Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][N:5]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[C@@H:4]([C:18]([O:20]CC2C=CC=C(C(F)(F)F)C=2)=[O:19])[CH2:3]1.[Li+:32].[OH-]>>[OH:1][C@H:2]1[CH2:6][N:5]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:16])([F:17])[F:15])[CH:9]=2)[C@@H:4]([C:18]([O-:20])=[O:19])[CH2:3]1.[Li+:32]
Reactant: O=C(OCc1cccc(C(F)(F)F)c1)[C@H]1C[C@@H](O)CN1Cc1cccc(C(F)(F)F)c1
Agent: [Li+]
Agent: [OH-]
Product: O=C([O-])[C@H]1C[C@@H](O)CN1Cc1cccc(C(F)(F)F)c1

Procedure:
The title compound (D15) (16 mg) was prepared according to the general procedure for esters hydrolysis starting from (2R,4R)-3-(trifluoromethyl)benzyl 4-hydroxy-1-(3-(trifluoromethyl)benzyl)pyrrolidine-2-carboxylate (D8) (50 mg). (LiOH: 2 eq; Reaction time: 4 hrs).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:17]=[N:16][C:15]3[C:14]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=[N:13][C:12]([C:24]4[CH:25]=[N:26][C:27]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[N:28][CH:29]=4)=[N:11][C:10]=3[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[Cl:38][CH2:39][C:40](Cl)=[O:41].C(N(CC)CC)C>C(Cl)Cl>[Cl:38][CH2:39][C:40]([NH:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:17]=[N:16][C:15]3[C:14]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=[N:13][C:12]([C:24]4[CH:25]=[N:26][C:27]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:34])([CH3:36])[CH3:35])=[N:28][CH:29]=4)=[N:11][C:10]=3[CH:9]=2)[CH:5]=[CH:6][CH:7]=1)=[O:41]
Reactant: O=C(Cl)CCl
Reactant: CC(C)(C)OC(=O)Nc1ncc(-c2nc(N3CCOCC3)c3ncc(-c4cccc(N)c4)cc3n2)cn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)Nc1ncc(-c2nc(N3CCOCC3)c3ncc(-c4cccc(NC(=O)CCl)c4)cc3n2)cn1
Temperature: 10 °C
Reaction time: 0.5 h
Yield: 86.6 %

Procedure:
To a 25 mL round bottom flask, tert-butyl (5-(7-(3-aminophenyl)-4-morpholinopyrido[3,2-d]pyrimidin-2-yl)pyrimidin-2-yl)carbamate (Example 7, Step 2) (0.15 g, 0.0003 mol), chloroacetyl chloride (0.051 g, 0.00045 mol) and DCM (10 mL) were added and then cooled to 10° C. To the same reaction flask, triethylamine (0.12 mL, 0.0009 mol) was added. The reaction mass was stirred at room temperature for 30 minutes. The reaction mixture was diluted with DCM, washed with water and brine. The organic layer was dried over anhydrous sodium sulfate and evaporated to provide the crude product. The crude product was purified by column chromatography (60-120 silica-gel and 0-2% methanol in chloroform) to afford the title compound (0.15 g, 87%). 1H NMR (300 MHz, DMSO-d6): δ 10.52 (s, 1H), 10.42 (s, 1H), 9.48 (s, 1H), 9.08 (d, J=1.8 Hz, 1H), 8.33 (d, J=2.1 Hz, 1H), 8.18 (s, 1H), 7.68 (t, J=4.8 Hz, 2H), 7.57 (t, J=7.8 Hz, 1H), 4.65-4.52 (br s, 4H), 4.33 (s, 2H), 3.84 (s, 4H), 1.49 (s, 9H): LC-MS (ESI): Calculated mass. 576.2, Observed mass [M+H]+: 577.2 (RT=1.53 min).
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH2:12][OH:13])=[C:10]([CH2:14]Cl)[C:9]2[C:4](=[CH:5][C:6]([Cl:17])=[C:7]([CH3:16])[CH:8]=2)[N:3]=1.[CH3:18][CH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.O.ClC(Cl)C>C1COCC1>[Cl:1][C:2]1[C:11]([CH2:12][OH:13])=[C:10]([CH2:14][N:22]2[CH2:23][CH2:24][CH:19]([CH3:18])[CH2:20][CH2:21]2)[C:9]2[C:4](=[CH:5][C:6]([Cl:17])=[C:7]([CH3:16])[CH:8]=2)[N:3]=1
Reactant: Cc1cc2c(CCl)c(CO)c(Cl)nc2cc1Cl
Reactant: CC1CCNCC1
Solvent: O
Solvent: C1CCOC1
Solvent: CC(Cl)Cl
Product: Cc1cc2c(CN3CCC(C)CC3)c(CO)c(Cl)nc2cc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 93 %

