Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2](=[O:47])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]#[C:11][C:12]1[C:17]([C:18]([F:21])([F:20])[F:19])=[CH:16][N:15]=[C:14]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([CH:29]3[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31][CH2:30]3)=[CH:25][C:24]=2[O:42][C:43]([F:46])([F:45])[F:44])[N:13]=1>CN(C=O)C.CCOC(C)=O.[OH-].[OH-].[Pd+2]>[NH2:1][C:2](=[O:47])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][CH2:11][C:12]1[C:17]([C:18]([F:19])([F:21])[F:20])=[CH:16][N:15]=[C:14]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([CH:29]3[CH2:30][CH2:31][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:33][CH2:34]3)=[CH:25][C:24]=2[O:42][C:43]([F:46])([F:45])[F:44])[N:13]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(Nc3ncc(C(F)(F)F)c(C#Cc4ccccc4CC(N)=O)n3)c(OC(F)(F)F)c2)CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(Nc3ncc(C(F)(F)F)c(CCc4ccccc4CC(N)=O)n3)c(OC(F)(F)F)c2)CC1
Reaction time: 24 h
Yield: 88 %

Procedure:
tert-Butyl 4-(4-((4-((2-(2-amino-2-oxoethyl)phenyl)ethynyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-(trifluoromethoxy)phenyl)piperidine-1-carboxylate (I49) (72.0 mg, 0.108 mmol) was dissolved in dry DMF (7 mL) under an atmosphere of nitrogen, and a slurry of 10% Pd(OH)2/C (0.050 g) in EtOAc (2 mL) was added. The mixture then was stirred vigorously under hydrogen for 24 hours. Upon completion, the reaction was filtered through a pad of celite, which was washed with EtOAc (40 mL). The combined filtrates were concentrated in vacuo to give a pale yellow oil. The crude product was purified by silica gel chromatography (12 g Si Cartridge, 0-100% EtOAc in petroleum benzine 40-60° C.) to give the title compound (I50) (0.064 g, 88% yield) as an off-white solid; 1H NMR (400 MHz, d6-DMSO) δ 9.80 (s, 1H), 8.60 (s, 1H), 7.61 (d, J=8.1 Hz, 1H), 7.39 (s, 1H), 7.32-7.26 (m, 2H), 7.21 (dt, J=6.7, 3.4 Hz, 1H), 7.18-7.08 (m, 3H), 6.90 (s, 1H), 4.09 (d, J=12.1 Hz, 2H), 3.45 (s, 2H), 3.09-2.94 (m, 4H), 2.88-2.72 (m, 3H) 1.79 (d, J=12.3 Hz, 2H), 1.59-1.38 (m, 11H). LCMS Method C: rt 6.75 min, m/z 668.1 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][CH:6]3[CH2:11][CH2:12][N:13]([CH2:15][CH2:16][CH2:17][C:18](=[O:26])[C:19]4[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=4)[CH2:14][CH:5]3[C:4]=2[CH:3]=1.[CH2:27](I)[CH3:28].C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[CH2:27]([N:7]1[C:8]2[CH:9]=[CH:10][C:2]([CH3:1])=[CH:3][C:4]=2[CH:5]2[CH2:14][N:13]([CH2:15][CH2:16][CH2:17][C:18](=[O:26])[C:19]3[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=3)[CH2:12][CH2:11][CH:6]12)[CH3:28]
Reactant: CCI
Reactant: Cc1ccc2c(c1)C1CN(CCCC(=O)c3ccc(F)cc3)CCC1N2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCN1c2ccc(C)cc2C2CN(CCCC(=O)c3ccc(F)cc3)CCC21
Reaction time: 20 h

Procedure:
To methyl ethyl ketone (60 ml) are added 8-methyl-2-[γ-(p-fluorobenzoyl)propyl]-2,3,4,4a,5,9b-hexahydro-1H-pyrido-[4,3-b]indole (6.6 g), ethyl iodide (3.8 g) and potassium carbonate (5.3 g) and the mixture is refluxed with stirring for 20 hours. After cooling, the insoluble materials are filtered off and the filtrate is concentrated. To the resulting residue is added water and the mixture is extracted with benzene. The benzene layer is dried over anhydrous sodium sulfate and distilled to remove benzene. The resulting residue is treated with ethanolic hydrogen chloride in the same manner as described in Example 1 (1) to give the dihydrochloride of the titled compound (5.2 g), m.p. 150° - 153°C (recrystallized from ethanol).
