Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[N:12]=[CH:11][NH:10][N:9]=1.Br[CH:14]([CH2:24][CH2:25]Cl)[C:15]([C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1)=[O:16]>CC(C)=O>[Cl:23][C:20]1[CH:21]=[CH:22][C:17]([C:15]([C:14]2([N:10]3[CH:11]=[N:12][C:8]([Cl:7])=[N:9]3)[CH2:25][CH2:24]2)=[O:16])=[CH:18][CH:19]=1
Reactant: O=C(c1ccc(Cl)cc1)C(Br)CCCl
Reactant: Clc1nc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(c1ccc(Cl)cc1)C1(n2cnc(Cl)n2)CC1
Yield: 90 %

Procedure:
A mixture of 34 g (246 mmol) of potassium carbonate and 35 g (338 mmol) of 3-chloro-1,2,4-triazole in 130 ml of acetone is refluxed. To this mixture there is added dropwise a solution of 50 g (169 mmol) of 2-bromo-4-chloro-1-(4-chlorophenyl)-butan-1-one in 60 ml of acetone. The mixture is boiled under reflux for a further 8 hours, the solid residue is then filtered off with suction, and the solvent is stripped off under reduced pressure. The residue which remains is taken up in ethyl acetate. The solution is washed with water, dried over sodium sulphate and concentrated under reduced pressure. The residue which remains is chromatographed on silica gel using dichloromethane as the eluent. Concentration of the eluate by evaporation gives 42.9 g (90% of theory) of 1-(4-chlorobenzoyl)-1-(3-chloro-1,2,4-triazol-1-yl)-cyclopropane in the form of a solid of melting point 85° C.
Reaction SMILES: CS(O)(=O)=O.C(OC([NH:16][CH2:17][C:18]1[CH:37]=[CH:36][C:21]([C:22]([O:24][C:25]2[CH:30]=[CH:29][C:28]([C:31](=[NH:33])[NH2:32])=[CH:27][C:26]=2[O:34][CH3:35])=[O:23])=[CH:20][CH:19]=1)=O)C1C=CC=CC=1.C1(OC)C=CC=CC=1.Br>C(O)(=O)C>[NH2:16][CH2:17][C:18]1[CH:19]=[CH:20][C:21]([C:22]([O:24][C:25]2[CH:30]=[CH:29][C:28]([C:31](=[NH:32])[NH2:33])=[CH:27][C:26]=2[O:34][CH3:35])=[O:23])=[CH:36][CH:37]=1
Reactant: COc1cc(C(=N)N)ccc1OC(=O)c1ccc(CNC(=O)OCc2ccccc2)cc1
Agent: Br
Agent: CS(=O)(=O)O
Solvent: CC(=O)O
Solvent: COc1ccccc1
Product: COc1cc(C(=N)N)ccc1OC(=O)c1ccc(CN)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 129.7 %

Procedure:
To 1.5 g of 4-amidino-2-methoxyphenyl 4-benzyloxycarbonylaminomethylbenzoate methanesulfonate, was added 15 ml of acetic acid followed by 1 ml of anisole. To the mixture, while being cooled in ice, was added 3.0 ml of an acetic acid solution containing 30% of hydrogen bromide. The mixture was then stirred overnight at room temperature. The insoluble substance precipitated from the reaction mixture was collected by filtration and recrystallized from a methanol-ethyl ether mixture to obtain 1.1 g of colorless crystals of 4-amidino-2-methoxyphenyl 4-aminomethylbenzoate dihydrobromide.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:19]3[C:27]4[C:22](=[N:23][CH:24]=[C:25](B(O)O)[CH:26]=4)[C:21]([CH3:32])([CH3:31])[CH2:20]3)=[C:7]([CH3:18])[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)=[N:9]2)=[CH:4][CH:3]=1.Cl[C:34]1[N:42]=[CH:41][N:40]=[C:39]2[C:35]=1[NH:36][CH:37]=[N:38]2.C(=O)([O-])[O-].[Na+].[Na+]>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>[CH3:32][C:21]1([CH3:31])[C:22]2=[N:23][CH:24]=[C:25]([C:34]3[N:42]=[CH:41][N:40]=[C:39]4[C:35]=3[N:36]=[CH:37][NH:38]4)[CH:26]=[C:27]2[N:19]([C:6]2[C:5]3[C:10](=[CH:11][C:2]([F:1])=[CH:3][CH:4]=3)[N:9]=[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)[C:7]=2[CH3:18])[CH2:20]1
Reactant: Clc1ncnc2nc[nH]c12
Reactant: Cc1c(-c2ccccn2)nc2cc(F)ccc2c1N1CC(C)(C)c2ncc(B(O)O)cc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Cc1c(-c2ccccn2)nc2cc(F)ccc2c1N1CC(C)(C)c2ncc(-c3ncnc4[nH]cnc34)cc21
Temperature: 120 °C

