Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:8])[C:3](=[NH:7])[N:4]([CH3:6])[CH3:5].S(OC)(O[CH3:13])(=O)=O>CN(C=O)C>[CH3:1][N:2]([CH3:8])[C:3](=[N:7][CH3:13])[N:4]([CH3:6])[CH3:5]
Reactant: CN(C)C(=N)N(C)C
Reactant: COS(=O)(=O)OC
Solvent: CN(C)C=O
Product: CN=C(N(C)C)N(C)C

Procedure:
Tetramethlguanidine functionalized perfluorinated polymers were further treated with dimethyl sulfate (DMS) in DMF at 90° C. for 24 hr. Pentamethylguanidine functionalized perfluorinated polymer was obtained. Guanidine functionalized perfluorinated polymers was further treated with 1 M NaOH followed by washing with water.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][OH:15])=[CH:9][CH:8]=2)=[CH:4][C:3]=1[C:18]([F:21])([F:20])[F:19].Cl[C:23]1[CH:33]=[C:27]2[N:28]([CH3:32])[CH2:29][CH2:30][CH2:31][N:26]2[C:25](=[O:34])[N:24]=1>>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][O:15][C:23]3[CH:33]=[C:27]4[N:28]([CH3:32])[CH2:29][CH2:30][CH2:31][N:26]4[C:25](=[O:34])[N:24]=3)=[CH:9][CH:8]=2)=[CH:4][C:3]=1[C:18]([F:19])([F:20])[F:21]
Reactant: OCCc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1
Reactant: CN1CCCn2c1cc(Cl)nc2=O
Product: CN1CCCn2c1cc(OCCc1ccc(Oc3ccc(Cl)c(C(F)(F)F)c3)cc1)nc2=O

Procedure:
The title compound or its salt was prepared by a procedure similar to that described for E2 starting from 2-(4-(4-chloro-3-(trifluoromethyl)phenoxy)phenyl) ethanol and 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido[1,6-a]pyrimidin-6(2H)-one.
Reaction SMILES: O[CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1.C([O:22][C:23]([CH:25]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:24])C>C1(C)C=CC=CC=1>[O:11]=[C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:2]([CH2:25][C:23]([OH:24])=[O:22])[N:3]1[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1
Reactant: COc1ccc(N2C(=O)c3ccccc3C2O)cc1
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: COc1ccc(N2C(=O)c3ccccc3C2CC(=O)O)cc1
Yield: 87.9 %

Procedure:
A solution of 3-hydroxy-2-(4-methoxyphenyl)isoindolin-1-one (12.0 g) and ethoxycarbonylmethylenetriphenylphosphorane (16.0 g) in toluene (200 ml) was refluxed for 3 hours. After cooling, the toluene was distilled off and the residue was dissolved in 100 ml of methanol. A solution of 10 g of potassium carbonate in 70 ml of water was added to the above methanol solution and the mixture was refluxed gently for an hour. After cooling, 200 ml of water and 300 ml of ether were added and the mixture was shaken well. The aqueous layer was separated and acidified with 5N hydrochloric acid to give 12 g of 3oxo-2-(4-methoxyphenyl)isoindoline-1-acetic acid, which was described in (iv) of Example 2.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[N:9]=[CH:8][NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:17](Cl)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C)C=O>[CH2:17]([N:7]1[C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[C:10]=2[N:9]=[CH:8]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: ClCc1ccccc1
Reactant: Cc1cccc2[nH]cnc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cccc2c1ncn2Cc1ccccc1

