Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1F)[C:5]#[N:6].[CH3:11][NH2:12].O>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[NH:12][CH3:11])[C:5]#[N:6]
Reactant: CN
Reactant: N#Cc1ccc(F)c(Cl)c1
Solvent: C1CCOC1
Solvent: O
Product: CNc1ccc(C#N)cc1Cl
Temperature: 65 °C
Yield: 95 %

Procedure:
A mixture of 3-chloro-4-fluorobenzonitrile (5.2 g, 33 mmol), THF (55 mL), and 40% methylamine in water (25 mL, 290 mmol) in a sealed tube was heated to 65° C. for 1.5 hours, cooled to room temperature. The organic phase was washed with brine, dried (Na2SO4), filtered, and concentrated. The resulting solid was dried for about 16 hours under high vacuum in the presence of P2O5 to provide 6.3 g (95%) of the desired product. MS (DCI/NH3) m/z 184, 186 (M+H+NH3)+; 1H NMR (DMSO-d6) δ 7.72 (d, 1H), 7.55 (dd, 1H), 6.70 (d, 1H), 6.52 (br q, 1H), 2.80 (d, 3H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C:5]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:9]=[C:8]([C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=2[F:17])[CH2:7][N:6]1[C:18]([N:20]([CH3:22])[CH3:21])=[O:19].C(N(CC)CC)C.Cl[C:37]([O:39][CH3:40])=[O:38]>C(Cl)Cl>[Cl:16][C:14]1[CH:13]=[CH:12][C:11]([F:17])=[C:10]([C:8]2[CH2:7][N:6]([C:18]([N:20]([CH3:22])[CH3:21])=[O:19])[C:5]([CH2:4][CH2:3][CH2:2][NH:1][C:37](=[O:38])[O:39][CH3:40])([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:9]=2)[CH:15]=1
Reactant: CN(C)C(=O)N1CC(c2cc(Cl)ccc2F)=CC1(CCCN)c1ccccc1
Reactant: COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)NCCCC1(c2ccccc2)C=C(c2cc(Cl)ccc2F)CN1C(=O)N(C)C
Reaction time: 8 h

Procedure:
To 20 mg (0.05 mmol) of amine 20-2 in CH2Cl2 was added 21 μL (0.15 mmol) of triethylamine and 5.8 μL (0.10 mmol) of methyl chloroformate. After stirring overnight the reaction was partitioned between EtOAc and 10% KHSO4, the organic phase was washed with saturated NaHCO3, brine, dried over MgSO4, and concentrated by rotary evaporation. The residue was purified by column chromatography on silica gel with EtOAc/hexanes to provide 22-1 as a white solid. Data for 22-1: 1HNMR (500 MHz, d6-DMSO) δ 7.6 (m, 1H), 7.5-7.1 (m, 8H), 6.2 (s, 1H), 4.95 (m, 1H), 4.7 (m, 1H), 3.55 (s, 3H), 3.0 (m, 2H), 2.7 (s, 6H), 2.7-2.5 (m, 1H), 2.05 (m, 1H), 1.4 (m, 2H) ppm. HRMS (ES) calc'd M+H for C24H27ClFN3O3: 460.1798. Found: 460.1797.
Reaction SMILES: [ClH:1].C(OC(=O)[NH:8][C:9]1[S:13][C:12]2[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=2[C:10]=1[CH3:18])(C)(C)C>O1CCOCC1>[ClH:1].[CH3:18][C:10]1[C:11]2[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=2[S:13][C:9]=1[NH2:8]
Reactant: Cc1c(NC(=O)OC(C)(C)C)sc2ccccc12
Agent: Cl
Solvent: C1COCCO1
Product: Cc1c(N)sc2ccccc12
Temperature: 22 °C
Reaction time: 18 h

