Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([C@H:13]([O:15][C@H:16]2[O:21][CH2:20][CH2:19][N:18]([CH2:22][C:23]#[C:24][CH2:25]Cl)[C@H:17]2[C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[N-:36]=[N+:37]=[N-:38].[Na+].[Cl-].[NH4+].C(OCC)(=O)C>CS(C)=O>[N:36]([CH2:25][C:24]#[C:23][CH2:22][N:18]1[CH2:19][CH2:20][O:21][C@H:16]([O:15][C@@H:13]([C:5]2[CH:4]=[C:3]([C:2]([F:35])([F:34])[F:1])[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=2)[CH3:14])[C@@H:17]1[C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=1)=[N+:37]=[N-:38]
Reactant: [N-]=[N+]=[N-]
Reactant: C[C@@H](O[C@H]1OCCN(CC#CCCl)[C@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: C[C@@H](O[C@H]1OCCN(CC#CCN=[N+]=[N-])[C@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 20 h

Procedure:
To a solution of 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl) ethoxy)-3-(S)-(4-fluorophenyl)-4-(4-chlorobut -2-ynyl)morpholine (4 g) in dimethyl sulphoxide (17 ml) was added sodium azide (0.562 g). The solution was stirred for 20 h and aqueous ammonium chloride and ethyl acetate were added. The organic phase was washed with water (2 times), saturated brine and dried (MgSO4). The solvent was removed in vacuo and the residue chromatographed on silica gel (eluting with 20% ethyl acetate in petroleum ether bp 60°-80° C.) to give the title compound. 1H NMR (360 MHz, CDCl3) δ 1.48 (3H, s, J=6.6 Hz), 2.87 (1H, app t, J=10.2 Hz), 2.98 (1H, td, J=3.6, 11.7 Hz), 3.35 (2H, t, J=1.9 Hz), 3.61 (1H, d, J=2.8 Hz), 3.72 (1H, dq, J=1.4 Hz, 10.0 Hz), 3.92 (2H, t, J=1.9 Hz), 4.30-4.40 (2H, m), 4.89(1H, q, J=6.6 Hz), 7.03 (2H, t, J=8.7 Hz), 7.17 (2H, s), 7.27 (2H, br s), 7.63 (1H, s).
Reaction SMILES: [C:1](O)(=O)[CH2:2][C:3]([OH:5])=[O:4].N1CCCCC1.[S:14]1[CH:18]=[CH:17][C:16](C=O)=[CH:15]1.Cl>N1C=CC=CC=1>[S:14]1[CH:18]=[CH:17][C:16](/[CH:1]=[CH:2]/[C:3]([OH:5])=[O:4])=[CH:15]1
Reactant: O=Cc1ccsc1
Reactant: O=C(O)CC(=O)O
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: O=C(O)/C=C/c1ccsc1
Temperature: 100 °C

