Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([N:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH2:22]([OH:24])[CH3:23]>Cl>[CH2:22]([O:24][C:2]1[N:11]=[C:10]([N:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1)[CH3:23]
Reactant: COc1ccc(N(C)c2nc(Cl)nc3ccccc23)cc1
Reactant: CCO
Agent: Cl
Product: CCOc1nc(N(C)c2ccc(OC)cc2)c2ccccc2n1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A mixture of (2-chloroquinazolin-4-yl)-(4-methoxyphenyl)-methylamine 3.98 g (20.0 mmol) in ethanol 4 mL and concd HCl 3 mL was stirred at room temperature for 14 h. After removal of ethanol, the residue was dissolved in ethyl acetate, and the organic solution was washed with water, satd Na2CO3, and dried over anhydrous MgSO4. After removal of solvent under reduced pressure, the crude product was purified by MPLC (SiO2, EtOAc 0˜100% in hexanes) to give the title compound. 1H NMR (CDCl3, 400 MHz) δ 7.91-7.94 (m, 1H), 7.54-7.61 (m, 2H), 7.25-7.29 (m, 2H), 7.12-7.16 (m, 1H), 6.90-6.94 (m, 1H), 4.29 (q, J=7.0 Hz, 2H), 3.84 (s, 3H), 3.60 (s, 3H), 1.34 (t, J=7.0 Hz, 3H); LC-MS (ESI+; 310 ([M+H]+)).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]([NH:10][CH:11]([C:13]2[CH:14]=[N:15][C:16]([O:20][CH2:21][C:22]([F:25])([F:24])[F:23])=[C:17]([Cl:19])[CH:18]=2)[CH3:12])=[O:9])[CH:5]=[CH:4][N:3]=1.[C:26](Cl)(=[O:29])[CH2:27][CH3:28]>>[Cl:19][C:17]1[CH:18]=[C:13]([CH:11]([NH:10][C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:1][C:26](=[O:29])[CH2:27][CH3:28])[N:7]=2)=[O:9])[CH3:12])[CH:14]=[N:15][C:16]=1[O:20][CH2:21][C:22]([F:24])([F:23])[F:25]
Reactant: CCC(=O)Cl
Reactant: CC(NC(=O)c1ccnc(N)n1)c1cnc(OCC(F)(F)F)c(Cl)c1
Product: CCC(=O)Nc1nccc(C(=O)NC(C)c2cnc(OCC(F)(F)F)c(Cl)c2)n1

Procedure:
The title compound is prepared from 2-amino-N-(1-(5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)pyrimidine-4-carb oxamide (20 mg, 0.05 mmol, Step-1, single enantiomer) and propionyl chloride (25 mg, 0.27 mmol) according to the procedure similar to that described in Step-2 of Example 8.
Reaction SMILES: [C:1]([C:5]1[CH:14]=[CH:13][C:8]([CH2:9][NH:10][CH2:11][CH3:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)C(C)C)C.Cl[C:25](=[O:47])[CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([CH2:34][CH2:35][O:36][C:37]2[CH:46]=[CH:45][CH:44]=[CH:43][C:38]=2[C:39]([O:41][CH3:42])=[O:40])=[CH:30][CH:29]=1>C(#N)C>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH2:9][N:10]([CH2:11][CH3:12])[C:25](=[O:47])[CH2:26][O:27][C:28]2[CH:33]=[CH:32][C:31]([CH2:34][CH2:35][O:36][C:37]3[CH:46]=[CH:45][CH:44]=[CH:43][C:38]=3[C:39]([O:41][CH3:42])=[O:40])=[CH:30][CH:29]=2)=[CH:13][CH:14]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CCNCc1ccc(C(C)(C)C)cc1
Reactant: COC(=O)c1ccccc1OCCc1ccc(OCC(=O)Cl)cc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCN(Cc1ccc(C(C)(C)C)cc1)C(=O)COc1ccc(CCOc2ccccc2C(=O)OC)cc1
Reaction time: 0.5 h
Yield: 79.4 %

