Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1C2C(=CC=CC=2)[C@@H](N)[C@H]1O.B.CCN(C1C=CC=CC=1)CC.[CH:24]([C:27]1[C:36]2[C:37](=[O:45])[O:38][C:39]3([CH2:44][CH2:43][O:42][CH2:41][CH2:40]3)[C:35]=2[C:34]2[C:33](=[O:46])[CH2:32][C:31]([CH3:48])([CH3:47])[CH2:30][C:29]=2[N:28]=1)([CH3:26])[CH3:25].CO>O1CCCC1>[OH:46][C@H:33]1[CH2:32][C:31]([CH3:48])([CH3:47])[CH2:30][C:29]2[N:28]=[C:27]([CH:24]([CH3:26])[CH3:25])[C:36]3[C:37](=[O:45])[O:38][C:39]4([CH2:40][CH2:41][O:42][CH2:43][CH2:44]4)[C:35]=3[C:34]1=2
Reactant: CC(C)c1nc2c(c3c1C(=O)OC31CCOCC1)C(=O)CC(C)(C)C2
Agent: B
Agent: N[C@@H]1c2ccccc2C[C@@H]1O
Solvent: CO
Solvent: CCN(CC)c1ccccc1
Solvent: C1CCOC1
Product: CC(C)c1nc2c(c3c1C(=O)OC31CCOCC1)[C@@H](O)CC(C)(C)C2
Temperature: 0 °C
Reaction time: 24 h

Procedure:
0.700 g (1R,2S)-(+)-cis-1-Amino-2-indanol are dissolved in 150 ml tetrahydrofurane and to this solution are dropwise added 6.12 ml of a borane-diethylaniline-complex. After completion of gas evolution the solution is cooled to 0° C. and 5.54 g 4-Isopropyl-7,7-dimethyl-2′,3′,5′,6′,7,8-hexahydro-3H-spiro[furo[3,4-c]quinoline-1,4′-pyran]-3,9(6H)-dione in 150 ml tetrahydrofurane are added dropwise. The temperature is raised during 2 hours to room temperature and the mixture is stirred for 24 hours. 10 ml Methanol are added dropwise and the solvents are evaporated in vacuo. The residue was dissolved in dichloromethane and is washed with 0.1 M hydrochloric acid and saturated aqueous sodium bicarbonate solution consecutively. The combined organic phases are dried with sodium sulphate and the solvents are evaporated in vacuo. The residue is chromatographed on silica gel (petrole ether/ethylacetate 100:0 to 3:2).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9](=[O:11])[CH3:10])[CH:5]=[CH:6][C:7]=1[F:8].[C:12]([Cu])#[N:13]>CN(C=O)C>[C:9]([C:4]1[CH:5]=[CH:6][C:7]([F:8])=[C:2]([CH:3]=1)[C:12]#[N:13])(=[O:11])[CH3:10]
Reactant: CC(=O)c1ccc(F)c(Br)c1
Reactant: N#C[Cu]
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(F)c(C#N)c1
Reaction time: 10 h

Procedure:
A solution of 1-(3-bromo-4-fluorophenyl)ethanone (81.3 g, 0.344 mol) in 300 mL of DMF was added CuCN (67.4 g, 0.749 mol) and the mixture was heated to reflux and stirred under N2 for 10 h. The reaction mixture was quenched with water and extracted with ether. The organic layer was washed with brine dried over Na2SO4 and concentrated in vacuum. The residue was purified with silica gel column chromatography to give the product 5-acetyl-2-fluorobenzonitrile.
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][C:11]([CH:14](Br)[CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:25][CH2:26][CH2:27][C:28]1[C:33]([OH:34])=[C:32]([C:35]([CH3:37])=[O:36])[CH:31]=[CH:30][C:29]=1[OH:38].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(C)=O>[C:35]([C:32]1[CH:31]=[CH:30][C:29]([O:38][CH:14]([C:11]2[CH:12]=[CH:13][C:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:9][CH:10]=2)[CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:28]([CH2:27][CH2:26][CH3:25])[C:33]=1[OH:34])(=[O:36])[CH3:37]
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Reactant: CCOC(=O)CCCCC(Br)c1ccc(Cc2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCc1c(OC(CCCCC(=O)OCC)c2ccc(Cc3ccccc3)cc2)ccc(C(C)=O)c1O

