Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.BrBr.[S-:10][C:11]#[N:12].[Na+]>>[OH:7][C:1]1[CH:6]=[CH:5][C:4]([S:10][C:11]#[N:12])=[CH:3][CH:2]=1
Reactant: N#C[S-]
Reactant: Oc1ccccc1
Agent: BrBr
Agent: [Na+]
Product: N#CSc1ccc(O)cc1

Procedure:
The title compound was prepared according to the method of Example 32 from phenol (0.35 mole), bromine (0.35 mole) and sodium thiocyanate (0.35 mole).
Reaction SMILES: Cl[C:2]1[C:10]2[C:6](=[C:7]([C:13]([O:15]CC)=[O:14])[S:8][C:9]=2[S:11][CH3:12])[CH2:5][CH2:4][C:3]=1[CH:18]=O.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.[OH-].[Na+]>C(O)C.O.Cl>[CH3:12][S:11][C:9]1[S:8][C:7]([C:13]([OH:15])=[O:14])=[C:6]2[CH2:5][CH2:4][C:3]3[CH:18]=[C:7]([C:6]4[CH:10]=[CH:2][CH:3]=[CH:4][CH:5]=4)[S:8][C:2]=3[C:10]=12
Reactant: CCOC(=O)c1sc(SC)c2c1CCC(C=O)=C2Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CN(C)C=O
Solvent: O
Product: CSc1sc(C(=O)O)c2c1-c1sc(-c3ccccc3)cc1CC2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Ethyl 4-chloro-5-formyl-6,7-dihydro-3-methylthiobenzo[c]thiophene-1-carboxylate (1.32 g), methyl α-mercaptophenyl acetate (0.76 g) and potassium carbonate (0.69 g) were added to N,N-dimethylformamide (15 ml). The mixture was stirred at room temperature for 2 hours. The reaction mixture was poured over water, and extracted with ethyl acetate. The organic layer was washed with water and dried (MgSO4), after which the solvent was distilled off. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (1:5, v/v) to yield yellow powder. The powder was dissolved in ethanol (10 ml), to which an aqueous sodium hydroxide (0.10 g) in water (2 ml) was added. The obtained solution was stirred at 60° C. for 7 hours. To the reaction solution was added concentrated hydrochloric acid (1 drop). After the mixture was poured over water, it was extracted with ethyl acetate. The organic layer was washed with water and dried (MgSO4), after which the solvent was distilled off. The residue was subjected to silica gel column chromatography and eluted with chloroform-methanol to yield 4,5-dihydro-8-methylthio-2-phenylbenzo[2,1-c:3,4-b']dithiophene-6-carboxylic acid, which was then recrystallized from ethyl acetate-hexane. Yellow prisms. Melting point 215-217° C.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[CH2:8]([OH:14])[CH2:9][CH2:10][CH2:11][C:12]#[CH:13]>C(N(CC)CC)C.ClCCl.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:13]#[C:12][CH2:11][CH2:10][CH2:9][CH2:8][OH:14])[CH:3]=1
Reactant: Brc1cccnc1
Reactant: C#CCCCCO
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: OCCCCC#Cc1cccnc1
Yield: 76.5 %

