Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][C:10]2[CH:18]=[CH:17][C:13]([C:14](O)=[O:15])=[CH:12][CH:11]=2)=[C:4]([NH:19][S:20]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([C:30]([F:33])([F:32])[F:31])[CH:24]=2)(=[O:22])=[O:21])[CH:3]=1.[N:34]1([CH2:39][CH2:40][NH2:41])[CH2:38][CH2:37][CH2:36][CH2:35]1.C(Cl)CCl>CN(C1C=CN=CC=1)C.CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][C:10]2[CH:18]=[CH:17][C:13]([C:14]([NH:41][CH2:40][CH2:39][N:34]3[CH2:38][CH2:37][CH2:36][CH2:35]3)=[O:15])=[CH:12][CH:11]=2)=[C:4]([NH:19][S:20]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([C:30]([F:31])([F:32])[F:33])[CH:24]=2)(=[O:22])=[O:21])[CH:3]=1
Reactant: NCCN1CCCC1
Reactant: O=C(O)c1ccc(CSc2ccc(Cl)cc2NS(=O)(=O)c2ccc(Cl)c(C(F)(F)F)c2)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: O=C(NCCN1CCCC1)c1ccc(CSc2ccc(Cl)cc2NS(=O)(=O)c2ccc(Cl)c(C(F)(F)F)c2)cc1
Yield: 71.3 %

Procedure:
Following General Procedure R, the title compound (345 mg, 71%) was prepared from 4-({[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfanyl}methyl)benzoic acid (410 mg, 0.765 mmol), 2-(pyrrolidin-1-yl)ethanamine (0.15 ml, 1.15 mmol), EDC (293 mg, 1.53 mmol) and DMAP (cat.) in DMF (5 ml).
Reaction SMILES: [H-].[Na+].[C:3]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])(=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH2:16]([O:23][C:24]1[CH:29]=[C:28](F)[CH:27]=[CH:26][C:25]=1[N+:31]([O-:33])=[O:32])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C=O)C>[CH2:8]([O:7][C:5](=[O:6])[CH:4]([C:28]1[CH:27]=[CH:26][C:25]([N+:31]([O-:33])=[O:32])=[C:24]([O:23][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:29]=1)[C:3]([O:11][C:12]([CH3:14])([CH3:13])[CH3:15])=[O:10])[CH3:9]
Reactant: O=[N+]([O-])c1ccc(F)cc1OCc1ccccc1
Reactant: CCOC(=O)CC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C(=O)OC(C)(C)C)c1ccc([N+](=O)[O-])c(OCc2ccccc2)c1
Temperature: 50 °C
Reaction time: 1.5 h

Procedure:
To a suspension of NaH (60%, 9.38 g, 235 mmol) in DMF (200 mL) at 0° C. under N2 is added tert-butyl ethyl malonate (45.7 mL, 243 mmol) over 30 min. The reaction is stirred for 1.5 h in an ice bath. 2-Benzyloxy-4-fluoro-1-nitrobenzene (20.0 g, 80.9 mmol) is added and the reaction heated to 50° C. for 7.5 h. The reaction is quenched with H2O (600 mL) and extracted with EtOAc (2 L). The organic phase is concentrated to ˜1 L, washed with H2O (2×500 mL) and brine (300 mL), and dried over Na2SO4. Evaporation yields a yellow oil. The oil is azeotroped with DCM and the resulting solid is triturated with a hexanes/Et2O solution, affording a yellow solid. Two additional crops of the solid are obtained from the filtrate upon standing. The solids are combined to afford 2-(3-benzyloxy-4-nitrophenyl) -malonic acid tert-butyl ester ethyl ester: MS (M−H)−=414.
