Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5]([C:7]1[CH:8]=[C:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:21])[F:20])[CH:10]=[CH:11][CH:12]=1)=O.[NH:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1)[NH2:25]>C(O)C.CCOC(C)=O>[F:20][C:19]([F:21])([F:22])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:9]1[CH:10]=[CH:11][CH:12]=[C:7]([C:5]2[CH:4]=[CH:3][N:24]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=3)[N:25]=2)[CH:8]=1
Reactant: NNc1ccccn1
Reactant: CN(C)C=CC(=O)c1cccc(-c2ccccc2C(F)(F)F)c1
Solvent: CCO
Solvent: CCOC(C)=O
Product: FC(F)(F)c1ccccc1-c1cccc(-c2ccn(-c3ccccn3)n2)c1
Yield: 12.9 %

Procedure:
To a solution of the product from Step 1 (0.224 g, 0.7 mmol) in ethanol (3.5 mL) was added 2-hydrazinopyridine (0.076 g, 0.7 mmol) and the solution was refluxed for 16 hours. The reaction was cooled, diluted with EtOAc, washed with saturated sodium bicarbonate, brine and dried over sodium sulfate. The organic phase was filtered, concentrated, and the crude product was purified by reverse phase HPLC (acetonitrile/water system) (gradient: 30% to 100% acetonitrile over 12 minutes) to give product A (0.033 g, 29% yield, retention time 5.28 minutes) and the regioisomeric product B (0.021 g, 18% yield, retention time 7.25 minutes).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[O:17][CH2:16][CH2:15][C:14]([C:18]([NH:20][C:21]4[CH:26]=[CH:25][C:24]([CH2:27][N:28]5[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]5)=[CH:23][CH:22]=4)=[O:19])=[CH:13][C:12]=3[CH:34]=2)=[CH:4][CH:3]=1.[CH3:35][I:36]>CN(C)C=O>[I-:36].[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[O:17][CH2:16][CH2:15][C:14]([C:18]([NH:20][C:21]4[CH:22]=[CH:23][C:24]([CH2:27][N+:28]5([CH3:35])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]5)=[CH:25][CH:26]=4)=[O:19])=[CH:13][C:12]=3[CH:34]=2)=[CH:6][CH:7]=1
Reactant: CI
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN4CCCCC4)cc2)CCO3)cc1
Solvent: CN(C)C=O
Product: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(C[N+]4(C)CCCCC4)cc2)CCO3)cc1
Product: [I-]

Procedure:
A solution of 7-(4-methylphenyl)-N-(4-(piperidinomethyl)phenyl)-2,3-dihydro-1-benzoxepine-4-carboxamide (1.4 g) and methyl iodide (0.58 ml) in dimethylformamide (50 ml) was stirred at room temperature over night. The solvent was evaporated, and to the residue was added ethyl acetate. Precipitated crude crystal was filtered, which were recrystallized from ethanol-ethyl acetate to give 1-(N-(7-(4-methylphenyl)-2,3-dihydro-1-benzoxepin-4-carbonyl) -4-aminobenzyl) -1-methylpiperidinium iodide (Compound 96) (1.6 g) as colorless crystals.
Reaction SMILES: C([C:3]([C:10](=O)[CH3:11])([CH2:7][CH2:8][CH3:9])[C:4]([OH:6])=O)C.[Na].[F:14][C:15]([F:20])([F:19])[C:16]([NH2:18])=[NH:17]>CCO>[CH3:11][C:10]1[N:17]=[C:16]([C:15]([F:20])([F:19])[F:14])[NH:18][C:4](=[O:6])[C:3]=1[CH2:7][CH2:8][CH3:9]
Reactant: N=C(N)C(F)(F)F
Reactant: CCCC(CC)(C(C)=O)C(=O)O
Agent: [Na]
Solvent: CCO
Product: CCCc1c(C)nc(C(F)(F)F)[nH]c1=O
Yield: 34.1 %