Procedure:
A solution of 45 ml (0.47 mol) of 3-bromopyridine and 52 g (0.53 mol) of 5-hexyn-l-ol in 150 ml of triethylamine and 500 ml of dichloromethane is degassed for 15 minutes with argon, and 3 g (4.3 mmol) of bis(triphenylphosphine)palladium(II)chloride and -350 mg of cuprous iodide is added. The mixture is heated at reflux for 3 h. The cooled reaction mixture is diluted with 1 liter of dichloromethane and is washed with water and brine, dried (K2CO3), concentrated and bulb-to-bulb distilled (b.p. 120°-130° C./0.05 mbar), to give 63 g of 6-(3-pyridyl)hex-5-ynol as a yellow oil, which is dissolved in 300 ml of isopropanol and hydrogenated for 16 h over 6 g 10% palladium on carbon in a Parr-hydrogenator. The crude product is evaporatively distilled (b.p. 120-130° C./0.05 mbar), yielding 61.8 g (65%) of 6-(3-pyridyl)hexanol as a faintly yellow, viscous liquid. (C11H17NO; F.W. 179.3)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:18]1[N:23]2[N:24]=[CH:25][CH:26]=[C:22]2[C:21]([C:27]#[N:28])=[C:20]([OH:29])[C:19]=1[CH2:30][CH:31]=C)[C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH3:17])=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].I([O-])(=O)(=O)=[O:34].[Na+]>O1CCCC1.O.C(OCC)(=O)C.S([O-])([O-])(=O)=S.[Na+].[Na+].[Os](=O)(=O)(=O)=O>[C:1]([O:5][C:6]([N:8]([C:18]1[N:23]2[N:24]=[CH:25][CH:26]=[C:22]2[C:21]([C:27]#[N:28])=[C:20]([OH:29])[C:19]=1[CH2:30][CH2:31][OH:34])[C:9]1[CH:10]=[CH:11][C:12]([O:15][CH2:16][CH3:17])=[CH:13][CH:14]=1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: C=CCc1c(O)c(C#N)c2ccnn2c1N(C(=O)OC(C)(C)C)c1ccc(OCC)cc1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CCOc1ccc(N(C(=O)OC(C)(C)C)c2c(CCO)c(O)c(C#N)c3ccnn23)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 51.1 %

Procedure:
tert-Butoxy-N-[4-cyano-5-hydroxy-6-(2-propenyl)pyrazolo[1,5-a]pyridin-7-yl]-N-(4-ethoxyphenyl)carboxamide (27) (248 mg) was dissolved in a mixture of tetrahydrofuran (4.6 mL) and water (1.1 mL). To this solution, sodium periodate (611 mg) was added and the solution was cooled to 0° C. To this solution, osmium tetroxide (0.58 mL, 2.5 wt. % 2-methyl-2-propanol solution) was added dropwise and the mixture was stirred at room temperature for 2 h. The reaction solution was diluted with ethyl acetate and aqueous sodium thiosulfate solution was added to quench the reaction. After the organic layer was separated, the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with a mixture of brine and saturated aqueous ammonium chloride solution (9:1) and dried over sodium sulfate. The solvent was removed under reduced pressure and the residue was dissolved in methanol (5.7 mL). Here sodium borohydride (21.6 mg) was added and the solution was stirred at room temperature for 1 h. The reaction solution was diluted with ethyl acetate and washed with brine. The organic layer was dried over sodium sulfate, the solvent was removed under reduced pressure and the resultant crude product was purified with silica-gel column chromatography (hexane/ethyl acetate=2/1 to 1/2) to obtain the title compound (42) (128 mg, Yield 51%).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[CH:4]=O.[OH-].[Na+].[CH3:13][C:14]([CH3:16])=[O:15]>[Cl-].[Na+]>[F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[CH:4]=[CH:13][C:14](=[O:15])[CH3:16]
Reactant: O=Cc1c(F)cccc1F
Reactant: CC(C)=O
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Product: CC(=O)C=Cc1c(F)cccc1F
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a mixture of 2,6-difluorobenzaldehyde (10.0 g, 70 mmol) in acetone (85 mL) was added sodium hydroxide (1 N solution, 106 mL). After stirring at room temperature for 1.5 h, the reaction mixture was diluted with saturated aqueous sodium chloride solution and extracted with chloroform (2×150 mL). The combined organic layers were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The resulting material was purified by MPLC (0 to 20% gradient of ethyl acetate in hexanes as eluant) to afford the title product as a solid (8.1 g).
Reaction SMILES: [O:1]=[C:2]1[N:25]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([OH:34])=[O:33])[C:6]2=[N:7][C:8]([C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=3)=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=3)[N:10]=[C:5]2[CH2:4][CH2:3]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH3:45][C:46]([CH3:48])=[O:47]>C1COCC1>[OH:47][C:46]([CH:3]1[C:2](=[O:1])[N:25]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([OH:34])=[O:33])[C:6]2=[N:7][C:8]([C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=3)=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([CH3:17])=[CH:15][CH:16]=3)[N:10]=[C:5]2[CH2:4]1)([CH3:48])[CH3:45]
Reactant: CC(C)=O
Reactant: Cc1ccc(-c2nc3c(nc2-c2ccc(C)cc2)N(CCCCCCC(=O)O)C(=O)CC3)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1ccc(-c2nc3c(nc2-c2ccc(C)cc2)N(CCCCCCC(=O)O)C(=O)C(C(C)(C)O)C3)cc1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
A cooled (−78° C.) solution of 7-(6-oxo-2,3-di-p-tolyl-7,8-dihydropyrido[2,3-b]pyrazin-5(6H)-yl)heptanoic acid (step 2) (100 mg, 0.219 mmol) in THF (5 ml) under a nitrogen atmosphere was treated dropwise with lithium bis trimethylsilylamide (1M in THF, 0.546 ml, 0.546 mmol). The mixture was stirred at −78° C. for 10 minutes and treated with acetone (0.100 ml, 0.546 mmol) in THF (2 ml) maintaining the internal temperature below −65° C. Once addition was complete, the reaction was quenched with sat. NH4Cl (aq). The organic portion was separated and the aqueous was extracted with ethyl acetate (×2). The combined organic extracts were concentrated under reduced pressure and the crude product was purified by chromatography on silica eluting with 0-10% MeOH in DCM to afford the titled compound;
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:15]=[C:16](OS(C(F)(F)F)(=O)=O)[C:17]4[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:21][CH2:20][C:18]=4[N:19]=3)=[CH:9][CH:8]=2)[CH:4]=[N:3]1.[C:39]1([NH:45][CH2:46][CH2:47][OH:48])[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>CS(C)=O>[OH:48][CH2:47][CH2:46][N:45]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:16]1[C:17]2[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:28])([CH3:29])[CH3:30])=[O:25])[CH2:21][CH2:20][C:18]=2[N:19]=[C:14]([NH:13][C:10]2[CH:11]=[CH:12][C:7]([C:5]3[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=3)=[CH:8][CH:9]=2)[N:15]=1
Reactant: Cn1cc(-c2ccc(Nc3nc4c(c(OS(=O)(=O)C(F)(F)F)n3)CN(C(=O)OC(C)(C)C)CC4)cc2)cn1
Reactant: OCCNc1ccccc1
Solvent: CS(C)=O
Product: Cn1cc(-c2ccc(Nc3nc4c(c(N(CCO)c5ccccc5)n3)CN(C(=O)OC(C)(C)C)CC4)cc2)cn1
Temperature: 70 °C
Yield: 90.5 %

