Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=O.[C:11]([CH2:13][C:14]([NH2:16])=[S:15])#[N:12].N>CCO>[C:5]1([C:3]2[N:16]=[C:14]([CH2:13][C:11]#[N:12])[S:15][CH:2]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=C(CBr)c1ccccc1
Reactant: N#CCC(N)=S
Agent: N
Solvent: CCO
Product: N#CCc1nc(-c2ccccc2)cs1
Temperature: 80 °C
Yield: 74.9 %

Procedure:
A mixture of 2-bromoacetophenone (2 g, 10 mmol) and 2-cyanothioacetamide (1 g, 10 mmol) in EtOH (25 mL) was heated to 80° C. for 4 h. The reaction mixture was cooled to room temperature and poured into an aqueous ammonia solution (final pH was >7). The mixture was then extracted with EtOAc and the organic layer was washed with H2O and brine. Solvent was removed under reduced pressure and the crude product was purified by flash column chromatography (silica gel 230-400 mesh, eluent 8% EtOAc in petroleum ether) to afford 2-(4-phenylthiazol-2-yl)acetonitrile (1.5 g, yield 75%) as a yellow solid: 1H NMR (300 MHz, CDCl3) δ 7.88-7.91 (m, 2H), 7.49 (s, 1H), 7.27-7.48 (m, 3H), 4.19 (s, 2H). MS (ESI) m/z: Calculated for C11H8N2S: 200.04. found: 201.2 (M+H)+.
Reaction SMILES: Br[CH:2]([CH2:8]Br)[C:3]([O:5][CH2:6][CH3:7])=[O:4].C([N:17]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:18][CH2:19][NH2:20])C1C=CC=CC=1.C(N(CC)CC)C.[C:35]1([CH3:41])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>>[C:22]1([CH2:21][N:17]2[CH2:18][CH2:19][N:20]([CH2:41][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH2:8][CH:2]2[C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: Cc1ccccc1
Reactant: NCCN(Cc1ccccc1)Cc1ccccc1
Reactant: CCOC(=O)C(Br)CBr
Solvent: CCN(CC)CC
Product: CCOC(=O)C1CN(Cc2ccccc2)CCN1Cc1ccccc1

Procedure:
2,3-Dibromopropionic acid, ethyl ester 7, N,N-dibenzylethylenediamine 8 and triethylamine are reacted in toluene at 80°-100° C., giving 1,4-bis(phenylmethyl)-2-piperazinecarboxylic acid, ethyl ester 9. The ester 9 is then reacted with lithium aluminum hydride in ether, under an inert atmosphere at reflux followed by treatment with an alkali base and an alkali carbonate giving 1,4-bis(phenylmethyl)-2-piperazinemethanol 10, which is then reacted with thicnyl chloride in carbon tetrachloride at 50°-60° C. followed by treatment with an alkali hydroxide, giving 2-chloromethyl-1,4-bis(phenylmethyl)piperazine 11. The compound 11 is then reacted with an amine R4, where R4 is dimethylamine, N-methylpiperazine, etc., giving a 2-substituted methyl-1,4-bis(phenylmethyl)piperazine 12 which is then catalytically reduced in ethanol and cyclohexane, giving piperazine derivative 13. Derivative 13 is then reacted with 6 in pyridine in a sealed unit under argon at 120°-130° C., giving 14. ##STR8##
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4](=[S:6])[NH2:5].[S:12]([O:17]C)([O:15][CH3:16])(=[O:14])=[O:13]>C1(C)C=CC=CC=1>[CH3:16][O:15][S:12]([OH:17])(=[O:14])=[O:13].[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([S:6][CH3:16])=[NH:5]
Reactant: NC(=S)c1c(F)cccc1Cl
Reactant: COS(=O)(=O)OC
Solvent: Cc1ccccc1
Product: COS(=O)(=O)O
Product: CSC(=N)c1c(F)cccc1Cl
Temperature: 25 °C
Yield: 173 %

