Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:17][CH2:18][CH2:19]O)[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH2:10][O:9]2)=[CH:4][CH:3]=1.N1C=CC=CC=1.S(Cl)([Cl:29])=O>ClC(Cl)Cl>[Cl:29][CH2:19][CH2:18][CH2:17][C:8]1([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][O:9]1
Reactant: OCCCC1(c2ccc(F)cc2)OCc2ccccc21
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: Fc1ccc(C2(CCCCl)OCc3ccccc32)cc1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
To a stirred solution of 24.2 parts of 1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-1-propanol in 8 parts of pyridine and 90 parts of trichloromethane were added dropwise 12.1 parts of thionyl chloride. Upon completion, the whole was heated slowly to 50° C. and stirring at this temperature was continued for 3 hours. The reaction mixture was poured onto ice-water. The organic phase was separated, washed with a sodium hydrogen carbonate solution (10%), dried and evaporated, yielding 20 parts of 1-(3-chloropropyl)-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran as a residue (intermediate 12).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=O.Cl.C(NCC)C.[N+:17]([CH2:20][C:21](OC)=[O:22])([O-:19])=[O:18]>C1(C)C=CC=CC=1.O>[F:1][C:2]1[CH:9]=[C:6]2[C:5](=[CH:4][CH:3]=1)[O:10][C:21](=[O:22])[C:20]([N+:17]([O-:19])=[O:18])=[CH:7]2
Reactant: O=Cc1cc(F)ccc1O
Reactant: COC(=O)C[N+](=O)[O-]
Agent: Cl
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCNCC
Product: O=c1oc2ccc(F)cc2cc1[N+](=O)[O-]
Yield: 55.4 %

Procedure:
5-Fluoro-2-hydroxybenzaldehyde (7.14 g, 50.96 mmol), diethyl amine hydrochloride (6.70 g, 61.15 mmol) and methyl nitroacetate (5.62 mL, 61.15 mmol) were added together in toluene (90 mL) and stirred together at reflux under a N2 atmosphere. A Dean-Stark apparatus was fitted to the system to remove the H2O generated by the reaction. The reaction was allowed to reflux overnight, after which the mixture was cooled and diluted with H2O. The organic layer was separated, washed with brine, dried over anhydrous Na2SO4 and concentrated. Purification by flash chromatography on silica gel afforded the product as an orange solid (5.90 g, 55%)
Reaction SMILES: [I:1][C:2]1[N:3]=[C:4]([CH2:10][O:11][CH3:12])[N:5]([CH2:7][CH2:8][NH2:9])[CH:6]=1.[F:13][C:14]([F:26])([F:25])[C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH:23]=O)=[CH:17][CH:16]=1>>[I:1][C:2]1[N:3]=[C:4]([CH2:10][O:11][CH3:12])[N:5]2[CH2:7][CH2:8][NH:9][CH:23]([CH2:22][CH2:21][C:18]3[CH:19]=[CH:20][C:15]([C:14]([F:13])([F:25])[F:26])=[CH:16][CH:17]=3)[C:6]=12
Reactant: O=CCCc1ccc(C(F)(F)F)cc1
Reactant: COCc1nc(I)cn1CCN
Product: COCc1nc(I)c2n1CCNC2CCc1ccc(C(F)(F)F)cc1

