Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1C=C(C2C=CC(C3CCNCC3)=NC=2)C=CN=1.O.[NH2:21][NH2:22].[CH:23]([N:26]1[CH2:31][CH2:30][CH:29]([C:32](=O)[CH2:33][CH:34](N2CCOCC2)[C:35]([OH:37])=O)[CH2:28][CH2:27]1)([CH3:25])[CH3:24]>CC(O)CC>[CH:23]([N:26]1[CH2:27][CH2:28][CH:29]([C:32]2[CH:33]=[CH:34][C:35](=[O:37])[NH:21][N:22]=2)[CH2:30][CH2:31]1)([CH3:24])[CH3:25]
Reactant: NN
Reactant: CC(C)N1CCC(C(=O)CC(C(=O)O)N2CCOCC2)CC1
Agent: Cc1cc(-c2ccc(C3CCNCC3)nc2)ccn1
Solvent: CCC(C)O
Solvent: O
Product: CC(C)N1CCC(c2ccc(=O)[nH]n2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In analogy to Wermuth et al. in J. Med. Chem. 1987, 30 (2), 246, hydrazine hydrate (10 mL) was added to a solution of 4-(1-isopropylpiperidin-4-yl)-2-morpholin-4-yl-4-oxo-butyric acid (99.9 g, 0.25 mol) in 2-butanol (500 mL). The reaction mixture was stirred at room temperature for 1 h followed by reflux overnight. After cooling to room temperature the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography (SiO2, dichloromethane with 3% methanol followed by 5% and 7%.). Evaporation of the fractions containing the desired product yielded a yellow solid, which was used as such.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([C:18]#[N:19])=[C:12]([CH:17]=1)[C:13](OC)=[O:14].O.[OH-].[Na+]>C1COCC1>[NH2:19][CH2:18][C:11]1[CH:10]=[CH:9][C:8]([Cl:7])=[CH:17][C:12]=1[CH2:13][OH:14]
Reactant: COC(=O)c1cc(Cl)ccc1C#N
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: NCc1ccc(Cl)cc1CO

Procedure:
To LAH (1 M/Et2O, 104.4 ml, 104.4 mmol) in anhydrous THF (300 ml) at 0° C. was added methyl 5-chloro-2-cyanobenzoate (9.28 g, 0.512 mmol) maintaining the temperature below 20° C. After one half hour, quenched at OC with water (3.97 ml), NaOH (1N, 11.9 ml, 11.9 mmol) and water (3.97 ml). A precipitate was filtered out and washed with THF. The filtrate was concentrated in vacuo and was used immediately in the next step.
Reaction SMILES: N[C:2]1[S:3][C:4]([CH2:8][O:9][CH3:10])=[C:5]([CH3:7])[N:6]=1.C(ON=O)C>O1CCCC1>[CH3:10][O:9][CH2:8][C:4]1[S:3][CH:2]=[N:6][C:5]=1[CH3:7]
Reactant: COCc1sc(N)nc1C
Agent: CCON=O
Solvent: C1CCOC1
Product: COCc1scnc1C

Procedure:
A solution of 3.2 g. of 2-amino-5-methoxymethyl-4-methylthiazole in 100 ml. of dry tetrahydrofuran was brought to reflux and a solution of 6 g. of ethylnitrite in 75 ml. of dry tetrahydrofuran was added dropwise to the refluxing solution. After refluxing an additional 5 hours, the mixture was cooled and evaporated to give an oil. The oil was extracted into hexane and the hexane solution was evaporated to dryness to give 5-methoxymethyl-4-methylthiazole.
