Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].[Cl:2][C:3]1[CH:8]=[C:7]([S:9][CH2:10][C:11]([F:14])([F:13])[F:12])[CH:6]=[C:5]([Cl:15])[C:4]=1[OH:16].[CH2:17](Br)[CH2:18][Br:19]>C(O)C>[Cl:15][C:5]1[CH:6]=[C:7]([S:9][CH2:10][C:11]([F:13])([F:14])[F:12])[CH:8]=[C:3]([Cl:2])[C:4]=1[O:16][CH2:17][CH2:18][Br:19]
Reactant: BrCCBr
Reactant: Oc1c(Cl)cc(SCC(F)(F)F)cc1Cl
Agent: [Na]
Solvent: CCO
Product: FC(F)(F)CSc1cc(Cl)c(OCCBr)c(Cl)c1
Temperature: 40 °C
Reaction time: 2 h
Yield: 58.4 %

Procedure:
To an ethanol solution of sodium ethylate obtained by dissolving 0.7 g of metallic sodium in 50 ml of ethanol were added 8.9 g of 2,6-dichloro-4-(2,2,2-trifluoroethylthio)-phenol and 20 g of ethylene bromide. The mixture was stirred at 40° C. for 2 hours and under reflux for 4 hours. Ethanol and the excess of ethylene bromide were evaporated. The residue was taken into 150 ml of toluene, washed with a 5% aqueous solution of potassium hydroxide and water in this sequence, and dried over anhydrous sodium sulfate. Toluene was evaporated, and the residue was distilled under reduced pressure to give 7.2 g of 2-[2,6-dichloro-4-(2,2,2-trifluoroethylthio)-phenoxy]-ethyl bromide with the b.p.=124°-126° C./0.8 mmHg.
Reaction SMILES: [CH:1]([NH:4][C:5]1[S:6][CH:7]=[C:8]([C:10]2[CH:19]=[C:18]([OH:20])[C:17]3[C:12](=[CH:13][C:14]([O:21][CH3:22])=[CH:15][CH:16]=3)[N:11]=2)[N:9]=1)([CH3:3])[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+].[CH2:29]([O:31][C:32]([C:34]12[CH2:51][CH:50]1[CH:49]=[CH:48][CH2:47][CH2:46][CH2:45][CH2:44][N:43]([CH3:52])[C:42](=[O:53])[CH:41]1[CH:37]([CH2:38][CH:39](OS(C3C=CC(Br)=CC=3)(=O)=O)[CH2:40]1)[C:36](=[O:65])[NH:35]2)=[O:33])[CH3:30]>CN1C(=O)CCC1.C(Cl)(Cl)Cl>[CH2:29]([O:31][C:32]([C:34]12[CH2:51][CH:50]1[CH:49]=[CH:48][CH2:47][CH2:46][CH2:45][CH2:44][N:43]([CH3:52])[C:42](=[O:53])[CH:41]1[CH:37]([CH2:38][CH:39]([O:20][C:18]3[C:17]4[C:12](=[CH:13][C:14]([O:21][CH3:22])=[CH:15][CH:16]=4)[N:11]=[C:10]([C:8]4[N:9]=[C:5]([NH:4][CH:1]([CH3:3])[CH3:2])[S:6][CH:7]=4)[CH:19]=3)[CH2:40]1)[C:36](=[O:65])[NH:35]2)=[O:33])[CH3:30]
Reactant: CCOC(=O)C12CC1C=CCCCCN(C)C(=O)C1CC(OS(=O)(=O)c3ccc(Br)cc3)CC1C(=O)N2
Reactant: COc1ccc2c(O)cc(-c3csc(NC(C)C)n3)nc2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C12CC1C=CCCCCN(C)C(=O)C1CC(Oc3cc(-c4csc(NC(C)C)n4)nc4cc(OC)ccc34)CC1C(=O)N2
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 12.9 %

