Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(S[C:6](=[O:23])[CH:7]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH:22]=[CH:21][CH:20]=[N:19]2)=[CH:14][CH:13]=1)[C:8](=[O:10])[CH3:9])(C)(C)C.[NH2:24][C:25]1[CH:26]=[C:27]([OH:32])[CH:28]=[CH:29][C:30]=1[F:31]>>[F:31][C:30]1[CH:29]=[CH:28][C:27]([OH:32])=[CH:26][C:25]=1[NH:24][C:6](=[O:23])[CH:7]([CH2:11][C:12]1[CH:13]=[CH:14][C:15]([N:18]2[CH:22]=[CH:21][CH:20]=[N:19]2)=[CH:16][CH:17]=1)[C:8](=[O:10])[CH3:9]
Reactant: Nc1cc(O)ccc1F
Reactant: CC(=O)C(Cc1ccc(-n2cccn2)cc1)C(=O)SC(C)(C)C
Product: CC(=O)C(Cc1ccc(-n2cccn2)cc1)C(=O)Nc1cc(O)ccc1F

Procedure:
The title compound was prepared by the method of Preparation 11b using 3-oxo-2-(4-pyrazol-1-ylbenzyl)thiobutyric acid S-tert-butyl ester and 3-amino-4-fluorophenol.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=2[CH3:22])=[CH:9][C:8]=1[CH3:23])[CH3:2].C(O)(=O)C.[H][H]>C(O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:24])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=2[CH3:22])=[CH:9][C:8]=1[CH3:23])[CH3:2]
Reactant: CCOC(=O)C=Cc1ccc(Oc2cc(OC)ccc2C)cc1C
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)CCc1ccc(Oc2cc(OC)ccc2C)cc1C
Reaction time: 8 h
Yield: 85.6 %

Procedure:
A solution of 3-[4-(5-methoxy-2-methyl-phenoxy)-2-methyl-phenyl]-acrylic acid ethyl ester (1.18 g, 3.63 mmol) and palladium under carbon (10%) (0.39 g, 0.36 mmol) in ethanol (20 mL) and acetic acid (2 mL) is stirred under 1 atm of hydrogen. After stirring overnight, the mixture is filtered off through Celite and washed with methanol. The mixture is concentrated under reduced pressure and purified by flash chromatography by eluting with hexane:ethyl acetate 5:1 to afford the title compound (1.02 g, 85%). Rf=0.42 (hexane:ethyl acetate 5:1). 1H NMR (300 MHz, CDCl3): δ1.26 (t, 3H, J=6.9 Hz), 2.16 (s, 3H), 2.28 (s, 3H), 2.56 (t, 2H, J=7.3 Hz), 2.90 (t, 2H, J=7.3 Hz), 3.72 (s, 3H), 4.17 (q, 2H, J=6.9 Hz), 6.45 (d, 1H, J=2.4 Hz), 6.62 (dd, 1H, J=2.8, 8.5 Hz), 6.67 (dd, 1H, J=2.4, 8.1 Hz), 6.74 (d, 1H, J=2.4 Hz), 7.06 (d, 1H, J=8.1 Hz), 7.13 (d, 1H, J=8.1 Hz).
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@H:13]([CH2:14][CH3:15])[NH:12][C:11](=[O:16])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].I[C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[C:20]([C:26]([F:29])([F:28])[F:27])[CH:19]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(OCC)(=O)C.O>[Si:1]([O:8][C@H:9]1[CH2:10][C:11](=[O:16])[N:12]([C:18]2[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[C:20]([C:26]([F:27])([F:29])[F:28])[CH:19]=2)[C@H:13]1[CH2:14][CH3:15])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: N#Cc1ccc(I)cc1C(F)(F)F
Reactant: CC[C@@H]1NC(=O)C[C@@H]1O[Si](C)(C)C(C)(C)C
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC[C@H]1[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)N1c1ccc(C#N)c(C(F)(F)F)c1
Temperature: 80 °C
Reaction time: 18 h
Yield: 76.3 %

