Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@H:6]([C:10]([N:12]1[CH:26]([C:27]([O:29]CC)=[O:28])[CH2:25][C:14]2([CH2:17][N:16]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:15]2)[CH2:13]1)=[O:11])[CH:7]([CH3:9])[CH3:8])=[O:4].O.[OH-].[Li+].Cl>C1COCC1.O.CO>[CH3:24][C:21]([O:20][C:18]([N:16]1[CH2:15][C:14]2([CH2:25][CH:26]([C:27]([OH:29])=[O:28])[N:12]([C:10](=[O:11])[C@H:6]([CH:7]([CH3:8])[CH3:9])[NH:5][C:3]([O:2][CH3:1])=[O:4])[CH2:13]2)[CH2:17]1)=[O:19])([CH3:22])[CH3:23]
Reactant: CCOC(=O)C1CC2(CN(C(=O)OC(C)(C)C)C2)CN1C(=O)[C@@H](NC(=O)OC)C(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)N[C@H](C(=O)N1CC2(CC1C(=O)O)CN(C(=O)OC(C)(C)C)C2)C(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 76 %

Procedure:
To a solution of 2-(1,1-dimethylethyl) 7-ethyl 6-{N-[(methyloxy)carbonyl]-L-valyl}-2,6-diazaspiro[3.4]octane-2,7-dicarboxylate (146) (344 mg, 0.78 mmol) in THF/water/methanol (3 mL/1.5 mL/1.5 mL) was added lithium hydroxide monohydrate (65 mg, 1.56 mmol) and the reaction stirred at room temperature for 1.5 h whereupon it was treated with 1N HCl (1.5 mL). The reaction was partitioned between EtOAc and water (30 mL each), the aqueous layer was extracted with EtOAc (30 mL), the organic layers were combined and dried (MgSO4) and concentrated in vacuo to afford the title compound as a white solid (245 mg, 76% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 12.46 (br. s., 1H) 7.06-7.66 (m, 1H) 4.13-4.32 (m, 1H) 3.88-4.12 (m, 2H) 3.56-3.89 (m, 5H) 3.39-3.57 (m, 3H) 2.24-2.45 (m, 1H) 1.99-2.19 (m, 1H) 1.80-1.95 (m, 1H) 1.26-1.44 (m, 9H) 0.56-1.00 (m, 6H). LC-MS ESI (M−H)−=412.41.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][N:7]([CH2:12][CH2:13][NH2:14])[CH:6]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)[CH2:5]2.[CH:23]([C:25]1[CH:26]=[C:27]([CH:31]=[C:32]([N+:34]([O-:36])=[O:35])[CH:33]=1)[C:28](O)=[O:29])=[CH2:24].CCN=C=NCCCN(C)C.O>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][N:7]([CH2:12][CH2:13][NH:14][C:28](=[O:29])[C:27]1[CH:31]=[C:32]([N+:34]([O-:36])=[O:35])[CH:33]=[C:25]([CH:23]=[CH2:24])[CH:26]=1)[CH:6]([CH2:15][C:16]1[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=1)[CH2:5]2
Reactant: NCCN1Cc2ccc(F)cc2CC1Cc1ccc(F)cc1
Reactant: C=Cc1cc(C(=O)O)cc([N+](=O)[O-])c1
Agent: CCN=C=NCCCN(C)C
Solvent: ClC(Cl)Cl
Solvent: O
Product: C=Cc1cc(C(=O)NCCN2Cc3ccc(F)cc3CC2Cc2ccc(F)cc2)cc([N+](=O)[O-])c1
Reaction time: 0.5 h
Yield: 70.9 %

