Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1.[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1.[OH-].[Na+]>CN(C=O)C>[N:5]1([CH2:4][CH2:3][O:18][C:15]2[CH:16]=[CH:17][C:12]([NH2:11])=[CH:13][CH:14]=2)[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1
Reactant: ClCCN1CCOCC1
Reactant: Nc1ccc(O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Nc1ccc(OCCN2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 23.5 h

Procedure:
4-(2-Chloro-ethyl)-morpholine hydrochloride (4.2 g, 22 mmol, 1.2 equiv) is added in one portion to a mixture of 4-aminophenol (2 g, 18.3 mmol) and finely powdered sodium hydroxide (1.87 g, 45.8 mmol, 2.5 equiv) in DMF (32 mL), under an argon atmosphere. The reaction mixture is stirred for 23.5 h at RT. The resulting dark suspension is filtered. The filtrate is diluted with DCM (200 ml) and washed with brine (2×60 mL). The organic phase is dried (sodium sulfate), filtered and concentrated. Purification of the residue by silica gel column chromatography (DCM/EtOH, 95:5→7:3) provides the title compound as a yellow-brown solid: API-MS: 223.2 [MH]+; TLC: Rf=0.31 (DCM/EtOH, 9:1).
Reaction SMILES: C[N:2]1[CH2:7][CH2:6][CH:5]=[C:4]([C:8]2[O:9][CH:10]=[CH:11][N:12]=2)[CH2:3]1.[Cl:13]C(OC(Cl)C)=O>ClC(Cl)C>[ClH:13].[O:9]1[CH:10]=[CH:11][N:12]=[C:8]1[C:4]1[CH2:3][NH:2][CH2:7][CH2:6][CH:5]=1
Reactant: CC(Cl)OC(=O)Cl
Reactant: CN1CCC=C(c2ncco2)C1
Solvent: CC(Cl)Cl
Product: C1=C(c2ncco2)CNCC1
Product: Cl
Yield: 46.2 %

Procedure:
4 g of 1-methyl-3-(oxazol-2-yl)-1,2,5,6-tetrahydropyridine in 80 cm3 of dichloroethane is cooled to -5° C. under inert atmosphere and 3.88 g of alpha-chloroethyl chloroformate is added. The mixture is heated under reflux for one hour 30 minutes, evaporated, the residue is taken up in diethylether, followed by filtering. The ethereal phase is concentrated, the residue is taken up in 30 cm3 of methanol, heated at boiling point for 40 minutes and evaporated to dryness. After crystallization from ethanol and ether, 2.1 g of expected product is obtained. M.p.=188°-191° C.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH2:14].[C:15]1([C:21]2[O:25][N:24]=[C:23]([C:26](Cl)=[O:27])[CH:22]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(CC)CC)C.C(OCC)(=O)C>ClCCl>[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH:14][C:26]([C:23]1[CH:22]=[C:21]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[O:25][N:24]=1)=[O:27]
Reactant: O=C(Cl)c1cc(-c2ccccc2)on1
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cc(-c2ccccc2)on1
Yield: 33.8 %

