Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C)C(=O)C.[NH2:7][C:8]1[CH:9]=[C:10]([CH:19]=[CH:20][C:21]=1[NH2:22])[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:12].S([O-])(O)=O.[Na+].[CH:28]([C:30]1[NH:31][CH:32]=[CH:33][CH:34]=1)=O>O>[C:11]([C:10]1[CH:19]=[CH:20][C:21]2[N:22]=[C:28]([C:30]3[NH:31][CH:32]=[CH:33][CH:34]=3)[NH:7][C:8]=2[CH:9]=1)(=[O:12])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Nc1ccc(C(=O)c2ccccc2)cc1N
Reactant: O=Cc1ccc[nH]1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: O=C(c1ccccc1)c1ccc2nc(-c3ccc[nH]3)[nH]c2c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 0.1 %

Procedure:
N,N-Dimethylacetamide (5 ml) was heated to 130° C., and 3,4-diaminobenzophenone (150 mg, 0.71 mol) and sodium hydrogensulfite (89 mg, 0.85 mol) were added and stirred for 5 minutes. 2-Formyl-pyrrole (81 mg, 0.85 mol) was added and stirred at 130° C. for 1.5 hours. The reaction mixture was allowed to cool to room temperature with stirring, and after addition of water to reaction mixture, precipitate was collected by filtration to afford 5-benzoyl-2-(pyrrol-2-yl)-benzimidazole (129 mg, 63%) as a pale yellow solid.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][N:11]([C@H:19]1[C:27]2[C:22](=[C:23]([C:28]#[N:29])[CH:24]=[CH:25][CH:26]=2)[CH2:21][CH2:20]1)[C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Cl.[NH2:31][OH:32].C([O-])([O-])=O.[Na+].[Na+]>CCO>[Si:1]([O:8][CH2:9][CH2:10][N:11]([C@H:19]1[C:27]2[C:22](=[C:23]([C:28](=[NH:29])[NH:31][OH:32])[CH:24]=[CH:25][CH:26]=2)[CH2:21][CH2:20]1)[C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: NO
Reactant: CC(C)(C)OC(=O)N(CCO[Si](C)(C)C(C)(C)C)[C@@H]1CCc2c(C#N)cccc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)OC(=O)N(CCO[Si](C)(C)C(C)(C)C)[C@@H]1CCc2c(C(=N)NO)cccc21
Temperature: 85 °C
Yield: 100 %

Procedure:
Prepared using General Procedure 1. To (R)-tert-butyl 2-(tert-butyldimethyl silyloxy)ethyl(4-cyano-2,3-dihydro-1H-inden-1-yl)carbamate INT-59 (0.800 g, 1.9 mmol) in EtOH (8 mL) was added hydroxylamine hydrochloride (0.400 g, 5.8 mmol) and Na2CO3 (0.610 g, 5.8) and the reaction mixture was heated at 85° C. for 12 h. Once cooled to room temperature, the reaction mixture was filtered using EtOH to rinse the filter cake. The filtrate was concentrated under reduced pressure and washed with EA and brine. The combined organic layers were dried over MgSO4, filtered, and concentrated to produce 0.860 g (100%) of (R)-tert-butyl 2-(tert-butyldimethylsilyloxy)ethyl(4-(N-hydroxycarbamimidoyl)-2,3-dihydro-1H-inden-1-yl)carbamate INT-61 as a light yellow oil. LCMS-ESI (m/z) calculated for C23H39N3O4Si: 449.7; found 350.2 [M+H−Boc]+, tR=1.97 min.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[CH:10][C:11]3[N:12]([CH:14]=[C:15]([NH:17][C:18](=[O:20])[CH3:19])[N:16]=3)[N:13]=2)[CH:5]=[CH:4][N:3]=1.CN(C=O)C.[F:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[SH:33].[H-].[Na+]>O>[F:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[S:33][C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[CH:10][C:11]3[N:12]([CH:14]=[C:15]([NH:17][C:18](=[O:20])[CH3:19])[N:16]=3)[N:13]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CC(=O)Nc1cn2nc(-c3ccnc(F)c3)ccc2n1
Reactant: Fc1ccccc1S
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)Nc1cn2nc(-c3ccnc(Sc4ccccc4F)c3)ccc2n1
Temperature: 110 °C
Reaction time: 42 h

