Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([NH:4][C:5]1[S:6][CH:7]=[C:8]([C:10]2[CH:19]=[C:18]([O:20][CH:21]3[CH2:38][CH:37]4[CH:23]([C:24](=[O:44])[N:25]([CH3:43])[CH2:26][CH2:27][CH2:28][CH2:29][CH:30]=[CH:31][CH:32]5[C:34]([C:40](O)=[O:41])([NH:35][C:36]4=[O:39])[CH2:33]5)[CH2:22]3)[C:17]3[C:12](=[CH:13][C:14]([O:45][CH3:46])=[CH:15][CH:16]=3)[N:11]=2)[N:9]=1)([CH3:3])[CH3:2].CCN=C=NCCCN(C)C.[CH:58]1([S:61]([NH2:64])(=[O:63])=[O:62])[CH2:60][CH2:59]1.C1CCN2C(=NCCC2)CC1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C1C=CN=CC=1)C.CN(C=O)C>[CH:1]([NH:4][C:5]1[S:6][CH:7]=[C:8]([C:10]2[CH:19]=[C:18]([O:20][CH:21]3[CH2:38][CH:37]4[CH:23]([C:24](=[O:44])[N:25]([CH3:43])[CH2:26][CH2:27][CH2:28][CH2:29][CH:30]=[CH:31][CH:32]5[C:34]([C:40]([NH:64][S:61]([CH:58]6[CH2:60][CH2:59]6)(=[O:63])=[O:62])=[O:41])([NH:35][C:36]4=[O:39])[CH2:33]5)[CH2:22]3)[C:17]3[C:16](=[CH:15][C:14]([O:45][CH3:46])=[CH:13][CH:12]=3)[N:11]=2)[N:9]=1)([CH3:3])[CH3:2]
Reactant: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)O)CC5C=CCCCCN(C)C(=O)C4C3)cc(-c3csc(NC(C)C)n3)nc2c1
Reactant: NS(=O)(=O)C1CC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)NS(=O)(=O)C6CC6)CC5C=CCCCCN(C)C(=O)C4C3)cc(-c3csc(NC(C)C)n3)nc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 5 %

Procedure:
The acid 110 (20 mg, 0.15 mmol), DMAP (28 mg, 0.225 mmol) and EDAC (58 mg, 0.3 mmol) was dissolved in DMF (1.5 mL). The reaction mixture was stirred overnight at R.T. whereafter cyclopropylsulphonamide (91 mg, 1.125 mmol) and DBU (114 μL, 0.75 mmol) was added. After stirring at RT overnight the reaction mixture was added to 5% citric acid and extracted three times with chloroform. The organic phase was dried over sodium sulphate and evaporated. The afforded residue was purified by preparative HPLC to give the title product (5.6 mg) (yield 24%).
Reaction SMILES: [OH-:1].[Na+].Cl[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]([F:12])[CH:6]=1>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C1C=CC=CC=1.O>[F:12][C:7]1[CH:6]=[C:5]([CH2:4][C:5]([CH3:10])([CH3:6])[CH:4]=[O:1])[CH:10]=[CH:9][C:8]=1[CH3:11]
Reactant: [OH-]
Reactant: Cc1ccc(CCl)cc1F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Product: Cc1ccc(CC(C)(C)C=O)cc1F
Temperature: 70 °C

Procedure:
Under argon, a mixture of sodium hydroxide (2.8 g, 70 mmol) and tetrabutylammonium iodide (0.6 g, 1.6 mmol) in 8 ml benzene and 2.8 ml H2O was heated at 70° C. to form a homogeneous mixture. A mixture of the product of STEP 2 (10.5 g, 60.1 mmol) and isobutylaldehyde (5.76 g, 80 mmol) in 20 ml benzene was added to the above solution dropwise. The resulting reaction mixture was heated at 70-75° C. for 6 h. The product was extracted with ethyl acetate and washed with H2O. The aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with brine, dried with MgSO4, and concentrated. The residue was purified by chromatography (on silica gel, ethyl acetate/hexane=5/95) to yield a colorless oil in 7.3 g (58%). NMR spectra of the product were consistent for the proposed structure.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([S:16][C:17]4[CH:18]=[C:19]5[C:24](=[CH:25][CH:26]=4)[N:23]=[CH:22][C:21]([N:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)=[CH:20]5)=[N:14][N:15]=3)[CH:12]=2)[CH:4]=[N:3]1.[F:33][C:34]([F:38])([F:37])[CH2:35]I.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([S:16][C:17]4[CH:18]=[C:19]5[C:24](=[CH:25][CH:26]=4)[N:23]=[CH:22][C:21]([N:27]4[CH2:32][CH2:31][N:30]([CH2:35][C:34]([F:38])([F:37])[F:33])[CH2:29][CH2:28]4)=[CH:20]5)=[N:14][N:15]=3)[CH:12]=2)[CH:4]=[N:3]1
