Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([S:14]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([CH:23]4[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]4)[CH:18]=3)(=[O:16])=[O:15])[C@H:10]([CH3:29])[CH2:9]2)=[C:4]([C:30]([F:33])([F:32])[F:31])[CH:3]=1.[CH3:34]C(O)=O.[BH3-]C#N.[Na+]>CO.C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([S:14]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([CH:23]4[CH2:28][CH2:27][N:26]([CH3:34])[CH2:25][CH2:24]4)[CH:18]=3)(=[O:16])=[O:15])[C@H:10]([CH3:29])[CH2:9]2)=[C:4]([C:30]([F:33])([F:31])[F:32])[CH:3]=1
Reactant: C[C@@H]1CN(c2ccc(F)cc2C(F)(F)F)CCN1S(=O)(=O)c1cccc(C2CCNCC2)c1
Reactant: CC(=O)O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: C[C@@H]1CN(c2ccc(F)cc2C(F)(F)F)CCN1S(=O)(=O)c1cccc(C2CCN(C)CC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.9 %

Procedure:
To a solution of (2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methyl-1-[(3-piperidin-4-ylphenyl)sulfonyl]piperazine (81 mg, 0.155 mmol) in MeOH (2 mL) was added (CHO)n 27 mg, 0.93 mmol), HOAc (13.7 μL, 0.23 mmol) and NaBH3CN (6 mg, 0.093 mmol). The reaction mixture was stirred at room temperature overnight then 50° C. till disappearance of starting material. The reaction was diluted with DCM and quenched with aq. NaHCO3. The organic layer was separated and dried over Na2SO4 and purified on SiO2 gel column eluted with hexanes/EtOAc to give the desired product as a sticky oil (65 mg, 84%). It was redissolved in Et2O and acidified with 1N HCl in Et2O and triturated with hexanes/Et2O to give the titled compound as a white solid. HRMS: calcd for C24H29F4N3O2S+H+, 500.19893. found (ESI-FTMS, [M+H]1+), 500.19765.
Reaction SMILES: [CH2:1]([C:4]12[CH2:10][CH:7]([CH:8]=[CH:9]1)[CH:6]1[C:11]([O:13][C:14](=[O:15])[CH:5]21)=[O:12])[CH:2]=[CH2:3].[CH2:16]([NH2:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:16]([N:23]=[C:14]([CH:5]1[CH:6]([C:11]([OH:13])=[O:12])[CH:7]2[CH2:10][C:4]1([CH2:1][CH:2]=[CH2:3])[CH:9]=[CH:8]2)[OH:15])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: C=CCC12C=CC(C1)C1C(=O)OC(=O)C12
Reactant: NCc1ccccc1
Product: C=CCC12C=CC(C1)C(C(=O)O)C2C(O)=NCc1ccccc1

Procedure:
102 g of allyl-bicyclo[2.2.1]-hept-5-ene-2,3-dicarboxylic acid anhydride and 85.6 g of benzylamine are boiled under reflux for 2 hours. Water and excess benzylamine are then distilled off (39 ml at 105° C. under 4,132 Pa).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])[C:10]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:9]([CH3:24])[NH:8][C:7]=1[CH2:25][N:26]1C(=O)C2=CC=CC=C2C1=O)=[O:5])[CH3:2].O.NN>C(O)C>[CH2:1]([O:3][C:4]([C:6]1[CH:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])[C:10]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:9]([CH3:24])[NH:8][C:7]=1[CH2:25][NH2:26])=[O:5])[CH3:2]
Reactant: CCOC(=O)C1=C(C)NC(CN2C(=O)c3ccccc3C2=O)=C(C(=O)OCC)C1c1ccccc1Cl
Agent: NN
Solvent: CCO
Solvent: O
Product: CCOC(=O)C1=C(C)NC(CN)=C(C(=O)OCC)C1c1ccccc1Cl