Procedure:
N-(4-tert-butylbenzyl)-N-ethylamine (0.143 g, 0.746 mmol) was dissolved in dry acetonitrile under N2 and N-ethyl-N,N-diisopropylamine (0.371 g, 2.867 mmol) was added. The mixture was stirred for 30 min and methyl 2-{2-[4-(2-chloro-2-oxoethoxy)phenyl]ethoxy}benzoate (0.200 g, 0.573 mmol) was added. The solution was stirred overnight at room temperature. The crude was purified by flash cromatography (started with isocratic heptane/EtOAc 50/50 and then the EtOAc concentration was increased to 100%, (silica gel 60 0.004-0.063 mm). The product containing fractions were pooled and the EtOAc was removed by evaporation to give 0.229 g of methyl 2-[2-(4-{2-[(4-tert-butylbenzyl)(ethyl)amino]-2-oxoethoxy}phenyl)ethoxy]benzoate (yield 79.3%).
Reaction SMILES: Cl[CH:2]([C:7]1[CH:8]=[C:9]([C:13]2[CH:14]=[N:15][N:16]([CH3:18])[CH:17]=2)[O:10][C:11]=1[CH3:12])[CH2:3][CH:4]([CH3:6])[CH3:5].[NH2:19][C:20]1[CH:29]=[CH:28][C:23]([C:24]([O:26]C)=[O:25])=[CH:22][CH:21]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>CN(C)C(=O)C.O>[CH3:18][N:16]1[CH:17]=[C:13]([C:9]2[O:10][C:11]([CH3:12])=[C:7]([CH:2]([NH:19][C:20]3[CH:29]=[CH:28][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=3)[CH2:3][CH:4]([CH3:6])[CH3:5])[CH:8]=2)[CH:14]=[N:15]1
Reactant: Cc1oc(-c2cnn(C)c2)cc1C(Cl)CC(C)C
Reactant: COC(=O)c1ccc(N)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: Cc1oc(-c2cnn(C)c2)cc1C(CC(C)C)Nc1ccc(C(=O)O)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 36.3 %

Procedure:
A mixture of 4-[4-(1-chloro-3-methylbutyl)-5-methylfuran-2-yl]-1-methyl-1H-pyrazole (1.0 g), methyl 4-aminobenzoate (0.9 g), sodium carbonate (0.6 g) and sodium iodide (1.1 g) in N,N-dimethylacetamide (20 mL) was stirred overnight at 80° C. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in methanol (5 mL) and tetrahydrofuran (5 mL), 2N lithium hydroxide (4 mL) was added, and the mixture was stirred at 80° C. for 4 hr. The reaction mixture was poured into water, and the mixture was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (10% ethyl acetate/hexane to 55% ethyl acetate/hexane) to give the title compound (0.5 g, 39%) as an amorphous compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:19])=[C:6]([C:8]2[CH:17]=[C:16]3[C:11]([CH:12]=[C:13]([NH2:18])[N:14]=[CH:15]3)=[CH:10][CH:9]=2)[CH:7]=1.[F:20][C:21]1([F:27])[CH2:23][CH:22]1[C:24](O)=[O:25].F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2N=CC=CC=2N=N1.CN(C)C=O.C(N(CC)C(C)C)(C)C>CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[F:20][C:21]1([F:27])[CH2:23][CH:22]1[C:24]([NH:18][C:13]1[N:14]=[CH:15][C:16]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[C:8]([C:6]1[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=1[CH3:19])[CH:17]=2)=[O:25]
Reactant: Cc1ccc(F)cc1-c1ccc2cc(N)ncc2c1
Reactant: O=C(O)C1CC1(F)F
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1cnc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(F)cc1-c1ccc2cc(NC(=O)C3CC3(F)F)ncc2c1
Temperature: 50 °C
Reaction time: 2.5 h
Yield: 73 %

