Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]([CH3:21])[C:11](=[N:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[S:12][CH:13]=2)=[CH:5][C:4]=1[S:22](Cl)(=[O:24])=[O:23].[CH3:26][NH:27][CH3:28].CO>C(O)C>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]([CH3:21])[C:11](=[N:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[S:12][CH:13]=2)=[CH:5][C:4]=1[S:22](=[O:24])(=[O:23])[N:27]([CH3:28])[CH3:26]
Reactant: CNC
Reactant: Cn1c(-c2ccc(Cl)c(S(=O)(=O)Cl)c2)csc1=Nc1ccccc1
Agent: Br
Solvent: CO
Solvent: CCO
Product: CN(C)S(=O)(=O)c1cc(-c2csc(=Nc3ccccc3)n2C)ccc1Cl

Procedure:
4.8 g (0.01 mole) of 4-(4-chloro-3-chlorosulfonylphenyl)-3-methyl-2-phenylimino-4-thiazoline hydrobromide are added in portions to a mixture of 5 ml (about 0.05 mole) of 40% strength aqueous dimethylamine solution and 50 ml of methanol (or ethanol), with external cooling and stirring, at a rate such that the temperature as far as possible does not rise above 35° C. The reaction mixture is stirred for 14 hours at room temperature, the solvent is distilled off under a waterpump vacuum and the residue is crystallized under 50 ml of water, stirring with a magnetic stirrer. Colorless crystals; melting point 178°-181° C.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([S:7]([N:10]2[CH2:15][CH2:14][N:13](C3N=C(N)C4C(=CC(OC)=C(OC)C=4)N=3)[CH2:12][CH2:11]2)(=[O:9])=[O:8])=[CH:4][CH:3]=1.N1CCNCC1.ClC1SC(S(Cl)(=O)=O)=CC=1>CO>[Cl:1][C:2]1[S:6][C:5]([S:7]([N:10]2[CH2:11][CH2:12][NH:13][CH2:14][CH2:15]2)(=[O:8])=[O:9])=[CH:4][CH:3]=1
Reactant: COc1cc2nc(N3CCN(S(=O)(=O)c4ccc(Cl)s4)CC3)nc(N)c2cc1OC
Agent: C1CNCCN1
Agent: O=S(=O)(Cl)c1ccc(Cl)s1
Solvent: CO
Product: O=S(=O)(c1ccc(Cl)s1)N1CCNCC1

Procedure:
Method B (14, 20, 23, 32). 2-[4-(5-Chloro-thiophene-2-sulfonyl)-piperazin-1-yl]-6,7-dimethoxy-quinazolin-4-ylamine (14): To a solution of piperazine (0.517 g, 6.0 mmol) and 5-chloro-thiophene-2-sulfonyl chloride (0.436 g, 2.0 mmol) in methanol (10 mL), the mixture was stirred at room temperature for 1 h. The solvent was evaporated, and the residue was purified with silica gel chromatography to obtain 1-(5-chloro-thiophene-2-sulfonyl)-piperazine. The intermediate (0.266 g, 1.0 mmol) and 4-amino-2-chloro-6,7-dimethoxy-quinazoline (0.251 g, 1.0 mmol) in 1-butanol (5 mL) were stirred under reflux overnight, and cooled to 80° C. The collected solid product was washed with ethyl acetate (2×10 mL), stirred in methanol (30 mL) under reflux for 1 h, filtered, washed with methanol (2×10 ml) to yield compound 14. 1HNMR (DMSO-d6) δ 3.06-3.08 (m, 4H), 3.80 (s, 3H), 3.84 (s, 3H), 3.94 (s, 4H), 7.36 (s, 1H), 7.37 (s, 1H), 7.59 (s, 1H), 7.60 (s, 1H). HRMS (M+H)+ calcd for C18H21ClN5O4S2 470.0718, found 470.0740. Anal. (C18H20ClN5O4S2.HCl) C, H, N.
Reaction SMILES: [ClH:1].[CH2:2]([O:4][C:5]([CH:7]1[O:11][N:10]=[C:9]([C:12]2[N:13]=[C:14]([CH:17]3[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]3)[S:15][CH:16]=2)[CH2:8]1)=[O:6])C>O1CCOCC1>[Cl-:1].[CH3:2][O:4][C:5]([CH:7]1[O:11][N:10]=[C:9]([C:12]2[N:13]=[C:14]([CH:17]3[CH2:22][CH2:21][NH2+:20][CH2:19][CH2:18]3)[S:15][CH:16]=2)[CH2:8]1)=[O:6]
Reactant: Cl
Reactant: CCOC(=O)C1CC(c2csc(C3CCN(C(=O)OC(C)(C)C)CC3)n2)=NO1
Solvent: C1COCCO1
Product: COC(=O)C1CC(c2csc(C3CC[NH2+]CC3)n2)=NO1
Product: [Cl-]
Temperature: 0 °C
Reaction time: 4 h

