Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]=2[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:5][CH:4]=1.[H-].[Na+].[CH2:25](Cl)[C:26]1[CH:34]=[CH:33][C:32]2[O:31][CH2:30][O:29][C:28]=2[CH:27]=1>CN(P(N(C)C)(N(C)C)=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:17]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[N:11]([CH2:25][C:26]3[CH:34]=[CH:33][C:32]4[O:31][CH2:30][O:29][C:28]=4[CH:27]=3)[C:10]=2[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:7][CH:8]=1
Reactant: ClCc1ccc2c(c1)OCO2
Reactant: CCOC(=O)c1[nH]c2ncccc2c1-c1ccc(OC)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCOC(=O)c1c(-c2ccc(OC)cc2)c2cccnc2n1Cc1ccc2c(c1)OCO2
Temperature: 25 °C

Procedure:
To a solution of ethyl 3-(4-methoxyphenyl)pyrrolo[2,3-b]pyridine-2-carboxylate in HMPA stirred at ice bath temperature under an argon atmosphere is added NaH. A solution of piperonyl chloride in HMPA is added and the ice bath removed. The reaction mixture is stirred at room temperature then partitioned between 3 N HCl and EtOAc. The organic extract is washed successively with H2O, aqueous NaHCO3, H2O and saturated aqueous NaCl and dried (Na2SO4). The solvent is removed in vacuo. The residue is purified by chromatography to afford the title compound.
Reaction SMILES: [Si](O[O:9][CH2:10][C@H:11]1[O:15][C@@H:14]([N:16]2[CH:23]=[C:22]([CH2:24][C:25]#[C:26][CH2:27][O:28][CH2:29][CH2:30][NH:31][C:32](=[O:37])[C:33]([F:36])([F:35])[F:34])[C:20](=[O:21])[NH:19][C:17]2=[O:18])[CH2:13][CH2:12]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[F:35][C:33]([F:34])([F:36])[C:32]([NH:31][CH2:30][CH2:29][O:28][CH2:27][C:26]#[C:25][CH2:24][C:22]1[C:20](=[O:21])[NH:19][C:17](=[O:18])[N:16]([CH:23]=1)[C@@H:14]1[O:15][C@H:11]([CH2:10][OH:9])[CH2:12][CH2:13]1)=[O:37]
Reactant: CC(C)(C)[Si](C)(C)OOC[C@@H]1CC[C@H](n2cc(CC#CCOCCNC(=O)C(F)(F)F)c(=O)[nH]c2=O)O1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: O=C(NCCOCC#CCc1cn([C@H]2CC[C@@H](CO)O2)c(=O)[nH]c1=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 43.5 %

Procedure:
To a solution of 4 (90.0 mg, 0.17 mmol) in THF (5 mL) was added 1.0 M tetrabutylammonium fluoride (TBAF, 0.2 mL, 0.19 mmol), which was stirred at r.t. for 3 h. After evaporating solvent, the organic residue was purified by silica gel column chromatography with MeOH/CH2Cl2 to give the product 5 (30 mg, 0.074 mmol, 43%). 1H NMR (CDCl3, 300 MHz) δ 8.01 (t, 1H, H6, J=1.2 Hz), 6.08 (dd, 1H, H1′, J=3.6 and 6.6 Hz), 4.23 (t, 2H, CH2), 4.20-4.10 (m, 1H, H4′), 3.85 (dd, 1H, H5′, J=3.3 and 11.4 Hz), 3.75-3.63 (m, 3H, H5′, CH2), 3.50-3.45 (m, 2H, CH2), 3.30-3.25 (m, 2H, CH2), 2.47-2.34 (m, 1H, H2′), 2.15-1.80 (m, 3H, H2′, 2 H3′). 19F NMR (CDCl3, 282.2 MHz) δ −77.79 (s, CF3).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:10]([OH:20])[CH2:9]1)=O)(C)(C)C.[ClH:21]>CO>[ClH:21].[OH:20][CH:10]1[CH:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:12][NH:8][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CC(O)C(Nc2ccccc2)C1
Agent: Cl
Solvent: CO
Product: OC1CNCC1Nc1ccccc1

