Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:14]1[CH2:17][CH:16]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([B:24]3[O:28][C:27]([CH3:30])([CH3:29])[C:26]([CH3:32])([CH3:31])[O:25]3)[C:19]=2[CH2:33][CH3:34])[CH2:15]1)(C1C=CC=CC=1)C1C=CC=CC=1.ClC(OC(Cl)C)=O>>[CH2:33]([C:19]1[C:20]([B:24]2[O:25][C:26]([CH3:31])([CH3:32])[C:27]([CH3:29])([CH3:30])[O:28]2)=[CH:21][CH:22]=[CH:23][C:18]=1[CH:16]1[CH2:17][NH:14][CH2:15]1)[CH3:34]
Reactant: CCc1c(B2OC(C)(C)C(C)(C)O2)cccc1C1CN(C(c2ccccc2)c2ccccc2)C1
Agent: CC(Cl)OC(=O)Cl
Product: CCc1c(B2OC(C)(C)C(C)(C)O2)cccc1C1CNC1
Yield: 14.2 %

Procedure:
To a solution of 1-Benzhydryl-3-[2-ethyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-azetidine (D130) (3.4 g, 7.489 mmol) in 80 mL of 1,2-dicholoroethane was added proton sponges (200 mg, 0.933 mmol) and 1-chloroethyl chloroformate. The reaction mixture was refluxed for 10 hr, and then filtered. The filtrate was concentrated under reduced pressure to give the crude product, which was purified by Mass Directed AutoPrep to afford 3-[2-ethyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-azetidine (D131) (305 mg). δH (DMSO-d6, 400 MHz): 0.98 (3H, t), 1.25 (12H, s), 2.72 (2H, q), 4.10 (2H, m), 4.24 (2H, m), 4.33 (1H, m), 7.23 (1H, m), 7.55 (2H, m), 9.0 (1H, br, s).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].C(OC([NH:13][C:14]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:15]=1[CH:16]=[CH:17][N:18]2[CH:23]([C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=1)[C:24]([O:26][CH3:27])=[O:25])=O)(C)(C)C.C(N(CC)CC)C.O>C(Cl)Cl>[Cl:34][C:31]1[CH:30]=[CH:29][C:28]([CH:23]([N:18]2[C:19]3[C:15](=[C:14]([NH:13][S:2]([CH3:1])(=[O:4])=[O:3])[CH:22]=[CH:21][CH:20]=3)[CH:16]=[CH:17]2)[C:24]([O:26][CH3:27])=[O:25])=[CH:33][CH:32]=1
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)C(c1ccc(Cl)cc1)n1ccc2c(NC(=O)OC(C)(C)C)cccc21
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C(c1ccc(Cl)cc1)n1ccc2c(NS(C)(=O)=O)cccc21
Reaction time: 1 h

Procedure:
Methanesulfonyl chloride (159 μL, 2.04 mmol) was added to a stirred solution of 2b (320 mg, 1.02 mmol) and triethylamine (213 μL, 1.53 mmol) in DCM (3 mL) at rt. After 1 h, the reaction mixture was poured into water and extracted with DCM. The combined organics were washed with brine, dried (Na2SO4), filtered and concentrated in vacuo. The crude residue was purified by preparative reversed phase HPLC on YMC Pack Pro C18 stationary phase (CH3CN/H2O as eluent, 0.05% TFA as modifier), followed by lyophilization of the purified fractions to afford the title compound 17. m/z (ES) 393 (MH)+ IP=C rating.
Reaction SMILES: [C:1]([C:4]1[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][C:5]=1[O:6][CH2:7]C(OC)=O)(=O)[CH3:2].C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[Br:35]N1C(=O)CCC1=O>ClC1C=CC=CC=1>[Br:16][C:13]1[CH:14]=[CH:15][C:4]2[C:1]([CH2:2][Br:35])=[CH:7][O:6][C:5]=2[CH:12]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)COc1cc(Br)ccc1C(C)=O
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: Clc1ccccc1
Product: BrCc1coc2cc(Br)ccc12
Yield: 32 %

