Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([C:9]2[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[C:14]3[C:10]=2[CH:11]=[N:12][NH:13]3)=[CH:4][CH:3]=1.[C:22]([Zn]C#N)#[N:23]>CN(C=O)C>[CH3:8][C:6]1[N:7]=[C:2]([C:22]#[N:23])[CH:3]=[CH:4][C:5]=1[C:9]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[C:14]2[C:10]=1[CH:11]=[N:12][NH:13]2
Reactant: Cc1nc(Cl)ccc1-c1cc(C(F)(F)F)cc2[nH]ncc12
Reactant: N#C[Zn]C#N
Solvent: CN(C)C=O
Product: Cc1nc(C#N)ccc1-c1cc(C(F)(F)F)cc2[nH]ncc12
Temperature: 120 °C
Reaction time: 24 h
Yield: 34 %

Procedure:
A mixture of 4-(6-chloro-2-methylpyridin-3-yl)-6-(trifluoromethyl)-1H-indazole (0.97 g, 3.11 mmol), dicyanozinc (1.462 g, 12.45 mmol), and tetrakis(triphenylphoshine)palladium(0) (0.360 g, 0.311 mmol) in DMF (15 mL) was thoroughly degassed by nitrogen and stirred at 120° C. for 24 hours. The reaction mixture was subsequently cooled and diluted with EtOAc then washed with brine. The organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified by CombiFlash® chromatography, eluting with a gradient of 0-100% EtOAc in hexane. The product-containing fractions were combined and concentrated in vacuo to give the title compound as a white solid (0.32 g, 34%). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.39 (s, 3H), 7.45 (d, J=1.01 Hz, 1H), 7.90-8.16 (m, 4H), 13.81 (s, 1H); ESI-MS m/z [M+H]+ calc'd for C15H9F3N4, 303.1. found 303.18.
Reaction SMILES: [CH2:1](C1C=C2C=NNC2=CN=1)[CH3:2].[C:12]([C:15]1[C:23]2[C:18](=[CH:19][N:20]=[CH:21][CH:22]=2)[N:17]([CH2:24][C:25]([OH:27])=[O:26])[N:16]=1)(=[O:14])[NH2:13]>>[C:12]([C:15]1[C:23]2[C:18](=[CH:19][N:20]=[C:21]([CH2:1][CH3:2])[CH:22]=2)[N:17]([CH2:24][C:25]([OH:27])=[O:26])[N:16]=1)(=[O:14])[NH2:13]
Reactant: NC(=O)c1nn(CC(=O)O)c2cnccc12
Reactant: CCc1cc2cn[nH]c2cn1
Product: CCc1cc2c(C(N)=O)nn(CC(=O)O)c2cn1

Procedure:
was prepared from 5-ethyl-1H-pyrazolo[3,4-c]pyridine by using the same procedures as for the preparation of 2-(3-carbamoyl-1H-pyrazolo[3,4-c]pyridin-1-yl)acetic acid (Scheme A26). MS (LC-MS): 249 [M+H]+, tR (HPLC conditions k): 0.49 min.
Reaction SMILES: IC1C=CC=CC=1S([O-])(=O)=O.[Na+].OOS([O-])=O.[K+].S([O-])([O-])(=O)=O.[Na+].[Na+].[O:26]1[C:30]2([CH2:35][CH2:34][CH:33]([OH:36])[CH2:32][CH2:31]2)[O:29][CH2:28][CH2:27]1>C(OCC)(=O)C>[O:26]1[C:30]2([CH2:31][CH2:32][C:33](=[O:36])[CH2:34][CH2:35]2)[O:29][CH2:28][CH2:27]1
Reactant: OC1CCC2(CC1)OCCO2
Agent: O=S(=O)([O-])[O-]
Agent: O=S(=O)([O-])c1ccccc1I
Agent: O=S([O-])OO
Solvent: CCOC(C)=O
Product: O=C1CCC2(CC1)OCCO2
Temperature: 70 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
6.1 mg (0.02 mmol) of sodium 2-iodobenzenesulfonate prepared by Preparation Example 4, 0.49 g (0.8 mmol) of powdered Oxone (registered trademark), 0.5 g (3.5 mmol) of anhydrous sodium sulfate and 158 mg (1 mmol) of 1,4-dioxaspiro[4.5]decane-8-ol were added to 5 ml of ethyl acetate, and the mixture was heated at 70° C. while being stirred under a nitrogen for eight hours. The later treatment was carried out in the same way as in Example 1, and then 1,4-dioxaspiro[4.5]decane-8-one was obtained. The yield of the obtained 1,4-dioxaspiro[4.5]decane-8-one was determined and the result is shown in Table 1. (Yield 86%)
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[CH3:10][C:11]1[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][CH:12]=1>>[CH3:10][C:11]1[CH:17]=[CH:16][C:14]([NH:15][C:2]2[N:7]=[C:6]([NH:15][C:14]3[CH:16]=[CH:17][C:11]([CH3:10])=[CH:12][CH:13]=3)[C:5]([F:9])=[CH:4][N:3]=2)=[CH:13][CH:12]=1
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: Cc1ccc(N)cc1
Product: Cc1ccc(Nc2ncc(F)c(Nc3ccc(C)cc3)n2)cc1

