Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([O:13]C)=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[OH:27])=[CH:17][CH:16]=1.[OH-].[Na+].Cl.O1CCOCC1>CO>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([OH:13])=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:15]1[CH:16]=[CH:17][C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[OH:27])=[CH:19][CH:20]=1
Reactant: COC(=O)c1c[nH]c2cc(Br)c(-c3ccc(-c4ccccc4O)cc3)cc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Product: O=C(O)c1c[nH]c2cc(Br)c(-c3ccc(-c4ccccc4O)cc3)cc12
Temperature: 70 °C
Reaction time: 24 h
Yield: 7.8 %

Procedure:
To a semi suspension of crude methyl 6-bromo-5-(2′-hydroxybiphenyl-4-yl)-1H-indole-3-carboxylate (120 mg, 0.284 mmol) in methanol (4 ml) was added 1N NaOH (1 mL, 1 mmol) then heated to 70° C. for 16 hrs. 5N NaOH (1 mL, 5 mmol) was then added and heating continued for 24 hrs. The reaction was cooled and quenched with 4N HCl in dioxane (2 ml, 8 mmol) then concentrated to give a brown solid which was purified by reverse phase preparative HPLC to afford the title compound as a tan solid (9 mg, 8%) MS (AP−) 406.0 (M−H)−. 1H NMR (400 MHz, MeOH-d4) δ: 8.10 (s, 1H), 7.99 (s, 1H), 7.80 (s, 1H), 7.63 (d, 2H), 7.46 (d, 2H), 7.35 (dd, 1H), 7.17 (td, 1H), 6.86-6.98 (m, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[N:13][OH:14])[C:9]([O:11][CH3:12])=[O:10].[C:15](=O)(O)[O-].S(OC)(OC)(=O)=O.O>C(#N)C>[OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[N:13][O:14][CH3:15])[C:9]([O:11][CH3:12])=[O:10]
Reactant: COC(=O)C(=NO)c1ccccc1O
Reactant: O=C([O-])O
Solvent: O
Solvent: CC#N
Solvent: COS(=O)(=O)OC
Product: CON=C(C(=O)OC)c1ccccc1O

Procedure:
2.4 g (0.0106 mol) of methyl 2-(2-hydroxyphenyl)-2-hydroxyimino-acetate (Example VII-1a from process step 3; HPLC: 17.1% E, log p=0.95; 68.9% Z, log p=1.68) in 60 ml of acetonitrile are heated under reflux with 1.08 g (0.011 mol) of potassiun bicarbonate and 1.55 g (0.0123 mol) of dimethyl sulphate for 10 hours. The reaction mixture is poured into water and extracted with diethyl ether, and the solvent is distilled off under reduced pressure. This gives 2.1 g of crude product which is chromatographed over silica gel using a mixture of 7 parts of n-hexane and 3 parts of acetone. This gives 1.6 g of product which, according to HPLC, contains 36.9% of methyl Z-2-(2-hydroxyphenyl)-2-methoxyimino-acetate of log p=2.39.
Reaction SMILES: NC(N)=[S:3].[ClH:5].Cl.[Cl:7][C:8]1[CH:24]=[CH:23][C:11]([CH2:12][N:13]2[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][CH2:21]Cl)[CH2:15][CH2:14]2)=[CH:10][CH:9]=1.C(N(CC)CC)C.[OH-].[Na+]>O.C(O)C>[ClH:7].[ClH:5].[Cl:7][C:8]1[CH:24]=[CH:23][C:11]([CH2:12][N:13]2[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][CH2:21][SH:3])[CH2:15][CH2:14]2)=[CH:10][CH:9]=1
Reactant: ClCCCN1CCN(Cc2ccc(Cl)cc2)CC1
Reactant: NC(N)=S
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: CCN(CC)CC
Product: SCCCN1CCN(Cc2ccc(Cl)cc2)CC1
Yield: 75 %

Procedure:
Utilizing the procedure described in Example 1(b), 6.0 g of thiourea, was reacted with 25.2 g of 1-(4-chlorobenzyl-4-(3-chloropropyl)piperazine dihydrochloride and 8.7 g of triethylamine in 200 ml of reagent ethanol. The hydrolysis was effected with 5.0 g of sodium hydroxide in 50 ml of water. Work-up as described above gave 16.6 g (75% of theory) of 3-[4-(4-chlorobenzyl)piperazine-1-yl]propanethiol dihydrochloride as an off-white crystalline solid, M.p. 257°-260° C.