Procedure:
According to the general procedure (GP10), the microwave-assisted Pictet-Spengler reaction (60 W; 95° C.; 9 bars; 10 min.) between 2-(4-iodo-2-methoxymethyl-imidazol-1-yl)-ethylamine (596 mg; 2.119 mmol) and 3-(4-trifluoromethyl-phenyl)-propionaldehyde (428 mg; 2.119 mmol) afforded 1-iodo-3-methoxymethyl-8-[2-(4-trifluoromethyl-phenyl)-ethyl]-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine which was Boc-protected and finally purified by FC (DCM/MeOH=30/1).
Reaction SMILES: C([Li])CCC.[OH:6][CH2:7][CH2:8][C:9]1[S:13][CH:12]=[N:11][C:10]=1[CH3:14].[C:15]([C:18]1[CH:22]=[CH:21][S:20][CH:19]=1)(=[O:17])[CH3:16]>O1CCCC1>[OH:6][CH2:7][CH2:8][C:9]1[S:13][C:12]([C:15]([C:18]2[CH:22]=[CH:21][S:20][CH:19]=2)([OH:17])[CH3:16])=[N:11][C:10]=1[CH3:14]
Reactant: Cc1ncsc1CCO
Reactant: CC(=O)c1ccsc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1nc(C(C)(O)c2ccsc2)sc1CCO
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
n-Butyllithium (2.5M solution in hexanes, 75 mmoles) was added to a stirred solution of 5-(2-hydroxyethyl)-4-methylthiazole (35 mmoles) in dry tetrahydrofuran (80 ml) at -70° C. under an atmosphere of dry nitrogen. After 30 minutes, 3-acetylthiophene (38 mmoles) in dry tetrahydrofuran (10 ml) was added dropwise. After 1 hour the mixture was allowed to warm to room temperature and was then stirred overnight. The normal work-up followed by column chromatography then gave the title compound.
Reaction SMILES: [C:1]1([CH3:32])[CH:6]=[CH:5][C:4]([S:7]([N:10]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)=[C:11]2[C:22]2[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:24][CH:23]=2)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[Br:33]N1C(=O)CCC1=O>O1CCCC1.O>[C:1]1([CH3:32])[CH:2]=[CH:3][C:4]([S:7]([N:10]2[C:11]([C:22]3[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:29])=[O:30])=[CH:24][CH:23]=3)=[C:12]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[CH:13]=[C:14]2[Br:33])(=[O:8])=[O:9])=[CH:5][CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc(-c3ccc(F)cc3)c2-c2ccc(S(C)(=O)=O)cc2)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2c(Br)cc(-c3ccc(F)cc3)c2-c2ccc(S(C)(=O)=O)cc2)cc1
Reaction time: 5 h
Yield: 87 %

Procedure:
A solution of 1-(4-toluenesulfonyl)-2-(4-methylsulfonylphenyl)-3-(4-fluorophenyl)pyrrole (10.0 g, 0.021 mole) in 100 ml tetrahydrofuran was cooled in an ice bath and treated with N-bromosuccinimide (3.8 g, 0.021 mole) and stirred for five hours. The mixture was diluted with one liter of water and the resulting solid was collected by filtration, washed with water and dried. The crude product was recrystallized from ethyl acetate/hexane to yield 10.0 g (87% yield); m.p. 207°-207.5°.
Reaction SMILES: CCCCC.[H-].[Na+].[F:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[CH:11][CH:10]=1.[Cl:29][CH2:30][CH2:31][CH2:32]Br>CN(C=O)C>[Cl:29][CH2:30][CH2:31][CH2:32][N:26]1[CH2:25][CH2:24][N:23]([CH:15]([C:16]2[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=2)[C:12]2[CH:11]=[CH:10][C:9]([F:8])=[CH:14][CH:13]=2)[CH2:28][CH2:27]1
Reactant: Fc1ccc(C(c2ccc(F)cc2)N2CCNCC2)cc1
Reactant: ClCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCC
Product: Fc1ccc(C(c2ccc(F)cc2)N2CCN(CCCCl)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 63 %

