Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:21]=[C:22]([CH3:24])[CH:23]=1)[NH:5][C:6]([CH2:8][C:9]1[CH:20]=[CH:19][C:12]([O:13][CH:14]([CH3:18])[C:15]([OH:17])=[O:16])=[CH:11][CH:10]=1)=[O:7].[CH3:25]O>C(O)C>[CH3:24][C:22]1[CH:21]=[C:4]([CH:3]=[C:2]([CH3:1])[CH:23]=1)[NH:5][C:6]([CH2:8][C:9]1[CH:10]=[CH:11][C:12]([O:13][CH:14]([CH2:18][CH3:25])[C:15]([OH:17])=[O:16])=[CH:19][CH:20]=1)=[O:7]
Reactant: CO
Reactant: Cc1cc(C)cc(NC(=O)Cc2ccc(OC(C)C(=O)O)cc2)c1
Solvent: CCO
Product: CCC(Oc1ccc(CC(=O)Nc2cc(C)cc(C)c2)cc1)C(=O)O

Procedure:
The mother liquor from the recrystallization of (−)20-cinchonidine salt was concentrated under reduced pressure. The enriched (+)20 isomer was obtained from the mother liquor by neutralizing the salt to obtain the free acid, as described previously for compound 18. The optical rotation showed that the isomer was approximately 80% enantiomeric excess, optical rotation was measured at 21° C.: [α]D+18.2° (c=1.2, methanol). A stock solution (1 mg/mL) of the racemic mixture (20) was prepared in ethanol/mobile phase (1:1). The injected sample volume was 250 μL. The compound was eluted with a mobile phase of heptane/ethanol. with 1% TFA (88:12) at a flow rate of 2.5 mL/min. Under these conditions, the (−)isomer eluted at 15.8 min and the (+)isomer eluted at 18.2 min retention times. The collected fractions were concentrated under reduced pressure at room temperature. (+)20 was collected as a white solid, 0.14 g. mp 146-148° C. The optical rotation was measured at 21° C.: [α]D+25.3° (c=0.5, methanol).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([C:18](O)=[O:19])=[C:13]2[N:12]=[CH:11][C:10]=1[C:21]([N:23]1[CH2:28][CH2:27][C:26]2([C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:30]([CH3:37])=[CH:29]2)[CH2:25][CH2:24]1)=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:38][S:39]([NH2:42])(=[O:41])=[O:40]>>[CH2:1]([NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([C:18]([NH:42][S:39]([CH3:38])(=[O:41])=[O:40])=[O:19])=[C:13]2[N:12]=[CH:11][C:10]=1[C:21]([N:23]1[CH2:24][CH2:25][C:26]2([C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:30]([CH3:37])=[CH:29]2)[CH2:27][CH2:28]1)=[O:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1=CC2(CCN(C(=O)c3cnc4c(C(=O)O)cnn4c3NCc3ccccc3)CC2)c2ccccc21
Reactant: CS(N)(=O)=O
Product: CC1=CC2(CCN(C(=O)c3cnc4c(C(=O)NS(C)(=O)=O)cnn4c3NCc3ccccc3)CC2)c2ccccc21
Yield: 63.7 %

Procedure:
In the same manner as in Example 1, step 6 and using 7-benzylamino-6-(3-methylspiro[inden-1,4′-piperidine]-1′-ylcarbonyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0.130 g, 0.264 mmol) obtained in step 2 and methanesulfonamide (0.126 g, 1.32 mmol), the title compound (0.096 g, 64%) was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[O:7][CH2:8][C:4]=2[C:3]=1[CH:12]=[CH2:13].[CH3:14]COC(C)=O>CCOCC.CC([O-])=O.CC([O-])=O.[Pd+2]>[Br:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[O:7][CH2:8][C:4]=2[C:3]=1[CH:12]1[CH2:14][CH2:13]1
Reactant: CCOC(C)=O
Reactant: C=Cc1c(Br)ccc2c1COC2=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCOCC
Product: O=C1OCc2c1ccc(Br)c2C1CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a cooled (0° C.) mixture of 5-bromo-4-vinyl-2-benzofuran-1(3H)-one (2.2 g, 9.21 mol) and Pd(OAc)2 (100 mg) in EtOAc (50 mL) was added a solution of CH2N2 in ether (100 mL) slowly. The resulting mixture was stirred at room temperature overnight, then quenched with acetic acid, filtered and the filtrate washed with water and brine, dried and concentrated to provide the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:22]5[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]5)=[N:19][C:18]4=[O:29])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:32]([F:35])([F:34])[F:33])[CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[CH3:42][O:43][CH2:44][CH2:45]Br>CN(C=O)C.O>[CH3:42][O:43][CH2:44][CH2:45][O:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:22]5[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]5)=[N:19][C:18]4=[O:29])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:32]([F:35])([F:34])[F:33])[CH:3]=1
Reactant: CN1CCN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(O)cc4C(F)(F)F)c3)S2)CC1
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COCCOc1ccc(Cn2ncc3cc(C=C4SC(N5CCN(C)CC5)=NC4=O)ccc32)c(C(F)(F)F)c1
Temperature: 60 °C
Reaction time: 16 h
Yield: 76.6 %

