Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[CH2:13](Br)[CH:14]=[CH2:15].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:15]([O:12][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8])[CH:14]=[CH2:13]
Reactant: C=CCBr
Reactant: COC(=O)c1cc(Cl)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1ccc(Cl)cc1C(=O)OC

Procedure:
A mixture of methyl 5-chloro-2-hydroxybenzoate (2c) (45.0 g, 0.24 mol), allyl bromide (62.6 ml, 0.75 mol) and ground potassium carbonate (66.67 g, 0.48 mol) in 750 ml of dry acetone was heated under reflux for 21/2 hours. The inorganic salt was removed by filtration, and the solvent and excess allyl bromide in the filtrate was evaporated to dryness to yield compound 3c quantitatively as a white solid, mp 25°-26° C. IR (nujol) 1738 (ester) cm-1. NMR (CDCl3) δ 7.63 (d, 1H, JBC =3 Hz, HC), 7.27 (d of d, 1H, JAB =9 Hz, HB), 6.77 (d. 1H, HA), 6.30-6.47 (m, 3H, olefinic protons) and 3.87 (s, 3H, CH3).
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.[Li].[CH3:15][C:16]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[C:17]1[CH:21]=[CH:20][CH:19]=[CH:18]1.O>O1CCCC1>[CH:17]1([C:16]2[C:15]([CH:12]3[C:11]4[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=4[C:5]4[C:13]3=[CH:1][CH:2]=[CH:3][CH:4]=4)=[C:25]([CH2:24][CH3:23])[CH:26]=[CH:27][CH:22]=2)[CH2:18][CH2:19][CH:20]=[CH:21]1
Reactant: c1ccc2c(c1)Cc1ccccc1-2
Reactant: CC(=C1C=CC=C1)c1ccccc1
Agent: [Li]
Solvent: C1CCOC1
Solvent: O
Product: CCc1cccc(C2C=CCC2)c1C1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.7 %

Procedure:
A solution of 67.8 mmol of lithiumfluorene in 50 cm3 of tetrahydrofuran is added to a solution of 11.4 g (67.8 mmol) of 6-methyl-6-phenyl-fulvene in 40 cm3 of tetrahydrofuran at room temperature. After the mixture had been stirred at room temperature for 2 hours, 60 cm3 of water were added. The substance which precipitated during this procedure was filtered off with suction, washed with diethyl ether and dried under an oil pump vacuum. 19.1 g (84.2%) of 2,2-cyclopentadienyl(9-fluorenyl)-ethylbenzene were obtained (correct elemental analyses; 1H-NMR spectra).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4]1[C:5](=[O:19])[NH:6][C:7](=[O:18])[N:8]([CH:17]=1)[C@@H:9]1[O:16][C@H:13]([CH2:14]O)[C@@H:11]([OH:12])[CH2:10]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N-:39]=[N+:40]=[N-:41].[Li+].C(Br)(Br)(Br)Br>CN(C)C=O.CO>[N:39]([CH2:14][C@H:13]1[O:16][C@@H:9]([N:8]2[CH:17]=[C:4]([CH2:3][CH2:2][Cl:1])[C:5](=[O:19])[NH:6][C:7]2=[O:18])[CH2:10][C@@H:11]1[OH:12])=[N+:40]=[N-:41]
Reactant: [N-]=[N+]=[N-]
Reactant: O=c1[nH]c(=O)n([C@H]2C[C@H](O)[C@@H](CO)O2)cc1CCCl
Agent: BrC(Br)(Br)Br
Agent: [Li+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: CN(C)C=O
Product: [N-]=[N+]=NC[C@H]1O[C@@H](n2cc(CCCl)c(=O)[nH]c2=O)C[C@@H]1O
Temperature: 25 °C
Reaction time: 17 h
Yield: 31.6 %