Procedure:
A solution of the product of Stage 82.d (16.2 g; 55.7 mmol) in THF (70 ml) is treated with a solution of 4-methylpiperidine (23 ml; 195 mmol). The mixture obtained is agitated at ambient temperature for 2 hours. Water (200 ml) and dichloroethane (200 ml) are added. The organic phase is washed with an aqueous solution of sodium chloride (concentrated to 20% by weight; 100 ml), dried over magnesium sulphate and concentrated under reduced pressure. By crystallization of the residue from diethylether, the product in the title is obtained (18.3 g; 93% yield) in the form of a white crystalline solid (M.p. 170–171,5° C.).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3](B(O)O)=[N:2]1.COCCOC.I[C:16]1[CH:17]=[CH:18][C:19]2[O:24][CH2:23][CH2:22][CH2:21][C:20]=2[CH:25]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[O:24]1[C:19]2[CH:18]=[CH:17][C:16]([C:3]3[CH:4]=[CH:5][NH:1][N:2]=3)=[CH:25][C:20]=2[CH2:21][CH2:22][CH2:23]1
Reactant: Ic1ccc2c(c1)CCCO2
Reactant: OB(O)c1cc[nH]n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: COCCOC
Solvent: O
Product: c1cc(-c2ccc3c(c2)CCCO3)n[nH]1
Temperature: 90 °C
Yield: 14 %

Procedure:
To a solution of B-(1H-pyrazol-3-yl)boronic acid (400 mg, 3.57 mmol) in a mixture of tetrahydrofuran (THF), 1,2-dimethoxyethane and water (1:2:1), was added 3,4-dihydro-6-iodo-2H-1-benzopyran (1.53 g, 5.88 mmol; prepared according to Muraki et al., Tetrahedron Lett. 1996, 37, 2441) under nitrogen atmosphere. Then potassium carbonate (980 mg, 7.14 mmol) and bis(triphenylphosphine)palladium(II) dichloride (120 mg, 0.017 mmol) were added, and the reaction mixture was heated at 90° C. for 3 h. The reaction mixture was concentrated and purified by silica gel column chromatography using 30% ethyl acetate in petroleum ether as eluant to provide the title product as solid (100 mg).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].Br[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[Br:14].[Cl:15][C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1>C1(C)C=CC=CC=1.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>[Br:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:19]1[CH:20]=[CH:21][C:16]([Cl:15])=[CH:17][CH:18]=1
Reactant: Brc1ccccc1Br
Reactant: OB(O)c1ccc(Cl)cc1
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: Cc1ccccc1
Solvent: O
Product: Clc1ccc(-c2ccccc2Br)cc1
Temperature: 25 °C
Yield: 70.5 %

