Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[O:11][CH3:12].C(=O)([O-])[O-].[K+].[K+].Cl.[F:20][CH:21]1[CH2:24][NH:23][CH2:22]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:23]2[CH2:24][CH:21]([F:20])[CH2:22]2)=[O:8])=[CH:4][C:3]=1[O:11][CH3:12]
Reactant: COc1cc(C(=O)O)ccc1Br
Reactant: FC1CNC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C(=O)N2CC(F)C2)ccc1Br
Temperature: 25 °C
Reaction time: 18 h
Yield: 71.6 %

Procedure:
To a stirred solution of 4-bromo-3-methoxybenzoic acid (1.4 g) in DMF (15 mL) was added potassium carbonate (2.51 g), 3-fluoroazetidine hydrochloride (1.01 g) and HATU (3.69 g). The mixture was stirred at room temperature for 18 h. Water was added, the mixture was stirred for 15 minutes and the solvent was removed in vacuum. Water was added and the mixture was extracted with ethyl acetate. The organic phase was washed with water, saturated sodium chloride solution, dried (sodium sulfate) and the solvent was removed in vacuum, to give 1.25 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH:11]=O)=[CH:8][C:6]=2[N:7]=1.[NH:19]1[CH2:24][CH2:23][CH:22]([CH2:25][N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[CH2:21][CH2:20]1>>[Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH2:11][N:19]3[CH2:20][CH2:21][CH:22]([CH2:25][N:26]4[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]4)[CH2:23][CH2:24]3)=[CH:8][C:6]=2[N:7]=1
Reactant: C1CCN(CC2CCNCC2)CC1
Reactant: O=Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Product: Clc1nc(N2CCOCC2)c2sc(CN3CCC(CN4CCCCC4)CC3)cc2n1

Procedure:
2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carboxaldehyde 10 was reacted with 1-(piperidin-4-ylmethyl)piperidine using standard reductive amination conditions. The resulting crude solid was triturated with methanol to give 2-chloro-4-morpholin-4-yl-6-(4-piperidin-1-ylmethyl-piperidin-1-ylmethyl)-thieno[3,2-d]pyrimidine, which was reacted with 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidin-2-ylamine according to General Procedure A. The resulting solid was triturated with methanol to give 330 as an off white solid (23% yield). NMR (CDCl3, 400 MHz), 1.27-1.31 (3H, m), 1.42-1.46 (2H, m), 1.50-1.56 (4H, m), 1.77 (2H, d, J=13.1), 2.09 (2H, t, J=11.2), 2.15 (2H, d, J=7.1), 2.30-2.35 (4H, m), 2.97 (2H, d, J=10.9), 3.82 (2H, s), 3.88-3.91 (4H, m), 4.03-4.06 (4H, m), 5.21 (1H, br s), 7.27 (1H, s), 9.30 (2H, s). MS: (ESI+): MH+=509
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[C@H:9]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([F:17])[CH:11]=2)[O:8][CH2:7][CH2:6][N:5]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:4]1.[NH2:25][C:26]1[CH:34]=[CH:33][CH:32]=[CH:31][C:27]=1[C:28](O)=[O:29]>>[NH2:25][C:26]1[CH:34]=[CH:33][CH:32]=[CH:31][C:27]=1[C:28]([NH:1][CH2:2][C@H:3]1[C@H:9]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([F:17])[CH:11]=2)[O:8][CH2:7][CH2:6][N:5]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:4]1)=[O:29]
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(F)c2)[C@H](CN)C1
Reactant: Nc1ccccc1C(=O)O
Product: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(F)c2)[C@H](CNC(=O)c2ccccc2N)C1

Procedure:
Using tert-butyl (6R,7R)-6-(aminomethyl)-7-(4-chloro-3-fluorophenyl)-1,4-oxazepane-4-carboxylate and 2-aminobenzoic acid, and by a method similar to that of Example 39, step A, the title compound was obtained.
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4]2[CH:10]=[C:9]([O:11][CH2:12][CH3:13])[CH:8]=[CH:7][C:5]=2[N:6]=1.Cl.Cl[CH2:16][C:17]1[CH:23]=[C:22]([CH3:24])[CH:21]=[CH:20][C:18]=1[NH2:19]>C(O)(C)C>[CH2:12]([O:11][C:9]1[CH:8]=[CH:7][C:5]2[NH:6][C:2]([S:1][CH2:16][C:17]3[CH:23]=[C:22]([CH3:24])[CH:21]=[CH:20][C:18]=3[NH2:19])=[N:3][C:4]=2[CH:10]=1)[CH3:13]
Reactant: CCOc1ccc2nc(S)[nH]c2c1
Reactant: Cc1ccc(N)c(CCl)c1
Agent: Cl
Solvent: CC(C)O
Product: CCOc1ccc2[nH]c(SCc3cc(C)ccc3N)nc2c1
Yield: 44 %