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[N:14]2[C:8]([CH2:9][N:10]([C:19](=[O:29])[CH2:20][S:21][C:22]3[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][CH:23]=3)[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13]2)=[CH:7][CH:6]=1)=[O:4].[Cl:32][C:33]1[CH:34]=[C:35]([CH:38]=[CH:39][C:40]=1[Cl:41])[CH2:36][NH2:37].CS(C)=O>C(#N)C>[Br:28][C:25]1[CH:26]=[CH:27][C:22]([S:21][CH2:20][C:19]([N:10]2[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13][N:14]3[C:5]([C:3]([NH:37][CH2:36][C:35]4[CH:38]=[CH:39][C:40]([Cl:41])=[C:33]([Cl:32])[CH:34]=4)=[O:4])=[CH:6][CH:7]=[C:8]3[CH2:9]2)=[O:29])=[CH:23][CH:24]=1
Reactant: O=C(CSc1ccc(Br)cc1)N1Cc2ccc(C(=O)C(Cl)(Cl)Cl)n2Cc2ccccc21
Reactant: NCc1ccc(Cl)c(Cl)c1
Solvent: CC#N
Solvent: CS(C)=O
Product: O=C(NCc1ccc(Cl)c(Cl)c1)c1ccc2n1Cc1ccccc1N(C(=O)CSc1ccc(Br)cc1)C2
Temperature: 85 °C

Procedure:
To an 18×150 mm reaction vessel was added 2,2,2-trichloro-1-[10-{[(4-bromophenyl)thio]acetyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-yl]-ethanone of Example 80 (0.23 mmol), acetonitrile (2.5 mL), 3,4-dichlorobenzylamine (0.49 mmol), and dimethylsulfoxide (0.81 mmol). The stirred solution was heated to 85° C. for 20 hours. The solvent was evaporated and the residue was dissolved in 5 mL dichloromethane. The solution was washed twice with water, dried over anhydrous sodium sulfate, and evaporated. The crude product was purified using normal phase HPLC with a two phase solvent system (A=hexane, B=dichloromethane/methanol, 4:1) to give the title product, m.p. 150° C. MS [(+)ESI, m/z]: 614 [M+H]+ Anal. Calcd for C28H22BrCl2N3O2S: C, 54.65; H, 3.60; N, 6.83. Found: C, 54.68; H, 3.50; N, 6.73.
Reaction SMILES: [NH2:1][C:2]1[N:6]=[CH:5][NH:4][N:3]=1.[H-].[Na+].BrC[C:11]1[C:12]([C:17]#[N:18])=[CH:13][CH:14]=[CH:15][CH:16]=1.[CH3:19]N(C=O)C>>[NH2:1][C:2]1[N:6]=[CH:5][N:4]([CH2:19][C:15]2[CH:16]=[CH:11][C:12]([C:17]#[N:18])=[CH:13][CH:14]=2)[N:3]=1
Reactant: Nc1nc[nH]n1
Reactant: CN(C)C=O
Reactant: N#Cc1ccccc1CBr
Agent: [H-]
Agent: [Na+]
Product: N#Cc1ccc(Cn2cnc(N)n2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 32.6 %

Procedure:
3-Amino-1,2,4-triazole (883 mg, 10.5 mmol) was dissolved in DMF (20 ml) under argon atmosphere, sodium hydride (55%, 436 mg, 10 mmol) added at rt in small portions and stirred at rt for 1 hour. To the reaction mixture alpha bromotolunitrile (1.96 g, 10 mmol) was added and stirred at rt overnight. TLC: finished: The reaction mixture was poured onto water, extracted with ethyl acetate and water, the organic layers combined, dried over Na2SO4, filtered and the solvents evaporated. Purification by flash chromatography with CH2Cl2/MeOH 100:0 to 90:10; 35 min over a 100 g silica-gel column gave 650 mg (yield: 32.6%) white solid. MS ISP (m/e): 200.2 (100) [(M+H)+].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16]([OH:18])=[O:17])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[CH:23]1C=CC=CC=1>>[CH3:23][O:17][C:16](=[O:18])[CH2:15][C:12]1[CH:13]=[CH:14][C:9]([S:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[CH:10][CH:11]=1
Reactant: O=C(O)Cc1ccc(Sc2ccc(Cl)cc2)cc1
Reactant: c1ccccc1
Solvent: O=S(Cl)Cl
Product: COC(=O)Cc1ccc(Sc2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 21 g of [p-(p-chlorophenylthio)phenyl]acetic acid and 11.9 g of thionyl chloride are stirred overnight at room temperature. To the resulting greenish yellow solution is added 20 ml of benzene and the solvent is evaporated at reduced pressure. This procedure is repeated once. The residue is added dropwise to 300 ml of methanol, maintained at 0° C, and the resulting solution is stirred overnight. The solvent is evaporated at reduced pressure and the mixture is dissolved in 200 ml of ether. The ether layer is washed with 100 ml of water, 100 ml of saturated NaHCO3, 100 ml of saturated brine and dried over MgSO4. Evaporation of the solvent and distillation of the residue affords the product as a light yellow oil.