Procedure:
2-Chloro-6-fluorobenzthioamide (21.9 g, 0.12 mol) and dimethyl sulfate (12 mL, 16.0 g, 0.13 mol) were stirred together in 100 mL of toluene and refluxed for 2 h. The slurry was cooled to 25° C. and the white crystals collected on a glass buchner funnel and rinsed with a small quantity of acetone. After air suction drying for 1 h, 35.5 g of methyl 2-chloro-6-fluorobenzthioimidate methylsulfate salt was obtained, mp 147-151° C., representing a nominal wt. % yield of 96%.
Reaction SMILES: [O:1]1[C:5]2[CH2:6][N:7]([C:10](=[O:23])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[CH2:8][CH2:9][C:4]=2[CH:3]=[CH:2]1.[CH3:24][NH:25][CH3:26].[CH2:27]=O>C(O)(=O)C>[CH3:24][N:25]([CH2:27][C:2]1[O:1][C:5]2[CH2:6][N:7]([C:10](=[O:23])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]3[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=3)[CH2:8][CH2:9][C:4]=2[CH:3]=1)[CH3:26]
Reactant: C=O
Reactant: O=C(CCCCCc1ccc(F)cc1)N1CCc2ccoc2C1
Reactant: CNC
Solvent: CC(=O)O
Product: CN(C)Cc1cc2c(o1)CN(C(=O)CCCCCc1ccc(F)cc1)CC2
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To a solution of 0.280 g (0.888 mmol) of 1-(5,7-dihydro-4H-furo[2,3-c]pyridin-6-yl)-6-(4-fluorophenyl) hexan-1-one in 20 ml of acetic acid, 0.120 ml (1.33 mmol) of 50% aqueous dimethylamine and 0.108 ml (1.33 mmol) of 37% aqueous formaldehyde were added, followed by stirring at 100° C. for 60 minutes. After the solvent was distilled off under reduced pressure, the residual solution was alkalified with 5% aqueous sodium hydrogen carbonate, and extracted with dichloromethane 2 times. The combined organic layer was washed with water and dried over anhydrous sodium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (chloroform/methanol=50/1 to 25/1) to yield the desired product.
Reaction SMILES: [OH:1][CH:2]([CH2:6][CH3:7])[C:3]([OH:5])=[O:4].[OH-].[Na+].[CH2:10]([C@H:12]1[CH2:17][C@H:16]2[C@H:18]3[C@H:27]([CH2:28][CH2:29][C@:14]2([CH3:15])[C@H:13]1[O:31][C:32](=[O:35])[CH2:33]Br)[C@@H:26]1[C:21](=[CH:22][C:23](=[O:30])[CH2:24][CH2:25]1)[CH2:20][CH2:19]3)[CH3:11].C(OCC)(=O)C>CN(C=O)C>[CH2:10]([C@H:12]1[CH2:17][C@H:16]2[C@H:18]3[C@H:27]([CH2:28][CH2:29][C@:14]2([CH3:15])[C@H:13]1[O:31][C:32](=[O:35])[CH2:33][O:4][C:3](=[O:5])[CH:2]([OH:1])[CH2:6][CH3:7])[C@@H:26]1[C:21](=[CH:22][C:23](=[O:30])[CH2:24][CH2:25]1)[CH2:20][CH2:19]3)[CH3:11]
Reactant: CC[C@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@]2(C)[C@H]1OC(=O)CBr
Reactant: CCC(O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCC(O)C(=O)OCC(=O)O[C@H]1[C@@H](CC)C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@@]21C
Temperature: 25 °C
Reaction time: 16 h
Yield: 55.5 %