Procedure:
14 g of 2-phthalimidomethyl-6-methyl-4-(2-chlorophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester are heated to the boil in 150 ccs of ethanol, with the addition of 5 ccs of hydrazine hydrate, for 2-3 hours, the mixture is filtered hot and the filtrate is filtered again after cooling and concentrated in vacuo.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([CH2:20]I)[CH:9]([CH3:10])[C:8](=[O:11])[N:7]([C:12]2[C:17]([CH3:18])=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:19])[CH2:6]1)=[O:4].[CH2:22]([NH:24][CH3:25])[CH3:23]>CC#N>[CH3:1][O:2][C:3]([C:5]1([CH2:20][N:24]([CH2:22][CH3:23])[CH3:25])[CH:9]([CH3:10])[C:8](=[O:11])[N:7]([C:12]2[C:17]([CH3:18])=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:19])[CH2:6]1)=[O:4]
Reactant: COC(=O)C1(CI)CN(c2c(C)cccc2C)C(=O)C1C
Reactant: CCNC
Solvent: CC#N
Product: CCN(C)CC1(C(=O)OC)CN(c2c(C)cccc2C)C(=O)C1C
Temperature: 80 °C
Reaction time: 8 h
Yield: 12 %

Procedure:
To a solution of 1-(2,6-dimethylphenyl)-3-iodomethyl-4-methyl-5-oxo-pyrrolidine-3-carboxylic acid methyl ester (prepared from step d, 100 mg, 0.25 mmol) in CH3CN (3 mL) was added N-ethylmethylamine (215 μL, 2.5 mmol) and stirred at 80° C. for overnight. Volatiles were evaporated under reduced pressure and purified by automated flash chromatography (SiO2, 20→70% EtOAc/hexanes) to obtain 1-(2,6-dimethyl-phenyl)-3-[(ethylmethylamino)-methyl]-4-methyl-5-oxo-pyrrolidine-3-carboxylic acid methyl ester (10 mg, 12% yield). LC-MS: Rt (retention time): 0.61 min, MS: (ES) m/z 333.3 (M+H+).
Reaction SMILES: O(S(C(F)(F)F)(=O)=O)S(C(F)(F)F)(=O)=O.C([N:19]([C:21]([C@@H:23]1[CH2:29][CH2:28][C@@H:27]2[CH2:30][N:24]1[C:25](=[O:39])[N:26]2[O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:22])[NH2:20])(=O)C.N1C=CC=[CH:42][CH:41]=1>C(Cl)Cl>[CH2:32]([O:31][N:26]1[C:25](=[O:39])[N:24]2[CH2:30][C@H:27]1[CH2:28][CH2:29][C@H:23]2[C:21]1[O:22][C:41]([CH3:42])=[N:20][N:19]=1)[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: CC(=O)N(N)C(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Reactant: c1ccncc1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: Cc1nnc([C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)o1
Temperature: 0 °C
Reaction time: 1 h
Yield: 63 %

Procedure:
(CF3SO2)2O (0.50 mL) was slowly added to a solution of (2S,5R)—N-acetyl-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide (0.5 g) and pyridine (0.5 mL) in dry DCM (10 mL) at −10° C. The reaction mixture was stirred at 0° C. for 1 h and then quenched carefully with sat. NaHCO3. The organic layer was separated and the aqueous layer was exacted with EtOAc (3×). The combined organic layer was dried over Na2SO4, concentrated and purified by silica gel column chromatography (gradient elution 10:1 to 1:1 petroleum ether/EtOAc) to afford (2S,5R)-6-(benzyloxy)-2-(5-methyl-1,3,4-oxadiazol-2-yl)-1,6-diaza-bicyclo[3.2.1]octan-7-one (0.3 g, 63%) as a slight yellow solid. ESI-MS (EI+, m/z): 315.0 [M+H]+.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]([NH:12][C:13]1([C:19]([O:21]C)=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:11].[OH-].[Na+]>CO.O>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]([NH:12][C:13]1([C:19]([OH:21])=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:11]
Reactant: COC(=O)C1(NC(=O)c2cc3ccccc3o2)CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(NC1(C(=O)O)CCCCC1)c1cc2ccccc2o1
Yield: 49.4 %

