Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:15]([F:16])=[CH:14][C:13]2[O:12][C:11]3[C:6](=[CH:7][C:8]([O:18][CH3:19])=[CH:9][C:10]=3[F:17])[C:5](=[O:20])[C:4]=2[CH:3]=1.[CH3:21][Mg]Cl>C1COCC1>[Br:1][C:2]1[C:15]([F:16])=[CH:14][C:13]2[O:12][C:11]3[C:6](=[CH:7][C:8]([O:18][CH3:19])=[CH:9][C:10]=3[F:17])[C:5]([CH3:21])([OH:20])[C:4]=2[CH:3]=1
Reactant: COc1cc(F)c2oc3cc(F)c(Br)cc3c(=O)c2c1
Reactant: C[Mg]Cl
Solvent: C1CCOC1
Product: COc1cc(F)c2c(c1)C(C)(O)c1cc(Br)c(F)cc1O2
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
A mixture of 2-bromo-3,5-difluoro-7-methoxy-9H-xanthen-9-one (40 g, 117 mmol) and THF (300 mL) was cooled to 0° C. and treated with methylmagnesium chloride (58.6 mL, 176 mmol) (3M in THF). After stirring at this temperature for 20 minutes, the reaction was quenched by the addition of sataturated NH4Cl (500 mL). Brine was added and the mixture was extracted with EtOAc (3×100 mL). The combined organic extracts were dried with sodium sulfate, filtered and concentrated in vacuo to afford crude 2-bromo-3,5-difluoro-7-methoxy-9-methyl-9H-xanthen-9-ol as a brown solid that was carried on without further purification. MS m/z=339.0 [M+1−H2O].
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[N:6][CH:5]=[CH:4][N:3]=1.Cl[CH2:10][C:11](=O)[CH3:12]>>[Cl:8][C:7]1[C:2]2[N:3]([CH:10]=[C:11]([CH3:12])[N:1]=2)[CH:4]=[CH:5][N:6]=1
Reactant: Nc1nccnc1Cl
Reactant: CC(=O)CCl
Product: Cc1cn2ccnc(Cl)c2n1

Procedure:
For example, condensation of a 2-amino-3-chloropyrazine with chloroacetone gives an 8-chloro-2-methylimidazo[1,2-a]pyrazine as shown the following reaction Scheme II. ##STR14##
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[I:7][C:8]1[CH:13]=[CH:12][C:11]([C:14](=[O:20])[CH2:15][CH2:16][CH2:17][CH2:18]Cl)=[CH:10][CH:9]=1.[CH3:21][CH:22]([CH3:38])[C:23]([NH:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH:27]=1)=[O:24]>>[I:7][C:8]1[CH:13]=[CH:12][C:11]([C:14](=[O:20])[CH2:15][CH2:16][CH2:17][CH2:18][N:35]2[CH2:36][CH2:37][CH:32]([C:28]3[CH:27]=[C:26]([NH:25][C:23](=[O:24])[CH:22]([CH3:21])[CH3:38])[CH:31]=[CH:30][CH:29]=3)[CH2:33][CH2:34]2)=[CH:10][CH:9]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: O=C(CCCCCl)c1ccc(I)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3ccc(I)cc3)CC2)c1

Procedure:
Prepared by Procedure K and Scheme B1 (K2CO3) using 1-(4-iodophenyl)-5-chloro-1-pentanone and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 533 (M+H)+.
Reaction SMILES: [Cl:1]C(OCC)=O.CCN(C(C)C)C(C)C.[CH3:16][C:17]1[CH:18]=[CH:19][C:20]2[CH:21]([CH3:29])[CH:22]3[CH2:26][NH:25][CH2:24][CH:23]3[C:27]=2[CH:28]=1>C(Cl)Cl>[CH3:16][C:17]1[C:18]([Cl:1])=[CH:19][C:20]2[CH:21]([CH3:29])[CH:22]3[CH2:26][NH:25][CH2:24][CH:23]3[C:27]=2[CH:28]=1
Reactant: CCOC(=O)Cl
Reactant: Cc1ccc2c(c1)C1CNCC1C2C
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc2c(cc1Cl)C(C)C1CNCC21
Reaction time: 2 h
Yield: 54.1 %

