Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OP([CH2:9][C:10]#[N:11])(=O)OCC)C.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[O:22]1[C:27]2[CH:28]=[CH:29][C:30]([C:32]([C:34]3[CH:39]=[CH:38][CH:37]=[C:36]([O:40][CH3:41])[CH:35]=3)=O)=[CH:31][C:26]=2[O:25][CH2:24][CH2:23]1.O>C1COCC1>[O:22]1[C:27]2[CH:28]=[CH:29][C:30]([C:32]([C:34]3[CH:39]=[CH:38][CH:37]=[C:36]([O:40][CH3:41])[CH:35]=3)=[CH:9][C:10]#[N:11])=[CH:31][C:26]=2[O:25][CH2:24][CH2:23]1
Reactant: CCOP(=O)(CC#N)OCC
Reactant: COc1cccc(C(=O)c2ccc3c(c2)OCCO3)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COc1cccc(C(=CC#N)c2ccc3c(c2)OCCO3)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77.9 %

Procedure:
To a solution of cyanomethylphosphonic acid diethyl ester (2.1 mL, 13.5 mmol) in anhydrous THF (15 mL) was added lithium bis(trimethylsilyl)amide (1.0 M solution in THF, 13.5 mL, 13.5 mmol) at 0° C. and stirred for 30 min at room temperature followed by addition of (2,3-dihydro-benzo[1,4]dioxin-6-yl)-(3-methoxy-phenyl)-methanone (2.0 g crude, 6.7 mmol) in THF (15 mL) and refluxed for 30 min. The reaction mixture was poured into water (50 mL), extracted with CH2Cl2 (2×50 mL). The combined organic phases were washed with brine (50 mL), dried over MgSO4, and purified via flash column chromatography (EtOAc, Hexane) to give 3-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-3-(3-methoxy-phenyl)-acrylonitrile as an off-white solid (1.53 g, 77% yield): mp, 64-66° C.; 1H NMR (DMSO-d6) δ 3.77 and 3.78 (2s, 3H, OCH3), 4.24-4.36 (m, 4H, CH2CH2), 6.19 and 6.24 (2s, 1H, CH), 6.77-7.09 (m, 6H, Ar), 7.33-7.36 (m, 1H, Ar); 13C NMR (DMSO-d6) δ 55.2, 55.2, 64.0, 64.0, 64.2, 64.3, 94.3, 95.2, 113.7, 114.6, 114.9, 115.8, 116.7, 117.1, 117.2, 117.9, 118.3, 120.9, 121.2, 121.7, 122.5, 129.7, 129.8, 129.8, 130.6, 138.5, 139.7, 143.1, 143.3, 144.8, 145.6, 159.1, 159.2, 160.8, 160.9. Anal. Calcd for C18H15NO3: C, 73.71; H, 5.15; N, 4.78. Found: C, 73.48; H, 4.84; N, 4.64.
Reaction SMILES: [CH:1]1([CH:7]([O:20][CH3:21])[C:8]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:9]=2[CH:10]=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[F:22][C:23]([F:37])([F:36])[C:24]1[CH:25]=[C:26]([CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:31]=1)[CH2:27][NH2:28].[BH4-].[Na+]>C(O)C>[CH:1]1([CH:7]([O:20][CH3:21])[C:8]2[CH:15]=[CH:14][C:13]([C:16]([F:17])([F:19])[F:18])=[CH:12][C:9]=2[CH2:10][NH:28][CH2:27][C:26]2[CH:29]=[C:30]([C:32]([F:33])([F:34])[F:35])[CH:31]=[C:24]([C:23]([F:22])([F:36])[F:37])[CH:25]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: NCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: COC(c1ccc(C(F)(F)F)cc1C=O)C1CCCCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: COC(c1ccc(C(F)(F)F)cc1CNCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79 %