Procedure:
To the solution of methyl 1-[N-(benzofuran-2-ylcarbonyl)amino]-1-cyclohexanecarboxylate (105.0 g) in 450 ml of methanol, was added 2N-sodium hydroxide solution (170 ml, 0.34 mol). The reaction mixture was refluxed for 23 hours and concentrated to obtain a residue, which was diluted with 400 ml of water and washed with 300 ml of diethyl ether. 6N-hydrochloride was added dropwise to the resulting aqueous layer to adjust the pH of the solution to pH 3. The resulting white solid was filtered and dried to give the titled compound (49.5 g).
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][CH2:13][O:14][CH:15]=[C:16]([C:23]2[S:24][CH:25]=[CH:26][C:27]=2[CH3:28])[C:17]2[S:18][CH:19]=[CH:20][C:21]=2[CH3:22])[CH2:7]1)=[O:5])C.[OH-].[Na+].Cl>C(O)C>[CH3:22][C:21]1[CH:20]=[CH:19][S:18][C:17]=1[C:16]([C:23]1[S:24][CH:25]=[CH:26][C:27]=1[CH3:28])=[CH:15][O:14][CH2:13][CH2:12][N:8]1[CH2:9][CH2:10][CH2:11][C@@H:6]([C:4]([OH:5])=[O:3])[CH2:7]1
Reactant: CCOC(=O)[C@@H]1CCCN(CCOC=C(c2sccc2C)c2sccc2C)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccsc1C(=COCCN1CCC[C@@H](C(=O)O)C1)c1sccc1C
Yield: 86.8 %

Procedure:
(R)-1-(2-((2,2-bis(3-Methyl-2-thienyl)ethenyl)oxy)ethyl)3-piperidinecarboxylic ethyl ester (420 mg, 1 mmol, Example 65) was dissolved in ethanol (20 ml) and 10 N sodium hydroxide solution (1.00 ml) was introduced. After 3 h at room temperature the pH of the solution was adjusted to 9 with 2 N hydrochloric acid. The ethanol was removed by evaporation and the pH of the solution was adjusted to 2.5. Extraction with dichloromethane (4×15 ml), drying of the combined extracts (MgSO4) and evaporation of the filtrate provided a residue, which was recrystallized from water. This provided the title compound (0.34 g, 84%) as a cream solid.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:17])[CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[O:32]([CH2:43][CH2:44][NH:45][CH2:46][CH2:47][O:48][C@@H:49]1[O:57][C@@H:56]([CH3:58])[C@@H:54]([OH:55])[C@@H:52]([OH:53])[C@@H:50]1[OH:51])[C@@H:33]1[O:41][C@@H:40]([CH3:42])[C@@H:38]([OH:39])[C@@H:36]([OH:37])[C@@H:34]1[OH:35]>CN(C=O)C>[C@@H:49]1([O:48][CH2:47][CH2:46][N:45]([CH2:44][CH2:43][O:32][C@@H:33]2[O:41][C@@H:40]([CH3:42])[C@@H:38]([OH:39])[C@@H:36]([OH:37])[C@@H:34]2[OH:35])[C:14](=[O:16])[CH2:13][CH2:12][CH2:11][CH2:10][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:17])[O:57][C@@H:56]([CH3:58])[C@@H:54]([OH:55])[C@@H:52]([OH:53])[C@@H:50]1[OH:51]
Reactant: C[C@@H]1O[C@@H](OCCNCCO[C@@H]2O[C@@H](C)[C@@H](O)[C@@H](O)[C@@H]2O)[C@@H](O)[C@H](O)[C@@H]1O
Reactant: O=C(O)CCCCC(=O)OCc1ccccc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: C[C@@H]1O[C@@H](OCCN(CCO[C@@H]2O[C@@H](C)[C@@H](O)[C@@H](O)[C@@H]2O)C(=O)CCCCC(=O)OCc2ccccc2)[C@@H](O)[C@H](O)[C@@H]1O
Reaction time: 16 h

Procedure:
To a solution of 6-(benzyloxy)-6-oxohexanoic acid (40 mg, 0.169 mmol), EDC (114 mg, 0.593 mmol) and HOBt (2.59 mg, 0.017 mmol) in DMF (5 mL) at rt was added 2-({2-[(α-L-fucopyranosyl)oxy]ethyl}amino)ethyl α-L-fucopyranoside (190 mg, 0.478 mmol). After stirring for 16 hr, the reaction mixture was concentrated and the residue was purified by flash chromatography on C18 reverse phase silica gel (50 g), eluting with 5-40% AcCN in water to give the title compound. UPLC Method B: m/e=616.2923 [M+1]; Rt=3.114 min. 1H NMR (CD3OD) δ 1.24 (6H, d, J=6.58), 1.72-1.64 (4H, m), 2.45 (2H, t, J=7.11), 2.53 (2H, t, J=7.32), 3.91-3.55 (17H, m), 4.78-4.75 (2H, m), 5.14 (2H, s), 7.38-7.37 (5H, m).
Reaction SMILES: [C:1]([C:6]1[NH:7][C:8]([CH3:16])=[C:9]([CH3:15])[C:10]=1[CH2:11][CH:12]([CH3:14])[CH3:13])(OCC)=O.C=O>>[CH3:1][C:6]1[NH:7][C:8]([CH3:16])=[C:9]([CH3:15])[C:10]=1[CH2:11][CH:12]([CH3:14])[CH3:13]
Reactant: CCOC(=O)c1[nH]c(C)c(C)c1CC(C)C
Agent: C=O
Product: Cc1[nH]c(C)c(CC(C)C)c1C