Procedure:
A 5-L 3-neck flask equipped with an overhead mechanical stirrer, N2 inlet/outlet adapter, and thermocouple was charged with 4M HCl in 1,4-dioxane (3.1 L), tert-butyl-3-methylbenzo[b]thiophen-2-ylcarbamate (265 g, 1.0 mol) and stirred for 18 h at 22° C. The resulting white precipitate was collected by filtration, washed with diethyl ether (3×500 mL), and dried under house vacuum at 40° C. for 48 h to yield 3-methylbenzo[b]thiophen-2-amine hydrochloride as a white solid. 1H-NMR (DMSO-d6) δ 8.7 (br s, 3H), 7.71 (d, 1H), 7.44 (d, 1H), 7.29 (t, 1H), 7.14 (t, 1H), 2.184 (s, 3H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH:4]1[S:8][C:7]([C:9]2[NH:10][C:11]3[C:16]([CH:17]=2)=[CH:15][CH:14]=[CH:13][C:12]=3[N:18]([CH3:27])[S:19]([C:22]2[S:23][CH:24]=[CH:25][CH:26]=2)(=[O:21])=[O:20])=[N:6][CH2:5]1.C(=O)([O-])[O-].[K+].[K+].[SH:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37]>CN(C)C=O.C(OCC)(=O)C>[CH2:39]([O:38][C:36](=[O:37])[CH2:35][S:34][CH2:2][CH2:3][CH:4]1[S:8][C:7]([C:9]2[NH:10][C:11]3[C:16]([CH:17]=2)=[CH:15][CH:14]=[CH:13][C:12]=3[N:18]([CH3:27])[S:19]([C:22]2[S:23][CH:24]=[CH:25][CH:26]=2)(=[O:21])=[O:20])=[N:6][CH2:5]1)[CH3:40]
Reactant: CN(c1cccc2cc(C3=NCC(CCCl)S3)[nH]c12)S(=O)(=O)c1cccs1
Reactant: CCOC(=O)CS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)CSCCC1CN=C(c2cc3cccc(N(C)S(=O)(=O)c4cccs4)c3[nH]2)S1
Temperature: 50 °C
Reaction time: 8 h
Yield: 50 %

Procedure:
To a solution of N-{2-[5-(2-chloroethyl)-4,5-dihydro-1,3-thiazol-2-yl]-1H-indol-7-yl}-N-methylthiophene-2-sulfonamide (100 mg) in N,N-dimethylformamide (3 mL) were added potassium carbonate (65 mg) and ethyl mercaptoacetate (50 μL), and the mixture was stirred overnight at 50° C. Potassium carbonate (20 mg) was added to the reaction mixture, and the mixture was stirred at 50° C. for 3 hr, and cooled to room temperature. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to give the title compound (60 mg, yield 50%) as a colorless amorphous solid from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio). MS:524(MH+).
Reaction SMILES: [N:1]1([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=O.Cl.[NH2:20][NH:21][C:22]([NH2:24])=[O:23].C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1>CN(C=O)C.C(N(CC)CC)C>[N:1]1([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([NH:20][NH:21][C:22]([NH2:24])=[O:23])=[O:5]
Reactant: NNC(N)=O
Reactant: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: NC(=O)NNC(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1

Procedure:
To a solution of Cbz-Pro (1.25 g), semicarbazide hydrochloride (5.5 g), and HOBt (6.75 g) in DMF (100 mL) is added triethylamine (7.5 mL) and DCC (10.5 g) at 0° C. with stirring. The reaction is stirred at 0° C. for 24 hours. The precipitate is filtered and the filtrate is concentrated in vacuo. The residue is triturated with saturated NaHCO3 solution, filtered, washed with water and dried to give Cbz-Pro-azaGlyNH2. Cbz-Pro-azaGlyNH2 (10 g) is catalytically hydrogenated in (1:1) methanol/DMF at pH 4.5 in the presence of Pd catalyst. At the end of the hydrogenation the catalyst is filtered and the filtrate is concentrated in vacuo to give H-Pro-azaGlyNH2.HCl. To a solution of H-Pro-azaGlyNH2.HCl (2.08 g), HOBt (1.63 g), and Boc-Lys(N,N-epsilon-isopropyl,Cbz)-OH (1.26 g) in DMF (40 mL), DCC (2.1 g) is added with stirring at 0° C. for 2 hours and then at 4° C. for 24 hours. After workup and trituration with ether Boc-Lys(N,N-epsilon-isopropyl,Cbz)-Pro-azaGlyNH2 is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([C:8]2[CH:19]=[C:18]([Cl:20])[C:11]3[O:12][CH:13]([C:15]([OH:17])=[O:16])[CH2:14][C:10]=3[C:9]=2[Cl:21])=O)=[CH:4][CH:3]=1.Cl.[NH2:25][OH:26]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([C:8]2[CH:19]=[C:18]([Cl:20])[C:11]3[O:12][CH:13]([C:15]([OH:17])=[O:16])[CH2:14][C:10]=3[C:9]=2[Cl:21])=[N:25][OH:26])=[CH:4][CH:3]=1
Reactant: NO
Reactant: O=C(c1ccc(Cl)cc1)c1cc(Cl)c2c(c1Cl)CC(C(=O)O)O2
Agent: Cl
Solvent: c1ccncc1
Product: O=C(O)C1Cc2c(Cl)c(C(=NO)c3ccc(Cl)cc3)cc(Cl)c2O1
Yield: 97.9 %

