Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[CH3:22][O:23][C:24]([O:38][CH3:39])([CH3:37])[CH2:25][C:26]1[C:27]([F:36])=[C:28]([OH:35])[CH:29]=[CH:30][C:31]=1[N+:32]([O-:34])=[O:33]>O1CCOCC1.CCOC(C)=O.O>[CH2:15]([O:14][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([O:35][C:28]3[CH:29]=[CH:30][C:31]([N+:32]([O-:34])=[O:33])=[C:26]([CH2:25][C:24]([O:23][CH3:22])([O:38][CH3:39])[CH3:37])[C:27]=3[F:36])=[CH:3][CH:4]=[N:5]2)=[CH:10][C:9]=1[O:12][CH3:13])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COC(C)(Cc1c([N+](=O)[O-])ccc(O)c1F)OC
Reactant: COc1cc2c(Cl)ccnc2cc1OCc1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: COc1cc2c(Oc3ccc([N+](=O)[O-])c(CC(C)(OC)OC)c3F)ccnc2cc1OCc1ccccc1

Procedure:
4-Chloro-7-benzyloxy-6-methoxy-quinoline (WO2008112407, 1.5 g) was mixed with 3-(2,2-dimethoxypropyl)-2-fluoro-4-nitrophenol (WO0047212) (1.5 eq) in dioxane (30 ml). The reaction was refluxed for three days and diluted with EtOAc, water and extracted with EtOAc three times. The combined organic layer was washed with water, brine and dried. The solution was evaporated and purified with silica gel column to give 7-(benzyloxy)-4-(3-(2,2-dimethoxypropyl)-2-fluoro-4-nitrophenoxy)-6-methoxyquinoline (650 mg). This product was mixed with 2NHCl (3 ml) and acetone (30 ml) and refluxed for 6 hours. The reaction was diluted with EtOAc and neutralized with saturated NaHCO3, further extracted with EtOAc three times. The combined organic layer was washed with water, brine and dried. The solution was evaporated and purified with silica gel column to give 1-(3-(7-(benzyloxy)-6-methoxyquinolin-4-yloxy)-2-fluoro-6-nitrophenyl)propan-2-one (500 mg) which was mixed with iron (500 mg) and NH4Cl (50 mg) in EtOH/H2O (20 ml, 4/1). The reaction was refluxed for 4 hours, filter through Celite and evaporated. The residue was extracted with EtOAc three times. The combined organic layer was washed with water, brine and dried. The solution was evaporated and purified with silica gel column to give 4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxy-7-benzyloxyquinoline (250 mg).
Reaction SMILES: [CH:1]1([CH2:7][CH:8]([CH2:12][C:13]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[O:14])[C:9]([OH:11])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[NH2:22][CH:23]([CH2:33][CH2:34][CH3:35])[CH:24]([C:26]1[O:27][C:28]([CH2:31][CH3:32])=[N:29][N:30]=1)[OH:25].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.CN1CCOCC1>C(Cl)Cl>[CH:1]1([CH2:7][CH:8]([CH2:12][C:13]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[O:14])[C:9]([NH:22][CH:23]([CH:24]([C:26]2[O:27][C:28]([CH2:31][CH3:32])=[N:29][N:30]=2)[OH:25])[CH2:33][CH2:34][CH3:35])=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)C(CC(=O)N1CCOCC1)CC1CCCCC1
Reactant: CCCC(N)C(O)c1nnc(CC)o1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CN1CCOCC1
Product: CCCC(NC(=O)C(CC(=O)N1CCOCC1)CC1CCCCC1)C(O)c1nnc(CC)o1
Reaction time: 14 h
Yield: 102.2 %

