Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@@H:2]1[C@@H:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[O:5][C:4](=[O:13])[N:3]1[C:14](=[O:24])[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[O:22][CH3:23].CI.[C:27](O)(=O)C>O1CCCC1.C(OCC)(=O)C>[CH3:1][C@@H:2]1[C@@H:6]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[O:5][C:4](=[O:13])[N:3]1[C:14](=[O:24])[C@@H:15]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[O:22][CH3:23])[CH3:27]
Reactant: COc1ccccc1CC(=O)N1C(=O)O[C@H](c2ccccc2)[C@H]1C
Reactant: CC(=O)O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CI
Product: COc1ccccc1[C@@H](C)C(=O)N1C(=O)O[C@H](c2ccccc2)[C@H]1C
Reaction time: 0.75 h

Procedure:
To a solution, cooled to -50° C., of 22.82 g of (4R, 5R)-4-methyl-5-phenyl-3-[(2-methoxyphenyl)acetyl]-2-oxazolidinone in 190 cm3 of tetrahydrofuran are added 19.31 g of sodium 1,1,1,3,3,3-hexamethyldisilazide, and the mixture is stirred for 45 minutes at this temperature, followed by addition of 8.82 cm3 of methyl iodide. The reaction mixture is subsequently stirred for 15 hours at room temperature, and then 18.65 cm3 of acetic acid are added, and the mixture is diluted with 200 cm3 of ethyl acetate and washed with 200 cm3 of water and then with 250 cm3 of saturated aqueous sodium chloride solution, and dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The residue obtained is crystallized in isopropyl ether, filtered off and dried. 10.95 g of (4R, 5R)-4-methyl-5-phenyl-3-[(R)-2-(2-methoxyphenyl)propionyl]-2-oxazolidinone are obtained, in the form of a white solid melting at 110° C.
Reaction SMILES: C(OC([NH:8][C@H:9]([CH2:15][CH2:16][S:17][CH3:18])[CH:10]([OH:14])[C:11]([OH:13])=O)=O)(C)(C)C.[NH2:19][CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1>>[N:25]1[CH:26]=[CH:27][C:22]([CH2:21][CH2:20][NH:19][C:11](=[O:13])[CH:10]([OH:14])[C@H:9]([NH2:8])[CH2:15][CH2:16][S:17][CH3:18])=[CH:23][CH:24]=1
Reactant: NCCc1ccncc1
Reactant: CSCC[C@@H](NC(=O)OC(C)(C)C)C(O)C(=O)O
Product: CSCC[C@@H](N)C(O)C(=O)NCCc1ccncc1

Procedure:
The product of example 3A and 1-amino-2-(4-pyridyl)ethane were processed as in example 2 to provide the title compound.
Reaction SMILES: [Cl:1]Cl.[Cl:3][C:4]1[CH:5]=[C:6]([CH3:15])[CH:7]=[CH:8][C:9]=1[N:10]1[CH:14]=[CH:13][CH:12]=[N:11]1>C(Cl)(Cl)Cl>[Cl:1][C:13]1[CH:12]=[N:11][N:10]([C:9]2[CH:8]=[CH:7][C:6]([CH3:15])=[CH:5][C:4]=2[Cl:3])[CH:14]=1
Reactant: ClCl
Reactant: Cc1ccc(-n2cccn2)c(Cl)c1
Solvent: ClC(Cl)Cl
Product: Cc1ccc(-n2cc(Cl)cn2)c(Cl)c1
Reaction time: 2 h
Yield: 90.6 %

