Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:3]=1[CH2:4][CH:5]1[C:14]2[C:9](=[N:10][CH:11]=[CH:12][CH:13]=2)[NH:8][CH2:7][CH2:6]1.[Br:20]N1C(=O)CCC1=O>C(Cl)Cl.C(O)(=O)C>[Br:20][C:12]1[CH:13]=[C:14]2[C:9](=[N:10][CH:11]=1)[NH:8][CH2:7][CH2:6][CH:5]2[CH2:4][C:3]1[CH:15]=[C:16]([F:19])[CH:17]=[CH:18][C:2]=1[F:1]
Reactant: Fc1ccc(F)c(CC2CCNc3ncccc32)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC(=O)O
Solvent: ClCCl
Product: Fc1ccc(F)c(CC2CCNc3ncc(Br)cc32)c1

Procedure:
To a solution of 4-(2,5-difluorobenzyl)-1,2,3,4-tetrahydro-[1,8]naphthyridine (23 mg) in CH2Cl2/acetic acid (5.5 mL, 10:1, v/v) was added N-bromosuccinimide (18.8 mg, 1.2 eq). The reaction was stirred at room temperature for one (1) hour, concentrated under reduced pressure, and purified by silica gel chromatography using a gradient of 0-60% ethyl acetate/hexane as the eluting solvent to give the title compound as a clear, colorless oil (30% yield). LCMS: m/z=339 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 1.66-1.75 (m, 1H), 1.75-1.86 (m, 1H), 2.73 (dd, J=9.6 and 13.4 Hz, 1H), 2.95 (dd, J=6.0 and 13.4 Hz, 1H), 2.99-3.08 (m, 1H), 3.34-3.43 (m, 1H), 3.45-3.55 (m, 1H), 5.22 (bs, 1H), 6.80-6.86 (m, 1H), 6.88-6.96 (m, 1H), 6.98-7.05 (m, 1H), 7.16 (d, J=1.9 Hz, 1H), 7.91 (d, J=1.9 Hz, 1H).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:20]([CH:23]1[CH2:31][CH2:30][C:29]2[N:25]([C:26]3[N:45]=[CH:44][N:43]=[C:42]([NH2:46])[C:27]=3[C:28]=2[C:32]2[CH:33]=[N:34][C:35]3[C:40]([CH:41]=2)=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH2:24]1)=[N+]=[N-]>C1COCC1.O>[N:34]1[C:35]2[C:40](=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:41]=[C:32]([C:28]2[C:27]3[C:42]([NH2:46])=[N:43][CH:44]=[N:45][C:26]=3[N:25]3[C:29]=2[CH2:30][CH2:31][CH:23]([NH2:20])[CH2:24]3)[CH:33]=1
Reactant: [N-]=[N+]=NC1CCc2c(-c3cnc4ccccc4c3)c3c(N)ncnc3n2C1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: Nc1ncnc2c1c(-c1cnc3ccccc3c1)c1n2CC(N)CC1
Yield: 72.6 %

Procedure:
Polymer-supported triphenylphosphine (˜3.0 mmol/g, 1.42 g) was added to a solution of 8-azido-5-(quinolin-3-yl)-6,7,8,9-tetrahydropyrimido[5,4-b]indolizin-4-amine (508 mg) obtained in Step 10 in THF (10 ml) and water (1 ml) at room temperature. The reaction mixture was heated under reflux for 1 hour. After cooling, the reaction mixture was filtered through Celite, washed with ethanol, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (developing solvent: chloroform/methanol) to obtain the title compound as a yellow solid (342 mg). ESI-MS m/z 331 (MH+).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34](Br)=[CH:33][CH:32]=2)=[C:28]([CH:38]([CH3:40])[CH3:39])[NH:27][N:26]=1)(=[O:3])[CH3:2].[C:41]([OH:46])(=[O:45])[CH2:42][CH:43]=[CH2:44].C(N(CC)CC)C.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34](/[CH:44]=[CH:43]/[CH2:42][C:41]([OH:46])=[O:45])=[CH:33][CH:32]=2)=[C:28]([CH:38]([CH3:40])[CH3:39])[NH:27][N:26]=1)(=[O:3])[CH3:2]
Reactant: C=CCC(=O)O
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(Br)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(/C=C/CC(=O)O)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Yield: 57.5 %

