Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([Si:5]([CH3:25])([CH3:24])[O:6][C:7]1[CH:8]=[C:9]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15]1[C:14]3[CH:20]=[CH:21][CH:22]=[CH:23][C:13]=3[S:12][CH2:11][C:10]2=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[C:28](Cl)(=[O:30])[CH3:29]>CN(C=O)C>[C:1]([Si:5]([CH3:25])([CH3:24])[O:6][C:7]1[CH:8]=[C:9]2[C:17](=[CH:18][CH:19]=1)[N:16]([C:28](=[O:30])[CH3:29])[C:15]1[C:14]3[CH:20]=[CH:21][CH:22]=[CH:23][C:13]=3[S:12][CH2:11][C:10]2=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc2[nH]c3c(c2c1)CSc1ccccc1-3
Reactant: CC(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)n1c2c(c3cc(O[Si](C)(C)C(C)(C)C)ccc31)CSc1ccccc1-2
Temperature: 25 °C

Procedure:
8-(tert-Butyl-dimethyl-silanyloxy)-6,11-dihydro-5-thia-11-aza-benzo[a]fluorene (170 mg, 0.462 mmoL) in DMF (2 mL) was treated with NaH (60%, 37 mg, 0.925 mmoL) at 0° C. Acetyl chloride (52 mg, 0.693 mmoL) was added dropwise into the reaction 30 minutes later. The reaction mixture was than slowly warmed to room temperature over 2 hours. The reaction was quenched with saturated NH4Cl. The residue was partitioned between CH2Cl2 and saturated NaHCO3. The aqueous phase was extracted two times with CH2Cl2. The organic layer from each extraction was combined, washed with water, brine, dried over anhydrous Na2SO4, filtered and concentrated to yield a brown oil. The oil was then purified by column chromatography (silica gel, hexanes:EtOAc 5:1 as eluent) to yield the title compound as a pale solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7](Cl)=[O:8].[CH3:12][N:13]([CH3:40])[CH2:14][CH2:15][CH2:16][NH:17][C:18]1[N:23]=[CH:22][C:21]([C:24]([N:26]2[C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=3[CH2:30][N:29]3[CH:37]=[CH:38][CH:39]=[C:28]3[CH2:27]2)=[O:25])=[CH:20][CH:19]=1.C(N(C(C)C)CC)(C)C>ClCCl>[CH3:40][N:13]([CH3:12])[CH2:14][CH2:15][CH2:16][N:17]([C:18]1[CH:19]=[CH:20][C:21]([C:24]([N:26]2[C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=3[CH2:30][N:29]3[CH:37]=[CH:38][CH:39]=[C:28]3[CH2:27]2)=[O:25])=[CH:22][N:23]=1)[C:7](=[O:8])[C:6]1[CH:10]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=1[CH3:11]
Reactant: CN(C)CCCNc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cn1
Reactant: Cc1ccc(F)cc1C(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(F)cc1C(=O)N(CCCN(C)C)c1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 71.3 %

Procedure:
A solution of 6.35 g of 5-fluoro-2-methylbenzoyl chloride in 10 ml of dichloromethane is added to a solution of 2 mmol of 10-[[6-[3-(dimethylamino)-propylamino]-3-pyridinyl]carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine and 5 ml of diisopropylethylamine in 75 ml of dichloromethane. The solution is stirred 16 hours at room temperature, washed with water, dried (MgSO4) and the solvent removed. The residue is purified by column chromatography over silica gel with 30% methanol in chloroform as eluent to give 0.75 g of solid; mass spectrum (CI) 525 (M+1).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[C:10]([NH:14][C:15]3[CH:20]=[CH:19][N:18]4[N:21]=[CH:22][C:23]([CH:24]=O)=[C:17]4[N:16]=3)[CH:11]=[CH:12][CH:13]=2)[CH2:4][CH2:3]1.[NH:26]1[CH2:32][C:30](=[O:31])[NH:29][C:27]1=[O:28].N1CCCCC1>CCO>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([C:8]2[CH:9]=[C:10]([NH:14][C:15]3[CH:20]=[CH:19][N:18]4[N:21]=[CH:22][C:23]([CH:24]=[C:32]5[NH:26][C:27](=[O:28])[NH:29][C:30]5=[O:31])=[C:17]4[N:16]=3)[CH:11]=[CH:12][CH:13]=2)[CH2:6][CH2:7]1
Reactant: CN1CCN(c2cccc(Nc3ccn4ncc(C=O)c4n3)c2)CC1
Reactant: O=C1CNC(=O)N1
Solvent: C1CCNCC1
Solvent: CCO
Product: CN1CCN(c2cccc(Nc3ccn4ncc(C=C5NC(=O)NC5=O)c4n3)c2)CC1
Temperature: 70 °C

