Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:7]CC)(=O)[CH2:2][C:3]([CH3:5])=O.C(O)(=O)C(O)=O.[CH:16]1([NH:22][NH2:23])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>C(O)C>[CH:16]1([N:22]2[C:1]([OH:7])=[CH:2][C:3]([CH3:5])=[N:23]2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: NNC1CCCCC1
Reactant: CCOC(=O)CC(C)=O
Agent: O=C(O)C(=O)O
Solvent: CCO
Product: Cc1cc(O)n(C2CCCCC2)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 46.7 %

Procedure:
A solution of ethyl acetoacetate (26 g) and cyclohexylhydrazine oxalate (40 g) in ethanol (100 ml) was heated at sufficient temperature and in a manner to allow removal of the ethanol by distillation. The temperature was gradually raised to about 130°, and heating was continued at this temperature for 4 hours, during which time by-product water and additional ethanol were continuously removed by distillation. The reaction mixture, after cooling to room temperature, was dissolved in methylene chloride and extracted with a saturated solution of sodium bicarbonate. The methylene chloride layer was dried and concentrated to give a viscous residue, which was induced to crystallize upon trituration with diethyl ether. The solid was collected to give 2-cyclohexyl-3-hydroxy-5-methylpyrazole (16.5 g), m.p. 153°. The assigned structure of the product as consistent with its infrared spectrum.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[CH:10]=[C:9]([C:11]([O:13]CC)=O)[N:8]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=3)[C:5]2=[CH:6][N:7]=1.[NH2:24][C:25]1[CH:26]=[CH:27][C:28]2[S:32][C:31]([CH3:33])=[N:30][C:29]=2[CH:34]=1>>[CH3:33][C:31]1[S:32][C:28]2[CH:27]=[CH:26][C:25]([NH:24][C:11]([C:9]3[N:8]([CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=4)[C:5]4=[CH:6][N:7]=[C:2]([F:1])[CH:3]=[C:4]4[CH:10]=3)=[O:13])=[CH:34][C:29]=2[N:30]=1
Reactant: CCOC(=O)c1cc2cc(F)ncc2n1Cc1cccc(F)c1
Reactant: Cc1nc2cc(N)ccc2s1
Product: Cc1nc2cc(NC(=O)c3cc4cc(F)ncc4n3Cc3cccc(F)c3)ccc2s1
Yield: 87.2 %

Procedure:
The process is performed according to the method described in step 2.4 of Example 2, starting with 0.3 g (0.95 mmol) of ethyl 5-fluoro-1-[(3-fluorophenyl)methyl]-1H-pyrrolo[2,3-c]pyridine-2-carboxylate (Example 2.3) and 0.189 mg (1.14 mmol) of 5-amino-2-methylbenzothiazole. 0.36 g of expected compound is isolated.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.[H-].[Na+].Cl[CH2:9][CH2:10][CH2:11][CH:12]1[CH2:16][CH2:15][CH:14]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[N:13]1[S:24]([C:27]1[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=1)(=[O:26])=[O:25]>CN(C=O)C>[F:23][C:20]1[CH:19]=[CH:18][C:17]([CH:14]2[N:13]([S:24]([C:27]3[CH:28]=[CH:29][C:30]([CH3:33])=[CH:31][CH:32]=3)(=[O:25])=[O:26])[CH:12]([CH2:11][CH2:10][CH2:9][N:1]3[CH:5]=[N:4][CH:3]=[N:2]3)[CH2:16][CH2:15]2)=[CH:22][CH:21]=1
Reactant: Cc1ccc(S(=O)(=O)N2C(CCCCl)CCC2c2ccc(F)cc2)cc1
Reactant: c1nc[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)N2C(CCCn3cncn3)CCC2c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
To a stirred solution of 1,2,4-triazol (105 mg, 1.52 mmol) in DMF (15 ml) was added at 0° C. sodium hydride (61 mg, 1.52 mmol; 60%-disp.). The mixture was stirred at RT for 1 h, cooled to 0° C. and (2RS,5RS)-2-(3-chloro-propyl)-5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidine (0.50 g, 1.26 mmol) was added. The reaction mixture was stirred at RT for 3 h and at 50° C. for 16 h, poured into ice/water (70 ml) and extracted with dichloromethane (2×100 ml). The combined organic layers were washed with water (70 ml) and brine (70 ml), dried (MgSO4) and evaporated. The crude product was purified by column chromatography on silica gel (ethyl acetate) to yield the title compound (0.47 g, yield 87%) as a colorless oil, MS: m/e=429.5 (M+H+).
Reaction SMILES: Br[C:2]1[C:6]2[N:7]=[C:8]([Cl:11])[N:9]=[CH:10][C:5]=2[N:4]([C:12]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:3]=1.[Li]CCCC.CCCCCC.[Si:42]([O:49][CH:50]1[CH2:55][CH2:54][C:53](=[O:56])[CH2:52][CH2:51]1)([C:45]([CH3:48])([CH3:47])[CH3:46])([CH3:44])[CH3:43]>C1COCC1>[Si:42]([O:49][CH:50]1[CH2:55][CH2:54][C:53]([C:2]2[C:6]3[N:7]=[C:8]([Cl:11])[N:9]=[CH:10][C:5]=3[N:4]([C:12]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:3]=2)([OH:56])[CH2:52][CH2:51]1)([C:45]([CH3:48])([CH3:47])[CH3:46])([CH3:44])[CH3:43]
Reactant: Clc1ncc2c(n1)c(Br)cn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)[Si](C)(C)OC1CCC(=O)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(C)[Si](C)(C)OC1CCC(O)(c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3cnc(Cl)nc23)CC1
Temperature: -78 °C
Reaction time: 3 h
Yield: 76 %

