Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:22]=[CH:21][C:8]2[N:9]=[C:10]([S:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[S:11][C:7]=2[CH:6]=1.[CH3:23][NH2:24]>>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][S:12][C:10]2[S:11][C:7]3[CH:6]=[C:5]([O:4][CH2:3][CH2:2][NH:24][CH3:23])[CH:22]=[CH:21][C:8]=3[N:9]=2)=[CH:15][CH:16]=1
Reactant: Clc1ccc(CSc2nc3ccc(OCCBr)cc3s2)cc1
Reactant: CN
Product: CNCCOc1ccc2nc(SCc3ccc(Cl)cc3)sc2c1
Yield: 97.5 %

Procedure:
Prepared from 6-(2-bromoethoxy)-2-(4-chlorobenzyl-mercapto)-benzothiazole and methylamine analogously to Example 3. Yield: 97.5% of theory, Melting point: 56-58° C., 1H-NMR spectrum (200 MHz, CDCl3, signals at ppm): 1.56 (s, 1H); 2.52 (s, 3H); 3.0 (t, 2H); 4.22 (t, 2H); 4.51 (s, 2H); 7.03 (dd, 1H); 7.23 (d, 1H); 7.33 (AB, 4H); 7.77 (d, 1H).
Reaction SMILES: [OH-:1].[Li+].[C:3]1([CH2:9][CH2:10][CH2:11][CH2:12][C:13]2[CH:29]=[CH:28][C:16]([O:17][CH:18]3[CH2:22][CH:21]([C:23]([O:25]C)=[O:24])[NH:20][C:19]3=[O:27])=[CH:15][CH:14]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl>O.O1CCCC1>[C:3]1([CH2:9][CH2:10][CH2:11][CH2:12][C:13]2[CH:29]=[CH:28][C:16]([O:17][CH:18]([C:19]([OH:1])=[O:27])[CH2:22][C@@H:21]([C:23]([OH:25])=[O:24])[NH2:20])=[CH:15][CH:14]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: [OH-]
Reactant: COC(=O)C1CC(Oc2ccc(CCCCc3ccccc3)cc2)C(=O)N1
Agent: Cl
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: N[C@@H](CC(Oc1ccc(CCCCc2ccccc2)cc1)C(=O)O)C(=O)O
Temperature: 60 °C
Reaction time: 4 h
Yield: 28.3 %

Procedure:
A mixture of lithium hydroxide (0.072 g) in water (0.9 ml) and tetrahydrofuran (2.9 ml) was treated with methyl 3-[4-(4-phenylbutyl)phenoxy]-2-pyrrolidone-5-carboxylate (0.370 g), and heated to 60° C. After about 4.0 hours, the reaction mixture was allowed to cool to room temperature. After approximately 2.25 hours at room temperature, the reaction mixture was treated with 5N HCl (604 ml). The resulting biphasic solution was cooled to 5° C. for approximately 18 hours. The biphasic solution was treated with water (2 ml). The resulting milky solution was sonicated resulting in crystal formation. The crystals were collected by filtration, washed with 1:1 THF:water (10 ml), THF (10 ml), and water (10 ml). The crystals were then dried overnight in at vacuum oven at 60° C. to afford the title compound (106 mg).
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH:21]3[C:26]([O:28]C)=[O:27])=[CH:13][CH:12]=2)[C:8]2[CH:30]=[CH:31][CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+]>C(O)C>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH:21]3[C:26]([OH:28])=[O:27])=[CH:13][CH:12]=2)[C:8]2[CH:30]=[CH:31][CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2ccccc2n1Cc1ccc(OCCC2CCCCC2C(=O)OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCc1nc2ccccc2n1Cc1ccc(OCCC2CCCCC2C(=O)O)cc1

