Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[CH:10]=[C:9]2[C:11]([O:13][C:14](=[O:15])[C:7]3=[C:8]2[C:3](=[C:4]([NH2:16])[CH:5]=[CH:6]3)[CH:2]=1)=[O:12].S(=O)(=O)(O)O.[N+](C1C=CC=CC=1)([O-])=O.[CH3:31][C:32]([CH:34](OC(C)=O)OC(C)=O)=[CH2:33]>C(O)(=O)C.O>[CH3:34][C:32]1[CH:33]=[C:5]2[C:4]([C:3]3[CH:2]=[CH:1][CH:10]=[C:9]4[C:11](=[O:12])[O:13][C:14](=[O:15])[C:7](=[CH:6]2)[C:8]=34)=[N:16][CH:31]=1
Reactant: Nc1ccc2c3c(cccc13)C(=O)OC2=O
Reactant: C=C(C)C(OC(C)=O)OC(C)=O
Agent: O=S(=O)(O)O
Solvent: O=[N+]([O-])c1ccccc1
Solvent: CC(=O)O
Solvent: O
Product: Cc1cnc2c(c1)cc1c3c(cccc32)C(=O)OC1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 93.7 %

Procedure:
A mixture of 4-amino-1,8-naphthalic anhydride (Okazaki, M.; Ishikawa, N. Yuki Gosei Kagaku Kyokai Shi 1956, 14, 398; Chem. Abstr. 1957, 51, 8051c) (28.0 g, 131 mmol), ferrous sulfate heptahydrate (7.20 g, 25.8 mmol), concentrated sulfuric acid (13 mL, 234 mmol), and nitrobenzene (27.0 mL, 262 mmol) in acetic acid (260 mL) was heated to reflux. Methallylidene diacetate (43.5 mL, 262 mmol) was added dropwise over a period of 2.5 h using an addition funnel. After the addition was complete, the reaction mixture was heated for 1.5 h and poured into a beaker of ice/water (500 mL). The aqueous solution was further diluted to 800 mL with water, stirred for 1 h and filtered by suction. The residue was washed with water and dried in vacuo to obtain 32.3 g of a dark brown solid. The crude solid was heated at reflux in acetic acid (80 mL) and filtered hot to obtain 15.63 g (44%) of a light brown solid: mp >290° C.; MS m/e 264 (M+H+); 1H NMR (DMSO-d6, 300 MHz) δ 2.60 (s, 3H), 8.10 (t, 1H), 8.60 (s, 1H), 8.62 (s, 1H), 9.01 (s, 1H), 9.12 (d, 1H), 9.45 (d, 1H).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:9]([C:11](O)=[O:12])=[CH:8][C:7]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)=[N:6][C:5]=2[N:4]([CH:20]([CH3:22])[CH3:21])[N:3]=1.[NH2:23][CH2:24][C:25]1[C:26](=[O:33])[NH:27][C:28]([CH3:32])=[CH:29][C:30]=1[CH3:31].CN1CCOCC1.ON1C2N=CC=CC=2N=N1.C(Cl)CCl>CS(C)=O>[CH3:31][C:30]1[CH:29]=[C:28]([CH3:32])[NH:27][C:26](=[O:33])[C:25]=1[CH2:24][NH:23][C:11]([C:9]1[C:10]2[C:2]([CH3:1])=[N:3][N:4]([CH:20]([CH3:22])[CH3:21])[C:5]=2[N:6]=[C:7]([C:14]2[CH:15]=[CH:16][N:17]=[CH:18][CH:19]=2)[CH:8]=1)=[O:12]
Reactant: Cc1cc(C)c(CN)c(=O)[nH]1
Reactant: Cc1nn(C(C)C)c2nc(-c3ccncc3)cc(C(=O)O)c12
Agent: On1nnc2cccnc21
Solvent: CS(C)=O
Solvent: CN1CCOCC1
Solvent: ClCCCl
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccncc3)nc3c2c(C)nn3C(C)C)c(=O)[nH]1