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.[OH:13][C:14]1[CH:15]=[C:16]([C:24]([O:26][CH3:27])=[O:25])[CH:17]=[C:18]([CH:23]=1)[C:19]([O:21][CH3:22])=[O:20].[CH2:28](O)[CH2:29][O:30][CH2:31][CH2:32][O:33][CH2:34][CH2:35][O:36][CH2:37][CH2:38][O:39][CH2:40][CH2:41][O:42][CH2:43][CH2:44][OH:45].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[OH:45][CH2:44][CH2:43][O:42][CH2:41][CH2:40][O:39][CH2:38][CH2:37][O:36][CH2:35][CH2:34][O:33][CH2:32][CH2:31][O:30][CH2:29][CH2:28][O:13][C:14]1[CH:23]=[C:18]([C:19]([O:21][CH3:22])=[O:20])[CH:17]=[C:16]([CH:15]=1)[C:24]([O:26][CH3:27])=[O:25]
Reactant: OCCOCCOCCOCCOCCOCCO
Reactant: COC(=O)c1cc(O)cc(C(=O)OC)c1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cc(OCCOCCOCCOCCOCCOCCO)cc(C(=O)OC)c1
Temperature: 0 °C
Yield: 31.2 %

Procedure:
Diethylazodicarboxylate (22.7 g, 130 mmol) was added over 3 min to a stirred solution of dimethyl 5-hydroxyisophthalate (21 g, 100 mmol), hexaethylene glycol (32 g, 113 mmol) and triphenylphosphine (34 g, 130 mmol) in 250 mL of anhydrous THF. After 2 h the reaction was concentrated and the residue suspended in 200 mL of ethyl ether. After being cooled at 0° C. for 30 min the precipitated triphenylphosphine oxide was removed by filtration and filtrate concentrated. The resultant mixture was chromatographed on silica eluting, first, with ethyl acetate to separate Ph3PO and symmetrical bis-substituted hexaethylene glycol by-product and, second, with 5% MeOH in ethyl acetate to elute desired mono-substituted hexaethylene glycol derivative. Evaporation of the solvent and drying under high vacuum afforded 14.8 g (31%) of the title compound as viscous oil. 1H NMR (DMSO-d6) δ 8.08 (s, 1H), 7.70 (s, 2H), 4.58 (t, J=5.5 Hz, 1H), 4.25 (m, 2H), 3.90 (s, 6H), 3.76 (m, 2H), 3.60 (m, 2H), 3.51 (m, 16H), 3.40 (m, 2H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][Cl:18])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[NH2:19][C:20]1[CH:25]=[CH:24][N:23]=[C:22]2[O:26][CH2:27][O:28][C:21]=12>>[Cl:18][CH2:17][CH2:16][CH2:15][O:14][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([NH:19][C:20]3[CH:25]=[CH:24][N:23]=[C:22]4[O:26][CH2:27][O:28][C:21]=34)=[N:3][CH:4]=[N:5]2)=[CH:10][C:9]=1[O:12][CH3:13]
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCCl
Reactant: Nc1ccnc2c1OCO2
Product: COc1cc2c(Nc3ccnc4c3OCO4)ncnc2cc1OCCCCl
Yield: 68 %

Procedure:
Using an analogous procedure to that described in Example 14, 4-chloro-7-(3-chloropropoxy)-6-methoxyquinazoline was reacted with 4-amino-2,3-methylenedioxypyridine to give the title compound in 68% yield; NMR Spectrum: (DMSOd6) 2.26 (m, 2H), 3.83 (m, 2H), 3.96 (s, 3H), 4.28 (m, 2H), 6.12 (s, 2H), 7.15 (br d, 1H), 7.25 (s, 1H), 7.61 (d, 1H), 7.81 (s, 1H), 8.49 (s, 1H), 9.79 (br s, 1H); Mass Spectrum: M+H+ 389.
