Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I-].[C:2]([NH:10][C:11]1[CH:16]=[CH:15][N+:14]([CH2:17][CH3:18])=[CH:13][C:12]=1[F:19])(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[BH4-].[Na+].[Cl-].[NH4+].C(=O)(O)[O-].[Na+]>CO>[CH2:17]([N:14]1[CH2:15][CH2:16][C:11]([NH:10][C:2](=[O:9])[C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)=[C:12]([F:19])[CH2:13]1)[CH3:18]
Reactant: CC[n+]1ccc(NC(=O)c2ccccc2)c(F)c1
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Cl-]
Solvent: CO
Product: CCN1CCC(NC(=O)c2ccccc2)=C(F)C1
Reaction time: 1 h
Yield: 78.2 %

Procedure:
A solution of 4-benzamido-1-ethyl-3-fluoro-pyridinium iodide (6.45 kg, 17.3 mol) in methanol (40 L) was charged with sodium borohydride (1.82 kg, 43.3 mol) via portion-wise addition over five to six hours maintaining an internal reaction temperature between −5° C. and 10° C. Following this addition saturated aqueous ammonium chloride (10 L) was added and the reaction mixture stirred for 1 h, and then saturated aqueous sodium bicarbonate (12 L) was added and the mixture was left to stand overnight. Methanol was removed under vacuum and the resulting aqueous solution was extracted with ethyl acetate (3×30 L), washed with water, brine and dried over sodium sulfate. The concentrated organic layer yielded 3.36 kg of N-(1-ethyl-3-fluoro-1,2,5,6-tetrahydro-pyridin-4-yl)benzamide (78%). 1H NMR (400 MHz, CDCl3) δ 7.78 (2H, d, J=7.7 Hz), 7.48 (4H, dq, J=14.9, 7.4 Hz), 3.17 (2H, s), 2.89 (2H, s), 2.65 (2H, t, J=5.6 Hz), 2.55 (2H, q, J=7.1 Hz), 1.13 (3H t, J=7.2 Hz).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:15]([CH3:16])=[CH:14][C:13]([O:17][CH:18]([C:22]3[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][CH:23]=3)[CH:19]([CH3:21])[CH3:20])=[CH:12][C:11]=2[CH3:31])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:39][O:40][C:41](=[O:46])[CH:42]([OH:45])[CH2:43][NH2:44].CCN=C=NCCCN(C)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:39][O:40][C:41](=[O:46])[CH:42]([OH:45])[CH2:43][NH:44][C:26](=[O:27])[C:25]1[CH:29]=[CH:30][C:22]([CH:18]([O:17][C:13]2[CH:14]=[C:15]([CH3:16])[C:10]([C:7]3[CH:6]=[CH:5][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:9][CH:8]=3)=[C:11]([CH3:31])[CH:12]=2)[CH:19]([CH3:21])[CH3:20])=[CH:23][CH:24]=1
Reactant: COC(=O)C(O)CN
Reactant: Cc1cc(OC(c2ccc(C(=O)O)cc2)C(C)C)cc(C)c1-c1ccc(C(C)C)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C(O)CNC(=O)c1ccc(C(Oc2cc(C)c(-c3ccc(C(C)C)cc3)c(C)c2)C(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 4-[1-(4′-isopropyl-2,6-dimethyl-biphenyl-4-yloxy)-2-methyl-propyl]-benzoic acid (150 mg, 0.36 mmol) in methylene chloride (4 mL) is added triethyl amine (0.15 mL, 1.08 mmol), DMAP (5.0 mg), 3-Amino-2-hydroxy-propionic acid methyl ester (83 mg, 0.54 mmol) and EDCI (208 mg, 1.08 mmol) at room temperature. The reaction mixture is stirred at room temperature overnight, loaded on silica gel, eluted with eluted with hexanes with a gradient from 0% of ethyl acetate to 100% of ethyl acetate giving the titled compound (150 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][C:9]([CH:11]3[CH2:16][CH2:15][N:14]([C:17](OC(C)(C)C)=O)[CH2:13][CH2:12]3)=[CH:10][C:3]=12.FC(F)(F)C(O)=O.C=O.C([BH3-])#N.[Na+]>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][C:9]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:10][C:3]=12
Reactant: CC(C)(C)OC(=O)N1CCC(c2cc3c(Cl)ccnc3[nH]2)CC1
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN1CCC(c2cc3c(Cl)ccnc3[nH]2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of Example 17E (200 mg, 0.6 mmol) in dichloromethane (10 mL) was added 0.5 mL trifluoroacetic acid and the mixture was stirred at room temperature for 2 hours. The mixture was concentrated, dissolved in dichloromethane (20 mL), washed with sodium bicarbonate solution and concentrated. The residue was dissolved in methanol (2 mL) and treated with formaldehyde (120 mg, 37% in water) and sodium cyanoborohydride (57 mg, 0.9 mmol). The mixture was stirred at room temperature for 2 hours, diluted with dichloromethane and the organic phase was washed with water and concentrated to afford the title compound. LCMS: 250 (M+H)+.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([N:5]2[C:9]3=[N:10][CH:11]=[N:12][C:13]([NH2:14])=[C:8]3[C:7]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:17][CH:16]=3)=[N:6]2)[CH2:2]1.[O:28]1[C:30]2([CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:32][CH2:31]2)[CH2:29]1>C(O)(C)C>[NH2:14][C:13]1[N:12]=[CH:11][N:10]=[C:9]2[N:5]([CH:3]3[CH2:2][N:1]([CH2:29][C:30]4([OH:28])[CH2:31][CH2:32][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:34][CH2:35]4)[CH2:4]3)[N:6]=[C:7]([C:15]3[CH:16]=[CH:17][C:18]([O:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:19][CH:20]=3)[C:8]=12
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CO2
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)nn2C1CNC1
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)N1CCC(O)(CN2CC(n3nc(-c4ccc(Oc5ccccc5)cc4)c4c(N)ncnc43)C2)CC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 38.6 %

