Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.Cl[C:11]1[C:20]2[C:15](=[C:16]([CH3:21])[CH:17]=[CH:18][CH:19]=2)[CH:14]=[C:13]([NH:22][C:23]2[CH:27]=[C:26]([CH3:28])[NH:25][N:24]=2)[N:12]=1>>[CH3:21][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:15]=1[CH:14]=[C:13]([NH:22][C:23]1[CH:27]=[C:26]([CH3:28])[NH:25][N:24]=1)[N:12]=[C:11]2[O:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1
Reactant: Cc1cc(Nc2cc3c(C)cccc3c(Cl)n2)n[nH]1
Reactant: COc1ccc(O)cc1
Product: COc1ccc(Oc2nc(Nc3cc(C)[nH]n3)cc3c(C)cccc23)cc1

Procedure:
Similar procedure as described in example 10 was used, starting from 4-methoxy-phenol and (1-chloro-5-methyl-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine to give [5-methyl-1-(4-methoxy-phenoxy)-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 361(MH+).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:10]1[CH2:15][CH2:14][N:13]([C:16]([C:18]2[CH:23]=[CH:22][C:21](Br)=[CH:20][N:19]=2)=[O:17])[CH2:12][CH2:11]1.[C:25]1(B(O)O)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C([O-])(O)=O.[Na+]>CO.O1CCOCC1>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:10]1[CH2:15][CH2:14][N:13]([C:16]([C:18]2[CH:23]=[CH:22][C:21]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:20][N:19]=2)=[O:17])[CH2:12][CH2:11]1
Reactant: O=C(c1ccc(Br)cn1)N1CCC(c2nc3ccccc3[nH]2)CC1
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: C1COCCO1
Product: O=C(c1ccc(-c2ccccc2)cn1)N1CCC(c2nc3ccccc3[nH]2)CC1
Temperature: 100 °C
Yield: 80 %

Procedure:
To a stirred mixture of [4-(1H-benzimidazol-2-yl)piperidin-1-yl](5-bromopyridin-2-yl)methanone (39 mg, 0.10 mmol) and phenylboronic acid (20.1 mg, 0.17 mmol) in a mixture of MeOH (0.5 mL) and 1,4-dioxane (1.5 mL) is added 2M aqueous NaHCO3 (0.3 mL). The mixture is degassed with N2. 1,1′-bis(diphenylphosphino)ferrocene-palladium (II) dichloride dichloromethane complex (5 mol %) is added and the mixture is heated at 100° C. under microwave irradiation for 30 mins. The mixture is filtered through a pad of celite and the filtrate is concentrated under reduced pressure. Purification by column chromatography (Isolute column, eluent DCM, 5% MeOH) affords 30.6 mg of [4-(1H-benzimidazol-2-yl)piperidin-1-yl](5-phenylpyridin-2-yl)methanone.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[N:6][CH:7]=1.C(N(CC)CC)C.[F:17][C:18]([F:23])([F:22])[C:19](Cl)=[O:20]>O1CCCC1>[F:17][C:18]([F:23])([F:22])[C:19]([C:3]1[C:2]([Cl:1])=[CH:7][N:6]=[C:5]([NH2:8])[C:4]=1[NH2:9])=[O:20]
Reactant: Nc1cc(Cl)cnc1N
Reactant: O=C(Cl)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Nc1ncc(Cl)c(C(=O)C(F)(F)F)c1N
Reaction time: 2 h