Procedure:
A solution of the product from Example 58, Part C (1.0 g, 4.74 mmol) and dibenzoyl peroxide (287 mg, 1.19 mmol) in chlorobenzene (24 mL) at reflux was treated in four portions with N-bromosuccinimide (843 mg, 4.74 mmol) over 30 min. The mixture was then stirred at reflux for 2 h. The mixture was cooled, filtered and concentrated and purified by column chromatography on silica gel, eluting with 7-30% chloroform in hexanes. The procedures afforded the title compound as a light yellow oil (438 mg, 32%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[N:5]=[C:4]([C:17]([OH:19])=O)[CH:3]=1.S(Cl)([Cl:22])=O.CN(C)C=O.CN(C1C=CC=CN=1)C>C1(C)C=CC=CC=1.CO>[Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[N:5]=[C:4]([C:17]([Cl:22])=[O:19])[CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: COc1ccc(-c2nc(C(=O)O)cc(Cl)c2Cl)cc1
Agent: CN(C)c1ccccn1
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Solvent: CO
Product: COc1ccc(-c2nc(C(=O)Cl)cc(Cl)c2Cl)cc1
Temperature: 80 °C

Procedure:
To a mixture of 4,5-dichloro-6-(4-methoxyphenyl)-picolinic acid (4.50 g, 15.1 mmol) in toluene (40 mL) was added thionyl chloride (1.65 mL, 22.6 mmol) and dimethylformamide (0.06 mL, 0.8 mmol). Reaction mixture was heated at 80° C. for 12 h. HPLC analysis of an aliquot treated with methanol and dimethylaminopyridine indicated complete conversion of the starting material. Reaction mixture was allowed to cool to room temperature and concentrated under reduced pressure to provide a yellow solid. Toluene (40 mL) was added to dissolve the solid and concentrated under reduced pressure and then this process was performed a second time. 4,5-Dichloro-6-(4-methoxyphenyl)-picolinoyl chloride was isolated as a yellow solid (4.64 g, 97% yield). 1H NMR (400 MHz, CDCl3) δ 8.09 (s, 1H), 7.85-7.77 (m, 2H), 7.06-6.98 (m, 2H). 13C NMR (101 MHz, CDCl3) δ 168.91, 161.06, 158.35, 146.26, 145.13, 133.92, 131.35, 129.16, 124.13, 113.70, LRMS. Calcd. for C13H8Cl3NO2: 314.96. Found: m/z=253 (M+-COCl), 218.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:12]2[CH2:13][CH2:14][CH2:15][CH:11]2[NH:10][C:9]1=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].I[CH3:20]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH:12]2[CH2:13][CH2:14][CH2:15][CH:11]2[N:10]([CH3:20])[C:9]1=[O:16])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1C(=O)NC2CCCC21
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1C(=O)N(C(=O)OC(C)(C)C)C2CCCC21
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 106.1 %