Reactant: Cn1cc(-c2ccc3nnc(Sc4ccc5ncc(N6CCNCC6)cc5c4)n3c2)cn1
Reactant: FC(F)(F)CI
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1cc(-c2ccc3nnc(Sc4ccc5ncc(N6CCN(CC(F)(F)F)CC6)cc5c4)n3c2)cn1
Temperature: 120 °C
Yield: 21.2 %

Procedure:
A suspension of 6-(6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-ylthio)-3-(piperazin-1-yl)quinoline (Example 27—see in Table below) (12 mg, 0.027 mmol), 1,1,1-trifluoro-2-iodoethane (56.9 mg, 0.271 mmol) and DIPEA (17.5 mg, 0.136 mmol) in DMF (1 mL) was sealed in a microwave vial and heated at 120° C. for 6 hours. The solvent was removed and the residue was purified by prep-HPLC to give the title compound as yellow solid (3 mg, yield 20%). [Method 1C]
Reaction SMILES: C[Si]([C:5]#[N:6])(C)C.[CH3:7][C:8]1[CH:9]=[CH:10][C:11]([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[N+:12]([O-])[CH:13]=1.CN(C)C(Cl)=O.O>C(#N)C>[CH3:7][C:8]1[C:13]([C:5]#[N:6])=[N:12][C:11]([O:15][CH2:16][C:17]([F:20])([F:18])[F:19])=[CH:10][CH:9]=1
Reactant: C[Si](C)(C)C#N
Reactant: Cc1ccc(OCC(F)(F)F)[n+]([O-])c1
Agent: CN(C)C(=O)Cl
Solvent: O
Solvent: CC#N
Product: Cc1ccc(OCC(F)(F)F)nc1C#N
Temperature: 25 °C
Reaction time: 48 h
Yield: 29.1 %

Procedure:
Trimethylsilyl cyanide (0.19 mL, 1.40 mmol) is added dropwise a solution of 5-methyl-2-(2,2,2-trifluoroethoxy)pyridine 1-oxide (0.14 g, 0.70 mmol, Step-2) and dimethylcarbamoyl chloride (0.1 mL, 1.05 mmol) in acetonitrile (10 mL) is stirred at room temperature for 2 days. Then trimethylsilyl cyanide (0.19 mL, 1.40 mmol) and dimethylcarbamoyl chloride (0.1 mL, 1.05 mmol) is added to the reaction mixture and refluxed with stirring for 20 hours. After cooling to room temperature, the reaction mixture is poured into water, extracted with ethyl acetate and dried over sodium sulfate and concentrated in vacuo. The residue is purified by column chromatography on silica gel eluting with n-hexane/ethyl acetate (2:1 to 1:1) to give 44 mg (29% yield) of the title compound as colorless oil.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH2:7].[CH3:12][O:13][CH2:14][CH2:15][NH:16][CH3:17].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C(=O)C>[CH3:12][O:13][CH2:14][CH2:15][N:16]([CH3:17])[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH2:7])[CH:8]=1
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Reactant: CNCCOC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: COCCN(C)c1ccc([N+](=O)[O-])c(N)c1
Temperature: 117.5 °C
Reaction time: 48 h
Yield: 73.4 %

Procedure:
A mixture of 5-chloro-2-nitroaniline (2.2 g, 12.7 mmol), (2-methoxy-ethyl)-methyl-amine (3.0 g, 33.7 mmol) and anhydrous potassium carbonate (1.93 g, 14 mmol) in N,N-dimethylacetamide (5 ml) was stirred at 115-120° C. under nitrogen for 2 days. Sample NMR analysis showed complete conversion of the starting material. The resultant mixture was then cooled to room temperature, poured into cold water (20 ml) and stirred vigorously and cooled at 5° C. overnight. The resulting yellow brown precipitate was collected by filtration, washed well with water then dried on the filter funnel. The resulting yellow brown solid was slurried in diethyl ether (20 mL), filtered, washed with additional diethyl ether, dried to afford N1-(2-methoxy-ethyl)-N1-methyl-4-nitro-benzene-1,3-diamine (2.1 g, 72%) as a yellow brown powder.
