Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH:8]2[CH2:10][CH2:9]2)[N:3]=1.[BH:11]([OH:13])[OH:12].O1BOBOB1>>[CH:8]1([C:4]2[N:3]=[C:2]([B:11]([OH:13])[OH:12])[CH:7]=[CH:6][N:5]=2)[CH2:10][CH2:9]1
Reactant: OBO
Reactant: Brc1ccnc(C2CC2)n1
Agent: B1OBOBO1
Product: OB(O)c1ccnc(C2CC2)n1
Yield: 90 %

Procedure:
The title compound was prepared from 4-bromo-2-cyclopropylpyrimidine (WO 00/066566) in 90% yield (25 mmol scale) following the procedure by Li et al. (J. Org. Chem. 2002, 67, 5394-5397). LC-MS suggested that the product was composed of the boronic acid and the trimeric anhydride (sym-boroxine).
Reaction SMILES: C[O:2][C:3](=[O:33])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][O:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[N:17]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]([CH3:28])=[C:15]2[CH2:29][C:30]([NH2:32])=[O:31].[OH-].[Na+].Cl>C1COCC1.C(O)C>[NH2:32][C:30](=[O:31])[CH2:29][C:15]1[C:14]2[C:18](=[CH:19][CH:20]=[C:12]([O:11][CH2:10][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[C:3]([OH:33])=[O:2])[CH:13]=2)[N:17]([CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:16]=1[CH3:28]
Reactant: COC(=O)c1ccccc1COc1ccc2c(c1)c(CC(N)=O)c(C)n2Cc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1c(CC(N)=O)c2cc(OCc3ccccc3C(=O)O)ccc2n1Cc1ccccc1
Reaction time: 17.5 h
Yield: 58.3 %

Procedure:
A mixture of 195 mg (0.44 mmol) of 2-[[[3-(2-amino-2-oxoethyl)-2-methyl-1-(phenylmethyl)-1H-indol-5-yl]oxy]methyl]benzoic acid methyl ester and 2 mL of 2N NaOH in 10 mL of THF and 35 mL of ethanol was stirred for 17.5 hours, the mixture made acidic with 5N HCl and extracted with ethyl acetate. The ethyl acetate solution was washed with brine, dried (Na2SO4) and concentrated at reduced pressure. The residue was crystallized from methylene chloride to give 110 mg (59% yield) of 2-[[[3-(2-amino-2-oxoethyl)-2-methyl-1-(phenylmethyl)-1H-indol-5-yl]oxy]methyl]benzoic acid, mp, 173°-176° C.
Reaction SMILES: [O:1]1[CH2:22][CH:2]1[CH2:3][O:4][C:5]1[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([CH3:21])[C:6]=1[C:7]([C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1)=[O:8].[CH:23]([NH2:26])([CH3:25])[CH3:24]>CO>[CH3:21][C:16]1[C:6]([C:7]([C:9]2[CH:10]=[CH:11][C:12]([CH3:15])=[CH:13][CH:14]=2)=[O:8])=[C:5]([CH:19]=[C:18]([CH3:20])[CH:17]=1)[O:4][CH2:3][CH:2]([OH:1])[CH2:22][NH:26][CH:23]([CH3:25])[CH3:24]
Reactant: CC(C)N
Reactant: Cc1ccc(C(=O)c2c(C)cc(C)cc2OCC2CO2)cc1
Solvent: CO
Product: Cc1ccc(C(=O)c2c(C)cc(C)cc2OCC(O)CNC(C)C)cc1

