Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)(C(F)(F)F)=O.[C:8]([C:11]1([C:14]2[CH:48]=[CH:47][CH:46]=[CH:45][C:15]=2[CH2:16][CH2:17][C:18]2[C:23]([Cl:24])=[CH:22][N:21]=[C:20]([NH:25][C:26]3[CH:27]=[CH:28][C:29]([CH:32]4[CH2:37][CH2:36][N:35](C(OC(C)(C)C)=O)[CH2:34][CH2:33]4)=[N:30][CH:31]=3)[N:19]=2)[CH2:13][CH2:12]1)(=[O:10])[NH2:9]>C(Cl)Cl>[Cl:24][C:23]1[C:18]([CH2:17][CH2:16][C:15]2[CH:45]=[CH:46][CH:47]=[CH:48][C:14]=2[C:11]2([C:8]([NH2:9])=[O:10])[CH2:13][CH2:12]2)=[N:19][C:20]([NH:25][C:26]2[CH:31]=[N:30][C:29]([CH:32]3[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]3)=[CH:28][CH:27]=2)=[N:21][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(Nc3ncc(Cl)c(CCc4ccccc4C4(C(N)=O)CC4)n3)cn2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC(=O)C1(c2ccccc2CCc2nc(Nc3ccc(C4CCNCC4)nc3)ncc2Cl)CC1
Reaction time: 16 h
Yield: 77 %

Procedure:
TFA (1 mL) was added to a solution of tert-butyl 4-(5-((4-(2-(1-carbamoylcyclopropyl)phenethyl)-5-chloropyrimidin-2-yl)amino)pyridin-2-yl)piperidine-1-carboxylate A19 (79.0 mg, 0.137 mmol) in DCM (5 mL) and stirred for 16 hours. The volatiles were removed in vacuo and the resultant residue loaded onto an SCX cartridge (5 g). The cartridge was washed with MeOH (100 mL) and then with 5% NH4OH in MeOH (100 mL). The basic fractions were combined and the solvent was removed in vacuo to give the title compound 15 as a white solid (50 mg, 77%). 1H NMR (400 MHz, d4-MeOD) δ 8.74 (s, 1H), 8.36 (s, 1H), 8.21 (dd, J=8.6, 2.7 Hz, 1H), 7.45-7.22 (m, 5H), 3.30-3.17 (m, 6H), 2.95-2.80 (m, 3H), 1.99-1.96 (m, 2H), 1.86-1.76 (m, 2H), 1.64-1.63 (m, 2H), 1.19-1.07 (m, 2H). LCMS-C: rt 4.17 min; m/z 477.1 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:16]=[CH:15][C:7]([CH2:8][N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[CH:6][CH:5]=1)([O-])=O.[H][H]>C(OCC)(=O)C>[NH2:1][C:4]1[CH:16]=[CH:15][C:7]([CH2:8][N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(CN2CCOCC2)cc1
Reactant: [H][H]
Solvent: CCOC(C)=O
Product: Nc1ccc(CN2CCOCC2)cc1

Procedure:
To a solution of 4-(4-Nitrobenzyl)morpholine from Preparation No. 21 (0.89 g) in ethyl acetate (10 mL) is added 5% platinuim on carbon (0.04 g). The reaction is shaken under 30 psi of hydrogen gas for 1 hour. The mixture is filtered with ethyl acetate washes. The filtrate is concentrated under reduced pressure to afford 0.71 g of the title compound as a yellow solid.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:31])[C:11]2[CH:16]=[C:15]([N+:17]([O-])=O)[C:14]([NH:20][CH3:21])=[CH:13][C:12]=2[N:22]2[CH2:26][CH2:25][CH:24]([C:27]([F:30])([F:29])[F:28])[CH2:23]2)[CH2:5][CH2:4]1.C1COCC1>[Pd].CO>[F:32][C:2]([F:1])([F:33])[C@H:3]1[CH2:4][CH2:5][C@H:6]([NH:9][C:10](=[O:31])[C:11]2[CH:16]=[C:15]([NH2:17])[C:14]([NH:20][CH3:21])=[CH:13][C:12]=2[N:22]2[CH2:26][CH2:25][CH:24]([C:27]([F:30])([F:28])[F:29])[CH2:23]2)[CH2:7][CH2:8]1
Reactant: CNc1cc(N2CCC(C(F)(F)F)C2)c(C(=O)N[C@H]2CC[C@H](C(F)(F)F)CC2)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CNc1cc(N2CCC(C(F)(F)F)C2)c(C(=O)N[C@H]2CC[C@H](C(F)(F)F)CC2)cc1N
Reaction time: 48 h