Procedure:
Ethyl chloroformate (0.29 mL, 3.0 mmol) and DIEA (1.6 mL, 9.0 mmol) were added to a solution of 5-methyl-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole (from Example 13, Step F) (0.56 g, 3.0 mmol) in CH2Cl2 (15 mL) at 0° C. The reaction was stirred for 2 hours from 0° C. to room temperature. The reaction was quenched with aqueous HCl (15 mL, 1M). The desired product was extracted with CH2Cl2 (3×15 mL). The organic extracts were washed with brine, dried over MgSO4, and concentrated. The crude product was purified by column chromatography (SiO2) using a 10-60% EtOAc-hexanes gradient to afford 0.36 g (46%) of the subtitle compound. MS calculated for C16H21NO2+H: 260, observed: 260.
Reaction SMILES: Br[C:2]1[C:6]([Br:7])=[C:5]([NH:8][C:9]([C@@H:11]2[CH2:13][C@H:12]2[CH3:14])=[O:10])[S:4][N:3]=1.[C:15]([O:19][C:20]([N:22]1[C:30]2[C:25](=[CH:26][C:27]([Sn](C)(C)C)=[CH:28][CH:29]=2)[CH:24]=[N:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16]>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:15]([O:19][C:20]([N:22]1[C:30]2[C:25](=[CH:26][C:27]([C:2]3[C:6]([Br:7])=[C:5]([NH:8][C:9]([C@@H:11]4[CH2:13][C@H:12]4[CH3:14])=[O:10])[S:4][N:3]=3)=[CH:28][CH:29]=2)[CH:24]=[N:23]1)=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)OC(=O)n1ncc2cc([Sn](C)(C)C)ccc21
Reactant: C[C@@H]1C[C@H]1C(=O)Nc1snc(Br)c1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1COCCO1
Product: C[C@@H]1C[C@H]1C(=O)Nc1snc(-c2ccc3c(cnn3C(=O)OC(C)(C)C)c2)c1Br
Temperature: 85 °C

Procedure:
Dissolve (1R,2R)-2-methyl-cyclopropanecarboxylic acid (3,4-dibromo-isothiazol-5-yl)-amide (3.0; g, 8.82; mmol) in anhydrous 1,4-dioxane (88; mL) and add 5-trimethylstannanyl-indazole-1-carboxylic acid tert-butyl ester (4. 11; g, 9.70; mmol). Blanket under nitrogen, add bis(triphenylphosphine)palladium(II) chloride (0.62; g, 0.88 mmol) and heat to 85° C. for 4; days. Concentrate and purify the residue by silica gel chromatography, gradient eluting from 20:80; to 40:60; ethyl acetate:hexanes to give the title compound (1.04; g, 70% purity wt/wt, 17%) which is carried on with out further purification. MS (m/z): 477, 479; (M+1).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[NH:7][C:6](=[O:8])[CH2:5][CH2:4]1.CS(Cl)(=O)=O.[N:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]1[C:21]([C:28]2[C:37]3[C:32](=[CH:33][C:34](O)=[CH:35][CH:36]=3)[N:31]=[CH:30][CH:29]=2)=[C:22]2[CH2:27][CH2:26][CH2:25][N:23]2[N:24]=1>CN(C)C=O>[N:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]1[C:21]([C:28]2[C:37]3[C:32](=[CH:33][C:34]([O:1][CH2:2][CH:3]4[NH:7][C:6](=[O:8])[CH2:5][CH2:4]4)=[CH:35][CH:36]=3)[N:31]=[CH:30][CH:29]=2)=[C:22]2[CH2:27][CH2:26][CH2:25][N:23]2[N:24]=1
Reactant: Oc1ccc2c(-c3c(-c4ccccn4)nn4c3CCC4)ccnc2c1
Reactant: O=C1CC[C@H](CO)N1
Agent: CS(=O)(=O)Cl
Solvent: CN(C)C=O
Product: O=C1CCC(COc2ccc3c(-c4c(-c5ccccn5)nn5c4CCC5)ccnc3c2)N1
Temperature: 60 °C
Reaction time: 16 h

