Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)(=O)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[C:23]([O:27][C:28]([C@@:30]1([CH2:45][CH2:46][O:47][Si](C(C)(C)C)(C)C)[CH:34]([F:35])[C:33](=[O:36])[N:32]([C@@H:37]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH3:38])[CH2:31]1)=[O:29])([CH3:26])([CH3:25])[CH3:24].C(OCC)(=O)C>O1CCCC1>[C:23]([O:27][C:28]([C@@:30]1([CH2:45][CH2:46][OH:47])[CH:34]([F:35])[C:33](=[O:36])[N:32]([C@@H:37]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH3:38])[CH2:31]1)=[O:29])([CH3:26])([CH3:25])[CH3:24]
Reactant: C[C@H](c1ccccc1)N1C[C@@](CCO[Si](C)(C)C(C)(C)C)(C(=O)OC(C)(C)C)C(F)C1=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: C[C@H](c1ccccc1)N1C[C@@](CCO)(C(=O)OC(C)(C)C)C(F)C1=O
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Acetic acid (0.66 mL, 11.54 mmol) and a 1 M solution of tetrabutylammonium fluoride in tetrahydrofuran (8.3 mL, 8.3 mmol) were sequentially added to a solution of the crude (3S)-3-[2-(tert-butyldimethylsilyloxy)ethyl]-4-fluoro-5-oxo-1-[(1R)-1-phenylethyl]pyrrolidine-3-carboxylic acid tert-butyl ester (3.44 g) in tetrahydrofuran in a nitrogen atmosphere at 0° C. After stirring at room temperature for 20 hours, the reaction solution was poured into a mixture of ethyl acetate (100 mL) and a saturated sodium bicarbonate solution (50 mL), followed by extraction with ethyl acetate (200 mL). The organic layer was washed with brine (50 mL×2), and then dried over anhydrous sodium sulfate and filtered. The filtrate was then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to give 2.06 g (91%, two steps) of the title compound as colorless crystals.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:11][C@@H:12]([CH3:17])[C:13]([F:16])([F:15])[F:14])=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.[NH2:18][C:19]([CH:23]1[CH2:25][CH2:24]1)([CH3:22])[C:20]#[N:21]>>[CH3:22][C:19]([NH:18][C:8]([C:5]1[CH:4]=[C:3]([O:11][C@@H:12]([CH3:17])[C:13]([F:16])([F:15])[F:14])[C:2]([Br:1])=[CH:7][N:6]=1)=[O:10])([C:20]#[N:21])[CH:23]1[CH2:25][CH2:24]1
Reactant: CC(N)(C#N)C1CC1
Reactant: C[C@H](Oc1cc(C(=O)O)ncc1Br)C(F)(F)F
Product: C[C@H](Oc1cc(C(=O)NC(C)(C#N)C2CC2)ncc1Br)C(F)(F)F