Procedure:
To 5-(3-(4-methylpiperazin-1-yl)phenylamino)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde (74 mg, 0.221 mmol) in EtOH was added hydantoin (22 mg, 0.221 mmol) and piperidine (22 μL, 0.221 mmol). The mixture was heated at 70° C. The solid formed was filtered off and the filtrate was prepared by HPLC to yield 5-((5-(3-(4-methylpiperazin-1-yl)phenylamino)pyrazolo[1,5-a]pyrimidin-3-yl)methylene)imidazolidine-2,4-dione. LCMS (M+1=419)
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH2:9][C:10](=[O:16])[NH:11]3)[CH:2]=1.[CH3:17][C:18]1[C:22]([C:23]([N:25]2[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]2)=[O:24])=[C:21]([CH3:32])[NH:20][C:19]=1[CH:33]=O.N1CCCCC1>C(O)C>[CH3:17][C:18]1[C:22]([C:23]([N:25]2[CH2:26][CH2:27][N:28]([CH3:31])[CH2:29][CH2:30]2)=[O:24])=[C:21]([CH3:32])[NH:20][C:19]=1[CH:33]=[C:9]1[C:8]2[C:12](=[CH:13][CH:14]=[CH:15][C:7]=2[C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[NH:11][C:10]1=[O:16]
Reactant: O=C1Cc2c(cccc2-c2cccnc2)N1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)N1CCN(C)CC1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1[nH]c(C=C2C(=O)Nc3cccc(-c4cccnc4)c32)c(C)c1C(=O)N1CCN(C)CC1
Temperature: 70 °C

Procedure:
A mixture of 4-pyridin-3-yl-1,3-dihydroindol-2-one (42 mg, 0.2 mmol), 3,5-dimethyl-4-(4-methylpiperazine-1-carbonyl)-1H-pyrrole-2-carbaldehyde (50 mg, 0.2 mmol) and piperidine (0.1 mL) in ethanol was heated in a sealed tube at 70° C. for 5 hours. The reaction was concentrated and the residue was crystallized from ethyl acetate/hexane to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[C:11](N)[CH:12]=1)[N:9]=[CH:8][CH:7]=[CH:6]2.O.CCOC(C)=O.[BrH:21]>>[Br:21][C:11]1[CH:12]=[C:3]([O:2][CH3:1])[CH:4]=[C:5]2[C:10]=1[N:9]=[CH:8][CH:7]=[CH:6]2
Reactant: COc1cc(N)c2ncccc2c1
Reactant: Br
Solvent: O
Solvent: CCOC(C)=O
Product: COc1cc(Br)c2ncccc2c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 61 %