Procedure:
A mixture of N-(trans-4-trifluoromethyl-cyclohexyl)-2-[3-trifluoromethyl-pyrrolidinyl]-4-methylamino-5-nitro-benzoic acid amide (110 mg, 0.23 mmol), Pd/C (10 mg), THF (5 mL) and MeOH (10 mL) is stirred under 3 bar H2-atmosphere for 2 d. The mixture is filtered, and the filtrate is concentrated and directly used in the next step.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[N:6]1([C:11]2[CH:12]=[C:13]([CH:18]=[CH:19][CH:20]=2)[C:14]([O:16][CH3:17])=[O:15])[CH:10]=[CH:9][CH:8]=[CH:7]1.[C:21](=O)([O-])[O-:22].[K+].[K+]>CN(C)C=O>[CH:21]([C:10]1[N:6]([C:11]2[CH:12]=[C:13]([CH:18]=[CH:19][CH:20]=2)[C:14]([O:16][CH3:17])=[O:15])[CH:7]=[CH:8][CH:9]=1)=[O:22]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1cccc(-n2cccc2)c1
Agent: [K+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(-n2cccc2C=O)c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Phosphoryl chloride (5.5 ml) was dropwise added to N,N-dimethylformamide (4.6 ml) under ice-cooling and the mixture was stirred for 15 minutes at 40°-50° C. To the mixture was added a solution of methyl 3-(pyrrol-1-yl)benzoate (6.0 g) in N,N-dimethylformamide (30 ml) at ambient temperature and the whole was stirred for 3 hours at 110°-120° C. An ice-cooling mixture was poured into ice-water and the mixture was adjusted to pH 9 with potassium carbonate. The mixture was extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was triturated with diisopropyl ether to give methyl 3-(2-formylpyrrol-1-yl)benzoate (5.31 g).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([CH:13]=O)[N:5]=[CH:4][CH:3]=1.[C:15]([NH:18][NH2:19])(=[O:17])[CH3:16]>C(O)C>[C:15]([NH:18]/[N:19]=[CH:13]/[C:6]1[N:5]=[CH:4][CH:3]=[C:2]([Cl:1])[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9])(=[O:17])[CH3:16]
Reactant: CC(=O)NN
Reactant: CCOC(=O)c1c(Cl)ccnc1C=O
Solvent: CCO
Product: CCOC(=O)c1c(Cl)ccnc1/C=N/NC(C)=O
Yield: 73.6 %

Procedure:
To 2.1 g (9.83 mmol) of ethyl 4-chloro-2-formylnicotinate in 60 mL of ethanol was added 0.874 g (11.80 mmol) of acetohydrazide at room temperature. Then, the reaction mixture was heated under reflux for 2 h. The reaction mixture was extracted with water/DCM. The organic phase was washed with brine, dried, filtrated and concentrated to give 1.95 g (73.6%) of the title compound as white solid.
Reaction SMILES: C[Al](C)C.[CH3:5][C:6]([CH3:10])([CH3:9])[CH2:7][NH2:8].[C:11]([C:13]1[CH:18]=[CH:17][C:16]([CH:19]([CH3:25])[C:20](OCC)=[O:21])=[CH:15][CH:14]=1)#[N:12]>C(Cl)Cl>[CH3:5][C:6]([CH3:10])([CH3:9])[CH2:7][NH:8][C:20]([CH:19]([C:16]1[CH:15]=[CH:14][C:13]([C:11]#[N:12])=[CH:18][CH:17]=1)[CH3:25])=[O:21]
Reactant: CC(C)(C)CN
Reactant: CCOC(=O)C(C)c1ccc(C#N)cc1
Agent: C[Al](C)C
Solvent: ClCCl
Product: CC(C(=O)NCC(C)(C)C)c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 41 %

