Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:11][CH2:12][O:13][CH3:14])=[CH:4][C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=O.Br[CH2:16][C:17](=[O:19])[CH3:18].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:1][C:2]1[C:3]([O:11][CH2:12][O:13][CH3:14])=[CH:4][C:5]2[O:10][C:16]([C:17](=[O:19])[CH3:18])=[CH:7][C:6]=2[CH:9]=1
Reactant: CC(=O)CBr
Reactant: COCOc1cc(O)c(C=O)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COCOc1cc2oc(C(C)=O)cc2cc1Cl
Yield: 72.4 %

Procedure:
Using 5-chloro-2-hydroxy-4-(methoxymethoxy)benzaldehyde (1.50 g, 6.94 mmol), acetonitrile (14 mL), bromoacetone (1.57 g, 10.4 mmol) and potassium carbonate (2.87 g, 20.8 mmol), an operation in the same manner as in Reference Example 86 was performed to give the title compound (1.28 g, yield 72%).
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:24][CH2:23][C:22]4[N:25]=[C:26]([C:28]5[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=5)[S:27][C:21]=4[C:20]3=[O:35])=[CH:15][C:14]=2[O:36][CH3:37])[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.[OH-].[Na+]>C(Cl)Cl>[NH:8]1[CH2:11][CH:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:24][CH2:23][C:22]4[N:25]=[C:26]([C:28]5[CH:29]=[CH:30][C:31]([Cl:34])=[CH:32][CH:33]=5)[S:27][C:21]=4[C:20]3=[O:35])=[CH:15][C:14]=2[O:36][CH3:37])[CH2:9]1
Reactant: COc1cc(N2CCc3nc(-c4ccc(Cl)cc4)sc3C2=O)ccc1OC1CN(C(=O)OC(C)(C)C)C1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(N2CCc3nc(-c4ccc(Cl)cc4)sc3C2=O)ccc1OC1CNC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
Dissolve 3-{4-[2-(4-chloro-phenyl)-4-oxo-6,7-dihydro-4H-thiazolo[5,4-c]pyridin-5-yl]-2-methoxy-phenoxy}-azetidine-1-carboxylic acid tert-butyl ester (2.71 g, 5.00 mmol) in CH2Cl2 (20 mL). Add trifluoroacetic acid (5.88 mL, 77.79 mmol). Stir at room temperature for one hour and then add 5 N NaOH to pH=8-10. Collect a white/yellow precipitate via vacuum filtration, and wash the solid with EtOAc followed by Et2O. Dry the solid overnight in vacuo at about 50° C. to give 2.21 g (>99%) of the title compound. ES/MS m/z (35Cl) 442.0 [M+1]+.
Reaction SMILES: CS(O[CH2:6][C@H:7]1[CH2:12][N:11]([S:13]([C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)(=[O:15])=[O:14])[CH2:10][CH2:9][N:8]1[C:21]1[CH:26]=[CH:25][C:24]([C:27]([OH:33])([CH3:32])[C:28]([F:31])([F:30])[F:29])=[CH:23][CH:22]=1)(=O)=O.[NH:34]1[CH2:39][CH2:38][NH:37][CH2:36][C:35]1=[O:40].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.CCOC(C)=O>[S:17]1[CH:18]=[CH:19][CH:20]=[C:16]1[S:13]([N:11]1[CH2:10][CH2:9][N:8]([C:21]2[CH:22]=[CH:23][C:24]([C:27]([OH:33])([CH3:32])[C:28]([F:31])([F:30])[F:29])=[CH:25][CH:26]=2)[C@@H:7]([CH2:6][N:37]2[CH2:38][CH2:39][NH:34][C:35](=[O:40])[CH2:36]2)[CH2:12]1)(=[O:14])=[O:15]
Reactant: CC(O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@@H]2COS(C)(=O)=O)cc1)C(F)(F)F
Reactant: O=C1CNCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@@H]2CN2CCNC(=O)C2)cc1)C(F)(F)F
Temperature: 130 °C
Yield: 44.7 %

