Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH:2]1[CH2:8][CH2:7][CH:6]=[CH:5][CH2:4][CH2:3]1.Cl[C:10]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][N:12]([CH3:18])[N:11]=1.[F-].[K+].O>CS(C)=O.CCN(C(C)C)C(C)C>[CH3:18][N:12]1[CH:13]=[C:14]([N+:15]([O-:17])=[O:16])[C:10]([N:2]2[CH2:8][CH2:7][CH:6]=[CH:5][CH2:4][CH2:3]2)=[N:11]1
Reactant: Cn1cc([N+](=O)[O-])c(Cl)n1
Reactant: C1=CCCNCC1
Agent: Cl
Agent: [F-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1cc([N+](=O)[O-])c(N2CCC=CCC2)n1
Temperature: 75 °C
Yield: 99186 %

Procedure:
To a solution of (Z)-2,3,6,7-tetrahydro-1H-azepine hydrochloride (32.3 g, 0.24 mmol) in DMSO (650 mL) was added 3-chloro-1-methyl-4-nitro-1H-pyrazole (37.2 g, 0.23 mmol) followed by DIPEA (64 mL, 0.36 mmol) and potassium fluoride (56.2 g, 0.96 mmol). The reaction mixture was heated at 75° C. for 25 hr before being cooled to room temperature, poured into water (1.5 L) and extracted with EtOAc (4×500 mL). The combined organic layers were washed with water (400 mL) and brine (300 mL), separated, dried over MgSO4 and concentrated under reduced pressure to give (Z)-1-(1-methyl-4-nitro-1H-pyrazol-3-yl)-2,3,6,7-tetrahydro-1H-azepine as a light brown solid (50.7 g). To a solution of this solid (1.80 g, 8.1 mmol) in ethanol (80 mL) and water (8 mL) was added ammonium chloride (2.15 g, 40.1 mmol) and iron powder (1.77 g, 31.8 mmol). The reaction mixture was heated at 80° C. for 1.5 hr, before being cooled to room temperature, filtered through Celite® and concentrated under reduced pressure. The residue was dissolved in DCM (200 mL) and washed with water (200 mL). The aqueous layer was extracted with DCM (100 mL) and the combined organic layers were dried over MgSO4 and concentrated under reduced pressure to give (Z)-1-methyl-3-(2,3,6,7-tetrahydro-1H-azepin-1-yl)-1H-pyrazol-4-amine as a brown oil (1.36 g, 87%). A solution of HATU (3.22 g, 8.47 mmol), 5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)-thiazole-4-carboxylic acid (2.52 g, 7.07 mmol), (Z)-1-methyl-3-(2,3,6,7-tetrahydro-1H-azepin-1-yl)-1H-pyrazol-4-amine (1.36 g, 7.07 mmol) and DIPEA (2.48 mL, 14.2 mmol) in DMF (30 mL) was stirred at room temperature for 18 hr. The reaction mixture was diluted with DCM (50 mL) and washed with water (100 mL). The organic layer was passed through a phase separation cartridge and concentrated under reduced pressure. Purification of the residue via silica gel column chromatography (5-80% 10% MeOH in DCM/DCM) gave (Z)-tert-butyl 2-(2,6-difluorophenyl)-4-(1-methyl-5-(2,3,6,7-tetrahydro-1H-azepin-1-yl)-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamate as a brown solid (2.71 g, 72% over two steps). 1H NMR (400 MHz, CDCl3) δ 10.39 (s, 1H), 8.82 (s, 1H), 7.85 (s, 1H), 7.40-7.30 (m, 1H), 7.08-6.99 (m, 2H), 5.93-5.84 (m, 2H), 3.77 (s, 3H), 3.19 (t, J=5.1 Hz, 4H), 2.42-2.37 (m, 4H), 1.58-1.48 (m, 9H).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.[CH3:25][C:26]1[CH:27]=[CH:28][C:29](B2OC(C)(C)C(C)(C)O2)=[C:30]2[C:34]=1[NH:33][CH:32]=[CH:31]2.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.O>[CH3:25][C:26]1[CH:27]=[CH:28][C:29]([C:2]2[N:3]=[C:4]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[C:5]3[S:10][C:9]([CH2:11][N:12]4[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]4)=[CH:8][C:6]=3[N:7]=2)=[C:30]2[C:34]=1[NH:33][CH:32]=[CH:31]2
Reactant: CN1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Reactant: Cc1ccc(B2OC(C)(C)C(C)(C)O2)c2cc[nH]c12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: Cc1ccc(-c2nc(N3CCOCC3)c3sc(CN4CCN(C)CC4)cc3n2)c2cc[nH]c12
Temperature: 130 °C
Yield: 70.5 %

