Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(CC)CC.[Cl:17][C:18]1[CH:31]=[CH:30][C:21]([CH2:22][N:23]2[CH2:28][CH2:27][CH:26]([NH2:29])[CH2:25][CH2:24]2)=[CH:20][C:19]=1[O:32][CH2:33][CH3:34]>CN(C=O)C>[Cl:17][C:18]1[CH:31]=[CH:30][C:21]([CH2:22][N:23]2[CH2:28][CH2:27][CH:26]([NH:29][C:1](=[O:8])[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:25][CH2:24]2)=[CH:20][C:19]=1[O:32][CH2:33][CH3:34]
Reactant: O=C(Cl)c1ccccc1
Reactant: CCOc1cc(CN2CCC(N)CC2)ccc1Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOc1cc(CN2CCC(NC(=O)c3ccccc3)CC2)ccc1Cl
Yield: 59 %

Procedure:
Benzoyl chloride (17 mg, 0.11 mmol), Et3N (20 μL, 0.15 mmol) and 1-(4-chloro-3-ethoxy-benzyl)piperidin-4-ylamine (27 mg, 0.1 mmol) were shaken in DMF (0.5 ml) for 16 h, after which time the solvent was evaporated and the residue purified by reversed phase HPLC (MeCN:H2O) affording the title compound (22 mg, 60%). MS: 373.4 (MH+)
Reaction SMILES: [CH2:1]=[C:2]1[O:6][C:4](=[O:5])[CH2:3]1.[CH2:7]1[C:17]2=[C:18]3[C:13](=[CH:14][CH:15]=[CH:16]2)[CH:12]=[CH:11][CH:10]=[C:9]3[CH2:8]1>F>[C:4]([C:12]1[C:13]2[C:18]3[C:9]([CH2:8][CH2:7][C:17]=3[CH:16]=[CH:15][CH:14]=2)=[CH:10][CH:11]=1)(=[O:5])[CH2:3][C:2]([CH3:1])=[O:6]
Reactant: c1cc2c3c(cccc3c1)CC2
Reactant: C=C1CC(=O)O1
Agent: F
Product: CC(=O)CC(=O)c1ccc2c3c(cccc13)CC2

Procedure:
42 g (0.5 mol) of diketene were added dropwise to 77 g of acenaphthene (0.5 mole) in 300 ml of anhydrous hydrofluoric acid at -30°C while stirring. The temperature was maintained for 9 hours. The hydrofluoric acid was distilled off under reduced pressure at a temperature of the still of -30°C, the residue was washed until it was free from acid and distilled under reduced pressure. 10 g of unreacted acenaphthene were recovered (87 % conversion). At a transition temperature of 150° - 155°C under 0.4 torr 85 g (82 % of theory) of slightly yellowish 5-acetoacetyl-acenaphthene melting at 59°C were then obtained.
Reaction SMILES: Br[C:2]1[CH:26]=[CH:25][C:5]2[N:6]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:15]3[N:16]=[N:17][N:18]([CH3:20])[N:19]=3)=[N:8][C:4]=2[CH:3]=1.[NH2:27][C:28]1[N:33]=[CH:32][C:31](B2OC(C)(C)C(C)(C)O2)=[CH:30][N:29]=1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.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:21]([N:6]1[C:5]2[CH:25]=[CH:26][C:2]([C:31]3[CH:30]=[N:29][C:28]([NH2:27])=[N:33][CH:32]=3)=[CH:3][C:4]=2[N:8]=[C:7]1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[N:16]=[N:17][N:18]([CH3:20])[N:19]=1)([CH3:24])([CH3:22])[CH3:23]
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Reactant: Cn1nnc(-c2ccccc2-c2nc3cc(Br)ccc3n2C(C)(C)C)n1
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: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cn1nnc(-c2ccccc2-c2nc3cc(-c4cnc(N)nc4)ccc3n2C(C)(C)C)n1
Temperature: 110 °C
Yield: 63.1 %