Procedure:
To a mixture of 1-(3-azetanyl)-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.4 g, 0.0011 mol) in isopropanol (40 mL) was added tert-butyl 1-oxa-6-azaspiro[2.5]octane-6-carboxylate (0.27 g, 0.0013 mol) at room temperature under an atmosphere of nitrogen. The mixture was stirred at 80° C. for three and a half hours. Additional tert-butyl 1-oxa-6-azaspiro[2.5]octane-6-carboxylate (0.13 g, 0.00061 mol) was added and the mixture was stirred at 80° C. for seven hours. Furthermore, tert-butyl 1-oxa-6-azaspiro[2.5]octane-6-carboxylate (0.13 g, 0.00061 mol) was added and the mixture was stirred at 60° C. for 18 hours, then 80° C. for eight hours. The solvent was removed under reduced pressure. The residue was suspended in water (50 mL) and the aqueous phase was extracted with ethyl acetate (2×50 mL). The combined organic extracts were washed with water (1×50 mL) and brine (1×50 mL) and dried over magnesium sulfate. The solvent was removed under reduced pressure. The residue was purified by flash chromatography on silica gel using methanol/dichloromethane (5:95) followed by methanol/dichloromethane (10:90) as mobile phase to yield tert-butyl 4-(3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-azetanylmethyl)-4-hydroxy-1-piperidinecarboxylate (0.243 g, 0.000425 mol).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]2[CH2:17][CH2:18][CH:19]([CH2:21][C:22]3[O:23][CH2:24][C:25](C)(C)N=3)[S:20][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[OH:30].[Na+]>S(=O)(=O)(O)O.C(O)C>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]2[CH2:17][CH2:18][CH:19]([CH2:21][C:22]([O:23][CH2:24][CH3:25])=[O:30])[S:20][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(C)COC(CC2CCc3c(n(Cc4ccccc4)c4ccccc34)S2)=N1
Reactant: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CC1CCc2c(n(Cc3ccccc3)c3ccccc23)S1