Procedure:
To a mixture of 2-Chloro-6-(4-methyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (0.23 mmol, 84 mg) and 7-Methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indole (0.46 mmol, 117 mg) in toluene (2 mL), ethanol (1 mL) and water (0.5 mL) was added sodium carbonate (0.69 mmol, 73 mg). Pd (PPh3)2Cl2 (0.012 mmol, 8 mg) was added and the mixture heated in a microwave reactor at 130° C. for 1.5 hours. The mixture was allowed to cool and partitioned between water and dichloromethane. The combined organic layers were washed with brine, separated and dried (MgSO4). The solvent was evaporated and the crude product purified by column chromatography to yield 2-(7-methyl-1H-indol-4-yl)-6-(4-methyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine as a pale cream solid (75 mg).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[C:14]([CH3:23])=[N:15][C:16]4[C:21]([CH:22]=3)=[CH:20][CH:19]=[CH:18][N:17]=4)=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:24][CH3:25].C(=O)([O-])[O-].[K+].[K+].Br[CH2:33][CH2:34][CH2:35][CH2:36][OH:37]>CN(C)C=O>[CH3:25][O:24][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:2]=1[O:1][CH2:33][CH2:34][CH2:35][CH2:36][OH:37])[N:9]=[CH:8][CH:7]=[C:6]2[O:12][C:13]1[C:14]([CH3:23])=[N:15][C:16]2[C:21]([CH:22]=1)=[CH:20][CH:19]=[CH:18][N:17]=2
Reactant: OCCCCBr
Reactant: COc1cc2c(Oc3cc4cccnc4nc3C)ccnc2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3cc4cccnc4nc3C)ccnc2cc1OCCCCO
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.7 %

Procedure:
3-[7-Hydroxy-6-methoxy-quinolin-4-yloxy]-2-methyl-[1,8]naphthyridine (45 mg) was dissolved in N,N-dimethylformamide (2 ml) to prepare a solution. Potassium carbonate (56 mg) and 4-bromo-1-butanol (62 mg) were added to the solution, and the mixture was stirred at room temperature overnight. The solvent was removed by distillation under the reduced pressure. Water was then added to the residue, and the mixture was extracted with chloroform. The chloroform layer was washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-acetone to give the title compound (19 mg, yield 35%).
Reaction SMILES: [H-].[Li+].[CH2:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)[CH3:4].[CH2:12]1[CH2:16]O[CH2:14][CH2:13]1>>[CH2:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:14][CH2:13][CH2:12][C:16]2[CH:7]=[CH:6][CH:5]=[CH:3][CH:4]=2)=[CH:7][CH:6]=1)[CH3:4]
Reactant: CCc1ccc(O)cc1
Reactant: C1CCOC1
Agent: [H-]
Agent: [Li+]
Product: CCc1ccc(OCCCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93 %