Procedure:
A solution of 7-bromo-2-chloro-5-trityl-5H-pyrrolo[3,2-d]pyrimidine (2.00 g, 3.2 mmol) in THF (20 mL) was added a 2.5 N solution of BuLi in hexane (2.82 mL, 7.04 mmol) at −78° C. Then 4-((tert-butyldimethylsilyl)oxy)cyclohexanone (1.2 mL) was added after 15 min. The reaction was stirred at −78° C. for 3 hour, quenched with brine and extracted with EtOAc (3×). The combined organic layer was dried (MgSO4), filtered and concentrated. The residue was purified by ISCO to provide the desired product (1.52 g, 76%). 1H NMR (400 MHz, CDCl3, two isomers) δ 7.64-7.56 (m, 1H), 7.44-7.41 (m, 1H), 7.35-7.31 (m, 9H), 7.16-7.10 (m, 6H), 3.73-3.68 (m, 1H), 2.55-2.51 (m, 1H), 2.42-2.30 (m, 1H), 2.28-2.19 (m, 1H), 2.07-1.94 (m, 2H), 1.91-1.82 (m, 2H), 1.76-1.62 (m, 2H), 0.82 (s, 9H), 0.01 (s, 6H).
Reaction SMILES: C(OC1([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][C:29]=2[OH:36])C2C(=CC=C(C)C=2)N(CCCC(C)C)C1=O)(=O)C1C=CC=CC=1.[C:37]([O:45][CH:46]1[C:54]2[C:49](=[CH:50][CH:51]=[C:52]([Cl:55])[CH:53]=2)[N:48]([CH2:56][CH2:57][CH2:58][N:59]2[CH2:64][CH2:63][O:62][CH2:61][CH2:60]2)[C:47]1=[O:65])(=[O:44])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>>[C:37]([O:45][C:46]1([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][C:29]=2[OH:36])[C:54]2[C:49](=[CH:50][CH:51]=[C:52]([Cl:55])[CH:53]=2)[N:48]([CH2:56][CH2:57][CH2:58][N:59]2[CH2:64][CH2:63][O:62][CH2:61][CH2:60]2)[C:47]1=[O:65])(=[O:44])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: O=C(OC1C(=O)N(CCCN2CCOCC2)c2ccc(Cl)cc21)c1ccccc1
Reactant: COc1ccc(CC2(OC(=O)c3ccccc3)C(=O)N(CCCC(C)C)c3ccc(C)cc32)c(O)c1
Product: COc1ccc(CC2(OC(=O)c3ccccc3)C(=O)N(CCCN3CCOCC3)c3ccc(Cl)cc32)c(O)c1

