Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3](OS(C(F)(F)F)(=O)=O)=[C:4]([CH:9]=[C:10]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH:25]=[CH:24][CH:23]=[N:22]3)=[CH:17][CH:16]=2)[C:11]=1[O:12][CH3:13])[C:5]([O:7][CH3:8])=[O:6].O.[CH:35]([B-](F)(F)F)=[CH2:36].[K+].C(=O)([O-])[O-].[Cs+].[Cs+]>C1COCC1.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>[Cl:1][C:2]1[C:3]([CH:35]=[CH2:36])=[C:4]([CH:9]=[C:10]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH:25]=[CH:24][CH:23]=[N:22]3)=[CH:17][CH:16]=2)[C:11]=1[O:12][CH3:13])[C:5]([O:7][CH3:8])=[O:6]
Reactant: C=C[B-](F)(F)F
Reactant: COC(=O)c1cc(Cc2ccc(-n3cccn3)cc2)c(OC)c(Cl)c1OS(=O)(=O)C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1CCOC1
Product: C=Cc1c(C(=O)OC)cc(Cc2ccc(-n3cccn3)cc2)c(OC)c1Cl
Yield: 29.3 %

Procedure:
To a solution of methyl 3-chloro-4-methoxy-5-[4-(1H-pyrazol-1-yl)benzyl]-2-{[(trifluoromethyl)sulfonyl]oxy}benzoate (0.36 g) in THF (8.00 mL)-water (3.00 mL) were added potassium vinyltrifluoroborate (0.17 g), cesium carbonate (0.60 g) and tetrakis(triphenylphosphine)palladium(0) (0.04 g), and the mixture was heated with reflux for 16 hr under nitrogen atmosphere. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by thin layer chromatography (ethyl acetate/petroleum ether) to give the title compound (0.08 g).
Reaction SMILES: [ClH:1].Cl.[C:3]([C:6]1[CH:7]=[CH:8][C:9]2[O:13][C:12]([CH2:14][CH:15]([C:19]3[CH:24]=[CH:23][C:22]([O:25][C@H:26]4[CH2:30][CH2:29][NH:28][CH2:27]4)=[CH:21][CH:20]=3)[C:16]([OH:18])=[O:17])=[CH:11][C:10]=2[CH:31]=1)(=[NH:5])[NH2:4].Cl.[C:33](=[NH:38])(OCC)[CH3:34].[OH-].[Na+].Cl>O.O.C(#N)C>[ClH:1].[ClH:1].[C:33]([N:28]1[CH2:29][CH2:30][C@H:26]([O:25][C:22]2[CH:21]=[CH:20][C:19]([CH:15]([CH2:14][C:12]3[O:13][C:9]4[CH:8]=[CH:7][C:6]([C:3](=[NH:4])[NH2:5])=[CH:31][C:10]=4[CH:11]=3)[C:16]([OH:18])=[O:17])=[CH:24][CH:23]=2)[CH2:27]1)(=[NH:38])[CH3:34]
Reactant: N=C(N)c1ccc2oc(CC(C(=O)O)c3ccc(O[C@H]4CCNC4)cc3)cc2c1
Reactant: CCOC(C)=N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: CC(=N)N1CC[C@H](Oc2ccc(C(Cc3cc4cc(C(=N)N)ccc4o3)C(=O)O)cc2)C1
Yield: 130.3 %

Procedure:
1.1 g of 3-(5-amidino-2-benzofuranyl)-2-[4-[((3S)-3-pyrrolidinyl)oxy]phenyl]propionic acid dihydrochloride was dissolved in 20 ml of water. During ice cooling and stirring, 1.4 g of ethyl acetimidate hydrochloride was added gradually to the thus prepared solution while adjusting the pH of the solution to 8.5 with 1N sodium hydroxide aqueous solution. The resulting mixture was stirred for 15 minutes with ice cooling, and then adjusted to pH 2.0 with dilute hydrochloric acid. After concentrating the resulting reaction solution to dryness, the thus obtained residue was subjected to reversed phase high performance liquid chromatography using a column packed with octadecyl-bonded silica gel and using a water/acetonitrile mixture as an elution solvent. Thereafter, the thus eluted fractions of interest were pooled, mixed with dilute hydrochloric acid, and then concentrated to dryness. In this way, 780 mg of the title compound was obtained in a solid form.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[N:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(=O)(=O)(O)O.[CH2:16](O)[CH3:17]>>[Br:1][C:2]1[CH:10]=[N:9][CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH2:16][CH3:17])=[O:5]
Reactant: CCO
Reactant: O=C(O)c1ccncc1Br
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1ccncc1Br
Temperature: 25 °C