Procedure:
60 mg of 2-(9-benzyl-2,3,4,9-tetrahydrothiopyrano[2,3-b]indol-2-yl)methyl-4,4-dimethyl-2-oxazoline (prepared as described in Example 81) was dissolved in 5% v/v sulfuric acid in ethanol, and the mixture was refluxed for 6 hours. After this time, the reaction mixture was neutralized by the addition of a saturated aqueous solution of sodium hydrogencarbonate and then extracted with ethyl acetate. The ethyl acetate fraction was then washed with water and dried over anhydrous sodium sulfate. The solvent was then removed by evaporation under reduced pressure, and the resulting residue was purified by silica gel column chromatography, using a mixture of 20% v/v ethyl acetate in hexane as the eluent, to afford 46 mg of the title compound as an oil.
Reaction SMILES: O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[C:20]([O:24][C:25](=[O:65])[CH2:26][N:27]1[C:35]2[C:30](=[CH:31][CH:32]=[C:33]([O:36][CH:37]([C:49]3[S:53][C:52]([C:54]4[CH:59]=[CH:58][C:57]([C:60]([F:63])([F:62])[F:61])=[CH:56][CH:55]=4)=[N:51][C:50]=3[CH3:64])[CH2:38][CH2:39][CH2:40][O:41][Si](C(C)(C)C)(C)C)[CH:34]=2)[CH:29]=[CH:28]1)([CH3:23])([CH3:22])[CH3:21]>O1CCCC1>[C:20]([O:24][C:25](=[O:65])[CH2:26][N:27]1[C:35]2[C:30](=[CH:31][CH:32]=[C:33]([O:36][CH:37]([C:49]3[S:53][C:52]([C:54]4[CH:59]=[CH:58][C:57]([C:60]([F:62])([F:63])[F:61])=[CH:56][CH:55]=4)=[N:51][C:50]=3[CH3:64])[CH2:38][CH2:39][CH2:40][OH:41])[CH:34]=2)[CH:29]=[CH:28]1)([CH3:22])([CH3:23])[CH3:21]
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1C(CCCO[Si](C)(C)C(C)(C)C)Oc1ccc2ccn(CC(=O)OC(C)(C)C)c2c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1C(CCCO)Oc1ccc2ccn(CC(=O)OC(C)(C)C)c2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A 1 M solution of tetrabutylammonium fluoride hydrate (30 μl, 30 μmol) was added to an ice-cooled solution of [rac]-(6-[4-(tert-butyl-dimethyl-silanyloxy)-1-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-butoxy}-indol-1-yl)-acetic acid tert-butyl ester (17 mg, 25 μmol) in tetrahydrofuran (0.5 ml). The ice bath was removed and the solution stirred for 30 min at ambient temperature. Ethyl acetate was added and the solution was washed with 1 N HCl. The aqueous layer was extracted with ethyl acetate and the combined extracts were washed two times with brine and dried over sodium sulfate. Evaporation of the solvent gave 14 mg (25 μmol, quant.) of the title compound as yellow oil.
Reaction SMILES: [CH2:1]([N:9]=[C:10](Cl)[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].ClS(O)(=O)=O.[CH3:24][N:25]1[CH:29]=[C:28]([CH3:30])[CH:27]=[C:26]1[CH2:31][C:32]([O:34][CH3:35])=[O:33].[Cl:36]([OH:40])(=[O:39])(=[O:38])=[O:37]>>[Cl:36]([OH:40])(=[O:39])(=[O:38])=[O:37].[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([C:10](=[N:9][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[C:29]2[N:25]([CH3:24])[C:26]([CH2:31][C:32]([O:34][CH3:35])=[O:33])=[CH:27][C:28]=2[CH3:30])=[CH:12][CH:13]=1
Reactant: COC(=O)Cc1cc(C)cn1C
Reactant: CCCCCCCCN=C(Cl)c1ccc(Cl)cc1
Agent: O=S(=O)(O)Cl
Agent: [O-][Cl+3]([O-])([O-])O
Product: CCCCCCCCN=C(c1ccc(Cl)cc1)c1c(C)cc(CC(=O)OC)n1C

Procedure:
The title compound was prepared as in Example X from N-octyl 4-chlorobenzimidoyl chloride (1.44 g, 5 mmole), chlorosulfonic acid (0.58 g, 0.5 mmole), methyl 1,4-dimethyl-1H-pyrrole-2-acetate (0.84 g, 5 mmole), and 70% perchloric acid (0.79 g, 5.5 mmole) to yield 1.99 g (77%) of a red viscous oil.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1N)([CH3:3])[CH3:2].N([O-])=O.[Na+].[C:18]([Cu])#[N:19].[C-]#N.[Na+].N>Cl.O.C(OCC)(=O)C>[CH:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[C:18]#[N:19])([CH3:3])[CH3:2]
Reactant: CC(C)c1cc([N+](=O)[O-])ccc1N
Reactant: N#C[Cu]
Agent: Cl
Agent: N
Agent: O=N[O-]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)c1cc([N+](=O)[O-])ccc1C#N
Temperature: 0 °C
Reaction time: 1 h
Yield: 41.7 %

