Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@H:18]([CH2:28][C:29]3[CH:34]=[C:33]([CH3:35])[C:32]([OH:36])=[C:31]([CH3:37])[CH:30]=3)[C:19](=[O:27])[N:20]3[CH2:25][CH2:24][C:23](=O)[CH2:22][CH2:21]3)=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:38]=[CH:39][CH:40]=[CH:41][C:4]=2[NH:3]1.[CH3:42][C:43]1([OH:49])[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1.CC(O)=O.[Na].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C>C(Cl)Cl.CN(C=O)C>[O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@H:18]([CH2:28][C:29]3[CH:34]=[C:33]([CH3:35])[C:32]([OH:36])=[C:31]([CH3:37])[CH:30]=3)[C:19]([N:20]3[CH2:21][CH2:22][CH:23]([N:46]4[CH2:47][CH2:48][C:43]([OH:49])([CH3:42])[CH2:44][CH2:45]4)[CH2:24][CH2:25]3)=[O:27])=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:38]=[CH:39][CH:40]=[CH:41][C:4]=2[NH:3]1
Reactant: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCC(=O)CC2)cc(C)c1O
Reactant: CC1(O)CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCC(N3CCC(C)(O)CC3)CC2)cc(C)c1O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of 50 mg (0.09 mmol) of (R)-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-2-(4-oxo-piperidin-1-yl)-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate (Example 79) in 1.5 mL DCM was combined with 21 mg (0.18 mmol) 4-methyl-piperidin-4-ol and 10.3 μl (0.19 mmol) AcOH, cooled to 0° C. and stirred for 2 h. Then 28 mg (0.19 mmol) sodium-triacetoxyborohydride were added and the mixture was stirred overnight at 0° C. After the solvent had been eliminated the residue was combined with 2 mL DMF and purified by HPLC. The fractions containing the product were combined and lyophilised.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:11]#N)=[N:4][CH:5]=[C:6]([CH3:10])[C:7]=1[O:8][CH3:9].CC1C(CN)=NC=C(C)C=1[O:20]C>>[CH3:1][C:2]1[C:3]([CH2:11][OH:20])=[N:4][CH:5]=[C:6]([CH3:10])[C:7]=1[O:8][CH3:9]
Reactant: COc1c(C)cnc(C#N)c1C
Reactant: COc1c(C)cnc(CN)c1C
Product: COc1c(C)cnc(CO)c1C

Procedure:
A process for the preparation of compounds of formula I ##STR1## in which X is the radical OH or Cl, by the catalytic hydrogenation of 3,5-dimethyl-4-methoxy-2-cyanopyridine, subsequent reaction of the resulting 3,5-dimethyl-4-methoxy-2-aminomethylpyridine to give 3,5-dimethyl-4-methoxy-2-hydroxymethylpyridine and, if desired, chlorination to give 3,5-dimethyl-4-methoxy-2-chloromethylpyridine, and the novel intermediate 3,5-dimethyl-4-methoxy-2-aminomethylpyridine.
Reaction SMILES: [CH3:1][C@@:2]1([C:18]([F:21])([F:20])[F:19])[CH2:17][N:5]2[C:6](=[O:16])[CH:7]=[C:8]([N:10]3[CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)[N:9]=[C:4]2[NH:3]1.Br[CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[Cl:31].C(=O)([O-])[O-].[Cs+].[Cs+]>>[Cl:31][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[CH2:24][CH2:23][N:3]1[C:4]2=[N:9][C:8]([N:10]3[CH2:11][CH2:12][O:13][CH2:14][CH2:15]3)=[CH:7][C:6](=[O:16])[N:5]2[CH2:17][C@@:2]1([CH3:1])[C:18]([F:21])([F:19])[F:20]
Reactant: C[C@@]1(C(F)(F)F)Cn2c(nc(N3CCOCC3)cc2=O)N1
Reactant: Clc1ccccc1CCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: C[C@@]1(C(F)(F)F)Cn2c(nc(N3CCOCC3)cc2=O)N1CCc1ccccc1Cl

