Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[C:10](=[O:12])[CH3:11].[Br:13]Br>C(O)(=O)C>[Br:13][CH2:11][C:10]([C:3]1[C:4]([CH3:9])=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=1[CH3:1])=[O:12]
Reactant: CC(=O)c1c(C)cc(C)cc1C
Reactant: BrBr
Solvent: CC(=O)O
Product: Cc1cc(C)c(C(=O)CBr)c(C)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
0.3 mol of 1-(2,4,6-trimethylphenyl)-1-ethanone are dissolved in 200 ml of glacial acetic acid and 31.8 g of bromine are added dropwise, while maintaining the reaction medium at a temperature below 10° C. After the addition, the reaction medium is allowed to return to room temperature and is left at this temperature for 2 hours. The reaction medium is then poured into 500 ml of ice-water and the aqueous phase is extracted with ethyl ether. The organic extracts are washed with saturated aqueous sodium bicarbonate solution and then with salted water, and are dried over anhydrous magnesium sulphate.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][NH:8][N:7]=1.Cl[CH2:17][C:18]1[CH:36]=[CH:35][C:21]([O:22][CH2:23][C:24]2[N:25]=[C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[S:27][CH:28]=2)=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[C:29]1([C:26]2[S:27][CH:28]=[C:24]([CH2:23][O:22][C:21]3[CH:20]=[CH:19][C:18]([CH2:17][N:8]4[CH:9]=[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([C:2]5[S:1][CH:5]=[CH:4][CH:3]=5)=[N:7]4)=[CH:36][CH:35]=3)[N:25]=2)[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: CCOC(=O)c1c[nH]nc1-c1cccs1
Reactant: ClCc1ccc(OCc2csc(-c3ccccc3)n2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(Cc2ccc(OCc3csc(-c4ccccc4)n3)cc2)nc1-c1cccs1
Temperature: 80 °C
Reaction time: 8 h
Yield: 86.5 %

Procedure:
A mixture of ethyl 3-(2-thienyl)-1H-pyrazole-4-carboxylate (5.60 g), 4-(4-chloromethylphenoxy)methyl-2-phenylthiazole (7.96 g), potassium carbonate (6.98 g), and N,N-dimethylformamide (75 ml) was stirred at 80° C. for 8 hours. The reaction mixture was poured into water, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 1-[4-(2-phenyl-4-thiazolylmethoxy)benzyl]-3-(2-thienyl)-1H-pyrazole-4-carboxylate as colorless crystals (10.93 g, yield: 87%) from the fraction eluted with ethyl acetate-hexane (1:2, volume ratio). This was recrystallized from ethyl acetate-hexane. Melting point: 94˜95° C.
Reaction SMILES: [C:1]([C:5]1[CH:24]=[CH:23][CH:22]=[CH:21][C:6]=1[C:7]([NH:9][N:10]([CH3:20])[C:11]([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[S:12])=[O:8])(OC)=[O:2].C(N)(C)(C)C.[CH:30]([OH:33])([CH3:32])[CH3:31]>>[C:1]([C:5]1[CH:24]=[CH:23][CH:22]=[CH:21][C:6]=1[C:7]([NH:9][N:10]([CH3:20])[C:11]([NH:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[S:12])=[O:8])([O:33][CH:30]([CH3:32])[CH3:31])=[O:2]
Reactant: CC(C)O
Reactant: COC(=O)c1ccccc1C(=O)NN(C)C(=S)Nc1ccccc1
Solvent: CC(C)(C)N
Product: CC(C)OC(=O)c1ccccc1C(=O)NN(C)C(=S)Nc1ccccc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a solution of 5.0 g (0.014 mole) of 1-(2-carbomethoxybenzoyl)-2-methyl-4-phenyl-3-thiosemicarbazide in 75 ml of isopropyl alcohol was added 1.0 g (0.014 mole) of tert-butylamine and the solution was stirred at room temperature for 16-18 hours. Most of the isopropyl alcohol was removed at reduced pressure, and water was added and the resulting precipitate was collected. The title compound thus produced had a melting point of 115°-117°.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C@H:4]([NH:12][CH2:13][CH2:14][NH:15]C(OC(C)(C)C)=O)[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:23])[C@H:4]([NH:12][CH2:13][CH2:14][NH2:15])[CH2:5][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: COC(=O)[C@@H](Cc1ccccc1)NCCNC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@@H](Cc1ccccc1)NCCN
Temperature: 25 °C
Reaction time: 1 h
Yield: 125.3 %