Procedure:
The title compound was synthesized in analogy to Example 78e, using 5-Bromo-4-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-pyridine-2-carboxylic acid (Example 96d) and 2-amino-2-cyclopropylpropanenitrile (CAN 37024-73-0) as starting materials and isolated (607 mg, 65%) as a yellow oil; MS (ESI, m/z): 420.4 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[C:3]=1[C:12]1[NH:13][C:14]2[CH:20]=[C:19]([C:21](O)=[O:22])[CH:18]=[CH:17][C:15]=2[N:16]=1.O=S(Cl)[Cl:26]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[C:3]=1[C:12]1[NH:13][C:14]2[CH:20]=[C:19]([C:21]([Cl:26])=[O:22])[CH:18]=[CH:17][C:15]=2[N:16]=1
Reactant: O=C(O)c1ccc2nc(-c3c(Cl)cccc3C(F)(F)F)[nH]c2c1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc2nc(-c3c(Cl)cccc3C(F)(F)F)[nH]c2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred suspension of 2-(2-chloro-6-trifluoromethylphenyl)-3H-benzoimidazole-5-carboxylic acid (400 mg, 1.18 mmol) in SOCl2 (10 mL) was added 3 drops of DMF and the suspension was stirred at ambient temperature overnight. The suspension was filtered and washed with CH2Cl2 and the white solid was dried in under reduced pressure to give 2-(2-chloro-6-trifluoromethylphenyl)-3H-benzoimidazole-5-carbonyl chloride.
Reaction SMILES: [N:1]1([CH:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[CH2:6][CH2:5][CH2:4][C@@H:3]([C:7]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[O:8])[CH2:2]1.[F:21][C:22]([F:47])([F:46])[C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[N:29]=[C:28]([C:33]1[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:35][CH:34]=1)[CH:27]=[C:26]2[C:43](O)=[O:44].O.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>ClCCl>[N:9]1([C:7]([C@@H:3]2[CH2:4][CH2:5][CH2:6][N:1]([CH:15]3[CH2:20][CH2:19][N:18]([C:43]([C:26]4[C:25]5[C:30](=[CH:31][CH:32]=[C:23]([C:22]([F:21])([F:46])[F:47])[CH:24]=5)[N:29]=[C:28]([C:33]5[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:40])[F:41])=[CH:35][CH:34]=5)[CH:27]=4)=[O:44])[CH2:17][CH2:16]3)[CH2:2]2)=[O:8])[CH2:10][CH2:11][O:12][CH2:13][CH2:14]1
Reactant: O=C(O)c1cc(-c2ccc(C(F)(F)F)cc2)nc2ccc(C(F)(F)F)cc12
Reactant: O=C([C@@H]1CCCN(C2CCNCC2)C1)N1CCOCC1
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: O=C(c1cc(-c2ccc(C(F)(F)F)cc2)nc2ccc(C(F)(F)F)cc12)N1CCC(N2CCC[C@@H](C(=O)N3CCOCC3)C2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 22.6 %

Procedure:
To a solution of (3R)-[1,4′]bipiperidinyl-3-yl-morpholin-4-yl-methanone (0.314 mmol, 100 mg) and 6-trifluoromethyl-2-(4-trifluoromethyl-phenyl)-quinoline-4-carboxylic acid (0.346 mmol, 133 mg) in anhydrous dichloromethane was added 1-hydroxybenzotriazole hydrate (0.157 mmol, 21 mg) followed by diisopropylethylamine (0.942 mmol, 0.163 mL) then benzotriazo-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP, 0.942 mmol, 417 mg). The solution was stirred at ambient temperature for 16 hr, diluted with dichloromethane and washed with 1M potassium hydroxide solution. The aqueous layer was separated and extracted with dichloromethane (2×25 mL). The combined organic layers were dried over anhydrous sodium sulfate and evaporated to dryness under vacuum. The residue was redissolved in toluene, evaporated to dryness and purified by chromatography on a 1 mm silica gel rotor eluting with a 0 to 10% methanol in dichloromethane gradient. Final purification from residual hexamethylphosphoramide was achieved by precipitation of the hydrochloride salt (as described above in Example 6), trituration with 1M potassium hydroxide solution, filtration and rinsing with water to give the title compound (46 mg, 23%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:5]([C:15]2[CH:20]=[C:19]([OH:21])[C:18]([Br:22])=[CH:17][C:16]=2[F:23])[C:6](=[O:14])[CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[N:9]=1)[CH3:2].[CH3:24]I.[H-].[Na+]>CN(C)C=O>[CH2:1]([O:3][C:4]1[N:5]([C:15]2[CH:20]=[C:19]([O:21][CH3:24])[C:18]([Br:22])=[CH:17][C:16]=2[F:23])[C:6](=[O:14])[CH:7]=[C:8]([C:10]([F:13])([F:11])[F:12])[N:9]=1)[CH3:2]
Reactant: CCOc1nc(C(F)(F)F)cc(=O)n1-c1cc(O)c(Br)cc1F
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOc1nc(C(F)(F)F)cc(=O)n1-c1cc(OC)c(Br)cc1F