Procedure:
2-(Isopropylamino-thiazol-4-yl)-7-methoxy-quinolin-4-ol (220 mg, 0.7 mmol) (prepared as described in WO 00/59929) was dissolved in 7 ml of NMP (N-methyl pyrrolidinone), one spoon of Cs2CO3 was added, stirred at 60° C. for 1.5 h. Then compound 108 (150 mg, 0.24 mmol) was added. The reaction mixture was stirred at 80° C. overnight. Was diluted with chloroform and washed with sodium bicarbonate, brine. Water phases were back-extracted with chloroform. The combined organic layers were dried over sodium sulphate and evaporated. The crude product was purified by preparative HPLC (Gilson) (MeOH—H2O, 65%) to give 21 mg of product (yield 13%) as well as 12 mg of isomer.
Reaction SMILES: [CH:1]1([C:6]2[N:11]=[C:10](O)[C:9]3[CH2:13][CH2:14][CH2:15][C:8]=3[N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.P(Cl)(Cl)([Cl:18])=O>>[Cl:18][C:10]1[C:9]2[CH2:13][CH2:14][CH2:15][C:8]=2[N:7]=[C:6]([CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[N:11]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1nc(C2CCCC2)nc2c1CCC2
Product: Clc1nc(C2CCCC2)nc2c1CCC2
Reaction time: 1 h
Yield: 85.7 %

Procedure:
A mixture of 2-cyclopentyl-6,7-dihydro-5H-cyclopentapyrimidin-4-ol (4.5 g, 22 mmol) and phosphorus oxychloride (13 mL, 130 mmol) was heated to reflux for 4 hours. Thereafter, volatiles were evaporated under reduced pressure and the mixture was poured over ice-water. After stirring for 1 hour, the product was extracted with dichloromethane (3×50 mL). The combined organic extracts were washed with water, treated with activated charcoal, dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to afford the title compound as a light yellow solid (4.2 g, 86% yield)
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[N:3]=1.CN(C=O)C.[Cl-].[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]=[N:24][C:25]2[N:29]([CH3:30])[CH:28]=[CH:27][N+:26]=2[CH3:31])=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>O>[Cl-:8].[NH2:1][C:2]1[N:7]=[C:6]([NH:16][C:17]2[CH:18]=[CH:19][C:20]([N:23]=[N:24][C:25]3[N:26]([CH3:31])[CH:27]=[CH:28][N+:29]=3[CH3:30])=[CH:21][CH:22]=2)[CH:5]=[C:4]([Cl:9])[N:3]=1
Reactant: Nc1nc(Cl)cc(Cl)n1
Reactant: Cn1cc[n+](C)c1N=Nc1ccc(N)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1cc[n+](C)c1N=Nc1ccc(Nc2cc(Cl)nc(N)n2)cc1

Procedure:
0.164 g of 2-amino-4,6-dichloropyrimidine (0.001 mol) and 3 ml of dry DMF, 0.251 g (0.001 mol) of 2-(4-amino-phenylazo)-1,3-dimethyl-3H-imidazol-1-ium chloride and 0.138 g (0.001 mol) of potassium carbonate are charged to a fully equipped round-bottomed flask. The mixture is brought for 17 hours to 80° C. with stirring. After cooling, 4 ml of water are added and the precipitate is filtered off. 100 mg of a red powder containing the starting 2-(4-aminophenylazo)-1,3-dimethyl-3H-imidazol-1-ium chloride and the expected product are obtained. The latter, purified by preparative HPLC, has the following UV absorption characteristics:
Reaction SMILES: [SH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[OH:10][CH2:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[CH2:15]Br.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[OH:10][CH2:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[CH2:15][S:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6]
Reactant: O=Cc1cccc(S)c1
Reactant: OCc1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1cccc(SCc2cccc(CO)c2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 50.8 %

