Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([S:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[C:12]=2[F:19])[N:3]=1.[CH3:20][S:21]([NH2:24])(=[O:23])=[O:22].[H-].[Na+].[CH3:27][Si:28]([CH3:35])([CH3:34])[CH2:29][CH2:30][O:31][CH2:32]Cl>>[Cl:8][C:6]1[N:5]=[C:4]([S:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[C:12]=2[F:19])[N:3]=[C:2]([N:24]([CH2:32][O:31][CH2:30][CH2:29][Si:28]([CH3:35])([CH3:34])[CH3:27])[S:21]([CH3:20])(=[O:23])=[O:22])[CH:7]=1
Reactant: CS(N)(=O)=O
Reactant: COc1cccc(CSc2nc(Cl)cc(Cl)n2)c1F
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Product: COc1cccc(CSc2nc(Cl)cc(N(COCC[Si](C)(C)C)S(C)(=O)=O)n2)c1F

Procedure:
The subtitle compound was prepared as a colourless oil by the method of Example 39 step iii) using the subtitle product of step v) (2.0 g), methanesulfonamide (0.60 g), 60% sodium hydride (0.50 g) and 2-(trimethylsilyl)ethoxymethyl chloride (1.11 ml). Yield: 2.42 g.
Reaction SMILES: Cl.Cl.[F:3][C:4]1[C:12]([C:13]2[C:21]3[C:20]([NH2:22])=[N:19][CH:18]=[N:17][C:16]=3[N:15]([CH3:23])[CH:14]=2)=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][CH2:7][NH:8]2.[C:24]1([CH2:30][C:31](O)=[O:32])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>O>[F:3][C:4]1[C:12]([C:13]2[C:21]3[C:20]([NH2:22])=[N:19][CH:18]=[N:17][C:16]=3[N:15]([CH3:23])[CH:14]=2)=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][CH2:7][N:8]2[C:31](=[O:32])[CH2:30][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: Cn1cc(-c2ccc3c(c2F)CCN3)c2c(N)ncnc21
Reactant: O=C(O)Cc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1cc(-c2ccc3c(c2F)CCN3C(=O)Cc2ccccc2)c2c(N)ncnc21
Reaction time: 0.5 h
Yield: 71.1 %

Procedure:
A solution of 5-(4-fluoro-2,3-dihydro-1H-indol-5-yl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine 2HCl (100 mg, 0.281 mmol), Phenylacetic acid (38.2 mg, 0.281 mmol), HATU (107 mg, 0.281 mmol), DIEA (0.196 mL, 1.123 mmol) was stirred at room temperature for 3 days. The resulting suspension was poured into water (10 mL) and stirred for 30 min, and a precipitate formed. The precipitate was collected by filtration, and the residue was washed with water, then dried at the pump for an hour, then adsorbed onto silica and purified by flash chromatography (0-10% MeOH in EtOAc) to afford 5-[4-fluoro-1-(phenylacetyl)-2,3-dihydro-1H-indol-5-yl]-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (80.2 mg, 71.2% yield) as a white solid. LC-MS (ES) m/z=402 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.24 (t, J=8.46 Hz, 2H), 3.74 (s, 3H), 3.89 (s, 2H), 4.29 (t, J=8.46 Hz, 2H), 5.79-6.20 (m, 2H), 7.10-7.42 (m, 7H), 7.95 (d, J=8.08 Hz, 1H), 8.15 (s, 1H).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][O:7][C:6]2[CH:10]=[CH:11][C:12]([C:14]3[S:15][C:16](Cl)=[C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[N:18]=3)=[CH:13][C:5]1=2)(=[O:3])[CH3:2].[C:25]1(B(O)O)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[C:1]([N:4]1[CH2:9][CH2:8][O:7][C:6]2[CH:10]=[CH:11][C:12]([C:14]3[S:15][C:16]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[N:18]=3)=[CH:13][C:5]1=2)(=[O:3])[CH3:2]
Reactant: OB(O)c1ccccc1
Reactant: CCOC(=O)c1nc(-c2ccc3c(c2)N(C(C)=O)CCO3)sc1Cl
Product: CCOC(=O)c1nc(-c2ccc3c(c2)N(C(C)=O)CCO3)sc1-c1ccccc1