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][C:8]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]3[S:17][CH:18]=[C:19]([C:21](Cl)=[O:22])[N:20]=3)[CH2:12][CH2:11]2)=[O:9])[N:5]=[C:4]([C:24]([F:27])([F:26])[F:25])[CH:3]=1.[CH3:28][NH:29][C@H:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH2:32][CH:31]1C.C(N(CC)CC)C.Cl>ClCCl>[C@H:30]1([N:29]([CH3:28])[C:21]([C:19]2[N:20]=[C:16]([CH:13]3[CH2:14][CH2:15][N:10]([C:8](=[O:9])[CH2:7][N:6]4[C:2]([CH3:1])=[CH:3][C:4]([C:24]([F:27])([F:26])[F:25])=[N:5]4)[CH2:11][CH2:12]3)[S:17][CH:18]=2)=[O:22])[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH2:32][CH2:31]1
Reactant: CN[C@H]1c2ccccc2CC1C
Reactant: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(c2nc(C(=O)Cl)cs2)CC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(c2nc(C(=O)N(C)[C@@H]3CCc4ccccc43)cs2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.5 %

Procedure:
2-[1-[[5-Methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl]-4-piperidinyl]-4-thiazolecarbonyl chloride (210 mg, 0.5 mmol) (i.e. the product of Example 19, Step D) was treated with a solution of (1R)-2,3-dihydro-N,2-dimethyl-1H-inden-1-amine (147 μL, 1.0 mmol) and triethylamine (139 μL, 1.0 mmol) in 5 mL of dichloromethane. The reaction mixture was stirred at room temperature for 2 h, passed through a Varian 1005 Chem Elut™ column pretreated with 3 mL of 1 N aqueous hydrochloric acid. The column was flushed with three column volumes of dichloromethane. The collected dichloromethane solution was evaporated in vacuo and purified by medium-pressure liquid chromatography on silica gel using 50-100% of ethyl acetate in 1-chlorobutane as eluant to give 214 mg of the title compound, the product of present invention as a white foam.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.C([N-]C(C)C)(C)C.[Li+].[CH2:20]([N:27]1[CH2:32][CH2:31][CH2:30][CH2:29][C:28]1=O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[OH2:34]>C1COCC1>[CH2:20]([N:27]1[CH2:32][CH2:31][C:30]([C:11]2[C:2]([Cl:1])=[N:3][C:4]3[C:9]([CH:10]=2)=[CH:8][CH:7]=[CH:6][CH:5]=3)([OH:34])[CH2:29][CH2:28]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Clc1ccc2ccccc2n1
Reactant: O=C1CCCCN1Cc1ccccc1
Reactant: O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: OC1(c2cc3ccccc3nc2Cl)CCN(Cc2ccccc2)CC1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
