Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]1([NH:22][C:23]([NH:25][C:26](=[O:33])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[S:24])[C@H:14]([CH2:15]O)[CH2:13][C@H:12]([C@@H:17]2[CH2:21][CH2:20][CH2:19][O:18]2)[O:11][CH2:10]1.C(OC[C@@H]1OC[C@]2(C3C=CC(F)=CC=3F)N=C(NC(=O)C3C=CC=CC=3)SC[C@@H]2C1)C1C=CC=CC=1>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]12[CH2:10][O:11][C@@H:12]([C@@H:17]3[CH2:21][CH2:20][CH2:19][O:18]3)[CH2:13][C@H:14]1[CH2:15][S:24][C:23]([NH:25][C:26](=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[N:22]2
Reactant: O=C(NC(=S)N[C@@]1(c2ccc(F)cc2F)CO[C@@H]([C@@H]2CCCO2)C[C@H]1CO)c1ccccc1
Agent: O=C(NC1=N[C@@]2(c3ccc(F)cc3F)CO[C@@H](COCc3ccccc3)C[C@H]2CS1)c1ccccc1
Product: O=C(NC1=N[C@@]2(c3ccc(F)cc3F)CO[C@@H]([C@@H]3CCCO3)C[C@H]2CS1)c1ccccc1

Procedure:
N-({(3S,4R,6R)-3-(2,4-Difluorophenyl)-4-(hydroxymethyl)-6-[(2S)-tetrahydrofuran-2-yl]tetrahydro-2H-pyran-3-yl}carbamothioyl)benzamide (C102) was converted to the product using the method described for the synthesis of N-[(4aR,6R,8aS)-6-[(benzyloxy)methyl]-8a-(2,4-difluorophenyl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide (C8) in Preparation P1. Yield: 1.0 g, 2.2 mmol, 87%. LCMS m/z 458.9 [M+H+].
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([SH:8])[CH:5]=[CH:6][CH:7]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:16][CH2:17][CH2:18][OH:19]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([S:8][CH2:16][CH2:17][CH2:18][OH:19])[CH:5]=[CH:6][CH:7]=1
Reactant: OCCCBr
Reactant: Sc1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: OCCCSc1cccc(Br)c1
Temperature: 50 °C
Yield: 98.1 %

Procedure:
A solution of 3-bromobenzenethiol (5.00 g, 26.4 mmol) in anhydrous DMF (30 mL) was treated with Cs2CO3 (17.2 g, 52.9 mmol) followed by 3-bromopropan-1-ol (4.40 g, 31.6 mmol). The mixture was heated to 50° C. under nitrogen for 12 h. DMF was distilled out completely, and the residue was dissolved in DCM and washed with water, brine and dried over Na2SO4. The solvent was evaporated to afford 6.4 g (98%) of the title compound as pale yellow liquid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:14]([C:15]([F:18])([F:17])[F:16])=[CH:13][N:12]=[C:11]([NH:19][C:20]3[CH:34]=[CH:33][C:23]([CH2:24][P:25](=[O:32])([O:29][CH2:30][CH3:31])[O:26][CH2:27][CH3:28])=[CH:22][CH:21]=3)[N:10]=2)=[C:4]([C:35](=[O:38])[NH:36][CH3:37])[CH:3]=1.[CH2:39]([N:43]1[CH:47]=[C:46](B2OC(C)(C)C(C)(C)O2)[CH:45]=[N:44]1)[CH:40]([CH3:42])[CH3:41]>>[CH3:37][NH:36][C:35]([C:4]1[CH:3]=[C:2]([C:46]2[CH:45]=[N:44][N:43]([CH2:39][CH:40]([CH3:42])[CH3:41])[CH:47]=2)[CH:7]=[CH:6][C:5]=1[NH:8][C:9]1[C:14]([C:15]([F:16])([F:18])[F:17])=[CH:13][N:12]=[C:11]([NH:19][C:20]2[CH:21]=[CH:22][C:23]([CH2:24][P:25](=[O:32])([O:26][CH2:27][CH3:28])[O:29][CH2:30][CH3:31])=[CH:33][CH:34]=2)[N:10]=1)=[O:38]
Reactant: CC(C)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(Br)cc3C(=O)NC)n2)cc1)OCC
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn(CC(C)C)c4)cc3C(=O)NC)n2)cc1)OCC