Procedure:
To a suspension of LiH (0.005 g, 0.6 mmol) in THF was added p-ethyl phenol (0.08 g, 0.68 mmol) very slowly at 0° C. After 30 min of stirring at room temperature, the sulfonate ester, 2a (0.075 g, 0.17 mmol) was added to it and the reaction mixture was heated at 65° C. for 8 h. The reaction mixture was washed very carefully with cold water and extracted in EtOAc and dried over sodium sulfate. The organic layer was evaporated and the crude gummy material was purified by flash chromatography giving 0.038 g (93%) of an oil. 1H NMR (400 MHz, CDCl3) δ 7.31-7.18 (m, 5H), 7.13-7.09 (m, 2H), 6.85-6.81 (m, 2H), 3.94 (t, J=6.2 Hz, 2H), 2.84 (t, J=7.6 Hz, 2H), 2.58 (q, J=7.5, 2H), 2.13-2.03 (m, 2H), 1.21 (t, J=7.5 Hz, 3H); 13CNMR (100.75 MHz, CDCl3) 141.8, 130.6, 128.9, 128.7, 128.6, 126.1, 114.6, 67.1, 32.4, 31.1, 28.2, 16.1; HRMS (EI) [M]+: calcd for C17H20O 240.1514, found 240.1510.
Reaction SMILES: C(O)CCCCCCC#C.[CH2:11]([OH:26])[C:12]#[C:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].NCCCN>>[CH2:11]([OH:26])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]#[CH:25]
Reactant: CCCCCCCCCCCCC#CCO
Agent: C#CCCCCCCCO
Agent: NCCCN
Product: C#CCCCCCCCCCCCCCO

Procedure:
The same procedure for 8-nonyn-1-ol was followed with 2- pentadecyn-1-ol (4.51 g, 20.1 mmol), KH (2.38 g, 59.4 mmol), and 1,3-diaminopropane (65 mL). This produced 3.18 g of white solid (70%): mp 42-44° C. IR (thin film( ν 3430, 2926, 2252 cm−1: 1H—NMR δ4.30 (t, 1H, J=5.0 Hz), 3.64 (t, 2H, J=6.6 Hz), 2.18 (td, 2H, J=2.6 Hz, 6.6 Hz), 1.94 (t, 1H, J=2.6 Hz), 1.49-1.26 (bm, 22H); 13C—NMR δ 84.8, 68.0, 63.1, 32.8, 29.6, (2C), 29.5 (2C), 29.4, 28.9, 28.5, 28.7, 28.0, 25.7, 18.4; MS m/z 231.53 (M++Li). Anal. Calcd for C15H28O: C, 80.29; H, 12.58. Found: C, 18.20; H, 12.50.
Reaction SMILES: [CH2:1]([NH2:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[OH-].[Na+].[C:10](=[S:12])=[S:11].[CH3:13]I>O>[CH2:1]([NH:7][C:10](=[S:12])[S:11][CH3:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: S=C=S
Reactant: CCCCCCN
Reactant: CI
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCCCCNC(=S)SC
Reaction time: 2 h
Yield: 89.3 %

