Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:6]1[CH:22]=[C:21]([C:23]([CH2:26][CH3:27])([CH3:25])[CH3:24])[CH:20]=[CH:19][C:7]=1[O:8][C:9]1[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=1[C:11]([O:13]C)=[O:12])([CH2:4][CH3:5])([CH3:3])[CH3:2].[OH-].[K+].C(O)C>C(OCC)C>[C:1]([C:6]1[CH:22]=[C:21]([C:23]([CH2:26][CH3:27])([CH3:25])[CH3:24])[CH:20]=[CH:19][C:7]=1[O:8][C:9]1[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=1[C:11]([OH:13])=[O:12])([CH2:4][CH3:5])([CH3:3])[CH3:2]
Reactant: CCC(C)(C)c1ccc(Oc2ccccc2C(=O)OC)c(C(C)(C)CC)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CCO
Product: CCC(C)(C)c1ccc(Oc2ccccc2C(=O)O)c(C(C)(C)CC)c1

Procedure:
Next 2,4-di-(tert-amyl)phenoxybenzoic acid was prepared. A mixture of methyl 2,4-di-(tert-amyl)phenoxybenzoate (7.44 g, 20 mmol), potassium hydroxide (2.3 g, 40 mmol), and ethanol (60 mL) was heated at reflux for 4 h and then cooled to ambient. Diethyl ether (20 mL) was added, and the mixture was washed twice with 10% aqueous HCl. The organic layer was dried (Na2SO4) and the solvent was removed at reduced pressure to deposit a yellow solid. This crude product was purified by recrystallization from heptane to provide 5.0 g, 70% of theory) of 2,4-di-(tert-amyl)phenoxybenzoic acid as a tan solid. 1H NMR (CDCl3): δ 0.75 (t, 6H), 1.3 (s, 6H), 1.4 (s, 6H), 1.65 (q, 2H), 1.80 (q, 2H), 3.85 (s, 3H), 6.80 (d, 2H), 7.15 (m, 2H), 7.35(br s, 1H), 7.45 (t, 1H), 8.2 (d, 1H).
Reaction SMILES: [CH2:1]([O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][O:36][C:37]1([O:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][O:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][CH2:79][CH2:80][CH2:81][CH2:82][CH2:83][CH2:84][CH2:85][CH3:86])[CH:50]=[CH:49][C:40]([C:41]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)=[O:42])=[CH:39][CH2:38]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].CO.[BH4-].[Na+].Cl>C(Cl)(Cl)Cl>[CH2:1]([O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][O:36][C:37]1([O:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][O:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][CH2:79][CH2:80][CH2:81][CH2:82][CH2:83][CH2:84][CH2:85][CH3:86])[CH:38]=[CH:39][C:40]([CH:41]([OH:42])[C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)=[CH:49][CH2:50]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCCCCCCCCCCCCCCCCCOCCCCCCCCCCCCOC1(OCCCCCCCCCCCCOCCCCCCCCCCCCCCCCCCCCCC)C=CC(C(=O)c2ccccc2)=CC1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCCCCCCCCCOCCCCCCCCCCCCOC1(OCCCCCCCCCCCCOCCCCCCCCCCCCCCCCCCCCCC)C=CC(C(O)c2ccccc2)=CC1
Temperature: 60 °C
Reaction time: 4 h
Yield: 98.8 %

