Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:6](=O)[NH:7][C@H:8]1[CH2:12][CH2:11][N:10]([C:13]2[CH:14]=[CH:15][C:16]3[N:17]([C:19]([Br:22])=[CH:20][N:21]=3)[N:18]=2)[CH2:9]1)(C)(C)C.IC.[H-].[Na+]>CN(C=O)C>[Br:22][C:19]1[N:17]2[N:18]=[C:13]([N:10]3[CH2:11][CH2:12][C@H:8]([NH:7][CH3:6])[CH2:9]3)[CH:14]=[CH:15][C:16]2=[N:21][CH:20]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(c2ccc3ncc(Br)n3n2)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: CN[C@H]1CCN(c2ccc3ncc(Br)n3n2)C1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 103.6 %

Procedure:
[(S)-1-(3-Bromo-imidazo[1,2-b]pyridazin-6-yl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester (1.2 g, 3.1 mmol) taken up in 15 mL DMF and cooled to 0° C. in an ice bath. Iodomethane (342 uL, 5.42 mmol) added and stirred 5 minutes. Then sodium hydride 60% in oil (251 mg, 6.2 mmol) was slowly added. Reaction stirred 5 minutes at 0° C. then removed from ice bath and stirred 30 minutes at room temperature. Reaction was quenched with ice then extracted with ethyl acetate 2×. Ethyl acetate fractions combined dried over magnesium sulfate filtered reduce in vacuo. This was then taken up in 26 mL DCM and 4 mL TFA added. Stirred 1 hour until complete by LC/MS. Reaction washed with 1N NaOH, DCM layer removed dried over magnesium sulfate filtered, reduced in vacuo to get 951 mg crude product carried on as is to part B. LRMS (ESI) m/z 296/298 [(M+H)]+, calc'd for C11H14BrN5: 296.17.
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][N:7]2[C:11](=[O:12])[N:10]([C:13]3[S:14][C:15]([C:19]([NH2:21])=O)=[C:16]([CH3:18])[N:17]=3)[CH:9]=[N:8]2)=[CH:4][CH:3]=1.N1C=CC=CC=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O>O1CCOCC1>[F:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][N:7]2[C:11](=[O:12])[N:10]([C:13]3[S:14][C:15]([C:19]#[N:21])=[C:16]([CH3:18])[N:17]=3)[CH:9]=[N:8]2)=[CH:4][CH:3]=1
Reactant: Cc1nc(-n2cnn(Cc3ccc(F)cc3)c2=O)sc1C(N)=O
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Solvent: C1COCCO1
Product: Cc1nc(-n2cnn(Cc3ccc(F)cc3)c2=O)sc1C#N
Yield: 61.1 %

Procedure:
A mixture of 2-(1-(4-fluorobenzyl)-5-oxo-1H-1,2,4-triazol-4(5H)-yl)-4-methylthiazole-5-carboxamide (0.45 g, 1.35 mmol), pyridine (0.21 g, 2.71 mmol) and trifluoroacetic anhydride (0.57 g, 2.71 mmol) in dioxane (12.0 mL) was heated at reflux for 16 h and concentrated in vacuo to dryness. The residue was purified by column chromatography eluted with ethyl acetate in hexane (20%) to afford the title compound as a colourless solid (0.26 g, 63%): mp 190-192° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.80 (s, 1H), 7.38-7.33 (m, 2H), 7.18-7.12 (m, 2H), 4.97 (s, 2H), 2.49 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 162.2 (d), 161.3, 156.0, 150.3, 132.5, 132.4, 130.5 (d), 115.9 (d), 113.3, 97.5, 48.3, 17.2; MS (ES+) m/z 316.9 (M+1).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[C:16]([NH:18][C:19](=[O:30])[CH2:20][N:21]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH3:22])[CH:15]=[CH:14][C:13]=2[Cl:31])=[CH:8][CH:7]=1)=[O:5])C>[OH-].[Na+].C(O)C>[C:26]([O:25][C:23]([N:21]([CH3:22])[CH2:20][C:19]([NH:18][C:16]1[CH:15]=[CH:14][C:13]([Cl:31])=[C:12]([C:9]2[CH:8]=[CH:7][C:6]([C:4]([OH:5])=[O:3])=[CH:11][CH:10]=2)[CH:17]=1)=[O:30])=[O:24])([CH3:29])([CH3:28])[CH3:27]
Reactant: CCOC(=O)c1ccc(-c2cc(NC(=O)CN(C)C(=O)OC(C)(C)C)ccc2Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CN(CC(=O)Nc1ccc(Cl)c(-c2ccc(C(=O)O)cc2)c1)C(=O)OC(C)(C)C

