Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([N:6]1[CH2:11][CH2:10][CH:9]([S:12][C:13]2[CH:14]=[CH:15][C:16]3[O:25][CH2:24][CH2:23][N:22]4[C:18](=[N:19][C:20]([C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=5)=[CH:21]4)[C:17]=3[CH:32]=2)[CH2:8][CH2:7]1)([CH3:5])[CH2:3][OH:4].C(O)(C(F)(F)F)=[O:34].C1C=C(Cl)C=C(C(OO)=O)C=1>C(Cl)Cl>[CH3:5][C:2]([N:6]1[CH2:7][CH2:8][CH:9]([S:12]([C:13]2[CH:14]=[CH:15][C:16]3[O:25][CH2:24][CH2:23][N:22]4[CH:21]=[C:20]([C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=5)[N:19]=[C:18]4[C:17]=3[CH:32]=2)=[O:34])[CH2:10][CH2:11]1)([CH3:1])[CH2:3][OH:4]
Reactant: CC(C)(CO)N1CCC(Sc2ccc3c(c2)-c2nc(-c4ccccn4)cn2CCO3)CC1
Reactant: O=C(O)C(F)(F)F
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC(C)(CO)N1CCC(S(=O)c2ccc3c(c2)-c2nc(-c4ccccn4)cn2CCO3)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 52.7 %

Procedure:
To an ice-cooled solution of 2-methyl-2-[4-(2-pyridin-2-yl-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulen-9-ylsulfanyl)piperidin-1-yl]propan-1-ol from Example 3 (187 mg, 0.415 mmol) in DCM (20 mL) was added TFA (160 μL, 2.075 mmol) followed by a solution of m-CPBA (79 mg, 0.456 mmol) in DCM (2 mL). The resulting mixture was stirred for 30 min at 0° C. then volatiles were removed under reduced pressure. The crude material was purified by column chromatography (C18, gradient 10-30% MeOH in 0.5% TFA/H2O) and then loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH and the product was eluted with 0.5M NH3 in MeOH. Further purification by column chromatography (Si-PCC, gradient 2-17% 2M NH3/MeOH in DCM) afforded 197 as a light brown foam (102 mg, 52%). LCMS: RT1.87 min [M+H]+ 467.1. 1H NMR (DMSO, 400 MHz): δ 8.71 (1H, d, J=2.27 Hz), 8.53 (1H, ddd, J=4.81, 1.82, 0.94 Hz), 8.00 (1H, dt, J=7.92, 1.08 Hz), 7.95 (1H, s), 7.83 (1H, td, J=7.70, 1.85 Hz), 7.50 (1H, dd, J=8.51, 2.30 Hz), 7.26-7.21 (2H, m), 4.58-4.52 (4H, m), 4.18 (1H, t, J=5.42 Hz), 3.21 (2H, d, J=5.19 Hz), 3.07-2.98 (2H, m), 2.72-2.62 (1H, m), 2.17-2.04 (2H, m), 1.78-1.72 (1H, m), 1.48-1.41 (3H, m), 0.89 (6H, s)
Reaction SMILES: [Cl:1][C:2]1[C:13]([Cl:14])=[CH:12][C:5]2[O:6][C@@H:7]([CH2:10][OH:11])[CH2:8][O:9][C:4]=2[CH:3]=1.[H-].[Na+].[S:17](Cl)(=[O:20])(=[O:19])[NH2:18]>CN(C=O)C.O>[S:17](=[O:20])(=[O:19])([O:11][CH2:10][CH:7]1[O:6][C:5]2[CH:12]=[C:13]([Cl:14])[C:2]([Cl:1])=[CH:3][C:4]=2[O:9][CH2:8]1)[NH2:18]
Reactant: NS(=O)(=O)Cl
Reactant: OC[C@H]1COc2cc(Cl)c(Cl)cc2O1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: NS(=O)(=O)OCC1COc2cc(Cl)c(Cl)cc2O1
Reaction time: 0.5 h