Procedure:
Add AlMe3 (1.72 mL, 3.44 mmol, 2M solution in hexane) to a solution of 2,2-dimethyl-propylamine (402 μL, 3.44 mmol) in DCM (0.5 mL) under nitrogen atmosphere. Stir the mixture for 15 min at room temperature and add ethyl 2-(4-cyanophenyl)propanoate. Heat the mixture at 40° C. overnight. Quench the reaction with 10N aqueous HCl and extract twice with DCM. Dry the combined organics extracts over Na2SO4, filter and concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc (7:3) to obtain the desired intermediate (170 mg, 41%).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([S:35][C:36]1[C:44]([Br:45])=[CH:43][C:39]3[O:40][CH2:41][O:42][C:38]=3[CH:37]=1)[N:6]2[C:11]1[CH:34]=[CH:33][C:14]([CH2:15][C@@H:16]([C:25]([O:27][CH:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)=[O:26])[NH:17]C(OC(C)(C)C)=O)=[CH:13][CH:12]=1.C(O)(C(F)(F)F)=O.CO.C(Cl)Cl>C(Cl)Cl>[NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([S:35][C:36]1[C:44]([Br:45])=[CH:43][C:39]3[O:40][CH2:41][O:42][C:38]=3[CH:37]=1)[N:6]2[C:11]1[CH:12]=[CH:13][C:14]([CH2:15][C@@H:16]([C:25]([O:27][CH:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)=[O:26])[NH2:17])=[CH:33][CH:34]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(-n2c(Sc3cc4c(cc3Br)OCO4)nc3c(N)ncnc32)cc1)C(=O)OC1CCCC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: Nc1ncnc2c1nc(Sc1cc3c(cc1Br)OCO3)n2-c1ccc(C[C@H](N)C(=O)OC2CCCC2)cc1
Yield: 53.1 %

Procedure:
A solution of cyclopentyl 4-{6-amino-8-[(6-bromo-1,3-benzodioxol-5-yl)thio]-9H-purin-9-yl}-N-(tert-butoxycarbonyl)-L-phenylalaninate (44 mg, 0.063 mmol) in TFA (250 μl, 3.24 mmol) and DCM (1 ml) was stirred at room temp for 2 h. Chromatography (silica gel, 2-5% MeOH/DCM) afforded the title compound (20 mg) as a pale yellow solid. m/z 597 (M+H)+. 1H NMR (400 MHz, CHCl3-d) d: 8.28 (1H, s), 7.32-7.40 (4H, m), 7.03 (1H, s), 6.93 (1H, s), 6.00 (1H, s), 5.53 (2H, s), 5.20 (1H, m), 3.71 (1H, dd, J=7.8, 5.4 Hz), 3.13 (1H, dd, J=13.7, 5.4 Hz), 2.90 (1H, dd, J=13.7, 7.8 Hz), 1.86 (2H, m), 1.75-1.55 (10H, br m).
Reaction SMILES: [CH3:1][C:2]1[C:6]([OH:7])=[C:5]([C:8]([O:10][CH2:11][CH2:12][CH3:13])=[O:9])[S:4][C:3]=1[C:14]([O:16][CH2:17][CH2:18][CH3:19])=[O:15].O1CCOCC1.C(=O)([O-])[O-].[K+].[K+].[Br:32][C:33]1[CH:38]=[CH:37][C:36]([S:39](Cl)(=[O:41])=[O:40])=[CH:35][CH:34]=1>CC(C)=O>[CH3:1][C:2]1[C:6]([O:7][S:39]([C:36]2[CH:37]=[CH:38][C:33]([Br:32])=[CH:34][CH:35]=2)(=[O:41])=[O:40])=[C:5]([C:8]([O:10][CH2:11][CH2:12][CH3:13])=[O:9])[S:4][C:3]=1[C:14]([O:16][CH2:17][CH2:18][CH3:19])=[O:15]
Reactant: CCCOC(=O)c1sc(C(=O)OCCC)c(O)c1C
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CC(C)=O
Product: CCCOC(=O)c1sc(C(=O)OCCC)c(OS(=O)(=O)c2ccc(Br)cc2)c1C