Reaction SMILES: O/[CH:2]=[C:3]1\[C:4](=[O:13])[NH:5][C:6]2[C:11]\1=[CH:10][CH:9]=[C:8]([F:12])[CH:7]=2.O/C=C1\C(=O)NC2C\1=CC=CC=2.[C:26]1([C:32]2[NH:36][N:35]=[C:34]([NH2:37])[CH:33]=2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.NC1C=CNN=1>O1CCCC1>[F:12][C:8]1[CH:7]=[C:6]2[C:11]([C:3](=[CH:2][NH:37][C:34]3[CH:33]=[C:32]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[NH:36][N:35]=3)[C:4](=[O:13])[NH:5]2)=[CH:10][CH:9]=1
Reactant: Nc1cc(-c2ccccc2)[nH]n1
Reactant: O=C1Nc2cc(F)ccc2/C1=C/O
Agent: Nc1cc[nH]n1
Agent: O=C1Nc2ccccc2/C1=C/O
Solvent: C1CCOC1
Product: O=C1Nc2cc(F)ccc2C1=CNc1cc(-c2ccccc2)[nH]n1

Procedure:
The named compound is prepared by substituting E & Z-3-[(hydroxy)-methylene]-6-fluoro-1,3-dihydro-indol-2-one for E & Z-3-[(hydroxy)-methylene]-1,3-dihydro-indol-2-one and 5-phenyl-1H-pyrazol-3-ylamine for 3-aminopyrazole in the reaction of Example 1. Specifically, E & Z-3-[(hydroxy)-methylene]-6-fluoro-1,3-dihydro-indol-2-one (0.033 gms.) is reacted with 0.065 gms. 5-phenyl-1H-pyrazol-3-ylamine by refluxing in tetrahydrofuran (0.88 mL) to afford the named compound in the amount of 0.0417 gms.
Reaction SMILES: Br[C:2]1[C:7]([CH:8]=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][CH:20]([NH:23][CH3:24])[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11].C(N(C(C)C)CC)(C)C>>[C:10]([O:14][C:15]([N:17]1[CH2:18][CH2:19][CH:20]([N:23]([CH3:24])[C:2]2[C:7]([CH:8]=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=2)[CH2:21][CH2:22]1)=[O:16])([CH3:13])([CH3:12])[CH3:11]
Reactant: O=Cc1cccnc1Br
Reactant: CNC1CCN(C(=O)OC(C)(C)C)CC1
Solvent: CCN(C(C)C)C(C)C
Product: CN(c1ncccc1C=O)C1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
Following the general procedure of EXAMPLE 12 and making non-critical variations but starting with 2-bromo-3-formylpyridine (XVI, EXAMPLE 1, 2.67 g, 14.4 mmol), 1-tert-butoxycarbonyl-4-methylaminopiperidine (XIII, 2.8 g, 13.1 mmol), and diisopropylethylamine (2.3 ml), the title compound is obtained, mp 90°-91°.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH2:9])=[C:4]([NH2:10])[CH:3]=1.O.[NH:12]1[C:20](=[O:21])[C:18](=O)[C:16](=[O:17])[NH:15][C:13]1=[O:14]>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][C:7]=1[Cl:8])[N:9]=[C:16]([OH:17])[C:18]([C:20]([NH:12][C:13]([NH2:15])=[O:14])=[O:21])=[N:10]2
Reactant: Nc1cc(Cl)c(Cl)cc1N
Reactant: O=C1NC(=O)C(=O)C(=O)N1
Solvent: CC(=O)O
Solvent: O
Product: NC(=O)NC(=O)c1nc2cc(Cl)c(Cl)cc2nc1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 4,5-dichloro-o-phenylenediamine (36.2 mmole) and alloxan monohydrate (36.2 mmole) in 10% aqueous acetic acid was stirred at room temperature for a period of 2 hours. Concentration of the reaction mixture gave N-(6,7-dichloro-2-hydroxy-3-quinoxalinoyl)urea which was added to 50% aqueous sulfuric acid and the mixture was heated at a temperature of 135° C. for a period of 3 hours. After cooling the precipitated material was collected by filtration, washed with water and then was slowly added to a 5% aqueous solution of sodium bicarbonate. The insoluble material was collected by filtration and was washed successively with water and ethanol to give 6,7-dichloro-2-hydroxyquinoxaline.