Procedure:
tert-Butyl 2-(4-(1-methyl-1H-pyrazol-4-yl)phenylamino)-4-(trifluoromethylsulfonyloxy)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate (1 g, 1.80 mmol) and 2-(phenylamino)ethanol (0.228 mL, 1.80 mmol) in dimethylsulfoxide (3 mL) were charged in a thick wall glass, which was sealed and heated under microwave irradiation at 70° C. for 7 h. The solvent was evaporated together with toluene, the crude impregnated in silica gel and purified by flash chromatography (ISCO) using dichloromethane/methanol (0-10%) as eluent and the solvent evaporated under reduced pressure yielding tert-butyl 4-((2-hydroxyethyl)(phenyl)amino)-2-(4-(1-methyl-1H-pyrazol-4-yl)phenylamino)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate (0.882 g, 90%). MS (ESI) (M+H) m/z 542
Reaction SMILES: O1CCCC1.[BH4-].[Na+].[S:8]1[C:12]2[CH:13]=[CH:14][C:15]([CH2:17][C:18](O)=[O:19])=[CH:16][C:11]=2[CH:10]=[CH:9]1.S(=O)(=O)(O)O>C1(C)C=CC=CC=1.O.CC(C)=O>[S:8]1[C:12]2[CH:13]=[CH:14][C:15]([CH2:17][CH2:18][OH:19])=[CH:16][C:11]=2[CH:10]=[CH:9]1
Reactant: O=C(O)Cc1ccc2sccc2c1
Agent: O=S(=O)(O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: OCCc1ccc2sccc2c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 85.6 %

