Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](=[O:4])([O-])[O-:2].[Cs+].[Cs+].[C:7]1([C:13]#[CH:14])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(=O)=O>O>[C:7]1([C:13]#[C:14][C:1]([OH:2])=[O:4])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C([O-])[O-]
Reactant: C#Cc1ccccc1
Agent: O=C=O
Agent: [Cs+]
Solvent: O
Product: O=C(O)C#Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
(4,7-Diphenyl-1,10-phenanthroline)bis[tris(p-fluorophenyl)phosphine]copper(I) nitrate (10.9 mg, 0.01 mmol) and cesium carbonate (391 mg, 1.20 mmol) were placed in a flask. The reaction vessel was then flushed with nitrogen and closed by means of a septum. Degassed DMF (3.00 ml) was subsequently added and the resulting mixture was stirred for 5 minutes at room temperature. After repeated evacuation and admission of CO2 into the reaction vessel, phenylacetylene (110 μL, 1.00 mmol) was injected. The reaction mixture was stirred at 35° C. and 5 bar of CO2 pressure in a steel autoclave for 12 hours. After the reaction time had expired, the reaction mixture was cooled to room temperature, diluted with water and extracted three times with 100 ml each time of n-hexane. The aqueous fraction was admixed with dilute HCl (1N, 10.0 ml), forming a colorless solid which was filtered off and purified further by recrystallization from water and ethanol. The purified colorless solid (143 mg, 98%) having a melting point of 133-134° C. could be identified as the desired reaction product.
Reaction SMILES: [C:1]1([CH:7]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:8]2[CH2:13][CH2:12][NH:11][C:10]([CH3:25])([CH2:14][C:15]3[CH:20]=[CH:19][C:18]4[O:21][CH2:22][CH2:23][O:24][C:17]=4[CH:16]=3)[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:32](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[C:26]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]2[CH2:13][CH2:12][N:11]([CH3:32])[C:10]([CH3:25])([CH2:14][C:15]3[CH:20]=[CH:19][C:18]4[O:21][CH2:22][CH2:23][O:24][C:17]=4[CH:16]=3)[CH2:9]2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CC1(Cc2ccc3c(c2)OCCO3)CN(C(c2ccccc2)c2ccccc2)CCN1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: CN1CCN(C(c2ccccc2)c2ccccc2)CC1(C)Cc1ccc2c(c1)OCCO2
Yield: 83.2 %

Procedure:
15 g of 1-diphenylmethyl-3-methyl-3-(3,4-ethylenedioxybenzyl)-piperazine (3a) are dissolved in 200 ml of acetone, combined with 10 g of potassium carbonate, and heated to boiling with stirring. 5.6 g of methyl iodide in 50 ml of acetone are added dropwise in the course of two hours. After a further five hours at reflux with stirring, the mixture is filtered and the filtrate evaporated to dryness in vacuum. The residue is taken up in 200 ml of diethyl ether, washed free of halogen with water, dried over sodium sulfate, and the filtrate is evaporated to dryness is vacuum. 12.9 g (83%) of 1-diphenylmethyl-3-methyl-3-(3,4-ethylenedioxybenzyl)-4-methylpiperazine (4a) are obtained.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([CH2:10][C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[N:16]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH:15]=[CH:14]3)[CH2:6][CH2:5]1.N1C=CN=C1.[Si:32](Cl)([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33]>CN(C=O)C>[Si:32]([O:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([CH2:10][C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[N:16]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH:15]=[CH:14]3)[CH2:6][CH2:5]1)([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33]
Reactant: CC(C)(C)OC(=O)n1ccc2cc(CN3CCN(CCO)CC3)ccc21
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)n1ccc2cc(CN3CCN(CCO[Si](C)(C)C(C)(C)C)CC3)ccc21
Yield: 90 %