Procedure:
Ethyl 2-(4-acetyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-5-phenylthiazole-4-carboxylate (7E) was prepared following a similar procedure as that described in example 1, except ethyl 2-(4-acetyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-5-chlorothiazole-4-carboxylate (7D) was used instead of ethyl 2-(1-acetyl-1,2,3,4-tetrahydroquinolin-7-yl)-5-chlorothiazole-4-carboxylate (1J) and phenylboronic acid was used instead of 4-methoxyphenylboronic acid in step 11 of example 1. LC/MS (APCI): m/z 409.1 (M+H).
Reaction SMILES: [C:1]([OH:8])(=[O:7])[CH2:2][CH2:3][C:4]([CH3:6])=[O:5].[C:9]([O-])([O-])=O.[K+].[K+].[C:15]1([CH3:21])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C>[C:1]([O:8][CH2:9][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:15][CH3:21])(=[O:7])[CH2:2][CH2:3][C:4]([CH3:6])=[O:5]
Reactant: CC(=O)CCC(=O)O
Reactant: O=C([O-])[O-]
Reactant: Cc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCCCCOC(=O)CCC(C)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
I-Bromooctane (332 g, 1.72 mol) was added to a stirring mixture of levulinic acid (200 g, 1.72 mol), tetrabutylammonium bromide (55.1 g, 0.17 mol), and K2CO3 (357 g, 2.58 mol) in DMF (500 mL) drop-wise and stirred at room temperature for overnight. The resulting mixture was diluted in toluene and the organic layer was washed with HCl (10%), brine, and water. The solvent was concentrated in vacuo and the oil was purified by vacuum distillation to afford the product octyl levulinate as a clear oil.
Reaction SMILES: [F:1][C:2]1[C:3]2[C:4]([CH:45]([OH:51])[C:46]([O:48]CC)=[O:47])=[C:5]3[C:14]4[N:15]=[C:16]([C:19]5[C:20]([N:39]([CH3:44])[S:40]([CH3:43])(=[O:42])=[O:41])=[CH:21][C:22]6[O:26][C:25]([C:27]7[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=7)=[C:24]([C:34](=[O:37])[NH:35][CH3:36])[C:23]=6[CH:38]=5)[CH:17]=[CH:18][C:13]=4[O:12][CH2:11][N:6]3[C:7]=2[CH:8]=[CH:9][CH:10]=1.[OH-].[Li+]>C1COCC1.O.CO>[F:1][C:2]1[C:3]2[C:4]([CH:45]([OH:51])[C:46]([OH:48])=[O:47])=[C:5]3[C:14]4[N:15]=[C:16]([C:19]5[C:20]([N:39]([CH3:44])[S:40]([CH3:43])(=[O:42])=[O:41])=[CH:21][C:22]6[O:26][C:25]([C:27]7[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=7)=[C:24]([C:34](=[O:37])[NH:35][CH3:36])[C:23]=6[CH:38]=5)[CH:17]=[CH:18][C:13]=4[O:12][CH2:11][N:6]3[C:7]=2[CH:8]=[CH:9][CH:10]=1
Reactant: CCOC(=O)C(O)c1c2n(c3cccc(F)c13)COc1ccc(-c3cc4c(C(=O)NC)c(-c5ccc(F)cc5)oc4cc3N(C)S(C)(=O)=O)nc1-2
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc4c(n3)-c3c(C(O)C(=O)O)c5c(F)cccc5n3CO4)cc12
Temperature: 25 °C