Procedure:
To a flask were added 1.0 g 4-methyl-1H-benzimidazole, 1.6 g potassium carbonate, 25 ml N,N-dimethylformamide and the mixture was stirred under nitrogen. 1.4 g Benzyl chloride were added and the mixture was heated to 60 C for 16 hours. Another 0.4 g of benzyl chloride were added and the reaction was heated to 70 C for 24 hours. The reaction was cooled to 50 C and quenched with 50 ml water and extracted with ethyl acetate. After washing with water, the solvent was removed and the product was purified by column chromatography using a gradient from 40% ethyl acetate in hexane to 75% ethyl acetate in hexane. Following removal of the solvent, the partially crystallized product was dissolved in 20 ml acetonitrile and treated with 0.1 g activated carbon. After refluxing for 20 minutes, the mixture was filtered through celite and the solvent was removed leaving a yellow oil which crystallized on standing, 1.0 g.
Reaction SMILES: Cl.Cl.[S:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[C:4]1[NH:12][C:13]([C:15]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:24]=1[CH2:23][NH:22][CH2:21][CH2:20]2)=[O:14].Cl[C:26]1[S:27][CH:28]=[C:29]([C:31]([O:33][CH3:34])=[O:32])[N:30]=1.C([O-])([O-])=O.[Cs+].[Cs+].Cl>CC(N(C)C)=O>[S:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[C:4]1[NH:12][C:13]([C:15]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:24]=1[CH2:23][N:22]([C:26]1[S:27][CH:28]=[C:29]([C:31]([O:33][CH3:34])=[O:32])[N:30]=1)[CH2:21][CH2:20]2)=[O:14]
Reactant: O=C(Nc1nc2ccccc2s1)c1cccc2c1CNCC2
Reactant: COC(=O)c1csc(Cl)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: COC(=O)c1csc(N2CCc3cccc(C(=O)Nc4nc5ccccc5s4)c3C2)n1
Temperature: 50 °C
Reaction time: 8 h
Yield: 67.3 %

Procedure:
To a solution of N-(benzo[d]thiazol-2-yl)-1,2,3,4-tetrahydroisoquinoline-8-carboxamide dihydrochloride (1B) (5.3 g, 13.86 mmol) and methyl 2-chlorothiazole-4-carboxylate (2.5 g, 14 mmol) in DMA (60 mL) was added Cs2CO3 (25 g, 70 mmol). The reaction mixture was stirred at 50° C. overnight. The reaction mixture was cooled to rt, acidified with 5% HCl, extracted with DCM, washed with water, brine, dried over Na2SO4, and concentrated under reduced pressure. The crude material was purified by column chromatography on silica gel eluting with 5% MeOH in DCM to provide 4.2 g (67%) of the desired product methyl 2-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)thiazole-4-carboxylate (1C): LC/MS (APCI): m/z 451.0 (M+H).
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=1>N1C=CC=CC=1>[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([S:16]([NH:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[NH2:8])(=[O:18])=[O:17])=[CH:12][CH:11]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: Nc1ccccc1N
Solvent: c1ccncc1
Product: Nc1ccccc1NS(=O)(=O)c1ccc(Cl)cc1
Temperature: 10 °C
Reaction time: 0.25 h
Yield: 87.6 %

Procedure:
In a 1-L three-neck flask, o-phenylenediamine (56.13 g) was added to pyridine (350 ml) and the resultant solution was stirred with a stirrer bar to dissolve the compound. The solution was cooled in an ice-water bath, so that the temperature inside the reaction mixture became 2-3° C. 4-Chlorophenylsulfonyl chloride (73.04 g) was dissolved in pyridine (100 ml) and the resultant solution was added dropwise to the aforementioned mixture by using dropping funnel. The reaction temperature was maintained at 10° C. or lower and the dropping step required 70 minutes. The reaction mixture exhibited deep-purplish-red color. Subsequently, the mixture was stirred at 10° C. or lower for 15 minutes. The flask was removed from the ice-water bath and returned to room temperature. The mixture was further stirred for one hour. The solvent, pyridine, was removed with an aspirator under reduced pressure at 50° C. and the residue was diluted in ethyl acetate (1 L). The resultant solution was transferred to a 2-L separating funnel and water (0.5 L) and an adequate volume of a 2N hydrochloride solution were added thereto. The volume of the 2N hydrochloride solution to be added was regulated so that the pH of the washing solution became 2-3. The washing solution was extracted with ethyl acetate (0.3 L×2). The thus-obtained ethyl acetate layer was washed with saturated brine (0.3 L×3) and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and red crystals were precipitated. Ethyl acetate (0.3 L) was added to the thus-obtained crystals to dissolve the crystals. Subsequently, the crystals were re-crystallized from the mixture of solvents (hexane:ethyl acetate=10:1). The thus-produced crystals were collected through suction-filtration, washed with the same solvent mixture, and air-dried, to thereby yield pale-yellow crystals (79.28 g). The mother liquid for re-crystallization and the washing solution were combined. Subsequently, the solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate (30 ml), and the mixture of solvents (100 ml) (hexane:ethyl acetate=10:1) was added thereto, followed by re-crystallization. The thus-obtained crystals were subjected to suction-filtration, washed, and air-dried, to thereby produce pale-yellow crystals (6.41 g). Through the second re-crystallization, the target product (85.69 g) was obtained.
Reaction SMILES: [C:1](Cl)(=O)[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[CH3:10][CH:11]1[C:16]([C:17]2[CH:22]=[CH:21][C:20]([NH2:23])=[C:19]([NH2:24])[CH:18]=2)=[N:15][NH:14][C:13](=[O:25])[CH2:12]1.ClC1C=CC=CC=1>C(O)(=O)C>[CH3:10][CH:11]1[C:16]([C:17]2[CH:22]=[CH:21][C:20]3[N:23]=[C:1]([C:2]4[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=4)[NH:24][C:19]=3[CH:18]=2)=[N:15][NH:14][C:13](=[O:25])[CH2:12]1
Reactant: O=C(Cl)c1ccncc1
Reactant: CC1CC(=O)NN=C1c1ccc(N)c(N)c1
Solvent: CC(=O)O
Solvent: Clc1ccccc1
Product: CC1CC(=O)NN=C1c1ccc2nc(-c3ccncc3)[nH]c2c1
Reaction time: 2 h

