Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][Li].[CH2:3]([CH:10]1[C:15](=[O:16])[CH2:14][CH2:13][CH2:12][N:11]1[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].O>CCOCC>[CH2:3]([CH:10]1[C:15]([OH:16])([CH3:1])[CH2:14][CH2:13][CH2:12][N:11]1[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: [Li]C
Reactant: CCCCCCCCN1CCCC(=O)C1CCCCCCC
Solvent: CCOCC
Solvent: O
Product: CCCCCCCCN1CCCC(C)(O)C1CCCCCCC
Temperature: 25 °C
Reaction time: 3 h
Yield: 41 %

Procedure:
Methyl lithium (7 ml, 2 M solution in ether) was injected, under nitrogen, into a stirred solution of 2-n-heptyl-1-n-octylpiperidin-3-one (3.4 g) in dry ether (100 ml) at -78°. The mixture was allowed to warm gradually to room temperature. After 3 hours, thin layer chromatography indicated that some starting material remained. The solution was cooled to -78° and methyl lithium (3 ml, 2 M solution in ether) was injected. The mixture was allowed to warm gradually to room temperature and was allowed to stand for 2 days. Water (10 ml) was added dropwise and the ether phase was separated, dried over magnesium sulphate and evaporated in vacuo. The product was purified by column chromatography to give 2-n-heptyl-3-hydroxy-3-methyl-1-n-octylpiperidine as a yellow gum (1.47 g, 41% yield).
Reaction SMILES: [CH:1]1([CH2:4][C:5](F)(F)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:3][CH2:2]1.BrCC1CC1.C(C1[S:28][CH2:27][CH2:26][CH2:25][S:24]1)(OCC)=O>>[CH:1]1([CH2:4][C:5]2([C:6]([O:8][CH2:9][CH3:10])=[O:7])[S:28][CH2:27][CH2:26][CH2:25][S:24]2)[CH2:3][CH2:2]1
Reactant: CCOC(=O)C(F)(F)CC1CC1
Reactant: CCOC(=O)C1SCCCS1
Agent: BrCC1CC1
Product: CCOC(=O)C1(CC2CC2)SCCCS1

Procedure:
A fifth aspect of this invention is a process for the preparation of ethyl 3-cyclopropyl-2,2-difluoropropanoate, which process comprises: (a) reacting bromomethylcyclopropane with 2-carboethoxy-1,3-dithiane in the presence of strong base to give ethyl 2-(cyclopropylmethyl)-1,3-dithiane-2-carboxylate; (b) reacting the ethyl 2-(cyclopropylmethyl)-1,3-dithiane-2-carboxylate with N-bromosuccinimide to give ethyl 3-cyclopropyl-2-oxopropanoate; and (c) reacting the ethyl 3-cyclopropyl-2-oxopropanoate with a fluorinating agent.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-])=O)=[C:6]([O:8][CH3:9])[CH:7]=1.Br[C:14]1C=CC(OC)=C2[C:15]=1C=CN2>>[Br:1][C:2]1[CH:3]=[C:4]2[C:5](=[C:6]([O:8][CH3:9])[CH:7]=1)[NH:10][CH:15]=[CH:14]2
Reactant: COc1ccc(Br)c2cc[nH]c12
Reactant: COc1cc(Br)ccc1[N+](=O)[O-]
Product: COc1cc(Br)cc2cc[nH]c12

Procedure:
5-Bromo-7-methoxyindole CV was prepared from 5-bromo-2-nitroanisole using the procedure described above for preparation of 4-bromo-7-methoxyindole LII (Example 13).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:37])=[N:4][O:5][C:6]=1[N:7](COCCOC)[S:8]([C:11]1[C:19]2[C:14](=[N:15][CH:16]=[CH:17][CH:18]=2)[S:13][C:12]=1[C:20](=[O:30])[C:21]1[CH:26]=[CH:25][C:24]2[O:27][CH2:28][O:29][C:23]=2[CH:22]=1)(=[O:10])=[O:9]>CO.Cl>[Cl:1][C:2]1[C:3]([CH3:37])=[N:4][O:5][C:6]=1[NH:7][S:8]([C:11]1[C:19]2[C:14](=[N:15][CH:16]=[CH:17][CH:18]=2)[S:13][C:12]=1[C:20](=[O:30])[C:21]1[CH:26]=[CH:25][C:24]2[O:27][CH2:28][O:29][C:23]=2[CH:22]=1)(=[O:9])=[O:10]
Reactant: COCCOCN(c1onc(C)c1Cl)S(=O)(=O)c1c(C(=O)c2ccc3c(c2)OCO3)sc2ncccc12
Agent: Cl
Solvent: CO
Product: Cc1noc(NS(=O)(=O)c2c(C(=O)c3ccc4c(c3)OCO4)sc3ncccc23)c1Cl
Temperature: 25 °C