Reaction SMILES: F[C:2]1[C:7]([CH:8]2[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]2)=[CH:6][CH:5]=[CH:4][N:3]=1.[NH:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N:17]=[C:16]1[C:24]([C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=1)=[O:25].C(=O)([O-])[O-].[Cs+].[Cs+]>CN1C(=O)CCC1.O>[NH:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N:17]=[C:16]1[C:24]([C:26]1[CH:31]=[CH:30][C:29]([O:32][C:2]2[C:7]([CH:8]3[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]3)=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:28][CH:27]=1)=[O:25]
Reactant: O=C(c1ccc(O)cc1)c1nc2ccccc2[nH]1
Reactant: O=C1CCC(c2cccnc2F)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN1CCCC1=O
Product: O=C1CCC(c2cccnc2Oc2ccc(C(=O)c3nc4ccccc4[nH]3)cc2)CC1
Temperature: 140 °C
Reaction time: 48 h

Procedure:
4-(2-Fluoropyridin-3-yl)cyclohexanone (0.05 g, 0.26 mmol), (1H-benzo[d]imidazol-2-yl)(4-hydroxyphenyl)methanone (0.19 g, 0.78 mmol), and cesium carbonate (0.25 g, 0.78 mmol) were mixed in NMP (1 mL). The reaction mixture was placed under a nitrogen atmosphere and stirred at 140° C. for 48 h. The reaction mixture was cooled to room temperature, diluted with water, and extracted with EtOAc (3×). The combined organic layers were washed with 1 M aqueous sodium hydroxide, washed with sat. sodium chloride, dried over magnesium sulfate, and concentrated in vacuo. The resulting crude product was partially purified by silica gel chromatography. The impure product was then dissolved in a minimal amount of DCM, and hexanes were added until a precipitate formed. The resulting suspension was partially concentrated and filtered to give 4-(2-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)pyridin-3-yl)cyclohexanone. MS (ESI, pos. ion) m/z: 412.1 (M+1). IC50 (uM) +++++.
Reaction SMILES: [OH-:1].[K+].[C:3]([NH:6][C:7]1[C:8]([I:31])=[C:9]([C:23]([NH:25][CH2:26][CH:27]([OH:30])[CH2:28][OH:29])=[O:24])[C:10]([I:22])=[C:11]([C:20]=1[I:21])[C:12]([NH:14][CH2:15][CH:16]([OH:19])[CH2:17][OH:18])=[O:13])(=[O:5])[CH3:4].B(O)(O)O.[O:36]1[CH2:38][CH:37]1[CH2:39][CH2:40][CH2:41][CH2:42][CH:43]1[CH2:45][O:44]1.Cl>C(#N)C.O.O.CO>[OH:36][CH:37]([CH2:39][CH2:40][CH2:41][CH2:42][CH:43]([OH:44])[CH2:45][N:6]([C:7]1[C:20]([I:21])=[C:11]([C:12]([NH:14][CH2:15][CH:16]([OH:19])[CH2:17][OH:18])=[O:13])[C:10]([I:22])=[C:9]([C:8]=1[I:31])[C:23]([NH:25][CH2:26][CH:27]([OH:30])[CH2:28][OH:29])=[O:24])[C:3](=[O:1])[CH3:4])[CH2:38][N:6]([C:7]1[C:20]([I:21])=[C:11]([C:12]([NH:14][CH2:15][CH:16]([OH:19])[CH2:17][OH:18])=[O:13])[C:10]([I:22])=[C:9]([C:8]=1[I:31])[C:23]([NH:25][CH2:26][CH:27]([OH:30])[CH2:28][OH:29])=[O:24])[C:3](=[O:5])[CH3:4]
Reactant: CC(=O)Nc1c(I)c(C(=O)NCC(O)CO)c(I)c(C(=O)NCC(O)CO)c1I
Reactant: [OH-]
Reactant: C(CCC1CO1)CC1CO1
Agent: Cl
Agent: OB(O)O
Agent: [K+]
Solvent: CC#N
Solvent: CO
Solvent: O
Product: CC(=O)N(CC(O)CCCCC(O)CN(C(C)=O)c1c(I)c(C(=O)NCC(O)CO)c(I)c(C(=O)NCC(O)CO)c1I)c1c(I)c(C(=O)NCC(O)CO)c(I)c(C(=O)NCC(O)CO)c1I
