Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[Mg]Br.[CH3:11][C:12]1([CH3:33])[CH:20]2[CH:16]([CH2:17][N:18]([C:21](=[O:31])[CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[O:29][CH3:30])[CH2:19]2)[C:15](=[O:32])[CH:14]=[CH:13]1.[Cl-].[Ce+3].[Cl-].[Cl-].[Cl-].[NH4+]>O1CCCC1.C(OCC)(=O)C>[CH3:11][C:12]1([CH3:33])[CH:20]2[CH:16]([CH2:17][N:18]([C:21](=[O:31])[CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[O:29][CH3:30])[CH2:19]2)[C:15]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])([OH:32])[CH:14]=[CH:13]1
Reactant: COc1ccccc1CC(=O)N1CC2C(=O)C=CC(C)(C)C2C1
Reactant: COc1ccccc1[Mg]Br
Agent: [Ce+3]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccccc1CC(=O)N1CC2C(C1)C(O)(c1ccccc1OC)C=CC2(C)C
Temperature: 15 °C
Yield: 54.7 %

Procedure:
To a suspension of 22.73 g of 2-methoxyphenylmagnesium bromide in 70 cm3 of tetrahydrofuran, cooled to 15° C., are added, dropwise and with stirring, a solution of 6.77 g of (3aRS,7aRS)7, 7-dimethyl-2-[(2-methoxyphenyl)acetyl]-2,3,3a,4,7,7a -hexahydro-1H-4-isoindolone in 10 cm3 of tetrahydrofuran, followed by 5.3 g of anhydrous cerium chloride. The reaction mixture is stirred at room temperature for 18 hours, treated with 80 cm3 of saturated aqueous ammonium chloride solution, taken up in 100 cm3 of ethyl acetate and washed with 100 cm3 of saturated aqueous sodium chloride solution. The organic phase is separated out after settling has taken place, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a column of silica gel (particle size 0.04-0.06 mm, diameter 5.5 cm, height 30 cm), eluting under a pressure of 0.5 bar of nitrogen with a mixture of cyclohexane and ethyl acetate (50/50 by volume) and collecting 75 cm3 fractions. Fractions 17 to 40 are combined and then concentrated to dryness under reduced pressure (2.5 kPa). 4.98 g of (3aRS,4RS,7aRS)-7,7-dimethyl-4-(2-methoxyphenyl)-2-[(2-methoxyphenyl)acetyl]2,3,3a,4,7,7a-hexahydro-1H-4-isoindolol are obtained in the form of a colourless oil.
Reaction SMILES: C1(=O)[N:5]([C:6]#[C:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)C(=O)C2=CC=CC=C12.[H][H].O.NN>CO.CCOCC.[Pt]=O>[Cl:18][C:14]1[CH:13]=[C:12]([CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][NH2:5])[CH:17]=[CH:16][CH:15]=1
Reactant: [H][H]
Reactant: O=C1c2ccccc2C(=O)N1C#CCCCCc1cccc(Cl)c1
Agent: O=[Pt]
Agent: NN
Solvent: O
Solvent: CCOCC
Solvent: CO
Product: NCCCCCCc1cccc(Cl)c1
Temperature: 5 °C
Reaction time: 72 h

Procedure:
A suspension of 1-(phthalimido)-6-(3-chlorophenyl)hex-1-yne (10 g, 30 mmol) in methanol (100 ml) was treated with platinum oxide (250 mg) and the mixture hydrogenated at 50 psi for 72 h. Further quantities of catalyst were added at intervals and when the theoretical uptake of hydrogen was complete, the mixture was filtered and the filtrate evaporated to a brown oil (9.5 g, 96%). This was dissolved in IMS 99 (100 ml) and treated with hydrazine hydrate (2.8 g, 56 mmol) under reflux for 16 h. The mixture was cooled to 5° C. and the precipitated solid removed by filtration. Evaporation of the filtrate gave an oil which was taken up in ether, washed with water, dried (Na2SO4) and evaporated to a brown oil (5.8 g, 98%)
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]#[N:9])[C:5]([S:10][CH2:11][CH3:12])=[CH:4][CH:3]=1.[C:13]([C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=1)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CC([O-])(C)C.[K+]>C1COCC1.CS(C)=O>[C:13]([C:21]1[CH:22]=[CH:23][C:24]([O:27][C:2]2[N:7]=[C:6]([C:8]#[N:9])[C:5]([S:10][CH2:11][CH3:12])=[CH:4][CH:3]=2)=[CH:25][CH:26]=1)(=[O:20])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CCSc1ccc(Cl)nc1C#N
Reactant: O=C(c1ccccc1)c1ccc(O)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: CCSc1ccc(Oc2ccc(C(=O)c3ccccc3)cc2)nc1C#N
Yield: 28.7 %