Procedure:
5-[1-(4-Hydroxy-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(4-methyl-piperazin-1-yl)-thiazol-4-one (24.7 mg, 0.049 mmol) was dissolved in 1 mL of dry DMF. To the DMF solution was added Cs2CO3 (31.9 mg, 0.098 mmol), followed by methoxyethyl bromide (9.6 mg, 0.07 mmol). The mixture was stirred at 60° C. for 16 h and then diluted with water. It was extracted with EtOAc and the combined EtOAc extracts were washed with brine and dried over Na2SO4. The solvent was evaporated and the residue was purified by flash column chromatography on silica gel (0-100% gradient CH2Cl2/EtOAc, followed by 10% MeOH/EtOAc) to afford the title compound (21 mg, 76%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:11]([N:13]([CH2:17][CH2:18][CH3:19])[CH2:14][CH2:15][CH3:16])=[O:12])[CH:10]=1)[C:5]([OH:7])=[O:6].[CH3:20][N:21]1CCCC1=O>>[C:20]([C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:11]([N:13]([CH2:17][CH2:18][CH3:19])[CH2:14][CH2:15][CH3:16])=[O:12])[CH:10]=1)[C:5]([OH:7])=[O:6])#[N:21]
Reactant: CN1CCCC1=O
Reactant: CCCN(CCC)C(=O)c1cc(Br)cc(C(=O)O)c1
Product: CCCN(CCC)C(=O)c1cc(C#N)cc(C(=O)O)c1
Temperature: 175 °C
Reaction time: 2.5 h

Procedure:
A mixture of 3-bromo-5-[(dipropylamino)carbonyl]benzoic acid (PREPARATION 4, 0.596 g, 1.82 mmol) and copper nitrile (0.325 g, 3.63 mmol) in N-methylpyrrolidinone (1.5 mL) is stirred at 175 degrees C. for 2.5 hour, at which time the mixture is cooled and partitioned between ethyl acetate and hydrochloric acid (3N). The organic layer is washed twice more with hydrochloric acid (3N) and then twice more with saline which had been acidified with a small amount of hydrochloric acid (3N). The organic layer is dried over magnesium sulfate and concentrated under high vacuum to give the title compound, NMR (CDCl3) delta 0.80, 1.02, 1.60, 1.73, 3.17, 3.51, 7.90, 8.31 and 8.41; an aliquot is crystallized from ethyl ether/dichloromethane/hexane—IR (diffuse reflectance) 3017, 2970, 2937, 2898, 2877, 2473, 2432, 2350, 2318, 2236, 1721, 1608, 1588, 1206 and 1196 cm−1.
Reaction SMILES: [N+:1]([CH:4]([CH3:9])[CH:5]([OH:8])[CH2:6][CH3:7])([O-:3])=[O:2].[C:10](OC(=O)C)(=[O:12])[CH3:11]>>[C:10]([O:8][CH:5]([CH2:6][CH3:7])[CH:4]([N+:1]([O-:3])=[O:2])[CH3:9])(=[O:12])[CH3:11]
Reactant: CCC(O)C(C)[N+](=O)[O-]
Reactant: CC(=O)OC(C)=O
Product: CCC(OC(C)=O)C(C)[N+](=O)[O-]

