Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N(OCCC(C)C)=O.[CH2:9]([O:16][C:17]1[CH:44]=[CH:43][CH:42]=[CH:41][C:18]=1[O:19][C:20]1[CH:26]=[C:25]([N:27]2[C:32](=[O:33])[CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[N:29]([CH3:38])[C:28]2=[O:39])[C:24]([F:40])=[CH:23][C:21]=1N)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[ClH:45]>[Cu]Cl.[Cu](Cl)Cl.C(#N)C>[Cl:45][C:21]1[CH:23]=[C:24]([F:40])[C:25]([N:27]2[C:32](=[O:33])[CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[N:29]([CH3:38])[C:28]2=[O:39])=[CH:26][C:20]=1[O:19][C:18]1[CH:41]=[CH:42][CH:43]=[CH:44][C:17]=1[O:16][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(Oc3ccccc3OCc3ccccc3)c(N)cc2F)c1=O
Reactant: Cl
Agent: Cl[Cu]
Agent: Cl[Cu]Cl
Agent: CC(C)CCON=O
Solvent: CC#N
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(Oc3ccccc3OCc3ccccc3)c(Cl)cc2F)c1=O
Reaction time: 1 h

Procedure:
First, 4.46 g of isoamyl nitrite was added dropwise to a mixture of 6.46 g of 2-(2-benzyloxyphenoxy)-5-fluoro-4-[3-methyl-2,6,-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]aniline, 2.45 g of copper (I) chloride, 5.04 g of copper (II) chloride, and 90 ml of acetonitrile at room temperature, and the mixture was stirred for 1 hour. The reaction mixture was poured into 2% hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography to give 4.6 g of ([2-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}phenoxy]methyl)benzene.
Reaction SMILES: O=C1CCC(=O)N1O[C:9]([C:11]1[CH:12]=[CH:13][C:14]([C:18]2[C:23]([C:24]([F:27])([F:26])[F:25])=[CH:22][CH:21]=[CH:20][N:19]=2)=[N:15][C:16]=1[NH2:17])=[O:10].CC(C)([O-])C.[K+].[CH3:34][O:35][CH2:36][C:37](=O)[CH2:38][C:39]([O:41][CH3:42])=[O:40].O>C1COCC1>[CH3:42][O:41][C:39]([C:38]1[C:37]([CH2:36][O:35][CH3:34])=[N:17][C:16]2[C:11]([C:9]=1[OH:10])=[CH:12][CH:13]=[C:14]([C:18]1[C:23]([C:24]([F:25])([F:26])[F:27])=[CH:22][CH:21]=[CH:20][N:19]=1)[N:15]=2)=[O:40]
Reactant: COCC(=O)CC(=O)OC
Reactant: Nc1nc(-c2ncccc2C(F)(F)F)ccc1C(=O)ON1C(=O)CCC1=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: COCc1nc2nc(-c3ncccc3C(F)(F)F)ccc2c(O)c1C(=O)OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 6-amino-3′-trifluoromethyl-[2,2′]bipyridinyl-5-carboxylic acid 2,5-dioxo-pyrrolidin-1-yl ester (1-0.4 g, 27.3 mmol) in 50 mL dry THF is added in one portion to a mixture of potassium t-butoxide (7.36 g, 65.6 mmol) and methyl 4-methoxy-acetoacetate (8.77 g, 60.7 mmol) in dry THF (100 mL). The reaction is stirred overnight at room temperature. Water (30 mL) is added and the solution concentrated (˜30 mL). The resulting mixture is extracted with ether (2×50 mL). The aqueous portion is acidified with concentrated hydrochloric acid and extracted with CH2Cl2 (4×100 mL). The combined organic extracts are dried over Na2SO4 and the solvent removed under reduced pressure to yield the title compound as a light brown oil that solidifies upon standing.
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:5][CH2:4]1)#[N:2].C([N-]C(C)C)(C)C.[Li+].[Cl:22][CH2:23][CH2:24][CH2:25]I>O1CCCC1>[Cl:22][CH2:23][CH2:24][CH2:25][C:3]1([C:1]#[N:2])[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:5][CH2:4]1
Reactant: CCOC(=O)N1CCC(C#N)CC1
Reactant: ClCCCI
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)N1CCC(C#N)(CCCCl)CC1
Temperature: -10 °C
Yield: 64.6 %

