Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:12]([OH:14])=[O:13])=[CH:4][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=2[CH:11]=1.C(=O)([O-])[O-].[Na+].[Na+].[C:21](Cl)(=O)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[C:22]1([C:21]2[O:13][C:12](=[O:14])[C:3]3[CH:4]=[C:5]4[C:10]([CH2:9][CH2:8][CH2:7][CH2:6]4)=[CH:11][C:2]=3[N:1]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: Nc1cc2c(cc1C(=O)O)CCCC2
Reactant: O=C(Cl)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: O=c1oc(-c2ccccc2)nc2cc3c(cc12)CCCC3
Temperature: 25 °C
Yield: 44.5 %

Procedure:
2-Phenyl-6,7,8,9-tetrahydro-naphtho[2,3-d][1,3]oxazin-4-one was prepared by a modification of the route described in Okabe, M. and Sun, R. C.; Tetrahedron 1995, 51(7), 1861-1866. A 100 mL flask was charged with 3-amino-5,6,7,8-tetrahydro-napthalene-2-carboxylic acid, prepared in 36% yield as described in WO 2007/081572 (360 mg, 1.88 mmol) and sodium carbonate (399 mg, 3.77 mmol) and was then evacuated and backfilled with dry nitrogen gas twice before the addition of anhydrous tetrahydrofuran (50 mL). Cooled in an ice bath and added benzoyl chloride (662 mg, 4.71 mmol) and allowed to warm to ambient temperature overnight with stirring. Evaporated in vacuo and partitioned between ethyl acetate and water (20 mL each). Organic fraction was separated, dried with a hydrophobic frit, evaporated onto silica gel, and chromatographed using ISCO Companion with a Redisep silica gel 12 g cartridge and a gradient of heptane and ethyl acetate (0% to 50%). Impure fractions were combined and crystallized from refluxing heptane solution (˜100 mL). Pure material from the column was combined with material obtained by crystallization to give 2-phenyl-6,7,8,9-tetrahydro-naphtho[2,3-d][1,3]oxazin-4-one as a white solid 232.3 mg (44.5% Yield) LCMS (5 min acidic) 3.19 min 100% pure by ELSD, 36-100% pure by UV, ES+/AP+ 278. HNMR (CDCl3) >95% Pure 8.31-8.29 (m, 2H), 7.96 (s, 1H), 7.57-7.47 (m, 3H), 7.41 (s, 1H), 2.95-2.92 (m, 4H), 1.89-1.86 (m, 4H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([NH2:11])=[CH:9][C:8]([C:12]([F:15])([F:14])[F:13])=[C:7](Br)[N:6]=1)=[O:4].[CH3:17][C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][N:19]=1.NC1C(C(O)=O)=NC(C2C=CC(F)=CC=2)=C(C(F)(F)F)C=1>>[CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([C:21]2[CH:20]=[N:19][C:18]([CH3:17])=[CH:23][CH:22]=2)[C:8]([C:12]([F:15])([F:14])[F:13])=[CH:9][C:10]=1[NH2:11])=[O:4]
Reactant: Cc1ccc(B(O)O)cn1
Reactant: COC(=O)c1nc(Br)c(C(F)(F)F)cc1N
Agent: Nc1cc(C(F)(F)F)c(-c2ccc(F)cc2)nc1C(=O)O
Product: COC(=O)c1nc(-c2ccc(C)nc2)c(C(F)(F)F)cc1N