Procedure:
(2R)-2-(2-(tert-Butoxycarbonylamino)ethylamino)-3-phenylpropionic acid methyl ester (1.32 g; 4.094 mmol) was dissolved in methylene chloride (10 ml) and trifluoroacetic acid (10 ml) was added. The reaction mixture was stirred for 1 hour at room temperature. The solvent was evaporated in vacuo and the residue was dissolved in methylene chloride (5 ml) and evaporated in vacuo. Methylene chloride (5 ml) was added and evaporated in vacuo to afford 1.14 g of (2R)-2-(2-aminoethylamino)-3-phenylpropionic acid methyl ester as a trifluoroacetate salt.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][NH:18][C:19](=[O:27])OC3C=CC=CC=3)=[CH:12][CH:11]=2)[C:3]=1[N+:28]([O-:30])=[O:29].[CH3:31][C:32]1[CH:33]=[CH:34][C:35]([S:38]([NH2:41])(=[O:40])=[O:39])=[CH:36][CH:37]=1.[H-].[Na+].O>CN(C=O)C>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][NH:18][C:19]([NH:41][S:38]([C:35]3[CH:36]=[CH:37][C:32]([CH3:31])=[CH:33][CH:34]=3)(=[O:39])=[O:40])=[O:27])=[CH:12][CH:11]=2)[C:3]=1[N+:28]([O-:30])=[O:29]
Reactant: Cc1cc(C)c([N+](=O)[O-])c(Nc2ccc(CCNC(=O)Oc3ccccc3)cc2)n1
Reactant: Cc1ccc(S(N)(=O)=O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)NC(=O)NCCc2ccc(Nc3nc(C)cc(C)c3[N+](=O)[O-])cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.7 %

Procedure:
To a stirred solution of phenyl 2-{4-[(4,6-dimethyl-3-nitro-2-pyridinyl)amino]phenyl}ethylcarbamate (step 2, 10.0 g, 24.6 mmol) and p-toluenesulfonamide (6.3 g, 36.8 mmol) in DMF (100 mL) was added sodium hydride (2.0 g, 50 mmol). The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was poured into water (300 mL) and extracted with ethyl acetate/toluene (v/v, 2:1, 2×300 mL). The organic extracts were washed with water (100 mL) and brine (200 mL), then dried (Na2SO4). Removal of the solvent gave crude product. Recrystallization from ethyl acetate gave 9.6 g (81%) of the title compound as brown solids. The mother liquor was concentrated and the residue was purified by flash column chromatography on silica gel eluting with hexane/ethyl acetate (1:1) to afford 1.9 g (16%) of the title compound as brown solids.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH3:9].Br[CH2:11][C:12]1[C:13]([C:20]2[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][C:21]=2[Cl:27])=[N:14][O:15][C:16]=1[CH:17]1[CH2:19][CH2:18]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:11][C:12]2[C:13]([C:20]3[C:21]([Cl:27])=[CH:22][CH:23]=[CH:24][C:25]=3[Cl:26])=[N:14][O:15][C:16]=2[CH:17]2[CH2:19][CH2:18]2)=[CH:4][C:3]=1[CH3:9]
Reactant: Clc1cccc(Cl)c1-c1noc(C2CC2)c1CBr
Reactant: Cc1cc(O)ccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(OCc2c(-c3c(Cl)cccc3Cl)noc2C2CC2)ccc1Br
Temperature: 80 °C
Yield: 90.2 %

Procedure:
A solution of 4-bromo-3-methyl-phenol (143 mg, 0.764 mmol) and 4-bromomethyl-5-cyclopropyl-3-(2,6-dichloro-phenyl)-isoxazole (221 mg, 0.636 mmol) in dimethylformamide (1 mL) is treated with potassium carbonate (89 mg, 0.637-mmol). The reaction mixture is heated to 80° C. for 60 minutes and cooled to room temperature. The mixture is loaded directly onto a silica gel column and purified by flash chromatography eluting with 15% EtOAc/Hexanes. The fractions are combined to provide the title compound (0.26 g, 92%). LC-MS: (M+1);
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]3[CH:15]=[C:14]([CH2:16][C:17]([OH:19])=[O:18])[CH:13]=[CH:12][C:10]=3[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH2:21](O)[CH3:22]>>[CH2:21]([O:18][C:17](=[O:19])[CH2:16][C:14]1[CH:13]=[CH:12][C:10]2[N:11]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[O:8][C:9]=2[CH:15]=1)[CH3:22]
Reactant: CCO
Reactant: O=C(O)Cc1ccc2nc(-c3ccccc3)oc2c1
Agent: Cl
Product: CCOC(=O)Cc1ccc2nc(-c3ccccc3)oc2c1