Procedure:
Water (500 ml.) was added to hexylamine (490.0 g.) and a solution of sodium hydroxide (193.6 g.) in water (700 ml.) was added thereto under ice-cooling and stirring. Carbon disulfide (367.8 g.) was added dropwise thereto over 2 hours at 2° to 10° C. and then methyl iodide (687.3 g.) was added dropwise thereto over 1 hour at 0° to 5° C. The resulting mixture was stirred for 30 minutes at the same temperature and for 2 hours at ambient temperature. The reaction mixture was extracted with diethyl ether (1.5 l.). The extract was washed with a saturated aqueous solution of sodium chloride (300 ml.), dried over magnesium sulfate and concentrated to give an oil of methyl N-hexyldithiocarbamate (825.5 g.).
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[O:14]CC=C)[NH:10][C:9](=[O:18])[CH2:8][CH2:7]2)[CH:2]=[CH2:3].[CH2:19]([C:22]1[C:23](OCC=C)=[CH:24][CH:25]=[C:26]2[C:31]=1NC(=O)CC2)[CH:20]=[CH2:21].[H-].[Na+].[CH2:39](Br)[CH:40]=[CH:41]C1C=CC=CC=1>CN(C)C=O.C1C2C(=CC=CC=2)CCC1>[CH2:1]([C:4]1[CH:5]=[C:6]2[C:11](=[C:12]([CH2:41][CH:40]=[CH2:39])[C:13]=1[OH:14])[N:10]([CH2:21][CH:20]=[CH:19][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:31]=1)[C:9](=[O:18])[CH2:8][CH2:7]2)[CH:2]=[CH2:3]
Reactant: C=CCOc1ccc2c(c1CC=C)NC(=O)CC2
Reactant: BrCC=Cc1ccccc1
Reactant: C=CCOc1cc2c(cc1CC=C)CCC(=O)N2
Agent: [H-]
Agent: [Na+]
Solvent: c1ccc2c(c1)CCCC2
Solvent: CN(C)C=O
Product: C=CCc1cc2c(c(CC=C)c1O)N(CC=Cc1ccccc1)C(=O)CC2
Reaction time: 3 h
Yield: 33.4 %

Procedure:
2.4 Grams of the mixture of 6-allyl-7-allyloxy-3,4-dihydro-2(1H)-quinolinone and 6-allyl-7-allyloxy-3,4-dihydro-2(1H)-quinolinone as the reaction intermediate obtained in Example 14 was dissolved in 20 ml of dimethylformamide, then 0.6 g of 60% oily sodium hydride and 2.5 g of cinnamyl bromide were added thereto at room temperature and reacted similarly as in Reference example 7, there was obtained yellow oily product by treating thus obtained reaction mixture. Said oily product was dissolved in 50 ml of tetralin and stirred at 200° to 230° C. for 3 hours. After cooling, the reaction mixture was subjected to purification by passing through a silica gel column, there was obtained 1.2 g (33.4%) of 6,8-diallyl-1-cinnamyl-3,4-dihydro-7-hydroxy-2(1H)-quinolinone. Pale yellow flake crystals (recrystallized from isopropyl ether). Melting point: 132°-138° C.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([O:17][CH3:18])[CH:12]=3)=[CH:9][N:10]=2)[N:7]=1.[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][CH:29]([NH2:32])[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20]>>[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][CH:29]([NH:32][C:2]2[CH:3]=[CH:4][C:5]3[N:6]([C:8]([C:11]4[CH:16]=[CH:15][N:14]=[C:13]([O:17][CH3:18])[CH:12]=4)=[CH:9][N:10]=3)[N:7]=2)[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: COc1cc(-c2cnc3ccc(Cl)nn23)ccn1
Product: COc1cc(-c2cnc3ccc(NC4CCN(C(=O)OC(C)(C)C)CC4)nn23)ccn1
Yield: 59.8 %

Procedure:
292 mg of 4-[3-(2-methoxypyridin-4-yl)imidazo[1,2-b]pyridazin-6-ylamino]piperidine-1-carboxylic acid tert-butyl ester were prepared from 300 mg (1.15 mmol) of 6-chloro-3-(2-methoxypyridin-4-yl)imidazo[1,2-b]pyridazine (Example 1.14) and 230 mg (1.15 mmol) of 4-aminopiperidine-1-carboxylic acid tert-butyl ester (CAS No. 87120-72-7) by method A.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]=[C:4]2[N:9]([CH3:12])[N:10]=[CH:11][C:3]=12.[CH3:13][O:14][C:15]1[N:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1.CC([O-])=O.[K+]>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[C:6]([C:18]2[CH:19]=[N:20][C:15]([O:14][CH3:13])=[CH:16][CH:17]=2)[N:5]=[C:4]2[N:9]([CH3:12])[N:10]=[CH:11][C:3]=12
Reactant: Cn1ncc2c(Cl)cc(Cl)nc21
Reactant: COc1ccc(B(O)O)cn1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COc1ccc(-c2cc(Cl)c3cnn(C)c3n2)cn1
Temperature: 120 °C
Yield: 44.5 %