Procedure:
This compound was prepared from 3-Amino-6-bromo-5-trifluoromethyl-pyridine-2-carboxylic acid methyl ester (Intermediate A4) and 2-methylpyridine-5-boronic acid analogously to 3-amino-6-(4-fluoro-phenyl)-5-trifluoromethyl-pyridine-2-carboxylic acid (Intermediate G); LC-MS Rt 0.96 min [M+H]+ 312 (Method 2 minLC_v002); 1H NMR (400 MHz, DMSO-d6) δ 8.41 (1H, s), 7.79 (1H, s), 7.69 (1H, dd), 7.32 (1H, d), 7.10 (2H, s), 3.82 (3H, s), 2.52 (3H, s).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([CH3:11])[N:3]=1.[CH2:12]([O:14][C:15](=[O:22])[CH2:16][C@@H:17]([NH2:21])[CH2:18][CH2:19][CH3:20])[CH3:13].C(N(C(C)C)CC)(C)C>CN(C=O)C.C(OCC)(=O)C>[CH2:12]([O:14][C:15](=[O:22])[CH2:16][C@@H:17]([NH:21][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([CH3:11])[N:3]=1)[CH2:18][CH2:19][CH3:20])[CH3:13]
Reactant: CCC[C@H](N)CC(=O)OCC
Reactant: Cc1ccc([N+](=O)[O-])c(Cl)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCC[C@@H](CC(=O)OCC)Nc1nc(C)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 48 h
Yield: 40.5 %

Procedure:
To a solution of 2-chloro-3-nitro-6-picoline (500 mg, 2.99 mmol) in DMF (3 mL) were added the (S)-3-amino-hexanoic acid ethyl ester (554 mg, 3.48 mmol) and diisopropylethyl amine (DIPEA) (1.0 mL, 5.80 mmol). The reaction mixture was stirred at room temperature for 48 hours. The reaction mixture was then diluted with ethyl acetate and washed with water (×4). The organic phase was then dried over Na2SO4 and concentrated. The resulting residue was purified by preparative TLC using hexane and ethyl acetate (4:1) as an eluent to afford 358 mg (42%) of the title compound as orange oil. LCMS, M++1, m/z: 296.65.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]([CH2:21][CH:22]([OH:27])[CH2:23][N:24]([CH3:26])[CH3:25])[CH:10]=[C:11]3[C:16]=2[C:15](=[O:17])[N:14]([CH3:18])[C:13](=[O:19])[N:12]3[CH3:20])[CH:5]=[CH:6][CH:7]=1.[Cl:28][C:29]1[O:33][C:32]([CH:34]=O)=[CH:31][CH:30]=1>>[Cl:28][C:29]1[O:33][C:32]([C@H:34]2[C:10]3=[C:11]4[N:12]([CH3:20])[C:13](=[O:19])[N:14]([CH3:18])[C:15](=[O:17])[C:16]4=[C:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=4)[N:9]3[CH2:21][C@H:22]([CH2:23][N:24]([CH3:26])[CH3:25])[O:27]2)=[CH:31][CH:30]=1
Reactant: CN(C)CC(O)Cn1cc2c(c1-c1cccc(Cl)c1)c(=O)n(C)c(=O)n2C
Reactant: O=Cc1ccc(Cl)o1
Product: CN(C)C[C@H]1Cn2c(-c3cccc(Cl)c3)c3c(=O)n(C)c(=O)n(C)c3c2[C@H](c2ccc(Cl)o2)O1

Procedure:
The title compound was prepared from 5-(3-chlorophenyl)-6-(3-(dimethylamino)-2-hydroxypropyl)-1,3-dimethyl-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione and 5-chlorofuran-2-carbaldehyde analogously to Example 12, step 2. The first eluted diastereomer (by Agilent Prep. System (10-35%, low pH) was isolated and separated by SFC under the following conditions to yield the title compounds as single enantiomers.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:13])=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8].Cl[CH:15]([F:17])[F:16]>[OH-].[Na+].C(O)(C)C.ClCCl.O>[F:16][CH:15]([F:17])[O:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:13])=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)c1cc(O)ccc1C
Reactant: FC(F)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Solvent: CC(C)O
Product: CCOC(=O)c1cc(OC(F)F)ccc1C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 59 %

