Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[O:10])[CH:5]=[C:6]([Br:8])[CH:7]=1.C(N(C(C)C)CC)(C)C.[C:26](Cl)(=[O:29])[CH2:27][CH3:28].C(=O)(O)[O-].[Na+]>ClC(Cl)C>[Br:8][C:6]1[CH:7]=[C:2]([NH:1][C:26](=[O:29])[CH2:27][CH3:28])[CH:3]=[C:4]([C:9]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[O:10])[CH:5]=1
Reactant: Nc1cc(Br)cc(C(=O)c2cccnc2)c1
Reactant: CCC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(Cl)Cl
Product: CCC(=O)Nc1cc(Br)cc(C(=O)c2cccnc2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 0.20 g of (3-amino-5-bromo-phenyl)-pyridin-3-yl-methanone (0.72 mmol) in 10 mL of dichloroethane was added 0.25 mL of diisopropylethylamine and 0.065 mL of propionyl chloride. The reaction was stirred 1 h at ambient temperature, then poured into saturated aqueous sodium bicarbonate. The phases were separated and the aqueous phase was washed once with methylene chloride, dried over sodium sulfate, filtered and concentrated to give 0.24 g (quantitative yield) of N-[3-bromo-5-(pyridine-3-carbonyl)-phenyl]-propionamide.
Reaction SMILES: C(OC([NH:8][CH2:9][CH:10]1[CH2:15][CH2:14][CH:13]([CH2:16][NH:17][C:18]2[C:23]([C:24]([OH:26])=[O:25])=[CH:22][N:21]=[C:20]([NH:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[Cl:35])[N:19]=2)[CH2:12][CH2:11]1)=O)(C)(C)C.CCO.Cl.O1CCOCC1>C(Cl)(Cl)Cl>[NH2:8][CH2:9][CH:10]1[CH2:11][CH2:12][CH:13]([CH2:16][NH:17][C:18]2[C:23]([C:24]([OH:26])=[O:25])=[CH:22][N:21]=[C:20]([NH:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[Cl:35])[N:19]=2)[CH2:14][CH2:15]1
Reactant: CC(C)(C)OC(=O)NCC1CCC(CNc2nc(NCc3ccccc3Cl)ncc2C(=O)O)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: NCC1CCC(CNc2nc(NCc3ccccc3Cl)ncc2C(=O)O)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 52.9 %

Procedure:
To a solution of 4-{[4-(tert-butoxycarbonylamino-methyl)-cyclohexylmethyl]-amino}-2-(2-chloro-benzylamino)-pyrimidine-5-carboxylic acid (80 mg, 0.159 mmol) dissolved in 2:1 CHCl3:EtOH at room temperature was added 4.0 M HCl/dioxane (5.0 mL). The mixture was stirred at room temperature for 2 h then concentrated in vacuo to provide a crude white powder. The crude material was purified by preparative scale reverse phase HPLC using a 0.1% TFA-H2O/CH3CN mobile phase. The product-containing fractions were combined and concentrated in vacuo to provide 34 mg of the title compound as a white solid, 53%, m/z calculated for C20H26ClN5O2: 403.9, found: 404.4 (M+H)+.
Reaction SMILES: [H-].[Na+].C(O[C:6](=[O:22])[CH2:7][N:8]=[C:9]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)C.Br.[NH2:24][C:25]1[C:30]([CH2:31]Br)=[CH:29][C:28]([Br:33])=[CH:27][N:26]=1>CN(C=O)C>[C:9](=[N:8][CH:7]1[CH2:31][C:30]2[C:25](=[N:26][CH:27]=[C:28]([Br:33])[CH:29]=2)[NH:24][C:6]1=[O:22])([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CCOC(=O)CN=C(c1ccccc1)c1ccccc1
Reactant: Nc1ncc(Br)cc1CBr
Agent: Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1Nc2ncc(Br)cc2CC1N=C(c1ccccc1)c1ccccc1
Temperature: 0 °C
Yield: 55.9 %

