Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.ClC1C=CC=CC=1.Cl[C:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[S:17][N:16]=1>C(O)CO>[N:1]1([C:15]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[S:17][N:16]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1
Reactant: C1CNCCN1
Reactant: Clc1nsc2ccccc12
Solvent: OCCO
Solvent: Clc1ccccc1
Product: c1ccc2c(N3CCNCC3)nsc2c1
Yield: 92.3 %

Procedure:
215.4 g (2.50 mol) of piperazine, 50.0 g of chlorobenzene, 100.0 g of ethylene glycol were placed in a four-neck 1000 ml flask equipped with a stirrer, a thermometer, a dropping funnel and a condenser, 169.5 g (1.00 mol) of 3-chloro-1,2-benzisothiazole was added dropwise in the melted state at about 120° C. over 1 hour while stirring, which was thereafter stirred for 2 hours to complete the reaction. After excess piperazine was removed with water, the reaction mixture was made acidic with hydrochloric acid, extracted into an aqueous layer, which was made alkaline with aqueous sodium hydroxide to obtain 202.4 g (m.p. 89-90° C.) of 3-(1-piperazinyl)-1,2-benzisothiazole as crystals. Yield from 3-chloro-1,2-benzisothiazole was 92.4%.
Reaction SMILES: C[Si](C)(C)[O:3][C:4](O)(O)[CH2:5][CH2:6]O[Si](C)(C)C.[Br:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[CH2:23][C:22](=[O:27])[CH2:21][CH2:20]2.C(OCC)C>C(Cl)Cl.FC(F)(F)S(O[Si](C)(C)C)(=O)=O>[CH2:4]1[O:3][C:22]2([CH2:21][CH2:20][C:19]3[C:24](=[CH:25][CH:26]=[C:17]([Br:16])[CH:18]=3)[CH2:23]2)[O:27][CH:5]1[CH3:6]
Reactant: O=C1CCc2cc(Br)ccc2C1
Reactant: C[Si](C)(C)OCCC(O)(O)O[Si](C)(C)C
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: CC1COC2(CCc3cc(Br)ccc3C2)O1
Temperature: -70 °C
Reaction time: 0.17 h
Yield: 74.9 %

Procedure:
1,3-bis-trimethylsilyloxy propandiol (38.5 grams, 175 mmol, prepared from 1,3-propanediol, triethylamine, and chlorotrimethyl silane in tetrahydrofuran) was slowly added to a stirring solution of trimethylsilyl trifluoromethanesulfonate (0.5 mL, 2.6 mmol) in methylene chloride (100 mL, -70° C.), while keeping the reaction temperature between -70° and -60° C. The solution was allowed to stir for 10 minutes at -70° C. A solution of 6-bromo-2-tetralone (35.5 grams, 158 mmol) in methylene chloride (100 mL) was slowly added over a 10 minute period. The resulting reaction mixture was allowed to warm slowly to 15° C. over 15 hours, after which time thin layer chromatography (55:45 diethyl ether:hexanes) and high pressure liquid chromatography showed complete consumption of the starting tetralone. The reaction was quenched with saturated sodium bicarbonate (200 mL) and the layers were separated. The aqueous layer was extracted with methylene chloride (50 mL). The combined methylene chloride solution was washed with brine (200 mL), dried with sodium sulfate, and concentrated at reduced pressure to a gold colored residue. This was filtered through 300 grams of silica gel and eluted with 3:1 hexanes/ethyl acetate. The filtrate was concentrated at reduced pressure and the product recrystallized from hexanes to obtain 33.5 grams (75% yield) of 6-bromo-2-tetralone propylene ketal as white crystals (NMR, MS). Calculated for C13H15O2Br: C, 55.14; H, 5.34. Found C, 55.05; H, 5.52.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([OH:13])=[O:12])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.S([O-])([O-])(=O)=O.[CH3:19]O>>[CH3:19][O:12][C:11]([C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[N:1]=[CH:2][CH:3]=[CH:4]2)=[O:13]
Reactant: O=C(O)c1ccc2ncccc2c1
Reactant: CO
Agent: O=S(=O)([O-])[O-]
Product: COC(=O)c1ccc2ncccc2c1
Temperature: 70 °C
Reaction time: 22 h