Procedure:
In like manner to the preparation of N2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine, 2,4-dichloro-5-fluoropyrimidine and 4-methylaniline were reacted to yield N2,N4-bis(4-methylphenyl)-5-fluoro-2,4-pyrimidinediamine. 1H NMR (CDCl3): δ 7.73 (d, 1H, J=4.2 Hz), 7.43 (d, 2H, J=8.1 Hz), 7.36 (d, 2H, J=8.4 Hz), 7.14 (d, 2H, J=8.4 Hz), 7.10 (d, 2H, J=8.1 Hz), 2.39 (s, 3H), 2.35 (s, 3H); LCMS: ret. time: 25.81 min.; purity: 99.65%; MS (m/e): 309 (MH+).
Reaction SMILES: [NH:1]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C@H:2]([C:19]([OH:21])=[O:20])[CH2:3][C:4]1[N:8]=[CH:7][N:6]([S:9]([C:12]2[CH:18]=[CH:17][C:15]([CH3:16])=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH:5]=1.C[O:30][C:31](=O)[C@H:32]([CH2:34][CH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1)[NH2:33].[BH4-].[Li+]>C1COCC1.C(O)C>[NH:1]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C@H:2]([C:19]([OH:21])=[O:20])[CH2:3][C:4]1[N:8]=[CH:7][N:6]([S:9]([C:12]2[CH:13]=[CH:14][C:15]([CH3:16])=[CH:17][CH:18]=2)(=[O:11])=[O:10])[CH:5]=1.[CH:35]1([CH2:34][C@@H:32]([CH2:31][OH:30])[NH2:33])[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1
Reactant: COC(=O)[C@@H](N)CC1CCCCC1
Agent: Cc1ccc(S(=O)(=O)n2cnc(C[C@H](NC(=O)OC(C)(C)C)C(=O)O)c2)cc1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCO
Product: N[C@H](CO)CC1CCCCC1