Procedure:
Sodium carbonate (19.8 g, 186.81 mmol) and tetrakis(triphenylphosphine)palladium(0) (1.05 g, 0.90 mmol) were added to a solution of 1,2-dibromobenzene (12.8 ml, 105.98 mmol) and 4-chlorophenylboronic acid (14.1 g, 90.08 mmol) in toluene (170 ml) and water (80 ml). The mixture was purged with nitrogen and heated at reflux overnight. The reaction mixture was allowed to cool to room temperature, and partitioned between saturated aq. NH4Cl and ethyl acetate (500 ml). The organic layer was dried over MgSO4, filtered and the volatiles were evaporated under reduced pressure to give a residue. The residue was purified by column chromatography (ISCO, 330 g silica gel column, eluting with 100% hexanes) to give the title product (17.0 g, yield: 71%).
Reaction SMILES: O.Cl[C:3]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]4[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH3:32])[CH:24]=4)[N:18]=3)=[O:16])[CH2:11][CH2:10]2)[CH:6]=[CH:5][N:4]=1>[Pd].CO>[CH3:32][O:31][C:25]1[CH:24]=[C:23]([C:19]2[N:18]=[C:17]([C:15]([N:12]3[CH2:13][CH2:14][N:9]([C:7]4[CH:6]=[CH:5][N:4]=[CH:3][N:8]=4)[CH2:10][CH2:11]3)=[O:16])[CH:22]=[CH:21][CH:20]=2)[CH:28]=[CH:27][C:26]=1[O:29][CH3:30]
Reactant: COc1ccc(-c2cccc(C(=O)N3CCN(c4ccnc(Cl)n4)CC3)n2)cc1OC
Agent: [Pd]
Solvent: CO
Solvent: O
Product: COc1ccc(-c2cccc(C(=O)N3CCN(c4ccncn4)CC3)n2)cc1OC
Temperature: 25 °C
Reaction time: 23 h
Yield: 20.4 %

Procedure:
To a methanol (20 ml) solution of 460 mg of 2-chloro-4-{4-[6-(3,4-dimethoxyphenyl) pyridine-2-carbonyl]piperazin-1-yl}pyrimidine monohydrate was added 150 mg of 10% palladium/carbon, followed by 23 hours of stirring at room temperature under a hydrogen atmosphere of normal pressure. Insoluble matter was removed by filtration and the residue obtained by evaporation of the solvent was purified by silica gel column chromatography (chloroform-methanol) and further, recrystallization was carried out from acetonitrile-diisopropyl ether to obtain 83 mg of 4-{4-[6-(3,4-dimethoxyphenyl)pyridine-2-carbonyl]piperazin-1-yl}pyrimidine as colorless crystals.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[NH:7][C:8](=[O:15])OCC(Cl)(Cl)Cl.[C:16]1([C:22]2[N:26]=[C:25]([N:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[S:24][N:23]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(C(C)C)CC)(C)C.CS(C)=O>O>[C:16]1([C:22]2[N:26]=[C:25]([N:27]3[CH2:32][CH2:31][N:30]([C:8]([NH:7][C:2]4[CH:3]=[N:4][CH:5]=[CH:6][N:1]=4)=[O:15])[CH2:29][CH2:28]3)[S:24][N:23]=2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=C(Nc1cnccn1)OCC(Cl)(Cl)Cl
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CS(C)=O
Product: O=C(Nc1cnccn1)N1CCN(c2nc(-c3ccccc3)ns2)CC1
Yield: 36.4 %

Procedure:
A solution of 2,2,2-trichloroethyl pyrazin-2-ylcarbamate (150 mg, 0.556 mmol), 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (137 mg, 0.556 mmol), diisopropylethylamine (0.0968 ml, 0.556 mmol) and dimethylsulfoxide (3 ml) was stirred at 70° C. for 12 hours, the reaction mixture was poured into water and a solid was collected by filtration and washed with water. This was recrystallized from a mixed solvent of tetrahydrofuran and ethyl acetate to obtain the desired product (74.3 mg, 36.4%) as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[Cl:10][C:11]([Cl:16])([Cl:15])C(O)=O.[Na+].ClC(Cl)(Cl)C([O-])=O.O>CN(C)C=O>[Cl:10][C:11]([Cl:16])([Cl:15])[CH:6]([C:5]1[CH:8]=[CH:9][C:2]([Cl:1])=[CH:3][CH:4]=1)[OH:7]
Reactant: O=C(O)C(Cl)(Cl)Cl
Reactant: O=Cc1ccc(Cl)cc1
Agent: O=C([O-])C(Cl)(Cl)Cl
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: OC(c1ccc(Cl)cc1)C(Cl)(Cl)Cl
Temperature: 32.5 °C

