Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][N:7]2[C:16]=1[C:15]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:9][CH:8]2[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([O-:3])=[O:2].[C:23](OC(=O)C)(=[O:25])[CH3:24]>>[N+:1]([C:4]1[CH:5]=[N:6][N:7]2[C:16]=1[C:15]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:9]([C:23](=[O:25])[CH3:24])[CH:8]2[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cnn2c1-c1ccccc1NC2c1ccccc1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)N1c2ccccc2-c2c([N+](=O)[O-])cnn2C1c1ccccc1
Yield: 92 %

Procedure:
1-Nitro-5-phenyl-5,6-dihydropyrazolo[1,5-c]quinazoline is treated with acetic anhydride as described in Example 27 to give 1-nitro-5-phenyl-6-acetyl-5,6-dihydropyrazolo[1,5-c]quinazoline. M.p.: 156°-157° C. Yield: 92%.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[C:6]([N:11]2[CH2:22][CH2:21][N:20]3[C:13](=[CH:14][C:15]4[CH2:16][C:17]([CH3:24])([CH3:23])[CH2:18][C:19]=43)[C:12]2=[O:25])[C:3]=1[CH:4]=[O:5].C([OH:30])(C)(C)C.CC(=CC)C.[O-]Cl=O.[Na+]>O.ClCCl>[Br:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[C:6]([N:11]2[CH2:22][CH2:21][N:20]3[C:13](=[CH:14][C:15]4[CH2:16][C:17]([CH3:23])([CH3:24])[CH2:18][C:19]=43)[C:12]2=[O:25])[C:3]=1[C:4]([OH:30])=[O:5]
Reactant: CC1(C)Cc2cc3n(c2C1)CCN(c1cc(F)cc(Br)c1C=O)C3=O
Reactant: CC(C)(C)O
Agent: CC=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: ClCCl
Solvent: O
Product: CC1(C)Cc2cc3n(c2C1)CCN(c1cc(F)cc(Br)c1C(=O)O)C3=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 84 %

Procedure:
To a mixture of 2-bromo-6-{4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.02,6]dodeca-2(6),7-dien-10-yl}-4-fluorobenzaldehyde 128a (810 mg, 2.0 mmol), tert-butyl alcohol (50 mL), and dichloromethane (3 mL) was added 2-methyl-2-butene (22 mL, 262 mmol). An aqueous solution (20 mL) of NaClO2 (1.8 g, 20.0 mmol) and NaH2PO4 dihydrate (2.2 g, 14.0 mmol) was added dropwise at 0° C. The mixture was stirred at 0° C. for 1 h. It was then treated with water (30 mL) and extracted with ethyl acetate (4×90 mL). The combined organic extract was dried over MgSO4 and concentrated under reduced pressure to afford 129a (930 mg, 84%) as a yellow solid. MS-ESI: [M+H]+ 421.1
Reaction SMILES: [CH3:1][N:2]1[C:7]([NH2:8])=[N:6][C:4](=[O:5])[CH2:3]1.O.[C:10]1([CH3:19])[CH:15]=[CH:14][C:13]([N:16]=[C:17]=[O:18])=[CH:12][CH:11]=1>CN(C=O)C>[CH3:1][N:2]1[CH2:3][C:4](=[O:5])[NH:6][C:7]1=[N:8][C:17]([NH:16][C:13]1[CH:14]=[CH:15][C:10]([CH3:19])=[CH:11][CH:12]=1)=[O:18]
Reactant: Cc1ccc(N=C=O)cc1
Reactant: CN1CC(=O)N=C1N
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)N=C2NC(=O)CN2C)cc1
Reaction time: 3.5 h