Procedure:
To 5.05 g (29.0 mmol) 6-methoxy-quinolin-8-yl-amine in 25 mL of 48% HBr at 0° C. is added a solution of 2.60 g (37.7 mmol) and 20 mL H2O. After stirring at 0° C. for 15 min, the resulting mixture is added dropwise to a 75° C. solution of 5.0 g (34.8 mmol) CuBr and 60 mL of 48% HBr. After 5.5 h, the reaction mixture is neutralized with 150 mL of ice cold 5N NaOH, the resulting mixture is stirred with 300 mL EtOAc and filtered through a pad of celite. This mixture is extracted 2×100 mL EtOAc, and the combined organics are washed with 1×200 mL H2O, 1×200 mL brine, dried over Na2SO4, filtered, and the volatiles are evaporated. Flash chromatography on SiO2 gel, eluting with hexanes/EtOAc (4/1 to 1/1), gives 4.23 g (17.8 mmol, a 61% yield) of the title compound as a brown oil. MS (ES) m/z 239 (MH)+.
Reaction SMILES: O1CCOCC1.Cl[C:8]1[CH:13]=[C:12]([CH:14]([S:23][C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)[C:15]2[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=2[F:22])[C:11]([Cl:31])=[CH:10][N:9]=1.[NH2:32][CH2:33][CH2:34][N:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1>C(OCC)(=O)C>[Cl:31][C:11]1[C:12]([CH:14]([S:23][C:24]2[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=2)[C:15]2[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=2[F:22])=[CH:13][C:8]([NH:32][CH2:33][CH2:34][N:35]2[CH2:40][CH2:39][O:38][CH2:37][CH2:36]2)=[N:9][CH:10]=1
Reactant: Fc1ccc(F)c(C(Sc2ccc(Cl)cc2)c2cc(Cl)ncc2Cl)c1
Reactant: NCCN1CCOCC1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Fc1ccc(F)c(C(Sc2ccc(Cl)cc2)c2cc(NCCN3CCOCC3)ncc2Cl)c1
Temperature: 25 °C
Yield: 10 %

Procedure:
A 1,4-dioxane (1.0 ml) solution of the 2,5-dichloro-4-[(4-chlorophenylthio)-(2,5-difluorophenyl)methyl]pyridine (100 mg, 0.24 mmol) obtained in Example 54 and 4-(2-aminoethyl)morpholine (200 μl) was stirred at 100° C. for 2 days under a nitrogen atmosphere. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (40 ml). The diluted mixture was washed with water and brine, dried and concentrated under reduced pressure to give a residue. The resulting residue was purified by silica gel chromatography (3% methanol/chloroform) to give the title compound (12 mg, 10%) as an oil.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([CH2:9][O:10][CH3:11])([CH3:8])[C:5]([OH:7])=O.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:45][N:46]([CH2:64][CH2:65][CH2:66][NH:67][CH3:68])[CH2:47][CH2:48][C:49]1([OH:63])[CH2:54][CH:53]2[CH2:55][CH2:56][CH:50]1[CH:51]=[C:52]2[C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1>C(Cl)Cl>[OH:63][C@@:49]1([CH2:48][CH2:47][N:46]([CH3:45])[CH2:64][CH2:65][CH2:66][N:67]([CH3:68])[C:5](=[O:7])[C:4]([CH2:3][O:2][CH3:1])([CH3:8])[CH2:9][O:10][CH3:11])[CH2:54][C@H:53]2[CH2:55][CH2:56][C@@H:50]1[CH:51]=[C:52]2[C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1
Reactant: COCC(C)(COC)C(=O)O
Reactant: CNCCCN(C)CCC1(O)CC2CCC1C=C2c1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCC(C)(COC)C(=O)N(C)CCCN(C)CC[C@]1(O)C[C@H]2CC[C@@H]1C=C2c1ccccc1
Reaction time: 8 h
Yield: 90.8 %

Procedure:
To a solution of 65 mg 3-methoxy-2-methoxymethyl-2-methyl-propionic acid in 0.5 mL DCM was added 0.14 mL DIPEA followed by 133 mg HATU. The resulting mixture was stirred at rt for 20 min before 88 mg of rac-(1R*,2R*,4R*)-2-{2-[methyl-(3-methylamino-propyl)-amino]-ethyl}-5-phenyl-bicyclo[2.2.2]oct-5-en-2-ol, dissolved in 1 mL DCM was added. After stirring overnight the reaction was quenched with water. The water phase was extracted with DCM, the combined organic phases were washed with brine, dried and concentrated in vacuo. The residue was purified by CC with EtOAc-MeOH (3:1) to obtain 115 mg of rac-N-(3-{[2-((1R*,2R*,4R*)-2-hydroxy-5-phenyl-bicyclo[2.2.2]oct-5-en-2-yl)-ethyl]-methyl-amino}-propyl)-3-methoxy-2-methoxymethyl-2,N-dimethyl-propionamide as colorless oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=3)[CH:9]=2)=[CH:4][CH:3]=1.O1CCCC1.[OH-].[Na+].Cl[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][N:31]=1>CN(C)C=O>[F:36][C:33]1[CH:34]=[CH:35][C:30]([CH2:29][O:20][C:17]2[CH:18]=[CH:19][C:14]([CH2:13][C:10]3[CH:9]=[C:8]([C:5]4[CH:4]=[CH:3][C:2]([NH2:1])=[N:7][CH:6]=4)[O:12][N:11]=3)=[CH:15][CH:16]=2)=[N:31][CH:32]=1
Reactant: Fc1ccc(CCl)nc1
Reactant: Nc1ccc(-c2cc(Cc3ccc(O)cc3)no2)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Nc1ccc(-c2cc(Cc3ccc(OCc4ccc(F)cn4)cc3)no2)cn1
Temperature: 60 °C
Reaction time: 1 h
Yield: 11.4 %