Procedure:
NaH (60% dispersion in mineral oil, 1.2 g, 30 mmole) was added portionwise over 10 min to a solution of N-(diphenylmethylene)glycine ethyl ester (8.0 g, 30 mmole) in DMF (150 mL) with stirring under Ar at 0° C. The reaction was stirred for 15 min, then 2-amino-5-bromo-3-(bromomethyl)pyridine hydrobromide (5.0 g, 14.4 mmole) was added in one portion. The reaction was allowed to warm to RT and stir for 18 h, then was concentrated under vacuum. The remaining residue was taken up in EtOAc (150 mL), hexane (150 mL), and H2O (150 mL). The resulting suspension was triturated and filtered, and the solid was dried under vacuum to give the title compound (3.27 g, 56%) as an off-white solid: 1H NMR (400 MHz, d6-DMSO) δ 10.92 (s, 1 H), 8.23 (s, 1 H), 7.86 (s, 1 H), 7.26-7.55 (m, 10H), 4.05 (dd, 1 H), 3.10 (t, 2 H); MS (ES) m/e 406.0 (M+H)+.
Reaction SMILES: [C:1]1([NH:7][CH2:8][CH2:9][NH:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH:19]([CH2:23]Br)[C:20]([NH2:22])=[O:21].C(N(CC)CC)C.[OH-].[Na+]>C(OCC)C.CN(C)C=O>[C:1]1([N:7]2[CH2:8][CH2:9][N:10]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:19]([C:20]([NH2:22])=[O:21])[CH2:23]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NC(=O)C(Br)CBr
Reactant: c1ccc(CNCCNc2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: NC(=O)C1CN(c2ccccc2)CCN1Cc1ccccc1
Temperature: 110 °C

Procedure:
To dimethylformamide (300 mL) add N-phenyl-N'-phenylmethyl-1,2-ethanediamine (83 g, 0.37 mol), 2,3-dibromopropanamide (90 g, 0.39 mol) and triethylamine (41 g, 0.40 mol). Heat the resulting mixture at 110° C. and follow the progress of the reaction by thin-layer chromatography. Upon completion of the reaction add 1N NaOH until basic and add ethyl ether. Filter the precipitate that forms and recrystallize from 2-propanol to obtain the title compound.
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([C:21]3[NH:25][C:24]([C:26]4[S:27][C:28]([CH2:31][CH2:32][C:33]([O:35]CC)=[O:34])=[CH:29][N:30]=4)=[CH:23][CH:22]=3)[CH2:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[OH-].[Na+].Cl.[Cl-].[Ca+2].[Cl-]>O.CO.O1CCCC1>[CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([C:21]3[NH:25][C:24]([C:26]4[S:27][C:28]([CH2:31][CH2:32][C:33]([OH:35])=[O:34])=[CH:29][N:30]=4)=[CH:23][CH:22]=3)[CH2:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:9][CH:8]=2)(=[O:5])=[O:6])[CH2:3][CH2:2]1
Reactant: CCOC(=O)CCc1cnc(-c2ccc(C(CC3CCOCC3)c3ccc(S(=O)(=O)C4CC4)cc3)[nH]2)s1
Agent: Cl
Agent: [Ca+2]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)CCc1cnc(-c2ccc(C(CC3CCOCC3)c3ccc(S(=O)(=O)C4CC4)cc3)[nH]2)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.9 %

Procedure:
A mixture of ethyl 3-[2-(5-{1-[4-(cyclopropylsulfonyl)phenyl]-2-(tetrahydro-2H-pyran-4-yl)ethyl}-1H-pyrrol-2-yl)-1,3-thiazol-5-yl]propanoate (0.46 g), 1M aqueous sodium hydroxide solution (1.7 mL), methanol (3 mL) and tetrahydrofuran (6 mL) was stirred at room temperature overnight. To the reaction mixture was added 1M hydrochloric acid (1.7 mL), and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated to give a yellow amorphous solid. To a mixture of the obtained amorphous solid, 1M aqueous sodium hydroxide solution (1.0 mL), methanol (1 mL) and water (10 mL) was added a solution of calcium chloride (94 mg) in water (2 ml). The precipitated solid was collected by filtration, washed with water, and dried to give the title compound (0.34 g) as yellow crystals. melting point>194° C. (decomposition). MS: 515 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)=[CH:16][CH:15]=1)=[C:8](OS(C(F)(F)F)(=O)=O)[CH:7]=[CH:6]2.[F:37][C:38]1[CH:43]=[CH:42][CH:41]=[C:40]([F:44])[C:39]=1B(O)O.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C(#N)C.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>[F:37][C:38]1[CH:43]=[CH:42][CH:41]=[C:40]([F:44])[C:39]=1[C:8]1[CH:7]=[CH:6][C:5]2[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[C:9]=1[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[CH:16][CH:15]=1
Reactant: OB(O)c1c(F)cccc1F
Reactant: COc1ccc2c(Cc3ccc(OCCN4CCCCC4)cc3)c(OS(=O)(=O)C(F)(F)F)ccc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc2c(Cc3ccc(OCCN4CCCCC4)cc3)c(-c3c(F)cccc3F)ccc2c1
Temperature: 80 °C
Yield: 57.4 %