Procedure:
To a sealed vial is added 5-bromo-1-tert-butyl-2-[2-(2-methyl-2H-tetrazol-5-yl)-phenyl]-1H-benzimidazole (55 mg, 0.134 mmol) in DMF (3 mL), followed by the addition of 2-aminopyrimidine-5-boronic acid pinacol ester (35 mg, 0.158 mmol), tetrakis(triphenylphosphine)palladium(0) (15 mg, 0.013 mmol) and 2M aq. Na2CO3 (0.3 mL, 0.6 mmol). The reaction mixture is heated under Argon at 110° C. for 6 hours. The residue is diluted with EtOAc, washed with brine, dried under Na2SO4, filtered and concentrated. The residue is loaded onto a silica gel column. The column is eluted with 0-5% 7M NH3 in MeOH/CH2Cl2. The product fractions are collected and concentrated to afford the title compound (36 mg, 63%) as a off-white solid. LCMS (ESMS): m/z 426.70 (M++1)
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:23])[C:12]3[S:19][C:18]([CH2:20]Cl)=[C:17]([CH3:22])[C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1.[CH3:26][NH:27][CH2:28][C@H:29]([C:31]1[N:36]=[CH:35][CH:34]=[CH:33][N:32]=1)[OH:30].C(N(C(C)C)CC)(C)C>COCCOC>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:23])[C:12]3[S:19][C:18]([CH2:20][N:27]([CH2:28][C@@H:29]([OH:30])[C:31]4[N:32]=[CH:33][CH:34]=[CH:35][N:36]=4)[CH3:26])=[C:17]([CH3:22])[C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1c(CCl)sc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c12
Reactant: CNC[C@@H](O)c1ncccn1
Solvent: CCN(C(C)C)C(C)C
Solvent: COCCOC
Product: Cc1c(CN(C)C[C@@H](O)c2ncccn2)sc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c12
Temperature: 60 °C
Reaction time: 8 h
Yield: 41.9 %

Procedure:
A mixture of N-(4-chlorobenzyl)-2-(chloromethyl)-3,4-dimethyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide (195 mg, 0.49 mmol), (1R)-2-(methylamino)-1-pyrimidin-2-ylethanol (Preparation 104, 168 mg, 0.74 mmol) and diisopropylethylamine (430 μL, 2.5 mmol) in dry DME (10 mL) was heated to 60° C., becoming a solution. The reaction was stirred overnight at that temperature. After cooling to room temperature, the solution was diluted with ice water (30 mL). The resulting milky suspension was stirred vigorously for 30 minutes, and then left standing overnight at room temp. The mixture was filtered, and the collected solid was washed with water and dried in vacuo, leaving a white solid. Recrystallization from acetonitrile (30 mL, dissolved with warming and then cooled to 0° C. overnight) gave the title compound (105 mg) as a white solid.
Reaction SMILES: C(O[C:9](=[O:32])[C@@H:10]1[CH2:14][CH2:13][CH2:12][N:11]1[C:15](=[O:31])[C@@H:16]1[CH2:20][CH2:19][CH2:18][N:17]1[C:21]([NH:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22])C1C=CC=CC=1.[CH3:33][S@@:34]([C:36]1[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=1)=[O:35]>>[CH2:24]([NH:23][C:21]([N:17]1[CH2:18][CH2:19][CH2:20][C@H:16]1[C:15]([N:11]1[CH2:12][CH2:13][CH2:14][C@H:10]1[C:9](=[O:32])[CH2:33][S@@:34]([C:36]1[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=1)=[O:35])=[O:31])=[O:22])[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1C(=O)[C@@H]1CCCN1C(=O)NCc1ccccc1
Reactant: COc1ccc([S@](C)=O)cc1
Product: COc1ccc([S@@](=O)CC(=O)[C@@H]2CCCN2C(=O)[C@@H]2CCCN2C(=O)NCc2ccccc2)cc1
Yield: 27.6 %

Procedure:
By the same procedure as in Example 15-D) using N-benzylaminocarbonyl-L-prolyl-L-proline benzyl ester (2.00 g) and (S)-(-)-4-methoxyphenyl methyl sulfoxide (780 mg) as obtained in Example 15-C), there was obtained 629 mg of the title compound as colorless needles (See Table 7).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[N:9]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].[C:22]([CH:25]=[C:26]=[O:27])(=[O:24])[CH3:23]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:26](=[O:27])[CH2:25][C:22](=[O:24])[CH3:23])[CH:5]=[CH:4][C:3]=1[N:9]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CC(=O)C=C=O
Reactant: CCCCCCN(CCCCCC)c1ccc(N)cc1Cl
Solvent: Cc1ccccc1
Product: CCCCCCN(CCCCCC)c1ccc(NC(=O)CC(C)=O)cc1Cl
Temperature: 80 °C
Reaction time: 8 h
Yield: 99.8 %