Procedure:
A cooled solution of 8 g (113 mmoles) of chlorine in 50 ml of chloroform is added dropwise at 0° C. to a solution of 19.8 g (103 mmoles) of 1-(3-chloro-p-tolyl)pyrazole in 100 ml of chloroform, and stirring is effected for a further 2 hours at from 3° to 8° C. The organic phase is washed with water and dilute sodium dithionite solution; drying is effected, followed by concentration to dryness to produce 21.2 g (91% of theory) of 4-chloro-1-(3-chloro-p-tolyl)pyrazole (m.p. 69° to 70° C.).
Reaction SMILES: C([O:5][C:6](=O)[C@@H:7]([O:10][C:11]1[CH:34]=[CH:33][C:14]2[C:15]3[N:19]([CH2:20][CH2:21][O:22][C:13]=2[CH:12]=1)[CH:18]=[C:17]([C:23]1[N:24]([CH2:28][C:29]([F:32])([F:31])[F:30])[N:25]=[CH:26][N:27]=1)[N:16]=3)[CH2:8][CH3:9])(C)(C)C.C(O)(C(F)(F)F)=O.C[N:44](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl-].[NH4+].C(N(CC)CC)C>C(Cl)Cl>[F:30][C:29]([F:32])([F:31])[CH2:28][N:24]1[C:23]([C:17]2[N:16]=[C:15]3[C:14]4[CH:33]=[CH:34][C:11]([O:10][C@@H:7]([CH2:8][CH3:9])[C:6]([NH2:44])=[O:5])=[CH:12][C:13]=4[O:22][CH2:21][CH2:20][N:19]3[CH:18]=2)=[N:27][CH:26]=[N:25]1
Reactant: CC[C@H](Oc1ccc2c(c1)OCCn1cc(-c3ncnn3CC(F)(F)F)nc1-2)C(=O)OC(C)(C)C
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC[C@H](Oc1ccc2c(c1)OCCn1cc(-c3ncnn3CC(F)(F)F)nc1-2)C(N)=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 39 %

Procedure:
To a solution of (S)-2-{2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yloxy}-butyric acid tert-butyl ester in DCM (3 mL) was added TFA (0.5 mL) and the reaction mixture stirred at RT for 16 h. The reaction mixture was concentrated in vacuo, and the residue dissolved in DMF (3 mL). HATU (217 mg, 0.56 mmol), ammonium chloride (46 mg, 0.85 mmol) and triethylamine (119 μL, 0.85 mmol) were added and the reaction mixture stirred at RT for 1 hour. The reaction mixture was concentrated in vacuo, the residue dissolved in ethyl acetate (10 mL) and the mixture washed with water extracting with ethyl acetate (3×10 mL). The combined organic extracts were washed with brine, dried (MgSO4) and concentrated in vacuo. The residue was subjected to flash chromatography (SiO2 gradient 0-10% methanol in EtOAc) then reverse phase preparative HPLC (C-18 column, 10-90% MeCN in water, 0.1% formic acid, 25 min gradient) to yield 494 as a white solid (49 mg, 39%). LCMS: RT=3.78 min, [M+H]+=437; 1H NMR (400 MHz, d6-DMSO) 8.22 (1H, d, J=8.9 Hz), 8.03 (1H, s), 7.96 (1H, s), 7.50 (1H, br s), 7.24 (1H, br s), 6.74 (1H, dd, J=8.9, 2.5 Hz), 6.51 (1H, d, J=2.5 Hz), 5.86 (2H, q, J=8.9 Hz), 4.52-4.39 (5H, m), 1.79 (2H, pent, J=7.2 Hz), 0.92 (3H, t, J=7.2 Hz)
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:13][C:14]2[CH:23]=[CH:22][C:17]3[B:18]([OH:21])[O:19][CH2:20][C:16]=3[CH:15]=2)=[N:4][CH:5]=[C:6]([CH:12]=1)[C:7]([O:9]CC)=[O:8].[OH-].[Na+].Cl.CCOC(C)=O>CO.CCCCCC>[Cl:1][C:2]1[C:3]([O:13][C:14]2[CH:23]=[CH:22][C:17]3[B:18]([OH:21])[O:19][CH2:20][C:16]=3[CH:15]=2)=[N:4][CH:5]=[C:6]([CH:12]=1)[C:7]([OH:9])=[O:8]
Reactant: CCOC(=O)c1cnc(Oc2ccc3c(c2)COB3O)c(Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: CO
Solvent: CCOC(C)=O
Product: O=C(O)c1cnc(Oc2ccc3c(c2)COB3O)c(Cl)c1
Yield: 92.2 %

