Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:27])[CH2:5][O:6][C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[C:14](=[S:26])[NH:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=1)C.[OH-].[Na+]>C(O)C>[F:13][C:11]1[CH:10]=[CH:9][C:8]([C:14](=[S:26])[NH:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=2)=[C:7]([CH:12]=1)[O:6][CH2:5][C:4]([OH:27])=[O:3]
Reactant: CCOC(=O)COc1cc(F)ccc1C(=S)NCc1cccc([N+](=O)[O-])c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)COc1cc(F)ccc1C(=S)NCc1cccc([N+](=O)[O-])c1
Reaction time: 4 h
Yield: 98 %

Procedure:
A suspension of [5-Fluoro-2-(3-nitro-benzylthiocarbamoyl)-phenoxy]-acetic acid ethyl ester (4.39 g, 11.2 mmol) in ethanol (40 mL) was treated with aq 2 N NaOH (11 mL, 22.4 mmol). After stirring for 4 h, the solution was concentrated in vacuo until most of the ethanol was removed, and the mixture was acidified to pH of 1 with 2 N HCl. After extracting with ethyl acetate, the organic layer was washed with saturated aq NaCl, dried over MgSO4 and concentrated to give [5-fluoro-2-(3-nitro-benzylthiocarbamoyl)-phenoxy]-acetic acid (4.0 g, 98%) as an off-white solid: mp 147–150° C.; Rf 0.27 (20% methanol in dichloromethane); 1H NMR (DMSO-d6 300 MHz) δ 13.23 (s, 1 H), 10.79 (t, J=5.7 Hz, 1 H), 8.23 (t, J=1.8 Hz, 1 H), 8.11 (ddd, J1=8.3 Hz, J2=2.7 Hz, J3=1.2 Hz, 1 H), 7.85 (br d, J=7.5 Hz, 1 H), 7.73 (dd, J, =8.9 Hz, J2=7.1 Hz, 1 H), 7.63 (t, J=8.1 Hz, 1 H), 7.03 (dd, J1=11.4 Hz, J2=2.4 Hz, 1 H), 6.86 (dt, J1=8.4 Hz, J2=2.4 Hz, 1 H), 5.07 (d, J=5.7 Hz, 2 H), 4.83 (s, 2 H). ESI-LC/MS m/z calcd for CO6 H13FN2O5S: 364.4. Found 363.0 (M−1)−. Anal. calcd for C16H13FN2O5S: C, 52.74: H, 3.60; N, 7.69. Found C, 52.65; H, 3.62; N, 7.58.
Reaction SMILES: Cl.[N:2]1([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)[N:9]=2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.Br[CH:28]([OH:30])[CH3:29].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[OH:30][CH2:28][CH2:29][N:5]1[CH2:6][CH2:7][N:2]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:24])[F:25])=[CH:19][CH:18]=3)[N:9]=2)[CH2:3][CH2:4]1
Reactant: FC(F)(F)c1ccc(-n2nc(N3CCNCC3)c3ccccc32)cc1
Reactant: CC(O)Br
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: OCCN1CCN(c2nn(-c3ccc(C(F)(F)F)cc3)c3ccccc23)CC1
Yield: 44.6 %

Procedure:
A stirred mixture of 5.5 g of 3-(1-piperazinyl)-1-[4(trifluoromethyl)phenyl]-1H-indazole hydrochloride, 2.3 g of bromoethanol, 2.5 g of potassium carbonate and 60 ml of dimethylformamide was heated, under nitrogen, at 70°-75° for 16 hours. The reaction mixture was poured into water and the aqueous mixture extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate and concentrated to an oil. The oil was chromatographed on silica gel utilizing a Water's Model 500 High Pressure Liquid Chromatograph and eluting with dichloromethane/methanol (6%). Evaporation of the appropriate fractions gave an oil which solidified upon standing. Recrystallization of the solid from hexane (2×) gave 2.5 g (40%) of 3-[4-(2-hydroxyethyl)-1piperazinyl-]-1-[4-(trifluoromethyl)phenyl]-1H-indazole, mp 82°-84°.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:27]=[CH:26][C:16]([CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[CH:15][C:14]=2OC)[N:3]=1.[NH2:30][C:31]1[CH:32]=[CH:33][C:34]([C@H:42]2[CH2:47][CH2:46][C@H:45]([OH:48])[CH2:44][CH2:43]2)=[C:35]2[C:39]=1[C:38](=[O:40])[N:37]([CH3:41])[CH2:36]2>>[OH:48][C@H:45]1[CH2:46][CH2:47][C@H:42]([C:34]2[CH:33]=[CH:32][C:31]([NH:30][C:2]3[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]4[CH:27]=[CH:26][C:16]([CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[CH:15][CH:14]=4)[N:3]=3)=[C:39]3[C:35]=2[CH2:36][N:37]([CH3:41])[C:38]3=[O:40])[CH2:43][CH2:44]1
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)c(OC)c1)OCC
Reactant: CN1Cc2c(c(N)ccc2[C@H]2CC[C@H](O)CC2)C1=O
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc([C@H]4CC[C@H](O)CC4)c4c3C(=O)N(C)C4)n2)cc1)OCC