Procedure:
Under an argon atmosphere, at 0° C., a 4 N solution of hydrogen chloride in dioxane (11.4 ml) is added dropwise to a solution of tert-butyl 4-{4-[5-(methoxycarbonyl)-4,5-dihydro-1,2-oxazol-3-yl]-1,3-thiazol-2-yl}piperidine-1-carboxylate (B), 1.20 g) in dioxane (12 ml). The reaction mixture is stirred at 0° C. and then gradually warmed to room temperature. After 4 hours, the solvent and excess hydrogen chloride are removed. This gives 4-{4-[5-(methoxycarbonyl)-4,5-dihydro-1,2-oxazol-3-yl]-1,3-thiazol-2-yl}piperidinium chloride (1.10 g, 98%).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[C:4]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[N:5][CH:6]=[CH:7][CH:8]=1.FC1C=CC(N2CCNCC2)=CC=1.[CH:30]1([CH2:33][CH2:34][NH:35][C:36]([C:38]2[N:39]=[N:40][C:41](Cl)=[CH:42][CH:43]=2)=[O:37])[CH2:32][CH2:31]1>>[CH:30]1([CH2:33][CH2:34][NH:35][C:36]([C:38]2[N:39]=[N:40][C:41]([N:12]3[CH2:11][CH2:10][N:9]([C:4]4[C:3]([C:2]([F:1])([F:15])[F:16])=[CH:8][CH:7]=[CH:6][N:5]=4)[CH2:14][CH2:13]3)=[CH:42][CH:43]=2)=[O:37])[CH2:32][CH2:31]1
Reactant: FC(F)(F)c1cccnc1N1CCNCC1
Reactant: O=C(NCCC1CC1)c1ccc(Cl)nn1
Agent: Fc1ccc(N2CCNCC2)cc1
Product: O=C(NCCC1CC1)c1ccc(N2CCN(c3ncccc3C(F)(F)F)CC2)nn1
Yield: 43 %

Procedure:
Following the procedure as described in Example 1, making variation only as required to use 1-(3-trifluoromethylpyridin-2-yl)piperazine to replace 1-(4-fluorophenyl)-piperazine to react with 6-chloropyridazine-3-carboxylic acid (2-cyclopropylethyl)amide, the title compound was obtained as a white powder in 43% yield (0.061 g). 1H NMR (300 MHz, CDCl3) δ 8.44 (m, 1H), 8.01 (m, 2H), 7.89 (m, 1H), 7.02 (s, 2H), 3.88 (m, 4H), 3.54 (m, 2H), 3.41 (m, 4H), 1.51 (m, 2H), 0.78 (m, 1H), 0.45 (m, 2H), 0.07 (m, 2H). MS (ES+) m/z 421 (M+1).
Reaction SMILES: [CH3:1][CH:2]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]1[CH:14]=[CH:15][C:16]([C:18]([OH:20])=O)=[CH:17][N:8]1[C:7]2=[O:21])[CH3:3].C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.[N:39]1[CH:44]=[CH:43][CH:42]=[C:41]([CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][NH2:51])[CH:40]=1.C(N(CC)CC)C>CN(C)C=O.O.[OH-].[Na+]>[N:39]1[CH:44]=[CH:43][CH:42]=[C:41]([CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][NH:51][C:18]([C:16]2[CH:15]=[CH:14][C:9]3[N:8]([CH:17]=2)[C:7](=[O:21])[C:6]2[C:11](=[CH:12][CH:13]=[C:4]([CH:2]([CH3:1])[CH3:3])[CH:5]=2)[N:10]=3)=[O:20])[CH:40]=1
Reactant: NCCCCCCc1cccnc1
Reactant: CC(C)c1ccc2nc3ccc(C(=O)O)cn3c(=O)c2c1
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)c1ccc2nc3ccc(C(=O)NCCCCCCc4cccnc4)cn3c(=O)c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.8 %

