Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:28]([NH2:30])=[O:29])[CH:17]=[C:18]([C:21]4[CH:25]=[C:24]([CH:26]=O)[S:23][CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2].[CH3:31][C:32]1[C:36]([CH2:37][NH:38][CH3:39])=[C:35]([CH3:40])[NH:34][N:33]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CS(C)=O.C(O)(=O)C>[CH3:31][C:32]1[C:36]([CH2:37][N:38]([CH2:26][C:24]2[S:23][CH:22]=[C:21]([C:18]3[CH:19]=[C:20]4[C:15](=[C:16]([C:28]([NH2:30])=[O:29])[CH:17]=3)[NH:14][CH:13]=[C:12]4[CH:9]3[CH2:8][CH2:7][N:6]([S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])[CH2:11][CH2:10]3)[CH:25]=2)[CH3:39])=[C:35]([CH3:40])[NH:34][N:33]=1
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4csc(C=O)c4)cc23)CC1
Reactant: CNCc1c(C)n[nH]c1C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CS(C)=O
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4csc(CN(C)Cc5c(C)n[nH]c5C)c4)cc23)CC1
Reaction time: 8 h
Yield: 11 %

Procedure:
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-formyl-3-thienyl)-1H-indole-7-carboxamide (45 mg, 100 μmol) in dimethyl sulfoxide (1.0 mL) was added 1-(3,5-dimethyl-1H-pyrazol-4-yl)-N-methylmethanamine (320 μmol) and 2 to 3 drops of glacial acetic acid. The resulting mixture is agitated overnight. After 18 h, sodium triacetoxyborohydride (200 mg, 1000 μmol) is added. This mixture is agitated for 1.5 h followed by purification by Gilson Preparatory HPLC to give 6.24 mg of the title compound (11.0%).
Reaction SMILES: Cl[C:2]1[CH:8]2[CH2:9][CH:5]([CH2:6][CH2:7]2)[C:4](=[O:10])[CH:3]=1.[Cl:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=1.C(N(C(C)C)CC)(C)C.C1(C)C=CC=CC=1>ClCCl.[Cl-].[Cl-].[Zn+2]>[Cl:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([O:18][C:2]2[CH:8]3[CH2:9][CH:5]([CH2:6][CH2:7]3)[C:4](=[O:10])[CH:3]=2)=[O:17])=[CH:14][CH:13]=1
Reactant: O=C1C=C(Cl)C2CCC1C2
Reactant: O=C(O)c1ccc(Cl)cc1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: O=C(OC1=CC(=O)C2CCC1C2)c1ccc(Cl)cc1
Temperature: 25 °C
Yield: 84.9 %

Procedure:
A mixture of 500 mg of 4-chlorobicyclo[3.2.1]oct-3-en-2-one, 440 mg of ZnCl2, 400 mg of 4-chlorobenzoic acid, 1.05 g of diisopropylethylamine and 5 ml of toluene is stirred at room temperature under a nitrogen atmosphere at reflux temperature for 6 hours. After cooling, the reaction mixture is then diluted with dichloromethane and washed with 5% aqueous sulfuric acid and 5% aqueous sodium hydroxide. After concentration of the organic phase to dryness by evaporation, 0.6 g of 4-(4-chlorophenyl-carbonyloxy)-bicyclo[3.2.1]oct-3-en-2-one is obtained.
Reaction SMILES: Cl.[F:2][C:3]1[N:8]=[C:7]([C:9]2[C:10](=[O:16])[NH:11][C:12](=[O:15])[NH:13][CH:14]=2)[CH:6]=[CH:5][CH:4]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:24][CH2:25][CH:26]([O:29][CH3:30])[O:27][CH3:28].O>CN(C=O)C>[CH3:28][O:27][CH:26]([O:29][CH3:30])[CH2:25][CH2:24][N:13]1[CH:14]=[C:9]([C:7]2[CH:6]=[CH:5][CH:4]=[C:3]([F:2])[N:8]=2)[C:10](=[O:16])[NH:11][C:12]1=[O:15]
Reactant: COC(CCBr)OC
Reactant: O=c1[nH]cc(-c2cccc(F)n2)c(=O)[nH]1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(CCn1cc(-c2cccc(F)n2)c(=O)[nH]c1=O)OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.6 %