Procedure:
In a similar manner to Step 1 of Reference Example 18, 5-[4-(2-hydroxyethyl)-1-piperazinylmethyl]-1-(tert-butoxycarbonyl)indole (5.02 g, 14.0 mmol) was dissolved in DMF (50 mL), and the solution was treated with imidazole (1.43 g, 21.0 mmol) and tert-butyldimethylsilyl chloride (3.16 g, 21.0 mmol) to obtain 5-(4-[2-(tert-butyldimethylsilyloxy)ethyl]-1-piperazinylmethyl)-1-(tert-butoxycarbonyl)indole (5.97 g, yield 90%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][C:3]=1[N:9]1[CH:14]=[C:13]([O:15][CH3:16])[C:12](=[O:17])[C:11]([C:18]2[N:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:21]=[CH:20][CH:19]=2)=[N:10]1.[NH:29]1[CH2:33][CH2:32][CH2:31][C:30]1=[O:34].[O-]P([O-])([O-])=O.[K+].[K+].[K+].N[C@@H]1CCCC[C@H]1N>O1CCOCC1.C([O-])(O)=O.[Na+].[Cu]I>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:29]2[CH2:33][CH2:32][CH2:31][C:30]2=[O:34])=[CH:4][C:3]=1[N:9]1[CH:14]=[C:13]([O:15][CH3:16])[C:12](=[O:17])[C:11]([C:18]2[N:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:21]=[CH:20][CH:19]=2)=[N:10]1
Reactant: O=C1CCCN1
Reactant: COc1cn(-c2cc(I)ccc2F)nc(-c2ccnn2-c2ccccc2)c1=O
Agent: [Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=C([O-])O
Solvent: C1COCCO1
Product: COc1cn(-c2cc(N3CCCC3=O)ccc2F)nc(-c2ccnn2-c2ccccc2)c1=O
Yield: 56.6 %

Procedure:
A mixture of 1-(2-fluoro-5-iodophenyl)-5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one (244 mg, 0.5 mmol), pyrrolidin-2-one (0.0456 mL, 0.6 mmol), K3PO4 (212 mg, 1.0 mmol), trans-1,2-diaminocyclohexane (0.012 mL, 0.1 mmol) and CuI (9.5 mg, 0.05 mmol) in 1,4-dioxane (2 mL) was heated to reflux for 13 h under Ar. The mixture was diluted with saturated NaHCO3 aqueous solution, extracted with AcOEt, dried over Na2SO4, filtered, concentrated in vacuo, purified by column chromatography on basic silica gel (hexane/AcOEt=50/50 to 0/100) and recrystallized with AcOEt/hexane to yield the title compound (126 mg, 57% yield) as a white solid: mp 171-174° C. 1H NMR (DMSO-d6, 300 MHz): δ ppm 2.02-2.19 (2H, m), 2.47-2.58 (2H, m), 3.69-3.87 (5H, m), 6.92 (1H, d, J=1.9 Hz), 7.22-7.58 (7H, m), 7.74-7.89 (2H, m), 8.51 (1H, d, J=1.9 Hz). Anal. Calcd for C24H20FN5O3: C, 64.71; H, 4.53; N, 15.72. Found: C, 64.59; H, 4.45; N, 15.67.
Reaction SMILES: P(Br)(Br)[Br:2].[CH3:5][O:6][C:7]1[C:8]([CH2:12]O)=[CH:9][S:10][CH:11]=1>C(Cl)Cl>[Br:2][CH2:12][C:8]1[C:7]([O:6][CH3:5])=[CH:11][S:10][CH:9]=1
Reactant: COc1cscc1CO
Reactant: BrP(Br)Br
Solvent: ClCCl
Product: COc1cscc1CBr
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 96.6 %