Procedure:
The title compound was prepared in the same manner as described in example 109 using 3-methyl-1-(1-methylethyl)-6-(4-pyridinyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (20 mg, 0.067 mmol), DMSO (1 mL), 3-(aminomethyl)-4,6-dimethyl-2(1H)-pyridinone (19.10 mg, 0.101 mmol), N-methylmorpholine (0.030 mL, 0.270 mmol), 1-hydroxy-7-azabenzotriazole (18.37 mg, 0.135 mmol) and EDC (25.9 mg, 0.135 mmol). The final product was collected as 29 mg (100%). LCMS E-S (M+H)=431.2. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.52 (d, J=6.57 Hz, 6H), 2.12 (s, 3H), 2.25 (s, 3H), 2.46 (s, 3H), 4.40 (d, J=5.0 Hz, 2H), 5.29 (quin, J=6.7 Hz, 1H), 5.89 (s, 1H), 7.83 (s, 1H), 8.19 (d, J=6.1 Hz, 2H), 8.64-8.89 (m, 3H), 11.55 (br. s., 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]([NH:19][C:20]([CH:22]2[CH2:25][CH2:24][CH2:23]2)=[O:21])C(O)=O)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH2:32]([O:34][C:35](=[O:39])[C:36](Cl)=[O:37])[CH3:33].[O-]CC.[Na+]>CN(C1C=CN=CC=1)C.C1COCC1.CCO>[CH2:32]([O:34][C:35](=[O:39])[C:36](=[O:37])[CH:15]([C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:10]=1)[NH:19][C:20]([CH:22]1[CH2:25][CH2:24][CH2:23]1)=[O:21])[CH3:33]
Reactant: CCOC(=O)C(=O)Cl
Reactant: O=C(NC(C(=O)O)c1cccc(OCc2ccccc2)c1)C1CCC1
Agent: CC[O-]
Agent: CN(C)c1ccncc1
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)C(=O)C(NC(=O)C1CCC1)c1cccc(OCc2ccccc2)c1
Temperature: 25 °C

Procedure:
A slurry of (3-benzyloxy-phenyl)-(cyclobutanecarbonyl-amino)-acetic acid (4.77 g, 14.1 mmol), pyridine (3.4 mL, 42.2 mmol) and DMAP (cat.) in anhydrous THF (26 mL) was charged dropwise with chloro-oxo-acetic acid ethyl ester (3.13 mL, 28.1 mmol) and heated to reflux for 1.5 h. The white precipitate was filtered through a fritted glass Buchner funnel into a flask containing H2O and EtOAc and the aqueous phase was separated from the organic phase. The aqueous was washed with EtOAc (3×) and the combined EtOAc layers were washed with brine (1×), dried over Na2SO4, filtered and concentrated in vacuo resulting in a yellow/orange oil. The oil was dissolved in anhydrous EtOH (28 mL) and a solution of 21 wt % of sodium ethoxide (NaOEt) in EtOH (2.0 mnL) was added at 0° C. and warmed to rt. The reaction mixture was concentrated in vacuo and the crude material was chromatographed on silica gel [eluting with 2% EtOAc in CHCl3], yielding the title compound as a pale yellow oil. 1H NMR (CDCl3, 400 MHz) δ 1.26 (t, J=7.2 Hz, 3H), 1.80-2.04 (m, 2H), 2.09 (m, 4H), 3.06 (quint, J=8.4 Hz, 1H) 4.17-4.30 (m, 2H), 5.04 (s, 2H), 6.18-6.32 (m, 2H), 6.86-7.00 (m, 3H), 7.22-7.48 (m, 5H); MS (ES+): m/z 396.03 (100) [MH+]; HPLC: tR=3.09 min (MicromassZQ, nonpolar—5 min).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][C:6]([OH:12])=[CH:5]2.[CH3:13]N(C)C=O.CI>CO.C(=O)([O-])[O-].[Ag+2]>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][C:6]([O:12][CH3:13])=[CH:5]2
Reactant: CN(C)C=O
Reactant: Oc1cc2cc(Br)ccc2cn1
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: CI
Solvent: CO
Product: COc1cc2cc(Br)ccc2cn1
Temperature: 25 °C
Reaction time: 0.27 h
Yield: 14 %