Procedure:
To a stirred mixture of 2-cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyric acid (84.9 mg, 0.3 mmol), 2-amino-1-(5-ethyl-1,3,4-oxadiazole-2-yl)-1-pentanol HCl salt (70.5 mg), prepared as in reference 21, and HOBt (55.1 mg, 0.36 mmol) in MeCl2 (5 ml), was added EDC (86.4 mg, 0.45 mmol) and N-methylmorpholine (0.25 ml) at room temperature. After stirring for 14 hours, the reaction mixture was extracted with ethyl acetate. The organic layer was washed with saturated NaHCO3, brine, dried with MgSO4 and concentrated to yield 142 mg of 2-cyclohexylmethyl-N-{1-[(5-ethyl-[1,3,4]oxadiazol-2-yl)-hydroxy-methyl]-butyl}-4-morpholin-4-yl-4-oxo-butyramide; MS: 463.5(M−1), 465.3(M+1).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH2:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:15]1[C:20]2[CH:21]=[CH:22][CH:23]=[C:24]([C:25]([Cl:27])=[O:26])[C:19]=2[O:18][CH2:17][CH2:16]1>C(Cl)(Cl)Cl>[ClH:27].[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:25]([C:24]2[C:19]3[O:18][CH2:17][CH2:16][O:15][C:20]=3[CH:21]=[CH:22][CH:23]=2)=[O:26])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC1CCN(Cc2ccccc2)CC1
Reactant: O=C(Cl)c1cccc2c1OCCO2
Solvent: ClC(Cl)Cl
Product: Cl
Product: O=C(NC1CCN(Cc2ccccc2)CC1)c1cccc2c1OCCO2
Yield: 76.6 %

Procedure:
200 ml of chloroform and 50 g of 1-benzyl-4-amino piperidine were introduced into a balloon flask provided with an agitator and a thermometer, and then 50 g of 1,4-benzodioxane-5-carbonyl chloride was added in portions at a temperature of from 5°-10° C. After agitation of the mixture at ambient temperature the solvent was removed under vacuum and the residue was dissolved in 300 ml of water. After precipitation of the base by addition of ammonia, the water was removed and the resulting product was treated with a solution of hydrochloric acid. 75 g of N-(1-benzyl-4-piperidyl)-1,4-benzodioxane-5-carboxamide hydrochloride was produced (M.P.: 205° C.; yield: 77%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[C:6]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:5]=[CH:4][N:3]=1.O.NN>[Ni].CO>[NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([O:11][CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Nc1nccc(OCc2ccccc2)c1[N+](=O)[O-]
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: CO
Product: Nc1nccc(OCc2ccccc2)c1N
Yield: 85.4 %

Procedure:
A mixture of 0.88 g of 2-amino-4-benzyloxy-3-nitropyridine (starting material M2), 0.81 ml of hydrazine hydrate and 0.100 g of Raney nickel in 25 ml of methanol is heated under reflux until no starting material is detectable by TLC. After filtration and evaporation of the solvent the residue is chromatographed on silica gel (dichloromethane/methanol 20:1+1% triethylamine). Concentration of the pure fractions and drying in vacuo gives 0.66 g of the title compound as a brownish solid of m.p. 135–136° C. The mass spectrum shows the molecular peak MH+ at 216.1 Da.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]([NH2:15])[CH:11]=[CH:12][C:13]=2[CH3:14])=[C:5]([CH3:16])[CH:4]=1.CCO/[C:20](/[CH3:27])=[CH:21]/[C:22](OCC)=[O:23]>C(Cl)(Cl)Cl.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]3[N:15]=[C:20]([CH3:27])[CH:21]=[C:22]([OH:23])[C:11]3=[CH:12][C:13]=2[CH3:14])=[C:5]([CH3:16])[CH:4]=1
Reactant: COc1ccc(-c2c(C)ccn2N)c(C)c1
Reactant: CCOC(=O)/C=C(\C)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClC(Cl)Cl
Product: COc1ccc(-c2c(C)cc3c(O)cc(C)nn23)c(C)c1
Temperature: 25 °C
Yield: 64.8 %

