Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([C:6]([CH:22](OCC)OCC)([CH2:9][C:10]1[CH:15]=[C:14]([O:16][CH3:17])[C:13]([O:18][CH3:19])=[C:12]([O:20][CH3:21])[CH:11]=1)[C:7]#[N:8])(OCC)=O.[OH-].[K+].[NH2:31][C:32]([NH2:34])=[NH:33]>C(O)C>[NH2:34][C:32]1[N:33]=[C:7]([NH2:8])[C:6]([CH2:9][C:10]2[CH:15]=[C:14]([O:16][CH3:17])[C:13]([O:18][CH3:19])=[C:12]([O:20][CH3:21])[CH:11]=2)=[CH:22][N:31]=1
Reactant: N=C(N)N
Reactant: CCOC(=O)C(C#N)(Cc1cc(OC)c(OC)c(OC)c1)C(OCC)OCC
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: COc1cc(Cc2cnc(N)nc2N)cc(OC)c1OC

Procedure:
A solution of α-carbethoxy-α-diethoxymethyl-β-(3,4,5-trimethoxyphenyl)propionitrile (7.9 g, 0.02 mol) and an equivalent amount of potassium hydroxide in ethanol (50 ml) was heated at reflux for one hour. A solution of guanidine (0.07 mol) in ethanol (50 ml) was added, and reflux was resumed. Some ethanol was allowed to boil off bringing the reaction temperature up to 85°. After about 20 hours at reflux the mixture was allowed to cool, and the product was filtered and washed with ethanol. The crude product was purified by treating with hot aqueous acetic acid and reprecipitation with ammonium hydroxide. The yield of purified trimethoprim (m.p. 197°-198°) was 3.6g (62%), its identity being confirmed by an NMR spectrum.
Reaction SMILES: [Ti:1](Cl)(Cl)(Cl)[Cl:2].[CH3:6][CH:7]1[C:15]2[C:10](=[C:11]([CH3:19])[C:12]([CH3:18])=[C:13]([CH3:17])[C:14]=2[CH3:16])[C:9]([Si](C)(C)C)=[C:8]1[CH3:24]>C1(C)C=CC=CC=1>[Cl-:2].[Cl-:2].[Cl-:2].[CH3:6][CH:7]1[C:15]2[C:10](=[C:11]([CH3:19])[C:12]([CH3:18])=[C:13]([CH3:17])[C:14]=2[CH3:16])[C:9]([Ti+3:1])=[C:8]1[CH3:24]
Reactant: CC1=C([Si](C)(C)C)c2c(C)c(C)c(C)c(C)c2C1C
Reactant: Cl[Ti](Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: CC1=C([Ti+3])c2c(C)c(C)c(C)c(C)c2C1C
Product: [Cl-]