Procedure:
2-Carbethoxy-3-isobutyl-4,5-dimethyl-pyrrole was reductively alkylated with paraformaldehye to yield 2,4,5-trimethyl-3-isobutyl pyrrole. ##STR107##
Reaction SMILES: [CH2:1]([NH:8][C:9](=[N:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[S:10][CH2:11][CH3:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].C(N(CC)CC)C.[Cl:28][C:29]([Cl:33])([Cl:32])[S:30]Cl>O1CCCC1>[CH2:14]([N:13]([S:30][C:29]([Cl:33])([Cl:32])[Cl:28])[C:9](=[N:8][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])[S:10][CH2:11][CH3:12])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: ClSC(Cl)(Cl)Cl
Reactant: CCCCCCCN=C(NCCCCCCC)SCC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCCCCN=C(SCC)N(CCCCCCC)SC(Cl)(Cl)Cl
Reaction time: 0.17 h
Yield: 101.1 %

Procedure:
3 g (0.01 mole) 1,3-di-n-heptyl-2-ethyl isothiourea was mixed with 50 ml tetrahydrofuran in a stirred round bottom flask and cooled in an ice bath. 1.4 ml (0.01 mole) triethylamine was added and the mixture stirred for 10 minutes. 1.1 ml (0.01 mole) trichloromethyl sulfenyl chloride was added to the mixture dropwise over 2 minutes. A white precipitate formed and the mixture was stirred for 1 hour while coming to ambient temperature. The resultant reaction mixture was allowed to sit overnight. The mixture was suction filtered to remove the white solid which was rinsed twice with 10 ml of fresh tetrahydrofuran. The filtrate was evaporated under vacuum resulting in 4.55 g of the title product at a yield of 101.2 percent. The resulting liquid had a nD30 of 1.5084 and was identified as the title compound by IR spectrum and mass spectroscopy. Compound No. 297 in Table I.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][CH:7]=2)[N:3]=[CH:2]1.BrCC(C1C=CC(C#N)=CC=1)=O.[Br:26][C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[C:29](I)[CH:28]=1.C([O-])([O-])=O.[Cs+].[Cs+].OC1C=CC=C2C=1N=CC=C2>[Cu]I.CN(C=O)C.O>[Br:26][C:27]1[CH:28]=[CH:29][C:30]([Cl:33])=[C:31]([N:1]2[CH:5]=[C:4]([C:6]3[CH:7]=[CH:8][C:9]([C:10]#[N:11])=[CH:12][CH:13]=3)[N:3]=[CH:2]2)[CH:32]=1
Reactant: N#Cc1ccc(-c2c[nH]cn2)cc1
Reactant: Clc1ccc(Br)cc1I
Agent: [Cu]I
Agent: N#Cc1ccc(C(=O)CBr)cc1
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc(-c2cn(-c3cc(Br)ccc3Cl)cn2)cc1