Procedure:
A mixture of 2-(cyclohexyl(methoxy)methyl)-5-(trifluoromethyl)benzaldehyde (107 my, 0.36 mmol) and 3,5-bistrifluoromethylbenzylamine (113.8 mg, 0.37 mmol) in ethanol was stirred at room temperature overnight. Sodium borohydride (16.5 mg, 0.44 mmol) was added and the mixture was stirred at room temperature overnight. Solvent was removed and the residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by chromatography over 25+S Biotage silica column (eluted with 0-15% ethyl acetate in heptane) to afford the title compound (150 mg, 80%). 1H NMR (400 MHz, CDCl3) δ ppm 0.94-1.23 (m, 6H) 1.51-1.59 (m, 1H) 1.62 (d, J=7.05 Hz, 2H) 1.69-1.78 (m, 1H) 1.99 (d, J=12.45 Hz, 1H) 3.17 (s, 3H) 3.83 (d, J=12.86 Hz, 1H) 3.92 (d, J=12.86 Hz, 1H) 4.00 (d, J=6.64 Hz, 2H) 4.22 (d, J=7.05 Hz, 1H) 7.50 (d, J=8.30 Hz, 1H) 7.55 (d, J=7.88 Hz, 1H) 7.63 (s, 1H) 7.80 (s, 1H) 7.86 (s, 2H). MS (ES30) Calc: 527.2, Found: 528.5 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:29]=[CH:28][C:6]([C:7]([NH:9][NH:10][C:11](=O)[CH2:12][C:13]2[CH:26]=[CH:25][C:16]3[CH:17]=[C:18]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[S:19][C:15]=3[CH:14]=2)=[O:8])=[CH:5][CH:4]=1.[OH-].COC(NS([N+](CC)(CC)CC)(=O)=O)=O>C1COCC1>[CH3:1][O:2][C:3]1[CH:29]=[CH:28][C:6]([C:7]2[O:8][C:11]([CH2:12][C:13]3[CH:26]=[CH:25][C:16]4[CH:17]=[C:18]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[S:19][C:15]=4[CH:14]=3)=[N:10][N:9]=2)=[CH:5][CH:4]=1
Reactant: CCOC(=O)c1cc2ccc(CC(=O)NNC(=O)c3ccc(OC)cc3)cc2s1
Agent: CC[N+](CC)(CC)S(=O)(=O)NC(=O)OC
Agent: [OH-]
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2ccc(Cc3nnc(-c4ccc(OC)cc4)o3)cc2s1

Procedure:
A solution of ethyl 6-{2-[2-(4-methoxybenzoyl)hydrazino]-2-oxoethyl}-1-benzothiophene-2-carboxylate (78 mg, 0.19 mmol) and (methoxycarbonylsulfamoyl)-triethylammonium hydroxide, inner salt (113 mg, 0.47 mmol) in THF was heated to 100° C. in the microwave for 10 minutes. The reaction was filtered through a pad of silica and washed with ethyl acetate. The organics were evaporated to dryness to give the title compound as a clear oil. LC/MS (EI): cal'd 395.1 (MH+), exp 395.1 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[F:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[CH:21]([C:25]([F:28])([F:27])[F:26])[NH:20][CH2:19][CH2:18]2>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:20]3[CH2:19][CH2:18][C:17]4[C:22](=[CH:23][CH:24]=[C:15]([F:14])[CH:16]=4)[CH:21]3[C:25]([F:26])([F:27])[F:28])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Reactant: Fc1ccc2c(c1)CCNC2C(F)(F)F
Product: O=C(c1cc2ncc(Br)cn2n1)N1CCc2cc(F)ccc2C1C(F)(F)F

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 6-fluoro-1-trifluoromethyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].C(N(CC)CC)C.[CH2:20]([O:34][C:35]1[CH:40]=[CH:39][C:38]([CH2:41][C:42](Cl)=[O:43])=[CH:37][CH:36]=1)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]>C(Cl)Cl>[CH2:20]([O:34][C:35]1[CH:40]=[CH:39][C:38]([CH2:41][C:42]([NH:1][C:2]2[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=2)[C:5]([O:7][CH2:8][CH3:9])=[O:6])=[O:43])=[CH:37][CH:36]=1)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: CCCCCCCCCCCCCCOc1ccc(CC(=O)Cl)cc1
Reactant: CCOC(=O)c1cccc(N)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCCCCCCOc1ccc(CC(=O)Nc2cccc(C(=O)OCC)c2)cc1
Reaction time: 2.5 h