Procedure:
This compound was obtained following Method B starting from 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.0419 g, 0.178 mmol), 5-phenylisoxazole-3-carbonyl chloride (0.041 g; 0.178 mmol), and triethylamine (0.0624 mL; 0.444 mmol) in dichloromethane (3 mL). Flash chromatography on silica gel eluting with 2 to 16% of ethyl acetate in dichloromethane gave 0.022 g (34%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-5-phenylisoxazole-3-carboxamide as a solid.
Reaction SMILES: [CH2:1](Br)[CH:2]=[CH2:3].[OH:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([N:15]2[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]2)(=[O:14])=[O:13])=[CH:8][C:7]=1[C:22]1[NH:23][C:24](=[O:35])[C:25]2[N:30]([CH3:31])[N:29]=[C:28]([CH2:32][CH2:33][CH3:34])[C:26]=2[N:27]=1.C(=O)([O-])[O-].[K+].[K+].CO>CC(=O)CC.CC(C)=O>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([N:15]2[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]2)(=[O:13])=[O:14])=[CH:8][C:7]=1[C:22]1[NH:23][C:24](=[O:35])[C:25]2[N:30]([CH3:31])[N:29]=[C:28]([CH2:32][CH2:33][CH3:34])[C:26]=2[N:27]=1)[CH:2]=[CH2:3]
Reactant: CCCc1nn(C)c2c(=O)[nH]c(-c3cc(S(=O)(=O)N4CCN(C)CC4)ccc3O)nc12
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CC(C)=O
Solvent: CCC(C)=O
Product: C=CCOc1ccc(S(=O)(=O)N2CCN(C)CC2)cc1-c1nc2c(CCC)nn(C)c2c(=O)[nH]1
Yield: 9.8 %

Procedure:
Allyl bromide (0.02 ml, 0.00023 mol) was added to a stirred suspension of 5-[2-hydroxy-5-(4-methylpiperazinylsulphonyl)-phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]-pyrimidin-7-one (0.103 g, 0.00023 mol) and potassium carbonate (0.032 g, 0.00023 mol) in 2-butanone (10 ml) and the mixture heated under reflux for 8 hours. After cooling, the reaction mixture was evaporated under vacuum and the residue suspended in water (20 ml). The aqueous suspension was extracted with ethyl acetate (3×20 ml), the combined extracts dried (Na2SO4) and, after filtration, evaporated under vacuum to give an oil. Column chromatography on silica gel (2 g) using a methanol in. dichloromethane elution gradient (0-3%), followed by evaporation under vacuum of appropriate fractions, gave a semi-solid which was dissolved in acetone; evaporation under vacuum of the solution gave the title compound (0.011 g, 10%), m.p. 151°-153° C., Rf 0.5 (silica; dichloromethane, methanol; 95:5), m/e 487 (M+ +1).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=C[C:3]=1[C:8]([C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][C:19]=1[CH3:20])[C:16]([CH3:22])([CH3:21])[CH2:15][CH2:14][C:13]2([CH3:24])[CH3:23])=[CH2:9].C(N(CCCC)CCCC)CCC.[C]=O.[C:40]([O:43][CH2:44]C)(=[O:42])[CH3:41]>CO.C([O-])(=O)C.C([O-])(=O)C.[Pd+2]>[CH3:20][C:19]1[C:10]([C:8]([C:3]2[CH:2]=[CH:7][CH:6]=[CH:5][C:41]=2[C:40]([O:43][CH3:44])=[O:42])=[CH2:9])=[CH:11][C:12]2[C:13]([CH3:24])([CH3:23])[CH2:14][CH2:15][C:16]([CH3:21])([CH3:22])[C:17]=2[CH:18]=1
Reactant: C=C(c1cc2c(cc1C)C(C)(C)CCC2(C)C)c1ccccc1I
Reactant: CCOC(C)=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [C]=O
Solvent: CO
Solvent: CCCCN(CCCC)CCCC
Product: C=C(c1cc2c(cc1C)C(C)(C)CCC2(C)C)c1ccccc1C(=O)OC