Procedure:
200 mg of 3-mercaptobenzaldehyde was dissolved in 6 ml of dimethylformamide, and 291 mg of 3-hydroxymethylbenzyl bromide and 402 mg of potassium carbonate were added. The mixture was stirred for 3 hours at room temperature. The solvent was evaporated, water and ethyl ether were added to the residue to extract it. The extract was worked up in a customary manner, and purified by silica gel column chromatography [Wakogel C-200, 10 g; eluting solvent: hexane/ethyl acetate=2/1] to give 190 mg (yield 51%) of 3-[3-(hydroxymethyl)benzylthio]benzaldehyde as a pale yellow oil.
Reaction SMILES: [OH:1][C:2]1[C:3]2[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:4]=2[S:5][C:6]=1[C:7]([O:9][CH3:10])=[O:8].CS(C)=O.CC(C)([O-])C.[K+].Br[CH2:28][C:29]#[N:30]>C(OCC)(=O)C>[CH3:10][O:9][C:7]([C:6]1[S:5][C:4]2[CH:11]=[CH:12][C:13]([O:15][CH3:16])=[CH:14][C:3]=2[C:2]=1[O:1][CH2:28][C:29]#[N:30])=[O:8]
Reactant: N#CCBr
Reactant: COC(=O)c1sc2ccc(OC)cc2c1O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COC(=O)c1sc2ccc(OC)cc2c1OCC#N
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a room temperature solution of methyl 3-hydroxy-5-methoxybenzo[b]thiophene -2-carboxylate (1.00 g, 4.2 mmol) [Connor, et al., J. Med. Chem. 35:959 (1992)]in 20 mL of DMSO is added potassium t-butoxide (494 mg, 4.41 mmol) followed by bromoacetonitrile (878 μL, 12.58 mmol). The mixture is stirred at room temperature for 1.5 hours, then poured into ethyl acetate and 1N HC1. The organic layer is washed with 1N HCl, followed by several portions of brine, and dried over MgSO4. Filtration followed by removal of solvent in vacuo and recrystallization of the residue from ethyl acetate:hexane gives 413 mg. An additional crop of 112 mg can be obtained from the mother liquor, mp 159.5°-160° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5](Cl)=[O:6].[F:12][C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][C:14]=1[N+:20]([O-:22])=[O:21].C(N(CC)CC)C>C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5]([NH:17][C:16]1[CH:18]=[CH:19][C:13]([F:12])=[C:14]([N+:20]([O-:22])=[O:21])[CH:15]=1)=[O:6]
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Reactant: Nc1ccc(F)c([N+](=O)[O-])c1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: O=C(Nc1ccc(F)c([N+](=O)[O-])c1)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3,4-Dichlorobenzoyl chloride (4.3 g, 20.5 mmol) was added all at once to 4-fluoro-3-nitroaniline (3.14 g, 20.1 mmol) and triethylamine (3 mL, 21.5 mmol) in ethyl acetate (200 mL) at room temperature. The reaction mixture was stirred overnight at room temperature then diluted to ˜500 mL with ethyl acetate. The ethyl acetate was washed successively with 1N HCl (100 mL), saturated sodium bicarbonate (100 mL), and brine (100 mL), then dried (magnesium sulfate), filtered, and stripped of solvent under reduced pressure. Trituration of the residue in hexanes (125 mL) and a few milliliters of ethyl acetate afforded the product by filtration (5.6 g); m.p. 202-204° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[CH:21]1([NH:24][S:25]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39]Br)(=[O:27])=[O:26])[CH2:23][CH2:22]1>C(N(C(C)C)C(C)C)C>[CH:21]1([NH:24][S:25]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][N:12]2[CH2:11][CH2:10][N:9]([CH:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:14][CH2:13]2)(=[O:27])=[O:26])[CH2:23][CH2:22]1
Reactant: Clc1ccc(C(c2ccccc2)N2CCNCC2)cc1
Reactant: O=S(=O)(CCCCCCCCCCCCBr)NC1CC1
Solvent: CCN(C(C)C)C(C)C
Product: O=S(=O)(CCCCCCCCCCCCN1CCN(C(c2ccccc2)c2ccc(Cl)cc2)CC1)NC1CC1
Yield: 98.4 %

Procedure:
1-[(4-Chlorophenyl)phenylmethyl]piperazine (629.0 mg, 2.20 mmol) and N-cyclopropyl-12-bromododecanesulfonamide (891.0 mg, 2.42 mmol) were refluxed in N-ethyldiisopropylamine (2 ml) for 4 hours. The reaction mixture was concentrated in vacuo, and water was added thereto. The mixture was extracted with chloroform. The chloroform layer was washed with water, and dried over anhydrous magnesium sulfate. Subsequently, the solvent was removed by evaporation in vacuo. The resulting crude product was purified by column chromatography on silica gel with chloroform, to give N-cyclopropyl-12-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]dodecanesulfonamide (1243.0 mg) as a pale brown oil (yield based on 1-[(4-chlorophenyl)phenylmethyl]piperazine: 98.4%).
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][N:8]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([NH2:22])(=[O:21])=[O:20])=[CH:15][CH:14]=1)[C:7](=[O:23])[CH:6]=2.[C:24]1([CH2:30][C:31]#[CH:32])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(N(CC)CC)C>CN(C)C=O.[Cu]I.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>[O:23]=[C:7]1[CH:6]=[C:5]2[C:10]([CH:11]=[C:2]([C:32]#[C:31][CH2:30][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[N:3]=[CH:4]2)=[CH:9][N:8]1[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([NH2:22])(=[O:21])=[O:20])=[CH:15][CH:14]=1
Reactant: C#CCc1ccccc1
Reactant: NS(=O)(=O)c1ccc(Cn2cc3cc(Br)ncc3cc2=O)cc1
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: NS(=O)(=O)c1ccc(Cn2cc3cc(C#CCc4ccccc4)ncc3cc2=O)cc1