Procedure:
100 mg of 2-[6-fluoro-3-(4-fluorobenzyl)-3,4-dihydroisoquinolin-2(1H)-yl]ethanamine obtained in Example 120-b) and 65 mg of 3-vinyl-5-nitrobenzoic acid were dissolved in 1 mL of chloroform, and 96 mg of WSC was added thereto, followed by stirring for 30 minutes. After completion of the reaction, water was added to the reaction liquid, followed by extraction with ethyl acetate, and the organic layer was then washed with an aqueous sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue obtained was purified using silica gel chromatography (chloroform:methanol=10:1) to obtain 112 mg (yield 74%) of a title compound as a yellow solidified product.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12]([O-:14])=[O:13])=O)=[CH:4][C:3]=1[N+:19]([O-:21])=[O:20].[BH4-].[Na+]>C1COCC1.CO>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:10]3[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=3[C:12](=[O:14])[O:13]2)=[CH:4][C:3]=1[N+:19]([O-:21])=[O:20]
Reactant: Nc1ccc(C(=O)c2ccccc2C(=O)[O-])cc1[N+](=O)[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: Nc1ccc(C2OC(=O)c3ccccc32)cc1[N+](=O)[O-]
Reaction time: 0.67 h

Procedure:
To a solution of 2-[(4-amino-3-nitrophenyl)carbonyl]benzoate (8.36 g, 27.8 mmol) in THF (100 mL) and methanol (30 mL) at 0° C. was added sodium borohydride (3.0 g, 79 mmol). The mixture was stirred for 40 min, and then unreacted hydride was quenched with 10% aqueous citric acid. The organic solvents were removed in vacuo. An orange solid precipitated from the resulting aqueous mixture. This solid was collected by filtration, rinsed with water, triturated with ether, and dried in vacuo. Desired 3-(4-amino-3-nitrophenyl)-2-benzofuran-1(3H)-one was obtained as a bright orange solid (5.23 g, 19.4 mmol, 69% yield). 1H NMR (400 MHz, d6-DMSO): 8.03 (d, 1H), 7.90 (d, 1H), 7.76 (t, 1H), 7.65-7.60 (m, 3H), 7.45 (d, 1H), 7.11 (dd, 1H), 6.99 (d, 1H), 6.66 (s, 1H); MS (EI) for C14H10N2O4: 303 (MNa+).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:8]=[C:7]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:6]=1)=[O:4].C([N:30]([CH2:34][CH3:35])C(C)C)(C)C.[CH2:36]1[CH2:40][O:39][CH2:38][CH2:37]1>>[CH3:26][C:21]([CH:2]([NH:30][CH2:34][C:35]1[CH:15]=[CH:14][CH:13]=[CH:18][CH:17]=1)[C:3]([C:5]1[CH:10]=[C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:8]=[C:7]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:6]=1)=[O:4])([CH3:20])[CH2:22][CH2:23][CH2:24][CH2:36][CH2:40][O:39][CH2:38][CH2:37][C:8]1[CH:7]=[CH:6][CH:5]=[CH:10][CH:9]=1
Reactant: O=C(CBr)c1cc(OCc2ccccc2)cc(OCc2ccccc2)c1
Reactant: CCN(C(C)C)C(C)C
Reactant: C1CCOC1
Product: CC(C)(CCCCCOCCc1ccccc1)C(NCc1ccccc1)C(=O)c1cc(OCc2ccccc2)cc(OCc2ccccc2)c1

Procedure:
A solution of 2-bromo-1-[3,5-bis(phenylmethoxy)phenyl]ethanone (2.5 g), Intermediate 32 (2.0 g) and N,N-diisopropylethylamine (0.77 g) in THF (25 ml) was stirred at room temperature for 2 h and refluxed for 20 h. ER (100 ml) was added and the resulting suspension was filtered, the filtrate was evaporated and the residue was purified by [C] eluting with cyclohexane-ER (4:1) to give the title compound as a pale yellow oil (1.2g). T.l.c. (cyclohexane-ER 3:1) Rf 0.4
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](=[N:10]\O)/[CH3:9])=[CH:4][C:3]=1[NH:12][S:13]([CH3:16])(=[O:15])=[O:14].[H][H].CO>C1COCC1.[Ni].O>[NH2:10][CH:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH:4]=1)[CH3:9]
Reactant: C/C(=N/O)c1ccc(F)c(NS(C)(=O)=O)c1
Reactant: [H][H]
Agent: [Ni]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC(N)c1ccc(F)c(NS(C)(=O)=O)c1
Reaction time: 1 h

