Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[Br:10][C:11]1[CH:16]=[CH:15][C:14]([S:17]([O-:19])=[O:18])=[CH:13][CH:12]=1.[Na+]>CS(C)=O.C(OCC)(=O)C.[Cu]I>[Br:10][C:11]1[CH:16]=[CH:15][C:14]([S:17]([C:2]2[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=2)[CH:5]=[O:6])(=[O:19])=[O:18])=[CH:13][CH:12]=1
Reactant: O=S([O-])c1ccc(Br)cc1
Reactant: O=Cc1cccc(I)c1
Agent: [Cu]I
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: O=Cc1cccc(S(=O)(=O)c2ccc(Br)cc2)c1
Temperature: 110 °C
Yield: 35.8 %

Procedure:
3-Iodobenzaldehyde (1.0 g, 4.3 mmol), copper(I) iodide (2.45 g, 12.9 mmol) and sodium 4-bromophenylsulfinate (1.55 g, 5.59 mmol) were combined in dimethylsulfoxide (8.6 mL) and heated to 110° C. for 4 hours. The cooled reaction mixture was diluted with ethyl acetate and filtered through Hyflo®. The filtrate was washed with water (×2) and brine and dried over MgSO4. The solvent was removed in vacuo and the residue purified by flash column chromatography on silica, eluting with 25% ethyl acetate/isohexane, to give 3-[(4-bromophenyl)sulfonyl]benzaldehyde (0.5 g, 35%). δH (400 MHz, d6 DMSO): 10.09 (1H, s), 8.47-8.44 (1H, m), 8.29-8.25 (1H, m), 8.21 (1H, d, J=7.6 Hz), 7.96-7.94 (2H, m), 7.88-7.84 (3H, m).
Reaction SMILES: [C:1]([NH:5][C:6](=[O:33])[CH2:7][N:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([N:19]3[CH2:25][CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[CH:15]=2)[N:10]=[C:9]1[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[CH:27]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:34][C:35]([CH3:37])=O.C([BH3-])#N.[Na+].C(O)(=O)C>C1COCC1>[C:1]([NH:5][C:6](=[O:33])[CH2:7][N:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([N:19]3[CH2:25][CH2:24][CH2:23][N:22]([CH:35]([CH3:37])[CH3:34])[CH2:21][CH2:20]3)[CH:15]=2)[N:10]=[C:9]1[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[CH:27]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)=O
Reactant: CC(C)(C)NC(=O)Cn1c(-c2cccc(Cl)c2)nc2ccc(N3CCCNCC3)cc2c1=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(C)N1CCCN(c2ccc3nc(-c4cccc(Cl)c4)n(CC(=O)NC(C)(C)C)c(=O)c3c2)CC1
Yield: 47 %

Procedure:
N-tert-Butyl-2-[2-(3-chlorophenyl)-4-oxo-6-perhydro-1,4-diazepin-1-yl-4H-quinazolin-3-yl]acetamide (EXAMPLE 1a) (17 mg, 0.03 mmol), anhydrous acetone (30 μL), sodium cyanoborohydride (3 mg, 0.03 mmol) and glacial acetic acid (12 μL, 0.21 mmol) in anhydrous THF (0.15 mL) was heated in a microwave at 130° C. for 10 minutes. The resulting mixture was purified by preparative TLC on silica gel with DCM:MeOH:NH4OH (40:2:1, v/v) as eluent to give N-tert-butyl-2-[2-(3-chlorophenyl)-6-(4-isopropylperhydro-1,4-diazepin-1-yl)-4-oxo-4H-quinazolin-3-yl]acetamide (EXAMPLE 5a) (7.1 mg, 0.014 mmol, 47%).