Procedure:
A mixture of ethyl 2-(11-fluoro-2-(2-(4-fluorophenyl)-3-(methylcarbamoyl)-6-(N-methylmethylsulfonamido)benzofuran-5-yl)-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indol-12-yl)-2-hydroxyacetate (233 mg, 0.325 mmol) and lithium hydroxide (54.5 mg, 2.276 mmol) in THF (1 ml), water (0.5 ml) and MeOH (0.5 ml) was stirred at room temperature over night, then concentrated under vacuum. The resulting residue was purified using EP column (30 mm×250 mm), 60% IPA/CO2. This resulted in 128 mg (57.2%) of 2-(11-fluoro-2-(2-(4-fluorophenyl) -3-(methylcarbamoyl)-6-(N-methylmethylsulfonamido)benzofuran-5-yl)-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indol-12-yl)-2-hydroxyacetic acid (Compound 207) as a white solid. LC-MS (ES, m/z) C34H26F2N4O8S: 688. Found: 689 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:9][CH2:10][CH:11]2[CH2:13][CH2:12]2)=[N:4][C:5](Cl)=[N:6][CH:7]=1.[NH2:14][C:15]1[CH:16]=[CH:17][C:18]([S:21]([NH2:24])(=[O:23])=[O:22])=[N:19][CH:20]=1.Cl.O>C(#N)C.O1CCOCC1>[Br:1][C:2]1[C:3]([NH:9][CH2:10][CH:11]2[CH2:13][CH2:12]2)=[N:4][C:5]([NH:14][C:15]2[CH:16]=[CH:17][C:18]([S:21]([NH2:24])(=[O:23])=[O:22])=[N:19][CH:20]=2)=[N:6][CH:7]=1
Reactant: Nc1ccc(S(N)(=O)=O)nc1
Reactant: Clc1ncc(Br)c(NCC2CC2)n1
Agent: Cl
Solvent: C1COCCO1
Solvent: CC#N
Solvent: O
Product: NS(=O)(=O)c1ccc(Nc2ncc(Br)c(NCC3CC3)n2)cn1

Procedure:
263 mg (1.0 mmol) of (5-bromo-2-chloro-pyrimidin-4-yl)-cyclopropylmethyl-amine is dissolved in 2 ml of acetonitrile and added to a suspension of 172 mg (1.0 mmol) of 5-amino-pyridine-2-sulfonic acid amide (representation according to W. T. Caldwell, E. C. Kornfeld J. Am. Chem. Soc. 1942, 64, 1695-1698) in 1 ml of acetonitrile, 0.25 ml of a 4 molar solution of hydrochloric acid in 1,4-dioxane as well as 0.25 ml of water. The reaction mixture is stirred under reflux overnight. After cooling, the precipitate that is formed is filtered off and washed with warm water. After drying, 286 mg (0.72 mmol, 72% of theory) of the product 5-[5-bromo-4-(cyclopropylmethyl-amino)-pyrimidin-2-ylamino]-pyridine-2-sulfonic acid amide is obtained.
Reaction SMILES: Br[CH2:2][C:3]1[N:8]=[C:7]([NH:9]C(=O)C(C)(C)C)[CH:6]=[CH:5][CH:4]=1.C(OC([N:23]1[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[N:25]=[C:24]1[CH2:32][NH:33][CH:34]1[C:43]2[N:42]=[CH:41][CH:40]=[CH:39][C:38]=2[CH2:37][CH2:36][CH2:35]1)=O)(C)(C)C.C(N(CC)C(C)C)(C)C.[I-].[K+]>CC#N>[NH2:9][C:7]1[N:8]=[C:3]([CH2:2][N:33]([CH2:32][C:24]2[NH:23][C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=3[N:25]=2)[CH:34]2[C:43]3[N:42]=[CH:41][CH:40]=[CH:39][C:38]=3[CH2:37][CH2:36][CH2:35]2)[CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)n1c(CNC2CCCc3cccnc32)nc2ccccc21
Reactant: CC(C)(C)C(=O)Nc1cccc(CBr)n1
Agent: [I-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Nc1cccc(CN(Cc2nc3ccccc3[nH]2)C2CCCc3cccnc32)n1
Temperature: 60 °C
Reaction time: 3.75 h
Yield: 85.5 %

Procedure:
Using the general N-alkylation procedure: To a stirred solution of N-[6-(bromomethyl)-2-pyridyl]pivalamide (prepared as described by Harata, M.; Hasegawa, K.; Jitsukawa, K.; Masuda, H.; Einaga, H. Bull. Chem. Soc. Jpn 1998, 71, 1031-1038) (0.129 g, 0.45 mmol) in dry CH3CN (10 mL) was added (1-tert-butoxycarbonyl-1H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine (0.176 g, 0.47 mmol), N,N-diisopropylethylamine (0.20 mL, 1.15 mmol) and potassium iodide (12 mg, 0.048 mmol). The mixture was stirred under an argon atmosphere at 60° C. for 3.75 h. Purification of the crude material by column chromatography on silica gel (CH2Cl2/MeOH, 98:2 followed by 96:4) gave the alkylated product (0.148 g, 54%) as a brown oil.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11](F)[CH:12]=3)[C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5]2)[CH2:3][CH2:2]1.[NH:20]1[CH2:24][CH2:23][CH:22]([C:25]2[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=2)[CH2:21]1>>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11]([N:20]4[CH2:24][CH2:23][CH:22]([C:25]5[CH:26]=[CH:27][N:28]=[CH:29][CH:30]=5)[CH2:21]4)[CH:12]=3)[C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: c1cc(C2CCNC2)ccn1
Reactant: O=C(O)c1cn(C2CC2)c2cc(F)c(F)cc2c1=O
Product: O=C(O)c1cn(C2CC2)c2cc(N3CCC(c4ccncc4)C3)c(F)cc2c1=O
Yield: 52 %