Procedure:
The extract is dried over MgSO4 and evaporated to dryness in vacuo to quantitatively obtain 3-cyclohexylalanine methyl ester [16a] as an oil. The product is then, without further purification, dissolved in dichloromethane (50 ml). To the solution are added Boc-His(Ts).DCHA [8a](10.7 g, 18.11 mmol, 1.3 eq) and diethyl cyanophosphonate (2.95 g, 18.1 mmol, 1.3 eq), and the mixture is stirred for 1.5 hours at room temperature. The reaction mixture is subjected to silica gel chromatography (SiO2 :300 g, CH2Cl2 :MeOH=99:1) to give a purified Boc-His(Ts)-3-cyclohexylalanine methyl ester [17a] (7.43 g, 93%) as an oil. To a solution of the dipeptide ester [17a](3.0 g, 5.2mmol) in THF (6 ml) and ethanol (6 ml) is added a 2N solution of lithium borohydride in THF (3 ml, 6 mmol) with stirring and ice-cooling. After 20 minutes stirring, the mixture is allowed to react at room temperature for additional one hour. The solvent is removed in vacuo and the residue added ice water and saturated aqueous ammonium chloride is extracted with dichloromethane (20 ml×3). The organic layer is washed with saturated aqueous sodium chloride, dried over MgSO4, evaporated to dryness in vacuo and the residue is purified by silica gel chromatography (SiO2 : 200 g, CH2Cl2 :MeOH=98:2) to obtain Boc-His(Ts)-3-cyclohexyl-alaninol [18a] (2.06 g, 72%) as an oil.
Reaction SMILES: [CH3:1][NH:2][CH:3]1[CH2:16][C:15]2[C:6]([CH3:25])([CH:7]3[CH:12]([CH2:13][CH:14]=2)[CH:11]2[CH2:17][CH2:18][CH:19]4[CH:20]([CH3:24])[N:21]([CH3:23])[CH2:22][C:10]24[CH2:9][CH2:8]3)[CH2:5][CH2:4]1.[C:26](Cl)(=[O:28])[CH3:27].C(N(CC)CC)C>ClCCl>[CH3:1][N:2]([CH:3]1[CH2:16][C:15]2[C:6]([CH3:25])([CH:7]3[CH:12]([CH2:13][CH:14]=2)[CH:11]2[CH2:17][CH2:18][CH:19]4[CH:20]([CH3:24])[N:21]([CH3:23])[CH2:22][C:10]24[CH2:9][CH2:8]3)[CH2:5][CH2:4]1)[C:26](=[O:28])[CH3:27]
Reactant: CC(=O)Cl
Reactant: CNC1CCC2(C)C(=CCC3C2CCC24CN(C)C(C)C2CCC34)C1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N(C)C1CCC2(C)C(=CCC3C2CCC24CN(C)C(C)C2CCC34)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78 %

Procedure:
A mixture of compound 7B (15 mg, 0.044 mmol), acetyl chloride (2.8 μL, 1.1 eq), triethylamine (15 μL, 3.0 eq) and dichloromethane (1 mL) was stirred at room temperature for 2 h. The clear solution was directly loaded on silica gel column and eluted with 0.5% ammonium hydroxide and 5% methanol in dichloromethane to give the desired product (10.5 mg, 78% yield)
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3](=[O:10])[NH:2]1.[CH:11]1([N:17]=[C:18]=[O:19])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1>>[CH:11]1([NH:17][C:18]([N:2]2[C:3](=[O:10])[C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[S:1]2)=[O:19])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: O=C=NC1CCCCC1
Reactant: O=c1[nH]sc2ccccc12
Product: O=C(NC1CCCCC1)n1sc2ccccc2c1=O

Procedure:
Following the synthetic procedure of 6a as described in Example 1, compound 6h (52% yield) was synthesized from benzo[d]isothiazol-3-one and cyclohexyl isocyanate as a white solid. mp 49-51° C; IR(CHCl3) 3287, 1711, 1660, 1533 cm−1; 1H-NMR (CDCl3) δ 1.20-1.65 (m, 6H), 1.65-1.80 (m, 2H), 1.95-2.05 (m, 2H), 3.80-3.94 (m, 1H), 7.42 (t, J=7.6 Hz, 1H), 7.58 (d, J=7.6 Hz, 1H), 7.69 (t, J=7.6 Hz, 1H), 8.00 (d, J=7.6 Hz, 1H, 8.86 (br s, 1H); ESIMS m/e 277 (M++1).
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5](Cl)=[C:4]2[CH:9]=[N:10][C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:12][C:3]=12.[CH3:19][CH:20]1[O:25][CH2:24][CH2:23][NH:22][CH2:21]1>>[CH3:19][CH:20]1[CH2:21][N:22]([C:2]2[N:7]=[N:6][C:5]([N:22]3[CH2:23][CH2:24][O:25][CH:20]([CH3:19])[CH2:21]3)=[C:4]3[CH:9]=[N:10][C:11]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)=[CH:12][C:3]=23)[CH2:23][CH2:24][O:25]1
Reactant: CC1CNCCO1
Reactant: Clc1nnc(Cl)c2cc(-c3ccccc3)ncc12
Product: CC1CN(c2nnc(N3CCOC(C)C3)c3cc(-c4ccccc4)ncc23)CCO1