Reaction SMILES: [Cl:1][C:2]([Cl:23])([Cl:22])[CH:3]1[O:8][CH:7]([C:9]([Cl:12])([Cl:11])[Cl:10])[C:6]2[CH:13]=[C:14]([C:17](OCC)=[O:18])[CH:15]=[CH:16][C:5]=2[O:4]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)(=O)C.O>CCOCC>[OH:18][CH2:17][C:14]1[CH:15]=[CH:16][C:5]2[O:4][CH:3]([C:2]([Cl:1])([Cl:22])[Cl:23])[O:8][CH:7]([C:9]([Cl:12])([Cl:11])[Cl:10])[C:6]=2[CH:13]=1
Reactant: CCOC(=O)c1ccc2c(c1)C(C(Cl)(Cl)Cl)OC(C(Cl)(Cl)Cl)O2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Solvent: CCOC(C)=O
Product: OCc1ccc2c(c1)C(C(Cl)(Cl)Cl)OC(C(Cl)(Cl)Cl)O2
Reaction time: 1 h

Procedure:
A solution of ethyl 2,4-bis(trichloromethyl)benzo[1,3]dioxin-6-carboxylate (2.0 g.) in anhydrous ether (25 ml.) was added at room temperature during 20 minutes to a suspension of lithium aluminium hydride (0.2 g.) in anhydrous ether (25 ml.). The mixture was stirred for 1 hour, then ethyl acetate (5 ml.) was added, followed by water (10 ml.). The mixture was filtered, and the ether layer of the filtrate was separated. The aqueous phase was extracted with ether (3×10 ml.), the combined extracts were dried, and the solvent was evaporated. The residue was crystallised from ethanol to give 6-hydroxymethyl-2,4-bis(trichloromethyl)benzo[1,3]dioxin, m.p. 134°-136° C.
Reaction SMILES: C([O:8][C:9]1[C:14](=[O:15])[N:13]=[C:12]([CH2:16][C:17]2([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)[CH2:21][CH2:20][CH2:19][CH2:18]2)[N:11]2[CH2:32][CH2:33][N:34]([CH:37]([CH3:39])[CH3:38])[C:35](=[O:36])[C:10]=12)C1C=CC=CC=1.OC1C(=O)N=C(CC2(C3C=CC(C(F)(F)F)=CC=3)CCCC2)N2CCN(C(C)C)C(=O)C=12>>[OH:8][C:9]1[C:14](=[O:15])[N:13]=[C:12]([CH2:16][C:17]2([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:29])([F:30])[F:31])[CH:23]=3)[CH2:18][CH2:19][CH2:20][CH2:21]2)[N:11]2[CH2:32][CH2:33][N:34]([CH:37]([CH3:39])[CH3:38])[C:35](=[O:36])[C:10]=12
Reactant: CC(C)N1CCn2c(CC3(c4cccc(C(F)(F)F)c4)CCCC3)nc(=O)c(OCc3ccccc3)c2C1=O
Agent: CC(C)N1CCn2c(CC3(c4ccc(C(F)(F)F)cc4)CCCC3)nc(=O)c(O)c2C1=O
Product: CC(C)N1CCn2c(CC3(c4cccc(C(F)(F)F)c4)CCCC3)nc(=O)c(O)c2C1=O

Procedure:
9-Hydroxy-2-isopropyl-6-((1-(3-(trifluoromethyl)phenyl)cyclopentyl)methyl)-3,4-dihydro-1H-pyrazino[1,2-c]pyrimidine-1,8(2H)-dione (479) was synthesized as a white solid from 9-(benzyloxy)-2-isopropyl-6-((1-(3-(trifluoromethyl)phenyl)cyclopentyl)methyl)-3,4-dihydro-1H-pyrazino[1,2-c]pyrimidine-1,8(2H)-dione (478) following the procedure described for 6-[1-(4-trifluoromethyl-phenyl)-cyclopentylmethyl]-9-hydroxy-2-isopropyl-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (248).
