Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][O:5][C:4](=[O:7])[N:3]1[C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=1.Cl.[CH:18]1([C:21]2[CH:22]=[C:23]([CH3:33])[C:24]([N:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)=[N:25][CH:26]=2)[CH2:20][CH2:19]1>>[CH:18]1([C:21]2[CH:22]=[C:23]([CH3:33])[C:24]([N:27]3[CH2:28][CH2:29][N:30]([C:12]([C:11]4[CH:10]=[CH:9][C:8]([N:3]5[C@H:2]([CH3:1])[CH2:6][O:5][C:4]5=[O:7])=[CH:16][CH:15]=4)=[O:14])[CH2:31][CH2:32]3)=[N:25][CH:26]=2)[CH2:20][CH2:19]1
Reactant: Cc1cc(C2CC2)cnc1N1CCNCC1
Reactant: C[C@@H]1COC(=O)N1c1ccc(C(=O)O)cc1
Agent: Cl
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3C(=O)OC[C@H]3C)cc2)CC1
Yield: 70.5 %

Procedure:
By reaction and treatment in the same manner as in Example 49 and using (R)-4-(4-methyl-2-oxooxazolidin-3-yl)benzoic acid (221 mg) described in Preparation Example 37 and 1-(5-cyclopropyl-3-methylpyridin-2-yl)piperazine hydrochloride (254 mg) described in Preparation Example 49, the title compound (296 mg) was obtained.
Reaction SMILES: [C:1]([NH:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][C:10]=1[NH:19][C:20]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[O:21])([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[O:2].[N+:27]([O-])([OH:29])=[O:28]>C(O)(=O)C>[C:1]([NH:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([N+:27]([O-:29])=[O:28])=[CH:11][C:10]=1[NH:19][C:20]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[O:21])([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[O:2]
Reactant: CCOC(=O)C(=O)Nc1ccc2ccccc2c1NC(=O)C(=O)OCC
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: CCOC(=O)C(=O)Nc1cc([N+](=O)[O-])c2ccccc2c1NC(=O)C(=O)OCC
Temperature: 25 °C

Procedure:
A solution of 1,2-diethoxalylaminonaphthalene (10.8 g, 0.03 mol) in 150 ml of acetic acid was treated dropwise with nitric acid (1.24 ml, 0.03 mol, d 1.52) and stirred over night at room temperature. Then an additional amount of nitric acid (2.0 ml, d 1.52) was added dropwise and the mixture was stirred for 17 h at room temperature. The mixture was poured into 200 ml of ice/water and the resulting precipitate was isolated by filtration and washed with water, a small amount of cold ethanol and ether affording 3.3 g (27%) of pure product,
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[C:9]1([CH:15]([CH2:18][CH:19]=[CH2:20])[CH2:16][OH:17])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.O>C(Cl)(Cl)Cl>[Br:1][CH2:20][CH:19]1[CH2:18][CH:15]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:16][O:17]1
Reactant: O=C1CCC(=O)N1Br
Reactant: C=CCC(CO)c1ccccc1
Solvent: O
Solvent: ClC(Cl)Cl
Product: BrCC1CC(c2ccccc2)CO1
Temperature: 25 °C
Reaction time: 3 h
Yield: 70.2 %

Procedure:
N-Bromosuccinimide (1.78 g) is added to a stirred solution of 1.6 g of 2-phenyl-4-penten-1-ol in 15 ml of chloroform at room temperature. The resulting mixture is stirred at room temperature for 3 hours. The reaction mixture is then poured into 10 ml of water. The chloroform layer is separated and dried over magnesium sulfate, and the solvent is distilled off under reduced pressure. The residue is purified by column chromatography on silica gel with chloroform eluant to give 1.67 g of 2-(bromomethyl)-4-phenyltetrahydrofuran as colorless oil.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[SH:7][CH2:8][CH2:9][OH:10].[CH3:11][C:12]1[CH:13]=[C:14]([C:29]2[S:33][C:32]([N:34]3[CH2:40][CH2:39][CH2:38][NH:37][C:36](=[O:41])[CH2:35]3)=[N:31][CH:30]=2)[CH:15]=[C:16]([NH:18][C:19]2[N:24]=[C:23](S(C)(=O)=O)[CH:22]=[CH:21][N:20]=2)[CH:17]=1>CN(C=O)C.C(OCC)(=O)C>[OH:10][CH2:9][CH2:8][S:7][C:21]1[CH:22]=[CH:23][N:24]=[C:19]([NH:18][C:16]2[CH:15]=[C:14]([C:29]3[S:33][C:32]([N:34]4[CH2:40][CH2:39][CH2:38][NH:37][C:36](=[O:41])[CH2:35]4)=[N:31][CH:30]=3)[CH:13]=[C:12]([CH3:11])[CH:17]=2)[N:20]=1
Reactant: OCCS
Reactant: Cc1cc(Nc2nccc(S(C)(=O)=O)n2)cc(-c2cnc(N3CCCNC(=O)C3)s2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cc(Nc2nccc(SCCO)n2)cc(-c2cnc(N3CCCNC(=O)C3)s2)c1
Reaction time: 0.25 h
Yield: 27.7 %

