Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C@H:10]([C:23](=[O:37])N2[C@H](CC3C=CC=CC=3)COC2=O)[CH2:11][NH:12][C:13](=[O:22])[O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:5]=[CH:6][C:7]=1[F:8].[OH:38]O.[Li+].[OH-]>O1CCCC1.O>[F:1][C:2]1[CH:3]=[C:4]([CH2:9][C@@H:10]([CH2:11][NH:12][C:13]([O:14][CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[O:22])[C:23]([OH:37])=[O:38])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C(NC[C@H](Cc1ccc(F)c(F)c1)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1)OCc1ccccc1
Reactant: OO
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(NC[C@H](Cc1ccc(F)c(F)c1)C(=O)O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.9 %

Procedure:
To a solution of phenylmethyl {(2S)-2-[(3,4-difluorophenyl)methyl]-3-oxo-3-[(4R)-2-oxo-4-(phenylmethyl)-1,3-oxazolidin-3-yl]propyl}carbamate (548 mg, 1.078 mmol) in tetrahydrofuran (16.200 ml) and Water (5.40 ml) at 0° C. was added H2O2 (0.198 ml, 1.940 mmol)[30 wt %] followed by LiOH (2.69 ml, 2.155 mmol)[0.8M solution]. After 1 h, the solution warmed to 25° C. and stirred 2 h. The reaction mixture was quenched with Na2SO3 solution and the pH was carefully adjusted to ˜3 with 2N HCl solution. The aqueous phase was washed several times with DCM and the combined organic fractions were dried over Na2SO4, concentrated and purified by column chromatography (10-60% EtOAc in hexanes) affording (2S)-3-(3,4-difluorophenyl)-2-[({[(phenylmethyl)oxy]carbonyl}amino)methyl]propanoic acid (260 mg, 0.700 mmol, 64.9% yield) as a clear oil: LCMS (ES) m/e 350 (M+H)+, 1H NMR (400 MHz, DMSO-d6) δ ppm 12.36 (br. s., 1 H) 7.20-7.40 (m, 8 H) 7.03 (br. s., 1 H) 5.02 (s, 2 H) 4.52-4.75 (m, 1 H) 3.01-3.26 (m, 2 H) 2.77 (s, 2 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[N:11][C:12](Cl)=[CH:13][C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[CH:5][CH:4]=1.[CH2:24]([NH:27][C:28]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=1[F:35])[CH2:25][CH3:26]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[N:11][C:12]([N:27]([CH2:24][CH2:25][CH3:26])[C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=3[F:35])=[CH:13][C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2cc(Cl)nnc2-c2ccc(OC)cc2)cc1
Reactant: CCCNc1ccc(F)cc1F
Product: CCCN(c1cc(-c2ccc(OC)cc2)c(-c2ccc(OC)cc2)nn1)c1ccc(F)cc1F
Temperature: 100 °C
Reaction time: 12 h

Procedure:
In a similar manner as in Example 2, 3,4-bis-(4-methoxyphenyl)-6-chloropyridazine (180 mg, 0.551 mmol) and N-(n-propyl)-2,4-difluoroaniline, as starting materials, were stirred 100° C. for 12 hours and then reacted at 170° C. for 10 hours, and post-treatment was then conducted, whereby the title compound was obtained as a pale yellow-brown amorphous solid (137.5 mg, 54.1%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9](Cl)(=[O:11])=[O:10].[NH2:13][C:14]1[C:26]([C:27]([O:29][CH3:30])=[O:28])=[C:18]2[O:19][CH2:20][C@H:21]3[CH2:25][CH2:24][CH2:23][N:22]3[C:17]2=[CH:16][CH:15]=1>N1C=CC=CC=1.C(Cl)Cl>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH:13][C:14]1[C:26]([C:27]([O:29][CH3:30])=[O:28])=[C:18]2[O:19][CH2:20][C@H:21]3[CH2:25][CH2:24][CH2:23][N:22]3[C:17]2=[CH:16][CH:15]=1)(=[O:11])=[O:10]
Reactant: O=S(=O)(Cl)c1ccc(F)cc1Br
Reactant: COC(=O)c1c(N)ccc2c1OC[C@H]1CCCN21
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1c(NS(=O)(=O)c2ccc(F)cc2Br)ccc2c1OC[C@H]1CCCN21
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.9 %

