Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH:19][CH2:20][CH3:21])[N:14]=3)=[CH:11][N:10]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[F:31][C:32]1[CH:37]=[CH:36][C:35]([F:38])=[CH:34][C:33]=1[S:39](Cl)(=[O:41])=[O:40].[Na]>N1C=CC=CC=1>[CH2:20]([NH:19][C:15]1[N:14]=[C:13]([C:12]2[C:8]([C:4]3[CH:3]=[C:2]([NH:1][S:39]([C:33]4[CH:34]=[C:35]([F:38])[CH:36]=[CH:37][C:32]=4[F:31])(=[O:41])=[O:40])[CH:7]=[CH:6][CH:5]=3)=[N:9][N:10]([CH2:22][C:23]3[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=3)[CH:11]=2)[CH:18]=[CH:17][N:16]=1)[CH3:21]
Reactant: CCNc1nccc(-c2cn(Cc3ccc(OC)cc3)nc2-c2cccc(N)c2)n1
Reactant: O=S(=O)(Cl)c1cc(F)ccc1F
Agent: [Na]
Solvent: c1ccncc1
Product: CCNc1nccc(-c2cn(Cc3ccc(OC)cc3)nc2-c2cccc(NS(=O)(=O)c3cc(F)ccc3F)c2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.8 %

Procedure:
340 mg (0.85 mmol) of 4-[3-(3-aminophenyl)-1-(4-methoxybenzyl)-1H-pyrazol-4-yl]-N-ethylpyrimidin-2-amine were dissolved in 10 ml of dry pyridine and 114 μl (0.85 mmol) of 2,5-difluorobenzensulfonyl chloride were added. The resulting solution was stirred at room temperature overnight. The mixture was then poured into aqueous sodium hydrogenocarbonate and extracted with dichloromethane. The organic layer was finally dried over sodium sulphate and evaporated, giving 450 mg (91%) of the title compound.
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:5])[CH3:4].[F:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]2[N:17]([S:18]([C:21]3[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=3)(=[O:20])=[O:19])[CH:16]([CH2:28][CH2:29][C:30](O)=O)[CH2:15][CH2:14]2)=[CH:9][CH:8]=1>>[F:6][C:7]1[CH:8]=[CH:9][C:10]([CH:13]2[N:17]([S:18]([C:21]3[CH:22]=[CH:23][C:24]([CH3:27])=[CH:25][CH:26]=3)(=[O:19])=[O:20])[CH:16]([CH2:28][CH2:29][C:30]3[O:1][N:2]=[C:3]([CH3:4])[N:5]=3)[CH2:15][CH2:14]2)=[CH:11][CH:12]=1
Reactant: Cc1ccc(S(=O)(=O)N2C(CCC(=O)O)CCC2c2ccc(F)cc2)cc1
Reactant: CC(=N)NO
Product: Cc1ccc(S(=O)(=O)N2C(CCc3nc(C)no3)CCC2c2ccc(F)cc2)cc1

Procedure:
The title compound, white solid, m.p. 91° C. and MS: m/e=430.5 (M+) was prepared in accordance with the general method of example 13 from N-hydroxy-acetamidine and (2RS,5SR)-3-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propionic acid, which was prepared in accordance with the general method of example 6a from (2RS,5SR)-3-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propionic acid methyl ester.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C@@H:17]([OH:19])[CH3:18])(=[O:10])=[O:9])=[CH:4][C:3]=1[CH3:20].[F:21][C:22]1[CH:27]=[CH:26][C:25](/[CH:28]=[CH:29]/B(O)O)=[CH:24][CH:23]=1.C(=O)([O-])[O-].[Na+].[Na+]>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1COCC1>[F:21][C:22]1[CH:27]=[CH:26][C:25](/[CH:28]=[CH:29]/[C:2]2[CH:7]=[CH:6][C:5]([S:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C@@H:17]([OH:19])[CH3:18])(=[O:10])=[O:9])=[CH:4][C:3]=2[CH3:20])=[CH:24][CH:23]=1
Reactant: Cc1cc(S(=O)(=O)c2ccccc2[C@H](C)O)ccc1Br
Reactant: OB(O)/C=C/c1ccc(F)cc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(S(=O)(=O)c2ccccc2[C@H](C)O)ccc1/C=C/c1ccc(F)cc1
Temperature: 150 °C
Yield: 56.8 %