Procedure:
2.0 parts by weight of 1,4-dichloro-7-phenylpyrido(3,4-d)pyridazine is added to 20 parts by volume of 2-methylmorpholine, and the resulting mixture is heated at 130° to 140° C for 4 hours. The excess amount of 2-methylmorpholine is removed by evaporation under reduced pressure. Water is added to the residue to obtain crude crystals, which is recrystallized from n-hexane to obtain 1,4-bis(2'-methylmorpholino)-7-phenylpyrido(3,4-d)pyridazine as yellow prisms melting at 75° to 81° C. Elementary analysis for C23H27O2N5
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25]C)=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:27]=[C:28]([C:31](=[O:38])[CH2:32][CH2:33][C:34]([O:36]C)=[O:35])[CH:29]=[CH:30][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+]>C(O)C>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[C:18]([C:23]([OH:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:15][CH:16]=2)[C:8]2[CH:27]=[C:28]([C:31](=[O:38])[CH2:32][CH2:33][C:34]([OH:36])=[O:35])[CH:29]=[CH:30][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2ccc(C(=O)CCC(=O)OC)cc2n1Cc1ccc(-c2ccccc2C(=O)OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCc1nc2ccc(C(=O)CCC(=O)O)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared analogously to Example 64 from methyl 4'-[[2-n-butyl-6-(3-methoxycarbonyl-propionyl)-benzimidazol-1-yl]methyl]biphenyl-2-carboxylate and sodium hydroxide solution in ethanol.
Reaction SMILES: [BH4-].[Na+].[CH3:3][C:4]1[CH:5]=[C:6](/[CH:11]=[C:12](\[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=2)/[C:13]#[N:14])[CH:7]=[CH:8][C:9]=1[CH3:10]>CCO>[CH3:3][C:4]1[CH:5]=[C:6]([CH2:11][CH:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=2)[C:13]#[N:14])[CH:7]=[CH:8][C:9]=1[CH3:10]
Reactant: Cc1ccc(/C=C(/C#N)c2cccc(F)c2)cc1C
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: Cc1ccc(CC(C#N)c2cccc(F)c2)cc1C
Temperature: 70 °C
Reaction time: 16 h
Yield: 100.8 %

Procedure:
To a solution of 3,4-dimethylbenzaldehyde (CAS 68844-97-3) (4.0 g, 29.6 mmol) and 3-fluoro-benzeneacetonitrile (CAS 501-00-8) (4.35 g, 29.6 mmol) in absolute EtOH, 30 mL, was added NaOMe (0.1 equiv), then the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was cooled to 0° C. and filtered. The precipitate was washed with cold EtOH and gave (2E)-3-(3,4-dimethylphenyl)-2-(3-fluorophenyl)acrylonitrile as a white solid (6.20 g, 78%). NaBH4 (1.8 g, 47 mmol) was added slowly to a solution of (2E)-3-(3,4-dimethylphenyl)-2-(3-fluorophenyl)acrylonitrile (6.17 g, 23.5 mmol) in EtOH (100 mL) under argon. The mixture was stirred at 70° C. for 16 h. The solution was cooled to room temperature and quenched with water. The reaction mixture was diluted with 100 mL water and acidified with 6M HCl (aq.). After extraction with ether (3×100 mL), the combined organic layers were washed with water and brine, dried over MgSO4, filtered and concentrated and gave 3-(3,4-dimethylphenyl)-2-(3-fluorophenyl)propanenitrile as a white solid (6 g, 96%). DIBAL-H (1.0 M in toluene, 14 mL, 14 mmol) was added dropwise to a solution of 3-(3,4-dimethylphenyl)-2-(3-fluorophenyl)propanenitrile (2.93 g, 11.72 mmol) in Toluene (40 mL) at −78° C. under argon. The mixture was stirred at −78° C. to −20° C. for 3 h and then quenched by slow addition of saturated NH4Cl solution (2 mL) followed by Celite (2 g) at −20° C. The mixture was diluted with Et2O (50 mL), warmed slowly to room temperature, and stirred till all aluminum precipitated. The solid was filtered and washed with ether (3×50 mL), the combined organic layers were dried over MgSO4, filtered, concentrated and gave Intermediate 5 (2.34 g, 74%).
Reaction SMILES: [NH2:1][CH:2]1[C:11]2[CH:10]=[N:9][CH:8]=[C:7]([C:12]3[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=3)[C:6]=2[CH2:5][CH2:4][CH2:3]1.[CH2:20]([NH:23][S:24](Cl)(=[O:26])=[O:25])[CH2:21][CH3:22].CCN(CC)CC.CO>C(Cl)Cl>[C:16]([C:15]1[CH:14]=[CH:13][C:12]([C:7]2[C:6]3[CH2:5][CH2:4][CH2:3][CH:2]([NH:1][S:24](=[O:26])(=[O:25])[NH:23][CH2:20][CH2:21][CH3:22])[C:11]=3[CH:10]=[N:9][CH:8]=2)=[CH:19][CH:18]=1)#[N:17]
Reactant: CCCNS(=O)(=O)Cl
Reactant: N#Cc1ccc(-c2cncc3c2CCCC3N)cc1
Solvent: CCN(CC)CC
Solvent: CO
Solvent: ClCCl
Product: CCCNS(=O)(=O)NC1CCCc2c(-c3ccc(C#N)cc3)cncc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 68 %