Procedure:
Hydrolysis of ethyl 5-chloro-6-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yloxy)nicotinate (0.9 g, 2.7 mmol) with 1N NaOH (11 mL) in MeOH (50 mL) overnight at r.t. followed by acidification with 6N HCl, work-up and recrystallization from EtOAc and hexane afforded off-white solid of the title carboxylic acid compound (0.76 g, 2.49 mmol, yield 92%).
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[CH2:23]([N:30]1[CH2:35][CH2:34][CH2:33][CH:32]([CH:36]([C:38]2[C:43]([Cl:44])=[CH:42][N:41]=[C:40]3[N:45]([Si:48]([CH:55]([CH3:57])[CH3:56])([CH:52]([CH3:54])[CH3:53])[CH:49]([CH3:51])[CH3:50])[CH:46]=[CH:47][C:39]=23)[OH:37])[CH2:31]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(Cl)Cl>[CH2:23]([N:30]1[CH2:35][CH2:34][CH2:33][CH:32]([C:36]([C:38]2[C:43]([Cl:44])=[CH:42][N:41]=[C:40]3[N:45]([Si:48]([CH:52]([CH3:54])[CH3:53])([CH:55]([CH3:57])[CH3:56])[CH:49]([CH3:50])[CH3:51])[CH:46]=[CH:47][C:39]=23)=[O:37])[CH2:31]1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(C(O)C3CCCN(Cc4ccccc4)C3)c(Cl)cnc21
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(C(=O)C3CCCN(Cc4ccccc4)C3)c(Cl)cnc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 24.7 %

Procedure:
Dess-Martin periodinane (14.63 g, 34.5 mmol) was added to a solution of (1-benzylpiperidin-3-yl)(5-chloro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)methanol (5.89 g, 11.5 mmol) in DCM (120 mL) at about 0° C. and the resulting mixture was stirred for about 16 h while warming to ambient temperature. The solvent was removed under reduced pressure and the residue partitioned between saturated aqueous NaHCO3 (150 mL) and EtOAc (200 mL). The organic phase was washed with brine (120 mL) and concentrated under reduced pressure. Purification by silica gel chromatography eluting first with heptane (1 L) and then with 1:7 EtOAc:heptane (1 L) yielded (1-benzylpiperidin-3-yl)(5-chloro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)methanone (1.45 g, 25%) as a yellow oil: LC/MS (Table 2, Method a) Rt=3.24 min; MS m/z: 511 (M+H)+
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]3[N:15]=[C:16]([N:19]4[CH2:23][CH2:22][C@H:21]([NH2:24])[CH2:20]4)[S:17][CH:18]=3)[CH:5]=[CH:4][C:3]1=2.C([Si](C)(C)[O:31][CH2:32][CH2:33][CH:34]=O)(C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-].C1COCC1>>[CH3:1][C:2]1([CH3:25])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([C:14]3[N:15]=[C:16]([N:19]4[CH2:23][CH2:22][C@H:21]([NH:24][CH2:34][CH2:33][CH2:32][OH:31])[CH2:20]4)[S:17][CH:18]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CC1(C)CCC(C)(C)c2cc(-c3csc(N4CC[C@H](N)C4)n3)ccc21
Reactant: CC(C)(C)[Si](C)(C)OCCC=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC1(C)CCC(C)(C)c2cc(-c3csc(N4CC[C@H](NCCCO)C4)n3)ccc21

Procedure:
The preparation is carried out starting from (S)-1-[4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)thiazol-2-yl]pyrrolidin-3-ylamine and 3-(tertbutyldimethylsilanyloxy)propionaldehyde. The protecting group is cleaved off as already described by means of a 1M TBAF/THF solution. The product was purified by means of preparative HPLC and converted into the hydrochloride by treatment with methanolic HCl.
Reaction SMILES: [CH3:1][CH:2]([C:8](=[O:10])[CH3:9])[CH2:3][CH2:4][C:5]([OH:7])=[O:6].O=[C:12](CC)[CH2:13]CCC(O)=O.C(OCC)(=O)C=C>C(C(C)=O)C>[CH2:12]([O:6][C:5]([CH2:4][CH2:3][CH:2]([CH3:1])[C:8](=[O:10])[CH3:9])=[O:7])[CH3:13]
Reactant: CCC(=O)CCCC(=O)O
Reactant: CC(=O)C(C)CCC(=O)O
Agent: C=CC(=O)OCC
Solvent: CCC(C)=O
Product: CCOC(=O)CCC(C)C(C)=O