Procedure:
To a solution of (3aSR,6aRS)-2-oxo-hexahydro-cyclopentaimidazole-1-carboxylic acid tert-butyl ester (Example 106, step 1) (1.82 g, 8.04 mmol) in 30 ml of DMF was added a 60% suspension of sodium hydride in mineral oil (386 mg, 9.65 mmol, 1.2 equiv.). The suspension was stirred for 45 minutes at room temperature (gas evolution), then iodomethane (0.604 ml, 9.65 mmol, 1.2 equiv.) was added and the mixture was stirred at room temperature overnight. After concentration in vaccuo and workup with ethyl acetate/water, 2.05 g of a yellow oil were obtained containing mineral-oil drops which was directly used in the next step without further characterisation.
Reaction SMILES: [OH-].[Na+].[CH2:3]([NH:5][C:6]([NH:8][C:9]1[N:40]=[C:12]2[CH:13]=[C:14]([C:22]3[CH:23]=[N:24][C:25]([N:28]4[CH2:33][CH2:32][C:31]([CH3:39])([C:34]([O:36]CC)=[O:35])[CH2:30][CH2:29]4)=[N:26][CH:27]=3)[CH:15]=[C:16]([N:17]3[CH:21]=[CH:20][CH:19]=[N:18]3)[N:11]2[N:10]=1)=[O:7])[CH3:4]>CCO>[CH2:3]([NH:5][C:6]([NH:8][C:9]1[N:40]=[C:12]2[CH:13]=[C:14]([C:22]3[CH:23]=[N:24][C:25]([N:28]4[CH2:29][CH2:30][C:31]([CH3:39])([C:34]([OH:36])=[O:35])[CH2:32][CH2:33]4)=[N:26][CH:27]=3)[CH:15]=[C:16]([N:17]3[CH:21]=[CH:20][CH:19]=[N:18]3)[N:11]2[N:10]=1)=[O:7])[CH3:4]
Reactant: CCNC(=O)Nc1nc2cc(-c3cnc(N4CCC(C)(C(=O)OCC)CC4)nc3)cc(-n3cccn3)n2n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCNC(=O)Nc1nc2cc(-c3cnc(N4CCC(C)(C(=O)O)CC4)nc3)cc(-n3cccn3)n2n1
Temperature: 70 °C
Yield: 24 %

Procedure:
A 2N aqueous solution of NaOH (5 mL) was added to a solution of ethyl 1-(5-{2-[(ethylcarbamoyl)amino]-5-(1H-pyrazol-1-yl)[1,2,4]triazolo[1,5-a]pyridin-7-yl}pyrimidin-2-yl)-4-methylpiperidine-4-carboxylate (88 mg, 0.17 mmol) in EtOH (15 mL) at rt and was heated at 70° C. After 2 h the reaction mixture was cooled to rt and concentrated in vacuo to ˜⅓ volume. Water (10 mL) was added and the resultant solution extracted with EtOAc (2×10 mL). The aqueous was then acidified to pH 1-2 and extracted with 10% IPA/DCM (3×10 mL). The organic layers were combined and dried (MgSO4), filtered and concentrated in vacuo to give a off white solid which was purified by semi preparative HPLC to give Compound 227 as a cream solid (20 mg, 24%). 1H NMR (DMSO) δ 10.01 (s, 1H), 9.00 (d, J=2.4 Hz, 1H), 8.94 (s, 2H), 8.16-8.06 (m, 1H), 8.01 (s, 2H), 7.81 (s, 1H), 6.77-6.73 (m, 1H), 4.35 (d, J=13.5 Hz, 2H), 3.25 (s, 2H), 2.05 (d, J=12.9 Hz, 2H), 1.38 (s, 2H), 1.25 (s, 2H), 1.19 (s, 3H), 1.14 (d, J=7.2 Hz, 3H). MS: 491.1 [M+H]+.
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6](=[CH:16][C:17]3[N:22]=[C:21]([NH2:23])[CH:20]=[N:19][CH:18]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH3:31][S:32](Cl)(=[O:34])=[O:33].Cl>C(Cl)Cl>[CH:12]1[C:8]2[CH2:9][CH2:10][C:11]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=3[C:6](=[CH:16][C:17]3[N:22]=[C:21]([NH:23][S:32]([CH3:31])(=[O:34])=[O:33])[CH:20]=[N:19][CH:18]=3)[C:7]=2[CH:15]=[CH:14][CH:13]=1
Reactant: Nc1cncc(C=C2c3ccccc3CCc3ccccc32)n1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)Nc1cncc(C=C2c3ccccc3CCc3ccccc32)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 43 %