Procedure:
(2S)-6,7 dichloro-2,3-dihydro-benzo[1,4]dioxin-2-ylmethanol (2.0 g, 8.5 mmol), prepared according to the procedure described in Example 11 above, in DMF (20 mL) was cooled in an ice bath. Then, 95% sodium hydride (0.28 g, 11 mmol) was added under argon and the reaction mixture was stirred 30 min. Sulfamoyl chloride (1.97 g, 17 mmol) was added and the reaction mixture was stirred with ice bath cooling. After 1 h, the reaction mixture was diluted with water (50 mL) and extracted three times with ethyl acetate. The combined ethyl acetate was washed with brine, dried (Na2SO4) and evaporated in vacuo to an oil, which was purified by flash column chromatography (ethyl acetate/heptane 1:1) to yield a white solid. The white solid was recrystallized from benzene to yield the title compound as a white solid.
Reaction SMILES: Cl.[Cl:2][C:3]1[N:4]=[C:5]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][C@@H:13]2[CH3:18])[C:6]2[CH2:11][NH:10][CH2:9][C:7]=2[N:8]=1.[CH2:19]=O>>[Cl:2][C:3]1[N:4]=[C:5]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][C@@H:13]2[CH3:18])[C:6]2[CH2:11][N:10]([CH3:19])[CH2:9][C:7]=2[N:8]=1
Reactant: C=O
Reactant: C[C@H]1COCCN1c1nc(Cl)nc2c1CNC2
Agent: Cl
Product: C[C@H]1COCCN1c1nc(Cl)nc2c1CN(C)C2

Procedure:
Method as intermediate 8 using (S)-4-(2-chloro-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yl)-3-methylmorpholine hydrochloride (intermediate 6) and formaldehyde as starting materials.
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[CH3:6][C:7]1[O:8][C:9]2[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=2[N:11]=1>>[CH3:6][C:7]1[O:8][C:9]2[CH:15]=[C:14]([S:2]([Cl:1])(=[O:5])=[O:3])[CH:13]=[CH:12][C:10]=2[N:11]=1
Reactant: Cc1nc2ccccc2o1
Reactant: O=S(=O)(O)Cl
Product: Cc1nc2ccc(S(=O)(=O)Cl)cc2o1
Temperature: 117.5 °C
Yield: 59.9 %

Procedure:
Chlorosulfonic acid (12.5 ml, 187.8 mmol) was cooled in an ice bath and 2-methylbenzoxazole (5.0 g, 37.5 mmol) was carefully added drop wise over a period of 15 min. The combined mixture was heated at 115-120° C. for 16 hours. After cooling, the mixture was added very slowly to ca. 100 ml ice/water mix. The white solid that separated was collected by filtration, washed with water until washings were neutral and dried to yield 5.2 g (59%) of Compound 8, whose structure is given below:
Reaction SMILES: [CH3:1][C:2]([O:4][C@H:5]1[C:14]2[C@@:15]3([CH3:30])[C@@H:26]([CH2:27][O:28][CH3:29])[O:25][C:23](=[O:24])[C:17]4=[CH:18][O:19][C:20]([C:21](=[O:22])[C:13]=2[C@@H:8]2[CH2:9][CH2:10][C@H:11]([OH:12])[C@@:7]2([CH3:31])[CH2:6]1)=[C:16]34)=[O:3].[NH:32]1[CH2:36][CH2:35][CH2:34][CH2:33]1>C(Cl)Cl>[C:2]([O:4][C@H:5]1[C:14]2[C@:15]3([CH3:30])[C:16](/[C:17](=[CH:18]\[N:32]4[CH2:36][CH2:35][CH2:34][CH2:33]4)/[C:23](=[O:24])[O:25][C@@H:26]3[CH2:27][O:28][CH3:29])=[C:20]([OH:19])[C:21](=[O:22])[C:13]=2[C@H:8]2[C@@:7]([CH3:31])([C@@H:11]([OH:12])[CH2:10][CH2:9]2)[CH2:6]1)(=[O:3])[CH3:1]
Reactant: C1CCNC1
Reactant: COC[C@H]1OC(=O)c2coc3c2[C@@]1(C)C1=C(C3=O)[C@@H]2CC[C@H](O)[C@@]2(C)C[C@H]1OC(C)=O
Solvent: ClCCl
Product: COC[C@H]1OC(=O)/C(=C/N2CCCC2)C2=C(O)C(=O)C3=C([C@H](OC(C)=O)C[C@]4(C)[C@@H](O)CC[C@@H]34)[C@]21C
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.7 %