Procedure:
To a mixture of 7-(5-fluoro-2-methylphenyl)isoquinolin-3-amine (103.2 mg, 0.4090 mmol), 2,2-difluorocyclopropanecarboxylic acid (79.6 mg, 0.652 mmol) and (7-azabenzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (326.5 mg, 0.6298 mmol) in N,N-dimethylformamide (2 mL, 20 mmol) was added N,N-diisopropylethylamine (0.25 mL, 1.4 mmol) and 4-dimethylaminopyridine (6.7 mg, 0.055 mmol). The reaction mixture was stirred at 50° C. for 2.5 hours. The reaction mixture was then poured into ethyl acetate, which was washed with two portions water, dried with brine and MgSO4, and filtered through a plug of silica gel, which was rinsed with ethyl acetate, and evaporated in vacuo. The resulting residue was purified via reverse phase HPLC and lyophilized to yield 106.4 mg (73%) of 2,2-difluoro-N-(7-(5-fluoro-2-methylphenyl)isoquinolin-3-yl)cyclopropanecarboxamide. LCMS (ESI): RT (Min)=5.701, M+H=357.1, Method=E; 1H NMR (400 MHz, DMSO-d6) δ 11.14 (s, 1H), 9.21 (s, 1H), 8.50 (s, 1H), 8.07 (s, 1H), 7.98 (d, J=8.4 Hz, 1H), 7.74 (d, J=8.4 Hz, 1H), 7.39 (s, 1H), 7.18 (d, J=8.7 Hz, 2H), 3.07 (d, J=10.0 Hz, 1H), 2.25 (s, 3H), 2.07 (s, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:16][O:17][C:18](=[O:27])[C:19]1[CH:24]=[CH:23][C:22]([CH2:25]Br)=[CH:21][CH:20]=1>CN(C=O)C>[CH:6]([C:5]1[CH:8]=[CH:9][C:2]([O:1][CH2:25][C:22]2[CH:23]=[CH:24][C:19]([C:18]([O:17][CH3:16])=[O:27])=[CH:20][CH:21]=2)=[CH:3][CH:4]=1)=[O:7]
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(COc2ccc(C=O)cc2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 96.2 %

Procedure:
To a suspension of 4-hydroxybenzaldehyde (244.2 mg, 2 mmol) and cesium carbonate (445 mg, 1.36 mmol) in anhydrous DMF (8 mL) was added methyl-4-(bromomethyl)benzoate (481 mg, 2.1 mmol). The resulting mixture was stirred for 24 hours at room temperature, after which time the mixture was concentrated under reduced pressure. The resulting crude was partitioned between dichloromethane (30 mL) and water (10 mL). The mixture was filtered through a phase separator, washed with dichloromethane and the solvent was removed in vacuo to yield the title compound as an off-white solid (520 mg, 96%).
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[C:6]([C:7]2[CH:8]=[C:9]([CH:14]=[CH:15][C:16]=2OS(C(F)(F)F)(=O)=O)[C:10]([O:12][CH3:13])=[O:11])=[CH:5][CH2:4][CH2:3]1.[F:26][C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.[Cl-].[Na+].O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:25][C:2]1([CH3:1])[C:6]([C:7]2[CH:8]=[C:9]([C:10]([O:12][CH3:13])=[O:11])[CH:14]=[CH:15][C:16]=2[C:31]2[CH:32]=[C:27]([F:26])[CH:28]=[CH:29][C:30]=2[F:33])=[CH:5][CH2:4][CH2:3]1
Reactant: OB(O)c1cc(F)ccc1F
Reactant: COC(=O)c1ccc(OS(=O)(=O)C(F)(F)F)c(C2=CCCC2(C)C)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(-c2cc(F)ccc2F)c(C2=CCCC2(C)C)c1
Temperature: 90 °C
Reaction time: 23 h
Yield: 93 %

