Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=[O:15])=[C:12]([O:18][CH3:19])[CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH2:20]([Mg]Br)[CH2:21][CH2:22][CH2:23][CH3:24].[Cl-].[NH4+]>O1CCCC1>[Si:1]([O:8][CH2:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]([OH:15])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[C:12]([O:18][CH3:19])[CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: COc1cc(CO[Si](C)(C)C(C)(C)C)ccc1C=O
Reactant: CCCCC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCCCCC(O)c1ccc(CO[Si](C)(C)C(C)(C)C)cc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
A solution of 27.91 g (99.5 mmol) of 4-t-butyldimethylsilyloxymethyl-2-methoxybenzaldehyde (prepared as described in Preparation 40) in 100 ml of tetrahydrofuran was added dropwise to 100 ml of an ice-cooled 1.62 M solution of pentylmagnesium bromide in tetrahydrofuran over a period of 30 minutes, and then the resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was then mixed with a saturated aqueous solution of ammonium chloride, and the resulting mixture was extracted with a mixture of ethyl acetate and hexane. The extract was washed with a saturated aqueous solution of sodium chloride, after which it was dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and the resulting residue was purified by column chromatography through 250 g of silica gel using a 1:5 by volume mixture of ethyl acetate and hexane as the eluent, to give 30.67 g (yield 87%) of the title compound as an oily substance.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:7](Cl)=[O:8])[S:5][CH:6]=1.CCN(C(C)C)C(C)C.[NH2:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([C:7]([NH:19][CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[O:8])[S:5][CH:6]=1
Reactant: O=C(Cl)c1cc(Br)cs1
Reactant: NCCN1CCOCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCCN1CCOCC1)c1cc(Br)cs1

Procedure:
To a solution of 4-bromo-2-thiophenecarbonyl chloride (1.0 g, 4.4 mmol) in DCM (10 ml) cooled to 0° C. was added DIPEA (0.85 ml, 4.8 mml) and 4-(2-aminoethyl)morpholine (0.6 ml, 4.6 mmol) dropwise. Stirring was continued until complete consumption of the starting material was observed by LC-MS. The reaction was quenched by the addition of water, which was washed with further portions of 2N HCl, dried over sodium sulfate, filtered and concentrated in vacuo to yield the desired compound without need for further purification (1.6 g, 98%). δH (500 MHz, CHLOROFORM-d) 7.38 (1H, d, 1.3 Hz), 7.37 (1H, d, 1.1 Hz), 3.72-3.80 (4H, m), 3.53 (2H, q, 5.6 Hz), 2.59 (2H, t, 6.0 Hz), 2.48-2.54 (4H, m), TR=0.8 min.
Reaction SMILES: [NH2:1][CH:2]([C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1)[CH2:3][C:4]([OH:6])=[O:5].[C:14]1(=O)[O:19][C:17](=[O:18])[C:16]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:15]12.O>CN(C=O)C>[O:18]=[C:17]1[C:16]2[C:15](=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:14](=[O:19])[N:1]1[CH:2]([C:7]1[CH:8]=[CH:9][C:10]([F:13])=[CH:11][CH:12]=1)[CH2:3][C:4]([OH:6])=[O:5]
Reactant: NC(CC(=O)O)c1ccc(F)cc1
Reactant: O=C1OC(=O)c2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)CC(c1ccc(F)cc1)N1C(=O)c2ccccc2C1=O
Temperature: 135 °C
Reaction time: 0.5 h

Procedure:
2.0 g of rac-3-amino-3-(4-fluorophenyl)propanoic acid (10.92 mmol) and 1.62 g of phthalic anhydride (10.92 mmol) were dissolved in 9 ml of DMF and heated at reflux at 135° C. overnight. The reaction solution was added to about 200 ml of water. The solid formed was stirred at RT for about 30 min and then filtered off, washed with water and dried under high vacuum. This gave 3.43 g of the title compound (86% of theory, purity about 86%).
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[N:4][N:3]=1.[CH2:7]([O:9][CH:10](OCC)OCC)[CH3:8]>CCCCCC>[CH2:7]([O:9][CH:10]=[N:1][C:2]1[NH:6][N:5]=[N:4][N:3]=1)[CH3:8]
Reactant: Nc1nnn[nH]1
Reactant: CCOC(OCC)OCC
Solvent: CCCCCC
Product: CCOC=Nc1nnn[nH]1
Temperature: 25 °C

