Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[C:9]2[Cl:12])=[CH:4][CH:3]=1.C1C=C(Cl)C=C(C(OO)=[O:21])C=1>C(Cl)Cl>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N+:8]([O-:21])=[C:9]2[Cl:12])=[CH:4][CH:3]=1
Reactant: Clc1nccc2ccc(Br)cc12
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: [O-][n+]1ccc2ccc(Br)cc2c1Cl
Temperature: 25 °C
Reaction time: 24 h
Yield: 35 %

Procedure:
To a solution of 7-bromo-1-chloroisoquinoline (4.0 g, 15.8 mmol) in DCM (100 mL) at 0° C. was added mCPBA (˜77%, 7.46 g, 33.3 mmol). The reaction was allowed to stir at room temperature for 24 hours, diluted with DCM (100 mL) and washed with 1N NaOH and brine. The DCM extracts were dried over Na2SO4, filtered, concentrated and chromatographed on silica eluting with 5 to 15% acetone/DCM to give the title compound (1.43 g). LRMS (M+H)+=258.0.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[NH2:8].[CH3:9][S:10][C:11](SC)=[N:12][C:13]#[N:14]>N1C=CC=CC=1>[CH3:9][S:10][C:11](=[N:12][C:13]#[N:14])[NH:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[NH2:8]
Reactant: Nc1ccncc1N
Reactant: CSC(=NC#N)SC
Solvent: c1ccncc1
Product: CSC(=NC#N)Nc1cnccc1N
Temperature: 25 °C
Reaction time: 96 h
Yield: 25.2 %

Procedure:
3,4-Diaminopyridine (4 g, 36.6 mmol) was suspended in anhydrous pyridine (100 ml), and S,S'-dimethyl N-cyanodithioiminocarbonate (8.0 g, 55.0 mmol) was added thereto. The mixture was stirred at room temperature for 4 days. The resulting powder was collected from the reaction mixture by filtration, and washed with ether (100 ml) to obtain crude crystals. The crystals were purified by recrystallization from methanol-ether to obtain 1.91 g of the intended product as a white powder (yield: 58%). On the other hand, the filtrate was concentrated under reduced pressure, and the residue was purified by flash column chromatography (silica gel, eluent: chloroform:methanol=4:1 (v/v)) to obtain 2.8 g of the intended product (total yield: 95%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[O:8])[CH:2]=1.[C:9]([O:13][CH2:14][CH3:15])(=[O:12])[CH:10]=[CH2:11]>>[O:8]=[C:7]([C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)[CH2:11][CH2:10][C:9]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: C=CC(=O)OCC
Reactant: O=Cc1cccnc1
Product: CCOC(=O)CCC(=O)c1cccnc1

Procedure:
The title compound was prepared from 3-pyridinecarboxaldehyde (20 g) and ethyl acrylate (22.4 g) as described in Example 1 to yield 5.1 g, ESMS (M+1)+208.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([C:7]([OH:9])=[O:8])[CH2:3][CH2:2]1.O.[CH3:11]C1C=CC(S(O)(=O)=O)=CC=1>CO>[O:1]1[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH3:11])=[O:8])[CH2:3][CH2:2]1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C(O)C1CCOCC1
Solvent: O
Solvent: CO
Product: COC(=O)C1CCOCC1
Yield: 15 %

Procedure:
To a solution of tetrahydro-2H-pyran-4-carboxylic acid (50 g, 385 mmol) in anhydrous methanol (500 mL) was added 4-methylbenzenesulfonic acid hydrate (72.5 g, 385 mmol). The mixture was refluxed for 2 hr. The solvent was removed in vacuo. Ethyl ether and water was added. The organic phase was washed with water and brine, then dried over Na2SO4, filtered and concentrated to give methyl tetrahydro-2H-pyran-4-carboxylate (8.3 g, 75%) which was used in next step without purification.
Reaction SMILES: [C:1]12([O:11][C:12]3[CH:18]=[CH:17][C:15]([NH2:16])=[C:14]([F:19])[CH:13]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.Br[CH2:21][CH2:22][CH2:23][CH2:24]Br.C([O-])([O-])=O.[K+].[K+]>C(O)C>[C:1]12([O:11][C:12]3[CH:18]=[CH:17][C:15]([N:16]4[CH2:24][CH2:23][CH2:22][CH2:21]4)=[C:14]([F:19])[CH:13]=3)[CH2:2][CH:3]3[CH2:4][CH:5]([CH2:6][CH:7]([CH2:9]3)[CH2:8]1)[CH2:10]2
Reactant: BrCCCCBr
Reactant: Nc1ccc(OC23CC4CC(CC(C4)C2)C3)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: Fc1cc(OC23CC4CC(CC(C4)C2)C3)ccc1N1CCCC1