Procedure:
46 g of malonic acid and 2 ml of piperidine are added to 25 g of 3-thienaldehyde in solution in 100 ml of pyridine, and the mixture is heated at 100° C. for 4 hours. The reaction medium is cooled to 30° C. and it is poured over an aqueous hydrochloric acid solution (2N). The precipitate formed is filtered and it is rinsed with isopropyl ether to give, after drying, 30 g of a white solid.
Reaction SMILES: [C:1]([C:4]1([OH:19])[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:18])[C:15]([CH3:17])=[CH2:16])=[CH:9][CH:5]1[C:6]([OH:8])=[O:7])(=[O:3])[CH3:2].C1(N=C=NC2CCCCC2)CCCCC1.ON1C(=O)CCC1=O.[C:43](O)(=O)[C:44]1[C:45](=[CH:47][CH:48]=[CH:49][CH:50]=1)[OH:46].NC(N)=O.C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[C:1]([C:4]1([OH:19])[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:18])[C:15]([CH3:17])=[CH2:16])=[CH:9][CH:5]1[C:6]([O:8][CH2:43][C:44]1[C:45](=[CH:47][CH:48]=[CH:49][CH:50]=1)[OH:46])=[O:7])(=[O:3])[CH3:2]
Reactant: C=C(C)C(=O)NC1=CC(C(=O)O)C(O)(C(C)=O)C=C1
Reactant: O=C(O)c1ccccc1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: NC(N)=O
Agent: O=C1CCC(=O)N1O
Solvent: ClCCl
Product: C=C(C)C(=O)NC1=CC(C(=O)OCc2ccccc2O)C(O)(C(C)=O)C=C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-acetyl-5-methacrylamidosalicylic acid (1 part by mole), dicyclohexyl carbodiimide (1.1 part by mole) in dry dichloromethane is added N-hydroxysuccinimide. To the solution is further added salicylic acid (1.1 part by mole). The solution is stirred at room temperature overnight. After the reaction, the precipitate including dicyclohexyl carbodiimide urea is removed by filtration. The solution is washed by distilled water three times, by an aqueous solution of 5% by weight of acetic acid three times, and further by distilled water three times. The solution is filtrated again to remove the precipitate. The solvent is removed by evaporation, and the residue is recrystallized to give salicyl 2-acetyl-5-methacrylamidosalicylate.
Reaction SMILES: C[O:2][C:3](=[O:16])[CH2:4][C:5]1[CH:14]=[C:13]([OH:15])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=1.F[C:18]1[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][CH:19]=1>C(O)(=O)C>[CH3:27][S:24]([C:21]1[CH:22]=[CH:23][C:18]([O:15][C:13]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH:6]=[C:5]([CH2:4][C:3]([OH:2])=[O:16])[CH:14]=2)=[CH:19][CH:20]=1)(=[O:26])=[O:25]
Reactant: CS(=O)(=O)c1ccc(F)cc1
Reactant: COC(=O)Cc1cc(O)c2ccccc2c1
Solvent: CC(=O)O
Product: CS(=O)(=O)c1ccc(Oc2cc(CC(=O)O)cc3ccccc23)cc1

Procedure:
Starting with (4-hydroxy-naphthalen-2-yl)-acetic acid methyl ester (108 mg, 0.5 mmol) and 1-fluoro-4-methanesulfonyl-benzene (174 mg, 1.0 mmol), using a method analogous to the one described for example 1-1, the final two steps), 4-(4-methanesulfonyl-phenoxy)-naphthalen-2-yl]-acetic acid (65.8 mg, 37%) was obtained as a white solid. 1H NMR (400 MHz, CD3OD) δ ppm 7.89-7.94 (m, 4H), 7.71 (s, 1H), 7.54 (dt, J=8.08, 4.04 Hz, 1H), 7.48 (s, 2H), 7.14-7.19 (m, 3H), 3.80 (s, 2H), 3.11 (s, 3H); MS cald. for C19H16O5S 356, obsd. (ESI+) [(M+H)+] 357.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:10]=[C:9]([SH:11])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:4])[CH3:3].[CH2:17]([C:19]([CH:21]=[CH2:22])=[O:20])[CH3:18].C(N(CC)CC)C>CO>[CH3:4][C:2]([C:5]1[CH:10]=[C:9]([S:11][CH2:18][CH2:17][C:19](=[O:20])[CH2:21][CH3:22])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:1])[CH3:3]
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Reactant: C=CC(=O)CC
Solvent: CCN(CC)CC
Solvent: CO
Product: CCC(=O)CCSc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1

Procedure:
The title compound of Example 2 (5.0 g, 0.021 mole) was reacted with ethylvinyl ketone (6.3 ml) and triethylamine (1 ml) in methanol (30 ml) by the method of Example 3 to give the title compound, m.p. ca. 76°-79° C. Analysis calc. for C19H30O2S(332.50):
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[C:6](=[O:23])[N:7]([CH:15]1[CH2:20][CH2:19][C:18](=[O:21])[NH:17][C:16]1=[O:22])[C:8]([CH3:14])=[N:9]2.[F:24][C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=1)[C:28](Cl)=[O:29].C(N(CC)C(C)C)(C)C>C(#N)C>[O:22]=[C:16]1[CH:15]([N:7]2[C:6](=[O:23])[C:5]3[C:10](=[CH:11][CH:12]=[CH:13][C:4]=3[CH2:3][NH:2][C:28](=[O:29])[C:27]3[CH:31]=[CH:32][CH:33]=[C:25]([F:24])[CH:26]=3)[N:9]=[C:8]2[CH3:14])[CH2:20][CH2:19][C:18](=[O:21])[NH:17]1
Reactant: Cc1nc2cccc(CN)c2c(=O)n1C1CCC(=O)NC1=O
Reactant: O=C(Cl)c1cccc(F)c1
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc2cccc(CNC(=O)c3cccc(F)c3)c2c(=O)n1C1CCC(=O)NC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.9 %