Procedure:
Pentane (50 mL) was added to sodium hydride (0.50 g, 11 mmol of 50% suspension in mineral oil) and the mixture was stirred under nitrogen. The pentane was decanted. Anhydrous DMF (12 mL) was added and the suspension was cooled to 0° C. [Bis(4-fluorophenyl)methylpiperazine (2.9 g, 10 mmol) was added in anhydrous DMF (14 mL) at 0° C. within 10 min. The reaction mixture was allowed to warm to room temperature. After 1 h, the mixture was cooled to 0° C. and 1-chloro-3-bromopropane (5 mL, 50 mmol) in anhydrous DMF (5 mL) was added to the fight green solution over a period of 10 min. The mixture was stirred under nitrogen at room temperature for 72 h. The solvents were evaporated in vacuo (1 mm Hg) at 50° C. The residue was triturated in methylene chloride and filtered through Celite. The filtrate was washed with water (2× 100 mL), dried (sodium surfate), filtered, and the filtrate evaporated in vacuo to give crude chloropropyl compound (3.65 g). Pentane (50 mL) was added, and on the next day the pentane insoluble solid was filtered. The filtrate was evaporated in vacuo to give title compound (2.3 g, 75%) as a clear, colorless oil. 100 MHz 1H MR (CDCl3)δ7.32 (m, 4H), 6.95 (m, 4H), 4.2 (s, 1H), 3.57 (m, 2H), 2.2-2.6 (m, 10H), 1.9 (m, 2H). DCI/MS (M+1) 361.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10](OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:24][C@H:25]1[CH2:29][CH2:28][CH2:27][NH:26]1.C([O-])([O-])=O.[K+].[K+].O>C(#N)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([N:26]2[CH2:27][CH2:28][CH2:29][C@@H:25]2[CH3:24])[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@H]1CCCN1
Reactant: Cc1ccc(S(=O)(=O)O[C@H]2CCN(C(=O)OC(C)(C)C)C2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: C[C@H]1CCCN1[C@@H]1CCN(C(=O)OC(C)(C)C)C1
Temperature: 80 °C
Yield: 74.8 %

Procedure:
A suspension of 3-(3S)-(Toluene-4-sulfonyloxy)-pyrrolidine-1-carboxylic acid tert-butyl ester (4.51 g, 13.2 mmol), (S)-(+)-2-methylpyrrolidine (1.35 g, 15.84 mmol), and K2CO3 (4.01 g, 29.04 mmol) in acetonitrile (44 mL) was heated to 80° C. for 20 h and then added additional (S)-(+)-2-Methylpyrrolidine (834 mg, 9.79 mmol), and continued heating for 20 h. Removed from heating and concentrated to provide a residue which was taken up with H2O (100 mL) and extracted with CH2Cl2 (2×100 mL). Dried the organics over K2CO3, filtered and concentrated to provide a crude oil which was purified by flash column chromatography (0 to 5% MeOH/CH2Cl2) to provide 2.51 g (75% yield) of the title compound as a solid.
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([NH2:16])=[N:13][C:12]=1[CH3:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:18](O)(=[O:29])[CH2:19][C:20]1[C:21](=[CH:25][CH:26]=[CH:27][CH:28]=1)[C:22]([OH:24])=[O:23]>>[CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([NH:16][C:18]([CH2:19][C:20]2[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=2[C:22]([OH:24])=[O:23])=[O:29])=[N:13][C:12]=1[CH3:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1nc(N)sc1C(=O)NCc1ccccc1
Reactant: O=C(O)Cc1ccccc1C(=O)O
Product: Cc1nc(NC(=O)Cc2ccccc2C(=O)O)sc1C(=O)NCc1ccccc1
Temperature: 25 °C
Yield: 60 %

Procedure:
2-Amino-4-methylthiazole-5-carboxylic acid benzylamide (0.25 g, 1.00 mmol) and homophthalic acid (0.18 g, 1.00 mmol) were melted together at 170° C. for 2 hours. A colorless solid formed after the melt was cooled to ambient temperature. The solid was washed with ether (50 mL) and then crystallized from ethyl acetate/methanol to afford the title compound in 60% yield; 1H NMR (DMSO-d6, 300 MHz) δ 12.37 (s, 1H), 8.48 (t, J=5.9 Hz, 1H), 7.88 (dd, J=1.4, 7.6 Hz, 1H), 7.50 (dt, J=1.4, 7.6 Hz, 1H), 7.40-7.15 (m, 7H), 4.34 (d, J=5.9 Hz, 2H), 4.14 (s, 2H), 2.45 (s, 3H); MS (ES+) m/z 410.5 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[NH:8][C:7](=[O:13])[C:6]([NH2:14])=[N:5]2.Cl.N[OH:17]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[NH:8][C:7](=[O:13])[C:6](=[N:14][OH:17])[NH:5]2
Reactant: NO
Reactant: Nc1nc2cc(Cl)c(Cl)cc2[nH]c1=O
Agent: Cl
Solvent: CCO
Product: O=c1[nH]c2cc(Cl)c(Cl)cc2[nH]c1=NO
Temperature: 25 °C
Yield: 77.6 %