Procedure:
A mixture of 17 g of isonicotinoyl chloride, 21.8 g of 5-methyl-6-(3,4-diaminophenyl)-4,5-dihydropyridazin-3-one ("IIa"; m.p. 195°-196°) and 400 ml of chlorobenzene is boiled for 2 hours. After having been cooled, the usual working up is carried out and, initially, an oily mixture of 5-methyl-6-(3-amino-4-isonicotinamidophenyl)- and 5-methyl-6-(3-isonicotinamido-4-aminophenyl)-4,5-dihydropyridazin-3-one is obtained, which is dissolved in 400 ml of acetic acid and boiled for 3 hours. After having been cooled, 5-methyl-6-[2-(4-pyridyl)-5-benzimidazolyl]-4,5-dihydropyridazin-3-one ("M"), dihydrate, m.p.195°-198° (decomposition) is obtained. Dihydrochloride-dihydrate, m.p. 224°-227°. Methanesulphonate, m.p. 282°-285°.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:5])C.Br[CH2:16][C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([F:27])[CH:25]=2)[CH:20]=[CH:19][CH:18]=1>>[F:27][C:24]1[CH:25]=[C:26]2[C:21]([CH:20]=[CH:19][CH:18]=[C:17]2[CH2:16][N:7]2[C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:14]=[C:6]2[C:4]([OH:3])=[O:5])=[CH:22][CH:23]=1
Reactant: CCOC(=O)c1cc2ccccc2[nH]1
Reactant: Fc1ccc2cccc(CBr)c2c1
Product: O=C(O)c1cc2ccccc2n1Cc1cccc2ccc(F)cc12