Procedure:
A mixture of 6-bromoisoquinolin-3-ol (606 mg, 2.70 mmol), silver carbonate (1.5 g, 5.3 mmol), and N,N-dimethylformamide (12 mL) was stirred at room temperature for 16 minutes. Methyl iodide (186 μL, 2.97 mmol) was added and the reaction was left stirring for 18 hours. The reaction was diluted with methanol and filtered through Celite. The filtrate was concentrated and purified by flash column chromatography to give the title compound (90 mg, 14%). +ESI (M+H+1) 240.0; 1H NMR (400 MHz, CDCl3, δ): 8.91 (s, 1H), 7.86 (d, J=1.8 Hz, 1H), 7.73 (d, J=8.8 Hz, 1H), 7.43 (dd, J=8.8, 1.8 Hz, 1H), 6.90 (s, 1H), 4.02 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:16]=[C:15]([CH2:17][N:18]2[CH2:24][CH2:23][CH2:22][CH:21]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:20][CH2:19]2)[CH:14]=[CH:13][C:3]=1[O:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][N:6]=1.C(=O)([O-])[O-:32].[K+].[K+].OO.CO>CS(C)=O>[CH3:1][C:2]1[CH:16]=[C:15]([CH2:17][N:18]2[CH2:24][CH2:23][CH2:22][CH:21]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:20][CH2:19]2)[CH:14]=[CH:13][C:3]=1[O:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]([NH2:10])=[O:32])=[CH:7][N:6]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1cc(CN2CCCC(c3ccccc3)CC2)ccc1Oc1ccc(C#N)cn1
Agent: OO
Agent: [K+]
Solvent: CO
Solvent: CS(C)=O
Product: Cc1cc(CN2CCCC(c3ccccc3)CC2)ccc1Oc1ccc(C(N)=O)cn1
Yield: 173.1 %

Procedure:
Using a method similar to Example 371, (±)-6-[2-methyl-4-(4-phenyl-azepan-1ylmethyl)-phenoxy]-nicotinonitrile (compound of example 368) (0.246 g, 0.642 mmol), potassium carbonate (0.0429 g, 0.310 mmol), and 30% hydrogen peroxide solution (aq) (0.220 mL, 1.94 mmol) in dimethylsulfoxide provide, after ion exchange chromatography (methanol→2 M ammonia/methanol), 0.223 g (87%) of the title compound as a white solid: high resolution mass spectrum (electrospray): m/z calc for C25H28N3O2 402.2182, found 402.2172; 1H NMR (methanol-d4): 8.67 (d, 1H, J=2.0 Hz), 8.36 (dd, 1H, J=2.4, 8.8 Hz), 7.51 (d, 2H, J=8.3 Hz), 7.32-7.22 (m, 4H), 7.20-7.14 (m, 3H), 7.04 (d, 1H, J=8.8 Hz), 3.77 (s, 2H), 2.97 (ddd, 1H, J=3.4, 6.3, 13.2 Hz), 2.92-2.83 (m, 3H), 2.81-2.72 (m, 1H), 2.04-1.76 (m, 6H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@@:13]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)([CH2:16][CH2:17][CH2:18]O)[O:12][C:11]2=[O:27])[CH3:9])=[CH:4][CH:3]=1.[Cl:28][C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[N:33][CH:34]=1>>[CH2:16]([C@@:13]1([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[O:12][C:11](=[O:27])[N:10]([C@H:8]([C:5]2[CH:6]=[CH:7][C:2]([C:31]3[CH:32]=[N:33][CH:34]=[C:29]([Cl:28])[CH:30]=3)=[CH:3][CH:4]=2)[CH3:9])[CH2:15][CH2:14]1)[CH:17]=[CH2:18]
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CCCO)(c2ccc(F)cc2)OC1=O
Reactant: OB(O)c1cncc(Cl)c1
Product: C=CC[C@]1(c2ccc(F)cc2)CCN([C@@H](C)c2ccc(-c3cncc(Cl)c3)cc2)C(=O)O1

