Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][N:6]1[C:12](=[O:13])[C:11]2[CH:14]=[C:15]([N+:18]([O-])=O)[CH:16]=[CH:17][C:10]=2[N:9]([CH3:21])[C:8](=[O:22])[CH2:7]1)[CH3:2].C(N(CC)CC)C.C(O)=O>CC#N.[Pd]>[CH2:1]([O:3][C:4](=[O:23])[CH2:5][N:6]1[C:12](=[O:13])[C:11]2[CH:14]=[C:15]([NH2:18])[CH:16]=[CH:17][C:10]=2[N:9]([CH3:21])[C:8](=[O:22])[CH2:7]1)[CH3:2]
Reactant: CCOC(=O)CN1CC(=O)N(C)c2ccc([N+](=O)[O-])cc2C1=O
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: O=CO
Solvent: CC#N
Product: CCOC(=O)CN1CC(=O)N(C)c2ccc(N)cc2C1=O
Temperature: 5 °C
Yield: 65.2 %

Procedure:
To a solution of (1-methyl-7-nitro-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl)-acetic acid ethyl ester (3.21 g, 10 mmol) in MeCN(15 ml) was added triethylamine (5.85 ml, 42.5 mmol). After cooling of this mixture to about 5° C. Pd—C (10%, 200 mg) and a solution of formic acid (1.6 ml) in MeCN(2 ml) were added. The ice bath was removed, gas evolution started and the temperature of the reaction mixture rose to 35° C. After 1 h the reaction mixture was heated to reflux temperature until all starting material had disappeared according to TLC. After filtration, evaporation of the solvents, and chromatography (silica gel, dichloromethane/MeOH 19:1) (7-amino-1-methyl-2,5-dioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepin-4-yl)-acetic acid ethyl ester (1.9 g) was isolated: mp. 118-119° C.; MS (EI): 291 (M)+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][N:15]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]3[CH:32]=[CH:31][N:30]=[C:29](Cl)[N:28]=3)[CH:22]=2)[S:16]([CH3:19])(=[O:18])=[O:17])[CH2:10][CH2:9]1)=O)(C)(C)C.[NH2:34][CH2:35][CH2:36][C:37]1[CH:42]=[CH:41][C:40]([OH:43])=[CH:39][CH:38]=1>>[OH:43][C:40]1[CH:41]=[CH:42][C:37]([CH2:36][CH2:35][NH:34][C:29]2[N:28]=[C:27]([C:23]3[CH:22]=[C:21]([CH:26]=[CH:25][CH:24]=3)[CH2:20][N:15]([CH2:14][CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)[S:16]([CH3:19])(=[O:18])=[O:17])[CH:32]=[CH:31][N:30]=2)=[CH:38][CH:39]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CN(Cc2cccc(-c3ccnc(Cl)n3)c2)S(C)(=O)=O)CC1
Reactant: NCCc1ccc(O)cc1
Product: CS(=O)(=O)N(Cc1cccc(-c2ccnc(NCCc3ccc(O)cc3)n2)c1)CC1CCNCC1

Procedure:
Intermediate 34 was coupled with tyramine following procedure F. The resulting product was deprotected following procedure G. LC-MS showed the product had the expected M+H+ of 496. 1H NMR (Varian 0.300 MHz, CD3OD, shifts relative to the solvent peak at 3.3 ppm) δ 8.3 (d, 2H), 8.1 (d, 1H) 7.6 (d, 1H) 7.5 (t, 1H), 7.3 (d, 1H), 7.1 (d, 2H), 6.7 (d, 2H), δ 4.5 (s, 2H), 3.3-3.2 (m, 6H), δ 3.0 (s, 3H), 2.9 (t, 2H), δ 2.7 (t, 2H), δ 1.6 (m, 1H), δ 1.2 (m, 4H).
Reaction SMILES: [Cl:1][CH2:2][C:3](=O)[CH3:4].[CH2:6]([O:13][C:14]1[C:15]([NH:21][C:22]([NH2:24])=[S:23])=[N:16][CH:17]=[C:18]([Br:20])[CH:19]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C.C(O)C>O>[ClH:1].[CH2:6]([O:13][C:14]1[C:15]([NH:21][C:22]2[S:23][CH:2]=[C:3]([CH3:4])[N:24]=2)=[N:16][CH:17]=[C:18]([Br:20])[CH:19]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: NC(=S)Nc1ncc(Br)cc1OCc1ccccc1
Reactant: CC(=O)CCl
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: O
Product: Cc1csc(Nc2ncc(Br)cc2OCc2ccccc2)n1
Product: Cl
Yield: 74.7 %

