Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]2[N:8]([C:9]3[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=3)[N:7]=[C:6]([CH3:20])[C:5]=2[C:21](O)=[O:22])[CH2:3][CH2:2]1.Cl.Cl.[NH:26]1[CH2:31][CH2:30][CH:29]([N:32]2[CH2:36][CH2:35][CH2:34][C@H:33]2[CH2:37][OH:38])[CH2:28][CH2:27]1>>[CH:1]1([C:4]2[N:8]([C:9]3[CH:10]=[CH:11][C:12]([O:15][C:16]([F:18])([F:19])[F:17])=[CH:13][CH:14]=3)[N:7]=[C:6]([CH3:20])[C:5]=2[C:21]([N:26]2[CH2:27][CH2:28][CH:29]([N:32]3[CH2:36][CH2:35][CH2:34][C@H:33]3[CH2:37][OH:38])[CH2:30][CH2:31]2)=[O:22])[CH2:2][CH2:3]1
Reactant: OC[C@@H]1CCCN1C1CCNCC1
Reactant: Cc1nn(-c2ccc(OC(F)(F)F)cc2)c(C2CC2)c1C(=O)O
Agent: Cl
Product: Cc1nn(-c2ccc(OC(F)(F)F)cc2)c(C2CC2)c1C(=O)N1CCC(N2CCC[C@H]2CO)CC1

Procedure:
The title compound was prepared from 5-cyclopropyl-3-methyl-1-(4-trifluoromethoxy-phenyl)-1H-pyrazole-4-carboxylic acid and ((S)-1-piperidin-4-yl-pyrrolidin-2-yl)-methanoldihydrochloride (Example 161A]) in direct analogy to the general procedure used in example 150. MS: 493.2 (MH+).
Reaction SMILES: [F:1][C:2]1[C:7]([CH:8]=O)=[C:6]([F:10])[C:5]([F:11])=[C:4]([F:12])[C:3]=1[F:13].[C:14]([O:22][CH2:23][CH3:24])(=[O:21])[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17]>>[F:1][C:2]1[C:7]([CH2:8][CH:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:14]([O:22][CH2:23][CH3:24])=[O:21])=[C:6]([F:10])[C:5]([F:11])=[C:4]([F:12])[C:3]=1[F:13]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: O=Cc1c(F)c(F)c(F)c(F)c1F
Product: CCOC(=O)C(Cc1c(F)c(F)c(F)c(F)c1F)C(=O)OCC
Yield: 67.2 %

Procedure:
9 g of pentafluorobenzaldehyde are condensed on 7 g of diethyl malonate in accordance with the process described in Organic Synthesis vol. III, page 377. 10 g (69%) of diethyl pentafluorobenzylmalonate are obtained which is hydrogenated at ordinary pressure in the presence of palladium on charcoal into diethyl pentafluorobenzylmalonate (92%).
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[F:17][C:18]1[CH:27]=[CH:26][CH:25]=[C:24]2[C:19]=1[CH2:20][CH2:21][CH2:22][C:23]2=O>C1(C)C=CC=CC=1>[F:17][C:18]1[CH:27]=[CH:26][CH:25]=[C:24]2[C:19]=1[CH2:20][CH2:21][CH2:22][C:23]2=[CH:11][C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: O=C1CCCc2c(F)cccc21
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOC(=O)C=C1CCCc2c(F)cccc21
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a suspension of 60% sodium hydride (4.12 g) in toluene (200 ml) was added dropwise ethyl diethylphosphonoacetate (20.4 ml) under ice-cooling, and the mixture was stirred at room temperature for 45 min. Then, a solution of 5-fluoro-3,4-dihydro-2H-naphthalen-1-one (15.3 g) in toluene (50 ml) was added dropwise, and the mixture was stirred at 80° C. for 2 hr. After cooling to room temperature, the reaction mixture was poured into ice water, and the mixture was extracted with toluene. The extract was washed with water and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give ethyl (5-fluoro-3,4-dihydro-2H-naphthalen-1-ylidene)acetate.
Reaction SMILES: Cl.[NH2:2][N:3]=[CH:4][C:5]1[CH:22]=[CH:21][C:8]([CH2:9][CH:10]2[CH2:14][C:13](=[O:15])[N:12]([CH2:16][C:17]([OH:19])=O)[C:11]2=[O:20])=[CH:7][CH:6]=1.Cl.[CH3:24][O:25][C:26](=[O:39])[C@H:27]([CH2:29][C:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[NH:32][CH:31]=1)[NH2:28]>>[CH3:24][O:25][C:26](=[O:39])[C@H:27]([CH2:29][C:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[NH:32][CH:31]=1)[NH:28][C:17](=[O:19])[CH2:16][N:12]1[C:13](=[O:15])[CH2:14][CH:10]([CH2:9][C:8]2[CH:7]=[CH:6][C:5]([CH:4]=[N:3][NH2:2])=[CH:22][CH:21]=2)[C:11]1=[O:20]
Reactant: NN=Cc1ccc(CC2CC(=O)N(CC(=O)O)C2=O)cc1
Reactant: COC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Agent: Cl
Product: COC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)CN1C(=O)CC(Cc2ccc(C=NN)cc2)C1=O

