Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH:13]([N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][C:16]2=[O:21])[CH2:12][O:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].CC([N-]C(C)C)C.CCCCCCC.C1COCC1.C(C1C=CC=CC=1)C.C1(S(Cl)(=O)=O)C=CC=CC=1.[Cl:60][C:61]1[CH:62]=[C:63]([NH2:68])[CH:64]=[C:65]([F:67])[CH:66]=1.[H-].[Na+]>C1COCC1>[Cl:60][C:61]1[CH:62]=[C:63]([NH:68][CH:17]2[CH2:18][CH2:19][CH2:20][N:15]([CH:13]3[CH2:12][O:11][CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:14]3)[C:16]2=[O:21])[CH:64]=[C:65]([F:67])[CH:66]=1
Reactant: CC(C)(C)OC(=O)N1CCOCC(N2CCCCC2=O)C1
Reactant: Nc1cc(F)cc(Cl)c1
Agent: CC(C)[N-]C(C)C
Agent: O=S(=O)(Cl)c1ccccc1
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCc1ccccc1
Solvent: CCCCCCC
Product: CC(C)(C)OC(=O)N1CCOCC(N2CCCC(Nc3cc(F)cc(Cl)c3)C2=O)C1
Temperature: -30 °C
Yield: 46.2 %

Procedure:
To a solution of 6-(2-oxo-piperidin-1-yl)-perhydro-1,4-oxazepine-4-carboxylic acid tert-butyl ester 38.5 (0.31 g, 1.0 mmol) in THF (10 mL) at −78° C. was added dropwise 2.0 M LDA in heptane/THF/ethylbenzene (0.7 mL, 1.5 mmol) under nitrogen. The solution was allowed to warm to −30° C. for 1 h and then recooled to −78° C. prior to the dropwise addition of PhSO2Cl (0.15 mL, 1.1 mmol). The reaction was allowed to slowly warm to 10° C. and then quenched upon the addition NaHCO3 and extracted with EtOAc. The organic phase was washed with NaHCO3, brine and dried (MgSO4), filtered and concentrated in vacuo to afford a solid. The chloro intermediate was dissolved in THF (8.4 mL) and added to a suspension of 3-chloro-5-fluoro-phenylamine (0.15 g, 1.04 mmol) and sodium hydride (60% in mineral oil, 80 mg, 2.1 mmol) in THF (16 mL). The reaction mixture was heated to reflux for 90 minutes, cooled to room temperature, placed and quenched with MeOH, water, NaHCO3 and EtOAc. The organics phase was separated, washed with brine, dried (MgSO4), filtered and concentrated in vacuo to afford an oil. The oil was purified by silica gel chromatography (gradient MeOH/DCM) to afford the desired product (204 mg, 59%). LCMS, m/z 386.1 [M−tBu]+.
Reaction SMILES: [OH-].[K+].C([O:11][CH:12]1[CH2:17][C:16]([CH3:19])([CH3:18])[N:15]([O:20][CH:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:24]([O:31][N:32]3[C:37]([CH3:39])([CH3:38])[CH2:36][CH:35]([O:40]C(=O)C4C=CC=CC=4)[CH2:34][C:33]3([CH3:50])[CH3:49])[CH2:23][CH2:22]2)[C:14]([CH3:52])([CH3:51])[CH2:13]1)(=O)C1C=CC=CC=1>C(O)C>[OH:40][CH:35]1[CH2:36][C:37]([CH3:38])([CH3:39])[N:32]([O:31][CH:24]2[C:25]3[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:21]([O:20][N:15]3[C:14]([CH3:52])([CH3:51])[CH2:13][CH:12]([OH:11])[CH2:17][C:16]3([CH3:19])[CH3:18])[CH2:22][CH2:23]2)[C:33]([CH3:50])([CH3:49])[CH2:34]1
Reactant: CC1(C)CC(OC(=O)c2ccccc2)CC(C)(C)N1OC1CCC(ON2C(C)(C)CC(OC(=O)c3ccccc3)CC2(C)C)c2ccccc21
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CC1(C)CC(O)CC(C)(C)N1OC1CCC(ON2C(C)(C)CC(O)CC2(C)C)c2ccccc21