Procedure:
In 100 ml of methanol was dissolved 2.4 g (0.0086 mole) of 1-t-butoxycarbonyl-3-hydroxy-4-phenylaminopyrrolidine obtained as described above, and 30 ml of 6N hydrochloric acid was added thereto. After the mixture was refluxed by heating for 2.5 hours, the solvent was removed under reduced pressure. The resulting residue was washed with ethanol and ether to obtain 1.52 g of 3-hydroxy-4-phenylaminopyrrolidine hydrochloride as light brown powder.
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.[Cl:5][C:6]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:7]=1[C:8]([C:10](=[CH:13]OC)[C:11]#[N:12])=[O:9]>C(O)C>[Cl:5][C:6]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:7]=1[C:8]([C:10](=[CH:13][NH:4][CH:1]1[CH2:3][CH2:2]1)[C:11]#[N:12])=[O:9]
Reactant: NC1CC1
Reactant: COC=C(C#N)C(=O)c1ccc(Cl)cc1Cl
Solvent: CCO
Product: N#CC(=CNC1CC1)C(=O)c1ccc(Cl)cc1Cl
Yield: 86.9 %

Procedure:
2.5 g of cyclopropylamine are added dropwise to a solution of 11 g of 2-(2,4-dichloro-benzoyl)-3-methoxyacrylonitrile in 40 ml of ethanol, while cooling with ice and stirring. The mixture is stirred at room temperature for 25 minutes and then heated at the boiling point for 15 minutes. The solvent is removed in vacuo and the residue is recrystallized from ethanol/light petrol. 10.5 g of 2-(2,4-dichloro-benzoyl)-3-cyclopropylaminoacrylonitrile of melting point 93°-94° C. are obtained.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:19]=[C:18]([NH:20][CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=2)[C:12]([C:13](OCC)=[O:14])=[CH:11][N:10]=1)#[N:2].[NH2:30][CH2:31][C:32]1[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=1.C[Al](C)C>C1(C)C=CC=CC=1>[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:19]=[C:18]([NH:20][CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=2)[C:12]([C:13]([NH:30][CH2:31][C:32]2[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=2)=[O:14])=[CH:11][N:10]=1)#[N:2]
Reactant: NCc1cccnc1
Reactant: CCOC(=O)c1cnc(-c2ccccc2C#N)cc1NCCc1cccc(F)c1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: N#Cc1ccccc1-c1cc(NCCc2cccc(F)c2)c(C(=O)NCc2cccnc2)cn1
Temperature: 70 °C
Reaction time: 8 h
Yield: 8.5 %

Procedure:
To a solution of ethyl 6-(2-cyanophenyl)-4-(3-fluorophenethylamino)nicotinate (100 mg, 0.26 mmol) and 3-aminomethylpyridine (39 mg, 0.36 mmol) in toluene (1 mL) was added AlMe3 (0.2 mL, 2M in toluene, 0.39 mmol) at r.t. The reaction mixture was stirred at 70° C. overnight. The reaction was cooled, quenched with sat. NaHCO3, and diluted with EtOAc. The organic layer was separated, washed with brine, dried over Na2SO4, and filtered. The filtrate was concentrated under reduced pressure to give a crude oil. The crude mixture was purified on RP-HPLC using a mixture of acetonitrile and H2O to give 6-(2-cyanophenyl)-4-(3-fluorophenethylamino)-N-(pyridin-3-ylmethyl)nicotinamide (10 mg, 8.6%). LRMS (M+H+) m/z 452.0.
Reaction SMILES: Cl.[CH2:2]([O:9][CH2:10][CH2:11][CH2:12][C:13]([NH2:15])=[NH:14])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.Cl[C:24](=[CH2:27])[C:25]#[N:26]>CCO>[NH2:26][C:25]1[CH:24]=[CH:27][N:15]=[C:13]([CH2:12][CH2:11][CH2:10][O:9][CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[N:14]=1
Reactant: C=C(Cl)C#N
Reactant: N=C(N)CCCOCc1ccccc1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: Nc1ccnc(CCCOCc2ccccc2)n1
Yield: 63.1 %

