Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10])=[O:2].Cl.Cl[C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OCOCC)C>CC([O-])=O.CC([O-])=O.[Pd+2].C([O-])([O-])=O.[K+].[K+]>[CH3:10][O:9][C:8]1[CH:7]=[CH:6][C:5]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)=[CH:4][C:3]=1[CH:1]=[O:2]
Reactant: Clc1ccncc1
Reactant: COc1ccc(B(O)O)cc1C=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: CCOCOCC
Product: COc1ccc(-c2ccncc2)cc1C=O
Temperature: 80 °C

Procedure:
To a 1 L 3-neck RB flask equipped with a N2 inlet, condenser and temperature probe is added 3-formyl-4-methoxyphenylboronic acid P15 (25.62 g, 142.38 mmol), 4-chloropyridine hydrochloride (23.65 g, 157.66 mmol), triphenylphosphine (3.77 g, 14.37 mmol), diethoxymethane (140 mL), and a solution of K2CO3 (2.7M, 150 mL). The yellow slurry is degassed with N2 for 10 minutes and Pd(OAc)2 (840.9 mg, 3.74 mmol) is added. The mixture is heated to 80° C. for 19 h. The layers are separated and the aqueous layer is extracted with EtOAc. The combined organic extracts are concentrated in vacuo and purified by filter chromatography on SiO2 eluting with EtOAc/hexanes (30 to 100%) followed by 3% MeOH/EtOAc, to give 2-methoxy-5-(pyridin-4-yl)benzaldehyde P9 (29.97 g, 99%) as a yellow solid. (L30464-208, 266146). To remove excess palladium 2-methoxy-5-(pyridin-4-yl)benzaldehyde P9 (28.26 g, 132.53 mmol) in EtOAc (500 mL) is treated with N-acetylcysteine (2.22 g, 13.58 mmol) in H2O (100 mL). The mixture is stirred for 4 h diluted with H2O and the layers are separated. The aqueous layer is extracted with EtOAc (5×200 mL) and the combined organic extracts are concentrated in vacuo and filtered through a Magnesol pad to give 2-methoxy-5-(pyridin-4-yl)benzaldehyde P9 (25.33 g, 90%) as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[C:25]4[O:24][CH2:23][CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][C:18]=4[C:17]([F:33])=[C:16]([Cl:34])[CH:15]=3)[CH3:13])[N:9]=[C:10]([CH3:11])[C:3]=12.C(Cl)Cl.C(N(CC)C(C)C)(C)C.[CH3:47][S:48](Cl)(=[O:50])=[O:49]>>[Cl:34][C:16]1[CH:15]=[C:14]([CH:12]([N:8]2[C:4]3=[N:5][CH:6]=[N:7][C:2]([NH2:1])=[C:3]3[C:10]([CH3:11])=[N:9]2)[CH3:13])[C:25]2[O:24][CH2:23][CH2:22][CH2:21][N:20]([S:48]([CH3:47])(=[O:50])=[O:49])[CH2:19][C:18]=2[C:17]=1[F:33]
Reactant: Cc1nn(C(C)c2cc(Cl)c(F)c3c2OCCCN(C(=O)OC(C)(C)C)C3)c2ncnc(N)c12
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nn(C(C)c2cc(Cl)c(F)c3c2OCCCN(S(C)(=O)=O)C3)c2ncnc(N)c12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
tert-Butyl 10-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-8-chloro-7-fluoro-3,4-dihydro-2H-1,5-benzoxazocine-5(6H)-carboxylate (8 mg, 0.02 mmol) was stirred in methylene chloride (80 μL, 1 mmol) with N,N-diisopropylethylamine (8.5 μL, 0.049 mmol) and cooled to 0° C. Methanesulfonyl chloride (1.6 μL, 0.021 mmol) was added and the mixture was stirred at 0° C. for 1 hr. The mixture was evaporated and diluted with methanol and purified by preparative LCMS (pH 10) to give Example 45. LCMS calculated for C19H23ClFN6O3S (M+H)+: m/z=469.1; found: 469.1. 1H NMR (300 MHz, CD3OD): δ 8.14 (s, 1 H), 7.65 (m, 1 H), 6.36 (m, 1 H), 4.58 (m, 2 H), 4.21 (m, 2 H), 3.52 (m, 2 H), 2.87 (s, 3 H), 2.60 (s, 3 H), 1.91 (m, 2 H), 1.80 (m, 3 H).