Procedure:
5′-[2-(tert-Butoxycarbonyl-methyl-amino)-acetylamino]-2′-chloro-biphenyl-4-carboxylic acid ethyl ester (494 mg) in 2M NaOH (10 ml) and ethanol (15 ml) was stirred at room temp for 18 h. The ethanol was then evaporated and the residue acidified with HCl. The colourless solid formed was collected by filtration and dried (420 mg).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.[CH:12]1([C:15]2[C:16]([N:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)=[N:17][CH:18]=[C:19]([CH:21]3[CH2:23][CH2:22]3)[CH:20]=2)[CH2:14][CH2:13]1>>[CH:12]1([C:15]2[C:16]([N:24]3[CH2:25][CH2:26][N:27]([C:6]([C:5]4[CH:4]=[N:3][C:2]([F:1])=[CH:10][C:9]=4[CH3:11])=[O:8])[CH2:28][CH2:29]3)=[N:17][CH:18]=[C:19]([CH:21]3[CH2:23][CH2:22]3)[CH:20]=2)[CH2:13][CH2:14]1
Reactant: c1nc(N2CCNCC2)c(C2CC2)cc1C1CC1
Reactant: Cc1cc(F)ncc1C(=O)O
Product: Cc1cc(F)ncc1C(=O)N1CCN(c2ncc(C3CC3)cc2C2CC2)CC1
Yield: 85.3 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 60 and using 6-fluoro-4-methylnicotinic acid (600 mg) and 1-(3,5-dicyclopropylpyridin-2-yl)piperazine (922 mg) described in Preparation Example 62, the title compound (1.23 g) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:37])[C:4]1[CH:9]=[C:8]([N+:10]([O-])=O)[C:7]([N:13]2[CH2:18][CH2:17][N:16]([C:19]3[N:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[CH:21][N:20]=3)[C@H:15]([CH:29]([CH3:31])[CH3:30])[C:14]2=O)=[CH:6][C:5]=1[S:33]([CH3:36])(=[O:35])=[O:34]>C(O)(=O)C.[Fe]>[CH3:1][O:2][C:3]([C:4]1[C:5]([S:33]([CH3:36])(=[O:35])=[O:34])=[CH:6][C:7]2[N:13]3[CH2:18][CH2:17][N:16]([C:19]4[N:24]=[C:23]([C:25]([F:28])([F:26])[F:27])[CH:22]=[CH:21][N:20]=4)[CH:15]([CH:29]([CH3:31])[CH3:30])[C:14]3=[N:10][C:8]=2[CH:9]=1)=[O:37]
Reactant: COC(=O)c1cc([N+](=O)[O-])c(N2CCN(c3nccc(C(F)(F)F)n3)[C@H](C(C)C)C2=O)cc1S(C)(=O)=O
Agent: [Fe]
Solvent: CC(=O)O
Product: COC(=O)c1cc2nc3n(c2cc1S(C)(=O)=O)CCN(c1nccc(C(F)(F)F)n1)C3C(C)C
Temperature: 100 °C
Reaction time: 0.08 h
Yield: 51.4 %