Procedure:
Ethyl 2-acetylpentanoic acid (17.2 g, 0.1 mol) in absolute EtOH was treated with 2.3 g, 0.1 mol) sodium until the metal was dissolved. Trifluoroacetamidine (11.5 g, 0.1 mol) was added and the mixture was refluxed for 3 h, then evaporated to dryness. The residue was taken up in H2O, acidified with 2N HCl, and extracted with EtOAc. The organic layer was washed with water (twice), dried, and evaporated to give an oil. Purification by flash chromatography (CH2Cl2, CH2Cl2 -EtOAc 5%) afforded 7.5 g (34%) of the desired compound as crystals.
Reaction SMILES: [CH:1]([CH:4]([CH:7]([CH3:9])[CH3:8])[C:5]#[N:6])([CH3:3])[CH3:2].[Na].[CH:11](I)(C)C.[OH-:15].[Na+].[OH-:17].[K+]>>[CH:1]([C:4]([CH:7]([CH3:9])[CH3:8])([C:5]#[N:6])[C:11]([OH:17])=[O:15])([CH3:3])[CH3:2]
Reactant: CC(C)C(C#N)C(C)C
Reactant: CC(C)I
Reactant: [OH-]
Agent: [K+]
Agent: [Na+]
Agent: [Na]
Product: CC(C)C(C#N)(C(=O)O)C(C)C

Procedure:
Thus, MARSHALL prepares diisopropyl acetonitrile from a cyanacetic ester, by treating with sodium an alcoholic solution of this ester and by causing this mixture to react for several hours with an excess of isopropyl iodide. The monoalkylated product is eliminated by means of a 10% sodium hydroxide solution and the crude dialkyl ester obtained by this procedure is then treated with a 35% potassium hydroxide solution for 16 hours. After acidification, the diisopropyl cyanacetic acid obtained is decarboxylated by distillation in the presence of twice its weight of molten potassium hydroxide.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:24](=[O:26])[CH3:25])[CH:8]=[C:9]([O:13][CH2:14][CH2:15][CH2:16][O:17]C2CCCCO2)[C:10]=1[O:11][CH3:12])([CH3:4])([CH3:3])[CH3:2].[Br-:27].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1>CO.C1COCC1.C(Cl)Cl>[Br:27][CH2:25][C:24]([C:7]1[CH:8]=[C:9]([O:13][CH2:14][CH2:15][CH2:16][OH:17])[C:10]([O:11][CH3:12])=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:6]=1)=[O:26]
Reactant: COc1c(OCCCOC2CCCCO2)cc(C(C)=O)cc1C(C)(C)C
Reactant: [Br-]
Agent: C[N+](C)(C)c1ccccc1
Solvent: C1CCOC1
Solvent: CO
Solvent: ClCCl
Product: COc1c(OCCCO)cc(C(=O)CBr)cc1C(C)(C)C
Reaction time: 1 h
Yield: 45.3 %

