Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([Br:4])[C:2]#[CH:3].[CH3:5][C:6]1[N:7]2[CH2:13][CH2:12][N:11]=[C:8]2[S:9][CH:10]=1>C(#N)C>[Br-:4].[CH2:1]([N:11]1[C:8]2[S:9][CH:10]=[C:6]([CH3:5])[N+:7]=2[CH2:13][CH2:12]1)[C:2]#[CH:3]
Reactant: CC1=CSC2=NCCN12
Reactant: C#CCBr
Solvent: CC#N
Product: C#CCN1CC[n+]2c(C)csc21
Product: [Br-]
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 12 g. of propargyl bromide and 14 g. of 3-methyl-5,6-dihydroimidazo[2,1-b]thiazole (prepared by basification of 3-methyl-5,6-dihydroimidazo[2,1-b]thiazole hydrochloride with 5N sodium hydroxide solution) in 160 ml. of dry acetonitrile is allowed to stir at room temperature for 16 hrs. The solution is concentrated to a small volume and the precipitated product filtered. The purified product is obtained by recrystallization from acetonitrile-ethyl acetate, 21 g., m.p. 207°-208° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6]2)#[N:2].[H-].[Na+].[Cl:15][C:16]1[N:21]=[CH:20][C:19]([S:22]([N:25]([CH3:33])[CH2:26][CH2:27][N:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)(=[O:24])=[O:23])=[CH:18][CH:17]=1.C([O-])(O)=O.[Na+]>CN(C)C=O>[ClH:15].[C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([OH:12])=[C:6]2[C:16]1[N:21]=[CH:20][C:19]([S:22]([N:25]([CH3:33])[CH2:26][CH2:27][N:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)(=[O:24])=[O:23])=[CH:18][CH:17]=1)#[N:2]
Reactant: N#Cc1ccc2c(c1)CC(=O)N2
Reactant: CN(CCN1CCCC1)S(=O)(=O)c1ccc(Cl)nc1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(CCN1CCCC1)S(=O)(=O)c1ccc(-c2c(O)[nH]c3ccc(C#N)cc23)nc1
Product: Cl
Temperature: 130 °C
Yield: 34.6 %

Procedure:
To an ice-cooled solution of 5-cyanooxindole (200 mg, 1.26 mmol) in N,N-dimethylformamide (5 mL) was added sodium hydride (60 mg, 1.5 mmol). The reaction mixture was stirred for 25 min whereafter 6-chloro-N-methyl-N-(2-pyrrolidin-1-ylethyl)pyridine-3-sulfonamide (303 mg, 1 mmol) was added. The reaction mixture was heated at 130° C. for 1 h and then allowed to cool to room temperature. An aqueous saturated solution of NaHCO3 (50 mL) was added and the water phase was extracted with ethyl acetate. The organic phase was dried (Na2SO4) and purified on a silica gel column using chloroform/methanol/conc NH3(aq), (500:35:3.5 to 500:50:5), as the eluent. The solvents were evaporated in vacuo and the residue was stirred over night in ethyl acetate, filtered and dried to give 160 mg (38% yield) of the title compound as the base. The base, dissolved in chloroform/methanol, was treated with HCl in diethyl ether to give the title compound: MS (ES) m/z 426 (M++1).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][NH:9][C:10](=[O:25])/[C:11](/[C:15]2[N:16]=[C:17]([N:20]=CN(C)C)[S:18][CH:19]=2)=[N:12]\[O:13][CH3:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)O.C(=O)([O-])O.[Na+].C(OCC)(=O)C>CO>[C:1]1([CH2:7][CH2:8][NH:9][C:10](=[O:25])/[C:11](/[C:15]2[N:16]=[C:17]([NH2:20])[S:18][CH:19]=2)=[N:12]\[O:13][CH3:14])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CO/N=C(\C(=O)NCCc1ccccc1)c1csc(N=CN(C)C)n1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: CO/N=C(\C(=O)NCCc1ccccc1)c1csc(N)n1
Temperature: 25 °C
Reaction time: 72 h
Yield: 95.8 %

Procedure:
(Z)-N-(2-phenylethyl)-2-(2-dimethylaminomethylidenaminothiazol-4-yl)-2-methoxyiminoacetamide (130 ml, 0.36 mmol) was dissolved in 4 ml of methanol, followed by the addition of 0.5 ml of 1.8N sulfuric acid. The mixture so obtained was stirred for 3 days at room temperature. The reaction mixture was then added with 20 ml of a saturated aqueous solution of sodium hydrogencarbonate and 20 ml of ethyl acetate. The resulting mixture was then allowed to separate into an organic phase and an aqueous phase. The aqueous phase was further extracted twice with 10 ml portions of ethyl acetate. All the organic phases were combined, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure, whereby 105 mg of the title compound were obtained (yield: 95%).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]2=[N:6][C:7](=[O:9])[N:8]=[C:4]2[CH:3]=1.C(N(CC)CC)C.[CH2:19]([CH:29](CCCCCCCCCCCC)[C:30](Cl)=[O:31])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]>CN1CCCC1=O>[C:30]([NH:1][C:2]1[CH:11]=[CH:10][C:5]2=[N:6][C:7](=[O:9])[N:8]=[C:4]2[CH:3]=1)(=[O:31])[CH2:29][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCCCCCCCCCCCC(CCCCCCCCCC)C(=O)Cl
Reactant: Nc1ccc2c(c1)=NC(=O)N=2
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: CCCCCCCCCCCC(=O)Nc1ccc2c(c1)=NC(=O)N=2
Reaction time: 8 h

Procedure:
5-Aminobenzimidazolone (0.95 g, 6.36 mmol), triethylamine (1.1 mL, 7.89 mmol), N-methylpyrrolidinone (NMP, 5 mL), and dry THE (8 mL) are mixed in a 100 mL round bottom flask under an inert atmosphere. To this solution, a second solution of 2-decyltetradecanoyl chloride from Step I dissolved in dry THE (30 mL) is slowly added. After stirring overnight, deionized water (50 mL) is added and the THF removed by rotary evaporation to give an aqueous slurry. The solid was collected by vacuum filtration and washed with deionized water before suspending in methanol (60 mL) and heating to reflux. The suspension was then cooled and the solid was filtered and washed with fresh methanol to give 5-dodecanamido-2-benzimdazolone as a white powder (1.63 g). The product is identified by 1H and 13C NMR spectroscopy and ESI-MS and is of satisfactory purity.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[Cl:15][C:16]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:17]=1[CH2:18][NH2:19].C(O)(=O)C.[BH3-]C#N.[Na+]>CO.O>[Cl:15][C:16]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:17]=1[CH2:18][NH:19][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: NCc1ccc(Cl)cc1Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(NCc2ccc(Cl)cc2Cl)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of commercially available tert-butyl 4-oxo-1-piperidine carboxylate (400 mg, 2 mmol) in methanol (1 ml) and 2,4-di-chlorobenzylamine (0.135 ml, 1 mmol) in methanol (1 ml) was added acetic acid in methanol (1 M, 1.34 ml) followed by NaCNBH3 in methanol (0.3 M, 4.4 ml). The resulting solution was stirred at room temperature. After 24 h, water (2 ml) was added, and the mixture was stirred for 1 h, before it was concentrated. The resulting oil was redissolved in diethyl ether (20 ml), extracted with HCl (0.1 N, 1×15 ml). The aqueous layer was washed with diethyl ether (10 ml) and treated with 0.2 N NaOH until basic (pH>8), before extracted with dichloromethane (20 ml). The