Procedure:
To a solution of phosphorous tribromide (271 mg, 1.00 mmol) in CH2Cl2 (1.5 mL) cooled to 0° C. was added a solution of the above alcohol (144 mg, 1.00 mmol) in CH2Cl2 (1.5 mL) and the solution was stirred at 0° C. for 5 minutes to give 3-bromomethyl-4-methoxy-thiophene as an oil (200 mg, 97%) after work-up.
Reaction SMILES: [Cl-].[CH:2]1([CH2:6][NH2+:7][CH2:8][CH2:9]Cl)[CH2:5][CH2:4][CH2:3]1.[Cl:11][C:12]1[CH:13]=[C:14]([N:19]=[C:20]=[S:21])[CH:15]=[CH:16][C:17]=1[Cl:18]>>[Cl:11][C:12]1[CH:13]=[C:14]([N:19]=[C:20]2[N:7]([CH2:6][CH:2]3[CH2:3][CH2:4][CH2:5]3)[CH2:8][CH2:9][S:21]2)[CH:15]=[CH:16][C:17]=1[Cl:18]
Reactant: S=C=Nc1ccc(Cl)c(Cl)c1
Reactant: ClCC[NH2+]CC1CCC1
Agent: [Cl-]
Product: Clc1ccc(N=C2SCCN2CC2CCC2)cc1Cl

Procedure:
2-Hydroxyethylamine was reacted with cyclobutylmethyl bromide according to Method B2a to give N-cyclobutylmethyl-N-(2-hydroxyethyl)amine. The alcohol was reacted with SOCl2 according to Method B7c to give N-cyclobutylmethyl-N-(2-chloroethyl)ammonium chloride. The chloroethylamine was reacted with 3,4-dichlorophenyl isothiocyanate to give 2-(3,4-dichlorophenylimino)-3-(cyclobutylmethyl)-1,3-thiazolidine.
Reaction SMILES: [C:1]([CH:3]1[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)#[N:2].[NH2-].[Na+].[Cl:18][CH2:19][CH2:20][CH2:21]Cl>>[Cl:18][CH2:19][CH2:20][CH2:21][C:3]1([C:1]#[N:2])[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2
Reactant: ClCCCCl
Reactant: N#CC1c2ccccc2-c2ccccc21
Agent: [NH2-]
Agent: [Na+]
Product: N#CC1(CCCCl)c2ccccc2-c2ccccc21

Procedure:
9-Cyanofluorene was reacted with sodium amide and 1,3-dichloropropane to give 9-(3-chloropropyl)-9-cyanofluorene. A solution of 10.0 g. of 9-(3-chloropropyl)-9-cyanofluorene in 200 ml. of morpholine containing 2.0g. of potassium iodide was stirred at 160° C. for sixteen hours. After cooling the reaction mixture to room temperature, the solution was diluted with 500 ml. of water, and the aqueous mixture was extracted several times with ethylacetate. The organic extracts were combined, washed with water, and the product was extracted therefrom into 0.6 N hydrochloric acid. The aqueous acid layer was separated and made alkaline by the addition of 10 percent sodium hydroxide solution. The alkaline solution was extracted with fresh ethyl acetate, and the extracts were combined, washed with water and dried. Removal of the solvent by evaporation under reduced pressure provided 9-(3-morpholinopropyl)-9-cyanofluorene.
Reaction SMILES: C(OC1C2OC=2C=C([N+]([O-])=O)C=1C=C[N+]([O-])=O)C1C=CC=CC=1.[CH2:24]([O:31][C:32]1[C:42]([O:43][CH3:44])=[CH:41][CH:40]=[C:39]([N+:45]([O-])=O)[C:33]=1[CH:34]=[CH:35][N+]([O-])=O)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH2:24]([O:31][C:32]1[C:42]([O:43][CH3:44])=[CH:41][CH:40]=[C:39]2[C:33]=1[CH:34]=[CH:35][NH:45]2)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: COc1ccc([N+](=O)[O-])c(C=C[N+](=O)[O-])c1OCc1ccccc1
Agent: O=[N+]([O-])C=Cc1c([N+](=O)[O-])cc2c(c1OCc1ccccc1)O2
Product: COc1ccc2[nH]ccc2c1OCc1ccccc1
Yield: 86 %