Procedure:
403 mg of {3-[4-(aminoiminomethyl)benzyl]-2,5-dioxopyrrolidin-1-yl}acetic acid hydrochloride are coupled with 356.6 mg of L-tryptophan methyl ester hydrochloride by the process described above. After working up and chromatographic purification, 270 mg of {3-[4-(aminoiminomethyl)benzyl]-2,5-dioxopyrrolidin-1-yl}acetyl-L-tryptophan methyl ester are obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C@@H:14]1[C:22]2[C:17](=[C:18]([C:23]3[S:27][C:26]([C:28]4[CH:33]=[CH:32][C:31]([O:34][CH:35]([CH3:37])[CH3:36])=[C:30]([C:38]#[N:39])[CH:29]=4)=[N:25][CH:24]=3)[CH:19]=[CH:20][CH:21]=2)[CH2:16][CH2:15]1)[CH2:9][C:10]([O:12]C)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CO>[C:1]([O:5][C:6]([N:8]([C@@H:14]1[C:22]2[C:17](=[C:18]([C:23]3[S:27][C:26]([C:28]4[CH:33]=[CH:32][C:31]([O:34][CH:35]([CH3:36])[CH3:37])=[C:30]([C:38]#[N:39])[CH:29]=4)=[N:25][CH:24]=3)[CH:19]=[CH:20][CH:21]=2)[CH2:16][CH2:15]1)[CH2:9][C:10]([OH:12])=[O:11])=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: COC(=O)CN(C(=O)OC(C)(C)C)[C@H]1CCc2c(-c3cnc(-c4ccc(OC(C)C)c(C#N)c4)s3)cccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)Oc1ccc(-c2ncc(-c3cccc4c3CC[C@@H]4N(CC(=O)O)C(=O)OC(C)(C)C)s2)cc1C#N
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.7 %

Procedure:
To a stirred solution of (S)-methyl 2-((tert-butoxycarbonyl)(4-(2-(3-cyano-4-isopropoxyphenyl)thiazol-5-yl)-2,3-dihydro-1H-inden-1-yl)amino)acetate (120 mg, 0.22 mmol) in MeOH (2 mL) was added 6N sodium hydroxide (180 μL) and the mixture was stirred at room temperature for overnight. The solvent was evaporated and the residue was dissolved in water (5 mL) and acidified with 1N HCl. The mixture was extracted with EA (3×5 mL) and the organic layers washed with brine, dried over MgSO4, and concentrated to afford 110 mg (94%) of (S)-2-((tert-butoxycarbonyl)(4-(2-(3-cyano-4-isopropoxyphenyl)thiazol-5-yl)-2,3-dihydro-1H-inden-1-yl)amino)acetic acid as white solid which was used in the next experiments without purification. LCMS-ESI (m/z) calculated for C29H31N3O5S: 533.2; found 534.2 [M+H]+, tR=3.92 min.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:13])[C:8](Br)=[N:9][C:10]=1[CH3:11])=[O:5])[CH3:2].[C:14]([C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)#[CH:15]>>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:13])[C:8]([C:15]#[C:14][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[N:9][C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: C#Cc1ccc(F)cc1
Reactant: CCOC(=O)c1c(C)nc(Br)n1C
Product: CCOC(=O)c1c(C)nc(C#Cc2ccc(F)cc2)n1C

