Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH3:13][C:14]1[N:51]=[C:17]2[N:18]([CH2:41][C:42]3([C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)[CH2:44][CH2:43]3)[C:19](=[O:40])[C:20]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([C:32]4[C:33]([C:38]#[N:39])=[CH:34][CH:35]=[CH:36][CH:37]=4)=[CH:28][CH:27]=3)=[C:21]([CH2:22][CH2:23][CH3:24])[N:16]2[N:15]=1>C(OCC)(=O)C>[CH3:13][C:14]1[N:51]=[C:17]2[N:18]([CH2:41][C:42]3([C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)[CH2:44][CH2:43]3)[C:19](=[O:40])[C:20]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=4[C:38]4[NH:3][C:4](=[O:7])[O:5][N:39]=4)=[CH:28][CH:27]=3)=[C:21]([CH2:22][CH2:23][CH3:24])[N:16]2[N:15]=1
Reactant: [NH3+]O
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(CC2(c3ccccc3)CC2)c2nc(C)nn12
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(CC2(c3ccccc3)CC2)c2nc(C)nn12
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 14.4 %

Procedure:
A mixture of hydroxylammonium chloride (0.88 g), sodium hydrogen carbonate (1.4 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C. for 30 min, 4′-({2-methyl-5-oxo-4-[(1-phenylcyclopropyl)methyl]-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile (0.43 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (10 mL). N,N′-Carbonyldiimidazole (0.16 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.14 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.069 g, 14%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:41])[N:10]([C@H:13]2[C@H:17]([C:18]3[CH:23]=[CH:22][C:21](F)=[CH:20][CH:19]=3)[CH2:16][N:15]([C:25]([CH:27]3[CH2:32][CH2:31][N:30]([C:33]4[CH:38]=[CH:37][C:36](C#N)=[CH:35][N:34]=4)[CH2:29][CH2:28]3)=[O:26])[CH2:14]2)[CH2:11][CH3:12])=[CH:4][CH:3]=1.FC1C=CC(OC(=O)N([C@H]2[C@H](C3C=CC([Cl:65])=CC=3)CNC2)CC)=CC=1.OC1C=CC(N2CC[CH:77]([C:80]([OH:82])=[O:81])CC2)=NC=1.C(Cl)(=O)C>>[Cl:65][C:21]1[CH:22]=[CH:23][C:18]([C@H:17]2[C@H:13]([N:10]([CH2:11][CH3:12])[C:9]([O:8][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[O:41])[CH2:14][N:15]([C:25]([CH:27]3[CH2:32][CH2:31][N:30]([C:33]4[CH:38]=[CH:37][C:36]([O:82][C:80](=[O:81])[CH3:77])=[CH:35][N:34]=4)[CH2:29][CH2:28]3)=[O:26])[CH2:16]2)=[CH:19][CH:20]=1
Reactant: CCN(C(=O)Oc1ccc(F)cc1)[C@@H]1CNC[C@H]1c1ccc(Cl)cc1
Reactant: O=C(O)C1CCN(c2ccc(O)cn2)CC1
Reactant: CCN(C(=O)Oc1ccc(F)cc1)[C@@H]1CN(C(=O)C2CCN(c3ccc(C#N)cn3)CC2)C[C@H]1c1ccc(F)cc1
Solvent: CC(=O)Cl
Product: CCN(C(=O)Oc1ccc(F)cc1)[C@@H]1CN(C(=O)C2CCN(c3ccc(OC(C)=O)cn3)CC2)C[C@H]1c1ccc(Cl)cc1
Reaction time: 0.5 h

