Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1([F:30])[CH2:6][CH2:5][N:4]([C:7]2[N:12]=[C:11]([NH:13][C:14]3[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:16][N:15]=3)[CH:10]=[C:9]([C:24]3[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=3)[CH:8]=2)[CH2:3]1.CO.[CH2:33]([Br:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[Br-:40].[CH2:33]([N+:26]1[CH:27]=[CH:28][CH:29]=[C:24]([C:9]2[CH:10]=[C:11]([NH:13][C:14]3[CH:19]=[C:18]([C:20]([F:22])([F:23])[F:21])[CH:17]=[CH:16][N:15]=3)[N:12]=[C:7]([N:4]3[CH2:5][CH2:6][C:2]([F:1])([F:30])[CH2:3]3)[CH:8]=2)[CH:25]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: FC1(F)CCN(c2cc(-c3cccnc3)cc(Nc3cc(C(F)(F)F)ccn3)n2)C1
Reactant: BrCc1ccccc1
Solvent: CO
Product: FC1(F)CCN(c2cc(-c3ccc[n+](Cc4ccccc4)c3)cc(Nc3cc(C(F)(F)F)ccn3)n2)C1
Product: [Br-]
Reaction time: 8 h

Procedure:
To a suspension of 6-(3,3-difluoropyrrolidin-1-yl)-4-(3-pyridyl)-N-[4-(trifluoromethyl)-2-pyridyl]pyridin-2-amine (2-c, 320 mg, 0.7594 mmol) in methanol (5 ml, 100 mmol) was added benzyl bromide (0.46 ml, 5.0 equiv., 3.797 mmol), and the reaction was kept at 60° C. overnight. MeOH was removed as much as possible. Ethyl ether (3×10 mL) was used to wash away the excess BnBr. The leftover solid was used without further treatment. LCMS: m/z 512 (M+).
Reaction SMILES: [F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:10]=2[F:12])[CH:5]=[C:4]([C:21]2[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=2)[N:3]=1.[H-].[Na+].[CH2:30](Br)[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37].O>CN(C=O)C>[F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:10]=2[F:12])[CH:5]=[C:4]([C:21]2[CH:22]=[CH:23][C:24]([O:27][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[CH:25][CH:26]=2)[N:3]=1
Reactant: CCCCCCCCBr
Reactant: CCCCCCCCc1ccc2cc(-c3ccc(O)cc3)nc(F)c2c1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCCCOc1ccc(-c2cc3ccc(CCCCCCCC)c(F)c3c(F)n2)cc1
Reaction time: 0.5 h
Yield: 80 %

Procedure:
10 mmol of 1,8-difluoro-3-(4-hydroxyphenyl)-7-octylisoquinoline are dissolved in 50 ml of DMF, and 11 mmol of sodium hydride are added. After the mixture has been stirred for 30 minutes, 11 mmol of 1 -octyl bromide are added dropwise, and the mixture is stirred at 60° C. for a further 140 minutes and poured into water. The mixture is extracted with dichloromethane, the combined organic phases are dried, the solvent is removed in vacuo and the residue is chromatographed on silica gel, giving 8 mmol of 1,8-difluoro-3-[4-(octyloxy)phenyl]-7-octylisoquinoline.
Reaction SMILES: [CH3:1][C@H:2]1[NH:6][C:5](=[O:7])[C@@H:4]([CH2:8][CH2:9][C:10]2([CH3:15])[O:14][CH2:13][CH2:12][O:11]2)[CH2:3]1.C1COCC1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Br[CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34]>CCOC(C)=O>[CH2:36]([O:35][C:33](=[O:34])[CH2:32][N:6]1[C@H:2]([CH3:1])[CH2:3][C@H:4]([CH2:8][CH2:9][C:10]2([CH3:15])[O:14][CH2:13][CH2:12][O:11]2)[C:5]1=[O:7])[CH3:37]
Reactant: CCOC(=O)CBr
Reactant: C[C@@H]1C[C@H](CCC2(C)OCCO2)C(=O)N1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)CN1C(=O)[C@@H](CCC2(C)OCCO2)C[C@H]1C
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a stirred solution of 11-7 (355 mg, 1.67 mmol) and THF (10 mL) at -78° C. was added NaN(TMS)2 (1.83 mL, 1.83 mmol, 1.0M in THF). After 20 min, ethyl bromoacetate (0.203 mL, 1.84 mmol) was added and the reaction was warmed to 0° C. After 30 minutes, the reaction mixture was diluted with EtOAc and then washed with H2O, brine, dried (MgSO4), and concentrated to give 11-8 as a yellow oil.
Reaction SMILES: Cl[C:2]1[C:3](=[O:15])[N:4](C2CCCCO2)[N:5]=[CH:6][C:7]=1Cl.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[OH:24].C[O:26][C:27](=[O:36])[CH:28](Br)[CH2:29][CH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1>>[CH:30]1([CH2:29][CH:28]([N:4]2[C:3](=[O:15])[CH:2]=[C:7]([O:24][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[O:17][CH3:16])[CH:6]=[N:5]2)[C:27]([OH:26])=[O:36])[CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: O=c1c(Cl)c(Cl)cnn1C1CCCCO1
Reactant: COC(=O)C(Br)CC1CCCC1
Reactant: COc1ccccc1O
Product: COc1ccccc1Oc1cnn(C(CC2CCCC2)C(=O)O)c(=O)c1

