Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC1N=CN=C(C(NC2C=CC(S(NCC(OC)=O)(=O)=O)=CC=2C)=O)C=1.C(NC(C)C)(C)C.C1(CNCCC)CC1.[CH:42]1([CH2:45][N:46]([CH2:72][CH2:73][CH3:74])[C:47]2[N:52]=[CH:51][N:50]=[C:49]([C:53]([NH:55][C:56]3[CH:61]=[CH:60][C:59]([S:62]([NH:65][CH2:66][C:67]([O:69]C)=[O:68])(=[O:64])=[O:63])=[CH:58][C:57]=3[CH3:71])=[O:54])[CH:48]=2)[CH2:44][CH2:43]1.C1(CN(CCC)C2N=CN=C(C(NC3C=CC(S(NCC(OCC)=O)(=O)=O)=CC=3C)=O)C=2)CC1>C(O)C>[CH:42]1([CH2:45][N:46]([CH2:72][CH2:73][CH3:74])[C:47]2[N:52]=[CH:51][N:50]=[C:49]([C:53]([NH:55][C:56]3[CH:61]=[CH:60][C:59]([S:62]([NH:65][CH2:66][C:67]([OH:69])=[O:68])(=[O:63])=[O:64])=[CH:58][C:57]=3[CH3:71])=[O:54])[CH:48]=2)[CH2:44][CH2:43]1
Reactant: CCCN(CC1CC1)c1cc(C(=O)Nc2ccc(S(=O)(=O)NCC(=O)OC)cc2C)ncn1
Agent: CCCN(CC1CC1)c1cc(C(=O)Nc2ccc(S(=O)(=O)NCC(=O)OCC)cc2C)ncn1
Agent: CCCNCC1CC1
Agent: COC(=O)CNS(=O)(=O)c1ccc(NC(=O)c2cc(Cl)ncn2)c(C)c1
Solvent: CCO
Solvent: CC(C)NC(C)C
Product: CCCN(CC1CC1)c1cc(C(=O)Nc2ccc(S(=O)(=O)NCC(=O)O)cc2C)ncn1
Temperature: 160 °C
Reaction time: 5 h

Procedure:
A solution of methyl 2-(4-(6-chloropyrimidine-4-carboxamido)-3-methylphenylsulfonamido)acetate (Intermediate 33, 123 mg; 0.31 mmol) and diisopropylamine (105.5 mL; 0.61 mmol) in ethanol (4 ml) was treated with N-(cyclopropylmethyl)propan-1-amine (45.3 mg; 0.4 mmol). The mixture was heated to 160° C. in a microwave for 1 hour and the solvent removed in vacuo. The residue was purified by column chromatography (silica) eluting with petroleum ether containing increasing amounts of EtOAc to give a mixture of methyl 2-(4-(6-((cyclopropylmethyl)(propyl)amino)pyrimidine-4-carboxamido)-3-methylphenylsulfonamido)acetate and ethyl 2-(4-(6-((cyclopropylmethyl)(propyl)amino)pyrimidine-4-carboxamido)-3-methylphenylsulfonamido)acetate which was used directly without any further purification. The residue was redissolved in methanol (10 ml) and tetrahydrofuran (10 ml) and treated with 5 N NaOH solution (1 ml). After stirring at RT for 5 hours the solvent was removed in vacuo. The residue was redissolved in water (10 ml) and acidified with conc. HCl. The aqueous phase was extracted with EtOAc and the organic extracts passed through a hydrophobic frit and the solvent removed in vacuo. The residue was triturated with petroleum ether to yield the title compound as a white solid.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[CH2:15][CH2:14][NH:13][CH2:12][C:11]=2[C:10]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:24][C:25]([CH3:27])=O>>[CH2:1]([N:8]1[C:16]2[CH2:15][CH2:14][N:13]([CH:25]([CH3:27])[CH3:24])[CH2:12][C:11]=2[C:10]([C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)=[CH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Clc1ccc(-c2cn(Cc3ccccc3)c3c2CNCC3)cc1
Reactant: CC(C)=O
Product: CC(C)N1CCc2c(c(-c3ccc(Cl)cc3)cn2Cc2ccccc2)C1