Procedure:
The compound was prepared according to Liu et al. J. Org. Chem. 2005, 70, 10135. 4-(1H-Imidazol-4-yl)-benzonitrile (75 mg, 0.44 mmol; prepared from 4-(2-bromo-acetyl)-benzonitrile using the method of Lynch et al. J. Am. Chem. Soc. 1994, 116, 11030), 4-bromo-1-chloro-2-iodobenzene (169 mg, 0.532 mmol), Cs2CO3 (577 mg, 1.77 mmol), CuI (3 mg, 0.013 mmol), 8-hydroxyquinoline (2 mg, 0.013 mmol), and DMF/H2O (2 mL; 10:1 solution) were combined in a 10 mL CEM Microwave reaction vessel fitted with magnetic stir bar and subjected to microwave irradiation at 150° C. for 30 min. The contents were then filtered and concentrated to dryness affording intermediate 5-bromo-2-chlorophenyl)-1H-imidazol-4-yl]-benzonitrile (68 mg, 43%).
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@@:26]2([CH3:27])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:25]2[CH2:24][CH2:23][C@@:21]2([CH3:22])[C@H:17]3[CH2:18][CH2:19][C@@H:20]2[CH2:28][OH:29])[CH2:12][C@@H:11]([O:30][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:45][S:46](Cl)(=[O:48])=[O:47]>O1CCCC1.CCCCCC>[Si:1]([O:8][C@@H:9]1[C@@:26]2([CH3:27])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:25]2[CH2:24][CH2:23][C@@:21]2([CH3:22])[C@H:17]3[CH2:18][CH2:19][C@@H:20]2[CH2:28][O:29][S:46]([CH3:45])(=[O:48])=[O:47])[CH2:12][C@@H:11]([O:30][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:32])[CH3:33])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CC2=CC=C3[C@@H]4CC[C@H](CO)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](O[Si](C)(C)C(C)(C)C)C1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(C)[Si](C)(C)O[C@@H]1CC2=CC=C3[C@@H]4CC[C@H](COS(C)(=O)=O)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](O[Si](C)(C)C(C)(C)C)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 90.5 %

Procedure:
A solution of 1α,3β-bis(tert-butyldimethylsilyloxy)-17β-(hydroxymethyl)androsta-5,7-diene (150 mg, 0.274 mmol) and triethylamine (0.153 ml, 1.10 mmol) in tetrahydrofuran (2.3 ml) was cooled to 0° C., followed by the addition of methanesulfonyl chloride (63 μl, 0.814 mmol) and stirring at 0° C. for 1 hour. The reaction mixture was diluted with hexane, washed with water and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure to remove the solvent. The thus obtained residue was purified by column chromatography (hexane:ethyl acetate=9:1) to give the titled compound (155 mg, 91%) as a colorless foam.
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][CH:19]=[C:18]([O:22][CH3:23])[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][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=2)=[N:9][C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(C)nc(Br)n1C
Reactant: C#Cc1cccc(OC)c1
Product: CCOC(=O)c1c(C)nc(C#Cc2cccc(OC)c2)n1C

Procedure:
The title compound, MS: m/e=299.3 (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-3-methoxy-benzene.
Reaction SMILES: C1(C#CC2CC3(CCNCC3)ON=2)C=CC=CC=1.[C:19]1([C:25]#[C:26][C:27]2[CH2:41][C:30]3([CH2:33][N:32](C(OC(C)(C)C)=O)[CH2:31]3)[O:29][N:28]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(Cl)(Cl)Cl>[C:19]1([C:25]#[C:26][C:27]2[CH2:41][C:30]3([CH2:33][NH:32][CH2:31]3)[O:29][N:28]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC(C)(C)OC(=O)N1CC2(CC(C#Cc3ccccc3)=NO2)C1
Agent: C(#Cc1ccccc1)C1=NOC2(CCNCC2)C1
Solvent: ClC(Cl)Cl
Product: C(#Cc1ccccc1)C1=NOC2(CNC2)C1
Yield: 100 %

Procedure:
The title compound was synthesized following the method reported for Compound 1c, substituting Compound 1b with Compound 38a and running the reaction in chloroform. The crude brownish oily residue was used without further purification in the next reaction step. Yield: 100%.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[CH:11][N:10]=[C:9]1[CH2:13][CH:14]([C:19](=O)[CH2:20][CH3:21])[C:15](=O)[CH2:16][CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:23]([NH:26][NH2:27])([CH3:25])[CH3:24]>>[CH2:1]([N:8]1[CH:12]=[CH:11][N:10]=[C:9]1[CH2:13][C:14]1[C:19]([CH2:20][CH3:21])=[N:27][N:26]([CH:23]([CH3:25])[CH3:24])[C:15]=1[CH2:16][CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)NN
Reactant: CCC(=O)C(Cc1nccn1Cc1ccccc1)C(=O)CC
Product: CCc1nn(C(C)C)c(CC)c1Cc1nccn1Cc1ccccc1