Procedure:
2-Isopropyl-4-nitro-phenylamine (1.0 g, 5.55 mmol) was dissolved in 5N hydrochloric acid (10 mL) and cooled to 0° C. A solution of sodium nitrite (0.96 g, 13.9 mmol) in water (5 mL) was added and the mixture stirred at this temperature for 1 hr. The mixture was filtered and the solids washed with ice-water, the filtrate then being added to a previously-prepared and cooled (0° C.) solution of CuCN (0.82 g, 9.16 mmol) and NaCN (0.68 g, 13.9 mmol) in water. This mixture was warmed to r.t. and stirred for 1 hr, then ethyl acetate was added and the mixture basified with ammonia solution. Precipitated copper salts were filtered off, and the filtrate was extracted with ethyl acetate. The organic phase was washed with water and brine, dried over sodium sulfate and concentrated. The crude product was purified by column chromatography on silica gel (60-120 mesh), eluting with 4% ethyl acetate/petroleum ether to yield 2-isopropyl-4-nitro-benzonitrile (440 mg, 42%).
Reaction SMILES: [N:1]([CH:4]([C:6]1[N:7]=[C:8]2[S:23][CH:22]=[C:21]([CH3:24])[N:9]2[C:10](=[O:20])[C:11]=1[C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[C:14]([Cl:19])[CH:13]=1)[CH3:5])=[N+]=[N-].CP(C)C>O1CCCC1>[NH2:1][CH:4]([C:6]1[N:7]=[C:8]2[S:23][CH:22]=[C:21]([CH3:24])[N:9]2[C:10](=[O:20])[C:11]=1[C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[C:14]([Cl:19])[CH:13]=1)[CH3:5]
Reactant: Cc1csc2nc(C(C)N=[N+]=[N-])c(-c3cc(F)cc(Cl)c3)c(=O)n12
Agent: CP(C)C
Solvent: C1CCOC1
Product: Cc1csc2nc(C(C)N)c(-c3cc(F)cc(Cl)c3)c(=O)n12
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.7 %

Procedure:
To a stirred solution of 7-(1-azidoethyl)-6-(3-chloro-5-fluorophenyl)-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one (0.077 g, 0.21 mmol) in tetrahydrofuran (3 mL) was added 1.00 M of trimethylphosphine in tetrahydrofuran (0.25 mL, 0.25 mmol) and the mixture was stirred at room temperature for 1 hour. The mixture was concentrated to give crude product (0.070 g), which was used directly in the next step. LCMS calculated for C15H14ClFN3OS (M+H)+: m/z=338.1. Found: 338.0.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][C:3]=1[CH:12]([S:18]([OH:21])(=O)=[O:19])[CH2:13][C:14]([O:16][CH3:17])=[O:15].[N:22]1C=CC=CC=1.P(Cl)(Cl)(Cl)(Cl)Cl.[OH-].N>C(Cl)Cl>[NH2:22][S:18]([CH:12]([C:3]1[CH:4]=[CH:5][C:6]([C:8]([O:10][CH3:11])=[O:9])=[CH:7][C:2]=1[Br:1])[CH2:13][C:14]([O:16][CH3:17])=[O:15])(=[O:21])=[O:19]
Reactant: c1ccncc1
Reactant: COC(=O)CC(c1ccc(C(=O)OC)cc1Br)S(=O)(=O)O
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: N
Agent: [OH-]
Solvent: ClCCl
Product: COC(=O)CC(c1ccc(C(=O)OC)cc1Br)S(N)(=O)=O
Reaction time: 8 h
Yield: 62.7 %