Procedure:
A mixture was prepared from 50 g of 5-aminotetrazole, 347 g of triethoxymethane and 500 ml of hexane and this was heated under nitrogen so that distillation took place at a moderate rate (head temperature about 60°-68° C.). Distillate was collected over a period of 6 hours with hexane being replaced in the reaction mixture as necessary. The mixture was then cooled to room temperature and the fine white needles that formed were collected by filtration, washed with hexane and vacuum oven dried with heating to give 5-(ethoxymethyleneamino)tetrazole. This material hydrolyzes rapidly on exposure to atmospheric moisture so that it should be used promptly for any further reactions desired or it should be stored using appropriate conditions.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][S:9](Cl)(=[O:11])=[O:10].[Cl:13][C:14]1[C:23]([Cl:24])=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[C:16]([C:25]2[NH:26][C:27](=[O:34])[C:28]3[S:33][CH:32]=[CH:31][C:29]=3[N:30]=2)[CH:15]=1>C(Cl)(Cl)Cl>[Cl:13][C:14]1[C:23]([Cl:24])=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[C:16]([C:25]2[N:26]=[C:27]([O:34][S:9]([CH3:8])(=[O:11])=[O:10])[C:28]3[S:33][CH:32]=[CH:31][C:29]=3[N:30]=2)[CH:15]=1
Reactant: COC(=O)c1cc(Cl)c(Cl)cc1-c1nc2ccsc2c(=O)[nH]1
Reactant: CS(=O)(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(Cl)c(Cl)cc1-c1nc(OS(C)(=O)=O)c2sccc2n1
Reaction time: 0.5 h

Procedure:
Triethylamine and methanesulfonyl chloride were added to a chloroform solution of methyl 4,5-dichloro-2-(4-oxo-3,4-dihydrothieno[3,2-d]pyrimidine-2-yl)benzoate under ice cooling and stirred under ice cooling for 30 minutes to give methyl 4,5-dichloro-2-{4-[(methanesulfonyl)oxy]thieno[3,2-d]pyrimidine-2-yl}benzoate.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[CH:7][C:6]=2[CH:5]=[C:4]([C:16]#[N:17])[CH:3]=1.[N:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1>>[O:15]=[C:14]1[C:8]2=[CH:7][C:6]3[CH:5]=[C:4]([C:16]#[N:17])[CH:3]=[C:2]([C:21]4[CH:22]=[CH:23][N:18]=[CH:19][CH:20]=4)[C:10]=3[N:9]2[CH2:11][CH2:12][NH:13]1
Reactant: OB(O)c1ccncc1
Reactant: N#Cc1cc(Br)c2c(c1)cc1n2CCNC1=O
Product: N#Cc1cc(-c2ccncc2)c2c(c1)cc1n2CCNC1=O

Procedure:
The title compound, off-white solid (64 mg, 89%), MS (ISP) m/z=289.5 [(M+H)+], mp 315.5° C., was prepared in accordance with the general method of example 1 from 6-bromo-1-oxo-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole-8-carbonitrile (intermediate 15) (72.5 mg, 0.25 mmol) and commercially available pyridine-4-ylboronic acid (39.9 mg, 0.325 mmol).
Reaction SMILES: [Cl:1][C:2]1[NH:3][CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.[CH3:10][C:11]1([CH2:14][S:15][C:16]2[N:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:19]=[N:18][N:17]=2)[CH2:13][O:12]1.C([O-])(=O)C.[Na+]>C(O)C>[Cl:1][C:2]1[N:3]([CH2:10][C:11]([CH3:13])([OH:12])[CH2:14][S:15][C:16]2[N:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:19]=[N:18][N:17]=2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1
Reactant: CC1(CSc2nnnn2-c2ccccc2)CO1
Reactant: O=[N+]([O-])c1c[nH]c(Cl)n1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: CC(O)(CSc1nnnn1-c1ccccc1)Cn1cc([N+](=O)[O-])nc1Cl
Yield: 69 %