Procedure:
A cooled (0° C.) solution of (rac)-4-(8-amino-5,6,7,8-tetrahydroisoquinolin-4-yl)benzonitrile (example 1) (62.3 mg, 250 μmol) in CH2Cl2 (3 ml) was treated with propylsulfamoyl chloride (98.5 mg, 625 μmol) in CH2Cl2 (0.6 ml) and Et3N (69.7 μL, 500 μmol). After 1 h the mixture was stirred at room temperature for 1 h, cooled down (0° C.) and treated again with Et3N (69.7 μL, 500 μmol). After ½ h at room temperature, the mixture was treated with MeOH (0.2 mL) and extracted with water/AcOEt (3×). The organic phases were dried over Na2SO4, filtered and evaporated under reduced pressure. Purification by flash chromatography (50 g SiO2, Telos-cartridge, CH2Cl2/MeOH (1 to 3%)) and precipitation from CH2Cl2 with n-pentane gave the title compound (63 mg, 68%) as off-white powder. MS: 371.2 (M+H+).
Reaction SMILES: [CH:1]1([CH2:4][N:5]([CH2:24][CH2:25][CH3:26])[C:6]2[N:11]=[CH:10][N:9]=[C:8]([C:12]([NH:14][C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][CH:23]=3)[NH:20][N:19]=[CH:18]4)=[O:13])[CH:7]=2)[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Br[CH2:36][C:37]([NH2:39])=[O:38]>CN(C=O)C.O>[NH2:39][C:37](=[O:38])[CH2:36][N:20]1[C:21]2[C:17](=[CH:16][C:15]([NH:14][C:12]([C:8]3[CH:7]=[C:6]([N:5]([CH2:4][CH:1]4[CH2:3][CH2:2]4)[CH2:24][CH2:25][CH3:26])[N:11]=[CH:10][N:9]=3)=[O:13])=[CH:23][CH:22]=2)[CH:18]=[N:19]1
Reactant: NC(=O)CBr
Reactant: CCCN(CC1CC1)c1cc(C(=O)Nc2ccc3[nH]ncc3c2)ncn1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCN(CC1CC1)c1cc(C(=O)Nc2ccc3c(cnn3CC(N)=O)c2)ncn1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of 6-((cyclopropylmethyl)(propyl)amino)-N-(1H-indazol-5-yl)pyrimidine-4-carboxamide (Example 45, 350 mg; 1 mmol) in DMF (4 ml) was treated with potassium carbonate (140 mg; 1 mmol), potassium iodide (1 mg) and 2-bromoacetamide (160 mg; 1.16 mmol). After stirring at RT for 72 hours the mixture was poured in water (20 ml) and stirred at RT for 1 hour. The solid was removed by filtration, washed with water and dried. The residue was purified by column chromatography (silica) eluting with EtOAc containing increasing amounts of MeOH to give the title compound as an off-white solid, together with N-[2-(2-amino-2-oxoethyl)-2H-indazol-5-yl]-6-[(cyclopropylmethyl)(propyl)amino]pyrimidine-4-carboxamide (Example 118 below).
Reaction SMILES: [CH2:1]1[O:13][C:12]2[CH:11]=[C:10]3[C:5]([C:6]([N:14]([CH2:28][CH2:29][N:30]4[CH2:34][CH2:33][CH2:32][CH2:31]4)[C:15](=[O:27])[C:16]4[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[CH:18][C:17]=4I)=[CH:7][CH:8]=[N:9]3)=[CH:4][C:3]=2[O:2]1>C(Cl)(Cl)Cl>[CH3:23][O:22][C:20]1[C:19]([O:24][CH3:25])=[CH:18][C:17]2[C:7]3[C:6](=[C:5]4[CH:4]=[C:3]5[O:2][CH2:1][O:13][C:12]5=[CH:11][C:10]4=[N:9][CH:8]=3)[N:14]([CH2:28][CH2:29][N:30]3[CH2:34][CH2:33][CH2:32][CH2:31]3)[C:15](=[O:27])[C:16]=2[CH:21]=1
Reactant: COc1cc(I)c(C(=O)N(CCN2CCCC2)c2ccnc3cc4c(cc23)OCO4)cc1OC
Solvent: ClC(Cl)Cl
Product: COc1cc2c(=O)n(CCN3CCCC3)c3c4cc5c(cc4ncc3c2cc1OC)OCO5
Yield: 36 %