Procedure:
The title compound, MS: m/e=286.8 (M+H+) was prepared in accordance with the general method of example 1b from 2-bromo-3,5-dimethyl-3H-imidazole-4-carboxylic acid ethyl ester and 1-ethynyl-4-fluorobenzene.
Reaction SMILES: [I-].[CH2:2]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH:3]([CH3:5])[CH3:4].O1CCCC1.C([Li])CCC.[CH2:35]([O:42][CH2:43][CH:44]([CH3:53])[CH2:45]/[CH:46]=[CH:47]/[CH:48]([CH3:52])[CH2:49][CH:50]=O)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>CCCCCC.O>[CH3:53][CH:44]([CH2:45][CH:46]=[CH:47][CH:48]([CH3:52])[CH2:49][CH:50]=[CH:2][CH:3]([CH3:5])[CH3:4])[CH2:43][O:42][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: CC(C)C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(/C=C/CC(C)COCc1ccccc1)CC=O
Agent: [I-]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: O
Solvent: C1CCOC1
Product: CC(C)C=CCC(C)C=CCC(C)COCc1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A suspension of 1.52 g. (3.42 mmoles) of isobutyltriphenylphosphonium iodide in 30 ml. of anhydrous tetrahydrofuran was stirred and cooled to 0° C. while 1.55 ml. (3.42 mmoles) of n-butyllithium solution in hexane was added. The resulting red solution was stirred for 10 minutes at room temperature then treated with a solution of rac. E-8-benzyloxy-3,7-dimethyl-4-octenal (0.594 g.; 2.28 mmoles) in 10 ml. of anhydrous tetrahydrofuran. After stirring at room temperature for 30 minutes, the reaction mixture was treated with water and worked up by extraction with hexane as in Example 1. The semi-solid residue was treated with hexane and filtered to remove insoluble material. The filtrate was concentrated in vacuo to give 0.72 g. of yellow oil. This material was chromatographed on 30 g. of silica gel. Elution with 9:1 parts by volume hexane-ether afforded 0.427 g. (62.5%) of an oil. Evaporative distillation yielded rac. benzyl 2,6,10-trimethyl-undeca-4,8-dien-1-yl ether as a colorless liquid, b.p. 110°-115° C. (bath temperature) (0.03 mm Hg.).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].OS(O)(=O)=O.[Br:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=1[CH3:21])[C:16]#[N:17].[OH-].[Na+].[ClH:24]>C1COCC1.CCOCC.O>[ClH:24].[Br:12][C:13]1[CH:14]=[C:15]([CH2:16][NH2:17])[CH:18]=[CH:19][C:20]=1[CH3:21]
Reactant: Cc1ccc(C#N)cc1Br
Agent: Cl
Agent: O=S(=O)(O)O
Agent: [Al+3]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1ccc(CN)cc1Br
Temperature: 0 °C
Reaction time: 0.47 h
Yield: 92 %

Procedure:
To LiAlH4 (1M in ether) (400 mL, 400 mmol) in a 2 L 3-neck flask with mechanical stirring under nitrogen at −5° C. was added concentrated H2SO4 (10.94 mL, 219 mmol) dropwise. Gas evolution was observed and the solution became cloudy and the foamy mixture was not as easy to stir. Temperature got as high as 3° C. The addition took 28 min. This mixture was stirred for 60 min and then the 3-bromo-4-methylbenzonitrile (37.3 g, 190 mmol) in THF (850 mL) was added over 18 min (max temp=10° C.). The slightly peach-colored mixture was stirred in the ice bath. After 30 min water (90 mL) was added carefully to give a white mixture, followed by 2M sodium hydroxide. After adding 100 mL, a solid that appeared to be amenable to filtration had formed. This was stirred for 30 min. The slightly waxy solid was filtered off and the single-phase filtrate washed with brine, dried and evaporated. This gave a slightly cloudy yellowish oil, 39.64 g (>100%) that was re-dissolved in ether (350 mL), filtered to remove some solid, and to the oil was added 1M hydrogen chloride in ether (1 eq based on starting nitrile, 190 mmol, 190 mL) slowly with stirring under nitrogen, This gave a solid that was collected by vacuum filtration and sucked dry, then dried under high vacuum to give 41.34 g (92%) of a white solid that the lab HPLC showed to be 98.8% pure with a retention time of 1.56 min. LC-MS m/z 200, 202 (M+H)+, 1.05 min (ret time).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([CH2:14][N:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[O:22])[CH2:17][CH2:16]2)[CH2:9]1)=O)(C)(C)C>FC(F)(F)C(O)=O.ClCCl>[NH:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([CH2:14][N:15]2[CH2:16][CH2:17][N:18]([C:21]([O:23][CH2:24][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)=[O:22])[CH2:19][CH2:20]2)[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](CN2CCN(C(=O)OCc3ccccc3)CC2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(OCc1ccccc1)N1CCN(C[C@@H]2CCCNC2)CC1
Yield: 106.2 %