Procedure:
An Emrys microwave vial containing (1S)-1-[2-({4-bromo-3-methylphenyl}sulfonyl)phenyl]ethanol (71 mg, 0.2 mmol), [(E)-2-(4-fluorophenyl)vinyl]boronic acid (43 mg, 0.26 mmol), tetrakis(triphenylphosphine) palladium(0) (23 mg, 0.020 mmol), THF (2 mL) and 2M aqueous sodium carbonate (1 mL) was heated in an Emrys microwave reactor at 150° C. for 10 minutes. On cooling, the mixture was partitioned between EtOAc (15 mL) and water (15 mL) and the organic phase was washed with brine, dried (MgSO4), filtered and concentrated in vacuo. The crude material was purified by flash chromatography on silica (eluant 30% EtOAc/isohexane) to afford the title compound as a white solid (45 mg). δH (500 MHz, d6 DMSO): 8.01 (1H, d, J 7.9), 7.88 (1H, d, J 8.2), 7.80 (1H, d, J 7.8), 7.73–7.63 (5H, m), 7.52 (1H, t, J 7.6), 7.37 (1H, d, J 16.3), 7.29 (1H, d, J 16.2), 7.22 (2H, t, J 8.7), 5.45 (1H, s), 5.30 (1H, s), 2.46 (3H, s), 1.11 (3H, d, J 5.9). m/z (ES+) 379 [(M−OH)+].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[CH:20](OCC)=[O:21].[H-].[Na+]>COCCOC>[CH:20]([CH:14]([CH2:13][C:5]1[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:21]
Reactant: CCOC=O
Reactant: CCOC(=O)CCc1cc(OC)c(OC)c(OC)c1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CCOC(=O)C(C=O)Cc1cc(OC)c(OC)c(OC)c1
Yield: 44 %

Procedure:
Ethyl 3-(3,4,5-trimethoxyphenyl)propionate was reacted with ethyl formate and sodium hydride in 1,2-dimethoxyethane to give crude ethyl 2-formyl-3-(3,4,5-trimethoxyphenyl)propionate in 44% yield.
Reaction SMILES: CCN(C(C)C)C(C)C.Br[CH2:11][CH2:12][F:13].[NH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]2[N:22]([C:37]3[C:38]4[C@H:45]([CH3:46])[CH2:44][CH2:43][C:39]=4[N:40]=[CH:41][N:42]=3)[CH2:23][C:24]3([CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]3)[C:17]=12>CN(C=O)C>[F:13][CH2:12][CH2:11][NH:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]2[N:22]([C:37]3[C:38]4[C@H:45]([CH3:46])[CH2:44][CH2:43][C:39]=4[N:40]=[CH:41][N:42]=3)[CH2:23][C:24]3([CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:34])([CH3:35])[CH3:36])=[O:31])[CH2:26][CH2:25]3)[C:17]=12
Reactant: C[C@@H]1CCc2ncnc(N3CC4(CCN(C(=O)OC(C)(C)C)CC4)c4c(CN)cccc43)c21
Reactant: FCCBr
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1CCc2ncnc(N3CC4(CCN(C(=O)OC(C)(C)C)CC4)c4c(CNCCF)cccc43)c21
Temperature: 80 °C
Reaction time: 8 h
Yield: 39.1 %

Procedure:
DIEA (0.015 mL, 0.093 mmol) and 1-bromo-2-fluoroethane (0.0067 mL, 0.075 mmol) was added to a stirred solution of (R)-tert-butyl 4-(aminomethyl)-1-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,4′-piperidine]-1′-carboxylate (28 mg, 0.062 mmol) in DMF (0.6 mL) The reaction mixture was stirred at 80° C. overnight. After cooling, the reaction mixture was partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried and concentrated. The residue was purified by column chromatography (DCM:MeOH, 60:1) to give (R)-tert-butyl 4-((2-fluoroethylamino)methyl)-1-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,4′-piperidine]-1′-carboxylate (12 mg, 39%) as an oil. LCMS (APCI+) m/z 496 [M+H]+; Rt=3.03 min.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][C:6]=1I)[CH:2]=[CH2:3].C([O-])([O-])=O.[Na+].[Na+].C([O-])=O.[Na+]>[N+](CCCC)(CCCC)(CCCC)CCCC.[Cl-].O.CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:3][C:2]1[C:6]2[CH:7]=[C:8]([C:9]([O:11][CH3:12])=[O:10])[CH:13]=[CH:14][C:5]=2[O:4][CH:1]=1
Reactant: C=CCOc1ccc(C(=O)OC)cc1I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc2occ(C)c2c1
Temperature: 80 °C
Yield: 43.7 %