Procedure:
In 40 ml of DMF is dissolved 0.6 g of α-hydroxybutyric acid, and 6.0 ml of 1N-NaOH and 1.4 g of 16β-ethyl-17β-bromoacetoxy-4-estren-3-one are added. The mixture is stirred at room temperature (15°-25° C.) for 16 hours. To the reaction mixture is added 150 ml of ethyl acetate and the mixture is washed with water and saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The solvent is then distilled off under reduced pressure and the residue is subjected to column chromatography. Following passage of 50 ml of dichloromethane and 100 ml of diisopropyl ether in that order, elution is carried out with 150 ml of diisopropyl ether and 250 ml of diisopropyl ether-ethyl acetate (1:10). The eluates are combined and evaporated under reduced pressure to remove the solvent, giving 0.82 g of the above-identified compound as a colorless viscous oil.
Reaction SMILES: [C:1]([NH:4][CH:5]1[CH2:9][CH2:8][N:7]([C:10]2[C:23]([F:24])=[C:22]([F:25])[C:13]([C:14]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[O:15])=[C:12]([F:26])[C:11]=2[F:27])[CH2:6]1)(=[O:3])[CH3:2].[CH:28](OCC)(OCC)OCC.C(OC(=O)C)(=O)C.[NH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=1[OH:52]>>[OH:52][C:47]1[CH:48]=[CH:49][CH:50]=[CH:51][C:46]=1[NH:45][CH:28]=[C:16]([C:14](=[O:15])[C:13]1[C:22]([F:25])=[C:23]([F:24])[C:10]([N:7]2[CH2:8][CH2:9][CH:5]([NH:4][C:1](=[O:3])[CH3:2])[CH2:6]2)=[C:11]([F:27])[C:12]=1[F:26])[C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: CCOC(OCC)OCC
Reactant: Nc1ccccc1O
Reactant: CCOC(=O)CC(=O)c1c(F)c(F)c(N2CCC(NC(C)=O)C2)c(F)c1F
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)C(=CNc1ccccc1O)C(=O)c1c(F)c(F)c(N2CCC(NC(C)=O)C2)c(F)c1F
Temperature: 130 °C
Reaction time: 2.5 h

Procedure:
To a 6.82 g (17.5 mmol) sample of the beta-ketoester from step 3 was added 3.89 g (26.1 mmol) of triethyl orthoformate and 8.00 g (78 mmol) of acetic anhydride, and the reaction was stirred at 130° C. for 2.5 hours. The volatile materials were then removed under reduced pressure, and toluene was added and distilled from the residue to remove any remaining reagents. The dried residue was then dissolved in 150 mL of methylene chloride and 1.91 g (17.5 mmol) of o-aminophenol was added. The reaction was stirred at room temperature overnight. The solvent was removed under reduced pressure, and the residue was washed with ether, filtered and dried to afford 7.59 g of the title compound as a yellow solid, mp 221° C. (dec). MS M/Z: 510 (M+H). IR (KBr): 1623, 1643, 1684 cm-1. NMR (DMSO) d: 1.10 (m, 3H), 1.82 (m, 3H), 2.05 (m, 2H), 3.64 (m, 2H), 3.80 (m, 4H), 4.04 (m, 2H), 6.95 (m, 1H), 7.10 (m, 1H), 7.58 (m, 1H), 8.16 (m, 1H), 8.65 (m, 1H), 10.60 (m, 1H), 12.73 (m, 1 H). Analysis calculated for C24H23F4N3O5 : C, 56.58; H, 4.55; N, 8.25. Found: C, 56.30; H, 4.63; N, 8.22.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9](C)[CH:10]=[C:6]2[N:5]=[C:4]([NH:12][C:13](=[O:24])[C:14]2[CH:19]=[CH:18][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=2)[CH:3]=1.[CH3:25][O:26][CH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>CN1C(=O)CCC1.CS(C)=O.CO>[OH:23][C:20]([C:17]1[CH:18]=[CH:19][C:14]([C:13]([NH:12][C:4]2[CH:3]=[C:2]([N:30]3[CH2:31][CH2:32][CH:27]([O:26][CH3:25])[CH2:28][CH2:29]3)[N:7]3[N:8]=[CH:9][CH:10]=[C:6]3[N:5]=2)=[O:24])=[CH:15][CH:16]=1)([CH3:21])[CH3:22]
Reactant: COC1CCNCC1
Reactant: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)cc(Cl)n2n1
Solvent: CO
Solvent: CS(C)=O
Solvent: CN1CCCC1=O
Product: COC1CCN(c2cc(NC(=O)c3ccc(C(C)(C)O)cc3)nc3ccnn23)CC1
Temperature: 25 °C
Yield: 25.9 %

