Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS([C:4]1[N:5]=[CH:6][C:7]2[CH:12]=[C:11]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:10]([CH3:20])[C:8]=2[N:9]=1)=O.[CH:21]1([NH2:26])[CH2:25][CH2:24][CH2:23][CH2:22]1>>[CH:21]1([NH:26][C:4]2[N:5]=[CH:6][C:7]3[CH:12]=[C:11]([CH2:13][C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[N:10]([CH3:20])[C:8]=3[N:9]=2)[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: Cn1c(Cc2ccccc2)cc2cnc(S(C)=O)nc21
Reactant: NC1CCCC1
Product: Cn1c(Cc2ccccc2)cc2cnc(NC3CCCC3)nc21
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A mixture of the sulfoxide (50 mg) from Step 3 and cyclopentylamine (1 mL) was stirred at 100° C. overnight. Excess cyclopentylamine was removed and the residue was purified by preparative TLC (25% EtOAc/hexanes) to give the desired product (26 mg). MS: 307.3 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:8])[CH2:4][CH2:5][CH2:6]Cl.C[O-].[Na+].[CH2:12]([SH:15])[CH2:13][CH3:14]>O>[CH3:1][O:2][C:3](=[O:8])[CH2:4][CH2:5][CH2:6][S:15][CH2:12][CH2:13][CH3:14]
Reactant: CCCS
Reactant: COC(=O)CCCCl
Agent: C[O-]
Agent: [Na+]
Solvent: O
Product: CCCSCCCC(=O)OC
Reaction time: 1 h

Procedure:
Into a 1 liter reaction flask equipped with electric stirrer, reflux condenser, thermometer, addition funnel and cooling bath are placed 68.2 grams (0.5 moles) of methyl-4-chlorobutyrate having the structure: ##STR129## The methyl-4-chlorobutyrate is cooled to 20° C. The mixture of sodium methoxide and n-propyl mercaptan is then poured into the addition funnel. Over a period of 30 minutes while maintaining the pot temperature at 20°-30° C. the premix of n-propyl mercaptan and sodium methoxide is added slowly to the methyl-4-chlorobutyrate reactant. The reaction is exothermic and requires cooling. At the end of the 0.5 hour period, the reaction mass is stirred for a period of 1 hour and the temperature of the reaction mass is permitted to rise to 43° C. The reaction mass is then combined with 500 ml water and transferred to a separatory funnel. The resulting product is then extracted with three 50 ml portions of methylene dichloride. The methylene dichloride extract is then dried over anhydrous sodium sulfate, filtered and distilled on a micro Vigreux column yielding the following fractions:
Reaction SMILES: [CH3:1][CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][NH:5][C:4]2[CH:13]=[CH:14][CH:15]=[CH:16][C:3]1=2.C1C(=O)N([Br:24])C(=O)C1>CC(C)=O>[Br:24][C:15]1[CH:14]=[CH:13][C:4]2[NH:5][CH2:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[CH:2]([CH3:1])[C:3]=2[CH:16]=1
Reactant: CC1c2ccccc2CNc2ccccc21
Reactant: O=C1CCC(=O)N1Br
Solvent: CC(C)=O
Product: CC1c2ccccc2CNc2ccc(Br)cc21
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
A solution of 6,11-dihydro-11-methyl-5H-dibenzo[b,e]azepine (4) (8 g, 38.3 mmol) in aceton (1500 mL) was cooled to 0° C. and NBS (N-bromosuccinamide; 6.81 g, 38.3 mmol) was added. The reaction mixture was stirred for 20 min at 0° C., quenched by addition of aqueous NaHCO3 (300 mL) and concentrated under reduced pressure. The product was extracted into ethyl acetate which was washed with brine, dried (Na2SO4) and concentrated under reduced pressure. The crude product was purified by column chromatography on silica (Heptane:Ethyl acetate=8:2) to give 2-bromo-6,11-dihydro-11-methyl-5H-dibenzo[b,e]azepine (4, R8═Br; 32 g, 97%) Data: (m/z)=288/290 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([N:8]2[N:12]=[N:11][C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[CH3:19][O:20]C1C=CC=C(N)C=1.N1C=CC=CC=1C=O>>[CH3:19][O:20][C:2]1[CH:3]=[C:4]([N:8]2[N:12]=[N:11][C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1cccc(N)c1
Reactant: Clc1cccc(-n2nnc(-c3ccccn3)n2)c1
Agent: O=Cc1ccccn1
Product: COc1cccc(-n2nnc(-c3ccccn3)n2)c1

