Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:12][CH2:11][CH2:10][NH:9]2)=[CH:4][CH:3]=1.[CH2:13]([C:16]1[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1)[CH2:14][CH3:15]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:12][CH2:11][CH2:10][N:9]2[S:22]([C:19]2[CH:20]=[CH:21][C:16]([CH2:13][CH2:14][CH3:15])=[CH:17][CH:18]=2)(=[O:24])=[O:23])=[CH:6][CH:7]=1
Reactant: CCCc1ccc(S(=O)(=O)Cl)cc1
Reactant: Fc1ccc(C2CCCN2)cc1
Product: CCCc1ccc(S(=O)(=O)N2CCCC2c2ccc(F)cc2)cc1

Procedure:
The title compound, colorless oil, MS: m/e=347 (M+) was prepared in accordance with the general method of example 1e from (RS)-2-(4-fluoro-phenyl)-pyrrolidine and 4-propyl-benzenesulfonyl chloride.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:8]2[N:13]=[C:12]([CH3:14])[C:11]([OH:15])=[C:10]([CH3:16])[N:9]=2)[C:4]([CH3:7])=[CH:5][CH:6]=1.[H-].[Na+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O>C1COCC1>[CH3:1][C:2]1[N:3]([C:8]2[N:9]=[C:10]([CH3:16])[C:11]([O:15][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[C:12]([CH3:14])[N:13]=2)[C:4]([CH3:7])=[CH:5][CH:6]=1
Reactant: Cc1nc(-n2c(C)ccc2C)nc(C)c1O
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1nc(-n2c(C)ccc2C)nc(C)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a stirred solution containing 1.62 g (7.46 mmol) of 2-(2,5-dimethyl-1H-pyrrol-1-yl)-5-hydroxy-4,6-dimethylpyrimidine (5) in 30 mL of anhydrous THF were added 440 mg (11.00 mmol) of 60% sodium hydride suspension in mineral oil followed by 1.20 mL (10.10 mmol) of benzyl bromide. The reaction mixture was stirred at room temperature under argon atmosphere for 48 h. The reaction mixture was poured into 150 mL of water and extracted with two portions of 100 mL of ethyl acetate. The combined organic solution was washed with a portion of 100 of brine, dried (MgSO4) and then concentrated under diminished pressure. The residue was purified by chromatography on a silica gel column. Elution with hexanes-ethyl acetate 4:1 gave the expected product as light yellow oil: yield 2.20 g (96%). 1H-NMR (CDCl3) δ 7.42 (m, 5H), 5.86 (s, 2H), 4.92 (s, 2H), 2.47 (s, 6H), 2.29 (s, 6H); 13C-NMR (CDCl3) δ 161.59, 152.34, 147.66, 136.05, 129.16, 128.59, 128.26, 107.90, 75.29, 19.10, 14.10.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)CCl.[CH:21]1[CH:22]=[CH:23][C:24]2[N:29](O)N=[N:27][C:25]=2[CH:26]=1.N1C=CC=CC=1CN>ClCCl>[N:27]1[CH:23]=[CH:22][CH:21]=[CH:26][C:25]=1[CH2:24][NH:29][C:10](=[O:12])[C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C:13]([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)O)C(C)(C)C
Reactant: On1nnc2ccccc21
Agent: NCc1ccccn1
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H](C(=O)NCc1ccccn1)C(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 99.6 %