Procedure:
This compound was prepared in a similar manner to 3-(2-hydroxy-4-methoxybenzyl)-5-methyl-1-(4-methylpentyl)-2-oxoindolin-3-yl benzoate by reacting 5-chloro-1-(3-morpholinopropyl)-2-oxoindolin-3-yl benzoate with tert-butyl (2-(hydroxymethyl)-5-methoxyphenyl)carbonate. 1H-NMR δ 8.02 (dd, 2H), 7.58 (dd, 1H), 7.45 (dd, 2H), 7.26 (m, 1H), 7.22 (d, 1H), 6.87 (d, 1H), 6.51 (d, 1H), 6.42 (d, 1H), 6.26 (dd, 1H), 3.73-3.70 (m, 8H), 3.62 (m, 1H), 3.54-3.50 (2H), 3.39 (d, 1H), 2.37-2.15 (m, 6H), 1.78 (m, 2H). Calculated mass for C30H31ClN2O6, 550.19. Observed 551.1 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12]O)=[CH:6][CH:5]=1)([O-:3])=[O:2].S(Cl)([Cl:16])=O>>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][Cl:16])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=S(Cl)Cl
Reactant: O=[N+]([O-])c1ccc(OCCO)cc1
Product: O=[N+]([O-])c1ccc(OCCCl)cc1

Procedure:
4-Nitro-(2-Hydroxyethoxy)benzene (1.13 g, 6.2 mmol) in thionyl chloride (10 mL) is heated at reflux for 3 hours then concentrated in vacuo. After cooling the residue in an ice water bath, saturated aqueous sodium bicarbonate is added and the precipitate collected, rinsed with water, and dried to give 4-nitro-(2-chloroethoxy)benzene (909 mg).
Reaction SMILES: Br[C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[C:11](=[CH:12]2)[C:10]2([C:26]4[C:18]([C:19]5[C:24]([CH:25]=4)=[CH:23][CH:22]=[CH:21][CH:20]=5)=[CH:17][CH:16]=[CH:15]2)[C:9](Br)=[C:8](Br)[C:7]=3Br)=[C:4](Br)[C:3]=1Br.B(O)(O)[C:33]1[CH:34]=[CH:35][C:36]([C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)=[CH:37][CH:38]=1>C1(C)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].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>[C:36]1([C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH:35]=[CH:34][CH:33]=[CH:38][C:37]=1[C:2]1[CH:14]=[C:13]([C:12]2[CH:25]=[CH:26][CH:18]=[CH:17][C:11]=2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:5]2[C:6]3[C:15](=[CH:10][C:9]([C:40]4[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=4[C:36]4[CH:37]=[CH:38][CH:33]=[CH:34][CH:35]=4)=[CH:8][CH:7]=3)[C:16]3([C:17]4[CH:18]=[C:26]([C:40]5[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=5[C:36]5[CH:37]=[CH:38][CH:33]=[CH:34][CH:35]=5)[CH:25]=[C:24]([C:23]5[CH:22]=[CH:21][CH:20]=[CH:16][C:15]=5[C:10]5[CH:11]=[CH:6][CH:7]=[CH:8][CH:9]=5)[C:19]=4[C:42]4[C:41]3=[CH:40][C:39]([C:36]3[CH:37]=[CH:38][CH:33]=[CH:34][C:35]=3[C:13]3[CH:14]=[CH:2][CH:3]=[CH:4][CH:5]=3)=[CH:44][CH:43]=4)[C:4]=2[CH:3]=1
Reactant: BrC1=C2C(=Cc3cc(Br)c(Br)c(Br)c32)C2(C=CC=C3C2=Cc2ccccc23)C(Br)=C1Br
Reactant: OB(O)c1ccc(-c2ccccc2)cc1
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: [K+]
Solvent: Cc1ccccc1
Product: c1ccc(-c2ccccc2-c2ccc3c(c2)C2(c4cc(-c5ccccc5-c5ccccc5)ccc4-c4c(-c5ccccc5-c5ccccc5)cc(-c5ccccc5-c5ccccc5)cc42)c2cc(-c4ccccc4-c4ccccc4)cc(-c4ccccc4-c4ccccc4)c2-3)cc1

Procedure:
In a 250 ml two-necked flask fitted with reflux condenser and precision glass stirrer, 1.6 g of hexabromospirobifluorene and 3 g of biphenylboronic acid are slurried in a mixture of 50 ml of toluene and 50 ml of 1M potassium carbonate solution. The mixture is refluxed under nitrogen and 115 mg of tetrakis(triphenylphosphine)palladium in 5 ml of toluene are added. The mixture is boiled under reflux for 7 hours while stirring. After the reaction is complete, the cooled solution is filtered and the filtrate is extracted twice by shaking with water (to improve the phase separation, chloroform is added). The organic phase is dried over sodium sulfate, filtered through a short column of silica gel and subsequently evaporated on a rotary evaporator. The product is further purified by recrystallization from dichloromethane/pentane. This gives 2 g (80%) of colorless crystals which fluoresce blue under UV illumination.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([CH:17]=[CH2:18])=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].B1C2CCCC1CCC2.C1C[O:31]CC1>O.C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([CH2:17][CH2:18][OH:31])=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C1CCOC1
Reactant: C=Cc1ccc2c(ccn2C(=O)OC(C)(C)C)c1
Agent: B1C2CCCC1CCC2
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)n1ccc2cc(CCO)ccc21
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 76 %