Procedure:
The title compound is prepared by the basic hydrolysis (potassium hydroxide is ethanol) of the compound prepared in Example 28A.
Reaction SMILES: [CH3:1][N:2]1[CH2:14][CH2:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:15])[CH:10]=3)[NH:5][C:4]=2[CH2:3]1.N1CCC[C@H]1C(O)=O.[O-]P([O-])([O-])=O.[K+].[K+].[K+].Br[CH:33]=[C:34]([C:36]1[CH:41]=[CH:40][C:39]([F:42])=[C:38]([F:43])[CH:37]=1)[CH3:35]>CN(C=O)C.[Cu]I>[F:43][C:38]1[CH:37]=[C:36]([C:34]([CH3:35])=[CH:33][N:5]2[C:6]3[C:11](=[CH:10][C:9]([CH3:15])=[CH:8][CH:7]=3)[C:12]3[CH2:13][CH2:14][N:2]([CH3:1])[CH2:3][C:4]2=3)[CH:41]=[CH:40][C:39]=1[F:42]
Reactant: CC(=CBr)c1ccc(F)c(F)c1
Reactant: Cc1ccc2[nH]c3c(c2c1)CCN(C)C3
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Product: CC(=Cn1c2c(c3cc(C)ccc31)CCN(C)C2)c1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 58.5 %

Procedure:
2,6-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (72 mg, 0.359 mmol) was dissolved in DMF (5 mL). To this solution was added CuI (8 mg, 0.035 mmol), L-proline (9 mg, 0.086 mmol), K3PO4 (183 mg, 0.862 mmol). The reaction mixture was stirred for 10 min at room temperature followed by addition of 4-(1-bromoprop-1-en-2-yl)-1,2-difluorobenzene (100 mg, 0.431 mmol). The reaction mixture was heated at 80° C. overnight. Solvent was evaporated under reduced pressure; the residue was diluted with brine and extracted with ethyl acetate. Organic layer was dried over Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography to obtain 74 mg of 9-(2-(3,4-difluorophenyl)prop-1-enyl)-2,6-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole. 1H NMR (DMSO) OXALATE SALT 7.80 (m, 1H), 7.50 (m, 2H), 7.30 (s, 1H), 7.20 (s, 1H), 7.15 (d, 1H), 7.0 (d, 1H), 4.22 (m, 2H), 3.40 (m, 2H), 2.90 (m, 2H), 2.82 (s, 3H), 2.40 (s, 3H), 1.90 (s, 3H).
Reaction SMILES: [C:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]#[N:18])=[CH:14][CH:15]=2)[CH:10]=[C:9]1B(O)O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Br[C:23]1[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC>[C:4]([O:3][C:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]#[N:18])=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:23]1[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: Brc1cccnc1
Reactant: CC(C)(C)OC(=O)n1c(B(O)O)cc2cc(C#N)ccc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)(C)OC(=O)n1c(-c2cccnc2)cc2cc(C#N)ccc21
Temperature: 130 °C

Procedure:
A mixture of 1-Boc-5-cyanoindole-2-boronic acid (339 mg, 1.19 mmol), 3-bromo-pyridine (150 mg, 93 uL, 0.95 mmol), aqueous sodium carbonate (2M, 0.95 mL, 1.9 mmol) and DME (4 mL) is degassed with nitrogen and PS—Pd(PPh3) (285 mg, 0.11 mmol/g, 0.028 mmol) is added. The resulting mixture is then heated in the microwave at 120° C. for 20 min and at 130° C. for 25 min (three times). The reaction mixture is filtered through a sintered funnel and washed with dichloromethane (50 mL). The filtrate is dried over Na2SO4, filtered, and concentrated. The residue is purified by reverse phase HPLC (5 to 80% acetonitrile-0.1% aqueous ammonia) to give 5-cyano-2-pyridin-3-yl-indole-1-carboxylic acid tert-butyl ester as a solid. 1H NMR (400.3 MHz, CDCl3) δ ppm 1.34 (s, 9H), 6.67 (s, 1H), 7.39 (dd, J=4.9, 7.8 Hz, 1H), 7.61 (dd, J=1.6, 8.7 Hz, 1H), 7.74 (m, 1H), 7.92 (s, 1H), 8.35 (d, J=8.7 Hz, 1H), 8.65 (dd, J=1.6 Hz, 4.9 Hz, 1H), 8.69 (d, J=2.2 Hz, 1H). MS (ESI) m/z 320 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=O)=[CH:4][CH:3]=1.[Cl:16][CH2:17][CH2:18][C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=O>O1CCCC1.C(=O)([O-])[O-].[K+].[K+].[Zn]>[Cl:16][CH2:17][CH2:18][C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[C:6]([C:5]1[CH:14]=[CH:15][C:2]([OH:1])=[CH:3][CH:4]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C(c1ccccc1)c1ccc(O)cc1
Reactant: O=C(CCCl)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Zn]
Solvent: C1CCOC1
Product: Oc1ccc(C(=C(CCCl)c2ccccc2)c2ccccc2)cc1
Temperature: -10 °C
Reaction time: 3.5 h

