Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[Cl:9][C:10]1[C:18]2[C:17]([O:19][CH3:20])=[N:16][C:15]([NH:21][CH:22]=[O:23])=[N:14][C:13]=2[N:12]([C@@H:24]2[O:34][C@H:33]([CH2:35][O:36][C:37](=[O:41])[CH:38]([CH3:40])[CH3:39])[C@@H:26]([O:27][C:28](=[O:32])[CH:29]([CH3:31])[CH3:30])[CH2:25]2)[CH:11]=1>C(Cl)Cl>[CH3:30][CH:29]([CH3:31])[C:28]([O:27][C@@H:26]1[C@@H:33]([CH2:35][O:36][C:37](=[O:41])[CH:38]([CH3:40])[CH3:39])[O:34][C@@H:24]([N:12]2[C:13]3[N:14]=[C:15]([NH:21][CH:22]=[O:23])[N:16]=[C:17]([O:19][CH3:20])[C:18]=3[C:10]([Cl:9])=[C:11]2[Cl:1])[CH2:25]1)=[O:32]
Reactant: O=C1CCC(=O)N1Cl
Reactant: COc1nc(NC=O)nc2c1c(Cl)cn2[C@H]1C[C@H](OC(=O)C(C)C)[C@@H](COC(=O)C(C)C)O1
Solvent: ClCCl
Product: COc1nc(NC=O)nc2c1c(Cl)c(Cl)n2[C@H]1C[C@H](OC(=O)C(C)C)[C@@H](COC(=O)C(C)C)O1
Temperature: 25 °C
Reaction time: 16 h
Yield: 72 %

Procedure:
N-Chlorosuccinimide (117 mg, 0.9 mmol) is added to a solution of compound (45) (200 mg, 0.4 mmol in 5 ml of DMF). After it had been stirred (at room temperature for 16 h), the solution is added to a mixture of CH2Cl2/5% aq. NaHCO3 (50 ml, 9:1). The organic phase is separated off, washed with water, dried over Na2SO4, filtered and evaporated. The evaporated residue is dissolved in CH2Cl2 and this solution is chromatographed on silica gel (column: 5×20 cm, CH2Cl2/acetone, 95:5). The main zone is separated off. Colorless crystals (149 mg, 72%) are obtained after evaporating off the solvent and crystallizing from cyclohexane. Melting point: 127-128° C. 1H-NMR ([D6] DMSO): δ=1.01 (dd, CH3), 1.14 (d, J=7.0, CH3), 2.44, 2.47, 2.60, 3.53 (4 m, CH and Hα,β—C(2′)), 4.05 (s, OCH3), 4.17 (m, H—C(5′)), 4.30 (m, H—C(4′)), 5.56 (m, H—C(3′)), 6.41 (m, H—C(1′)), 9.44 (d, J=9.1, NH), 10.94 (d, J=9.8, HCO). Anal. calculated for C21H26Cl2N4O7 (517.4): C 48.75, H 5.07, N 10.83; found: C 49.04, H 5.09, N 10.66.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[CH:6]=[C:5]2[CH:21]1[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]1.[CH3:28][O:29][C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.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>[CH3:28][O:29][C:30]1[CH:35]=[CH:34][C:33]([C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][CH:6]=[C:5]3[CH:21]2[CH2:22][CH2:23][N:24]([CH3:27])[CH2:25][CH2:26]2)=[CH:32][CH:31]=1.[CH3:28][O:29][C:30]1[CH:35]=[CH:34][C:33]([C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[N:7]([Si:11]([CH:18]([CH3:19])[CH3:20])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:13])[CH3:14])[CH:6]=[C:5]3[CH:21]2[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]2)=[CH:32][CH:31]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cc(C2CCN(C)CC2)c2cc(Br)ccc21
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: Cc1ccccc1
Product: COc1ccc(-c2ccc3[nH]cc(C4CCN(C)CC4)c3c2)cc1
Product: COc1ccc(-c2ccc3c(c2)c(C2CCN(C)CC2)cn3[Si](C(C)C)(C(C)C)C(C)C)cc1
Yield: 47 %