Reaction SMILES: C[Si](C)(C)CC[O:5][C:6](=[O:29])[CH2:7][C:8]1[C:16]2[C:11](=[CH:12][C:13]([F:19])=[C:14]([O:17][CH3:18])[CH:15]=2)[N:10]([C:20]([C:22]2[S:23][C:24]([Cl:27])=[CH:25][CH:26]=2)=[O:21])[C:9]=1[CH3:28].ClC1SC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.[Cl-].[NH4+]>[Cl:27][C:24]1[S:23][C:22]([C:20]([N:10]2[C:11]3[C:16](=[CH:15][C:14]([O:17][CH3:18])=[C:13]([F:19])[CH:12]=3)[C:8]([CH2:7][C:6]([OH:29])=[O:5])=[C:9]2[CH3:28])=[O:21])=[CH:26][CH:25]=1
Reactant: COc1cc2c(CC(=O)OCC[Si](C)(C)C)c(C)n(C(=O)c3ccc(Cl)s3)c2cc1F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Clc1cccs1
Agent: [Cl-]
Solvent: C1CCOC1
Product: COc1cc2c(CC(=O)O)c(C)n(C(=O)c3ccc(Cl)s3)c2cc1F
Yield: 59 %

Procedure:
A solution of the product from Step 3, 2-trimethylsilylethyl-{1-[(5-chlorothien-2-yl)carbonyl]-6-fluoro-5-methoxy-2-methyl-1H-indol-3-yl}acetate 5, R1═H═B, R2═CH3, R3═F, R4═CH2CH2Si(CH3)3, A=5-chlorothiophene) (600 mg, 1.24 mmol) dissolved in 8 mL of THF was treated with a solution of tetrabutylammonium fluoride (1M, 3.1 mL, 3.1 mmol) in THF. The solution was stirred at room temperature until the ester had been cleaved (ca. 1 hour), and then the solution was diluted with saturated aqueous ammonium chloride and extracted with ethyl acetate. The combined extracts were washed with brine, dried over MgSO4 and concentrated to give a solid that was purified by chromatography eluting with hexanes and ethyl acetate to provide 280 mg, 59% of pure {1-[(5-chlorothien-2-yl)carbonyl]-6-fluoro-5-methoxy-2-methyl-1H-indol-3-yl}acetic acid (6, R1═H, R2═CH3, R3═F, R4═H, A=5-chlorothiophene), mp 169° C.
Reaction SMILES: [CH2:1]([O:4][N:5]([CH:18]1[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@H:21]([CH2:31][O:32][Si:33]([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34])[CH:20]=[C:19]1[CH2:40][O:41]CC1C=CC(OC)=CC=1)[S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16])(=[O:8])=[O:7])[CH:2]=[CH2:3].C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>C(Cl)Cl.O>[CH2:1]([O:4][N:5]([CH:18]1[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:29])([CH3:30])[CH3:28])=[O:25])[C@H:21]([CH2:31][O:32][Si:33]([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34])[CH:20]=[C:19]1[CH2:40][OH:41])[S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16])(=[O:8])=[O:7])[CH:2]=[CH2:3]
Reactant: C=CCON(C1CN(C(=O)OC(C)(C)C)[C@H](CO[Si](C)(C)C(C)(C)C)C=C1COCc1ccc(OC)cc1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: ClCCl
Solvent: O
Product: C=CCON(C1CN(C(=O)OC(C)(C)C)[C@H](CO[Si](C)(C)C(C)(C)C)C=C1CO)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of (2S)-tert-butyl 5-(N-(allyloxy)-2-nitrophenylsulfonamido)-2-(((tert-butyldimethylsilyl)oxy)methyl)-4-(((4-methoxybenzyl)oxy)methyl)-5,6-dihydropyridine-1(2H)-carboxylate (Intermediate 170, 18.70 g, 25.48 mmol) in DCM/water (180 mL/20 mL), was added DDQ (6.94 g, 30.57 mmol) at 0° C. The mixture was stirred at room temperature for 1 hour before it was concentrated. The residue was purified on silica gel column eluting with 0-100% ethyl acetate/hexanes to give a pale yellow oil, 12.38 g, 79%.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=1.[Cl:22]CCl.C(Cl)(=O)C(Cl)=O.CN(C)C=O>C(OCC)(=O)C>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([Cl:22])=[O:18])=[CH:15][CH:14]=1
Reactant: ClCCl
Reactant: O=C(O)c1ccc(CN2C(=O)c3ccccc3C2=O)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc(CN2C(=O)c3ccccc3C2=O)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Into a 500-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 4-[(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)methyl]benzoic acid (15.7 g, 55.82 mmol, 1.00 equiv), dichloromethane (200 mL), oxalic dichloride (10.56 g, 83.20 mmol, 1.49 equiv) and dimethylforamide (cat.). The resulting solution was stirred for 2 h at 25° C. The resulting mixture was concentrated under vacuum. This resulted in 16.7 g (crude) of 4-[(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)methyl]benzoyl chloride as a white solid. Rf: 0.30 (in ethyl acetate:petroleum ether=1:5).