Procedure:
Potassium carbonate (9.95 mg, 0.072 mmol) was added to a solution of 2-mercaptoethanol (18.34 μL, 0.262 mmol) stirring in DMF (327 μL) at room temperature in an oven-dried vial. Stirred for 15 minutes, then added 4-[5-(3-methyl-5-{[4-(methylsulfonyl)-2-pyrimidinyl]amino}phenyl)-1,3-thiazol-2-yl]-1,4-diazepan-2-one (30 mg, 0.065 mmol). Stirred at room temperature for 30 minutes, diluted with ethyl acetate (10 mL), and washed with 1:1 water:brine (10 mL). The organic extracts were dried (Na2SO4), filtered, and concentrated in vacuo. Purified by CombiFlash (100:0 to 0:20 dichloromethane:methanol) to afford 4-{5-[3-({4-[(2-hydroxyethyl)sulfanyl]pyrimidin-2-yl}amino)-5-methylphenyl]-1,3-thiazol-2-yl}-1,4-diazepan-2-one (8.4 mg, 0.018 mmol, 28.1% yield) as a yellow solid. MS APCI: [M+H]+ m/z 457.1. 1H NMR (500 MHz, DMSO) δ 9.52 (s, 1H), 8.14 (d, J=5.3 Hz, 1H), 7.58 (d, J=12.2 Hz, 2H), 7.47 (d, J=8.4 Hz, 2H), 6.92 (s, 1H), 6.75 (d, J=5.4 Hz, 1H), 4.97 (t, J=5.4 Hz, 1H), 4.16 (s, 2H), 3.79 (s, 2H), 3.64 (dd, J=6.3 Hz, 11.9 Hz, 2H), 3.29 (s, 1H), 3.21 (s, 2H), 3.15 (d, J=5.2 Hz, 1H), 2.27 (s, 3H), 1.78 (s, 2H). rhSYK activity=+++.
Reaction SMILES: [C:1]1([OH:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[Br:12][CH2:13][CH2:14][CH2:15]O.C(OC(N=NC(OC(C)(C)C)=O)=O)(C)(C)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[Br:12][CH2:13][CH2:14][CH2:15][O:11][C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: Oc1cccc2ccccc12
Reactant: OCCCBr
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: BrCCCOc1cccc2ccccc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 1-naphthol (3.45 g), 3-bromopropanol (1.75 mL), di-t-butyl-azo-dicarboxylate (5.52 g) and triphenylphosphine (6.28 g) in THF (30 mL) was stirred at room temperature for 16 hours and concentrated. The concentrate was diluted with ethyl acetate, washed with water and brine and dried (MgSO4), filtered, and concentrated. The concentrate was purified by silica gel chromatography with 0-7% ethyl acetate/hexane.
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=3)=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:3]1.Cl[CH2:37][C:38]1[CH:39]=[CH:40][C:41]2[O:46][CH2:45][C:44](=[O:47])[N:43]([CH2:48][CH2:49][CH2:50][O:51][CH3:52])[C:42]=2[CH:53]=1>>[CH3:52][O:51][CH2:50][CH2:49][CH2:48][N:43]1[C:42]2[CH:53]=[C:38]([CH2:37][O:1][CH:2]3[CH:7]([C:8]4[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][C:19]5[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:26])([F:28])[F:27])[CH:20]=5)=[CH:10][CH:9]=4)[CH2:6][CH2:5][N:4]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:3]3)[CH:39]=[CH:40][C:41]=2[O:46][CH2:45][C:44]1=[O:47]
Reactant: COCCCN1C(=O)COc2ccc(CCl)cc21
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCCOc3cccc(C(F)(F)F)c3)cc2)C(O)C1
Product: COCCCN1C(=O)COc2ccc(COC3CN(C(=O)OC(C)(C)C)CCC3c3ccc(OCCCOc4cccc(C(F)(F)F)c4)cc3)cc21

