Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][N:7]=1)(=O)C.C(N(CC)CC)C.C(OCC)(=O)C.C([O-])(=O)C>Cl>[OH:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][N:7]=1
Reactant: CC(=O)OCc1ccc(C)cn1
Agent: CC(=O)[O-]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Cc1ccc(CO)nc1
Yield: 83.5 %

Procedure:
2-Acetoxymethyl-5-methyl pyridine (30 g, 182 mmol) was dissolved in hydrochloric acid (100 mL, 4 N). The mixture was heated under reflux, until TLC (silica gel; triethylamine:ethyl acetate:petroleum ether 40-60=1:9:19) showed complete absence of the acetate (normally 1 hour). The mixture was cooled, brought to pH>11, extracted with dichloromethane (3×50 mL) and the solvent removed in vacuo. Pure 2-hydroxymethyl-5-methyl pyridine (18.80 g, 152 mmol, 84%) was obtained by Kugelrohr distillation (p=20 mm Hg, T=130° C.) as a slightly yellow oil.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[C:7]([O:11][CH2:12][CH3:13])(=[O:10])[C:8]#[CH:9]>ClCCl.CN(C)C=O>[S:3]1[CH:4]=[CH:5][N:6]=[C:2]1[NH:1]/[CH:9]=[CH:8]/[C:7]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: Nc1nccs1
Reactant: C#CC(=O)OCC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(=O)/C=C/Nc1nccs1
Yield: 51 %

Procedure:
A solution of 2.3 g of 2-aminothiazole and 1.55 ml of ethyl propiolate in 10 ml of dichloromethane and 5 ml of dimethylformamide was stirred at ambient temperature for 3 days. The resulting mixture was filtered, and the filtrate was concentrated in vacuo. The residue was chromatographed on silica gel using first 20% then 40% ethyl acetate in hexane to provide 1.54 g (51%) of the desired compound. 1H NMR (CDCl3) δ1.30 (t, J=7 Hz, 3H), 4.22 (q, J=7 Hz, 2H), 5.79 (d, J=15 Hz, 1H), 6.03 (d, J=5 Hz, 1H), 6.68 (d, J=5 Hz, 1H), 7.47 (br, 1H), 8.17 (d, J=15 Hz, 1H). Mass spectrum: (M+H)+ =199.
Reaction SMILES: O.[OH-].[Li+].C([O:6][C:7](=[O:32])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]([C:23](=[O:31])[NH:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:14](=[O:22])[NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)C>O.C(O)C>[C:16]1([NH:15][C:14]([CH:13]([C:23](=[O:31])[NH:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][C:7]([OH:32])=[O:6])=[O:22])[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CCOC(=O)CCCCCC(C(=O)Nc1ccccc1)C(=O)Nc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)CCCCCC(C(=O)Nc1ccccc1)C(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 95.5 %