Procedure:
This compound was prepared in a manner analogous to Example 87 using diethyl (4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate and 7-amino-4-(trans-4-hydroxycyclohexyl)-2-methyl-2,3-dihydro-1H-isoindol-1-one. Purification: ISCO Combi-flash Rf system, eluting with 0 to 5% MeOH in EtOAc. 1H NMR (400 MHz, DMSO-d6) δ 10.57 (s, 1H), 9.87 (s, 1H), 8.45 (s, 1H), 7.56 (br. s., 1H), 7.38 (d, J=8.59 Hz, 1H), 7.26 (dd, J=2.15, 8.46 Hz, 2H), 4.58 (d, J=4.55 Hz, 1H), 4.52 (s, 2H), 3.91-4.01 (m, 4H), 3.46-3.54 (m, 1H), 3.17-3.27 (m, 2H), 3.08 (s, 3H), 1.94 (d, J=9.85 Hz, 2H), 1.76 (d, J=12.13 Hz, 2H), 1.53-1.65 (m, 2H), 1.23-1.36 (m, 2H), 1.18 (t, J=7.07 Hz, 6H). MS (ES+): m/z: 648.1830 [MH+]. HPLC: tR=1.44 min (UPLC TOF MS: polar—3 min).
Reaction SMILES: CS[C:3]1[NH:8][C:7](=[O:9])[C:6]([CH2:10][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[N:5][N:4]=1.[S:17]1[CH:21]=[CH:20][N:19]=[C:18]1[CH2:22][S:23][CH2:24][CH2:25][NH2:26]>>[S:17]1[CH:21]=[CH:20][N:19]=[C:18]1[CH2:22][S:23][CH2:24][CH2:25][NH:26][C:3]1[NH:8][C:7](=[O:9])[C:6]([CH2:10][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[N:5][N:4]=1
Reactant: CSc1nnc(Cc2cccnc2)c(=O)[nH]1
Reactant: NCCSCc1nccs1
Product: O=c1[nH]c(NCCSCc2nccs2)nnc1Cc1cccnc1

Procedure:
3-Methylthio-6-(3-pyridylmethyl)-1,2,4-triazin-5-one (3.28 g) and 2-(2-thiazolylmethylthio)ethylamine (2.7 g) were heated together on an oil bath (160°-170° ) for 1 hour. The cooled mixture was triturated with isopropanol and the solid was twice recrystallised from ethanol to give the title compound as pale yellow plates (3.1 g) m.p. 158°-59°.
Reaction SMILES: [CH2:1]([O:8][CH:9]1[CH:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:12]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:11]([OH:39])[C:10]1([OH:43])[CH2:40][CH2:41][CH3:42])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO[C:46](OC)([CH3:48])[CH3:47].C1(C)C=CC(S(O)(=O)=O)=CC=1.C(N(CC)CC)C>CC(C)=O>[CH2:1]([O:8][CH:9]1[C:10]2([CH2:40][CH2:41][CH3:42])[CH:11]([O:39][C:46]([CH3:48])([CH3:47])[O:43]2)[CH:12]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:13]([O:23][CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:14]1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCC1(O)C(O)C(OCc2ccccc2)C(OCc2ccccc2)C(OCc2ccccc2)C1OCc1ccccc1
Reactant: COC(C)(C)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CCCC12OC(C)(C)OC1C(OCc1ccccc1)C(OCc1ccccc1)C(OCc1ccccc1)C2OCc1ccccc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 67.6 %