Procedure:
reacting 4-nitro-3-pentanol with acetic anhydride to form 3-acetoxy-2-nitropentane;
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([NH2:7])[NH:4][N:3]=1.[CH3:8][C@@H:9]1[CH2:14][C:13](=O)[CH2:12][C@H:11]([CH3:16])[O:10]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C>[CH3:8][C@@H:9]1[CH2:14][CH:13]([NH:7][C:5]2[NH:4][N:3]=[C:2]([CH3:1])[N:6]=2)[CH2:12][C@H:11]([CH3:16])[O:10]1
Reactant: Cc1n[nH]c(N)n1
Reactant: C[C@@H]1CC(=O)C[C@H](C)O1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1n[nH]c(NC2C[C@@H](C)O[C@@H](C)C2)n1
Reaction time: 0.5 h
Yield: 21.9 %

Procedure:
To a solution of 3-methyl-1H-1,2,4-triazol-5-amine (1.6 g) in acetic acid (30 mL) was added (2R,6S)-2,6-dimethyltetrahydro-4H-pyran-4-one (2.5 g) at room temperature, and the mixture was stirred for 30 min. Sodium triacetoxyborohydride (5.2 g) was added, and the mixture was stirred at room temperature for 20 hr. Acetic acid was evaporated and ethyl acetate and water were added to the residue. The mixture was neutralized with sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was dissolved in a small amount of ethyl acetate, and the mixture was crystallized from diisopropyl ether. The resulting solid was collected by filtration, washed with diisopropyl ether, and dried by heating under reduced pressure to give the title compound as a pale-yellow solid (0.75 g, 22%).
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][CH:11]=[CH:10][C:3]=1[O:4][CH:5]([CH3:9])[C:6]([OH:8])=O.[N+]([O-])(O)=O.[O:18]([CH2:22][CH2:23][NH2:24])[N+:19]([O-:21])=[O:20].C(OC(C)C)(C)C>>[O:18]([CH2:22][CH2:23][NH:24][C:6](=[O:8])[CH:5]([O:4][C:3]1[CH:10]=[CH:11][CH:12]=[CH:13][C:2]=1[Cl:1])[CH3:9])[N+:19]([O-:21])=[O:20]
Reactant: NCCO[N+](=O)[O-]
Reactant: CC(Oc1ccccc1Cl)C(=O)O
Solvent: CC(C)OC(C)C
Solvent: O=[N+]([O-])O
Product: CC(Oc1ccccc1Cl)C(=O)NCCO[N+](=O)[O-]
Yield: 42.1 %

Procedure:
Following a similar treatment to that in Example 2 and using 0.71 g of 2-(2-chlorophenoxy)propionic acid and 0.6 g of 2-nitroxyethylamine nitrate, 0.43 g of the title compound was obtained as colorless needles (solvent for recrystallization; diisopropyl ether).
Reaction SMILES: [C:1]([N:8]1[CH2:16][CH2:15][CH:11]([C:12](O)=[O:13])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CN1CCOCC1.ClC(OCC)=O.[BH4-].[Na+]>O1CCCC1>[C:1]([N:8]1[CH2:16][CH2:15][CH:11]([CH2:12][OH:13])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: CCOC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(CO)CC1
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 92.4 %

Procedure:
To a solution of Boc-isonipecotic acid (40 g, 0.17 mol) and N-methylmorpholine (19 mL, 0.17 mol) in tetrahydrofuran (900 mL) stirring at −10° C., ethyl chloroformate was slowly added (17 mL, 0.17 mol) via addition funnel. After 30 min, sodium borohydride was added (19.8 g, 0.5 mol) in one portion. The reaction mixture was stirred at −10° C. for 1 h; then it was slowly quenched with methanol. The solvent was removed in vacuo; the resulting residue was diluted with 10% aqueous acetic acid and partitioned between ethyl acetate and water. The aqueous layer was separated and extracted with additional ethyl acetate (2×500 mL). The combined organic extracts were dried with magnesium sulfate, filtered, and concentrated in vacuo to a solid residue which was chromatographed on silica gel. Elution with ethyl acetate-hexanes (1:9 to 1:1) provided the title compound (33.8 g, 90%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[CH2:13]([O:15][CH:16]([O:19][CH2:20][CH3:21])[CH2:17]Br)[CH3:14].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:13]([O:15][CH:16]([O:19][CH2:20][CH3:21])[CH2:17][O:12][C:9]1[CH:10]=[CH:11][C:2]([Cl:1])=[C:3]2[C:8]=1[N:7]=[CH:6][CH:5]=[CH:4]2)[CH3:14]
Reactant: Oc1ccc(Cl)c2cccnc12
Reactant: CCOC(CBr)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(COc1ccc(Cl)c2cccnc12)OCC