Procedure:
4.0 g of 6-quinolinecarboxylic acid were suspended in 30 ml of MeOH, 2.0 ml of conc. sulfate was added under ice cooling, and the mixture was stirred at 70° C. for 22 hours. The reaction solution was concentrated under reduced pressure, and the residue was mixed with water and neutralized with potassium carbonate. The thus-precipitated solid was filtered and dried to obtain 4.28 g of 6-quinolinecarboxylic acid methyl ester. 0.5 g of the obtained ester body was dissolved in 5 ml of formamide, 0.15 ml of conc. sulfate, 0.05 g of ferrous sulfate hepta-hydrate, and 0.4 ml of 31% hydrogen peroxide were sequentially added thereto, and the mixture was stirred at 80° C. for 50 minutes. The reaction solution was mixed with water and alkalinized with potassium carbonate. 10% MeOH-chloroform was added, and insoluble matter was filtered using celite. The obtained filtrate was separated, the obtained organic layer was dried over anhydrous sodium sulfate and concentrated, and the obtained residue was washed with EtOH to obtain 0.15 g of 6-methoxycarbonyl-2-quinolinecarboxamide.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=O.Cl.[CH3:13][O:14][NH:15][CH3:16].CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>C(Cl)Cl>[CH3:1][O:2][C:3]1[N:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([N:15]([O:14][CH3:13])[CH3:16])=[O:7]
Reactant: CNOC
Reactant: COc1ncccc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ncccc1C(=O)N(C)OC
Temperature: 0 °C
Reaction time: 18 h
Yield: 50.4 %

Procedure:
To a stirred ice-cooled mixture of 2-methoxy-nicotinic acid (1.43 g, 9.31 mmol) and O,N-dimethyl-hydroxylamine hydrochloride (1.0 g, 10.3 mmol) in DCM (50 mL) was added DIPEA (6.4 mL, 37.3 mmol). EDCI (2.14 g, 11.1 mmol) was added portionwise over 5 minutes. After 18 hours, the reaction mixture was washed successively with saturated sodium bicarbonate and water. The organic layer was dried (Na2SO4), filtered and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 50 to 75% EtOAc in cyclohexane) to afford the title compound (0.92 g, 51%) as a colourless oil. LCMS (Method A): RT=2.48 min, [M+H]+=197.
Reaction SMILES: O=[C:2]([CH2:16][CH2:17][C:18]([O-:20])=[O:19])[C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=1)=[O:4].[CH2:21]([O:28][C:29]([NH:31][C@@H:32]1[CH2:36][O:35][NH:34][C:33]1=[O:37])=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[I-].ClC1C=CC=C[N+]=1C.C(N(CC)CC)C>ClCCl>[CH2:21]([O:28][C:29]([NH:31][C@@H:32]1[CH2:36][O:35][N:34]([C:2]2([C:3]([O:5][CH2:6][C:7]3[CH:8]=[CH:9][C:10]([N+:13]([O-:15])=[O:14])=[CH:11][CH:12]=3)=[O:4])[CH2:16][CH2:17][C:18](=[O:19])[O:20]2)[C:33]1=[O:37])=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(N[C@@H]1CONC1=O)OCc1ccccc1
Reactant: O=C([O-])CCC(=O)C(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1CCC(C(=O)OCc2ccc([N+](=O)[O-])cc2)(N2OC[C@@H](NC(=O)OCc3ccccc3)C2=O)O1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 24.4 %