Procedure:
Titanium tetrachloride in an amount of 15.2 g (80 mmol, 8.8 mL) was dissolved in 100 mL of dehydrated toluene, and to the resultant solution was added dropwise, at room temperature, a solution of 18.02 g of 1,2,4,5,6,7-hexamethylindenyltrimethylsilane in 150 mL of toluene over a period of 3 hours. After one hour of heating refluxing of the mixed solution thus obtained, there was produced a toluene-soluble portion at 80° C., which then was extracted twice with 100 mL each of toluene. By filtering off the toluene-insoluble portion, there was obtained a green toluene solution, and the volatile components of which were distilled away at 40° C. under reduced pressure to afford dark green solid. Thereafter, the solid was incorporated with 20 mL of toluene and then with 200 mL of hexane, and the insoluble portion was collected by filtration. The insoluble portion was subjected to Soxhlet extraction by using boiling hexane to recover the title complex at 88% recovery rate from the extract solution in a yield of 21.07 g (60 mmol) and in a yield rate of 75%. The product was readily soluble in toluene, and was analyzed by NMR with the results as follows: 1H-NMR(tetramethylsilane as the standard and heavy chloroform (CDCl3) as the solvent); 6.89 ppm (3H, s), 2.86 ppm (3H, s), 2.68 ppm (3H, s), 2.53 ppm (3H, s), 2.47 ppm (3H, s), 2.37 ppm (3H, s), 2.35 ppm (3H, s), 49Ti-NMR(titanium tetrachloride as the standard and CDCl3 as the solvent); -75.54 ppm.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][O:6][CH2:5][CH2:4][N:3]1[C:8]1[N:12]2[CH:13]=[C:14]([O:17][C@H:18]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[C@@H:21]([NH2:28])[CH2:20][CH2:19]3)[CH:15]=[CH:16][C:11]2=[N:10][N:9]=1.ClC(Cl)(Cl)C[O:32][C:33](=[O:60])[NH:34][C:35]1[N:36]([C:44]2[CH:49]=[CH:48][CH:47]=[C:46]([O:50][CH2:51][CH2:52]OC3CCCCO3)[CH:45]=2)[N:37]=[C:38]([C:40]([CH3:43])([CH3:42])[CH3:41])[CH:39]=1.C[CH2:64][N:65](C(C)C)[CH:66](C)C>O1CCOCC1>[CH:33]([OH:60])=[O:32].[C:40]([C:38]1[CH:39]=[C:35]([NH:34][C:33]([NH:28][C@@H:21]2[C:22]3[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=3)[C@H:18]([O:17][C:14]3[CH:15]=[CH:16][C:11]4[N:12]([C:8]([N:3]5[CH2:4][CH2:5][O:6][CH2:7][C@@H:2]5[CH3:1])=[N:9][N:10]=4)[CH:13]=3)[CH2:19][CH2:20]2)=[O:60])[N:36]([C:44]2[CH:49]=[CH:48][CH:47]=[C:46]([O:50][CH2:51][CH2:52][N:65]([CH3:66])[CH3:64])[CH:45]=2)[N:37]=1)([CH3:42])([CH3:41])[CH3:43]
Reactant: C[C@H]1COCCN1c1nnc2ccc(O[C@@H]3CC[C@H](N)c4ccccc43)cn12
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(C)(C)c1cc(NC(=O)OCC(Cl)(Cl)Cl)n(-c2cccc(OCCOC3CCCCO3)c2)n1
Solvent: C1COCCO1
Product: C[C@H]1COCCN1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4cccc(OCCN(C)C)c4)c4ccccc43)cn12
Product: O=CO
Temperature: 80 °C
Reaction time: 8 h
Yield: 172 %

Procedure:
A mixture of Intermediate 139c (125 mg, 0.33 mmol), Intermediate 39b (177 mg, 0.33 mmol) and DIPEA (115 μL, 0.66 mmol) in dioxane (3 mL) was stirred at 80° C. overnight. After cooling, the reaction mixture was partitioned between water and DCM. The aqueous phase was extracted with EtOAc (×3) and the combined organic layers were washed with brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was purified by FCC on silica, using a gradient of 0-10% MeOH in DCM, to afford the title compound (214 mg, 85%). LCMS (Method 4): Rt 3.65 min, m/z 765 [MH+].
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][C:10]1[N:11]=[CH:12][N:13]([C:15]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:14]=1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].[CH3:34]CCCCC.C([Li])CCC.CI>C1COCC1>[C:16]1([C:15]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:13]2[CH:14]=[C:10]([CH:9]([P:4](=[O:8])([O:5][CH2:6][CH3:7])[O:3][CH2:1][CH3:2])[CH3:34])[N:11]=[CH:12]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CCOP(=O)(Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)OCC
Reactant: CCCCCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CI
Product: CCOP(=O)(OCC)C(C)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97 %