Procedure:
1 -cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (1.13 g, 4.3 mmol) and 4-(3-pyrrolidinyl)pyridine, a procedure analogous to that given in Example 1 provided the title compound (0.87 g, 52%) as an off-white solid, mp 260°-261° C.
Reaction SMILES: [CH:1](=[C:8]1[C:13](=[O:14])[CH:12]2[CH2:15][CH2:16][N:9]1[CH2:10][CH2:11]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1COCC1.[H][H]>CO.[Pd]>[CH:1](=[C:8]1[CH:13]([OH:14])[CH:12]2[CH2:11][CH2:10][N:9]1[CH2:16][CH2:15]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:1]([CH:8]1[C:13](=[O:14])[CH:12]2[CH2:11][CH2:10][N:9]1[CH2:16][CH2:15]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1C(=Cc2ccccc2)N2CCC1CC2
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: O=C1C2CCN(CC2)C1Cc1ccccc1
Product: OC1C(=Cc2ccccc2)N2CCC1CC2
Reaction time: 1 h
Yield: 7 %
Yield: 72 %

Procedure:
A mixture of 3-quinuclidinone (6.25 g, 50 mmol), benzaldehyde (5.83 g, 55 mmol) and KOH (0.84 g, 15 mmol) in 30 mL MeOH is heated under reflux for 16 h. The reaction is cooled and water is added. The mixture is extracted with CHCl3, dried (MgSO4), filtered and concentrated. The yellow solid is triturated with warm heptane, filtered and dried to provide 6.6 g (62%) of 2-benzylidene-1-azabicyclo[2.2.2]octan-3-one. A suspension of 2-benzylidene-1-azabicyclo[2.2.2]octan-3-one (6.6 g, 31 mmol) in MeOH is treated with a THF slurry of 10% Pd/C (0.38 g) in a Parr hydrogenation bottle. The bottle is charged with 40 psi of hydrogen gas and allowed to shake for 1 h. The mixture is filtered through Celite, and the solvent is removed in vacuo. The residue is purified by chromatography (Biotage 40M, 30% EtOAc/hexanes—100% EtOAc) to afford 0.48 g (7%) of 2-benzylidene-1-azabicyclo[2.2.2]octan-3-ol and 4.8 g (72%) of 2-benzylquinuclidin-3-one. MS (ESI+) for C14H17NO m/z 216.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4](Cl)=[O:5].[CH3:14][NH:15][CH2:16][CH2:17][OH:18].C(O)(C)C.[OH-].[K+]>O>[OH:18][CH2:17][CH2:16][N:15]([CH3:14])[C:4](=[O:5])[C:3]1[CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=[CH:10][C:2]=1[Cl:1].[N+:11]([C:8]1[CH:9]=[CH:10][C:2]2[O:18][CH2:17][CH2:16][N:15]([CH3:14])[C:4](=[O:5])[C:3]=2[CH:7]=1)([O-:13])=[O:12]
Reactant: O=C(Cl)c1cc([N+](=O)[O-])ccc1Cl
Reactant: CNCCO
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: CN(CCO)C(=O)c1cc([N+](=O)[O-])ccc1Cl
Product: CN1CCOc2ccc([N+](=O)[O-])cc2C1=O
Temperature: 0 °C