Procedure:
A solution of N-(7-chloro-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)-4-(2-hydroxypropan-2-yl)benzamide (2D, 50 mg, 0.151 mmol) and 4-methoxypiperidine (27 mg, 0.302 mmol) in NMP (0.950 mL) was stirred at 85° C. overnight. After cooling to room temperature, the mixture was diluted with a few drops of DMSO and methanol, and was then purified by preparatory HPLC, 5-95% (MeCN/H2O gradient+0.01% TFA). Lyophilization of the combined fractions gave the titled compound as a white solid (16 mg, 26%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.45 (s, 6H) 1.59-1.75 (m, 2H) 1.98-2.12 (m, 2H) 3.31 (s, 3H) 3.41-3.58 (m, 3H) 3.97-4.15 (m, 2H) 6.35 (d, J=2.27 Hz, 1H) 7.40 (s, 1H) 7.60 (m, J=8.34 Hz, 2H) 7.99 (m, J=8.59 Hz, 2H) 8.08 (d, J=2.27 Hz, 1H) 10.88 (s, 1H). ESI-MS: m/z 410.3 (M+H)+.
Reaction SMILES: [Mg:1].[CH2:2]([O:4][CH:5]([OH:7])[CH3:6])[CH3:3]>>[CH2:2]([O:4][CH:5]([CH3:6])[O-:7])[CH3:3].[Mg+2:1].[CH2:2]([O:4][CH:5]([CH3:6])[O-:7])[CH3:3].[Mg:1]
Reactant: CCOC(C)O
Agent: [Mg]
Product: CCOC(C)[O-]
Product: [Mg+2]
Yield: 5 %

Procedure:
16.5 g of magnesium turnings were dissolved in varying amounts of ethoxyethanol to give solutions of magnesium ethoxyethoxide containing 5% to 9% and 10% of magnesium. To the solutions thus obtained were added:
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH:7]=O)=[CH:5][N:4]=[CH:3]1.[NH:9]1[CH:13]=[CH:12][CH:11]=[CH:10]1>C(O)(=O)CC>[CH3:1][N:2]1[C:6]([C:7]2[C:13]3[NH:9][C:10]([C:7]([C:6]4[N:2]([CH3:1])[CH:3]=[N:4][CH:5]=4)=[C:10]4[N:9]=[C:13]([C:7]([C:6]5[N:2]([CH3:1])[CH:3]=[N:4][CH:5]=5)=[C:10]5[NH:9][C:13](=[C:7]([C:6]6[N:2]([CH3:1])[CH:3]=[N:4][CH:5]=6)[C:10]6[CH:11]=[CH:12][C:13]=2[N:9]=6)[CH:12]=[CH:11]5)[CH:12]=[CH:11]4)=[CH:11][CH:12]=3)=[CH:5][N:4]=[CH:3]1
Reactant: Cn1cncc1C=O
Reactant: c1cc[nH]c1
Solvent: CCC(=O)O
Product: Cn1cncc1-c1c2nc(c(-c3cncn3C)c3ccc([nH]3)c(-c3cncn3C)c3nc(c(-c4cncn4C)c4ccc1[nH]4)C=C3)C=C2
Reaction time: 60 h
Yield: 21 %

Procedure:
To a refluxing solution of propionic acid (400 mL) and 1-methylimidazole-5-carboxaldehyde (53, 2.0 g, 18.16 mmol), prepared according to literature procedure (Dener, J. M.; Zhang, L-H.; Rapoport, H. J. Org. Chem. 1993, 58, 1159-1166), was added pyrrole (1.26 mL, 18.16 mmol). The reaction was covered with foil then heated under reflux for 5 h. Upon cooling, the reaction mixture was exposed to air for 60 h. The propionic acid was then removed by vacuum distillation. The residue was dissolved in 10% MeOH/CH2Cl2, then adsorbed onto silica gel (6 g). Purification by column chromatography (gradient elution, 5-10% MeOH/CH2Cl2) provided porphyrin 54 as a purple solid (600 mg, 21%): 1H NMR (300 MHz, CDCl3) δ −2.80, −2.75 (2 s, 2 H, atropisomer NH), 3.42-3.58 (multiple s, 12 H, atropisomer N—CH3), 7.87-7.98 (multiple s, 4 H, atropisomer), 8.06 (s, 4 H), 8.95-8.99 (multiple s, 8 H, atropisomer).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:19]=[CH:20][CH:21]=1)[O:7][CH2:8][C:9]1[N:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1)([O-])=O.Cl.[OH-].[NH4+].C(OCC)(=O)C.CCCCCC>O.C(OCC)(=O)C>[N:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:17]=[N:18][C:9]=1[CH2:8][O:7][C:6]1[CH:5]=[C:4]([NH2:1])[CH:21]=[CH:20][CH:19]=1
Reactant: O=[N+]([O-])c1cccc(OCc2ncc3ccccc3n2)c1
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: O
Product: Nc1cccc(OCc2ncc3ccccc3n2)c1
Temperature: 90 °C
Yield: 55.3 %