Procedure:
Following the procedure described in EXAMPLE 1 for the synthesis of 2-[2-(3-chlorophenyl)-2H-tetrazol-5-yl]pyridine, m-anisidine (135 mg, 1.1 mmol) and pyridine-2-carboxaldehyde (118 mg, 1.1 mmol) were employed to obtain 2-[2-(3-methoxyphenyl)-2H-tetrazol-5-yl]pyridine as an orange solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH2:19])([CH3:4])([CH3:3])[CH3:2].C([O:25][C:26](=O)[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[CH:37]=[N:38][CH:39]=[CH:40][C:41]=2[CH3:42])[CH:31]=1)=[O:29])(C)(C)C>>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH:19][C:26](=[O:25])[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[CH:37]=[N:38][CH:39]=[CH:40][C:41]=2[CH3:42])[CH:31]=1)=[O:29])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Reactant: Cc1ccncc1-c1cccc(C(=O)CC(=O)OC(C)(C)C)c1
Product: Cc1ccncc1-c1cccc(C(=O)CC(=O)Nc2cc(C(F)(F)F)c(C)cc2NC(=O)OC(C)(C)C)c1

Procedure:
The title compound was prepared from (2-amino-5-methyl-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J20) (218 mg, 0.75 mmol) and 3-[3-(4-methyl-pyridin-3-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K30) (234 mg, 0.75 mmol) according to the general procedure M. Obtained as a white solid (301 mg, 76%).
Reaction SMILES: [CH3:1][C@@H:2]([OH:7])[CH2:3][C@H:4]([OH:6])[CH3:5].C(N(CC)CC)C.[CH3:15][S:16](Cl)(=[O:18])=[O:17]>ClCCl>[CH3:15][S:16]([O:6][C@@H:4]([CH2:3][C@H:2]([O:7][S:16]([CH3:15])(=[O:18])=[O:17])[CH3:1])[CH3:5])(=[O:18])=[O:17]
Reactant: C[C@@H](O)C[C@@H](C)O
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@H](C[C@@H](C)OS(C)(=O)=O)OS(C)(=O)=O
Reaction time: 3 h

Procedure:
A solution of (2R,4R)-2,4-pentanediol (15.0 g), triethylamine (45.2 mL) and dichloromethane (350 mL) is cooled at a temperature close to 0° C. Methanesulfonyl chloride (24.5 mL) is added dropwise. The mixture is stirred for 3 h at a temperature close to 0° C., hydrolysed with a 1.5 N aqueous hydrochloric solution (100 mL) and extracted with dichloromethane. The organic extracts are pooled, washed with a saturated aqueous solution of sodium hydrogenocarbonate, then a saturated aqueous solution of sodium chloride, dried over magnesium sulphate and concentrated under reduced pressure to give 36.06 g of (2R,4R)-2,4-pentanediol dimethanesulfonate as a brown oil used without further purification.
Reaction SMILES: [F:1][C:2]1[C:7](B(O)O)=[CH:6][C:5]([CH2:11][N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[CH:4][N:3]=1.Cl[C:19]1[N:24]=[C:23]([CH3:25])[N:22]=[C:21]([NH2:26])[N:20]=1.C([O-])(=O)C.[K+]>CCO.O>[F:1][C:2]1[C:7]([C:19]2[N:24]=[C:23]([CH3:25])[N:22]=[C:21]([NH2:26])[N:20]=2)=[CH:6][C:5]([CH2:11][N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[CH:4][N:3]=1
Reactant: OB(O)c1cc(CN2CCOCC2)cnc1F
Reactant: Cc1nc(N)nc(Cl)n1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: Cc1nc(N)nc(-c2cc(CN3CCOCC3)cnc2F)n1
Temperature: 100 °C
Yield: 25.6 %