Procedure:
A solution of 2-phenyl-6-benzoxazolylacetic acid (20 gm) in ethanol (200 ml) was heated under reflux for 6 hr., during which time dry hydrogen chloride gas was passed through the solution. The residual oil on evaporation of the solution was extracted with ether and this solution was evaporated to dryness. The solid formed was recrystallised from toluene/petroleum ether to yield while crystals of ethyl-2-phenyl-6-benzoxazolylacetate, m.p. 76° C.
Reaction SMILES: [F:1][CH:2]([F:12])[CH2:3][NH:4][C:5]1[C:6]([NH2:11])=[CH:7][CH:8]=[CH:9][CH:10]=1.O=[C:14]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:15](O)=[O:16]>CO>[F:1][CH:2]([F:12])[CH2:3][N:4]1[C:5]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:11]=[C:14]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:15]1=[O:16]
Reactant: O=C(O)C(=O)c1ccccc1
Reactant: Nc1ccccc1NCC(F)F
Solvent: CO
Product: O=c1c(-c2ccccc2)nc2ccccc2n1CC(F)F
Yield: 34.9 %

Procedure:
To a solution of 400 mg (2.32 mM) of N-(2,2-difluoroethyl)benzene-1,2-diamine in 7 ml of methanol were added 349 mg (2.32 mM) of 2-Oxo-2-phenylacetic acid. The mixture was refluxed for 3 h and the solvent was then removed under vacuum. The residue was further purified by silica gel column chromatography using dichloromethane/cyclohexane as eluant, to give 231.8 mg of 1-(2,2-difluoroethyl)-3-phenyl-quinoxalin-2(1H)-one as a pale beige solid. Yield: 35%.
Reaction SMILES: [CH3:1][C:2]12[CH2:13][NH:12][C:10]3[C:11]1=[C:6]([CH:7]=[CH:8][CH:9]=3)[NH:5][C:4](=[O:14])[CH2:3]2.[Br:15]N1C(=O)CCC1=O>C(Cl)Cl>[Br:15][C:7]1[C:6]2[NH:5][C:4](=[O:14])[CH2:3][C:2]3([CH3:1])[CH2:13][NH:12][C:10]([C:11]=23)=[CH:9][CH:8]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC12CNc3cccc(c31)NC(=O)C2
Solvent: ClCCl
Product: CC12CNc3ccc(Br)c(c31)NC(=O)C2
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of (±)-2a-methyl-1,2,2a,5-tetrahydropyrrolo[4,3,2-de]quinolin-4(3H)-one from Step A (525 mg, 2.79 mmol) in CH2Cl2 (15 mL) at 0° C. was added N-bromosuccinimide (496 mg, 2.79 mmol) and the mixture was allowed to warm slowly to ambient temperature. After 5 h, the reaction mixture was quenched with saturated aqueous NaHCO3 (10 mL) and extracted with EtOAc (150 mL). The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of CH2Cl2:CH3CN —100:0 to 75:25, to give the title compound. MS: m/z=267 (M+1).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[CH:5]=[CH:4][N:3]=[N:2]1.[H-].[Na+].Cl[CH2:20][C:21]1[CH:22]=[N:23][CH:24]=[C:25]([C:27]2[CH:32]=[CH:31][C:30]([O:33][C:34]([F:37])([F:36])[F:35])=[CH:29][CH:28]=2)[CH:26]=1.O>CN(C)C=O>[N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][C:10]2[CH:11]=[CH:12][C:13]([O:16][CH2:20][C:21]3[CH:22]=[N:23][CH:24]=[C:25]([C:27]4[CH:28]=[CH:29][C:30]([O:33][C:34]([F:37])([F:35])[F:36])=[CH:31][CH:32]=4)[CH:26]=3)=[CH:14][CH:15]=2)[CH:5]=[CH:4][N:3]=[N:2]1
Reactant: FC(F)(F)Oc1ccc(-c2cncc(CCl)c2)cc1
Reactant: Oc1ccc(CCCCn2ccnn2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: FC(F)(F)Oc1ccc(-c2cncc(COc3ccc(CCCCn4ccnn4)cc3)c2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 49.8 %