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of water/methanol (4.9 ml, 2.5 ml) and potassium hydroxide (0.49 g, 8.7 mmol) at 40° C. was added 5-acetylamino-N,N′-bis-(2,3-dihydroxypropyl)-2,4,6-triiodo isophthalamide (5.0 g, 6.7 mmol). To the clear solution was then added boric acid (0.29 g, 4.6 mmol). The mixture was cooled to room temperature and pH adjusted to 12.6. 2-(4-oxiran-2-ylbutyl)oxirane (0.327 g, 2.3 mmol) was added. The pH of the solution was adjusted to the interval 12.6-13. The reaction was left over weekend. To the solution was added HCl (18%) to pH 4. Salts were removed by treatment with ion exchanger AMB200C and IRA67. The solution was filtered from the resin and evaporated. An aliquot of the crude material was purified by preparative HPLC (column Phenomenex Luna C18(2) 10 μm 250×50.0 mm, solvents: A=water and B=acetonitrile; gradient 07-13% B over 60 min; flow 50.0 ml/min, UV detection at 214 nm and 254 nm). The product was obtained in 639 mg after lyophilisation. Analysis by LC-MS (column Agilent Zorbax SB-Aq 3.5 μm 3.0×100 mm, solvents: A=water/0.1% formic acid and B=acetonitrile/0.1% formic acid; gradient 0-30% B over 20 min; flow 0.3 ml/min, UV detection at 214 and 254 nm, ESI-MS) gave two isomeric peaks eluting between 12.50-12.85 minutes with m/z 1636.6 (MH+) corresponding to the structure.
Reaction SMILES: [C:1]([C:3]1[CH:29]=[CH:28][C:6]([C:7]([NH:9][C:10](=[O:27])[NH:11][C:12]2[CH:25]=[CH:24][C:15]([O:16][CH2:17][C:18]([O:20][CH:21]([CH3:23])[CH3:22])=[O:19])=[CH:14][C:13]=2[CH3:26])=[O:8])=[CH:5][CH:4]=1)#[N:2].N1C=CC=CC=1.[SH2:36]>C(N(CC)CC)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:9][C:10](=[O:27])[NH:11][C:12]2[CH:25]=[CH:24][C:15]([O:16][CH2:17][C:18]([O:20][CH:21]([CH3:23])[CH3:22])=[O:19])=[CH:14][C:13]=2[CH3:26])=[O:8])=[CH:28][CH:29]=1)(=[S:36])[NH2:2]
Reactant: S
Reactant: Cc1cc(OCC(=O)OC(C)C)ccc1NC(=O)NC(=O)c1ccc(C#N)cc1
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: Cc1cc(OCC(=O)OC(C)C)ccc1NC(=O)NC(=O)c1ccc(C(N)=S)cc1

Procedure:
In a similar manner to Example 1, starting material step (b), the product of step (c) (11.36 g), pyridine (500 ml), triethylamine (70 ml) and H2S gas were reacted to give isopropyl 4-[3-(4-thiocarbamoylbenzoyl)ureido]-3-methylphenoxyacetate (12.23 g) as a yellow solid: NMR Spectrum (DMSO-d6) 1.24 (6H, d), 2.28 (3H, s), 4.69 (2H, s), 5.01 (1H, m), 6.78 (1H, dd), 6.85 (1H, d), 7.77 (1H, d), 7.96 (2H, d), 8.05 (2H, d), 9.65 (1H, br s), 10.04 (1H, br s), 10.56 (1H, s), 11.11 (1H, s); Mass Spectrum m/Z 452 (M+Na)+.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[CH2:7][S:8][CH2:9][CH2:10][NH:11][C:12]([NH2:14])=[S:13].[CH3:15][I:16]>CO>[I-:16].[CH3:15][S:13][C:12]([NH2:14])=[NH+:11][CH2:10][CH2:9][S:8][CH2:7][C:6]1[NH:5][CH:4]=[N:3][C:2]=1[CH3:1]
Reactant: CI
Reactant: Cc1nc[nH]c1CSCCNC(N)=S
Solvent: CO
Product: CSC(N)=[NH+]CCSCc1[nH]cnc1C
Product: [I-]
Yield: 62.1 %

Procedure:
A solution of N-[2-((4-methyl-5-imidazolyl)methylthio)ethylthiourea (2.29 g.) and methyl iodide (1.56 g.) in methanol (5 ml) was kept at room temperature for 18 hours affording S-methyl-N-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]thiouronium iodide (2.3g.), m.p. 128°-131°. The iodide was concentrated to the corresponding sulphate by ion-exchange on an ion-exchange resin (IRA 401) in the sulphate form.