Procedure:
A solution of N-(4-chloro-3-methyl-5-isoxazolyl)-N-(methoxyethoxymethyl)-2-[3,4-(methylenedioxy)benzoyl]thieno[2,3-b]pyridine-3-sulfonamide (0.15 g, 0.26 mmoles) in methanol (5 ml) and 4N HCl (2 ml) was heated to reflux for 3 hours then cooled to ambient temperature and concentrated. The residue was diluted with EtOAc (50 ml) and washed with saturated NaCl (2×50 ml). The organic layer was dried (MgSO4), filtered and concentrated to collect 0.10 g (81%) of the title compound as a foamy yellow solid, m.p. 75°-90° C.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:15]=[CH:14][C:10]3[O:11][CH2:12][O:13][C:9]=3[C:8]=2[C:16]2[CH:21]=[CH:20][N:19]=[C:18]3[C:22]([C:26]([NH:28][CH:29]4[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]4)=[O:27])=[C:23]([CH3:25])[NH:24][C:17]=23)[CH2:4][CH2:3]1.C([O:38][C@@H:39]([CH3:43])[C:40](Cl)=[O:41])(=O)C>>[CH:2]1([CH2:5][O:6][C:7]2[CH:15]=[CH:14][C:10]3[O:11][CH2:12][O:13][C:9]=3[C:8]=2[C:16]2[CH:21]=[CH:20][N:19]=[C:18]3[C:22]([C:26]([NH:28][CH:29]4[CH2:30][CH2:31][N:32]([C:40](=[O:41])[C@@H:39]([OH:38])[CH3:43])[CH2:33][CH2:34]4)=[O:27])=[C:23]([CH3:25])[NH:24][C:17]=23)[CH2:4][CH2:3]1
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Reactant: Cc1[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ccnc2c1C(=O)NC1CCNCC1
Agent: Cl
Product: Cc1[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ccnc2c1C(=O)NC1CCN(C(=O)[C@H](C)O)CC1

Procedure:
Starting from 7-[5-(cyclopropylmethoxy)-1,3-benzodioxol-4-yl]-2-methyl-N-piperidin-4-yl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f1) and commercially available (2S)-1-chloro-1-oxopropan-2-yl acetate the title compound is obtained as colorless solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][C@@H:15]2[C@@H:10]([C@@H:11](OS(C(F)(F)F)(=O)=O)[CH2:12][CH2:13][C:14]2([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F-:37].C([N+](CCCC)(CCCC)CCCC)CCC>FCF.O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:16][C@@H:15]2[C@@H:10]([C@H:11]([F:37])[CH2:12][CH2:13][C:14]2([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:9]1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2[C@@H](OS(=O)(=O)C(F)(F)F)CCC(c3ccccc3)(c3ccccc3)[C@@H]2C1
Reactant: [F-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: FCF
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C[C@@H]2[C@H](F)CCC(c3ccccc3)(c3ccccc3)[C@@H]2C1
Temperature: 20 °C
Reaction time: 17 h