Procedure:
Prepared from N-(6,7-Methylenedioxyquinolin-4-yl)-N-[(2-pyrrolidin-1-yl)ethyl]-2-iodo-4,5-dimethoxybenzamide; (36% yield); reaction time 30 min; mp 255-257° C. (dec.); IR (CHCl3) 1653; 1H NMR (CDCl3) δ 1.79 (m, 4H), 2.64 (m, 4H), 3.20 (t, 2H, J=7.1), 4.07 (s, 3H), 4.14 (s, 3H), 4.69 (t, 2H, J=7.1), 6.18 (s, 2H), 7.46 (s, 1H), 7.68 (s, 1H), 7.89 (s, 1H), 7.95 (s, 1H), 9.37 (s, 1H); 13C NMR (CDCl3) δ 23.7, 49.6, 54.3, 56.3, 56.4, 56.4, 101.3, 102.0, 102.3, 107.0, 108.7, 111.7, 114.8, 119.3, 127.7, 140.9, 143.4, 147.3, 147.8, 150.0, 150.3, 154.2, 164.2; HRMS calcd for C25H25N3O5H, 448.1872; found 448.1872.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12](=[O:14])(=[O:13])[NH:11][C:10]([CH3:16])([CH3:15])[C:9]=2[CH3:17])=[CH:4][CH:3]=1.Br[N:19]1C(=O)C[CH2:21][C:20]1=O.N(C(C)(C)C#N)=NC(C)(C)C#N.C(N)C>C(Cl)(Cl)(Cl)Cl.C(O)C.C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:12](=[O:14])(=[O:13])[NH:11][C:10]([CH3:16])([CH3:15])[C:9]=2[CH2:17][NH:19][CH2:20][CH3:21])=[CH:6][CH:7]=1
Reactant: CC1=C(c2ccc(Cl)cc2)S(=O)(=O)NC1(C)C
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CCN
Solvent: ClC(Cl)Cl
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCO
Product: CCNCC1=C(c2ccc(Cl)cc2)S(=O)(=O)NC1(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 12 %