Procedure:
A mixture of 2-chloro-4-nitro-1H-imidazole (1.2 g, 8.13 mmol), 5-(2-methyloxiran-2-ylmethylthio)-1-phenyl-1H-tetrazole (1.9 g, 7.65 mmol), sodium acetate (700 mg, 8.53 mmol) and ethanol (20 ml) was stirred under reflux overnight. The reaction mixture was allowed to return to room temperature and concentrated under reduced pressure. To the residue, water was added, and the resulting mixture was extracted with ethyl acetate twice. The organic phases were combined, washed with a saturated aqueous sodium bicarbonate solution twice, then washed with water and a saturated saline solution in this order, dried over sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride/methanol=50/1) to afford 1-(2-chloro-4-nitroimidazol-1-yl)-2-methyl-3-(1-phenyl-1H-tetrazol-5-ylthio)propane-2-ol to afford (2.1 g, yield 69%) as a light yellow powder.
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:10])[CH2:4]/[CH:5]=[CH:6]/[C:7](O)=[O:8].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[O:35]([C:42]1[CH:47]=[CH:46][C:45]([C:48]2[C:59]([C:60]([NH2:62])=[O:61])=[C:51]3[NH:52][C:53]4[CH2:58][CH2:57][NH:56][CH2:55][C:54]=4[N:50]3[N:49]=2)=[CH:44][CH:43]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>C(Cl)Cl>[CH3:2][N:3]([CH3:10])[CH2:4]/[CH:5]=[CH:6]/[C:7]([N:56]1[CH2:57][CH2:58][C:53]2[NH:52][C:51]3[N:50]([N:49]=[C:48]([C:45]4[CH:44]=[CH:43][C:42]([O:35][C:36]5[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=5)=[CH:47][CH:46]=4)[C:59]=3[C:60]([NH2:62])=[O:61])[C:54]=2[CH2:55]1)=[O:8]
Reactant: CN(C)C/C=C/C(=O)O
Reactant: NC(=O)c1c(-c2ccc(Oc3ccccc3)cc2)nn2c3c([nH]c12)CCNC3
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: CN(C)C/C=C/C(=O)N1CCc2[nH]c3c(C(N)=O)c(-c4ccc(Oc5ccccc5)cc4)nn3c2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.4 %

Procedure:
A mixture of (E)-4-(dimethylamino)but-2-enoic acid hydrochloride (147 mg, 0.88 mmol), HATU (611 mg, 1.6 mmol) and TEA (328 mg, 3.2 mmol) in 50 mL of DCM was stirred at RT for about 2 hr before 2-(4-phenoxyphenyl)-5,6,7,8-tetrahydro-4H-pyrazolo[5′,1′:2,3]imidazo[4,5-c]pyridine-3-carboxamide (300 mg, 0.8 mmol) was added. The mixture was stirred at RT overnight. TLC and LCMS analysis showed that starting material was consumed. To the reaction were added 100 mL of water and 50 mL of DCM. Aqueous phase was further extracted with 50 mL of DCM. The combined organic layers were washed with brine, dried over Na2SO4, concentrated to get crude product which was chromatographed on 5 g of silica gel using DCM/MeOH (20/1 to 10/1) as eluant to afford 145 mg (37%) of (E)-7-(4-(dimethylamino) but-2-enoyl)-2-(4-phenoxyphenyl)-5,6,7,8-tetrahydro-4H-pyrazolo[5′,1′:2,3]imidazo[4,5-c]pyridine-3-carboxamide, which was dried by lyophilization. 1H NMR (400 MHz, DMSO-d6 at 80° C.) δ 11.52 (s, 1H), 7.69 (d, J=8.6 Hz, 2H), 7.42 (d, J=7.6 Hz, 1H), 7.41 (d, J=7.6 Hz, 1H), 7.16 (t, J=7.6 Hz, 1H), 7.12-6.99 (m, 4H), 6.78-6.56 (m, 2H), 6.22 (s, 2H), 4.75 (s, 2H), 3.89 (t, J=5.6 Hz, 2H), 3.12 (d, J=5.6 Hz, 2H), 2.80-2.72 (m, 2H), 2.22 (s, 6H). MS (ESI) m/e [M+1]+ 484.9.
Reaction SMILES: [OH-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2.[CH2:13](I)[CH:14]=[CH2:15]>CS(C)=O.O>[CH2:15]([N:9]1[C:10]2[C:6](=[CH:5][C:4]([Br:3])=[CH:12][CH:11]=2)[CH:7]=[CH:8]1)[CH:14]=[CH2:13]
Reactant: Brc1ccc2[nH]ccc2c1
Reactant: C=CCI
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: C=CCn1ccc2cc(Br)ccc21
Yield: 60.6 %