Procedure:
3-bromoisonicotinic acid (3.0 g, 14.9 mmol) in ethanol (100 mL) was treated with concentrated sulfuric acid (5 mL). The mixture was brought to reflux at which time everything went into solution. After 12 hours at reflux, LCMS indicated that the reaction was complete. The reaction mixture was cooled to room temperature and concentrated on a rotary evaporator to a third of its original volume. The mixture was then diluted with 250 mL of ethyl acetate and washed twice with saturated aqueous sodium bicarbonate. Concentration on a rotary evaporator yielded 3.25 g of ethyl 3-bromoisonicotinate as a yellowish oil which was sufficiently pure enough for subsequent chemical transformations. LCMS (ESI) 216.2 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[CH3:10].[Br:11]N1C(=O)CCC1=O>C(CC(O)=O)(C)(C)C.N(C(C)(C)C#N)=NC(C)(C)C#N>[Br:11][CH2:10][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:2]=1[Cl:1])[C:6]#[N:7]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(C#N)ccc1Cl
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CC(C)(C)CC(=O)O
Product: N#Cc1ccc(Cl)c(CBr)c1
Temperature: 90 °C
Reaction time: 12 h
Yield: 98.7 %

Procedure:
(Step 1) To a solution of 4-chloro-3-methylbenzonitrile (1 g) in t-butylacetic acid (10 ml) were added N-bromosuccinimide (1.5 g) and azobisisobutyronitrile (0.05 g), and the mixture was stirred at 90° C. for 12 hr. The reaction mixture was quenched with saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate:hexane=0:1-1:9) to give 3-(bromomethyl)-4-chlorobenzonitrile (1.5 g) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:10]=[N:9][N:8]([CH:11]3[CH2:15][CH2:14][CH:13]=[CH:12]3)[C:4]=2[N:5]=[CH:6][N:7]=1.[OH2:16].C[N+]1([O-])CCOCC1.[OH2:25]>C(O)(C)(C)C.[Os](=O)(=O)(=O)=O>[NH2:1][C:2]1[C:3]2[N:10]=[N:9][N:8]([C@@H:11]3[CH2:15][CH2:14][C@@H:13]([OH:16])[C@H:12]3[OH:25])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Nc1ncnc2c1nnn2C1C=CCC1
Reactant: O
Agent: O=[Os](=O)(=O)=O
Agent: C[N+]1([O-])CCOCC1
Solvent: CC(C)(C)O
Product: Nc1ncnc2c1nnn2[C@@H]1CC[C@@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
(±)-7-Amino-3-(2-cyclopenten-1-yl)-1,2,3-triazolo[4,5-d]pyrimidine (4.80 g, 23.7 mmol), N-methylmorpholine N-oxide monohydrate (3.15 g, 26.1 mmol as 97%), water (35 ml), t-butylalcohol (175 ml) and 2.5% osmium tetroxide in t-butyl alcohol (1.0 ml) were refluxed for 3 hours and then stirred at 25° C. for 18 hours. The resulting mixture was evaporated to dryness and chromatographed on silica gel. Title compound was eluted with MeOH:CHCl3 /1:3 to give white crystals after two recrystallizations from ethanol-water (3.74 g, 67%); mp 244°-245° C.; 1H-NMR (Me2SO-d6) δ8.26 (s, 1, H-5'), 8.35 and 8.05 (both br s) overlapping 8.26 (s) (total 3 protons, tautomers NH2 and H-5'), 5.2-5.0 (m) overlapping 5.01 (d, J=7.3) (total 2, OH and H-3 ), 4.72 (d, J=3.5, 1, OH), 4.5-4.4 (m, 1, H-2), 4.1-4.0 (m, 1, H-1), 2.4-1.6 (m, 4, two CH2).
Reaction SMILES: [OH-].[Na+].C1COCC1.[Cl:8][C:9]1[C:10]([CH2:35][NH:36][C:37]2[CH:42]=[CH:41][C:40]([C:43]3[CH:48]=[CH:47][C:46]([Cl:49])=[CH:45][C:44]=3[Cl:50])=[CH:39][CH:38]=2)=[C:11]([C:19]2[CH:20]=[CH:21][C:22]([C:25]([NH:27][CH2:28][CH2:29][C:30]([O:32]CC)=[O:31])=[O:26])=[N:23][CH:24]=2)[CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:14]=1.Cl>CCOC(C)=O.[Na+].[Cl-].CO>[Cl:8][C:9]1[C:10]([CH2:35][NH:36][C:37]2[CH:42]=[CH:41][C:40]([C:43]3[CH:48]=[CH:47][C:46]([Cl:49])=[CH:45][C:44]=3[Cl:50])=[CH:39][CH:38]=2)=[C:11]([C:19]2[CH:20]=[CH:21][C:22]([C:25]([NH:27][CH2:28][CH2:29][C:30]([OH:32])=[O:31])=[O:26])=[N:23][CH:24]=2)[CH:12]=[C:13]([C:15]([F:16])([F:17])[F:18])[CH:14]=1
Reactant: CCOC(=O)CCNC(=O)c1ccc(-c2cc(C(F)(F)F)cc(Cl)c2CNc2ccc(-c3ccc(Cl)cc3Cl)cc2)cn1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)CCNC(=O)c1ccc(-c2cc(C(F)(F)F)cc(Cl)c2CNc2ccc(-c3ccc(Cl)cc3Cl)cc2)cn1
Temperature: 40 °C