Procedure:
The title compound was prepared from (R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-1,3-oxazinan-2-one and 5-chloropyridine-3-boronic acid following a procedure analogous to that described in Example 64. LC-MS Method 1 tR=1.97 min, m/z=451 (M+1); 1H NMR (CDCl3) 8.68 (d, 1H, J=2 Hz), 8.59 (d, 1H, J=2 Hz), 7.94 (t, 1H, J=2.2 Hz), 7.33-7.27 (m, 4H), 7.04 (ap q, 2H, J=9, 17 Hz), 5.75-5.65 (m, 2H), 5.12-5.02 (m, 2H), 3.03-2.98 (m, 1H), 2.66-2.54 (m, 2H), 2.41-2.17 (m, 3H), 1.56 (d, 3H, J=7 Hz).
Reaction SMILES: [O-][CH2:2]C.[Na+].[CH2:5]([O:7][C:8]([CH:10]=[C:11]([CH3:21])[CH2:12]P(=O)(OCC)OCC)=[O:9])[CH3:6].[CH3:22][S:23][C:24]([CH3:34])([CH3:33])[CH2:25][CH2:26][CH2:27][CH:28]([CH3:32])[CH2:29]C=O.CN(C)C=O>O>[CH3:22][S:23][C:24]([CH3:33])([CH2:25][CH2:26][CH2:27][CH:28]([CH3:29])[CH3:32])[CH2:34][CH:2]=[CH:12][C:11]([CH3:21])=[CH:10][C:8]([O:7][CH2:5][CH3:6])=[O:9]
Reactant: CCOC(=O)C=C(C)CP(=O)(OCC)OCC
Reactant: CSC(C)(C)CCCC(C)CC=O
Reactant: CC[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C=C(C)C=CCC(C)(CCCC(C)C)SC
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Sodium ethoxide (490 mg.) is added, during about 10 minutes and under nitrogen, to a stirred solution of diethyl 3-ethoxycarbonyl-2-methylprop-2-enylphosphonate (1.93 g.) and 7-methylthio-3,7-dimethyloctan-1-al (1.35 g.) in 20 ml. of dimethylformamide, cooled to 0°. The reaction mixture is stirred at room temperature for about 16 hours and then is diluted with water and extracted with ether. The ethereal extracts are washed with brine, dried over calcium sulfate and evaporated to yield ethyl 7-methylthio-3,7,11-trimethyldodeca-2,4-dienoate, predominantly the trans, trans isomer, which can be purified by chromatography or distillation.
Reaction SMILES: [Cl:1][C:2]1[S:14][C:5]2[NH:6][C:7](=[O:13])[C:8]([C:11]#[N:12])=[C:9]([OH:10])[C:4]=2[C:3]=1[C:15]1[CH:25]=[CH:24][C:18]([O:19][CH2:20][C:21]([OH:23])=O)=[CH:17][CH:16]=1.C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1.[NH2:51][CH2:52][CH2:53][CH2:54][OH:55]>>[Cl:1][C:2]1[S:14][C:5]2[NH:6][C:7](=[O:13])[C:8]([C:11]#[N:12])=[C:9]([OH:10])[C:4]=2[C:3]=1[C:15]1[CH:16]=[CH:17][C:18]([O:19][CH2:20][C:21]([NH:51][CH2:52][CH2:53][CH2:54][OH:55])=[O:23])=[CH:24][CH:25]=1
Reactant: N#Cc1c(O)c2c(-c3ccc(OCC(=O)O)cc3)c(Cl)sc2[nH]c1=O
Reactant: NCCCO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Product: N#Cc1c(O)c2c(-c3ccc(OCC(=O)NCCCO)cc3)c(Cl)sc2[nH]c1=O
Reaction time: 18 h

