Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8](Cl)=[O:9])[CH:5]=[CH:4][N:3]=1.[NH2:11][C:12]1[CH:13]=[C:14]([NH:19][C:20]([C:22]2[CH:27]=[CH:26][N:25]=[C:24]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[CH:23]=2)=[O:21])[CH:15]=[CH:16][C:17]=1[CH3:18].C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([NH:11][C:12]2[CH:13]=[C:14]([NH:19][C:20]([C:22]3[CH:27]=[CH:26][N:25]=[C:24]([N:28]4[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)[CH:23]=3)=[O:21])[CH:15]=[CH:16][C:17]=2[CH3:18])=[O:9])[CH:5]=[CH:4][N:3]=1
Reactant: O=C(Cl)c1ccnc(Cl)c1
Reactant: Cc1ccc(NC(=O)c2ccnc(N3CCOCC3)c2)cc1N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(NC(=O)c2ccnc(N3CCOCC3)c2)cc1NC(=O)c1ccnc(Cl)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 90.4 %

Procedure:
2-Chloropyridine4-carbonyl chloride (0.143 g) was added to a stirred mixture of N-(3-amino4-methylphenyl)-2-morpholinopyridine4 carboxamide (0.211 g), triethylamine (0.164 g) and methylene chloride (10 ml) and the mixture was stirred at ambient temperature for 16 hours. The precipitate was isolated, washed with a saturated aqueous sodium bicarbonate solution and with methylene chloride and dried under vacuum at 40° C. There was thus obtained the title compound (0.276 g); NMR Spectrum: (DMSOd6) 2.2 (s, 3H), 3.50-3.53 (m, 4H), 3.69-3.73 (m, 4H), 7.08 (d, 1H), 7.24 (d, 2H), 7.34 (d, 1H) 7.81 (s, 1H), 7.88 (d, 1H), 7.98 (s, 1H), 8.26 (d, 1H), 8.6 (d, 1H); Mass Spectrum M+H+ 452 and 454.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:16](=[O:23])[CH2:17][N:18]1[CH:22]=[N:21][CH:20]=[N:19]1.[CH2:24]([Mg]Cl)[CH2:25][CH3:26]>ClCCl.C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]([Cl:15])=[CH:13][CH:14]=2)[CH:5]=[CH:4][C:3]=1[C:16]([OH:23])([CH2:24][CH2:25][CH3:26])[CH2:17][N:18]1[CH:22]=[N:21][CH:20]=[N:19]1
Reactant: CCC[Mg]Cl
Reactant: O=C(Cn1cncn1)c1ccc(Oc2ccc(Cl)cc2)cc1Cl
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCCC(O)(Cn1cncn1)c1ccc(Oc2ccc(Cl)cc2)cc1Cl
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 36 %

Procedure:
MgBr diethyl etherate (10.5 g, 40.2 mmol) was added to a solution of the above-mentioned ethanone (6.0 g, 16.8 mmol) in dichloromethane (DCM, 65 ml) and the mixture stirred at room temperature for about 90 min. This mixture was then cooled to about 0° C. and n-propylmagnesium chloride (22.8 ml of a 2 M solution in THF, 45.6 mmol) was added dropwise. After stirring for about two hours, the mixture was allowed to warm to room temperature and was then quenched by addition of a saturated ammonium chloride solution. The organic components were extracted three times with DCM, the organic phases combined, washed again with saturated ammonium chloride solution, dried and the solvents evaporated. Addition of diisopropyl ether resulted in precipitation of the unreacted starting material, which was filtered off. The filtrate was then purified using reverse phase chromatography, to give the product as a light brown colored solid (2.5 g, 36%, HPLC2 Rt=1.26 min, masse=392).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:27][CH:28]2[CH2:30][CH2:29]2)[C:5]2[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=3)=[CH:9][N:8](S(C3C=CC(C)=CC=3)(=O)=O)[C:6]=2[N:7]=1.[NH2:31][C:32]1[CH:40]=[C:39]2[C:35]([CH:36]=[N:37][NH:38]2)=[CH:34][CH:33]=1.C[Si](Cl)(C)C>C(O)CCC>[CH:28]1([NH:27][C:4]2[C:5]3[C:10]([C:11]4[CH:12]=[CH:13][N:14]=[CH:15][CH:16]=4)=[CH:9][NH:8][C:6]=3[N:7]=[C:2]([NH:31][C:32]3[CH:40]=[C:39]4[C:35]([CH:36]=[N:37][NH:38]4)=[CH:34][CH:33]=3)[N:3]=2)[CH2:29][CH2:30]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ccncc3)c3c(NC4CC4)nc(Cl)nc32)cc1
Reactant: Nc1ccc2cn[nH]c2c1
Agent: C[Si](C)(C)Cl
Solvent: CCCCO
Product: c1cc(-c2c[nH]c3nc(Nc4ccc5cn[nH]c5c4)nc(NC4CC4)c23)ccn1
Temperature: 116 °C
Reaction time: 18 h
Yield: 26.1 %