Procedure:
((2R)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl methanesulfonate (100 mg, 0.189 mmol, Intermediate B) was combined with piperazin-2-one (18.9 mg, 0.189 mmol, Alfa-Aesar) and potassium carbonate (78 mg, 0.57 mmol, Sigma-Aldrich, St. Louis, Mo.) in acetonitrile (1.89 mL) and heated at 130° C. for 30 min. After the reaction was allowed to cool to room temperature, the mixture was diluted with EtOAc and the solids were removed by filtering through a 0.2 μm millipore Millex-FG filter (Millipore, Billerica, Mass.). After concentration of the filtrate, the crude residue was purified by silica gel chromatography (0 to 7% MeOH in CH2Cl2) followed by purification via reverse-phase HPLC (Phenomenex Gemini-NX 10μ, 110 Å, AXIA packed column, 100×50 mm, 60 mL/min, 10-95% CH3CN/H2O, 0.1% TFA, 10 min gradient). The collected fractions were partitioned between CH2Cl2 and saturated aqueous NaHCO3 and then the organic extracts were dried (Na2SO4), filtered and concentrated. The residue was taken up in MeOH and was passed through an AccuBond SPE SCX cartridge eluting with 2M ammonia in MeOH to give the title compound (45 mg) as a mixture of two isomers.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:16])=[CH:4][C:5]2[O:10][CH2:9][C:8](=[O:11])[N:7]([CH2:12][C:13]#[CH:14])[C:6]=2[CH:15]=1.[C:17](Cl)(Cl)=[O:18]>>[F:16][C:3]1[C:2]([N:1]=[C:17]=[O:18])=[CH:15][C:6]2[N:7]([CH2:12][C:13]#[CH:14])[C:8](=[O:11])[CH2:9][O:10][C:5]=2[CH:4]=1
Reactant: O=C(Cl)Cl
Reactant: C#CCN1C(=O)COc2cc(F)c(N)cc21
Product: C#CCN1C(=O)COc2cc(F)c(N=C=O)cc21

Procedure:
6-Amino-3,4-dihydro-7-fluoro-3-oxo-4-(2-propynyl)-2H-1,4-benzoxazine is treated with phosgene analogously to the procedure described in Example 103 in order to produce the 3,4-dihydro-7-fluoro-6-isocyanato-3-oxo-4-(2-propynyl)-2H-1,4-benzoxazine which is used as the starting material in Example 2. 1H-NMR (CDCl3, 60 MHz): 7.02 ppm (d, 1H), 6.88 ppm (d, 1H), 4.88-4.60 ppm (m, 4H), 2.35 ppm (t, 1H).
Reaction SMILES: C([O:3][C:4](=[O:32])[CH2:5][S:6][C:7]1[S:11][C:10]([NH:12][C:13]([N:15]([C:22]2[CH:23]=[N:24][C:25]([NH:28][C:29](=[O:31])[CH3:30])=[CH:26][CH:27]=2)[CH2:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[O:14])=[N:9][CH:8]=1)C.C1(CN(C2C=CC(S(C)(=O)=O)=CC=2)C(=O)NC2SC=C(CC(O)=O)N=2)CCCC1.C1(CNC2C=CC(NC(=O)C)=NC=2)CCCC1.C(OC(=O)CSC1SC(N)=NC=1)C>>[C:29]([NH:28][C:25]1[N:24]=[CH:23][C:22]([N:15]([CH2:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[C:13](=[O:14])[NH:12][C:10]2[S:11][C:7]([S:6][CH2:5][C:4]([OH:32])=[O:3])=[CH:8][N:9]=2)=[CH:27][CH:26]=1)(=[O:31])[CH3:30]
Reactant: CCOC(=O)CSc1cnc(NC(=O)N(CC2CCCC2)c2ccc(NC(C)=O)nc2)s1
Agent: CC(=O)Nc1ccc(NCC2CCCC2)cn1
Agent: CCOC(=O)CSc1cnc(N)s1
Agent: CS(=O)(=O)c1ccc(N(CC2CCCC2)C(=O)Nc2nc(CC(=O)O)cs2)cc1
Product: CC(=O)Nc1ccc(N(CC2CCCC2)C(=O)Nc2ncc(SCC(=O)O)s2)cn1