Procedure:
A mixture of 2-(4-methoxy-2-methylphenyl)-3-methyl-1H-pyrrol-1-amine (0.23 g, 1.06 mmol), ethyl trans-3-ethoxycrotonate (0.17 g, 1.06 mmol) and p-toluenesulfonic acid (0.01 g, 0.053 mmol) in CHCl3 (7.0 mL) was refluxed with a Dean-Stark tube charged with molecular sieves for 24 h. After cooling down to room temperature, the mixture was concentrated in vacuo to dryness and the residue was subjected to column chromatography (silica gel, 1/4 EtOAc/heptane) to give 0.194 g (65%) of beige foam as the desired product: mp 234–237° C.; 1H NMR (300 MHz, CDCl3) δ 7.22 (d, J=8 Hz, 1H), 6.89–6.87 (m, 1H), 6.84–6.79 (m, 1H), 6.54 (br s, 1H), 5.94 (br s, 1H), 3.85 (s, 3H), 2.34 (s, 3H), 2.18 (s, 3H), 2.08 (s, 3H); MS m/z 283.2 (M++H).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.Br.Br.Br.[NH2:11][CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][CH:17]([NH:20][C:21]2[N:25]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)[C:24]3[CH:34]=[CH:35][C:36]([OH:38])=[CH:37][C:23]=3[N:22]=2)[CH2:16][CH2:15]1.C(=O)([O-])O.[Na+]>C(O)C>[F:33][C:30]1[CH:31]=[CH:32][C:27]([CH2:26][N:25]2[C:24]3[CH:34]=[CH:35][C:36]([OH:38])=[CH:37][C:23]=3[N:22]=[C:21]2[NH:20][CH:17]2[CH2:18][CH2:19][N:14]([CH2:13][CH2:12][NH:11][C:2]3[N:7]=[CH:6][CH:5]=[CH:4][N:3]=3)[CH2:15][CH2:16]2)=[CH:28][CH:29]=1
Reactant: NCCN1CCC(Nc2nc3cc(O)ccc3n2Cc2ccc(F)cc2)CC1
Reactant: Clc1ncccn1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Oc1ccc2c(c1)nc(NC1CCN(CCNc3ncccn3)CC1)n2Cc1ccc(F)cc1
Yield: 83 %

Procedure:
A mixture of 1.7 parts of 2-chloropyrimidine, 9.66 parts of 2-[[1-(2-aminoethyl)-4-piperidinyl]amino]-1-[(4-fluorophenyl)-methyl]-1H-benzimidazol-5-ol trihydrobromide, 5 parts of sodium hydrogen carbonate and 80 parts of ethanol was stirred and refluxed overnight. The reaction mixture was evaporated and the residue was taken up in trichloromethane. The organic phase was washed with water, dried, filtered and evaporated. The residue was crystallized from a mixture of acetonitrile and methanol, yielding 5.2 parts (83%) of 1-[(4-fluorophenyl)methyl]-2-[[1-[2-(2-pyrimidinylamino)-ethyl]-4-piperidinyl]amino]-1H-benzimidazol-5-ol; mp. 194.4° C. (compound 64).
Reaction SMILES: [CH3:1][C:2]1[C:15]2[C:16]3=[C:17]4[C:12](=[CH:13][CH:14]=2)[CH:11]=[CH:10][CH:9]=[C:8]4[CH:7]=[CH:6][C:5]3=[CH:4][CH:3]=1.[C:18](Cl)([CH3:21])([CH3:20])[CH3:19].ClCCl.[Cl-].[Al+3].[Cl-].[Cl-]>O>[C:18]([C:10]1[CH:9]=[C:8]2[C:17]3=[C:16]4[C:5](=[CH:4][CH:3]=[C:2]([CH3:1])[C:15]4=[CH:14][CH:13]=[C:12]3[CH:11]=1)[CH:6]=[CH:7]2)([CH3:21])([CH3:20])[CH3:19]
Reactant: Cc1ccc2ccc3cccc4ccc1c2c34
Reactant: CC(C)(C)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: Cc1ccc2ccc3cc(C(C)(C)C)cc4ccc1c2c34
Temperature: 25 °C
Reaction time: 3 h
Yield: 54.1 %

