Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:7](=[O:8])[NH:6][C:5]2[CH:9]=[C:10]([N+:13]([O-:15])=[O:14])[CH:11]=[CH:12][C:4]=2[O:3]1.Br[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].C(=O)([O-])[O-].[K+].[K+].C(#N)C>CN(C)C=O>[CH3:1][C:2]1([CH3:16])[C:7](=[O:8])[N:6]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:5]2[CH:9]=[C:10]([N+:13]([O-:15])=[O:14])[CH:11]=[CH:12][C:4]=2[O:3]1
Reactant: CCOC(=O)CBr
Reactant: CC1(C)Oc2ccc([N+](=O)[O-])cc2NC1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC#N
Product: CCOC(=O)CN1C(=O)C(C)(C)Oc2ccc([N+](=O)[O-])cc21
Temperature: 80 °C
Reaction time: 2 h
Yield: 80.1 %

Procedure:
A mixture of 6.66 g of 3,4-dihydro-2,2-dimethyl-6-nitro-3-oxo-2H-1,4-benzoxazine, 5.51 g of ethyl bromoacetate, 4.5.6 g of potassium carbonate and 20 ml of acetonitrile was refluxed under heating for 2.5 hours. Then, 10 ml of N,N-dimethylformamide was added and the mixture was stirred at 80° C. for 2 hours. To this mixture was added 2-80 g of ethyl bromoacetate. After an hour of stirring at 80° C., 2.28 g of potassium carbonate was added and the mixture was further stirred at 80° C. for 1 hour. The reaction mixture was then concentrated under reduced pressure and the residue was chromatographed on a silica gel column, elution being carried out with hexane-ethyl acetate (10:.1). The crystals from the eluate were recrystallized from ethyl acetate-hexane to give 7.4 g of ethyl (3,4-dihydro-2,2-dimethyl-6-nitro-3-oxo-2H1,4 -benzoxazin-4-yl)acetate. This compound has the following physicochemical properties.
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[F:19][C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][C:21]=1[C:27]([F:30])([F:29])[F:28]>>[F:19][C:20]1[CH:26]=[CH:25][C:23]([NH:24][C:15](=[O:17])[CH2:14][C:9]2[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]3[CH2:2][CH2:3][O:4][CH2:5][CH2:6]3)[N:8]=2)=[CH:22][C:21]=1[C:27]([F:28])([F:29])[F:30]
Reactant: Nc1ccc(F)c(C(F)(F)F)c1
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Agent: [Na+]
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)Nc1ccc(F)c(C(F)(F)F)c1
Yield: 55.7 %

Procedure:
The product is prepared according to the procedure described in Example 5, using 260 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate and 358 mg of 4-fluoro-3-(trifluoromethyl)aniline in place of the 2,4-difluoroaniline. 222 mg of N-[4-fluoro-3-(trifluoromethyl)phenyl]-2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetamide are obtained in the form of a white solid, the characteristics of which are the following:
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[C:23]1=[CH:27][C:28]([O:32][CH2:33][CH:34]3[CH2:39][O:38][CH2:37][CH2:36][O:35]3)=[N:29][C:30](=[O:31])[N:22]1[CH2:21][CH2:20]2)=O)(C)(C)C>C1COCC1.CN(C=O)C>[O:35]1[CH2:36][CH2:37][O:38][CH2:39][CH:34]1[CH2:33][O:32][C:28]1[CH:27]=[C:23]2[C:24]3[C:19]([CH2:20][CH2:21][N:22]2[C:30](=[O:31])[N:29]=1)=[CH:18][C:17]([C:9]1[NH:8][C:16]2[C:11]([CH:10]=1)=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:26][CH:25]=3
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc3c(c2)CCn2c-3cc(OCC3COCCO3)nc2=O)cc2ccccc21
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=c1nc(OCC2COCCO2)cc2n1CCc1cc(-c3cc4ccccc4[nH]3)ccc1-2
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Compound 12 (57 mg, 0.11 mmol) was dissolved in a mixture of DCM/TFA (1/1, 2 mL) and the reaction was stirred at RT for 6 h. The mixture was evaporated to dryness to recover compound 13 as a TFA salt.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[N:10]=[CH:9][N:8]=[C:7]([NH:11][S:12](=[O:26])(=[O:25])[NH:13][CH:14]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:15][CH3:16])[C:6]=1[C:27]1[CH:32]=[CH:31][C:30]([Br:33])=[CH:29][CH:28]=1.[H-].[Na+].Cl[C:37]1[N:42]=[CH:41][C:40]([Br:43])=[CH:39][N:38]=1>C1COCC1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[Br:43][C:40]1[CH:39]=[N:38][C:37]([O:1][CH2:2][CH2:3][O:4][C:5]2[N:10]=[CH:9][N:8]=[C:7]([NH:11][S:12](=[O:26])(=[O:25])[NH:13][CH:14]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:15][CH3:16])[C:6]=2[C:27]2[CH:28]=[CH:29][C:30]([Br:33])=[CH:31][CH:32]=2)=[N:42][CH:41]=1
Reactant: CCC(NS(=O)(=O)Nc1ncnc(OCCO)c1-c1ccc(Br)cc1)OCc1ccccc1
Reactant: Clc1ncc(Br)cn1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCC(NS(=O)(=O)Nc1ncnc(OCCOc2ncc(Br)cn2)c1-c1ccc(Br)cc1)OCc1ccccc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 92.4 %

