Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(Cl)(Cl)=O.O[CH:6]([NH:11][C:12](=[O:20])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[OH:19])[C:7]([Cl:10])([Cl:9])[Cl:8].C(Cl)(Cl)(Cl)[Cl:22]>CN(C)C=O>[Cl:22][CH:6]([NH:11][C:12](=[O:20])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[OH:19])[C:7]([Cl:10])([Cl:9])[Cl:8]
Reactant: ClC(Cl)(Cl)Cl
Reactant: O=C(NC(O)C(Cl)(Cl)Cl)c1ccccc1O
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: O=C(NC(Cl)C(Cl)(Cl)Cl)c1ccccc1O

Procedure:
5 g of thionyl chloride was added dropwise to the mixture of 10 g of N-(1-hydroxy-2,2,2-trichloroethyl)-2-hydroxybenzamide, 50 ml of carbon tetrachloride and 0.1 g of N,N-dimethylformamide under stirring. After effecting the reaction under reflux for one hour, the solvent was distilled off under reduced pressure to obtain N-(1,2,2,2-tetrachloroethyl)-2-hydroxybenzamide (m.p.: 113°-113.5° C.). Without taking out the compound thus resulted, thereto were added 50 ml of acetone and also 7.2 g of octyl thioglycolate (n), and the mixture was stirred at room temperature for one hour. The solvent was distilled off and the rest was purified by silica gel column chromatography to obtain 3.0 g of N-(1-n-octyloxycarbonylmethylthio-2,2,2-trichloroethyl)-2-hydroxybenzamide as a light yellow oily substance. nD25 1.5031
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.[Cl:15][C:16]1[CH:24]=[C:23]([S:25](=[O:28])(=[O:27])[NH2:26])[CH:22]=[CH:21][C:17]=1[C:18](O)=[O:19]>>[Cl:15][C:16]1[CH:24]=[C:23]([S:25](=[O:28])(=[O:27])[NH2:26])[CH:22]=[CH:21][C:17]=1[C:18]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([Cl:1])=[C:3]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[CH:4]=1)=[O:19]
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
Reactant: NS(=O)(=O)c1ccc(C(=O)O)c(Cl)c1
Product: NS(=O)(=O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1

Procedure:
A solution of 818 mg of Sodium Nitrite in 13 mL of water was added dropwise to a solution of 2 g of methyl 4-amino-2-chlorobenzoate in 5 mL of HCl and 15 mL of AcOH at 0° C. The reaction was removed from the ice bath and stirred at room temperature for 15 minutes. Simultaneously a solution of 460 mg of Copper II Chloride Dihydrate in 1 mL of water was added to a saturated solution of sulfur dioxide gas in 10 mL of AcOH at 0° C. The cooled solution containing Copper II Chloride and sulfur dioxide gas was slowly added to the re-cooled initial solution containing Sodium Nitrite. The reaction was warmed to room temperature and stirred until gas no longer evolved. The reaction was filtered through celite and poured into a beaker of stirred icewater until a yellow-orange solid crashed out. The icewater solution was filtered thru a Buchner funnel to collect the methyl 2-chloro-4-(chlorosulfonyl)benzoate precipitate and was dried for 24 hours under vacuum. 1 g of methyl 2-chloro-4-(chlorosulfonyl)benzoate was added to a solution of 2 mL of 2M solution of Ammonia in MeOH and 970 μL DIPEA in 5 mL MeOH. Upon completion the reaction was concentrated, extracted twice with saturated bicarbonate, dried with Magnesium Sulfate, filtered and concentrated to give methyl 2-chloro-4-sulfamoylbenzoate. 777 mg of methyl 2-chloro-4-sulfamoylbenzoate was hydrolyzed via Procedure M to yield crude 2-chloro-4-sulfamoylbenzoic acid. 75 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 91 mg of crude 2-chloro-4-sulfamoylbenzoic acid via Procedure G. The crude product was purified by reverse phase HPLC to yield 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-sulfamoylbenzamide. MS (Q1) 422 (M)+.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([O:13][CH3:14])[CH:6]=[CH:7][C:8]=2[CH3:12])[N:3]=1.[H][H]>[Ni].C(O)(C)C>[CH3:1][CH:2]1[CH2:11][CH2:10][C:9]2[C:4](=[C:5]([O:13][CH3:14])[CH:6]=[CH:7][C:8]=2[CH3:12])[NH:3]1
Reactant: COc1ccc(C)c2ccc(C)nc12
Reactant: [H][H]
Agent: [Ni]
Solvent: CC(C)O
Product: COc1ccc(C)c2c1NC(C)CC2