Procedure:
Next, a mixed solution of 4.4 g of 1-methylpyrene, 2 g of t-butylchloride and 33 ml of dichloromethane was cooled to 0° C. under a nitrogen gas stream and then 2.7 g of aluminum chloride was added. This mixed solution was stirred at room temperature for 3 hours and 30 ml of water was poured into the solution, followed by extraction with 30 ml of dichloromethane. The organic layer was washed twice with 20 ml of water, dried over magnesium sulfate and then evaporated. The concentrate was purified by silica gel column chromatography and then vacuum-dried to obtain 3 g of 7-t-butyl-1-methylpyrene.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[C:7]([C:9]1[CH:10]=[C:11](B(O)O)[CH:12]=[CH:13][CH:14]=1)#[N:8].ClCCl.Br[C:22]1[N:26]2[N:27]=[C:28]([N:31]3[CH2:35][CH2:34][C@H:33]([OH:36])[CH:32]3[C:37]3[CH:42]=[CH:41][CH:40]=[C:39]([F:43])[CH:38]=3)[CH:29]=[CH:30][C:25]2=[N:24][CH:23]=1>O1CCOCC1.O>[F:43][C:39]1[CH:38]=[C:37]([CH:32]2[C@@H:33]([OH:36])[CH2:34][CH2:35][N:31]2[C:28]2[CH:29]=[CH:30][C:25]3[N:26]([C:22]([C:13]4[CH:14]=[C:9]([CH:10]=[CH:11][CH:12]=4)[C:7]#[N:8])=[CH:23][N:24]=3)[N:27]=2)[CH:42]=[CH:41][CH:40]=1
Reactant: O[C@H]1CCN(c2ccc3ncc(Br)n3n2)C1c1cccc(F)c1
Reactant: N#Cc1cccc(B(O)O)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: C1COCCO1
Product: N#Cc1cccc(-c2cnc3ccc(N4CC[C@H](O)C4c4cccc(F)c4)nn23)c1

Procedure:
In step 3-5, in a microwave vessel sodium carbonate (105 mg, 1.0 mmol), 3-cyano phenylboronic acid (200 mg, 1.36 mmol) and Pd(DPPF)-dichloride catalyst (1,1′ bis(diphenylsphosphino-ferrocene)-dichloropalladium (II) adduct with dichloromethane) (100 mg, 0.12 mmol) were added to a solution (3S)-1-(3-bromoimidazo[1,2-b]pyridazin-6-yl)-2-(3-fluorophenyl)pyrrolidin-3-ol (1.40 g, 0.36 mmol) and 4 mL of 1,4-dioxane/water (3:1). This solution was then subjected to the following microwave conditions using a laboratory microwave instrument (conditions: 150° C., 200 W max threshold, 20 atm. max pressure, 20 minute reaction time). The reaction mixture was purified directly with reverse phase C-18 HPLC (water/acetonitrile 90:10 to 10:90 gradient) to yield 3-(6-((3S)-2-(3-fluorophenyl)-3-hydroxypyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)benzonitrile (3-5) as a mixture of diastereomers. 1H NMR (400 MHz, D6 acetone) δ ppm 8.85 (br s, 1H), 8.40-8.03 (m, 3H), 7.90-7.22 (m, 5H), 7.10 (app d, J=5.5 Hz, 1H), 6.98 (app t, J=4.5 Hz, 1H), 5.25 (app d, J=4.5 Hz, 1H), 4.80 (app q, J=7.5 Hz, 1H), 4.30 (br s, 1H), 3.82-3.75 (m, 1H), 3.3-3.55 (m, 1H), 2.42-2.34 (m, 1H), 2.25-2.12 (m, 1H). LCMS observed m/z 400.2.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:37]=[CH:38][CH:39]=1)[CH2:5][N:6]1[CH:11]([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][CH:13]=2)[C:10]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:9]([CH3:25])[N:8]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=2)[C:7]1=[O:36].[S:40]1[CH:44]=[CH:43][CH:42]=[C:41]1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O.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>[C:18]([C:15]1[CH:14]=[CH:13][C:12]([CH:11]2[C:10]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:9]([CH3:25])[N:8]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:33])([F:34])[F:35])[CH:27]=3)[C:7](=[O:36])[N:6]2[CH2:5][C:4]2[CH:37]=[CH:38][CH:39]=[C:2]([C:41]3[S:40][CH:44]=[CH:43][CH:42]=3)[CH:3]=2)=[CH:17][CH:16]=1)#[N:19]
Reactant: CCOC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)C(=O)N(Cc2cccc(Br)c2)C1c1ccc(C#N)cc1
Reactant: OB(O)c1cccs1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)C(=O)N(Cc2cccc(-c3cccs3)c2)C1c1ccc(C#N)cc1
Temperature: 90 °C
Reaction time: 24 h