Procedure:
A mixture of ethyl 5-hydroxy-2-methylbenzoate (3.29 g, 18.2 mmol) in aqueous 30% sodium hydroxide (20 mL) and isopropyl alcohol (20 mL) was charged with 20 psi of chlorodifluoromethane in a high pressure flask, and stirred at room temperature for 10 min. After this time, the resulting mixture was heated at 50° C. for 0.5 h. After this time, the reaction mixture was cooled to room temperature and diluted with dichloromethane (50 mL) and water (200 mL). The organic layer was separated, dried over sodium sulfate, filtered, and concentrated under reduced pressure. Purification by flash chromatography (silica, gradient 0-7%, hexanes/ethyl acetate) afforded 2.50 g (59%) of ethyl 5-(difluoromethoxy)-2-methylbenzoate as colorless oil: 1H NMR (500 MHz, CDCl3) δ 7.67 (d, J=2.5 Hz, 1H), 7.26-7.22 (m, 1H), 7.18-7.16 (m, 1H), 6.50 (t, J=73.6 Hz, 1H), 4.37 (q, J=7.0 Hz, 2H), 2.57 (s, 3H), 1.40 (t, J=7.0 Hz, 3H); ESI MS m/z 231 [M+H]+.
Reaction SMILES: [H-].[Na+].[C:3]([SH:6])(=[O:5])[CH3:4].CS(O[C@H:12]1[CH2:16][N:15]([C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=2)=[O:18])[C@H:14]([CH2:30][N:31]2[CH2:35][CH2:34][N:33]([CH3:36])[C:32]2=[O:37])[CH2:13]1)(=O)=O>CN(C)C=O>[C:3]([S:6][C@@H:12]1[CH2:16][N:15]([C:17]([O:19][CH2:20][C:21]2[CH:22]=[CH:23][C:24]([N+:27]([O-:29])=[O:28])=[CH:25][CH:26]=2)=[O:18])[C@H:14]([CH2:30][N:31]2[CH2:35][CH2:34][N:33]([CH3:36])[C:32]2=[O:37])[CH2:13]1)(=[O:5])[CH3:4]
Reactant: CN1CCN(C[C@@H]2C[C@@H](OS(C)(=O)=O)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)C1=O
Reactant: CC(=O)S
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)S[C@H]1C[C@@H](CN2CCN(C)C2=O)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Temperature: 0 °C

Procedure:
To a solution of sodium hydride (0.35 g) in N,N-dimethylformamide (30 ml) was added dropwise thioacetic S-acid (0.74 ml) with stirring under ice-cooling. The mixture was stirred at the same temperature for 30 minutes. A solution of (2S,4R)-4-methanesulfonyloxy-2-(3-methyl-2-oxoimidazolidin-1-yl)methyl-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (3.17 g) in N,N-dimethylformamide (7 ml) was added to the mixture obtained above with stirring at the same temperature. The mixture was stirred at 80°-90° C. for 2 hours. The reaction mixture was poured into ice-water (100 ml) and extracted twice with ethyl acetate (100 ml). The extract was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated in vacuo. The resulting residue was chromatographed on silica gel (100 g) eluting with a mixture of chloroform and methanol (19:1, V/V). The fractions containing the desired compound were collected and evaporated in vacuo to give (2S,4S)-4-acetylthio-2-(3-methyl-2-oxoimidazolidin-1-yl)methyl-1(4 -nitrobenzyloxycarbonyl)pyrrolidine (1.74 g).
Reaction SMILES: [CH3:1][C:2]1[CH:15]=[C:14]2[C:5]([O:6][CH2:7][CH2:8][N:9]3[C:13]2=[N:12][C:11]([C:16]2[N:20]([CH:21]([CH3:23])[CH3:22])[N:19]=[CH:18][N:17]=2)=[CH:10]3)=[CH:4][C:3]=1[C:24](=[O:26])[CH3:25].[CH3:27][N:28]([CH:30](OC)OC)[CH3:29]>>[CH3:27][N:28]([CH3:30])/[CH:29]=[CH:25]/[C:24]([C:3]1[CH:4]=[C:5]2[C:14](=[CH:15][C:2]=1[CH3:1])[C:13]1[N:9]([CH:10]=[C:11]([C:16]3[N:20]([CH:21]([CH3:23])[CH3:22])[N:19]=[CH:18][N:17]=3)[N:12]=1)[CH2:8][CH2:7][O:6]2)=[O:26]
Reactant: COC(OC)N(C)C
Reactant: CC(=O)c1cc2c(cc1C)-c1nc(-c3ncnn3C(C)C)cn1CCO2
Product: Cc1cc2c(cc1C(=O)/C=C/N(C)C)OCCn1cc(-c3ncnn3C(C)C)nc1-2
Temperature: 130 °C
Reaction time: 48 h
Yield: 82 %