Procedure:
The title compound was prepared by the procedure of Example 10, beginning with 5-bromo-3-(1-methylpiperidin-4-yl)-1-(triisopropylsilyl)-indole (0.600 g, 1.34 mmol), 4-methoxyphenylboronic acid (0.213g, 1.40 mmol), tetrakis(triphenylphosphine)palladium(0) (0.077g, 0.067 mmol), and 2M aqueous sodium carbonate solution (2 mL) in toluene (15 mL) to give 0.150 g of 5-(4-methoxyphenyl)-3-(1-methylpiperidin-4-yl)-1-(triisopropylsilyl)-indole (24%) as a solid, which was desilylated by dissolving in 1 mL of tetrahydrofuran and treating with tetrabutylammonium fluoride (1M in tetrahydrofuran, 4 mL) to give the title compound (0.050 g, 45%) as an amorphous solid. FDMS m/e 320 (M+). EA calculated for C21H24N2O.⅛ H2O: C, 78.17; H, 7.57; N, 8.68. Found: C, 78.13; H, 7.92; H, 8.43.
Reaction SMILES: [C:1]1([CH3:14])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[S:9]([O:12][NH2:13])(=[O:11])=[O:10].[N:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[NH2:21]>ClCCl>[CH3:8][C:3]1[CH:4]=[C:5]([CH3:7])[CH:6]=[C:1]([CH3:14])[C:2]=1[S:9]([O-:12])(=[O:11])=[O:10].[NH2:13][N+:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[NH2:21]
Reactant: Cc1cc(C)c(S(=O)(=O)ON)c(C)c1
Reactant: Nc1ccccn1
Solvent: ClCCl
Product: Cc1cc(C)c(S(=O)(=O)[O-])c(C)c1
Product: Nc1cccc[n+]1N
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 82.4 %

Procedure:
To a suspension of O-(mesitylsulfonyl)hydroxylamine (9.2 g, 42.7 mmol) in dichloromethane (110 mL) was added pyridin-2-amine (4.02 g, 42.7 mmol) in four portions at 0-5° C. to give a yellow solution. After 5 min the yellow solution turned into a light yellow suspension. The ice bath was removed after 10 min and the reaction mixture was stirred at RT for 1 h. The suspension was diluted with diethyl ether (100 mL), filtered, washed with diethyl ether and dried in vacuo to give the product (10.9 g, 35.2 mmol, 82.4%) as light red solid which was used without further purification for the next step.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:25])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:24])[CH2:19][CH2:20][CH2:21][CH2:22]Br)=[CH:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:26][NH:27][CH3:28].O>ClCCl>[CH2:1]([O:8][C:9](=[O:25])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:24])[CH2:19][CH2:20][CH2:21][CH2:22][N:27]([CH3:28])[CH3:26])=[CH:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CCCCBr)Nc1ccc(NC(=O)OCc2ccccc2)cc1
Reactant: CNC
Solvent: ClCCl
Solvent: O
Product: CN(C)CCCCC(=O)Nc1ccc(NC(=O)OCc2ccccc2)cc1
Yield: 68 %