Procedure:
A solution of (R)-(−)-5-(hydroxymethyl)-2-pyrrolidinone (315 mg, 2.74 mmol) in N,N-dimethylformamide (3 mL) is treated with methansulfonyl chloride (320 mg, 2.74 mmol) and heated at 60° C. for 5 h. The reaction mixture is diluted with N,N-dimethylformamide (1 mL) and 4-(2-pyridin-2-yl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-quinolin-7-ol (200 mg, 0.91 mmol) added. The mixture is stirred at 60° C. for additional 16 h, cooled to room temperature, and partitioned between ethyl acetate and water. The organic portion is washed three times with water, once with brine, dried (sodium sulfate), filtered and concentrated in vacuo. The crude residue is chromatographed on SiO2 (89% dichloromethane 10% methanol 1% concentrated ammonium hydroxide) to yield the title compound, 32 mg (8%), as a light red solid.
Reaction SMILES: [H-].[Na+].[C:3]1([CH2:9][C:10](=[O:12])[CH3:11])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Cl:13][C:14]1[CH:15]=[C:16]([CH:21]=[CH:22][CH:23]=1)[CH:17]=[CH:18][CH2:19]Br>C(COC)OC>[Cl:13][C:14]1[CH:15]=[C:16]([CH:17]=[CH:18][CH2:19][CH:9]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[C:10](=[O:12])[CH3:11])[CH:21]=[CH:22][CH:23]=1
Reactant: Clc1cccc(C=CCBr)c1
Reactant: CC(=O)Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(=O)C(CC=Cc1cccc(Cl)c1)c1ccccc1
Temperature: 25 °C

Procedure:
Sodium hydride (25.20 g., 0.60 mole, oil dispersion) is suspended in glyme (800 ml.) and phenyl acetone (80.50 g., 0.60 mole) in glyme (100 ml.) is added dropwise with stirring. After complete addition the mixture is heated to reflux for one hour. The mixture is cooled to room temperature and a solution of crude m-chlorocinnamyl bromide (139 g., 0.6 mole) in glyme (100 ml.) is added dropwise. When addition is complete the mixture is refluxed for 24 hours then allowed to cool. After filtration of inorganic salts and removal of solvent from the filtrate, vacuum distillation provides 36.11 g., b.p. 158.5°-163°/0.1 mm.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4](=[O:7])[NH:3][CH:2]=1.[CH3:8][C:9]1([CH3:20])[O:18][C:17]2[CH:16]=[CH:15][N:14]=[CH:13][C:12]=2[CH:11]2[O:19][CH:10]12>>[CH3:8][C:9]1([CH3:20])[O:18][C:17]2[CH:16]=[CH:15][N:14]=[CH:13][C:12]=2[C@@H:11]([N:1]2[CH:6]=[CH:5][C:4](=[O:7])[N:3]=[CH:2]2)[C@@H:10]1[OH:19]
Reactant: O=c1ccnc[nH]1
Reactant: CC1(C)Oc2ccncc2C2OC21
Product: CC1(C)Oc2ccncc2[C@@H](n2ccc(=O)nc2)[C@@H]1O

Procedure:
This example was also prepared by heating an equimolar mixture of 4(3H)-pyrimidone and 3,4-dihydro-2,2-dimethyl-3,4-epoxy-2H-pyrano[3,2-c]pyridine at 60° C. for 1 hour followed by chromatography as above.
Reaction SMILES: [CH2:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH2:4][C:3](=[O:11])[O:2]1.[H-].[Al+3].[H-].[H-].CCOCC.Cl>ClCCl>[CH2:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH2:4][CH:3]([OH:11])[O:2]1
Reactant: O=C1Cc2ccccc2CO1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: ClCCl
Solvent: CCOCC
Product: OC1Cc2ccccc2CO1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 93.2 %