Procedure:
180 g of 5-chloro-8-hydroxyquinoline, 237 g of 2-bromoacetaldehyde diethyl acetal and 200 g of potassium carbonate are stirred for 4 h at 120° C. in 800 ml of dimethylformamide. After cooling, the mixture is poured into 2.5 liters of water, and the product is filtered off under suction and dried in vacuo, melting point 51°-53° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:42])[C:5]([CH3:41])([O:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]=[CH:14][CH2:15][CH:16]2[CH2:20][N:19]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=3)[C:18](=[O:32])[N:17]2[CH3:33])=[CH:9][CH:8]=1)[CH3:2]>CCOC(C)=O.[Pd]>[CH2:1]([O:3][C:4](=[O:42])[C:5]([CH3:41])([O:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH2:15][CH:16]2[CH2:20][N:19]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:29])([F:30])[F:31])=[CH:24][CH:23]=3)[C:18](=[O:32])[N:17]2[CH3:33])=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)C(C)(Cc1ccc(C=CCC2CN(Cc3ccc(C(F)(F)F)cc3)C(=O)N2C)cc1)Oc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C)(Cc1ccc(CCCC2CN(Cc3ccc(C(F)(F)F)cc3)C(=O)N2C)cc1)Oc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.5 %

Procedure:
A mixture of 2-methyl-3-(4-{3-[3-methyl-2-oxo-1-(4-trifluoromethyl-benzyl)-imidazolidin-4-yl]-propenyl}-phenyl)-2-phenoxy-propionic acid ethyl ester (0.069 g, 0.119 mmol) and 10% Pd/C (70 mg) in EtOAc (50 mL) is purged with N2 then H2 and then stirred under a H2 balloon at room temperature for 2 h. The reaction mixture is filtered through hyflo and the solvent removed in vacuo to afford 0.069 g (100%) 2-methyl-3-(4-{3-[3-methyl-2-oxo-1-(4-trifluoromethyl-benzyl)-imidazolidin-4-yl]-propyl}-phenyl)-2-phenoxy-propionic acid ethyl ester. 1H NMR. MS (ES+) Calc'd for C33H38N2O4F3 (M+1) 583. Found m/z 583 (100%).
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][CH:7]([N:14]2[CH:18]=[N:17][CH:16]=[N:15]2)[CH:8]([OH:13])[C:9]([CH3:12])([CH3:11])[CH3:10])=[CH:4][CH:3]=1.[H-].[Na+].[CH3:23][N:24]([S:28][C:29]([Cl:32])([Cl:31])[Cl:30])[C:25](F)=[O:26].[Na]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH:7]([N:14]2[CH:18]=[N:17][CH:16]=[N:15]2)[CH:8]([O:13][C:25](=[O:26])[N:24]([CH3:23])[S:28][C:29]([Cl:32])([Cl:31])[Cl:30])[C:9]([CH3:11])([CH3:12])[CH3:10])=[CH:19][CH:20]=1
Reactant: CN(SC(Cl)(Cl)Cl)C(=O)F
Reactant: CC(C)(C)C(O)C(Oc1ccc(Cl)cc1)n1cncn1
Agent: [H-]
Agent: [Na+]
Agent: [Na]
Solvent: C1CCOC1
Product: CN(SC(Cl)(Cl)Cl)C(=O)OC(C(Oc1ccc(Cl)cc1)n1cncn1)C(C)(C)C
Yield: 38.5 %