Procedure:
A 1 L round-bottomed flask was charged with 1-chloropropan-2-one (4.833 g, 52.24 mmol), 1-(3-(benzyloxy)-5-bromopyridin-2-yl)thiourea (12.62 g, 37.31 mmol), triethylamine (8.841 mL, 63.43 mmol), and ethanol (30 mL). The reaction mixture was heated to reflux overnight, then poured into water and extracted with methylene chloride. The organic layer was dried over sodium sulfate, filtered, and concentrated to provide 3-(benzyloxy)-5-bromo-N-(4-methylthiazol-2-yl)pyridin-2-amine hydrochloride (11.5 g, 81.9% yield) as a white powder. 1H NMR (d6-DMSO) 8.05 (d, 1H), 7.77 (m, 1H), 7.59 (m, 2H), 7.43 (m, 2H), 7.37 (m, 1H), 6.79 (s, 1H), 5.33 (s, 2H), 2.29 (s, 3H). Mass spectrum (apci) m/z=378.0 (M+H-HCl). Analysis calculated for C16H15BrClN3OS: C, 46.56; H, 3.66; N, 10.18. found: C, 46.56; H, 3.77; N, 10.02.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH:10]=[CH:9][N:8]([CH:11]3[CH2:13][CH2:12]3)[C:6]=2[N:7]=1.[OH-:15].[K+].Cl>O>[Cl:1][C:2]1[NH:3][C:4](=[O:15])[C:5]2[CH:10]=[CH:9][N:8]([CH:11]3[CH2:13][CH2:12]3)[C:6]=2[N:7]=1
Reactant: Clc1nc(Cl)c2ccn(C3CC3)c2n1
Reactant: [OH-]
Agent: Cl
Agent: [K+]
Solvent: O
Product: O=c1[nH]c(Cl)nc2c1ccn2C1CC1
Temperature: 100 °C
Yield: 95.9 %

Procedure:
A mixture of 2,4-dichloro-7-cyclopropyl-7H-pyrrolo[2,3-d]pyrimidine (68 mg, 298 μmol) in a 2N aqueous potassium hydroxide solution (1.67 ml, 3.34 mmol) was heated to 100° C. overnight. At this time, the reaction was cooled to room temperature. The reaction was diluted with water (−50 mL) and then neutralized by the addition of a 2N aqueous hydrochloric acid solution. The product was extracted into a 10% methanol/methylene chloride solution (3×25 mL), dried over sodium sulfate, filtered and concentrated in vacuo to afford 2-chloro-7-cyclopropyl-3,7-dihydro-pyrrolo[2,3-d]pyrimidin-4-one as a light yellow solid (59.9 mg, 95.8%). 1H NMR (300 MHz, DMSO-d6) δ ppm 0.78-1.17 (m, 4H) 3.50 (s, 1H) 6.42 (d, J=3.39 Hz, 1H) 7.07 (br. s., 1H) 12.87 (br. s., 1H). LC-MS calcd. for C9H9ClN3O [(M+H)+] 210, obsd. 209.9.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]([O:13][CH2:14][O:15][C:16](=[O:19])[CH2:17][CH3:18])[CH2:11]Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20]([O-:24])(=[O:23])[CH2:21][CH3:22].[Na+]>[Cl-].C([P+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[CH2:1]([O:8][CH2:9][CH:10]([O:13][CH2:14][O:15][C:16](=[O:19])[CH2:17][CH3:18])[CH2:11][O:24][C:20](=[O:23])[CH2:21][CH3:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCC(=O)OCOC(CCl)COCc1ccccc1
Reactant: CCC(=O)[O-]
Agent: CCCC[P+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCC(=O)OCOC(COCc1ccccc1)COC(=O)CC
Temperature: 90 °C