Procedure:
A solution of 9.75 g. of ethyl 6-(4-benzylphenyl)-6-bromo-hexanoate, 5.03 g. of 2,4-dihydroxy-3-propylacetophenone, 3.57 g. of potassium carbonate, and 1.0 g. of potassium iodide in 175 ml. of acetone was heated to reflux for about 86 hours. The reaction was evaporated in vacuo and the residue was purified by chromatography over silica gel eluting with a 0-20% ethyl acetate gradient in hexane. The appropriate fractions were pooled and evaporated, giving 2.5 g. of the desired product which was used for the subsequent hydrolysis. NMR was consistent with the compound ethyl 6-(4-acetyl-3-hydroxy-2-propylphenoxy)-6-(4-benzylphenyl)hexanoate.
Reaction SMILES: [CH3:1][O:2][Si:3]([O:10][CH3:11])([O:8][CH3:9])[C:4]([CH:6]=[CH2:7])=[CH2:5].[C:12]1(=[O:18])[O:17][C:15](=[O:16])[CH:14]=[CH:13]1>>[CH3:1][O:2][Si:3]([O:8][CH3:9])([O:10][CH3:11])[C:4]1[CH2:5][CH:13]2[C:12](=[O:18])[O:17][C:15](=[O:16])[CH:14]2[CH2:7][CH:6]=1
Reactant: O=C1C=CC(=O)O1
Reactant: C=CC(=C)[Si](OC)(OC)OC
Product: CO[Si](OC)(OC)C1=CCC2C(=O)OC(=O)C2C1
Reaction time: 1 h
Yield: 85 %

Procedure:
To 0.36 g (2.1 mmol) of 2-(trimethoxy)silyl-1,3-butadiene [II], were added 0.19 g (1.9 mmol) of maleic acid anhydride [III]at room temperature and stirred for one hour. After the reaction was over, the reaction product was separated on chromotography using silica gel and developing with a mixed solvent of n-hexane-diethyl ether to obtain 0.44 g of 4-(trimethoxy)silyl-1,2,3,6-tetrahydrophthalic acid anhydride [I](yield: 80 %, liquid).
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@H:17]4[CH2:19][O:18]4)=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1.[Cl:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27][NH2:28])=[CH:25][CH:24]=1>CN(C)C=O.C(O)C>[Cl:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27][NH:28][CH2:19][C@@H:17]([OH:18])[CH2:16][O:15][C:12]2[CH:11]=[CH:10][C:9]([C:6]3[C:5]4[CH:20]=[CH:21][C:2]([F:1])=[CH:3][C:4]=4[O:8][N:7]=3)=[CH:14][CH:13]=2)=[CH:25][CH:24]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: Fc1ccc2c(-c3ccc(OC[C@H]4CO4)cc3)noc2c1
Solvent: CCO
Solvent: CN(C)C=O
Product: O[C@H](CNCc1ccc(Cl)cc1)COc1ccc(-c2noc3cc(F)ccc23)cc1