Procedure:
Analogously to Method D, 0.560 g of tert-butyl 3-hydroxy-4-{4-[3-(3-trifluoromethylphenoxy)propoxy]phenyl}piperidine-1-carboxylate and 0.339 g of 6-chloromethyl-4-(3-methoxypropyl)-4H-benzo[1,4]oxazin-3-one (Example 2a) are reacted. The title compound is obtained as a yellowish oil. Rf=0.30 (1:1 EtOAc-heptane); Rt=6.15.
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][NH:15][C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17])(=O)=O.[N-:26]=[N+:27]=[N-:28].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C>[N:26]([CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][NH:15][C:16](=[O:17])[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[N+:27]=[N-:28]
Reactant: CS(=O)(=O)OCCc1ccccc1CNC(=O)OCc1ccccc1
Reactant: [N-]=[N+]=[N-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCCc1ccccc1CNC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1.15 g (3.16 mmol) of 2-[2-({[(benzyloxy)carbonyl]amino}methyl)phenyl]ethyl methanesulfonate in 8.0 mL of DMF was added 0.411 g (6.33 mmol) of sodium azide. After stirring at room temperature overnight, an additional 0.205 g (3.15 mmol) of sodium azide was added and the reaction warmed to 40° C. for 4 h. The reaction was cooled to room temperature, treated with saturated sodium carbonate (aq) and extracted with ethyl acetate (3×). The organic extracts were combined, washed with water (1×) and brine (1×), dried over sodium sulfate and concentrated to dryness in vacuo to give 1.2 g of a crude oil. Flash chromatography on silica gel (20% ethyl acetate in hexane) gave benzyl 2-(2-azidoethyl)benzylcarbamate as a colorless oil: 1H NMR (CDCl3, 400 MHz): δ7.39-7.20 (m, 9H), 5.14 (s, 2H), 5.05 (br s, 1H), 4.42 (d, 2H, J=5.6 Hz), 3.56-3.49 (t, 2H, J=7.0 Hz), 2.91 (t, 2H, J=7.0 Hz); MS (Electrospray): M+Na=333.1; TLC Rf=0.32 (20% ethyl acetate in hexane).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[SH:9].C(=O)([O-])[O-].[K+].[K+].Cl[C:17]1[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=1[CH:19]=[O:20]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[S:9][C:17]1[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=1[CH:19]=[O:20]
Reactant: Sc1ccc(Cl)cc1Cl
Reactant: O=Cc1ccccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1ccccc1Sc1ccc(Cl)cc1Cl
Temperature: 70 °C
Yield: 82.6 %

Procedure:
To a stirred solution of 2,4-dichlorothiophenol (2.0 g, 11.2 mmol) in 25 mL of anhydrous DMF was added potassium carbonate (3.09 g, 22.4 mmol), followed by 2-chlorobenzaldehyde (1.26 mL, 11.3 mmol). The mixture was then heated under nitrogen atmosphere at 70° C. for 5 hours. The reaction mixture was then allowed to cool to room temperature and partitioned between ether and water. The aqueous layer was extracted with ether once and the combined organic layer was washed with water and brine, dried over sodium sulfate and condensed in vacuo. The crude product was purified via silica gel flash chromatography, eluting with 5-10% ether/hexanes, to give 2.62 g (9.25 mmol, 83%) of the desired aldehyde as a colorless oil, which solidified slowly upon standing at room temperature.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)=[N:8][C:9]2[C:14]([C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[CH:13][C:12]([Cl:22])=[CH:11][CH:10]=2)=[O:5])C.[I-].[Li+]>N1C=CC=CC=1>[Cl:22][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH:23]1[CH2:24][CH2:25][CH2:26][CH2:27]1)[C:6]([C:4]([OH:5])=[O:3])=[C:15]2[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CCOC(=O)c1c(C2CCCC2)nc2ccc(Cl)cc2c1-c1ccccc1
Agent: [I-]
Agent: [Li+]
Solvent: c1ccncc1
Product: O=C(O)c1c(C2CCCC2)nc2ccc(Cl)cc2c1-c1ccccc1