Procedure:
A mixture of 5-(6-Fluoro-pyridin-2-yl)-1H-pyrimidine-2,4-dione hydrochloride (Prep75, 200 mg, 0.82 mmol), and K2CO3 (169 mg, 1.23 mmol) in DMF (4 ml) was stirred 1 hour at room temperature. 3-Bromo-1,1dimethoxy-propane (165 mg, 0.90 mmol) was added and stirring was continued for 48 hours. Water (50 ml) was added and the product was extracted with ethyl acetate. The organic phase was dried (Na2SO4) and evaporated. The crude was triturated with iPr2O to give 179 mg of the final compound as a white solid (70% yield).
Reaction SMILES: [H-].[Na+:2].C1[C:8]([NH2:9])=[CH:7]C=C(O)C=1.[H][H].[O:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1>>[NH2:9][C:8]1[CH:7]=[CH:14][CH:15]=[CH:16][C:17]=1[O-:13].[Na+:2]
Reactant: C1CCOC1
Reactant: Nc1ccc(O)cc1
Reactant: [H][H]
Agent: [H-]
Agent: [Na+]
Product: Nc1ccccc1[O-]

Procedure:
Sodium aminophenoxide reactant was prepared by slowly adding sodium hydride (100%, 2.6 g, 0.11 mole) to a slurry of p-aminophenol (10.9 g, 0.1 mole) in about 100 mL tetrahydrofuran (THF). The reaction mixture was heated at 60°-67° C. for 3 hours, or until evolution of hydrogen was no longer visible. Sodium aminophenoxide salt, a purplish solid, formed during this time. The salt was either filtered and washed with THF, or used as prepared, as a slurry. The entire procedure was carried out under nitrogen.
Reaction SMILES: Br[C:2]1[C:3]([CH3:13])=[C:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[NH:5][C:6]=1[CH3:7].[F:14][C:15]([F:26])([F:25])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.O.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>[CH2:11]([O:10][C:8]([C:4]1[NH:5][C:6]([CH3:7])=[C:2]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[C:15]([F:26])([F:25])[F:14])[C:3]=1[CH3:13])=[O:9])[CH3:12]
Reactant: OB(O)c1ccccc1C(F)(F)F
Reactant: CCOC(=O)c1[nH]c(C)c(Br)c1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1[nH]c(C)c(-c2ccccc2C(F)(F)F)c1C
Reaction time: 0.25 h
Yield: 48.2 %

Procedure:
To a solution of ethyl 4-bromo-3,5-dimethyl-1H-pyrrole-2-carboxylate (2.4 g, 10 mmol) in DMF (25 mL) was added tetrakis(triphenylphosphine)palladium (2.3 g, 1 mmol). After stirring 15 min, the reaction mixture was charged with 2-(trifluoromethyl)-benzeneboronic acid (2.4 g, 12.5 mmol) and sodium carbonate (in 5 mL of water). The reaction mixture was heated to reflux overnight with stirring. After cooling, the reaction mixture was then diluted with water and extracted with DCM. The combined extracts were washed with water and dried over Na2SO4. Evaporation of solvent gave a crude material, which was purified by chromatography on silica gel column eluting with EtOAc-hexane (1:1) to give the title compound (1.5 g). MS (ES): 312 (MH+)
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[N:7]([CH2:9][CH2:10][O:11][C:12]1[CH:17]=[C:16]([N:18]=[N+]=[N-])[N:15]=[C:14]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[N:13]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2]>O1CCCC1.CO.[Pd]>[C:1]([O:5][C:6](=[O:27])[N:7]([CH2:9][CH2:10][O:11][C:12]1[CH:17]=[C:16]([NH2:18])[N:15]=[C:14]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[N:13]=1)[CH3:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(CCOc1cc(N=[N+]=[N-])nc(N2CCOCC2)n1)C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CN(CCOc1cc(N)nc(N2CCOCC2)n1)C(=O)OC(C)(C)C
Reaction time: 24 h

