Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7]([S:12]([N:15]([CH2:26][CH2:27][S:28]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)(=[O:30])=[O:29])[CH2:16][CH2:17][NH:18]C(OC(C)(C)C)=O)(=[O:14])=[O:13])[CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[ClH:37].CO>C(OCC)C>[ClH:37].[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([S:12]([N:15]([CH2:26][CH2:27][S:28]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)(=[O:30])=[O:29])[CH2:16][CH2:17][NH2:18])(=[O:13])=[O:14])[CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)NCCN(CCS(=O)(=O)c1ccccc1)S(=O)(=O)c1cccc2c(N)nccc12
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: NCCN(CCS(=O)(=O)c1ccccc1)S(=O)(=O)c1cccc2c(N)nccc12
Temperature: 25 °C

Procedure:
According to the method of Example 1, Step C, deprotection was performed (50° C., 2 hours) by using Intermediate 17 (134 mg) and 10% hydrogen chloride/methanol solution (2.5 ml). The reaction mixture was cooled to room temperature and then added with diethyl ether (2.5 ml). The deposited precipitates were collected by filtration and washed with diethyl ether to obtain the title compound (100 mg) as white powdery solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[C:4]([CH3:9])[CH:3]=1.FC(F)(F)S(O[CH2:16][C:17]([F:20])([F:19])[CH3:18])(=O)=O>>[Cl:1][C:2]1[CH:3]=[C:4]([CH3:9])[C:5]([O:8][CH2:16][C:17]([F:20])([F:19])[CH3:18])=[CH:6][N:7]=1
Reactant: CC(F)(F)COS(=O)(=O)C(F)(F)F
Reactant: Cc1cc(Cl)ncc1O
Product: Cc1cc(Cl)ncc1OCC(C)(F)F
Yield: 98 %

Procedure:
The title compound is prepared in 98% yield (4.52 g, pale yellow oil) from 6-chloro-4-methylpyridin-3-ol (3.00 g, 20.9 mmol) and 2,2-difluoropropyl trifluoromethanesulfonate (11.9 g, 52.2 mmol) in a similar manner to Step-1 of Amine-49.
Reaction SMILES: C(O[C:6]([NH:8][C@@H:9]([CH2:13][C:14]1[N:15]=[CH:16][NH:17][CH:18]=1)[C:10](O)=[O:11])=O)(C)(C)C.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[NH:17]1[CH:18]=[C:14]([CH2:13][C@H:9]([NH:8][CH3:6])[CH2:10][OH:11])[N:15]=[CH:16]1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1c[nH]cn1)C(=O)O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN[C@H](CO)Cc1c[nH]cn1
Temperature: 2.5 °C
Reaction time: 0.5 h
Yield: 65.7 %

Procedure:
To a solution of (S)-2-(tert-butoxycarbonylamino)-3-(1H-imidazol-4-yl)propanoic acid (1.0 g, 3.92 mmol) in THF (20 mL) was added LAH (2 M, 10 mL, 20 mmol) at 0-5° C. The reaction mixture was stirred at 0-5° C. for 30 min and heat to reflux for 2 h. The reaction mixture was cooled to 0-5° C. and quenched with water (0.8 mL), NaOH (0.8 mL), and water (2.4 mL). The resulting suspension was stirred RT for 30 min and filtered. The filtrate was concentrated to give (S)-3-(1H-imidazol-4-yl)-2-(methylamino)propan-1-ol (400 mg, crude), which was used without further purification. LRMS (M−Boc+H+) m/z 156.1.
Reaction SMILES: IC.[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([C:18]2[CH:19]=[C:20]3[C:25](=[CH:26][CH:27]=2)[N:24]2[N:28]=[N:29][N:30]=[C:23]2[CH:22]=[C:21]3[C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([Cl:37])[CH:32]=2)[C:11]2[N:12]([CH3:17])[C:13]([SH:16])=[N:14][N:15]=2)=[CH:6][CH:5]=1.[CH3:38]O[Na].CO.O>CO>[Cl:37][C:33]1[CH:32]=[C:31]([C:21]2[C:20]3[C:25](=[CH:26][CH:27]=[C:18]([CH:10]([C:7]4[CH:8]=[CH:9][C:4]([Cl:3])=[CH:5][CH:6]=4)[C:11]4[N:12]([CH3:17])[C:13]([S:16][CH3:38])=[N:14][N:15]=4)[CH:19]=3)[N:24]3[N:28]=[N:29][N:30]=[C:23]3[CH:22]=2)[CH:36]=[CH:35][CH:34]=1
Reactant: CO[Na]
Reactant: Cn1c(S)nnc1C(c1ccc(Cl)cc1)c1ccc2c(c1)c(-c1cccc(Cl)c1)cc1nnnn12
Solvent: CO
Solvent: CI
Solvent: O
Product: CSc1nnc(C(c2ccc(Cl)cc2)c2ccc3c(c2)c(-c2cccc(Cl)c2)cc2nnnn23)n1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 98 %