Procedure:
A mixture of 5-(4-chlorobenzoyl)-4,7-dichloro-2,3-dihydrobenzo[b]furan-2-carboxylic acid (10.8 g), hydroxylamine hydrochloride (20.7 g) and pyridine (100 ml) was refluxed for 13 hours. After distilling off the solvent, water was added to the mixture which then was rendered acidic with HCl and subjected to extraction with ether. The ether layer was washed with water and dried. By distilling off the solvent, 11.0 g of 5-(4-chloro-α-hydroxyiminobenzyl)4,7-dichloro-2,3-dihydrobenzo[b]furan-2-carboxylic acid was obtained. This compound (11 g) was dissolved in anhydrous dimethylformamide (140 ml), and to the ice-cooled solution, 4.0 g of 60% sodium hydride was added in small portions under agitation. After continuing the agitation for 5 hours at room temperature, the mixture was left to stand overnight. Water was added to the mixture, which then was rendered acidic with HCl and subjected to extraction with ether. The ether layer was washed with water and dried. After distilling off the solvent, the residue was recrystallized from acetone-water, yielding 6.5 g of 5-chloro-3-(4-chlorophenyl)-7,8-dihydrofuro[2,3-g]-1,2-benzisoxazole-7-carboxylic acid. m.p. 240°-243° C. (with decomposition). This compound exhibited a mass spectrum having a molecular ion peak at m/e 349.
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:10]=[CH:9][C:8]([C@H:11]([NH2:13])[CH3:12])=[CH:7][CH:6]=1)([O-:4])=[O:3].[C:14](=[O:17])(O)[O-:15].[Na+]>C(Cl)Cl>[N+:2]([C:5]1[CH:6]=[CH:7][C:8]([C@H:11]([NH:13][C:14](=[O:17])[O:15][C:8]([CH3:11])([CH3:9])[CH3:7])[CH3:12])=[CH:9][CH:10]=1)([O-:4])=[O:3]
Reactant: C[C@@H](N)c1ccc([N+](=O)[O-])cc1
Reactant: O=C([O-])O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Product: C[C@@H](NC(=O)OC(C)(C)C)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
(R)-1-(4-nitrophenyl)ethanamine hydrochloride salt (1.0 g, 4.9 mmol), tert-butoxycarbonyl (BOC) anhydride (1.18 g, 5.43 mmol), and 10.0 mL of 1M sodium bicarbonate solution were dissolved in DCM (15 mL) and allowed to stir at 25° C. for 24 h. The organic layer was collected, and the aqueous layer was washed with DCM. The combined organic layers were then washed with water and 0.1 N HCl, dried over MgSO4, filtered, and concentrated to provide C1 as a white solid. Yield: 1.2 g, 92%. GC-MS=266. 1H NMR (500 MHz, d6-DMSO) δ: 8.15 (d, 2H), 7.56 (d, 1H), 7.52 (d, 2H), 4.68 (m, 1H), 1.32 (s, 9H), 1.27 (d, 3H).
Reaction SMILES: [CH3:1][Si:2]([CH3:11])([CH3:10])[C:3]1[O:7][CH:6]=[C:5]([CH:8]=[O:9])[CH:4]=1.B(F)(F)F.CCOCC.[CH3:21][C:22]([CH:29]=[CH2:30])=[CH:23][O:24][Si](C)(C)C>C(Cl)Cl>[OH:9][CH:8]([C:5]1[CH:4]=[C:3]([Si:2]([CH3:11])([CH3:10])[CH3:1])[O:7][CH:6]=1)[CH2:30][CH:29]=[C:22]([CH3:21])[CH:23]=[O:24]
Reactant: C=CC(C)=CO[Si](C)(C)C
Reactant: C[Si](C)(C)c1cc(C=O)co1
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: CC(C=O)=CCC(O)c1coc([Si](C)(C)C)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 5-trimethylsilyl-3-furaldehyde (0.382 g., 2.27 mmol) in dry methylene chloride (15 ml) at -50° under argon was added dropwise boron trifloride etherate (0.28 ml, 2.3 mmol). This addition was followed by the dropwise addition of 2-methyl-1-trimethylsilyloxy-1,3-butadiene (0.356 g., 2.3 mmol). The solution was stirred at -50° to -60° for 18 hours, quenched by the addition of several ml saturated sodium bicarbonate solution, warmed to room temperature and poured into methylene chloride. The organic portion was washed once with saturated bicarbonate solution, once with water, once with saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated to give a yellow oil which consisted of several components by TLC. The mixture was applied to a chromatography column (silica) and eluted with 30% ethyl acetate/hexane. Eluted last was the desired alcohol, which was concentrated to give a yellow gum.
Reaction SMILES: [CH3:1][S:2]([N:5]([S:7]([NH2:10])(=[O:9])=[O:8])[CH3:6])(=[O:4])=[O:3].[CH3:11][O:12][C:13]1[CH:18]=[C:17]([O:19][CH3:20])[N:16]=[C:15]([NH:21][C:22](=O)[O:23]C2C=CC=CC=2)[N:14]=1>C(#N)C>[CH3:1][S:2]([N:5]([S:7]([NH:10][C:22]([NH:21][C:15]1[N:14]=[C:13]([O:12][CH3:11])[CH:18]=[C:17]([O:19][CH3:20])[N:16]=1)=[O:23])(=[O:9])=[O:8])[CH3:6])(=[O:4])=[O:3]
Reactant: COc1cc(OC)nc(NC(=O)Oc2ccccc2)n1
Reactant: CN(S(C)(=O)=O)S(N)(=O)=O
Solvent: CC#N
Product: COc1cc(OC)nc(NC(=O)NS(=O)(=O)N(C)S(C)(=O)=O)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 98.4 %

