Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH:2]([F:18])[C:3](=O)[CH2:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=1)=O.[NH2:19][C:20]1[CH:24]=[CH:23][NH:22][N:21]=1>C(O)(=O)C>[F:14][C:13]([F:16])([F:15])[C:9]1[CH:8]=[C:7]([C:5]2[CH:4]=[C:3]([CH:2]([F:18])[F:1])[N:21]3[N:22]=[CH:23][CH:24]=[C:20]3[N:19]=2)[CH:12]=[CH:11][CH:10]=1
Reactant: O=C(CC(=O)C(F)F)c1cccc(C(F)(F)F)c1
Reactant: Nc1cc[nH]n1
Solvent: CC(=O)O
Product: FC(F)c1cc(-c2cccc(C(F)(F)F)c2)nc2ccnn12
Yield: 82 %

Procedure:
A mixture of 4,4-difluoro-1-(3-trifluoromethyl-phenyl)-butane-1,3-dione (6.75 g, 25.4 mmol) and commercially available 3-aminopyrazole (2.11 g, 25.4 mmol) in acetic acid (70 mL) was refluxed for 7 h and evaporated. The crude product was further purified by crystallization (ethyl acetate/hexane) to yield 5-(3-trifluoromethyl-phenyl)-7-difluoromethyl-pyrazolo [1,5-a]pyrimidine (6.52 g, 82%) as a light yellow solid. MS (EI) 313.1 [(M)+]; mp 127° C.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[CH:5]=[CH:4][C:3]=1[C@H:10]1[CH2:15][CH2:14][C@H:13]([C@H:16]2[CH2:21][CH2:20][C@H:19]([CH2:22][CH2:23][CH3:24])[CH2:18][CH2:17]2)[CH2:12][CH2:11]1.C([Li])CCC.[I:30]I.S([O-])([O-])(=O)=S.[Na+].[Na+]>C1COCC1>[I:30][C:5]1[C:6]([F:9])=[C:7]([F:8])[C:2]([F:1])=[C:3]([C@H:10]2[CH2:11][CH2:12][C@H:13]([C@H:16]3[CH2:21][CH2:20][C@H:19]([CH2:22][CH2:23][CH3:24])[CH2:18][CH2:17]3)[CH2:14][CH2:15]2)[CH:4]=1
Reactant: CCC[C@H]1CC[C@H]([C@H]2CC[C@H](c3ccc(F)c(F)c3F)CC2)CC1
Reactant: II
Agent: O=S([O-])([O-])=S
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: CCC[C@H]1CC[C@H]([C@H]2CC[C@H](c3cc(I)c(F)c(F)c3F)CC2)CC1
Temperature: -60 °C
Reaction time: 2 h

Procedure:
In a nitrogen atmosphere, 17 g of 2,3,4-trifluoro-1-[trans-4-(trans-4-propylcyclohexyl)cyclohexyl]benzene was dissolved into 300 mL of THF, and cooled to −60° C. Into this, 39 mL of butyllithium (1.56 M of hexane solution) was added dropwise for 30 minutes, and stirred for 2 hours. Into this, a THF solution (50 mL) containing 14 g of iodine was added dropwise for 1 hour, and warmed to room temperature. After the reaction solution was poured into a sodium thiosulfate aqueous solution, and stirred for a while, an organic layer was separated, and an aqueous layer was extracted with toluene. After the extract and the organic layer were mixed together, washed using water and a saturated saline solution in that order, and dried using anhydrous magnesium sulfate, the solvent was evaporated under a reduced pressure to obtain 25 g of 5-iodo-2,3,4-trifluoro-1-[trans-4-(trans-4-propylcyclohexyl)cyclohexyl]benzene.
Reaction SMILES: [CH2:1]([O:4][C:5]1[S:6][C:7]([CH:10]=O)=[CH:8][N:9]=1)[C:2]#[CH:3].[C:12](#[N:16])[CH2:13][C:14]#[N:15]>O.C(O)C>[CH2:1]([O:4][C:5]1[S:6][C:7]([CH:10]=[C:13]([C:12]#[N:16])[C:14]#[N:15])=[CH:8][N:9]=1)[C:2]#[CH:3]
Reactant: C#CCOc1ncc(C=O)s1
Reactant: N#CCC#N
Solvent: O
Solvent: CCO
Product: C#CCOc1ncc(C=C(C#N)C#N)s1
Temperature: 25 °C
Reaction time: 3 h
Yield: 86 %