Procedure:
A mixture of 4-chloro-benzaldehyde (35.5 g) and trichloro acetic acid (61.5 g) in N,N-dimethylformamide (200 ml) is stirred at 30-35° C. Trichloro acetic acid sodium salt (71.5 g) is added in portions over 20 minutes. Occasionally cooling is necessary. The reaction mixture is stirred at 30° C. for 2 hours. Towards the end it becomes viscous and additional N,N-dimethylformamide (150 ml) is charged. The reaction mixture is poured into water (700 ml). The aqueous phase is extracted with ethyl acetate (600 ml). The organic phase is separated, washed with water (300 ml), dried (magnesium sulfate) and evaporated. 2,2,2-Trichloro-1-(4-chloro-phenyl)-ethanol is obtained as oil.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([NH:15][C:16]([NH2:18])=[NH:17])[CH:12]=[CH:13][CH:14]=1)C1C=CC=CC=1>CCO.[Pd]>[OH:8][C:9]1[CH:10]=[C:11]([NH:15][C:16]([NH2:18])=[NH:17])[CH:12]=[CH:13][CH:14]=1
Reactant: N=C(N)Nc1cccc(OCc2ccccc2)c1
Agent: [Pd]
Solvent: CCO
Product: N=C(N)Nc1cccc(O)c1
Reaction time: 8 h

Procedure:
To a solution of N-(3-benzyloxy-phenyl)guanidine (5.0 g, 20.6 mmol) in EtOH (150 mL) was added palladium on carbon (10%, wet, 50% water, 0.5 g)). The mixture was stirred under hydrogen atmosphere overnight. The reaction was filtered through a plug of celite and the filtrate concentrated in vacuo. with toluene azeotroping to affored the desired material (2.83 g, 91%). 1H NMR (MeOH-d4) δ6.4-7 (m, 4H)
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8]C)[CH:5]=[C:4]([CH3:10])[C:3]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(O)(=O)C.Br>O>[CH3:10][C:4]1[CH:5]=[C:6]([OH:8])[CH:7]=[C:2]([CH3:1])[C:3]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: COc1cc(C)c(-c2ccccc2)c(C)c1
Agent: Br
Solvent: O
Solvent: CC(=O)O
Product: Cc1cc(O)cc(C)c1-c1ccccc1

Procedure:
2,6-dimethyl-4-methoxybiphenyl (3.0 g), acetic acid (30 ml) and 48% aqueous hydrobromic acid (30 ml) were heated at reflux temperature for 4 hours. The mixture was then cooled, poured into water and extracted with ether. After extracting the organic solution with aqueous sodium hydroxide, the aqueous extract was acidified with aqueous hydrochloric acid and further extracted with ether. The resulting extract was dried and evaporated and the residue was recrystallized from acetone/hexane to afford 2,6-dimethyl-4-hydroxybiphenyl, mp 128°-130° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[N:11]3[CH:20]=[CH:21][N:22]=[C:10]23)=[C:4]([F:23])[CH:3]=1.[CH2:24](Br)[C:25]#[CH:26].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:1][C:2]1[C:7]([O:8][CH2:26][C:25]#[CH:24])=[CH:6][C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:18])([F:19])[F:17])[N:11]3[CH:20]=[CH:21][N:22]=[C:10]23)=[C:4]([F:23])[CH:3]=1
Reactant: O=c1cc(C(F)(F)F)n2ccnc2n1-c1cc(O)c(Cl)cc1F
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C#CCOc1cc(-n2c(=O)cc(C(F)(F)F)n3ccnc23)c(F)cc1Cl

