Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:8]1[CH2:39][C:10]2([CH2:17][N:16]3[C:18]4[CH:19]=[C:20]([C:31]([O:33][CH3:34])=[O:32])[CH:21]=[CH:22][C:23]=4[C:24]([CH:25]4[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]4)=[C:15]3[C:14]3[CH:35]=[CH:36][CH:37]=[CH:38][C:13]=3[O:12][CH2:11]2)[CH2:9]1)C1C=CC=CC=1.[ClH:40]>CO.CCOC(C)=O.[Pd]>[CH:25]1([C:24]2[C:23]3[CH:22]=[CH:21][C:20]([C:31]([O:33][CH3:34])=[O:32])=[CH:19][C:18]=3[N:16]3[C:15]=2[C:14]2[CH:35]=[CH:36][CH:37]=[CH:38][C:13]=2[O:12][CH2:11][C:10]2([CH2:9][NH:8][CH2:39]2)[CH2:17]3)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]1.[ClH:40]
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC1(COc2ccccc2-3)CN(Cc2ccccc2)C1
Agent: [Pd]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC1(CNC1)COc1ccccc1-3

Procedure:
A 0.07M solution of methyl 1-benzyl-14′-cyclohexylspiro[azetidine-3,7′-indolo[1,2-e][1,5]benzoxazocine]-11′-carboxylate in MeOH and EtOAc (2:1) was stirred in the presence of 10% Pd/C and 3M HCl under H2-atmosphere for 3 days. The reaction mixture was filtered on CELITE and co-evaporated with toluene, pentane and Et2O until a solid was obtained; this solid was washed with Et2O and dried to afford the title compound as its HCl salt (46%). MS (ES+) m/z 431 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH:3]=[CH:4][C:5]#[N:6].C(N(CC)CC)C.[F:15][C:16]1[C:24]([F:25])=[C:23]([F:26])[C:22]([F:27])=[CH:21][C:17]=1[C:18](Cl)=[O:19]>O1CCOCC1>[CH3:1][N:2]([CH3:7])[CH:3]=[C:4]([C:18](=[O:19])[C:17]1[CH:21]=[C:22]([F:27])[C:23]([F:26])=[C:24]([F:25])[C:16]=1[F:15])[C:5]#[N:6]
Reactant: O=C(Cl)c1cc(F)c(F)c(F)c1F
Reactant: CN(C)C=CC#N
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CN(C)C=C(C#N)C(=O)c1cc(F)c(F)c(F)c1F

Procedure:
First 9.7 g of 3-dimethylaminoacrylonitrile are added dropwise, then 10.5 g of triethylamine are added to a solution of 21.25 g of 2,3,4,5-tetrafluorobenzoyl chloride in 75 ml of anhydrous dioxane, while cooling in ice and stirring at about 10°-15° C. The mixture is heated to boiling under reflux for 4 hours, the solvent is removed by distillation in vacuo, and the residue is taken up in methylene chloride/water. The phases are separated, and the aqueous solution is again extracted with methylene chloride. The combined organic phases are washed with water, dried with sodium sulphate, and the methylene chloride is removed in vacuo. After recrystallization of the crystalline residue from ethanol, 23.5 g of 3-dimethylamino-2-(2,3,4,5-tetrafluorobenzoyl)acrylonitrile of melting point 149°-151° C. are obtained.
Reaction SMILES: [N:1]([C@H:4]([CH3:21])[CH2:5][N:6]1[C:10]2=[CH:11][C:12]3[C:17]([CH2:16][CH:15]=[CH:14][C:13]=3[O:18][CH2:19][CH3:20])=[C:9]2[CH:8]=[N:7]1)=[N+]=[N-].[C:22]([OH:29])(=[O:28])/[CH:23]=[CH:24]/[C:25]([OH:27])=[O:26]>C(O)C.C(OCC)C.CO.[Pt]=O>[C:22]([OH:29])(=[O:28])/[CH:23]=[CH:24]/[C:25]([OH:27])=[O:26].[CH2:19]([O:18][C:13]1[CH:14]=[CH:15][CH2:16][C:17]2[C:12]=1[CH:11]=[C:10]1[C:9]=2[CH:8]=[N:7][N:6]1[CH2:5][C@H:4]([NH2:1])[CH3:21])[CH3:20]
Reactant: CCOC1=C2C=c3c(cnn3C[C@@H](C)N=[N+]=[N-])=C2CC=C1
Agent: O=[Pt]
Agent: O=C(O)/C=C/C(=O)O
Solvent: CO
Solvent: CCOCC
Solvent: CCO
Product: CCOC1=C2C=c3c(cnn3C[C@@H](C)N)=C2CC=C1
Temperature: 25 °C
Reaction time: 15 h
Yield: 86.3 %