Procedure:
In 2 ml of dichloromethane were dissolved 85 mg of Compound (1) and 60 mg of (4R)-4-benzyloxycarbonylamino-3-isoxazolidinone. To the solution were added 77 mg of 2-chloro-1-methylpyridinium iodide and 84 μ1 of triethylamine. The mixture was stirred at room temperature for 40 minutes, followed by concentration under reduced pressure. The residue was dissolved in ethyl acetate, followed by conducting workup similar to that in Example 8(a) to give 31 mg of the subject Compound (8).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][C@H:5]([OH:7])[C@H:4]([CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][C:14](O)=[O:15])[C@H:3]1[CH:17]=[CH:18][C@H:19]([OH:28])[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C.[CH2:43]([NH2:45])[CH3:44]>C(Cl)Cl>[CH3:44][CH2:43][NH:45][C:14]([CH2:13][CH2:12][CH2:11]/[CH:10]=[CH:9]\[CH2:8][C@@H:4]1[C@@H:3](/[CH:17]=[CH:18]/[C@@H:19]([OH:28])[CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C@H:2]([OH:1])[CH2:6][C@@H:5]1[OH:7])=[O:15]
Reactant: O=C(O)CCC/C=C\C[C@@H]1[C@@H](C=C[C@H](O)CCc2ccccc2)[C@H](O)C[C@@H]1O
Reactant: CCN
Agent: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCNC(=O)CCC/C=C\C[C@@H]1[C@@H](/C=C/[C@@H](O)CCc2ccccc2)[C@H](O)C[C@@H]1O
Temperature: -10 °C
Reaction time: 2 h
Yield: 169.6 %

Procedure:
Under an atmosphere of nitrogen 250 mL methylenechloride were added to 12.34 g of (Z)-7-[(1R,2R,3R,5S)-3,5-dihydroxy-2-((R)-3-hydroxy-5-phenyl-pent-1-enyl)-cyclopentyl]-hept-5-enoic acid (compound (7), MW=402.54; 26.1 mmol; 1 equivalents) and the solution was cooled to −10° C. At this temperature 5.1 g of triethylamine (MW=101.19; 50.4 mmol; 1.9 equivalents) and 5.8 g of pivalic acid chloride (MW=120.58; 48.1 mmol; 1.8 equivalents) were added. The reaction mixture was stirred for two hours. Then a solution of 2.3 g ethylamine (MW=45.08; 2.0 equivalents) in 10 mL of methylene chloride was added. After stirring the reaction mixture for two hours at −10° C., the mixture was warmed to room temperature. The reaction was quenched by adding 250 mL of water and adjusting the pH to 2.0 with 1M aqueous hydrochloric acid. After separation of the layers, the organic layers was washed with 250 mL of saturated aqueous sodium bicarbonate, water and brine. After filtration the solution was concentrated under reduced pressure to give 18.4 g of bimatoprost crude (yield: 95%; as determined by NMR). Bimatoprost crude was purified as described below.
Reaction SMILES: CO[C:3](=[O:28])[CH:4]([N:8]1[C:14](=[O:15])[CH2:13][CH2:12][N:11]([C:16](=[O:27])/[CH:17]=[CH:18]/[C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=2)[CH2:10][CH2:9]1)[CH2:5][CH2:6][OH:7].ClC1C=C(/C=C/[C:39]([N:41]2CCC(=O)N(C3CCOC3=O)C[CH2:42]2)=O)C=CC=1Cl.CNC>C1COCC1>[Cl:26][C:21]1[CH:20]=[C:19](/[CH:18]=[CH:17]/[C:16]([N:11]2[CH2:12][CH2:13][C:14](=[O:15])[N:8]([CH:4]([CH2:5][CH2:6][OH:7])[C:3]([N:41]([CH3:42])[CH3:39])=[O:28])[CH2:9][CH2:10]2)=[O:27])[CH:24]=[CH:23][C:22]=1[Cl:25]
Reactant: COC(=O)C(CCO)N1CCN(C(=O)/C=C/c2ccc(Cl)c(Cl)c2)CCC1=O
Reactant: O=C1OCCC1N1CCN(C(=O)/C=C/c2ccc(Cl)c(Cl)c2)CCC1=O
Agent: CNC
Solvent: C1CCOC1
Product: CN(C)C(=O)C(CCO)N1CCN(C(=O)/C=C/c2ccc(Cl)c(Cl)c2)CCC1=O
Temperature: 50 °C
Yield: 96 %