Procedure:
A solution of 6-[1-(2-iodophenyl)vinyl]-1,1,4,4,7-pentamethyl-1,2,3,4-tetrahydronaphthalene (17.2 g, 40 mmol), palladium diacetate (1.02 g, 4.5 mmol) and tributylamine (21.9 ml, 92 mmol) in methanol (500 ml) is heated for 3 h at 100° C. under a pressure of carbon monoxide (3 bar). After concentration on an evaporator under vacuum at 40° C., the oil obtained is diluted in ethyl acetate and washed three times with water. The product is purified by flash chromatography on a column of silica.
Reaction SMILES: [CH2:1]([C:3]1([C:40]2[CH:45]=[CH:44][C:43]([OH:46])=[CH:42][CH:41]=2)[CH:12]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH:22]([CH2:26][CH2:27][CH2:28]CCCC(F)(F)C(F)(F)F)[C:23]([OH:25])=[O:24])[C:11]2[C:6](=[CH:7][C:8]([OH:39])=[CH:9][CH:10]=2)[O:5][CH2:4]1)[CH3:2].[F:47][C:48]([F:71])([C:67]([F:70])([F:69])[F:68])[CH2:49]CCCC(CCCCCCC=C)C(OCC)=O>>[CH2:1]([C:3]1([C:40]2[CH:41]=[CH:42][C:43]([OH:46])=[CH:44][CH:45]=2)[CH:12]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH:22]([CH2:26][CH2:27][CH2:28][CH2:49][C:48]([F:71])([F:47])[C:67]([F:70])([F:69])[F:68])[C:23]([OH:25])=[O:24])[C:11]2[C:6](=[CH:7][C:8]([OH:39])=[CH:9][CH:10]=2)[O:5][CH2:4]1)[CH3:2]
Reactant: C=CCCCCCCC(CCCCC(F)(F)C(F)(F)F)C(=O)OCC
Reactant: CCC1(c2ccc(O)cc2)COc2cc(O)ccc2C1CCCCCCCCCC(CCCCCCC(F)(F)C(F)(F)F)C(=O)O
Product: CCC1(c2ccc(O)cc2)COc2cc(O)ccc2C1CCCCCCCCCC(CCCCC(F)(F)C(F)(F)F)C(=O)O

Procedure:
Starting with the allyl compound prepared in Example 21 and the ethyl 2-(5,5,6,6,6-pentafluorohexyl)-9-decenoate prepared in Example 5, the same procedure as shown in Example 21 was repeated to give 11-[(3RS,4RS)-3-ethyl-7-hydroxy-3-(4-hydroxyphenyl)chroman-4-yl]-2-(5,5,6,6,6-pentafluorohexyl)undecanoic acid.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:15])[N:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:5]([CH3:8])[C:6]=1[CH3:7].[C:16]1([CH3:23])[C:21]([OH:22])=[CH:20][CH:19]=[CH:18][CH:17]=1.N>O.CC(O)C.[Fe-3](C#N)(C#N)(C#N)(C#N)(C#N)C#N.[K+].[K+].[K+]>[CH3:8][N:5]1[C:6]([CH3:7])=[C:2](/[N:1]=[C:18]2\[CH:17]=[C:16]([CH3:23])[C:21](=[O:22])[CH:20]=[CH:19]\2)[C:3](=[O:15])[N:4]1[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: Cc1ccccc1O
Reactant: Cc1c(N)c(=O)n(-c2ccccc2)n1C
Agent: N#C[Fe-3](C#N)(C#N)(C#N)(C#N)C#N
Agent: N
Agent: [K+]
Solvent: O
Solvent: CC(C)O
Product: CC1=C/C(=N\c2c(C)n(C)n(-c3ccccc3)c2=O)C=CC1=O

Procedure:
10 mmol of 4-amino-1,5-dimethyl-2-phenyl-1,2-dihydro-3H-pyrazol-3-one was dissolved in 30 ml of water. This solution was admixed with 10 mmol of o-cresol in solution in 30 ml of 2-propanol, 3 ml of 20% aqueous ammonia and 22 mmol of potassium ferricyanide at a temperature ranging from 5 to 10° C.
Reaction SMILES: [CH2:1]([C:5]1[N:10]=[C:9](O)[N:8]=[C:7]([C:12]([O:14][CH3:15])=[O:13])[CH:6]=1)[CH2:2][CH2:3][CH3:4].P(Cl)(Cl)([Cl:18])=O.CC1N=C(O)N=C(C(OC)=O)C=1>>[CH2:1]([C:5]1[N:10]=[C:9]([Cl:18])[N:8]=[C:7]([C:12]([O:14][CH3:15])=[O:13])[CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1cc(C(=O)OC)nc(O)n1
Reactant: O=P(Cl)(Cl)Cl
Agent: COC(=O)c1cc(C)nc(O)n1
Product: CCCCc1cc(C(=O)OC)nc(Cl)n1