Procedure:
22.3 g (0.075 mol) of 1-(4-chlorophenoxy)-3,3-dimethyl-1-(1,2,4-triazol-1-yl)-butan-2-ol, in the form of the pure diastereomer, were dissolved in 200 ml of tetrahydrofuran and the solution was added dropwise to 2.3 g of 80% pure sodium hydride in 150 ml of tetrahydrofuran at room temperature, while stirring. Thereafter, the mixture was stirred at 50° C. for 12 hours. After cooling, 17 g (0.075 mol) of N-methyl-N-trichloromethylmercaptocarbamoyl fluoride were added dropwise, at room temperature, to the sodium salt thus obtained, whereupon the temperature rose to about 35° C. The mixture was then heated under reflux for 16 hours, left to cool and concentrated by distilling off the solvent. The oily residue was taken up in 500 ml of methylene chloride, washed twice with 1,000 ml of water each time, dried over sodium sulphate and concentrated. The oil which remained was taken up in 300 ml of isopropyl ether, whereupon it crystallized out. 14.5 g (37% of theory) of 1-(4-chlorophenoxy)-3,3-dimethyl-2-(N-methyl-N-trichloromethylmercapto-carbamoyloxy)-1-(1,2,4-triazol-1-yl)-butane were obtained in the form of the pure diastereomer of melting point 110°-112° C.
Reaction SMILES: [C-]#N.[Na+].[N:4]12CCN(CC1)C[CH2:5]2.[CH3:12][O:13][C:14]1[CH:36]=[CH:35][C:17]([CH2:18][NH:19][C:20]([C:22]2[C:23]([NH:29][CH2:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[N:24][C:25](Cl)=[N:26][CH:27]=2)=[O:21])=[CH:16][CH:15]=1>O.CS(C)=O>[CH3:12][O:13][C:14]1[CH:36]=[CH:35][C:17]([CH2:18][NH:19][C:20]([C:22]2[C:23]([NH:29][CH2:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[N:24][C:25]([C:5]#[N:4])=[N:26][CH:27]=2)=[O:21])=[CH:16][CH:15]=1
Reactant: C1CN2CCN1CC2
Reactant: COc1ccc(CNC(=O)c2cnc(Cl)nc2NCC(C)(C)C)cc1
Agent: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COc1ccc(CNC(=O)c2cnc(C#N)nc2NCC(C)(C)C)cc1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
To a solution of NaCN (95 mg, 1.9 mmol) in water (1 ml) and DMSO (10 ml) are added 1,4-diazabicyclo[2,2,2]octane (48 mg, 0.43 mmol) and 2-chloro-4-(2,2-dimethyl-propylamino)-pyrimidine-5-carboxylic acid 4-methoxy-benzylamide (470 mg, 1.3 mmol) in DMSO (2 ml) successively at ambient temperature. After being stirred for 2 hours at 50° C., the reaction mixture is poured into cold water and extracted with AcOEt. The combined extracts are washed with water, brine and dried over MgSO4. The concentrated residue is purified by silica gel column chromatography (eluent:n-hexane:AcOEt=2:1) give 2-cyano-4-(2,2-dimethyl-propylamino)-pyrimidine-5-carboxylic acid 4-methoxy-benzylamide. Rf=0.45 (n-hexane:AcOEt=2:1). 1H NMR (400 MHz, DMSO-d6) δ 1.00 (s, 9H), 3.37 (d, 2H), 3.81 (s, 3H), 4.53 (d, 2H), 6.36 (brs, 1H), 6.89 (d, 2H), 7.25 (d, 2H), 8.28 (s, 1H), 9.08 (brs, 1H).
Reaction SMILES: [OH:1][C@@H:2]([CH2:17][N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)[CH2:3][N:4]1[CH2:9][CH2:8][C:7]2[NH:10][C:11]([CH:14]=O)=[C:12]([CH3:13])[C:6]=2[C:5]1=[O:16].[Cl:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[NH:30][C:29](=[O:34])[CH2:28]2>>[Cl:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[NH:30][C:29](=[O:34])/[C:28]/2=[CH:14]\[C:11]1[NH:10][C:7]2[CH2:8][CH2:9][N:4]([CH2:3][C@@H:2]([OH:1])[CH2:17][N:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)[C:5](=[O:16])[C:6]=2[C:12]=1[CH3:13]
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(C[C@@H](O)CN1CCOCC1)CC2
Reactant: O=C1Cc2cc(Cl)ccc2N1
Product: Cc1c(/C=C2\C(=O)Nc3ccc(Cl)cc32)[nH]c2c1C(=O)N(C[C@@H](O)CN1CCOCC1)CC2
Yield: 85 %