Procedure:
A 3M aqueous solution of NaOH (3.1 mL, 9.3 mmol) was added to a THF (12.6 mL) and MeOH (6.3 mL) solution of ethyl 3-(5-(3-chloro-2-(((2′,4′-dichloro-[1,1′-biphenyl]-4-yl)amino)methyl)-5-(trifluoromethyl)phenyl)picolinamido)propanoate (4.1 g, 6.3 mmol) and the resulting homogeneous mixture was heated to 40° C. After 30 min the resulting mixture was acidified with 6M aqueous HCl (1.6 mL, 9.6 mmol) diluted with EtOAc and 4M aqueous NaCl, and the layers were separated. The aqueous layer was extracted with EtOAc and the combined organics were washed with 4M NaCl, dried (Na2SO4), concentrated, and purified via HPLC to yield the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH3:13])[C:6]([NH:14][C:15](=[O:19])OCC)=[N:5]2.[C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)#[N:21]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH3:13])[C:6]([NH:14][C:15]([N:31]1[CH2:30][CH2:29][N:28]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[C:20]#[N:21])[CH2:33][CH2:32]1)=[O:19])=[N:5]2
Reactant: N#Cc1ccccc1N1CCNCC1
Reactant: CCOC(=O)Nc1nc2cc(Cl)ccc2nc1OC
Product: COc1nc2ccc(Cl)cc2nc1NC(=O)N1CCN(c2ccccc2C#N)CC1
Yield: 91 %

Procedure:
Ethyl N-(6-chloro-2-methoxyquinoxalin-3-yl)carbamate and 1-(2-cyanophenyl)piperazine were reacted by the same way with the example 22 to obtain the titled compound (yield, 91%). 1H NMR (300 MHz, CDCl3): δ 3.25-3.32 (m, 4H), 3.84 (s, 3H), 4.08-4.15 (m, 4H), 7.06-7.08 (m, 2H), 7.21 (m, 1H), 7.41-7.67 (m, 4H), 7.82 (s, 1H).
Reaction SMILES: [CH2:1]([O:8][NH:9][CH:10]([CH2:13][CH3:14])[CH2:11][CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CCCC1.[CH3:20][N:21]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:22](Cl)=[O:23]>CN(C)C1C=CN=CC=1.C(N(CC)CC)C>[CH2:1]([O:8][N:9]([CH:10]([CH2:13][CH3:14])[CH2:11][CH3:12])[C:22]([N:21]([CH3:20])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCC(CC)NOCc1ccccc1
Reactant: CN(C(=O)Cl)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCC(CC)N(OCc1ccccc1)C(=O)N(C)c1ccccc1
Temperature: 130 °C
Yield: 59.5 %