Procedure:
A mixture of 2-(2,3-epoxypropoxy)-4,4',6-trimethylbenzophenone (10.0 g.), isopropylamine (10 ml.) and anhydrous methanol (50 ml.) was heated at reflux for 17 hours. The solution was then evaporated in vacuo, and the residue was dissolved in water (100 ml.) containing concentrated hydrochloric acid (10 ml.). The solution was adjusted to a pH between 6 and 7 and was shaken with ethyl acetate. The aqueous phase was then adjusted to pH 12 by the addition of aqueous sodium hydroxide solution. The precipitated oil was extracted with ethyl acetate and the extract was washed with water, dried over anhydrous sodium sulphate and evaporated. The residue was dissolved in a hot mixture of light petroleum (b.p. 40°-60° C.; 75 ml.) and cyclohexane (3 ml.) and allowed to cool slowly. The solid was filtered off and recrystallized from cyclohexane (25 ml.) to give DL-1-(3,5-dimethyl-2-p-toluoylphenoxy)-2-hydroxy-3-isopropylaminopropane (5.9 g.), m.p. 89°-91° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([CH2:9][CH2:10][CH2:11][CH3:12])=[C:4]([Cl:13])[N:3]=1.ClC1C=CC=C(C(OO)=[O:22])C=1>C(Cl)Cl>[CH3:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([CH2:9][CH2:10][CH2:11][CH3:12])=[C:4]([Cl:13])[N+:3]=1[O-:22]
Reactant: CCCCc1c(Cl)cc(C)nc1Cl
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCCCc1c(Cl)cc(C)[n+]([O-])c1Cl

Procedure:
66 g of 2-methyl-4,6-dichloro-5-n-butyl-pyridine are dissolved in 600 ml of methylene chloride and a solution of 66 g of 85% strength m-chloroperbenzoic acid in 600 ml of methylene chloride is added dropwise over the course of 21/2 hours whilst stirring. Thereafter, the mixture is stirred for a further 48 hours at room temperature. The reaction solution is extracted by shaking with aqueous ferrous sulphate solution and with 2 N sodium carbonate solution. The methylene chloride solution is dried and evaporated. 2-Methyl-4,6-dichloro-5-n-butyl-pyridine-N-oxide is thus obtained as the residue. This is taken up in 300 ml of toluene and 82 ml of acetic anhydride are added over the course of 15 minutes whilst stirring. Thereafter the mixture is boiled under reflux for 15 hours. The reaction solution is evaporated. The residue is taken up in ether and extracted by shaking with 2 N sodium carbonate solution. The ether solution is dried and evaporated. After fractionation of the residue, 2-acetoxymethyl- 4,6-dichloro-5-n-butyl-pyridine is obtained.
Reaction SMILES: O=[C:2]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([C:11]([OH:13])=[O:12])[C:5]=2[CH2:4][CH2:3]1.Cl.[F:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22]N)=[CH:18][CH:17]=1>>[F:15][C:16]1[CH:21]=[CH:20][C:19]2[NH:22][C:2]3[C:10]4[CH:9]=[CH:8][CH:7]=[C:6]([C:11]([OH:13])=[O:12])[C:5]=4[CH2:4][C:3]=3[C:18]=2[CH:17]=1
Reactant: NNc1ccc(F)cc1
Reactant: O=C(O)c1cccc2c1CCC2=O
Agent: Cl
Product: O=C(O)c1cccc2c1Cc1c-2[nH]c2ccc(F)cc12
Yield: 9.2 %

Procedure:
In a manner similar to Example 17, 1-oxo-indan-4-carboxylic acid (1.00 g, 5.68 mmol) and 4-fluorophenylhydrazine hydrochloride (0.923 g, 5.68 mmol) were converted to the title compound (0.140 g, 10%) as an off-white solid: mp>300° C.; 1H NMR (DMSO-d6): δ 3.98 (s, 2H), 6.93 (d of t, 1H), 7.38 (d of d, 1H), 7.44 (d of d, 1H), 7.50 (d, 1H), 7.77-7.80 (m, 2H), 11.72 (s, 1H), 13.43 (s, 1H); MS [EI, m/z]: 267 [M]+.
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[N:3]=[C:2]1[SH:10].[C:11](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[CH3:11][S:10][C:2]1[NH:1][C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[N:3]=1
Reactant: Sc1nc2cnccc2[nH]1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: CSc1nc2cnccc2[nH]1
Reaction time: 3 h
Yield: 93.1 %