Procedure:
2-Bromo-4-fluorobenzenesulfonyl chloride (0.656 g) was added to a solution of methyl (R)-7-amino-2,3,3a,4-tetrahydro-1H-benzo[b]pyrrolo[1,2-d][1,4]oxazine-6-carboxylate (Intermediate 6, 0.525 g) in pyridine (10 mL) and DCM (10 mL) and the mixture was stirred at room temperature overnight. The mixture was concentrated in vacuo and the residue was partitioned between ethyl acetate and 0.5M hydrochloric acid solution. The organic layer was dried (Na2SO4), filtered and the filtrate was concentrated in vacuo. The residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 0-40% to give a pale yellow solid which was triturated with ether and cyclohexane (1:2) to give methyl (R)-7-(2-bromo-4-fluorobenzenesulfonylamino]-2,3,3a,4-tetrahydro-1H-benzo[b]pyrrolo[1,2-d][1,4]oxazine-6-carboxylate (0.820 g).
Reaction SMILES: I[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([C:11]3[N:12]=[N:13][N:14]([CH3:16])[N:15]=3)=[CH:10][C:5]2=[N:4][CH:3]=1.CC1(C)C(C)(C)OB([C:25]2[CH:26]=[C:27]([NH:31][C:32]([NH:34][CH2:35][C:36]([F:39])([F:38])[F:37])=[O:33])[CH:28]=[CH:29][CH:30]=2)O1.C([O-])([O-])=O.[Cs+].[Cs+]>COCCOC>[CH3:16][N:14]1[N:13]=[N:12][C:11]([C:9]2[CH:8]=[CH:7][N:6]3[C:2]([C:29]4[CH:28]=[C:27]([NH:31][C:32]([NH:34][CH2:35][C:36]([F:37])([F:38])[F:39])=[O:33])[CH:26]=[CH:25][CH:30]=4)=[CH:3][N:4]=[C:5]3[CH:10]=2)=[N:15]1
Reactant: CC1(C)OB(c2cccc(NC(=O)NCC(F)(F)F)c2)OC1(C)C
Reactant: Cn1nnc(-c2ccn3c(I)cnc3c2)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Product: Cn1nnc(-c2ccn3c(-c4cccc(NC(=O)NCC(F)(F)F)c4)cnc3c2)n1
Temperature: 80 °C
Yield: 27.7 %

Procedure:
A mixture of 3-iodo-7-(2-methyl-2H-tetrazol-5-yl)-imidazo[1,2-a]pyridine (170 mg, 0.52 mmol), 1-[3-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-3-(2,2,2-trifluoro-ethyl)-urea (16, 225 mg, 0.65 mmol) and Cs2CO3 (340 mg, 1.04 mmol) in dry DME (2.5 ml) was deoxygenated by evacuate/fill N2 (×2). PdCl2dppf (38 mg, 0.05 mmol) was added, and the mixture was deoxygenated again (×3). The reaction was stirred and heated at 80° C. for 16 hours. After cooling to RT the mixture was partitioned between EtOAc/H2O. The aqueous layer was extracted with EtOAc (×2). The combined EtOAc extracts were dried (Na2SO4) and filtered and evaporated. The residue was purified by preparative HPLC to give the title compound (60 mg) as a solid.
Reaction SMILES: C([NH:8][CH:9]([CH3:28])[CH2:10][N:11]1[CH:20]=[C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]1=[O:27])C1C=CC=CC=1.C(O)(=O)C.[H][H]>[C].[Pd].C(O)C>[NH2:8][CH:9]([CH3:28])[CH2:10][N:11]1[CH:20]=[C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]1=[O:27]
Reactant: [H][H]
Reactant: CC(Cn1cc(-c2ccccc2)c2ccccc2c1=O)NCc1ccccc1
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: CC(N)Cn1cc(-c2ccccc2)c2ccccc2c1=O
Yield: 75.2 %