Procedure:
In analogy to the procedure described for the synthesis of [(3S,4R)-1-(5′-Cyano-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carbonyl)-4-(4-fluoro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic acid 4-fluoro-phenyl ester (example 35, step f) the intermediate was prepared from [(3S,4R)-4-(4-Chloro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic acid 4-fluoro-phenyl ester and 1-(5-hydroxypyridin-2-yl)piperidine-4-carboxylic acid. Afterwards, acetyl chloride was added and stirring was continued for 30 min at room temperature. The mixture was directly subjected to preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile, water and NEt3. The product containing fractions were evaporated to yield the title compound as off-white solid. MS m/e: 608.2 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@H:17]4[CH2:19][O:18]4)=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1.[S:22]1[CH:26]=[CH:25][CH:24]=[C:23]1[CH2:27][NH2:28]>CN(C)C=O.C(O)C>[F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@H:17]([OH:18])[CH2:19][NH:28][CH2:27][C:23]4[S:22][CH:26]=[CH:25][CH:24]=4)=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: NCc1cccs1
Reactant: Fc1ccc2c(-c3ccc(OC[C@H]4CO4)cc3)noc2c1
Solvent: CN(C)C=O
Solvent: CCO
Product: O[C@H](CNCc1cccs1)COc1ccc(-c2noc3cc(F)ccc23)cc1

Procedure:
The title compound is prepared from a mixture of (R)-6-fluoro-3-(4-oxiranylmethoxy-phenyl)-benzo[d]isoxazole in dimethylformamide and 2-thiophenemethylamine in ethanol, essentially as described above in Example 70. Purity by LC/MS=100%, [M+H]+=399.
Reaction SMILES: BrCC[C:4]1[CH:14]=[CH:13][CH:12]=[C:6]2[C:7]([NH:9][C:10](=[O:11])[C:5]=12)=[O:8].[CH2:15]([O:22][NH2:23])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[C:24](OCC)(=O)[CH3:25]>>[CH2:15]([O:22][NH:23][CH2:24][CH2:25][N:9]1[C:10](=[O:11])[C:5]2=[CH:4][CH:14]=[CH:13][CH:12]=[C:6]2[C:7]1=[O:8])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: NOCc1ccccc1
Reactant: O=C1NC(=O)c2c(CCBr)cccc21
Reactant: CCOC(C)=O
Product: O=C1c2ccccc2C(=O)N1CCNOCc1ccccc1
Reaction time: 8 h

Procedure:
A mixture of 12.30 g. of 2-bromoethyl-phthalimide and 12.31 g. of O-benzylhydroxylamine is warmed to 80° for 48 hours. Ethyl acetate is then added, and the precipitate formed is filtered off with suction. The mother liquor is evaporated in vacuo. 35 ml. of methanol are added to the oily residue and the mixture is left to stand at room temperature overnight. The crystalline precipitate is filtered off with suction and dried. The resulting crude product melts at 90°-91°. Analytically pure N-{2-[(benzyloxy)amino]ethyl}phthalimide, m.p. 92°-94°, is obtained by recrystallization from methanol.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[CH2:2][C:3]([NH:5][C@@H:6]([C:14]([NH:16][CH2:17][C:18]([NH:20][C@H:21]([C:26]([NH:28][C@H:29]([C:37]([NH:39][C@H:40]([C:44]([O:46]C)=[O:45])[CH:41]([CH3:43])[CH3:42])=[O:38])[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:27])[CH2:22][C:23](=[O:25])[OH:24])=[O:19])=[O:15])[CH2:7][CH2:8][CH2:9][NH:10][C:11](=[NH:13])[NH2:12])=[O:4].[OH-].[Na+]>CO>[NH2:1][CH2:2][C:3]([NH:5][C@@H:6]([C:14]([NH:16][CH2:17][C:18]([NH:20][C@H:21]([C:26]([NH:28][C@H:29]([C:37]([NH:39][C@H:40]([C:44]([OH:46])=[O:45])[CH:41]([CH3:43])[CH3:42])=[O:38])[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:27])[CH2:22][C:23](=[O:24])[OH:25])=[O:19])=[O:15])[CH2:7][CH2:8][CH2:9][NH:10][C:11](=[NH:12])[NH2:13])=[O:4]
Reactant: COC(=O)[C@@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(=O)O)NC(=O)CNC(=O)[C@@H](CCCNC(=N)N)NC(=O)CNC(=O)OC(C)(C)C)C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(=O)O)NC(=O)CNC(=O)[C@@H](CCCNC(=N)N)NC(=O)CN)C(=O)O
Temperature: 20 °C
Reaction time: 3 h