Procedure:
N-{2-Fluoro-5-[(1Z)—N-hydroxyethanimidoyl]phenyl}methanesulfonamide (Method 62, 200 mg, 812 μmol) was dissolved in 15 ml THF, to which was added Raney nickel 2800 slurry in water (200 μl). The mixture was charged with nitrogen and stirred over 1 atm of hydrogen. After 1 hour, MeOH (4 ml) was added and the reaction mixture was stirred overnight. The following morning the solution was filtered through celite, and the cake washed with MeOH, and the organic layer was concentrated to a yellow solid which was dried under high vacuum (181 mg, 96%). 1H NMR: 1.26 (d, 3H, CH3), 2.92 (s, 3H, SO2Me), 3.33 (HOD), 4.04 (q, 1H, CH), 5.70 (br, 2H, NH2), 7.06-7.16 (m, 2H, Ar), 7.35 (m, 1H, Ar). LC/MS: 0.79 min, 231.08 (M−H)−.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][CH3:15])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.IC[C:45]1[N:49](C)[C:48]([S:51]([CH3:54])(=[O:53])=[O:52])=[N:47][N:46]=1>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[N:49]([CH3:45])[C:48]([S:51]([CH3:54])(=[O:53])=[O:52])=[N:47][N:46]=3)[C:9]=2[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Cn1c(CI)nnc1S(C)(=O)=O
Reactant: CCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: Cn1c(Cn2nnc3c(N4CCC(F)(F)C4)nc(C(C)(C)C)nc32)nnc1S(C)(=O)=O

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 3-(iodomethyl)-4-methyl-5-(methylsulfonyl)-4H-1,2,4-triazole and isolated as white solid. MS (m/e): 456.3 (MH+).
Reaction SMILES: Cl[C:2]1[C:7]([Br:8])=[C:6]([NH:9][C@H:10]2[CH2:15][CH2:14][C@@H:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:12][CH2:11]2)[CH:5]=[CH:4][N:3]=1.[CH3:22][O-:23].[Na+].O.Cl>CN(C)C=O.CO>[CH3:22][O:23][C:2]1[C:7]([Br:8])=[C:6]([NH:9][C@H:10]2[CH2:15][CH2:14][C@@H:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:12][CH2:11]2)[CH:5]=[CH:4][N:3]=1
Reactant: C[O-]
Reactant: Clc1nccc(N[C@H]2CC[C@@H](c3ccccc3)CC2)c1Br
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CO
Product: COc1nccc(N[C@H]2CC[C@@H](c3ccccc3)CC2)c1Br
Temperature: 80 °C

Procedure:
2.21 g (6.04 mmol) of 2-chloro-3-bromo-4-(cis-4-phenylcyclohexylamino)pyridine in 30 ml of dimethylformamide are treated with 4.31 ml of 30% strength solution of sodium methoxide in methanol and the mixture is heated at 80° C. for 1 hour. After cooling, water is added, the mixture is adjusted to pH 8 using 1/2 conc. hydrochloric acid and the reaction product is extracted with ethyl acetate. For purification it is chromatographed. Yield: 1.72 g (79%); Rf =0.4 (diisopropyl ether)
Reaction SMILES: [CH:1]1([C:5](=[O:9])[CH2:6][C:7]#[N:8])[CH2:4][CH2:3][CH2:2]1.[CH3:10][N:11]=[C:12]=[O:13]>C(O)C>[CH:1]1([C:5](=[O:9])[CH:6]([C:12](=[O:13])[NH:11][CH3:10])[C:7]#[N:8])[CH2:4][CH2:3][CH2:2]1
Reactant: CN=C=O
Reactant: N#CCC(=O)C1CCC1
Solvent: CCO
Product: CNC(=O)C(C#N)C(=O)C1CCC1
Yield: 77.9 %