Procedure:
6-Chloro-3-ethylthio-2-pyridinecarbonitrile (23.8 g) was mixed with 25.8 g of 4-benzoylphenol in the presence of 15.7 g of t-BuOK in 150 ml of THF and 30 ml DMSO. After reaction, the mixture was filtered leaving a solid residue from which 12.4 g of the desired 6-(4-benzoylphenoxy)-3-ethylthio-2-pyridinecarbonitrile (m.p. 88°-90° C.) was recovered. An additional 6.5 g of desired product was isolated from the filtrate by separation on a Water's Prep LC 500 instrument (using a 10% acetone in hexane eluant).
Reaction SMILES: Cl[C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[N:5]=[C:4]([Cl:11])[C:3]=1[C:12]1[C:17]([F:18])=[CH:16][C:15]([F:19])=[CH:14][C:13]=1[F:20].[CH3:21][CH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.[Cl-].[NH4+]>C(Cl)(Cl)Cl>[CH3:21][CH:22]1[CH2:27][CH2:26][N:25]([C:2]2[N:7]3[CH:8]=[CH:9][N:10]=[C:6]3[N:5]=[C:4]([Cl:11])[C:3]=2[C:12]2[C:17]([F:18])=[CH:16][C:15]([F:19])=[CH:14][C:13]=2[F:20])[CH2:24][CH2:23]1
Reactant: CC1CCNCC1
Reactant: Fc1cc(F)c(-c2c(Cl)nc3nccn3c2Cl)c(F)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClC(Cl)Cl
Product: CC1CCN(c2c(-c3c(F)cc(F)cc3F)c(Cl)nc3nccn23)CC1
Reaction time: 1 h
Yield: 80.9 %

Procedure:
Under ice-cooling, 0.64 g of 5,7-dichloro-6-(2,4,6-trifluorophenyl)imidazo[1,2-a]pyrimidine and 0.79 g of 4-methylpiperidine were mixed. The mixture was allowed to stand at room temperature for one hour, and chloroform and aqueous saturated ammonium chloride solution were added to the reaction mixture. The separated organic layer was washed with water, dried over sodium sulfate and concentrated. The residue was washed with t-butyl methyl ether to give 0.62 g of 5-(4-methylpiperidin-1-yl)-6-(2,4,6-trifluorophenyl)-7-chloroimidazo[1,2-a]pyrimidine
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[OH:12])[N:8]=[C:7]([NH:13][C:14]1[CH:25]=[CH:24][C:17]([C:18]([NH:20][CH:21]([CH3:23])[CH3:22])=[O:19])=[CH:16][CH:15]=1)[N:6]=[CH:5]2.C(N(CC)CC)C.[CH3:33][Si:34]([C:37]#[CH:38])([CH3:36])[CH3:35]>CN(C=O)C.C(OCC)(=O)C.[Cu]I>[OH:12][C:11]1[CH:10]=[C:9]2[C:4]([CH:5]=[N:6][C:7]([NH:13][C:14]3[CH:25]=[CH:24][C:17]([C:18]([NH:20][CH:21]([CH3:23])[CH3:22])=[O:19])=[CH:16][CH:15]=3)=[N:8]2)=[CH:3][C:2]=1[C:38]#[C:37][Si:34]([CH3:36])([CH3:35])[CH3:33]
Reactant: CC(C)NC(=O)c1ccc(Nc2ncc3cc(Br)c(O)cc3n2)cc1
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)NC(=O)c1ccc(Nc2ncc3cc(C#C[Si](C)(C)C)c(O)cc3n2)cc1