Procedure:
To a solution of diethyl(1-triphenylmethylimidazol-4-yl)methylphosphonate (690 mg, 1.5 mmol) in THF (20 ml) was added 1.6M hexane solution of n-butyllithium (0.94 ml, 1.5 mmol) dropwise over 10 minutes at −72° C. under argon flow, followed by adding a solution of methyl iodide (213 mg, 1.5 mmol) in THF (5 ml) dropwise over 10 minutes. After stirring at the same temperature for 30 minutes, the reaction mixture was heated to room temperature, and then stirred at room temperature for 2 hours. The reaction was quenched with water (1 ml), and then the THF was removed under reduced pressure. Saturated brine (40 ml) was added to the residue, and the mixture was extracted 3 times with ethyl acetate (40 ml). The resultant organic layers were dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product as a light yellow solid. It was purified through chromatography on silica gel column using methanol-ethyl acetate (1:9) to provide the titled compound (690 mg, 97%) as a white powder (m.p. 124-126° C.). This powder was recrystallized from a mixture of ethyl acetate and hexane to provide the title compound as a small needle crystal (m.p. 125-128° C.).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH3:11][CH:12]1[CH2:16][NH:15][C:14]([C:17]2[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24](=[O:31])[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:18]=2)=[N:13]1.C(N(CC)CC)C>ClCCl>[CH3:11][C:12]1[N:13]=[C:14]([C:17]2[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24](=[O:31])[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:18]=2)[NH:15][CH:16]=1
Reactant: CC1CNC(c2ccnc(NC(=O)c3ccccc3)c2)=N1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1c[nH]c(-c2ccnc(NC(=O)c3ccccc3)c2)n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 29.9 %

Procedure:
To a solution of oxalyl chloride (0.06 mL, 0.72 mmol) in anhydrous dichloromethane (1.0 mL) was added anhydrous dimethyl sulfoxide (0.09 mL, 1.20 mmol) dropwise at −78° C. under nitrogen atmosphere. The resulting solution was stirred for 10 minutes, followed by dropwise addition of a solution of N-(4-(4-methyl-4,5-dihydro-1H-imidazol-2-yl)pyridin-2-yl)benzamide (0.17 g, 0.60 mmol) in anhydrous dichloromethane (1.5 mL). The reaction mixture was stirred for 40 minutes, followed by the addition of anhydrous triethyl amine (0.33 mL, 2.38 mmol), warmed to ambient temperature during 3 hours and partitioned between water (15 mL) and dichloromethane (25 mL). The aqueous layer was extracted with dichloromethane (2×25 mL). The organic layer was dried over sodium sulphate, filtered and concentrated in vacuo to dryness. The residue was purified by column chromatography eluting with ethyl acetate followed by methanol in ethyl acetate (1:25 ratio) to give N-(4-(4-methyl-1H-imidazol-2-yl)pyridin-2-yl)benzamide as a colorless solid (0.05 g, 38%): mp 133-135° C.; 1H NMR (300 MHz, DMSO-d6) δ 12.70 (s, 1H), 10.81 (s, 1H), 8.69 (s, 1H), 8.40 (d, J=5.3 Hz, 1H), 8.08-8.03 (m, 2H), 7.64-7.49 (m, 4H), 6.95 (br s, 1H), 2.24 (s, 3H); 13C NMR (75 MHz, CD3OD) δ 168.5, 154.1, 149.8, 144.5, 140.8, 135.6, 133.4, 129.8, 128.8, 116.9, 111.4, 11.6; MS (ES+) m/z 279.4 (M+1).
Reaction SMILES: C(OC([N:8]1[CH:13]([CH3:14])[CH2:12][N:11]([C:15]2[CH:16]=[N:17][C:18]([NH:21][C:22]3[N:23]=[CH:24][C:25]4[C:31]([CH3:32])=[C:30]([Br:33])[C:29](=[O:34])[N:28]([CH:35]5[CH2:39][CH2:38][CH2:37][CH2:36]5)[C:26]=4[N:27]=3)=[CH:19][CH:20]=2)[CH2:10][CH:9]1[CH3:40])=O)(C)(C)C.[Cl:41]CCl>Cl>[ClH:41].[Br:33][C:30]1[C:29](=[O:34])[N:28]([CH:35]2[CH2:36][CH2:37][CH2:38][CH2:39]2)[C:26]2[N:27]=[C:22]([NH:21][C:18]3[CH:19]=[CH:20][C:15]([N:11]4[CH2:12][CH:13]([CH3:14])[NH:8][CH:9]([CH3:40])[CH2:10]4)=[CH:16][N:17]=3)[N:23]=[CH:24][C:25]=2[C:31]=1[CH3:32]
Reactant: Cc1c(Br)c(=O)n(C2CCCC2)c2nc(Nc3ccc(N4CC(C)N(C(=O)OC(C)(C)C)C(C)C4)cn3)ncc12
Reactant: ClCCl
Agent: Cl
Product: Cc1c(Br)c(=O)n(C2CCCC2)c2nc(Nc3ccc(N4CC(C)NC(C)C4)cn3)ncc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.4 %