Procedure:
The title compound is prepared from a mixture of (R)-6-fluoro-3-(4-oxiranylmethoxy-phenyl)-benzo[d]isoxazole in dimethylformamide and 4-chlorobenzylamine in ethanol, essentially as described above in Example 70. Purity by LC/MS=<100%, [M+H]+=427.
Reaction SMILES: [C:1]1([N:7]2[C:15](=[O:16])[C:14]3[C:9]([C:10]4[C:11](=[CH:17][NH:18][CH:19]=4)[NH:12][CH:13]=3)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(C(C)C)CC)(C)C.[CH3:29][N:30]=[C:31]=[O:32]>CN(C=O)C>[CH3:29][NH:30][C:31]([N:18]1[CH:19]=[C:10]2[C:11]([NH:12][CH:13]=[C:14]3[C:15](=[O:16])[N:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[N:8]=[C:9]32)=[CH:17]1)=[O:32]
Reactant: O=c1c2c[nH]c3c[nH]cc3c-2nn1-c1ccccc1
Reactant: CN=C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CNC(=O)n1cc2[nH]cc3c(=O)n(-c4ccccc4)nc-3c2c1
Reaction time: 8 h

Procedure:
One equivalent of pyrrolo-pyridine 12a was dissolved in DMF (0.1 M) under an atmosphere of nitrogen. 3 equivalents of di-iso-propylethylamine was added, followed by 1.5 equivalents of methylisocyanate and stirred overnight. The crude reaction mixture was concentrated to dryness and purification by column chromatography afforded the compound 13a. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.84 (d, J=3.52 Hz, 3H) 7.02-7.18 (m, 1H) 7.30-7.47 (m, 2H) 7.57-7.78 (m, 1H) 7.90-8.04 (m, 1H) 8.05-8.20 (m, 2H) 8.32-8.50 (m, 1H) 8.52-8.68 (m, 1H) 12.28-12.49 (m, 1H)
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][N:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH2:11](Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[Na+].[I-].[BH4-].[Na+]>C(#N)C.CO.O>[CH2:11]([N:7]1[CH2:8][CH2:9][C:10]2[N:1]=[CH:2][CH:3]=[CH:4][C:5]=2[CH2:6]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: BrCc1ccccc1
Reactant: c1cnc2ccncc2c1
Agent: [BH4-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: CC#N
Product: c1ccc(CN2CCc3ncccc3C2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution 1,6-naphthyridine (2.09 g, 16.05 mmol) in acetonitrile (50.0 ml) is added benzylbromide (3.30 g, 19.27 mmol, 1.2 eq.) and NaI (50.0 mg). The resulting mixture is refluxed under nitrogen overnight. Acetonitrile is evaporated, and the residue is washed with ether (20 ml), and dried in vacuo to give the quaternary salt, which is dissolved in a mixture of MeOH (90 ml) and water (30 ml). To the solution at 0° C. is added sodium borohydride (2.28 g, 96.5 mmol, about 6.0 eq.). The resulting mixture is warmed to rt, and stirred overnight. The organic solvent is evaporated, and the residue is taken up in water (50 ml), extracted with EtOAc (50 ml×3). The combined organic phase is washed with brine, dried over sodium sulfate, and concentrated. The crude product is purified by silica gel chromatography (Hexane/EtOAc 1:1 plus 4% TEA) to give the title compound. MS (+VE) m/z 225.1 (M++1).
Reaction SMILES: [C:1]1([CH:7]2[NH:12][CH2:11][CH2:10][N:9]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[C:26]([F:29])([F:28])[F:27])=[CH:16][CH:15]=3)[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O[BH-](O[C:40](=O)[CH3:41])OC(=O)C)(=O)C.[Na+].[C:44](O)(=O)C>ClC(Cl)C.CC(C)=O.ClCCl>[CH:40]([N:12]1[CH2:11][CH2:10][N:9]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]([F:28])([F:29])[F:27])=[CH:16][CH:15]=2)[CH2:8][CH:7]1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)([CH3:41])[CH3:44]
Reactant: CC(=O)O
Reactant: FC(F)(F)c1ccccc1-c1ccc(CN2CCNC(c3ccccc3)C2)cc1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(Cl)Cl
Solvent: CC(C)=O
Product: CC(C)N1CCN(Cc2ccc(-c3ccccc3C(F)(F)F)cc2)CC1c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 41 %