Procedure:
The title compound was prepared via {2-[3-(6-acetylamino-pyridin-3-yl)-3-cyclopentylmethyl-ureido]-thiazol-5-ylsulfanyl}-acetic acid ethyl ester in a similar manner as described for the synthesis of {2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-4-yl}-acetic acid, using N-[5-(cyclopentylmethyl-amino)-pyridin-2-yl]-acetamide and (2-amino-thiazol-5-ylsulfanyl)acetic acid ethyl ester
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]=[CH:17][N:18]([C:20]3[N:25]=[C:24]([CH3:26])[CH:23]=[C:22]([C:27]4[CH:32]=[CH:31][C:30]([Cl:33])=[C:29]([Cl:34])[CH:28]=4)[N:21]=3)[CH:19]=2)=[CH:11][CH:10]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[Cl:34][C:29]1[CH:28]=[C:27]([C:22]2[CH:23]=[C:24]([CH3:26])[N:25]=[C:20]([N:18]3[CH:19]=[C:15]([C:12]4[CH:11]=[CH:10][C:9]([S:6]([NH2:5])(=[O:8])=[O:7])=[CH:14][CH:13]=4)[N:16]=[CH:17]3)[N:21]=2)[CH:32]=[CH:31][C:30]=1[Cl:33]
Reactant: Cc1cc(-c2ccc(Cl)c(Cl)c2)nc(-n2cnc(-c3ccc(S(=O)(=O)NC(C)(C)C)cc3)c2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(-c2ccc(Cl)c(Cl)c2)nc(-n2cnc(-c3ccc(S(N)(=O)=O)cc3)c2)n1
Temperature: 25 °C
Reaction time: 15 h
Yield: 72.9 %

Procedure:
To a cooled and stirred solution of N-tert-butyl-4-{1-[6-(3,4-dichloro-phenyl)-4-methyl-pyrimidin-2-yl]-1H-imidazol-4-yl}-benzenesulfonamide (0.2 g) in dichloromethane (3 mL) was added TFA (3 mL) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness and saturated NaHCO3 solution (3 mL), diethyl ether and heptane were added. The mixture was stirred at room temperature for 1 h, the precipitate was collected by filtration, washed with water and heptane and dried to yield the title compound as a white solid (0.13 g, 33%). MS (ISP) 460.1 [(M+H)+]; mp 282.5° C.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:5]([CH3:13])[N:4]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][C:23](=[O:31])OC3C=CC=CC=3)=[CH:16][CH:15]=2)[N:3]=1.[OH:32][C:33]1[CH:38]=[CH:37][C:36]([S:39]([NH2:42])(=[O:41])=[O:40])=[CH:35][CH:34]=1.C(#N)C.CCCCCCC=CCCC>ClCCl>[CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:5]([CH3:13])[N:4]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][C:23]([NH:42][S:39]([C:36]3[CH:35]=[CH:34][C:33]([OH:32])=[CH:38][CH:37]=3)(=[O:40])=[O:41])=[O:31])=[CH:16][CH:15]=2)[N:3]=1
Reactant: Cc1nn(-c2ccc(CCNC(=O)Oc3ccccc3)cc2)c(C)c1-c1ccccc1
Reactant: NS(=O)(=O)c1ccc(O)cc1
Agent: CCCC=CCCCCCC
Solvent: CC#N
Solvent: ClCCl
Product: Cc1nn(-c2ccc(CCNC(=O)NS(=O)(=O)c3ccc(O)cc3)cc2)c(C)c1-c1ccccc1
Yield: 75.6 %