Procedure:
The title compound was prepared using the procedure from Example 97 with Diethyl (4-{[4-{[4-bromo-2-(methylcarbamoyl)phenyl]amino}-5-(trifluoromethyl)pyrimidin-2-yl]amino}benzyl)phosphonate (Example 106) and the commercially available 1-isobutyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole. MS (ES+): m/z 666.20(100) [MH+]; HPLC: tR=3.60 min (ZQ3, polar—5 min).
Reaction SMILES: BrCBr.O1CCC[CH2:5]1.[OH:9][C@H:10]1[CH2:14][C:13](=O)[C:12]([CH2:16][C:17]#[CH:18])=[C:11]1[CH3:19].C(=O)(O)[O-].[Na+]>ClCCl.[Zn].[Ti](Cl)(Cl)(Cl)Cl.O.CCCCCC>[CH3:19][C:11]1[C@@H:10]([OH:9])[CH2:14][C:13](=[CH2:5])[C:12]=1[CH2:16][C:17]#[CH:18]
Reactant: C1CCOC1
Reactant: C#CCC1=C(C)[C@@H](O)CC1=O
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCCC
Solvent: ClCCl
Solvent: O
Product: C#CCC1=C(C)[C@@H](O)CC1=C
Reaction time: 2 h
Yield: 2.6 %

Procedure:
Dibromomethane (1.3 g) and zinc dust (1.5 g) were added to dry tetrahydrofuran (20ml), and the resulting mixture was cooled to 0°~5° C. A dichloromethane solution (5 ml) of 1M titanium tetrachloride was added to the tetrahydrofuran solution over about 10 min, and the resulting mixture was allowed to react for 3 days at 0°5° C. Then a solution of (S)-4-hydroxy-3-methyl-2-(2-propynyl)cyclopent-2-ene-1-one (675 mg) in dichloromethane (10 ml) was added at 0°~5° C. over about 10 min. After the resulting mixture was allowed to react for 2 hours at the same temperature, hexane (40 ml) and then a slurry consisting of sodium bicarbonate (8 g) and water (4 ml) were added. After stirring for 2 hours at 0°~5° C., the organic layer was separated by decantation. The obtained residue was extracted three times with n-hexane (20 ml). The combined organic layer was washed with saturated aqueous sodium bicarbonate solution, and dried over anhydrous magnesium sulfate. Then the solvent was evaporated under reduced pressure, and the resultant residue was subjected to silica gel column chromatography (eluent; n-hexane: ethyl acetate=3:1) to afford the desired product, (S)-2-methyl-4-methylidene-3-(2-propynyl)cyclopent-2-ene-1-ol (17 mg, yield 2.6% as a pale yellow oil.
Reaction SMILES: [I:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[C:3]=1[C:4](OC)=[O:5].C1C(=O)[N:17](Br)C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>ClC1C=CC=CC=1>[I:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:5])[NH:17][CH2:12]2
Reactant: COC(=O)c1c(C)cccc1I
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: Clc1ccccc1
Product: O=C1NCc2cccc(I)c21
Temperature: 90 °C
Reaction time: 18 h
Yield: 40 %