Procedure:
A tube was charged with a stir bar, N-benzyloxy-N-(1-ethylpropyl)amine (2.0 g, 10.3 mmole), tetrahydrofuran (5 mL), triethylamine (4.31 mL), N-methyl-N-phenylcarbamoyl chloride (1.75 g, 10.3 mmole), and 4-dimethylaminopyridine (1 mg). The tube was flushed with nitrogen, sealed and then heated to 130° C. After 48 hours the reaction mixture was cooled to ambient temperature and concentrated under vacuum. The residue was purified by chromatography (silica gel; 9:1 hexanes:ethyl acetate) to provide 2.0 g of 1-benzyloxy-1-(1-ethylpropyl)-3-methyl-3-phenylurea.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([Cl:14])=[C:8]([S:10](Cl)(=[O:12])=[O:11])[CH:9]=1)([OH:3])=[O:2].S([O-])([O-])=O.[Na+:19].[Na+].Cl>O>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([Cl:14])=[C:8]([S:10]([O-:12])=[O:11])[CH:9]=1)([OH:3])=[O:2].[Na+:19].[Na+:19].[C:1]([C:4]1[CH:5]=[CH:6][C:7]([Cl:14])=[C:8]([S:10]([O-:12])=[O:11])[CH:9]=1)([OH:3])=[O:2]
Reactant: O=C(O)c1ccc(Cl)c(S(=O)(=O)Cl)c1
Agent: Cl
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=C(O)c1ccc(Cl)c(S(=O)[O-])c1

Procedure:
is obtained from 186 g of 5-carboxy-2-chlorobenzenesulfinic acid, prepared by reduction of 261 g of 5-carboxy-2-chlorobenzenesulfonyl chloride with 157 g of sodium sulfite in 700 ml of water at 70° C. at pH 9-10 and subsequent acidification using HCl, by neutralization with 67.6 g of caustic soda in 2 liters of water, removal the latter by distillation and crystallization of the residue with acetone.
Reaction SMILES: CC(C)([O-])C.[K+].[CH2:7]([N:14]([CH2:18][C:19]1[C:24](Cl)=[N:23][C:22]([N:26]([CH3:31])[CH:27]([CH3:30])[CH2:28][CH3:29])=[CH:21][N:20]=1)[CH2:15][CH2:16][OH:17])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O>CN(C=O)C>[CH2:7]([N:14]1[CH2:18][C:19]2[N:20]=[CH:21][C:22]([N:26]([CH3:31])[CH:27]([CH3:30])[CH2:28][CH3:29])=[N:23][C:24]=2[O:17][CH2:16][CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCC(C)N(C)c1cnc(CN(CCO)Cc2ccccc2)c(Cl)n1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCC(C)N(C)c1cnc2c(n1)OCCN(Cc1ccccc1)C2
Reaction time: 2.5 h
Yield: 77.3 %

Procedure:
To a solution of potassium tert-butoxide (0.77 g) in DMF (5 mL) was added dropwise a solution of 2-[benzyl({3-chloro-5-[methyl(1-methylpropyl)amino]pyrazin-2-yl}methyl)amino]ethanol (2.07 g) in DMF (5 mL) at 0° C., and the mixture was stirred for 2.5 hr. Water (10 mL) was added, and the mixture was extracted with ethyl acetate. The aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with water and saturated brine, dried over magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (solvent gradient: 20→80% ethyl acetate/hexane) to give the title compound (1.44 g, 77%) as a pale-yellow oil.
Reaction SMILES: [H][H].[N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[C:13]1[C:25]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18](=[N:26]O)[C:17]=2[CH:16]=[CH:15][CH:14]=1>C(O)C.O1CCCC1.[Ni]>[N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[C:13]1[C:25]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]([NH2:26])[C:17]=2[CH:16]=[CH:15][CH:14]=1
Reactant: ON=C1c2ccccc2-c2c1cccc2-c1ccc2ccccc2n1
Reactant: [H][H]
Agent: [Ni]
Solvent: CCO
Solvent: C1CCOC1
Product: NC1c2ccccc2-c2c(-c3ccc4ccccc4n3)cccc21
Temperature: 60 °C