Procedure:
1.4 g of 2-(2-propynyloxy)-1,3-thiazole-5-carbaldehyde was dissolved in a mixture of 6 ml of water and 14 ml of ethanol, and 0.56 g of malononitrile was added dropwise. The mixture was stirred at room temperature for 3 hours. Thereafter, the reaction mixture was filtered, and the resulting cake was washed with 5 ml of ethanol two times and dried under reduced pressure to obtain 1.55 g of {[2-(2-propynyloxy)-1,3-thiazol-5-yl]methylidene}malononitrile.
Reaction SMILES: COC1C=CC=CC=1C1NC(=O)C2C(=CC=CC=2)N=1.[NH2:20][C:21]1[CH:29]=[CH:28][C:27]([N:30]([CH3:32])[CH3:31])=[CH:26][C:22]=1[C:23]([NH2:25])=[O:24].[CH3:33][O:34][C:35]1[CH:36]=[C:37]([CH:40]=[CH:41][CH:42]=1)[CH:38]=O>>[CH3:33][O:34][C:35]1[CH:36]=[C:37]([C:38]2[NH:25][C:23](=[O:24])[C:22]3[C:21](=[CH:29][CH:28]=[C:27]([N:30]([CH3:32])[CH3:31])[CH:26]=3)[N:20]=2)[CH:40]=[CH:41][CH:42]=1
Reactant: CN(C)c1ccc(N)c(C(N)=O)c1
Reactant: COc1cccc(C=O)c1
Agent: COc1ccccc1-c1nc2ccccc2c(=O)[nH]1
Product: COc1cccc(-c2nc3ccc(N(C)C)cc3c(=O)[nH]2)c1
Yield: 48.4 %

Procedure:
According to the preparation of 42, 25 (1.0 g, 5.6 mmol) and 3-methoxybenzaldehyde (34) (0.8 g, 5.6 mmol) were used to afford 55 (0.8 g, 51.2%) as pale yellow needles.
Reaction SMILES: ClCCl.[CH3:4][O:5][N:6]([CH3:14])[C:7]([C:9]1[CH:10]=[N:11][NH:12][CH:13]=1)=[O:8].[CH3:15][Si:16]([CH3:23])([CH3:22])[CH2:17][CH2:18][O:19][CH2:20]Cl.C(N(CC)C(C)C)(C)C>C(OCC)(=O)C>[CH3:4][O:5][N:6]([CH3:14])[C:7]([C:9]1[CH:13]=[N:12][N:11]([CH2:20][O:19][CH2:18][CH2:17][Si:16]([CH3:23])([CH3:22])[CH3:15])[CH:10]=1)=[O:8]
Reactant: C[Si](C)(C)CCOCCl
Reactant: CON(C)C(=O)c1cn[nH]c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CON(C)C(=O)c1cnn(COCC[Si](C)(C)C)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 42.6 %