Procedure:
A mixture of 2.3 g (8 mmol) of dipropyl 3-methyl-4-hydroxy-2,5-thiophene-dicarboxylate, 20 ml of dioxane, 40 ml of acetone, 1.6 g (12 mmol) of anhydrous potassium carbonate and 2.3 g (10 mmol) of 4-bromobenzene-sulfonyl chloride was refluxed for about 10 hours, removed of dioxane and acetone by distillation, added with ethyl ether, washed with water, and dried with anhydrous magnessium sulfate. The solvent was removed by distillation, and recrystallization was effected with use of methanol to give 3.8 g (94%) of the desired white crystalline compound, m.p. 73°-74° C.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([N:10]([CH3:12])[CH3:11])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[N+:13]([CH2:16][CH2:17][CH3:18])([O-:15])=[O:14].C([O-])(=O)C.[NH4+].O>C(O)CC>[CH3:11][N:10]([CH3:12])[C:8]1[CH:7]=[CH:6][C:3]([CH:4]=[C:16]([N+:13]([O-:15])=[O:14])[CH2:17][CH3:18])=[C:2]([Cl:1])[CH:9]=1
Reactant: CN(C)c1ccc(C=O)c(Cl)c1
Reactant: CCC[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CCCO
Solvent: O
Product: CCC(=Cc1ccc(N(C)C)cc1Cl)[N+](=O)[O-]

Procedure:
A solution of 36.8 g of 2-chloro-4-dimethylaminobenzaldehyde, 25 ml of 1-nitropropane and 20 g of ammonium acetate in 150 ml of 1-propanol is refluxed for 15 hours. The mixture is then poured into 1.5 l of water whereupon the compound separates as a viscous red oil. Recrystallization twice from aqueous acetic acid yields 5.0 g of the compound, melting at 90°-91°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[CH:9]=2)[C:4]=1Br.C([Li])CCC.C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:37])(=O)=O)=CC=1>C1COCC1.O>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[CH:9]=2)[C:4]=1[F:37]
Reactant: COc1ccc(-c2ccc3c(Br)c(OC)ccc3c2)cc1
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(-c2ccc3c(F)c(OC)ccc3c2)cc1
Temperature: -78 °C
Yield: 62.8 %

Procedure:
To a solution of 2-methoxy-6-(4-methoxyphenyl)-1-bromonaphthalene (1.28 g, 3.72 mmol) in THF (25 mL) at −78° C. was slowly added n-butyl lithium (1.9 mL of 2.5 N in hexanes). The resulting solution was stirred at −78° C. for thirty minutes and a solution of N-fluorobenzenesulfonimide (1.40 g, 4.5 mmol) in THF (10 mL) was added. After 2 additional hr at −78° C., the reaction was warmed to room temperature, poured in water, and extracted with ethyl acetate (2×250 mL). The combined organic layers were washed with water, dried over sodium sulfate, filtered, evaporation of the solvent, and purification by silica chromatography (5% THF—hexanes) yielded 0.66 g (63%) of a white solid: mp 150-155° C.; 1H NMR (CDCl3): δ 3.88 (3H, s), 4.04 (3H, s), 7.02 (2H, d, J=8.69 Hz), 7.28-7.34 (1H, m), 7.62-7.67 (3H, m), 7.74 (1H, dd, J=1.60 Hz, J=8.79 Hz), 7.93 (1H, s), 8.09 (1H, d, J=8.77 Hz).
Reaction SMILES: [CH:1]1([C:4]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][C:11]=3[N+:13]([O-])=O)[N:6]([CH2:16][C:17]3[C:18](=[O:24])[N:19]([CH3:23])[CH:20]=[CH:21][CH:22]=3)[N:5]=2)[CH2:3][CH2:2]1.[Cl-].[NH4+]>C(O)C.O.C(OCC)(=O)C.[Fe]>[NH2:13][C:11]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:12]=1[C:4]([CH:1]1[CH2:3][CH2:2]1)=[N:5][N:6]2[CH2:16][C:17]1[C:18](=[O:24])[N:19]([CH3:23])[CH:20]=[CH:21][CH:22]=1
Reactant: Cn1cccc(Cn2nc(C3CC3)c3c([N+](=O)[O-])cccc32)c1=O
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cn1cccc(Cn2nc(C3CC3)c3c(N)cccc32)c1=O
Temperature: 75 °C