Procedure:
The title compound was prepared by the method of Example 1 using 3.00 g of 2-mercapto-5-ethoxybenzimidazole instead of 2-mercaptobenzimidazole and 3.71 g of 2-(chloromethyl)-4-methylaniline hydrochloride instead of 2-(chloromethyl)-N,N-dimethylaniline in isopropyl alcohol. The basic extraction used 10% sodium hydroxide instead of sodium carbonate. Crystallization during concentration of the dichloromethane extract gave 2.13 g of the title compound, which was used in subsequent reactions without further purification.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)=[C:5]([C:19]2[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=2)[N:4]=[C:3]1[C:25]#N>C1COCC1>[CH3:1][N:2]1[C:7](=[O:8])[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:17])([F:16])[F:18])[CH:10]=2)=[C:5]([C:19]2[CH:20]=[CH:21][N:22]=[CH:23][CH:24]=2)[N:4]=[C:3]1[CH2:25][CH2:6][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Cn1c(C#N)nc(-c2ccncc2)c(-c2cccc(C(F)(F)F)c2)c1=O
Solvent: C1CCOC1
Product: Cn1c(CCc2ccccc2)nc(-c2ccncc2)c(-c2cccc(C(F)(F)F)c2)c1=O
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a solution of 3-methyl-4-oxo-6-(4-pyridyl)-5-(3-(trifluoromethyl)-phenyl)-3H-pyrimidine-2-carbonitrile (280 mg, 0.79 mmole) in THF (20 mL) was added phenethylene magnesium chloride (1.0M in THF, 1.2 mL) at 0° C. The reaction solution was then stirred at 0° C. for 5 mins. The mixture was partitioned between sat. ammonium chloride and ethyl acetate. The organic layer was separated, dried over sodium sulfate, filtered and concentrated to a syrup. The residue was purified by column chromatography on silica gel (30% ethyl acetate in hexane) to give the product as a syrup; MS (m/z) 436(M+H)+; C25H20F3N3O requir. 435.4.
Reaction SMILES: [C:1]([C:5]1[CH:14]=[CH:13][C:12]2[CH2:11][CH2:10][CH2:9][CH2:8][C:7]=2[C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2].[CH3:16][O:17]C(Cl)Cl>ClCCl>[C:1]([C:5]1[CH:14]=[C:13]([CH:16]=[O:17])[C:12]2[CH2:11][CH2:10][CH2:9][CH2:8][C:7]=2[C:6]=1[OH:15])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(Cl)Cl
Reactant: CC(C)(C)c1ccc2c(c1O)CCCC2
Solvent: ClCCl
Product: CC(C)(C)c1cc(C=O)c2c(c1O)CCCC2
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Stannic chloride (36.71 g, 0.141 mole) was added to a solution of 2-tert-butyl-5,6,7,8-tetrahydro-1-naphthol (16.0 g, 0.0783 mole) in dry dichloromethane (150 ml) at -10°. To the stirred solution was added 1,1-dichloromethyl methyl ether (13.45 g, 0.118 mole) dropwise at 0°. After 10 minutes, the reaction mixture was treated with ice-water and extracted with ethyl acetate (2×200 ml). The organic extract washed with aqueous saturated sodium chloride and dried over magnesium sulphate. The solvents were removed in vacuo and the solid residue was triturated with n-pentane:diethyl ether (4:1) mixture to give a grey white crystalline solid which was filtered off and air-dried to yield 10.15 g (55.7%), m.p. 193°-94°.
Reaction SMILES: [OH-].[K+].[C:3]([OH:11])(=[S:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl[CH:13]([C:17]1[CH:26]=[CH:25][C:24]2[C:19](=[CH:20][CH:21]=[C:22]([O:27][CH3:28])[CH:23]=2)[CH:18]=1)[C:14]([OH:16])=[O:15]>>[C:3]([S:10][CH:13]([C:17]1[CH:26]=[CH:25][C:24]2[C:19](=[CH:20][CH:21]=[C:22]([O:27][CH3:28])[CH:23]=2)[CH:18]=1)[C:14]([OH:16])=[O:15])(=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: COc1ccc2cc(C(Cl)C(=O)O)ccc2c1
Reactant: OC(=S)c1ccccc1
Agent: [K+]
Agent: [OH-]
Product: COc1ccc2cc(C(SC(=O)c3ccccc3)C(=O)O)ccc2c1
Temperature: 25 °C
Reaction time: 25 h