Procedure:
100 mg of 3-phenyl-1-(2′-trifluoromethyl-biphenyl-4-ylmethyl)-piperazine was dissolved in a 2:1 mixture of dichloroethane and acetone, 2 equiv. of sodium triacetoxyborohydride was added followed by 30 μL of acetic acid. The reaction was stirred at room temperature under nitrogen overnight. The reaction was diluted with 5 mL of dichloromethane. The reaction mixture was washed with 1M aqueous sodium hydroxide solution and brine, then dried over sodium sulfate, filtered and concentrated in vacuo. The crude residue was purified by column chromatography to afford the title compound. Yield 41% ES MS m/z 439.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]([N:22]([CH3:39])[C:23](=[O:38])[CH2:24][N:25]3[C:30]4[CH:31]=[C:32]([Cl:36])[C:33]([Cl:35])=[CH:34][C:29]=4[O:28][CH2:27][C:26]3=[O:37])[CH2:15][N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[N:40]([CH2:43][CH3:44])=[C:41]=[O:42].C(N(CC)CC)C>ClCCl>[Cl:36][C:32]1[C:33]([Cl:35])=[CH:34][C:29]2[O:28][CH2:27][C:26](=[O:37])[N:25]([CH2:24][C:23]([N:22]([CH:14]([C:11]3[CH:12]=[CH:13][C:8]([C:5]4[CH:4]=[CH:3][C:2]([NH:1][C:41]([NH:40][CH2:43][CH3:44])=[O:42])=[CH:7][CH:6]=4)=[CH:9][CH:10]=3)[CH2:15][N:16]3[CH2:17][CH2:18][O:19][CH2:20][CH2:21]3)[CH3:39])=[O:38])[C:30]=2[CH:31]=1
Reactant: CCN=C=O
Reactant: CN(C(=O)CN1C(=O)COc2cc(Cl)c(Cl)cc21)C(CN1CCOCC1)c1ccc(-c2ccc(N)cc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCNC(=O)Nc1ccc(-c2ccc(C(CN3CCOCC3)N(C)C(=O)CN3C(=O)COc4cc(Cl)c(Cl)cc43)cc2)cc1
Reaction time: 0.25 h
Yield: 69.6 %

Procedure:
To a solution of N-[1-(4′-amino-4-biphenylyl)-2-(4-morpholinyl)ethyl]-2-(6,7-dichloro-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)-N-methylacetamide (68 mg, 0.12 mmol) in dichloromethane (2 mL) was added isocyanatoethane (36.5 mg, 0.51 mmol). Triethylamine (36 mg, 0.36 mmol) was added, and the resultant mixture was stirred at room temperature for 18 h. The mixture was concentrated under reduced pressure, and the residue was purified by Gilson preparative HPLC (Xterra Prep RP, 30×100 mm, 45 mL/min, A: acetonitrile with 0.1% TFA B: water with 0.1% TFA, A: 20 to 50% over 15 min, UV detection at 214 nm) to give 53.5 mg (70%) of the title compound as an off white solid. MS (ES) m/e 640.2 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:51])([F:50])[C:3]1[CH:4]=[C:5]([CH:43]=[C:44]([C:46]([F:49])([F:48])[F:47])[CH:45]=1)[CH2:6][N:7]([CH2:25][C:26]1[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:28][C:27]=1[N:36]([CH2:41][CH3:42])[CH2:37][CH2:38][O:39][CH3:40])[C:8]1[N:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][CH:17]([C:20]([O:22]CC)=[O:21])[CH2:16][CH2:15]2)=[CH:10][N:9]=1.[OH-].[Na+].C(OCC)(=O)C>C(O)C>[F:51][C:2]([F:1])([F:50])[C:3]1[CH:4]=[C:5]([CH:43]=[C:44]([C:46]([F:49])([F:48])[F:47])[CH:45]=1)[CH2:6][N:7]([CH2:25][C:26]1[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:28][C:27]=1[N:36]([CH2:41][CH3:42])[CH2:37][CH2:38][O:39][CH3:40])[C:8]1[N:13]=[CH:12][C:11]([N:14]2[CH2:15][CH2:16][CH:17]([C:20]([OH:22])=[O:21])[CH2:18][CH2:19]2)=[CH:10][N:9]=1
Reactant: CCOC(=O)C1CCN(c2cnc(N(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)Cc3cc(C(F)(F)F)ccc3N(CC)CCOC)nc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCN(CCOC)c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(N2CCC(C(=O)O)CC2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.6 %