Procedure:
To a stirred mixture of 3-(5-aminomethyl-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione hydrogen chloride (0.47 g, 1.4 mmol) in acetonitrile (10 mL), was added 3-fluoro-benzoyl chloride (0.25 mL, 2.1 mmol) and N,N-diisopropyl ethylamine (0.61 mL, 3.5 mmol). The mixture was stirred at room temp overnight. The solvent was evaporated, and the residue was purified by flash column chromatography (Silica gel, methanol/methylene chloride 4%/96%) to give N-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-5-ylmethyl]-3-fluoro-benzamide as a white solid (230 mg, 40% yield); HPLC, Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 10/90 CH3CN/0.1% H3PO4, gradient to 95/5 in 5 min, kept for 5 min, 5.80 min (98.8%); mp, 240-242° C.; 1HNMR (DMSO-d6) 2.18-2.24 (m, 1H, CHH), 2.59-2.93 (m, 6H, CHCH2, CH3), 4.93-5.10 (m, 2H, CH2NH), 5.28 (dd, J=6, 11 Hz, 1H, CH), 7.36-7.80 (m, 7H, Ar), 9.08 (t, 1H, J=6 Hz, CH2NH), 11.06 (s, 1H, NH); 13C NMR (DMSO-d6) δ 20.79, 23.07, 30.58, 42.16, 56.58, 113.94, 114.24, 117.52, 118.09, 118.36, 123.38, 123.41, 124.16, 124.99, 130.52, 130.62, 134.12, 136.52, 136.61, 140.79, 147.84, 155.29, 160.39, 160.90, 163.62, 164.99, 165.02, 169.45, 172.60. LCMS MH=423; Anal Calcd For C22H19N4O4F+0.4H2O: C, 61.51; H, 4.65; N, 13.04; F, 4.42. Found: C, 61.32; H, 4.44; N, 12.97; F, 4.27.
Reaction SMILES: [NH:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][CH:14]([N:17]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH3:18])[CH2:13][CH2:12]2)=[CH:7][CH:6]=1)C(C)=O>[OH-].[Na+].CO>[NH2:1][C:5]1[CH:6]=[CH:7][C:8]([N:11]2[CH2:12][CH2:13][CH:14]([N:17]([CH2:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH3:18])[CH2:15][CH2:16]2)=[CH:9][CH:10]=1
Reactant: CC(=O)Nc1ccc(N2CCC(N(C)Cc3ccccc3)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CN(Cc1ccccc1)C1CCN(c2ccc(N)cc2)CC1
Yield: 58.1 %

Procedure:
5.5 g (16.3 mmol) of the product from Example 7 were refluxed in a mixture of 100 ml of 2M sodium hydroxide solution and 200 ml of methanol for 12 h. The reaction mixture was then concentrated under reduced pressure, the residue was partitioned between water and methylene chloride, and the organic phase was dried and concentrated under reduced pressure. 2.8 g of 1-(4-aminophenyl)-4-(N-benzyl-N-methylamino)piperidine were obtained as an oil which crystallized as difumarate. Melting point 138° C.
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([N:12]2[CH2:17][CH2:16][S:15](=[O:19])(=[O:18])[CH2:14][CH2:13]2)[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:8]1[CH2:11][CH:10]([N:12]2[CH2:17][CH2:16][S:15](=[O:19])(=[O:18])[CH2:14][CH2:13]2)[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CC(N2CCS(=O)(=O)CC2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=S1(=O)CCN(C2CNC2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.4 %

