Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][CH2:5][C:6]1[NH:15][C:14](=[O:16])[C:13]2[C:8](=[CH:9][C:10]([Cl:35])=[C:11]([CH2:17][N:18]([C:22]3[CH:34]=[CH:33][C:25]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[CH:24][CH:23]=3)[CH2:19][C:20]#[CH:21])[CH:12]=2)[N:7]=1)(=O)C.[OH-].[Na+].O>C1COCC1>[Cl:35][C:10]1[CH:9]=[C:8]2[C:13]([C:14](=[O:16])[NH:15][C:6]([CH2:5][OH:4])=[N:7]2)=[CH:12][C:11]=1[CH2:17][N:18]([C:22]1[CH:23]=[CH:24][C:25]([C:26]([O:28][C:29]([CH3:30])([CH3:31])[CH3:32])=[O:27])=[CH:33][CH:34]=1)[CH2:19][C:20]#[CH:21]
Reactant: C#CCN(Cc1cc2c(=O)[nH]c(COC(C)=O)nc2cc1Cl)c1ccc(C(=O)OC(C)(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: C#CCN(Cc1cc2c(=O)[nH]c(CO)nc2cc1Cl)c1ccc(C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.2 %

Procedure:
To a solution of tert-butyl 4-[N-[2-acetoxymethyl-7-chloro-4-oxo-3,4-dihydroquinazolin-6-ylmethyl]-N-(prop-2-ynyl)amino]benzoate (0.070 g, 0.14 mmol) in THF (2.7 ml) was dropwise added aqueous NaOH (1N, 0.27 ml, 0.27 mmol) followed by water (0.2 ml). The reaction mixture was stirred at room temperature for 2 hours, then the THF was removed in vacuo. The residue was suspended in water (10 ml) and the pH was adjusted to ˜5 with 1N HCl. The white precipitate was. collected by filtration, dried in vacuo and then it was reprecipitated from dichloromethane/hexanes to afford the title compound as a white solid (0.044 g, 70%), mp 185-187° C.; 1H-NMR (DMSO-d6) 1.49 (s, 9H, But), 3.25 (s, 1H, C≡CH), 4.35, 4.38 (2×s, 4H, CH2C≡C and 2-CH2), 4.78 (s, 2H, 6-CH2), 5.62 (br s, 1H, OH), 6.78 (d, J=8.7 Hz, 2H, 3′,5′-ArH), 7.73 (d, J=8.6 Hz, 2H, 2′,6′-ArH), 7.78, 7.84 (2×s, 2H, 5-H, 8-H), 12.07 (s, 1H, N3—H); FAB-HRMS: measured: 453.1463, calculated for C24H24ClN3O4: 453.1455.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[N:9]=[C:8]([O:11][C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]([F:22])([F:21])[F:20])[CH:13]=3)[N:7]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:6]=2[C:5](=[O:31])[NH:4][C:3]1=[O:32].Cl[CH2:34][CH2:35][O:36][CH2:37][CH2:38][O:39][CH:40]1[CH2:45][CH2:44][CH2:43][CH2:42][O:41]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCCC[N+](CCCC)(CCCC)CCCC.[I-]>[CH3:1][N:2]1[C:10]2[N:9]=[C:8]([O:11][C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]([F:21])([F:22])[F:20])[CH:13]=3)[N:7]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:28])([CH3:30])[CH3:29])[C:6]=2[C:5](=[O:31])[N:4]([CH2:34][CH2:35][O:36][CH2:37][CH2:38][O:39][CH:40]2[CH2:45][CH2:44][CH2:43][CH2:42][O:41]2)[C:3]1=[O:32]
Reactant: Cn1c(=O)[nH]c(=O)c2c1nc(Oc1cccc(OC(F)(F)F)c1)n2COCC[Si](C)(C)C
Reactant: ClCCOCCOC1CCCCO1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Product: Cn1c(=O)n(CCOCCOC2CCCCO2)c(=O)c2c1nc(Oc1cccc(OC(F)(F)F)c1)n2COCC[Si](C)(C)C
Temperature: 80 °C
Yield: 97.7 %