Procedure:
4,6-Dichloro-1-methyl-1H-pyrazolo[3,4-b]pyridine 5 (0.5 g, 4.9 mmol) was dissolved in 1,4-dioxane (8 mL) and 6-methoxypyridin-3-ylboronic acid (0.4 g) and 1 M KOAc (8 mL) were added in a microwave tube. Nitrogen was bubbled through the solution for 1 minute. 1,1′-Bis(diphenylphosphino)ferrocenepalladium (II) chloride (1.2 g) was added and the resultant mixture was heated by microwave at 120° C. for 5 minutes. The reaction mixture was concentrated in vacuo and purified by flash chromatography (30% EtOAc in hexane) to provide 4-chloro-6-(6-methoxypyridin-3-yl)-1-methyl-1H-pyrazolo[3,4-b]pyridine (0.32 g).
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]([NH:12][OH:13])=[NH:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[C:14]([CH:18]1[CH2:23][CH2:22][CH:21]([C:24]([Cl:26])=O)[CH2:20][CH2:19]1)([CH3:17])([CH3:16])[CH3:15]>>[ClH:26].[CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]2[N:11]=[C:24]([CH:21]3[CH2:22][CH2:23][CH:18]([C:14]([CH3:15])([CH3:17])[CH3:16])[CH2:19][CH2:20]3)[O:13][N:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)N1CCC(C(=N)NO)CC1
Reactant: CC(C)(C)C1CCC(C(=O)Cl)CC1
Product: CC(C)N1CCC(c2noc(C3CCC(C(C)(C)C)CC3)n2)CC1
Product: Cl

Procedure:
The title compound was prepared by a similar procedure to that described in Example 56, starting from 1-isopropyl-N-hydroxypiperidine-4-carboxamidine and 4-tert-butylcyclohexanecarbonyl chloride.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[C:9]([O:16][CH2:17][CH3:18])=[N:10][N:11]2[CH:15]=[CH:14][S:13][C:12]=12)([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.[Br:25]C(F)(F)C(F)(F)Br.[Cl-].[NH4+]>C(O)(=O)C.CCCCCC.C1COCC1>[C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[C:9]([O:16][CH2:17][CH3:18])=[N:10][N:11]2[C:15]([Br:25])=[CH:14][S:13][C:12]=12)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOc1nn2ccsc2c1NC(=O)OC(C)(C)C
Reactant: FC(F)(Br)C(F)(F)Br
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CCCCCC
Product: CCOc1nn2c(Br)csc2c1NC(=O)OC(C)(C)C
Temperature: -78 °C
Yield: 62.3 %

Procedure:
To a THF (150 mL) solution of (6-ethoxy-pyrazolo[5,1-b][1,3]thiazol-7-yl)-carbamic acid tert-butyl ester (16.5 g, 61.4 mmol), was added a 2.77M n-hexane solution of n-butyllithium (15.9 mL, 44 mmol) while stirring at −78° C. The mixture was stirred at −78° C. for one hour, and then 1,2-dibromotetrafluoroethane (2.61 mL, 22 mmol) was added, and the mixture was stirred while heating to room temperature for three hours. A saturated aqueous solution of ammonium chloride was added and acetic acid was added, and the mixture was extracted with ethyl acetate and washed with brine, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by medium pressure silica gel column chromatography (n-heptane/ethyl acetate: 0% then 30%) to obtain 4.95 g (13.7 mmol) of the title compound.
Reaction SMILES: N1C=CC=CC=1.[CH:7]1([CH:10]([C:12]2[CH:13]=[N:14][CH:15]=[N:16][CH:17]=2)[OH:11])[CH2:9][CH2:8]1.CCOCC>ClCCl.[O-2].[Cr+6].[O-2].[O-2]>[N:14]1[CH:13]=[C:12]([C:10]([CH:7]2[CH2:8][CH2:9]2)=[O:11])[CH:17]=[N:16][CH:15]=1
Reactant: OC(c1cncnc1)C1CC1
Agent: [Cr+6]
Agent: [O-2]
Solvent: ClCCl
Solvent: CCOCC
Solvent: c1ccncc1
Product: O=C(c1cncnc1)C1CC1
Reaction time: 2 h