Procedure:
1.4 g of 5-(2-chloroethyl)-2'-deoxyuridine and 1.3 g of triphenylphosphine were dissolved in 20 ml of dimethylformamide and stirred while 1.2 g of lithium azide were added to give a solution within 5 minutes at room temperature. 1.7 g of carbon tetrabromide were added portionwise during 5 minutes to give a hazy orange colored solution which was stirred at room temperature for 17 hours. 5 ml of methanol were added to give a clear solution. After 0.5 hour, the solvents were removed by evaporation under an oil pump vacuum to give a gum which was partitioned between 30 ml of ethyl acetate and 20 ml of water. The white solid which formed was removed by filtration to give 0.64 g of crude product of melting point 179°-182° C. (decomposition). This crude product was stirred with methanol and then removed by filtration to give 0.48 g of pure 5'-azido-2',5'-dideoxy- 5-(2-chloroethyl)-uridine of melting point 197°-199° C. (decomposition).
Reaction SMILES: [NH2:1][C:2](=[N:38][OH:39])[CH2:3][O:4][NH:5][C:6]([CH:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:18])[N:10]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH:20]2[NH:25][S:26]([CH3:29])(=[O:28])=[O:27])[CH:9]1[C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=1[Cl:37])=[O:7].N1C=CC=CC=1.Cl[C:47](=O)[C:48]([O:50][CH3:51])=[O:49]>ClC(Cl)C>[Cl:37][C:31]1[CH:32]=[C:33]([Cl:36])[CH:34]=[CH:35][C:30]=1[CH:9]1[CH:8]([C:6]([NH:5][O:4][CH2:3][C:2]2[N:1]=[C:47]([C:48]([O:50][CH3:51])=[O:49])[O:39][N:38]=2)=[O:7])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:18])[N:10]1[CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH:20]1[NH:25][S:26]([CH3:29])(=[O:27])=[O:28]
Reactant: CS(=O)(=O)NC1CCCCC1N1C(=O)c2ccccc2C(C(=O)NOCC(N)=NO)C1c1ccc(Cl)cc1Cl
Reactant: COC(=O)C(=O)Cl
Solvent: CC(Cl)Cl
Solvent: c1ccncc1
Product: COC(=O)c1nc(CONC(=O)C2c3ccccc3C(=O)N(C3CCCCC3NS(C)(=O)=O)C2c2ccc(Cl)cc2Cl)no1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a solution of 1000 mg of (3RS,4RS)—N-[2-amino-2-(hydroxyimino)ethoxy]-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(mesyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide in 26 ml of dichloroethane was added dropwise 0.4 ml of pyridine, and then 0.23 ml of methyl chloro(oxo)acetate was added dropwise thereto under ice-cooling, followed by stirring at 0° C. for 10 minutes, at room temperature for 20 minutes, and at 80° C. for 2 hours. The reaction solution was cooled to room temperature, washed with 0.1 M hydrochloric acid and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:chloroform-methanol) to obtain 670 mg of methyl 3-{[({[(3RS,4RS)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(mesyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinolin-4-yl]carbonyl}amino)oxy]methyl}-1,2,4-oxadiazole-5-carboxylate as a white amorphous substance.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=3[N:14]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[CH:19]1[C:24]([C:25]([OH:27])=[O:26])=[CH:23][C:22]2[C:28]([O:30][C:31](=O)[C:21]=2[CH:20]=1)=[O:29]>>[CH3:9][O:8][C:7]1[CH:6]=[CH:5][C:4]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=3[N:14]=2)=[CH:3][C:2]=1[N:1]1[C:28](=[O:29])[C:22]2[C:21](=[CH:20][CH:19]=[C:24]([C:25]([OH:27])=[O:26])[CH:23]=2)[C:31]1=[O:30]
Reactant: O=C(O)c1ccc2c(c1)C(=O)OC2=O
Reactant: COc1ccc(-c2nc3ccccc3o2)cc1N
Product: COc1ccc(-c2nc3ccccc3o2)cc1N1C(=O)c2ccc(C(=O)O)cc2C1=O

Procedure:
Prepared by the method of Example 1b), from 2-(3-amino-4-methoxyphenyl)benzoxazole (55 mg, 0.23 mmol) and 1,2,4-benzenetricarboxylic anhydride (50 mg, 0.26 mmol) the title compound was obtained, 64 mg (67%). 1H NMR (DMSO) δ 8.45(dd, 1H), 8.32(m, 3H), 8.12(d, 1H), 7.78(m, 2H), 7.49(d, 1H), 7.41(m, 2H), 3.88(s, 3H). MS 413 m/z (M−H)−.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4](Cl)[N:3]=1.[F:10][C:11]1[CH:12]=[C:13]([CH:15]=[CH:16][C:17]=1[S:18][C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1)[NH2:14].[OH-].[NH4+]>O.Cl>[NH2:1][C:2]1[N:3]=[C:4]([NH:14][C:13]2[CH:15]=[CH:16][C:17]([S:18][C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)=[C:11]([F:10])[CH:12]=2)[CH:5]=[C:6]([Cl:8])[N:7]=1
Reactant: Nc1ccc(Sc2ccncc2)c(F)c1
Reactant: Nc1nc(Cl)cc(Cl)n1
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: Nc1nc(Cl)cc(Nc2ccc(Sc3ccncc3)c(F)c2)n1
Temperature: 100 °C
Reaction time: 8 h
Yield: 47.4 %