Procedure:
Zinc (15.0 g, 0.23 mol) and tetrahydrofuran (THF) (180 ml) was added to the reaction vessel and cooled to −10° C. Titan tetrachloride was added dropwise to the mixture (21.6 g, 0.114 mol) at about −10° C. After the addition was completed the mixture was refluxed for two hours. Then the mixture was cooled to 40° C. and 4-hydroxybenzophenone (7.68 g, 0.039 mol) and 3-chloropropiophenone (6.48 g, 0.039 mol) dissolved in THF (75 ml) were added to the mixture. Refluxing was continued for additional 3.5 hours. The cooled reaction mixture was poured in aqueous potassium carbonate solution (21 g K2CO3+210 ml water) and allowed to stand overnight at the ambient temperature. The mixture was filtered and the precipitate was washed with THF. The filtrate was evaporated to dryness. The residue was dissolved in ethyl acetate and washed with water. Ethyl acetate phase was evaporated to dryness and the residue was crystallized first from methanol-water (8:2) and then from methanol-water (9:1). Yield 5.4 g.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[NH:12][C:11](=[O:13])[NH:10][N:9]=2)[CH:5]=[C:4]([CH3:14])[CH:3]=1.[OH:15][C@H:16]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17]1.[H-].[Na+].O>CN1CCCC1=O>[CH3:14][C:4]1[CH:5]=[C:6]([C:8]2[NH:12][C:11](=[O:13])[NH:10][N:9]=2)[N:7]=[C:2]([O:15][C@H:16]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17]2)[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](O)C1
Reactant: Cc1cc(Cl)nc(-c2n[nH]c(=O)[nH]2)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: Cc1cc(O[C@H]2CCN(C(=O)OC(C)(C)C)C2)nc(-c2n[nH]c(=O)[nH]2)c1
Temperature: 140 °C

Procedure:
A mixture of 3-(6-chloro-4-methylpyridin-2-yl)-1H-1,2,4-triazol-5(4H)-one (428 mg, 2.032 mmol), (S)-tert-butyl 3-hydroxypyrrolidine-1-carboxylate (457 mg, 2.439 mmol) and sodium hydride (81 mg, 2.032 mmol) in N-methyl-2-pyrrolidinone (7 mL) was heated in a microwave reactor at 140° C. for 30 minutes. After cooling, water was added and the mixture was extracted with EtOAc. The aqueous layer was acidified with 1M HCl aq and extracted with EtOAc. The organic layers were combined, dried over MgSO4, filtered, and evaporated in vacuo to give the title compound, which was used without further purification. ESI-MS [M+H-tert-butyl]+ 306.2.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10].N1C=CC=CC=1.[C:20](Cl)(=[O:24])[O:21][CH2:22][CH3:23]>C(OCC)(=O)C>[C:20](=[O:24])([O:21][CH2:22][CH3:23])[O:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][C:7]([O:8][C:9]([CH3:10])([CH3:12])[CH3:11])=[O:13]
Reactant: CCOC(=O)Cl
Reactant: CC(C)(C)OC(=O)NCCCCO
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCOC(=O)OCCCCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 96 %

Procedure:
To a mixture of tert-butyl 4-hydroxybutylcarbamate (3.71 g) obtained in Reference Example 35 and ethyl acetate (20 mL) were added pyridine (1.71 mL) and ethyl chlorocarbonate (2.55 g) under ice-cooling, and the mixture was stirred at room temperature for 24 hrs. Ethyl acetate (100 mL) was added to the reaction mixture, and the mixture was washed with water (50 mL), an aqueous copper sulfate solution (30 mL), water (30 mL) and saturated brine (30 mL) and dried over anhydrous magnesium sulfate. Concentration under reduced pressure gave the title compound (4.92 g) as a colorless oil.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:8](O)[CH2:9][C:10]#[CH:11]>>[C:1]1([O:7][CH2:11][CH2:10][C:9]#[CH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C#CCCO
Reactant: Oc1ccccc1
Product: C#CCCOc1ccccc1