Procedure:
Compound 2 (5.88 g, 0.012 mol) was stirred in dichloromethane (150 mL) with 40% aqueous dimethylamine (10 mL) and water (25 mL) for 24 h. The solution was diluted with dichloromethane (50 mL) and washed with water (1×100 mL), 1 M aqueous sodium hydroxide (1×100 mL), and saturated brine (1×100 mL). The organic phase was dried (MgSO4) and concentrated in vacuo to give 3 as a white solid (3 g, 68%).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]([OH:11])([C:7]([F:10])([F:9])[F:8])[C:4]([OH:6])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:26][C:27]1[CH:41]=[CH:40][C:30]([C:31]([C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[CH:34]=2)=[O:32])=[CH:29][CH:28]=1>O1CCCC1>[F:39][C:35]1[CH:34]=[C:33]([C:31]([C:30]2[CH:29]=[CH:28][C:27]([NH:26][C:4](=[O:6])[C:3]([OH:11])([C:2]([F:1])([F:13])[F:12])[C:7]([F:10])([F:9])[F:8])=[CH:41][CH:40]=2)=[O:32])[CH:38]=[CH:37][CH:36]=1
Reactant: O=C(O)C(O)(C(F)(F)F)C(F)(F)F
Reactant: Nc1ccc(C(=O)c2cccc(F)c2)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=C(c1ccc(NC(=O)C(O)(C(F)(F)F)C(F)(F)F)cc1)c1cccc(F)c1
Temperature: 25 °C
Yield: 55.2 %

Procedure:
To a stirred solution of 3,3,3-trifluoro-2-hydroxy-2-trifluoromethylpropanoic acid (1.17 g, 5.5 mmol) in dry tetrahydrofuran (35 mL) was added 1,1'-carbonyldiimidazole (0.89 g, 5.5 mmol). The mixture was heated at reflux for 45 minutes, then cooled to room temperature. 4-Amino-3'-fluorobenzophenone (1.08 g, 5.0 mmol) was added in one portion and the reaction mixture heated at reflux for 48 hours. Tetrahydrofuran was removed from the reaction mixture in vacuo, and the residue dissolved in ethyl ether and filtered. The filtrate was washed with 3N HCl (50 mL) and water. The ether extract was dried (MgSO4) and concentrated in vacuo to an off-white solid. Purification by flash column chromatography (5% v/v ethyl ether/methylene chloride) yielded the title propanamide as a tan solid (1.13 g, 55%); mp 169°-171° C. 1H-NMR (300 MHz, d6 -DMSO): 7.50-7.64 (m, 4H, aromatic) 7.77-7.82 (m, 2H, aromatic) 7.94-7.98 (m, 2H, aromatic) 9.84 (s, 1H, NH) 10.85 (bs, 1H, OH). MS (CI, CH4): 410 (M+1).
Reaction SMILES: [Na].[CH2:2]([OH:5])[CH:3]=[CH2:4].Cl[C:7]1[N:8]=[C:9]([N:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[C:10]2[N:15]=[C:14](Cl)[N:13]=[C:12]([N:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[C:11]=2[N:23]=1.O.[CH2:31]1C[O:34][CH2:33][CH2:32]1>>[CH2:2]([O:5][C:7]1[N:8]=[C:9]([N:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[C:10]2[N:15]=[C:14]([O:34][CH2:33][CH:32]=[CH2:31])[N:13]=[C:12]([N:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[C:11]=2[N:23]=1)[CH:3]=[CH2:4]
Reactant: Clc1nc(N2CCCCC2)c2nc(Cl)nc(N3CCCCC3)c2n1
Reactant: C=CCO
Reactant: C1CCOC1
Agent: [Na]
Solvent: O
Product: C=CCOc1nc(N2CCCCC2)c2nc(OCC=C)nc(N3CCCCC3)c2n1
Temperature: 25 °C
Yield: 40 %