Procedure:
To a solution of 3-methyl-8-(3-(trifluoromethoxy)phenoxy)-7-((2-(trimethylsilyl)ethoxy)methyl)-1H-purine-2,6(3H,7H)-dione (1.2 g, 2.54 mmol) in DMF (15 mL) were added 2-(2-(2-chloroethoxy)ethoxy)tetrahydro-2H-pyran (0.79 g, 3.82 mmol, intermediate 1), potassium carbonate (0.7 g, 5.08 mmol), TBAI (2 mg, 0.02 mmol). It was heated at 80° C. overnight. The mixture was cooled, partitioned between ethyl acetate and water. The organic layers were combined, dried over sodium sulfate, filtered and concentrated to give a crude product (1.6 g, 98.1%) as a yellow oil which was used without purification. LCMS retention time 2.179 min, LCMS MH+-THP 561.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([NH2:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH:14]=[N:15][C:16]3[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[C:18]([O:26][CH3:27])[CH:17]=3)[C:8]=2[CH3:13])[N:3]=1>O1CCCC1.O>[CH3:13][C:8]1[C:9]2[C:10]([NH2:12])=[N:11][C:2]([NH2:1])=[N:3][C:4]=2[CH:5]=[CH:6][C:7]=1[CH2:14][NH:15][C:16]1[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[C:18]([O:26][CH3:27])[CH:17]=1
Reactant: COc1cc(N=Cc2ccc3nc(N)nc(N)c3c2C)cc(OC)c1OC
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(NCc2ccc3nc(N)nc(N)c3c2C)cc(OC)c1OC

Procedure:
The method of claim 21 wherein step (c) comprises heating the 2,4-diamino-5-methyl-6-[(3,4,5-trimethoxyphenylimino)methyl]quinazoline in a mixture of tetrahydrofuran and water in the presence of a reducing agent to produce a crude trimetrexate base, and converting the crude trimetrexate base to trimetrexate acetate.
Reaction SMILES: Cl.Cl.[CH2:3]([NH:10][NH2:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[OH-].[Na+].CN([CH:17]=[C:18]1[C:22](=[O:23])[CH2:21][CH2:20][C:19]1=[O:24])C>CO>[CH2:3]([NH:10][NH:11][CH:17]=[C:18]1[C:22](=[O:23])[CH2:21][CH2:20][C:19]1=[O:24])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CN(C)C=C1C(=O)CCC1=O
Reactant: NNCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C1CCC(=O)C1=CNNCc1ccccc1
Temperature: 0 °C

Procedure:
A mixture of 1.3 grams of benzylhydrazine dihydrochloride and 2.8 ml of 5 N sodium hydroxide in 10 ml of methanol was added to an ice-cold solution of 2-dimethylaminomethylene-1,3-cyclopentanedione in 20 ml of methanol. The mixture was heated at reflux for 2 hours and concentrated under reduced pressure. The residue was extracted several times with dichloromethane and the combined dichloromethane extracts were dried over magnesium sulfate and concentrated under reduced pressure to give a fluffy yellow solid. This was recrystallized from a mixture of toluene and hexane to give 2-[(2-benzylhydrazino)methylene]-1,3-cyclopentanedione melting about 164° C. with decomposition.
Reaction SMILES: C([O:4][CH:5]1[O:9][CH:8]([N:10]2[CH:15]=[C:14]([CH3:16])[C:13](=[O:17])[NH:12][C:11]2=[O:18])[CH2:7][CH:6]1[Si:19]([C:32]([CH3:35])([CH3:34])[CH3:33])([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)(=O)C.C1CCN2C(=NCCC2)CC1>>[OH:4][CH:5]1[O:9][CH:8]([N:10]2[CH:15]=[C:14]([CH3:16])[C:13](=[O:17])[NH:12][C:11]2=[O:18])[CH2:7][CH:6]1[Si:19]([C:32]([CH3:35])([CH3:34])[CH3:33])([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CC(=O)OC1OC(n2cc(C)c(=O)[nH]c2=O)CC1[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1cn(C2CC([Si](c3ccccc3)(c3ccccc3)C(C)(C)C)C(O)O2)c(=O)[nH]c1=O

Procedure:
Compound 97 is treated as per the protocol of Baptistella et. al., Synthesis 1989, 436 with DBU to give the title compound, 98. The compound was identified by a reduction in its Rf on a TLC. The compound proved to be unstable to isolation. It is therefore further used directly in situ following its preparation.
Reaction SMILES: O(C(C)(C)C)[Na].Cl[C:8]1[C:13]([Cl:14])=[N:12][CH:11]=[CH:10][N:9]=1.[O:15]([CH2:22][CH2:23][OH:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O1CCOCC1>[Cl:14][C:13]1[C:8]([O:24][CH2:23][CH2:22][O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:9][CH:10]=[CH:11][N:12]=1
Reactant: OCCOc1ccccc1
Reactant: Clc1nccnc1Cl
Agent: CC(C)(C)O[Na]
Solvent: C1COCCO1
Product: Clc1nccnc1OCCOc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 57.9 %