organic layer was dried (Na2SO4), filtered, and concentrated to give tert-butyl 4-((2,4-di-chlorophenyl)methyl)amino-piperidine carboxylate. Yield: 97 mg. To a solution of tert-butyl 4-((2,4-di-chlorophenyl)methyl)amino-piperidine carboxylate (50 mg, 0.14 mmol) in dichloromethane (6 ml) was added diisopropylethylamine (0.070 ml, 0.4 mmol) followed by 4-methoxyphenylacetyl chloride (0.055 ml, 0.35 mmol). The reaction mixture was stirred at room temperature. After 18 h, water (2 ml) was added. The mixture was stirred for another 2 h. The mixture was sequentially washed with HCl (0.2 N, 2×15 ml), NaOH (0.2 N, 2×15 ml), and water (10 ml), dried (Na2SO4), filtered and concentrated to give N-((2,4-di-chlorophenyl)methyl)-N-(1-(tert-butyloxycarbonyl)piperidin-4-yl)-4-methoxyphenylacetamide. The crude product was used without any further purification. N-((2,4-Di-chlorophenyl)methyl)-N-(1-(tert-butyloxycarbonyl)piperidin-4-yl)-4-methoxyphenylacetamide was dissolved in diethyl ether (2 ml) and HCl (1 ml, 4 M in dioxane) was added. The reaction mixture was stirred at room temperature. After 2.5 h, NaOH (1 ml, 6 N) was added followed by dichloromethane (10 ml). The mixture was extracted with water (2×15 ml), dried (Na2SO4), filtered to give a clear solution. The solution was added on to a column carrying strongly acidic cation exchange resin (0.3 mmol/g resin), which was washed with methanol (3×6 ml), and eluted with 10% NH3 in methanol, and concentrated to give the title compound. Yield: 39 mg; 13C-NMR (CD3OD, rotamers): δ 25.7, 26.8, 40.0, 42.6, 43.3, 43.7, 51.2, 53.0, 54.5, 54.6, 113.8, 113.8, 114.0, 114.1, 127.0, 128.4, 128.8, 129.8, 130.0, 130.1, 131.0, 132.7, 132.9, 134.5, 159.1, 173.4, 173.6.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6](/[CH:14]=[CH:15]\[CH2:16][OH:17])[CH:5]=[CH:4][C:3]1=2.[Zn](CC)[CH2:20]C.II>C(Cl)Cl.ClCl.[Zn]>[CH3:1][C:2]1([CH3:18])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([C@H:14]3[CH2:20][C@H:15]3[CH2:16][OH:17])[CH:5]=[CH:4][C:3]1=2
Reactant: CC1(C)CCC(C)(C)c2cc(/C=C\CO)ccc21
Reactant: CC[Zn]CC
Agent: ClCl
Agent: II
Agent: [Zn]
Solvent: ClCCl
Product: CC1(C)CCC(C)(C)c2cc([C@H]3C[C@H]3CO)ccc21
Temperature: -22 °C
Reaction time: 0.75 h

Procedure:
1.67 g of of (Z)-3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-prop-2-en-1-ol were dissolved in 36 ml of CH2Cl2. At 0° C. 7.62 ml of Et2Zn-solution (1M[hexane]) was added, followed 15 min. later by 1.33 ml of L-(+)-diethyl tartrate, dissolved in 18 ml of CH2 Cl2. Stirring was continued for 45 min. The reaction flask was then cooled to -22° C. and another portion of 13.8 ml of Et2 Zn-solution (1M[hexane]) was added, followed by 2.23 ml of CH2 I2. The reaction flask was allowed to reach +18° C. during 16 h. After quenching with crushed ice/NH4CI-solution, the mixture was extracted with EtOEt, washed with dil. HCI and H2O, dried over Na2SO4 and evaporated to dryness. Flash chromatography (silica gel, hexane/AcOEt=87/13) yielded 1.057 g of (1R,2S)-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-cyclopropylmethanol, 99% pure according to GC. The absolute configuration was assigned in analogy to Chemistry Letters 1992, 61, but not rigorously proven; the optical purity was determined at the next stage.