Procedure:
Mix 6-(10,11-dihydro-dibenzo[a,d]cyclohepten-5-ylidenemethyl)-pyrazin-2-ylamine (35 mg, 0.117 mmol), triethylamine (34 μL, 0.234 mmol), N,N-dimethylaminopyridine (2 mg, 0.018 mmol), and methanesulfonyl chloride (10 μL, 0.123 mmol) in CH2Cl2 (2 mL). Stir at room temperature overnight and add 150 μL triethylamine and 40 μL methanesulfonyl chloride. Stir at room temperature for 6 h and add 1.00N aqueous HCl (1 mL). Load mixture onto a Varian ChemElut CE1005 solid-phase extraction cartridge, then elute, collect, and concentrate 45 mL CH2Cl2. Dissolve crude product in THF (5 mL), add 1.0M tetrabutylammonium fluoride (0.30 mL), and heat to reflux for 1 h. Cool to room temperature and dilute with H2O and brine. Extract into ethyl acetate, dry (MgSO4) and concentrate organics. Chromatograph on silica gel (4 g), eluting with 20%→35% ethyl acetate/hexanes to afford 19 mg (43%) of the title compound as a white solid. MS (ES) 378 (M+H), 376 (M−H); HPLC shows 100% purity.
Reaction SMILES: [Sn](Cl)(Cl)(Cl)Cl.[CH3:6][CH:7]=[CH:8][C:9]1[S:13][C:12]2[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=2[CH:10]=1.[C:18](Cl)(=[O:27])[C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1.ClCCl>O>[CH3:6][CH:7]=[CH:8][C:9]1[S:13][C:12]2[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=2[C:10]=1[C:18]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1)=[O:27]
Reactant: CC=Cc1cc2ccccc2s1
Reactant: COc1ccc(C(=O)Cl)cc1
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: O
Solvent: ClCCl
Product: CC=Cc1sc2ccccc2c1C(=O)c1ccc(OC)cc1
Temperature: 0 °C
Reaction time: 5 h
Yield: 71.3 %

Procedure:
Tin tetrachloride (2.83 mL, 24.12 mmol) was added dropwise over a 10 minute period to a stirred solution of 2-all-3-yl-benzo[b]thiophene (3.51 g, 20.1 mmol), anisoyl chloride (3.61 g, 21.1 mmol) and dichloromethane (70 mL) under a dry nitrogen atmosphere. After 5 h., the mixture was warmed up and stirred at 0° C. for 1 h. The reaction mixture was added to water and extracted with ethyl ether. The ethyl ether extract was washed with sat. aq. sodium bicarbonate and brine. Silica gel (100 mL) was added. Solvents were removed and the silica adsorbate was flash chromatographed (eluent 92:8 petroleum ether:ethyl acetate) to provide the title compound as an oil (4.42 g, 71 %): NMR (CDCl3); δ 7.88-7.76 (multiplet with overlapping doublet at 7.84, J=9 Hz, 3H), 7.50-7.44 (m, 1H), 7.34-7.24 (m, 2H), 6.94 (d, J=9 Hz, 2H), 6.00-5.85 (m, 1H), 5.20-5.13 (m, 2H), 3.90 (s, 3H), 3.62 (d, J=6 Hz, 2H); MS (EI): [M+] 308 (50%); Anal. Calc. for C19H16O2S: C, 74.00, H, 5.23, N, 0.00. Found: C, 73.16, H, 5.13, N, 0.09.
Reaction SMILES: [CH2:1]([N:4]([CH2:20][CH2:21][CH3:22])[CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][C:9]([C:17]([O-:19])=O)=[C:10]([C:14]([O-:16])=O)[CH:11]=2)[CH2:6]1)[CH2:2][CH3:3].[NH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1.Cl>>[CH2:20]([N:4]([CH2:1][CH2:2][CH3:3])[CH:5]1[CH2:6][C:7]2=[CH:8][C:9]3[C:17](=[O:19])[N:23]([CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=4)[C:14](=[O:16])[C:10]=3[CH:11]=[C:12]2[CH2:13]1)[CH2:21][CH3:22]
Reactant: NCc1ccccn1
Reactant: CCCN(CCC)C1Cc2cc(C(=O)[O-])c(C(=O)[O-])cc2C1
Agent: Cl
Product: CCCN(CCC)C1Cc2cc3c(cc2C1)C(=O)N(Cc1ccccn1)C3=O