Procedure:
21 (0.22 g, 0.37 mmol) was dissolved in 20 mL dry acetone. 5 mL (40.8 mmol) 2.2-dimethoxypropane and 48 mg (0.25 mmol) p-toluene sulfonic acid were added an the solution was stirred for three days at room temperature. Then the reaction was stopped by adding 150 μL (1.08 mmole) triethylamine. All volatile components were removed under reduced pressure and the residue was dissolved in t-butylmethyl ether and washed with 0.5 M phosphate buffer pH=7 and brine. The organic phase was dried over Na2SO4, filtered and dried under reduced pressure. The residue was purified by preparative HPLC (RP18, 94% MeOH, 40 mL/min, tRet=35.10 min) to give 22 (160 mg, 0.25 mmol, 69.3% yield) as a slightly yellow oil.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:6]=[CH:7][C:8]=1F)#[N:2].[Cl:18][C:19]1[CH:20]=[C:21]([CH:32]=[CH:33][C:34]=1[Cl:35])[C:22]([NH:24][C:25]1[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=1)=[O:23].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.C(OCC)(=O)C.C(=O)([O-])[O-].[Na+].[Na+]>[C:1]([C:3]1[CH:4]=[C:5]([CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:6]=[CH:7][C:8]=1[O:31][C:28]1[CH:29]=[CH:30][C:25]([NH:24][C:22](=[O:23])[C:21]2[CH:32]=[CH:33][C:34]([Cl:35])=[C:19]([Cl:18])[CH:20]=2)=[CH:26][CH:27]=1)#[N:2]
Reactant: CC(C)(C)OC(=O)Cc1ccc(F)c(C#N)c1
Reactant: O=C(Nc1ccc(O)cc1)c1ccc(Cl)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)Cc1ccc(Oc2ccc(NC(=O)c3ccc(Cl)c(Cl)c3)cc2)c(C#N)c1
Temperature: 125 °C
Reaction time: 12 h
Yield: 59.1 %

Procedure:
tert-Butyl 2-(3-cyano-4-fluorophenyl)acetate (2.0 g, 8.5 mmol) and the product of step A (2.9 g, 10 mmol) were diluted with DMSO (22 mL) followed by the addition of potassium carbonate (1.4 g, 10 mmol). The reaction was heated to 125° C. and stirred for 12 hours. The reaction mixture was then cooled to room temperature, diluted with ethyl acetate and 10% aqueous sodium carbonate. The layers were separated and the organic layer was washed with 10% aqueous sodium carbonate two more times followed by water and brine. The organic material was dried over MgSO4, filtered and concentrated. The material was purified using a biotage 40M column eluting with hexanes:ethyl acetate (8:2) to yield tert-butyl 2-(3-cyano-4-(4-(3,4-dichlorobenzamido)phenoxy)phenyl)acetate (2.5 g, 59% yield) as a white solid.
Reaction SMILES: [CH3:1][C@H:2]1[NH:7][C@@H:6]([CH3:8])[CH2:5][N:4]([C:9]2[CH:14]=[C:13]([N+:15]([O-])=O)[CH:12]=[CH:11][C:10]=2[O:18][CH3:19])[CH2:3]1>[Pd].C(O)C.[H][H]>[CH3:1][C@H:2]1[NH:7][C@@H:6]([CH3:8])[CH2:5][N:4]([C:9]2[CH:14]=[C:13]([CH:12]=[CH:11][C:10]=2[O:18][CH3:19])[NH2:15])[CH2:3]1
Reactant: COc1ccc([N+](=O)[O-])cc1N1C[C@@H](C)N[C@@H](C)C1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: COc1ccc(N)cc1N1C[C@@H](C)N[C@@H](C)C1

Procedure:
cis-3,5-Dimethyl-1-[2-(methyloxy)-5-nitrophenyl]piperazine (D1) (10 g, 38 mmol) and 10% palladium on charcoal were dissolved in ethanol (200 ml) and hydrogenated at room temperature under an atmosphere hydrogen for 16 hours. The mixture was filtered through celite and the filtrate concentrated in vacuo to afford the title product (D2). MS (ES+) m/e 236 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:23](O)=[O:24])=[N:11][CH:12]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[C:27]([O:31][C:32](=[O:35])[CH2:33][NH2:34])([CH3:30])([CH3:29])[CH3:28].C(N(C(C)C)CC)(C)C>CN(C=O)C.ON1C2C=CC=CC=2N=N1>[C:27]([O:31][C:32](=[O:35])[CH2:33][NH:34][C:23]([C:10]1[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:14][C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:12][N:11]=1)=[O:24])([CH3:30])([CH3:29])[CH3:28]
Reactant: CC(C)(C)OC(=O)CN
Reactant: O=C(O)c1ncc(OCc2ccccc2)cc1OCc1ccccc1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)CNC(=O)c1ncc(OCc2ccccc2)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 99 %