Procedure:
Sodium metal (0.115 g, 5 mmol) was added to allyl alcohol (0.291 g, 5 mmol) in dry THF (5 ml) and stirred until all had dissolved. 2,6-dichloro-4,8-dipiperidinopyrimidopyrimidine (0.184 g, 0.5 mmol) dissolved in dry THF (10 ml) was added to the alkoxide and the mixture heated under reflux for 72 hours. After cooling to room temperature, water (20 ml) was added and the product extracted into ethyl acetate (4×20 ml). The organic layers were combined, dried (MgSO4), filtered and the solvent removed in vacuo. Recrystallisation from methanol/water yielded the title compound as a white crystalline solid (0.079 g, 40%), m.p. 109-110° C.
Reaction SMILES: [F:1][C:2]1([F:18])[CH2:7][CH2:6][C:5]([C:15](=O)[CH3:16])([C:8]2[CH:9]=[N:10][C:11]([CH3:14])=[N:12][CH:13]=2)[CH2:4][CH2:3]1.[NH2:19][OH:20].Cl.[OH-].[Na+]>CCO.O>[F:1][C:2]1([F:18])[CH2:7][CH2:6][C:5](/[C:15](=[N:19]\[OH:20])/[CH3:16])([C:8]2[CH:9]=[N:10][C:11]([CH3:14])=[N:12][CH:13]=2)[CH2:4][CH2:3]1
Reactant: NO
Reactant: CC(=O)C1(c2cnc(C)nc2)CCC(F)(F)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: C/C(=N/O)C1(c2cnc(C)nc2)CCC(F)(F)CC1
Temperature: 80 °C
Yield: 86.1 %

Procedure:
A mixture of 1-(4,4-difluoro-1-(2-methylpyrimidin-5-yl)cyclohexyl)ethanone (350 mg, 1.38 mmol), NH2OH.HCl (143.7 mg, 2.07 mmol) and NaOH (165.6 mg, 4.14 mmol) in EtOH/H2O (16 mL, 1:1) was heated to 80° C. overnight. The EtOH was removed. The residue was extracted with EtOAc (2×20 mL). The organic layer was dried over Na2SO4 and concentrated to give (Z)-1-(4,4-difluoro-1-(2-methylpyrimidin-5-yl)cyclohexyl)ethanone oxime (320 mg), which was used for the next step directly.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:8](=O)[CH2:9]Br)=[C:5]([CH3:7])[N:6]=1.[CH3:12][C:13]([CH3:18])([CH3:17])[C:14](=[S:16])[NH2:15].C(N(CC)CC)C>C(O)C>[C:13]([C:14]1[S:16][CH:9]=[C:8]([C:4]2[S:3][C:2]([NH2:1])=[N:6][C:5]=2[CH3:7])[N:15]=1)([CH3:18])([CH3:17])[CH3:12]
Reactant: CC(C)(C)C(N)=S
Reactant: Cc1nc(N)sc1C(=O)CBr
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1nc(N)sc1-c1csc(C(C)(C)C)n1
Temperature: 25 °C