Procedure:
Iodomethane (0.0092 mol) was added to a mixture of intermediate (62) (0.0092 mol) and MeONa/MeOH (0.0092 mol) in methanol (50 ml). The mixture was stirred at room temperature overnight and poured out into water. The precipitate was filtered washed with diethyl ether and dried, yielding 4.8 g (98%) of 5-(3-chlorophenyl)-7-[(4-chlorophenyl)[4-methyl-5-(methylthio)-4H-1,2,4triazol-3-yl]methyl]-tetrazolo[1,5-a]quinoline, MS (ESI) m/z:532, 534, 536 (MH+) (intermediate 63).
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][CH:7]=[CH:8][C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]([CH3:18])[C:10]=1[C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1)([OH:3])=[O:2]>C(O)C.[Pd]>[CH3:18][N:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]([CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:1]([OH:3])=[O:2])=[C:10]1[C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1
Reactant: Cn1c(-c2cccnc2)c(C=CCCCC(=O)O)c2ccccc21
Agent: [Pd]
Solvent: CCO
Product: Cn1c(-c2cccnc2)c(CCCCCC(=O)O)c2ccccc21
Reaction time: 2 h

Procedure:
A solution of 3-(5-carboxypent-1-enyl)-1-methyl-2-(3-pyridyl)indole (0.51 g) in absolute ethanol (20 ml), to which is added 10% Pd/C (0.05 g), is hydrogenated at 3 atmospheres pressure for 2 hours. The catalyst is removed by filtration and the filtrate concentrated to dryness. Trituration of the residue with absolute ethanol gives a while solid, m.p. 117°-120°. Recrystallization from acetonitrile yields 1-methyl-2-(3-pyridyl)-3-(5-carboxypentyl)indole (the compound of Example 3), m.p. 128°-130°.
Reaction SMILES: [O-]P([O-])([O-])=O.[K+].[K+].[K+].Br[C:10]1[CH:11]=[C:12]([C:16]2[N:20]([CH3:21])[N:19]=[C:18]([C:22]([N:24]3[CH2:28][CH2:27][CH:26]([N:29]([CH2:32][CH3:33])[CH2:30][CH3:31])[CH2:25]3)=[O:23])[C:17]=2[CH3:34])[CH:13]=[CH:14][CH:15]=1.[Cl:35][C:36]1[CH:41]=[CH:40][C:39](B(O)O)=[CH:38][CH:37]=1>>[Cl:35][C:36]1[CH:41]=[CH:40][C:39]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]3[N:20]([CH3:21])[N:19]=[C:18]([C:22]([N:24]4[CH2:28][CH2:27][CH:26]([N:29]([CH2:30][CH3:31])[CH2:32][CH3:33])[CH2:25]4)=[O:23])[C:17]=3[CH3:34])[CH:11]=2)=[CH:38][CH:37]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: CCN(CC)C1CCN(C(=O)c2nn(C)c(-c3cccc(Br)c3)c2C)C1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: CCN(CC)C1CCN(C(=O)c2nn(C)c(-c3cccc(-c4ccc(Cl)cc4)c3)c2C)C1
Yield: 39 %