Procedure:
A solution of ethyl 3-(3-bromobenzyl)-4-(4-cyanophenyl)-6-methyl-2-oxo-1-[3-(trifluoromethyl)-phenyl]-1,2,3,4-tetrahydropyrimidin-5-carboxylate (Example 35) (40 mg, 0.07 mmol), 2-thiophen-boronic acid (10.69 mg, 0.08 mmol), 2 M aqueous sodium carbonate (100 μl, 0.2 mmol) and bis-(triphenylphosphine)palladium(II) chloride (4.7 mg, 0.01 mmol) in dimethylformamide (2.0 ml) is stirred at 90° C. overnight (16 h). Additional bis(triphenylphosphine)palladium(II) chloride (4.7 mg, 0.01 mmol) is added, and the reaction is stirred at 90° C. for another 24 h, after which time additional bis(triphenylphosphine)palladium(II) chloride (4.7 mg, 0.01 mmol) is added and the reaction stirred 3 h longer at 90° C. The reaction mixture is diluted with dimethylformamide (5 ml) and purified directly by preparative HPLC(RP18 column; eluent: acetonitrile/0.1% aq. formic acid 10:90→90:10). The product fractions are concentrated and pulled through a thin layer of silica gel 60 with dichloromethane as eluent. Concentration in vacuo gives the title compound.
Reaction SMILES: N1CCC[C@H]1C(O)=O.[NH2:9][C:10]1[N:14]([C:15]2[CH:24]=[CH:23][C:18]3[NH:19][C:20]([CH3:22])=[N:21][C:17]=3[CH:16]=2)[N:13]=[CH:12][C:11]=1[C:25]([C:27]1[N:28]([S:37]([C:40]2[CH:45]=[CH:44][C:43]([CH3:46])=[CH:42][CH:41]=2)(=[O:39])=[O:38])[C:29]2[C:34]([CH:35]=1)=[CH:33][CH:32]=[C:31](I)[CH:30]=2)=[O:26].N12CCCN=C1CCCCC2.[CH3:58][O:59][CH2:60][CH2:61][NH2:62].O.N>CS(C)=O.[Cu]I>[NH2:9][C:10]1[N:14]([C:15]2[CH:24]=[CH:23][C:18]3[NH:19][C:20]([CH3:22])=[N:21][C:17]=3[CH:16]=2)[N:13]=[CH:12][C:11]=1[C:25]([C:27]1[N:28]([S:37]([C:40]2[CH:45]=[CH:44][C:43]([CH3:46])=[CH:42][CH:41]=2)(=[O:39])=[O:38])[C:29]2[C:34]([CH:35]=1)=[C:33]([NH:62][CH2:61][CH2:60][O:59][CH3:58])[CH:32]=[CH:31][CH:30]=2)=[O:26]
Reactant: COCCN
Reactant: Cc1ccc(S(=O)(=O)n2c(C(=O)c3cnn(-c4ccc5[nH]c(C)nc5c4)c3N)cc3ccc(I)cc32)cc1
Agent: [Cu]I
Agent: N
Agent: O=C(O)[C@@H]1CCCN1
Solvent: CS(C)=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Product: COCCNc1cccc2c1cc(C(=O)c1cnn(-c3ccc4[nH]c(C)nc4c3)c1N)n2S(=O)(=O)c1ccc(C)cc1
Temperature: 80 °C
Reaction time: 18 h