Procedure:
A mixture of 1-(2-amino-4-methyl-thiazol-5-yl)-2-bromo-ethanone (7.0 g, prepared as described in WO 2006/125805), 2,2-dimethylpropanethioamide (2.25 g, prepared as described by Boys and Downs in Synthetic Communications 2006, 36, 295-298.), triethylamine (7.2 ml) and ethanol (173 ml) are heated at reflux for 3.5 hours. On cooling to room temperature the reaction mixture is filtered, the filtrate evaporated and then partitioned between aqueous NaHCO3 and CH2Cl2, extracting 3×CH2Cl2. The organic layers are dried and evaporated then triturated 4× with diethyl ether (50 ml), the diethyl ether layers combined and extracted with 1M HCl (100 ml). The HCl layer is then washed 3× diethyl ether, basified with aqueous NaOH and extracted 4× diethyl ether and 2×CH2Cl2. The organic layers dried over Na2SO4 and evaporated to give the title compound as a red solid. Hplc/MS (Method B) RT 1.95 minutes, M+H 253.9.
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[CH3:7][O:8][C:9]([C:11]1C=[CH:18][CH:17]=[CH:16][C:12]=1C(O)=O)=[O:10]>CN(C=O)C.ClCCl>[Cl:4][C:2]([C:1]1[CH:18]=[CH:17][CH:16]=[CH:12][C:11]=1[C:9]([O:8][CH3:7])=[O:10])=[O:3]
Reactant: COC(=O)c1ccccc1C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)c1ccccc1C(=O)Cl
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Oxalyl chloride (0.86 ml, 9.8 mml) and two drops of DMF were added to a solution of 2-(methoxycarbonyl)benzoic acid (590 mg, 3.27 mmol) in dichloromethane (10 ml) and cooled to 0° C. and stirred at RT for 30 min. After 30 min, the solvent was removed to obtain methyl 2-(chloroformyl)benzoate (quantitative). A solution of this intermediate (401 mg, 2.03 mmol) in dichloromethane was added to a solution of intermediate 10 (540 mg, 2.03 mmol) and pyridine (0.19 ml, 2.43 mmol) in dichloromethane (5 ml) at 0° C. and stirred at RT for 30 min. Work-up (CH2Cl2/H2O) and purification gave methyl 2-(3-chloro-3′-ethoxy-5-fluorobiphenyl-4-ylcarbamoyl)benzoate (250 mg) as an off-white solid. Lithium borohydride (20 mg, 0.94 mmol) was added to a solution of this product (200 mg, 0.47 mmol) in THF (5 ml) at 0° C. and the mixture stirred at RT for 2 hrs. Work-up (EtOAc/aq. 10% NH4Cl then H2O) and purification afforded the title compound (30 mg) as a white solid. M.P.: 139.2-141.5° C. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 10.22 (s, 1H), 7.76 (s, 1H), 7.73-7.60 (m, 3H), 7.54 (t, J 6.7, 1H), 7.43-7.36 (m, 2H), 7.33-7.26 (m, 2H), 6.97 (dd, J 1.8, 8.1, 1H), 5.32 (t, J 5.6, 1H), 4.72 (d, J 5.6, 2H), 4.12 (q, J 7, 2H), 1.35 (t, J 7, 3H).
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:23][C:6]2[N:7]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[C:8]3[CH:9]=[CH:10][C:11]([C:14]#[N:15])=[CH:12][C:13]=3[C:5]=2[CH2:4]1.ClCCl.Cl[C:28]([O:30][CH:31]([CH3:33])[CH3:32])=[O:29]>N1C=CC=CC=1>[CH:31]([O:30][C:28](=[O:29])[NH:2][CH:3]1[CH2:23][C:6]2[N:7]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[C:8]3[CH:9]=[CH:10][C:11]([C:14]#[N:15])=[CH:12][C:13]=3[C:5]=2[CH2:4]1)([CH3:33])[CH3:32]
Reactant: CC(C)OC(=O)Cl
Reactant: N#Cc1ccc2c(c1)c1c(n2Cc2ccccn2)CC(N)C1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)OC(=O)NC1Cc2c(n(Cc3ccccn3)c3ccc(C#N)cc23)C1
Temperature: 5 °C
Yield: 56.9 %

Procedure:
Add (±)-2-amino-4-pyridin-2-ylmethyl-1,2,3,4-tetrahydro-cyclopenta[b]indole-7-carbonitrile hydrochloride (35 g, 108 mmol) to a mixture of dichloromethane (350 mL) and pyridine (70 mL). Stir the mixture under nitrogen and cool to 5° C. Add isopropyl chloroformate (1M solution in toluene, 162 mL, 162 mmol). Remove the ice bath and stir the mixture at 22° C. After 16 h evaporate the solvent. Add the resulting residue to water (350 mL) and stir 2 h. Filter and dry the collected solid under vacuum at 45° C. Add the solid to ethyl acetate (400 mL) and heat the mixture to reflux. Then cool to 22° C. and filter the solid. Add the wet solid to ethyl acetate (200 mL) and heat to reflux for 30 min. Cool the mixture to 22° C. over one hour and then cool to 0-5° C. during 5 min. Filter the mixture and dry the isolated solid under vacuum to constant weight to provide 23 g (62%) of the title compound. MS (m/z): 374 (M+1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[CH2:12][C:13]([O:15][CH3:16])=[O:14].F[B-](F)(F)F.[CH3:22][Si:23]([C:26]#[CH:27])([CH3:25])[CH3:24].CN(C=O)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.CCN(CC)CC>[F:9][C:8]([F:11])([F:10])[C:5]1[CH:6]=[CH:7][C:2]([C:27]#[C:26][Si:23]([CH3:25])([CH3:24])[CH3:22])=[C:3]([CH2:12][C:13]([O:15][CH3:16])=[O:14])[CH:4]=1
Reactant: COC(=O)Cc1cc(C(F)(F)F)ccc1Br
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)Cc1cc(C(F)(F)F)ccc1C#C[Si](C)(C)C
Temperature: 80 °C
Reaction time: 16 h