Procedure:
A mixture of the above 2,5-dimethyl-8-methoxyquinoline (260 g, 1.3 m), isopropanol (600 ml), and Raney nickel catalyst (25.0 g) was subjected to 1000 psi hydrogen for 3 hrs. in a stainless steel autoclave. The reaction mixture from the autoclave was filtered to remove the catalyst. Essentially a quantitative yield of product was obtained, after the removal of the isopropanol under vacuum, and the product was used without further purification.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=3)[C:10]([CH3:19])([CH3:18])[CH2:9]2)[CH:2]=1.[CH3:20][N:21]([CH3:31])[C:22]1[CH:27]=[CH:26][C:25]([N:28]=[C:29]=[O:30])=[CH:24][CH:23]=1>>[CH3:20][N:21]([CH3:31])[C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29](=[O:30])[O:17][C:13]2[CH:12]=[C:11]3[C:16](=[CH:15][CH:14]=2)[N:8]([CH2:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[CH2:9][C:10]3([CH3:19])[CH3:18])=[CH:24][CH:23]=1
Reactant: CC1(C)CN(Cc2cccnc2)c2ccc(O)cc21
Reactant: CN(C)c1ccc(N=C=O)cc1
Product: CN(C)c1ccc(NC(=O)Oc2ccc3c(c2)C(C)(C)CN3Cc2cccnc2)cc1

Procedure:
The title compound was synthesized from 1-(3-pyridylmethyl)-3,3-dimethylindolin-5-ol (20.0 mg, 0.09 mmol) using the same procedure employed for Example 2 (2), but with 4-dimethylaminophenylisocyanate instead of 4-isopropylphenylisocyanate. The product was obtained as a white solid (4.7 mg, 14%) having the following characteristics.
Reaction SMILES: Cl.[NH2:2][N:3]1[CH2:7][C:6](=[O:8])[NH:5][C:4]1=[O:9].[N:10]1[C:19]2[C:14](=[CH:15][C:16]([CH2:20][N:21]3[C:25]4=[N:26][C:27]([C:30](=O)[CH3:31])=[CH:28][N:29]=[C:24]4[N:23]=[N:22]3)=[CH:17][CH:18]=2)[CH:13]=[CH:12][CH:11]=1>>[N:10]1[C:19]2[C:14](=[CH:15][C:16]([CH2:20][N:21]3[C:25]4=[N:26][C:27](/[C:30](=[N:2]/[N:3]5[CH2:7][C:6](=[O:8])[NH:5][C:4]5=[O:9])/[CH3:31])=[CH:28][N:29]=[C:24]4[N:23]=[N:22]3)=[CH:17][CH:18]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: CC(=O)c1cnc2nnn(Cc3ccc4ncccc4c3)c2n1
Reactant: NN1CC(=O)NC1=O
Agent: Cl
Product: C/C(=N\N1CC(=O)NC1=O)c1cnc2nnn(Cc3ccc4ncccc4c3)c2n1
Yield: 58 %