Procedure:
To a solution of ethyl 4-cyano-1-piperidinecarboxylate (6.0 g) in tetrahydrofuran (120 ml) at −70° C., under nitrogen, was added a solution of lithium diisopropylamide (4.6 g) in tetrahydrofuran (21.5 ml), dropwise, with stirring. The reaction was allowed to warm to −10° C. and after 30 min was recooled to −70° C. A solution of 1-chloro-3-iodopropane (7.4 g) in tetrahydrofuran (20 ml) was added to the mixture over 30 min. The reaction mixture was quenched with water and allowed to warm to ambient temperature. The mixture was extracted with ethyl acetate. The extracts were washed with water, saturated sodium chloride solution, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was flash chromatographed (silica), eluting with 2:1 heptane/ethyl acetate. The appropriate fractions were collected and concentrated to afford 5.5 g (64%) of product.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][N:5]([CH2:7][CH:8]([C:28]2[S:29][CH:30]=[CH:31][N:32]=2)[O:9][C:10]2[CH:11]=[CH:12][C:13]([CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)=[C:14]([CH:18]=2)[C:15](O)=[O:16])[CH:6]=1.Cl.[CH3:34][O:35][C:36](=[O:43])[C@H:37]([CH2:39][CH2:40][S:41][CH3:42])[NH2:38].C(Cl)CCl>CN(C1C=CN=CC=1)C.ClCCl>[CH3:1][C:2]1[N:3]=[CH:4][N:5]([CH2:7][CH:8]([C:28]2[S:29][CH:30]=[CH:31][N:32]=2)[O:9][C:10]2[CH:11]=[CH:12][C:13]([CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)=[C:14]([CH:18]=2)[C:15]([NH:38][C@@H:37]([CH2:39][CH2:40][S:41][CH3:42])[C:36]([O:35][CH3:34])=[O:43])=[O:16])[CH:6]=1
Reactant: Cc1cn(CC(Oc2ccc(CCc3ccc(F)cc3)c(C(=O)O)c2)c2nccs2)cn1
Reactant: COC(=O)[C@@H](N)CCSC
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: ClCCCl
Product: COC(=O)[C@H](CCSC)NC(=O)c1cc(OC(Cn2cnc(C)c2)c2nccs2)ccc1CCc1ccc(F)cc1
Reaction time: 18 h
Yield: 88.9 %

Procedure:
A mixture of 5-[2-(4-methylimidazol-1-yl)-1-(thiazol-2-yl)ethoxy]-2-(4-fluorophenethyl)benzoic acid (0.4 g; 0.89 mM), L-methionine methyl ester hydrochloride (0.27 g, 1.35 mM) and DMAP (0.54 g, 4.43 mM) was stirred until solution and EDC (0.026 g, 1.35 mM) in dichloromethane was added and the mixture stirred for 18 hours. It was purified on silica using dichloromethane then methanol/dichloromethane (5:95) as eluant to give the title product (0.47 g, 89%) as a foam.
Reaction SMILES: [O:1]([C:8]1[N:13]=[CH:12][C:11]([CH2:14]O)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:18])=O.C(=O)(O)[O-].[Na+]>ClCCl>[Cl:18][CH2:14][C:11]1[CH:10]=[CH:9][C:8]([O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[N:13][CH:12]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1ccc(Oc2ccccc2)nc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: ClCc1ccc(Oc2ccccc2)nc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 89.8 %

Procedure:
To a dichloromethane (5.00 mL) solution of (6-phenoxy-pyridin-3-yl)-methanol (458 mg, 2.28 mmol) described in Manufacturing Example 193-1-1 was added dropwise thionyl chloride (333 μL, 4.56 mmol) on an ice bath (0° C.) under nitrogen atmosphere, which was stirred for 5 minutes at room temperature. Aqueous sodium bicarbonate was added to the reaction solution at room temperature, which was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was evaporated under a reduced pressure to obtain the title compound (450 mg, 89.8%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[CH2:10][CH2:11][NH:12][CH:13]1[CH2:18][CH2:17][N:16]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:15][CH2:14]1.CN([CH:29]=[O:30])C>>[CH2:19]([N:16]1[CH2:17][CH2:18][CH:13]([N:12]2[CH2:11][CH2:10][C:3]3[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=3[NH:1][C:29]2=[O:30])[CH2:14][CH2:15]1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CN(C)C=O
Reactant: COc1ccc(N)c(CCNC2CCN(Cc3ccccc3)CC2)c1
Product: COc1ccc2c(c1)CCN(C1CCN(Cc3ccccc3)CC1)C(=O)N2
Temperature: 100 °C
Reaction time: 2 h