Under an argon atmosphere 22.3 g (136 mmol) 2-chloroquinoline in 60 mL THF was slowly added dropwise at −78° C. to 68.0 mL (136 mmol) of a 2M lithium diisopropylamide (in THF) solution in 280 mL THF. The reaction mixture was stirred for 1 h at −78° C. and then 24.3 mL (136 mmol) N-benzylpiperidone in 50 mL of THF were added dropwise. The reaction mixture was stirred for 40 min at −70° C. and for 3 h at RT. The reaction mixture was cooled to −20° C., and 200 mL water were added dropwise. The reaction mixture was allowed to come up to RT and extracted with EtOAc. The organic phase was dried, filtered and concentrated to dryness by rotary evaporation. The product was purified using an Alox column. The product-containing fractions were combined and concentrated to dryness by rotary evaporation.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([O:13]C)=[O:12])[CH:10]=1)[N:7]([CH3:15])[CH:6]=[C:5]2[CH:16]([CH3:18])[CH3:17].CS(O)=O.[Na].[CH3:24][CH2:25][O:26][C:27]([CH3:29])=O.C[N:31]1CCCC1=O>[Cu]I>[CH3:15][N:7]1[C:8]2[C:4](=[CH:3][C:2]([N:31]3[CH2:29][CH2:27][O:26][CH2:25][CH2:24]3)=[CH:10][C:9]=2[C:11]([OH:13])=[O:12])[C:5]([CH:16]([CH3:18])[CH3:17])=[CH:6]1
Reactant: COC(=O)c1cc(Br)cc2c(C(C)C)cn(C)c12
Reactant: CN1CCCC1=O
Reactant: CCOC(C)=O
Agent: [Cu]I
Agent: CS(=O)O
Agent: [Na]
Product: CC(C)c1cn(C)c2c(C(=O)O)cc(N3CCOCC3)cc12
Temperature: 150 °C
Reaction time: 10 h
Yield: 62.2 %

Procedure:
Methyl 5-bromo-3-isopropyl-1-methyl-1H-indole-7-carboxylate (502 mg, 1.62 mmol), methanesulfinic acid, Sodium salt (811 mg, 7.9 mmol) and copper(I) iodide 1.51 g, 7.9 mmol) were suspended in N-Methyl-2-pyrrolidone (5 mL) in a sealed vial and the mixture was stirred at 150° C. for 10 hours. The suspension was cooled down, EtOAc was added and insoluble materials were removed by filtration. The filtrate was extracted with EtOAc and DCM and the combined organics were washed with brine, dried over MgSO4, filtered and the solvent evaporated. The residue was purified using normal phase chromatography Hexanes/EtOAc (gradient 0 to 100% EtOAc). Solids that crashed out were filtered, air-dried for 15 min and dried in vacuum-oven overnight to give 1-methyl-3-(1-methylethyl)-5-(4-morpholinyl)-1H-indole-7-carboxylic acid (125 mg, 62.2% yield). EtOAc was added along with some hexanes, it was sonicated, the solids that crashed out were filtered, air-dried for 15 min and dried in vacuum-oven overnight to give methyl 3-isopropyl-1-methyl-5-(methylsulfonyl)-1H-indole-7-carboxylate (198 mg, 39%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.31 (s, 3H) 1.33 (s, 3H) 3.22-3.28 (m, 4H) 3.82 (s, 3H) 3.96 (s, 3H) 7.43 (s, 1H) 7.99 (d, J=1.77 Hz, 1H) 8.32 (d, J=1.77 Hz, 1H). MS (ES) [M+H]+ 310.1.