Procedure:
[2-(6-azido-2-morpholin-4-yl-pyrimidin-4-yloxy)-ethyl]-methyl-carbamic acid tert-butyl ester was dissolved in a mixture of tetrahydrofuran (200 mL) and methanol (20 mL). To the solution was added 10% palladium on carbon (2 g) and the reaction was stirred under an atmosphere of hydrogen for 24 hours. The reaction was then filtered through celite and evaporated to give [2-(6-amino-2-morpholin-4-yl-pyrimidin-4-yloxy)-ethyl]-methyl-carbamic acid tert-butyl ester (5.0 g).
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5](=[O:23])[NH:6][C@H:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]#[CH:18])[CH:15]=2)[N:10]([C:19](=[O:21])[CH3:20])[C@@H:9]([CH3:22])[CH2:8]1)[CH3:3].CN(C)C=O.C[Si]([N:33]=[N+:34]=[N-:35])(C)C>[Cu]I.CO>[CH3:3][CH:2]([O:4][C:5](=[O:23])[NH:6][C@H:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]3[N:33]=[N:34][NH:35][CH:18]=3)[CH:15]=2)[N:10]([C:19](=[O:21])[CH3:20])[C@@H:9]([CH3:22])[CH2:8]1)[CH3:1]
Reactant: C#Cc1ccc2c(c1)[C@H](NC(=O)OC(C)C)C[C@H](C)N2C(C)=O
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CO
Product: CC(=O)N1c2ccc(-c3c[nH]nn3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Temperature: 100 °C
Reaction time: 5 h
Yield: 33 %

Procedure:
A flask was charged with 1-methylethyl[(2S,4R)-1-acetyl-6-ethynyl-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl]carbamate (for a preparation, see Intermediate 58) (80 mg, 0.254 mmol) and copper(I) iodide (2.423 mg, 0.013 mmol) then filled with N,N-dimethylformamide (DMF) (1.8 mL) and Methanol (0.200 mL). Trimethylsilyl azide (0.059 mL, 0.509 mmol) was added and the resulting mixture was stirred under microwave irradiation at 100° C. for 5 h then cooled to room temperature. The solution was partitioned between AcOEt and water/brine (1/1) and the layers were separated. The aqueous phase was extracted three times with AcOEt and the combined organic phases were washed with water then brine, dried over MgSO4 and concentrated in vacuo. The residue was purified using MDAP (modifier: ammonium bicarbonate). The appropriate fractions were concentrated in vacuo and the residue dissolved in DCM. The organic phase was dried using a phase separator then concentrated in vacuo to give 1-methylethyl[(2S,4R)-1-acetyl-2-methyl-6-(1H-1,2,3-triazol-4-yl)-1,2,3,4-tetrahydro-4-quinolinyl]carbamate (30 mg, 0.084 mmol, 33.0% yield) as a white foam.
Reaction SMILES: [CH3:1][Li].[Br:3][C:4]1[CH:17]=[CH:16][CH:15]=[CH:14][C:5]=1[C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:7]>>[Br:3][C:4]1[CH:17]=[CH:16][CH:15]=[CH:14][C:5]=1[C:6]([CH3:1])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[OH:7]
Reactant: O=C(c1ccccc1)c1ccccc1Br
Reactant: [Li]C
Product: CC(O)(c1ccccc1)c1ccccc1Br

Procedure:
Addition of methyllithium to 2-bromobenzophenone provides 2-bromophenyl methyl phenyl carbinol. Addition of methyl magnesium iodide to methyl o-bromobenzoate provides 2-bromophenyl dimethyl carbinol.
Reaction SMILES: C1(C)C=CC=CC=1.Cl[CH2:9][CH2:10][CH:11]1[N:24]([CH3:25])[C:16]2=[N:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[N:15]2[C:14](=[O:26])[N:13]([CH3:27])[CH2:12]1.[F:28][C:29]1[CH:34]=[CH:33][C:32]([CH:35]([C:42]2[CH:47]=[CH:46][C:45]([F:48])=[CH:44][CH:43]=2)[CH:36]2[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)=[CH:31][CH:30]=1>C(N(CC)CC)C>[F:48][C:45]1[CH:46]=[CH:47][C:42]([CH:35]([C:32]2[CH:31]=[CH:30][C:29]([F:28])=[CH:34][CH:33]=2)[CH:36]2[CH2:41][CH2:40][N:39]([CH2:9][CH2:10][CH:11]3[N:24]([CH3:25])[C:16]4=[N:17][C:18]5[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=5[N:15]4[C:14](=[O:26])[N:13]([CH3:27])[CH2:12]3)[CH2:38][CH2:37]2)=[CH:43][CH:44]=1
Reactant: CN1CC(CCCl)N(C)c2nc3ccccc3n2C1=O
Reactant: Fc1ccc(C(c2ccc(F)cc2)C2CCNCC2)cc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CN1CC(CCN2CCC(C(c3ccc(F)cc3)c3ccc(F)cc3)CC2)N(C)c2nc3ccccc3n2C1=O
Reaction time: 24 h