Procedure:
To a suspension of chromium (VI) oxide (42.4 g, 0.41 mol) in dry dichloromethane (1000 ml) was added dry pyridine (66 ml, 0.825 mol) and the mixture was stirred for half an hour. A solution of the product of Stage 1 (10 g, 66 mmol) in dry dichloromethane (125 ml) was then added dropwise with stirring. After 2 hours, the reaction mixture was poured into ether and filtered. The filtrate was washed with copper sulphate solution, and brine and then dried over magnesiums sulphate before removing the solvent. Flash chromatography gave the product as a pale yellow oil.
Reaction SMILES: ClC1C=C(C=CC=1)C(O)=[O:6].[F:11][C:12]1[C:17]([CH:18]([CH3:20])[CH3:19])=[CH:16][C:15]([C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][C:22]=2[CH2:31][N:32]2[C@@H:36]([CH3:37])[C@@H:35]([C:38]3[CH:43]=[CH:42][N:41]=[CH:40][CH:39]=3)[O:34][C:33]2=[O:44])=[C:14]([O:45][CH3:46])[CH:13]=1>C(Cl)Cl>[F:11][C:12]1[C:17]([CH:18]([CH3:19])[CH3:20])=[CH:16][C:15]([C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:28])[F:29])=[CH:23][C:22]=2[CH2:31][N:32]2[C@@H:36]([CH3:37])[C@@H:35]([C:38]3[CH:43]=[CH:42][N+:41]([O-:6])=[CH:40][CH:39]=3)[O:34][C:33]2=[O:44])=[C:14]([O:45][CH3:46])[CH:13]=1
Reactant: O=C(O)c1cccc(Cl)c1
Reactant: COc1cc(F)c(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN1C(=O)O[C@H](c2ccncc2)[C@@H]1C
Solvent: ClCCl
Product: COc1cc(F)c(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN1C(=O)O[C@H](c2cc[n+]([O-])cc2)[C@@H]1C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
m-Chlorobenzoic acid (77%, 47.9 mg, 0.214 mmol) was added to a solution of (4S,5R)-3-{[4′-fluoro-5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-5-pyridin-4-yl-1,3-oxazolidin-2-one (53.7, 0.107 mmol) in dry CH2Cl2 (10.8 mL) at 0° C. After 15 min at 0° C., the reaction was stirred at room temperature for 3 h. The reaction was diluted with CH2Cl2 (40 mL) and washed with saturated Na2SO3 (20 mL) and saturated K2CO3 (2×20 mL). The organic layer was dried (Na2SO4) and concentrated in vacuo to afford (4S,5R)-3-{[4′-fluoro-5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-5-(1-oxidopyridin-4-yl)-1,3-oxazolidin-2-one as an oil. LCMS calc.=519.2; found=519.3 (M+1)+.
Reaction SMILES: [Al:1].N[CH2:3][C:4]([OH:6])=[O:5].C([N+]([O-])=[O:10])C>>[C:4]([O-:6])(=[O+:5][O-:10])[CH3:3].[Al+3:1].[C:4]([O-:6])(=[O+:5][O-:10])[CH3:3].[C:4]([O-:6])(=[O+:5][O-:10])[CH3:3]
Reactant: [Al]
Reactant: NCC(=O)O
Reactant: CC[N+](=O)[O-]
Product: CC([O-])=[O+][O-]
Product: [Al+3]
Temperature: 98.88888888888889 °C