Reaction SMILES: N1C(C)=CC=CC=1C.[CH2:9]([C:11]([C:30]1[CH:35]=[CH:34][C:33]([C:36]#[C:37][C:38]2([OH:44])[CH2:43][CH2:42][S:41][CH2:40][CH2:39]2)=[C:32]([CH3:45])[CH:31]=1)([C:14]1[CH:19]=[CH:18][C:17]([B:20]2[O:24][C:23]([CH3:26])([CH3:25])[C:22]([CH3:28])([CH3:27])[O:21]2)=[C:16]([CH3:29])[CH:15]=1)[CH2:12][CH3:13])[CH3:10].O([Si:54]([CH3:57])([CH3:56])[CH3:55])S(C(F)(F)F)(=O)=O.O>ClCCl>[CH2:9]([C:11]([C:14]1[CH:19]=[CH:18][C:17]([B:20]2[O:24][C:23]([CH3:25])([CH3:26])[C:22]([CH3:27])([CH3:28])[O:21]2)=[C:16]([CH3:29])[CH:15]=1)([C:30]1[CH:35]=[CH:34][C:33]([C:36]#[C:37][C:38]2([O:44][Si:54]([CH3:57])([CH3:56])[CH3:55])[CH2:39][CH2:40][S:41][CH2:42][CH2:43]2)=[C:32]([CH3:45])[CH:31]=1)[CH2:12][CH3:13])[CH3:10]
Reactant: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: CCC(CC)(c1ccc(C#CC2(O)CCSCC2)c(C)c1)c1ccc(B2OC(C)(C)C(C)(C)O2)c(C)c1
Solvent: ClCCl
Solvent: O
Solvent: Cc1cccc(C)n1
Product: CCC(CC)(c1ccc(C#CC2(O[Si](C)(C)C)CCSCC2)c(C)c1)c1ccc(B2OC(C)(C)C(C)(C)O2)c(C)c1
Reaction time: 4 h
Yield: 86.3 %

Procedure:
2,6-Lutidine (0.76 mL, 5 mmol) was added to a solution of 4-(4-{1-ethyl-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-propyl}-2-methyl-phenylethynyl)-tetrahydro-thiopyran-4-ol (Example 136-(3); 0.53 g, 1 mmol) in dichloromethane (5 mL). Trimethylsilyl triflate (0.32 mL, 2.5 mmol) was added at 0° C., and the mixture was stirred at the same temperature for four hours. Water was added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (hexane:ethyl acetate=1:1) to give the title compound (0.51 g, 84%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH:5]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:6](O)=O)[CH3:2].N1CCCCC1.C=O>N1C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:16])[C:5]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[CH2:6])[CH3:2]
Reactant: CCOC(=O)C(Cc1ccccc1)C(=O)O
Agent: C=O
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: C=C(Cc1ccccc1)C(=O)OCC
Temperature: 130 °C
Yield: 84.7 %

Procedure:
Benzylmalonic acid monoethyl ester (8.0 g, 36 mmol), 7 mL of pyridine, 0.36 mL (3.6 mmol) of piperidine, and 1.06 g (35 mmol) of paraformaldehyde is refluxed under nitrogen for 1.5 hours in an oil bath maintained at 130° C. After cooling for 0.5 hours the mixture is partitioned between 100 mL of water and 100 mL of hexane. The aqueous phase is re-extracted with 50 mL of hexane. The organic phase is washed with aqueous 10% HCl, water, 1M sodium bicarbonate, and brine. It is dried over anhydrous sodium sulfate and concentrated in vacuo, yielding 5.8 g of the title compound as a colorless oil.