Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[S:5][CH:6]=[CH:7][C:8]=1Br)(=[O:3])[CH3:2].[Cu](C#N)[C:11]#[N:12]>CN1C(=O)CCC1.O>[C:1]([C:4]1[S:5][CH:6]=[CH:7][C:8]=1[C:11]#[N:12])(=[O:3])[CH3:2]
Reactant: CC(=O)c1sccc1Br
Reactant: N#C[Cu]C#N
Solvent: CN1CCCC1=O
Solvent: O
Product: CC(=O)c1sccc1C#N
Yield: 99.8 %

Procedure:
Heat a stirred solution of 2-acetyl-3-bromothiophene (1.49 g, 7.29 mmol) (Chem. Pharm. Bull. 2000, 48, 1558-1566) in dry NMP (72 mL) for 10 h at 150° C. in the presence of copper cyanide (3.26 g, 36.5 mmol). Dilute the mixture with water, extract three times with diethyl ether, dry over anhydrous Na2SO4 and concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc (10:1) to give the desired intermediate as a dark oil (1.1 g, 99%).
Reaction SMILES: [N:1]1[N:2]([C:6]2[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=2[C:8]([Cl:10])=[O:9])[N:3]=[CH:4][CH:5]=1.[NH2:15][CH:16]1[CH2:20][CH2:19][CH2:18][C:17]1([NH:22]C(=O)OC(C)(C)C)[CH3:21].CCN(C(C)C)C(C)C.Cl.O1CCOCC1>C(Cl)Cl>[ClH:10].[NH2:22][C:17]1([CH3:21])[CH2:18][CH2:19][CH2:20][CH:16]1[NH:15][C:8](=[O:9])[C:7]1[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=1[N:2]1[N:3]=[CH:4][CH:5]=[N:1]1
Reactant: O=C(Cl)c1ccccc1-n1nccn1
Reactant: CC(C)(C)OC(=O)NC1(C)CCCC1N
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC1(N)CCCC1NC(=O)c1ccccc1-n1nccn1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a solution of 2-(2H-1,2,3-triazol-2-yl)benzoyl chloride (213 mg, 1.03 mmol) (which was prepared from 2-(2H-1,2,3-triazol-2-yl)benzoic acid (CAS number 1001401-62-2; 0.194 g, 1.03 mmol) and thionyl chloride (0.112 ml, 1.541 mmol)) in dry DCM (3.1 ml) was added tert-butyl N-(2-amino-1-methylcyclopentyl)carbamate (Intermediate 24; 200 mg, 0.93 mmol) and DIPEA (489 μl, 2.80 mmol). The reaction was stirred at room temperature for 17 hours and was then partitioned between a saturated solution of sodium bicarbonate and DCM, filtered through a hydrophobic frit and concentrated in vacuo. This was then purified by column chromatography (silica, 0-100% ethyl acetate/petrol). The resulting product was then dissolved in 1,4-dioxane (5 ml) and to this was then added HCl in 1,4-dioxane (4 M, 2.3 ml, 9.33 mmol). The reaction was stirred at room temperature for 1 hour and then concentrated in vacuo, azeotropically distilled with toluene to afford the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]([NH:14][C:15]2[CH:16]=[N:17][CH:18]=[C:19]([F:34])[C:20]=2[N:21]2[CH2:26][CH2:25][CH:24]([C:27]([O:29]C(C)(C)C)=[O:28])[CH2:23][CH2:22]2)=[O:13])=[C:5]2[N:6]=[CH:7][C:8]([F:10])=[CH:9][N:4]2[N:3]=1.C([SiH](CC)CC)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:1][C:2]1[C:11]([C:12]([NH:14][C:15]2[CH:16]=[N:17][CH:18]=[C:19]([F:34])[C:20]=2[N:21]2[CH2:22][CH2:23][CH:24]([C:27]([OH:29])=[O:28])[CH2:25][CH2:26]2)=[O:13])=[C:5]2[N:6]=[CH:7][C:8]([F:10])=[CH:9][N:4]2[N:3]=1
Reactant: CC(C)(C)OC(=O)C1CCN(c2c(F)cncc2NC(=O)c2c(N)nn3cc(F)cnc23)CC1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1nn2cc(F)cnc2c1C(=O)Nc1cncc(F)c1N1CCC(C(=O)O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 134.8 %