Procedure:
Using procedure 49, 2-(dipropylamino)-2,3-dihydro-1H-indene-5,6-dicarboxylate (92, 0.35 g, 1.0 mmol) was treated with 2-aminomethylpyridine (0.4 mL, 4.0 mmol). Purification via using silica gel, eluting with 2:1 CH2Cl2 /acetone, afforded an oil that was converted to an HCl salt and recrystallized from hot MeOH/EtOAc to give 115 as a white solid (m.p. 130-135° C.).
Reaction SMILES: [CH3:1][C:2]1[CH:3]([C:10]2[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=2[CH:12]=O)[C:4]([CH3:9])=[C:5]([CH3:8])[C:6]=1[CH3:7].[CH3:18][C:19]1[CH:20]=[C:21]([CH:23]=[C:24]([CH3:26])[CH:25]=1)[NH2:22].C(O)(=O)C.[BH4-].[Na+]>C(O)C.C1(C)C=CC=CC=1.O>[CH3:1][C:2]1[CH:3]([C:10]2[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=2[CH2:12][NH:22][C:21]2[CH:23]=[C:24]([CH3:26])[CH:25]=[C:19]([CH3:18])[CH:20]=2)[C:4]([CH3:9])=[C:5]([CH3:8])[C:6]=1[CH3:7]
Reactant: CC1=C(C)C(c2ccccc2C=O)C(C)=C1C
Reactant: Cc1cc(C)cc(N)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: CC1=C(C)C(c2ccccc2CNc2cc(C)cc(C)c2)C(C)=C1C
Temperature: 25 °C
Yield: 98.1 %

Procedure:
To a solution of 2-(2,3,4,5-tetramethylcyclopentadienyl)benzaldehyde (15.0 mmol) in ethanol (44.6 mL) were added dropwise 3,5-dimethylaniline (15.8 mmol) and acetic acid (1.5 mmol) under a nitrogen atmosphere. The mixture was stirred at room temperature. After disappearance of the aldehyde was confirmed by gas chromatography, sodium borohydride (19.5 mmol) was added to the solution and reacted at room temperature for 3 hrs. Water and toluene were then added to the reaction mixture. The organic layer was dried and concentrated. The obtained oily substance was purified by silica gel column chromatography to give N-[2-(2,3,4,5-tetramethylcyclopentadienyl)phenylmethyl]-N-(3,5-dimethylphenyl)amine (4.88 g, yield 73.3%) as a yellow oily substance.
Reaction SMILES: Cl.[NH2+:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]2[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[CH2:14][C@@H:3]12.C(N(CC)CC)C.Br[CH2:23][CH2:24][CH3:25]>CN(C)C=O>[CH2:23]([N:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]2[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[CH2:14][C@@H:3]12)[CH2:24][CH3:25]
Reactant: c1ccc2c(c1)C[C@H]1[NH2+]CCC[C@H]21
Reactant: CCCBr
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCN1CCC[C@@H]2c3ccccc3C[C@H]21
Temperature: 25 °C
Reaction time: 18 h
Yield: 378.7 %

Procedure:
A solution of trans-2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridinium hydrochloride (3.00 g, 14.3 mmol) and triethylamine (4.36 g, 43.1 mmol) in 95 ml of N,N-dimethylformamide was stirred at room temperature and bromopropane (1.85 g, 15.04 mmol) added dropwise. After the mixture was stirred for 18 h at room temperature, the solvent was removed and ethyl acetate/water were added. The organic layer was washed with water and dried over MgSO4. The filtrate was concentrated to give a yellow oil (11.66 g, 82%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[O:13][C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[N:11][C:10]=2[C:20]2[CH:29]=[CH:28][C:23]([C:24](OC)=[O:25])=[CH:22][CH:21]=2)=[CH:4][CH:3]=1.CCOC(C)=O.[NH2:36][NH2:37]>CCO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[O:13][C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[N:11][C:10]=2[C:20]2[CH:29]=[CH:28][C:23]([C:24]([NH:36][NH2:37])=[O:25])=[CH:22][CH:21]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(-c2nc(-c3ccccc3)oc2Sc2ccc(Cl)cc2)cc1
Reactant: NN
Solvent: CCO
Solvent: CCOC(C)=O
Product: NNC(=O)c1ccc(-c2nc(-c3ccccc3)oc2Sc2ccc(Cl)cc2)cc1