Procedure:
To a solution of 3-(2,3,4,6-tetra-O-acetyl-β-D-gluco-pyranosyloxy)-4-[(4-bromophenyl)methyl]-5-isopropyl-1H-pyrazole (3.0 g) and 3-butenoic acid (1.0 g) in acetonitrile (15 mL) were added triethylamine (2.4 g), palladium acetate (II) (0.11 g) and tris(2-methylphenyl)phosphine (0.29 g), and the mixture was refluxed overnight under shading the light. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: ethyl acetate-dichloromethane/methanol=10/1) to give the title compound (1.74 g).
Reaction SMILES: Cl[C:2]1[C:7]([F:8])=[CH:6][N:5]=[CH:4][C:3]=1[CH:9]=[O:10].[N-:11]=[N+:12]=[N-:13].[Na+]>CN(C=O)C>[N:11]([C:2]1[C:7]([F:8])=[CH:6][N:5]=[CH:4][C:3]=1[CH:9]=[O:10])=[N+:12]=[N-:13]
Reactant: [N-]=[N+]=[N-]
Reactant: O=Cc1cncc(F)c1Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=Nc1c(F)cncc1C=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 83.6 %

Procedure:
A mixture of 4-chloro-5-fluoro-pyridine-3-carbaldehyde (4.15 g, 26.0 mmol) and sodium azide (1.86 g, 28.6 mmol) in DMF (15 mL) was stirred at room temperature for 18 hours. The reaction mixture was quenched with brine (200 mL) and extracted with ethyl acetate (3×75 mL). The combined organic extracts were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (0-50% ethyl acetate in cyclohexane) to afford the title compound as an off-white solid (3.61 g, 84% yield). 1H NMR (300 MHz, CDCl3): δ 10.32 (s, 1H), 8.79 (s, 1H), 8.58 (d, J=3.0 Hz, 1H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:7]([CH:9]1[O:11][CH2:10]1)Cl.CC(C)([O-])C.[K+]>C(O)(C)(C)C.O1CCCC1>[O:11]1[CH2:10][CH:9]1[CH2:7][N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: ClCC1CO1
Reactant: C1CCNCC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: C1CCOC1
Product: C1CCN(CC2CO2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Piperidine (3 ml) was dissolved in t-butyl alcohol (1.2 ml), and the solution was added dropwise with (±)-epichlorohydrin (2.45 ml) on an ice bath. The mixture was slowly warmed to room temperature as it was, and stirred for 18 hours. Then, the mixture was added dropwise with a solution of potassium t-butoxide (3.39 g) in tetrahydrofuran (18 ml) under ice cooling so that the internal temperature should not exceed 15° C. After the addition, the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, the resulting residue was added to distilled water, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, then dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform:methanol=50:1) to obtain the title compound (1.55 g).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([F:11])[CH:3]=1.Cl.[CH2:13]([NH2:15])[CH3:14]>C(N(CC)CC)C>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:15][CH2:13][CH3:14])=[O:8])=[C:4]([F:11])[CH:3]=1
Reactant: CCN
Reactant: O=C(O)c1ccc(Br)cc1F
Agent: Cl
Solvent: CCN(CC)CC
Product: CCNC(=O)c1ccc(Br)cc1F