Procedure:
1.76 g (6.21 mmol) of (R)-1-(2-azido-propyl)-7-ethoxy-1,4-dihydro-indeno[2,1-c]pyrazole dissolved in 100 ml of anhydrous ethanol were hydrogenated on 180 mg of platinum oxide for 17 hours. The catalyst was subsequently filtered off, rinsed with ethanol and the solvent was removed in a vacuum. The colorless oil obtained was dissolved in 100 ml of anhydrous diethyl ether, filtered and treated while stirring with a solution of 721 mg (6.21 mmol) of fumaric acid in 10 ml of methanol. The mixture was stirred at room temperature for 15 hours and the white crystals were subsequently filtered off. 2.0 g (86%) of (R)-2-(7-ethoxy-1,4-dihydro-indeno[2,1-c]pyrazol-1-yl)-1-methyl-ethylamine fumarate (1:1) with m.p. 161° were obtained.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]1(=[O:22])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][CH2:14]1.[CH3:23][Si:24](Cl)([CH3:26])[CH3:25]>O1CCCC1.CCCCCC>[CH3:23][Si:24]([CH3:26])([CH3:25])[O:22][C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][CH:14]=1
Reactant: C[Si](C)(C)Cl
Reactant: O=C1CCc2ccccc21
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C[Si](C)(C)OC1=CCc2ccccc21
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
In a 2-liter flask were charged 38.2 g (0.378 mol) of diisopropylamine and 265 ml of tetrahydrofuran (THF). The mixture was cooled to 0° C. and 229 ml of a hexane solution of 1.65 M n-butyllithium was added thereto. After 15 minutes' stirring, the mixture turned dark brown. The solution was further cooled to -78° C., to which was added 50 ml of a THF solution of 50 g (378 mmol) of 1-indanone and the resulting mixture was stirred for 30 minutes. Then, 205 g (1.89 mol) of trimethylsilyl chloride was added at -78° C., and the coolant was removed to raise the temperature to room temperature followed by stirring for 2 hours.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:12][NH2:13]>>[CH3:12][NH:13][S:8]([C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1)(=[O:10])=[O:9]
Reactant: CN
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Product: CNS(=O)(=O)c1ccc(Br)cc1

Procedure:
Entry 54: 4-Bromobenzenesulfonyl chloride was reacted with methylamine according to Method A15, Step 1 to afford N-methyl-4-bromobenzenesulfonamide. N-Methyl-4-bromobenzenesulfonamide was coupled with phenol according to Method 15, Step 2 to afford 4-(4-(N-methylsulfamoyl)phenoxy)benzene. 4-(4-(N-Methylsulfamoyl)phenoxy)benzene was converted into 4-(4-(N-methylsulfamoyl)phenoxy)-1-nitrobenzene according to Method A15, Step 3. 4-(4-(N-Methylsulfamoyl)phenoxy)-1-nitrobenzene was reduced to 4-(4-N-methylsulfamoyl)phenyloxy)aniline according to Method A15, Step 4. According to Method C1a, 4-chloro-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(3-N-methylsulfamoyl)phenyloxy)aniline to afford the urea.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:50])[C@@H:13]([NH:23][C:24]([C:26]2[CH:30]=[C:29]([O:31][CH2:32][C:33]([O:35]CC3C=CC=CC=3)=[O:34])[N:28]([C:43]3[CH:48]=[CH:47][CH:46]=[C:45]([F:49])[CH:44]=3)[N:27]=2)=[O:25])[CH2:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2]>C(OCC)(=O)C>[CH2:1]([O:3][C:4]([N:6]1[CH2:7][CH2:8][N:9]([C:12](=[O:50])[C@@H:13]([NH:23][C:24]([C:26]2[CH:30]=[C:29]([O:31][CH2:32][C:33]([OH:35])=[O:34])[N:28]([C:43]3[CH:48]=[CH:47][CH:46]=[C:45]([F:49])[CH:44]=3)[N:27]=2)=[O:25])[CH2:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(OCC(=O)OCc3ccccc3)n(-c3cccc(F)c3)n2)CC1
Solvent: CCOC(C)=O
Product: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(OCC(=O)O)n(-c3cccc(F)c3)n2)CC1
Reaction time: 16 h

