Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][CH:4]=1.[CH:11]1([C:14]2[C:15]([N:24]3[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]3)=[C:16]3[C:22]([I:23])=[N:21][NH:20][C:17]3=[N:18][CH:19]=2)[CH2:13][CH2:12]1.C(=O)([O-])[O-].[K+].[K+].CCOC(C)=O>CN(C=O)C.O>[CH:11]1([C:14]2[C:15]([N:24]3[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]3)=[C:16]3[C:22]([I:23])=[N:21][N:20]([CH2:2][C:3]4[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][CH:4]=4)[C:17]3=[N:18][CH:19]=2)[CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2c(C3CC3)cnc3[nH]nc(I)c23)CC1
Reactant: COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(Cn2nc(I)c3c(N4CCN(C(=O)OC(C)(C)C)CC4)c(C4CC4)cnc32)cc1
Reaction time: 2 h
Yield: 57.3 %

Procedure:
1-(Chloromethyl)-4-methoxybenzene (734 mg, 4.69 mmol) was slowly added to a stirring mixture of tert-butyl 4-(5-cyclopropyl-3-iodo-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazine-1-carboxylate (2.00 g, 4.26 mmol, see Example J) and potassium carbonate (883 mg, 6.39 mmol) in DMF (30 mL) at room temperature. After 2 hours, EtOAc (200 mL) and water (100 mL) were added to the mixture, and the phases were separated. The organic suspension was washed with water (3×50 mL), dried (MgSO4), filtered, and concentrated in vacuo. The residue obtained was purified by flash chromatography on silica gel (Biotage Flash 40M+) eluting with 15% EtOAc/hexane to provide tert-butyl 4-(5-cyclopropyl-3-iodo-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazine-1-carboxylate (1.44 g, 57% yield) as a solid. LCMS (APCI+) m/z 590.1 (M+H)+.
Reaction SMILES: [C:1]([N:5]1[C:10](=[O:11])[CH:9]2[CH2:12][CH:6]1[CH:7]=[CH:8]2)(=[O:4])[CH2:2][CH3:3].CC(O)CC.[BH4-].[Na+].Cl>O>[C:1]([NH:5][CH:6]1[CH2:12][CH:9]([CH2:10][OH:11])[CH:8]=[CH:7]1)(=[O:4])[CH2:2][CH3:3]
Reactant: CCC(=O)N1C(=O)C2C=CC1C2
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCC(C)O
Product: CCC(=O)NC1C=CC(CO)C1
Temperature: 10 °C
Reaction time: 2.5 h
Yield: 65.3 %

Procedure:
16.6 g of (±)-2-propionyl-2-azabicyclo[2.2.1]-hept-5-en-3-one were dissolved in water (140 ml) and 2-butanol (66 ml) under nitrogen and cooled to −5° C. 3 g of sodium borohydride were added in portions over the course of 2 h. The mixture was stirred at 10° C. for 2.5 h and then adjusted to pH 2.2 with a mixture of conc. hydrochloric acid and water (1/1). The solution was evaporated to 40 g and adjusted to pH 6.2 with 2N NaOH. The mixture was extracted with 5×50 ml of dichloromethane. The combined organic phases were completely evaporated, and the residue was recrystallized in toluene (150 ml). 11.1 g of title compound were obtained. The yield was 65%.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Si](C)(C)C)=[C:10]([F:18])[C:9]=2[F:19])[N:5]=[C:4]([C:20]([O:22][CH3:23])=[O:21])[C:3]=1[O:24][CH3:25].[I:26]Cl>ClCCCl.C(OCC)(=O)C>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([I:26])=[C:10]([F:18])[C:9]=2[F:19])[N:5]=[C:4]([C:20]([O:22][CH3:23])=[O:21])[C:3]=1[O:24][CH3:25]
Reactant: ClI
Reactant: COC(=O)c1nc(-c2ccc([Si](C)(C)C)c(F)c2F)nc(N)c1OC
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: COC(=O)c1nc(-c2ccc(I)c(F)c2F)nc(N)c1OC
Temperature: 70 °C
Yield: 66 %