Procedure:
36.8 g of 2-(2-benzylaminopropyl)-4-phenyl-1(2H)-isoquinolone preapred as described above, 12 g of 5% palladium-carbon, 50 ml of glacial acetic acid and 200 ml of ethanol were mixed, and the mixture was catalytically reduced while introducing hydrogen gas into the mixture at 60° to 70° C. After completion of the reduction reaction, the mixture was filtered, and the solvent was distilled off from the filtrate. The resulting residue was dissolved in 5% hydrochloric acid and the solution was washed with ethyl acetate. The aqueous layer was separated and rendered neutral with a 10% aqueous solution of sodium hydroxide. The resulting precipitate was filtered and recrystallized from a mixture of ethyl acetate and petroleum ether to obtain 20.9 g (75% yield) of 2-(2-aminopropyl)-4-phenyl-1(2H)-isoquinolone having a melting point of 104° C. as colorless prisms.
Reaction SMILES: C([O:8][NH:9][C:10](=[O:41])[CH2:11][CH:12]([C:17](=[O:40])[NH:18][C@H:19]1[CH2:37][C:36]2=[CH:38][N:29]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][C:35]=32)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][NH:21][C:20]1=[O:39])[CH2:13][CH:14]([CH3:16])[CH3:15])C1C=CC=CC=1.[H][H]>C(O)C.O1CCCC1.[Pd]>[OH:8][NH:9][C:10](=[O:41])[CH2:11][CH:12]([C:17](=[O:40])[NH:18][C@H:19]1[CH2:37][C:36]2=[CH:38][N:29]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][C:35]=32)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][NH:21][C:20]1=[O:39])[CH2:13][CH:14]([CH3:16])[CH3:15]
Reactant: CC(C)CC(CC(=O)NOCc1ccccc1)C(=O)N[C@H]1Cc2cn(c3ccccc23)CCCCCCCNC1=O
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)CC(CC(=O)NO)C(=O)N[C@H]1Cc2cn(c3ccccc23)CCCCCCCNC1=O
Reaction time: 3 h

Procedure:
To a solution of the more polar stereoisomer of (11S)-N-benzyloxy-5-methyl-3-(10-oxo-1,9-diazatricyclo-[11.6.1.014,19 ]eicosa-13(20),14(19),15,17-tetraen-11-ylcarbamoyl)hexanamide (90 mg) in ethanol/tetrahydrofuran (350 mL; 2:1) was added 10% palladium on charcoal (30 mg). The material was stirred with a constant stream of hydrogen gas bubbling through it. After 3 hours TLC (10% CH3OH/CH2Cl2) showed the reaction was complete. The material was filtered through a bed of celite (3×) and concentrated under reduced pressure to an almost dry residue. Methylene chloride (15 mL) was added and the material was again concentrated under reduced pressure until almost dried and then repeated. To the residue was added 3-4 drops of methanol followed by methylene chloride (15 mL). The material was stirred with cooling (ice bath) and ether (5 mL) and then hexane (2 mL) was added. A crystalline material slowly emerged and was collected by filtration to yield 50 mg of the more polar stereoisomer of (11S)-N-hydroxy-5-methyl-3-(10-oxo-1,9-diazatricyclo[11.6.1.014,19 ]eicosa-13(20),14(19),15,17-tetraen-11-ylcarbamoyl)hexanamide, m.p. 197°-201° C., [α]D23 =-85.1° (3.5 mg/1.0 mL DMSO).
Reaction SMILES: Br[CH:2]1[CH2:8][O:7][C:6]2[CH:9]=[CH:10][C:11]([I:13])=[CH:12][C:5]=2[N:4]2[N:14]=[C:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:16]=[C:3]12.CC(C)=[O:24]>O.[N+]([O-])([O-])=O.[Ag+]>[OH:24][CH:2]1[CH2:8][O:7][C:6]2[CH:9]=[CH:10][C:11]([I:13])=[CH:12][C:5]=2[N:4]2[N:14]=[C:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:16]=[C:3]12
Reactant: CCOC(=O)c1cc2n(n1)-c1cc(I)ccc1OCC2Br
Reactant: CC(C)=O
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: O
Product: CCOC(=O)c1cc2n(n1)-c1cc(I)ccc1OCC2O
Temperature: 25 °C
Reaction time: 12 h
Yield: 35 %