Procedure:
To a solution of 3.100 g 4-((S)-2-{[5-Benzyloxycarbonylmethoxy-1-(3-fluoro-phenyl)-1H-pyrazole-3-carbonyl]-amino}-4-tert-butoxycarbonyl-butyryl)-piperazine-1-carboxylic acid ethyl ester in 20 ml ethyl acetate were added under argon 0.5 g Pd/C (10%) and the suspension was stirred under an atmosphere of hydrogen (3 bar) for 16 h. The suspension was filtered over a plug of Celite® and washed with ethyl acetate. The crude product obtained after evaporation of the solvent was dried under vacuo. Yield: 2.77 g.
Reaction SMILES: C(OC([N:8]1[CH2:16][C:15]2([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][CH:19]=3)[N:11]([C:12](=[O:34])[N:13]([C:26]3[CH:31]=[C:30]([Cl:32])[CH:29]=[C:28]([Cl:33])[CH:27]=3)[C:14]2=[O:25])[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Br:24][C:21]1[CH:22]=[CH:23][C:18]([CH2:17][C:15]23[C:14](=[O:25])[N:13]([C:26]4[CH:31]=[C:30]([Cl:32])[CH:29]=[C:28]([Cl:33])[CH:27]=4)[C:12](=[O:34])[N:11]2[CH2:10][CH2:9][NH:8][CH2:16]3)=[CH:19][CH:20]=1
Reactant: CC(C)(C)OC(=O)N1CCN2C(=O)N(c3cc(Cl)cc(Cl)c3)C(=O)C2(Cc2ccc(Br)cc2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1N(c2cc(Cl)cc(Cl)c2)C(=O)C2(Cc3ccc(Br)cc3)CNCCN12
Reaction time: 5 h
Yield: 93.2 %

Procedure:
To a solution of 4-(tert-butoxycarbonyl)-6-(4-bromobenzyl)-8-(3,5-dichlorophenyl)-1,4,8-triazabicyclo[4.3.0]nonane-7,9-dione (0.82 g) in CH2Cl2 (10 mL) was added TFA (0.5 mL). Additional TFA (0.5 mL) was added after 1 hour and 2.5 hours. After 5 hours, the reaction mixture was diluted with CH2Cl2, washed with aqueous NaHCO3, and brine, dried (Na2SO4), filtered, and concentrated to yield the titled compound (0.63 g). MS (m/z) 468 (MH+). mp 92.5° C.
Reaction SMILES: [O:1]([C:8]1[CH:23]=[CH:22][C:11]([O:12][CH2:13][CH2:14][S:15][C:16]2[N:21]=[CH:20][CH:19]=[CH:18][N:17]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:24]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Cl:24][CH:14]([S:15][C:16]1[N:17]=[CH:18][CH:19]=[CH:20][N:21]=1)[CH2:13][O:12][C:11]1[CH:22]=[CH:23][C:8]([O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:9][CH:10]=1
Reactant: c1ccc(Oc2ccc(OCCSc3ncccn3)cc2)cc1
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClC(Cl)(Cl)Cl
Product: ClC(COc1ccc(Oc2ccccc2)cc1)Sc1ncccn1
Reaction time: 8 h
Yield: 74.7 %

Procedure:
To a solution of 2-[2-(4-phenoxyphenoxy)ethylthio]pyrimidine (324 mg, 1.0 mmol) in carbon tetrachloride (3 ml), there was added N-chlorosuccinimide (160 mg, 1.2 mmol) with stirring under ice-cooling. The reaction system was gradually elevated to room temperature, and stirring was continued overnight. The precipitate was separated by filtration, and the filtrate was concentrated. Recrystallization of the residue from cyclohexane gave 2-[1-chloro-2-(4-phenoxyphenoxy)ethylthio]pyrimidine (268 mg) as pale yellow crystals. M.P., 86.0° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([CH2:23][O:24][C:25]2[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=2)[C:13]([NH:15][CH2:16][CH2:17][CH2:18][C:19]([O:21]C)=[O:20])=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl>>[ClH:1].[C:19]([CH2:18][CH2:17][CH2:16][NH:15][C:13](=[O:14])[CH:12]([NH:11][S:8]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)(=[O:10])=[O:9])[CH2:23][O:24][C:25]1[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=1)([OH:21])=[O:20]
Reactant: COC(=O)CCCNC(=O)C(COc1cccnc1)NS(=O)(=O)c1ccc(Cl)cc1
Agent: Cl
Product: O=C(O)CCCNC(=O)C(COc1cccnc1)NS(=O)(=O)c1ccc(Cl)cc1
Yield: 151.1 %