Procedure:
To a solution of 1H-imidazo[4,5-c]pyridine-2-thiol (4 g) in acetone (50 mL) were added potassium carbonate (11 g) and MeI (1.8 mL). After stirring for 3 h, the mixture was filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, eluted with 10%-70% EtOAc in hexane) to give 2-(methylsulfanyl)-1H-imidazo[4,5-c]pyridine (4.07 g) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:15]=[C:16]([N:29]4[CH2:37][CH2:36][C:31]5(OCC[O:32]5)[CH2:30]4)[C:17]4[CH2:22][CH2:21][CH:20]([C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=5)[C:18]=4[N:19]=3)=[CH:9][C:8]=2[O:38][CH3:39])[CH:6]=1.Cl.CC(C)=O>C1COCC1>[Cl:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:15]=[C:16]([N:29]4[CH2:37][CH2:36][C:31](=[O:32])[CH2:30]4)[C:17]4[CH2:22][CH2:21][CH:20]([C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=5)[C:18]=4[N:19]=3)=[CH:9][C:8]=2[O:38][CH3:39])[CH:6]=1
Reactant: COc1cc(Nc2nc3c(c(N4CCC5(C4)OCCO5)n2)CCC3c2ccccc2)ccc1-n1cnc(Cl)c1
Agent: Cl
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: COc1cc(Nc2nc3c(c(N4CCC(=O)C4)n2)CCC3c2ccccc2)ccc1-n1cnc(Cl)c1
Temperature: 60 °C
Yield: 5.3 %

Procedure:
The mixture of N-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-phenyl-4-(1,4-dioxa-7-azaspiro[4.4]nonan-7-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine (Example 205) (37 mg, 0.068 mmol) and HCl (272 μL, 0.272 mmol) in THF (339 μL) was heated at 60° C. overnight. Concentrated to remove THF and added Acetone (339 μL) and HCl (272 μL, 0.272 mmol) to the mixture. The mixture was heated at 60° C. for 6 h. The crude product was purified by Prep-HPLC (Solvent A=10% MeOH-90% H2O-0.1% TFA, Solvent B=90% MeOH-10% H2O-0.1% TFA. Column. PHENOMENEX LUNA 30×100 mm, S10, Flow rate: 40 ml/min, 35-100% B, 40 min) and then was purified by Prep-HPLC (Column: PHENOMENEX LUNA C18 30×100 mm, Solvent A=10 mM Ammonium Acetate in 95:5 H2O/ACN, Solvent B=10 mM Ammonium Acetate in 5:95 H2O/ACN. Flow rate: 40 ml/min, 30-100% B, 35 min) to get 1-(2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenylamino)-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)pyrrolidin-3-one (2.0 mg, 3.59 μmol, 5.29% yield).
Reaction SMILES: [F:1][C:2]1[CH:29]=[CH:28][C:5]2[NH:6][C:7]([CH:9]([O:20][CH:21]3[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]3)[C:10]3[CH:11]=[C:12]([S:16][CH2:17][CH2:18][NH2:19])[CH:13]=[CH:14][CH:15]=3)=[N:8][C:4]=2[CH:3]=1.C(N1C=CC([C:42](=[NH:44])[NH2:43])N1C(OC(C)(C)C)=O)(OC(C)(C)C)=O.C(N(C(C)C)CC)(C)C>C(#N)C>[F:1][C:2]1[CH:29]=[CH:28][C:5]2[NH:6][C:7]([CH:9]([O:20][CH:21]3[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]3)[C:10]3[CH:11]=[C:12]([S:16][CH2:17][CH2:18][NH:19][C:42]([NH2:44])=[NH:43])[CH:13]=[CH:14][CH:15]=3)=[N:8][C:4]=2[CH:3]=1
Reactant: CN1CCC(OC(c2cccc(SCCN)c2)c2nc3cc(F)ccc3[nH]2)CC1
Reactant: CC(C)(C)OC(=O)N1C=CC(C(=N)N)N1C(=O)OC(C)(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CN1CCC(OC(c2cccc(SCCNC(=N)N)c2)c2nc3cc(F)ccc3[nH]2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-{3-[(5-fluoro-1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}ethylamine (example 437B, 230 mg) in acetonitrile (15 mL) is added is added N,N′-bis-Boc-guanylpyrazole (172 mg) and diisopropylethylamine (1 equivalent) at room temperature. The mixture is stirred at room temperature for 3 h. The solvent and volatiles are removed under reduced pressure. The residue is purified by chromatography on silica gel (gradient dichloromethane/methanol from 100/0 to 95/5). The residue is then dissolved in 5N aqueous hydrochloric acid (8 mL) and the solution is stirred overnight at room temperature. The solvent and volatiles are removed under reduced pressure and the residue is triturated with diethyl ether and filtered to afford N-(2-{3-[(5-fluoro-1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}ethyl) guanidine trihydrochlorhide as a white crystalline solid melting at 170° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9].[Br:11]Br>C(Cl)(Cl)Cl.C(OCC)C>[Br:11][CH2:9][C:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[CH3:1])=[O:10]
Reactant: BrBr
Reactant: CC(=O)c1ccccc1C
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Product: Cc1ccccc1C(=O)CBr
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100.3 %