Procedure:
The title compound (0.1 g) was prepared from 1-benzyl-3-(4-chloro-phenyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine (Example 25; 0.10 g) and 32 μL of acetone as in Example 35. MS (ESI): exact mass calculated for C23H25ClN2, 364.17; found, m/z 365.2 [M+H]+, 367.2 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.37-7.27 (m, 7H), 7.21-7.17 (m, 3H), 5.15 (d, J=5.2 Hz, 2H), 4.58-4.54 (m, 1H), 4.28-4.25 (m, 1H), 3.78-3.65 (m, 2H), 3.45-3.35 (m, 1H), 3.03-2.85 (m, 2H), 1.42 (t, J=6.6 Hz, 6H).
Reaction SMILES: Br[C:2]1[C:12]2[O:11][CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[S:20]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21]1.O>CO.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1.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>[S:20]1[CH:24]=[CH:23][C:22]([C:2]2[C:12]3[O:11][CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][C:6]=3[CH:5]=[CH:4][CH:3]=2)=[CH:21]1
Reactant: OB(O)c1ccsc1
Reactant: CC(C)(C)OC(=O)N1CCOc2c(Br)cccc2C1
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: Cc1ccccc1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCOc2c(cccc2-c2ccsc2)C1
Yield: 69.8 %

Procedure:
A mixture of tert-butyl 9-bromo-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (200 mg, 0.605 mmol), a solution of 3-thiopheneboronic acid (117 mg, 0.912 mmol) in methanol (0.7 ml), 2N aqueous sodium carbonate solution (2.5 ml), and tetrakis(triphenylphosphine)palladium(0) (84.0 mg, 0.0730 mmol) in toluene (5 ml) was stirred under a nitrogen atmosphere at 95° C. for 12 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to give the desired product (140 mg, 69.7%) as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[NH:8][C:7](=[O:12])[C:6]3[NH:13][CH:14]=[CH:15][C:5]=3[C:4]=2[CH:3]=1.Cl.[CH2:17]([C:19]([OH:21])=[O:20])[CH3:18].[C:22]1([CH3:32])[CH:27]=[CH:26][CH:25]=[C:24]([S:28](Cl)(=[O:30])=[O:29])[CH:23]=1>>[O:12]=[C:7]1[C:6]2[NH:13][CH:14]=[CH:15][C:5]=2[C:4]2[CH:3]=[C:2]([NH:1][S:28]([C:24]3[CH:23]=[C:22]([CH3:32])[CH:27]=[CH:26][CH:25]=3)(=[O:30])=[O:29])[CH:11]=[CH:10][C:9]=2[NH:8]1.[CH2:17]([C:19]([O-:21])=[O:20])[CH3:18]
Reactant: Nc1ccc2[nH]c(=O)c3[nH]ccc3c2c1
Reactant: CCC(=O)O
Reactant: Cc1cccc(S(=O)(=O)Cl)c1
Agent: Cl
Product: CCC(=O)[O-]
Product: Cc1cccc(S(=O)(=O)Nc2ccc3[nH]c(=O)c4[nH]ccc4c3c2)c1
Yield: 38.7 %

Procedure:
This compound is prepared according to synthesis 43, from 60 mg (0.20 mmol) of 8-amino-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate hydrochloride (synthesis 64) and 31 mg (0.21 mmol) of 3-toluenesulfonyl chloride. After recrystallization from methanol, 33 mg (40%) of 4-oxo-8-(3-toluenesulfonylamino)-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate is obtained in the form of a beige solid.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[C:11]([S:13]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)(=[O:15])=[O:14])[CH:10]=[CH:9][C:8]=2[NH:22][C:23]([C:25]2[N:26](COCC[Si](C)(C)C)[CH:27]=[C:28]([C:30]#[N:31])[N:29]=2)=[O:24])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl.CO>[C:1]1([C:7]2[CH:12]=[C:11]([S:13]([N:16]3[CH2:17][CH2:18][O:19][CH2:20][CH2:21]3)(=[O:14])=[O:15])[CH:10]=[CH:9][C:8]=2[NH:22][C:23]([C:25]2[NH:26][CH:27]=[C:28]([C:30]#[N:31])[N:29]=2)=[O:24])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)Nc1ccc(S(=O)(=O)N2CCOCC2)cc1C1=CCCCC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: N#Cc1c[nH]c(C(=O)Nc2ccc(S(=O)(=O)N3CCOCC3)cc2C2=CCCCC2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 29.4 %