Procedure:
A mixture of 2-chloro-N-cyclopropyl-5-(pyridin-4-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (51 mg, 0.12 mmol), 6-aminoindazole (31 mg, 0.23 mmol) and TMSCl (0.040 mL, 0.32 mmol) in nBuOH (2 mL) was stirred at 116° C. for 18 h. It was then concentrated in vacuo. The residue was purified by HPLC to give the titled compound (12 mg). MS 383.2 (M+H); UV 204.9, 250.9, 307.9 nm.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([O:13][CH3:14])=[C:11]([O:15][CH:16]([CH2:19][CH3:20])[CH2:17][CH3:18])[CH:10]=[C:9]2[C:4]=1[C:5](=[O:29])[CH:6]=[C:7]([S:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1)[O:8]2.C(OC([N:37](C(OC(C)(C)C)=O)[CH2:38][C:39](O)=[O:40])=O)(C)(C)C.C1(N=C=NC2CCCCC2)CCCCC1.[ClH:64]>ClCCl.C(OCC)(=O)C>[ClH:64].[CH2:19]([CH:16]([O:15][C:11]1[CH:10]=[C:9]2[C:4]([C:5](=[O:29])[CH:6]=[C:7]([S:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][C:39](=[O:40])[CH2:38][NH2:37])=[CH:24][CH:23]=3)[O:8]2)=[C:3]([O:2][CH3:1])[C:12]=1[O:13][CH3:14])[CH2:17][CH3:18])[CH3:20]
Reactant: CC(C)(C)OC(=O)N(CC(=O)O)C(=O)OC(C)(C)C
Reactant: CCC(CC)Oc1cc2oc(Sc3ccc(O)cc3)cc(=O)c2c(OC)c1OC
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCC(CC)Oc1cc2oc(Sc3ccc(OC(=O)CN)cc3)cc(=O)c2c(OC)c1OC
Reaction time: 3 h