Procedure:
To a solution of 2-chloro-N1,N1-dihexylbenzene-1,4-diamine (3.11 g, 10 mmol) in toluene (50 mL) was added acetyl ketene (1.68 g, 20 mmol) and the mixture was stirred at 80° C. overnight. The mixture was cooled to rt and concentrated in vacuo to give the title compound as blackish oil (3.94 g, 100%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][CH:6]=[C:5]2[CH2:13][N:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1.C(=O)([O-])[O-].[Cs+].[Cs+].CS(O[CH2:38][C:39]1([CH2:43][O:44][Si:45]([C:48]([CH3:51])([CH3:50])[CH3:49])([CH3:47])[CH3:46])[CH2:42][CH2:41][CH2:40]1)(=O)=O>CN(C=O)C.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:38][C:39]1([CH2:43][O:44][Si:45]([C:48]([CH3:51])([CH3:50])[CH3:49])([CH3:47])[CH3:46])[CH2:42][CH2:41][CH2:40]1)[CH:6]=[C:5]2[CH2:13][N:14]1[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:18][CH2:19]1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2c[nH]c(=O)c3ccc(Br)cc23)CC1
Reactant: CC(C)(C)[Si](C)(C)OCC1(COS(C)(=O)=O)CCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(Cc2cn(CC3(CO[Si](C)(C)C(C)(C)C)CCC3)c(=O)c3ccc(Br)cc23)CC1
Temperature: 70 °C
Reaction time: 7 h
Yield: 59.5 %

Procedure:
A solution of tert-butyl 4-[(6-bromo-1-oxo-1,2-dihydroisoquinolin-4-yl)methyl]piperazine-1-carboxylate (Example 27b, 0.171 g) dissolved in DMF (5 mL) was treated with cesium carbonate (0.264 g) and [1-({[tert-butyl(dimethyl)silyl]oxy}methyl)cyclobutyl]methyl methanesulfonate [Archiv der Pharmazie (Weinheim, Germany), 2005, 338 (11), 522-7] (0.187 g) under nitrogen. The resulting mixture was stirred at 70° C. for 7 h. The reaction was diluted with water (300 mL), and extracted with diethyl ether (300 mL×3). The organic was dried (MgSO4), filtered and evaporated to afford crude product. The crude product was purified (SiO2 chromatography, elution with 6-12% ethyl acetate/isohexane) to afford the subtitle compound (0.153 g).
Reaction SMILES: [N:1]([CH:4]([CH2:7][NH:8][C:9]([P:11]([O:16][CH2:17][CH3:18])([O:13][CH2:14][CH3:15])=[O:12])=[O:10])[CH2:5][NH2:6])=[N+:2]=[N-:3].C(N(CC)CC)C.[O:26]([C:33]1[CH:38]=[CH:37][C:36]([S:39](Cl)(=[O:41])=[O:40])=[CH:35][CH:34]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CC#N>[N:1]([CH:4]([CH2:7][NH:8][C:9]([P:11]([O:16][CH2:17][CH3:18])([O:13][CH2:14][CH3:15])=[O:12])=[O:10])[CH2:5][NH:6][S:39]([C:36]1[CH:35]=[CH:34][C:33]([O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:38][CH:37]=1)(=[O:41])=[O:40])=[N+:2]=[N-:3]
Reactant: O=S(=O)(Cl)c1ccc(Oc2ccccc2)cc1
Reactant: CCOP(=O)(OCC)C(=O)NCC(CN)N=[N+]=[N-]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOP(=O)(OCC)C(=O)NCC(CNS(=O)(=O)c1ccc(Oc2ccccc2)cc1)N=[N+]=[N-]
Yield: 59.1 %