Procedure:
2-Amino-4,6 dichloropyrimidine (A21, 12 mmol) and 3-fluoro-4-(4-pyridinylthio)-aniline (B7,12 mmol) were suspended in water (150 mL) and treated with 10 drops of concentrated hydrochloric acid. The mixture was stirred at 100° C. overnight. The clear solution was then neutralized with ammonium hydroxide. The precipitated yellow product was filtered, washed with water, and purified by column chromatography with 1-3% MeOH in CH2Cl2 to give the desired product as a white solid (1.98 g, 47%).
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21](O)[N:20]=[CH:19][C:16]=43)[CH:10]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].[H-].[Na+].[CH:26]12[NH:33][CH:30]([CH2:31][CH2:32]1)[CH2:29][NH:28][C:27]2=[O:34].C(N(CC)CC)C>CN1C(=O)CCC1>[CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[C:16]4[CH:19]=[N:20][C:21]([N:33]5[CH:30]6[CH2:31][CH2:32][CH:26]5[C:27](=[O:34])[NH:28][CH2:29]6)=[CH:22][C:15]=4[O:14][CH2:13][CH2:12][N:11]3[CH:10]=2)=[N:7][CH:6]=[N:5]1)([CH3:2])[CH3:3]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1cnc(O)cc1OCC2
Reactant: O=C1NCC2CCC1N2
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1cnc(N3C4CCC3C(=O)NC4)cc1OCC2
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 29.2 %

Procedure:
To a suspension of 2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulen-8-ol from Example 93 (137 mg, 0.44 mmol) in NMP (1.2 mL) was added sodium hydride (60% in mineral oil, 21 mg, 0.53 mmol). The reaction mixture was stirred at RT for 45 min, then at 45° C. for 45 min then cooled to RT. Phenyl trifluorosulphonimide (189 mg, 0.53 mmol) was added and the reaction stirred at RT for 1 h. 3,8-diaza-bicyclo[3.2.1]octan-2-one (69 mg, 0.48 mmol) and triethylamine (77 μL, 0.44 mmol) were added and the reaction mixture heated at 100° C. for 72 h then 120° C. for 7 h. The reaction mixture was cooled to RT, quenched with water and the resulting solid filtered and dried in vacuo. The resultant solid was loaded onto an Isolute SCX-2 cartridge, washed with methanol and eluted with 2M ammonia in methanol. Basic fractions were combined and concentrated in vacuo, the resultant residue was subjected to flash chromatography (SiO2, gradient 0 to 10% methanol in DCM) to give 466 (54 mg, 29%). LCMS: RT=2.33 min, [M+H]+=421. 1H NMR 300 MHz (DMSO-d6) δ: 9.13 (1H, s), 7.88 (2H, d, J=8.29 Hz), 7.19 (1H, br, s), 6.42 (1H, s), 5.95 (1H, m), 4.53 (4H, d, J=10.45 Hz), 4.50 (1H, m), 3.49 (1H, m), 3.17 (1H, d, J=5.21 Hz), 2.98 (1H, m), 2.05-2.20 (2H, m), 1.99 (1H, m), 1.95-1.98 (1H, m), 1.48 (6H, dd, J=6.57, 2.41 Hz)
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:14]=[C:13]([CH3:15])[CH:12]=[CH:11][C:8]=1[CH:9]=[O:10].[BH4-].[Na+].O>CO>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:14]=[C:13]([CH3:15])[CH:12]=[CH:11][C:8]=1[CH2:9][OH:10]
Reactant: COCCCOc1cc(C)ccc1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COCCCOc1cc(C)ccc1CO
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of the title B compound, 2-(3-methoxy-propoxy)-4-methyl-benzaldehyde (3.7 g, 17.41 mmol) in 30 mL of methanol is added portion wise sodium borohydride (1.03 g, 26.12 mmol). The reaction mixture is stirred for 30 min at room temperature. Sodium borohydride (1.03 g, 26.12 mmol) is added and the mixture further stirred overnight to complete the reaction. After addition of H2O, the aqueous layer is extracted twice with ethyl acetate. The combined organic extracts are dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue is purified by flash column chromatography on silica gel (hexane/EtOAc 4/1 to 1/2) to afford the title compound as a colorless oil: TLC, Rf (hexane/AcOEt 2/1)=0.2. Rt (HPLC, Nucleosil C18, 10:90-100:0 CH3CN/H2O+0.1% TFA within 5 min, then 100% CH3CN+0.1% TFA): 4.88 min.
Reaction SMILES: Cl[CH:2]([F:4])[F:3].[Cl:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([C:13]2[NH:17][N:16]([CH3:18])[C:15](=[O:19])[CH:14]=2)=[C:8]([F:20])[CH:7]=1.[OH-].[Na+]>O1CCOCC1.O>[Cl:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([C:13]2[CH:14]=[C:15]([O:19][CH:2]([F:4])[F:3])[N:16]([CH3:18])[N:17]=2)=[C:8]([F:20])[CH:7]=1
Reactant: Cc1cc(-c2cc(=O)n(C)[nH]2)c(F)cc1Cl
Reactant: FC(F)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(-c2cc(OC(F)F)n(C)n2)c(F)cc1Cl