Procedure:
The title compound was prepared in analogy to example 20 step D from 6-chloro-2-cyclopentyl-4-phenyl-quinoline-3-carboxylic acid ethyl ester (35 mg, 0.09 mmol) and lithium iodide in pyridine. Off-white solid (15 mg, 46%). LC-MS: 350 (M−H)−.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][C:14]([O:19][CH3:20])([O:17][CH3:18])[CH2:13][CH:12]1[C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=1[CH3:28])=O)C1C=CC=CC=1>C(O)C.[C].[Pd]>[F:27][C:24]1[CH:25]=[CH:26][C:21]([CH:12]2[CH2:13][C:14]([O:19][CH3:20])([O:17][CH3:18])[CH2:15][CH2:16][NH:11]2)=[C:22]([CH3:28])[CH:23]=1
Reactant: COC1(OC)CCN(C(=O)OCc2ccccc2)C(c2ccc(F)cc2C)C1
Agent: [Pd]
Solvent: CCO
Product: COC1(OC)CCNC(c2ccc(F)cc2C)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 85.1 %

Procedure:
In 300 ml of ethanol were added 30 g of 1-benzyloxycarbonyl-2-(4-fluoro-2-methylphenyl)-4,4-dimethoxypiperidine and 3.0 g of 10% palladium-carbon, and the mixture was stirred under hydrogen atmosphere at room temperature for 3 hours. From the reaction mixture was removed insoluble matters by filtration, and the solvent was removed by distillation under reduced pressure. To the residue was added 300 ml of ethyl acetate. Under ice-cooling 20 ml of 4M hydrochloric acid-ethyl acetate solution was slowly added dropwise. The crystals were collected by filtration and washed with ethyl acetate. After drying, the crystals were added to a mixture of dichloromethane—an aqueous sodium carbonate solution, and the mixture was stirred. After the organic layer was separated, the aqueous layer was further extracted with dichloromethane. The organic layers were combined and dried over sodium sulfate, the solvent was removed by distillation under reduced pressure, to give 16.7 g of 2-(4-fluoro-2-methylphenyl)-4,4-dimethoxypiperidine as shown in Table 125 below.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]1[CH:7]=[CH:6][NH:5][N:4]=1.[H-].[Na+].[CH2:12]([O:19][C:20](=[O:26])[CH:21](Br)[C:22](=[O:24])[CH3:23])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1COCC1.O>[CH2:12]([O:19][C:20](=[O:26])[CH:21]([N:5]1[CH:6]=[CH:7][C:3]([C:2]([F:9])([F:8])[F:1])=[N:4]1)[C:22](=[O:24])[CH3:23])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC(=O)C(Br)C(=O)OCc1ccccc1
Reactant: FC(F)(F)c1cc[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)C(C(=O)OCc1ccccc1)n1ccc(C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirring solution of 3-trifluoromethylpyrazole (0.703 g, 5.16 mmol) in THF (36.9 ml) is added NaH (0.199 g, 4.98 mmol). The reaction mixture is stirred at RT for 10 mins and then treated with 2-bromo-3-oxo-butyric acid benzyl ester (1.0 g, 3.69 mmol). After stirring at 40° C. for 30 mins, the mixture is diluted with water (50 ml) and extracted with EtOAc (2×50 ml). The combined organics are washed with brine, dried over MgSO4 and concentrated in vacuo. The crude product is purified by ISCO combiflash chromatography, eluting with 0 to 100% (iso-hexane/EtOAc) on a 24 g SiO2-column to afford the title compound; MS: m/z 327.22 [M+H]+
Reaction SMILES: [S:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][NH:5][C:4]=2[CH:3]=[CH:2]1.C(N(CC)CC)C.[Cl:18][C:19]1[CH:27]=[C:26]([N+:28]([O-:30])=[O:29])[CH:25]=[CH:24][C:20]=1[C:21](Cl)=[O:22]>ClCCl>[Cl:18][C:19]1[CH:27]=[C:26]([N+:28]([O-:30])=[O:29])[CH:25]=[CH:24][C:20]=1[C:21]([N:5]1[CH2:6][CH2:7][CH2:8][CH2:9][C:10]2[S:1][CH:2]=[CH:3][C:4]1=2)=[O:22]
Reactant: c1cc2c(s1)CCCCN2
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1ccc([N+](=O)[O-])cc1Cl)N1CCCCc2sccc21
Reaction time: 0.08 h
Yield: 73.7 %