Procedure:
260 g of N-(2-hydroxyethyl)-N-methyl-2-chloro-5-nitrobenzamide, which is prepared from 2-chloro-5-nitrobenzoyl chloride and 2-(methylamino)-ethanol, are heated to reflux temperature in 500 ml of water/500 ml of isopropanol. A solution of 65 g of potassium hydroxide in 250 ml of water is added dropwise in the course of one hour and the mixture is maintained at reflux temperature for a further 3 hours. The pH is lowered to 9, the reaction solution is cooled to 0° C. and the crystalline precipitate is filtered off with suction and dried. 174 g of 7-nitro-4-methyl -2,3-dihydro-1,4-benzoxazepin-5-one of melting point 116° C. are obtained. ##STR21##
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C@@H:10]([NH:13][C:14]2[N:19]=[CH:18][C:17](/[CH:20]=[CH:21]/[C:22]([O:24]CC)=[O:23])=[CH:16][C:15]=2[CH3:27])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl>CO.O1CCOCC1.C1(C)C=CC=CC=1>[CH2:1]([N:8]1[CH2:12][CH2:11][C@@H:10]([NH:13][C:14]2[N:19]=[CH:18][C:17](/[CH:20]=[CH:21]/[C:22]([OH:24])=[O:23])=[CH:16][C:15]=2[CH3:27])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)/C=C/c1cnc(N[C@@H]2CCN(Cc3ccccc3)C2)c(C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: Cc1cc(/C=C/C(=O)O)cnc1N[C@@H]1CCN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of ethyl (2E)-3-(6-{[(3R)-1-benzyl-3-pyrrolidinyl]amino}-5-methyl-3-pyridyl)acrylate (366 mg) in MeOH (2 mL) and dioxane (2 mL) was added 1N NaOH aq solution (2.0 mL), and the mixture was stirred at ambient temperature for 3 hours. The pH value of the mixture was adjusted to 7 with 1N HCl, and the solvent was removed in vacuo. Obtained solid was suspended in toluene and the residual water was geotropically removed to give (2E)-3-(6-{[(3R)-1-benzyl-3-pyrrolidinyl]amino}-5-methyl-3-pyridyl)acrylic acid and the crude product was used in next reaction without further purification.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([NH:8][NH2:9])=O.[C:10]1([N:16]=[C:17]=[S:18])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[F:19][C:20]([F:30])([F:29])[C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Br)=[CH:23][CH:22]=1>>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:16]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:17]([S:18][CH2:25][C:24]2[CH:23]=[CH:22][C:21]([C:20]([F:19])([F:29])[F:30])=[CH:28][CH:27]=2)=[N:9][N:8]=1
Reactant: S=C=Nc1ccccc1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Reactant: NNC(=O)c1ccco1
Product: FC(F)(F)c1ccc(CSc2nnc(-c3ccco3)n2-c2ccccc2)cc1

Procedure:
This compound was synthesized using the same methodology as described in Example 1 above, using 2-furancarboxylic acid hydrazide, phenyl isothiocyanate and 4-trifluoromethylbenzyl bromide as the starting materials. (M+H)+−402.
Reaction SMILES: [C:1]([C:9]1[CH:13]=[C:12]([CH:14]([OH:17])[CH2:15][CH3:16])[O:11][N:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.BrC1C=C(C(=O)CC)ON=1.C(O)(C)C>CC(C)=O.CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O>[C:1]([C:9]1[CH:13]=[C:12]([C:14](=[O:17])[CH2:15][CH3:16])[O:11][N:10]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCC(O)c1cc(C(=O)c2ccccc2)no1
Agent: O=[Cr](=O)=O
Agent: CCC(=O)c1cc(Br)no1
Agent: O=S(=O)(O)O
Solvent: CC(C)O
Solvent: CC(C)=O
Product: CCC(=O)c1cc(C(=O)c2ccccc2)no1

Procedure:
Reacted under reflux for 2 hours were 5.0 g (27.3 mmol) of benzoylacetohydroxamoyl chloride prepared by a known process [J.Org.Chem., 409 (1942)] and 5.0 g (59.5 mmol) of 1-pentyne-3-ol. The reaction mixture was added into water, followed by extraction with ethyl ether. The extract was concentrated and then purified by silica gel chromatography (eluent: chloroform), whereby the title compound, namely, 3-benzoyl-5-(1-hydroxypropyl)isoxazole was obtained. It was dissolved in acetone, to which the Jones' reagent was added dropwise under ice cooling so that it was oxidized from the alcohol form to a ketone form. Isopropyl alcohol was added to the reaction mixture. After an insoluble material was filtered off, the solvent was distilled off so that 3-benzoyl-5-propionylisoxazole was obtained as colorless crystals.
Reaction SMILES: [C:1]1(C)[CH:6]=[CH:5][C:4]([N:7]=[N+:8]=[N-:9])=[CH:3][CH:2]=1.[C:11]1([C:17]#[CH:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[CH2:19]1COCC1>C[C-]1C(C)=C(C)C(C)=C1C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Ru+]>[C:3]1([CH3:19])[CH:2]=[CH:1][CH:6]=[CH:5][C:4]=1[N:7]1[C:17]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:18][N:9]=[N:8]1
Reactant: Cc1ccc(N=[N+]=[N-])cc1
Reactant: C1CCOC1
Reactant: C#Cc1ccccc1
Agent: Cl[Ru+]
Agent: Cc1c(C)c(C)[c-](C)c1C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: Cc1ccccc1-n1nncc1-c1ccccc1
Yield: 51 %