Procedure:
To a solution of 5-(4-chlorophenyl)-3,3,4-trimethyl-1,1-dioxo-2,3-dihydro-isothiazole, 1.5 g (5.5 mmol) in 150 mL of carbon tetrachloride was added 1.5 g (8.25 mmol) of N-bromosuccinimide and 0.13 g of 2,2′-azobis(2-methylpropionitrile). The mixture was heated to reflux for 4 h and then cooled to ambient temperature. Chloroform was added and the solution was washed with water, washed with brine, dried over sodium sulfate, filtered and concentrated to dryness. To a solution of the residue in 75 mL of absolute ethanol was added 3.6 mL (55.0 mmol) of ethylamine (70% solution in water). The reaction mixture was stirred 24 h at ambient temperature then concentrated to dryness. The residue was purified by chromatography on silica gel with methanol/chloroform as eluant to yield 0.21 g (12%) of the desired title amine as a tan oil. 1H-NMR is consistent with structure; MS (ion spray) 313.0 (M−1); Anal. Calc'd for C14H19ClN2O2S.0.1CHCl3: C, 51.83; H, 5.89; N, 8.57. Found: C, 51.58; H, 6.38; N, 8.04.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:20]C)=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:7]=1.B(Br)(Br)Br>C(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:5]([OH:20])=[CH:4][CH:3]=1
Reactant: COc1ccc(F)cc1-c1ccccc1-c1ccccc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1ccc(F)cc1-c1ccccc1-c1ccccc1
Temperature: 25 °C
Yield: 98.2 %

Procedure:
To a solution of 5-fluoro-2-methoxy-2′-phenylbiphenyl (7.3 g, 26.2 mmol) in methylene chloride (100 mL) cooled to −78° C. was added through syringe boron tribromide (1.0 M in dichloromethane, 40.0 mL, 40.0 mmol). The reaction mixture was stirred and allowed to warm up to room temperature overnight. The resulting mixture was diluted with dichloromethane, washed with water and saturated sodium chloride, dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification by ISCO using a solvent gradient of 0 to 40% ethyl acetate in hexanes provided 6.8 g (98%) of 5-fluoro-2′-phenylbiphenyl-2-ol as a light brown oil.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]#[C:16][C:17]3[CH:32]=[CH:31][C:20]([C:21]([O:23][CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[O:22])=[CH:19][CH:18]=3)=[C:11]([N+:33]([O-])=O)[CH:10]=2)=[O:8])=[CH:4][C:3]=1[CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38].C([O-])(O)=O.[Na+]>CCOC(C)=O>[NH2:33][C:11]1[CH:10]=[C:9]([C:7]([C:5]2[S:6][C:2]([Br:1])=[C:3]([CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])[CH:4]=2)=[O:8])[CH:14]=[CH:13][C:12]=1[C:15]#[C:16][C:17]1[CH:18]=[CH:19][C:20]([C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:22])=[CH:31][CH:32]=1
Reactant: CCOC(=O)Cc1cc(C(=O)c2ccc(C#Cc3ccc(C(=O)OCc4ccccc4)cc3)c([N+](=O)[O-])c2)sc1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CCOC(=O)Cc1cc(C(=O)c2ccc(C#Cc3ccc(C(=O)OCc4ccccc4)cc3)c(N)c2)sc1Br
Yield: 105.2 %

