Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]([CH3:17])[C@@H:3]([C:5]1[CH:6]=[CH:7][C:8]([OH:16])=[C:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=1)[OH:4].[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:25]=[C:26]([O:28][CH3:29])[CH:27]=1)[CH:23]=O>CO>[CH3:29][O:28][C:26]1[CH:25]=[C:22]([CH:21]=[C:20]([O:19][CH3:18])[CH:27]=1)[CH2:23][NH:1][C@@H:2]([CH3:17])[C@@H:3]([C:5]1[CH:6]=[CH:7][C:8]([OH:16])=[C:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=1)[OH:4]
Reactant: COc1cc(C=O)cc(OC)c1
Reactant: C[C@H](N)[C@H](O)c1ccc(O)c(NS(C)(=O)=O)c1
Solvent: CO
Product: COc1cc(CN[C@@H](C)[C@H](O)c2ccc(O)c(NS(C)(=O)=O)c2)cc(OC)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 57.7 %

Procedure:
Borane-pyridine complex (445 μL, 4.18 mmol) was added to a methanol solution (10 mL) of an amine (3) (363 mg, 1.39 mmol) and 3,5-dimethoxybenzaldehyde (301 mg, 1.81 mmol), and the mixture was stirred for two hours. The reaction mixture was allowed to cool to room temperature and extracted after addition of water with a mixed solvent (ethyl acetate: methanol=10:1), and the organic layer was washed with saturated aqueous sodium chloride solution. The organic layer was dried and concentrated, and the crude product obtained was purified by amine silica gel column chromatography (eluant:chloroform:methanol=7:1), to give a desired amine (4) as a pale yellow solid (329 mg, yield: 57%).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([C:11]#[N:12])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[NH2:13][OH:14]>C(O)C>[OH:14][NH:13][C:11]([CH:8]1[CH2:9][CH2:10][C:5]2([O:4][CH2:3][CH2:2][O:1]2)[CH2:6][CH2:7]1)=[NH:12]
Reactant: NO
Reactant: N#CC1CCC2(CC1)OCCO2
Solvent: CCO
Product: N=C(NO)C1CCC2(CC1)OCCO2

Procedure:
A mixture of 1,4-dioxa-spiro[4.5]decane-8-carbonitrile (0.40 g, 2.4 mmol, prepared according to the procedure from Tremblay, Maxime, PCT Int. Appl. (2007), WO 2007013848) and hydroxylamine (Aldrich, 50% in H2O, 0.7 mL, 9.6 mmol) in ethanol (1.5 mL) in a sealed tube was heated to 80° C. for 6 h. After removal of organic solvent by evaporation, the residue was dissolved in water, extracted with EtOAc and dried over Na2SO4. Filtration and evaporation to dryness gave the product as a white solid.
Reaction SMILES: CC(C)([O-:4])C.[K+].[C:7]([N:10]1[CH2:22][CH2:21][C:20]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:23][CH3:24])[CH:18]=3)[NH:13][C:12]=2[C:11]1([CH3:26])[CH3:25])(=[O:9])[CH3:8].C(OCC)(=O)C.CO>CN(C=O)C>[C:7]([N:10]1[CH2:22][C:21]2[C:20](=[O:4])[C:19]3[CH:18]=[C:17]([O:23][CH3:24])[CH:16]=[CH:15][C:14]=3[NH:13][C:12]=2[C:11]1([CH3:26])[CH3:25])(=[O:9])[CH3:8]
Reactant: COc1ccc2[nH]c3c(c2c1)CCN(C(C)=O)C3(C)C
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc2[nH]c3c(c(=O)c2c1)CN(C(C)=O)C3(C)C
Reaction time: 8 h