Procedure:
A solution of 56 mg (0.24 mmol) 4-(4-[1,2,3]triazol-1-yl-butyl)phenol in 4.0 ml N,N-dimethylformamide was treated at 0° C. with 10 mg (0.24 mmol) of 60% sodium hydride and stirred at 0° C. for 30 min. Then 74 mg (0.24 mmol) 3-Chloromethyl-5-(4-trifluoromethoxy-phenyl)-pyridine were added and stirred continued at r.t. over night. After addition of 8 ml water, the precipitate was isolated, washed thoroughly with water, n-heptane and diisopropylether. The residue was dried at 40° C. to give 56 mg (49%) of the title compound as light brown powder.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:11][C:10]([C:12]3[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=3)=[N:9][C:8]=2[CH:19]=1)([O-])=O>C(OCC)(=O)C.C(O)(=O)C.[Pd]>[C:15]1([CH3:18])[CH:14]=[CH:13][C:12]([C:10]2[O:11][C:7]3[CH:6]=[CH:5][C:4]([NH2:1])=[CH:19][C:8]=3[N:9]=2)=[CH:17][CH:16]=1
Reactant: Cc1ccc(-c2nc3cc([N+](=O)[O-])ccc3o2)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Cc1ccc(-c2nc3cc(N)ccc3o2)cc1
Reaction time: 16 h
Yield: 59 %

Procedure:
To 5-nitro-2-p-tolylbenzo[d]oxazole (4.8 g, 18.90 mmol) in ethyl acetate/acetic acid (250 ml/1 mL) was added palladium on carbon (480 mg). The reaction vessel was purged three times with nitrogen, followed by hydrogen three times, and then left stirring under hydrogen for 16 h. The reaction vessel was finally purged three times with nitrogen, before filtration on a pad of Celite®, which was washed with ethyl acetate. The organic solution was washed with saturated aqueous Na2CO3, followed by brine. The combined organic layers were dried over anhydrous MgSO4 and evaporated to afford 2.5 g (60%) of the title compound.
Reaction SMILES: [CH2:1]([NH:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([C:12]([C:15]([OH:17])=O)=[CH:13][N:14]=2)[N:11]=1)[CH2:2][CH2:3][CH3:4].CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[NH2:52][C:53]1[CH:67]=[CH:66][C:56]([CH2:57][NH:58][C:59](=[O:65])[O:60][C:61]([CH3:64])([CH3:63])[CH3:62])=[CH:55][CH:54]=1>CC#N>[CH2:1]([NH:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([C:12]([C:15]([NH:52][C:53]3[CH:67]=[CH:66][C:56]([CH2:57][NH:58][C:59](=[O:65])[O:60][C:61]([CH3:63])([CH3:64])[CH3:62])=[CH:55][CH:54]=3)=[O:17])=[CH:13][N:14]=2)[N:11]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CC(C)(C)OC(=O)NCc1ccc(N)cc1
Reactant: CCCCNc1ccc2ncc(C(=O)O)n2n1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCCCNc1ccc2ncc(C(=O)Nc3ccc(CNC(=O)OC(C)(C)C)cc3)n2n1
Reaction time: 8 h
Yield: 99.8 %

