Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:6]2[C:15]3[C@@H:14]([OH:16])[CH2:13][C:12]([CH3:18])([CH3:17])[CH2:11][C:10]=3[N:9]=[C:8]([CH:19]([CH3:21])[CH3:20])[C:7]=2[C:22]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)=[O:23])[CH2:5][CH2:4][CH2:3][CH2:2]1.N1C(C)=CC=CC=1C.FC(F)(F)S(O[Si:48]([C:51]([CH3:54])([CH3:53])[CH3:52])([CH3:50])[CH3:49])(=O)=O.[Cl-].[NH4+]>C1(C)C=CC=CC=1>[Si:48]([O:16][C@H:14]1[CH2:13][C:12]([CH3:17])([CH3:18])[CH2:11][C:10]2[N:9]=[C:8]([CH:19]([CH3:21])[CH3:20])[C:7]([C:22]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:31])[F:32])=[CH:26][CH:25]=3)=[O:23])=[C:6]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)[C:15]1=2)([C:51]([CH3:54])([CH3:53])[CH3:52])([CH3:50])[CH3:49]
Reactant: CC(C)c1nc2c(c(C3CCCC3)c1C(=O)c1ccc(C(F)(F)F)cc1)[C@@H](O)CC(C)(C)C2
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: Cc1cccc(C)n1
Product: CC(C)c1nc2c(c(C3CCCC3)c1C(=O)c1ccc(C(F)(F)F)cc1)[C@@H](O[Si](C)(C)C(C)(C)C)CC(C)(C)C2
Temperature: -18 °C
Reaction time: 0.33 h

Procedure:
Under argon, 3.65 g (7.95 mmol) of the compound from Example 3A are initially charged in 80 ml of dry toluene. At room temperature, 3.41 g (31.8 mmol, 4 eq.) of 2,6-lutidine are then added, and the mixture is cooled to −18° C. 3.65 ml (15.9 mmol, 2 eq.) of tert-butyldimethylsilyl trifluoromethanesulphonate are added dropwise to this solution. After 20 min, the reaction mixture is warmed to 0° C. and stirred at this temperature for a further 55 min. For work-up, saturated ammonium chloride solution (100 ml) is added and the mixture is, after warming to room temperature, extracted with ethyl acetate. The aqueous phase is extracted two more times with ethyl acetate and the combined organic phases are washed with saturated sodium chloride solution, dried over sodium sulphate, filtered and concentrated under reduced pressure. The residue is purified by chromatography (silica gel, mobile phase: isohexane/ethyl acetate 9:1).
Reaction SMILES: [CH:1]1([C@H:7]([OH:9])[CH3:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:10](OC(=O)C)(=[O:12])[CH3:11]>C1(C)C=CC(S(O)(=O)=O)=CC=1>[C:10]([O:9][C@@H:7]([CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[CH3:8])(=[O:12])[CH3:11]
Reactant: C[C@@H](O)C1CCCCC1
Reactant: CC(=O)OC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CC(=O)O[C@H](C)C1CCCCC1
Temperature: 35 °C
Yield: 99.9 %

Procedure:
A 2 L reaction flask was charged with (R)-1-cyclohexylethanol (980 g, synthesized as above), acetic anhydride (1 Kg), and p-toluene sulphonic acid (0.4 g), and heated at 30-40° C. for 6 hours. The reaction mixture was then transferred into a separatory funnel and washed twice in 200 mL water followed by once in 200 mL 10% sodium hydroxide (NaOH). The resulted organic layer was distilled at 5-10 mmHg to provide (R)-1-cyclohexylethyl acetate (1.3 Kg) (optical rotation: [α]D+2.59°; optical purity: 80.5% ee).
Reaction SMILES: [CH:1]1([N:4]2[C:12]([CH3:13])=[C:11]3[C:6]([CH:7]=[CH:8][C:9]([N:14]4[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:15]4=[O:21])=[CH:10]3)=[N:5]2)[CH2:3][CH2:2]1.Cl[CH2:23][C:24]1[S:25][CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[CH:1]1([N:4]2[C:12]([CH3:13])=[C:11]3[C:6]([CH:7]=[CH:8][C:9]([N:14]4[CH:19]=[CH:18][C:17]([O:20][CH2:23][C:24]5[S:25][CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=5)=[CH:16][C:15]4=[O:21])=[CH:10]3)=[N:5]2)[CH2:2][CH2:3]1
Reactant: FC(F)(F)c1csc(CCl)c1
Reactant: Cc1c2cc(-n3ccc(O)cc3=O)ccc2nn1C1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1c2cc(-n3ccc(OCc4cc(C(F)(F)F)cs4)cc3=O)ccc2nn1C1CC1
Reaction time: 8 h
Yield: 48 %