Procedure:
To a 0.09M mixture of 4-(6-bromo-7-hydroxyquinazolin-2-ylamino)-N-isopropylbenzamide (0.17 mM), triethylamine (0.5 ml), Pd(dppf)2Cl2CH2Cl2 (0.1 eq), Copper(I) iodide (0.1 eq), in DMF was added trimethylsilylacetylene (10 eq). The suspension was microwaved at 120° C. for 20 min. Reaction mixture was diluted with ethyl acetate and was washed with water, brine, dried and concentrated to give crude product. ES/MS m/z 419 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1.C([N:19]1[CH:23]=[CH:22]N=C1)(N1C=CN=C1)=O.[CH3:24][C:25]1[CH:26]=[C:27](CCN)[CH:28]=[CH:29][CH:30]=1>C1COCC1.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:19][CH2:23][CH2:22][C:30]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH3:24])=[O:9])=[CH:10][CH:11]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Cc1cccc(CCN)c1
Reactant: COc1ccc(C(=O)O)cc1
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(C(=O)NCCc2ccccc2C)cc1
Reaction time: 8 h

Procedure:
A solution of 4-methoxybenzoic acid (5.7 g, 0,038 mol) and carbonyldimidazole (6.1 g, 0.050 mol) in 100 ml of THF was stirred for 1 h protected from moisture. To this was added 2-(3-methylphenyl)ethylamine and stirring was continued overnight. The reaction mixture was diluted with water (500 ml) and extracted with two 150 ml portions of methylene chloride. The methylene chloride solution was washed with 250 ml of water and evaporated to give the crystalline amide which was recrystallized from CH3OH/water to give 6.8 g (67%) H1, mp 87°-92°.
Reaction SMILES: [C:1]([C@@H:4]1[CH2:12][C@H:11]2[C@H:6]([CH2:7][CH2:8][CH2:9][CH2:10]2)[NH:5]1)([OH:3])=[O:2].[C:13]([C@@H:18]([NH:22][C@H](C(O)=O)C)[CH2:19]CC)([O:15]CC)=[O:14]>>[C:1]([C:4]1[NH:5][C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2)([OH:3])=[O:2].[NH2:22][C@H:18]([C:13]([OH:15])=[O:14])[CH3:19]
Reactant: CCC[C@H](N[C@@H](C)C(=O)O)C(=O)OCC
Reactant: O=C(O)[C@@H]1C[C@@H]2CCCC[C@@H]2N1
Product: C[C@H](N)C(=O)O
Product: O=C(O)c1cc2ccccc2[nH]1

Procedure:
The (2S,3aS,7aS)-2-carboxyperhydroindole and N-[(S)-1-carbethoxybutyl]-(S)-alanine are themselves obtained in excellent conditions from 2-carboxyindole and from L-alanine respectively, both available on an industrial scale.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][C:16]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:17][CH:18]=3)[CH:13]=2)=[O:11])=[CH:5][CH:4]=1.[CH2:28]([C:30]1[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=1)[CH3:29]>CN(C=O)C>[Cl-:1].[CH2:28]([C:30]1[CH:31]=[N+:32]([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]3[CH2:21][CH2:20][C:19]4[C:14](=[CH:15][C:16]([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)=[CH:17][CH:18]=4)[CH:13]=3)=[O:11])=[CH:5][CH:4]=2)[CH:33]=[CH:34][CH:35]=1)[CH3:29]
Reactant: CCc1cccnc1
Reactant: O=C(Nc1ccc(CCl)cc1)C1=Cc2cc(-c3ccccc3)ccc2CC1
Solvent: CN(C)C=O
Product: CCc1ccc[n+](Cc2ccc(NC(=O)C3=Cc4cc(-c5ccccc5)ccc4CC3)cc2)c1
Product: [Cl-]
Temperature: 70 °C
Reaction time: 72 h