Procedure:
β-Cyclobutyl-β-oxopropionitrile (2.25 g, 18.3 mmoles) [prepared in Step A]was reacted with methyl isocyanate (1.10 g, 19.2 mmoles) according to the general procedure of Example 1, Step B to yield 2.57 g of the title compound as a white solid afater recrysstallization from 50% aqueous ethanol, mp 81°-83° C.
Reaction SMILES: [C:1]([CH:4]1[CH2:8][CH2:7][O:6][C:5]1=[O:9])(=O)[CH3:2].Cl.[C:11]([NH2:14])(=[NH:13])[CH3:12].C[O-].[Na+].C(O)(=O)C>CO>[OH:6][CH2:7][CH2:8][C:4]1[C:5](=[O:9])[NH:14][C:11]([CH3:12])=[N:13][C:1]=1[CH3:2]
Reactant: CC(=O)C1CCOC1=O
Reactant: CC(=N)N
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: Cc1nc(C)c(CCO)c(=O)[nH]1
Yield: 22.6 %

Procedure:
3-acetyldihydro-2(3H)-furanone (25.6 g) was added to a stirred mixture of acetamidine hydrochloride (20 g) and sodium methylate (110 g) in methanol (150 ml). The reaction mixture was stirred and refluxed overnight. The reaction mixture was cooled and acetic acid (36 g) was added dropwise. The precipitate was filtered off and the filtrate evaporated. The residue was purified by column chromatography over silica gel (eluent: CHCl3 /(CH3OH/NH3) 90/10). The pure fractions were collected and the solvent was evaporated. The residue was crystallized from 2-propanol. The crystals were filtered off and dried, yielding 7.6 g (22%) of 5-(2-hydroxyethyl)-2,6-dimethyl-4(3H)-pyrimidinone (intermediate 4).
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[C:3]=1[S:12](Cl)(=[O:14])=[O:13].[NH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24].C(N(CC)CC)C>>[C:23]([O:22][C:21]([NH:20][CH2:19][CH2:18][CH2:17][NH:16][S:12]([C:3]1[C:4]([Cl:11])=[CH:5][CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=1[Cl:1])(=[O:14])=[O:13])=[O:27])([CH3:26])([CH3:25])[CH3:24]
Reactant: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)Cl)c1Cl
Reactant: CC(C)(C)OC(=O)NCCCN
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCCCNS(=O)(=O)c1c(Cl)ccc([N+](=O)[O-])c1Cl
Yield: 97.7 %

Procedure:
Following the general procedure for sulfonamide formation outlined in example 15, 2,6-dichloro-3-nitrobenzenesulfonyl chloride (1.0 g, 3.44 mmnol), t-butyl N-(3-aminopropyl)carbamate (0.60 mg, 3.44 mmol) and triethylamine(960 μL, 6.88 mmol) were reacted to form the desired product (1.44 g, 98%). EI-MS (m/z) 426.1, 428.1, 430.1 (M-H)−.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:33]=[CH:32][C:6]2[NH:7][C:8]([C:13]3[C:14](=[O:31])[C@:15]([CH2:25][CH2:26][C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:24])[C:16]4[C:21]([C:22]=3[OH:23])=[CH:20][CH:19]=[CH:18][CH:17]=4)=[N:9][S:10](=[O:12])(=[O:11])[C:5]=2[CH:4]=1.[S:34](Cl)([CH3:37])(=[O:36])=[O:35].N1C=CC=CC=1>CC(C)=O>[CH3:30][C:27]([CH3:28])([CH3:29])[CH2:26][CH2:25][C@@:15]1([CH3:24])[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:22]([OH:23])=[C:13]([C:8]2[NH:7][C:6]3[CH:32]=[CH:33][C:3]([NH:2][S:34]([CH3:37])(=[O:36])=[O:35])=[CH:4][C:5]=3[S:10](=[O:12])(=[O:11])[N:9]=2)[C:14]1=[O:31]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)CC[C@]1(C)C(=O)C(C2=NS(=O)(=O)c3cc(N)ccc3N2)=C(O)c2ccccc21
Agent: Cl
Solvent: c1ccncc1
Solvent: CC(C)=O
Product: CC(C)(C)CC[C@]1(C)C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C(O)c2ccccc21