Procedure:
Methyl 6-n-butyl-2-hydroxypyrimidine-4-carboxylate (prepared as described by Z. Budesinsky and F. Roubinek in Collection Czechoslovak Chem Commun., 26, 2871-2885 (1991)) is refluxed with phosphorous oxychloride, as described by the same authors for the chlorination of methyl 6-methyl-2-hydroxypyrimidine-4-carboxylate, to give the title compound.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:5]=[CH:6][C:7]([N:11]2[CH2:16][CH2:15][CH2:14][C@@H:13]([C:17]([N:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)=[O:18])[CH2:12]2)=[N:8][C:9]=1[NH2:10].[CH3:24][S:25][C:26]1[CH:27]=[N:28][N:29]([C:31]2([C:34](=N)OCC)[CH2:33][CH2:32]2)[CH:30]=1.C(O)(=O)C.C(N(CC)CC)C>C(O)C>[CH3:24][S:25][C:26]1[CH:27]=[N:28][N:29]([C:31]2([C:34]3[NH:10][C:9]4=[N:8][C:7]([N:11]5[CH2:16][CH2:15][CH2:14][C@@H:13]([C:17]([N:19]6[CH2:23][CH2:22][CH2:21][CH2:20]6)=[O:18])[CH2:12]5)=[CH:6][CH:5]=[C:4]4[N:3]=3)[CH2:32][CH2:33]2)[CH:30]=1
Reactant: Nc1ccc(N2CCC[C@@H](C(=O)N3CCCC3)C2)nc1N
Reactant: CCOC(=N)C1(n2cc(SC)cn2)CC1
Agent: Cl
Solvent: CCO
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Product: CSc1cnn(C2(c3nc4ccc(N5CCC[C@@H](C(=O)N6CCCC6)C5)nc4[nH]3)CC2)c1
Temperature: 110 °C

Procedure:
To a solution of (R)-(1-(5,6-diaminopyridin-2-yl)piperidin-3-yl)(pyrrolidin-1-yl)methanone dihydrochloride (189 mg, 0.653 mmol) and ethyl 1-(4-(methylthio)-1H-pyrazol-1-yl)cyclopropanecarbimidate (157 mg, 0.697 mmol) in ethanol (1.86 mL) was added acetic acid (0.372 mL) followed by triethylamine (0.545 mL, 3.91 mmol). The reaction mixture was heated to 110° C. for 2 h. The mixture was cooled to room temperature, the solvent was removed under reduced pressure and the residue was partitioned between a saturated aqueous solution of ammonium chloride (100 mL) and dichloromethane (200 mL). The aqueous layer was extracted with dichloromethane (100 mL) and the combined organics were dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified via HPLC to afford the title compound. MS (ESI+) (M+H) 452.2; HPLC retention time 2.11 min (Method A).
Reaction SMILES: CO[C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8]C=2)[C:4]=1[CH:13]([NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:23])[C:14]#[N:15].C(N(CC)CC)C.C[C:32](=[O:34])C.C(=O)=O.[SH2:38]>O.N1C=CC=CC=1>[CH3:32][O:34][CH:8]1[CH:7]=[CH:6][C:5]2[C:4](=[CH:3][CH:12]=[CH:11][CH:10]=2)[C:13]1([NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:23])[C:14](=[S:38])[NH2:15]
Reactant: COc1ccc2ccccc2c1C(C#N)Nc1ccccc1C
Reactant: S
Reactant: CC(C)=O
Agent: O=C=O
Solvent: CCN(CC)CC
Solvent: O
Solvent: c1ccncc1
Product: COC1C=Cc2ccccc2C1(Nc1ccccc1C)C(N)=S
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A mixture of 12.1 parts of 2-methoxy-α-[(2-methylphenyl)amino]-1-naphthaleneacetonitrile, 4.1 parts of N,N-diethylethanamine and 20 parts of dry pyridine is stirred and cooled to 0° C. (cooling in a 2-propanone/CO2 -bath). During 2 hours, gaseous hydrogen sulfide is introduced. The whole is stored overnight at 0° C. The reaction mixture is poured onto 600 parts of water. The precipitated product is filtered off and dissolved in 450 parts of trichloromethane. The solution is washed with 100 parts of water, dried, filtered and evaporated. The residue is crystallized from 120 parts of acetonitrile. The product is filtered off (the filtrate is set aside) and dried, yielding a first fraction of 6.9 parts of 2-methoxy-α-[(2-methylphenyl)amino]-1-naphthalenecarbothioamide.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[CH3:11].S(Cl)(Cl)=O.C(N(CC)CC)C.[CH3:23][C:24]([CH3:27])([O-])[CH3:25].[Li+]>C1(C)C=CC=CC=1>[C:24]([O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([Br:1])=[C:3]([CH3:11])[CH:4]=1)([CH3:27])([CH3:25])[CH3:23]
Reactant: Cc1cc(C(=O)O)ccc1Br
Reactant: CC(C)(C)[O-]
Agent: [Li+]
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: Cc1cc(C(=O)OC(C)(C)C)ccc1Br
Temperature: 25 °C
Reaction time: 18 h
Yield: 71.5 %