Procedure:
NaO-t-Bu (2.91 g, 30.29 mmol) was added to a mixture of 2,3-dichloropyrazine (4.75 g, 31.9 mmol) and 2-phenoxyethanol (4.18 g, 30.3 mmol) in dioxane (25 mL). The reaction mixture was stirred at ambient temperature for 1.5 h and then filtered. The filtrate was concentrated under reduced pressure and the crystalline residue obtained was dried in a vacuum oven affording 4.4 g (62%) of the title compound as white waxy crystals: mp 55-54° C. Anal. (C12H11ClN2O2) C, H, N.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][N:11]1[CH2:15][C@H:14]([CH:16]([CH3:18])[CH3:17])[N:13]([C:19]2[CH:24]=[CH:23][N:22]3[N:25]=[CH:26][C:27]([C:28]4[CH:33]=[CH:32][C:31]([C:34]5[N:38]=[CH:37][N:36]([CH2:39][O:40][CH2:41][CH2:42][Si:43]([CH3:46])([CH3:45])[CH3:44])[N:35]=5)=[CH:30][CH:29]=4)=[C:21]3[N:20]=2)[C:12]1=[O:47])(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>C1COCC1>[OH:8][CH2:9][CH2:10][N:11]1[CH2:15][C@H:14]([CH:16]([CH3:18])[CH3:17])[N:13]([C:19]2[CH:24]=[CH:23][N:22]3[N:25]=[CH:26][C:27]([C:28]4[CH:29]=[CH:30][C:31]([C:34]5[N:38]=[CH:37][N:36]([CH2:39][O:40][CH2:41][CH2:42][Si:43]([CH3:45])([CH3:44])[CH3:46])[N:35]=5)=[CH:32][CH:33]=4)=[C:21]3[N:20]=2)[C:12]1=[O:47]
Reactant: CC(C)[C@H]1CN(CCO[Si](C)(C)C(C)(C)C)C(=O)N1c1ccn2ncc(-c3ccc(-c4ncn(COCC[Si](C)(C)C)n4)cc3)c2n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)[C@H]1CN(CCO)C(=O)N1c1ccn2ncc(-c3ccc(-c4ncn(COCC[Si](C)(C)C)n4)cc3)c2n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.7 %

Procedure:
To a solution of (S)-1-(2-(tert-butyldimethylsilyloxy)ethyl)-4-isopropyl-3-(3-(4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)phenyl)pyrazolo[1,5-a]pyrimidin-5-yl)imidazolidin-2-one (0.18 g, 0.27 mmol) in THF was added Tetra-n-butylammonium fluoride (1 mmol, 1 mL, 1M solution in THF) and the reaction was stirred at ambient temperature for 3 hours. The reaction was poured into water and extracted into EtOAc. The combined organic layers were washed with water, brine, dried over magnesium sulfate and concentrated in vacuo. The crude material was chromatographed using 3% MeOH/dichloromethane as eluent to yield (S)-1-(2-hydroxyethyl)-4-isopropyl-3-(3-(4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)phenyl)pyrazolo[1,5-a]pyrimidin-5-yl)imidazolidin-2-one (0.15 g, 100%).
Reaction SMILES: C([O:3][C:4]([C:6]1([CH2:10][C:11]#[C:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:15][CH:14]=2)[CH2:9][CH2:8][CH2:7]1)=O)C.CC(C[AlH]CC(C)C)C>>[F:21][C:20]([F:22])([F:23])[O:19][C:16]1[CH:15]=[CH:14][C:13]([C:12]#[C:11][CH2:10][C:6]2([CH2:4][OH:3])[CH2:7][CH2:8][CH2:9]2)=[CH:18][CH:17]=1
Reactant: CCOC(=O)C1(CC#Cc2ccc(OC(F)(F)F)cc2)CCC1
Agent: CC(C)C[AlH]CC(C)C
Product: OCC1(CC#Cc2ccc(OC(F)(F)F)cc2)CCC1