Procedure:
Two grams (g) of BOC-Gly-DArg-Gly-Asp-Phe-Val-OMe (SEQ ID NO 1) were first dissolved in 60 milliliters (ml) of methanol to which was added 1.5 ml of 2 N sodium hydroxide solution to form an admixture. The admixture was then stirred for 3 hours at 20 degrees C. (20° C.) After evaporation, the residue was taken up in water, acidified to pH 3 with diluted HCl and extracted with ethyl acetate. The extract was dried over Na2SO4, evaporated again and the resultant BOC-Gly-DArg-Gly-Asp-Phe-Val-OH (SEQ ID NO 2) was stirred at 20° C. for 2 hours with 20 ml of 2 N HCl in dioxane. The resultant admixture was evaporated to obtain H-Gly-DArg-Gly-Asp-Phe-Val-OH (SEQ ID NO 3) that was subsequently dissolved in a mixture of 1800 ml of dichloromethane and 200 ml of dimethylformamide (DMF) followed by cooling to 0° C. Thereafter, 0.5 g of dicyclohexylcarbodiimide (DCCI), 0.3 g of 1-hydroxybenzotriazole (HOBt) and 0.23 ml of N-methylmorpholine were added successively with stirring.
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:9][CH2:8][CH2:7][CH2:6][CH:5]([NH:10][C:11]([NH:13][C:14]2[N:15]=[C:16]3[CH:22]=[CH:21][N:20]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:17]3=[N:18][CH:19]=2)=[O:12])[CH2:4]1.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>>[CH3:31][S:32]([N:3]1[CH2:9][CH2:8][CH2:7][CH2:6][CH:5]([NH:10][C:11]([NH:13][C:14]2[N:15]=[C:16]3[CH:22]=[CH:21][N:20]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:17]3=[N:18][CH:19]=2)=[O:12])[CH2:4]1)(=[O:34])=[O:33]
Reactant: CS(=O)(=O)Cl
Reactant: C[Si](C)(C)CCOCn1ccc2nc(NC(=O)NC3CCCCNC3)cnc21
Agent: Cl
Product: C[Si](C)(C)CCOCn1ccc2nc(NC(=O)NC3CCCCN(S(C)(=O)=O)C3)cnc21

Procedure:
Racemic 1-(1-methanesulfonyl-azepan-3-yl)-3-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-urea was prepared in the same manner from racemic 1-azepan-3-yl-3-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-urea dihydrochloride and methanesulfonyl chloride.
Reaction SMILES: [OH:1][CH2:2][C@@:3]12[C@@H:20]3[C@H:11]([C@H:12]4[C@@:16]([CH2:18][CH2:19]3)([CH3:17])[C:15](=[O:21])[CH2:14][CH2:13]4)[CH2:10][CH2:9][C:8]1=[CH:7][C:6](=[O:22])[CH2:5][C@H:4]2[CH3:23].[OH:24][CH2:25][C@@:26]12[C@@H:43]3[C@H:34]([C@H:35]4[C@@:39]([CH2:41][CH2:42]3)([CH3:40])[C:38](=[O:44])[CH2:37][CH2:36]4)[CH2:33][C@H:32]([CH3:45])[C:31]1=[CH:30][C:29](=[O:46])[CH2:28][CH2:27]2.C[O-].[C:49]1([Si:55]([C:84]2[CH:89]=[CH:88][CH:87]=[CH:86][CH:85]=2)([C:78]2[CH:83]=[CH:82][CH:81]=[CH:80][CH:79]=2)OC[C@@]23[C@@H]4[C@H]([C@H]5[C@@](CC4)(C)C(=O)CC5)CCC2=CC(=O)CC3)[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1>>[CH3:23][C@H:4]1[C@@:3]2([CH2:2][O:1][Si:55]([C:78]3[CH:79]=[CH:80][CH:81]=[CH:82][CH:83]=3)([C:84]3[CH:89]=[CH:88][CH:87]=[CH:86][CH:85]=3)[C:49]3[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=3)[C:8]([CH2:9][CH2:10][C@@H:11]3[C@@H:20]2[CH2:19][CH2:18][C@@:16]2([CH3:17])[C@H:12]3[CH2:13][CH2:14][C:15]2=[O:21])=[CH:7][C:6](=[O:22])[CH2:5]1.[CH3:45][C@@H:32]1[C:31]2[C@:26]([CH2:25][O:24][Si:55]([C:78]3[CH:79]=[CH:80][CH:81]=[CH:82][CH:83]=3)([C:84]3[CH:89]=[CH:88][CH:87]=[CH:86][CH:85]=3)[C:49]3[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=3)([CH2:27][CH2:28][C:29](=[O:46])[CH:30]=2)[C@@H:43]2[C@H:34]([C@H:35]3[C@@:39]([CH2:41][CH2:42]2)([CH3:40])[C:38](=[O:44])[CH2:37][CH2:36]3)[CH2:33]1
Reactant: C[C@@H]1CC(=O)C=C2CC[C@@H]3[C@H](CC[C@]4(C)C(=O)CC[C@@H]34)[C@]21CO
Reactant: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43CO[Si](c3ccccc3)(c3ccccc3)c3ccccc3)[C@@H]1CCC2=O
Reactant: C[C@H]1C[C@@H]2[C@H](CC[C@]3(C)C(=O)CC[C@@H]23)[C@@]2(CO)CCC(=O)C=C12
Agent: C[O-]
Product: C[C@@H]1CC(=O)C=C2CC[C@@H]3[C@H](CC[C@]4(C)C(=O)CC[C@@H]34)[C@]21CO[Si](c1ccccc1)(c1ccccc1)c1ccccc1
Product: C[C@H]1C[C@@H]2[C@H](CC[C@]3(C)C(=O)CC[C@@H]23)[C@@]2(CO[Si](c3ccccc3)(c3ccccc3)c3ccccc3)CCC(=O)C=C12