Procedure:
Benzyl 4-{[(3S)-1-(tert-butoxycarbonyl)piperidin-3-yl]methyl}piperazine-1-carboxylate (4.46 g) was stirred in a mixture of trifluoroacetic acid (20 ml) and dichloromethane (200 ml) for two hours at room temperature. The reaction mixture was concentrated in vacuo and the resulting oil separated between ethyl acetate (200 ml) and saturated aqueous sodium bicarbonate solution (500 ml). The ethyl acetate layer was separated, dried over magnesium sulphate, filtered then concentrated in vacuo to give the title compound (3.6 g).
Reaction SMILES: [CH3:1][N:2]([CH3:11])[C:3]([C@@H:5]1[CH2:10][CH2:9][CH2:8][NH:7][CH2:6]1)=[O:4].C(N(CC)CC)C.Cl[C:20]1[N:25]=[C:24]([NH2:26])[C:23]([N+:27]([O-:29])=[O:28])=[CH:22][CH:21]=1.O>CS(C)=O>[NH2:26][C:24]1[N:25]=[C:20]([N:7]2[CH2:8][CH2:9][CH2:10][C@@H:5]([C:3]([N:2]([CH3:11])[CH3:1])=[O:4])[CH2:6]2)[CH:21]=[CH:22][C:23]=1[N+:27]([O-:29])=[O:28]
Reactant: Nc1nc(Cl)ccc1[N+](=O)[O-]
Reactant: CN(C)C(=O)[C@@H]1CCCNC1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: O
Product: CN(C)C(=O)[C@@H]1CCCN(c2ccc([N+](=O)[O-])c(N)n2)C1
Temperature: 110 °C
Yield: 83.7 %

Procedure:
To a solution of (R)—N,N-dimethylpiperidine-3-carboxamide (10 g, 64.04 mmol) in dimethylsulfoxide (100 mL) were added triethylamine (17.8 mL, 128.08 mmol) and 6-chloro-3-nitropyridin-2-amine (7.76 g, 44.82 mmol) at room temperature under a nitrogen atmosphere. The reaction mixture was heated at 110° C. for 16 h. The reaction mixture was added to cold water and extracted with ethyl acetate. The organic layer was washed with cold water 3 times, dried over sodium sulfate and evaporated under reduced pressure. The crude compound was purified via flash chromatography and then treated with 1:1 petroleum ether and diethyl ether to afford (R)-1-(6-amino-5-nitropyridin-2-yl)-N,N-dimethylpiperidine-3-carboxamide (11 g, 72%). MS (ES+APCI) (M+H) 294.1; LCMS retention time: 2.777 min (Method E1)
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].C[N:15](C=O)C.C(Cl)(=O)C(Cl)=O>C(Cl)Cl>[F:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:15])=[O:5]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1F
Reactant: CN(C)C=O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: NC(=O)c1ccc([N+](=O)[O-])cc1F
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To 2-fluoro-4-nitrobenzoic acid suspended in CH2Cl2 under Ar was added DMF then oxalyl chloride. The reaction was stirred at room temperature 1.5 h then the solvent was evaporated. The residue was dissolved in THF and ammonia gas was bubbled through the reaction for 15 min. The solvent was evaporated and the residue partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc. The extracts were dried (MgSO4), filtered, and evaporated. Column chromatography (SiO2, 0-100% EtOAc/Hex) gave pure 2-fluoro-4-nitrobenzamide (E335).
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][CH2:11][NH2:12])[CH2:5][CH2:4]1.Cl[C:14]1[N:15]=[N+:16]([O-:27])[C:17]2[CH:26]=[C:25]3[C:21]([CH2:22][CH2:23][CH2:24]3)=[CH:20][C:18]=2[N:19]=1.CCN(CC)CC>COCCOC>[CH3:1][O:2][CH:3]1[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][CH2:11][NH:12][C:14]2[N:15]=[N+:16]([O-:27])[C:17]3[CH:26]=[C:25]4[C:21]([CH2:22][CH2:23][CH2:24]4)=[CH:20][C:18]=3[N:19]=2)[CH2:5][CH2:4]1
Reactant: COC1CCN(CCCN)CC1
Reactant: [O-][n+]1nc(Cl)nc2cc3c(cc21)CCC3
Solvent: CCN(CC)CC
Solvent: COCCOC
Product: COC1CCN(CCCNc2nc3cc4c(cc3[n+]([O-])n2)CCC4)CC1
Yield: 82.8 %