Procedure:
In analogy to the procedure described in example 31E], reduction of 1-[3-(4-trifluoromethoxy-phenyl)-prop-2-ynyl]-cyclobutanecarboxylic acid ethyl ester with 3 equivalent of DIBAL-H (1.2 M solution in toluene) gave the title compound as yellow oil.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH2:10][C:11]1[CH:26]=[CH:25][C:14]([O:15][C:16]2[CH:24]=[CH:23][C:19]([C:20]([NH2:22])=[O:21])=[CH:18][N:17]=2)=[CH:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:27]C(O)=O.C=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl.C(Cl)Cl>[CH2:1]([N:8]([CH3:27])[CH2:9][CH2:10][C:11]1[CH:26]=[CH:25][C:14]([O:15][C:16]2[CH:24]=[CH:23][C:19]([C:20]([NH2:22])=[O:21])=[CH:18][N:17]=2)=[CH:13][CH:12]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC(=O)c1ccc(Oc2ccc(CCNCc3ccccc3)cc2)nc1
Reactant: CC(=O)O
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: ClCCl
Product: CN(CCc1ccc(Oc2ccc(C(N)=O)cn2)cc1)Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Combine amine (65 mg, 0.20 mmol) from example 1, AcOH (70 μL, 1.2 mmol), formaldehyde (0.6 mmol) and NaBH(OAc)3 (0.40 mmol) in 1,2-DCE (2 mL). Stir the mixture at room temperature overnight. Dilute the mixture with CH2Cl2 and wash with NaHCO3 sat. Extract the aqueous layer with CH2Cl2, combine the organic layers and dry over Na2SO4. Purify by flash chromatography on silica gel (eluent: EtOAc). Electrospray MS M+1 ion=362, 1H-NMR (CDCl3, 400 MHz): 8.58 (d, 1H, J=2.6 Hz), 8.15 (dd, 1H, J=2.6 and 8.6 Hz), 7.32-7.22 (m, 7H), 7.06-7.04 (m, 2H), 6.95 (d, 1H, J=8.6 Hz), 3.61 (bs, 2H), 2.91-2.84 (m, 2H), 2.74-2.66 (m, 2H), 2.32 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:20])[NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)=[CH:4][C:3]=1[NH:21][C:22]([C:24]1[C:28]2[N:29]=[CH:30][N:31]=[C:32](S(C)=O)[C:27]=2[S:26][CH:25]=1)=[O:23].Cl.[CH3:37][NH2:38]>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:20])[NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:17])([F:18])[F:19])[CH:11]=2)=[CH:4][C:3]=1[NH:21][C:22]([C:24]1[C:28]2[N:29]=[CH:30][N:31]=[C:32]([NH:38][CH3:37])[C:27]=2[S:26][CH:25]=1)=[O:23]
Reactant: Cc1ccc(C(=O)Nc2cccc(C(F)(F)F)c2)cc1NC(=O)c1csc2c(S(C)=O)ncnc12
Reactant: CN
Agent: Cl
Product: CNc1ncnc2c(C(=O)Nc3cc(C(=O)Nc4cccc(C(F)(F)F)c4)ccc3C)csc12

Procedure:
The procedure of Step 3 of Example 13 was repeated except for using the compound obtained in Step 2 of Example 13 and methylamine hydrochloride to obtain the title compound (see Table 1).
Reaction SMILES: [F:1][C:2]1[CH:27]=[C:26]([S:28]([CH3:31])(=[O:30])=[O:29])[CH:25]=[CH:24][C:3]=1[O:4][C@H:5]1[CH2:9][CH2:8][N:7]([CH:10]2[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][CH2:11]2)[C:6]1=[O:23].[ClH:32]>C(Cl)Cl.O1CCOCC1>[ClH:32].[F:1][C:2]1[CH:27]=[C:26]([S:28]([CH3:31])(=[O:30])=[O:29])[CH:25]=[CH:24][C:3]=1[O:4][C@H:5]1[CH2:9][CH2:8][N:7]([CH:10]2[CH2:11][CH2:12][NH:13][CH2:14][CH2:15]2)[C:6]1=[O:23]
Reactant: CC(C)(C)OC(=O)N1CCC(N2CC[C@H](Oc3ccc(S(C)(=O)=O)cc3F)C2=O)CC1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CS(=O)(=O)c1ccc(O[C@H]2CCN(C3CCNCC3)C2=O)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 109 %