Procedure:
The procedure described in Example 115 was repeated, except that (RS)-2-(4-chlorobenzenesulfonylamino)-N-(3-methoxycarbonylpropyl)-3-(pyridin-3-yloxy)propanamide (39.6 mg) was hydrolyzed, and then reacted with HCl to obtain (RS)-N-(3-carboxypropyl)-2-(4-chlorobenzenesulfonylamino)-3-(pyridin-3-yloxy)propanamide hydrochloride (31.4 mg).
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[CH3:19])[CH2:10][CH2:9][C:8]2=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.Cl.[NH2:29][OH:30]>CO.C(Cl)Cl>[C:1]1([CH:7]2[CH2:12][CH:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[CH3:19])[CH2:10][CH2:9][C:8]2=[N:29][OH:30])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NO
Reactant: Cc1ccccc1C1CCC(=O)C(c2ccccc2)C1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccccc1C1CCC(=NO)C(c2ccccc2)C1
Temperature: 25 °C
Reaction time: 48 h
Yield: 59 %

Procedure:
2-Phenyl-4-(2-methylphenyl)cyclohexanone, 13.1 grams (49.5 mmol), was dissolved in 200 mL methanol/methylene chloride, followed by 11.1 mL (79.3 mmol) triethylamine and 5.5 grams (79.3 mmol) hydroxylamine hydrochloride. The solution was stirred at room temperature for 48 hours, the solvent evaporated, and the resulting solid washed with methanol and dried to afford 8.2 grams (59%) of a yellow solid.
Reaction SMILES: [N+](C1C=CC(O[C:11]([C:13]2[C:14]3[CH:23]=[C:22]([CH2:24][CH3:25])[O:21][C:15]=3[C:16]([O:19][CH3:20])=[N:17][CH:18]=2)=[O:12])=CC=1)([O-])=O.[NH2:26][C:27]1[N:31]([CH3:32])[N:30]=[CH:29][C:28]=1[C:33]#[N:34]>>[C:33]([C:28]1[CH:29]=[N:30][N:31]([CH3:32])[C:27]=1[NH:26][C:11]([C:13]1[C:14]2[CH:23]=[C:22]([CH2:24][CH3:25])[O:21][C:15]=2[C:16]([O:19][CH3:20])=[N:17][CH:18]=1)=[O:12])#[N:34]
Reactant: CCc1cc2c(C(=O)Oc3ccc([N+](=O)[O-])cc3)cnc(OC)c2o1
Reactant: Cn1ncc(C#N)c1N
Product: CCc1cc2c(C(=O)Nc3c(C#N)cnn3C)cnc(OC)c2o1
Yield: 17.9 %

Procedure:
Starting from 2-ethyl-7-methoxyfuro[2,3-c]pyridine-4-carboxylic acid 4-nitrophenyl ester (100 mg) and 5-amino-1-methyl-1H-pyrazole-4-carbonitrile (71 mg). Purification by column chromatography on silica eluting with 50% hexane in ethyl acetate followed by trituration with ether gave the title compound (17 mg) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23]C)[CH:18]=2)(=[O:16])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([S-])C.[Na+]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([OH:23])[CH:18]=2)(=[O:16])=[O:15])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cccc(S(=O)(=O)N2CCN(C(=O)OC(C)(C)C)CC2)c1
Agent: CC[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2cccc(O)c2)CC1