Procedure:
A mixture of phenyl 2-[4-(3,5-dimethyl-4-phenyl-1H-pyrazol-1-yl)phenyl]ethylcarbamate (step 1 of Example 22, 100 mg, 0.24 mmol), 4-hydroxybenzenesulfonamide (42 mg, 0.24 mmol), acetonitrile (3 mL) and 1,8-[5.4.0]-7-undecene (36 μL, 0.24 mmol) was stirred at room temperature for 16 h. The mixture was diluted with dichloromethane, and washed with 1 M hydrochloric acid and sat. NaHCO3 aq. The organic fraction was dried over MgSO4 and concentrated under reduced pressure. The residue was purified by TLC with dichloromethane/methanol (10:1) to afford 89 mg (74%) of the title compound as white solids: 1H-NMR [CDCl3/CD3OD(4:1)] δ 7.73-7.68 (2H, m), 7.48-7.23 (9H, m), 6.88-6.83 (2H, m), 3.47 (2H, t, J=6.7 Hz), 2.84 (2H, t, J=6.7 Hz), 2.33 (3H, s), 2.26 (3H, s).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH2:5][NH:4][C:3]1=[O:8].C(N(CC)CC)C.[CH3:16][S:17](Cl)(=[O:19])=[O:18]>ClCCl>[O:8]=[C:3]1[CH:2]([O:1][S:17]([CH3:16])(=[O:19])=[O:18])[CH2:7][CH2:6][CH2:5][NH:4]1
Reactant: O=C1NCCCC1O
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OC1CCCNC1=O
Reaction time: 0.5 h

Procedure:
To a suspension of 3-hydroxy-piperidin-2-one (500 mg, 4.34 mmol, 1.0 eq) and triethylamine (0.908 mL, 6.51 mmol, 1.5 eq) in dichloromethane (3 mL) at 0° C. was added dropwise methanesulfonyl chloride (497 mg, 4.34 mmol, 1.0 eq) dissolved in dichloromethane (1 mL). The reaction was complete within 30 min as judged by LCMS. An orange precipitate was filtered, redissolved in dichloromethane and purified by column chromatography (MeOH/CH2Cl2) to give the title compound as a white waxy solid (204 mg, 1.056 mmol, 24.3% yield). 1H NMR (400 MHz, chloroform-d) δ ppm 5.78 (br. s, 1H) 4.94-5.05 (m, 1H) 3.30-3.44 (m, 2H) 3.27 (s, 3H) 2.24-2.37 (m, 1H) 2.08-2.21 (m, 1H) 1.98-2.08 (m, 1H) 1.79-1.96 (m, 1H). MS (m/z, MH+): 193.7
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][CH2:7][NH:8][C:9]1[S:10][C:11]([CH:14]=[O:15])=[CH:12][N:13]=1)[C:3]([OH:5])=[O:4].C(=O)(O)[O-].[Na+].[C:21](=O)([O:37]N1C(=O)CCC1=O)[O:22][CH2:23][CH:24]1[C:36]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:30]2[C:25]1=[CH:26][CH:27]=[CH:28][CH:29]=2>C1COCC1.O>[CH:35]1[C:36]2[CH:24]([CH2:23][O:22][C:21]([NH:1][C@@H:2]([CH2:6][CH2:7][NH:8][C:9]3[S:10][C:11]([CH:14]=[O:15])=[CH:12][N:13]=3)[C:3]([OH:5])=[O:4])=[O:37])[C:25]3[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:31]=2[CH:32]=[CH:33][CH:34]=1
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)ON1C(=O)CCC1=O
Reactant: N[C@@H](CCNc1ncc(C=O)s1)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=Cc1cnc(NCC[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)O)s1
Reaction time: 1.5 h
Yield: 23.1 %