Procedure:
A mixture of 2.3 g (8.8 mmoles) of 4-(1-adamantyloxy)-2-fluoroaniline, 1.90 g (8.80 mmoles) of 1,4-dibromobutane, and 2.68 g (19.4 mmoles) of K2CO3 in deaerated absolute ethanol (25 ml) is refluxed for 24 hours. The solvent is evaporated, and the residue taken up in methylene chloride (125 ml) and water (125 ml). The methylene chloride layer is washed with 2×125 ml of water, and the combined aqueous portions are extracted with methylene chloride (50 ml). The combined methylene chloride layers are dried and concentrated. The crude product is chromatographed by high pressure liquid chromatography on a 2.54 × 109 cm column at approximately 40 psi, eluting with 0.5% acetone in methylene chloride and collectint 200 ml fractions. Fraction 3 contains 1.5 g of tan solid, m.p. 99.0°-105.9° C.
Reaction SMILES: I[C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[C:9]([N:16]1[CH2:20][CH2:19][CH2:18][C@@H:17]1[C:21]#[CH:22])([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10]>CN(C=O)C.CCOCC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[C:9]([N:16]1[CH2:20][CH2:19][CH2:18][C@@H:17]1[C:21]1[O:8][C:7]2[C:2](=[N:3][CH:4]=[CH:5][CH:6]=2)[CH:22]=1)([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10]
Reactant: C#C[C@H]1CCCN1C(=O)OC(C)(C)C
Reactant: Oc1cccnc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1c1cc2ncccc2o1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A 3.14 g (14.4 mmol) sample of 2-iodo-3-hydroxypyridine (Lancaster Chem. Co.) was dissolved in 5 mL of DMF, and (Ph3P)2PdCl2 (0.34 g, 0.50 mmol), CuI (0.371 g, 1.98 mmol) and triethylanine (1.80 mL, 13.2 mmol) were added. The mixture was stirred under N2 at room temperature for 1 hour, then 2.15 g (11.0 mmol) of the compound from step 3a above, dissolved in 5 mL of DMF, was added carefully. The mixture was stirred at 60° C. for 16 hours, then cooled to room temperature. The reaction mixture was diluted with ether and filtered. The solution was washed with 10% NaOH, 50% brine, dried over MgSO4, and the solvent Awas removed. The residue was chromatographed on silica gel, eluting with 100:0 to 60:40 hexane:EtOAc to give 620 mg of title compound: 1H NMR (CDCl3, 300 MHz) δ 1.73 (s, 9H), 1.85-2.30 (m, 4H), 3.05-3.22 (m, 2H), 4.42 (m, 1H), 6.78 (s, 1H), 7.16 (dd, 1H), 7.68 (dd, 1H), 8.48 (dd, 1H); MS m/z: 289 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:39]/[O:40][C:41]([C:44]([OH:46])=[O:45])([CH3:43])[CH3:42])/[C:8]([NH:10][CH:11]2[C:37](=[O:38])[N:13]3[C:14]([C:34]([OH:36])=[O:35])=[C:15]([CH2:18][NH:19][CH2:20][C:21]4[CH:26]=[C:25]([OH:27])[C:24]([OH:28])=[CH:23][C:22]=4[CH2:29][C:30](OC)=[O:31])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.C(N(CC)CC)C>C(#N)C.O>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:39]/[O:40][C:41]([C:44]([OH:46])=[O:45])([CH3:43])[CH3:42])/[C:8]([NH:10][CH:11]2[C:37](=[O:38])[N:13]3[C:14]([C:34]([OH:36])=[O:35])=[C:15]([CH2:18][N:19]4[C:30](=[O:31])[CH2:29][CH:22]5[C:21](=[CH:26][C:25]([OH:27])=[C:24]([OH:28])[CH2:23]5)[CH2:20]4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: COC(=O)Cc1cc(O)c(O)cc1CNCC1=C(C(=O)O)N2C(=O)C(NC(=O)/C(=N\OC(C)(C)C(=O)O)c3csc(N)n3)[C@H]2SC1
Solvent: CC#N
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(O/N=C(\C(=O)NC1C(=O)N2C(C(=O)O)=C(CN3CC4=CC(O)=C(O)CC4CC3=O)CS[C@H]12)c1csc(N)n1)C(=O)O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 7.6 %