Procedure:
To a mixture of 4-benzyloxybutanamidine hydrochloride (14.6 g.) and triethylamine (33 g.) in EtOH (80 ml.) was added 2-chloroacrylonitrile (11.3 g.) and the solution was heated under reflux for 2 hours and then evaporated to dryness. The residue was partitioned between 10% aqueous HOAc (100 ml.) and EtOAc (200 ml.) and the EtOAc was reextracted with 10% v/v aqueous HOAc (2×100 ml.). The combined aqueous layers were basified with concentrated aqueous NaOH and extracted with EtOAc (3×75 ml.) and the EtOAc solution was washed with brine and dried to give 4-amino-2-(3-benzyloxypropyl)pyrimidine (9.8 g.). This amino-derivative was heated under reflux with 2,2,2-trifluoroethylisothiocyanate (10 g.) in acetonitrile (20 ml.) for 23 hours and the mixture evaporated to dryness. The residue was chromatographed on silica gel using CH2Cl2 containing 1% v/v MeOH as eluant to give 2-(3-benzyloxypropyl)-4-[3-(2,2,2-trifluoroethyl)thioureido]pyrimidine (10 g.).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][CH2:11][CH3:12])[CH3:2].[C:13]1(=[O:23])[O:18][C:16](=[O:17])[C@H:15]2[CH2:19][CH:20]=[CH:21][CH2:22][C@@H:14]12>>[CH2:11]([O:10][C:5]1[CH:6]=[C:7]([CH:8]=[CH:9][C:4]=1[O:3][CH2:1][CH3:2])[C:13]([C@H:14]1[CH2:22][CH:21]=[CH:20][CH2:19][C@H:15]1[C:16]([OH:18])=[O:17])=[O:23])[CH3:12]
Reactant: CCOc1ccccc1OCC
Reactant: O=C1OC(=O)[C@@H]2CC=CC[C@H]12
Product: CCOc1ccc(C(=O)[C@H]2CC=CC[C@H]2C(=O)O)cc1OCC

Procedure:
Prepared from 1,2-Diethoxybenzene and cis-1,2,3,6-tetrahydrophthalic anhydride as described for compound A3. M.p. 125-127° C.
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]=[O:9])=[CH:4][CH:3]=1.[CH2:10]([Mg]Cl)[CH3:11]>C1COCC1.[Cl-].[NH4+]>[Br:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]([OH:9])[CH2:10][CH3:11])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Br)nc1
Reactant: CC[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCC(O)c1ccc(Br)nc1
Reaction time: 4 h

Procedure:
To a chilled (0° C.) solution of 6-bromo-pyridine-3-carboxaldehyde (15.0 g, 80.6 mmol) in a 1:1 mixture of ether-toluene (400 mL) was added a 2 M solution of ethyl magnesium chloride (40.0 mL, 80.0 mmol) in THF over a 15 minute period. The solution was stirred for 4 hours, and a more polar product was observed by TLC (ethyl acetate-hexanes 3:7). The mixture was diluted with saturated aqueous ammonium chloride (300 mL) and the organic phase separated. The aqueous layer was extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with brine (2×50 mL), dried over magnesium sulfate, filtered and concentrated. The crude material was passed through a pad of silica gel eluting 0-100% dichloromethane in hexanes. The material from the pad was purified by silica gel chromatography eluting with a gradient of 2-15% ethyl acetate in hexanes to afford 1-(6-bromo-pyridin-3-yl)-propan-1-ol.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([CH2:8][CH2:9][N:10]2[C:14](=[O:15])[CH2:13][O:12][C:11]2=[O:16])[CH2:4][CH2:3]1.Cl[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:21][CH:20]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C>[C:22]1([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:21]=[CH:20][C:19]([CH2:18][N:2]2[CH2:7][CH2:6][CH:5]([CH2:8][CH2:9][N:10]3[C:14](=[O:15])[CH2:13][O:12][C:11]3=[O:16])[CH2:4][CH2:3]2)=[CH:24][CH:23]=1
Reactant: O=C1COC(=O)N1CCC1CCNCC1
Reactant: ClCc1ccc(-c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: O=C1COC(=O)N1CCC1CCN(Cc2ccc(-c3ccccc3)cc2)CC1