Procedure:
To a suspension of tert-butyl 1-[3-[(2-amino-6-fluoro-pyrazolo[1,5-a]pyrimidine-3-carbonyl)amino]-5-fluoro-4-pyridyl]piperidine-4-carboxylate 28 (69.7 g, 147.2 mmol) in DCM (348.5 mL) and triethylsilane (18.83 g, 25.87 mL, 161.9 mmol) was added TFA (151.1 g, 102.1 mL, 1.325 mol) (mixture sets solid on initial addition of TFA then goes into solution after complete addition). Resulting orange solution was stirred at room temperature overnight. Additional TFA (16.78 g, 11.34 mL, 147.2 mmol) was added and the mixture stirred at room temperature for 2 h. Mixture then heated at 40° C. for 20 mins to force reaction to completion. Mixture was concentrated in vacuo, chloroform (300 mL) was added and mixture again concentrated in vacuo to leave an orange solid suspension. Mixture triturated in DCM (approx. 200 mL), stirred for 20 mins then solid collected by filtration, washed with minimal DCM and dried by suction to leave a yellow solid. Filtrate was concentrated in vacuo, residue re-slurried in DCM (approx 50 mL), stirred for 20 mins then solid collected by filtration, washed with minimal DCM and dried by suction to leave a yellow solid which was combined with first crop of solid. Solid dried under vacuum overnight to leave desired product 29 as a yellow solid (82.8 g, 96%). 1H NMR (500 MHz, DMSO-d6) δ 10.44 (s, 1H), 9.59 (s, 1H), 9.50 (dd, 1H), 8.84 (dd, 1H), 8.33 (d, 1H), 3.13-3.10 (m, 4H), 2.57-2.47 (masked signal, 1H) and 2.08-1.93 (m, 4H). MS (ES+) 418.1.
Reaction SMILES: BrC1C=C2C(=CC=1)C=C(O)C=C2.[CH3:13][C@H:14](C(O)=O)[C:15]1[CH:16]=[CH:17][C:18]2[CH:19]=[C:20]([O:25][CH3:26])[CH:21]=[CH:22][C:23]=2[CH:24]=1.BrC1C=C2C(=CC=1)C=C(OC)C=C2.C=C>>[CH3:26][O:25][C:20]1[CH:21]=[CH:22][C:23]2[C:18](=[CH:17][CH:16]=[C:15]([CH:14]=[CH2:13])[CH:24]=2)[CH:19]=1
Reactant: COc1ccc2cc([C@H](C)C(=O)O)ccc2c1
Agent: C=C
Agent: COc1ccc2cc(Br)ccc2c1
Agent: Oc1ccc2cc(Br)ccc2c1
Product: C=Cc1ccc2cc(OC)ccc2c1

Procedure:
When it is desired to convert the 6-bromo-2-naphthol to naproxen, the 6-bromo-2-naphthol is first converted to a 6-bromo-2-methoxynaphthalene intermediate as described above, and the intermediate is then converted to naproxen by any of the techniques already known for that conversion. For example, as disclosed in U.S. Pat. No. 5,536,870 (Wu), the 6-bromo-2-methoxynaphthalene may be reacted with ethylene to form 2-methoxy-6-vinylnapthalene, which is then carbonylated to racemic 2-(6-methoxy-2-naphthyl)propionic acid, which can be subsequently resolved to isolate the desired naproxen enantiomer.
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8](=[O:12])[CH:9]([CH3:11])[CH3:10])=[CH:6][N:5]=[C:4]2[S:13][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[C:15]([CH3:16])[C:3]=12.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.[F:34][C:35]1[CH:42]=[CH:41][CH:40]=[C:39]([F:43])[C:36]=1[CH2:37]Br>O>[F:34][C:35]1[CH:42]=[CH:41][CH:40]=[C:39]([F:43])[C:36]=1[CH2:37][N:5]1[CH:6]=[C:7]([C:8](=[O:12])[CH:9]([CH3:11])[CH3:10])[C:2](=[O:1])[C:3]2[C:15]([CH3:16])=[C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[S:13][C:4]1=2
Reactant: Fc1cccc(F)c1CBr
Reactant: Cc1c(-c2ccccc2)sc2ncc(C(=O)C(C)C)c(O)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(-c2ccccc2)sc2c1c(=O)c(C(=O)C(C)C)cn2Cc1c(F)cccc1F
Temperature: 45 °C
Reaction time: 2 h
Yield: 94.6 %