Procedure:
5-Chloro-2,3-pyridinediamine (2.8 grams) was dissolved in 50 milliliters of tetrahydrofuran and 2.02 milliliters of triethylamine and the solution treated with trifluoroacetyl chloride (2.6 grams) in 100 milliliters of tetrahydrofuran. The addition was carried out at room temperature over a period of 2 hours, and the reaction mixture was then held at room temperature for another hour with stirring. Solvent was removed by evaporation, and the residue recrystallized from a chloroform/acetone mixture to obtain the desired N3 -trifluoroacetyl-5-chloro-2,3-pyridinediamine product, m.p., 292°-93°C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([C:12]2[S:16][C:15]3[CH:17]=[CH:18][C:19]([F:21])=[CH:20][C:14]=3[C:13]=2[CH3:22])(=[O:11])=[O:10])=[C:4]([CH2:23][S:24]([CH3:27])(=[O:26])=[O:25])[CH:3]=1.[N:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1>COCCOC.C(O)C.C(=O)([O-])[O-].[Na+].[Na+].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:27][S:24]([CH2:23][C:4]1[CH:3]=[C:2]([C:31]2[CH:32]=[CH:33][N:28]=[CH:29][CH:30]=2)[CH:7]=[CH:6][C:5]=1[NH:8][S:9]([C:12]1[S:16][C:15]2[CH:17]=[CH:18][C:19]([F:21])=[CH:20][C:14]=2[C:13]=1[CH3:22])(=[O:11])=[O:10])(=[O:26])=[O:25]
Reactant: Cc1c(S(=O)(=O)Nc2ccc(Br)cc2CS(C)(=O)=O)sc2ccc(F)cc12
Reactant: OB(O)c1ccncc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCO
Product: Cc1c(S(=O)(=O)Nc2ccc(-c3ccncc3)cc2CS(C)(=O)=O)sc2ccc(F)cc12
Yield: 23.7 %

Procedure:
This compound was prepared in analogy to Example 2 starting from 5-fluoro-3-methyl-benzo[b]thiophene-2-sulfonic acid(4-bromo-2-methanesulfonylmethyl-phenyl)-amide (0.123 g) and 4-pyridineboronic acid (0.0462 g) in 1,2-dimethoxyethane (5 ml), ethanol (1 ml) and 2 M aqueous sodium carbonate solution (2 ml) with tetrakis(triphenylphosphine)palladium (0.035 g) to obtain the title compound (0.029 g) as a yellowish foam. MS (ISN): 489.1 (M−H)−
Reaction SMILES: C[O:2][C:3]1[C:4]([CH3:29])=[C:5]([C:20]([O:27]C)=[C:21]([O:25][CH3:26])[C:22]=1[O:23][CH3:24])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:16][CH:17]([CH3:19])[CH3:18])=[C:11]([CH:15]=1)[C:12]([OH:14])=[O:13].O=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+]>C(#N)C.O>[CH3:24][O:23][C:22]1[C:3](=[O:2])[C:4]([CH3:29])=[C:5]([CH2:6][C:7]2[CH:8]=[CH:9][C:10]([O:16][CH:17]([CH3:18])[CH3:19])=[C:11]([CH:15]=2)[C:12]([OH:14])=[O:13])[C:20](=[O:27])[C:21]=1[O:25][CH3:26]
Reactant: COc1c(C)c(Cc2ccc(OC(C)C)c(C(=O)O)c2)c(OC)c(OC)c1OC
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: CC#N
Solvent: O
Product: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)C)c(C(=O)O)c2)=C(C)C1=O
Yield: 83.1 %

Procedure:
5-(3,4,5,6-Tetramethoxy-2-methylbenzyl)-2-isopropoxybenzoic acid (0.472 g, 1.17 mmol) was dissolved in a mixed solution of acetonitrile (9 ml) and water (3 ml) and after adding thereto CAN (1.60 g, 2.92 mmol) at room temperature, the solution was stirred at room temperature for 1 hour. The reaction solution was diluted with water and then extracted with ether. The extract was washed with water and then dried, and the solvent was removed by distillation. The residue was recrystallized from ether to obtain the titled compound (0.364 g, 0.972 mmol, 83%).
Reaction SMILES: Cl[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:17])[C:7]=1[N:8]1[CH2:13][CH2:12][CH:11]([C:14]([NH2:16])=[O:15])[CH2:10][CH2:9]1.[F:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][C:24]=1[F:25].C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(#N)C>[Cl:17][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([C:22]2[CH:21]=[CH:20][C:19]([F:18])=[C:24]([F:25])[CH:23]=2)[C:7]=1[N:8]1[CH2:13][CH2:12][CH:11]([C:14]([NH2:16])=[O:15])[CH2:10][CH2:9]1
Reactant: OB(O)c1ccc(F)c(F)c1
Reactant: NC(=O)C1CCN(c2c(Cl)cncc2Cl)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: NC(=O)C1CCN(c2c(Cl)cncc2-c2ccc(F)c(F)c2)CC1
Yield: 51.7 %