Procedure:
Dissolve trifluoromethanesulfonic acid 6-methoxy-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-naphthalen-2-yl ester (1.50 g, 2.86 mmol) in 50 mL of acetonitrile and add 2,6-difluorophenyl boronic acid (0.90 g, 5.73 mmol), tetrakis(triphenylphosphine)palladium(0) (0.66 g, 0.57 mmol). Next add potassium phosphate (3.64 g, 17.16 mmol) and heat to 80° C. for one hour. Add Celite and filter. Concentrate the solvent under vacuum to a dark oil, dissolve in methanol and purify on an SCX cartridge, eluting with 2N ammonia/methanol. Purify further on a silica gel column eluting with a 0-10% methanol/methylene chloride gradient. Evaporate the solvent to yield 800 mg (58%) of the title compound.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:15]=[CH:14][C:13]2[N:12]3[CH2:16][CH2:17][CH2:18][C:11]3=[CH:10][C:9]=2[CH:8]=1.C([O:22]B(OC(C)C)OC(C)C)(C)C.C(O)(=O)C.OO>CCCCCC.O1CCCC1.C(OCC)C.O>[CH2:18]1[C:11]2=[CH:10][C:9]3[CH:8]=[C:7]([OH:22])[CH:15]=[CH:14][C:13]=3[N:12]2[CH2:16][CH2:17]1
Reactant: Brc1ccc2c(c1)cc1n2CCC1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: OO
Agent: [Li]CCCC
Solvent: CC(=O)O
Solvent: O
Solvent: CCCCCC
Product: Oc1ccc2c(c1)cc1n2CCC1
Temperature: -50 °C
Reaction time: 0.75 h
Yield: 94 %

Procedure:
187.5 mL of a 1.6M solution of n-butyllithium (0.30 mol) in n-hexane was added over 20 min to a cooled (−78° C.) solution of 47.2 g 6-bromo-2,3-dihydro-1H-3a-aza-cyclopenta[a]indene (0.20 mol) in 800 mL tetrahydrofuran. The resulting beige suspension was warmed to −50° C. and stirred at this temperature for 45 min. The mixture was cooled to −78° C., and 92.0 mL (0.40 mol) triisoproyl-borate was added over 10 min. The mixture was stirred 30 min at −78° C. and allowed to warm to 0° C. over 30 min. The slightly turbid mixture was stirred at 0-10° C. for 15 min and 100 mL (0.875 mol) 50% acetic acid were added dropwise. To the resulting solution were added over 15 min 30 mL of a 35% hydrogen peroxide solution (0.31 mol) at a temperature of 0-5° C. The mixture was stirred at 0° C. for 30 min and at room temperature for 1 h. The reaction mixture was diluted with 2500 mL diethyl ether and 1000 mL water. The phases were separated and the organic phase was washed with 1000 mL water, twice with 1000 mL 5% sodium thiosulfate, again with 1000 mL water and finally with 1000 mL brine, dried over sodium sulfate and concentrated under aspirator vacuum. The solid residue was stirred with 500 mL n-hexane for 1 h. The product was collected by filtration and dried to constant weight under aspirator vacuum at room temperature to yield 32.56 g (94%) of the title compound as beige crystals melting at 116-118° C.
Reaction SMILES: [CH:1]1([N:7]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[C:8]([NH:10][C:11]2[S:12][CH:13]=[C:14]([CH:16]=[N:17][OH:18])[N:15]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:25][S:26](Cl)(=[O:28])=[O:27].CCN(C(C)C)C(C)C>C(Cl)Cl>[CH:19]1([N:7]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[C:8]([NH:10][C:11]2[S:12][CH:13]=[C:14]([C:16]([S:26]([CH3:25])(=[O:28])=[O:27])=[N:17][OH:18])[N:15]=2)=[O:9])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: CS(=O)(=O)Cl
Reactant: O=C(Nc1nc(C=NO)cs1)N(C1CCCCC1)C1CCCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)C(=NO)c1csc(NC(=O)N(C2CCCCC2)C2CCCCC2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 30 %