Procedure:
4-[6-(6-Bromo-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl]-2,6-dimethyl-piperazine-1-carboxylic acid tert-butyl ester (0.051 g, 0.083 mmol) was dissolved in dichloromethane (3 mL) to which 2 N HCl (2 mL) was added and the mixture was stirred at room temperature for 2 hours. This mixture was concentrated and allowed to sit for 10 days, it was then dissolved in 2 N HCl (2 mL) and stirred at room temperature for 5 hours. The solvent was removed to give 6-bromo-8-cyclopentyl-2-[5-(3,5-dimethyl-piperazin-1-yl)-pyridin-2-ylamino]-5-methyl-8H-pyrido[2,3-d]pyrimidin-7-one hydrochloride salt as a yellow solid (0.039 g, 71.4%). 1H NMR δ (400 MHz, DMSO-d6) 9.51 (m, 1H), 9.02 (m, 1H), 8.98 (s, 1H), 8.07 (s, 1H), 7.83 (s, 2H), 5.90 (m, 1H), 3.85 (d, J=11.2 Hz, 2H), 3.35 (m, 2H), 2.76 (dd, J=12.0, 12.0 Hz 2H), 2.58 (s, 3H), 2.14 (m, 2H), 1.92 (m, 2H), 1.77 (m, 2H), 1.58 (m, 2H), 1.28 (d, J=6.4 Hz, 6H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([NH2:10])=[NH:9])=[N:6][CH:7]=1.C([O:13][C:14](=O)[CH:15]([Cl:19])[C:16]([CH3:18])=O)C.C(=O)([O-])[O-].[Na+].[Na+]>O.C(O)C>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:10]=[C:14]([OH:13])[C:15]([Cl:19])=[C:16]([CH3:18])[N:9]=2)=[N:6][CH:7]=1
Reactant: N=C(N)c1ccc(N)cn1
Reactant: CCOC(=O)C(Cl)C(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1nc(-c2ccc(N)cn2)nc(O)c1Cl
Temperature: 25 °C
Reaction time: 26 h

Procedure:
To a solution of compound of example 12 (0.05 g, 0.36 mmol) in water (2 mL) and ethanol (1 mL) was added ethyl-2-chloroacetoacetate (0.096 g, 0.58 mmol) and sodium carbonate (0.070 g, 0.66 mmol) and the reaction mixture was stirred at room temperature for 26 hours. Ethanol was removed under reduced pressure, and the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated to obtain the crude product, which was purified by column chromatography (silica gel, 1% methanol in chloroform as an eluent) to obtain the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6](Cl)[N:5]=[C:4]([C:10]([O:12][CH3:13])=[O:11])[C:3]=1[Cl:14].[Cl:15][C:16]1[CH:21]=[CH:20][C:19](B2OCCCO2)=[C:18]([F:28])[C:17]=1[O:29][CH3:30].[F-].[K+].C(#N)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.O>[NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:19]2[CH:20]=[CH:21][C:16]([Cl:15])=[C:17]([O:29][CH3:30])[C:18]=2[F:28])[N:5]=[C:4]([C:10]([O:12][CH3:13])=[O:11])[C:3]=1[Cl:14]
Reactant: COC(=O)c1nc(Cl)c(F)c(N)c1Cl
Reactant: COc1c(Cl)ccc(B2OCCCO2)c1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COC(=O)c1nc(-c2ccc(Cl)c(OC)c2F)c(F)c(N)c1Cl
Temperature: 70 °C
Yield: 76 %