Procedure:
A solution of 10.13 g of ethyl 3-amino-benzoate and 6.82 g of triethylamine in 100 ml of methylene 35 chloride is added dropwise to a solution of p-tetradecyloxyphenylacetyl chloride in 100 ml of methylene chloride over 15 minutes. The mixture is stirred for an additional 2.5 hours then washed with dilute hydrochloric acid. The organic layer is evaporated and the residue dissolved in 1.5 liter of ether then washed with dilute sodium hydroxide. The organic layer is dried and evaporated to a residue which is crystallized from carbon tetrachloride:hexane to give 24.4 g of the desired product as a white solid, m.p. 91°-94° C.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[C:23]([CH2:25]O)[CH:22]=[C:21]([Cl:27])[C:3]=1[C:4]([N:6]1[C:14]2[CH:13]=[CH:12][N:11]=[C:10]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[C:9]=2[CH:8]=[CH:7]1)=[O:5].P(Br)(Br)[Br:29]>ClCCl>[Br:29][CH2:25][C:23]1[CH:24]=[C:2]([Cl:1])[C:3]([C:4]([N:6]2[C:14]3[CH:13]=[CH:12][N:11]=[C:10]([NH:15][C:16]([CH:18]4[CH2:20][CH2:19]4)=[O:17])[C:9]=3[CH:8]=[CH:7]2)=[O:5])=[C:21]([Cl:27])[CH:22]=1
Reactant: BrP(Br)Br
Reactant: O=C(Nc1nccc2c1ccn2C(=O)c1c(Cl)cc(CO)cc1Cl)C1CC1
Solvent: ClCCl
Product: O=C(Nc1nccc2c1ccn2C(=O)c1c(Cl)cc(CBr)cc1Cl)C1CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of N-{1-[2,6-dichloro-4-(hydroxymethyl)benzoyl]-1H-pyrrolo[3,2-c]pyridin-4-yl}cyclopropanecarboxamide (0.37 mmol) in dichloromethane was cooled to 0° C. and was treated dropwise with phosphorous tribromide (0.74 mmol). The reaction mixture was then stirred at room temperature for about 2 hours, diluted with dichloromethane and washed with saturated sodium bicarbonate solution. The organic layer was separated, dried over anhydrous sodium sulfate and concentrated to get N-{1-[4-(bromomethyl)-2,6-dichlorobenzoyl]-1H-pyrrolo[3,2-c]pyridin-4-yl}cyclopropanecarboxamide as white solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]([CH3:15])[CH3:14])=[N:10][C:9]=2[C:16]2[CH:17]=[C:18]([NH:22][S:23]([C:26]3[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=3[O:33][CH3:34])(=[O:25])=[O:24])[CH:19]=[CH:20][CH:21]=2)[CH:5]=[CH:4][N:3]=1.[CH2:35]([NH2:39])[CH:36]([CH3:38])[CH3:37]>>[F:32][C:30]1[CH:29]=[CH:28][C:27]([O:33][CH3:34])=[C:26]([S:23]([NH:22][C:18]2[CH:19]=[CH:20][CH:21]=[C:16]([C:9]3[N:10]=[C:11]([CH:13]([CH3:15])[CH3:14])[S:12][C:8]=3[C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:39][CH2:35][CH:36]([CH3:38])[CH3:37])[N:7]=3)[CH:17]=2)(=[O:25])=[O:24])[CH:31]=1
Reactant: COc1ccc(F)cc1S(=O)(=O)Nc1cccc(-c2nc(C(C)C)sc2-c2ccnc(Cl)n2)c1
Reactant: CC(C)CN
Product: COc1ccc(F)cc1S(=O)(=O)Nc1cccc(-c2nc(C(C)C)sc2-c2ccnc(NCC(C)C)n2)c1

