Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[CH3:9].[C:10](Cl)(=[O:19])[CH:11]=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>ClCCl.N1C=CC=CC=1>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:10](=[O:19])[CH:11]=[CH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:4][C:3]=1[CH3:9]
Reactant: Cc1cc(N)ccc1Cl
Reactant: O=C(Cl)C=Cc1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1cc(NC(=O)C=Cc2ccccc2)ccc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
To 4-chloro-3-methylaniline (3.33 g, 19.98 mmole) in dichloromethane (100 mL) and pyridine (20 mL) was added cinnamoyl chloride (2.83 g, 19.98 mmole) at 0° C. The mixture was stirred at room temperature for 2 h. Solvent and pyridine were removed by rotary evaporator under reduced pressure. The residue was diluted with ethyl acetate and washed 1N HCl (2×100 mL), water (2×100 mL), sodium bicarbonate solution (2×100 mL) and dried over sodium sulfate. After removing solvent a white solid was recovered (5.38 g, 99% yield). The product was used for the next step without further purification. 1H NMR (400 MHz, DMSO-d6): δ 7.76-7.24 (m, 10H), 6.58 (d, 1H), 2.55 (s, 3H); MS (ESI) m/z: Calculated for C16H14ClNO: 271.1. found: 272 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[C:12]1([CH3:22])[C:13]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:15]=[CH:16][CH:17]=1>CN(C1C=CN=CC=1)C.CCCCCC>[CH3:22][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[S:18]([NH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2)(=[O:20])=[O:19]
Reactant: Nc1cccc2cccnc12
Reactant: Cc1ccccc1S(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCCCCC
Product: Cc1ccccc1S(=O)(=O)Nc1cccc2cccnc12
Yield: 64.5 %

Procedure:
In the similar fashion using route 14 general procedure 27, 8-aminoquinoline (200 mg, 1.38 mmol), o-toluenesulfonyl chloride (260 mg, 1.3 mmol) and DMAP (cat.) gave the title compound (250 mg, 60%) after trituration from n-hexane.
Reaction SMILES: [CH3:1][N:2]([CH3:13])/[C:3](/SC)=[N:4]/[C:5](=O)[CH:6]=[C:7]([CH3:9])[CH3:8].[CH3:14][NH:15][NH2:16]>C(OCC)(=O)C>[CH3:1][N:2]([CH3:13])[C:3]1[N:4]=[C:5]([CH:6]=[C:7]([CH3:9])[CH3:8])[N:15]([CH3:14])[N:16]=1
Reactant: CS/C(=N\C(=O)C=C(C)C)N(C)C
Reactant: CNN
Solvent: CCOC(C)=O
Product: CC(C)=Cc1nc(N(C)C)nn1C
Temperature: 100 °C
Yield: 38.1 %

Procedure:
A mixture of (Z)-methyl N,N-dimethyl-N′-(3-methylbut-2-enoyl)carbamimidothioate (2.41 g, 12.0 mmol, Eq: 1.00) and methylhydrazine (5.54 g, 6.34 ml, 120 mmol, Eq: 10) was heated to 100° C. for 30 minutes. The mixture was dissolved in ethyl acetate and washed with water 3 times and once with brine. The organic layer was separated, dried over magnesium sulfate, filtrated and evaporated affording dimethyl-[1-methyl-5-(2-methyl-propenyl)-1H-[1,2,4]triazol-3-yl]-amine (824 mg/38.0%) as a yellow liquid. A mixture of N,N,1-trimethyl-5-(2-methylprop-1-enyl)-1H-1,2,4-triazol-3-amine (824 mg, 4.57 mmol, Eq: 1.00), osmium tetroxide 4% aq. (872 mg, 872 μl, 137 μmol, Eq: 0.03), sodium periodate (3.91 g, 18.3 mmol, Eq: 4) and benzyltriethylammonium chloride (416 mg, 1.83 mmol, Eq: 0.4) in dioxane (42 ml) and water (13 ml) was stirred for 2 hours at 60° C. The mixture was diluted with ethyl acetate and washed with 2× water and brine. The organic layer was separated, dried over magnesium sulfate, filtrated and evaporated affording 1.0 g dark brown oil. The crude material was applied on silicagel and purified by flash chromatography over a 50 g silicagel column using ethyl acetate/methanol 0-10% as eluent affording 5-dimethylamino-2-methyl-2H-[1,2,4]triazole-3-carbaldehyde (127 mg/60.0%) as a brown oil. MS: m/e=155.3 (M+H+)
Reaction SMILES: [O:1]1[CH2:4][CH:3]([N:5]2[CH2:10][CH2:9][CH:8]([N:11]3[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]3)[CH2:7][CH2:6]2)[CH2:2]1.FC(F)(F)C(O)=O>ClCCl>[O:1]1[CH2:4][CH:3]([N:5]2[CH2:6][CH2:7][CH:8]([N:11]3[CH2:12][CH2:13][NH:14][CH2:15][CH2:16]3)[CH2:9][CH2:10]2)[CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCN(C2CCN(C3COC3)CC2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C1CN(C2CCN(C3COC3)CC2)CCN1
Reaction time: 0.5 h