Procedure:
To a solution of 50 mg (0.116 mmol) 17-hydroxywortmannin in 1 mL methylene chloride (CH2Cl2) is added 12.1 mL (0.145 mmol) pyrrolidine. The reaction mixture is stirred at room temperature for 2 hours and then concentrated in vacuo. The residue is dissolved in EtOAc and precipitated with hexane. The precipitate is washed two times with hexane to give 40 mg (68.7%) product as a yellow solid. HRMS (ESI) m/z calcd for C27 H35NO8 501.2364, found: 502.24250 (M+H)+1.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@H:11]([CH3:13])[C@@H:10]([C:14]([NH:16][CH:17]2[CH2:19][CH2:18]2)=O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1>[CH2:1]([N:8]1[CH2:12][C@H:11]([CH3:13])[C@@H:10]([CH2:14][NH:16][CH:17]2[CH2:19][CH2:18]2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@H]1CN(Cc2ccccc2)C[C@@H]1C(=O)NC1CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: C[C@H]1CN(Cc2ccccc2)C[C@@H]1CNC1CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 93.8 %

Procedure:
(3R,4R)-1-Benzyl-N-cyclopropyl-4-methyl-3-pyrrolidinecarboxamide (70.0 g) was dissolved in toluene (700 mL). While this solution was cooled on an ice bath, a borane-dimethyl sulfide complex (90%, 34.3 mL) was added dropwise. The mixture was then stirred for 15 min and was heat-refluxed. After the reaction mixture was cooled to room temperature, a 10% aqueous solution of Na2CO3 (400 mL) was added and the mixture was stirred at 100° C. for 2 hours. The mixture was cooled to room temperature and the toluene layer was separated. The toluene layer was then washed with water (2×250 mL), was dried over anhydrous sodium sulfate, and was concentrated under reduced pressure. The resulting residue was purified by distillation under reduced pressure to obtain (3S,4R)-1-benzyl-3-cyclopropylaminomethyl-4-methylpyrrolidine (62.1 g) as a colorless oil.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[N:11]3[N:12]=[C:13](Cl)[CH:14]=[CH:15][C:10]3=[N:9][N:8]=2)=[CH:5][N:4]=[C:3]1[N+:17]([O-:19])=[O:18].[CH3:20][NH:21][CH2:22][CH2:23][N:24]([CH3:26])[CH3:25]>CN(C)C=O>[CH3:1][N:2]1[C:6]([C:7]2[N:11]3[N:12]=[C:13]([N:21]([CH3:20])[CH2:22][CH2:23][N:24]([CH3:26])[CH3:25])[CH:14]=[CH:15][C:10]3=[N:9][N:8]=2)=[CH:5][N:4]=[C:3]1[N+:17]([O-:19])=[O:18]
Reactant: CNCCN(C)C
Reactant: Cn1c(-c2nnc3ccc(Cl)nn23)cnc1[N+](=O)[O-]
Solvent: CN(C)C=O
Product: CN(C)CCN(C)c1ccc2nnc(-c3cnc([N+](=O)[O-])n3C)n2n1

Procedure:
0.65 g. 3-(1-methyl-2-nitro-5-imidazolyl)-6-chloro-s-triazolo[4,3-b]pyridazine were reacted in 13 ml. dimethyl formamide with 0.5 g. trimethylethylenediamine at 60° C. for 15 minutes. After working up the reaction mixture in a manner analogous to that described in Example 47, there was obtained 0.6 g. (75% of theory) of the desired 3-(1-methyl-2-nitro-5-imidazolyl)-6[N-methyl-N-(β-dimethyl-aminoethyl)-amino]-s-triazolo[4,3-b]pyridazine in the form of yellow crystals which have a melting point of 196° - 198° C.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([O:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)=[CH:16][CH:15]=1)=[C:8]([C:29]1[CH:34]=[CH:33][C:32]([S:35]([NH:38][CH3:39])(=[O:37])=[O:36])=[CH:31][CH:30]=1)[CH:7]=[CH:6]2.[ClH:40].C(OCC)C.B(Br)(Br)Br>ClCCl>[ClH:40].[OH:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([O:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][N:23]3[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]3)=[CH:16][CH:15]=1)=[C:8]([C:29]1[CH:30]=[CH:31][C:32]([S:35]([NH:38][CH3:39])(=[O:36])=[O:37])=[CH:33][CH:34]=1)[CH:7]=[CH:6]2
Reactant: CNS(=O)(=O)c1ccc(-c2ccc3cc(OC)ccc3c2Oc2ccc(OCCN3CCCCC3)cc2)cc1
Agent: BrB(Br)Br
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: CNS(=O)(=O)c1ccc(-c2ccc3cc(O)ccc3c2Oc2ccc(OCCN3CCCCC3)cc2)cc1
Reaction time: 0.03 h
Yield: 85 %