Procedure:
A dichloromethane solution (3 mL) of N-methoxy-N-methyl-1H-pyrazole-4-carboxamide (142.7 mg, 2.68 mmol) was mixed with 2-(trimethysilyl)ethoxymethyl chloride (0.47 mL, 2.68 mmol) and N,N-diisopropylethylamine (0.94 mL, 5.36 mmol) and stirred at room temperature for 16 hours. After completion of the reaction, the reaction solution was mixed with ethyl acetate washed with saturated aqueous sodium chloride and the organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate=10/1) to give the desired product (325.8 mg, 85% yield).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14](N(OC)C)=[O:15])=[CH:9][CH:8]=1)=[O:6].[OH-:20].[K+].Cl>C(O)C>[CH:4]1([C:5]([C:7]2[CH:8]=[CH:9][C:10]([CH2:13][C:14]([OH:15])=[O:20])=[CH:11][CH:12]=2)=[O:6])[CH2:3][CH2:2]1
Reactant: CON(C)C(=O)Cc1ccc(C(=O)CCCCl)cc1
Reactant: [OH-]
Agent: Cl
Agent: [K+]
Solvent: CCO
Product: O=C(O)Cc1ccc(C(=O)C2CC2)cc1
Reaction time: 18 h
Yield: 9.5 %

Procedure:
Add purified [4-(4-chloro-1-oxobutyl)]-N-methoxy-N-methyl-benzeneacetamide (9.4 g, 330 mmol) to a solution of potassium hydroxide (22.0 g) in ethanol (160 mL). Stir 18 hours. Pour the solution into dilute hydrochloric acid (30 mL of concentrated hydrochloric acid in 500 mL of water). Extract the solution with three 500-mL portions of ethyl acetate. Dry the combined organic phases over anhydrous magnesium sulfate and concentrate to give the title compound (6.4 g, 95%).
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:32])=[C:7]2[C:12](=[C:13]([C:15]#[N:16])[N:14]=1)[N:11]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:10](=[O:24])[C:9]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[CH:8]2)=[O:4].[NH2:33][CH2:34][C:35]([OH:37])=[O:36].C[O-].[Na+]>>[CH2:17]([N:11]1[C:12]2[C:7](=[C:6]([OH:32])[C:5]([C:3]([NH:33][CH2:34][C:35]([OH:37])=[O:36])=[O:4])=[N:14][C:13]=2[C:15]#[N:16])[CH:8]=[C:9]([CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:10]1=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: COC(=O)c1nc(C#N)c2c(cc(Cc3ccccc3)c(=O)n2Cc2ccccc2)c1O
Reactant: NCC(=O)O
Agent: C[O-]
Agent: [Na+]
Product: N#Cc1nc(C(=O)NCC(=O)O)c(O)c2cc(Cc3ccccc3)c(=O)n(Cc3ccccc3)c12
Temperature: 25 °C
Yield: 93.2 %

Procedure:
A mixture of 1,3-dibenzyl-8-cyano-5-hydroxy-2-oxo-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (30 mg, 0.071 mmol), glycine (2.82 g, 37.6 mmol) and NaOMe solution (56 mL, 28.2 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was dissolved in saturated NaHCO3 and washed with ether. The aqueous layer was acidified to pH 2 with 4M HCl, and the resulting mixture was extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated to give 31 mg of the title compound. MS: (−) m/z 467.10 (M−1).
Reaction SMILES: [CH:1]1[C:2]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[CH2:9][O:8][C:3]=2[NH:4][C:5](=[O:7])[CH:6]=1.[Cl:16]Cl>C(O)(=O)C>[Cl:16][C:6]1[C:5](=[O:7])[NH:4][C:3]2[O:8][CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[C:2]=2[CH:1]=1
Reactant: O=c1ccc2c([nH]1)OCc1ccccc1-2
Reactant: ClCl
Solvent: CC(=O)O
Product: O=c1[nH]c2c(cc1Cl)-c1ccccc1CO2