Procedure:
Epichlorohydrin is reacted with benzyl alcohol in the presence of tetrabutylammonium bisulfate in aqueous sodium hydroxide, at room temperature. The product of this reaction, benzyl glycidyl ether, is isolated by conventional means and is then added slowly to a suspension of lithium chloride in tetrahydrofuran and acetic acid, at 40°-70° C., preferably below 60° C. The reaction mixture is allowed to cool to room temperature, and stirred for 2-10 hours, preferably 3-6 hours. The product is isolated by extraction, washed and dried to provide 1-benzyloxy-3-chloro-2-propanol. To this product is then added methoxymethyl propionate, which is prepared by adding propionic anhydride to dimethoxymethane in the presence of an ion exchange resin, e.g., Amberlyst 15, maintaining the temperature between 40°-60° C., preferably between 40°-50° C. during the addition. The reaction mixture is aged and cooled, then filtered, washed and distilled. This product, methoxymethyl propionate, is reacted with 1-benzyloxy-3-chloro-2-propanol in an aprotic solvent, e.g., hexanes, in the presence of p-toluenesulfonic acid hydrate at reflux. Distillation and washing affords the product 1-benzyloxy-3-chloro-2-(propionyloxy)methoxypropane. Finally, to prepare the compounds of Formula (III), 1-benzyloxy-3-chloro-2-(propionyloxy)methoxypropane, is refluxed with an alkali metal alkanoate, e.g., sodium propionate, in an aprotic solvent, e.g., toluene, after which a phase transfer catalyst such as tetrabutylphosphonium chloride is added. The reaction mixture is stirred at 90° C. to reflux temperature for 1-3 days, preferably 2 days, at which time more tetrabutylphosphonium chloride and solvent may be added, if required. The mixture is heated to reflux and the distillate removed, then stirred at 90° C. to reflux temperature for 3-16 hours, preferably 5-10 hours, then cooled to ambient temperature. The mixture is then washed with water and brine, and the organic phase is separated and concentrated to yield 1-benzyloxy-3-propionyloxy-2-(propionyloxy)methoxy propane. In an analogous manner, other glycerol derivatives of Formula (III) may be prepared.
Reaction SMILES: [CH3:1][C@@H:2]([OH:6])[CH2:3][C:4]#[CH:5].[F:7][C:8]1[C:9](I)=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])/[C:11]/2=[CH:18]\[C:19]1[NH:20][CH:21]=[CH:22][C:23]=1[O:24][CH3:25]>CN(C=O)C.CCN(CC)CC.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>[F:7][C:8]1[C:9]([C:5]#[C:4][CH2:3][C@H:2]([OH:6])[CH3:1])=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])/[C:11]/2=[CH:18]\[C:19]1[NH:20][CH:21]=[CH:22][C:23]=1[O:24][CH3:25]
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(I)c21
Reactant: C#CC[C@@H](C)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(C#CC[C@@H](C)O)c21

Procedure:
Using Method C above, (R)-pent-4-yn-2-ol (44 mg, 0.52 mmol) (see below) was coupled with (Z)-1,3-dihydro-5-fluoro-4-iodo-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (50 mg, 0.13 mmol) (Starting Material 6) using (Ph3P)4Pd (15 mg, 0.01 mol) and Cul (2 mg) in a mixture of DMF (5 mL) and Et3N (5 mL) as solvent at 80° C. for 7 hrs. Upon completion, the reaction mixture was diluted with EtOAc and extracted with H2O. The organic layer was dried over Na2SO4 and concentrated. (R)-(Z)-1,3-Dihydro-5-fluoro-4-(4-hydroxy-1-pentynyl)-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one was obtained after silica gel column chromatography with a 0-70% EtOAc in hexanes gradient and trituration with Et2O. (Yield 20 mg, 45%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11]1[N:12]([CH2:17][CH:18]([CH3:20])[CH3:19])[C:13](S)=[N:14][N:15]=1>C(O)C.[Ni]>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11]1[N:12]([CH2:17][CH:18]([CH3:20])[CH3:19])[CH:13]=[N:14][N:15]=1
Reactant: COc1ccc(-c2nnc(S)n2CC(C)C)c(OC)c1
Agent: [Ni]
Solvent: CCO
Product: COc1ccc(-c2nncn2CC(C)C)c(OC)c1
Yield: 101.3 %