Procedure:
The title compound was prepared under the same conditions as described in step 6 of Example 5 with (S)-5-(2-hydroxy-3-morpholin-4-yl-propyl)-3-methyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde 5f obtained from step 5 of Example 5 and 5-chloro-1,3-dihydro-indol-2-one as starting materials to give (S,Z)-2-(5-chloro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-5-(2-hydroxy-3-morpholin-4-yl-propyl)-3-methyl-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one 6 (87 mg, yield 85%) as a yellow solid.
Reaction SMILES: [C:1]([C:3]1[C:8]([CH:9]=[C:10]([CH3:12])[CH3:11])=[CH:7][CH:6]=[CH:5][C:4]=1[NH:13][C:14]([NH:16]C(=O)C1C=CC=CC=1)=[O:15])#[N:2].[OH-].[Na+].CC(O)=O>CCO>[NH2:2][C:1]1[C:3]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[CH:9]=[C:10]([CH3:12])[CH3:11])[NH:13][C:14](=[O:15])[N:16]=1
Reactant: CC(C)=Cc1cccc(NC(=O)NC(=O)c2ccccc2)c1C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)=Cc1cccc2[nH]c(=O)nc(N)c12
Temperature: 90 °C
Yield: 77.1 %

Procedure:
A suspension of N-(2-cyano-3-(2-methylprop-1-enyl)phenyl carbamoyl)benzamide (Example 150a) (0.133 g, 0.416 mmol) in EtOH (3 mL) was treated with a solution of NaOH (2 M, 0.416 mL, 0.832 mmol) at room temperature. The obtained mixture was heated at 90° C. for 30 min, cooled to room temperature and neutralized with 10% AcOH. The precipitated product was collected by filtration to give 69.0 mg (77%) of 4-amino-5-(2-methylprop-1-enyl)quinazolin-2(1H)-one as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 1.60 (d, J=1.2 Hz, 3H), 1.93 (d, J=1.2 Hz, 3H), 6.58 (s, 1H), 6.67 (broad s, 1H), 6.73 (m, 1H), 7.05 (m, 1H), 7.48 (m, 1H), 7.93 (broad s, 1H), 10.72 (broad s, 1H). MS 216 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:6]2[C:7]([CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:8][O:9][C:5]=2[CH:4]=1.[O:17]1CCOCC1>>[CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:6]2[C:7]([C:10](=[O:17])[C:11]([O:13][CH3:14])=[O:12])=[CH:8][O:9][C:5]=2[CH:4]=1
Reactant: COC(=O)Cc1coc2cc(OC)ccc12
Reactant: C1COCCO1
Product: COC(=O)C(=O)c1coc2cc(OC)ccc12
Yield: 85 %

Procedure:
A mixture of methyl 2-(6-methoxybenzofuran-3-yl)acetate (0.500 g, 2.27 mmol) and SeO2 (0.303 g, 2.73 mmol) in 1,4-dioxane (10 mL) was refluxed for 2 days and then filtered. The filtrate was concentrated in vacuo and the residue was purified on a silica gel column to give methyl 2-(6-methoxybenzofuran-3-yl)-2-oxoacetate (0.452 g, 85%)
Reaction SMILES: [CH2:1]([CH:3]1[O:5][CH2:4]1)[Cl:2].[CH3:6][O:7][CH2:8][CH2:9][OH:10].S(=O)(=O)(O)O>CCOCC>[Cl:2][CH2:1][CH:3]([OH:5])[CH2:4][O:10][CH2:9][CH2:8][O:7][CH3:6]
Reactant: COCCO
Reactant: ClCC1CO1
Agent: O=S(=O)(O)O
Solvent: CCOCC
Product: COCCOCC(O)CCl
Yield: 43929.9 %

Procedure:
To 25 g (0.27 mmol) of epichlorohydrin, 20.8 g (0.27 mmol) of methylcellosolve and 0.1 ml of conc. sulfuric acid were added and reacted for 10 hours at 100° C. After the reaction, 500 ml of ether was added and washed with saturated sodium hydrogen carbonate solution and with saturated sodium chloride solution. The ether phase was dried on magnesium sulfate, filtered and concentrated to give 20 g of 1-chloro-2-hydroxy-3-(2'-methoxyethoxy)propane. 1H-NMR (CDCl3): δ=3.40 (3H, s, --OCH3), 3.45-3.82 (9H, m, H1, H3, H1', H2', --OH), 3.84-4.18 (1H, m, H2).
Reaction SMILES: C([Li])CCC.[CH2:6]([NH:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH2:7][CH2:8][CH3:9].[O:15]1[C:19]([CH3:26])([CH2:20][CH2:21][CH2:22][CH:23]([CH3:25])[CH3:24])[CH:16]1[CH2:17][OH:18]>O1CCCC1>[CH2:6]([N:10]([CH2:11][CH2:12][CH2:13][CH3:14])[CH:16]([C:19]([CH3:26])([OH:15])[CH2:20][CH2:21][CH2:22][CH:23]([CH3:25])[CH3:24])[CH2:17][OH:18])[CH2:7][CH2:8][CH3:9]
Reactant: CCCCNCCCC
Reactant: CC(C)CCCC1(C)OC1CO
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCN(CCCC)C(CO)C(C)(O)CCCC(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 79.7 %