Procedure:
Following essentially the same procedure but substituting 19-hydroxy-1β-methyl-4-androstene-3,17-dione and 19-hydroxy-6α-methyl-4-androstene-3,17-dione for the 19-hydroxy-4-androstene-3,17-dione above results in the preparation of 1β-methyl-19-triphenylsiloxy-4-androstene-3,17-dione and 6α-methyl-19-triphenylsiloxy-4-androstene-3,17-dione.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH2:11][C:12]([O:14][CH3:15])=[O:13])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].CN1CCCC1=O.[CH3:23][O:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][SH:30])=[CH:27][CH:26]=1.[H-].[Na+]>O>[CH3:23][O:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][S:30][C:2]2[CH:3]=[C:4]([CH2:11][C:12]([O:14][CH3:15])=[O:13])[CH:5]=[CH:6][C:7]=2[N+:8]([O-:10])=[O:9])=[CH:27][CH:26]=1
Reactant: COc1ccc(CS)cc1
Reactant: COC(=O)Cc1ccc([N+](=O)[O-])c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: COC(=O)Cc1ccc([N+](=O)[O-])c(SCc2ccc(OC)cc2)c1

Procedure:
A mixture of methyl 3-fluoro4-nitrophenylacetate(1.05 g), N-methylpyrrolidinone(10 mL) and 4-methoxybenzyl mercaptan was stirred under argon and treated with sodium hydride(0.22 g of a 60% dispersion in mineral oil) and the resulting mixture was stirred at ambient temperature for 0.5 h. Water was added and the mixture was extracted with ether, and the extract was washed with brine, dried and evaporated to dryness. The residue was purified by flash chromatography eluting with increasingly polar mixtures of ethyl acetate and hexane to give the product (1.35 g), [m/e365, (M+NH4)+].
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[C:14]2[S:15][CH:16]([CH3:18])[CH2:17][C:13]=2[CH:12]=[CH:11][CH:10]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.[CH3:24][O:25][CH2:26]Br.Cl>O1CCCC1.CCCCCC>[C:1]([NH:5][S:6]([C:9]1[C:14]2[S:15][CH:16]([CH3:18])[CH2:17][C:13]=2[CH:12]=[CH:11][C:10]=1[CH2:24][O:25][CH3:26])(=[O:7])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1Cc2cccc(S(=O)(=O)NC(C)(C)C)c2S1
Reactant: COCBr
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COCc1ccc2c(c1S(=O)(=O)NC(C)(C)C)SC(C)C2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 7.14 g of N-t-butyl-2,3-dihydro-2-methylbezo[b]thiophene-7-sulfonamide in 175 ml of dry tetrahydrofuran was added 34 ml of a 1.6M hexane solution of n-butyl lithium at -40° C. to -30° C. under an inert atmosphere. The mixture was allowed to warm and was stirred at room temperature for 30 minutes. It was recooled to -30° C. and was contacted with 2.2 ml of bromomethyl methyl ether. The mixture was allowed to come to room temperature overnight and was acidified with 10 ml of 6N hydrochloric acid. The organic layer was separated, was dried over magnesium sulfate, and was concentrated to give 7.4 g of the title compound as a brown oil.