Procedure:
Ex-109D: To a solution of 5-(2,4-dimethoxy-phenyl)-4-isobutyl-4H-[1,2,4]triazole-3-thiol (Ex-109C, 0.1 g, 0.34 mmol) in ethanol (10 mL) was added wet Raney Ni (0.27 g, 4.6 mmol). The suspension of ethanol was refluxed overnight and then passed through a bed of Hyflo Super Gel and diatomaceous earth. The filtrate was concentrated to afford 3-(2,4-dimethoxy-phenyl)-4-isobutyl-4H-[1,2,4]triazole (0.09 g, 100%) as a white solid: 1H NMR (CDCl3) δ 8.15 (s, 1H), 7.34 (d, J=7.8 Hz, 1H), 6.57 (dd, J=7.8, 2.3 Hz, 1H), 6.51 (d, J=2.3 Hz, 1H), 3.85 (s, 3H), 3.75 (s, 3H), 3.62 (d, J=7.5 Hz, 2H), 1.89–1.80 (m, 1H), 0.76 (d, J=6.6 Hz, 6H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:10](O)[CH3:11])[CH:5]=[C:6]([F:9])[C:7]=1[F:8].C1C=CC(OP(OC2C=CC=CC=2)([N:22]=[N+:23]=[N-:24])=O)=CC=1.O>C1(C)C=CC=CC=1.N12CCCN=C1CCCCC2>[N:22]([C@H:10]([C:4]1[CH:5]=[C:6]([F:9])[C:7]([F:8])=[C:2]([F:1])[CH:3]=1)[CH3:11])=[N+:23]=[N-:24]
Reactant: [N-]=[N+]=NP(=O)(Oc1ccccc1)Oc1ccccc1
Reactant: C[C@@H](O)c1cc(F)c(F)c(F)c1
Solvent: Cc1ccccc1
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Product: C[C@H](N=[N+]=[N-])c1cc(F)c(F)c(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (R)-1-(3,4,5-trifluorophenyl)ethanol (3.6 g) and diphenylphosphoric azide (6.0 ml) in toluene (70 ml), 1,8-diazabicyclo[5,4,0]undec-7-ene (4.1 ml) was added dropwise under ice-cooling. The reaction solution was stirred at the same temperature for one hour and at room temperature overnight. Water was added to the reaction solution, and the organic layer was separated. Then, the aqueous layer was subjected to extraction with toluene again. The organic layers were combined and sequentially washed with 1 N hydrochloric acid, water, a saturated sodium bicarbonate solution, and brine. The organic layers were dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (heptane:ethyl acetate=49:1) to obtain 858 mg of the title compound.
Reaction SMILES: [C:1]([BH3-])#[N:2].[Na+].[OH:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18](/[CH:21]=[CH:22]/[C:23]2[CH:28]=[CH:27][C:26](N)=[CH:25][CH:24]=2)=[CH:17][N:16]=1.C=O.[C:32](=O)(O)[O-].[Na+]>C(O)(=O)C>[OH:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18](/[CH:21]=[CH:22]/[C:23]2[CH:28]=[CH:27][C:26]([N:2]([CH3:1])[CH3:32])=[CH:25][CH:24]=2)=[CH:17][N:16]=1
Reactant: [BH3-]C#N
Reactant: O=C([O-])O
Reactant: Nc1ccc(/C=C/c2ccc(OCCOCCOCCO)nc2)cc1
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Product: CN(C)c1ccc(/C=C/c2ccc(OCCOCCOCCO)nc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
Sodium cyanoborohydride (36 mg, 0.57 mmol) was added to a solution of compound 8 (65 mg, 0.19 mmol) and paraformaldehyde (57 mg, 1.9 mmol) in acetic acid (10 ml). The reaction mixture was stirred at room temperature overnight and poured onto ice. Sodium bicarbonate was used to adjust pH to 9. Reaction mixture was extracted with ethyl acetate. Organic layer was separated, washed with brine, dried over anhydrous sodium sulfate and evaporated. The residue was purified with PTLC (5% MeOH in DCM as the developing solvent) to give product 9 (67 mg, Yield: 95%): 1H NMR (200 MHz, CDCl3): δ.8.14 (1H, d, J=2.4 Hz), 7.76 (1H, d, d, J=8.6 Hz, J2=2.4 Hz), 7.39 (2H, d, J=8.8 Hz), 6.87 (2H, m), 6.76 (3H, m), 4.50 (2H, t, J=4.8 Hz), 3.87 (2H, t, J=4.8 Hz), 3.70 (6H, m), 3.61 (2H, m), 2.98 (6H, s), 2.49 (1H, b), HRMS (EI) m/z calcd. for [C21H28N2O4]+ 372.2049.
Reaction SMILES: [F:1][CH:2]([F:26])[O:3][C:4]1[C:5]([OH:25])=[C:6](/[CH:10]=[CH:11]/[C:12]2[N:13]=[C:14]3[N:18]([C:19]=2[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:17]=[CH:16][S:15]3)[CH:7]=[CH:8][CH:9]=1.Br[CH2:28][CH:29]1[CH2:32][CH2:31][CH2:30]1.C(=O)([O-])[O-].[K+].[K+].FC(F)OC1C(OCC(C)(C)C)=C(/C=C/C2N=C3N(C=2C(O)=O)C=CS3)C=CC=1>CN(C)C=O>[CH:29]1([CH2:28][O:25][C:5]2[C:4]([O:3][CH:2]([F:1])[F:26])=[CH:9][CH:8]=[CH:7][C:6]=2/[CH:10]=[CH:11]/[C:12]2[N:13]=[C:14]3[N:18]([C:19]=2[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:17]=[CH:16][S:15]3)[CH2:32][CH2:31][CH2:30]1
Reactant: BrCC1CCC1
Reactant: CCOC(=O)c1c(/C=C/c2cccc(OC(F)F)c2O)nc2sccn12
Agent: CC(C)(C)COc1c(/C=C/c2nc3sccn3c2C(=O)O)cccc1OC(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(/C=C/c2cccc(OC(F)F)c2OCC2CCC2)nc2sccn12
Yield: 88.2 %