Procedure:
To a solution of 3,5-bis-benzyloxy-pyridine-2-carboxylic acid, 2, (2.36 g, 6.36 mmol) in DMF (20 mL) at room temperature under N2 is added 1-(3-dimethyl-aminopropyl)-3-ethylcarbodiimide (EDCI) (1.83 g, 9.54 mmol) and 1-hydroxybenzo-triazole (HOBt) (0.086 g, 0.64 mmol). The mixture is stirred for 15 minutes after which time glycine tert-butyl ester hydrochloride (1.60 g, 9.54 mmol) and diisopropylethylamine (DIPEA) (3.32 ml, 19.08 mmol) are added. The resulting solution is stirred at room temperature for 48 hours then concentrated under reduced pressure. The resulting brown oil is purified over silica (EtOAc) to afford 3.04 g (99% yield) of the desired compound as a yellow solid. 1H NMR (250 MHz, CDCl3) δ ppm 8.19 (1H, t, J=5.2 Hz), 8.01-8.08 (2H, m), 7.27-7.54 (9H, m), 6.97 (1H, d, J=2.4 Hz), 5.24 (2H, s), 5.13 (2H, s), 4.17 (2H, d, J=5.2 Hz), 1.51 (9H, s). HPLC-MS: m/z 449 [M+H]+.
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[CH:20]=[C:19]([C:21]3[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[C:23]([C:31]4[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][CH:32]=4)[N:22]=3)[CH:18]=[CH:17][N:16]=2)[CH:10]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[F:30][C:27]([F:28])([F:29])[C:25]1[CH:24]=[C:23]([C:31]2[CH:36]=[CH:35][C:34]([C:37]([F:38])([F:39])[F:40])=[CH:33][CH:32]=2)[N:22]=[C:21]([C:19]2[CH:18]=[CH:17][N:16]=[C:15]([C:11]3[CH:10]=[C:9]([S:6]([NH2:5])(=[O:8])=[O:7])[CH:14]=[CH:13][CH:12]=3)[CH:20]=2)[CH:26]=1
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(-c2cc(-c3cc(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)n3)ccn2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NS(=O)(=O)c1cccc(-c2cc(-c3cc(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)n3)ccn2)c1
Yield: 80.9 %

Procedure:
To a stirred and cooled solution of N-tert-butyl-3-[4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-[2,4′]bipyridinyl-2′-yl]-benzenesulfonamide (example 285) (0.248 g, 0.43 mmol) in dichloromethane (3 mL) was added TFA (3 mL) and the reaction mixture was allowed to stir at room temperature for 16 h. The mixture was evaporated to dryness and saturated NaHCO3 solution (5 mL), diethyl ether and heptane were added. The mixture was stirred at room temperature for 1 h, the precipitate was collected by filtration, washed with water and heptane/diethyl ether and dried to yield the title compound as a white solid (0.182 g, 81%). MS (ISP) 524.3 [(M+H)+]; mp 227° C. (dec.).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6][CH2:7][CH2:8][CH2:9][NH:10][C:11](=[O:13])[CH3:12].C1C(=O)N([Br:21])C(=O)C1>CN(C=O)C>[Br:21][C:5]1[S:1][C:2]([S:6][CH2:7][CH2:8][CH2:9][NH:10][C:11](=[O:13])[CH3:12])=[CH:3][CH:4]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=O)NCCCSc1cccs1
Solvent: CN(C)C=O
Product: CC(=O)NCCCSc1ccc(Br)s1
Temperature: 23 °C
Reaction time: 1 h
Yield: 46.9 %