Procedure:
Ethyl 1-[2-((3,5-bis-trifluoromethyl-benzyl)-{2-[ethyl-(2-methoxy-ethyl)-amino]-5-trifluoromethyl-benzyl}-amino)-pyrimidin-5-yl]-piperidine-4-carboxylate (205 mg) is dissolved in ethanol (2 ml) and thereto is added 2N-aqueous sodium hydroxide solution (418 μl) and the mixture is stirred at room temperature overnight. Thereto are added ethyl acetate and a saturated aqueous citric acid solution, and the mixture is separated and the organic layer is washed with a saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=1:1→0:1) to give 1-[2-((3,5-bis-trifluoromethyl-benzyl)-{2-[ethyl-(2-methoxy-ethyl)-amino]-5-trifluoromethyl-benzyl}-amino)-pyrimidin-5-yl]-piperidine-4-carboxylic acid (155 mg). The resulting carboxylic acid is dissolved in ethanol (1 ml) and thereto is added 2N-aqueous sodium hydroxide solution (110 μl) and the reaction solution is concentrated under reduced pressure to give 1-[2-((3,5-bis-trifluoromethyl-benzyl)-{2-[ethyl-(2-methoxy-ethyl)-amino]-5-trifluoromethyl-benzyl}-amino)-pyrimidin-5-yl]-piperidine-4-carboxylic acid sodium salt (159 mg). MS (m/z): 706 [M−Na]−
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:7]=[N:8][CH:9]=[N:10][CH:11]=1.[CH3:12][I:13]>C(#N)C>[I-:13].[CH3:12][N+:10]1[CH:11]=[C:6]([CH:2]2[O:1][CH2:5][CH2:4][O:3]2)[CH:7]=[N:8][CH:9]=1
Reactant: c1ncc(C2OCCO2)cn1
Reactant: CI
Solvent: CC#N
Product: C[n+]1cncc(C2OCCO2)c1
Product: [I-]
Reaction time: 8 h

Procedure:
5-(1,3-dioxolan-2-yl)pyrimidine (0.573 g, 3.77 mmol) and acetonitrile (3 ml) were stirred under dry nitrogen in a bomb tube with rubber seal. Methyl iodide (0.7 ml, 11.30 mmol) was added, the bomb properly sealed and stirring continued at room temperature overnight. This resulted in a yellow suspension which was vacuum-filtered to obtain yellow powdery crystals. The powder was put in drying pistol to give 0.881 g (84%) yellow crystals Recrystallization from ethanol gave fine crystals mp 188°-190° C. 300 MHz nmr in dimethyl sulfoxide (DMSO) indicated product. Microanalysis calc: C 32.67, H 3.77, N 9.53; found: C 32.66, H 3.81, N 9.42.
Reaction SMILES: N([O-])=O.[Na+].[N:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:15][CH:14]([CH2:16][O:17][C:18]2[CH:24]=[CH:23][C:21](N)=[CH:20][CH:19]=2)[O:13][C:12]1=[O:25].[BrH:26].[C:27]([O:31][CH3:32])(=[O:30])[CH:28]=[CH2:29]>CO.CC(C)=O>[N:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:15][CH:14]([CH2:16][O:17][C:18]2[CH:24]=[CH:23][C:21]([CH2:29][CH:28]([Br:26])[C:27]([O:31][CH3:32])=[O:30])=[CH:20][CH:19]=2)[O:13][C:12]1=[O:25]
Reactant: Nc1ccc(OCC2CN(c3ccccn3)C(=O)O2)cc1
Reactant: Br
Reactant: C=CC(=O)OC
Agent: O=N[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC(C)=O
Product: COC(=O)C(Br)Cc1ccc(OCC2CN(c3ccccn3)C(=O)O2)cc1
Yield: 53 %