Procedure:
Potassium tert-butoxide (269 mg; 2.39 mmol) is added to a solution of 2-acetyl-1,1-dimethyl-6-methoxy-1,2,3,4-tetrahydro-β-carboline (164 mg; 0.60 mmol) in DMF (15 ml). The mixture is stirred under an oxygen atmosphere overnight. A 1/1 ethyl acetate/methanol mixture (10 ml) is then added. After evaporating the solvent and washing the solid, 2-acetyl-3,3-dimethyl-7-methoxy-9-oxo-1,3,4,9-tetrahydropyrrolo[3,4-b]quinoline is obtained (38 mg; 22%)
Reaction SMILES: Cl[C:2]1[NH:6][C:5]2[CH:7]=[CH:8][C:9]([Cl:11])=[CH:10][C:4]=2[N:3]=1.Cl.[Cl:13][C:14]1[C:15]([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[N:16][CH:17]=[CH:18][CH:19]=1.C(N(CC)C(C)C)(C)C>>[Cl:11][C:9]1[CH:8]=[CH:7][C:5]2[N:6]=[C:2]([N:23]3[CH2:24][CH2:25][N:20]([C:15]4[C:14]([Cl:13])=[CH:19][CH:18]=[CH:17][N:16]=4)[CH2:21][CH2:22]3)[NH:3][C:4]=2[CH:10]=1
Reactant: Clc1cccnc1N1CCNCC1
Reactant: Clc1ccc2[nH]c(Cl)nc2c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: Clc1ccc2nc(N3CCN(c4ncccc4Cl)CC3)[nH]c2c1

Procedure:
The 2,5-dichloro-1H-benzoimidazole (0.244 g, 1.3 mmol, Example 20b), 1(3-chloropyridin-2-yl)piperazine hydrochloride (0.4 g, 1.7 mmol, Example 3b) and N,N-diisopropylethylamine (0.59 mL, 3.4 mmol, Aldrich) were reacted under the conditions of Example 3c to give the title compound as a white solid. M.p. 214-215° C. MS (ESI, pos. ion) m/z: 348 (M+1).
Reaction SMILES: [CH2:1]=[C:2]1[C:7](=[CH2:8])[CH:6]2[O:9][CH:3]1[C:4](=[CH2:11])[C:5]2=[CH2:10].[C:12]1(=[O:19])[CH:17]=[CH:16][C:15](=[O:18])[CH:14]=[CH:13]1>C(Cl)(Cl)Cl>[CH2:11]=[C:4]1[C:5](=[CH2:10])[CH:6]2[O:9][CH:3]1[C:2]1[CH2:1][CH:17]3[CH:16]([CH2:8][C:7]=12)[C:15](=[O:18])[CH:14]=[CH:13][C:12]3=[O:19]
Reactant: C=C1C(=C)C2OC1C(=C)C2=C
Reactant: O=C1C=CC(=O)C=C1
Solvent: ClC(Cl)Cl
Product: C=C1C(=C)C2OC1C1=C2CC2C(=O)C=CC(=O)C2C1
Temperature: 80 °C
Yield: 95 %

Procedure:
A mixture of 2 g (13.7 mmol) of 2,3,5,6-tetramethylene-7-oxabicyclo[2.2.1]heptane, 1.47 g (13.7 mmol) of freshly sublimed p-benzoquinone and 20 ml of chloroform was heated at 80° C. for 5 hours under nitrogen. After cooling, the mixture was concentrated to dryness and recrystallised from acetone/methanol (4:1). There were obtained 3.28 g (95%) of 1,2,3,4,8a,9,10,10a-octahydro-2,3-dimethylene-1,4-epoxyanthracene-5,8-dione of melting point 147° C. (decomposition) in the form of yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([OH:22])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].Br[CH2:24][C:25]([O:27][CH3:28])=[O:26].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH2:24][C:25]([O:27][CH3:28])=[O:26])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COC(=O)CBr
Reactant: COc1cc2c(Nc3ccc(Cl)c(Cl)c3)ncnc2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)COc1cc2ncnc(Nc3ccc(Cl)c(Cl)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 4-[(3,4-dichlorophenyl)amino]-6-(methyloxy)quinazolin-7-ol (3.67 g), methyl bromoacetate (0.81 mL), and potassium carbonate (4.66 g) in DMF (21 mL) was stirred at room temperature for 18 hours. The reaction mixture was diluted with ethyl acetate and filtered. The solid was combined with the filtrate and washed with water, dried over sodium sulfate and evaporated to give a brown solid which was recrystallized in methanol to give methyl {[4-[(3,4-dichlorophenyl)amino]-6-(methyloxy)quinazolin-7-yl]oxy}acetate (2.80 g). 1H-NMR (400 MHz; DMSO-d6): 9.62 (s, 1H), 8.46 (s, 1H), 8.24 (s, 1H), 7.94-7.85 (m, 2H), 7.63 (d, 1H), 7.17 (s, 1H), 5.04 (s, 2H), 4.00 (s, 3H), 3.72 (s, 3H); MS (EI) for C18H15N3O4Cl2: 408 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[C:9](=O)[CH2:8][S:7][CH2:6]1)=[O:4].[Cl:11][C:12]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:13]=1[NH2:14].C1(C)C=CC(S(O)(=O)=O)=CC=1.BrBr.S([O-])([O-])=O.[Na+].[Na+]>ClC(Cl)C.O>[CH3:1][O:2][C:3]([C:5]1[C:9]([NH:14][C:13]2[C:12]([Cl:11])=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:19])=[CH:8][S:7][CH:6]=1)=[O:4]
Reactant: Nc1c(Cl)cccc1Cl
Reactant: COC(=O)C1CSCC1=O
Agent: BrBr
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])[O-]
Solvent: O
Solvent: CC(Cl)Cl
Product: COC(=O)c1cscc1Nc1c(Cl)cccc1Cl
Reaction time: 0.08 h