Procedure:
1-{3-tert-Butyl-4-methoxy-5-[3-(tetrahydropyran-2-yloxy)propoxy]phenyl}ethanone (O2.071; 12.7 g) was dissolved in methanol/THF (200/200 ml) and admixed with phenyltrimethylammonium tribromide (13.1 g) while stirring. The mixture was stirred at RT for 1 h, then diluted with DCM and washed once with 5% sodium thiosulfate solution. The DCM phase was dried over magnesium sulfate, filtered and concentrated. The residue was taken up in acetonitrile (100 ml) and admixed with 48% hydrobromic acid (5.91 ml). The mixture was left to stand for 1 h, then admixed with water, extracted by shaking with EA, and the combined EA phases were dried over magnesium sulfate, filtered and concentrated. The residue was purified using silica gel (120 g cartridge, n-heptane/MtB ether gradient of 0-100% in 60 min). 3.29 g of the title compound were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([S:19]([NH2:22])(=[O:21])=[O:20])=[C:14]2[N:13]=[CH:12][C:11]=1[C:23]([N:25]1[CH2:30][CH2:29][CH:28]([C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)[CH2:27][CH2:26]1)=[O:24].[C:38](O)(=[O:41])[CH2:39][CH3:40]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([S:19]([NH:22][C:38](=[O:41])[CH2:39][CH3:40])(=[O:21])=[O:20])=[C:14]2[N:13]=[CH:12][C:11]=1[C:23]([N:25]1[CH2:30][CH2:29][CH:28]([C:31]2[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=2)[CH2:27][CH2:26]1)=[O:24]
Reactant: NS(=O)(=O)c1cnn2c(Nc3cc(Cl)ccc3Cl)c(C(=O)N3CCC(c4ccc(F)cc4)CC3)cnc12
Reactant: CCC(=O)O
Product: CCC(=O)NS(=O)(=O)c1cnn2c(Nc3cc(Cl)ccc3Cl)c(C(=O)N3CCC(c4ccc(F)cc4)CC3)cnc12
Yield: 90.7 %

Procedure:
Using 7-(2,5-dichlorophenylamino)-6-[4-(4-fluorophenyl)piperidine-1-carbonyl]pyrazolo[1,5-a]pyrimidine-3-sulfonamide (0.050 g, 0.089 mmol) obtained in step 5 and propionic acid (0.033 mL, 0.444 mmol) instead of cyclopropanecarboxylic acid, and in the same manner as in Example 1 step 6, the title compound (0.050 g, 92%) was obtained.
Reaction SMILES: [H-].[Na+].CCCCCC.[F:9][C:10]([F:18])=[CH:11][CH:12]1[CH2:16][NH:15][C:14](=[O:17])[CH2:13]1.Br[CH2:20][C:21]1[N:25]2[N:26]=[C:27]([Cl:30])[CH:28]=[CH:29][C:24]2=[N:23][C:22]=1[C:31]([F:34])([F:33])[F:32]>C1COCC1.O>[Cl:30][C:27]1[CH:28]=[CH:29][C:24]2[N:25]([C:21]([CH2:20][N:15]3[CH2:16][CH:12]([CH:11]=[C:10]([F:18])[F:9])[CH2:13][C:14]3=[O:17])=[C:22]([C:31]([F:34])([F:33])[F:32])[N:23]=2)[N:26]=1
Reactant: O=C1CC(C=C(F)F)CN1
Reactant: FC(F)(F)c1nc2ccc(Cl)nn2c1CBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C1CC(C=C(F)F)CN1Cc1c(C(F)(F)F)nc2ccc(Cl)nn12
Temperature: 25 °C
Reaction time: 3 h
Yield: 72 %

Procedure:
Sodium hydride (60% wt mineral oil dispersion, 0.82 g, 1.3 eq, 20.5 mmol) is washed three times by hexane (15 ml). THF (15 ml) is added at room temperature to this clean sodium hydride, a solution of 4-(2,2-difluorovinyl)pyrrolidin-2-one x98 (3.42 g, 23 mmol, 1.4 eq) and 3-(bromomethyl)-6-chloro-2-(trifluoromethyl)imidazo[1,2-b]pyridazine x36 (4.97 mg, 15.8 mmol, 1 eq) in THF (15 ml). After 3 hours of stirring at room temperature, a small amount of sodium hydride is added in order to complete the reaction and stirring is pursue overnight. Water (25 ml) is then added to the mixture and THF is removed evaporation under reduced pressure. The aqueous layer is extracted by ethyl acetate (2×50 ml), the resulting organic layer is dried over MgSO4, filtered and concentrated to dryness. The residue is purified by preparative chromatography (benzine/AcOEt: 50/50) to afford 4.33 g of {[6-chloro-2-(trifluoromethyl)imidazo[1,2-b]pyridazin-3-yl]methyl}-4-(2,2-difluoro-vinyl)-pyrrolidin-2-one 33.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13](=[O:32])[NH:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[S:27]([CH3:30])(=[O:29])=[O:28])=[CH:17][C:16]=1[Cl:31])=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl.C(Cl)(Cl)Cl>[Cl:31][C:16]1[CH:17]=[C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[S:27]([CH3:30])(=[O:28])=[O:29])[CH:19]=[CH:20][C:15]=1[NH:14][C:13]([CH:9]1[CH2:10][CH2:11][CH2:12][NH:8]1)=[O:32]
Reactant: CC(C)(C)OC(=O)N1CCCC1C(=O)Nc1ccc(-c2ccccc2S(C)(=O)=O)cc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CS(=O)(=O)c1ccccc1-c1ccc(NC(=O)C2CCCN2)c(Cl)c1