Procedure:
Methyl 2-iodo-6-methylbenzoate (I58) (2.00 g, 7.245 mmol) and NBS (1.418 g, 7.969 mmol) were stirred in chlorobenzene (50 mL) and benzoyl peroxide (75% w/w, 0.234 g, 0.724 mmol) was added. The reaction was stirred at 90° C. for 18 hours, cooled to room temperature, filtered and the precipitate was washed with cyclohexane (4×10 mL). The combined filtrates were evaporated, and the resulting brown oil was diluted with THF (50 mL). Aqueous ammonia solution (20 mL) was added, and the mixture was stirred vigorously for 17 hours. The mixture was diluted with water (20 mL) and the THF was removed in vacuo. DCM (150 mL) was added, the layers were separated and the aqueous layer was extracted with DCM (2×100 mL), the combined organics were washed with brine (100 mL), dried (MgSO4) and filtered. Silica gel was added and the volatiles were removed in vacuo to give the crude material absorbed onto silica gel. The material was purified by silica gel chromatography (Biotage Isolera, 40 g Si cartridge, 0-100% EtOAc in petroleum benzine 40-60° C., then 0-20% methanol in EtOAc) to give the title compound (I59) (0.757 g, 40% yield) as a beige solid; 1H NMR (400 MHz, CDCl3) δ 7.93 (dd, J=7.8, 0.7 Hz, 1H), 7.46 (dd, J=7.5, 0.8 Hz, 1H), 7.26-7.21 (m, 1H), 7.10 (brs, 1H), 4.37 (d, J=0.6 Hz, 2H). LCMS Method C: rt 5.06 min; m/z 260.0 [M+H]+.
Reaction SMILES: [BrH:1].[Br:2][C:3]([CH3:28])([CH3:27])[C:4]([C:6]1[CH:11]=[CH:10][C:9]([S:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[O:20])=[CH:15][CH:14]=2)=[CH:8][CH:7]=1)=[O:5].BrBr>ClCCl>[Br:2][C:3]([CH3:28])([CH3:27])[C:4]([C:6]1[CH:7]=[CH:8][C:9]([S:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([C:21]3([Br:1])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[O:20])=[CH:15][CH:14]=2)=[CH:10][CH:11]=1)=[O:5]
Reactant: CC(C)(Br)C(=O)c1ccc(Sc2ccc(C(=O)C3CCCCC3)cc2)cc1
Reactant: Br
Agent: BrBr
Solvent: ClCCl
Product: CC(C)(Br)C(=O)c1ccc(Sc2ccc(C(=O)C3(Br)CCCCC3)cc2)cc1

Procedure:
A drop of 48% HBr was added to a solution of 11.95 g (26.83 mmol) of 2-bromo-1-[4-(4-cyclohexancarbonyl-phenylsulphanyl)-phenyl]-2-methyl-propan-1-one dissolved in 120 ml of dichloromethane; in 15′ 1.37 ml (26.83 mmol) of bromine dissolved in 10 ml of dichloromethane were added drop wise. After 1 h the organic phase was washed with water and with a sodium metabisulphite solution. The organic phase was separated, washed with brine, dried with sodium sulphate, filtered and evaporated under vacuum obtaining 14.07 g of a yellowish oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][N:13]([C:16]3[CH:17]=[CH:18][C:19]4[C:23]5[CH2:24][N:25](C(OC(C)(C)C)=O)[CH2:26][CH2:27][CH2:28][C:22]=5[N:21]([CH3:36])[C:20]=4[N:37]=3)[C:12](=[O:38])[CH:11]=2)=[N:6][CH:7]=1.[ClH:39]>CO>[ClH:39].[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][N:13]([C:16]3[CH:17]=[CH:18][C:19]4[C:23]5[CH2:24][NH:25][CH2:26][CH2:27][CH2:28][C:22]=5[N:21]([CH3:36])[C:20]=4[N:37]=3)[C:12](=[O:38])[CH:11]=2)=[N:6][CH:7]=1
Reactant: Cn1c2c(c3ccc(-n4ccc(OCc5ccc(F)cn5)cc4=O)nc31)CN(C(=O)OC(C)(C)C)CCC2
Agent: Cl
Solvent: CO
Product: Cn1c2c(c3ccc(-n4ccc(OCc5ccc(F)cn5)cc4=O)nc31)CNCCC2
Temperature: 25 °C
Reaction time: 72 h
Yield: 95 %