Procedure:
300 ml in dichloromethane of 5.66 g of 5,6-dimethoxy-7-(1-ethylpropoxy)-2-(4-hydroxyphenylthio)chromone obtained in Example 25, 2.62 g of N-t-butoxycarbonyl(Boc)glycine, and 3.08 g of 1,3-dicyclohexylcarbodiimide (DCC) was stirred over 5.5 hours at room temperature. The solution thus reacted was gravitationally filtered. The solvent was distilled out from the filtrate, so that N-t-butoxycarbonyl(Boc)glycine ester was obtained. This product was dissolved in 100 ml of ethyl acetate. Then, hydrochloric acid gas was introduced and bubbled in the solution for 10 min., followed by stirring for 3 hours. Subsequently, 200 ml ether was added and the resulting crystals were collected by filtration and dried, whereby 6.44 g of 7-(1-ethylpropoxy)-5,6-dimethoxy-2-(4-glycyloxyphenylthio)chromone hydrochloride with the following physicochemical properties was obtained.
Reaction SMILES: C(N(CC)CC)C.ClC(OCC(C)C)=O.[N+:16]([C:19]1[CH:34]=[CH:33][C:22]([CH2:23][O:24][C:25]([NH:27][CH2:28][CH2:29][C:30](O)=[O:31])=[O:26])=[CH:21][CH:20]=1)([O-:18])=[O:17].S.[S:36](=O)(=O)(O)O>C(Cl)Cl>[N+:16]([C:19]1[CH:34]=[CH:33][C:22]([CH2:23][O:24][C:25]([NH:27][CH2:28][CH2:29][C:30]([OH:31])=[S:36])=[O:26])=[CH:21][CH:20]=1)([O-:18])=[O:17]
Reactant: O=S(=O)(O)O
Reactant: O=C(O)CCNC(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: CC(C)COC(=O)Cl
Agent: S
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCCC(O)=S)OCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4.4 g (40 mmol) of triethylamine and a solution of 2.8 ml (2 mmol) of isobutyl chloroformate in 20 ml of dry methylene chloride are added dropwise, in succession, to a solution, cooled to -10°, of 5.36 g (20 mmol) of 3-p-nitrobenzyloxycarbonylaminopropionic acid in 100 l of dry methylene chloride. The reaction mixture is stirred for one hour at -18°, then for 11/2 hours a strong current of hydrogen sulphide is passed through and the mixture allowed to heat up to room temperature. After acidifying with 2 N sulphuric acid, again in the cold, the organic phase is separated, dried and concentrated in vacuo. The 3-p-nitrobenzyloxycarbonylaminothiopropionic acid obtained can be used without further purification.
Reaction SMILES: C[C:2]1[C:7]2[C:8](=[O:17])[N:9]([CH2:13][C:14]([O-:16])=[O:15])[S:10](=[O:12])(=[O:11])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH3:18][O-].[Na+].Cl>CN(C=O)C.O>[OH:17][C:8]1[C:7]2[CH:2]=[CH:3][CH:4]=[CH:5][C:6]=2[S:10](=[O:12])(=[O:11])[NH:9][C:13]=1[C:14]([O:16][CH3:18])=[O:15]
Reactant: Cc1cccc2c1C(=O)N(CC(=O)[O-])S2(=O)=O
Reactant: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C1=C(O)c2ccccc2S(=O)(=O)N1
Temperature: 10 °C
Reaction time: 0.5 h

Procedure:
In a nitrogen atmosphere, a solution of 30 grams (0.117 moles) of methyl-2,3-dihydro-3-oxo-1,2-benzisothiazoline-2-acetate 1,1-dioxide in 50 ml DMF is added, with stirring, to a suspension of 18.9 grams (0.351 moles) of sodium methoxide in 100 ml DMF over a period of about 5 minutes and the internal temperature is maintained at 15°-30°C. by means of an ice bath. The stirring acidification continued for 30 minutes at about 30°C. after the completion of the addition. With external cooling, a solution of 35 ml concentrated HCl in 600 ml of water is added, maintaining the internal temperature below 35°C. After this addition, the mixture is cooled to 10°C. and filtered. The filter cake is washed thoroughly with water and the product is dried. Yield is 23.5 grams (78.2%) m.p. 173°-175°C. The total addition and stirring time prior to acidification should be less than 1 hour. For example, if the addition should take 30 minutes the batch should be stirred only an additional 15-20 minutes.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH:12]=[N:13]O)[CH:6]=[CH:5]2.[H][H]>CO.O1CCCC1.[Ni]>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH2:12][NH2:13])[CH:6]=[CH:5]2
Reactant: ON=Cc1ccc2cc(Cl)ccc2n1
Reactant: [H][H]
Agent: [Ni]
Solvent: C1CCOC1
Solvent: CO
Product: NCc1ccc2cc(Cl)ccc2n1

Procedure:
A solution of 0.78 g (3.79 mmol) of 6-chloroquinoline-2-carbaldehydeoxime in 30 mL of saturated ammoniacal methanol and 10 mL of tetrahydrofuran is hydrogenated with Raney nickel for 48 hours at 3 bar hydrogen pressure. The catalyst is filtered off and the solution is concentrated. The residue is chromatographed on silica gel, eluting with a gradient of dichloromethane/methanol (90:10) to dichloromethane/methanol/25% aqueous ammonia (90:10:1). The corresponding fractions are combined and concentrated by evaporation. Yield: 0.33 g (45% of theory); Rf value: 0.43 (silica gel; dichloromethane/methanol=9:1); C10H9ClN2 (192.65); mass spectrum: (M+H)+=193/195 (chlorine isotope).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:16])[CH3:15].[O-:17][C:18]#[N:19].[Na+]>C(O)(=O)C.O>[NH:1]([C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:16])[CH3:15])[C:18]([NH2:19])=[O:17]
Reactant: N#C[O-]
Reactant: CC(=O)NCCc1c[nH]c2ccc(N)cc12
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)NCCc1c[nH]c2ccc(NC(N)=O)cc12