Procedure:
In an analogous manner to the stepwise sequence outlined in intermediate 19, starting from 4,5-dichloro-2-(tetrahydropyran-2-yl)-2H-pyridazin-3-one (Intermediate 20) and 2-methoxy-phenol and alkylating with 2-bromo-3-cyclopentyl-propionic acid methyl ester (Intermediate 10) afforded 3-cyclopentyl-2-[4-(2-methoxy-phenoxy)-6-oxo-6H-pyridazin-1-yl]-propionic acid as a white solid (614.1 mg, 95% for the final step); ES+-HRMS m/e calcd for C19H22N2O5 [M+H+] 359.1602, found 359.1601. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.11 (s, 2H), 1.31-1.78 (m, 7H), 1.86-2.06 (m, 1H), 2.09-2.24 (m, 1H), 3.79 (s, 3H), 5.30 (dd, J=10.7, 4.1 Hz, 1H), 5.59 (d, J=2.7 Hz, 1H), 7.05 (td, J=7.5, 1.5 Hz, 1H), 7.23-7.40 (m, 3H), 8.10 (d, J=2.7 Hz, 1H), 13.02 (br s, 1H).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][CH:23]=1)[O:6][CH2:7][CH2:8][CH2:9][N:10]1C(=O)C2C(=CC=CC=2)C1=O)=[O:2].[CH2:24](O)[CH2:25][OH:26]>C1C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[O:26]1[CH2:25][CH2:24][O:2][CH:1]1[C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][CH:23]=1)[O:6][CH2:7][CH2:8][CH2:9][NH2:10]
Reactant: OCCO
Reactant: O=Cc1cccc(OCCCN2C(=O)c3ccccc3C2=O)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: NCCCOc1cccc(C2OCCO2)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 85 %