Procedure:
General procedure D was followed using 1-(3,5-dichloropyridin-4-yl)piperidine-4-carboxamide 23 (24 mg, 0.088 mmol), 3,4-difluorobenzene boronic acid (17 mg, 0.11 mmol), tetrakis(triphenylphosphine)palladium(0) (5 mg, 5 mol %), acetonitrile (1 mL) and 0.5 M sodium carbonate (0.25 mL, 0.12 mmol) for 30 min. The crude product was purified by preparative tlc on silica gel (CH2Cl2, MeOH, 10:1), to give impure title compound as a white solid (16 mg) followed by preparative hplc (CH3CN, H2O, gradient 1:9 to 9:1) to furnish the title compound as a white solid, LC-MS (ESI, 3.5 min) Rt 1.91 min, m/z 352 (100%, [M+H]+); m/z (ESI) C17H16ClF2N3O requires 352.1023 found [M+H]+ 352.1017.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][NH:9][C:10]2[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:11]=2[CH:12]=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:19][C:20]([CH3:25])([CH3:24])[CH2:21][CH2:22][NH2:23]>C1(C)C=CC=CC=1>[CH3:19][C:20]([CH3:25])([CH3:24])[CH2:21][CH2:22]/[N:23]=[CH:12]/[C:11]1[CH:14]=[CH:15][CH:16]=[C:17]([F:18])[C:10]=1[NH:9][CH2:8][CH2:7][N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)CCN
Reactant: O=Cc1cccc(F)c1NCCN1CCCCC1
Solvent: Cc1ccccc1
Product: CC(C)(C)CC/N=C/c1cccc(F)c1NCCN1CCCCC1
Yield: 95.9 %

Procedure:
Crude 2-(2-(piperidin-1-yl)ethylamino)-3-fluorobenzaldehyde (372 mg, 1.486 mmol) and 3,3-dimethylbutan-1-amine (225.6 mg, 300.0 μL, 2.229 mmol) were stirred in toluene (7 mL) with 4A MS at RT overnight. The mixture was filtered and the volatiles were removed on rotary evaporator at 40° C. to give 475 mg of crude 2-((E)-(3,3-dimethylbutylimino)methyl)-6-fluoro-N-(2-(piperidin-1-yl)ethyl)benzenamine which was used directly in the next step.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:14])[CH2:9][CH2:10][C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1N=CN(C(N2C=NC=C2)=O)C=1.[Br-:27].[NH2:28][CH2:29][CH2:30][CH2:31][CH2:32][P+:33]([C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>CN(C)C=O.C(Cl)Cl>[C:1]([O:5][C:6]([N:8]([CH3:14])[CH2:9][CH2:10][C:11]([NH:28][CH2:29][CH2:30][CH2:31][CH2:32][P+:33]([C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)([C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)=[O:13])=[O:7])([CH3:2])([CH3:3])[CH3:4].[Br-:27]
Reactant: NCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CN(CCC(=O)O)C(=O)OC(C)(C)C
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Br-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CN(CCC(=O)NCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 116.1 %

Procedure:
N-(tert-butoxycarbonyl)-N-methyl-β-alanine (Matrix Scientific, 368 mg, 1.81 mmol) was dissolved in N,N-dimethylformamide (3.7 mL) and treated with N,N-carbonyldiimidazole (308 mg, 1.90 mmol). The reaction mixture was stirred at room temperature for 30 minutes. (4-Aminobutyl)(triphenyl)phosphonium bromide (1.12 g, 2.72 mmol) was added, and the reaction was stirred overnight at room temperature. The reaction was then diluted with methylene chloride and washed with 5% aqueous lithium chloride (3 times), 1N aqueous hydrogen chloride, and saturated sodium bicarbonate. The organic solution was dried over anhydrous sodium sulfate, filtered, and concentrated to give the title compound (1.26 g, 100%, 86% pure) as a white foam. Sample was used crude in next step.
Reaction SMILES: [H-].[Na+].Br[C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2.C([Li])CCC.[CH2:18]1[O:20][CH2:19]1>C1COCC1.CCCCCC>[OH:20][CH2:19][CH2:18][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2
Reactant: C1CO1
Reactant: Brc1ccc2[nH]ccc2c1
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: OCCc1ccc2[nH]ccc2c1
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 54 %