Procedure:
To a 10-mL, round-bottomed flask was added N-(6-(2-fluoropyridin-4-yl)imidazo[1,2-b]pyridazin-2-yl)acetamide (Example 3) (0.034 g, 0.13 mmol), DMF (2.0 mL), 2-fluorothiophenol (0.045 mL, 0.42 mmol, Aldrich, St. Louis, Mo.), and sodium hydride (17 mg, 0.45 mmol, 60% dispersion in mineral oil, Aldrich, St. Louis, Mo.). The mixture was stirred at 110° C. for 42 h. The mixture was poured into water and extracted with EtOAc (3×30 mL). The combined extracts were washed with water (2×30 mL) and brine (30 mL) then dried (Na2SO4), and concentrated onto silica. Purification by silica gel chromatography (0 to 3.5% MeOH (2 M in NH3)/CH2Cl2), followed by further purification by preparative HPLC (Phenomenex Synergi 4μ MAX-RP 150×21.2 mm, 2 to 100% CH3CN/H2O, 0.1% TFA, over 15 min) (Phenomenex, Torrance, Calif.) and conversion to the free base by elution of the isolated material through an SCX cartridge (Radleys Discovery Technologies, Essex, UK) with MeOH (2 M in NH3)/CH2Cl2 afforded the title compound as a yellow solid. MS (ESI positive ion) m/z: 380 (M+1). 1H NMR (400 MHz, DMSO-d6): δ ppm 10.99 (s, 1H), 8.53 (d, J=5.0 Hz, 1H), 8.28 (s, 1H), 8.13 (d, J=9.5 Hz, 1H), 7.82-7.84 (m, 3H), 7.71 (t, J=7.3 Hz, 1H), 7.62 (q, J=6.7 Hz, 1H), 7.43 (t, J=8.8 Hz, 1H), 7.35 (t, J=7.5 Hz, 1H), 2.11 (s, 3H).
Reaction SMILES: [N:1]([C@@H:4]1[C@H:16]([O:17][C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C@H:15]([CH3:26])[O:14][C@H:6]([S:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C@H:5]1[OH:27])=[N+:2]=[N-:3].[C:28](Cl)(=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[N:1]([C@@H:4]1[C@H:16]([O:17][C:18](=[O:25])[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C@H:15]([CH3:26])[O:14][C@H:6]([S:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C@H:5]1[O:27][C:28](=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30])=[N+:2]=[N-:3]
Reactant: C[C@@H]1O[C@H](Sc2ccccc2)[C@@H](O)[C@H](N=[N+]=[N-])[C@@H]1OC(=O)c1ccccc1
Reactant: CC(C)(C)C(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: C[C@@H]1O[C@H](Sc2ccccc2)[C@@H](OC(=O)C(C)(C)C)[C@H](N=[N+]=[N-])[C@@H]1OC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 79.1 %

