Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]([CH2:10][CH2:11][S:12][C:13]1[CH:18]=[CH:17][N:16]=[C:15]([CH2:19]O)[C:14]=1[CH3:21])[CH3:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:24])=O>>[CH2:1]([N:8]([CH2:10][CH2:11][S:12][C:13]1[CH:18]=[CH:17][N:16]=[C:15]([CH2:19][Cl:24])[C:14]=1[CH3:21])[CH3:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1c(SCCN(C)Cc2ccccc2)ccnc1CO
Reactant: O=S(Cl)Cl
Product: Cc1c(SCCN(C)Cc2ccccc2)ccnc1CCl
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Thionyl chloride (10 ml) was dropwise added to 4-(2-(N-benzyl-N-methylamino)ethylthio)-2-hydroxymethyl-3-methylpyridine (1.8 g) under ice-cooling and the mixture was stirred at room temperature for 1.5 hours. After the completion of the reaction, thionyl chloride was distilled away. The residue was alkali-oversaturated with potassium carbonate and extracted with chloroform. The chloroform layer was dried over anhydrous magnesium sulfate and the solvent was distilled away to give 1.7 g of 4-(2-(N-benzyl-N-methylamino)ethylthio)-2-chloromethyl-3-methylpyridine. The product was added to ethanol (30 ml) containing a solution of 2-mercaptobenzimidazole (0.9 g) and sodium hydroxide (0.5 g) in water (10 ml) and the mixture was refluxed under heating for 7 hours. After the completion of the reaction, the ethanol was distilled away and water was added to the residue, followed by extraction with chloroform. The extract was dried over anhydrous magnesium sulfate and the solvent was distilled away. Acetone was added to the residue to allow crystallization. The obtained crystals were recrystallized from a mixed solvent of acetone-isopropyl ether to give 2-((4-(2-(N-benzyl-N-methylamino)ethylthio)-3-methyl-2-pyridyl)methylthio)-1H-benzimidazole as crystals, melting point 110°-112° C.
Reaction SMILES: [CH2:1]1[N:12]2[C:13]3[C:9]([C@@H:10]4[CH2:17][NH:16][CH2:15][CH2:14][C@@H:11]42)=[CH:8][CH:7]=[CH:6][C:5]=3[CH2:4][S:3][CH2:2]1.Cl[CH2:19][CH2:20][CH2:21][C:22]([C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=1)=[O:23].C([O-])([O-])=O.[K+].[K+].O>O1CCOCC1>[CH2:1]1[N:12]2[C:13]3[C:9]([C@@H:10]4[CH2:17][N:16]([CH2:19][CH2:20][CH2:21][C:22]([C:24]5[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=5)=[O:23])[CH2:15][CH2:14][C@@H:11]42)=[CH:8][CH:7]=[CH:6][C:5]=3[CH2:4][S:3][CH2:2]1
Reactant: O=C(CCCCl)c1ccc(F)cc1
Reactant: c1cc2c3c(c1)[C@@H]1CNCC[C@@H]1N3CCSC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: O=C(CCCN1CC[C@H]2[C@@H](C1)c1cccc3c1N2CCSC3)c1ccc(F)cc1
Yield: 67 %