Procedure:
Silver nitrate (0.3 g, 2.00 equiv) was added to a stirred solution of ethyl 4-bromo-9-iodo-4,5-dihydrobenzo[b]pyrazolo[1,5-d][1,4]oxazepine-2-carboxylate (400 mg, 0.86 mmol, 1.00 equiv) in acetone (20 mL)/water (20 mL) was added. The resulting mixture was stirred for 12 hours at room temperature, diluted with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by a silica gel column with ethyl acetate/petroleum ether (1:3) to give 0.12 g (35%) of the titled compound as a white solid. LC-MS (ES, m/z) 401[M+H]+.
Reaction SMILES: CS(O[CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[N:21]=[CH:20][C:19]([Br:22])=[CH:18][N:17]=2)=[CH:11][CH:10]=1)(=O)=O.[NH:23]1[CH2:32][CH2:31][CH:26]([C:27]([O:29][CH3:30])=[O:28])[CH2:25][CH2:24]1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C>[Br:22][C:19]1[CH:20]=[N:21][C:16]([NH:15][C:12]2[CH:11]=[CH:10][C:9]([O:8][CH2:7][CH2:6][N:23]3[CH2:32][CH2:31][CH:26]([C:27]([O:29][CH3:30])=[O:28])[CH2:25][CH2:24]3)=[CH:14][CH:13]=2)=[N:17][CH:18]=1
Reactant: COC(=O)C1CCNCC1
Reactant: CS(=O)(=O)OCCOc1ccc(Nc2ncc(Br)cn2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C1CCN(CCOc2ccc(Nc3ncc(Br)cn3)cc2)CC1
Temperature: 90 °C
Reaction time: 12 h

Procedure:
2-(4-(5-Bromopyrimidin-2-ylamino)phenoxy)ethyl methanesulfonate 11 (1.55 mmol) and methyl isonipecotate (3.10 mmol) are dissolved in DMF (5 mL) and stirred at 90° C. for 12 h. After the reaction is completed, 2M Na2CO3 (20 mL) is added and the resulting mixture is extracted with EtOAc (50 mL). The organic layer is separated and concentrated to give crude methyl 1-(2-(4-(5-bromopyrimidin-2-ylamino)phenoxy)ethyl)piperidine-4-carboxylate 12. MS (m/z) (M+1)+: 435.1, 437.1.
Reaction SMILES: Br[CH:2]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[F:15])[C:6]2[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:5]=2[NH:4][C:3]1=[O:21].[N-:22]=[N+:23]=[N-:24].[Na+]>CC(C)=O.O>[N:22]([CH:2]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[F:15])[C:6]2[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:5]=2[NH:4][C:3]1=[O:21])=[N+:23]=[N-:24]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C1Nc2ccc(Cl)cc2C(c2ccccc2F)=CC1Br
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: [N-]=[N+]=NC1C=C(c2ccccc2F)c2cc(Cl)ccc2NC1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.6 %

Procedure:
A solution of rac-3-bromo-7-chloro-5-(2-fluorophenyl)-1,3-dihydro-2H-1-benzazepin-2-one (13.2 g, 36.0 mmole) in 180 ml acetone and 24 mL water was treated with a solution of sodium azide (3.51 g, 54.0 mmole) dissolved in 24 mL of water and stirred at ambient temperature. After 30 minutes, 500 mL of water was added. The precipitated product was collected and dried, yielding 10.6 g (89%) of the title compound as a solid.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([NH2:25])=[O:24])[C:7]2[C:16]3[N:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH3:2].C1C=C(Cl)C=C(C(OO)=O)C=1.[OH-].[NH4+:38].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>>[NH2:38][C:9]1[C:8]2[N:17]=[C:5]([CH2:4][O:3][CH2:1][CH3:2])[N:6]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([NH2:25])=[O:24])[C:7]=2[C:16]2[N:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1
Reactant: [NH4+]
Reactant: CCOCc1nc2cnc3cccnc3c2n1CCCCCC(N)=O
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Product: CCOCc1nc2c(N)nc3cccnc3c2n1CCCCCC(N)=O
Reaction time: 1 h