Procedure:
To a 20 mL microwave reaction tube was added 2-fluoro-5-(morpholinomethyl)pyridin-3-ylboronic acid (Example 129, Step 3) (2.00 g, 8.33 mmol), 4-chloro-6-methyl-1,3,5-triazin-2-amine (Example 9, 0.501 g, 3.47 mmol), Am-Phos (Aldrich, 0.124 g, 0.175 mmol) and potassium acetate (Aldrich, 1.14 g, 11.6 mmol) in EtOH (10 mL) and water (1 mL). The mixture was degassed by bubbling argon through for 10 min. The tube was heated in a microwave reactor (Biotage) at 100° C. for 20 min. After the reaction mixture was cooled to room temperature, insoluble material was removed via filtration. The filtrate was partitioned between saturated aqueous sodium chloride (60 mL) and 10% isopropanol in chloroform (60 mL). The aqueous phase was extracted with 10% isopropanol in chloroform (2×60 mL). The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by silica gel column chromatography (100 g, eluent: iPrOH in CHCl3 0% to 25%) to afford 4-(2-fluoro-5-(morpholinomethyl)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (0.27 g, 26% yield) as a white foam. 1H NMR (400 MHz, CDCl3) δ ppm 8.46 (dd, J=9.00, 2.35 Hz, 1H) 8.27 (s, 1H) 5.83 (br. s., 2H) 3.70-3.75 (m, 4H) 3.56 (s, 2H) 2.54 (s, 3H) 2.44-2.50 (m, 4H). m/z (ESI, positive ion): 305.0 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH2:4][N:5]([C:10]2[C:15]([Cl:16])=[CH:14][C:13]([C:17]([F:20])([F:19])[F:18])=[CH:12][N:11]=2)[NH:6][C:7]=1[CH:8]=O)#[N:2].C(O)(=O)[CH2:22][C:23]([OH:25])=[O:24]>N1CCCCC1.N1C=CC=CC=1>[C:1]([C:3]1[CH2:4][N:5]([C:10]2[C:15]([Cl:16])=[CH:14][C:13]([C:17]([F:20])([F:19])[F:18])=[CH:12][N:11]=2)[NH:6][C:7]=1[CH:8]=[CH:22][C:23]([OH:25])=[O:24])#[N:2]
Reactant: O=C(O)CC(=O)O
Reactant: N#CC1=C(C=O)NN(c2ncc(C(F)(F)F)cc2Cl)C1
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: N#CC1=C(C=CC(=O)O)NN(c2ncc(C(F)(F)F)cc2Cl)C1

Procedure:
A stirred solution of 0.3 gram (0.001 mole) of 4-cyano-5-formyl-2-(3-chloro-5-trifluoromethylpyridin-2-yl)-1H-pyrazole, 0.2 gram (0.002 mole) of malonic acid, two drops of piperidine, and 3 mL of pyridine was heated at reflux for about 18 hours. After this time, the reaction mixture was cooled and was concentrated under reduced pressure to a residue. The residue was stirred with excess aqueous 2N hydrochloric acid and ethyl acetate. The organic layer was separated and washed with aqueous 2N hydrochloric acid and then with water. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residue. The residue was triturated several times with petroleum ether, and each time the supernatent liquid was discarded. The resultant solid was dried, yielding 3-[4-cyano-2-(3-chloro-5-trifluoromethylpyridin-2-yl)-1H-pyrazol-5-yl]acrylic acid. The nmr spectrum was consistent with the proposed structure and was identical to the nmr spectrum of this compound prepared by the method of Example 4.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[C:17]([C:24]([NH:26][CH2:27][C:28]([O:30][CH3:31])=[O:29])=[O:25])[CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O>CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[C:17]([C:24]([NH:26][CH2:27][C:28]([O:30][CH3:31])=[O:29])=[O:25])[CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)CNC(=O)c1cc(N2CCCN(C(=O)OC(C)(C)C)CC2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Solvent: O
Product: COC(=O)CNC(=O)c1cc(N2CCCN(C(=O)OC(C)(C)C)CC2)ccc1N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-[3-(Methoxycarbonylmethyl-aminocarbonyl)-4-nitro-phenyl]-[1,4]diazepane-1-carboxylic acid tert-butyl ester (38.4 g) was dissolved in methanol and 4 g of 10% (wt/wt) palladium on carbon catalyst was added with water (1000 mL) under a nitrogen atmosphere. The mixture was then degassed before stirring under 1 atmosphere of hydrogen gas at room temperature for approximately 8 hours. At this time, the reaction mixture was filtered through celite and washed with copious volumes of methanol. The filtrate was concentrated in vacuo, To the residue was added acetonitrile before evaporation of the solvent. To give 4-[4-amino-3-(methoxycarbonylmethyl-aminocarbonyl)-phenyl]-[1,4]diazepane-1-carboxylic acid tert-butyl ester as a dark green oil: 34.05 g (95%).
Reaction SMILES: [CH3:1][N:2]([CH3:31])[C:3](=[O:30])[CH2:4][N:5]1[C:14]2[C:9](=[N:10][CH:11]=[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[CH:13]=2)[C:8]([OH:23])=[C:7]([C:24](OCC)=[O:25])[C:6]1=[O:29].[NH2:32][C@@H:33]([CH3:36])[CH2:34][OH:35]>>[CH3:31][N:2]([CH3:1])[C:3](=[O:30])[CH2:4][N:5]1[C:14]2[C:9](=[N:10][CH:11]=[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[CH:13]=2)[C:8]([OH:23])=[C:7]([C:24]([NH:32][C@@H:33]([CH3:36])[CH2:34][OH:35])=[O:25])[C:6]1=[O:29]
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC(=O)N(C)C)c1=O
Reactant: C[C@H](N)CO
Product: C[C@@H](CO)NC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC(=O)N(C)C)c1=O