Reaction SMILES: [F:1][C:2]([F:32])([O:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]#[C:26][CH2:27][CH2:28][CH2:29][CH2:30][OH:31])=[CH:21][CH:20]=1)[C:3]1[C:8]([F:9])=[CH:7][C:6]([C:10]#[C:11][CH2:12][CH2:13][CH2:14][CH2:15][OH:16])=[CH:5][C:4]=1[F:17]>C1COCC1>[F:32][C:2]([F:1])([O:18][C:19]1[CH:20]=[CH:21][C:22]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][OH:31])=[CH:23][CH:24]=1)[C:3]1[C:4]([F:17])=[CH:5][C:6]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][OH:16])=[CH:7][C:8]=1[F:9]
Reactant: OCCCCC#Cc1ccc(OC(F)(F)c2c(F)cc(C#CCCCCO)cc2F)cc1
Solvent: C1CCOC1
Product: OCCCCCCc1ccc(OC(F)(F)c2c(F)cc(CCCCCCO)cc2F)cc1

Procedure:
6-(4-{Difluoro[4-(6-hydroxyhex-1-ynyl)phenoxy]methyl}-3,5-difluorophenyl)-hex-5-yn-1-ol is hydrogenated to completion on palladium/active carbon catalyst in THF. The catalyst is filtered off, the solvent is removed in vacuo, and the crude product is chromatographed on silica gel with toluene/ethyl acetate (1:2), giving 6-(4-{difluoro[4-(6-hydroxyhexyl)-phenoxy]methyl}-3,5-difluorophenyl)hexan-1-ol as a colorless solid.
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:25]C)[N:12]2[CH2:15][CH2:16][CH2:17][CH2:18][CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)=[C:8]([NH2:27])[N:7]=1)[CH2:2][CH2:3][CH3:4].Br[CH2:29][CH2:30][OH:31].CCN(C(C)C)C(C)C>CN(C=O)C.CS(C)=O>[NH2:27][C:8]1[N:7]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:25])[N:12]2[CH2:15][CH2:16][CH2:17][CH2:18][CH:19]1[CH2:20][CH2:21][N:22]([CH2:29][CH2:30][OH:31])[CH2:23][CH2:24]1
Reactant: OCCBr
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCCC3CCNCC3)c2n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: CN(C)C=O
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCCCC3CCN(CCO)CC3)c2n1
Temperature: 50 °C
Reaction time: 7 h
Yield: 32.7 %

Procedure:
2-(Butyloxy)-8-(methyloxy)-9-[4-(4-piperidinyl)butyl]-9H-purin-6-amine (for example, as prepared for Intermediate 34) (0.038 g, 0.10 mmol) in DMF (0.4 mL) was added to 2-bromoethanol (0.0085 mL, 0.12 mmol). DIPEA (0.040 mL, 0.23 mmol) was added and the reaction mixture heated at 50° C. for 18 hours. An additional aliquot of the 2-bromoethanol (commercially available, for example, from Aldrich) (0.015 mL) and DIPEA (0.040 mL, 0.23 mmol) were added and heating continued for a further 7 hours. The reaction mixture were stirred at room temperature for 72 hours then diluted with DMSO:MeOH (0.2 mL) and the resultant solution purified by MDAP (Method A). Appropriate fractions were combined and evaporated in vacuo. The residue was dissolved in 4M HCl in dioxane (0.2 mL) and allowed to stand at room temperature for 18 hours. The solvent was dried under a stream of nitrogen in the Radleys blowdown apparatus. The samples were dissolved in 1:1 MeOH:DMSO (0.6 mL) and purified by Mass Directed AutoPrep on Sunfire C18 column using Acetonitrile Water with a TFA modifier. The solvent was evaporated in vacuo. The residue was redissolved in methanol (0.5 mL) and applied to top of 0.1 g aminopropyl SPE (preconditioned with methanol, 1.5 mL). The cartridge was washed with methanol (1.5 mL). The solvent was dried under a stream of nitrogen in the Radleys blowdown apparatus to give the title compound (0.0133 g).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[CH:9]([CH2:11][O:12][C:13]1[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=1)=O.C(B)#N.[Na]>CO>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][CH2:9][CH2:11][O:12][C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(OCC=O)cc1