Procedure:
The product is prepared according to the procedure described in stage k of Example 1, using 100 mg of (2S)-2-methyl-7-(morpholin-4-yl)-2-(trifluoromethyl)-2,3-dihydroimidazo[1,2-a]pyrimidin-5(1H)-one (Example 1j) and 87 mg of 1-(2-bromoethyl)-2-chlorobenzene, replacing the sodium hydride with 214 mg of caesium carbonate. After purification by preparative HPLC/MS (method C), 40 mg of (2S)-1-[2-(2-chlorophenyl)ethyl]-2-methyl-7-(morpholin-4-yl)-2-(trifluoromethyl)-2,3-dihydroimidazo[1,2-a]pyrimidin-5(1H)one are obtained in the form of an off-white solid, the characteristics of which are the following:
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH:12]=O)=[CH:4][CH:3]=1.[C:14]([C:16]([C:25]#[N:26])=[C:17]1[CH:22]=[C:21]([CH3:23])[O:20][C:19]([CH3:24])=[CH:18]1)#[N:15].N1CCCCC1>C(O)C>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](/[CH:12]=[CH:23]/[C:21]2[O:20][C:19]([CH3:24])=[CH:18][C:17](=[C:16]([C:25]#[N:26])[C:14]#[N:15])[CH:22]=2)=[CH:4][CH:3]=1
Reactant: CC1=CC(=C(C#N)C#N)C=C(C)O1
Reactant: O=Cc1ccc(O)c2ccccc12
Solvent: C1CCNCC1
Solvent: CCO
Product: CC1=CC(=C(C#N)C#N)C=C(/C=C/c2ccc(O)c3ccccc23)O1
Yield: 48.2 %

Procedure:
4-hydroxy-1-naphtaldehyde (0.70 g (5.81 mmol)), 4-(dicyanomethylene)-2,6-dimethyl-4H-pyrane (1.0 g (5.81 mmol)), piperidine (0.50 g (5.81 mmol)), and ethanol (50 mL) were added to a 50-mL three-neck flask. The resultant was heated and refluxed under an argon atmosphere for 6 hours and then the solvent was removed under reduced pressure, followed by purification by column chromatography (SiO2, CHCl3:MeOH=10:1 (v/v)). Thus a desired compound was obtained (yield: 48.2%).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][N:11]1[C:17](=[O:18])[C@@H:16]([NH:19][C:20](=[O:27])[C@@:21]([F:26])([CH3:25])[C:22]([OH:24])=O)[C:15]2[CH:28]=[CH:29][CH:30]=[CH:31][C:14]=2[C:13]2[CH:32]=[CH:33][CH:34]=[CH:35][C:12]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:36][C:37]([F:44])([C:40]([F:43])([F:42])[F:41])[CH2:38][NH2:39]>>[CH2:1]([O:8][CH2:9][CH2:10][N:11]1[C:17](=[O:18])[C@@H:16]([NH:19][C:20](=[O:27])[C@@:21]([F:26])([CH3:25])[C:22]([NH:39][CH2:38][C:37]([F:44])([F:36])[C:40]([F:43])([F:42])[F:41])=[O:24])[C:15]2[CH:28]=[CH:29][CH:30]=[CH:31][C:14]=2[C:13]2[CH:32]=[CH:33][CH:34]=[CH:35][C:12]1=2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCC(F)(F)C(F)(F)F
Reactant: C[C@@](F)(C(=O)O)C(=O)N[C@@H]1C(=O)N(CCOCc2ccccc2)c2ccccc2-c2ccccc21
Product: C[C@@](F)(C(=O)NCC(F)(F)C(F)(F)F)C(=O)N[C@@H]1C(=O)N(CCOCc2ccccc2)c2ccccc2-c2ccccc21