Procedure:
The product from Example 3 is dissolved in acetic acid-water (1:2, 3 mL) and sodium cyanate (2 mmol) added. This is stirred until a brownish gum is precipitated. The mixture is extracted with chloroform (3×30 mL), and the organic extracts washed with saturated sodium bicarbonate, dried with magnesium sulfate and the solvent evaporated in vacuo. The resulting product is purified by reverse-phase HPLC as above.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][C:11]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[O:16][CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.C(Cl)(Cl)Cl>[OH:8][CH2:9][CH2:10][C:11]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[O:16][CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:21])[CH3:22])=[O:18])[CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCOC(CCO[Si](C)(C)C(C)(C)C)(c2ccccc2)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCOC(CCO)(c2ccccc2)C1
Yield: 83 %

Procedure:
The above tert-butyl 2-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-2-phenylmorpholine-4-carboxylate was stirred in 4 mL of a 1 M solution of tetrabutylammonium fluoride in THF for 1 h at room temperature. The reaction mixture was then diluted with CHCl3, washed with saturated aqueous NaHCO3, and purified (1:1 hex:EtOAc) to provide tert-butyl 2-(2-hydroxyethyl)-2-phenylmorpholine-4-carboxylate (449 mg, 83%) as an oil: 1H NMR (400 MHz, CDCl3), δ 7.47-7.41 (m, 2H), 7.40-7.35 (m, 2H), 7.28 (m, 1H), 4.34 (m, 1H), 3.77-3.63 (m, 2H), 3.63-3.48 (m, 3H), 3.35 (m, 1H), 3.17 (m, 1H), 2.08 (m, 1H), 1.89 (m, 1H), 1.50-1.37 (br., 9H); ESI-MS 330 (M+Na).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:11](Cl)(=[O:13])=[O:12])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH3:15][NH:16][CH2:17][C:18]#[CH:19].C(N(CC)CC)C>O1CCCC1>[CH2:17]([N:16]([CH3:15])[S:11]([C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)(=[O:13])=[O:12])[C:18]#[CH:19]
Reactant: COc1ccc(S(=O)(=O)Cl)cc1OC
Reactant: C#CCNC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C#CCN(C)S(=O)(=O)c1ccc(OC)c(OC)c1
Yield: 64.8 %

Procedure:
3,4-Dimethoxybenzene sulfonyl chloride (11.8 g) in tetrahydrofuran (100 mL) is added slowly with stirring to a mixture of N-methylpropargylamine (3.5 g), triethylamine (5.05 g), and tetrahydrofuran (100 mL). The resulting mixture is refluxed 1 hour, cooled, filtered, and evaporated to dryness. The residue is treated with water, filtered, washed with water, and dried. Recrystallization from ethanol gave 8.7 g of the title product.
Reaction SMILES: O[CH:2]=[C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][CH:4]1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[NH:20]1[CH:24]=[CH:23][N:22]=[CH:21]1>C(O)C>[N:20]1([CH:2]=[C:3]2[C:12](=[O:13])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[O:5][CH:4]2[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:24]=[CH:23][N:22]=[CH:21]1
Reactant: O=C1C(=CO)C(c2ccccc2)Oc2ccccc21
Reactant: c1c[nH]cn1
Solvent: CCO
Product: O=C1C(=Cn2ccnc2)C(c2ccccc2)Oc2ccccc21