Reaction SMILES: Br[C:2](=[C:6]1[C:12]2[CH:13]=[CH:14][C:15]([Cl:17])=[CH:16][C:11]=2[CH2:10][CH2:9][C:8]2[CH:18]=[CH:19][CH:20]=[CH:21][C:7]1=2)[CH2:3][O:4][CH3:5].CC1(C)C(C)(C)OB([C:30]2[CH:31]=[C:32]([NH:36][S:37]([CH3:40])(=[O:39])=[O:38])[CH:33]=[CH:34][CH:35]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>>[Cl:17][C:15]1[CH:14]=[CH:13][C:12]2[C:6](=[C:2]([C:30]3[CH:31]=[C:32]([NH:36][S:37]([CH3:40])(=[O:38])=[O:39])[CH:33]=[CH:34][CH:35]=3)[CH2:3][O:4][CH3:5])[C:7]3[CH:21]=[CH:20][CH:19]=[CH:18][C:8]=3[CH2:9][CH2:10][C:11]=2[CH:16]=1
Reactant: CC1(C)OB(c2cccc(NS(C)(=O)=O)c2)OC1(C)C
Reactant: COCC(Br)=C1c2ccccc2CCc2cc(Cl)ccc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COCC(=C1c2ccccc2CCc2cc(Cl)ccc21)c1cccc(NS(C)(=O)=O)c1
Yield: 62 %

Procedure:
Following procedures essentially as described in Example 219, mix 5-(1-bromo-2-methoxy-ethylidene)-2-chloro-10,11-dihydro-5H-dibenzo[a,d]cycloheptene (1 equivalent), N-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-methanesulfonamide (1.25 equivalents), 2N Na2CO3 (2 equivalents) and tetrakistriphenylphosphine palladium (0.65 equivalents)in a suitable solvent. Purify the product by silica gel chromatography to obtain a 62% yield of the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N:8]2[C:12](=[O:13])[CH:11]3[CH2:14][CH2:15][CH:16]=[CH:17][CH:10]3[C:9]2=[O:18])=[C:6]([F:19])[CH:5]=[C:4]([Cl:20])[C:3]=1[OH:21].[CH:22](I)([CH3:24])[CH3:23].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[NH2:1][C:2]1[C:3]([O:21][CH:22]([CH3:24])[CH3:23])=[C:4]([Cl:20])[CH:5]=[C:6]([F:19])[C:7]=1[N:8]1[C:12](=[O:13])[CH:11]2[CH2:14][CH2:15][CH:16]=[CH:17][CH:10]2[C:9]1=[O:18]
Reactant: Nc1c(O)c(Cl)cc(F)c1N1C(=O)C2C=CCCC2C1=O
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)Oc1c(Cl)cc(F)c(N2C(=O)C3C=CCCC3C2=O)c1N

Procedure:
A mixture of 2-amino-6-chloro-4-fluoro-3-(tetrahydrophthalimido)phenol (0.31 g), isopropyl iodide (1.2 ml), potassium carbonate (0.14 g), and acetonitrile (5 ml) was heated under reflux for 2 hr. The solvent and excess reagent were removed under reduced pressure. The residue was purified by a silica gel column, eluted with ethyl acetate to give the title product (0.21 g).