Procedure:
This compound was prepared from ethyl 1-[2-(dimethylamino)-2-oxoethyl]-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate and (2S)-2-amino-1-propanol employing methods similar to those described in Example 245 and was purified by reverse phase preparative HPLC (C-18 stationary phase; 10-100% CH3CN/water/0.1% formic acid mobile phase). The product was obtained as an off-white solid: 1H NMR (d6-DMSO) δ 10.23 (1H, d, J=8 Hz), 8.50 (1H, s), 7.77 (1H, s), 7.32 (2H, dd, J=8.6, 6 Hz), 7.12 (2H, t, J=8.6 Hz), 5.12 (2H, m), 4.98 (1H, t, J=5 Hz), 4.11 (2H, s), 4.03 (1H, m), 3.44 (2H, m), 3.12 (3H, s), 2.82 (3H, s), 1.15 (3H, d, J=7 Hz); HRMS calcd for C23H25FN4O5+H+: 457.1887. Found: 457.1879.
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[C:7]([CH2:9][OH:10])[NH:6][N:5]=1)([O-:3])=[O:2].C([O-])([O-])=O.[Cs+].[Cs+].[CH3:17][CH:18]1[CH2:20][O:19]1>ClCCl>[OH:10][CH2:9][C:7]1[N:6]([CH2:17][CH:18]([OH:19])[CH3:20])[N:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:8]=1
Reactant: CC1CO1
Reactant: O=[N+]([O-])c1cc(CO)[nH]n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Product: CC(O)Cn1nc([N+](=O)[O-])cc1CO
Temperature: 30 °C
Reaction time: 48 h
Yield: 50 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer was charged with (3-nitro-1H-pyrazol-5-yl)methanol (0.57 g, 4.0 mmol), Cs2CO3 (261 mg, 0.8 mmol), and 2-methyloxirane (20 mL). The mixture was stirred at 30° C. for 2 days. The mixture was cooled to room temperature and diluted with dichloromethane (100 mL). The resulting mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica-gel column chromatography eluting with 30:1 dichloromethane/methanol to afford 250a (0.40 g, 50%) as a white solid. MS-ESI: [M+H]+ 202.3
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[O:7][CH:6]([CH3:13])[CH2:5]2.[CH2:14](N(CC)CC)[CH3:15].C([B-](F)(F)F)=C.[K+]>CCO.C(Cl)(Cl)Cl>[CH:14]([C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[O:7][CH:6]([CH3:13])[CH2:5]2)=[CH2:15]
Reactant: CCN(CC)CC
Reactant: CC1Cc2cc(Br)ccc2C(=O)O1
Agent: C=C[B-](F)(F)F
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: C=Cc1ccc2c(c1)CC(C)OC2=O
Temperature: 100 °C