Procedure:
Methyl 6-amino-2-(2,3-difluoro-4-(trimethylsilyl)phenyl)-5-methoxypyrimidine-4-carboxylate (330 mg, 0.90 mmol) was stirred in 1,2-dichloroethane (5 mL), treated with iodine monochloride (1.0 g, 6.9 mmol), and heated to 70° C. for 21 h. After cooling, the mixture was diluted with ethyl acetate, washed with 15% sodium bisulfite, washed with saturated NaCl, dried (Na2SO4), and evaporated. The material was purified by RP-HPLC using 70% acetonitrile to provide the title compound as a white solid (250 mg, 66%).
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1.[CH:20](=[O:22])[CH3:21]>C1COCC1.Cl.O>[Cl:13][C:14]1[C:19]([CH:20]([OH:22])[CH3:21])=[CH:18][CH:17]=[CH:16][N:15]=1
Reactant: CC=O
Reactant: Clc1ccccn1
Agent: Cl
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(O)c1cccnc1Cl
Temperature: -70 °C
Reaction time: 1 h
Yield: 63.5 %

Procedure:
Dry THF (400 mL) and n-butyllithium (1.6 M in hexane, 63 mL, 0.1 mol) were introduced into a 1 L flask under nitrogen at −70° C. A solution of dry diisopropylamine (10.1 g, 0.1 mol) in THF (25 mL) was added dropwise to the mixture at −70° C. The mixture was then kept for 1 h at 0° C. and then cooled to −70° C. A solution of 2-chloropyridine (11.3 g, 0.1 mol) in THF (25 mL) was added dropwise to the mixture at −70° C. and the mixture was stirred for 3 h at this temperature. A solution of acetaldehyde (4.85 g, 0.11 mol) in dry THF (50 mL) was then added dropwise and the mixture was kept for 3 h at −70° C. A solution of water (4 mL) in THF (40 mL), acidified by a few drops of concentrated hydrochloric acid, was added to the mixture at −40° C. and then water (200 mL) was introduced at −10° C. Extraction with diethyl ether (3×150 mL), drying over anhydrous sodium sulfate, and evaporation gave a crude product, which was purified by column chromatography to yield an oil (10 g, 64%). *1H NMR (CDCl3) 8.15 (dd, J=5 and 2 Hz, 1H), 7.95 (dd, J=8 and 2 Hz, 1H), 7.20 (dd, J=8 and 5 Hz, 1H), 5.15 (d, J=7 Hz, 1H), 3.90 (s, 1H), 1.45 (d, J=7 Hz, 3H).
Reaction SMILES: CCCCCC.C([Li])CCC.[CH2:12]([O:19][C:20]1[C:25]([O:26][CH3:27])=[CH:24][C:23]([CH3:28])=[C:22](Br)[CH:21]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[Cl-].[NH4+].[C:32](OCC)(=[O:34])C>CN(C)C=O.O1CCCC1>[CH2:12]([O:19][C:20]1[C:25]([O:26][CH3:27])=[CH:24][C:23]([CH3:28])=[C:22]([CH:21]=1)[CH:32]=[O:34])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCOC(C)=O
Reactant: COc1cc(C)c(Br)cc1OCc1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: COc1cc(C)c(C=O)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 48 %