Reaction SMILES: [OH:1]/[N:2]=[C:3](\[C:10]1[N:14]([CH3:15])[N:13]=[CH:12][N:11]=1)/[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:23][C:24]1[N:29]=[C:28]([N:30]2[C:38](=[O:39])[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[C:31]2=[O:40])[CH:27]=[CH:26][CH:25]=1>CC#N>[CH3:15][N:14]1[C:10]([C:3](=[N:2][O:1][CH2:23][C:24]2[N:29]=[C:28]([N:30]3[C:31](=[O:40])[C:32]4[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=4)[C:38]3=[O:39])[CH:27]=[CH:26][CH:25]=2)[C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)=[N:11][CH:12]=[N:13]1
Reactant: O=C1c2ccccc2C(=O)N1c1cccc(CBr)n1
Reactant: Cn1ncnc1/C(=N\O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: Cn1ncnc1C(=NOCc1cccc(N2C(=O)c3ccccc3C2=O)n1)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 74.3 %

Procedure:
To a stirred solution of ((Z)-N-hydroxy-1-(1-methyl-1H-1,2,4-triazol-5-yl)-1-phenylmethanimine (7 g, 34.61 mmol, 1.0 eq.) in 500 ml of MeCN was added Cs2CO3 (12.40 g, 38.07 mmol, 1.1 eq.) followed by Kl (0.575 g, 3.46 mmol, 0.1 eq.) in one portion. The resulting suspension was stirred for 5 mins before addition of 2-[6-(bromomethyl)pyridin-2-yl]-1H-isoindole-1,3(2H)-dione (10.97 g, 34.61 mmol, 1.0 eq.) in one portion. The reaction was stirred for 4 h at room temperature. The solid was removed by filtration and washed with 250 ml of fresh MeCN. The filtrate was evaporated, and 500 ml of EtOAc were added. The organic layer was washed with H2O and dried over MgSO4 then concentrated. Chromatography of the crude on silica gel gave 2-{6-[({[(1-methyl-1H-1,2,4-triazol-5-yl)(phenyl)methylene]amino}oxy)methyl]pyridin-2-yl}-1H-isoindole-1,3(2H)-dione (11.27 g, 74% yield) as a white solid.