Procedure:
In a round bottom flask place the product of Example 69 (85 mg, 0.146 mmol), dichloromethane (5 mL) and a solution of 1.0 M hydrochloric acid in diethyl ether (0.150 mL, 0.150 mmol). Shake this solution at ambient temperature for 2 minutes and then evaporate it in vacuo. After drying in vacuo, add dichloromethane (6 mL) and place this solution in an ice bath with stirring. Add a solution of 1.0 M boron tribromide in dichloromethane (0.32 mL, 0.32 mmol) and stir the reaction for 2-3 hours, keeping the temperature between 0° C.-10° C. Quench the reaction over saturated aqueous sodium bicarbonate then extract it into ethyl acetate. Wash the combined extracts with saturated aqueous sodium bicarbonate, water and brine; then dry (sodium sulfate) and evaporate in vacuo. Purify the crude solid on a Chromatotron (silica gel; 6%-10% MeOH gradient in CH2Cl2). Dissolve the purified material in methanol (5 mL) and add a solution of 1.0 M hydrochloric acid in diethyl ether (0.30 mL). Shake the resulting solution for two minutes at room temperature then evaporate in vacuo to give 71 mg of the title compound (85%). MS (IS+) m/e 533 (M+1-HCl).
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.Br.Br.[C:22]12[CH2:29][NH:28][CH2:27][C:26]=1[CH2:25][NH:24][CH2:23]2.C(N(C(C)C)CC)(C)C>C(#N)C>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11]([N:24]4[CH2:25][C:26]5[CH2:27][NH:28][CH2:29][C:22]=5[CH2:23]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: O=C(O)c1cn(C2CC2)c2cc(F)c(F)cc2c1=O
Reactant: C1NCC2=C1CNC2
Agent: Br
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=C(O)c1cn(C2CC2)c2cc(N3CC4=C(CNC4)C3)c(F)cc2c1=O
Yield: 76.5 %

Procedure:
1-Cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (4.4 g) and 3,7-diazabicyclo[3.3.0] oct-1(5)-ene dihydrobromide (4.2 g) were added to diisopropyl ethylamine (11.6 ml) in acetonitrile (120 ml) and refluxed for 7 hours. The produced precipitate was filtered, washed with acetonitrile (100 ml), water (50 ml), ethanol (50 ml) and them ethyl ether (50 ml) to give the title compound (4.2 g, yield 77%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH:5]=[N:4][C:3]=1[C:16]([F:19])([F:18])[F:17].[Cl:20][C:21]1[C:22](B(O)O)=[CH:23][C:24]([F:27])=[N:25][CH:26]=1.C(=O)([O-])[O-].[Na+].[Na+].B(O)O>COCCOC>[Cl:20][C:21]1[C:22]([C:2]2[N:7]=[C:6]([NH:8][CH2:9][CH:10]3[CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)[CH:5]=[N:4][C:3]=2[C:16]([F:19])([F:18])[F:17])=[CH:23][C:24]([F:27])=[N:25][CH:26]=1
Reactant: FC(F)(F)c1ncc(NCC2CCOCC2)nc1Cl
Reactant: OB(O)c1cc(F)ncc1Cl
Agent: O=C([O-])[O-]
Agent: OBO
Agent: [Na+]
Solvent: COCCOC
Product: Fc1cc(-c2nc(NCC3CCOCC3)cnc2C(F)(F)F)c(Cl)cn1
Temperature: 110 °C
Reaction time: 0.42 h
Yield: 67 %