Reaction SMILES: [C:1]([CH2:4][N:5]1[C:9](=[O:10])[CH2:8][S:7][C:6]1=[S:11])([OH:3])=O.[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][NH:20][CH:21]=[O:22])=[CH:15][CH:14]=1.C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1>[CH:21]([NH:20][NH:19][C:16]1[CH:17]=[CH:18][C:13]([NH:12][C:1]([CH2:4][N:5]2[C:9](=[O:10])[CH2:8][S:7][C:6]2=[S:11])=[O:3])=[CH:14][CH:15]=1)=[O:22]
Reactant: Nc1ccc(NNC=O)cc1
Reactant: O=C(O)CN1C(=O)CSC1=S
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: O=CNNc1ccc(NC(=O)CN2C(=O)CSC2=S)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a mixture of 1.91 g (10 millimole) of 3-carboxymethylrhodanine, 1.51 g (10 millimole) of 2-(4-aminophenyl)-1-formylhydrazine and 2.06 g (10 millimole) of N,N'-dicyclohexylcarbodiimide was added 50 ml of tetrahydrofuran. The resulting mixture was stirred for 5 hours at room temperature to precipitate crystals. These were filtered off, and dissolved in 50 ml of N,N-dimethylformamide (DMF). The matter remaining insoluble was removed from the solution. 100 ml of water was added to the filtrate, and allowed to stand for one night to precipitate crystals. These were filtered off, and washed with water and methanol. Thus, the intended compound was obtained. Yield, 2.98 g (92%). Melting Point, 260° C. (decomposed).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[C:8]([C:11]1[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1)(=[O:10])[CH3:9]>N1C=CC=CC=1>[C:8]([C:11]1[CH:12]=[CH:13][C:14]([S:17]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)(=[O:19])=[O:18])=[CH:15][CH:16]=1)(=[O:10])[CH3:9]
Reactant: CC(=O)c1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1ccccn1
Solvent: c1ccncc1
Product: CC(=O)c1ccc(S(=O)(=O)Nc2ccccn2)cc1

Procedure:
A solution of 13.4 g. of 2-aminopyridine in 300 ml. of pyridine is treated with 31.0 g. of 4-acetylbenzenesulfonyl chloride and the solution is stirred at room temperature for 6 hours. The solution is poured into 1 l. of cold water and the resulting precipitate of 4-acetyl-N-(2-pyridyl)benzenesulfonamide is collected by filtration, washed with water and dried; m.p. 201°-202° C. after crystallization from methanol.
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[C:6]([CH:17]=O)[C:7]3[C:12]([C:13]=2[CH:15]=O)=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1.[NH2:19][NH:20][C:21]([NH2:23])=[S:22].C(O)C>C(O)(=O)C>[N:19](=[CH:15][C:13]1[C:14]2[C:5]([C:6]([CH:17]=[N:19][NH:20][C:21]([NH2:23])=[S:22])=[C:7]3[C:12]=1[CH:11]=[CH:10][CH:9]=[CH:8]3)=[CH:4][CH:3]=[CH:2][CH:1]=2)[NH:20][C:21]([NH2:23])=[S:22]
Reactant: O=Cc1c2ccccc2c(C=O)c2ccccc12
Reactant: NNC(N)=S
Solvent: CCO
Solvent: CC(=O)O
Product: NC(=S)NN=Cc1c2ccccc2c(C=NNC(N)=S)c2ccccc12
Reaction time: 8 h

Procedure:
A mixture of 2.34 g. of 9,10-anthracenedicarboxaldehyde and 3.65 g. of thiosemicarbazide in 250 ml. of absolute ethanol containing 2.0 ml. of glacial acetic acid is heated on a steam bath for 24 hours, allowed to cool and then let stand overnight. The solid is collected, washed with absolute ethanol, dried and recrystallized from aqueous dimethylformamide giving the desired product as orange crystals, m.p. 275°-277° C.