Procedure:
To a stirred solution of methyl 3-(5,5-dimethylcyclopent-1-enyl)-4-(trifluoromethylsulfonyloxy)benzoate 66.6I (0.50 g, 1 mmol) in DMF (7 mL) at 23° C. was added 2,5-difluorophenylboronic acid (0.3 g, 2 mmol, commercially available from Aldrich), and potassium carbonate (0.5 g, 4 mmol). Tetrakis(triphenylphosphine)palladium (0.2 g, 0.1 mmol) was then added to the mixture. The mixture was heated to 90° C. and the reaction was further stirred for 23 hours. The reaction was then cooled to room temperature, diluted with brine and extracted three times with EtOAc. After drying over anhydrous magnesium sulfate and filtering, the organic solvent was removed under reduced pressure and the product was purified on silica gel (0-10% EtOAc in hexanes) to yield 83.25A as a colorless oil (0.42 g, 93% yield).
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:23][CH2:24][C:25]1[N:29]([C:30]2[S:31][C:32]([CH2:44][CH3:45])=[CH:33][C:34]=2[C:35](=[O:43])[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2[Cl:42])[CH:28]=[N:27][N:26]=1.[C:46]1([N:52]=[C:53]=[O:54])[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>CN(C)C=O>[Cl:42][C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=1[C:35]([C:34]1[CH:33]=[C:32]([CH2:44][CH3:45])[S:31][C:30]=1[N:29]1[CH:28]=[N:27][N:26]=[C:25]1[CH2:24][NH:23][C:53]([NH:52][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)=[O:54])=[O:43]
Reactant: O=C=Nc1ccccc1
Reactant: CCc1cc(C(=O)c2ccccc2Cl)c(-n2cnnc2CN)s1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCc1cc(C(=O)c2ccccc2Cl)c(-n2cnnc2CNC(=O)Nc2ccccc2)s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-Aminomethyl-4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl) [1,2,4]triazole di-p-toluenesulfonate (5.0 g) was dissolved in dimethylformamide (20 ml). Phenyl isocyanate (0.87 ml) and triethylamine (3.0 ml) were added under ice-cooling, and the mixture was stirred at room temperature for 1 hour. A saturated aqueous sodium hydrogencarbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous citric acid solution and saturated brine, and dried over magnesium sulfate. The solvent was evaporated, and the residue was recrystallized from ethyl acetate-hexane to give 2.47 g of N-(4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl) [1,2,4]triazol-3-ylmethyl)-N'-phenylurea.
Reaction SMILES: [C-:1]#[N:2].[Na+].CS(C)=O.Br[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[O:17][C:18]3[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=3[N:20]=2)=[CH:12][C:11]=1[F:25]>O>[O:17]1[C:18]2[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=2[N:20]=[C:16]1[C:13]1[CH:14]=[CH:15][C:10]([CH2:9][C:1]#[N:2])=[C:11]([F:25])[CH:12]=1
Reactant: [C-]#N
Reactant: Fc1cc(-c2nc3ccccc3o2)ccc1CBr
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: N#CCc1ccc(-c2nc3ccccc3o2)cc1F

Procedure:
To a solution of 0.6 gm. of sodium cyanide in 25 ml. of dimethyl sulfoxide preheated to 65°-70°C. is slowly added 2.5 gm. of 2-(4-bromomethyl-3-fluorophenyl)-benzoxazole. The reaction mixture is heated at 60°-70°C. for 1 hour, then cooled and poured into water. The resulting precipitate is filtered off and chromatographed on 300 gm. of silica gel. Elution with methylene chloride gives 4-(benzoxazol-2-yl)-2-fluorophenylacetonitrile.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][N:13]=2)=[CH:7][CH:6]=1)=[O:3].Cl.[CH2:23]([N:25]([CH2:33][CH:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1)[CH2:26][C:27]1[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=1)[CH3:24].C(NC(C)C)(C)C>>[F:19][C:18]([F:21])([F:20])[C:15]1[CH:16]=[CH:17][C:12]([O:11][C:8]2[CH:9]=[CH:10][C:5]([O:4][C:2]([N:37]3[CH2:36][CH2:35][CH:34]([CH2:33][N:25]([CH2:23][CH3:24])[CH2:26][C:27]4[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=4)[CH2:39][CH2:38]3)=[O:3])=[CH:6][CH:7]=2)=[N:13][CH:14]=1
Reactant: CCN(Cc1ccncc1)CC1CCNCC1
Reactant: O=C(Cl)Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Agent: Cl
Solvent: CC(C)NC(C)C
Product: CCN(Cc1ccncc1)CC1CCN(C(=O)Oc2ccc(Oc3ccc(C(F)(F)F)cn3)cc2)CC1