Procedure:
4-Hydroxy-5-isobutyryl-3-methyl-2-phenylthieno[2,3-b]pyridine (35 g), potassium carbonate (18.6 g) and N,N-dimethylformamide (280 ml) were mixed and 2,6-difluorobenzyl bromide (27.9 g) was added and the reaction mixture was stirred at 40 to 50° C. for 2 hours. The reaction mixture was treated dropwise with water (560 ml), and the mixture was stirred for 1 hour and then cooled on ice, and then stirred further for 1 hour. The crude crystal was recovered by a filtration, washed with water (about 1000 ml), dried in air, suspended in a 1:1 solvent mixture (250 ml) of ethyl acetate and diisopropylether, and then the mixture was stirred at room temperature for 1 hour, and then stirred with cooling on ice for 1 hour. The crystal obtained by a filtration was washed with the same solvent mixture (180 ml), dried in vacuo at 40° C. for 5 hours to obtain the title compound (46.53 g, 94.6%).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:22]=[CH:21][C:9]3[C:10]4[N:11]=[C:12]([C:18]([OH:20])=O)[S:13][C:14]=4[CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:3]=[N:2]1.[N:23]1[CH:28]=[CH:27][C:26]([N:29]2[CH2:35][CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[CH:25][CH:24]=1>>[NH:1]1[CH:5]=[C:4]([C:6]2[CH:22]=[CH:21][C:9]3[C:10]4[N:11]=[C:12]([C:18]([N:32]5[CH2:33][CH2:34][CH2:35][N:29]([C:26]6[CH:27]=[CH:28][N:23]=[CH:24][CH:25]=6)[CH2:30][CH2:31]5)=[O:20])[S:13][C:14]=4[CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:3]=[N:2]1
Reactant: c1cc(N2CCCNCC2)ccn1
Reactant: O=C(O)c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2
Product: O=C(c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2)N1CCCN(c2ccncc2)CC1

Procedure:
Following the procedure for 103, 8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid (50.0 mg, 0.2 mmol) was reacted with 1-(pyridin-4-yl)-1,4-diazepane (1.2 equiv) to give 208 (M+1 473.0)
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[C:10]=1[N+:16]([O-])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Ni].O.[H][H]>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[C:10]=1[NH2:16])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cccc(F)c1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Ni]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)Nc1cccc(F)c1N
Reaction time: 8 h
Yield: 66 %

Procedure:
To a solution of the N-tert-Butyloxycarbonyl-3-fluoro-2-nitro aniline (950 mg, 2.5 mmol) in MeOH was added catalytic amount of Raney Nickel in water, hydrogen was applied at 40 psi and the mixture was stirred overnight. The mixture was filtered over Celite and the solvent was evaporated to give the desired product in 66% yield (550 mg). MS (ESI)=226 (MH+)
Reaction SMILES: O[C:2]1([C:23]2[S:24][CH:25]=[CH:26][CH:27]=2)[C:6]2[CH:7]=[C:8]([NH:13][C:14](=[O:20])[CH2:15][C:16]([CH3:19])([CH3:18])[CH3:17])[C:9]([CH3:12])=[C:10]([CH3:11])[C:5]=2[O:4][C:3]1([CH3:22])[CH3:21]>C(OCC)(=O)C.CCCCCC>[CH3:21][C:3]1([CH3:22])[CH:2]([C:23]2[S:24][CH:25]=[CH:26][CH:27]=2)[C:6]2[CH:7]=[C:8]([NH:13][C:14](=[O:20])[CH2:15][C:16]([CH3:19])([CH3:18])[CH3:17])[C:9]([CH3:12])=[C:10]([CH3:11])[C:5]=2[O:4]1
Reactant: Cc1c(NC(=O)CC(C)(C)C)cc2c(c1C)OC(C)(C)C2(O)c1cccs1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Cc1c(NC(=O)CC(C)(C)C)cc2c(c1C)OC(C)(C)C2c1cccs1
Yield: 65 %