Procedure:
6-chloro-N-((tetrahydro-2H-pyran-4-yl)methyl)-5-(trifluoromethyl)pyrazin-2-amine (0.020 g, 0.068 mmol), 5-chloro-2-fluoropyridin-4-ylboronic acid (0.036 g, 0.203 mmol), and sodium carbonate (0.088 ml, 0.176 mmol, 2 M in H2O) were dissolved in DME (0.70 ml). The solution was then degassed by sparging with argon for 5 min. It was then treated with PdCl2(dppf)CH2Cl2 adduct (0.011 g, 0.014 mmol). The reaction mixture was then heated in a microwave at 110° C. for 25 min. Boronic acid (˜0.036 g, 0.203 mmol) and PdCl2(dppf)CH2Cl2 adduct (˜0.011 g, 0.014 mmol) were added. Heating in the microwave was continued at 110° C. for 25 min. The reaction mixture was then filtered through a pad of Celite. The filtrate was then concentrated in vacuo to give 0.0759 g of crude product. The resulting residue was subjected to silica gel column chromatography. Elution using 25 EtOAc/75 heptane to 100 EtOAc gave 0.0178 g (67%) of 6-(5-chloro-2-fluoropyridin-4-yl)-N-((tetrahydro-2H-pyran-4-yl)methyl)-5-(trifluoromethyl)pyrazin-2-amine. LCMS (m/z): 391.1 (MH+), retention time=0.96 min.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl.Cl.[NH2:9][CH2:10][CH2:11][S:12][CH2:13][C:14]1[N:15]=[CH:16][NH:17][C:18]=1[CH3:19].[CH3:20][N:21]=[C:22]=[S:23]>O>[CH3:20][NH:21][C:22]([NH:9][CH2:10][CH2:11][S:12][CH2:13][C:14]1[N:15]=[CH:16][NH:17][C:18]=1[CH3:19])=[S:23]
Reactant: Cc1[nH]cnc1CSCCN
Reactant: CN=C=S
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CNC(=S)NCCSCc1nc[nH]c1C
Temperature: 25 °C

Procedure:
Potassium carbonate (7.75 g.) was added to a solution of 14.6 g. of 4-(2-aminoethyl)thiomethyl-5-methylimidazole dihydrochloride in 120 ml. of water. The solution was maintained at ambient temperature for 15 minutes and 5.15 g. of methyl isothiocyanate was added. After heating under reflux for 0.5 hour, the solution was slowly cooled to 5°. The product was collected and recrystallized from water to give N-methyl-N'-[2-(5-methyl-4-imidazolylmethylthio)ethyl]thiourea, m.p. 150°-152°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:41])[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[N:11]([C:21](Cl)=[O:22])[C:10]([C:24]3[CH:29]=[CH:28][C:27]([S:30]([N:33]4[CH2:37][CH2:36][CH2:35][CH2:34]4)(=[O:32])=[O:31])=[CH:26][C:25]=3[O:38][CH2:39][CH3:40])=[N:9]2)=[CH:4][CH:3]=1.Cl.Cl.[N:44]1([CH2:50][CH2:51][NH:52][C:53](=[O:55])[CH3:54])[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([CH3:41])[C@:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[N:11]([C:21]([N:47]3[CH2:46][CH2:45][N:44]([CH2:50][CH2:51][NH:52][C:53](=[O:55])[CH3:54])[CH2:49][CH2:48]3)=[O:22])[C:10]([C:24]3[CH:29]=[CH:28][C:27]([S:30]([N:33]4[CH2:37][CH2:36][CH2:35][CH2:34]4)(=[O:31])=[O:32])=[CH:26][C:25]=3[O:38][CH2:39][CH3:40])=[N:9]2)=[CH:4][CH:3]=1
Reactant: CC(=O)NCCN1CCNCC1
Reactant: CCOc1cc(S(=O)(=O)N2CCCC2)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl
Agent: Cl
Product: CCOc1cc(S(=O)(=O)N2CCCC2)ccc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CCNC(C)=O)CC1

Procedure:
In a manner analogous to the method described in example 5, rac-(4S*,5R*)-4,5-bis-(4-chloro-phenyl)-2-[2-ethoxy-4-(pyrrolidine-1-sulfonyl)-phenyl]-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with N-(2-piperazin-1-yl-ethyl)-acetamide dihydrochloride (prepared as described in Fotouhi, N. et al. WO 2005110996) to give the title compound as a racemic mixture. The enantiomers were then separated by supercritical fluid chromatography (Berger Instrument Multi-Gram II, Daicel ChiralPak OD-H 3×25 cm, 35° C. at 100 bar, eluting with 25% methanol in carbon dioxide). HR-MS (ES, m/z) calculated for C38H46N6O5SCl2 [(M+H)+] 769.2700, observed 769.2697.
Reaction SMILES: C([O:4][C:5]1[CH:6]=[CH:7][C:8]2[CH2:9][C@H:10]3[N:21]([C:22]([O:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[O:23])[CH2:20][CH2:19][C@@:16]4([C:17]=2[CH:18]=1)[C@H:11]3[CH2:12][CH2:13][O:14][CH2:15]4)(=O)C.[OH-].[K+].P(=O)(O)(O)O>CC(O)C.O>[C:22]([N:21]1[CH2:20][CH2:19][C@@:16]23[C:17]4[CH:18]=[C:5]([OH:4])[CH:6]=[CH:7][C:8]=4[CH2:9][C@@H:10]1[C@@H:11]2[CH2:12][CH2:13][O:14][CH2:15]3)([O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:23]
Reactant: CC(=O)Oc1ccc2c(c1)[C@]13CCN(C(=O)Oc4ccccc4)[C@H](C2)[C@@H]1CCOC3
Agent: O=P(O)(O)O
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: O=C(Oc1ccccc1)N1CC[C@]23COCC[C@H]2[C@H]1Cc1ccc(O)cc13
Temperature: 10 °C
Reaction time: 2 h