Procedure:
1-[2-bromo-4-(methoxycarbonyl)phenyl]-3-methoxy-3-oxopropane-1-sulfonic acid—pyridine (1:1) (0.220 g, 0.478 mmol) was dissolved in methylene chloride (2 mL) at room temperature, and phosphorus pentachloride (0.199 g, 0.956 mmol) were added. The mixture was stirred overnight. The reaction solution was cannulated into a 2 mL ammonia hydroxide solution at 0° C. dropwise. After stirring for 1 h, the organic layer was isolated, aqueous layer was extracted with methylene chloride twice. The combined organic solutions were dried over sodium sulfate, filtered, concentrated. The residue was purified by preparative LCMS to afford product as slight yellow solid (114 mg, 63%). 1H NMR (400 MHz, CD3OD): δ 8.24 (d, J=1.5 Hz, 1H), 7.99 (dd, J=8.2, 1.5 Hz, 1H), 7.70 (d, J=8.2 Hz, 1H), 5.39 (dd, J=10.1, 4.9 Hz, 1H), 3.91 (s, 3H), 3.58 (s, 3H), 3.43 (dd, J=16.6, 4.9 Hz, 1H), 3.18 (dd, J=16.6, 10.1 Hz, 1H). LCMS found for C12H14BrNO6SNa (M+Na)+: m/z=401, 403.
Reaction SMILES: [C:1]([C:4]1[CH:17]=[CH:16][C:15]2[O:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[S:7][C:6]=2[CH:5]=1)(=[O:3])[CH3:2].ClC1C=C(C=CC=1)C(OO)=O.[OH-:29].[Ca+2].[OH-:31]>C(Cl)Cl>[C:1]([C:4]1[CH:17]=[CH:16][C:15]2[O:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[S:7](=[O:31])(=[O:29])[C:6]=2[CH:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc2c(c1)Sc1ccccc1O2
Reactant: [OH-]
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Ca+2]
Solvent: ClCCl
Product: CC(=O)c1ccc2c(c1)S(=O)(=O)c1ccccc1O2
Temperature: 25 °C
Reaction time: 3 h
Yield: 75.6 %

Procedure:
To a solution of 2-acetyl phenoxathiin (J.A.C.S. 1936, 58, 717) (484 mg, 2 mmol) in methylene chloride (25 mL) there was added 85% m-chloroperoxy benzoic acid (MCPBA 1.015 g, 5 mmol) and the mixture stirred at room temperature. After 3 hours, more MCPBA was added (250 mg) and stirring was continued for a further hour. Enough methylene chloride was added to dissolve the solids, followed by calcium hydroxide (3 g); after stirring for a further 5 minutes, the mixture was filtered and the filtrate evaporated to a solid residue which was triturated with ether (10 mL) and filtered to afford the sulfone (415 mg) as a white solid, m.p.: 163°-165° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][N:5]([CH2:8][CH3:9])[C:4](=[O:10])[CH:3]=1.[I:11][C:12]1[N:13]=[C:14]([CH3:17])[NH:15][CH:16]=1>>[CH2:8]([N:5]1[C:4](=[O:10])[CH:3]=[C:2]([N:15]2[CH:16]=[C:12]([I:11])[N:13]=[C:14]2[CH3:17])[CH:7]=[N:6]1)[CH3:9]
Reactant: Cc1nc(I)c[nH]1
Reactant: CCn1ncc(Cl)cc1=O
Product: CCn1ncc(-n2cc(I)nc2C)cc1=O

Procedure:
The title compound, white crystalline solid, MS: m/e=331.0 (M+H+), was prepared in accordance with the general method of example 23b from 5-chloro-2-ethyl-2H-pyridazin-3-one and 4-Iodo-2-methyl-1H-imidazole.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][N:15]([CH2:33][CH3:34])[CH:16]2[CH2:25][CH2:24][C:23]3[C:18](=[CH:19][C:20]([NH:26][C:27](=[O:32])[C:28]([F:31])([F:30])[F:29])=[CH:21][CH:22]=3)[CH2:17]2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:33]([N:15]([CH2:14][CH:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)[CH:16]1[CH2:17][C:18]2[CH:19]=[C:20]([NH:26][C:27](=[O:32])[C:28]([F:29])([F:30])[F:31])[CH:21]=[CH:22][C:23]=2[CH2:24][CH2:25]1)[CH3:34]
Reactant: CCN(CC1CCN(C(=O)OC(C)(C)C)CC1)C1CCc2ccc(NC(=O)C(F)(F)F)cc2C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCN(CC1CCNCC1)C1CCc2ccc(NC(=O)C(F)(F)F)cc2C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of the 4-({ethyl-[7-(2,2,2-trifluoro-acetylamino)-1,2,3,4-tetrahydro-naphthalen-2-yl]-amino}-methyl)-piperidine-1-carboxylic acid tert-butyl ester (800 mg, 1.7 mmol) in methylene chloride (20 mL) under an inert atmosphere was added trifluoroacetic acid (5 mL) and the solution was allowed to stir at room temperature for 1 h. The reaction was concentrated in vacuo and partitioned between 10% KOH and EtOAc. The organic layer was washed with brine, dried (MgSO4), and concentrated to afford N-[7-(ethyl-piperidin-4-ylmethyl-amino)-5,6,7,8-tetrahydro-naphthalen-2-yl]-2,2,2-trifluoro-acetamide as an oil which was used directly for the next step.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:9][C:10]1[N:11]=[C:12](Cl)[C:13]2[C:18]([Cl:19])=[C:17]([CH3:20])[S:16][C:14]=2[N:15]=1>>[Cl:9][C:10]1[N:11]=[C:12]([NH:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:13]2[C:18]([Cl:19])=[C:17]([CH3:20])[S:16][C:14]=2[N:15]=1
Reactant: Cc1sc2nc(Cl)nc(Cl)c2c1Cl
Reactant: NCc1ccccc1
Product: Cc1sc2nc(Cl)nc(NCc3ccccc3)c2c1Cl