Procedure:
In analogy to the procedure described in example 14C] but with 2.8 eq of K3PO4, [5-(3-bromo-phenyl)-1,4-dimethyl-1H-pyrazol-3-yl]-(3-diethylamino-pyrrolidin-1-yl)-methanone and 4-chlorophenylboronic acid gave [5-(4′-chloro-biphenyl-3-yl)-1,4-dimethyl-1H-pyrazol-3-yl]-(3-diethylamino-pyrrolidin-1-yl)-methanone in 39% yield as light brown foam. MS: 451.3 (MH+, 1 Cl).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9]CC2C=CC(OC)=CC=2)[C:4]=1[C:19]1[NH:23][N:22]=[C:21]([NH:24][C:25]2[N:26]=[CH:27][C:28]([C:31]#[N:32])=[N:29][CH:30]=2)[CH:20]=1.Cl.CCCC(C)C>O1CCOCC1.O1CCCC1>[OH:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[C:4]=1[C:19]1[NH:23][N:22]=[C:21]([NH:24][C:25]2[N:26]=[CH:27][C:28]([C:31]#[N:32])=[N:29][CH:30]=2)[CH:20]=1
Reactant: COc1ccc(COc2cccc(OC)c2-c2cc(Nc3cnc(C#N)cn3)n[nH]2)cc1
Agent: Cl
Solvent: CCCC(C)C
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: COc1cccc(O)c1-c1cc(Nc2cnc(C#N)cn2)n[nH]1
Temperature: 62.5 °C
Reaction time: 1.5 h

Procedure:
A 10 L flange-neck flask equipped with an air stirrer rod and paddle, thermometer, water condenser, and outlet to caustic solution gas scrubbers is charged with 5-(5-(2-methoxy-6-(4-methoxybenzyloxy)phenyl)-1H-pyrazol-3-ylamino)pyrazine-2-carbonitrile (140 g, 326.76 mmol) and 4 N hydrogen chloride (2500 mL, 10.0 mole) solution in 1,4-dioxane. The mixture is well stirred at 60-65° C. for 1.5 h, then the mixture is allowed to cool to 50° C. After a total of 4 h, more 4 N hydrogen chloride in 1,4-dioxane is added (1000 mL) and heating to 65° C. resumed. After one hour at this temperature the heating is stopped and the mixture allowed to cool to room temperature overnight with stirring. The mixture is filtered through a large sintered funnel The solid collected is washed with fresh 1,4-dioxane and then pulled dry briefly. The bulk filter cake is returned to the 10 L flask and vigorously stirred with water (2 L) and ethyl acetate (3.5 L). The mixture is then made alkaline by adding concentrated ammonia (440 mL). The solution is filtered and then transferred to a 5 L separatory funnel The aqueous layer is separated and extracted again with ethyl acetate (0.5 L). The combined organic layers are washed with brine, dried over sodium sulfate, filtered, and concentrated. The solid is dried in vacuo at 45° C. to give 101.3 g. The crude product is suspended in warm anhydrous tetrahydrofuran (2.2 L) and loaded onto a pad of silica (1 kg) wet packed using iso-hexane. The product is eluted with ethyl acetate. The combined fractions are partially concentrated and the resulting precipitate is collected by filtration and dried in vacuo at 40° C. overnight to give 60.9 g. LC-ES/MS m/z 309.2 [M+1]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:28])[NH:8][C:9]2[C:13]([C:14]=1[N:15]1[CH2:20][CH2:19][N:18]([C:21]([C:23]3[S:24][CH:25]=[CH:26][CH:27]=3)=[O:22])[CH2:17][CH2:16]1)=[CH:12][S:11][CH:10]=2)=[O:5])[CH3:2].[F:29][C:30]1[CH:37]=[CH:36][C:33]([CH2:34]Br)=[CH:32][CH:31]=1>>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:28])[N:8]([CH2:34][C:33]2[CH:36]=[CH:37][C:30]([F:29])=[CH:31][CH:32]=2)[C:9]2[C:13]([C:14]=1[N:15]1[CH2:16][CH2:17][N:18]([C:21]([C:23]3[S:24][CH:25]=[CH:26][CH:27]=3)=[O:22])[CH2:19][CH2:20]1)=[CH:12][S:11][CH:10]=2)=[O:5])[CH3:2]
Reactant: Fc1ccc(CBr)cc1
Reactant: CCOC(=O)c1c(N2CCN(C(=O)c3cccs3)CC2)c2cscc2[nH]c1=O
Product: CCOC(=O)c1c(N2CCN(C(=O)c3cccs3)CC2)c2cscc2n(Cc2ccc(F)cc2)c1=O
Yield: 54 %