Procedure:
To a solution of 5-vinyl-indole-1-carboxylic acid tert-butyl ester (4.5 g, 18.5 mmol, 1.0 eq.) in THF (46 mL) at 0° C. was added 9-BBN (0.5 M in THF, 87 mL, 2.4 eq.) over 10 min. The resulting reaction mixture was stirred for 2.5 h and diluted with THF (150 mL) and water (150 mL) while keeping the temperature at 0° C. Then NaBO3. 4H2O (44 g) was introduced and resulting reaction mixture was stirred and warmed to room temperature and stirred. The reaction mixture was diluted with methylene chloride (100 mL) and the separated aqueous layer was extracted 3×100 mL methylene chloride. The combined organic layers were dried over sodium sulfate, filtered and concentrated. The residue was purified by chromatography (methylene chloride to 5% acetone/methylene chloride) to give 5-(2-hydroxy-ethyl)-indole-1-carboxylic acid tert-butyl ester (3.82 g, 76%) or similarly 6-(2-hydroxy-ethyl)-indole-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([F:11])[CH:3]=1.[C:12](Cl)(=[O:22])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].CN(C1C=CC=CN=1)C.Cl>ClCCl.C(N(CC)CC)C>[C:12]([O:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([F:11])[CH:3]=1)(=[O:22])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: O=C(O)c1ccc(O)cc1F
Reactant: CCCCCCCCCC(=O)Cl
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCC(=O)Oc1ccc(C(=O)O)c(F)c1
Temperature: 25 °C
Yield: 82.2 %

Procedure:
15.6 Grams (0.1 mol) of 4-hydroxy-2-fluorobenzoic acid was dissolved in 140 ml of dichloromethane. To the mixture were consecutively added 16 ml of triethylamine, 0.1 g (0.11 mol) of n-decanoic acid chloride and 0.97 (0.0079 mol) of dimethylaminopyridine, and the mixture was stirred at room temperature for a whole day. 10% Hydrochloric acid in an amount of 50 ml was added, and the mixture was subjected to extraction with 100 ml of ether three times. The organic layer was washed with a sodium chloride aqueous solution three times and dried over anhydrous sodium sulfate. The solvent was distilled off, the residue was washed with 400 ml of hexane to give 25.5 g of the intended product.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([CH2:8][CH2:9]O)[CH:5]=[CH:4][CH:3]=1.[C:11]1(=[O:21])[NH:15][C:14](=[O:16])[C:13]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:12]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>O1CCCC1>[CH3:1][C:2]1[N:7]=[C:6]([CH2:8][CH2:9][N:15]2[C:14](=[O:16])[C:13]3=[CH:17][CH:18]=[CH:19][CH:20]=[C:12]3[C:11]2=[O:21])[CH:5]=[CH:4][CH:3]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: Cc1cccc(CCO)n1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: Cc1cccc(CCN2C(=O)c3ccccc3C2=O)n1
Reaction time: 8 h
Yield: 66.9 %

Procedure:
45.6 g (262 mmol) of diethyl azadicarboxylate (DEAD) was added dropwise to a solution of 30.0 g (219 mmol) of 2-(6-methyl-2-pyridyl)ethanol, 38.6 g (262 mmol) of phthalimide and 68.6 g (262 mmol) of triphenylphosphine in 300 ml of tetrahydrofuran at a temperature of 15° to 25° C. The mixture was stirred overnight. Water was added to the mixture. After extraction with ethyl acetate, the organic layer was washed with water. After extraction with 2N hydrochloric acid, a 3N sodium hydroxide solution was added to the aqueous layer at 0° C. to make it alkaline. White crystals thus formed were collected by filtration to give 39.04 g (yield: 67%) of the intended compound.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[C:9](=[O:11])[CH3:10].Cl[CH2:13][CH:14]1[CH2:16][O:15]1.C[O-].[Na+]>CO>[CH3:8][C:5]1[CH:6]=[CH:7][C:2]([O:1][CH2:13][CH:14]2[CH2:16][O:15]2)=[C:3]([C:9](=[O:11])[CH3:10])[CH:4]=1
Reactant: CC(=O)c1cc(C)ccc1O
Reactant: ClCC1CO1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CC(=O)c1cc(C)ccc1OCC1CO1
Reaction time: 1 h
Yield: 55 %