Procedure:
(S)-tert-Butyl 4-(3-(2-fluoro-4-(methylsulfonyl)phenoxy)-2-oxopyrrolidin-1-yl)piperidine-1-carboxylate (1.6 g, 3.5 mmol) was dissolved in CH2Cl2 (20 mL) and 4N HCl in dioxane (˜15 mL) was added and stirred at ambient temperature overnight. The reaction was concentrated to afford (S)-3-(2-fluoro-4-(methylsulfonyl)phenoxy)-1-(piperidin-4-yl)pyrrolidin-2-one hydrochloride (1.5 g, 3.8 mmol, 109% yield) as a white solid. Mass spectrum (apci) m/z=357.2 (M+H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[OH-].[K+].[C:13]1([CH2:19][CH2:20][SH:21])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(O)C>[C:13]1([CH2:19][CH2:20][S:21][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Reactant: SCCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=[N+]([O-])c1ccc(SCCc2ccccc2)cc1
Temperature: 0 °C

Procedure:
75 g of 4-chloronitrobenzene in 300 ml of ethanol is heated to 70°. At this temperature there is then added dropwise 27 g of anhydrous potassium hydroxide and 65.9 g of 2-phenylethyl mercaptan in 250 ml of ethanol; the reaction mixture is refluxed for one hour and is then poured, with stirring into 1.5 liters of ice-water. The precipitated oil is extracted with methylene chloride, and the methylene chloride phases are dried over sodium sulphate. After purification through silica gel with methylene chloride as the eluant, there is obtained 4-(2'-phenyl-ethylthio)-nitrobenzene having a melting point of 35° - 37°.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([CH3:13])([CH3:12])[CH:6]=[C:5]2[N:14]1[CH2:18][CH2:17][CH2:16][C:15]1=[O:19].C(C1C=C2C(=CC=1)NC(C)(C)C=C2N1CCCC1=[O:39])#N>>[CH3:13][C:7]1([CH3:12])[C@@H:6]([OH:39])[C@H:5]([N:14]2[CH2:18][CH2:17][CH2:16][C:15]2=[O:19])[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([Br:1])[CH:3]=2)[NH:8]1
Reactant: CC1(C)C=C(N2CCCC2=O)c2cc(C#N)ccc2N1
Reactant: CC1(C)C=C(N2CCCC2=O)c2cc(Br)ccc2N1
Product: CC1(C)Nc2ccc(Br)cc2[C@@H](N2CCCC2=O)[C@@H]1O

Procedure:
A method according to claim 11, wherein the compound of formula (I) is 6-bromo-2,2-dimethyl-4-(2-oxo-1-pyrrolidinyl)-1,2-dihydroquinoline or 6-cyano-2,2-dimethyl-4-(2-oxo-1-pyrrolidinyl)-1,2-dihydroquinoline.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:13]([C:14](=[O:25])[NH:15][CH2:16][CH:17]=[CH:18][C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)=[C:12]([CH3:26])[NH:11][C:10]([CH3:27])=[C:9]2[C:28]([O:30]CCC#N)=[O:29])[CH:5]=[CH:6][CH:7]=1.[OH-].[Na+].Cl>CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:13]([C:14](=[O:25])[NH:15][CH2:16][CH:17]=[CH:18][C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)=[C:12]([CH3:26])[NH:11][C:10]([CH3:27])=[C:9]2[C:28]([OH:30])=[O:29])[CH:5]=[CH:6][CH:7]=1
Reactant: CC1=C(C(=O)NCC=Cc2ccncc2)C(c2cccc(Cl)c2)C(C(=O)OCCC#N)=C(C)N1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC1=C(C(=O)O)C(c2cccc(Cl)c2)C(C(=O)NCC=Cc2ccncc2)=C(C)N1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
161 mg (0.338 mmol) of the compound obtained in Example 25 was dissolved in 10 ml of methanol. 0.372 ml of 1 N aqueous sodium hydroxide solution was added to the obtained solution, and they were stirred at room temperature for 4 hours. After the addition of 1 N hydrochloric acid, methanol was evaporated under reduced pressure. Water was added to the residue, and a precipitate thus formed was taken by the filtration and then recrystallized (recrystallization solvent: methanol/isopropyl ether) to obtain the title compound.
Reaction SMILES: N[CH2:2][CH2:3][N:4]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:11]2[C:6]([N:7]([CH3:22])[C:8](=[O:21])[N:9]([CH3:20])[C:10]2=[O:19])=[CH:5]1.C(CN)[OH:24].C(Cl)Cl.O>CCO>[OH:24][CH2:2][CH2:3][N:4]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:11]2[C:6]([N:7]([CH3:22])[C:8](=[O:21])[N:9]([CH3:20])[C:10]2=[O:19])=[CH:5]1
Reactant: NCCO
Reactant: Cn1c(=O)c2c(-c3ccccc3)n(CCN)cc2n(C)c1=O
Solvent: O
Solvent: CCO
Solvent: ClCCl
Product: Cn1c(=O)c2c(-c3ccccc3)n(CCO)cc2n(C)c1=O
Temperature: 100 °C
Reaction time: 0.33 h