Procedure:
In DMF (3 ml) was dissolved N-[4—(chloromethyl)-phenyl]-7-phenyl-3,4-dihydronaphthalene-2-carboxamide (160 mg), and to the mixture was added 3-ethylpyridine (146 μl). The mixture was stirred at 70° C. for 72 hours and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-methanol to give 3-ethyl-1-[4—(7-phenyl-3,4-dihydro-naphthalene-2-carboxamido)benzyl]pyridinium chloride (Compound 27) (185 mg) as colorless crystals.
Reaction SMILES: [N+:1]([C:4]1[C:5]([C:9]([OH:11])=[O:10])=[N:6][NH:7][CH:8]=1)([O-:3])=[O:2].[C:12](Cl)(=O)C(Cl)=O.CO>ClCCl.CN(C)C=O>[CH3:12][O:10][C:9]([C:5]1[C:4]([N+:1]([O-:3])=[O:2])=[CH:8][NH:7][N:6]=1)=[O:11]
Reactant: O=C(O)c1n[nH]cc1[N+](=O)[O-]
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1n[nH]cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A stirred suspension of 4-nitro-3-pyrazolecarboxylic acid (1 g) in dichloromethane under nitrogen at 0° C. was treated with oxalyl chloride (1.11 ml) followed by dimethylformamide (5 drops). The reaction mixture was warmed to room temperature and stirred overnight. Methanol (10 ml) was added and the reaction mixture was stirred overnight. The solvent was removed under reduced pressure and azeotroped with toluene twice to yield 4-nitro-1H-pyrazole-3-carboxylic acid methyl ester (1.3 g) as a pale green solid. LC-MS (Method H): RT=1.94 minutes, 170.23 (M−H)−.
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7].[C:13]1([P:19]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1(C)C=CC=CC=1>[Br-:1].[CH3:9][O:8][C:6]([C:5]1[CH:4]=[C:3]([CH:12]=[CH:11][CH:10]=1)[CH2:2][P+:19]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)=[O:7]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: COC(=O)c1cccc(CBr)c1
Solvent: Cc1ccccc1
Product: COC(=O)c1cccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c1
Product: [Br-]
Temperature: 90 °C
Reaction time: 8 h
Yield: 95.6 %

Procedure:
Methyl 3-(bromomethyl)benzoate (4.0 g) was mixed with toluene (40 ml), and triphenylphosphine (5.0 g) was added thereto, followed by stirring at 90° C. overnight. The precipitated solid was collected by filtration to obtain [3-(methoxycarbonyl)benzyl](triphenyl)phosphonium bromide (8.2 g).
Reaction SMILES: [CH:1]1([CH3:11])[CH2:6][CH2:5][CH:4]([CH:7]([CH3:9])[CH3:8])[CH:3]([OH:10])[CH2:2]1.[Br:12][CH2:13][C:14](O)=[O:15].O>C1(C)C=CC=CC=1>[Br:12][CH2:13][C:14]([O:10][CH:3]1[CH:4]([CH:7]([CH3:8])[CH3:9])[CH2:5][CH2:6][CH:1]([CH3:11])[CH2:2]1)=[O:15]
Reactant: CC1CCC(C(C)C)C(O)C1
Reactant: O=C(O)CBr
Solvent: O
Solvent: Cc1ccccc1
Product: CC1CCC(C(C)C)C(OC(=O)CBr)C1

Procedure:
For the first stage, a solution of (−)-menthol (1.56 g, 10 mmol), 2-bromoacetic acid (1.39 g, 10 mmol) and monohydrated p-toluenesulphonic acid (0.5 g, 2.6 mmol) was brought to reflux for 3 h in 100 ml toluene. The water given off during the reaction is separated by azeotropic distillation. 100 ml toluene is added, and the mixture is washed 3 times with 10 ml of a 5% NaOH solution, then twice with 100 ml of brine, the organic solvent is dried on Na2SO4 and the solvent evaporated under vacuum. The menthyl 2-bromoacetate obtained (2.45 g, 89%) is used in the next step without purification.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[CH3:6][NH:7][CH2:8][CH2:9][C:10]1[NH:11][C:12]2[C:17]([C:18]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2.C(N(CC)CC)C.N>C(Cl)(Cl)Cl>[Cl:1][CH2:2][C:3]([N:7]([CH3:6])[CH2:8][CH2:9][C:10]1[NH:11][C:12]2[C:17]([C:18]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:4]
Reactant: CNCCc1[nH]c2ccccc2c1-c1ccccc1
Reactant: O=C(Cl)CCl
Agent: N
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CN(CCc1[nH]c2ccccc2c1-c1ccccc1)C(=O)CCl
Reaction time: 0.5 h