Procedure:
4-Bromo-3-methyl-benzoic acid (2.06 g, 9.6 mmol) and thionyl chloride (2.2 ml, 30.2 mmol) in toluene (50 ml) were heated at reflux for 2 h then concentrated in vacuo and azeotroped with toluene. The residue was dissolved in THF (100 ml) and triethylamine (2.8 ml, 20.1 mmol), cooled down to 0° C. and lithium tert-butoxide (1.24 g, 15.5 mmol) was added portionwise. The mixture was stirred for 18 h at room temperature then concentrated in vacuo. The residue was dissolved in EtOAc, washed with 1M HCl, saturated NaHCO3 then brine, dried and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; 5% EtOAc:95% pet. ether) to yield the title compound (1.86 g, 71%).
Reaction SMILES: [NH2:1][C:2]1[C:7](I)=[CH:6][C:5]([Br:9])=[CH:4][C:3]=1[S:10]([OH:13])(=[O:12])=[O:11].[S:14]1[CH:18]=[CH:17][CH:16]=[C:15]1B(O)O.C(=O)([O-])[O-].[Na+:26].[Na+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:1][C:2]1[C:7]([C:15]2[S:14][CH:18]=[CH:17][CH:16]=2)=[CH:6][C:5]([Br:9])=[CH:4][C:3]=1[S:10]([O-:13])(=[O:12])=[O:11].[Na+:26]
Reactant: Nc1c(I)cc(Br)cc1S(=O)(=O)O
Reactant: OB(O)c1cccs1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Nc1c(-c2cccs2)cc(Br)cc1S(=O)(=O)[O-]
Temperature: 0 °C