Procedure:
A solution of 15.0 mg (0.0262 mmol) of 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylic acid [2-cyclohex-1-enyl-4-(morpholine-4-sulfonyl)-phenyl]-amide (as prepared in the previous step) in CH2Cl2 (5 mL) was treated with MeOH (1 drop) and TFA (1 mL). The mixture was stirred at RT for 2 h, and the solvents were evaporated in vacuo. Purification of the residue by RP-HPLC (C18) with 10-80% CH3CN in 0.1% TFA/H2O over 30 min afforded 3.4 mg (29%) of the title compound as a white solid: 1H-NMR (CD3OD; 400 MHz): δ 8.62 (d, 1H, J=8.8 Hz), 8.07 (s, 1H), 7.72 (dd, 1H, J=8.8, 2.0 Hz), 7.57 (d, 1H, J=2.0 Hz), 6.01-5.96 (m, 1H), 3.77-3.70 (m, 4H), 3.02-2.95 (m, 4H), 2.40-2.30 (m, 4H), 1.97-1.82 (m, 4H). Mass spectrum (ESI, m/z): Calcd. for C21H23N5O4S, 442.2 (M+H), found 441.9.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[OH:11][C@@H:12]1[C@@H:19]2[N:15]([C:16](=[O:31])[N:17]([C:21]3[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[C:23]([Cl:29])[C:22]=3[CH3:30])[C@H:18]2[CH3:20])[CH2:14][CH2:13]1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:20][C@H:18]1[N:17]([C:21]2[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[C:23]([Cl:29])[C:22]=2[CH3:30])[C:16](=[O:31])[N:15]2[CH2:14][CH2:13][C:12](=[O:11])[C@H:19]12
Reactant: Cc1c(N2C(=O)N3CC[C@H](O)[C@H]3[C@@H]2C)ccc(C#N)c1Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: ClCCl
Product: Cc1c(N2C(=O)N3CCC(=O)[C@@H]3[C@H]2C)ccc(C#N)c1Cl
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of DMSO (20 μL) in CH2Cl2 (1 mL) at −78° C. was added oxalyl chloride (1.0 M in CH2Cl2, 131 μL). This mixture was stirred at −78° C. for 30 min. and then a solution of 61K in CH2Cl2 (20 mg in 1 mL). The reaction was stirred at −78° C. for 1 h and then i-Pr2NEt (100 μL) was added and the reaction was allowed to warm to rt over 1 h. The reaction was extracted with EtOAc and washed twice with 1N HCl and once with saturated NaHCO3. The organic layer was dried over MgSO4, filtered and concentrated. Purification by flash chromatography (silica gel, 40% EtOAc/CH2Cl2) provided the title compound (18 mg): MS (ES) m/z 304.42 [M+H]+
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[Cl:12][CH:13]1[CH2:18][CH2:17][N:16]([CH:19]([C:22]2[CH:23]=[N:24][C:25]([CH3:28])=[N:26][CH:27]=2)[CH2:20][NH2:21])[CH2:15][CH2:14]1>>[Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH:21][CH2:20][CH:19]([N:16]1[CH2:15][CH2:14][CH:13]([Cl:12])[CH2:18][CH2:17]1)[C:22]1[CH:23]=[N:24][C:25]([CH3:28])=[N:26][CH:27]=1)=[O:6]
Reactant: Cc1ncc(C(CN)N2CCC(Cl)CC2)cn1
Reactant: O=C(O)c1ccc(Cl)cc1Cl
Product: Cc1ncc(C(CNC(=O)c2ccc(Cl)cc2Cl)N2CCC(Cl)CC2)cn1