Procedure:
The title compound was prepared from 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate and ethyl-piperidin-4-ylmethyl-pyridin-4-ylmethyl-amine, hydrochloride, 5 equivalent of diisopropylamine was added, preparative HPLC (Method C) (25%, off-white crystals). HPLC-MS m/z=515.2 (M+1), Rt: 2.77 min.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:13]([O:15]CC)=O.[Cl:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][NH2:24])=[CH:21][CH:20]=1>C1(C)C=CC=CC=1>[Cl:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][NH:24][C:13]([C:3]2[CH:4]=[N:5][C:6]3[C:11]([C:2]=2[OH:1])=[CH:10][C:9]([CH3:12])=[CH:8][CH:7]=3)=[O:15])=[CH:21][CH:20]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: CCOC(=O)c1cnc2ccc(C)cc2c1O
Solvent: Cc1ccccc1
Product: Cc1ccc2ncc(C(=O)NCc3ccc(Cl)cc3)c(O)c2c1
Temperature: 210 °C
Reaction time: 1 h

Procedure:
A mixture of 230 mg of ethyl 4-hydroxy-6-methyl-3-quinolinecarboxylate (J. Chem. Soc., 893 (1948)) and 0.7 mL of 4-chlorobenzylamine is stirred for 1 h at 210 ° C. The mixture is cooled to 25° C. and it is diluted with 1.5 mL of toluene. The mixture is filtered and the filtrant is dissolved in a minimum volume of refluxing glacial acetic acid. The hot solution is treated with distilled water dropwise until it becomes cloudy, and it is allowed to cool to 25° C. The precipitate is collected by filtration and it is washed with a small amount of dilute aqueous acetic acid. The solid is dried for 48 h at 20 torr and 85° C. This procedure gives the title compound as 47 mg of a light tan solid.
Reaction SMILES: [N+:1]([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.N>CCCCC>[NH2:1][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
Reactant: O=C1c2cc([N+](=O)[O-])ccc2C(=O)c2c1cccc2[N+](=O)[O-]
Agent: N
Solvent: CCCCC
Product: Nc1cccc2c1C(=O)c1ccc([N+](=O)[O-])cc1C2=O
Yield: 91.5 %

Procedure:
310 g of 1,6-dinitroanthraquinone (96%) were reacted 0.5 hours with 340 g of ammonia (molar ratio 20:1; pressure 80 atms) in 1 liter of n-pentane in an autoclave at 150° C.; the reaction mixture obtained was freed from the solvent by distillation. Residue: 269 g of a 91.5% 1-amino-6-nitroanthraquinone (89% of the theoretical yield).
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][N:8]=1)=[O:4]>[Pd].C(OCC)(=O)C>[NH2:13][C:10]1[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:3]([O:2][CH3:1])=[O:4])=[N:8][CH:9]=1
Reactant: COC(=O)COc1ccc([N+](=O)[O-])cn1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)COc1ccc(N)cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
A mixture of 5.18 g of 2-(methoxycarbonyl)methoxy-5-nitropyridine, 0.8 g of 10% palladium/carbon and 50 ml of ethyl acetate was stirred for 3 hours at room temperature under hydrogen atmosphere. The reaction system was purged with nitrogen, then, the reaction solution was filtrated through Celite, and the filtrate was concentrated. The residue was subjected to silica gel column chromatography to obtain 4.45 g of 5-amino-2-(methoxycarbonyl)methoxypyridine.
Reaction SMILES: [O:1]1CCO[CH:2]1[C:6]1[CH:19]=[CH:18][C:9]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[CH:8][C:7]=1[F:20].O1CCCC1.Cl.C(=O)([O-])O.[Na+]>CO>[F:20][C:7]1[CH:8]=[C:9]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[CH:18]=[CH:19][C:6]=1[CH:2]=[O:1]
Reactant: Fc1cc(COc2ccccn2)ccc1C1OCCO1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: O=Cc1ccc(COc2ccccn2)cc1F
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 99.3 %