Procedure:
Using (S)—N—[(S)-5-(2-benzyloxy-ethyl)-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl]-2-fluoro-2-methyl-malonamic acid and 2,2,3,3,3-pentafluoropropylamine, the title compound was prepared in the same manner as described for example 1c. White solid (74%). MS: m/e=608(M+H+).
Reaction SMILES: C(OC([NH:8][C@@:9]1([C:33]([O:35]C(C)(C)C)=[O:34])[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=2)[C@@H:13]([OH:25])[C@@H:12]2[C@H:10]1[C@H:11]2[C:26]([O:28]C(C)(C)C)=[O:27])=O)(C)(C)C.O>C(O)(=O)C>[NH2:8][C@@:9]1([C:33]([OH:35])=[O:34])[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=2)[C@@H:13]([OH:25])[C@@H:12]2[C@H:10]1[C@H:11]2[C:26]([OH:28])=[O:27]
Reactant: CC(C)(C)OC(=O)N[C@]1(C(=O)OC(C)(C)C)[C@@H]2[C@@H](C(=O)OC(C)(C)C)[C@@H]2[C@H](O)[C@H]1OCc1ccc(Cl)c(Cl)c1
Solvent: CC(=O)O
Solvent: O
Product: N[C@]1(C(=O)O)[C@@H]2[C@@H](C(=O)O)[C@@H]2[C@H](O)[C@H]1OCc1ccc(Cl)c(Cl)c1
Yield: 97.3 %

Procedure:
Di-tert-butyl (1S,2R,3S,4S,5R,6R)-2-[(tert-butoxycarbonyl)amino]-3-[(3,4-dichlorobenzyl)oxy]-4-hydroxybicyclo[3.1.0]hexane-2,6-dicarboxylate (5.30 g, 9.01 mmol) is added to water (30.02 mL) and acetic acid (30.02 mL). Heat the reaction at reflux until the complete consumption of the starting material. Cool and concentrate on a rotary evaporator. Triturate the concentrate with diethyl ether, collect the precipitate, then dry in a vacuum oven to give the title compound (3.30 g, 8.77 mmol, 97%). MS (m/z): 376/378 (M+1).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[CH:5]=[C:4]([NH:16][C:17]2[CH:21]=[C:20]([CH3:22])[NH:19][N:18]=2)[N:3]=1.[C:23](B1OC(C)(C)C(C)(C)O1)([CH3:25])=[CH2:24]>>[CH:23]([C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[CH:5]=[C:4]([NH:16][C:17]2[CH:21]=[C:20]([CH3:22])[NH:19][N:18]=2)[N:3]=1)([CH3:25])[CH3:24]
Reactant: C=C(C)B1OC(C)(C)C(C)(C)O1
Reactant: COc1cc2cc(Nc3cc(C)[nH]n3)nc(Cl)c2cc1OC
Product: COc1cc2cc(Nc3cc(C)[nH]n3)nc(C(C)C)c2cc1OC

Procedure:
Similar procedure as described in example 330 was used, starting from (1-Chloro-6,7-dimethoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and isopropenylboronic acid pinacol ester to give (1-Isopropyl-6,7-dimethoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 327(MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][CH:26]=1)[C:5]([NH:7][C:8]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=1[N:15]1[CH2:20][CH2:19][CH:18]([CH2:21][CH2:22]O)[CH2:17][CH2:16]1)=[O:6].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:47]>C(Cl)Cl>[Br:47][CH2:22][CH2:21][CH:18]1[CH2:19][CH2:20][N:15]([C:9]2[CH:10]=[CH:11][C:12]([Cl:14])=[CH:13][C:8]=2[NH:7][C:5](=[O:6])[C:4]2[CH:24]=[CH:25][CH:26]=[C:2]([Cl:1])[CH:3]=2)[CH2:16][CH2:17]1
Reactant: O=C(Nc1cc(Cl)ccc1N1CCC(CCO)CC1)c1cccc(Cl)c1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=C(Nc1cc(Cl)ccc1N1CCC(CCBr)CC1)c1cccc(Cl)c1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 43.2 %