Procedure:
Under nitrogen atmosphere, 65 ml of n-butyllithium (1.6M in hexane) was added dropwise to a solution of 12.9 g of di-n-butylamine in 30 ml of tetrahydrofuran at -78° C. and after completion of addition, the mixture was stirred at 0° C. for 30 minutes. To this solution was added a solution of 8.6 g of 2,3-epoxy-3,7-dimethyl-1-octanol in 20 ml of tetrahydrofuran slowly in portions at 0° C. The mixture was then stirred at room temperature for 2 hours, after which it was poured into ice-water and extracted with diethyl ether. The extract was washed with water and after drying over anhydrous magnesium sulfate, the solvent was distilled off. The residue was further distilled under reduced pressure to give 12 g of 2-(dibutylamino)-3,7-dimethyl-1,3-octanediol [Compound (59)]. Yield 80%.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2].[N:25]1([CH2:30][CH2:31][CH2:32][NH2:33])[CH:29]=[CH:28][N:27]=[CH:26]1>>[N:25]1([CH2:30][CH2:31][CH2:32][NH:33][C:19](=[O:20])[C:18]2[CH:22]=[CH:23][C:15]([N:12]3[C:13]([OH:14])=[C:9]([C:6]4[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][C:5]=4[CH3:24])[CH:10]=[N:11]3)=[N:16][CH:17]=2)[CH:29]=[CH:28][N:27]=[CH:26]1
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Reactant: NCCCn1ccnc1
Product: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)NCCCn3ccnc3)cn2)c1O

Procedure:
The title compound was prepared in a manner similar to Example 74 using 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and 3-(1H-imidazol-1-yl)propan-1-amine. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.09-2.17 (m, 2H) 2.44 (s, 3H) 3.32 (q, J=6.40 Hz, 2H) 4.28 (t, J=6.95 Hz, 2H) 7.63-7.72 (m, 2H) 7.74 (s, 1H) 7.78 (d, J=8.08 Hz, 1H) 7.83 (t, J=1.64 Hz, 1H) 8.19 (br. s., 1H) 8.35-8.55 (m, 2H) 8.82 (t, J=5.68 Hz, 1H) 8.89-8.96 (m, 1H) 9.11 (s, 1H) 13.26-14.08 (m, 1H). MS m/z [M+H]+ 428.2
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][CH2:13][OH:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C(O[CH:18](OCC)[CH2:19][Br:20])C.FC(F)(F)C(O)=O>[N+](C)([O-])=O>[CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][C:6]2[CH:18]([CH2:19][Br:20])[O:14][CH2:13][CH2:12][CH2:11][C:5]=2[CH:4]=1
Reactant: CCOC(CBr)OCC
Reactant: COc1ccc(CCCO)cc1OC
Solvent: C[N+](=O)[O-]
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2c(cc1OC)C(CBr)OCCC2

Procedure:
A solution of 5.00 g. of 3-(3,4-dimethoxyphenyl)-1-propanol, 9.76 ml of bromoacetaldehyde diethyl acetal, 2.0 ml of trifluoroacetic acid, and 125 ml of nitromethane is heated at 65° under a nitrogen atmosphere for 2 hours. After cooling, the reaction mixture is extracted with methylene chloride and aqueous sodium bicarbonate. The organic layer is taken to dryness in vacuo and the residue is chromatographed first with 100% CH2Cl2 and a second time with 10% ethyl acetate:SSB to give 300 g of 7,8-dimethoxy-1-bromomethyl-1,3,4,5-tetrahydro-2-benzoxepin, m.p., 44°-45°.