Procedure:
A suspension of tert-butyl 2-(4-((5-fluoropyridin-2-yl)methoxy)-2-oxopyridin-1(2H)-yl)-10-methyl-7,8,9,10-tetrahydropyrido[3′,2′:4,5]pyrrolo[3,2-c]azepine-6(5H)-carboxylate (130 mg, 0.250 mmol) in 1.25 M HCl in MeOH (4.0 mL) was stirred at ambient temperature for 72 h. The solution was concentrated and dried to provide the title compound (108 mg, 95%) as a brown-yellow powder: 1H NMR (500 MHz, DMSO-d6) δ 9.15 (s, 2H), 8.62 (d, J=3.0 Hz, 1H), 8.16 (d, J=8.5 Hz, 1H), 7.88-7.80 (m, 2H), 7.67-7.64 (m, 1H), 7.35 (d, J=8.0 Hz, 1H), 6.19 (dd, J=8.0, 2.5 Hz, 1H), 5.99 (d, J=2.5 Hz, 1H), 5.23 (s, 2H), 4.46 (s, 2H), 3.75 (s, 3H), 3.49-3.40 (m, 2H), 3.36-3.20 (m, 2H), 2.19-2.08 (m, 2H); ESI MS m/z 420 [M+H]+; HPLC (Method A) 98.2% (AUC), tR=12.2 min.
Reaction SMILES: N1C2C(=CC=CC=2)C=CC=1.[F:11][C:12]1[CH:17]=[CH:16][C:15]([CH:18]([OH:39])[C:19]#[C:20][CH2:21][N:22]2[CH2:38][CH2:37][C:25]3([N:29]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[CH2:28][NH:27][C:26]3=[O:36])[CH2:24][CH2:23]2)=[CH:14][CH:13]=1.[H][H]>[Pd].C(O)C.C(Cl)(Cl)Cl>[F:11][C:12]1[CH:17]=[CH:16][C:15]([CH:18]([OH:39])[CH:19]=[CH:20][CH2:21][N:22]2[CH2:38][CH2:37][C:25]3([N:29]([C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)[CH2:28][NH:27][C:26]3=[O:36])[CH2:24][CH2:23]2)=[CH:14][CH:13]=1
Reactant: [H][H]
Reactant: O=C1NCN(c2ccccc2)C12CCN(CC#CC(O)c1ccc(F)cc1)CC2
Agent: [Pd]
Solvent: ClC(Cl)Cl
Solvent: CCO
Solvent: c1ccc2ncccc2c1
Product: O=C1NCN(c2ccccc2)C12CCN(CC=CC(O)c1ccc(F)cc1)CC2
Reaction time: 0.25 h

Procedure:
To a deactivated palladium catalyst, which was prepared from 5% palladium on barium sulfate (30 mg) and quinoline (15 mg) in ethanol (6 ml) and chloroform (2 ml) by stirring for 15 minutes under hydrogen, was added a solution of 8-[4(p-fluorophenyl)-4-hydroxy-2-butynyl]-1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one (0.80 g) in ethanol (3 ml), and the resulting mixture was stirred under hydrogen at 25° C until an equimolar amount of hydrogen (48 ml) was consumed. The catalyst was filtered off, and the filtrate was concentrated in vacuum and chromatographed to afford 8-[4(p-fluorophenyl)-4-hydroxy-2-butenyl]-1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one as oily materials. νC=Oneat 1700 cm-1.
Reaction SMILES: [Na].Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH2:12][N:13]([CH2:16][CH3:17])[CH2:14][CH3:15])=[O:9])=[C:6]([OH:21])[CH:5]=1.Cl[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:25]>>[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH2:12][N:13]([CH2:14][CH3:15])[CH2:16][CH3:17])=[O:9])=[C:6]([O:21][CH2:23][C:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:25])[CH:5]=1
Reactant: O=C(CCl)c1ccccc1
Reactant: CCN(CC)CCNC(=O)c1cc(Cl)c(N)cc1O
Agent: Cl
Agent: [Na]
Product: CCN(CC)CCNC(=O)c1cc(Cl)c(N)cc1OCC(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 50.1 %