Procedure:
A solution of 2-[3-(3-formylphenoxy)propyl]-1H-isoindole-1,3-(2H)-dione (90 g) and p-toluenesulphonic acid, monohydrate (200 mg) in benzene (900 ml) and ethane-1,2-diol (25 g) was heated under reflux using a Dean-Stark separator for 8 h. The cooled solution was washed successively with sodium carbonate solution, water, sodium chloride solution, and evaporated in vacuo. The resulting oil was dissolved in tetrahydrofuran (1 liter) and stirred with hydrazine hydrate (50 ml) at room temperature for 24 hr. The mixture was diluted with ether and filtered. The filtrate was distilled to give the title compound as a colourless oil (55.2 g) b.p. 134°-6° (0.7 mm). TLC silica; methanol:ammonia 80:1; Rf 0.4.
Reaction SMILES: CCN=C=NCCCN(C)C.C1C=NC2N(O)N=NC=2C=1.C(N(CC)CC)C.[C:29]([O:33][C:34]([N:36]([C:63]([O:65][C:66]([CH3:69])([CH3:68])[CH3:67])=[O:64])[C:37]1[C:46]2[C:41](=[CH:42][C:43]([NH:47][CH:48]([C:52]3[CH:57]=[C:56]([CH3:58])[C:55]([CH2:59][CH2:60][OH:61])=[C:54]([CH3:62])[CH:53]=3)[C:49]([OH:51])=O)=[CH:44][CH:45]=2)[CH:40]=[CH:39][N:38]=1)=[O:35])([CH3:32])([CH3:31])[CH3:30].[N+:70]([C:73]1[CH:74]=[C:75]([CH:86]=[CH:87][CH:88]=1)[CH2:76][NH:77][CH2:78][C:79]([O:81][C:82]([CH3:85])([CH3:84])[CH3:83])=[O:80])([O-:72])=[O:71]>CCOC(C)=O>[C:29]([O:33][C:34]([N:36]([C:63]([O:65][C:66]([CH3:68])([CH3:67])[CH3:69])=[O:64])[C:37]1[C:46]2[C:41](=[CH:42][C:43]([NH:47][CH:48]([C:52]3[CH:57]=[C:56]([CH3:58])[C:55]([CH2:59][CH2:60][OH:61])=[C:54]([CH3:62])[CH:53]=3)[C:49]([N:77]([CH2:78][C:79]([O:81][C:82]([CH3:85])([CH3:84])[CH3:83])=[O:80])[CH2:76][C:75]3[CH:86]=[CH:87][CH:88]=[C:73]([N+:70]([O-:72])=[O:71])[CH:74]=3)=[O:51])=[CH:44][CH:45]=2)[CH:40]=[CH:39][N:38]=1)=[O:35])([CH3:31])([CH3:32])[CH3:30]
Reactant: Cc1cc(C(Nc2ccc3c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nccc3c2)C(=O)O)cc(C)c1CCO
Reactant: CC(C)(C)OC(=O)CNCc1cccc([N+](=O)[O-])c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2cccnc21
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Cc1cc(C(Nc2ccc3c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nccc3c2)C(=O)N(CC(=O)OC(C)(C)C)Cc2cccc([N+](=O)[O-])c2)cc(C)c1CCO
Temperature: 60 °C
Reaction time: 3 h
Yield: 42.2 %

Procedure:
EDCI (142 mg, 0.74), HOAt (101 mg, 0.74 mmol), and triethylamine (0.18 mL, 1.35 mmol) were added to a solution of 50C (380 mg, 0.67 mmol) and 52C (197 mg, 0.74 mmol) in that order. The reaction mixture was stirred at 60° C. for 3 h. The solution was diluted with EtOAc, washed with brine, dried over Na2SO4 and concentrated in vacuo. The crude solid was purified by flash chromatography (0% to 100% EtOAc in hexanes) to afford 52D (230 mg, 42%) as a yellow solid. MS (ESI) m/z 814.9 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.[CH3:10][C@@:11]1([CH2:14][O:15][C:16]2[CH:17]=[C:18]([C:22]3[C:26]4[S:27][CH:28]=[CH:29][C:25]=4[O:24][N:23]=3)[CH:19]=[CH:20][CH:21]=2)[CH2:13][O:12]1.ClC(Cl)C>C(O)C>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:7][CH2:10][C@:11]([CH3:13])([OH:12])[CH2:14][O:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]3[C:26]4[S:27][CH:28]=[CH:29][C:25]=4[O:24][N:23]=3)[CH:17]=2)=[CH:4][CH:3]=1
Reactant: NCc1ccc(F)cc1
Reactant: C[C@@]1(COc2cccc(-c3noc4ccsc34)c2)CO1
Solvent: CCO
Solvent: CC(Cl)Cl
Product: C[C@](O)(CNCc1ccc(F)cc1)COc1cccc(-c2noc3ccsc23)c1