Procedure:
4-(1-Benzyl-1H-imidazol-2-ylmethyl)-3,5-diethyl-1-isopropyl-1H-pyrazole was prepared from 4-(1-benzyl-1H-imidazol-2-ylmethyl)-heptane-3,5-dione and isopropylhydrazine in analogy to Example 190 b): light yellow viscous oil; MS (ISP): 337.3 ((M+H)+.).
Reaction SMILES: C1C2C(COC(=O)[NH:17][CH2:18][CH2:19][CH2:20][NH:21][C:22](=[O:52])[C:23]3[CH:28]=[CH:27][C:26]([NH:29][C:30]4[N:31]=[CH:32][C:33]5[N:39]([CH3:40])[C:38](=[O:41])[C:37]([F:43])([F:42])[CH2:36][N:35]([CH:44]6[CH2:48][CH2:47][CH2:46][CH2:45]6)[C:34]=5[N:49]=4)=[C:25]([O:50][CH3:51])[CH:24]=3)C3C(=CC=CC=3)C=2C=CC=1.N1CCCCC1>ClCCl>[NH2:17][CH2:18][CH2:19][CH2:20][NH:21][C:22](=[O:52])[C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:30]2[N:31]=[CH:32][C:33]3[N:39]([CH3:40])[C:38](=[O:41])[C:37]([F:42])([F:43])[CH2:36][N:35]([CH:44]4[CH2:48][CH2:47][CH2:46][CH2:45]4)[C:34]=3[N:49]=2)=[C:25]([O:50][CH3:51])[CH:24]=1
Reactant: COc1cc(C(=O)NCCCNC(=O)OCC2c3ccccc3-c3ccccc32)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Solvent: ClCCl
Solvent: C1CCNCC1
Product: COc1cc(C(=O)NCCCN)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Temperature: 25 °C
Reaction time: 1 h
Yield: 33.5 %

Procedure:
To the suspension 0.12 g (0.16 mmole) of {3-[4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoylamino]-propyl}-carbamic acid 9H-fluoren-9-ylmethyl ester (I-73) in 2 mL of dichloromethane was added 0.4 mL of piperidine. The mixture was stirred at room temperature for 1 hour, then volatiles were removed under reduced pressure. Purification by silica gel chromatography, eluting with dichloromethane-methanol (gradient, 100:0-0:100) gave 0.027 g of N-(3-amino-propyl)-4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzamide (I-74) as a white solid.
Reaction SMILES: C1C(/C=N/O)=CC=[N+](C[N+]2C=CC(/C=N/[OH:16])=CC=2)C=1.[Br-].[Br-].[C:22]([CH:25]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]1[C:32](=NOC)[CH2:33][CH2:34][CH:35]=1)([OH:24])=[O:23]>>[C:22]([CH:25]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]1[C:32](=[O:16])[CH2:33][CH2:34][CH:35]=1)([OH:24])=[O:23]
Reactant: CON=C1CCC=C1CCCCCC(C(=O)O)c1ccccc1
Reactant: O/N=C/c1cc[n+](C[n+]2ccc(/C=N/O)cc2)cc1
Agent: [Br-]
Product: O=C1CCC=C1CCCCCC(C(=O)O)c1ccccc1

Procedure:
Methoxime cleavage of 2-(6-carboxy-6-phenylhexyl)-1 -methoxiimino-2-cyclopentene (Example 466) in the manner of Example 38 is productive of the subject ketone.
Reaction SMILES: C(O[CH:5]1[CH2:9][O:8][C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:6]1)(C)C.C([SiH](CC)CC)C.C([O-])(O)=O.[Na+]>C(O)(C(F)(F)F)=O>[C:15]1([C:7]2([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:6][CH2:5][CH2:9][O:8]2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CCOC(=O)C1(c2ccccc2)CC(OC(C)C)CO1
Agent: CC[SiH](CC)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C1(c2ccccc2)CCCO1
Temperature: 70 °C
Yield: 113.5 %