Procedure:
A solution containing 1 g 3-hydroxymethylidene-flavanone and 0.3 g imidazole in 10 ml absolute ethanol is refluxed for 10 minutes then cooled on an ice bath. After evaporation the oil is dissolved in methylene chloride and purified by acidic extraction. The resulting oil is crystallized in a mixture of hexane and ethyl acetate. Pure 3-(1-imidazolyl)methylidene-flavanone is obtained as white crystals; m.p. 129°-131° C.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([CH2:6][NH:7][CH2:8][CH2:9][NH2:10])=[N:2]1.CS[C:13](=[NH:18])[NH:14][N+:15]([O-:17])=[O:16]>>[N+:15]([NH:14][C:13]([NH:10][CH2:9][CH2:8][NH:7][CH2:6][C:3]1[CH:4]=[CH:5][NH:1][N:2]=1)=[NH:18])([O-:17])=[O:16]
Reactant: CSC(=N)N[N+](=O)[O-]
Reactant: NCCNCc1cc[nH]n1
Product: N=C(NCCNCc1cc[nH]n1)N[N+](=O)[O-]

Procedure:
Reaction of N-(3-pyrazolylmethyl)ethylenediamine with S-methyl-N-nitroisothiourea by the procedure of Example 2(ii) gives N-nitro-N'-[2-(3-pyrazolylmethylamino)-ethyl]guanidine, and in the procedure of Example 2(iii) gives N-methyl-N'-[2-(3-pyrazolylmethylamino)ethyl]-N"-nitroguanidine.
Reaction SMILES: [Cl:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[F:12][C:13]([F:17])([CH3:16])[CH2:14][OH:15]>>[Cl:1][C:2]1[C:3]([O:15][CH2:14][C:13]([F:17])([F:12])[CH3:16])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]
Reactant: O=C(O)c1cnc(Cl)c(Cl)c1
Reactant: CC(F)(F)CO
Product: CC(F)(F)COc1ncc(C(=O)O)cc1Cl
Yield: 85 %

Procedure:
The title compound is prepared in 85% yield (1.12 g, colorless oil) from 5,6-dichloronicotinic acid (1.00 g, 5.21 mmol) and 2,2-difluoropropan-1-ol (0.50 g, 5.21 mmol) in a similar manner to Step-1 of Intermediate-A3.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][C:6]=1[C:7]([OH:9])=O)([CH3:3])[CH3:2].[CH2:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20][NH:19]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20][N:19]1[C:7]([C:6]1[CH:10]=[C:11]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:12]=[CH:13][C:5]=1[O:4][CH:1]([CH3:2])[CH3:3])=[O:9]
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)O
Reactant: c1ccc2c(c1)CNC2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
A mixture of 0.387 mmol 2-isopropoxy-5-methanesulfonyl-benzoic acid (example BI), 0.464 mmol 2,3-Dihydro-1H-isoindole (commercial), 0.426 mmol TBTU and 1.935 mmol DIPEA in 1.4 ml DMF was stirred at RT for 2 h. The reaction mixture was evaporated in vacuo. The residue was taken in water and extracted with ethylacetate. The combined organic phases were washed with saturated sodium bicarbonate solution, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by chromatography (SiO2, heptane/ethyl acetate) to yield the title compound as a light brown solid (88% yield). MS (m/e): 360.2 [M+H]+, 100%)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:28])[C:10]2[CH:15]=[C:14]([C:16]([O:18][CH3:19])=[O:17])[CH:13]=[CH:12][C:11]=2[NH:20][CH2:21][CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[N:6][CH:7]=1.Cl[C:30]1[CH:35]=[CH:34][N:33]=[C:32]([C:36]#[N:37])[CH:31]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:28])[C:10]2[CH:15]=[C:14]([C:16]([O:18][CH3:19])=[O:17])[CH:13]=[CH:12][C:11]=2[NH:20][CH2:21][CH:22]2[CH2:27][CH2:26][N:25]([C:30]3[CH:35]=[CH:34][N:33]=[C:32]([C:36]#[N:37])[CH:31]=3)[CH2:24][CH2:23]2)=[N:6][CH:7]=1
Reactant: N#Cc1cc(Cl)ccn1
Reactant: COC(=O)c1ccc(NCC2CCNCC2)c(C(=O)Nc2ccc(Cl)cn2)c1
Product: COC(=O)c1ccc(NCC2CCN(c3ccnc(C#N)c3)CC2)c(C(=O)Nc2ccc(Cl)cn2)c1
Yield: 96.3 %