Procedure:
A suspension of methyl 2-(2-bromo-5-(trifluoromethyl)phenyl)acetate (A103) (1.00 g, 3.36 mmol), PdCl2(PPh3)2 (0.118 g, 0.168 mmol), t-Bu3PH.BF4 (0.049 g, 0.17 mmol), CuI (0.032 g, 0.17 mmol) and trimethylsilylacetylene (0.951 mL, 6.73 mmol) in anhydrous degassed DMF (10 mL) and Et3N (10 mL) was stirred at 80° C. for 16 hours. The resulting mixture was adsorbed onto silica gel and purified by column chromatography (Biotage Isolera, SiO2 cartridge, 0-10% EtOAc in petroleum benzine 40-60° C.) to give the title compound A104 as an orange liquid (0.863 g, 82%); 1H NMR (400 MHz, CDCl3) δ 7.57 (d, J=8.0 Hz, 1H), 7.53 (d, J=0.5 Hz, 1H), 7.50-7.44 (m, 1H), 3.87 (s, 2H), 3.7s (s, 3H), 0.24 (s, 9H). LCMS: rt 6.931 min; m/z 315.1 [M+H]+.
Reaction SMILES: [Br-:1].[Li+].C1(C)C=CC(S(O[CH2:13][CH2:14][C:15]2([OH:21])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)(=O)=O)=CC=1>CC(C)=O>[Br:1][CH2:13][CH2:14][C:15]1([OH:21])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: Cc1ccc(S(=O)(=O)OCCC2(O)CCCCC2)cc1
Reactant: [Br-]
Agent: [Li+]
Solvent: CC(C)=O
Product: OC1(CCBr)CCCCC1

Procedure:
A stirred solution of lithium bromide (70 g) and 1-(2-p-toluenesulphonyloxyethyl)cyclohexanol (16.4 g) in acetone (350 ml) was heated under reflux for 1 hour. The cooled reaction mixture was partially concentrated in vacuo and then partitioned between ether (300 ml) and water. The ether phase was washed with water and brine, dried and concentrated in vacuo to give 1-(2-bromoethyl)cyclohexanol [H; n=1, R1 +R2 =--(CH2)5 --] as an oil.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[N:16][C:17]([NH:20][C:21]3[N:22]=[CH:23][C:24]4[CH:30]=[C:29]([O:31][CH2:32][CH:33]([CH3:35])[CH3:34])[C:28](=[O:36])[N:27]([CH:37]5[CH2:41][CH2:40][CH2:39][CH2:38]5)[C:25]=4[N:26]=3)=[CH:18][CH:19]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(Cl)(Cl)[Cl:43]>>[ClH:43].[CH:37]1([N:27]2[C:25]3[N:26]=[C:21]([NH:20][C:17]4[CH:18]=[CH:19][C:14]([N:11]5[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]5)=[CH:15][N:16]=4)[N:22]=[CH:23][C:24]=3[CH:30]=[C:29]([O:31][CH2:32][CH:33]([CH3:34])[CH3:35])[C:28]2=[O:36])[CH2:41][CH2:40][CH2:39][CH2:38]1
Reactant: CC(C)COc1cc2cnc(Nc3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cn3)nc2n(C2CCCC2)c1=O
Reactant: ClC(Cl)Cl
Product: CC(C)COc1cc2cnc(Nc3ccc(N4CCNCC4)cn3)nc2n(C2CCCC2)c1=O
Product: Cl
Temperature: 0 °C
Reaction time: 3 h