Reaction SMILES: [NH:1]([C:31]([O:33]C(C)(C)C)=O)[C@H:2]([C:6]([NH:8][C@H:9]([C:11]([NH:13][C@H:14]([C:19]([NH:21][C:22]1[CH:30]=[CH:29][C:25]([N+:26]([O-:28])=[O:27])=[CH:24][CH:23]=1)=[O:20])[CH2:15][C:16](=[O:18])[OH:17])=[O:12])[CH3:10])=[O:7])[CH:3]([CH3:5])[CH3:4].[CH3:38]C(ON1C(=O)CCC1=O)=O.C([O-])(O)=O.[Na+].CN(C=O)C>C(O)(C(F)(F)F)=O.Cl>[NH:1]([C:31]([CH3:38])=[O:33])[C@H:2]([C:6]([NH:8][C@H:9]([C:11]([NH:13][C@H:14]([C:19]([NH:21][C:22]1[CH:30]=[CH:29][C:25]([N+:26]([O-:28])=[O:27])=[CH:24][CH:23]=1)=[O:20])[CH2:15][C:16](=[O:18])[OH:17])=[O:12])[CH3:10])=[O:7])[CH:3]([CH3:4])[CH3:5]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(=O)O)C(=O)Nc1ccc([N+](=O)[O-])cc1
Reactant: CC(=O)ON1C(=O)CCC1=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)N[C@H](C(=O)N[C@@H](C)C(=O)N[C@@H](CC(=O)O)C(=O)Nc1ccc([N+](=O)[O-])cc1)C(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
t-BOCValAlaAsp-p-nitroanilide (174 mg, 0.33 mmole) was dissolved in neat TFA (5 mL) and stirred at room temperature for 1 hour. The TFA was removed in vacuo and the residue was then dissolved in 5 mL of CH2Cl2 which was then evaporated in vacuo. This dissolution with CH2 Cl2 and subsequent evaporation repeated two more times. The residue was dissolved in dioxane/water (5 mL, 4:1) and treated with acetic acid N-hydroxysuccinimide ester (63 mg, 0.40 mmole) and NaHCO3 (139 mg, 1.65 mmole). After 18 hours, the mixture was diluted with 1N HCl (25 mL) and extracted three times with ethyl acetate. The combined extracts were dried with MgSO4, filtered and concentrated to a yellow solid which was recrystallized from ethyl acetate/ethanol to give 33 mg (21%) of light yellow powder: mp 196°-200° C. (dec.); 1H NMR (DMSO-d6) δ 0.80 (d, J=6.6 Hz, 3H), 0.82 (d, J=5.1 Hz, 3H), 1.20 (d, J=7.2 Hz, 3H), 1.85 (s, 3H), 1.85-2.0 (m, 1H), 2.60 (dd, J=7.5, 16.6 Hz, 1H), 2.75 (dd, J=6.2, 16.6 Hz, 1H), 4.1-4.2 (m, 1H), 4.2-4.3 (m, 1H), 4.6-4.7 (m, 1H), 7.8-7.9 (m, 3H), 8.11 (d, J=6.8 Hz, 1H), 8.21 (d, J=9.3 Hz, 2H), 8.27 (d, J=7.2 Hz, 1H), 10.51 (s, 1H), 12.45 (br s, 1H); MS (LSIMS) m/e 488 (6, M+ +Na), 466 (23, M+ +1), 449 (7) 328 (15), 213 (44), 142 (100); [α]D20 -24.9° (c=1.0, DMF); Analysis calculated for C20H27N5O8 : C, 51.60; H, 5.85; N, 15.05; found: C, 50.16; H, 5.79; N, 14.06.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][CH:10]=[C:11]([C:14]([CH3:16])=O)[C:12]=2[OH:13])=[CH:4][CH:3]=1.[NH:17]([C:19]([NH:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[C:24]([Cl:31])[CH:23]=1)=[S:20])[NH2:18]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][CH:10]=[C:11]([C:14](=[N:18][NH:17][C:19]([NH:21][C:22]3[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[C:24]([Cl:31])[CH:23]=3)=[S:20])[CH3:16])[C:12]=2[OH:13])=[CH:4][CH:3]=1
Reactant: NNC(=S)Nc1ccc(C(=O)O)c(Cl)c1
Reactant: CC(=O)c1csc(-c2ccc(Cl)cc2)c1O
Product: CC(=NNC(=S)Nc1ccc(C(=O)O)c(Cl)c1)c1csc(-c2ccc(Cl)cc2)c1O

Procedure:
From 2-(4-chlorophenyl)-3-hydroxy-4-methylcarbonylthiophene (25.2 mg, 0.1 mmol) and 4-hydrazinocabonothioylamino-2-chlorobenzoic acid (24.5 mg, 0.1 mmol), the desired product was obtained in the same manner as in Synthetic Example 50 as a pale yellow solid (41.9 mg, yield 88%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH:7]([C:9]([OH:11])=[O:10])[NH2:8].C(=O)([O-])[O-].[K+].[K+].[C:18](Cl)([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19]>O.O1CCOCC1>[CH2:21]([O:20][C:18]([NH:8][CH:7]([C:9]([OH:11])=[O:10])[CH2:6][C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)=[O:19])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NC(Cc1cccs1)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: O=C(NC(Cc1cccs1)C(=O)O)OCc1ccccc1
Reaction time: 1 h
Yield: 97.9 %

Procedure:
To a mixture of 3.0 g (16.9 mmol) of β-thienyl-D,L-alanine in 75 mL of water and 60 mL of dioxane, was added 5.6 g (40.6 mmol) of anhydrous potassium carbonate, followed by 2.85 mL (20 mmol) of carbobenzyloxychloride. The resulting mixture was stirred rapidly for approximately one hour. When the reaction was substantially complete, as indicated by thin layer chromatography (21/7/7/9, EtOAc/AcOH/CH3 CN/H2O), the reaction mixture was concentrated. The resultant layers were separated and the aqueous layer was washed with 75 mL of diethyl ether and then layered with 150 mL of methylene chloride. The resultant mixture was acidified with rapid stirring to pH=2.0 using 5N hydrochloric acid. The layers were then separated, and the organic layer was dried with sodium sulfate (Na2SO4), filtered and concentrated to provide 5.05 g of desired compound (98%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[CH3:11].C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:19]([CH3:26])([CH3:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21]>C(#N)C.C(OCC)(=O)C>[C:8]([C:5]1[CH:6]=[CH:7][C:2]([O:1][C:19]([CH3:26])([CH3:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:3]([CH3:11])[CH:4]=1)(=[O:10])[CH3:9]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: CC(=O)c1ccc(O)c(C)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C)(C)Oc1ccc(C(C)=O)cc1C
Temperature: 25 °C
Reaction time: 0.03 h

Procedure:
A suspension of 1-(4-hydroxy-3-methylphenyl)ethanone (20.1 g) in acetonitrile (200 ml) was added to a suspension of cesium carbonate (86.6 g) in acetonitrile (400 ml) and the mixture stirred under nitrogen at room temperature for 2 minutes. ethyl 2-bromo-2-methylpropanoate (33 g) was added and the mixture stirred for 25 hours, further ethyl 2-bromo-2-methylpropanoate (33 g) was added and the mixture stirred for a further 16 hours. The mixture was filtered and the filtrate concentrated to give an orange oil, the oil was dissolved in ethyl acetate and the solution washed thrice with 1M sodium hydroxide and brine. The organic layer was separated, dried over sodium sulfate, filtered and the filtrate concentrated; the resulting oil was purified by Biotage® chromatography eluting with cyclohexane:ethyl acetate (9:1) to give the title compound as a clear oil.