Procedure:
The title compound was prepared in 58% yield as a light yellow solid in analogy to the synthesis of example 52 from 1-aminoimidazolidine-2,4-dione hydrochloride and 1-(1-(quinolin-6-ylmethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)ethanone. 1H-NMR (400 MHz, DMSO-d6) δ ppm 11.45 (s, 1H), 9.41 (s, 1H), 8.89 (d, 1H), 8.35 (d, 1H), 8.02 (m, 2H), 7.84 (d, 1H), 7.53 (dd, 1H), 6.23 (s, 2H), 4.56 (s, 2H), 2.49 (s, 3H). LCMS (method B): [MH]+=402, tR=1.81 min.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C@@H:22]([OH:24])[CH3:23])=[CH:17][CH:16]=1>>[OH:24][C@@H:22]([CH3:23])[CH2:21][C:18]1[CH:19]=[CH:20][C:15]([NH:14][C:2]2[N:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=2[N+:11]([O-:13])=[O:12])=[CH:16][CH:17]=1
Reactant: C[C@H](O)Cc1ccc(N)cc1
Reactant: CC(=O)c1cnc(Cl)c([N+](=O)[O-])c1
Product: CC(=O)c1cnc(Nc2ccc(C[C@H](C)O)cc2)c([N+](=O)[O-])c1

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 162 from 1-(6-chloro-5-nitro-3-pyridinyl)ethanone (Paul, B. et al. J. Med. Chem., 1990, 33, 2231-2239.) and (2S)-1-(4-aminophenyl)-2-propanol (step 2 of Example 248).
Reaction SMILES: [CH2:1]([N:8]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:9][CH2:10]Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[F:20][CH2:21][CH2:22][NH2:23].CCN(C(C)C)C(C)C>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C>[CH2:1]([N:8]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:9][CH2:10][NH:23][CH2:22][CH2:21][F:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCCF
Reactant: ClCCN(Cc1ccccc1)Cc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [Br-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: FCCNCCN(Cc1ccccc1)Cc1ccccc1
Yield: 27.9 %

Procedure:
N,N-Dibenzyl-N′-(2-fluoro-ethyl)ethane-1,2-diamine (160 mg) was prepared by following General Procedure S starting from dibenzyl-(2-chloro-ethyl)-amine (520 mg), 2-fluoro-ethylamine hydrochloride (250 mg), DIEA (900 uL) and tetrabutylammonium bromide (60 mg) in DMF (2 mL).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].C(=O)=O.CC(C)=O.[CH2:17]([Mg]Cl)[CH2:18][CH2:19][CH3:20]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]([OH:6])[CH2:17][CH2:18][CH2:19][CH3:20])[CH:7]=[CH:8][CH:9]=1
Reactant: CCCC[Mg]Cl
Reactant: O=Cc1cccc(Br)c1
Agent: O=C=O
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: CCCCC(O)c1cccc(Br)c1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To 3-bromobenzaldehyde (5.00 g, 27.02 mmol) in dry THF (100 mL), under nitrogen at −78° C. (dry ice/acetone bath) was added nBuMgCl (16.2 mL of a 2.0M solution in THF, 0.032 mol) and the reaction stirred for 1 hour at −78° C. and then allowed to warm to rt overnight. The reaction was then quenched with water, extracted with EtOAc and the layers separated. The organic layer was washed with water then brine, dried (Na2SO4) and reduced under vacuum to give a colourless oil. Purification by Biotage™ chromatography (silica, 90 g cartridge) eluting with cyclohexane:EtOAc 9:1 afforded the title compound as a colourless oil (4.07 g).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[N+:19]([O-:21])=[O:20])[O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]([OH:15])=O)=[CH:8][CH:7]=1.[NH2:22][C:23]1[CH:28]=[CH:27][C:26]([Br:29])=[CH:25][N:24]=1.CC(C)N=C=NC(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.CN(C1C=CN=CC=1)C>[Br:29][C:26]1[CH:27]=[CH:28][C:23]([NH:22][C:13](=[O:15])[CH2:12][C:9]2[CH:8]=[CH:7][C:6]([O:5][C:4]3[CH:16]=[CH:17][C:18]([N+:19]([O-:21])=[O:20])=[C:2]([OH:1])[CH:3]=3)=[CH:11][CH:10]=2)=[N:24][CH:25]=1
Reactant: Nc1ccc(Br)cn1
Reactant: O=C(O)Cc1ccc(Oc2ccc([N+](=O)[O-])c(O)c2)cc1
Agent: CC(C)N=C=NC(C)C
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C(Cc1ccc(Oc2ccc([N+](=O)[O-])c(O)c2)cc1)Nc1ccc(Br)cn1
Reaction time: 8 h