Reactant: Nc1ccc(Cl)cc1
Agent: BC#N
Agent: [Na]
Solvent: CO
Product: COC(=O)c1ccc(OCCNc2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 17.8 %

Procedure:
p-Chloroaniline (0.99 g) and methyl 4-formylmethoxybenzoate (1.5 g) were dissolved in anhydrous methanol (10 ml), and stirred at room temperature for 30 minutes. To the mixture was added sodium cyanoboron hydride (in solid form) (0.24 g) over a period of 30 minutes and further stirred for 30 minutes. After the reaction solution was concentrated under reduced pressure, water and chloroform were added thereto, and the mixture was separated into layers. The organic layer was concentrated under reduced pressure, and subjected to column chromatograpy on silica gel and eluted with chloroform to give the desired product (0.42 g).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C@H:9]2[CH2:14][CH2:13][CH2:12][C:11](=[O:15])[CH2:10]2)[C:5]([F:16])=[CH:4][N:3]=1.Br[CH2:18][CH:19]=[CH2:20].[NH4+].[Cl-]>CN(C=O)C.[Zn]>[CH2:20]([C:11]1([OH:15])[CH2:12][CH2:13][CH2:14][C@H:9]([NH:8][C:6]2[C:5]([F:16])=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=2)[CH2:10]1)[CH:19]=[CH2:18]
Reactant: O=C1CCC[C@H](Nc2nc(Cl)ncc2F)C1
Reactant: C=CCBr
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CN(C)C=O
Product: C=CCC1(O)CCC[C@H](Nc2nc(Cl)ncc2F)C1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of (3S)-3-[(2-chloro-5-fluoro-pyrimidin-4-yl)amino]cyclohexanone, 29b, (0.60 g, 2.46 mmol) and 3-bromoprop-1-ene (0.43 mL, 4.92 mmol) in DMF was added Zn dust (0.32 g, 4.92 mmol). The reaction was stirred at room temperature for 3 days. The mixture was diluted into aqueous saturated NH4Cl solution, extracted twice with EtOAc. The combined organic phases were washed twice with brine, dried (MgSO4), filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography using 0-50% EtOAc/hexanes gradient to afford 553 mg of desired product, 58a, as an oil. LC/MS two peaks corresponding to two diastereomeric products: 286.4 (M+H), RT=3.41 and 3.78.
Reaction SMILES: [C:1]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])(=[O:4])[CH:2]=[CH2:3].[OH:10][CH2:11][CH2:12][NH:13][CH2:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[C:18]#[N:19]>CN(C=O)C.O>[C:18]([C:17]1[CH:16]=[C:15]([CH:22]=[CH:21][CH:20]=1)[CH2:14][N:13]([CH2:12][CH2:11][OH:10])[CH2:3][CH2:2][C:1]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])#[N:19]
Reactant: N#Cc1cccc(CNCCO)c1
Reactant: C=CC(=O)OC(C)(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)CCN(CCO)Cc1cccc(C#N)c1
Temperature: 80 °C

Procedure:
Tert-butyl acrylate (3.56 ml, 29 mmol) was added into a solution of 3-{[(2-hydroxyethyl)amino]methyl}benzonitrile (4.9 g, 28 mmol) in anhydrous DMF (5 mL) under nitrogen atmosphere. The resulting mixture was heated at 80° C. for 12 hours. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (100 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure to afford the title compound as colorless liquid. 1H NMR (DMSO-d6, 400 MHz) δ 7.75 (s, 1H), 7.69 (d, J=7.6 Hz, 1H), 7.62 (d, J=7.9 Hz, 1H), 7.50 (m, 1H), 4.36 (t, 1H), 3.62 (s, 2H), 3.43 (m, 2H), 2.69 (t, 2H), 2.47 (m, 2H), 2.34 (t, 2H), 1.38 (s, 9H).