Reaction SMILES: [CH3:1][CH:2]([S:4](Cl)(=[O:6])=[O:5])[CH3:3].[F:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](=[O:21])[C:14]([OH:20])=[CH:15][N:16]2[CH3:19])=[CH:11][CH:10]=1.ClCCl>C(N(CC)CC)C>[CH3:1][CH:2]([S:4]([O:20][C:14]1[C:13](=[O:21])[C:12]2[C:17](=[CH:18][C:9]([F:8])=[CH:10][CH:11]=2)[N:16]([CH3:19])[CH:15]=1)(=[O:6])=[O:5])[CH3:3]
Reactant: CC(C)S(=O)(=O)Cl
Reactant: Cn1cc(O)c(=O)c2ccc(F)cc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)S(=O)(=O)Oc1cn(C)c2cc(F)ccc2c1=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
2-Propanesulphonyl chloride (1.74 ml) was added to a stirred mixture of 7-fluoro-3-hydroxy-1-methyl-4quinolone (3.0 g), obtained as described in Example 3 a-f, triethylamine (4.35 ml) and dry dichloromethane (180 ml) and the mixture stirred at ambient temperature for 24 hours. Further quantities of 2-propanesulphonyl chloride (1.75 ml then 1 ml) and triethylamine (4.35 ml then 2.5 ml) were added after stirring for 24 hours and 48 hours respectively. After stirring for a further 24 hours, the mixture was filtered and the filter bed was washed with dichloromethane (30 ml). The combined filtrate and washing were washed with water (200 ml), saturated aqueous sodium bicarbonate (2×200 ml), then water (200 ml) and then dried over magnesium sulphate. The dichloromethane was removed by distillation to give a residue which was purified by flash chromatography on a silica gel column eluted with dichloromethane: industrial methylated spirit (19:1) followed by crystallisation from 2-propanol (25 ml) to give the novel compound 7-fluoro-1-methyl-4-oxo-1,4-dihydroquinol-3-yl 2-propanesulphonate, m.p. 130°-133°.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2([CH3:14])[O:13][CH2:12][CH2:11][O:10]2)=[CH:5][CH:4]=1)=[O:2].S([CH2:25][N+:26]#[C-:27])(C1C=CC(C)=CC=1)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CO.O>[O:2]1[C:1]([C:3]2[CH:4]=[CH:5][C:6]([C:9]3([CH3:14])[O:10][CH2:11][CH2:12][O:13]3)=[CH:7][CH:8]=2)=[CH:27][N:26]=[CH:25]1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: CC1(c2ccc(C=O)cc2)OCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CC1(c2ccc(-c3cnco3)cc2)OCCO1
Yield: 37.4 %

Procedure:
To a stirred solution of 2-(4-formylphenyl)-2-methyl-1,3-dioxolane (1.58 g, 8.23 mmol) in methanol (10 ml) was added tosylmethyl isocyanide (2.0 g, 10.3 mmol), potassium carbonate (1.42 g, 10.3 mmol), and the mixture was heated at reflux temperature for 2 hours. The reaction mixture was diluted with water and the whole was extracted with CH2Cl2. The organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by flash chromatography eluting with ethyl acetate-hexane (1:4) to give the title compound (711 mg, 37% yield).