Procedure:
To a solution of 50 mL of toluene containing 4.0 g (0.04 mol) of triethylamine was added 3.0 g (0.01 mol) of 2-(2-chloroethyl)-3,4-dihydro-1,4-dimethyl-1H-[1,3,5]triazepino[3,2-a]benzimidazol-5(2H)-one and 4.0 g (0.014 mol) of 4-[bis(4-fluorophenyl)methyl]piperidine. The mixture was heated to reflux for 3 days after which time 1.0 g (0.003 mL) of 4-[bis(4-fluorophenyl)methyl]piperidine and 1.0 g (0.01 mol) of triethylamine was added. Heating under reflux was continued for 24 hr. The solvent was removed by rotary evaporation and the residue dissolved in 100 mL of CH2Cl2. The organic phase was washed with 2×100 mL of 1N NaOH, dried over Na2SO4, filtered, and concentrated by rotary evaporation. The residue was subjected to preparative HPLC using silica gel as the stationary phase and eluting with ethanol. Combination of like fractions afforded 3.1 g (57%) of analytically pure material as a glass.
Reaction SMILES: [F:1][C:2]1[C:11]([F:12])=[CH:10][C:9]([CH:13]=O)=[C:8]2[C:3]=1[C:4](=[O:16])[CH:5]=[C:6]([CH3:15])[O:7]2.[C:17]([CH:19]=[C:20]([O-])[CH3:21])#[N:18].[Na+].[NH2:24]/[C:25](/[CH3:33])=[CH:26]\[C:27]([O:29][CH2:30][CH2:31][CH3:32])=[O:28].C(O)(=O)C>CC(O)C>[C:17]([C:19]1[CH:13]([C:9]2[CH:10]=[C:11]([F:12])[C:2]([F:1])=[C:3]3[C:8]=2[O:7][C:6]([CH3:15])=[CH:5][C:4]3=[O:16])[C:26]([C:27]([O:29][CH2:30][CH2:31][CH3:32])=[O:28])=[C:25]([CH3:33])[NH:24][C:20]=1[CH3:21])#[N:18]
Reactant: CC([O-])=CC#N
Reactant: CCCOC(=O)/C=C(/C)N
Reactant: Cc1cc(=O)c2c(F)c(F)cc(C=O)c2o1
Agent: [Na+]
Solvent: CC(C)O
Solvent: CC(=O)O
Product: CCCOC(=O)C1=C(C)NC(C)=C(C#N)C1c1cc(F)c(F)c2c(=O)cc(C)oc12

Procedure:
A solution of 100 mg (0.45 mmol) of 5,6-difluoro-2-methyl-4-oxo-4H-chromene-8-carbaldehyde in 5 ml of 2-propanol is mixed with 46.9 mg (0.45 mmol) of sodium 1-cyanoprop-1-en-2-olate, 63.88 mg (0.45 mmol) of propyl 3-aminocrotonate and 0.04 ml (0.67 mmol) of acetic acid and stirred under reflux for 3 h. After cooling, the mixture is concentrated. The residue is taken up in dichloromethane and washed with water. The organic phase is dried over sodium sulfate and concentrated. The resulting residue is crystallized from diethyl ether. The beige-colored crystals are filtered off with suction and dried at 40° C. in a vacuum drying oven. 74.6 mg (40.35% of theory) of the title compound are obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:12][OH:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I:25]I>C(Cl)(Cl)Cl.FC(F)(F)C([O-])=O.[Ag+]>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:14]([I:25])=[CH:15][C:16]=1[O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:12][OH:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: II
Reactant: OCc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1
Agent: [Ag+]
Agent: O=C([O-])C(F)(F)F
Solvent: ClC(Cl)Cl
Product: OCc1cc(OCc2ccccc2)c(OCc2ccccc2)cc1I
Yield: 84 %