Procedure:
A solution of 4.87 g of (3aR, 7S, 7aR)-2-t-butoxycarbonyl-4,4-diphenyl-7trifluoromethylsulphonyloxyperhydroisoindole in 150 cm3 of dry difluoromethane is treated with 22.6 cm3 of a 1M solution of tetrabutylammonium fluoride in tetrahydrofuran and then stirred for 17 hours at 20° C and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a silica gel column (particle size 0.2-0.063 mm, diameter 4.5 cm, height 35 cm), eluting under a nitrogen pressure of 0.4 bar with a cyclohexane and ethyl acetate mixture (75/25) and collecting fractions of 20 cm3. Fractions 28 to 38 are pooled and concentrated to dryness under reduced pressure (2.7 kPa) to give 1.44 g of (3aR, 7R,7aR)-2-t-butoxycarbonyl-4,4-diphenyl-7-fluoroperhydroisoindole in the form of white crystals; melting point 200° C., [α]D20 =-225° C. (c=1, CHCl3).
Reaction SMILES: C(N(CC)CC)C.[Br:8][C:9]1[CH:10]=[C:11]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][C:22]([O:29][CH2:30][CH2:31][CH2:32][OH:33])=[C:23]([N+:26]([O-:28])=[O:27])[CH:24]=3)[N:19]=[CH:18][N:17]=2)[CH:12]=[CH:13][CH:14]=1.[CH3:34][S:35](Cl)(=[O:37])=[O:36].O>C(Cl)Cl.C(N(CC)CC)C.CS(Cl)(=O)=O.C(Cl)Cl.CO>[Br:8][C:9]1[CH:10]=[C:11]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][C:22]([O:29][CH2:30][CH2:31][CH2:32][O:33][S:35]([CH3:34])(=[O:37])=[O:36])=[C:23]([N+:26]([O-:28])=[O:27])[CH:24]=3)[N:19]=[CH:18][N:17]=2)[CH:12]=[CH:13][CH:14]=1
Reactant: O=[N+]([O-])c1cc2c(Nc3cccc(Br)c3)ncnc2cc1OCCCO
Reactant: CS(=O)(=O)Cl
Solvent: CO
Solvent: O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCCOc1cc2ncnc(Nc3cccc(Br)c3)c2cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1.10 ml of the triethylamine are added to 1.28 g of 4-[(3-bromophenyl)amino]-7-(3-hydroxy-propyloxy)-6-nitro-quinazoline in 55 ml of methylene chloride. Then, whilst cooling with an ice bath, a solution of 0.47 ml of methanesulphonic acid chloride in 5 ml of methylene chloride is added dropwise. The reaction mixture is stirred for about one hour at ambient temperature. Since some starting material can still be detected, another 20 drops of triethylamine and 10 drops of methanesulphonic acid chloride are added, whilst cooling with an ice bath. The mixture is stirred for a further 30 minutes at ambient temperature, whereupon a clear, reddish-orange solution is formed. For work-up, this is diluted with methylene chloride and added to 100 ml of water. The organic phase is washed with 3% sodium hydrogen carbonate solution and water, dried over sodium sulphate and concentrated by evaporation. A brownish-yellow resin remains, which is further reacted as the crude product. Yield: 1.4 g (92% of theory) Rf value: 0.70 (silica gel, methylene chloride/methanol=9:1)
Reaction SMILES: [OH:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[N:3]1.C(N(CC)CC)C.[CH:18]([S:26](Cl)(=[O:28])=[O:27])=[CH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>ClCCl>[CH:18]([S:26]([O:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[N:3]1)(=[O:28])=[O:27])=[CH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=S(=O)(Cl)C=Cc1ccccc1
Reactant: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(C=Cc1ccccc1)On1nnc2ccccc21
Temperature: 25 °C
Yield: 75.7 %

Procedure:
In dichloromethane (100 ml) are dissolved 1-hydroxy-1,2,3-benzotriazole (5.4 g) and triethylamine (5.6 ml). To the solution is added β-styrenesulfonyl chloride (8.0 g) with stirring at room temperature, and the mixture is stirred for 1 hour. The reaction mixture is washed twice with water (30 ml) and dried over anhydrous magnesium sulfate-charcoal. After drying, the solvent is distilled off. The residue is dissolved in ethyl acetate (20 ml) and thereto is added n-hexane (50 ml) to give needles of 1-(β-styrenesulfonyloxy)-1,2,3-benzotriazole (9.0 g). A part of the product is recrystallized from ethyl acetate-n-hexane to give a pure product, melting point: 102°-103° C.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:19]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]=[C:11]([NH2:20])[C:10]=2[N:9]=[C:8]1[CH2:21][CH2:22][O:23][CH3:24].C(N(CC)CC)C.[C:32](Cl)(=[O:36])[CH:33]([CH3:35])[CH3:34].C(=O)(O)[O-].[Na+]>N1C=CC=CC=1>[NH2:20][C:11]1[C:10]2[N:9]=[C:8]([CH2:21][CH2:22][O:23][CH3:24])[N:7]([CH2:6][CH2:5][CH2:4][NH:3][C:32](=[O:36])[CH:33]([CH3:35])[CH3:34])[C:19]=2[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:12]=1
Reactant: COCCc1nc2c(N)nc3ccccc3c2n1CCCN
Reactant: CC(C)C(=O)Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: COCCc1nc2c(N)nc3ccccc3c2n1CCCNC(=O)C(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 104.9 %