Procedure:
To 7-[2-(2-aminothiazol-4-yl)-2-((Z)-1-carboxy-1-methylethoxyimino)acetamido]-3-(4,5-dihydroxy-2-methoxycarbonylmethylbenzylaminomethyl)ceph-3-em-4-carboxylic acid (800 mg) in acetonitrile (5 ml) and water (5 ml), at 0° C., was added triethylamine (260 μl). The mixture was stirred, at ambient temperature, for 90 minutes and evaporated under reduced pressure. The residue was dissolved in water (25 ml) containing acetic acid (a few drops) and sodium acetate, filtered and purified by chromatography (HPLC; Dynamax column) using 17.5% acetonitrile/water. Freeze-drying afforded the title compound (58 mg); NMR (DMSO-d6 /CF3COOH) 1.49(s,3H); 1.52(s,3H); 3.35(dd,2H); 3.4(s,3H); 4.3(m,2H); 4.5(dd,2H); 5.18(d,1H); 5.85(dd,1H); 6.58(d,1H); 6.62(s,1H); 9.7(d,1H): FAB M/S (M-H)- 645.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][CH2:8][N:7]([CH:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)[C:6]=2[N:18]=1.[CH3:19]N(C)C(=O)C.IC.[H-].[Na+]>O>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:19])[C:10](=[O:12])[CH2:9][CH2:8][N:7]([CH:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)[C:6]=2[N:18]=1
Reactant: O=C1CCN(C2CCCC2)c2nc(Cl)ncc2N1
Reactant: CC(=O)N(C)C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: CN1C(=O)CCN(C2CCCC2)c2nc(Cl)ncc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 0.13 g (0.0005 mole) of 2-chloro-9-cyclopentyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VI-10), 1 mL of N,N-dimethylacetamide and 0.047 mL (0.00075 mole) of iodomethane at 0 degrees was added 0.03 g (0.00075 mole) of 60% sodium hydride in oil. The mixture was stirred at ambient temperature for 1 hour, then 20 mL of water was added. The precipitate was collected by filtration to give 0.135 g of 2-chloro-9-cyclopentyl-5-methyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-10) as an yellow solid.
Reaction SMILES: C([Mg]Br)C.C1C[O:8][CH2:7][CH2:6]1.I[C:11]1[N:18]2[C:14]([S:15][CH:16]=[CH:17]2)=[C:13]([S:19][CH3:20])[N:12]=1.C(Cl)(=O)C.[Cl-].[NH4+]>C1COCC1.C(OCC)(=O)C>[C:7]([C:11]1[N:18]2[C:14]([S:15][CH:16]=[CH:17]2)=[C:13]([S:19][CH3:20])[N:12]=1)(=[O:8])[CH3:6]
Reactant: CSc1nc(I)n2ccsc12
Reactant: C1CCOC1
Agent: CC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CC(=O)Cl
Product: CSc1nc(C(C)=O)n2ccsc12
Temperature: -5 °C
Reaction time: 0.5 h

Procedure:
A 1 M ethylmagnesium bromide/THF solution (4.78 ml) was added in an argon atmosphere at −40° C. to a solution of 963 mg of 5-iodo-7-methylthioimidazo[5,1-b]thiazole in 30 ml of dry THF. The mixture was stirred at the same temperature for 30 min. Acetyl chloride (0.35 ml) was added thereto. The temperature of the system was raised to −5° C. over a period of 2 hr. A saturated aqueous ammonium chloride solution was added to the reaction mixture. Ethyl acetate was added thereto, followed by washing with a dilute aqueous sodium thiosulfate solution and saturated brine in that order. The organic layer was dried over anhydrous magnesium sulfate. The solvent was removed by distillation. The residue was purified by column chromatography on silica gel (dichloromethane:ethyl acetate:hexane=2:1:1) to give 384 mg of 5-acetyl-7-methylthioimidazo[5,1-b]thiazole.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.Br[CH2:9][CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12]>C(OCC)(=O)C.C(Cl)Cl>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:9][CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:4][CH2:3]1
Reactant: CC(C)(C)OC(=O)CCBr
Reactant: CN1CCNCC1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CN1CCN(CCC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.8 %