Procedure:
A mixture of 3-(1,1-dioxo-1-thiomorpholin-4-yl)-azetidine-1-carboxylic acid tert-butyl ester (3.35 g, 11.5 mmol) and TFA (15 mL) in DCM (30 mL) was stirred at room temperature for 2 h. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH/DCM and the product eluted with 2M NH3/MeOH affording 4-Azetidin-3-yl-thiomorpholine 1,1-dioxide as a white solid (2.0 g, 91%). 1H NMR (CDCl3, 300 MHz): δ 3.64-3.53 (m, 4H); 3.49-3.39 (m, 1H); 3.08 (m, 4H); 2.86-2.79 (m, 4H); 1.83 (s, 1H).
Reaction SMILES: [OH-].[Li+].[CH:3]([N:16]1[CH2:21][CH2:20][N:19]([CH2:22][C:23]([O:25]C)=[O:24])[CH2:18][CH2:17]1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>C1COCC1.O>[CH:3]([N:16]1[CH2:17][CH2:18][N:19]([CH2:22][C:23]([OH:25])=[O:24])[CH2:20][CH2:21]1)([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: COC(=O)CN1CCN(C(c2ccccc2)c2ccccc2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CN1CCN(C(c2ccccc2)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
An aqueous solution of lithium hydroxide (486 mg, 11.58 mmol, 2 ml water) was added to a solution of (4-benzhydrylpiperazin-1-yl)-acetic acid, methyl ester (2.5 g, 7.72 mmol) in a 5:1 mixture of THF/water (20 ml). The reaction was stirred at room temperature overnight. THF was removed under reduced pressure. The reaction mixture was partitioned between ethyl acetate and water. The aqueous layer was separated and neutralised to pH7 with 1M HCI. A white gelatinous precipitate of (4-benzhydrylpiperazin-1-yl)-acetic acid was formed which was collected by filtration and dried (1.10 g, 46%).
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[C:44]2[C:39](=[CH:40][CH:41]=[C:42]([Cl:45])[CH:43]=2)[C:17]2([CH:22]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=3)[CH2:21][C:20](=[O:30])[N:19]([CH3:31])[CH:18]2[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[CH3:38])[C:16]1=[O:46])=O)(C)(C)C>ClCCl>[Cl:45][C:42]1[CH:43]=[C:44]2[NH:15][C:16](=[O:46])[C:17]3([CH:22]([C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=4)[CH2:21][C:20](=[O:30])[N:19]([CH3:31])[CH:18]3[C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[CH3:38])[C:39]2=[CH:40][CH:41]=1
Reactant: Cc1ccccc1C1N(C)C(=O)CC(c2cccc(Cl)c2)C12C(=O)N(C(=O)OC(C)(C)C)c1cc(Cl)ccc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccccc1C1N(C)C(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 46 %

Procedure:
Trifluoroacetic acid (5 mL) was added to a solution of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2,3-dihydro-1′-methyl-2′-(2-methylphenyl)-2,6′-dioxospiro[indole-3,3′-piperidine]-1-carboxylic acid tert-butyl ester (0.20 g, 0.35 mmol) prepared in example 24c in dichloromethane (10 mL). The mixture was stirred at room temperature for 1 h. The solvent was evaporated in vacuo. To this residue was added saturated NaHCO3 solution, and extracted with ethyl acetate. The organic layers were combined, washed with water and brine, dried over MgSO4. The solvent was removed and the residue was purified by chromatography (EtOAc:CH2Cl2=1:4) to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-1′-methyl-2′-(2-methylphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (Yield: 0.075 g, 46%).
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([O:11][CH3:12])=[N:10][C:5]2=[N:4][CH:3]=1.CC1(C)C(C)(C)OB([C:21]2[CH:22]=[C:23]([C:27]3[C:28]([C:33]#[N:34])=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:24]=[CH:25][CH:26]=2)O1>>[CH3:12][O:11][C:9]1[CH:8]=[CH:7][N:6]2[C:2]([C:25]3[CH:24]=[C:23]([C:27]4[C:28]([C:33]#[N:34])=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH:22]=[CH:21][CH:26]=3)=[CH:3][N:4]=[C:5]2[N:10]=1
Reactant: COc1ccn2c(Br)cnc2n1
Reactant: CC1(C)OB(c2cccc(-c3ccccc3C#N)c2)OC1(C)C
Product: COc1ccn2c(-c3cccc(-c4ccccc4C#N)c3)cnc2n1
Yield: 66 %