Procedure:
Add a solution of 4-fluorobenzylamine (Aldrich Chemical Company) in ethanol (3 mL, 0.2774 M, 1.77 equivalents) to a reaction tube. Add ethanol (3 mL) to the reaction tube and then add a solution of (S)-3-[3-(2-methyloxiranylmethoxy)phenyl]thieno[2,3-d]isoxazole (example 7, 1.38 mL, 0.337 M) and dichloroethane. Shake the reaction mixture under argon at reflux temperature overnight in a Bohdan apparatus. Cool and concentrate to remove the solvent. Purify the residue by flash chromatography (silica gel) eluting in step gradient fashion sequentially with 1%, 3%, 6%, and 10% methanol in dichloromethane. Combine and concentrate the desired fractions to give the title compound (0.18 g), LC/MS (APCI, condition 6) m/e 413 (MH+), retention time 2.23 min. Preparation of a larger sample and conversion to the hydrochloride salt is described as example 102.
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][C:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:14][C:5]=1[CH2:6][N:7]1[CH:11]=[CH:10][CH:9]=[C:8]1[CH:12]=O)([O-])=O.[H][H]>C(O)C.[Pd]>[CH:9]1[CH:10]=[CH:11][N:7]2[CH2:6][C:5]3[CH:14]=[C:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:16]=[CH:17][C:4]=3[NH:1][CH2:12][C:8]=12
Reactant: [H][H]
Reactant: CCOC(=O)c1ccc([N+](=O)[O-])c(Cn2cccc2C=O)c1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)c1ccc2c(c1)Cn1cccc1CN2

Procedure:
A solution of 10.0 g of 1-[2-nitro-5-(ethoxycarbonyl)benzyl]-pyrrole-2-carboxaldehyde in 150 ml of absolute ethanol containing 1.0 g of 10% Pd/c is hydrogenated in a Parr apparatus for 16 hours under 40 psi of hydrogen. The reaction mixture is filtered through a pad of diatomaceous earth and the filtrate concentrated in vacuo to a residue of 5.5 g of the desired product as a solid; mass spectrum (M+H)255.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:8]([Br:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(=O)(=O)(O)O.[C:18](OCC)(=O)C>CO>[Br:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:8]([Br:12])=[CH:7][C:3]=1[C:4]([O:6][CH3:18])=[O:5]
Reactant: Cc1cc(Br)c(C(=O)O)cc1Br
Reactant: CCOC(C)=O
Agent: O=S(=O)(O)O
Solvent: CO
Product: COC(=O)c1cc(Br)c(C)cc1Br

Procedure:
To a solution of 2,5-dibromo-4-methylbenzoic acid 5.88 g, 20 mmol) in 50 mL of methanol was added 0.2 mL of concentrated sulfuric acid. The resulting solution was refluxed for 24 hours. Evaporation of the solvent gave a residue, which was redissolved into 100 mL of ethyl acetate. The organic layer was washed with saturated sodium biocarbonate solution, water and brine. The resulting organic layer was dried over sodium sulfate. Filtration off sodium sulfate and evaporation of the solvent gave methyl 2,5-dibromo-4-methylbenzoate as a white solid: 6.20 g (100%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[NH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.F[C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][N:18]=1>>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[N:13]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][N:18]=3)[CH:14]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Cc1nc(C#Cc2ccnc(Cl)c2)c[nH]1
Reactant: Cc1ccc(F)nc1
Product: Cc1ccc(-n2cc(C#Cc3ccnc(Cl)c3)nc2C)nc1

Procedure:
The title compound, MS: m/e=309.5 (M+H+), was prepared in accordance with the general method of example 3 from 2-chloro-4-(2-methyl-1H-imidazol-4-ylethynyl)-pyridine and 2-fluoro-5-methyl-pyridine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9](=[CH:15][C:16](=[O:18])[NH2:17])[NH:8][CH2:7][CH2:6]2.[O-:19][CH2:20]C.[Na+].C(=O)(OCC)OCC>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]1=[CH:15][C:16](=[O:18])[NH:17][C:20](=[O:19])[N:8]1[CH2:7][CH2:6]2
Reactant: COc1cc2c(cc1OC)C(=CC(N)=O)NCC2
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(=O)OCC
Product: COc1cc2c(cc1OC)-c1cc(=O)[nH]c(=O)n1CC2