Procedure:
To a cooled (0° C.) mixture of 1.56 g (38.9 mmol) of a 60% dispersion of sodium hydride in 10 mL THF is slowly added a solution of 5.05 g (25.9 mmol) 5-bromoindole (Acros) in 20 mL THF. After H2 evolution stopped (˜10 min) the mixture is cooled to −78° C., and 25.9 mL (64.8 mmol) of a 2.5 M hexane solution of n-butyllithium is added dropwise. After five minutes, added 16.8 mL (38.9 mmol) of a 2.3 M THF stock solution of ethylene oxide and removed cooling bath. After 90 minutes, quenched with 5 mL distilled water. The organic layer is then poured away from the inorganic salts and concentrated. The resulting residue is chromatographed (1:1 hexane:ethyl acetate) to provide 2.24 g of the product as a yellow oil in 54% yield. 1H NMR (CDCl3): δ 2.96 (2H, t, J=6.5 Hz), 3.88 (2H, m), 6.51 (1H, m), 7.06 (1H, dd, J1=8.5 Hz, J2=1.5 Hz), 7.19 (1H, m), 7.33 (1H, d, J=8.5 Hz), 7.49 (1H, s), 8.19 (1H, br). MS (EI) m/z 161 M+, 130 (M−CH2OH)+.
Reaction SMILES: [CH2:1]([N:5]1[C:13](=[O:14])[C:12]2[NH:11][C:10]([CH3:15])=[N:9][C:8]=2[N:7]([CH2:16][CH2:17][CH2:18][CH3:19])[C:6]1=[O:20])[CH2:2][CH2:3][CH3:4].[Cl:21][CH2:22][CH2:23][CH2:24][S:25](Cl)(=[O:27])=[O:26].[K+].[Br-]>>[CH2:1]([N:5]1[C:13](=[O:14])[C:12]2[N:11]([S:25]([CH2:24][CH2:23][CH2:22][Cl:21])(=[O:27])=[O:26])[C:10]([CH3:15])=[N:9][C:8]=2[N:7]([CH2:16][CH2:17][CH2:18][CH3:19])[C:6]1=[O:20])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1c(=O)c2[nH]c(C)nc2n(CCCC)c1=O
Reactant: O=S(=O)(Cl)CCCCl
Agent: [Br-]
Agent: [K+]
Product: CCCCn1c(=O)c2c(nc(C)n2S(=O)(=O)CCCCl)n(CCCC)c1=O
Yield: 71 %

Procedure:
The title compound was prepared according to the procedure of example 3 except that 1,3-dibutyl-8-methyl-3,7-dihydro-purine-2,6-dione was used in place of 1,3-dibutyl-3,7-dihydro-purine-2,6-dione and 3-chloropropanesulfonyl chloride was used in place of methanesulfonyl chloride. Yield: 71%: mp: 76-78° C.; 1H NMR (300 MHz, CDCl3): δ 0.92-0.99 (m, 6H), 1.33-1.42 (m, 4H), 1.57-1.65 (m, 2H), 1.67-1.74 (m, 2H), 2.32-2.41 (m, 2H) 2.74 (s, 3H), 3.69 (t, J=6.2 Hz, 2H), 3.99 (t, J=7.6 Hz, 2H), 4.08 (t, J=7.5 Hz, 2H), 4.23 (t, J=7.5 Hz, 2H); IR (KBr, cm−1): 2959m, 2874m, 1705s, 1620w, 1537m, 1522s, 1485m, 1183s, 1121s, 938m, 751m, 570m; MS (ES) m/z (relative intensity): 419 (M++H, 100).
Reaction SMILES: CC(C)([O-])C.[Na+].[CH3:7][O:8][CH2:9][O:10][C@H:11]([CH3:14])[CH2:12][OH:13].[CH2:15]([N:19]1[C:23]2[CH:24]=[N:25][CH:26]=[CH:27][C:22]=2[S:21]/[C:20]/1=[N:28]\[C:29](=[O:41])[C:30]1[CH:35]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:33]=[CH:32][C:31]=1F)[CH2:16][CH2:17][CH3:18].OP(O)(O)=O>O1CCCC1>[CH2:15]([N:19]1[C:23]2[CH:24]=[N:25][CH:26]=[CH:27][C:22]=2[S:21]/[C:20]/1=[N:28]\[C:29](=[O:41])[C:30]1[CH:35]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:33]=[CH:32][C:31]=1[O:13][CH2:12][C@H:11]([O:10][CH2:9][O:8][CH3:7])[CH3:14])[CH2:16][CH2:17][CH3:18]
Reactant: COCO[C@H](C)CO
Reactant: CCCCn1/c(=N/C(=O)c2cc(C(F)(F)F)ccc2F)sc2ccncc21
Agent: CC(C)(C)[O-]
Agent: O=P(O)(O)O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCn1/c(=N/C(=O)c2cc(C(F)(F)F)ccc2OC[C@@H](C)OCOC)sc2ccncc21
Temperature: 0 °C
Yield: 73.4 %