Procedure:
Methyl 4-{5-[(4-chlorophenyl)thio]-2-phenyl-1,3-oxazol-4-yl}benzoate from Step B (33 mg, 0.077 mmol) was suspended in 1 mL of EtOH and 0.5 mL of anhydrous hydrazine, and heated to reflux for 2 h. EtOAc was added and washed with water 3 times. The organics were dried (MgSO4), and concentrated to afford 4-{5-[(4-chlorophenyl)thio]-2-phenyl-1,3-oxazol-4-yl}benzohydrazide which was used with out further purification. LCMS: m/z 421.1 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([S:22]([C:25]1[S:26][CH:27]=[CH:28][CH:29]=1)(=[O:24])=[O:23])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:13][C:14]([CH2:17][CH2:18][C:19]([OH:21])=O)=[CH:15][N:16]=1)=[CH:8]2.[N:30]1(O)C2C=CC=CC=2N=[N:31]1.Cl.CN(C)CCCN=C=NCC.O.NN>O.CN(C)C=O>[NH:30]([C:19](=[O:21])[CH2:18][CH2:17][C:14]1[S:13][C:12]([C:9]2[NH:10][C:11]3[C:7]([CH:8]=2)=[CH:6][CH:5]=[CH:4][C:3]=3[N:2]([CH3:1])[S:22]([C:25]2[S:26][CH:27]=[CH:28][CH:29]=2)(=[O:24])=[O:23])=[N:16][CH:15]=1)[NH2:31]
Reactant: CN(c1cccc2cc(-c3ncc(CCC(=O)O)s3)[nH]c12)S(=O)(=O)c1cccs1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: NN
Solvent: CN(C)C=O
Solvent: O
Product: CN(c1cccc2cc(-c3ncc(CCC(=O)NN)s3)[nH]c12)S(=O)(=O)c1cccs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 56.2 %

Procedure:
To a mixture of 3-(2-{7-[methyl(2-thienylsulfonyl)amino]-1H-indol-2-yl}-1,3-thiazol-5-yl)propanoic acid (0.50 g), 1H-1,2,3-benzotriazol-1-ol (0.18 g) and N,N-dimethylformamide (15 mL) was added N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (0.26 g) at room temperature. The mixture was stirred at room temperature for 1 hr and hydrazine monohydrate (0.28 g) was added. The reaction mixture was stirred at room temperature overnight, and water was added. The resulting crystals were filtrated, washed with water, and dried to give the title compound (0.29 g, yield 57%) as yellow crystals. melting point 224-226° C.
Reaction SMILES: C[O:2][C:3](=[O:19])[CH2:4][C@@:5]([CH3:18])([NH:11][S@](C(C)(C)C)=O)[CH2:6][C@@H:7]([CH3:10])[CH2:8][CH3:9].Cl>CC(C)=O.O>[NH2:11][C@@:5]([CH3:18])([CH2:6][C@@H:7]([CH3:10])[CH2:8][CH3:9])[CH2:4][C:3]([OH:19])=[O:2]
Reactant: CC[C@H](C)C[C@@](C)(CC(=O)OC)N[S@@](=O)C(C)(C)C
Agent: Cl
Solvent: O
Solvent: CC(C)=O
Product: CC[C@H](C)C[C@](C)(N)CC(=O)O
Temperature: 40 °C
Reaction time: 0.33 h
Yield: 76.7 %