Procedure:
A solution of lithium hydroxide monohydrate (0.17 g, 4.05 mmol) in water (5 mL) was added to a stirred solution of 7,7-bis-phenylcarbamoyl-heptanoic acid ethyl ester (16a) (1.07 g, 2.7 mmol) in ethanol (50 mL) at 0° C. The mixture was allowed to warm to room temperature and stirred for 16 hours. The solvent was removed under reduced pressure and the resulting residue was taken up in water (50 mL), washed with ethyl acetate (60 mL) and acidified with 1 M hydrochloric acid. The aqueous layer was extracted with ethyl acetate (3×60 mL), and the combined extracts were dried (MgSO4), filtered and organic solvent evaporated to give 7,7-bis-phenylcarbamoyl-heptanoic acid (16b) as a white solid (0.95 g, 95%); Rf=0.25 (3:1, petroleum ether 60-80° C.:ethyl acetate); 1H NMR (300 MHz, CDCl3): δ 9.83 (2H, s, NH), 7.56 (4H, d, J=7.8 Hz, Ar—H), 7.32 (4H, t, J=8.1 Hz, Ar—H), 7.14 (2H, t, J=7.6 Hz, Ar—H), 3.43 (1H, t, J=7.2 Hz, COCH), 2.58 (2H, t, J=7.1 Hz, CH2CO), 1.86 (2H, br m, CHCH2CH2CH2CH2), 1.49 (2H, t, J=7.1 Hz, CHCH2), 1.33 (4H, br m, CHCH2CH2CH2); 13C NMR (75 MHz, CDCl3): δ 172.10 (CO), 170.17 (CO), 137.13 (quaternary Ar—C), 128.73 (Ar—C—H), 124.68 (Ar—C—H), 120.52 (Ar—C—H), 56.32 (COCH), 34.18 (CH2CO), 33.43 (CHCH2CH2CH2), 28.32 (CHCH2), 27.23 (CHCH2CH2), 24.54 (CHCH2CH2CH2CH2).
Reaction SMILES: [C:1]([OH:11])(=[O:10])[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[Cl:12][S:13](O)(=[O:15])=[O:14]>>[Cl:12][S:13]([C:6]1[CH:7]=[C:2]([CH:3]=[CH:4][C:5]=1[O:8][CH3:9])[C:1]([OH:11])=[O:10])(=[O:15])=[O:14]
Reactant: COc1ccc(C(=O)O)cc1
Reactant: O=S(=O)(O)Cl
Product: COc1ccc(C(=O)O)cc1S(=O)(=O)Cl
Temperature: 90 °C
Reaction time: 0.5 h

Procedure:
A stirred solution of chlorosulfonic acid (90 mL) at room temperature is treated with p-anisic acid (40 g), portionwise, during 30 minutes. When the addition is complete, the mixture is stirred at 90° C. for 75 minutes, then it is cooled and poured onto ice. The white precipitate is collected and dissolved in ethyl acetate (300 mL). The organic extract is washed with brine (2×250 mL), dried over magnesium sulfate, and concentrated, to give 3-chlorosulfonyl-4-methoxybenzoic acid (34 g), in the form of a white solid m.p. 168-170° C.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]2[C:20](=[O:21])[C:19]([CH2:22]Cl)=[C:18]([CH3:24])[N:17]([CH3:25])[C:16]2=[O:26])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5].C(=O)(O)[O-:28].[Na+]>COCCOC.O>[Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]2[C:20](=[O:21])[C:19]([CH2:22][OH:28])=[C:18]([CH3:24])[N:17]([CH3:25])[C:16]2=[O:26])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5]
Reactant: O=C([O-])O
Reactant: Cc1c(CCl)c(=O)n(-c2cc(C(=O)OC(C)C)c(Cl)cc2F)c(=O)n1C
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cc1c(CO)c(=O)n(-c2cc(C(=O)OC(C)C)c(Cl)cc2F)c(=O)n1C

Procedure:
A solution of 1.14 g of isopropyl 2-chloro-4-fluoro-5-[5-chloromethyl-3,6-dihydro-3,4-dimethyl-2,6-dioxo-1(2H)-pyrimidinyl]-benzoate in 20 ml 1,2-dimethoxyethane is stirred at room temperature for 3 hours with a solution of 0.47 g of sodium bicarbonate in 10 ml of water. The solvent is evaporated off under reduced pressure and the residue is extracted with ethyl acetate. The organic phase is dried over anhydrous sodium sulphate and evaporated to dryness. The residue is purifed by chromatography on a silica gel column using methylene chloride/ethyl acetate (2:1) as the eluent. There is obtained isopropyl 2-chloro-4-fluoro-5-[3,6-dihydro-3,4-dimethyl-5-hydroxymethyl-2,6-dioxo-1(2H)-pyrimidinyl]-benzoate, 1H--NMR (CDCl3, 400 MHz) 7.83 ppm (d, 1H), 7.35 ppm (d, 1H), 5.24 ppm (m, 1H), 4.59 ppm (d, 1H), 4.54 ppm (d, 1H), 3.50 ppm (s, 3H), 2.44 ppm (s, 3H), 2.34 ppm (s, approx. 1H, very broad), 1.36 ppm (d, 6H).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH2:26][CH3:27])[CH2:23][CH2:22][C:21]([C:28]([NH:30][C:31]4[CH:36]=[CH:35][C:34]([S:37][CH2:38][CH2:39][C:40]5[N:44]([CH2:45][CH2:46][CH3:47])[CH:43]=[N:42][N:41]=5)=[CH:33][CH:32]=4)=[O:29])=[CH:20][C:19]=3[CH:48]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:57])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH2:26][CH3:27])[CH2:23][CH2:22][C:21]([C:28]([NH:30][C:31]4[CH:32]=[CH:33][C:34]([S:37]([CH2:38][CH2:39][C:40]5[N:44]([CH2:45][CH2:46][CH3:47])[CH:43]=[N:42][N:41]=5)=[O:57])=[CH:35][CH:36]=4)=[O:29])=[CH:20][C:19]=3[CH:48]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCCc4nncn4CCC)cc2)CCN3CCC)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)CCc4nncn4CCC)cc2)CCN3CCC)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 60 %