Procedure:
3-(4-Methoxy-1-piperidinyl)propylamine (304) (0.59 g, 3.4 mmol) was added to a stirred solution of chloride 21 (505 mg, 2.3 mmol) and Et3N (0.64 mL, 2.6 mmol) in DME (50 mL) and the solution stirred at reflux temperature for 16 h. The solvent was evaporated and the residue partitioned between DCM (100 mL) and dilute aqueous NH3 solution (50 mL). The organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give 1-oxide 58 (681 mg, 84%) as a yellow solid: mp (EtOAc/pet. ether) 120-121° C.; 1H NMR δ 8.07 (s, 1H, H-9), 7.38 (s, 1H, H-5), 6.25 (br s, 1H, NH), 3.56-3.61 (m, 2H, CH2N), 3.33 (s, 3H, OCH3), 3.24-3.30 (m, 1H, CHO), 2.97-3.03 (m, 4H, H-6, H-8), 2.71-2.78 (m, 2H, CH2N), 2.52 (br t, J=6.6 Hz, 2H, CH2N), 2.21-2.30 (m, 2H, CH2), 2.15 (br p, J=7.5 Hz, 2H, H-7), 1.91-1.98 (m, 2H, CH2), 1.85 (br p, J=6.5 Hz, 2H, CH2), 1.65-1.73 (m, 2H, CH2); 13C NMR δ 158.8, 154.4, 148.8, 143.0, 129.8, 120.5, 114.7, 75.8, 56.8, 55.5, 50.9 (2), 40.9, 33.1, 32.3, 30.5 (2), 25.7 (2). Anal. calcd for C19H27N5O2: C, 63.8; H, 7.6; N, 19.6. Found: C, 63.6; H, 7.6; N, 19.4%.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:15][N:14]=[C:13]([C:16]3[N:17]=[CH:18][C:19]([CH2:22][OH:23])=[N:20][CH:21]=3)[N:12]=2)=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].C(C1C=CC(C2N=C(C3C=CC(C=O)=NC=3)ON=2)=CC=1)C(C)C>>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[O:15][N:14]=[C:13]([C:16]3[N:17]=[CH:18][C:19]([CH:22]=[O:23])=[N:20][CH:21]=3)[N:12]=2)=[CH:9][CH:10]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)Cc1ccc(-c2nc(-c3cnc(CO)cn3)no2)cc1
Agent: CC(C)Cc1ccc(-c2noc(-c3ccc(C=O)nc3)n2)cc1
Product: CC(C)Cc1ccc(-c2nc(-c3cnc(C=O)cn3)no2)cc1