Procedure:
A mixture of N-(3-(thiophen-2-ylthio)propyl)acetamide (2.5 g, 11.6 mmol, 1.0 eq), NBS (2.1 g, 11.6 mmol, 1.0 eq) in DMF (5 mL) was stirred at 23° C. for 1 hour. The mixture was extracted with CH2Cl2. The combined organic layers were dried (Na2SO4), filtered and concentrated to give yellow oil N-(3-(5-bromothiophen-2-ylthio)propyl)acetamide (1.6 g, 46.8%);
Reaction SMILES: [F:1][CH:2]([F:18])[O:3][C:4]1[C:9]2[O:10][CH:11]([CH3:15])[C:12](=[O:14])[NH:13][C:8]=2[CH:7]=[C:6]([CH:16]=O)[CH:5]=1.[Cl:19][C:20]1[CH:21]=[C:22]([CH:28]=[CH:29][C:30]=1[N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1)[C:23]([NH:25][CH2:26][CH3:27])=[O:24]>>[Cl:19][C:20]1[CH:21]=[C:22]([CH:28]=[CH:29][C:30]=1[N:31]1[CH2:32][CH2:33][N:34]([CH2:16][C:6]2[CH:5]=[C:4]([O:3][CH:2]([F:18])[F:1])[C:9]3[O:10][CH:11]([CH3:15])[C:12](=[O:14])[NH:13][C:8]=3[CH:7]=2)[CH2:35][CH2:36]1)[C:23]([NH:25][CH2:26][CH3:27])=[O:24]
Reactant: CCNC(=O)c1ccc(N2CCNCC2)c(Cl)c1
Reactant: CC1Oc2c(cc(C=O)cc2OC(F)F)NC1=O
Product: CCNC(=O)c1ccc(N2CCN(Cc3cc4c(c(OC(F)F)c3)OC(C)C(=O)N4)CC2)c(Cl)c1

Procedure:
Using 403A and 3-chloro-N-ethyl-4-(piperazin-1-yl)benzamide 286 in the general procedure for reductive aminations, the title compound was obtained as a white solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 1.10 (t, J=7.20 Hz, 3H) 1.39-1.46 (m, 3H) 2.52-2.61 (m, 4H) 3.05 (br. s., 4H) 3.21-3.30 (m, 2H) 3.45 (s, 2H) 4.70-4.78 (m, 1H) 6.78-6.83 (m, 2H) 7.13-7.21 (m, 2H) 7.77 (dd, J=8.59, 2.02 Hz, 1H) 7.87 (d, J=2.02 Hz, 1H) 8.43 (t, J=5.56 Hz, 1H) 10.81 (s, 1H). ESI-MS: m/z 509.3 (M+H)+. mp 101.7-104.0° C.
Reaction SMILES: [CH2:1]([N:4]([C@@H:33]([CH3:38])[C:34]([F:37])([F:36])[F:35])[S:5]([C:8]1[CH:9]=[CH:10][C:11]([C:14]2[N:15](C(OC(C)(C)C)=O)[C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[C:18]([CH:23]2[CH2:25][CH2:24]2)[CH:17]=3)=[N:12][CH:13]=1)(=[O:7])=[O:6])[CH:2]=[CH2:3].N1CCCC1>C(#N)C>[CH2:1]([N:4]([C@@H:33]([CH3:38])[C:34]([F:35])([F:37])[F:36])[S:5]([C:8]1[CH:13]=[N:12][C:11]([C:14]2[NH:15][C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[C:18]([CH:23]2[CH2:25][CH2:24]2)[CH:17]=3)=[CH:10][CH:9]=1)(=[O:6])=[O:7])[CH:2]=[CH2:3]
Reactant: C=CCN([C@@H](C)C(F)(F)F)S(=O)(=O)c1ccc(-c2cc3ccc(C4CC4)cc3n2C(=O)OC(C)(C)C)nc1
Solvent: C1CCNC1
Solvent: CC#N
Product: C=CCN([C@@H](C)C(F)(F)F)S(=O)(=O)c1ccc(-c2cc3ccc(C4CC4)cc3[nH]2)nc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 90.5 %