Procedure:
A hexane solution (17 ml) of n-butyllithium was dropwise added to a tetrahydrofuran (190 ml) solution of 4-benzyloxy-2-bromo-5-methoxytoluene (7.83 g) at −78° C. over a period of 20 minutes, followed by stirring at the same temperature for 1 hour. A tetrahydrofuran (10 ml) solution of dimethylformamide (3.73 g) was dropwise added thereto at −78° C., followed by stirring at the same temperature for 1 hour. The temperature was gradually raised to room temperature, and stirring was further carried out for one night. The reaction solution was poured into an aqueous ammonium chloride solution (200 ml), and extraction with ethyl acetate (150 ml) was carried out twice. The ethyl acetate phase was washed with an aqueous sodium chloride solution (100 ml) twice and dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain 3.14 g (yield 48%) of 5-benzyloxy-4-methoxy-2-methylbenzaldehyde (m.p. 107-109° C.), and its structure was confirmed by nuclear magnetic resonance spectrum.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:14])[CH2:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([NH2:13])[CH2:9][CH2:8]1)[CH3:3].C(N(CC)CC)C.[C:22](Cl)(=[O:24])[CH3:23]>ClCCl>[CH2:2]([O:4][C:5](=[O:14])[CH2:6][C@H:7]1[CH2:8][CH2:9][C@H:10]([NH:13][C:22](=[O:24])[CH3:23])[CH2:11][CH2:12]1)[CH3:3]
Reactant: CC(=O)Cl
Reactant: CCOC(=O)C[C@H]1CC[C@H](N)CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C[C@H]1CC[C@H](NC(C)=O)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Trans-(4-Amino-cyclohexyl)-acetic acid ethyl ester hydrochloride (1.0 g, 4.51 mmol) (Example A, step 2) was dissolved in dichloromethane and triethylamine (1.89 ml, 13.5 mmol) was added. Acetyl chloride (0.35 ml, 4.96 mmol) was added drop wise and the reaction mixture stirred for 5 hours at room temperature. The reaction mixture was quenched with saturated NaHCO3-solution and extracted with dichloromethane. The organic extracts were washed with brine, dried with sodium sulfate, filtered and evaporated. The crude product (804 mg, 78%) [MS: m/e=228.3/229.3 (M+H+)] was obtained as a white solid and used without any further purification for the next step.
Reaction SMILES: [C:1]([O:6][CH3:7])(=[O:5])[CH2:2][CH:3]=[CH2:4].[Cl:8][C:9]([Cl:14])(Cl)[C:10](Cl)=[O:11]>COCCOC.CCOCC.[Cu].[Zn]>[Cl:8][C:9]1([Cl:14])[C:10](=[O:11])[CH2:4][CH:3]1[CH2:2][C:1]([O:6][CH3:7])=[O:5]
Reactant: C=CCC(=O)OC
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Agent: [Cu]
Agent: [Zn]
Solvent: CCOCC
Solvent: COCCOC
Product: COC(=O)CC1CC(=O)C1(Cl)Cl
Temperature: 25 °C
Reaction time: 60 h
Yield: 47.4 %

Procedure:
To a reaction mixture of methyl but-3-enoate (1.0 g, 10 mmol) and zinc-copper couple (2.0 g, 15.5 mmol) in DME (5 mL) and ether (30 mL) was added trichloroacetyl chloride (2.98 mL, 26.7 mmol) under N2 at rt. The reaction mixture was stirred at rt for 2.5 days. The reaction mixture was filtrated through diatomaceous earth (Celite®) and washed with DCM. The filtrate was concentrated and purified by 80 g silica gel cartridge which was eluted with a 20 min gradient of 0-60% EtOAc in hexane to yield methyl 2-(2,2-dichloro-3-oxocyclobutyl)acetate (1.0 g). 1H NMR (400 MHz, CDCl3) ppm 3.66-3.70 (3H, m), 3.42-3.55 (1H, m), 3.23-3.39 (1H, m), 3.05 (1H, dd, J=17.82, 8.78 Hz), 2.90 (1H, dd, J=16.94, 6.65 Hz), 2.67 (1H, dd, J=16.94, 8.16 Hz).
Reaction SMILES: [C:1]1([CH3:9])[CH:6]=[CH:5][C:4]([NH:7][NH2:8])=[CH:3][CH:2]=1.[CH2:10]([O:12][C:13](=[O:21])[CH:14]([C:18](=O)[CH3:19])[C:15](=O)[CH3:16])[CH3:11].N1C=CC=CC=1>C(O)C>[CH2:10]([O:12][C:13]([C:14]1[C:15]([CH3:16])=[N:8][N:7]([C:4]2[CH:5]=[CH:6][C:1]([CH3:9])=[CH:2][CH:3]=2)[C:18]=1[CH3:19])=[O:21])[CH3:11]
Reactant: Cc1ccc(NN)cc1
Reactant: CCOC(=O)C(C(C)=O)C(C)=O
Solvent: c1ccncc1
Solvent: CCO
Product: CCOC(=O)c1c(C)nn(-c2ccc(C)cc2)c1C