Procedure:
A mixture of 0.800 g (2.03 mmol) of 3-chloro-N-{5-chloro-2-[4-(2-hydroxy-ethyl)-piperidin-1-yl]-phenyl}-benzamide and 0.533 g (2.03 mmol) of triphenylphosphine in methylene chloride (20 mL), cooled to 0° C., is stirred for 20 minutes. To this is added 0.674 g (2.03 mmol) of carbon tetrabromide and the mixture is warmed to room temperature and stirred overnight. The mixture is concentrated under reduced pressure and the residue is purified by flash silica gel chromatography to provide 0.400 g (70.0%) of N-{2-[4-(2-bromo-ethyl)-piperidin-1-yl]-5-chloro-phenyl}-3-chloro-benzamide as a light red oil.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]2.[CH3:18][C:19]1[CH:24]=[CH:23][C:22]([SH:25])=[CH:21][CH:20]=1>>[CH3:18][C:19]1[CH:24]=[CH:23][C:22]([S:25][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]3)=[CH:21][CH:20]=1
Reactant: O=C1CCc2cc(OCCCCCl)ccc2N1
Reactant: Cc1ccc(S)cc1
Product: Cc1ccc(SCCCCOc2ccc3c(c2)CCC(=O)N3)cc1

Procedure:
Prepared analogous to Example 1 from 6-(4-chlorobutoxy)-3,4-dihydro-carbostyril (m.p. 147°-148° C.) and 4-methyl-thiophenol.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=[O:18])[C:5]2[CH:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[S:8][C:6]=2[N:7]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)[C:30]2C=CC=C[C:29]=2N=N1.C1CCN2C(=NCCC2)CC1.[O-]CC.[Na+]>CCO>[CH2:29]([O:18][C:4]1[C:5]2[CH:10]=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=3)[S:8][C:6]=2[N:7]=[C:2]([NH2:1])[N:3]=1)[CH3:30]
Reactant: Nc1nc2sc(-c3ccc(F)cc3)cc2c(=O)[nH]1
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: CC[O-]
Agent: F[P-](F)(F)(F)(F)F
Agent: [Na+]
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCO
Product: CCOc1nc(N)nc2sc(-c3ccc(F)cc3)cc12
Temperature: 60 °C
Yield: 54.6 %

Procedure:
To a solution of 2-amino-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4(3H)-one (50 mg, 0.19 mmol) and BOP (110 mg, 0.25 mmol) in EtOH (1 ml) was added DBU (43 μl, 0.29 mmol). The resulting mixture was heated at 60° C. for 4 hours. After cooling down to room temperature, sodium ethoxide (26 mg, 0.38 mmol) was added. The mixture was again heated at 60° C. overnight. The solvents were removed under reduced pressure and the crude residue was purified by flash chromatography on silica gel (CH2Cl2/MeOH 60:1) yielding the title compound as a white solid (30 mg, 54%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:25]#[N:26])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:10](=[O:24])[CH:9]=2)[CH:7]=1.FC(F)(F)S(O[CH2:33][CH:34]1[CH2:39][CH2:38][S:37](=[O:41])(=[O:40])[CH2:36][CH2:35]1)(=O)=O>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:25]#[N:26])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:33][CH:34]3[CH2:39][CH2:38][S:37](=[O:41])(=[O:40])[CH2:36][CH2:35]3)[C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[C:10](=[O:24])[CH:9]=2)[CH:7]=1
Reactant: COc1cn(CC(=O)OC(C)(C)C)c(=O)cc1-c1cc(Cl)ccc1C#N
Reactant: O=S1(=O)CCC(COS(=O)(=O)C(F)(F)F)CC1
Solvent: C1CCOC1
Product: COc1cn(C(CC2CCS(=O)(=O)CC2)C(=O)OC(C)(C)C)c(=O)cc1-c1cc(Cl)ccc1C#N