Procedure:
To a stirred mixture of NaOH (204 mg., 5.1 mmol., 1 eq.) in DMSO (10 mL.) was added 5-bromoindole (1.0 g., 5.1 mmol., 1 eq.). The solution was stirred for three hours upon complete dissolution of the NaOH (approximately 1 h.). To this solution was added allyl iodide (0.466 mL., 5.1 mmol., 1 eq.) via syringe. After 2 h. the mixture was diluted with water and extracted 2×with diethyl ether. The organic extracts were combined, dried over anhydrous MgSO4, filtered and concentrated in vacuo. The product was purified by flash column chromatography on silica gel (4:1 hexanes/acetone) affording 730 mg 1-allyl-5-bromoindole.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]([N+:14]([O-])=O)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]=1[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])([O-:3])=[O:2].O>CCO>[NH2:14][C:12]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:4]([N+:1]([O-:3])=[O:2])[CH:13]=1
Reactant: CCOC(=O)Cc1c([N+](=O)[O-])cc([N+](=O)[O-])c2ccccc12
Solvent: CCO
Solvent: O
Product: CCOC(=O)Cc1c([N+](=O)[O-])cc(N)c2ccccc12
Reaction time: 0.5 h
Yield: 11.1 %

Procedure:
Na2S (60%, 4.27 g, 32.87 mmol) was added to a refluxing solution of ethyl (2,4-dinitronaphthalen-1-yl)acetate (10.0 g, 32.87 mmol) in EtOH (200 mL) and stirred for 0.5 h. The mixture was poured into water (200 mL), concentrated and extracted with AcOEt (300 mL). The organic layer was washed with H2O (100 mL) and saturated aqueous NaCl (50 mL). The each aqueous layer was extracted with AcOEt (100 mL). The combined organic layer was washed with saturated aqueous NaCl (50 mL), dried (Na2SO4) and concentrated under reduced pressure. Flash chromatography (20% AcOEt-Petroleum ether) afforded ethyl (4-amino-2-nitronaphthalen-1-yl)acetate (1.0 g, 11%) as a dark purple solid. M.p. 93-100° C. (decomp.); 1H NMR (CDCl3, 500 MHz) δ 8.08 (d, 8.0, 1H), 7.86 (d, 7.5, 1H), 7.66 (t, 7.0, 1H), 7.62 (t, 7.0, 1H), 7.20 (s, 1H), 4.40 (brs, 2H), 4.26 (s, 2H), 4.20 (q, 7.0, 2H), 1.26 (t, 7.0, 3H); IR (neat) 3459, 3379, 3255, 2980, 1728, 1634, 1590, 1515, 1466, 1439, 1368, 1337, 1249, 1200, 1156, 1027, 841, 756 cm−1. FABMS (NBA) m/z 274 (M+).
Reaction SMILES: [C:1]1([S:7]([CH2:10][CH2:11][N:12]2C(=O)C3C(=CC=CC=3)C2=O)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.NN.[ClH:26]>C(O)C>[ClH:26].[C:1]1([S:7]([CH2:10][CH2:11][NH2:12])(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1c2ccccc2C(=O)N1CCS(=O)(=O)c1ccccc1
Agent: Cl
Agent: NN
Solvent: CCO
Solvent: O
Product: NCCS(=O)(=O)c1ccccc1
Temperature: 25 °C
Yield: 40.5 %

Procedure:
A solution of 32.3 g (0.102 mole) of 2-[2-(phenylsulfonyl)ethyl]-1H-isoindole-1,3-(2H)-dione and 11.8 g (0.2 mole) of 85% hydrazine hydrate in 500 ml of absolute ethanol was refluxed for 6 hr. The reaction mixture was cooled to room temperature, filtered and concentrated. The concentrate was dissolved in chloroform and extracted with 5% sodium hydroxide. The chloroform layer was dried and evaporated to give a clear oil. The oil, the free base of the title compound, was reacted with ethereal hydrogen chloride. Recrystallization of the precipitated salt from methanol-diethyl ether gave white crystalline product, m.p. 151°-154° C. in 40.5% yield.
Reaction SMILES: [CH3:1][CH:2]([CH3:22])[CH2:3][O:4][C:5]1[N:13]=[C:12]2[C:8]([N:9]=[CH:10][N:11]2[CH2:14][CH:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[C:7]([NH2:21])[N:6]=1.C([O-])(=O)C.[Na+].[Br:28]Br>C(O)(=O)C>[Br:28][C:10]1[N:11]([CH2:14][CH:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[C:12]2[C:8]([N:9]=1)=[C:7]([NH2:21])[N:6]=[C:5]([O:4][CH2:3][CH:2]([CH3:22])[CH3:1])[N:13]=2
Reactant: CC(C)COc1nc(N)c2ncn(CC3CCOCC3)c2n1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)COc1nc(N)c2nc(Br)n(CC3CCOCC3)c2n1
Temperature: 25 °C