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:7]([OH:8])[CH2:6][N:5]([CH2:9][CH2:10][N:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([F:21])[CH:19]=3)[CH:14]=[CH:13][C:12]2=[O:22])[CH2:4]1.[O:23]1[C:32]2[CH:31]=[C:30]([CH:33]=O)[N:29]=[CH:28][C:27]=2[O:26][CH2:25][CH2:24]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[ClH:49]>CO.CCOCC.C(Cl)Cl>[ClH:49].[ClH:49].[O:23]1[C:32]2[CH:31]=[C:30]([CH2:33][NH:1][CH2:2][C@@H:3]3[C@H:7]([OH:8])[CH2:6][N:5]([CH2:9][CH2:10][N:11]4[C:20]5[C:15](=[CH:16][CH:17]=[C:18]([F:21])[CH:19]=5)[CH:14]=[CH:13][C:12]4=[O:22])[CH2:4]3)[N:29]=[CH:28][C:27]=2[O:26][CH2:25][CH2:24]1
Reactant: O=Cc1cc2c(cn1)OCCO2
Reactant: NC[C@H]1CN(CCn2c(=O)ccc3ccc(F)cc32)C[C@H]1O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CCOCC
Solvent: ClCCl
Product: O=c1ccc2ccc(F)cc2n1CCN1C[C@H](CNCc2cc3c(cn2)OCCO3)[C@H](O)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 1-{2-[(3S,4S)-3-(aminomethyl)-4-hydroxy-1-pyrrolidinyl]ethyl}-7-fluoro-2(1H)-quinolinone (60 mg; 0.2 mmol) and 2,3-dihydro[1,4]dioxino[2,3-c]pyridine-7-carboxaldehyde (for a synthesis see WO2004058144, Example 2(c) or WO03/087098, Example 19(d)) (32 mg, 0.2 mmol) in methanol (1 mL), DCM (3 mL) was stirred at room temperature overnight. Sodium triacetoxyborohydride (85 mg; 0.4 mmol) was added and the mixture was stirred at room temperature for 1 hour. The reaction was evaporated and chromatographed on silica gel, eluting with 0-10% methanol-DCM-1% NH4OH to give an oil. The oil was treated with 1M HCl in Et2O to give the title compound (50 mg) as a hydrochloride salt.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]2[CH:16]=[CH:15][C:14](OS(C(F)(F)F)(=O)=O)=[CH:13][CH:12]=2)[CH2:7][CH2:6]1.[C:26]([Si:30]([CH3:36])([CH3:35])[O:31][CH2:32][CH2:33][NH2:34])([CH3:29])([CH3:28])[CH3:27].C(=O)([O-])[O-].[Cs+].[Cs+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CCCCCCC.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:25])[CH2:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]2[CH:16]=[CH:15][C:14]([NH:34][CH2:33][CH2:32][O:31][Si:30]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:36])[CH3:35])=[CH:13][CH:12]=2)[CH2:7][CH2:6]1
Reactant: COC(=O)C[C@H]1CC[C@H](c2ccc(OS(=O)(=O)C(F)(F)F)cc2)CC1
Reactant: CC(C)(C)[Si](C)(C)OCCN
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: COC(=O)C[C@H]1CC[C@H](c2ccc(NCCO[Si](C)(C)C(C)(C)C)cc2)CC1

Procedure:
Methyl[trans-4-[4-[[(trifluoromethyl)sulfonyl]oxy]phenyl]cyclohexyl]acetate, shown above, which is identified as Compound 55 in U.S. Pat. No. 7,244,727, issued Jul. 17, 2007, was prepared according to the method described therein. A mixture of methyl[trans-4-[4-[[(trifluoromethyl)-sulfonyl]oxy]phenyl]cyclohexyl]acetate (10.1 g, 26.6 mmol), 2-{[tert-butyl (dimethyl)silyl]oxy}ethanamine (5.59 g, 31.9 mmol), which can be prepared by various methods including those disclosed in Journal of the American Chemical Society, 129(37), 11408-11420; 2007, Organic Letters, 9(1), 101-104; 2007 or Bioorganic & Medicinal Chemistry, 13(11), 3821-3839; 2005, cesium carbonate (8.65 g, 26.6 mmol), palladium acetate (0.60 g, 2.66 mmol) and X-PHOS (1.27 g, 2.66 mmol) in toluene (53 mL) under nitrogen was heated in a sealed tube at 120° C. for 16 hours. The reaction was cooled, diluted into EtOAc, washed with water (2×), saturated aqueous brine, dried over sodium sulfate and concentrated to afford a dark oil. Chromatography (330 g Biotage Snap Cartridge® silica gel column, 0-15% EtOAc:heptane) afforded methyl(trans-4-{4-[(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-amino]phenyl}cyclohexyl)acetate as a light-yellow oil, 6.70 g. 1H NMR (400 MHz, CDCl3): δ 7.02, (d, 2H), 6.61 (d, 2H), 3.80 (m, 2H), 3.64 (s, 3H), 3.20 (m, 2H), 2.37 (m, 1H), 2.24 (m, 2H), 1.85 (m, 5H), 1.44 (m, 2H), 1.13 (m, 2H), 0.87 (s, 9H), 0.04 (s, 6H). m/z=406.4 (M+1).
Reaction SMILES: [CH2:1]([N:4]([CH2:22][CH2:23][CH3:24])[C:5]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:8]([C:14]([F:17])([F:16])[F:15])=[C:7](Cl)[C:6]=1[N+:19]([O-:21])=[O:20])[CH2:2][CH3:3].[NH3:25]>C(O)C>[CH2:1]([N:4]([CH2:22][CH2:23][CH3:24])[C:5]1[C:6]([N+:19]([O-:21])=[O:20])=[C:7]([NH2:25])[C:8]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[CH2:2][CH3:3]
Reactant: N
Reactant: CCCN(CCC)c1c([N+](=O)[O-])cc(C(F)(F)F)c(Cl)c1[N+](=O)[O-]
Solvent: CCO
Product: CCCN(CCC)c1c([N+](=O)[O-])cc(C(F)(F)F)c(N)c1[N+](=O)[O-]
Temperature: 100 °C

Procedure:
A glass reaction tube was charged with 4.0 grams (0.0108 mole) of N,N-di-n-propyl-3-chloro-2,6-dinitro-4-trifluoromethylaniline, 5.82 grams (0.0237 mole) of 6.95% ethanolic ammonia and 35 ml. of ethanol. The tube was sealed and heated in an oven at 100°C. for 68 hours. The contents of the tube were cooled and the ethanol removed by evaporation. Water was added to the solid orange rsidue to dissolve the ammnium chloride and the insoluble produced was separated by filtration. The product was dissolved in refluxing 95% ethanol. Upon cooling, orange needles and a yellow powder crystallized. The yellow powder was identified as 2,4-dinitro-6-trifluoromethyl-1,3-phenylenediamine and was separated from the desired product by filtration after extracting with boiling hexane. The desired product dissolved in the hexane and was isolated from the filtrate by evaporation of the hexane. The residue was recyrstallized from 95% ethanol to give orange needles, m.p. 124° - 125°C.