Procedure:
A solution of 6,7-dimethoxy-1-carbamoylmethylene-1,2,3,4-tetrahydroisoquinoline (5.0 g) and an excess of sodium ethoxide (prepared from 12.0 g of sodium metal and 600 ml of ethanol) in ethanol is heated. 150.0 ml of diethyl carbonate is added to the solution. The reaction mixture is refluxed for an additional 2.5 hr. The solvent is removed under vacuum and the residue is acidified to give a white precipitate, yield 4.80 g. The product crystallizes from dimethylformamide, mp. 323°-325° C.
Reaction SMILES: [Cl:1][C:2]1[CH2:8][CH:7]2[N:4]([C:5](=[O:9])[CH2:6]2)[C:3]=1[C:10]([O-:12])=[O:11].[Na+].[C:14]([C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Br)=[CH:20][CH:19]=1)([CH3:17])([CH3:16])[CH3:15].CN(C)P(N(C)C)(N(C)C)=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH2:8][CH:7]2[N:4]([C:5](=[O:9])[CH2:6]2)[C:3]=1[C:10]([O:12][CH2:22][C:21]1[CH:24]=[CH:25][C:18]([C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:19][CH:20]=1)=[O:11]
Reactant: O=C([O-])C1=C(Cl)CC2CC(=O)N12
Reactant: CC(C)(C)c1ccc(CBr)cc1
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CC(C)(C)c1ccc(COC(=O)C2=C(Cl)CC3CC(=O)N23)cc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A mixture of sodium 3-chloro-1-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylate (20 mg), p-(t-butyl)benzyl bromide (34 mg), and anhydrous hexamethylphosphoramide (0.4 ml) is stirred under a nitrogen atmosphere at room temperature for 2.5 hrs. The mixture is diluted with toluene (5 ml), washed with water (5×2 ml) and brine, dried with MgSO4, filtered, and concentrated in vacuo. Chromatography of the residue on a silica gel plate yields p-(t-butyl)benzyl 3-chloro-1-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylate.
Reaction SMILES: Cl.[CH2:2]([O:9][C@H:10]([CH3:25])[C@@H:11]([CH3:24])[O:12][C:13]1[C:18]([C:19]([F:22])([F:21])[F:20])=[CH:17][N:16]=[C:15](Cl)[N:14]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[NH2:26][C:27]1[CH:32]=[CH:31][C:30]([S:33]([CH:42]2[CH2:44][CH2:43]2)(=[N:35][C:36](=[O:41])[C:37]([F:40])([F:39])[F:38])=[O:34])=[CH:29][CH:28]=1>O1CCOCC1.C(#N)C.C(OCC)(=O)C>[CH2:2]([O:9][C@H:10]([CH3:25])[C@H:11]([O:12][C:13]1[C:18]([C:19]([F:22])([F:21])[F:20])=[CH:17][N:16]=[C:15]([NH:26][C:27]2[CH:28]=[CH:29][C:30]([S:33]([CH:42]3[CH2:44][CH2:43]3)(=[N:35][C:36](=[O:41])[C:37]([F:40])([F:38])[F:39])=[O:34])=[CH:31][CH:32]=2)[N:14]=1)[CH3:24])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Nc1ccc(S(=O)(=NC(=O)C(F)(F)F)C2CC2)cc1
Reactant: C[C@@H](OCc1ccccc1)[C@@H](C)Oc1nc(Cl)ncc1C(F)(F)F
Agent: Cl
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: C[C@@H](OCc1ccccc1)[C@@H](C)Oc1nc(Nc2ccc(S(=O)(=NC(=O)C(F)(F)F)C3CC3)cc2)ncc1C(F)(F)F
Temperature: 80 °C
Reaction time: 5 h
Yield: 55.6 %

Procedure:
0.96 ml of 4N solution of hydrogen chloride in dioxane was added to 1.39 g (3.85 mmol) of 4-((1R,2R)-2-benzyloxy-1-methyl-propoxy)-2-chloro-5-trifluoromethyl-pyrimidine and 1.35 g (4.62 mmol) (RS)-S-(4-aminophenyl)-S-cyclopropyl-N-(trifluoroacetyl)sulfoximide in 18.8 ml acetonitrile and stirred for 5 hours at 80° C. After cooling, the mixture was diluted with ethyl acetate and washed with saturated sodium hydrogencarbonate solution and saturated sodium chloride solution, dried (Na2SO4), filtered and concentrated by evaporation. The residue obtained was purified chromatographically (hexane/ethyl acetate 4:1). 1.32 g (2.14 mmol, yield: 56%) of the product was obtained.
Reaction SMILES: [OH:1][C:2]1[C:7](=[O:8])[CH:6]=[C:5]([CH3:9])[N:4]([CH2:10][C:11]([F:14])([F:13])[F:12])[C:3]=1[CH2:15]O.S(Cl)([Cl:19])=O>C(#N)C>[ClH:19].[Cl:19][CH2:15][C:3]1[N:4]([CH2:10][C:11]([F:14])([F:13])[F:12])[C:5]([CH3:9])=[CH:6][C:7](=[O:8])[C:2]=1[OH:1]
Reactant: Cc1cc(=O)c(O)c(CO)n1CC(F)(F)F
Reactant: O=S(Cl)Cl
Solvent: CC#N
Product: Cc1cc(=O)c(O)c(CCl)n1CC(F)(F)F
Product: Cl
Reaction time: 0.08 h