Procedure:
A suspension of (4S,5S)-4-(tert-butyldimethylsilyloxy)-5-ethylpyrrolidin-2-one (6.00 g), 4-iodo-2-trifluoromethylbenzonitrile (8.42 g), cesium carbonate (12.05 g), tris(dibenzylideneacetone)dipalladium(0) (1.13 g) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (2.14 g) in toluene (70 mL) was stirred at 80° C. for 18 hr. Water and ethyl acetate were added to the reaction mixture and insuluble material was filtered off. The filtrate was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=50/1→1/2) to give the title compound as a pale-yellow solid (yield: 7.76 g, 76%).
Reaction SMILES: B1C2CCCC1CCC2.[CH2:10]([NH:13][S:14]([CH2:17][CH2:18][CH3:19])(=[O:16])=[O:15])[CH:11]=[CH2:12].FC(F)(F)S(O[C:26]1[CH:35]=[CH:34][C:33]2[CH2:32][CH2:31][CH:30]([NH:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH:29]([CH2:44][C:45]3[CH:50]=[CH:49][C:48]([Cl:51])=[CH:47][CH:46]=3)[C:28]=2[CH:27]=1)(=O)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCCC1.C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O1CCOCC1>[C:40]([O:39][C:37](=[O:38])[NH:36][CH:30]1[CH2:31][CH2:32][C:33]2[C:28](=[CH:27][C:26]([CH2:12][CH2:11][CH2:10][NH:13][S:14]([CH2:17][CH2:18][CH3:19])(=[O:16])=[O:15])=[CH:35][CH:34]=2)[CH:29]1[CH2:44][C:45]1[CH:50]=[CH:49][C:48]([Cl:51])=[CH:47][CH:46]=1)([CH3:43])([CH3:41])[CH3:42]
Reactant: C=CCNS(=O)(=O)CCC
Reactant: CC(C)(C)OC(=O)NC1CCc2ccc(OS(=O)(=O)C(F)(F)F)cc2C1Cc1ccc(Cl)cc1
Agent: [Pd+2]
Agent: B1C2CCCC1CCC2
Agent: CC(=O)[O-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCCS(=O)(=O)NCCCc1ccc2c(c1)C(Cc1ccc(Cl)cc1)C(NC(=O)OC(C)(C)C)CC2

Procedure:
To a solution of 9-BBN (0.5 M in tetrahydrofuran, 8.85 mL, 4.42 mmol) was added dropwise a solution N-allylpropane-1-sulfonamide (1152 mg, 7.06 mmol) in tetrahydrofuran (1 mL) a 0° C. After stirring at 0° C. to 5° C. for 3.5 hours dioxane (25 mL) was added followed by 7-(tert-butoxycarbonylamino)-8-(4-chlorobenzyl)-5,6,7,8-tetrahydronaphthalen-2-yl trifluoromethanesulfonate (1000 mg, 1.923 mmol, prepared analogously to example 34.3), palladium acetate (43.2 mg, 0.192 mmol), triphenylphosphine (101 mg, 0.385 mmol) and cesium carbonate (1253 mg, 3.85 mmol). The yellow reaction mixture was heated under reflux for 3 hours. The reaction mixture was diluted with ethyl acetate (60 mL) and washed with water (2×40 mL). The organic layer was dried and concentrated in vacuo. The crude product was purified by flash chromatography (silica gel, dichloro methane, methanol).
Reaction SMILES: C([O:3][C:4](=[O:19])[CH2:5][NH:6][C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([C:16](=[NH:18])[NH2:17])=[CH:12][CH:11]=1)=[O:8])C.[OH-].[Na+]>C(O)C>[C:16]([C:13]1[CH:12]=[CH:11][C:10]([NH:9][C:7](=[O:8])[NH:6][CH2:5][C:4]([OH:19])=[O:3])=[CH:15][CH:14]=1)(=[NH:17])[NH2:18]
Reactant: CCOC(=O)CNC(=O)Nc1ccc(C(=N)N)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: N=C(N)c1ccc(NC(=O)NCC(=O)O)cc1
Yield: 113.3 %