Procedure:
To a solution of (2S)-2-tert-butoxycarbonylamino-3,3-dimethylbutanoic acid (11.6 g, 50 mmol) in dichloromethane (100 mL) is added EDC (14.4 g, 75 mmol), HOBT (7.65 g, 50 mmol), and 2-pyridylmethylamine (6.48 g, 60 mmol). The resulting solution is stirred at 25° C. for 18 h, then diluted with dichloromethane (200 mL) and washed with 2 M hydrochloric acid and 2 M sodium hydroxide. The organic layer is dried over anhydrous magnesium sulfate and concentrated in vacuo to provide (2S)-2-tert-butoxycarbonylamino-3,3-dimethylbutanoic acid 2-pyridylmethylamide as a white solid (16 g, 100% yield).
Reaction SMILES: [OH-:1].[K+].FC(F)(F)C([N:7]1[CH2:16][CH2:15][C:14]2[C:9](=[CH:10][C:11]([S:17]([NH:20][CH2:21][CH2:22][C@@H:23]3[CH2:27][CH2:26][CH2:25][N:24]3[CH3:28])(=[O:19])=[O:18])=[CH:12][CH:13]=2)[CH2:8]1)=[O:6].[ClH:31]>>[OH2:6].[ClH:31].[ClH:31].[CH3:28][N:24]1[CH2:25][CH2:26][CH2:27][C@H:23]1[CH2:22][CH2:21][NH:20][S:17]([C:11]1[CH:10]=[C:9]2[C:14]([CH2:15][CH2:16][NH:7][CH2:8]2)=[CH:13][CH:12]=1)(=[O:19])=[O:18].[OH2:1].[OH2:6].[CH3:28][N:24]1[CH2:25][CH2:26][CH2:27][C@H:23]1[CH2:22][CH2:21][NH:20][S:17]([C:11]1[CH:10]=[C:9]2[C:14]([CH2:15][CH2:16][NH:7][CH2:8]2)=[CH:13][CH:12]=1)(=[O:19])=[O:18].[ClH:31].[ClH:31]
Reactant: [OH-]
Reactant: CN1CCC[C@H]1CCNS(=O)(=O)c1ccc2c(c1)CN(C(=O)C(F)(F)F)CC2
Agent: Cl
Agent: [K+]
Product: CN1CCC[C@H]1CCNS(=O)(=O)c1ccc2c(c1)CNCC2
Product: O
Temperature: 25 °C
Yield: 87.5 %

Procedure:
A 45.7% solution of potassium hydroxide (105 g, 0.855 mol) was added to a 30.66% (w/w) ethanolic solution of 2-(2,2,2-trifluoroacetyl)-N-{2-[(2S)-1-methylpyrrolidin-2-yl]ethyl}-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide (1023.6, 0.748 mol) at a rate that limited the temperature to no more than 45° C. After cooling to room temperature, the reaction was monitored by HPLC. Upon completion of the deprotection, the reaction was acidified by the dropwise addition of concentrated hydrochloric acid (194 mL, 2.35 mol). The precipitated KCl was removed by filtration at between 39-51° C. The reactor was rinsed with ethanol (300 mL) which in turn was used to rinse the collected KCl. The ethanol filtrates were combined and returned to the reactor. The reactor was heated to approximately 55° C. and 2-methyltetrahydrofuran (375 mL) was added. Seed crystals of N-{2-[(2S)-1-methylpyrrolidin-2-yl]ethyl}-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide dihydrochloride sesquihydrate (1 g) were added. After cooling to approximately −5° C., the product was collected by filtration. The product was rinsed with a solution prepared from 2-methyltetrahydrofuran (200 mL), ethanol (200 mL) and water (5 mL). Following drying in a vacuum oven at 40° C., 277 g (87%) of N-{2-[(2S)-1-methylpyrrolidin-2-yl]ethyl}-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide dihydrochloride sesquihydrate was isolated as a colorless solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[N:10]([CH3:15])[C:11](=[S:14])[NH:12][N:13]=2)[CH:5]=[CH:6][C:7]=1[F:8].Br[CH2:17][CH2:18][CH2:19][Cl:20].C(O)(=O)C>C(O)C>[Cl:20][CH2:19][CH2:18][CH2:17][S:14][C:11]1[N:10]([CH3:15])[C:9]([C:4]2[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=2)=[N:13][N:12]=1
Reactant: ClCCCBr
Reactant: Cn1c(-c2ccc(F)c(F)c2)n[nH]c1=S
Solvent: CC(=O)O
Solvent: CCO
Product: Cn1c(SCCCCl)nnc1-c1ccc(F)c(F)c1
Temperature: 90 °C