Procedure:
A solution of 6-bromo-3-methyl-3,4-dihydro-1H-isochromen-1-one (2.4 g, 9.96 mmol) and triethylamine (2.78 ml, 19.91 mmol) in EtOH (39.8 ml) was added to a microwave vial containing Cl2Pd(dppf)2-DCM (0.406 g, 0.498 mmol) and potassium vinyltrifluoroborate (2.000 g, 14.93 mmol). The contents of the vial were heated to 100° C. for 1 hour after which the mixture was cooled, diluted with chloroform (50 mL) and washed with aqueous ammonium chloride (25 mL). The organic layer was then dried over magnesium sulfate, filtered and the solvent was evaporated under reduced pressure. MPLC purification (15-60% EtOAc/Hex) gave 6-ethenyl-3-methyl-3,4-dihydro-1H-isochromen-1-one.
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]([OH:14])=[O:13])=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[Cl:15][C:16]1[C:17]([N:22]2[C:26]([C:27](O)=O)=[CH:25][C:24]([C:30]([F:33])([F:32])[F:31])=[N:23]2)=[N:18][CH:19]=[CH:20][CH:21]=1.N1C=CC=CC=1.CS(Cl)(=O)=O>O1CCCC1>[Cl:15][C:16]1[C:17]([N:22]2[C:26]([C:27]3[O:13][C:12](=[O:14])[C:11]4[C:10]5[C:5](=[CH:6][CH:7]=[CH:8][N:9]=5)[CH:4]=[CH:3][C:2]=4[N:1]=3)=[CH:25][C:24]([C:30]([F:33])([F:31])[F:32])=[N:23]2)=[N:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=C(O)c1cc(C(F)(F)F)nn1-c1ncccc1Cl
Reactant: Nc1ccc2cccnc2c1C(=O)O
Agent: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: O=c1oc(-c2cc(C(F)(F)F)nn2-c2ncccc2Cl)nc2ccc3cccnc3c12
Temperature: 0 °C
Reaction time: 48 h
Yield: 15.2 %

Procedure:
To a suspension of 500 mg (2.66 mmol) of 7-amino-quinoline-8-carboxylic acid in 20 mL of anhydrous tetrahydrofuran at 10° C., is added 775 mg (2.66 mmol) of 2-(3-chloro-pyridin-2-yl)-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid followed by 1.07 mL (13.28 mmol) of pyridine. Then the suspension is cooled to 0° C. and 830 μL (10.63 mmol) of methanesulfonyl chloride are added dropwise. The mixture is stirred at ambient temperature for 48 hours. Then the solvent is evaporated and the residue is precipitated with a minimum of water. The filtration gave 180 mg of product after drying on high vacuum pump. The filtrate is evaporated and the residue obtained is purified by flash chromatography to afford 100 mg more of product as a solid. The overall yield is 24%; LC/MS:444/446 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][CH2:10][O:11][CH3:12])=[CH:4][CH:3]=1.[C:13](N1C=CN=C1)([N:15]1[CH:19]=[CH:18][N:17]=[CH:16]1)=[O:14]>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH2:9][CH2:10][O:11][CH3:12])[C:13]([N:15]2[CH:19]=[CH:18][N:17]=[CH:16]2)=[O:14])=[CH:6][CH:7]=1
Reactant: COCCNc1ccc(F)cc1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: COCCN(C(=O)n1ccnc1)c1ccc(F)cc1
Temperature: 80 °C
Reaction time: 28 h

Procedure:
To a 50 mL round-bottomed flask was added 4-fluoro-N-(2-methoxyethyl)-benzenamine (512 mg, 3026 μmol, from step 1), 1,1′-carbonyldiimidazole (736 mg, 4539 μmol, Aldrich), THF (2 mL). The reaction mixture was stirred at 80° C. for 28 h. The solvent was removed in vacuo and the residue was purified by silica gel chromatography, eluting with 80% EtOAc/hexanes to give N-(4-fluoro-phenyl)-N-(2-methoxyethyl)-1H-imidazole-1-carboxamide. MS (ESI pos. ion) m/z: 264 (M+1).
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH3:6])[C:3](Cl)=[O:4].[NH2:8][C:9]1[C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13]([N+:19]([O-:21])=[O:20])[C:12]([Br:22])=[CH:11][CH:10]=1>N1C=CC=CC=1.C(Cl)Cl>[Br:22][C:12]1[C:13]([N+:19]([O-:21])=[O:20])=[C:14]([C:9]([NH:8][C:3](=[O:4])[C:2]([CH3:7])([CH3:6])[CH3:1])=[CH:10][CH:11]=1)[C:15]([O:17][CH3:18])=[O:16]
Reactant: COC(=O)c1c(N)ccc(Br)c1[N+](=O)[O-]
Reactant: CC(C)(C)C(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1c(NC(=O)C(C)(C)C)ccc(Br)c1[N+](=O)[O-]
Reaction time: 3 h
Yield: 90.7 %