Procedure:
Fraction (b) contains 95% by weight of ethyl ester of 3-methyl-4-oxopentane-1-carboxylic acid and 2% by weight of ethyl ester of 4-oxo-hexane-1-carboxylic acid. 41% of the total amount of ethyl acrylate has been converted. The efficiency in ethyl ester of 3-methyl-4-oxo-pentane-1-carboxylic acid amounts to 56% referred to the quantity of converted methyl ethyl ketone, and to 58% referred to the quantity of converted ethyl acrylate.
Reaction SMILES: O[C:2]1([C:16]2[C:24]([OH:25])=[CH:23][C:19]3[O:20][CH2:21][O:22][C:18]=3[CH:17]=2)[C:6](=[O:7])[N:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[C:4]2[CH:13]=[CH:14][S:15][C:3]1=2.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>C(Cl)Cl>[OH:25][C:24]1[C:16]([CH:2]2[C:6](=[O:7])[N:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[C:4]3[CH:13]=[CH:14][S:15][C:3]2=3)=[CH:17][C:18]2[O:22][CH2:21][O:20][C:19]=2[CH:23]=1
Reactant: CCCCCN1C(=O)C(O)(c2cc3c(cc2O)OCO3)c2sccc21
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCCN1C(=O)C(c2cc3c(cc2O)OCO3)c2sccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 49.3 %

Procedure:
To a solution of 6-hydroxy-6-(6-hydroxy-1,3-benzodioxol-5-yl)-4-pentyl-4,6-dihydro-5H-thieno[3,2-b]pyrrol-5-one (1.71 g, 4.70 mmol) in CH2Cl2 (30.0 mL) were added trifluoroacetic acid (6.00 g, 52.6 mmol) and triethylsilane (5.00 g, 43.0 mmol) at 0° C. The reaction mixture was stirred at ambient temperature for 16 hours and diluted with CH2Cl2 (50.0 mL). The mixture was washed with water (2×50.0 mL), dried over Na2SO4 and filtered. The filtrate was evaporated under reduced pressure. The residue was subjected to column chromatography to give the title compound (0.80 g, 49%) as a green solid: MS (ES+) m/z 346.4 (M+1).
Reaction SMILES: C[O:2][C:3](=[O:35])[CH2:4][O:5][C:6]1[C:11]([O:12][CH3:13])=[CH:10][C:9]([C:14](=[O:32])[C:15]#[C:16][C:17]2[CH:22]=[C:21]([C:23]3[S:24][CH:25]=[CH:26][CH:27]=3)[C:20]([O:28][CH3:29])=[CH:19][C:18]=2[O:30][CH3:31])=[CH:8][C:7]=1[O:33][CH3:34].[OH-].[Na+]>C1COCC1.CO.Cl.C(OC(C)C)(=O)C>[CH3:31][O:30][C:18]1[CH:19]=[C:20]([O:28][CH3:29])[C:21]([C:23]2[S:24][CH:25]=[CH:26][CH:27]=2)=[CH:22][C:17]=1[C:16]#[C:15][C:14]([C:9]1[CH:10]=[C:11]([O:12][CH3:13])[C:6]([O:5][CH2:4][C:3]([OH:35])=[O:2])=[C:7]([O:33][CH3:34])[CH:8]=1)=[O:32]
Reactant: COC(=O)COc1c(OC)cc(C(=O)C#Cc2cc(-c3cccs3)c(OC)cc2OC)cc1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)OC(C)C
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc(OC)c(-c2cccs2)cc1C#CC(=O)c1cc(OC)c(OCC(=O)O)c(OC)c1
Reaction time: 0.5 h
Yield: 71.8 %