Procedure:
In a 100 ml round-bottom flask 1.63 g (5.01 mmol) of tert-butyl 4-(1-(oxetan-3-yl)-piperidin-4-yl)-piperazine-1-carboxylate were dissolved in 5 ml of dichloromethane. 3 ml (38.9 mmol) of trifluoroacetic acid were added and the reaction was stirred for 30 min. The solution was concentrated and digested in 40 ml of methyl-tert-butyl ether. The solid was filtered and washed with 20 ml of methyl-tert-butyl ether to yield 2.79 of the title compound as a white solid.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[Br:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=1.[CH3:24][N:25]1[CH2:39][CH2:38][N:28]2[C:29]3[CH:37]=[CH:36][CH:35]=[CH:34][C:30]=3[NH:31][CH2:32][CH2:33][CH:27]2[CH2:26]1.C(O)(=O)C>O1CCCC1.Cl>[Br:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][N:31]2[C:30]3[CH:34]=[CH:35][CH:36]=[CH:37][C:29]=3[N:28]3[CH2:38][CH2:39][N:25]([CH3:24])[CH2:26][CH:27]3[CH2:33][CH2:32]2)=[CH:18][CH:17]=1
Reactant: CN1CCN2c3ccccc3NCCC2C1
Reactant: O=Cc1ccc(Br)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CN1CCN2c3ccccc3N(Cc3ccc(Br)cc3)CCC2C1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Sodium triacetoxyborohydride (200 mg, 0.944 mmol) was added to an ice-cooled solution of 4-bromobenzaldehyde (122 mg, 0.659 mmol) and the product of Example 22F (63 mg, 0.290 mmol) in tetrahydrofuran (5 mL). A few drops of 10% HCl (aq) were added, and the mixture was allowed to warm to room temperature. After 5 hours, acetic acid (2 mL) and additional sodium triacetoxyborohydride (200 mg, 0.944 mmol) were added, and the mixture was stirred an additional 15 hours. The reaction mixture was concentrated under vacuum, and the residue was purified by flash chromatography (SiO2, eluted with CH2Cl2, then CH2Cl2-methanol-15 M NH4OH, 95:5:0.5-90:10:1) to provide the title compound: 1H NMR (300 MHz, CD3OD) δ ppm 1.62 (tt, J=15.3, 5.3, 2.6 Hz, 1H), 1.84-2.00 (m, 1H), 2.33 (t, J=10.9 Hz, 1H), 2.42-2.51 (m, 1H), 2.43 (s, 3H), 2.77 (dt, J=10.7, 2.0 Hz, 1H), 2.85 (ddd, J=11.1, 5.2, 3.6 Hz, 1H), 2.89-3.04 (m, 2H), 3.13 (dt, J=11.9, 2.8 Hz, 1H), 3.30 (s, 1H), 3.45 (td, J=11.3, 2.8 Hz, 1H), 4.22 (d, J=15.1 Hz, 1H), 4.46 (d, J=15.1 Hz, 1H), 6.77-6.96 (m, 4H), 7.27 (d, J=8.3 Hz, 2H), 7.44 (d, J=8.3 Hz, 2H); MS (DCI) m/z 386/388 (M+H)+.
Reaction SMILES: [CH2:1]([C:4]1[C:13]2[O:12][C:11]([C:14]3[NH:18][N:17]=[N:16][N:15]=3)=[CH:10][C:9](=[O:19])[C:8]=2[C:7]([O:20][CH2:21][CH2:22][CH:23]([CH3:25])[CH3:24])=[CH:6][CH:5]=1)[CH:2]=[CH2:3].[CH2:26](Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.[OH-].[Na+].C(O)C>O>[CH2:1]([C:4]1[C:13]2[O:12][C:11]([C:14]3[N:15]([CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[N:16]=[N:17][N:18]=3)=[CH:10][C:9](=[O:19])[C:8]=2[C:7]([O:20][CH2:21][CH2:22][CH:23]([CH3:25])[CH3:24])=[CH:6][CH:5]=1)[CH:2]=[CH2:3]
Reactant: BrCc1ccccc1
Reactant: C=CCc1ccc(OCCC(C)C)c2c(=O)cc(-c3nnn[nH]3)oc12
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: C=CCc1ccc(OCCC(C)C)c2c(=O)cc(-c3nnnn3Cc3ccccc3)oc12