Reaction SMILES: [C:1]1(=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:8][O:9][CH2:10][CH2:11][NH2:12].[BH4-].[Na+]>C1(C)C=CC=CC=1.C(O)C>[CH3:8][O:9][CH2:10][CH2:11][NH:12][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COCCN
Reactant: O=C1CCCCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: COCCNC1CCCCC1
Temperature: 110 °C
Reaction time: 12 h

Procedure:
A solution of cyclohexanone (10 g, 0.10 mol) in Toluene (100 ml) was treated with 2-methoxy ethylamine (8.4 g, 0.11 mol) and refluxed at 110° C. for 3 h. The reaction mass was cooled and diluted with ethanol (50 ml) and sodium borohydride (5.8 g, 0.15 mol) was added in portions at 0° C. The reaction mass was stirred at RT for 12 h and concentrated under reduced pressure. The residue was dissolved in water (100 ml), extracted with DCM (2×100ml), dried over sodium sulphate and evaporated. The crude material was purified by column chromatography by using DCM and methanol (98:2) as eluent to afford the title compound as a pale yellow liquid.
Reaction SMILES: C(OC(C1C(=O)N(CCC(C)C)N2C=CC=C2C=1O)=O)C.NC1C=CC(NS(C)(=O)=O)=CC=1S(N)(=O)=O.[CH3:38][S:39]([NH:42][C:43]1[CH:48]=[CH:47][C:46]([NH:49][C:50]([C:52]2[C:57](=[O:58])[N:56]([CH2:59][CH2:60][CH:61]([CH3:63])[CH3:62])[N:55]3[CH:64]=[CH:65][CH:66]=[C:54]3[C:53]=2[OH:67])=O)=[C:45]([S:68](=[O:71])(=[O:70])[NH2:69])[CH:44]=1)(=[O:41])=[O:40].N12CCCN=C1CCCCC2>N1C=CC=CC=1>[OH:67][C:53]1[C:54]2[N:55]([CH:64]=[CH:65][CH:66]=2)[N:56]([CH2:59][CH2:60][CH:61]([CH3:63])[CH3:62])[C:57](=[O:58])[C:52]=1[C:50]1[NH:49][C:46]2[CH:47]=[CH:48][C:43]([NH:42][S:39]([CH3:38])(=[O:41])=[O:40])=[CH:44][C:45]=2[S:68](=[O:71])(=[O:70])[N:69]=1
Reactant: CC(C)CCn1c(=O)c(C(=O)Nc2ccc(NS(C)(=O)=O)cc2S(N)(=O)=O)c(O)c2cccn21
Agent: CCOC(=O)c1c(O)c2cccn2n(CCC(C)C)c1=O
Agent: CS(=O)(=O)Nc1ccc(N)c(S(N)(=O)=O)c1
Solvent: c1ccncc1
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)CCn1c(=O)c(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)c(O)c2cccn21
Temperature: 120 °C
Reaction time: 3 h
Yield: 9.7 %

Procedure:
4-Hydroxy-1-(3-methyl-butyl)-2-oxo-1,2-dihydro-pyrrolo[1,2-b]pyridazine-3-carboxylic acid ethyl ester (Example 1f, 0.098 g, 0.33 mmol) and 2-amino-5-methanesulfonylamino-benzenesulfonamide (Example 3d or Example 3d′, 0.089 g, 0.33 mmol) were mixed in pyridine (1.5 mL) and the mixture was stirred under a nitrogen atmosphere at 120° C. for 3 h. LC-MS analysis confirmed the disappearance of the starting material and the formation of the uncyclized intermediate 4-hydroxy-1-(3-methyl-butyl)-2-oxo-1,2-dihydro-pyrrolo[1,2-b]pyridazine-3-carboxylic acid (4-methanesulfonylamino-2-sulfamoyl-phenyl)-amide. 1,8-Diazabicyclo[5,4,0]undec-7-ene (DBU) (150 μL, 1.0 mmol) was added and the mixture was stirred under nitrogen atmosphere at 120° C. for 16 h. LC-MS analysis indicated completion of the reaction and the mixture was concentrated in vacuo. The crude material was dissolved in dimethylsulfoxide and purified by preparative HPLC (Column ODS-A 100 Å, 5μ. 150×21.2 mm. Flow 22 mL/min, 30-100% acetonitrile/water with 0.01% trifluoroacetic acid) and lyophilized from water and 1,4-dioxane to afford the desired product, N-{3-[4-hydroxy-1-(3-methyl-butyl)-2-oxo-1,2-dihydro-pyrrolo[1,2-b]pyridazin-3-yl]-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-7-yl}-methanesulfonamide (0.016 g, 0.032 mmol, 9.7% yield) as a light brown powder. 1H NMR (DMSO-d6) δ 0.96 (6H, d, J=6.3 Hz), 1.55-1.60 (2H, m), 1.67-1.77 (1H, m), 3.07 (1H, s), 4.40 (2H, t, J=7.8 Hz), 6.70 (1H, s), 7.02 (1H, s), 7.52-7.67 (3H, m), 7.90 (1H, s), 10.20 (1H, s); LC-MS (ESI) calcd for C20H23N5O6S2 493.1 found 494.3 [M+H+].