Procedure:
A modification of the methods described in Part F of Example 53 was used to treat 6-[2-(ethoxymethyl)-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)hexanamide (1.70 g, 5.0 mmol) with mCPBA (3.34 g of 70-77% purity) followed by ammonium hydroxide (5.5 mL), and p-toluenesulfonyl chloride (0.95 g). After the amination reaction was stirred for one hour, a precipitate was present and was isolated by filtration and washed with chloroform and water. The precipitate was triturated with 2-propanol (7.5 mL/g at 97° C.), and the mixture was filtered hot. The isolated solid was dried overnight under vacuum and then in a vacuum oven for six days at 65° C. The product was then sonicated in 1 M aqueous sodium hydroxide for 15 minutes, isolated by filtration, washed with deionized water, and dried in a vacuum oven for three days at 90° C. to provide 0.32 g of 6-[4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl]hexanamide as a yellow solid, mp 215-217° C.
Reaction SMILES: [CH:1]1([CH2:6][C:7]([OH:9])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:10][NH:11][C@H:12]1[CH2:31][N:16]2[C:17]3[C:22]([C:23]([CH2:24][C:25]([O:27]CCC)=[O:26])=[C:15]2[CH2:14][CH2:13]1)=[CH:21][CH:20]=[CH:19][CH:18]=3>>[CH:1]1([CH2:6][C:7]([N:11]([CH3:10])[C@H:12]2[CH2:31][N:16]3[C:17]4[C:22]([C:23]([CH2:24][C:25]([OH:27])=[O:26])=[C:15]3[CH2:14][CH2:13]2)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCCOC(=O)Cc1c2n(c3ccccc13)C[C@H](NC)CC2
Reactant: O=C(O)CC1CCCC1
Product: CN(C(=O)CC1CCCC1)[C@@H]1CCc2c(CC(=O)O)c3ccccc3n2C1

Procedure:
The title compound was prepared using analogous procedures described in Example 1 (Method A) from cyclopentylacetic acid and propyl [(7R)-7-(methylamino)-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl]acetate. MS (+ESI) m/z: 369.
Reaction SMILES: [CH:1]1([C:7]2[CH:20]=[C:19]3[C:10]([N:11]=[C:12]4[C:17](=[C:18]3O)[CH2:16][CH2:15][CH2:14][CH2:13]4)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O=P(Cl)(Cl)[Cl:24]>>[Cl:24][C:18]1[C:19]2[C:10]([N:11]=[C:12]3[C:17]=1[CH2:16][CH2:15][CH2:14][CH2:13]3)=[CH:9][CH:8]=[C:7]([CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[CH:20]=2
Reactant: Oc1c2c(nc3ccc(C4CCCCC4)cc13)CCCC2
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1c2c(nc3ccc(C4CCCCC4)cc13)CCCC2

Procedure:
7-Cyclohexyl-9-hydroxy-1,2,3,4-tetrahydroacridine (15.539 g) was refluxed for 45 minutes in 100 mL of POCl3. At the end of this time the reaction mixture was concentrated under reduced pressure and the residue was distributed between water and ether. Aqueous ammonia was added portionwise with shaking until all the organic material was dissolved in the ether layer. Evaporation and recrystallization of the residue from methanol gave 14.81 g of analytically pure product, mp 89°-91° C.
Reaction SMILES: [C:1]([C:5]1[C:6]([O:29][CH3:30])=[C:7](/[CH:20]=[CH:21]/[C:22]2[N:27]=[CH:26][C:25]([NH2:28])=[CH:24][CH:23]=2)[CH:8]=[C:9]([C:11]2[C:12]([O:18][CH3:19])=[N:13][CH:14]=[C:15]([F:17])[CH:16]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[F:31][C:32]([F:39])([F:38])[CH2:33][S:34](Cl)(=[O:36])=[O:35]>N1C=CC=CC=1>[C:1]([C:5]1[C:6]([O:29][CH3:30])=[C:7](/[CH:20]=[CH:21]/[C:22]2[N:27]=[CH:26][C:25]([NH:28][S:34]([CH2:33][C:32]([F:39])([F:38])[F:31])(=[O:36])=[O:35])=[CH:24][CH:23]=2)[CH:8]=[C:9]([C:11]2[C:12]([O:18][CH3:19])=[N:13][CH:14]=[C:15]([F:17])[CH:16]=2)[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S(=O)(Cl)CC(F)(F)F
Reactant: COc1ncc(F)cc1-c1cc(/C=C/c2ccc(N)cn2)c(OC)c(C(C)(C)C)c1
Solvent: c1ccncc1
Product: COc1ncc(F)cc1-c1cc(/C=C/c2ccc(NS(=O)(=O)CC(F)(F)F)cn2)c(OC)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72 %