Reaction SMILES: [C:1]([NH:9][N:10]=[CH:11][C:12](Cl)([Cl:14])[Cl:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])=O.[Na+]>CC(C)=O>[C:1]([N:9]=[N:10][CH:11]=[C:12]([Cl:13])[Cl:14])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(NN=CC(Cl)(Cl)Cl)c1ccccc1
Agent: O=C[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: O=C(N=NC=C(Cl)Cl)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
14 g of N-benzoyl-N'-(2,2,2-trichloroethylidene) hydrazine was dissolved in 350 ml of acetone, to which was added 5.0 g of sodium formate, followed by stirring at room temperature for 2 hours to obtain a red reaction mixture. The acetone was distilled off under reduced pressure and the residue was subjected to extraction with benzene. The benzene layer was washed with water, dried and subjected to distillation to remove the solvent to obtain 9.7 g of dark red, oily 1-benzoylazo-2,2-dichloroethylene (at 80% of the theoretical).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH:13]([CH2:15][N:16]3[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][C:24]([O:26]CC)=[O:25])[CH2:18][CH2:17]3)[O:12][C:11]2=[O:29])=[CH:6][CH:5]=1)(=[NH:3])[NH2:2].[OH-].[Na+].O1CCOCC1>O>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:14][CH:13]([CH2:15][N:16]3[CH2:17][CH2:18][N:19]([CH2:22][CH2:23][C:24]([OH:26])=[O:25])[CH2:20][CH2:21]3)[O:12][C:11]2=[O:29])=[CH:8][CH:9]=1)(=[NH:2])[NH2:3]
Reactant: CCOC(=O)CCN1CCN(CC2CN(c3ccc(C(=N)N)cc3)C(=O)O2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: N=C(N)c1ccc(N2CC(CN3CCN(CCC(=O)O)CC3)OC2=O)cc1
Reaction time: 5 h

Procedure:
A mixture of 1 g of ethyl 3-(4-(3-(4-amidinophenyl)-2-oxo-5-oxazolidinylmethyl)-1-piperazinyl)propionate, 0.2 g of NaOH, 8 ml of dioxane and 2 ml of water is stirred at 20° for 5 hours. After acidification and conventional work-up, 3-(4-(3-(4-amidinophenyl)-2-oxo-5oxazolidinylmethyl)-1-piperazinyl)propionic acid m.p. 269°, is obtained
Reaction SMILES: Br[C:2]1[N:6]=[CH:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([O:13][C:14]([F:17])([F:16])[F:15])=[CH:9][CH:8]=2)[N:3]=1.CC1(C)C(C)(C)OB([C:26]2[CH:31]=[CH:30][C:29]([CH2:32][C:33]([O:35][CH3:36])=[O:34])=[CH:28][CH:27]=2)O1.F[B-](F)(F)F.C([PH+](C(C)(C)C)C(C)(C)C)(C)(C)C.[F-].[Cs+]>O1CCOCC1.O.C(O[Pd]OC(=O)C)(=O)C>[F:15][C:14]([F:17])([F:16])[O:13][C:10]1[CH:11]=[CH:12][C:7]([N:4]2[CH:5]=[N:6][C:2]([C:26]3[CH:31]=[CH:30][C:29]([CH2:32][C:33]([O:35][CH3:36])=[O:34])=[CH:28][CH:27]=3)=[N:3]2)=[CH:8][CH:9]=1
Reactant: COC(=O)Cc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: FC(F)(F)Oc1ccc(-n2cnc(Br)n2)cc1
Agent: CC(=O)O[Pd]OC(C)=O
Agent: CC(C)(C)[PH+](C(C)(C)C)C(C)(C)C
Agent: F[B-](F)(F)F
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)Cc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Temperature: 60 °C
Reaction time: 18 h

Procedure:
In a 200 mL flask, 3-bromo-1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazole (3.45 g, 11.2 mmol), and methyl 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetate (3.71 g, 13.4 mmol) were diluted with dioxane (45 mL) and water (11 mL). This solution was sparged with nitrogen gas for 10 minutes. Then tri-tert-butylphosphonium tetrafluoroborate (0.325 g, 1.12 mmol), diacetoxypalladium (0.126 g, 0.560 mmol) and cesium fluoride (3.40 g, 22.4 mmol) were added as solids. The flask was sealed and evacuated with vacuum and purged with nitrogen gas. The reaction was warmed to an internal temperature of 60° C. and stirred for 18 hours. The reaction was poured into a brine solution and extracted