Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:24]1[N:25]([CH2:32][C@:33]2([CH3:36])[CH2:35][O:34]2)[CH:26]=[C:27]([N+:29]([O-:31])=[O:30])[N:28]=1>CN(C=O)C>[CH3:35][C@@:33]1([CH2:36][O:1][C:2]2[CH:7]=[CH:6][C:5]([N:8]3[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]3)=[CH:4][CH:3]=2)[O:34][C:24]2=[N:28][C:27]([N+:29]([O-:31])=[O:30])=[CH:26][N:25]2[CH2:32]1
Reactant: C[C@@]1(Cn2cc([N+](=O)[O-])nc2Cl)CO1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(O)cc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(OC[C@@]3(C)Cn4cc([N+](=O)[O-])nc4O3)cc2)CC1
Temperature: 70 °C
Reaction time: 0.33 h
Yield: 44.2 %

Procedure:
Tert-butyl 4-(4-hydroxyphenyl)piperazine-1-carboxylate (13.5 g, 48.8 mmol) was dissolved in DMF (100 ml). To the solution, sodium hydride (2.15 g, 53.7 mmol) was added at room temperature, and the solution was stirred for 20 minutes at 70° C. To the solution, (R)-2-chloro-1-(2-methyloxiran-2-ylmethyl)-4-nitroimidazole prepared in Example 12 (10.6 g, 48.8 mmol) was added with cooling on ice-bath, and the solution was stirred for further 20 minutes at 80° C. To the reaction mixture, ice-water was added, and the solution was stirred vigorously. The precipitates were filtered off, washed with water and dissolved in methylene chloride. The solution was washed with a saturated saline solution, dried over magnesium sulfate and then filtered. The resulting filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride/methanol=100/1) and then crystallized from methylene chloride-ethyl acetate to afford tert-butyl (R)-4-[4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethoxy)phenyl]piperazine-1-carboxylate (9.9 g, yield 44%) as a white powder.
Reaction SMILES: [CH2:1]([O:19][CH2:20][CH:21]([O:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50]/[CH:51]=[CH:52]\[CH2:53]/[CH:54]=[CH:55]\[CH2:56][CH2:57][CH2:58][CH2:59][CH3:60])[CH:22]([OH:41])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]/[CH:31]=[CH:32]\[CH2:33]/[CH:34]=[CH:35]\[CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].Cl.[CH3:62][N:63]([CH3:70])[CH2:64][CH2:65][CH2:66][C:67](O)=[O:68].CCN=C=NCCCN(C)C.Cl.CCN(C(C)C)C(C)C>ClCCl.CN(C1C=CN=CC=1)C>[CH3:62][N:63]([CH3:70])[CH2:64][CH2:65][CH2:66][C:67]([O:41][CH:22]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]/[CH:31]=[CH:32]\[CH2:33]/[CH:34]=[CH:35]\[CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[CH:21]([O:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50]/[CH:51]=[CH:52]\[CH2:53]/[CH:54]=[CH:55]\[CH2:56][CH2:57][CH2:58][CH2:59][CH3:60])[CH2:20][O:19][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:68]
Reactant: CCCCC/C=C\C/C=C\CCCCCCCCOCC(OCCCCCCCC/C=C\C/C=C\CCCCC)C(O)CCCCCCCC/C=C\C/C=C\CCCCC
Reactant: CN(C)CCCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCCC/C=C\C/C=C\CCCCCCCCOCC(OCCCCCCCC/C=C\C/C=C\CCCCC)C(CCCCCCCC/C=C\C/C=C\CCCCC)OC(=O)CCCN(C)C
Temperature: 25 °C
Yield: 46 %