Procedure:
To a mixture of 1-(2-cyclopropyl-3-methyl-2H-indazol-5-yl)-4-hydroxypyridin-2(1H)-one (200 mg) and 2-(chloromethyl)-4-(trifluoromethyl)thiophene (171 mg) in DMF (4 ml) was added potassium carbonate (118 mg) at room temperature, and the mixture was stirred at the same temperature overnight. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was fractionated by HPLC (C18, mobile phase: water/acetonitrile (containing 0.1% NH4HCO3)), and saturated aqueous sodium hydrogen carbonate solution was added to the obtained fraction. The mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was crystallized from methanol-water to give the title compound (152 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7](B2OC(C)(C)C(C)(C)O2)=[CH:6][C:5]=1[C:19]([F:22])([F:21])[F:20])[CH3:2].C([O-])([O-])=O.[Na+].[Na+].[Cl:29][C:30]1[N:31]=[C:32](Cl)[C:33]2[CH:38]=[CH:37][N:36]([CH3:39])[C:34]=2[N:35]=1.O1CCOCC1>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>[Cl:29][C:30]1[N:31]=[C:32]([C:7]2[CH:8]=[CH:9][C:4]([O:3][CH2:1][CH3:2])=[C:5]([C:19]([F:20])([F:21])[F:22])[CH:6]=2)[C:33]2[CH:38]=[CH:37][N:36]([CH3:39])[C:34]=2[N:35]=1
Reactant: Cn1ccc2c(Cl)nc(Cl)nc21
Reactant: CCOc1ccc(B2OC(C)(C)C(C)(C)O2)cc1C(F)(F)F
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: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CCOc1ccc(-c2nc(Cl)nc3c2ccn3C)cc1C(F)(F)F
Temperature: 100 °C
Reaction time: 6 h
Yield: 73.8 %

Procedure:
2-[4-ethoxy-3-(trifluoromethyl)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (188 mg), Na2CO3 (217 mg), and tetrakis(triphenylphosphine)palladium (0) (29 mg) were added to a mixture of 2,4-dichloro-7-methyl-7H-pyrrolo[2,3-d]pyrimidine (100 mg), dioxane (2 mL), and water (0.3 mL) in an argon atmosphere, and the reaction mixture was stirred at 100° C. for 6 hours. After the reaction mixture was cooled to room temperature, extraction thereof was performed using EtOAc, and the extract was washed with water and saturated brine. The organic layer was dried over MgSO4 and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Hex:EtOAc=9:1 to 7:3), whereby 2-chloro-4-[4-ethoxy-3-(trifluoromethyl)phenyl]-7-methyl-7H-pyrrolo[2,3-d]pyrimidine (130 mg) was obtained as a light yellow solid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:11])[CH3:10])=[CH:5][CH:4]=1)#[N:2].[Br:12]Br.C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl.Br>[Br:12][CH2:10][C:9]([C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1)=[O:11]
Reactant: BrBr
Reactant: CC(=O)c1ccc(C#N)cc1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: N#Cc1ccc(C(=O)CBr)cc1

Procedure:
To a mixture of para-cyanoacetophenone (52 g, 0.36 mol) in chloroform (520 ml) and 48% HBr (5.2 ml), a solution of bromine (19.3 ml) in chloroform (52 ml) was added dropwise over a period of 20 min. The mixture was stirred for 3 h at room temperature and neutralized to pH7 with sat. NaHCO3. The organic layer was washed with sat. NaCl and dried over anhydrous Na2SO4 and concentrated. The residue was chromatographed on silica gel (AcOEt/n-hexane=1/3 as an eluent) and recrystallized to obtain 2-bromo-4′-cyanoacetophenone as a colourless plate (23.4 g, 29%).
Reaction SMILES: Cl.[F:2][C:3]([F:17])([F:16])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH2:11][CH2:12][NH:13][CH2:14][CH:15]=2)=[CH:6][CH:5]=1.N1C=CC=CC=1.[Cl:24][C:25](Cl)([O:27]C(=O)OC(Cl)(Cl)Cl)Cl>>[F:17][C:3]([F:2])([F:16])[C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH2:15][CH2:14][N:13]([C:25]([Cl:24])=[O:27])[CH2:12][CH:11]=2)=[CH:8][CH:9]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: FC(F)(F)c1ccc(C2=CCNCC2)cc1
Agent: Cl
Solvent: c1ccncc1
Product: O=C(Cl)N1CC=C(c2ccc(C(F)(F)F)cc2)CC1
Yield: 199.9 %