Procedure:
To 340 mL of tetrahydrofuran was suspended 50.2 g of sodium borohydride, to which were dropped tetrahydrofuran (340 mL) solution of 170 g of (1-benzothiophen-5-yl)acetic acid, and 65.1 g of sulfuric acid successively, which was then stirred at room temperature for 2.5 hours. To this reaction mixture was dropwise added 85 mL of acetone, which was then stirred for 30 minutes. Thereto were added 510 mL of water and 680 mL of toluene. The organic layer was separated, to which was added 510 mL of water, and the pH was adjusted to 12 with 48 mL of 20% (w/w) sodium hydroxide aqueous solution. The organic layer was separated, and washed with water, followed by distilling off the solvent. Thereto were added cyclohexane and toluene. The precipitate was collected by filtration to provide 135 g of 2-(1-benzothiophen-5-yl)ethanol as white solid form.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.C([CH2:13][S:14]([CH2:17][S:18]([CH2:21][C:22](O)=O)(=[O:20])=[O:19])(=[O:16])=[O:15])(O)=O>C(O)(=O)C>[Br:1][C:2]1[CH:9]=[CH:8][C:5](/[CH:6]=[CH:13]/[S:14]([CH2:17][S:18](/[CH:21]=[CH:22]/[C:5]2[CH:8]=[CH:9][C:2]([Br:1])=[CH:3][CH:4]=2)(=[O:20])=[O:19])(=[O:16])=[O:15])=[CH:4][CH:3]=1
Reactant: O=C(O)CS(=O)(=O)CS(=O)(=O)CC(=O)O
Reactant: O=Cc1ccc(Br)cc1
Solvent: CC(=O)O
Product: O=S(=O)(/C=C/c1ccc(Br)cc1)CS(=O)(=O)/C=C/c1ccc(Br)cc1
Yield: 82 %

Procedure:
A solution of 4-bromobenzaldehyde (2 mmol) and carboxymethane-sulfonylmethanesulfonyl-acetic acid (1 mmol) in acetic acid (10 mL) was subjected to General Procedure 1, to yield the title compound in 82% yield. m.p. 213-215° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[S:9][C:10]([Cl:13])=[CH:11][CH:12]=2)=[CH:6][CH:5]=[C:4]([Cl:14])[C:3]=1[CH2:15][C:16]([N:18]([CH2:28][CH:29]([F:31])[F:30])[C:19]1[N:20]=[CH:21][S:22][C:23]=1[C:24]([O:26]C)=O)=[O:17].[H-].[Na+]>C1COCC1>[Cl:1][C:2]1[C:7]([C:8]2[S:9][C:10]([Cl:13])=[CH:11][CH:12]=2)=[CH:6][CH:5]=[C:4]([Cl:14])[C:3]=1[C:15]1[C:16](=[O:17])[N:18]([CH2:28][CH:29]([F:30])[F:31])[C:19]2[N:20]=[CH:21][S:22][C:23]=2[C:24]=1[OH:26]
Reactant: COC(=O)c1scnc1N(CC(F)F)C(=O)Cc1c(Cl)ccc(-c2ccc(Cl)s2)c1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=c1c(-c2c(Cl)ccc(-c3ccc(Cl)s3)c2Cl)c(O)c2scnc2n1CC(F)F
Temperature: 25 °C
Reaction time: 4 h

Procedure:
120 mg (0.23 mmol) of methyl 4-[{[2,6-dichloro-3-(5-chloro-2-thienyl)phenyl]acetyl}(2,2-difluoroethyl)amino]-1,3-thiazole-5-carboxylate were dissolved in 10 ml of THF, and 6.6 mg (0.27 mmol) of sodium hydride were added under an atmosphere of argon. The reaction mixture was stirred at RT for 4 h. The THF was then removed under reduced pressure and the residue was taken up in water. The aqueous phase was extracted with dichloromethane, the organic phase was dried and concentrated by evaporation, the aqueous phase was acidified with 1N hydrochloric acid. After extraction with dichloromethane, the organic phase was dried and concentrated by evaporation. The product-containing residues were chromatographed (acetonitrile/water (0.05% trifluoroacetic acid) 20/80 to 100/0)). This gave 50 mg of 6-[2,6-dichloro-3-(5-chloro-2-thienyl)phenyl]-4-(2,2-difluoroethyl)-7-hydroxy[1,3]thiazolo[4,5-b]pyridin-5(4H)-one.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1.[N:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[C:11]=[O:12]>ClCCl>[OH:7][CH2:6][C:5]1[CH:8]=[CH:9][C:2]([NH:1][C:11]([NH:10][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:12])=[CH:3][CH:4]=1
Reactant: O=C=Nc1ccccc1
Reactant: Nc1ccc(CO)cc1
Solvent: ClCCl
Product: O=C(Nc1ccccc1)Nc1ccc(CO)cc1