Procedure:
To a solution of phenyl 3-azido-4-O-benzoyl-3,6di-deoxy-1-thio-β-L-galactopyranoside (β-18) (118 mg, 0.307 mmol) in 5 mL of CH2C2 is added TEA (256 μL, 1.87 mmol), pivaloyl chloride (114 μL, 0.921 mmol) and DMAP (19 mg, 0.154 mmol). The reaction mixture is stirred at room temperature for 12 h, diluted with 15 mL of CH2Cl2, washed with 1M HCl (2×10 mL), dried over Na2SO4, filtered and concentrated. The crude product is purified by flash chromatography (20% EtOAc/petroleum ether) to give 114 mg (80%) of phenyl 3-azido-4-O-benzoyl-3,6-di-deoxy-2-O-pivaloyl-1-thio-β-L-galactopyranoside (β-19): Rf 0.54 (20% EtOAc/petroleum ether); 1H NMR (CDCl3, 270 MHz) δ 7.93 (d, 2H, ArH), 7.59-7.56 (m, 3H, ArH), 7.46-7.26 (m, 5H, ArH), 5.53 (d, J=2.6 Hz, 1H, H-4), 5.25 (t, J=9.9 Hz, 1H, H-2) 4.73 (d, J=9.9 Hz, 1H, H-1), 3.92 (q, J=6.3 Hz, 1H, H-5), 3.79 (dd, J=2.6, 9.9 Hz, 1H, H-3), 1.42-1.21 (m, 12H, H-6, CH3); 13C NMR (CDCl3, 68 MHz) δ 176.8, 165.9, 133.8, 133.7, 131.8, 130.2, 129.0, 128.9, 128.6, 128.4, 86.1, 74.4, 71.6, 68.3, 63.9, 39.1, 27.3, 16.9; FAMS C24H27O5N3 (MNa+) calcd 492.1569, found 492.1579.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12][CH2:11]1)([O-:3])=[O:2].[Br:20]N1C(=O)CCC1=O.[OH-].[Na+]>CN(C)C=O>[Br:20][C:16]1[CH:15]=[C:14]2[C:19](=[CH:18][CH:17]=1)[N:10]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])[CH2:11][CH2:12][CH2:13]2
Reactant: O=[N+]([O-])c1ccccc1N1CCCc2ccccc21
Reactant: O=C1CCC(=O)N1Br
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccccc1N1CCCc2cc(Br)ccc21
Yield: 82.7 %

Procedure:
A stirred solution, under nitrogen, of 1-(2-nitrophenyl)-1,2,3,4-tetrahydroquinoline (76.3 g, 0.30 mole) in dimethylformamide (1000 ml) was cooled to -10° C. A solution of of N-bromosuccinimide(58.7 g, 0.33 mole) in dimethylformamide (250 ml) was added dropwise at such a rate as to keep the reaction temperature below 0° C. (1.5 hours). Half-an hour after the addition was completed, the reaction mixture was poured into 7 liters of 2N-sodium hydroxide solution/ice, with stirring. The product separated as an oil. The quench fluids were decanted and the oil was rinsed several times with water. The oil was dissolved in dichloromethane (1.5 1). The organic solution was extracted once with 2N-sodium hydroxide solution, thrice with water, dried over sodium sulfate and concentrated. The residue was dissolved in 1:1 hexane:toluene (250 ml) and the solution was adsorbed on a chromatography column containing 2 kg of silica gel packed in 1:1 hexane:toluene. Elution with this solvent mixture provided 82.7 g (82%) of product, as an oil. For analysis, a sample was Kugelrohr distilled at a vessel temperature of 166°-168° C. (0.2 mm Hg).
Reaction SMILES: [Cl-].[Ca+2].[Cl-].C([O:6][C:7](=O)[NH:8][C:9]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=1[Cl:20])=[CH:10][C:11]#[N:12])C.[NH:22]([C:24]([CH:26]1[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]1)=O)[NH2:23].O>CN1CCCC1=O>[Cl:20][C:14]1[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:13]=1[C:9]1[NH:8][C:7](=[O:6])[N:23]2[N:22]=[C:24]([CH:26]3[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]3)[N:12]=[C:11]2[CH:10]=1
Reactant: CCOC(=O)NC(=CC#N)c1ccc(Cl)cc1Cl
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)NN)CC1
Agent: [Ca+2]
Agent: [Cl-]
Solvent: CN1CCCC1=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(c2nc3cc(-c4ccc(Cl)cc4Cl)[nH]c(=O)n3n2)CC1
Temperature: 150 °C
Reaction time: 3 h

