Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:10]2OC[CH:7](OC)[C:6]=2[C:5]([CH:13]2[C@H:18]([O:19]CC3C=CC=CC=3)[C@@H:17]([O:27]CC3C=CC=CC=3)[C@H:16]([O:35]CC3C=CC=CC=3)[C@@H:15]([CH2:43][O:44]CC3C=CC=CC=3)[O:14]2)=[CH:4][C:3]=1[CH2:52][C:53]1[CH:58]=[CH:57][C:56]([O:59][CH2:60][CH3:61])=[CH:55][CH:54]=1.[CH2:62]1[CH2:66][O:65][CH2:64][CH2:63]1.CO>[Pd]>[CH:10]1([C:2]2[C:66]3[O:65][CH2:64][CH2:63][C:62]=3[C:5]([C@H:13]3[C@H:18]([OH:19])[C@@H:17]([OH:27])[C@H:16]([OH:35])[C@@H:15]([CH2:43][OH:44])[O:14]3)=[CH:4][C:3]=2[CH2:52][C:53]2[CH:54]=[CH:55][C:56]([O:59][CH2:60][CH3:61])=[CH:57][CH:58]=2)[CH2:6][CH2:7]1
Reactant: CCOc1ccc(Cc2cc(C3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c3c(c2Cl)OCC3OC)cc1
Reactant: C1CCOC1
Agent: [Pd]
Solvent: CO
Product: CCOc1ccc(Cc2cc([C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)c3c(c2C2CC2)OCC3)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 29 %

Procedure:
To a solution of 7-chloro-6-(4-ethoxybenzyl)-3-methoxy-4-((3S,4R,5R,6R)-3,4,5-tris(benzyloxy)-6-(benzyloxymethyl)-tetrahydro-2H-pyran-2-yl)-2,3-dihydrobenzofuran (102 mg, 0.125 mmol) in THF/MeOH (4 mL/2 mL) was added 10% Pd/C (10 mg) at rt. The reaction mixture was stirred at r.t. for 15 hours under hydrogen and filtered off. The filtrate was concentrated in vacuo and the residue was purified using reverse phase preparative HPLC to provide the title compound (17 mg, 29%) as a white solid.
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH3:18])(=[O:5])[CH2:2][CH2:3][CH3:4].[NH2:19][C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH2:22][OH:23]>>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:19][C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH2:22][OH:23])=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH3:18])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: Nc1ccccc1CO
Reactant: CCCC(=O)c1cnc2c(OC)cccc2c1Cl
Product: CCCC(=O)c1cnc2c(OC)cccc2c1Nc1ccccc1CO
Yield: 53.1 %

Procedure:
3-Butyryl-4-chloro-8-methoxyquinoline (2.64 g, 10 mmol) was dissolved in I,4-dioxan (10 ml), 2-aminobenzyl alcohol (1.85 g, I5 mmol) added, and the mixture heated to reflux for 5 minutes. The dioxan was evaporated, water added, and the product extracted into dichloromethane. Chromatography (silica gel, ethyl acetate) and recrystallisation from ethyl acetate gave 3-butyryl-4-(2-(hydroxymethyl)phenylamino)-8-methoxyquinoline (1.86 g, 53%), m.p. 159°-161°.
Reaction SMILES: Cl.[NH:2]([C:6]1[CH:14]=[CH:13][C:9]([C:10](Cl)=[O:11])=[CH:8][CH:7]=1)[C:3]([NH2:5])=[NH:4].[C:15]([O:19][C:20](=[O:42])[CH2:21][C:22]1([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[O:26][N:25]=[C:24]([C:27]2[CH:32]=[C:31]([OH:33])[CH:30]=[CH:29][C:28]=2[CH3:34])[CH2:23]1)([CH3:18])([CH3:17])[CH3:16].N1C=CC=CC=1>CN1C(=O)CCC1>[C:15]([O:19][C:20](=[O:42])[CH2:21][C:22]1([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[O:26][N:25]=[C:24]([C:27]2[CH:32]=[C:31]([O:33][C:10](=[O:11])[C:9]3[CH:8]=[CH:7][C:6]([NH:2][C:3]([NH2:5])=[NH:4])=[CH:14][CH:13]=3)[CH:30]=[CH:29][C:28]=2[CH3:34])[CH2:23]1)([CH3:18])([CH3:17])[CH3:16]
Reactant: N=C(N)Nc1ccc(C(=O)Cl)cc1
Reactant: Cc1ccc(O)cc1C1=NOC(CC(=O)OC(C)(C)C)(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: c1ccncc1
Product: Cc1ccc(OC(=O)c2ccc(NC(=N)N)cc2)cc1C1=NOC(CC(=O)OC(C)(C)C)(C(=O)OC(C)(C)C)C1
Reaction time: 0.33 h
Yield: 51.4 %