Procedure:
Prepared analogously to Example 1b from 2-n-butyl-1-[4-[(1-methoxycarbonyl-2-cyclohexyl)ethoxy]benzyl]-benzimidazole and 1N sodium hydroxide solution in ethanol.
Reaction SMILES: N1C=CC=CC=1.[N+:7]([C:10]1[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=1)([O-:9])=[O:8].[CH3:20][C:21]1([CH3:28])[O:25][CH:24]([CH2:26][OH:27])[CH2:23][O:22]1.[N+]([O-])([O-])=O>ClCCl>[N+:7]([C:10]1[CH:11]=[CH:12][C:13]([S:16]([O:27][CH2:26][CH:24]2[CH2:23][O:22][C:21]([CH3:28])([CH3:20])[O:25]2)(=[O:18])=[O:17])=[CH:14][CH:15]=1)([O-:9])=[O:8]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Reactant: CC1(C)OCC(CO)O1
Agent: O=[N+]([O-])[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC1(C)OCC(COS(=O)(=O)c2ccc([N+](=O)[O-])cc2)O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.7 %

Procedure:
Pyridine (29.96 g, 0.37 mol) was added to a solution of 4-nitrobenzenesulfonyl chloride (58.7 g, 0.26 mol) in dichloromethane (300 mL) at 0° C. followed by the dropwise addition of 2,2-dimethyl-1,3-dioxolane-4-methanol (50 g, 0.37 mol). After stirring the mixture at temperature for 1 h, the reaction mixture was allowed to warm to room temperature and stirring continued for 4 h. The reaction nitrate was washed with 1N HCl (2×200 mL), dried (MgSO4), and evaporated to a solid which was recrystallized (ethyl acetate/hexane) to give 60 g (50%) of the desired product: mp 92°-94° C.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([N+:11]([O-:13])=[O:12])=[CH:4][N:3]=1.[NH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].C(N(CC)CC)C>O1CCOCC1>[N+:8]([C:7]1[C:2]([NH:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[N:3][CH:4]=[C:5]([N+:11]([O-:13])=[O:12])[CH:6]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cnc(Cl)c([N+](=O)[O-])c1
Reactant: CCOC(=O)CCCCN
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CCOC(=O)CCCCNc1ncc([N+](=O)[O-])cc1[N+](=O)[O-]
Yield: 76 %

Procedure:
A procedure similar to that of the method described in step C.1 is carried out, starting from 1.2 g (5.9 mmol) of 2-chloro-3,5-dinitropyridine, 1.03 g (7.07 mmol) of ethyl 5-aminovalerate and 0.9 g (8.84 mmol) of triethylamine in 20 ml of dioxane. This gives 1.4 g of expected product.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH:10]([NH2:12])[CH3:11])=[CH:5][CH:4]=1.C(N(CC)CC)C.[Cl:20][C:21]1[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[C:22]=1[C:23](Cl)=[O:24].[Cl-].[NH4+]>ClCCl>[Cl:20][C:21]1[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[C:22]=1[C:23]([NH:12][CH:10]([CH3:11])[CH2:9][C:6]1[CH:5]=[CH:4][C:3]([Cl:2])=[CH:8][CH:7]=1)=[O:24]
Reactant: CC(N)Cc1ccc(Cl)cc1
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(Cc1ccc(Cl)cc1)NC(=O)c1c(Cl)cccc1Cl
Reaction time: 24 h

Procedure:
100 mg of 1-(4-chlorophenyl)propan-2-amine hydrochloride (0.728 mmol) and 0.10 ml of triethylamine (0.728 mmol) are diluted in 3 ml of dichloromethane at room temperature, 152 mg of 2,6-dichlorobenzoyl chloride (0.728 mmol) are added to the reaction mixture. After 24 hours of stirring, 20 ml of DCM an 10 ml of saturated solution of ammonium chloride are added to the reaction mixture.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](I)[C:8]([F:12])=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:14]([NH:16][CH:17]1[CH2:19][CH2:18]1)=[O:15].[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:23]=1B(O)O>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:26]3[CH:27]=[C:22]([O:21][CH3:20])[CH:23]=[CH:24][C:25]=3[O:28][CH3:29])[C:8]([F:12])=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:14]([NH:16][CH:17]1[CH2:19][CH2:18]1)=[O:15]
Reactant: Nc1c(C(=O)NC2CC2)nnc2c(I)c(F)ccc12
Reactant: COc1ccc(OC)c(B(O)O)c1
Product: COc1ccc(OC)c(-c2c(F)ccc3c(N)c(C(=O)NC4CC4)nnc23)c1
Yield: 77.4 %