Procedure:
Alkylation of Intermediate 6 (500 mg, 1.315 mmol) with (bromomethyl)cyclobutane (178 mg, 1.578 mmol) in presence of potassium carbonate (199 mg, 1.446 mmol) in anhydrous N,N-dimethylformamide (5 mL) as described in Intermediate 7A gave 520 mg of the product as a white solid; 1H NMR (300 MHz, DMSO-d6) δ 1.40 (t, J=6.9 Hz, 3H), 1.84-1.93 (m, 4H), 2.02-2.10 (m, 2H), 2.70-2.76 (m, 1H), 3.93 (d, J=6.9 Hz, 2H), 4.41 (q, J=6.9 Hz, 2H), 7.19 (t, J=74.7 Hz, 1H), 7.20-7.28 (m, 2H), 7.42-7.51 (m, 1H), 7.54-7.60 (m, 1H), 7.70-7.78 (m, 1H), 7.85 (d, J=15.9 Hz, 1H), 8.13 (d, J=4.2 Hz, 1H); APCI-MS (m/z) 449.18 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][F:9])[N:3]=1.[C:10]([O:14][C:15](=[O:30])[N:16]([C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1)[C:17](=[O:22])[C:18]#[C:19][CH2:20][CH3:21])([CH3:13])([CH3:12])[CH3:11]>>[C:10]([O:14][C:15](=[O:30])[N:16]([C:17](=[O:22])[CH2:18][CH2:19][C:20]#[C:21][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][F:9])[N:3]=1)[C:23]1[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=1)([CH3:13])([CH3:11])[CH3:12]
Reactant: FCc1cccc(Br)n1
Reactant: CCC#CC(=O)N(C(=O)OC(C)(C)C)c1ccc(F)cc1
Product: CC(C)(C)OC(=O)N(C(=O)CCC#Cc1cccc(CF)n1)c1ccc(F)cc1
Yield: 78.9 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-bromo-6-(fluoromethyl)pyridine (180 mg, 0.95 mmol, Example 190(E)) and (4-fluoro-phenyl)-pentynoyl-carbamic acid tert-butyl ester (276 mg, 0.95 mmol). Reaction time: 3 hours. The crude residue was purified by flash chromatography (cyclohexane/AcOEt 4:1) to yield 300 mg (0.75 mmol, 79%) of [5-(6-fluoromethyl-pyridin-2-yl)-pent-4-ynoyl]-(4-fluoro-phenyl)-carbamic acid tert-butyl ester as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:20])=[C:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[NH:9][C:10]=1[CH:11]=O)=[O:5])[CH3:2].[CH2:21]([O:23][C:24]([CH:26]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:25])[CH3:22]>O1CCCC1.CCCCCC.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:20])=[C:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[NH:9][C:10]=1[CH:11]=[CH:26][C:24]([O:23][CH2:21][CH3:22])=[O:25])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(C=O)[nH]c(C(=O)OC(C)(C)C)c1C
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCOC(=O)C=Cc1[nH]c(C(=O)OC(C)(C)C)c(C)c1C(=O)OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
5-Formyl-3-methyl-1H-pyrrole-2,4-dicarboxylic acid 2-tert-butyl ester 4-ethyl ester 1 b (23 g, 81.7 mmol) and (ethoxycarbonylmethylene)triphenylphosphorane (34.66 g, 99.4 mmol) were dissolved in 450 ml of tetrahydrofuran, and stirred at room temperature overnight under an argon atmosphere. After thin lay chromatography showed the disappearance of starting materials, the reaction mixture was concentrated under reduced pressure to obtain a yellow oil. The residue was dissolved in the solvent mixture of n-hexane and ethyl acetate (V:V=20:1), and purified by sand funnel decompression column chromatography to obtain the title compound 5-(2-ethoxycarbonyl-vinyl)-3-methyl-1H-pyrrole-2,4-dicarboxylic acid 2-tert-butyl ester 4-ethyl ester 1c (24 g, yield 84%) as a light yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][CH:14]([CH3:33])[CH2:15][CH2:16][C:17]2[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:18]=2[C:25]#[C:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH2:34]=O.[BH4-].[Na+]>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][N:13]([CH3:34])[CH:14]([CH3:33])[CH2:15][CH2:16][C:17]2[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:18]=2[C:25]#[C:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: C=O
Reactant: COc1ccc(C#Cc2ccccc2)c(CCC(C)NCCc2ccc(OC)c(OC)c2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(C#Cc2ccccc2)c(CCC(C)N(C)CCc2ccc(OC)c(OC)c2)c1