Procedure:
To a stirred mixture of 20 parts of 1-(2-hydroxy-5-methylphenyl)ethanone, 50.5 parts of (chloromethyl)oxirane and 40 parts of methanol are added dropwise 25 parts of sodium methoxide solution 30%. Upon completion, stirring is continued for 1 hour at room temperature. The reaction mixture is filtered and the filtrate is evaporated. The residue is dissolved in methylbenzene. The latter is washed with water, dried, filtered and evaporated. The residue is distilled, yielding 15 parts (55%) of 1-[5-methyl-2-(oxiranylmethoxy)phenyl]ethanone; bp. 140°-150° C. at 0.3 mm. pressure.
Reaction SMILES: [CH2:1]([C:3]1[NH:7][N:6]=[C:5]([C:8]([NH2:10])=[O:9])[C:4]=1[N+:11]([O-:13])=[O:12])[CH3:2].C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+].CS(O[CH:27]1[CH2:30][N:29]([CH:31]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:28]1)(=O)=O>O1CCCC1.O>[CH:31]([N:29]1[CH2:30][CH:27]([N:7]2[C:3]([CH2:1][CH3:2])=[C:4]([N+:11]([O-:13])=[O:12])[C:5]([C:8]([NH2:10])=[O:9])=[N:6]2)[CH2:28]1)([C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: CCc1[nH]nc(C(N)=O)c1[N+](=O)[O-]
Reactant: CS(=O)(=O)OC1CN(C(c2ccccc2)c2ccccc2)C1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCc1c([N+](=O)[O-])c(C(N)=O)nn1C1CN(C(c2ccccc2)c2ccccc2)C1
Yield: 30.8 %

Procedure:
5-Ethyl-4-nitro-1H-pyrazole-3-carboxamide (WO 98/49166) (25.0 g, 136 mmol), sodium carbonate (57.6 g, 543 mmol), sodium iodide (40.7 g, 272 mmol) and 1-benzhydryl-3-azetidinyl methanesulfonate (86.2 g, 272 mmol) were suspended in tetrahydrofuran (338 mL) and water (38 mL) and heated under reflux for 5 days. The reaction mixture was then concentrated in vacuo and taken up in ethyl acetate (500 mL) and water (300 mL). The resulting precipitate was filtered, washed with ethyl acetate and water to yield the title compound as a white solid (17 g, 41.9 mmol, 31%): mp 257-260° C.; 1H NMR (400 MHz, DMSO-d6): δ=1.09 (t, 3H, J=7.6 Hz), 2.95 (q, 2H, J=7.3 Hz), 3.43 (t, 2H, J=7.6 Hz), 3.61 (t 2H, J=7.6 Hz), 4.59 (s, 1H), 5.23 (quintet, 1H, J=7.3 Hz), 7.15-7.20 (m, 2H), 7.24-7.31 (m, 4H), 7.43-7.48 (m, 4H), 7.70 (br s, 1H), 7.95 (br s, 1H); LRMS (m/z) (TSP+) 406.2 (MH+).
Reaction SMILES: [NH2:1][C@H:2]([C:18]([NH:20][C@H:21]([C:32]([NH:34][C@H:35]([C:51]([NH:53][CH2:54][C:55]([NH:57][C@H:58]([C:68]([NH:70][CH2:71][C:72]([NH:74][C@H:75]([C:83]([NH:85][C@H:86]([C:94]([O:96][CH3:97])=[O:95])[CH2:87][C:88]1[CH:93]=[CH:92][CH:91]=[CH:90][CH:89]=1)=[O:84])[CH2:76][C:77]1[CH:82]=[CH:81][CH:80]=[CH:79][CH:78]=1)=[O:73])=[O:69])[CH2:59][O:60]CC1C=CC=CC=1)=[O:56])=[O:52])[CH2:36][CH2:37][CH2:38][CH2:39][NH:40]C(OCC1C=CC=CC=1)=O)=[O:33])[C@@H:22]([CH3:31])[O:23]CC1C=CC=CC=1)=[O:19])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7]C(OCC1C=CC=CC=1)=O.Cl.[H][H]>CC(O)=O.[Pd]>[NH2:1][C@H:2]([C:18]([NH:20][C@H:21]([C:32]([NH:34][C@H:35]([C:51]([NH:53][CH2:54][C:55]([NH:57][C@H:58]([C:68]([NH:70][CH2:71][C:72]([NH:74][C@H:75]([C:83]([NH:85][C@H:86]([C:94]([O:96][CH3:97])=[O:95])[CH2:87][C:88]1[CH:93]=[CH:92][CH:91]=[CH:90][CH:89]=1)=[O:84])[CH2:76][C:77]1[CH:78]=[CH:79][CH:80]=[CH:81][CH:82]=1)=[O:73])=[O:69])[CH2:59][OH:60])=[O:56])=[O:52])[CH2:36][CH2:37][CH2:38][CH2:39][NH2:40])=[O:33])[C@@H:22]([CH3:31])[OH:23])=[O:19])[CH2:3][CH2:4][CH2:5][CH2:6][NH2:7]
Reactant: [H][H]
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](Cc1ccccc1)NC(=O)CNC(=O)[C@H](COCc1ccccc1)NC(=O)CNC(=O)[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)[C@@H](NC(=O)[C@@H](N)CCCCNC(=O)OCc1ccccc1)[C@@H](C)OCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CC(=O)O
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](Cc1ccccc1)NC(=O)CNC(=O)[C@H](CO)NC(=O)CNC(=O)[C@H](CCCCN)NC(=O)[C@@H](NC(=O)[C@@H](N)CCCCN)[C@@H](C)O
Yield: 46.4 %