Procedure:
To a stirred suspension of sodium hdride (320 mg of 60%, 8 mmoles, washed with n-pentane) in DMF (15 ml) was added 4-amino-5-chloro-N-[2-(diethylamino)ethyl]-2-hydroxybenzamide hydrochloride (1.289 g, 4 mmoles) and the mixture stirred for 20 minutes followed by addition of chloroacetophenone (619 mg, 4 mmoles). The mixture was stirred 4 hours, poured into ice-cold water (50 ml) whereupon a solid separated out. This was isolated by filtration, dried and recrystallized from methanol to give 810 mg (50%) of the title compound as white solid mp 153°-4°. The NMR spectrum (90 MHz) in CDCl3 gave the following resonances: δ8.64 (bs, 1H); 8.2 (s, 1H); 8 (m, 2H); 7.6 (m, 3H); 6.22 (s, 1H); 5.36 (s, 2H); 4.4 (s, 2H); 3.52 (m, 2H); 2.64 (m, 6H); 1.01 (m, 6H).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([N:5]2[C:9]3=[N:10][CH:11]=[N:12][C:13]([NH2:14])=[C:8]3[C:7]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:17][CH:16]=3)=[N:6]2)[CH2:2]1.Cl.[CH2:29]([N:31]([CH2:37][CH3:38])[CH2:32][CH2:33][C:34](O)=[O:35])[CH3:30].Cl.CN(C)CCCN=C=NCC.CCN(C(C)C)C(C)C.ON1C2N=CC=CC=2N=N1>CN(C)C=O>[NH2:14][C:13]1[N:12]=[CH:11][N:10]=[C:9]2[N:5]([CH:3]3[CH2:2][N:1]([C:34](=[O:35])[CH2:33][CH2:32][N:31]([CH2:37][CH3:38])[CH2:29][CH3:30])[CH2:4]3)[N:6]=[C:7]([C:15]3[CH:16]=[CH:17][C:18]([O:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:19][CH:20]=3)[C:8]=12
Reactant: CCN(CC)CCC(=O)O
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)nn2C1CNC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCN(CC)CCC(=O)N1CC(n2nc(-c3ccc(Oc4ccccc4)cc3)c3c(N)ncnc32)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 35.7 %

Procedure:
A mixture of 1-(3-azetanyl)-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.05 g, 0.00014 mol), 3-(diethylamino)propionic acid hydrochloride (0.0032 g, 0.000175 mol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.0034 g, 0.000175 mol), N,N′-diisopropylethylamine (0.068 g, 0.00053 mol) and 1-hydroxy-7-azabenzotriazole (0.019 g, 0.00014 mol) in anhydrous N,N-dimethylformamide (6 mL) was stirred for 18 hours at room temperature. The solvent was removed under reduced pressure. The residue was dissolved in dichloromethane (3 mL) and washed with water (2 mL). The solvent was removed under reduced pressure. The residue was purified by RP-HPLC (Hypersilprep HS C18, 8 μm, 250×21.1 mm; 5%-100% over 35 min with 0.1 M ammonium acetate, 21 mL/min) to yield 1-{3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-azetanyl}-3-(diethylamino)-1-propanone (0.025 g, 0.00005 mol).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([OH:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[NH2:34][C:35]1[C:44]2[C:39](=[CH:40][C:41](O)=[C:42]([CH3:45])[CH:43]=2)[CH:38]=[CH:37][N:36]=1.CCOC(/N=N/C(OCC)=O)=O>CN(C=O)C.CO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([O:14][C:41]2[CH:40]=[C:39]3[C:44](=[CH:43][C:42]=2[CH3:45])[C:35]([NH2:34])=[N:36][CH:37]=[CH:38]3)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCCC(O)C1
Reactant: Cc1cc2c(N)nccc2cc1O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: CN(C)C=O
Product: Cc1cc2c(N)nccc2cc1OC1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 3-hydroxypiperidine-1-carboxylic acid tert-butyl ester (231 mg, 1.15 mmol), triphenylphosphine (301 mg, 1.15 mmol), 1-amino-7-methylisoquinolin-6-ol (200 mg, 1.15 mmol) in DMF (5 ml) at 0° C., under argon, was added dropwise diethylazodicarboxylate (181 [μL, 1.15 mmol). The mixture was then warmed to ambient temperature and stirred for 24 h. Methanol was added and the mixture loaded onto a pre-acidified SCX column, washed with methanol and then eluted with 2M ammonia in methanol. The crude product was isolated and further purified using prep-HPLC to give 3-(1-Amino-7-methylisoquinolin-6-yloxy)piperidine-1-carboxylic acid tert-butyl ester. A mixture of the (3-(1-Amino-7-methylisoquinolin-6-yloxy)piperidine-1-carboxylic acid tert-butyl ester in dichloromethane (10 ml) and trifluoroacetic acid (3 ml) was stirred at ambient temperature overnight. The mixture was concentrated in vacuo to give a residue. The residue was loaded onto a pre-acidified SCX column, washed with methanol and then eluted with 2M ammonia in methanol. The crude product was isolated and further purified using prep-HPLC to give 7-methyl-6-(piperidin-3-yloxy)isoquinolin-1-ylamine, El-MS: m/z=258.3 [M+H]+.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH2:26][CH3:27])[CH2:23][CH2:22][C:21]([C:28]([NH:30][C:31]4[CH:36]=[CH:35][C:34]([S:37][CH2:38][C:39]5[N:43]6[CH:44]=[CH:45][CH:46]=[CH:47][C:42]6=[N:41][C:40]=5[CH3:48])=[CH:33][CH:32]=4)=[O:29])=[CH:20][C:19]=3[CH:49]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:58])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH2:26][CH3:27])[CH2:23][CH2:22][C:21]([C:28]([NH:30][C:31]4[CH:32]=[CH:33][C:34]([S:37]([CH2:38][C:39]5[N:43]6[CH:44]=[CH:45][CH:46]=[CH:47][C:42]6=[N:41][C:40]=5[CH3:48])=[O:58])=[CH:35][CH:36]=4)=[O:29])=[CH:20][C:19]=3[CH:49]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4c(C)nc5ccccn45)cc2)CCN3CCC)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4c(C)nc5ccccn45)cc2)CCN3CCC)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 67.5 %