Procedure:
2′-Methylacetophenone (16.0 g) was dissolved in chloroform (50 mL) and diethyl ether (50 mL), and a solution of bromine (16.0 g) in chloroform (15 mL) was added dropwise while maintaining the reaction temperature at not higher than 25° C. After completion of the dropwise addition, the reaction mixture was stirred at room temperature for 30 min, and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give crude 2-bromo-1-(2-methylphenyl)ethanone (21.4 g) as an oil. To a solution (700 mL) of methyl cyanoacetate (10.9 g) and diisopropylethylamine (31.0 g) in tetrahydrofuran was added dropwise a solution (100 mL) of crude 2-bromo-1-(2-methylphenyl)ethanone (21.4 g) obtained above in tetrahydrofuran. The reaction mixture was stirred at room temperature for 16 hr, then at 70° C. for 2 hr. The reaction mixture was filtrated, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=4:1) to give methyl 2-cyano-4-(2-methylphenyl)-4-oxobutanoate as an oil (yield 16.0 g). This was dissolved in ethyl acetate (16 mL), 4 mol/L hydrogen chloride-ethyl acetate solution (80 mL) was added, and the mixture was stirred at room temperature for 16 hr. The reaction mixture was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with water, 6% aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=4:1) to give methyl 2-chloro-5-(2-methylphenyl)-1H-pyrrole-3-carboxylate as an oil (yield 2.7 g). This was dissolved in methanol (15 mL), 10% palladium carbon (50% containing water, 1.0 g) was added, and the mixture was stirred under a hydrogen atmosphere at room temperature for 18 hr. The reaction mixture was filtrated, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=4:1) to give the title compound as a colorless solid (yield 0.66 g, 3%).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:23][O:24][CH3:25])=[C:10](/[CH:19]=[CH:20]/[CH2:21][OH:22])[C:11]([C:12]3[CH:13]=[N:14][CH:15]=[C:16]([CH3:18])[CH:17]=3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].C(N(C(C)C)CC)(C)C.Cl[C:36]([O:38][CH3:39])=[O:37]>C(Cl)Cl>[C:36](=[O:37])([O:38][CH3:39])[O:22][CH2:21]/[CH:20]=[CH:19]/[C:10]1[C:11]([C:12]2[CH:13]=[N:14][CH:15]=[C:16]([CH3:18])[CH:17]=2)=[C:6]2[CH:5]=[N:4][N:3]([CH2:1][CH3:2])[C:7]2=[N:8][C:9]=1[CH2:23][O:24][CH3:25]
Reactant: CCn1ncc2c(-c3cncc(C)c3)c(/C=C/CO)c(COC)nc21
Reactant: COC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCn1ncc2c(-c3cncc(C)c3)c(/C=C/COC(=O)OC)c(COC)nc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To an ice-cooled solution of (2E)-3-[1-ethyl-6-(methoxymethyl)-4-(5-methyl-3-pyridinyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-2-propen-1-ol (44 mg) and diisopropylethylamine (20 mg) in DCM (1 ml) was added methyl chloroformate (13.5 mg) and stirred for 2 hours at room temperature. The solvent was dried up and the residue was purified with silica gel column chromatography (CHCl3-MeOH 0-2%). (2E)-3-[1-Ethyl-6-(methoxymethyl)-4-(5-methyl-3-pyridyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-2-propen-1-yl methyl carbonate was obtained as a clear oil.
Reaction SMILES: CO[C:3]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]([CH3:21])=[C:13]1[C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1)=[O:4].[CH3:28][NH2:29]>C(O)CCC>[CH3:28][NH:29][C:3]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]([CH3:21])=[C:13]1[C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1)=[O:4]
Reactant: COC(=O)CCCCCCCn1c(-c2cccnc2)c(C)c2ccccc21
Reactant: CN
Solvent: CCCCO
Product: CNC(=O)CCCCCCCn1c(-c2cccnc2)c(C)c2ccccc21