Procedure:
using 2-ethoxy-1-(4-bromo-2-fluoro-5-hydroxyphenyl)-4-trifluoromethyl-6(1H)-pyrimidinone and methyl iodide with sodium hydride in dimethylformamide there is obtained 2-ethoxy-1-(4-bromo-2-fluoro-5-methoxyphenyl)-4-trifluoromethyl-6(1H)-pyrimidinone, m.p. 126°-128° C.
Reaction SMILES: [OH-:1].[K+].[CH3:3][O:4][C:5]1[CH:35]=[CH:34][C:8]([O:9][CH:10]2[CH2:13][N:12]([C:14]([CH3:33])([CH3:32])[CH2:15][CH2:16][C:17]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:18]#[N:19])[CH2:11]2)=[CH:7][CH:6]=1>CC(O)(CC)CC>[CH3:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([O:9][CH:10]2[CH2:11][N:12]([C:14]([CH3:32])([CH3:33])[CH2:15][CH2:16][C:17]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:18]([NH2:19])=[O:1])[CH2:13]2)=[CH:34][CH:35]=1
Reactant: COc1ccc(OC2CN(C(C)(C)CCC(C#N)(c3ccccc3)c3ccccc3)C2)cc1
Reactant: [OH-]
Agent: CCC(C)(O)CC
Agent: [K+]
Product: COc1ccc(OC2CN(C(C)(C)CCC(C(N)=O)(c3ccccc3)c3ccccc3)C2)cc1
Temperature: 25 °C
Yield: 96 %

Procedure:
Potassium hydroxide (135 mg, 2.41 mmol) was added to a solution of the product of example 105 (53 mg, 0.12 mmol) in 3-methyl-3-pentanol (5 mL) and the mixture was heated under reflux for 18 hours. The reaction mixture was then cooled to room temperature, concentrated in vacuo and the residue was partitioned between ethyl acetate (20 mL) and water (5 mL). The aqueous layer was separated, extracted with ethyl acetate (2×20 mL) and the combined organic solution was dried over magnesium sulfate and concentrated in vacuo to give a colourless oil in 96% yield, 53 mg.
Reaction SMILES: C([BH3-])#N.[Na+].[NH2:5][CH:6]1[CH2:15][C:14]2[C:9]3=[C:10]([NH:16][C:17](=[O:18])[N:8]3[CH2:7]1)[CH:11]=[CH:12][CH:13]=2.C[O-].[Na+].[CH:22](=O)[CH2:23][CH3:24].N>CO.C(Cl)(Cl)Cl>[CH2:22]([NH:5][CH:6]1[CH2:15][C:14]2[C:9]3=[C:10]([NH:16][C:17](=[O:18])[N:8]3[CH2:7]1)[CH:11]=[CH:12][CH:13]=2)[CH2:23][CH3:24]
Reactant: CCC=O
Reactant: NC1Cc2cccc3[nH]c(=O)n(c23)C1
Agent: C[O-]
Agent: N
Agent: [BH3-]C#N
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CCCNC1Cc2cccc3[nH]c(=O)n(c23)C1
Reaction time: 0.5 h
Yield: 53.4 %

Procedure:
Sodium cyanoborohydride (0.17 g) was added in small portions over a 5-hour period to a stirred solution of 1.90 g (8.4 retool) 5-amino-5,6-dihydro-4H-imidazo(4,5,1-ij) quinolin-2(1H)-one, 0.85 mL sodium methoxide and 1.5 g propionaldehyde in methanol (175 mL). Methanolic ammonia solution was added, and after 30 minutes, the solvent was evaporated. The residual oil was partitioned between ethyl acetate and water and the crude product obtained by evaporating the ethyl acetate was dissolved in chloroform and chromatographed on silica gel eluting with 2.5% methanol:chloroform to give 1.24 g (64% yield) of 5,6-dihydro-5-(propylamino)-4H-imidazo(4,5,1-ij)quinolin-2(1H)-one.
Reaction SMILES: [CH:1]1([CH2:6][N:7]([CH2:20][CH3:21])[C:8]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:9]=2[CH:10]=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:22][S:23][CH2:24][CH2:25][O:26][C:27]1[CH:28]=[N:29][C:30]([NH2:33])=[N:31][CH:32]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1(C)C=CC=CC=1.O>[CH:1]1([CH2:6][N:7]([CH2:20][CH3:21])[C:8]2[CH:15]=[CH:14][C:13]([C:16]([F:17])([F:18])[F:19])=[CH:12][C:9]=2[CH2:10][NH:33][C:30]2[N:29]=[CH:28][C:27]([O:26][CH2:25][CH2:24][S:23][CH3:22])=[CH:32][N:31]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CSCCOc1cnc(N)nc1
Reactant: CCN(CC1CCCC1)c1ccc(C(F)(F)F)cc1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Solvent: O
Product: CCN(CC1CCCC1)c1ccc(C(F)(F)F)cc1CNc1ncc(OCCSC)cn1
Temperature: 25 °C
Yield: 83.6 %