Procedure:
A mixture of of N-[2-(3,4-dimethoxyphenyl)ethyl]-5-methoxy-α-methyl-2-(phenylethynyl)benzenepropanamine (0.3 g, 0.68 mmole), the free base of the product of Example 1e, and 37% aqueous formaldehyde (0.5 mL) were combined in absolute methanol (5 mL). With stirring, sodium borohydride (0.05 g, 1.3 mmole) was added, and the resulting reaction mixture stirred overnight. The mixture was concentrated in vacuo, the resulting residue dissolved in 5 mL of EtOAc, 5 mL of 1N sodium hydroxide was added and the resulting layers separated. The aqueous layer was extracted with EtOAc and washed with water, brine and dried over anhydrous sodium sulfate. After filtering, the filtrate was concentrated in vacuo to give 0.3 g of the title product as a golden oil. The title product is the antihypertensive pharmaceutical prepared in Example 32 of European Pat. No. 146,271.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:5]=2[N:6]=1.Cl[C:13]1[N:18]=[N:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:15]([C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=2)[CH:14]=1.[H-].[Na+]>CN(C=O)C>[CH3:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([O:11][C:13]3[N:18]=[N:17][C:16]([C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)=[C:15]([C:25]4[CH:26]=[CH:27][C:28]([C:31]([F:32])([F:34])[F:33])=[CH:29][CH:30]=4)[CH:14]=3)=[CH:7][C:5]=2[N:6]=1
Reactant: Cc1nc2cc(O)ccc2s1
Reactant: FC(F)(F)c1ccc(-c2cc(Cl)nnc2-c2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nc2cc(Oc3cc(-c4ccc(C(F)(F)F)cc4)c(-c4ccccc4)nn3)ccc2s1