Procedure:
To a solution of 2-azido-3-[diethylphosphonoformamido]propylamine (1.26 g, 4.5 mmol) and triethylamine (1.2 eq, 1.46 g, 5.4 mmol) in 15 ml CH3CN was added dropwise 4-phenoxybenzenesulfonyl chloride solution (1.5 eq, 68 mmol, 5.25 ml) in 15 ml CH3CN at 0° C. with stirring. After the addition, the reaction was stirred overnight at room temperature. The solvent was evaporated and the residue was purified by silica gel chromatography [eluent: DCM/1% MeOH] to yield 1.36 g (60%) a pale yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:21]([NH:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[C:27]([F:32])[CH:26]=3)=[O:22])=[C:7]([CH:18]([CH3:20])[CH3:19])[N:8]2[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:4][C:3]=1[F:33].Cl[CH2:35][CH2:36][N:37]=[C:38]=[S:39]>C(Cl)Cl.CCN(CC)CC>[CH2:11]([N:8]1[C:9]2[C:5](=[CH:4][C:3]([F:33])=[C:2]([NH:1][C:38]3[S:39][CH2:35][CH2:36][N:37]=3)[CH:10]=2)[C:6]([C:21]([NH:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([F:31])=[C:27]([F:32])[CH:26]=2)=[O:22])=[C:7]1[CH:18]([CH3:19])[CH3:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: S=C=NCCCl
Reactant: CC(C)c1c(C(=O)NCc2ccc(F)c(F)c2)c2cc(F)c(N)cc2n1Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)c1c(C(=O)NCc2ccc(F)c(F)c2)c2cc(F)c(NC3=NCCS3)cc2n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
General Procedure AA. To a solution of 6-amino-1-benzyl-N-(3,4-difluorobenzyl)-5-fluoro-2-isopropyl-1H-indole-3-carboxamide (Compound 172, 39 mg, 0.086 mmol) in CH2Cl2 (1 ml) was added 2-chloroethyl isothiocyanate (25 μl, 0.26 mmol) and Et3N (1 drop). The reaction was stirred at room temperature for 16 h and was purified directly by chromatography on silica gel (0→60% EtOAc-hexanes) to yield the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@H:18]4[CH2:22][CH2:21][N:20]([S:23]([CH3:26])(=[O:25])=[O:24])[CH2:19]4)[C:14]([F:27])=[CH:13][N:12]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH2:28](S(Cl)(=O)=O)[CH2:29][CH2:30]C>>[CH2:26]([S:23]([N:20]1[CH2:21][CH2:22][C@H:18]([NH:17][C:15]2[C:14]([F:27])=[CH:13][N:12]=[C:11]([C:10]3[C:4]4[C:5](=[N:6][CH:7]=[C:2]([Cl:1])[CH:3]=4)[NH:8][CH:9]=3)[N:16]=2)[CH2:19]1)(=[O:24])=[O:25])[CH2:28][CH2:29][CH3:30]
Reactant: CCCCS(=O)(=O)Cl
Reactant: CS(=O)(=O)N1CC[C@H](Nc2nc(-c3c[nH]c4ncc(Cl)cc34)ncc2F)C1
Product: CCCCS(=O)(=O)N1CC[C@H](Nc2nc(-c3c[nH]c4ncc(Cl)cc34)ncc2F)C1
Yield: 45 %

Procedure:
According to the procedure for compound 398 using 1-butanesulfonyl chloride (90 mg, 0.57 mmol) afforded 21 mg (45% yield) of 402, as a solid.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]2[N:8]=[CH:9][CH:10]=[N:11][C:12]=2[C:13]([C:16]2[C:21]([F:22])=[C:20]([O:23][CH3:24])[CH:19]=[C:18]([O:25][CH3:26])[C:17]=2[F:27])=[CH:14][CH:15]=1)=O)C.[CH3:28][N:29]1[CH2:34][CH2:33][N:32]([CH2:35][C:36]2[CH:37]=[CH:38][C:39]([NH2:42])=[N:40][CH:41]=2)[CH2:31][CH2:30]1>C(Cl)Cl.CO>[CH3:28][N:29]1[CH2:34][CH2:33][N:32]([CH2:35][C:36]2[CH:37]=[CH:38][C:39]([NH:42][C:4]([C:6]3[C:7]4[N:8]=[CH:9][CH:10]=[N:11][C:12]=4[C:13]([C:16]4[C:17]([F:27])=[C:18]([O:25][CH3:26])[CH:19]=[C:20]([O:23][CH3:24])[C:21]=4[F:22])=[CH:14][CH:15]=3)=[O:3])=[N:40][CH:41]=2)[CH2:31][CH2:30]1
Reactant: CN1CCN(Cc2ccc(N)nc2)CC1
Reactant: CCOC(=O)c1ccc(-c2c(F)c(OC)cc(OC)c2F)c2nccnc12
Solvent: CO
Solvent: ClCCl
Product: COc1cc(OC)c(F)c(-c2ccc(C(=O)Nc3ccc(CN4CCN(C)CC4)cn3)c3nccnc23)c1F