Procedure:
To a solution of 2-[(cyclopentylmethyl)(ethyl)amino]-5-(trifluoromethyl)benzaldehyde (3.34 g, 11.2 mmol) obtained in Step 3 and 5-[2-(methylthio)ethoxy]pyrimidin-2-amine (2.27 g, 12.3 mmol) obtained in Step 1 in toluene (80 mL) was added acetic acid (317 mg, 5.19 mmol), and the mixture was refluxed by heating for 4 hours with a Dean-Stark apparatus. The reaction mixture was left to cool to room temperature, and then added with sodium triacetoxyborohydride (4.73 g, 22.3 mmol) on an ice bath with stirring, and the mixture was stirred at room temperature for 60 hours. The reaction mixture was added with water, and extracted with chloroform, and then the organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=20:1→10:1→4:1) to obtain N-({2-[(cyclopentylmethyl)(ethyl)amino]-5-(trifluoromethyl)phenyl}methyl)-5-[2-(methylthio)ethoxy]pyrimidin-2-amine (4.39 g, 84%) as a pale yellow oil.
Reaction SMILES: [CH3:1][C:2]([CH3:8])([C:5](=[O:7])[CH3:6])[C:3]#[N:4].[Cl:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=O)=[CH:12][C:11]=1[O:18][CH3:19]>>[Cl:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=[CH:6][C:5](=[O:7])[C:2]([CH3:8])([CH3:1])[C:3]#[N:4])=[CH:12][C:11]=1[O:18][CH3:19]
Reactant: COc1cc(C=O)ccc1Cl
Reactant: CC(=O)C(C)(C)C#N
Product: COc1cc(C=CC(=O)C(C)(C)C#N)ccc1Cl

Procedure:
The title compound was prepared from 2,2-dimethyl-3-oxo-butyronitrile {J. K. Rasmussen et al., Synthesis, 1973, 682} and 4-chloro-3-methoxy-benzaldehyde (F. Claudi et al., J. Med. Chem., 1992, 35, 4408) as described in Example 1 Step 1; MS (ES−) m/e 263, 265 [M−H]−.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][C@@H:3]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:2]1.[Br:15][C:16]1[C:17](F)=[C:18]2[C:24]([NH:25][C:26]([C:28]3([O:31][CH3:32])[CH2:30][CH2:29]3)=[O:27])=[CH:23][NH:22][C:19]2=[N:20][CH:21]=1.CC#N.O>CCCCO.O>[Br:15][C:16]1[C:17]([N:1]2[CH2:6][CH2:5][CH2:4][C@@H:3]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:13])[CH3:12])[CH2:2]2)=[C:18]2[C:24]([NH:25][C:26]([C:28]3([O:31][CH3:32])[CH2:30][CH2:29]3)=[O:27])=[CH:23][NH:22][C:19]2=[N:20][CH:21]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1
Reactant: COC1(C(=O)Nc2c[nH]c3ncc(Br)c(F)c23)CC1
Solvent: CC#N
Solvent: O
Solvent: CCCCO
Product: COC1(C(=O)Nc2c[nH]c3ncc(Br)c(N4CCC[C@@H](NC(=O)OC(C)(C)C)C4)c23)CC1
Temperature: 160 °C
Yield: 33.2 %

Procedure:
(R)-tert-Butyl piperidin-3-ylcarbamate (366 mg, 1.83 mmol) was added to a suspension of N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-1-methoxycyclopropanecarboxamide (200 mg, 0.61 mmol) in n-BuOH (3 mL). The resulting mixture was heated in a sealed tube at 160° C. for 24 hours. The cooled mixture was diluted with water (40 mL) and extracted with EtOAc (3×20 mL). The combined organic layers were dried over MgSO4 and filtered, and the filtrate was concentrated. The residue was purified by reverse phase chromatography (Biotage SP4, C-18 25M+, 15-85% CH3CN/water, 25 CV) to give (R)-tert-butyl 1-(5-bromo-3-(1-methoxycyclopropanecarboxamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate (103 mg, 33% yield) as a solid. LCMS (APCI+) m/z 510 (M+2H)+, Retention time=3.84 minutes.
Reaction SMILES: [CH2:1]([N:8]([CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[C:9](=[O:31])[CH2:10][C:11]1[CH:28]=[CH:27][C:14]([O:15][CH2:16][C:17]2[CH:26]=[CH:25][CH:24]=[CH:23][C:18]=2[C:19]([O:21]C)=[O:20])=[C:13]([O:29][CH3:30])[CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Li+].Cl>C1COCC1.O>[CH2:1]([N:8]([CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[C:9](=[O:31])[CH2:10][C:11]1[CH:28]=[CH:27][C:14]([O:15][CH2:16][C:17]2[CH:26]=[CH:25][CH:24]=[CH:23][C:18]=2[C:19]([OH:21])=[O:20])=[C:13]([O:29][CH3:30])[CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCCCN(Cc1ccccc1)C(=O)Cc1ccc(OCc2ccccc2C(=O)OC)c(OC)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCN(Cc1ccccc1)C(=O)Cc1ccc(OCc2ccccc2C(=O)O)c(OC)c1
Reaction time: 0.12 h
Yield: 45 %