Procedure:
A solution of 17.5 ml chloroacetyl chloride in 100 ml chloroform is added dropwise within 15 minutes to a solution of 50.1 g N-methyl-3-phenyl-1H-indol-2-ethanamine and 30.7 ml triethylamine in 500 ml chloroform. After 30 minutes the mixture is made alkaline with aqueous ammonia. The organic phase is separated, washed with water and dried. Evaporation of the solvent gives the heading compound, m.p. 135°-138° (from methylene chloride/ether).
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[NH:5][CH:4]([C:13]2[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=2[NH2:15])[CH2:3]1.N1C=CC=CC=1.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>ClCCl.O>[CH3:1][C:2]1([CH3:20])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[NH:5][CH:4]([C:13]2[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=2[NH:15][S:28]([CH3:27])(=[O:30])=[O:29])[CH2:3]1
Reactant: Cc1ccc2c(c1)C(C)(C)CC(c1ccccc1N)N2
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O
Product: Cc1ccc2c(c1)C(C)(C)CC(c1ccccc1NS(C)(=O)=O)N2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-(4,4,6-trimethyl-1,2,3,4-tetrahydroquinolin-2-yl)aniline (150 mg, 0.56 mmol) and pyridine (0.5 mL) in anhydrous dichloromethane (2 mL) was added methanesulfonyl chloride (44 μL) at ice-bath under nitrogen. After addition, the resulting mixture was stirred at room temperature for 3 h. The reaction mixture was diluted with water, and extracted with ethyl acetate. The combined organic layer was dried over anhydrous Sodium sulfate, and then concentrated. The residue was purified by HPLC to give N-[2-(4,4,6-trimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenyl]methanesulfonamide LC/MS m/e obsd. (ESI+) [(M+H)+] 345.2.
Reaction SMILES: F[C:2]1[CH:19]=[CH:18][C:5]([O:6][CH2:7][C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)=[CH:4][C:3]=1[N+:20]([O-:22])=[O:21].[Br:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH2:27][NH2:28].CCN(C(C)C)C(C)C.O>CC(N(C)C)=O>[Br:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH2:27][NH:28][C:2]1[CH:19]=[CH:18][C:5]([O:6][CH2:7][C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)=[CH:4][C:3]=1[N+:20]([O-:22])=[O:21]
Reactant: NCc1cccc(Br)c1
Reactant: O=[N+]([O-])c1cc(OCc2ccc3ccccc3n2)ccc1F
Solvent: O
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1cc(OCc2ccc3ccccc3n2)ccc1NCc1cccc(Br)c1
Temperature: 130 °C
Yield: 105.9 %

Procedure:
To a mixture of 2-((4-fluoro-3-nitrophenoxy)methyl)quinoline (3.6 g, 12 mmol) and 3-bromobenzyl amine (2 mL, 15 mmol) in DMA (50 mL) was added DIPEA (6 mL, 35 mmol) and heated to 130° C. for 16 h. The mixture was cooled to RT and poured into water (400 mL). The resulting orange/red suspension was extracted with EtOAc and the combined organics were washed with water and brine. The organic layer was concentrated to dryness to afford 5.9 g of a solid that was used without further purification. MS (ESI): mass calcd. for C23H18BrN3O3, 464.32; m/z found 465.0 [M+H]+. 1H NMR (400 MHz; CDCl3) δ 8.32-8.27 (m, 1H), 8.20 (d, J=8.3, 1H), 8.09 (d, J=8.3, 1H), 7.86 (d, J=3.0, 1H), 7.85-7.81 (m, 1H), 7.77-7.71 (m, 1H), 7.63 (d, J=8.3, 1H), 7.58-7.53 (m, 1H), 7.48 (s, 1H), 7.44-7.40 (m, 1H), 7.28-7.20 (m, 3H), 6.71 (d, J=9.3, 1H), 5.33 (s, 2H), 4.51 (d, J=5.8, 2H).
Reaction SMILES: [C-:1]#[N:2].[CH2:3]([NH3+:7])[CH2:4][CH2:5][CH3:6].NN.[CH2:10]([NH2:14])CCC>>[CH2:3]([N:7]1[CH:10]=[N:14][N:2]=[CH:1]1)[CH2:4][CH2:5][CH3:6]
Reactant: [C-]#N
Reactant: CCCC[NH3+]
Reactant: CCCCN
Agent: NN
Product: CCCCn1cnnc1
Temperature: 75 °C
Yield: 63 %