Procedure:
A solution of 2-[3-(4-carbamimidoylphenyl)ureido]acetic acid ethyl ester (24.48 g, 0.0926 mol, compound of example 3c) in ethanol (100 ml) and NaOH (3.705 g, 0.0926 mol, in 5 ml water) was stirred for 22 h at room temperature. The precipitate was filtered off and washed with ethanol to give 24.78 g of the title compound. MS 258.2 (M)+
Reaction SMILES: Cl.Cl.[N:3]1([CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:22]=[C:21]3[C:16]([CH2:17][CH2:18][NH:19][CH2:20]3)=[CH:15][CH:14]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.CCN(CC)CC.[CH2:30]([C:34]1[CH:39]=[CH:38][C:37]([S:40](Cl)(=[O:42])=[O:41])=[CH:36][CH:35]=1)[CH2:31][CH2:32][CH3:33]>>[CH2:30]([C:34]1[CH:39]=[CH:38][C:37]([S:40]([N:19]2[CH2:18][CH2:17][C:16]3[C:21](=[CH:22][C:13]([O:12][CH2:11][CH2:10][CH2:9][N:3]4[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]4)=[CH:14][CH:15]=3)[CH2:20]2)(=[O:42])=[O:41])=[CH:36][CH:35]=1)[CH2:31][CH2:32][CH3:33]
Reactant: c1cc2c(cc1OCCCN1CCCCC1)CNCC2
Reactant: CCCCc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: CCN(CC)CC
Product: CCCCc1ccc(S(=O)(=O)N2CCc3ccc(OCCCN4CCCCC4)cc3C2)cc1

Procedure:
2-(4-n-Butyl-benzenesulfonyl)-7-(3-piperidin-1-yl-propoxy)-1,2,3,4-tetrahydro-isoquinoline is prepared from 7-(3-piperidin-1-yl-propoxy)-1,2,3,4-tetrahydro-isoquinoline dihydrochloride (175 mg, 0.5 mmol), NEt3 (0.25 mL, 1.8 mmol), and 4-(n-butyl)benzenesulfonyl chloride (140 mg, 0.60 mmol) via a procedure substantially analogous to Procedure F except that an additional SCX column purification step is performed to give the product (165 mg, 70% yld). MS(ES+)471.1(M+H)+.
Reaction SMILES: Cl.[NH2:2][OH:3].C[O-].[Na+].[Na].[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=1)#[N:9]>CS(C)=O.CO>[CH3:22][C:19]1[CH:18]=[CH:17][C:16]([C:11]2[C:10]([C:8](=[N:2][OH:3])[NH2:9])=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:21][CH:20]=1
Reactant: NO
Reactant: Cc1ccc(-c2ccccc2C#N)cc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CS(C)=O
Product: Cc1ccc(-c2ccccc2C(N)=NO)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of hydroxylamine hydrochloride (17.9 g) in dimethyl sulfoxide (120 ml) was added a methanol solution of sodium methoxide prepared from metallic sodium (5.92 g) and anhydrous methanol (50 ml). The mixture was stirred for 10 minutes at room temperature, to which was added 2'-cyano-4-methylbiphenyl (10 g). The reaction mixture was stirred for 5 hours at 100° C. The reaction mixture was partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate. Organic layers were combined, washed with water and dried, then the solvent was evaporated in vacuo. The residue was purified by column chromatography on silica gel to afford the title compound as a white amorphous product (11.2 g, 96%).
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][CH:4]([CH3:10])[C:5]([O:7]CC)=O.[N:21]1[CH:26]=[CH:25][CH:24]=[N:23][C:22]=1[C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=1)[CH:30]=O>>[CH3:18][O:17][C:16]1[CH:15]=[CH:14][CH:13]=[C:12]([O:19][CH3:20])[C:11]=1[CH:2]1[N:1]([CH2:30][C:29]2[CH:32]=[CH:33][CH:34]=[C:27]([C:22]3[N:21]=[CH:26][CH:25]=[CH:24][N:23]=3)[CH:28]=2)[C:5](=[O:7])[CH:4]([CH3:10])[CH2:3]1
Reactant: O=Cc1cccc(-c2ncccn2)c1
Reactant: CCOC(=O)C(C)CC(N)c1c(OC)cccc1OC
Product: COc1cccc(OC)c1C1CC(C)C(=O)N1Cc1cccc(-c2ncccn2)c1