Procedure:
The title compound was prepared analogous to the procedure used to prepare Example 45(f), using 2-methyl-5-benzothiazolol (117 mg, 0.7 mmol, Aldrich), 6-chloro-3-phenyl-4-(4-trifluoromethyl-phenyl)-pyridazine, (Example 13(e)), (197 mg, 0.6 mmol) and NaH (37 mg, 0.9 mmol, 60% suspension in mineral oil, Aldrich) in DMF (5 mL). Purification by flash silica gel chromatography with 2M NH3 in MeOH/CH2Cl2 (0:1→1:49) as eluant gave the title compound as a pale-orange amorphous solid. Mp: 208–209° C. MS (ESI, pos ion.) m/z: 464 (M+1).
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([CH2:7][CH3:8])[C:3]=1[CH2:9][C:10]1[CH:17]=[CH:16]C(C#N)=[CH:12][CH:11]=1.[CH3:18][C:19](=O)[CH2:20][C:21](=O)[CH3:22].[CH3:25][C:26]([OH:28])=[O:27].Cl>O>[CH2:7]([C:4]1[C:3]([CH2:9][C:10]2[CH:11]=[CH:12][C:25]([C:26]([OH:28])=[O:27])=[CH:16][CH:17]=2)=[C:2]2[N:1]=[C:19]([CH3:18])[CH:20]=[C:21]([CH3:22])[N:6]2[N:5]=1)[CH3:8]
Reactant: CC(=O)CC(C)=O
Reactant: CCc1n[nH]c(N)c1Cc1ccc(C#N)cc1
Reactant: CC(=O)O
Agent: Cl
Solvent: O
Product: CCc1nn2c(C)cc(C)nc2c1Cc1ccc(C(=O)O)cc1
Temperature: 110 °C
Reaction time: 43 h

Procedure:
To a 500 ml, four-necked flask equipped with an overhead stirrer, a thermocouple and a condenser was charged with 4-((5-amino-3-ethyl-1H-pyrazol-4-yl)methyl)benzonitrile (26) (12.8 g, 56.5 mmol), pentane-2,4-dione (6.8 g, 67.9 mmol, 1.2 eq), 20 ml of HOAc and 40 ml of concentrated HCl. The mixture was stirred at 110° C. for 43 hours. It was cooled to room temperature and 300 ml of water was added. Slowly, the solution became a suspension. It was stirred at room temperature for 1 h. The precipitate was collected by vacuum filtration and the solid was washed with water. The solid was vacuum oven dried at 50° C. for 5 h.
Reaction SMILES: [CH2:1]([N:8]1[C:14](=[O:15])[CH:13]2[CH2:16][CH2:17][CH2:18][C:12]2=[N:11][C:10]2[CH:19]=[CH:20][C:21]([Cl:23])=[CH:22][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(OC(=O)C)C.CCCCCC>[CH2:1]([N:8]1[C:14](=[O:15])[C@H:13]2[CH2:16][CH2:17][CH2:18][C@H:12]2[NH:11][C:10]2[CH:19]=[CH:20][C:21]([Cl:23])=[CH:22][C:9]1=2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1C2CCCC2=Nc2ccc(Cl)cc2N1Cc1ccccc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: O=C1[C@H]2CCC[C@H]2Nc2ccc(Cl)cc2N1Cc1ccccc1
Yield: 53 %

Procedure:
Using 9-benzyl-7-chloro-2,3,9,10a-tetrahydrobenzo[b]cyclopenta[e][1,4]diazepin-10(1H)-one, the titled compound was synthesized in substantially the same manner as in Working Example 26 in a yield of 53%, m.p. 160°-163° C. (ethylacetate-hexane).
Reaction SMILES: [NH2:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4].[Br:7][C:8]1[CH:9]=[CH:10][C:11]([O:18][CH3:19])=[C:12]([S:14](Cl)(=[O:16])=[O:15])[CH:13]=1>>[Br:7][C:8]1[CH:9]=[CH:10][C:11]([O:18][CH3:19])=[C:12]([S:14]([NH:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4])(=[O:15])=[O:16])[CH:13]=1
Reactant: COc1ccc(Br)cc1S(=O)(=O)Cl
Reactant: CC(C)(N)CO
Product: COc1ccc(Br)cc1S(=O)(=O)NC(C)(C)CO
Yield: 99.3 %

Procedure:
Prepared by general procedure III from 2-amino-2-methyl-1-propanol (2.23 g, 25 mmol) and commercially available 5-bromo-2-methoxybenzenesulfonyl chloride (1.43 g, 5 mmol) to give the title compound as an off-white solid (1.68 g, 99%). MS (ISN) 336.2 [(M−H)−], 338.1 [(M+2−H)−]. mp 168° C.