Procedure:
To a solution of 2-(4-[1,3]dioxolan-2-yl-3-fluoro-benzyloxy)-pyridine (2.17 g, 7.88 mmol) described in Manufacturing Example 204-1-4 in methanol (10 mL) and tetrahydrofuran (10 mL) was added 5 N hydrochloric acid (8.43 mL, 8.43 mmol). This solution was stirred for 15 minutes at room temperature. This mixture was cooled to 0° C. and neutralized with a saturated sodium hydrogencarbonate aqueous solution, after which it was extracted with ethyl acetate. The organic layer was separated, washed with water, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure to obtain the title compound (1.81 g). The title compound was used in the following reaction without any further purification.
Reaction SMILES: Br[C:2]1[C:15]2[C:6](=[C:7]3[C:12](=[CH:13][CH:14]=2)[C:11](Br)=[CH:10][C:9]([CH3:17])=[N:8]3)[N:5]=[C:4]([CH3:18])[CH:3]=1.[CH2:19]([C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1)[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]>>[CH3:17][C:9]1[CH:10]=[C:11]([C:28]2[CH:29]=[CH:30][C:25]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:26][CH:27]=2)[C:12]2[C:7](=[C:6]3[C:15](=[CH:14][CH:13]=2)[C:2]([C:28]2[CH:27]=[CH:26][C:25]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:30][CH:29]=2)=[CH:3][C:4]([CH3:18])=[N:5]3)[N:8]=1
Reactant: CCCCCCc1ccc(B(O)O)cc1
Reactant: Cc1cc(Br)c2ccc3c(Br)cc(C)nc3c2n1
Product: CCCCCCc1ccc(-c2cc(C)nc3c2ccc2c(-c4ccc(CCCCCC)cc4)cc(C)nc23)cc1

Procedure:
Starting with 4,7-dibromo-2,9-dimethyl-1,10-phenanthroline, Phen8, (M. Schmittel, H. Ammon Eur. J. Org. Chem. 1998, 785) and the p-hexylphenylboronic acid (commercially available), the ligand Phen9 is synthesized by a Suzuki-coupling.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[CH:9][CH:10]=[C:4]2[N:3]=1.[NH2:11][CH2:12][C@@H:13]1[CH2:17][CH2:16][CH2:15][N:14]1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19]>>[N:8]1[N:5]2[CH:6]=[CH:7][C:2]([NH:11][CH2:12][C@@H:13]3[CH2:17][CH2:16][CH2:15][N:14]3[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[N:3][C:4]2=[CH:10][CH:9]=1
Reactant: Clc1ccn2nccc2n1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CN
Product: CC(C)(C)OC(=O)N1CCC[C@H]1CNc1ccn2nccc2n1
Yield: 96 %

Procedure:
The commercially available 5-chloropyrazolo[1,5-a]pyrimidine is reacted with (S)-tert-butyl 2-(aminomethyl)pyrrolidine-1-carboxylate under the amine displacement conditions described in example 5.6.5 to give 96% product.
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:39])[NH:5][C:6]1[S:7][C:8]2[C:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)=[CH:13][C:12]([C:21]3[CH:22]=[C:23]([N:27]4[CH2:32][CH2:31][C:30]([CH3:38])([C:33]([O:35]CC)=[O:34])[CH2:29][CH2:28]4)[N:24]=[N:25][CH:26]=3)=[CH:11][C:9]=2[N:10]=1)[CH3:2].CC(C)([O-])C.[K+].O>CS(C)=O>[CH2:1]([NH:3][C:4](=[O:39])[NH:5][C:6]1[S:7][C:8]2[C:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)=[CH:13][C:12]([C:21]3[CH:22]=[C:23]([N:27]4[CH2:32][CH2:31][C:30]([CH3:38])([C:33]([OH:35])=[O:34])[CH2:29][CH2:28]4)[N:24]=[N:25][CH:26]=3)=[CH:11][C:9]=2[N:10]=1)[CH3:2]
Reactant: CCNC(=O)Nc1nc2cc(-c3cnnc(N4CCC(C)(C(=O)OCC)CC4)c3)cc(-c3ccccn3)c2s1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CCNC(=O)Nc1nc2cc(-c3cnnc(N4CCC(C)(C(=O)O)CC4)c3)cc(-c3ccccn3)c2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 52.5 %