Procedure:
Prepared according to procedure P using 1-(7-fluoro-3-methyl-2-(pyridin-2-yl)-quinolin-4-yl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-ylboronic acid (25 mg, 0.058 mmol), 6-chloropurine (9 mg, 0.058 mmol), PdCl2(PPh3)2 (4.1 mg, 0.0058 mmol), sodium carbonate (12.3 mg, 0.117 mmol) and heating in the microwave for 1 h at 120° C. After purification 4-(3,3-dimethyl-6-(9H-purin-6-yl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-7-fluoro-3-methyl-2-(2-pyridinyl)quinoline was obtained as a yellow film. 1H NMR (400 MHz, MeOH) δ ppm 9.27 (1H, br. s.), 8.83 (1H, s), 8.67-8.73 (1H, m), 8.41 (1H, br. s.), 8.01-8.12 (2H, m), 7.92 (1H, d, J=7.8 Hz), 7.83 (1H, dd, J=10.0, 2.5 Hz), 7.52-7.60 (2H, m), 7.48 (1H, ddd, J=9.3, 8.3, 2.5 Hz), 4.06-4.12 (1H, m), 3.95-4.03 (1H, m), 2.33 (3H, s), 1.70 (3H, s), 1.62 (3H, s). Mass Spectrum (ESI) m/e=503 (M+1).
Reaction SMILES: [CH2:1]([CH:4]1[CH2:8][CH2:7][CH2:6][CH2:5]1)[C:2]#[CH:3].[Li]CCCC.C1(O[C:21]#[N:22])C=CC=CC=1>CCOCC>[CH:4]1([CH2:1][C:2]#[C:3][C:21]#[N:22])[CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: N#COc1ccccc1
Reactant: C#CCC1CCCC1
Agent: [Li]CCCC
Solvent: CCOCC
Product: N#CC#CCC1CCCC1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 47 %

Procedure:
Prop-2-ynyl-cyclopentane (46.2 mmol) was dissolved in 100 mL of anhydrous Et2O under N2 and the reaction was cooled to −78° C. A 2.5 M solution of BuLi in hexanes (55.5 mmol) was added dropwise to the reaction over 30 minutes. The reaction was stirred for an additional 20 minutes and phenyl cyanate (55.5 mmol) was then added in solution with 20 mL of Et2O dropwise over 20 minutes. The resultant solution was allowed to slowly warm to rt and stir for 3 hours. The reaction material was then diluted in 200 mL of fresh Et2O and washed with three 100 mL portions of 1 N aqueous NaOH solution. The organics were then washed with 200 mL of brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified through flash chromatography on silica gel to give 4-cyclopentyl-but-2-ynenitrile (21.7 mmol).
Reaction SMILES: C1(=O)[N:5]([C:6]#[C:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)C(=O)C2=CC=CC=C12.[H][H].O.NN>CO.[Pt]=O>[Cl:18][C:14]1[CH:13]=[C:12]([CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][NH2:5])[CH:17]=[CH:16][CH:15]=1
Reactant: O=C1c2ccccc2C(=O)N1C#CCCCCc1cccc(Cl)c1
Reactant: [H][H]
Agent: O=[Pt]
Agent: NN
Solvent: O
Solvent: CO
Product: NCCCCCCc1cccc(Cl)c1
Reaction time: 72 h