Procedure:
Using N-(3-hydroxy-2,2,6,7-tetramethyl-3-(2-thienyl)-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide obtained in Example 248, the title compound was synthesized in the same manner as in Example 271. Yield: 65%. Melting point: 137-138° C. (ethyl acetate-hexane).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C@H:4]1[C:9]2[CH:10]=[CH:11][C:12]([C:14]([NH2:16])=[O:15])=[CH:13][C:8]=2[CH2:7][CH2:6][O:5]1.C(N(CC)CC)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>O1CCCC1.CN(C)C=O>[CH3:24][S:25]([O:1][CH2:2][CH2:3][C@H:4]1[C:9]2[CH:10]=[CH:11][C:12]([C:14]([NH2:16])=[O:15])=[CH:13][C:8]=2[CH2:7][CH2:6][O:5]1)(=[O:27])=[O:26]
Reactant: NC(=O)c1ccc2c(c1)CCO[C@H]2CCO
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CS(=O)(=O)OCC[C@@H]1OCCc2cc(C(N)=O)ccc21
Temperature: 25 °C
Reaction time: 24 h

Procedure:
(1S)-1-(2-Hydroxyethyl)-3,4-dihydro-1H-2-benzopyran-6-carboxamide (5 g, 22.6 mmol) was dissolved in a mixture of dry tetrahydrofuran (375 mL) and dry dimethylformamide (15 mL) with the aid of gentle heating. Triethylamine (4.6 g, 45.5 mmol) was added, followed by methanesulfonyl chloride (2.72 g, 23.8 mmol). The mixture was stirred under nitrogen at room temperature for 1 day. The reaction mixture was quenched with water (1000 mL) and the product extracted into ethyl acetate (2×500 mL). The combined organic extracts were washed with brine (2×500 mL), dried (MgSO4), and evaporated in vacuo to give the crude product as a white solid (6.5 g, 97%). The solid was triturated with ether (300 mL) to give 2-[(1S)-6-(aminocarbonyl)-3,4-dihydro-1H-2-benzopyran-1-yl]ethyl methanesulfonate as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([C@@H:11]1[CH2:15][C@@H:14]([OH:16])[CH2:13][N:12]1[S:17]([C:20]1[CH:29]=[CH:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=1)(=[O:19])=[O:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(F)(F)F.CCOCC.[CH3:39][C:40](=[CH2:42])[CH3:41].C(=O)(O)[O-].[Na+]>ClCCl>[CH2:1]([O:8][C:9]([C@@H:11]1[CH2:15][C@@H:14]([O:16][C:40]([CH3:42])([CH3:41])[CH3:39])[CH2:13][N:12]1[S:17]([C:20]1[CH:29]=[CH:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=1)(=[O:19])=[O:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=C(C)C
Reactant: O=C(OCc1ccccc1)[C@@H]1C[C@@H](O)CN1S(=O)(=O)c1ccc2ccccc2c1
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOCC
Product: CC(C)(C)O[C@@H]1C[C@@H](C(=O)OCc2ccccc2)N(S(=O)(=O)c2ccc3ccccc3c2)C1
Temperature: -20 °C
Reaction time: 2 h