Procedure:
To an ice-cold suspension of 16.15 g of 2-(1-methylethyl)-11-oxo-11H-pyrido[2,1-b]quinazoline-8-carboxylic acid, 15.75 g of diphenylphosphorylazide, and 10.2 g of 6-(3-pyridyl)-hexanamine in 100 ml of dry dimethylformamide was added 8.0 ml of triethylamine. The reaction mixture was held at 0° C. for 2 hours and allowed to warm to room temperature over night. The resulting clear, yellow solution was diluted with water and 5M sodium hydroxide solution and was extracted with 3×300 ml of dichloromethane. The combined organic layers were dried over potassium carbonate and evaporated to a yellow semi-solid which was recrystallized from ethyl acetate-hexane to give 21.22 g (84%) of N-[6-(3-pyridyl)hexyl]-2-(1-methylethyl)-11-oxo-pyrido[2,1-b]-quinazoline-8-carboxamide, mp 94°-96° C. Recrystallization gave mp 100°-103° C. Conversion to the dihydrochloride salt gave 22.12 g, mp 230°-236° C. (dec.) and recrystallization from ethanol-ether gave 21.06 g, mp 234°-240° C. (dec.).
Reaction SMILES: [C:1]([Si:5]([CH3:38])([CH3:37])[O:6][C@H:7]1[C@H:20](/[CH:21]=[CH:22]/[C@@H:23]([O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])[CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C@H:10]2[CH2:11][C:12]3[CH:13]=[CH:14][CH:15]=[C:16]([OH:19])[C:17]=3[CH2:18][C@H:9]2[CH2:8]1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[C:41](Cl)(=[O:48])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>O1CCCC1>[C:41]([O:19][C:16]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:17]=1[CH2:18][C@H:9]1[CH2:8][C@@H:7]([O:6][Si:5]([C:1]([CH3:3])([CH3:4])[CH3:2])([CH3:37])[CH3:38])[C@H:20](/[CH:21]=[CH:22]/[C@@H:23]([O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])[CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C@H:10]1[CH2:11]2)(=[O:48])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CCCCC[C@@H](/C=C/[C@@H]1[C@H]2Cc3cccc(O)c3C[C@H]2C[C@H]1O[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCC[C@@H](/C=C/[C@@H]1[C@H]2Cc3cccc(OC(=O)c4ccccc4)c3C[C@H]2C[C@H]1O[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 88.5 %

Procedure:
2 g (3.58 mmole, from Example 18) of (1R,2R,3aS,9aS)-2,3,3a,4,9,9a-hexahydro-2-(tert-butyldimethyl-silyoxy)-1-((S,E)-3-(tert-butyldimethylsilyoxy)oct-1-enyl)-1H-cyclopenta[b]naphthalen-5-ol, which contains 6% para-cyclized isomer, in dry tetrahydrofuran (20 ml) was treated with sodium hydride (0.29 g, 7.16 mol) at 0° C. and stirred for 10 minutes at room temperature, followed by dropwise addition of benzoyl chloride (0.63 ml, 5.37 mmol). After 30 minutes, the reaction was cooled to 10° C., diluted with ice cold brine (10 ml) and extracted with ethyl acetate (10 ml). The reaction mixture was phase separated and the aqueous layer was extracted with ethyl acetate. The organic layers were combined and dried over anhydrous magnesium sulfate. The solid was filtered off. The solvent was evaporated off under vacuum. The crude product was purified by chromatography on silica gel using a mixture of hexane and ethyl acetate as a gradient eluent. 2.1 g of (1R,2R,3aS,9aS)-2,3,3a,4,9,9a-hexahydro-2-(tert-butyldimethylsilyoxy)-1-((S,E)-3-(tert-butyldimethylsilyoxy)oct-1-enyl)-1H-cyclopenta[b]naphthalen-5-yl benzoate was obtained. The product was then dissolved in tetrahydrofuran (4.2 ml), and treated with acetic acid (12.6 ml) and distilled water (4.2 ml) overnight at room temperature. The reaction then was diluted with saturated sodium bicarbonate aqueous (50 ml) and extracted with ethyl acetate (60 ml). The reaction mixture was phase separated and the aqueous layer was extracted with ethyl acetate. The organic layers were combined and dried over anhydrous magnesium sulfate. The solid was filtered off. The solvent was evaporated off under vacuum. The crude product was purified by chromatography on silica gel using a mixture of hexane and ethyl acetate as a gradient eluent. The product was obtained in a crystalline form. MP: 140˜141° C. Yield: 68%.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.CN(C)[CH:8]=[O:9].[CH:11]([N:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][CH2:16][CH2:15]1)([CH3:13])[CH3:12].C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.CCCCCC>[CH:11]([N:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][CH2:16][CH:15]1[CH:8]=[O:9])([CH3:13])[CH3:12]
Reactant: CN(C)C=O
Reactant: CC(C)N1CCCc2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)N1c2ccccc2CCC1C=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56.2 %