Procedure:
In a round-bottom flask fitted with reflux condenser and a drying tube filled with calcium chloride, 5.86 g (20.6 mmol) of ethyl[2-cyano-1-(2,4-dichlorophenyl)ethenyl]carbamate and 5.00 g (20.6 mmol) of tert-butyl 4-(hydrazinylcarbonyl)piperidine-1-carboxylate were dissolved in 11 ml of 1-methyl-2-pyrrolidone, and the reaction mixture was stirred at 150° C. for 3 h. The reaction solution was cooled to RT, water (150 ml) was added and the mixture was stirred in an ultrasonic bath for another 2 min. The solid was filtered off with suction and dried under high vacuum. This gave 7.23 g (76% of theory) of the product.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:28]=[CH:27][C:6]([C:7]([NH:9][C:10]2[S:11][C:12]3[C:18]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[CH:17][CH:16]=[C:15]([O:25][CH3:26])[C:13]=3[N:14]=2)=[O:8])=[CH:5][CH:4]=1.[CH3:29][O-:30].[Na+]>C1COCC1>[CH3:29][O:30][CH2:2][C:3]1[CH:28]=[CH:27][C:6]([C:7]([NH:9][C:10]2[S:11][C:12]3[C:18]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[CH:17][CH:16]=[C:15]([O:25][CH3:26])[C:13]=3[N:14]=2)=[O:8])=[CH:5][CH:4]=1
Reactant: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccc(CCl)cc3)nc12
Reactant: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCc1ccc(C(=O)Nc2nc3c(OC)ccc(N4CCOCC4)c3s2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 41 %

Procedure:
4-Chloromethyl-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-benzamide (200 mg, 0.48 mmol) were suspended in THF (5 ml) and sodium methoxide (0.27 ml 5.4 M in MeOH, 1.4 mmol) were added at 0° C. The mixture was stirred at ambient temperature for 18 h. Workup and purification as described in the general procedure C afforded the title compound as light yellow solid (41%), MS: m/e=414 (M+H+).
Reaction SMILES: Cl[C:2]1[N:3]([CH2:10][C:11]2([OH:33])[CH2:16][CH2:15][N:14]([C:17](=[O:32])[CH2:18][N:19]3[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]3)[CH2:13][CH2:12]2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.[H-].[Na+]>O1CCOCC1>[N+:7]([C:5]1[N:6]=[C:2]2[N:3]([CH:4]=1)[CH2:10][C:11]1([CH2:16][CH2:15][N:14]([C:17](=[O:32])[CH2:18][N:19]3[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]3)[CH2:13][CH2:12]1)[O:33]2)([O-:9])=[O:8]
Reactant: CC(C)(C)OC(=O)N1CCN(CC(=O)N2CCC(O)(Cn3cc([N+](=O)[O-])nc3Cl)CC2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCN(CC(=O)N2CCC3(CC2)Cn2cc([N+](=O)[O-])nc2O3)CC1
Yield: 41.7 %

Procedure:
Tert-butyl 4-{2-[4-(2-chloro-4-nitroimidazol-1-ylmethyl)-4-hydroxypiperidin-1-yl]-2-oxoethyl}-piperazine carboxylate prepared in Example 650 (2.58 g, 5.3 mmol) was dissolved in dioxane (30 ml). To the solution, sodium hydride (254 mg, 6.36 mmol) was added with cooling on ice-bath followed by stirring under reflux overnight. The reaction mixture was concentrated under reduced pressure. To the residue, ice-water and ethyl acetate were added followed by stirring vigorously. The precipitates were filtered off, washed with water and ethyl acetate, and then dried under reduced pressure to afford tert-butyl 4-[2-(2,3-dihydro-6-nitrospiro[imidazo[2,1-b]oxazol-2,4′-piperidine]-1′-yl)-2-oxoethyl]piperazine-1-carboxylate (996 mg, yield 42%) as a white powder.
Reaction SMILES: CC1[N:7]=[CH:6][C:5]2C=NNC=2C=1.[C:11]([C:14]1[C:22]2[C:17](=[CH:18]N=C(C)[CH:21]=2)[N:16]([CH2:24][C:25]([OH:27])=[O:26])[N:15]=1)(=[O:13])[NH2:12]>>[C:11]([C:14]1[C:22]2[CH:21]=[N:7][C:6]([CH3:5])=[CH:18][C:17]=2[N:16]([CH2:24][C:25]([OH:27])=[O:26])[N:15]=1)(=[O:13])[NH2:12]
Reactant: Cc1cc2c(C(N)=O)nn(CC(=O)O)c2cn1
Reactant: Cc1cc2[nH]ncc2cn1
Product: Cc1cc2c(cn1)c(C(N)=O)nn2CC(=O)O