Procedure:
A mixture of 30 parts of 5-[8-allyl-5-(3-methyl-n-butoxy)-4-oxo-4H-1-benzopyran-2-yl]tetrazole, 16.6 parts of benzyl bromide, 3.53 parts of sodium hydroxide, 120 parts of ethanol and 60 parts of water was refluxed for 64 hours. The mixture was cooled, was extracted with chloroform and the chloroform extract washed with sodium bicarbonate solution and water. Evaporation of the chloroform gave a residue which was chromatographed in silica gel. Elution with 3 : 1 toluene/acetic acid and chloroform gave, after crystallisation from ethanol, a total of 7.31 parts of 5-[8-allyl-5-(3-methyl-n-butoxy)-4-oxo-4H-1-benzopyran-2-yl]-N-benzyltetrazole, m.p. 92.5°-94°C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][CH:3]=1.[Cl:9][CH2:10][C:11](Cl)=[O:12].[Cl-].[Al+3].[Cl-].[Cl-].Cl>>[Cl:9][CH2:10][C:11]([C:6]1[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=1[F:8])=[O:12]
Reactant: O=C(Cl)CCl
Reactant: Fc1ccc(F)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: O=C(CCl)c1cc(F)ccc1F
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 62.3 %

Procedure:
100.0 g (876.5 mmol) of 1,4-difluorobenzene and 90.83 ml (1139 mmol) of chloroacetyl chloride were cooled to 10° C. Within 5 minutes at 10–17° C. 153.5 g (1139 mmol) of aluminium chloride (99%) were added and the mixture warmed to room temperature. The mixture was heated for 30 minutes to 60° C. and the heating continued at this temperature for another 70 minutes. The reaction mixture was cooled to room temperature and poured onto a mixture of 0.8 l of ice and 400 ml at concentrated aqueous hydrochloric acid, extracted twice with each 500 ml of ethyl acetate, and the organic phases were washed once with 200 ml of water, three times with 400 ml of half-saturated aqueous sodium bicarbonate solution, dried over sodium sulfate, dissolved for 1 hour at 80° C. in 400 ml of n-hexane and, after the addition of 4 g of active carbon, filtered hot, stirred at room temperature and cooled to 0° C.; the crystals formed were dried at room temperature under reduced pressure to give 104 g (69%) of 2-chloro-1-(2,5-difluoro-phenyl)-ethanone.
Reaction SMILES: C[C:2]1(C)[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][CH2:4][C:3]1=[O:10].Cl.[CH3:13]C(C)=O>[Cl-].[Na+].O>[CH3:9][C:6]1([CH:8]=[CH2:13])[CH2:7][CH2:2][C:3](=[O:10])[CH2:4][CH2:5]1
Reactant: CC1(C)CCC(=O)C(C)(C)C1
Reactant: CC(C)=O
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: C=CC1(C)CCC(=O)CC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 94 %