Procedure:
Methyl 4-(allyloxy)-3-iodobenzoate (587 mg, 1.84 mmol) is combined with Pd(OAc)2 (5%, 20 mg, 0.1 mmol), Na2CO3 (487 mg, 4.6 mmol), sodium formate (125 mg, 1.8 mmol) and n-Bu4NCl.H2O (561 mg, 2.0 mmol) in DMF (5 mL) and heated to 80° C. for 2 days. The mixture is concentrated under high vacuum and partitioned between 50% saturated NaCl (10 mL) and CH2Cl2 (4×10 mL). The combined organics are washed with 5% HCl (10 mL), dried (Na2SO4) and concentrated to a brown oil. The crude material is chromatographed over 15 g slurry-packed silica gel, eluting with 15% EtOAc/hexane. The appropriate fractions are combined and concentrated to afford 153 mg (44%) of methyl 3-methyl-1-benzofuran-5-carboxylate as a white solid. HRMS (FAB) calcd for C11H10O3+H: 191.0708, found: 191.0705 (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.Cl[S:13]([C:16]1[CH:17]=[C:18]([CH:23]=[CH:24][CH:25]=1)[C:19]([O:21][CH3:22])=[O:20])(=[O:15])=[O:14]>CN(C1C=CN=CC=1)C>[CH3:22][O:21][C:19](=[O:20])[C:18]1[CH:23]=[CH:24][CH:25]=[C:16]([S:13](=[O:14])(=[O:15])[NH:1][C:2]2[CH:3]=[CH:4][CH:5]=[C:6]3[C:11]=2[N:10]=[CH:9][CH:8]=[CH:7]3)[CH:17]=1
Reactant: Nc1cccc2cccnc12
Reactant: COC(=O)c1cccc(S(=O)(=O)Cl)c1
Agent: CN(C)c1ccncc1
Product: COC(=O)c1cccc(S(=O)(=O)Nc2cccc3cccnc23)c1
Yield: 63.5 %

Procedure:
In the similar fashion using route 14 general procedure 27, 8-aminoquinoline (100 mg, 0.69 mmol), methyl 3-chlorosulfonylbenzoate (160 mg, 0.69 mmol) and DMAP (cat.) gave the title compound (150 mg, 64%) after purification by column chromatography with DCM as the eluent.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][NH2:20])=[CH:15][CH:14]=1.[Cl:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26]Cl)=[CH:24][CH:23]=1.C(N(C(C)C)CC)(C)C>O.CO.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[Cl:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][N:19]([C:16]2[CH:15]=[CH:14][C:13]([O:12][CH2:11][C:2]3[CH:3]=[CH:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[N:1]=3)=[CH:18][CH:17]=2)[NH2:20])=[CH:24][CH:23]=1
Reactant: NNc1ccc(OCc2ccc3ccccc3n2)cc1
Reactant: ClCc1ccc(Cl)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: NN(Cc1ccc(Cl)cc1)c1ccc(OCc2ccc3ccccc3n2)cc1

Procedure:
in said step (5) reacting the 4-(quinolin-2-ylmethoxy)phenylhydrazine product of said step (4) in H2O/methanol with p-chlorobenzyl chloride, tetrabutylammonium bromide and diisopropyl ethyl amine to yield 1-(p-chlorobenzyl)-1-[4(quinolin-2-ylmethoxy)phenyl]hydrazine;
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH3:16])=[C:11]([CH:17]2[C:19]3([C:23](=[O:24])[C:22]([CH3:26])([CH3:25])[O:21][C:20]3([CH3:28])[CH3:27])[O:18]2)[CH:10]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH3:16])=[C:11]([CH:17]2[C:23](=[O:24])[C:22]([CH3:26])([CH3:25])[O:21][C:20]([CH3:28])([CH3:27])[C:19]2=[O:18])[CH:10]=1
Reactant: CCc1ccc(-c2ccc(Cl)cc2Cl)cc1C1OC12C(=O)C(C)(C)OC2(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCc1ccc(-c2ccc(Cl)cc2Cl)cc1C1C(=O)C(C)(C)OC(C)(C)C1=O
Temperature: 150 °C