Procedure:
In a 100 mL autoclave, dissolve 0.9 g of equimolecular mixture of the Z and E isomers of 4-(quinolin-2-yl)-fluoren-9-one oxime, obtained in Stage 3, in a mixture of 40 mL of ethanol and 40 mL of tetrahydrofuran, add a spatula tip of Raney nickel, then submit to an initial hydrogen pressure of 1 bar and heat the autoclave at 60° C. for 2 hours. After cooling, filter the catalyst on Celite and concentrate the filtrate at reduced pressure. After purification by flash chromatography on silica gel (20-40 μm), eluting with a mixture of dichloromethane and methanol (95-05 by volume), we obtain 0.72 g of 4-(quinolin-2-yl)-9H-fluoren-9-(R,S)-yl-amine in the form of a white meringue with the following characteristics:
Reaction SMILES: [Zn](CC)[CH2:2]C.C(O)(C(F)(F)F)=O.C(I)I.[F:16][CH:17]([F:31])[C:18]([O:20][Si:21]([CH:28]([CH3:30])[CH3:29])([CH:25]([CH3:27])[CH3:26])[CH:22]([CH3:24])[CH3:23])=[CH2:19].C(Cl)Cl>C(Cl)Cl>[F:31][CH:17]([F:16])[C:18]1([O:20][Si:21]([CH:25]([CH3:27])[CH3:26])([CH:28]([CH3:30])[CH3:29])[CH:22]([CH3:24])[CH3:23])[CH2:2][CH2:19]1
Reactant: C=C(O[Si](C(C)C)(C(C)C)C(C)C)C(F)F
Reactant: CC[Zn]CC
Solvent: ClCCl
Solvent: ICI
Solvent: O=C(O)C(F)(F)F
Product: CC(C)[Si](OC1(C(F)F)CC1)(C(C)C)C(C)C
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
A round bottom flask (fitted with glass inlet and outlet) was charged with 60 ml DCM followed by Et2Zn (60 mmol, 60 ml, 1 M in hexane) and cooled to 0° C. TFA (60 mmol, 4.62 ml dissolved in 30 ml DCM) was slowly added to the stirring solution. The reaction was stirred for 20 minutes, followed by addition of CH2I2 (60 mmol, 4.83 ml dissolved in 20 ml DCM) and 20 minutes further stirring. At this point, (1-Difluoromethyl-vinyloxy)-triisopropyl-silane DCM (11.98 mmol, 3 g dissolved in 30 mL) was added and the mixture warmed to rt and stirred for 1 hour. The reaction was then quenched with 1 N HCl and water and extracted two times with hexane. The combined organics were washed with saturated NaHCO3 and dried over sodium sulfate and concentrated, providing (1-difluoromethyl-cyclopropoxy)-triisopropyl-silane which was used crude in the next reaction.
Reaction SMILES: CC(C)[C@H](N1CC2C(=CC(C3C=CC(NC(C4SC(C5C=CC=CC=5)=CN=4)=O)=CC=3)=CC=2)C1=O)C(OC)=O.[NH2:39][C:40]1[CH:41]=[CH:42][C:43]([C:46]2[CH:54]=[C:53]3[C:49]([CH2:50][N:51]([C@@H:56]([CH:61]([CH3:63])[CH3:62])[C:57]([O:59][CH3:60])=[O:58])[C:52]3=[O:55])=[CH:48][CH:47]=2)=[N:44][CH:45]=1.[C:64]1([C:70]2[O:74][C:73]([C:75](OCC)=[O:76])=[N:72][CH:71]=2)[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1>>[CH3:62][CH:61]([CH3:63])[C@H:56]([N:51]1[CH2:50][C:49]2[C:53](=[CH:54][C:46]([C:43]3[CH:42]=[CH:41][C:40]([NH:39][C:75]([C:73]4[O:74][C:70]([C:64]5[CH:65]=[CH:66][CH:67]=[CH:68][CH:69]=5)=[CH:71][N:72]=4)=[O:76])=[CH:45][N:44]=3)=[CH:47][CH:48]=2)[C:52]1=[O:55])[C:57]([O:59][CH3:60])=[O:58]
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(N)cn3)cc2C1=O
Reactant: CCOC(=O)c1ncc(-c2ccccc2)o1
Agent: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ncc(-c5ccccc5)s4)cc3)cc2C1=O
Product: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ncc(-c5ccccc5)o4)cn3)cc2C1=O
Yield: 83 %