Procedure:
To a solution of (12Z,15Z)-1,2-bis((9Z,12Z)-octadeca-9,12-dienyloxy)henicosa-12,15-dien-3-ol (450 mg, 0.54 mmol), 4-(dimethylamino)butanoic acid hydrochloride (135 mg, 0.8 mmol), EDCI hydrochloride (153 mg, 0.8 mmol), DIPEA (260 μL, 1.6 mmol) in anhydrous dichloromethane (10 mL) was added DMAP (5 mg). The solution was refluxed for 3 hours, cooled to room temperature and concentrated in vacuo to dryness. The reaction mixture was purified by column chromatography on silica gel 60 (eluted with a gradient of 100% hexanes to 1:1 hexanes/ethyl acetate) to afford (12Z,15Z)-1,2-bis((9Z,12Z)-octadeca-9,12-dienyloxy)henicosa-12,15-dien-3-yl 4-(dimethylamino)butanoate as a colorless oil (236 mg). 5.43-5.29 (m, 2H), 5.05-4.98 (m, 1H), 3.68-3.64 (m, 1H), 3.52-3.46 (m, 1H), 3.40 (t, 2H, J=6.7 Hz), 2.78 (t, 6H, J=6.4 Hz), 2.46-2.35 (m, 4H), 2.32 (s, 6H), 2.09-2.02 (m, 12H), 1.91-1.81 (m, 2H), 1.70-1.48 (m, 6H), 1.41-1.23 (m, 50H), 0.90 (t, 9H, J=6.7 Hz).
Reaction SMILES: C[N:2](/[CH:4]=[C:5](/[C:11](=O)[C:12]([CH3:15])([CH3:14])[CH3:13])\[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.Cl.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25]N)=[CH:21][C:20]=1[C:27]([F:30])([F:29])[F:28]>>[C:12]([C:11]1[N:25]([C:22]2[CH:23]=[CH:24][C:19]([Cl:18])=[C:20]([C:27]([F:30])([F:28])[F:29])[CH:21]=2)[N:2]=[CH:4][C:5]=1[C:6]([O:8][CH2:9][CH3:10])=[O:7])([CH3:15])([CH3:14])[CH3:13]
Reactant: NNc1ccc(Cl)c(C(F)(F)F)c1
Reactant: CCOC(=O)/C(=C\N(C)C)C(=O)C(C)(C)C
Agent: Cl
Product: CCOC(=O)c1cnn(-c2ccc(Cl)c(C(F)(F)F)c2)c1C(C)(C)C

Procedure:
Ethyl 5-tert-butyl-1-(4-chloro-3-(trifluoromethyl)phenyl)-1H-pyrazole-4-carboxylate was prepared from (Z)-ethyl 2-((dimethylamino)methylene)-4,4-dimethyl-3-oxopentanoate (Intermediate#83) and (4-chloro-3-(trifluoromethyl)phenyl)hydrazine hydrochloride by the same process used for Intermediate#116.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([OH:12])=[O:11])[CH:8]=2)[CH:3]=[CH:2]1.[CH3:13][Si](C=[N+]=[N-])(C)C>CO.ClCCl>[CH3:13][O:11][C:10]([C:7]1[CH:8]=[C:9]2[C:4]([CH:3]=[CH:2][NH:1]2)=[CH:5][CH:6]=1)=[O:12]
Reactant: O=C(O)c1ccc2cc[nH]c2c1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1ccc2cc[nH]c2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of indole-6-carboxylic acid (39.5 g, 245 mmol) in methanol (200 mL) and dichloromethane (750 mL) was added 2 M (trimethylsilyl)diazomethane in hexanes (160 mL, 320 mmol) dropwise over 1 hour. The reaction was stirred at room temperature overnight. The following day the reaction was concentrated to a thick brown crude oil that was diluted with ethyl acetate (500 mL) and washed with saturated aqueous sodium bicarbonate (2×200 mL), saturated aqueous sodium chloride (2×200 mL) and dried over sodium sulfate. The mixture was then filtered and the filtrate concentrated under reduced pressure to form a suspension. The suspension was filtered to provide 43 g of the desired compound as an off-white solid.
Reaction SMILES: C(OC([NH:8][C:9]([CH3:36])([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:10][O:11][CH2:12][C:13]1[CH:14]=[C:15]([CH:19]=[C:20]([C:22]2([C:27]#[N:28])[CH2:26][CH2:25][CH2:24][CH2:23]2)[CH:21]=1)[C:16]([OH:18])=O)=O)(C)(C)C.[CH3:37][CH:38]([NH2:42])[C:39]#[C:40][CH3:41]>>[NH2:8][C:9]([CH3:36])([CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[CH2:10][O:11][CH2:12][C:13]1[CH:14]=[C:15]([CH:19]=[C:20]([C:22]2([C:27]#[N:28])[CH2:26][CH2:25][CH2:24][CH2:23]2)[CH:21]=1)[C:16]([NH:42][CH:38]([C:39]#[C:40][CH3:41])[CH3:37])=[O:18]
Reactant: CC#CC(C)N
Reactant: CC(COCc1cc(C(=O)O)cc(C2(C#N)CCCC2)c1)(Cc1ccccc1)NC(=O)OC(C)(C)C
Product: CC#CC(C)NC(=O)c1cc(COCC(C)(N)Cc2ccccc2)cc(C2(C#N)CCCC2)c1