Procedure:
Methyl 2-[(4-{2-[benzyl(hexyl)amino]-2-oxoethyl}-2-methoxyphenoxy)methyl]benzoate (98 mg, 0.195 mmol) was dissolved in THF (2 ml). Lithium hydroxide (9.3 mg, 0.389 mmol) solved in water (1 ml) was added. The mixture was put in a microwave oven (Smith Synthesizer) at 150° C. for 7 minutes. It was then acidified with 1% hydrochloric acid, pH˜3, and extracted with ethyl acetate. The organic extract was washed with brine and dried (magnesium sulphate) and evaporated. Chromatography of the residue on a column (ISOLUTE®) SI, 2 g/6 ml) using DCM and then MeOH/DCM (0.5:99.5, then 1:99) as eluant gave 43 mg the desired product, yield 45%.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].O.[CH:13]([NH2:15])=O>>[F:11][C:9]1[CH:10]=[C:2]2[C:3]([C:4](=[O:5])[NH:15][CH:13]=[N:1]2)=[CH:7][CH:8]=1
Reactant: NC=O
Reactant: Nc1cc(F)ccc1C(=O)O
Solvent: O
Product: O=c1[nH]cnc2cc(F)ccc12

Procedure:
A solution of 2-amino-4-fluorobenzoic acid (3 g) in formamide (30 ml) was heated to 150° C. for 6 hour. The reaction mixture was poured onto a 1:1 mixture of ice and water (250 ml) and the precipitated solid was collected, washed with water and dried to give 7-fluoro-3,4-dihydroquinazolin-4-one (2.6 g).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][CH:17]=1)[O:7][C:8]1[CH:9]=[N+:10]([O-])[CH:11]=[CH:12][CH:13]=1)[CH3:2].COS(OC)(=O)=O.C(OC1C=C(C=CC=1)OC1[CH:33]=[N+:34](OC)C=CC=1)C.[Na]>O>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][CH:17]=1)[O:7][C:8]1[C:9]([C:33]#[N:34])=[N:10][CH:11]=[CH:12][CH:13]=1)[CH3:2]
Reactant: CCOc1cccc(Oc2ccc[n+]([O-])c2)c1
Reactant: CCOc1cccc(Oc2ccc[n+](OC)c2)c1
Agent: [Na]
Solvent: O
Solvent: COS(=O)(=O)OC
Product: CCOc1cccc(Oc2cccnc2C#N)c1
Temperature: 100 °C
Reaction time: 16 h

Procedure:
A mixture of 68 g of 3-(3-ethoxyphenoxy)pyridine 1-oxide and 40 g of dimethylsulfate is heated at 100° C. for 4 hours. The 3-(3-ethoxyphenoxy)-1-methoxy pyridinium methosulfate is dissolved in 200 ml of water and is added dropwise to a cooled, stirred solution of 75 g sodium cyamide in 200 ml of water at 0°-5° C. under a nitrogen atmosphere. The mixture is stirred 16 hours and is extracted with 500 ml of dichloromethane. The dichloromethane layer is washed with 100 ml of water, dried, concentrated and distilled to yield 3-(3-ethoxyphenoxy)-2-pyridinecarbonitrile, bp 145°-150° C. at 0.2 mM, mp 83°-84° C. after recrystallization from methanol.
Reaction SMILES: [C:1](Cl)(=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH2:12][C:13]1[CH:27]=[CH:26][CH:25]=[CH:24][C:14]=1[CH2:15][CH2:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][N:18]1[CH3:23]>N1C=CC=CC=1>[CH3:23][N:18]1[CH2:19][CH2:20][CH2:21][CH2:22][CH:17]1[CH2:16][CH2:15][C:14]1[CH:24]=[CH:25][CH:26]=[CH:27][C:13]=1[NH:12][C:1](=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C(Cl)C=Cc1ccccc1
Reactant: CN1CCCCC1CCc1ccccc1N
Solvent: c1ccncc1
Product: CN1CCCCC1CCc1ccccc1NC(=O)C=Cc1ccccc1
Reaction time: 3 h
Yield: 70 %