Procedure:
Using general procedure B, 1H-indole-2-carboxylic acid ethyl ester was coupled with 1-bromomethyl-7-fluoro-naphthalene and the product obtained was hydrolyzed to give 1-(7-fluoro-naphthalen-1-ylmethyl)-1H-indole-2-carboxylic acid as a white solid. MS: 318.0 ([M−H]).
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].F[C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][N:12]=2)=[CH:7][C:6]=1[N+:19]([O-:21])=[O:20].O>C(O)C>[CH2:1]([NH:3][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][N:12]=2)=[CH:7][C:6]=1[N+:19]([O-:21])=[O:20])[CH3:2]
Reactant: CCN
Reactant: COc1ccnc(-c2ccc(F)c([N+](=O)[O-])c2)c1
Solvent: CCO
Solvent: O
Product: CCNc1ccc(-c2cc(OC)ccn2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of ethylamine in ethanol (20% w/w, 2 ml) was added 1-fluoro-4-(4-methoxypyridin-2-yl)-2-nitrobenzene (200 mg). The mixture was stirred at ambient temperature for 4 hours and poured into water. The precipitate was collected by filtration and dried to give 1-ethylamino-4-(4-methoxypyridin-2-yl)-2-nitrobenzene (206 mg).
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][CH:13]([CH3:15])[C:12](=[O:16])[N:11]([CH3:17])[C:10]2[CH:18]=[N:19][C:20](Cl)=[N:21][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:23][C:24]1[CH:39]=[CH:38][C:27]([C:28]([NH:30][CH:31]2[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]2)=[O:29])=[CH:26][C:25]=1[O:40][CH3:41].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(O)C>[CH2:1]([N:8]1[CH2:14][CH:13]([CH3:15])[C:12](=[O:16])[N:11]([CH3:17])[C:10]2[CH:18]=[N:19][C:20]([NH:23][C:24]3[CH:39]=[CH:38][C:27]([C:28]([NH:30][CH:31]4[CH2:32][CH2:33][N:34]([CH3:37])[CH2:35][CH2:36]4)=[O:29])=[CH:26][C:25]=3[O:40][CH3:41])=[N:21][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1CN(Cc2ccccc2)c2nc(Cl)ncc2N(C)C1=O
Reactant: COc1cc(C(=O)NC2CCN(C)CC2)ccc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(C)O
Product: COc1cc(C(=O)NC2CCN(C)CC2)ccc1Nc1ncc2c(n1)N(Cc1ccccc1)CC(C)C(=O)N2C
Yield: 51.8 %

Procedure:
A solution of 0.050 g (0.00016 mole) of (rac)-9-benzyl-2-chloro-5,7-dimethyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-42), 0.042 g (0.00016 mole) of 4-amino-3-methoxy-N-(1-methyl-piperidin-4-yl)-benzamide, 0.046 g (0.00024 mole) of p-toluenesulfonic acid monohydrate in 4.0 mL of 2-propanol was heated at 180 degrees for 2 hours in a microwave reactor. The reaction mixture was concentrated under reduced pressure. The residue was diluted with dichloromethane and washed twice with saturated sodium bicarbonate solution. The aqueous phase was extracted with dichloromethane and the combined organic phases washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with dichloromethane-methanol (100:0-75:25) to give 0.0451 g of (rac)-4-(9-benzyl-5,7-dimethyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(1-methyl-piperidin-4-yl)-benzamide (I-42) as white powder. HRMS (ES+) m/z Calcd for C30H37N7O3+H [(M+H)+]: 544.3031. Found: 544.3031.
Reaction SMILES: [NH2:1][CH:2]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[C:18](OC(=O)C)(=[O:20])[CH3:19]>>[C:18]([NH:1][CH:2]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4])(=[O:20])[CH3:19]
Reactant: CCOC(=O)C(N)Cc1cccc([N+](=O)[O-])c1
Reactant: CC(=O)OC(C)=O
Product: CCOC(=O)C(Cc1cccc([N+](=O)[O-])c1)NC(C)=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
9.52 cm3 of acetic anhydride are added dropwise to 12 g of ethyl 2-amino-3-(3-nitrophenyl)propanoate at a temperature in the region of 0° C. After stirring at 0° C. for 1 hour, the mixture sets to a solid. 10 cm3 of acetic anhydride are then added and stirring is continued at 0° C. for a further 1 hour. The precipitate is filtered off on a sinter funnel, washed with 3 times 25 cm3 of water and dried in a fume cupboard and then in an oven under vacuum (10 Pa) at a temperature in the region of 50° C. 12 g of ethyl 2-(acetylamino)-3-(3-nitrophenyl)propanoate are obtained in the form of white crystals melting at 91° C. 1H NMR spectrum (250 MHz, (CD3)2SO-d6, δ in ppm): 1.14 (t, J=7 Hz: 3H); 1.80 (s: 3H); 3.04 (dd, J=14 and 9 Hz: 1H); 3.18 (t, J=14 and 4 Hz: 1H); 4.08 (q, J=7 Hz: 2H); 4.52 (mt: 1H); 7.61 (broad t, J=8 Hz: 1H); 7.72 (broad d, J=8 Hz: 1H); 8.12 (mt: 2H); 8.42 (d, J=8.5 Hz: 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:5]=[C:6]([C@H:9]([OH:12])[CH2:10]I)[C:7]=1[F:8].[CH2:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][CH:21]1[CH2:29][C:30]([NH2:33])([CH3:32])[CH3:31].C([O-])([O-])=O.[K+].[K+]>C(O)C>[CH2:22]1[C:23]2[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:20][CH:21]1[CH2:29][C:30]([NH:33][CH2:10][C@H:9]([C:6]1[CH:5]=[C:4]([CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:3]=[C:2]([F:1])[C:7]=1[F:8])[OH:12])([CH3:31])[CH3:32]
Reactant: CCOC(=O)CCc1cc(F)c(F)c([C@H](O)CI)c1
Reactant: CC(C)(N)CC1Cc2ccccc2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)CCc1cc(F)c(F)c([C@H](O)CNC(C)(C)CC2Cc3ccccc3C2)c1
Temperature: 90 °C
Yield: 49.4 %