Procedure:
4,4-Di(12-docosoxydodecyloxy)benzophenone (1.04 g, 867 μmol) was dissolved in chloroform (20 ml), and methanol (2 ml) and sodium borohydride (98 mg, 2.60 mmol) were added, and the mixture was stirred at 60° C. for 4 hr. The reaction mixture was cooled to room temperature, 0.5N hydrochloric acid (20 ml) was added and the mixture was stirred for a while. The aqueous layer was removed, and the organic layer was washed with water (10 ml)×2. The organic layer was evaporated under reduced pressure, and the residue was crystallized from methanol to give 4,4-di(12-docosoxydodecyloxy)benzhydrol (1.03 g, 857 μmol, 98%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]1[CH2:20][CH2:19][N:18]([C:21](=[O:34])[C:22]3[CH:27]=[CH:26][C:25]([C:28]4[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=4)=[CH:24][CH:23]=3)[CH2:17][CH2:16]1)(=[O:14])=[O:13])[CH:6]=[CH:5]2.ClC1C=CC=C(C(OO)=[O:43])C=1>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]1[CH2:20][CH2:19][N:18]([C:21]([C:22]3[CH:23]=[CH:24][C:25]([C:28]4[CH:33]=[CH:32][N+:31]([O-:43])=[CH:30][CH:29]=4)=[CH:26][CH:27]=3)=[O:34])[CH2:17][CH2:16]1)(=[O:14])=[O:13])[CH:6]=[CH:5]2
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=C(c1ccc(-c2ccncc2)cc1)N1CCN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CC1
Solvent: ClCCl
Product: O=C(c1ccc(-c2cc[n+]([O-])cc2)cc1)N1CCN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
To a solution of 1-(6-chloronaphthalene-2-sulfonyl)-4-[4-(4-pyridyl)benzoyl]piperazine (200 mg) in dichloromethane (25 ml) was added m-chloroperbenzoic acid (140 mg) and the solution was stirred at room temperature for 2 hours. The reaction solution was diluted with dichloromethane, washed with 1 N sodium hydroxide solution and sodium chloride solution, dried and concentrated. The residue was crystallized with dichloromethane/hexane to give a colorless solid of the title compound (188 mg).
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([CH:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)=[CH:8][CH:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.Cl[C:26]1[N:31]([CH3:32])[C:30](=[O:33])[CH:29]=[C:28]([C:34]2[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=2)[N:27]=1>O1CCCC1>[CH3:32][N:31]1[C:30](=[O:33])[CH:29]=[C:28]([C:34]2[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=2)[N:27]=[C:26]1[N:15]1[CH2:16][CH2:17][CH:12]([C:9]2[CH:8]=[CH:7][C:6]([N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[CH:11][CH:10]=2)[CH2:13][CH2:14]1
Reactant: Cn1c(Cl)nc(-c2ccncc2)cc1=O
Reactant: c1cc(N2CCCC2)ccc1C1CCNCC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cn1c(N2CCC(c3ccc(N4CCCC4)cc3)CC2)nc(-c2ccncc2)cc1=O
Yield: 81 %

Procedure:
A solution of 4-(4-pyrrolidin-1-yl-phenyl)-piperidine (215 mg, 0.933 mmol) and triethylamine (391 mg, 3.86 mmol), 2-chloro-3-methyl-6-(pyridin-4-yl)-3H-pyrimidin-4-one (187 mg, 0.844 mmol) in tetrahydrofuran (10 mL) was refluxed for 5 hr. The resulting solution was diluted with tetrahydrofuran and filtrated. After removal of the solvents under reduced pressure and the purification of the resulting residue by CHEM ELUT CE1010 (manufactured by VARIAN) eluting dichloromethane/ethanol (15/1, v/v) and wash with ethyl acetate afforded 3-methyl-6-pyridin-4-yl-2-(4-(4-pyrrolidin-1-yl-phenyl)-piperidin-1-yl)-3H-pyrimidin-4-one (284 mg, 81%) as a solid.
Reaction SMILES: [CH3:1][N:2]([C:13]1[CH:26]=[CH:25][C:16]([O:17][CH:18]([CH3:24])[C:19]([O:21]CC)=[O:20])=[CH:15][CH:14]=1)[C:3]1[O:4][C:5]2[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:6]=2[N:7]=1.[OH-].[Na+]>C(O)(C)C.O>[CH3:1][N:2]([C:13]1[CH:26]=[CH:25][C:16]([O:17][CH:18]([CH3:24])[C:19]([OH:21])=[O:20])=[CH:15][CH:14]=1)[C:3]1[O:4][C:5]2[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:6]=2[N:7]=1
Reactant: CCOC(=O)C(C)Oc1ccc(N(C)c2nc3cc(Cl)ccc3o2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: CC(Oc1ccc(N(C)c2nc3cc(Cl)ccc3o2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 48 h
Yield: 63 %