Procedure:
To a solution of 6-(butylamino)imidazo[1,2-b]pyridazine-3-carboxylic acid (150 mg, 0.64 mmol) in CH3CN (1 mL) were added BOP reagent (567 mg, 1.28 mmol), triethyl amine (0.26 mL, 1.92 mmol) and tert-butyl 4-aminobenzylcarbamate (143 mg, 0.64 mmol). The reaction was stirred for overnight. Then the reaction was purified ISCO column chromatography on silica gel (10% MeOH/DCM) to give tert-butyl 4-(6-(butylamino)imidazo[1,2-b]pyridazine-3-carboxamido)benzylcarbamate as white solid (280 mg, 100% yield). 20 mg was further purified by prep HPLC (neutral) to afford tert-butyl 4-(6-(butylamino)imidazo[1,2-b]pyridazine-3-carboxamido)benzylcarbamate (5 mg) as white solid. 1H NMR (400 MHz, METHANOL-d4) δ ppm 8.10 (s, 1H), 7.76 (d, J=9.70 Hz, 1H), 7.67 (d, J=8.38 Hz, 2H), 7.32 (d, J=8.38 Hz, 2H), 6.90 (d, J=9.70 Hz, 1H), 4.62 (s, 1H), 4.24 (s, 2H), 3.47 (t, J=7.28 Hz, 2H), 1.79 (t, J=7.39 Hz, 2H), 1.46-1.57 (m, 10H), 1.02 (t, J=7.39 Hz, 3H); LRMS (ESI) m/e 439.9 [(M+H)+, calcd for C23H31N6O3 439.5].
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1Cl)([O-:3])=[O:2].[CH2:11]([O:13][CH2:14][CH2:15][NH2:16])[CH3:12]>C(OCC)(=O)C>[CH2:11]([O:13][CH2:14][CH2:15][NH:16][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])[CH3:12]
Reactant: O=[N+]([O-])c1ccccc1Cl
Reactant: CCOCCN
Solvent: CCOC(C)=O
Product: CCOCCNc1ccccc1[N+](=O)[O-]
Temperature: 130 °C
Reaction time: 3 h
Yield: 107.2 %

Procedure:
A mixture of o-nitrochlorobenzene (30 g) and 2-ethoxyethylamine (51 g) is stirred at 130° C. for 3 hours. After allowing to cool, ethyl acetate (150 ml) is added to the reaction mixture, and the ethyl acetate layer is separated, washed three times with saturated aqueous saline, dried over anhydrous magnesium sulfate, and then concentrated. The residue is distilled under reduced pressure to give N-(2-ethoxyethyl)-o-nitroaniline (42.9 g) as a reddish brown liquid, b.p. 144°-145.5° C./1.0 mmHg.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][OH:9])=[CH:6][CH:5]=[C:4]([Cl:10])[N:3]=1.C1C=CC(N=NC2C=CC(N)=NC=2N)=CC=1.Cl.[Cr](Cl)([O-])(=O)=O.C(OCC)C>ClCCl>[Cl:1][C:2]1[C:7]([CH:8]=[O:9])=[CH:6][CH:5]=[C:4]([Cl:10])[N:3]=1
Reactant: OCc1ccc(Cl)nc1Cl
Agent: O=[Cr](=O)([O-])Cl
Agent: Cl
Agent: Nc1ccc(N=Nc2ccccc2)c(N)n1
Solvent: ClCCl
Solvent: CCOCC
Product: O=Cc1ccc(Cl)nc1Cl
Reaction time: 2 h
Yield: 66.4 %

Procedure:
Dissolve (2,6-dichloropyridin-3-yl)-methanol (876 mg, 4.92 mmol) in dichloromethane (20 mL). Add pyridium chlorochromate (2.12 g, 9.84 mmol). Stir for 2 hours. Add diethyl ether and stir for 20 minutes. Filter the mixture through a pad of Celite® and silica gel and concentrate to give 2,6-dichloropyridine-3-carbaldehyde (575 mg, 66%): 1H NMR (400 MHz, CDCl3) δ 10.39 (s, 1H), 8.18 (d, 1H, J=8.0 Hz), 7.43 (d, 1H, J=8.0 Hz).
Reaction SMILES: [C:1]([C:4]1[C:5](=[O:19])[NH:6][C:7](=[O:18])[N:8]([CH:17]=1)[C@@H:9]1[O:16][C@H:13]([CH2:14]O)[C@@H:11]([OH:12])[CH2:10]1)(=[O:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N-:39]=[N+:40]=[N-:41].[Na+].C(Br)(Br)(Br)Br>CN(C)C=O>[C:1]([C:4]1[C:5](=[O:19])[NH:6][C:7](=[O:18])[N:8]([CH:17]=1)[C@@H:9]1[O:16][C@H:13]([CH2:14][N:39]=[N+:40]=[N-:41])[C@@H:11]([OH:12])[CH2:10]1)(=[O:3])[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(=O)c1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Agent: BrC(Br)(Br)Br
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CC(=O)c1cn([C@H]2C[C@H](O)[C@@H](CN=[N+]=[N-])O2)c(=O)[nH]c1=O
Yield: 58.1 %