Procedure:
To a solution of 1-benzyloxypropanesulfamic acid[6-(2-hydroxyethoxy)-5-(4-bromophenyl)-pyrimidin-4-yl]-amide (237 mg, 0.441 mmol) in THF (10 mL) is added NaH (58 mg, 60% dispersion in mineral oil, 1.32 mmol). The mixture is stirred for 5 min before 2-chloro-5-bromopyrimidine (128 mg, 0.662 mmol) is added. The reaction mixture is stirred at 60° C. for 2 h, diluted with 10% aq. citric acid solution (75 mL) and extracted with EA (75 mL). The organic extract is washed twice with water (2×50 mL) and concentrated. The remaining residue is purified on prep. tlc plates (silica gel, heptane/EA 1:1) to afford 1-benzyloxypropanesulfamic acid[6-(2-(5-bromopyrimid-2-yloxy)-ethoxy)-5-(4-bromophenyl)-pyrimidin-4-yl]-amide (283 mg) as a colourless foam. LC-MS: tR=1.09 min, [M+H]+=693.12; 1H NMR (CDCl3): δ 8.48 (s, 2H), 8.34 (s, 1H), 7.58-7.53 (m, 2H), 7.38-7.28 (m, 5H), 7.16-7.11 (m, 2H), 6.84 (s, 1H), 5.97 (t, J=5.9 Hz, 1H), 4.73-4.68 (m, 2H), 4.64-4.60 (m, 2H), 4.50 (s, 2H), 3.56 (t, J=5.9 Hz, 2H), 3.17 (q, J=6.4 Hz, 2H), 1.88 (p, J=5.9 Hz, 2H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:30]([Cl:32])=[O:31])[C@H:13]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[C@H:14]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[N:15]=2)=[C:7]([O:33][CH2:34][CH3:35])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.Cl.[CH3:38][S:39]([CH2:42][CH2:43][N:44]1[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1)(=[O:41])=[O:40]>>[ClH:32].[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:30]([N:47]3[CH2:46][CH2:45][N:44]([CH2:43][CH2:42][S:39]([CH3:38])(=[O:40])=[O:41])[CH2:49][CH2:48]3)=[O:31])[C@H:13]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[C@H:14]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[N:15]=2)=[C:7]([O:33][CH2:34][CH3:35])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)CCN1CCNCC1
Reactant: CCOc1cc(C(C)(C)C)ccc1C1=N[C@@H](c2ccc(F)cc2)[C@@H](c2ccc(F)cc2)N1C(=O)Cl
Agent: Cl
Product: CCOc1cc(C(C)(C)C)ccc1C1=N[C@@H](c2ccc(F)cc2)[C@@H](c2ccc(F)cc2)N1C(=O)N1CCN(CCS(C)(=O)=O)CC1