Procedure:
To a solution of 1,1-dicyclohexyl-3-[4-(hydroxyimino-methyl)-thiazol-2-yl]-urea (0.15 mmol) in DCM (4 mL) was added methansulfonyl chloride (0.15 mmol) and DIEA (0.15 mL). The mixture was stirred at rt for 2 h and quenched with water (10 mL). The reaction mixture was extracted with ethyl acetate (3×10 mL). The combined organic extracts was washed with water (2×30 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by flash chromatography (silica, EtOAc/hexanes 1:4 to EtOAc/hexanes 1:1) to give the desired product in 30% yield.
Reaction SMILES: [CH:1]1([C:7]2[CH:31]=[CH:30][CH:29]=[C:28]3[C:8]=2[CH:9]=[C:10]2[C:16]4[CH:17]=[C:18]([C:21]([O:23]C)=[O:22])[CH:19]=[CH:20][C:15]=4[N:14]4[CH2:25][CH:26]=[N:27][C:13]4=[CH:12][N:11]23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].Cl>C1COCC1.CO>[CH:1]1([C:7]2[CH:31]=[CH:30][CH:29]=[C:28]3[C:8]=2[CH:9]=[C:10]2[C:16]4[CH:17]=[C:18]([C:21]([OH:23])=[O:22])[CH:19]=[CH:20][C:15]=4[N:14]4[CH2:25][CH:26]=[N:27][C:13]4=[CH:12][N:11]23)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)c1ccc2c(c1)-c1cc3c(C4CCCCC4)cccc3n1C=C1N=CCN12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccc2c(c1)-c1cc3c(C4CCCCC4)cccc3n1C=C1N=CCN12
Temperature: 70 °C
Yield: 144.6 %

Procedure:
To a solution of methyl 10-cyclohexyl-4H-imidazo[1,2-a]indolo[1,2-d][1,4]benzodiazepine-7-carboxylate (34 mg, 0.083 mmol) in THF (1.5 mL) and MeOH (1 mL), was added aq NaOH (1.0N, 0.4 mL, 0.4 mmol). The reaction mixture was heated at 70° C. for 2 h, cooled to rt, neutralized with aq HCl (1.0N, 0.4 mL) and concentrated to dryness. The solid residue was dissolved into MeOH, filtered, concentrated and dried under N2 to yield 10-cyclohexyl-4H-imidazo[1,2-a]indolo[1,2-d][1,4]benzodiazepine-7-carboxylic acid (47 mg, 0.12 mmol) as an off-white solid which was used without further purification. 1H NMR (500 MHz, d6-DMSO) δ 1.04-1.22 (m, 1H), 1.32-1.50 (m, 3H), 1.61-1.77 (m, 2H), 1.84-2.15 (m, 4H), 2.74-2.90 (m, 1H), 5.05 (d, J=15.7 Hz, 1H), 6.00 (d, J=15.7 Hz, 1H), 7.31 (s, 1H), 7.63-7.85 (m, 5H), 7.91-7.99 (m, 2H), 8.37 (s, 1H). LCMS: m/e 398 (M+H)+, ret time 1.87 min.
Reaction SMILES: [Si:1]([O:8]S(C(F)(F)F)(=O)=O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Br:16][C:17]1[CH:22]=[CH:21][C:20]([CH:23](O)[CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:19][CH:18]=1.N1C(C)=CC=CC=1C.C(=O)(O)[O-].[Na+]>ClCCl>[Br:16][C:17]1[CH:22]=[CH:21][C:20]([CH:23]([O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:19][CH:18]=1
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: CCCCCC(O)c1ccc(Br)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CCCCCC(O[Si](C)(C)C(C)(C)C)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.4 %