Procedure:
To a solution of (7bR,11aS)-1,2,7b,8,9,10,11,11a-octahydro-4H-pyrido[4,3-b][1,4]thiazepino[6,5,4-hi]indole from EXAMPLE 1 (80 mg, 0.32 mmol) in 1,4-dioxane (15 ml) at 25° C. was added 4-chloro-1-(4-fluorophenyl)butan-1-one (96 mg, 0.48 mmol), K2CO3 (100 mg, 0.72 mmol), and KI (32 mg, 0.19 mmol), respectively. The mixture was stirred at ambient temperature for 16 hours before H2O (10 mL) was added and then extracted with EtOAc (2×20 mL). The combined extracts were dried over magnesium sulfate, concentrated, and purified by flash chromatography to give the title compound of EXAMPLE 4 as an oil (88 mg, 67%). 1H NMR (CDCl3, 300 MHz): δ 8.01 (m, 2H), 7.15 (m, 2H), 6.96 (d, 1H, J=6.6 Hz), 6.92 (d, 1H, J 6.6 Hz), 3.82 (m, 2H), 3.25 (m, 2H), 3.19-2.60 (m, 8H), 2.42 (m, 2H), 1.95 (m, 5H). LRMS (ES)+: 411 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[N:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[N+:12]([O-])([OH:14])=[O:13]>S(=O)(=O)(O)O>[OH:1][C:2]1[N:10]=[C:9]([CH3:11])[C:8]([N+:12]([O-:14])=[O:13])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=[N+]([O-])O
Reactant: Cc1ccc(C(=O)O)c(O)n1
Agent: O=S(=O)(O)O
Product: Cc1nc(O)c(C(=O)O)cc1[N+](=O)[O-]
Temperature: 90 °C
Reaction time: 2 h
Yield: 87.2 %

Procedure:
To a solution of 2-hydroxy-6-methylnicotinic acid (14.0 g, 91.5 mmol, 1.00 equiv) in sulfuric acid (conc.) (140 mL) at 0° C. was added dropwise a solution of HNO3 (12.0 g, 190 mmol, 2.00 equiv) in sulfuric acid (conc.) (10 mL). The resulting mixture was then stirred for 2 h at 90° C., cooled to ambient temperature, and then quenched with 250 mL of ice water. The resulting solids were collected by filtration and dried in an oven under reduced pressure to yield 15.8 g (87%) of the title compound as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:15]=[C:14]([CH3:16])[N:13]=[C:12]([C:17]3[CH2:21][CH:20]([C:22]4[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][CH:23]=4)[O:19][N:18]=3)[CH:11]=2)=[O:9])=[CH:4][C:3]=1[O:33][CH3:34].C[N:36](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.N>CN(C=O)C>[C:26]([C:25]1[CH:29]=[CH:30][C:22]([CH:20]2[O:19][N:18]=[C:17]([C:12]3[N:13]=[C:14]([CH3:16])[N:15]=[C:10]([C:8]([NH:7][CH2:6][C:5]4[CH:31]=[CH:32][C:2]([F:1])=[C:3]([O:33][CH3:34])[CH:4]=4)=[O:9])[CH:11]=3)[CH2:21]2)=[CH:23][CH:24]=1)(=[O:28])[NH2:36]
Reactant: COc1cc(CNC(=O)c2cc(C3=NOC(c4ccc(C(=O)O)cc4)C3)nc(C)n2)ccc1F
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(CNC(=O)c2cc(C3=NOC(c4ccc(C(N)=O)cc4)C3)nc(C)n2)ccc1F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 50.2 %

Procedure:
To a stirred solution of 4-(3-(6-(4-fluoro-3-methoxybenzylcarbamoyl)-2-methylpyrimidin-4-yl)-4,5-dihydroisoxazol-5-yl)benzoic acid (0.1 g, 0.215 mmol) in DMF (10 mL) was added HATU (0.123 g, 0.323 mmol) and DIEA (0.055 g, 0.43 mmol). The reaction mixture was stirred at RT for about 10 min. Ammonia solution (3 mL) was added and the reaction mixture stirred for about another 2 h. The reaction mixture was diluted with ice cold water (20 mL). The solid which was obtained was filtered, washed with water and dried under vacuum to afford 6-(5-(4-carbamoylphenyl)-4,5-dihydroisoxazol-3-yl)-N-(4-fluoro-3-methoxybenzyl)-2-methylpyrimidine-4-carboxamide (0.05 g), (50%) as an off white solid. LC/MS (Table 1, Method c) R1=4.48 min. MS m/z: 464.2 (M+H)+.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1.O.O.O.O.O.O.[NH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1>>[ClH:1].[ClH:1].[ClH:1].[N:5]1[CH:6]=[CH:7][CH:8]=[C:3]([CH2:2][N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[CH:4]=1
Reactant: C1CNCCN1
Reactant: ClCc1cccnc1
Solvent: O
Product: Cl
Product: c1cncc(CN2CCNCC2)c1
Yield: 62 %