Procedure:
Add 19.7 gm of 4,6-dihydro-3H[2]benzopyrano-[3,4-b]pyridin-3-one to 300 ml of acetic acid. Bubble chlorine into the reaction solution for 4 hours at 100°. Cool the system and collect the product as a precipitate. Dissolve the solid into water and neutralize the solution with 1N NaOH. Extract the product with chloroform. Dry the chloroform over anhydrous magnesium sulfate and filter the solution. Remove the solvent by stripping to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:36])=[C:14]([C:31](OCC)=[O:32])[C:15](=[O:30])[N:16]3[CH2:19][CH2:20][CH2:21][N:22]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][C:23]3=[O:29])=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[NH2:37][CH2:38][CH2:39][CH2:40][N:41]1[CH2:45][CH2:44][CH2:43][C:42]1=[O:46]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:36])=[C:14]([C:31]([NH:37][CH2:38][CH2:39][CH2:40][N:41]4[CH2:45][CH2:44][CH2:43][C:42]4=[O:46])=[O:32])[C:15](=[O:30])[N:16]3[CH2:19][CH2:20][CH2:21][N:22]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][C:23]3=[O:29])=[N:11][CH:10]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCN2CCCCCC2=O)c1=O
Reactant: NCCCN1CCCC1=O
Product: O=C(NCCCN1CCCC1=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCN2CCCCCC2=O)c1=O

Procedure:
This compound was prepared from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1-[3-(2-oxohexahydro-1H-azepin-1-yl)propyl]-1,2-dihydro-1,5-naphthyridine-3-carboxylate and 1-(3-aminopropyl)-2-pyrrolidinone using methods similar to Example 563 to provide an off-white solid: 1H NMR (300 MHz, DMSO-d6) δ ppm 1.54 (d, J=3.58 Hz, 4 H), 1.59-1.65 (m, 2 H), 1.65-1.81 (m, 4 H), 1.84-1.97 (m, 2 H), 2.21 (t, J=8.21 Hz, 2 H), 2.35-2.47 (m, 2 H), 3.24 (t, J=6.74 Hz, 2 H), 3.35 (td, J=7.05, 2.95 Hz, 8 H), 4.15-4.25 (m, 4 H), 7.14 (t, J=8.95 Hz, 2 H), 7.31-7.54 (m, 2 H), 8.00 (s, 1 H), 8.56 (d, J=1.47 Hz, 1 H), 10.31 (t, J=5.90 Hz, 1 H), 17.15 (s, 1 H); ES+ MS: 592 (M+H+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH3:9].[CH3:10][O:11][CH2:12][O:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][C:15]=1[CH:22]([CH3:24])[CH3:23]>C(OCC)(=O)C>[CH3:10][O:11][CH2:12][O:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][C:2]2[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=2[CH3:9])=[CH:16][C:15]=1[CH:22]([CH3:24])[CH3:23]
Reactant: Cc1cc(O)ccc1Br
Reactant: COCOc1ccc(C=O)cc1C(C)C
Solvent: CCOC(C)=O
Product: COCOc1ccc(Cc2ccc(O)cc2C)cc1C(C)C

Procedure:
Intermediate 4-(4′-methoxymethoxy-3′-iso-propylbenzyl)-3-methyl-phenol was prepared from 4-bromo-3-methyl-phenol (J. Med. Chem. 1980, 12, 1350) and 4-methoxymethoxy-3-iso-propylbenzaldehyde according to the procedure described in G. Chiellini et al. Biorg. Med. Chem. Lett. 2000, 10, 2607 and transformed into the title compound by the procedure used for the synthesis of compound 7. 1H NMR (300 MHz, DMSO-d6): δ 9.04 (s, 1 H), 7.02-6.99 (d, J=8.7 Hz, 1 H), 6.92 (s, 1 H), 6.81-6.76 (m, 2 H), 6.67 (s, 2 H), 4.03 (d, J=10.5 Hz, 2 H), 3.76 (s, 2 H), 3.16-3.14 (m, 1 H), 2.19 (s, 3 H), 1.14-1.12 (d, J=6.9 Hz, 6 H); TLC conditions: Uniplate silica gel, 250 microns; Mobile phase=ethyl acetate; Rf=0.11;
Reaction SMILES: O[CH2:2][C:3]1[CH:17]=[CH:16][C:6]([O:7][CH2:8][CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5][CH:4]=1.[Cl-:18]>>[Cl:18][CH2:2][C:3]1[CH:17]=[CH:16][C:6]([O:7][CH2:8][CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5][CH:4]=1
Reactant: [Cl-]
Reactant: CCOC(=O)CCCOc1ccc(CO)cc1
Product: CCOC(=O)CCCOc1ccc(CCl)cc1