Procedure:
2-(3-Chloro-2′-methanesulfonyl-biphenyl-4-ylcarbamoyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (1 g, 2 mmol) was dissolved in 20 mL DCM and 20 mL trifluoroacetic acid and stirred at ambient temperature for 2 hours. Concentrated solution, redissolved in 100 mL CHCl3, repeated CHCl3 co-concentration 4 times to yield title compound as a yellow foam. (quant. yield) APCI (AP+): 379.1, 381.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][C:8]2[NH:7][C:6]3[N:11]=[CH:12][CH:13]=[CH:14][C:5]=3[C:4]=2[C:3]=1[F:15].[H-].[Na+].[CH3:18][Si:19]([CH3:26])([CH3:25])[CH2:20][CH2:21][O:22][CH2:23]Cl>CN(C=O)C>[Cl:1][C:2]1[N:10]=[CH:9][C:8]2[N:7]([CH2:23][O:22][CH2:21][CH2:20][Si:19]([CH3:26])([CH3:25])[CH3:18])[C:6]3[N:11]=[CH:12][CH:13]=[CH:14][C:5]=3[C:4]=2[C:3]=1[F:15]
Reactant: C[Si](C)(C)CCOCCl
Reactant: Fc1c(Cl)ncc2[nH]c3ncccc3c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1c2cnc(Cl)c(F)c2c2cccnc21
Reaction time: 1 h
Yield: 79.8 %

Procedure:
A suspension of 6-chloro-5-fluoro-9H-dipyrido[2,3-b;4′3′-d]pyrrole (9 g, 40.6 mmol) in DMF (90 mL) was placed in a cold water bath and treated portionwise with sodium hydride (60% suspension in mineral oil) (1.94 g, 48.5 mmol) keeping the internal temperature at 20-25° C. When gas evolution ceased (ca. 1 hour) the mixture was treated dropwise with 2-(trimethylsilyl)ethoxymethyl chloride (8.1 g, 8.7 mL, 48.5 mmol) keeping the internal temperature at 25-30° C. After stirring for a further 1 hour the mixture was partitioned between ethyl acetate and ice-cold 1N hydrochloric acid. The aqueous phase was further extracted with ethyl acetate and the combined organic phase was washed with water, aqueous potassium carbonate solution, water, and brine, dried (Na2SO4), filtered and evaporated in-vacuo. The residue was triturated with pentane:diethyl ether (ca. 20:1) to afford the title compound as a beige solid (11.4 g, 80%). The trituration liquors were evaporated and purified by chromatography to afford a second crop of title compound (0.85 g, 6%). Total yield=12.3 g, 86%. 1H NMR (400 MHz, CDCl3): 8.68-8.68 (m, 2H), 8.52 (dd, J=7.8, 1.7 Hz, 1H), 7.35 (dd, J=7.8, 4.8 Hz, 1H), 5.95 (s, 2H), 3.59 (t, J=8.2 Hz, 2H), 0.92 (t, J=8.2 Hz, 2H), −0.09 (d, J=0.5 Hz, 9H).
Reaction SMILES: [C:1]([NH:9][N:10]=[C:11]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:12](OC)=[O:13])(=O)[CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.O.[NH2:23][NH2:24]>N1C=CC=CC=1>[CH:2]1([C:1]2[N:23]([NH2:24])[C:12](=[O:13])[C:11]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:10][N:9]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: NN
Reactant: COC(=O)C(=NNC(=O)C1CCCCC1)c1ccccc1
Solvent: c1ccncc1
Solvent: O
Product: Nn1c(C2CCCCC2)nnc(-c2ccccc2)c1=O
Yield: 19.6 %