Procedure:
1.26 g of 5-acetyl-2'-deoxyuridine, 1.35 g of triphenylphosphine, 1.52 g of sodium azide and 1.7 g of carbon tetrabromide in 40 ml of dimethylformamide were reacted as described in Example 54 and the product was purified by chromatography on 400 g of silica gel in dichloromethane/methanol (9:1) to give 0.80 g of 5-acetyl-5'-azido-2',5'-dideoxyuridine of melting point 159°-162° C. (decomposition).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][O:9][C@H:10]2[CH2:15][CH2:14][C@H:13]([NH2:16])[CH2:12][CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:18]1[N:23]=[CH:22][N:21]=[C:20]2[NH:24][N:25]=[CH:26][C:19]=12.C(N(CC)C(C)C)(C)C>CC(O)C>[CH2:8]([O:9][CH:10]1[CH2:15][CH2:14][CH:13]([NH:16][C:18]2[N:23]=[CH:22][N:21]=[C:20]3[NH:24][N:25]=[CH:26][C:19]=23)[CH2:12][CH2:11]1)[CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Clc1ncnc2[nH]ncc12
Reactant: N[C@H]1CC[C@H](OCCc2ccccc2)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: c1ccc(CCOC2CCC(Nc3ncnc4[nH]ncc34)CC2)cc1
Temperature: 80 °C
Yield: 60 %

Procedure:
A mixture of 219 mg of trans-4-(2-phenyl-ethoxy)-cyclohexylamine, 154 mg of 4-chloro-1H-pyrazolo[3,4-d]pyrimidine (R. K. Robins, J. Amer. Chem. Soc., 78, 784-790 (1956)), 10 mL of 2-propanol and 0.174 mL of N,N-diisopropyl-ethylamine was heated to 80° C. for 12 hours. The mixture was cooled and concentrated under reduced pressure and purified by either preparative TLC eluting with 50:50:5 THF:diethyl ether:NH4OH or preparative reverse phase chromatography on delta Pak C (C-18 column) eluting with a gradient of 90:10 to 0:100 of 0.1% TFA in H2O: CH3CN gave 60-92% of (4-phenethyloxy-cyclohexyl)-(1H-pyrazolo[3,4-d]pyrimidin-4-yl)-amine as a white crystalline solid. MS (m+1)=338.32; 1H NMR (400 MHz, CDCl3) 8.43 (s, 1H), 7.92 (s, 1H), 7.3-7.2 (m, 5H), 3.7 (t, 2H), 3.3 (m, 1H), 2.9 (t, 2H), 2.22 (d, 2H), 2.1 (d, 2H), 1.7 (m, 1H), 1.5 (dd, 2H), 1.4 (m, 2H).
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[O:6]=[CH:7][C:8]1[CH:16]=[CH:15][CH:14]=[C:11]([O:12][CH3:13])[C:9]=1[OH:10].O>C1(C)C=CC=CC=1>[Cl:4][C:15]1[CH:14]=[C:11]([O:12][CH3:13])[C:9]([OH:10])=[C:8]([CH:16]=1)[CH:7]=[O:6]
Reactant: O=S(=O)(Cl)Cl
Reactant: COc1cccc(C=O)c1O
Solvent: O
Solvent: Cc1ccccc1
Product: COc1cc(Cl)cc(C=O)c1O
Reaction time: 16 h

Procedure:
A solution of sulfuryl chloride (15 mL, 190 mmol) in toluene (20 mL) is added dropwise over 1.5 h to a solution of o-vanillin (25.0 g, 164 mmol) in toluene (90 mL) and the reaction is then stirred 16 h. Water (30 mL) is added over 10 minutes with ice-bath cooling. The solid is filtered, washed with water and dried to provide the title compound. MS (EI) 186 (M)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([F:27])=[C:11]([F:26])[C:12]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[F:25])=[C:13]([CH:17]=1)[C:14]([OH:16])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)(O)[O-].[K+].[CH2:33](Br)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.O>CN(C=O)C>[CH2:1]([O:8][C:9]1[C:10]([F:27])=[C:11]([F:26])[C:12]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[F:25])=[C:13]([CH:17]=1)[C:14]([O:16][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1cc(OCc2ccccc2)c(F)c(F)c1Nc1ccccc1F
Reactant: BrCc1ccccc1
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)c1cc(OCc2ccccc2)c(F)c(F)c1Nc1ccccc1F
Temperature: 25 °C
Reaction time: 5 h
Yield: 90 %