Procedure:
95.1 g of lemon-flavored hard candy stock was placed in an aluminum pan and heated at 210° F. to a mobile syrup. To this hot stock was added 4.90 g of a dry, finely-ground mixture containing 0.99 g of Al2O(CH3CO2)4.4H2O and 3.91 g of anhydrous glycine, C2H5NO2. The dry component was evenly distributed in the melted stock by thorough mixing and the product was poured onto a greased aluminum pan, forming a circular mass approximately 4 mm thick. As it cooled toward room temperature, it was scored with a lightly greased knife into pieces approximately 1.5 cm square. On cooling to room temperature, the squares were easily broken out of the mass. The yield was 32 pieces with an average weight of 2.5 g. The aluminum content was 1.40 mg per gram and glycine content was 39.1 mg per gram. The molar ratio of glycine to aluminum was 10 to 1. The flavor was very pleasant, without unpleasant aftertaste, but with a moderately astringent and persistant mouth-feel.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([C:8](=O)[CH2:9][N:10]2[CH2:14][CH2:13][CH2:12][CH:11]2[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][CH2:23][CH2:24][N:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[CH:16]=2)[CH:5]=[CH:6][CH:7]=1.N>CO.C(Cl)Cl>[I:1][C:2]1[CH:3]=[C:4]([C@H:8]2[C:20]3[C:15](=[CH:16][C:17]([O:21][CH2:22][CH2:23][CH2:24][N:25]4[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]4)=[CH:18][CH:19]=3)[C@@H:11]3[CH2:12][CH2:13][CH2:14][N:10]3[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(CN1CCCC1c1cccc(OCCCN2CCCCC2)c1)c1cccc(I)c1
Agent: N
Solvent: CO
Solvent: ClCCl
Product: Ic1cccc([C@@H]2CN3CCC[C@H]3c3cc(OCCCN4CCCCC4)ccc32)c1
Yield: 54 %

Procedure:
1-(3-Iodo-phenyl)-2-{2-[3-(3-piperidin-1-yl-propoxy)-phenyl]-pyrrolidin-1-yl}-ethanone. Prepared as described in Example 8, Step 1, on a 3.46 mmol scale, to give 1.0 g (54%) of the desired product as an orange semi-solid after chromatography (NH3 in MeOH/CH2Cl2). MS: exact mass calcd for C26H33IN2O2, 532.2; m/z found, 533.4 [M+H]+. 1H NMR (CDCl3): 8.20 (m, 1H), 7.82 (m, 2H), 7.24 (t, J=7.9, 1H), 7.12 (t, J=7.9, 1H), 6.97 (d, J=7.6, 1H), 6.93 (m, 1H), 6.78 (m, 1H), 3.97 (m, 2H), 3.42 (t, J=8.7, 1H), 3.35 (m, 2H), 2.61 (m, 6H), 2.34 (m, 1H), 2.18 (m, 1H), 2.05 (m, 4H), 1.85 (m, 2H), 1.68 (m, 4h), 1.48 (m, 2H).
Reaction SMILES: Cl.[C:2]([OH:10])(=O)[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC.[NH2:32][C:33]1[S:34][CH:35]=[C:36]([C:38]2[C:43]([CH3:44])=[CH:42][C:41]([OH:45])=[CH:40][C:39]=2[CH3:46])[N:37]=1>CN(C=O)C>[OH:45][C:41]1[CH:40]=[C:39]([CH3:46])[C:38]([C:36]2[N:37]=[C:33]([NH:32][C:2](=[O:10])[C:3]3[CH:4]=[CH:5][N:6]=[CH:7][CH:8]=3)[S:34][CH:35]=2)=[C:43]([CH3:44])[CH:42]=1
Reactant: Cc1cc(O)cc(C)c1-c1csc(N)n1
Reactant: O=C(O)c1ccncc1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: Cc1cc(O)cc(C)c1-c1csc(NC(=O)c2ccncc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64 %