Procedure:
To a solution of (R)-methyl-4-(3-isopropyl-2-oxo-4-(4-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)-2-(methylsulfonyl)-5-nitrobenzoate (1.45 g, 2.66 mmol) in glacial acetic acid (17 mL) was added iron powder (445 mg, 7.97 mmol). The mixture was heated to 100° C. After 5 min, the suspended iron dissolved into solution. The mixture was stirred at 100° C. for 48 h, at which point the flask was cooled to rt and the contents were poured into ice. The mixture was extracted with EtOAc (2×75 mL), then the combined organic layers were washed with water (2×50 mL) and brine (50 mL). The solution was dried over MgSO4, filtered through cotton, and concentrated in vacuo. The residue was purified on a silica cartridge (0% EtOAc in hexanes, then 50%) to yield 680 mg of methyl-1-isopropyl-7-(methylsulfonyl)-2-(4-(trifluoromethyl)pyrimidin-2-yl)-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazine-8-carboxylate as a racemic mixture (51%). LC-MS: m/z 498.32 (M+H]+. 1H NMR (CDCl3, 400 MHz): δ 8.58 (d, J=4.8 Hz, 1H), 8.20 (s, 1H), 8.12 (s, 1H), 6.90 (d, J=4.8 Hz, 1H), 6.13 (d, J=8.4 Hz, 1H), 5.39 (dd, J=4.8 Hz, 14.4 Hz, 1H), 4.35 (ddd, J=1.2 Hz, 4.4 Hz, 12.0 Hz, 1H), 4.21 (dt, J=4.8 Hz, 12.0 Hz, 1H), 4.00 (s, 3H), 3.78 (ddd, J=4.4 Hz, 11.6 Hz, 14.4 Hz, 1H), 3.45 (s, 3H), 2.48 (sept, J=7.2 Hz, 1H), 1.32 (d, J=6.4 Hz, 3H), 1.08 (d, J=6.8 Hz, 3H).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([CH3:12])[C:9]([N+:13]([O-])=O)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C([O-])=O.[NH4+]>CO.[Pd]>[NH2:13][C:9]1[C:10]([CH3:12])=[N:11][CH:2]=[C:3]([CH:8]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cc([N+](=O)[O-])c(C)nc1Cl
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: COC(=O)c1cnc(C)c(N)c1
Temperature: 25 °C

Procedure:
Methyl 2-chloro-6-methyl-5-nitronicotinate (step 1) (6.9 g, 29.9 mmol) was added to a suspension of ammonium formate (18.87 g, 299 mmol) and 10% Pd (Carbon) (0.522 g, 0.491 mmol) in MeOH (330 ml) and the mixture was heated at reflux for 3 hrs. After cooling to RT, the mixture was filtered through Celite® (filter material) and washed through with MeOH. The solvent was removed in vacuo and the crude product was triturated with EtOAc to give an orange solid. Purification by chromatography on silica eluting with 0-100% EtOAc in iso-hexane afforded the title product.
Reaction SMILES: ClCC1C=CC(C#N)=CC=1.Br[CH2:12][C:13]1[CH:14]=[C:15]([CH:20]=[CH:21][CH:22]=1)[C:16]([O:18][CH3:19])=[O:17].[CH2:23]([NH:30][C:31]([C:33]1[S:37][C:36]([N:38]2[CH2:42][CH2:41][NH:40][C:39]2=[O:43])=[N:35][C:34]=1[CH3:44])=[O:32])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:23]([NH:30][C:31]([C:33]1[S:37][C:36]([N:38]2[CH2:42][CH2:41][N:40]([CH2:12][C:13]3[CH:14]=[C:15]([CH:20]=[CH:21][CH:22]=3)[C:16]([O:18][CH3:19])=[O:17])[C:39]2=[O:43])=[N:35][C:34]=1[CH3:44])=[O:32])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: Cc1nc(N2CCNC2=O)sc1C(=O)NCc1ccccc1
Reactant: COC(=O)c1cccc(CBr)c1
Agent: N#Cc1ccc(CCl)cc1
Product: COC(=O)c1cccc(CN2CCN(c3nc(C)c(C(=O)NCc4ccccc4)s3)C2=O)c1
Yield: 43 %