Reaction SMILES: [CH2:1]([CH:3]([C:6]1[C:7]2[N:8]([C:13]([C:17]3[N:21]4[CH:22]=[CH:23][CH:24]=[C:25]([CH:26]([OH:28])[CH3:27])[C:20]4=[N:19][C:18]=3[CH3:29])=[C:14]([CH3:16])[N:15]=2)[N:9]=[C:10]([CH3:12])[CH:11]=1)[CH2:4][CH3:5])[CH3:2].C[N+]1([O-])CCOCC1>C(Cl)Cl.CCC[N+](CCC)(CCC)CCC.[O-][Ru](=O)(=O)=O>[CH2:1]([CH:3]([C:6]1[C:7]2[N:8]([C:13]([C:17]3[N:21]4[CH:22]=[CH:23][CH:24]=[C:25]([C:26](=[O:28])[CH3:27])[C:20]4=[N:19][C:18]=3[CH3:29])=[C:14]([CH3:16])[N:15]=2)[N:9]=[C:10]([CH3:12])[CH:11]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(CC)c1cc(C)nn2c(-c3c(C)nc4c(C(C)O)cccn34)c(C)nc12
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Product: CCC(CC)c1cc(C)nn2c(-c3c(C)nc4c(C(C)=O)cccn34)c(C)nc12
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 82.1 %

Procedure:
A solution of 1-{3-[8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazin-3-yl]-2-methyl-imidazo[1,2-a]pyridin-8-yl}-ethanol (0.77 g, 1.96 mmol) dissolved in CH2Cl2 (20 mL) is cooled to 0° C., treated with NMO (0.34 g, 2.94 mmol) and TPAP (34 mg, 0.098 mmol). The reaction is stirred at 0° C. for 10 min, then at RT for 4 h. It is filtered through silica gel, washed with EtOAc. Purification of the crude material by silica gel chromatography gives the title compound (0.63 g, 1.61 mmol, 82%) as a yellow solid. 1H NMR (CDCl3): δ 0.92 (t, J=7.5 Hz, 3H), 0.93 (t, J=7.5 Hz, J=7.5 Hz, 3H), 1.80-1.95 (m, 4H), 2.43 (s, 3H), 2.45 (s, 3H), 2.48 (s, 3H), 3.12 (s, 3H), 3.34-3.46 (m, 1H), 6.75 (s, 1H), 6.83 (t, J=7.0 Hz, 1H), 7.67 (dd, J=7.1, 1.4 Hz, 1H), 7.91 (dd, J=7.1, 1.4 Hz, 1H) ppm. ES-MS (m/z): calcd for C23H27N5O (M+H)+: 390.5. found: 390.2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].O.C1COCC1.[Cl:15][C:16]1[CH:17]=[C:18](/[CH:22]=[CH:23]/[S:24](Cl)(=[O:26])=[O:25])[CH:19]=[CH:20][CH:21]=1.C([O-])([O-])=O.[Na+].[Na+]>O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][S:24](/[CH:23]=[CH:22]/[C:18]2[CH:19]=[CH:20][CH:21]=[C:16]([Cl:15])[CH:17]=2)(=[O:25])=[O:26])[CH:6]=[CH:7][CH:8]=1
Reactant: O=S(=O)(Cl)/C=C/c1cccc(Cl)c1
Reactant: Nc1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=S(=O)(/C=C/c1cccc(Cl)c1)Nc1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 22 h
Yield: 85.7 %

Procedure:
To a well-stirred solution of 3-chloroaniline (367.9 mg, 2.87 mmol, 1 eq.) in a solvent system of H2O-THF (14 mL, 1:1 ratio) was sequentially added first compound 1 (676.6 mg, 2.87 mmol, 1 eq.) and then a 1M-solution of Na2CO3 (2.2 mL, 0.77 mmol, 0.77 eq.) until the pH was about 8. After the reaction mixture was stirred for 22 hours at room temperature, water was added and the product was extracted 3 times with EtOAc from the aqueous phase. The resulting organic phase was washed with brine, dried under Na2SO4 and the solvent evaporated. After the product was purified from the crude by flash column chromatography (10% EtOAc/hexanes), compound 2 (808.5 mg, 2.46 mmol) was obtained in an 86% yield. 1H NMR (400 MHz, CDCl3) δ 7.48 (d, J=15.4 Hz, C═CH, 1H), 7.43 (s, ArH, 1H), 7.39 (dt, J=6.8, 2.3 Hz, ArH, 1H), 7.33 (m, ArH, 2H), 7.25 (t, J=8.0, ArH, 1H), 7.22 (t, J=2.1, ArH, 1H), 7.13 (ddd, J=8.0, 1.9, 0.9 Hz, ArH, 1H), 7.07 (ddd, J=8.0, 2.1, 0.9 Hz, ArH, 1H), 6.79 (d, J=15.4 Hz, C═CH, 1H), 6.61 (s, NH, 1H). 13C NMR (100 MHz, CDCl3, δ): 142.03 (CH), 137.53 (C), 135.17 (C), 133.76 (C), 131.14 (CH), 130.55 (CH), 130.36 (CH), 128.11 (CH), 126.67 (CH), 125.38 (CH), 125.30 (CH), 120.49 (CH), 118.46 (CH). GC-MS m/z (% relative intensity, ion): 330.85 (0.8, M+4), 328.95 (4, M+2), 326.90 (6, M+), 262.95 (28), 151.95 (48), 136.95 (99), 126.95 (54), 102.00 (100), 98.80 (51), 90.95 (19).