Procedure:
Using 4-(4-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine hydrochloride (300 mg, 1.14 mmol) prepared in Reference Example 97, pyridine (0.18 ml, 2.28 mmol) and triphosgene (112 mg, 0.38 mmol), 4-(4-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine-1-carbonylchloride (220 mg, yield 67%) as a yellow oil was prepared in the same manner as described in Reference Example 94.
Reaction SMILES: [H-].[Na+].Br[CH2:4][C:5]([O:7][CH3:8])=[O:6].[Cl:9][C:10]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:11]=1[C:18]1[N:19]=[C:20]([N:24]([C:28]2[CH:29]=[C:30]3[C:34](=[CH:35][CH:36]=2)[NH:33][CH:32]=[CH:31]3)[CH2:25][CH2:26][CH3:27])[S:21][C:22]=1[CH3:23]>CN(C)C=O>[Cl:9][C:10]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:11]=1[C:18]1[N:19]=[C:20]([N:24]([C:28]2[CH:29]=[C:30]3[C:34](=[CH:35][CH:36]=2)[N:33]([CH2:4][C:5]([O:7][CH3:8])=[O:6])[CH:32]=[CH:31]3)[CH2:25][CH2:26][CH3:27])[S:21][C:22]=1[CH3:23]
Reactant: COC(=O)CBr
Reactant: CCCN(c1ccc2[nH]ccc2c1)c1nc(-c2ccc(OC)cc2Cl)c(C)s1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCN(c1ccc2c(ccn2CC(=O)OC)c1)c1nc(-c2ccc(OC)cc2Cl)c(C)s1
Temperature: 25 °C

Procedure:
0.093 g of 55% sodium hydride in oil and then 0.95 ml of methyl bromoacetate are added, at 0° C., to 0.8 g of 4-(2-chloro-4-methoxyphenyl)-5-methyl-2-[N-(indol-5-yl)-N-propylamino]thiazole obtained above (EXAMPLE 7) in solution in 20 ml of dimethylformamide. After stirring for twelve hours at room temperature, the reaction mixture is poured into ice-water. The mixture is extracted with ethyl acetate and the organic phase is washed a number of times with water, dried over sodium sulphate and evaporated to dryness. The residue is purified by chromatography on a column of silica gel eluted with a 9/1 (v/v) cyclohexane/ethyl acetate mixture. The expected product is isolated in the form of a white solid (Y=95%); M.p.=80° C. 1H NMR (DMSO): 0.84 (t, 3H), 1.51-1.62 (m, 2H), 1.94 (s, 3H), 3.68 (s, 3H), 3.79 (s, 3H), 3.75-3.82 (m, 2H), 5.17 (s, 2H), 6.50 (d, 1H), 6.91-7.58 (m, 7H).
Reaction SMILES: Br[C:2]1[C:12]2[CH2:11][CH2:10][N:9]([CH3:13])[CH2:8][CH2:7][C:6]=2[CH:5]=[C:4]([O:14][CH3:15])[CH:3]=1.C([Li])CCC.[CH3:21][S:22]SC.Cl>C1(C)C=CC=CC=1.O>[CH3:15][O:14][C:4]1[CH:3]=[C:2]([S:22][CH3:21])[C:12]2[CH2:11][CH2:10][N:9]([CH3:13])[CH2:8][CH2:7][C:6]=2[CH:5]=1
Reactant: COc1cc(Br)c2c(c1)CCN(C)CC2
Reactant: CSSC
Agent: Cl
Agent: [Li]CCCC
Solvent: O
Solvent: Cc1ccccc1
Product: COc1cc2c(c(SC)c1)CCN(C)CC2