Procedure:
To a solution of ethyl 3-{3,4-difluoro-5-[(1S)-1-hydroxy-2-iodoethyl]phenyl}propanoate (0.550 g, 1.43 mmol) in ethanol (2.8 mL) was added [2-(2,3-dihydro-1H-inden-2-yl)-1,1-dimethylethyl]amine (0.273 g, 1.44 mmol) and K2CO3 (0.218 g, 1.58 mmol). The reaction was heated at 90° C. for 17 h. Upon cooling, the reaction was filtered and concentrated. Column chromatography (0-12% CH3OH:CH2Cl2) provided 0.315 g (49%) of the title compound: MS (ESI) 446.0 (M+H).
Reaction SMILES: [BrH:1].[CH2:2]([C:6]1[CH:11]=[CH:10][C:9]([CH2:12]O)=[CH:8][CH:7]=1)[CH2:3][CH2:4][CH3:5]>C(Cl)Cl>[Br:1][CH2:12][C:9]1[CH:10]=[CH:11][C:6]([CH2:2][CH2:3][CH2:4][CH3:5])=[CH:7][CH:8]=1
Reactant: Br
Reactant: CCCCc1ccc(CO)cc1
Solvent: ClCCl
Product: CCCCc1ccc(CBr)cc1
Reaction time: 0.75 h

Procedure:
HBr was bubbled into a solution of (4-butyl-phenyl)-methanol (10.0 g, 60.9 mmol) in CH2Cl2 (100 mL) for 15 minutes. The reaction was stirred for an additional 45 minutes and was poured onto ice water. The aqueous solution was extracted with CH2Cl2 (2×) and was dried (MgSO4), filtered, and concentrated to provide the title compound which was used without further purification. 1H NMR (400 MHz, CDCl3) δ 7.29 (d, 2H), 7.14 (d, 2H), 4.49 (s, 2H), 2.60 (t, 2H), 1.58 (m, 2H), 1.36 (m, 2H), 0.92 (t, 3H).
Reaction SMILES: [CH2:1]1[CH2:6][CH2:5][C:4]([CH2:11][NH2:12])([CH2:7][C:8]([OH:10])=[O:9])[CH2:3][CH2:2]1.C(N(CC)CC)C.Cl[Si](C)(C)C.Cl[C:26]([O:28][CH:29]([Cl:31])[CH3:30])=[O:27]>ClCCl>[Cl:31][CH:29]([O:28][C:26]([NH:12][CH2:11][C:4]1([CH2:7][C:8]([OH:10])=[O:9])[CH2:3][CH2:2][CH2:1][CH2:6][CH2:5]1)=[O:27])[CH3:30]
Reactant: CC(Cl)OC(=O)Cl
Reactant: NCC1(CC(=O)O)CCCCC1
Agent: C[Si](C)(C)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(Cl)OC(=O)NCC1(CC(=O)O)CCCCC1
Reaction time: 0.5 h
Yield: 97.2 %