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[F:15])[C:6]2[CH:16]=[CH:17][CH:18]=[CH:19][C:5]=2[N:4]([CH2:20][C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)[C:3]1=[O:27].[CH3:28][C:29]1[CH:30]=[C:31]([N:35]=[C:36]=[O:37])[CH:32]=[CH:33][CH:34]=1>C(Cl)Cl>[F:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[C:7]1[C:6]2[CH:16]=[CH:17][CH:18]=[CH:19][C:5]=2[N:4]([CH2:20][C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)[C:3](=[O:27])[CH:2]([NH:1][C:36]([NH:35][C:31]2[CH:32]=[CH:33][CH:34]=[C:29]([CH3:28])[CH:30]=2)=[O:37])[N:8]=1
Reactant: NC1N=C(c2ccccc2F)c2ccccc2N(Cc2cccnc2)C1=O
Reactant: Cc1cccc(N=C=O)c1
Solvent: ClCCl
Product: Cc1cccc(NC(=O)NC2N=C(c3ccccc3F)c3ccccc3N(Cc3cccnc3)C2=O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (3RS)-3-amino-2,3-dihydro-5-(2-fluorophenyl)-1-(pyridin-3-yl)methyl-1H-1,4-benzodiazepin-2-one (0.48 g) in dry methylene chloride (30 ml) was added dropwise a solution of 3-methylphenyl isocyanate (0.195 g) in dry methylene chloride (5 ml) under nitrogen atmosphere at cooling in an ice-bath. The mixture was stirred under the same temperature for 1 hour and at ambient temperature overnight. The resultant precipitates were collected by filtration and washed with isopropyl ether to afford N-[(3RS)-2,3-dihydro-5-(2-fluorophenyl)-2-oxo-1-(pyridin-3-yl)methyl-1H-1,4-benzodiazepin-3-yl]-N'-(3-methylphenyl)urea.
Reaction SMILES: [C:1]([CH2:5][C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7])(=[O:4])[CH2:2][CH3:3].[F:16][C:17]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:18]=1[CH:19]=O>C1C=CC=CC=1.C([O-])(=O)C.[NH2+]1CCCCC1>[F:16][C:17]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:18]=1[CH:19]=[C:5]([C:1](=[O:4])[CH2:2][CH3:3])[C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7]
Reactant: CCC(=O)CC(=O)OCc1ccccc1
Reactant: O=Cc1ccc(F)cc1F
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: c1ccccc1
Product: CCC(=O)C(=Cc1ccc(F)cc1F)C(=O)OCc1ccccc1
Yield: 100.3 %

Procedure:
A solution of benzyl propionylacetate (157 g, 0.758 mol), 2,4-difluorobenzaldehyde (107.65 g, 0.758 mol), and piperidinium acetate (5.49 g, 38 mmol) in benzene (1 L) were stirred at room temperature for 96 h. The mixture was washed with water (2×100 mL), dried (magnesium sulfate) and the solvent evaporated under reduced pressure to yield the product as a pale yellow syrup (251.2 g) which was used in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[C:13]2[C:8](=[C:9]([N+:15]([O-])=O)[C:10]([Cl:14])=[CH:11][CH:12]=2)[CH:7]=[C:6]1[CH3:18])=[O:4].C(O)(=O)C.OS(O)(=O)=O>C(O)C.[Fe]>[CH3:1][O:2][C:3]([N:5]1[C:13]2[C:8](=[C:9]([NH2:15])[C:10]([Cl:14])=[CH:11][CH:12]=2)[CH:7]=[C:6]1[CH3:18])=[O:4]
Reactant: COC(=O)n1c(C)cc2c([N+](=O)[O-])c(Cl)ccc21
Agent: [Fe]
Agent: O=S(=O)(O)O
Solvent: CCO
Solvent: CC(=O)O
Product: COC(=O)n1c(C)cc2c(N)c(Cl)ccc21
Temperature: 85 °C
Reaction time: 0.5 h

Procedure:
5-Chloro-2-methyl-4-nitro-indole-1-carboxylic acid methyl ester (2.1 g, 7.81 mmol) is dissolved in ethanol (40 ml) and glacial acetic acid (40 ml). Iron powder (1.74 g, 31.26 mmol, activated previously with H2SO4 conc and then washed with water) is added, and the reaction mixture is heated to 85° C. for 90 minutes. The reaction mixture is poured into water and stirred at RT for 30 minutes, after which a slightly brownish colored precipitate forms which is filtered off. After washing with water and drying, the title compound is obtained in pure form. 1H NMR (DMSO, 400 MHz, 120° C.) δ 2.51 (s, 3H), 4.05 (s, 3H), 5.0-5.2 (br s, 2H), 6.66 (s, 1H), 7.05 (d, J=9 Hz, 1H), 7.31 (d, J=9 Hz, 1H); ES-MS: 238 [M+H]+.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].O/[N:7]=[C:8](\[NH2:15])/[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.C(N(CC)CC)C>ClCCl>[Cl:1][CH2:2][C:3]1[O:4][N:15]=[C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[N:7]=1
Reactant: N/C(=N\O)c1ccccn1
Reactant: O=C(Cl)CCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: ClCc1nc(-c2ccccn2)no1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 2-chloroacetyl chloride (0.209 mL) in dichloromethane (3 mL) was added dropwise to a solution of (Z)—N′-hydroxypicolinamidine (0.300 g) in dichloromethane (7 mL). Triethylamine (0.366 mL) was added dropwise to the reaction solution and stirring at room temperature continued for 18 hours. The mixture was purified by column chromatography on silica gel (10-50% ethyl acetate in hexane). Desired fractions were evaporated in vacuo to a pale pink residue (0.21 g). This material was taken in toluene and refluxed for 18 hours. The solvent was evaporated in vacuo and the residue purified by column chromatography on silica gel (1-3% methanol in dichloromethane) to provide the title compound (0.085 g) having the following physical data.
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[CH:13]=[CH:14][C:15]([F:22])=[C:16]2[C:21]=1[N:20]=[CH:19][CH:18]=[CH:17]2)(=[O:10])=[O:9].N(OC(C)(C)C)=O.CC(O)=O>C1COCC1>[F:22][C:15]1[CH:14]=[C:13]2[C:12](=[C:21]3[C:16]=1[CH:17]=[CH:18][CH:19]=[N:20]3)[NH:11][S:8](=[O:10])(=[O:9])[C:3]1[C:4]2=[CH:5][CH:6]=[CH:7][CH:2]=1
Reactant: Nc1ccccc1S(=O)(=O)Nc1ccc(F)c2cccnc12
Agent: CC(C)(C)ON=O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: O=S1(=O)Nc2c(cc(F)c3cccnc23)-c2ccccc21
Yield: 10 %

Procedure:
In a similar fashion using route 16 general procedure 61, 2-amino-N-(5-fluoro-quinolin-8-yl)-benzenesulfonamide (Intermediate 291) (350 mg, 1.1 mmol), t-butyl nitrite (0.2 ml, 1.65 mmol), AcOH (3.5 ml) and THF (3.5 ml) gave the title compound (33 mg, 10%) after purification by column chromatography with DCM/MeOH (99:1) as the eluent followed by recrystallisation with DCM/pentane.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6](F)[N:5]=[CH:4][N:3]=1.[CH2:10]([OH:14])[C:11]#[C:12][CH3:13].C(N(CC)C(C)C)(C)C>C1(C)C=CC=CC=1>[CH2:10]([O:14][C:6]1[C:7]([F:8])=[C:2]([F:1])[N:3]=[CH:4][N:5]=1)[C:11]#[C:12][CH3:13]
Reactant: Fc1ncnc(F)c1F
Reactant: CC#CCO
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: CC#CCOc1ncnc(F)c1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83 %

Procedure:
0.5 g of 4,5,6-trifluoropyrimidine, 0.31 g of 2-butyn-1-ol and 0.78 ml of N,N-diisopropylethylamine were added to 1 ml of toluene, then the mixture was stirred at room temperature for 30 minutes. Then the reaction mixture was subjected to silica gel column chromatography to obtain 0.57 g of 4-(2-butynyloxy)-5,6-difluoropyrimidine.