Procedure:
In Example 6, Example 5 was repeated except that the butylamine-HCN mixture was not heated so as to avoid polymerizing the hydrogen cyanide. An NMR spectrum of this mixture gave no evidence of butylformamidine formation but rather was consistent with a simple solution of butylammonium cyanide in butylamine. Hydrazine was added and the reaction mixture was heated to 75° C. to give a 63% yield of 4-n-butyl-1,2,4-triazole in only four hours. The only differences between this experiment and Examples 3 and 4 were the order of the HCN--H2NNH2 additions and the amount of NH4Cl catalyst used; the former seems to have had no discernible effect while the latter is presumably responsible for the significant rate increase.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:10][CH2:11][CH2:12][C:13]([OH:20])([CH2:17][CH:18]=[CH2:19])[CH:14]([CH3:16])[CH3:15])[CH3:9])=[CH:4][CH:3]=1.Cl[C:22](Cl)([O:24]C(=O)OC(Cl)(Cl)Cl)Cl.O>C(Cl)Cl>[CH2:17]([C:13]1([CH:14]([CH3:15])[CH3:16])[O:20][C:22](=[O:24])[N:10]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=2)[CH3:9])[CH2:11][CH2:12]1)[CH:18]=[CH2:19]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: C=CCC(O)(CCNC(C)c1ccc(Br)cc1)C(C)C
Solvent: O
Solvent: ClCCl
Product: C=CCC1(C(C)C)CCN(C(C)c2ccc(Br)cc2)C(=O)O1
Temperature: 25 °C
Yield: 21.1 %

Procedure:
To a solution of 3-{2-[1-(4-bromo-phenyl)-ethylamino]-ethyl}-2-methyl-hex-5-en-3-ol (2.2 g, crude) and TEA (4 eq) in dried CH2Cl2 (60 mL) at 0° C. was added triphosgene (2.12 g, 7.12 mmol). The mixture was stirred at rt till the reaction was over. Water was added, and the layers were separated. The aqueous layer was extracted with CH2Cl2. The combined organic phase was washed with water, dried over Na2SO4, and condensed to give the crude product, which was purified by column to give 6-allyl-3-[1-(4-bromo-phenyl)-ethyl]-6-isopropyl-[1,3]oxazinan-2-one (500 mg, crude).
Reaction SMILES: [C:1]([CH2:3][S:4][C:5]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:6]=1[NH:12][C:13](=[O:15])[CH3:14])#[N:2].OO.[OH2:18].C(O)(=[O:21])C>>[C:1]([CH2:3][S:4]([C:5]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:6]=1[NH:12][C:13](=[O:15])[CH3:14])(=[O:21])=[O:18])#[N:2]
Reactant: CC(=O)Nc1ccc(F)cc1SCC#N
Reactant: CC(=O)O
Reactant: O
Agent: OO
Product: CC(=O)Nc1ccc(F)cc1S(=O)(=O)CC#N
Temperature: 100 °C
Reaction time: 1 h

Procedure:
N-(2-Cyanomethylsulfanyl-4-fluoro-phenyl)acetamide (0.43 g) was suspended in glacial acetic acid (2 ml). Hydrogen peroxide (35%, 1 ml) was added and the mixture was stirred at 100° C. for 1 h. Then the mixture was cooled to 0° C. and water (15 ml) was added. After stirring for 10 min a white precipitate was isolated by filtration, washed with water and dried. Recrystallization from 96% ethanol afforded the title compound as white needles, mp 154-157° C.; yield 0.28 g (58%); 1H-NMR (DMSO-d6), δ (ppm): 9.64 (s, 1H, NH), 7.99-7.64 (m, 3H, Ar—H), 5.30 (s, 2H, CH2), 2.08 (s, 3H, CH3).
Reaction SMILES: C[O:2][C:3]1[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[CH:18][C:4]=1[C:5]([NH:7][C:8]1[S:9][CH:10]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:12]=1)=[O:6].C(NCCCC)CCC.Cl.O>CN(C)C(=O)C>[CH3:23][O:22][C:20]1[C:19]([O:24][CH3:25])=[CH:18][C:4]([C:5]([NH:7][C:8]2[S:9][CH:10]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:12]=2)=[O:6])=[C:3]([OH:2])[CH:21]=1
Reactant: CCOC(=O)c1csc(NC(=O)c2cc(OC)c(OC)cc2OC)n1
Agent: Cl
Solvent: O
Solvent: CC(=O)N(C)C
Solvent: CCCCNCCCC
Product: CCOC(=O)c1csc(NC(=O)c2cc(OC)c(OC)cc2O)n1
Temperature: 0 °C
Yield: 92.5 %