Procedure:
1-(3-Aminopropyl)-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amine dihydrochloride (6 g, 16 mmol) was combined with triethylamine (11.2 mL, 80 mmol) and pyridine (100 mL). Isobutyryl chloride (1.9 g, 18 mmol) was added dropwise and the reaction mixture was stirred at ambient temperature for 1 hour. The reaction mixture was combined with saturated aqueous sodium bicarbonate and extracted with dichloromethane (3×200 mL). The combined organics were dried over magnesium sulfate, filtered through a layer of CELITE filter aid, and then concentrated under reduced pressure to provide 6.2 g of crude N-{3-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]propyl}-2-methylpropionamide as a brown solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[NH:10][CH2:9][CH:8]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:7]2.[C:20](Cl)(Cl)=[O:21].CN>C1COCC1>[O:21]=[C:20]1[N:10]2[C:11]3[C:6]([CH2:7][CH:8]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:16])([CH3:18])[CH3:17])[CH2:9]2)=[CH:5][CH:4]=[CH:3][C:2]=3[NH:1]1
Reactant: CC(C)(C)OC(=O)NC1CNc2c(N)cccc2C1
Reactant: O=C(Cl)Cl
Agent: CN
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1Cc2cccc3[nH]c(=O)n(c23)C1
Reaction time: 0.08 h

Procedure:
t-Butyl (8-amino-1,2,3,4-tetrahydro-3-quinolyl)carbamate (2.70 g) was dissolved in THF (100 mL) and stirred while a solution of phosgene in THF (20.7 mL of 0.40 M, 0.093 mol) was added. After 5 minutes, methylamine (2.08 g, 0.020 mol) was added and the solution stirred for an additional 10 minutes. The THF was removed under reduced pressure and the material was partitioned between chloroform (250 mL) and water (20 nil,). The chloroform was washed with 4N sodium hydroxide (5 mL) and evaporated. The crude material was combined with that of an earlier reaction (0.002 mol scale) and purified by chromatography on silica gel in 1% methanol: chloroform to give 2.28 g of product. Crystallization from methanol:ether (1:1) gave 1.60 g (54%) white solid, mp 235°-36° C. Anal. Calc'd for C15H19N3O3 : C, 62.26; H, 6.62; N, 14.52. Found: C, 61.65; H, 6.94; N, 14.23.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10](=[O:17])[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(NC1(C(O)=O)CC1)(O[C:21](C)(C)[CH3:22])=O>>[C:1]([O:5][C:6]([NH:8][C:9]1([C:10](=[O:17])[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:22][CH2:21]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CCOC(=O)CC(=O)CNC(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CC1
Product: CCOC(=O)CC(=O)C1(NC(=O)OC(C)(C)C)CC1

Procedure:
A tautomeric mixture of ethyl 3-(1-((tert-butoxycarbonyl)amino)cyclopropyl)-3-oxopropanoate and (Z)-ethyl 3-(1-((tert-butoxycarbonyl)amino)cyclopropyl)-3-hydroxyacrylate (3.15 g, 11.61 mmol, 90% yield) as an off white solid was prepared according the procedures described for Intermediate 601, using 1-(Boc-amino)cyclopropanecarboxylic acid (Chem-Impex International, Inc., cat #04052) (2.59 g, 12.87 mmol) as the reagent. m/z (ESI, +ve) 294.2 (M+23)+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[S:25]1[CH:29]=[CH:28][C:27]([C:30](Cl)=[O:31])=[CH:26]1>>[S:25]1[CH:29]=[CH:28][C:27]([C:30]([NH:1][C:2]2[N:7]=[C:6]3[C:8]([CH:11]4[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C:19]5[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=5)[CH2:13][CH2:12]4)=[CH:9][NH:10][C:5]3=[CH:4][CH:3]=2)=[O:31])=[CH:26]1
Reactant: O=C(Cl)c1ccsc1
Reactant: Nc1ccc2[nH]cc(C3CCN(CCc4ccccc4)CC3)c2n1
Product: O=C(Nc1ccc2[nH]cc(C3CCN(CCc4ccccc4)CC3)c2n1)c1ccsc1