Procedure:
To 17.5 ml. of 2N alcoholic potassium hydroxide solution (0.035 mole) is added 4.84 g. (0.035 mole) of thiobenzoic acid. The solution is cooled to room temperature and to this is added in small portions 0.035 mole of α-chloro-6-methoxy-2-naphthylacetic acid. The reaction mixture is stirred at room temperature for 25 hours, then the solvent is removed, the residue dissolved in ether, filtered and washed with cold water. The ethereal solution is then dried over magnesium sulfate and evaporated to dryness to obtain α-benzoylthio-6-methoxy-2-naphthylacetic acid.
Reaction SMILES: Br[C:2]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:3]=1[CH2:4][N:5]([CH3:16])[C:6](=[O:15])[O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.N1CCC[C@H]1C(O)=O.C(=O)([O-])[O-].[Cs+].[Cs+].[C:38]([O:46][CH2:47][CH3:48])(=[O:45])[CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41]>CS(C)=O.[Cu]I>[CH2:8]([O:7][C:6]([N:5]([CH2:4][C:3]1[CH:17]=[C:18]([N+:21]([O-:23])=[O:22])[CH:19]=[CH:20][C:2]=1[CH:39]([C:40]([O:42][CH2:43][CH3:44])=[O:41])[C:38]([O:46][CH2:47][CH3:48])=[O:45])[CH3:16])=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CN(Cc1cc([N+](=O)[O-])ccc1Br)C(=O)OCc1ccccc1
Reactant: CCOC(=O)CC(=O)OCC
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Product: CCOC(=O)C(C(=O)OCC)c1ccc([N+](=O)[O-])cc1CN(C)C(=O)OCc1ccccc1
Temperature: 50 °C
Reaction time: 72 h
Yield: 73.6 %

Procedure:
Benzyl 2-bromo-5-nitrobenzyl(methyl)carbamate (3.000 g, 7.91 mmol), copper(i) iodide (0.301 g, 1.582 mmol), L-proline (0.364 g, 3.16 mmol) and cesium carbonate (5.16 g, 15.82 mmol) were mixed in a pressure vial and degassed (3×). A solution of diethyl malonate (1.501 mL, 9.89 mmol) in DMSO (10 mL) was added, the reaction mixture was degassed again and stirred at 50° C. for 3 days. The cooled reaction mixture was partitioned between EtOAc (100 mL) and NH4Cl (aq. std.; 100 mL). The organic layer was washed with brine (2×50 mL) and dried (Na2SO4). EtOAc was removed under reduced pressure and the residue was purified by flash chromatography (0-40% EtOAc/hexane). Fractions were combined and concentrated under reduced pressure to give 15A (2.668 g, 5.82 mmol, 73.6% yield) as a colorless syrup. MS (ESI) m/z: 459.2 [M+1]+. 1H NMR: (400 MHz, CDCl3) δ ppm 8.18 (1H, d, J=8.53 Hz), 8.09 (1H, br. s.), 7.72 (1H, d, J=7.28 Hz), 7.36 (5H, d, J=15.81 Hz), 5.20 (3H, br. s.), 4.67 (2H, br. s.), 4.07-4.28 (4H, m), 2.81 (3H, s), 1.24 (6H, t, J=7.15 Hz).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[NH:14][C:15]4[CH:21]=[C:20]([NH2:22])[CH:19]=[CH:18][C:16]=4[N:17]=3)=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.[OH:23][CH2:24][CH2:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2[NH:34][C:35]3[CH:41]=[C:40]([C:42]([O-])=[O:43])[CH:39]=[CH:38][C:36]=3[N:37]=2)=[CH:29][CH:28]=1>>[OH:23][CH2:24][CH2:25][O:26][C:27]1[CH:28]=[CH:29][C:30]([C:33]2[NH:34][C:35]3[CH:41]=[C:40]([C:42]([NH:22][C:20]4[CH:19]=[CH:18][C:16]5[NH:17][C:13]([C:10]6[CH:11]=[CH:12][C:7]([N:4]7[CH2:5][CH2:6][O:1][CH2:2][CH2:3]7)=[CH:8][CH:9]=6)=[N:14][C:15]=5[CH:21]=4)=[O:43])[CH:39]=[CH:38][C:36]=3[N:37]=2)=[CH:31][CH:32]=1
Reactant: Nc1ccc2nc(-c3ccc(N4CCOCC4)cc3)[nH]c2c1
Reactant: O=C([O-])c1ccc2nc(-c3ccc(OCCO)cc3)[nH]c2c1
Product: O=C(Nc1ccc2[nH]c(-c3ccc(N4CCOCC4)cc3)nc2c1)c1ccc2nc(-c3ccc(OCCO)cc3)[nH]c2c1