Procedure:
A solution of Example 48G (0.250 g, 0.510 mmol), mesyl chloride (0.158 mL, 2.04 mmol), and pyridine (0.330 mL, 4.08 mmol) in acetone (3 mL) was stirred at 25° C. for 18 hours. The solution was partitioned between ethyl acetate and dilute citric acid and the layers were separated. The ethyl acetate layer was dried with sodium sulfate, filtered, and concentrated in vacuo. The residue was chromatographed on silica gel eluting with methylene chloride and 2.5% methanol in methylene chloride to give a yellow solid.
Reaction SMILES: [CH3:1][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([CH2:24][CH2:25]2)[C@:21]2([CH3:22])[C:16](=[CH:17][C:18](=[O:28])[CH2:19][CH2:20]2)[CH2:15][CH2:14]3)[CH2:11][CH2:10]1)[CH3:8])[CH3:3].[BrH:29].[Br:30]Br>C(O)(=O)C.CCOCC>[Br:29][CH:19]1[CH2:20][C@@:21]2([CH3:22])[C:16]([CH:15]([Br:30])[CH2:14][C@@H:13]3[C@@H:23]2[CH2:24][CH2:25][C@@:26]2([CH3:27])[C@H:12]3[CH2:11][CH2:10][C@@H:9]2[C@H:7]([CH3:8])[CH2:6][CH2:5][CH2:4][CH:2]([CH3:1])[CH3:3])=[CH:17][C:18]1=[O:28]
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: BrBr
Reactant: Br
Solvent: CC(=O)O
Solvent: CCOCC
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC(Br)C4=CC(=O)C(Br)C[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 0.25 h

Procedure:
60 g. of 4-cholesten-3-one is dissolved in 2 l. of ether and 1 ml. of hydrobromic acid in acetic acid, 37% strength. It is combined, with agitation, with a solution of 52.4 g. of bromine in 300 ml. of acetic acid. The mixture is then further stirred for 15 minutes, thereafter diluted with a small quantity of ether, and washed in succession with water, sodium bicarbonate solution, and water. After drying and evaporation, 90 g. of crude 2,6-dibromo-4-cholesten-3-one is obtained in the form of an oil.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:8]([F:9])=[CH:7][CH:6]=[CH:5][C:4]=1[CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][C:26]2[NH:29][N:30]=[C:31]([C:32](O)=[O:33])[C:25]=2[CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17].C(N(C(C)C)CC)(C)C.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.O>[Cl:2][C:3]1[C:8]([F:9])=[CH:7][CH:6]=[CH:5][C:4]=1[CH:10]1[CH2:15][CH2:14][N:13]([C:32]([C:31]2[C:25]3[CH2:24][N:23]([C:21]([O:20][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:22])[CH2:28][CH2:27][C:26]=3[NH:29][N:30]=2)=[O:33])[CH2:12][CH2:11]1
Reactant: Fc1cccc(C2CCNCC2)c1Cl
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]nc(C(=O)O)c2C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(C)(C)OC(=O)N1CCc2[nH]nc(C(=O)N3CCC(c4cccc(F)c4Cl)CC3)c2C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 83.4 %