Procedure:
To a stirring suspension of creatinine (11.88 g, 0.105 mole) in 100 ml dry DMF, p-tolylisocyanate (13.31 g- 0.100 mole) is added dropwise over a period of about 15 minutes with cooling. After stirring for 3.5 hrs., the mixture is poured into about 500 ml iced-water to give white crystals of product which are filtered off and washed with water. Recrystallization of the product from acetone-methanol and then from THF-methanol affords the product, 1-(1-methyl-4-oxo-2-imidazolidinylidene)-3-p-tolyl urea. The crystalline particles are reduced to finer size by adding a solution of the thus-obtained product in minimal DMF to about 1.1 liters of vigorously stirring water, filtering off and drying the resultant fine crystals in vacuo for 24 hours; m.p. 198°-200° C. dec.
Reaction SMILES: [Ca].[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C@H:10]([NH:12][CH:13]2[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14]2)[CH3:11])[CH:7]=[CH:8][CH:9]=1.[ClH:25]>C(Cl)(Cl)Cl.O1CCOCC1>[ClH:25].[ClH:25].[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C@H:10]([NH:12][C@@H:13]2[CH2:17][CH2:16][NH:15][CH2:14]2)[CH3:11])[CH:7]=[CH:8][CH:9]=1
Reactant: COc1cccc([C@@H](C)NC2CCN(C(=O)OC(C)(C)C)C2)c1
Agent: Cl
Agent: [Ca]
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Product: COc1cccc([C@@H](C)N[C@@H]2CCNC2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 25 g of tert-butyl(S)-3-hydroxypyrrolidine-1-carboxylate and 25.9 g of diisopropylethylamine dissolved in 500 ml of methylene chloride was added dropwise 100 ml of a solution of 49 g of anhydrous trifluoromethanesulfonic acid in methylene chloride at −20° C. or lower. The reaction mixture was stirred for 15 minutes while maintaining it to −20° C., and then, to the mixture was added dropwise 100 ml of a solution of 24.2 g of (R)-1-(3-methoxyphenyl)ethylamine in methylene chloride at −20° C. or lower, and the reaction mixture was stirred at room temperature for 16 hours. To the reaction mixture were added a saturated aqueous sodium bicarbonate solution and chloroform, the mixture was stirred and the liquids were separated. The organic layer was dried and the solvent was evaporated, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1→1:2) to obtain 19.32 g of tert-butyl 3-[(R)-1-(3-methoxyphenyl)ethylamino]pyrrolidine-1-carboxylate. (2) To a solution of 19.32 g of tert-butyl 3-[(R)-1-(3-methoxyphenyl)ethylamino]pyrrolidine-1-carboxylate dissolved in 30 ml of chloroform was added 300 ml of a solution of 4M hydrochloric acid in dioxane, and the mixture was stirred at room temperature for 16 hours. The resulting precipitates were collected by filtration, washed with ethyl acetate, and recrystallized from methanol and tetrahydrofuran twice to obtain 8.54 g of (R)-3-[(R)-1-(3-methoxyphenyl)ethylamino]pyrrolidine dihydrochloride (the following Reference example Table, Reference example 1.003).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C@H:3]1[CH2:8][CH2:7][C@H:6]([NH2:9])[CH2:5][CH2:4]1.[OH:12][CH2:13][CH2:14][O:15][C:16]1[N:24]=[C:23]([NH2:25])[C:22]([N+:26]([O-:28])=[O:27])=[CH:21][C:17]=1[C:18](O)=[O:19].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>>[F:1][C:2]([F:10])([F:11])[C@H:3]1[CH2:4][CH2:5][C@H:6]([NH:9][C:18](=[O:19])[C:17]2[CH:21]=[C:22]([N+:26]([O-:28])=[O:27])[C:23]([NH2:25])=[N:24][C:16]=2[O:15][CH2:14][CH2:13][OH:12])[CH2:7][CH2:8]1
Reactant: N[C@H]1CC[C@H](C(F)(F)F)CC1
Reactant: Nc1nc(OCCO)c(C(=O)O)cc1[N+](=O)[O-]
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Product: Nc1nc(OCCO)c(C(=O)N[C@H]2CC[C@H](C(F)(F)F)CC2)cc1[N+](=O)[O-]
Reaction time: 1.5 h