Procedure:
37.6 g of (N-methylsulfonyl-N-methylamino)sulfonamide are dissolved in 500 ml of acetonitrile, 55.0 g of phenyl 4,6-dimethoxy-2-pyrimidylcarbamate are added dropwise at room temperature, and the mixture is stirred for 18 hours at room temperature. Approx. 400 ml of acetonitrile are distilled off, and then 200 ml of water are added at 0° C., and the mixture is brought to pH 2-3 using 2N HCl. The product which has precipitated is filtered off with suction and washed with water. 72.6 g of the desired product of a purity of 98.4% are obtained, which corresponds to a yield of 96.8% of theory. The melting point of the product is 185-186° C.
Reaction SMILES: [C:1]([N:4]1[C:8]([CH3:9])=[C:7]([C:10](=[O:19])[C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[N:6]([C:20](=[O:22])[CH3:21])[C:5]1=[O:23])(=[O:3])[CH3:2].[Br:24]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:24][CH2:9][C:8]1[N:4]([C:1](=[O:3])[CH3:2])[C:5](=[O:23])[N:6]([C:20](=[O:22])[CH3:21])[C:7]=1[C:10](=[O:19])[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccc(C(=O)c2c(C)n(C(C)=O)c(=O)n2C(C)=O)cc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COc1ccc(C(=O)c2c(CBr)n(C(C)=O)c(=O)n2C(C)=O)cc1

Procedure:
A mixture of 55.5 g (0.176 mole) of 1,3-diacetyl-1,3-dihydro-4-(4-methoxybenzoyl)-5-methyl-2H-imidazol-2-one, 37.4 g (0.210 mole) of N-bromosuccinimide and about 100 mg of benzoyl peroxide in 500 ml of carbon tetrachloride is stirred at reflux temperature for 4 hours. The mixture is then cooled and filtered to remove the succinimide which formed. The solvent is evaporated from the filtrate and the resulting residue is crystallized from a mixture of 300 ml of ethyl acetate and 300 ml of hexane to give 5-(bromomethyl)-1,3-diacetyl-1,3-dihydro-4-(4-methoxybenzoyl)-2H-imidazol-2-one melting at about 135°-136° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)[CH:5]=[CH:6][CH:7]=1.Cl[CH2:17][C:18]1[N:19]=[C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[S:21][CH:22]=1>>[N:11]1([CH2:10][CH2:9][CH2:8][C:4]2[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=2)[O:1][CH2:17][C:18]2[N:19]=[C:20]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[S:21][CH:22]=2)[CH:15]=[CH:14][N:13]=[CH:12]1
Reactant: ClCc1csc(-c2ccccc2)n1
Reactant: Oc1cccc(CCCn2ccnc2)c1
Product: c1ccc(-c2nc(COc3cccc(CCCn4ccnc4)c3)cs2)cc1
Yield: 81 %