Procedure:
Copper (I) iodide (16 mg, 0.086 mmol), L-proline (37 mg, 0.32 mmol), and [5-amino-1-(2-methyl-1H-benzimidazol-5-yl)-1H-pyrazol-4-yl]-[6-iodo-1-(toluene-4-sulfonyl)-1H-indol-2-yl]-methanone (104 mg) were dissolved in anhydrous dimethylsulfoxide (DMSO), and then 1,8-diazabicyclo[5.4.0]undec-7-ene (49 μl) and 2-methoxyethylamine (43 μl) were added thereto. The mixture was heated at 80° C. with stirring under a nitrogen atmosphere for 18 hours. After the reaction mixture was cooled to room temperature, 25% ammonia water was added thereto. The resulting mixture was extracted with ethyl acetate. The organic layer was isolated, washed with an aqueous solution of 1 M hydrochloric acid and then with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate. After the desiccant was removed by filtration, the solvent was distilled off under reduced pressure. The resulting residue was purified by chromatography (dichloromethane/methanol=100/5) using a small amount of silica gel to give crude product of [5-amino-1-(2-methyl-1H-benzimidazol-5-yl)-1H-pyrazol-4-yl]-[4-(2-methoxy-ethylamino)-1-(toluene-4-sulfonyl)-1H-indol-2-yl]-methanone. The obtained crude product was used in subsequent reactions without purification.
Reaction SMILES: S(Cl)(Cl)=O.COC1C=CC=CC=1CCC(O)=O.C1(CCCC(Cl)=O)C=CC=CC=1.[CH3:30][O:31][C:32]1[CH:33]=[C:34]2[C:39](=[CH:40][C:41]=1[O:42][CH3:43])[N:38]=[CH:37][CH:36]=[C:35]2[O:44][C:45]1[CH:50]=[CH:49][C:48]([NH:51][CH2:52][CH3:53])=[CH:47][CH:46]=1.[CH3:54][O:55][C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][C:57]=1[CH2:62][CH2:63][C:64]([N:66]=[C:67]=[S:68])=[O:65]>C1(C)C=CC=CC=1.C(O)C>[CH3:30][O:31][C:32]1[CH:33]=[C:34]2[C:39](=[CH:40][C:41]=1[O:42][CH3:43])[N:38]=[CH:37][CH:36]=[C:35]2[O:44][C:45]1[CH:50]=[CH:49][C:48]([N:51]([CH2:52][CH3:53])[C:67]([NH:66][C:64](=[O:65])[CH2:63][CH2:62][C:57]2[CH:58]=[CH:59][CH:60]=[CH:61][C:56]=2[O:55][CH3:54])=[S:68])=[CH:47][CH:46]=1
Reactant: CCNc1ccc(Oc2ccnc3cc(OC)c(OC)cc23)cc1
Reactant: COc1ccccc1CCC(=O)N=C=S
Agent: COc1ccccc1CCC(=O)O
Agent: O=C(Cl)CCCc1ccccc1
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCN(C(=S)NC(=O)CCc1ccccc1OC)c1ccc(Oc2ccnc3cc(OC)c(OC)cc23)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 52 %

Procedure:
Toluene (20 ml) and thionyl chloride (1 ml) were added to commercially available 3-(2-methoxyphenyl)propanoic acid (80 mg), and the mixture was heated at 100° C. for one hr. The solvent was removed by distillation, and 3-(2-methoxyphenyl)propanoyl isothiocyanate was prepared using the resultant 4-phenylbutanoyl chloride as a starting compound according to the description of the literature. N-{4-[(6,7-Dimethoxy-4-quinolyl)oxy]phenyl}-N-ethylamine (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 3-(2-methoxyphenyl)propanoyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (44 mg, yield 52%).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:28])[CH2:4][NH:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([Cl:16])[CH:14]=2)[N:9]=[C:8]([N:17]2[CH2:23][CH2:22][CH2:21][C:20]3[CH:24]=[CH:25][CH:26]=[CH:27][C:19]=3[CH2:18]2)[CH:7]=1.[CH2:29]1C2C=CC=CC=2CCC[NH:30]1.NCC(O)CN.C(N)CN.NCC(O)CNC1C2C(=CC=CC=2)N=C(N2CCCC3C=CC=CC=3C2)C=1>>[NH2:30][C:29]1[O:28][CH:3]([CH2:4][NH:5][C:6]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([Cl:16])[CH:14]=3)[N:9]=[C:8]([N:17]3[CH2:23][CH2:22][CH2:21][C:20]4[CH:24]=[CH:25][CH:26]=[CH:27][C:19]=4[CH2:18]3)[CH:7]=2)[CH2:2][N:1]=1
Reactant: c1ccc2c(c1)CCCNC2
Reactant: NCC(O)CNc1cc(N2CCCc3ccccc3C2)nc2ccc(Cl)cc12
Agent: NCC(O)CN
Agent: NCC(O)CNc1cc(N2CCCc3ccccc3C2)nc2ccccc12
Solvent: NCCN
Product: NC1=NCC(CNc2cc(N3CCCc4ccccc4C3)nc3ccc(Cl)cc23)O1