Procedure:
trans-4-Trifluoromethyl-cyclohexylamine (285 mg, 1.40 mmol) and TEA (410 μl) are added successively to a mixture of 2-(2-hydroxy-ethoxy)-6-amino-5-nitro-nicotinic acid (360 mg, 1.33 mmol), TBTU (285 mg, 1.33 mmol) and TEA (195 μl) and it is stirred for 1.5 h. The mixture is concentrated filtered and purified via chromatography.
Reaction SMILES: C([O:9][C:10]1[C:11]([C:22]([O:24]C)=O)=[N:12][C:13]([CH:17]2[CH2:21][CH2:20][CH2:19][NH:18]2)=[N:14][C:15]=1[OH:16])(=O)C1C=CC=CC=1.[F:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31][NH2:32])=[CH:29][CH:28]=1>CO>[F:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31][NH:32][C:22]([C:11]2[C:10]([OH:9])=[C:15]([OH:16])[N:14]=[C:13]([CH:17]3[CH2:21][CH2:20][CH2:19][NH:18]3)[N:12]=2)=[O:24])=[CH:29][CH:28]=1
Reactant: COC(=O)c1nc(C2CCCN2)nc(O)c1OC(=O)c1ccccc1
Reactant: NCc1ccc(F)cc1
Solvent: CO
Product: O=C(NCc1ccc(F)cc1)c1nc(C2CCCN2)nc(O)c1O

Procedure:
A solution of methyl 5-(benzoyloxy)-6-hydroxy-2-pyrrolidin-2-ylpyrimidine-4-carboxylate (C-16) (1.0 eq.) in MeOH was treated with 4-fluorobenzylamine (3.0 eq.). The solution was stirred at reflux until the starting material was consumed as determined by MS analysis. The reaction was concentrated and the product (C-17) was precipitated with MeOH and collected by filtration.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([CH2:21]Cl)[CH:17]=3)[N:12]([CH3:23])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1.[N-:26]=[N+:27]=[N-:28].[Na+].O>CN(C=O)C>[N:26]([CH2:21][C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH3:23])[CH:11]=[C:10]([C:8]([NH:7][CH2:6][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:25][CH:24]=1)=[O:9])[C:19]2=[O:20])=[N+:27]=[N-:28]
Reactant: [N-]=[N+]=[N-]
Reactant: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CCl)ccc21
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CN=[N+]=[N-])ccc21
Temperature: 25 °C
Yield: 90 %

Procedure:
A solution of N-(4-chlorobenzyl)-6-(chloromethyl)-1-methyl-4-oxo-1,4-dihydro-3-quinolinecarboxamide from Preparation No. 35 (200 mg) and sodium azide (176.8 mg) in anhydrous DMF (7 mL) is heated at 60° C. overnight. The reaction is cooled to room temperature and poured into water to precipitate the product. The solid is adsorbed onto silica and purified by chromatography (eluent 100% CH2Cl2 (1 L), 0.5% MeOH in CH2Cl2 (1 L), and 1% MeOH in CH2Cl2 (1 L)). Fractions homogenous by TLC were combined and concentrated to afford 182.7 mg (90%) of the title compound as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[N:14]([CH2:15][C:16]([OH:18])=O)[C:13](=[O:19])[C:12]([CH3:21])([CH3:20])[CH2:11][CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:22][C:23]1[CH:24]=[C:25]2[C:46](=[CH:47][CH:48]=1)[CH2:45][C@:27]1([C:35]3[C:30](=[N:31][CH:32]=[CH:33][CH:34]=3)[N:29]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])[C:28]1=[O:44])[CH2:26]2.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[N:14]([CH2:15][C:16]([NH:22][C:23]3[CH:24]=[C:25]4[C:46](=[CH:47][CH:48]=3)[CH2:45][C@:27]3([C:35]5[C:30](=[N:31][CH:32]=[CH:33][CH:34]=5)[N:29]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:41])([CH3:42])[CH3:43])[C:28]3=[O:44])[CH2:26]4)=[O:18])[C:13](=[O:19])[C:12]([CH3:21])([CH3:20])[CH2:11][CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CC1(C)CC[C@@H](c2cc(F)cc(F)c2)N(CC(=O)O)C1=O
Reactant: C[Si](C)(C)CCOCN1C(=O)[C@@]2(Cc3ccc(N)cc3C2)c2cccnc21
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC1(C)CC[C@@H](c2cc(F)cc(F)c2)N(CC(=O)Nc2ccc3c(c2)C[C@@]2(C3)C(=O)N(COCC[Si](C)(C)C)c3ncccc32)C1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of [(6S)-6-(3,5-difluorophenyl)-3,3-dimethyl-2-oxopiperidin-1-yl]acetic acid (21 mg, 0.07 mmol, described in Intermediate 49), (R)-5-amino-1′-{[2-(trimethylsilyl)ethoxy]methyl}-1,3-dihydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one (26 mg, 0.07 mmol, described in Intermediate 9, step B), HOBT (15 mg, 0.10 mmol), and EDC (19 mg, 0.10 mmol) in DMF (0.5 mL) was stirred at ambient temperature for 18 h. The reaction mixture was partitioned between saturated aqueous NaHCO3 (10 mL) and EtOAc (20 mL). The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to give the title compound. MS: m/z=661 (M+1).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([CH2:14][CH2:15][CH3:16])=[C:12]([C:17]([NH:19][CH:20]3[CH2:22][CH2:21]3)=[O:18])[N:11]=[N:10]2)=[CH:5][CH:4]=1)#[N:2].C([OH:25])C>[Ni]>[NH2:2][C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([CH2:14][CH2:15][CH3:16])=[C:12]([C:17]([NH:19][CH:20]3[CH2:22][CH2:21]3)=[O:18])[N:11]=[N:10]2)=[CH:5][CH:4]=1)=[O:25]
Reactant: CCCc1c(C(=O)NC2CC2)nnn1-c1ccc(C#N)cc1
Reactant: CCO
Agent: [Ni]
Product: CCCc1c(C(=O)NC2CC2)nnn1-c1ccc(C(N)=O)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 24 %