with ethyl acetate (3×50 mL). The combined organics were dried over magnesium sulfate, filtered, and concentrated. The resulting residue was purified by flash chromatography using 0-10% ethyl acetate/hexanes as eluent to afford the title compound as an off white solid (3.45 g, 82%): 1H NMR (400 MHz, DMSO-d6) δ 9.41 (s, 1H), 8.11-8.04 (m, 4H), 7.63 (ddt, J=7.9, 2.1, 1.1 Hz, 2H), 7.48-7.36 (m, 2H), 3.77 (s, 2H), 3.64 (s, 3H); 19F NMR (376 MHz, DMSO-d6) δ −57.02; ESIMS m/z 378 ([M+H]+)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9](=[N:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:10][CH3:11])[CH:5]=[CH:6][C:7]=1[Cl:8].[C:19]1([C:25]#[C:26][C:27]([O:29]CC)=O)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[Cl-].[Al+3].[Cl-].[Cl-].S(=O)(=O)(O)O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:12]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:25]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:26][C:27](=[O:29])[C:10]=2[CH3:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CCC(=Nc1ccccc1)c1ccc(Cl)c(Cl)c1
Reactant: CCOC(=O)C#Cc1ccccc1
Agent: O=S(=O)(O)O
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: Cc1c(-c2ccc(Cl)c(Cl)c2)n(-c2ccccc2)c(-c2ccccc2)cc1=O
Reaction time: 96 h
Yield: 21.3 %

Procedure:
To 500 ml of toluene were added 6.2 g (0.022 mole) of 1-(3,4-dichlorophenyl)-N-phenylpropaneimine and 3.9 g (0.022 mole) of ethyl phenylpropiolate, followed by addition of 3.6 g (0.023 mole) of aluminum chloride. After heating the reaction mixture with stirring at 60°-70° C. for 4 days under a nitrogen atmosphere, the reaction mixture was poured into 400 ml of 2N sulfuric acid which had been ice-cooled, followed by extraction with dichloromethane. After washing the organic layer with water, it was dried over anhydrous sodium sulfate. Subsequent to removal of the sodium sulfate, the solvent was distilled off and the residue was purified by chromatography on a silica gel column (eluent: ethyl acetate). The resulting crystals were recrystallized from a 2:1 mixed solvent of acetone and hexane to afford 1.9 g of 2-(3,4-dichlorophenyl)-3-methyl-1,6-diphenyl-4(1H)-pyridinone having a melting point of 188°-191° C.
Reaction SMILES: [C:1]1([C:7]2[C:11]([C:12]([F:15])([F:14])[F:13])=[C:10]([C:16]([OH:18])=[O:17])[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[CH2:20]Cl>CO>[C:1]1([C:7]2[C:11]([C:12]([F:13])([F:14])[F:15])=[C:10]([C:16]([O:18][CH3:20])=[O:17])[O:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: ClCCl
Reactant: O=C(O)c1onc(-c2ccccc2)c1C(F)(F)F
Solvent: CO
Product: COC(=O)c1onc(-c2ccccc2)c1C(F)(F)F
Reaction time: 0.5 h
Yield: 97 %

Procedure:
To a solution of 3-phenyl-4-(trifluoromethyl)isoxazole-5-carboxylic acid (Intermediate I-3D, 0.500 g, 1.94 mmol) in dichloromethane (5 mL) and methanol (1 mL) at room temperature was added trimethyldiazomethane (2.0 M in ether) (1.26 mL, 2.53 mmol) slowly over 5 min. The resulting reaction mixture was stirred for 30 min. The reaction mixture was diluted with dichloromethane (40 mL) and washed with brine (20 mL). The aqueous layer was extracted with dichloromethane (2×20 mL), and the organic layers were combined and dried over anhydrous sodium sulfate. Concentration under reduced pressure afforded methyl 3-phenyl-4-(trifluoromethyl)isoxazole-5-carboxylate (0.513 g, 1.89 mmol, 97% yield) as a yellow oil. The product had an HPLC ret. time=2.55 min. (condition A); LC/MS M+1=272.0; 1H NMR (400 MHz, CDCl3) δ ppm 4.07 (s, 3H), 7.47-7.56 (m, 3H), and 7.59 (d, J=7.04 Hz, 2H).