Procedure:
Prepared according to the described general procedure 2 (GP2) by reaction of ethyl 4-amino-4-(2,6-dimethoxyphenyl)-2-methylbutanoate with commercially available 3-(pyrimidin-2-yl)benzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.79 min.; [M+H]+: 403.86 g/mol.
Reaction SMILES: [N:1]([C:4]([C:12]1[CH:16]=[CH:15][O:14][CH:13]=1)([C:6]1[O:10][CH:9]=[N:8][C:7]=1[CH3:11])[CH3:5])=[N+]=[N-]>C(O)C.[Pd]>[O:14]1[CH:15]=[CH:16][C:12]([C:4]([NH2:1])([C:6]2[O:10][CH:9]=[N:8][C:7]=2[CH3:11])[CH3:5])=[CH:13]1
Reactant: Cc1ncoc1C(C)(N=[N+]=[N-])c1ccoc1
Agent: [Pd]
Solvent: CCO
Product: Cc1ncoc1C(C)(N)c1ccoc1

Procedure:
The product from Example 65 in ethanol was hydrogenated in the presence of 10% palladium-on-charcoal to give the title compound.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].Cl.[C:16]([O:20][C:21](=[O:24])[CH2:22][NH2:23])([CH3:19])([CH3:18])[CH3:17].C([O-])(O)=O.[Na+].O>CS(C)=O>[N+:12]([C:3]1[CH:4]=[C:5]([C:8]([F:11])([F:10])[F:9])[CH:6]=[CH:7][C:2]=1[NH:23][CH2:22][C:21]([O:20][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:24])([O-:14])=[O:13]
Reactant: CC(C)(C)OC(=O)CN
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1F
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)CNc1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 65 °C
Reaction time: 8 h
Yield: 79.3 %

Procedure:
A mixture of 4-fluoro-3-nitrobenzotrifluoride (209 mg, 1 mmol), glycine tert-butyl ester hydrochloride (201 mg, 1.2 mmol) and NaHCO3 (128 mg, 2 mmol) in dry DMSO (1 ml) is stirred overnight at 50 or 65° C. In case the reaction is not complete a further heating at 85° C. to 100° C. for 3 h is necessary. The reaction is then cooled to rt and water is added. The yellow to orange solid formed is filtered over a fritted funnel, rinsed thoroughly with water and dried under high vacuum. This yields the title compound (254 mg) in 79% as a yellow solid: tR=1.08 min (LC-3), ESI-MS (pos.): m/z 403.2 [M+2AcCN]+, m/z 321.56 [M+H]+, 1H-NMR (DMSO-d6): δ (ppm) 1.44 (s, 9H, tBu), 4.23 (d, 2H, NHCH2CO2), 7.08 (d, 1H, Harom), 7.80 (dd, 1H, H, m), 8.34 (br. s, 1H, Harom), 8.65 (t, 1H, NH).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][CH:8]=[CH:9][N:10]=1)=[O:5])[CH3:2].C([O-])([O-])=O.[K+].[K+].[CH3:17][Si:18]([CH2:21][CH2:22][O:23][CH2:24]Cl)([CH3:20])[CH3:19].CC(C)=O>CCOC(C)=O>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:24][O:23][CH2:22][CH2:21][Si:18]([CH3:20])([CH3:19])[CH3:17])[CH:8]=[CH:9][N:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ncc[nH]1
Reactant: C[Si](C)(C)CCOCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: CCOC(=O)c1nccn1COCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 10 h
Yield: 75.4 %