Procedure:
A solution of 6-bromo-8-methoxy-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (2.7 g, 0.01 m) in toluene (30 ml) is added to a solution of n-butyl lithium (0.044 m) in toluene (15 ml) stirred at -78°. The mixture is stirred for thirty minutes, treated with a solution of methyl disulfide (8.2 g, 0.087 m) in toluene (10 ml), stirred for fifteen minutes and poured into water (125 ml). The mixture is acidified with 10% hydrochloric acid and the aqueous phase is washed with ether, made alkaline with aqueous sodium hydroxide and extracted with ethyl acetate. The ethyl acetate extract is washed, dried with sodium sulfate and concentrated in vacuo to give 8-methoxy-3-methyl-6-methylthio-2,3,4,5-tetrahydro-1H-3-benzazepine.
Reaction SMILES: Cl[C:2]1[C:10]([S:11](=[O:14])(=[O:13])[NH2:12])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16].[NH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[CH:20]=1>O>[N+:15]([C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([S:11](=[O:14])(=[O:13])[NH2:12])[C:2]=1[NH:18][C:19]1[CH:20]=[C:21]([CH3:25])[CH:22]=[CH:23][CH:24]=1)[C:6]([OH:8])=[O:7])([O-:17])=[O:16]
Reactant: NS(=O)(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1Cl
Reactant: Cc1cccc(N)c1
Solvent: O
Product: Cc1cccc(Nc2c([N+](=O)[O-])cc(C(=O)O)cc2S(N)(=O)=O)c1

Procedure:
A mixture of 4-chloro-3-nitro-5-sulphamyl-benzoic acid (28 g), m-toluidine (32.2 g), and water (500 ml) was refluxed for 3 hours. After cooling and acidification with 2N hydrochloric acid, the precipitated 3-nitro-5-sulphamyl-4-(m-toluidino)-benzoic acid was collected by suction, washed with water, and recrystallized from isopropanol. After drying at 115°C in vacuo, the melting point was 256°-259°C.
Reaction SMILES: [CH:1]1([C:5]2[N:9]3[CH:10]=[CH:11][N:12]=[C:13]([NH2:14])[C:8]3=[C:7](I)[N:6]=2)[CH2:4][CH2:3][CH2:2]1.[C:16]([C:18]1[CH:19]=[C:20](B(O)O)[CH:21]=[CH:22][C:23]=1[F:24])#[N:17]>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.COCCOC.O>[NH2:14][C:13]1[C:8]2[N:9]([C:5]([CH:1]3[CH2:4][CH2:3][CH2:2]3)=[N:6][C:7]=2[C:20]2[CH:21]=[CH:22][C:23]([F:24])=[C:18]([CH:19]=2)[C:16]#[N:17])[CH:10]=[CH:11][N:12]=1
Reactant: Nc1nccn2c(C3CCC3)nc(I)c12
Reactant: N#Cc1cc(B(O)O)ccc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: COCCOC
Product: N#Cc1cc(-c2nc(C3CCC3)n3ccnc(N)c23)ccc1F

Procedure:
Into a 10 mL microwave vessel were added 3-cyclobutyl-1-iodoimidazo[1,5-a]pyrazin-8-amine (100 mg, 0.0003 mol), 3-cyano-4-fluorophenylboronic acid (0.068 g, 0.00041 mol) potassium carbonate (88 mg, 0.00063 mol), Pd(PPh3)4 (40 my, 0.00003 mol), DME/Water (5:1) (5:1, DME:H2O, 1 mL) and the vessel was degassed 3× with N2. The reaction was microwaved on 300 watts, 100° C. for 45 min. The reaction vessel was resubjected to the microwave heating under the same conditions as before for 45 min. Purification by prep TLC using 4% MeOH in DCM eluting twice afforded 54 mg of the title compound as a yellow solid. MS (ES+): m/z 308.11 (100)[MH+]. HPLC: tR=2.14 min (Open Lynx polar—5 min).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@@H:8]([NH2:10])[CH3:9].C([O:15][C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24]1[CH:29]=[CH:28][C:27]([CH2:30][N:31]2[C:39]3[C:34](=[CH:35][C:36]([C:40](O)=[O:41])=[CH:37][CH:38]=3)[C:33]([CH3:43])=[C:32]2[CH3:44])=[CH:26][CH:25]=1)=[O:17])(C)(C)C>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@@H:8]([NH:10][C:40]([C:36]1[CH:35]=[C:34]2[C:39](=[CH:38][CH:37]=1)[N:31]([CH2:30][C:27]1[CH:26]=[CH:25][C:24]([C:19]3[C:18]([C:16]([OH:17])=[O:15])=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:29][CH:28]=1)[C:32]([CH3:44])=[C:33]2[CH3:43])=[O:41])[CH3:9]
Reactant: C[C@H](N)c1ccccc1Cl
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Product: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)O)cc2)c2ccc(C(=O)N[C@@H](C)c3ccccc3Cl)cc12