Reaction SMILES: [OH:1][C@H:2]1[C@H:6]2[O:7][CH2:8][C@:3]1([CH2:25][OH:26])[O:4][C@H:5]2[N:9]1[CH:17]=[N:16][C:15]2[C:14](=[O:18])[NH:13][C:12]([NH:19][C:20](=[O:24])[CH:21]([CH3:23])[CH3:22])=[N:11][C:10]1=2.[CH3:27][O:28][C:29]1[CH:50]=[CH:49][C:32]([C:33](Cl)([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)=[CH:31][CH:30]=1>N1C=CC=CC=1>[CH3:41][O:40][C:37]1[CH:36]=[CH:35][C:34]([C:33]([O:26][CH2:25][C@@:3]23[C@@H:2]([OH:1])[C@@H:6]([O:7][CH2:8]2)[C@H:5]([N:9]2[CH:17]=[N:16][C:15]4[C:14](=[O:18])[NH:13][C:12]([NH:19][C:20](=[O:24])[CH:21]([CH3:22])[CH3:23])=[N:11][C:10]2=4)[O:4]3)([C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)[C:32]2[CH:49]=[CH:50][C:29]([O:28][CH3:27])=[CH:30][CH:31]=2)=[CH:39][CH:38]=1
Reactant: CC(C)C(=O)Nc1nc2c(ncn2[C@@H]2O[C@@]3(CO)CO[C@@H]2[C@@H]3O)c(=O)[nH]1
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Solvent: c1ccncc1
Product: COc1ccc(C(OC[C@@]23CO[C@@H]([C@H](n4cnc5c(=O)[nH]c(NC(=O)C(C)C)nc54)O2)[C@@H]3O)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of compound 51 (440 mg, 1.21 mmol) and 4,4′-dimethoxytrityl chloride (573 mg, 1.69 mmol) was dissolved in anhydrous pyridine (7 cm3) and was stirred at room temperature for 4 h. The mixture was evaporated under reduced pressure to give an oil. Extraction was performed in a system of dichloromethane/water (1:1, v/v, 40 cm3). The organic phase was separated and concentrated to give a solution in a minimal volume of dichloromethane containing 0.5% of pyridine (v/v) which was applied to a silica gel column equilibrated by the same solvent. The product was eluted in gradient concentrations of methanol (0.6-2%, v/v) in dichloromethane containing 0.5% of pyridine (v/v) to give compound 52 as a white solid material (695 mg, 86%). δH (CDCl3) 12.17 (1H, br s, NHCO), 10.09 (1H, br s, NH), 7.87 (1H, s, 8-H), 7.42-6.72 (13H, m, DMT), 5.69 (1H, s, 1′-H), 4.59 (1H, s, 2′-H), 4.50 (1H, s, 3′-H), 3.98 (1H, d, J 8.1, 1″-Ha), 3.69-3.39 (9H, m, DMT, 5′-H, 1″-Hb), 2.72 (1H, m, CHCO), 1.17 (6H, d, J 6.8, CH3CH). (CDCl3) 179.8 (COCH), 158.8, 144.5, 135.6, 135.5, 130.1, 128.1, 127.7, 126.9, 113.2 (DMT), 155.8, 147.9, 147.5, 137.0, 120.8 (guanine), 87.6, 86.4, 86.1 (C-1′, C-4′, DMT), 79.7 (C-3′), 72.6, 71.4 (C-2′, C-5′), 59.8 (C-1″), 55.2 (DMT), 36.1 (COCH), 19.1, 18.8 (CH3CH). FAB-MS m/z 668 [M+H]+.