Procedure:
To a solution of 3 (450 mg, 0.71 mmol) in EtOAc (10 mL) was added stannous chloride dihydrate (642 mg, 2.84 mmol). The resulting mixture was refluxed for one hour under N2. The reaction mixture was poured onto ice (5 g), and basified with saturated NaHCO3 solution to pH 8. The white milky mixture was filtered through a Celite pad to remove tin oxides. The organic layer from the filtrate was dried over MgSO4, filtered, and then concentrated in vacuo. MPLC purification (Hex:EtOAc/4:1) of the crude product gave the desired intermediate benzyl 4-((2-amino-4-(5-bromo-4-(2-ethoxy-2-oxoethyl)thiophene-2-carbonyl)phenyl)ethynyl)benzoate as a yellow foam (450 mg, 95%). 1H NMR (400 MHz, CDCl3) δ 8.07 (d, J=8.0 Hz, 2H), 7.60 (d, J=8.0 Hz, 2H), 7.51-7.36 (m, 7H), 7.22-7.18 (m, 2H), 5.38 (s, 2H), 4.18 (q, J=7.2 Hz, 2H), 3.64 (s, 2H), and 1.27 (t, J=7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 186.72, 169.84, 166.01, 148.31, 143.21, 138.58, 136.12, 136.05, 135.39, 132.55, 131.71, 130.02, 129.98, 128.90, 128.62, 128.51, 127.71, 122.93, 118.70, 114.66, 111.47, 96.66, 88.41, 67.21, 61.63, 53.75, 35.32, and 14.44.
Reaction SMILES: CON(C)[C:4]([C:6]1[C:14]2[N:13]([CH3:15])[C:12](=[O:16])[NH:11][C:10]=2[CH:9]=[CH:8][CH:7]=1)=[O:5].Br[C:19]1[C:24]([N:25]([CH2:40][O:41][CH3:42])[S:26]([C:29]2[CH:34]=[CH:33][C:32]([CH3:35])=[C:31]([C:36]([F:39])([F:38])[F:37])[CH:30]=2)(=[O:28])=[O:27])=[CH:23][C:22]([Cl:43])=[CH:21][N:20]=1>>[Cl:43][C:22]1[CH:23]=[C:24]([N:25]([CH2:40][O:41][CH3:42])[S:26]([C:29]2[CH:34]=[CH:33][C:32]([CH3:35])=[C:31]([C:36]([F:38])([F:37])[F:39])[CH:30]=2)(=[O:28])=[O:27])[C:19]([C:4]([C:6]2[C:14]3[N:13]([CH3:15])[C:12](=[O:16])[NH:11][C:10]=3[CH:9]=[CH:8][CH:7]=2)=[O:5])=[N:20][CH:21]=1
Reactant: COCN(c1cc(Cl)cnc1Br)S(=O)(=O)c1ccc(C)c(C(F)(F)F)c1
Reactant: CON(C)C(=O)c1cccc2[nH]c(=O)n(C)c12
Product: COCN(c1cc(Cl)cnc1C(=O)c1cccc2[nH]c(=O)n(C)c12)S(=O)(=O)c1ccc(C)c(C(F)(F)F)c1

Procedure:
N-[5-Chloro-2-(3-methyl-2-oxo-2,3-dihydro-1H-benzoimidazole-4-carbonyl)-pyridin-3-yl]-N-methoxymethyl-4-methyl-3-trifluoromethyl-benzenesulfonamide was prepared from 3-methyl-2-oxo-2,3-dihydro-1H-benzoimidazole-4-carboxylic acid methoxy-methyl-amide and N-(2-bromo-5-chloro-pyridin-3-yl)-N-methoxymethyl-4-methyl-3-trifluoromethyl-benzenesulfonamide according to previously described procedure in example 29, step 1. The product was purified by flash column chromatography on silica gel using ethyl acetate-hexane. MS m/z: 569.0 (M+H)+.
Reaction SMILES: [NH2:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1)[C:3]([OH:5])=[O:4].Cl[C:14](Cl)([O:16]C(=O)OC(Cl)(Cl)Cl)Cl>C1COCC1>[F:12][C:9]1[CH:10]=[CH:11][C:6]([CH:2]2[C:3](=[O:5])[O:4][C:14](=[O:16])[NH:1]2)=[CH:7][CH:8]=1
Reactant: NC(C(=O)O)c1ccc(F)cc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: C1CCOC1
Product: O=C1NC(c2ccc(F)cc2)C(=O)O1
Temperature: -20 °C
Reaction time: 3 h
Yield: 87.4 %

Procedure:
To a solution of 2-amino-2-(4-fluorophenyl)acetic acid (5 g, 29.5 mmol) in THF (50 mL) at 50° C. was added triphosgene (8.77 g, 29.5 mmol), then heating was continued for 3 h. The reaction mixture was then filtered and evaporated to a volume of about10 mL, followed by addition of 150 mL of hexanes. The mixture was heated slightly, and then cooled to −20° C. for 1 h. The crude slurry was filtered to give 4-(4-fluorophenyl)oxazolidine-2,5-dione (5.03 g, 87%) which was used without further purification.