Procedure:
A mixture of (3S,5S)-3,5-dimethyl-3-((S)-2-methyl-propane-2-sulfinylamino)-heptanoic acid methyl ester (0.4 g, 1.37 mmol) and concentrated hydrochloric acid (7.6 mL) in acetone (10 mL) was refluxed for 3 hours. The solvents were stripped under reduced pressure. The residue was dissolved in water (10 mL) and extracted by EtOAc (2×15 mL). The aqueous phase was evaporated to dryness. The residue was dissolved in a mixture of water (10 mL) and triethylamine (0.5 mL). The mixture was stirred at 40° C. for 20 minutes and then was evaporated to dryness. The residue was washed thoroughly with acetonitrile, filtered, and dried under vacuum to give the final product, (3S,5S)-3-amino-3,5-dimethyl-heptanoic acid (0.182 g, 77% yield) as a white solid. m.p. 215–217° C.: 1H NMR (CDCl3) δ 4.85 (s, 3H), 2.38 (m, 2H), 1.75 (m, 1H), 1.39 (m, 4H), 1.35(s, 3H), 0.98 (d, J=6.6 Hz, 3H), 0.90 (t, J=7.5 Hz, 3H); MS (APCl) (M+1)+ 174.1.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH:12]1[CH2:17][CH2:16][CH:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:14][CH2:13]1>C(Cl)Cl>[CH2:21]([O:20][C:18]([CH:15]1[CH2:16][CH2:17][C:12](=[O:11])[CH2:13][CH2:14]1)=[O:19])[CH3:22]
Reactant: CCOC(=O)C1CCC(O)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Product: CCOC(=O)C1CCC(=O)CC1
Temperature: 25 °C
Yield: 90.1 %

Procedure:
To a solution of oxalyl chloride (6 mL, 68.8 mmol) in DCM (100 mL) at −78° C. was added dropwise a solution of DMSO (6.4 mL, 90 mmol) in DCM (20 mL). The mixture was stirred at this temperature for 15 min before the dropwise addition of a solution of ethyl 4-hydroxycyclohexane carboxylate (4.8 mL, 30 mmol) in DCM (20 mL). The mixture was stirred at −78° C. for 3 h before addition of TEA (29.3 mL, 210 mmol) in DCM (20 mL). The mixture was then gradually warmed to rt, washed with a sat. aq. NH4Cl solution and brine, dried over MgSO4 and concentrated. The residue was purified by chromatography over SiO2 (Hex/EA 1:1) to give the title ketone (4.6 g, 90% yield) as a colourless oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[S:13][CH:14]=[CH:15][N:16]=2)(=[O:10])=[O:9])=[C:4]([F:17])[CH:3]=1.CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.[C:60]1([C:67]2[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=2)[C:61]([NH2:66])=[CH:62][CH:63]=[CH:64][CH:65]=1.CC(C)([O-])C.[Na+].C(O)(C)(C)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:60]1([C:67]2[CH:68]=[CH:69][CH:70]=[CH:71][CH:72]=2)[CH:65]=[CH:64][CH:63]=[CH:62][C:61]=1[NH:66][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[S:13][CH:14]=[CH:15][N:16]=2)(=[O:10])=[O:9])=[C:4]([F:17])[CH:3]=1
Reactant: O=S(=O)(Nc1nccs1)c1ccc(Br)cc1F
Reactant: Nc1ccccc1-c1ccccc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: CC(C)(C)O
Product: O=S(=O)(Nc1nccs1)c1ccc(Nc2ccccc2-c2ccccc2)cc1F
Temperature: 120 °C