Procedure:
[(4S,5R)-2-(4-tert-Butyl-2-ethoxy-phenyl)-4,5-bis-(4-fluoro-phenyl)-4,5-dihydro-imidazol-1-yl]-[4-(2-methanesulfonyl-ethyl)-piperazin-1-yl]-methanone hydrochloride was prepared from (4S,5R)-2-(4-tert-butyl-2-ethoxy-phenyl)-4,5-bis-(4-fluoro-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride (example 12a) and 1-(2-methanesulfonylethyl)piperazine dihydrochloride (example 17) in an analogous manner as described in example 25. LR-MS: 653.4 [(M+H)+]
Reaction SMILES: C([O:8][C:9](=[O:31])[C@@H:10]1[CH2:14][CH2:13][CH2:12][N:11]1[C:15](=[O:30])[CH:16]([CH:26]([CH2:28][CH3:29])[CH3:27])[NH:17][C:18](=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)C1C=CC=CC=1.[H][H]>CO.[C].[Pd]>[C:18]([NH:17][CH:16]([C:15]([N:11]1[CH2:12][CH2:13][CH2:14][C@H:10]1[C:9]([OH:31])=[O:8])=[O:30])[CH:26]([CH2:28][CH3:29])[CH3:27])(=[O:25])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CCC(C)C(NC(=O)c1ccccc1)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCC(C)C(NC(=O)c1ccccc1)C(=O)N1CCC[C@H]1C(=O)O

Procedure:
N-benzoyl-D,L-isoleucyl-L-proline benzyl ester (1.1 g) was dissolved in methanol (15 ml), and 10% palladium-carbon (120 mg) was added. The resulting mixture aerated with hydrogen was allowed to react at room temperature for 3 h, filtered and concentrated under reduced pressure to remove the solvent to give a colourless sticky matter (1.04 g, 99%), which was directly used for the next reaction.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]=[CH2:15])=[CH:10][N:9]=2)[CH2:4][CH2:3]1.I[C:17]1[C:25]2[C:20](=[CH:21][C:22]([CH:26]=[O:27])=[CH:23][CH:24]=2)[N:19]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])[N:18]=1>>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([C:8]2[N:9]=[CH:10][C:11](/[CH:14]=[CH:15]/[C:17]3[C:25]4[C:20](=[CH:21][C:22]([CH:26]=[O:27])=[CH:23][CH:24]=4)[N:19]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])[N:18]=3)=[CH:12][CH:13]=2)[CH2:6][CH2:7]1
Reactant: C[Si](C)(C)CCOCn1nc(I)c2ccc(C=O)cc21
Reactant: C=Cc1ccc(N2CCN(C)CC2)nc1
Product: CN1CCN(c2ccc(/C=C/c3nn(COCC[Si](C)(C)C)c4cc(C=O)ccc34)cn2)CC1
Temperature: 90 °C

Procedure:
The title compound was synthesized according to the method of Example A15A, utilizing 1-methyl-4-(5-vinylpyridin-2-yl)piperazine (65 mg, 0.32 mmol) and 3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-6-carbaldehyde (100 mg, 0.25 mmol), with heating in a sealed tube at 90° C. overnight instead of with microwave irradiation. Purified by prepTLC (SiO2 10% MeOH/DCM) to provide the title compound to as a pale orange material (46 mg, 39%). 1H NMR (400 MHz, CD3OD) δ ppm 10.14 (s, 1H), 8.34 (d, J=2.26 Hz, 1.0H), 8.24-8.28 (m, 2H), 8.00 (dd, J=8.91, 2.38 Hz, 1H), 7.80 (d, J=8.78 Hz, 1H), 7.51 (d, J=16.56 Hz, 1H), 7.36 (d, J=16.56 Hz, 1H), 6.97 (d, J=9.29 Hz, 1H), 5.85 (s, 2H), 3.77-3.87 (m, 4H), 3.63 (t, J=7.91 Hz, 2H), 3.06-3.15 (m, 4H), 2.75 (s, 3H), 0.88 (t, J=8.03 Hz, 2H), −0.09 (s, 9H); MS ESI 478.3 [M+H]+, calcd for [C26H35N5O2Si+H]+ 478.7.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[C:5]([C:9]#[N:10])=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:3]=1.[CH:17]1([OH:23])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([O:23][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[C:5]([C:9]#[N:10])=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:3]=1
Reactant: OC1CCCCC1
Reactant: N#Cc1c(Cl)nc(N)nc1-c1ccccc1
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: N#Cc1c(OC2CCCCC2)nc(N)nc1-c1ccccc1