Reaction SMILES: [CH:1]1([N:4]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])[CH:5]2[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[CH2:3][CH2:2]1.Cl[C:20]([O:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][C:30]2[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][N:31]=2)=[CH:25][CH:24]=1)=[O:21].C(NC(C)C)(C)C>CN(C)C=O>[F:38][C:36]([F:37])([F:39])[C:33]1[CH:34]=[CH:35][C:30]([O:29][C:26]2[CH:27]=[CH:28][C:23]([O:22][C:20]([N:8]3[CH2:9][CH2:10][CH:5]([N:4]([CH:1]4[CH2:3][CH2:2]4)[CH2:11][C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=4[F:18])[CH2:6][CH2:7]3)=[O:21])=[CH:24][CH:25]=2)=[N:31][CH:32]=1
Reactant: O=C(Cl)Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Reactant: Fc1ccccc1CN(C1CCNCC1)C1CC1
Solvent: CN(C)C=O
Solvent: CC(C)NC(C)C
Product: O=C(Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1)N1CCC(N(Cc2ccccc2F)C2CC2)CC1

Procedure:
The title product was prepared from cyclopropyl-(2-fluoro-benzyl)-piperidin-4-yl-amine and 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate, 3 equivalent of diisopropylamine was added, solvent: dimethylformamide. The crude reaction mixture was evaporated without addition of acetic acid, preparative HPLC (method C) (60%, colourless oil). HPLC-MS m/z=(M+1), Rt: 3.02 min.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41](O)=[O:42])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:47]([NH:50][CH2:51][CH2:52][CH3:53])[CH2:48][CH3:49]>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41]([N:50]([CH2:51][CH2:52][CH3:53])[CH2:47][CH2:48][CH3:49])=[O:42])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CCCNCCC
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)O)CC1
Product: CCCN(CCC)C(=O)CC1CCN(C(=O)N2C(c3cnc(C(C)(C)C)cc3OCC)=N[C@@](C)(c3ccc(Cl)cc3)[C@@]2(C)c2ccc(Cl)cc2)CC1

Procedure:
In a manner analogous to the method described in example 163, {1-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperidin-4-yl}-acetic acid was reacted with dipropylamine (Pennwalt) to give the title product. LC-MS (ES+) 748 [(M+H)+].
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]1[C:13]([CH3:14])=[C:12]([OH:15])[C:11](=[O:16])[N:10]1[C:17]1[CH:32]=[CH:31][C:20]2[N:21](C(OC(C)(C)C)=O)[CH:22]=[N:23][C:19]=2[CH:18]=1.Br[CH2:34][CH3:35]>>[NH:21]1[C:20]2[CH:31]=[CH:32][C:17]([N:10]3[CH:9]([C:3]4[CH:4]=[CH:5][CH:6]=[C:7]([F:8])[C:2]=4[F:1])[C:13]([CH3:14])=[C:12]([O:15][CH2:34][CH3:35])[C:11]3=[O:16])=[CH:18][C:19]=2[N:23]=[CH:22]1
Reactant: CC1=C(O)C(=O)N(c2ccc3c(c2)ncn3C(=O)OC(C)(C)C)C1c1cccc(F)c1F
Reactant: CCBr
Product: CCOC1=C(C)C(c2cccc(F)c2F)N(c2ccc3[nH]cnc3c2)C1=O

Procedure:
The compound was synthesized starting from tert-butyl 5-(2-(2,3-difluorophenyl)-4-hydroxy-3-methyl-5-oxo-2H-pyrrol-1(5H)-yl)-1H-benzo[d]imidazole-1-carboxylate (0.22 g, 0.5 mmol), bromoethane (0.056 ml, 0.75 mmol) and PrtBu (0.191 ml, 0.75 mmol) according to the method described above.