Procedure:
2-[(2-Methylpropyl)oxy]-9-(tetrahydro-2H-pyran-4-ylmethyl)-9H-purin-6-amine (88 mg) was dissolved in glacial acetic acid (1.5 mL) before adding sodium acetate (355 mg). The above was then cooled in an ice-bath before bromine (0.2 mL) which was added gradually. The reaction mixture was warmed to room temperature before being heated to 70° C. (external temperature) for 4 hours. The reaction mixture was quenched with 10% (w/v) sodium thiosulphate solution (to a pale yellow colour with no further change) and then the pH was adjusted to 6-7 by the addition of 2M sodium hydroxide. This was then extracted into ethyl acetate (20 mL, 3 times). The organic layer was separated, combined and dried by passing through a hydrophobic frit. The organic layer was evaporated under reduced pressure and then azeotroped with toluene to give the title compound as a pale yellow solid (0.10 g). This material then used in the next stage without the need for purification
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:13])[C:8](Br)=[N:9][C:10]=1[CH3:11])=[O:5])[CH3:2].[C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[F:22])#[CH:15]>>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:13])[C:8]([C:15]#[C:14][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[F:22])=[N:9][C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: C#Cc1ccccc1F
Reactant: CCOC(=O)c1c(C)nc(Br)n1C
Product: CCOC(=O)c1c(C)nc(C#Cc2ccccc2F)n1C

Procedure:
The title compound, MS: m/e=287.4 (M+H+) was prepared in accordance with the general method of example 1b from 2-bromo-3,5-dimethyl-3H-imidazole-4-carboxylic acid ethyl ester and 1-ethynyl-2-fluorobenzene.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[O:15][C:16]4[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=4[N:18]=3)=[CH:10][C:9]=2[O:23][CH3:24])[CH:5]=[CH:4][CH:3]=1.COC1C=C(C2OC3C=CC=CC=3N=2)C=CC=1B1OC(C)(C)C(C)(C)O1.FC(F)(F)S(OC1C=CC([Cl:63])=CC=1)(=O)=O>>[Cl:63][C:3]1[CH:4]=[CH:5][C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[O:15][C:16]4[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=4[N:18]=3)=[CH:10][C:9]=2[O:23][CH3:24])=[N:7][CH:2]=1
Reactant: O=S(=O)(Oc1ccc(Cl)cc1)C(F)(F)F
Reactant: COc1cc(-c2nc3ccccc3o2)ccc1-c1cccc(Br)n1
Agent: COc1cc(-c2nc3ccccc3o2)ccc1B1OC(C)(C)C(C)(C)O1
Product: COc1cc(-c2nc3ccccc3o2)ccc1-c1ccc(Cl)cn1