Procedure:
Phosphorus oxychloride (18.6 g) was added dropwise to 29.2 g of N,N-dimethylformamide under ice cooling. The resulting mixture was stirred at room temperature for 30 minutes, followed by the dropwise addition of 17.5 g of 1-isopropyl-1,2,3,4-tetrahydroquinoline slowly under ice cooling. After stirring at room temperature for one hour, the reaction mixture was poured into ice water, neutralized with a saturated aqueous solution of sodium bicarbonate and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue so obtained was subjected to chromatography on a silica gel column (developing solvent: 10% ethyl acetate/n-hexane), whereby 11.4 g of the title compound were obtained as a reddish brown oil.
Reaction SMILES: [CH3:1][C:2]([C@H:6]1[CH2:11][CH2:10][C@H:9]([O:12][C:13]2[C:14]([C:30]([F:33])([F:32])[F:31])=[C:15]3[C:20](=[CH:21][CH:22]=2)[CH:19]=[C:18]([C@:23]2([CH3:29])[CH2:27][O:26]C(=O)[NH:24]2)[CH:17]=[CH:16]3)[CH2:8][CH2:7]1)([CH3:5])[CH2:3][CH3:4].O.C(O)C>[OH-].[Li+]>[NH2:24][C@@:23]([C:18]1[CH:17]=[CH:16][C:15]2[C:20](=[CH:21][CH:22]=[C:13]([O:12][C@H:9]3[CH2:8][CH2:7][C@H:6]([C:2]([CH3:1])([CH3:5])[CH2:3][CH3:4])[CH2:11][CH2:10]3)[C:14]=2[C:30]([F:32])([F:33])[F:31])[CH:19]=1)([CH3:29])[CH2:27][OH:26]
Reactant: CCC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc([C@]4(C)COC(=O)N4)ccc3c2C(F)(F)F)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc([C@@](C)(N)CO)ccc3c2C(F)(F)F)CC1
Temperature: 80 °C

Procedure:
A mixture of (R)-4-{6-[trans-4-(1,1-dimethyl-propyl)-cyclohexyloxy]-5-trifluoromethyl-naphthalen-2-yl}-4-methyl-oxazolidin-2-one (33.00 mg, 0.07119 mmol) in 4.2 M lithium hydroxide in a mixture solvent of water (0.9 mL) and ethanol (0.9 mL) was heated at 80° C. overnight. The solution was concentrated and the residue was partitioned between methylene chloride (4 mL) and water (2 mL). The organic phase was washed with water, dried over MgSO4, filtered and concentrated to give 28 mg of white precipitate, (R)-2-amino-2-{6-[trans-4-(1,1-dimethyl-propyl)-cyclohexyloxy]-5-trifluoromethyl-naphthalen-2-yl}-propan-1-ol (90% yield). MS: m/z=421.30 M-16. 1H NMR (400 MHz, CDCl3) δ ppm 0.74-0.89 (m, 10 H), 1.04-1.22 (m, 2H), 1.22-1.35 (m, 2 H), 1.43-1.61 (m, 5H), 1.82 (d, J=11.29 Hz, 2H), 2.18 (d, J=12.80 Hz, 2H), 2.35 (s, 3H), 3.63-3.82 (m, 2H), 4.23-4.36 (m, 1H), 7.28 (d, 1H), 7.61 (dd, J=9.16, 1.88 Hz, 1H), 7.82-7.95 (m, 2H), 8.19 (d, J=7.78 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]([S:20]([C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1)(=[O:22])=[O:21])[C:10]1[C:11]([CH3:19])=[CH:12][C:13]([C:16]([OH:18])=O)=[N:14][CH:15]=1.[CH3:30][NH:31][CH2:32][CH2:33][OH:34].ON1C2C=CC=CC=2N=N1.CN1CCOCC1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]([S:20]([C:23]1[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=1)(=[O:22])=[O:21])[C:10]1[C:11]([CH3:19])=[CH:12][C:13]([C:16]([N:31]([CH2:32][CH2:33][OH:34])[CH3:30])=[O:18])=[N:14][CH:15]=1
Reactant: CNCCO
Reactant: Cc1cc(C(=O)O)ncc1C(c1cc(F)ccc1F)S(=O)(=O)c1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: Cc1cc(C(=O)N(C)CCO)ncc1C(c1cc(F)ccc1F)S(=O)(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 86.3 %