Procedure:
A solution of 3.75 g 4-aminobenzylalcohol and 3.3 ml isocyanato-benzene in 120 ml dichloromethane was stirred at 23° C. for 2 hours. Afterwards, the reaction mixture was filtered. The crystalline product was washed with diethylether. 6.82 g product was obtained which was used without further purification.
Reaction SMILES: [C:1]1([C:7]2[N:12]=[CH:11][C:10]([C:13](Cl)=[O:14])=[CH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:16][CH2:17][CH2:18][S:19]([NH2:22])(=[O:21])=[O:20].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[S:19]([CH2:18][CH2:17][NH:16][C:13]([C:10]1[CH:9]=[N:8][C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[N:12][CH:11]=1)=[O:14])(=[O:21])(=[O:20])[NH2:22]
Reactant: NCCS(N)(=O)=O
Reactant: O=C(Cl)c1cnc(-c2ccccc2)nc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: NS(=O)(=O)CCNC(=O)c1cnc(-c2ccccc2)nc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-phenyl-pyrimidine-5-carboxylic acid chloride (1.51 mmol) and 2-amino-ethanesulfonic acid amide (1.51 mmol) in DCM (15 mL) is added diisopropylethylamine (4.53 mmol). The mixture is stirred at room temperature overnight. The mixture is concentrated in vacuo. The residue is washed with water and DCM to afford 2-phenyl-pyrimidine-5-carboxylic acid (2-sulfamoyl-ethyl)-amide as a solid. MS: 307 (M+H); 1H NMR (300 MHz, DMSO-d6): δ 3.25 (q, 2H), 3.67 (m, 2H), 6.93 (s, N—H), 7.47-7.60 (m, 3H), 8.36-8.48 (m, 2H), 8.92-9.15 (m, N—H), 9.16-9.36 (m, 2H); IC50=55 nM.
Reaction SMILES: [CH3:1][S:2]([NH:5][NH2:6])(=[O:4])=[O:3].C[O:8][C:9](=O)[C:10]1[CH:15]=[C:14]([C:16](=[O:21])[CH2:17][CH2:18][O:19][CH3:20])[C:13]([C:22]([F:25])([F:24])[F:23])=[CH:12][C:11]=1[N:26]=[C:27]=[O:28].[OH-].[Na+]>C1COCC1>[CH3:20][O:19][CH2:18][CH2:17][C:16]([C:14]1[CH:15]=[C:10]2[C:11](=[CH:12][C:13]=1[C:22]([F:23])([F:24])[F:25])[NH:26][C:27](=[O:28])[N:6]([NH:5][S:2]([CH3:1])(=[O:4])=[O:3])[C:9]2=[O:8])=[O:21]
Reactant: CS(=O)(=O)NN
Reactant: COCCC(=O)c1cc(C(=O)OC)c(N=C=O)cc1C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COCCC(=O)c1cc2c(=O)n(NS(C)(=O)=O)c(=O)[nH]c2cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1.75 h
Yield: 93.8 %

Procedure:
A solution of CH3SO2NHNH2 (61 mg, 0.555 mmol) in THF (1 mL) was slowly added dropwise to a solution of 2-isocyanato-5-(3-methoxy-propionyl)-4-trifluoromethyl-benzoic acid methyl ester (167 mg, 0.505 mmol) in dry THF (2.6 mL). After stirring the mixture at r.t. for 105 min, aq NaOH (1 M, 0.53 mL) was added and stirring was continued for 60 min. The reaction mixture was concentrated and the residue was taken in EtOAc and washed with water. The aqueous phase was extracted with EtOAc (3×), all organic phases are combined, washed with brine and dried (Na2SO4) and the solvent was evaporated to dryness yielding the title compound (194 mg, 94%) as a white powder, mp 186-191° C.
Reaction SMILES: Cl.C(OC(=O)[NH:8][C:9]1[C:10]([C:16](=[O:25])[NH:17][C:18]2[CH:23]=[CH:22][N:21]=[C:20]([Cl:24])[CH:19]=2)=[N:11][C:12]([CH3:15])=[CH:13][CH:14]=1)(C)(C)C>CO>[Cl:24][C:20]1[CH:19]=[C:18]([NH:17][C:16]([C:10]2[C:9]([NH2:8])=[CH:14][CH:13]=[C:12]([CH3:15])[N:11]=2)=[O:25])[CH:23]=[CH:22][N:21]=1
Reactant: Cc1ccc(NC(=O)OC(C)(C)C)c(C(=O)Nc2ccnc(Cl)c2)n1
Agent: Cl
Solvent: CO
Product: Cc1ccc(N)c(C(=O)Nc2ccnc(Cl)c2)n1
Yield: 96.5 %