Procedure:
Similar to Example 1, p-tolylhydrazine (10 mmol, 1.8 g) and 2-acetyl-3-oxo-butyric acid ethyl ester (10 mmol, 1.7 g) were mixed in a solution of 50% pyridine in ethanol. The solvents were removed under vacuum. The named product was purified over silica gel (m.p. 47° C.-49° C.).
Reaction SMILES: [CH3:1][C:2]1[C:7]2[C:8]([O:10][C:11]3[C:12]([CH3:23])=[C:13]([O:21][CH3:22])[CH:14]=C(C(O)=O)C=3[O:17][C:6]=2[C:5]([CH:24]=[O:25])=[C:4]([OH:26])[CH:3]=1)=[O:9].CCN=C=N[CH2:32][CH2:33][CH2:34][N:35]([CH3:37])[CH3:36].C1C=CC2N([OH:47])N=NC=2C=1.Cl.CNC.C(N(CC)CC)C>CN(C=O)C.O>[CH3:37][N:35]([CH3:36])[C:34]([C:33]1[C:32]2[O:17][C:6]3[C:5]([CH:24]=[O:25])=[C:4]([OH:26])[CH:3]=[C:2]([CH3:1])[C:7]=3[C:8](=[O:9])[O:10][C:11]=2[C:12]([CH3:23])=[C:13]([O:21][CH3:22])[CH:14]=1)=[O:47]
Reactant: CCN=C=NCCCN(C)C
Reactant: COc1cc(C(=O)O)c2c(c1C)OC(=O)c1c(C)cc(O)c(C=O)c1O2
Reactant: On1nnc2ccccc21
Agent: CNC
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: COc1cc(C(=O)N(C)C)c2c(c1C)OC(=O)c1c(C)cc(O)c(C=O)c1O2

Procedure:
Psoromic acid (35 mg, 1 mmol), EDCI (20 mg, 1.5 mmol) and HOBt (23 mg, 1.5 mmol) were added into DMF (5 ml) under ice bath. The solution was stirred for half an hour, and then to the reaction mixture was added dropwise a solution of dimethyl-amine hydrochloride (8.7 mg, 1 mmol) and triethylamine (0.014 ml, 1 mmol) in anhydrous DMF (3 ml). The reaction was monitored by TLC. Upon completion, the reaction mixture was poured into 60 mL of water and extracted with ethyl acetate. The organic layer was subsequently washed with saturated NaHCO3, saturated brine, dried over anhydrous MgSO4, filtered, evaporated by a rotatory evaporator, and purified by column chromatography to give a white solid product.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]1[N:13]=[C:12]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([Cl:24])[CH:17]=2)[C:11](C=O)=[CH:10][N:9]=1.C([Mg]Br)=C.[Cl-].[NH4+].[O:33]1[CH2:37][CH2:36][CH2:35][CH2:34]1>>[OH:1][CH2:2][CH:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]1[N:13]=[C:12]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([Cl:24])[CH:17]=2)[C:11]([C@@H:35]([CH2:34][OH:33])[CH:36]=[CH2:37])=[CH:10][N:9]=1
Reactant: C1CCOC1
Reactant: COc1ccc(CNc2nc(N3CCC[C@H]3CO)ncc2C=O)cc1Cl
Agent: C=C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Product: C=C[C@H](CO)c1cnc(N2CCCC2CO)nc1NCc1ccc(OC)c(Cl)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of (S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-5-formyl-4-(3-chloro-4-methoxybenzylamino)pyrimidine (4.1 g) in tetrahydrofuran (30 ml) is added to a solution of vinyl magnesium bromide in tetrahydrofuran (43.5 ml) at 0° C., and the mixture is stirred at 0° C. for 1 hour. To the mixture is added a saturated aqueous ammonium chloride solution, and the mixture is extracted with ethyl acetate. The extract is washed with water and then brine, and dried over sodium sulfate. Sodium sulfate is removed by filtration, and the filtrate is concentrated in vacuo. The residue is purified by column chromatography (silica gel, 100 g; ethyl acetate→ethyl acetate:methanol=20:1, and then silica gel, 50 g; chloroform:methanol=50:1) to give (S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-5-(1-hydroxymethyl-2-propen-1-yl)-4-(3-chloro-4-methoxybenzylamino)pyrimidine (2.70 g) as colorless amorphous. MS(APCI): 405 (MH+).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH2:8][CH2:7]2)([O-:3])=[O:2].[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O.C(OCC)(=O)C>[CH2:13]([N:9]1[C:10]2[C:6](=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=2)[CH2:7][CH2:8]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=[N+]([O-])c1ccc2c(c1)CCN2
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc2c(c1)CCN2Cc1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 58 %