Reaction SMILES: [C:1]([O:4][CH:5]1[CH:10]([O:11][C:12](=[O:14])[CH3:13])[CH:9]([O:15][C:16](=[O:18])[CH3:17])[CH:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][CH:6]1[O:24][C:25]1[CH:29]=[C:28]([CH:30]([CH3:32])[CH3:31])[S:27][C:26]=1[C:33](=O)[C:34]1[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=1)(=[O:3])[CH3:2].C[Si](C)(C)Cl.C([BH3-])#N.[Na+]>C(#N)C>[C:1]([O:4][CH:5]1[CH:10]([O:11][C:12](=[O:14])[CH3:13])[CH:9]([O:15][C:16](=[O:18])[CH3:17])[CH:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][CH:6]1[O:24][C:25]1[CH:29]=[C:28]([CH:30]([CH3:32])[CH3:31])[S:27][C:26]=1[CH2:33][C:34]1[CH:35]=[CH:36][C:37]([O:40][CH3:41])=[CH:38][CH:39]=1)(=[O:3])[CH3:2]
Reactant: COc1ccc(C(=O)c2sc(C(C)C)cc2OC2OC(COC(C)=O)C(OC(C)=O)C(OC(C)=O)C2OC(C)=O)cc1
Agent: C[Si](C)(C)Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC#N
Product: COc1ccc(Cc2sc(C(C)C)cc2OC2OC(COC(C)=O)C(OC(C)=O)C(OC(C)=O)C2OC(C)=O)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
630 mg of (4,5-diacetoxy-6-acetoxymethyl-2-[5-isopropyl-2-(4-methoxy-benzoyl)-thiophen-3-yloxy]-tetrahydro-pyran-3-yl) acetate were dissolved in 30 ml of acetonitrile and cooled to 0° C. in an ice bath. 1.31 ml of trimethylchlorosilane and 652 mg of sodium cyanoborohydride were added, the ice bath was removed and the reaction was stirred for 2 h. 100 ml of water were added to the reaction mixture, which was extracted twice with 70 ml of dichloromethane each time. The combined organic phases were washed with 50 ml of saturated sodium chloride solution, dried over sodium sulfate and concentrated. The crude product was purified by column chromatography (SiO2, ethyl acetate/n-heptane=1:1).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][O:11][C@H:10]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17](C=O)[CH:16]=2)[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl.[NH2:26][OH:27].C([O-])(=O)C.[Na+]>C(O)C.O>[C:1]([N:8]1[CH2:13][CH2:12][O:11][C@H:10]([CH2:14][C:15]2[CH2:16][C:17](=[N:26][OH:27])[C:18]([O:21][CH3:22])=[CH:19][CH:20]=2)[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: COc1ccc(C[C@@H]2CN(C(=O)OC(C)(C)C)CCO2)cc1C=O
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COC1=CC=C(C[C@@H]2CN(C(=O)OC(C)(C)C)CCO2)CC1=NO
Temperature: 25 °C
Reaction time: 18 h
Yield: 53.7 %

Procedure:
Intermediate (b) N-BOC-(R)-2-(3-formyl-4-hydroxybenzyl)morpholine (0.192 g, 0.06 mmol) was dissolved in dry acetone (5 mL) with potassium carbonate (0.165 g, 1.19 mmol), under an atmosphere of nitrogen and iodomethane (0.074 mL, 1.19 mmol) added in one portion. The resulting mixture was stirred at room temperature for 18 hrs and then concentrated in vacuo. The residue was dissolved in water (10 mL) and extracted with diethyl ether (10 mL). The organic