Procedure:
Following the procedure as described in Example 23, making variations as required to replace 4-(chloromethyl)benzonitrile with methyl 3-(bromomethyl)benzoate to react with N-benzyl-4-methyl-2-(2-oxoimidazolidin-1-yl)thiazole-5-carboxamide, the title compound was obtained as a colorless solid in 43% yield: mp 49-51° C. (dichloromethane/hexanes); 1H NMR (300 MHz, CDCl3) δ 8.01-7.94 (m, 2H), 7.53-7.31 (m, 7H), 5.91 (br s, 1H), 4.58 (d, J=6.0 Hz, 2H), 4.53 (s, 2H), 4.12-4.06 (m, 2H), 3.92 (s, 3H), 3.50-3.44 (m, 2H), 2.62 (s, 3H); MS (ES+) m/z 465.2 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([C@H:8]1[NH:13][C:12]([CH3:18])([C:14](OC)=[O:15])[CH2:11][C:10](=[O:19])[N:9]1[CH3:20])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:21][NH2:22]>CCO>[C:1]([O:5][C:6]([C@H:8]1[NH:13][C:12]([CH3:18])([C:14]([NH:21][NH2:22])=[O:15])[CH2:11][C:10](=[O:19])[N:9]1[CH3:20])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)C1(C)CC(=O)N(C)[C@@H](C(=O)OC(C)(C)C)N1
Reactant: NN
Solvent: CCO
Product: CN1C(=O)CC(C)(C(=O)NN)N[C@@H]1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 103.4 %

Procedure:
To a solution of (S)-methyl 2-(tert-butoxycarbonyl)-1,4-dimethyl-6-oxo-hexahydropyrimidine-4-carboxylate (0.074 g, 0.25 mmol) in EtOH (0.5 mL) was added NH2NH2 (0.023 mL, 0.75 mmol, 3 eq) and the mixture was stirred at RT for 4 h. The mixture was concentrated in vacuo to give 0.074 g (100%) of (S)-2-(tert-butoxycarbonyl)-1,4-dimethyl-6-oxo-hexahydropyrimidine-4-carbohydrazide (CY1, R6=Me) as a yellow solid. 1H NMR (CDCl3) 8.95 (s, 1H), 3.11 (s, 3H), 2.28 (m, 2H), 1.50 (s, 9H), 1.47 (s, 3H).
Reaction SMILES: [C:1]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@H:8]([CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C:9](O)=[O:10])=[CH:3][CH:2]=1.Cl.[CH3:27][O:28][C:29](=[O:33])[CH2:30][CH2:31][NH2:32].CCN=C=NCCCN(C)C.Cl.ON1C2N=CC=CC=2N=N1.CCN(C(C)C)C(C)C>CN(C=O)C>[C:1]1([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:2]=[CH:3][C:4]([CH2:7][C@@H:8]([C:9]([NH:32][CH2:31][CH2:30][C:29]([O:28][CH3:27])=[O:33])=[O:10])[CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)C[C@@H](Cc1ccc(-c2ccccc2)cc1)C(=O)O
Reactant: COC(=O)CCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)CCNC(=O)[C@@H](CC(=O)OC(C)(C)C)Cc1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 13 h
Yield: 92.4 %