Procedure:
Beginning with 0.015 gm (0.047 mMol) 5-amino-3-(1-(2-phenyleth-1-yl)piperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.009 mL (0.061 mMol) 3-thiophenecarbonyl chloride, the title compound was prepared essentially by the procedure described in Example 7.
Reaction SMILES: [O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5][C:4]([C:12]2[CH:17]=[C:16]([CH2:18][CH2:19][NH:20]C(=O)OC(C)(C)C)[CH:15]=[CH:14][N:13]=2)=[N:3]1.[F:28][C:29]([F:34])([F:33])[C:30]([OH:32])=[O:31]>>[F:28][C:29]([F:34])([F:33])[C:30]([OH:32])=[O:31].[NH2:20][CH2:19][CH2:18][C:16]1[CH:15]=[CH:14][N:13]=[C:12]([C:4]2[S:5][C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[C:2](=[O:1])[N:3]=2)[CH:17]=1
Reactant: CC(C)(C)OC(=O)NCCc1ccnc(-c2nc(=O)c3ccccc3s2)c1
Solvent: O=C(O)C(F)(F)F
Product: NCCc1ccnc(-c2nc(=O)c3ccccc3s2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89 %

Procedure:
tert-Butyl 2-[2-(4-oxo-4H-1,3-benzothiazin-2-yl)-4-pyridyl]ethylcarbamate (0.82 g, 2.1 mmol) was dissolved in trifluoroacetic acid (10 ml), and the mixture was stirred at room temperature for 2 hrs. The solvent was evaporated, and the residue was recrystallized from methanol-diisopropyl ether to give the titled compound (0.75 g, 89%) as white crystals.
Reaction SMILES: [H][H].[F:3][C:4]1[CH:5]=[C:6]([N:13]2[CH:17]=[N:16][CH:15]=[N:14]2)[CH:7]=[CH:8][C:9]=1[N+:10]([O-])=O>[Pd].O1CCCC1>[NH2:10][C:9]1[CH:8]=[CH:7][C:6]([N:13]2[CH:17]=[N:16][CH:15]=[N:14]2)=[CH:5][C:4]=1[F:3]
Reactant: O=[N+]([O-])c1ccc(-n2cncn2)cc1F
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: Nc1ccc(-n2cncn2)cc1F