Procedure:
4-(3-Methoxy-benzenesulfonyl)-piperazine-1-carboxylic acid tert-butyl ester (8.21 g, 0.023 mol) and sodium ethanethiolate (3.9 g, 0.046 mol) were heated in DMF (50 mL) at reflux under Ar for 1 h, then concentrated in vacuo to remove a portion of the DMF. The residue was added to ice-H2O and extracted with EtOAc (3×). The aqueous basic layer was acidified with 1N HCl and extracted with EtOAc (4×100 mL). The organic layers were combined, washed with H2O (2×), brine, and dried (Na2SO4). Filtration and concentration in vacuo gave the title compound. 1H NMR (CDCl3) δ 7.40 (t, 1H, J=8 Hz), 7.27-7.29 (m, 1H), 7.22 (d, 1H, J=2 Hz), 7.08 (dd, 1H, J=2, 5 Hz), 6.21 (br s, 1H), 3.51 (t, 2H, J=5 Hz), 2.98 (t, 2H, J=5 Hz), 1.42 (s, 9H).
Reaction SMILES: O[CH2:2][C@@H:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]([S:14]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH2:6][CH2:5][CH2:4]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:44].C(=O)([O-])O.[Na+]>ClCCl>[Br:44][CH2:2][C@@H:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]([S:14]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH2:6][CH2:5][CH2:4]1
Reactant: BrC(Br)(Br)Br
Reactant: Cc1ccc(S(=O)(=O)N2CCC[C@H](CO)c3ccccc32)cc1
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)N2CCC[C@H](CBr)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.6 %

Procedure:
A mixture of (5S)-5-hydroxymethyl-1-(p-toluenesulfonyl)-2,3,4,5-tetrahydro-1H-benzazepine (1.33 g), triphenylphosphine (2.10 g), carbon tetrabromide (2.65 g) and dichloromethane (50 ml) is stirred at room temperature for 30 minutes. The reaction solution is poured into a saturated aqueous sodium hydrogen carbonate solution, and the mixture is extracted with dichloromethane. The extract is dried over sodium sulfate, and concentrated under reduced pressure to remove the solvent, and the resulting residue is purified by silica gel column chromatography (solvent; dichloromethane:n-hexane=4:1), and recrystallized from diethyl ether--n-hexane to give (5S)-5-bromomethyl-1-(p-toluenesulfonyl)-2,3,4,5-tetrahydro-1H-benzazepine (1.26 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:8]([C:11]1[CH:16]=[CH:15][C:14](Cl)=[CH:13][CH:12]=1)([O-:10])=[O:9]>>[CH:5]1[CH:6]=[CH:7][C:2]([NH:1][C:14]2[CH:15]=[CH:16][C:11]([N+:8]([O-:10])=[O:9])=[CH:12][CH:13]=2)=[CH:3][CH:4]=1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Reactant: Nc1ccccc1
Product: O=[N+]([O-])c1ccc(Nc2ccccc2)cc1

Procedure:
aniline method, where p-nitro-chlorobenzene and aniline as raw materials react in the presence of a catalyst to produce 4-nitrodiphenylamine, then, 4-nitrodiphenylamine is reduced by sodium sulfide to form 4-aminodiphenylamine;
Reaction SMILES: O=[C:2]1[C:14]2[C:13]3[C:12]([C:15]([O:17]C)=O)=[CH:11][CH:10]=[CH:9][C:8]=3[NH:7][C:6]=2[CH2:5][N:4]([C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:20])[CH2:3]1.C(O)(=O)C.O.[NH2:34][NH2:35]>CO>[O:17]=[C:15]1[C:12]2=[CH:11][CH:10]=[CH:9][C:8]3[NH:7][C:6]4[CH2:5][N:4]([C:19]([O:21][CH2:22][C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=5)=[O:20])[CH2:3][C:2]([C:14]=4[C:13]=32)=[N:35][NH:34]1
Reactant: NN
Reactant: COC(=O)c1cccc2[nH]c3c(c12)C(=O)CN(C(=O)OCc1ccccc1)C3
Solvent: CO
Solvent: O
Solvent: CC(=O)O
Product: O=C1NN=C2CN(C(=O)OCc3ccccc3)Cc3[nH]c4cccc1c4c32
Reaction time: 8 h
Yield: 94 %