Procedure:
A suspension of 2-[4-(2-chloro-5-cyano-4-hydroxy-6-oxo-6,7-dihydrothieno[2,3-b]pyridin-3-yl)phenoxy]acetic acid (35 mg, 0.093 mmol), HOBt (13 mg, 0.093 mmol), PS-DCC (88 m, 0.121 mmol, 1.37 mmol/g loading), and 3-amino-propan-1-ol (7 mg, 0.0098 mmol) were shaken in a vial at 50 C for 18 h. The reaction was then filtered through celite, eluting with MeOH, and the eluent was concentrated under reduced pressure. The residue was purified by RP-HPLC to give the title compound. MS (ESI) m/e 432 (M−H)−; 1H NMR (300 MHz, DMSO-d6) δ ppm 1.60 (m, 2H), 3.21 (m, 2H), 3.42 (t, J=6.27 Hz, 2H), 4.49 (s, 2H), 6.95 (d, J=8.81 Hz, 2H), 7.23 (d, J=8.81 Hz, 2H), 8.11 (m, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH:5]=[C:6]([C:13]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[C:18]2[C:14]=1[CH:15]=[CH:16][NH:17]2)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:2]>CCO.C(Cl)Cl.[Pd]>[CH2:1]([O:3][C:4](=[O:24])[CH2:5][CH:6]([C:13]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[C:18]2[C:14]=1[CH:15]=[CH:16][NH:17]2)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)C=C(c1ccccc1)c1cc(OC)cc2[nH]ccc12
Agent: [Pd]
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)CC(c1ccccc1)c1cc(OC)cc2[nH]ccc12
Reaction time: 16 h

Procedure:
Degoussa-type catalyst (50% Pd/C, 45 mg) was added to a solution of 3-(6-Methoxy-1H-Indol-4-yl)-3-phenyl-acrylic acid ethyl ester CXVI (0.40 g, 1.2 mmol) in EtOH/DCM (6/1, 40 ml). The resulting mixture was hydrogenated in a Parr apparatus at 50 psi of H2 for 16 hours, filtered through celite, and the filter cake was washed with EtOH and DCM. The filtrate was concentrated, affording 3-(6-Methoxy-1H-Indol-4-yl)-3-phenyl-propionic acid ethyl ester CXVII.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:23]=[C:11]3[NH:12][C:13]([CH:16]4[CH2:21][CH2:20][NH:19][CH:18]([CH3:22])[CH2:17]4)=[N:14][CH:15]=[C:10]3[N:9]=2)[CH:5]=[CH:4][C:3]=1[O:24]C.B(Br)(Br)Br.CCN(CC)CC>C(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:23]=[C:11]3[NH:12][C:13]([C:16]4[CH:21]=[CH:20][N:19]=[C:18]([CH3:22])[CH:17]=4)=[N:14][CH:15]=[C:10]3[N:9]=2)[CH:5]=[CH:4][C:3]=1[OH:24]
Reactant: COc1ccc(-c2cc3[nH]c(C4CCNC(C)C4)ncc-3n2)cc1F
Agent: BrB(Br)Br
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(-c2ncc3nc(-c4ccc(O)c(F)c4)cc-3[nH]2)ccn1
Temperature: 25 °C
Reaction time: 20 h
Yield: 64.2 %

Procedure:
To a −78° C. solution of 2-fluoro-1-methoxy-4-[2-methyl-4-piperidylpyrrolo[4,5-d]pyrimidin-6-yl]benzene (Example 119) (0.80 g, 2.35 mmol) in CH2Cl2 (40 mL) under a N2 atmosphere was added 1 M BBr3 (4.7 mL, 4.70 mmol). The reaction mixture was allowed to warm to room temperature. The mixture was stirred at room temperature for an additional 20 h. The reaction mixture was then poured onto ice-water (200 mL) and the pH of the aqueous solution was adjusted to pH 9 with the addition of NEt3 (4 mL). The resulting mixture was stirred at room temperature for 2 h. The solid which formed was removed by filtration and dicarded. The remaining solution was transferred to a separatory funnel. The organic solution was separated, washed with H2O (100 mL), saturated NaCl (100 mL), dried (MgSO4), filtered and concentrated under reduced pressure to afford 483 mg (62%) of 2-fluoro-4-(2-methyl-4-pyridylpyrrolo[4,5-d]pyrimidin-6-yl)phenol as a pale yellow colored solid. This compound (481 mg, 1.50 mmol) was dissolved in 4:2:1 EtOAc/MeOH/CH2Cl2 (50 mL) and heated to boiling. To the hot solution was added 1 M ethereal HCl (1.50 mL, 1.50 mmol). The solution was allowed to cool to room temperature. The resulting solid was collected by filtration, washed with EtOAc (2×10 mL), Et2O (3×15 mL) and dried under vacuum at 60° C. to give 315 mg (37%) of the title compound as a pale yellow colored solid. Mp: >280° C. 1H NMR (DMSO-d6; 400 MHz): δ 1.63 (br s, 6), 2.49 (s, 3), 3.96 (br s, 4), 6.76 (s, 1), 7.06 (dt, 1, J=1.9, 8.7), 7;58 (d, 1, J=8.5), 7.83 (dd, 1, J=1.9, 12.5), 10.47 (s, 1), 11.79 (s, 1), 14.12 (s, 1). MS m/z: 327 (M+1 for free base). Anal. Calcd for C18H19FN4O.HCl.1.5H2O: C, 55.45; H, 5.95; N, 14.37; Cl, 9.09. Found: C, 55.49; H, 5.87; N, 14.07; Cl, 9.03.
Reaction SMILES: Cl.[S:2]1[CH:6]=[CH:5][C:4]2[CH:7]([NH2:11])[CH2:8][CH2:9][CH2:10][C:3]1=2.[C:12](Cl)(Cl)=[O:13]>C1(C)C=CC=CC=1>[S:2]1[CH:6]=[CH:5][C:4]2[CH:7]([N:11]=[C:12]=[O:13])[CH2:8][CH2:9][CH2:10][C:3]1=2
Reactant: O=C(Cl)Cl
Reactant: NC1CCCc2sccc21
Agent: Cl
Solvent: Cc1ccccc1
Product: O=C=NC1CCCc2sccc21