Procedure:
Trimethylacetyl chloride (5.09 g) was added to a solution of methyl 6-amino-3-bromo-2-nitro-benzoate (prepared according to Brock et al Tertrahedron, 1963, 19, 1911, 7.74 g) in pyridine (40 mL) and DCM (40 mL) and left to stand at room temperature for 3 hours. The mixture was concentrated in vacuo and the residue was dissolved in DCM and 1M hydrochloric acid and filtered through a phase separator. The filtrate was concentrated in vacuo and the residue was triturated with pentane. The solid was filtered to give methyl 3-bromo-6-(2,2-dimethylpropionyl-amino)-2-nitrobenzoate (9.17 g).
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].[NH2:5][C:6]1[CH:7]=[CH:8][C:9]([Cl:36])=[C:10]([CH:35]=1)[C:11]([C:13]1[C:18]([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:17][C:16]([CH3:34])=[CH:15][N:14]=1)=[O:12]>C1COCC1.CC(O)=O>[Cl:29][C:26]1[CH:27]=[CH:28][C:23]([S:20]([NH:19][C:18]2[C:13]([C:11](=[O:12])[C:10]3[CH:35]=[C:6]([NH:5][C:3]([NH:2][CH3:1])=[O:4])[CH:7]=[CH:8][C:9]=3[Cl:36])=[N:14][CH:15]=[C:16]([CH3:34])[CH:17]=2)(=[O:22])=[O:21])=[CH:24][C:25]=1[C:30]([F:33])([F:32])[F:31]
Reactant: Cc1cnc(C(=O)c2cc(N)ccc2Cl)c(NS(=O)(=O)c2ccc(Cl)c(C(F)(F)F)c2)c1
Reactant: CN=C=O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CNC(=O)Nc1ccc(Cl)c(C(=O)c2ncc(C)cc2NS(=O)(=O)c2ccc(Cl)c(C(F)(F)F)c2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 38.1 %

Procedure:
Methylisocyanate (17 μL, 0.235 mmol) was added to N-[2-(5-amino-2-chloro-benzoyl)-5-methyl-pyridin-3-yl]-4-chloro-3-trifluoromethyl-benzene sulfonamide (59 mg, 0.117 mmol) in THF (2 mL) and AcOH (0.5 mL) and stirred at room temperature for 4 h. The reaction mixture was directly purified by preparative HPLC (20-80% acetonitrile in water) to afford 4-chloro-N-{2-[2-chloro-5-(3-methyl-ureido)-benzoyl]-5-methyl-pyridin-3-yl}-3-trifluoromethyl-benzene sulfonamide (25 mg) in 38% yield. 1H NMR (400 MHz, CDCl3+CD3OD) δ 8.14 (m, 2H), 7.95 (m, 2H), 7.63 (d, 1H), 7.58 (dd, 1H), 7.41 (dd, 1H), 7.19 (d, 1H), 2.76 (s, 3H), 2.42 (s, 3H); ESMS m/z (relative intensity): 561 (M+H)+ (100).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16](I)=[CH:15][CH:14]=2)[S:9][CH:10]=1)=[O:5])C.[Cl:20][C:21]1[C:26](B(O)O)=[CH:25][CH:24]=[CH:23][N:22]=1>>[Cl:20][C:21]1[C:26]([C:16]2[CH:15]=[CH:14][C:13]([O:12][CH2:11][C:8]3[S:9][CH:10]=[C:6]([C:4]([OH:3])=[O:5])[N:7]=3)=[CH:18][CH:17]=2)=[CH:25][CH:24]=[CH:23][N:22]=1
Reactant: CCOC(=O)c1csc(COc2ccc(I)cc2)n1
Reactant: OB(O)c1cccnc1Cl
Product: O=C(O)c1csc(COc2ccc(-c3cccnc3Cl)cc2)n1