Procedure:
The title compound was prepared in analogy to the procedure described in Example 115 but using 8-(2,6-difluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid ethyl ester (Step 124.1) and 5-(4-methyl-piperazin-1-ylmethyl)-pyridin-2-ylamine (Example 31; purified by silica gel column chromatography). Title compound: ESI-MS: 535.1 [M+H]+; tR=3.45 min (System 1); TLC: Rf=0.19 (DCM/MeOH/NH3aq, 94:5:1).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:9]([CH:10]([CH3:12])[CH3:11])=[C:8]([C:13](O)=[O:14])[N:7]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[N:6]=1)=[O:4].B.C1COCC1.CO>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[C:9]([CH:10]([CH3:12])[CH3:11])=[C:8]([CH2:13][OH:14])[N:7]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[N:6]=1)=[O:4]
Reactant: COC(=O)c1nn(-c2ccc(F)cc2)c(C(=O)O)c1C(C)C
Agent: B
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1nn(-c2ccc(F)cc2)c(CO)c1C(C)C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 89.8 %

Procedure:
(Reference: J. Med. Chem. 1996, 549-555) To a solution of 1-(4-fluoro-phenyl)-4-isopropyl-1H-pyrazole-3,5-dicarboxylic acid 3-methyl ester (15.9 g, 51.8 mmol) in THF (300 mL) at 0° C. was slowly added BH3.THF (1.0 M solution in THF, 104 mL, 104 mmol; commercially available from Sigma Aldrich). The reaction was allowed to warm to 25° C. for 30 min and then heated to 65° C. for 3 hr. After cooling to 25° C., MeOH (50 mL) was slowly added. Subsequently, the solvent was removed under reduced pressure and a second portion of MeOH (100 mL) was slowly added and the solution was stirred at 25° C. for an additional 20 min. The MeOH was then evaporated and EtOAc was added and the organic layer was washed with 1N NaOH and brine prior to drying over Na2SO4. The organic layer was concentrated and purified by silica gel chromatography (15-35% EtOAc/Hex) to provide 1-(4-fluoro-phenyl)-5-hydroxymethyl-4-isopropyl-1H-pyrazole-3-carboxylic acid methyl ester (13.6 g, 90%): H-NMR (CDCl3) δ 7.59-7.56 (m, 2 H), 7.15-7.11 (m, 2 H), 4.57 (s, 2 H), 3.89 (s, 3 H), 3.66-3.62 (m, 1 H), 1.36 (d, 6 H).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:7]=[CH:6][NH:5][C:4]=1[C:8]([O:10][CH3:11])=[O:9].[C:14]1(B(O)O)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.N1C=CC=CC=1>CC([O-])=O.CC([O-])=O.[Cu+2].ClCCl>[C:14]1([N:5]2[CH:6]=[CH:7][C:3]([C:2]([F:1])([F:12])[F:13])=[C:4]2[C:8]([O:10][CH3:11])=[O:9])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: OB(O)c1ccccc1
Reactant: COC(=O)c1[nH]ccc1C(F)(F)F
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1c(C(F)(F)F)ccn1-c1ccccc1
Temperature: 20 °C
Reaction time: 48 h
Yield: 59.4 %