Procedure:
4-[6-(8-Cyclopentyl-6-isobutoxy-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl]-piperazine-1-carboxylic acid tert-butyl ester (0.067 g, 0.119 mmol) was dissolved in chloroform (5 ml), cooled to 0° C. This solution was purged with anhydrous hydrogen chloride gas and stoppered for 3 hours. Diethyl ether was added to the mixture giving a precipitate that was filtered and dried in vacuo to provide 8-cyclopentyl-6-isobutoxy-2-(5-piperazin-1-yl-pyridin-2-ylamino)-8H-pyrido[2,3-d]pyrimidin-7-one hydrochloride as a solid (0.056 g). MS (APCI); M++1: Calc'd, 464.5. Found, 464.3. Analyses for C25H33N7O2.1.0 H2O.2.0HCl: Calc'd: C, 54.15; H, 6.72; N, 17.68; Cl (ionic), 12.78; H2O, 3.25. Found: C, 54.18; H, 6.98; N, 17.51; Cl (ionic), 12.15; H2O, 2.60.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@H:10]([C:14]([OH:16])=O)[CH2:9]2)[CH:5]=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[C:19]([F:25])[CH:18]=2)[N:3]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[F:40][C:41]1[CH:42]=[C:43]([CH:45]=[CH:46][CH:47]=1)[NH2:44]>CN(C=O)C.CCOC(C)=O>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@H:10]([C:14]([NH:44][C:43]3[CH:45]=[CH:46][CH:47]=[C:41]([F:40])[CH:42]=3)=[O:16])[CH2:9]2)[CH:5]=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[C:19]([F:25])[CH:18]=2)[N:3]=1
Reactant: N#Cc1ccc(-c2cc(N3CCC[C@H](C(=O)O)C3)nc(N)n2)cc1F
Reactant: Nc1cccc(F)c1
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: N#Cc1ccc(-c2cc(N3CCC[C@H](C(=O)Nc4cccc(F)c4)C3)nc(N)n2)cc1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 50.9 %

Procedure:
To a solution of (3S)-1-[2-amino-6-(4-cyano-3-fluorophenyl)-4-pyrimidinyl]-3-piperidinecarboxylic acid (150 mg, 0.439 mmol), EDC (118 mg, 0.615 mmol), and HOBT (83 mg, 0.615 mmol) in DMF (8 mL) was added 3-fluoroaniline (68.4 mg, 0.615 mmol), and the reaction mixture was stirred at room temperature for 4 hours. LCMS showed reaction was completed. The reaction was poured onto water, and EtOAc was added to extract the product. The product stayed in the EtOAc layer. The organic solution was concentrated to dryness to give the title compound (97 mg) as a yellow solid. LC-MS (ES) m/z=434 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[C:5]([C:8]2[CH:9]=[C:10]([CH:25]=[CH:26][CH:27]=2)[CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][C:21]([O:23]C)=[O:22])=[CH:15][CH:14]=2)[C:4]([CH3:28])=[N:3]1.[OH-].[Na+].O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CO.O1CCCC1>[CH3:1][N:2]1[C:6]([CH3:7])=[C:5]([C:8]2[CH:9]=[C:10]([CH:25]=[CH:26][CH:27]=2)[CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:15][CH:14]=2)[C:4]([CH3:28])=[N:3]1
Reactant: COC(=O)CCc1ccc(OCc2cccc(-c3c(C)nn(C)c3C)c2)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1nn(C)c(C)c1-c1cccc(COc2ccc(CCC(=O)O)cc2)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 100.3 %