Procedure:
A solution of 4 g of 1-(7-methoxycarbonylheptyl)-3-methyl-2-(3-pyridyl)indole in 40 ml of n-butanol is saturated with methylamine and heated on a steam bath in a pressure bottle for 3 days. The reaction mixture is evaporated to dryness and the product is crystallized to yield the 1-[7-(N-methylcarbamoyl)heptyl]-3-methyl-2-(3-pyridyl)indole.
Reaction SMILES: [ClH:1].Cl.[NH2:3][C:4]1[NH:5][C:6](=[CH:10][CH2:11][CH2:12][NH2:13])[C:7](=[O:9])[N:8]=1.Cl.NC1NC=C(CCCN[C:25]([C:27]2[N:28]([CH3:34])[C:29]([Br:33])=[C:30]([Br:32])[CH:31]=2)=[O:26])N=1>>[ClH:1].[NH2:3][C:4]1[NH:5][C:6](=[CH:10][CH2:11][CH2:12][NH:13][C:25]([C:27]2[N:28]([CH3:34])[C:29]([Br:33])=[C:30]([Br:32])[CH:31]=2)=[O:26])[C:7](=[O:9])[N:8]=1
Reactant: NCCC=C1NC(N)=NC1=O
Reactant: Cn1c(C(=O)NCCCc2c[nH]c(N)n2)cc(Br)c1Br
Agent: Cl
Product: Cn1c(C(=O)NCCC=C2NC(N)=NC2=O)cc(Br)c1Br
Yield: 47 %

Procedure:
Using the same general procedure as used for 2-amino-5-(3-amino-propylidene)-1,5-dihydro-imidazol-4 -one dihydrochloride, 0.100 g of dihydrosventrin hydrochloride 23 gave 0.048 g (47%) of the title compound 32 as a tan solid ((Z)-isomer exclusively). 1H NMR (300 MHz, CD3OD) δ 6.84 (s, 1H), 6.16 (t, 1H, J=7.8 Hz), 3.91 (s, 3H), 3.46 (t, 2H, J=6.9 Hz), 2.59 (dt, 2H, J=6.9, 14.7 Hz); 13C NMR (100 MHz, DMSO-d6) δ 163.80, 163.00, 157.19, 130.63, 129.04, 119.42, 115.92, 112.67, 99.09, 39.06, 36.28, 28.73; HRMS (ESI) calcd for C12H14Br2N5O2 (MH+) 417.9509, found 417.9511.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.[N:7]#[C:8][NH2:9].[ClH:10].O1CCOCC1>CCOCC>[ClH:10].[CH3:1][C:2]1[CH:3]=[N:4][N:5]([C:8](=[NH:7])[NH2:9])[CH:6]=1
Reactant: N#CN
Reactant: Cc1cn[nH]c1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: Cc1cnn(C(=N)N)c1
Temperature: 110 °C
Reaction time: 8 h

Procedure:
To 4-Methyl-1H-pyrazole (4.9 g, 60 mmol) was added cyanamide (2.5 g, 60 mmol), HCl (5.6 mL, 62 mmol, 4 M in dioxane) and dioxane (60 mL). The reaction was heated to 110° C. and aged for 9 h. It was then aged at rt overnight. The mixture was diluted with Et2O and stirred for 10 min. The product was isolated by filtration and washed with Et2O to afford the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].[Cl:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][C:25]=1[Cl:26])[CH2:21]Cl.O>CN(C=O)C.[I-].[K+]>[Cl:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][C:25]=1[Cl:26])[CH2:21][O:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)c1cccc(O)c1
Reactant: ClCc1ccc(Cl)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)c1cccc(OCc2ccc(Cl)c(Cl)c2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 72.8 %