Procedure:
A solution of 0.081 g (0.19 mmol) of (rac)-2-{4-[(E)-3-(3,4-dichloro-phenyl)-acryloyl]-7-oxo-[1,4]diazepan-1-yl}-4-hydroxy-butyric acid methyl ester (with 50% of the lactone, 1-[(E)-3-(3,4-dichloro-phenyl)-acryloyl]-4-(2-oxo-tetrahydro-furan-3-yl)-[1,4]diazepan-5-one) (intermediate 6) was suspended in 1 ml of THF, treated with 0.34 ml (1.89 mmol, 33% in EtOH) of dimethylamine and heated at 50° C. for 16 h. Evaporation of the solvent and drying gave 0.08 g (96%) of the titled compound as light yellow foam. MS: 442.3 (MH+, 2Cl).
Reaction SMILES: Br[CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[N-:15]=[N+:16]=[N-:17].[Na+].O.C(=O)(O)[O-].[Na+]>CN(C=O)C.[I-].[Na+]>[N:15]([CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1)=[N+:16]=[N-:17]
Reactant: CC(C)(C)OC(=O)N1CCC(Br)CC1
Reactant: [N-]=[N+]=[N-]
Agent: O=C([O-])O
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(N=[N+]=[N-])CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 100.2 %

Procedure:
To a solution of 45.3 g (172 mmol) of 4-bromo-1-t-butoxycarbonylpiperidine in 750 mL of DMF was added 22.3 g (343 mmol) of sodium azide and 2.5 g (17 mmol) of sodium iodide. The reaction was stirred at rt for 24 h and then at 60° C. for 4 h. The mixture was poured into water containing 20 mL of sodium bicarbonate and extracted twice with 1:1 ether:hexanes. The organic layers were each washed with a portion of water and brine, dried over sodium sulfate, combined and concentrated. The residue was purified by FC eluting with 5-10% ethyl acetate in hexanes to afford 39 g of title compound having a trace of elimination byproduct.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][N:19]([C:22]2[CH:23]=[CH:24][C:25]3[O:29][C:28]([C:30]([O:32]C)=O)=[CH:27][C:26]=3[CH:34]=2)[CH2:18][CH2:17]1)#[N:2].[NH3:35]>CO>[CH:11]1[C:3]([C:1]#[N:2])=[CH:4][C:5]2[C:6]([CH2:12][CH2:13][CH2:14][CH2:15][N:16]3[CH2:21][CH2:20][N:19]([C:22]4[CH:23]=[CH:24][C:25]5[O:29][C:28]([C:30]([NH2:35])=[O:32])=[CH:27][C:26]=5[CH:34]=4)[CH2:18][CH2:17]3)=[CH:7][NH:8][C:9]=2[CH:10]=1
Reactant: COC(=O)c1cc2cc(N3CCN(CCCCc4c[nH]c5ccc(C#N)cc45)CC3)ccc2o1
Reactant: N
Solvent: CO
Product: N#Cc1ccc2[nH]cc(CCCCN3CCN(c4ccc5oc(C(N)=O)cc5c4)CC3)c2c1
Temperature: 30 °C

Procedure:
Methyl 5-[4-[4-(5-cyanoindol-3-yl)butyl]piperazin-1-yl]benzofuran-2-carboxylate (41 g) was taken in methanol (1000 ml) under stirring at 25-35° C., followed by reacting with ammonia gas for 2 hours under pressure of 4 Kg/cm2. The separated solid was filtered and then dried to produce 32 g of vilazodone. The mother liquors were taken and the solvent was distilled off under vacuum until the solvent quantity reaches around 50 ml of the initial volume. The resulting mass was cooled to 25-30° C., followed by filtration and then drying to produce 6 g of Vilazodone (Purity by HPLC: 99.5%; Yield: 96%).
Reaction SMILES: C[O:2][C:3](=[O:26])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)=[CH:6][C:5]=1[O:24][CH3:25].[OH-].[Na+].C(Cl)Cl>CO>[C:20]([O:19][C:17]([N:14]1[CH2:13][CH2:12][CH:11]([O:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:26])=[O:2])=[C:5]([O:24][CH3:25])[CH:6]=2)[CH2:16][CH2:15]1)=[O:18])([CH3:23])([CH3:22])[CH3:21]
Reactant: COC(=O)c1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: COc1cc(OC2CCN(C(=O)OC(C)(C)C)CC2)ccc1C(=O)O
Yield: 95 %