Procedure:
The compound was prepared from 5-oxo-7-[4-(thiophene-2-carbonyl)-piperazin-1-yl]-4,5-dihydro-2-thia-4-aza-indene-6-carboxylic acid ethyl ester (40) and 4-fluorobenzylbromide by applying general procedure A. Yield 54%; MP 227° C. 1H NMR (400 MHz, DMSO-d6) δ 1.27 (t, J=7.2 Hz, 3H), 3.30 (m, 4H), 3.83 (m, 4H), 4.27 (q, J=7.2 Hz, 2H), 5.18 (s, 2H), 7.14-7.17 (m, 3H), 7.20 (d, J=3.2 Hz, 1H), 7.33 (m, 2H), 7.46 (dd, J=1.2, 4.8 Hz, 1H), 7.80 (dd, J=1.2, 4.8 Hz, 1H), 8.13 (d, J=3.2 Hz, 1H) ppm; MS m/z=526 amu (M++1). Anal. (C26H24FN3O4S2) C, H, N.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[F:9][CH:10]([F:28])[O:11][C:12]1[CH:13]=[CH:14][C:15]2[N:16]([N:18]=[C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=3)[CH:20]=2)[N:17]=1.C(=O)(O)[O-].[Na+]>CN(C=O)C.C(OCC)(=O)C>[Br:1][C:20]1[C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=2)=[N:18][N:16]2[C:15]=1[CH:14]=[CH:13][C:12]([O:11][CH:10]([F:9])[F:28])=[N:17]2
Reactant: O=C1CCC(=O)N1Br
Reactant: Fc1cccc(-c2cc3ccc(OC(F)F)nn3n2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Fc1cccc(-c2nn3nc(OC(F)F)ccc3c2Br)c1
Reaction time: 18 h
Yield: 91 %

Procedure:
N-bromo succinimide (195 mg) was added to a solution of 6-difluoromethoxy-2-(3-fluoro-phenyl)-pyrazolo[1,5-b]pyridazine (251 mg) and sodium bicarbonate (185 mg) in anhydrous DMF (10 ml) and stirred for 18 h. The reaction mixture was diluted with ethyl acetate (300 ml) and washed with water (10×20 ml), brine (20 ml), dried (Na2SO4) and concentrated to give the title compound as a solid (293 mg, 91%).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][CH:17]=1)[O:6][CH:7]([CH2:13][CH3:14])[C:8]([O:10][CH2:11][CH3:12])=[O:9])=O.[F:18][C:19]1[CH:29]=[CH:28][C:22]([O:23][CH2:24][CH2:25][CH2:26][NH2:27])=[CH:21][CH:20]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>ClCCCl.C(O)(=O)C>[F:18][C:19]1[CH:29]=[CH:28][C:22]([O:23][CH2:24][CH2:25][CH2:26][NH:27][CH2:1][C:3]2[CH:4]=[C:5]([CH:15]=[CH:16][CH:17]=2)[O:6][CH:7]([CH2:13][CH3:14])[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:21][CH:20]=1
Reactant: NCCCOc1ccc(F)cc1
Reactant: CCOC(=O)C(CC)Oc1cccc(C=O)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CCOC(=O)C(CC)Oc1cccc(CNCCCOc2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Ethyl 2-(3-formylphenoxy)butyrate (5.0 g, 21.2 mmol) was dissolved in 1,2-dichloroethane (20 mL). Subsequently, 3-(4-fluorophenoxy)propylamine (4.65 g, 27.5 mmol) was added thereto, and the resultant mixture was stirred for 20 minutes. Subsequently, sodium triacetoxyborohydride (95%, 7.1 g, 31.8 mmol) and small amount of acetic acid were added thereto, and the mixture was stirred overnight at room temperature. A saturated aqueous sodium hydrogencarbonate solution was added thereto. The reaction mixture was extracted with chloroform, and the organic layer was washed with brine. The resultant mixture was subjected to drying over anhydrous sodium sulfate, concentration under reduced pressure, and purification by silica gel chromatography (chloroform/methanol=30/1), whereby the target compound was obtained (6.7 g, 81%).
Reaction SMILES: [C:1]([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][C:13](Br)=[CH:14][CH:15]=2)[O:10][C:9]([C:18]2[N:19]=[CH:20][C:21]3[C:26]([CH:27]=2)=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:8]1)([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(NCC)C.[CH3:52][Si:53]([C:56]#[CH:57])([CH3:55])[CH3:54].Cl>CN(C)C=O.C(#N)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu](I)I>[C:1]([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][C:13]([C:57]#[C:56][Si:53]([CH3:55])([CH3:54])[CH3:52])=[CH:14][CH:15]=2)[O:10][C:9]([C:18]2[N:19]=[CH:20][C:21]3[C:26]([CH:27]=2)=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:8]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)ON=c1cc(-c2cc3ccccc3cn2)oc2cc(Br)ccc12
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Agent: Cl
Solvent: CCNCC
Solvent: CC#N
Solvent: CN(C)C=O
Product: CC(C)(C)ON=c1cc(-c2cc3ccccc3cn2)oc2cc(C#C[Si](C)(C)C)ccc12
Temperature: 90 °C
Yield: 51.1 %