Procedure:
3-Bromo-7-methoxyimidazo[1,2-a]pyrimidine (0.48 g, 2.12 mmol) was coupled with 3′-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)biphenyl-2-carbonitrile as described in Example 1 to give 3′-(7-methoxyimidazo[1,2-a]pyrimidin-3-yl)biphenyl-2-carbonitrile (458 mg, 66%) as a white powder: δH (400 MHz, CDCl3) 4.08 (3H, s), 6.49 (1H, d, J 7), 7.50 (1H, td, J 8 and 1), 7.51-7.71 (8H, m), 7.81 (1H, dd, J 8 and 1), 8.66 (1H, d, J 7); m/z (ES+) 327 (M++H).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([C:12]1[CH:37]=[CH:36][C:15]([O:16][C:17]2[C:22]([C:23]3[CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH:24]=3)=[CH:21][N:20]=[CH:19][N:18]=2)=[CH:14][CH:13]=1)=[O:11].Cl>C(O)=O>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([C:12]1[CH:37]=[CH:36][C:15]([O:16][C:17]2[C:22]([C:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH:24]=3)=[CH:21][N:20]=[CH:19][N:18]=2)=[CH:14][CH:13]=1)=[O:11]
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cncnc2Oc2ccc(C(=O)c3nc4ccccc4[nH]3)cc2)CC1
Agent: Cl
Solvent: O=CO
Product: O=C(c1ccc(Oc2ncncc2C2=CCNCC2)cc1)c1nc2ccccc2[nH]1

Procedure:
To a round bottom was added tert-butyl 4-(4-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)pyrimidin-5-yl)-5,6-dihydropyridine-1(2H)-carboxylate (500 mg, 1.005 mmol), formic acid (10 ml), and hydrochloric acid, 5.0N (0.256 ml, 7.03 mmol) with stirring. The reaction was quenched after 15 minutes with saturated aqueous sodium bicarbonate and extracted with dichloromethane before drying over sodium sulfate, filtering, and concentrating under reduced pressure, affording (1H-benzo[d]imidazol-2-yl)(4-(5-(1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-4-yloxy)phenyl)methanone as a pale yellow solid. IC50 (uM) +++++.
Reaction SMILES: Cl.[CH2:2]([N:4]([C:12]1[N:17]=[CH:16][N:15]=[C:14]2[N:18]([C:21]3[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][C:22]=3[F:31])[N:19]=[CH:20][C:13]=12)[CH2:5][CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)[CH3:3].Br[C:33]1[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:35][N:34]=1.C(N(CC)CC)C>CN(C=O)C>[CH2:2]([N:4]([C:12]1[N:17]=[CH:16][N:15]=[C:14]2[N:18]([C:21]3[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][C:22]=3[F:31])[N:19]=[CH:20][C:13]=12)[CH2:5][CH:6]1[CH2:7][CH2:8][N:9]([C:33]2[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:35][N:34]=2)[CH2:10][CH2:11]1)[CH3:3]
Reactant: CCN(CC1CCNCC1)c1ncnc2c1cnn2-c1ccc(S(C)(=O)=O)cc1F
Reactant: FC(F)(F)c1ccc(Br)nc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCN(CC1CCN(c2ccc(C(F)(F)F)cn2)CC1)c1ncnc2c1cnn2-c1ccc(S(C)(=O)=O)cc1F
Temperature: 165 °C
Yield: 51.4 %

Procedure:
A mixture of ethyl-[1-(2-fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]-piperidin-4-ylmethyl-amine hydrochloride salt (30 mg, 0.064 mmol), 2-bromo-5-trifluoromethylpyridine (188 mg, 0.83 mmol), and triethylamine (27 μL, 0.19 mmol) in DMF (1.0 mL) was heated under microwave irradiation for 20 minutes at 165° C. The crude mixture was purified by HPLC to provide compound A127 as a white solid (19 mg, 51%). Exact mass calculated for C26H27F4N7O2S 557.19, found 578.3 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:15]3[C:10]([CH:11]=[CH:12][CH:13]=[CH:14]3)=[N:9]2)=[CH:4][CH:3]=1.[CH3:24][O:25][C:26](=[O:37])[C:27]1[CH:32]=[CH:31][C:30]([N:33]=[C:34]=[O:35])=[C:29]([Cl:36])[CH:28]=1>C1(C)C=CC=CC=1>[CH3:24][O:25][C:26](=[O:37])[C:27]1[CH:32]=[CH:31][C:30]([NH:33][C:34]([N:17]([C:16]2[N:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[N:9]=[C:10]3[C:15]=2[CH:14]=[CH:13][CH:12]=[CH:11]3)[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[O:35])=[C:29]([Cl:36])[CH:28]=1
Reactant: COC(=O)c1ccc(N=C=O)c(Cl)c1
Reactant: Clc1ccc(-n2nc3ccccc3c2Nc2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(NC(=O)N(c2ccccc2)c2c3ccccc3nn2-c2ccc(Cl)cc2)c(Cl)c1