Procedure:
Compound 299 was prepared according to the procedure similar to that described in Scheme V from 2-(4-morpholinophenyl)-5-aminobenzimidazole and 2-(4-(2-hydroxyethoxy)phenyl)benzimidazole-5-carboxylate. [M+H]+ calcd for C33H30N6O4: 575.23; found: 575.07.
Reaction SMILES: Cl[C:2]1[N:27]=[CH:26][C:5]2[N:6]=[CH:7][N:8]=[C:9]([NH:10][C:11]3[CH:16]=[CH:15][C:14]([S:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)(=[O:19])=[O:18])=[CH:13][CH:12]=3)[C:4]=2[CH:3]=1.[CH3:28][N:29]([CH3:34])[CH2:30][CH2:31][NH:32][CH3:33]>>[CH3:33][N:32]([C:2]1[N:27]=[CH:26][C:5]2[N:6]=[CH:7][N:8]=[C:9]([NH:10][C:11]3[CH:16]=[CH:15][C:14]([S:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)(=[O:19])=[O:18])=[CH:13][CH:12]=3)[C:4]=2[CH:3]=1)[CH2:31][CH2:30][N:29]([CH3:34])[CH3:28]
Reactant: O=S(=O)(c1ccccc1)c1ccc(Nc2ncnc3cnc(Cl)cc23)cc1
Reactant: CNCCN(C)C
Product: CN(C)CCN(C)c1cc2c(Nc3ccc(S(=O)(=O)c4ccccc4)cc3)ncnc2cn1

Procedure:
Prepared according to Procedure C from 6-chloro-4-(4-phenylsulphonylanilino)-pyrido[3,4-d]pyrimidine and N,N,N′-trimethylethylenediamine; δH (CDCl3) 8.92 (1H,s), 8.69 (1H,s), 8.49 (1H,s), 7.80-8.05 (6H,m), 7.38-7.60 (3H,m), 6.79 (1H,s), 3.68 (2H,t), 3.42 (3H,s), 2.51 (1H,t), 2.29 (6H,s); m/z (M+1)+463.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9])#[N:2].[H-].[Na+].Br[CH:13]([CH3:18])[C:14]([O:16][CH3:17])=[O:15].O>CN(C)C=O>[CH3:17][O:16][C:14]([CH:13]([O:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[C:1]#[N:2])[CH3:18])=[O:15]
Reactant: COC(=O)C(C)Br
Reactant: N#Cc1ccccc1O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C(C)Oc1ccccc1C#N
Reaction time: 1 h
Yield: 98.7 %

Procedure:
2-Cyanophenol (1.0 g, 8.39 mmol) was dissolved in N,N-dimethylformamide (5 ml), and 60% sodium hydride (0.40 g, 10 mmol) was added thereto under ice-cooling, followed by stirring for one hour. Methyl (±)-2-bromopropionate (1.03 ml, 9.23 mmol) was added to the mixture followed by stirring at room temperature for one night. After the reaction, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried, the drying agent was filtered off, and the filtrate was concentrated under reduced pressure to give 2-[1-(methoxycarbonyl)ethoxy]benzonitrile (1.70 g, 99%).
Reaction SMILES: [N:1]1(C(OCC2C=CC=CC=2)=O)[CH2:6][CH2:5][CH:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3][CH2:2]1>CCOC(C)=O.[Pd]>[NH:1]1[CH2:6][CH2:5][CH:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)C1CCN(C(=O)OCc2ccccc2)CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)C1CCNCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76 %