Procedure:
35.0 g (216 mmol) N,N′-carbonyldiimidazole were added to 23.9 g (70.3 mmol) [2-(2-amino-5-methoxyphenyl)-ethyl]-(1-benzylpiperidin-4-yl)-amine in 175 mL DMF and the mixture was stirred for 2 h at 100° C. The reaction mixture was poured onto approx. 1 kg ice water and stirred overnight. The precipitated product was suction filtered, washed with water and dried. The residue was stirred with DIPE and suction filtered. The solid product was washed with DIPE and dried.
Reaction SMILES: Cl[CH2:2][C:3]1[N:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[C:11](=[O:20])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[F:21])[N:4]=1.[N:22]1[C:30]([NH2:31])=[C:29]2[C:25]([N:26]=[CH:27][NH:28]2)=[N:24][CH:23]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[NH2:31][C:30]1[N:22]=[CH:23][N:24]=[C:25]2[C:29]=1[N:28]=[CH:27][N:26]2[CH2:2][C:3]1[N:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[C:11](=[O:20])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[F:21])[N:4]=1
Reactant: O=c1c2c(F)cccc2nc(CCl)n1-c1ccccc1Cl
Reactant: Nc1ncnc2nc[nH]c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1ncnc2c1ncn2Cc1nc2cccc(F)c2c(=O)n1-c1ccccc1Cl
Yield: 64.3 %

Procedure:
Prepared according to Procedure C using Intermediate 2e (200 mg, 0.619 mmol), adenine (92 mg, 0.681 mmol), K2CO3 (94 mg, 0.680 mmol), and DMF (4 mL). The crude product was chromatographed in MeOH/CH2Cl2 to provide 168 mg of an off-white solid (64%), mp 159-172° C. (gradually decomposes). 1H NMR (DMSO-d6) δ: 8.10 (s, 1H); 8.08 (s, 1H); 7.73-7.89 (m, 3H); 7.57-7.71 (m, 2H); 7.37-7.48 (m, 2H); 7.34 (d, J=11 Hz, 1H); 7.30 (d, J=8.3 Hz, 1H); 5.14 (d, J=17 Hz, 1H); 4.94 (d, J=17 Hz, 1H). 13C NMR (DMSO-d6) ppm: 160.8 (d, J=264 Hz), 157.5 (d, J=4.2 Hz), 155.8, 152.4, 152.4, 150.0, 148.7, 142.1, 136.4 (d, J=11 Hz), 133.0, 132.2, 132.1, 131.2, 130.9, 129.4, 123.8 (d, J=3.6 Hz), 118.4, 114.5 (d, J=20 Hz), 110.2 (d, J=6.0 Hz), 44.9. MS (ES): m/z 422.0 (M+). Anal. calcd. for C20H13ClFN7O: C, 56.95; H, 3.11; Cl, 8.40; N, 23.24. Found: C, 54.62; H, 3.32; Cl, 9.40; N, 21.29.
Reaction SMILES: Cl.[F:2][C:3]1[C:8]([F:9])=[CH:7][CH:6]=[CH:5][C:4]=1[C@H:10]1[CH2:16][N:15]2[C:17]([CH2:20][C:21]([F:24])([F:23])[F:22])=[CH:18][N:19]=[C:14]2[C@H:13]([NH:25]C(=O)OC(C)(C)C)[CH2:12][CH2:11]1>O1CCOCC1>[F:2][C:3]1[C:8]([F:9])=[CH:7][CH:6]=[CH:5][C:4]=1[C@H:10]1[CH2:16][N:15]2[C:17]([CH2:20][C:21]([F:24])([F:22])[F:23])=[CH:18][N:19]=[C:14]2[C@H:13]([NH2:25])[CH2:12][CH2:11]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](c2cccc(F)c2F)Cn2c(CC(F)(F)F)cnc21
Agent: Cl
Solvent: C1COCCO1
Product: N[C@@H]1CC[C@@H](c2cccc(F)c2F)Cn2c(CC(F)(F)F)cnc21
Reaction time: 18 h