Reaction SMILES: Cl[C:2]1[CH2:6][C:5]([CH3:8])([CH3:7])[CH2:4][C:3]=1[CH:9]=O.C(N(CC)CC)C.[SH:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]>ClCCl>[CH3:8][C:5]1([CH3:7])[CH2:6][C:2]2[S:18][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:9][C:3]=2[CH2:4]1
Reactant: CC1(C)CC(Cl)=C(C=O)C1
Reactant: CCOC(=O)CS
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1cc2c(s1)CC(C)(C)C2

Procedure:
To a solution of 131b (33.0 g, crude) in dichloromethane (400 mL) and triethylamine (60 g, 600 mmol) was added ethyl 2-mercaptoacetate (19.2 g, 160 mmol). See FIG. 15. The reaction mixture was heated at reflux for 6 h. It was then concentrated under reduced pressure. The residue was dissolved in ethanol (400 mL) and triethylamine (60 g, 600 mmol). The mixture was heated at reflux for 12 h. It was concentrated again under reduced pressure and the residue was purified by silica-gel column chromatography eluting with 40:1 petroleum ether/ethyl acetate to 131c as a yellow solid (18.0 g, 32%, over two steps). MS-ESI: [M+H]+ 225.3. 1H NMR (500 MHz, DMSO-d6) δ 7.49 (s, 1H), 4.32 (q, J=7.0 Hz, 2H), 2.72 (s, 2H), 2.56 (s, 2H), 1.35 (t, J=7.0 Hz, 3H), 1.22 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:10]=[C:11]([N:16]3[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[N:17]3)[C:12]([NH2:15])=[N:13][CH:14]=2)=[CH:4][CH:3]=1.[CH:23](=O)[CH3:24].[Na].C(=O)([O-])O.[Na+]>ClC(Cl)C.ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]2[N:10]=[C:11]([N:16]3[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[N:17]3)[C:12]([NH:15][CH2:23][CH3:24])=[N:13][CH:14]=2)=[CH:6][CH:7]=1
Reactant: Cc1cc(C)n(-c2nc(Nc3ccc(Cl)cc3)cnc2N)n1
Reactant: CC=O
Agent: O=C([O-])O
Agent: [Na+]
Agent: [Na]
Solvent: CC(Cl)Cl
Solvent: ClCCl
Product: CCNc1ncc(Nc2ccc(Cl)cc2)nc1-n1nc(C)cc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 9.5 %

Procedure:
5-(4-Chloro-phenylamino)-3-(3,5-dimethyl-pyrazol-1-yl) -pyrazine-2-amine (84 mg, 1.5 mmol) was dissolved in dichloroethane (4 mL). Acetaldehyde (83 μL, 1.5 mmol) was added and the reaction mixture was stirred for one hour at room temperature. Sodium triaceoxyborohydride (70 mg, 0.3 mmol) was added and the reaction mixture was stirred overnight at room temperature. Aqueous sodium hydrogen carbonate and dichloromethane were added. The phases were separated and the aqueous phase was extracted with dichloromethane (3×20 mL). The combined organic phases were washed with brine, dried over sodium sulphate, filtrated and concentrated in vacuo. The crude product was purified by flash chromatography (ethyl acetate/heptane as eluent) to give 5-(4-chloro-phenylamino)-3-(3,5-dimethyl-pyrazol-1-yl)-2-ethylamino-pyrazine (49 mg, 80%) as a green solid. Mp. 122-124° C. LC-ESI-HRMS of [M+H]+ shows 343.1444 Da. Calc. 343.143797 Da, dev. 1.8 ppm