Procedure:
15.9 g (0.1 mole) of 4-oxotetrahydro-3-thiophencarboxylic acid methyl ester, 17.5 g of 2,6-dichloroaniline and 200 mg of p-toluenesulfonic acid are heated in 500 ml of dichloroethane for six hours using a water separator. The solution is cooled to -25° and 52.5 g of bromine in 100 ml of dichloroethane are added dropwise. The mixture is stirred for a further 5 minutes; 100 ml of 10 percent strength (aq) sodium sulfite solution are added thereto, and the organic phase is separated off, washed with water and a sodium carbonate solution, dried and concentrated. Pure 4-(2,6-dichloroanilino)-3-thiophencarboxylic acid methyl ester is obtained after a bulb tube distillation (bp. 140°/10-2Pascal).
Reaction SMILES: Br[C:2]1[C:6]2[CH:7]=[N:8][C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:10][C:5]=2[N:4]([CH2:16][CH2:17][CH2:18][O:19][CH3:20])[CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH:27]1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCC[CH2:28]1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:20][O:19][CH2:18][CH2:17][CH2:16][N:4]1[C:5]2[CH:10]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:8]=[CH:7][C:6]=2[C:2]([CH:27]=[CH2:28])=[CH:3]1
Reactant: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Reactant: CCOC(=O)c1cc2c(cn1)c(Br)cn2CCCOC
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: C=Cc1cn(CCCOC)c2cc(C(=O)OCC)ncc12
Temperature: 100 °C
Reaction time: 1 h
Yield: 348.4 %

Procedure:
To a solution of ethyl 3-bromo-1-(3-methoxypropyl)-1H-pyrrolo[3,2-c]pyridine-6-carboxylate (200 mg) in 1,4-dioxane (2 mL) were added trivinylboroxine pyridine complex (141 mg), cesium carbonate (573 mg), 2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl (X-Phos) (56 mg) and tris(dibenzylideneacetone)dipalladium (27 mg) under argon, and the mixture was stirred at 100° C. for 1 hour. The reaction solution was cooled, and then thereto was washed with saturated saline, dried over sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=9/1→4/1) to give ethyl 1-(3-methoxypropyl)-3-vinyl-1H-pyrrolo[3,2-c]pyridine-6-carboxylate [REx(106-1)] (118 mg) as a yellow oil.
Reaction SMILES: C([N:4]1[C:8]([S:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[N:7][N:6]=[C:5]1[NH:23][C:24]([NH:26][C:27]1[C:32]([CH:33]([CH3:35])[CH3:34])=[CH:31][CH:30]=[CH:29][C:28]=1[CH:36]([CH3:38])[CH3:37])=[O:25])(=O)C>CO>[CH3:38][CH:36]([C:28]1[CH:29]=[CH:30][CH:31]=[C:32]([CH:33]([CH3:34])[CH3:35])[C:27]=1[NH:26][C:24]([NH:23][C:5]1[NH:4][C:8]([S:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[N:7][N:6]=1)=[O:25])[CH3:37]
Reactant: CCCCCCCCCCCCCSc1nnc(NC(=O)Nc2c(C(C)C)cccc2C(C)C)n1C(C)=O
Solvent: CO
Product: CCCCCCCCCCCCCSc1nnc(NC(=O)Nc2c(C(C)C)cccc2C(C)C)[nH]1
Reaction time: 8 h
Yield: 63.2 %