Procedure:
Gaseous chlorodifluoromethane was passed for 2 hours into a solution of 133 g (0.55 mol) of 5-(4-chloro-2-fluoro-5-methylphenyl)-1,2-dihydro-2-methyl-3H-pyrazol-3-one and 110 g (2.7 mol) of sodium hydroxide in 1 l of dioxane and 0.5 l of water at room temperature. The reaction solution was then poured into 2 l of water, whereupon the aqueous phase was extracted three times using ethyl acetate. The combined organic phases were dried over magnesium sulfate and then filtered and concentrated. The residue was purified by means of column chromatography on silica gel (eluent: cyclohexane/ethyl acetate=9:1) followed by preparative MPLC on silica gel (identical eluent). Yield: 43 g.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][NH:12][CH:13]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-])=O)[CH:15]=2)=[CH:2]1.[BH4-].[Na+]>C(O)C.O.O.O.O.O.O.[Ni](Cl)Cl>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][NH:12][CH:13]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)[C:14]2[CH:15]=[C:16]([NH2:20])[CH:17]=[CH:18][CH:19]=2)=[CH:2]1
Reactant: COc1ccc(C(NCCc2c[nH]c3ccccc23)c2cccc([N+](=O)[O-])c2)cc1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1ccc(C(NCCc2c[nH]c3ccccc23)c2cccc(N)c2)cc1
Yield: 22.4 %

Procedure:
In a similar manner to that described in Example (1b), a solution of N-[2-(1H-indol-3-yl)ethyl]-N-[(4-methoxyphenyl)-(3-nitrophenyl)methyl]amine (2.33 g) [prepared as described in step (a) above] in ethanol (50 ml), nickel chloride hexahydrate (2.76 g) and sodium borohydride (878 mg) were reacted, to afford the title compound (484 mg) as a pale yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][N:15]2[CH2:20][CH2:19][NH:18][CH2:17][C:16]2=[O:21])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.Cl[CH2:30][CH2:31][S:32](Cl)(=[O:34])=[O:33]>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][N:15]2[CH2:20][CH2:19][N:18]([S:32]([CH:31]=[CH2:30])(=[O:34])=[O:33])[CH2:17][C:16]2=[O:21])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S(=O)(Cl)CCCl
Reactant: CC(C)(C)OC(=O)N1CCC(CN2CCNCC2=O)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CS(=O)(=O)N1CCN(CC2CCN(C(=O)OC(C)(C)C)CC2)C(=O)C1
Reaction time: 0.5 h
Yield: 61.2 %