Procedure:
Prepared from 3-((2-tert-butoxycarbonylamino-2-methyl-3-phenylpropoxy)methyl)-5-(1-cyanocyclopentyl)benzoic acid and pent-3-yn-2-amine using a similar procedure as described for the preparation of Example 20. HRMS ES calculated for C29H35N3O2: 458.2802, found: 458.2813.
Reaction SMILES: [N+:1]([C:4]1[CH:19]=[CH:18][C:7]([C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)([CH3:11])[C:9]#[N:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].S(=O)(=O)(O)[OH:21].[OH-].[Na+]>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:8]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)([CH3:11])[C:9]([NH2:10])=[O:21])=[CH:18][CH:19]=1)([O-:3])=[O:2]
Reactant: CC(C#N)(c1ccccc1)c1ccc([N+](=O)[O-])cc1
Reactant: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: CC(C(N)=O)(c1ccccc1)c1ccc([N+](=O)[O-])cc1

Procedure:
) A mixture of 0.020 mol of p-nitro-α-phenylhydratroponitrile and 28 ml of concentrated sulfuric acid solution (90%) is heated in a water-bath for 3.5 hours. The reaction mixture is poured onto crushed ice, neutralized with a sodium hydroxide solution and the product is extracted with chloroform. The organic layer is washed with water, dried and evaporated in vacuo and the residue is crystallized from ether, yielding 2.4 grams of p-nitro-α-phenylhydratropamide. (interm. 7)
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:4]=1Br.[C:16]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].CC([O-])(C)C.[Na+].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1.O>[C:19]([O:18][C:16]([N:23]1[CH2:28][CH2:27][N:26]([C:4]2[CH:5]=[CH:6][C:7]([C:9]([F:12])([F:11])[F:10])=[CH:8][C:3]=2[C:2]([F:15])([F:14])[F:1])[CH2:25][CH2:24]1)=[O:17])([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: FC(F)(F)c1ccc(Br)c(C(F)(F)F)c1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
A mixture of 5 mmol 2,4-bis(trifluoromethyl)bromobenzene, 6 mmol N-BOC-piperazine, 8 mmol NaOtBu, 0.5 mmol rac-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl and 1 mmol tris-(dibenzylideneacetone)dipalladium chloroform complex in 20 ml toluene was stirred at 80° C. for 3 hours. The mixture was then diluted with water, extracted with ethyl acetate, dried and purified by column chromatography (SiO2; cyclohexane/ethyl acetate 9:1) to yield the title compound as a yellowish oil.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]2[CH2:18][CH2:17][CH2:16][CH2:15][O:14]2)(=O)=O)=CC=1.[C:19]([O-:22])(=[S:21])[CH3:20].[K+]>CN(C=O)C.C(OCC)(=O)C>[O:14]1[CH2:15][CH2:16][CH2:17][CH2:18][C@H:13]1[CH2:12][S:21][C:19](=[O:22])[CH3:20]
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2CCCCO2)cc1
Reactant: CC([O-])=S
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)SC[C@@H]1CCCCO1
Temperature: 25 °C
Reaction time: 18 h
Yield: 111.1 %