Procedure:
To a solution of 2-(2′,4′-dichloro-4-ethylbiphenyl-3-yl)-4,4,6,6-tetramethyl-1,5-dioxaspiro[2.4]heptan-7-one (0.0418 g, 0.10 mmol) in toluene (0.3 ml) is added p-toluenesulfonic acid monohydrate (0.019 g, 0.10 mmol). The mixture is then heated at 150° C. for 1 hour, after which it is allowed to cool to room temperature. The reaction mixture is poured into distilled water, dried over sodium sulfate, then concentrated in vacuo to afford 4-(2′,4′-dichloro-4-ethylbiphenyl-3-yl)-2,2,6,6-tetramethylpyran-3,5-dione.
Reaction SMILES: CC(C(N[C@@:8]([CH3:20])([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)[C:9](O)=[O:10])=O)(C)C.C1OC2C=CC([NH2:26])=CC=2O1>>[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([CH:8]([CH3:20])[C:9]([NH2:26])=[O:10])=[CH:13][CH:14]=1
Reactant: COc1ccc([C@](C)(NC(=O)C(C)(C)C)C(=O)O)cc1
Reactant: Nc1ccc2c(c1)OCO2
Product: COc1ccc(C(C)C(N)=O)cc1

Procedure:
(S)-α-[N-[(1,1-Dimethylethyl)carbonyl]amino]-4-methoxy-α-methylbenzeneacetic acid (preparation described in step A of Example 101) was condensed with 3,4-(methylenedioxy)aniline following the procedure described in step A of Example 99. Pure (S)-N-(1,3-benzodioxol-5-yl)-α-[N-[(1,1-dimethylethyl)carbonyl]]amino!-4-methoxy-α-methyl-benzeneacetamide, obtained after chromatography on silica gel using 30% EtOAc/hexane as eluant, was converted to the title compound following the procedure described in step A of Example 98.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][CH:12]([NH:15][CH2:16][CH2:17][NH:18][C:19]([N:21]2[C@@H:25]([C:26]3[CH:31]=[CH:30][C:29]([F:32])=[C:28]([F:33])[CH:27]=3)[CH2:24][O:23][C:22]2=[O:34])=[O:20])[CH2:11][CH2:10]1)#[N:2].C(=O)([O-])[O-].[Cs+].[Cs+].[F:41][C:42]([F:46])([F:45])[CH2:43]I>C(#N)C.ClCCl.O>[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][CH:12]([N:15]([CH2:43][C:42]([F:46])([F:45])[F:41])[CH2:16][CH2:17][NH:18][C:19]([N:21]2[C@@H:25]([C:26]3[CH:31]=[CH:30][C:29]([F:32])=[C:28]([F:33])[CH:27]=3)[CH2:24][O:23][C:22]2=[O:34])=[O:20])[CH2:11][CH2:10]1)#[N:2]
Reactant: FC(F)(F)CI
Reactant: N#Cc1ccccc1N1CCC(NCCNC(=O)N2C(=O)OC[C@@H]2c2ccc(F)c(F)c2)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: O
Solvent: CC#N
Product: N#Cc1ccccc1N1CCC(N(CCNC(=O)N2C(=O)OC[C@@H]2c2ccc(F)c(F)c2)CC(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 18 (36 mg, 0.076 mmol) and cesium carbonate (50 mg, 0.153 mmol) in acetonitrile (100 mL) was treated with 2,2,2-trifluoroethyliodide (21.3 mg, 0.101 mmol) at room temperature. The resulting mixture was stirred at room temperature overnight. The mixture was diluted with dichloromethane and water and the aqueous layer was extracted with two additional portions of dichloromethane. The combined organic extracts were concentrated under reduced pressure and purified by PCTLC (SiO2, 4 mm, 1% NH4OEt-1% NH4OEt-10% EtOH-90% CHCl3) to afford the title compound (49) which was converted to the hydrochloride salt after treatment with EtOAc/HCl.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[N:10]2[C:11](=[O:17])[NH:12][C:13]3=[CH:14][CH:15]=[CH:16][C:8](=[C:9]23)[O:7][CH2:6]1)=[O:4].[Br:24]N1C(=O)CCC1=O>C(#N)C.C(O)(=O)C.C(OCC)(=O)C>[Br:24][C:16]1[C:8]2[O:7][CH2:6][C:5]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)([C:3]([NH:2][CH3:1])=[O:4])[N:10]3[C:11](=[O:17])[NH:12][C:13]([C:9]=23)=[CH:14][CH:15]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CNC(=O)C1(c2ccccn2)COc2cccc3[nH]c(=O)n1c23
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: CC(=O)O
Product: CNC(=O)C1(c2ccccn2)COc2c(Br)ccc3[nH]c(=O)n1c23
Reaction time: 1 h
Yield: 51.4 %