Procedure:
To a solution of 1-[1-(tert-butoxycarbonyl)piperidin-4-ylmethyl]-2-piperazinone (5.0 g) and triethylamine (6.792 g) in dichloromethane (80 ml) was added dropwise at 0° C. a solution of 2-chloroethanesulfonyl chloride (4.11 g) in dichloromethane (20 ml), and the mixture was stirred at 0 for 30 minutes. The reaction solution was diluted with dichloromethane, washed with water, citric acid solution, sodium bicarbonate solution and brine, dried and concentrated, and the residue was purified with silica gel column chromatography (ethyl acetate) to give colorless amorphous of 1-[1-(tert-butoxycarbonyl)piperidin-4-ylmethyl]-4-vinylsulfonyl-2-piperazinone (3.99 g).
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]2[CH:27]=[CH:26][CH:25]=[CH:24][C:15]=2[C:16]([N:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[O:17])=[CH:9][CH:8]=1.C(=O)=O.C(O)(C)C>C(Cl)Cl>[OH:6][C:7]1[CH:8]=[CH:9][C:10]([NH:13][C:14]2[CH:27]=[CH:26][CH:25]=[CH:24][C:15]=2[C:16]([N:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[O:17])=[CH:11][CH:12]=1
Reactant: COc1ccc(Nc2ccccc2C(=O)N2CCCCC2)cc1
Agent: BrB(Br)Br
Agent: O=C=O
Solvent: ClCCl
Solvent: CC(C)O
Product: O=C(c1ccccc1Nc1ccc(O)cc1)N1CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.9 %

Procedure:
Boron tribromide (10 ml in 25 ml of methylene dichloride) was added dropwise over a 30 minute period to a solution of 15.5 g of 1-[2-(4-methoxyphenylamino)benzoyl]piperidine in 80 ml of dry methylene dichloride cooled in a bath of Dry Ice and isopropyl alcohol. The reaction mixture was allowed to warm to room temperature and to stand overnight. The solvent was then removed in vacuo, and the residue was treated with 100 ml of distilled water and made basic with about 250 ml of saturated sodium bicarbonate solution. The solid which formed was collected by filtration and recrystallized from ethanol to give 10.2 g of 1-[2-(4-hydroxyphenylamino)benzoyl]piperidine, colorless powder, m.p. 199°-201° C. (decompn.).
Reaction SMILES: [C:1]1([C:7]2([C:10]([OH:12])=[O:11])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[I:13]([O-])(=O)=O.[Na+].S(=O)(=O)(O)O>C(O)(=O)C>[I:13][C:4]1[CH:5]=[CH:6][C:1]([C:7]2([C:10]([OH:12])=[O:11])[CH2:9][CH2:8]2)=[CH:2][CH:3]=1
Reactant: [O-][I+2]([O-])[O-]
Reactant: O=C(O)C1(c2ccccc2)CC1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C(O)C1(c2ccc(I)cc2)CC1
Temperature: 70 °C
Reaction time: 24 h
Yield: 106 %

Procedure:
A mixture of 1-phenylcyclopropane carboxylic acid (16.5 g, 101 mmol), sodium iodate (5.04 g) and concentrated sulfuric acid (1 mL) in acetic acid (70 mL) was stirred and heated at 70° C. for 2 days. Additional sodium iodate (1.88 g) and sulfuric acid (1 mL) were added, and stirring was continued for 1 day. The acetic acid was evaporated, and the residue was partitioned between ethyl acetate and water. The organic phase was washed with aqueous sodium thiosulfate, dried, filtered, and evaporated. The solid residue was recrystallized form methanol/water to give 1-(4-iodophenyl)cyclopropane-1-carboxylic acid (7.98 g, 27 mmol, 27%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:11]=[CH:10][N:9]2[CH:12]=[CH:13][N:14]=[C:8]2[CH:7]=1.C1C(=O)N([Br:22])C(=O)C1>C(O)C.ClCCl>[Br:22][C:12]1[N:9]2[CH:10]=[CH:11][C:6]([C:2]3[S:1][CH:5]=[CH:4][N:3]=3)=[CH:7][C:8]2=[N:14][CH:13]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: c1csc(-c2ccn3ccnc3c2)n1
Solvent: ClCCl
Solvent: CCO
Product: Brc1cnc2cc(-c3nccs3)ccn12
Yield: 67.5 %