Procedure:
4-Carbamimidamidobenzoyl chloride hydrochloride (173 mg) was added to a mixture of tert-butyl 5-(2-tert-butoxy-2-oxoethyl)-3-(5-hydroxy-2-methylphenyl)-4,5-dihydro-1,2-oxazole-5-carboxylate (290 mg), pyridine (1 mL), and NMP (3 mL) at 50 C, and the obtained mixture was stirred at 50 C for 20 minutes. Further, 4-carbamimidamidobenzoyl chloride hydrochloride (173 mg) was added thereto, and the obtained mixture was stirred at 50 C for 20 minutes. Further, 4-carbamimidamidobenzoyl chloride hydrochloride (173 mg) was added thereto, and the obtained mixture was stirred at 50 C for 3 hours. Further, 4-carbamimidamidobenzoyl chloride hydrochloride (173 mg) was added thereto, and the obtained mixture was stirred overnight at 50 C. The reaction mixture was purified by silica gel column chromatography (NH, ethyl acetate/hexane, subsequently methanol/ethyl acetate) and then further fractionated by HPLC (C18, mobile phase: water/acetonitrile (system containing 0.1% TFA)). To the obtained fraction, a saturated aqueous solution of sodium bicarbonate was added, followed by extraction with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain the title compound (210 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[C:23]([F:26])([F:25])[F:24])[CH2:5][CH:6]1[CH2:11][CH:10]([C:12]([O:14]C)=[O:13])[CH2:9][CH2:8][N:7]1[C:16]([O:18][CH3:19])=[O:17].[Br-].[Li+].C(N(CC)CC)C>C(#N)C.O>[F:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[C:23]([F:26])([F:24])[F:25])[CH2:5][CH:6]1[CH2:11][CH:10]([C:12]([OH:14])=[O:13])[CH2:9][CH2:8][N:7]1[C:16]([O:18][CH3:19])=[O:17]
Reactant: COC(=O)C1CCN(C(=O)OC)C(Cc2ccc(C(F)(F)F)c(F)c2)C1
Agent: [Br-]
Agent: [Li+]
Solvent: O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)N1CCC(C(=O)O)CC1Cc1ccc(C(F)(F)F)c(F)c1
Temperature: 25 °C
Yield: 95 %

Procedure:
To a solution of dimethyl 2-(3-fluoro-4-(trifluoromethyl)benzyl)piperidine-1,4-dicarboxylate (7.17 g, 19.00 mmol) in acetonitrile (60 mL) and water (1.2 mL) was added lithium bromide (13.20 g, 152.02 mmol) and triethylamine (10.54 mL, 76.01 mmol). The resulting mixture was heated under reflux for 2 h, then cooled to room temperature. Water was added and acetonitrile removed by evaporation. The aqueous layer was further diluted with water, then washed with MTBE. The organic layer was extracted with water. The combined aqueous layers were acidified with 3.8 M HCl, a colorless precipitate formed. The solids were extracted with DCM 6 times. The aqueous layer was extracted twice again with DCM. The combined organic layers were dried over MgSO4 and evaporated. 2-(3-Fluoro-4-(trifluoromethyl)benzyl)-1-(methoxycarbonyl)piperidine-4-carboxylic acid (6.56 g, 95%) was isolated as an off-white solid. MS m/z 364 (M+H)+
Reaction SMILES: [CH3:1][C:2]1[N:6]2[CH:7]=[C:8]([C:11]#[N:12])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.N>CO.[Ni]>[CH3:1][C:2]1[N:6]2[CH:7]=[C:8]([CH2:11][NH2:12])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1
Reactant: Cc1cnc2ccc(C#N)cn12
Agent: [Ni]
Agent: N
Solvent: CO
Product: Cc1cnc2ccc(CN)cn12
Reaction time: 2 h
Yield: 97.7 %