Procedure:
A mixture of 3-chloromethylpyridine and piperazine hexahydrate was treated according to the general preparation 1 to obtain N-(3-pyridylmethyl) piperazine trihydrochloride (62%). A mixture of the above product (3 mmol) and 2-chloro-1-phenylethanol (3.2 mmol) was treated according to the general preparation 2 to obtain the N1-(3-pyridylmethyl)-N4-phenacyl piperazine trihydrochloride (0.85 g, 2 mmol), which was reduced according to the general preparation 3 to obtain 0.61 g of the title compound, yield 72%, mp. 180-182° C.).
Reaction SMILES: Br[C:2]1[S:22][C:5]2=[N:6][C:7]([CH3:21])=[CH:8][C:9]([NH:10][S:11]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=3)(=[O:13])=[O:12])=[C:4]2[C:3]=1[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+].[N:37]1[CH:42]=[CH:41][CH:40]=[C:39](B(O)O)[CH:38]=1>C(#N)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:20][C:16]1[CH:15]=[C:14]([S:11]([NH:10][C:9]2[CH:8]=[C:7]([CH3:21])[N:6]=[C:5]3[S:22][C:2]([C:39]4[CH:38]=[N:37][CH:42]=[CH:41][CH:40]=4)=[C:3]([C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=4)[C:4]=23)(=[O:13])=[O:12])[CH:19]=[CH:18][CH:17]=1
Reactant: OB(O)c1cccnc1
Reactant: COc1cccc(-c2c(Br)sc3nc(C)cc(NS(=O)(=O)c4cccc(Cl)c4)c23)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: COc1cccc(-c2c(-c3cccnc3)sc3nc(C)cc(NS(=O)(=O)c4cccc(Cl)c4)c23)c1
Temperature: 80 °C
Yield: 41.3 %

Procedure:
A mixture of N-{2-bromo-6-methyl-3-[3-(methyloxy)phenyl]thieno[2,3-b]pyridin-4-yl}-3-chlorobenzenesulfonamide (50 mg, 0.095 mmol) (Example 33), tetrakis(triphenylphosphine)palladium(0) (5.51 mg, 4.77 μmol), sodium carbonate (20.23 mg, 0.191 mmol) and 3-pyridineboronic acid (14.08 mg, 0.115 mmol) in acetonitrile (1 mL) and water (250 μl) was heated at 80° C. under nitrogen for 17 h. The reaction mixture was then cooled to RT and concentrated. Purification by chromatography on silica gel, eluting with a gradient of 0-50% ethyl acetate in DCM, afforded the title compound (20.5 mg). LCMS (A) m/z: 522 [M+1]+, Rt 1.33 min (acidic), Rt 0.89 min (basic).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[CH:18]=[CH:17][C:16](Br)=[CH:15][CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:20][CH:21]([Cl:40])[C:22]([NH:24][C@H:25]([CH2:38][F:39])[C@H:26]([OH:37])[C:27]1[CH:32]=[CH:31][C:30]([Sn](C)(C)C)=[CH:29][CH:28]=1)=[O:23]>CN(C=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:20][CH:21]([Cl:40])[C:22]([NH:24][C@H:25]([CH2:38][F:39])[C@@H:26]([C:27]1[CH:28]=[CH:29][C:30]([C:16]2[CH:17]=[CH:18][C:13]([CH:9]3[CH2:10][CH2:11][CH2:12][N:8]3[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[CH:14][CH:15]=2)=[CH:31][CH:32]=1)[OH:37])=[O:23]
Reactant: C[Sn](C)(C)c1ccc([C@@H](O)[C@@H](CF)NC(=O)C(Cl)Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCCC1c1ccc(Br)cc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCCC1c1ccc(-c2ccc([C@@H](O)[C@@H](CF)NC(=O)C(Cl)Cl)cc2)cc1
Temperature: 80 °C
Yield: 29.9 %