Procedure:
To 3.0 g (2.5 mmol) of above resin-bound [4-(3-hydroxy-4-nitro-phenoxy)-phenyl]-acetic acid were added 1.30 g (7.5 mmol) of 2-amino-5-bromopyridine, 7.5 mL (7.5 mmol) of 1.0 M DIC in DMF, 7.5 mL (7.5 mmol) of 1.0 M HOBt in DMF, and catalytic amount of DMAP. The resulting mixture was left on a shaker overnight. The resin was washed with DMF, MeOH, DCM three times of each to give resin-bound N-(5-bromo-pyridin-2-yl)-2-[4-(3-hydroxy-4-nitro-phenoxy)-phenyl]-acetamide
Reaction SMILES: [CH2:1]([C:3]1[N:4]([CH:25]2[CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26]2)[N:5]=[C:6]2[C:11](=[O:12])[NH:10][C:9]([C:13]3[C:14]([O:21][CH2:22][CH2:23][CH3:24])=[N:15][CH:16]=[C:17](C#C)[CH:18]=3)=[N:8][C:7]=12)[CH3:2].[CH3:36][C:37](C)=[O:38]>S(=O)(=O)(O)O>[C:37]([C:17]1[CH:18]=[C:13]([C:9]2[NH:10][C:11](=[O:12])[C:6]3[C:7](=[C:3]([CH2:1][CH3:2])[N:4]([CH:25]4[CH2:26][NH:27][CH2:28]4)[N:5]=3)[N:8]=2)[C:14]([O:21][CH2:22][CH2:23][CH3:24])=[N:15][CH:16]=1)(=[O:38])[CH3:36]
Reactant: CC(C)=O
Reactant: C#Cc1cnc(OCCC)c(-c2nc3c(CC)n(C4CN(C(=O)OC(C)(C)C)C4)nc3c(=O)[nH]2)c1
Agent: O=S(=O)(O)O
Product: CCCOc1ncc(C(C)=O)cc1-c1nc2c(CC)n(C3CNC3)nc2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The title compound of example 111 (1.44 g, 3.0 mmol) in acetone (50 ml) and sulphuric acid (1N, 3 ml) was treated with mercuric sulphate (268 mg, 9.0 mmol) and heated to reflux for 6 h. The reaction mixture was concentrated to 20 ml in vacuo, poured into sodium bicarbonate (sat. aq., 20 ml) and extracted into methylene chloride (6×20 ml). Combined organics were washed with brine (20 ml), dried over MgSO4, and concentrated to a brown oil which was taken up in 40% trifluoroacetic acid in methylene chloride (50 ml) and water (1 ml) and stirred for 1 h at room temperature. After evaporation in vacuo, the residue was purified by column chromatography (eluting with 95:5:1 methylene chloride:methanol:0.88 ammonia) to afford the title compound as a white hydroscopic foam (1.65 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:18]=[C:17]([C:19]([OH:21])=O)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1.Cl.[OH:23][C:24]1[C:33]([CH3:34])=[CH:32][CH:31]=[C:30]2[C:25]=1[CH2:26][CH2:27][NH:28][CH2:29]2>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:18]=[C:17]([C:19]([N:28]2[CH2:27][CH2:26][C:25]3[C:30](=[CH:31][CH:32]=[C:33]([CH3:34])[C:24]=3[OH:23])[CH2:29]2)=[O:21])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1
Reactant: O=C(O)c1nc(-c2ccc(F)cc2F)nc2ccccc12
Reactant: Cc1ccc2c(c1O)CCNC2
Agent: Cl
Product: Cc1ccc2c(c1O)CCN(C(=O)c1nc(-c3ccc(F)cc3F)nc3ccccc13)C2
Yield: 22 %