Procedure:
A solution of 0.40 g (1.61 mmol) of 3-(2-piperidin-4-ylethyl)-1,3-oxazolidine-2,4-dione hydrochloride, prepared in step 1.1., 0.326 g (1.61 mmol) of 4-(chloromethyl)biphenyl and 0.51 g (4.82 mmol) of sodium carbonate in 3 ml of acetonitrile is heated at reflux for 17 hours. It is left to return to ambient temperature and filtered and the filtrate is concentrated under reduced pressure. The residue is taken up in dichloromethane and water and the aqueous phase is separated off and extracted twice with dichloromethane. The combined organic phases are washed with saturated aqueous sodium chloride solution and dried over sodium sulphate. Following evaporation of the solvent, the residue obtained is purified by chromatography on silica gel, eluting with a 97/3 then 95/5 mixture of dichloromethane and methanol.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][C:8]([C:11]3[CH:12]=[N:13][N:14]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[CH:15]=3)=[CH:7][CH2:6]2)[O:4][CH2:3][CH2:2]1>CCOC(C)=O>[O:4]1[C:5]2([CH2:6][CH2:7][CH:8]([C:11]3[CH:12]=[N:13][N:14]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[CH:15]=3)[CH2:9][CH2:10]2)[O:1][CH2:2][CH2:3]1
Reactant: C[Si](C)(C)CCOCn1cc(C2=CCC3(CC2)OCCO3)cn1
Solvent: CCOC(C)=O
Product: C[Si](C)(C)CCOCn1cc(C2CCC3(CC2)OCCO3)cn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 96.4 %

Procedure:
4-(1,4-Dioxaspiro[4.5]dec-7-en-8-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (505 μmol, 170 mg) was dissolved in 10 mL EtOAc in a 50 mL roundbottom flask. The flask was flushed with argon and 5% palladium on carbon (50 mg) was added. The flask was sealed, degassed under vacuum, and hydrogen gas was added with a balloon. The reaction mixture was stirred at room temperature under hydrogen atmosphere for 18 hours. The reaction was then filtered through celite to yield 4-(1,4-dioxaspiro[4.5]decan-8-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (165 mg, 487 μmol, 97% yield) as a clear oil.
Reaction SMILES: [OH:1][CH:2]([CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])[C:3]#[CH:4].N1C=CN=C1.[C:15]([Si:19]([CH3:22])([CH3:21])Cl)([CH3:18])([CH3:17])[CH3:16].O>CN(C)C=O.CCCCCC>[Si:19]([O:1][CH:2]([CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])[C:3]#[CH:4])([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:22])[CH3:21]
Reactant: C#CC(O)CCCCC
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CCCCCC
Solvent: O
Solvent: CN(C)C=O
Product: C#CC(CCCCC)O[Si](C)(C)C(C)(C)C
Reaction time: 3 h

Procedure:
To a solution of 3-hydroxyoct-1-yne (see Preparation 3.A.) (2.89 g, 0.02 mol), in N,N-dimethylformamide (DMF), cooled to 0° C., was added imidazole (2.1 g), followed by tert-butyldimethylchlorosilane (3.1 g, 0.02 mol), and the mixture was stirred for 3 h. Water (80 ml) and hexane (80 ml) were added; the organic layer was separated and combined with 2×80 ml of hexane extractions of the aqueous layer. The solvent was removed (in vacuo), after drying over sodium sulfate, to give a crude residue (4.3 g) which was chromatographed on silica gel (80 g), eluting with ethyl acetate-hexane (2:1, v/v) to afford 3-tert-butyldimethylsilyloxyoct-1-yne. JACS, 94, 6190, (1972).
Reaction SMILES: Br[C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]2[CH2:10][CH2:11][N:12]([CH3:15])[CH2:13][CH:14]=2)=[C:4]([F:16])[CH:3]=1.[CH3:17][N:18](C)C=O>>[F:8][C:7]1[CH:6]=[C:5]([C:9]2[CH2:10][CH2:11][N:12]([CH3:15])[CH2:13][CH:14]=2)[C:4]([F:16])=[CH:3][C:2]=1[C:17]#[N:18]
Reactant: CN(C)C=O
Reactant: CN1CC=C(c2cc(F)c(Br)cc2F)CC1
Product: CN1CC=C(c2cc(F)c(C#N)cc2F)CC1