Procedure:
A 250 mL three-neck flask equipped with a reflux condenser, a nitrogen inlet and a thermocouple was charged with methyl 4-amino-3,6-dichloro-5-fluoropicolinate (9.965 g, 41.7 mmol), 2-(4-chloro-2-fluoro-3-methoxyphenyl)-1,3,2-dioxaborinane (12.74 g, 52.1 mmol) and KF (4.84 g, 83 mmol). Acetonitrile (78 mL) and water (26 mL) were added. The reaction mixture was purged with nitrogen. Pd(PPh3)2Cl2 (1.477 g, 2.10 mmol, 5 mol %) was added, and the solution was heated to 70° C. under nitrogen for 2 h. Upon cooling to room temperature, a precipitate formed which was filtered and washed with water. The precipitate was dissolved in EtOAc (ca 500 mL) and washed with water and then brine. The organic layer was dried (MgSO4) and the solvent was removed using a rotary evaporator to give an orange solid, which was dried in a vacuum oven at 50° C. (11.46 g, 76% yield): mp 169-170.5° C.; 1H NMR (400 MHz, DMSO-d6) δ 7.48 (d, J=8.4 Hz, 1H), 7.32 (t, J=7.7 Hz, 1H), 7.15 (s, 2H), 3.96 (s, 3H), 3.90 (s, 3H); 13C NMR (101 MHz, DMSO-d6) δ 164.85 (s), 153.11 (d, J=252.5 Hz), 146.29 (s), 144.52 (d, J=4.3 Hz), 143.74 (s), 142.75 (dd, J=227.1, 14.0 Hz), 136.38 (d, J=13.4 Hz), 128.58 (d, J=3.2 Hz), 125.87 (s), 125.54 (d, J=3.5 Hz), 122.89 (dd, J=13.8, 4.0 Hz), 113.01 (d, J=3.0 Hz), 61.61 (d, J=4.2 Hz), 52.70 (s); ESIMS m/z 364 ([M+H]+). Anal. Calcd for C14H10Cl2F2N2O3: C, 46.30; H, 2.78; N, 7.71. Found: C, 46.60; H, 2.68; N, 7.51.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:33])[C@H:4]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[C:21](=[O:32])[N:22]([CH3:31])[C:23]([CH3:30])=[CH:24][C:25]=2[C:26]([F:29])([F:28])[F:27])=[CH:16][CH:15]=1)[NH:5]C(OC(C)(C)C)=O.[ClH:34]>O1CCOCC1.C(OCC)C>[ClH:34].[CH3:1][O:2][C:3](=[O:33])[C@H:4]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[C:21](=[O:32])[N:22]([CH3:31])[C:23]([CH3:30])=[CH:24][C:25]=2[C:26]([F:27])([F:28])[F:29])=[CH:18][CH:19]=1)[NH2:5]
Reactant: COC(=O)[C@H](Cc1ccc(-c2c(C(F)(F)F)cc(C)n(C)c2=O)cc1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: COC(=O)[C@@H](N)Cc1ccc(-c2c(C(F)(F)F)cc(C)n(C)c2=O)cc1
Reaction time: 4 h
Yield: 92 %