Procedure:
The coupling of 4-(7-bromo-3-oxo-2H-6-azaisoquinolin-2-ylmethyl)benzenesulfonamide (0.71 g, 1.81 mmol) with 3-phenyl-1-propyne (0.56 mL, 4.51 mmol) using triethylamine (0.50 mL, 3.61 mmol), CuI (0.025 g, 0.13 mmol), and Pd(Ph3P)4 (0.084 g, 0.07 mmol) in dimethylformamide is carried out as described in Example 1, Step (2). Purification is carried out on a silica gel column eluted with hexanes/ethyl acetate 3:1 to give the desired product.
Reaction SMILES: [ClH:1].Cl.CN[C@H]1CCN([CH2:10][CH:11]([C:22]2([OH:28])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)C1.OC1(C(C2C=CC=C(C(F)(F)F)C=2)C([N:39]2[CH2:43][CH2:42][C@H:41]([NH:44][C:45](=O)OC(C)(C)C)[CH2:40]2)=O)CCCCC1>>[ClH:1].[ClH:1].[CH3:45][NH:44][C@H:41]1[CH2:42][CH2:43][N:39]([CH:27]2[CH2:26][CH2:25][CH2:24][CH2:23][C:22]2([CH:11]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:20])([F:21])[F:19])[CH:13]=2)[CH3:10])[OH:28])[CH2:40]1
Reactant: CN[C@H]1CCN(CC(c2cccc(C(F)(F)F)c2)C2(O)CCCCC2)C1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(C(=O)C(c2cccc(C(F)(F)F)c2)C2(O)CCCCC2)C1
Agent: Cl
Product: CN[C@H]1CCN(C2CCCCC2(O)C(C)c2cccc(C(F)(F)F)c2)C1

Procedure:
In an analogous manner to Example 13, step 2, 1-{2-[(3S)-3-(methylamino)pyrrolidin-1-yl]-1-[3-(trifluoromethyl)phenyl]ethyl}cyclohexanol dihydrochloride was prepared from tert-butyl ((3S)-1-{(1-hydroxycyclohexyl)[3-(trifluoromethyl)phenyl]acetyl}pyrrolidin-3-yl)carbamate MS (ESI) m/z 371; HRMS: calcd for C20H29F3N2O+H, 371.23102; found (ESI, [M+H]+), 371.2293.
Reaction SMILES: [CH:1]1([NH:4][C:5]2[C:6]([NH2:13])=[CH:7][C:8]([O:11][CH3:12])=[CH:9][CH:10]=2)[CH2:3][CH2:2]1.[N:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH:20]=O)[CH:15]=1.OOS([O-])=O.[K+].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[CH:1]1([N:4]2[C:5]3[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:6]=3[N:13]=[C:20]2[C:16]2[CH:15]=[N:14][CH:19]=[CH:18][CH:17]=2)[CH2:3][CH2:2]1
Reactant: COc1ccc(NC2CC2)c(N)c1
Reactant: O=Cc1cccnc1
Agent: O=C([O-])[O-]
Agent: O=S([O-])OO
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2c(c1)nc(-c1cccnc1)n2C1CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of N1-cyclopropyl-4-methoxy-benzene-1,2-diamine (0.2 g, 0.0011 mol) and pyridine-3-carbaldehyde (0.12 g, 0.0011 mol) in DMF (5 ml) and H2O (2 ml) was added OXONE® monopersulphate (0.81 g, 0.00132 map. Reaction mass was stirred at room temperature for 3 h. The reaction mixture was basified with 10% K2CO3 solution to pH˜8-10 and extracted with EtOAc (3×20 ml). The combined organic layers were washed with brine dried over Na2SO4 and concentrated under vacuum to afford the crude compound which was purified by column chromatography to obtain title compound 1-cyclopropyl-5-methoxy-2-(pyridin-3-yl)-1H-benzimidazole (376). 1H NMR (400 MHz, DMSO-d6), δ: 9.16 (s, 1H), 8.70 (s, 1H), 8.37 (d, J=8.8 Hz, 1H), 7.55 (d, J=8.4 Hz, 2H), 7.23 (s, 1H), 6.96 (d, J=8.8 Hz, 1H), 3.80 (s, 3H), 1.10 (d, J=6.4 Hz, 2H), 0.64 (s, 2H). MS (M+1): 266.1, Purity 98.98%.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][NH2:12])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[O:13]1[CH2:18][CH2:17][C:16](=O)[CH2:15][CH2:14]1>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][N:12]=[C:16]2[CH2:17][CH2:18][O:13][CH2:14][CH2:15]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=C1CCOCC1
Reactant: Cc1ccc(S(=O)(=O)NN)cc1
Product: Cc1ccc(S(=O)(=O)NN=C2CCOCC2)cc1
Yield: 40.2 %