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[H-].[Na+].C([Li])CCC.[F:16][C:17]1[C:22](C=O)=[C:21]([F:25])[C:20]([F:26])=[C:19]([F:27])[C:18]=1[F:28]>CCCCCC.O1CCCC1>[OH:4][C:3]1[CH2:5][CH:8]([C:22]2[C:21]([F:25])=[C:20]([F:26])[C:19]([F:27])=[C:18]([F:28])[C:17]=2[F:16])[O:7][C:1](=[O:6])[CH:2]=1
Reactant: COC(=O)CC(C)=O
Reactant: O=Cc1c(F)c(F)c(F)c(F)c1F
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C1C=C(O)CC(c2c(F)c(F)c(F)c(F)c2F)O1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
The title compound was prepared as described in General Method 1 using 2.5 mL of methyl acetoacetate, 1.0 g of NaH 60% dispersion in oil, 12.5 mL of 2.0M n-butyl lithium in hexane, 3.4 mL of pentafluorobenzaldehyde and 75 mL of tetrahydrofuran. After addition of the aldehyde, the reaction was stirred for 10 minutes at 0° C. then allowed to warm to room temperature overnight. The crude product was triturated from diethyl ether to afford a solid (m.p. 176°-178° C.). 1H NMR (CDCl3) δ 2.89 (dd, 1 H), 3.15 (dd, 1 H), 3.70 (dd, 2 H), 6.02 (dd, 1 H).
Reaction SMILES: CN(C)C=O.[NH2:6][C:7]1[N:12]=[C:11]([N:13]2[C:22]3[C:17](=[CH:18][C:19]([F:25])=[C:20](F)[C:21]=3[Br:23])[C:16](=[O:26])[C:15]([C:27]([OH:29])=[O:28])=[CH:14]2)[C:10]([F:30])=[CH:9][C:8]=1[F:31].Cl.Cl.[NH2:34][CH:35]1[CH2:38][NH:37][CH2:36]1.CN1CCCC1>C(O)C>[NH2:34][CH:35]1[CH2:38][N:37]([C:20]2[C:21]([Br:23])=[C:22]3[C:17]([C:16](=[O:26])[C:15]([C:27]([OH:29])=[O:28])=[CH:14][N:13]3[C:11]3[C:10]([F:30])=[CH:9][C:8]([F:31])=[C:7]([NH2:6])[N:12]=3)=[CH:18][C:19]=2[F:25])[CH2:36]1
Reactant: Nc1nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Br)c32)c(F)cc1F
Reactant: NC1CNC1
Agent: CN1CCCC1
Agent: Cl
Solvent: CCO
Solvent: CN(C)C=O
Product: Nc1nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(N4CC(N)C4)c(Br)c32)c(F)cc1F
Temperature: 90 °C
Reaction time: 1 h
Yield: 67.1 %

Procedure:
To 300 mg of N,N-dimethylformamide were added 105 mg of 1-(6-amino-3,5-difluoropyridin-2-yl)-8-bromo-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 70 mg of 3-aminoazetidine dihydrochloride, and 150 mg of N-methylpyrrolidine, and the mixture was stirred at 90° C. for 1 hour. After adding 0.3 ml of ethanol, the mixture was allowed to cool, and the precipitate was collected by filtration and washed with ethanol and diisopropylether successively to obtain 79 mg of the title compound as a colorless powder.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][N:9]([C:14]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:15]=2[CH:16]=[CH:17][N:18]3[CH2:23][C:24]([OH:26])=[O:25])[S:10]([CH3:13])(=[O:12])=[O:11])[CH2:3][CH2:2]1.[Cl:27][C:28]1[CH:29]=[N+:30]([O-:53])[CH:31]=[C:32]([Cl:52])[C:33]=1[CH2:34][C@@H:35]([C:37]1[CH:42]=[CH:41][C:40]([O:43][CH:44]([F:46])[F:45])=[C:39]([O:47][CH2:48][CH:49]2[CH2:51][CH2:50]2)[CH:38]=1)O.C(Cl)CCl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:27][C:28]1[CH:29]=[N+:30]([O-:53])[CH:31]=[C:32]([Cl:52])[C:33]=1[CH2:34][C@@H:35]([C:37]1[CH:42]=[CH:41][C:40]([O:43][CH:44]([F:46])[F:45])=[C:39]([O:47][CH2:48][CH:49]2[CH2:51][CH2:50]2)[CH:38]=1)[O:25][C:24](=[O:26])[CH2:23][N:18]1[C:19]2[C:15](=[C:14]([N:9]([CH2:8][CH2:7][N:4]3[CH2:5][CH2:6][O:1][CH2:2][CH2:3]3)[S:10]([CH3:13])(=[O:12])=[O:11])[CH:22]=[CH:21][CH:20]=2)[CH:16]=[CH:17]1