Procedure:
A 0.90 g quantity of sodium nitrite was added to a solution of 3.30 g of 4-[3-(2-pyridyl)-2-oxooxazolidin-5-yl]methoxyaniline obtained in Reference Example 21 in 40 ml of methanol, 10 ml of acetone and 8.0 g of 47% hydrobromic acid. The mixture was stirred with ice-cooling for 0.5 hour. To the mixture was added 6.4 ml of methyl acrylate, and 256 mg of cuprous oxide was added thereto at 40° C. and the mixture was stirred at the same temperature for 20 minutes. The reaction mixture was concentrated under reduced pressure and the obtained residue was extracted with ethyl acetate. The extract was washed successively with aqueous ammonia and an aqueous solution of sodium chlorides, dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and purified by hexane-ethyl acetate gradient elution to give 2.7 g of the title compound (compound 196) as an oil (yield 53%).
Reaction SMILES: [CH3:1][C:2]([C:6]1[CH:10]=[C:9]([NH:11][C:12]2[N:20]=[CH:19][CH:18]=[CH:17][C:13]=2[C:14](O)=[O:15])[N:8]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:22]=2[O:28][CH3:29])[N:7]=1)([CH3:5])[CH2:3][CH3:4].C(Cl)(=O)C(Cl)=O.[CH3:36]N.C[C:39]#[N:40]>CN(C)C=O.O>[CH3:5][C:2]([C:6]1[CH:10]=[C:9]([NH:11][C:12]2[N:20]=[CH:19][CH:18]=[CH:17][C:13]=2[C:14]([N:40]([CH3:39])[CH3:36])=[O:15])[N:8]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:22]=2[O:28][CH3:29])[N:7]=1)([CH3:1])[CH2:3][CH3:4]
Reactant: CN
Reactant: CCC(C)(C)c1cc(Nc2ncccc2C(=O)O)n(-c2cccc(F)c2OC)n1
Reactant: CC#N
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: O
Product: CCC(C)(C)c1cc(Nc2ncccc2C(=O)N(C)C)n(-c2cccc(F)c2OC)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70 %

Procedure:
To a solution 2-{[3-(1,1-dimethylpropyl)-1-(3-fluoro-2-methoxyphenyl)-1H-pyrazol-5-yl]amino}nicotinic acid, (Example 140, synthesized in a manner similar to that of Example 8, 50 mg, 0.13 mmol) in CH3CN (1 mL) was added 1 drop of dimethyl formamide followed by oxalyl chloride (9 μL, 0.13 mmol). The mixture was stirred at rt for 1 h, followed by addition of methyl amine (16 μL of a 40% solution in water, 0.25 mmol). The mixture was again stirred at rt for 1 h and concentrated to dryness. The residue was dissolved in methanol (1 mL), filtered through an octyl solid phase extraction tube and subjected to HPLC purification with a gradient elution from 10% to 90% acetonitrile in water to afford 33 mg (70%) of the desired product. 1H NMR (300 MHz, CD2Cl2) δ 8.30 (d, 1H), 8.23 (s, 1H), 7.50 (d, 1H), 7.15-7.30 (m, 3H), 6.80 (t, 1H), 6.60 (s, 1H), 3.77 (s, 3H), 2.95 (br s, 6H), 1.70 (q, 2H), 1.32 (s, 6H), 0.85 (t, 3H). ES-MS m/z 426.2 (MH+); HPLC RT (min) 3.57.
Reaction SMILES: [OH:1][CH2:2][C:3]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[S:4].[CH3:12][Si:13](Cl)([CH3:15])[CH3:14].C(N(CC)CC)C>C1COCC1.C(OCC)C>[CH3:12][Si:13]([CH3:15])([CH3:14])[O:1][CH2:2][C:3]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[S:4]
Reactant: C[Si](C)(C)Cl
Reactant: OCC(=S)Oc1ccccc1
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: C1CCOC1
Product: C[Si](C)(C)OCC(=S)Oc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.3 %