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-N-[4-(2-methylimidazo[1,2-a]pyridin-3-ylmethylthio)phenyl]-1-propyl-2,3-dihydro-1H-benzazepine-4-carboxamide (0.96 g) in dichloromethane (10 ml) was added dropwise a solution of 3-chloroperbenzoic acid (70%, 0.52 g) in dichloromethane (10 ml) at −78° C. The mixture was stirred for 1 hour at −78° C., sodium thiosulfate solution was added to the mixture at room temperature and the mixture was stirred for several minutes. The mixture was extracted with ethyl acetate, and the organic layer was washed with sodium bicarbonate solution and saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (basic silica gel, ethyl acetate:hexane 3:1→ethyl acetate), and was further recrystallized from ethyl acetate-diisopropylether, to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-(2-methylimidazo[1,2-a]pyridin-3-ylmethylsulfinyl)phenyl]-1-propyl-2,3-dihydro-1H-benzazepine-4-carboxamide (Compound 165) (663.1 mg) as yellow crystals.
Reaction SMILES: C[O-].[Na+].[H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:10][C:11]1[O:15][C:14]2[CH:16]=[CH:17][C:18]([C:20]#[C:21][CH2:22][OH:23])=[CH:19][C:13]=2[CH:12]=1.C(OCC)(=O)C.[I:30][C:31]1[CH:36]=[CH:35][C:34](I)=[CH:33][CH:32]=1.O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1>O1CCCC1.CCOCC.[Cl-].[NH4+].[Cl-].[Zn+2].[Cl-].CO>[I:30][C:31]1[CH:36]=[CH:35][C:34](/[C:20](/[C:18]2[CH:17]=[CH:16][C:14]3[O:15][C:11]([CH3:10])=[CH:12][C:13]=3[CH:19]=2)=[CH:21]/[CH2:22][OH:23])=[CH:33][CH:32]=1
Reactant: Ic1ccc(I)cc1
Reactant: Cc1cc2cc(C#CCO)ccc2o1
Agent: C[O-]
Agent: [Al+3]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1cc2cc(/C(=C\CO)c3ccc(I)cc3)ccc2o1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
Sodium methoxide (0.05 g, 0.9 mmol) was added to 1 M solution of lithium aluminum hydride in tetrahydrofuran (20 mL, 20 mmol). The mixture was cooled to 0° C., and a solution of the above alcohol (3.67 g, 19.7 mmol) in tetrahydrofuran (30 mL) was slowly added. The reaction mixture was stirred at 0° C. for 1.5 h and subsequently for 1.5 h at ambient temperature. Ethyl acetate (3.3 mL, 34 mmol) was added at 0° C. and the mixture was then stirred for 20 min without cooling. 1,4-Diiodobenzene (6.6 g, 20 mmol), anhydrous zinc chloride (1.64 g, 12 mmol), tris(dibenzylideneacetone)dipalladium chloroform complex (0.41 g, 0.4 mmol), and tri-(2-furyl)phosphine (0.37 g, 1.6 mmol) were added; the mixture was evacuated and kept under nitrogen. Reaction mixture was heated at 65° C. for 16 h, and then cooled down. Methanol (10 mL) was added and the mixture was stirred for additional 1 h. The reaction suspension was diluted with ether (150 mL), and saturated aqueous solution of ammonium chloride (5 mL) was added. The mixture was filtered through a paddle of silica gel and the solid phase was thoroughly washed with ether. Solvents were evaporated in vacuo and the residue was submitted to column chromatography (silica gel Fluka 60; benzene/chloroform 1:0-0:1) affording (Z)-3-(4-iodophenyl)-3-(2-methylbenzo[b]furan-5-yl)allyl alcohol as light brown solid.
Reaction SMILES: [CH2:1]([C:4]1[S:8][C:7]([N:9]2[CH:14]([OH:15])[CH2:13][CH2:12][N:11]([CH2:16][Cl:17])[C:10]2=[O:18])=[N:6][N:5]=1)[CH:2]=[CH2:3].[C:19]1(C)C(S(O)(=O)=O)=CC=CC=1>CO>[CH2:1]([C:4]1[S:8][C:7]([N:9]2[CH:14]([O:15][CH3:19])[CH2:13][CH2:12][N:11]([CH2:16][Cl:17])[C:10]2=[O:18])=[N:6][N:5]=1)[CH:2]=[CH2:3]
Reactant: C=CCc1nnc(N2C(=O)N(CCl)CCC2O)s1
Reactant: Cc1ccccc1S(=O)(=O)O
Solvent: CO
Product: C=CCc1nnc(N2C(=O)N(CCl)CCC2OC)s1