Procedure:
The urea of Example 14 (4.4 g, 0.0081 mol) was stirred in methanol (100 mL) at room temperature for 2 hours, the solution was then allowed to stand overnight. The solid obtained was filtered and dried in vacuo to give a white solid (2.57 g), m.p. 131°-135° C.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([NH:6][NH2:7])=[O:5].[C:12]1([N:18]=[C:19]=[O:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CO>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([NH:6][NH:7][C:19]([NH:18][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:20])=[O:5]
Reactant: O=C=Nc1ccccc1
Reactant: NNC(=O)c1ccccc1Br
Solvent: CO
Product: O=C(NNC(=O)c1ccccc1Br)Nc1ccccc1
Temperature: 25 °C
Yield: 48.1 %

Procedure:
To a solution of 2-bromobenzohydrazide (500 mg, 2.3 mmol) in methanol (5 mL) was added phenyl isocyanate (280 mg, 2.4 mmol) at room temperature, and then the mixture was refluxed for one hour. The reaction mixture was cooled to room temperature. The precipitated solid was filtered off and dried under a reduced pressure to give 370 mg (48%) of the titled compound as a colorless solid.
Reaction SMILES: [BH4-].[Na+].[C:3]([C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][C:8]=1[F:16])([CH3:6])([CH3:5])[CH3:4].O>CO>[C:3]([C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][C:8]=1[F:16])([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)c1ccc([N+](=O)[O-])cc1F
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(C)(C)c1ccc(N)cc1F
Reaction time: 0.03 h
Yield: 74 %

Procedure:
NaBH4 (144 mg, 152 μL, 3.8 mmol) was added to a solution of 1-tert-butyl-2-fluoro-4-nitro-benzene (750 mg, 3.8 mmol) and NiCl2.6H2O (2.6 g, 11 mmol) in methanol (15 mL) at −15° C. After addition, the mixture was stirred for 2 minutes and water was added to quench the reaction. The reaction mixture was extracted with ethyl acetate (50 mL×3). The combined organic layers were dried over anhydrous Na2SO4 and evaporated in vacuo to afford 4-tert-butyl-3-fluoro-aniline (470 mg, 74%) which was used without further purification. 1H NMR (300 MHz, CDCl3) δ 7.08-7.02 (m, 1H), 6.42-6.34 (m, 2H), 1.32 (s, 9H). MS (ESI) m/z: 168.2 [M+H]
Reaction SMILES: Cl.C(O)(=O)C.[Cl:6][C:7]1[C:8]([F:34])=[C:9]([F:33])[CH:10]=[C:11]2[C:16]=1[N:15]([C:17]1[C:22]([F:23])=[CH:21][C:20]([F:24])=[C:19]([O:25][CH3:26])[N:18]=1)[CH:14]=[C:13]([C:27]([O:29]CC)=[O:28])[C:12]2=[O:32]>O>[Cl:6][C:7]1[C:8]([F:34])=[C:9]([F:33])[CH:10]=[C:11]2[C:16]=1[N:15]([C:17]1[C:22]([F:23])=[CH:21][C:20]([F:24])=[C:19]([O:25][CH3:26])[N:18]=1)[CH:14]=[C:13]([C:27]([OH:29])=[O:28])[C:12]2=[O:32]
Reactant: CCOC(=O)c1cn(-c2nc(OC)c(F)cc2F)c2c(Cl)c(F)c(F)cc2c1=O
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: COc1nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Cl)c32)c(F)cc1F
Reaction time: 0.5 h
Yield: 82.5 %