Procedure:
Hydrochloric acid (4.0 M in dioxane; 1 mL, 4.0 mmol) was added to a solution of tert-butyl [(6S,9R)-6-(2,3-difluorophenyl)-3-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydro-5H-imidazo[1,2-a]azepin-9-yl]carbamate (36.0 mg, 0.081 mmol) in dioxane (1 mL). After 18 h, the reaction mixture was concentrated to give the hydrochloride salt of the title compound. MS 346.1 (M+1).
Reaction SMILES: [S:1](=[O:5])(=[O:4])([OH:3])N.[C:6]1([NH2:16])[C:15]2[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=2[CH:9]=[CH:8][CH:7]=1>CN1CCCC1=O.ClC1C=CC=CC=1Cl>[NH2:16][C:6]1[C:15]2[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=2[C:9]([S:1]([OH:3])(=[O:5])=[O:4])=[CH:8][CH:7]=1
Reactant: Nc1cccc2c1CCCC2
Reactant: NS(=O)(=O)O
Solvent: Clc1ccccc1Cl
Solvent: CN1CCCC1=O
Product: Nc1ccc(S(=O)(=O)O)c2c1CCCC2
Temperature: 150 °C
Reaction time: 7 h
Yield: 48.6 %

Procedure:
A hot suspension of 20 g of sulphamic acid in 40 ml of N-methylpyrrolidone is added to a solution of 10 g of 5,6,7,8-tetrahydronaphthylamine in 100 ml of 1,2-dichlorobenzene. The mixture is heated with stirring for 7 hours at 150° C. The product is filtered off and washed with dichlorobenzene and then with toluene. The precipitate is resuspended in 70 ml of water and neutralized to pH 7 with 5.5 ml of 30% sodium hydroxide. The insoluble matter is filtered off and the aqueous phase is extracted with ether. The aqueous phase is adjusted to pH 5 by adding HCl, at 5° C.; the mixture is filtered, and the residue is washed with water and dried to obtain 7.5 g of the expected product.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)=[CH:11][C:10]=1[NH:20][C:21](=[O:27])[C:22]([O:24]CC)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH3:28]>CO>[NH2:28][C:22](=[O:24])[C:21]([NH:20][C:10]1[CH:11]=[C:12]([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)[CH:13]=[CH:14][C:9]=1[NH:8][C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:27]
Reactant: CCOC(=O)C(=O)Nc1cc(-c2cccs2)ccc1NC(=O)OC(C)(C)C
Reactant: N
Solvent: CO
Product: CC(C)(C)OC(=O)Nc1ccc(-c2cccs2)cc1NC(=O)C(N)=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 59.4 %

Procedure:
To a solution of ethyl 2-((2-((tert-butoxycarbonyl)amino)-5-(thiophen-2-yl)phenyl)amino)-2-oxoacetate (0.2 g, 0.512 mmol) in MeOH (2 mL) was added methanolic ammonia (5 mL, 0.512 mmol, 1 equiv.) in a sealed tube. The reaction was stirred at room temperature for five h. The obtained white solid was filtered and dried to afford tert-butyl (2-(2-amino-2-oxoacetamido)-4-(thiophen-2-yl)phenyl)carbamate (0.11 g, 59% yield).
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([C:12]([OH:14])=O)[S:7][C:8]=1[CH:9]([CH3:11])[CH3:10])([CH3:3])[CH3:2].[NH2:15][C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:17]=1>>[CH:1]([C:4]1[CH:5]=[C:6]([C:12]([NH:15][C:16]2[CH:17]=[CH:18][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:24][CH:25]=2)=[O:14])[S:7][C:8]=1[CH:9]([CH3:10])[CH3:11])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc(N)cc1
Reactant: CC(C)c1cc(C(=O)O)sc1C(C)C
Product: COC(=O)c1ccc(NC(=O)c2cc(C(C)C)c(C(C)C)s2)cc1
Yield: 86.3 %

Procedure:
In the same manner as that of Example 2, 4,5-diisopropylthiophene-2-carboxylic acid (86 mg, 0.406 mmol) was condensed with methyl 4-aminobenzoate (123 mg, 0.815 mmol), and the resultant was purified by silica gel chromatography [hexane-ethyl acetate (3:1)] to obtain methyl 4-[(4,5-diisopropylthiophene-2-carbonyl)amino]benzoate (121 mg, 86%) as colorless needles.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl[C:12]1[N:20]=[CH:19][N:18]=[C:17]2[C:13]=1[NH:14][CH:15]=[N:16]2>O>[CH2:3]([O:10][C:12]1[N:20]=[CH:19][N:18]=[C:17]2[C:13]=1[NH:14][CH:15]=[N:16]2)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: Clc1ncnc2nc[nH]c12
Reactant: OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: c1ccc(COc2ncnc3nc[nH]c23)cc1
Temperature: 100 °C