Reactant: CS(=O)(=O)N(CCN1CCOCC1)c1cccc2c1ccn2CC(=O)O
Reactant: [O-][n+]1cc(Cl)c(C[C@H](O)c2ccc(OC(F)F)c(OCC3CC3)c2)c(Cl)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: CS(=O)(=O)N(CCN1CCOCC1)c1cccc2c1ccn2CC(=O)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Yield: 10.3 %

Procedure:
To a solution of 2-(4-(N-(2-morpholinoethyl)methylsulfonamido)-1H-indol-1-yl)acetic acid (100 mg, 0.262 mmol) in DCM (5 ml), (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-hydroxyethyl)pyridine 1-oxide (110 mg, 0.262 mmol), EDC (151 mg, 0.786 mmol) and DMAP (64.1 mg, 0.524 mmol) were added, and the mixture was reacted overnight at room temperature. The solvent was evaporated and the residue was partitioned between 1N HCl (10 ml) and EtOAc; the aqueous phase was extracted with EtOAc, the combined organic layers were dried over sodium sulfate and the solvent was removed under vacuum. Three flash chromatographic column on silica gel (DCM/MeOH 97/3) were required to afford (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-(4-(N-(2-morpholinoethyl)methylsulfonamido)-1H-indol-1-yl)acetoxy)ethyl)pyridine 1-oxide (21.4 mg, 0.027 mmol, 10.4% yield, MS/ESI+ 783.19 [MH]+, [αD]=+14.1, c=0.2 DCM). 1H NMR (300 MHz, DMSO-d6) δ ppm 8.50 (s, 2H), 7.34 (d, 1H), 7.07-7.21 (m, 5H), 6.90 (dd, 1H), 7.06 (t, 1H), 6.55 (d, 1H), 6.02 (dd, 1H), 5.25 (d, 1H), 5.10 (d, 1H), 3.91 (d, 2H), 3.80 (t, 2H), 3.46-3.54 (m, 4H), 3.41 (dd, 1H), 3.21 (dd, 1H), 3.09 (s, 3H), 2.32 (dd, 2H), 2.23-2.31 (m, 4H), 1.07-1.36 (m, 1H), 0.54-0.65 (m, 2H), 0.29-0.47 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:7](=[O:8])[O:6][CH2:5]2.BrN1C(=[O:18])CCC1=O.O>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:7](=[O:8])[O:6][CH:5]2[OH:18]
Reactant: O=C1CCC(=O)N1Br
Reactant: O=C1OCc2cc(Br)ccc21
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: O=C1OC(O)c2cc(Br)ccc21
Reaction time: 4 h

Procedure:
A mixture of 13.3 gm 5-bromophthalide and 12.7 gm N-bromosuccinimide in 480 ml carbon tetrachloride was irradiated with a tungsten floor lamp and refluxed for 3 hours. The reaction was followed by NMR. The succinimide was filtered off and the cake washed with carbon tetrachloride. The solvent was removed in vacuo leaving a residue of 19.2 gm, to which was added 100 ml water. This mixture was refluxed with stirring for 4 hours, then the mixture was cooled and the product filtered off, washed neutral with water and dried. Wt=9.9 gm.