Reaction SMILES: CO[C:3]([C:5]1[CH:14]=[CH:13][C:12]2[CH2:11][CH2:10][CH:9]([NH2:15])[CH2:8][C:7]=2[CH:6]=1)=[O:4].[F:16][C:17]([F:29])([F:28])[C:18]1[CH:19]=[C:20]([S:24](Cl)(=[O:26])=[O:25])[CH:21]=[CH:22][CH:23]=1.[OH:30][NH2:31].[OH-].[K+]>ClCCl>[OH:30][NH:31][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[CH2:11][CH2:10][CH:9]([NH:15][S:24]([C:20]3[CH:21]=[CH:22][CH:23]=[C:18]([C:17]([F:29])([F:28])[F:16])[CH:19]=3)(=[O:26])=[O:25])[CH2:8][C:7]=2[CH:6]=1)=[O:4]
Reactant: O=S(=O)(Cl)c1cccc(C(F)(F)F)c1
Reactant: COC(=O)c1ccc2c(c1)CC(N)CC2
Reactant: NO
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Product: O=C(NO)c1ccc2c(c1)CC(NS(=O)(=O)c1cccc(C(F)(F)F)c1)CC2

Procedure:
The title compound was prepared in two steps according to Scheme 6 by (1) treating amine VII with 3-trifluoromethyl-benzenesulfonyl chloride and TEA in dichloromethane, and (2) treating the ester intermediate with aqueous HONH2 and KOH. MS: calc'd (MH+) 415, exp (MH+) 415.4. 1H NMR (CD3OD, 400 MHz), 8.20 (s, 1H), 8.18 (d, 1H, J=8.8 Hz), 7.97 (d, 1H, J=8.0 Hz), 7.82 (t, 1H, J=7.6 Hz), 7.46 (d, 1H, J=7.6 Hz), 7.36 (s, 1H), 7.15 (d, 1H, J=8.0 Hz), 3.55 (m, 1H), 2.95 (m, 2H), 2.82 (m, 1H), 2.69 (m, 1H), 1.95 (m, 1H) 1.73 (m, 1H).
Reaction SMILES: OO.[C:3]1([S:9][CH2:10][C:11]2[C:16]([C:17]([O:19]CC)=[O:18])=[C:15]([O:22][CH3:23])[C:14]([CH2:24][CH3:25])=[CH:13][CH:12]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[OH-:26].[Li+].C(O)(=[O:30])C>O1CCOCC1.O>[C:3]1([S:9]([CH2:10][C:11]2[C:16]([C:17]([OH:19])=[O:18])=[C:15]([O:22][CH3:23])[C:14]([CH2:24][CH3:25])=[CH:13][CH:12]=2)(=[O:30])=[O:26])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: [OH-]
Reactant: CCOC(=O)c1c(CSc2ccccc2)ccc(CC)c1OC
Reactant: CC(=O)O
Agent: OO
Agent: [Li+]
Solvent: C1COCCO1
Solvent: O
Product: CCc1ccc(CS(=O)(=O)c2ccccc2)c(C(=O)O)c1OC
Temperature: 60 °C

Procedure:
Hydrogen peroxide (30% aqueous solution, 0.117 ml) was added to a solution of ethyl 6-(phenylthiomethyl)-3-ethyl-2-methoxybenzoate (Intermediate 19, 0.057 g) in acetic acid (1.7 ml) and the resultant solution was stirred and heated at 60° C. for 2 hours. After cooling, the solution was evaporated to dryness to give the crude sulphone. The residue was dissolved in a mixture of dioxane (1 ml) and water (1 ml) and lithium hydroxide (0.072 g) was added. The mixture was stirred and heated in the microwave at 160° C. for 15 minutes. After cooling, the mixture was evaporated to dryness and the residue was acidified by addition of hydrochloric acid (1M) and then immediately purified by preparative HPLC (C18) eluting with a mixture of methanol and water containing 0.1% formic acid to give 6-(benzenesulphonylmethyl)-3-ethyl-2-methoxy-benzoic acid (0.022 g) as a white solid.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([C@H:13]([NH:15][C@H:16]2[CH2:20][CH2:19][C@H:18]([NH:21][CH3:22])[C@@H:17]2[C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.I[CH2:33][C:34]([NH2:36])=[O:35].CCN(C(C)C)C(C)C>C(#N)C>[F:12][C:9]([F:10])([F:11])[C:7]1[CH:6]=[C:5]([C@H:13]([NH:15][C@H:16]2[CH2:20][CH2:19][C@H:18]([N:21]([CH2:33][C:34]([NH2:36])=[O:35])[CH3:22])[C@H:17]2[C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[CH3:14])[CH:4]=[C:3]([C:2]([F:1])([F:30])[F:31])[CH:8]=1
Reactant: CN[C@H]1CC[C@H](N[C@H](C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H]1c1ccc(F)cc1
Reactant: NC(=O)CI
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](N[C@H]1CC[C@H](N(C)CC(N)=O)[C@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Yield: 66.5 %