Reaction SMILES: [CH:1]([NH:4][C:5]1[C:6]([N:11]2[CH2:16][CH2:15][N:14]([C:17]([C:19]3[CH:27]=[CH:26][C:22]([C:23]([OH:25])=O)=[CH:21][CH:20]=3)=[O:18])[CH2:13][CH2:12]2)=[N:7][CH:8]=[CH:9][CH:10]=1)([CH3:3])[CH3:2].C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C.[NH2:42][C:43]([CH3:47])([CH3:46])[CH2:44][OH:45]>C(Cl)Cl.N1C=CC=CC=1>[CH3:46][C:43]([NH:42][C:23]([C:22]1[CH:21]=[CH:20][C:19]([C:17]([N:14]2[CH2:15][CH2:16][N:11]([C:6]3[C:5]([NH:4][CH:1]([CH3:3])[CH3:2])=[CH:10][CH:9]=[CH:8][N:7]=3)[CH2:12][CH2:13]2)=[O:18])=[CH:27][CH:26]=1)=[O:25])([CH3:47])[CH2:44][OH:45]
Reactant: CC(C)(N)CO
Reactant: CC(C)Nc1cccnc1N1CCN(C(=O)c2ccc(C(=O)O)cc2)CC1
Agent: CC(C)(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: CC(C)Nc1cccnc1N1CCN(C(=O)c2ccc(C(=O)NC(C)(C)CO)cc2)CC1
Temperature: 5 °C
Reaction time: 2 h
Yield: 83.8 %

Procedure:
4-[1-[3-(Isopropylamino)-2-pyridyl]piperazin-4-yl-carbonyl]benzoic acid (1.5 g) was dissolved in methylene chloride (45 ml), and then triethylamine (0.73 ml) was added and cooled. Pivaloyl chloride (0.58 ml) was added slowly to the solution at 0~5° C. and the mixture was stirred at 5° C. for 2 hours. And then, pyridine (0.65 ml) and 2-amino-2-methyl-1-propanol (0.4 g) were added in order, the solution was stirred at 0~5° C. for 2 hours and heated to 20° C. and stirred for 1 hour. The reaction mixture was washed with water twice and dried over anhydrous magnesium sulfate. Then, the solvent was concentrated under reduced pressure. The concentrated residue was crystallized by treatment with ether and further recrystallized using ethyl acetate and ether. The recrystallized product was filtered and dried to give 1.5 g (yield: 84%) of a desired compound.
Reaction SMILES: C(N(CC)CC)C.Cl.[CH3:9][NH:10][OH:11].[F:12][C:13]([F:27])([F:26])[C:14]1[CH:15]=[C:16]([N:23]=[C:24]=[O:25])[CH:17]=[CH:18][C:19]=1[N+:20]([O-:22])=[O:21].O>C(Cl)(Cl)Cl>[OH:11][N:10]([CH3:9])[C:24]([NH:23][C:16]1[CH:17]=[CH:18][C:19]([N+:20]([O-:22])=[O:21])=[C:14]([C:13]([F:26])([F:27])[F:12])[CH:15]=1)=[O:25]
Reactant: CNO
Reactant: O=C=Nc1ccc([N+](=O)[O-])c(C(F)(F)F)c1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: O
Product: CN(O)C(=O)Nc1ccc([N+](=O)[O-])c(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 16 h
Yield: 44.3 %