Procedure:
To a solution of (S)-tert-butyl 2-(5-(N-allyl-N-(1,1,1-trifluoropropan-2-yl)sulfamoyl)pyridin-2-yl)-6-cyclopropyl-1H-indole-1-carboxylate (500 mg, 0.91 mmol) in acetonitrile was added pyrrolidine (0.35 mL, 4.55 mmol). The mixture was stirred at room temperature for 5 hrs and the solvent was evaporated. The residue was purified on silica gel eluting with 0 to 10% ethyl acetate in CH2Cl2 to provide (S)-N-allyl-6-(6-cyclopropyl-1H-indol-2-yl)-N-(1,1,1-trifluoropropan-2-yl)pyridine-3-sulfonamide (370 mg, 91% yield). MS m/z 450.2 M+H+; 1H NMR (500 MHz, CDCl3): δ 9.28 (1H, s), 8.85 (1H, s), 7.96 (1H, d, J=5.5 Hz), 7.74 (1H, d, J=9.5 Hz), 7.49 (1H, d, J=5.5 Hz), 7.09 (1H, s), 7.01 (1H, s), 6.82-6.80 (1H, m), 5.75 (1H, m), 5.16-5.10 (2H, m), 4.64-4.62 (1H, m), 3.89 (2H, d, J=5.0 Hz), 2.00-1.96 (1H, m), 1.35 (3H, d, J=6.0 Hz), 0.98-0.96 (2H, m), 0.75-0.72 (2H, m).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[C:8]3[N:9]([N:13]=[C:14]([NH2:16])[N:15]=3)[CH:10]=[CH:11][CH:12]=2)=[CH:3][CH:2]=1.Br[C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[CH:20][CH:19]=1>>[N:24]1([C:21]2[CH:22]=[CH:23][C:18]([NH:16][C:14]3[N:15]=[C:8]4[C:7]([C:4]5[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=5)=[CH:12][CH:11]=[CH:10][N:9]4[N:13]=3)=[CH:19][CH:20]=2)[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1
Reactant: Brc1ccc(N2CCOCC2)cc1
Reactant: Nc1nc2c(-c3ccncc3)cccn2n1
Product: c1cc(-c2ccncc2)c2nc(Nc3ccc(N4CCOCC4)cc3)nn2c1

Procedure:
8-Pyridin-4-yl-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine was prepared from 8-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (1.0 g, 4.7 mmol) and 4-pyridylboronic acid (0.81 g, 6.6 mmol) in a manner analogous to Step 2c. The product of the reaction was isolated as a pale yellow solid (0.54 g, 54%). MP=209-215° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 8.69 (dd, J=4.8, 1.4 Hz, 2H), 8.65 (dd, J=6.5, 0.8 Hz, 1H), 8.18 (dd, J=4.7, 1.6 Hz, 2H), 7.94 (dd, J=7.5, 0.9 Hz, 1H), 7.03 (t, J=6.8 Hz, 1H), 6.24 (s, 2H). MS=212 (MH)+. 11b) (4-Morpholin-4-yl-phenyl)-(8-pyridin-4-yl-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-amine was prepared from 8-Pyridin-4-yl-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (100.0 mg, 0.4734 mmol) and 4-(4-Bromo-phenyl)-morpholine (160.0 mg, 0.6608 mmol) in an anlogous manner to Step 2d. The title compound was isolated as yellow solid (0.035 g, 20%). MP=266-270° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 9.54 (s, 1H), 8.86 (d, J=6.5 Hz, 1H), 8.75-8.70 (m, 2H), 8.23-8.20 (m, 2H), 8.04 (d, J=7.3 Hz, 1H), 7.62-7.57 (m, 2H), 7.14 (t, J=7.0 Hz, 1H), 6.96-6.90 (m, 2H), 3.76-3.72 (m, 4H), 3.05-3.00 (m, 4H). MS=373 (MH)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:7]2[N:8]([C:16]([NH2:18])=[O:17])[C:9]3[C:14]([CH:15]=2)=[CH:13][CH:12]=[CH:11][CH:10]=3)[S:5][CH:6]=1.[CH3:19][C:20]1[CH:24]=[CH:23][O:22][C:21]=1[C:25](O)=[O:26].Cl.CN(C)CCCN=C=NCC>ClCCCl.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[CH3:19][C:20]1[CH:24]=[CH:23][O:22][C:21]=1[C:25]([NH:1][C:2]1[CH:3]=[C:4]([C:7]2[N:8]([C:16]([NH2:18])=[O:17])[C:9]3[C:14]([CH:15]=2)=[CH:13][CH:12]=[CH:11][CH:10]=3)[S:5][CH:6]=1)=[O:26]
Reactant: NC(=O)n1c(-c2cc(N)cs2)cc2ccccc21
Reactant: Cc1ccoc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: Cc1ccoc1C(=O)Nc1csc(-c2cc3ccccc3n2C(N)=O)c1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
To the solution of 2-(4-amino-2-thienyl)-1H-indole-1-carboxamide (51.4 mg, 0.2 mmol, 1 eq) and 3-methyl-furan-2-carboxylic acid (25.2 mg, 1 eq) in anhydrous DCE (2 mL) was added 4-(dimethylamino)pyridine (4.9 mg, 0.2 eq) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (46.1 mg, 1.2 eq). After the reaction was stirred at 60° C. for 1 hour, it was diluted with ethyl acetate, washed sequentially with aqueous ammonium chloride, saturated aqueous sodium bicarbonate, brine, and lastly dried with anhydrous sodium sulfate. The upper clear solution was decanted, concentrated, and the oily residue was subject to a gradient column chromatography (EtOAc-Hex 1:100 to 1:2) to yield 2-{4-[(3-methyl-2-furoyl)amino]-2-thienyl}-1H-indole-1-carboxamide as a yellow solid in amount of 42 mg.
Reaction SMILES: [Br:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([N+:9]([O-])=O)[C:3]=1[NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[NH4+].[Cl-]>CO.O.[Fe]>[Br:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([NH2:9])[C:3]=1[NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=[N+]([O-])c1ccc(F)c(Br)c1Nc1ccccc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: Nc1ccc(F)c(Br)c1Nc1ccccc1
Temperature: 90 °C
Yield: 90.1 %