Procedure:
4-Tolyl azide (133 mg, 1 mmol), phenylacetylene (113 mg, 1.1 mmol), Cp*RuCl(PPh3)2 (16 mg, 0.02 mmol, 2 mol %). Solvent: THF, 10 mL, 60° C., 6 hours. Slightly yellow product obtained in 51% yield (120 mg). ESI-MS: m/z 236, [M+H].
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2([C:14]#N)[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:4][N:3]=1.[OH-:16].[Na+].C[OH:19].O>>[CH3:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2([C:14]([OH:19])=[O:16])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:4][N:3]=1
Reactant: CO
Reactant: [OH-]
Reactant: Cc1ncc(C2(C#N)CCOCC2)cn1
Agent: [Na+]
Solvent: O
Product: Cc1ncc(C2(C(=O)O)CCOCC2)cn1
Temperature: 100 °C
Yield: 67 %

Procedure:
A mixture of 4-(2-methylpyrimidin-5-yl)tetrahydro-2H-pyran-4-carbonitrile (5.5 g, 0.027 mol) in MeOH/H2O (60 mL, 1:1) was added NaOH (3.25 g, 0.081 mol) and heated to 100° C. overnight. The MeOH was removed in vacuo. The aqueous layer was extracted with EtOAc (2×30 mL) and the organic layers was discarded. The aqueous layer was adjusted pH to 2˜3 with 3N HCl and extracted with EtOAc (6×50 mL). The organic layer was dried over Na2SO4 and concentracted to give 4-(2-methylpyrimidin-5-yl)tetrahydro-2H-pyran-4-carboxylic acid (4.0 g, yield: 67%). 1H NMR (DMSO-d6 400 MHz): δ13.04 (br, 1H), 8.71 (s, 2H), 3.80-3.70 (m, 2H), 3.60-3.40 (m, 2H), 2.61 (s, 3H), 2.40-2.30 (m, 2H), 2.00-1.85 (m, 2H).
Reaction SMILES: [CH2:1](N(CC)CC)C.Cl.[Br:9][C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:19](=[NH:23])OCC)[CH:17]=2)[NH:12][N:11]=1.C[NH:25][NH:26][C:27]([C@@H:29]1[CH2:34][CH2:33][CH2:32][N:31]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:30]1)=O>CCO>[Br:9][C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:19]3[N:23]=[C:27]([C@@H:29]4[CH2:34][CH2:33][CH2:32][N:31]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:30]4)[N:26]([CH3:1])[N:25]=3)[CH:17]=2)[NH:12][N:11]=1
Reactant: CCOC(=N)c1ccc2[nH]nc(Br)c2c1
Reactant: CCN(CC)CC
Reactant: CNNC(=O)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: CCO
Product: Cn1nc(-c2ccc3[nH]nc(Br)c3c2)nc1[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 100 °C
Yield: 32.9 %