Reaction SMILES: CS(C)=O.[CH2:5]([O:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20]([NH:22][NH2:23])=[O:21])=[CH:15][CH:14]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[NH2:24][C:25]1[N:33]=[CH:32][CH:31]=[CH:30][C:26]=1[C:27](O)=[O:28].CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F>O.C(N(CC)CC)C>[CH2:5]([O:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20]([NH:22][NH:23][C:27](=[O:28])[C:26]2[CH:30]=[CH:31][CH:32]=[N:33][C:25]=2[NH2:24])=[O:21])=[CH:15][CH:14]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: Nc1ncccc1C(=O)O
Reactant: NNC(=O)Cc1ccc(OCc2ccccc2)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: O
Solvent: CS(C)=O
Product: Nc1ncccc1C(=O)NNC(=O)Cc1ccc(OCc2ccccc2)cc1
Reaction time: 1 h
Yield: 89.1 %

Procedure:
To a solution of DMSO (3 mL) of (4-benzyloxy-phenyl)-acetic acid hydrazide (130 mg) described in Manufacturing Example 8-1 were added triethylamine (0.21 mL), 2-aminonicotinic acid (70 mg), and BOP reagent (benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate) (250 mg), which was stirred for 1 hour at the same temperature. Water was added to the reaction solution, and the solids thus precipitated were filtered off to obtain the titled compound (170 mg).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][O:11][CH:10]([CH2:14][OH:15])[CH2:9]1)C1C=CC=CC=1.C(N1CCCOCC1)C1C=CC=CC=1.[F:30][C:31]([F:36])([F:35])[C:32]([OH:34])=[O:33]>[C].[Pd].CO>[F:30][C:31]([F:36])([F:35])[C:32]([OH:34])=[O:33].[OH:15][CH2:14][C@@H:10]1[O:11][CH2:12][CH2:13][NH:8][CH2:9]1
Reactant: OCC1CN(Cc2ccccc2)CCO1
Agent: [Pd]
Agent: c1ccc(CN2CCCOCC2)cc1
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: OC[C@H]1CNCCO1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
In the same manner as in Example 3, a mixture containing N-benzyl-2-hydroxymethylmorpholine, N-benzyl-1,4-oxazepane and other byproducts (121.1 g, N-benzyl-2-hydroxymethylmorpholine:N-benzyl-1,4-oxazepane compound=75.1:24.9). To this mixture were added methanol (200 ml), trifluoroacetic acid (61.8 g, 0.540 mol), and palladium carbon (11.0 g when dry), and the mixture was reacted under a hydrogen stream at 25° C. for 15 hr. Palladium carbon was filtered off, and methanol was evaporated under reduced pressure. The residue was subjected twice to azeotropic distillation with dehydrating with 2-propanol (100 ml). To the residue after azeotropic distillation with dehydrating was added ethyl acetate (450 ml) at 40° C., and the mixture was cooled to 20° C. Seed crystal was added and, after crystallization, the mixture was cooled to 0° C. and stirred for 1 hr. The crystals were collected by filtration, washed withed twice with ethyl acetate (100 ml) and dried (1 mmHg, 40° C.) to give (R)-2-hydroxymethylmorpholine trifluoroacetate (53.7 g) (yield from (S)-epichlorohydrin: 43.0%). The obtained (R)-2-hydroxymethylmorpholine trifluoroacetate was analyzed by HPLC to find an optical purity of 99% ee.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]2[CH:10]=[CH:9][C:8]([N:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)=[N:7][C:6]=12.[NH:17](C(OC(C)(C)C)=O)[C@H:18]([C:22](O)=[O:23])[CH2:19][O:20][CH3:21].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C.C(Cl)Cl>[NH2:17][C@@H:18]([CH2:19][O:20][CH3:21])[C:22]([N:14]1[CH2:15][CH2:16][N:11]([C:8]2[CH:9]=[CH:10][N:5]3[N:4]=[CH:3][C:2]([Br:1])=[C:6]3[N:7]=2)[CH2:12][CH2:13]1)=[O:23]