Procedure:
N-Methyl-2-oxo-4-pyridin-2-yl-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazine-4-carboxamide (20 mg, 0.1 mmol) was dissolved in acetonitrile (3 mL) and acetic acid (2 mL), and cooled to 0° C., followed by addition of N-bromosuccinimide (20 mg, 0.1 mmol). The reaction mixture was stirred for 1 h and was then concentrated to give a crude residue. The residue was dissolved in ethyl acetate, washed with saturated aqueous sodium bicarbonate, washed with brine, dried over magnesium sulfate, filtered, and concentrated to give crude 7-bromo-N-methyl-2-oxo-4-pyridin-2-yl-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazine-4-carboxamide (0.020 g, 50%). LCMS calculated for C16H14BrN4O3 (M+H)+: m/z=389.1, 391.1. found: 388.9, 390.9.
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].N1C=CN=C1.[F:14][C:15]1[C:20]([CH:21]([CH3:23])[CH3:22])=[CH:19][C:18]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][C:25]=2[CH2:34][OH:35])=[C:17]([O:36][CH3:37])[CH:16]=1.O>C(Cl)Cl>[C:4]([Si:1]([O:35][CH2:34][C:25]1[CH:26]=[C:27]([C:30]([F:32])([F:33])[F:31])[CH:28]=[CH:29][C:24]=1[C:18]1[CH:19]=[C:20]([CH:21]([CH3:23])[CH3:22])[C:15]([F:14])=[CH:16][C:17]=1[O:36][CH3:37])([CH3:3])[CH3:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: COc1cc(F)c(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: ClCCl
Product: COc1cc(F)c(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CO[Si](C)(C)C(C)(C)C
Reaction time: 8 h

Procedure:
tert-Butyldimethylsilyl chloride (0.48 g, 3.21 mmol) and imidazole (0.50 g, 7.30 mmol) were added successively to a stirred solution of [4′-fluoro-5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methanol (1.00 g, 2.93 mmol) in dry CH2Cl2 (13.4 mL) at room temperature under N2 and the reaction was stirred overnight. Water (50 mL) was added and the mixture was extracted with EtOAc (3×50 mL). The combined extracts were dried (MgSO4) and concentrated in vacuo to give the crude product. This was purified by flash chromatography (Si, 25×160 mm, 1% EtOAc in hexanes) to afford tert-butyl {[4′-fluoro-5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methoxy}dimethylsilane as a colorless oil. Rf=0.16 (1% EtOAc in hexanes). LCMS calc.=457.2; found=457.2 (M+1)+. 1H NMR (500 MHz, CDCl3) δ 7.94 (s, 1H), 7.57 (d, J=7.8 Hz, 1H), 7.29 (d, J=7.6 Hz, 1H), 7.00 (d, J=8.6 Hz, 1H), 6.69 (d, J=12.1 Hz, 1H), 4.63 (br s, 1H), 4.50 (br s, 1H), 3.75 (s, 3H), 3.29-3.21 (m, 1H), 1.28 (d, J=6.9 Hz, 6H), 0.93 (s, 9H), 0.03 (s, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH2:9][S:10][C:11]2[NH:12][C:13]3[C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=4[S:16][C:14]=3[N:15]=2)[CH:4]=1.ClC1C=CC=C(C(OO)=[O:31])C=1.C(=O)(O)[O-].[Na+]>ClCCl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH2:9][S:10]([C:11]2[NH:12][C:13]3[C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=4[S:16][C:14]=3[N:15]=2)=[O:31])[CH:4]=1
Reactant: COc1ccnc(CSc2nc3sc4ccccc4c3[nH]2)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccnc(CS(=O)c2nc3sc4ccccc4c3[nH]2)c1
Reaction time: 0.33 h