Procedure:
3-((3-Cyclopropyl-4-nitro-1H-indazol-1-yl)methyl)-1-methylpyridin-2(1H)-one (413 mg, 1.27 mmol) was dissolved in a mixture of ethanol (6.8 mL) and water (1.7 mL). Ammonium chloride (34 mg; 0.63 mmol) and iron powder (709 mg; 12.7 mmol) were added and the mixture was stirred with heating to 75° C. under a nitrogen atmosphere for 16 hours. The mixture was allowed to cool, diluted with ethyl acetate (50 mL) and filtered through a pad of Celite®. The filtrate was concentrated under reduced pressure to give the crude product as a colored oil. Purification using a silica gel preparative thin layer chromatography plate (20×20 cm, 2 mm) developed in a chamber with 40% ethyl acetate/dichloromethane, drying, and eluting with 80% ethyl acetate/dichloromethane gave 3-((4-amino-3-cyclopropyl-1H-indazol-1-yl)methyl)-1-methylpyridin-2(1H)-one as a viscous oil which began to crystallize upon drying under high vacuum (175 mg).
Reaction SMILES: [C:1]([C:3]([C:6]1[CH:7]=[C:8]([CH:33]=[CH:34][CH:35]=1)[C:9]([NH:11][C:12]1[CH:13]=[CH:14][C:15]([CH3:32])=[C:16]([NH:18][C:19]([C:21]2[S:31][C:24]3=[N:25][C:26]([NH:29][CH3:30])=[CH:27][N:28]=[C:23]3[CH:22]=2)=[O:20])[CH:17]=1)=[O:10])([CH3:5])[CH3:4])#[N:2].Cl[C:37]1N=C2SC(C(NC3C=C(NC(=O)C4C=CC=C(C(C#N)(C)C)C=4)C=CC=3C)=O)=CC2=NC=1.Cl.C(N)C.C(N(CC)CC)C>>[C:1]([C:3]([C:6]1[CH:7]=[C:8]([CH:33]=[CH:34][CH:35]=1)[C:9]([NH:11][C:12]1[CH:13]=[CH:14][C:15]([CH3:32])=[C:16]([NH:18][C:19]([C:21]2[S:31][C:24]3=[N:25][C:26]([NH:29][CH2:30][CH3:37])=[CH:27][N:28]=[C:23]3[CH:22]=2)=[O:20])[CH:17]=1)=[O:10])([CH3:5])[CH3:4])#[N:2]
Reactant: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1NC(=O)c1cc2ncc(Cl)nc2s1
Reactant: CNc1cnc2cc(C(=O)Nc3cc(NC(=O)c4cccc(C(C)(C)C#N)c4)ccc3C)sc2n1
Agent: CCN
Agent: Cl
Solvent: CCN(CC)CC
Product: CCNc1cnc2cc(C(=O)Nc3cc(NC(=O)c4cccc(C(C)(C)C#N)c4)ccc3C)sc2n1
Yield: 12 %