Reactant: COC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: Brc1cnn2ccc(N3CCNCC3)nc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC[C@H](N)C(=O)N1CCN(c2ccn3ncc(Br)c3n2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-Bromo-5-(piperazin-1-yl)pyrazolo[1,5-a]pyrimidine (300 mg, 1.1 mmol) taken up in 10 mL DMF. Boc-Ser(Me)-OH (280 mg, 1.3 mmol), HATU (368 mg, 1.6 mmol), and triethylamine (590 uL, 4.25 mmol) was added and stirred at room temp overnight. Reaction was diluted with DCM and washed with water. DCM layer was dried over magnesium sulfate reduced in vacuo. This was then taken up in 30% TFA in DCM solution and stirred at room temperature for 2 hours. It was then cooled to 0° C. and conc Aq NaOH added slowly until aqueous layer remains basic. DCM layer extracted dried over magnesium sulfate, reduced in vacuo for 405 mg crude product for further reaction as is. LRMS (ESI) m/z 383/385 [(M+H)]+, calc'd for C14H19BrN6O2: 383.25.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[N:7]1[CH2:12][CH2:11][CH:10]([OH:13])[CH2:9][CH2:8]1.CC(C)([O-])C.[K+].[F:20][C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=1[C@@:28]1([CH2:32][N:33]2[CH:37]=[N:36][CH:35]=[N:34]2)[C@@H:30]([CH3:31])[O:29]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[F:20][C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=1[C@:28]([OH:29])([C@H:30]([O:13][CH:10]1[CH2:9][CH2:8][N:7]([C:2]2[N:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[CH2:12][CH2:11]1)[CH3:31])[CH2:32][N:33]1[CH:37]=[N:36][CH:35]=[N:34]1
Reactant: C[C@H]1O[C@@]1(Cn1cncn1)c1ccc(F)cc1F
Reactant: OC1CCN(c2ncccn2)CC1
Agent: CC(C)(C)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[C@@H](OC1CCN(c2ncccn2)CC1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 21 %

Procedure:
To a solution of 1-(pyrimidin-2-yl)piperidin-4-ol (19.4 mg, 0.08 mmol) in N,N-dimethylformamide (0.5 mL) was added potassium tert-butoxide (10.7 mg, 0.01 mmol), followed by stirring at room temperature for 2 hrs. The resulting solution was mixed with 1-(((2R,3R)-2-(2,4-difluorophenyl)-3-methyloxiran-2-yl)methyl)-1H-1,2,4-triazole (20.0 mg, 0.08 mmol) and anhydrous potassium carbonate (13.2 mg, 0.01 mmol) and stirred at room temperature for one hr. The resulting reaction mixture was diluted with ethyl acetate, and washed with a saturated aqueous ammonium chloride solution and then with saline to separate an organic solvent layer. The organic solvent layer was dried over anhydrous magnesium sulfate and concentrated by evaporation at reduced pressure. The concentrate was purified using silica gel chromatography to afford the title compound (yield 21%).
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([C:12]([CH2:15][CH3:16])=[N:13][N:14]=2)[C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH3:17][O:18][C:19]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=1[NH2:26].C1(N)CCCC1>>[Cl:25][C:23]1[CH:22]=[CH:21][C:20]([NH:26][C:2]2[C:3]3[N:4]([C:12]([CH2:15][CH3:16])=[N:13][N:14]=3)[C:5]3[C:10]([N:11]=2)=[CH:9][CH:8]=[CH:7][CH:6]=3)=[C:19]([O:18][CH3:17])[CH:24]=1
Reactant: COc1cc(Cl)ccc1N
Reactant: CCc1nnc2c(Cl)nc3ccccc3n12
Agent: NC1CCCC1
Product: CCc1nnc2c(Nc3ccc(Cl)cc3OC)nc3ccccc3n12

Procedure:
The title compound was prepared essentially as described in Example 2 substituting 4-chloro-1-ethyl [1,2,4]triazolo[4,3-a]quinoxaline and 2-methoxy-4-chlorobenzenamine for 4-chloro-1-methyl1,2,4]triazolo[4,3-a]quinoxaline and cyclopentanamine respectively; mp 245°-248° C.
Reaction SMILES: [N:1]([O-])=O.[Na+].[NH2:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[CH:8][C:7]=1[O:15][CH3:16].O.O.[Cl:19][Sn]Cl>O.Cl>[ClH:19].[NH:5]([C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[CH:8][C:7]=1[O:15][CH3:16])[NH2:1]
Reactant: Cl[Sn]Cl
Reactant: O=N[O-]
Reactant: COc1cc(C(=O)O)ccc1N
Agent: Cl
Agent: [Na+]
Solvent: O
Product: COc1cc(C(=O)O)ccc1NN
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A solution of 2.17 g of NaNO2 in 40 ml of H2O is added slowly to a solution, cooled to 0° C., of 5 g of 4-amino-3-methoxybenzoic acid in 50 ml of concentrated HCl. After 1 hour 15 minutes of stirring at 0° C., the mixture is cooled to -10° C., and a solution of 23.6 g of SnCl2.2H2O in 20 ml of concentrated HCl and 20 ml of water is added over 30 min. After one and a half hours of stirring at -10° C., the mixture is filtered, and the precipitate is washed with 50 ml of pentane to obtain, after drying, 6 g of expected product.