Procedure:
A cooled solution of XXVII from Step (b) above (0.01 m) in 25 ml 2-propanol (~10° C.) is treated with a solution of potassium hydroxide (3 g) in 25 ml water and is stirred under nitrogen at 10° C. for 2 hours. The reaction mixture is acidified with phosphoric acid and the 2-propanol removed at reduced pressure. The aqueous mixture is extracted with methylene chloride. The extracts are dried (MgSO4) and concentrated to produce the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH2:11][C:10]2[NH:9][C:8](=[O:12])[CH:7]=[CH:6][C:5]=2[C:4](=[O:13])[CH2:3]1.CI.[C:17](=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[O:13]=[C:4]1[CH2:3][C:2]([CH3:14])([CH3:1])[CH2:11][C:10]2[N:9]([CH3:17])[C:8](=[O:12])[CH:7]=[CH:6][C:5]1=2
Reactant: CC1(C)CC(=O)c2ccc(=O)[nH]c2C1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1c2c(ccc1=O)C(=O)CC(C)(C)C2
Temperature: 25 °C
Reaction time: 21 h
Yield: 50.3 %

Procedure:
A mixture of 5,6,7,8-tetrahydro-7,7-dimethyl-5-oxo-2(1H)-quinolinone (15.0 g), methyl iodide (12.3 g), potassium carbonate (21.6 g), and dimethylformamide (230 ml) was stirred at room temperature for 21 hrs. The reaction mixture was filtered, and the filtrate was concentrated. Ethyl acetate was added to the residue, and the mixture was filtered. The filtrate was washed with brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated to give 8.1 g (50%) of 5,6,7,8-tetrahydro-5-oxo-1,7,7-trimethyl-2(1H)-quinolinone.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]3[C:14]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=4[F:21])=[CH:13][N:12]=[C:11]([C:22]([NH2:24])=[O:23])[C:7]=3[NH:8]2)=[CH:4][CH:3]=1.[CH3:25][S:26](Cl)(=[O:28])=[O:27].N1C=CC=CC=1>ClCCl>[F:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[C:14]1[C:6]2[C:5]3[C:9](=[CH:10][C:2]([NH:1][S:26]([CH3:25])(=[O:28])=[O:27])=[CH:3][CH:4]=3)[NH:8][C:7]=2[C:11]([C:22]([NH2:24])=[O:23])=[N:12][CH:13]=1
Reactant: CS(=O)(=O)Cl
Reactant: NC(=O)c1ncc(-c2ccccc2F)c2c1[nH]c1cc(N)ccc12
Solvent: c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)Nc1ccc2c(c1)[nH]c1c(C(N)=O)ncc(-c3ccccc3F)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 15.4 %