Procedure:
To a solution of 5-benzyloxy-3,4-difluoro-2-((2-fluorophenyl)amino)benzoic acid (19.17 g, 51.35 mmol) in DMF (30 mL) was added potassium bicarbonate (6.16 g, 61.62 mmol) followed by benzyl bromide (6.2 mL, 51.41 mmol). The mixture was stirred for 5 h at room temperature and then water (150 mL) was added. The solution was extracted with ethyl acetate (150 mL×3). The combined organic extracts were washed with water (100 mL×3) and brine (200 mL) sequentially, dried over Na2SO4, filtered and concentrated in vacuo to afford the corresponding product (21.42 g, 90% yield). 1H NMR (400 MHz, CDCl3): δ 8.51 (s, 1H), 7.51 (dd, J=8.5, 2.1 Hz, 1H), 7.46-7.36 (m, 10H), 7.12-7.06 (m, 1H), 7.03 (m, 1H), 6.94 (m, 1H), 6.85 (m, 1H), 5.33 (s, 2H), 5.15 (s, 2H).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]([S:10][CH3:11])[N:3]=1.[NH2:12][C@@H:13]1[CH2:18][CH2:17][C@H:16]([OH:19])[C:15]([CH3:21])([CH3:20])[CH2:14]1.CCN(C(C)C)C(C)C>C(O)(C)C>[OH:19][C@H:16]1[CH2:17][CH2:18][C@@H:13]([NH:12][C:2]2[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]([S:10][CH3:11])[N:3]=2)[CH2:14][C:15]1([CH3:21])[CH3:20]
Reactant: CSc1ncc(C#N)c(Cl)n1
Reactant: CC1(C)C[C@H](N)CC[C@@H]1O
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CSc1ncc(C#N)c(N[C@@H]2CC[C@H](O)C(C)(C)C2)n1
Temperature: 100 °C
Yield: 71.7 %

Procedure:
A mixture of 4-chloro-2-(methylthio)pyrimidine-5-carbonitrile (2.15 g, 11.6 mmol)), (1S,4R)-4-amino-2,2-dimethylcyclohexanol (1.51 g, 10.5 mmol) and DIEA (2.72 g, 21.1 mmol) in isopropanol (30 mL) was heated at 100° C. for 3 h. After removal of the organic solvent under reduced pressure, the residue was treated with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated to give a crude product, which was purified by silica gel column chromatography (15% ethyl acetate in petroleum) to afford the title compound as a pale yellow solid (2.2 g, 7.53 mmol, 72% yield). MS (ESI) m/z 293.2 [M+H]+.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([CH3:4])=O.[C:7](=[O:11])([O:9][CH3:10])[NH2:8].C1(C=CC(O)=CC=1)O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1C=CC=CC=1>[CH3:10][O:9][C:7]([NH:8][C:2](=[CH2:4])[C:1]([OH:6])=[O:5])=[O:11]
Reactant: CC(=O)C(=O)O
Reactant: COC(N)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Oc1ccc(O)cc1
Solvent: O
Solvent: c1ccccc1
Product: C=C(NC(=O)OC)C(=O)O
Reaction time: 2 h

Procedure:
A solution pyruvic acid (4.40 g, 50.0 mmol), methyl carbamate (3.75 g, 50.0 mmol), hydroquinone (used for a polymerization inhibitor, 0.05 g), and p-toluene sulfonic acid (50 mg) in 30 ml benzene is refluxed in a 100 ml round bottom flask to which is attached a Dean-Stark trap. The system is exposed to air during the reaction. After 2 hours, 25 minutes, 0.60 ml water (33 mmol) accumulates in the trap. The yellow solution is hazy while warm, but a small amount of gelatinous precipitate accumulated upon cooling. The suspension is filtered and is evaporated. Proton nuclear magnetic resonance spectrosopy confirms the presence of the title compound; (CDCl3, ppm) 10.0-10.5 (1H, broad singlet), 5.4 (1H, broad singlet), 5.1 (1H, broad singlet), 4.5-5.0 (1H, broad singlet), 3.9 (3H, singlet).