Procedure:
Ex-4: {4-[3-(2,4-dimethoxy-5-thiophen-2-yl-phenyl)-propynoyl]-2,6-dimethoxy-phenoxy}-acetic acid methyl ester (500 mg, 1.01 mmol) from Ex-3 was dissolved in THF (5 mL) and methanol (5 mL). Sodium hydroxide solution (1 N, 5 mL) was added and the resulting solution was stirred at room termperature under nitrogen for 30 min. The reaction-was then diluted with 1 N HCl and isopropyl acetate and the layers cut. The organic phase was concentrated to dryness under reduced pressure, diluted with a small amount of ethanol and filtered to afford 350 mg (73%) of the desired {4-[3-(2,4-dimethoxy-5-thiophen-2-yl-phenyl)-propynoyl]-2,6-dimethoxy-phenoxy}-acetic acid as a yellow solid, m.p. 192–194° C. 1H-NMR (300 MHz, d6-DMSO) δ 7.95 (s, 1H), 7.56 (dd, 1H, J=3.5 and 1.4 Hz), 7.49 (m, 1H), 7.47 (s, 2H), 7.07 (dd, 1H, J=5.1 and 3.5 Hz), 6.86 (s, 1H), 4.61 (s, 2H), 4.00 (s, 3H), 3.97 (s, 3H), 3.84 (s, 6H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].C(=O)([O-])[O-].[K+].[K+].[CH3:21][O:22][CH2:23]Cl.O>CN(C)C=O>[CH3:21][O:22][CH2:23][O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[C:11]([F:12])([F:13])[F:14]
Reactant: COCCl
Reactant: CC(=O)c1ccc(O)c(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COCOc1ccc(C(C)=O)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1-(4-hydroxy-3-trifluoromethylphenyl)ethanone (2.01 g) was dissolved in N,N-dimethylformamide (20 mL), and potassium carbonate (2.70 g) and chloromethyl methyl ether (1.10 mL) were added to the solution, and then the mixture was stirred at room temperature for 1 hour. Water was added to the reaction solution and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (2.33 g) as a pale yellow oily substance.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9](=[O:11])[CH3:10])[CH:5]=[CH:6][C:7]=1[F:8].[CH2:12]([O:14][CH:15]([O:21][CH2:22][CH3:23])[C:16](OCC)=[O:17])[CH3:13].[Li+].CC([N-]C(C)C)C>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:9](=[O:11])/[CH:10]=[C:16](\[OH:17])/[CH:15]([O:21][CH2:22][CH3:23])[O:14][CH2:12][CH3:13])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CCOC(=O)C(OCC)OCC
Reactant: CC(=O)c1ccc(F)c(Cl)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(OCC)/C(O)=C/C(=O)c1ccc(F)c(Cl)c1
Reaction time: 16 h

Procedure:
To a −78° C. solution of 1-(3-chloro-4-fluorophenyl)ethanone (16.25 g, 94 mmol) and ethyl 2,2-diethoxyacetate (20.73 mL, 113 mmol) in THF (392 mL) was added, dropwise, a solution of LDA (51.8 mL, 104 mmol, 2M in THF). The resultant reaction mixture was gradually allowed to reach room temperature and continued stirring for 16 h. The reaction was carefully quenched with water and diluted with EtOAc. The two layers were separated and the aq. layer was extracted with EtOAc (2×150 mL) The combined organic layer was washed with brine, dried over anhydrous MgSO4, filtered and the filtrate was concentrated under reduced pressure to provide a crude oil. It was purified by silica gel chromatography (1500 g Commodity column, eluting with a 10% EtOAc in hexanes). Fractions containing the product were combined and evaporated to afford Intermediate A39A (9.97 g, 35%) as a solid. MS(ES): m/z=257 [M-OEt]+.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:10][C@@:11]1([C:19]([O:21][CH3:22])=[O:20])[CH2:17][C@@H:16]([OH:18])[C@@H:15]2[C@@H:13]([O:14]2)[CH2:12]1.C(N(CC)CC)C>ClCCl>[C:1]([O:18][C@H:16]1[C@@H:15]2[C@@H:13]([O:14]2)[CH2:12][C@:11]([OH:10])([C:19]([O:21][CH3:22])=[O:20])[CH2:17]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)[C@]1(O)C[C@@H](O)[C@H]2O[C@H]2C1
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@@]1(O)C[C@@H]2O[C@@H]2[C@H](OC(=O)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.1 %

Procedure:
Benzoyl chloride (0.216 mL, 1.86 mmol) was added dropwise to a 0° C. solution of Example 17C (0.35 g, 1.86 mmol) and triethylamine (0.52 mL, 3.74 mmol) in dichloromethane (20 mL). The reaction mixture was stirred overnight at room temperature, washed with saturated NaHCO3 solution, brine, dried (MgSO4), filtered and concentrated. The concentrate was purified by flash column chromatography using hexanes/ethyl acetate (3/2) to afford 495 mg (91%) of the desired product as a colorless oil.
Reaction SMILES: [CH2:1]([N:5]([CH2:18][CH2:19][CH2:20][CH3:21])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][CH:14]=O)=[C:8]([O:16][CH3:17])[CH:7]=1)[CH2:2][CH2:3][CH3:4].[C:22]([C:24]1[C:25](=[C:40]([C:43]#[N:44])[C:41]#[N:42])[O:26][C:27]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)([C:30]([F:33])([F:32])[F:31])[C:28]=1[CH3:29])#[N:23]>C(O)C>[CH2:1]([N:5]([CH2:18][CH2:19][CH2:20][CH3:21])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][CH:14]=[CH:29][C:28]2[C:27]([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)([C:30]([F:33])([F:31])[F:32])[O:26][C:25](=[C:40]([C:43]#[N:44])[C:41]#[N:42])[C:24]=2[C:22]#[N:23])=[C:8]([O:16][CH3:17])[CH:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CC1=C(C#N)C(=C(C#N)C#N)OC1(c1ccccc1)C(F)(F)F
Reactant: CCCCN(CCCC)c1ccc(C=CC=O)c(OC)c1
Solvent: CCO
Product: CCCCN(CCCC)c1ccc(C=CC=CC2=C(C#N)C(=C(C#N)C#N)OC2(c2ccccc2)C(F)(F)F)c(OC)c1
Temperature: 50 °C
Yield: 86.7 %