Procedure:
To 4-(5-(6-amino-pyridin-3-yl)-isoxazol-3-ylmethyl)-phenol (20.0 mg, 0.07 mmol) described in Manufacturing Example 177-1-1 were added tetrahydrofuran (3 mL) and a 5 N sodium hydroxide aqueous solution (14.9 μL, 0.07 mmol), which was dissolved by irradiating ultrasonic wave for 1 minute. The reaction solution was concentrated under a reduced pressure, which gave a white solid. To a mixture of the solid obtained above and N,N-dimethylformamide (1 mL) was added an N,N-dimethylformamide (1 mL) solution of the 2-chloromethyl-5-fluoro-pyridine (12.0 mg, 0.08 mmol) described in Manufacturing Example 41-1-2, which was stirred for 1 hour at 60° C. The reaction mixture was cooled to room temperature and then partitioned into water and ethyl acetate. The organic layer was separated, washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=1:1) to obtain the title compound (3.0 mg, 11%).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.[N:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH2:21][NH:22][C:23]([C:25]1[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][N:26]=1)=[O:24]>>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:29]([C:28]2[CH:32]=[CH:33][C:25]([C:23]([NH:22][CH2:21][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][N:15]=3)=[O:24])=[N:26][CH:27]=2)=[O:30])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
Reactant: O=C(O)c1ccc(C(=O)NCc2ccccn2)nc1
Product: O=C(Nc1ccc(Cl)c(-c2ccccn2)c1)c1ccc(C(=O)NCc2ccccn2)nc1

Procedure:
250 mg of 5-(methoxycarbonyl)picolinic acid was coupled to pyridin-2-ylmethanamine via Procedure G. Crude methyl 6-(pyridin-2-ylmethylcarbamoyl)nicotinate was hydrolyzed via Procedure M to yield 250 mg of 6-(pyridin-2-ylmethylcarbamoyl)nicotinic acid. 60 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 6-(pyridin-2-ylmethylcarbamoyl)nicotinic acid via Procedure G. The crude product was purified by reverse phase HPLC to yield N5-(4-chloro-3-(pyridin-2-yl)phenyl)-N2-(pyridin-2-ylmethyl)pyridine-2,5-dicarboxamide. MS (Q1) 444.1 (M)+.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([C:16](=[O:18])[CH3:17])[CH:9]=[CH:10][C:11]=2[O:12][CH:13]([F:15])[F:14])[CH2:3][CH2:2]1.[Br-:19].[Br-].[Br-].C[N+](C)(C)C1C=CC=CC=1.C[N+](C1C=CC=CC=1)(C)C.C[N+](C1C=CC=CC=1)(C)C.C(=O)([O-])O.[Na+]>C(O)(C)C>[Br:19][CH2:17][C:16]([C:8]1[CH:9]=[CH:10][C:11]([O:12][CH:13]([F:15])[F:14])=[C:6]([O:5][CH2:4][CH:1]2[CH2:3][CH2:2]2)[CH:7]=1)=[O:18]
Reactant: CC(=O)c1ccc(OC(F)F)c(OCC2CC2)c1
Reactant: [Br-]
Agent: C[N+](C)(C)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: O=C(CBr)c1ccc(OC(F)F)c(OCC2CC2)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 116.4 %