Procedure:
A mixture of 1-{13-methyl-4-[1-(propan-2-yl)-1H-1,2,4-triazol-5-yl]-9-oxa-3,6-diazatricyclo[8.4.0.02,6]tetradeca1(14),2,4,10,12-pentaen-12-yl}ethan-1-one (250 mg, 0.720 mmol) and DMF-DMA (170 mg, 1.44 mmol) in xylenes (10 mL) was stirred at 130° C. for 48 h under nitrogen atmosphere. After concentration, the residue was purified by reverse phase combiflash eluting with a 0-40% gradient of CH3CN in 0.3% NH4HCO3 to afford (2E)-3-(dimethylamino)-1-{13-methyl-4-[1-(propan-2-yl)-1H-1,2,4-triazol-5-yl]-9-oxa-3,6-diazatricyclo[8.4.0.02,6]tetradeca-1(14),2,4,10,12-pentaen-12-yl}prop-2-en-1-one (240 mg, 77% yield). LCMS (ESI) m/z: 407.3 [M+H+].
Reaction SMILES: C(C[O:5][C:6]1[CH:7]=[CH:8][C:9]2[CH2:10][C@H:11]3[N:23]([CH3:24])[CH2:22][CH2:21][C@:17]45[C:18]=2[C:19]=1[O:20][C@H:16]4[C@@H:15]([OH:25])[CH:14]=[CH:13][C@@H:12]35)(O)=O.ClC(OCC(C)C)=O>CN(C)C=O.O>[CH:8]1[C:9]2[CH2:10][C@H:11]3[N:23]([CH2:22][CH2:21][C@@:17]45[C@H:12]3[CH:13]=[CH:14][C@H:15]([OH:25])[C@@H:16]4[O:20][C:19]([C:18]=25)=[C:6]([OH:5])[CH:7]=1)[CH3:24]
Reactant: CN1CC[C@]23c4c5ccc(OCC(=O)O)c4O[C@H]2[C@@H](O)C=C[C@H]3[C@H]1C5
Agent: CC(C)COC(=O)Cl
Solvent: O
Solvent: CN(C)C=O
Product: CN1CC[C@]23c4c5ccc(O)c4O[C@H]2[C@@H](O)C=C[C@H]3[C@H]1C5
Temperature: -15 °C
Reaction time: 0.5 h

Procedure:
Carboxymethyl morphine (240 mg) suspended in 8 ml dry dimethyl formamide (DMF) was cooled to -15° C and treated with 84 μl isobutyl chloroformate. The solid dissolved while stirring for 30 minutes at -15° C. Bovine serum albumin (BSA) (400 mg) dissolved in 56 ml water containing 2.6 g sodium bicarbonate was added to this solution and the mixture was kept at 0° C overnight. It was then dialyzed against distilled water with four changes of water (dialysis 1:80) and lyophilized to give 350 mg of conjugate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:11]=[C:10]([CH:20]([CH3:22])[CH3:21])[C:9]=2[C:23]#[C:24][C:25]([OH:27])=[O:26])=[CH:4][CH:3]=1.[N+](=[CH2:30])=[N-]>C(OCC)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:11]=[C:10]([CH:20]([CH3:22])[CH3:21])[C:9]=2[C:23]#[C:24][C:25]([O:27][CH3:30])=[O:26])=[CH:4][CH:3]=1
Reactant: C=[N+]=[N-]
Reactant: CC(C)c1nc(-c2ccccc2)cc(-c2ccc(F)cc2)c1C#CC(=O)O
Solvent: CCOCC
Product: COC(=O)C#Cc1c(-c2ccc(F)cc2)cc(-c2ccccc2)nc1C(C)C