Procedure:
was prepared from 6-methyl-1H-pyrazolo[4,3-c]pyridine by using the same procedures as for the preparation of (3-carbamoyl-5-methyl-pyrazolo[3,4-c]pyridin-1-yl)-acetic acid (Scheme A27). MS (LC-MS): 235 [M+H]+, tR (HPLC conditions k): 0.29 min.
Reaction SMILES: C([Li])CCC.[O:6]([C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=1[F:21])[CH2:16]Br)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[Cl:22][C:23]1[CH:36]=[CH:35][C:26]([C:27]([CH:32]2[CH2:34][CH2:33]2)=[C:28]([F:31])[CH:29]=[O:30])=[CH:25][CH:24]=1>O1CCCC1>[Cl:22][C:23]1[CH:24]=[CH:25][C:26]([C:27]([CH:32]2[CH2:34][CH2:33]2)=[C:28]([F:31])[CH:29]([OH:30])[CH2:16][C:15]2[CH:18]=[CH:19][C:20]([F:21])=[C:13]([O:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:14]=2)=[CH:35][CH:36]=1
Reactant: O=CC(F)=C(c1ccc(Cl)cc1)C1CC1
Reactant: Fc1ccc(CBr)cc1Oc1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OC(Cc1ccc(F)c(Oc2ccccc2)c1)C(F)=C(c1ccc(Cl)cc1)C1CC1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 82 %

Procedure:
A solution of lithium n-butyltellurolate (10.5 mmol, n-BuTeLi), generated in situ from n-butyllithium (4.2 ml of 2.5 M solution in hexane, 10.5 mmol) and Te powder (1.34 g, 10.5 mmol) in tetrahydrofuran (10 ml) at 0° C., is treated with a solution of 3-phenoxy-4-fluorobenzyl bromide (2.81 g, 10 mmol) in tetrahydrofuran (10 ml) at 0° C., stirred for 30 minutes, cooled to −78° C., treated with a solution of n-butyllithium (4.2 ml of 2.5 M solution in hexane, 10.5 mmol), stirred for 30 minutes at −78° C., treated with a solution of p-chloro-β-cyclopropyl-α-fluorocinnamaldehyde (2.24 g, 10 mmol) in tetrahydrofuran (5 ml), warmed to room temperature with stirring for 3 hours, quenched with 2 N hydrochloric acid, and extracted with ethyl acetate. The combined organic extracts are washed with water, dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain a residue. Flash chromatography of the residue on silica gel using a 1:4 ethyl acetate/hexanes solution gives the title product (3.5 g, 82% yield) which is identified by 1H, 19F and 13C NMR spectral analyses.
Reaction SMILES: [C:1]([C:5]12[CH2:12][O:11][C:8]([CH2:13][CH2:14][CH2:15][CH2:16][C:17]#[CH:18])([O:9][CH2:10]1)[O:7][CH:6]2[C:19]#[N:20])([CH3:4])(C)C.[C:21](C(CO)(CO)CO)(C)(C)[CH3:22]>>[CH2:1]([C:5]12[CH2:10][O:9][C:8]([CH2:13][CH2:14][CH2:15][CH2:16][C:17]#[CH:18])([O:11][CH2:12]1)[O:7][CH:6]2[C:19]#[N:20])[CH2:4][CH2:21][CH3:22]
Reactant: CC(C)(C)C(CO)(CO)CO
Reactant: C#CCCCCC12OCC(C(C)(C)C)(CO1)C(C#N)O2
Product: C#CCCCCC12OCC(CCCC)(CO1)C(C#N)O2