Procedure:
To a 250 mL three-necked flask were charged sodium tert-butoxide (97%, 0.69 g, 7.0 mmol), and anhydrous tetrahydrofuran (17 mL). The mixture was stirred, and cooled down to about 0° C. A solution of (R)-2-(methoxymethoxy)propan-1-ol (0.96 g, 8.0 mmol) in tetrahydrofuran (2.0 mL) was added slowly at the internal temperature <5° C. The solution was mixed at <5° C. for 30 minutes, followed by addition of the N-[(2Z)-3-butyl[1,3]thiazolo[4,5-c]pyridin-2(3H)-ylidene]-2-fluoro-5-(trifluoromethyl)benzamide (1.59 g, 4.0 mmol) from Part B of Example 1 in tetrahydrofuran (36 mL) at <0° C. The resulting mixture was stirred at about 0° C. for 4 hours or until less than 5% of starting material remains. 125 g of 1.5% H3PO4 aqueous solution was added slowly to the reaction mixture at <5° C. The resulting slurry was mixed at about 0° C. for 1 hour, and then allowed to warm up to room temperature. The slurry was stirred at room temperature for 5 hours, and the product collected by filtration. The wet cake was washed with water-acetonitrile (2:1) (20 mL), and dried under vacuum at 50° C. overnight with a slow flow of nitrogen to give a white solid (1.46 g, 73%). MS-ESI: 498 (M+1); 1H-NMR (DMSO-d6) δ 0.94 (3H, t, J=7.4 Hz), 1.24 (3H, d, J=5.9 Hz), 1.41 (2H, m), 1.81 (2H, m), 3.23 (3H, s), 4.08 (3H, m), 4.52 (2H, t, J=7.5 Hz), 4.60 (1H, d, J=6.6 Hz), 4.75 (1H, d, J=6.9 Hz), 7.28 (1H, d, J=8.8 Hz), 7.75 (1H, d, J=8.8 Hz), 7.94 (1H, d, J=5.2 Hz), 8.24 (1H, d, J=2.2 Hz), 8.44 (1H, d, J=5.2 Hz), 8.95 (1H, s). 13C-NMR (CDCl3-DMSO-d6) δ 13.51, 17.28, 19.51, 29.28, 45.17, 54.50, 70.16, 72.23, 94.42, 113.39, 117.32, 120.10 (q, J=33 Hz, C—CF3), 123.66 (q, J=268 Hz, CF3), 126.05, 127.62, 128.75, 132.90, 133.14, 134.36, 142.71, 159.70, 164.56, 172.26.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([NH:14][C:15]2[N:20]=[C:19]([NH2:21])[C:18]([C:22](=[O:32])[C:23]3[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=3[O:30][CH3:31])=[CH:17][N:16]=2)[CH2:10][CH2:9]1)(C)(C)C>FC(F)(F)C(O)=O.ClCCl>[NH2:21][C:19]1[C:18]([C:22]([C:23]2[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=2[O:30][CH3:31])=[O:32])=[CH:17][N:16]=[C:15]([NH:14][C@H:11]2[CH2:12][CH2:13][C@H:8]([NH2:7])[CH2:9][CH2:10]2)[N:20]=1
Reactant: COc1ccc(F)cc1C(=O)c1cnc(N[C@H]2CC[C@H](NC(=O)OC(C)(C)C)CC2)nc1N
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(F)cc1C(=O)c1cnc(N[C@H]2CC[C@H](N)CC2)nc1N
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Trans-[4-[4-amino-5-(5-fluoro-2-methoxy-benzoyl)-pyrimidin-2-ylamino]-cyclohexyl]-carbamic acid tert-butyl ester (1.32 g) obtained from Example 113 was dissolved in 50% trifluoroacetic acid/dichloromethane (30 mL) and the solution was stirred at room temperature for 30 minutes. The solvent was removed and the residue was treated with saturated aqueous sodium bicarbonate solution. The mixture was extracted three times with ethyl acetate/tetrahydrofuran (3:1, 30 mL). The extracts were combined, dried (Na2SO4) and concentrated under reduced pressure to a solid (980 mg). Yield, 95%. MS(ES) (M+H)+=360.
Reaction SMILES: C(O[C:4]1[C:7](=[O:8])[C:6](=[O:9])[C:5]=1[NH:10][C:11]1[CH:12]=[C:13]([CH:18]2[C:23]([C:24]([O:26][CH3:27])=[O:25])=[C:22]([CH3:28])[NH:21][C:20]([CH3:29])=[C:19]2[C:30]([O:32][CH3:33])=[O:31])[CH:14]=[CH:15][C:16]=1[F:17])C.[CH3:34][N:35]([CH:37]=O)[CH3:36]>>[CH:34]1([N:35]2[CH2:37][CH2:36][N:35]([CH2:37][CH2:4][CH2:5][NH:10][C:4]3[C:7](=[O:8])[C:6](=[O:9])[C:5]=3[NH:10][C:11]3[CH:12]=[C:13]([CH:18]4[C:23]([C:24]([O:26][CH3:27])=[O:25])=[C:22]([CH3:28])[NH:21][C:20]([CH3:29])=[C:19]4[C:30]([O:32][CH3:33])=[O:31])[CH:14]=[CH:15][C:16]=3[F:17])[CH2:34][CH2:36]2)[CH2:13][CH2:12][CH2:11][CH2:16][CH2:15]1
Reactant: CN(C)C=O
Reactant: CCOc1c(Nc2cc(C3C(C(=O)OC)=C(C)NC(C)=C3C(=O)OC)ccc2F)c(=O)c1=O
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1c1ccc(F)c(Nc2c(NCCCN3CCN(C4CCCCC4)CC3)c(=O)c2=O)c1