Procedure:
To a solution of 15.0 g of 5,6,7,8-tetrahydro-4H-thieno[3,2-b]azepine in 150 ml of dichloromethane cooled to 0° C. is added 27.2 ml of triethylamine. After stirring 5 minutes, a solution of 28.0 g of 2-chloro-4-nitrobenzoyl chloride in 140 ml of dichloromethane is added slowly. The solution is stirred at room temperature overnight, diluted with 450 ml of dichloromethane and the solution washed with 200 ml each of water, 2N citric acid, 1M sodium bicarbonate and brine. The organic layer is dried over N2SO4, filtered through a thin pad of hydrated magnesium silicate and the filtrate concentrated under vacuum. The residue is crystallized from ethyl acetate to give 24.3 g of off-white crystals, m.p. 131°-134° C.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH2:12]([S:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]1[N:22]=[C:23]([NH:35][NH2:36])[C:24]2[N:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][C:25]=2[N:26]=1)[CH3:13].N1C=CC=CC=1.C(=O)(O)[O-].[Na+]>C(#N)C>[CH2:12]([S:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]1[N:22]=[C:23]([NH:35][NH:36][S:7]([C:4]2[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=2)(=[O:9])=[O:8])[C:24]2[N:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][C:25]=2[N:26]=1)[CH3:13]
Reactant: CCSc1ccccc1-c1nc(NN)c2ncc(C(F)(F)F)cc2n1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CC#N
Product: CCSc1ccccc1-c1nc(NNS(=O)(=O)c2ccc(C)cc2)c2ncc(C(F)(F)F)cc2n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 44.6 %

Procedure:
152 mg of p-toluenesulfonyl chloride was added to a mixture of 246 mg of [2-(2-ethylsulfanylphenyl)-7-trifluoromethylpyrido[3,2-d]pyrimidin-4-yl]-hydrazine, 74 mg of pyridine and 5 ml of acetonitrile, under ice cooling, and the mixture was stirred at room temperature for 15 minutes. A saturated aqueous sodium bicarbonate solution was added to the reaction mixture, and the mixture was extracted with t-butyl methyl ether. The organic layer was washed with water and dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was washed with t-butyl methyl ether and n-hexane, and then dried to obtain 156 mg of 1-[2-(2-ethylsulfanylphenyl)-7-trifluoromethylpyrido[3,2-d]pyrimidin-4-yl]-2-tosylhydrazine.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4]([OH:7])(=[O:6])=[O:5].[Cl:8][C:9]1[C:10]([F:34])=[N:11][C:12](NCC(OC)=O)=[C:13]([Cl:27])[C:14]=1[O:15][C:16]1[CH:21]=[CH:20][C:19]([O:22]C)=[C:18]([CH:24]([CH3:26])[CH3:25])[CH:17]=1>>[Cl:8][C:9]1[C:10]([F:34])=[N:11][C:12]([NH:1][CH2:2][CH2:3][S:4]([OH:7])(=[O:6])=[O:5])=[C:13]([Cl:27])[C:14]=1[O:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([CH:24]([CH3:26])[CH3:25])[CH:17]=1
Reactant: NCCS(=O)(=O)O
Reactant: COC(=O)CNc1nc(F)c(Cl)c(Oc2ccc(OC)c(C(C)C)c2)c1Cl
Product: CC(C)c1cc(Oc2c(Cl)c(F)nc(NCCS(=O)(=O)O)c2Cl)ccc1O

Procedure:
By use of 2-aminoethylsulfonic acid in place of glycine methyl ester for the preparation of Compound 1e followed by deprotection as described for example 2.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7][NH2:8])([O-:3])=[O:2].[Cl:12][C:13]1[N:14]=[C:15](Cl)[C:16]2[CH:21]=[C:20]([Cl:22])[S:19][C:17]=2[N:18]=1>>[Cl:12][C:13]1[N:14]=[C:15]([NH:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[C:16]2[CH:21]=[C:20]([Cl:22])[S:19][C:17]=2[N:18]=1
Reactant: NCc1cccc([N+](=O)[O-])c1
Reactant: Clc1nc(Cl)c2cc(Cl)sc2n1
Product: O=[N+]([O-])c1cccc(CNc2nc(Cl)nc3sc(Cl)cc23)c1