Procedure:
A mixture of commercially available 2-(4-Bromo-phenyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (500 mg, 1.53 mmol), 2,2-dichloro-N-((1R,2S)-3-fluoro-1-hydroxy-1-(4-(trimethylstannyl)phenyl)propan-2-yl)acetamide (679 mg, 1.53 mmol, 1 eq.), P(2-fur)3 (72 mg, 0.31 mmol, 0.2 eq.) and Pd2(dba)3 (142 mg, 0.153 mmol, 0.1 eq.) are dissolved in DMF (8 mL, 0.2 M) and de-oxygenated. The mixture is heated to 80° C. for 16 hours. Reaction is concentrated under vacuum to a syrup and purified on a 24 g silica column eluting from 0-100% EtOAc/heptane) to give the title compound 240 mg.
Reaction SMILES: [CH:1]1([CH2:4][NH:5][C:6]([C:8]2[NH:9][CH:10]=[C:11]([C:13]([C:15]3[C:16]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=4)=[N:17][O:18][C:19]=3[CH3:20])=[O:14])[CH:12]=2)=[O:7])[CH2:3][CH2:2]1.[F:28]C1C=C(C2C(C(C3C=C(C(=O)C(Cl)(Cl)Cl)NC=3)=O)=C(C)ON=2)C=CC=1F.C1(CN)CC1>>[CH:1]1([CH2:4][NH:5][C:6]([C:8]2[NH:9][CH:10]=[C:11]([C:13]([C:15]3[C:16]([C:21]4[CH:22]=[CH:23][C:24]([F:27])=[C:25]([F:28])[CH:26]=4)=[N:17][O:18][C:19]=3[CH3:20])=[O:14])[CH:12]=2)=[O:7])[CH2:3][CH2:2]1
Reactant: Cc1onc(-c2ccc(F)cc2)c1C(=O)c1c[nH]c(C(=O)NCC2CC2)c1
Reactant: Cc1onc(-c2ccc(F)c(F)c2)c1C(=O)c1c[nH]c(C(=O)C(Cl)(Cl)Cl)c1
Agent: NCC1CC1
Product: Cc1onc(-c2ccc(F)c(F)c2)c1C(=O)c1c[nH]c(C(=O)NCC2CC2)c1

Procedure:
According to the procedure described for the synthesis of 4-(5-methyl-3-(4-fluorophenyl)-isoxazole-4-carbonyl)-1H-pyrrole-2-carboxylic acid (cyclopropylmethyl)-amide (example 229, step 2), the title compound has been synthesized from 4-[3-(3,4-difluoro-phenyl)-5-methyl-isoxazole-4-carbonyl]-2-trichloroacetyl-1H-pyrrole (intermediate 19) and cyclopropylmethylamine (commercially available) in 35.8 yield. (m/e): 386.1 (MH+; 100%).
Reaction SMILES: [Cl:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH:12]1([CH2:15][CH:16]([C:19]2[CH:20]=[N:21][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:23][CH:24]=2)[CH2:17][NH2:18])[CH2:14][CH2:13]1>>[Cl:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:18][CH2:17][CH:16]([C:19]1[CH:20]=[N:21][C:22]([C:25]([F:28])([F:26])[F:27])=[CH:23][CH:24]=1)[CH2:15][CH:12]1[CH2:13][CH2:14]1)=[O:6]
Reactant: O=C(O)c1cccc(F)c1Cl
Reactant: NCC(CC1CC1)c1ccc(C(F)(F)F)nc1
Product: O=C(NCC(CC1CC1)c1ccc(C(F)(F)F)nc1)c1cccc(F)c1Cl

Procedure:
From 2-chloro-3-fluorobenzoic acid and 3-cyclopropyl-2-(6-(trifluoromethyl)pyridin-3-yl)propan-1-amine. LCMS (MH+): m/z=401.1, tR (minutes, Method G)=2.51
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]1([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][OH:22])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.CCN(CC)CC>C(Cl)Cl>[C:11]1([CH2:17][CH2:18][CH2:19][CH2:20][CH:21]=[O:22])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: OCCCCCc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=CCCCCc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 97.3 %