Procedure:
Reaction of 2-(2,4-difluorophenyl)quinazoline-4-carboxylic acid with 5-hydroxy-6-methyl-1,2,3,4-tetrahydroisoquinoline hydrochloride gave compound 61 (22% yield) as a white solid. 1H NMR (300 MHz, CDCl3) δ 2.25 and 2.28 (2s, 3H), 2.82 and 3.04 (2t, 2H), 3.65 and 4.21 (2t, 2H), 4.54 and 5.08 (2s, 2H), 6.39 and 6.81 (2d, 1H), 6.90-7.08 (m, 3H), 7.63-7.73 (m, 1H), 7.99-8.11 (m, 2H), 8.22-8.28 (m, 2H); MS (ESI) m/z 432 ([M+H]+).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@@H:11]1[O:16][C@H:15]([C:17]([O:19][CH3:20])=[O:18])[C@@H:14]([NH2:21])[C@H:12]1[OH:13].[C:22]([O:26][C:27]([NH:29][CH:30]([C:39](O)=[O:40])[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[CH:33]=1)=[O:28])([CH3:25])([CH3:24])[CH3:23]>>[NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@@H:11]1[O:16][C@H:15]([C:17]([O:19][CH3:20])=[O:18])[C@@H:14]([NH:21][C:39](=[O:40])[CH:30]([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[CH:33]=2)[NH:29][C:27]([O:26][C:22]([CH3:25])([CH3:23])[CH3:24])=[O:28])[C@H:12]1[OH:13]
Reactant: CC(C)(C)OC(=O)NC(Cc1cccc(Cl)c1)C(=O)O
Reactant: COC(=O)[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@H](O)[C@@H]1N
Product: COC(=O)[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@H](O)[C@@H]1NC(=O)C(Cc1cccc(Cl)c1)NC(=O)OC(C)(C)C
Yield: 54.2 %

Procedure:
Methyl 1-(6-amino-9H-purin-9-yl)-1,3-dideoxy-3-[N-tert-butoxycarbonyl-β-(3-chlorophenyl)-D,L-alanylamino]-β-D-ribofuranuronate (312 mg) was prepared by reacting methyl 1-(6-amino-9H-purin-9-yl)-1,3-dideoxy-3-amino-β-D-ribofuranuronate (294 mg) prepared in Example 62 with N-tert-butoxycarbonyl-β-(3-chlorophenyl)-D,L-alanine (300 mg) according to a similar manner to that of Example 64, mp. 115°-125° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]([CH:11]2[CH2:13][CH2:12]2)=[O:10])[CH:5]=[N:4][C:3]=1[C:14]1[CH:19]=[CH:18][N:17]=[CH:16][C:15]=1[Cl:20].C([Sn](CCCC)(CCCC)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1)CCC>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.C1(C)C(C)=CC=CC=1>[Cl:20][C:15]1[CH:16]=[N:17][CH:18]=[CH:19][C:14]=1[C:3]1[N:4]=[CH:5][C:6]([NH:8][C:9]([CH:11]2[CH2:13][CH2:12]2)=[O:10])=[N:7][C:2]=1[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1
Reactant: O=C(Nc1cnc(-c2ccncc2Cl)c(Cl)n1)C1CC1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1C
Product: O=C(Nc1cnc(-c2ccncc2Cl)c(-c2ccccn2)n1)C1CC1
Reaction time: 20 h
Yield: 48.1 %