Procedure:
To a solution of 3.90 g (14.41 mmol) of (2S)-oxan-2-ylmethyl 4-methylbenzene-1-sulfonate in DMF (40 mL) are added 3.29 g (28.83 mmol) potassium thioacetate at room temperature. After complete addition, the reaction is stirred at room temperature for 18 h, then heated to 50° C. for further 20 h. The reaction mixture is diluted with ethyl acetate (250 mL) and washed with saturated aqueous NaHCO3 solution (2×100 mL) and water (2×100 mL). The organic layer is dried (MgSO4), filtered and the filtrate is concentrated under reduced pressure to afford 2.79 g of 1-{[(2S)-oxan-2-ylmethyl]sulfanyl}ethan-1-one. Yield: 93%; ES-MS: m/z 175 [M+H]; 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 1.17-1.36 (2 H, m), 1.42-1.59 (2 H, m), 1.63-1.72 (1 H, m), 1.79-1.88 (1 H, m), 2.34 (3 H, s), 2.84-2.93 (1 H, m), 3.10 (1 H, dd, J=13.73, 4.27 Hz), 3.30-3.47 (2 H, m), 3.98 (1 H, dt, J=11.41, 2.08 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([O:6][C:7]2[N:12]=[CH:11][C:10]([NH:13][C:14](=[O:24])[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[N+:21]([O-])=O)=[CH:9][CH:8]=2)=[C:4]([CH3:27])[CH:3]=1.[H][H]>C(O)C.[OH-].[OH-].[Pd+2]>[NH2:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[C:14]([NH:13][C:10]1[CH:11]=[N:12][C:7]([O:6][C:5]2[CH:25]=[CH:26][C:2]([Cl:1])=[CH:3][C:4]=2[CH3:27])=[CH:8][CH:9]=1)=[O:24]
Reactant: [H][H]
Reactant: Cc1cc(Cl)ccc1Oc1ccc(NC(=O)c2ccccc2[N+](=O)[O-])cn1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(Cl)ccc1Oc1ccc(NC(=O)c2ccccc2N)cn1

Procedure:
N-(6-(4-chloro-2-methyl-phenoxy)-pyridin-3-yl)-2-nitro-benzamide (301 mg, 0.7 mmol) was dissolved in 95% ethanol (4 mL) and treated with 20% palladium hydroxide on carbon (Pearlman's catalyst, 50 mg) and subjected to a hydrogen atmosphere (40 psi) for 2 hours. The catalyst was removed by filtration and the solvents were removed in vacuo. The product was purified by chromatography on SiO2 using 1:1 ethyl acetate/hexanes as eluent. MS (m/z): 353/355 (M+H)+; C19H16N3O2Cl requires 353.8.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20]Br)[NH:12][C:11]([N:22]2[CH:26]=[N:25][CH:24]=[N:23]2)=[N:10]1.[NH:27]1[CH2:31][CH2:30][CH2:29][C@H:28]1[C:32]([OH:34])=[O:33]>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[N:10]=[C:11]([N:22]2[CH:26]=[N:25][CH:24]=[N:23]2)[NH:12][C:13]([CH2:20][N:27]2[CH2:31][CH2:30][CH2:29][C@H:28]2[C:32]([OH:34])=[O:33])=[C:14]1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)C1=C(CBr)NC(n2cncn2)=NC1c1ccc(F)cc1Br
Reactant: O=C(O)[C@@H]1CCCN1
Product: CCOC(=O)C1=C(CN2CCC[C@H]2C(=O)O)NC(n2cncn2)=NC1c1ccc(F)cc1Br
Yield: 33.5 %