Procedure:
Tetrahydro-1-(5-allyl-1,3,4-thiadiazol-2-yl)-3-chloromethyl-6-hydroxy-2(1H)-pyrimidinone (7 grams), methyl alcohol (50 ml) and toluenesulfonic acid (0.2 grams) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture is then heated at reflux for a period of about 24 hours. After this time the mixture is stripped of unreacted alcohol under reduced pressure to yield a solid product. This product is then recrystallized to yield the desired product tetrahydro-1-(5-allyl-1,3,4-thiadiazol-2-yl)-3-chloromethyl-6-methoxy-2(1H)-pyrimidinone.
Reaction SMILES: C(OC([NH:11][C@H:12]([C:23]([NH:25][C@H:26]([C:31]([NH:33][C@H:34]([C:39]([NH:41][CH:42]([C:46]([NH2:48])=[O:47])[CH2:43][CH2:44][CH3:45])=[O:40])[CH2:35][C:36](=[O:38])[OH:37])=[O:32])[CH2:27][CH2:28][S:29][CH3:30])=[O:24])[CH2:13][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[NH:16][CH:15]=1)=O)C1C=CC=CC=1.[BrH:49]>C(O)(=O)C.CSCC>[BrH:49].[NH2:11][C@H:12]([C:23]([NH:25][C@H:26]([C:31]([NH:33][C@H:34]([C:39]([NH:41][CH:42]([C:46]([NH2:48])=[O:47])[CH2:43][CH2:44][CH3:45])=[O:40])[CH2:35][C:36](=[O:37])[OH:38])=[O:32])[CH2:27][CH2:28][S:29][CH3:30])=[O:24])[CH2:13][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[NH:16][CH:15]=1
Reactant: CCCC(NC(=O)[C@H](CC(=O)O)NC(=O)[C@H](CCSC)NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)OCc1ccccc1)C(N)=O
Agent: Br
Agent: CCSC
Solvent: CC(=O)O
Product: CCCC(NC(=O)[C@H](CC(=O)O)NC(=O)[C@H](CCSC)NC(=O)[C@@H](N)Cc1c[nH]c2ccccc12)C(N)=O
Reaction time: 1 h

Procedure:
N-benzyloxycarbonyl-L-tryptophanyl-L-methionyl-L-aspartyl-DL-norvaline amide is dissolved in 10 parts glacial acetic acid containing 2 parts methylethyl sulfide. Then, 10 parts of 6 M hydrobromic acid in acetic acid is added and the solution is allowed to stand for one hour at room temperature. The solvents are removed under vacuum below 40° C. and the residue shaken with ether to afford L-tryptophanyl-L-methionyl-L-aspartyl-DL-norvaline amide hydrobromide. This compound is represented by the following formula.