Procedure:
Alternatively, 5.7 grams of 4,5,6,7-tetrahydrobenzo[b]thien-4-amine hydrochloride is stirred in 20 ml. of toluene at 97°C., and phosgene is slowly introduced into the mixture via a capillary delivery tube. The mixture is heated to reflux temperature, and the flow of phosgene is continued until most of the amine hydrochloride disappears. The mixture is then filtered to remove unreacted amine hydrochloride, and the filtrate is evaporated to dryness under reduced pressure to give the 4,5,6,7-tetrahydrobenzo[b]thien-4-yl isocyanate.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]1[CH:7]=[CH:6][NH:5][N:4]=1.[H-].[Na+].F[C:13]1[CH:14]=[C:15]([CH:18]=[C:19]([O:21][C:22]2[N:26]([CH3:27])[N:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=2)[CH:20]=1)[C:16]#[N:17].O>CC(N(C)C)=O>[CH3:27][N:26]1[C:22]([O:21][C:19]2[CH:18]=[C:15]([CH:14]=[C:13]([N:5]3[CH:6]=[CH:7][C:3]([C:2]([F:9])([F:8])[F:1])=[N:4]3)[CH:20]=2)[C:16]#[N:17])=[CH:23][C:24]([C:28]([F:31])([F:30])[F:29])=[N:25]1
Reactant: Cn1nc(C(F)(F)F)cc1Oc1cc(F)cc(C#N)c1
Reactant: FC(F)(F)c1cc[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: Cn1nc(C(F)(F)F)cc1Oc1cc(C#N)cc(-n2ccc(C(F)(F)F)n2)c1
Temperature: 25 °C
Yield: 68 %

Procedure:
Under an atmosphere of nitrogen, 0.131 g (0.96 mmol) of 3-trifluoromethylpyrazole was initially charged in 5 ml of dimethylacetamide, and 0.033 g (1.1 mmol) of sodium hydride (80%) was added at 0° C. The mixture was allowed to warm to room temperature, and 0.250 g (0.88 mmol) of 3-fluoro-5-(1-methyl-3-trifluoromethylpyrazol-5-yloxy)benzonitrile was added, the mixture was heated at 140° C. for 8 h and cooled to room temperature, water was added to the reaction solution and the solution was stirred for a number of minutes. The mixture was extracted twice with heptane/ethyl acetate (1:1) and twice with ethyl acetate. The combined phases were washed with water and then dried over magnesium sulfate, filtered and concentrated. Column chromatography of the crude product gave 0.240 g of 3-(1-methyl-3-trifluoromethylpyrazol-5-yloxy)-5-(3-trifluoromethylpyrazol-1-yl)benzonitrile in the form of white crystals of melting point of 116-117° C.
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6](=[O:37])[CH2:7][C:8]1[C:17]([CH3:18])=[C:16]([C:19]2[CH:24]=[CH:23][C:22]([S:25]([C:28]3[CH:33]=[C:32]([F:34])[CH:31]=[C:30]([F:35])[CH:29]=3)(=[O:27])=[O:26])=[CH:21][CH:20]=2)[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([F:36])[CH:14]=2)[CH:9]=1>C1COCC1.O>[F:34][C:32]1[CH:33]=[C:28]([S:25]([C:22]2[CH:21]=[CH:20][C:19]([C:16]3[C:15]4[C:10](=[CH:11][CH:12]=[C:13]([F:36])[CH:14]=4)[CH:9]=[C:8]([CH2:7][C:6]([OH:37])=[O:5])[C:17]=3[CH3:18])=[CH:24][CH:23]=2)(=[O:27])=[O:26])[CH:29]=[C:30]([F:35])[CH:31]=1
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(-c2ccc(S(=O)(=O)c3cc(F)cc(F)c3)cc2)c1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(CC(=O)O)cc2ccc(F)cc2c1-c1ccc(S(=O)(=O)c2cc(F)cc(F)c2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 98.5 %