Procedure:
To a solution of 4-(2-chloro-3-fluorophenyl)piperidine hydrochloride (14, 90 mg, 0.36 mmol), 5-(tert-butoxycarbonyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-3-carboxylic acid (96 mg, 0.36 mmol), and diisopropylethylamine (0.19 mL, 1.08 mmol) in DMF (7.8 mL) was added EDCI (83 mg, 0.43 mmol) and HOBt (58 mg, 0.43 mmol). The resulting solution was stirred at ambient temperature for 24 h. The reaction mixture was diluted with H2O (30 mL), and the resulting precipitate was collected by filtration. The obtained solids were chromatographed over silica gel (Isco CombiFlash Rf unit, 12 g Redisep column, 0% to 5% CH3OH in CH2Cl2 with 0.1% NH4OH in CH2Cl2) to provide tert-butyl 3-(4-(2-chloro-3-fluorophenyl)piperidine-1-carbonyl)-6,7-dihydro-1Hpyrazolo[4,3-c]pyridine-5(4H)-carboxylate (41) as a white foam (139 mg, 82%): 1H NMR (500 MHz, DMSO-d6) δ 13.11-12.91 (m, 1H), 7.39-7.32 (m, 1H), 7.30-7.22 (m, 2H), 5.28-5.13 (m, 1H), 4.75-4.60 (m, 1H), 4.49-4.36 (m, 2H), 3.65-3.53 (m, 2H), 3.33-3.25 (m, 1H, overlaps with H2O), 3.24-3.08 (m, 1H), 2.91-276 (m, 1H), 2.67 (t, J=5.5 Hz, 2H), 1.91-1.75 (m, 2H), 1.67-1.50 (m, 2H), 1.41 (s, 9H); ESI MS m/z 463 [M+H]+.
Reaction SMILES: [BH4-].[Na+].B(F)(F)F.CCOCC.[Br:12][C:13]1[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=1[C:15](O)=[O:16].CCCCCC>O1CCCC1>[Br:12][C:13]1[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=1[CH2:15][OH:16]
Reactant: O=C(O)c1ccccc1Br
Agent: FB(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: OCc1ccccc1Br
Reaction time: 0.25 h
Yield: 78.3 %

Procedure:
A 5-liter, 3-necked glass reaction vessel equipped as described in Example 1 was charged with 62.4 grams (1.65 moles) of sodium borohydride, 1 liter of tetrahydrofuran, and 0.26 liter (2.1 moles) of boron trifluoride diethyl etherate at 0°-5°C using essentially the same procedure as described in Example 1. After stirring the reaction mixture for an additional 15 minutes, a solution of 400 grams (2 moles) of 2-bromobenzoic acid in 1 liter of tetrahydrofuran was added dropwise over a 1.5 hour period while maintaining a temperature of 0°-10°C. When the addition was complete, the reaction mixture was stirred for 6 hours at room temperature. Hydrolysis of the reaction mixture and recrystallization of the product from hexane gave 293 grams (78.5% yield) of 2-bromobenzyl alcohol as light-orange crystals, mp 78°-80°C.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH2:12][CH2:13][C:14]2([CH:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)[O:19][C:18](=[O:20])[CH2:17][C:16](=[O:21])[CH2:15]2)[CH:8]=[CH:9][C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].[CH3:27][C:28]1[CH:33]=[C:32]([CH3:34])[N:31]2[N:35]=[C:36]([CH:38]=O)[N:37]=[C:30]2[N:29]=1>>[C:1]([C:5]1[CH:6]=[C:7]([CH2:12][CH2:13][C:14]2([CH:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)[O:19][C:18](=[O:20])[C:17]([CH2:38][C:36]3[N:37]=[C:30]4[N:29]=[C:28]([CH3:27])[CH:33]=[C:32]([CH3:34])[N:31]4[N:35]=3)=[C:16]([OH:21])[CH2:15]2)[CH:8]=[CH:9][C:10]=1[OH:11])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(C)n2nc(C=O)nc2n1
Reactant: CC(C)(C)c1cc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)ccc1O
Product: Cc1cc(C)n2nc(CC3=C(O)CC(CCc4ccc(O)c(C(C)(C)C)c4)(C4CCCC4)OC3=O)nc2n1