Procedure:
An adaptation of the method of Harsanyi et al., Liebigs Ann. Chem. 190 (1973), was used. A mixture of 6,7-dichloro-3-aminoquinoxalin-2(1H)-one (50 mg, 0.22 mmol) and hydroxylamine hydrochloride (33 mg, 0.47 mmol; Aldrich Co.) in 2 mL of ethanol was heated to reflux. The resulting brown suspension was stirred under reflux for 12 h. The resulting brown suspension was allowed to cool to 25° C. A brown precipitate appeared. The mixture was vacuum filtered and the brown solid was washed with EtOH (5×2 mL) and dried in vacuum at 60° C. overnight to yield 42 mg (79%) of 6,7-dichloro-3-(hydroxyimino)-1,4-dihydroquinoxalin-2-one: mp dec.>270° C. 1H NMR (300 MHz, DMSO-d6) δ 11.306 (br s, 1H, NH), 11.049 (br s, 1H, NH), 10.148 (br s, 1H, NOH), 7.403 (s, 1H, H-5), 7.018 (s, 1H, H-8). Mass: calcd. for C8H5Cl2N3O2 (M+) M/Z 244.9759, found 244.9769.
Reaction SMILES: [CH2:1]([C:3]1[N:13]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][C:23]([NH:25][S:26]([C:29]3[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=3)(=[O:28])=[O:27])=[O:24])=[CH:16][CH:15]=2)[C:6]2=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)[CH3:2].[C:36](Cl)(=O)CCC>>[CH3:12][C:8]1[N:7]=[C:6]2[N:13]([C:14]3[CH:15]=[CH:16][C:17]([CH2:20][CH2:21][NH:22][C:23]([NH:25][S:26]([C:29]4[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=4)(=[O:28])=[O:27])=[O:24])=[CH:18][CH:19]=3)[C:3]([CH2:1][CH2:2][CH3:36])=[N:4][C:5]2=[C:10]([CH3:11])[CH:9]=1
Reactant: CCCC(=O)Cl
Reactant: CCc1nc2c(C)cc(C)nc2n1-c1ccc(CCNC(=O)NS(=O)(=O)c2ccc(C)cc2)cc1
Product: CCCc1nc2c(C)cc(C)nc2n1-c1ccc(CCNC(=O)NS(=O)(=O)c2ccc(C)cc2)cc1

Procedure:
The title compound was prepared according to the procedure described in step 5 of Example 1 from 2-{4-[(3-amino-4,6-dimethyl-2-pyridinyl)amino]phenyl}ethanol (step 4 of Example 1) and butyryl chloride.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1F)[N:8]1[CH:13]([CH3:15])[S:14][C:7]1=[C:6]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:5]2=[O:21].[NH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)[N:8]1[CH:13]([CH3:15])[S:14][C:7]1=[C:6]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:5]2=[O:21]
Reactant: CCOC(=O)c1c2n(c3cc(F)c(F)cc3c1=O)C(C)S2
Reactant: C1CNCCN1
Solvent: CN(C)C=O
Product: CCOC(=O)c1c2n(c3cc(N4CCNCC4)c(F)cc3c1=O)C(C)S2
Yield: 49.5 %

Procedure:
Ethyl 6,7-difluoro-1-methyl-4-oxo-4H-(1,3)thiazeto(3,2-a)quinoline-3-carboxylate (5.0 g) was suspended in 150 ml of N,N-dimethylformamide and the suspension was stirred with 4.6 g of piperazine at room temperature for 48 hours. N,N-Dimethylformamide was evaporated in vacuo and to the residue was added ice water to collect the crystals by filtration. Purification by a column chromatography (silica gel/chloroform-methanol (1:1)) gave 3.0 g of desired compound, m.p. 224° C. (decompn.).
Reaction SMILES: IC.[CH2:3]([C:5]1[CH:14]=[C:13]2[C:8]([C:9]([OH:20])=[C:10]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:11]=[N:12]2)=[CH:7][CH:6]=1)[CH3:4].[C:21](=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:3]([C:5]1[CH:14]=[C:13]2[C:8]([C:9](=[O:20])[C:10]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:11][N:12]2[CH3:21])=[CH:7][CH:6]=1)[CH3:4]
Reactant: CCOC(=O)c1cnc2cc(CC)ccc2c1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: CCOC(=O)c1cn(C)c2cc(CC)ccc2c1=O
Reaction time: 30 h