Procedure:
Following a procedure analogous to the procedure described in Example 18, Step B using N-{3-[5-(2-Chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]phenyl}-5-fluoro-2-(methyloxy)benzenesulfonamide (89 mg, 0.171 mmol) and isobutylamine (0.172 mL, 1.715 mmol) the title compound was obtained as a yellow foam (58 mg, 61% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.27 (s, 1H), 7.92 (d, J=5.1 Hz, 1H), 7.36-7.52 (m, 2H), 7.29 (t, J=5.9 Hz, 1H), 7.09-7.26 (m, 4H), 7.06 (d, J=7.5 Hz, 1H), 5.92 (dd, J=6.6, 0.9 Hz, 1H), 3.79 (s, 3H), 3.15-3.27 (m, 1H), 2.99 (d, J=0.9 Hz, 2H), 1.71-1.87 (m, 1H), 1.31 (d, J=6.9 Hz, 6H), 0.82 (d, J=6.7 Hz, 6H). MS (ESI): 556.0 [M+H]+.
Reaction SMILES: C[Si](C)(C)[C:3]1[O:7][C:6]([CH3:8])=[C:5]([CH2:9][O:10][C:11](=[O:23])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C:4]=1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C1C(I)=C([OH:39])C(I)=C2OC3C(C4(OC(=O)C5C(Cl)=C(Cl)C(Cl)=C(Cl)C4=5)C=12)=CC(I)=C(O)C=3I.O=O.C(=O)=O.CC(C)=O>C1COCC1>[C:11]([O:10][CH2:9][C:5]1[CH:6]([CH3:8])[O:7][C:3](=[O:39])[C:4]=1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)(=[O:23])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCCCCCCC(=O)OCc1c(C)oc([Si](C)(C)C)c1-c1ccccc1
Reactant: O=C1OC2(c3cc(I)c(O)c(I)c3Oc3c2cc(I)c(O)c3I)c2c(Cl)c(Cl)c(Cl)c(Cl)c21
Agent: O=C=O
Agent: O=O
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: CCCCCCCCCCCC(=O)OCC1=C(c2ccccc2)C(=O)OC1C
Yield: 27 %

Procedure:
The solution of Compound 15 and Rose Bengal in THF was saturated with O2, then cooled to approximately -5° C. (dry ice/acetone bath) and irradiated with a 150 watt flood lamp (maintaining the temperature of the mixture at -5° to 0° C.) for 3 hours. The reaction mixture was then filtered and concentrated to a pink oil which was purified by column chromatography (eluent, EtOAc/hexanes, 1:20 to 1:4) to give 3.4 g (27%) of pure title compound as a colorless oil. An additional 3 g (approximately 25%) of a mixture of the title compound and the 5-desmethyl derivative (ratio 1:1 by proton NMR integration) was also obtained as a yellow oil.
Reaction SMILES: C([O:7][CH2:8][C@@H:9]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[C:10]1[C:11]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)=[C:12]2[C:17](=[CH:18][C:19]=1[CH3:20])[NH:16][C:15](=O)[CH:14]=[CH:13]2)(=O)C(C)(C)C.[H-].[Na+].C([O:40][C@@H:41]([C:45]1[C:46](C2C=CC(Cl)=CC=2)=[C:47]2[C:52](=[CH:53][C:54]=1C)N1N=NN=C1C=C2)C(O)=O)(C)(C)C>CN(C=O)C>[CH2:41]([O:40][C:15]1[CH:14]=[CH:13][C:12]2[C:17](=[CH:18][C:19]([CH3:20])=[C:10]([C@H:9]([O:29][C:30]([CH3:32])([CH3:33])[CH3:31])[CH2:8][OH:7])[C:11]=2[C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)[N:16]=1)[C:45]1[CH:46]=[CH:47][CH:52]=[CH:53][CH:54]=1
Reactant: Cc1cc2[nH]c(=O)ccc2c(-c2ccc(Cl)cc2)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Reactant: Cc1cc2c(ccc3nnnn32)c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc2nc(OCc3ccccc3)ccc2c(-c2ccc(Cl)cc2)c1[C@@H](CO)OC(C)(C)C
Reaction time: 0.5 h
Yield: 21.7 %