Procedure:
From 2,4-dichlorobenzoic acid and 2-(4-chloropiperidin-1-yl)-2-(2-methylpyrimidin-5-yl)ethanamine.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][CH:17]=1)[O:6][C:7]([CH3:14])([CH3:13])[C:8]([O:10]CC)=[O:9])=O.[NH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[SH:25].[OH-].[Na+]>CO>[S:25]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[N:18]=[C:1]1[C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][CH:17]=1)[O:6][C:7]([CH3:13])([CH3:14])[C:8]([OH:10])=[O:9]
Reactant: Nc1ccccc1S
Reactant: CCOC(=O)C(C)(C)Oc1cccc(C=O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(Oc1cccc(-c2nc3ccccc3s2)c1)C(=O)O
Temperature: 25 °C
Reaction time: 22 h
Yield: 67.7 %

Procedure:
In a methanol solvent, a solution including Compound 97b (1.0 eq.) and 2-aminothiophenol (1.0 eq.) was stirred at room temperature for 22 hours. After methanol was evaporated, the residual was purified by silica gel column chromatography using hexane and ethyl acetate (14:1) as a developer. The obtained product was dissolved with 1,4-dioxane, and then, 1 N NaOH (1.5 eq.) was added thereto. The reaction mixture was stirred at room temperature for 17 hours, and 1,4-dioxane was evaporated. The reaction mixture was stirred at room temperature for 17 hours, and 1,4-dioxane was evaporated therefrom. The residual was distributed between ethyl acetate and water, an aqueous layer was acidified with 6 N HCl. The produced precipitate was filtered and washed with water to obtain Compound 120.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH:19]([CH3:21])[CH3:20])=[C:14]([N:22]3[CH:26]=[N:25][N:24]=[N:23]3)[CH:13]=2)[S:5][C:6]=1[C:7]([O:9]CC)=[O:8].[OH-].[Na+].Cl.O>O1CCCC1.CO>[CH3:1][C:2]1[N:3]=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH:19]([CH3:21])[CH3:20])=[C:14]([N:22]3[CH:26]=[N:25][N:24]=[N:23]3)[CH:13]=2)[S:5][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: CCOC(=O)c1sc(-c2ccc(OC(C)C)c(-n3cnnn3)c2)nc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: Cc1nc(-c2ccc(OC(C)C)c(-n3cnnn3)c2)sc1C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 88 %

Procedure:
A reaction mixture solution prepared by dissolving 1.13 g of ethyl 4-methyl-2-[4-(propan-2-yloxy)-3-(1H-1,2,3,4-tetrazol-1-yl)phenyl]-1,3-thiazole-5-carboxylate in 15 mL of a mixed solution of tetrahydrofuran/methanol=1/1 and adding 3.0 mL of 2 M sodium hydroxide aqueous solution to the mixture was stirred at room temperature for 3 hours. After the addition of 3.0 mL of 2 M hydrochloric acid to the reaction solution under stirring, 7 mL of water was added and extraction was performed using 30 mL of ethyl acetate. The organic layer was concentrated, followed by purifying by a conventional method to obtain 920 mg of 4-methyl-2-[4-(propan-2-yloxy)-3-(1H-1,2,3,4-tetrazol-1-yl)phenyl]-1,3-thiazole-5-carboxylic acid.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][N:3]=1.[NH2:10][CH2:11][CH2:12][CH2:13][OH:14].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.CCOC(C)=O>[Br:1][C:2]1[N:3]=[CH:4][C:5]([CH2:6][NH:10][CH2:11][CH2:12][CH2:13][OH:14])=[CH:8][CH:9]=1
Reactant: O=Cc1ccc(Br)nc1
Reactant: NCCCO
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: OCCCNCc1ccc(Br)nc1
Reaction time: 0.17 h
Yield: 54.6 %