Procedure:
The dibenzyloxybenzyl alcohol 28 (21.44 mmol) and silver trifluoroacetate (21.44 mmol) were suspended in 100 mL of dry chloroform and stirred under argon. A solution of iodine (21.44 mmol) in dry chloroform (50 mL) was added to the suspension dropwise at room temperature. The reaction mixture was then stirred for a further period of 2 h and filtered. The filtrate was washed with 20% sodium thiosulfate solution in water. The organic layer was separated and dried over anhydrous Na2SO4. Filtration was followed by evaporation of the chloroform solution resulting in the pure iodo compound, 3,4-Dibenzyloxy-6-iodobenzyl alcohol (29), as a pale yellow solid in 84% yield.
Reaction SMILES: [Mg].II.Cl[C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[CH2:7][Cl:8].[Cl:13][C:14]1[CH:21]=[CH:20][C:17]([C:18]#N)=[CH:16][CH:15]=1.Cl.[O:23]1CCCC1.C(OCC)C>C(OCC)C>[Cl:8][CH:7]([C:20]1[CH:21]=[C:14]([Cl:13])[CH:15]=[CH:16][C:17]=1[CH:18]=[O:23])[C:6]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:5]=1
Reactant: N#Cc1ccc(Cl)cc1
Reactant: C1CCOC1
Reactant: ClCc1ccccc1Cl
Agent: Cl
Agent: II
Agent: [Mg]
Solvent: CCOCC
Product: O=Cc1ccc(Cl)cc1C(Cl)c1ccccc1
Reaction time: 1 h
Yield: 74 %

Procedure:
To diethylether (250 mL) was added magnesium (6.04 g) and a catalytic amount of iodine and the mixture was stirred and thereto was gradually added dropwise 2-chlorobenzyl chloride (20.0 g). After stirring for 1 hour from the time when the temperature of such mixture began to rise, thereto was added a solution of 4-chlorobenzonitrile (18.8 g) in tetrahydrofuran/diethylether (20 mL/50 mL) and the mixture was stirred for 3 hours. To the reaction mixture was added 2N HCl (150 mL) under ice-cooling and the mixture was stirred at room temperature for 2 hours. The reaction mixture was extracted with ethyl acetate and the organic layer was washed with 1N HCl, water and saturated brine, dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo and the resultant crude product was purified by column chromatography on silica gel (solvent: hexane/ethyl acetate=40/1 to 20/1) to obtain 2-(chlorobenzyl)(4-chlorophenyl)methanone (24.40 g; yield: 74%) as a powder.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[S:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[CH2:12]([OH:14])[CH3:13].[OH-].[Na+]>O>[Cl:1][C:2]1[N:3]=[C:4]([O:14][CH2:12][CH3:13])[C:5]2[S:10][CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: Clc1nc(Cl)c2sccc2n1
Reactant: CCO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCOc1nc(Cl)nc2ccsc12
Temperature: 25 °C

Procedure:
A mixture of 2,4-dichlorothieno[3,2-d]pyrimidine (0.1 g), ethanol (5 mL), water (0.5 mL) and sodium hydroxide (0.04 g) was stirred at room temperature. The precipitated solids were collected by filtration and washed with diethyl ether to obtain 2-chloro-4-ethoxythieno[3,2-d]pyrimidine (0.07 g).
Reaction SMILES: [C@@H:1]1(C(O)=O)[CH2:6][CH2:5][CH2:4][CH2:3][C@H:2]1[C:7]([OH:9])=[O:8].C(Cl)(Cl)Cl.[N-:17]=[N+]=[N-].[Na+].CCOCC>S(=O)(=O)(O)O>[NH2:17][C@@H:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C@H:2]1[C:7]([OH:9])=[O:8]
Reactant: O=C(O)[C@@H]1CCCC[C@H]1C(=O)O
Reactant: [N-]=[N+]=[N-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Product: N[C@@H]1CCCC[C@H]1C(=O)O
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
Trans-cyclohexane-1,2-dicarboxylic acid (8.105 g; racemic modification) is dissolved in conc. sulfuric acid (25 ml) and chloroform (50 ml) and kept at a temperature of 45° C., to which is added sodium azide (3.6 g) in one hour. After this, the solution is stirred for 90 minutes, added with ice water (25 ml) and is added with ether to remove chloroform. Barium carbonate (90 g) is added to the water layer of the solution to effect the neutralization. Barium sulfate is removed from the solution by filtration and the filtrate is concentrated to dryness to result in needle crystals of rac-trans-2-aminocyclohexanecarboxylic acid (referred to as A) having the following characteristics. When a corresponding rac-cis-compound is used as starting material, there is obtained the corresponding cis-compound i.e. rac-cis-aminocyclohexanecarboxylic acid, referred to as B).
Reaction SMILES: [CH3:1][S:2]([N:5]1[C:17]2[C:12](=[CH:13][C:14]([Cl:18])=[CH:15][CH:16]=2)[C:7]2([CH2:11][CH2:10][NH:9][CH2:8]2)[CH2:6]1)(=[O:4])=[O:3].C(N(C(C)C)CC)(C)C.[Cl:28][C:29]1[CH:38]=[CH:37][C:32]([CH:33]=[CH:34][CH2:35]Cl)=[CH:31][CH:30]=1>C(#N)C.C(OCC)(=O)C>[CH3:1][S:2]([N:5]1[C:17]2[C:12](=[CH:13][C:14]([Cl:18])=[CH:15][CH:16]=2)[C:7]2([CH2:11][CH2:10][N:9]([CH2:35]/[CH:34]=[CH:33]/[C:32]3[CH:37]=[CH:38][C:29]([Cl:28])=[CH:30][CH:31]=3)[CH2:8]2)[CH2:6]1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)N1CC2(CCNC2)c2cc(Cl)ccc21
Reactant: ClCC=Cc1ccc(Cl)cc1
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)N1CC2(CCN(C/C=C/c3ccc(Cl)cc3)C2)c2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 12 h
Yield: 45.8 %