Procedure:
Into a vial was added 4-bromo-2-fluoro-N-thiazol-2-yl-benzenesulfonamide (100 mg, 0.3 mmol), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (2.0 μl mg, 0.036 mmol), tris(dibenzylideneacetone)dipalladium(0) (11 mg, 0.012 mmol), [1,1′-Biphenyl]-2-amine (50.2 mg, 0.296 mmol), sodium tert-butoxide (86 mg, 0.89 mmol) and anhydrous tert-butyl alcohol (4.1 mL, 43 mmol). The reaction mixture was sparged with argon for ˜5 min. The septum was replaced with a microwave vial cap, and the reaction mixture was heated for 5 min at 120° C. The reaction mixture was then filtered through a syringe filter and the filtrate concentrated in vacuo. The vial and syringe were washed with 3 mL of DMSO and this was combined with the concentrated filtrate. The resulting solution was filtered through a plug of cotton then purified by reverse phase HPLC (Prep: Phenomenex 250×30.0 mm 15 micron C18 column. 40 mL/min. Gradient 15% B to 100% B over 25 min. Solvent A: 7800 water/200 acetonitrile/8 TFA. Solvent B: 7200 acetonitrile/800 water/8 TFA). The clean fractions were concentrated in vacuo to afford the product as an off-white solid. LC/MS analysis: Retention time: 1.52 minutes, M+H=426.
Reaction SMILES: C([O-])=O.[NH4+].[CH3:5][N:6]1[C:12]2[CH:13]=[CH:14][C:15]([N+:21]([O-])=O)=[C:16]([O:17][CH:18]([CH3:20])[CH3:19])[C:11]=2[CH2:10][CH2:9][CH2:8][C:7]1=[O:24]>CO.[Pd]>[NH2:21][C:15]1[CH:14]=[CH:13][C:12]2[N:6]([CH3:5])[C:7](=[O:24])[CH2:8][CH2:9][CH2:10][C:11]=2[C:16]=1[O:17][CH:18]([CH3:20])[CH3:19]
Reactant: CC(C)Oc1c([N+](=O)[O-])ccc2c1CCCC(=O)N2C
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CC(C)Oc1c(N)ccc2c1CCCC(=O)N2C
Temperature: 80 °C
Yield: 102.4 %

Procedure:
567 mg of ammonium formate and 478 mg of Pd/C (10%) are added to a solution of 416 mg of 1-methyl-7-nitro-6-(propan-2-yloxy)-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one in 30 ml of methanol. The reaction medium is microwave-heated at 80° C. for 5 minutes. The mixture is filtered on Clarcel, and the Clarcel is rinsed with methanol. The filtrate is concentrated under reduced pressure, so as to give 380 mg of 7-amino-1-methyl-6-(propan-2-yloxy)-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one in the form of a colourless gum.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[NH2:8][C:9]1[N:14]=[C:13]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[C:12]([O:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)=[CH:11][N:10]=1.C(N(CC)CC)C.ClCCl>O1CCCC1>[C:1]([N:18]1[CH2:17][CH2:16][N:15]([C:13]2[C:12]([O:21][C:22]3[CH:23]=[CH:24][C:25]([Cl:28])=[CH:26][CH:27]=3)=[CH:11][N:10]=[C:9]([NH2:8])[N:14]=2)[CH2:20][CH2:19]1)(=[O:3])[CH3:2]
Reactant: Nc1ncc(Oc2ccc(Cl)cc2)c(N2CCNCC2)n1
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(=O)N1CCN(c2nc(N)ncc2Oc2ccc(Cl)cc2)CC1
Temperature: 0 °C
Yield: 59.9 %

Procedure:
Acetic anhydride (Aldrich) (0.318 g, 3.11 mmoles) in tetrahydrofuran (1.5 mL) was added to a solution of 2-amino-5-(4-chlorophenoxy)-4-(piperazino)pyrimidine (0.511 g, 1.67 mmoles) and triethylamine (0.526 g, 5.20 mmoles) in tetrahydrofuran (13 mL). After 0.5 hours the solution was diluted with ice water (40 mL) and poured into dichloromethane (75 mL). The layers were separated, and the organic layer was washed with saturated aqueous sodium bicarbonate (40 mL), brine (40 mL) and then dried over sodium sulfate. The dry solution was spin evaporated in vacuo to give a white foam. The foam was recrystallized from hexanes-ethyl acetate to give 0.348 g (60% yield) of 4-(4-acetylpiperazino)-2-amino-5-(4-chlorophenoxy)pyrimidine as beige pins, mp 153-157° C.