Procedure:
To a solution of the crude material from Example 50 (6.76 g, 9.86 mmol) in a mixture of THF (74.0 ml) and water (24.7 ml) is added sequentially sodium bicarbonate (4.97 g, 59.2 mmol), and (9H-fluoren-9-yl)methyl 2,5-dioxopyrrolidin-1-yl carbonate (3.33 g, 9.86 mmol) and the reaction is stirred at room temp. for 1.5 h. The solvent is removed in vacuo and the residue is partitioned between water (25 mL) and EtOAc (25 mL). The organic layer is discarded, and the aqueous layer treated with 1N HCl until pH 3 is achieved. The aqueous layer is extracted with CH2Cl2 (3×25 mL), the organic layers are combined, washed with brine, dried over MgSO4, filtered and evaporated to dryness to give 1.03 g (20.8%) of the title compound as a pale orange solid. LC/MS (Condition A): ret. T=3.59 min, (M+H)+ 452.14. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.75 (1 H, br. s.), 9.65 (1 H, s), 8.98 (1 H, br. s.), 8.06 (1 H, s), 7.91 (2 H, d, J=7.53 Hz), 7.68-7.83 (3 H, m), 7.39-7.47 (3 H, m), 7.30-7.39 (3 H, m), 4.19-4.39 (3 H, m), 3.97-4.10 (1 H, m), 3.41 (2 H, d, J=4.52 Hz), 2.10 (1 H, dd, J=13.55, 4.77 Hz), 1.90 (1 H, dd, J=13.55, 9.79 Hz).
Reaction SMILES: [CH:1]([OH:14])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[CH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH:1]([O:14][CH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OC1CCNCC1
Reactant: OC(c1ccccc1)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: c1ccc(C(OC2CCNCC2)c2ccccc2)cc1
Temperature: 25 °C
Yield: 92 %

Procedure:
To a round bottom flask, benzhydrol (1.84 g, 10 mmol, 1.0 eq.), 4-hydroxypiperidine (1.01 g, 10 mmol, 1.0 eq.), and p-toluenesulfonic acid monohydrate (2.09 g, 1.1 eq.) were suspended in toluene (400 ml). The mixture was refluxed with a Dean-Stark condenser for 3-4 hours. After cooling to room temperature, the solution was washed with 5% NaOH solution (2×20 ml), then with water (2×20 ml). The solution was then dried over anhydrous Na2SO4. The solvent was then removed under vacuum. The crude product, 4-benzhydryloxy-piperidine was obtained (2.46 g, 92.0% yield). 1H-NMR (CDCl3, ppm): 7.10-7.25 (m, 10H), 5.41 (s, 1H), 3.48 (m, 1H), 3.13 (m, 2H), 2.78 (m, 2), 1.86 (m, 2H), 1.66 (m, 2H). ESMS 268.1 (M+1), 290.1 (M+23).
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[N:9]([C:17]1[C:22]([F:23])=[C:21](Cl)[N:20]=[C:19]([Cl:25])[N:18]=1)[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[O:7])([CH3:4])[CH3:3].C(N(CC)CC)C.[S:40]1[CH:44]=[CH:43][C:42]([CH2:45][NH2:46])=[CH:41]1>C1COCC1.O>[CH3:4][C:2]([O:5][C:6]([N:8]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[N:9]([C:17]1[C:22]([F:23])=[C:21]([NH:46][CH2:45][C:42]2[CH:43]=[CH:44][S:40][CH:41]=2)[N:20]=[C:19]([Cl:25])[N:18]=1)[C:10]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:11])=[O:7])([CH3:1])[CH3:3]
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)N(C(=O)OC(C)(C)C)c1nc(Cl)nc(Cl)c1F
Reactant: NCc1ccsc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)N(C(=O)OC(C)(C)C)c1nc(Cl)nc(NCc2ccsc2)c1F
Yield: 99.1 %