Procedure:
Preparation analogous to 96a by using 3-chloro-N-(5-(3-(2-cyanopropan-2-yl)benzamido)-2-methylphenyl)thieno[2,3-b]pyrazine-6-carboxamide 95 (0.049 mmol, 24 mg), ethylamine hydrochloride (1.22 mmol, 100 mg) and triethylamine (1.71 mmol, 239 μL) to give N-(5-(3-(2-cyanopropan-2-yl)benzamido)-2-methylphenyl)-3-(ethylamino)thieno[2,3-b]pyrazine-6-carboxamide 96i (3 mg, 12%). NMR (400 MHz, DMSO-d6) 1.21 (t, J=7.0 Hz, 3H), 1.76 (s, 6H), 2.25 (s, 3H), 3.37 (m, 2H), 7.28 (d, J=8.2 Hz, 1H), 7.61 (m, 2H), 7.75 (d, J=8.2 Hz, 1H), 7.83 (m, 2H), 7.95 (d, J=7.8 Hz, 1H), 8.05 (s, 1H), 8.10 (s, 1H), 8.24 (s, 1H), 10.08 (s, 1H), 10.33 (s, 1H). (m/z)=500 (M+H)+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(OC([NH:14][CH2:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][CH:17]=1)=O)(C)(C)C>>[N:1]1([C:20]([C:19]2[CH:23]=[CH:24][C:16]([CH2:15][NH2:14])=[CH:17][CH:18]=2)=[O:21])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)NCc1ccc(C(=O)O)cc1
Reactant: C1CCNCC1
Product: NCc1ccc(C(=O)N2CCCCC2)cc1
Yield: 100 %

Procedure:
Use the General Procedure 6-1, using piperidine (373 mg, 4.4 mmol) and 4-(tert-butoxycabonylamino-methyl)-benzoic acid to give the title compound as a white solid (1.03 g, 100%). MS (ES+) m/z: 219 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[N:10]([CH3:19])[C:9]2=[O:20])=[C:4]([O:21]C)[CH:3]=1.B(Br)(Br)Br.C(=O)([O-])O.[Na+]>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[CH:12]=[C:11]([C:15]([F:18])([F:16])[F:17])[N:10]([CH3:19])[C:9]2=[O:20])=[C:4]([OH:21])[CH:3]=1
Reactant: COc1cc(Cl)ccc1-n1c(=O)cc(C(F)(F)F)n(C)c1=O
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc(Cl)cc2O)c1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 70.3 %

Procedure:
41.0 g (122.5 mmol) of 3-(4-chloro-2-methoxyphenyl)-1-methyl-6-trifluoromethyluracil was dissolved in 1000 ml of dichloromethane, and 470 ml (470.8 mmol) of boron tribromide (1.0M dichloromethane solution) was dropwise added at from -10° C. to -5° C. After stirring at room temperature for 3 hours, the reaction solution was poured into ice water and neutralized with sodium hydrogencarbonate. It was extracted with dichloromethane. The organic layer was washed sequentially with water and a saturated sodium chloride aqueous solution and then, dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. Then, the obtained crude crystals were washed with isopropyl ether to obtain 27.6 g (yield: 70.3%) of the desired product as white crystals. Melting point: 198-202° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][N:3]=1.[C-]#N.[K+].O.C(N)[CH2:14][NH2:15]>CC(N(C)C)=O>[F:8][C:5]1[CH:6]=[CH:7][C:2]([C:14]#[N:15])=[N:3][CH:4]=1
Reactant: Fc1ccc(Br)nc1
Reactant: NCCN
Agent: [C-]#N
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: N#Cc1ccc(F)cn1
Temperature: 65 °C