Procedure:
2-[4-(2-Chloro-pyridin-3-yl)-phenoxymethyl]-thiazole-4-carboxylic acid was prepared using the procedure described above for the preparation of Example 23 from 2-(4-iodo-phenoxymethyl)-thiazole-4-carboxylic acid ethyl ester (of Intermediate 2) and 2-chloropyridine-3-boronic acid (available from Lancaster Synthesis Ltd., Morecambe, UK). Mass spectrum MH+=347.
Reaction SMILES: [CH2:1]([C@H:3]1[N:12]([C:13](=[O:22])[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:23])[CH:10]=2)[NH:5][C:4]1=[O:24])[CH3:2].Br[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30].[I-].[K+].C([C@H]1N(C(=O)C2C=CC=C(OC)C=2)C2C(=CC(F)=CC=2)N(C)C1=O)C>>[CH2:1]([C@H:3]1[N:12]([C:13](=[O:22])[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:23])[CH:10]=2)[N:5]([CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[C:4]1=[O:24])[CH3:2]
Reactant: CCCCCBr
Reactant: CC[C@@H]1C(=O)Nc2ccc(F)cc2N1C(=O)c1ccc(OC)cc1
Agent: CC[C@@H]1C(=O)N(C)c2cc(F)ccc2N1C(=O)c1cccc(OC)c1
Agent: [I-]
Agent: [K+]
Product: CCCCCN1C(=O)[C@@H](CC)N(C(=O)c2ccc(OC)cc2)c2cc(F)ccc21
Yield: 55 %

Procedure:
(3R)-3-Ethyl-6-fluoro-4-(4-methoxybenzoyl)-3,4-dihydroquinoxalin-2(1H)-one (see Example 8) was treated with 1-bromopentane and potassium iodide (1.2 eq) according to the procedure for the preparation of (3R)-3-ethyl-7-fluoro-4-(3-methoxybenzoyl)-1-methyl-3,4-dihydroquinoxalin-2(1H)-one (see Example 4) to yield (3R)-3-ethyl-6-fluoro-4-(4-methoxybenzoyl)-1-pentyl-3,4-dihydroquinoxalin-2(1H)-one (55%). MS (ESI) m/z 399 ([M+H]+).
Reaction SMILES: [F:1][CH:2]([F:19])[O:3][CH2:4][C@@H:5]([O:7][C:8]1[CH:9]=[C:10]([CH:15]=[C:16]([OH:18])[CH:17]=1)[C:11]([O:13][CH3:14])=[O:12])[CH3:6].[N:20]1([C:24]([C:26]2[CH:31]=[N:30][C:29](Cl)=[CH:28][N:27]=2)=[O:25])[CH2:23][CH2:22][CH2:21]1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>C(#N)C>[N:20]1([C:24]([C:26]2[N:27]=[CH:28][C:29]([O:18][C:16]3[CH:15]=[C:10]([CH:9]=[C:8]([O:7][C@@H:5]([CH3:6])[CH2:4][O:3][CH:2]([F:19])[F:1])[CH:17]=3)[C:11]([O:13][CH3:14])=[O:12])=[N:30][CH:31]=2)=[O:25])[CH2:23][CH2:22][CH2:21]1
Reactant: COC(=O)c1cc(O)cc(O[C@@H](C)COC(F)F)c1
Reactant: O=C(c1cnc(Cl)cn1)N1CCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COC(=O)c1cc(Oc2cnc(C(=O)N3CCC3)cn2)cc(O[C@@H](C)COC(F)F)c1
Temperature: 140 °C
Reaction time: 5 h
Yield: 74.7 %

Procedure:
A mixture of methyl 3-({(1S)-2-[(difluoromethyl)oxy]-1-methylethyl}oxy)-5-hydroxybenzoate (0.28 g, 1.01 mmol), 2-(azetidin-1-ylcarbonyl)-5-chloropyrazine (201 mg, 1.01 mmol) and potassium carbonate (280 mg, 2.03 mmol) in acetonitrile (5 mL) was stirred in a microwave reactor at 140° C. for 5 hours. The reaction mixture was reduced in vacuo, ethyl acetate (50 mL) added and the organics washed with water (50 mL), brine (50 mL), dried (MgSO4), filtered and reduced in vacuo. The crude oil was chromatographed on silica, eluting with 20 to 70% ethyl acetate in isohexane, to give the desired compound as a colourless oil (330 mg). 1H NMR δ (CDCl3): 1.38 (d, 3H), 2.37 (quin, 2H), 3.90 (s, 3H), 3.93-4.04 (m, 2H), 4.26 (d, 2H), 4.61-4.70 (m, 3H), 6.25 (t, 1H), 6.95 (t, 1H), 7.43-7.44 (m, 1H), 7.49-7.50 (m, 1H), 8.32 (d, 1H), 8.85 (d, 1H); m/z 438 (M+H)+