Procedure:
Using a similar procedure to that described in Example 52, N-(5-chloropyridin-2-yl)-5-methoxycarbonyl-2-[(4-piperidinylmethyl)amino]benzamide (0.30 g, 0.74 mmol) and 4-chloro-2-cyanopyridine (0.21 g, 1.5 mmol) afforded 360 mg (96%) of the title compound.
Reaction SMILES: S([O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][OH:23])(C1C=CC(C)=CC=1)(=O)=O.[C:24]1(=[O:34])[NH:28][C:27](=[O:29])[C:26]2=[CH:30][CH:31]=[CH:32][CH:33]=[C:25]12.N12CCCN=C1CCCCC2>CN(C=O)C>[C:24]1(=[O:34])[NH:28][C:27](=[O:29])[C:26]2=[CH:30][CH:31]=[CH:32][CH:33]=[C:25]12.[CH2:22]([OH:23])[CH2:21][O:20][CH2:19][CH2:18][O:17][CH2:16][CH2:15][O:14][CH2:13][CH2:12][OH:11]
Reactant: Cc1ccc(S(=O)(=O)OCCOCCOCCOCCO)cc1
Agent: O=C1NC(=O)c2ccccc21
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: OCCOCCOCCOCCO
Temperature: 70 °C

Procedure:
To a stirred solution of 31.96 g (0.092 mol) of 2a in 400 mL of anhydrous DMF was added 14.2 g (1.05 equiv.) of phthalimide and 14.4 mL (1.05 equiv.) of 1,8-diazabicyclo[5.4.0]undec-7-ene. The solution was heated at 70° C. for 18 h then concentrated in vacuo. The crude yellow oil was purified by flash chromatography using 1600 mL of silica gel and eluting with 25% EtOAc-50% EtOAc-75% EtOAc in hexane, then EtOAc, then 10% MeOH-20% MeOH in EtOAc to afford 23.8 g (80%) of 3a as an oil. Upon standing, 3a became a waxy white solid. 1H NMR (300 MHz, CDCl3) d 7.84-7.78 (m, 2H), 7.70-7.66 (m, 2H), 3.86 (t, J=5.6 Hz, 2H) 3.70 (t, J=5.6 Hz, 2H), 3.64-3.51 (m, 12H), 2.67 (bs, 1H); 13C NMR (75 MHz, CDCl3) d 168.2, 133.8, 132.0, 123.1, 72.4, 70.5, 70.4, 70.2, 70.0, 67.8, 61.6, 37.2.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:6]=1[O:13][CH3:14])(=[O:3])[CH3:2].S(=O)(=O)(O)O.[Br:20]Br>O>[C:1]([NH:4][C:5]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([Br:20])=[CH:7][C:6]=1[O:13][CH3:14])(=[O:3])[CH3:2]
Reactant: BrBr
Reactant: COc1ccc(OC)c(NC(C)=O)c1
Agent: O=S(=O)(O)O
Solvent: O
Product: COc1cc(NC(C)=O)c(OC)cc1Br

Procedure:
300 Parts of 1-acetylamino-2,5-dimethoxybenzene were introduced at about 5°C in 1500 parts of 95 % sulfuric acid while stirring, 127 Parts of bromine were added dropwise at about 5°C with outside cooling. The mixture was stirred at 20°C for about 3 hours, 6000 parts by volume of water were added dropwise (a temperature of 25°C is not to be exceeded), the precipitate was suction-filtered and dried. 381 parts of 1-acetylamino-2,5-dimethoxy-4-bromobenzene (=90.4 % of the theory) were obtained.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH2:10][C:11]([C:33]([OH:35])=O)=[CH:12][C:13]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([N:28]4[CH2:32][CH2:31][CH2:30][CH2:29]4)=[O:27])=[CH:22][CH:21]=3)=[CH:16][C:14]=2[N:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH2:37]([NH:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=1[OH:48])[CH2:38][CH3:39]>>[OH:48][C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=1[CH2:41][N:40]([CH2:37][CH2:38][CH3:39])[C:33]([C:11]1=[CH:12][C:13]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([N:28]4[CH2:32][CH2:31][CH2:30][CH2:29]4)=[O:27])=[CH:22][CH:21]=3)=[CH:16][C:14]=2[N:15]=[C:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:10]1)=[O:35]
Reactant: CCCNCc1ccccc1O
Reactant: CC(C)(C)OC(=O)NC1=Nc2cc(-c3ccc(C(=O)N4CCCC4)cc3)ccc2C=C(C(=O)O)C1
Agent: Cl
Product: CCCN(Cc1ccccc1O)C(=O)C1=Cc2ccc(-c3ccc(C(=O)N4CCCC4)cc3)cc2N=C(NC(=O)OC(C)(C)C)C1