Procedure:
11.0 g of the crude 3-(4-(4-fluorophenyl)-2-(1-methylethyl)-6-phenylpyridin-3-yl)prop-2-ynoic acid were dissolved in 400 ml of diethyl ether, and ethereal diazomethane solution was added in portions until the reaction was complete according to TLC. The solvent was evaporated off and then the remaining crude ester was purified by column chromatography (silica gel; cyclohexane/dichloromethane 1:1). The title compound was obtained in a yield of 8.85 g, corresponding to 98% based on the dibromide employed.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]1([CH2:17][C:18](O)=[O:19])([CH2:13][C:14](O)=[O:15])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.[OH-].[Na+]>O1CCCC1.O.C(OCC)C>[OH:15][CH2:14][CH2:13][C:7]1([CH2:17][CH2:18][OH:19])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]1
Reactant: O=C(O)CC1(CC(=O)O)CCCCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: OCCC1(CCO)CCCCC1
Reaction time: 0.08 h
Yield: 84 %

Procedure:
After suspending lithium aluminum hydride (11.4 g, 0.300 mol) in tetrahydrofuran (300 mL), a solution of 1,1-cyclohexanediacetic acid (30.0 g, 0.150 mol) in tetrahydrofuran (200 mL) was added dropwise at room temperature. After completion of the dropwise addition, the mixture was stirred for 5 minutes while cooling on ice, and then water (11.5 mL) was added dropwise over a period of 5 minutes while cooling on ice. After stirring for 10 minutes, 15% aqueous sodium hydroxide (11.5 mL) was added dropwise over a period of 5 minutes. Diethyl ether (500 mL, special grade) was added, and after stirring for 5 minutes, water (34.5 mL) was added. The mixture was then stirred for 2 hours while cooling on ice, and then celite was added and the mixture was filtered. The filtrate was concentrated under reduced pressure and azeotropically distilled with toluene to obtain the title compound as a colorless oil (21.7 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[CH:11]=[C:10]([C:17]([O:19]C)=[O:18])[C:9]2=[O:21])=[CH:4][CH:3]=1.[OH-].[Na+].Cl>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[CH:11]=[C:10]([C:17]([OH:19])=[O:18])[C:9]2=[O:21])=[CH:4][CH:3]=1
Reactant: COC(=O)c1cc([N+](=O)[O-])cn(-c2ccc(F)cc2)c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1cc([N+](=O)[O-])cn(-c2ccc(F)cc2)c1=O
Temperature: 80 °C
Reaction time: 2 h
Yield: 66 %

Procedure:
A mixture of methyl 1-(4-fluorophenyl)-5-nitro-2-oxo-1,2-dihydropyridine-3-carboxylate (75 mg, 0.245 mmol) and 2 N NaOH solution (1 mL) was stirred at 80° C. for 2 h. The reaction mixture was cooled to rt and acidified with 1 N HCl solution. The solid that formed was collected, washed with water and dried to afford the title compound (45 mg, 66%), which was used directly in the next reaction. 1H NMR (DMSO-d6) δ 13.41 (s, 1H), 9.28 (d, 1H, J=3.2 Hz), 8.70 (d, 1H, J=3.2 Hz), 7.60 (m, 2H), 7.41 (m, 2H); MS(ESI+) m/z 279 (M+H)+.
Reaction SMILES: C([O-])(=O)C.[Na+].[C:6]([C:9]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:10]=1[O:11][CH2:12]C(O)=O)(=O)[CH3:7].O>C(OC(=O)C)(=O)C>[F:20][C:18]1[CH:17]=[CH:16][C:10]2[O:11][CH:12]=[C:6]([CH3:7])[C:9]=2[CH:19]=1
Reactant: CC(=O)c1cc(F)ccc1OCC(=O)O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: Cc1coc2ccc(F)cc12
Temperature: 110 °C
Reaction time: 1 h
Yield: 0.4 %