Procedure:
A solution of 4-methylbenzenesulfonohydrazide (819 mg, 4.4 mmol) and dihydro-2H-pyran-4(3H)-one (487 μl, 5.28 mmol) was stirred in a Dean-Stark apparatus at 120° C. for 24 hours. The reaction mixture was cooled and evaporated at reduced pressure. The residue was purified by chromatography using a gradient of dichloromethane/ethyl acetate=100:0 to 80:20 as the eluent to give the 4-methyl-N′-(2H-pyran-4(3H,5H,6H)-ylidene)benzenesulfonohydrazide (475 mg, 40% yield) as an off white solid. MS (ISP): m/z=269.3 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]#[C:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:8][C:9]=1Br)=[O:4].C([O-])([O-])=O.[K+].[K+].[CH:23]1([C@H:29]2[NH:34][C:33](=[O:35])[CH2:32][CH2:31][CH2:30]2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>[Cu]I.O1CCOCC1>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]#[C:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:8][C:9]=1[N:34]1[C:33](=[O:35])[CH2:32][CH2:31][CH2:30][C@H:29]1[CH:23]1[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]1)=[O:4]
Reactant: O=C1CCC[C@@H](C2CCCCC2)N1
Reactant: COC(=O)c1sc(C#CC(C)(C)C)cc1Br
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COC(=O)c1sc(C#CC(C)(C)C)cc1N1C(=O)CCC[C@H]1C1CCCCC1
Temperature: 110 °C
Reaction time: 48 h
Yield: 39.8 %

Procedure:
To a 10 mL vial was added trans-cyclohexane diamine (283 mg, 2.5 mmol, 0.5 equiv), 3-Bromo-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic acid methyl ester (2.24 g, 7.4 mmol, 1.5 equiv), K2CO3 (1.37 g, 9.9 mmol, 2.0 equiv), CuI (473 mg, 2.5 mmol, 0.5 equiv), (S)-6-Cyclohexyl-piperidin-2-one (900 mg, 5.0 mmol, 1.0 equiv) and 1,4-dioxane (5.0 mL). The mixture was flushed with N2 and stirred at 110° C. for 48 hours. The mixture was filtered through Celite and the filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography, EtOAc/heptane 30% to give product 800 mg (yield 40%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C@H:4]([CH2:6][NH:7][C:8](=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[NH2:5].[Cl:17][C:18]1[CH:26]=[C:25]([C:27]([NH:29][CH2:30][C:31]2[CH:39]=[CH:38][CH:37]=[C:36]3[C:32]=2[CH:33]=[CH:34][NH:35]3)=[O:28])[CH:24]=[CH:23][C:19]=1[C:20](O)=[O:21].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C.O>[CH3:1][O:2][C:3](=[O:16])[C@H:4]([CH2:6][NH:7][C:8](=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[NH:5][C:20](=[O:21])[C:19]1[CH:23]=[CH:24][C:25]([C:27]([NH:29][CH2:30][C:31]2[CH:39]=[CH:38][CH:37]=[C:36]3[C:32]=2[CH:33]=[CH:34][NH:35]3)=[O:28])=[CH:26][C:18]=1[Cl:17]
Reactant: COC(=O)[C@@H](N)CNC(=O)c1ccccc1
Reactant: O=C(NCc1cccc2[nH]ccc12)c1ccc(C(=O)O)c(Cl)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)[C@H](CNC(=O)c1ccccc1)NC(=O)c1ccc(C(=O)NCc2cccc3[nH]ccc23)cc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 47.2 %