Procedure:
A mixture of 36 g (95.3 mmol) of 2-amino-5-bromo-3-iodobenzenesulphonic acid and 12.2 g (95.3 mmol) of 2-thienylboronic acid in 140 ml of 1,2-dimethoxyethane in the presence of 5.5 g of tetrakis(triphenylphosphine)palladium (0) and 30.3 g of sodium carbonate is heated at 70°-75° C. for 8.5 hours. The solvent is evaporated off under vacuum, the mixture is cooled to 0° C. and washed with water to pH=7, and the residue is then taken up in an ether/ethanol mixture (95:5).
Reaction SMILES: [CH2:1]([CH:8]1[N:13]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-])=O)[N:15]=2)[CH2:12][CH2:11][N:10]([C:23]2[CH:31]=[C:30]3[C:26]([C:27]([CH2:36][CH3:37])=[N:28][N:29]3[CH:32]3[CH2:35][CH2:34][CH2:33]3)=[CH:25][CH:24]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(S([O-])=O)([O-])=O.[Na+].[Na+]>C1COCC1.O>[CH2:1]([C@H:8]1[CH2:9][N:10]([C:23]2[CH:31]=[C:30]3[C:26]([C:27]([CH2:36][CH3:37])=[N:28][N:29]3[CH:32]3[CH2:35][CH2:34][CH2:33]3)=[CH:25][CH:24]=2)[CH2:11][CH2:12][N:13]1[C:14]1[N:15]=[C:16]([NH2:20])[CH:17]=[CH:18][CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCc1nn(C2CCC2)c2cc(N3CCN(c4cccc([N+](=O)[O-])n4)C(Cc4ccccc4)C3)ccc12
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCc1nn(C2CCC2)c2cc(N3CCN(c4cccc(N)n4)[C@@H](Cc4ccccc4)C3)ccc12
Yield: 2 %

Procedure:
Prepared using the same procedure described in Example 410 from 6-(3-benzyl-piperazin-1-yl)-1-cyclobutyl-3-ethyl-1H-indazole and 2-chloro-6-nitro-pyridine to afford the intermediate 6-[3-benzyl-4-(6-nitro-pyridin-2-yl)-piperazin-1-yl]-1-cyclobutyl-3-ethyl-1H-indazole {20.5 mg; LC/MS (Method B) 5.09 min, [M+1]+ 497]}. The nitro-intermediate was reduced with sodium hydrosulfite (48 mg, 0.28 mmol) in 50:50 THF/water at room temperature to obtain the title compound as a tan solid (6 mg, 2% overall). LC/MS (Method B) 4.02 min, [M+1]+ 467.
Reaction SMILES: C1COCC1.Br[CH2:7][CH2:8][CH2:9][CH2:10][CH:11]=[CH2:12].C[O:14][C:15]1[CH2:19][CH2:18][C:17](=O)[CH:16]=1>C(OCC)(=O)C>[CH2:7]([C:17]1[CH2:18][CH2:19][C:15](=[O:14])[CH:16]=1)[CH2:8][CH2:9][CH2:10][CH:11]=[CH2:12]
Reactant: COC1=CC(=O)CC1
Reactant: C=CCCCCBr
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=CCCCCC1=CC(=O)CC1
Temperature: 60 °C
Yield: 81.3 %

Procedure:
Mg turnings (972 mg, 40 mmol) were placed into a dry Schlenk flask, then THF (20 mL) was added. 6-Bromo-1-hexene (5.3 mL, 40 mmol) was placed into a separate dry flask, dissolved in THF (20 mL), then added via syringe to the Mg solution. The resulting mixture was heated at 60° C. for 12 h, then cooled to room temperature. The solution of the Grignard reagent was then separated from remaining Mg solid by transferring the solution via syringe to another Schlenk flask. The general procedure for the preparation of substrates using 3-methoxycyclopentenone (2.24 g, 20 mmol) and the solution of the Grignard reagent described above gave, after 24 h and and flash chromatography (4:1 hexanes:ethyl acetate), the title compound as a colorless liquid (2.67 g, 81%). 1H NMR (300 MHz, CDCl3): δ5.95-5.92 (m, 1 H), 5.79 (dddd, J=17.1, 10.2, 6.6, 6.6 Hz, 1 H), 5.06-4.92 (m, 2 H), 2.66 -2.54 (m, 2 H), 2.48-2.37 (m, 4 H), 2.15 -2.04 (m, 2 H), 1.69-1.54 (m, 2 H), 1.53-1.39 (m, 2 H). 13C NMR (75 MHz, CDCl3): δ6209.9, 182.9, 138.3, 129.4, 114.8, 35.4, 33.5, 33.4, 31.6, 28.6, 26.6. IR (neat): 2929, 2860, 1706, 1615, 1437, 1183, 994, 909, 839 cm−1.
Reaction SMILES: [N:1]([CH:4]1[CH2:10][CH2:9][C:8]2[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=2[NH:6][C:5]1=[O:15])=[N+]=[N-].C(O)C.CCOCC>[Ni].O>[NH2:1][CH:4]1[CH2:10][CH2:9][C:8]2[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=2[NH:6][C:5]1=[O:15]
Reactant: [N-]=[N+]=NC1CCc2ccccc2NC1=O
Agent: [Ni]
Solvent: O
Solvent: CCO
Solvent: CCOCC
Product: NC1CCc2ccccc2NC1=O
Reaction time: 0.5 h