Procedure:
To a solution of 3′-hydroxyacetophenone (19 g) in DMF (400 mL) was added K2CO3 (38.5 g) and the mixture was stirred for 3 hours at room temperature. 3,4-Dichlorobenzyl chloride (32.7 g) and potassium iodide (1.16 g) were added to the reaction mixture and stirred for 48 hours. After completion of the reaction, the mixture was poured into ice and water mixture and stirred for 15 minutes, solid was filtered and washed with water and hexanes. Solid was dissolved in DCM and precipitated by adding hexanes to get pure 1-[3-(3,4-dichloro-benzyloxy)-phenyl]-ethanone (30 g) 1H NMR (400 MHz, CDCl3) 7.53-7.60 (m, 3H), 7.46 (d, 1H), 7.39 (t, 1H), 7.25-7.30 (m, 1H), 7.14-7.19 (m, 1H), 5.07 (s, 2H), 2.60 (s, 3H).
Reaction SMILES: C([O:9][C@@H:10]1[CH2:15][CH2:14][C@H:13]([NH:16][C:17]2[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][C:18]=2[C:19]([NH:21][CH2:22][C:23]2[CH:31]=[CH:30][C:26]3[O:27][CH2:28][O:29][C:25]=3[CH:24]=2)=[O:20])[CH2:12][CH2:11]1)(=O)C1C=CC=CC=1.CO.[OH-].[Na+]>O1CCCC1>[OH:9][C@@H:10]1[CH2:15][CH2:14][C@H:13]([NH:16][C:17]2[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][C:18]=2[C:19]([NH:21][CH2:22][C:23]2[CH:31]=[CH:30][C:26]3[O:27][CH2:28][O:29][C:25]=3[CH:24]=2)=[O:20])[CH2:12][CH2:11]1
Reactant: O=C(O[C@H]1CC[C@@H](Nc2ccc([N+](=O)[O-])cc2C(=O)NCc2ccc3c(c2)OCO3)CC1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(NCc1ccc2c(c1)OCO2)c1cc([N+](=O)[O-])ccc1N[C@H]1CC[C@@H](O)CC1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
A mixture of 2-(cis4-benzoyloxycyclohexylamino)-5-nitro-N-(1,3-benzodioxol-5-ylmethyl)benzamide (64.0 mg), methanol (5 mL), tetrahydrofuran (5 mL) and 1N-sodium hydroxide solution (1 mL) was stirred for 2 hours at 60° C. After evaporation of the organic solvent, the aqueous layer was diluted with water and extracted with ethyl acetate. The extract was washed with an aqueous saturated sodium bicarbonate solution, water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was triturated with diisopropyl ether to give 2-(cis-4-hydroxycyclohexylamino)-5-nitro-N-(1,3-benzodioxol-5-ylmethyl)benzamide as yellow powders (50.5 mg).
Reaction SMILES: C[Si:2]([CH3:11])([O:7][CH2:8][CH2:9][SH:10])[O:3][CH2:4][CH2:5][SH:6].C(N(CC)CC)C.ClC([SiH3])(Cl)Cl.[SH:24][CH2:25][CH2:26][OH:27]>CCOCC>[CH3:11][Si:2]([O:3][CH2:4][CH2:5][SH:6])([O:7][CH2:8][CH2:9][SH:10])[O:27][CH2:26][CH2:25][SH:24]
Reactant: OCCS
Reactant: C[Si](C)(OCCS)OCCS
Agent: [SiH3]C(Cl)(Cl)Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: C[Si](OCCS)(OCCS)OCCS