Procedure:
To a solution of 1 g of 2-(4-methoxy-2-picolylmercapto)-1H-benzothieno[2,3-d]imidazole in 75 ml of dichloromethane at room temperature was added 0.6 g of m-chloroperbenzoic acid and, after stirring for 20 minutes, saturated aqueous sodium bicarbonate solution was added, and the organic phase was separated off. After the solvent had been evaporated off under reduced pressure, crystallization was induced by treatment with a little ethyl acetate and diisopropyl ether. Colorless solid, decomposition above 90° C.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([N:17]2[C:25]3[C:20](=[C:21]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])[CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18]2)([C:15]#[N:16])[CH2:13][CH3:14])=[CH:8][CH:7]=1.[Cl-].[NH4+]>CN(C=O)C>[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([N:17]2[C:25]3[C:20](=[C:21]([NH:26][S:27]([CH3:30])(=[O:28])=[O:29])[CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18]2)([C:15]2[N:1]=[N:2][NH:3][N:16]=2)[CH2:13][CH3:14])=[CH:8][CH:7]=1
Reactant: CCC(C#N)(c1ccc(Cl)cc1)n1ccc2c(NS(C)(=O)=O)cccc21
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCC(c1ccc(Cl)cc1)(c1nn[nH]n1)n1ccc2c(NS(C)(=O)=O)cccc21
Temperature: 130 °C

Procedure:
Sodium azide (117.6 m g, 1.809 mmol) was added to a stirred solution of N-(1-(1-(4-chlorophenyl)-1-cyanopropyl)-1H-indol-4-yl)methanesulfonamide (100 mg, 0.258 mmol) and ammonium chloride (110.6 g, 2.067 mmol) in DMF (2 mL) was heated at 130° C. for 3 h in microwave reactor. The reaction was quenched with water, and extracted with ethyl acetate (100 mL). The organic layer was washed with brine, dried over sodium sulfate, filtered and evaporated. The residue was purified by silica gel chromatography eluting with PE/EA (5/1 to 1/1, v/v) to afford the title compound as a yellow solid. LC/MS m/z=431.0 [M+H]+.
Reaction SMILES: [OH-].[Na+].[C:3]1([CH3:13])[CH:8]=[CH:7][C:6]([S:9]([NH2:12])(=[O:11])=[O:10])=[CH:5][CH:4]=1.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]=[C:22]=[S:23])=[CH:17][CH:16]=1.C(O)(=O)C>CC(C)=O.O>[CH3:13][C:3]1[CH:4]=[CH:5][C:6]([S:9]([NH:12][C:22]([NH:21][C:18]2[CH:19]=[CH:20][C:15]([Cl:14])=[CH:16][CH:17]=2)=[S:23])(=[O:10])=[O:11])=[CH:7][CH:8]=1
Reactant: Cc1ccc(S(N)(=O)=O)cc1
Reactant: S=C=Nc1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: CC(=O)O
Solvent: O
Product: Cc1ccc(S(=O)(=O)NC(=S)Nc2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 132 %