Procedure:
To a mixed solution of 1 ml of 4N hydrochloric acid and 1 ml of acetic acid was added 385 mg of ethyl 8-chloro-1-(3,5-difluoro-6-methoxypyridin-2-yl)-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate, and the mixture heated under reflux with stirring for 30 minutes. After adding 2 ml of distilled water, the solution was allowed to cool and stand. The precipitate was collected by filtration, and washed with ethanol and diisopropylether successively to obtain 297 mg of the title compound as a colorless powder.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Cl:19][C:20]1[CH:28]=[C:27]2[C:23]([C:24]([NH:37][C:38](=[O:42])[CH2:39][CH2:40][CH3:41])=[N:25][N:26]2COCC[Si](C)(C)C)=[CH:22][C:21]=1[C:43]1[CH:48]=[CH:47][C:46]([CH2:49][CH3:50])=[CH:45][CH:44]=1.C(OCC)(=O)C>O1CCCC1>[Cl:19][C:20]1[CH:28]=[C:27]2[C:23]([C:24]([NH:37][C:38](=[O:42])[CH2:39][CH2:40][CH3:41])=[N:25][NH:26]2)=[CH:22][C:21]=1[C:43]1[CH:44]=[CH:45][C:46]([CH2:49][CH3:50])=[CH:47][CH:48]=1
Reactant: CCCC(=O)Nc1nn(COCC[Si](C)(C)C)c2cc(Cl)c(-c3ccc(CC)cc3)cc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCC(=O)Nc1n[nH]c2cc(Cl)c(-c3ccc(CC)cc3)cc12

Procedure:
14 cm3 of tetrabutylammonium fluoride as a 1M solution in tetrahydrofuran are added to 1.1 g of N-[6-chloro-5-(4-ethylphenyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indazol-3-yl]butanamide, described previously, in 50 cm3 of tetrahydrofuran. The medium is then refluxed for 18 hours and the mixture is then allowed to return to room temperature and 75 cm3 of ethyl acetate are added; the organic phase is washed with 2×100 cm3 of saturated aqueous sodium hydrogen carbonate solution and then with 75 cm3 of saturated aqueous sodium chloride solution. The organic phase is separated out after settling of the phases has taken place, dried over magnesium sulphate, filtered and evaporated to dryness under reduced pressure (2 kPa; 45° C.). The residue is purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-60 μm; diameter 3 cm), eluting with a cyclohexane/ethyl acetate mixture (70/30 by volume). The fractions containing the expected product are combined and evaporated under reduced pressure (2 kPa; 50° C.); the residue is taken up in 20 cm3 of diisopropyl ether, filtered off on a sinter funnel and washed with 2×10 cm3 of diisopropyl ether. After drying under reduced pressure (90 Pa; 50° C.), 440 mg of N-(6-chloro-5-phenyl-1H-indazol-3-yl)butanamide are obtained in the form of white crystals melting at 240° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](S(C)(=O)=O)[N:5]=[C:4]([NH:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[Cl:22])[CH:3]=1.[CH:23]([Mg]Br)=[CH2:24].O>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([CH:23]=[CH2:24])[N:5]=[C:4]([NH:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[Cl:22])[CH:3]=1
Reactant: CS(=O)(=O)c1nc(Cl)cc(NCCc2ccc(Cl)cc2Cl)n1
Reactant: C=C[Mg]Br
Solvent: O
Solvent: C1CCOC1
Product: C=Cc1nc(Cl)cc(NCCc2ccc(Cl)cc2Cl)n1
Reaction time: 0.5 h

Procedure:
A solution of (6-chloro-2-methanesulfonyl-pyrimidin-4-yl)-[2-(2,4-dichloro-phenyl)-ethyl]-amine (821 mg, 2.16 mmol) in THF (15 mL) is cooled to 0° C. A 1 M solution of vinyl magnesium bromide in THF (5.4 mL, 5.4 mmol) is added and the mixture is stirred for 30 minutes before adding water (30 mL) and extracted thrice with EtOAc (50 mL). The organic extracts are combined and dried over magnesium sulfate, filtered and evaporated. The residue is subjected to chromatography on silica gel eluting with 30% ethyl acetate:heptane to afford (6-chloro-2-vinyl-pyrimidin-4-yl)-[2-(2,4-dichloro-phenyl)-ethyl]-amine (600 mg) as a solid.
Reaction SMILES: C(OC([C@@H:8]([CH2:43][C:44]1[CH:49]=[CH:48][C:47]([C:50]([F:53])([F:52])[F:51])=[CH:46][CH:45]=1)[CH2:9][N:10]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[C:11]1[S:15][C:14]([C:16]2[CH:17]=[CH:18][C:19]([N+:33]([O-:35])=[O:34])=[C:20]([CH:22](C(OCC)=O)[C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:21]=2)=[N:13][N:12]=1)=O)(C)(C)C.[Cl-].[Li+].[OH2:56].CS(C)=O>[Cl-].[Na+].O.CCOC(C)=O>[C:39]([O:38][C:36]([N:10]([CH2:9][C@@H:8]([NH:10][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:56])[CH2:43][C:44]1[CH:45]=[CH:46][C:47]([C:50]([F:52])([F:53])[F:51])=[CH:48][CH:49]=1)[C:11]1[S:15][C:14]([C:16]2[CH:17]=[CH:18][C:19]([N+:33]([O-:35])=[O:34])=[C:20]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:21]=2)=[N:13][N:12]=1)=[O:37])([CH3:41])([CH3:42])[CH3:40]
Reactant: CCOC(=O)C(C(=O)OCC)c1cc(-c2nnc(N(C[C@H](Cc3ccc(C(F)(F)F)cc3)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)s2)ccc1[N+](=O)[O-]
Reactant: O
Agent: [Cl-]
Agent: [Li+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCOC(=O)Cc1cc(-c2nnc(N(C[C@H](Cc3ccc(C(F)(F)F)cc3)NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)s2)ccc1[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 3 h