Procedure:
7-[4-(2-butoxyethoxy)phenyl]-1-propyl-N-[4-[2-(4-propyl-4H-1,2,4-triazol-3-yl)ethylthio]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (0.7 g) was dissolved in dichloromethane (50 ml), and the mixture was cooled to −78° C. To the mixture, a solution of 3-chloroperbenzoic acid (0.39 g) in dichloromethane (5 ml) was added dropwise. The mixture was stirred for 1 hour at −78° C., and then, sodium thiosulfate solution was added to the mixture, and the mixture was concentrated, and extracted with ethyl acetate. The organic layer was washed with sodium bicarbonate solution, water and saturated brine, and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off. The residue was purified by silica gel column chromatography (elution solvent: triethylamine/methanol/ethyl acetate), to give 7-[4-(2-butoxyethoxy)phenyl]-1-propyl-N-[4-[2-(4-propyl-4H-1,2,4-triazol-3-yl)ethylsulfinyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 52) (0.43 g) as pale yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][CH2:7][NH:8][C:9]([C:11]2[CH:30]=[CH:29][C:14]([O:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:18][C:17]=3Br)=[CH:13][CH:12]=2)=[O:10])=[CH:4][CH:3]=1.[CH3:33][S:34]([C:37]1[CH:38]=[C:39](B(O)O)[CH:40]=[CH:41][CH:42]=1)(=[O:36])=[O:35].C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][CH2:7][NH:8][C:9]([C:11]2[CH:30]=[CH:29][C:14]([O:15][C:16]3[C:17]([C:41]4[CH:40]=[CH:39][CH:38]=[C:37]([S:34]([CH3:33])(=[O:36])=[O:35])[CH:42]=4)=[CH:18][C:19]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:20][CH:21]=3)=[CH:13][CH:12]=2)=[O:10])=[CH:4][CH:3]=1
Reactant: CCOC(=O)Cc1ccc(Oc2ccc(C(=O)NCCc3ccc(Cl)cc3)cc2)c(Br)c1
Reactant: CS(=O)(=O)c1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)Cc1ccc(Oc2ccc(C(=O)NCCc3ccc(Cl)cc3)cc2)c(-c2cccc(S(C)(=O)=O)c2)c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 70 %

Procedure:
Ethyl 2-(4-(4-((4-chlorophenethyl)carbamoyl)phenoxy)-3-bromophenyl)acetate (Example 46 step C; 100 mg, 0.193 mmol), 3-(methanesulfonyl)phenylboronic acid (58.1 mg, 0.290 mmol), K2CO3 (80.2 mg, 0.580 mmol) and Pd(PPh3)4 (22.4 mg, 0.0193 mmol) were diluted with dioxane (2 mL) and water (1 mL). The reaction was purged three times with nitrogen and stirred at 60° C. overnight. The reaction was cooled and loaded directly onto a silica gel column eluting with hexanes:ethyl acetate (2:1) to yield ethyl 2-(6-(4-(4-chlorophenethylcarbamoyl)phenoxy)-3′-(methylsulfonyl)biphenyl-3-yl)acetate (80 mg, 69.8% yield).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([Cl:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([F:24])[CH:3]=1.[CH3:25][C@@H:26]1[CH2:30][O:29][C:28](=[O:31])[NH:27]1>>[Cl:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([N:27]4[C@H:26]([CH3:25])[CH2:30][O:29][C:28]4=[O:31])=[CH:3][C:4]=3[F:24])=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=1
Reactant: C[C@@H]1COC(=O)N1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3F)CC2)c(Cl)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)OC[C@H]4C)cc3F)CC2)c(Cl)c1
Yield: 95.5 %