Procedure:
Tris(1,1-dimethylethyl)2-(2,6-dichloro-5-fluoro-4-pyrimidinyl)-1,1,2-hydrazinetricarboxylate (1.413 g, 2.85 mmol) was dissolved in THF (5 mL). To this solution was added triethylamine (0.48 mL, 3.4438 mmol), followed by commercially available (3-thienylmethyl)amine (0.322 g, 2.85 mmol) which was dissolved in THF (1 mL). After stirring, the reaction mixture was diluted with water, and the aqueous layer was extracted with ethyl acetate. The organics were dried (Na2SO4) and concentrated to produce tris(1,1-dimethylethyl)2-{2-chloro-5-fluoro-6-[(3-thienylmethyl)amino]-4-pyrimidinyl}-1,1,2-hydrazinetricarboxylate as a white solid (1.6214 g, 99%). LCMS: (M+H−3Boc)+=374.1.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]([O:13][CH3:14])[C:10]([OH:12])=O.[NH2:15][CH2:16][C:17]1[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=1>>[C:16]([C:17]1[CH:24]=[CH:23][C:20]([CH2:21][NH:22][C:10](=[O:12])[CH:9]([C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([F:8])[C:2]=2[F:1])[O:13][CH3:14])=[CH:19][CH:18]=1)#[N:15]
Reactant: COC(C(=O)O)c1cccc(F)c1F
Reactant: N#Cc1ccc(CN)cc1
Product: COC(C(=O)NCc1ccc(C#N)cc1)c1cccc(F)c1F

Procedure:
(RS)-(2,3-Difluoro-phenyl)-methoxy-acetic acid was coupled with 4-aminomethyl benzonitrile according to general procedure C to give (RS)-N-(4-cyano-benzyl)-2-(2,3-difluoro-phenyl)-2-methoxy-acetamide. Off-white solid.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][C:40]([OH:42])=O)=[CH:33][C:32]=2[CH3:43])=[C:28]([CH:44]([CH3:46])[CH3:45])[NH:27][N:26]=1)(=O)C.Cl.[NH2:48][CH2:49][CH2:50][CH2:51][CH2:52][C@H:53]([NH:57]C(OCC1C=CC=CC=1)=O)[C:54]([NH2:56])=[O:55].C(N1CCNCC1)C1C=CC=CC=1>>[NH2:57][C@H:53]([C:54](=[O:55])[NH2:56])[CH2:52][CH2:51][CH2:50][CH2:49][NH:48][C:40]([CH2:39][CH2:38][O:37][C:34]1[CH:35]=[CH:36][C:31]([CH2:30][C:29]2[C:25]([O:24][C@@H:6]3[O:7][C@H:8]([CH2:19][OH:20])[C@@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]3[OH:4])=[N:26][NH:27][C:28]=2[CH:44]([CH3:46])[CH3:45])=[C:32]([CH3:43])[CH:33]=1)=[O:42]
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(OCCC(=O)O)cc2C)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: NCCCC[C@H](NC(=O)OCc1ccccc1)C(N)=O
Agent: Cl
Agent: c1ccc(CN2CCNCC2)cc1
Product: Cc1cc(OCCC(=O)NCCCC[C@H](N)C(N)=O)ccc1Cc1c(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)n[nH]c1C(C)C

Procedure:
The title compound was prepared in a similar manner to that described in Example 99 using 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(2-carboxyethoxy)-2-methylphenyl]methyl}-5-isopropyl-1H-pyrazole and (S)-6-amino-2-(benzyloxycarbonylamino)hexanamide hydrochloride instead of 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-[(4-{2-[1-carboxy-1-(methyl)-ethylcarbamoyl]ethoxy}-2-methylphenyl)methyl]-5-isopropyl-1H-pyrazole and 1-benzylpiperazine, respectively.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][NH2:6].[Cl:10][C:11]1[C:20]([C:21](Cl)=[O:22])=[C:19]([CH3:24])[C:18]2[C:13](=[CH:14][C:15]([C:25]([F:28])([F:27])[F:26])=[CH:16][CH:17]=2)[N:12]=1>O1CCOCC1>[Cl:10][C:11]1[C:20]([C:21]([NH:6][CH2:5][C:4]2[CH:7]=[CH:8][CH:9]=[C:2]([F:1])[CH:3]=2)=[O:22])=[C:19]([CH3:24])[C:18]2[C:13](=[CH:14][C:15]([C:25]([F:26])([F:28])[F:27])=[CH:16][CH:17]=2)[N:12]=1
Reactant: Cc1c(C(=O)Cl)c(Cl)nc2cc(C(F)(F)F)ccc12
Reactant: NCc1cccc(F)c1
Solvent: C1COCCO1
Product: Cc1c(C(=O)NCc2cccc(F)c2)c(Cl)nc2cc(C(F)(F)F)ccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.6 %