Procedure:
Sodiumhydride (60% Dispersion in mineral oil; 3.23 g; 80 mmol) was slowly added to benzyl alcohol (30 ml; 34.7 mmol). After the addition of more benzyl alcohol (10 ml) and 6-chloropurine (5.36 g;). The reaction mixture was heated to 100° C. for 4 hours. When the reaction mixture has reached room temperature, water (1 ml) was slowly added. 6-Benzyloxypurine was precipitated by the addition of acetic acid (4.6 ml) and diethylether (550 ml). The precipitate was separated by filtration (11.72 g). Re-crystallization from ether gave (4.78 g; 65.4%). Melting point was 175-177° C. (litt. 170-172° C.) [Ramazaeva N., 1989 #473] 1H-NMR (DMSO-d6): 8.53 (1H, s); 8.39 (1H, s); 7.54-7.35 (5H, m); 5.62 (2H, s).
Reaction SMILES: [CH:1]1([OH:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(OC([NH:14][C@:15]([C:24]1[O:28][C:27]([C:29]2[CH:30]=[C:31]([N:37]([CH3:42])[S:38]([CH3:41])(=[O:40])=[O:39])[CH:32]=[C:33]([CH2:35]Br)[CH:34]=2)=[N:26][N:25]=1)([CH3:23])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=O)(C)(C)C>>[NH2:14][C@:15]([C:24]1[O:28][C:27]([C:29]2[CH:30]=[C:31]([N:37]([CH3:42])[S:38]([CH3:41])(=[O:40])=[O:39])[CH:32]=[C:33]([CH2:35][O:6][CH:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[CH:34]=2)=[N:26][N:25]=1)([CH3:23])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: OC1CCCC1
Reactant: CN(c1cc(CBr)cc(-c2nnc([C@@](C)(Cc3ccccc3)NC(=O)OC(C)(C)C)o2)c1)S(C)(=O)=O
Product: CN(c1cc(COC2CCCC2)cc(-c2nnc([C@](C)(N)Cc3ccccc3)o2)c1)S(C)(=O)=O

Procedure:
Prepared from cyclopentanol and 3-(5-((R)-2-tert-butoxycarbonylamino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-5-(bromomethyl)-N-methyl-N-(methylsulfonyl)benzenamine using a similar procedure as described for the preparation of Example 40. 1H NMR (CD3OD) δ 7.93 (m, 2H), 7.68 (s, 1H), 7.32 (m, 3H), 7.09 (m, 2H), 4.59 (s, 2H), 4.10 (m, 1H), 3.45 (s, 2H), 3.38 (s, 3H), 2.96 (s, 3H), 1.88 (s, 3H), 1.78 (m, 6H), 1.60 (m, 2H).
Reaction SMILES: [OH:1][CH:2]([CH:6]([S:21][CH2:22][C:23](=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)[C:3]([NH2:5])=[O:4].N1C=CC=CC=1.[C:37](Cl)(=[O:39])[CH3:38]>C(Cl)Cl>[C:37]([O:1][CH:2]([CH:6]([S:21][CH2:22][C:23](=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)[C:3]([NH2:5])=[O:4])(=[O:39])[CH3:38]
Reactant: CC(=O)Cl
Reactant: COc1ccc(-c2ccccc2C(SCC(=O)c2ccccc2)C(O)C(N)=O)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(-c2ccccc2C(SCC(=O)c2ccccc2)C(OC(C)=O)C(N)=O)cc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a mixture of 4.0 g (0.0116 mol) of rac.-(R, R*)-α-hydroxy-4-methoxyphenyl-β-[(2-oxo-2-phenylethyl) thio]benzenepropanamide, 130 mL of methylene chloride and 5 mL of pyridine cooled in an ice-bath was added dropwise a solution of 1.25 g (0.0126 mol) of acetyl chloride in 25 mL of methylene chloride. The mixture was stirred at this temperature for one hour and at room temperature for 17 hours. After dilution with water the aqueous suspension was extracted with methylene chloride. The methylene chloride solution was dried (MgSO4) and removal of the solvent gave a residue which was washed with hexane. The crude product was crystallized from ethyl acetate to give 4.1 g (93%) of rac.-(R,*R*)-α-(acetyloxy)-4-methoxyphenyl-β-[(2-oxo-2-phenylethyl)thio]benzeneprop anamide, mp 154°-155°.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:13]([N:15]1[CH2:19][C:18]([F:21])([F:20])[C:17]([F:23])([F:22])[CH2:16]1)=[O:14])[C@@H:9]([CH3:12])[CH2:10][CH3:11])(C)(C)C.[ClH:25]>C(OCC)(=O)C>[ClH:25].[NH2:7][C@@H:8]([C@@H:9]([CH3:12])[CH2:10][CH3:11])[C:13]([N:15]1[CH2:19][C:18]([F:20])([F:21])[C:17]([F:23])([F:22])[CH2:16]1)=[O:14]
Reactant: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CC(F)(F)C(F)(F)C1
Agent: Cl
Solvent: CCOC(C)=O
Product: CC[C@H](C)[C@H](N)C(=O)N1CC(F)(F)C(F)(F)C1
Reaction time: 0.25 h