Procedure:
Ethyl 2-{4-[N-methyl-N-(5-chloro-2-benzoxazolyl)amino]phenoxy}propionate (10.0 g; see Example 7) was suspended in isopropyl alcohol (50 ml) and a solution of sodium hydroxide (1.12 g) in water (50 ml) was added over a period of 45 minutes. Further isopropyl alcohol (60 ml) was added and the mixture was stirred at room temperature for a period of 48 hours. The alcohol was removed by distillation under reduced pressure, the residue was dissolved in water and the aqueous solution was acidified to pH 4 by the addition of aqueous 2 M hydrochloric acid. The precipitate was collected by filtration, dried and recrystallised from ethyl acetate to give the title compound (5.83 g; 63%), mp 152°-154° C. The pmr spectrum of the compound was consistent with the assigned structure.
Reaction SMILES: [C:1]([N:4]([CH:23]1[CH2:25][CH2:24]1)[C:5]1[N:10]=[C:9]([N:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:13][CH2:12]2)[C:8]([NH2:22])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].C(O)C.[F:29][B-:30]([F:33])([F:32])[F:31].[H+].[N:35]([O-])=O.[Na+]>O.CCOCC>[F:29][B-:30]([F:33])([F:32])[F:31].[CH2:20]([O:19][C:17]([N:14]1[CH2:15][CH2:16][N:11]([C:9]2[C:8]([N+:22]#[N:35])=[CH:7][CH:6]=[C:5]([N:4]([C:1](=[O:3])[CH3:2])[CH:23]3[CH2:24][CH2:25]3)[N:10]=2)[CH2:12][CH2:13]1)=[O:18])[CH3:21]
Reactant: CCOC(=O)N1CCN(c2nc(N(C(C)=O)C3CC3)ccc2N)CC1
Reactant: O=N[O-]
Agent: F[B-](F)(F)F
Agent: [H+]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: CCOCC
Product: CCOC(=O)N1CCN(c2nc(N(C(C)=O)C3CC3)ccc2[N+]#N)CC1
Reaction time: 1 h

Procedure:
A solution of 20.8 g (60 mmole) of 4-[6-(acetylcyclopropylamino)-3-amino-2-pyridinyl]-1-piperazinecarboxylic acid, ethyl ester, 44 ml of ethanol and 27 ml of 48% tetrafluoroboric acid was cooled to 0° C. and treated dropwise with a solution of 4.56 g (66 mmol) of sodium nitrite in 8 ml of water under a nitrogen atmosphere keeping the temperature 0°-5° C. After the addition was complete, the reaction was stirred at 0°-5° C. for one hour and treated with 150 ml of anhydrous ether keeping the temperature below 10° C. The solid was removed by filtration, the precipitate was washed with ethanol/ether (1:1), ether and dried in vacuo to give 24.5 g of the title compound, mp 100°-105° C. (dec.).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:39]=[C:40]([F:42])[CH:41]=1)[C:5]([C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][N:11]=[C:10]2[NH:16][C:17](=[O:38])[C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]2)=[CH:20][C:19]=1[NH:31][CH:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1)=[O:6].[BH4-].[Na+]>C(O)(C)C>[F:1][C:2]1[CH:3]=[C:4]([CH:5]([OH:6])[C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[NH:12][N:11]=[C:10]3[NH:16][C:17](=[O:38])[C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]3)=[CH:20][C:19]=2[NH:31][CH:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH:39]=[C:40]([F:42])[CH:41]=1
Reactant: CN1CCN(c2ccc(C(=O)Nc3n[nH]c4ccc(C(=O)c5cc(F)cc(F)c5)cc34)c(NC3CCOCC3)c2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Product: CN1CCN(c2ccc(C(=O)Nc3n[nH]c4ccc(C(O)c5cc(F)cc(F)c5)cc34)c(NC3CCOCC3)c2)CC1
Reaction time: 4 h
Yield: 45 %

Procedure:
A mixture of N-[5-(3,5-Difluoro-benzoyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide (130 mg, 0.226 mmol) and sodium borohydride (15 mg, 0.39 mmol) was dissolved at room temperature in i-propanol (20 mL). The reaction mixture was stirred for 4 hours, quenched with methanol and evaporated to dryness. Crude material was redissolved in DCM and washed with brine. After trituration with diethyl ether, 59 mg of the title compound were recovered (45% yield).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH:6]([CH3:8])[CH3:7])=[O:3].[CH2:9]([NH:12][CH:13]1[CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[C:18]([C:22]3[CH2:23][CH2:24][C:25](=[O:28])[NH:26][N:27]=3)[CH:19]=2)[CH2:14]1)[CH2:10][CH3:11].C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH2:9]([N:12]([CH:13]1[CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[C:18]([C:22]3[CH2:23][CH2:24][C:25](=[O:28])[NH:26][N:27]=3)[CH:19]=2)[CH2:14]1)[C:2]([O:4][CH2:5][CH:6]([CH3:8])[CH3:7])=[O:3])[CH2:10][CH3:11]
Reactant: CCCNC1Cc2ccc(C3=NNC(=O)CC3)cc2C1
Reactant: CC(C)COC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCCN(C(=O)OCC(C)C)C1Cc2ccc(C3=NNC(=O)CC3)cc2C1
Reaction time: 1 h
Yield: 67.3 %