Reaction SMILES: [CH:1]([N:4]1[CH:8]=[CH:7][C:6]([CH2:9]O)=[N:5]1)([CH3:3])[CH3:2].S(Cl)([Cl:13])=O>C(Cl)Cl>[ClH:13].[Cl:13][CH2:9][C:6]1[CH:7]=[CH:8][N:4]([CH:1]([CH3:3])[CH3:2])[N:5]=1
Reactant: CC(C)n1ccc(CO)n1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: CC(C)n1ccc(CCl)n1
Product: Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 85.4 %

Procedure:
To a solution of (1-isopropyl-1H-pyrazol-3-yl)methanol (3.45 g, 24.61 mmol) in DCM (50 mL) was added thionyl chloride (5.386 mL, 73.83 mmol) at ambient temperature. The mixture was allowed to stir at ambient temperature for 18 hours. The mixture was concentrated under vacuum to afford 3-(chloromethyl)-1-isopropyl-1H-pyrazole hydrochloride (4.1 g, 85% yield) as a yellow gum.
Reaction SMILES: [NH:1]([C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])[C@H:2]([C:7]([OH:9])=O)[C:3]([CH3:6])([CH3:5])[CH3:4].[NH2:20][C@H:21]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:22][CH:23]([CH3:25])[CH3:24].Cl.CN1CCOCC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[NH:1]([C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])[C@H:2]([C:7]([NH:20][C@H:21]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:22][CH:23]([CH3:25])[CH3:24])=[O:9])[C:3]([CH3:4])([CH3:5])[CH3:6]
Reactant: CCOC(=O)[C@@H](N)CC(C)C
Reactant: CC(C)(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CCOC(=O)[C@H](CC(C)C)NC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)(C)C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 100.3 %

Procedure:
Z-Tle (15.6 g, 59.1 mmol), Leu-OEt HCl (11.56 g, 59.1 mmol), and N-methyl morpholine (NMM) (12.75 mL) are mixed with 45 mL of DMF and a cloudy suspension forms. The mixture is cooled to 0° C. and treated with TBTU (19.1 g, 59.48 mmol), then stirred at 0° C. for 15 minutes, then removed from the cold bath and stirred for 1.5 hours. The mixture is poured into 500 mL of a saturated solution of sodium carbonate which is then extracted with two 350 mL portions of ethyl acetate. The combined organic extracts are washed with 500 mL of 1 M KHSO4 water and brine and then dried over sodium sulfate. The solvents are removed to give Z-Tle-Leu-OEt (24.1 g). FABMS M+1 407
Reaction SMILES: OC(C(F)(F)F)=O.[NH:8]1[CH2:11][CH:10]([NH:12][C:13](=[O:30])[CH2:14][NH:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([C:26]([F:29])([F:28])[F:27])[CH:24]=3)[N:19]=[CH:18][N:17]=2)[CH2:9]1.O=[C:32]1[CH2:37][CH2:36][CH:35]([N:38]2[CH2:42][CH2:41][CH2:40][C:39]2=[O:43])[CH2:34][CH2:33]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CO>C(#N)C>[O:43]=[C:39]1[CH2:40][CH2:41][CH2:42][N:38]1[CH:35]1[CH2:34][CH2:33][CH:32]([N:8]2[CH2:9][CH:10]([NH:12][C:13](=[O:30])[CH2:14][NH:15][C:16]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([C:26]([F:28])([F:27])[F:29])[CH:24]=4)[N:19]=[CH:18][N:17]=3)[CH2:11]2)[CH2:37][CH2:36]1
Reactant: O=C(CNc1ncnc2ccc(C(F)(F)F)cc12)NC1CNC1
Reactant: O=C1CCC(N2CCCC2=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: O=C(CNc1ncnc2ccc(C(F)(F)F)cc12)NC1CN(C2CCC(N3CCCC3=O)CC2)C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