Procedure:
The title compound was prepared by coupling 6-[2-(3-tert-Butyl-4-hydroxy-phenyl)-ethyl]-6-cyclopentyl-dihydro-pyran-2,4-dione from Example A(2), to 5,7-Dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde (described in Step 3 of example B(75)) using the Me2NHBH3 method described in the synthesis of Example B(31) 1H NMR (CDCl3): δ 1.37 (s, 9H), 1.43-1.86 (br m, 8H), 1.93-2.05 (m, 2H), 2.37 (m, 1H), 2.53-2.79 (m, 10), 3.49 (s, 2H), 4.06 (d, J=15.4 Hz, 1H), 4.11 (d, J=15.4 Hz, 1H), 6.58 (d, J=8.1 Hz 1H)), 6.81-6.84 (m, 2H), 7.00 (s, 1H).
Reaction SMILES: [CH3:1][C:2]([CH3:15])=[CH:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([CH3:14])[C:11]([O-:13])=[O:12])=[CH:6][CH:5]=1.[Na+].[C:17]([O:23][CH2:24]Cl)(=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19].C(OCC)C>C1(C)C=CC=CC=1>[CH3:1][C:2]([CH3:15])=[CH:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([CH3:14])[C:11]([O:13][CH2:24][O:23][C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19])=[O:12])=[CH:6][CH:5]=1
Reactant: CC(C)(C)C(=O)OCCl
Reactant: CC(C)=Cc1ccc(C(C)C(=O)[O-])cc1
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CC(C)=Cc1ccc(C(C)C(=O)OCOC(=O)C(C)(C)C)cc1

Procedure:
A solution of sodium 2-(4-dimethylvinylphenyl)propionate (3 g) and chloro-methyl pivalate (3.9 g) in toluene (50 ml) was refluxed for 6 hours. After cooling, 50 ml of ethyl ether were added and the mixture was washed with 10% NaHCO3. The solvent was removed, and the residue dried at 60° for 3 hours in a vacuum stove to yield the title ester as an oily product (2 g). Found: C% 71.5 (Calc. 71.66); H% 8.2 (8.23).
Reaction SMILES: [N+:1]([C:4]1[C:9]([CH3:10])=[CH:8]C(C)=[CH:6][C:5]=1[CH3:12])([O-:3])=[O:2].[CH:13]([OH:16])([CH3:15])C.[OH2:17]>C(O)(=O)C>[N+:1]([C:4]1[C:9]([CH3:10])=[CH:8][C:15]([C:13]([OH:16])=[O:17])=[CH:6][C:5]=1[CH3:12])([O-:3])=[O:2]
Reactant: Cc1cc(C)c([N+](=O)[O-])c(C)c1
Reactant: CC(C)O
Reactant: O
Solvent: CC(=O)O
Product: Cc1cc(C(=O)O)cc(C)c1[N+](=O)[O-]
Temperature: 67.5 °C
Reaction time: 0.5 h