Procedure:
Under ice cooling, 2.46 g of isobutyl chloroformate was added to 4.07 g of 2-propylamino-5-[4,5-dihydropyridazin-3(2H)-on-6-yl]indane and 2.02 g of triethylamine dissolved in 40 ml of chloroform, and the mixture was stirred for 1 hour. The organic layer was washed with water and dried, and the solvent was removed. The resulting crude crystals were recrystallized from ethyl acetate to obtain 3.75 g of 2-(N-propyl-N-isobutoxycarbonylamino)-5-[4,5-dihydropyridazin-3(2H)-on-6-yl]indane.
Reaction SMILES: ClC[C:3]([N:5]([CH2:16][CH:17]1[C:26]2[C:21](=[CH:22][C:23]([C:27]#[N:28])=[CH:24][CH:25]=2)[CH2:20][CH2:19][CH2:18]1)[CH2:6][CH2:7][NH:8][C:9](=O)OC(C)(C)C)=[O:4].CCO.C([O-])([O-])=O.[K+].[K+]>Cl.O1CCOCC1>[O:4]=[C:3]1[CH2:9][NH:8][CH2:7][CH2:6][N:5]1[CH2:16][CH:17]1[CH2:18][CH2:19][CH2:20][C:21]2[CH:22]=[C:23]([C:27]#[N:28])[CH:24]=[CH:25][C:26]1=2
Reactant: CC(C)(C)OC(=O)NCCN(CC1CCCc2cc(C#N)ccc21)C(=O)CCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: C1COCCO1
Product: N#Cc1ccc2c(c1)CCCC2CN1CCNCC1=O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of tert-Butyl (2-{(chloroacetyl)[(6-cyano-1,2,3,4-tetrahydronaphthalen-1-yl)methyl]amino}ethyl)carbamate (140 mg, 0.35 mmol) in HCl/dioxane (20 mL) was stirred at RT for 12 hours and then concentrated to dryness. To the residue was added 2 mL EtOH and K2CO3 (143 mg, 1.04 mmol). The resulting mixture was heated to reflux for 4 hours before cooled to RT and filtered. The filtrate was concentrate and the residue was partitioned between EtOAc and water. The organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated to dryness to give the title compound. MS m/z: 270 [M+1]+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20](O)=[O:21])=[CH:16][CH:15]=1.[CH:23]1([NH:29][CH2:30][CH3:31])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>>[CH:23]1([N:29]([CH2:30][CH3:31])[C:20]([C:17]2[CH:16]=[CH:15][C:14]([C:3]3[CH:4]=[C:5]([C:8]4[O:9][C:10]([CH3:13])=[N:11][N:12]=4)[CH:6]=[CH:7][C:2]=3[CH3:1])=[CH:19][CH:18]=2)=[O:21])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)O)cc3)c2)o1
Reactant: CCNC1CCCCC1
Product: CCN(C(=O)c1ccc(-c2cc(-c3nnc(C)o3)ccc2C)cc1)C1CCCCC1

Procedure:
N-Cyclohexyl-N-ethyl-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide was prepared from 2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxylic acid and N-cyclohexyl-N-ethylamine using method I.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[C:7]([C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=1[N:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]1[CH3:24])[C:12]([OH:14])=O)#[N:8].[F:25][C:26]1[CH:27]=[CH:28][C:29]([O:36][CH3:37])=[C:30]([C:32](=[N:34]O)[NH2:33])[CH:31]=1.CCN(C(C)C)C(C)C>>[F:25][C:26]1[CH:27]=[CH:28][C:29]([O:36][CH3:37])=[C:30]([C:32]2[N:33]=[C:12]([C:11]3[CH:15]=[CH:16][C:17]([N:18]4[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]4[CH3:24])=[C:9]([CH:10]=3)[C:7]#[N:8])[O:14][N:34]=2)[CH:31]=1
Reactant: COc1ccc(F)cc1C(N)=NO
Reactant: CC1CCCCN1c1ccc(C(=O)O)cc1C#N
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(F)cc1-c1noc(-c2ccc(N3CCCCC3C)c(C#N)c2)n1