Procedure:
This compound is obtained according to the operating method described in Example 1c, in which the 2-benzyloxy-3-epoxy-6,β-dinitrostyrene is replaced with 2-benzyloxy-3-methoxy-6,β-dinitrostyrene. A white powder (yield=86%, m.p.=83°-84° C.) is obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:24]=[CH:23][C:7]([C:8]([N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]3[CH:20]=[CH:21][CH:22]=[C:12]3[CH2:11]2)=[O:9])=[CH:6][CH:5]=1)([O-])=O.C(OCC)(=O)C>C(O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:8]([N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]3[CH:20]=[CH:21][CH:22]=[C:12]3[CH2:11]2)=[O:9])=[CH:23][CH:24]=1
Reactant: O=C(c1ccc([N+](=O)[O-])cc1)N1Cc2cccn2-c2ccccc21
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Nc1ccc(C(=O)N2Cc3cccn3-c3ccccc32)cc1
Reaction time: 5 h

Procedure:
A mixture of 1 mmol of 4,5-dihydro-5-(4-nitrobenzoyl)pyrrolo[1,2-a]quinoxaline in 10 ml of ethyl alcohol and 10 ml of ethyl acetate containing 0.2 g of 10% Pd/C is hydrogenated for 5 hours. The reaction mixture is filtered through a pad of diatomaceous earth. The filtrate is concentrated in vacuo to a solid which is purified by flash chromatography to give the desired product, m.p. 225°-228° C.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[C:6]([C:29]([F:32])([F:31])[F:30])=[C:7]2[C:12](=[CH:13][CH:14]=1)[C:11]([C:15]([NH:17][C:18](=[O:22])[O:19][CH2:20][CH3:21])=[O:16])=[C:10]([O:23][CH2:24][C:25]([F:28])([F:27])[F:26])[CH:9]=[CH:8]2.Br[CH2:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36]>O1CCCC1>[CH2:20]([O:19][C:18]([N:17]([C:15]([C:11]1[C:12]2[C:7](=[C:6]([C:29]([F:31])([F:30])[F:32])[C:5]([O:4][CH3:3])=[CH:14][CH:13]=2)[CH:8]=[CH:9][C:10]=1[O:23][CH2:24][C:25]([F:26])([F:27])[F:28])=[O:16])[CH2:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])=[O:22])[CH3:21]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CCOC(=O)NC(=O)c1c(OCC(F)(F)F)ccc2c(C(F)(F)F)c(OC)ccc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)N(CC(=O)OC(C)(C)C)C(=O)c1c(OCC(F)(F)F)ccc2c(C(F)(F)F)c(OC)ccc12
Temperature: 65 °C
Reaction time: 1 h
Yield: 79 %

Procedure:
Sodium hydride (80% by weight dispersion in mineral oil, 0.346 g, 1.1 eq) was added to a stirred solution of N-[[6-methoxy-2-(2,2,2-trifluoroethoxy)-5-(trifluoromethyl)-1-naphthalenyl]carbonyl]carbamic acid, ethyl ester (4.60 g, 10.5 mmol) in anhydrous tetrahydrofuran (125 mL) at room temperature under a dry nitrogen atmosphere. After 1 hour, the t-butyl bromoacetate (2.54 mL, 1.5 eq) was added. The reaction was heated to 65° C. for 1 hour, cooled to room temperature, and the THF was removed. The residue was dissolved in ether (200 mL), washed with water (2×50 mL) and saturated aqueous NaCl (1×50 mL). The ether phase was dried with magnesium sulfate and the ether was removed. The crude product was flash chromatographed (17:3 petroleum ether:ethyl acetate, silica) and triturated with petroleum ether to provide the title compound as a white powder (4.60 g, 79%), m.p. 84°-86° C.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([NH2:16])=[S:15])=[CH:9][CH:8]=2)[CH:6]=1.[C:17]1([C:23]([CH:25](Br)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=O)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[C:17]1([C:23]2[N:16]=[C:14]([NH:13][C:10]3[CH:9]=[CH:8][C:7]([N:5]4[CH:6]=[C:2]([CH3:1])[N:3]=[CH:4]4)=[CH:12][CH:11]=3)[S:15][C:25]=2[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(c1ccccc1)C(Br)c1ccccc1
Reactant: Cc1cn(-c2ccc(NC(N)=S)cc2)cn1
Product: Cc1cn(-c2ccc(Nc3nc(-c4ccccc4)c(-c4ccccc4)s3)cc2)cn1
Yield: 88.2 %