Procedure:
A solution of 7-bromo-2-isoquinolin-3-yl-chromen-4-one O-tert-butyl oxime (120 mg, 0.28 mmol), trans-dichlorobis(triphenylphosphine)palladium (19 mg, 0.028 mmol), copper iodide (10 mg, 0.056 mmol), triphenylphosphine (14 mg, 0.056 mmol) in a mixture of dimethylformamide (3 ml) and acetonitrile (3 ml) was degassed with argon for 10 min and then treated with diethylamine (42 μl, 0.40 mmol) and trimethylsilylacetylene (46 μl, 0.326 mmol). The solution was warmed to 90° C. for 20 hours and then poured onto a 0.5N aqueous solution of hydrogen chloride, extracted with ethyl acetate and purified by flash chromatography over silica gel (gradient cyclohexane/ethyl acetate: 20-50%) to yield 2-isoquinolin-3-yl-7-trimethylsilylethynyl-chromen-4-one O-tert-butyl oxime (63 mg, 50%) as a yellow solid. The solid was dissolved in methanol (10 ml) and treated with potassium carbonate (39 mg, 0.28 mmol) and stirred at room temperature for 18 hours. Methanol was evaporated and the residue was extracted with ethyl acetate washed with water and brine, dried over sodium sulfate and the solution concentrated to dryness to yield 7-ethynyl-2-isoquinolin-3-yl-chromen-4-one O-tert-butyl oxime (49 mg, 89%) as beige solid.
Reaction SMILES: [Br-].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[CH2:22]([N:25]([CH2:37][CH2:38][CH3:39])[CH2:26][CH2:27][C:28]1[CH:36]=[CH:35][CH:34]=[C:33]2[C:29]=1[CH:30]=[CH:31][NH:32]2)[CH2:23][CH3:24].[OH-:40].[Na+]>C(O)(=O)C.O>[CH2:37]([N:25]([CH2:22][CH2:23][CH3:24])[CH2:26][CH2:27][C:28]1[C:29]2[C:33]([CH:34]=[CH:35][CH:36]=1)=[N:32][C:31](=[O:40])[CH:30]=2)[CH2:38][CH3:39]
Reactant: CCCN(CCC)CCc1cccc2[nH]ccc12
Reactant: [OH-]
Agent: [Br-]
Agent: [Na+]
Agent: c1cc[nH+]cc1
Solvent: CC(=O)O
Solvent: O
Product: CCCN(CCC)CCc1cccc2c1=CC(=O)N=2
Temperature: 50 °C
Reaction time: 3 h
Yield: 81 %

Procedure:
A solution of pyridinium tribromide 90% (8.72 g, 24.5 mmol) in acetic acid 50% (50 mL) was added to a solution of 4-[2-(dipropylamino)ethyl]indol (IV) (5 g, 20.5 mmol) in acetic acid 50% (100 mL) and was stirred at 50° C. for 3 h. When the resultant mixture reached room temperature, it was stirred at this temperature for 16 h. The reaction mixture was concentrated to obtain an aqueous residue, which was diluted with water (100 mL), basified with an aqueous solution of NaOH 10% and extracted with AcOEt. The organic layer was dried, filtered and concentrated to obtain 4.3 g (81%) of 4-[2-(dipropylamino)ethyl]indol-2-one (I).
Reaction SMILES: C(C1C2C(=CC(OC)=CC=2)CCC1C(CC1C=CC=CC=1)=O)#N.[C:24]([CH:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH2:29][CH2:28][CH:27]1[C:36]([CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[C:41]([CH3:45])[CH:40]=1)=O)#[N:25]>>[CH3:45][C:41]1[CH:40]=[C:39]([CH2:38][CH:36]2[CH:27]3[CH:26]([C:35]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[CH2:29][CH2:28]3)[CH2:24][NH:25]2)[CH:44]=[CH:43][CH:42]=1
Reactant: Cc1cccc(CC(=O)C2CCc3ccccc3C2C#N)c1
Agent: COc1ccc2c(c1)CCC(C(=O)Cc1ccccc1)C2C#N
Product: Cc1cccc(CC2NCC3c4ccccc4CCC23)c1