Procedure:
421 mg (1.13 mmol) of tert-butyl [4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]acetate, 500 mg (1.69 mmol) of (1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methyl trifluoromethanesulphonate and 1.46 ml (1.46 mmol) of bis(trimethylsilyl)lithium amide (1M in THF) in 15 ml of THF were reacted according to General Method 7B. Aqueous work-up gave the title compound. Yield: 862 mg (purity 91%, quant.)
Reaction SMILES: [OH-].[Na+].[C:3]([C:7]1[N:11]([CH2:12][CH:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:10]2[CH:19]=[CH:20][C:21]([S:23]([N:26]3[CH2:31][CH2:30][CH:29]([C:32]([O:34]C)=[O:33])[CH2:28][CH2:27]3)(=[O:25])=[O:24])=[CH:22][C:9]=2[N:8]=1)([CH3:6])([CH3:5])[CH3:4]>CO.O.O>[C:3]([C:7]1[N:11]([CH2:12][CH:13]2[CH2:14][CH2:15][O:16][CH2:17][CH2:18]2)[C:10]2[CH:19]=[CH:20][C:21]([S:23]([N:26]3[CH2:27][CH2:28][CH:29]([C:32]([OH:34])=[O:33])[CH2:30][CH2:31]3)(=[O:25])=[O:24])=[CH:22][C:9]=2[N:8]=1)([CH3:6])([CH3:4])[CH3:5]
Reactant: COC(=O)C1CCN(S(=O)(=O)c2ccc3c(c2)nc(C(C)(C)C)n3CC2CCOCC2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C)c1nc2cc(S(=O)(=O)N3CCC(C(=O)O)CC3)ccc2n1CC1CCOCC1
Reaction time: 8 h

Procedure:
NaOH (0.75 mL, 2M, 1.5 mmol) was added to a solution of methyl 1-{[2-tert-butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5-yl]sulfonyl}piperidine-4-carboxylate (173 mg, 0.36 mmol) in 10 mL MeOH—H2O (1:1) at ambient temperature. The reaction mixture was stirred overnight and diluted with water (40 mL). The solvent was concentrated to 40 mL. The resulting solution was neutralized with HCl solution and the product was extracted with EtOAc and dried over anhydrous Na2SO4. The solvent was concentrated to provide the title compound as white solid. Yield: 60 mg (95%); MS (ESI) (M+H)+=464.0.
Reaction SMILES: O1CCCC1.B.[CH2:7]([N:14]1[C:23](=O)[C:22]([F:26])([F:25])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]1[C:27]1[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl>C1COCC1>[CH2:7]([N:14]1[CH2:23][C:22]([F:26])([F:25])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]1[C:27]1[CH:28]=[CH:29][C:30]([C:33]([F:36])([F:34])[F:35])=[CH:31][CH:32]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C1N(Cc2ccccc2)C(c2ccc(C(F)(F)F)cc2)c2ccccc2C1(F)F
Agent: B
Agent: Cl
Solvent: C1CCOC1
Product: FC(F)(F)c1ccc(C2c3ccccc3C(F)(F)CN2Cc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirred solution of borane tetrahydrofuran complex (1M in THF, 0.750 mL, 0.750 mmol) in 5 mL of THF, 2-benzyl-4,4-difluoro-1-(4-(trifluoromethyl)-phenyl)-1,2-dihydroisoquinolin-3(4H)-one (0.103 g, 0.246 mmol) in a total of 5 mL THF was added dropwise. The clear solution was refluxed for 5 h. After the reaction mixture was cooled to 0° C., 5 mL of 5 N hydrochloric acid was added. The solution was stirred at 0° C. to RT over 1 h. Then the most organic solvent was evaporated and the pH was adjusted to ˜8 by solid sodium bicarbonate. The aqueous phase was extracted with EtOAc. The combined organic phases were washed with water and saturated aqueous sodium chloride. The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo to afford the title compound as a white solid. 11-1 NMR (300 MHz, CHLOROFORM-d) δ ppm 7.76 (d, J=7.75 Hz, 1H) 7.62 (d, J=8.18 Hz, 2H) 7.46 (d, J=8.04 Hz, 2H) 7.28-7.42 (m, 7H) 6.77 (d, J=7.75 Hz, 1H) 4.80 (d, J=3.65 Hz, 1H) 3.82 (dd, J=13.59, 1.75 Hz, 1H) 3.37-3.54 (m, 2H) 2.87-3.06 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:6][CH:7]=1.C(N(CC)CC)C.[Cl-].ClC1N(C)CC[NH+]1C.[CH3:30][O:31][C:32]1[C:33](=[O:56])[C:34]([CH3:55])=[C:35]([CH2:41][C:42]2[CH:43]=[CH:44][C:45]([O:51][C:52](=[O:54])[CH3:53])=[C:46]([CH:50]=2)[C:47](O)=[O:48])[C:36](=[O:40])[C:37]=1[O:38][CH3:39]>C(Cl)Cl>[O:11]1[CH2:10][CH2:9][N:8]([C:5]2[N:4]=[CH:3][C:2]([NH:1][C:47](=[O:48])[C:46]3[CH:50]=[C:42]([CH2:41][C:35]4[C:36](=[O:40])[C:37]([O:38][CH3:39])=[C:32]([O:31][CH3:30])[C:33](=[O:56])[C:34]=4[CH3:55])[CH:43]=[CH:44][C:45]=3[O:51][C:52](=[O:54])[CH3:53])=[CH:7][CH:6]=2)[CH2:13][CH2:12]1
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)O)c2)=C(C)C1=O
Reactant: Nc1ccc(N2CCOCC2)nc1
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)Nc3ccc(N4CCOCC4)nc3)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 59.5 %