Procedure:
Under the presence of nitrogen, 5-nitroindolin (50 mg, 0.30 mmol) was dissolved in dimethylformamide (2 ml) at room temperature and benzyl bromide (0.04 ml. 0.34 mmol) and potassium carbonate (0.126 ml, 3.0 equivalent) were added and stirred at room temperature for 48 hours. After completing the reaction, water and ethyl acetate (respectively 5 ml) were added to separate layers, washed with brine, dried over anhydrous magnesium sulfate, and concentrated. Finally, the residue was purified through flash column chromatography (an eluent:ethyl acetate/n-hexane=1/4, v/v). As a result, the present compound (45 mg, productive yield 58%) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][NH:7][S:8]([C:10]([CH3:13])([CH3:12])[CH3:11])=[O:9])=[CH:4][C:3]=1[C:16]1[NH:20][C:19](=[O:21])[N:18]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)[N:17]=1.C(Cl)Cl.C(#N)C.I([O-])(=O)(=O)=[O:39].[Na+]>[Ru](Cl)(Cl)Cl.O>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][NH:7][S:8]([C:10]([CH3:13])([CH3:12])[CH3:11])(=[O:39])=[O:9])=[CH:4][C:3]=1[C:16]1[NH:20][C:19](=[O:21])[N:18]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:29])([F:31])[F:30])=[CH:24][CH:23]=2)[N:17]=1
Reactant: CC(C)(C)S(=O)NCc1ccc(Cl)c(-c2nn(-c3ccc(C(F)(F)F)cc3)c(=O)[nH]2)c1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: Cl[Ru](Cl)Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CC#N
Product: CC(C)(C)S(=O)(=O)NCc1ccc(Cl)c(-c2nn(-c3ccc(C(F)(F)F)cc3)c(=O)[nH]2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 25.9 %

Procedure:
To a solution of N-(4-chloro-3-(5-oxo-1-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-1,2,4-triazol-3-yl)benzyl)-2-methylpropane-2-sulfinamide (Intermediate-144, 0.075 g, 0.158 mmol) in mixture of DCM:acetonitrile:water (0.2 ml:0.2 mL:0.3 mL), sodium periodate (0.050 g, 0.238 mmol) and ruthenium chloride (0.001 g, 0.003 mmol) were added and the reaction mass was stirred at RT for 4 h. After completion of the reaction the reaction mass was filtered through celite bed and extracted with DCM. The organic layer was separated, dried over anhydrous sodium sulphate and concentrated. The obtained product was purified with column chromatography on neutral alumina eluting with 10% MeOH:DCM to afford 0.020 g of the desired product. 1H NMR (300 MHz, DMSO d6): δ 1.30 (s, 9H), 4.31 (d, J=6.0 Hz, 2H), 7.55-7.71 (m, 4H), 7.86 (d, J=8.7 Hz, 2H), 8.19 (d, J=9.0 Hz, 2H), 12.71 (s, 1H). MS (m/z): 489.04 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][C:9](=[O:13])[NH:10]2)=[CH:5][CH:4]=1.S(Cl)([Cl:17])(=O)=O>C(O)(=O)C>[Cl:17][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:3]=1[O:2][CH3:1])[NH:10][C:9](=[O:13])[CH2:8][CH2:7]2
Reactant: COc1ccc2c(c1)NC(=O)CC2
Reactant: O=S(=O)(Cl)Cl
Solvent: CC(=O)O
Product: COc1cc2c(cc1Cl)CCC(=O)N2
Temperature: 0 °C
Reaction time: 8 h