Procedure:
In analogy to the procedure described in example 1.2, [2-(4-chloro-phenyl)-2H-indazol-3-yl]-phenyl-amine (example 15.1) was reacted with 3-chloro-4-isocyanato-benzoic acid methyl ester (example 9.1) in toluene for 7 days under reflux conditions to give the title compound as yellow foam. MS: m/e=530.7 [M+H+].
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH2:23][CH3:24])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[CH3:25][N:26]1[C:30](=[O:31])[CH2:29][NH:28][C:27]1=[O:32]>>[CH2:23]([C:19]1[CH:20]=[C:21]([CH3:22])[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:4]=[CH:3][C:2]([N:28]4[CH2:29][C:30](=[O:31])[N:26]([CH3:25])[C:27]4=[O:32])=[N:7][CH:6]=3)=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=1)[CH3:24]
Reactant: CN1C(=O)CNC1=O
Reactant: CCc1cnc(N2CCN(C(=O)c3ccc(Br)nc3)CC2)c(C)c1
Product: CCc1cnc(N2CCN(C(=O)c3ccc(N4CC(=O)N(C)C4=O)nc3)CC2)c(C)c1
Yield: 36 %

Procedure:
Using (6-bromopyridin-3-yl) [4-(5-ethyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (156 mg) described in Preparation Example 145 and 3-methylimidazolidine-2,4-dione (68 mg) described in Preparation Example 214 and by the reaction and treatment in the same manner as in Example 536, the title compound (61 mg) was obtained.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH2:10])=[C:4]([NH2:9])[C:5]([Br:8])=[CH:6][CH:7]=1.[N+:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([O-])=O.[OH-].[Na+]>ClCCl>[Br:1][C:2]1[C:3]([N:10]=[N:11][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:4]([NH2:9])[C:5]([Br:8])=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccccc1
Reactant: Nc1c(Br)ccc(Br)c1N
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: Nc1c(Br)ccc(Br)c1N=Nc1ccccc1
Temperature: 160 °C
Yield: 3.5 %

Procedure:
3,6-dibromo-1,2-phenylenediamine (1.33 g, 5.0 mmol), nitrobenzene (2.06 mL, 20 mmol), and sodium hydroxide (0.20 g, 5 mmol) were mixed in an 1-neck 100-mL round bottomed flask. The flask was heated in an oil bath at 160° C. for 3 h. The mixture was cooled to room temperature and dichloromethane was added to extract the product. The extract was filtered and the solution concentrated using a rotary evaporator. The solution was chromatographed on a silica gel column using dichloromethane as eluent. The fractions were combined and solvent removed under reduced pressure. The solid was further dried under high vacuum for 1 h. Yield: 3.5%.
Reaction SMILES: [O:1]1CCO[CH:2]1[C:6]1[CH:21]=[CH:20][C:9]([O:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]([NH2:19])=[O:18])=[N:15][CH:16]=2)=[C:8]([F:22])[CH:7]=1>C(O)=O.O>[F:22][C:8]1[CH:7]=[C:6]([CH:2]=[O:1])[CH:21]=[CH:20][C:9]=1[O:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]([NH2:19])=[O:18])=[N:15][CH:16]=1
Reactant: NC(=O)c1ccc(Oc2ccc(C3OCCO3)cc2F)cn1
Solvent: O
Solvent: O=CO
Product: NC(=O)c1ccc(Oc2ccc(C=O)cc2F)cn1
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 99.4 %