Procedure:
To 250 ml of isopropanol solution containing 10.8 g (42.3 mmol) of 1-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)ethanone (see WO 9206963) was added 36.5 g (97.1 mmol) of trimethylphenylammonium tribromide at room temperature, and the mixture was stirred at room temperature for 5 hours. After completion of the reaction, a saturated aqueous solution of sodium hydrogencarbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer after separation was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and then, concentrated under reduced pressure to obtain 16.5 g of the title compound as a pale yellowish solid substantially quantitatively.
Reaction SMILES: [H-].[Na+].[CH:3]1([C:6]2[CH:7]=[C:8]([CH:18]=[C:19]([O:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][N:23]=3)[CH:20]=2)[CH2:9]P(=O)(OCC)OCC)[CH2:5][CH2:4]1.[C:32]([N:39]1[CH2:44][CH2:43][CH2:42][CH2:41][C:40]1=O)([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33]>C1COCC1>[CH:3]1([C:6]2[CH:7]=[C:8]([CH:18]=[C:19]([O:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:29])[F:30])=[CH:24][N:23]=3)[CH:20]=2)[CH:9]=[C:42]2[CH2:43][CH2:44][N:39]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:40][CH2:41]2)[CH2:4][CH2:5]1
Reactant: CCOP(=O)(Cc1cc(Oc2ccc(C(F)(F)F)cn2)cc(C2CC2)c1)OCC
Reactant: CC(C)(C)OC(=O)N1CCCCC1=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(=Cc2cc(Oc3ccc(C(F)(F)F)cn3)cc(C3CC3)c2)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 46.2 %

Procedure:
To a suspension of sodium hydride (0.11 g, 4.65 mmol) in dry THF (1.5 mL) under an inert atmosphere cooled to 0° C. was added diethyl 3-cyclopropyl-5-(5-(trifluoromethyl)pyridin-2-yloxy)benzylphosphonate (0.8 g, 1.86 mmol) as a solution in THF (6 mL). The mixture was stirred for 30 min at 0° C. N-Boc piperidone (0.37 g, 1.86 mmol) was added as a solution in THF (3 mL) and the mixture was stirred at RT for 5 h. The reaction was cooled to 0° C. and quenched with saturated aqueous ammonium chloride. The mixture was extracted with ethyl acetate three times. The organic layer was washed with brine, dried over Na2SO4 and evaporated to dryness. The residue was purified by silica gel column chromatography (10% ethyl acetate in hexane) to give the title compound (0.408 g, 46%). 1H NMR (500 MHz, CDCl3): δ 8.45 (s, 1H), 7.87 (d, J=8 Hz, 1H), 6.97 (d, J=8.5 Hz, 1H), 6.79 (s, 1H), 6.74 (s, 1H), 6.68 (s, 1H), 6.30 (s, 1H), 3.49 (m, 2H), 3.39 (m, 2H), 2.45 (m, 2H), 2.31 (m, 2H), 1.88 (m, 1H), 1.46 (s, 9H), 0.96 (d, J=8.5 Hz, 2H), 0.69 (d, J=4.5 Hz, 2H); m/z (475.1, M+ H+).
Reaction SMILES: F[C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[NH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.C(=O)([O-])[O-].[K+].[K+].CS(C)=O>O>[N:16]1([C:2]2[CH:15]=[CH:14][C:5]([C:6]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)=[O:7])=[CH:4][CH:3]=2)[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1
Reactant: C1CNCCN1
Reactant: O=C(c1ccccc1)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: O=C(c1ccccc1)c1ccc(N2CCNCC2)cc1
Temperature: 100 °C
Yield: 99.5 %