Procedure:
To a solution of 3-azido-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one (see Example 1) (27 g) in 2B ethanol (3500 ml) stirring at room temperature under an atmosphere of nitrogen, a suspension of Raney nickel in water (50 ml, washed with 10 volumes of ethanol) was added. The mixture was stirred at room temperature for 2 hours when an additional 30 ml of Raney nickel suspension was added. After stirring for an additional 30 minutes, the catalyst was filtered off and the solvent removed under reduced pressure to give an oil which solidified on addition of ether to give 3-amino-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one, melting at 161°-2°.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][OH:4].C[O:6][C:7]([C:9]1[C:13]([NH:14][C:15]([C:17]2[C:22]([NH:23][C:24]3[CH:25]=[N:26][CH:27]=[N:28][CH:29]=3)=[CH:21][CH:20]=[C:19]([CH:30]3[CH2:32][CH2:31]3)[N:18]=2)=[O:16])=[CH:12][N:11]([CH3:33])[N:10]=1)=O>>[OH:4][CH2:3][CH2:2][NH:1][C:7]([C:9]1[C:13]([NH:14][C:15]([C:17]2[C:22]([NH:23][C:24]3[CH:25]=[N:26][CH:27]=[N:28][CH:29]=3)=[CH:21][CH:20]=[C:19]([CH:30]3[CH2:32][CH2:31]3)[N:18]=2)=[O:16])=[CH:12][N:11]([CH3:33])[N:10]=1)=[O:6]
Reactant: NCCO
Reactant: COC(=O)c1nn(C)cc1NC(=O)c1nc(C2CC2)ccc1Nc1cncnc1
Product: Cn1cc(NC(=O)c2nc(C3CC3)ccc2Nc2cncnc2)c(C(=O)NCCO)n1
Yield: 6 %

Procedure:
According to the general method described in step 5 of example 27, reaction of 2-amino-ethanol with 4-{[6-cyclopropyl-3-(pyrimidin-5-ylamino)-pyridine-2-carbonyl]-amino}-1-methyl-1H-pyrazole-3-carboxylic acid methyl ester provided the title compound (6%) as amorphous yellow solid.
Reaction SMILES: [S:1]([N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12]1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].[Br:20]Br>C(Cl)Cl>[Br:20][C:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:11]([S:1]([C:4]2[CH:5]=[CH:6][C:7]([CH3:8])=[CH:9][CH:10]=2)(=[O:2])=[O:3])[CH:12]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3ccccc32)cc1
Reactant: BrBr
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2cc(Br)c3ccccc32)cc1