Procedure:
Dissolve 7-thiazol-2-yl-imidazo[1,2-a]pyridine (1.14 g, 5.66 mmol) in 25 mL absolute ethanol, then add NBS (1.0 g, 5.66 mmol), stir the mixture at room temperature for 15 minutes, dilute with 35 mL dichloromethane and apply to a 10 g SCX Mega Bond-Elut™ cartridge (Varian) pre-washed with 150 mL 1:1 CH2Cl2:MeOH. Wash the SCX cartridge with 300 mL 1:1 CH2Cl2:MeOH, elute with 150 mL CH2Cl2:2 M NH3-MeOH, and concentrate the eluates and dry to provide 1.07 g (67%) of the title compound as a tan solid. MS (ES) 280, 282.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([C:9]#[N:10])=[C:4]([S:11][CH3:12])[N:3]=1.C1(C2[O:21]N2S(C2C=CC=CC=2)(=O)=O)C=CC=CC=1>ClCCl.CN(C=O)C>[NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([C:9]#[N:10])=[C:4]([S:11]([CH3:12])=[O:21])[N:3]=1
Reactant: CSc1nc(N)nc(Cl)c1C#N
Reactant: O=S(=O)(c1ccccc1)N1OC1c1ccccc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CS(=O)c1nc(N)nc(Cl)c1C#N
Reaction time: 16 h
Yield: 69.4 %

Procedure:
To a stirred suspension of 2.00 g (9.97 mmol) 2-amino-4-chloro-6-methylsulfanyl-pyrimidine-5-carbonitrile in 6 ml dichloromethane and 20 ml DMF was added 5.21 g (19.9 mmol) 3-phenyl-2-(phenylsulfonyl)oxaziridine and stirring continued for 16 hours at room temperature. The reaction mixture was then concentrated in vacuo and the residue recrystallised from ether/dichloromethane to afford 1.50 g (69%) 2-amino-4-chloro-6-methanesulfinyl-pyrimidine-5-carbonitrile as a white crystalline solid. ES-MS m/e (%): 239 (M+Na+, 45), 234 (M+NH4+, 55), 217 (M+H+, 100).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:19]2[C:18](=[O:20])[NH:17][CH:16]=[N:15][C:14]=2[N:13]([CH3:21])[C:12](=[O:22])[CH:11]=1.C(=O)([O-])[O-].[K+].[K+].CC1(C)[O:34][C@@H:33]([CH2:35][O:36]N)[CH2:32][O:31]1>CC(N(C)C)=O>[OH:34][C@H:33]([CH2:35][OH:36])[CH2:32][O:31][N:17]1[C:18](=[O:20])[C:19]2[C:10]([NH:9][C:3]3[CH:4]=[CH:5][C:6]([I:8])=[CH:7][C:2]=3[F:1])=[CH:11][C:12](=[O:22])[N:13]([CH3:21])[C:14]=2[N:15]=[CH:16]1
Reactant: CC1(C)OC[C@H](CON)O1
Reactant: Cn1c(=O)cc(Nc2ccc(I)cc2F)c2c(=O)[nH]cnc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: Cn1c(=O)cc(Nc2ccc(I)cc2F)c2c(=O)n(OC[C@H](O)CO)cnc21
Temperature: 80 °C
Reaction time: 1 h
Yield: 13.2 %