Procedure:
The title compound was synthesized using phenol and 3-butyn-1-ol by conducting a reaction similar to that mentioned in Reference example 35.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([CH2:11][CH:12]=C)[CH:8]=[CH:7][C:4]=1[C:5]#[N:6].Cl.[N:15]1([C:21](=[O:34])[CH2:22][C:23]2[CH:28]=[CH:27][C:26]([N:29]3[CH:33]=[N:32][N:31]=[N:30]3)=[CH:25][CH:24]=2)[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.C([BH3-])#N.[Na+]>CO.C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:10]=[C:9]([CH2:11][CH2:12][N:18]2[CH2:17][CH2:16][N:15]([C:21](=[O:34])[CH2:22][C:23]3[CH:24]=[CH:25][C:26]([N:29]4[CH:33]=[N:32][N:31]=[N:30]4)=[CH:27][CH:28]=3)[CH2:20][CH2:19]2)[CH:8]=[CH:7][C:4]=1[C:5]#[N:6]
Reactant: O=C(Cc1ccc(-n2cnnn2)cc1)N1CCNCC1
Reactant: C=CCc1ccc(C#N)c(OC)c1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COc1cc(CCN2CCN(C(=O)Cc3ccc(-n4cnnn4)cc3)CC2)ccc1C#N
Temperature: -78 °C
Reaction time: 2 h

Procedure:
2-Methoxy-4-(prop-2-en-1-yl)benzonitrile (100 mg, 0.577 mmol) was dissolved in methanol (13 mL) and the resulting solution was cooled to −78° C. Ozone was bubbled through the solution until a blue color appeared (˜15 minutes). 1-(Piperazin-1-yl)-2-[4-(1H-tetrazol-1-yl)phenyl]ethanone hydrochloride (178 mg, 0.577 mmol) was added, followed by sodium cyanoborohydride (363 mg, 5.77 mmol). After stirring the reaction mixture for ˜5 minutes 3 drops of acetic acid were added and the mixture was permitted to warm to rt and stir for 2 h. The reaction mixture was concentrated to dryness, dissolved in EtOAc (40 mL) and washed with brine, saturated NaHCO3 solution. The organic layer was dried over Na2SO4, filtered and concentrated to dryness. The residue was then purified by mass directed HPLC to afford the title compound. LC/MS: [(M+1)]+=432.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH:19][C:20](=[O:35])[CH2:21][C:22](=O)[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([N:29]2[CH:33]=[N:32][CH:31]=[N:30]2)[CH:24]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:14][C:12]1[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]2[NH:19][C:20](=[O:35])[CH2:21][C:22]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([N:29]4[CH:33]=[N:32][CH:31]=[N:30]4)[CH:24]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(Cl)c(C(F)(F)F)cc1NC(=O)CC(=O)c1cccc(-n2cncn2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1CC(c2cccc(-n3cncn3)c2)=Nc2cc(Cl)c(C(F)(F)F)cc2N1