N-(azetidin-3-yl)-2-((6-(trifluoromethyl)quinazolin-4-yl)amino)acetamide TFA salt (100 mg, 0.22 mmol) from example 1, step G, and 1-(4-oxocyclohexyl)pyrrolidin-2-one (40.5 mg, 0.22 mmol) from above step B, Sodium triacetoxyborohydride (138 mg, 0.64 mmol), were taken in acetonitrile and stirred for 24 h at room temperature. The mixture was treated with MeOH and concentrated under vacuum. The residue was purified by preparative TLC (nBuOH/aq NH4OH 4:1) and reverse phase HPLC to give the title compound as a white solid. ESI-MS (m/z): Calcd. for C24H29F3N6O2: 490.23. found: 491.23 (M+1).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[C:18]([CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:17]=1)[C:10]([CH3:30])([CH3:29])[CH2:9]2)=[O:5])C.O.[OH-].[Li+].O.Cl>CO.O1CCCC1>[CH:23]1([C:18]2[CH:17]=[C:16]([CH:11]3[C:10]([CH3:29])([CH3:30])[CH2:9][C:8]4[C:13](=[CH:14][CH:15]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=4)[NH:12]3)[CH:21]=[C:20]([F:22])[CH:19]=2)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]1
Reactant: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cc(F)cc(C3CCCCC3)c1)N2
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1cc(F)cc(C2CCCCC2)c1
Temperature: 60 °C
Reaction time: 12 h
Yield: 61.7 %

Procedure:
A mixture of 2-(3-cyclohexyl-5-fluoro-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (0.21 g, 0.51 mmol), lithium hydroxide hydrate (0.22 g, 5.1 mmol), water (1 mL) in methanol (2 mL) and tetrahydrofuran (10 mL) was stirred at 60° C. for 12 h. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×50 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford an oil residue. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% formic acid in water) afforded 2-(3-cyclohexyl-5-fluoro-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (120 mg, 62%) as a white solid: LC/MS m/e calcd for C24H28FNO2 (M+H)+: 382.5, observed: 382.2.
Reaction SMILES: [Na].[O:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]3[C:12]([O:38][CH3:39])=[N:13][N:14]([CH3:37])[C:15]=3[N:16](S(C3C=CC(Cl)=CC=3)(=O)=O)[S:17]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)(=[O:19])=[O:18])=[CH:10][C:5]=2[O:4][CH2:3]1.[Cl-].[NH4+].O>CO.ClCCl>[O:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]3[C:12]([O:38][CH3:39])=[N:13][N:14]([CH3:37])[C:15]=3[NH:16][S:17]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)(=[O:19])=[O:18])=[CH:10][C:5]=2[O:4][CH2:3]1
Reactant: COc1nn(C)c(N(S(=O)(=O)c2ccc(Cl)cc2)S(=O)(=O)c2ccc(Cl)cc2)c1-c1ccc2c(c1)OCO2
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na]
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: COc1nn(C)c(NS(=O)(=O)c2ccc(Cl)cc2)c1-c1ccc2c(c1)OCO2
Reaction time: 1 h
Yield: 66.7 %

Procedure:
An aqueous solution of sodium hydroxyde (2M, 270□1), was added at room temperature to a solution of N-[4-(1,3-benzodioxol-5-yl)-3-methoxy-1-methyl-1H-pyrazol-5-yl]-4-chloro-N-[(4-chlorophenyl)sulfonyl]benzenesulfonamide (Preparation 43) (32 mg) in a mixture of methanol (1 ml) and dichloromethane (1 ml). After 1 h, an aqueous saturated solution of ammonium chloride (4 ml) and water (4 ml) were added and the mixture was extracted with dichloromethane (3×5 ml). The combined organic fractions were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative TLC (silica) eluted with dichloromethane methanol (95:5) to yield the title compound as colourless oil (15.1 mg).