Procedure:
3-Amino-6-morpholinopyridine (0.269 g, 1.500 mmol), triethylamine (0.197 g, 1.950 mmol) and 2-chloro-1,3-dimethylimidazolinium chloride (0.165 g, 0.975 mmol) were added to a methylene chloride solution (100 ml) of 5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoic acid (0.281 g, 0.750 mmol) and the resulting solution was stirred at room temperature for 12 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (chloroform:methanol=10:1) to obtain the titled compound (0.239 g, 0.446 mmol, 59%).
Reaction SMILES: Br[CH:2]([CH2:5][CH2:6]Br)[C:3]#[N:4].[CH:8]([NH2:21])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(=O)(O)[O-].[Na+]>C(#N)C>[CH:8]([N:21]1[CH2:6][CH2:5][CH:2]1[C:3]#[N:4])([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: N#CC(Br)CCBr
Reactant: NC(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: N#CC1CCN1C(c1ccccc1)c1ccccc1

Procedure:
Reflux for 18 hours, a stirred mixture of 10 g of 2,4-dibromobutyronitrile, 7.35 g of benzhydrylamine, and 7.41 g of sodium bicarbonate in 100 ml of acetonitrile. Filter off the solids and remove the acetonitrile in vacuo. Treat the residue with ether and filter out insoluble solids. Wash the ether solution first with water, then with a solution of 5.40 g of oxalic acid in 200 ml of water, and finally with brine (saturated aqueous NaCl solution). Dry the solution over anhydrous magnesium sulfate and remove solvent in vacuo. Crystallize the solid residue from methylene chloride-hexane to obtain the analytically pure title compound, m.p. 103.5°-105.0° C.
Reaction SMILES: [CH3:1][S:2][C:3]1[C:4](=[O:34])[C:5](=[CH:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([O:32][CH3:33])=[O:31])[CH:6]([CH:8]=[CH:9][CH:10]([O:16][Si](C(C)(C)C)(C)C)[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH:7]=1.C(O)(=O)C.O1CCCC1.C(=O)([O-])O.[Na+]>C(OCC)(=O)C.O>[CH3:1][S:2][C:3]1[C:4](=[O:34])[C:5](=[CH:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([O:32][CH3:33])=[O:31])[CH:6]([CH:8]=[CH:9][CH:10]([OH:16])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH:7]=1
Reactant: CCCCCC(C=CC1C=C(SC)C(=O)C1=CCCCCCC(=O)OC)O[Si](C)(C)C(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCCCCC(O)C=CC1C=C(SC)C(=O)C1=CCCCCCC(=O)OC
Temperature: 25 °C
Reaction time: 48 h
Yield: 85 %