Procedure:
TBSOTf (2.9 mL, 12.6 mmol) was added to an ice-cold solution of 4 (3.017 g, 11.7 mmol) and 2,6-lutidine (1.6 mL, 13.7 mmol) in dichloromethane (30 mL). The reaction was stirred for 2 h at room temperature and then 100 mL saturated sodium bicarbonate solution was added. The resulting mixture was extracted with dichloromethane (30 mL) and the dichloromethane layer was washed with 1 M HCl (2×50 mL) and brine (50 mL). The dichloromethane solution was then dried (MgSO4), filtered and evaporated. Purification of the residue by flash chromatography on silica gel (hexanes) gave compound 5 (3.843 g, 88%).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C@H:10]([N:13]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[C:26]([Cl:31])[CH:25]=2)[C:14]2[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=2)[CH2:9]1)=O)(C)(C)C.Cl.C(OCC)(=O)C>>[ClH:31].[Cl:31][C:26]1[CH:25]=[C:24]([N:13]([C:14]2[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=2)[C@H:10]2[CH2:11][CH2:12][NH:8][CH2:9]2)[CH:29]=[CH:28][C:27]=1[F:30]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N(c2ccc(S(C)(=O)=O)cc2)c2ccc(F)c(Cl)c2)C1
Agent: Cl
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1ccc(N(c2ccc(F)c(Cl)c2)[C@H]2CCNC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 191.9 %

Procedure:
3(S)-[(3-chloro-4-fluorophenyl)-(4-methanesulfonylphenyl)amino]pyrrolidine-1-carboxylic acid tert-butyl ester (0.42 g, 0.9 mmol) was added to 4 N hydrochloric acid/ethyl acetate, followed by stirring at room temperature for one hour. The reaction solution was concentrated to dryness under reduced pressure to thereby obtain 0.35 g of white powdery (3-chloro-4-fluorophenyl)-(4-methanesulfonylphenyl)-(S)-pyrrolidin-3-ylamine hydrochloride.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5]([C:8]#[N:9])=[N:6][CH:7]=1.[CH2:10]1COC[CH2:11]1.C([Mg]Br)C.B(F)(F)F>CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-].O>[F:1][C:2]1[CH:3]=[N:4][C:5]([C:8]2([NH2:9])[CH2:11][CH2:10]2)=[N:6][CH:7]=1
Reactant: N#Cc1ncc(F)cn1
Reactant: C1CCOC1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: CC[Mg]Br
Solvent: O
Product: NC1(c2ncc(F)cn2)CC1
Reaction time: 0.25 h

Procedure:
To a solution of 5-fluoropyrimidine-2-carbonitrile (200 mg, 1.6 mmol, 1 eq) in a dry THF under an argon atmosphere was added titanium isopropoxide (0.55 ml, 1.9 mmol, 1.2 eq) at ambient temperature and the reaction mixture was stirred for 15 min. Ethyl magnesium bromide (1M solution) in THF (4 ml, 4.0 mmol, 2.5 eq) was added via syringe slowly at ambient temperature. Then the reaction mixture was stirred for an hour. BF3.EtO (0.34 ml, 2.4 mmol, 1.5 eq) was added slowly through syringe to the mixture at 0° C. The mixture was allowed to attain ambient temperature and stirred for another one hour. 10 ml of water was added to the reaction mixture which was then filtered through Celite and the bed washed with water and ethyl acetate. The filtrate was basified with 10% NaOH solution (pH=9) then extracted with DCM and washed with brine solution, dried over sodium sulphate and concentrated to give the crude product which was taken for coupling reaction without further purification. Yield: 125 mg (crude).
Reaction SMILES: N(C(OC(C)C)=O)=NC(OC(C)C)=O.[OH:15][C:16]1[CH:21]=[CH:20][C:19]([C@@H:22]2[O:27][CH2:26][CH2:25][N:24]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:23]2)=[CH:18][CH:17]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:54][CH2:55][CH2:56][CH2:57]O>O1CCCC1>[Br:54][CH2:55][CH2:56][CH2:57][O:15][C:16]1[CH:21]=[CH:20][C:19]([C@@H:22]2[O:27][CH2:26][CH2:25][N:24]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:23]2)=[CH:18][CH:17]=1
Reactant: OCCCBr
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(O)cc2)C1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(OCCCBr)cc2)C1
Temperature: 25 °C
Reaction time: 10 h
Yield: 99.9 %