Procedure:
To a stirred solution of 2 (1.98 mmol, 360 mg) in acetone (7.76 mL) was added 10% aqueous hydrochloric acid solution (3.02 mL), and the resulting mixture was stirred at room temperature for 2.5 hours. The reaction mixture was then diluted with brine (40 mL) and extracted with methylene chloride/ethyl ether (1:2, 3×30 mL). The organic layers were combined and washed with saturated aqueous sodium bicarbonate solution (2×30 mL) and brine (1×30 mL), then dried over magnesium sulfate, filtered, and concentrated in vacuo to give 19 (251.6 mg, 1.92 mmol, 94%) as a yellow oil that was used in the next reaction without further purification: 1H NMR (CDCl3) δ 5.89 (1H, dd, J=0.5, 17.3 Hz), 5.15 (1H, dd, J=1, 3.5 Hz), 5.12 (1H, dd, J=0.5, 10 Hz), 2.42-2.28 (4H, m), 1.97-1.91 (2H, m), 1.74-1.68 (2H, m), 1.12 (3H, s); 13C NMR (CDCl3) δ 212.4, 145.5, 112.9, 38.2, 37.1, 27.4; MS (EI) m/z 138.1 [M+], 123.1, 110.1, 105.1, 97.1, 86.0 (100%), 68.1, 63.0, 54.9; HRMS (EI) calcd for C9H14O 138.1045 found 138.1048.
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][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([S:38][CH2:39][CH2:40][S:41][C:42]5[N:43]([CH3:47])[CH:44]=[CH:45][N:46]=5)=[CH:34][CH:33]=4)=[O:30])=[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+]>C(Cl)Cl>[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][CH:26]([CH3:27])[CH3:28])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:33]=[CH:34][C:35]([S:38]([CH2:39][CH2:40][S:41][C:42]5[N:43]([CH3:47])[CH:44]=[CH:45][N:46]=5)=[O:57])=[CH:36][CH:37]=4)=[O:30])=[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(SCCSc4nccn4C)cc2)CCN3CC(C)C)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)CCSc4nccn4C)cc2)CCN3CC(C)C)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 55.4 %

Procedure:
7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[2-[(1-methylimidazol-2-yl)sulfanyl]ethyl]sulfanyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (1.20 g) was dissolved in methylene chloride (24.0 ml), and a solution of metachloroperbenzoic acid (0.52 g) in methylene chloride (24.0 ml) was added dropwise to the solution at −78° C. The mixture was stirred for 15 minutes, and to the mixture was added an aqueous solution of saturated sodium thiosulfate, and the mixture was allowed to be warmed to room temperature. The mixture was extracted with ethyl acetate, washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[2-[(1-methylimidazol-2-yl)sulfanyl]ethyl]sulfinyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 310) (0.68 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[O:17][CH3:18])=[CH:9][N:8]([S:19]([C:22]3[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=3)(=[O:21])=[O:20])[C:5]2=[N:6][CH:7]=1.[C:29]([O:33][C:34]([C:36]1[CH:37]=[C:38](B(O)O)[CH:39]=[CH:40][CH:41]=1)=[O:35])([CH3:32])([CH3:31])[CH3:30].ClCCl>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(#N)C>[C:29]([O:33][C:34](=[O:35])[C:36]1[CH:37]=[CH:38][CH:39]=[C:40]([C:2]2[CH:3]=[C:4]3[C:10]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=4[O:17][CH3:18])=[CH:9][N:8]([S:19]([C:22]4[CH:23]=[CH:24][C:25]([CH3:28])=[CH:26][CH:27]=4)(=[O:20])=[O:21])[C:5]3=[N:6][CH:7]=2)[CH:41]=1)([CH3:32])([CH3:30])[CH3:31]
Reactant: COc1ccccc1-c1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(Br)cc12
Reactant: CC(C)(C)OC(=O)c1cccc(B(O)O)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CC#N
Solvent: ClCCl
Product: COc1ccccc1-c1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(-c3cccc(C(=O)OC(C)(C)C)c3)cc12
Temperature: 90 °C
Yield: 87.3 %