Procedure:
To a 500 mL one-neck flask was added 4-fluorobenzophenone (35 g), piperazine (13 g), potassium carbonate (22 g) and dimethyl sulfoxide (100 mL). The reaction mixture was heated to 100° C. for 20 hours. The mixture was cooled to room temperature and poured into water (400 mL). The mixture was extracted with chloroform (200 mL) and the recovered bottom layer was dried over sodium sulfate. The solvent was removed and the product was dried in vacuum oven at 60° C. for 6 hours to afford 40 g of waxy 4-piperazinobenzophenone. The product was used as is in next step without further purification.
Reaction SMILES: O1CCCC1.[NH:6]1[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1.[Cl:12]([O-:16])(=[O:15])(=[O:14])=[O:13].CS[C:19]1[S:23][CH:22]=[CH:21][S+:20]=1>C(O)C>[Cl:12]([O-:16])(=[O:15])(=[O:14])=[O:13].[S:20]1[CH:21]=[CH:22][S:23][C:19]1=[N+:6]1[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1
Reactant: C1COCCN1
Reactant: CSc1scc[s+]1
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: C1CCOC1
Solvent: CCO
Product: c1csc(=[N+]2CCOCC2)s1
Temperature: 25 °C

Procedure:
To 20 ml of tetrahydrofuran, 1.0 ml of morpholine was dissolved, and 2.5 g of 2-methylthio-1,3-dithiolium perchlorate was gradually added thereto under stirring at room temperature. The mixture was stirred at room temperature for 1 hour, and then the precipitated crystals were collected by filtration and recrystallized from ethanol, whereby 2.4 g (yield: 83.3%) of 4-(1,3-dithiol-2-ylidene)morpholinium perchlorate (Compound No. 26) was obtained as crystals having a melting point of from 177° to 178° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:16])[CH2:13][CH2:14][CH3:15])=[C:5]2[NH:17][C@H:18]1[CH2:23][CH2:22][C@H:21]([CH2:24][N:25]([CH3:27])[CH3:26])[CH2:20][CH2:19]1.[Cl:28][C:29]1[CH:34]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH:32]=[C:31]([Cl:44])[C:30]=1[OH:45]>>[Cl:28][C:29]1[CH:34]=[C:33]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12](=[O:16])[CH2:13][CH2:14][CH3:15])=[C:5]3[NH:17][C@H:18]2[CH2:19][CH2:20][C@H:21]([CH2:24][N:25]([CH3:27])[CH3:26])[CH2:22][CH2:23]2)[CH:32]=[C:31]([Cl:44])[C:30]=1[OH:45]
Reactant: CCCC(=O)c1cnc2ccc(Br)cc2c1N[C@H]1CC[C@H](CN(C)C)CC1
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Product: CCCC(=O)c1cnc2ccc(-c3cc(Cl)c(O)c(Cl)c3)cc2c1N[C@H]1CC[C@H](CN(C)C)CC1

Procedure:
Following general procedure A-1, 1-{6-bromo-4-[trans-4-((dimethylamino)methyl)cyclohexylamino]quinolin-3-yl}butan-1-one (48 mg, 0.110 mmol) was reacted with 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (47 mg, 0.165 mmol) to afford the desired product (20 mg, 35%) as a yellow solid: 1H NMR (500 MHz, CD3OD+TFA-d) δ 9.14 (s, 1H), 8.47 (s, 1H), 8.27 (dd, J=8.7, 1.8 Hz, 1H), 8.98 (d, J=8.7 Hz, 1H), 7.72 (s, 2H), 4.53 (s, 1H), 3.16-3.06 (m, 4H), 2.94 (s, 6H), 2.50-2.43 (m, 2H), 2.08-2.02 (m, 3H), 1.88-1.74 (m, 4H), 1.39-1.32 (m, 1H), 1.06 (t, J=7.4 Hz, 3H); ESI MS m/z 514 [C28H33Cl2N3O2+H]+; HPLC 98.7% (AUC), tR=11.27 min.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][N:37]([CH2:40][C:41]([OH:43])=O)[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:47]([NH2:53])[C:48]1[O:52][CH:51]=[CH:50][CH:49]=1>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:35][CH2:36][N:37]([CH2:40][C:41]([NH:53][CH2:47][C:48]4[O:52][CH:51]=[CH:50][CH:49]=4)=[O:43])[CH2:38][CH2:39]3)=[O:33])[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: NCc1ccco1
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)O)CC1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)NCc2ccco2)CC1