Procedure:
A solution of (R)-2-(biphenyl-4-ylmethyl)-4-tert-butoxy-4-oxobutanoic acid (142 mg, 0.417 mmol), 3-amino-propionic acid methyl ester hydrochloride (76 mg, 0.542 mmol), WSC hydrochloride (120 mg, 0.626 mmol), 1-hydroxy-7-azabenzotriazole (85 mg, 0.626 mmol) and DIPEA (0.219 ml, 1.251 mmol) in DMF (4 mL) is allowed to stir at room temperature under nitrogen for 13 hours. The reaction is quenched with H2O. The products are extracted with ethyl acetate, washed with aqueous 1M HCl and then with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The obtained residue is purified by flash column chromatography on 12 g of silica gel (heptane/EtOAc=70:30 to 0:100) to give (R)-tert-butyl 3-(biphenyl-4-ylmethyl)-4-(3-methoxy-3-oxopropylamino)-4-oxobutanoate (164 mg, 91%). HPLC retention time=1.59 minutes (condition A); MS (ES+)=425.4 (m); 369.4 (m-tBu+1; 100%); 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.24-2.44 (m, 2H) 2.67-2.79 (m, 3H) 2.89-2.96 (m, 1H) 3.28-3.36 (m, 1H) 3.45-3.53 (m, 1H) 7.23 (d, J=5.8 Hz, 2H) 7.33 (t, J=7.35 Hz, 1H) 7.41-7.44 (m, 2H) 7.51 (d, J=8.1 Hz, 2H) 7.58 (d, J=7.4 Hz, 2H).
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[C:6]([CH2:8][NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH:5]=[CH:4][NH:3]1.C[Sn](C)(C)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[O:1]=[C:2]1[CH:7]=[C:6]([CH2:8][NH:9][C:10](=[O:16])[O:11][C:12]([CH3:13])([CH3:15])[CH3:14])[CH:5]=[CH:4][N:3]1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: C[Sn](C)(C)c1ccccc1
Reactant: CC(C)(C)OC(=O)NCc1cc[nH]c(=O)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCc1ccn(-c2ccccc2)c(=O)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 50.5 %

Procedure:
To a solution of tert-butyl (2-oxo-1,2-dihydro-pyridin-4-ylmethyl)-carbamate (0.13 g, 0.58 mmol) in dichloromethane (5 mL) is added trimethylphenylstannane (210 μL, 1.2 mmol), followed successively by copper (II) acetate (0.12 g, 0.64 mmol) and tetra-n-butylammonium fluoride (1.0 M solution in tetrahydrofuran, 1.2 mL). The reaction mixture is stirred for 2 days at room temperature and then is quenched by the addition of methanolic ammonia (2 M, 4 mL). The reaction mixture is concentrated and then purified by flash silica gel chromatography (methanol/chloroform) to give tert-butyl (2-oxo-1-phenyl-1,2-dihydropyridin-4-ylmethyl)-carbamate (88 mg, 52%).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]2[NH:9][N:8]=[C:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=3)[N:6]=2)[CH2:2]1.C(N(CC)CC)C.[CH:23]([NH:26][C:27]1[N:32]2[CH:33]=[CH:34][N:35]=[C:31]2[N:30]=[C:29]([C:36]2[CH:43]=[CH:42][C:39]([CH:40]=O)=[CH:38][CH:37]=2)[C:28]=1[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)([CH3:25])[CH3:24].C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>CN1C(=O)CCC1>[CH:23]([NH:26][C:27]1[N:32]2[CH:33]=[CH:34][N:35]=[C:31]2[N:30]=[C:29]([C:36]2[CH:43]=[CH:42][C:39]([CH2:40][N:1]3[CH2:4][CH:3]([C:5]4[N:6]=[C:7]([C:10]5[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=5)[NH:8][N:9]=4)[CH2:2]3)=[CH:38][CH:37]=2)[C:28]=1[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)([CH3:25])[CH3:24]
Reactant: c1ccc(-c2n[nH]c(C3CNC3)n2)nc1
Reactant: CC(C)Nc1c(-c2ccccc2)c(-c2ccc(C=O)cc2)nc2nccn12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Solvent: CC(=O)O
Product: CC(C)Nc1c(-c2ccccc2)c(-c2ccc(CN3CC(c4n[nH]c(-c5ccccn5)n4)C3)cc2)nc2nccn12
Reaction time: 1 h