Procedure:
Ethyl 4-(4-(chloromethyl)phenoxy)butanoate 13i was prepared from 29b according to the protocol described for the compound 13h in Example 26 (Scheme 9). The title chloride 13i was isolated as colorless oil in 96% yield (1.25 g). 1H NMR (400 MHz, CDCl3): δ 1.24 (3H, t, J=7.2 Hz); 2.06 (2H, m); 2.18 (2H, t, J=7.2 Hz)); 4.00 (2H, t, J=6.4 Hz); 4.14 (2H, q, J=7.2 Hz); 4.54 (2H, s); 6.83 (1H, s); 6.86 (1H, s); 7.27 (1H, m); 7.29 (1H, s). MS (ESI): m/z=258.10 (M+H+).
Reaction SMILES: [SH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13].[CH3:15]I.O=O.[OH-].[Na+]>O.C(O)C>[CH3:15][S:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13]
Reactant: O=C(O)CCCCCCCCCCS
Reactant: CI
Agent: O=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CSCCCCCCCCCCC(=O)O
Yield: 58.7 %

Procedure:
Into a 3-neck round-bottom flask fitted with a condenser and an addition funnel were added 20 g of 11-mercaptoundecanoic acid, 13 g of methyl iodide and 200 mL of ethanol. A slow flow of nitrogen through the reactor was started to exclude oxygen because mercaptans can be converted into disulfides in the presence of air and strong alkali. A solution of 7.33 g of sodium hydroxide in 14.66 g of water was added dropwise to the reaction mixture via the addition funnel. Any unreacted methyl iodide, the ethanol and the water were removed using a rotovap. The residue was acidified using a mixture of concentrated hydrochloric acid and ice. After isolation the product was distilled. After a small amount of a low boiling fraction was collected, the crude product was collected at ~1 mm of Hg at 180° C. weighing 22.75 g. The crude product was distilled to yield 12.5 g of desired product representing 58.7% of theoretical based upon the weight of starting 11-mercaptoundecanoic acid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[CH:14]=O)[N:10]=[CH:9][CH:8]=[CH:7]2)([O-:3])=[O:2].[CH3:16][O:17][C:18]([CH:20]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:19]>C1(C)C=CC=CC=1>[CH3:16][O:17][C:18](=[O:19])/[CH:20]=[CH:14]/[C:13]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[N:10]2)=[CH:5][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1cc2ncccc2cc1[N+](=O)[O-]
Solvent: Cc1ccccc1
Product: COC(=O)/C=C/c1cc2ncccc2cc1[N+](=O)[O-]
Yield: 59.6 %

Procedure:
6-Nitroquinolin-7-carbaldehyde (920 mg; 4.55 mmol) in toluene (46 ml) and (methoxycarbonylmethylen)triphenylphosphoran (1.67 g; 5.0 mmol) were refluxed for 1 h. The title compound crystallised upon cooling and was filtered off. Recrystallisation from hot EtOAc (250 ml) gave pure title compound (700 mg). The mother liquor was purified via chromatography (SiO2; acetone/hexanes 30/70) to yield a further batch of pure title compound (300 mg). Total yield: 1 g; 85%.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:11]=[CH:12][C:13]([NH:17][CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[C:14]([CH:16]=1)[NH2:15].[N:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH:30]=O.OOS([O-])=O.[K+].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:11]=[CH:12][C:13]2[N:17]([CH:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[C:30]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][N:24]=3)=[N:15][C:14]=2[CH:16]=1
Reactant: O=Cc1ccccn1
Reactant: Nc1cc(-c2nc3ccccc3o2)ccc1NC1CCOCC1
Agent: O=C([O-])[O-]
Agent: O=S([O-])OO
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: c1ccc(-c2nc3cc(-c4nc5ccccc5o4)ccc3n2C2CCOCC2)nc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 70.4 %