layer was dried (Na2SO4), filtered and concentrated in vacuo. The orange oil was purified by column chromatography (silica; 35% ethyl acetate/isohexane) to yield the desired product as a yellow oil (0.157 g, 78%). The material was used directly in the next step. N-BOC-(R)-2-(3-formyl-4-methoxybenzyl)morpholine (0.157 g, 0.468 mmol) was dissolved in ethanol (5 mL) and added to a solution of hydroxylamine hydrochloride (42 mg, 0.61 mmol) and sodium acetate (88 mg, 1.08 mmol) in ethanol (5 mL) at room temperature. The resulting mixture was stirred at room temperature for 18 hrs and then heated at 80° C. for 72 hrs. The reaction mixture was diluted with water (40 mL) and extracted with ethyl acetate (20 mL×2). Combined organic layers were washed with brine (10 mL), dried (Na2SO4), filtered and concentrated in vacuo to yield the desired intermediate (a), N-BOC-(R)-2-(3-hydroxyimino-4-methoxybenzyl)morpholine as a yellow oil (85 mg).
Reaction SMILES: [CH:1]([O:4][C:5]([C:7]1[C:12]([C:13]([CH3:21])([CH3:20])[O:14][SiH2:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:11][CH:10]=[CH:9][N:8]=1)=[O:6])([CH3:3])[CH3:2].[H][H]>CO.O=[Pt]=O.[Rh]>[CH:1]([O:4][C:5]([C@H:7]1[C@@H:12]([C:13]([CH3:21])([CH3:20])[O:14][SiH2:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:11][CH2:10][CH2:9][NH:8]1)=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)OC(=O)c1ncccc1C(C)(C)O[SiH2]C(C)(C)C
Reactant: [H][H]
Agent: O=[Pt]=O
Agent: [Rh]
Solvent: CO
Product: CC(C)OC(=O)[C@@H]1NCCC[C@@H]1C(C)(C)O[SiH2]C(C)(C)C

Procedure:
3-(tert-Butyl-dimethyl-silanyloxymethyl)-pyridine-2-carboxylic acid isopropyl ester (800 mg, 2.6 mmol) was dissolved in 6 mL of methanol in a pressure hydrogenation vessel to which 100 mg of PtO2 was added (Rh on alumina may also be used). The vessel was shaken under 50 psi of hydrogen for 5 hrs. The suspension was filtered through Celite and the solution was concentrated in vacuo to provide the desired compound, cis-3-(tert-butyl-dimethyl-silanyloxymethyl)-piperidine-2-carboxylic acid isopropyl ester. MS 316 (M+1). Without further purification the product was acylated under standard conditions with 1-(4-chloro-phenyl)-cyclobutanecarbonyl chloride (itself prepared from the carboxylic acid using excess thionyl chloride at reflux for 1 hr. followed by concentration in vacuo). Water/ether extractive workup gave, after concentration of the organic layers in vacuo and chromatography on silica gel, the desired compound, cis-3-(tert-Butyl-dimethyl-silanyloxymethyl)-1-[1-(4-chloro-phenyl)-cyclobutanecarbonyl]-piperidine-2-carboxylic acid isopropyl ester (720 mg, 55% for two steps) MS 508 (M+l). The cis stereochemistry was assigned based upon a 1H NMR coupling constant of 4 Hz for the proton at C-2 of the piperidine ring.