Procedure:
253.8 mg (0.93 mmol) 2-(5-Azetidine-3-yl-[1,2,4]triazole-3-yl)-pyridine×2HCl are dissolved in 7.2 mL NMP. 0.26 mL (1.85 mmol) triethylamine are added and the reaction mixture is stirred for one hour. 300 mg (0.84 mmol) 4-(5-Isopropylamino-6-phenyl-imidazo[1,2-a]pyrimidin-7-yl)-benzaldehyde and 0.12 mL (2.02 mmol) acetic acid are added. The reaction mixture is stirred for 24 hours at room temperature. 463.8 mg (2.2 mmol) NaBH(OAc)3, are added in portions and the reaction mixture is stirred at room temperature over night. After the usual work-up and purification by column chromatography (silicagel, eluents: dichloromethane/methanol) 132 mg (27.5%) of the pure title compound and 42 mg (9.2%) of the slightly contaminated title compound are obtained.
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=O.C([O-])C.[Na+].[F:14][C:15]([F:33])([F:32])[C:16]1[CH:17]=[C:18]([NH:22][N:23]=[C:24](Br)[C:25]2[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=2)[CH:19]=[CH:20][CH:21]=1>C(O)C>[CH2:8]([O:7][C:1]([C:2]1[C:24]([C:25]2[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=2)=[N:23][N:22]([C:18]2[CH:19]=[CH:20][CH:21]=[C:16]([C:15]([F:33])([F:14])[F:32])[CH:17]=2)[C:3]=1[CH3:5])=[O:6])[CH3:9]
Reactant: FC(F)(F)c1cccc(NN=C(Br)c2ccncc2)c1
Reactant: CCOC(=O)CC(C)=O
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1c(-c2ccncc2)nn(-c2cccc(C(F)(F)F)c2)c1C
Temperature: 0 °C
Reaction time: 1 h
Yield: 21.2 %

Procedure:
An ice cooled solution of ethyl acetoacetate (0.21 ml, 1.63 mmol) in 10 ml ethanol was treated with a solution of sodium ethanolate 21% (in ethanol, 0.6 ml, 1.63 mmol). The reaction mixture was stirred 1 h at 0° C., then N-[3-(trifluoromethyl)phenyl]pyridine-4-carbohydrazonoyl bromide (562 mg, 1.63 mmol) in 5 ml ethanol was added drop wise. The yellow suspension was stirred 1 h at room temperature and 2 days at 50° C. The reaction mixture was concentrated in vacuo and the residual product partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc. The organic phases were dried over magnesium sulfate and evaporated. Column chromatography (EtOAc:n-heptane 1:1) gave the title compound as a light brown oil (130 mg, 21%). MS: 376.5 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][S:10]([N:13]2[CH2:18][CH2:17][CH:16]([CH2:19][NH2:20])[CH2:15][CH2:14]2)(=[O:12])=[O:11])=[CH:4][CH:3]=1.[OH:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][CH:23]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][S:10]([N:13]2[CH2:14][CH2:15][CH:16]([CH2:19][NH:20][C:26](=[O:27])[C:25]3[CH:29]=[CH:30][C:22]([OH:21])=[CH:23][CH:24]=3)[CH2:17][CH2:18]2)(=[O:11])=[O:12])=[CH:4][CH:3]=1
Reactant: NCC1CCN(S(=O)(=O)CCc2ccc(F)cc2)CC1
Reactant: O=C(O)c1ccc(O)cc1
Product: O=C(NCC1CCN(S(=O)(=O)CCc2ccc(F)cc2)CC1)c1ccc(O)cc1

Procedure:
N-{1-[2-(4-Fluoro-phenyl)-ethanesulfonyl]-piperidin-4-ylmethyl}-4-hydroxy-benzamide was prepared from C-{1-[2-(4-fluoro-phenyl)-ethanesulfonyl]-piperidin-4-yl}-methylamine and 4-hydroxybenzoic acid as described above in EXAMPLE 1, Step 2
Reaction SMILES: [CH:1]#[CH:2].[Cl:3][SiH:4]([CH:6]([SiH:11]([Cl:13])[Cl:12])[Si:7]([Cl:10])([Cl:9])[Cl:8])[Cl:5]>C1C=CC=CC=1>[Cl:5][Si:4]1([Cl:3])[CH:2]=[CH:1][Si:11]([Cl:12])([Cl:13])[CH:6]1[Si:7]([Cl:8])([Cl:10])[Cl:9]
Reactant: Cl[SiH](Cl)C([SiH](Cl)Cl)[Si](Cl)(Cl)Cl
Reactant: C#C
Solvent: c1ccccc1
Product: Cl[Si](Cl)(Cl)C1[Si](Cl)(Cl)C=C[Si]1(Cl)Cl
Yield: 50.8 %