Procedure:
To a solution of 3-methylimidazo[1,2-a]pyridine-6-carbonitrile (6-2) (200 mg, 1.27 mmol) in methanol (30 mL) were added Raney nickel (slurry in water, 100 mg) and 1N ammonia. The reaction mixture was stirred under H2 for 2 h, then filtered and concentrated to afford the title compound (200 mg). MS (m/z): 162 (M+H)+
Reaction SMILES: [H-].[Na+].[CH:3]1([N:6]2[C:15]3[C:10](=[CH:11][C:12]([F:24])=[C:13]([N:17]4[CH2:21][CH2:20][CH2:19][C@H:18]4[CH2:22][OH:23])[C:14]=3F)[C:9](=[O:25])[C:8]([C:26]([OH:28])=[O:27])=[CH:7]2)[CH2:5][CH2:4]1.[H][H]>CN(C=O)C>[CH:3]1([N:6]2[C:15]3[C:14]4[O:23][CH2:22][C@@H:18]5[CH2:19][CH2:20][CH2:21][N:17]5[C:13]=4[C:12]([F:24])=[CH:11][C:10]=3[C:9](=[O:25])[C:8]([C:26]([OH:28])=[O:27])=[CH:7]2)[CH2:5][CH2:4]1
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(N3CCC[C@H]3CO)c(F)cc2c1=O
Reactant: [H][H]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(O)c1cn(C2CC2)c2c3c(c(F)cc2c1=O)N1CCC[C@H]1CO3

Procedure:
9.2 mg of a 55% sodium hydride dispersion were added to a solution of 0.364 g (1 mmol) of 1-cyclopropyl-6,8-difluoro-1,4-dihydro-7-[(S)-2-hydroxymethyl-1-pyrrolidinyl]-4-oxoquinoline-3-carboxylic acid in 8 ml of DMF. After completion of the hydrogen evolution, the mixture was stirred at 140° C. for 35 minutes, the solvent was evaporated, the residue was taken up in water, adjusted to pH 6 with glacial acetic acid and suction filtered. Crystallization from ethanol gave (S)-4-cyclopropyl-11-fluoro-1,4,6a,7,8,9-hexahydro-1-oxo-6H-pyrrolo[1',2':4,5][1,4]oxazino[3,2-h]quinoline-2-carboxylic acid, m.p. >275° C. (dec.), MS: 344 (M+, 58%), 300 (100), 271 (12), 245 (8), 216 (17), 189 (4), 158 (4), 41 (24).
Reaction SMILES: [NH2:1][C:2]1[CH2:8][N:7]=[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:15])[C:5]2[CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=[CH:19][C:4]=2[N:3]=1.[C:23](OC)(=[O:26])[C:24]#[CH:25]>CO>[N+:20]([C:17]1[CH:18]=[CH:19][C:4]2[N:3]3[CH:25]=[CH:24][C:23](=[O:26])[N:1]=[C:2]3[CH2:8][N:7]=[C:6]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[Cl:15])[C:5]=2[CH:16]=1)([O-:22])=[O:21]
Reactant: NC1=Nc2ccc([N+](=O)[O-])cc2C(c2ccccc2Cl)=NC1
Reactant: C#CC(=O)OC
Solvent: CO
Product: O=c1ccn2c(n1)CN=C(c1ccccc1Cl)c1cc([N+](=O)[O-])ccc1-2