Procedure:
A suspension of 10 g (0.036 mol) of 2-[(3-nitrophenoxy)methyl]-quinazoline in a solution of 105 g (0.38 mol) of ferrous sulfate heptahydrate and 0.5 ml of concentrated hydrochloric acid in 175 ml of water is heated on a steam bath to 90° C. Concentrated ammonium hydroxide is added in increments of 25 ml, and 3×10 ml over a period of 15 minutes. Heating is discontinued and the reaction mixture is allowed to cool over a period of 45 minutes while vigorously stirring. The reaction mixture is diluted with 500 ml of water/500 ml of ethyl acetate and filtered through Celite. The layers are separated and the ethyl acetate solution is charcoaled, filtered and concentrated to obtain an oil, which is subjected to high pressure liquid chromatography (ethyl acetate/hexane as eluent). Fractions 14-20 are combined and concentrated to obtain 5 g (56%) of off-white crystals, m.p. 103°-7° C.
Reaction SMILES: [C:1](OC)(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[H-].[Na+].C([Li])CCC.[CH3:16][CH:17]([CH3:30])[CH2:18][CH2:19][C:20](=[O:29])[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CCCCCC.O.C1COCC1>[OH:4][C:3]1[CH2:5][C:20]([CH2:19][CH2:18][CH:17]([CH3:30])[CH3:16])([CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[O:29][C:1](=[O:6])[CH:2]=1
Reactant: COC(=O)CC(C)=O
Reactant: CC(C)CCC(=O)CCc1ccccc1
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)CCC1(CCc2ccccc2)CC(O)=CC(=O)O1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
The title compound was prepared as described in General Method 5 using 2.56 g (22 mmol) of methyl acetoacetate, 0.97 g (24.2 mmol) of NaH 60% dispersion in oil, 14.4 mL (23.1 mmol) of 1.6 M n-butyl lithium in hexane, 4.5 g (22.0 mmol) of 6-methyl-1-phenyl-heptan-3-one (A. Katritzky, et al., J. Org. Chem., 1995, 60 (23), 7605) and 60 mL of THF. After addition of the ketone, the reaction was stirred for 90 minutes at 0° C. and then for 30 minutes at room temperature. Water (400 mL) was slowly added with vigorous stirring, and the reaction was allowed to stir overnight. The reaction was worked up as in General Method 6. The product was triturated from ether to afford a solid, m.p. 99-100.5° C. 1H NMR (CDCl3) δ 0.89-0.92 (d,d, 6 H), 1.24-1.32 (m, 2 H), 1.48-1.57 (m, 1 H), 1.64-1.83 (m, 2 H), 1.94-2.03 (m, 2 H), 2.68-2.77 (m, s, 4 H), 3.42 (s, 2 H), 7.16-7.32 (m, 5 H).
Reaction SMILES: [CH3:1][C@:2]([N+:8]([O-])=O)([C@H:5]([OH:7])[CH3:6])[CH2:3][OH:4].[C:11]([OH:14])(=[O:13])[CH3:12]>CCO.[Pd]>[C:11]([OH:14])(=[O:13])[CH3:12].[NH2:8][C@@:2]([CH3:1])([C@H:5]([OH:7])[CH3:6])[CH2:3][OH:4]
Reactant: C[C@@H](O)[C@@](C)(CO)[N+](=O)[O-]
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: C[C@@H](O)[C@](C)(N)CO
Reaction time: 48 h