Procedure:
Utilizing the general procedure outlined in the synthesis of 2-[4-(6-bromopyridin-2-yl)-3-methoxyphenyl]-1,3-benzoxazole, 2-[3-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1,3-benzoxazole (100 mg, 0.28 mmol) was reacted with 4-chlorophenyl trifluoromethanesulfonate (74 mg, 0.28 mmol) to afford the desired 2-[4-(5-chloropyridin-2-yl)-3-methoxyphenyl]-1,3-benzoxazole as a colorless solid: 1H NMR (CDCl3, 300 MHz) δ 8.69–8.68 (d, 1H), 7.98 (s, 2H), 7.94–7.90 (m, 2H), 7.86–7.78 (m, 1H), 7.74–7.73 (m, 1H), 7.65–7.58 (m, 1H), 7.40–7.37 (m, 2H), 4.03 (s, 3H). MS (ESI) 337 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][C:8]([CH:13]=[CH2:14])=[C:9]([C:11]#[N:12])[CH:10]=[C:5]2[C:4]([CH3:15])=[N:3]1.C(O)(=O)C.[NH:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1>CO>[CH3:1][N:2]1[C:6]2=[N:7][C:8]([CH2:13][CH2:14][N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)=[C:9]([C:11]#[N:12])[CH:10]=[C:5]2[C:4]([CH3:15])=[N:3]1
Reactant: C=Cc1nc2c(cc1C#N)c(C)nn2C
Reactant: C1CCNC1
Solvent: CC(=O)O
Solvent: CO
Product: Cc1nn(C)c2nc(CCN3CCCC3)c(C#N)cc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 1,3-dimethyl-6-vinyl-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile (2.20 g, 11.1 mmol) in methanol (110 mL) was treated with acetic acid (635 μL, 11.1 mmol) and pyrrolidine (4.59 mL, 55.5 mmol). The mixture was stirred at room temperature for 3 hours and the solvent removed under reduced pressure. The residue was suspended in water and extracted with ethyl acetate. The combined organic layers were dried over Na2SO4 and concentrated to give 1,3-dimethyl-6-[2-(pyrrolidin-1-yl)ethyl]-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile as a tan solid.
Reaction SMILES: [O:1]=[C:2]1[N:14]2[C:5](=[N:6][C:7]3[C:12]([CH2:13]2)=[CH:11][CH:10]=[CH:9][CH:8]=3)[S:4][C:3]1=[CH:15][C:16]([OH:18])=O.[C:19]([NH:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([CH3:22])([CH3:21])[CH3:20].O=C1N(N(N2CCOC2=O)P(Cl)(N)=O)CCO1.Cl>ClCCl.C(N(CC)CC)C>[C:19]([N:23]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:16](=[O:18])[CH:15]=[C:3]1[S:4][C:5]2=[N:6][C:7]3[C:12]([CH2:13][N:14]2[C:2]1=[O:1])=[CH:11][CH:10]=[CH:9][CH:8]=3)([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)NCc1ccccc1
Reactant: O=C(O)C=c1sc2n(c1=O)Cc1ccccc1N=2
Agent: Cl
Agent: NP(=O)(Cl)N(N1CCOC1=O)N1CCOC1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)N(Cc1ccccc1)C(=O)C=c1sc2n(c1=O)Cc1ccccc1N=2
Temperature: 10 °C
Reaction time: 2 h

Procedure:
The compound, (3-oxo-5H-thiazolo[2,3-b]quinazolin-2(3H)-ylidene)acetic acid (compound IIIa), triethylamine, and N-(tert-butyl)benzylamine, in relative molar amounts of 1, 2, and 1, respectively, are dissolved in dichloromethane, and the solution is cooled to 10° C. The compound, N,N-bis(2-oxo-3-oxazolidinyl)phosphorodiamidic chloride, (relative molar amount, 1) is added to the reaction mixture, which is then stirred at about 25° C. for about 2 hours. Following acidification with dilute hydrochloric acid, the reaction mixture is filtered, and the organic phase is washed with water, dried over anhydrous magnesium sulfate, and evaporated to dryness under reduced pressure, leaving the N-tert-butyl-N-benzyl(3-oxo-5H-thiazolo[2,3-b]quinazolin-2(3H)-ylidene)acetamide as a solid. The N-tert-butyl-N-benzyl(3-oxo-5H-thiazolo[2,3-b]quinazolin-2(3H)-ylidene)acetamide (compound VI) is then recrystallized from anhydrous ethanol. Replacement of (3-oxo-5H-thiazolo[2,3-b]2(3H)-ylidene)acetic acid with a derivative thereof in which a nuclear hydrogen of the benzene ring has been substituted with lower alkyl, alkoxy, halogen, trifluoromethyl, NO2 or NH2, results in the formation of the corresponding derivative of N-tert-butyl-N-benzyl(3-oxo-5H-thiazolo[2,3-b]quinazolin-2(3H)-ylidene)acetamide.
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH3:10].[CH2:11](I)[CH:12]=[CH2:13]>C1COCC1>[CH2:13]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH3:10])[CH:12]=[CH2:11]
Reactant: C=CCI
Reactant: CCc1ccccc1Br
Agent: [Mg]
Solvent: C1CCOC1
Product: C=CCc1ccccc1CC
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To a suspension of 8.53 g (350 mmol) of magnesium in 270 mL of dry THF was added 50 g (270 mmol) of 1-bromo-2-ethyl benzene. The temperature was maintained at 50° C. during addition, then was heated under reflux. After 1 h, the solution was cooled to -78° C. under N2, and 54.42 g (324 mmol) of allyl iodide was added dropwise. The mixture was allowed to warm to room temperature, stirred for an additional 2 h, then cooled to 0° C. The reaction was quenched by addition of 2M HCl and 500 mL of ether and the layers were separated. The organic layer was washed with 30 mL of saturated NaHCO3 solution and brine, dried over MgSO4, filtered and concentrated. The oily residue was filtered through silica gel with 20% ethyl acetate-hexane and the eluate was concentrated to afford the crude 1-allyl-2-ethylbenzene as a colorless oil.
Reaction SMILES: C[O:2][C:3](=[O:35])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([N:13]([C:18]2[N:19]([C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=3)[N:20]=[C:21]3[C:26]=2[CH:25]=[CH:24][CH:23]=[CH:22]3)[CH2:14][CH2:15][O:16][CH3:17])=[O:12])=[C:6]([Cl:34])[CH:5]=1.[OH-].[Li+]>C(Cl)Cl.CCCCCCC>[Cl:34][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][C:7]=1[NH:10][C:11]([N:13]([C:18]1[N:19]([C:27]2[CH:28]=[CH:29][C:30]([Cl:33])=[CH:31][CH:32]=2)[N:20]=[C:21]2[C:26]=1[CH:25]=[CH:24][CH:23]=[CH:22]2)[CH2:14][CH2:15][O:16][CH3:17])=[O:12])[C:3]([OH:35])=[O:2]
Reactant: COCCN(C(=O)Nc1ccc(C(=O)OC)cc1Cl)c1c2ccccc2nn1-c1ccc(Cl)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCCCCCC
Product: COCCN(C(=O)Nc1ccc(C(=O)O)cc1Cl)c1c2ccccc2nn1-c1ccc(Cl)cc1