Procedure:
Hydrosilation of acetylene with bis(dichlorosilyl)trichlorosilylmethane in the presence of Pt(C2H4)(PPh3)2. Into the same apparatus as described in Example 1 were placed 0.103 g of Pt(C2H4)(PPh3)2, 2.99 g of bis(dichlorosilyl)trichlorosilylmethane, and 20 ml of dried benzene forming a mixture. The mixture was brought to reflux and acetylene gas was blown into the mixture at 90 ml per minute for 4 hours. The mixture was vacuum distilled at 67 Pa to yield a mixture comprising 2.02 g of 1,1,3,3-tetrachloro-2-trichlorosilyl-1,3-disilacyclopent-4-ene (TCD-GC area 50.8%).
Reaction SMILES: C(OC([NH:8][CH:9]([CH3:27])[CH2:10][N:11]1[C:15]([C:16](OCC)=[O:17])=[C:14]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:13]([I:26])=[N:12]1)=O)(C)(C)C.Cl>O1CCOCC1>[I:26][C:13]1[C:14]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:15]2[C:16](=[O:17])[NH:8][CH:9]([CH3:27])[CH2:10][N:11]2[N:12]=1
Reactant: CCOC(=O)c1c(I)nn(CC(C)NC(=O)OC(C)(C)C)c1C(=O)OCC
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=O)c1c(I)nn2c1C(=O)NC(C)C2
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.1 %

Procedure:
To a stirred solution of Intermediate 340A (7.0 g, 14.13 mmol) in 1,4-dioxane (10 mL) was added 4 M HCl in dioxane (25 mL, 100 mmol) and the solution was stirred at RT for 2 h. The reaction mixture was concentrated and the residue was diluted with EtOAc (20 mL). The EtOAc solution was washed successively with water, a saturated aq. solution of NaHCO3, and brine. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The residue obtained was heated in a ROTAVAPOR® at 60° C. for 5 h. The solid product was washed with ether to afford Intermediate 340B (4.0 g, 87%). MS(ES): m/z=350 [M+H]+; 1H NMR (300 MHz, DMSO-d6) δ ppm 8.49 (s, 1H), 4.27-4.49 (m, 1H), 4.11-4.26 (m, 2H), 4.03 (d, J=11.71 Hz, 2H), 1.06-1.39 (m, 6H).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[C:7]([NH2:9])[N:6]=[C:5]([NH2:10])[CH:4]=1.I[CH2:12][CH2:13][F:14].C([O-])([O-])=O.[Cs+].[Cs+]>C(#N)C>[F:14][CH2:13][CH2:12][NH:10][C:5]1[CH:4]=[C:3]([S:2][CH3:1])[CH:8]=[C:7]([NH2:9])[N:6]=1
Reactant: CSc1cc(N)nc(N)c1
Reactant: FCCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CSc1cc(N)nc(NCCF)c1

Procedure:
In a glass vessel were mixed together the above prepared 4-methylsulfanyl-pyridine-2,6-diamine (0.100 g, 0.644 mmol), 1-iodo-2-fluoroethane, 0.123 g, 1.10 eq.), and 1.2 eq. of Cs2CO3 (0.252 g) in 1.0 mL of abs. acetonitrile, and the mixture allowed to react for 1 h at 125° C. in a microwave oven. Cooling, pouring onto crashed ice, twofold extraction with AcOEt, washing with water and brine, drying over sodium sulfate, and evaporation of the solvents, followed by flash chromatography (SiO2, hexane/AcOEt=3/7) afforded 0.037 g of the title compound as brown solid.
Reaction SMILES: [CH2:1]([C@:3]12[CH2:11][CH2:10][C@@H:9]3[C@@H:12]4[C:17]([CH2:18][CH2:19][C@H:8]3[C@@H:7]1[CH2:6][CH2:5][C@@H:4]2[OH:21])=[CH:16][C:15](=[O:20])[CH2:14][CH2:13]4)[CH3:2].[C:22](Cl)(=[O:27])[CH2:23][CH:24]([CH3:26])[CH3:25]>N1C=CC=CC=1>[CH2:1]([C@:3]12[CH2:11][CH2:10][C@@H:9]3[C@@H:12]4[C:17]([CH2:18][CH2:19][C@H:8]3[C@@H:7]1[CH2:6][CH2:5][C@@H:4]2[O:21][C:22](=[O:27])[CH2:23][CH:24]([CH3:26])[CH3:25])=[CH:16][C:15](=[O:20])[CH2:14][CH2:13]4)[CH3:2]
Reactant: CC[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1CC[C@@H]2O
Reactant: CC(C)CC(=O)Cl
Solvent: c1ccncc1
Product: CC[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1CC[C@@H]2OC(=O)CC(C)C