Reaction SMILES: [C:1]([C:3]1[CH:50]=[CH:49][C:6]2[N:7](COCC[Si](C)(C)C)[C:8]([C:10]([C:22]3[C:30]([O:31][CH3:32])=[CH:29][C:28]([CH3:33])=[C:27]4[C:23]=3[CH:24]=[CH:25][N:26]4C(OC(C)(C)C)=O)([NH:15]S(C(C)(C)C)=O)[C:11]([F:14])([F:13])[F:12])=[N:9][C:5]=2[CH:4]=1)#[N:2].C(C1C=CC2N=C(C(C3C(OC)=CC(C)=C4C=3C=CN4C(OC(C)(C)C)=O)(NS(C(C)(C)C)=O)C(F)(F)F)N(COCC[Si](C)(C)C)C=2C=1)#N.CO.C([O-])([O-])=O.[Cs+].[Cs+]>Cl.[NH4+].[Cl-]>[NH2:15][C:10]([C:8]1[NH:7][C:6]2[CH:49]=[CH:50][C:3]([C:1]#[N:2])=[CH:4][C:5]=2[N:9]=1)([C:22]1[C:30]([O:31][CH3:32])=[CH:29][C:28]([CH3:33])=[C:27]2[C:23]=1[CH:24]=[CH:25][NH:26]2)[C:11]([F:14])([F:13])[F:12]
Reactant: COc1cc(C)c2c(ccn2C(=O)OC(C)(C)C)c1C(NS(=O)C(C)(C)C)(c1nc2cc(C#N)ccc2n1COCC[Si](C)(C)C)C(F)(F)F
Agent: COc1cc(C)c2c(ccn2C(=O)OC(C)(C)C)c1C(NS(=O)C(C)(C)C)(c1nc2ccc(C#N)cc2n1COCC[Si](C)(C)C)C(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CO
Product: COc1cc(C)c2[nH]ccc2c1C(N)(c1nc2cc(C#N)ccc2[nH]1)C(F)(F)F
Temperature: 60 °C

Procedure:
A mixture of (±)-tert-butyl 4-(1-(5-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-1-(1,1-dimethylethylsulfinamido)-2,2,2-trifluoroethyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate and (±)-tert-butyl 4-(1-(6-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-1-(1,1-dimethylethylsulfinamido)-2,2,2-trifluoroethyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (0.50 g, 0.68 mmol) was dissolved in 1.25M HCl in MeOH (10.9 mL, 13.63 mmol) and the mixture was heated at 60° C. After 4 hours the reaction was cooled to room temperature and concentrated. The residue was dissolved in MeOH (6.81 mL) and Cs2CO3 (2.22 g, 6.81 mmol) was added, and the mixture was stirred at 60° C. After 30 minutes additional Cs2CO3 (1.11 g, 3.4 mmol) was added. After 10 minutes the reaction was diluted with sat. aq. NH4Cl and the layers separated. The aqueous layer was extracted with EtOAc, dried over MgSO4, filtered and concentrated. The resulting residues was purified by flash column chromatography (0-100% EtOAc in heptanes) to provide the title compound. 1H NMR (400 MHz, DMSO-d6 with about 5 μL TFA) δ ppm 11.19 (br. s., 1H) 8.27 (br. s., 1H) 7.78 (d, J=7.96 Hz, 1H) 7.69 (dd, J=8.46, 1.52 Hz, 1H) 7.13 (t, J=2.91 Hz, 1H) 6.94 (s, 1H) 5.09 (br. s., 1H) 3.77 (s, 3H). HRMS calcd. for C20H16F3N6O (M+H)+ 400.138. found 400.1385.
Reaction SMILES: [Cl:1][C:2]1[C:3]([Cl:16])=[CH:4][C:5]2[C:6]3[CH2:15][CH2:14][NH:13][CH2:12][CH2:11][C:7]=3[NH:8][C:9]=2[CH:10]=1>C(O)(C(F)(F)F)=O.CO>[Cl:1][C:2]1[C:3]([Cl:16])=[CH:4][C:5]2[C@@H:6]3[CH2:15][CH2:14][NH:13][CH2:12][CH2:11][C@@H:7]3[NH:8][C:9]=2[CH:10]=1
Reactant: Clc1cc2[nH]c3c(c2cc1Cl)CCNCC3
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: Clc1cc2c(cc1Cl)[C@@H]1CCNCC[C@@H]1N2
Reaction time: 2.5 h
Yield: 34 %

Procedure:
A solution of 8,9-dichloro-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (0.40 g, 1.6 mmol) in TFA (4.0 mL) was cooled to 0° C., then a freshly prepared solution of Na(CN)BH3 (0.49 g, 7.8 mmol) in MeOH (.1.5 mL) was added dropwise. The ice bath was removed after the addition was complete. After 2.5 h, the reaction was diluted with H2O, made basic with 50% aqueous NaOH, and extracted with EtOAc. The combined organic extracts were washed with brine, dried over Na2SO4, decanted, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography and prep HPLC to give 0.14 g (36%) of the title compound as pale orange solid. 1H NMR (d-CHCl3) δ 7.00, 6.58, 4.22, 3.81, 3.58, 3.14-2.98, 2.79, 2.07-1.87: IR (drift) 3201, 3170, 3149, 3031, 2927, 2852, 2838, 2750, 1608, 1483, 1450, 1365, 1273, 832, 660 cm−1; HRMS (FAB) calcd for C12H14Cl2N2+H 257.0612, found 257.0614.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:10]2[O:14]CCO2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[CH2:15]([NH2:17])[CH3:16].O(C(C)(C)C)[K].Cl>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:15]([NH:17][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[O:8][CH3:9])[CH:10]=[O:14])[CH3:16]
Reactant: COc1ccc(C2OCCO2)cc1Br
Reactant: CCN
Agent: [Pd]
Agent: CC(C)(C)O[K]
Agent: Cl
Solvent: Cc1ccccc1
Product: CCNc1cc(C=O)ccc1OC
Temperature: 110 °C
Yield: 63 %

Procedure:
Through a solution of 2-(3-bromo-4-methoxy-phenyl)-[1,3]dioxolane (1.2 g, 4.63 mmol 1.0 equiv; prepared as described in WO 01/74775 A1, Sanofi-Synthelabo) in toluene (6 mL) was bubbled ethylamine for 10 min. To this solution was added KOtert-Bu (0.67 g, 6.95 mmol, 1.5 equiv), rac-2,2′-bis(diphenylphosphino)-1,1′-binaphthalene (0.029 g, 0.046 mmol, 0.01 equiv) and tris(dibenzylideneacetone)dipalladium(0) (0.021 g, 0.023 mmol, 0.005 equiv) and the solution heated to 110° C. under microwave irradiation for 20 min. A few drops of a solution of 37% HCl were added and the reaction mixture heated again under microwave irradiation to 100° C. for 5 min. Evaporation of the solvent and purification of the crude reaction product by column chromatography on silica eluting with hexane/ethyl acetate (7:3) provided 0.52 g (63%) of the title compound. 1H NMR (300 MHz, CDCl3): δ 1.24 (t, J=7.1 Hz, 3H), 3.16 (q, J=7.1 Hz, 2H), 3.86 (s, 3H), 4.17 (br s, 1H), 6.78 (d, J=8.1 Hz, 1H), 7.01 (d, J=1.9 Hz, 1H), 7.13 (dd, J=8.1 Hz, J=1.9 Hz, 1H). MS (ISP): 179.9 [M+H]+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C:10](=[O:13])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:14][Mg]Br>C1COCC1>[CH2:1]([N:8]1[CH2:12][CH2:11][C:10]([CH3:14])([OH:13])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[Mg]Br
Reactant: O=C1CCN(Cc2ccccc2)C1
Solvent: C1CCOC1
Product: CC1(O)CCN(Cc2ccccc2)C1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Add 1-benzyl-3-pyrrolidinone (10 g, 61.7 mmol) in dry THF (40 mL) to methyl magnesium bromide (3 M in diethyl ether, 44 mL, 132 mmol) at −20° C. Stir for 3 h and allow the reaction to warm up to 0° C. Pour onto crushed ice and extract with diethyl ether. Combine the organic layers and wash with saturated aqueous sodium chloride, dry (magnesium sulfate) and concentrate to give 1-benzyl-3-methylpyrrolidin-3-ol which may be used directly in the next step without further purification (8.6 g, 73%). 1H NMR (400 MHz, CDCl3) δ 7.22-7.33 (5H, m), 3.63 (2H, s), 2.92-2.99 (1H, m), 2.71 (1H, d, J=9.29 Hz), 2.28-2.36 (1H, m), 2.22 (1H, d, J=9.78 Hz), 1.84-1.91 (2H, m), 1.33 (3H, s), MS (ES): m/z=192 [M+H].