Procedure:
5-(Benzoxazol-2-yl)-2-(tetrahydropyran-4-yl)aminoaniline (see Working Example 20-2) (0.15 g, 0.484 mmol) was dissolved in DMF (3 mL) and water (0.1 mL), 2-pyridinecarboxaldehyde (0.06 g, 0.561 mmol) was added followed by oxone (0.19 g, 0.310 mmol), and this was stirred at room temperature for 2.5 hours. Aqueous potassium carbonate solution (0.09 g/15 mL) was added to the reaction solution. This was extracted with chloroform, washed with water, and after drying over magnesium sulfate, this was concentrated and purified by silica gel column chromatography. The crystals obtained were washed with hexane and a small amount of ethyl acetate, and dried to yield the title compound (135 mg, 70.2% yield) as white crystals.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])/[CH:4]=[CH:5]/[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18][C:19](=[O:21])[CH3:20])[CH:7]=1>CO>[CH3:1][O:2][C:3](=[O:22])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18][C:19](=[O:21])[CH3:20])[CH:7]=1
Reactant: COC(=O)/C=C/c1cccc(OCCCCCOC(C)=O)c1
Solvent: CO
Product: COC(=O)CCc1cccc(OCCCCCOC(C)=O)c1
Yield: 97 %

Procedure:
Using the procedure of example 29, except that methanol was used as the solvent, (E)-3-[3-[[5-(acetyloxy)pentyl]oxy]phenyl]-2-propenoic acid methyl ester was hydrogenated giving 3-[[5-(acetyloxy)pentyl]oxy]benzenepropanoic acid methyl ester as a pale-yellow oil, in 97% yield.
Reaction SMILES: C(N(C[N:7]1[CH2:12][CH2:11][CH2:10][C:9](=[C:13](O)[C:14]2[CH:15]=[N:16][CH:17]=[C:18]([CH3:20])[CH:19]=2)C1=O)CC)C.[ClH:23]>CC(C)=O.C(O)(C)C>[ClH:23].[ClH:23].[CH3:20][C:18]1[CH:19]=[C:14]([C:13]2[CH2:9][CH2:10][CH2:11][CH2:12][N:7]=2)[CH:15]=[N:16][CH:17]=1
Reactant: CCN(CC)CN1CCCC(=C(O)c2cncc(C)c2)C1=O
Agent: Cl
Solvent: CC(C)O
Solvent: CC(C)=O
Product: Cc1cncc(C2=NCCCC2)c1
Temperature: 100 °C
Yield: 85 %