Procedure:
To 5-(3,4-difluorophenyl)-4-methyl-2,4-dihydro-3H-1,2,4-triazole-3-thione (0.4 g, preparation reported in WO 02/40471) in ethanol (6 ml) sodium ethanolate (0.72 ml) was carefully added with stirring followed by 1-bromo-3-chloropropane (0.26 ml). The mixture was heated at 90° C. for 1 h. Acetic acid was added at room temperature until pH=4. After elimination of the solvent under reduced pressure the residue was partitioned between aqueous NaHCO3 (saturated) and DCM. The organic layer was collected and the aqueous phase extracted twice with DCM. The combined DCM layers were concentrated and submitted to column chromatography (EtOAc—acetone gradient) to provide the title compound as white solid (0.36 g).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:13])[C@@H:5]([CH2:11]O)[NH:6][CH2:7][CH:8]([CH3:10])[CH3:9].COC(=O)[C@@H](CO)N.O=S(Cl)[Cl:24].[CH3:26][C:27]1[CH:32]=[C:31]([N+:33]([O-:35])=[O:34])[CH:30]=[CH:29][C:28]=1[N:36]=[C:37]=[S:38]>>[ClH:24].[CH3:26][C:27]1[CH:32]=[C:31]([N+:33]([O-:35])=[O:34])[CH:30]=[CH:29][C:28]=1[N:36]=[C:37]1[N:6]([CH2:7][CH:8]([CH3:10])[CH3:9])[C@@H:5]([C:4]([O:3][CH3:2])=[O:13])[CH2:11][S:38]1
Reactant: O=S(Cl)Cl
Reactant: COC(=O)[C@@H](CO)NCC(C)C
Reactant: Cc1cc([N+](=O)[O-])ccc1N=C=S
Agent: COC(=O)[C@H](N)CO
Agent: Cl
Product: COC(=O)[C@H]1CSC(=Nc2ccc([N+](=O)[O-])cc2C)N1CC(C)C

Procedure:
(R)-N-isobutylserine methyl ester HCl salt was made from (D)-serine methyl ester as described in Method B3a. The ester was reacted with SOCl2, followed by 2-methyl-4-nitrophenyl isothiocyanate according to Method C2a to afford (4S)-2-(2-methyl-4-nitrophenylimino)-4-(methoxycarbonyl)-3-isobutyl-1,3-thiazolidine HCl salt.
Reaction SMILES: [CH2:1]([O:17][CH2:18][CH:19]([CH2:41]OS(C)(=O)=O)[CH2:20][O:21][C:22]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[F-:47].C([N+](CCCC)(CCCC)CCCC)CCC>CN(C)C=O>[CH2:1]([O:17][CH2:18][CH:19]([CH2:41][F:47])[CH2:20][O:21][C:22]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: [F-]
Reactant: CCCCCCCCCCCCCCCCOCC(COC(c1ccccc1)(c1ccccc1)c1ccccc1)COS(C)(=O)=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCCOCC(CF)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 18 h
Yield: 89.1 %

Procedure:
A solution of 9 (1.10 g, 1.70 mmol) and tetrabutylammonium fluoride (2.00 g, 7.60 mmol) in dry N,N-dimethylformamide was stirred under N2 at 60°. After 18 hours, the solution was concentrated and the residue was partitioned between hexane and water. The hexane layer was washed 3 times with water, dried over Na2SO4 and concentrated. Chromatography on silica gel using hexane-CH2Cl2 (1:1, v/v) afforded 0.871 g (87%) of the title compound (10) as a colorless wax, m.p. 32°. NMR (CDCl3, --(CH3)4Si); δ0.90 (t, 3H, J=6 Hz, --CH3), 1.25 (s, 26H, --CH2 --), 1.55 (m, 2H, --OCH2CH2R), 2.32 (d of septets, 1H, JH--H =6 Hz, JH--F =23.5 Hz, --CH), 3.19 (d, 2H, J=6.0 Hz, --CH2OTr), 3.36 (t, 2H, J=6.5 Hz, --OCH2R), 3.49 (d, 2H, J=6.0 Hz, --CH2OR), 4.59 (d of d, 2H, JHH =6.0 Hz, JH--F =47.5 Hz, --CH2F), 7.2-7.52 (m, 15H, --C(C6H5)3)
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[C@@H:8]([CH2:9][O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:7][CH:6]=[CH:5][CH2:4]1.[C:18]1([CH3:28])[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1>N1C=CC=CC=1>[C:18]1([CH3:28])[CH:23]=[CH:22][C:21]([S:24]([O:1][CH2:2][C@H:3]2[C@@H:8]([CH2:9][O:10][CH2:11][C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:7][CH:6]=[CH:5][CH2:4]2)(=[O:26])=[O:25])=[CH:20][CH:19]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OC[C@@H]1CC=CC[C@@H]1COCc1ccccc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC[C@@H]2CC=CC[C@@H]2COCc2ccccc2)cc1
Reaction time: 8 h
Yield: 84.2 %