Procedure:
To a solution of 3.00 g (0.020 mol) of 1,4-dihydro-3H-2-benzopyran-3-one in 100 mL of dry dichloromethane, cooled to -78° C., was added dropwise, over 1 hour, 24 mL (0.022 mol) of a 1M solution of disobutyl aluminum hydride in dichloromethane. After stirring at -78° C. for 2 hours and at 0° C. for 15 minutes, 100 mL of ether was added, followed by dropwise addition of 1.2N HCl until a pH of 1-2 was reached. Separation of the organic phase, extraction of the aqueous phase with ether and concentration of the combined dried (MgSO4) extracts provided 2.8 g (91%) of 3,4-dihydro-1H-2-benzopyran-3-ol. This product decomposes on standing or on chromatography on silica gel and consequently was used directly for the next reaction step. TLC Rf 0.13 (SiO2, CH2Cl2, brown-orange CAS and heat).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].C([O:11][CH:12]=[C:13]([C:19](OCC)=O)[C:14]([O:16][CH2:17][CH3:18])=[O:15])C.C1(OC2C=CC=CC=2)C=CC=CC=1>C(O)C>[OH:11][C:12]1[C:7]2[C:2](=[C:3]([OH:8])[CH:4]=[CH:5][CH:6]=2)[N:1]=[CH:19][C:13]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: Nc1ccccc1O
Solvent: CCO
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)c1cnc2c(O)cccc2c1O
Temperature: 25 °C
Yield: 5.6 %

Procedure:
A mixture of 2-aminophenol (5.457 g) and diethyl ethoxymethylenemalonate (10.81 g) is heated to 130° C. for 2 h with removal of ethanol by a Dean-Stark trap. The reaction is cooled to room temperature. Diphenyl ether (50 mL) is added and the mixture is heated to 240° C. for 90 min with removal of ethanol by a Dean-Stark trap. The solution is cooled to room temperature and the resulting solid is collected and washed with hexanes. The crude solid is recrystallized from acetone to yield 0.650 g of ethyl 4,8-dihydroxyquinoline-3-carboxylate. A mixture of this ester (0.500 g) and 4-chlorobenzylamine (1.518 g) are heated to 180° C. for 1 h. The solution is cooled to room temperature and diluted with CH2Cl2. The resulting solid is collected and chromatographed on silica, eluting with 3% MeOH/CH2Cl2. Fractions homogeneous by TLC are combined and concentrated in vacuo. The residue is sonicated with CH2Cl2 /hexanes. The resulting solid is collected and dried to afford 0.349 g of the desired product as an off-white solid.
Reaction SMILES: [C:1]([C:4]1[CH:16]=[CH:15][C:14]2[C:13]3[C:8](=[CH:9][C:10](Br)=[CH:11][CH:12]=3)[CH2:7][C:6]=2[CH:5]=1)(=[O:3])[CH3:2].ClCCl.[N:21]1C2C(=CC=CC=2)C=C[CH:22]=1>>[C:1]([C:4]1[CH:16]=[CH:15][C:14]2[C:13]3[C:8](=[CH:9][C:10]([C:22]#[N:21])=[CH:11][CH:12]=3)[CH2:7][C:6]=2[CH:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc2c(c1)Cc1cc(Br)ccc1-2
Reactant: c1ccc2ncccc2c1
Solvent: ClCCl
Product: CC(=O)c1ccc2c(c1)Cc1cc(C#N)ccc1-2

Procedure:
A mixture of 2-acetyl-7-bromofluorene (13.2 g.) and cuprous cyanide (8.2 g.) in quinoline (40 ml.) was heated to reflux for 40 minutes, cooled to 100° and poured into a mixture of ice-cold dilute aqueous ammonia and dichloromethane. The organic layer was separated, filtered to remove a yellow solid, washed with N-hydrochloric acid, dried over sodium sulphate and evaporated. The residual solid was recrystallised from ethanol containing a small amount of dimethylformamide to give 2-acetyl-7-cyanofluorene m.p. 182°-188°.
Reaction SMILES: [O:1]=[C:2]1[C:5]2([CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]2)[CH:4]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[NH:3]1.[H-].[Na+].Br[CH:28]([CH3:30])[CH3:29]>CN(C=O)C>[O:1]=[C:2]1[C:5]2([CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]2)[CH:4]([C:18]2[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=2)[N:3]1[CH:28]([CH3:30])[CH3:29]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)C(=O)NC2c1ccc(Cl)cc1
Reactant: CC(C)Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)N1C(=O)C2(CCN(C(=O)OC(C)(C)C)CC2)C1c1ccc(Cl)cc1
Temperature: 50 °C
Reaction time: 0.08 h