Procedure:
2-Bromo-5-fluoropyridine (recrystallized from 0.3 volumes of pentane, 1240 g, 1 equivalent) was dissolved in dimethylacetamide (2 volumes), the mixture was heated to 60-70° C. and cuprous cyanide (0.4 equivalents) was added in one portion, giving a dark green solution. Heating was continued and potassium cyanide (1.2 equivalents) was added in portions above 90° C. After completion of the addition, the resulting brown suspension was heated to 145° C. for 5 hours. The reaction mixture was allowed to cool to room temperature and poured into cold water (14 volumes). Ethylene diamine (1.2 equivalents) was added and the solution extracted with methyl t-butyl ether (4×5 volumes). The combined extracts were dried filtered and evaporated in vacuo with a bath temperature no higher than 45° C. The crude solid was purified by silica pad chromatography (5 w/w silica; 10-33% methyl t-butyl ether in 40/60 petroleum ether). Product containing fractions were evaporated to give a white crystalline solid. Mp 40-41° C., 541 g, 62.9% theory.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:14](=[O:34])[CH2:15][N:16]4[CH2:21][CH2:20][CH2:19][CH:18]([CH2:22][O:23][C:24]5[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=5)[CH2:17]4)[CH2:13][CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.[BH4-].[Na+].O>CO>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([CH:14]([OH:34])[CH2:15][N:16]4[CH2:21][CH2:20][CH2:19][CH:18]([CH2:22][O:23][C:24]5[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:31])[F:32])=[CH:26][CH:25]=5)[CH2:17]4)[CH2:13][CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: O=C(CN1CCCC(COc2ccc(C(F)(F)F)cc2)C1)C1(c2ccc3c(c2)OCO3)CCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: OC(CN1CCCC(COc2ccc(C(F)(F)F)cc2)C1)C1(c2ccc3c(c2)OCO3)CCC1
Yield: 66.4 %

Procedure:
1-(1-Benzo[1,3]dioxol-5-yl-cyclobutyl)-2-[3-(4-trifluoromethyl-phenoxymethyl)-piperidin-1-yl]-ethanone (15 mg) was dissolved in 2 mL of dry methanol and solid sodium borohydride (10 equiv.) was added in portions. Water (5 mL) was added and the mixture was extracted with ether and the ether extracts were concentrated in vacuo and purified on silica gel to give the desired 1-(1-benzo[1,3]dioxol-5-yl-cyclobutyl)-2-[3-(4-trifluoromethyl-phenoxymethyl)-piperidin-1-yl]-ethanol (10 mg, 66%). Data for this mixture of diastereomeric amino alcohols: MS 478 (M+1); 1H NMR (300 MHz, CDCl3) partial: δ 6.7-7.8 (m, 7H), 3.85-3.95 (m, 2H, methylene adjacent to aryl ether), the δ 3.1 singlet for the starting material was absent.
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=1[O:19][CH3:20])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9]C)=O.[C:21]1([N:27]2[CH:31]=[C:30]([CH:32]=O)[CH:29]=[N:28]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH3:20][O:19][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]([O:17][CH3:18])[C:11]=1[CH:2]1[N:1]([CH2:32][C:30]2[CH:29]=[N:28][N:27]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:31]=2)[C:7](=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: O=Cc1cnn(-c2ccccc2)c1
Reactant: COC(=O)CCCCC(N)c1c(OC)cccc1OC
Product: COc1cccc(OC)c1C1CCCCC(=O)N1Cc1cnn(-c2ccccc2)c1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 6-amino-6-(2,6-dimethoxyphenyl)hexanoate with commercially available 1-phenyl-1H-pyrazole-4-carbaldehyde. Subsequent purification by preparative HPLC the target compound. LC-MS (conditions I): tR=1.27 min.; [M+H]+: 405.81 g/mol.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][N:12]=[CH:11][C:10]=2[C:14]([OH:16])=O)=[CH:5][CH:4]=1.C(O)(=O)C(O)=O.[CH3:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([CH:33]2[CH2:37][CH2:36][NH:35][CH2:34]2)=[CH:29][CH:28]=1>>[CH3:25][O:26][C:27]1[CH:28]=[CH:29][C:30]([CH:33]2[CH2:37][CH2:36][N:35]([C:14]([C:10]3[CH:11]=[N:12][O:13][C:9]=3[C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:18])[F:17])=[CH:8][CH:7]=3)=[O:16])[CH2:34]2)=[CH:31][CH:32]=1
Reactant: COc1ccc(C2CCNC2)cc1
Reactant: O=C(O)c1cnoc1-c1ccc(C(F)(F)F)cc1
Agent: O=C(O)C(=O)O
Product: COc1ccc(C2CCN(C(=O)c3cnoc3-c3ccc(C(F)(F)F)cc3)C2)cc1