Procedure:
To a 500 mL round bottom flask was added diethyl 2-(5-(5-((S)-2-(tert-butoxycarbonyl)-3-(4-(trifluoromethyl)phenyl)propyl-boc-amino)-1,3,4-thiadiazol-2-yl)-2-nitrophenyl)malonate (3.60 g, 4.60 mmol), lithium chloride (0.390 g, 9.21 mmol), distilled water (0.0830 g, 4.60 mmol) and 50 mL DMSO. The reaction mixture was heated to 100° C. and stirred at this temperature for 3 hours. LC-MS indicated the reaction was not complete. Another 4 equivalents of LiCl was added. The reaction mixture was stirred at 100° C. overnight. The reaction mixture was cooled to ambient temperature, and 200 mL EtOAc and 200 mL brine were added. The organic portion was separated. The aqueous portion was extracted with EtOAc. The combined organic portions were washed with brine and dried over sodium sulfate. The crude mixture (3.40 g) was used in the following reaction without further purification.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:28]=[CH:27][C:23]4[O:24][CH2:25][O:26][C:22]=4[CH:21]=3)=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.O.[OH-].[Na+]>C(Cl)Cl>[O:24]1[C:23]2[CH:27]=[CH:28][C:20]([C:17]3[CH:18]=[CH:19][C:14]([CH:11]4[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]4)=[N:15][CH:16]=3)=[CH:21][C:22]=2[O:26][CH2:25]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(-c3ccc4c(c3)OCO4)cn2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: c1cc(C2CCNCC2)ncc1-c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.7 %

Procedure:
5-1,3-Benzodioxol-5-yl-3′,4′,5′,6′-tetrahydro-2′H-2,4′-bipyridinyl-1′-carboxylic acid tert-butyl ester (0.250 g, 0.65 mmol) was dissolved in DCM (12 ml), TFA (3 ml) was added and the reaction mixture was stirred at room temperature for two hours. Water and 1 N NaOH was added, the DCM phase was washed and dried with Na2SO4. Evaporation afforded 150 mg white crystalline compound (81%).
Reaction SMILES: B(Cl)(Cl)Cl.C([O:12][CH2:13][CH2:14][N:15]([C:22]1[CH:27]=[C:26]([CH3:28])[C:25]([Br:29])=[C:24]([CH3:30])[CH:23]=1)[C:16]([NH:18][CH2:19][CH2:20][OH:21])=[O:17])C1C=CC=CC=1.C(=O)(O)[O-].[Na+]>ClCCl>[Br:29][C:25]1[C:24]([CH3:30])=[CH:23][C:22]([N:15]([CH2:14][CH2:13][OH:12])[C:16]([NH:18][CH2:19][CH2:20][OH:21])=[O:17])=[CH:27][C:26]=1[CH3:28]
Reactant: Cc1cc(N(CCOCc2ccccc2)C(=O)NCCO)cc(C)c1Br
Agent: ClB(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cc(N(CCO)C(=O)NCCO)cc(C)c1Br
Reaction time: 2 h
Yield: 84 %