Procedure:
To a mixed solution of methyl 3-(4-{[3-(1,3,5-trimethyl-1H-pyrazol-4-yl)benzyl]oxy}phenyl)propanoate (0.406 g, 1.07 mmol) in methanol (5 mL) and tetrahydrofuran (5 mL) was added 2 M aqueous sodium hydroxide solution (1.5 mL), and the mixture was stirred at room temperature for 20 hr. Water was added to the reaction mixture, and the mixture was neutralized with 10% aqueous citric acid solution and extracted with ethyl acetate. The extract washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (0.391 g, quantitative) as colorless needle crystals. MS: m/z 365 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([S:13][CH3:14])=[N:10][C:9]=2[CH2:15][OH:16])=[CH:4][CH:3]=1.[F:17][C:18]([F:22])([F:21])[CH2:19]O.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][C:11]([S:13][CH3:14])=[N:10][C:9]=2[CH2:15][O:16][CH2:19][C:18]([F:22])([F:21])[F:17])=[CH:6][CH:7]=1
Reactant: OCC(F)(F)F
Reactant: CSc1nc(CO)c(-c2ccc(F)cc2)o1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Product: CSc1nc(COCC(F)(F)F)c(-c2ccc(F)cc2)o1
Reaction time: 2 h

Procedure:
A suspension of [5-(4-fluoro-phenyl)-2-methylsulfanyl-oxazol-4-yl]-methanol (4.15 g; 17.34 mmol) in dry toluene (100 ml) was treated with 2,2,2-trifluoroethanol (12.63 ml; 173.4 mmol), 1,1'-(azodicarbonyl)dipiperidine (5.03 g; 19.94 mmol) and tributylphosphine (4.97 ml; 19.94 mmol) and stirred for 2 hours. The reaction mixture is partitioned between ethyl acetate (150 ml) and dilute sodium chloride solution (150 ml). The organic phase is washed with saturated brine (30 ml), dried over sodium sulfate and concentrated to dryness. Purification by flash chromatography on silica gel using an ethyl acetate/hexane gradient (2%-30%) afforded the product as a colorless residue (3.0 g; 49%). HNMR (CDCl3): 7.65 (m, 2H), 7.18 (t, 2H, J=8.7 Hz), 4.72 (s, 2H), 4.01 (qt, 2H, J=8.6 Hz), 2.73 (s, 3H). Mass spectrum: m/e calculated (MH+)=322; observed (MH+)=322.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[CH:7]=[C:6]2[CH2:13][C:14]1[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][C:15]=1[O:24][CH3:25])=[O:2].[CH3:26][N:27]1[CH2:31][CH2:30][CH2:29][C:28]1=[O:32]>>[OH:2][CH:1]([CH:29]1[CH2:30][CH2:31][N:27]([CH3:26])[C:28]1=[O:32])[C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[CH:7]=[C:6]2[CH2:13][C:14]1[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][C:15]=1[O:24][CH3:25]
Reactant: COC(=O)c1ccc(Cc2cn(C)c3ccc(C=O)cc23)c(OC)c1
Reactant: CN1CCCC1=O
Product: COC(=O)c1ccc(Cc2cn(C)c3ccc(C(O)C4CCN(C)C4=O)cc23)c(OC)c1

Procedure:
Using a similar procedure to that described in Example 1, part d, except starting from methyl 4-(5-formyl-1-methylindol-3-ylmethyl)-3-methoxybenzoate and N-methylpyrrolidone, methyl 4-[5-[(hydroxy)-(1-methyl -2-oxopyrrolidin-3-yl)methyl]-1-methylindol-3-ylmethyl]-3-methoxybenzoate was obtained (40%) as a foam; NMR (300 MHz, DMSO-d6): 1.43-1.65 (m, 1.5H), 1.95 (m, 0.5H), 2.40-2.60 (m, 2.5H), 2.65-2.80 (m, 2H), 2.90-3.25 (m, 1.5H), 3.70 (s, 3H), 3.83 (s, 3H), 3.85-4.08 (m, 5H), 4.92 (d, 0.5H), 5.17 (s, 0.5H), 7.0-7.55 (m, 7H).