Procedure:
4-methyl piperazine (7.68 mL, 70 mmol, 4 equiv) was added to a stirred solution of tert-butyl 3-bromopropionate (3.0 mL, 18 mmol) in ethyl acetate (15 mL) at 0° C. The solution was stirred at 25° C. for 1 h with evolution of a white precipitate, then heated on an oil bath to 55° C. for 2 h. TLC analysis (20% EtOAc in Hexanes, Rf=0.9 (starting material), 0.1 (product)) indicated complete consumption of the bromide reagent. The reaction was diluted with EtOAc (100 mL) and transferred to a separatory funnel, and the organic phase was washed with water (100 mL), NaHCO3 (sat'd, 2×100 mL), and brine (100 mL), dried over MgSO4 and concentrated to give a slightly yellow oil. The oil was dissolved in methylene chloride (20 mL), loaded on to a pre-equilibrated plug of silica gel (20% EtOAc in Hexanes, 150 mL SiO2) and the desired product was eluted from the silica with increasingly polar eluent (EtOAc in hexanes, starting at 20%, 200 mL volumes increasing in 15% increments to 100%). Fractions containing the desired material were concentrated to give tert-butyl 3-(4-methylpiperazin-1-yl)propanoate (4.1 g, quantitative). 1H NMR (400 MHz, CDCl3) δ (ppm)=3.45 (d, J=3 Hz, 2H), 2.64 (t, J=7.3 Hz, 2H), 2.47 (br s, 6H), 2.38 (t, J=7.3 Hz, 2H), 2.25 (s, 3H), 1.42 (s, 9H).
Reaction SMILES: [NH:1]1[C:8](=[O:9])[CH2:7][C:5](=[O:6])[NH:4][C:2]1=[S:3].[CH3:10]O.[OH-].[Na+].CI>O>[CH3:10][S:3][C:2]1[N:4]=[C:5]([OH:6])[CH:7]=[C:8]([OH:9])[N:1]=1
Reactant: CO
Reactant: O=C1CC(=O)NC(=S)N1
Agent: [Na+]
Agent: [OH-]
Solvent: CI
Solvent: O
Product: CSc1nc(O)cc(O)n1
Temperature: 41 °C

Procedure:
A quantity (72.07 g., 0.5 mole) of 2-thiobarbituric acid was dissolved in a reaction medium consisting of 500 ml. methanol, 500 ml. water, and 20 g. sodium hydroxide. The medium was heated in order to effect solution. After cooling the solution to 41° C., 142 g. (1.0 mole) methyl iodide was added, with stirring. The reaction mixture was heated at the reflux temperature for 1 hr. The desired 2-(methylthio)-4,6-pyrimidinediol crystallized out as the refluxing continued, and it was recovered on a filter by cooling the reaction mixture to 60° C. and filtering. The initial crop of crystalline product weighed 51.5 g. and had a melting point at >300° C. After refrigerating the mother liquor, an additional 19.08 g. of product was obtained.
Reaction SMILES: [BrH:1].Br.[CH3:3][O:4][C:5]1[CH:6]=[C:7]([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[CH:8]=[CH:9][CH:10]=1.[OH-].[Na+]>CS(C)=O>[Br:1][C:10]1[CH:9]=[CH:8][C:7]([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[CH:6][C:5]=1[O:4][CH3:3]
Reactant: Br
Reactant: COc1cccc(N2CCNCC2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: COc1cc(N2CCNCC2)ccc1Br
Temperature: 65 °C