Procedure:
A mixture of 8-(4-chloro-2-fluoro-5-hydroxyphenyl)-7,8-dihydro-5-trifluoromethylimidazo[1,2-a]pyrimidin-7-one (4.3 g), propargyl bromide (2.3 g), potassium carbonate (2.1 g) and acetonitrile (100 ml) was heated to reflux for 2 hours. The solvent was distilled off under reduced pressure. The residue was added with water and extracted with ethyl acetate. The extract layer was washed with water and dried on anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was recrystallized from diisopropyl ether to give the compound of interest (4.2 g) as a milk white crystal.
Reaction SMILES: N[C:2]1[S:3][C:4]2[CH2:13][C@H:12]3[C@@H:7]([CH2:8][CH2:9][CH2:10][N:11]3[CH2:14][CH2:15][CH3:16])[CH2:6][C:5]=2[N:17]=1.P(=O)(O)(O)O.N([O-])=O.[Na+].OP=O.[OH-].[NH4+]>O>[CH2:14]([N:11]1[C@@H:12]2[C@H:7]([CH2:6][C:5]3[N:17]=[CH:2][S:3][C:4]=3[CH2:13]2)[CH2:8][CH2:9][CH2:10]1)[CH2:15][CH3:16]
Reactant: CCCN1CCC[C@H]2Cc3nc(N)sc3C[C@@H]21
Agent: O=N[O-]
Agent: O=P(O)(O)O
Agent: O=PO
Solvent: O
Product: CCCN1CCC[C@H]2Cc3ncsc3C[C@@H]21

Procedure:
A solution of 0.24 g. of trans-(±)-2-amino-5-n-propyl-4,4a,5,6,7,8,8a,9-octahydrothiazolo[4,5-g]quinoline in 10 ml. of 85% phosphoric acid was cooled to about -8° C. A saturated solution of 1.17 g. of sodium nitrite in water was added below the surface of the phosphoric acid solution at such a rate as to keep the reaction temperature from going above about -4° C. The reaction mixture was then added in dropwise fashion to 10 ml. of 50% aqueous hypophosphorus acid kept at a temperature of about 0° C. This new reaction mixture was stirred until gas evolution had ceased, at which time it was poured over ice. The aqueous mixture was made strongly basic with aqueous ammonium hydroxide. The aqueous layer was extracted several times with chloroform. The chloroform extracts were combined, and the combined extracts washed, first with water and then with saturated aqueous sodium chloride, and then dried. Removal of the chloroform in vacuo yielded trans-(±)-5-n-propyl-4,4a,5,6,7,8,8a,9-octahydrothiazolo[4,5-g]quinoline free base having the following physical characteristics: tlc (9:1 CHCl3 /MeOH+Tr.NH4OH)Rf =0.70.
Reaction SMILES: [CH3:1][C:2]1[S:10][C:9]2[CH:8]([OH:11])[CH2:7][NH:6][CH2:5][C:4]=2[CH:3]=1.[C:12]([C:15]1[CH:20]=[CH:19][C:18](F)=[C:17]([Cl:22])[CH:16]=1)(=[O:14])[NH2:13]>>[C:12]([C:15]1[CH:20]=[CH:19][C:18]([O:11][CH:8]2[CH2:7][NH:6][CH2:5][C:4]3[CH:3]=[C:2]([CH3:1])[S:10][C:9]2=3)=[C:17]([Cl:22])[CH:16]=1)(=[O:14])[NH2:13]
Reactant: NC(=O)c1ccc(F)c(Cl)c1
Reactant: Cc1cc2c(s1)C(O)CNC2
Product: Cc1cc2c(s1)C(Oc1ccc(C(N)=O)cc1Cl)CNC2