Procedure:
In a 5-liter, 3-neck, round bottom flask containing dichloromethane (1.6 L) is added gabapentin (120.4 g, 0.704 mol) followed by triethylamine (294 mL, 2.11 mol). Chlorotrimethylsilane (178 mL, 1.40 mol) is slowly added while maintaining the reaction temperature below 15° C. and the resulting suspension is stirred for 30 min. 1-Chloroethyl chloroformate (100 g, 0.704 mol) is then added slowly while maintaining the temperature below 15° C. After the addition is complete, additional triethylamine (88 mL, 0.63 mol) is added and the resulting suspension is stirred at room temperature for 30 min. The resulting silyl ester is converted via acidic work-up to the corresponding acid by washing the reaction mixture with water (2×1 L), followed by 1N HCI (2×2 L) then brine (2×500 mL). After drying over anhydrous sodium sulfate and removal of the solvent in vacuo, the crude product (190 g) is obtained as an orange oil and used in Step B without further purification. 1H NMR (CDCI3, 400 MHz): δ 1.41-1.57 (m, 10H), 1.78 (d, 3H), 2.33 (s, 2H), 3.27 (d, 2H), 5.42 (br. s, 1H), 6.55 (q, 1H).
Reaction SMILES: [CH:1]1([N:6]2[C:11]3[N:12]=[C:13](S(C)(=O)=O)[N:14]=[CH:15][C:10]=3[CH:9]=[C:8]([CH2:20][CH3:21])[C:7]2=[O:22])[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:23][C:24]1[N:29]=[CH:28][C:27]([N:30]2[CH2:35][CH2:34][CH:33]([OH:36])[CH2:32][CH2:31]2)=[CH:26][CH:25]=1>C(Cl)Cl>[CH:1]1([N:6]2[C:11]3[N:12]=[C:13]([NH:23][C:24]4[N:29]=[CH:28][C:27]([N:30]5[CH2:35][CH2:34][CH:33]([OH:36])[CH2:32][CH2:31]5)=[CH:26][CH:25]=4)[N:14]=[CH:15][C:10]=3[CH:9]=[C:8]([CH2:20][CH3:21])[C:7]2=[O:22])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCc1cc2cnc(S(C)(=O)=O)nc2n(C2CCCC2)c1=O
Reactant: Nc1ccc(N2CCC(O)CC2)cn1
Solvent: ClCCl
Product: CCc1cc2cnc(Nc3ccc(N4CCC(O)CC4)cn3)nc2n(C2CCCC2)c1=O
Temperature: 140 °C
Yield: 7.3 %

Procedure:
8-Cyclopentyl-6-ethyl-2-methanesulfonyl-8H-pyrido[2,3-d]pyrimidin-7-one (0.115 g, 0.47 mmol) and 6′-amino-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-4-ol (0.117 g, 0.61 mmol) were combined in dry xylenes and heated at 140° C. under nitrogen overnight. The crude reaction mixture then was allowed to cool and diluted with CH2Cl2. A precipitate was collected by filtration and dried in vacuo to give 8-cyclopentyl-6-ethyl-2-(4-hydroxy-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-6′-ylamino)-8H-pyrido[2,3-d]pyrimidin-7-one (15 mg, 7%). MS (APCI); M++1: Calc'd, 435.2, Found 435.2.
Reaction SMILES: B(F)(F)F.CCOCC.[N+](=[CH:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[N-].[CH3:18][C:19]1([CH:25]=[O:26])[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1.[Na+].[Cl-]>C(Cl)Cl>[CH2:16]([O:15][C:13](=[O:14])[CH2:12][C:25]([C:19]1([CH3:18])[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1)=[O:26])[CH3:17]
Reactant: CC1(C=O)CCOCC1
Reactant: CCOC(=O)C=[N+]=[N-]
Agent: FB(F)F
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOCC
Product: CCOC(=O)CC(=O)C1(C)CCOCC1
Reaction time: 0.33 h
Yield: 78.8 %