Procedure:
1N sodium hydroxide solution (6 mL, 6 mmol) was added to a solution containing the 4-toluenesulfonamide (1 g, 5.85 mmol) in acetone (25 mL). After stirring at room temperature for 30 min, the 4-chlorophenyl isothiocyanate (1.0 mmol) was added. After refluxing for 4 h, the mixture was cooled to room temperature and neutralized with 1N acetic acid solution to pH 5. The mixture was allowed to stir at room temperature for 30 min before adding water (45 mL) to produce a white precipitate which was collected by filtration. After the solid was dried in the oven, it was recrystallized to give 0.45 g (22.6%) of N-[(4-methylphenyl)sulfonyl]-N'-(4-chlorophenyl)thiourea. To an aqueous solution (50 mL) of sulfonylthiourea (1.2 g, 3.67 mmol), 1N sodium hydroxide solution (4 mL) was added and stirred for 2 minutes, followed by addition of methyl iodide (4.04 mmol). The reaction mixture was stirred at room temperature for 20 minutes, and neutralized with 1N acetic acid (4 mL). The resulting mixture was extracted with chloroform to give 1.06 g (85%) of N-[(4-methylphenyl)sulfonyl]-N'-(4-chlorophenyl)-S-methylpseudothiourea. The S-methyl pseudourea (0.99 g, 2.8 mmol) was added to a stirred solution of hydroxylamine hydrochloride (8.4 mmol) and triethylamine (1.2 mL, 8.4 mmol) in chloroform (50 mL). The solution was refluxed for 48 h and the solvent was removed by evaporation to produce a solid residue. Ether (20 mL) was added to the residue and the white precipitate was collected by filtration. The solid was then heated with toluene and the undissolved solid was removed by filtration. The filtrate was again evaporated to obtain a solid which was subsequently recrystallized from methanol to yield the target compound (0.12 g, 12.7%); mp: 201-203° C.; MS m/z 294 (M+ -32); 1H NMR (300 MHz, DMSO-d6) d 2.36 (s, 3H, CH3), 7.31-7.36 (m, 4H, ArH), 7.45 (d, J=8.8 Hz, 2H, ArH), 7.71 (d, J=8.1 Hz, 2H, ArH), 9.40 (s, 1H, NH), 9.69 (br s, 2H, NH & OH); 13C NMR (100 MHz, DMSO-d6) d 20.9, 124.7, 125.9, 128.2, 128.3, 129.1, 136.2, 140.6, 141.6, 154.0. Analysis for C14H14ClN3O3S (339.8): theory: C, 49.49; H, 4.15; N, 12.37. Found: C, 49.67; H, 4.16; N, 12.47.
Reaction SMILES: [N+:1]([C:4]1[N:9]=[CH:8][C:7]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:6][CH:5]=1)([O-])=O>CO.[Pd]>[NH2:1][C:4]1[N:9]=[CH:8][C:7]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:6][CH:5]=1
Reactant: CCOC(=O)Cc1ccc([N+](=O)[O-])nc1
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)Cc1ccc(N)nc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of ethyl (6-nitropyridin-3-yl)acetate (0.9 g, 4.28 mmol), Pd/C (10%, 0.1 g) in MeOH (50 mL) was stirred for 2 hours under H2 atmosphere at room temperature. The mixture was filtered and concentrated to give ethyl (6-aminopyridin-3-yl)acetate.
Reaction SMILES: [C:1]1([C:7]2[C:16]3[C:11](=[CH:12][C:13]([S:17][C:18]4[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=4)[C:21](O)=[O:22])=[CH:14][CH:15]=3)[N:10]3[CH:27]=[N:28][N:29]=[C:9]3[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C(Cl)=O.[CH3:36][N:37](C=O)[CH3:38].CNC>C(Cl)Cl>[CH3:36][N:37]([CH3:38])[C:21](=[O:22])[C:20]1[CH:24]=[CH:25][CH:26]=[C:18]([S:17][C:13]2[CH:12]=[C:11]3[C:16]([C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)=[CH:8][C:9]4[N:10]3[CH:27]=[N:28][N:29]=4)=[CH:15][CH:14]=2)[CH:19]=1
Reactant: CN(C)C=O
Reactant: O=C(O)c1cccc(Sc2ccc3c(-c4ccccc4)cc4nncn4c3c2)c1
Agent: CNC
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: CN(C)C(=O)c1cccc(Sc2ccc3c(-c4ccccc4)cc4nncn4c3c2)c1
Temperature: 25 °C

Procedure:
To 11a (219 mg, 0.67 mmol) in CH2Cl2 (30 mL) was added oxalyl chloride (0.07 mL, 0.80 mmol) and a drop of DMF. The mixture was then concentrated, and the residue was redissolved in CH2Cl2 and divided into 5 portions. To one portion, dimethylamine (2.0M, 0.3 mL, 0.54 mmol) was added, and the mixture was stirred at room temperature until no SM was observed by LCMS analysis. The reaction was concentrated and purified by preparative HPLC to give the desired product, 11b.