Procedure:
Prepared in analogy to example 64d) from 100 mg (0.43 mmol) [4-(4-methyl-imidazol-1-yl)-phenyl]-thiourea (example 72c)) and 130 mg (0.47 mmol) desyl bromide. 155 mg (88%) of the product was isolated as a colorless solid. MS ISP (m/e): 409.3 (100) (M+H)+. 1H NMR (DMSO-D6, 300 MHz): δ (ppm)=10.74 (s, 1H), 9.50 (s, 1H), 8.00-7.90 (m, 3H), 7.73 (d, 2H), 7.49 (d, 2H), 7.40-7.30 (m, 8H), 2.35 (s, 3H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([S:10][CH:11]2[CH2:16][CH2:15][N:14]([C:17]([NH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[O:18])[CH2:13][CH2:12]2)=[CH:6][CH:5]=1.C([Si]([O:43][C:44]1[CH:49]=[CH:48][C:47]([O:50][CH2:51][CH:52]2[CH2:54][O:53]2)=[CH:46][CH:45]=1)(C1C=CC=CC=1)C1C=CC=CC=1)(C)(C)C>>[CH2:20]([NH:19][C:17]([N:14]1[CH2:15][CH2:16][CH:11]([S:10][C:7]2[CH:6]=[CH:5][C:4]([CH2:3][CH2:2][NH:1][CH2:54][C@H:52]([OH:53])[CH2:51][O:50][C:47]3[CH:48]=[CH:49][C:44]([OH:43])=[CH:45][CH:46]=3)=[CH:9][CH:8]=2)[CH2:12][CH2:13]1)=[O:18])[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CC(C)(C)[Si](Oc1ccc(OCC2CO2)cc1)(c1ccccc1)c1ccccc1
Reactant: CCCCCCNC(=O)N1CCC(Sc2ccc(CCN)cc2)CC1
Product: CCCCCCNC(=O)N1CCC(Sc2ccc(CCNC[C@H](O)COc3ccc(O)cc3)cc2)CC1
Yield: 35.3 %

Procedure:
4-{[4-(2-Aminoethyl)phenyl]sulfanyl}-N-hexyl-1-piperidinecarboxamide (0.588 g, 1.617 mmol) was reacted with tert-butyl-(4-oxiranylmethoxy-phenoxy)-diphenylsilane (0.589 g, 1.455 mmol) according to Procedure G to give the title compound (eluant: 20/1 chloroform-methanol) (0.395 g, 0.514 mmol).
Reaction SMILES: F[C:2](F)(F)[C:3]([OH:5])=O.[CH:8]([O:11][C:12]1[N:17]=[CH:16][C:15]([O:18][C:19]2[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][CH:27]([NH:29][CH3:30])[CH3:28])=[CH:21][CH:20]=2)=[CH:14][CH:13]=1)([CH3:10])[CH3:9].C(OC(=O)C)(=O)C>>[CH:8]([O:11][C:12]1[N:17]=[CH:16][C:15]([O:18][C:19]2[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][CH:27]([N:29]([CH3:30])[C:3](=[O:5])[CH3:2])[CH3:28])=[CH:21][CH:20]=2)=[CH:14][CH:13]=1)([CH3:10])[CH3:9]
Reactant: CNC(C)CCc1ccc(Oc2ccc(OC(C)C)nc2)cc1
Reactant: O=C(O)C(F)(F)F
Solvent: CC(=O)OC(C)=O
Product: CC(=O)N(C)C(C)CCc1ccc(Oc2ccc(OC(C)C)nc2)cc1