Procedure:
3-(Benzoylamino)-L-alanine methyl ester (Example 299; 77 mg, 0.35 mmol) was mixed with 2-chloro-4-[[(1H-indol-4-yl-methyl)amino]carbonyl]benzoic acid (Example 36; 115 mg, 0.35 mmol), HOBT (57 mg, 0.42 mmol) and EDCl (80.5 mg, 0.42 mmol) in DMF (4 mL). The reaction mixture was stirred at room temperature for 16 h and then diluted with water (about 20 ml). The solution was extracted with ethyl acetate (3×10 ml) and the ethyl acetate layer was washed with dilute aqueous NaCl solution and then brine, dried (Na2SO4), concentrated, and chromatographed (40-80% ethyl acetate/hexanes) to give 3-(benzoylamino)-N-[2-chloro-4-[[(1H-indol-4-ylmethyl)amino]carbonyl]benzoyl]-L-alanine methyl ester (88 mg, 47%). A solution of the ester (51 mg, 0.096 mmol) and lithium hydroxide monohydrate (8 mg, 0.19 mmol) in tetrahydrofuran/methanol/water (3:1:1; 2 mL) was stirred at room temperature for 3 h. The solvent was removed and the product was purified by HPLC to give 3-(benzoylamino)-N-[2-chloro-4-[[(1H-indol-4-ylmethyl)amino]carbonyl]benzoyl]-L-alanine (37 mg, 75%) as a white fluffy powder.
Reaction SMILES: C(OC([N:8]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[CH:11]=1)[NH2:9])=O)(C)(C)C.[ClH:22]>CO.O1CCOCC1>[ClH:22].[ClH:22].[ClH:22].[N:16]1([C:12]2[CH:11]=[C:10]([NH:8][NH2:9])[CH:15]=[CH:14][CH:13]=2)[CH2:17][CH2:18][O:19][CH2:20][CH2:21]1
Reactant: CC(C)(C)OC(=O)N(N)c1cccc(N2CCOCC2)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: NNc1cccc(N2CCOCC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a solution of N-(3-morpholin-4-yl-phenyl)-hydrazinecarboxylic acid tert-butyl ester (468 mg, 1.60 mmol) in methanol (20 mL) was added a solution of 4 N HCl in dioxane (10 mL). The mixture was stirred at room temperature overnight, then concentrated to give (3-morpholin-4-yl-phenyl)-hydrazine 3 HCl salt (484 mg, 100%) as a yellow solid. MS (ES+): m/z=194.1; 1H NMR (CD3OD, 500 MHz): δ 3.60-3.71 (m, 4H), 4.06-4.15 (m, 4H), 7.06 (d, 1H), 7.26-7.35 (m, 2H), 7.50-7.58 (m, 1H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[CH3:10][N+:11]([CH3:13])=[CH2:12].[I-]>C(#N)C>[CH3:10][N:11]([CH2:13][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][CH:2]=1)[CH3:12]
Reactant: c1ccc2[nH]ccc2c1
Reactant: C=[N+](C)C
Agent: [I-]
Solvent: CC#N
Product: CN(C)Cc1c[nH]c2ccccc12
Reaction time: 0.5 h