Procedure:
In a dry 100 mL 3-necked flask, add 1,1-dimethylethyl 1-oxo-3-(4-chlorophenyl) -2,7-diazaspiro[3.5]nonane-7-carboxylate (7.0 g) and dry DMF (50 mL) and cool to ˜2 C. Add portionwise sodium hydride in 60% oil dispersion (1.10 g) keeping temperature at 2-5 C. After 5 min., add portionwise 2-bromopropane (2.6 mL) keeping temperature 3 to 8° C. Warm mixture to 50° C. After 4.5 h, cool to ˜20° C. and add ice water (400 mL). Extract with EtOAc (2×499 mL). Extract EtOAc with brine (50 mL). Concentrate the dried (MgSO4) EtOAc in vacuo to give the title compound as an amber oil (8.80 g). Add EtOAc:hexane (1:2, 20 mL) and keep overnight at RT to give the title compound as a yellow solid (5.75 g).
Reaction SMILES: [CH:1]([C:3]1[N:8]=[CH:7][C:6]([C:9]2[CH:17]=[CH:16][C:12]([C:13]([NH2:15])=[O:14])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)=[O:2].[CH2:18]([Mg]Br)[CH3:19]>C1COCC1.C(OCC)(=O)C>[OH:2][CH:1]([C:3]1[N:8]=[CH:7][C:6]([C:9]2[CH:17]=[CH:16][C:12]([C:13]([NH2:15])=[O:14])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)[CH2:18][CH3:19]
Reactant: CC[Mg]Br
Reactant: NC(=O)c1ccc(-c2ccc(C=O)nc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCC(O)c1ccc(-c2ccc(C(N)=O)cc2)cn1
Reaction time: 3 h
Yield: 50.2 %

Procedure:
To a solution of 4-(6-formylpyridin-3-yl)benzamide (0.30 g, 1.32 mmol), in THF (30 mL) was added ethyl magnesium bromide (0.53 g, 3.97 mmol, 3M in diethyl ether) under nitrogen at 0° C. and the contents were stirred for 3 h at the same temperature. The contents were diluted with ethyl acetate (150 mL), quenched with ammonium chloride solution (100 mL), the organic layer washed with brine solution (2×100 mL), the layers separated, the organic layer dried over sodium sulphate and distilled off to get the crude product. The compound was purified by flash chromatography (100-200 micron; 60% ethyl acetate in hexane) to give 4-(6-(1-hydroxypropyl)pyridin-3-yl)benzamide (0.17 g, 51% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.83 (s, 1H), 8.10 (dd, 1H), 8.00 (s, 1H), 7.97 (d, 2H), 7.79 (d, 2H), 7.55 (d, 1H), 7.36 (s, 1H), 5.30 (d, 1H), 4.53 (q, 1H), 1.17 (m, 1H), 1.65 (m, 1H), 0.86 (t, 3H); LC-MS m/z calcd for [M+H]+ 257.31. found 257.4.
Reaction SMILES: [CH:1](=[C:8]1[C:21]2[O:20][C:19]3[C:14](=[CH:15][C:16]([C:22]([O:24]C)=[O:23])=[CH:17][CH:18]=3)[C:13](=[O:26])[C:12]=2[CH2:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+]>C(O)C>[CH:1](=[C:8]1[C:21]2[O:20][C:19]3[C:14](=[CH:15][C:16]([C:22]([OH:24])=[O:23])=[CH:17][CH:18]=3)[C:13](=[O:26])[C:12]=2[CH2:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc2oc3c(c(=O)c2c1)CCCC3=Cc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccc2oc3c(c(=O)c2c1)CCCC3=Cc1ccccc1
Yield: 86.9 %