Procedure:
Iodomethane (7.7 g) was added dropwise to a stirred mixture of ethyl 7-ethyl-4-hydroxyquinoline-3-carboxylate (12.1 g), anhydrous potassium carbonate (6.8 g) and dimethylformamide (125 ml) at ambient temperature. Stirring was continued for 30 hours. The solution was cooled in ice, diluted with 2 volumes of water and extracted with dichloromethane (3×100 ml). The extracts were combined, washed with water, dried over anhydrous sodium sulphate and evaporated. The residual oil was triturated with cold ethyl acetate. The resulting solid was collected, washed with ethyl acetate and recrystallised from ethyl acetate to give the novel compound ethyl 7-ethyl-1-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylate, m.p. 92°-94°.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)=[CH:6][CH:7]=1.CCO.[CH3:19][C:20]1[CH:25]=[C:24]([CH3:26])[CH:23]=[CH:22][C:21]=1B(O)O.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.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.O>[CH3:19][C:20]1[CH:25]=[C:24]([CH3:26])[CH:23]=[CH:22][C:21]=1[C:2]1[N:3]=[N:4][C:5]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)=[CH:6][CH:7]=1
Reactant: Clc1ccc(OCc2ccccn2)nn1
Reactant: Cc1ccc(B(O)O)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: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccc(-c2ccc(OCc3ccccn3)nn2)c(C)c1
Yield: 58 %