Procedure:
To a solution of BF3.OEt2 (0.350 mL, 2.50 mmol) and ethyl diazoacetate (0.390 mL, 3.42 mmol) was added a solution of 4-methyl-tetrahydro-pyran-4-carboxaldehyde (350 mg, 2.73 mmol) in CH2Cl2 (15 mL). After 20 min, the mixture was poured into half-saturated aq. NaCl and extracted with CH2Cl2. The combined organic layers were dried and concentrated. Chromatography (EtOAc/hexanes) afforded the title compound (461 mg, 79%) as a colorless oil. MS (ESI): mass calcd. for C11H18O4, 214.1; m/z found, 215.2 [M+H]+. 1H NMR (mixture of tautomers; CDCl3): 12.5 (s, 0.5H), 5.05 (s, 0.5H), 4.25-4.17 (m, 2H), 3.76-3.53 (m, 2H), 5.52 (s, 3H), 2.05-1.92 (m, 2H), 1.56-1.47 (m, 2H), 1.26-1.22 (m, 3H), 1.38-1.34 (m, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:12]([CH3:16])[C:13]([OH:15])=[O:14])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[CH2:17]([S:19]([C:22]1[CH:27]=[CH:26][C:25](F)=[C:24]([Cl:29])[CH:23]=1)(=[O:21])=[O:20])[CH3:18]>>[Cl:29][C:24]1[CH:23]=[C:22]([S:19]([CH2:17][CH3:18])(=[O:21])=[O:20])[CH:27]=[CH:26][C:25]=1[O:1][C:2]1[CH:3]=[C:4]([CH:12]([CH3:16])[C:13]([OH:15])=[O:14])[CH:5]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:7]=1
Reactant: CC(C(=O)O)c1cc(O)cc(C(F)(F)F)c1
Reactant: CCS(=O)(=O)c1ccc(F)c(Cl)c1
Product: CCS(=O)(=O)c1ccc(Oc2cc(C(C)C(=O)O)cc(C(F)(F)F)c2)c(Cl)c1

Procedure:
The title compound was prepared as described in example 2 step (iii) but instead using the product from example 50 step (iii) and the product from example 3 step (i).
Reaction SMILES: [CH:1]1([N:6]2[C:14]3[CH:13]=[C:12]([C:15]4[CH2:16][C:17]([CH3:24])([CH3:23])[NH:18][C:19]([CH3:22])([CH3:21])[CH:20]=4)[CH:11]=[C:10]([C:25]([NH:27][CH2:28][C:29]4[C:30](=[O:37])[NH:31][C:32]([CH3:36])=[CH:33][C:34]=4[CH3:35])=[O:26])[C:9]=3[CH:8]=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1>CO.[Pd]>[CH:1]1([N:6]2[C:14]3[CH:13]=[C:12]([CH:15]4[CH2:16][C:17]([CH3:23])([CH3:24])[NH:18][C:19]([CH3:22])([CH3:21])[CH2:20]4)[CH:11]=[C:10]([C:25]([NH:27][CH2:28][C:29]4[C:30](=[O:37])[NH:31][C:32]([CH3:36])=[CH:33][C:34]=4[CH3:35])=[O:26])[C:9]=3[CH:8]=[N:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(C3=CC(C)(C)NC(C)(C)C3)cc3c2cnn3C2CCCC2)c(=O)[nH]1
Agent: [Pd]
Solvent: CO
Product: Cc1cc(C)c(CNC(=O)c2cc(C3CC(C)(C)NC(C)(C)C3)cc3c2cnn3C2CCCC2)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 3 h
Yield: 66.4 %

Procedure:
To a stirred solution of 1-cyclopentyl-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-(2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indazole-4-carboxamide (0.15 g, 0.29 mmol) in MeOH (2 mL), 10% Pd/C in catalytic amount was added and stirred it at room temperature under a hydrogen balloon for 3 hr. On completion of reaction, reaction mixture was filtered through a celite bed and the filtrate concentrated under reduced pressure to give 1-cyclopentyl-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-(2,2,6,6-tetramethylpiperidin-4-yl)-1H-indazole-4-carboxamide (0.09, 66.4%). LCMS: 504.25 (M+1)+; HPLC: 99.77% (@ 254 nm) (Rt; 5.460); 1H NMR (DMSO-d6, 400 MHz) δ 11.55 (bs, 1H), 8.43 (t, 1H, J=5.2 Hz), 8.26 (s, 1H), 7.70 (s, 1H), 7.50 (s, 1H), 5.89 (s, 1H), 5.22-5.18 (m, 1H), 4.36 (d, 2H, J=5.2 Hz), 3.33 (1H merged with DMSO peak), 2.22 (s, 3H), 2.12 (s, 3H), 2.09 (m, 2H), 1.99-1.87 (m, 4H), 1.73-1.66 (m, 4H), 1.52 (m, 2H), 1.32 (s, 6H), 1.18 (s, 6H).