Reaction SMILES: [C:1]1([CH2:7][CH:8]=[CH:9][C:10]([OH:12])=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([SH:23])[CH:18]=[CH:19][C:20]=1[O:21][CH3:22].N1CCCCC1>>[CH3:13][O:14][C:15]1[CH:16]=[C:17]([S:23][CH:8]([CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:9][C:10]([OH:12])=[O:11])[CH:18]=[CH:19][C:20]=1[O:21][CH3:22]
Reactant: O=C(O)C=CCc1ccccc1
Reactant: COc1ccc(S)cc1OC
Solvent: C1CCNCC1
Product: COc1ccc(SC(CC(=O)O)Cc2ccccc2)cc1OC
Temperature: 110 °C

Procedure:
A mixture of 4-phenylbut-2-enoic acid (2 g, 12.33 mmol) prepared as in Example 6, Step B, 3,4-dimethoxybenzenethiol (2.1 mL, 14.79 mmol, 1.2 eq), and piperidine (0.4 mL (3.7 mmol, 0.3 eq) is heated at 110° C. in a bomb for 18 hours. The reaction is partitioned between ethyl ether and 1 N HCl. The organic layer is dried over anhydrous MgSO4 and concentrated in vacuo. The product is purified by flash silica gel chromatography to afford 3-(3,4-dimethoxyphenylsulfanyl)-4-phenylbutanoic acid as a yellow oil. (4.1 g, 100%): 1H-NMR (300 MHz, CDCl3) δ (TMS) 2.54(d, 0.5×2H), 2.56(d, 0.5×2H), 2.83(d, 0.5×2H), 2.98(d, 0.5×2H), 3.56(m, 1H), 3.85(s, 3H), 3.88(s, 3H), 6.8(d, 1H), 6.97(d, 1H), 7.05(d, 0.5×1H), 7.09(d, 0.5×1H), 7.15-7.32(m, 5H).