Procedure:
Oxalyl chloride (190 mg; 1.5 mmol; 3 eq.), Intermediate 36 (122 mg; 0.5 mmol; 1 eq.), Intermediate 23 (92 mg; 0.5 mmol, 1 eq.) and DIEA (194 mg; 1.5 mmol; 3 eq.) were reacted according to general procedure 2. Purification by column chromatography (c-hexane/ethyl acetate, 70/30) afforded the title compound as a white solid.
Reaction SMILES: [C:1]([C:4]1[CH:29]=[CH:28][C:7]([O:8][CH2:9][CH2:10][CH:11]2[O:15][C:14]3[CH:16]=[CH:17][C:18]([C:20](=[O:27])[CH2:21][CH2:22][C:23]([O:25]C)=[O:24])=[CH:19][C:13]=3[CH2:12]2)=[C:6]([CH2:30][CH2:31][CH3:32])[C:5]=1[OH:33])(=[O:3])[CH3:2]>C1COCC1.[OH-].[Na+]>[C:1]([C:4]1[CH:29]=[CH:28][C:7]([O:8][CH2:9][CH2:10][CH:11]2[O:15][C:14]3[CH:16]=[CH:17][C:18]([C:20](=[O:27])[CH2:21][CH2:22][C:23]([OH:25])=[O:24])=[CH:19][C:13]=3[CH2:12]2)=[C:6]([CH2:30][CH2:31][CH3:32])[C:5]=1[OH:33])(=[O:3])[CH3:2]
Reactant: CCCc1c(OCCC2Cc3cc(C(=O)CCC(=O)OC)ccc3O2)ccc(C(C)=O)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCc1c(OCCC2Cc3cc(C(=O)CCC(=O)O)ccc3O2)ccc(C(C)=O)c1O
Reaction time: 2 h

Procedure:
The compound of Example 4 (275 mg, 0.61 mmoles) was taken up in approximately 5 ml THF to which was added in NaOH (1.3 ml). After 2 hours, the THF was removed in vacuo and the aqueous phase was diluted with two volumes of distilled H2O acidified with concentrated HCl. The title compound was extracted into CHCl3, dried and concentrated to a beige solid, m.p. 156°-158°
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[C:8]([N:10]2[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]2)[C:7]([F:17])=[CH:6][C:5]=1[NH:18][C:19]([NH2:21])=[O:20])[CH3:2].C[O-].[Na+].[C:25](OCC)(=O)[CH2:26][C:27](OCC)=[O:28].Cl>CO>[CH2:1]([N:3]1[C:4]2[CH:9]=[C:8]([N:10]3[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]3)[C:7]([F:17])=[CH:6][C:5]=2[N:18]2[C:19](=[O:20])[NH:21][C:27](=[O:28])[CH:26]=[C:25]12)[CH3:2]
Reactant: CCNc1cc(N2CCN(C)CC2)c(F)cc1NC(N)=O
Reactant: CCOC(=O)CC(=O)OCC
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CCn1c2cc(N3CCN(C)CC3)c(F)cc2n2c(=O)[nH]c(=O)cc12
Reaction time: 6 h
Yield: 17 %