Procedure:
To a solution of N-[(1,1-dimethylethoxyl)carbonyl]-4-[1,6-dimethyl-4-(trifluoromethyl)-2-oxo-3-pyridinyl]-L-phenylalanine methyl ester (132 mg, 0.33 mmol) in dioxane (3 mL) was added 4 N HCl solution in dioxane (4.5 mL) at room temperature. The solution was stirred for 4 h as a white solid was formed. The mixture was diluted with diethyl ether (50 mL) and solid was collected by filtration washing with diethyl ether. After drying under high vacuum, 315 mg (92% yield) of 4-[1,6-dimethyl-4-(trifluoromethyl)-2-oxo-3-pyridinyl]-L-phenylalanine methyl ester hydrochloride salt was obtained as an amorphous white solid. ES-HRMS m/e calcd for C18H19F3N2O3 (M+Na) 391.1241. found 391.1241. e) Preparation of N-[(2,6-dichlorophenyl)carbonyl]-4-[1,6-dimethyl-4-(trifluoromethyl)-2-oxo-3-pyridinyl]-L-phenylalanine methyl ester
Reaction SMILES: C(OC1C=CN([CH2:15][C:16]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][OH:25])=[CH:20][C:19]=2[CH3:26])=[O:17])C(=O)C=1)C1C=CC=CC=1.[Cl:28][C:29]1[CH:30]=[CH:31][C:32]([CH2:35][O:36][C:37]2[CH:42]=[CH:41][NH:40][C:39](=[O:43])[CH:38]=2)=[N:33][CH:34]=1>>[Cl:28][C:29]1[CH:30]=[CH:31][C:32]([CH2:35][O:36][C:37]2[CH:42]=[CH:41][N:40]([CH2:15][C:16]([C:18]3[CH:23]=[CH:22][C:21]([CH2:24][OH:25])=[CH:20][C:19]=3[CH3:26])=[O:17])[C:39](=[O:43])[CH:38]=2)=[N:33][CH:34]=1
Reactant: O=c1cc(OCc2ccc(Cl)cn2)cc[nH]1
Reactant: Cc1cc(CO)ccc1C(=O)Cn1ccc(OCc2ccccc2)cc1=O
Product: Cc1cc(CO)ccc1C(=O)Cn1ccc(OCc2ccc(Cl)cn2)cc1=O
Yield: 99 %

Procedure:
4-(5-Chloro-pyridin-2-ylmethoxy)-1-[2-(4-hydroxymethyl-2-methyl-phenyl)-2-oxo-ethyl]-1H-pyridin-2-one is prepared following preparation 1c employing 4-(5-chloro-pyridin-2-ylmethoxy)-1H-pyridin-2-one (described in WO 09/103,478) instead of 4-benzyloxy-1H-pyridin-2-one.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][N:13]([C:16]2[C:17]3[CH:24]=[CH:23][NH:22][C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:12][C:9]21[CH2:11]C2)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OC(N1CC2CC1CN2)=O)(C)(C)C.C(OC(N1CCNCC21CC2)=O)(C)(C)C>>[C:1]([O:5][C:6]([N:8]1[CH2:15][CH:14]2[CH2:11][CH:9]1[CH2:12][N:13]2[C:16]1[C:17]2[CH:24]=[CH:23][NH:22][C:18]=2[N:19]=[CH:20][N:21]=1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncnc3[nH]ccc23)CC12CC2
Agent: CC(C)(C)OC(=O)N1CC2CC1CN2
Agent: CC(C)(C)OC(=O)N1CCNCC12CC2
Product: CC(C)(C)OC(=O)N1CC2CC1CN2c1ncnc2[nH]ccc12

Procedure:
Prepared in a way similar to Intermediate 1, using 2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester, instead of 4,7-diaza-spiro[2.5]octane-4-carboxylic acid tert-butyl ester.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][O:22][CH2:23][C:24]([O:26]CC)=[O:25])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1.O.[Li+].[OH-]>C1COCC1.CO>[CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][O:22][CH2:23][C:24]([OH:26])=[O:25])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1
Reactant: CCOC(=O)COCc1ccc(-c2ccc(CCN3CCC[C@H]3C)cc2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: C[C@@H]1CCCN1CCc1ccc(-c2ccc(COCC(=O)O)cc2)cc1
Temperature: 50 °C