Procedure:
4-(N-t-Butoxycarbonyl-4-piperidinyloxy)-2-methoxybenzoic acid methyl ester from Step 2 was saponified to the carboxylic acid with aqueous NaOH in MeOH using the procedure of Step 3 in Example 11. 4-(N-t-Butoxycarbonyl-4-piperidinyloxy)-2-methoxybenzoic acid was obtained as a foam by evaporation of a DCM solution under reduced pressure (95% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9]O.S(=O)(=O)(O)O.[BrH:16]>O>[Br:16][CH2:9][CH2:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[F:1]
Reactant: OCCc1ccccc1F
Reactant: Br
Agent: O=S(=O)(O)O
Solvent: O
Product: Fc1ccccc1CCBr

Procedure:
50 g 2-(2-fluorophenyl)ethanol, 19 ml concentrated sulfuric acid and 58 ml aqueous hydrobromic acid (47 per cent by weight) were heated at 100° C. overnight in a high-grade steel autoclave. After cooling, the mixture was diluted with 500 ml water and extracted twice with 250 ml methylene chloride each time, the combined extracts were dried over potassium carbonate, filtered and concentrated and the residue was largely freed from solvent residues in vacuo. 61.8 g 1-(2-bromoethyl)-2-fluorobenzene were obtained.
Reaction SMILES: O1CCOCC1.Cl[C:8]1[CH:13]=[C:12]([CH:14]([S:23][C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)[C:15]2[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=2[F:22])[C:11]([Cl:31])=[CH:10][N:9]=1.[NH:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1>C(OCC)(=O)C>[Cl:31][C:11]1[C:12]([CH:14]([S:23][C:24]2[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=2)[C:15]2[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=2[F:22])=[CH:13][C:8]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)=[N:9][CH:10]=1
Reactant: Fc1ccc(F)c(C(Sc2ccc(Cl)cc2)c2cc(Cl)ncc2Cl)c1
Reactant: C1COCCN1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Fc1ccc(F)c(C(Sc2ccc(Cl)cc2)c2cc(N3CCOCC3)ncc2Cl)c1
Temperature: 25 °C
Yield: 89 %

Procedure:
A 1,4-dioxane (1.0 ml) solution of the 2,5-dichloro-4-[(4-chlorophenylthio)-(2,5-difluorophenyl)methyl]pyridine (100 mg, 0.24 mmol) obtained in Example 54 and morpholine (200 μl) was stirred at 100° C. for 2 days under a nitrogen atmosphere. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (40 ml). The diluted mixture was washed with water and brine, dried and then concentrated under reduced pressure to give a residue. The resulting residue was purified by silica gel chromatography (hexane:ethyl acetate=5:1) to give the title compound (100 mg, 89%) as an oil.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([CH2:9][P:10]([O:15][CH2:16][CH3:17])([O:12][CH2:13][CH3:14])=[O:11])[CH:6]=[CH:5][N:4]=1)#[N:2].S(=O)(=O)(O)[OH:19].[Na]>>[CH2:13]([O:12][P:10]([CH2:9][C:7]1[CH:6]=[CH:5][N:4]=[C:3]([C:1]([NH2:2])=[O:19])[CH:8]=1)([O:15][CH2:16][CH3:17])=[O:11])[CH3:14]
Reactant: O=S(=O)(O)O
Reactant: CCOP(=O)(Cc1ccnc(C#N)c1)OCC
Agent: [Na]
Product: CCOP(=O)(Cc1ccnc(C(N)=O)c1)OCC

Procedure:
A mixture of 1.10 g of 2-cyano-4-(diethylphosphonomethyl)pyridine and 4.5 ml of concentrated sulfuric acid is heated at 90° for 5 minutes. The reaction mixture is poured onto ice and neutralized with 10% sodium hdroxide. The resulting precipitate is collected to afford 4-(diethylphosphonomethyl)-2-pyridinecarboxamide melting at 140°-142°.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.[CH2:12](Br)[CH:13]=[CH2:14].C([O-])([O-])=O.[Cs+].[Cs+]>O.CN(C=O)C>[CH2:14]([O:9][C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:10])([F:11])[F:1])=[CH:8][CH:7]=1)[CH:13]=[CH2:12]
Reactant: Oc1ccc(C(F)(F)F)cc1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCOc1ccc(C(F)(F)F)cc1
Reaction time: 12 h
Yield: 51.3 %