Procedure:
Ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(1H-1,2,4-triazol-1-yl)-1,4-dihydropyrimidine-5-carboxylate (0.5 g, 1.03 mmol) was reacted with (S)-pyrrolidine-2-carboxylic acid (0.12 g, 1.03 mmol) according to the procedure as described in Example 28 to give the title compound as a yellow solid (0.18 g, 33%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [OH:1][CH:2]([CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12](I)=[CH:11][CH:10]=1)[CH2:3][C:4]([OH:6])=[O:5].C(=O)([O-])[O-].[Cs+].[Cs+].[N+:22]([C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1)([O-:24])=[O:23]>CN(C)C=O.[Pd]>[OH:1][CH:2]([CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:29]2[CH:28]=[CH:27][CH:26]=[C:25]([N+:22]([O-:24])=[O:23])[CH:30]=2)=[CH:11][CH:10]=1)[CH2:3][C:4]([OH:6])=[O:5]
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Reactant: O=C(O)CC(O)CCc1ccc(I)cc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=C(O)CC(O)CCc1ccc(-c2cccc([N+](=O)[O-])c2)cc1
Temperature: 100 °C
Yield: 31.7 %

Procedure:
3-Hydroxy-5-(4iodo-phenyl)-pentanoic acid (Intermediate 10, 16 mg, 50 μmol), cesium carbonate (40 mg, 125 μmol), 3-nitrophenylboronic acid (10 mg, 60 μmol) and FibreCat™ 1001 (20 mg, 2.7% w/w palladium) were suspended in dimethylformamide (200 μL) and then heated at 100° C. for 1 hour. The reaction was cooled to room temperature and the solvent removed under reduced pressure. The residue was partitioned between 10% methanol/dichloromethane and 2 M HCl then the phases separated. The organic phase was evaporated under reduced pressure and the residue purified via mass directed HPLC to give the title compound (5 mg, 32%) as a white solid. LC/MS: 3.18 min; z/e 314, calcd (M−1) 314. 1H NMR (400 MHz: DMSO-d6): 8.4 (1 H), 8.15 (2 H), 7.7 (3 H), 7.35 (2 H), 3.85 (1 H), 2.7 (2 H), 2.32 (2 H), 1.7 (2 H).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][C:8]([OH:10])=O)=[CH:4][C:3]=1[C:13]([F:16])([F:15])[F:14].Cl.[NH2:18][N:19]1[CH2:25][C:23](=[O:24])[NH:22][C:20]1=[O:21]>O=S(Cl)Cl.N1C=CC=CC=1>[Cl:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][C:8]([NH:18][N:19]2[CH2:25][C:23](=[O:24])[NH:22][C:20]2=[O:21])=[O:10])=[CH:4][C:3]=1[C:13]([F:16])([F:15])[F:14]
Reactant: O=C(O)C=Cc1ccc(Cl)c(C(F)(F)F)c1
Reactant: NN1CC(=O)NC1=O
Agent: Cl
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Product: O=C(C=Cc1ccc(Cl)c(C(F)(F)F)c1)NN1CC(=O)NC1=O

Procedure:
A stirred mixture of 4-chloro-3-trifluoromethylcinnamic acid (50 g, 0.2 mole) in 200 ml of SOCl2 was heated at reflux for 2 hours. The excess SOCl2 was removed in vacuo and the residue flushed with dry benzene. The residue was treated with a mixture of 1-aminohydantoin hydrochloride (30 g, 0.2 mole) in 400 ml of pyridine. The reaction mixture was heated at reflux for 3 hours; then poured into ice/HCl. The crude residue (74 g, 100%) was recrystallized from CH3NO2 (Darco) to give an analytical sample melting at 270°-273°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH:11]=[C:12]([F:15])[CH2:13]Br)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[F:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][C:18]=1[O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH:11]=[C:12]([F:15])[CH2:13][C:20]3[CH:21]=[CH:22][C:17]([F:16])=[C:18]([O:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH:19]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: OB(O)c1ccc(F)c(Oc2ccccc2)c1
Reactant: FC(=CC1(c2ccc(Cl)cc2)CC1)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: FC(=CC1(c2ccc(Cl)cc2)CC1)Cc1ccc(F)c(Oc2ccccc2)c1
Temperature: 25 °C
Yield: 63 %