Procedure:
To a solution of 7-amino-4-(2-fluorophenyl)-9H-pyrido[3,4-b]indole-1-carboxamide (25 mg, 0.078 mmol) in dichloromethane (2 mL) at rt was sequentially added methanesulfonyl chloride (22.35 mg, 0.195 mmol) and pyridine (0.016 mL, 0.195 mmol). The mixture was stirred at room temperature for 1 hr and then at 50° C. in a closed vial for 30 min. The mixture was concentrated. The residue was diluted with MeOH (1.5 mL) and subjected to prep. reverse phase HPLC purification. The correct fraction was concentrated under vacuum, basified with saturated NaHCO3 solution to pH 9, and extracted with ethyl acetate (3×30 mL). The combined extracts were washed with brine (25 mL) and dried over anhydrous MgSO4. Removal of solvent under vacuum provided the desired product (4.81 mg, 0.012 mmol, 15.00% yield) as a pale solid. LCMS (M+H)+=399.03. 1H NMR (500 MHz, DMSO-d6) δ: 11.85 (s, 1H), 10.03 (s, 1H), 8.30 (s, 1H), 8.23 (s, 1H), 7.77 (s, 1H), 7.75 (s, 1H), 7.67-7.63 (m, 2H), 7.50-7.43 (m, 2H), 7.19 (d, J=7.7 Hz, 1H), 6.92 (dd, J1=8.8 Hz, J2=2.2 Hz, 1H), 3.02 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH2:9][NH:8][CH2:7]1)=[O:5])[CH3:2].[O:12]1[CH2:14][C@@H:13]1[CH2:15][O:16][C:17]1[CH:26]=[CH:25][CH:24]=[C:23]2[C:18]=1[CH:19]=[CH:20][CH:21]=[N:22]2>C(O)C>[CH2:1]([O:3][C:4]([C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([CH2:14][CH:13]([OH:12])[CH2:15][O:16][C:17]2[CH:26]=[CH:25][CH:24]=[C:23]3[C:18]=2[CH:19]=[CH:20][CH:21]=[N:22]3)[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CCCNC1
Reactant: c1cc(OC[C@H]2CO2)c2cccnc2c1
Solvent: CCO
Product: CCOC(=O)[C@@H]1CCCN(CC(O)COc2cccc3ncccc23)C1
Temperature: 25 °C

Procedure:
Piperidine-3-carboxylic acid ethyl ester (43) (1.0 g; 6.36 mmol) and (R)-5-oxiranylmethoxy-quinoline (2) (1.28 g; 6.36 mmol) are combined in 10 mL of absolute ethanol. The mixture is heated at reflux for 16 hours. After cooling to ambient temperature, the solution is concentrated in vacuo at 40° C. The residue is chromatographed on silica gel (1:1 acetone:hexanes) affording the desired product (44) as an oil. ESMS:MH+ 359
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:8]=[C:9]([CH:15]=[CH:16][CH:17]=2)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:3][CH:2]=1.O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[Pd].C(O)(C)C.O>[NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:8]=[C:9]([CH:15]=[CH:16][CH:17]=2)[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:3][CH2:2]1
Reactant: CCOC(=O)c1cccc(-c2ccncc2)c1
Agent: [Pd]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: O
Solvent: CC(C)O
Product: CCOC(=O)c1cccc(C2CCNCC2)c1
Temperature: 70 °C
Reaction time: 15 h
Yield: 79.4 %

Procedure:
Ethyl 3-(pyridin-4-yl)benzoate (1.46 g, 6.42 mmol), 5% palladium on carbon (50% wet) (0.301 g, 0.07 mmol) and citric acid monohydrate (0.601 g, 2.86 mmol) in a mixture of isopropanol (50 mL) and water (5 mL) were stirred under an atmosphere of hydrogen at 20 atmosphere and 70° C. for 15 hours. The reaction was cooled to room temperature, the catalyst removed by filtration and the solvent evaporated to give the crude product, which was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 2M ammonia in methanol to give ethyl 3-(piperidin-4-yl)benzoate (1.190 g, 79%) as a liquid.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[C:12]([F:15])([F:14])[F:13])[NH:8][CH2:7][CH2:6]2.I[Si](C)(C)C.CO>C(Cl)(Cl)Cl>[OH:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[C:12]([F:15])([F:13])[F:14])[NH:8][CH2:7][CH2:6]2
Reactant: COc1cc2c(cc1C(F)(F)F)NCC2
Agent: C[Si](C)(C)I
Solvent: ClC(Cl)Cl
Solvent: CO
Product: Oc1cc2c(cc1C(F)(F)F)NCC2

Procedure:
A mixture of 5-methoxy-6-trifluoromethylindoline (D9, 7.5 g, 34.3 mmol) and iodotrimethylsilane (12.5 ml, 89.3 mmol) in dry chloroform (70 ml) was heated under reflux for 65 h. Methanol was then added cautiously with stirring to the cooled mixture, and solvent was then removed in vacuo. The residue was treated with saturated sodium bicarbonate solution and water until basic, and then extracted with dichloromethane/methanol. The organic extract was washed with brine, dried and evaporated. The residue was extracted with ether in a Soxhlet apparatus, and concentration of the resultant solution gave the title compound in three crops (total 2.85 g, 41%), m.p.>180° (decomp.).