Procedure:
Under nitrogen atmosphere, at −78° C., to a stirred solution of oxalyl chloride (0.53 mL, 6.17 mmol) in dry CH2Cl2 (12 mL), DMSO (0.40 mL, 5.7 mmol) was added in a fast manner. After 15 min, a solution of 5-phenylpentan-1-ol (0.78 g, 4.75 mmol) in dry CH2Cl2 (6 mL) was added. The reaction mixture was stirred for 2 h at −78° C. before addition of Et3N (1.98 mL, 14.24 mmol). The solution was allowed to warm at rt, and after evaporation of CH2Cl2 the residue was taken up in Et2O and a saturated NH4Cl solution. After separation of phases the organic fraction was dried over Na2SO4, filtered and concentrated to dryness affording the title compound (0.75 g, 97%) as a pure product. 1H NMR (CDCl3): δ 1.67-1.73 (m, 4H), 2.44-2.52 (m, 2H), 2.60-2.71 (m, 2H), 7.16-7.35 (m, 5H), 9.78 (t, J=1.8 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:10]2[CH2:19][CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][C:16]=3[F:20])[CH:11]2[CH3:21])=[N:4][C:5]([Cl:9])=[N:6][C:7]=1[CH3:8].[F:22][C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][CH:24]=1>CN(C)C=O>[ClH:9].[CH3:1][C:2]1[C:3]([N:10]2[CH2:19][CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][C:16]=3[F:20])[CH:11]2[CH3:21])=[N:4][C:5]([NH:27][C:26]2[CH:28]=[CH:29][C:23]([F:22])=[CH:24][CH:25]=2)=[N:6][C:7]=1[CH3:8]
Reactant: Cc1nc(Cl)nc(N2CCc3c(F)cccc3C2C)c1C
Reactant: Nc1ccc(F)cc1
Solvent: CN(C)C=O
Product: Cc1nc(Nc2ccc(F)cc2)nc(N2CCc3c(F)cccc3C2C)c1C
Product: Cl
Yield: 54.5 %