Procedure:
A solution of phenyl (hydroxy)thioacetate (0.237 g, 1.41 mmol) in THF (14.0 ml) was treated with trimethylsilyl chloride (0.643 ml, 5.07 mmol) and triethylamine (0.726 ml, 5.21 mmol) at room temperature. After stirring for 2 h at RT, the mixture was diluted with ethyl ether, washed with pH 7 phosphate buffer, dried (Na2SO4) and evaporated to give phenyl (trimethylsilyloxy)thioacetate (0.2315 g, 93%).
Reaction SMILES: [OH-].[Na+].CO.[F:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:12]1[C:16]([C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=O)=[CH:19][CH:18]=2)=[CH:15][CH:14]=[N:13]1.[F:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33]C#N)=[CH:29][CH:28]=1>O>[F:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2[O:25][N:23]=[C:20]3[CH:21]=[CH:22][C:17]([C:16]4[N:12]([C:7]5[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=5[F:5])[N:13]=[CH:14][CH:15]=4)=[CH:18][C:19]=23)=[CH:29][CH:28]=1
Reactant: N#CCc1ccc(F)cc1
Reactant: O=[N+]([O-])c1ccc(-c2ccnn2-c2ccccc2F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Fc1ccc(-c2onc3ccc(-c4ccnn4-c4ccccc4F)cc23)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.8 %

Procedure:
A mixture of sodium hydroxide (282 mg, 7.06 mmol) and MeOH (2.5 ml) was allowed to stir for 1 h at room temperature, 1-(2-fluoro-phenyl)-5-(4-nitro-phenyl)-1H-pyrazole (intermediate B) (200 mg, 706 μmol) and commercially available 2-(4-fluoro-phenyl)-acetonitrile (143 mg, 127 μl, 1.06 mmol) were added, and the reaction mixture was allowed to stir for 2 h at 60° C. The reaction mixture was poured into water (20 ml) and extracted with diethyl ether (2×40 ml). The combined organic layers were washed with brine (30 ml), dried (MgSO4) and evaporated. The crude product was further purified by column chromatography on silica gel (toluene/ethyl acetate 95:5) followed by crystallization (ethyl acetate/heptane) to yield the title compound as a light yellow solid (184 mg, 70%), MS (ISP) m/z=374.1 [(M+H)+], mp 171° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[O:10][C:9](=[O:11])[NH:8][C:5]2=[N:6][CH:7]=1.[CH3:12][CH:13]1[CH2:18][CH2:17][N:16]([C:19](Cl)=[O:20])[CH2:15][CH2:14]1>>[Br:1][C:2]1[CH:3]=[C:4]2[O:10][C:9](=[O:11])[N:8]([C:19]([N:16]3[CH2:17][CH2:18][CH:13]([CH3:12])[CH2:14][CH2:15]3)=[O:20])[C:5]2=[N:6][CH:7]=1
Reactant: CC1CCN(C(=O)Cl)CC1
Reactant: O=c1[nH]c2ncc(Br)cc2o1
Product: CC1CCN(C(=O)n2c(=O)oc3cc(Br)cnc32)CC1