Procedure:
Anhydrous sodium acetate (139.3 mmol, 11.4 g) was added to a solution of the title compound of Example 14, Step A (3.24 mmol, 1.6 g) in acetic anhydride (70 mL) and heated for 3 hours at 110° C. After cooling, the reaction mixture was poured into water (100 mL) and stirred for 1 hour. The aqueous solution was extracted with ether (2×100 mL), washed with 3% aqueous KOH (2×20 mL) and water (2×20 mL). The washed ether layer was collected, dried, filtered and the filtrate was evaporated to a brown residue, which was purified by silica gel chromatography (eluent:hexanes) to obtain the desired product, 5-fluoro-3-methyl benzofuran (59%, 1.77 mg).
Reaction SMILES: [F:1][C:2]([C:5]1[O:9][C:8]([CH2:10][N:11]2[CH:15]=[C:14]([NH2:16])[CH:13]=[N:12]2)=[CH:7][CH:6]=1)([F:4])[CH3:3].[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22](/[CH:25]=[CH:26]/[C:27](O)=[O:28])=[CH:21][CH:20]=1>>[F:4][C:2]([C:5]1[O:9][C:8]([CH2:10][N:11]2[CH:15]=[C:14]([NH:16][C:27](=[O:28])/[CH:26]=[CH:25]/[C:22]3[CH:23]=[CH:24][C:19]([O:18][CH3:17])=[CH:20][CH:21]=3)[CH:13]=[N:12]2)=[CH:7][CH:6]=1)([F:1])[CH3:3]
Reactant: COc1ccc(/C=C/C(=O)O)cc1
Reactant: CC(F)(F)c1ccc(Cn2cc(N)cn2)o1
Product: COc1ccc(/C=C/C(=O)Nc2cnn(Cc3ccc(C(C)(F)F)o3)c2)cc1

Procedure:
Following general procedure B, starting from 1-[5-(1,1-difluoro-ethyl)-furan-2-ylmethyl]-1H-pyrazol-4-ylamine and (E)-3-(4-methoxy-phenyl)-acrylic acid. LC-MS-conditions 05b: tR=1.06 min; [M+H]+=388.10.
Reaction SMILES: [C:1]([NH:5][S:6]([CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([NH2:17])=[C:13](Br)[CH:12]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:19][C:20]1([CH3:29])[CH2:25][CH2:24][C:23](B(O)O)=[CH:22][CH2:21]1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.CCO.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([NH:5][S:6]([CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([NH2:17])=[C:13]([C:23]2[CH2:24][CH2:25][C:20]([CH3:29])([CH3:19])[CH2:21][CH:22]=2)[CH:12]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC1(C)CC=C(B(O)O)CC1
Reactant: CC(C)(C)NS(=O)(=O)CCc1ccc(N)c(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CCO
Product: CC1(C)CC=C(c2cc(CCS(=O)(=O)NC(C)(C)C)ccc2N)CC1
Temperature: 80 °C
Yield: 64.8 %