Procedure:
To a solution of chromic anhydride (40 g) in acetic acid (450 ml) was added a solution of nitromesitylene (20 g) in acetic acid (50 ml) at 65-70° C. over 20 min. This reaction mixture was stirred at 65-70° C. for 30 min and isopropyl alcohol (45 ml) was added. This reaction mixture was further stirred at 50° C. for 30 min. Water was added to the reaction mixture to make the total amount 500 ml and the mixture was ice-cooled. The precipitated crystals were collected by filtration to give the title compound (13 g) as pale-green crystals.
Reaction SMILES: [OH-].[Na+].[CH3:3][N:4]1[C:12]2[N:11]=[C:10]([CH3:13])[NH:9][C:8]=2[C:7](=[O:14])[NH:6][C:5]1=[O:15].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>O.CO>[CH2:16]([N:9]1[C:8]2[C:7](=[O:14])[NH:6][C:5](=[O:15])[N:4]([CH3:3])[C:12]=2[N:11]=[C:10]1[CH3:13])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: BrCc1ccccc1
Reactant: Cc1nc2c([nH]1)c(=O)[nH]c(=O)n2C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1nc2c(c(=O)[nH]c(=O)n2C)n1Cc1ccccc1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
A solution of sodium hydroxide (400 mg) in water (5 ml) was added to a suspension of 3,8-dimethylxanthine (1.80 g) in methanol (10 ml). After stirring for 1 hour at 70° C., benzyl bromide (1.2 ml) was added. After stirring for 5 hours at 70-80° C., the solvent was evaporated under reduced pressure. The residue was treated with saturated aqueous ammonium chloride solution (50 ml) and extracted with ethyl acetate (3×75 ml). The combined extracts were washed with saturated aqueous sodium chloride solution (30 ml), dried over magnesium sulfate and concentrated under reduced pressure. The solid was purified by recrystallization from ethanol to provide 7-benzyl-3,8-dimethylxanthine (1.06 g).
Reaction SMILES: O=[C:2]([C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[N:13]([CH3:17])[C:12](=[O:18])[CH2:11]2)[CH2:3][CH2:4][C:5](O)=[O:6].O.[NH2:20][NH2:21]>CN(C)C=O>[O:6]=[C:5]1[CH2:4][CH2:3][C:2]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[N:13]([CH3:17])[C:12](=[O:18])[CH2:11]3)=[N:21][NH:20]1
Reactant: NN
Reactant: CN1C(=O)Cc2cc(C(=O)CCC(=O)O)ccc21
Solvent: CN(C)C=O
Solvent: O
Product: CN1C(=O)Cc2cc(C3=NNC(=O)CC3)ccc21

Procedure:
A solution of 7 g of 4-oxo-4-(1-methyl-2-oxoindolin-5-yl)butanoic acid and 3 ml of hydrazine hydrate in 70 ml of dimethylformamide was heated on a water bath for 4 hours. The precipitated crystals were filtered off and recrystallized from dimethylformamide to give 4.0 g of 5-(3-oxo-2,3,4,5-tetrahydropyridazin-6-yl)-1-methylindolin-2-one as pale yellow prisms, melting at 261°-264° C.
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][C:10](=O)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C-:14]#[N:15].[Na+].[NH4+:17].[Cl-].N.CO>N.CO>[NH2:17][C:10]1([C:14]#[N:15])[CH2:11][CH2:12][N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:8][CH2:9]1
Reactant: [C-]#N
Reactant: O=C1CCN(c2ccccc2)CC1
Reactant: [NH4+]
Agent: N
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: N#CC1(N)CCN(c2ccccc2)CC1
Reaction time: 2 h
Yield: 73.4 %

Procedure:
N-Phenyl-4-piperidone (2.3 g, 13 mmol, 1.0 equiv) was dissolved in 26 mL of 2 M NH3 in MeOH and NaCN (0.76 g, 15 mmol, 1.2 equiv) and NH4Cl (0.80 g, 15 mmol, 1.2 equiv) were added and the mixture was refluxed for 2 h at which time an additional 26 mL of 2 M NH3/MeOH was added followed by another 2 h of reflux. The reaction mixture was cooled and filtered. The filtrate was concentrated. The crude product was purified by flash chromatography on SiO2 eluting with 100% CH2Cl2 and 2% MeOH in CH2Cl2 to give the pure product (1.92 g) as a thick yellow oil which solidified on standing; MS, m/z 202=M+1.