Procedure:
From 2-amino-4-chloro-6-phenyl-pyrimidine-5-carbonitrile, cyclohexanol and DBU in DME. EI-MS m/e (%): 294 (M+, 12), 213 ([M—C6H9]+, 100), 212 ([M—C6H10]+, 48), 170 (60).
Reaction SMILES: [C:1]1([C:13]2[NH:22][C:16]3[N:17]=[CH:18][N:19]=[C:20](O)[C:15]=3[CH:14]=2)[CH:6]=[CH:5][C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:3][CH:2]=1.C(OCC)(=O)C.P(Cl)(Cl)([Cl:31])=O>>[Cl:31][C:20]1[C:15]2[CH:14]=[C:13]([C:1]3[CH:6]=[CH:5][C:4]([C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=4)=[CH:3][CH:2]=3)[NH:22][C:16]=2[N:17]=[CH:18][N:19]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1ncnc2[nH]c(-c3ccc(-c4ccccc4)cc3)cc12
Solvent: CCOC(C)=O
Product: Clc1ncnc2[nH]c(-c3ccc(-c4ccccc4)cc3)cc12
Temperature: 0 °C
Reaction time: 4 h

Procedure:
Under a protective gas, 430.5 mg (1.5 mmol) of 6-(biphen-4-yl)-7H-pyrrolo[2,3-d]-pyrimidin-4-ol in 6 ml of phosphorus oxychloride are heated at boiling for 4 hours. The reaction mixture is poured into ice-water and ethyl acetate. The aqueous phase is separated off and extracted with ethyl acetate. Concentrating the organic phases by evaporation and stirring the residue in hot THF/isopropanol yield the title compound; m.p. 295-300° C. (decomposition); FAB-MS: (M+H)+ =306.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH:11]([N:13]([CH2:16][CH:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[CH2:14][CH3:15])[CH3:12])=[CH:6][CH:5]=1.[O-:23][C:24]#[N:25].[K+]>O>[CH3:2][O:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH:11]([N:13]([CH2:16][CH:17]2[CH2:22][CH2:21][N:20]([C:24]([NH2:25])=[O:23])[CH2:19][CH2:18]2)[CH2:14][CH3:15])[CH3:12])=[CH:8][CH:9]=1
Reactant: N#C[O-]
Reactant: CCN(CC1CCNCC1)C(C)Cc1ccc(OC)cc1
Agent: Cl
Agent: [K+]
Solvent: O
Product: CCN(CC1CCN(C(N)=O)CC1)C(C)Cc1ccc(OC)cc1
Yield: 77.6 %

Procedure:
A mixture of N-[2-(4-methoxyphenyl)-1-methylethyl]-N-ethyl-(piperidin-4-ylmethyl)amine hydrochloride (0.42 grams, 1.16 mmole) and potassium cyanate (1.5 grams, 18.5 mmole) in water (5 ml) was heated under reflux for about 20 minutes. The white solid which formed upon cooling was collected and recrystallized from chloroform/hexane to give N-[2-(4-methoxyphenyl)-1-methylethyl]-N-ethyl-(1-aminocarbonylpiperidin-4-ylmethyl)amine (0.3 grams, 77%), m.p. 104-10° C.
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:13]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:14]([CH:19]=O)=[CH:15][CH:16]=[CH:17][CH:18]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>CO.ClCCl.C([O-])(O)=O.[Na+]>[C:13]1([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH2:19][N:10]1[CH2:11][CH2:12][N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:8][CH2:9]1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: O=Cc1ccccc1-c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: c1ccc(-c2ccccc2CN2CCN(c3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 18.3 %

Procedure:
1-Phenylpiperazine (266 mg, 1.64 mmol) was dissolved in methanol (7 mL) in a reaction vessel and, after adding biphenyl-2-carbaldehyde (150 mg, 0.82 mmol), the mixture was stirred at room temperature for 2 hours. 2 hours later, NaBH(OAc)3 (529 mg, 2.46 mmol) was added and the mixture was further stirred for 8 hours. After the reaction was completed, the reaction solution was diluted with dichloromethane and saturated NaHCO3 solution was added. After extraction, organic layer was dried with anhydrous MgSO4 and then filtered. The filtrate was concentrated and the concentrate was purified by column chromatography (hexane:diethyl ether=8:1) to obtain 50 mg of the target compound (0.15 mmol, 18.3%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([C:13]([NH:15][NH:16]C(OC(C)(C)C)=O)=[O:14])=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.C(O)(=O)C>C(Cl)Cl>[CH3:1][O:2][C:3]1[C:12]([C:13]([NH:15][NH2:16])=[O:14])=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: COc1nc2ccccc2cc1C(=O)NNC(=O)OC(C)(C)C
Solvent: CC(=O)O
Solvent: ClCCl
Product: COc1nc2ccccc2cc1C(=O)NN
Temperature: 0 °C
Reaction time: 1 h