Procedure:
A solution of 380 mg (1.13 mmol) of 2-(4-amino-3-bromo-phenyl)-ethanesulfonic acid tert-butylamide (as prepared in Example 47, step (a)) in toluene (10 mL) and EtOH (5 mL) was treated with 321 mg (1.36 mmol) of 4,4-dimethylcyclohex-1-enylboronic acid and 4.53 mL (9.06 mmol) of 2.0 M aqueous Na2CO3. The mixture was degassed via sonication, placed under Ar, treated with 131 mg (0.113 mmol) of Pd(PPh3)4, and heated to 80° C. for 19 h. The mixture was diluted with EtOAc (30 mL) and washed with water (1×20 mL). The organic layer was dried (MgSO4) and concentrated in vacuo. Silica gel chromatography of the residue on a 50-g Varian MegaBond Elut SPE column with 1% MeOH—CH2Cl2 afforded 267 mg (64%) of the title compound as an off-white solid: Mass spectrum (ESI, m/z): Calcd. for C20H32N2O2S, 365.2 (M+H), found 365.2.
Reaction SMILES: [Cl:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[C:3]=1/[C:14](/[C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=1[CH3:27])=[CH:15]\[CH2:16][C:17]([O-:19])=[O:18].[CH3:28][C:29]([NH3+:32])([CH3:31])[CH3:30]>C1CC=CCCC=C1.C1CC=CCCC=C1.[Cl-].[Cl-].[Rh].[Rh]>[Cl:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[C:3]=1[CH:14]([C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=1[CH3:27])[CH2:15][CH2:16][C:17]([O-:19])=[O:18].[CH3:28][C:29]([NH3+:32])([CH3:31])[CH3:30]
Reactant: Cc1cc(Cl)ccc1/C(=C/CC(=O)[O-])c1c(-c2ccccn2)nn(C)c1Cl
Agent: [Rh]
Agent: C1=C\CC/C=C\CC/1
Agent: CC(C)(C)[NH3+]
Solvent: C1=CCCC=CCC1
Product: Cc1cc(Cl)ccc1C(CCC(=O)[O-])c1c(-c2ccccn2)nn(C)c1Cl
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 99.8 %

Procedure:
Chloro(1,5-cyclooctadiene)rhodium(I) dimer (0.068 g, 0.277 mmol), (S)-1-[(RP)-2-[Bis(4-methoxy-3,5-dimethylphenyl)phosphino]ferrocenyl}ethyldi-tert-butylphosphine (0.182 g, 0.277 mmol), and 2-methylpropan-2-aminium (Z)-4-(5-chloro-1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-4-(4-chloro-2-methylphenyl)but-3-enoate (13.17 g, 27.7 mmol) were combined in a 250 mL stainless steel pressure bottle. A stir bar was added, and the system was degassed with 20 psi argon, and then vented. Argon-degassed MeOH (131 mL) was added against an argon stream by cannula, and the vessel was again sealed and degassed with argon. The system was shaken for about 30 min at about 50° C. The reactor was pressurized to 55 psi with hydrogen shaken at about 70° C. for about 14.5 h. The mixture was filtered through glass wool and concentrated in vacuo to give 2-methylpropan-2-aminium 4-(5-chloro-1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-4-(4-chloro-2-methylphenyl)butanoate (13.2 g, 100%) as a foam. 4-(5-Chloro-1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-4-(4-chloro-2-methylphenyl)butanoate (14.4 g, 30.2 mmol) in DCM (250 mL) and was washed with 20% citric acid (2×300 mL). The combined aqueous layers were extracted with DCM (250 mL). The combined organic layers were washed with H2O (400 mL). The aqueous layer was extracted with EtOAc (250 mL). The combined organic layers were concentrated in vacuo. The residue was dissolved in THF (150 mL) and loaded on a silica gel pad (600 g) then eluted with THF. The product containing fractions were concentrated in vacuo. The material was dissolved in 2-methyltetrahydrofuran (500 mL) then washed with 20% citric acid (400 mL), H2O (3×400 mL) and brine (400 mL). The organic layer was dried over Na2SO4, filtered and concentrated in vacuo to give 4-(5-chloro-1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-4-(4-chloro-2-methylphenyl)butanoic acid (12.2 g, 100%): LC-MS (Table 1, Method g) Rt=2.37 min, m/z 404/406 (M+H)+; 1H-NMR (DMSO, Bruker 400 MHz) δ 11.98 (s, 1H), 8.60-8.56 (m, 1H), 7.86-7.79 (m, 2H), 7.39 (d, J=8.4 Hz, 1H), 7.36-7.28 (m, 1H), 7.19-7.14 (m, 1H), 7.13-7.11 (m, 1H), 5.30-5.24 (m, 1H), 3.83 (s, 3H), 2.45-2.32 (m, 1H), 2.29-2.14 (m, 3H), 2.08 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[NH:6][N:5]=[C:4]([C:7]([OH:9])=O)[CH:3]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.[F:32][C:33]([C:36]1[CH:41]=[CH:40][C:39]([C:42](=[N:44]O)[NH2:43])=[CH:38][CH:37]=1)([CH3:35])[CH3:34]>CN(C=O)C>[F:32][C:33]([C:36]1[CH:41]=[CH:40][C:39]([C:42]2[N:43]=[C:7]([C:4]3[CH:3]=[C:2]([CH3:1])[NH:6][N:5]=3)[O:9][N:44]=2)=[CH:38][CH:37]=1)([CH3:35])[CH3:34]
Reactant: Cc1cc(C(=O)O)n[nH]1
Reactant: CC(C)(F)c1ccc(C(N)=NO)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1cc(-c2nc(-c3ccc(C(C)(C)F)cc3)no2)n[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.5 %