Procedure:
A solution of 1-(3-methoxyphenyl)piperazine dihydrobromide (3.5 g, 10 mmol) is dissolved in DMSO (30 mL) and heated at 65° C. for 4 h in a flask which is open to the atmosphere. After cooling, the mixture is poured into a separatory funnel containing 100 mL of 1 N sodium hydroxide solution and extracted with ethyl ether (3×100 mL). The organic extracts are dried (Na2SO4), filtered, and concentrated to provide 1-(4-bromo-3 -methoxyphenyl)piperazine as a solid. 1H NMR (400 MHz, CDCl3) 7.34-7.36 (d, J=2.2 Hz, 1H,), 6.47 (s, 1H), 6.38-6.41 (d, J=2.8 Hz, 1H), 3.87 (s, 3H, OMe), 3.11 -3.13 (m, 4H), 3.01 -3.03 (m, 4H)
Reaction SMILES: CC(OC(/N=N/C(OC(C)(C)C)=O)=O)(C)C.C(P(CCCC)CCCC)CCC.[CH2:30]([O:37][C:38]1[CH:39]=[C:40]([C:44]2[CH:49]=[CH:48][C:47]([Cl:50])=[CH:46][C:45]=2[NH:51][C:52](=[O:62])[CH2:53][NH:54][C@@H:55]([CH2:58][CH2:59][S:60][CH3:61])[CH2:56]O)[CH:41]=[CH:42][CH:43]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.CCOC(C)=O>C1COCC1>[ClH:50].[CH2:30]([O:37][C:38]1[CH:39]=[C:40]([C:44]2[CH:49]=[CH:48][C:47]([Cl:50])=[CH:46][C:45]=2[N:51]2[CH2:56][C@H:55]([CH2:58][CH2:59][S:60][CH3:61])[NH:54][CH2:53][C:52]2=[O:62])[CH:41]=[CH:42][CH:43]=1)[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: CSCC[C@@H](CO)NCC(=O)Nc1cc(Cl)ccc1-c1cccc(OCc2ccccc2)c1
Agent: CC(C)(C)OC(=O)/N=N/C(=O)OC(C)(C)C
Agent: CCCCP(CCCC)CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CSCC[C@H]1CN(c2cc(Cl)ccc2-c2cccc(OCc3ccccc3)c2)C(=O)CN1
Product: Cl
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of di-tert-butylazodicarboxylate (733 mg, 3.2 mmol) in 7 mL of THF at 0° C. was added tributylphosphine (0.797 mL, 3.2 mmol) dropwise. After 10 minutes, a solution of the product from Step A (1.062 mg, 2.12 mmol) in 4 mL of THF was added dropwise over 15 minutes, and the reaction was allowed to warm to room temperature. After 30 minutes, the solution was poured into EtOAc, washed with sat. aq. NaHCO3 and brine, dried (Na2SO4), filtered, and concentrated in vacuo. The crude product mixture was purified by silica gel chromatography (5-7% MeOH/CH2Cl2). The resulting product was taken up in ether, excess 1N HCl/Ether was added, the solution was concentrated in vacuo, and the resulting residue was triturated with hexane. The titled product, containing tributylphosphine oxide impurity, was used in the next reaction without further purification.
Reaction SMILES: [C:1]([OH:13])(=O)[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[CH2:36]([CH2:38][NH2:39])[OH:37].CN1CCOCC1>CN(C=O)C.C(OCC)(=O)C>[OH:37][CH2:36][CH2:38][NH:39][C:1]([C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1)=[O:13]
Reactant: NCCO
Reactant: O=C(O)c1ccc2ccccc2n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(NCCO)c1ccc2ccccc2n1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 24 %

Procedure:
To a solution of quinaldic acid (5.0 g, 28.87 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (5.5 g, 28.87 mmol), and 1-hydroxybenzotriazole (5.1 g, 37.49 mmol) in DMF (60 mL) at 0° C. was added ethanolamine (1.74 mL, 28.87 mmol) and 4-methylmorpholine (4.76 mL, 43.31 mmol). The reaction was stirred at 0° C. for an additional 10 minutes and then warmed to room temperature and stirred for 2 hours. The reaction mixture was then diluted with ethyl acetate, washed 3 times with H2O, once with NaHCO3 (sat), once with brine, dried over MgSO4, and concentrated in vacuo to provide 1.5 g (24% yield) of a pale yellow solid. Electrospray Mass Spec: m/z 216.8 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:16]2[C:24]3[CH:23]=[C:22]([O:25][CH3:26])[CH:21]=[C:20]([OH:27])[C:19]=3[CH:18]=[N:17]2)[CH:5]=[CH:6][C:7]=1[O:8]CC1C=CC=CC=1>C(O)C.C(OCC)(=O)C.[Pd]>[F:1][C:2]1[CH:3]=[C:4]([N:16]2[C:24]3[CH:23]=[C:22]([O:25][CH3:26])[CH:21]=[C:20]([OH:27])[C:19]=3[CH:18]=[N:17]2)[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: COc1cc(O)c2cnn(-c3ccc(OCc4ccccc4)c(F)c3)c2c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1cc(O)c2cnn(-c3ccc(O)c(F)c3)c2c1
Yield: 74.1 %