Procedure:
The alcohol/benzyl ether (2) (10 g) ml of dry pyridine is added slowly at 0° C. to p-toluenesulphonyl chloride (10.4 g) in pyridine (60 ml). The mixture is kept overnight at room temperature and is then quenched by pouring over crushed ice with vigorous shaking. The product is extracted with ether, washed consecutively with water, 0.1M sodium carbonate and brine, dried (MgSO4), and concentrated in vacuo at room temperature. The crude product is purified on a silica gel column, eluting with benzene-ethyl acetate (95%: 5% v/v) to give the title compound (14 g, 90%). The i.r. spectrum shows the absence of a hydroxyl group.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:11][CH:10]([NH:12][C:13]2[N:14]=[N:15][C:16]([C:19](=[O:26])[NH:20][CH2:21][CH2:22][CH:23]3[CH2:25][CH2:24]3)=[CH:17][CH:18]=2)[CH2:9]1)=[O:7])(C)(C)C.FC(F)(F)C(O)=O.C1(CCNC(C2N=NC(NC3CNC3)=CC=2)=O)CC1.[F:53][C:54]([F:65])([F:64])[C:55]1[CH:63]=[CH:62][CH:61]=[CH:60][C:56]=1C(Cl)=O>ClCCl.C(N(CC)CC)C>[CH:23]1([CH2:22][CH2:21][NH:20][C:19]([C:16]2[N:15]=[N:14][C:13]([NH:12][CH:10]3[CH2:9][N:8]([C:6](=[O:7])[C:56]4[CH:60]=[CH:61][CH:62]=[CH:63][C:55]=4[C:54]([F:65])([F:64])[F:53])[CH2:11]3)=[CH:18][CH:17]=2)=[O:26])[CH2:24][CH2:25]1
Reactant: O=C(Cl)c1ccccc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CC(Nc2ccc(C(=O)NCCC3CC3)nn2)C1
Agent: O=C(NCCC1CC1)c1ccc(NC2CNC2)nn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: O=C(NCCC1CC1)c1ccc(NC2CN(C(=O)c3ccccc3C(F)(F)F)C2)nn1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 57 %

Procedure:
3-[6-(2-Cyclopropylethylcarbamoyl)pyridazin-3-ylamino]azetidine-1-carboxylic acid tert-butyl ester dissolved in dichloromethane (15 mL) was treated with trifluoroacetic acid. The isolated 6-(azetidin-3-ylamino)pyridazine-3-carboxylic acid (2-cyclopropylethyl)amide (0.026 g, 0.100 mmol) was dissolved in dichloromethane (8 mL) and then 2-trifluoromethylbenzoyl chloride (0.022 g, 0.110 mmol) was added at ambient temperature in the presence of triethylamine (0.2 mL). The mixture was stirred at ambient temperature for 15 minutes. The solvent was evaporated and the residue was purified by column chromatography. The title compound was obtained as a white solid in 57% yield (0.0246 g). 1H NMR (300 MHz, CDCl3) (8.0 (d, J=9.0 Hz, 1H), 7.9 (br., t, 1H), 7.7 (d, J=7.0 Hz, 1H), 7.6-7.5 (m, 2H), 7.4 (d, J=7.0 Hz, 1H), 6.8 (d, J=9.0 Hz, 1H), 5.7 (br., s, 1H), 4.8 (m, 1H), 4.6 (m, 1H), 4.3 (m, 1H), 4.15 (m, 1H), 3.75 (m, 1H), 3.5 (q, J=7.0 Hz, 2H), 1.5 (q, J=7.0 Hz, 2H), 0.7 (m, 1H), 0.4 (m, 2H), 0.06 (m, 2H). MS (ES+) m/z 434 (M+1).
Reaction SMILES: [C:1](Cl)([CH3:3])=[O:2].Cl.Cl.[CH2:7]([O:14][C:15]1[CH:20]=[CH:19][N:18]([C:21]2[CH:29]=[C:28]3[C:24]([C:25]4[CH2:34][CH2:33][NH:32][CH2:31][C:26]=4[N:27]3[CH3:30])=[CH:23][CH:22]=2)[C:17](=[O:35])[CH:16]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.CCN(CC)CC.O>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:1]([N:32]1[CH2:33][CH2:34][C:25]2[C:24]3[C:28](=[CH:29][C:21]([N:18]4[CH:19]=[CH:20][C:15]([O:14][CH2:7][C:8]5[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=5)=[CH:16][C:17]4=[O:35])=[CH:22][CH:23]=3)[N:27]([CH3:30])[C:26]=2[CH2:31]1)(=[O:2])[CH3:3]
Reactant: CC(=O)Cl
Reactant: Cn1c2c(c3ccc(-n4ccc(OCc5ccccc5)cc4=O)cc31)CCNC2
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1CCc2c(n(C)c3cc(-n4ccc(OCc5ccccc5)cc4=O)ccc23)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 66.1 %