Procedure:
The title compound was prepared from {5-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]pyrazin-2-yl}methanol by procedures analogous to those described in Preparation 4F for the preparation of 5-[3-(4-isobutyl-phenyl)-[1,2,4]oxadiazol-5-yl]-pyridine-2-carbaldehyde.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][CH2:11][N:10]3[N:14]=[C:15]([NH2:17])[N:16]=[C:9]23)=[CH:4][CH:3]=1.[CH3:18][C:19]1[N:23]=[C:22]([N:24]2[CH2:29][CH2:28][C:27](=O)[CH2:26][CH2:25]2)[S:21][N:20]=1.[BH4-].[Na+].C(O)C>ClC(Cl)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][CH2:11][N:10]3[N:14]=[C:15]([NH:17][CH:27]4[CH2:26][CH2:25][N:24]([C:22]5[S:21][N:20]=[C:19]([CH3:18])[N:23]=5)[CH2:29][CH2:28]4)[N:16]=[C:9]23)=[CH:4][CH:3]=1
Reactant: Nc1nc2n(n1)CCCC2c1ccc(F)cc1
Reactant: Cc1nsc(N2CCC(=O)CC2)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CCO
Product: Cc1nsc(N2CCC(Nc3nc4n(n3)CCCC4c3ccc(F)cc3)CC2)n1
Temperature: 85 °C
Reaction time: 0.5 h

Procedure:
To a solution of 8-(4-fluoro-phenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (60 mg, 0.258 mmol) and 1-(3-methyl-[1,2,4]thiadiazol-5-yl)-piperidin-4-one (76 mg, 0.387 mmol) in dry dichloroethane (3 mL) was added tetraisopropyl-orthotitanate (236 μL, 0.775 mmol) under an argon atmosphere and heated to 85° C. for 12 hours. The reaction mixture was cooled to room temperature, sodium borohydride (20 mg, 0.517 mmol) and ethanol (1.5 mL) were added and stirred at room temperature for 3 hour and at 50° C. for 30 minutes. The reaction mixture was cooled to room temperature and evaporated. An aqueous solution of Na2CO3 (2M) was added to the residue. The aqueous phase was extracted with ethyl acetate, the combined organic phases were dried over sodium sulfate, the solvent was evaporated and the residue purified by silica gel chromatography using dichloromethane/methanol (with 10% ammonia) as eluent. The title compound was obtained as a white solid (28.8 mg, 27%).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[C:12]([F:15])([F:14])[F:13].CCN(CC)CC.[CH3:23][N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.O>C(Cl)Cl>[CH3:23][N:24]1[CH2:29][CH2:28][N:27]([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=2[C:12]([F:15])([F:14])[F:13])[CH2:26][CH2:25]1
Reactant: O=[N+]([O-])c1ccc(CBr)c(C(F)(F)F)c1
Reactant: CN1CCNCC1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CN1CCN(Cc2ccc([N+](=O)[O-])cc2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 67.4 %

Procedure:
To a solution of crude 1-(bromomethyl)-2-(trifluoromethyl)-4-nitrobenzene (13.7 mmol, 60% pure) in CH2Cl2 (20 mL) was added Et3N (1.5 g, 15 mmol) and 4-methylpiperazine (1.5 g, 15 mmol). After stirring for 5 hrs at rt, 50 mL H2O was added, and the mixture was extracted with 50 mL CH2Cl2. The combined organic layer was dried over Na2SO4, filtered, concentrated, and the resulting residue was purified by silica gel chromatography (eluent: 10% MeOH in CH2Cl2) to give the product (67.4%, 2.8 g). 1H NMR (300 MHz, CDCl3) δ: 8.52 (1H, s), 8.37-8.40 (1H, d, J=9.0 Hz), 8.00-8.03 (1H, d, J=9.0 Hz), 3.85 (2H, s), 3.09-3.15 (2H, m), 2.90-2.93 (2H, m), 2.80-2.83 (2H, m), 2.67 (3H, s), 2.53-2.59 (2H, m).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[C:3]=1[C:14](=[O:16])[CH3:15].[O:17]=[C:18]1[NH:27][C:26]2[N:25]=[C:24]([O:28][CH2:29][CH2:30][CH2:31][CH:32]=O)[CH:23]=[CH:22][C:21]=2[CH:20]=[CH:19]1>>[C:14]([C:3]1[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=1[N:8]1[CH2:13][CH2:12][N:11]([CH2:32][CH2:31][CH2:30][CH2:29][O:28][C:24]2[N:25]=[C:26]3[C:21]([CH:20]=[CH:19][C:18](=[O:17])[NH:27]3)=[CH:22][CH:23]=2)[CH2:10][CH2:9]1)(=[O:16])[CH3:15]
Reactant: O=CCCCOc1ccc2ccc(=O)[nH]c2n1
Reactant: CC(=O)c1c(F)cccc1N1CCNCC1
Product: CC(=O)c1c(F)cccc1N1CCN(CCCCOc2ccc3ccc(=O)[nH]c3n2)CC1