Procedure:
A suspension of 1-(phthalimido)-6-(3-chlorophenyl)hex-1-yne (10 g, 30 mmol) in methanol (100 ml) was treated with platinum oxide (250 mg) and the mixture hydrogenated at 50 psi for 72 h. Further quantities of catalyst were added at intervals and when the theoretical uptake of hydrogen was complete, the mixture was filtered and the filtrate evaporated to a brown oil (9.5 g, 96%). This was dissolved in ethanol (100 ml) and treated with hydrazine hydrate (2.8 g, 56 mmol) under reflux for 16 h. The mixture was cooled to 5°
Reaction SMILES: [Br:1][C:2]1[C:3]([NH2:9])=[N:4][CH:5]=[C:6]([Br:8])[N:7]=1.[Cl:10][C:11]1[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:12]=1[S:18](Cl)(=[O:20])=[O:19]>>[Cl:10][C:11]1[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:12]=1[S:18]([NH:9][C:3]1[C:2]([Br:1])=[N:7][C:6]([Br:8])=[CH:5][N:4]=1)(=[O:20])=[O:19]
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1Cl
Reactant: Nc1ncc(Br)nc1Br
Product: O=S(=O)(Nc1ncc(Br)nc1Br)c1cccc(Cl)c1Cl

Procedure:
Prepared by the method of Example 1 (reaction performed at room temperature) using 3,5-dibromo-2-pyrazinamine (2.9 g) and 2,3-dichloro benzenesulphonyl chloride (2.8 g). Yield 4.4 g.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([CH:19]=2)=[C:17]([O:20][CH3:21])[CH:16]=[CH:15][CH:14]=3)=[O:9])=[CH:4][CH:3]=1.C1C=C(Cl)C=C(C(OO)=[O:30])C=1.[OH-].[Na+]>C(Cl)Cl>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([CH:19]=2)=[C:17]([O:20][CH3:21])[CH:16]=[CH:15][CH:14]=3)(=[O:30])=[O:9])=[CH:4][CH:3]=1
Reactant: COc1cccc2ncc(S(=O)c3ccc(C)cc3)cc12
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: COc1cccc2ncc(S(=O)(=O)c3ccc(C)cc3)cc12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of (+/−)-3-(4-methylphenylsulfinyl)-5-methoxyquinoline (2.97 g, 10 mmol) prepared in stage B of example 10 in CH2Cl2 is added m-CPBA (2.13 g, 80%, 10 mmol). The solution is stirred at room temperature for 12 hours. A solution of 1M NaOH is added. After extraction of the aqueous phase with CH2Cl2, the combined organic layers are dried (MgSO4) and the solvent evaporated giving the title compound.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:14]([NH2:15])=[CH:13][NH:12][N:11]=1.[C:16]([N:20]=[C:21]=[O:22])([CH3:19])([CH3:18])[CH3:17]>CN(C=O)C>[NH:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:1]=[C:2]1[C:10]1[C:14]([NH:15][C:21]([NH:20][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:22])=[CH:13][NH:12][N:11]=1
Reactant: CC(C)(C)N=C=O
Reactant: Nc1c[nH]nc1-c1nc2ccccc2[nH]1
Solvent: CN(C)C=O
Product: CC(C)(C)NC(=O)Nc1c[nH]nc1-c1nc2ccccc2[nH]1
Yield: 34.9 %

Procedure:
A mixture or 3-(1H-Benzimidazol-2-yl)-1H-pyrazol-4-ylamine (100 mg, 0.50 mmol), tert-butyl isocyanate (60 ul, 0.60 mmol) in DMF (5 ml) was stirred at ambient temperature for 4 h. The mixture was reduced in vacuo. The residue was purified by preparative LC/MS, and following evaporation, gave 52 mg of the title compound as a white solid (35%). (LC/MS: Rt 2.61, [M+H]+ 299.15).
Reaction SMILES: C([O:4][C:5]1[CH:14]=[CH:13][C:12]([CH3:15])=[C:11]2[C:6]=1[CH:7]=[C:8]([CH:17]([CH3:19])[CH3:18])[C:9](=[O:16])[NH:10]2)C=C.CN(C)[C:22]1[CH:27]=CC=C[CH:23]=1>>[CH2:27]([C:14]1[C:5]([OH:4])=[C:6]2[C:11](=[C:12]([CH3:15])[CH:13]=1)[NH:10][C:9](=[O:16])[C:8]([CH:17]([CH3:18])[CH3:19])=[CH:7]2)[CH:22]=[CH2:23]
Reactant: CN(C)c1ccccc1
Reactant: C=CCOc1ccc(C)c2[nH]c(=O)c(C(C)C)cc12
Product: C=CCc1cc(C)c2[nH]c(=O)c(C(C)C)cc2c1O
Temperature: 202 °C
Reaction time: 1.5 h
Yield: 81.1 %