Procedure:
A mixture of 2.88 g (10 mmoles) of 4-(4-bromo-2,5-difluorophenyl)-1,2,3,6-tetrahydro-1-methylpyridine and 0.90 g (10 mmoles) of cuprous cyanide in 30 ml of dimethylformamide was refluxed overnight. The solvent was evaporated, the residue treated with ammonium hydroxide, and the solution extracted with dichloromethane. Evaporation of the organic phase afforded the title compound.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:10]=[C:11]([CH:22]=[CH:23][C:24]=1[Cl:25])[O:12][CH:13]1[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][NH2:21])[CH2:15][CH2:14]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH3:40][O:41][C:42]1[CH:43]=[C:44]([CH:47]=[CH:48][CH:49]=1)[CH:45]=O.C([O-])(O)=O.[Na+].[ClH:55]>CN(C=O)C.ClCCCl.C(Cl)(Cl)Cl.C(N(CC)CC)C>[ClH:8].[ClH:55].[Cl:8][C:9]1[CH:10]=[C:11]([CH:22]=[CH:23][C:24]=1[Cl:25])[O:12][CH:13]1[CH2:14][CH2:15][N:16]([CH2:19][CH2:20][NH:21][CH2:45][C:44]2[CH:47]=[CH:48][CH:49]=[C:42]([O:41][CH3:40])[CH:43]=2)[CH2:17][CH2:18]1
Reactant: NCCN1CCC(Oc2ccc(Cl)c(Cl)c2)CC1
Reactant: COc1cccc(C=O)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: COc1cccc(CNCCN2CCC(Oc3ccc(Cl)c(Cl)c3)CC2)c1

Procedure:
A suspension of the product of Example 1 step (iv) (0.11 g) in a mixture of DMF (1.5 ml) and 1,2-dichloroethane (3 ml) was stirred under an atmosphere of nitrogen. Sodium triacetoxyborohydride (0.097 g), 3-methoxybenzaldehyde (0.041 g) and triethylamine (0.046 g) were added and the mixture stirred for 18 hours at room temperature. Chloroform and aqueous NaHCO3 solution were added, the organic phase separated, dried and concentrated to a gum. Purification by chromatography (chloroform:triethylamine:methanol, 89:10:1) gave an oil which was treated with 1.0M ethereal hydrogen chloride solution to give the titled product as a solid (0.067 g).
Reaction SMILES: C([Si](C)(C)[O:6][C@@H:7]1[C:15]2[C:10](=[C:11]([CH2:18][C:19]3[CH:20]=[N:21][C:22]([Cl:25])=[CH:23][CH:24]=3)[C:12]([C:16]#[N:17])=[CH:13][CH:14]=2)[CH2:9][CH2:8]1)(C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[Cl:25][C:22]1[N:21]=[CH:20][C:19]([CH2:18][C:11]2[C:12]([C:16]#[N:17])=[CH:13][CH:14]=[C:15]3[C:10]=2[CH2:9][CH2:8][C@@H:7]3[OH:6])=[CH:24][CH:23]=1
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CCc2c1ccc(C#N)c2Cc1ccc(Cl)nc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: N#Cc1ccc2c(c1Cc1ccc(Cl)nc1)CC[C@@H]2O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
(S)-1-(tert-Butyl-dimethyl-silanyloxy)-4-(6-chloro-pyridin-3-ylmethyl)-indan-5-carbonitrile (130 mg, 0.33 mmol) is suspended in dry tetrahydrofuran (5 mL) and cooled in an ice bath. Tetrabutylammonium fluoride (1 M in tetrahydrofuran, 0.65 mL, 0.65 mmol) is added, the mixture allowed to warm to room temperature and stirred for 3 hours. The mixture is concentrated under vacuum, diluted with ethyl acetate and washed with saturated ammonium chloride solution. The organic phase is evaporated to give crude title compound which is used directly in the next step (Yield 143 mg). LC (METHOD 6): tR=0.47 min; Mass spectrum (ES+): m/z=285 [M+H]+.
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[F:15])[C:6]2[CH:16]=[CH:17][CH:18]=[CH:19][C:5]=2[NH:4][C:3]1=[O:20].[C:21]1([CH3:31])[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:31][C:21]1[CH:26]=[CH:25][C:24]([S:27]([NH:1][CH:2]2[N:8]=[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[F:15])[C:6]3[CH:16]=[CH:17][CH:18]=[CH:19][C:5]=3[NH:4][C:3]2=[O:20])(=[O:29])=[O:28])=[CH:23][CH:22]=1
Reactant: NC1N=C(c2ccccc2F)c2ccccc2NC1=O
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)NC2N=C(c3ccccc3F)c3ccccc3NC2=O)cc1
Reaction time: 8 h
Yield: 109.8 %