Procedure:
Diisopropyl azodicarboxylate (40% in toluene, 13.6 g, 26.9 mmol) was added to a solution of tert-butyl (2S)-2-(4-hydroxyphenyl)morpholine-4-carboxylate (5.0 g, 17.9 mmol), triphenylphosphine (7.1 g, 27.1 mmol) and 3-bromopropanol (3.75 g, 27.0 mmol) in tetrahydrofuran (100 ml) and the solution was stirred for 10 hours at room temperature. The mixture was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography eluting 5-10% methanol in chloroform to furnish tert-butyl (2S)-2-(4-(3-bromopropyloxy)phenyl)morpholine-4-carboxylate (7.16 g, 100%) as a colorless oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][SH:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:12]([CH:14]1[O:16][CH2:15]1)[Cl:13].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][S:11][CH2:15][CH:14]([OH:16])[CH2:12][Cl:13])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: ClCC1CO1
Reactant: CC(C)(C)OC(=O)NCCS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CC(C)(C)OC(=O)NCCSCC(O)CCl
Temperature: 25 °C
Yield: 102.3 %

Procedure:
N-(t-butyloxycarbonyl)-aminoethanethiol (40 g, 225 mmole) from Example 2, and epichlorohydrin (35.4 g, 383 mmole) in 300 mL of ethanol were cooled to 0° C. and treated with potassium carbonate (35.4 g). The reaction was warmed to room temperature over 90 minutes and filtered through celite. The volatiles were removed under reduced pressure to give a clear oil (62.09 g, 100% yield) D.C.I.M.S. 270(M+H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH2:10][C@H:9]1[CH2:12][O:13][C:14]1[CH:15]=[C:16]([C:20]#[C:21][C:22]2[CH:23]=[C:24]([CH2:28][OH:29])[CH:25]=[CH:26][CH:27]=2)[CH:17]=[N:18][CH:19]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCOC(C)=O.CCCCCC>CCOC(C)=O.O=[Pt]=O>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH2:10][C@H:9]1[CH2:12][O:13][C:14]1[CH:15]=[C:16]([CH2:20][CH2:21][C:22]2[CH:23]=[C:24]([CH2:28][OH:29])[CH:25]=[CH:26][CH:27]=2)[CH:17]=[N:18][CH:19]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1COc1cncc(C#Cc2cccc(CO)c2)c1
Agent: O=[Pt]=O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)N1CC[C@H]1COc1cncc(CCc2cccc(CO)c2)c1
Temperature: 25 °C
Reaction time: 6.25 h