Procedure:
A flask charged with 1H-imidazole-2-carboxylic acid ethyl ester (1.03 g, 7.36 mmol), K2CO3 (2.00 g, 14.5 mmol), SEM-Cl (1.56 mL, 8.89 mmol), and 20 mL of acetone was stirred for 10 h at RT. The reaction was diluted with EtOAc (100 mL), washed with NaHCO3 (2×100 mL), brine (100 mL), and the organic layer dried over Na2SO4 and concentrated. The title compound was eluted from a 20-g SPE with 50% EtOAc/hexanes to give 1.50 g (76%) of a colorless oil. Mass spectrum (ESI, m/z): Calcd. for C12H22N3O3Si, 271.1 (M+H), found 271.1.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:6]=2[N:7]=1.[NH2:22][C:23]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][C:24]=1[C:25]([NH2:27])=[O:26]>>[Cl:32][C:29]1[CH:30]=[CH:31][C:23]([NH:22][C:4]2[C:5]3[CH:10]=[CH:9][N:8]([S:11]([C:14]4[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=4)(=[O:13])=[O:12])[C:6]=3[N:7]=[C:2]([Cl:1])[N:3]=2)=[C:24]([CH:28]=1)[C:25]([NH2:27])=[O:26]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Cl)nc(Cl)nc32)cc1
Reactant: NC(=O)c1cc(Cl)ccc1N
Product: Cc1ccc(S(=O)(=O)n2ccc3c(Nc4ccc(Cl)cc4C(N)=O)nc(Cl)nc32)cc1

Procedure:
Using General Protocol II and starting with 2,4-dichloro-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidine (2.5 g, 7.3 mmol) and 2-amino-5-chlorobenzamide (3.73 g, 22 mmol), 5-chloro-2-({2-chloro-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)benzamide was isolated as a yellow solid (2.0 g, 57% Yield); 1H NMR (400 MHz, DMSO-d6) δ ppm 2.36 (s, 3 H), 6.70 (d, J=4.03 Hz, 1 H), 7.47 (d, J=8.23 Hz, 2 H), 7.64 (dd, J=8.87, 2.47 Hz, 1 H), 7.76 (d, J=3.84 Hz, 1 H), 7.88 (d, J=2.38 Hz, 2 H), 7.98 (d, J=8.60 Hz, 2 H), 8.38 (s, 1 H), 8.41 (d, J=8.97 Hz, 1 H), 12.14 (s, 1 H).
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[N:13][C:14]([C:17]3[CH:25]=[CH:24][C:20]([C:21]([NH2:23])=O)=[CH:19][CH:18]=3)=[N:15][CH:16]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].C(Cl)CCl.P(Cl)(Cl)(Cl)=O>CCOCC>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[CH:16]=[N:15][C:14]([C:17]3[CH:18]=[CH:19][C:20]([C:21]#[N:23])=[CH:24][CH:25]=3)=[N:13][CH:12]=2)=[CH:9][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(-c2cnc(-c3ccc(C(N)=O)cc3)nc2)cc1
Solvent: CCOCC
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCCl
Product: CCCCc1ccc(-c2cnc(-c3ccc(C#N)cc3)nc2)cc1