Procedure:
3-Chloro-6-(pyridin-2-ylmethoxy)pyridazine (Example 15a) (221 mg, 1 mmol) was dissolved in toluene (10 mL), EtOH (2 mL), and water (1.5 mL). Then 2,4-dimethylphenylboronic acid (150 mg, 1 mmol) was added, followed by K2CO3 (276 mg, 2 mmol) and the mixture was degassed using argon stream. Tetrakis(triphenylphosphine)palladium (232 mg, 0.2 mmol) was added under argon and the mixture was refluxed overnight. The solvents were removed under vacuum and a residual solid was extracted with EtOAc, and successively washed with water and brine dried over MgSO4 filtered and evaporated. The crude material was purified on silica gel (Eluent: 50% EtOAc in hexanes) to give 3-(2,4-Dimethylphenyl)-6-(pyridin-2-ylmethoxy)pyridazine (169 mg, 58%) as a white solid. 1H NMR (300 MHz, dMSO): δ 2.26 (s, 3H), 2.32 (s, 3H), 5.62 (s, 2H), 7.13-7.15 (m, 2H), 7.28-7.40 (m, 2H), 7.55-7.56 (d, 1H), 7.78-7.84 (m, 2H), 8.58-8.60 (d, 1H); MS (M+H, 292).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([CH:35]=[C:36]([NH:38][C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH:37]=1)[CH2:12][NH:13][CH2:14][CH2:15][N:16]1[CH:25]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)[CH2:24][C:23]2[C:18](=[CH:19][CH:20]=[C:21]([F:34])[CH:22]=2)[CH2:17]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:53](Cl)([O:55][CH2:56][C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1)=[O:54].C(=O)(O)[O-].[Na+]>ClCCl.C(Cl)(Cl)Cl>[CH2:56]([O:55][C:53]([N:13]([CH2:12][C:11]1[CH:35]=[C:36]([NH:38][C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH:37]=[C:9]([NH:8][C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])[CH:10]=1)[CH2:14][CH2:15][N:16]1[CH:25]([CH2:26][C:27]2[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=2)[CH2:24][C:23]2[C:18](=[CH:19][CH:20]=[C:21]([F:34])[CH:22]=2)[CH2:17]1)=[O:54])[C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(CNCCN2Cc3ccc(F)cc3CC2Cc2ccc(F)cc2)cc(NC(=O)OC(C)(C)C)c1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1cc(CN(CCN2Cc3ccc(F)cc3CC2Cc2ccc(F)cc2)C(=O)OCc2ccccc2)cc(NC(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
31.5 mg of N-[3,5-bis(tert-butyloxycarbonyl)aminobenzyl]-2-[6-fluoro-3-(4-fluorobenzyl)-3,4-dihydroisoquinolin-2(1H)-yl]ethanamine was taken into a 20-mL eggplant flask and dissolved in 1.5 mL of dichloromethane, and 0.01 mL of triethylamine and 0.01 mL of Cbz-chloride were sequentially added thereto under ice-cooling, followed by stirring for 1 hour at room temperature. After completion of the reaction, to the reaction liquid were added a saturated aqueous sodium bicarbonate solution and chloroform under ice-cooling. The organic layer was separated, the aqueous layer was further extracted by addition of chloroform, and the organic layer was combined and washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the solvent was removed by evaporation to obtain 120.0 mg of a crude composition. The crude composition was purified by PLC to obtain 35.8 mg (yield 93%) of a title compound as a pale yellow oily substance.
Reaction SMILES: [CH3:1][O:2][C:3]([CH3:31])([CH3:30])[C@H:4]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[N:5](CC1C=CC(OC)=CC=1)CC1C=CC(OC)=CC=1>CO.[Pd]>[CH3:1][O:2][C:3]([CH3:31])([CH3:30])[C@H:4]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[NH2:5]
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)[C@@H](c2ccccc2)C(C)(C)OC)cc1
Agent: [Pd]
Solvent: CO
Product: COC(C)(C)[C@@H](N)c1ccccc1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A solution of (S)-2-methoxy-N,N-bis(4-methoxybenzyl)-2-methyl-1-phenylpropan-1-amine 5 (0.7 g, 1.67 mmol) in anhydrous MeOH was added Pd on C (0.1 g) and the contents were stirred at ambient temperature in H2 atmosphere. After 14 h, the reaction mixture was filtered through a pad of celite and the volatiles were removed under reduced pressure. The residue thus obtained was further purified by preparative HPLC to afford (S)-2-methoxy-2-methyl-1-phenylpropan-1-amine H1NMR (CDCl3, 400 MHz) δ 7.45-7.44 (m, 2H), 7.35-7.33 (m, 3H), 4.1 (s, 1H), 3.32 (s, 3H), 1.2 (s, 3H), 1.12 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[N:7]([CH2:9][CH2:10][NH:11][C:12]1[CH:13]=[CH:14][C:15]2[N:16]([C:18](Br)=[CH:19][N:20]=2)[N:17]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[C:23]([C:26]1[S:30][C:29](B(O)O)=[CH:28][CH:27]=1)(=[O:25])[CH3:24].O.[O-]P([O-])([O-])=O.[K+].[K+].[K+].ClCCl.N#N>COCCOC.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].O>[C:1]([O:5][C:6](=[O:22])[N:7]([CH2:9][CH2:10][NH:11][C:12]1[CH:13]=[CH:14][C:15]2[N:16]([C:18]([C:29]3[S:30][C:26]([C:23](=[O:25])[CH3:24])=[CH:27][CH:28]=3)=[CH:19][N:20]=2)[N:17]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(=O)c1ccc(B(O)O)s1
Reactant: CN(CCNc1ccc2ncc(Br)n2n1)C(=O)OC(C)(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: N#N
Solvent: ClCCl
Solvent: COCCOC
Solvent: O
Product: CC(=O)c1ccc(-c2cnc3ccc(NCCN(C)C(=O)OC(C)(C)C)nn23)s1
Temperature: 85 °C