Procedure:
Tert-Butyletherification: To a solution of (2S,4R)-4-hydroxy-1-(naphthalene-2-sulfonyl)-pyrrolidine-2-carboxylic acid benzyl ester (14.8 g) in dichloromethane (140 ml) were added boron trifluoride ethyl etherate (3 ml) and isobutylene (cooled and liquefied at −30° C., 170 ml) at −30° C. The turbid reaction mixture was stirred at −20° C. for 2 h, poured onto a saturated sodium bicarbonate solution, and extracted with dichloromethane. The organic phases were washed with water, dried over magnesium sulphate and concentrated. The residue was chromatographed on silica gel using EtOAc/hexane 1:4 and 1:2 as eluents to obtain (2S,4R)-4-tert-butoxy-1-(naphthalene-2-sulfonyl)-pyrrolidine-2-carboxylic acid benzyl ester (16.4 g) as a glassy syrup, MS: 467 (M).
Reaction SMILES: CN(CCN(C)C)C.C([Li])CCC.[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:24]2[O:29]CCCO2)[CH:19]=[C:20]([O:22][CH3:23])[CH:21]=1.[C:30](=[O:32])=[O:31].Cl>C1COCC1.C(OCC)C>[CH3:23][O:22][C:20]1[CH:19]=[C:18]([CH:24]=[O:29])[CH:17]=[C:16]([O:15][CH3:14])[C:21]=1[C:30]([OH:32])=[O:31]
Reactant: COc1cc(OC)cc(C2OCCCO2)c1
Reactant: O=C=O
Agent: CN(C)CCN(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1cc(C=O)cc(OC)c1C(=O)O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Anhydrous TMEDA (2.05 ml, 13.62 mmole) and 90 ml dry THF was cooled to -78° C. under an argon atmosphere. n-Butyllithium (11.35 ml of a 1.20M soln.) was added and after 15 minutes, 2-(3,5-dimethoxyphenyl)-1,3-dioxane (44) (FIG. 23) (3.05 g, 13.62 mmole) predissolved in 50 ml dry THF was added. The reaction was warmed to 0° C. and was stirred at that temperature for an additional 60 minutes (the solution turned from a blood red color to a dark brown color). The aryl lithium solution was then poured onto solid carbon dioxide covered with anhydrous diethyl ether. A white precipitate formed immediately. When the reaction warmed to room temperature, 15 ml of 10% HCl was added and the reaction was stirred overnight. The product was then extracted into chloroform. The organic layer was dried over MgSO4, and concentrated in vacuo to a white solid (1.311 g, 46%). The solid can be recrystallized from hexane/ethyl acetate.
Reaction SMILES: [CH:1]1([CH2:4][N:5]([C:13]2[C:14]([CH2:22][CH3:23])=[N:15][N:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=23)[CH2:6][CH:7]2[CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)[CH2:3][CH2:2]1.C([Li])CCC.FC1C([I:36])=C(F)C(F)=C(F)C=1F.O.O1CCCC1>O1CCCC1.CCCCCCC.O>[CH:1]1([CH2:4][N:5]([C:13]2[C:14]([CH2:22][CH3:23])=[N:15][N:16]3[C:21]([I:36])=[CH:20][CH:19]=[CH:18][C:17]=23)[CH2:6][CH:7]2[CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)[CH2:3][CH2:2]1
Reactant: CCc1nn2ccccc2c1N(CC1CCOCC1)CC1CC1
Reactant: Fc1c(F)c(F)c(I)c(F)c1F
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCCC
Product: CCc1nn2c(I)cccc2c1N(CC1CCOCC1)CC1CC1
Reaction time: 1 h
Yield: 87.2 %

Procedure:
A solution of N-cyclopropylmethyl-N-(2-ethylpyrazolo[1,5-a]pyridine-3-yl)-N-(tetrahydro-2H-4-pyranylmethyl)amine (180 g, 574 mmol) in tetrahydrofuran (1620 mL) was cooled in a dry ice-ethanol bath. Into the reaction mixture was dropped n-butyllithium (1.6M hexane solution; 538 mL, 854 mmol) at an inner temperature of −73° C. to −64.5° C. At the same temperature, the reaction mixture was stirred for 1 hour, and into the reaction mixture was dropped pentafluoroiodobenzene (115 mL, 861 mmol). The reaction mixture was further stirred for 1 hour and 20 minutes at the same temperature, and to the reaction mixture was added water/tetrahydrofuran (1/1, v/v, 360 mL). Into the reaction mixture was added water (3600 mL) and heptane (3600 mL). An aqueous layer was removed, and an organic layer was washed with water (3600 mL). Then, to the organic layer was added 5N hydrochloric acid (1800 mL) and the aqueous layer was separated. Then, the aqueous layer was cooled in an ice water bath, and a 5N sodium hydroxide aqueous solution (1620 mL) was added, then, toluene (3600 mL) was added, and an organic layer was separated. The remaining aqueous layer was further extracted with toluene (3600 mL), and both the organic layers were combined. The solution was concentrated under reduced pressure, to obtain 220 g of a title compound as deep green oil (yield: 87.3%).
Reaction SMILES: [C:1]([C:3]1[CH:24]=[CH:23][C:6]([NH:7][CH2:8][C:9]([NH:12][C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[O:14])([CH3:11])[CH3:10])=[CH:5][C:4]=1[C:25]([F:28])([F:27])[F:26])#[N:2].[CH2:29]=O>C(O)(=O)C>[C:1]([C:3]1[CH:24]=[CH:23][C:6]([N:7]2[CH2:8][C:9]([CH3:11])([CH3:10])[N:12]([C:13]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)=[O:14])[CH2:29]2)=[CH:5][C:4]=1[C:25]([F:26])([F:27])[F:28])#[N:2]
Reactant: C=O
Reactant: CC(C)(CNc1ccc(C#N)c(C(F)(F)F)c1)NC(=O)Nc1ccc(F)cc1
Solvent: CC(=O)O
Product: CC1(C)CN(c2ccc(C#N)c(C(F)(F)F)c2)CN1C(=O)Nc1ccc(F)cc1
Temperature: 50 °C