Procedure:
Keep 13β-ethyl-17β-hydroxy-gon-4-en-3-one (6 g.) with isovaleroyl chloride (7.2 g.) in pyridine at room temperature for 20 hours. Add aqueous sodium bicarbonate and extract the product with ether. Wash, dry and evaporate the extracts and purify the residue by chromatography upon neutral alumina. Distill at 200°-230°/.01 mm. and crystallize from hexane to obtain the title compound, m.p. 82°- 89°; ultraviolet absorption peak at 240 mμ (ε15,650); infrared absorption peaks at 5.76, 5.99, 6.18 μ.
Reaction SMILES: C([O:4][CH:5]1[CH2:9][CH:8]([O:10][Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12])[CH:7]=[CH:6]1)(=O)C>CO.[OH-].[Ba+2].[OH-]>[O:10]([CH:8]1[CH2:9][CH:5]([OH:4])[CH:6]=[CH:7]1)[Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12]
Reactant: CC(=O)OC1C=CC(O[Si](C)(C)C(C)(C)C)C1
Agent: [Ba+2]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)[Si](C)(C)OC1C=CC(O)C1
Yield: 44.9 %

Procedure:
Two hundred milligrams (0.78 mmol) of 3-acetoxy-5-t-butyldimethylsiloxycyclopent-1-ene was dissolved in 1.0 milliliter of a methanol solution of 1 normal barium hydroxide, after which the resulting solution was heated under reflux for 15 minutes in an atmosphere of nitrogen. The methanol was then distilled off under reduced pressure, after which ethanol was added to precipitate a solid, which was filtered off. Ehtanol was then distilled off from the filtrate, after which the concentrated residue was extracted with ether after addition of water thereto. The resulting organic layer was then thoroughly washed in water, dried with anhydrous sodium sulfate and thereafter concentrated to obtain a crude product. The so obtained product was then separated by preparative thin-layer chromatography (silica gel 2mm, hexane:ethyl acetate = 4:1) to obtain 75 milligrams (0.35 mmol, 45%) of 3-t-butyldimethylsiloxy-5-hydroxycyclopent-1-ene.
Reaction SMILES: N1C=CN=C1.[C:6]([Si:10]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)Cl)([CH3:9])([CH3:8])[CH3:7].Cl.[CH3:25][O:26][C:27](=[O:32])[CH:28]([CH2:30][OH:31])[NH2:29]>CN(C)C=O>[Si:10]([O:31][CH2:30][C@@H:28]([C:27]([O:26][CH3:25])=[O:32])[NH2:29])([C:6]([CH3:9])([CH3:8])[CH3:7])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: COC(=O)C(N)CO
Agent: Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: COC(=O)[C@@H](N)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reaction time: 16 h

Procedure:
Imidazole (2.82 g, 41.43 mmol) and tert-butyldiphenylchlorosilane (3.23 mL, 12.43 mmol) was added to a solution of DL-serine methyl ester hydrochloride (1.41 g, 11.84 mmol) in dimethylformamide (6 mL). After 16 h, the mixture was concentrated and partitioned between ethyl acetate and saturated sodium bicarbonate solution. The organic layer was dried over sodium sulfate, filtered, and concentrated. Purification by silica gel chromatography (100% dichloromethane=10% methanol {1% ammonium hydroxide}/dichloromethane) gave the title compound. MS 358.22 (M+1)