Procedure:
A HCl saturated solution of [2-(2-Chloro-pyridin-4-ylcarbamoyl)-6-methyl-pyridin-3-yl]-carbamic acid tert-butyl ester (0.50 g, 1.38 mmol) in methanol (13.0 ml) was stirred overnight at r.t. and evaporated to dryness in vaccuo. The residual hydrochloride salt was taken up in 15 ml of water, the pH was adjusted to 8.5 by addition of sat. sodium carbonate solution. The resulting suspension was extracted twice with ethyl acetate. The combined organic phases were dried over magnesium sulfate and concentrated in vaccuo to yield the title compound as a white solid (total 0.35 g, 97%), MS (ISP): m/e=263.1, 265.1 (M+H+).
Reaction SMILES: [CH2:1]([C:4]1([CH:19]=[CH:20][CH2:21][OH:22])[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[CH2:8][CH2:7][C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]1=2)[CH:2]=[CH2:3].[H][H]>C(O)C.[Pd]>[CH2:1]([C:4]1([CH2:19][CH2:20][CH2:21][OH:22])[C:5]2[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=2[CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]1=2)[CH2:2][CH3:3]
Reactant: C=CCC1(C=CCO)c2ccccc2CCc2ccccc21
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCCC1(CCCO)c2ccccc2CCc2ccccc21
Yield: 90.1 %

Procedure:
Dissolved 3-[10,11-dihydro-5-(2-propenyl)-5H-dibenzo[a,d]cyclohepten-5-yl]-prop-2-en-1-ol (4.85 g, 16.70 mmol) in 75 mL of absolute ethanol. Added 10% palladium on carbon catalyst (1.20 g), and hydrogenated on Paar shaker at 58 psi of hydrogen pressure for 16 hours. Filtered to remove catalyst, and evaporated filtrate to give 4.43 g (90% yield) of 3-[10,11-dihydro-5-propyl-5H-dibenzo[a,d]cyclohepten-5-yl]-propanol as a colorless oil. ##STR36##
Reaction SMILES: [Br:1][C:2]([Cl:13])([C:9]([F:12])([F:11])[F:10])[CH:3](O)[CH:4]=[C:5]([CH3:7])[CH3:6].[C:14](OC)([O:18][CH3:19])([O:16]C)[CH3:15].O.[O-2].[O-2].[O-2].O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.[Al+3].[Al+3]>>[Br:1][C:2]([Cl:13])([C:9]([F:10])([F:11])[F:12])[CH:3]=[CH:4][C:5]([CH3:7])([CH3:6])[CH2:15][C:14]([O:18][CH3:19])=[O:16]
Reactant: CC(C)=CC(O)C(Cl)(Br)C(F)(F)F
Reactant: COC(C)(OC)OC
Agent: O=[Si]=O
Agent: [Al+3]
Agent: [O-2]
Solvent: O
Product: COC(=O)CC(C)(C)C=CC(Cl)(Br)C(F)(F)F
Temperature: 111 °C
Reaction time: 1 h