Procedure:
The same procedures as in Step 2 of Example 3 above were repeated using 5,6-dimethyl-2-chloro-(1-methyl-5-fluoro-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine (0.1 g, 0.33 mmol) prepared in Step 1 above, dimethylformamide (5 ml), and 4-fluoroaniline (0.08 ml, 0.84 mmol) to afford 75 mg (54.5 %) of the titled compound.
Reaction SMILES: [CH:1]([S:3]([C:6]1[CH:7]=[CH:8][C:9]([O:35][CH3:36])=[C:10]([S:12]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[NH:22][S:23]([C:26]2[S:30][C:29]3[CH:31]=[CH:32][CH:33]=[CH:34][C:28]=3[CH:27]=2)(=[O:25])=[O:24])(=[O:14])=[O:13])[CH:11]=1)(=[O:5])=[O:4])=[CH2:2].C[N:38]1[CH2:43][CH2:42]N[CH2:40][CH2:39]1>C1COCC1.C(Cl)Cl>[CH3:36][O:35][C:9]1[CH:8]=[CH:7][C:6]([S:3]([CH2:1][CH2:2][N:38]2[CH2:43][CH2:42][CH2:40][CH2:39]2)(=[O:4])=[O:5])=[CH:11][C:10]=1[S:12]([NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[NH:22][S:23]([C:26]1[S:30][C:29]2[CH:31]=[CH:32][CH:33]=[CH:34][C:28]=2[CH:27]=1)(=[O:25])=[O:24])(=[O:13])=[O:14]
Reactant: C=CS(=O)(=O)c1ccc(OC)c(S(=O)(=O)Nc2ccccc2NS(=O)(=O)c2cc3ccccc3s2)c1
Reactant: CN1CCNCC1
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1ccc(S(=O)(=O)CCN2CCCC2)cc1S(=O)(=O)Nc1ccccc1NS(=O)(=O)c1cc2ccccc2s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of benzo[b]thiophene-2-sulfonic acid [2-(5-ethenesulfonyl-2-methoxybenzenesulfonylamino)phenyl] amide (0.2 mmol, prepared as in Example 19) in dry THF (2 mL) was added 0.2 mL of 1-methylpiperazine. The resulting reaction mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with DCM (10 mL) and washed with saturated sodium chloride aqueous solution (25 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue obtained was purified by flash column chromatography eluting with EtOAc then DCM/methanol/AcOH (100:2:1 to 100:10:2) to furnish 118 mg of benzo[b]thiophene-2-sulfonic acid {2-[2-methoxy-5-(2-pyrrolidin-1-yl-ethanesulfonyl)-benzenesulfonylamino]-phenyl}-amide. LC: Tr 0.84 min; MS: 666.0 (M+1)+.
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([C:18]4([O:22][CH3:23])[CH2:21][NH:20][CH2:19]4)[N:14]3[CH3:17])=[C:10]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[N:9]=2)[C:6]2[CH:30]=[CH:31][CH:32]=[CH:33][C:5]=2[N:4]=1)[CH3:2].[CH3:34][S:35]([CH:38]=[CH2:39])(=[O:37])=[O:36]>>[CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([C:18]4([O:22][CH3:23])[CH2:21][N:20]([CH2:39][CH2:38][S:35]([CH3:34])(=[O:37])=[O:36])[CH2:19]4)[N:14]3[CH3:17])=[C:10]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[N:9]=2)[C:6]2[CH:30]=[CH:31][CH:32]=[CH:33][C:5]=2[N:4]=1)[CH3:2]
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C3(OC)CNC3)n(C)c2n1
Reactant: C=CS(C)(=O)=O
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C3(OC)CN(CCS(C)(=O)=O)C3)n(C)c2n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 68 %

Procedure:
To a solution of 2-(2-ethylbenzoimidazol-1-yl)-8-(3-methoxyazetidin-3-yl)-9-methyl-6-morpholin-4-yl-9H-purine (100 mg, 0.22 mmol) in IMS (2 mL) was added methanesulfonylethene (21 μL, 0.25 mmol) and the resulting mixture allowed to stir at r.t. for 18 h. The reaction mixture was concentrated in vacuo and the resulting residue purified by column chromatography (Si-PCC, MeOH:EtOAc, 0-10%). The resulting residue was triturated with EtOAc and cyclohexane and the resulting solid dried in vacuo affording 826 (83 mg, 67%). LCMS (method I): RT 2.65 min, [M+H]+ 555.3. 1H NMR (DMSO, 400 MHz): δ 8.05-8.05 (1 H, m), 7.64-7.63 (1 H, m), 7.26-7.25 (2 H, m), 4.27 (4 H, brd s), 4.02 (2 H, d, J=7.94 Hz), 3.79 (4 H, t, J=4.57 Hz), 3.72 (3 H, s), 3.42 (2 H, d, J=7.99 Hz), 3.28-3.25 (2 H, m), 3.17 (2 H, t, J=6.52 Hz), 3.05 (3 H, s), 2.89 (2 H, t, J=6.53 Hz), 1.40 (3 H, s), 1.35 (3 H, t, J=7.43 Hz)
Reaction SMILES: Br[C:2]1[CH:15]=[CH:14][C:13]2[O:12][C:11]3[C:6](=[CH:7][C:8]([C:16]4[C:17]([F:22])=[N:18][CH:19]=[CH:20][CH:21]=4)=[CH:9][CH:10]=3)[C@@:5]3([CH2:26][O:25][C:24]([NH2:27])=[N:23]3)[C:4]=2[CH:3]=1.[CH3:28][C:29]1[CH:33]=[C:32]([Sn](CCCC)(CCCC)CCCC)[O:31][N:30]=1.CC(N)CC1C=CC=CC=1.OP(O)(O)=O>>[F:22][C:17]1[C:16]([C:8]2[CH:9]=[CH:10][C:11]3[O:12][C:13]4[C:4](=[CH:3][C:2]([C:32]5[O:31][N:30]=[C:29]([CH3:28])[CH:33]=5)=[CH:15][CH:14]=4)[C@:5]4([CH2:26][O:25][C:24]([NH2:27])=[N:23]4)[C:6]=3[CH:7]=2)=[CH:21][CH:20]=[CH:19][N:18]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc(C)no1
Reactant: NC1=N[C@]2(CO1)c1cc(Br)ccc1Oc1ccc(-c3cccnc3F)cc12
Agent: CC(N)Cc1ccccc1
Agent: O=P(O)(O)O
Product: Cc1cc(-c2ccc3c(c2)[C@]2(COC(N)=N2)c2cc(-c4cccnc4F)ccc2O3)on1
Temperature: 100 °C