Procedure:
Partially protected octapeptide (IV) (0.10 g) was hydrogenated in 85% AcOH (70 ml) with 10% Pd/C catalyst (0.20 g) over a steady stream of hydrogen for 20 hours. The mixture was filtered, evaporated in vacuo and residue filtered on Sephadex LH20 eluting with water to give the desired octapeptide methyl ester (V) (0.03 g, 46% yield). TLC examination showed 1 spot at Rf 0.2 in 5:2:2 BAW (t-BuOCl/KI-starch stain) and Rf 0.5 in 5:2:3 BAW (Ninhydrin stain). Amino acid analysis:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.C(O)C.O.O.[Sn](Cl)Cl>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[N:11]1[CH2:12][CH2:13][O:14][CH2:15][CH2:16]1
Reactant: O=[N+]([O-])c1ccc(F)c(N2CCOCC2)c1
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Product: Nc1ccc(F)c(N2CCOCC2)c1
Temperature: 70 °C
Yield: 80.9 %

Procedure:
4-(2-Fluoro-5-nitro-phenyl)-morpholine (335.0 mg, 1.481 mmol) was dissolved in Ethanol (10.0 mL, 171 mmol) and the reaction was treated with Tin(II) chloride dihydrate (1671 mg, 7.405 mmol). The reaction was then heated at 70° C. until HPLC showed consumption of starting material. The mixture was then made basic with 10% NaOH and the product was extracted with ethyl acetate. Note: When adding the NaOH, solid precipitate formed and was filtered and washed with ethyl acetate. The solid was discarded and the combined organics were then washed with water and dried over sodium sulfate, filtered and reduced to afford 235 mg of 4-Fluoro-3-morpholin-4-yl-phenylamine. 1H NMR (400 MHz, DMSO, d6) δ 6.75 (m, 1H), 6.21 (d, 1H, J=7.56 Hz), 6.10 (m, 1H), 4.84 (s, 2H), 3.70 (m, 4H), 2.92 (m, 4H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]([C:17]1[C:25]([OH:26])=[CH:24][C:20]3[O:21][CH2:22][O:23][C:19]=3[CH:18]=1)[C:5](=[O:16])[N:6]2[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].C(N(CC)CC)C.Cl[Si](C)(C)C.[CH2:39]=[O:40].FC(F)(F)S([O-])(=O)=O.[Yb+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O>ClCCl>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([C:17]1[C:25]([OH:26])=[CH:24][C:20]3[O:21][CH2:22][O:23][C:19]=3[CH:18]=1)([CH2:39][OH:40])[C:5](=[O:16])[N:6]2[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: C=O
Reactant: CCCCCN1C(=O)C(c2cc3c(cc2O)OCO3)c2c(Br)cccc21
Agent: C[Si](C)(C)Cl
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCN1C(=O)C(CO)(c2cc3c(cc2O)OCO3)c2c(Br)cccc21
Temperature: 0 °C
Reaction time: 2 h
Yield: 78.8 %