Procedure:
102.75 G. of 4-[5-(4-n-butylphenyl)-2-pyrimidyl] benzoic acid amide are refluxed for 80 minutes in a mixture of 1500 ml. of ethylene chloride and 34 ml. of phosphorus oxychloride with stirring. The mixture, diluted with ether, is washed with 2-N sodium hydroxide solution and then with water until neutral. After evaporation of the organic phase, which has been dried over sodium sulfate, there is obtained 5-(4-n-butylphenyl)-2-(4-cyanophenyl)pyrimidine which is filtered on a short silica gel column and subsequently recrystallized from methylene chloride/methanol; melting point 94.7° C.; clearing point 246°-246.7° C.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][N:4]([CH2:7][CH2:8][CH2:9][OH:10])[N:3]=1.N1C(C)=CC=CC=1C.[CH:19]1([CH2:24][C@H:25]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:38])([F:37])[F:36])[CH:30]=2)[C:26](Cl)=[O:27])[CH2:23][CH2:22][CH2:21][CH2:20]1>C(Cl)Cl>[CH:19]1([CH2:24][C@H:25]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:36])([F:37])[F:38])[CH:30]=2)[C:26]([NH:1][C:2]2[CH:6]=[CH:5][N:4]([CH2:7][CH2:8][CH2:9][OH:10])[N:3]=2)=[O:27])[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: O=C(Cl)[C@H](CC1CCCC1)c1cccc(C(F)(F)F)c1
Reactant: Nc1ccn(CCCO)n1
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: O=C(Nc1ccn(CCCO)n1)[C@H](CC1CCCC1)c1cccc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 16 h
Yield: 57 %

Procedure:
In a round bottom flask was placed 3-(3-amino-pyrazol-1-yl)-propan-1-ol (prepared in Example 23, 38 mg, 0.27 mmol), 2,6-lutidine (42 μL, 0.37 mmol) and methylene chloride (5 mL). This solution was then cooled to 0° C. and to it was added dropwise a solution of 3-cyclopentyl-2(R)-(3-trifluoromethyl-phenyl)-propionyl chloride in methylene chloride (prepared in Example 83, 0.12 M solution, 2 mL, 0.24 mmol). The reaction was then allowed to warm up to 25° C. and stirred for 16 h. After this time the reaction was diluted with methylene chloride (5 mL). The reaction was then washed with a saturated aqueous sodium bicarbonate solution (10 mL) and a 1 N aqueous hydrochloric acid solution (1×10 mL) and then dried over magnesium sulfate, filtered and concentrated in vacuo. Purification on an AnaLogix Intelliflash system (4 g column, 50% ethyl acetate/hexanes to 80% ethyl acetate/hexanes) afforded 3-cyclopentyl-N-[1-(3-hydroxy-propyl)-1H-pyrazol-3-yl]-2(R)-(3-trifluoromethyl-phenyl)-propionamide (56 mg, 57%) as a colorless oil: [α]30589=−20.0° (c=0.11, methylene chloride); ES-HRMS m/e calcd for C21H26N3O2F3 (M+H)+ 410.2050, observed 410.2050; 1H NMR (300 MHz, DMSO-d6) δ ppm 1.01-1.19 (m, 2H, CH2), 1.34-1.80 (m, 8H, 4×CH2), 1.79-1.91 (m, 2H, CH2), 2.03-2.21 (m, 1H, CH), 3.29-3.38 (m, 2H, OCH2), 3.84-3.93 (m, 1H, ArCH), 4.01 (t, J=6.9 Hz, 2H, NCH2), 4.55 (t, J=5.0 Hz, 1H, OH), 6.41 (d, J=2.3 Hz, 1H, Ar), 7.54 (d, J=2.3 Hz, 1H, Ar), 7.55-7.74 (m, 4H, Ar), 10.74 (s, 1H, NH).
Reaction SMILES: [C:1]([C:3]1[C:4]([S:15]([NH:18][C:19]([NH:21][CH:22]([CH3:24])[CH3:23])=S)(=[O:17])=[O:16])=[C:5]([NH:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[S:6][C:7]=1[CH3:8])#[N:2].C(N(CC)CC)C.C(Cl)(Cl)=O>C1COCC1.C1(C)C=CC=CC=1>[C:1]([C:3]1[C:4]2[S:15](=[O:17])(=[O:16])[N:18]=[C:19]([NH:21][CH:22]([CH3:24])[CH3:23])[N:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5]=2[S:6][C:7]=1[CH3:8])#[N:2]
Reactant: CCOC(=O)Nc1sc(C)c(C#N)c1S(=O)(=O)NC(=S)NC(C)C
Agent: O=C(Cl)Cl
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)N1C(NC(C)C)=NS(=O)(=O)c2c1sc(C)c2C#N
Temperature: 0 °C
Reaction time: 1 h
Yield: 87.6 %