Procedure:
To a solution of 5-[(2,5-difluorophenyl)[(4-fluorophenyl)sulfonyl]methyl]-4-methylpyridine-2-carboxylic acid (337 mg, 0.80 mmol) obtained in Example 12 in methylene chloride (8 ml), 2-(methylamino)ethanol (0.077 ml, 0.96 mmol), 1-hydroxybenzotriazole (130 mg, 0.96 mmol), 4-methylmorpholine (0.194 ml, 1.76 mmol), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (184 mg, 0.96 mmol) were added at room temperature. After stirring for 24 hours at room temperature, the reaction mixture was washed with 1 N hydrochloric acid. The organic layer was dried over anhydrous sodium sulfate and filtered, then the filtrate was concentrated under reduced pressure, and the resulting residue was subjected to flash silica gel chromatography. The fraction obtained from an elution with ethyl acetate was concentrated under reduced pressure, and the resulting residue was washed with a mixed solvent of ethanol and diethyl ether, and was collected by filtration, to obtain the title compound (328 mg, 0.69 mmol, 85%) as a white solid.
Reaction SMILES: C(NC(C)C)(C)C.[CH2:8]([Li])[CH2:9][CH2:10][CH3:11].[Si](C=[N+]=[N-])(C)(C)C.[F:20][C:21]1[C:22]([CH2:31][CH2:32][CH3:33])=C(C=[CH:27][C:28]=1[O:29][CH3:30])C=O>O1CCCC1>[C:10]([C:9]1[CH:8]=[CH:27][C:28]([O:29][CH3:30])=[C:21]([F:20])[C:22]=1[CH2:31][CH2:32][CH3:33])#[CH:11]
Reactant: [Li]CCCC
Reactant: CCCc1c(C=O)ccc(OC)c1F
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: C#Cc1ccc(OC)c(F)c1CCC
Reaction time: 0.5 h
Yield: 31.2 %