Procedure:
Following the procedure of Example 1, the reaction of benzylamine with 2,4,5-trichloro-6-methyl-thieno-[2,3-d]-pyrimidine yields 2,5-dichloro-6-methyl-4-benzylamino-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [F:1][C:2]([C@H:27]1[CH2:32][CH2:31][C@H:30]([C:33]([O:35]CCCC)=[O:34])[CH2:29][CH2:28]1)([C:4]1[S:5][C:6]([C:9]2[CH:14]=[C:13]([NH:15][C:16]3[N:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][N:17]=3)[CH:12]=[C:11]([CH3:26])[CH:10]=2)=[CH:7][N:8]=1)[CH3:3].[OH-].[Na+].Cl>CO.O.C(OCC)(=O)C>[F:1][C:2]([C@H:27]1[CH2:32][CH2:31][C@H:30]([C:33]([OH:35])=[O:34])[CH2:29][CH2:28]1)([C:4]1[S:5][C:6]([C:9]2[CH:14]=[C:13]([NH:15][C:16]3[N:21]=[C:20]([C:22]([F:24])([F:25])[F:23])[CH:19]=[CH:18][N:17]=3)[CH:12]=[C:11]([CH3:26])[CH:10]=2)=[CH:7][N:8]=1)[CH3:3]
Reactant: CCCCOC(=O)[C@H]1CC[C@H](C(C)(F)c2ncc(-c3cc(C)cc(Nc4nccc(C(F)(F)F)n4)c3)s2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C(C)(F)[C@H]3CC[C@H](C(=O)O)CC3)s2)c1
Temperature: 60 °C

Procedure:
To a solution of butyl trans-4-{1-fluoro-1-[5-(3-methyl-5-{[4-(trifluoromethyl)-pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]ethyl}cyclohexanecarboxylate (80 mg, 0.14 mmol) in methanol (1.5 mL) was added sodium hydroxide (1.0 M in H2O, 0.28 mL, 0.28 mmol) and the reaction was heated to 60° C. overnight. Then, the reaction was cooled to room temperature, acidified to a pH of ˜3 with HCl (1.0 M in water) and diluted with water and ethyl acetate. The organic layer was separated, dried over magnesium sulfate, filtered and concentrated in vacuo to afford racemic trans-4-{1-fluoro-1-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]ethyl}cyclohexanecarboxylic acid. MS ESI calc'd. for C24H25F4N4O2S [M+H]+ 509. found 509. 1H NMR (500 MHz, DMSO-d6) 12.01 (s, 1H), 10.28 (s, 1H), 8.84 (d, J=4.8, 1H), 8.07 (d, J=3.3, 1H), 8.02 (s, 1H), 7.47 (s, 1H), 7.29 (d, J=4.9, 1H), 7.19 (s, 1H), 2.32 (s, 3H), 2.16-2.01 (m, 1H), 2.00-1.87 (m, 4H), 1.85 (s, 1H), 1.67 (s, 3H), 1.35-1.19 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[S:10][CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.ClC1C=CN=C2C=C([CH:21]=[O:22])SC=12>>[Cl:1][C:2]1[C:3]2[S:10][C:9]([CH:21]=[O:22])=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Clc1ncnc2ccsc12
Reactant: O=Cc1cc2nccc(Cl)c2s1
Product: O=Cc1cc2ncnc(Cl)c2s1
Yield: 84 %