Reaction SMILES: C([NH:3][CH2:4][C:5]([OH:7])=[O:6])C.Cl.[CH2:9](N(CC)CC)[CH3:10].[CH2:16]([O:18][C:19](=[O:23])[C:20](Cl)=[O:21])[CH3:17]>ClCCCl>[CH2:9]([CH:4]([C:5]([OH:7])=[O:6])[NH:3][C:20](=[O:21])[C:19]([O:18][CH2:16][CH3:17])=[O:23])[CH3:10]
Reactant: CCOC(=O)C(=O)Cl
Reactant: CCNCC(=O)O
Reactant: CCN(CC)CC
Agent: Cl
Solvent: ClCCCl
Product: CCOC(=O)C(=O)NC(CC)C(=O)O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a suspension of ethyl glycine·HCl 2 (38.4 g, 275 mmol) in 1,2-dichloroethane (360 mL) was added triethylamine (77.0 mL, 550 mmol) at room temperature. After stirring for 30 minutes the heterogenous mixture was cooled to 0° C. and ethyl oxalyl chloride 1 (30.3 mL, 275 mol) was added dropwise over the course of 1 h. Upon completion of the addition, the cooling bath was removed and the reaction was stirred at room temperature overnight. The reaction was diluted with water (250 mL) and the layers separated. The aqueous layer was backwashed with 2 portions of dichloromethane (250 mL). The combined organic layers were washed with water (250 mL), followed by brine (250 mL), dried over MgSO4 and concentrated to give an oil 3 that was taken directly onto the next step.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[C:4]([NH:21][C:22]1[CH:23]=[N:24][CH:25]=[C:26]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[CH:27]=1)=[C:5]([CH3:20])[C:6]([N:13]1[CH2:18][CH2:17][NH:16][C@@H:15]([CH3:19])[CH2:14]1)=[N:7]2.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>>[F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[C:4]([NH:21][C:22]1[CH:23]=[N:24][CH:25]=[C:26]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[CH:27]=1)=[C:5]([CH3:20])[C:6]([N:13]1[CH2:18][CH2:17][N:16]([S:35]([CH3:34])(=[O:37])=[O:36])[C@@H:15]([CH3:19])[CH2:14]1)=[N:7]2
Reactant: Cc1c(N2CCN[C@@H](C)C2)nc2cc(F)cc(F)c2c1Nc1cncc(N2CCOCC2)c1
Reactant: CS(=O)(=O)Cl
Product: Cc1c(N2CCN(S(C)(=O)=O)[C@@H](C)C2)nc2cc(F)cc(F)c2c1Nc1cncc(N2CCOCC2)c1

Procedure:
Essentially prepared according to Procedure M using (S)-5,7-difluoro-3-methyl-2-(3-methylpiperazin-1-yl)-N-(5-morpholinopyridin-3-yl)quinolin-4-amine (50 mg, 0.11 mmol) and methylsulfonyl chloride to give (S)-5,7-difluoro-3-methyl-2-(3-methyl-4-(methylsulfonyl)piperazin-1-yl)-N-(5-morpholinopyridin-3-yl)quinolin-4-amine. 1H NMR (CDCl3) δ ppm 7.95 (1H, d, J=2.5 Hz), 7.66 (1H, d, J=2.3 Hz), 7.30 (1H, ddd, J=9.9, 2.5, 1.3 Hz), 6.92 (1H, d, J=13.3 Hz), 6.83 (1H, ddd, J=13.9, 8.7, 2.6 Hz), 6.60 (1H, t, J=2.3 Hz), 4.15-4.28 (1H, m), 3.86 (4H, dd, J=5.7, 4.1 Hz), 3.65-3.80 (2H, m), 3.58 (1H, dt, J=12.9, 1.9 Hz), 3.51 (1H, td, J=12.3, 2.9 Hz), 3.22 (1H, dd, J=12.9, 3.5 Hz), 3.13-3.19 (4H, m), 3.06 (1H, td, J=12.3, 3.2 Hz), 2.93 (3H, s), 2.09 (3H, s), 1.41 (3H, d, J=6.8 Hz). Mass Spectrum (ESI) m/e=533.2 (M+1).