Procedure:
To a solution of 5-bromo-3-(2-methoxy-phenyl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine (1.01 g, 2.21 mmol) in a 1:1 acetonitrile/saturated aqueous NaHCO3 solution (20 mL total) was added (3-tert-butoxycarbonylphenyl)boronic acid (0.54 g, 2.43 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II), complex with dichloromethane (1:1) (0.90 g, 0.11 mmol) in a microwave vial. The vial was capped, flushed with N2, evacuated under vacuum, and subsequently heated in a microwave at 90° C. for 1800 seconds. The material was diluted with ethyl acetate and the organic layer was washed with H2O then dried over Na2SO4. The solution was adsorbed onto silica gel and purified by flash chromatography with a gradient of ethyl acetate and hexanes, affording 3-[3-(2-methoxy-phenyl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine-5-yl]-benzoic acid tert-butyl ester as a white solid (1.07 g, 87% yield). 1H NMR (500 MHz, CDCl3) δ 8.68 (s, 1H), 8.17 (br s, 3H), 8.09 (s, 1H), 7.99 (m, 2H), 7.71 (d, J=6.5 Hz, 1H), 7.50 (m, 2H), 7.34 (t, J=8.0 Hz, 1H), 7.32 (d, J=6.5 Hz, 2H), 7.06 (m, 2H), 3.88 (s, 3H), 2.39 (s, 3H), 1.60 (s, 9H). MS: m/e 555.1 (M+H+).
Reaction SMILES: Cl.[CH3:2][C:3]1[N:4]=[C:5]([NH:20]C(=O)C)[S:6][C:7]=1[C:8]1[N:9]=[C:10]([C:13]2([C:16]([F:19])([F:18])[F:17])[CH2:15][CH2:14]2)[S:11][CH:12]=1>CCO>[CH3:2][C:3]1[N:4]=[C:5]([NH2:20])[S:6][C:7]=1[C:8]1[N:9]=[C:10]([C:13]2([C:16]([F:19])([F:18])[F:17])[CH2:14][CH2:15]2)[S:11][CH:12]=1
Reactant: CC(=O)Nc1nc(C)c(-c2csc(C3(C(F)(F)F)CC3)n2)s1
Agent: Cl
Solvent: CCO
Product: Cc1nc(N)sc1-c1csc(C2(C(F)(F)F)CC2)n1

Procedure:
HCl (1.17 g 32% aqueous solution) was added to a solution of N-[4′-methyl-2-(1-trifluoromethyl-cyclopropyl)-[4,5′]bithiazolyl-2′-yl]-acetamide (Step 10.3) (0.18 g) in EtOH (10 mL) and the reaction mixture heated at reflux for 7 h. The cooled reaction mixture was partitioned between EtOAc and aqueous NaHCO3 solution, the organic layers dried over Na2SO4 and evaporated to give the title compound. MS (ESI): positive 306.1 (M+H), negative 304.1 (M−H).
Reaction SMILES: Cl[C:2]1[C:3]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH3:20])=[CH:14][CH:13]=2)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1.[C@H:27]1([NH2:34])[CH2:32][CH2:31][C@H:30]([NH2:33])[CH2:29][CH2:28]1>C(Cl)Cl>[NH2:33][C@H:30]1[CH2:31][CH2:32][C@H:27]([NH:34][C:2]2[C:3]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[C:4]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH3:20])=[CH:14][CH:13]=3)[C:5]3[N:6]([CH:8]=[CH:9][N:10]=3)[N:7]=2)[CH2:28][CH2:29]1
Reactant: CCOc1ccc(Nc2c(-c3ccccc3)c(Cl)nn3ccnc23)cc1
Reactant: N[C@H]1CC[C@H](N)CC1
Solvent: ClCCl
Product: CCOc1ccc(Nc2c(-c3ccccc3)c(N[C@H]3CC[C@H](N)CC3)nn3ccnc23)cc1
Temperature: 25 °C