Procedure:
Following the procedures described in Step 2 of Example 6, replacing 1-cyano-6-methoxy-2-phenylmethylcarbonyl-1,2,3,4-tetrahydronaphthalene (the product of Step 1 of Example 6) with the product of Step 1 above, 1-cyano-2-(3-methylphenyl)methylcarbonyl-1,2,3,4-tetrahydronaphthalene, the title compound was prepared; MS DCl--NH3M/Z: 278 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[O:3][CH2:4][C@:5]2([C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]#[C:21][C:22]([CH3:25])([OH:24])[CH3:23])[CH:18]=3)[O:13][C:12]3[C:7]2=[CH:8][C:9]([C:26]2[CH:27]=[N:28][CH:29]=[N:30][CH:31]=2)=[CH:10][CH:11]=3)[N:6]=1.CO.[CH3:34]S(O)(=O)=O>C(=O)(O)[O-].[Na+]>[CH3:34][O:24][C:22]([CH3:25])([CH3:23])[C:21]#[C:20][C:17]1[CH:18]=[C:19]2[C@:5]3([CH2:4][O:3][C:2]([NH2:1])=[N:6]3)[C:7]3[C:12](=[CH:11][CH:10]=[C:9]([C:26]4[CH:27]=[N:28][CH:29]=[N:30][CH:31]=4)[CH:8]=3)[O:13][C:14]2=[N:15][CH:16]=1
Reactant: CS(=O)(=O)O
Reactant: CC(C)(O)C#Cc1cnc2c(c1)[C@]1(COC(N)=N1)c1cc(-c3cncnc3)ccc1O2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: COC(C)(C)C#Cc1cnc2c(c1)[C@]1(COC(N)=N1)c1cc(-c3cncnc3)ccc1O2

Procedure:
To a solution of (S)-4-(2′-amino-7-(pyrimidin-5-yl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazole]-3-yl)-2-methylbut-3-yn-2-ol (58 mg, 0.140 mmol) in MeOH (1703 μL, 42.1 mmol) was added methane sulfonic acid (91 μL, 1.403 mmol) in a vial. The vial was sealed and placed in a 70° C. oil bath for 3 hours. The mixture was poured into saturated aqueous sodium bicarbonate solution (20 mL) and extracted with DCM (3×10 mL). The combined organic extracts were dried over sodium sulfate, filtered, and evaporated. The residue was purified by chromatography on a 25-g SNAP column, eluting with 0-70% of a 90:10:1 mixture of DCM/MeOH/NH4OH in DCM to give (S)-3-(3-methoxy-3-methylbut-1-ynyl)-7-(pyrimidin-5-yl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-2′-amine as a white solid after evaporation from DCM/hexane.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][CH2:11][C@H:12]([CH:14]([CH3:16])[CH3:15])[N:13]=2)=[CH:5][CH:4]=1)=[O:2].[C:17]([C@@H:21]([C@H:23]([C:25]([O:27][CH3:28])=[O:26])[OH:24])O)([O:19][CH3:20])=[O:18].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[CH:14]([C@H:12]1[CH2:11][O:10][C:9]([C:6]2[CH:5]=[CH:4][C:3]([CH:1]3[O:24][C@@H:23]([C:25]([O:27][CH3:28])=[O:26])[C@H:21]([C:17]([O:19][CH3:20])=[O:18])[O:2]3)=[CH:8][CH:7]=2)=[N:13]1)([CH3:16])[CH3:15]
Reactant: CC(C)[C@H]1COC(c2ccc(C=O)cc2)=N1
Reactant: COC(=O)[C@H](O)[C@@H](O)C(=O)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)[C@@H]1OC(c2ccc(C3=N[C@@H](C(C)C)CO3)cc2)O[C@H]1C(=O)OC
Reaction time: 2.5 h