Procedure:
In a manner similar to that of other examples above, 1-(2-fluoro-6-piperazin-1-yl-phenyl)-ethanone was coupled by reductive amination to 4-(7-oxo-7,8-dihydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde followed by typical workup and purification to give the title compound. MS: APCI: M+1: 439.2 (Exact Mass: 438.21).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:14]([CH3:15])[C:13]2[CH:12]=[CH:11][N:10]=[CH:9][C:8]=2[C:7]=1[NH2:16])=[O:5])[CH3:2].[CH:17]1([C:20]2[CH:25]=[CH:24][C:23](I)=[C:22]([F:27])[CH:21]=2)[CH2:19][CH2:18]1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:1]([O:3][C:4]([C:6]1[N:14]([CH3:15])[C:13]2[CH:12]=[CH:11][N:10]=[CH:9][C:8]=2[C:7]=1[NH:16][C:23]1[CH:24]=[CH:25][C:20]([CH:17]2[CH2:19][CH2:18]2)=[CH:21][C:22]=1[F:27])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(N)c2cnccc2n1C
Reactant: Fc1cc(C2CC2)ccc1I
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1c(Nc2ccc(C3CC3)cc2F)c2cnccc2n1C
Temperature: 25 °C
Yield: 23.2 %

Procedure:
A degassed solution of 3-amino-1-methyl-1H-pyrrolo[3,2-c]pyridine-2-carboxylic acid ethyl ester (521 mg, 2.4 mmol), 4-cyclopropyl-2-fluoro-1-iodo-benzene (810 mg, 3.09 mmol), Pd2dba3 (154 mg, 0.168 mmol), Xantphos (194 mg, 0.336 mmol) and cesium carbonate (1.95 g, 6.0 mmol) in toluene (5 ml) was heated at 110° C. for 18 hours. The reaction mixture was cooled to ambient temperature then filtered through a pad of Celite®. The filtrate was washed with water and brine, dried over magnesium sulphate and concentrated in vacuo to give a brown gum. The gum was purified by flash chromatography (Si-PPC, DCM:MeOH, 90:10) to provide the title compound as an orange oil (197 mg, 23%). LCMS (method B): RT=2.65 min, M+H+=354.
Reaction SMILES: [OH-].[Na+].O.[S:4]1[CH:8]=[CH:7][CH:6]=[C:5]1[C:9]1([CH2:14][NH2:15])[CH2:13][CH2:12][CH2:11][CH2:10]1.ClC(OCC)=O.[C:22](=S)=[S:23]>>[S:4]1[CH:8]=[CH:7][CH:6]=[C:5]1[C:9]1([CH2:14][N:15]=[C:22]=[S:23])[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: S=C=S
Reactant: NCC1(c2cccs2)CCCC1
Agent: CCOC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: S=C=NCC1(c2cccs2)CCCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 21.2 parts of sodium hydroxide in 500 parts of water is cooled to 10° C. and there is added successively 45.6 parts of carbon disulfide and then dropwise 95.83 parts of 1-(2-thienyl)-cyclopentanemethylamine (exothermic reaction). After the addition is complete, the whole is stirred for 30 minutes at room temperature. Then there are added 57.5 parts of ethyl chloroformate at 30° C. (exothermic reaction: cooling is necessary). The whole is stirred for 3 hours at 50° C. and further stirred overnight without heating. The product is extracted with benzene. The extract is dried, filtered and evaporated. The residue is poured onto 350 parts of water and the whole is heated for 3 hours at 80°-90° C. The mixture is cooled and the product is extracted with dichloromethane. The extract is dried, filtered and evaporated. The oily residue is distilled twice, yielding 88 parts of [1-(2-thienyl)cyclopentylmethyl]isothiocyanate; bp. 110° C. at 0.1 mm pressure; nD20 :1.5960; d2020 :1.1743.