Procedure:
The title compound was prepared from {5-chloro-2-[3-oxo-3-(3-[1,2,4]triazol-1-yl-phenyl)-propionylamino]-4-trifluoromethyl-phenyl}-carbamic acid tert-butyl ester (Example M48) (0.35 g, 0.67 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (211 mg, 78%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10]([CH:12]=C)=[N:9][C:8]([C@@H:14]([NH:16][C:17]1[N:25]=[CH:24][N:23]=[C:22]3[C:18]=1[N:19]=[CH:20][N:21]3[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=1)[CH3:15])=[CH:7]2.I([O-])(=O)(=O)=[O:36].[Na+]>O1CCOCC1.O.[Os](=O)(=O)(=O)=O>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10]([CH:12]=[O:36])=[N:9][C:8]([C@@H:14]([NH:16][C:17]1[N:25]=[CH:24][N:23]=[C:22]3[C:18]=1[N:19]=[CH:20][N:21]3[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=1)[CH3:15])=[CH:7]2
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=Cc1nc([C@H](C)Nc2ncnc3c2ncn3Cc2ccc(OC)cc2)cc2cccc(Cl)c12
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(Cn2cnc3c(N[C@@H](C)c4cc5cccc(Cl)c5c(C=O)n4)ncnc32)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred mixture of (S)—N-(1-(8-chloro-1-vinylisoquinolin-3-yl)ethyl)-9-(4-methoxybenzyl)-9H-purin-6-amine 2 (3.6 g, 7.6 mmol, 1 eq) in a mixture of 1,4-dioxane (40 mL) and H2O (40 mL) at RT, osmium tetraoxide (5 mg) was added and the resulting mixture was stirred at RT for 30 min. To this mixture, sodium periodate (3.3 g, 15.2 mmol, 2 eq) was added and the resulting mixture was stirred at RT overnight. The reaction mixture was filtered through silica gel (10 g). The filtrate was extracted with DCM (3×60 mL), washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was purified by flash column chromatography on silica gel (1-5% MeOH-DCM) to afford the product, (S)-8-chloro-3-(1-((9-(4-methoxybenzyl)-9H-purin-6-yl)amino)ethyl)isoquinoline-1-carbaldehyde 5.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[C:7]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)=[C:18]([Cl:30])[CH:17]=1)=[N:8][CH:9]=[N:10]2.[OH:31][C@@H:32]1[CH2:37][CH2:36][O:35][C:33]1=[O:34]>>[Cl:30][C:18]1[CH:17]=[C:16]([NH:15][C:7]2[C:6]3[C:11](=[CH:12][CH:13]=[CH:14][C:5]=3[O:4][CH2:3][CH2:2][NH:1][C:33](=[O:34])[C@H:32]([OH:31])[CH2:37][CH2:36][OH:35])[N:10]=[CH:9][N:8]=2)[CH:21]=[CH:20][C:19]=1[O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1
Reactant: NCCOc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Reactant: O=C1OCC[C@H]1O
Product: O=C(NCCOc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12)[C@H](O)CCO
Yield: 55 %

Procedure:
The procedure described in Example 63 was repeated using 5-(2-aminoethoxy)-N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]quinazolin-4-amine (obtained as described in Example 2.6, preparation of starting materials) and (R)-(+)-α-hydroxy-γ-butyrolactone to give the title compound in 55% yield; NMR spectrum (DMSO-d6) 1.38-1.55 (m, 1H), 1.69-1.85 (m, 1H), 3.37-3.50 (m, 2H), 3.61-3.77 (m, 2H), 3.89-4.00 (m, 1H), 4.28-4.45 (m, 3H), 5.29 (s, 2H), 5.51 (d, 1H), 7.13 (d, 1H), 7.22 (d, 1H), 7.28-7.41 (m, 2H), 7.49-7.62 (m, 2H), 7.71 (t, 1H), 8.01 (d, 1H), 8.14-8.25 (m, 1H), 8.45 (s, 1H), 8.59 (d, 1H), 9.82 (s, 1H); Mass spectrum MH+ 523.9.
Reaction SMILES: [C:1]([O:5][CH:6]([C:11]1[C:12]([C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[O:27][CH2:26][CH2:25][CH2:24]3)=[C:13]2[CH:20]=[CH:19][NH:18][C:14]2=[N:15][C:16]=1[CH3:17])[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].[CH3:31][O:32][C:33]1[CH:40]=[CH:39][C:36]([CH2:37]Br)=[CH:35][C:34]=1[C:41]([F:44])([F:43])[F:42]>>[C:1]([O:5][CH:6]([C:11]1[C:12]([C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[O:27][CH2:26][CH2:25][CH2:24]3)=[C:13]2[CH:20]=[CH:19][N:18]([CH2:37][C:36]3[CH:39]=[CH:40][C:33]([O:32][CH3:31])=[C:34]([C:41]([F:42])([F:43])[F:44])[CH:35]=3)[C:14]2=[N:15][C:16]=1[CH3:17])[C:7]([OH:9])=[O:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: COc1ccc(CBr)cc1C(F)(F)F
Reactant: COC(=O)C(OC(C)(C)C)c1c(C)nc2[nH]ccc2c1-c1ccc2c(c1)CCCO2
Product: COc1ccc(Cn2ccc3c(-c4ccc5c(c4)CCCO5)c(C(OC(C)(C)C)C(=O)O)c(C)nc32)cc1C(F)(F)F