Procedure:
A solution of 1-{3-fluoro-4-[(phenylmethyl)oxy]phenyl}-6-(methyloxy)-1H-indazol-4-ol (D4) (116 mg, 0.32 mmol) in ethanol (5 mL) and ethyl acetate (5 mL) was hydrogenated in an H-cube over a 10% palladium on charcoal catalyst. The resulting solution was concentrated and the product purified by silica gel chromatography eluting with 5-80% ethyl acetate in hexane to yield the title compound (E2) (65 mg).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:9][CH:10]=2)[C:5]([N+:17]([O-:19])=[O:18])=[CH:4][CH:3]=1.[Br:20]N1C(=O)CCC1=O.O.C(Cl)Cl>C(O)(=O)C>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][C:13]([CH3:16])([CH3:14])[CH3:15])=[CH:9][CH:10]=2)[C:5]([N+:17]([O-:19])=[O:18])=[CH:4][C:3]=1[Br:20]
Reactant: CC(C)(C)Oc1ccc2c(N)ccc([N+](=O)[O-])c2c1
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)(C)Oc1ccc2c(N)c(Br)cc([N+](=O)[O-])c2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 1-amino-6-tert-butoxy-4-nitronaphthalene, as described above in Step E, (2.02 g, 7.76 mmol) in acetic acid (55 mL) was added N-bromosuccinimide (1.45 g, 8.15 mmol), portionwise. The reaction mixture was stirred at ambient temperature for 1 hour, then H2O (150 mL) and CH2Cl2 (300 mL) were added and the organic layer was extracted. The organic extract was washed with saturated aqueous Na2CO3 (2×100 mL), then brine (100 mL), then dried over Na2SO4, filtered, and concentrated in vacuo. The residue was triturated with hexane-Et2O to provide the titled product.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([CH3:4])=[CH2:3].C(C1C=C(C)C=C(C(C)(C)C)C=1O)(C)(C)C.C(N(CC)CC)C.[C:30]([Si:36]([CH2:42][CH:43]([CH3:45])[CH3:44])([CH2:38][CH:39]([CH3:41])[CH3:40])Cl)([CH:33]([CH3:35])[CH3:34])([CH3:32])[CH3:31]>C1(C)C=CC=CC=1>[C:1]([O:6][Si:36]([C:30]([CH:33]([CH3:35])[CH3:34])([CH3:31])[CH3:32])([CH2:38][CH:39]([CH3:40])[CH3:41])[CH2:42][CH:43]([CH3:45])[CH3:44])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C=C(C)C(=O)O
Reactant: CC(C)C[Si](Cl)(CC(C)C)C(C)(C)C(C)C
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: C=C(C)C(=O)O[Si](CC(C)C)(CC(C)C)C(C)(C)C(C)C
Temperature: 80 °C
Reaction time: 5 h