Procedure:
In the manner given in Example 1, 2-amino-7-nitro-5-(o-chlorophenyl)-3H-1,4-benzodiazepine, methyl propiolate and methanol were refluxed. The mixture was chromatographed to give 9-nitro-7-(o-chlorophenyl)pyrimido[1,2-a][1,4]benzodiazepin-3(5H)-one.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.[Cl:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][C:31]=1[Cl:32])[C:26](Cl)=[O:27]>>[Cl:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][C:31]=1[Cl:32])[C:26]([N:1]1[CH2:2][CH2:3][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:5][CH2:6]1)=[O:27]
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCNCC1)O2
Product: O=C1C(=O)c2ccccc2C2=C1SCC1(CCN(C(=O)c3ccc(Cl)c(Cl)c3)CC1)O2

Procedure:
Compound 53 was synthesized using spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, 3,4-dichlorobenzoyl chloride and conditions outlined in procedure N. M.p.=221° C.; 300 MHz 1H NMR (DMSO-d6) δ 7.89 (m, 2H), 7.74 (m, 3H), 7.58 (t, 1H), 7.46 (d, J=8.1 Hz, 1H), 4.40 (m, 1H), 3.56 (brm, 2H), 3.30 (m, 1H), 3.10 (s, 2H), 2.08 (m, 2H), 1.85 (m, 2H); LCMS: 474 [M+H].
Reaction SMILES: [NH2:1][C:2]1[C:7]([N:8]=[O:9])=[C:6]([NH2:10])[N:5]=[C:4](SC)[N:3]=1.[CH3:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([CH2:19][CH2:20][NH2:21])=[CH:17][CH:16]=1>O>[NH2:1][C:2]1[C:7]([N:8]=[O:9])=[C:6]([NH2:10])[N:5]=[C:4]([NH:21][CH2:20][CH2:19][C:18]2[CH:22]=[CH:23][C:15]([O:14][CH3:13])=[CH:16][CH:17]=2)[N:3]=1
Reactant: COc1ccc(CCN)cc1
Reactant: CSc1nc(N)c(N=O)c(N)n1
Solvent: O
Product: COc1ccc(CCNc2nc(N)c(N=O)c(N)n2)cc1
Yield: 84 %

Procedure:
A mixture of 4,6-diamino-2-methylthio-5-nitrosopyrimidine (10 g, 5.4 mM), 4-methoxyphenethylamine (7.92 ml, 5.4 mM) and water (180 ml) was heated to reflux for one hour. After cooling the red solid was separated by filtration, washed with water, and dried. There was thus obtained 4,6-diamino-2-[2-(4-methoxyphenyl)ethyl]amino-5-nitrosopyrimidine (13.4 g, 84% yield). NMR: DMSO-d6 ; 2.7-2.85(m,2H, CH2 --CH2), 3.4-3.6(m, 2H, CH2 --NH), 3.7 (s, 3H, OCH3), 6.75-6.8(m,2H, aromatic-H), 7.05-7.25 (m, 2H, aromatic-H), 7.4-10.5 (m, 5H, NH2 ×2, NH), m/e [M+H[+ 289.
Reaction SMILES: [F:1][C:2]1[C:3]2[N:4]([CH:12]=[CH:13][N:14]=2)[CH:5]=[CH:6][C:7]=1[C:8]([OH:11])([CH3:10])[CH3:9].[Br:15]Br.[Br-].[K+].C([O-])(=O)C.[Na+]>CO>[Br:15][C:12]1[N:4]2[CH:5]=[CH:6][C:7]([C:8]([OH:11])([CH3:10])[CH3:9])=[C:2]([F:1])[C:3]2=[N:14][CH:13]=1
Reactant: CC(C)(O)c1ccn2ccnc2c1F
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: CO
Product: CC(C)(O)c1ccn2c(Br)cnc2c1F
Yield: 45 %