Procedure:
The title compound was prepared in a manner similar to that described in Example 27, Step H from methyl 2-(tert-butoxy)-2-(4-(chroman-6-yl)-6-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)acetate and 4-methoxy-3-(trifluoromethyl)benzyl bromide. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.58 (s, 1 H), 7.50-7.37 (m, 2 H), 7.26-7.19 (m, 1 H), 7.04-7.00 (m, 1 H), 6.98-6.89 (m, 2 H), 6.27-6.20 (m, 1 H), 5.62-5.56 (m, 1 H), 5.53-5.44 (m, 1 H), 5.43-5.34 (m, 1 H), 4.32-4.24 (m, 2 H), 3.89 (s, 3 H), 2.96-2.79 (m, 2 H), 2.72 (s, 3 H), 2.15-2.06 (m, 2 H), 1.00-0.92 (s, 9 H); LC/MS (m/z) ES+=583.38 (M+1).
Reaction SMILES: [OH:1][C:2]1[C:7]([CH:8]=[O:9])=[CH:6][C:5]([O:10][CH3:11])=[N:4][CH:3]=1.[CH2:12](O)[CH2:13][OH:14].CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[O:9]1[CH2:12][CH2:13][O:14][CH:8]1[C:7]1[CH:6]=[C:5]([O:10][CH3:11])[N:4]=[CH:3][C:2]=1[OH:1]
Reactant: COc1cc(C=O)c(O)cn1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: COc1cc(C2OCCO2)c(O)cn1
Temperature: 25 °C
Yield: 76 %

Procedure:
To 5-hydroxy-2-methoxyisonicotinaldehyde (1.0 g, 6.54 mmol, 1.0 eq.) in toluene (50.0 mL) were added ethane-1,2-diol (10.0 mL) and PTSA (248 mg, 1.31 mmol, 0.2 eq.). The mixture was heated to reflux O/N, cooled to rt, neutralized to pH 8, and extracted with EtOAc three times. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated to give 4-(1,3-dioxolan-2-yl)-6-methoxypyridin-3-ol (980 mg, 76%) as an off-white solid. LRMS (M+H+) m/z 198.1.
Reaction SMILES: [O:1]1[CH2:15][CH:2]1[CH2:3][O:4][C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=1.[C:16]([NH2:20])([CH3:19])([CH3:18])[CH3:17]>CO>[OH:1][CH:2]([CH2:15][NH:20][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:3][O:4][C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=1
Reactant: CC(C)(C)N
Reactant: COC(=O)c1ccc(OCC2CO2)cc1
Solvent: CO
Product: COC(=O)c1ccc(OCC(O)CNC(C)(C)C)cc1
Yield: 65 %

Procedure:
A mixture of methyl 4-(2,3-epoxypropoxy)benzoate (prepared as described in Example I) (2.1 g, 0.01 mole), 10 mL of t-butylamine and 10 mL of methanol was heated to reflux for three hours. The reaction medium was then evaporated under reduced pressure to provide the amine as an oil. The free amine was crystallized from hexane-ethyl acetate in 65% yield: m.p. 88°-89° C. The NMR spectrum and elemental analysis were consistent with the assigned structure.
Reaction SMILES: O1CCCCC1[N:7]1[C:11]2[CH:12]=[CH:13][C:14]([C:16]([NH2:19])([CH3:18])[CH3:17])=[CH:15][C:10]=2[N:9]=[CH:8]1.Cl[C:21]1[N:26]=[C:25]([NH:27][C:28]2[NH:32][N:31]=[C:30]([CH:33]3[CH2:35][CH2:34]3)[CH:29]=2)[CH:24]=[CH:23][N:22]=1>>[NH:7]1[C:11]2[CH:12]=[CH:13][C:14]([C:16]([NH:19][C:21]3[N:26]=[C:25]([NH:27][C:28]4[CH:29]=[C:30]([CH:33]5[CH2:35][CH2:34]5)[NH:31][N:32]=4)[CH:24]=[CH:23][N:22]=3)([CH3:17])[CH3:18])=[CH:15][C:10]=2[N:9]=[CH:8]1
Reactant: CC(C)(N)c1ccc2c(c1)ncn2C1CCCCO1
Reactant: Clc1nccc(Nc2cc(C3CC3)n[nH]2)n1
Product: CC(C)(Nc1nccc(Nc2cc(C3CC3)[nH]n2)n1)c1ccc2[nH]cnc2c1
Temperature: 140 °C
Reaction time: 18 h