Procedure:
Lithium hydroxide monohydrate (0.019 g, 0.45 mmol) was added to a stirred solution of {4-[4-(3,5-difluorobenzenesulfonyl)-phenyl]-6-fluoro-3-methyl-naphthalen-2-yl}-acetic acid methyl ester (0.055 g, 0.11 mmol) in a 3:1 THF—H2O mixture (4 mL). The reaction mixture was stirred for 16 hours at room temperature. The THF was distilled off under reduced pressure, and the crude residue was diluted with water, acidified [pH˜2] via the drop-wise addition of an aqueous solution of hydrochloric acid (6.0 N). The mixture was extracted twice with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product. Trituration with hexanes afforded {4-[4-(3,5-difluorobenzenesulfonyl)-phenyl]-6-fluoro-3-methyl-naphthalen-2-yl}-acetic acid (0.051 g, 96%) as a solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.48 (br. s., 1 H) 8.22 (d, J=7.82 Hz, 2 H) 7.97-8.05 (m, 1 H) 7.87-7.92 (m, 3 H) 7.74 (t, J=9.29 Hz, 1 H) 7.55 (d, J=7.82 Hz, 2 H) 7.35-7.42 (m, 1 H) 6.66 (d, J=11.74 Hz, 1 H) 3.84 (s, 2 H) 2.03 (s, 3 H) MS calcd. for C25H16F3O4S [(M−H)−] 469, obsd. 469.4.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][CH3:15])[C:10]([CH3:17])([CH3:16])[CH2:9]1)C1C=CC=CC=1>CO.[H][H].[OH-].[OH-].[Pd+2]>[CH3:15][NH:14][CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][C:10]1([CH3:17])[CH3:16]
Reactant: [H][H]
Reactant: CNC1CCN(Cc2ccccc2)CC1(C)C
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CNC1CCNCC1(C)C

Procedure:
A mixture of 20% Pd(OH)2 on carbon (0.15 g) and 1-benzyl-4-methylamino-3,3-dimethylpiperidine (0.5 g, 2.1 mmol) in methanol (10 ml) was stirred in hydrogen atmosphere (1 atm.) at 60° C. for 6 hr. The catalyst was filtered off, washed with methanol and filtrate was concentrated to dryness to afford 4-methylamino-3,3-dimethyl-piperidine. Yield 0.3 g (99%), C8H18N2, m/z 143 (M+1), PMR (CDCl3): 0.88 (s, 6H), 1.24 (m, 2H), 1.8 (bs, 2H, D2O exchangeable), 1.8 (m, 1H), 2.1 (m, 1H), 2.4 (s, 3H), 2.6 (d, 2H), 2.86 (m, 1H).
Reaction SMILES: [CH2:1]([NH:8][C:9]([N:11]1[CH2:16][CH2:15][C:14](=[O:17])[N:13]2[C@@H:18]([CH2:35][C:36]3[CH:41]=[CH:40][C:39]([OH:42])=[CH:38][CH:37]=3)[C:19](=[O:34])[N:20]([CH2:23][C:24]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH:27]=[CH:26][CH:25]=3)[C@@H:21]([CH3:22])[CH:12]12)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1COCC1.[C:48](Cl)(=[O:60])[CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH3:59].C(N(CC)CC)C>C(OCC)(=O)C>[C:48]([O:42][C:39]1[CH:40]=[CH:41][C:36]([CH2:35][C@@H:18]2[N:13]3[C:14](=[O:17])[CH2:15][CH2:16][N:11]([C:9](=[O:10])[NH:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[CH:12]3[C@H:21]([CH3:22])[N:20]([CH2:23][C:24]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH:27]=[CH:26][CH:25]=3)[C:19]2=[O:34])=[CH:37][CH:38]=1)(=[O:60])[CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH3:59]
Reactant: CCCCCCCCCCCC(=O)Cl
Reactant: C[C@H]1C2N(C(=O)NCc3ccccc3)CCC(=O)N2[C@@H](Cc2ccc(O)cc2)C(=O)N1Cc1cccc2ccccc12
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCC(=O)Oc1ccc(C[C@H]2C(=O)N(Cc3cccc4ccccc34)[C@@H](C)C3N(C(=O)NCc4ccccc4)CCC(=O)N32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78 %