Procedure:
1,3-Dihydro-3-(RS)-amino-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one (116 mg, 0.43 mmole) and p-toluenesulfonyl chloride (82 mg, 0.43 mmole) were combined at room temperature in 5 ml of methylene chloride. The pH of the reaction mixture was then adjusted to 8.5 with triethylamine and stirring was continued at room temperature overnight. The reaction mixture was partitioned between methylene chloride and 10% citric acid solution. The phases were separated and the organic layer was washed in succession with 10% citric acid solution (1×30 ml), saturated sodium bicarbonate solution (2×30 ml) and brine. The dried (MgSO4) extracts were concentrated to yield 200 mg of crude product. Recrystallization from ethyl acetate afforded the analytical sample as white needles, m.p. 215°-216° C.
Reaction SMILES: CC1C=CC2C(C3C(=O)NC(=O)N(C4C=CN=C(NCC(NC5SC=C(CC(O)=O)N=5)=O)N=4)C=3)C3C=CC(CCC)=CC=3C=CC=2C=1.[CH3:48][C:49]1[CH:57]=[CH:56][C:52]([C:53]([OH:55])=[O:54])=[C:51]([CH2:58][CH2:59][C:60]2[CH:65]=[CH:64][CH:63]=[C:62]([CH:66]=[CH:67][CH3:68])[CH:61]=2)[CH:50]=1>C(OCC)(=O)C.[Pd]>[CH3:48][C:49]1[CH:57]=[CH:56][C:52]([C:53]([OH:55])=[O:54])=[C:51]([CH2:58][CH2:59][C:60]2[CH:65]=[CH:64][CH:63]=[C:62]([CH2:66][CH2:67][CH3:68])[CH:61]=2)[CH:50]=1
Reactant: CC=Cc1cccc(CCc2cc(C)ccc2C(=O)O)c1
Agent: [Pd]
Agent: CCCc1ccc2c(c1)C=Cc1cc(C)ccc1C2c1cn(-c2ccnc(NCC(=O)Nc3nc(CC(=O)O)cs3)n2)c(=O)[nH]c1=O
Solvent: CCOC(C)=O
Product: CCCc1cccc(CCc2cc(C)ccc2C(=O)O)c1

Procedure:
The subtitle compound was prepared from the product of step (iv) (15.4 g) by the method of example 15 step (v). The crude reaction product was contaminated with 4-methyl-2-[2-[3-[1-propenyl]phenyl]ethyl]benzoic acid. The crude reaction product was dissolved in ethyl acetate (100 ml) and the solution was hydrogenated over 10% palladium on carbon (1 g) at 3 atmospheres pressure for 2 hours. The catalyst was removed by filtration and the filtrate was evaporated. Yield 12.8 g.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([OH:11])[CH:9]=2)[CH2:4][O:3]1.Cl[C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][N:15]=1.CN(C=O)C.Cl>[Fe]>[CH3:1][C:2]1([CH3:12])[C:10]2[CH:9]=[C:8]([O:11][C:14]3[N:15]=[CH:16][C:17]([NH2:20])=[CH:18][CH:19]=3)[CH:7]=[CH:6][C:5]=2[CH2:4][O:3]1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: CC1(C)OCc2ccc(O)cc21
Agent: [Fe]
Agent: Cl
Solvent: CN(C)C=O
Product: CC1(C)OCc2ccc(Oc3ccc(N)cn3)cc21
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 45 %