Procedure:
Take up 5-(4-[1,3]dioxolan-2-yl-2-fluorophenoxy)pyridine-2-carboxamide (0.316 g, 1.04 mmol) in 88% formic acid (5.2 mL). Stir at room temperature for 1.25 hours before diluting with water. Extract with dichloroethane (2× 50 mL). Wash the organic layer with brine (1× 25 mL), dry over Na2SO4, filter and concentrate to give the title compound (0.269 g, 99.6%): TOF MS ES+ 261.1 (M+H)+, HRMS calcd for C13H10N2O3F 261.0675 (M+H)+, found 261.0682, time 0.37 min; HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), 0.1% TFA/acetonitrile in 0.1% TFA/water at 1.0 mL/min, 20-99% over 23 min], tR 9.0 min, 100% purity.
Reaction SMILES: [Br:1]Br.[F:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10]>C(O)(=O)C>[Br:1][C:8]1[CH:7]=[CH:6][C:5]([OH:10])=[C:4]([F:3])[CH:9]=1
Reactant: Oc1ccccc1F
Reactant: BrBr
Solvent: CC(=O)O
Product: Oc1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.1 %

Procedure:
Bromine (68.7 ml, 1.339 mol) dissolved in acetic acid (300 ml) was added drop by drop to a cooled solution of 2-fluorophenol (150 g, 1.339 mol) in acetic acid (1300 ml) and the reaction mixture was stirred at room temperature overnight. The reaction mixture was quenched with aq. sodium bisulfite solution and extracted with dichloromethane. The organic layer was washed with water and brine and dried over sodium sulfate. Solvent evaporation under reduced pressure afforded 4-bromo-2-fluorophenol (210 g) as a liquid. This was directly taken for next step without further purification.
Reaction SMILES: [C:1]([O:7][CH2:8][CH:9]([CH3:11])[CH3:10])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].O.[Cl-].[C:14]1([N+:20]#[N:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(O)C>[C:14]1([NH:20][N:21]=[C:2]([C:3](=[O:4])[CH3:5])[C:1]([O:7][CH2:8][CH:9]([CH3:11])[CH3:10])=[O:6])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: N#[N+]c1ccccc1
Reactant: CC(=O)CC(=O)OCC(C)C
Agent: [Cl-]
Solvent: O
Solvent: CCO
Product: CC(=O)C(=NNc1ccccc1)C(=O)OCC(C)C
Yield: 88.1 %

Procedure:
15.8 g (0.1 mol) of i-butyl acetoacetate, 12 g (0.146 mol) of CH3 COONa, 20 ml of water, 75 ml of ethanol and a solution of 0.1 mol of phenyldiazonium chloride were treated as described in preparation 2. The precipitated solid was filtered an dried in vacuo yielding 23.1 g of the title compound. M.p.=45°-50° C.
Reaction SMILES: [NH2:1][NH2:2].Cl.[C:4]([CH:6]1[C:10](=O)[CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]1)#[N:5]>C(O)C.C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>[NH2:5][C:4]1[C:6]2[CH2:7][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:9][C:10]=2[NH:1][N:2]=1
Reactant: CC(C)(C)OC(=O)N1CC(=O)C(C#N)C1
Reactant: NN
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1Cc2[nH]nc(N)c2C1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of anhydrous hydrazine (0.082 mL) in ethanol (6.5 mL) was added hydrogen chloride (1.43 mL, 2N solution in diethyl ether). The reaction mixture was stirred for 5 min, then tert-butyl 3-cyano-4-oxopyrrolidine-1-carboxylate was added and the mixture heated to reflux. After 1 h the mixture was cooled to ambient temperature and diluted with a mixture of ethyl acetate and saturated aqueous sodium bicarbonate solution (1:1, 20 mL). The layers were separated and the aqueous phase extracted with ethyl acetate (3×15 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered and evaporated in vacuo. The residue was purified on a Biotage Horizon® system (silica gel, 0 to 100% ethyl acetate/hexanes followed by 0 to 20% methanol/ethyl acetate gradient) to give the title compound. LC/MS 225.2 (M+1).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][CH2:8][CH2:9][C:10](O)=[O:11].[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][OH:11]
Reactant: O=C(O)CCCCc1ccco1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCCCCCc1ccco1
Yield: 92.8 %

Procedure:
5-(2-Furanyl)pentanoic acid (60.4 g) was reduced with 13.7 g of lithium aluminum hydride in 400 ml of tetrahydrofuran, heated at reflux for about 16 hours. The product was isolated and purified by distillation to give 51.4 g of 5-(2-furanyl)pentanol, b.p. 70°-73° C. (0.1 mm).