Procedure:
To a solution of (6S,9S)—N-benzyl-6-(4-hydroxybenzyl)-9-methyl-8-(naphthalen-1-ylmethyl)-4,7-dioxooctahydro-1H-pyrazino[1,2-a]pyrimidine-1-carboxamide 60 mg (0.106 mmol) in dry-THF (2 ml), dodecanoyl chloride 76 μl (0.319 mmol) and then triethylamine 45 μl (0.319 mmol) were added and stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate (10 ml) and washed with water (10 ml), saturated sodium bicarbonate (10 ml), water (10 ml), and brine (10 ml). The organic layer was dried with sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified by Büchi silica gel column chromatography (chloroform:methanol=99:1 to 98:2) to obtain title compound 61.6 mg (78%).
Reaction SMILES: [CH2:1]([C@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]([OH:14])=O)[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5].S(Cl)([Cl:17])=O>>[CH2:1]([C@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]([Cl:17])=[O:14])[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCC[C@H]1CC[C@H](C(=O)O)CC1
Reactant: O=S(Cl)Cl
Product: CCCCC[C@H]1CC[C@H](C(=O)Cl)CC1

Procedure:
5.58 g Of trans-4-pentylcyclohexylcarboxylic acid was heated with 20 ml of thionyl chloride under reflux conditions. After the reaction was completed, the excess of thionyl chloride was removed completely under reduced pressure and the product residue obtained was distilled under reduced pressure. Trans-4-pentylcyclohexylcarbonyl chloride having a boiling point of 103° to 105° C./0.5 mmHg was obtained.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)=[N:4][O:5][C:6]=1[C:7]([F:10])([F:9])[F:8].[C:16](Cl)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH3:1][C:2]1[C:3]([C:11]2[S:12][C:13]([C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:23])=[CH:14][CH:15]=2)=[N:4][O:5][C:6]=1[C:7]([F:8])([F:10])[F:9]
Reactant: O=C(Cl)c1ccccc1
Reactant: Cc1c(-c2cccs2)noc1C(F)(F)F
Product: Cc1c(-c2ccc(C(=O)c3ccccc3)s2)noc1C(F)(F)F
Yield: 70 %

Procedure:
Prepared from 4-Methyl-3-thiophen-2-yl-5-trifluoromethyl-isoxazole and benzoyl chloride by the method described in Example 3. Crude product was chromatographed on silica gel with EtOAc/hexanes (10 then 20%) as eluant to afford product as a colorless solid (118 mg, 70%). 1H NMR (CDCl3) 2.33 (d, J=1.3, 3 H), 7.43-7.59 (m, 4 H), 7.62 (d, J=4.0, 1 H), 7.80-7.83 (m, 2 H). 13C NMR 7.9, 118.7 (q, J =271), 128.8, 128.9, 129.4, 133.0, 134.8, 136.3, 137.7, 145.8, 155.5 (q, J=40), 157.9, 188.0. 19F NMR −63.1. LC/MS 7.29 min, [M+1]+ 338.