Procedure:
In 5 ml of ethanol were dissolved 130 mg (0.45 mmol) of 3-(4-dibutylamino-2-methoxyphenyl)propenal and 156 mg (0.50 mmol) of 2-(3-cyano-4-methyl-5-phenyl-5-trifluoromethyl-2(5H)-furanylidene)propanedinitrile. After the mixture was stirred with heating at 50° C. for 2 hours, the solvent was evaporated off. The residue was purified by silica gel column chromatography to give 229 mg of a dark greenish brown crystal (yield: 86.9%; mp: 190-192° C.)
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[NH2:16][C:17]1[CH:29]=[CH:28][C:20]([O:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:19][CH:18]=1>>[CH2:26]([O:25][C:23]([CH2:22][O:21][C:20]1[CH:19]=[CH:18][C:17]([NH:16][C:2]2[CH:7]=[C:6]([NH:8][C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[CH:10]=3)[N:5]=[CH:4][N:3]=2)=[CH:29][CH:28]=1)=[O:24])[CH3:27]
Reactant: Cc1cccc(Nc2cc(Cl)ncn2)c1
Reactant: CCOC(=O)COc1ccc(N)cc1
Product: CCOC(=O)COc1ccc(Nc2cc(Nc3cccc(C)c3)ncn2)cc1
Yield: 33.1 %

Procedure:
Using an analogous reaction procedure to that described in Example 6, 4-chloro-6-(3'-methylanilino)pyrimidine (1.0 g) was reacted with ethyl 4-aminophenoxyacetate (1.0 g). The product so obtained was chromatographed on silica to give 4-[4'-(ethoxycarbonylmethoxy)anilino]6-(3'-methylanilino)pyrimidine (0.57 g).
Reaction SMILES: Cl.[CH2:2]1[C:14]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N:7]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:6]=2[CH2:5][CH2:4][NH:3]1.CCN([CH:27]([CH3:29])[CH3:28])C(C)C.Cl>ClCCl>[CH2:19]([O:18][C:16]([N:3]1[CH2:4][CH2:5][C:6]2[N:7]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[C:14]=2[CH2:2]1)=[O:17])[C:28]1[CH:27]=[CH:29][CH:6]=[CH:5][CH:4]=1
Reactant: CCOC(=O)Cn1c2c(c3ccccc31)CNCC2
Reactant: CCN(C(C)C)C(C)C
Agent: Cl
Solvent: ClCCl
Product: CCOC(=O)Cn1c2c(c3ccccc31)CN(C(=O)OCc1ccccc1)CC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of Intermediate 1 (29.5 mg, 0.10 mmol) and DIEA (51 μl, 0.30 mmol) in dichloromethane (1 ml) is added benzyl chlorofornate (16 μl, 0.11 mmol). The reaction mixture is stirred at rt for 1 h, 1 N aqueous HCl (2 ml). The aqueous layer is extracted twice with dichloromethane. The combined organic layers are washed with water, saturated NaHCO3 solution, then are concentrated to dryness to afford crude ethyl (2-benzyloxycarbonyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-acetate: tR (LC-1) 2.52 min; ESI-MS (positive ion): m/z 393.19 [M]+ (calcd 392.45 for C23H24N2O4).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=2)[N:3]=1.[CH3:16][N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.C(O)C>O>[Cl:8][C:6]1[CH:7]=[C:2]([N:20]2[CH2:21][CH2:22][N:17]([CH3:16])[CH2:18][CH2:19]2)[N:3]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=2)[N:5]=1
Reactant: Clc1cccc(-c2nc(Cl)cc(Cl)n2)c1
Reactant: CN1CCNCC1
Solvent: O
Solvent: CCO
Product: CN1CCN(c2cc(Cl)nc(-c3cccc(Cl)c3)n2)CC1