Procedure:
Added triethylamine (0.5 ml, 3.59 mmol) to a solution of ethyl 3-bromo-1H-indazole-5-carbimidate hydrochloride (200 mg, 0.658 mmol) and (R)-tert-butyl 3-(2-methylhydrazine-carbonyl)piperidine-1-carboxylate (200 mg, 0.78 mmol) in EtOH (USP, 5 ml) and heated in a microwave oven at 100° C. for 12 hours. Evaporated solvent then chromatographed residue on silica gel eluting with 1/1 v/v EtOAc/Hexanes to yield (R)-tert-butyl 3-(3-(3-bromo-1H-indazol-5-yl)-1-methyl-1H-1,2,4-triazol-5-yl)piperidine-1-carboxylate as a white solid (100 mg).
Reaction SMILES: N1C2C(=CC=CC=2[S:11]([NH:14][C:15]2[CH:33]=[CH:32][C:18]3[C:19]([Br:31])=[C:20]([CH2:22][C:23]4[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=4)[O:21][C:17]=3[CH:16]=2)(=[O:13])=[O:12])C=CC=1.[H-].[Na+].Br[CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39].O1[CH2:47][CH2:46][CH2:45][CH2:44]1>C(OCC)(=O)C>[CH2:41]([O:40][C:38]([CH2:37][N:14]1[C:15]2[C:47](=[CH:19][CH:18]=[CH:17][C:16]=2[C:32]2[CH:33]=[C:15]([N:14]=[S:11](=[O:12])=[O:13])[C:16]3[C:19]([Br:31])=[C:20]([CH2:22][C:23]4[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=4)[O:21][C:17]=3[CH:18]=2)[CH:46]=[CH:45][CH2:44]1)=[O:39])[CH3:42]
Reactant: CCOC(=O)CBr
Reactant: C1CCOC1
Reactant: N#Cc1ccc(Cc2oc3cc(NS(=O)(=O)c4cccc5cccnc45)ccc3c2Br)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CCOC(=O)CN1CC=Cc2cccc(-c3cc(N=S(=O)=O)c4c(Br)c(Cc5ccc(C#N)cc5)oc4c3)c21
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
1.0 g (2 mmol) of 4-[(6-(quinolin-8-yl-sulphonylamino)-3-bromo-benzofuran-2-yl)-methyl]-benzonitrile are dissolved in 20 ml absolute tetrahydrofuran and after the addition of 100 g (2 mmol) of sodium hydride (50% in oil) stirred for 20 minutes at ambient temperature. Then 0.22 ml (2 mmol) of ethyl bromoacetate are added under a nitrogen atmosphere. The reaction mixture is refluxed for 6 hours, cooled, diluted with ethyl acetate and washed with sodium chloride solution. The combined organic extracts are dried and concentrated by evaporation. The residue is chromatographed on silica gel and eluted with petroleum ether/ethyl acetate (90:10 and 75:25). The desired fractions are combined and concentrated by evaporation.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Cl:10])[CH:9]=1)[C:5]#[N:6].CO>C1COCC1>[NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Cl:10])[CH:9]=1)[CH2:5][NH2:6]
Reactant: N#Cc1cc(N)cc(Cl)c1
Solvent: CO
Solvent: C1CCOC1
Product: NCc1cc(N)cc(Cl)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To the solution of 3-amino-5-chlorobenzonitrile in THF at RT was added slowly borane methyl sulfide complex (2.5 eq.). The resulting reaction mixture was stirred at RT for 1 h and heated at reflux for 2 hrs. The reaction mixture was cooled to −30° C. and MeOH was added slowly to quench the reaction. Solvent was evaporated in vacuo after the reaction mixture was stirred at RT for 30 min. to give 3-amino-5-chlorobenzylamine, which was used without purification. LCMS (Method A) RT 0.16 min., MH+ 157.
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([OH:11])(=[O:10])[CH:8]=[CH2:9].[C:12](=[O:21])([O:18][CH2:19]Cl)[O:13][CH2:14][CH2:15][CH2:16][CH3:17].C1OCCOCCOCCOCCOCCOC1>CN(C=O)C>[C:12](=[O:21])([O:18][CH2:19][O:10][C:7](=[O:11])[CH:8]=[CH2:9])[O:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCOC(=O)OCCl
Reactant: C=CC(=O)O
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CC(=O)OCOC(=O)OCCCC
Temperature: 25 °C
Reaction time: 48 h
Yield: 50.2 %

Procedure:
Potassium tert. butoxide (5.84 g, 0.052 mol) was added to a solution of acrylic acid (4.47 g, 0.045 mol) in DMF (220 ml). Butyl chloromethyl carbonate (6.5 g, 0.052 mol) in DMF (150 ml) was added to the resulting suspension. 18-crown-6 (0.6 g) was then added and the reaction mixture was left with stirring at room temperature for 2 days. The reaction mixture was filtered and the solvent was removed under reduced pressure. The residue was dissolved in chloroform (100 ml) and washed with saturated aqueous sodium hydrogen carbonate (50 ml) and water (50 ml). The organic phase was dried (MgSO4) and the solvent removed under reduced pressure. Flash chromatography gave 4.57 g of the title product.