Procedure:
To a solution of 1-methanesulfonyl-5-chloro-spiro[indoline-3,3′-pyrrolidine] (725 mg) in acetonitrile (40 ml) were added diisopropylethylamine (0.66 ml) and 4-chloro-cinnamyl chloride (467 mg). The resulting solution was stirred at room temperature for 12 hours, diluted with ethyl acetate, washed with water, brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified by silica gel chromatography (eluent cyclohexane:ethyl acetate 6:4) to afford 1-methanesulfonyl-5-chloro-1′-[trans-3-(4-chlorophenyl)allyl]spiro[indoline-3,3′-pyrrolidine] (500 mg) which was characterised by its mass and NMR spectra. MS (ES+) 437/439 (M+H+).
Reaction SMILES: Br[C:2]1[CH:35]=[CH:34][C:5]([CH2:6][C:7]2[N:8]([C:20]3[CH:21]=[C:22]([N:26]4[S:30](=[O:32])(=[O:31])[NH:29][C:28](=[O:33])[CH2:27]4)[CH:23]=[CH:24][CH:25]=3)[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=3[Cl:19])[N:11]=2)=[CH:4][CH:3]=1.[CH:36](/B(O)O)=[CH:37]\[CH2:38][CH2:39][CH2:40][CH2:41][CH3:42]>>[Cl:19][C:13]1[CH:14]=[C:15]([Cl:18])[CH:16]=[CH:17][C:12]=1[C:10]1[N:11]=[C:7]([CH2:6][C:5]2[CH:34]=[CH:35][C:2]([CH:36]=[CH:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])=[CH:3][CH:4]=2)[N:8]([C:20]2[CH:21]=[C:22]([N:26]3[S:30](=[O:32])(=[O:31])[NH:29][C:28](=[O:33])[CH2:27]3)[CH:23]=[CH:24][CH:25]=2)[CH:9]=1
Reactant: CCCCC/C=C/B(O)O
Reactant: O=C1CN(c2cccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(Br)cc3)c2)S(=O)(=O)N1
Product: CCCCCC=Cc1ccc(Cc2nc(-c3ccc(Cl)cc3Cl)cn2-c2cccc(N3CC(=O)NS3(=O)=O)c2)cc1

Procedure:
5-{3-[2-(4-Bromo-benzyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide (59 mg, 0.1 mmol) was treated as described in general procedure G using trans-1-heptenylboronic acid (43 mg, 0.3 mmol) to give 5-{3-[4-(2,4-dichloro-phenyl)-2-(4-hept-1-enyl-benzyl)-imidazol-1-yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([C:15]([OH:17])=[O:16])=[CH:10][CH:9]=2)=[O:5].Cl.[CH3:19][CH2:20]O>>[CH2:2]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([C:15]([O:17][CH2:19][CH3:20])=[O:16])=[CH:10][CH:9]=2)=[O:5])[CH3:1]
Reactant: CCOC(=O)c1cc2cc(C(=O)O)ccc2[nH]1
Reactant: CCO
Agent: Cl
Product: CCOC(=O)c1ccc2[nH]c(C(=O)OCC)cc2c1
Reaction time: 24 h
Yield: 99 %