Procedure:
A solution of 40 mg of product from Step F, 25 mg of iodoacetamide and 0.10 mL of DIPEA in 0.5 ml of acetonitrile was stirred at room temperature for 16 h and then evaporated. The residue was purified on a 1 mm preparative silica gel plate eluted with 5% methanol in methylene chloride to give 30 mg of title compound as an oil. Mass specs (NH3 /CI): 506 (M+1).
Reaction SMILES: C[O:2][C:3]1[N:8]=[C:7]([C:9]([O:11]C)=[O:10])[CH:6]=[CH:5][C:4]=1[N:13]1[CH:17]=[C:16]([CH3:18])[N:15]=[CH:14]1.[Br:19]C1N=C(OC)C(N2C=C(C)N=C2)=CC=1.C(N(CC)CC)C>CO.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[BrH:19].[CH3:18][C:16]1[N:15]=[CH:14][N:13]([C:4]2[C:3](=[O:2])[NH:8][C:7]([C:9]([OH:11])=[O:10])=[CH:6][CH:5]=2)[CH:17]=1
Reactant: COC(=O)c1ccc(-n2cnc(C)c2)c(OC)n1
Reactant: COc1nc(Br)ccc1-n1cnc(C)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CCN(CC)CC
Solvent: CO
Product: Br
Product: Cc1cn(-c2ccc(C(=O)O)[nH]c2=O)cn1
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
Synthesis of methyl 6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridine-2-carboxylate (C2). To a solution of the known 6-bromo-2-methoxy-3-(4-methyl-1H-imidazol-1-yl)pyridine (C1, T. Kimura et al., U.S. Pat. Appl. Publ. (2009), US 20090062529 A1) (44.2 g, 165 mmol) in methanol (165 mL) was added triethylamine (46 mL, 330 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), dichloromethane complex (6.7 g, 8.24 mmol). The mixture was degassed several times with nitrogen. The reaction was heated to 70° C. under CO atmosphere (3 bar) in a Parr apparatus. After 30 minutes, the pressure dropped to 0.5 bar; additional CO was added until the pressure stayed constant for a period of 30 minutes. The mixture was allowed to cool to room temperature and filtered through a pad of Celite. The Celite pad was washed twice with methanol and the combined filtrates were concentrated under reduced pressure. The residue (88 g) was dissolved in ethyl acetate (1 L) and water (700 mL), and the layers were separated. The organic layer was washed with water (200 mL), and the aqueous layer was extracted with ethyl acetate (500 mL). The combined organic layers were dried over magnesium sulfate, filtered and concentrated to provide the title compound. Yield: 42.6 g, 175 mmol, quantitative.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:12][C:13]2[S:17][C:16]([C:18]3[CH:33]=[CH:32][C:21]([CH2:22][NH:23][CH:24]4[CH2:29][O:28]C(C)(C)[O:26][CH2:25]4)=[CH:20][CH:19]=3)=[CH:15][CH:14]=2)[CH:9]([CH3:11])[CH3:10])=[CH:4][CH:3]=1.CO.Cl>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH2:12][C:13]2[S:17][C:16]([C:18]3[CH:19]=[CH:20][C:21]([CH2:22][NH:23][CH:24]([CH2:25][OH:26])[CH2:29][OH:28])=[CH:32][CH:33]=3)=[CH:15][CH:14]=2)[CH:9]([CH3:10])[CH3:11])=[CH:6][CH:7]=1
Reactant: CC(C)N(Cc1ccc(-c2ccc(CNC3COC(C)(C)OC3)cc2)s1)c1ccc(F)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: CC(C)N(Cc1ccc(-c2ccc(CNC(CO)CO)cc2)s1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 56 %

Procedure:
A solution of the product of Step A (0.025 g, 0.05 mmol) in a mixture of solvents (CH3OH, CH2Cl2, 30% HCl: 1 ml, 3 ml, 15 drops) was stirred for 3 h at room temperature. The solvents were evaporated and co-evaporated with iPrOH to give the title compound (0.012 g, 48%) as creamy paste. 1H-NMR (CDCl3) 7.45 (d, 2H, J=8.12 Hz); 7.23-7.33 (m, 4H); 7.16-7.09 (m, 3H); 6.88 (d, 2H, J=3.68 Hz); 4.95 (bs, 1H); 4.21 (s, 2H); 4.07-4.02 (m, 1H); 3.92-3.68 (m, 6H); 3.29-3.26 (m, 1H); 1.03 (d, 6H, J=6.6 Hz).