Procedure:
A solution of 1-[2-(N-ethylamino)-5-fluoro-4-(4-methyl-1-piperazinyl]phenyl-urea (640 mg) in methanol is treated with a freshly prepared methanolic solution of sodium methylate (from 150 mg of sodium) and heated under reflux for a short time. After cooling the solution is treated with diethyl malonate and stirred for 6 hours. The solution obtained is poured into a mixture of ice and 2N HCl (50 ml). The methanol is evaporated and the aqueous phase is extracted with ethyl acetate (3×100 ml) and methylene chloride (2×100 ml). After drying over magnesium sulfate the solvent mixture is evaporated and the residue is suspended in a small amount of cold ethyl acetate and filtered off. There are obtained 130 mg (17%) of 5-ethyl-8-fluoro-7-(4-methyl-1-piperazinyl)pyrimido[1,6-a]benzimidazole-1,3(2H,5H)-dione.
Reaction SMILES: [OH-].[Na+].C([O:5][C:6]([C:8]1[C:9](/[CH:23]=[CH:24]/[CH3:25])=[N:10][C:11]2[C:16]([C:17]=1[CH3:18])=[CH:15][CH:14]=[C:13]([C:19]([F:22])([F:21])[F:20])[CH:12]=2)=[O:7])C>O.CCO>[CH3:18][C:17]1[C:16]2[C:11](=[CH:12][C:13]([C:19]([F:20])([F:21])[F:22])=[CH:14][CH:15]=2)[N:10]=[C:9](/[CH:23]=[CH:24]/[CH3:25])[C:8]=1[C:6]([OH:7])=[O:5]
Reactant: C/C=C/c1nc2cc(C(F)(F)F)ccc2c(C)c1C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: C/C=C/c1nc2cc(C(F)(F)F)ccc2c(C)c1C(=O)O
Temperature: 90 °C
Yield: 85.7 %

Procedure:
560 mg (13.9 mmol) NaOH flocs were added to a solution of 450 mg (1.4 mmol) (E)-4-methyl-2-(prop-1-enyl)-7-(trifluoromethyl)quinoline-3-carboxylic acid ethyl ester in a water/EtOH mixture (in each case 21 ml) at 0° C. The mixture was subsequently heated to 90° C. for 16 h. It was then concentrated in a vacuum and the residue was taken up with water (20 ml) and washed with EtOAc. Thereafter, the aqueous phase was set to pH ˜2 with a 2M hydrochloric acid and extracted with EtOAc. The organic phase was dried over Na2SO4 and concentrated in a vacuum. 350 mg (1.2 mmol, 85%) (E)-4-methyl-2-(prop-1-enyl)-7-(trifluoromethyl)quinoline-3-carboxylic acid was obtained as a residue. The raw product was further converted without additional purification.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[S:12][C:13]([C:17]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[O:18])=[C:14]([CH3:16])[N:15]=3)[S:10][C:3]=12.[C:25]1([C:31]2[NH:35][NH:34][C:33](=[O:36])[CH:32]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH3:16][C:14]1[N:15]=[C:11]([C:9]2[S:10][C:3]3[C:4](=[N:5][CH:6]=[CH:7][C:2]=3[O:36][C:33]3[CH:32]=[C:31]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[NH:35][N:34]=3)[CH:8]=2)[S:12][C:13]=1[C:17]([N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1)=[O:18]
Reactant: Cc1nc(-c2cc3nccc(Cl)c3s2)sc1C(=O)N1CCOCC1
Reactant: O=c1cc(-c2ccccc2)[nH][nH]1
Product: Cc1nc(-c2cc3nccc(Oc4cc(-c5ccccc5)[nH]n4)c3s2)sc1C(=O)N1CCOCC1
Yield: 17 %

Procedure:
The title compound (37 mg, 17%) was prepared from [2-(7-Chloro-thieno[3,2-b]pyridin-2-yl)-4-methyl-thiazol-5-yl]-morpholin-4-yl-methanone and 5-Phenyl-1,2-dihydro-pyrazol-3-one by a procedure analogous to Example 16 1. C25H21N5O3S2: APCI m/z 503.5 (pos.); 1H NMR (CD3OD): δ 8.55 (d, 1H, J=5.8 Hz), 8.00 (s, 1H), 7.72 (d, 2H, J=7.1 Hz), 7.46 (t, 2H, J=7.1 Hz), 7.41 (t, 1H, J=7.1 Hz), 7.08 (d, 1H, J=5.8 Hz), 6.53 (s, 1H), 3.71–3.60 (bm, 8H), 2.46 (s, 3H) ppm.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:8][CH2:9][C@@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[CH3:15])[CH:5]=[N:6][CH:7]=1.[C:16]([CH:18](C)[CH2:19][CH2:20][C:21]#[CH:22])#[N:17].O.C(=O)(O)[O-].[Na+]>C(Cl)Cl.CCN(CC)CC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[C:16]([CH2:18][CH2:19][CH2:20][C:21]#[C:22][C:2]1[CH:3]=[C:4]([O:8][CH2:9][C@@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[CH3:15])[CH:5]=[N:6][CH:7]=1)#[N:17]
Reactant: C#CCCC(C)C#N
Reactant: CN1CCC[C@H]1COc1cncc(Br)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CN1CCC[C@H]1COc1cncc(C#CCCCC#N)c1
Temperature: 25 °C
Yield: 79.3 %