Procedure:
A solution of 2.9 g (23.4 mmol) 3-fluorobenzylamine was added dropwise at RT to a solution of 6.0 g (19.5 mmol) 2-chloro-4-methyl-7-(trifluoromethyl)quinoline-3-carbonyl chloride in dioxane (35 ml). The mixture was then stirred for 60 min at RT and then quenched with water. The reaction solution was extracted with EE and the organic phase was washed with a 1M aqueous NH4Cl solution and brine, dried over MgSO4, filtered and concentrated to small volume under vacuum. Crystallisation of the residue (EE) yielded 6.4 g (16.1 mmol, 83%) 2-chloro-N-[(3-fluorophenyl)-methyl]-4-methyl-7-(trifluoromethyl)-quinoline-3-carboxamide.
Reaction SMILES: [C:1]([NH:4][C:5]([CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([CH2:11][O:12][C:13](=[O:15])[CH3:14])[CH2:6][O:7][C:8](=[O:10])[CH3:9])(=[O:3])[CH3:2].[CH3:24][O:25]C(Cl)Cl>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[C:1]([NH:4][C:5]([CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([CH:24]=[O:25])=[CH:20][CH:19]=1)([CH2:11][O:12][C:13](=[O:15])[CH3:14])[CH2:6][O:7][C:8](=[O:10])[CH3:9])(=[O:3])[CH3:2]
Reactant: COC(Cl)Cl
Reactant: CC(=O)NC(CCc1ccccc1)(COC(C)=O)COC(C)=O
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: CC(=O)NC(CCc1ccc(C=O)cc1)(COC(C)=O)COC(C)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-acetamido-1, 3-diacetoxy-2-(2-phenylethyl)propane (10 g) in anhydrous dichloromethane (150 ml) were added titanium tetrachloride (15.4 ml) and dichloromethyl methyl ether (5.63 ml) under a nitrogen atmosphere at −15° C. The mixture was stirred at room temperature for 2 hours, poured into ice water and extracted with chloroform. The chloroform layer was washed with water, a saturated aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous magnesium sulfate and the solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent; diisopropyl ether: ethyl acetate =1:1) to give the title compound (5.1 g) as a white solid, melting point 98-100° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:19]#[N:20])=[N:4][C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)=[CH:6][C:7]=1[NH2:8].[Cl:21][CH2:22][C:23](OCC)(OCC)OCC.[O-]S(C(F)(F)F)(=O)=O.[Yb+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O>C(#N)C>[Cl:21][CH2:22][C:23]1[NH:8][C:7]2[CH:6]=[C:5]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:16])[F:17])[CH:10]=3)[N:4]=[C:3]([C:19]#[N:20])[C:2]=2[N:1]=1
Reactant: CCOC(CCl)(OCC)OCC
Reactant: N#Cc1nc(-c2cccc(C(F)(F)F)c2)cc(N)c1N
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: CC#N
Product: N#Cc1nc(-c2cccc(C(F)(F)F)c2)cc2[nH]c(CCl)nc12