Procedure:
5-Benzoyl-6-(bromomethyl)-1,3-dimethylpyrimidine-2,4(1H,3H)-dione (Intermediate A step 3) (400 mg 1.19 mmol) in EtOH (4 mL) was treated with TEA (0.16 mL, 1.19 mmol) and ethanolamine (72.5 mg, 1.19 mmol). The mixture was heated to 100° C. for 1 h under microwave irradiation. A further portion of ethanolamine (96 μL) was added and heating continued for a further 20 min. The reaction was poured into DCM (75 mL) and water (75 mL). The layers were separated and the aqueous phase extracted with DCM (2×50 mL). The combined organic phases were washed with water (2×50 mL), then passed through a hydrophobic frit. The solvent was removed under reduced pressure affording a pale yellow solid. The solid was triturated in hot EtOH and allowed to cool. The title product was collected by reduced pressure filtration as a white powder.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]([C:12]2[C:13]([C:18]3[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=3[O:25][CH2:26][CH2:27][CH:28]([CH3:30])[CH3:29])=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:9]=[CH:10][CH:11]=1)=[O:5])C.[OH-].[Na+].Cl>C(O)C.O>[Cl:24][C:22]1[CH:21]=[CH:20][C:19]([O:25][CH2:26][CH2:27][CH:28]([CH3:30])[CH3:29])=[C:18]([C:13]2[C:12]([C:8]3[CH:9]=[CH:10][CH:11]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=3)=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:23]=1
Reactant: CCOC(=O)c1cccc(-c2ccccc2-c2cc(Cl)ccc2OCCC(C)C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)CCOc1ccc(Cl)cc1-c1ccccc1-c1cccc(C(=O)O)c1
Temperature: 25 °C
Yield: 97.9 %

Procedure:
5-Chloro-2-(3-methyl-butoxy)-[1,1′;2′,1″]terphenyl-3″-carboxylic acid ethyl ester (45 mg, 0.106 mmol) and NaOH (excess) were heated at 60° C. in ethanol (3 ml) for 2 hrs. The mixture was then cooled to room temperature, diluted with water, acidified with HCl (1M solution) and extracted with ethyl acetate. The combined extracts were dried (MgSO4) and evaporated to yield the title compound (41 mg, 98%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:33])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[N:12]([CH2:24][C:25](F)=[O:26])[CH:11]3[C:28]([CH2:31][CH3:32])=[CH:29][CH3:30])[C:5]2=[CH:4][CH:3]=1.[NH2:34][C:35]([CH3:39])([CH3:38])[CH2:36][OH:37].CN1CCOCC1>CN(C)C1C=CN=CC=1.O1CCCC1>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:33])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[N:12]([CH2:24][C:25]([NH:34][C:35]([CH3:39])([CH3:38])[CH2:36][OH:37])=[O:26])[CH:11]3[C:28]([CH2:31][CH3:32])=[CH:29][CH3:30])[C:5]2=[CH:4][CH:3]=1
Reactant: CC(C)(N)CO
Reactant: CC=C(CC)C1N(CC(=O)F)C(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CC=C(CC)C1N(CC(=O)NC(C)(C)CO)C(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Yield: 68.6 %