Procedure:
To a solution of 1-(4-cyanophenyl)-N-cyclopropyl-5-propyl-1H-1,2,3-triazole-4-carboxamide (0.43 g) obtained in Example 64b) in ethanol (15 ml) was added Raney-nickel (0.09 g), and the mixture was stirred at room temperature for 14 hr under a hydrogen atmosphere. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column (ethyl acetate/hexane=1/1 to ethyl acetate) to give the title compound as a pale-yellow powder (0.11 g, 24%).
Reaction SMILES: [CH2:1]([C:3]1([CH2:7][OH:8])[CH2:6][O:5][CH2:4]1)[CH3:2].C(N(CC)CC)C.[CH3:16][S:17](Cl)(=[O:19])=[O:18].C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[CH2:1]([C:3]1([CH2:7][O:8][S:17]([CH3:16])(=[O:19])=[O:18])[CH2:6][O:5][CH2:4]1)[CH3:2]
Reactant: CCC1(CO)COC1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCC1(COS(C)(=O)=O)COC1
Yield: 100 %

Procedure:
After adding 3-ethyl-3-hydroxymethyloxetane (465 g (4.0 mol)), triethylamine (486 g (4.8 mol)) and toluene (1,840 ml) to a glass flask having an inner volume of 5,000 ml equipped with a stirrer, a thermometer and a dropping funnel, while keeping the liquid temperature at 5-10° C., methanesulfonyl chloride (504 g (4.4 mol)) was gradually added to react at the same temperature for 3 hours and at room temperature for 3 hours with stirring. After the completion of the reaction, an aqueous saturated sodium bicarbonate solution (930 ml) was added to the reaction solution and a liquid separation was performed. Subsequently an aqueous layer was extracted with toluene (930 ml), an extract was combined with a previously extracted organic layer, and the combined liquid was washed with water (465 ml). A resultant organic layer was concentrated under reduced pressure to give, as a brown liquid, 3-ethyl-3-methanesulfonyloxymethyloxetane (777 g) having a purity of 95% (a value measured by 1H-NMR) (an isolated yield based on 3-ethyl-3-hydroxymethyloxetane: 95%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.[H-].[Na+].[CH3:12][O:13][CH2:14]Br.O>O1CCCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH2:12][O:13][CH3:14])[CH:4]=1
Reactant: COCBr
Reactant: COc1cccc(O)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COCOc1cccc(OC)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.8 %