Procedure:
To a solution of 1-benzyl 4-tert-butyl piperidine-1,4-dicarboxylate in EtOAc (0.1 M), a catalytic amount of Pd/C (5%) was added and the atmosphere in the reaction vessel charged with H2 (1 atmosphere). The reaction mixture was stirred vigorously at RT for 8 h. The solution was filtered and the filtrate concentrated in vacuo to afford the title compound (76%); MS (ES+) m/z 186(M+H)+
Reaction SMILES: C([O:3][C:4](=[O:32])[CH2:5][S:6][C:7]1[S:11][C:10]([NH:12][C:13]([N:15]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([NH:28][C:29](=[O:31])[CH3:30])[CH:23]=2)[CH2:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[O:14])=[N:9][CH:8]=1)C.C1(CN(C2C=CC(F)=C(F)C=2)C(=O)NC2SC=C(CC(O)=O)N=2)CCCC1.NC1C=C(NC(=O)C)C=CC=1.C1(C=O)CCCC1.C(OC(=O)CSC1SC(N)=NC=1)C>>[C:29]([NH:28][C:24]1[CH:23]=[C:22]([N:15]([CH2:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[C:13](=[O:14])[NH:12][C:10]2[S:11][C:7]([S:6][CH2:5][C:4]([OH:32])=[O:3])=[CH:8][N:9]=2)[CH:27]=[CH:26][CH:25]=1)(=[O:31])[CH3:30]
Reactant: CCOC(=O)CSc1cnc(NC(=O)N(CC2CCCC2)c2cccc(NC(C)=O)c2)s1
Agent: CC(=O)Nc1cccc(N)c1
Agent: CCOC(=O)CSc1cnc(N)s1
Agent: O=C(O)Cc1csc(NC(=O)N(CC2CCCC2)c2ccc(F)c(F)c2)n1
Product: CC(=O)Nc1cccc(N(CC2CCCC2)C(=O)Nc2ncc(SCC(=O)O)s2)c1

Procedure:
The title compound was prepared via {2-[3-(3-acetylamino-phenyl)-3-cyclopentylmethyl-ureido]-thiazol-5-ylsulfanyl}-acetic acid ethyl ester in a similar manner as described for the synthesis of {2-[3-cyclopentylmethyl-3-(3,4-difluoro-phenyl)-ureido]-thiazol-4-yl}-acetic acid, using N-(3-amino-phenyl)-acetamide, cyclopentanecarbaldehyde and (2-amino-thiazol-5-ylsulfanyl)acetic acid ethyl ester.
Reaction SMILES: [CH3:1][N:2]([CH3:24])[C:3]([C:5]1[CH:6]=[C:7]([S:11]([NH:14][C:15]2[CH:19]=[CH:18][S:17][C:16]=2[C:20]([O:22]C)=[O:21])(=[O:13])=[O:12])[CH:8]=[CH:9][CH:10]=1)=[O:4].CO.[OH-].[Na+]>Cl>[CH3:1][N:2]([CH3:24])[C:3]([C:5]1[CH:6]=[C:7]([S:11]([NH:14][C:15]2[CH:19]=[CH:18][S:17][C:16]=2[C:20]([OH:22])=[O:21])(=[O:13])=[O:12])[CH:8]=[CH:9][CH:10]=1)=[O:4]
Reactant: COC(=O)c1sccc1NS(=O)(=O)c1cccc(C(=O)N(C)C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CN(C)C(=O)c1cccc(S(=O)(=O)Nc2ccsc2C(=O)O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.9 %