Procedure:
Using Method A, 4-amino-7-fluoro-8-iodo-N-cyclopropyl-cinnoline-3-carboxamide (178 mg, 0.48 mmol) and 2,5-dimethoxyphenylboronic acid (174 mg, 0.96 mmol) were reacted. After purification the title compound (142 mg, 77% yield) was obtained as a white solid. 1H NMR (500 MHz, DMSO-d6) δ 8.99 (d, J=4.8 Hz, 1H), 8.51 (a dd, J=5.5, 9.3 Hz, 1H), 7.72 (t, J=9.0 Hz, 1H), 7.06 (a d, J=9.0 Hz, 1H), 7.00 (m, 1H), 6.86 (a d, J=3.0 Hz, 1 H), 3.72 (s, 3H), 3.58 (s, 3H), 2.93 (m, 1H), 0.68 (m, 4H). MS APCI, m/z=383.
Reaction SMILES: [CH3:1][N:2]1[C:8](=[O:9])[C:7]2[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=2[N:5]2[CH:14]=[N:15][C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:4]2[CH2:3]1.N.[N+:23]([O-])([OH:25])=[O:24]>S(=O)(=O)(O)O>[CH3:1][N:2]1[C:8](=[O:9])[C:7]2[CH:10]=[C:11]([N+:23]([O-:25])=[O:24])[CH:12]=[CH:13][C:6]=2[N:5]2[CH:14]=[N:15][C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:4]2[CH2:3]1
Reactant: O=[N+]([O-])O
Reactant: CCOC(=O)c1ncn2c1CN(C)C(=O)c1ccccc1-2
Agent: N
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1ncn2c1CN(C)C(=O)c1cc([N+](=O)[O-])ccc1-2
Temperature: 25 °C

Procedure:
2.85 g of ethyl 5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate are dissolved in a mixture of 10 ml of 98 percent nitric acid and 15 ml of 98 percent sulphuric acid and heated to 120° for 2 hours. Subsequently, the mixture obtained is cooled to room temperature, poured onto ice, neutralized with about 25 percent ammonia and extracted with chloroform. The chloroform extracts are dried over magnesium sulphate and evaporated. After recrystallization of the residue from ethyl acetate, there is obtained ethyl 5,6-dihydro-5-methyl-8-nitro-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate of melting point 197°-198°.
Reaction SMILES: C1(O[C:8](=[O:21])[NH:9][C:10]2[C:11]([O:19][CH3:20])=[N:12][C:13]([CH3:18])=[C:14]([CH2:16][CH3:17])[CH:15]=2)C=CC=CC=1.[Cl:22][C:23]1[CH:24]=[C:25]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH:26]=[CH:27][CH:28]=1>>[CH2:16]([C:14]1[CH:15]=[C:10]([NH:9][C:8]([N:32]2[CH2:31][CH2:30][N:29]([C:25]3[CH:26]=[CH:27][CH:28]=[C:23]([Cl:22])[CH:24]=3)[CH2:34][CH2:33]2)=[O:21])[C:11]([O:19][CH3:20])=[N:12][C:13]=1[CH3:18])[CH3:17]
Reactant: Clc1cccc(N2CCNCC2)c1
Reactant: CCc1cc(NC(=O)Oc2ccccc2)c(OC)nc1C
Product: CCc1cc(NC(=O)N2CCN(c3cccc(Cl)c3)CC2)c(OC)nc1C
Yield: 84 %