Procedure:
To the solution of (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-oxo-1,2-dihydroquinolin-6-yl)ethyl pivalate (8J) (16 mg, 0.03 mmol) in DMF (1 mL) was added sodium hydride (7 mg, 60% oil, 0.17 mmol). The mixture was stirred for 30 minutes, and benzyl bromide (64, 0.05 mmol) was added. The mixture was stirred another 90 minutes, and was quenched with water, and left for 12 hours. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and brine, and dried over sodium sulfate. Concentration and purification by flash column chromatography (hexanes/EtOAc) gave (S)-2-(2-(benzyloxy)-5-(4-chlorophenyl)-7-methylquinolin-6-yl)-2-tert-butoxyethanol (3.1 mg). LCMS-ESI+ (m/z): [M-FH]+ calcd for C29H30ClNO3: 476.2. Found: 476.1. (S)-1-Benzyl-6-(1-tert-butoxy-2-hydroxyethyl)-5-(4-chlorophenyl)-7-methylquinolin-2(1H)-one was also isolated 6.1 mg LCMS-ESI+ (m/z): [M+H]+ calcd for LCMS-ESI+ (m/z): [M+H]+ calcd for C29H31ClNO3: 476.2. Found: 476.2.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[OH:7].[C:8]1([C:14](Cl)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(N(CC)CC)C>C(Cl)Cl>[C:8]1([C:14]([NH:1][C@@H:2]2[CH2:6][CH2:5][CH2:4][C@H:3]2[OH:7])([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: N[C@@H]1CCC[C@H]1O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O[C@@H]1CCC[C@H]1NC(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
A mixture of trans-2-aminocyclopentanol (45.84 mmol), triphenylmethylchloride (11.50 g; 41.26 mmol) and triethylamine (15.97 ml; 114.60 mmol) in 100 ml CH2Cl2 is refluxed overnight. The reaction mixture is cooled and concentrated in vacuo and flash chromatographed using 5:1; hexane:EtOAc to obtain trans-2-triphenylmethylaminocyclopentanol which is used directly in the next step.
Reaction SMILES: [CH2:1]([C:5]1([O:10][CH2:11][CH3:12])[CH2:7][C:6]1(Cl)[F:8])[CH2:2][CH2:3]C.C(=O)([O-])[O-].[K+].[K+].[CH2:19]([OH:21])[CH3:20]>>[CH2:19]([O:21][C:5]([O:10][CH2:11][CH3:12])([CH2:1][CH2:2][CH3:3])[C:6]([F:8])=[CH2:7])[CH3:20]
Reactant: CCCCC1(OCC)CC1(F)Cl
Reactant: CCO
Agent: O=C([O-])[O-]
Agent: [K+]
Product: C=C(F)C(CCC)(OCC)OCC

Procedure:
A stirred solution of 58.4 g. of 2-butyl-1-chloro-2-ethoxy-1-fluorocyclopropane and 166 g. of anhydrous potassium carbonate in 400 ml. of absolute ethanol is heated at reflux for 18 hours. The solution is cooled and the bulk of the ethanol is removed in vacuo. The residue is partitioned with 500 ml. of water and 750 ml. of ether. The ether phase is washed with three 100 ml. portions of brine, dried over potassium carbonate and concentrated in vacuo to provide 54 g. of a pale yellow oil. A 4.45 g. portion of this oil is distilled through a 6 inch Vigreux column giving 2.5 g. of the desired product as a colorless liquid, b.p. 80°-81° C., 24 mm.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:18])=[C:4]([CH3:17])[C:5]2[O:10][C@@:9]([CH3:14])([C:11]([OH:13])=[O:12])[CH2:8][CH2:7][C:6]=2[C:15]=1[CH3:16].O.[C:20]1(C)C=CC(S(O)(=O)=O)=CC=1>CO.O>[OH:1][C:2]1[C:3]([CH3:18])=[C:4]([CH3:17])[C:5]2[O:10][C@@:9]([CH3:14])([C:11]([O:13][CH3:20])=[O:12])[CH2:8][CH2:7][C:6]=2[C:15]=1[CH3:16]
Reactant: Cc1c(C)c2c(c(C)c1O)CC[C@](C)(C(=O)O)O2
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: COC(=O)[C@@]1(C)CCc2c(C)c(O)c(C)c(C)c2O1
Reaction time: 4 h

Procedure:
A solution of 2 g (8 mmol) of optically pure (R)-(+)-3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl2 H-1-benzopyran-2-carboxylic acid (1) and 0.1 g of p-toluenesulphonic acid monohydrate in 40 ml methanol were stirred and re-fluxed for 4 hours. After cooling, the solution was diluted with water, extracted three times into ether that was subsequently washed with brine and aqueous sodium bicarbonate solution. The ether solution was washed, dried with MgSO4 and evaporated to give (R)-(+)-methyl 3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2 H- 1-benzopyran-2 carboxylate (2).
Reaction SMILES: [C:1]([OH:4])(=O)[CH3:2].C(N(CC)CC)C.CS(ON=C(C#N)C(OCC)=O)(=O)=O.[NH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(OCC)(=O)C>[C:1]([NH:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)(=[O:4])[CH3:2]
Reactant: CC(=O)O
Reactant: Nc1ccccc1
Agent: CCOC(=O)C(C#N)=NOS(C)(=O)=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(=O)Nc1ccccc1
Reaction time: 0.67 h
Yield: 88.9 %