Procedure:
Following the procedure of Example 1, the reaction of 3-nitrobenzylamine with 2,4,6-trichloro-thieno-[2,3-d]-pyrimidine yields 2,6-dichloro-4-(3-nitrobenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:12][C:13]1[CH:14]=[N:15][N:16]([CH3:18])[CH:17]=1>N1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:12][C:13]2[CH:14]=[N:15][N:16]([CH3:18])[CH:17]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Cn1cc(N)cn1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Solvent: c1ccncc1
Product: Cn1cc(NS(=O)(=O)c2ccc(Br)cc2)cn1
Yield: 87 %

Procedure:
Prepared from 4-bromobenzenesulfonyl chloride (m396 g, 1.55 mmol) and 4-amino-1-methyl-1H-pyrazole (206 mg, 1.54 mmol) in pyridine (3 ml) according to the method of intermediate 1, to give the title compound as a white solid (424 mg, 1.34 mmol, 87%). δH (D-6 DMSO, 300K) 9.80 (1H, s), 7.79 (2H, d J 8.7 Hz), 7.61 (2H, d J 8.7 Hz), 7.48 (1H, s), 7.05 (1H, s), 3.71 (3H, s). m/z (ES+, 70V) 318.0 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([O:14][C:15]([CH3:20])([CH3:19])[C:16]([OH:18])=[O:17])=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=1.[CH3:21][C:22]1[O:26][C:25]([C:27]2[CH:32]=[CH:31][C:30]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[CH:29][CH:28]=2)=[N:24][C:23]=1[CH2:39][CH2:40]OS(C1C=CC(C)=CC=1)(=O)=O>CCO>[C:30]1([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:31]=[CH:32][C:27]([C:25]2[O:26][C:22]([CH3:21])=[C:23]([CH2:39][CH2:40][O:1][C:2]3[CH:3]=[CH:4][C:5]([O:14][C:15]([CH3:20])([CH3:19])[C:16]([OH:18])=[O:17])=[C:6]([C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=4)[CH:7]=3)[N:24]=2)=[CH:28][CH:29]=1
Reactant: CC(C)(Oc1ccc(O)cc1-c1ccccc1)C(=O)O
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3ccc(-c4ccccc4)cc3)oc2C)cc1
Solvent: CCO
Product: Cc1oc(-c2ccc(-c3ccccc3)cc2)nc1CCOc1ccc(OC(C)(C)C(=O)O)c(-c2ccccc2)c1
Temperature: 67.5 °C

Procedure:
A mixture of 2-(5-hydroxy-biphenyl-2-yloxy)-2-methyl-propionic acid (80 mg, 0.26 mmol), toluene-4-sulfonic acid 2-(5-methyl-2-biphenyl-4-yl-oxazol-4-yl)ethyl ester (0.22 mmol) (see Ex. 1, part F), and 1,5,7-triazobicyclo[4.4.0]dec-5-ene bound to polystyrene (200 mg, 2.6 mmol/g resin, Fluka) was diluted with absolute EtOH (2 mL) and was heated at 65-70° C. for 20 h. The warm mixture was filtered through a cotton plug, and the resin was washed with EtOH (2 mL). The combined filtrates were treated with aqueous 5N NaOH (0.3 mL), heated at 55° C. for 1.5 h, cooled to ambient temperature, and concentrated in vacuo. The residue was treated with ice water (1 mL) and acidified with 5N aqueous HCl (0.5 mL). The mixture with CH2Cl2 (1 mL) was transferred to a ChemElute cartridge (3 g) and eluted with CH2Cl2. The eluent was concentrated to crude product which was purified by mass guided HPLC to afford a white foam. 1H NMR (400 MHz, CDCl3) δ 1.26 (s, 6H), 2.44 (s, 3H), 3.10 (t, 2H, J=5.9 Hz), 4.28 (t, 2H, J=6.1 Hz), 6.81 (dd, 1H, J=2.9, 8.8 Hz), 6.86 (d, 1H, J=2.9 Hz), 7.01 (d, 1H, J=8.8 Hz), 7.30-7.48 (m, 8H), 7.63 (d, 2H, J=7.3 Hz), 7.70 (d, 2H, J=8.3 Hz), 8.11 (d, 2H, J=8.3 Hz); MS (ES) m/e [M−1].
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][C:7]([CH2:8][NH:9][C:10](=[O:12])[CH3:11])=[CH:6][CH:5]=1)([O-])=O.[H][H]>C1COCC1.[Ni]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][NH:9][C:10](=[O:12])[CH3:11])=[CH:13][CH:14]=1
Reactant: CC(=O)NCc1ccc([N+](=O)[O-])cc1
Reactant: [H][H]
Agent: [Ni]
Solvent: C1CCOC1
Product: CC(=O)NCc1ccc(N)cc1
Yield: 100 %