Reaction SMILES: ClC1C=CC=CC=1C(N[C@H]1CCC[C@@H]1N[C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][N:14]=1)=O.Cl.[NH2:28][C@H:29]1[CH2:33][CH2:32][CH2:31][C@@H:30]1[NH:34][C:35](=[O:44])[C:36]1[C:41]([F:42])=[CH:40][CH:39]=[CH:38][C:37]=1[F:43].ClC1C=CC(C(F)(F)F)=CN=1>>[F:42][C:41]1[CH:40]=[CH:39][CH:38]=[C:37]([F:43])[C:36]=1[C:35]([NH:34][C@H:30]1[CH2:31][CH2:32][CH2:33][C@@H:29]1[NH:28][C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][N:14]=1)=[O:44]
Reactant: N[C@H]1CCC[C@@H]1NC(=O)c1c(F)cccc1F
Reactant: O=C(N[C@H]1CCC[C@@H]1Nc1ccc(C(F)(F)F)cn1)c1ccccc1Cl
Agent: Cl
Agent: FC(F)(F)c1ccc(Cl)nc1
Product: O=C(N[C@H]1CCC[C@@H]1Nc1ccc(C(F)(F)F)cn1)c1c(F)cccc1F

Procedure:
Prepared according to the procedure for 2-chloro-N-[(1S,2S)-2-{[5-(trifluoromethyl)pyridin-2-yl]amino}cyclopentyl]benzamide (Example 69) from N-[(1S,2S)-2-amino cyclopentyl]-2,6-difluorobenzamide hydrochloride (Intermediate 21; 100 mg, 0.36 mmol) and 2-chloro-5-(trifluoromethyl)pyridine (CAS number 52334-81-3; 79 mg, 0.43 mmol) to afford the title compound.
Reaction SMILES: [CH2:1]([O:4][C:5]1([CH3:34])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[N:17]=[C:18]([CH2:20]O)[CH:19]=[C:15]3[N:14]=[C:13]([CH3:22])[C:12]=2[C@H:23]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:7][CH2:6]1)[CH:2]=[CH2:3].P([N:51]=[N+:52]=[N-:53])(=O)(OC1C=CC=CC=1)OC1C=CC=CC=1.C1CCN2C(=NCCC2)CC1>C1(C)C=CC=CC=1.CCOCC>[CH2:1]([O:4][C:5]1([CH3:34])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[N:17]=[C:18]([CH2:20][N:51]=[N+:52]=[N-:53])[CH:19]=[C:15]3[N:14]=[C:13]([CH3:22])[C:12]=2[C@H:23]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:7][CH2:6]1)[CH:2]=[CH2:3]
Reactant: [N-]=[N+]=NP(=O)(Oc1ccccc1)Oc1ccccc1
Reactant: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OCC)c(C)nc3cc(CO)nn23)CC1
Solvent: CCOCC
Solvent: Cc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OCC)c(C)nc3cc(CN=[N+]=[N-])nn23)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.3 %

Procedure:
To a stirred solution of (S)-ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(hydroxymethyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (0.70 g, 1.475 mmol) and diphenyl phosphorazidate (0.381 ml, 1.770 mmol) in toluene (10 mL) was added DBU (0.222 ml, 1.475 mmol) at 0° C. After 2 h, cold bath was removed, stirred for 22 h at rt. LCMS at 8 and 22 h is same and incomplete. So, added THF (10 mL) to the turbid reaction mixture and heated at 55° C. for 5 h. Then diluted with Et2O (100 mL), washed with water (2×10 mL), brine (10 mL), dried (MgSO4), filtered, concentrated and purified by flash chromatography using 15 and 20% EtOAc/Hex to provide (S)-ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(azidomethyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (0.5038 g, 1.008 mmol, 68.4% yield) as colorless viscous oil. 1H NMR (500 MHz, CDCl3) δ 6.51 (s, 1H), 6.00-6.09 (m, 1H), 5.92 (br. s., 1H), 5.46 (d, J=16.6 Hz, 1H), 5.23 (dd, J=1.4, 10.4 Hz, 1H), 4.46-4.53 (m, 2H), 4.15-4.29 (m, 2H), 4.00-4.04 (m, 2H), 2.63 (s, 3H), 1.90-2.04 (m, 3H), 1.67-1.76 (m, 1H), 1.36 (s, 3H), 1.23-1.27 (m, 12H). 