Procedure:
step 2—To a solution of 370 (90.0 mg, 0.221 mmol) in pyridine (3 mL) cooled to 0° C. was added 2,2,2 trifluoroethane sulfonyl chloride (40 μL, 0.364 mmol). After 20 min the reaction mixture was warmed to RT and stirred overnight. The reaction mixture was quenched with 30 mL of 1N HCl and thrice extracted with EtOAc (20 mL). The combined extracts were washed with sat'd. aq. CuSO4 (3×30 mL) and brine, dried (Na2SO4), filtered, and concentrated. The crude product was purified by SiO2 chromatography eluting with an EtOAc/hexane gradient (25 to 35% EtOAc) to afford 88.1 mg (72%) of 2,2,2-trifluoro-ethanesulfonic acid (6-{(E)-2-[3-tert-butyl-5-(5-fluoro-2-methoxy-pyridin-3-yl)-2-methoxy-phenyl]-vinyl}-pyridin-3-yl)-amide (372).
Reaction SMILES: CC([O-])(C)C.[K+].[C:7]([CH2:9][C:10]([NH2:12])=[O:11])#[N:8].[CH3:13][C:14](=O)/[CH:15]=[CH:16]/[CH2:17][CH2:18][CH3:19]>CS(C)=O.O.Cl>[CH3:13][C:14]1[NH:12][C:10](=[O:11])[C:9]([C:7]#[N:8])=[C:16]([CH2:17][CH2:18][CH3:19])[CH:15]=1
Reactant: CCC/C=C/C(C)=O
Reactant: N#CCC(N)=O
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CCCc1cc(C)[nH]c(=O)c1C#N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 31.8 %

Procedure:
To a stirred solution of t-BuOK (1 g, 8.9 mmol) in DMSO (15 mL) at rt, was added compound cyanoacetamide (0.824 g, 9.8 mmol) and (E)-hept-3-en-2-one (1 g, 8.91 mmol). Reaction mixture was stirred for 30 min at rt. Additional t-BuOK (3 g, 26.7 mmol) was added and reaction was stirred at rt in presence of air. On completion, it was diluted with H2O and slowly by 4N HCl. Precipitated solid was filtered, washed with water and dried. Crude product was triturated with ether to afford the title compound (0.5 g, 33%).
Reaction SMILES: OO[S:3]([O-:5])=[O:4].[K+].[OH:7][CH:8]1[C:13]([CH3:15])([CH3:14])[CH2:12]S[C:10]2[S:16][C:17]([S:19]([NH2:22])(=[O:21])=[O:20])=[CH:18][C:9]1=2>O.CO>[OH:7][CH:8]1[C:13]([CH3:12])([CH3:14])[CH2:15][S:3](=[O:5])(=[O:4])[C:10]2[S:16][C:17]([S:19]([NH2:22])(=[O:21])=[O:20])=[CH:18][C:9]1=2
Reactant: CC1(C)CSc2sc(S(N)(=O)=O)cc2C1O
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: CO
Solvent: O
Product: CC1(C)CS(=O)(=O)c2sc(S(N)(=O)=O)cc2C1O
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 91 %