Procedure:
5-Allyloxy-3-isopropyl-8-methylcarbostyril (1.85 g, 7.20 mmol) was suspended in N,N-dimethylaniline (20 ml). The suspension was heated and dissolved while stirring at 202° C. for 90 minutes. The reaction system was heated under reduced pressure until condensed. The resultant residue was recrystallized from methanol-ether-hexane to obtain 1.50 g of the title compound as pale yellow powdery crystals (81.1%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].C([O:27][C:28](=O)[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][N:35]=[C:34]([C:38]#[N:39])[CH:33]=1)=[O:31])(C)(C)C>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])=[CH:10][C:9]=1[NH:21][C:28](=[O:27])[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][N:35]=[C:34]([C:38]#[N:39])[CH:33]=1)=[O:31])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CC(=O)c1ccnc(C#N)c1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2F)cc1N
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2F)cc1NC(=O)CC(=O)c1ccnc(C#N)c1

Procedure:
Prepared from (3-amino-2′-fluoro-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example G37) and 3-(2-cyano-pyridin-4-yl)-3-oxo-propionic acid tert.-butyl ester (Example H10) according to the general procedure K. Obtained as a white solid (151 mg).
Reaction SMILES: [CH2:1]([C@:3]12[C:16]3[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=3)[CH2:10][CH2:9][C@@H:8]1[CH2:7][C@:6]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1)([OH:18])[C@:5]([CH3:26])([OH:25])[CH2:4]2)[CH3:2].I[CH2:28][C:29]([NH2:31])=[O:30]>>[CH2:1]([C@@:3]12[CH2:4][C@:5]([OH:25])([CH3:26])[C@:6]([OH:18])([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)[CH2:7][C@H:8]1[CH2:9][CH2:10][C:11]1[CH:12]=[C:13]([O:17][CH2:28][C:29]([NH2:31])=[O:30])[CH:14]=[CH:15][C:16]2=1)[CH3:2]
Reactant: CC[C@@]12C[C@@](C)(O)[C@](O)(c3ccccn3)C[C@H]1CCc1cc(O)ccc12
Reactant: NC(=O)CI
Product: CC[C@@]12C[C@@](C)(O)[C@](O)(c3ccccn3)C[C@H]1CCc1cc(OCC(N)=O)ccc12

Procedure:
The title compound was prepared from the compound of Example 102 according to the procedure of Example 57, running the reaction at room temperature overnight and using iodoacetamide as the alkylating agent. Mass spectrum (m/e) 411 (M++1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]12[CH2:17][O:16][C@H:15]([CH2:18][O:19]C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[C@H:14]1[CH2:13][S:12][C:11]([NH:39][C:40](=[O:47])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)=[N:10]2.O.C(=O)([O-])[O-].[K+].[K+]>C(O)=O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]12[CH2:17][O:16][C@H:15]([CH2:18][OH:19])[C@H:14]1[CH2:13][S:12][C:11]([NH:39][C:40](=[O:47])[C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1)=[N:10]2
Reactant: O=C(NC1=N[C@@]2(c3ccc(F)cc3F)CO[C@H](COC(c3ccccc3)(c3ccccc3)c3ccccc3)[C@H]2CS1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: O=CO
Product: O=C(NC1=N[C@@]2(c3ccc(F)cc3F)CO[C@H](CO)[C@H]2CS1)c1ccccc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 89.4 %