Procedure:
AcCl (0.023 mL, 0.32 mmol) was added to a solution of 4-(benzyloxy)-1-(9-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)pyridin-2(1H)-one dihydrochloride (100 mg, 0.216 mmol), DMAP (5 mg, 0.04 mmol) and Et3N (0.09 mL, 0.6 mmol) in CH2Cl2 (20 mL) under N2, and the resulting solution was stirred at 25° C. for 4 h. H2O was added to the solution, and the phases were separated. The organic phase was washed with saturated NH4Cl solution, dried over Na2SO4 and concentrated under reduced pressure. Flash chromatography (silica gel, (1:1 EtOAc/hexanes)/(9:0.9:0.1 CH2Cl2/MeOH/NH4OH), 100:0 to 0:100) afforded the title compound (61 mg, 66%) as a mixture of rotomers as a white powder: mp 80-82° C.; 1H NMR (500 MHz, DMSO-d6) δ 7.56 (d, J=7.5 Hz, 1H), 7.52-7.35 (m, 7H), 6.94 (dd, J=8.0, 1.5 Hz, 1H), 6.12-6.08 (m, 1H), 5.97 (d, J=3.0 Hz, 1H), 5.15 (s, 2H), 4.77-4.72 (m, 2H), 3.82-3.72 (m, 2H), 3.69-3.65 (m, 3H), 3.82-2.78 (m, 1.3H), 2.71-2.68 (m, 0.7H), 2.16 (s, 3H); ESI MS m/z 428 [M+H]+.
Reaction SMILES: Cl[S:2]([N:5]=C=O)(=[O:4])=[O:3].CO.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][N:15]=[C:14]([NH:18][C:19]2[CH:20]=[C:21]([C:26]3[S:30][C:29]([C:31]4(O)[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]4)=[N:28][CH:27]=3)[CH:22]=[C:23]([CH3:25])[CH:24]=2)[N:13]=1.C(N(CC)CC)C.[Cl:45]CCl>>[Cl:45][C:31]1([C:29]2[S:30][C:26]([C:21]3[CH:22]=[C:23]([CH3:25])[CH:24]=[C:19]([NH:18][C:14]4[N:13]=[C:12]([O:11][CH3:10])[CH:17]=[CH:16][N:15]=4)[CH:20]=3)=[CH:27][N:28]=2)[CH2:36][CH2:35][N:34]([S:2]([NH2:5])(=[O:4])=[O:3])[CH2:33][CH2:32]1
Reactant: COc1ccnc(Nc2cc(C)cc(-c3cnc(C4(O)CCNCC4)s3)c2)n1
Reactant: ClCCl
Reactant: O=C=NS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: COc1ccnc(Nc2cc(C)cc(-c3cnc(C4(Cl)CCN(S(N)(=O)=O)CC4)s3)c2)n1
Reaction time: 0.5 h