Procedure:
To a solution of diisopropylamine (0.841 mL, 6.0 mmol) in tetrahydrofuran (15 mL) at −78° C. under nitrogen was added slowly the solution of n-butyllithium (3.75 mL, 6.0 mmol, 1.6M in hexanes). After stirring for 30 minutes, the solution of TMS-diazomethane (3.0 mL, 6.0 mmol, 2M in hexanes) was added slowly into the reaction mixture. The mixture was stirred for 30 minutes then was added the solution of 3-fluoro-4-methoxy-2-propylbenzaldehyde (597) (0.589 g, 3.0 mmol) in tetrahydrofuran (3 mL). The resulting mixture was stirred at room temperature for 12 hours, quenched with saturated ammonium chloride and extracted with ethyl ether. The organic phase was washed with water, brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (10% EtOAc in hexanes) to provide 1-ethynyl-3-fluoro-4-methoxy-2-propylbenzene (626) (0.180 g, 31.2%) as a colorless oil.
Reaction SMILES: [P:1]([O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH:17]=O)([S:6][CH2:7][CH2:8][CH3:9])([O:3][CH2:4][CH3:5])=[O:2].[C:19]([NH:27][NH2:28])(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O>CO>[P:1]([O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH:17]=[N:28][NH:27][C:19](=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([S:6][CH2:7][CH2:8][CH3:9])([O:3][CH2:4][CH3:5])=[O:2].[P:1]([O-:10])([O-:3])([O-:2])=[S:6]
Reactant: CCCSP(=O)(OCC)Oc1ccccc1C=O
Reactant: NNC(=O)c1ccccc1
Solvent: CO
Solvent: O
Product: CCCSP(=O)(OCC)Oc1ccccc1C=NNC(=O)c1ccccc1
Product: [O-]P([O-])([O-])=S
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of O-ethyl S-propyl O-(2-formylphenyl) thiophosphate (4.1 grams; 0.0142 mole) in methanol (50 ml) was charged into a glass reaction vessel equipped with a mechanical stirrer. Benzoylhydrazine (1.939 grams; 0.0142 mole) was added and the reaction mixture was stirred at room temperature overnight. After this time water was added to the reaction mixture until it became cloudy. The mixture was then heated on a steam bath until it became clear again. The reaction mixture was then cooled in an ice bath resulting in the formation of a solid precipitate. The precipitate was recovered by filtration and washed with isopropyl ether. The washed product was then air dried for 15 minutes and thereafter dried overnight in a vacuum oven to yield the desired product O-ethyl S-propyl O-[2-benzoylhydrazonomethyl)phenyl] thiophosphate as a white powder.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[C:9]=1[OH:10])[CH:5]=O.[C:14]1([C:20](=O)[CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[NH2:29][C:30]([NH2:32])=[O:31].Cl>C(O)C>[OH:1][C:2]1[CH:3]=[C:4]([CH:5]2[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[C:20]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[NH:32][C:30](=[O:31])[NH:29]2)[CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[C:9]=1[OH:10]
Reactant: O=C(Cc1ccccc1)c1ccccc1
Reactant: O=Cc1cc(O)c(O)c([N+](=O)[O-])c1
Reactant: NC(N)=O
Agent: Cl
Solvent: CCO
Product: O=C1NC(c2ccccc2)=C(c2ccccc2)C(c2cc(O)c(O)c([N+](=O)[O-])c2)N1
Yield: 12.3 %

Procedure:
To a mixture of 3,4-dihydroxy-5-nitrobenzaldehyde (196 mg, 1.0 mmol), 1,2-diphenylethanone (183 mg, 1.0 mmol) and urea (180 mg, 3.0 mmol) in ethanol (50 mL) was added concentrated HCl (0.2 mL) and the reaction solution was heated to reflux for three days. The reaction solution was concentrated in vacuo and purified by silica gel column chromatography (DCM:THF=20:1) to afford Compound 10 as a yellow solid (49.7 mg, 12.3%). 1H NMR (DMSO-d6 500 MHz): δ 10.23 (br, 1H), 8.72 (s, 1H), 7.51 (s, 1H), 7.20-7.28 (m, 7H), 6.81-7.04 (m, 3H), 6.80 (d, J=6.5 Hz, 2H), 5.08 (s, 1H); MS (ESI): m/z 404 [M+1]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:4]=1[CH2:5][NH:6][CH2:7][C:8]#[CH:9].I[C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=1>CN(C)C=O.C(N(CC)CC)C.[Cu]I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:4]=1[CH2:5][NH:6][CH2:7][C:8]#[C:9][C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=1
Reactant: O=[N+]([O-])c1ccc(I)cc1
Reactant: C#CCNCc1ccc(OC)cc1OC
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc(CNCC#Cc2ccc([N+](=O)[O-])cc2)c(OC)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of EXAMPLE 23A (12.47 g, 60.83 mmol) in a mixture of N,N-dimethylformamide (150 mL) and triethylamine (150 mL) was added 1-iodo-4-nitrobenzene (18.18 g, 73 mmol), CuI (2.33 g, 12.2 mmol) and tetrakis(triphenylphosphine)palladium(0) (3.51 g, 3.04 mmol). The reaction mixture was stirred at room temperature overnight, and partitioned between ethyl acetate and brine. The organic phase was washed with brine, and concentrated. The crude material was purified by flash chromatography (20% ethyl acetate in hexane) to afford the title compound 1H NMR (400 MHz, dimethylsulfoxide-d6): δ 2.36 (br s, 1H), 3.59 (s, 2H), 3.72 (s, 2H), 3.74 (s, 3H), 3.77 (s, 3H), 6.48 (dd, J=6.0, 2.4 Hz, 1H), 6.53 (d, J=2.0 Hz, 1H), 7.20 (d, J=8.4 Hz, 1H), 7.67 (d, J=8.8 Hz, 2H), 8.22 (d, J=8.8 Hz, 2H).
Reaction SMILES: [CH:1]1([C:6]([O:8]CC)=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:11](#[N:13])[CH3:12].[H-].[Na+]>C1COCC1>[CH:1]1([C:6](=[O:8])[CH2:12][C:11]#[N:13])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCOC(=O)C1CCCC1
Reactant: CC#N
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#CCC(=O)C1CCCC1
Yield: 90 %