Procedure:
The compound of example 634 was prepared analogous to the compound of example 611 by reaction of compound of example 392 with ethyl 5-phenyloxazole-2-carboxylate.
Reaction SMILES: [NH2:1][C@H:2]([CH3:31])[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:32][C@H:33]1[CH2:38][CH2:37][O:36][C:34]1=[O:35]>>[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][C@H:2]([NH:1][C:34](=[O:35])[C@@H:33]([OH:32])[CH2:38][CH2:37][OH:36])[CH3:31])[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: O=C1OCC[C@@H]1O
Reactant: C[C@@H](N)COc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Product: C[C@H](COc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12)NC(=O)[C@@H](O)CCO
Yield: 79 %

Procedure:
The procedure described in Example 63 was repeated using 5-{[(2R)-2-aminopropyl]oxy}-N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]quinazolin-4-amine (obtained as described in Example 2.4, preparation of starting materials) and (S)-(−)-α-hydroxy-γ-butyrolactone to give the title compound in 79% yield; NMR spectrum (DMSO-d6 400 MHz) 1.24 (d, 3H), 1.30-1.41 (m, 1H), 1.63-1.74 (m, 1H), 3.32-3.46 (m, 2H), 3.91-3.98 (m, 1H), 4.24 (dd, 1H), 4.31 (t, 1H), 4.38 (t, 1H), 4.47-4.57 (m, 1H), 5.30 (s, 2H), 5.43 (d, 1H), 7.16 (d, 1H), 7.23 (d, 1H), 7.31-7.41 (m, 2H), 7.56 (dd, 1H), 7.60 (d, 1H), 7.73 (t, 1H), 7.89 (dt, 1H), 7.95 (d, 1H), 8.06 (d, 1H), 8.48 (s, 1H), 8.61 (d, 1H) 9.79 (s, 1H); Mass spectrum MH+ 538.0.
Reaction SMILES: [C:1](=[O:6])([O-])[O:2][CH2:3][CH3:4].[H-].[Na+].[CH3:9][C:10](=[O:15])[CH2:11][CH2:12][CH2:13][CH3:14].C(=O)(O)[O-].[Na+]>CCOCC.CCCCCCC.O.C(O)(=O)C.C(O)C>[O:15]=[C:10]([CH2:11][CH2:12][CH2:13][CH3:14])[CH2:9][C:1]([O:2][CH2:3][CH3:4])=[O:6]
Reactant: CCOC(=O)[O-]
Reactant: CCCCC(C)=O
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCCC
Solvent: CC(=O)O
Solvent: O
Product: CCCCC(=O)CC(=O)OCC
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 63 %

Procedure:
70.8 g of ethyl carbonate in solution in 50 ml of ether were added to a suspension of 27.3 g of sodium hydride at 50% in oil (washed beforehand in heptane) and 250 ml of ether and the mixture was stirred for 10 minutes. 30 g of hexanone were added over 30 minutes and the mixture was refluxed for 2 hours. 35 ml of ether with 12 ml of ethanol were added and the mixture was stirred for 16 hours at ambient temperature. After cooling to 0° C., a solution of 36 ml of acetic acid in 300 ml of water, then 12 ml of a saturated sodium bicarbonate solution were added, and the pH was 7. Extraction was carried out with ether and the extracts were washed with water, dried and evaporated to dryness. After distillation to 70° C. under a reduced pressure of 7 mbar, 32.5 g of the desired product were obtained.
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([C:18](=[O:32])[CH:19]=[CH:20][C:21]2[CH:31]=[CH:30][C:24]([O:25][CH2:26][C:27]([OH:29])=[O:28])=[CH:23][CH:22]=2)[CH:15]=[CH:16][CH:17]=1)=O)(C)(C)C.[ClH:33].C(OCC)C>O1CCOCC1>[NH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([C:18](=[O:32])/[CH:19]=[CH:20]/[C:21]2[CH:22]=[CH:23][C:24]([O:25][CH2:26][C:27]([OH:29])=[O:28])=[CH:30][CH:31]=2)[CH:15]=[CH:16][CH:17]=1.[ClH:33]
Reactant: CC(C)(C)OC(=O)NCCOc1cccc(C(=O)C=Cc2ccc(OCC(=O)O)cc2)c1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: NCCOc1cccc(C(=O)/C=C/c2ccc(OCC(=O)O)cc2)c1
Temperature: 25 °C
Reaction time: 3.3 h