Procedure:
A neat mixture of 94 (691 mg, 2.67 mmol) and 53 (210 mg, 0.89 mmol) was stirred under nitrogen at 140° C. for 18 h. The dark brown mixture was cooled to RT and was purified by preparative HPLC to afford 25 mg (7.5%) of I-17 as white solid.
Reaction SMILES: C(N(CC)C(C)C)(C)C.Br[CH2:11][CH2:12][OH:13].[I-].[K+].[CH3:16][C:17]1([CH3:30])[CH:26]=[C:25]([CH3:27])[C:24]2[C:19](=[CH:20][C:21]([O:28][CH3:29])=[CH:22][CH:23]=2)[NH:18]1>>[OH:13][CH2:12][CH2:11][N:18]1[C:19]2[C:24](=[CH:23][CH:22]=[C:21]([O:28][CH3:29])[CH:20]=2)[C:25]([CH3:27])=[CH:26][C:17]1([CH3:30])[CH3:16]
Reactant: OCCBr
Reactant: COc1ccc2c(c1)NC(C)(C)C=C2C
Agent: [I-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2c(c1)N(CCO)C(C)(C)C=C2C
Temperature: 115 °C
Reaction time: 24 h

Procedure:
51 g (0.4 mol) N,N-diisopropylethylamine, 72.5 g (0.57 mol) 2-bromoethanol and a spatula tip of potassium iodide were added to 50 g (0.24 mol) 2,2,4-trimethyl-7-methoxy-1,2-dihydroquinoline. The solution was stirred for 24 hours at 110 to 120° C. The organic phase was subsequently washed with dilute sodium hydroxide solution and water and dried over sodium sulfate. The solvent was then completely removed by distillation. A light-green oil was obtained as the product.
Reaction SMILES: [N+:1]([CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[C:8]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH:7]=1)([O-])=O.[H][H]>C(O)C.Cl.[Pd]>[NH2:1][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[C:8]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH:7]=1
Reactant: [H][H]
Reactant: CCCCCCOc1ccc(C=C[N+](=O)[O-])cc1OCCCCCC
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CCCCCCOc1ccc(CCN)cc1OCCCCCC

Procedure:
1-Nitro-2-(3,4-dihexyloxyphenyl)ethene (30 g; 85.8 mmol) is dissolved in ethanol with the addition of hydrochloric acid and transferred to a hydrogenation autoclave charged with Pd/C. Cooling is then carried out, and hydrogen is introduced until no further reaction takes place. Filtration is then carried out over a silica gel column, followed by concentration to dryness by evaporation.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([CH3:10])[N:3]=1.[CH2:11]([O:13][C:14](=[N:18][S:19]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[O:28][CH:29]([F:31])[F:30])(=[O:21])=[O:20])OCC)[CH3:12]>O1CCCC1.CCOCC>[F:31][CH:29]([F:30])[O:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[S:19]([NH:18][C:14](=[N:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([CH3:10])[N:3]=1)[O:13][CH2:11][CH3:12])(=[O:21])=[O:20]
Reactant: COc1cc(C)nc(N)n1
Reactant: CCOC(=NS(=O)(=O)c1ccccc1OC(F)F)OCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCOC(=Nc1nc(C)cc(OC)n1)NS(=O)(=O)c1ccccc1OC(F)F
Temperature: 25 °C

Procedure:
To a solution of 11.2 g (0.1 mol) of potassium tertbutylate in 125 ml of tetrahydrofuran are added at room temperature, with stirring, 13.9 g (0.1 mol) of 2-amino-4-methoxy-6-methylpyrimidine. Stirring is maintained for 2 hours at room temperature, and 32.3 g (0.1 mol) of N-(2-difluoromethoxy-benzenesulfonyl)-imido carbonic acid diethyl ester (obtained according to Example 1) are then added, the reaction mixture being stirred for a further 20 hours. The mixture is subsequently concentrated by evaporation, and the residue is taken up in water and rendered acid with hydrochloric acid. The acid solution is extracted with ethyl acetate; the organic phases are then collected, dried, and concentrated by evaporation to leave a solid residue, which is suspended in ether and again filtered off. The yield is 34.5 g (83% of theory) of the above sulfonylisourea, m.p. 131°-133° C.