Procedure:
Hydrogen was introduced under atmospheric pressure into the mixture consisting of 260 mg of 1-(3-fluoro-4-nitrophenyl)-1H-[1,2,4]triazole, 30 mg of Pd/C and 30 ml of tetrahydrofuran until the theoretical amount had been taken up. After filtering off the catalyst with suction and concentrating the mixture under reduced pressure, the remaining oily residue was purified by column chromatography (solvent: 98:2 dichloromethane:methanol; silica gel).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[N:13]([CH2:38][O:39][CH2:40][CH2:41][Si:42]([CH3:45])([CH3:44])[CH3:43])[C:14]([N:16]([C:18]1[CH:23]=[C:22]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([CH2:31][N:32]([CH3:34])[CH3:33])=[CH:27][C:26]=2[N+:35]([O-])=O)[N:21]=[CH:20][N:19]=1)[CH3:17])=[O:15]>CO.ClC1C=CC=CC=1.O=[Pt]=O>[NH2:35][C:26]1[CH:27]=[C:28]([CH2:31][N:32]([CH3:34])[CH3:33])[CH:29]=[CH:30][C:25]=1[NH:24][C:22]1[N:21]=[CH:20][N:19]=[C:18]([N:16]([CH3:17])[C:14]([N:13]([C:3]2[C:4]([Cl:12])=[C:5]([O:10][CH3:11])[CH:6]=[C:7]([O:8][CH3:9])[C:2]=2[Cl:1])[CH2:38][O:39][CH2:40][CH2:41][Si:42]([CH3:45])([CH3:44])[CH3:43])=[O:15])[CH:23]=1
Reactant: COc1cc(OC)c(Cl)c(N(COCC[Si](C)(C)C)C(=O)N(C)c2cc(Nc3ccc(CN(C)C)cc3[N+](=O)[O-])ncn2)c1Cl
Agent: O=[Pt]=O
Solvent: Clc1ccccc1
Solvent: CO
Product: COc1cc(OC)c(Cl)c(N(COCC[Si](C)(C)C)C(=O)N(C)c2cc(Nc3ccc(CN(C)C)cc3N)ncn2)c1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 1-(2,6-dichloro-3,5-dimethoxy-phenyl)-3-[6-(4-dimethylaminomethyl-2-nitro-phenylamino)-pyrimidin-4-yl]-3-methyl-1-(2-trimethylsilanyl-ethoxymethyl)-urea (100 g, 0.15 mmol) in MeOH (10 mL) was added 4 drops of chlorobenzene and then PtO2 (30 mg, 30% wt). The solution was stirred under hydrogen atmosphere at room temperature overnight. The reaction was filtered and concentrated. The residue was taken to the next step without further purification. MS (ESI): 650 [M+H]+.
Reaction SMILES: N([C:4]([C:6]1[N:7]=[CH:8][C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[N:10][CH:11]=1)=[O:5])=[N+]=[N-].[C:17]([OH:21])([CH3:20])([CH3:19])[CH3:18]>C1(C)C=CC=CC=1>[C:17]([O:21][C:4]([C:6]1[N:7]=[CH:8][C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[N:10][CH:11]=1)=[O:5])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)O
Reactant: CCOC(=O)c1cnc(C(=O)N=[N+]=[N-])cn1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cnc(C(=O)OC(C)(C)C)cn1
Temperature: 25 °C
Yield: 65.8 %

Procedure:
A mixture of ethyl 5-(azidocarbonyl)pyrazine-2-carboxylate (1.00 g, 4.52 mmol), tert-butanol (1.5 mL, 20.2 mmol) and toluene (15 mL) was heated to reflux for 1 hour. After cooling to room temperature, the solid precipitate was collected to afford the title compound (0.75 g).
Reaction SMILES: O1CCCCC1O[CH2:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]([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)[CH:10]=1.S(Cl)([Cl:33])=O.O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:33][CH2:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]([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)[CH:10]=1
Reactant: O=C(OCc1ccccc1)N1CCN(c2cc(COC3CCCCO3)ccn2)CC1
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: O=C(OCc1ccccc1)N1CCN(c2cc(CCl)ccn2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.7 %

Procedure:
To a solution of benzyl 4-(4-((tetrahydro-2H-pyran-2-yloxy)methyl)pyridin-2-yl)piperazine-1-carboxylate (7.3 g, 17.7 mmol) in DCM (30 mL), thionyl chloride (7.7 mL, 106.6 mmol) was added slowly at RT, followed by the addition of H2O (0.05 mL). The mixture was stirred at RT overnight, poured into a solution of aqueous NaHCO3 (sat., 50 mL), and extracted with DCM (2×30 mL). The combined organic layers were washed with H2O (50 mL) and brine (20 mL), dried over Na2SO4, filtered, and concentrated to afford the crude product, which was purified by silica gel column chromatography (Petroleum ether:EtOAc=3:1) to give benzyl 4-(4-(chloromethyl)pyridin-2-yl)piperazine-1-carboxylate as a yellow solid (5.0 g, 82%). MS (ES+) C18H20ClN3O2 requires: 345, found: 346 [M+H]+.
Reaction SMILES: C[O:2][C:3]1[C:8]([CH3:9])=[CH:7][C:6]([C:10]2[C:14]3[CH:15]=[C:16]([N:19]4[C:24](=[O:25])[CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[N:21]([CH3:30])[C:20]4=[O:31])[CH:17]=[CH:18][C:13]=3[O:12][N:11]=2)=[CH:5][CH:4]=1.B(Br)(Br)Br.Cl>C(Cl)Cl.CC(C)=O>[OH:2][C:3]1[C:8]([CH3:9])=[CH:7][C:6]([C:10]2[C:14]3[CH:15]=[C:16]([N:19]4[C:24](=[O:25])[CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[N:21]([CH3:30])[C:20]4=[O:31])[CH:17]=[CH:18][C:13]=3[O:12][N:11]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2noc3ccc(-n4c(=O)cc(C(F)(F)F)n(C)c4=O)cc23)cc1C
Agent: BrB(Br)Br
Agent: Cl
Solvent: ClCCl
Solvent: CC(C)=O
Product: Cc1cc(-c2noc3ccc(-n4c(=O)cc(C(F)(F)F)n(C)c4=O)cc23)ccc1O
Temperature: -10 °C
Reaction time: 1 h