Procedure:
4-benzylidene-1,2,3,4-tetrahydro-9-oxo-9H-xanthen-7-carboxylic acid, methyl ester (1.2 g) was hydrolized by treatment with 1% KOH in 95% ethanol (19.5 ml) at reflux temperature for 15 minutes. After cooling and acidification with 37% HCl the precipitate was filtered and washed with methanol and then with water to give 1 g of 4-benzylidene-1,2,3,4-tetrahydro-9-oxo-9H-xanthen-7-carboxylic acid, m.p. 284°-286° C., NMR (CF3COOD) δ ppm: 2.12 (m) (2H, C-2 protons), 3.13 (m) (4H, C-1 and C-3 protons), 7.64 (m) (5H, phenyl protons), 8.14 (d) (1H, C-5 proton), 8.43 (bs) (1H, =CH--), 8.88 (dd) (1H, C-6 proton), 9.38 (d) (1H, C-8 proton).
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][CH3:3].N1(CC([C:15]2[C:28]3[NH:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[S:20][C:19]=3[CH:18]=[CH:17][C:16]=2[C:29](=[S:31])[NH2:30])C)CCCCCC1.S>C(O)C>[N:4]1([CH2:17][CH:18]([N:27]2[C:28]3[CH:15]=[C:16]([C:29](=[S:31])[NH:30][CH2:22][CH2:21][CH3:26])[CH:17]=[CH:18][C:19]=3[S:20][C:21]3[C:26]2=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH3:19])[CH2:28][CH2:15][CH2:16][CH2:3][CH2:2][CH2:1]1
Reactant: CCCN
Reactant: CC(CN1CCCCCC1)c1c(C(N)=S)ccc2c1Nc1ccccc1S2
Agent: S
Solvent: CCO
Product: CCCNC(=S)c1ccc2c(c1)N(C(C)CN1CCCCCC1)c1ccccc1S2
Reaction time: 16 h

Procedure:
n-Propylamine (3.3 cc) is added to a solution of -[(2RS)-1-(perhydro-1-azepinyl)-2-propyl]-2-phenothiazinecarbothioamide (3.2 g) in absolute ethanol (80 cc). The mixture is saturated with hydrogen sulphide and then brought to 150° C. for 16 hours. The reaction mixture is concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa). The residue is diluted with ethyl 5 acetate (150 cc), washed with distilled water (3×100 cc) and with saturated sodium chloride solution (100 cc), dried over magnesium sulphate and then concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) before being purified by chromatography on a column (height: 32 cm; diameter: 4 cm) of silica gel (0.06-0.2 mm), eluting with a 60:40 (by volume) mixture (1,000 cc) of cyclohexane and ethyl acetate, collecting 60-cc fractions. Fractions 3 to 11 are combined and concentrated to dryness at 50° C. under reduced pressure (30 mm Hg; 4 kPa) to give 10-[(2RS)-1-(perhydro-1-azepinyl)-2-propyl]-N-propyl-2-phenothiazinethiocarboxamide (2.5 g) in the form of a clear orange oil.
Reaction SMILES: C([Li])CCC.[S:6]1[CH:10]=[CH:9][N:8]=[CH:7]1.[CH3:11][C:12]([S:15]([N:17]=[C:18]1[CH2:21][O:20][CH2:19]1)=[O:16])([CH3:14])[CH3:13]>O1CCCC1>[S:6]1[CH:10]=[CH:9][N:8]=[C:7]1[C:18]1([NH:17][S:15]([C:12]([CH3:14])([CH3:13])[CH3:11])=[O:16])[CH2:21][O:20][CH2:19]1
Reactant: CC(C)(C)S(=O)N=C1COC1
Reactant: c1cscn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)S(=O)NC1(c2nccs2)COC1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 66.7 %

Procedure:
A solution of n-butyllithium in hexanes (1.6 M, 2.5 mL, 3.99 mmol) was added dropwise to a solution of thiazole (364 mg, 4.23 mmol) in tetrahydrofuran (30 mL) at −78° C. The resulting mixture was stirred for 30 min at −78° C. before a solution of 2-methyl-n-(oxetan-3-ylidene)propane-2-sulfinamide (CAN 1158098-73-7) (500 mg, 2.85 mmol) in tetrahydrofuran (3.5 mL) was added dropwise at −78° C. The reaction solution was stirred for an additional 30 min at −78° C. before being warmed to 22° C., and then was quenched with saturated aqueous ammonium chloride solution. The crude reaction mixture was then partitioned between water and ethyl acetate. The aqueous layer was further extracted with ethyl acetate and the organic layers were combined. The combined layers were washed with saturated aqueous sodium chloride solution, and the washed solution was dried with anhydrous sodium sulfate and evaporated down to dryness. The crude product was purified by flash-column chromatography (40% ethyl acetate-hexanes, grading to 100% ethyl acetate, then flushing with 10% methanol-dichloromethane) to give the title compound (495 mg, 67%). MS (EI): m/e=261.0 [M+H]+.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([CH2:10][C@@H:11]([O:15][C:16]([C:18]2[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=2)=[O:17])[C@@H:12]([NH2:14])[CH3:13])[CH:6]=[CH:7][C:8]=1[Cl:9].C(N(CC)CC)C.[Si]([O:42][CH:43]1[CH2:49][C:48](=[O:50])[O:47][C:45](=[O:46])[CH2:44]1)(C(C)(C)C)(C)C>C(Cl)Cl>[Cl:2][C:3]1[CH:4]=[C:5]([CH2:10][C@@H:11]([O:15][C:16]([C:18]2[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=2)=[O:17])[C@@H:12]([NH:14][C:48]([CH2:49][CH:43]([OH:42])[CH2:44][C:45]([OH:47])=[O:46])=[O:50])[CH3:13])[CH:6]=[CH:7][C:8]=1[Cl:9]
Reactant: CC(C)(C)[Si](C)(C)OC1CC(=O)OC(=O)C1
Reactant: C[C@H](N)[C@@H](Cc1ccc(Cl)c(Cl)c1)OC(=O)c1ccc2ccccc2c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@H](NC(=O)CC(O)CC(=O)O)[C@@H](Cc1ccc(Cl)c(Cl)c1)OC(=O)c1ccc2ccccc2c1
Reaction time: 8 h
Yield: 71.1 %