Procedure:
To a solution of 6-bromonicotinaldehyde (1.25 g, 6.72 mmol) in DCM (25 mL) was added 3-aminopropan-1-ol (1.514 g, 20.16 mmol) and acetic acid (0.385 mL, 6.72 mmol), and the reaction mixture was stirred for 10 min. Sodium triacetoxyborohydride (3.56 g, 16.80 mmol) was added and the reaction mixture was stirred at RT overnight. The reaction mixture was then diluted with EtOAc and extracted with water. The organic phase was discarded. The aqueous phase was concentrated and the resultant solid was stirred with a mixture of DCM and acetone then filtered. The filtrate was collected, dried over Na2SO4, and concentrated to give a yellowish material, which upon trituration with Et2O afforded title compound 196 (0.9 g, 55% yield) as an off-white solid. MS: 246 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([S:8](Cl)(=[O:10])=[O:9])=[N:6][CH:7]=1.N1C=CC=CC=1.[F:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][CH2:26][CH:27]([CH3:29])[CH3:28])=[CH:21][CH:20]=1.C([O-])(O)=O.[Na+]>C(Cl)Cl.O>[F:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]([CH2:26][CH:27]([CH3:29])[CH3:28])[S:8]([C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][N:6]=2)(=[O:10])=[O:9])=[CH:21][CH:20]=1
Reactant: CC(C)CNc1ccc(F)cc1
Reactant: O=S(=O)(Cl)c1ccc(Br)cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)CN(c1ccc(F)cc1)S(=O)(=O)c1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 82.9 %

Procedure:
To a solution of 5-bromo-pyridine-2-sulfonyl chloride (330 mg, 1.29 mmol) in DCM (10 mL) was added pyridine (208 μL, 2.57 mmol) followed by a solution of (4-fluoro-phenyl)-isobutyl-amine (215 mg, 1.29 mmol) in DCM (10 mL) and the reaction was stirred at room temperature for 16 hours. Water and saturated aqueous NaHCO3 were added and then extracted with DCM, filtered through a phase separator, concentrated then purified by silica gel column chromatography (0-20% EtOAc in cyclohexane) to give 5-bromo-pyridine-2-sulfonic acid (4-fluoro-phenyl)-isobutyl-amide (414 mg, 78%). LCMS (m/z, Method A) ES+ 387/389 [M+1]+.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][C:6]1([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH3:27])[CH:19]=2)[C:11](=[O:12])[N:10]([CH3:13])[C:9]2[CH:14]=[CH:15][CH:16]=[CH:17][C:8]=2[S:7]1.[C:28](=[O:31])([O-:30])[O-].[Na+].[Na+].[CH3:34][NH:35][CH2:36][CH2:37][C:38]1[CH:43]=[C:42]([O:44][CH3:45])[C:41]([O:46][CH3:47])=[C:40]([O:48][CH3:49])[CH:39]=1.Cl>CN(C)C=O.C(Cl)(Cl)Cl>[C:27]([OH:26])(=[O:44])[C:28]([OH:30])=[O:31].[CH3:27][O:26][C:20]1[CH:19]=[C:18]([C:6]2([CH2:5][CH2:4][CH2:3][CH2:2][N:35]([CH2:36][CH2:37][C:38]3[CH:39]=[C:40]([O:48][CH3:49])[C:41]([O:46][CH3:47])=[C:42]([O:44][CH3:45])[CH:43]=3)[CH3:34])[C:11](=[O:12])[N:10]([CH3:13])[C:9]3[CH:14]=[CH:15][CH:16]=[CH:17][C:8]=3[S:7]2)[CH:23]=[CH:22][C:21]=1[O:24][CH3:25]
Reactant: COc1ccc(C2(CCCCBr)Sc3ccccc3N(C)C2=O)cc1OC
Reactant: O=C([O-])[O-]
Reactant: CNCCc1cc(OC)c(OC)c(OC)c1
Agent: Cl
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: COc1ccc(C2(CCCCN(C)CCc3cc(OC)c(OC)c(OC)c3)Sc3ccccc3N(C)C2=O)cc1OC
Product: O=C(O)C(=O)O
Reaction time: 1 h
Yield: 131.5 %