Procedure:
A resealable was charged with (S)-2′-bromo-7′-(2-fluoropyridin-3-yl)-5H-spiro[oxazole-4,9′-xanthen]-2-amine (300 mg, 0.704 mmol), 3-methyl-5-(tributylstannyl)isoxazole (786 mg, 2.111 mmol), amphos (18.68 mg, 0.070 mmol) and argon purged dry dioxane (3 mL). The tube was purged with argon, sealed and heated with microwave at 100° C. for 1 h. The solution was concentrated. The crude product was purified via silica gel column chromatography (RediSep 12 g column) using 10-50% 90/10/1 DCM/MeOH/ammonia in DCM to afford (S)-2′-(2-fluoropyridin-3-yl)-7′-(3-methylisoxazol-5-yl)-5H-spiro[oxazole-4,9′-xanthen]-2-amine as a white solid. MS m/z=429.2 [M+H]+. Calcd for C24H17FN4O3: 428.42.
Reaction SMILES: [CH:1]1([OH:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N+](=[CH:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N-]>ClCCl.CCOCC.CC(O)=O.CC(O)=O.CC(O)=O.CC(O)=O.[Rh].[Rh]>[CH2:14]([O:13][C:11](=[O:12])[CH2:10][O:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[CH3:15]
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: OC1CCCCC1
Agent: [Rh]
Solvent: CCOCC
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCOC(=O)COC1CCCCC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 887.3 %

Procedure:
To a solution of cyclohexanol (1.0 g, 0.95 mmol) in dichloromethane (30 mL) is added rhodium (II) acetate dimer (44 mg) followed by ethyl diazoacetate (1.14 g, 10.0 mmol). The reaction mixture is stirred at RT for 20 min. The reaction mixture is diluted with Et2O, filtered through celite, and the filtrate is evaporated and the residue is vacuum distilled at 150° C. to give 1.57 g of the product 407. 1H NMR (CDCl3) δ 4.23 (q, 2H), 4.10 (s, 2H), 3.33 (m, 1H), 1.93 (m, 2H), 1.74 (m, 2H), 1.54 (m, 1H), 1.4-1.1 (m, 8H)
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][CH3:17])=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.I[C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][C:28](I)=[CH:27][CH:26]=2)=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>[Cu]>[CH2:14]([C:11]1[CH:10]=[CH:9][C:8]([N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][C:28]([N:7]([C:8]4[CH:9]=[CH:10][C:11]([CH2:14][CH2:15][CH2:16][CH3:17])=[CH:12][CH:13]=4)[C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)=[CH:27][CH:26]=3)=[CH:21][CH:20]=2)=[CH:13][CH:12]=1)[CH2:15][CH2:16][CH3:17]
Reactant: Ic1ccc(-c2ccc(I)cc2)cc1
Reactant: CCCCc1ccc(Nc2ccccc2)cc1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCCCc1ccc(N(c2ccccc2)c2ccc(-c3ccc(N(c4ccccc4)c4ccc(CCCC)cc4)cc3)cc2)cc1
Yield: 58.7 %