Procedure:
To a solution of (R)-Ethyl 2-((4′-(2-(2-methylpyrrolidin-1-yl)ethyl)biphenyl-4-yl)methoxy)acetate (125.6 mg, 0.329 mmol) in THF (0.5 mL), MeOH (0.5 mL), and H2O (1 mL) was added LiOH (23.65 mg, 0.988 mmol). The reaction was heated briefly to ˜50° C. and concentrated. The resulting aqueous mixture was acidified (HCl, 3 eq) and purified by HPLC to give the title compound. LCMS m/z=354.4 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.37 (t, J=5.94 Hz, 3H), 1.53-1.70 (m, 1H), 1.86-2.13 (m, 2H), 2.16-2.28 (m, 1H), 2.91-3.13 (m, 2H), 3.16-3.27 (m, 2H), 3.51-3.71 (m, 3H), 4.09 (s, 2H), 4.58 (s, 2H), 7.37-7.47 (m, 4H), 7.61-7.70 (m, 4H), 9.26-9.84 (m, 1H), 12.68 (bs, 1H).
Reaction SMILES: COC(=O)C(O)=CC(=O)N(CC1C=CC(Cl)=C(Cl)C=1)C.C=O.[NH2:23][CH2:24][C:25]([OH:27])=[O:26].[Cl:28][C:29]1[CH:30]=[C:31]([CH:45]=[CH:46][C:47]=1[Cl:48])[CH2:32][N:33]([CH3:44])[C:34]([C:36]1[CH2:37]N(C)[C:39](=[O:42])[C:40]=1[OH:41])=[O:35]>>[Cl:28][C:29]1[CH:30]=[C:31]([CH:45]=[CH:46][C:47]=1[Cl:48])[CH2:32][N:33]([CH3:44])[C:34]([C:36]1[CH2:37][N:23]([CH2:24][C:25]([OH:27])=[O:26])[C:39](=[O:42])[C:40]=1[OH:41])=[O:35]
Reactant: NCC(=O)O
Reactant: CN1CC(C(=O)N(C)Cc2ccc(Cl)c(Cl)c2)=C(O)C1=O
Agent: C=O
Agent: COC(=O)C(O)=CC(=O)N(C)Cc1ccc(Cl)c(Cl)c1
Product: CN(Cc1ccc(Cl)c(Cl)c1)C(=O)C1=C(O)C(=O)N(CC(=O)O)C1

Procedure:
3-[(3,4-Dichloro-benzyl-methyl-carbamoyl]-2-hydroxy-acrylic acid methyl ester (Compound 12-B) was treated with paraformaldehyde and glycine as described in the preparation of Compound 12. The title compound was isolated as a white solid (80 mg, 43% yield). Mp=178–180° C. 1H NMR (300 MHz, DMSO) δ: 12.97 (bs, 1H), 11.07 (s, 1H), 7.62 (d, 1H, J=8.41), 7.53 (s, 1H), 7.25 (d, 1H, J=6.95), 4.59 (s, 2H), 4.15 (s, 2H), 4.10 (s, 2H), 2.98 (s, 3H). HRMS (M−H) calcd for C15H13N2Cl2O5: 371.0201. found: 371.0216.
Reaction SMILES: [CH:1]1([CH:6]2[CH2:15][CH2:14][C:13]3[C:8](=[C:9]([CH3:19])[C:10]([CH3:18])=[C:11]([O:16][CH3:17])[CH:12]=3)[C:7]2=[O:20])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:21]C(C)([O-])C.[K+].CI>C(O)(C)(C)C>[CH:1]1([C:6]2([CH3:21])[CH2:15][CH2:14][C:13]3[C:8](=[C:9]([CH3:19])[C:10]([CH3:18])=[C:11]([O:16][CH3:17])[CH:12]=3)[C:7]2=[O:20])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1cc2c(c(C)c1C)C(=O)C(C1CCCC1)CC2
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: CI
Product: COc1cc2c(c(C)c1C)C(=O)C(C)(C1CCCC1)CC2
Temperature: 20 °C