Procedure:
In substantially the same manner as in Working Example 72, 1-[3-(3-hydroxyphenyl)propyl]imidazole was allowed to react with 4-chloromethyl-2-phenylthiazole to give 4-[3-[3-(1-imidazolyl)propyl]phenoxymethyl]-2-phenylthiazole. The yield was 81%. Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 63-64° C.
Reaction SMILES: [CH:1]1([Mg]Br)[CH2:3][CH2:2]1.[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([CH:28]=[O:29])=[C:11]2[C:15]=1[N:14]=[C:13]1[N:16]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=3[Cl:27])[CH2:17][CH2:18][CH2:19][N:12]21>O1CCCC1>[Cl:6][C:7]1[C:15]2[N:14]=[C:13]3[N:16]([C:20]4[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=4[Cl:27])[CH2:17][CH2:18][CH2:19][N:12]3[C:11]=2[C:10]([CH:28]([CH:1]2[CH2:3][CH2:2]2)[OH:29])=[CH:9][CH:8]=1
Reactant: O=Cc1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Reactant: Br[Mg]C1CC1
Solvent: C1CCOC1
Product: OC(c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl)C1CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 77.6 %

Procedure:
Cyclopropylmagnesium bromide (1.0 M solution in tetrahydrofuran, 2.9 mL, 2.9 mmol) was added to a stirred solution of 9-chloro-1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole-6-carbaldehyde (1.00 g, 2.63 mmol) in tetrahydrofuran (13 mL) at 0° C., and the mixture was stirred at 0° C. for 1 hr. The reaction was quenched by aqueous saturated ammonium chloride, and the mixture was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue was recrystallized from ethanol to give the title compound as a colorless crystal (863 mg, 2.04 mmol, 78%).
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[C:4]([CH3:15])[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.O>CN(C=O)C>[CH2:22]([O:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[C:4]([CH3:15])[CH:3]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Cc1cc(O)n(-c2cc(C#N)ccn2)n1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(OCc2ccccc2)n(-c2cc(C#N)ccn2)n1
Temperature: 0 °C
Reaction time: 3 h
Yield: 4.6 %

Procedure:
To a solution of 2-(5-hydroxy-3-methyl-1H-pyrazol-1-yl)pyridine-4-carbonitrile (300 mg, 1.5 mmol) and K2CO3 (518 mg, 3.75 mmol) in DMF was added benzyl bromide (308 mg, 1.8 mmol) dropwise at −20° C., then the mixture was warmed to 0° C. and stirred for 3 h. Water was added, and the reaction mixture was extracted with EtOAc, then washed with water and brine. The organic phase was dried, concentrated, and purified by prep-HPLC to afford the title compound (20 mg). [M+H] calc'd for C17H14N4O 291; Found, 291.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:16]=[C:15]3[C:11]([C:12]([C:17]4[NH:18][C:19]5[CH2:24][CH2:23][NH:22][CH2:21][C:20]=5[N:25]=4)=[N:13][NH:14]3)=[CH:10][CH:9]=2)[C:5]([CH2:26][C:27]([F:30])([F:29])[F:28])=[CH:4][C:3]=1[OH:31].[CH3:32][O:33][C:34]1[CH:35]=[C:36]([CH:39]=[CH:40][CH:41]=1)[CH:37]=O>>[F:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:16]=[C:15]3[C:11]([C:12]([C:17]4[NH:18][C:19]5[CH2:24][CH2:23][N:22]([CH2:37][C:36]6[CH:39]=[CH:40][CH:41]=[C:34]([O:33][CH3:32])[CH:35]=6)[CH2:21][C:20]=5[N:25]=4)=[N:13][NH:14]3)=[CH:10][CH:9]=2)[C:5]([CH2:26][C:27]([F:28])([F:29])[F:30])=[CH:4][C:3]=1[OH:31]
Reactant: COc1cccc(C=O)c1
Reactant: Oc1cc(CC(F)(F)F)c(-c2ccc3c(-c4nc5c([nH]4)CCNC5)n[nH]c3c2)cc1F
Product: COc1cccc(CN2CCc3[nH]c(-c4n[nH]c5cc(-c6cc(F)c(O)cc6CC(F)(F)F)ccc45)nc3C2)c1