Procedure:
To a stirred solution of 2-(4-bromobutyl)-3,4-dihydro-2-(3,4-dimethoxyphenyl)-4-methyl-3-oxo-2H-1,4-benzothiazine (1.5 g, compound No. 32) in dimethylformamide (20 ml), sodium carbonate (0.7 g) and N-methyl-3,4,5-trimethoxyphenethylamine (1.1 g) are added, and the mixture is stirred for 1 hour at 80°-90° C. The mixture is poured into a mixture of chloroform and 1N hydrochloric acid, and the organic layer is concentrated in vacuo. The residue is treated by the similar method as in Example 24 to give 1.5 g (65.8%) of the titled compound.
Reaction SMILES: Br[C:2]1[C:3]2[C:8]([C:9]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:10]3[C:15]=1[CH:14]=[CH:13][CH:12]=[CH:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.[Li]CCCC.[I:27]I.S([O-])([O-])(=O)=S.[Na+].[Na+]>O1CCCC1>[I:27][C:2]1[C:3]2[C:8]([C:9]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:10]3[C:15]=1[CH:14]=[CH:13][CH:12]=[CH:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2
Reactant: II
Reactant: Brc1c2ccccc2c(-c2ccccc2)c2ccccc12
Agent: O=S([O-])([O-])=S
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: Ic1c2ccccc2c(-c2ccccc2)c2ccccc12
Reaction time: 1 h
Yield: 83 %

Procedure:
3.33 g (10 mmol) of 9-bromo-10-phenylanthracene was dissolved in 80 ml of tetrahydrofuran (abbrev.: THF). After bringing the temperature to −78° C., 7.5 ml (12.0 mmol) of n-BuLi (1.6M) was added to the reaction solution dropwise with a dropping funnel, and the mixture was stirred for 1 hour. A solution of 5 g (20.0 mmol) of iodine dissolved in 20 ml of THF was added dropwise, and the mixture was stirred for another 2 hours at −78° C. After the reaction, a sodium thiosulfate solution was added and the reaction was stopped. The organic layer was washed with a sodium thiosulfate solution and a saturated saline solution, and dried with magnesium sulfate. After natural filtration, the filtrate was concentrated, and the solid obtained was recrystallized with ethanol. The target substance of 9-iodo-10-phenylanthracene was obtained as a pale yellow solid, weighing 3.1 g in a yield of 83% (synthesis scheme (j-5)).
Reaction SMILES: Cl.[C:2]1([C:8]2([C:14]#[N:15])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>C1COCC1.O>[C:2]1([C:8]2([C:14]#[N:15])[CH2:9][CH2:10][N:11]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:12][CH2:13]2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#CC1(c2ccccc2)CCNCC1
Reactant: BrCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: N#CC1(c2ccccc2)CCN(Cc2ccccc2)CC1

Procedure:
4-Phenyl-4-cyano-piperidine hydrochloride (10 g, 44.9 mmol), Benzyl bromide (5.4 mL, 45.4 mmol), and potassium carbonate (25.2 g, 182.3 mmol) were combined in THF/water (80 mL/20 mL). After 18 hours the reaction mixture was partitioned between water and dichloromethane. The organic layer was separated and extracted with water, dried over MgSO4, filtered and evaporated in vacuo to give a residue. The residue was recrystallized from hexane to give 4-phenyl-4-cyano-1-benzyl-piperidine as a solid: mp=73°-74° C.
Reaction SMILES: [CH3:1][N:2]1C2C(=CC=CC=2)C=C1CNC.[CH3:14][N:15]1[C:19]2=[N:20][CH:21]=[CH:22][CH:23]=[C:18]2[C:17]([CH:24]=O)=[CH:16]1.CN1C2C(=CC=CC=2)C(C)=C1C=O>>[CH3:14][N:15]1[C:19]2=[N:20][CH:21]=[CH:22][CH:23]=[C:18]2[C:17]([CH2:24][NH:2][CH3:1])=[CH:16]1
Reactant: Cn1cc(C=O)c2cccnc21
Reactant: CNCc1cc2ccccc2n1C
Agent: Cc1c(C=O)n(C)c2ccccc12
Product: CNCc1cn(C)c2ncccc12
Yield: 45 %