Procedure:
The title compound was prepared from 5-(4-trifluoromethylphenyl)isoxazole-4-carboxylic acid (12.9 mg, 0.050 mmol) and 3-(4-methoxyphenyl)pyrrolidine oxalat (16.0 mg, 0.060 mmol) as described in synthetic method C and thereafter purified by preparative HPLC method B to give a solid (6.5 mg). Calcd for C22H19F3N2O3: 416.1348, found 416.1348.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([NH2:10])=[CH:9][C:4]=2[O:3][CH2:2]1.CCN(CC)CC.[C:18](Cl)(=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20]>CCOCC.C1COCC1>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([NH:10][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CC(C)(C)C(=O)Cl
Reactant: Nc1ccc2c(c1)OCO2
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)Nc1ccc2c(c1)OCO2
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 1,3-benzodioxol-5-amine (10 g, 73 mmol) in 200 ml Et2O and 100 ml THF, NEt3 (12.3 ml, 87.6 mmol) is added. The reaction mixture is cooled to 0° C. and pivaloyl chloride (10.5 ml, 87.6 mmol) in THF is added. After stirring for 1 h at 25° C., ice water is added, the mixture extracted with EtOAc and washed with brine, followed by drying (Na2SO4), evaporation of volatiles, and crystallization (CH2Cl2/hexanes) which gives N-benzo[1,3]dioxol-5-yl-2,2-dimethyl-propionamide.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[C:8]([O:10][CH2:11][C:12]([F:15])([F:14])[F:13])[CH:7]=[CH:6][C:5]=1[O:16][CH2:17][C:18]([F:21])([F:20])[F:19])=[O:3].[Cl:22][C:23]1[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][CH:24]=1.CO.[OH-].[Na+]>C(OCC)(=O)C>[F:21][C:18]([F:19])([F:20])[CH2:17][O:16][C:5]1[CH:6]=[CH:7][C:8]([O:10][CH2:11][C:12]([F:13])([F:14])[F:15])=[CH:9][C:4]=1[C:2](=[O:3])[CH:1]=[CH:27][C:26]1[CH:29]=[CH:30][C:23]([Cl:22])=[CH:24][CH:25]=1
Reactant: CC(=O)c1cc(OCC(F)(F)F)ccc1OCC(F)(F)F
Reactant: O=Cc1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: O=C(C=Cc1ccc(Cl)cc1)c1cc(OCC(F)(F)F)ccc1OCC(F)(F)F

Procedure:
The title compound was prepared by stirring a mixture of 2,5-bis(2,2,2-trifluoroethoxy)acetophenone (200 mg, 0.633 mmol), 4-chlorobenzaldehyde (89 mg, 0.633 mmol), methanol (5 ml) and saturated NaOH (200 ul) at room temperature for 4 h. The mixture was diluted with ethyl acetate (100 ml), wash with water (50 ml) and saturated aqueous NaCl (50 ml), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography using hexane:ethyl acetate (5:1, 4:1) to give a yellow solid (143 mg, 51%). 1H NMR (CDCl3): 7.65 (d, J=15.9 Hz, 1H), 7.54 (d, J=8.4 Hz, 2H), 7.44 (d, J=15.9 Hz, 1H), 7.38 (d, J=8.4 Hz, 2H), 7.31 (d, J=3.3 Hz, 1H), 7.14 (dd, J=3.3, 9.3 Hz, 1H), 6.95 (d, J=9.0 Hz, 1H), 4.45-4.32 (m, 4H).