Procedure:
Cinnamoyl chloride (6.0 g., 0.036 mole) is added to a solution of 2-(o-aminophenethyl)-1-methylpiperidine (7.8 g., 0.036 mole) in 100 ml. of pyridine in one portion with vigorous stirring. Stirring is continued for 3 hours and the pyridine solution is then concentrated in vacuo. The resulting residue is taken up to 150 ml. of water and made basic with 40% sodium hydroxide. The basified solution is extracted with several 200 ml. portions of ether, which are combined, washed with water, dried over magnesium sulfate and the ether solvent evaporated. The residue thus obtained crystallizes and is further purified by crystallizing from isopropyl ether providing 8.7 g. (70% yield) of analytically pure 2'-[2-(1-methyl-2-piperidyl)ethyl]cinnamanilide melting at 101.5°-103.5° C. (corr.).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:33])[CH2:5][N:6]1[C:14]2[CH2:13][CH2:12][CH2:11][C@@H:10]([N:15]([S:17]([C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[C:22]([S:30][CH2:31][CH3:32])[CH:21]=3)(=[O:19])=[O:18])[CH3:16])[C:9]=2[CH:8]=[N:7]1)[CH3:2].ClC1C=C(C(OO)=[O:42])C=CC=1>ClCCl>[CH2:1]([O:3][C:4](=[O:33])[CH2:5][N:6]1[C:14]2[CH2:13][CH2:12][CH2:11][C@@H:10]([N:15]([S:17]([C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:27])[F:28])[CH:23]=[C:22]([S:30]([CH2:31][CH3:32])=[O:42])[CH:21]=3)(=[O:19])=[O:18])[CH3:16])[C:9]=2[CH:8]=[N:7]1)[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCOC(=O)Cn1ncc2c1CCC[C@H]2N(C)S(=O)(=O)c1cc(SCC)cc(C(F)(F)F)c1
Solvent: ClCCl
Product: CCOC(=O)Cn1ncc2c1CCC[C@H]2N(C)S(=O)(=O)c1cc(S(=O)CC)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 76.2 %

Procedure:
To a solution of {(R)-4-[(3-ethylsulfanyl-5-trifluoromethyl-benzenesulfonyl)-methyl-amino]-4,5,6,7-tetrahydro-indazol-1-yl}-acetic acid ethyl ester (50.6 mg, 0.10 mmol) in dichloromethane was added 3-chloro-benzenecarboperoxoic acid (m-CPBA) mg, 0.11 mmol) at 0° C. After stirring at room temperature for 3 hours, the resulting mixture was concentrated in vacuo. The residue was purified by flash column (gradient elution, 5% methanol in dichloromethane) to afford {(R)-4-[(3-ethanesulfinyl-5-trifluoromethyl-benzenesulfonyl)-methyl-amino]-4,5,6,7-tetrahydro-indazol-1-yl}-acetic acid ethyl ester (39.6 mg, 76.2%) as a semisolid. MS cald. for C21H26F3N3O5S2 521, obsd. (ESI+) [(M+H)+] 522.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:7][C:8]1[CH:31]=[CH:30][C:11]2[CH:12]([C:22]3[C:23](=[O:29])[NH:24][C:25](=[O:28])[NH:26][CH:27]=3)[C:13]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][C:14]=3[CH:15]=[CH:16][C:10]=2[CH:9]=1.[Cl:32][C:33]1[N:38]=[C:37](Cl)[CH:36]=[C:35]([Cl:40])[N:34]=1>CN1CCCC1=O>[Cl:32][C:33]1[N:38]=[C:37]([N:26]2[CH:27]=[C:22]([CH:12]3[C:13]4[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][C:14]=4[CH:15]=[CH:16][C:10]4[CH:9]=[C:8]([CH3:7])[CH:31]=[CH:30][C:11]3=4)[C:23](=[O:29])[NH:24][C:25]2=[O:28])[CH:36]=[C:35]([Cl:40])[N:34]=1
Reactant: Cc1ccc2c(c1)C=Cc1cc(C)ccc1C2c1c[nH]c(=O)[nH]c1=O
Reactant: Clc1cc(Cl)nc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: Cc1ccc2c(c1)C=Cc1cc(C)ccc1C2c1cn(-c2cc(Cl)nc(Cl)n2)c(=O)[nH]c1=O