Procedure:
A solution of 0.8 g of (S)-2-(4-formylphenyl)-4-isopropyl-2-oxazoline and 1 g of dimethyl L(+)-tartrate in 50 ml of toluene is treated with 0.1 g of toluene-4-sulphonic acid. The mixture is heated to boiling for 2.5 hours and the water formed is distilled off simultaneously. Then, 4 drops of triethylamine are added to the reaction mixture. After cooling the mixture is washed with 20 ml of 1N sodium hydrogen carbonate solution and twice with 20 ml of water each time, dried over sodium sulphate and concentrated. Chromatography of the residue on silica gel with toluene/ethyl acetate (vol. 1:1) and recrystallization from ethanol gives pure dimethyl (4R,5R)-2-(4-[(S)-4-isopropyl-2-oxazolinyl]phenyl)-1,3-dioxolane-4,5-dicarboxylate
Reaction SMILES: [F:1][CH:2]([F:13])[O:3][C:4]1[C:5]([N+:10]([O-])=O)=[N:6][CH:7]=[CH:8][CH:9]=1>C(O)C.C(O)(=O)C>[F:13][CH:2]([F:1])[O:3][C:4]1[C:5]([NH2:10])=[N:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=[N+]([O-])c1ncccc1OC(F)F
Solvent: CCO
Solvent: CC(=O)O
Product: Nc1ncccc1OC(F)F
Temperature: 100 °C
Reaction time: 8 h
Yield: 65.9 %

Procedure:
[step 2] 3-(Difluoromethoxy)-2-nitropyridine (450 mg, 2.37 mmol) obtained in step 1 was dissolved in ethanol (2 mL)-acetic acid (2 mL), reduced iron (397 mg, 7.10 mmol) was added, and the mixture was stirred at 100° C. overnight. Since the starting material did not disappear, reduced iron (397 mg, 7.10 mmol) was added, and the mixture was further stirred at 100° C. overnight. The mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. To the obtained residue was added saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted 3 times with ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate, and purified by silica gel column chromatography (chloroform/methanol=9/1 v/v) to give 3-(difluoromethoxy)pyridin-2-amine (250 mg, 66%).
Reaction SMILES: N1C=CC=CC=1.[CH3:7][CH:8]([CH3:17])[CH:9]([C:11]1[CH:12]=[N:13][CH:14]=[N:15][CH:16]=1)[OH:10].CCOCC>ClCCl.[O-2].[Cr+6].[O-2].[O-2]>[CH3:7][CH:8]([CH3:17])[C:9]([C:11]1[CH:16]=[N:15][CH:14]=[N:13][CH:12]=1)=[O:10]
Reactant: CC(C)C(O)c1cncnc1
Agent: [Cr+6]
Agent: [O-2]
Solvent: CCOCC
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)C(=O)c1cncnc1
Reaction time: 5 h
Yield: 48 %

Procedure:
To a suspension of chromium (VI) oxide (12.87 g, 65 mmol) in dry dichloromethane (500 ml) was added dry pyridine (10.27 g, 130 mmol) and the mixture stirred for 0 5 h. Then a solution of 2-methyl-1-(pyrimid-5-yl)-propan-1-ol, prepared in stage 1, (1.52 g, 10 mmol) in dry dichloromethane (100 ml) was added dropwise with stirring. After 2 hours the reaction mixture was poured into ether (1000 ml) and then filtered. The filtrate was washed with copper sulphate solution (4×400 ml), brine solution (2×400 ml), and dried over magnesium sulphate before removing the solvent. Flash chromatography (silica gel, petrol/ether elution) gave the product as a colourless oil (0.72 g, 48%).
Reaction SMILES: Cl.Cl.[NH2:3][CH:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][CH2:12][C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:14])[CH2:6][CH2:5]1.[Cl:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1>>[Cl:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([NH:3][CH:4]2[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][CH2:12][C:13]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)=[O:14])[CH2:6][CH2:5]2)=[O:27])=[CH:24][CH:23]=1
Reactant: NC1CCN(CCCC(=O)c2ccccc2)CC1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Agent: Cl
Product: O=C(CCCN1CCC(NC(=O)c2ccc(Cl)cc2)CC1)c1ccccc1

Procedure:
4-Amino-1-(4-phenyl-4-oxobutyl)piperidine dihydrochloride (3.19 g.) was acylated with p-chloro-benzoyl chloride (1.75 g.) in the manner of example75. Filtration afforded the title compound as the base (3.277 g.). This wassuspended in boiling ethanol (15 ml). and ethanol/HCl added until acid. On cooling the title compound crystallised out as the hydrochloride, colourless needles (3.41 g.), m.p. 261.1°. Analysis: Found: C, 62.89; H, 6.33; N, 6.64. C22H25CIN2O2.HCl requires C, 62.69; H, 6.22; N, 6.65%.