Procedure:
A solution of compound 2-benzyl 5-methyl 4-oxo-3,4-dihydro-1H-pyrido[3,4-b]indole-2,5(9H)-dicarboxylate (70 mg, 0.18 mmol), acetic acid (0.15 mL, 2.6 mmol), and hydrazine hydrate (0.86 mL, 1.5 mmol) in methanol (4 mL) was heated at reflux. After 8 h, the solid was collected by hot filtration and washed with water, EtOAc, and dichloromethane, to give the target compound (61 mg, 94%). 1H NMR DMSO-d6) δ 11.8 (s, 1H), 10.1 (s, 1H), 7.54 (d, 1H, J=8.4 Hz), 7.48 (d, 1H, J=7.2 Hz), 7.38 (m, 4H), 7.32 (m, 1H), 7.18 (dd, 1H, J=8.4, 7.2 Hz), 5.15 (s, 2H), 4.82 (m, 2H), 4.28 (m, 2H). MS (ESI) m/e [M+1]+ 361.
Reaction SMILES: [NH2:1][C:2]([CH3:6])([CH3:5])[C:3]#[CH:4].[F:7][C:8]1[C:9](I)=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])/[C:11]/2=[CH:18]\[C:19]1[NH:23][CH:22]=[N:21][C:20]=1[CH3:24]>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.[Cu]I.CN(C=O)C.CCN(CC)CC>[NH2:1][C:2]([CH3:6])([CH3:5])[C:3]#[C:4][C:9]1[C:8]([F:7])=[CH:16][CH:15]=[C:14]2[C:10]=1/[C:11](=[CH:18]/[C:19]1[NH:23][CH:22]=[N:21][C:20]=1[CH3:24])/[C:12](=[O:17])[NH:13]2
Reactant: Cc1nc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(I)c21
Reactant: C#CC(C)(C)N
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1nc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(C#CC(C)(C)N)c21

Procedure:
Using Method C above, 3-amino-3-methyl-1-butyne (42.2 mg, 0.51 mmol) (Aldrich) was coupled with (Z)-1,3-dihydro-5-fluoro-4-iodo-3-[(4-methyl-1H-imidazol-5-yl)methylene]-2H-indol-2-one (Starting Material 3 supra) (75 mg, 5 0.203 mmol) using (Ph3P)4Pd (23.5 mg) and CuI (4 mg) as catalyst in DMF (3 mL) and Et3N (3 mL) as solvent at 80° C. for 18 h to give (Z)-4-[3-amino-3-methyl-1-butynyl]-1,3-dihydro-5-fluoro-3-[(4-methyl-1H-imidazol-5-yl)methylene]-2H-indol-2-one. (Yield 44 mg, 67%).
Reaction SMILES: [CH3:1][O:2][C:3](/[CH:5]=[CH:6]/[C:7]([OH:9])=[O:8])=[O:4].Cl.CN(C)CCCN=C=NCC.[CH2:22]([N:24]([CH2:30][CH3:31])[C:25](=[O:29])[C@@H:26](O)[CH3:27])[CH3:23]>ClCCl.CN(C1C=CN=CC=1)C>[C:7]([O:9][C@H:26]([C:25](=[O:29])[N:24]([CH2:30][CH3:31])[CH2:22][CH3:23])[CH3:27])(=[O:8])/[CH:6]=[CH:5]/[C:3]([O:2][CH3:1])=[O:4]
Reactant: CCN(CC)C(=O)[C@H](C)O
Reactant: COC(=O)/C=C/C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CCN(CC)C(=O)[C@H](C)OC(=O)/C=C/C(=O)OC
Yield: 21.5 %

Procedure:
Following general procedure B2, (2E)-3-(methoxycarbonyl)prop-2-enoic acid (methyl hydrogen fumarate, MHF) (0.50 g, 3.84 mmol) was activated with N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDAC) (0.88 g, 4.60 mmol) in 12 mL of dichloromethane (DCM) at ca. 0° C. (2S)—N,N-Diethyl-2-hydroxypropanamide (0.44 g, 3.07 mmol) (0.44 g, 3.07 mmol) and 4-(N,N-dimethyl)aminopyridine (DMAP) (0.40 g, 3.18 mmol) were added to the activated carboxylic acid. After work-up and isolation, and purification by mass-guided preparative HPLC/lyophilization and by silica gel flash column chromatography (Biotage) using ethyl acetate (EtOAc) and hexanes afforded 0.17 g (18% yield) of the title compound (33) as a clear oil. 1H NMR (CDCl3, 400 MHz): δ 6.95-6.87 (m, 2H), 5.43 (q, J=6.8 Hz, 1H) 3.80 (s, 3H), 3.50-3.26 (m, 4H), 1.49 (d, J=6.4 Hz, 3H), 1.26 (t, J=6.8, 3H), 1.12 (t, J=7.6 Hz, 3H). MS (ESI): m/z 258.06 (M+H)+.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:11]=[C:12]([CH:21]=[CH:22][C:23]=1[CH2:24][O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27])[O:13][CH2:14][C:15]1[S:19][CH:18]=[C:17](Br)[CH:16]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C([Li])CCC.CN(C)[CH:40]=[O:41]>>[Si:1]([O:8][CH2:9][C:10]1[CH:11]=[C:12]([CH:21]=[CH:22][C:23]=1[CH2:24][O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27])[O:13][CH2:14][C:15]1[S:19][CH:18]=[C:17]([CH:40]=[O:41])[CH:16]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCc1ccc(OCc2cc(Br)cs2)cc1CO[Si](C)(C)C(C)(C)C
Reactant: CN(C)C=O
Agent: [Li]CCCC
Product: CC(C)(C)[Si](C)(C)OCc1ccc(OCc2cc(C=O)cs2)cc1CO[Si](C)(C)C(C)(C)C