Procedure:
Under a nitrogen atmosphere, a mixture of 1-(p-chlorophenyl)-1-(3-bromo-2-fluoropropenyl)cyclopropane, (Z)—(0.434 g, 1.5 mmol), 4-fluoro-3-phenoxybenzene-boronic acid (0.452 g, 1.95 mmol), potassium carbonate (1.86 g, 13.5 mmol) and bis(dibenzylideneacetone)-palladium(O) (Pd(dba)2, 4.3 mg, 0.075 mmol) in toluene is heated at 80° C. for one hour, cooled to room temperature, diluted with water, and filtered through diatomaceous earth. The phases are separated and the aqueous phase is extracted with ethyl acetate. The organic phase and ethyl acetate extract are combined, washed with water, dried over anhydrous sodium sulfate and concentrated in vacuo to obtain a residue. Flash column chromatography of the residue using silica gel and a 3:20 methylene chloride/hexanes solution gives the title product as an oil (0.274 g, 63% yield) which is identified by NMR spectral analyses.
Reaction SMILES: C[O:2][C:3](=[O:27])[CH2:4][C:5]1[S:9][C:8]([NH:10][C:11](=[O:20])[C:12]2[CH:17]=[C:16]([Br:18])[CH:15]=[CH:14][C:13]=2[OH:19])=[N:7][C:6]=1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[OH-].[Na+].Cl>CO>[Br:18][C:16]1[CH:15]=[CH:14][C:13]([OH:19])=[C:12]([CH:17]=1)[C:11]([NH:10][C:8]1[S:9][C:5]([CH2:4][C:3]([OH:27])=[O:2])=[C:6]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:7]=1)=[O:20]
Reactant: COC(=O)Cc1sc(NC(=O)c2cc(Br)ccc2O)nc1-c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)Cc1sc(NC(=O)c2cc(Br)ccc2O)nc1-c1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 76 %