Procedure:
By reaction and treatment in the same manner as in Example 1 and using (4-bromo-2-fluorophenyl)[4-(3-chloro-5-methylpyridin-2-yl)piperazin-1-yl]methanone (626 mg) described in Preparation Example 110 and (R)-4-methyloxazolidin-2-one (227 mg) described in Preparation Example 25, the title compound (627 mg) was obtained.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([OH:11])[C:8]([CH3:12])=[CH:7][C:6]=1[S:13][S:14]([C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=1)(=[O:16])=[O:15])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.[C:31]([NH:35][S:36](Cl)(=[O:38])=[O:37])([CH3:34])([CH3:33])[CH3:32]>CCOCC>[C:1]([C:5]1[CH:10]=[C:9]([O:11][S:36](=[O:38])(=[O:37])[NH:35][C:31]([CH3:34])([CH3:33])[CH3:32])[C:8]([CH3:12])=[CH:7][C:6]=1[S:13][S:14]([C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=1)(=[O:15])=[O:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)NS(=O)(=O)Cl
Reactant: Cc1ccc(S(=O)(=O)Sc2cc(C)c(O)cc2C(C)(C)C)cc1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: Cc1ccc(S(=O)(=O)Sc2cc(C)c(OS(=O)(=O)NC(C)(C)C)cc2C(C)(C)C)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a round bottom flask equipped with a magnetic stirrer were added 1.10 g (3.20 mmol) of toluene-4-thiosulfonic acid S-(2-tert-butyl-4-hydroxy-5-methyl-phenyl) ester (prepared in Example RRR), Et2O (50 mL), and 0.90 mL (6.40 mmol) of NEt3, in that order. The solution was cooled to 0° C. To this solution was rapidly added a solution of 1.10 g (6.40 mmol) of (tert-butyl amino)sulfonyl chloride (Matler, W. L., Comer, W. T., and Deitchman, D., Journal of Medicinal Chemistry, 1972,15 (5), 538-541) in Et2O (10 mL). A precipitate ensued and the reaction was allowed to stir for 30 minutes. Another two equivalents of (tert-butyl amino)sulfonyl chloride (1.10 g, 6.40 mmol) in Et2O (10 mL) and NEt3 (0.90 mL, 6.40 mmol) were added, and the reaction mixture was stirred for another 30 minutes. The reaction was quenched with brine and the organics extracted with Et2O. The organics were dried (MgSO4) and concentrated. The residue was submitted to flash chromatography (EtOAc:CHCl3 1:9) to yield the title compound. 1H NMR (CDCl3) δ 1.23 (s, 9 H), 1.46 (s, 9 H), 2.25 (s, 3 H), 2.42 (s, 3 H), 4.63 (br s, 1 H), 7.23 (s, 1 H), 7.26 (s, obscured by CDCl3, 1 H), 7.42 (d, 2 H), 7.46 (d, 2 H).
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[O:17]1[CH2:22][CH2:21][N:20]([C:23]2[CH:31]=[CH:30][C:26]([C:27]([O-])=[O:28])=[CH:25][CH:24]=2)[CH2:19][CH2:18]1>>[NH2:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:27](=[O:28])[C:26]3[CH:25]=[CH:24][C:23]([N:20]4[CH2:21][CH2:22][O:17][CH2:18][CH2:19]4)=[CH:31][CH:30]=3)=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C([O-])c1ccc(N2CCOCC2)cc1
Reactant: Nc1ccc(C(=O)c2ccc(N)cc2)cc1
Product: Nc1ccc(C(=O)c2ccc(NC(=O)c3ccc(N4CCOCC4)cc3)cc2)cc1