Procedure:
The sub-title compound was prepared by the method of example 18 step a) using 4-bromo-2-fluorobenzoic acid, ethylamine hydrochloride and triethylamine.
Reaction SMILES: [CH:1]1([C:4]2[C:5](O)=[N:6][C:7]3[C:12]([CH:13]=2)=[CH:11][CH:10]=[CH:9][N:8]=3)[CH2:3][CH2:2]1.O=P(Cl)(Cl)[Cl:17]>CN(C=O)C>[Cl:17][C:5]1[C:4]([CH:1]2[CH2:3][CH2:2]2)=[CH:13][C:12]2[C:7](=[N:8][CH:9]=[CH:10][CH:11]=2)[N:6]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1nc2ncccc2cc1C1CC1
Solvent: CN(C)C=O
Product: Clc1nc2ncccc2cc1C1CC1
Temperature: 120 °C

Procedure:
A mixture of naphthyridine 4-4 (14 g, 77 mmol) and 100 mL POCl3 and 0.1 mL DMF was refluxed at 120° C. for 3 hr and concentrated. The residue was treated with 300 mL ice-water and solid K2CO3 until pH=9. The mixture was extracted with ethyl acetate (×3), washed with brine and dried over MgSO4. After solvent removal, the desired compound 4-5 was obtained as a yellowish solid.
Reaction SMILES: [C:1]1([C:11]([OH:13])=O)[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C(Cl)=O.[CH2:20]([O:22][C:23]([C:25]1([NH2:34])[CH2:33][C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26]1)=[O:24])[CH3:21].CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:20]([O:22][C:23]([C:25]1([NH:34][C:11]([C:1]2[C:10]3[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=3[CH:4]=[CH:3][CH:2]=2)=[O:13])[CH2:33][C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26]1)=[O:24])[CH3:21]
Reactant: CCOC(=O)C1(N)Cc2ccccc2C1
Reactant: O=C(O)c1cccc2c1CCCC2
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)C1(NC(=O)c2cccc3c2CCCC3)Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 59.1 %

Procedure:
To a solution of 5,6,7,8-tetrahydro-naphthalene-1-carboxylic acid (500 mg, 2.84 mmol) in DCM (10 mL) is added oxalyl chloride (0.50 mL, 5.68 mmol) dropwise. The resulting solution is stirred at RT for 2 h. After the removal of DCM and excess oxalyl chloride, the residue, 2-amino-indan-2-carboxylic acid ethyl ester (583 mg, 2.84 mmol) and DIPEA (1.88 mL, 11.3 mmol) are dissolved in DCM (20 mL). The resulting solution is stirred overnight. The reaction solution is diluted with DCM (30 mL) and washed with water (1×5 mL) and brine (2×5 mL). The organic layer is dried over anhydrous Na2SO4 and concentrated in vacuo. The residue is purified by flash column chromatography (120 g silica gel, gradient elution: 0%-20% EtOAc in heptane) to give the pure product (37) as white solid (610 mg, 59%).
Reaction SMILES: [CH3:1][N:2]1[C:15]([C:16](OC)=[O:17])=[C:14]([OH:20])[C:5]2[N:6]([CH3:13])[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[C:4]=2[S:3]1(=[O:22])=[O:21].[NH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1(C)C=CC=CC=1>[CH3:1][N:2]1[C:15]([C:16]([NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:17])=[C:14]([OH:20])[C:5]2[N:6]([CH3:13])[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[C:4]=2[S:3]1(=[O:21])=[O:22]
Reactant: Nc1ccccc1
Reactant: COC(=O)C1=C(O)c2c(c3ccccc3n2C)S(=O)(=O)N1C
Solvent: Cc1ccccc1
Product: CN1C(C(=O)Nc2ccccc2)=C(O)c2c(c3ccccc3n2C)S1(=O)=O