Procedure:
To a mixture of (2-bromo-3-fluoro-6-nitrophenyl)phenylamine (2.4 g, 7.7 mmol) in MeOH (40 mL) and water (15 mL) were added NH4Cl (2.38 g, 46.3 mmol) and iron powder (1.72 g, 30.9 mmol) and the reaction mixture heated at 90° C. for 1 h. After cooling to RT, the crude mixture was filtered through a pad of Celite® and the filtrate concentrated in vacuo. The resulting residue was partitioned between EtOAc and water. The aqueous phase was extracted with EtOAc (×3) and the combined organic fractions washed with brine, dried (MgSO4) and concentrated in vacuo to afford the title compound (1.95 g, 90%). LCMS (Method C): RT 3.48 min [M+H]+ 281.1/283.1.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][S:5][C:6]1[N:11]2[CH:12]=[CH:13][N:14]=[C:10]2[CH:9]=[CH:8][CH:7]=1.C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>C(Cl)Cl>[CH3:22][S:23]([O:1][CH2:2][CH2:3][CH2:4][S:5][C:6]1[N:11]2[CH:12]=[CH:13][N:14]=[C:10]2[CH:9]=[CH:8][CH:7]=1)(=[O:25])=[O:24]
Reactant: CS(=O)(=O)Cl
Reactant: OCCCSc1cccc2nccn12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCCSc1cccc2nccn12

Procedure:
To a solution of 5-[3-(hydroxy)propylthio]imidazo[1,2-a]pyridine (1.030 g, 4.95 moles) and triethylamine (1.03 ml, 7.4 mmoles) in methylene chloride (30 ml) was added methanesulfonyl chloride (0.46 ml, 5.9 mmoles) with stirring under ice-cooling and the mixture was further stirred under ice-cooling for 10 minutes. The reaction mixture was washed with water and the aqueous layer was extracted with methylene chloride (30 ml×3). The methylene chloride layers were combined and dried over anhydrous magnesium sulfate. Then, the solvent was distilled off to obtain crude 5-[3-(methanesulfonyloxy)propylthio]imidazo[1,2-a]pyridine as a yellow oily product.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].[H-].[Na+].[Cl:11][C:12]1[CH:17]=[C:16]([N+]([O-])=O)[CH:15]=[CH:14][N:13]=1>>[Cl:11][C:12]1[CH:17]=[C:16]([S:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[CH3:1])[CH:15]=[CH:14][N:13]=1
Reactant: Cc1ccccc1S
Reactant: O=[N+]([O-])c1ccnc(Cl)c1
Agent: [H-]
Agent: [Na+]
Product: Cc1ccccc1Sc1ccnc(Cl)c1
Yield: 88.7 %

Procedure:
Using the method of Example 3, Step A, 2-methylbenzenethiol (0.783 g, 6.31 mmol), 60% sodium hydride in mineral oil (252 mg, 6.31 mmol), and 2-chloro-4-nitropyridine (1.00 g, 12.6 mmol) to provide 2-chloro-4-(o-tolylthio)pyridine (1.32 g, 89% yield) as an oil. 1H NMR (CDCl3) δ 8.09 (d, 1H), 7.55 (d, 1H), 7.37-7.44 (m, 2H), 7.29 (t, 1H), 6.81 (s, 1H), 6.75-6.78 (m, 2H), 2.38 (s, 3H).