Procedure:
The title compound was prepared from 2-fluoro-4-[3-(4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-yl)-1H-indazol-6-yl]-5-(2,2,2-trifluoro-ethyl)-phenol (100 mg, 0.21 mmol) and 3-methoxybenzaldehyde (63.1 mg, 0.46 mmol) using the method of Example 51. The crude material was purified initially over silica and finally by Prep TLC (Mobile Phase: 10% MeOH-DCM) to afford the title compound as an off white solid in 21.2% yield, 25 mg.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[NH:12][C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)[C:5]([O:7][CH3:8])=[O:6].[CH:20](OC)(OC)OC.O>CN(C=O)C>[F:19][C:16]1[CH:17]=[CH:18][C:13]([N:12]2[C:11]3[CH:10]=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:3][C:2]=3[N:1]=[CH:20]2)=[CH:14][CH:15]=1
Reactant: COC(OC)OC
Reactant: COC(=O)c1ccc(Nc2ccc(F)cc2)c(N)c1
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc2c(c1)ncn2-c1ccc(F)cc1
Temperature: 25 °C

Procedure:
A mixture of 60d (0.18 g, 0.693 mmol) and trimethyl orthoformate (0.7 mL, 6.39 mmol) in DMF (2 mL) was refluxed for 5 h and then cooled to room temperature. Water was added to the mixture. The resulting solid was filtered, washed, with water, and dried. The crude product 60e was used in the next reaction without purification. MS m/z (M+H+) 271.1.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7](B2OC(C)(C)C(C)(C)O2)=[CH:8][C:9]=1[O:10][CH:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[Cl:19])[CH3:12])=[O:4].Br[C:30]1[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=1.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.CCO.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:30]2[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=2)=[CH:8][C:9]=1[O:10][CH:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[Cl:19])[CH3:12])=[O:4]
Reactant: COC(=O)c1sc(B2OC(C)(C)C(C)(C)O2)cc1OC(C)c1ccccc1Cl
Reactant: Brc1cccnc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: COC(=O)c1sc(-c2cccnc2)cc1OC(C)c1ccccc1Cl

Procedure:
3-[1-(2-Chloro-phenyl)-ethoxy]-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-thiophene-2-carboxylic acid methyl ester (150 mg, 0.37 mmol, 1.0 Eq.), 3-bromopyridine (69 mg, 0.44 mmol, 1.2 Eq.) and Pd(PPh3)4 (42 mg, 0.04 mmol, 0.1 Eq.) were dissolved in toluene (1.6 mL) and EtOH (0.4 mL). 2M K2CO3 (0.55 mL, 1.10 mmol, 3.0 Eq) and the reaction heated under microwave conditions at 140° C. for 15 minutes. The reaction was partitioned between EtOAc (10 mL) and water (10 mL) and the aqueous phase extracted with EtOAc (3×10 mL). The combined organic layers were dried (MgSO4) and concentrated in vacuo. The crude product was purified by column chromatography (ISCO Companion™, 12 g column, 0-100% EtOAc/petroleum Ether) to give the sub-title compound as am off-white solid (58 mg, 0.16 mmol, 42%); 1H NMR (400 MHz, CDCl3) δ 1.74 (3H, d), 3.93 (3H, s), 5.87 (1H, q), 6.93 (1H, s), 7.25-7.41 (4H, m), 7.68 (1H, dd), 7.72 (1H, dd), 8.58 (1H, dd), 8.78 (1H, d).
Reaction SMILES: [NH:1]1[C:8](=[O:9])[CH2:7][C:5](=[O:6])[NH:4][C:2]1=[O:3].[OH:10][C:11]1[CH:12]=[C:13]([CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[C:18]=1[OH:19])[CH:14]=O.S(Cl)(Cl)=O>CC(O)C>[OH:10][C:11]1[CH:12]=[C:13]([CH:14]=[C:7]2[C:5](=[O:6])[NH:4][C:2](=[O:3])[NH:1][C:8]2=[O:9])[CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[C:18]=1[OH:19]
Reactant: O=Cc1cc(O)c(O)c([N+](=O)[O-])c1
Reactant: O=C1CC(=O)NC(=O)N1
Solvent: O=S(Cl)Cl
Solvent: CC(C)O
Product: O=C1NC(=O)C(=Cc2cc(O)c(O)c([N+](=O)[O-])c2)C(=O)N1
Temperature: 25 °C
Reaction time: 100 h