Procedure:
Phenyl-N-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)carbamate and 1-(3-chlorophenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C([Li])CCC.CCCCCC.[C:25]([C:29]1[CH:33]=[CH:32][C:31](=[C:34]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:30]=1)([CH3:28])([CH3:27])[CH3:26].Cl>C(OCC)C>[C:25]([C:29]1[CH:33]=[CH:32][CH:31]([C:34]([C:1]2[C:13]3[CH2:12][C:11]4[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=4)[C:5]=3[CH:4]=[CH:3][CH:2]=2)([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)[CH:30]=1)([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)C1=CC(=C(c2ccccc2)c2ccccc2)C=C1
Reactant: c1ccc2c(c1)Cc1ccccc1-2
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: CC(C)(C)C1=CC(C(c2ccccc2)(c2ccccc2)c2cccc3c2Cc2ccccc2-3)C=C1
Temperature: 25 °C

Procedure:
In a 200 ml three-necked flask equipped with a magnetic stirrer chip and three-way cock thoroughly purged with nitrogen, 0.76 g of fluorene (4.57 mmol) was dissolved in 40 ml of dehydrated diethyl ether in a nitrogen atmosphere. To the solution, 3.1 ml of a n-butyl lithium/hexane solution (1.57M: 4.87 mmol) was gradually added dropwise in an ice bath and stirred at room temperature for over night. The solvent was distilled off under reduced pressure and thereby a reddish-orange solid was obtained. To the solid, a solution prepared by dissolving 2.40 g of 2-tert-butyl-6,6-diphenyl fulvene (8.38 mmol) in 150 ml of dehydrated diethyl ether was added and stirred under reflux for 7 days. The reaction mixture was added to 150 ml of a hydrochloric acid aqueous solution (2%) and then diethyl ether was added therein to separate an organic phase. The organic phase was washed with water and saturated brine. The organic phase was dried with anhydrous magnesium sulfate and the drying agent was filtered off. The solvent was distilled off under reduced pressure from the filtrate and thereby orange brown oil was obtained. The oil was re-crystallized using hexane and thereby the aimed compound was obtained in an amount of 1.03 g (2.28 mmol) as a pale yellow solid. The solid further was purified with a chromatography using 100 g of silica gel (developing solvent: n-hexane) and the developing solvent was distilled off under reduced pressure and thereby the aimed compound was obtained in an amount of 0.370 g (0.817 mmol) as a yellow solid (yield: 67%).
Reaction SMILES: [N:1]([CH2:4][CH2:5][C@@H:6]([O:12][C:13]1[CH:20]=[C:19]([Cl:21])[C:18]([F:22])=[CH:17][C:14]=1[C:15]#[N:16])[C:7]1[CH:11]=[CH:10][S:9][CH:8]=1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O.[C:43]([OH:48])(=[O:47])[C:44]([OH:46])=[O:45]>O1CCCC1>[C:43]([OH:48])(=[O:47])[C:44]([OH:46])=[O:45].[NH2:1][CH2:4][CH2:5][C@@H:6]([O:12][C:13]1[CH:20]=[C:19]([Cl:21])[C:18]([F:22])=[CH:17][C:14]=1[C:15]#[N:16])[C:7]1[CH:11]=[CH:10][S:9][CH:8]=1
Reactant: N#Cc1cc(F)c(Cl)cc1O[C@H](CCN=[N+]=[N-])c1ccsc1
Agent: O=C(O)C(=O)O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1cc(F)c(Cl)cc1O[C@H](CCN)c1ccsc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 60 %