Procedure:
In a manner similar to that of Example 9(g), by reaction of 34 g (61 mmol) of 5-[3,4-bis(tert-butyldimethylsilanyloxymethyl)phenoxymethyl]-3-bromothiophene with 27 mL (67 mmol) of 2.5 M butyllithium and 5.2 mL (67 mmol) of dimethylformamide, the crude product obtained (33.8 g; Y=99%) is in the form of a brown oil.
Reaction SMILES: [OH-].[Na+].Cl.[C:4]([NH:14][CH2:15][CH2:16][CH2:17][C@H:18]([C:20]([OH:22])=[O:21])[NH2:19])([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5].[C:23]1([CH:29]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:30](Cl)=[O:31])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.Cl>C1COCC1>[C:4]([NH:14][CH2:15][CH2:16][CH2:17][C@H:18]([C:20]([OH:22])=[O:21])[NH:19][C:30](=[O:31])[CH:29]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5]
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Reactant: N[C@H](CCCNC(=O)OCc1ccccc1)C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(NCCC[C@@H](NC(=O)C(c1ccccc1)c1ccccc1)C(=O)O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 91.2 %

Procedure:
1 N NaOH (75 mL) was added to a stirred suspension of (R)-N5 -(Cbz)-ornithine hydrochloride (7.5 g; 25 mmol) in THF (114 mL). Once the starting material had dissolved, diphenylacetyl chloride (6.7 g; 26.3 mmol) was added. The reaction was stirred for 3 h at room temperature, then made acidic with cold 1 N HCl and extracted with EtOAc (3×75 mL). The EtOAc extract was washed with brine, dried with Na2SO4, and concentrated to afford the crude product. Purification by flash chromatography on silica eluting with EtOAc:hexanes (1:1) afforded the sub-title compound (10.5 g; 91%).
Reaction SMILES: [O:1]([C:8]1[CH:24]=[CH:23][C:11]([N:12]=[CH:13][C:14]2[CH:19]=[CH:18][C:17]3[O:20][CH2:21][O:22][C:16]=3[CH:15]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1OC2C=CC(C=O)=CC=2O1.C1C=CC(OC2C=CC(N)=CC=2)=CC=1.O>C1C=CC=CC=1>[O:1]([C:8]1[CH:24]=[CH:23][C:11]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]3[O:20][CH2:21][O:22][C:16]=3[CH:15]=2)=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C(=Nc1ccc(Oc2ccccc2)cc1)c1ccc2c(c1)OCO2
Agent: Nc1ccc(Oc2ccccc2)cc1
Agent: O=Cc1ccc2c(c1)OCO2
Solvent: O
Solvent: c1ccccc1
Product: c1ccc(Oc2ccc(NCc3ccc4c(c3)OCO4)cc2)cc1

Procedure:
The starting material used for catalytic hydrogenation, 4-phenoxy-(3,4-methylenedioxy-benzylidene)-aniline, is prepared as follows: the solution of 75 g of 3,4-methylenedioxy-benzaldehyde (piperonal) and 92.5 g of 4-aminodiphenyl ether in 500 ml of benzene is refluxed, with separation of water, for 8 hours. After the water has been completely separated, the reaction mixture is concentrated by evaporation; the crystals precipitated after cooling to about +5° C. are filtered off under suction; the crystal mass is recrystallised firstly in anhydrous benzene and subsequently in acetonitrile to thus obtain pure 4-phenoxy-(3,4-methylenedioxybenzylidene)-aniline, M.P. 89°-91° C.