Procedure:
2,5-Dihydro-2,5-dimethyl-4-hydroxy-N-phenyl-1,2-thiazino [5,6-b]-indole-3-carboxamide-1,1-dioxide was prepared analogous to Example 9 from methyl 2,5-dihydro-2,5-dimethyl-4-hydroxy-1,2-thiazino[5,6-b]indole-3-carboxylate-1,1-dioxide and aniline in toluene; M.p.: 269°-270° C. (decomposition);
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH2:11][CH3:12])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:13][CH2:14][OH:15].B(F)(F)F.CCOCC.[C:25]([CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])(=O)[CH2:26][CH3:27]>ClCCl>[CH2:33]([O:32][C:30](=[O:31])[CH2:29][C:25]1([CH2:26][CH3:27])[C:6]2[NH:7][C:8]3[C:4]([C:5]=2[CH2:13][CH2:14][O:15]1)=[CH:3][C:2]([Br:1])=[CH:10][C:9]=3[CH2:11][CH3:12])[CH3:34]
Reactant: CCc1cc(Br)cc2c(CCO)c[nH]c12
Reactant: CCOC(=O)CC(=O)CC
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: CCOC(=O)CC1(CC)OCCc2c1[nH]c1c(CC)cc(Br)cc21
Temperature: 25 °C
Reaction time: 5 h
Yield: 53 %

Procedure:
To a solution of 2-(5-bromo-7-ethyl-1H-indol-3-yl)-ethanol in dichloromethane at room temperature under nitrogen was added boron trifluoride diethyl etherate (0.809 g, 5.7 mmol), followed by ethyl propionylacetate (1.038 g, 7.2 mmol). The reaction mixture was stirred at room temperature for 5 hours. It was quenched with saturated sodium bicarbonate solution and extracted with dichloromethane. The extract was dried over magnesium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, 15-20% ethyl acetate/hexane) to give the title compound (0.994 g, 53% yield). ES-MS (m/z) 394 [M+1]+, 392 [M−1]−.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH2:10])[C:6]([NH2:9])=[CH:7][CH:8]=1)#[N:2].[S:11]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[CH:13]=[C:12]1[S:20](Cl)(=[O:22])=[O:21]>N1C=CC=CC=1.C(OCC)(=O)C>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][S:20]([C:12]2[S:11][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[CH:13]=2)(=[O:22])=[O:21])=[C:5]([NH:10][S:20]([C:12]2[S:11][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[CH:13]=2)(=[O:21])=[O:22])[CH:4]=1)#[N:2]
Reactant: O=S(=O)(Cl)c1cc2ccccc2s1
Reactant: N#Cc1ccc(N)c(N)c1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: N#Cc1ccc(NS(=O)(=O)c2cc3ccccc3s2)c(NS(=O)(=O)c2cc3ccccc3s2)c1
Temperature: 80 °C
Yield: 35 %