Procedure:
The title compound was prepared in analogy to Example 9-1 by using 1-amino-3-{6-chloro-[2-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl]amino}propan-2-ol [It was prepared in Scheme 1 by using 2,3,4,5-tetrahydro-1H-2-benzazepine (commercial available) and 1,3-diamino-propan-2-ol (commercial available) instead of 7-bromo-2,3,4,5-tetrahydro-1H-2-benzazepine and ethane-1,2-diamine respectively.] instead of 1-amino-3-{[2-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl]amino}propan-2-ol. MS obsd. (ESI+) [(M+H)+] 422. 1H NMR (400 MHz, CD3OD) δ ppm 8.17 (s, 1 H), 7.82 (d, J=8.8 Hz, 1 H), 7.69 (m, 1 H), 7.52 (s, 1 H), 7.22 (m, 3 H), 6.15 (s, 1 H), 5.42 (m, 1 H), 4.99 (s, 2 H), 4.11 (m, 3 H), 3.94 (d, J=5.6 Hz, 2 H), 3.77 (dd, J=9.6, 6.8 Hz, 1 H), 3.09 (m, 2 H), 2.00 (d, J=5.6 Hz, 2 H).
Reaction SMILES: [CH2:1]([N:3]1[CH2:11][C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[CH2:4]1)[CH3:2].O>COCCO.[Pd]>[CH2:1]([N:3]1[CH2:11][CH:10]2[CH:5]([NH:6][CH2:7][CH2:8][CH2:9]2)[CH2:4]1)[CH3:2]
Reactant: CCN1Cc2cccnc2C1
Agent: [Pd]
Solvent: O
Solvent: COCCO
Product: CCN1CC2CCCNC2C1
Temperature: 70 °C
Reaction time: 6 h
Yield: 72.1 %

Procedure:
To a solution of 6-ethyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine (2.00 g) in glycol monomethyl ether was added a catalytic amount of 10% Pd/C. The suspension was heated to 70° C. and stirred for 6 h under H2 (2 MPa), then cooled to rt, and poured into 100 mL of water. The mixture was extracted with CH2Cl2 (50 mL×3). The combined organic phases were dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo to give the title compound as yellow oil (1.50 g, 70.00%). The crude product was used for the next step without further purification. The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 155.0 (M+1).
Reaction SMILES: [C:1]([OH:9])(=[O:8])[CH:2]([CH2:4][C:5]([OH:7])=[O:6])[OH:3].[O-2:10].[Zn+2:11].C(=O)([O-])[O-:13].[Ca+2:16]>O>[C:1]([OH:9])(=[O:8])[CH:2]([CH2:4][C:5]([OH:7])=[O:6])[OH:3].[C:1]([O-:9])(=[O:8])[CH:2]([CH2:4][C:5]([O-:7])=[O:6])[OH:3].[Zn+2:11].[OH:10][Ca:16][OH:13].[C:1]([O-:9])(=[O:8])[CH:2]([CH2:4][C:5]([O-:7])=[O:6])[OH:3]
Reactant: [O-2]
Reactant: O=C([O-])[O-]
Reactant: [Ca+2]
Agent: O=C(O)CC(O)C(=O)O
Agent: [Zn+2]
Solvent: O
Product: O=C([O-])CC(O)C(=O)[O-]
Product: O[Ca]O