Procedure:
A 1.0 g portion of 1-[2-(4-cyano-3-trifluoromethylanilino)-1,1-dimethylethyl]-3-(4-fluorophenyl)urea synthesized in Reference Example 9-1 was dissolved in 10 ml of acetic acid, and the solution was mixed with 0.4 ml of formalin and heated at 50° C. for 2 hours. The solvent was evaporated, the resulting residue was purified by a silica gel column chromatography, and the compound obtained from chloroform-methanol (30:1, v/v) eluate was washed with diisopropyl ether to obtain 751 mg of the title compound.
Reaction SMILES: CC([NH:4][C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:6]=1[F:12])=O.[OH-].[Na+]>C(O)C.O>[Cl:11][C:8]1[CH:9]=[CH:10][C:5]([NH2:4])=[C:6]([F:12])[CH:7]=1
Reactant: CC(=O)Nc1ccc(Cl)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Nc1ccc(Cl)cc1F
Temperature: 25 °C
Yield: 0.8 %

Procedure:
To a stirred solution of 155 g (0.83 mole) of 4-chloro-2-fluoroacetanilide in 400 ml of ethanol was added dropwise a solution of 72.0 g (1.8 moles) of sodium hydroxide in 100 ml of water. Upon completion of addition the reaction mixture was heated under reflux for three hours. The reaction mixture was cooled to ambient temperature and extracted with diethyl ether. The combined extracts were concentrated under reduced pressure to a residual oil. The oil was distilled under reduced pressure to yield 1.0 g of 4-chloro-2-fluoroaniline; b.p. 83-85/12 mm. The reaction was repeated several times.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1.Cl[CH2:14][C:15]1[CH:20]=[CH:19][N:18]=[C:17]([C:21]2[CH:26]=[C:25]([O:27][CH3:28])[C:24]([O:29][CH3:30])=[C:23]([O:31][CH3:32])[CH:22]=2)[CH:16]=1>>[CH2:11]([O:10][C:8]([N:5]1[CH2:4][CH2:3][CH:2]([NH:1][CH2:14][C:15]2[CH:20]=[CH:19][N:18]=[C:17]([C:21]3[CH:26]=[C:25]([O:27][CH3:28])[C:24]([O:29][CH3:30])=[C:23]([O:31][CH3:32])[CH:22]=3)[CH:16]=2)[CH2:7][CH2:6]1)=[O:9])[CH3:12]
Reactant: CCOC(=O)N1CCC(N)CC1
Reactant: COc1cc(-c2cc(CCl)ccn2)cc(OC)c1OC
Product: CCOC(=O)N1CCC(NCc2ccnc(-c3cc(OC)c(OC)c(OC)c3)c2)CC1

Procedure:
4-Amino-1-(ethoxycarbonyl)piperidine (341 mg) and 4-chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine (300 mg) were condensed in the same manner as described in Example 2 to give the title compound.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[N:5]=[CH:4][CH:3]=1.C([Li])CCC.CCCCCC.[Li][CH:24]1C2N=CC=C(C)C=2CCC1.[C:35](=[O:37])=[O:36].Cl>C1C=CC=CC=1>[CH3:24][O:36][C:35]([CH:7]1[C:6]2[N:5]=[CH:4][CH:3]=[C:2]([CH3:1])[C:11]=2[CH2:10][CH2:9][CH2:8]1)=[O:37]
Reactant: [Li]C1CCCc2c(C)ccnc21
Reactant: O=C=O
Reactant: Cc1ccnc2c1CCCC2
Agent: Cl
Agent: [Li]CCCC
Solvent: c1ccccc1
Solvent: CCCCCC
Product: COC(=O)C1CCCc2c(C)ccnc21
Reaction time: 0.5 h