Procedure:
A suspension of 1H-Indole-2,5-dicarboxylic acid 2-ethyl ester (20.0 g, 85.75 mmole) in a saturated HCl/EtOH (200 ml) was stirred at 55 C. for 24 h and evaporated in vacuo to dryness. The residue was freeze-dried from dioxane to give 22.18 g (99%) of 1H-indole-2,5-dicarboxylic acid diethyl ester, 16 as white powder. MS: 262.12 (M+H). 1-NMR (DMSO-d6): 12.23 (s, 1H, H-1, indole); 8.34 (m, 1H, H-4, indole); 7.83 (m, 1H, H-6, indole); 7.49 (m, 1H, H-7, indole); 7.30 (s, 1H, H-3, indole); 4.31 (m, 4H, —OCH2CH3); 1.32 (m, 4H, —OCH2CH3).
Reaction SMILES: [CH2:1]([S:8][CH2:9][C:10]([NH2:12])=[S:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH:14]1[CH2:22][C:21]2[C:16](=[CH:17][CH:18]=[C:19]([Cl:23])[CH:20]=2)[C:15]1=[O:24]>CC(C)=O>[CH2:1]([S:8][CH2:9][C:10]1[S:11][CH:14]2[CH2:22][C:21]3[CH:20]=[C:19]([Cl:23])[CH:18]=[CH:17][C:16]=3[C:15]2([OH:24])[N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(=S)CSCc1ccccc1
Reactant: O=C1c2ccc(Cl)cc2CC1Br
Solvent: CC(C)=O
Product: OC12N=C(CSCc3ccccc3)SC1Cc1cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
At room temperature, 0.54 g of 2-benzylsulfanyl-thioacetamide were dissolved in 10 ml of dry acetone and mixed with 0.67 g of 2-bromo-5-chlorindan-1-on, and the mixture was stirred at room temperature for 4 h. The resulting precipitate was filtered off with suction, washed with acetone, taken up in ethyl acetate, mixed with saturated sodium bicarbonate solution and extracted twice. The organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. This synthesis yielded 2-benzylsulfanylmethyl-6-chloro-8,8a-dihydroindeno[1,2-d]thiazol-3a-ol having a melting point of 102-104° C.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:27])[C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[N:13][C:12]=2[O:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([S:25][CH3:26])[CH:20]=2)[CH2:5][CH2:4]1.C(N(CC)CC)C.[C:35](Cl)(=[O:37])[CH3:36]>ClCCl>[C:35]([NH:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:27])[C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[N:13][C:12]=2[O:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([S:25][CH3:26])[CH:20]=2)[CH2:5][CH2:4]1)(=[O:37])[CH3:36]
Reactant: CSc1cccc(Oc2ncc(F)cc2C(=O)N[C@H]2CC[C@@H](N)CC2)c1
Reactant: CC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CSc1cccc(Oc2ncc(F)cc2C(=O)N[C@H]2CC[C@@H](NC(C)=O)CC2)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
N-(cis-4-Amino-cyclohexyl)-5-fluoro-2-(3-methylsulfanyl-phenoxy)-nicotinamide hydrochloride (150 mg, 0.364 mmol) was suspended in dichloromethane (2 ml) under nitrogen at room temperature and triethylamine (153 μl, 1.09 mmol) was added followed by acetyl chloride (29 μl, 0.4 mmol). The reaction was stirred at room temperature for 1.5 h and the mixture was quenched with sat. sodium bicarbonate solution (3 ml). The organic phase was separated and the aqueous phase was washed with dichloromethane (2×5 ml). The combined organic extracts were dried over MgSO4 and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography on silica gel eluting with dichloromethane:methanol:concentrated aqueous ammonia (95:5:0.5, by volume) and the product was triturated with diethylether (2×3 ml) to give N-(cis-4-Acetylamino-cyclohexyl)-5-fluoro-2-(3-methylsulfanyl-phenoxy)-nicotinamide (50 mg) as a white solid.