Procedure:
In a manner similar to the method described in example 34b, racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(1-ethyl-propenyl)-1′-fluorocarbonylmethyl-spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (0.12 g, 0.24 mmol) prepared in example 82a was reacted with 2-amino-2-methyl-propan-1-ol (73 mg, 0.82 mmol), N-methylmorpholine (0.2 g, 1.98 mmol) and 4-dimethylaminopyridine (2 mg, 0.016 mmol) in tetrahydrofuran to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(1-ethyl-propenyl)-1′-[(2-hydroxy-1,1-dimethylethyl)aminocarbonylmethyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as an off-white solid (Yield 92 mg, 67%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([Cl:8])=[N:6][CH:7]=1.[NH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1.C1(P(C2CCCCC2)C2(C(C)C)CC(C(C)C)=CC(C(C)C)=C2C2C=CC=CC=2)CCCCC1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O>[Cl:8][C:5]1[C:4]([NH2:9])=[CH:3][C:2]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[CH:7][N:6]=1
Reactant: C1COCCN1
Reactant: Nc1cc(Br)cnc1Cl
Agent: [Pd]
Agent: CC(C)C1=CC(C(C)C)=C(c2ccccc2)C(C(C)C)(P(C2CCCCC2)C2CCCCC2)C1
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: O
Solvent: C1CCOC1
Product: Nc1cc(N2CCOCC2)cnc1Cl
Temperature: 60 °C
Reaction time: 2.5 h

Procedure:
A mixture of 5-bromo-2-chloropyridin-3-amine (1.01 g, 4.89 mmol), morpholine (0.85 mL, 9.76 mmol), 2-dicyclohexylphosphino-2,4,6,-triisopropylbiphenyl, (X-Phos) (187.2 mg, 0.39 mmol), and tris(dibenzylideneacetone)dipalladium (0) (180.6 mg, 0.20 mmol) in dry THF (10 mL) was degassed by nitrogen. To this mixture was added lithium bis(trimethylsilyl)amide, 1.0M in THF (15.0 mL, 15.0 mmol) dropwise, and the resulting reaction was heated to 60° C. After 2.5 h, the reaction was cooled to rt then poured into water. After extracting twice with EtOAc and twice with DCM, the combined organic layers were dried over anhydrous magnesium sulfate. After filtration and concentration, the residue was purified on basic alumina (0-20% EtOAc in hexanes) to afford an off-white solid as 2-chloro-5-morpholinopyridin-3-amine. 1H NMR (400 MHz, CDCl3) δ ppm 7.49 (1H, d, J=2.7 Hz), 6.57 (1H, d, J=2.7 Hz), 3.93 (4H, m), 3.49 (2H, s), 3.22 (4H, m).
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[C:24]([N:27]1[CH2:31][CH2:30][NH:29][C:28]1=[O:32])(=[O:26])[CH3:25]>>[C:24]([N:27]1[CH2:31][CH2:30][N:29]([C:2]2[CH:3]=[CH:4][C:5]([C:8]([N:10]3[CH2:15][CH2:14][N:13]([C:16]4[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=4)[CH2:12][CH2:11]3)=[O:9])=[CH:6][N:7]=2)[C:28]1=[O:32])(=[O:26])[CH3:25]
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)nc3)CC2)c(C)c1
Reactant: CC(=O)N1CCNC1=O
Product: CC(=O)N1CCN(c2ccc(C(=O)N3CCN(c4ncc(C)cc4C)CC3)cn2)C1=O
Yield: 63.6 %

Procedure:
Using (6-bromopyridin-3-yl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (225 mg) described in Preparation Example 127 and 1-acetylimidazolidin-2-one (115 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (161 mg) was obtained.
Reaction SMILES: [C:1]1([C:7]2[NH:11][C:10]([C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15]4)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:24][C:25]#[N:26].C(=O)([O-])[O-].[Cs+].[Cs+]>>[C:1]1([C:7]2[NH:11][C:10]([C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[CH:18]=[C:17]([O:22][CH2:24][C:25]#[N:26])[CH:16]=[CH:15]4)=[CH:9][CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: N#CCBr
Reactant: Oc1ccc2cc(-c3ccc(-c4ccccc4)[nH]3)ccc2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: N#CCOc1ccc2cc(-c3ccc(-c4ccccc4)[nH]3)ccc2c1
Reaction time: 2 h

Procedure:
In a similar manner as described in step 6 of Example 1, the title compound was prepared from 6-(5-phenyl-1H-pyrrol-2-yl)-2-naphthol (0.285 g, 1.00 mmol), prepared in step 5 of Example 1, bromoacetonitrile (0.144 g, 1.20 mmol) and cesium carbonate (1.63 g, 5.00 mmol) with the exception that the reaction was complete after 2 hours at ambient temperature. The isolated tan solids (0.323 g, 100%) were used without further purification, mp 141.5–142.5° C. Elemental Analysis for C22H16N2O Calc'd: C, 81.46; H, 4.97; N, 8.64. Found: C, 80.37; H, 4.93; N,