Procedure:
4-(Trifluoromethyl)phenol (1.50 g, 9.25 mmol), allyl bromide (14.55 g, 12.03 mmol), Cs2CO3 (3.62 g, 11.10 mmol), and water (15 drops) were combined in DMF (40 mL) and the mixture stirred for 12 h. The reaction mixture was then concentrated under reduced pressure, diluted with water, and extracted with EtOAc (2×). The combined organic phases were dried over Na2SO4, filtered, and concentrated under reduced pressure to give 0.96 g (51%) of the title compound as a light-yellow oil. 1H NMR (400 MHz, CDCl3): δ 4.59 (d, 2H), 5.32 (d, 1H), 5.43 (d, 1H), 6.05 (m, 1H), 6.97 (d, 2H), 7.53 (d, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][CH2:15][C:16]1([OH:22])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1)=[CH:11][CH:10]=[CH:9][CH:8]=2)([O-])=O>[Pt]>[NH2:1][C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][CH2:15][C:16]1([OH:22])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1)=[CH:11][CH:10]=[CH:9][CH:8]=2
Reactant: O=[N+]([O-])c1cnc2ccccc2c1NCC1(O)CCOCC1
Agent: [Pt]
Product: Nc1cnc2ccccc2c1NCC1(O)CCOCC1
Yield: 93.6 %

Procedure:
A mixture of 4-{[(3-nitroquinolin-4-yl)amino]methyl}tetrahydro-2H-pyran-4-ol (9.00 g, 29.7 mmol) and 5% platinum on carbon (0.90 g) in acetonitrle (180 mL) was hydrogenated according to the method described in Part D of Example 9 to yield 4-{[(3-aminoquinolin-4-yl)amino]methyl}tetrahydro-2H-pyran-4-ol as a brown solid (7.60 g, 94%).
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C:3](=[O:11])[O:2]1.[BrH:12]>C(O)(=O)C>[Br:12][CH2:1][C:10]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:4][C:3]([OH:2])=[O:11]
Reactant: Br
Reactant: O=C1Cc2ccccc2CO1
Solvent: CC(=O)O
Product: O=C(O)Cc1ccccc1CBr
Temperature: 25 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
A solution of isochroman-3-one (1.5 g, 10 mmol) in 30% HBr in acetic acid (13 mL) was stirred at room temperature for 2 h, and 70° C. for 1 h. The reaction mixture was cooled to room temperature, and poured into ice-water. The precipitate was collected to afford (2-bromomethylphenyl)acetic acid as an off-white solid (2.15 g, 93%): 1H NMR (300 MHz, DMSO-d6) δ 7.45-7.23 (m, 4H), 4.73 (s, 2H), 3.73 (s, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[N:8][CH:9]=1)([O-])=O.O>C1COCC1.[Ni]>[O:13]1[CH2:14][CH2:15][N:10]([C:7]2[N:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=2)[CH2:11][CH2:12]1
Reactant: O=[N+]([O-])c1ccc(N2CCOCC2)nc1
Agent: [Ni]
Solvent: C1CCOC1
Solvent: O
Product: Nc1ccc(N2CCOCC2)nc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of the product from Example 154A (12.5, 59.5 mmol) in THF (150 mL) was added to Ra-Ni 2800, water slurry (12.5 g, 212 mmol) in a 500 mL SS pressure bottle. The mixture was pressurized (H2, 30 psi) and stirred for 2 hours at room temperature. The mixture was filtered and then concentrated under reduced pressure to provide the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]2[C:20]3[C:11](=[C:12]4[C:17](=[CH:18][CH:19]=3)[NH:16][C:15]([CH3:22])([CH3:21])[CH:14]=[C:13]4[CH3:23])[CH:10]([OH:24])[O:9][C:5]=2[CH:6]=[CH:7][CH:8]=1.[CH2:25]([Si](C)(C)C)[CH:26]=[CH2:27]>>[CH2:27]([O:24][CH:10]1[C:11]2=[C:12]3[C:17](=[CH:18][CH:19]=[C:20]2[C:4]2[C:3]([O:2][CH3:1])=[CH:8][CH:7]=[CH:6][C:5]=2[O:9]1)[NH:16][C:15]([CH3:21])([CH3:22])[CH:14]=[C:13]3[CH3:23])[CH:26]=[CH2:25]
Reactant: C=CC[Si](C)(C)C
Reactant: COc1cccc2c1-c1ccc3c(c1C(O)O2)C(C)=CC(C)(C)N3
Product: C=CCOC1Oc2cccc(OC)c2-c2ccc3c(c21)C(C)=CC(C)(C)N3