Procedure:
To a solution of 4-cyanobenzene-1,2-diamine (1 mmol) in pyridine (4 mL), benzothiophene-2-sulfonyl chloride (2.2 mmol) was added in small portions. The reaction mixture was then heated at 80° C. with stirring until the reaction was complete as determined by TLC or LC-MS. The reaction mixture was then diluted with ethyl acetate (20 mL). The organic phase was washed with 10% aqueous HCl solution (15 mL), water (15 mL) and brine (5 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue obtained was purified by flash column chromatography eluting with DCM/EtOAc to obtain 184 mg of N,N′-(4-cyano-1,2-phenylene)bis(1-benzothiophene-2-sulfonamide) as a solid.
Reaction SMILES: [OH:1][CH:2]([CH2:41][OH:42])[CH2:3][N:4]([CH3:40])[C:5]([C:7]1[N:16]2[C:10]([CH2:11][N:12]([C:21]([C:23]3[CH:28]=[CH:27][C:26]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[C:35]([F:38])([F:37])[F:36])=[C:25]([CH3:39])[CH:24]=3)=[O:22])[C:13]3[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=3[CH2:15]2)=[CH:9][CH:8]=1)=[O:6].C(N(CC)C(C)C)(C)C.[C:52](N1C=CN=C1)(N1C=CN=C1)=[O:53]>ClCCl>[CH3:40][N:4]([CH2:3][CH:2]1[CH2:41][O:42][C:52](=[O:53])[O:1]1)[C:5]([C:7]1[N:16]2[C:10]([CH2:11][N:12]([C:21]([C:23]3[CH:28]=[CH:27][C:26]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[C:35]([F:37])([F:38])[F:36])=[C:25]([CH3:39])[CH:24]=3)=[O:22])[C:13]3[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=3[CH2:15]2)=[CH:9][CH:8]=1)=[O:6]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Cc1cc(C(=O)N2Cc3ccc(C(=O)N(C)CC(O)CO)n3Cc3ccccc32)ccc1-c1ccccc1C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C(=O)N2Cc3ccc(C(=O)N(C)CC4COC(=O)O4)n3Cc3ccccc32)ccc1-c1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 10-[(2-methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylic acid (2,3-dihydroxypropyl)-methyl-amide of Example 2 (0.50 g, 0.87 mmol) in dichloromethane (17 mL) at 0° C. was added N,N-diisopropylethyl amine (0.30 mL, 1.72 mmol) followed by 1,1′-carbonyldiimidazole (0.14 g, 0.87 mmol). The reaction was allowed to warm to room temperature while stirring overnight then concentrated in vacuo to give a white solid. The residue was partitioned between dichloromethane and water. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a white foam. Purification by flash chromatography using a solvent system of 80% ethyl acetate in hexane provided the title product, which was redissolved in dichloromethane and evaporated to dryness in vacuo to a white foam (0.48 g).
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:11]=1[CH:20]([CH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1)[OH:21])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].[Na+].[CH3:29]I>C1COCC1>[CH:22]1([CH:20]([O:21][CH3:29])[C:11]2[CH:12]=[CH:13][C:14]([C:16]([F:18])([F:19])[F:17])=[CH:15][C:10]=2[CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[CH2:23][CH2:24][CH2:25][CH2:26]1
Reactant: CI
Reactant: CC(C)(C)[Si](C)(C)OCc1cc(C(F)(F)F)ccc1C(O)C1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(c1ccc(C(F)(F)F)cc1CO[Si](C)(C)C(C)(C)C)C1CCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.3 %

Procedure:
To a solution of (2-((tert-butyldimethylsilyloxy)methyl)-4-(trifluoromethyl)-phenyl)-(cyclopentyl)-methanol (126.8 mg, 0.33 mmol) in THF at 0° C. was added sodium hydride (39.2 mg, 0.98 mmol). The mixture was stirred at room temperature for 30 minutes, cooled to 0° C. and methyl iodide (100 μL, 1.6 mmol) was added. The mixture was stirred at room temperature overnight. Solvent was removed and the residue was purified by chromatography over 12+S Biotage silica column (eluted with 0-20% ethyl acetate in hexanes) to afford the title compound as a colorless oil (120 mg, 91%). 1H NMR (400 MHz, CDCl3) δ ppm 0.13 (s, 6H) 0.96 (s, 9H) 1.11-1.21 (m, 1H) 1.30-1.40 (m, 1H) 1.44-1.70 (m, 5H) 1.77-1.86 (m, 1H) 2.13-2.23 (m, 1H) 3.15 (s, 3H) 4.20 (d, J=7.88 Hz, 1H) 4.77 (d, J=13.69 Hz, 1H) 4.89 (d, J=13.28 Hz, 1H) 7.46-7.55 (m, 2H) 7.77 (s, 1H).
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[CH:7][C:6]=2[CH:5]=[C:4]([O:16][CH3:17])[CH:3]=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1>>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]4=[CH:7][C:6]=3[CH:5]=[C:4]([O:16][CH3:17])[CH:3]=2)=[CH:21][CH:20]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: COc1cc(Br)c2c(c1)cc1n2CCNC1=O
Product: COc1cc(-c2ccc(Cl)cc2)c2c(c1)cc1n2CCNC1=O