Procedure:
At 0° C., chlorosulfonyl isocyanate (16.38 μL, 0.189 mmol) in dichloromethane was added methanol (7.63 μL, 0.189 mmol). After stirring for 30 min, to the mixture was added 4-(5-{3-[(4-methoxypyrimidin-2-yl)amino]-5-methylphenyl}-1,3-thiazol-2-yl)piperidin-4-ol (50 mg, 0.126 mmol) and triethylamine (52.6 μL, 0.377 mmol). The reaction was aged for 20 min and ice bath removed, and stirred for 3 h. LCMS indicates product formation. The material was directly subject to column chromatography on silica gel (0-100% 10:1 ethyl acetate: methanol in hexanes) to afford:
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[NH2:7][C:8]1[N:9]=[C:10]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:11]([C:15]2[CH:16]=[CH:17][C:18](=[O:24])[N:19]([CH:21]([CH3:23])[CH3:22])[N:20]=2)=[N:12][C:13]=1Br.CC1(C)C(C)(C)OB([C:39]2[CH:40]=[N:41][N:42](C(OC(C)(C)C)=O)[CH:43]=2)O1>O.O1CCOCC1.CC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:7][C:8]1[N:9]=[C:10]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:11]([C:15]2[CH:16]=[CH:17][C:18](=[O:24])[N:19]([CH:21]([CH3:23])[CH3:22])[N:20]=2)=[N:12][C:13]=1[C:39]1[CH:40]=[N:41][NH:42][CH:43]=1
Reactant: CC(C)(C)OC(=O)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CC(C)n1nc(-c2nc(Br)c(N)nc2-c2ccccc2)ccc1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Solvent: C1COCCO1
Product: CC(C)n1nc(-c2nc(-c3cn[nH]c3)c(N)nc2-c2ccccc2)ccc1=O
Temperature: 102.5 °C
Reaction time: 4 h
Yield: 72.8 %

Procedure:
Under nitrogen atmosphere, a solution of sodium carbonate (330 mg) in water (2.4 ml) was added to a suspension of 6-(5-amino-6-bromo-3-phenyl-2-pyrazinyl)-2-isopropyl-3(2H)-pyridazinone (300 mg), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (573 mg) and tetrakis(triphenylphosphine)palladium (27 mg) in dioxane (6 ml) and the mixture was stirred at 100-105° C. for 4 hours. After addition of water (30 ml), a precipitate was collected by filtration and purified by column chromatography on silica gel eluting with a mixture of n-hexane and EtOAc (10:90 v/v) to give a solid. The solid was suspended in acetone and collected by filtration to give 6-[5-amino-3-phenyl-6-(1H-pyrazol-4-yl)-2-pyrazinyl]-2-isopropyl-3(2H)-pyridazinone (211 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:23])[CH:5]=[CH:6][C:7]=1[CH:8]([CH3:22])[C:9]([OH:21])([C:14]1[CH:19]=[CH:18][N:17]=[C:16]([CH3:20])[CH:15]=1)[C:10]([F:13])([F:12])[F:11].[CH3:24][O:25][C:26](=[O:37])[C:27]1[CH:32]=[CH:31][C:30]([CH2:33]Br)=[C:29]([O:35][CH3:36])[CH:28]=1>>[CH3:24][O:25][C:26](=[O:37])[C:27]1[CH:32]=[CH:31][C:30]([CH2:33][O:23][C:4]2[CH:5]=[CH:6][C:7]([CH:8]([CH3:22])[C:9]([OH:21])([C:14]3[CH:19]=[CH:18][N:17]=[C:16]([CH3:20])[CH:15]=3)[C:10]([F:13])([F:11])[F:12])=[C:2]([Cl:1])[CH:3]=2)=[C:29]([O:35][CH3:36])[CH:28]=1
Reactant: Cc1cc(C(O)(C(C)c2ccc(O)cc2Cl)C(F)(F)F)ccn1
Reactant: COC(=O)c1ccc(CBr)c(OC)c1
Product: COC(=O)c1ccc(COc2ccc(C(C)C(O)(c3ccnc(C)c3)C(F)(F)F)c(Cl)c2)c(OC)c1

Procedure:
The title compound was prepared in analogy to Example 93, step 7 from 3-chloro-4-[3,3,3-trifluoro-2-hydroxy-1-methyl-2-(2-methyl-pyridin-4-yl)-propyl]-phenol (obtained in Example 93, step 6) by alkylation with methyl-4-(bromomethyl)-3-methoxybenzoate [CAS Reg. No. 70264-94-7]. MS (m/e)=524.0 [MH+].
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([OH:18])[CH:14]=3)[CH:9]2[CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][CH:29]3[CH2:34][CH2:33][CH2:32][CH2:31][NH:30]3)=[CH:22][CH:21]=2)=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:38][C:39]([NH2:41])=[O:40]>C1COCC1.CN(C=O)C>[C:39]([CH2:38][NH:41][C:39](=[O:40])[CH2:38][O:18][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[CH:9]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][CH:29]3[CH2:34][CH2:33][CH2:32][CH2:31][NH:30]3)=[CH:22][CH:21]=1)[N:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[CH2:17][CH2:16]2)(=[O:40])[NH2:41]
Reactant: NC(=O)CBr
Reactant: Oc1ccc2c(c1)CCN(c1ccc(F)cc1)C2Cc1ccc(OCCC2CCCCN2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: NC(=O)CNC(=O)COc1ccc2c(c1)CCN(c1ccc(F)cc1)C2Cc1ccc(OCCC2CCCCN2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 7 %