Procedure:
A solution of 4-methyl-5,6,7,8-tetrahydroquinoline (5.83 g., 0.04 mole) in dry benzene (40 ml.) was cooled to 0° and to the stirred solution was added dropwise a 15% w/w solution of butyl lithium in hexane (17.5 ml., 0.04 mole) under an atmosphere of nitrogen. The red reaction mixture of 8-lithio-4-methyl-5,6,7,8-tetrahydroquinoline was stirred at 0° for a further 30 minutes. It can then be treated with carbon dioxide followed by methanolic HCl to obtain methyl-4-methyl-5,6,7,8-tetrahydroquinoline-8-carboxylate which can be converted to 4-methyl-5,6,7,8-tetrahydroquinoline-8-thiocarboxamide by the procedures described in copending U.S. Ser. No. 460,265.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)=O)=[CH:4][CH:3]=1.O.[NH2:18][NH2:19]>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[N:18][NH2:19])[C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1
Reactant: NN
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Solvent: O
Solvent: CCO
Product: NN=C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Temperature: 21 °C

Procedure:
A solution of bis-(4-chloro-phenyl)-methanone (5.0 g, 19.9 mmol) and hydrazine monohydrate (5 mL, 103 mmol) in ethanol (25 mL) was heated to reflux 18 h, cooled to 21° C., and filtered to afforded the [bis-(4-chloro-phenyl)-methylene]-hydrazine compound as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[C:8]([CH3:13])[CH:9]=[CH:10][CH:11]=2)[C:6]([CH:14]=[O:15])=[CH:5][CH:4]=1.CC(=CC)C.[O-:21]Cl=O.[Na+]>CC(O)(C)C.O>[CH3:1][O:2][C:3]1[C:12]2[C:7](=[C:8]([CH3:13])[CH:9]=[CH:10][CH:11]=2)[C:6]([C:14]([OH:21])=[O:15])=[CH:5][CH:4]=1
Reactant: [O-][Cl+][O-]
Reactant: COc1ccc(C=O)c2c(C)cccc12
Agent: CC=C(C)C
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Product: COc1ccc(C(=O)O)c2c(C)cccc12

Procedure:
To a solution of 4-methoxy-8-methyl-1-naphthaldehyde (above Step-4 intermediate) (4.4 g, 22 mmol) in tBuOH (50 mL) and 2-methyl-2-butene (23.3 mL, 220 mmol) at 0° C. was added, a solution of NaClO2 (6.0 g, 66 mmol) and NaH2PO4 (9.1 g, 66 mmol) in water (40 mL) drop wise and the reaction mixture was stirred at RT overnight. After completion (TLC), the solvent was evaporated and the residue was basified with 10% NaOH solution and washed with CH2Cl2 (2×50 mL). The aqueous layer was then acidified with 1 N HCl and extracted with EtOAc (4×100 mL). The combined organic layer was washed with water (100 mL), brine (100 mL), dried and filtered. After removal of solvent, the desired compound was obtained (4.5 g, 95%) as an off white solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:9][C:8]2[CH:10]=[CH:11][C:12]([N+:14]([O-])=O)=[CH:13][C:7]=2[CH:6]=1)=[O:4].Cl>CO.[Fe]>[CH3:1][O:2][C:3]([C:5]1[S:9][C:8]2[CH:10]=[CH:11][C:12]([NH2:14])=[CH:13][C:7]=2[CH:6]=1)=[O:4]
Reactant: COC(=O)c1cc2cc([N+](=O)[O-])ccc2s1
Agent: [Fe]
Agent: Cl
Solvent: CO
Product: COC(=O)c1cc2cc(N)ccc2s1

Procedure:
A suspension of 584 (3.52 g, 14.8 mmol) in methanol (100 ml) was treated with Fe powder (6.63 g, 118.7 mmol). The resulting suspension was heated to reflux, and 12M HCl (8.5 ml) was slowly added over 15 min. The resulting green dark suspension was refluxed for an additional 3 h, then cooled and concentrated. The residue was taken up in EtOAc and washed with saturated aqueous NaHCO3, then brine, dried over MgSO4, filtered and concentrated to afford (2.57 g, 84%). 1H NMR: (DMSO) δ (ppm): 7.92 (s, 1H), 7.65 (d, J=8.8 Hz, 1H), 7.05 (d, J=1.5 Hz, 1H), 6.88 (dd, J=1.8, 8.4 Hz, 1H), 5.27 (s, 2H), 3.85 (s, 3H). LRMS : 207.0 (Calc.); 208.1 (found).