Procedure:
24 ml of triethylamine were added over 5 minutes to a stirred mixture of 15 g of N-methylhydroxylamine hydrochloride in 100 ml of chloroform cooled to 0° C and then 37.5g of 3-trifluoromethyl-4-nitrophenyl isocyanate were added at 20° to 25° C. The mixture was stirred at 20° C for 16 hours and was then poured into water. The mixture was vacuum filtered and the recovered crystals were dried under reduced pressure. The raw product was taken up in hot isopropyl ether and the solution was treated with activated carbon and was evaporated to dryness under reduced pressure to obtain 20 g of N-hydroxy-N-methyl-N'-(3'-trifluoromethyl-4'-nitrophenyl)-urea melting at 129°-130° C.
Reaction SMILES: [CH3:1]I.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:9][C:10]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:11]=1[CH:12]=[CH:13][NH:14]2>CN(C)C=O>[CH3:1][N:14]1[C:15]2[C:11](=[C:10]([CH3:9])[CH:18]=[CH:17][CH:16]=2)[CH:12]=[CH:13]1
Reactant: Cc1cccc2[nH]ccc12
Reactant: CI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1cccc2c1ccn2C
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.2 %

Procedure:
Methyl iodide (28.44 g) and cesium carbonate (82.26 g) were added to a solution of 4-methylindole (22.08 g) in dimethylformamide (200 mL), and the reaction mixture was stirred at room temperature overnight. The reaction mixture was filtered with Celite (trade name), and the filtrate was concentrated under reduced pressure. A saturated aqueous solution of ammonium chloride was added to the obtained residue, and the reaction mixture was extracted with ethyl acetate. The obtained organic layer was washed with water and a saturated salt solution, and concentrated under reduced pressure after drying with anhydrous sodium sulfate. The obtained residue was purified by column chromatography on silica gel (hexane:ethyl acetate=100:0→85:15) to give the title compound (20.83 g) having the following physical data.
Reaction SMILES: [C:1]12([C:11]3[CH:20]=[C:19]4[C:14]([CH:15]=[CH:16][C:17]([Br:21])=[CH:18]4)=[CH:13][C:12]=3[OH:22])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.CN(C=O)C.C(N(CC)CC)C.[Si:35](Cl)([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36]>CN(C)C1C=CN=CC=1.O>[C:1]12([C:11]3[CH:20]=[C:19]4[C:14]([CH:15]=[CH:16][C:17]([Br:21])=[CH:18]4)=[CH:13][C:12]=3[O:22][Si:35]([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36])[CH2:8][CH:7]3[CH2:9][CH:3]([CH2:4][CH:5]([CH2:6]3)[CH2:10]1)[CH2:2]2
Reactant: Oc1cc2ccc(Br)cc2cc1C12CC3CC(CC(C3)C1)C2
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1cc2ccc(Br)cc2cc1C12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 12 h