Procedure:
Into a 100-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed methyl 3-(trifluoromethyl)-1H-pyrrole-2-carboxylate (810 mg, 4.19 mmol, 1.00 equiv), phenylboronic acid (1.54 g, 12.63 mmol, 3.01 equiv), Cu(OAc)2 (1.52 g, 8.37 mmol, 2.00 equiv), pyridine (1.327 g, 16.78 mmol, 4.00 equiv), 4 {acute over (Å)} Molecular Sieves (1.2 g) and dichloromethane (20.0 mL). The resulting solution was stirred for 2 days at 20° C. The reaction progress was monitored by LCMS. The solids were filtered out and the resulting mixture was concentrated under vacuum. The resulting residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:9) to yield methyl 1-phenyl-3-(trifluoromethyl)-1H-pyrrole-2-carboxylate as a pink solid (0.67 g, 59%)
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.C(N(CC)CC)C.[C:13]([O:16][CH:17]([CH3:30])[CH2:18][CH2:19][C:20]1[CH:25]=[C:24](O)[N:23]2[N:27]=[CH:28][CH:29]=[C:22]2[N:21]=1)(=[O:15])[CH3:14]>C1(C)C=CC=CC=1>[C:13]([O:16][CH:17]([CH3:30])[CH2:18][CH2:19][C:20]1[CH:25]=[C:24]([Cl:3])[N:23]2[N:27]=[CH:28][CH:29]=[C:22]2[N:21]=1)(=[O:15])[CH3:14]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(=O)OC(C)CCc1cc(O)n2nccc2n1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(=O)OC(C)CCc1cc(Cl)n2nccc2n1

Procedure:
Phosphorus oxychloride (6.4 ml) and triethylamine (3.5 ml) were added to 40 ml of a toluene suspension containing 4.2 g of the crystals obtained in step (4), and the mixture was refluxed with heating for 6 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure and the residue was poured into ice water. The mixture was neutralized with sodium acetate and extracted with ethyl acetate. The organic layer was collected, washed with a saturated saline solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate: n-hexane=4:1) to provide 4.3 g of 5-(3-acetoxybutyl)-7-chloropyrazolo[1,5-a]pyrimidine as a light yellow oily compound.
Reaction SMILES: O[CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[NH:46]1[CH:50]=[C:49]([C:51]([O:53][CH2:54][CH3:55])=[O:52])[N:48]=[N:47]1>O1CCCC1>[CH2:54]([O:53][C:51]([C:49]1[CH:50]=[N:46][N:47]([CH:2]2[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]2)[N:48]=1)=[O:52])[CH3:55]
Reactant: CCOC(=O)c1c[nH]nn1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1cnn(C2CCN(C(=O)OC(C)(C)C)CC2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.2 %

Procedure:
To a solution of t-butyl 4-hydroxypiperidine-1-carboxylate (0.43 g, 3.3 mmol) and triphenylphosphine (1.05 g, 4.0 mmol) in tetrahydrofuran (15 mL) at 0° C. was added dropwise diethyl azodicarboxylate (0.63 mL, 4.0 mmol). After 5 minutes ethyl 1H-1,2,3-triazole-4-carboxylate (0.43 g, 3.0 mmol, prepared according to D. R. Buckle, C. J. M. Rockell, J. Chem. Soc., Perkin Transaction 1 1982, 2, 627-630) was added in tetrahydrofuran (5 mL). The reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure and the residue was purified by medium pressure liquid chromatography (HPLC) using 15 to 40% ethyl acetate in hexanes as eluant to afford 0.42 g of the title compound as an oil.
Reaction SMILES: [C:1]([C:3]1([OH:13])[CH2:12][CH2:11][C:6]2([O:10][CH2:9][CH2:8][O:7]2)[CH2:5][CH2:4]1)#[CH:2].C([Li])CCC.CON(C)[C:22](=[O:30])[C:23]1[CH:28]=[CH:27][C:26]([CH3:29])=[N:25][CH:24]=1.[Cl-].[NH4+]>O1CCCC1>[OH:13][C:3]1([C:1]#[C:2][C:22]([C:23]2[CH:24]=[N:25][C:26]([CH3:29])=[CH:27][CH:28]=2)=[O:30])[CH2:12][CH2:11][C:6]2([O:7][CH2:8][CH2:9][O:10]2)[CH2:5][CH2:4]1
Reactant: CON(C)C(=O)c1ccc(C)nc1
Reactant: C#CC1(O)CCC2(CC1)OCCO2
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)C#CC2(O)CCC3(CC2)OCCO3)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64 %