Procedure:
Compound 485 was prepared according to the procedure described in Scheme IV from 4,4′-diaminobenzophenone and 4-morpholinobenzoate. [M+H]+ calcd for C24H23N3O3: 402.08; found: 402.03.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([N:17]3[CH:21]([C:22]([OH:24])=[O:23])[CH2:20][CH:19]4[CH2:25][CH2:26][CH2:27][CH:18]34)(=[O:16])=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:34](Cl)(=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>CN(C=O)C>[C:34]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([S:14]([N:17]3[CH:21]([C:22]([OH:24])=[O:23])[CH2:20][CH:19]4[CH2:25][CH2:26][CH2:27][CH:18]34)(=[O:16])=[O:15])=[CH:12][CH:13]=2)=[CH:4][CH:3]=1)(=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1ccc(-c2ccc(S(=O)(=O)N3C(C(=O)O)CC4CCCC43)cc2)cc1
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: O=C(Nc1ccc(-c2ccc(S(=O)(=O)N3C(C(=O)O)CC4CCCC43)cc2)cc1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
500 mg (1.30 mmol) of 1-(4′-aminobiphenyl-4-sulfonyl)octahydrocyclopenta[b]pyrrole-2-carboxylic acid were dissolved in 3 ml of DMF, after which the solution was cooled down to 0° C. in an ice bath and 2.6 mmol of pyridine were added. After the mixture had been stirred at 0° C. for 15 min, 1.8 mmol of benzoyl chloride in 3 ml of DMF were added. The reaction solution was then stirred at RT for a further 20 h. The crude product was purified using chromatographic methods.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH:11][C:12]([CH:14]3[CH2:16][CH2:15]3)=[O:13])[N:10]=2)[CH:7]=1.F[C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][C:19]=1[F:27].C(=O)([O-])[O-].[Cs+].[Cs+].O>CS(C)=O>[F:27][C:19]1[CH:20]=[C:21]([N+:24]([O-:26])=[O:25])[CH:22]=[CH:23][C:18]=1[O:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH:11][C:12]([CH:14]3[CH2:15][CH2:16]3)=[O:13])[N:10]=2)[CH:7]=1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Reactant: O=C(Nc1cn2cc(O)ccc2n1)C1CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: O=C(Nc1cn2cc(Oc3ccc([N+](=O)[O-])cc3F)ccc2n1)C1CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 94.6 %

Procedure:
To a solution of N-(6-hydroxyimidazo[1,2-a]pyridin-2-yl)cyclopropanecarboxamide (30 g, 138 mmol) and 1,2-difluoro-4-nitrobenzene (24.2 g, 152 mmol) in dimethyl sulfoxide (180 mL) was added cesium carbonate (58.5 g, 180 mmol), and the mixture was stirred at room temperature for 5 hr under an argon atmosphere. Water (1080 mL) was added to the reaction mixture, and the mixture was stirred for 20 min. The precipitate was collected by filtration and washed with water and ethyl acetate. After air drying for one day, the mixture was dried under reduced pressure at 100° C. for 5 hr to give the title compound (46.5 g, 95%) as a yellow solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]([O:9][CH3:10])=[O:8])=[CH:3][C:2]=1[C:11](OC)=[O:12].[H-].C([Al+]CC(C)C)C(C)C.C(OCC)C.CCCCCC.C(OCC)(=O)C>C1(C)C=CC=CC=1>[CH:11]([C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][N:1]=1)[C:7]([O:9][CH3:10])=[O:8])=[O:12]
Reactant: COC(=O)c1ccnc(C(=O)OC)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: COC(=O)c1ccnc(C=O)c1
Temperature: 0 °C
Yield: 29.8 %