Procedure:
The title compound was prepared following the same general protocol as described in Step 8-9, Example 1, using the (S)-1-(2-chlorophenyl)ethanamine and the 1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid. ESI-MS (m/z): 537/538/539 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:19]([O-:21])=[O:20].[CH3:22][N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.C([O-])([O-])=O.[K+].[K+]>CC#N>[Cl:18][C:14]1[CH:13]=[C:12]([NH:11][S:8]([C:5]2[CH:6]=[CH:7][C:2]([N:26]3[CH2:27][CH2:28][N:23]([CH3:22])[CH2:24][CH2:25]3)=[C:3]([N+:19]([O-:21])=[O:20])[CH:4]=2)(=[O:10])=[O:9])[CH:17]=[CH:16][CH:15]=1
Reactant: CN1CCNCC1
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)Nc2cccc(Cl)c2)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CN1CCN(c2ccc(S(=O)(=O)Nc3cccc(Cl)c3)cc2[N+](=O)[O-])CC1
Yield: 78.6 %

Procedure:
A mixture of 4-chloro-3-nitrobenzenesulfonylchloride (1g, 3.9 mmol), 3-chloroaniline (0.5 mL, 4.7 mmol) and pyridine (1.6 mL) in CH2Cl2 (2 mL) was stirred at room temperature. The reaction was quenched with NaHCO3 (sat aq solution, 30 mL×3). The organic phase was separated, dried (MgSO4), and filtered. The volatiles were evaporated and the residue was purified by column chromatography (SiO2, pentane:EtOAc, 4:1) to give 4-chloro-N-(3-chlorophenyl)-3-nitrobenzenesulfonamide; MS (posESI) m/z=349.2 (M+H+). 1H NMR (CDCl3) δ 7.00-7.40 (m, 3H), 7.60-7.90 (m, 3H), 8.70 (bs, 1H). 4-Chloro-N-(3-chlorophenyl)-3-nitrobenzenesulfonamide (0.45 g, 1.3 mmol), N-methylpiperazine (0.191 mL, 1.73 mmol) and K2CO3 (359 mg, 2.6 mmol) in CH3CN (2.5 mL) as the filtrated was concentrated to give a residue which was purified by column (SiO2, CHCl3:MeOH: NH3 9:1:0.4%) to give 420 mg of N-(3-chlorophenyl)-4-(4-methyl-1-piperazinyl)-3-nitrobenzenesulfonamide (85%). Purity>95% according to HPLC analysis. The compound was dissolved in THF (1 mL) and ethanol (5 mL) was added. The solution was treated with Raney-Ni (50 mg) and hydrazine monohydrate (0.05 mL) overnight. The Raney-Ni was filtered (celite pad), the volatiles were evaporated and the residue was purified by column chromatography (SiO2, CHCl3:MeOH: NH3 9:1:0.4%). The product was isolated as hydrochloride salt by treatment with HCl gas in diethyl ether to yield 170 mg of final product (32%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[OH:12].[CH:13]1(Br)[CH2:17][CH2:16][CH2:15][CH2:14]1.C(=O)([O-])[O-].[Cs+].[Cs+].C([O-])([O-])=O.[Na+].[Na+]>CN(C)C=O>[CH:13]1([O:12][C:4]2[CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: BrC1CCCC1
Reactant: COc1ccc([N+](=O)[O-])cc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc([N+](=O)[O-])cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.9 %