Procedure:
The title compound, white solid (64 mg, 78%), MS (ISP) m/z=327.5 [(M+H)+], mp 246° C., was prepared in accordance with the general method of example 1 from 6-bromo-8-methoxy-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 18) (73.8 mg, 0.25 mmol) and commercially available 4-chloro-phenylboronic acid (50.8 mg, 0.325 mmol).
Reaction SMILES: C([O:4][C:5]1[C:6]([O:11][CH:12]([C:14]([O:16][CH3:17])=[O:15])[CH3:13])=[N:7][CH:8]=[CH:9][CH:10]=1)(=O)C.C(=O)([O-])[O-].[K+].[K+].CO>O>[OH:4][C:5]1[C:6]([O:11][CH:12]([C:14]([O:16][CH3:17])=[O:15])[CH3:13])=[N:7][CH:8]=[CH:9][CH:10]=1
Reactant: COC(=O)C(C)Oc1ncccc1OC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: COC(=O)C(C)Oc1ncccc1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.8 %

Procedure:
A mixture of 0.34 g of 3-acetoxy-2-{1-(methoxycarbonyl)ethoxy}pyridine, 0.11 g of potassium carbonate and 2 ml methanol was stirred for 1 hour at room temperature. The reaction solution was poured into water, and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 190 mg of 3-hydroxy-2-{1-(methoxycarbonyl)ethoxy}pyridine.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([Cl:24])(Cl)(Cl)Cl.CN(C)C=O.OC[C:32]1[CH2:33][C@@H:34]2[C@H:37]([CH:38]=1)[C@@:36]([CH2:43][C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])([CH2:39][N+:40]([O-:42])=[O:41])[CH2:35]2>O>[Cl:24][CH2:20][C:32]1[CH2:33][C@@H:34]2[C@H:37]([CH:38]=1)[C@@:36]([CH2:43][C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])([CH2:39][N+:40]([O-:42])=[O:41])[CH2:35]2
Reactant: ClC(Cl)(Cl)Cl
Reactant: CC(C)(C)OC(=O)C[C@]1(C[N+](=O)[O-])C[C@@H]2CC(CO)=C[C@@H]21
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)C[C@]1(C[N+](=O)[O-])C[C@@H]2CC(CCl)=C[C@@H]21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Triphenylphosphine (1.85 g, 7.05 mmol) and carbon tetrachloride (0.78 mL, 8.14 mmol) were added to a dimethylformamide solution (8.0 mL) of tert-butyl(±)-[(1R,5R,6R)-3-(hydroxymethyl)-6-(nitromethyl)bicyclo[3.2.0]hept-3-en-6-yl]acetate (807 mg, 2.71 mmol), and the mixture was stirred at room temperature for 1 hour. To the reaction solution, water was added, followed by extraction with diethyl ether. The organic layer was washed with saturated saline and then dried over anhydrous sodium sulfate. The residue was filtered and concentrated under reduced pressure. Then, the obtained crude product of tert-butyl(±)-[(1R,5R,6R)-3-(chloromethyl)-6-(nitromethyl)bicyclo[3.2.0]hept-3-en-6-yl]acetate was dissolved in dimethylformamide (10 mL). To the solution, sodium thiomethoxide (570 mg, 8.14 mmol) was added with stirring at 0° C., and the mixture was stirred at this temperature for 4 hours. The reaction solution was diluted with ethyl acetate and separated into aqueous and organic layers. The organic layer was washed with a 1 M aqueous sodium hydroxide solution, water, and saturated saline and then dried over anhydrous sodium sulfate. The residue was filtered and concentrated under reduced pressure. Then, the obtained crude product was purified by silica gel column chromatography to obtain the compound of interest as an oil substance (632 mg, 71%).
Reaction SMILES: [CH2:1]([C:5]1[CH:6]=[C:7]([C:11]([OH:13])=[O:12])[S:8][C:9]=1[CH3:10])[CH:2]([CH3:4])[CH3:3].[CH3:14]C#N>>[CH2:1]([C:5]1[C:6]([CH3:14])=[C:7]([C:11]([OH:13])=[O:12])[S:8][C:9]=1[CH3:10])[CH:2]([CH3:4])[CH3:3]
Reactant: Cc1sc(C(=O)O)cc1CC(C)C
Reactant: CC#N
Product: Cc1sc(C(=O)O)c(C)c1CC(C)C