Procedure:
To a suspension of isonicotinic acid hydrochloride (1.48 g, 10.0 mmol, 1.2 equiv) in DMF was added EDC (3.90 g, 2.0 equiv), HOBt (2.7 g, 2.0 equiv) and NEt3 (3.03 g, 3.0 equiv). After being stirred at room temperature for 1.0 h, the solution was added with 4-(2-aminothiazol-4-yl)-3,5-dimethylphenol (5-2, 2.2 g, 1.0 equiv). The reaction mixture was stirred at room temperature overnight. The solution was concentrated and the residue was re-dissolved in EtOAc. The solution was washed with brine, dried over MgSO4, and concentrated under reduced pressure to give brown solid. The brown solid was washed with 50% EtOAc in hexanes to give 5-3 (2.08 g) as white solids in 64% yield: 1H NMR (500 MHz, CDCl3) δ 9.29 (s, 1 H), 8.80 (d, 2 H), 7.98 (d, 2 H), 7.06 (s, 1 H), 6.51 (s, 2 H), 2.01 (s, 6H).
Reaction SMILES: [F-:1].[K+].[F:3][C:4]([F:12])([F:11])[C:5]([O:7][CH2:8][CH2:9]Cl)=[O:6].[F:13][C:14]([F:18])=[C:15]([F:17])[F:16].[OH-].[Na+]>CS(C)=O>[F:3][C:4]([F:12])([F:11])[C:5]1([C:15]([F:17])([F:16])[C:14]([F:1])([F:18])[F:13])[O:7][CH2:8][CH2:9][O:6]1
Reactant: O=C(OCCCl)C(F)(F)F
Reactant: FC(F)=C(F)F
Reactant: [F-]
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: FC(F)(F)C(F)(F)C1(C(F)(F)F)OCCO1
Reaction time: 18 h
Yield: 47.4 %

Procedure:
A mixture of 29.1 g (0.50 mol) of dry potassium fluoride, 88.3 g (0.50 mol) of 2-chloroethyl trifluoroacetate, 150 mL of dimethylsulfoxide, and 50 g (0.50 mol) of tetrafluoroethylene was shaken in a 400-mL metal tube at 75° for 18 h. Volatile products were transferred from the reaction mixture held at 43° (1.2 mm). These volatiles were stirred with 500 mL of 10% aqueous NaOH to remove unreacted ester and a small amount of dimethylsulfoxide, then fractionated to afford 61.6 g (47%) of 2-trifluoromethyl-2-pentafluoroethyl-1,3-dioxolane, b.p. 118°-120°. IR (CCl4) and NMR (CCl4) spectra for the product were consistent with the assigned structure. Anal.: Calcd. for C6H4F8O2 : C, 27.71; H, 1.55; F, 58.44. Found: C, 27.57; H, 1.65; F, 58 40.
Reaction SMILES: CO.[O:3]1CCO[CH:4]1[C:8]1[CH:21]=[CH:20][C:11]([CH2:12][NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:10][CH:9]=1.Cl.C(=O)([O-])O.[Na+]>O1CCCC1>[C:14]1([NH:13][CH2:12][C:11]2[CH:10]=[CH:9][C:8]([CH:4]=[O:3])=[CH:21][CH:20]=2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: c1ccc(NCc2ccc(C3OCCO3)cc2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: O=Cc1ccc(CNc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 101.6 %

Procedure:
To a mixture solution of methanol and tetrahydrofuran (1:1, 20 mL) of (4-[1,3] dioxolane-2-yl-benzyl)-phenyl-amine (4.16 g, 16.3 mmol) described in Manufacturing Example 73-1-2 was added 5N hydrochloric acid (20 mL). This mixture was stirred for 1 hour at room temperature. This mixture was neutralized with saturated aqueous sodium hydrogencarbonate solution, and extracted with ethyl acetate. The organic layer was separated, washed with water, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure to obtain the title compound (3.5 g). This compound was used in the subsequent reaction without being purified.