Procedure:
35.4 Grams of 7-methoxy-3,4-dihydrocarbostyril was dissolved in 300 ml of acetic acid and under ice-cooled condition with stirring 27 g of sulfuryl chloride dissolved in 100 ml of acetic acid was added dropwise, then the reaction mixture was allowed to stand overnight. The reaction mixture was poured into 1 liter of ice water and the precipitates were obtained by filtration, washed with water, dried and recrystallized from methanol. 30 Grams of 6-chloro-7-methoxy-3,4-dihydrocarbostyril having the melting point of 212° C. was obtained as in the form of colorless needle-like crystals.
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6](=[O:27])[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[N:16]([CH3:26])[N:17]=[N:18][C:19]=2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)=[N:9][CH:8]=1>O.C1COCC1.CO>[CH3:26][N:16]1[C:15]([CH2:14][O:13][C:10]2[CH:11]=[CH:12][C:7]([C:6]([OH:27])=[O:5])=[CH:8][N:9]=2)=[C:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[N:18]=[N:17]1
Reactant: COC(=O)c1ccc(OCc2c(-c3ccccn3)nnn2C)nc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Cn1nnc(-c2ccccn2)c1COc1ccc(C(=O)O)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.3 %

Procedure:
A solution of lithium hydroxide monohydrate (51 mg, 1.22 mmol) in water (1.5 mL) was added dropwise to a suspension of 6-(3-methyl-5-pyridin-2-yl-3H-[1,2,3]triazol-4-ylmethoxy)-nicotinic acid methyl ester (199 mg, 0.61 mmol) in THF (1.5 mL) and MeOH (0.3 mL). The reaction mixture was then stirred at room temperature for 2 h. The reaction mixture was then evaporated and the residue dissolved in water, acidified with HCl (1N), and the resulting precipitate filtered off to afford the title product (162 mg, 70%) as a white solid. MS: m/e=310.3 [M−H]−.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N+:4]([O-])[CH:5]=[CH:6][CH:7]=1.C[Si](C[C:14]#[N:15])(C)C.C(N(CC)CC)C>C(#N)C>[Cl:1][C:2]1[C:3]([C:14]#[N:15])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: [O-][n+]1cccc(Cl)c1
Reactant: C[Si](C)(C)CC#N
Solvent: CC#N
Solvent: CCN(CC)CC
Product: N#Cc1ncccc1Cl
Yield: 84.1 %

Procedure:
A mixture of 3-chloropyridine-N-oxide (2.12 g, 16.30 mmol), trimethylsilyl(acetonitrile) (3.25 g, 32.80 mmol), triethylamine (3.30 g, 32.60 mmol) and acetonitrile (10 mL) was heated at reflux for 6 h. After concentration under reduced pressure, the resulting residue was basified with aqueous sodium carbonate (3N) and extracted with methylene chloride. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 3-chloropicolinonitrile (1.90 g). The crude product was carried forward without further purification. MW=139 confirmed by LC-MS, tr=2.33 min (Method E) MH+=140.
Reaction SMILES: CCCCCC.[H-].[Na+].[CH3:9][O:10][C:11]1[CH:12]=[C:13]([CH2:17][C:18]#[N:19])[CH:14]=[CH:15][CH:16]=1.Br[C:21]1[CH:26]=[CH:25][C:24]([Br:27])=[CH:23][N:22]=1>CN(C=O)C.CCOCC>[Br:27][C:24]1[CH:25]=[CH:26][C:21]([CH:17]([C:13]2[CH:14]=[CH:15][CH:16]=[C:11]([O:10][CH3:9])[CH:12]=2)[C:18]#[N:19])=[N:22][CH:23]=1
Reactant: Brc1ccc(Br)nc1
Reactant: COc1cccc(CC#N)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Solvent: CCOCC
Product: COc1cccc(C(C#N)c2ccc(Br)cn2)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 64.4 %