Procedure:
21.1 g (0.094 mol) of N-phenyl-p-normalbutylaniline, 15.4 g (0.038 mol) of 4,4'-diiodobiphenyl, 15.7 g (0.11 mol) of anhydrous potassium carbonate, and 1.1 g (0.017 mol) of copper powder were mixed. The mixture was then allowed to undergo reaction at a temperature of 170° to 220° C. for 27 hours. The reaction product was then extracted with 140 ml of toluene. The insoluble contents were removed by filtration. The filtrate was then concentrated to obtain an oily material. The crude product thus obtained was then purified by column chromatography (carrier: silica gel; elute: 1/5 mixture of toluene and n-hexane) to obtain 13.4 g (yield: 58.6%) of N,N'-bis(p-normalbutylphenyl)-N,N'-diphenylbenzidine. The melting point of the product was from 135.0° C. to 135.5° C.
Reaction SMILES: O.[OH-].[Na+].[OH:4][C:5]1[CH:6]=[CH:7][C:8]2[C:9]3[C:14]([C:15]4[C:20]=2[C:19]=1[CH:18]=[CH:17][CH:16]=4)=[CH:13][CH:12]=[C:11]([OH:21])[CH:10]=3.Cl.[N:23]1([CH2:29][CH2:30][CH2:31]Cl)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>C1(C)C=CC=CC=1>[N:23]1([CH2:29][CH2:30][CH2:31][O:4][C:5]2[CH:6]=[CH:7][C:8]3[C:9]4[C:14]([C:15]5[C:20]=3[C:19]=2[CH:18]=[CH:17][CH:16]=5)=[CH:13][CH:12]=[C:11]([O:21][CH2:31][CH2:30][CH2:29][N:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)[CH:10]=4)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: ClCCCN1CCCCC1
Reactant: Oc1ccc2c(c1)-c1ccc(O)c3cccc-2c13
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: c1cc2c3c(ccc(OCCCN4CCCCC4)c3c1)-c1cc(OCCCN3CCCCC3)ccc1-2

Procedure:
To 200 ml of water containing 16.0 g (0.4 mole) of sodium hydroxide and 15.7 g (0.067 mole) of 3,9-dihydroxyfluoranthene are added 200 ml of toluene and 29.8 (0.15 mole) of 3-piperidinopropyl chloride hydrochloride and the heterogeneous reaction mixture is stirred at reflux for 24 hours. After cooling, the organic layer is washed with water, dried over magnesium sulfate, and concentrated in vacuo. The residue is crystallized from ether to give 3,9-bis(3-piperidinopropoxy)fluoroanthene, M.P. 92°-93° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]O)=[CH:4][C:3]=1[F:10].[CH2:11]([N:13](CC)CC)C.CS(Cl)(=O)=O.[Cl-].[NH4+]>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:11]#[N:13])=[CH:4][C:3]=1[F:10]
Reactant: CCN(CC)CC
Reactant: OCc1ccc(Br)c(F)c1
Agent: CS(=O)(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Product: N#CCc1ccc(Br)c(F)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a −78° C. solution of (4-bromo-3-fluorophenyl)methanol from Step 2 (7.2 g) and triethylamine (5.9 mL) in dichloromethane (300 mL) was slowly added methanesulphonyl chloride (3.0 mL). The reaction mixture was stirred at 0° C. for 1 hour. Then poured into ice and saturated aqueous ammonium chloride and partitioned. The aqueous layer was extracted with dichloromethane (1×150 mL). The combined extracts were washed with brine, dried with magnesium sulfate and the solvent removed in vacuo. The residue was dissolved in DMF (150 mL) and sodium cyanide (5.1 g) was added. The reaction mixture was stirred at room temperature for 2 hours and poured into ice and water (100 mL). Extracted with ethyl acetate (2×100 mL). The combined extracts were washed with brine, dried with magnesium sulfate and the solvent removed in vacuo. The residue was purified by chromatography on SiO2 using ethyl acetate and hexanes (1:10 to 1:5) to yield the title compound.