Procedure:
3-Hydroxy-2-(hydroxymethyl)-6-methyl-1-(2,2,2-trifluoroethyl)pyridin-4(1H)-one (375 mg, 1.6 mmol) was mixed with acetonitrile at 80° C. and the thionyl chloride (753 mg, 6.3 mmol) was added. The reaction mixture was stirred for 5 minutes and then concentrated by rotary evaporator to give 2-(chloromethyl)-3-hydroxy-6-methyl-1-(2,2,2-trifluoroethyl)pyridin-4(1H)-one hydrochloride. The chloride compound was added to a solution of piperidine (672 mg, 7.9 mmol) in isopropanol (5 mL) at room temperature. Five minutes later, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water twice and brine, dried and concentrated. The residue was triturated with ether/hexanes to give 3-hydroxy-6-methyl-2-(piperidin-1-ylmethyl)-1-(2,2,2-trifluoroethyl)pyridin-4(1H)-one (165 mg) as pale orange solid. Yield=34%; 1H NMR (MeOD-D4, 90 MHz) δ (ppm): 6.37 (s, 1H), 3.72 (br. s, 2H), 2.45 (br. m, 7H) and 1.51 (br. m, 6H); MS m/z 305 [M+1]+.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:30])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[C:19](=[O:23])[N:18]([CH2:24][CH:25]3[CH2:27][CH2:26]3)[CH:17]=[C:16]4C=O)[CH:7]=2)[CH2:3][CH2:2]1.C[C@H:32]1[CH2:37][NH:36][CH2:35][CH2:34][N:33]1[C:38](OC(C)(C)C)=O.[C:45](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>ClCCl>[CH:1]1([NH:4][C:5](=[O:30])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[C:19](=[O:23])[N:18]([CH2:24][CH:25]3[CH2:26][CH2:27]3)[CH:17]=[C:16]4[CH2:38][N:33]3[CH2:32][CH2:37][NH:36][C@@H:35]([CH3:45])[CH2:34]3)[CH:7]=2)[CH2:2][CH2:3]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC3CC3)cc(C=O)c2c1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: C[C@H]1CNCCN1C(=O)OC(C)(C)C
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC3CC3)cc(CN3CCN[C@@H](C)C3)c2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The product of Example 59 step iii) (0.25 g), (S)-2-methylpiperazine-1-carboxylic acid, tert-butyl ester (0.37 g) and sodium triacetoxyborohydride (0.40 g) were stirred in dichloromethane (20 mL) under nitrogen for 16 hours. Water (20 mL) and dichloromethane (20 mL) were then added and the organics separated. The organics were evaporated under reduced pressure. The residue was dissolved in methanol (5 mL) and 4M HCl in 1,4-dioxane (2 mL) added. The mixture was stirred overnight at room temperature. The volatiles were removed under vacuum and the residue purified by HPLC to give the title compound as a solid (0.11 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:9])=[C:6]([OH:8])[CH:7]=1.O.C(=O)([O-])O.[Na+].[F:16][C:17]([F:28])([F:27])[C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=1)[C:21](Cl)=[O:22]>O1CCCC1>[OH:8][C:6]1[CH:7]=[C:2]([NH:1][C:21](=[O:22])[C:20]2[CH:24]=[CH:25][CH:26]=[C:18]([C:17]([F:16])([F:27])[F:28])[CH:19]=2)[CH:3]=[CH:4][C:5]=1[CH3:9]
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Reactant: Cc1ccc(N)cc1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1O
Temperature: 25 °C
Yield: 83.7 %