Procedure:
To a solution of 3-(methyloxy)phenol (10.38 g, 84 mmol) in tetrahydrofurane (100 ml, SCRC) was added NaH (60% wt., 1.824 g, 76 mmol, Aldrich) portionwise under ice-cooling. The reaction mixture was stirred at room temperature for 1 hour and bromomethyl methyl ether (9.5 g, 76 mmol, SCRC) was then added. The resulting mixture was stirred at room temperature for 2 hours and water (50 ml) was added. The reaction mixture was extracted with ethyl acetate (2 times 50 ml, SCRC) and the combined organic layers were dried over sodium sulphate, evaporated. The residue was purified by column chromatography on silica gel (EtOAc: PE=1:100) to afford the title compound (10.2 g) as a colorless liquid.
Reaction SMILES: [CH3:1][NH:2][CH3:3].CO.Cl[CH2:7][C:8]([NH:10][CH2:11][C:12]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:13]=1[C:14](=[O:39])[N:15]([CH:22]([C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[C:30]([O:36][CH2:37][CH3:38])[CH:29]=1)[CH2:23][S:24]([CH3:27])(=[O:26])=[O:25])[C:16]2=[O:21])=[O:9]>O1CCCC1>[CH3:1][N:2]([CH3:3])[CH2:7][C:8]([NH:10][CH2:11][C:12]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:13]=1[C:14](=[O:39])[N:15]([CH:22]([C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[C:30]([O:36][CH2:37][CH3:38])[CH:29]=1)[CH2:23][S:24]([CH3:27])(=[O:26])=[O:25])[C:16]2=[O:21])=[O:9]
Reactant: CCOc1cc(C(CS(C)(=O)=O)N2C(=O)c3cccc(CNC(=O)CCl)c3C2=O)ccc1OC
Reactant: CNC
Solvent: CO
Solvent: C1CCOC1
Product: CCOc1cc(C(CS(C)(=O)=O)N2C(=O)c3cccc(CNC(=O)CN(C)C)c3C2=O)ccc1OC
Temperature: 25 °C
Reaction time: 24 h
Yield: 59 %

Procedure:
Dimethylamine/methanol (2.0 M, 2.95 mL) was added to a stirred solution of 2-chloro-N-({2-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-1,3-dioxoisoindolin-4-yl}methyl)acetamide (1.0 g, 1.96 mmol) in tetrahydrofuran and the mixture was stirred at room temperature for 24 hours. The tetrahydrofuran was removed in vacuo and the residue was dissolved in methylene chloride (60 mL). The methylene chloride solution was washed with water (30 mL), brine (30 mL) and dried over magnesium sulfate. The solvent was removed in vacuo and the residue was purified by chromatography (silica gel, methylene chloride:methanol 97.5:2.5) to give 2-(dimethylamino)-N-({2-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-1,3-dioxoisoindolin-4-yl}methyl)acetamide (0.6 g, 59%). To as stirred solution of the amine in ethyl acetate (10 mL) was added 1N hydrogen chloride in ether (4 mL). The resulting suspension was filtered and washed with ether to give 2-(dimethylamino)-N-({2-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]1,3-dioxoisoindolin-4-yl}methyl)acetamide hydrochloride (0.55 g) as a white solid: mp 103-105° C.; 1H NMR (DMSO-d6) δ 10.06 (s, 1H), 9.37 (m, 1H), 7.83-7.73 (m, 3H), 7.10 (s, 1H), 6.97-6.92 (m, 2H), 5.82-5.76 (dd, J=4.1, 10.2 Hz, 1H), 4.81 (d, J=5.6 Hz, 2H), 4.38-4.32 (dd, J=10.3, 14.1 Hz, 1H), 4.19-4.12 (dd, J=4.4, 14.4 Hz, 1H), 4.05-3.08 (m, 4H), 3.73 (s, 3H0, 3.02 (s, 3H), 2.82 (s, 6H0, 1.32 (t, J=6.9 Hz, 3H); 13C NMR (DMSO-d6) δ 167.60, 167.20, 164.79, 148.88, 147.85, 137.84, 134.69, 133.36, 131.51, 129.59, 127.09, 122.14, 119.79, 112.41, 111.76, 63.84, 57.17, 55.49, 52.98, 47.29, 43.13, 41.09, 37.82, 14.67; Anal. Calcd. for C26H32N3O7SCl+0.56H2O: C, 53.23; H, 5.92; N, 7.45, S, 5.68; Cl, 6.28. Found: C, 53.22; H, 5.87; N, 7.37; S, 5.64; Cl, 6.52.
Reaction SMILES: C(OC(=O)[N:7]([C:16]1[S:17][C:18]([CH2:21][C:22]2[C:30]3[C:25](=[N:26][CH:27]=[C:28]([Cl:31])[CH:29]=3)[NH:24][CH:23]=2)=[CH:19][N:20]=1)[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[Cl:31][C:28]1[CH:29]=[C:30]2[C:22]([CH2:21][C:18]3[S:17][C:16]([NH:7][CH2:8][C:9]4[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=4)=[N:20][CH:19]=3)=[CH:23][NH:24][C:25]2=[N:26][CH:27]=1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(F)cc1)c1ncc(Cc2c[nH]c3ncc(Cl)cc23)s1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Fc1ccc(CNc2ncc(Cc3c[nH]c4ncc(Cl)cc34)s2)cc1
Reaction time: 8 h
Yield: 28.8 %