Procedure:
The title compound was prepared by the procedure as described in Example 101 (Step H) using (1E,4E)-2-(tert-butoxycarbonylamino)-8-(4-(pyrrolidine-1-carbonyl)phenyl)-3H-benzo[b]azepine-4-carboxylic acid and 2-((propylamino)methyl)phenol hydrochloride.
Reaction SMILES: [F:1][C:2]1[C:3]([C:22]([NH:24][CH2:25][C:26]2([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[O:23])=[N:4][CH:5]=[CH:6][C:7]=1[S:8][C:9]1[S:13][C:12]([NH:14][C:15]2[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][N:16]=2)=[N:11][CH:10]=1.C(OC([NH:45][C@@H:46]([CH:50]([CH3:52])[CH3:51])[C:47](O)=[O:48])=O)(C)(C)C>>[NH2:45][C@@H:46]([CH:50]([CH3:52])[CH3:51])[C:47]([N:29]1[CH2:28][CH2:27][C:26]([CH2:25][NH:24][C:22](=[O:23])[C:3]2[C:2]([F:1])=[C:7]([S:8][C:9]3[S:13][C:12]([NH:14][C:15]4[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][N:16]=4)=[N:11][CH:10]=3)[CH:6]=[CH:5][N:4]=2)([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH2:31][CH2:30]1)=[O:48]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: Cc1ccnc(Nc2ncc(Sc3ccnc(C(=O)NCC4(c5ccccc5)CCNCC4)c3F)s2)c1
Product: Cc1ccnc(Nc2ncc(Sc3ccnc(C(=O)NCC4(c5ccccc5)CCN(C(=O)[C@@H](N)C(C)C)CC4)c3F)s2)c1

Procedure:
Following the procedure given for example 94, 3-fluoro-4-(2-(4-methylpyridin-2-ylamino)thiazol-5-ylthio)-N-((4-phenylpiperidin-4-yl)methyl)picolinamide (compound example 11) was reacted with (S)-2-(tert-butoxycarbonylamino)-3-methylbutanoic acid give the title compound. LC/MS (M+H)+: 634. Ret. time: 1.42 min. (Condition G); analytical HPLC Ret. time: 6.58 min (Condition Q).
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([NH2:13])[CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[CH3:14][N:15]([CH2:19][CH2:20]Cl)[CH2:16][CH2:17]Cl.Cl.C(=O)([O-])[O-].[K+].[K+].CCOCC>C(O)CCC>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([N:13]3[CH2:20][CH2:19][N:15]([CH3:14])[CH2:16][CH2:17]3)[CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CN(CCCl)CCCl
Reactant: CC(=O)N1CCc2ccc(N)cc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CCCCO
Product: CC(=O)N1CCc2ccc(N3CCN(C)CC3)cc21
Reaction time: 3 h
Yield: 21.4 %

Procedure:
A stirred mixture of 1-acetyl-6-amino-2,3-dihydro-1H-indole (D10, 37.8 g, 0.22 mole), mechlorethamine hydrochloride (46 g, 0.24 mole) and anhydrous potassium carbonate (80 g, 0.58 mole) in 1-butanol (1800 ml) was heated at reflux for 8 h, then additional mechlorethamine hydrochloride (25 g, 0.13 mole) and potassium carbonate (41 g, 0.30 mole) were added and reflux continued for 3 h. The reaction mixture was allowed to cool and then washed with water (1000 ml). The aqueous wash was extracted with ethyl acetate, and the extract combined with the 1-butanol solution and concentrated in vacuo. The brown oily residue (60 g) was chromatographed on silica gel eluting with 0-8% MeOH/DCM to give an orange oil, which was trituated with ether to afford the title compound as a beige solid (12.2 g, 22%).