Procedure:
To a solution of 8-ethynyl-1,4-dioxaspiro[4.5]decan-8-ol (Reference Example 1) (592 mg, 3.25 mmol) in tetrahydrofuran (6 mL), 2.63 M n-butyllithium (solution in n-hexane, 2.6 mL, 6.82 mmol) was added dropwise at −78° C. for 5 minutes, and the obtained solution was stirred at the same temperature for 30 minutes. Thereafter, a solution of N-methoxy-N-methyl-6-methylnicotinamide (614.5 mg, 3.41 mmol) in tetrahydrofuran (5 ml) was added dropwise at −78° C. for 20 minutes, and the obtained solution was stirred at the same temperature for 30 minutes. The reaction solution was allowed to warm to room temperature and poured into saturated aqueous ammonium chloride solution. The reaction solution was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, n-hexane/ethyl acetate) to obtain the captioned compound (626.3 mg, 2.08 mmol, 65%) as a pale yellow solid.
Reaction SMILES: Cl[C:2]1[N:22]=[C:5]2[C:6]([C:10]3[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:11]=3[O:20][CH3:21])=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[C:23]([O:27][C:28]([N:30]1[CH2:36][CH2:35][C:34]2[CH:37]=[CH:38][C:39]([NH2:41])=[CH:40][C:33]=2[CH2:32][CH2:31]1)=[O:29])([CH3:26])([CH3:25])[CH3:24]>>[C:23]([O:27][C:28]([N:30]1[CH2:36][CH2:35][C:34]2[CH:37]=[CH:38][C:39]([NH:41][C:2]3[N:22]=[C:5]4[C:6]([C:10]5[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:11]=5[O:20][CH3:21])=[CH:7][CH:8]=[CH:9][N:4]4[N:3]=3)=[CH:40][C:33]=2[CH2:32][CH2:31]1)=[O:29])([CH3:26])([CH3:24])[CH3:25]
Reactant: COc1ccc(C(F)(F)F)cc1-c1cccn2nc(Cl)nc12
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(N)cc2CC1
Product: COc1ccc(C(F)(F)F)cc1-c1cccn2nc(Nc3ccc4c(c3)CCN(C(=O)OC(C)(C)C)CC4)nc12

Procedure:
2-Chloro-8-(2-methoxy-5-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridine was prepared from 8-bromo-2-chloro-[1,2,4]triazolo[1,5-a]pyridine (0.500 g, 2.15 mmol) and 2-methoxy-5-trifluoromethylbenzeneboronic acid (0.710 g, 3.23 mmol) in a manner analogous to Example 311a to give product (0.636 g, 90%). MS=328 (MH)+. 315b) 7-[8-(2-Methoxy-5-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino]-1,2,4,5-tetrahydro-3-benzazepine-3-carboxylic acid tert-butyl ester was prepared from 2-chloro-8-(2-methoxy-5-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridine (0.630 g, 1.92 mmol) and 7-amino-1,2,4,5-tetrahydro-3-benzazepine-3-carboxylic acid tert-butyl ester (0.605 g, 2.31 mmol) in a manner analogous to Example 311b to give product (0.750 g, 71%). 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.56 (s, 1H), 8.79 (d, 1H), 7.95 (s, 1H), 7.82 (d, 1H), 7.65 (d, 1H), 7.42 (m, 3H), 7.05 (m, 2H), 3.85 (s, 3H), 3.42 (m, 4H), 2.75 (m, 4H), 1.41 (s, 9H): MS=554 (MH)+.
Reaction SMILES: [CH2:1]([O:3][CH:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH:5]=[O:6])C.[CH3:13][O:14]C(C1C=CC=CC=1)C=O>>[CH3:1][O:3][C:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([CH2:13][OH:14])[CH2:5][OH:6]
Reactant: CCOC(C=O)c1ccccc1
Reactant: COC(C=O)c1ccccc1
Product: COC(CO)(CO)c1ccccc1

Procedure:
The procedure in Example 6 was repeated except that 2-ethoxy-2-phenylethanal was replaced with 2-methoxy-2-phenylethanal, to obtain 2-methoxy-2-phenyl-1,3-propanediol.