Procedure:
2-Methyloxy-5-nitrophenol (14.27 g, 84.4 mmol) was dissolved in dry dimethylformamide (80 ml). Cyclopentylbromide (176 g, 127 ml, 118.2 mmol) and cesium carbonate (38.5 g, 118.2 mmol) were added and the suspension stirred overnight at room temperature. The mixture was poured into saturated Na2CO3 (200 ml) and extracted with ethyl acetate (700 ml). The organic layer was washed with saturated Na2CO3 until no yellow colour was detected. The organic layer was then dried (MgSO4) and concentrated in vacuo to give the title compound as a yellow solid (15.0 g).
Reaction SMILES: [Na].C(O)C.[NH2:5][C:6]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[N:12]=2)[N:7]=1.[Cl:18][C:19]1[CH:28]=[CH:27][C:22](C=CC#N)=[CH:21][CH:20]=1>ClCCl>[NH2:5][C:6]1[CH2:10][CH:9]([C:22]2[CH:27]=[CH:28][C:19]([Cl:18])=[CH:20][CH:21]=2)[N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[N:12]=2)[N:7]=1
Reactant: N#CC=Cc1ccc(Cl)cc1
Reactant: NC1=NN(c2cccc(Cl)n2)CC1
Agent: [Na]
Solvent: ClCCl
Solvent: CCO
Product: NC1=NN(c2cccc(Cl)n2)C(c2ccc(Cl)cc2)C1

Procedure:
An 0.3 g. amount of sodium metal is dissolved in 100 ml. of absolute ethanol, then 7.2 g. of 2-chloro-6-hydrazinopyridine (Example 2) is added, followed by 8.2 g. of 4-chlorocinnamonitrile. The reaction mixture is refluxed for 18 hours, then is evaporated in vacuo to a gum. Water is added to give a solid. The solid is collected and dissolved in dichloromethane, dried over magnesium sulfate and filtered. The filtrate is concentrated while adding hexane to separate yellow crystals on cooling. The product is collected and washed with ether-hexane to give 10.3 g. of tan solid. The solid is dissolved in dichloromethane, filtered through absorbent magnesium silicate, then is concentrated while adding hexane to give the product of the Example as white crystals, m.p. 157°-158°.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=[O:18])[N:8]([CH2:11][CH2:12][N:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)[CH2:9][CH2:10][C:5]=2[NH:4][C:3]=1[CH:19]=O.[F:21][C:22]1[C:27]([F:28])=[CH:26][CH:25]=[CH:24][C:23]=1[C:29]1[CH:37]=[CH:36][CH:35]=[C:34]2[C:30]=1[CH2:31][C:32](=[O:38])[NH:33]2>>[F:21][C:22]1[C:27]([F:28])=[CH:26][CH:25]=[CH:24][C:23]=1[C:29]1[CH:37]=[CH:36][CH:35]=[C:34]2[C:30]=1[C:31](=[CH:19][C:3]1[NH:4][C:5]3[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][N:13]4[CH2:14][CH2:15][CH2:16][CH2:17]4)[C:7](=[O:18])[C:6]=3[C:2]=1[CH3:1])[C:32](=[O:38])[NH:33]2
Reactant: O=C1Cc2c(cccc2-c2cccc(F)c2F)N1
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCCC1)CC2
Product: Cc1c(C=C2C(=O)Nc3cccc(-c4cccc(F)c4F)c32)[nH]c2c1C(=O)N(CCN1CCCC1)CC2
Yield: 33.3 %