Procedure:
To a stirred solution of N-(4-cyano-2-ethoxycarbonylamino-5-methyl-3-thienylsulfonyl)-N′-isopropylthiourea (0.3 g) and triethylamine (320 μl) in 10 ml of dry THF at 0° C. was added 750 μl of a 20% solution of phosgene in toluene. The mixture was stirred at 0° C. for 1 h and then evaporated to dryness. The residue was triturated with 10 ml of water, filtered off, rinsed on the filter with water and dried to give 0.24 g of crude title compound; m.p. 116-119° C. The product was used for the next step without purification.
Reaction SMILES: C([O:3][C:4](=[O:29])[C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:15][C:14]([C:20]3[CH:25]=[C:24]([Cl:26])[CH:23]=[C:22]([Cl:27])[CH:21]=3)([C:16]([F:19])([F:18])[F:17])[CH:13]=[N:12]2)=[CH:7][C:6]=1[CH3:28])C.[OH-].[Na+].Cl.C(OCC)(=O)C>C(O)C.O>[Cl:27][C:22]1[CH:21]=[C:20]([C:14]2([C:16]([F:18])([F:19])[F:17])[CH2:13][N:12]=[C:11]([C:8]3[CH:9]=[CH:10][C:5]([C:4]([OH:29])=[O:3])=[C:6]([CH3:28])[CH:7]=3)[CH2:15]2)[CH:25]=[C:24]([Cl:26])[CH:23]=1
Reactant: CCOC(=O)c1ccc(C2CC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C=N2)cc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCO
Product: Cc1cc(C2=NCC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)O
Yield: 77 %

Procedure:
To a solution of 4-[4-(3,5-dichloro-phenyl)-4-trifluoromethyl-3,4-dihydro-2H-pyrrol-2-yl]-2-methyl-benzoic acid ethyl ester (Example I5) (2.8 g) in ethanol (40 ml) was added a solution of sodium hydroxide (0.51 g) in water (15 ml). The reaction mixture was stirred at reflux for 1 hour. After cooling to ambient temperature aqueous hydrochloric acid (1M) (20 ml), water (150 ml) and ethyl acetate (200 ml) was added. The phases were separated and the organic phase was washed with brine, dried over sodium sulfate and concentrated. The residue was recrystallised from diisopropyl ether to give 4-[4-(3,5-dichloro-phenyl)-4-trifluoromethyl-4,5-dihydro-3H-pyrrol-2-yl]-2-methyl-benzoic acid (2.02 g) as a white solid. 1H-NMR (d6-DMSO, 400 MHz): 13.07 (s, 1H), 7.91-7.58 (m, 6H), 4.85 (d, 1H), 4.44 (d, 1H), 3.92-3.35 (m, 2H), 2.58 (s, 3H) ppm.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8](OC)=[O:9])[CH:5]=[C:4]([N:12]([CH2:17][CH:18]2[CH2:22][O:21][C:20]([CH3:24])([CH3:23])[O:19]2)[S:13]([CH3:16])(=[O:15])=[O:14])[N:3]=1.[NH3:25]>CO>[Cl:1][C:2]1[N:7]=[C:6]([C:8]([NH2:25])=[O:9])[CH:5]=[C:4]([N:12]([CH2:17][CH:18]2[CH2:22][O:21][C:20]([CH3:24])([CH3:23])[O:19]2)[S:13]([CH3:16])(=[O:15])=[O:14])[N:3]=1
Reactant: COC(=O)c1cc(N(CC2COC(C)(C)O2)S(C)(=O)=O)nc(Cl)n1
Reactant: N
Solvent: CO
Product: CC1(C)OCC(CN(c2cc(C(N)=O)nc(Cl)n2)S(C)(=O)=O)O1
Yield: 82 %