Procedure:
129 mg of (1S, 2R)-3-(3,4-dichlorophenyl)-1-methyl-2-(2-naphthoyloxy)propylamine hydrochloride and 120 μl of triethylamine were dissolved in 15 ml of methylene chloride, and 82 mg of 3-(tert-butyldimethylsilyloxy)glutaric anhydride was added thereto with stirring under cooling with ice. The mixture was stirred at room temperature for 3 hours. The reaction solution was extracted by an addition of 1N hydrochloric acid and methylene chloride. The organic layer was dried over anhydrous magnesium sulfate. The drying agent was separated by filtration, and the solvent was distilled off under reduced pressure. The residue was dissolved in a liquid mixture of 10 ml of tetrahydrofuran and 5 ml of 1N hydrochloric acid, and the solution was left to stand at room temperature overnight. The reaction solution was extracted by an addition of water and ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution and then dried over anhydrous magnesium sulfate. The drying agent is separated by filtration, and then the solvent was distilled off under reduced pressure. The residue was subjected to silica gel thin layer chromatography (Kieselgel™ 60F254, Art 5744, manufactured by Merck Co.; chloroform/methanol=6/1) to obtain 112 mg (yield: 71%) of the above-identified compound as white powder.
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.[F:13][C:14]1[CH:15]=[CH:16][C:17]([N+:21]([O-:23])=[O:22])=[C:18]([OH:20])[CH:19]=1.[CH3:24][O:25][CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]1O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.C(Cl)Cl>[F:13][C:14]1[CH:15]=[CH:16][C:17]([N+:21]([O-:23])=[O:22])=[C:18]([O:20][C@@H:27]2[CH2:28][CH2:29][CH2:30][CH2:31][C@@H:26]2[O:25][CH3:24])[CH:19]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1O
Reactant: COC1CCCCC1O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: CO[C@H]1CCCC[C@H]1Oc1cc(F)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 48 h

Procedure:
2.36 ml DEAD were added to an ice-cooled solution of the 1.57 g 5-fluoro-2-nitrophenol, 1.95 ml 2-methoxycyclohexanol and 3.93 g triphenylphosphine in 30 ml THF. The reaction mixture was allowed to warm to rt overnight. The mixture was stirred additional 48 hours. Then the reaction mixture was diluted with methylene chloride and washed with 10% aq. potassium carbonate solution. The organic phase was passed through a hydrophobic frit and evaporated. Purification was achieved by silica gel column chromatography (solvent:10:1 iso-hexane: EtOAc).
Reaction SMILES: [CH:1]([CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9]C)=[O:8])=[O:2].O>CO>[CH:1]([CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8])=[O:2]
Reactant: COC(=O)CCCCC=O
Solvent: O
Solvent: CO
Product: O=CCCCCC(=O)O
Yield: 40.9 %

Procedure:
36 g of methyl 5-formylvalerate, 90 g of water and 1 g of p-toluenesclfonic acid were heated under reflux for 8 hours, the methanol formed being distilled off continuously. Fractional vacuum distillation gave 13.3 g of 5-formylvaleric acid (yield 41% of theory).