Procedure:
To the solution of crude [5-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(4-fluoro-benzyl)-carbamic acid tert-butyl ester (628, 0.186 mmol theory) in dichloromethane (5 mL) at room temperature was added trifluoroacetic acid (1 mL) and the reaction was allowed to stir overnight. The solvent was removed in vacuo and the residue taken up in ethyl acetate and then washed with saturated aqueous potassium carbonate making sure basicity was reached. The layers were separated and the aqueous layer was back-extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate and evaporated in vacuo to give the crude product which was purified by silica gel chromatography (0-10% methanol/ethyl acetate). The solvent was removed in vacuo and the material was triturated with dichloromethane to give the desired compound as an off-white solid (20 mg, 29% over 2 steps) consistent with compound structure by 1H-NMR and MS (ESI): [M+H+]+=372.9.
Reaction SMILES: [C:1]([O:9]CC)(=[O:8])[CH2:2][C:3](OCC)=O.[H-].[Na+].ClC[C:16]1[CH:17]=[N:18][O:19][C:20]=1[C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=1[F:28].Cl>O1CCCC1>[F:28][C:22]1[CH:23]=[C:24]([F:27])[CH:25]=[CH:26][C:21]=1[C:20]1[O:19][N:18]=[CH:17][C:16]=1[CH2:3][CH2:2][C:1]([OH:9])=[O:8]
Reactant: Fc1ccc(-c2oncc2CCl)c(F)c1
Reactant: CCOC(=O)CC(=O)OCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(O)CCc1cnoc1-c1ccc(F)cc1F
Reaction time: 0.17 h
Yield: 86.6 %

Procedure:
To a solution of diethyl malonate (3.38 g) in tetrahydrofuran (40 ml) was gradually added sodium hydride (60%, oil, 770 mg) at 0° C. The mixture was stirred for 10 min and a solution of 4-chloromethyl-5-(2,4-difluorophenyl)isoxazole (2.20 g) in tetrahydrofuran (40 ml) was added dropwise at 0° C. The mixture was stirred at room temperature for 15 hr. The reaction mixture was acidified by pouring into 2N hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was concentrated, and the residue was dissolved in a mixture of 6N hydrochloric acid (40 ml) and acetic acid (60 ml) and heated under reflux for 8 hr. The reaction mixture was concentrated, and water was added to the residue. The obtained colorless crystals were filtrated, dried and recrystallized from ethyl acetate-hexane to give a colorless prism (2.10 g, yield 87%) of 3-[5-(2,4-difluorophenyl)-4-isoxazolyl]propionic acid. melting point: 125–126° C.
Reaction SMILES: Cl[C:2]1[C:11]([CH3:13])([CH3:12])[C:10]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([OH:14])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[C:21]([NH:29]C1CCNCC1)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>O1CCOCC1.C(N(CC)CC)C>[OH:14][C:10]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]([N:3]2[CH2:4][CH2:9][CH:10]([C:27]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:21]([NH2:29])=[O:28])[CH2:11][CH2:2]2)[C:11]1([CH3:13])[CH3:12]
Reactant: O=C(NC1CCNCC1)c1ccccc1
Reactant: CC1(C)C(Cl)=Nc2ccccc2C1(O)c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CC1(C)C(N2CCC(c3ccccc3C(N)=O)CC2)=Nc2ccccc2C1(O)c1ccccc1
Temperature: 80 °C