Procedure:
The same method as in Example 1 was conducted using 2-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-7-ol (Reference Example 30) instead of 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 6) and was conducted using 4-carbamoyl-2-chloro-1-fluorobenzene instead of 1-fluoronaphthalene to give the objective compound.
Reaction SMILES: [CH3:1][NH:2][CH3:3].Cl[S:5]([CH2:8][C:9]1[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=1[C:11]([O:13]C)=[O:12])(=[O:7])=[O:6]>ClC1C=CC=CC=1>[CH3:1][N:2]([CH3:3])[S:5]([CH2:8][C:9]1[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=1[C:11]([OH:13])=[O:12])(=[O:7])=[O:6]
Reactant: CNC
Reactant: COC(=O)c1ccccc1CS(=O)(=O)Cl
Solvent: Clc1ccccc1
Product: CN(C)S(=O)(=O)Cc1ccccc1C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Liquified dimethylamine (73 ml) was added slowly with cooling to a 15% (w/w) solution of methyl 2-[(chlorosulfonyl)methyl]benzoate (42.0 g) in chlorobenzene. When addition was complete, the suspension was stirred 0.5 hour at room temperature, then filtered. The filtrate was concentrated to approximately 250 ml and added dropwise to a mixture of 150 ml of ethanol, 50 ml of water and 40 ml of 50% sodium hydroxide. The resulting suspension was stirred overnight at room temperature. The reaction solution was concentrated to dryness and the residue partitioned between 1000 ml water and 1000 ml of methylene chloride for 1.5 hour. The aqueous phase was separated, washed with 400 ml of methylene chloride, then acidified with concentrated hydrochloric acid. The precipitated solid was collected and dried overnight in vacuo to give 34.9 of 2-[(dimethylamino)sulfonylmethyl]benzoic acid, m.p. 112°-119°.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([F:14])([F:13])[F:12])=[N:9][N:10]=2)[CH:7]=1.[CH:15]1([C:18]2[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=2)[CH2:17][CH2:16]1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[CH:15]1([C:18]2[CH:23]=[CH:22][C:21]([C:2]3[CH:3]=[CH:4][C:5]4[N:6]([C:8]([C:11]([F:14])([F:13])[F:12])=[N:9][N:10]=4)[CH:7]=3)=[CH:20][CH:19]=2)[CH2:17][CH2:16]1
Reactant: FC(F)(F)c1nnc2ccc(Br)cn12
Reactant: OB(O)c1ccc(C2CC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: FC(F)(F)c1nnc2ccc(-c3ccc(C4CC4)cc3)cn12
Temperature: 90 °C

Procedure:
A suspension of 6-bromo-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine (50 mg, 0.19 mmol), 4-cyclopropyl phenylboronic acid (34 mg, 0.21 mmol), dppf(Pd)Cl2 (6.9 mg, 0.094 mmol), potassium carbonate (52 mg, 0.62 mmol) in degassed toluene (1 mL), degassed water (0.5 mL) and degassed ethanol (0.5 mL) was heated at 90° C. for 1 hour. The layers are separated, the organic layer was concentrated and the residue was purified by column chromatography to provide 6-(4-cyclopropylphenyl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine as a white powder.
Reaction SMILES: [F:1][C:2]1[C:9]([CH:10]=O)=[C:8](F)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].O.[NH2:14][NH2:15].C(OCC)(=O)C>O1CCCC1.CO>[F:1][C:2]1[C:3]([C:4]#[N:5])=[CH:6][CH:7]=[C:8]2[C:9]=1[CH:10]=[N:14][NH:15]2
Reactant: NN
Reactant: N#Cc1ccc(F)c(C=O)c1F
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: N#Cc1ccc2[nH]ncc2c1F
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A total of 8.55 g of 2,4-difluoro-3-formyl-benzonitrile obtained in Production Example II-13-a was dissolved in 40 ml of tetrahydrofuran and 40 ml of methanol, and 5.1 ml of hydrazine monohydrate was added, followed by stirring at room temperature for three days and was further stirred at 50° C. for 3 hours and at 70° C. for 3 hours. The reaction mixture was added with 150 ml of ice-water, 300 ml of ethyl acetate and 100 ml of tetrahydrofuran were added, and unnecessary matters were filtered off. The organic layer was sequentially washed with water and brine, dried over anhydrous magnesium sulfate and the solvent was evaporated. The crude product was purified and separated by silica gel column chromatography (ethyl acetate:toluene=1:9 to 1:4), to give 509 mg of the title compound as bright yellow crystals. In addition, a portion with impurities was purified again by silica gel column chromatography (ethyl acetate:n-hexane=1:4 to 1:0), to give 1.80 g of the title compound as bright yellow crystals.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][CH2:8][OH:9].C(N(CC)CC)C.Cl[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19]>C(OCC)(=O)C>[CH2:21]([O:20][C:18]([N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][CH2:8][OH:9])=[O:19])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: OCCC1CCCCN1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: O=C(OCc1ccccc1)N1CCCCC1CCO
Reaction time: 2 h