Procedure:
To a solution of 4.0 g (21 mmol, 1.0 eq.) of N-(4-nitrobenzyl)acetamide (I-21) in 100 mL of THF was added a catalytic amount of Raney Nickel. The mixture was stirred under 1 atm. of hydrogen at room temperature for 16 h. The mixture was filtered through Celite® and the pad was washed with 100 mL of THF. The solvent was removed in vacuo to provide 3.4 g (21 mmol, 100%) of N-(4-aminobenzyl)acetamide (I-22).
Reaction SMILES: [C:1]([O:8][CH2:9][CH3:10])(=[O:7])[C:2]([O:4]CC)=O.[C:11]([C:14]1[O:18][CH:17]=[N:16][C:15]=1[CH3:19])(=[O:13])[CH3:12]>[O-]CC.[Na+]>[CH2:9]([O:8][C:1](=[O:7])[C:2](=[O:4])[CH2:12][C:11](=[O:13])[C:14]1[O:18][CH:17]=[N:16][C:15]=1[CH3:19])[CH3:10]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CC(=O)c1ocnc1C
Agent: CC[O-]
Agent: [Na+]
Product: CCOC(=O)C(=O)CC(=O)c1ocnc1C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 78.4 %

Procedure:
To a sodium ethoxide solution (2.7 g of sodium and 50 ml of ethanol), a mixture of diethyl oxalate (14.48 g) and 5-acetyl-4-methyloxazole (12.4 g) was added dropwise at 0° C. The resulting mixture as stirred at room temperature for 1.5 hours, and concentrated. The residue was treated with 150 ml of water, and neutralized with 6N HCl. The resulting mixture was filtered to afford 17.5 g of 2,4-diketo-4-(4-methyloxazol-5-yl)butyric acid ethyl ester as white solids. NMR: 1.41 (t, 3H), 2.60 (s, 3H, oxazolyl methyl), 4.40 (q, 2H), 6.93 (s, 1H), 7.99 (s, 1H, 2-oxazolyl H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:14][C:13]2[C:12]([Cl:15])=[CH:11][N:10]=[CH:9][C:8]=2[C:7]=1[NH:16][C:17]1[CH:22]=[CH:21][C:20]([Si](C)(C)C)=[CH:19][C:18]=1[F:27])=[O:5])[CH3:2].[I:28]Cl.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[CH2:1]([O:3][C:4]([C:6]1[NH:14][C:13]2[C:12]([Cl:15])=[CH:11][N:10]=[CH:9][C:8]=2[C:7]=1[NH:16][C:17]1[CH:22]=[CH:21][C:20]([I:28])=[CH:19][C:18]=1[F:27])=[O:5])[CH3:2]
Reactant: ClI
Reactant: CCOC(=O)c1[nH]c2c(Cl)cncc2c1Nc1ccc([Si](C)(C)C)cc1F
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)c1[nH]c2c(Cl)cncc2c1Nc1ccc(I)cc1F
Yield: 84.1 %

Procedure:
To a solution of 7-chloro-3-(2-fluoro-4-trimethylsilanyl-phenylamino)-1H-pyrrolo[3,2-c]pyridine-2-carboxylic acid ethyl ester (0.91 g, 2.25 mmol) in dichloromethane (20 ml) at −10° C. was added iodine monochloride (4.95 ml, 4.95 mmol, 1M solution in dichloromethane) and the resultant mixture was stirred at −10° C. to 0° C. for 2 h. A saturated solution of sodium thiosulfate (25 ml) was added and the mixture was poured into saturated sodium thiosulfate (40 ml). The aqueous layer was extracted with ethyl acetate (3×35 ml) and the combined organic layers were washed with brine, dried over magnesium sulfate and concentrated in vacuo. The resultant residue was triturated in dichloromethane:cyclohexane 1:4 to afford the title compound as a yellow solid (0.87 g, 84%). LCMS (method B): RT=3.17 min, M+H+=460.