Reaction SMILES: [C:1]1([O:7][NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:9][C:10]1[N:14]([CH2:15][C:16]([N:18]2[CH2:23][CH2:22][CH:21]([C:24]3[S:25][CH:26]=[C:27]([CH:29]=O)[N:28]=3)[CH2:20][CH2:19]2)=[O:17])[N:13]=[C:12]([C:31]([F:34])([F:33])[F:32])[CH:11]=1>C(O)C>[C:1]1([O:7][N:8]=[CH:29][C:27]2[N:28]=[C:24]([CH:21]3[CH2:20][CH2:19][N:18]([C:16](=[O:17])[CH2:15][N:14]4[C:10]([CH3:9])=[CH:11][C:12]([C:31]([F:32])([F:34])[F:33])=[N:13]4)[CH2:23][CH2:22]3)[S:25][CH:26]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(c2nc(C=O)cs2)CC1
Reactant: NOc1ccccc1
Solvent: CCO
Product: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(c2nc(C=NOc3ccccc3)cs2)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
At room temperature, O-phenylhydroxylamine (41 mg) and Amberlyst A21 (200 mg) are added to a solution of 2-(1-{[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazole-4-carbaldehyde (100 mg) in ethanol. The reaction mixture is stirred at room temperature for 24 hours. The solvent is then removed under reduced pressure. The residue is purified by column chromatography (silica gel, ethyl acetate:hexane 0%-100% elution gradient). This gives 2-(1-{[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazole-4-carbaldehyde O-phenyl oxime (50 mg, 40%) which consists of an about 9:1 mixture of cis and trans isomers (log P(pH2.7)=3.74 (93%), 3.94 (7%)).
Reaction SMILES: CC(OC([NH:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][S:14](=[O:18])(=[O:17])[CH2:13][CH:12]1[C:19]([O:21]C)=O)=O)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH2:13]1[CH:12]2[C:19](=[O:21])[NH:8][CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][S:14]1(=[O:17])=[O:18]
Reactant: COC(=O)C1CS(=O)(=O)CCN1CCNC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1NCCN2CCS(=O)(=O)CC12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.8 %

Procedure:
To a solution of methyl 4-[2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)ethyl]-3-thiomorpholinecarboxylate 1,1-dioxide (D17; 295 mg, 0.88 mmol) in 3 ml of anhydrous dichloromethane was added 1 ml of trifluoroacetic acid and the resulting solution was stirred at room temperature under nitrogen for 1 h 30 min. The solvent was removed under reduced pressure and the residue loaded on a SCX column, washed with methanol and eluted with methanolic ammonia. The product was purified further by chromatography (silica cartridge, cyclohexane to ethyl acetate, then dichloromethane to dichloromethane:methanol 70:30) to give 165 mg of the target compound.
Reaction SMILES: O[CH2:2][C:3]1[C:4]([I:13])=[N:5][C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:33]N1C(=O)CCC1=O.C([O-])(O)=O.[Na+]>CN(C=O)C>[Cl:33][CH2:2][C:3]1[C:4]([I:13])=[N:5][C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2
Reactant: O=C1CCC(=O)N1Cl
Reactant: OCc1cc2ccccc2nc1I
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: ClCc1cc2ccccc2nc1I
Temperature: -23 °C
Reaction time: 1 h
Yield: 84 %

Procedure:
To a stirred mixture of 3-hydroxymethyl-2-iodoquinoline prepared in accordance with Example 10 above (350 mg, 1.23 mmol) and triphenylphosphine (483 mg, 1.84 mmol) in 10 mL of dry DMF at -23° C. was added N-chlorosuccinimide (246 mg, 1.84 mmol), and the mixture was stirred for 1 h at -23° C. After the addition of 40 mL of dilute aqueous NaHCO3, the mixture was extracted with ethyl acetate (20 mL) and then ether (2×15 mL). The combined organic extracts were washed successively with 20-mL portions of dilute NaHCO3, water and brine, and were dried over MgSO4. Concentration and purification of the residue by radial PLC (silica gel, 10% ethyl acetate/hexanes) afforded 312 mg (84%) of 3-chloromethyl-2-iodoquinoline as a white crystalline solid: mp 138°-140° C. Recrystallization from hexanes afforded an analytical sample as colorless needles: mp 139°-140° C. 1H NMR (300 MHz, CDCl3) δ 8.17 (s, 1H), 8.07 (d, 1H, J=9 Hz), 7.84 (d, 1H, J=9 Hz), 7.75 (t, 1H, J=9 Hz), 7.62 (t, 1H, J=9 Hz), 4.80 (s, 1H); IR (nujol) 1585, 1555, 1260, 1010, 780, 755, 710 cm-1.