Reaction SMILES: [OH-:1].[Na+:2].C(C(CCCC)[CH2:6][OH:7])C.[C:12]1([CH3:19])[C:17]([OH:18])=[CH:16][CH:15]=[CH:14][CH:13]=1>C1(C)C(C)=CC=CC=1>[C:12]1([CH3:19])[C:13]([C:6]([O-:7])=[O:1])=[CH:14][CH:15]=[CH:16][C:17]=1[OH:18].[Na+:2]
Reactant: [OH-]
Reactant: Cc1ccccc1O
Reactant: CCCCC(CC)CO
Agent: [Na+]
Solvent: Cc1ccccc1C
Product: Cc1c(O)cccc1C(=O)[O-]

Procedure:
A five liter flask was equipped with a stirrer, thermometer dropping funnel, heating mantle, Dean-Stark trap and a reflux condenser. 329 grams of a 48.6% aqueous solution of NaOH was added to the flask along with 2000 ml of a 4:1 mixture of xylene and 2-ethyl-1-hexanol. 433 grams of commercial cresol (99.4% pure) was slowly added. The batch was heated to reflux to collect the water. The product was a solution of sodium cresolate:xylene-2-ethyl-1-hexanol mixture.
Reaction SMILES: [CH2:1]([N:5]1[CH2:9][CH2:8][CH2:7][CH:6]1[CH3:10])[CH2:2][C:3]#[CH:4].[Br:11][C:12]1[CH:17]=[CH:16][C:15]([NH2:18])=[C:14](I)[CH:13]=1>>[Br:11][C:12]1[CH:17]=[CH:16][C:15]([NH2:18])=[C:14]([C:4]#[C:3][CH2:2][CH2:1][N:5]2[CH2:9][CH2:8][CH2:7][CH:6]2[CH3:10])[CH:13]=1
Reactant: C#CCCN1CCCC1C
Reactant: Nc1ccc(Br)cc1I
Product: CC1CCCN1CCC#Cc1cc(Br)ccc1N

Procedure:
The compound of formula (43) can be prepared from 3-butynyl p-toluenesulfonate (42) and 2(R)-methylpyrrrolidine L-tartrate (40) as shown in Scheme 5. 2(R)-Methylpyrrolidine L-tartrate (40) is treated with potassium carbonate in acetonitrile to provide 2(R)-methylpyrrolidine (41), which is combined with 3-butynyl p-toluenesulfonate (42) to give 1-but-3-ynyl-2-methyl-pyrrolidine (43). Compound (43) is reacted with 4-bromo-2-iodo-phenylamine (44) to provide 4-bromo-2-[4-(2-methyl-pyrrolidin-1-yl)-but-1-ynyl]-phenylamine (45). Compound (45) undergoes cyclization to compound (46) in the presence of a strong base, such as potassium t-butoxide. Compound (46) then is subjected to the Suzuki reaction conditions with an aryl or heteroaryl boronic acid, such as 4-cyanophenylboronic acid, to give compound (47) and (47a). Alternatively, in the presence of base and an alkylating agent, compounds (45) and (46) are alkylated with an alkyl halide such as methyl iodide to give an N-alkyl indole compounds, such as compound (48). Compound formula (48) is then subjected to the Suzuki reaction conditions with an aryl or heteroaryl boronic acid, such as 4-cyanophenylboronic acid, to give compounds such as compound (49) and (49a). Similarly, the compounds (40) and (41) can be substituted with any other suitable amine to provide the corresponding amine-substituted indole compound. In addition, the 4-cyanophenylboronic acid can be substituted with other boronic acids of the formula RcB(OH)2, wherein Rc is aryl or heteroaryl, to provide compounds of general structures (47a) and (49a), wherein R1 is aryl, heteroaryl, or heterocycle.