Procedure:
To a stirred solution of indole (5.6 g, 47.8 mmol) in acetonitrile (130 ml) is added Eschenmoser's salt (10 g, 54 mmol) under nitrogen atmosphere and the mixture is stirred for 30 min. The mixture is concentrated in vacuo and the residue is diluted with 1M sodium hydroxide solution and extracted with methylene chloride. The organic layer is dried over sodium carbonate and concentrated in vacuo to give 3-(dimethylaminomethyl)indole as a brown oil. To a solution of 3-(dimethylaminomethyl)indole in methylene chloride (200 ml) is dropped methyl iodide (5 ml, 80 mmol). The mixture is stirred at r.t. for 6 hrs. and concentrated in vacuo to give (3-indolylmethyl)trimethylammonium iodide as a brown foam. To a cooled (0° C.) suspension of sodium hydroxide (1.5 g, 37 mmol) in DMF (100 ml) is added trimethyl phosphonoacetate (6.7 ml, 41 mmol) and the mixture is stirred at 0° C. for 30 min. To the mixture is added (3-indolylmethyl)trimethylammonium iodide and the whole is stirred at r.t. overnight. The mixture is diluted with water and extracted with ethyl acetate. The organic layer is dried over magnesium sulfate and concentrated in vacuo. The residue is chromatographed on silica gel with ethyl acetate to give methyl 3-(3-indolyl)-2-(dimethylphosphono)propionate a a brown oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH:9]([C:12]1[CH:16]=[CH:15][S:14][C:13]=1[CH3:17])[NH:10][CH3:11].[Br:18]N1C(=O)CCC1=O>CN(C)C=O>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:18])=[CH:4][C:3]=1[CH2:8][CH:9]([C:12]1[CH:16]=[CH:15][S:14][C:13]=1[CH3:17])[NH:10][CH3:11]
Reactant: O=C1CCC(=O)N1Br
Reactant: CNC(Cc1ccccc1N)c1ccsc1C
Solvent: CN(C)C=O
Product: CNC(Cc1cc(Br)ccc1N)c1ccsc1C
Reaction time: 8 h
Yield: 30.3 %

Procedure:
A stirred solution of 3.0 g of 2-amino-N-methyl-α-(2-methyl-3-thienyl)benzeneethanamine in 50 ml of N,N-dimethylformamide was treated with a solution of 2.6 g of N-bromosuccinimide in 50 ml of N,N-dimethylformamide and allowed to stand overnight at room temperature. Evaporation of the volatiles afforded an oil :which was purified by HPLC (Water's Associates Prep LC/System 500, silica gel, elution with methanol). The resultant oil was dissolved in diethyl ether, filtered and concentrated. Trituration with diethyl ether afforded 1.2 g of 2-amino-5-bromo-N-methyl-α-(2-methyl-3-thienyl)benzeneethanamine, mp 72.5°-74° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:4]3[C:5]4[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[C:27]([CH3:33])[C:6]=4[N:7]=[C:8](OS(C4C=CC(C)=CC=4)(=O)=O)[C:9]=3[C:10](=[O:15])[C:11]=2[CH:12]=[CH:13][N:14]=1.[NH2:34][CH2:35][CH2:36][N:37]([CH3:46])[CH2:38][CH2:39][CH2:40][N:41]([CH2:43][CH2:44][NH2:45])[CH3:42]>>[Cl:1][C:2]1[C:3]2[C:4]3[C:5]4[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[C:27]([CH3:33])[C:6]=4[N:7]=[C:8]([NH:45][CH2:44][CH2:43][N:41]([CH2:40][CH2:39][CH2:38][N:37]([CH2:36][CH2:35][NH:34][C:8]4[C:9]5[C:10](=[O:15])[C:11]6[CH:12]=[CH:13][N:14]=[C:2]([Cl:1])[C:3]=6[C:4]=5[C:5]5[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[C:27]([CH3:33])[C:6]=5[N:7]=4)[CH3:46])[CH3:42])[C:9]=3[C:10](=[O:15])[C:11]=2[CH:12]=[CH:13][N:14]=1
Reactant: CN(CCN)CCCN(C)CCN
Reactant: COc1ccc2c3c(c(OS(=O)(=O)c4ccc(C)cc4)nc2c1C)C(=O)c1ccnc(Cl)c1-3
Product: COc1ccc2c3c(c(NCCN(C)CCCN(C)CCNc4nc5c(C)c(OC)ccc5c5c4C(=O)c4ccnc(Cl)c4-5)nc2c1C)C(=O)c1ccnc(Cl)c1-3

Procedure:
In a similar manner to Example 4, this compound was obtained starting from toluene-4-sulfonic acid 11-chloro-3-methoxy-4-methyl-7-oxo-7H-5,10-diaza-benzo[c]fluoren-6-yl ester (the compound of Reference Example 5) and N,N′-bis-(2-amino-ethyl)-N,N′-dimethyl-propane-1,3-diamine. The desired product was obtained as a reddish powder.