Procedure:
In a 50 mL round-bottom flask, a solution of 3-[[5-[[1-(tert-butoxycarbonyl)-(2S)-azetidinyl]methoxy]-3-pyridyl]ethynyl]phenylmethanol in EtOAc was hydrogenated over PtO2 with stirring at room temperature for 6.25 h. TLC (silica gel, EtOAc/hexane 3:1) showed a new spot (Rf 0.15) in place of the starting material (Rf 0.3), which was accompanied by a nonpolar impurity. The solution was concentrated and filtered over silica gel (11×1.3 cm, EtOAc). Evaporation of the product-containing fractions gave a quantitative yield of crude product, which by 1H NMR was shown to be a mixture of two major components in a molar ratio of approx. 4.5-5:1.
Reaction SMILES: C(OC([N:8]([CH2:27][CH2:28][CH3:29])[CH:9]1[CH2:18][C:17]2[C:12](=[CH:13][C:14]([O:19][S:20]([C:23]([F:26])([F:25])[F:24])(=[O:22])=[O:21])=[CH:15][CH:16]=2)[O:11][CH2:10]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH2:27]([NH:8][CH:9]1[CH2:18][C:17]2[C:12](=[CH:13][C:14]([O:19][S:20]([C:23]([F:25])([F:26])[F:24])(=[O:22])=[O:21])=[CH:15][CH:16]=2)[O:11][CH2:10]1)[CH2:28][CH3:29]
Reactant: CCCN(C(=O)OC(C)(C)C)C1COc2cc(OS(=O)(=O)C(F)(F)F)ccc2C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCNC1COc2cc(OS(=O)(=O)C(F)(F)F)ccc2C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Trifluoro-methanesulfonic acid 3-(tert-butoxycarbonyl-propyl-amino)-chroman-7-yl ester (2.1 g, 4.78 mmol) was dissolved in dichloromethane (30 ml). Trifluoroacetic acid (3 ml) was added and the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was evaporated to dryness. Dichloromethane was added (twice) and the reaction mixture was evaporated to dryness to give the product (2.6 g, 65% purity).
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:14]=[CH:13][C:11](N)=[CH:10][CH:9]=2)[CH:6]=[CH:5]C=CC=1.[Cl-].[In+3].[Cl-].[Cl-]>O>[NH:7]1[C:8]2[C:9](=[CH:10][CH:11]=[CH:13][CH:14]=2)[CH2:5][CH2:6][CH2:1]1
Reactant: Nc1ccc(Nc2ccccc2)cc1
Agent: [Cl-]
Agent: [In+3]
Solvent: O
Product: c1ccc2c(c1)CCCN2
Temperature: 25 °C
Reaction time: 10 h
Yield: 65 %

Procedure:
The mixture of 4-(N-phenylamino)-aniline (2 mmol), 2,3-dihrdrofuran (4 mmol) and indium chloride (0.2-0.4 mmol) in water was stirred at room temperature for 10 h. TLC showed the completion of the reaction. The reaction mixture was extracted with diethyl ether (3×20 ml) and drived over MgSO4. Removal of solvent and flash column chromatography on silica gel gave the 1,2,3,4-tetrahydroquinoline derivative 3-1 in 65% yield (cis/trans=86:14). IR (film): 3326, 2932, 1595, 1504, 1047 cm−1. 1HNMR and —13CNMR(DMSO-d6/TMS): cis-isomer, 7.53(s, 1H, NH), 7.08(m, 2H, Ar—H), 6.85(s, 1H, Ar—H), 6.76(m, 3H, Ar—H), 6.58(m, 2H, Ar—H), 5.09(s, 1H, NH), 4.92(d, 9b-H, J=8.0 Hz), 4.50(t, 1H, OH, J=4.8 Hz), 3.60(m, 2H), 3.30(m, 2H), 3.23(m, 1H), 2.48(m, 1H), 1.35-1.85(m, 6H). 146.77, 141.62, 133.52, 129.66, 123.36, 122.18, 121.69, 118.01, 115.69, 114.66, 75.75, 66.39, 61.52, 52.58, 42.35, 31.03, 29.42, 24.21. trans-isomer, 7.60(s, 1H, NH), 7.08(m, 2H, Ar—H), 6.91(s, 1H, Ar—H), 6.76(m, 3H, Ar—H), 6.58(m, 2H, Ar—H), 5.42(s, 1H, NH), 4.50(t, 1H, OH, J=4.8 Hz), 4.35(d, 9b-H, J=6.0 Hz), 3.75(m, 2H), 3.60(m, 2H), 3.30(m, 2H), 3.55(m, 1H), 2.24(m, 1H), 1.35-1.85(m, 5H). 146.94, 141.75, 132.65, 129.66, 123.46, 122.59, 121.00, 118.01, 115.69, 114.58, 79.81, 65.39, 61.69, 52.34, 41.41, 30.10, 29.53, 29.07. Anal. Calcd. For C20H24N2O2: C, 74.05; H, 7.46; N, 8.63. Found: C, 73.84; H, 7.81; N, 8.56.