Procedure:
An oven dried resealable Schlenk tube was charged with N-[6-chloro-5-(3-chloropyridin-4-yl)pyrazin-2-yl]cyclopropanecarboxamide (0.2 g, 0.65 mmol), 2-(tributylstannyl)pyridine (0.38 g, 1.04 mmol) and xylene (4 mL). The Schienk tube was subjected to three cycles of evacuation-backfilling with argon, and tetrakis(triphenylphosphine)palladium (75 mg, 0.065 mmol) was added. After three new cycles of evacuation-backfilling with argon, the Schlenk tube was capped and placed in a 150° C. oil bath. After 20 h, the mixture was cooled, partitioned between water and ethyl acetate, the aqueous phase was extracted twice with ethyl acetate, the organic layers washed with brine, dried (MgSO4) and evaporated. Silica gel flash chromatography (98:2 dichloromethane/methanol) furnished the title compound of Example 22 as a light brown solid (110 mg, 48%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[CH:13]=[C:14]([CH2:23][CH3:24])[C:15]3[O:19][CH2:18][C:17]([CH3:21])([CH3:20])[C:16]=3[CH:22]=2)=[CH:7][CH:6]=1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].IC.CN(C)[C:36](=O)[CH3:37]>>[CH2:1]([O:3][C:4](=[O:25])[C:5]1[CH:6]=[CH:7][C:8]([N:11]([CH2:36][CH3:37])[C:12]2[CH:13]=[C:14]([CH2:23][CH3:24])[C:15]3[O:19][CH2:18][C:17]([CH3:21])([CH3:20])[C:16]=3[CH:22]=2)=[CH:9][CH:10]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(Nc2cc(CC)c3c(c2)C(C)(C)CO3)cc1
Reactant: CC(=O)N(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Product: CCOC(=O)c1ccc(N(CC)c2cc(CC)c3c(c2)C(C)(C)CO3)cc1
Yield: 68 %

Procedure:
Following general procedure G and using 4-[(3,3-dimethyl-7-ethyl-2,3-dihydro-benzofuran-5-yl)-amino]-benzoic acid ethyl ester (Compound 16, 0.18 g, 0.53 mmol), potassium carbonate (0.73 g, 5.3 mmol) and iodomethane (0.83 g, 5.3 mmol) in 2 mL of anhydrous N,N-dimethylacetamide, the title compound (0.134 g, 68%) was obtained as a pale yellow oil. The reaction was performed in a sealed tube. 1H NMR (300 MHz, CDCl3): δ 7.82 (d, 2H, J=9.0 Hz), 6.79 (d, 1H, J=2.0 Hz), 6.76 (d, 1H, J=2.0 Hz), 6.57 (d, 2H, J=9.0 Hz), 4.31 (q, 2H, J=7.1 Hz), 4.27 (s, 2H), 3.72 (q, 2H, J=7.1 Hz), 2.60 (q, 2H J=7.6 Hz), 1.35 (t, 3H, J=7.1 Hz), 1.33 (s, 6H), 1.26-1.19 (m, 6H).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[C:15]([O:19][C:20](=[O:25])[NH:21][CH2:22][CH2:23][NH2:24])([CH3:18])([CH3:17])[CH3:16]>CN(C=O)C>[CH3:9][O:8][C:6](=[O:7])[C:5]1[CH:10]=[CH:11][C:2]([NH:24][CH2:23][CH2:22][NH:21][C:20]([O:19][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:25])=[C:3]([N+:12]([O-:14])=[O:13])[CH:4]=1
Reactant: COC(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: CC(C)(C)OC(=O)NCCN
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(NCCNC(=O)OC(C)(C)C)c([N+](=O)[O-])c1
Yield: 76.2 %