Reaction SMILES: [C:1](=[O:13])(SC)[O:2][CH:3]([O:5][C:6](=[O:10])[CH:7]([CH3:9])[CH3:8])[CH3:4].O[N:15]1[C:19](=[O:20])[CH2:18][CH2:17][C:16]1=[O:21].C(OO)(=[O:24])C.C(O)(=O)C>C(Cl)Cl.CCOCC>[C:6]([O:5][CH:3]([O:2][C:1]([O:13][CH:17]1[CH2:18][C:19](=[O:20])[NH:15][C:16]1=[O:21])=[O:24])[CH3:4])(=[O:10])[CH:7]([CH3:9])[CH3:8]
Reactant: CC(=O)OO
Reactant: CSC(=O)OC(C)OC(=O)C(C)C
Reactant: O=C1CCC(=O)N1O
Solvent: CCOCC
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(OC(=O)OC1CC(=O)NC1=O)OC(=O)C(C)C
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a solution of compound (2) (1 g, 4.8 mmol) in CH2Cl2 (10 mL) was added N-hydroxysuccinimide (1.1 g, 9.5 mmol) and the reaction mixture cooled to 0° C. A solution of 32% (v/v) peracetic acid in acetic acid (3.4 mL, 1.1 g, 14.4 mmol) was added dropwise over a period of 10 min, then the solution allowed to stir at room temperature for 3 h. The reaction mixture was diluted with ether (50 mL) and washed with water (2×10 mL), saturated sodium bicarbonate solution (10 mL) and brine (10 nm), then dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the title compound (17) as a as colorless oil (1 g, 77% yield). After trituration with hexane (20 mL) the product solidified to a white solid. m.p: 50-54° C. 1H NMR (CDCl3, 400 MHz): δ 1.17 (d, J=6.8 Hz, 6H), 1.56 (d, J=5.6 Hz, 3H), 2.55 (m, 1H), 2.82 (s, 4H), 6.80 (q, J=5.2 Hz, 1H). MS (ESI) m/z 296.4 (M+Na)+.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.[CH3:11][C:12]1=[C:13]([CH3:19])[C:14]([O:16][C:17]1=O)=[O:15].[ClH:20]>[OH-].[Na+].CC(N(C)C)=O>[CH3:11][C:12]1[C:17](=[O:16])[N:1]([C:2]2[CH:3]=[CH:4][C:5]([C:6]([Cl:20])=[O:8])=[CH:9][CH:10]=2)[C:14](=[O:15])[C:13]=1[CH3:19]
Reactant: CC1=C(C)C(=O)OC1=O
Reactant: Cl
Reactant: Nc1ccc(C(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)N(C)C
Product: CC1=C(C)C(=O)N(c2ccc(C(=O)Cl)cc2)C1=O
Temperature: 90 °C
Yield: 88 %

Procedure:
48 g (0.35 mol) of 4-aminobenzoic acid are dissolved in sodium hydroxide solution (14 g of NaOH in 300 ml of water). To that mixture there is added dropwise, with stirring, a solution of 44.2 g of dimethylmaleic acid anhydride in 300 ml of dimethylacetamide. The solution is then heated at 90° C. and, after 1.30 hours, 175 ml of aqueous hydrochloric acid (2N) are added. After the addition of hydrochloric acid, the solution is cooled to room temperature and the stirrer is switched off. The crystalline product that has precipitated is filtered off, washed with water and dried in vacuo at 60° C. Yield: 73.6 g (85.7%). Melting point: 230-231° C. 73.6 g of that intermediate are suspended in 700 ml of dry toluene. At 70° C., 32 ml of thionyl chloride are added dropwise. As soon as the evolution of gas has ceased (approx. 2 hours), the temperature is increased to 80° C. for 2 hours. After cooling, the solution is concentrated using a rotary evaporator. The solid residue is recrystallised from toluene and then dried at 60° C. Yield: 88%. Melting point: 199-200° C. 1H-NMR (CDCl3): 2.08 (s, CH3), 7.68 (d, phenyl), 8.20 (d, phenyl).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([N:8](C)[CH2:9][C:10](O)=[O:11])=S)=[CH:4][CH:3]=1.O.[NH2:17][NH2:18]>CO>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]2[NH:8][CH2:9][C:10](=[O:11])[NH:18][N:17]=2)=[CH:4][CH:3]=1