Procedure:
Cesium carbonate (5 g) was added to a solution of the product of example 8 step (i) (5 g) in 1-methyl-2-pyrrolidinone (50 ml). After 5 minutes 2,4,6-trichloropyrimidine (2.8 g) was added. After 2 hours the reaction was partitioned between brine and ethyl acetate. The organic phase was washed with water, dried (MgSO4) and evaporated under reduced pressure. Purification was by chromatography eluting with 30% ethyl acetate in toluene. Yield 2.9 g.
Reaction SMILES: C(=O)(O)O.[NH2:5][C:6]([NH2:8])=[NH:7].CO.[CH3:11][O:12][C:13]1[C:18]([O:19][CH3:20])=[CH:17][C:16]([CH:21]=[C:22]([CH2:25]OC)[C:23]#[N:24])=[C:15]([CH3:28])[CH:14]=1>C[O-].[Na+].CS(C)=O>[CH3:11][O:12][C:13]1[C:18]([O:19][CH3:20])=[CH:17][C:16]([CH2:21][C:22]2[C:23]([NH2:24])=[N:7][C:6]([NH2:8])=[N:5][CH:25]=2)=[C:15]([CH3:28])[CH:14]=1
Reactant: N=C(N)N
Reactant: COCC(C#N)=Cc1cc(OC)c(OC)cc1C
Agent: C[O-]
Agent: O=C(O)O
Agent: [Na+]
Solvent: CO
Solvent: CS(C)=O
Product: COc1cc(C)c(Cc2cnc(N)nc2N)cc1OC
Temperature: 85 °C
Reaction time: 3.5 h

Procedure:
In step 2, 3-(4,5-dimethoxy-2-methyl-phenyl)-2-methoxymethyl-acrylonitrile and sodium methoxide were dissolved in dry DMSO and stirred for 3.5 hours at 85° C. under nitrogen. Guanidine carbonate was then added to the stirring solution, after which the temperature was raised to 125° C. for three hours, during which methanol removed via a Dean-Stark trap. The solution was cooled to room temperature, diluted with water, and the crude filtrate was recrystallized in DMF to yield 5-(4,5-dimethoxy-2-methyl-benzyl)-pyrimidine-2,4-diamine as a white solid. Mp: 232° C. Mass Spec (M+H): 275.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[S:12][CH:13]=[CH:14][C:15]=2[NH2:16])=[O:10])=[CH:4][CH:3]=1.ClC1C=CC(N)=CC=1.[NH:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][N:32]=2)[C:27]([CH:34]=O)=[CH:26]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[S:12][CH:13]=[CH:14][C:15]=2[NH:16][CH2:34][C:27]2[C:28]3[C:33](=[N:32][CH:31]=[CH:30][CH:29]=3)[NH:25][CH:26]=2)=[O:10])=[CH:6][CH:7]=1
Reactant: O=Cc1c[nH]c2ncccc12
Reactant: Nc1ccsc1C(=O)Nc1ccc(Cl)cc1
Agent: Nc1ccc(Cl)cc1
Product: O=C(Nc1ccc(Cl)cc1)c1sccc1NCc1c[nH]c2ncccc12

Procedure:
Prepared according to the procedure described in EXAMPLE 5 using N-(4-chlorophenyl) 3-aminothiophene-2-carboxamide (prepared as described in EXAMPLE 1, part 1, using 4-chloroaniline instead of 4-trifluoromethoxyaniline) and 7-azaindole-3-carboxaldehyde (EXAMPLE 8, part 1) instead of 2-(N-methylcarbamoyl)pyridine-4-carboxaldehyde. MS (ES+): 383, 385 [MH+]