Procedure:
To a solution of 3,3-dimethyl-1H-isobenzofuran-5-ol (Intermediate 18, 30 mg, 0.18 mmol) and 2-chloro-5-nitro-pyridine (27.5 mg, 0.1736 mmol) in DMF (1 mL) dipotassium carbonate (37.8 mg, 0.2741 mmol) was added and the reaction mixture was stirred for 1.5 hours at 80° C. After cooling the reaction was quenched with water (1 ml), diluted with brine (5 ml) and extracted with ethyl acetate (2×10 ml). The organic layer was dried (Na2SO4), filtered and evaporated and the residue was dissolved in ethanol (3 mL)/water (1 mL). Iron (61.2 mg, 1.1 mmol) and an aqueous 6M solution of hydrogen chloride (0.03 ml, 0.18 mmol) were added and the reaction mixture was stirred for 4 hours at 50° C. The catalyst was filtered off and the resulting solution was diluted with a saturated solution of NaHCO3 (15 ml) and extracted with ethyl acetate (2×20 ml). The organic layer was dried (Na2SO4), filtered and evaporated and the residue was purified by flash chromatography (Biotage system) on silica gel using a SNAP 10 g as column and cyclohexane/ethyl acetate from 80:20 to 30:70 as eluent affording the title compound (20 mg) as colourless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.[Li]CCCC.Cl[Si:15]([CH3:27])([CH3:26])[C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:24]=1[CH2:23][C:22]([CH3:25])=[CH:21]2>C1COCC1>[CH3:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][Si:15]([CH3:26])([CH3:27])[C:16]2[CH:17]=[CH:18][CH:19]=[C:20]3[C:24]=2[CH2:23][C:22]([CH3:25])=[CH:21]3)=[CH:3][CH:4]=1
Reactant: CC1=Cc2cccc([Si](C)(C)Cl)c2C1
Reactant: Cc1ccc(N)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC1=Cc2cccc([Si](C)(C)Nc3ccc(C)cc3)c2C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 6.44 g (60.0 mmol) of p-toluidine in 180 mL of THF 24.0 mL (60.0 mmol) of 2.5 M nBuLi in hexanes was added at 0° C. This mixture was additionally stirred for 4 hours at room temperature, then cooled to −40° C., and a solution of 13.4 g (60.0 mmol) of chloro(dimethyl)(2-methyl-1H-inden-7-yl)silane in 50 mL of THF was added in one portion. The resulting mixture was stirred for 12 hours at room temperature and then evaporated to dryness. To the residue 100 mL of ether was added, and the obtained suspension was stirred for 20 minutes, and then filtered through glass frit (G3). The precipitate was additionally washed with 2×100 mL of ether. The combined filtrate was evaporated to dryness, and the residue was washed with 2×15 mL of cold hexanes and then dried in vacuum. Yield 11.3 g (64%) of white solid. 1H NMR (CD2Cl2): δ 7.40 (dd, J=7.3 Hz, J=1.3 Hz, 1H, 6-H in indenyl), 7.32 (dd, J=7.3 Hz, J=1.3 Hz, 1H, 4-H in indenyl), 7.26 (t, J=7.3 Hz, 1H, 5-H in indenyl), 6.88-6.91 (m, 2H, 2,6-H in p-tolyl), 6.53-6.57 (m, 2H, 3,5-H in p-tolyl), 6.52 (m, 1H, 3-H in indenyl), 3.68 (br.s, 1H, NH), 3.40 (s, 2H, 1,1′-H in indenyl), 2.20 (s, 3H, 4-Me in p-tolyl), 2.16 (m, 3H, 2-Me in indenyl), 0.57 (s, 6H, SiMe2). Anal. Calc. for C19H23NSi: C, 77.76; H, 7.90; N, 4.77%. Found: C, 77.94; H, 8.05; N, 4.94%.