Procedure:
Methyl 3-(3-(dimethylcarbamoyl)phenylsulfonamido)thiophene-2-carboxylate (Int. 79, 200 mg, 0.543 mmol) was dissolved in MeOH (4 ml, 99 mmol). NaOH 1M (2 ml) was added, and the reaction was stirred at RT for 8 hours to achieve completion. The reaction mixture was diluted with HCl 1N and extracted with AcOEt. The organic phase was washed with HCl 1N and brine, dried over Na2SO4 and concentrated under vacuum to give 3-(3-(dimethylcarbamoyl)phenylsulfonamido)thiophene-2-carboxylic acid (Int. 80, 150 mg, 0.423 mmol).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]1.CCOCC.[ClH:27]>C(Cl)Cl>[ClH:27].[OH:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccccc2CO)CC1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: OCc1ccccc1C1CCNCC1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
260 mg (0.89 mmol) of 4-(2-hydroxymethylphenyl)-1-piperidinecarboxylic acid, 1,1-dimethylethyl ester were dissolved in 20 mL of CH2Cl2, 4 mL of a saturated Et2O/HCl solution were added and the reaction mixture was stirred at room temperature for 45 min. The solvent was removed in vacuo and the resulting crude solid was triturated with CH2Cl2, filtered and dried, yielding 180 mg of the title compound.
Reaction SMILES: Cl.C([O-])(=O)C.[F:6][C:7]1[C:8]([N:22]2[C:31]3[C:26](=[CH:27][C:28]([F:34])=[C:29]([F:33])[C:30]=3[Cl:32])[C:25](=[O:35])[C:24]([C:36]([O:38]CC)=[O:37])=[CH:23]2)=[N:9][C:10]([NH:13]C(C)(C)CC(C)(C)C)=[CH:11][CH:12]=1>>[NH2:13][C:10]1[N:9]=[C:8]([N:22]2[C:31]3[C:26](=[CH:27][C:28]([F:34])=[C:29]([F:33])[C:30]=3[Cl:32])[C:25](=[O:35])[C:24]([C:36]([OH:38])=[O:37])=[CH:23]2)[C:7]([F:6])=[CH:12][CH:11]=1
Reactant: CCOC(=O)c1cn(-c2nc(NC(C)(C)CC(C)(C)C)ccc2F)c2c(Cl)c(F)c(F)cc2c1=O
Agent: CC(=O)[O-]
Agent: Cl
Product: Nc1ccc(F)c(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Cl)c32)n1
Yield: 85.1 %

Procedure:
To 1.2 ml of the mixed solution of 4N hydrochloric acid and acetate (1:1) was added 235 mg of ethyl 1-[3-fluoro-6-(1,1,3,3-tetramethylbutylamino)pyridine-2-yl]-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate and the mixture was heated under reflux for 6 hours with stirring and allowed to cool. The precipitate was collected by filtration and washed with ethanol to obtain 145 mg of the title compound as a gray powder.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[NH:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1>>[N:10]1([C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=2)[CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: N#Cc1ccc(Cl)cc1
Reactant: C1CCNC1
Product: N#Cc1ccc(N2CCCC2)cc1
Temperature: 100 °C
Yield: 33 %

Procedure:
To commercially available 4-chlorobenzonitrile 17 (5 g, 36 mmol) 12 ml of pyrrolidine were added and the reaction was heated at 100° C. for 24 hours in closed vessel. The reaction was evaporated and the residue was dissolved in AcOEt and washed with water and brine. The purification of the crude residue by chromatographic column using AcOEt 1/Petroleum ether 9 as eluant gave 1.68 g of a pale yellow solid. Yield=33% 1HNMR (DMSO, 200 MHz) δ 1.96 (4H, m), 3.28 (4H, m), 6.58 (2H, d, J=9 Hz), 7.51 (2H, d, J=9 Hz)
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].Cl[C:9]1[N:10]=[C:11]([NH:33][C:34]2[CH:39]=[CH:38][N:37]=[CH:36][N:35]=2)[C:12]2[N:17]([CH2:18][CH2:19][O:20][CH2:21][C:22]([F:25])([F:24])[F:23])[N:16]=[C:15]([CH2:26][N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[C:13]=2[N:14]=1.[CH3:40][C@@H:41]1[CH2:46][NH:45][CH2:44][CH2:43][NH:42]1.C(N(CC)C(C)C)(C)C.FC(F)(F)C(O)=O>CS(C)=O>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:40][C@H:41]1[NH:42][CH2:43][CH2:44][N:45]([C:9]2[N:10]=[C:11]([NH:33][C:34]3[CH:39]=[CH:38][N:37]=[CH:36][N:35]=3)[C:12]3[N:17]([CH2:18][CH2:19][O:20][CH2:21][C:22]([F:25])([F:23])[F:24])[N:16]=[C:15]([CH2:26][N:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)[C:13]=3[N:14]=2)[CH2:46]1
Reactant: C[C@@H]1CNCCN1
Reactant: FC(F)(F)COCCn1nc(CN2CCOCC2)c2nc(Cl)nc(Nc3ccncn3)c21
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H]1CN(c2nc(Nc3ccncn3)c3c(n2)c(CN2CCOCC2)nn3CCOCC(F)(F)F)CCN1
Temperature: 110 °C
Yield: 109.9 %