Procedure:
11.9 g (33.3 mmol) of 7-(1-adamantyl)-6-hydroxy-2-bromonaphthalene, 120 ml of DMF, 5.1 ml (36.6 mmol) of triethylamine and 203 mg of 4-dimethylaminopyridine were introduced successively into a three-necked flask. A solution of 5.52 g (36.6 mmol) of tert-butyldimethylsilyl chloride was added dropwise and the mixture was stirred at room temperature for 12 hours. The reaction medium was poured into water, extracted with ethyl ether, the organic phase decanted, dried over magnesium sulfate and evaporated. The residue obtained was purified by chromatography on a silica column eluted with heptane; 12 g (76%) of 7-(1-adamantyl)-6-tert-butyldimethylsilyloxy-2-bromonaphthalene of melting point 120°-121° C. were recovered.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][OH:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[F:13][C:14]1[C:19](F)=[CH:18][C:17]([NH2:21])=[C:16]([N+:22]([O-:24])=[O:23])[CH:15]=1.C(=O)(O)[O-].[Na+]>CN(C)C=O.O.C(OCC)(=O)C>[F:13][C:14]1[C:19]([O:10][CH2:9][CH2:8][CH2:7][N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[CH:18][C:17]([NH2:21])=[C:16]([N+:22]([O-:24])=[O:23])[CH:15]=1
Reactant: Nc1cc(F)c(F)cc1[N+](=O)[O-]
Reactant: OCCCN1CCCCC1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: Nc1cc(OCCCN2CCCCC2)c(F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 1.3 mL of 3-piperidin-1-ylpropan-1-ol in 16 mL of N,N-dimethylformamide (DMF) is cooled to 0° C. with an ice bath. 345 mg of sodium hydride (60% in suspension in oil) are added in small portions. The suspension obtained is added dropwise to a suspension containing 500 mg of 4,5-difluoro-2-nitrophenylamine and 724 mg of sodium bicarbonate in 15 mL of DMF. The reaction medium is stirred for one hour at ambient temperature and then heated for 1 hour at 90° C. The cooled reaction medium is treated with 70 mL of ethyl acetate and 70 mL of distilled water. The aqueous phase is extracted with 70 mL of ethyl acetate. The combined organic phases are washed with 100 mL of distilled water and 100 mL of a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. The solvent is concentrated to dryness in a rotary evaporator and the crude is then purified by chromatography on a 50 g silica cartridge, eluent: 100/0 to 80/20 dichloromethane/methanol. 300 mg of 4-fluoro-2-nitro-5-(3-piperidin-1-ylpropoxy)phenylamine are isolated in the form of a yellow oil which crystallizes. Analytical LC/MS: Tr=2.26 min, [M+H]+=298.04 DAD=87%.
Reaction SMILES: [N:1]([C:4]1[C:11]([Br:12])=[CH:10][C:9]([Cl:13])=[CH:8][C:5]=1[CH:6]=O)=[N+:2]=[N-].[CH:14]1(N)[CH2:16][CH2:15]1>C(Cl)Cl>[Br:12][C:11]1[C:4]2[C:5](=[CH:6][N:2]([CH:14]3[CH2:16][CH2:15]3)[N:1]=2)[CH:8]=[C:9]([Cl:13])[CH:10]=1
Reactant: [N-]=[N+]=Nc1c(Br)cc(Cl)cc1C=O
Reactant: NC1CC1
Solvent: ClCCl
Product: Clc1cc(Br)c2nn(C3CC3)cc2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-Azido-3-bromo-5-chlorobenzaldehyde (1.38 g, 5.30 mmol) and cyclopropylamine (0.37 mL, 5.30 mmol) in methylene chloride (20 mL) were treated with molecular sieves (1.5 g). The reaction was stirred at room temperature for 2 h, filtered over celite and the resulting solution evaporated in vacuo. The resulting oil was suspended in toluene (15 mL) and heated at reflux for 2 h. After cooling to room temperature, the mixture was poured into ice water and extracted with diethyl ether (2×). The organic layers were pooled together, washed with brine (2×), dried over sodium sulfate, and concentrated. Column chromatography on silica gel (15% ethyl acetate/hexanes) gave 1.1 g (76%) as a light yellow solid. 1H-NMR (CDCl3, 500 MHz) δ 8.7 (s, 1H), 7.81 (d, J=2.6 Hz, 1H), 7.53 (d, J=2.6 Hz, 1H), 3.05-3.09 (m, 1H), 0.95-0.99 (m, 4H). Mass spec.: 273.03 (MH)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH3:17])[CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1)=[CH:7]2.CCN(CC)CC.[C:25](Cl)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>ClCCl.O>[CH3:17][C:4]1[CH:5]=[C:6]2[C:10](=[C:2]([NH:1][C:25](=[O:32])[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:3]=1)[NH:9][C:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1)=[CH:7]2
Reactant: Cc1cc(N)c2[nH]c(-c3ccccn3)cc2c1
Reactant: O=C(Cl)c1ccccc1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(NC(=O)c2ccccc2)c2[nH]c(-c3ccccn3)cc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 27.5 %

Procedure:
7-Amino-5-methyl-2-(pyridin-2-yl)-1H-indole (45 mg, 0.20 mmol) prepared in Step A of Example 1 was dissolved in dichloromethane (10 mL). Et3N (0.56 mL, 0.4 mmol) and benzoyl chloride (0.03 mL, 0.22 mmol) were added thereto, and the mixture was stirred for 2 h at room temperature. After completion of the reaction, the reaction mixture was diluted with water, extracted with EtOAc, and dried over anhydrous MgSO4. The solvent was removed under reduced pressure, and the residue was purified by column chromatography (eluent EtOAc/n-Hex=1/5) to give the title compound (18 mg, Yield 27%).