Procedure:
1.07 g of dimethyl pyridine-2,4-dicarboxylate was dissolved in 20 ml of toluene, and with stirring under cooling at -80° to -70° C., 6.04 ml of a 1M toluene solution of diisobutylaluminium hydride was added dropwise over 2.5 hours, and the mixture was stirred at this temperature for 1 hour. The reaction mixture was poured into ice water, and ethyl ether was added. The organic layer was separated, worked up in a customary manner, and then purified by medium-pressure liquid chromatography Lobar column, size B, Lichroprep Si 60 (E. Merck Co.); eluting solvent: hexane/ethyl acetate=4/1→3/1) to give 0.27 g (yield 30%) of methyl 2-formylisonicotinate as a colorless crystalline powder.
Reaction SMILES: [C:1]1(=[O:21])[N:5]([CH2:6][CH2:7][CH2:8][S:9][C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)[C:4](=[O:16])[C:3]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:2]12.[BH4-].[Na+]>C(O)C>[OH:21][CH:1]1[C:2]2[C:3](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:4](=[O:16])[N:5]1[CH2:6][CH2:7][CH2:8][S:9][C:10]1[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCSc1ccncc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: O=C1c2ccccc2C(O)N1CCCSc1ccncc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 54.4 %

Procedure:
To a solution of 5.97 g (20.0 mmol) of 4-(3-phthalimidopropylthio)pyridine in 300 ml of ethanol, 1.51 g (40 mmol) of sodium borohydride was added, and the mixture was stirred at room temperature for 5 hours. The solvent was distilled off and saturated saline was added to the residue. The mixture was extracted with chloroform and the extract was dried over anhydrous magnesium sulfate. The solvent was distilled off and the residue was purified by column chromatography (eluent: ethanol/ethyl acetate=1:10) to give 3.27 g of the desired compound (54.4% yield, colorless crystals), mp. 132°-134° C.
Reaction SMILES: [C:1]([N:4]1[CH:10]([CH3:11])[CH2:9][C:8]2[CH:12]=[C:13](Br)[C:14]([O:16][CH3:17])=[CH:15][C:7]=2[C:6]([C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-])=O)=[C:21]([CH3:28])[CH:20]=2)=[N:5]1)(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].O.NN>COCCO.[Pd]>[C:1]([N:4]1[CH:10]([CH3:11])[CH2:9][C:8]2[CH:12]=[CH:13][C:14]([O:16][CH3:17])=[CH:15][C:7]=2[C:6]([C:19]2[CH:24]=[CH:23][C:22]([NH2:25])=[C:21]([CH3:28])[CH:20]=2)=[N:5]1)(=[O:3])[CH3:2]
Reactant: COc1cc2c(cc1Br)CC(C)N(C(C)=O)N=C2c1ccc([N+](=O)[O-])c(C)c1
Agent: [Pd]
Agent: NN
Agent: O=C([O-])[O-]
Solvent: O
Solvent: COCCO
Product: COc1ccc2c(c1)C(c1ccc(N)c(C)c1)=NN(C(C)=O)C(C)C2
Temperature: 100 °C
Reaction time: 1 h
Yield: 47.4 %

Procedure:
4.46 g (10 mmoles) of (±)-3-acetyl-7-bromo4,5-dihydro-1-(3-methyl-4-nitrophenyl)-4-methyl-8-methoxy-3H-2,3-benzo-diazepine are dissolved in 190 cm3 of methyl cellosolve, then 2.1 g (15 mmoles) of potassium carbonate and 1.8 g of 10% palladium/charcoal catalyst and, under vigorous stirring, 1.95 cm3 (40 mmoles) of 98% hydrazine hydrate are added. The reaction mixture is stirred at 100° C. for 1 hour, the catalyst is filtered, the filtrate is evaporated, and the residue is rubbed with 50 cm3 of water to obtain solid matter. The crude product is purified by chromatography over a column containing silica gel and using a mixture of ethyl acetate and hexane, then the product is recrystallized from acetonitrile. Thus, 1.6 g (47%) of the title compound are obtained in the form of cream coloured solids melting at 169–171° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:12]O.N1C=CC=CC=1.P(Br)(Br)[Br:21]>ClCCl>[Br:21][CH2:12][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]([N+:9]([O-:11])=[O:10])[C:3]=1[O:2][CH3:1]
Reactant: BrP(Br)Br
Reactant: COc1c(CO)cccc1[N+](=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1c(CBr)cccc1[N+](=O)[O-]
Reaction time: 0.75 h