Procedure:
A suspension (30 ml) of 2-[N-(2,4,5-trimethoxybenzoyl)amino]-4-(ethoxycarbonyl)-1,3-thiazole (10.0 g) in N,N-dimethylacetamide was allowed to dissolve with heat at a temperature of at least 150° C., and di-n-butylamine (8.8 g) was added dropwise to the solution, refluxed for 5 hours. The reaction mixture was allowed to cool, poured into a mixture of 1 N hydrochloric acid (100 ml) and ice water (100 ml), and further, water was added thereto. The crystals so precipitated were collected by filtration, washed with water, and then subjected to air drying and drying under reduced pressure to thereby obtain crude crystals (10.0 g). The crystals were followed by recrystallization from 1,4-dioxane, thereby 8.9 g of 2-[N-(4,5-dimethoxy-2-hydroxybenzoyl)amino]-4-(ethoxycarbonyl)-1,3-thiazole was obtained (yield: 82.3%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:20][C:21]1[N:26]2[CH:27]=[CH:28][N:29]=[C:25]2[CH:24]=[CH:23][CH:22]=1)[CH2:9][CH2:10][CH2:11][NH:12][S:13]([C:16]([F:19])([F:18])[F:17])(=[O:15])=[O:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:30][C:31]([Cl:36])([Cl:35])[C:32](Cl)=[O:33].C(=O)([O-])O.[Na+]>CN(C)C1C=CN=CC=1.C(Cl)(Cl)Cl>[Cl:30][C:31]([Cl:36])([Cl:35])[C:32]([C:27]1[N:26]2[C:21]([CH2:20][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH2:10][CH2:11][NH:12][S:13]([C:16]([F:19])([F:17])[F:18])(=[O:14])=[O:15])=[CH:22][CH:23]=[CH:24][C:25]2=[N:29][CH:28]=1)=[O:33]
Reactant: CC(C)(C)OC(=O)N(CCCNS(=O)(=O)C(F)(F)F)Cc1cccc2nccn12
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N(CCCNS(=O)(=O)C(F)(F)F)Cc1cccc2ncc(C(=O)C(Cl)(Cl)Cl)n12
Temperature: 25 °C
Reaction time: 0.05 h
Yield: 55 %

Procedure:
To a solution of 3.15 g (7.22 mmol) of 5-[N-tert-butoxycarbonyl-N-[3-(trifluoromethanesulfonamido)propan-1-yl]aminomethyl]imidazo[1,2-a]pyridine and 2.65 g (21.65 mmol) of 4-dimethylaminopyridine in 30 ml of chloroform was added dropwise, while stirring at room temperature for 3 minutes, 2.4 ml (21.65 mmol) of trichloroacetyl chloride. The reaction mixture was heated for 15 hours under reflux. After completion of the reaction, the reaction mixture was poured into ice-water, which was neutralized with a saturated aqueous solution of sodium hydrogencarbonate. The solution was extracted with 150 ml of chloroform. The organic layer was washed with 250 ml of a saturated aqueous saline solution and dried over magnesium sulfate. The solvent was then distilled off under reduced pressure. The residue was purified by silicagel column chromatography (eluent: chloroform/methanol=100:1) to give 2.31 g of the desired compound (54.8%, pale yellow liquid).
Reaction SMILES: [CH3:1][NH:2][C@@H:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][C@H:4]1[N:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1.[C:17]1([C:23]2[S:27][C:26]([CH2:28][C:29]([OH:31])=O)=[CH:25][CH:24]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N1C=CN=C1)(N1C=CN=C1)=O>>[N:12]1([C@@H:4]2[CH2:5][C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C@H:3]2[N:2]([CH3:1])[C:29](=[O:31])[CH2:28][C:26]2[S:27][C:23]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:24][CH:25]=2)[CH2:13][CH2:14][CH2:15][CH2:16]1
Reactant: O=C(O)Cc1ccc(-c2ccccc2)s1
Reactant: CN[C@@H]1c2ccccc2C[C@H]1N1CCCC1
Agent: O=C(n1ccnc1)n1ccnc1
Product: CN(C(=O)Cc1ccc(-c2ccccc2)s1)[C@@H]1c2ccccc2C[C@H]1N1CCCC1
Yield: 68.6 %

Procedure:
Using the procedure of Step C of Example 1, 0.432 g of the product of Step B of Example 1, 0.567 g of 5-phenyl-2-thiophene-acetic acid and 0.422 g of carbonyldiimidazole were reacted to obtain 0.571 g of trans-(±) N-[2,3-dihydro-2-(1-pyrrolidinyl)-1H-inden-1-yl]-N-methyl-5-phenyl-2-thiophene-acetamide and then 0.457 g of its hydrochloride melting at ≃ 249° C.