Procedure:
{3-[4-(6-Isopropoxy-pyridin-3-yloxy)-phenyl]-1-methyl-propyl}-methyl-amine trifluoroacetate (27 mg, 0.086 mmol) was reacted with acetic anhydride in analogy to example 2a. M+H+: 357.2.
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][N:10]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:9]([C:20](N)=[O:21])[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-:23].[K+].Cl.O>C(O)CO>[C:1]1([N:7]2[CH2:12][CH2:11][N:10]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:9]([C:20]([OH:21])=[O:23])[CH2:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: [OH-]
Reactant: NC(=O)C1CN(c2ccccc2)CCN1Cc1ccccc1
Agent: Cl
Agent: [K+]
Solvent: OCCO
Solvent: O
Product: O=C(O)C1CN(c2ccccc2)CCN1Cc1ccccc1
Temperature: 150 °C

Procedure:
Suspend 4-phenyl-1-(phenylmethyl)-2-piperazinecarboxamide (14.5 g, 49 mmol) in ethylene glycol (400 mL) and add potassium hydroxide (27.5 g, 490 mmol). Heat this mixture to 150° C. for 18 h. After this time, remove the solvent in vacuo. Add 6M hydrochloric acid (81.5 mL, 0.49 mol) and water (300 mL) and filter the resultant solid to obtain the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:20][CH:19]=1)=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClS([N:36]=[C:37]=O)(=O)=O.ClS([NH-])(=O)=O.CCN(CC)CC>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:20][CH:19]=1)=[C:12]2[C:37]#[N:36])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C=NS(=O)(=O)Cl
Reactant: c1ccc(COc2ccc(-c3cc4cc(OCc5ccccc5)ccc4[nH]3)cc2)cc1
Agent: [NH-]S(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#Cc1c(-c2ccc(OCc3ccccc3)cc2)[nH]c2ccc(OCc3ccccc3)cc12
Temperature: 0 °C
Reaction time: 2 h

Procedure:
In a reaction flask 5-Benzyloxy-2-(4-benzyloxy-phenyl)-1H-indole No. 141 (5.90 g, 14.6 mmol) was mixed with CH2Cl2 (90 mL) was cooled down to 0° C. (the starting material did not completely dissolve in CH2Cl2). While stirring vigorously, a solution of chlorosulfonyl isocyanate (2.26 g, 16.0 mmol) in CH2Cl2 (25 mL) was added dropwise over a period of 45 min. The reaction was run at 0° C. for 2 hrs while detected by TLC for the formation of the insoluble N-chlorosulfonylamide intermediate. After this period, Et3N (1.47 g, 14.6 mL) in CH2Cl2 (25 mL) was added dropwise over 45 min at 0° C. The insoluble residue became soluble in the reaction solvent as the Et3N addition was approaching completion. The reaction was let go for the additional 1 hr at 0° C. and 2 hrs at rt. The progress of the reaction could be observed by the insoluble solid formation of the product as the reaction time went on. The solvent was stripped down and the solid residue purified by trituration with methanol to yield (4.0 g, 63.8%). Mp=238-242° C.; 1H NMR (DMSO) 12.31 (s, 1 H), 7.88 (d, 2 H, J=8.8 Hz), 7.48 (d, 4 H, J=7.25 Hz), 7.55-7.30 (m, 7 H), 7.23 (d, 2 H, J=8.8 Hz), 7.14 (d, 1 H, J=2.4 Hz), 6.97 (dd, 1 H, J=2.2 Hz, 8.8 Hz), 5.20 (s, 2 H), 5.17 (s, 2 H); MS eI m/z 430 (M+).
Reaction SMILES: [O:1]=[S:2]1(=[O:18])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:17]=[CH:16][C:10]([C:11]([O:13]CC)=O)=[CH:9][N:8]=1.[CH:19]1([C:22]2[C:23]([N:32]3[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]3)=[N:24][CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=2)[CH2:21][CH2:20]1>>[CH:19]1([C:22]2[C:23]([N:32]3[CH2:37][CH2:36][N:35]([C:11]([C:10]4[CH:9]=[N:8][C:7]([N:3]5[CH2:4][CH2:5][CH2:6][S:2]5(=[O:1])=[O:18])=[CH:17][CH:16]=4)=[O:13])[CH2:34][CH2:33]3)=[N:24][CH:25]=[C:26]([C:28]([F:31])([F:29])[F:30])[CH:27]=2)[CH2:20][CH2:21]1
Reactant: FC(F)(F)c1cnc(N2CCNCC2)c(C2CC2)c1
Reactant: CCOC(=O)c1ccc(N2CCCS2(=O)=O)nc1
Product: O=C(c1ccc(N2CCCS2(=O)=O)nc1)N1CCN(c2ncc(C(F)(F)F)cc2C2CC2)CC1
Yield: 68.2 %