Procedure:
To a solution of 2-chloro-3,4-dihydro-3,3-dimethyl-4-phenylquinolin-4-ol (1.0g., 0.0035 mole) in dry dioxan (15 ml.) and triethylamine (1 ml.) was added 4-benzamidopiperidine (0.67 g., 0.0035 mole). After heating at 80° C for 41/2 hours, the reaction mixture was cooled, a small amount of solid was filtered off and the filtrate evaporated down to a residue. Trituration with hexane yielded the title compound as the crude free base (m.p. 78° - 81° C). The hydrobromide (1.05g., m.p. 166° - 168° C) was obtained as the monohydrate on crystallisation from isopropyl alcohol. [Found: C, 62.75; H, 6.2; N, 7.3% C29H31N3O2H2O HBr requires: C, 63.0; H, 6.2; N, 7.6%].
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4]([OH:9])[N:3]=1.Cl[C:11]([O:13][CH:14]([CH3:16])[CH3:15])=[O:12]>>[NH2:1][C:2]1[C:7]([F:8])=[CH:6][N:5]([C:11]([O:13][CH:14]([CH3:16])[CH3:15])=[O:12])[C:4](=[O:9])[N:3]=1
Reactant: CC(C)OC(=O)Cl
Reactant: Nc1nc(O)ncc1F
Product: CC(C)OC(=O)n1cc(F)c(N)nc1=O
Yield: 55 %

Procedure:
Using the procedure of Example 2, 4-amino-5-fluoro-pyrimidin-2-ol (0.25 g, 1.9 mmol), BSA (1.41 mL, 5.8 mmol) and isopropyl chloroformate (1 M solution in toluene; 2.9 mL, 2.9 mmol) were reacted, and the resulting material was purified via reverse phase chromatography (gradient, CH3CN/H2O) to give isopropyl 4-amino-5-fluoro-2-oxopyrimidine-1(2H)-carboxylate (0.225 g, 55%) as a white solid: mp 217-219° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.28 (s, 1H), 8.02-7.99 (m, 2H), 4.97 (septet, J=6.26 Hz, 1H), 1.28 (d, J=6.26 Hz, 6H); ESIMS m/z 216 ([M+H]+).
Reaction SMILES: Br[C:2]1[C:15]([O:16][CH3:17])=[CH:14][C:5]2[S:6][CH:7]=[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:4]=2[CH:3]=1.[F:18][C:19]([F:24])([F:23])C([O-])=O.[K+]>CN(C)C=O.C1(C)C=CC=CC=1.[Cu]I>[F:18][C:19]([F:24])([F:23])[C:2]1[C:15]([O:16][CH3:17])=[CH:14][C:5]2[S:6][CH:7]=[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:4]=2[CH:3]=1
Reactant: CCOC(=O)c1csc2cc(OC)c(Br)cc12
Reactant: O=C([O-])C(F)(F)F
Agent: [Cu]I
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CCOC(=O)c1csc2cc(OC)c(C(F)(F)F)cc12
Yield: 54.8 %

Procedure:
Ethyl-5-bromo-6-methoxybenzo[b]thiophene-3-carboxylate (D4) (0.81 g, 3 mmoles) in dry dimethylformamide (20 ml) and toluene (10 ml) was treated with potassium trifluoroacetate (0.78 g, 6 mmoles) and copper (I) iodide (0.98 g, 6 mmoles). The mixture was heated under reflux for 1 hr using a Dean-Stark trap to collect the toluene. The mixture was cooled and poured into water (150 ml) and extracted with diethyl ether. The resulting emulsion was filtered through kieselguhr. The combined organic extracts were washed several times with water then dried (Na2SO4). Flash chromatography on TLC silica gel eluting with dichloromethane/60-80 petrol ether 1:1 gave the title compound (D6) (0.5 g, 64%)