Procedure:
The compound of Example 2 (147 mg, 0.321 mmol) and 4-cyclohexyl-1-piperazine-1-propanamine (72 mg, 0.320 mmol) were stirred in 2 mL DMF at room temperature for 64 hours. The crude reaction mixture was evaporated to dryness under high vacuum (0.1 mmHg) at 50-55° C. The resulting gum was triturated with methylene chloride followed by the addition of hexanes. The titled compound precipitated out as fine creamy white crystalline solid (158 mg, 77.5%): mp 229-230° C.; 1H NMR (DMSO-d6) δ 9.37 (br. s, 1H), 8.96 (br. s, 1H), 8.03 (br. 1H), 7.79 (d, 1H, J=7.6 Hz), 7.59 (dd, 1H, J=8.98, 5.21 Hz), 7.07 (dd, 1H, J=8.46, 11.37 Hz), 6.2 (m, 1H), 4.84 (s, 1H), 3.62-3.60 (m, 2H), 3.54 (s, 6H), 2.45 (m, 5H), 2.33-2.26 (m, 4H), 2.26 (s, 6H), 1.70-1.68 (m, 7H), 1.59-1.52 (br. 1H), 1.18-1.04 (m, 6H), 13C NMR (DMSO-d6) δ 179.63, 169.50, 167.31, 146.22, 129.07, 126.75, 125.98, 122.13, 119.68, 100.93, 62.55, 54.87, 50.60, 48.22, 42.13, 28.20, 27.62, 25.86, 25.57, 25.21, 18.31. Anal Calcd. for C34H44FN5O6•0.05 H2O: C, 63.94; H, 6.96; N, 10.97. Found: C, 63.95; H, 6.94; N, 10.74.
Reaction SMILES: [OH-].[K+].[C:3]([O:7][C@@H:8]([C:15]1[C:16]([CH3:47])=[N:17][C:18]([CH3:46])=[C:19]([C:30]2[CH:35]=[CH:34][C:33]([O:36][CH2:37][CH2:38][C:39]3[CH:44]=[CH:43][C:42]([F:45])=[CH:41][CH:40]=3)=[CH:32][CH:31]=2)[C:20]=1[N:21]1[CH2:26][CH2:25][C:24]([C:28]#[N:29])([CH3:27])[CH2:23][CH2:22]1)[C:9]([O:11]C(C)C)=[O:10])([CH3:6])([CH3:5])[CH3:4].Cl>C(O)C>[C:3]([O:7][C@@H:8]([C:15]1[C:16]([CH3:47])=[N:17][C:18]([CH3:46])=[C:19]([C:30]2[CH:31]=[CH:32][C:33]([O:36][CH2:37][CH2:38][C:39]3[CH:44]=[CH:43][C:42]([F:45])=[CH:41][CH:40]=3)=[CH:34][CH:35]=2)[C:20]=1[N:21]1[CH2:22][CH2:23][C:24]([C:28]#[N:29])([CH3:27])[CH2:25][CH2:26]1)[C:9]([OH:11])=[O:10])([CH3:6])([CH3:5])[CH3:4]
Reactant: Cc1nc(C)c([C@H](OC(C)(C)C)C(=O)OC(C)C)c(N2CCC(C)(C#N)CC2)c1-c1ccc(OCCc2ccc(F)cc2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Cc1nc(C)c([C@H](OC(C)(C)C)C(=O)O)c(N2CCC(C)(C#N)CC2)c1-c1ccc(OCCc2ccc(F)cc2)cc1
Temperature: 90 °C
Reaction time: 6 h
Yield: 19.2 %