Procedure:
A mixture of N-BOC amine 1d (0.20 g, 0.45 mmol) and 4 M hydrogen chloride in 1,4-dioxane (1.0 mL) was stirred at room temperature under a CaSO4 drying tube for 3.3 h. Dilution with diethyl ether produced a precipitate, which was collected by filtration and dried to give a yellow powder (0.17 g). 1H-NMR(300 MHz, d6 -DMSO): 13.1 (br, 1H), 8.09 (br, 3H), 7.87-7.82 (m, 3H), 7.78 and 7.74 (AB quartet, 2H, J=15 Hz), 7.63 (s, 1H), 7.53 (t, 1H, J=8 Hz), 7.28 (dd, 1H, J=8,2 Hz), 7.01 (d, 2H, J=9Hz), 4.78 (s, 2H), 4.30-4.26 (m, 2H), 3.36 (br, 2H). HR-MS: Calc. 342.1341, Found 342.1349. IR(KBr) cm-1 3398, 1744, 1656.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][C:10]=1[OH:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27]>CC(C)=O>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][C:10]=1[O:17][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1ccc(OCc2ccccc2)c(O)c1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)COc1cc(C=O)ccc1OCc1ccccc1
Temperature: 0 °C
Yield: 98 %

Procedure:
To a solution of 4-benzyloxy-3-hydroxybenzaldehyde(0.5 g) in acetone (12.5 ml) was added milled potassium carbonate (1.20 g) and ethyl bromoacetate (0.48 ml), with stirring. The reaction mixture was heated under reflux for ˜1 hr, with stirring, poured into ice/water and extracted with ethyl acetate. The extracts were washed with water, saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was dissolved in dichloromethane and flash chromatographed (silica gel), eluting with dichloromethane, followed by 1% methanol:dichloromethane). The appropriate fractions were collected and combined to give 0.63 g (98%) of product, mp 36-43° C.
Reaction SMILES: [C:1]([C:5]1[N:6]([CH3:17])[C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([N+:14]([O-])=O)=[CH:9][CH:8]=2)([CH3:4])([CH3:3])[CH3:2]>CO.[Ni]>[C:1]([C:5]1[N:6]([CH3:17])[C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([NH2:14])=[CH:9][CH:8]=2)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cn1c(C(C)(C)C)cc2cc([N+](=O)[O-])ccc21
Agent: [Ni]
Solvent: CO
Product: Cn1c(C(C)(C)C)cc2cc(N)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.3 %

Procedure:
To a solution of 2-tert-butyl-1-methyl-5-nitro-1H-indole (3.00 g, 13.7 mmol) in MeOH (30 mL) was added Raney Ni (0.3 g) under nitrogen atmosphere. The mixture was stirred under hydrogen atmosphere (1 atm) at room temperature overnight. The mixture was filtered through a Celite pad and the filtrate was evaporated under vacuum. The crude residue was purified by column chromatography on silica gel (P.E/EtOAc 20:1) to give 2-tert-butyl-1-methyl-1H-indol-5-amine (1.7 g, 66%). 1H NMR (300 MHz, CDCl3) δ 7.09 (d, J=8.4 Hz, 1H), 6.89-6.9 (m, 1H), 6.66 (dd, J=2.4, 8.7 Hz, 1H), 6.14 (d, J=0.6 Hz, 1H), 3.83 (s, 3H), 3.40 (brs, 2H), 1.45 (s, 9H); MS (ESI) m/e (M+H+) 203.1.