Reaction SMILES: [ClH:1].[CH2:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][C:4](=[O:12])[O:3]1.[CH3:13]O>O>[Cl:1][CH2:2][C:11]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:5][C:4]([O:3][CH3:13])=[O:12]
Reactant: O=C1Cc2ccccc2CO1
Reactant: CO
Reactant: Cl
Solvent: O
Product: COC(=O)Cc1ccccc1CCl
Temperature: 25 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
Hydrogen chloride gas was bubbled though a solution of 3-isochromanone (1.2 g, 8.1 mmol) in methanol (30 mL) for 3 minutes. Reaction stirred at room temperature for 8 hours. Mixture was diluted with water (70 mL). Mixture was extracted with dichloromethane (2×40 mL). Combined organic layers were washed with brine (20 mL). Mixture was dried (magnesium sulfate), filtered and concentrated in vacuo. Title compound was obtained as clear colorless oil in 90% yield. 1H NMR (300 MHz, CDCl3): δ=7.40-7.26 (m, 4H), 4.67 (s, 2H), 3.80 (s, 2H), 3.69 (s, 3H).
Reaction SMILES: Cl.Cl.[CH3:3][S:4]([C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C@@H:14]([N:16]([CH2:29][CH2:30]C)[CH2:17][CH2:18][CH2:19][CH2:20][N:21]2[C:27](=[O:28])[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[CH3:15])=[CH:9][CH:8]=1)(=[O:6])=[O:5].[O:32]1[C:36]([C:37](Cl)=[O:38])=[CH:35][CH:34]=[N:33]1>C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+].O>[CH2:29]([N:16]([CH:14]([CH3:15])[CH2:13][C:10]1[CH:11]=[CH:12][C:7]([S:4]([CH3:3])(=[O:5])=[O:6])=[CH:8][CH:9]=1)[CH2:17][CH2:18][CH2:19][CH2:20][N:21]1[C:27](=[O:28])[CH2:26][CH2:25][N:24]([C:37]([C:36]2[O:32][N:33]=[CH:34][CH:35]=2)=[O:38])[CH2:23][CH2:22]1)[CH3:30]
Reactant: CCCN(CCCCN1CCNCCC1=O)[C@@H](C)Cc1ccc(S(C)(=O)=O)cc1
Reactant: O=C(Cl)c1ccno1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCN(CCCCN1CCN(C(=O)c2ccno2)CCC1=O)C(C)Cc1ccc(S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a mixture of 4-(4-{[(S)-2-(4-methanesulfonylphenyl)-1-methylethyl]-propylamino)butyl)-[1,4]diazepan-5-one dihydrochloride (0.15 g, 0.3 mmole) in toluene (5 mL) and saturated sodium carbonate (2 mL) was added isoxazole-5-carbonyl chloride (0.04 g, 0.31 mmole). The reaction mixture was stirred at room temperature for 4 hours. The mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride, dried (magnesium sulfate), and concentrated to give 4-(4-[ethyl-[2-(4-methanesulfonyl-phenyl)-1-methylethyl]amino}butyl)-1-(isoxazole-5-carbonyl)-[1,4]diazepan-5-one as a hygroscopic hydrochloride salt (0.14 g) in ethyl acetate/diethyl ether, 316, M+H=505.