Procedure:
To a solution of (+-)(2R*,3R*)-2-methyl-2-nitro-1,3-butanediol (30 B, 22.1 g, 0.148 mol) in 95% EtOH (150 mL) was added glacial acetic acid (25 mL) and 10% Pd/C (MCB, 2.0 g). The reduction was carried out in a Parr apparatus at 50 psi of H2 during a 48 h period at RT. The catalyst was removed by filtration through a Millipore® filter, and the solvent removed under vacuum (2 days). The viscous, colorless syrup was dissolved in abs. EtOH (30 mL). Dilution with abs. Et2O (300 mL) gave a cloudy liquid which was placed in a refrigerator for two days. During this time, colorless crystals formed. They were washed with Et2O and dried in a vacuum oven at RT for two days. The yield of (+-)(2R*,3R*)-2-amino-2-methyl-1,3-butanediol acetate was 25.6 g (97%) mp 117°-121°, (C, H, N).
Reaction SMILES: [C:1]12[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH:6]C(=O)[O:4][C:2]2=O.[NH2:13][CH2:14][C:15]1[N:16]([C:20]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:17]=[CH:18][N:19]=1>C(Cl)Cl.C(O)(C)C.C(OCC)(=O)C>[NH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:1]=1[C:2]([NH:13][CH2:14][C:15]1[N:16]([C:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:17]=[CH:18][N:19]=1)=[O:4]
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Reactant: NCc1nccn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CC(C)O
Product: Nc1ccccc1C(=O)NCc1nccn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 80.1 %

Procedure:
Isatoic anhydride (2.65 g; 0.0162 mol) was slowly added to a room temperature solution of 5.51 g (0.0162 mol) of 2-(aminomethyl)-1-tritylimidazole in 30 ml of methylene chloride and 65 ml of isopropanol. The reaction mixture was then allowed to react overnight. The next morning the solution was reduced to dryness under reduced pressure and the resultant residue was redissolved in an ethyl acetate/aqueous sodium bicarbonate mixture. The resulting layers were separated, the organic layer was washed with water and then a saturated sodium chloride solution, dried over anhydrous sodium sulfate and finally reduced to dryness to provide a yellow solid. This solid was filtered through silica gel using 1000 ml of methylene chloride followed by 1000 ml of a 2% methanol in methylene chloride solution. The resulting filtrate was reduced to dryness to provide a white solid. This solid was recrystallized from a 1:1 ethyl acetate/hexanes solution to provide 5.95 g of the desired subtitled intermediate (m.p 171°-175° C.).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12)#[CH:2].Cl[C:27]1[S:28][C:29]([S:33]([NH2:36])(=[O:35])=[O:34])=[C:30]([CH3:32])[N:31]=1>>[CH3:32][C:30]1[N:31]=[C:27]([C:2]#[C:1][C:3]2[CH:4]=[N:5][N:6]3[C:11]([C:12]([F:14])([F:13])[F:15])=[CH:10][C:9]([C:16]4[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=4)=[N:8][C:7]=23)[S:28][C:29]=1[S:33]([NH2:36])(=[O:35])=[O:34]
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: Cc1nc(Cl)sc1S(N)(=O)=O
Product: Cc1nc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)sc1S(N)(=O)=O

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.1) (355 mg, 1.0 mmol) and 2-Chloro-4-methyl-thiazole-5-sulfonic acid amide (example B.23)(191 mg, 1.0 mmol) according to general procedure II. Obtained as a yellow solid (160 mg, 30%). MS (ISP) 532.1 [(M+H)+]; mp 245–246° C.
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[Cl:28][C:29]1[C:34]([F:35])=[CH:33][C:32](B2OC(C)(C)C(C)(C)O2)=[CH:31][N:30]=1.C([O-])(O)=O.[Na+]>COCCOC.CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:28][C:29]1[N:30]=[CH:31][C:32]([C:2]2[C:3]([N:22]3[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]3)=[N:4][CH:5]=[C:6]([C:7]([NH:9][C:10]3[CH:11]=[CH:12][C:13]([O:16][C:17]([F:18])([F:20])[F:19])=[CH:14][CH:15]=3)=[O:8])[CH:21]=2)=[CH:33][C:34]=1[F:35]
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(Br)c1
Reactant: CC1(C)OB(c2cnc(Cl)c(F)c2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(-c2cnc(Cl)c(F)c2)c1
Temperature: 95 °C
Reaction time: 2 h