Procedure:
Compound 5F (1.31 g, 3.17 mmol), potassium carbonate (1.1 g, 7.92 mmol) and 1-chloro-2,4-dinitronbenzene (1.60 g, 7.92 mmol) were stirred in DMA at 80° C. for 2 hours. (R)—O-((2,2-Dimethyl-1,3-dioxolan-4-yl)methyl)hydroxylamine (4.66 g, 31.7 mmol) was added at r.t and the reaction was stirred for 1 hour at 80° C. Purification by prep-HPLC gave 210 mg (13%) of the title compound as a clear yellow solid (Deprotection occurred while concentrating the purification fractions containing 0.5% of TFA). 1H NMR (400 MHz, DMSO-d6): δ ppm 10.18 (s, 1 H) 8.93 (s, 1 H) 7.81 (dd, J=10.11, 1.77 Hz, 1 H) 7.62 (dd, J=7.58, 1.01 Hz, 1 H) 7.37 (t, J=8.46 Hz, 1 H) 5.56 (s, 1 H) 4.39 (dd, J=10.74, 3.16 Hz, 1 H) 4.21 (dd, J=10.61, 7.33 Hz, 1 H) 3.82-3.88 (m, 1 H) 3.50 (s, 3 H) 3.42-3.46 (m, 2 H). MS (ES) [m+H] calc'd for C17H16FIN4O5, 503; found 503.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]2[CH:6]=[N:7][CH:8]=[CH:9][CH:10]=2)[CH2:2]1.C(N(C(C)C)CC)(C)C.[N:20]([C:23]1[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=1)=[C:21]=[O:22]>ClCCl>[N:7]1[CH:8]=[CH:9][CH:10]=[C:5]([CH:3]2[CH2:4][N:1]([C:21]([NH:20][C:23]3[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=3)=[O:22])[CH2:2]2)[CH:6]=1
Reactant: COC(=O)c1ccc(N=C=O)cc1
Reactant: c1cncc(C2CNC2)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(NC(=O)N2CC(c3cccnc3)C2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a 20 mL vial was added 3-(azetidin-3-yl)pyridine, bistrifluoroacetic acid (75 mg, 0.207 mmol) and diisopropylethylamine (0.109 ml, 0.622 mmol) in dichloromethane (2072 μl. Methyl 4-isocyanatobenzoate (47.7 mg, 0.269 mmol) was added, and the mixture was stirred at room temperature for 2 hours and concentrated by rotary evaporation. The residue was purified by regular phase chromatography to give the title compound. 1H NMR (300 MHz, DMSO-d6) δ 8.90 (s, 1H), 8.57 (d, J=2.1 Hz, 1H), 8.48 (dd, J=4.8, 1.6 Hz, 1H), 7.91-7.82 (m, 3H), 7.71-7.64 (m, 2H), 7.41 (ddd, J=7.9, 4.7, 0.8 Hz, 1H), 4.42 (t, J=8.4 Hz, 2H), 4.05-3.96 (m, 2H), 3.89 (dt, J=8.1, 7.0 Hz, 1H), 3.81 (s, 1H); MS (ESI(+)) m/e 312 (M+H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([CH3:17])([CH3:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12].[N+:18]([O-])([O-:20])=[O:19].[Na+]>S(=O)(=O)(O)O>[CH3:17][C:10]([C:2]1[NH:1][C:9]2[C:4]([CH:3]=1)=[CH:5][C:6]([N+:18]([O-:20])=[O:19])=[CH:7][CH:8]=2)([CH3:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: O=[N+]([O-])[O-]
Reactant: CCOC(=O)C(C)(C)c1cc2ccccc2[nH]1
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCOC(=O)C(C)(C)c1cc2cc([N+](=O)[O-])ccc2[nH]1
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 57.2 %

Procedure:
Ethyl 2-(1H-indol-2-yl)-2-methylpropanoate (1.0 g, 4.3 mmol) was dissolved in concentrated sulfuric acid (6 mL) and cooled to −10° C. (salt/ice-mixture). A solution of sodium nitrate (370 mg, 4.33 mmol) in concentrated sulfuric acid (3 mL) was added dropwise over 30 min. Stirring was continued for another 30 min at −10° C. The mixture was poured into ice and the product was extracted with dichloromethane. The combined organic phases were washed with a small amount of sat. aq. sodium bicarbonate. The product was purified by column chromatography on silica gel (5-30% EtOAc in hexane) to give ethyl 2-methyl-2-(5-nitro-1H-indol-2-yl)propanoate (0.68 g, 57%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([Cl:9])=[CH:4][N:3]=1.C[Mg+].[Br-].[CH3:13]COCC>C1COCC1.CN1C(=O)CCC1>[Cl:1][C:2]1[N:7]=[C:6]([CH3:13])[C:5]([Cl:9])=[CH:4][N:3]=1
Reactant: Clc1ncc(Cl)c(Cl)n1
Reactant: CCOCC
Agent: C[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CN1CCCC1=O
Product: Cc1nc(Cl)ncc1Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 64.7 %

Procedure:
To a solution of 2,4,5-trichloropyrimidine (2.52 g, 13.74 mmol) in THF/NMP (86 mL/6 mL) was added Fe(acac)3 (485 mg, 1.37) and the mixture was cooled to 0° C. 3.0 M MeMgBr in Et2O (6.87 mL, 20.61 mmol) was added dropwise. After 30 min at 0° C., the reaction was complete and quenched with saturated aqueous NH4Cl solution. Et2O was added and the layers were separated and the aqueous layer was further extracted with several portions of Et2O. The combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo. Chromatography (Hex to 10% EtOAc/Hex) gave the desired product as a white solid (1.45 g, 65%). 1H NMR (500 MHz, CDCl3): 8.47 (s, 1H), 2.61 (s, 3H).