Procedure:
4-t-Butyl-1-(hex-5-ynyl)-2,6,7-trioxabicyclo[2.2.2]octane-3-carbonitrile (Preparation of 2-t-butyl-2-hydroxymethylpropan-1,3-diol,
Reaction SMILES: Br[C:2]1[C:7]2[CH:8]=[C:9]([C:12]([F:15])([F:14])[F:13])[CH:10]=[CH:11][C:6]=2[O:5][C:4]([CH2:18][F:19])([CH2:16][F:17])[CH:3]=1.C([Li])CCC.[C:25](=[S:32])(OCC)[O:26][CH2:27][CH3:28].[Cl-].[NH4+]>COC(C)(C)C>[F:17][CH2:16][C:4]1([CH2:18][F:19])[CH:3]=[C:2]([C:25](=[S:32])[O:26][CH2:27][CH3:28])[C:7]2[CH:8]=[C:9]([C:12]([F:15])([F:14])[F:13])[CH:10]=[CH:11][C:6]=2[O:5]1
Reactant: CCOC(=S)OCC
Reactant: FCC1(CF)C=C(Br)c2cc(C(F)(F)F)ccc2O1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: COC(C)(C)C
Product: CCOC(=S)C1=CC(CF)(CF)Oc2ccc(C(F)(F)F)cc21
Reaction time: 0.25 h
Yield: 52 %

Procedure:
An amount (58 mg) of 4-bromo-2,2-bis(fluoromethyl)-6-trifluoromethyl-2H-1-benzopyran was dissolved in t-butyl methyl ether (2 ml); to the solution, 1.69 M n-butyllithium (0.108 ml) was added at −70° C. under a nitrogen atmosphere and the mixture was stirred for 15 minutes. Then, diethyl thiocarbonate (67 mg) was added dropwise to the reaction mixture, which was stirred for 30 minutes at −70° C. To the reaction mixture, a saturated aqueous solution of ammonium chloride was added, followed by extraction with hexane/ethyl acetate (3/1). The resulting organic layers were washed with a saturated aqueous solution of sodium chloride, dried with anhydrous sodium sulfate and concentrated under reduced pressure; the resulting residue was subjected to silica gel column chromatography (eluent; hexane/ethyl acetate=2/1) to give the titled compound (31 mg) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][CH:12]2[CH2:15][N:14]([C:16]3[S:17][C:18]4[C:24]([C:25]([O:27]CC)=[O:26])=[CH:23][CH:22]=[CH:21][C:19]=4[N:20]=3)[CH2:13]2)=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].[OH-].[Li+].O>CO>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][CH:12]2[CH2:15][N:14]([C:16]3[S:17][C:18]4[C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=[CH:21][C:19]=4[N:20]=3)[CH2:13]2)=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCOC(=O)c1cccc2nc(N3CC(NC(=O)c4nc(Cl)c(CC)[nH]4)C3)sc12
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCc1[nH]c(C(=O)NC2CN(c3nc4cccc(C(=O)O)c4s3)C2)nc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 58.1 %

Procedure:
Ethyl 2-(3-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}azetidin-1-yl)-1,3-benzothiazole-7-carboxylate obtained in Example (224c) (350 mg, 0.81 mmol) was dissolved in methanol (8 mL). A 2 N aqueous lithium hydroxide solution (4.03 mL, 8.07 mmol) was added, and the mixture was stirred at room temperature for 18 hours. Water was added to the reaction solution, and then the mixture was washed with ethyl acetate. A 1 N aqueous hydrochloric acid solution (8 mL) was added to the aqueous layer, and then the solvent was evaporated under reduced pressure. The resulting residue was suspended and washed in methanol. Following filtration, the resulting solid was washed with water to obtain 191 mg of the title compound as a white solid (58%).
Reaction SMILES: [OH-].[Na+].[CH2:3]([OH:6])[CH2:4][CH3:5].Cl[C:8]1[CH:13]=[CH:12][N+:11]([O-:14])=[C:10]([CH3:15])[C:9]=1[CH3:16]>CS(C)=O.O>[CH2:3]([O:6][C:8]1[CH:13]=[CH:12][N+:11]([O-:14])=[C:10]([CH3:15])[C:9]=1[CH3:16])[CH2:4][CH3:5]
Reactant: CCCO
Reactant: Cc1c(Cl)cc[n+]([O-])c1C
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CCCOc1cc[n+]([O-])c(C)c1C
Temperature: 30 °C
Reaction time: 8 h
Yield: 103.8 %