Procedure:
Acetic acid (0.3 g) and triethylamine (0.7 ml) are dissolved in ethyl acetate (10 ml), and thereto is added ethyl 2-methanesulfonyloxyimino-2-cyanoacetate (1.1 g) and the mixture is stirred for 40 minutes. To the solution is added aniline (0.5 g) and the mixture is stirred for 2 hours. The reaction mixture is washed well with 1 N aqueous sodium hydrogen carbonate, water and 1 N hydrochloric acid in order and then dried over anhydrous magnesium sulfate. After drying, the solvent is distilled off to give flasks of acetanilide (0.6 g), melting poit: 95°-105° C. The product recrystallized from water has a melting point of 104°-108° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([OH:11])[CH:5]=1.C[O-].[Na+].Br[CH2:17][CH2:18]Br>CO>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]2[O:10][CH2:17][CH2:18][O:11][C:6]=2[CH:5]=1
Reactant: COC(=O)c1ccc(O)c(O)c1
Reactant: BrCCBr
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ccc2c(c1)OCCO2

Procedure:
A solution of 4.20 g. of 3,4-dihydroxybenzoic acid methyl ester in 10.0 ml. of methanol is combined with 7.0 g. of sodium methoxide and then 15.0 g. of 1,2-dibromoethane is added. The resulting mixture is refluxed under nitrogen for 24 hours, then cooled, filtered, evaporated in vacuo and the resulting oil dissolved in 50 ml. of chloroform. The resulting solution after again filtering is chromatographed over 100 ml. of silica gel eluting with chloroform to obtain 3,4-ethylenedioxybenzoic acid methyl ester, m.p. 43°-45° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@@H:12]2[C@@:10]([CH2:14]O)([CH2:11]2)[C@@H:9]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:41]1(=[O:51])[NH:45][C:44](=[O:46])[C:43]2=[CH:47][CH:48]=[CH:49][CH:50]=[C:42]12.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]2[C:10]([CH2:14][N:45]3[C:41](=[O:51])[C:42]4[C:43](=[CH:47][CH:48]=[CH:49][CH:50]=4)[C:44]3=[O:46])([CH2:11]2)[CH:9]1[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1C[C@H]2C[C@@]2(CO)[C@@H]1c1ccccc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC2CC2(CN2C(=O)c3ccccc3C2=O)C1c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 95.6 %

Procedure:
To racemic Intermediate 19, one enantiomer being (1S,2S,5S)-1-hydroxymethyl-2-phenyl-3-aza-bicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (0.40 g, 1.4 mmol), was added anhydrous THF (5 mL), triphenylphosphine (0.43 g, 1.6 mmol), phthalimide (0.30 g, 2.1 mmol), and diethylazodicarboxylate (0.22 mL, 1.7 mmol). The reaction was allowed to stir at room temperature for 16 hours. The solvent was removed at reduced pressure and the residue partitioned between saturated sodium bicarbonate solution and methylene chloride, the organics were washed with brine, dried over sodium sulfate, filtered, and concentrated to an oil. The material was purified by chromatography on silica by elution with a gradient of 5 to 20% EtOAc/Hexanes to give the title compound as an white solid (0.56 g, 97% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([Mg]Br)[CH:3]=1.C1C[O:13][CH2:12]C1.CN(C=O)C>>[CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH:12]=[O:13])[CH:3]=1
Reactant: C1CCOC1
Reactant: Cc1ccnc([Mg]Br)c1
Solvent: CN(C)C=O
Product: Cc1ccnc(C=O)c1
Yield: 71.5 %