4H of piperidine are missing. LCMS (M+H)=500.5.
Reaction SMILES: C[O:2][C:3](=[O:37])[C@H:4]([CH2:27][C:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[NH:30][CH:29]=1)[NH:5][C:6](=[O:26])[C@H:7]([C@H:22]([CH2:24][CH3:25])[CH3:23])[NH:8][S:9]([C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1)(=[O:11])=[O:10].C1COCC1.[OH-].[K+].Cl>O.CO>[C:12]1([S:9]([NH:8][C@H:7]([C:6]([NH:5][C@H:4]([C:3]([OH:37])=[O:2])[CH2:27][C:28]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[NH:30][CH:29]=2)=[O:26])[C@H:22]([CH2:24][CH3:25])[CH3:23])(=[O:11])=[O:10])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1
Reactant: CC[C@H](C)[C@H](NS(=O)(=O)c1cccc2ccccc12)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)OC
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC[C@H](C)[C@H](NS(=O)(=O)c1cccc2ccccc12)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Temperature: 0 °C
Reaction time: 20 h
Yield: 98.3 %

Procedure:
To an ice-cooled mixture of N-(1-naphthylsulfonyl)-(L)-isoleucyl-(L)-tryptophan methyl ester (6.9 g) and THF (40 ml)-methanol (20 ml) was added dropwise a solution of KOH (1.5 g) in water (10 ml). After stirring at 0° C. for 20 hours, the reaction mixture was acidified with 1N HCl (35 ml) with ice-cooling, diluted with water and extracted with ethyl acetate. The ethyl acetate layer was washed with brine and dried (MgSO4). The organic solvent was evaporated off to yield N-(1-naphthylsulfonyl)-(L)-isoleucyl-(L)-tryptophan (6.6 g, 98%) as crystals. Melting point: 167°-168° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:11])[CH:7]=[CH:8][C:9]=1[CH3:10])([O-])=O.[H][H]>[Ni].O1CCCC1>[NH2:1][C:4]1[CH:5]=[C:6]([OH:11])[CH:7]=[CH:8][C:9]=1[CH3:10]
Reactant: Cc1ccc(O)cc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Ni]
Solvent: C1CCOC1
Product: Cc1ccc(O)cc1N
Reaction time: 3.5 h

Procedure:
70 g of 3-nitro-4-methylphenol, prepared according to German Offenalegungschrift No. 2,213,568, 200 ml of tetrahydrofuran and 2 g of activated Raney nickel catalyst were placed in a Parr bomb. The mixture was shaken for 3.5 hours under 60 p.s.i. hydrogen pressure. The mixture then was filtered and the solvent was evaporated from the filtrate. The residue was recrystallized from ether to give 3-amino-4-methylphenol (3A), as a grey solid, mp: 145°-148° C.