Procedure:
To a solution of 5-amino-2-methylphenol (7.38 g, 59.9 mmol) in tetrahydrofuran (30 mL) was added water (30 mL) in which sodium hydrogen carbonate (6.00 g, 71.9 mmol) has been suspended, and the mixture was vigorously stirred at room temperature. 3-(Trifluoromethyl)benzoyl chloride (15.0 g, 71.9 mmol) was added dropwise to the mixture under ice-cooling, and the mixture was stirred at room temperature for 24 hr. The aqueous layer of the reaction mixture was separated, and the organic layer was diluted with ethyl acetate, and washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and was filtrated, and the solvent was evaporated under reduced pressure. A mixture of the obtained residue, methanol (30 mL) and 2N aqueous sodium hydroxide solution (30 mL) was stirred at room temperature for 24 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and decolorized with activated carbon. The insoluble material was filtered off through a pad with two layers of silica gel and celite. The solvent was evaporated under reduced pressure, and the obtained solid was washed with a mixed solvent of ethyl acetate and hexane to give the title compound (14.8 g, 84%) as a white powder.
Reaction SMILES: [CH3:1][N:2]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][NH:20]C(=O)OC(C)(C)C)[S:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N+:12]([O-:14])=[O:13])(=[O:5])=[O:4].FC(F)(F)C(O)=O>C(Cl)Cl.C(OC(C)C)(C)C>[NH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][N:2]([CH3:1])[S:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N+:12]([O-:14])=[O:13])(=[O:4])=[O:5]
Reactant: CN(CCCCCNC(=O)OC(C)(C)C)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Solvent: CC(C)OC(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(CCCCCN)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Yield: 99.5 %

Procedure:
A solution of tert-butyl 5-(N-methyl-2-nitrophenylsulfonamido)pentylcarbamate 30d (31.5 g, 79 mmoles) and trifluoro acetic acid (29.2 mL, 5 eq) in DCM (300 mL) was stirred at RT until completion (˜16 h). The RM was then concentrated under vacuo, redissolved in DCM, washed with a saturated sodium bicarbonate aqueous solution (2 times), then brine, dried over magnesium sulfate, filtered and concentrated. Trituration in diisopropyl ether afforded 23.7 g (quantitative yield) of N-(5-aminopentyl)-N-methyl-2-nitrobenzenesulfonamide 26a as a slightly yellow solid; m/z 302 [M+H]+.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([CH2:20][C:21]([OH:23])=[O:22])=[CH:16][CH:15]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.C(C1NC=CN=1)(C1NC=CN=1)=O.[NH2:36][CH:37]1[CH2:42][CH2:41][CH2:40][N:39]([CH2:43][CH3:44])[CH2:38]1.O>CS(C)=O>[OH2:22].[Cl:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([NH:13][C:14]3[CH:15]=[CH:16][C:17]([CH2:20][C:21]([NH:36][CH:37]4[CH2:42][CH2:41][CH2:40][N:39]([CH2:43][CH3:44])[CH2:38]4)=[O:23])=[CH:18][CH:19]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1
Reactant: CCN1CCCC(N)C1
Reactant: O=C(O)Cc1ccc(Nc2ccnc3cc(Cl)ccc23)cc1
Agent: Cl
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: CS(C)=O
Solvent: O
Product: CCN1CCCC(NC(=O)Cc2ccc(Nc3ccnc4cc(Cl)ccc34)cc2)C1
Temperature: 100 °C
Reaction time: 2 h
Yield: 92.4 %

Procedure:
7.0 Grams (0.02 mole) of 2-[4-(7-chloro-4-quinolylamino)phenyl]acetic acid hydrochloride were dissolved in 150 milliliters of dimethyl sulphoxide by heating the stirred mixture to 100° C. under nitrogen. The solution was cooled to room temperature, 6.48 grams (0.04 mole) of carbonyl di-imidazole were added and the mixture was stirred for 21/2 hours under nitrogen. 7.68 Grams (0.06 mole) of 3-amino-1-ethylpiperidine were added, the solution was stirred for another 21/2 hours and poured into 500 milliliters of water. The mixture was refrigerated overnight and the resulting solid was broken up, stirred with water, collected and dried. The solid was dissolved in chloroform and chromatographed on an alumina column made up in chloroform. Elution with chloroform/methanol (4:1) gave 8.15 grams (92.5% yield) of 2-[4-(7-chloro-4-quinolylamino)phenyl]-N-(1-ethyl-3-piperidyl)acetamide monohydrate, melting point 160°-162° C.