Procedure:
6-chloro-N-(4-ethoxyphenyl)-7-phenylimidazo[1,2-b]pyridazin-8-amine (0.0201 g, 0.058 mmol) from 1d and (trans)-cyclohexane-1,4-diamine (0.1702 g, 1.49 mmol) were heated at 165° C. for 6 d. After cooling to room temperature, the mixture was taken up in CH2Cl2 and water, and the layers were separated. The aqueous layer was extracted with CH2Cl2 (2×). The organic layers were combined, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified using preparative HPLC. The appropriate fraction was collected, and NaHCO3 (solid) was added to it. It was concentrated in vacuo not to dryness, and extracted with CH2Cl2 (2×). The organic layers were combined, dried over Na2SO4, filtered, and concentrated in vacuo to give the above titled compound (1.5 mg, 4.0% yield). LC/MS, m/e 443.40 (M+1). HPLC RT, 2.29 min. YMC ODSC18 column (4.6×50 mm). 0%-100% B. Solvent B: (90% MeOH, 10% H2O, 0.1% TFA). Solvent A: (10% MeOH, 90% H2O, 0.1% TFA). Gradient, start % B=0, final % B=100, gradient time 4 min, hold at 100% B 1 min, flow rate 4 mL/min.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:12][O:13][CH2:14][CH2:15][NH2:16].C(N(CC)CC)C>C(Cl)Cl>[CH3:12][O:13][CH2:14][CH2:15][NH:16][S:8]([C:5]1[CH:6]=[CH:7][C:2]([I:1])=[CH:3][CH:4]=1)(=[O:10])=[O:9]
Reactant: O=S(=O)(Cl)c1ccc(I)cc1
Reactant: COCCN
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCCNS(=O)(=O)c1ccc(I)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 100.1 %

Procedure:
A solution of 4-iodophenylsulphonyl chloride (3.64 g, 12 mmol) in DCM (30 ml) was added dropwise to a solution of 2-methoxyethylamine (1.3 ml, 15 mmol) and triethylamine (2 ml, 15 mmol) in DCM (60 ml) cooled by an ice bath to 0° C. The mixture was then allowed to warm to ambient temperature and stirred for 1 hour. The solvent was removed by evaporation and the resulting oil dissolved EtOAc (100 ml) and washed with 1N aqueous citric acid solution (2×100 ml), brine (100 ml) and dried. The volatiles were removed by evaporation to give the title compound (4.1 g, 100%) as a clear oil. NMR 3.12 (2H, q), 3.28 (3H, s), 3.44 (2H, t), 4.90 (1H, t), 7.57 (2H, d), 7.81 (2H, d); m/z: 342.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:18]=1[NH:17][C:16]([C:19]([NH2:21])=[O:20])=[C:15]2[S:22]([N:25]1[CH2:30][CH2:29][O:28][C@H:27]([CH2:31][O:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:26]1)(=[O:24])=[O:23]>>[CH2:1]([NH:9][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:18]=1[NH:17][C:16]([C:19]([NH2:21])=[O:20])=[C:15]2[S:22]([N:25]1[CH2:30][CH2:29][O:28][C@H:27]([CH2:31][O:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:26]1)(=[O:24])=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1
Reactant: NC(=O)c1[nH]c2c(N)cccc2c1S(=O)(=O)N1CCO[C@H](COc2ccccc2)C1
Product: NC(=O)c1[nH]c2c(NCc3ccccc3)cccc2c1S(=O)(=O)N1CCO[C@H](COc2ccccc2)C1

Procedure:
Using the method described in Example 85, replacing 4-formylpyridine with benzaldehyde, 7-Amino-3-{[(2S)-2-(phenoxymethyl)morpholin-4-yl]sulfonyl}-1H-indole-2-carboxamide was converted to the titled product. Proton NMR for the product was consistent with the titled compound. HRMS (ES) exact mass calculated for C27H29N4O5S (M+H+): 521.1853. Found 521.1856.
Reaction SMILES: [C:1]([O:6][CH2:7][CH2:8][NH:9][C:10]([NH:12][C:13]1[CH:18]=[C:17]([N+:19]([O-])=O)[CH:16]=[C:15]([N+:22]([O-])=O)[CH:14]=1)=[O:11])(=[O:5])[CH:2]([CH3:4])[CH3:3].[H][H]>[C].[Pd].C(O)C>[C:1]([O:6][CH2:7][CH2:8][NH:9][C:10]([NH:12][C:13]1[CH:18]=[C:17]([NH2:19])[CH:16]=[C:15]([NH2:22])[CH:14]=1)=[O:11])(=[O:5])[CH:2]([CH3:4])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)C(=O)OCCNC(=O)Nc1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCO
Product: CC(C)C(=O)OCCNC(=O)Nc1cc(N)cc(N)c1
Temperature: 17 °C
Reaction time: 1 h