Procedure:
An aqueous solution of malic acid was prepared by mixing 134.09 g of malic acid with 50 mL of water. An aqueous solution of zinc oxide was also prepared in a separate container by thoroughly mixing 81.38 g of zinc oxide in 25 mL of water. An aqueous solution of calcium carbonate was also prepared in a separate container by thoroughly mixing 100.09 g of calcium carbonate in 25 mL of water. The zinc oxide solution and the calcium carbonate solution were then slowly added to the malic acid solution. The resulting solution was then spray dried to produce a powdered dihydroxycalcium zinc malate (or calciumhydroxy zinchydroxy malate).
Reaction SMILES: [Mg].[Cu](C#N)C#N.F[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([O:18][CH:19]([C:23]2[CH:28]=[CH:27][C:26](F)=[CH:25][CH:24]=2)C2OC2)C2OC2)=[CH:10][CH:9]=1.C(OCC)(=O)C.CCCCCC>C1COCC1>[CH2:14]([O:18][CH2:19][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:11]1[CH:12]=[CH:13][CH:8]=[CH:9][CH:10]=1
Reactant: Fc1ccc(C(OC(c2ccc(F)cc2)C2CO2)C2CO2)cc1
Agent: N#C[Cu]C#N
Agent: [Mg]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCCCCCOCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Magnesium (2.4 g, 98 mmol) was added to a 250 ml flask and flame dried. Dry THF, 25 ml, and 1 ml of dibromoethane were then added. 1-Bromo-4-6enzyloxy-butane 41 (12 g, 49.4 mmol) dissolved in 50 ml of dry THF was added dropwise and the reaction mixture was stirred at room temperature. After 1 hour, the reaction mixture is cooled in an ice-water bath and 90 mg of copper cyanide is added. After 10 minutes in an ice-bath, 4-fluorophenyl-glycidyl ether (5 g, 29.6 mmol) dissolved in 30 ml of dry THF is added slowly. The reaction is monitored by TLC (ethyl acetate:hexane 3:7). After 15 minutes, the reaction is quenched with saturated aqueous ammonium chloride, concentrated and partitioned between water-ethyl acetate. The ethyl acetate layer is then washed with brine, dried over Na2SO4 and concentrated to give the desired benzyloxy-heptane 42. The structure was confirmed by 1H-NMR.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH3:17])[C:10]=1[O:11][CH2:12][CH2:13][CH2:14][C:15]#[CH:16])[C:5]([NH2:7])=[O:6].CO[C:20](OC)([N:22](C)C)[CH3:21].Cl.NO>>[CH3:1][C:2]1[CH:3]=[C:4]([C:5]2[O:6][N:22]=[C:20]([CH3:21])[N:7]=2)[CH:8]=[C:9]([CH3:17])[C:10]=1[O:11][CH2:12][CH2:13][CH2:14][C:15]#[CH:16]
Reactant: COC(C)(OC)N(C)C
Reactant: C#CCCCOc1c(C)cc(C(N)=O)cc1C
Agent: Cl
Agent: NO
Product: C#CCCCOc1c(C)cc(-c2nc(C)no2)cc1C

Procedure:
5-[3,5-Dimethyl-4-(3-ethynylpropoxy)phenyl]-3-methyl-1,2,4-oxadiazole [XIV; Y=(CH2)3, R1 and R2 =3,5-(CH3)2, R8 =CH3 ] was prepared from 4.7 g 3,5-dimethyl-4-(3-ethynylpropoxy)benzamide, 31 ml dimethylacetamide dimethyl acetal and 1.7 g hydroxylamine hydrochloride according to the procedure of Example 2, part (b), and was obtained (4.4 g) in the form of a viscous oil used directly in the next reaction. A sample when crystallized from isopropyl acetate/hexane had the m.p. 38°-40° C.