Procedure:
To a solution of 3,4-diamino-6-(3-trifluoromethyl-phenyl)-pyridine-2-carbonitrile (1.6 g) and 2-chloro-1,1,1-triethoxyethane (3.41 g,) in acetonitrile (40 ml) was added ytterbium triflate (180 mg, 5 mol %) and the mixture heated to reflux over-night. The mixture was concentrated under reduced pressure before partitioning between ethyl acetate (100 ml) and water (100 ml). The organic layer was dried over sodium sulfate and concentrated before addition of diethylether (20 ml). The precipitate was filtered and dried under a stream of air to afford the title compound. 1H NMR (MeOD) δ 8.40 (s, 1H) 8.32-8.38 (m, 2H) 8.13-8.15 (d, 2H) 7.68-7.78 (m, 2H) 4.96 (s, 2H). MS m/z 337.5, 339.1 (M+1).
Reaction SMILES: [CH2:1]([NH:4][C:5]([NH2:7])=[S:6])[CH:2]=[CH2:3].[CH3:8][O:9][CH2:10][CH2:11][Br:12]>>[Br-:12].[CH2:1]([NH+:4]=[C:5]([NH2:7])[S:6][CH2:11][CH2:10][O:9][CH3:8])[CH:2]=[CH2:3]
Reactant: COCCBr
Reactant: C=CCNC(N)=S
Product: C=CC[NH+]=C(N)SCCOC
Product: [Br-]
Yield: 69 %

Procedure:
Example 1 was repeated with -allylthiourea and 2-bromoethyl methyl ether, affording the title compound in a yield of 69%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]([S:13]([CH3:16])(=[O:15])=[O:14])=[N:10][C:9]=2[C:17]([NH:19][C:20]2[CH:36]=[CH:35][C:23]([O:24][C:25]3[CH:30]=[CH:29][N:28]=[C:27]([C:31]([NH:33][CH3:34])=[O:32])[CH:26]=3)=[CH:22][CH:21]=2)=[O:18])=[CH:4][CH:3]=1.[C:37]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH3:37])[C:11]([S:13]([CH3:16])(=[O:15])=[O:14])=[N:10][C:9]=2[C:17]([NH:19][C:20]2[CH:21]=[CH:22][C:23]([O:24][C:25]3[CH:30]=[CH:29][N:28]=[C:27]([C:31]([NH:33][CH3:34])=[O:32])[CH:26]=3)=[CH:35][CH:36]=2)=[O:18])=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: CNC(=O)c1cc(Oc2ccc(NC(=O)c3nc(S(C)(=O)=O)[nH]c3-c3ccc(F)cc3)cc2)ccn1
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CNC(=O)c1cc(Oc2ccc(NC(=O)c3nc(S(C)(=O)=O)n(C)c3-c3ccc(F)cc3)cc2)ccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73 %

Procedure:
To a chilled solution of 4-(4-(5-(4-fluorophenyl)-2-(methylsulfonyl)-1H-imidazole-4-carboxamido)phenoxy)-N-methylpicolinamide (200 mg, 0.39 mmol) and K2CO3 (119 mg, 0.86 mmol) in DMF (3.9 mL), was added methyl iodide (29 μL, 67 mg, 0.47 mmol). The reaction mixture was allowed to warm to room temperature and stirred overnight. TLC indicates completion of reaction with a single major product. Solvent was removed under reduced pressure and the crude material was dissolved in H2O (20 mL) and extracted with EtOAc (3×10 mL). The organic fractions were dried over Na2SO4 and concentrated. The crude material was purified by SiO2 chromatography (DCM/MeOH from 100% DCM to 94% DCM/6% MeOH, the desired product elutes in 97% DCM/3% MeOH) to yield a white solid (149 mg, 72% yield). 1HNMR (400 MHz, CDCl3): δ 8.88 (s, 1H), 8.33 (d, 1H, J=6.0 Hz), 7.97 (m, 1H), 7.66 (m, 3H), 7.50 (m, 1H), 7.43 (m, 2H), 7.22 (t, 2H, J=8.4 Hz), 7.03 (d, 2H, J=9.2 Hz), 3.79 (s, 3H), 3.50 (s, 3H), 2.98 (d, 3H, J=5.2 Hz). MS (ESI): m/z 524.0 [M+H]+