Procedure:
To a solution of 2-(4-fluorophenyl)-1-{4-[(2-piperidyl)ethoxy]benzyl}-1,2,3,4-tetrahydroisoquinolin-6-ol (0.100 g, 0.2 mmol) in THF (1 ml) and DMF (5 drops) on ice was added sodium hydride (0.024 g, 0.6 mmol). To the flask was added bromoacetamide (0.083 g, 0.6 mmol). While warming to room temperature the reaction was allowed to sit for 6 hours. The reaction was quenched with an aqueous solution of sodium bicarbonate and extracted with dichloromethane. The organic layer was dried over MgSO4, filtered and concentrated. The product was purified by semipreparative HPLC (C-18 column, 10-100% acetonitrile/water with 0.1% trifluoroacetic acid) to yield the title compound (0.008 g, 7.0% yield):1H NMR (CDCl3) 6.6-7.3 (m, 11H), 6.0 (broad s, 2H), 5.55 (broad s, 1H), 4.7 (t, 1H), 4.5 (s, 2H), 4.1 (m, 4H), 3.5 (m, 2H), 3.05 (m, 1H), 2.9 (m, 4H), 2.65 (m, 1H), 2.55 (m, 4H), 1.65 (m, 4H), 1.5 (m, 2H); ES−MS (m/z) 575 [M+H]+.
Reaction SMILES: S(Cl)([Cl:3])=O.[NH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23].[CH3:25]O>>[ClH:3].[NH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23]
Reactant: CO
Reactant: NCCCCCCCCCCCCCCCCC(=O)O
Reactant: O=S(Cl)Cl
Product: COC(=O)CCCCCCCCCCCCCCCCN
Product: Cl
Temperature: -20 °C
Reaction time: 12 h

Procedure:
0.37 cm3 of thionyl chloride are added to 23 cm3 of methanol cooled to -20° C. and 980 mg of 17-aminoheptadecanoic acid are added. The solution is stirred for 12 hours at a temperature in the region of 20° C. and the solvent is removed under reduced pressure (2.7 kPa) at a temperature in the region of 40° C. 1.08 g of methyl 17-aminoheptadecanoate hydrochloride are thus obtained in the form of a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:29])=[C:4]([C@H:8]([O:22][CH2:23][C:24](OCC)=[O:25])[C@@H:9]2[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]2)[CH:5]=[CH:6][CH:7]=1.[NH3:30]>CO>[NH2:30][C:24](=[O:25])[CH2:23][O:22][CH:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[F:29])[C@@H:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]1
Reactant: CCOC(=O)CO[C@@H](c1cccc(Cl)c1F)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Reactant: N
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC[C@@H](C(OCC(N)=O)c2cccc(Cl)c2F)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
To a solution of (R)-tert-butyl 3-((R)-(3-chloro-2-fluorophenyl)(2-ethoxy-2-oxoethoxy)-methyl)piperidine-1-carboxylate (500 mg, 1.16 mmol) in MeOH (10 mL) was added NH3 (aq) (28%, 15 mL) at rt. The resulting clear solution was stirred at rt overnight. Solvent and excess ammonia was removed in vacuo to afford (R)-tert-butyl 3-((2-amino-2-oxoethoxy)(3-chloro-2-fluorophenyl)methyl)piperidine-1-carboxylate (350 mg, 0.87 mmol, 75%). 1H NMR (400 MHz, CD3OD): 1.45 (s, 9H), 1.56 (m, 1H), 1.90 (m, 1H), 2.95 (m, 2H), 3.55-3.85 (m, 3H), 4.15 (m, 1H), 4.56 (m, 1H), 7.22 (m, 1H), 7.42 (m, 2H); MS (E/Z): 401 (M+H+). The diastereomers can be separated by preparative HPLC if desired.