Procedure:
To a solution containing 1.28 g (0.01 mol) of barbituric acid and 1.83 g (0.01 mol) of 3,4-dihydroxy-5-nitrobenzaldehyde in 20 ml of 2-propanol was gradually added 5.0 ml of thionyl chloride. The mixture was stirred for 100 h at room temperature. The product was filtered, washed with 2-propanol and recrystallized from acetic acid. Yield 1.28 g (44%), mp 269°-272° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:10])=[C:4]([CH:6]=[CH:7][C:8]=1[F:9])[NH2:5].Cl.Cl[C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:37][CH3:38])=[C:20]([O:23][CH:24]3[CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][CH2:25]3)[CH:21]=2)[N:16]=[CH:15][N:14]=1>C(O)(C)C>[Cl:1][C:2]1[C:3]([F:10])=[C:4]([CH:6]=[CH:7][C:8]=1[F:9])[NH:5][C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:37][CH3:38])=[C:20]([O:23][CH:24]3[CH2:25][CH2:26][NH:27][CH2:28][CH2:29]3)[CH:21]=2)[N:16]=[CH:15][N:14]=1
Reactant: COc1cc2ncnc(Cl)c2cc1OC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: Nc1ccc(F)c(Cl)c1F
Agent: Cl
Solvent: CC(C)O
Product: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3F)c2cc1OC1CCNCC1
Temperature: 80 °C
Reaction time: 3 h
Yield: 85.4 %

Procedure:
3-Chloro-2,4-difluoroaniline (1.7 g, 10.1 mmol) and 5N hydrogen chloride in isopropanol (2 ml) were added to a suspension of tert-butyl 4-[(4-chloro-7-methoxyquinazolin-6-yl)oxy]piperidine-1-carboxylate (4 g, 10.1 mmol, PCT Int. Appl. WO2003082831, AstraZeneca) in isopropanol (50 ml). The mixture was stirred at 80° C. for 3 hours. After evaporation of the solvents, the residue was purified by chromatography on silica gel (eluant: 5-10% 7N methanolic ammonia in dichloromethane) to give 4-(3-chloro-2,4-difluoroanilino)-7-methoxy-6-[(piperidin-4-yl)oxy]quinazoline (3.63 g, 85%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[CH:11]1[C:19]2[N:14]([CH:15]=[CH:16][C:17](=O)[CH:18]=2)[CH2:13][CH:12]=1>>[CH2:11]1[CH:19]2[N:14]([CH2:15][CH:16]=[C:17]([C:5]3[C:4]4[C:8](=[CH:9][CH:10]=[C:2]([Cl:1])[CH:3]=4)[NH:7][CH:6]=3)[CH2:18]2)[CH2:13][CH2:12]1
Reactant: Clc1ccc2[nH]ccc2c1
Reactant: O=c1ccn2c(c1)C=CC2
Product: Clc1ccc2[nH]cc(C3=CCN4CCCC4C3)c2c1

Procedure:
The 5-chloro-1H-indole (1.00 g, 6.63 mmol) and 7-indolizinone (1.39 g, 9.95 mmol) were converted to product by the procedure of Example 2 to give 595 mg. (33.1%).
Reaction SMILES: [C:1]([CH2:3][CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1)#[N:2].[NH2:17][OH:18]>C(O)C>[NH2:2][C:1](=[N:17][OH:18])[CH2:3][CH:4]1[CH2:5][CH2:6][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:8][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(CC#N)CC1
Reactant: NO
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(CC(N)=NO)CC1

Procedure:
tert-Butyl 4-(cyanomethyl)piperidine-1-carboxylate (91 mmol) was dissolved in ethanol (200 mL), and an aqueous hydroxylamine solution (50%, 17 mL, 170 mmol) was added, followed by heating to reflux for 3.5 hours. The reaction solution was cooled, and subsequently concentrated under reduced pressure to afford tert-butyl 4-[2-amino-2-(hydroxyimino)ethyl]piperidine-1-carboxylate as a colorless amorphous solid.