Procedure:
To a mixture of methyl 2-chloro-6-(N-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)methylsulfonamido)pyrimidine-4-carboxylate (0.911 g, 2.40 mmol) in MeOH (10 mL) was added 7M ammonia in MeOH (10 mL, 70 mmol). It started as a suspension, then dissolved, and then gave a precipitate. After 3 h the solid was filtered, rinsed once with 5 mL MeOH and air-dried to give the product 2-chloro-6-(N-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)methylsulfonamido)pyrimidine-4-carboxamide as a white powder (0.715 g, 1.96 mmol, 82% yield). LC/MS: m/z=365.2 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:18][CH:17]2[CH2:19][CH:10]([C:11]3[CH:12]=[C:13]([NH:21][CH2:22][CH:23]([CH3:25])[CH3:24])[C:14]([NH2:20])=[CH:15][C:16]=32)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:26][C:27](O)=O.CO.C(Cl)Cl>C(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:18][CH:17]2[CH2:19][CH:10]([C:11]3[CH:12]=[C:13]4[C:14](=[CH:15][C:16]=32)[N:20]=[C:26]([CH3:27])[N:21]4[CH2:22][CH:23]([CH3:25])[CH3:24])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(=O)O
Reactant: CC(C)CNc1cc2c(cc1N)C1CC2CN(C(=O)OC(C)(C)C)C1
Solvent: ClCCl
Solvent: CO
Solvent: CCO
Product: Cc1nc2cc3c(cc2n1CC(C)C)C1CC3CN(C(=O)OC(C)(C)C)C1

Procedure:
4-Amino-5-isobutylamino-10-aza-tricyclo[6.3.1.02,7]dodeca-2(7),3,5-triene-10-carboxylic acid tert-butyl ester (250 mg, 0.74 mmol) from Example 19B was dissolved in ethanol (10 mL) and HOAc (2 mL) and treated with 1-ethoxyethylenemalononitrile (118 mg, 0.87 mmol). The reaction proceeded as in Example 18C (18h) and was worked up similarly to provide product (TLC 3% methanol/CH2Cl2 (NH3) Rf 0.57).
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:27]=[CH:26][C:6]([O:7][CH2:8][CH:9]2[CH2:14][CH2:13][CH2:12][N:11]([CH2:15][CH2:16][C:17]3C4C(=CC=CC=4)N[CH:18]=3)[CH2:10]2)=[CH:5][CH:4]=1.[C:30]1([C:40]2[CH:45]=CC=[CH:42][CH:41]=2)[CH:35]=[CH:34][C:33](CC(O)=O)=[CH:32][CH:31]=1>>[C:40]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:45]=[CH:18][C:17]([CH2:16][CH2:15][N:11]2[CH2:12][CH2:13][CH2:14][CH:9]([CH2:8][O:7][C:6]3[CH:26]=[CH:27][C:3]([C:2]([F:1])([F:28])[F:29])=[CH:4][CH:5]=3)[CH2:10]2)=[CH:42][CH:41]=1
Reactant: FC(F)(F)c1ccc(OCC2CCCN(CCc3c[nH]c4ccccc34)C2)cc1
Reactant: O=C(O)Cc1ccc(-c2ccccc2)cc1
Product: FC(F)(F)c1ccc(OCC2CCCN(CCc3ccc(-c4ccccc4)cc3)C2)cc1

Procedure:
Following exactly the same two step procedure used in the previous example for the preparation of 3-{2-[3-(4-Trifluoromethyl-phenoxymethyl)-piperidin-1-yl]-ethyl}-1H-indole but using biphenyl-4-yl-acetic acid in place of (1H-Indol-3-yl)-acetic acid, 1-(2-Biphenyl-4-yl-ethyl)-3-(4-trifluoromethyl-phenoxymethyl)-piperidine was obtained in 54% overall yield from 0.19 mmol of 3-(4-Trifluoromethyl-phenoxymethyl)-piperidine, 181. Data for this compound: MS 440 (M++1).