Procedure:
4-(2-tert-Butoxycarbonylamino-ethylamino)-3-nitro-benzoic acid methyl ester (650.0 mg) was prepared by following General Procedure A starting from methyl 4-chloro-3-nitrobenzoate (542.0 mg) and (2-amino-ethyl)-carbamic acid tert-butyl ester (500.0 mg) in DMF (3.0 mL). The crude product was used in the next step without further purification.
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10](OS(C)(=O)=O)[CH2:9][C@H:8]1[CH2:17][CH2:18][N:19]1[CH:23]=[C:22]([CH2:24][C:25](=[O:27])[NH2:26])[N:21]=[CH:20]1)=[O:6])[CH:2]=[CH2:3].[C:28]([OH:36])(=[S:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.CC(C)([O-])C.[K+]>>[CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@@H:10]([S:35][C:28](=[O:36])[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:9][C@H:8]1[CH2:17][CH2:18][N:19]1[CH:23]=[C:22]([CH2:24][C:25](=[O:27])[NH2:26])[N:21]=[CH:20]1)=[O:6])[CH:2]=[CH2:3]
Reactant: OC(=S)c1ccccc1
Reactant: C=CCOC(=O)N1C[C@H](OS(C)(=O)=O)C[C@H]1CCn1cnc(CC(N)=O)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: C=CCOC(=O)N1C[C@@H](SC(=O)c2ccccc2)C[C@H]1CCn1cnc(CC(N)=O)c1

Procedure:
(2R,4R)-1-Allyloxycarbonyl-2-{2-(4-carbamoylmethyl-imidazol-1-yl) ethyl}-4-methanesulfonyloxypyrrolidine (2.74 g) were reacted with thiobenzoic acid (1.69 ml) and potassium t-butoxide (1.54 g) in substantially the same manner as Preparation 19-2) to give (2R,4S)-1-allyloxycarbonyl-4-benzoylthio-2-[2-(4-carbamoylmethyl-imidazol-1-yl) ethyl]pyrrolidine (2.30 g) as a yellow solid.
Reaction SMILES: [C:1]1([CH2:13][CH2:14][C:15]#[N:16])[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][N:3]3[CH:2]=1.[OH2:17]>>[C:1]1([CH2:13][CH2:14][C:15]([NH2:16])=[O:17])[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][N:3]3[CH:2]=1
Reactant: O
Reactant: N#CCCc1cn2c3c(cccc13)CCC2
Product: NC(=O)CCc1cn2c3c(cccc13)CCC2

Procedure:
3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-propionitrile (300 mg, 1.4 mmol) in polyphosphoric acid (8 ml) was heated to 100° C. for 3 hours. The mixture was then added to water (150 ml) and triturated to give a precipitate. The precipitate was filtered off, washed with water and dried under reduced pressure to give 3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-propionamide as a tan powder (249 mg). 400 MHz 1H NMR (DMSO-d6) δ: 7.31 (s, 2H), 7.06 (s, 1H), 6.9-6.7 (m, 3H), 4.08 (s, 2H), 2.89 (s, 4H), 2.4 (m, 2H), 2.1 (m, 2H); LCMS: 229 [M+H].
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CN(C=O)C.[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([O:19][CH:20]2[CH2:25][CH2:24][N:23]([S:26]([NH:29][C@H:30]([CH:34]([CH3:36])[CH3:35])[C:31]([OH:33])=O)(=[O:28])=[O:27])[CH2:22][CH2:21]2)=[N:17][CH:18]=1.C[Si](C)(C)[NH:39][O:40][Si](C)(C)C>C(Cl)Cl>[OH:40][NH:39][C:31](=[O:33])[C@H:30]([NH:29][S:26]([N:23]1[CH2:22][CH2:21][CH:20]([O:19][C:16]2[CH:15]=[CH:14][C:13]([Cl:12])=[CH:18][N:17]=2)[CH2:25][CH2:24]1)(=[O:28])=[O:27])[CH:34]([CH3:35])[CH3:36]
Reactant: CC(C)[C@@H](NS(=O)(=O)N1CCC(Oc2ccc(Cl)cn2)CC1)C(=O)O
Reactant: C[Si](C)(C)NO[Si](C)(C)C
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)[C@@H](NS(=O)(=O)N1CCC(Oc2ccc(Cl)cn2)CC1)C(=O)NO
Temperature: 25 °C
Reaction time: 8 h
Yield: 35 %