Procedure:
The product from step (a) (529 mg, 1.57 mmol) was dissolved in anhydrous tetrahydrofuran (80 ml), triphenylphosphine (1.235 g, 4.71 mmol) added and the reaction mixture stirred for 1 h at room temperature. Water (5 ml) was added and the reaction stirred for 64 h. Water (100 ml) was added and the reaction extracted with ethyl acetate (4×70 ml). The combined organic extracts were washed with water (3×25 ml), dried (sodium sulphate) and evaporated in vacuo. The residue was chromatographed on flash silica, eluting with 5% 7N ammonia in methanol in dichloromethane, and the product dissolved in methanol and treated with one equivalent of oxalic acid. The mixture was stirred for 10 minutes then the solvent removed in vacuo and the solid residue triturated with ethyl acetate. The white solid was filtered off and dried to give the title compound (380 mg, 60%).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=[N:3]1.C(Cl)(=O)C([Cl:13])=O.CN(C=O)C>C(Cl)Cl>[CH3:1][N:2]1[C:6]([C:7]([Cl:13])=[O:9])=[CH:5][CH:4]=[N:3]1
Reactant: Cn1nccc1C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cn1nccc1C(=O)Cl
Temperature: 0 °C
Reaction time: 2 h
Yield: 97.5 %

Procedure:
A suspension of 800 mg (6.03 mmol) of 2-methyl-2H-pyrazole-3-carboxylic acid in 30 mL of DCM is placed under argon and cooled to 0° C. When the temperature is reached, 1.32 mL (15.07 mmol) of oxalyl chloride and a catalytic amount of DMF are added. The reaction mixture is stirred at room temperature for 2 hours and then evaporated to dryness and the residue is taken up in DCM and evaporated again to give 850 mg of 2-methyl-2H-pyrazole-3-carbonyl chloride, the characteristics of which are as follows:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:6]([O:7][C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:19])OCC)=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.[CH3:22][O:23][CH:24]([O:28][CH3:29])[CH2:25][NH:26][CH3:27]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([O:7][C:8]2[CH:9]=[CH:10][C:11]([NH:14][C:15]([N:26]([CH2:25][CH:24]([O:28][CH3:29])[O:23][CH3:22])[CH3:27])=[O:19])=[CH:12][CH:13]=2)=[CH:20][CH:21]=1
Reactant: CCOC(=O)Nc1ccc(Oc2ccc(OC)cc2)cc1
Reactant: CNCC(OC)OC
Solvent: Cc1ccccc1
Product: COc1ccc(Oc2ccc(NC(=O)N(C)CC(OC)OC)cc2)cc1

Procedure:
Ethyl [4-(4-methoxyphenoxy)phenyl]carbamate (0.1 mole) and toluene (100 ml) are charged into a glass reaction vessel fitted with a mechanical stirrer, thermometer and condenser. N-(2,2-dimethoxyethyl)methanamine (0.15 mole) is added to the vessel and the mixture is refluxed for 16 hours. Solvent is then removed by mild warming under reduced pressure to yield the desired product N-[4(4-methoxyphenoxy) phenyl]-N'-(2,2-dimethoxyethyl)-N'-methylurea.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH2:11])=[S:10])=[CH:4][CH:3]=1.Br[CH2:13][C:14](=O)[C:15]([O:17][CH2:18][CH3:19])=[O:16]>C(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]2[S:10][CH:13]=[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:11]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(=O)CBr
Reactant: NC(=S)Nc1ccc(F)cc1
Solvent: CCO
Product: CCOC(=O)c1csc(Nc2ccc(F)cc2)n1

Procedure:
The reaction described in Preparation 42 was repeated, but using 12 g of p-fluorophenylthiourea, 14.8 g of ethyl bromopyruvate, and 120 ml of ethanol, giving the title compound as pale yellow prisms.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[C:10](=[O:12])[CH3:11].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Cl[Si](C)(C)C.[C:28]1([CH2:34][S:35][CH:36]([C:40](O)=[O:41])[C:37](O)=[O:38])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C1COCC1>[OH:41][C:40]1[CH:11]=[C:10]([C:3]2[C:4]([CH3:9])=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=2[CH3:1])[O:12][C:37](=[O:38])[C:36]=1[S:35][CH2:34][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CC(=O)c1c(C)cc(C)cc1C
Reactant: O=C(O)C(SCc1ccccc1)C(=O)O
Agent: C[Si](C)(C)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cc(C)c(-c2cc(O)c(SCc3ccccc3)c(=O)o2)c(C)c1