Procedure:
In analogy to the procedure described in example 2.2, 3-chloro-4-[3-[2-(4-chloro-phenyl)-2H-indazol-3-yl]-3-(2-methoxy-ethyl)-ureido]-benzoic acid methyl ester was treated with 1 N aqueous lithium hydroxide solution in THF/MeOH 1/1 for 14 h at ambient temperature to give the title compound as yellow foam. MS: m/e=497.1 [M−H−].
Reaction SMILES: [CH3:1][O:2][CH:3]([O:7][CH3:8])[CH2:4][NH:5][CH3:6].C1C=CC=CC=1.[Cl:15][C:16]1[CH:17]=[C:18]([CH:30]=[C:31]([Cl:33])[CH:32]=1)[O:19][CH:20]([C:22]1[S:26][C:25]([N:27]=[C:28]=[O:29])=[N:24][N:23]=1)[CH3:21]>CCCCCC>[Cl:15][C:16]1[CH:17]=[C:18]([CH:30]=[C:31]([Cl:33])[CH:32]=1)[O:19][CH:20]([C:22]1[S:26][C:25]([NH:27][C:28](=[O:29])[N:5]([CH3:6])[CH2:4][CH:3]([O:7][CH3:8])[O:2][CH3:1])=[N:24][N:23]=1)[CH3:21]
Reactant: CNCC(OC)OC
Reactant: CC(Oc1cc(Cl)cc(Cl)c1)c1nnc(N=C=O)s1
Solvent: c1ccccc1
Solvent: CCCCCC
Product: COC(CN(C)C(=O)Nc1nnc(C(C)Oc2cc(Cl)cc(Cl)c2)s1)OC

Procedure:
3.8 grams (0.032 mole) of methylaminoacetaldehyde dimethylacetal was added to a 50 milliliter benzene solution containing 10.0 grams (0.032 mole) of the 5-[1-(3,5-dichlorophenoxy)ethyl]-1,3,4-thiadiazol-2-yl isocyanate dimer (prepared above). The resulting solution was heated to reflux, 50 milliliters of hexane was added, and the solution cooled. The crystals were filtered off, and dried in a vacuum oven at 80° C. to give 7.9 grams of fluffy waxy crystals of 3-[5-[1-(3,5-dichlorophenoxy)ethyl]-1,3,4-thiadiazol-2-yl]-1-methyl-1-(2,2-dimethoxyethyl)urea. (Melting point 149°-152° C.).