Procedure:
100 mg (0.46 mmol) of 6-bromo-3H-oxazolo[4,5-b]pyridin-2-one were reacted in analogy to Example 6 with 150 mg (0.93 mmol) of 4-methylpiperidin-1-carbonyl chloride. Yield: 78 mg (50%), M+H+: 340.09.
Reaction SMILES: [F:1][CH2:2][C:3]1[N:4]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([CH3:19])=[CH:11][CH:10]=2)[C:5]([SH:8])=[N:6][N:7]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:27][C:28]([NH:30][C:31]1[CH:36]=[CH:35][C:34]([S:37](=[O:40])(=[O:39])[NH2:38])=[CH:33][C:32]=1[CH3:41])=[O:29].O>CN(C=O)C>[F:1][CH2:2][C:3]1[N:4]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([CH3:19])=[CH:11][CH:10]=2)[C:5]([S:8][CH2:27][C:28]([NH:30][C:31]2[CH:36]=[CH:35][C:34]([S:37](=[O:40])(=[O:39])[NH2:38])=[CH:33][C:32]=2[CH3:41])=[O:29])=[N:6][N:7]=1
Reactant: Cc1cc(S(N)(=O)=O)ccc1NC(=O)CCl
Reactant: Cc1ccc(-n2c(S)nnc2CF)c2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(S(N)(=O)=O)ccc1NC(=O)CSc1nnc(CF)n1-c1ccc(C)c2ccccc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 50 %

Procedure:
In a solution of 5-fluoromethyl-4-(4-methyl-naphthalen-1-yl)-4H-[1,2,4]triazole-3-thiol (89 mg, 0.33 mmol), K2CO3 (50.0 mg, 0.36 mmol) in DMF (2.0 mL) was added 2-chloro-N-(2-methyl-4-sulfamoyl-phenyl)-acetamide (87 mg, 0.33 mmol). The reaction mixture was stirred at room temperature for 16 h. Upon the completion of the reaction, H2O (2.0 mL) was added to the reaction and stirred till precipitation occurred and filtered. Purified by reverse phase HPLC resulted product as a solid in (53.3 mg, 50% yield). NMR (DMSO, 300 MHz) δ 9.84 (broad s, 1H), 8.18 (d, J=8.4 Hz, 1H), 7.71-7.53 (m, 7H), 7.26 (s, 2H), 7.10 (d, J=8.7 Hz, 1H), 5.34 (dd, J=12.0, 27.3 Hz, 1H), 5.18 (dd, J=12.3, 26.4 Hz, 1H), 4.22 (s, 2H), 2.75 (s, 3H), 2.25 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:8][C:9]([OH:11])=[O:10])=[N:4][CH:5]=[CH:6][N:7]=1.C(N1C=CN=C1)(N1[CH:18]=[CH:17]N=C1)=O.C(O)C>CN(C)C=O>[CH2:17]([O:10][C:9](=[O:11])[CH2:8][C:3]1[C:2]([Cl:1])=[N:7][CH:6]=[CH:5][N:4]=1)[CH3:18]
Reactant: O=C(O)Cc1nccnc1Cl
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: CCO
Product: CCOC(=O)Cc1nccnc1Cl
Reaction time: 1 h
Yield: 83 %

Procedure:
To a solution of (3-chloro-pyrazin-2-yl)-acetic acid (2.00 g) in N,N-dimethylformamide (“DMF”) (20 ml) was added 1,1′-carbonyldiimidazole (1.88 g) and the mixture stirred for 1 hour. To the reaction mixture was added ethanol (20 ml) and the mixture stirred for 1 hour at ambient temperature. The reaction mixture was concentrated and then purified by chromatography on silica gel (eluent 5-95% ethyl acetate in isohexane) to give (3-chloro-pyrazin-2-yl)-acetic acid ethyl ester (1.93 g). 1H-NMR (400 MHz, CDCl3): 8.50 (s, 1H), 8.30 (s, 1H), 4.20 (q, 2H), 4.00 (s, 2H), 1.30 (t, 3H) ppm.