Procedure:
4-Methyl-pyridine-2-carbaldehyde (433 mg, 71.5%) was obtained from 0.25 M 4-methyl-2-pyridinylmagnesium bromide of THF solution (20 mL, 5 mmol) with DMF (0.773 mL, 10 mmol) at room temperature under argon.
Reaction SMILES: [CH3:1][N:2]([CH3:47])[CH2:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][C:11]([O:45][CH3:46])=[C:12]([NH:15][C:16]3[N:29]4[C:20](=[N:21][C:22]5[C:27]([C:28]4=[O:30])=[C:26]([F:31])[CH:25]=[CH:24][CH:23]=5)[C:19]4[CH:32]=[CH:33][N:34]([S:35]([C:38]5[CH:43]=[CH:42][C:41]([CH3:44])=[CH:40][CH:39]=5)(=[O:37])=[O:36])[C:18]=4[N:17]=3)[CH:13]=2)[CH2:8][CH2:7]1)=[O:5].[CH3:48][CH:49]([CH3:52])[CH2:50][NH2:51]>C1COCC1.C(OCC)(=O)C>[CH3:1][N:2]([CH3:47])[CH2:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][C:11]([O:45][CH3:46])=[C:12]([NH:15][C:16]3[N:29]=[C:20]([NH:21][C:22]4[CH:23]=[CH:24][CH:25]=[C:26]([F:31])[C:27]=4[C:28]([NH:51][CH2:50][CH:49]([CH3:52])[CH3:48])=[O:30])[C:19]4[CH:32]=[CH:33][N:34]([S:35]([C:38]5[CH:43]=[CH:42][C:41]([CH3:44])=[CH:40][CH:39]=5)(=[O:37])=[O:36])[C:18]=4[N:17]=3)[CH:13]=2)[CH2:8][CH2:7]1)=[O:5]
Reactant: CC(C)CN
Reactant: COc1cc2c(cc1Nc1nc3c(ccn3S(=O)(=O)c3ccc(C)cc3)c3nc4cccc(F)c4c(=O)n13)N(C(=O)CN(C)C)CC2
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cc2c(cc1Nc1nc(Nc3cccc(F)c3C(=O)NCC(C)C)c3ccn(S(=O)(=O)c4ccc(C)cc4)c3n1)N(C(=O)CN(C)C)CC2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 5-{[1-(N,N-dimethylglycyl)-5-(methyloxy)-2,3-dihydro-1H-indol-6-yl]amino}-8-fluoro-3-[(4-methylphenyl)sulfonyl]pyrrolo[2′,3′:4,5]pyrimido[6,1-b]quinazolin-7(3H)-one (200 mg, 0.305 mmol) in THF (5 mL) was added (2-methylpropyl)amine (0.153 mL, 1.52 mmol). The resulting mixture was let stir at rt for 16 h at which time it was diluted with ethyl acetate and washed with a saturated ammonium chloride solution,a saturated sodium bicarbonate solution, water and a saturated brine solution. Organics were dried over sodium sulfate and solvents removed under reduced pressure to afford a brown solid 2-({2-{[1-(N,N-dimethylglycyl)-5-(methyloxy)-2,3-dihydro-1H-indol-6-yl]amino}-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)-6-fluoro-N-(2-methylpropyl)benzamide. This crude material was dissolved in 1,4-dioxane (5 mL) and transferred to a 20 ml microwave vessel. A solution of 2M NaOH (5 ml) was added and reaction heated in microwave at 120° C. for 8 minutes. Resulting brown solution was diluted with ethyl acetate and washed with a saturated sodium bicarbonate solution, water and a saturated brine solution. Organics were dried over sodium sulfate and solvents removed under reduced pressure to afford a brown solid which was purified via chromatography on SiO2 to afford 2-[(2-{[1-(N,N-dimethylglycyl)-5-(methyloxy)-2,3-dihydro-1H-indol-6-yl]amino}-1H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-6-fluoro-N-(2-methylpropyl)benzamide (106 mg, 0.184 mmol) as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.87 (d, J=6.68 Hz, 6 H), 1.73-1.89 (m, 1 H), 2.26 (s, 6 H), 3.05-3.23 (m, 6 H), 3.77 (s, 3 H), 4.18 (t, J=8.33 Hz, 2 H), 6.24 (br. s., 1 H), 6.83-7.00 (m, 3 H), 7.24-7.38 (m, 1 H), 7.56 (s, 1 H), 8.32 (d, J=8.42 Hz, 1 H), 8.57-8.68 (m, 2 H), 9.77 (s, 1 H), 11.26 (br. s., 1 H). (ESIMS (M+H)+=575)