Procedure:
Oxalyl chloride (0.58 ml, 6.7 mmol) and DMF (few drops) were added to a solution of (R)-2-{[4-(5-chloropyridin-2-yloxy)piperidine-1sulfonyl)amino}-3-methylbutyric acid (1.05 g, 2.7 mmol), [prepared as described in Step 1 above], in methylene chloride (85 ml) and the reaction mixture was stirred overnight at RT. After removal of the organics, the residue was redissolved in methylene chloride (40 ml) and N,O-bis-trimethylsilylhydroxylamine (1.7 g, 9.4 mmol) was added. After 3 h, the reaction was concentrated, methanol (20 ml) was added and after stirring for an additional 30 min., the solvent was removed in vacuo. The residue was dissolved in ethyl acetate and washed with water and brine, dried over MgSO4, and concentrated. Chromatography (SiO2, 1-2% methanol/methylene chloride) gave N-hydroxy-2-(R)-{[4-(5-chloropyridin-2-yl-oxy)piperidine-1-sulfonyl]amino}-3-methylbutyramide as a white solid (35%), mp 97.0-98.4° C.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[S:10][CH2:9][CH2:8][C:7](=[O:12])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[N-:13]=[N+]=[N-].[Na+].OS(O)(=O)=O>CC(O)=O>[CH3:1][C:2]1[C:11]2[S:10][CH2:9][CH2:8][C:7](=[O:12])[NH:13][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1cccc2c1SCCC2=O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1cccc2c1SCCC(=O)N2
Temperature: 50 °C

Procedure:
To a solution of 8-methyl-2,3-dihydro-4H-1-benzothiopyran-4-one (2.24 g, 12.6 mmol) and NaN3 (1.64 g, 25.2 mmol) in AcOH (7.6 mL) was added dropwise at 50° C. conc. H2SO4 (1.9 mL). The reaction was maintained at 50° C. for 2 h and poured onto ice chips. The solid was collected by vacuum filtration and dried under vacuum at 23° C. This crude sample was a mixture of starting material, desired product and regioisomeric product with a ratio of 1:11:7 (by 1H NMR). Purification of the crude solid by column silica gel chromatography eluting with 20:1 CHCl3-MeOH provided a mixture 9-methyl-2,3-dihydro-1,5-benzothiazepin-4(5H)-one and its regioisomer (500 mg, 4:1, by 1H NMR). This sample was used without further purification. 1H NMR (CHCl3, 300 MHz) δ7.22 (t, 1H, J=7.7 Hz), 7.15 (d, 1H, J=7.3 Hz), 6.94 (d, 1H, J=7.4 Hz), 3.39 (t, 2H, J=7.3 Hz), 2.59 (t, 2H, J=7.0 Hz), 2.54 (s, 3H) ppm.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1([OH:8])[CH2:7][CH2:6]1.C(N(CC)CC)C.[CH3:16][S:17](Cl)(=[O:19])=[O:18]>ClCCl>[CH3:16][S:17]([O:1][CH2:2][CH2:3][CH2:4][C:5]1([OH:8])[CH2:7][CH2:6]1)(=[O:19])=[O:18]
Reactant: CS(=O)(=O)Cl
Reactant: OCCCC1(O)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCCC1(O)CC1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A mixture of 1-(3-hydroxypropyl)cyclopropanol (140 mg, 1.2 mmol) and triethylamine (0.3 mL, 2.1 mmol) in 8 mL of dichloromethane was stirred at 0° C. for 10 min. Methane-sulfonyl chloride (180 mg, 1.6 mmol) was then added to the mixture via a syringe. After stirring at 0° C. for 1 hr, the mixture was quenched with 2 mL of ice-water and extracted with dichloromethane (10 mL×3). The combined organic phases were dried over Na2SO4 and concentrated in vacuo to give 3-(1-hydroxycyclo-propyl)propyl methanesulfonate as yellow oil (used for the next step immediately).