Procedure:
To a solution of 4-isopropoxy-2-phenyl-2-tetrahydrofuroic acid, ethyl ester (189 mg, 0.68 mmol) in 4 ml of TFA was added triethylsilane (395 mg, 3.40 mmol). After heating at 70° C. for 4 h, the reaction mixture was poured into NaHCO3 (saturated) and extracted with ethyl acetate. The extracts were washed with brine and dried over MgSO4, filtered, and concentrated. The residue was purified by preparative TLC eluting with ethyl acetate/hexane=5:95 to give ethyl 2-phenyl-2-tetrahydrofuroate (170 mg).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:7]=[CH:8][C:9]3[N:10]([CH:12]=[C:13]([C:15]([O:17]CC)=[O:16])[N:14]=3)[CH:11]=2)=[CH:2]1.CC(C)(OC(NC1N=C(C2C=CC3N(C=C(C(O)=O)N=3)C=2)C=CC=1)=O)C>>[S:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:7]=[CH:8][C:9]3[N:10]([CH:12]=[C:13]([C:15]([OH:17])=[O:16])[N:14]=3)[CH:11]=2)=[CH:2]1
Reactant: CCOC(=O)c1cn2cc(-c3ccsc3)ccc2n1
Agent: CC(C)(C)OC(=O)Nc1cccc(-c2ccc3nc(C(=O)O)cn3c2)n1
Product: O=C(O)c1cn2cc(-c3ccsc3)ccc2n1
Yield: 89.9 %

Procedure:
310 mg of ethyl 6-(thiophen-3-yl)imidazo[1,2-a]pyridine-2-carboxylate are saponified under conditions similar to those described for the preparation of Intermediate 11 (step 11.3) to give 250 mg of 6-(thiophen-3-yl)imidazo[1,2-a]pyridine-2-carboxylic acid.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=1.[OH-].[K+].[F:14][CH:15]([F:18])[CH2:16]I.[NH4+].[Cl-]>CN(C=O)C>[F:14][CH:15]([F:18])[CH2:16][N:3]1[CH:4]=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=[C:2]1[CH3:1]
Reactant: CCOC(=O)c1c[nH]c(C)n1
Reactant: FC(F)CI
Agent: [Cl-]
Agent: [K+]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(CC(F)F)c(C)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.8 %

Procedure:
Ethyl 2-methyl-1H-imidazole-4-carboxylate (1.622 mmol, 250 mg) and KOH (2.432 mmol, 136 mg) were suspended in DMF (2 ml). 1,1-Difluoro-2-iodoethane (4.86 mmol, 934 mg) was added and the resulting mixture was stirred overnight at RT. During the stirring additional 0.3 ml of 1,1-difluoro-2-iodoethane was added to complete the reaction. Aqueous NH4Cl solution was added and the mixture was extracted three times with EtOAc. The combined organics were washed with water, dried, filtered and evaporated. The crude product was purified by flash chromatography. 0.3 g of the title compound was obtained. Two isomers were obtained in the reaction and separated in later steps. Isomer 1: 1H-NMR (400 MHz, DMSO-d6): δ 1.28 (t, 3H), 2.33 (s, 3H), 4.25 (q, 2H), 4.45-4.58 (m, 2H), 6.23-6.53 (m, 1H), 7.80 (s, 1H). Isomer 2: 1H-NMR (400 MHz, DMSO-d6): δ 1.25 (t, 3H), 2.39 (s, 3H), 4.19 (q, 2H), 4.70-4.83 (m, 2H), 6.18-6.49 (m, 1H), 7.59 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14](=[O:16])[CH3:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C1C(=O)N([Br:24])C(=O)C1>C(Cl)Cl>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14](=[O:16])[CH3:15])[CH2:10][CH2:9]2)=[CH:4][C:3]=1[Br:24]
Reactant: CC(=O)N1CCC(c2ccc(N)cc2)CC1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: CC(=O)N1CCC(c2ccc(N)c(Br)c2)CC1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A solution of 1-[4-(4-amino-phenyl)-piperidin-1-yl]-ethanone (as prepared in the previous step, 0.36 g, 1.66 mmol) in CH2Cl2 (10 mL) was cooled to −78° C. and treated with NBS (0.28 g, 1.58 mmol) as a suspension in CH2Cl2 (4 mL). The reaction was allowed to warm to room temperature and stir for 30 min. The reaction was diluted with CH2Cl2 and washed with saturated aqueous NaHCO3. The organic layer was dried over MgSO4 and concentrated in vacuo. The crude material was used directly in the next reaction. LC-MS (ESI, m/z): Calcd. for C13H17BrN2O 297.1 (M+H). found 297.1.