Procedure:
[(1S, 2S)-2-Methyl-1-(3,3,4,4-tetrafluoro-pyrrolidine-1-carbonyl)-butyl]-carbamic acid tert-butyl ester (200 mg, 0.56 mmol) was dissolved in ethyl acetate (4 mL), cooled to ° C. and treated with gaseous HCl for about 1 minute. After 15 minute at 0° C. and 30 minute at room temperature, the mixture was concentrated to dryness and the solid was triturated with hexane, collected and dried under vacuum overnight (124 mg, 76%, mp>250° C.).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C:5](=[CH:11]OCC)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].[I:16][C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][CH:23]=1)[NH2:20]>C1(C)C=CC=CC=1>[I:16][C:17]1[CH:18]=[C:19]([NH:20][CH:11]=[C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:15])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH:21]=[CH:22][CH:23]=1
Reactant: Nc1cccc(I)c1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Solvent: Cc1ccccc1
Product: CCOC(=O)C(=CNc1cccc(I)c1)C(=O)OCC

Procedure:
A mixture of ethoxymethylene malonic acid diethyl ester (13.72 g, 0.068 mol) and 3-iodoaniline (15 g, 0.068 mole) in toluene (230 ml) was refluxed for 1 h. After this period of time, solvents were removed under vacuum, and the crude material was precipitated in methyl tert-butyl ether and the resulting white solid was filtered, and dried under vacuum (24.3 g, 93%).
Reaction SMILES: [N:1]1([C:7]([OH:9])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[C:16]([N:19]1[C:27]2[C:22](=[CH:23][C:24]([C:28](=O)[CH2:29]Br)=[CH:25][CH:26]=2)[CH2:21][CH2:20]1)(=[O:18])[CH3:17]>C(#N)C>[C:16]([N:19]1[C:27]2[C:22](=[CH:23][C:24]([CH2:28][CH2:29][N:4]3[CH2:5][CH2:6][N:1]([C:7]([O:9][C:22]([CH3:27])([CH3:23])[CH3:21])=[O:8])[CH2:2][CH2:3]3)=[CH:25][CH:26]=2)[CH2:21][CH2:20]1)(=[O:18])[CH3:17]
Reactant: O=C(O)N1CCNCC1
Reactant: CC(=O)N1CCc2cc(C(=O)CBr)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(=O)N1CCc2cc(CCN3CCN(C(=O)OC(C)(C)C)CC3)ccc21
Temperature: 70 °C
Yield: 55 %

Procedure:
To a solution of piperazine-1-carboxylic acid tent-butyl ester (0.750 g, 4.03 mmol) in dry acetonitrile (20 mL) grounded potassium carbonate (0.486 mL, 8.05 mmol) was added followed by the product mixture from Example 38a (1.134 g) and the reaction was heated at 70° C. under argon over night. The acetonitrile was evaporated and DCM and water was added. The layers were separated and the aq phase was extracted with DCM (3×). The combined organic phases were dried (Na2SO4), filtered and evaporated. The crude mixture was purified by flash chromatography (heptane/EtOAc 75/25 to 0/100) to give 0.823 g (55%) of the title compound.
Reaction SMILES: [H-].[Na+].[CH:3]1[C:13]2[CH2:12][C:11]3[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=3[CH2:9][N:8]([C:18]([C:20]3[CH:25]=[CH:24][C:23]([NH:26][C:27](=[O:35])[C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[CH3:34])=[CH:22][CH:21]=3)=[O:19])[C:7]=2[CH:6]=[CH:5][CH:4]=1>O1CCCC1.CCOCC>[CH:3]1[C:13]2[CH2:12][C:11]3[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=3[CH2:9][N:8]([C:18]([C:20]3[CH:25]=[CH:24][C:23]([N:26]([CH2:7][N:8]([CH3:18])[CH3:9])[C:27](=[O:35])[C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[CH3:34])=[CH:22][CH:21]=3)=[O:19])[C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1ccccc1C(=O)N(CN(C)C)c1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc1
Reaction time: 1 h
Yield: 176.7 %