Procedure:
A solution of ethyl cyclopentanecarboxylate (prepared by esterification of commercially available cyclopentantecarboxylic acid, 30 g, 0.21 mol) and acetonitrile (10.1 g, 0.25 mol) in dry THF (80 mL) was added dropwise to a suspension of NaH (12.5 g, 0.31 mol) in dry THF (80 mL) and the resulting mixture was refluxed overnight. The reaction mixture was concentrated under reduced pressure and partitioned between water and EtOAc. The aqueous layer was separated, adjusted to pH 8 and extracted with EtOAc. The combined extracts were washed with brine, dried (MgSO4), and concentrated to give 3-cyclopentyl-3-oxopropanenitrile (26 g, 90% yield), which was used in the next step without further purification. 1H NMR (400 MHz, DMSO-d6): δ 4.06 (s, 2 H), 2.92 (m, 1 H), 1.41-1.77 (m, 8 H).
Reaction SMILES: [CH3:1][C:2]1([CH:5]2[CH2:10][CH2:9][C:8](=O)[CH2:7][CH2:6]2)[CH2:4][CH2:3]1.[NH3:12].[H][H]>CO.[Rh]>[CH3:1][C:2]1([C@@H:5]2[CH2:10][CH2:9][C@H:8]([NH2:12])[CH2:7][CH2:6]2)[CH2:4][CH2:3]1
Reactant: CC1(C2CCC(=O)CC2)CC1
Reactant: [H][H]
Reactant: N
Agent: [Rh]
Solvent: CO
Product: CC1([C@H]2CC[C@@H](N)CC2)CC1

Procedure:
11.0 g (72.3 mmol) of 4-(1 -methylcyclopropyl)cyclohexanone were stirred for 24 hours with 7.0 g (410 mmol) of NH3 dissolved in 120 ml of methanol, in the presence of 3.0 g of Rh/C (5%) at a hydrogen pressure of 20 bar and at a reaction temperature of 50° C. The reaction solution was filtered and the filtrate was concentrated. 9.8 g (88% of theory) were obtained of a colorless oil which was reacted without further purification.
Reaction SMILES: [CH2:1]1[CH:10]([OH:11])[CH2:9][C:8]2[C:3](=[CH:4][CH:5]=CC=2)[CH2:2]1.N[C:13](N)=S.[C:16]([OH:19])(=O)[CH3:17]>C(OCC)C>[CH3:13][O:11][C:10]1[CH:1]=[C:2]2[C:17](=[CH:8][CH:9]=1)[C:16](=[O:19])[CH2:5][CH2:4][CH2:3]2
Reactant: CC(=O)O
Reactant: OC1CCc2ccccc2C1
Reactant: NC(N)=S
Solvent: CCOCC
Product: COc1ccc2c(c1)CCCC2=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
At 0° C., to a stirred mixture of crude tetralol 46 (269 g, 1.32 mol) and thiourea (100 g, 1.32 mol) was added 370 mL of glacial acetic acid. The reaction mixture was stirred at rt for approximatively 1 h. When thiourea was completely dissolved, the reaction mixture was poured in diethyl ether (8 L), stirred for 2 h and the precipitated salt was filtered to afford 285 g (62% from 6-methoxy-1-tetralone) of compound 47. 1H NMR (400 MHz, acetone-d6) δ 1.82 (m, 2H), 1.89 (s, 3H), 2.61 (m, 2H), 2.77 (m, 2H), 3.77 (s, 3H), 3.86 (d, J=7.8 Hz, 2H), 6.04 (m, 1H), 6.69 (m, 1H), 6.75 (m, 1H), 7.56 (d, J=8.8 Hz, 1H) ppm (described in JOC, 33, 3126 (1968)).