Procedure:
A solution of OXONE® (2.71 g, 0.0044 m) in water (15 ml) was added to a solution of 5,6-dihydro-4-hydroxy-5,5-dimethyl-4H-thieno[2,3-b]thiopyran-2-sulfonamide (0.90 g, 0.0032 m) in methanol (15 ml) over 10 minutes and the mixture was stirred at ambient temperature for 2.5 hours. The mixture was filtered, the solid was washed with methanol, and the combined filtrate and washings were concentrated in vacuo below 65° C. to remove methanol. The aqueous suspension was extracted with ethyl acetate (3×50 ml), the combined extracts were washed with water, dried over sodium sulfate and evaporated under reduced pressure to give 0.91 g (91%) of crude product which was purified by chromatography on silica gel, eluting with 10% methanol-chloroform.
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC(=O)[NH:14][C@H:15]([C:17]1[N:21]([C:22]2[CH:23]=[N:24][N:25]([CH3:27])[CH:26]=2)[C:20]2[CH:28]=[C:29]([F:32])[CH:30]=[CH:31][C:19]=2[N:18]=1)[CH3:16])(C)(C)C>C(Cl)Cl>[F:32][C:29]1[CH:30]=[CH:31][C:19]2[N:18]=[C:17]([C@@H:15]([NH2:14])[CH3:16])[N:21]([C:22]3[CH:23]=[N:24][N:25]([CH3:27])[CH:26]=3)[C:20]=2[CH:28]=1
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1nc2ccc(F)cc2n1-c1cnn(C)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](N)c1nc2ccc(F)cc2n1-c1cnn(C)c1
Reaction time: 0.25 h
Yield: 58.1 %

Procedure:
TFA (10 mL) was added to a solution of {(S)-1-[6-fluoro-1-(1-methyl-1H-pyrazol-4-yl)-1H-benzoimidazol-2-yl]ethyl}carbamic acid tert-butyl ester (0.268 g, 0.75 mmol) in DCM (5 mL) and stirred for 15 minutes. The reaction mixture was concentrated in vacuo and the residue partitioned between DCM (×3) and saturated aqueous NaHCO3. The combined DCM extracts were dried (Na2SO4) and concentrated in vacuo. The resultant residue was purified by chromatography (SiO2, 0-10% (2M ammonia in methanol) in DCM) to give the title compound as an oil (0.113 g, 59%). LCMS (Method C): RT 1.72 min [M+H]+ 260.1
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:12]=[CH:11][C:10]2[NH:9][C:8]3[CH2:13][CH2:14][N:15]([CH3:17])[CH2:16][C:7]=3[C:6]=2[CH:5]=1.Br[CH2:19][CH2:20][CH2:21][C:22]1[CH:23]=[CH:24][C:25]([C:28]([F:31])([F:30])[F:29])=[N:26][CH:27]=1.O>CN(C=O)C>[Cl:3][C:4]1[CH:12]=[CH:11][C:10]2[N:9]([CH2:19][CH2:20][CH2:21][C:22]3[CH:27]=[N:26][C:25]([C:28]([F:31])([F:29])[F:30])=[CH:24][CH:23]=3)[C:8]3[CH2:13][CH2:14][N:15]([CH3:17])[CH2:16][C:7]=3[C:6]=2[CH:5]=1
Reactant: FC(F)(F)c1ccc(CCCBr)cn1
Reactant: CN1CCc2[nH]c3ccc(Cl)cc3c2C1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN1CCc2c(c3cc(Cl)ccc3n2CCCc2ccc(C(F)(F)F)nc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 32.7 %

Procedure:
To a suspension of sodium hydride (0.014 g, 0.00054 mol) in dry DMF (3 mL), 8-Chloro-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.1 g, 0.00045 mol) was added at ice cold temp and stirred for 2 h at room temperature. Reaction mix was cooled to −20° C. and 5-(3-Bromo-propyl)-2-trifluoromethyl-pyridine (0.183 g, 0.00068 mol) was added, stirred for 1 h at 15° C., Reaction was monitor by TLC. After completion (TLC), reaction mix was cooled to 0° C. and water (10 mL) was added, extracted with ethyl acetate (3×100 mL). The organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure using rotary evaporator. The crude was purified through column chromatography (4% Methanol:DCM in silica 100-200 mesh, Diameter of column—2.5 cm, Height of silica—approx. 5 inch) to provide desired compound as brown oil (0.06 g, 32% yield). 8-Chloro-2-methyl-5-[3-(6-trifluoromethyl-pyridin-3-yl)-propyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.06 g, 0.000147 mol) was dissolved in THF (1.0 mL), A solution of oxalic acid dihydrate (0.016 g, 0.000126 mol) in THF (1.0 mL) was added and stirred for 30 min at RT. The precipitate was filtered and dried to give oxalate salt as off white solid (0.050 g, 68% yield).