Procedure:
The title compound was prepared by Method A using 2',4', 6'-trimethylacetophenone (1.86 g, 11.5 mmol), lithium bis(trimethylsilyl)amide (2.11 g, 12.65 mmol), chlorotrimethylsilane (1.60 mL, 12.65 mmol), THF (127 mL), and diethyl ester of [(phenylmethyl)thio]propanedioic acid (2.95 g, 10.4 mmol). m.p. 134-136° C.; 1H NMR (250 MHz, DMSO-d6) δ 2.11 (s, 6 H), 2.26 (s, 3 H), 3.98 (s, 2 H), 6.03 (s, 1 H), 6.96 (s, 2 H), 7.25 (m, 5 H), 11.85 (bs, 1 H).
Reaction SMILES: [OH:1][CH:2]([CH2:20][OH:21])[CH2:3][NH:4][C:5]([C:7]1[CH:12]=[C:11]([CH:13]([OH:16])[CH2:14][OH:15])[CH:10]=[C:9]([N+:17]([O-])=O)[CH:8]=1)=[O:6]>CO.O.[Pd]>[OH:1][CH:2]([CH2:20][OH:21])[CH2:3][NH:4][C:5]([C:7]1[CH:8]=[C:9]([CH:10]=[C:11]([CH:13]([OH:16])[CH2:14][OH:15])[CH:12]=1)[NH2:17])=[O:6]
Reactant: O=C(NCC(O)CO)c1cc(C(O)CO)cc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Solvent: O
Product: Nc1cc(C(=O)NCC(O)CO)cc(C(O)CO)c1

Procedure:
1-(2,3-Dihydroxypropylaminocarbonyl)-3-nitro-5-(1,2-dihydroxyethyl)benzene (0.40 g, 1.32 mmol) was dissolved in a mixture of methanol (40 ml) and water (20 ml). The solution was hydrogenated at 60 psi using a Pd/C catalyst (10%, 50 mg). The solution was filtered through celite and the solvents were removed by evaporation. The product was >95% pure by HPLC analysis and was used without further purification.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:5]1[C:9]([NH:10][CH2:11][CH2:12][NH:13][S:14]([CH3:17])(=[O:16])=[O:15])=[N:8][O:7][N:6]=1)[NH2:4].[F:18][C:19]([F:29])([F:28])[C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][C:26]=1[F:27])N>>[F:27][C:26]1[CH:25]=[CH:24][C:22]([NH:4][C:3]([C:5]2[C:9]([NH:10][CH2:11][CH2:12][NH:13][S:14]([CH3:17])(=[O:16])=[O:15])=[N:8][O:7][N:6]=2)=[N:2][OH:1])=[CH:21][C:20]=1[C:19]([F:18])([F:28])[F:29]
Reactant: CS(=O)(=O)NCCNc1nonc1C(N)=NO
Reactant: Nc1ccc(F)c(C(F)(F)F)c1
Product: CS(=O)(=O)NCCNc1nonc1C(=NO)Nc1ccc(F)c(C(F)(F)F)c1