Procedure:
2-(8-Fluoroimidazo[1,2-α]pyridin-7-yl)propan-2-ol (1.00 g, 5.2 mmol) was brominated by treatment with bromine in methanol, in the presence of potassium bromide and sodium acetate, affording 2-(3-bromo-8-fluoroimidazo[1,2-α]pyridin-7-yl)propan-2-ol (637 mg, 45%): δH (360 MHz, CDCl3) 1.72 (6H, s), 7.32 (1H, t, J 6.9), 7.59 (1H, s), 7.89 (1H, d, J 7.3); m/z (ES+) 275 (100%, [M]+), 273 (100).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([N:13]3[CH2:18][CH2:17][N:16]([CH:19]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)[CH2:15][CH2:14]3)[CH:12]=1)[N:9]=[CH:8][CH:7]=[CH:6]2.Br[CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[C:31]2[C:36]=1[N:35]=[CH:34][CH:33]=[CH:32]2.C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([N:13]3[CH2:14][CH2:15][N:16]([CH:19]4[CH2:24][CH2:23][N:22]([CH2:26][C:27]5[CH:28]=[CH:29][CH:30]=[C:31]6[C:36]=5[N:35]=[CH:34][CH:33]=[CH:32]6)[CH2:21][CH2:20]4)[CH2:17][CH2:18]3)[CH:12]=1)[N:9]=[CH:8][CH:7]=[CH:6]2
Reactant: COc1cc(N2CCN(C3CCNCC3)CC2)c2ncccc2c1
Reactant: BrCc1cccc2cccnc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COc1cc(N2CCN(C3CCN(Cc4cccc5cccnc45)CC3)CC2)c2ncccc2c1
Temperature: 70 °C
Reaction time: 18 h

Procedure:
To a mixture of 6-methoxy-8-(4-piperidin-4-ylpiperazin-1-yl)quinoline (Step 2, 0.06 g) and 8-(bromo)methylquinoline (commercially available, 0.055 g) in anhydrous dimethylsulfoxide (5 mL) was added anhydrous K2CO3 (0.051 g). The resulting mixture was stirred at 70° C. for 18 hours. The reaction mixture was cooled to room temperature and partitioned between ethyl acetate and water. The organic layer was washed with water and brine and was then dried over anhydrous Na2SO4, filtered and concentrated on a rotary evaporator to give the desired product, which was converted to its dihydrochloride salt in CH2Cl2 using 1N HCl/Et2O to give 0.31 g of a light yellow solid; MS (ES) m/z (relative intensity); 468 (M+H)+ (100).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([NH2:10])=O)[CH:3]=1.[C:11]1(N)[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[NH2:17]>O>[CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[NH:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:17]=2)[CH:3]=1
Reactant: Nc1ccccc1N
Reactant: Cc1ccnc(C(N)=O)c1
Solvent: O
Product: Cc1ccnc(-c2nc3ccccc3[nH]2)c1
Temperature: 210 °C
Yield: 85 %

Procedure:
450 g of polyphosphoric acid, 40 g (0.29 mol) of 4-methyl-pyridine-2-carboxylic acid amide and 31 g (0.29 mol) of o-phenylendiamine are added in a three-neck round-bottom flask, equipped with a condenser, a thermometer and mechanical stirring. The mixture is heated at 210° C. for 4 hours. At the end, the mixture is cooled at 70° C. and the crude is added to 1 L of water. Basify with a 50% aqueous solution of sodium hydroxide and filter the solid obtained. Crystallize from absolute ethanol. The product 2-(4-methylpyridin-2-yl)-1H-benzoimidazol is obtained with a yield of 85%. Melting point: 228-9° C.
Reaction SMILES: [N+:1]([C:4]1[C:5](=O)[NH:6][CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].P(Cl)(Cl)([Cl:13])=O>>[Cl:13][C:9]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]cccc1[N+](=O)[O-]
Product: O=[N+]([O-])c1cnccc1Cl