Reactant: NN
Reactant: CN(CC(=O)O)C(=S)c1ccc(Cl)cc1
Solvent: CO
Solvent: O
Product: O=C1CNC(c2ccc(Cl)cc2)=NN1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-Chlorothiobenzoyl methyl glycine (4.87 g, 20 mmol), 2.2 g of hydrazine hydrate (44 mmol) and 20 mL of methanol were combined and stirred at room temperature overnight, then heated to reflux. The reaction mixture was cooled and filtered. The solids were washed, then dried, giving 3-(4-chlorophenyl)-4,5-dihydro-1,2,4-triazin-6-one.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]2[C:8]3[C:9]([NH:17]CC4C=CC(OC)=CC=4)=[N:10][CH:11]=[C:12]([C:15]#[N:16])[C:13]=3[S:14][C:4]=2[CH:3]=1.[CH3:27][N:28](C=O)C>[C-]#N.[C-]#N.[Zn+2].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>[NH2:17][C:9]1[C:8]2[C:5]3[CH:6]=[CH:7][C:2]([C:27]#[N:28])=[CH:3][C:4]=3[S:14][C:13]=2[C:12]([C:15]#[N:16])=[CH:11][N:10]=1
Reactant: CN(C)C=O
Reactant: COc1ccc(CNc2ncc(C#N)c3sc4cc(Br)ccc4c23)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: N#Cc1ccc2c(c1)sc1c(C#N)cnc(N)c12
Reaction time: 0.08 h

Procedure:
To a microwave reaction vessel was added 7-bromo-1-[(4-methoxybenzyl)amino][1]benzothieno[3,2-c]pyridine-4-carbonitrile (Example 12, Step 9), Zn(CN)2 (1.3 equiv), Pd(Ph3P)4 (0.1 equiv), and DMF (0.06 M). After sealing, the tube was degassed via a needle through the septum, and the reaction was set up on the Smith Creator microwave machine for 5 min at 150° C. The mixture was then added to H2O and the resulting solid was collected by filtration and dried under vacuum. The crude was then stirred with 1:10 EtOAc:hexanes containing a trace of acetone, to give after filtration, a pale brown solid which was used as such for the next step.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH3:7][N:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[CH:13]=[O:14].[CH2:15]=O>C(O)(=O)C.O>[CH3:7][N:8]1[CH:12]=[C:11]([CH2:15][N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)[CH:10]=[C:9]1[CH:13]=[O:14].[CH3:7][N:8]1[C:12]([CH2:15][N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[CH:11][CH:10]=[C:9]1[CH:13]=[O:14]
Reactant: C=O
Reactant: Cn1cccc1C=O
Reactant: C1COCCN1
Solvent: CC(=O)O
Solvent: O
Product: Cn1c(C=O)ccc1CN1CCOCC1
Product: Cn1cc(CN2CCOCC2)cc1C=O
Temperature: 50 °C
Reaction time: 16 h

Procedure:
To a solution of morpholine (130 mmoles) in acetic acid (60 ml) at 0° C. there are added 1-methyl-1H-pyrrole-2-carbaldehyde (110 mmoles) and formaldehyde (110 mmoles) 37% in water. The reaction mixture is stirred for 16 hours at 50° C. After evaporation to dryness, about 100 ml of 25% aqueous sodium hydroxide solution are added. After extraction with DCM, the organic phase is washed with water and with saturated aqueous NaCl solution, dried over sodium sulphate, filtered and evaporated to dryness. The residue is purified by flash chromatography on silica gel (SiO2; gradient AcOEt/MeOH) to yield the title products 1-methyl-4-morpholin-4-ylmethyl-1H-pyrrole-2-carbaldehyde and 1-methyl-5-morpholin-4-ylmethyl-1H-pyrrole-2-carbaldehyde in a ratio of 1/5.