Procedure:
a solution of 7.8 g. of 4,6-dichloro-2-(m-chlorophenyl)-pyrimidine and 6.0 g. of N-methylpiperazine in 35 ml. of absolute ethanol is refluxed for fifteen minutes. Pouring of the resulting solution into 700 ml. of water causes separation of a gummy material which solidifies on standing over a weekend. The crude product weighs 6.5 g. and recrystallization from n-heptane affords cotton-like crystals of 4-chloro-2-(3-chlorophenyl)-6-(4-methylpiperazin-1-yl)-pyrimidine, m.p. 93°-94°C.
Reaction SMILES: Cl[CH2:2][CH:3]([OH:17])[CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([CH2:10][CH2:11][C:12](=[O:16])[NH:13]2)=[CH:8][CH:7]=1.[C:18]1([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CN(C)C=O>C(Cl)(Cl)Cl>[OH:17][CH:3]([CH2:2][N:27]1[CH2:28][CH2:29][N:24]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:25][CH2:26]1)[CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([CH2:10][CH2:11][C:12](=[O:16])[NH:13]2)=[CH:8][CH:7]=1
Reactant: O=C1CCc2ccc(OCC(O)CCl)cc2N1
Reactant: c1ccc(N2CCNCC2)cc1
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: O=C1CCc2ccc(OCC(O)CN3CCN(c4ccccc4)CC3)cc2N1
Yield: 73.6 %

Procedure:
5.1 grams of 7-(3-chloro-2-hydroxypropoxy)-3,4-dihydrocarbostyril and 8 g of 4-phenylpiperazine are mixed with 50 ml of dimethylformamide and reacted at 50°-60° C. for 5 hours under stirring conditions. The reaction mixture is concentrated under a reduced pressure to dryness and the residue thus obtained is dissolved in 80 ml of chloroform, then the chloroform layer is washed 3 times with 5% of sodium hydrogencarbonate aqueous solution and washed 3 times with water and dried with anhydrous sodium sulfate. Chloroform is removed by distillation under a reduced pressure and the residue thus obtained is purified by a silica gel chromatography [silica gel: Wako C-200, extracting solvent: chloroform:methanol=30:1 (v/v)]. Then the extracted product is converted into its hydrochloride by using ethanol containing hydrogen chloride and ethanol is removed by distillation under a reduced pressure. The thus obtained residue is recrystallized from ater to obtain 5.6 g of 7-[2-hydroxy-3-(4-phenylpiperazinyl)-propoxy]-3,4-dihydro carbostyril.monohydrochloride.1/2hydrate in the form of colorless crystals with a melting point of 122° C. (decomp.).
Reaction SMILES: [CH2:1](O)[CH2:2][C:3]1[CH:11]=[CH:10][C:9]2[O:8][CH2:7][O:6][C:5]=2[CH:4]=1.[CH2:13](N(CC)CC)C.CS(Cl)(=O)=O>C(Cl)Cl>[CH2:7]1[O:8][C:9]2[CH:10]=[CH:11][C:3]([CH2:2][CH2:1][CH3:13])=[CH:4][C:5]=2[O:6]1
Reactant: CCN(CC)CC
Reactant: OCCc1ccc2c(c1)OCO2
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Product: CCCc1ccc2c(c1)OCO2
Reaction time: 0.5 h
Yield: 140.2 %

Procedure:
Homopiperonyl alcohol (1) (7.03g, 42.4 mmol)1,2,3 and triethylamine (8.59 g., 85.0 mmol) were dissolved in methylene chloride (100 ml). The mixture was cooled to 0°-5°, then methanesulfonyl chloride (7.31 g., 63.6 mmol) was added slowly dropwise to the vigorously stirred solution. The mixture was stirred an additional 30 mins., then transferred to a separatory funnel where it was washed with water (3 × 50 ml), 4% hydrochloric acid (3 × 50 ml), saturated sodium bicarbonate solution (25 ml), saturated brine (25 ml) and dried over sodium sulfate. Filtration and evaporation of the methylene chloride yielded 9.76 g of a brown oil (94%); NMR--(CDCl3) 6.72 (m, 3H), 5.92 (S, 2H), 4.34 (t, J=7, 2H), 2.95 (t, J=7), lying under 2.89 (s) giving a total integration of 5H. This material was used without further purification.