Procedure:
(R)-5-Bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 35.1, 300 mg, 0.672 mmol) and 2-chloro-3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (346 mg, 1.345 mmol) were dissolved in DME (2.7 mL). A solution of 2 M NaHCO3 (1.01 mL, 2.03 mmol) was added, the RM was flushed with argon and Pd(PPh3)2Cl2 (56.6 mg, 0.081 mmol) was added. The RM was stirred under argon at 95° C. for 2 h in a capped pressure safe tube. After cooling to RT, the RM was dissolved in EtOAc, and washed with brine. The organic phase was dried over Na2SO4 and evaporated to dryness under reduced pressure. The crude product was purified by flash chromatography (RediSep® Silica gel column, DCM/MeOH from 2% to 5% MeOH), followed by a second purification (RediSep® Silica gel column, n-hexane/EtOAc, 50 to 100% EtOAc) and treatment with Si-Thiol (200 mg) in MeOH to afford the title compound as a white powder. HPLC (Condition 4) tR=5.63 min, UPLC-MS (Condition 7) m/z=497.1 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.65-1.80 (m, 1H) 1.80-1.91 (m, 1H) 2.87 (d, J=10.56 Hz, 1H) 3.18-3.28 (m, 2H) 3.33-3.50 (m, 1H) 4.20 (br. s, 1H) 4.86 (d, J=3.52 Hz, 1H) 7.34 (d, J=8.99 Hz, 2H) 7.84 (d, J=8.99 Hz, 2H) 7.99-8.11 (m, 2H) 8.34 (s, 1H) 8.77 (d, J=2.35 Hz, 1H) 10.16 (s, 1H).
Reaction SMILES: C.ClC([O:5][C:6](Cl)(Cl)Cl)=O.[CH2:10]([O:17][C:18](=[O:28])[C@@H:19]([OH:27])[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[NH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1>O1CCCC1.ClCCl.C(N(CC)CC)C>[CH2:10]([O:17][C:18](=[O:28])[C@@H:19]([O:27][C:6]([N:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1)=[O:5])[CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: O=C(OCc1ccccc1)[C@@H](O)Cc1ccccc1
Reactant: C1CCNCC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=C(OCc1ccccc1)[C@H](Cc1ccccc1)OC(=O)N1CCCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Active charcoal (30 mg) and trichloromethyl chloroformate (1.06 ml) were added to a solution of (2S)-2-hydroxy-3-phenylpropionic acid benzyl ester (3.0 g) in dry tetrahydrofuran (10 ml) and the mixture was stirred at room temperature overnight. A solution of piperidine (3.47 ml) and triethylamine (4.89 ml) in dichloromethane (10 ml) was added and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. Ethyl acetate (50 ml) was added and the mixture was washed with 0.01N hydrochloric acid, a saturated aqueous solution of NaHCO3 and saturated brine. The organic layer was dried over MgSO4 and the solvent was distilled away under reduced pressure. The residue was purified by silica gel column chromatography (eluted with AcOEt/Hex=1/9→2/8 v/v) to give 4.71 g of the title compound as a colorless oil (see Table 9).
Reaction SMILES: [SH:1][C:2]1[NH:6][N:5]=[N:4][CH:3]=1.ClC[CH:9]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:10][Si:11]([O:16][CH3:17])([O:14][CH3:15])[O:12][CH3:13].[CH3:24]O>>[CH3:17][O:16][Si:11]([O:12][CH3:13])([O:14][CH3:15])[CH2:10][CH2:9][C:18]1[CH:19]=[CH:20][C:21]([CH2:24][S:1][C:2]2[NH:6][N:5]=[N:4][CH:3]=2)=[CH:22][CH:23]=1
Reactant: CO
Reactant: Sc1cnn[nH]1
Reactant: CO[Si](CC(CCl)c1ccccc1)(OC)OC
Product: CO[Si](CCc1ccc(CSc2cnn[nH]2)cc1)(OC)OC
Reaction time: 0.08 h
Yield: 64.8 %

Procedure:
10 mmole of 5-mercapto-1H-1,2,3-triazole (sodium salt) was dissolved in 20 ml methanol and stirred for 5 minutes. 10 mmole of ((chloromethyl)phenylethyl)-trimethoxysilane was added to the solution, and stirred for 6 hours. The white precipitate was removed by filtration, the solvent in the filtrate was removed in vacuum. The filtrate was dissolved in small amount of methanol, and separated with a Si gel column (solvents: 5 ethylacetate/5 hexane in volume). 2.2 g product as liquid was obtained. Yield: 64.8%. 1H NMR (CDCl3) of Precursors 5: δ(ppm) 7.47 (1H, s), 7.12 (4H, m), 4.06 (2H, s), 3.55 (9H, s), 2.69 (2H, t, JH-H=8.50), 1.00 (2H, t, JH-H=8.50).