Procedure:
The title compound was prepared according to the procedure of Example 17 step E, using N′-hydroxy-4-({2-[(methylsulfonyl)amino]ethyl}amino)-1,2,5-oxadiazole-3-carboximidamide and 3-trifluoromethyl-4-fluoroaniline [Aldrich, product #217778] as the starting materials. LCMS for C13H15F4N6O4S (M+H)+: m/z=427.0. 1H NMR (400 MHz, DMSO-d6): δ 11.60 (s, 1H), 9.07 (s, 1H), 7.30 (t, J=10.1 Hz, 1H), 7.18 (t, J=6.0 Hz, 1H), 7.13 (dd, J=6.0, 2.7 Hz, 1H), 7.03 (m, 1H), 6.27 (t, J=6.3 Hz, 1H), 3.32 (m, 2H), 3.13 (q, J=6.0 Hz, 2H), 2.89 (s, 3H).
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[N:5][C:6]([C@@H:9]([NH2:11])[CH3:10])=[N:7][CH:8]=1.Cl[C:13]1[N:18]=[C:17]([NH:19][C:20]2[CH:24]=[C:23]([O:25][CH3:26])[NH:22][N:21]=2)[CH:16]=[C:15]([Cl:27])[N:14]=1.CCN(C(C)C)C(C)C>CCCCO>[Cl:27][C:15]1[N:14]=[C:13]([NH:11][C@H:9]([C:6]2[N:7]=[CH:8][C:3]([F:2])=[CH:4][N:5]=2)[CH3:10])[N:18]=[C:17]([NH:19][C:20]2[CH:24]=[C:23]([O:25][CH3:26])[NH:22][N:21]=2)[CH:16]=1
Reactant: COc1cc(Nc2cc(Cl)nc(Cl)n2)n[nH]1
Reactant: C[C@H](N)c1ncc(F)cn1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: COc1cc(Nc2cc(Cl)nc(N[C@@H](C)c3ncc(F)cn3)n2)n[nH]1
Temperature: 105 °C
Yield: 52.3 %

Procedure:
A mixture of (S)-1-(5-fluoropyrimidin-2-yl)ethanamine hydrochloride (Method 7, 512 mg), 2,6-dichloro-N-(5-methoxy-1H-pyrazol-3-yl)pyrimidin-4-amine (Method 42, 682 mg) and DIPEA (1.16 ml) in n-BuOH (13 ml) was heated at 105° C. over night. The solvent was removed under reduced pressure and the residue was purified by Gilson (10-50% MeCN/H2O, 15 minutes) to give the titled compound as solid (500 mg). 1H NMR δ 8.92 (s, 2H) 5.95 (s, 1H) 5.18 (s, 1H) 3.77 (s, 3H) 1.49 (d, 3H); m/z 366.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C:14]([CH3:19])([CH3:18])[C:15]([OH:17])=O)[N:5]=[C:4]([CH3:20])[C:3]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22].Cl.[CH2:27]([NH2:29])[CH3:28]>>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C:14]([CH3:19])([CH3:18])[C:15]([NH:29][CH2:27][CH3:28])=[O:17])[N:5]=[C:4]([CH3:20])[C:3]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: CCOC(=O)c1c(C)nc2cccc(OCC(C)(C)C(=O)O)c2c1N
Reactant: CCN
Agent: Cl
Product: CCNC(=O)C(C)(C)COc1cccc2nc(C)c(C(=O)OCC)c(N)c12

Procedure:
Prepared as in Example Da from 3-((4-amino-3-(ethoxycarbonyl)-2-methylquinolin-5-yl)oxy)-2,2-dimethylpropanoic acid (Example Eb) and ethylamine hydrochloride as an off-white solid (61%). MS 374 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:13]=[C:14]([N+:16]([O-:18])=[O:17])[CH:15]=1)[O:5][CH:6]1[CH2:10][NH:9][CH:8]([CH2:11][OH:12])[CH2:7]1.[C:19](N1C=CN=C1)(N1C=CN=C1)=[O:20]>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([CH:13]=[C:14]([N+:16]([O-:18])=[O:17])[CH:15]=1)[O:5][CH:6]1[CH2:10][N:9]2[C:19](=[O:20])[O:12][CH2:11][CH:8]2[CH2:7]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=[N+]([O-])c1cc(F)cc(OC2CNC(CO)C2)c1
Solvent: ClCCl
Product: O=C1OCC2CC(Oc3cc(F)cc([N+](=O)[O-])c3)CN12
Yield: 128.1 %