Procedure:
Using ethyl 6-(1,1-dioxo-1λ6-isothiazolidin-2-yl)nicotinate (300 mg) described in Preparation Example 25 and 1-(3-cyclopropyl-5-trifluoromethylpyridin-2-yl)piperazine (331 mg) described in Preparation Example 90 and by the reaction and treatment in the same manner as in Example 109, the title compound (375 mg) was obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:10][OH:11])[CH:5]=[C:6]([F:9])[C:7]=1[F:8].Cl[C:13]1[CH:14]=[C:15]2[N:22]([CH3:23])[C@@H:21]([CH3:24])[CH2:20][N:16]2[C:17](=[O:19])[N:18]=1>>[CH3:23][N:22]1[C:15]2[N:16]([C:17](=[O:19])[N:18]=[C:13]([O:11][CH2:10][C:4]3[CH:3]=[C:2]([F:1])[C:7]([F:8])=[C:6]([F:9])[CH:5]=3)[CH:14]=2)[CH2:20][C@@H:21]1[CH3:24]
Reactant: OCc1cc(F)c(F)c(F)c1
Reactant: C[C@H]1Cn2c(cc(Cl)nc2=O)N1C
Product: C[C@H]1Cn2c(cc(OCc3cc(F)c(F)c(F)c3)nc2=O)N1C