Procedure:
To a solution of 4-bromo-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1-pentyl-1,3-dihydro-2H-indol-2-one (7.50 g, 17.9 mmol) in dry dichloromethane (150 mL) was added triethylamine (10.9 g, 108 mmol) and chlorotrimethylsilane (7.80 g, 71.8 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 2 h and diluted with dichloromethane (100 mL). The mixture was washed with water (3×50.0 mL), dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated in vacuo to dryness. The residue was dissolved in THF (150 mL) followed by the additions of formaldehyde solution (4.90 mL, 179 mmol, 37 wt % in water) and ytterbium (III) trifluoromethanesulfonate (1.11 g, 1.79 mmol). The resulting mixture was stirred at ambient temperature for 36 h. After the solvent was removed under reduced pressure, the residue was diluted with dichloromethane (200 mL), washed with saturated sodium bicarbonate (50.0 mL), saturated ammonium chloride (50.0 mL) and water (100 mL). The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to dryness to yield the title compound (6.32 g, 79%) as a fluffy solid: 1H NMR (300 MHz, CDCl3) δ 8.28 (s, 1H), 7.10 (t, 1H), 7.00 (dd, 1H), 6.89 (dd, 1H), 6.83 (s, 1H), 6.27 (s, 1H), 6.85 (dd, 2H), 4.52-4.41 (m, 2H), 3.90 (dd, 1H), 3.70-3.65 (m, 2H), 1.68-1.57 (m, 2H), 1.36-1.29 (m, 4H), 0.83 (t, 3H); 13C NMR (75 MHz, CDCl3) δ 178.1, 150.3, 147.2, 147.2, 140.5, 129.6, 129.2, 125.6, 118.4, 114.8, 109.2, 106.9, 101.0, 98.2, 62.6, 57.6, 39.9, 28.9, 26.7, 22.2, 13.5.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[CH3:11].O=P(Cl)(Cl)Cl.CN(C1C=CC=CC=1)[CH:19]=[O:20]>>[CH3:10][O:9][C:7]1[CH:8]=[C:3]([O:2][CH3:1])[C:4]([CH3:11])=[CH:5][C:6]=1[CH:19]=[O:20]
Reactant: COc1ccc(C)c(OC)c1
Reactant: CN(C=O)c1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: COc1cc(OC)c(C=O)cc1C

Procedure:
To a solution of 2,4-dimethoxytoluene (5.50 g, 36.1 mmol) in 55 mL of N-methyl-N-phenyl-formamide was added at 0° C. POCl3 (10.9 mL, 3 eq.), and the mixture was heated for 60 Min. to 80° C. After cooling, the reaction mixture was poured onto crashed ice, the precipitate filtered and washed twice with water/MeOH=8/2 to leave after drying 5.40 g of the title product as light yellow crystals.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=O)[C:9]2=[O:18])=[CH:4][CH:3]=1.[F:19][C:20]1[CH:21]=[C:22]([CH:24]=[C:25]([F:27])[CH:26]=1)[NH2:23].C(O)(=O)C>C(Cl)Cl>[F:19][C:20]1[CH:21]=[C:22]([N:23]=[C:10]2[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:8]([C:5]3[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=3)[C:9]2=[O:18])[CH:24]=[C:25]([F:27])[CH:26]=1
Reactant: Nc1cc(F)cc(F)c1
Reactant: O=C1C(=O)N(c2ccc(O)cc2)c2ccccc21
Solvent: ClCCl
Solvent: CC(=O)O
Product: O=C1C(=Nc2cc(F)cc(F)c2)c2ccccc2N1c1ccc(O)cc1

Procedure:
A mixture of 1-(4-hydroxyphenyl)-1H-indole-2,3-dione (30 mg, 0.126 mmol), 3,5-difluoroaniline (170 mg, 1.32 mmol), and a drop of acetic acid was heated at 140° C. for 4 hours in a 3 mL vial. The crude product was suspended in CH2Cl2 and purified by preparative TLC [Eluent: EtOAc/hexane (1:1)] giving the desired product. Procedure D