Procedure:
In a manner analogous to the method described in example 99, {4-[(4S,5R)-2-(6-tert-Butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-acetic acid was coupled with furfurylamine (Acros Organics) to give the title compound. HR-MS (ES, m/z) calculated for C40H47Cl2N6O4 [(M+H)+] 745.3031, observed 745.3028.
Reaction SMILES: [N+]([C:4]1[C:17]2[C:16](=[O:18])[C:15]3[C:10](=[CH:11][C:12]([N+:19]([O-:21])=[O:20])=[CH:13][CH:14]=3)[C:9](=[O:22])[C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-])=O.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([NH2:31])=[CH:27][CH:26]=1>[N+](C1C=CC=CC=1)([O-])=O>[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([NH:31][C:4]2[C:17]3[C:16](=[O:18])[C:15]4[C:10](=[CH:11][C:12]([N+:19]([O-:21])=[O:20])=[CH:13][CH:14]=4)[C:9](=[O:22])[C:8]=3[CH:7]=[CH:6][CH:5]=2)=[CH:27][CH:26]=1
Reactant: COc1ccc(N)cc1
Reactant: O=C1c2cc([N+](=O)[O-])ccc2C(=O)c2c1cccc2[N+](=O)[O-]
Solvent: O=[N+]([O-])c1ccccc1
Product: COc1ccc(Nc2cccc3c2C(=O)c2ccc([N+](=O)[O-])cc2C3=O)cc1
Yield: 99.6 %

Procedure:
100 g of 1,6-dinitro-anthraquinone and 84 g of p-anisidine are stirred in 300 ml of nitrobenzene at 150° C until no further starting material is detectable in a sample. The mixture is now distilled to dryness in a Venuleth apparatus under a vacuum of 5 mm and the finely ground residue is thoroughly stirred with dilute sulphuric acid, filtered off, washed until neutral and dried. 125 g of 1-p-anisidino-6-nitro-anthraquinone are obtained.
Reaction SMILES: [CH3:1][N:2]([CH3:22])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]=[C:11]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]>C(O)C.[Pd]>[CH3:1][N:2]([CH3:22])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCC(=CCCCCCCCN(C)C)CCCCC
Agent: [Pd]
Solvent: CCO
Product: CCCCCC(CCCCC)CCCCCCCCN(C)C
Yield: 75.5 %

Procedure:
1-Dimethylamino-9-pentyl-8-tetradecene (Example 26c) (7.5 g) was hydrogenated in ethanol (75 ml) at 45 psi in the presence of 10% Pd/C (0.7 g) at room temperature for 5 hours. The reaction mixture was filtered and evaporated to dryness. The resulting oil was purified by distillation at 0 01 torr (in a Kugelrohr apparatus at 210°) to give 1-dimethylamino-9-pentyltetradecane as a colourless oil (5.7 g, 76%).
Reaction SMILES: [C:1]([NH2:8])(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH2:9]([N:11]([CH2:20][CH3:21])[C:12]1[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=1)[CH3:10]>>[CH2:9]([N:11]([CH2:20][CH3:21])[C:12]1[CH:19]=[CH:18][C:15]([CH:16]([NH:8][C:1](=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[NH:8][C:1](=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])=[CH:14][CH:13]=1)[CH3:10]
Reactant: CCN(CC)c1ccc(C=O)cc1
Reactant: CCCCCC(N)=O
Product: CCCCCC(=O)NC(NC(=O)CCCCC)c1ccc(N(CC)CC)cc1
Yield: 76 %

Procedure:
Compound 53 was prepared from hexanamide and 4-(diethylamino)benzaldehyde using method 1. Yield: 76%. 1H NMR (400 MHz, CD3OD) δ 7.19 (d, J=8.8 Hz, 2H), 6.71 (d, J=8.8 Hz, 2H), 6.58 (t, J=8.4 Hz, 1H), 3.35-3.41 (m, 4H), 2.19-2.26 (m, 4H), 1.61-1.68 (m, 4H), 1.32-1.35 (m, 8H), 1.14 (t, J=6.8 Hz, 6H), 0.94 (t, J=2.8 Hz, 6H). LC-MS (ESI): m/z 390.3 (M+H)+. HRMS (ESI) for C23H40N3O2 (MH+): calcd, 390.3115. found 390.3108.