, 2H), 1.87-1.82 (m, 2H), 1.75 (s, 9H); 13C NMR (125 MHz CDCl3): δ 159.8, 158.2, 135.3, 133.8, 131.8, 129.8, 128.9, 128.8, 125.3, 114.7, 107.2, 66.1, 65.2, 61.7, 42.5, 28.9, 27.8, Mass Spectrum M+H+ 445.
Reaction SMILES: [CH3:1][N:2]([C:4](=[O:28])[C:5]([N:7]([CH3:27])[CH:8]1[CH2:14][N:13]([CH2:15][CH3:16])[CH2:12][CH2:11][N:10]2[C:17](=[O:26])[C:18]([OH:25])=[C:19]([C:21]([O:23]C)=O)[N:20]=[C:9]12)=[O:6])[CH3:3].C(N(CC)CC)C.[F:36][C:37]1[CH:44]=[CH:43][C:40]([CH2:41][NH2:42])=[CH:39][C:38]=1[CH3:45]>CO>[CH2:15]([N:13]1[CH2:14][CH:8]([N:7]([CH3:27])[C:5](=[O:6])[C:4]([N:2]([CH3:3])[CH3:1])=[O:28])[C:9]2=[N:20][C:19]([C:21]([NH:42][CH2:41][C:40]3[CH:43]=[CH:44][C:37]([F:36])=[C:38]([CH3:45])[CH:39]=3)=[O:23])=[C:18]([OH:25])[C:17](=[O:26])[N:10]2[CH2:11][CH2:12]1)[CH3:16]
Reactant: Cc1cc(CN)ccc1F
Reactant: CCN1CCn2c(nc(C(=O)OC)c(O)c2=O)C(N(C)C(=O)C(=O)N(C)C)C1
Solvent: CO
Solvent: CCN(CC)CC
Product: CCN1CCn2c(nc(C(=O)NCc3ccc(F)c(C)c3)c(O)c2=O)C(N(C)C(=O)C(=O)N(C)C)C1
Temperature: 25 °C

Procedure:
Crude methyl 10-[[(dimethylamino)(oxo)acetyl](methyl)amino]-8-ethyl-3-hydroxy-4-oxo-4,6,7,8,9,10-hexahydropyrimido[1,2-d][1,4]diazepine-2-carboxylate was dissolved in methanol and treated with 1.2 eq. of triethylamine and 1.2 eq. of 4-fluoro-3-methylbenzylamine. The reaction mixture was refluxed overnight, then cooled to room temperature and purified by RP HPLC (C18, 5 μM, H2O/MeCN with 1% of TFA as eluant) affording desired compound as a white solid. 1H NMR (300 MHz, CD3CN) δ 12.4 (bs, 1H), 9.74 (bs, 1H), 7.26-7.16 (m, 2H), 6.96 (t, J=8.62 Hz, 1H), 5.40-5.22 (m, 2H), 4.51 (dd, J=14.6 Hz, J=6.86 Hz, 1H), 4.42 (dd, J=14.6 Hz, J=6.41 Hz, 1H), 4.18-3.92 (m, 3H), 3.78-3.73 (ms, 1H), 3.28-3.18 (m, 3H), 3.01 (s, 3H), 2.95 (s, 3H), 2.93 (s, 3H), 2.21 (s, 3H), 1.30 (t, J=5.97 Hz, 3H). MS (ES) C24H31FN6O5 requires 502. Found: 503 (M+H+).
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]3=[CH:7][C:6]=2[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=1.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1>>[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]4=[CH:7][C:6]=3[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=2)=[CH:23][CH:22]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: N#Cc1cc(Br)c2c(c1)cc1n2CCCNC1=O
Product: COc1ccc(-c2cc(C#N)cc3cc4n(c23)CCCNC4=O)cc1

Procedure:
The title compound, light grey solid (73 mg, 88%), MS (ISP) m/z=332.5 [(M+H)+], mp 260.5° C., was prepared in accordance with the general method of example 1 from 7-bromo-1-oxo-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indole-9-carbonitrile (intermediate 20) (76.0 mg, 0.25 mmol) and commercially available 4-methoxy-phenylboronic acid (49.4 mg, 0.325 mmol).
Reaction SMILES: [NH2:1][C:2]1[C:3](Br)=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([CH3:15])([CH3:14])[N:8]=[C:7]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:22])[C:6]=2[C:23]=1Br>C(Cl)Cl.C1CCCCC1>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([CH3:15])([CH3:14])[N:8]=[C:7]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:22])[C:6]=2[CH:23]=1
Reactant: CN1C(=O)C(C)(C)N=C(c2ccccc2Cl)c2c1cc(Br)c(N)c2Br
Solvent: ClCCl
Solvent: C1CCCCC1
Product: CN1C(=O)C(C)(C)N=C(c2ccccc2Cl)c2cc(N)ccc21

Procedure:
From 20 g (0.061 mol) of 7-amino-5-(o-chlorophenyl)-1,3-dihydro-1,3,3-trimethyl-2H-1,4-benzodiazepin-2-one there is obtained, in analogy to the details of Example 45, 7-amino-6,8-dibromo-5-(o-chlorophenyl)-1,3-dihydro-1,3,3-trimethyl-2H-1,4-benzodiazepin-2-one of melting point 110° (methylene chloride/cyclohexane).
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[CH:24]([CH:27]1[NH:31][C:30](=[O:32])[N:29]([CH3:33])[C:28]1=[O:34])([CH3:26])[CH3:25]>>[CH3:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:4]=[CH:3][C:2]([N:31]4[CH:27]([CH:24]([CH3:25])[CH3:26])[C:28](=[O:34])[N:29]([CH3:33])[C:30]4=[O:32])=[N:7][CH:6]=3)=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)nc3)CC2)c(C)c1
Reactant: CC(C)C1NC(=O)N(C)C1=O
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)N(C)C(=O)C4C(C)C)nc3)CC2)c(C)c1
Yield: 55 %

Procedure:
Using (6-bromopyridin-3-yl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (150 mg) described in Preparation Example 127 and 5-isopropyl-3-methylimidazolidine-2,4-dione (69 mg) described in Preparation Example 216 and by the reaction and treatment in the same manner as in Example 536, the title compound (99 mg) was obtained.