Procedure:
The potassium hydroxide (213 mg, 3.8 mmol) was added to a (S)-isopropyl 2-(tert-butoxy)-2-(4-(4-cyano-4-methylpiperidin-1-yl)-5-(4-(4-fluorophenethoxy)phenyl)-2,6-dimethylpyridin-3-yl)acetate (233 mg, 0.38 mmol) in ethanol (4 mL) and stirred for 6 h at 90° C. The reaction mixture was neutralized with 1N HCl solution, extracted with EtOAc, and the organic layer was washed with brine, and dried (MgSO4). The crude material was purified by prep HPLC to afford (S)-2-(tert-butoxy)-2-(4-(4-cyano-4-methylpiperidin-1-yl)-5-(4-(4-fluorophenethoxy)phenyl)-2,6-dimethylpyridin-3-yl)acetic acid 41.8 mg (19%) as a mixture of diastereomers. 1H NMR (500 MHz, DMSO-d6) δ 7.38-7.35 (m, 2H), 7.19 (d, J=7.3 Hz, 1H), 7.13 (d, J=8.8 Hz, 2H), 7.07-7.05 (m, 1H), 7.01-6.99 (m, 2H), 5.61 (s, 1H), 4.27-4.23 (m, 1H), 4.19-4.15 (m, 1H), 3.51 (br. s, 4H), 3.04 (t, J=6.6 Hz, 2H), 2.48 (s, 3H), 2.05 (s, 3H), 1.73-1.59 (m, 3H), 1.39-1.35 (m, 1H), 1.26 (s, 3H), 1.12 (s, 9H). UPLC (M+H)=574.5.
Reaction SMILES: [OH-].[Na+].[CH2:3]([NH:6][C:7](=[O:18])[NH:8][NH:9][C:10](=O)[C:11]1[CH:16]=[CH:15][CH:14]=[N:13][CH:12]=1)[CH:4]=[CH2:5].Cl>O>[CH2:3]([N:6]1[C:10]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[N:9][NH:8][C:7]1=[O:18])[CH:4]=[CH2:5]
Reactant: C=CCNC(=O)NNC(=O)c1cccnc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: C=CCn1c(-c2cccnc2)n[nH]c1=O
Temperature: 92.5 °C
Yield: 88.6 %