Procedure:
N-((4aS,5S,7aS)-7a-(2,4-Difluorophenyl)-5-((trityloxy)methyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-yl)benzamide (3.99 g, 6.169 mmol) was taken up in formic acid (12 mL) at RT. The mixture was stirred at RT for 2.5 hours, then water (12 mL) was added. The mixture was stirred for 10 minutes and then filtered—washing with formic acid/water (1:1, 20 mL). The filtrate was evaporated and the residue was azeotroped with toluene (×2). The residue was taken up in dry MeOH (20 mL) and treated with potassium carbonate (1.0 g, 7.2 mmol). The mixture was stirred at RT for 30 minutes. The volatiles were removed in vacuo and the residue was partitioned between DCM and water. The layers were separated and the aqueous layer was further extracted with DCM (×4). The combined extracts were dried (Na2SO4), filtered and evaporated. The residue was purified by column chromatography (normal phase, 50 g, Biotage SNAP cartridge KP-Sil, 50 mL per min, gradient 40% to 90% EtOAc in n-hexane) to give the title compound (2.23 g). 1H NMR (400 MHz, MeOH-d4) δ ppm: 2.85-3.05 (m, 1 H) 3.10-3.27 (m, 2 H) 3.68-3.80 (m, 2 H) 4.02 (br. d, J=7.90 Hz, 1 H) 4.36-4.43 (m, 1 H) 4.47 (d, J=9.16 Hz, 1 H) 6.95-7.13 (m, 2 H) 7.39-7.50 (m, 2 H) 7.50-7.60 (m, 2 H) 7.96-8.16 (m, 2 H)
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]1[N:7]=[C:8]([NH:11][C:12](=[O:28])[CH:13]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=2)[CH2:14][CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[S:9][CH:10]=1)C.[BH4-].[Na+]>O1CCCC1>[CH:15]1([CH2:14][CH:13]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=2)[C:12]([NH:11][C:8]2[S:9][CH:10]=[C:6]([CH2:5][CH2:4][OH:3])[N:7]=2)=[O:28])[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: CCOC(=O)Cc1csc(NC(=O)C(CC2CCCC2)c2ccc(Cl)c(Cl)c2)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(Nc1nc(CCO)cs1)C(CC1CCCC1)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 10 h
Yield: 58.8 %

Procedure:
A solution of {2-[3-cyclopentyl-2-(3,4-dichlorophenyl)-propionylamino]-thiazol-4-yl}-acetic acid ethyl ester (prepared in Example 1 (B)(c), 129 mg, 0.28 mmol) in tetrahydrofuran (1.4 mL) at 25° C. was slowly treated with sodium borohydride (22.5 mg, 0.59 mmol). The resulting reaction mixture was stirred at 25° C. for 10 h. After 10 h at 25° C., a substantial amount of starting material still remained. An additional amount of sodium borohydride powder (21.4 mg, 0.57 mmol) was added to the reaction mixture, and the reaction mixture was heated under reflux for 14 h. The reaction mixture was allowed to cool to 25° C., and then slowly quenched by the dropwise addition of water. The resulting reaction mixture was concentrated in vacuo to remove tetrahydrofuran. The resulting residue was diluted with ethyl acetate (100 mL) and washed with a saturated aqueous sodium chloride solution (1×50 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 3/1 then 1/1 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(3,4-dichlorophenyl)-N-[4-(2-hydroxyethyl)-thiazol-2-yl]-propionamide (68.1 mg, 58%) as a white foam: mp 85-86° C.; FAB-HRMS m/e calcd for C19H22Cl2N2O2S (M+H)+ 413.0858, found 413.0838.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][CH2:5][O:6][C:7]1[C:15]2[CH:14]=[C:13]([C:16]3[O:20][C:19](=[O:21])[NH:18][N:17]=3)[O:12][C:11]=2[CH:10]=[CH:9][CH:8]=1.[CH3:22]I>CN(C=O)C>[CH3:3][O:4][CH2:5][O:6][C:7]1[C:15]2[CH:14]=[C:13]([C:16]3[O:20][C:19]([O:21][CH3:22])=[N:18][N:17]=3)[O:12][C:11]=2[CH:10]=[CH:9][CH:8]=1
Reactant: COCOc1cccc2oc(-c3n[nH]c(=O)o3)cc12
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCOc1cccc2oc(-c3nnc(OC)o3)cc12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a suspension of sodium hydride (0.17 g) in DMF was added dropwise a solution (20 ml) of 5-(4-(methoxymethyloxy)-benzo(b)furan-2-yl)-2,3-dihydro-1,3,4-oxadiazol-2-one (1.0 g) obtained in Starting Material Synthesis Example 116 in DMF at room temperature, and the mixture was stirred for 30 min. Thereto was added methyl iodide (0.26 ml), and the mixture was further stirred for 30 min. The reaction mixture was poured into ice water and extracted with ethyl acetate. The extract was washed with water and dried. The solvent was evaporated under reduced pressure to give the title compound (0.80 g) as pale-yellow crystals.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([O:11][CH3:12])[CH:3]=1.[C:13]([O:17][C:18]([N:20]1[CH2:25][CH:24]=[C:23](B2OC(C)(C)C(C)(C)O2)[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].C(=O)(O)[O-].[K+].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.O1CCOCC1>[C:13]([O:17][C:18]([N:20]1[CH2:21][CH:22]=[C:23]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([O:11][CH3:12])[CH:3]=2)[CH2:24][CH2:25]1)=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: COc1cc(Cl)ccc1[N+](=O)[O-]
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: O
Solvent: C1COCCO1
Product: COc1cc(C2=CCN(C(=O)OC(C)(C)C)CC2)ccc1[N+](=O)[O-]
Temperature: 80 °C
Yield: 90 %