Procedure:
A solution of technical grade 3-nitropyridone (25 g, 177 mmol) (contains about 20% 3,5-dinitropyridone by weight) in 150 mL of phosphorous oxychloride was heated at 90° C. for 2 h. The excess phosphorous oxychloride was removed by distillation and the remaining oil poured into ice/water. The aqueous solution was extracted with five 300 mL portions of CH2Cl2. The CH2Cl2 extracts were dried (MgSO4), filtered and concentrated in vacuo to yield 26.7 g of crude 4-chloro-3-nitropyridine. To a solution of the crude 4-chloro-3-nitropyridine (26.7 g) in 200 mL of MeCN was added potassium carbonate (25.7 g, 186 mmol) and ethyl 1-piperazinecarboxylate (27.2 mL, 186 mmol). The reaction mixture was stirred at 23° C. for 16 h and then concentrated in vacuo. The mixture was diluted with ethyl acetate (1 L), and the organic solution was washed with water, dried (brine, MgSO4), filtered and concentrated in vacuo to a solid mass. Silica gel chromatography of the mixture gave ethyl 4-(3-nitro-4-pyridinyl)-1-piperazinecarboxylate (34.73 g, 73%): mp 101°-103° C., and ethyl 4-(3,5-dinitro-4-pyridinyl)-1-piperazinecarboxylate (7.07 g, 22%): mp 165°-167° C. Anal. Calcd for C12H16N4O4 : C, 51.42; H, 5.75; N, 19.99. Found: C, 51.26; H, 5.69; N, 19.91. Anal. Calcd for C12H15N5O6 : C, 44.31; H, 4.65; N, 21.53. Found: C, 44.51; H, 4.65; N, 21.36.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([O:11][CH3:12])[CH:7]=[CH:8][C:9]=1[CH3:10])([O-])=O.[H][H]>[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([O:11][CH3:12])[CH:7]=[CH:8][C:9]=1[CH3:10]
Reactant: COc1ccc(C)c([N+](=O)[O-])c1
Reactant: [H][H]
Agent: [Pd]
Product: COc1ccc(C)c(N)c1
Yield: 72 %

Procedure:
A mixture of 10 gm. (60 mmol) of 3-nitro-4-methylanisole and 4 gm. of 10% Pd/C was stirred under 1 atm. of hydrogen for 30 hours, filtered, and evaporated in vacuo to give 3-amino-4-methylanisole as a residue which was dissolved in 250 ml. of tetrahydrofuran containing 13 gm. (60 mmol) of tert-butyl dicarbonate, refluxed for 3 hours, cooled, and evaporated in vacuo. The residue was chromatographed on silica gel eluting with a gradient 5-10% Et2O /hexane to give 2 (R1=5-OMe), 10.3 gm., 72% yield, mp 72°-74° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[F:9].C([Li])CCC.[CH2:15]([N:22]1[CH2:26][CH2:25][C:24](=[O:27])[CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[Cl-].[NH4+]>C(OCC)C>[CH2:15]([N:22]1[CH2:26][CH2:25][C:24]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=2[F:9])([OH:27])[CH2:23]1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=C1CCN(Cc2ccccc2)C1
Reactant: Fc1c(Cl)cccc1Br
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOCC
Product: OC1(c2cccc(Cl)c2F)CCN(Cc2ccccc2)C1
Yield: 92.9 %