Procedure:
treating 10-methoxy-2,2,4-trimethyl-2,5-dihydro-1H-chromeno [3,4-f]quinolin-5-ol with allyltrimethylsilane and a Lewis acid to provide 5-(allyloxy)-10-methoxy-2,2,4-trimethyl-2,5-dihydro-1H-chromeno[3,4-f]quinoline; and
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[CH:4][CH:3]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[NH:56]1[CH2:61][CH2:60][O:59][CH2:58][CH2:57]1>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[N:16]=[CH:17][C:18]([C:19]([N:56]4[CH2:61][CH2:60][O:59][CH2:58][CH2:57]4)=[O:21])=[CH:22][CH:23]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: C1COCCN1
Reactant: Cc1onc(-c2ccc(F)cc2)c1COc1ccc(C(=O)O)cn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1onc(-c2ccc(F)cc2)c1COc1ccc(C(=O)N2CCOCC2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 12.6 %

Procedure:
To a solution of 6-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid (60 mg, 0.2 mmol) in DMF (300 μL) were added 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (71 mg, 0.22 mmol), N,N-diisopropyl ethyl amine (171 μL, 1.0 mmol) and morpholine (0.22 mmol). The resulting reaction mixture was stirred for 1 h at room temperature. Concentration and purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 1:1) afforded the title compound (10 mg, 13%) which was obtained as a white solid. MS: m/e=398.3 [M+H]+.
Reaction SMILES: [C-:1]#[N:2].[Na+].[F:4][C:5]1[CH:12]=[C:11]([Br:13])[CH:10]=[CH:9][C:6]=1[CH2:7]Br.O>CS(C)=O>[Br:13][C:11]1[CH:10]=[CH:9][C:6]([CH2:7][C:1]#[N:2])=[C:5]([F:4])[CH:12]=1
Reactant: Fc1cc(Br)ccc1CBr
Reactant: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: N#CCc1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 96.4 %

Procedure:
Sodium cyanide (1.37 g, 28.00 mmol) was added to a stirred solution of 2-fluoro-4-bromo benzyl bromide (5.0 g, 18.66 mmol) in dry DMSO (60 mL) at ambient temperature under nitrogen. The reaction was stirred for 4 h at ambient temperature then poured into H2O (150 mL) and extracted with EtOAc. The organic layer was washed with brine, dried (MgSO4), filtered, and concentrated in vacuo to give the intermediate title compound as a brown oil (3.85 g, 96%). Electrospray mass spectrum: M=213, M+2=215
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Br)=[C:4]([F:10])[CH:3]=1.[C-:11]#[N:12].[Na+]>CN(C=O)C.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:11]#[N:12])=[C:4]([F:10])[CH:3]=1
Reactant: Fc1cc(Br)ccc1CBr
Reactant: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CCc1ccc(Br)cc1F
Yield: 46.5 %

Procedure:
To a solution of 4-bromo-1-bromomethyl-2-fluoro-benzene (100 g, 373 mmol) in DMF (190 mL) and water (10 mL) was added sodium cyanide (22 g, 448 mmol). The reaction was heated to 70 degrees Celsius for 3 hours, concentrated to a volume of 100 mL, and then the solution was diluted with 100 mL of ethyl acetate. After the solids were removed by filtration, water (250 mL) was added and the layers were separated. The organic layer was further washed with 3×100 mL of water. The organic layer was dried over MgSO4, filtered to remove solids, and then concentrated. Purification by distillation gave the desired product (37.124 g, 46%). B.P.=72-75 degrees Celsius.