Procedure:
The title compound was prepared by a procedure similar to that described for E9 starting from (3,4,5-trifluorophenyl)methanol and (S)-7-chloro-1,2-dimethyl-2,3-dihydroimidazo-[1,2-c]pyrimidin-5(1H)-one.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH:10]([CH3:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:16]([N-]C(C)C)(C)C.[Li+].IC>C1COCC1>[CH2:1]([N:8]1[CH2:13][CH:12]([CH3:16])[C:11](=[O:14])[CH:10]([CH3:15])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)[N-]C(C)C
Reactant: CC1CN(Cc2ccccc2)CCC1=O
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: CC1CN(Cc2ccccc2)CC(C)C1=O
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To 1-benzyl-3-methyl-4-piperidone (2.0 g, 9.8 mmol) in THF at about −78° C. under argon, was added Lithium diisopropylamide (7.35 mL, 14.7 mmol, 2 M in heptane/THF/ethylbenzene). After stirring for about 1 hour at about −78° C., iodomethane (0.73 mL, 11.8 mmol) was added. The reaction mixture was stirred for about 1 hour at about −78° C., then warmed to room temperature. Stirring was continued overnight at room temperature. The reaction was quenched with saturated ammonium chloride solution, and extracted with ethyl acetate. The organic layer was washed with water, then brine and dried over magnesium sulfate. The crude product was chromatographed on silica gel, eluting with EtOAc/hexane (3:10) to give a yellow oil of the title compound.
Reaction SMILES: [CH2:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1)[CH3:2].[C:12]1([O:18][CH3:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl>[CH2:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([C:15]2[CH:16]=[CH:17][C:12]([O:18][CH3:19])=[CH:13][CH:14]=2)=[O:8])=[CH:5][CH:4]=1)[CH3:2]
Reactant: COc1ccccc1
Reactant: CCc1ccc(C(=O)Cl)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCc1ccc(C(=O)c2ccc(OC)cc2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a solution of 4-ethylbenzoyl chloride (8.6 g, 51.0 mmol) in anhydrous DCM (200 mL) at −5 to 0° C., was added anisole (5.46 g, 50.5 mmol), followed by addition of aluminum chloride (7.0 g, 52.5 mmol) over 5 minutes. The resulting yellow reaction mixture was stirred at 0° C. for 1 h and then at rt for 2 h. The reaction mixture was poured into ice water (300 mL), extracted with DCM (300 mL×2). Combined DCM solution was washed with 1M aqueous HCl (300 mL×1), 2 N aqueous NaOH (200 ml×1), brine (400 mL×2), dried over MgSO4 and evaporated to give the product, 12.2 g, yield 100%. 1H NMR (300 MHz, CDCl3) δ 7.80 (d, J=8.7 Hz, 2H), 7.68 (d, J=8.1 Hz, 2H), 7.27 (d, J=8.1 Hz, 2H), 6.93 (d, J=8.7 Hz, 2H), 3.87 (s, 3H), 2.71 (q, J=7.5 Hz, 2H), 1.28 (t, J=7.5 Hz, 3H). ESI-MS m/z 240.9 (M+H)+.
Reaction SMILES: [CH2:1]([N:3]([CH2:6][CH3:7])[CH2:4][CH3:5])C.COS(OC)(=O)=O.[O:15]=[C:16]1[C:25]2[NH:26][CH:27]=[CH:28][C:24]=2[C:23]2[CH:22]=[C:21]([S:29](=[O:38])(=[O:37])[NH:30][CH:31]3CCNCC3)[CH:20]=[CH:19][C:18]=2[NH:17]1.[CH:39]1([C:44]([O-:46])=[O:45])[CH2:43][CH2:42][CH2:41][CH2:40]1.N>CN(C)C=O.O>[CH3:1][N:3]1[CH2:6][CH2:7][CH:31]([NH:30][S:29]([C:21]2[CH:20]=[CH:19][C:18]3[NH:17][C:16](=[O:15])[C:25]4[NH:26][CH:27]=[CH:28][C:24]=4[C:23]=3[CH:22]=2)(=[O:37])=[O:38])[CH2:5][CH2:4]1.[CH:39]1([C:44]([O-:46])=[O:45])[CH2:43][CH2:42][CH2:41][CH2:40]1
Reactant: O=c1[nH]c2ccc(S(=O)(=O)NC3CCNCC3)cc2c2cc[nH]c12
Reactant: CCN(CC)CC
Agent: N
Agent: O=C([O-])C1CCCC1
Solvent: O
Solvent: COS(=O)(=O)OC
Solvent: CN(C)C=O
Product: CN1CCC(NS(=O)(=O)c2ccc3[nH]c(=O)c4[nH]ccc4c3c2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 38.7 %

Procedure:
83 μL (0.6 mmol) of triethylamine and 22 μL (0.24 mmol) of dimethylsulfate are added to a solution of 55 mg (0.12 mmol) of 4-oxo-8-(piperidin-4-ylsulfamoyl)-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-cyclopentyl carboxylate dissolved in 5 mL of anhydrous dimethylformamide. The solution is stirred at room temperature for 3 hours before adding 2 mL of ammonia. After stirring for a further 10 minutes, water is added and the product is extracted with ethyl acetate. The organic phases are dried over magnesium sulfate, filtered and evaporated. The residue is purified by chromatography on silica (eluent chloroform/methanol/ammonia 300/24/4) to give 22 mg (39%) of 8-(1-methyl-piperidin-4-ylsulfamoyl)-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-cyclopentyl carboxylate in the form of a white solid.