Procedure:
The 2-[methyl-bis(2-sulfanylethoxy) silyl]oxyethanethiol (2) was synthesized according to the same procedure as 2-[dimethyl(2-sulfanylethoxy)silyl]oxyethanethiol (1), using triethylamine (8.08 g, 0.080 mol), trichloromethylsilane (3.98 g, 0.027 mol), and 2-mercaptoethanol (6.24 g, 0.080 mol) in ether (400 mL). 2-[methyl-bis(2-sulfanylethoxy) silyl]oxyethanethiol (2) was obtained as a clear, colorless, foul-smelling liquid (6.81 g, 93.2%). The product was purified by distillation under reduced pressure and obtained as a clear, colorless, foul-smelling liquid (4.53 g, 62.0%), Bp=128-129° C. at 0.25 mmHg.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[O:9][C:10]([CH3:34])=[C:11]([CH2:13][N:14]3[C:22]4[C:17](=[CH:18][C:19]([C:23]([OH:32])([C:28]([F:31])([F:30])[F:29])[C:24]([F:27])([F:26])[F:25])=[CH:20][CH:21]=4)[CH:16]=[C:15]3[CH3:33])[N:12]=2)[CH:5]=[CH:6][CH:7]=1.CN([CH:38]=[O:39])C.O=P(Cl)(Cl)Cl>ClC(Cl)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[O:9][C:10]([CH3:34])=[C:11]([CH2:13][N:14]3[C:22]4[C:17](=[CH:18][C:19]([C:23]([OH:32])([C:24]([F:26])([F:27])[F:25])[C:28]([F:29])([F:30])[F:31])=[CH:20][CH:21]=4)[C:16]([CH:38]=[O:39])=[C:15]3[CH3:33])[N:12]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1oc(-c2cccc(Cl)c2)nc1Cn1c(C)cc2cc(C(O)(C(F)(F)F)C(F)(F)F)ccc21
Reactant: CN(C)C=O
Solvent: CC(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1oc(-c2cccc(Cl)c2)nc1Cn1c(C)c(C=O)c2cc(C(O)(C(F)(F)F)C(F)(F)F)ccc21
Temperature: 0 °C
Yield: 51.8 %

Procedure:
A solution of 200 mg (0.4 mmol) of 2-{1-[2-(3-chloro-phenyl)-5-methyl-oxazol-4-ylmethyl]-2-methyl-1H-indol-5-yl}-1,1,1,3,3,3-hexafluoro-propan-2-ol (example 12) in 2 mL of dichloroethane was treated with 0.06 mL (0.8 mmol) of DMF and cooled to 0° C. After addition of 0.04 mL (0.44 mmol) of POCl3 the mixture was allowed to reach RT and stirred for an additional hour. Distribution of the mixture between Et2O and H2O, drying of the combined organic phases over Na2SO4 and column chromatography on silica gel with n-heptane/EtOAc 1:2 yielded 110 mg (52%) of 1-[2-(3-chloro-phenyl)-5-methyl-oxazol-4-ylmethyl]-2-methyl-5-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-1H-indole-3-carbaldehyde, light brown solid, MS: 531 (MH+).
Reaction SMILES: [Br:1]Br.[S:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1>C(Cl)Cl>[Br:1][C:7]1[S:3][C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:5][CH:6]=1
Reactant: c1ccc(-c2cccs2)nc1
Reactant: BrBr
Solvent: ClCCl
Product: Brc1ccc(-c2ccccn2)s1
Reaction time: 0.17 h

Procedure:
Bromine, 16 g (0.1 mol), was added to a solution of 8.05 g (0.05 mol) of 2-(2-thienyl)pyridine in 250 ml of methylene chloride. After stirring for 10 minutes, the reaction mixture was washed with 10% aqueous sodium carbonate solution, dried and evaporated. Crystallization from ethanol gave 9.5 g of the title compound with m.p. 85°-87°.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][S:6][C:7]1[CH:14]=[CH:13][C:10]([CH2:11]O)=[CH:9][CH:8]=1>C(Cl)Cl.N1C=CC=CC=1>[CH3:5][S:6][C:7]1[CH:14]=[CH:13][C:10]([CH2:11][Cl:3])=[CH:9][CH:8]=1
Reactant: CSc1ccc(CO)cc1
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CSc1ccc(CCl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.6 %

Procedure:
A solution of thionyl chloride (47.6 g) in methylene chloride is slowly added to a solution of 4-(methylthio)benzyl alcohol (50.0 g) in pyridine (37.2 g) such that the temperature never exceeds 25° C. After the addition is complete the mixture is stirred an additional 2 hours at room temperature, then washed with water, dried, and the solvents removed. The resulting red oil is mixed with hexane which is decanted and evaporated to give 49.6 g of 4-(methylthio)benzyl chloride as a yellow oil, suitable for use in the reaction described next below.