Procedure:
A mixture of 3-[3-(6-methoxy-m-tolyl)-1,2-benzisoxazol-5-yl]-1-methyl-6-(trifluoromethyl)-2,4(1H,3H)-pyrimidinedione (5.00 g, 0.0116 mol) in methylene chloride is cooled to -10° C., treated dropwise with 15.1 mL of 1 M boron tribromide in methylene chloride while maintaining the reaction mixture temperature at -15° C. to 0° C., warmed to room temperature, treated dropwise with 5 mL of the boron tribromide solution, stirred at room temperature for one hour, and poured into dilute hydrochloric acid. The resultant aqueous mixture is diluted with acetone, concentrated In vacuo, diluted with water, and filtered to obtain a solid. The solid is washed with water and dried in a vacuum oven at 60° C. to give the title product as a yellow solid which is identified by mass spectral analysis.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11](Cl)=[O:12])[CH:6]=1)(=[O:3])[CH3:2].C(N(CC)CC)C.[CH3:21][S:22][C:23]1[S:27][C:26]([NH2:28])=[N:25][CH:24]=1>C1COCC1>[C:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11](=[O:12])[NH:28][C:26]2[S:27][C:23]([S:22][CH3:21])=[CH:24][N:25]=2)[CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1cccc(C(=O)Cl)c1
Reactant: CSc1cnc(N)s1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CSc1cnc(NC(=O)c2cccc(OC(C)=O)c2)s1
Yield: 64.6 %

Procedure:
Following the procedure for the synthesis of example 513, intermediate 511 (0.815 g, 4.10 mmol) dissolved in dry THF (25.0 mL), triethylamine (0.572 mL, 4.10 mmol), and 514 (0.500 g, 3.42 mmol) dissolved in dry THF (10.0 mL) gave 516 (0.681 g, 65%) as a tan solid.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].C(N(CC)CC)C.[NH2:12][C:13]1[CH:14]=[N:15][C:16]2[C:21]([C:22]=1[Cl:23])=[CH:20][CH:19]=[CH:18][CH:17]=2>ClCCl>[Cl:23][C:22]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]=[CH:14][C:13]=1[NH:12][C:1](=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: Nc1cnc2ccccc2c1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Nc1cnc2ccccc2c1Cl
Reaction time: 8 h

Procedure:
Acetyl chloride (3.41 mL, 1.25 eq) and triethylamine (6.79 mL, 1.4 eq) were added sequentially to a solution of 3-amino-4-chloroquinoline (6.22 g, 1.0 eq) in dichloromethane (100 mL). The reaction mixture was stirred overnight and then washed sequentially with aqueous saturated sodium bicarbonate and brine, dried over magnesium sulfate, and then concentrated under reduced pressure to provide 6.68 g of N-(4-chloroquinolin-3-yl)acetamide.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([CH2:24][C:25]([OH:27])=O)[C:15]2[CH:23]=[C:22]3[C:18]([CH:19]=[N:20][NH:21]3)=[CH:17][CH:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:28]([NH:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=1)[CH3:29]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([C:15]2[CH:23]=[C:22]3[C:18]([CH:19]=[N:20][NH:21]3)=[CH:17][CH:16]=2)[CH2:24][C:25]([N:30]([CH2:28][CH3:29])[CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=2)=[O:27])(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CCNCc1ccccn1
Reactant: CC(C)(C)c1ccc(S(=O)(=O)N(CC(=O)O)c2ccc3cn[nH]c3c2)cc1
Product: CCN(Cc1ccccn1)C(=O)CN(c1ccc2cn[nH]c2c1)S(=O)(=O)c1ccc(C(C)(C)C)cc1

Procedure:
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-(1H-indazol-6-yl)-amino]-acetic acid with ethyl-pyridin-2-ylmethyl-amine