Procedure:
To a solution of diisopropylamine (4.4 mL, 31.4 mmol) in tetrahydrofuran (20 mL) at −78° C. was added a 2.5 M solution of n-butyllithium in hexanes (12 mL, 30 mmol). The solution was allowed to warm to rt over 30 min and was re-cooled to −78° C. A solution of 1-diethylaminomethyl-piperidin-2-one (3.87 g, 21.0 mmol) in tetrahydrofuran (10 mL) was added to the lithium diisopropylamide via syringe. The reaction mixture was maintained at −78° C. for 1 h and was treated with a solution of 5-methylnicotinic acid methyl ester (2.12 g, 14.0 mmol) in tetrahydrofuran (20 mL) via syringe. The reaction mixture was allowed to warm to rt and was maintained overnight. The reaction mixture was quenched with water (30 mL) and was extracted with ether (2×). The combined organic layers were dried over magnesium sulfate and concentrated in vacuo. The residue was purified by chromatography [1/0 to 1/1 ethyl acetate/(70/30/1 ethyl acetate/methanol/ammonium hydroxide)] to provide 560 mg (13%) of 1-diethylaminomethyl-3-[hydroxy-(5-methylpyridin-3-yl)methylene]piperidin-2-one. To a solution of the piperidin-2-one (550 mg, 1.8 mmol) in acetone (10 mL) was added conc. hydrochloric acid (2 L) and the reaction mixture was heated at 100° C. overnight. The reaction mixture was allowed to cool to rt, diluted with isopropyl alcohol, and allowed to stand at 0° C. The product was isolated by filtration, thus providing 400 mg (85%) of 5′-methyl-3,4,5,6-tetrahydro[2,3′]bipyridinyl dihydrochloride.
Reaction SMILES: [N+:1]([C:4]1[CH:35]=[CH:34][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:16][C@H:15](OS(C)(=O)=O)[CH2:14][C@H:13]2[CH2:22][N:23]2[C:27](=[O:28])[C:26]3=[CH:29][CH:30]=[CH:31][CH:32]=[C:25]3[C:24]2=[O:33])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:36]([O-:39])(=[S:38])[CH3:37].[K+]>CN(C)C=O>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:16][C@@H:15]([S:38][C:36](=[O:39])[CH3:37])[CH2:14][C@H:13]2[CH2:22][N:23]2[C:27](=[O:28])[C:26]3=[CH:29][CH:30]=[CH:31][CH:32]=[C:25]3[C:24]2=[O:33])=[O:11])=[CH:34][CH:35]=1)([O-:3])=[O:2]
Reactant: CS(=O)(=O)O[C@@H]1C[C@@H](CN2C(=O)c3ccccc3C2=O)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reactant: CC([O-])=S
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)S[C@H]1C[C@@H](CN2C(=O)c3ccccc3C2=O)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Temperature: 0 °C
Yield: 90.5 %

Procedure:
A solution of (2S,4R)-1-p-nitrobenzyloxycarbonyl-2-phthalimidomethyl-4-methanesulfonyloxypyrrolidine (10 g: 19.88 mmole) and potassium thioacetate (4.54 g: 2 eq.) in dimethylformamide (60 ml) is stirred at 60° C. for 3 hours. The reaction mixture is poured into ice water (200 ml) and filtered. The precipitate is dissolved in ethyl acetate, dried over magnesium sulfate, and concentrated in vacuo. The residue is purified by silica gel column chromatography (toluene: ethyl acetate) to give (2S,4S)-1-p-nitrobenzyloxycarbonyl-2-phthalimidomethyl-4-acetylthiopyrrolidine (8.7 g). Yield: 90%.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:12]=[C:11]2[C:6]([C:7]([NH:13][C:14]3[CH:27]=[CH:26][C:17]([C:18]([N:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)=[O:19])=[CH:16][CH:15]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.[Cl:30][C:31]1[CH:36]=[CH:35][C:34]([S:37](Cl)(=[O:39])=[O:38])=[CH:33][CH:32]=1>C(N(CC)CC)C>[Cl:30][C:31]1[CH:36]=[CH:35][C:34]([S:37]([N:23]2[CH2:24][CH2:25][N:20]([C:18](=[O:19])[C:17]3[CH:26]=[CH:27][C:14]([NH:13][C:7]4[C:6]5[C:11](=[CH:12][C:3]([C:2]([F:1])([F:28])[F:29])=[CH:4][CH:5]=5)[N:10]=[CH:9][CH:8]=4)=[CH:15][CH:16]=3)[CH2:21][CH2:22]2)(=[O:39])=[O:38])=[CH:33][CH:32]=1
Reactant: O=C(c1ccc(Nc2ccnc3cc(C(F)(F)F)ccc23)cc1)N1CCNCC1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Solvent: CCN(CC)CC
Product: O=C(c1ccc(Nc2ccnc3cc(C(F)(F)F)ccc23)cc1)N1CCN(S(=O)(=O)c2ccc(Cl)cc2)CC1
Yield: 77 %