Procedure:
tert-Butyl 2-(2-methoxyquinoline-3-carbonyl)hydrazinecarboxylate (1.23 g, 3.87 mmol) was dissolved in DCM (10 mL) and cooled to 0° C. Trifluoroacetic acetic acid (10 mL) was added and the mixture was stirred at room temperature for 1 h. Solvents were evaporated and the residue was washed with water. The product was used without purification in the next step. MS (ES) C11H11N3O2 requires: 217.22, found: 218.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([C:11]([NH2:13])=O)[N:4]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:23])=CC=1>C1COCC1>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([C:11](=[S:23])[NH2:13])[N:4]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: COc1cc(OC)nc(C(N)=O)n1
Solvent: C1CCOC1
Product: COc1cc(OC)nc(C(N)=S)n1
Temperature: 90 °C
Reaction time: 1 h
Yield: 72 %

Procedure:
To a stirred solution of compound 286 (21.86 g, 1 eq.) in dry THF (200 mL) was added Lawesson's reagent (29 g, 0.6 eq.) under nitrogen. The mixture was then stirred at 90° C. for 1 hr and then concentrated in vacuo. The residue obtained was triturated in a DCM/diisopropyl ether mixture to yield compound 287 as an orange solid in 72% yield. MS (ESI, E1 m/z=200 (MH+).
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2].C(N(CC)CC)C.[N+:18]([C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1)([O-:20])=[O:19]>ClCCl>[N+:1]([C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[NH:6][C:25](=[O:26])[C:24]1[CH:23]=[CH:22][C:21]([N+:18]([O-:20])=[O:19])=[CH:29][CH:28]=1)([O-:3])=[O:2]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: Nc1ccccc1[N+](=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1ccccc1[N+](=O)[O-])c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 63.6 %

Procedure:
To a mixture of 2-nitroaniline (1.38 g) and triethylamine (1.67 ml) in dichloromethane (30 ml) were added 4-nitrobenzoyl chloride (1.85 g) and the solution was stirred at ambient temperature for 4 hours. The solution was washed successively with 1N hydrochloric acid, saturated aqueous sodium hydrogencarbonate, water and brine, and the organic layer was dried over magnesium sulfate. The solvent was evaporated in vacuo and the residue was solidified with n-hexane to give 2-nitro-N-(4nitrobenzoyl)aniline (1.82 g).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[CH3:2].I[CH2:20][CH2:21][CH3:22]>O1CCOCC1>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([N:13]2[CH2:14][CH2:15][N:16]([CH2:20][CH2:21][CH3:22])[CH2:17][CH2:18]2)[CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[CH3:2]
Reactant: CCCI
Reactant: CCOc1cc(N2CCNCC2)ccc1[N+](=O)[O-]
Solvent: C1COCCO1
Product: CCCN1CCN(c2ccc([N+](=O)[O-])c(OCC)c2)CC1
Temperature: 102 °C
Yield: 89.4 %