Procedure:
To a solution prepared by diluting 8.6 g (2.0 eq.) of 60% sodium hydroxide with 200 mL of dimethylsulfoxide, 13.0 g of 1-propanol (2.0 eq.) was added, and the mixture was allowed to react for one hour at 60° C. The reaction liquid was cooled to 30° C., and then a solution containing 17.0 g of 4-chlor-2,3-dimethylpyridine-1-oxide dissolved in dimethylsulfoxide (70 mL) was added dropwise. The mixture was allowed to react for 3 hours at 40 to 50° C., and then was left to stand overnight at room temperature. 15 mL of water was added to the reaction liquid, and the mixture was concentrated, to obtain a residue in the form of a black paste. Subsequently, the residue was dissolved in 500 mL of water, and then the aqueous solution was extracted three times with 670 mL of chloroform. The extract was dried over anhydrous magnesium sulfate, and then concentrated to dryness under reduced pressure, and the obtained residue was purified on a silica gel column, to obtain 20.3 g of 4-propoxy-2,3-dimethylpyridine-1-oxide.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]([C@@H:17]2[CH2:21][CH2:20][C:19]([F:23])([F:22])[CH2:18]2)[CH2:9][C:10]([CH3:16])([CH3:15])[C:11]([O:13]C)=O)[C:5]([N+:24]([O-])=O)=[CH:4][N:3]=1>C(O)(=O)C.[Fe]>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[NH:24][C:11](=[O:13])[C:10]([CH3:16])([CH3:15])[CH2:9][N:8]([C@@H:17]3[CH2:21][CH2:20][C:19]([F:22])([F:23])[CH2:18]3)[C:6]=2[N:7]=1
Reactant: COC(=O)C(C)(C)CN(c1nc(Cl)ncc1[N+](=O)[O-])[C@@H]1CCC(F)(F)C1
Agent: [Fe]
Solvent: CC(=O)O
Product: CC1(C)CN([C@@H]2CCC(F)(F)C2)c2nc(Cl)ncc2NC1=O
Temperature: 70 °C
Yield: 72.3 %

Procedure:
A mixture of (R)-methyl 3-((2-chloro-5-nitropyrimidin-4-yl)(3,3-difluorocyclopentyl)amino)-2,2-dimethylpropanoate (2.74 g, 6.98 mmol) and iron powder (0.799 g, 14.31 mmol) in glacial acetic acid (30 mL) was heated to 70° C. for 2 hours. The reaction mixture was filtered hot and the cake was further washed with acetic acid. The mother liquors were concentrated in vacuo. The residue was taken up in a 15% solution of methanol in dichloromethane and filtered through a pad of silica gel rinsing with more methanol-dichloromethane solution. The filtrates were concentrated in vacuo. The residue was triturated with methanol and the solid was filtered to afford the title compound as an off-white solid (1.67 g, 72% yield).
Reaction SMILES: Cl.Cl.[N:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:13][CH2:12][C@H:11]([NH2:14])[CH2:10]1.[CH:15]1[N:19]=[CH:18][N:17]([C:20](N2C=NC=C2)=[O:21])[CH:16]=1>C(Cl)Cl>[N:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:13][CH2:12][C@H:11]([NH:14][C:20]([N:17]2[CH:16]=[CH:15][N:19]=[CH:18]2)=[O:21])[CH2:10]1
Reactant: N[C@H]1CCN(c2ccccn2)C1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: Cl
Solvent: ClCCl
Product: O=C(N[C@H]1CCN(c2ccccn2)C1)n1ccnc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture comprising ((S)-1-Pyridin-2-yl-pyrrolidin-3-ylamine dihydrochloride (0.242 g, 1.02 mmol), TEA (0.2 ml) in DCM (10.2 ml) is treated with CDI (0.364 g, 2.26 mmol). The reaction mixture is stirred at room temperature for 2 hours to yield the titled compound as 0.1 M solution in DCM. This solution consists of the imidazole-urea intermediate together with variable amounts of the corresponding isocyanate and imidazole. This solution is used in the subsequent steps since the imidazole-urea intermediate and isocyanate intermediate are equally suitable as precursors to ureas.