Procedure:
To an ice-cold solution of ethyl 1-(5-(2-(3-ethylureido)-7-(pyridin-2-yl)benzo[d]thiazol-5-yl)pyridazin-3-yl)-4-methylpiperidine-4-carboxylate (0.05 g, 0.092 mmol) in DMSO (2 mL) was added potassium tert-butoxide (0.051 g, 0.45 mmol) and the mixture stirred at rt for 2 h. After completion of reaction (by TLC), water (10 mL) was added followed by extraction with EtOAc (3×50 mL) and the organic layer discarded. The pH of the aqueous layer was adjusted up to 4-5, extracted with EtOAc (3×50 mL) and the combined organic layer dried over Na2SO4, filtered and evaporated under reduced pressure. The residue thus obtained was triturated with ether to obtain Compound 195 as an off-white solid (0.025 g, 53%). 1H NMR (DMSO-d6): δ 9.15 (s, 1H), 8.82 (m, 1H), 8.55 (d, J=8.0 Hz, 1H), 8.38 (s, 1H), 8.21 (s, 1H), 8.02 (t, J=8.0 Hz, 1H), 7.90 (m, 1H), 7.64 (s, 1H), 7.46 (m, 1H), 7.17 (br s, 1H), 4.20 (m, 2H), 3.19-3.24 (m, 4H), 2.10 (m, 2H), 1.43 (m, 2H), 1.22 (s, 3H) and 1.01 (t, J=7.2 Hz, 3H). MS: 518.29 [M+H]+.
Reaction SMILES: CO[C:3]([C:5]1[S:6][C:7]([Br:15])=[CH:8][C:9]=1[N:10]=[CH:11][N:12]([CH3:14])C)=[O:4].NC1[CH:22]=[CH:21][C:20]([N:23]2[CH2:27][CH2:26][C@@H:25]([N:28]([CH3:30])[CH3:29])[CH2:24]2)=[CH:19][CH:18]=1>>[Br:15][C:7]1[S:6][C:5]2[C:3](=[O:4])[N:12]([C:14]3[CH:22]=[CH:21][C:20]([N:23]4[CH2:27][CH2:26][C@@H:25]([N:28]([CH3:30])[CH3:29])[CH2:24]4)=[CH:19][CH:18]=3)[CH:11]=[N:10][C:9]=2[CH:8]=1
Reactant: COC(=O)c1sc(Br)cc1N=CN(C)C
Reactant: CN(C)[C@@H]1CCN(c2ccc(N)cc2)C1
Product: CN(C)[C@@H]1CCN(c2ccc(-n3cnc4cc(Br)sc4c3=O)cc2)C1

Procedure:
5-Bromo-3-(dimethylaminomethyleneamino)thiophene-2-carboxylic acid methyl ester was reacted with [(R)-1-(4-aminophenyl)pyrrolidin-3-yl]dimethylamine by method A1. The product with the molecular weight of 418.05 (C18H19BrN4OS) was obtained in this way; MS (ESI): 419 (M+H+).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Br:5][CH2:6][C:7](Br)=[O:8].[Cl:10][C:11]1[CH:12]=[C:13]([CH:23]=[CH:24][CH:25]=1)[O:14][C:15]([CH3:22])([CH3:21])[C:16]([O:18][CH2:19][CH3:20])=[O:17]>ClCCCl>[Br:5][CH2:6][C:7]([C:25]1[CH:24]=[CH:23][C:13]([O:14][C:15]([CH3:21])([CH3:22])[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:12][C:11]=1[Cl:10])=[O:8]
Reactant: CCOC(=O)C(C)(C)Oc1cccc(Cl)c1
Reactant: O=C(Br)CBr
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CCOC(=O)C(C)(C)Oc1ccc(C(=O)CBr)c(Cl)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirred suspension of aluminum chloride (1.8 g) in 1,2-dichloroethane (25 ml) was added bromoacetyl bromide (400 μl) under ice-cooling, and the mixture was stirred for 30 minutes. To the stirred mixture was added dropwise a solution of ethyl 2-(3-chlorophenoxy)-2-methylpropionate (1.1 g) in 1,2-dichloroethane (5 ml) under ice-cooling, and the mixture was stirred for 3 hours at 60° C. The reaction mixture was poured into ice-water and extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. Purification of the residue by flash column chromatography on silica gel (eluent: hexane/ethyl acetate=10/1) gave ethyl 2-[4-(2-bromoacetyl)-3-chlorophenoxy]-2-methylpropionate (204 mg).