Procedure:
4-Chloro-2-methoxy-1-nitro-benzene (1.12 g, 5.96 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (1.84 g, 5.95 mmol), tetrakis(triphenylphosphine)palladium(0) (380 mg, 0.33 mmol), a 2 M solution of potassium bicarbonate in water (7.45 mL, 14.9 mmol), and 1,4-dioxane (18 mL) were combined in a sealed tube, and the mixture was stirred and heated at 80° C. overnight. HPLC indicated the complete conversion of the starting material. The product, 4-(3-methoxy-4-nitro-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester was isolated by flash chromatography (Silicagel, EtOAc/Hexanes 25-50%) in 90% yield.
Reaction SMILES: N(OC(C)(C)C)=O.N[C:9]1[CH:14]=[C:13]([F:15])[C:12]([C:16]2[C:21]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)=[C:20]([CH3:29])[N:19]=[N:18][C:17]=2[Cl:30])=[C:11]([F:31])[CH:10]=1.[ClH:32]>[Cu](Cl)Cl.C(#N)C>[Cl:30][C:17]1[N:18]=[N:19][C:20]([CH3:29])=[C:21]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)[C:16]=1[C:12]1[C:11]([F:31])=[CH:10][C:9]([Cl:32])=[CH:14][C:13]=1[F:15]
Reactant: Cl
Reactant: Cc1nnc(Cl)c(-c2c(F)cc(N)cc2F)c1-c1ccc(Cl)cc1
Agent: Cl[Cu]Cl
Agent: CC(C)(C)ON=O
Solvent: CC#N
Product: Cc1nnc(Cl)c(-c2c(F)cc(Cl)cc2F)c1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 323 mg of copper (II) chloride (CuCl2), 309 mg of tert-butyl nitrite and 13 ml of acetonitrile was added 732 mg of 4-(4-amino-2,6-difluorophenyl)-3-chloro-5-(4-chlorophenyl)-6-methylpyridazine portion-wise under ice-cooling. Thereafter, the reaction mixture was stirred at room temperature for 2 hours. Then, the reaction mixture was poured into a mixture of ice and dilute hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed sequentially with sodium bicarbonate water and saturated brine, and dried over anhydrous magnesium sulfate then concentrated. The residue was subjected to silica gel column chromatography (elution solvent; hexane:ethyl acetate=7:1), to obtain 0.62 g of 3-chloro-4-(4-chloro-2,6-difluorophenyl)-5-(4-chlorophenyl)-6-methylpyridazine (hereinafter, referred to as compound (xi) of the present invention).
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH:11]=[CH:12][NH:13]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:18]1([CH2:24][O:25][C:26]2[CH:31]=[C:30]([F:32])[C:29](Br)=[CH:28][C:27]=2[F:34])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].N1CCC[C@H]1C(O)=O>CN(C=O)C>[F:32][C:30]1[CH:31]=[C:26]([O:25][CH2:24][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:27]([F:34])=[CH:28][C:29]=1[N:13]1[C:14]2[C:10](=[C:9]([O:8][CH2:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH:17]=[CH:16][CH:15]=2)[CH:11]=[CH:12]1
Reactant: Fc1cc(OCc2ccccc2)c(F)cc1Br
Reactant: c1ccc(COc2cccc3[nH]ccc23)cc1
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Fc1cc(-n2ccc3c(OCc4ccccc4)cccc32)c(F)cc1OCc1ccccc1
Temperature: 140 °C