Procedure:
In the manner given in Example 15, 4-[4-[[7-(trifluoromethyl)-4-quinolinyl]amino]benzoyl]piperazine is reacted with 4-chlorophenylsulfonyl chloride in the presence of triethylamine under nitrogen to give 1-[(4-chlorophenyl)sulfonyl]-4-[4-[[7-(trifluoromethyl)-4-quinolinyl]amino]benzoyl]piperazine of melting point 234°-236° C. in 77% yield.
Reaction SMILES: [CH2:1]([N:8]1[CH2:17][C:16]2[C:15](Cl)=[N:14][C:13](Cl)=[C:12]([C:20]#[N:21])[C:11]=2[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C>CO.ClCCl.[Pd]>[CH2:1]([N:8]1[CH2:17][C:16]2[CH:15]=[N:14][CH:13]=[C:12]([C:20]#[N:21])[C:11]=2[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1c(Cl)nc(Cl)c2c1CCN(Cc1ccccc1)C2
Agent: [Pd]
Solvent: CO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#Cc1cncc2c1CCN(Cc1ccccc1)C2
Yield: 88.4 %

Procedure:
A mixture of 7-benzyl-1,3-dichloro-5,6,7,8-tetrahydro-[2,7]-naphthyridine-4-carbonitrile (70 g, 0.22 mol) and triethylamine (70 mL) in methanol (1 L) was placed in a 2.5 L hydrogenation bottle and hydrogenated over 10% Pd/C (15 g) for 3 hr. The reaction mixture was filtered to remove catalyst. The catalyst on filter paper was washed with methanol (100 mL). The filtrate was concentrated under reduced pressure to give an oil. The oil was dissolved in dichloromethane (500 mL), washed with water (2×200 mL), brine (200 mL), dried over anhydrous magnesium sulfate (10 g), filtered and concentrated under reduced pressure to give an oil. The oil was placed under high vacuum line overnight to give the title compound (48.5 g, 88%). 1H NMR 60 MHz, (CDCl3), δ 8.5 (s, 1H), 8.3 (s, 1H), 7.3 (s, 5H), 3.7 (s, 2H), 3.6 (s, 2H), 2.8 (m, 4H).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1([O:13][CH3:14])[CH2:12][NH:11][CH2:10]1.C(=O)([O-])[O-].[K+].[K+].I[CH2:22][CH3:23].O>C(#N)C.C(OCC)(=O)C>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1([O:13][CH3:14])[CH2:12][N:11]([CH2:22][CH3:23])[CH2:10]1
Reactant: COC1(c2cccc(F)c2F)CNC1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC#N
Product: CCN1CC(OC)(c2cccc(F)c2F)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 63 %

Procedure:
A mixture of 3-(2,3-difluorophenyl)-3-methoxyazetidine (0.75 g, 4.05 mmol), potassium carbonate (0.99 g, 8.1 mmol) and iodoethane (0.388 ml, 4.05 mmol) in acetonitrile (25 ml) was stirred at ambient temperature for 1 h. Water (50 mL) and ethyl acetate (50 mL) was added, the organic phase was collected and the aqueous phase was extracted with ethyl acetate (2×50 ml). The combined organic phase was dried (Na2SO4), filtered and evaporated to dryness. The crude product was purified by flash column chromatography on silica gel (ethyl acetate/methanol 1:1) to give the title compound (0.58 g, 63%). The amine was converted to the oxalic acid salt and recrystallized from ethanol/diethyl ether/diisopropyl ether: M.p. 147-148° C. MS m/z (relative intensity, 70 eV) 227 (M+, 4), 170 (66), 169 (bp), 140 (63), 127 (39).