Procedure:
To a solution of 2-piperidin-2-yl-ethanol (2.04 g in 50 mL methylene chloride) at 0° C. was added 2.64 mL of triethylamine and 5 mg N,N-dimethylaminopyridine. To the stirred solution, 2.45 mL of benzyl chloroformate was added dropwise and the reaction allowed to proceed at room temperature. After 2 hours, the mixture was diluted with ethyl acetate and washed sequentially with 10% aqueous sodium bisulfate, water and brine. The organic portion was dried over magnesium sulfate and purified by flash chromatography on silica gel (hexane:ethyl acetate, 70:30) to give the title compound (2.05 g).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][C:18](OC)=[O:19])=[CH:12][CH:11]=1>Cl>[CH2:1]([NH:8][C:18](=[O:19])[CH2:17][CH2:16][C:13]1[CH:14]=[CH:15][C:10]([OH:9])=[CH:11][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: COC(=O)CCc1ccc(O)cc1
Agent: Cl
Product: O=C(CCc1ccc(O)cc1)NCc1ccccc1
Temperature: 150 °C
Yield: 98.1 %

Procedure:
Add benzylamine (32.0 mL, 293 mmol) to methyl 3-(4-hydroxyphenyl)propionate (7.01 g, 38.9 mmol) and heat to 150° C. for 18 h under nitrogen. Cool to room temperature and pour the reaction mixture into 5 N hydrochloric acid (200 mL) and extract with ethyl acetate (3×150 mL). Wash the ethyl acetate extracts with 5 N hydrochloric acid (200 mL), dry the extracts over magnesium sulfate, filter, and concentrate on a rotary evaporator to yield 9.74 g (98%) of N-benzyl-3-(4-hydroxy-phenyl)-propionamide: mass spectrum (ion spray): m/z=256.2 (M+1); 1H NMR (DMSO-d6): 9.15 (s, 1H), 8.28 (t, 1H), 7.39-6.96 (m, 7H), 6.66-6.63 (m, 2H), 4.23 (d, 2H), 2.72 (t, 2H), 2.37 (t, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH3:11])=[CH:5]2.[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[OH-].[K+]>C1OCCOCCOCCOCCOCCOC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:6]([CH3:11])=[CH:5]2
Reactant: Cc1cc2cc(Cl)ccc2[nH]1
Reactant: BrCc1ccccc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Agent: [OH-]
Product: Cc1cc2cc(Cl)ccc2n1Cc1ccccc1
Yield: 42 %

Procedure:
4.97 g (30 mmol) 5-chloro-2-methylindole was treated with 6.84 g (40 mmol) benzyl bromide, 1.97 g (30 mmol) potassium hydroxide (85% powdered in mortar) and 0.25 g (1 mmol) 18-crown-6 as described in Synthesis 1979, p. 618 to give 3.22 g (42%) 5-chloro-2-methyl-1-benzyl-1H-indole, mp: 75-76°, MS (Ei 70 eV) m/Z M+255.
Reaction SMILES: [F:1][C:2]([F:19])([C:15]([F:18])([F:17])[F:16])[C:3]([F:14])([F:13])[C:4]1[C:8]([N+:9]([O-])=O)=[C:7]([CH3:12])[NH:6][N:5]=1>C(O)(=O)C.[Zn]>[F:19][C:2]([F:1])([C:15]([F:17])([F:18])[F:16])[C:3]([F:13])([F:14])[C:4]1[C:8]([NH2:9])=[C:7]([CH3:12])[NH:6][N:5]=1
Reactant: Cc1[nH]nc(C(F)(F)C(F)(F)C(F)(F)F)c1[N+](=O)[O-]
Agent: [Zn]
Solvent: CC(=O)O
Product: Cc1[nH]nc(C(F)(F)C(F)(F)C(F)(F)F)c1N
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a suspension of zinc dust (1.5 g) in glacial acetic acid (10 mL) was added drop-wise, a solution of 3-Heptafluoropropyl-5-methyl-4-nitro-1H-pyrazole (0.295 g, 1.0 mmol) in glacial acetic acid (5 mL). The reaction mixture was then allowed to stir at room temperature for 14 h. The zinc salts were then removed by filtration and the residue washed with ethyl acetate. The combined organic extract was concentrated in vacuum, re-dissolved in CHCl3, washed with NaHCO3, water and brine. Finally the organic layer was dried with Na2SO4 and solvent evaporated to give the title compound as white solid.