Procedure:
In two microwave vials were placed 4-[(phenylmethyl)oxy]-1H-indole (500 mg, 2.24 mmoL), 4-bromo-2,5-difluorophenyl phenylmethyl ether (prepared as described in part a), 559 mg, 1.87 mmoL), K3PO4 (990 mg, 4.67 mmoL), L-Proline (43 mg, 0.373 mmoL) and DMF (5 mL) and the mixture was degassed by sonication under a flow of argon. To each vial was added CuI (71 mg, 0.373 mmoL) and the solutions were heated to 140° C. in the microwave reactor. After 4 hours a second portion of L-Proline (43 mg, 0.373 mmoL) was added and heated for an additional hour. The two mixtures were partitioned between ethyl acetate (100 mL)/water (100 mL), the phases were separated and the aqueous phase re-extracted with ethyl acetate (100 mL). The combined organic phases were washed with sat. NH4Cl (2×100 mL), water (100 mL) and brine (2×100 mL) and finally dried over MgSO4. The combined crude materials were purified by flash chromatography (Biotage SP4, 40+M Cartridge) eluting with a gradient of 0 to 30% Et2O in hexane to give the title compound (D22), (258 mg).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[C:9](\Cl)/[C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH3:17])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[OH-].[K+]>O1CCOCC1.CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]#[C:9][C:10]2[CH:11]=[CH:12][C:13]([CH2:16][CH3:17])=[CH:14][CH:15]=2)=[CH:6][CH:7]=1
Reactant: CCc1ccc(/C(Cl)=C/c2ccc(Br)cc2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Product: CCc1ccc(C#Cc2ccc(Br)cc2)cc1
Yield: 99.2 %

Procedure:
To a 100 mL flask containing a solution of 1-bromo-4-[(Z)-2-chloro-2-(4-ethylphenyl) vinyl] benzene (VIc) (9.540 g; 29.66 mmol) in 1,4-dioxane (48 mL; 5 vols) and MeOH (14 mL; 1.5 vols), KOH (3.328 g; 59.32 mmol) was added in one portion. Protocol and work-up was then similar with those described above. Title compound (m=8.39 g) was obtained in a 99% yield. Melting point: 117° C.
Reaction SMILES: C(O[C:4]([C:6]1[N:7]=[N:8][C:9]([O:12][CH2:13][C:14]2[C:15]([C:20]3[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=3)=[N:16][O:17][C:18]=2[CH3:19])=[CH:10][CH:11]=1)=[O:5])C.[CH3:26][NH2:27]>>[CH3:26][NH:27][C:4]([C:6]1[N:7]=[N:8][C:9]([O:12][CH2:13][C:14]2[C:15]([C:20]3[CH:21]=[CH:22][N:23]=[CH:24][CH:25]=3)=[N:16][O:17][C:18]=2[CH3:19])=[CH:10][CH:11]=1)=[O:5]
Reactant: CCOC(=O)c1ccc(OCc2c(-c3ccncc3)noc2C)nn1
Reactant: CN
Product: CNC(=O)c1ccc(OCc2c(-c3ccncc3)noc2C)nn1
Yield: 17 %

Procedure:
As described for example 69, 6-(5-methyl-3-pyridin-4-yl-isoxazol-4-ylmethoxy)-pyridazine-3-carboxylic acid ethyl ester (100 mg, 0.29 mmol) was converted, using methylamine (2 M solution in THF) instead of isopropylamine, to the title compound (16 mg, 17%) which was obtained as a white solid. MS: m/e=326.1 [M+H]−.