Procedure:
A solution of 14.7 g of (2-methoxy-3-nitro-phenyl)-methanol dissolved in 140 ml of dichloromethane and 5.5 ml of pyridine was cooled in an ice bath and slowly added 6.48 ml of phosphorus tribromide. After 45 minutes at 5° C., the reaction mixture was diluted with dichloromethane, washed with water, dried, and evaporated to dryness. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate/hexane (5:95) giving 7.3 g of 1-bromomethyl-2-methoxy-3-nitrobenzene as a yellow solid. ##STR137##
Reaction SMILES: [Li+].[CH3:2]C([N-]C(C)C)C.C(NC(C)C)(C)C.[Li].C(NC(C)C)(C)C.[Li]CCCC.[Br:29][C:30]1[CH:39]=[CH:38][CH:37]=[C:36]2[C:31]=1[CH:32]=[CH:33][C:34]([CH2:40][C:41]#[N:42])=[CH:35]2.CI>C1COCC1>[Br:29][C:30]1[CH:39]=[CH:38][CH:37]=[C:36]2[C:31]=1[CH:32]=[CH:33][C:34]([CH:40]([CH3:2])[C:41]#[N:42])=[CH:35]2
Reactant: N#CCc1ccc2c(Br)cccc2c1
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: CI
Product: CC(C#N)c1ccc2c(Br)cccc2c1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 79 %

Procedure:
To a solution of LDA [lithium diisopropylamine prepared from diisopropylamine (1.49 g, 14.8 mmol) and n-BuLi (9.25 mL, 14.8 mmol, 1.6M solution in hexanes)]in THF (80 mL) at -78° C. was added (5-bromo-2-naphthalenyl) acetonitrile (3.80 g, 13.4 mmol) in THF (70 mL) dropwise over 45 minutes. The resulting orange solution was stirred at -78° C. for 10 minutes and MeI (1.90 g, 13.4 mmol) was added in one portion. The reaction mixture was stirred at -78° C. for 1 hour and quenched with saturated NH4Cl (20 mL). The solution was warmed to room temperature and the volatiles removed in vacuo. The residue was diluted with H2O (100 mL) and extracted with Et2O (3×150 mL). The combined organic layers were dried (MgSO)4) and concentrated in vacuo to give the crude product as a yellow oil. This residue was purified by flash chromatography (SiO2) with elution by hexane/CH2Cl2 (2:1), followed by hexane/CH2Cl2 (3:2) to give the title compound as a colorless oil (2.74 g, 79%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)=[C:7]([CH3:18])[CH:6]=1)=[O:4].C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[Br:37]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.ClCCl>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)=[C:7]([CH2:18][Br:37])[CH:6]=1)=[O:4]
Reactant: COC(=O)c1ccc(-c2ccc(Cl)cc2)c(C)c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: COC(=O)c1ccc(-c2ccc(Cl)cc2)c(CBr)c1
Temperature: 25 °C
Yield: 55.8 %

Procedure:
To a solution of 191 mg (0.73 mmol) of 4′-chloro-2-methyl-biphenyl-4-carboxylic acid methyl ester in 4 mL of carbon tetrachloride (CCl4) was added 9.7 mg (0.04 mmol) of benzoyl peroxide, followed by 124 mg (0.696 mmol) of N-bromosuccinimide (NBS), and the reaction mixture was heated at reflux for 6 h. The mixture was cooled to rt, diluted with dichloromethane and washed with water and brine. The organic layer was dried over sodium sulfate and concentrated to give 132 mg (53%) of 2-bromomethyl-4′-chloro-biphenyl-4-carboxylic acid methyl ester, as an oil, which was used without any further purification in the next step. 1H NMR δCDCl3 8.10 (s, 1H), 7.91-7.89 (d, J=8.0 Hz, 1-H), 7.37-7.35 (d, J=8.3 Hz, 2H), 7.30-7.18 (d, J=8.7 Hz, 2H), 7.22-7.20 (d, J=8.0 Hz, 1H), 4.30 (s, 2H), 3.87 (s, 3H).