Procedure:
The title compound was prepared under the same conditions as described in Example 13 with 3-methyl-4-oxo-5-(2-pyrrolidin-1-yl-ethyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde and 4-(2,3-difluoro-phenyl)-1,3-dihydro-indol-2-one (prepared according to WO2002055517) as starting materials to give 2-[4-(2,3-difluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-3-methyl-5-(2-pyrrolidin-1-yl-ethyl)-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one (30 mg, 33.3%) as a yellow solid.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[N:7]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[OH:19])[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1>ClCCl>[OH:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[N:7]1[CH2:12][CH2:11][N:10]([C:2]([O:4][CH2:5][CH3:6])=[O:3])[CH2:9][CH2:8]1
Reactant: CCOC(=O)Cl
Reactant: Oc1ccccc1N1CCNCC1
Solvent: ClCCl
Product: CCOC(=O)N1CCN(c2ccccc2O)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
15 ml (156 mmol) of ethyl chloroformate are added to a solution of 18 g (100 mmol) of 2-(1-piperazinyl)phenol in 250 ml of dichloromethane. After stirring at ambient temperature for one hour, the mixture is hydrolysed and then extracted with dichloromethane. The organic phase is washed with a 1N hydrochloric acid solution and dried. Following concentration, the residue obtained is recrystallised from ether to yield the expected product.
Reaction SMILES: C[Al](C)C.[Cl-].[NH4+:6].[Cl:7][C:8]1[CH:9]=[CH:10][C:11]2[N:17]([CH2:18][CH2:19][CH2:20][CH2:21][I:22])[C:16](=[O:23])[C@@H:15]([CH2:24][C:25](OCC)=O)[O:14][C@H:13]([C:30]3[C:39]4[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=4)[CH:33]=[CH:32][CH:31]=3)[C:12]=2[CH:40]=1.Cl>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]2[N:17]([CH2:18][CH2:19][CH2:20][CH2:21][I:22])[C:16](=[O:23])[C@@H:15]([CH2:24][C:25]#[N:6])[O:14][C@H:13]([C:30]3[C:39]4[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=4)[CH:33]=[CH:32][CH:31]=3)[C:12]=2[CH:40]=1
Reactant: [NH4+]
Reactant: CCOC(=O)C[C@H]1O[C@H](c2cccc3ccccc23)c2cc(Cl)ccc2N(CCCCI)C1=O
Agent: C[Al](C)C
Agent: Cl
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: N#CC[C@H]1O[C@H](c2cccc3ccccc23)c2cc(Cl)ccc2N(CCCCI)C1=O
Temperature: 85 °C
Reaction time: 1 h
Yield: 33.7 %

Procedure:
Trimethylaluminium (2M in toluene, 15.0 ml, 30.1 mmol) was added dropwise to a suspension of ammonium chloride (1.6 g, 30.1 mmol) in toluene (25 ml) at ice bath temperature under a nitrogen atmosphere. The resulting solution was stirred for 1 hour. Ethyl trans-7-chloro-5-(1-naphthyl)-1-(4-iodobutyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetate (5.1 g, 8.6 mmol) was added as a solid and the solution heated at 85° C. for 18 hours. The solution was cooled and acidified with 2 N hydrochloric acid cautiously. Ethyl acetate (100 ml) was added and the layers were separated. The organic layer was washed with 2 N hydrochloric acid. The combined acidic layers were re-extracted once with ethyl acetate. The combined organic layers were washed with 1N sodium hydroxide solution (2×), dried (MgSO4), concentrated under reduced pressure. The residue was purified by flash column chromatography (ethyl acetate/hexane 1:4→2:3) to give a solid which was recrystallized from ethyl acetate/hexane to afford the title compound (1.58 g, 34%) as a pink solid.
Reaction SMILES: [H-].[Na+].[CH:3]1([OH:9])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.Cl[C:11]1[CH:20]=[N:19][C:18]2[C:13](=[CH:14][C:15]([O:23][CH3:24])=[C:16]([O:21][CH3:22])[CH:17]=2)[N:12]=1>CN(C=O)C>[CH:3]1([O:9][C:11]2[CH:20]=[N:19][C:18]3[C:13](=[CH:14][C:15]([O:23][CH:24]4[CH2:7][CH2:8][CH2:3][CH2:4][CH2:5]4)=[C:16]([O:21][CH3:22])[CH:17]=3)[N:12]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: OC1CCCCC1
Reactant: COc1cc2ncc(Cl)nc2cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc2ncc(OC3CCCCC3)nc2cc1OC1CCCCC1
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
To a DMF solution (5 mL) of NaH (0.32 g, 8 mmol) under argon, cyclohexanol (0.7 mL, 6.7 mmol) is added dropwise. The mixture is stirred at room temperature for 25 minutes, then 2-chloro-6,7-dimethoxyquinoxaline is added portionwise. The reaction is stirred for 15 minutes at room temperature, at 90° C. for 2 hours, and at 110° C. for 1 hour. The mixture is cooled, quenched with H2O, and partitioned between EtOAc/H2O. The organic layer is washed with H2O and brine, dried (MgSO4), and chromatographed (10% EtOAc/hexanes) to provide a waxy white solid (m.p. 75-78° C.). Anal. Calcd. for C21H28N2O3: C, 70.76; H, 7.92; N, 7.86; Found: C, 70.81; H, 7.79; N, 7.70.