Procedure:
An amount of 1.42 g of 2-methylthio-5-(6-methoxycarbonylhexylidene-4-(3-t-butyldimethylsilyloxy-1-octenyl)-2-cyclopentenone obtained in Example 22 was added to a mixture of acetic acid (2.1 ml), tetrahydrofuran (1.4 ml) and water (0.7 ml), and the mixture was stirred at room temperature for 2 days. To the reaction mixture saturated aqueous sodium hydrogencarbonate and ethyl acetate were added, and the product was extracted into the organic layer. The extract was washed with saturated aqueous sodium chloride, then dried over anhydrous magnesium sulfate and filtered, followed by concentration. The concentrate was subjected to silica gel chromatography to give 0.93 g (yield 85%) of 2-methylthio-5-(6-methoxycarbonylhexylidene)-4-(3-hydroxy-1-octenyl)-2-cyclopentenone.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][O:13][C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[C:19]([C:24]3[CH:29]=[CH:28][C:27]([S:30][CH3:31])=[CH:26][CH:25]=3)[CH:20]=2)[N:15]=1>ClCCl>[CH3:12][O:13][C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[C:19]([C:24]3[CH:29]=[CH:28][C:27]([S:30]([CH3:31])=[O:9])=[CH:26][CH:25]=3)[CH:20]=2)[N:15]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1ccc2cc(-c3ccc(SC)cc3)ccc2n1
Solvent: ClCCl
Product: COc1ccc2cc(-c3ccc(S(C)=O)cc3)ccc2n1
Temperature: 25 °C

Procedure:
A solution of m-chloroperbenzoic acid (0.56 g) in dichloromethane (5 cm3) was added dropwise at -70° to a stirred solution of 2-methoxy-6-[4-methylthiophenyl]quinoline (0.7 g) in dichloromethane (10 cm3). The mixture was warmed to room temperature over 1 hour, taken into dichloromethane (25 cm3) and washed with sodium carbonate solution (10 cm3). The organic phase was dried (MgSO4) and evaporated and the residue was chromatographed on silica (Merck "MK 60.9385" [Trade Mark]) eluting with chloroform:methanol, 19:1. The appropriate fractions were combined and evaporated to give a solid which was recrystallised from acetone-hexane to afford the title compound, m.p. 163.5°-165.5°, (0.55 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][C:13]([N:16]4[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]4)=[N:12][N:11]3[C:23]=2I)=[CH:4][CH:3]=1.C(COC)OC.C(=O)(O)[O-].[Na+].[N:36]1[CH:41]=[CH:40][C:39](B(O)O)=[CH:38][CH:37]=1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].ClCCl.O.ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][C:13]([N:16]4[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]4)=[N:12][N:11]3[C:23]=2[C:39]2[CH:40]=[CH:41][N:36]=[CH:37][CH:38]=2)=[CH:4][CH:3]=1
Reactant: CN1CCN(c2ccc3nc(-c4ccc(F)cc4)c(I)n3n2)CC1
Reactant: OB(O)c1ccncc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: O
Solvent: ClCCl
Solvent: COCCOC
Product: CN1CCN(c2ccc3nc(-c4ccc(F)cc4)c(-c4ccncc4)n3n2)CC1
Reaction time: 24 h
Yield: 100.6 %

Procedure:
To a suspension of 2.80 g (6.40 mmol) of 2-(4-fluorophenyl)-3-iodo-6-(4-methylpiperazin-1-yl)imidazo[1,2-b]pyridazine in 200 mL of a mixture of dimethoxyethane and water (9:1), are added 1.36 g (12.8 mmol) of sodium bicarbonate and 0.95 g (7.7 mmol) of (pyrid-4-yl)boronic acid. After sparging with a stream of argon for a few moments, 0.21 g (0.26 mmol) of a complex of [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) and dichloromethane (PdCl2(dppf).CH2Cl2) is added and the reaction mixture is refluxed under argon for 18 hours. A further 0.95 g (7.7 mmol) of (pyrid-4-yl)boronic acid, 0.21 g (0.26 mmol) of [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane and 10 mL of water are then added. Heating is continued for 24 hours. The solvent is then evaporated off under reduced pressure and the brown residue is triturated with aqueous 3N hydrochloric acid and then filtered on a Büchner funnel. The aqueous phase is washed twice with diethyl ether and then cautiously neutralized, using aqueous ammonia diluted with ice, to basic pH. The product is extracted with chloroform, the organic phase is dried over sodium sulfate and filtered, and the solvent is evaporated off to give 2.5 g of a yellowish powder.