Procedure:
To a solution of 5-bromo-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)-pyridine (816 mg, 3.00 mmol), bis(triphenylphosphine)palladium(II) chloride (42 mg, 0.06 mmol) and copper (I) iodide (10 mg, 0.06 mmol) in CH2Cl2 (6.0 mL) and NEt3 (2.0 mL) was added 5-cyanohexyne (0.481 mL, 4.5 mmol). The mixture was refluxed overnight then cooled to room temperature. Water (4 mL) was added, and solid sodium bicarbonate was added until the aqueous layer was saturated. The mixture was extracted with EtOAc, which was dried over MgSO4, filtered and concentrated. The residue was chromatographed on a silica gel column, eluting with NH4OH/MeOH/EtOAc 0:1:9 and 1:10:90 to afford a light yellowish oil (674 mg, 79%). MS (CI/NH3) m/z 284 (M+H)+. 1H NMR (CDCl3, 300 MHz) δ 1.66-2.10 (m, 6H), 2.26-2.87 (m, 1H), 2.48 (s, 3H), 2.54-2.71 (m, 6H), 3.08-3.16 (m, 1H), 3.89-4.03 (m, 2H), 7.20 (dd, J=3.0 Hz, J=2.1 Hz, 1H), 8.23 (d, J=2.1 Hz, 1H), 8.24 (d, J=3.0 Hz, 1H).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5]([N:15]([CH:22]1[CH2:27][CH2:26][N:25]([C:28](=O)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:24][CH2:23]1)C1C=CC=CC=1)(=[O:14])[CH:6]=[CH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[OH-:36].[Na+]>ClC1C=CC=CC=1>[C:28]([N:25]1[CH2:24][CH2:23][CH:22]([N:15]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH:7]=[CH:6][C:5]2=[O:14])[CH2:27][CH2:26]1)(=[O:36])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=C(c1ccccc1)N1CCC(N(C(=O)C=Cc2ccccc2)c2ccccc2)CC1
Reactant: [OH-]
Agent: [Al+3]
Agent: [Cl-]
Agent: [Na+]
Solvent: Clc1ccccc1
Product: O=C(c1ccccc1)N1CCC(n2c(=O)ccc3ccccc32)CC1
Temperature: 0 °C

Procedure:
To crushed aluminum chloride (26 g) are added chlorobenzene (26 ml) and N-cinnamoyl-N-(1-benzoyl-4-piperidinyl)aniline (8.7 g) and the mixture is reacted at 110° C. for 1 hour. After cooling, the reaction mixture is poured into ice-water and the mixture is basified with aqueous sodium hydroxide solution. The mixture is extracted with dichloromethane and the solvent is concentrated. The residue is purified by silica gel column chromatography (solvent: methylene chloride) to give 1-(1-benzoyl-4-piperidinyl)carbostyril (5.9 g).
Reaction SMILES: S(=O)(=O)(O)O.[Br:6][C:7]1[C:16]2[C:11](=[CH:12][C:13]([C:17]([OH:19])=[O:18])=[CH:14][CH:15]=2)[C:10](=[O:20])[NH:9][N:8]=1.[CH3:21][CH2:22]O>>[CH2:21]([O:18][C:17]([C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[C:7]([Br:6])=[N:8][NH:9][C:10]2=[O:20])=[O:19])[CH3:22]
Reactant: CCO
Reactant: O=C(O)c1ccc2c(Br)n[nH]c(=O)c2c1
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1ccc2c(Br)n[nH]c(=O)c2c1
Yield: 31 %

Procedure:
Concentrated sulfuric acid (40 ml) was added to a stirred solution of 1-Bromo-4-oxo-3,4-dihydro-phthalazine-6-carboxylic acid (85 g, 0.32 mol) in EtOH (500 ml) and the mixture was heated to reflux for 48 hours. After this time, the reaction mixture was cooled and the resulting precipitate was filtered. The precipitate was partitioned between EtOAc (1 L) and saturated NaHCO3 (500 ml), the organic layer was separated and washed with water (500 ml) before being dried (MgSO4), filtered and concentrated under vacuum to give the title compound (30 g, 31% yield) as a white solid. MS (ESI+)=(M+H)+ 297 & 299