Procedure:
To a solution of 1-bromo-3-chloro-2-fluorobenzene (11.8 g, 56.3 mmol) in dry diethyl ether (100 mL), under nitrogen at −78° C. was added drop wise n-butyllithium (2.5 M in hexane, 22.5 mL, 56.3 mmol). The mixture was stirred at −78° C. for 10 min after which a solution of 1-benzylpyrrolidin-3-one (10 g, 56.3 mmol) in dry diethyl ether (50 mL) was added drop wise. The resulting mixture was brought to ambient temperature, aqueous ammonium chloride solution (50%, 50 mL) was added and the mixture was extracted with ethyl acetate (2×50 mL). The combined organic phase was dried (MgSO4), filtered and evaporated. Purification by flash chromatography on silica gel (isooctane/ethyl acetate, 1:1) gave the title compound (16 g). MS m/z (relative intensity, 70 eV) 305 (M+, 9), 214 (41), 133 (71), 132 (50), 91 (bp).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[OH:12])[N:8]=[C:7]([CH3:13])[CH:6]=[CH:5]2.C([O-])([O-])=O.[Cs+].[Cs+].CC1C=CC(S(O[CH2:31][C@H:32]([O:34][CH3:35])[CH3:33])(=O)=O)=CC=1>CN1C(=O)CCC1>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH2:31][C@H:32]([O:34][CH3:35])[CH3:33])[N:8]=[C:7]([CH3:13])[CH:6]=[CH:5]2
Reactant: Cc1ccc2cc(F)c(O)cc2n1
Reactant: CO[C@H](C)COS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: CO[C@H](C)COc1cc2nc(C)ccc2cc1F
Temperature: 80 °C
Yield: 102.6 %

Procedure:
To a stirred mixture of 6-fluoro-2-methylquinolin-7-ol (0.200 g, 1.13 mmol), Cs2CO3 (0.552 g, 1.69 mmol) and NMP (2.3 mL) was added (R)-2-methoxypropyl 4-methylbenzenesulfonate (0.303 g, 1.24 mmol). The reaction mixture was heated at 80° C. for 1 hour. After cooling, the reaction was partitioned between toluene and water. The aqueous layer was extracted with toluene (2×). The combined organic layers were washed with water and brine, dried and concentrated. The residue was purified by flash chromatography on silica gel (hexanes:EtOAc, 1:1) to give (R)-6-fluoro-7-(2-methoxypropoxy)-2-methylquinoline (0.289 g, 103%).
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][N:14]([CH2:27][C:28]([F:31])([F:30])[F:29])[C:15]2[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[C:17]([C:23]([F:26])([F:25])[F:24])[CH:16]=2)=[CH:7][CH:6]=1)=[O:4].[F:34][C:35]([Si](C)(C)C)([F:37])[F:36].[F-].[Cs+].Cl>COCCOC.O>[F:31][C:28]([F:30])([F:29])[CH2:27][N:14]([CH2:13][CH2:12][O:11][C:8]1[CH:7]=[CH:6][C:5]([C:3]([OH:4])([C:35]([F:37])([F:36])[F:34])[C:2]([F:32])([F:33])[F:1])=[CH:10][CH:9]=1)[C:15]1[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[C:17]([C:23]([F:24])([F:25])[F:26])[CH:16]=1
Reactant: N#Cc1ccc(N(CCOc2ccc(C(=O)C(F)(F)F)cc2)CC(F)(F)F)cc1C(F)(F)F
Reactant: C[Si](C)(C)C(F)(F)F
Agent: Cl
Agent: [Cs+]
Agent: [F-]
Solvent: COCCOC
Solvent: O
Product: N#Cc1ccc(N(CCOc2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2)CC(F)(F)F)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 41.8 %

Procedure:
To a solution of 4-[(2-{[4-(trifluoroacetyl)phenyl]oxy}ethyl)(2,2,2-trifluoroethyl)amino]-2-(trifluoromethyl)benzonitrile (0.106 g, 0.22 mmol, example 37) and (trifluoromethyl)trimethylsilane (0.040 mL, 0.26 mmol) in dry DME at rt, under N2, was added anhydrous CsF (0.0020 g, 0.011 mmol). The mixture was stirred 3 h at rt and an additional portion of (trifluoromethyl)trimethylsilane (0.040 mL, 0.26 mmol) was added, and the mixture stirred another 2 h. 2N HCl (5 mL) was added, and the mixture was stirred for 60 h at rt. The mixture was diluted with water and the whole extracted with EtOAc (×2). Combined organics were washed (water, brine, dried over Na2SO4 and concentrated in vacuo, affording 0.051 g of the title compound as a pale yellow solid: MS (ESI) m/z 553 (M−1).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][OH:8])[CH2:3][CH2:2]1.Cl[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11].C(=O)(O)[O-].[Na+]>C(Cl)Cl.O>[CH2:13]([O:12][C:10]([N:1]1[CH2:6][CH2:5][CH:4]([CH2:7][OH:8])[CH2:3][CH2:2]1)=[O:11])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: OCC1CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: O=C(OCc1ccccc1)N1CCC(CO)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 76 %