Procedure:
5-Bromo-5-chloro-4-hydroxy-2-methyl-6,6,6-trifluorohex-2-ene (10.0 g), trimethyl orthoacetate (16.0 g) and Montmorillonite KSF (0.5 g) were charged to a round-bottomed flask fitted with: nitrogen inlet/bubbler, thermometer and still-head. The mixture was heated with agitation, and the methanol-trimethyl orthoacetate distillates were collected until the reactor temperature increased to 111° C. (ca. 1 hr). The reaction was then heated to 135° C. and held for a further 1 hour. The methanol/trimethyl orthoacetate distillates were recharged and the distillation procedure repeated twice. Once the reaction was complete, the Montmorillonite was removed by filtration. The residual trimethyl orthoacetate was then removed by distillation under vacuum (ca. 50° C. ≃100 mmHg) to give the product, methyl 6-bromo-6-chloro-3,3-dimethyl-7,7,7-trifluorohept-4-enoate as a brown oil (7.8 g, 59 g yield).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:23]3[C:18](=[CH:19][C:20]([O:24][CH2:25][CH2:26][CH2:27][N:28]4[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]4)=[CH:21][CH:22]=3)[N:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])(C)(C)C.CCN(CC)CC.C(Cl)(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O.Cl.[N+](C1C=CC(OC(=O)[NH:71][C:72]2[CH:77]=[CH:76][C:75]([N:78]3[CH2:83][CH2:82][O:81][CH2:80][CH2:79]3)=[CH:74][CH:73]=2)=CC=1)([O-])=O.C(NCC)C>C(Cl)Cl>[N:78]1([C:75]2[CH:74]=[CH:73][C:72]([NH:71][C:6]([N:8]3[CH2:13][CH2:12][CH:11]([C:14]4[C:23]5[C:18](=[CH:19][C:20]([O:24][CH2:25][CH2:26][CH2:27][N:28]6[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]6)=[CH:21][CH:22]=5)[N:17]=[CH:16][N:15]=4)[CH2:10][CH2:9]3)=[O:7])=[CH:77][CH:76]=2)[CH2:79][CH2:80][O:81][CH2:82][CH2:83]1
Reactant: O=C(Nc1ccc(N2CCOCC2)cc1)Oc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ncnc3cc(OCCCN4CCNCC4)ccc23)CC1
Agent: Cl
Agent: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Solvent: ClCCl
Solvent: CCNCC
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(N2CCOCC2)cc1)N1CCC(c2ncnc3cc(OCCCN4CCNCC4)ccc23)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 10 %

Procedure:
4-[7-(3-piperazin-1-yl-propoxy)-quinazolin-4-yl]-piperidine-1-carboxylic acid tert-butyl ester (0.05 mmol), prepared as described in Example 118, was dissolved in anhydrous DCM (1 mL) and treated with Et3N (0.05 mmol) followed by FMOC-Cl (0.1 mmol) and the mixture was stirred at rt overnight and then washed with water thrice, then dried over anhydrous MgSO4, filtered and concentrated in vacuo. To this was added 3M HCl/MeOH (1 mL) and the mixture was stirred at rt for 2 h and then concentrated in vacuo and the residue was dissolved in a 1:1 mixture of DCM:MeOH, neutralized with excess Et3N and treated with (4-morpholin-4-yl-phenyl)-carbamic acid 4-nitrophenyl ester hydrochloride (0.06 mmol), as prepared by the method outlined in Example 66a. The mixture was stirred at rt overnight and then concentrated in vacuo and partitioned between water and DCM. DCM layer was drawn off, washed with water thrice, then dried over anhydrous MgSO4, filtered and concentrated in vacuo. The residue was purified by Preparative TLC (silica gel; DCM:MeOH:NH4OH; 90:9:1) to obtain the pure product. This was dissolved in anhydrous DCM (1 mL) and diethylamine (0.25 mL) was added and the mixture was stirred at rt overnight. It was then concentrated in vacuo and purified by Preparative TLC (silica gel; DCM:MeOH:NH4OH; 90:9:1) to obtain 2.8 mg (10%) of the title compound. 1H-NMR (300 MHz, CDCl3): 9.13 (s, 1H), 8.05 (d, 1H), 7.35-7.23 (m, 4H), 6.88 (d, 2H), 6.35 (s, 1H), 4.32-4.14 (m, 4H), 3.90-3.80 (m, 4H), 3.75-3.60 (m, 1H), 3.20-2.91 (m, 10H), 2.75-2.55 (m, 6H), 2.18-1.85 (m, 7H). LC/MS (ESI): 560.0 (MH)+.