Procedure:
2-Cyclopentyl-6-methoxy-7,8-dimethyl-1-tetralone (Example V, Step 4) (12.5 g., 0.046 mole) is dissolved in t-butyl alcohol (250 ml.) under a stream of nitrogen. The mixture is heated to reflux and then a solution of potassium t-butoxide (7.5 g., 0.067 mole) dissolved in t-butyl alcohol (175 ml.) is added. The dark solution is refluxed for 1 hour, cooled to 20° C. and methyl iodide (14.2 g., 0.1 mole) is added. The mixture is refluxed for 10 minutes. Potassium iodide precipitates and the color of the mixture becomes lighter. The mixture is cooled, water (25 ml.) is added and the mixture is evaporated to dryness. The crude product is collected, washed with water and air dried to obtain 2-cyclopentyl-2,7,8-trimethyl-6-methoxy-1-tetralone.
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]([CH2:31][O:32][CH2:33][CH2:34][O:35][CH3:36])[C:28](=[O:37])[N:27]([CH:38]5[CH2:42][CH2:41][CH2:40][CH2:39]5)[C:25]=4[N:26]=3)=[CH:18][CH:19]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:43]>ClCCl.C(OCC)C>[ClH:43].[CH:38]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]([CH2:31][O:32][CH2:33][CH2:34][O:35][CH3:36])[C:28]2=[O:37])[CH2:39][CH2:40][CH2:41][CH2:42]1
Reactant: COCCOCc1cc2cnc(Nc3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cn3)nc2n(C2CCCC2)c1=O
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: COCCOCc1cc2cnc(Nc3ccc(N4CCNCC4)cn3)nc2n(C2CCCC2)c1=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 92.1 %

Procedure:
4-{6-[8-Cyclopentyl-6-(2-methoxy-ethoxymethyl)-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino]-pyridin-3-yl}-piperazine-1-carboxylic acid tert-butyl ester (0.110 g, 0.205 mmol) was dissolved in dichloromethane (2 mL). 2 N HCl in diethyl ether (2 mL) was added and the reaction mixture was stirred at room temperature for 18 hours. The solvent was evaporated to give 8-cyclopentyl-6-(2-methoxy-ethoxymethyl)-2-(5-piperazin-1-yl-pyridin-2-ylamino)-8H-pyrido[2,3-d]pyrimidin-7-one hydrochloride salt as a yellow solid (0.096 g, 92.1%). MS (APCl) Calc'd for M+1: 450.3. Found: 450.1. 1H NMR δ(400 MHz, DMSO-d6) 9.12 (s, 2H), 8.34 (s, 1H), 8.01 (d, J=2.7 Hz, 1H), 7.86 (s, 1H), 7.83 (s, 1H), 7.76 (d, J=9.5 Hz, 1H), 5.84 (m, 1H), 4.32 (d, J=1.2 Hz, 1H), 3.57 (q, J=6.8 Hz, 2H), 3.38 (m, 4H), 3.23 (m, 4H), 2.26 (m, 2H), 1.89 (m, 2H), 1.75 (m, 2H), 1.58 (m, 2H), 1.19 (t, J=6.8 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:28][CH3:29])[C:12]([NH:17][C@@H:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][C@@H:19]2[OH:27])=[N:13][C:14]=1[CH2:15][CH3:16].[CH2:30]1C2C(=CC=CC=2)CCC1O>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.COCCOC>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:28][CH3:29])[C:12]([NH:17][C@@H:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:30][CH2:20][C@@H:19]2[OH:27])=[N:13][C:14]=1[CH2:15][CH3:16]
Reactant: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1N[C@@H]1c2ccccc2C[C@@H]1O
Reactant: OC1CCc2ccccc2C1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Product: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1N[C@@H]1c2ccccc2CC[C@@H]1O

Procedure:
Following the procedure for the preparation of (1R,2S)-1-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ol but substituting cis-(5-bromo-3,6-diethylpyrazin-2-yl)amino]-1,2,3,4-tetrahydronaphthalen-2-ol, ethylene glycol dimethyl ether and tetrakis(triphenylphosphine) palladium and making non-critical variations provided the title compound as a oil: 1H NMR (CDCl3) δ 1.18-1.31, 2.09, 2.54, 2.64, 2.95, 2.99, 4.33, 4.69, 5.43, 7.22-7.35, 7.51; HRMS (FAB) calcd for C24H25Cl2N3O+H 442.1453, found 442.1454.