Procedure:
4-Isobutyl-3,5-dimethyl-thiophene-2-carboxylic acid is prepared from 4-isobutyl-5-methyl-thiophene-2-carboxylic acid in analogy to Intermediate A2; LC-MS: tR=0.97 min, [M+1+CH3CN]=254.26; 1H NMR (CDCl3): δ 2.46 (s, 3H), 2.39 (s, 3H), 2.36 (d, J=7.0 Hz, 2H), 1.78 (hept, J=7.0 Hz, 1H), 0.91 (d, J=7.0 Hz, 6H).
Reaction SMILES: [CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([C:27]4[CH:32]=[CH:31][C:30]([CH2:33]Br)=[CH:29][CH:28]=4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:35]1[CH2:39][CH2:38][CH2:37][CH2:36]1>>[CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([C:27]4[CH:32]=[CH:31][C:30]([CH2:33][N:35]5[CH2:39][CH2:38][CH2:37][CH2:36]5)=[CH:29][CH:28]=4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CCNC1
Reactant: Nc1ncnn2c(-c3ccc(CBr)cc3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Product: Nc1ncnn2c(-c3ccc(CN4CCCC4)cc3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Yield: 8 %

Procedure:
Using a procedure similar to that of Example 282 (step 2) with 5-(2-benzyl-2H-indazol-6-yl)-7-(4-bromomethyl-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-4-ylamine and pyrrolidine as starting materials, 17 mg (8%) of the desired product was isolated. 1H NMR (300 MHz, DMSO-d6) δ 8.80 (s, 1 H), 8.05 (d, 2 H), 8.0 (s, 1 H), 7.90 (d, 1 H), 7.70 (s, 1 H), 7.60-7.40 (m, 7 H), 7.25 (d, 1 H), 7.20 (s, 1 H), 5.70 (s, 2 H), 3.70 (m, 2 H), 3.40 (s, 2 H), 2.60 (m, 2 H), 1.70 (m, 4 H); ES-MS m/z 500.03 [M+H]+, HPLC RT (min) 2.30.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([NH:6][C:7](=O)[C:8]3[N:9]2[CH:12]=[CH:13][N:14]=3)=[CH:4][C:3]=1[C:16]([F:19])([F:18])[F:17].CN(C)C1C=CC=CC=1.P(Cl)(Cl)([Cl:31])=O>O.[OH-].[Na+]>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[C:7]([Cl:31])[C:8]3[N:9]2[CH:12]=[CH:13][N:14]=3)=[CH:4][C:3]=1[C:16]([F:19])([F:18])[F:17]
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]c2cc(C(F)(F)F)c(Br)cc2n2ccnc12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)c1ccccc1
Product: FC(F)(F)c1cc2nc(Cl)c3nccn3c2cc1Br
Temperature: 120 °C
Yield: 80.4 %

Procedure:
8-Bromo-7-(trifluoromethyl)imidazo[1,2-a]quinoxalin-4(5H)-one (9.4 g, 0.0283 mol) is stirred under nitrogen with N,N-dimethylaniline (14.5 mL, 0.1123 mol) and phosphoryl chloride (190 mL, 2.0119 mol) at reflux (120° C.) for 1.5 hour. After cooling down to room temperature, the mixture is slowly poured in a mixture of water (2 L) and sodium hydroxide 5N (1 L) below 10° C. The mixture is extracted four times with ethyl acetate (200 mL) and the combined organic phases are washed with water (200 mL), dried over sodium sulfate and concentrated to about 100 mL. Cyclohexane (500 mL) is added at room temperature. The mixture is cooled to 0-5° C. and filtered. The cake is washed with cyclohexane and dried under vacuum to afford the title compound as a yellow solid (7.98 g, 80.4%)