Procedure:
According to the procedure of Preparation 40 (c), except substituting 1-methyl-1H-pyrrolo[2,3-b]pyridine-3-carboxaldehyde (0.4 g, 2.5 mmole) for the 1,3-dimethyl-1H-indole-2-carboxaldehyde, the title compound (0.2 g, 45%) was prepared as a yellow oil: MS (ES) m/e 176 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[NH:11][N:10]=2)[C:5]([CH2:17][OH:18])=[CH:4][N:3]=1.N1C=CN=C1.[CH3:24][C:25]([Si:28](Cl)([CH3:30])[CH3:29])([CH3:27])[CH3:26].O>C(Cl)Cl>[Si:28]([O:18][CH2:17][C:5]1[C:6]([NH:8][C:9]2[CH:13]=[C:12]([CH:14]3[CH2:15][CH2:16]3)[NH:11][N:10]=2)=[N:7][C:2]([Cl:1])=[N:3][CH:4]=1)([C:25]([CH3:27])([CH3:26])[CH3:24])([CH3:30])[CH3:29]
Reactant: OCc1cnc(Cl)nc1Nc1cc(C2CC2)[nH]n1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCc1cnc(Cl)nc1Nc1cc(C2CC2)[nH]n1
Temperature: 20 °C
Reaction time: 16 h
Yield: 99.7 %

Procedure:
A mixture of (2-chloro-4-(5-cyclopropyl-1H-pyrazol-3-ylamino)pyrimidin-5-yl)methanol (350 mg, 1.32 mmol), imidazole (107.6 mg, 1.58 mmol, 1.2 eq), TBDMSCl (238 mg, 1.58 mmol, 1.2 eq) in CH2Cl2 (10 mL) was stirred at 20° C. for 16 h. Water (30 mL) was added and the reaction was extracted with CH2Cl2 (4×30 mL). The combined organic phases were washed (brine), dried (Na2SO4), filtered and concentrated to afford 5-((tert-butyldimethylsilyloxy)methyl)-2-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidin-4-amine (500 mg, 99%). LC-MS (m/z)=380.0 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:41]=[CH:40][C:5]([CH2:6][CH2:7][NH:8][C:9]([C:11]2[CH:39]=[CH:38][C:14]([O:15][C:16]3[C:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([S:28]([CH3:31])(=[O:30])=[O:29])[CH:23]=4)=[CH:20][C:19]([CH2:32][C:33]([O:35]CC)=[O:34])=[CH:18][CH:17]=3)=[CH:13][CH:12]=2)=[O:10])=[CH:4][CH:3]=1.[OH-].[Na+].O>O1CCOCC1.C(OCC)(=O)C.Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH2:7][NH:8][C:9]([C:11]2[CH:12]=[CH:13][C:14]([O:15][C:16]3[C:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([S:28]([CH3:31])(=[O:30])=[O:29])[CH:23]=4)=[CH:20][C:19]([CH2:32][C:33]([OH:35])=[O:34])=[CH:18][CH:17]=3)=[CH:38][CH:39]=2)=[O:10])=[CH:40][CH:41]=1
Reactant: CCOC(=O)Cc1ccc(Oc2ccc(C(=O)NCCc3ccc(Cl)cc3)cc2)c(-c2cccc(S(C)(=O)=O)c2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CS(=O)(=O)c1cccc(-c2cc(CC(=O)O)ccc2Oc2ccc(C(=O)NCCc3ccc(Cl)cc3)cc2)c1
Reaction time: 2 h
Yield: 6.6 %

Procedure:
Ethyl 2-(6-(4-(4-chlorophenethylcarbamoyl)phenoxy)-3′-(methylsulfonyl)biphenyl-3-yl)acetate (80 mg, 0.135 mmol) was diluted with dioxane (1 mL) followed by the addition of NaOH (0.270 ml, 1.35 mmol) and 300 μL of water. After stirring for 2 hours, the reaction was diluted with ethyl acetate and 2N HCl. The layers were separated and the organic layer was dried over MgSO4, filtered and concentrated. The material was purified using a biotage 12i cartridge eluting with 1-4% methanol/DCM to yield 2-(6-(4-(4-chlorophenethylcarbamoyl)phenoxy)-3′-(methylsulfonyl)biphenyl-3-yl)acetic acid (5 mg, 6.56% yield). 1H NMR (400 MHz, CD3Cl3, CD3OD) 8.05 (s, 1H), 7.81 (d, 1H), 7.78 (d, 1H), 7.50-7.60 (m, 3H), 7.42 (s, 1H), 7.38 (d, 1H), 7.25 (d, 2H), 7.19 (d, 2H), 7.05 (d, 1H), 6.85 (d, 1H), 3.75 (s, 2H), 3.62 (q, 2H), 3.0 (s, 3H), 2.90 (t, 2H).