Procedure:
Boron trichloride (0.93 ml, 0.93 mmol, 1.0 M solution in dichloromethane) was added to a solution of 1-(2-(benzyloxy)ethyl)-1-(4-bromo-3,5-dimethylphenyl)-3-(2-hydroxyethyl)urea (98 mg, 0.23 mmol) in anhydrous dichloromethane (4.6 ml) at −78° C., and the mixture was stirred at the same temperature for two hours. A saturated aqueous sodium bicarbonate solution was added to the reaction mixture, followed by extraction with ethyl acetate. The organic phase was sequentially washed with water and saturated brine and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (dichloromethane-methanol) to give 1-(4-bromo-3,5-dimethylphenyl)-1,3-bis(2-hydroxyethyl)urea (64 mg, 83%).
Reaction SMILES: [CH:1](NN=NC1C=CC(C)=CC=1)([CH3:3])[CH3:2].[OH:14][C@@H:15]1[CH2:19][C:18](=[O:20])[C@H:17]([S:21][CH2:22][CH2:23][CH2:24][S:25][CH2:26][C:27]([OH:29])=[O:28])[C@H:16]1/[CH:30]=[CH:31]/[C@@H:32]([OH:38])[CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]>CC(C)=O>[CH:1]([O:28][C:27](=[O:29])[CH2:26][S:25][CH2:24][CH2:23][CH2:22][S:21][C@H:17]1[C:18](=[O:20])[CH2:19][C@@H:15]([OH:14])[C@@H:16]1/[CH:30]=[CH:31]/[C@@H:32]([OH:38])[CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])([CH3:3])[CH3:2]
Reactant: CCCCC[C@H](O)/C=C/[C@H]1[C@H](O)CC(=O)[C@@H]1SCCCSCC(=O)O
Reactant: Cc1ccc(N=NNC(C)C)cc1
Solvent: CC(C)=O
Product: CCCCC[C@H](O)/C=C/[C@H]1[C@H](O)CC(=O)[C@@H]1SCCCSCC(=O)OC(C)C
Reaction time: 1 h
Yield: 38 %

Procedure:
Isopropyl-p-tolyltriazene (200 μL) was added dropwise to a solution of carboxylic acid 9 (10.5 mg, 0.026 mmol) in acetone (5.0 mL) at 23° C. After stirring for 1 h the reaction was quenched with 1N HCl and the solvent was removed in vacuo. The residue was extracted with CH2Cl2 (2×). The combined organics were dried (Na2SO4), filtered and concentrated in vacuo. Purification of the residue by flash column chromatography (silica gel, 4:1 hex/EtOAc) gave 4.3 mg (38%) of the above titled compound.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=[O:7])=O.[F:12][C:13]1[CH:14]=[C:15]([NH2:20])[C:16]([NH2:19])=[CH:17][CH:18]=1>C(O)C>[F:12][C:13]1[CH:18]=[CH:17][C:16]2[NH:19][C:1]([C:3]3[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=3)[C:6]([OH:8])=[O:7])=[N:20][C:15]=2[CH:14]=1
Reactant: O=Cc1cccc(C(=O)O)c1
Reactant: Nc1ccc(F)cc1N
Solvent: CCO
Product: O=C(O)c1cccc(-c2nc3cc(F)ccc3[nH]2)c1
Temperature: 25 °C
Yield: 36.4 %

Procedure:
A mixture of 3-formylbenzoic acid (500 mg, 3.33 mmol) and 4-fluorobenzene-1,2-diamine (420 mg, 3.33 mmol) in ethanol (10 mL) was refluxed for 5 hours. After cooling to room temperature, the precipitate was collected by filtration and dried to give 311 mg (36%) of the title compound as a brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([NH:8][CH:9]([C:16]([C:18]2[CH:22]=[CH:21][S:20][CH:19]=2)=[O:17])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=O)=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)=O>CN(C)C=O>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]2[O:17][C:16]([C:18]3[CH:22]=[CH:21][S:20][CH:19]=3)=[C:9]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:8]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC(NC(=O)c1ccc(Cl)cc1)C(=O)c1ccsc1
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(=O)Cc1nc(-c2ccc(Cl)cc2)oc1-c1ccsc1
Yield: 78.3 %

Procedure:
9.0 g of ethyl 3-(4-chlorobenzoylamino)-3-(3-thienylcarbonyl)propionate, 50 ml of dimethylformamide and 5.3 g of phosphorus oxychloride are treated in the same manner as described in Example 1. 6.7 g of ethyl 2-[2-(4-chlorophenyl)-5-(3-thienyl)-4-oxazolyl]acetate are thereby obtained.