Procedure:
8.3 g of 5% palladium carbon, 83.0 g (0.244 mol) of 2-(3,5-dinitrophenylureido)ethyl isobutyrate (compound 12) and 800 ml of ethanol were placed in a 5-l autoclave equipped with a thermocouple thermometer and a mixing blade, and the autoclave was sealed. The atmosphere inside the autoclave was replaced by hydrogen and the hydrogen pressure was raised to 5 kg/cm2. The autoclave contents were stirred at room temperature (17° C.). Ten minutes later, the autoclave inside temperature rose to 43° C. and the autoclave inside pressure dropped to 1 kg/cm2. Then, hydrogen was introduced to raise the pressure to 5 kg/cm2, and stirring was continued. Ten minutes later, the temperature became 58° C. and the pressure dropped to 1 kg/cm2. Hydrogen was again introduced to raise the pressure to 5 kg/cm2, and stirring was continued. Since the temperature began to drop and the pressure became constant (4.5 kg/cm2), stirring was continued for 60 minutes (the temperature dropped to 26° C.). The atmosphere inside the autoclave was replaced by nitrogen, and the autoclave contents were taken out and filtered to remove palladium carbon. The filtrate was concentrated by the use of an evaporator, whereby a solid was separated. The solid was recrystallized from 300 ml of butanol to obtain 2-(3,5-diaminophenylureido)ethyl isobutyrate (compound 13). Yield: 55.0 g (81%) Melting point: 89-90° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:14]([F:17])([F:16])[F:15])=[N:4][N:5]([CH:8]([CH2:12][CH3:13])[C:9]([OH:11])=O)[C:6]=1[CH3:7].[F:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[C:33]3[CH2:32][CH2:31][CH2:30][NH:29][C:28]=3[CH:27]=[N:26]2)=[CH:21][CH:20]=1>>[Cl:1][C:2]1[C:3]([C:14]([F:17])([F:16])[F:15])=[N:4][N:5]([CH:8]([CH2:12][CH3:13])[C:9]([N:29]2[CH2:30][CH2:31][CH2:32][C:33]3[N:25]([C:22]4[CH:23]=[CH:24][C:19]([F:18])=[CH:20][CH:21]=4)[N:26]=[CH:27][C:28]2=3)=[O:11])[C:6]=1[CH3:7]
Reactant: Fc1ccc(-n2ncc3c2CCCN3)cc1
Reactant: CCC(C(=O)O)n1nc(C(F)(F)F)c(Cl)c1C
Product: CCC(C(=O)N1CCCc2c1cnn2-c1ccc(F)cc1)n1nc(C(F)(F)F)c(Cl)c1C
Yield: 69 %

Procedure:
The title compound was prepared from 2-(4-chloro-5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)butanoic acid and 1-(4-fluorophenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridine using General Method B. The product mixture was washed with 2×1 M NaHSO4. The reaction slurry was purified by flash chromatography (SiO2, 24 g column, eluting with 5-50% EtOAc in hexanes) to provide 81 mg (69%) of the title compound as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.43 (s, 1H), 7.44 (m, 2H), 7.16 (m, 2H), 5.30 (dd, J=6.7, 8.6 Hz, 1H), 3.81 (ddd, J=3.2, 8.6, 11.5 Hz, 1H), 3.50 (ddd, J=3.1, 7.4, 10.2 Hz, 1H), 2.79 (dt, J=2.8, 6.3 Hz, 2H), 2.33 (m, 1H), 2.30 (s, 3H), 2.22 (m, 1H), 1.96 (m, 1H), 1.86 (m, 1H), 0.98 (t, J=7.0 Hz, 3H); MS: (ES) m/z calculated for C20H19ClF4N5O [M+H]+ 470.1, found 470.1.