Procedure:
1M Aqueous sodium hydroxide solution (175 ml) was added over 10 minutes to a stirred suspension of 4-allyl-1-nicotinoylsemicarbazide (17.2 g) in water (100 ml), then the stirred mixture was heated at 90-95° C. for 17 hours, cooled to ambient temperature, and acidified to pH 5 by the addition of 5M hydrochloric acid. The mixture was concentrated in vacuo, and the resulting solid was collected by filtration and dried in vacuo at ambient temperature to give 4-allyl-5-(3-pyridyl)-1,2,4-triazol-3(2H,4H)-one as an off-white solid (14 g), m.p. 120-125° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[CH2:8][C:9]([CH3:12])([CH3:11])[O:10][C:6]=2[C:5]([N+:13]([O-:15])=[O:14])=[CH:4][CH:3]=1.[Br:16]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:16][CH:8]1[C:7]2[C:2]([Cl:1])=[CH:3][CH:4]=[C:5]([N+:13]([O-:15])=[O:14])[C:6]=2[O:10][C:9]1([CH3:12])[CH3:11]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC1(C)Cc2c(Cl)ccc([N+](=O)[O-])c2O1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC1(C)Oc2c([N+](=O)[O-])ccc(Cl)c2C1Br
Yield: 95.4 %

Procedure:
A mixture of 11.82 g (0.052 mole) of 4-chloro-2,3-dihydro-2,2-dimethyl-7-nitrobenzofuran (Example 1, Step C) and 9.3 g (0.052 mole) of N-bromosuccinimide in 200 mL of carbon tetrachloride was irradiated with a sun lamp for approximately 16 hours. No reaction occurred during this time. To this mixture was then added 0.10 g of benzoyl peroxide, and the reaction mixture was then heated at reflux and irradiated simultaneously for a period of five hours. The sun lamp was turned off, and the mixture was allowed to stir while being heated at reflux for an additional hour. The mixture was then passed through a column of silica gel, and product-containing fractions were combined. The solvent was evaporated from the combined fractions under reduced pressure, leaving 15.2 g of 3-bromo-4-chloro-2,3-dihydro-2,2-dimethyl-7-nitrobenzofuran as a solid, m.p. 103°-104° C.
Reaction SMILES: [Cl:1][C:2]([Cl:7])([Cl:6])[CH:3](O)[OH:4].[C:8]1([CH3:17])[C:9]([C:14]([NH2:16])=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=1>>[CH3:17][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]([NH:16][CH:3]([OH:4])[C:2]([Cl:7])([Cl:6])[Cl:1])=[O:15]
Reactant: OC(O)C(Cl)(Cl)Cl
Reactant: Cc1ccccc1C(N)=O
Product: Cc1ccccc1C(=O)NC(O)C(Cl)(Cl)Cl

Procedure:
2,2,2-Trichloro-1,1-ethanediol and o-toluamide were processed as described in Example 37C to provide the desired product.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][OH:10].[OH:11][CH:12]([OH:16])[C:13](O)=O>C(O)(C(F)(F)F)=O>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:3]=1[CH2:8][CH2:9][O:10][CH:13]2[C:12]([OH:16])=[O:11]
Reactant: Cc1ccccc1CCO
Reactant: O=C(O)C(O)O
Solvent: O=C(O)C(F)(F)F
Product: Cc1cccc2c1CCOC2C(=O)O
Yield: 92.1 %

Procedure:
The mixture of 2-(2-methylphenyl)ethanol (2 g), TFA (10 ml) and 2,2-dihydroxyacetic acid (1.5 g) was refluxed for 23 hrs and volatiles were evaporated. Separation method I yielded the title compound (2.6 g) as an off-white solid. Alternatively, sulphuric acid can be used in cyclization.