Procedure:
To a suspension of hexane washed 60% sodium hydride (2.65, 66.0 mmol) in DMF (30 mL) at 0° C. was added 3-methoxyphenyl acetonitrile (8.0 g, 54.3 mmol). The reaction mixture was stirred at 0° C. for 30 min. A solution of 2,5-dibromopyridine (15.45g, 65.2 mmol) in DMF(20 mL) was added and the reaction was stirred at room temperature for 20 min and at 50° C. for 30 min. To the reaction mixture was added H20 (20 mL) and Et2O (200 mL). The organic layer was washed with brine (5x50 mL), dried over Na2SO4 and concentrated. Purification by flash chromatography with hexanes/EtOAc (10:1) afforded 10.6 g of (5-Bromopyridin-2-yl)-(3-methoxy-phenyl)-acetonitrile. 1HNMR (400 MHz, CDCl3) 6 8.63 (s,1H), 7.80 (dd, 1H), 7.27 (comp, 2H), 6.98 (d, 1H), 6.87 (s,1H), 6.84 (m, 1H), 5.28 (s, 1H), 5.23 (s, 3H); MS (M+1) 303.0, 305.0.
Reaction SMILES: C(N=C=NCCCN(C)C)C.Cl.[CH:13]([C:16]1[CH:21]=[CH:20][C:19]([NH:22][NH2:23])=[CH:18][CH:17]=1)([CH3:15])[CH3:14].[C:24](O)(=[O:26])[CH3:25].O.ON1C2C=CC=CC=2N=N1>ClCCl.C(N(CC)CC)C>[C:24]([NH:23][NH:22][C:19]1[CH:20]=[CH:21][C:16]([CH:13]([CH3:15])[CH3:14])=[CH:17][CH:18]=1)(=[O:26])[CH3:25]
Reactant: CC(=O)O
Reactant: CC(C)c1ccc(NN)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NNc1ccc(C(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-Ethyl-3-(3'-dimethylamino-propyl)carbodiimide (5.87 ml) was added to a mixture of 4-isopropylphenylhydrazine hydrochloride (5.0 g), acetic acid (1.84 ml), triethylamine (3.73 ml) and 1-hydroxybenzotriazole hydrate (40.4 mg) in dichloromethane (50 ml) under ice-cooling and then the mixture was stirred overnight at room temperature. After removal of solvent by evaporation, the resulting residue was partitioned between diluted hydrochloric acid and ethyl acetate. The organic layer was washed successively with aqueous sodium hydrogen carbonate solution, water, and brine, and was dried over magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to column chromatography on silica gel and eluted with a mixture of dichloromethane and methanol. The fractions containing the objective compound were combined and concentrated under reduced pressure to give 1-acetyl-2-(4-iso-propylphenyl)-hydrazine (3.00 g).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([OH:10])=O)[CH:3]=1.S(Cl)([Cl:13])=O>>[ClH:13].[OH:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([Cl:13])=[O:10])[CH:3]=1
Reactant: O=C(O)c1cc(O)ccn1
Reactant: O=S(Cl)Cl
Product: Cl
Product: O=C(Cl)c1cc(O)ccn1

Procedure:
A mixture of 139.0 g of 4-hydroxypicolinic acid and 238.0 g of thionyl chloride are heated in an oil bath at 70° until solution occurs. The mixture is concentrated in vacuo to remove the excess thionyl chloride and to leave a residue of 4-hydroxypicolinoyl chloride hydrochloride as a colorless solid.
Reaction SMILES: [OH:1][C:2]1[C:3]2[S:16][CH:15]=[CH:14][C:4]=2[NH:5][C:6](=[O:13])[C:7]=1[C:8]([O:10]CC)=O.[NH2:17][C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1.C1(C)C(C)=CC=CC=1>CN(C)C=O>[OH:1][C:2]1[C:3]2[S:16][CH:15]=[CH:14][C:4]=2[NH:5][C:6](=[O:13])[C:7]=1[C:8]([NH:17][C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1)=[O:10]
Reactant: CCOC(=O)c1c(O)c2sccc2[nH]c1=O
Reactant: Nc1ccncc1
Solvent: Cc1ccccc1C
Solvent: CN(C)C=O
Product: O=C(Nc1ccncc1)c1c(O)c2sccc2[nH]c1=O
Temperature: 140 °C
Yield: 66.6 %

Procedure:
A mixture of 2.48 g (10.4 mmols) of ethyl 4,5-dihydro-7-hydroxy-5-oxothieno[3,2-b]pyridine-6-carboxylate [J. Chem. Res. (S), 6 (1980); J. Chem. Res. (M), 113 (1980)], 1.01 g (10.7 mmols) of 4-aminopyridine, 50 ml of xylene and 10 ml of dimethylformamide was heated at 140° C. for an hour. After completion of the reaction, insoluble matters were filtered and tritylated with dimethylformamide with heating to give 1.99 g (yield: 67%) of Compound 2.