Procedure:
A flask equipped with a stirrer, reflux condenser, dropping funnel and thermometer was charged with 17.2 g (0.2 mol) of methacrylic acid, 120 ml of toluene, and 0.06 g of 2,6-di-tert-butyl-4-methylphenol. At room temperature, 22.3 g (0.22 mol) of triethylamine was added dropwise over one hour. At the end of dropwise addition, the flask was heated at 80° C. After the internal temperature became constant, 52.6 g (0.20 mol) of thexyldiisobutylchlorosilane was added dropwise over two hours. After the completion of dropwise addition, the reaction solution was stirred for 5 hours at 80° C. The reaction solution was then cooled to room temperature, and the resulting hydrochloric acid salt removed by filtration. The filtrate was distilled, collecting 46.3 g of a fraction having a boiling point of 104-110° C./0.13 kPa.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:10])=[C:4]([CH:6]=[CH:7][C:8]=1[F:9])[NH2:5].[CH2:11]([S:14](Cl)(=[O:16])=[O:15])[CH2:12][CH3:13].N1C=CC=CC=1.C(=O)(O)[O-].[Na+]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Br:1][C:2]1[C:3]([F:10])=[C:4]([NH:5][S:14]([CH2:11][CH2:12][CH3:13])(=[O:16])=[O:15])[CH:6]=[CH:7][C:8]=1[F:9]
Reactant: Nc1ccc(F)c(Br)c1F
Reactant: CCCS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCS(=O)(=O)Nc1ccc(F)c(Br)c1F

Procedure:
A solution of 3-bromo-2,4-difluoroaniline (4.16 g, 20 mmol, EP184384), n-propanesulfonyl chloride (4.6 ml, 40 mmol), pyridine (8 ml), DMAP (97 mg), and DCM (100 ml) was stirred at rt for 16 h. Aqueous sodium bicarbonate solution was added and the mixture was extracted with ethyl acetate. The organic layer was washed with aqueous sodium bicarbonate and brine. The crude product was purified by silica gel chromatography (8:1 to 3:1 hexanes/ethyl acetate eluant) to give the title compound. MS m/z 313.9 (M+1).
Reaction SMILES: Cl.[NH2:2][OH:3].CCN(CC)CC.[C:11]([C:15]1[C:16]([OH:23])=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH:18]=O)([CH3:14])([CH3:13])[CH3:12]>CC#N>[C:11]([C:15]1[C:16]([OH:23])=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH:18]=[N:2][OH:3])([CH3:14])([CH3:13])[CH3:12]
Reactant: NO
Reactant: CC(C)(C)c1cccc(C=O)c1O
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)c1cccc(C=NO)c1O
Temperature: 25 °C
Reaction time: 24 h
Yield: 91.7 %

Procedure:
To a stirred solution of hydroxylamine hydrochloride (437 mg, 6.3 mmol) in CH3CN at 0° C. was added Et3N and 3-tert-butyl-2-hydroxybenzaldehyde (1.02 g, 5.7 mmol). The reaction mixture was warmed up to room temperature and stirred for 24 h. The solvent was removed and the residue was dissolved in EtOAc and H2O. The layers were separated and the aqueous layer was extracted with EtOAc (2×20 mL). The combined organic layer was washed with brine, dried with Na2SO4 and concentrated under reduced pressure to provide 3-tert-butyl-2-hydroxybenzaldehyde oxime (1.01 g, 92%) as a pale yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[C:5]1[CH:10]=[C:9]([OH:11])[CH:8]=[C:7]([O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[CH:15][CH:14]=2)[CH:6]=1)[CH3:2].[C:22]([C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Br)=[CH:26][CH:25]=1)#[N:23]>>[CH2:1]([O:3][C:4](=[O:21])[C:5]1[CH:6]=[C:7]([O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[CH:15][CH:14]=2)[CH:8]=[C:9]([O:11][CH2:28][C:27]2[CH:30]=[CH:31][C:24]([C:22]#[N:23])=[CH:25][CH:26]=2)[CH:10]=1)[CH3:2]
Reactant: N#Cc1ccc(CBr)cc1
Reactant: CCOC(=O)c1cc(O)cc(Oc2ccc(C#N)cc2)c1
Product: CCOC(=O)c1cc(OCc2ccc(C#N)cc2)cc(Oc2ccc(C#N)cc2)c1
Yield: 78.6 %

Procedure:
Using 0.66 g (2.3 mmol) of 3-(4-cyano phenoxy)-5-hydroxy benzoic acid ethyl ester and 4-cyanobenzylbromide (0.45 g, 2.3 mmol) and following the procedure of Example 42(b) afforded 0.72 g of the required product. 1H NMR (DMSO-d6): δ 1.3 (3H, t), 4.3 (2H, q), 5.35 (2H, s), 7.16 (4H, m), 7.44 (1H, s), 7.66 (2H, s), 7.88 (4H, d).