Procedure:
To a mixture of [2-(3-bromo-imidazo[1,2-b]pyridazin-6-ylamino)-ethyl]-methyl-carbamic acid tert-butyl ester (285.5 mg, 0.8 mmol), (5-acetylthiophen-2-yl)boronic acid [206551-43-1] (157.3 mg, 0.9 mmol), potassium phosphate tribasic monohydrate [27176-10-9] (354.8 mg, 1.5 mmol), and [1,1′bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane [95464-05-4] (63.4 mg, 0.1 mmol) contained in a 25 mL round bottomed flask was added a solution of 30% (v/v) water in 1,2-dimethoxyethane (12.5 mL) and a magnetic stir bar. The reaction pot was fitted to a reflux condenser, lowered into an ambient temperature oil bath, and the system taken through 10 evacuation/N2 blanket cycles while being rapidly stirred. The rapidly stirred, N2 blanketed, reaction was heated to an oil bath temperature of 85° C. for 17 h then cooled and partitioned between brine and ethyl acetate. The phase separated extract was dried (MgSO4), evaporated, flash chromatographed (silica gel eluted with 100% ethyl acetate) and crystallized (ethyl acetate/heptane) to provide {2-[3-(5-acetyl-thiophen-2-yl)-imidazo[1,2-b]pyridazin-6-ylamino]-ethyl}-methyl-carbamic acid tert-butyl ester as 121.3 mg of yellow powder, mp. 174-175° C. 1H NMR (400 MHz, DMSO-d6) δ ppm (rotamers present) 1.11 (br. s., 6H) 1.39 (br. s., 3H) 2.54 (s, 3H) 2.87 (br. s., 2H) 2.92 (br. s., 1H) 3.32 (s, 1H) 3.52 (br. s., 3H) 3.62 (br. s., 1H) 7.78-7.85 (m, 2H) 7.96 (d, J=4.29 Hz, 1H) 8.14 (s, 1H). 13C NMR (100 MHz, DMSO-d6) δ ppm 26.95, 28.16, 28.50, 34.07, 46.09, 78.50, 113.14, 123.02, 124.18, 126.13, 130.89, 134.37, 137.71, 138.38, 141.77, 154.32, 155.43, 191.11. LRMS (ESI) m/z 416.2 [(M+H)]+, calc'd for C14H20BrN6O2: 415.52.
Reaction SMILES: [C:1]([O:5][CH2:6][CH:7]=[CH:8][CH2:9][O:10][C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:4])([CH3:3])[CH3:2].[O:15]1CCC[CH2:16]1>>[CH:16]([CH:8]([CH2:7][CH2:6][O:5][C:1]([CH3:3])([CH3:4])[CH3:2])[CH2:9][O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:15]
Reactant: C1CCOC1
Reactant: CC(C)(C)OCC=CCOC(C)(C)C
Product: CC(C)(C)OCCC(C=O)COC(C)(C)C
Reaction time: 24 h

Procedure:
2,500 g of 1,4-bis-tert.-butoxybut-2-ene were hydroformylated in a conventional manner by means of an equimolar mixture of CO and H2 and 50 mg of the Rh catalyst mentioned in Example 1, in the presence of 2,000 g of tetrahydrofuran, at 100° C. and 650 bar for 24 hours.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:23])[CH:5]=[CH:6][CH:7]=1.Br[CH2:31][CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][O:33]1>>[C:24]1([C:22]([C:9]2[CH:10]=[N:11][C:12]3[C:17]([C:8]=2[C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([O:1][CH2:31][CH:32]4[CH2:37][CH2:36][CH2:35][CH2:34][O:33]4)[CH:3]=2)=[CH:16][CH:15]=[CH:14][C:13]=3[C:18]([F:21])([F:19])[F:20])=[O:23])[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: O=C(c1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1-c1cccc(O)c1
Reactant: BrCC1CCCCO1
Product: O=C(c1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1-c1cccc(OCC2CCCCO2)c1

Procedure:
The title compound was prepared from [4-(3-hydroxyphenyl)-8-(trifluoromethyl)quinolin-3-yl](phenyl)methanone and 2-Bromomethyl-tetrahydropyran following the procedure of Example 478: MS (ESI) m/z 492.