Procedure:
A mixture of piperidin-4-yl-methanol (0.57 g, 5 mmoles), benzyl chloroformate (0.75 ml, 5.5 mmoles), and sodium bicarbonate (0.46 g, 5.5 mmoles) in CH2Cl2 was stirred at room temperature for 2 hours, diluted with H2O and extracted with EtOAc. The extracts were combined, washed sequentially with water and brine, dried over Na2SO4 and concentrated under vacuum to afford the title compound (0.95 g, 3.8 mmoles).
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:3]=1[S-:4].[K+].Cl[C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][C:19]=1[N+:20]([O-:22])=[O:21])[C:15]#[N:16]>CO.C1(C)C=CC=CC=1>[F:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:3]=1[S:4][C:18]1[CH:17]=[C:14]([CH:13]=[CH:12][C:19]=1[N+:20]([O-:22])=[O:21])[C:15]#[N:16]
Reactant: Fc1ccc([S-])c(F)c1
Reactant: N#Cc1ccc([N+](=O)[O-])c(Cl)c1
Agent: [K+]
Solvent: CO
Solvent: Cc1ccccc1
Product: N#Cc1ccc([N+](=O)[O-])c(Sc2ccc(F)cc2F)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 45 %

Procedure:
A solution of potassium 2,4-difluorothiophenoxide (6.1 g) in methanol (30 ml) was added dropwise to a solution of 3-chloro-4-nitrobenzonitrile (5 g) in toluene (50 ml). The mixture was stirred for 5 hours at room temperature, washed with water, and concentrated to dryness. The oily residue was crystallized from a mixture of ethanol and hexane to give crystals of 3-(2,4-difluorophenylthio)-4-nitrobenzonitrile (3.6 g).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][C@H:9]([OH:14])[C:10]([O:12][CH3:13])=[O:11])[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[C:22](Cl)(=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24].Cl>C(OC)(C)(C)C>[C:22]([O:1][C:2]1[CH:3]=[C:4]([CH2:8][C@H:9]([OH:14])[C:10]([O:12][CH3:13])=[O:11])[CH:5]=[CH:6][CH:7]=1)(=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)C(=O)Cl
Reactant: COC(=O)[C@@H](O)Cc1cccc(O)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: COC(C)(C)C
Product: COC(=O)[C@@H](O)Cc1cccc(OC(=O)C(C)(C)C)c1
Temperature: 10 °C
Reaction time: 17 h
Yield: 87 %

Procedure:
Methyl (2S)-3-(3-hydroxyphenyl)-2-hydroxypropionate (8.93 kg, 45.1 mol) was dissolved in tert-butylmethyl ether (133 L), and triethylamine (12.7 L, 91 mol) was added to the reaction mixture at room temperature, followed by cooling. Pivaloyl chloride (5.89 L, 48 mol) was added dropwise to the reaction mixture at an internal temperature of 2° C. After the end of the dropwise addition, the reaction mixture was stirred at 10° C. for 17 hours. To the reaction mixture was added 43 L of a 1N hydrochloric acid aqueous solution before stirring, followed by allowing to stand and then separating the mixture. The organic layer was washed twice each with a 0.25N sodium hydroxide aqueous solution (45 L) and water (45 L), and further washed with 42 L of a 5% sodium chloride solution, and then the organic layer was subjected to vacuum concentration at 50° C. After that, 1,2-dimethoxyethane (45 L) was added to the residue and then again subjected to vacuum concentration to obtain 11.0 kg of the title compound (yield: 86%).