Procedure:
Starting from 4-chloro-thieno[3,2-d]pyrimidine (20, scheme 4) and following procedure described above for the synthesis of aldehyde 14 (scheme 3, step 1, example 20), title compound 186 was obtained in 84% yield. LRMS (M+1) 199.0 (100%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:25]([F:26])=[CH:24][C:19]2[N:20]=[C:21]([NH2:23])[S:22][C:18]=2[CH:17]=1.CCN(CC)CC.[C:34]1([CH2:40][C:41](Cl)=[O:42])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.C1COCC1>C(C#N)(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:25]([F:26])=[CH:24][C:19]2[N:20]=[C:21]([NH:23][C:41](=[O:42])[CH2:40][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[S:22][C:18]=2[CH:17]=1
Reactant: COc1cc2nccc(Oc3cc4sc(N)nc4cc3F)c2cc1OC
Reactant: O=C(Cl)Cc1ccccc1
Agent: CC(=O)C#N
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1cc2nccc(Oc3cc4sc(NC(=O)Cc5ccccc5)nc4cc3F)c2cc1OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
6-(6,7-dimethoxy-quinolin-4-yloxy)-5-fluoro-benzothiazol-2-ylamine (95 mg, 0.25 mmol), Et3N (0.10 ml, 0.72 mmol), phenylacetyl chloride (0.044 ml, 0.33 mmol), and THF (1.0 ml) were combined and stirred at room temperature for 1 hr. Additional phenylacetyl chloride (0.044 ml, 0.33 mmol) was added and the mixture heated to reflux for 1-2 hrs. After cooling to room temperature, the reaction mixture was diluted with 1:1 AcCN:H2O (1.0 ml) and the resulting solids filtered, washed with 1:1 AcCN:H2O and dried under high vacuum to give N-[6-(6,7-dimethoxy-quinolin-4-yloxy)-5-fluoro-benzothiazol-2-yl]-2-phenyl-acetamidc (72 mgs, 59%). 1H-NMR (400 MHz, DMSO): 12.80 (s, 1H), 8.54 (d, 1H), 8.18 (d, 1H), 7.91 (d, 1H), 7.60 (s, 1H), 7.45 (s, 1H), 7.34 (m, 4H), 7.28 (m, 1H), 6.60 (d, 1H), 3.98 (s, 3H), 3.96 (s, 3H), 3.86 (s, 2H). LC/MS Calcd for [M+H]+ 490.1. found 490.0.
Reaction SMILES: CN(C)C=O.Br.[NH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:19]=[CH:20][C:21](=[O:24])[NH:22][N:23]=2)=[CH:14][CH:13]=1.[C:25](O)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[N:28][CH:27]=1>C(N(CC)CC)C>[N:28]1[CH:29]=[CH:30][CH:31]=[C:26]([C:25]([NH:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]2[CH:13]=[CH:14][C:15]([C:18]3[CH:19]=[CH:20][C:21](=[O:24])[NH:22][N:23]=3)=[CH:16][CH:17]=2)=[O:32])[CH:27]=1
Reactant: NCCCCc1ccc(-c2ccc(=O)[nH]n2)cc1
Reactant: O=C(O)c1cccnc1
Agent: Br
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(NCCCCc1ccc(-c2ccc(=O)[nH]n2)cc1)c1cccnc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 62.6 %

Procedure:
Under ice cooling, a dimethylformamide solution (10 ml) containing 1.06 g of diethylphosphoric cyanide was added dropwise to a dimethylformamide suspension (30 ml) containing 1.65 g of 6-[4-(4-aminobutyl)phenyl]pyridazin-3(2H)-one hydrobromide, 0.78 g of nicotinic acid and 1.55 g of triethylamine, and the mixture was stirred for 1 hour. The reaction mixture was poured into ice water, and precipitated crystal was collected by filtration. The obtained crystal was washed with water, dried and then recrystallized from methanol to obtain 1.11 g of 6-[4-(4-(pyridin-3-ylcarbonylamino)butyl)phenyl]pyridazin-3(2H)-one.