Procedure:
{2-[(5-Bromo-2-hydroxybenzoyl)amino]-4-phenylthiazol-5-yl}acetic acid methyl ester (75 mg, 0.17 mmol) was dissolved in methanol (5 mL). 2N Sodium hydroxide (0.5 mL, 1 mmol) was added, and the mixture was stirred at room temperature for 12 hours. The reaction mixture was poured into 2N hydrochloric acid and extracted with ethyl acetate. After the ethyl acetate layer was washed successively with water and brine, dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure. The obtained residue was suspended and washed with n-hexane-ethyl acetate under heating at reflux to give the title compound (56 mg, 77.3%) as a light yellow white crystal.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[Cl:6][C:7]1[CH:8]=[C:9]([CH:13]([CH2:15][NH:16][C:17]([CH3:20])([CH3:19])[CH3:18])[OH:14])[CH:10]=[CH:11][CH:12]=1.C(N(CC)CC)C>ClCCl>[Cl:1][CH2:2][C:3]([N:16]([CH2:15][CH:13]([C:9]1[CH:10]=[CH:11][CH:12]=[C:7]([Cl:6])[CH:8]=1)[OH:14])[C:17]([CH3:20])([CH3:18])[CH3:19])=[O:4]
Reactant: CC(C)(C)NCC(O)c1cccc(Cl)c1
Reactant: O=C(Cl)CCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)N(CC(O)c1cccc(Cl)c1)C(=O)CCl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Chloroacetyl chloride (0.21 g, 0.15 ml) in dichloromethane (5 ml) was added dropwise, under nitrogen to a stirred, ice-cooled solution of 3-chloro-α-[[[1,1-dimethylethyl]amino]methyl]benzenemethanol (0.5 g) and triethylamine (0.38 g, 0.53 ml) in dichloromethane (40 ml). The reaction mixture was stirred at ambient temperature for 2 h., washed with hydrochloric acid (2N), brine, dried (MgSO4), evaporated and chromatographed on silica. Elution with chloroform gave α-chloro-N-[2-(3-chlorophenyl)-2-hydroxyethyl]-N-[1,1-dimethylethyl]acetamide as a colourless oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[S:10][C:11]([NH:38]C(=O)OC(C)(C)C)=[C:12]([C:14](=[O:37])[NH:15][C:16]2[CH:17]=[N:18][N:19]([CH3:36])[C:20]=2[CH:21]2[CH2:27][CH2:26][CH:25]([NH:28]C(=O)C(F)(F)F)[CH:24]([F:35])[CH2:23][CH2:22]2)[N:13]=1.Cl.O1CCOCC1.C([O-])([O-])=O.[K+].[K+]>CO>[NH2:38][C:11]1[S:10][C:9]([C:3]2[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=2[F:8])=[N:13][C:12]=1[C:14]([NH:15][C:16]1[CH:17]=[N:18][N:19]([CH3:36])[C:20]=1[CH:21]1[CH2:22][CH2:23][C@@H:24]([F:35])[C@H:25]([NH2:28])[CH2:26][CH2:27]1)=[O:37]
Reactant: Cn1ncc(NC(=O)c2nc(-c3c(F)cccc3F)sc2NC(=O)OC(C)(C)C)c1C1CCC(F)C(NC(=O)C(F)(F)F)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CO
Product: Cn1ncc(NC(=O)c2nc(-c3c(F)cccc3F)sc2N)c1C1CC[C@@H](N)[C@H](F)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a suspension of tert-butyl 2-(2,6-difluorophenyl)-4-(5-(4-fluoro-5-(2,2,2-trifluoroacetamido)cycloheptyl)-1-methyl-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamate (Diastereomer 2) (28 mg, 0.042 mmol) in MeOH (2 mL) was added a solution of HCl in dioxane (4 M, 1.1 mL, 4.24 mmol) and the mixture was stirred at room temperature for 18 hr. The solvent was removed under reduced pressure and the residue was dissolved in MeOH/water (3 mL/3 mL), treated with K2CO3 (29 mg, 0.21 mmol) and heated at 60° C. for 18 hr. The MeOH was removed under reduced pressure and the aqueous residue was extracted with 5% MeOH/DCM (2×40 mL). The organic layers were combined, passed through a phase separation cartridge and concentrated under reduced pressure to give 358 (Diastereomer 2) as an off-white solid (17 mg, 86% over two steps). 1H NMR (400 MHz, CDCl3) δ 8.44 (s, 1H), 7.76 (s, 1H), 7.34-7.29 (m, 1H), 7.03 (t, J=8.7 Hz, 2H), 6.11 (s, 2H), 4.47-4.29 (m, 1H), 3.83 (s, 3H), 3.23-3.12 (m, 1H), 2.86-2.75 (m, 1H), 2.25-1.84 (m, 6H), 1.60-1.40 (m, 2H). Alkyl NH2 not observed. LCMS (ES+) m/z 465 (M+1)
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:3]=1[C:4]([NH:6][C:7]1[C:8]([C:12]([OH:14])=[O:13])=[N:9][NH:10][CH:11]=1)=[O:5].FC1C=C(OC)C=C(F)C=1[C:23](O)=[O:24]>>[F:19][C:15]1[CH:16]=[C:17]([O:24][CH3:23])[CH:18]=[C:2]([F:1])[C:3]=1[C:4]([NH:6][C:7]1[C:8]([C:12]([OH:14])=[O:13])=[N:9][NH:10][CH:11]=1)=[O:5]
Reactant: O=C(O)c1n[nH]cc1NC(=O)c1c(F)cccc1F
Reactant: COc1cc(F)c(C(=O)O)c(F)c1
Product: COc1cc(F)c(C(=O)Nc2c[nH]nc2C(=O)O)c(F)c1

Procedure:
The compound was prepared in a manner analogous to 4-(2,6-difluoro-benzoylamino)-1H-pyrazole-3-carboxylic acid (Example 16D), but using 2,6-difluoro-4-methoxybenzoic acid as the starting acid, to give 4-(2,6-difluoro-4-methoxy-benzoylamino)-1H-pyrazole-3-carboxylic acid (1.58 g) as a white solid. (1H NMR (300 MHz, DMSO-d6) δ 13.0 (s, 2H), 10.7 (s, 1H), 8.0 (s, 1H), 6.9 (s, 1H), 6.8 (s, 1H), 3.7 (s, 3H)).