Procedure:
To a solution of 1.29 g of [4-(3-fluoro-5-nitro-phenoxy)-pyrrolidin-2-yl]-methanol in 20 mL of anhydrous dichloromethane was added in one portion 0.82 g of 1,1′-carbonyldiimidazole and the resultant mixture stirred at room temperature under N2 for 3 hours. The reaction mixture was diluted with 30 mL of dichloromethane and washed with H2O (2×25 mL) and brine (25 mL). The organic layer was dried over Na2SO4, filtered, and concentrated to give 1.82 g of a light yellow solid. Purification over silica gel resulted in 0.825 g of 6-(3-Fluoro-5-nitro-phenoxy)-tetrahydro-pyrrolo[1,2-c]oxazol-3-one as a white solid.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6](CN)=[C:5]([N:11]2[CH:15]=[N:14][CH:13]=[N:12]2)[CH:4]=1.FC1C=CC([C:21]#[N:22])=C(N2C=NC=N2)C=1.Cl>C(O)C.[Pd]>[N:11]1([C:5]2[CH:6]=[CH:7][C:8]([C:21]#[N:22])=[C:3]([F:2])[CH:4]=2)[CH:15]=[N:14][CH:13]=[N:12]1
Reactant: N#Cc1ccc(F)cc1-n1cncn1
Reactant: NCc1ccc(F)cc1-n1cncn1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: N#Cc1ccc(-n2cncn2)cc1F
Yield: 99 %

Procedure:
(4-Fluoro-2-(1H-1,2,4-triazol-1-yl)phenyl)methanamine hydrochloride). Intermediate 67, 4-fluoro-2-(1H-1,2,4-triazol-1-yl)benzonitrile, (2.46 g, 13.13 mmol) was dissolved in hot ethanol (150 mL). To this was added 1N HCl (15 mL) followed by 10% Pd—C (200 mg). The mixture was treated with H2 at 55 psi for 4 h in a Parr shaker then filtered over Celite and the solvent removed under reduced pressure. The resulting residue was partitioned between ethyl acetate and water. The aqueous phase was separated and lyophilized to afford the title compound as a white powder (2.96 g, 99% yield). 1H NMR (500 MHz, CD3OD) δ ppm: 9.51 (1H, s), 8.63 (1H, s), 7.85 (1H, dd, J=8.5, 5.8 Hz), 7.68 (1H, dd, J=8.8, 2.4 Hz), 7.49 (1H, td, J=8.3, 2.4 Hz), 4.20 (2H, s). LCMS (M+H) calcd for C9H10N4F: 193.08. found: 193.16.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=2)=[C:10]([CH2:14]O)[CH:11]=[CH:12][CH:13]=1.S(Cl)([Cl:25])=O>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=2)=[C:10]([CH2:14][Cl:25])[CH:11]=[CH:12][CH:13]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1cccc(-c2ccccc2F)c1-c1cccc(F)c1
Product: Fc1cccc(-c2c(CCl)cccc2-c2ccccc2F)c1
Temperature: 0 °C

Procedure:
To a cooled (0° C.) flask containing [(2-fluorophenyl)(3-fluorophenyl)phenyl]carbinol (20 g, 67.5 mmol) (obtained in example 1) was slowly added thionyl chloride (12.82 g, 108 mmol) with vigorous stirring. Once the reaction had been initiated (gas evolution), the rest of the thionyl chloride was added at once and the reaction mixture heated to reflux for 4 h. Volatiles were removed in vacuo and the remaining traces of thionyl chloride were removed by azeotropic evaporation with toluene (2×). The resulting residue was dissolved in petroleum ether and precipitated by cooling to -20° C. The solid was filtered and dried to afford the title compound as a slightly cream-colored solid (18.1 g, 85%).