Procedure:
To a solution of compound 82 (13 g, 47.9 mmol) in methylene chloride (100 mL) at 0° C. was added bromine (2.7 mL, 52.7 mmol) dropwise. After reaction complete, the resulting solution was evaporated under reduced pressure. The residue was quenched with saturated Na2S2O4 solution, work-up with Et2O. After evaporation of volatile solvent, the title compound was obtained by trituration with hexane.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:7][CH:8]=1.[Br:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][C:26](Cl)=[O:27])=[CH:21][CH:20]=1.BrC(C1C=CC=CC=1)C(Cl)=O.C(Cl)(=O)C(Cl)=O>C(OCC)(=O)C.C(Cl)Cl.O>[Br:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][C:26]([N:11]([CH2:10][CH2:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:27])=[CH:21][CH:20]=1
Reactant: COc1cccc(CCNc2ccccc2)c1
Reactant: O=C(Cl)Cc1ccc(Br)cc1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C(Cl)C(Br)c1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: ClCCl
Product: COc1cccc(CCN(C(=O)Cc2ccc(Br)cc2)c2ccccc2)c1
Reaction time: 1 h
Yield: 97.3 %

Procedure:
To a solution of {2-(3-methoxyphenyl)ethyl}phenylamine (1.06 g, 4.65 mmol) in ethyl acetate (80 mL) under nitrogen was added a solution of 4-bromophenylacetyl chloride (1.06 g, 4.65 mmol) in ethyl acetate (20 mL), the bromophenylacetyl chloride being prepared from the corresponding carboxylic acid (1 g, 4.65 mmol) and oxalyl chloride (0.61 mL, 6.98 mmol) in CH2Cl2 (20 mL). After 1 hour, the reaction was poured into water (50 mL). The organic layer was dried over MgSO4, filtered and concentrated to provide the title compound (1.92 g, 98% yield): EI−MS (m/z) 423.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[NH:4][C:3]=1/[CH:8]=[C:9]1\[C:10](=[O:25])[N:11]([C:18](N2C=CN=C2)=[O:19])[C:12]2[C:17]\1=[CH:16][CH:15]=[CH:14][CH:13]=2.[N:26]1([CH2:31][CH2:32][OH:33])[CH2:30][CH2:29][CH2:28][CH2:27]1.C(O)(C(F)(F)F)=O.ClCCl>C1COCC1>[N:26]1([CH2:31][CH2:32][O:33][C:18]([N:11]2[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)/[C:9](=[CH:8]/[C:3]3[NH:4][C:5]([CH3:7])=[CH:6][C:2]=3[CH3:1])/[C:10]2=[O:25])=[O:19])[CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: OCCN1CCCC1
Reactant: Cc1cc(C)c(/C=C2\C(=O)N(C(=O)n3ccnc3)c3ccccc32)[nH]1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cc1cc(C)c(/C=C2\C(=O)N(C(=O)OCCN3CCCC3)c3ccccc32)[nH]1
Yield: 14.8 %

Procedure:
A reaction mixture containing 3-[1-(3,5-dimethyl-1h-pyrrol-2-yl)-meth-(z)-ylidene]-1-(imidazol-1-ylcarbonyl)-1,3-dihydro-indole-2-one (166 mg, 0.5 mmol), 2-pyrrolidin-1-yl-ethanol (115 mg, 1.0 mmol), and TFA (0.13 mL, 1.5 mmol) in 2 mL of THF, and 2 mL of dichloromethane gave 3-[1-(3,5-dimethyl-1H-pyrrol-2-yl)-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-indole-1-carboxylic acid 2-pyrrolidin-1-yl-ethyl ester (28 mg, 15%) as a yellow solid. 1HNMR (400 MHz, DMSO-d6) δ 12.56 (s, br, 1H, N-1′), 7.80–7.86 (m, 2H), 7.64 (s, 1H, H-vinyl), 7.16–7.20 (m, 2H), 6.10 (s, 1H, H-4′), 4.46 (t, J=5.47 Hz, 2H, CH2), 2.83 (m, br, 2H, CH2), 2.56 (m, br, 4H, CH2×2), 2.36 (s, 3H, CH3), 2.33 (s, 3H, CH3), and 1.69 (m, br, 4H, CH2×2).