Procedure:
To a suspension of 14 mg of 60% sodium hydride in oil, in 2 ml of tetrahydrofuran is added 0.13 g of N-[4-[(6,11-dihydro-5H-dibenz[b,e]azepin-5-yl)carbonyl]phenyl]-2-methylbenzamide. The reactants are stirred for 1 hour and 62 mg of N,N-dimethyl-15 methylene ammonium iodide added followed by stirring for 2 hours. The mixture is diluted with 10 ml of ether and filtered. The filtrate is evaporated in vacuo to a residue which is stirred with hexanes to give 0.13 g of the desired product as a white solid, m.p. 131°-133° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][N:8]=2)[CH:3]=[CH:2]1.[Cl:10][C:11]1[CH:27]=[CH:26][C:14]([CH2:15][O:16][C:17]2[CH:24]=[CH:23][C:20]([CH:21]=[O:22])=[CH:19][C:18]=2[F:25])=[CH:13][CH:12]=1.[OH-].[K+].O>CO>[Cl:10][C:11]1[CH:27]=[CH:26][C:14]([CH2:15][O:16][C:17]2[CH:24]=[CH:23][C:20]([CH:21]([C:3]3[C:4]4[C:9](=[N:8][CH:7]=[CH:6][CH:5]=4)[NH:1][CH:2]=3)[OH:22])=[CH:19][C:18]=2[F:25])=[CH:13][CH:12]=1
Reactant: c1cnc2[nH]ccc2c1
Reactant: O=Cc1ccc(OCc2ccc(Cl)cc2)c(F)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: OC(c1ccc(OCc2ccc(Cl)cc2)c(F)c1)c1c[nH]c2ncccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 1H-Pyrrolo[2,3-b]pyridine (6, 100.0 mg, 0.85 mmol) in methanol (50.0 mL) were added 4-(4-chloro-benzyloxy)-3-fluoro-benzaldehyde (46, 250.0 mg, 0.94 mmol, prepared as described in Example 15) and potassium hydroxide (1.00 g, 17.82 mmol) under an atmosphere of nitrogen. The reaction was stirred at room temperature overnight. The reaction was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 30% ethyl acetate in hexane to give the compound (P-1895, 55 mg, 17.0%). MS (ESI) [M+H+]+=383.3.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH2:31])=[N:4][CH:5]=[N:6][C:7]=1[N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[N:15]([CH3:30])[CH:16]=[C:17](C3C=CC(F)=C(C(F)(F)F)C=3)[N:18]=2)[CH2:10][CH2:9]1.[F:32][C:33]1[CH:38]=[CH:37][C:36](C2N(C)C(C3CCNCC3)=NC=2)=[CH:35][C:34]=1[C:51]([F:54])([F:53])[F:52]>>[Br:1][C:2]1[C:3]([NH2:31])=[N:4][CH:5]=[N:6][C:7]=1[N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[N:15]([CH3:30])[C:16]([C:36]3[CH:37]=[CH:38][C:33]([F:32])=[C:34]([C:51]([F:54])([F:53])[F:52])[CH:35]=3)=[CH:17][N:18]=2)[CH2:12][CH2:13]1
Reactant: Cn1c(-c2ccc(F)c(C(F)(F)F)c2)cnc1C1CCNCC1
Reactant: Cn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2Br)CC1
Product: Cn1c(-c2ccc(F)c(C(F)(F)F)c2)cnc1C1CCN(c2ncnc(N)c2Br)CC1

Procedure:
The title compound was prepared in an analogous manner as 5-Bromo-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine using 4-[5-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1h-imidazol-2-yl]-piperidine instead of 4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1h-imidazol-2-yl]-piperidine. LC-MS: (M+1=499, obsd.=499).