Procedure:
5-Chloro-3-(morpholin-4-ylmethyl)-N-pyrimidin-4-yl-1-[2-(2,2,2-trifluoroethoxy)ethyl]-1H-pyrazolo[4,3-d]pyrimidin-7-amine trifluoroacetate (150 mg, 0.2 mmol), (R)(−)-2-methylpiperazine (86 mg, 0.85 mmol) and N,N-diisopropylethylamine (140 mg, 1.0 mmol) were mixed in methyl sulfoxide (1.0 ml) in a reaction vial. The reaction mixture was heated at 110° C. for 18 hours. The reaction was cooled to room temperature and brought to acidic condition by adding trifluoroacetic acid. The crude reaction mixture was purified on reverse phase HPLC (5-95% acetonitrile in water with 0.05% trifluoroacetic acid) and lyophilized to give 5-[(3R)-3-methylpiperazin-1-yl]-3-(morpholin-4-ylmethyl)-N-pyrimidin-4-yl-1-[2-(2,2,2-trifluoroethoxy)ethyl]-1H-pyrazolo[4,3-d]pyrimidin-7-amine trifluoroacetate (143 mg).
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH2:16])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(C(C)C)C(C)C)C.[F:26][C:27]([F:45])([F:44])[C:28]1[CH:29]=[C:30]([C:38]([CH3:43])([CH3:42])[C:39](Cl)=[O:40])[CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:33]=1>ClCCl>[C:1]1([S:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH:16][C:39](=[O:40])[C:38]([C:30]2[CH:29]=[C:28]([C:27]([F:26])([F:44])[F:45])[CH:33]=[C:32]([C:34]([F:35])([F:36])[F:37])[CH:31]=2)([CH3:43])[CH3:42])(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C(=O)Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: Nc1ccccc1S(=O)(=O)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C(=O)Nc1ccccc1S(=O)(=O)c1ccccc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.1 %

Procedure:
A solution of 233 mg (1.0 mmol) 2-aminophenyl phenyl sulfone and 0.25 ml (1.5 mmol) N-ethyldiisopropylamine in 2 ml dichloromethane was cooled in an ice bath and a solution of 350 mg (1.1 mmol) 2-(3,5-bis-trifluoromethyl-phenyl)-2-methyl-propionyl chloride in 1 ml dichloromethane was added dropwise. The reaction mixture was stirred at room temperature overnight, evaporated and the residue was purified by flash chromatography to give 490 mg (95%) of the title compound as a pale yellow oil.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[C:6]([CH:15]([OH:17])[CH3:16])=[CH:7][C:8]([C:11]([F:14])([F:13])[F:12])=[N:9][CH:10]=1.C([O-])(O)=O.[Na+].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[CH3:1][O:2][CH2:3][O:4][C:5]1[C:6]([C:15](=[O:17])[CH3:16])=[CH:7][C:8]([C:11]([F:14])([F:12])[F:13])=[N:9][CH:10]=1
Reactant: COCOc1cnc(C(F)(F)F)cc1C(C)O
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COCOc1cnc(C(F)(F)F)cc1C(C)=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred mixture of 1-(5-(methoxymethoxy)-2-(trifluoromethyl)pyridin-4-yl)ethanol (3.2 g, 13 mmol) and NaHCO3 (3.2 g, 38 mmol) in DCM (100 ml) was added Dess Martin Periodinane (5.9 g, 14 mmol). The reaction mixture was stirred at rt in 16 h, the solid was filtered, the filtrate was concentrated, then taken up and stirred in ether/EtOAc.