Procedure:
To a mechanically stirred solution of 5-methyl-1H-pyrazole-3-carboxylic acid (1.59 g, 12.64 mmol) in dry DMF (64 mL) was added EDCl (2.42 g, 12.64 mmol), HOBT (1.71 g, 12.64 mmol) and 4-(2-fluoropropan-2-yl)-N′-hydroxybenzenecarboximidamide (Intermediate Q, 2.48 g, 12.64 mmol). The mixture was stirred at rt for 2 h, and then heated to 140° C. and stirred for additional 1 h. After being cooled to it, the solvent was removed under reduced pressure. Ethyl acetate (150 mL) and 2% aqueous citric acid solution (150 mL) were added, and the organic phase was separated and washed with saturated aqueous sodium bicarbonate solution (150 mL) and saturated aqueous sodium chloride solution. After drying over anhydrous magnesium sulfate and filtration, the solvent was removed in vacuo and the residue was purified by MPLC (silica, cyclohexane/ethyl acetate 3:1) to afford the title compound (2.48 g, 64%): 1H NMR (400 MHz, DMSO-d6) δ 13.54 (broad s, 1H), 8.08 (d, 2H), 7.62 (d, 2H), 6.81 (s, 1H), 2.33 (s, 3H), 1.72 (s, 3H), 1.68 (s, 3H); ES-MS m/z 287 (MH)+; HPLC RT (Method F) 2.19 min.
Reaction SMILES: [F:1][CH:2]([F:14])[N:3]1[C:8](=[O:9])[CH:7]=[CH:6][C:5]([C:10]([O:12]C)=[O:11])=[CH:4]1.O.[OH-].[Li+]>CO.O>[F:14][CH:2]([F:1])[N:3]1[C:8](=[O:9])[CH:7]=[CH:6][C:5]([C:10]([OH:12])=[O:11])=[CH:4]1
Reactant: COC(=O)c1ccc(=O)n(C(F)F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc(=O)n(C(F)F)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of methyl 1-(difluoromethyl)-6-oxo-1,6-dihydropyridine-3-carboxylate (0.500 g, 2.461 mmol) in MeOH (12 mL) and water (4 mL) was added lithium hydroxide hydrate (0.207 g, 4.92 mmol, Aldrich). The resulting mixture was then stirred at room temperature for 4 h. Solvent (MeOH) was removed in vacuok, and the remaining aqueous solution was adjusted to pH=5-6 by addition of concentrated HCl. The mixture was then extracted with EtOAc (3×10 mL). The combined organic layers were dried (MgSO4), and the solvent removed to give the title compound as a yellow solid. MS (ESI, positive ion) m/z: 190 (M+H).