Procedure:
To 1-[3-(ethyloxy)-4-nitrophenyl]piperazine (Example 143, step A) (0.405 g, 1.61 mmol) in 10 mL of dioxane was added, 1-iodopropane (0.55 g, 3.22 mmol). The mixture was heated to 102° C. for 1 h. The solvent was rotovaped down and the crude product was purified by flash chromatography to give the title compound of step A (0.422 g, 1.44 mmol, 90%). 1H NMR (400 MHz, CD3OD) δ ppm 7.88 (d, J=9.34 Hz, 1H), 6.53 (dd, J=9.34, 2.56 Hz, 1H), 6.49 (d, J=2.56 Hz, 1H), 4.16 (q, J=7.02 Hz, 2H), 3.42-3.48 (m, 4H), 2.64-2.70 (m, 4H), 2.40-2.48 (m, 2H), 1.54-1.64 (m, 2H), 1.42 (t, J=6.96 Hz, 3H), 0.94 (t, J=7.42 Hz, 3H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[CH2:7][C@H:8]([NH:16][S:17]([C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:27](=[O:34])[CH2:28][CH2:29][CH2:30][N:31]([CH3:33])[CH3:32])=[CH:22][C:21]=1[OH:35])(=[O:19])=[O:18])[CH:9]([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12])([CH3:4])([CH3:3])[CH3:2].[N:37]1[C:46]2[C:41](=[C:42]([CH2:47][CH2:48]O)[CH:43]=[CH:44][CH:45]=2)[CH:40]=[CH:39][CH:38]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C(Cl)Cl>[C:1]([O:5][C:6](=[O:36])[CH2:7][C@H:8]([NH:16][S:17]([C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:27](=[O:34])[CH2:28][CH2:29][CH2:30][N:31]([CH3:33])[CH3:32])=[CH:22][C:21]=1[O:35][CH2:48][CH2:47][C:42]1[CH:43]=[CH:44][CH:45]=[C:46]2[C:41]=1[CH:40]=[CH:39][CH:38]=[N:37]2)(=[O:19])=[O:18])[CH:9]([O:10][CH2:11][CH3:12])[O:13][CH2:14][CH3:15])([CH3:3])([CH3:2])[CH3:4]
Reactant: CCOC(OCC)[C@H](CC(=O)OC(C)(C)C)NS(=O)(=O)c1ccc(NC(=O)CCCN(C)C)cc1O
Reactant: OCCc1cccc2ncccc12
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCOC(OCC)[C@H](CC(=O)OC(C)(C)C)NS(=O)(=O)c1ccc(NC(=O)CCCN(C)C)cc1OCCc1cccc2ncccc12
Temperature: 25 °C
Yield: 41 %

Procedure:
A mixture of 0.22 g (0.41 mmol), (S)-3-[4-(4-dimethylamino-butanoylamino)-2-hydroxy-benzensulfonylamino]-4,4-diethoxy-butyric acid tert-butyl ester, 0.079 g (0.41 mmol), 2-quinolin-5-yl-ethanol, 0.14 g (0.62 mmol) triphenylphosphine, and anhydrous methylene chloride (5 mL) was stirred at room temperature. Diethyl azodicarboxylate 0.1 mL (0.62 mmol) was added dropwise and the resulting orange solution was stirred at room temperature for 24 h. TLC analysis indicated complete reaction. The reaction mixture was concentrated in vacuo to give a deep yellow oil. The product was purified over silica eluting with 10% (8:1 EtOH/NH4OH): 90% methylene chloride to yield 0.115 g (0.17 mmol, 41%) of (S)-3-[4-(4-dimethylamino-butanoylamino)-2-(2-quinolin-5-yl-ethoxy) benzensulfonylamino]-4,4-diethoxy-butyric acid tert-butyl ester as a yellow oil. MS (APCI) m/z 685.5 (M−1).
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH2:13][CH3:14])=[CH:9][CH:10]=2)[N:5]([CH2:15][CH3:16])[C:4]=1[C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:32])[NH:25][CH2:26][C:27](OCC)=[O:28])=[CH:19][CH:18]=1)#[N:2].Cl.CC(C)=[O:36]>>[CH2:13]([O:12][C:8]1[CH:7]=[C:6]2[C:11]([C:3]([C:1]([NH2:2])=[O:36])=[C:4]([C:17]3[CH:22]=[CH:21][C:20]([N:23]4[C:27](=[O:28])[CH2:26][NH:25][C:24]4=[O:32])=[CH:19][CH:18]=3)[N:5]2[CH2:15][CH3:16])=[CH:10][CH:9]=1)[CH3:14]
Reactant: CCOC(=O)CNC(=O)Nc1ccc(-c2c(C#N)c3ccc(OCC)cc3n2CC)cc1
Reactant: CC(C)=O
Agent: Cl
Product: CCOc1ccc2c(C(N)=O)c(-c3ccc(N4C(=O)CNC4=O)cc3)n(CC)c2c1
Yield: 87 %

Procedure:
A solution of ethyl {3-[4-(3-cyano-6-ethoxy-1-ethyl-1H-indol-2-yl)-phenyl]-ureido}acetate (compound 773, 325 mg, 0.748 mmol), prepared in procedure 1AV, step A, in acetone (5 mL) is treated with HCl (3 mL, 6 N), and the resulting solution is heated to reflux overnight. The reaction mixture is cooled, and the resulting precipitate is collected by filtration, washed with ether and dried under high vacuum to afford the product, 6-ethoxy-1-ethyl-2-[4-(2,5-dioxo-imidazolidin-1-yl)-phenyl]-1H-indole-3-carboxamide (264 mg, 0.650 mmol, 87%).
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH3:18])(=[O:5])[CH2:2][CH2:3][CH3:4].[NH2:19][C:20]1[C:21]([CH3:26])=[CH:22][CH:23]=[CH:24][CH:25]=1>O1CCOCC1>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH3:26])=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH3:18])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)c1cnc2c(OC)cccc2c1Cl
Reactant: Cc1ccccc1N
Solvent: C1COCCO1
Product: CCCC(=O)c1cnc2c(OC)cccc2c1Nc1ccccc1C
Reaction time: 1 h

Procedure:
A mixture of 3-butyryl-4-chloro-8-methoxyquinoline (6.0 g, 0.023 mol) and o-toluidine (6.0 ml, 0.056 mol) in 1,4-dioxan (100 ml) was heated under reflux with stirring for 1 hour. The mixture was evaporated and chromatographed (silica gel, 2% methanol in dichloromethane) to give 3-butyryl-4-(2-methylphenylamino)-8-methoxyquinoline as an oil which was isolated as the hydrochloride salt (2.12 g, 25.1%), m.p. 215°-217° by crystallisation from ethyl acetate and then recrystallisation from acetone.
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:7][N:8]([CH3:12])[CH2:9][CH2:10]Cl>O>[C:1]([NH:5][CH2:10][CH2:9][N:8]([CH3:12])[CH3:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)N
Reactant: CN(C)CCCl
Agent: Cl
Solvent: O
Product: CN(C)CCNC(C)(C)C
Yield: 59.4 %

Procedure:
Into a 50 mL-volume flask equipped with a stirrer, a thermometer and a dropping funnel were placed 16 g (0.22 mol) of t-butylamine, 5.0 g (35 mmol) of 2-(dimethylamino)ethyl chloride hydrochloride and 1 ml of water. And then, the mixture was reacted at 70° C. for 10 hours. After the completion of the reaction, the reaction solution was subjected to extraction with 25 ml of hexane twice, and the hexane layer was concentrated under reduced pressure. The resultant concentrate was distilled under reduced pressure (60° C., 2.4 kPa), to provide 3.0 g of 1-(t-butylamino)-2-dimethylaminoethane. (Isolation yield: 60%)
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:12][C:13]([OH:15])=[O:14])[C:4]2[CH2:5][CH2:6][CH2:7][C:8](=O)[C:9]=2[CH:10]=1.Cl.[NH2:17][OH:18].C([O-])(=O)C.[Na+]>C(O)C>[OH:18][N:17]=[C:8]1[CH2:7][CH2:6][CH2:5][C:4]2[N:3]([CH2:12][C:13]([OH:15])=[O:14])[C:2]([CH3:1])=[CH:10][C:9]1=2
Reactant: Cc1cc2c(n1CC(=O)O)CCCC2=O
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: Cc1cc2c(n1CC(=O)O)CCCC2=NO
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2-(2-methyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1-yl)acetic acid (4.0 g, 19 mmol), hydroxylamine hydrochloride (2.0 g, 29 mmol) and anhydrous sodium acetate (2.4 g, 29 mmol) in ethanol (40 mL) was heated under reflux for 6 h with stirring. After cooling to r.t. and holding overnight, the mixture was further cooled to 4° C. The solid product was collected by filtration, washed with water (15 mL) followed by ethanol (15 mL) then dried under vacuum at 40° C. to afford the title compound as a pale brown solid; 3.68 g (86%); purity: 96.7 area % by HPLC; m/z: 223 (MH+); 1H-NMR: 9.82 (1H, br s), 6.48 (1H, d, J=0.90 Hz), 4.58 (2H, s), 2.56-2.51 (2H, m), 2.29-2.24 (2H, m), 2.09 (3H, s), 1.86-1.79 (2H, m).