Procedure:
28.8 g (0.1 mol) of phenylglyoxylic acid methyl ester-2-hexahydrobenzoylhydrazone and 10 g of hydrazine hydrate (0.2 mol) were stirred in 100 ml of pyridine, which had been dried over potassium hydroxide, for 45 minutes at 100°C and the mixture was subsequently cooled. Thereupon, the mixture solidifed to a paste. 100 ml of water were added and the whole was stirred for some hours and the product filtered off. After washing with water and drying, 5.3 g (19.7% of theory) of 3-cyclohexyl-4-amino-6-phenyl-5-H-1,2,4-triazin-5-one were obtained in colorless flakes of melting point 178°-180°C.
Reaction SMILES: [C:1]([CH2:4][C@@H:5]1[C:14]2[C:9](=[CH:10][C:11]([Cl:16])=[CH:12][C:13]=2[Cl:15])[NH:8][C@@H:7]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:6]1)([OH:3])=O.O[C:25]1[C:33]2N=N[NH:30][C:29]=2[CH:28]=[CH:27][CH:26]=1.NC1C=CC=CC=1.Cl.CN(C)CCCN=C=NCC>C1COCC1.C(N(CC)CC)C>[C:29]1([NH:30][C:1]([CH2:4][C@@H:5]2[C:14]3[C:9](=[CH:10][C:11]([Cl:16])=[CH:12][C:13]=3[Cl:15])[NH:8][C@@H:7]([C:17]([O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:18])[CH2:6]2)=[O:3])[CH:33]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CC(C)(C)OC(=O)[C@H]1C[C@H](CC(=O)O)c2c(Cl)cc(Cl)cc2N1
Reactant: Oc1cccc2[nH]nnc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: Nc1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)[C@H]1C[C@H](CC(=O)Nc2ccccc2)c2c(Cl)cc(Cl)cc2N1
Temperature: 25 °C
Reaction time: 14 h
Yield: 46.3 %

Procedure:
Trans-4-carboxymethyl-2-tertiarybutyloxycarbonyl-5,7-dichloro-1,2,3,4-tetrahydroquinoline (0.25 g, 0.000696M) was dissolved in dry THF with dry triethylamine (0.29 ml, 3 molar equivalents), hydroxybenzotriazole (0.141 g, 1.5 molar equivalents), aniline (0.0925 ml, 1.5 molar equivalents) and 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (0.2 g, 1.5 molar equivalents) and the reaction mixture was stirred at room temperature for 14 h. The solvents were removed in vacuo and the residue was dissolved in ethyl acetate (100 ml) and washed successively with 0.5 normal citric acid solution (3×50 ml), saturated sodium hydrogen carbonate solution (3×50 ml) and brine (1×50 ml), dried (Na2SO4), filtered and evaporated under vacuum. The residue obtained was purified by chromatography on silica gel using 10% ethyl acetate in hexane as eluent to give the title compound (0.14 g) as a colourless oil; δ (250 MHz, DMSO) 1.48 (9H, s, (CH3)3C), 1.69 (1H, ddd, J=13.0, 12.4 and 4.0 Hz, CHACHBHCCHD), 2.47 (2H, m, CHACHBHCCHDCHEHFCONHPh), 2.73 (1H, dd, J=16.5 and 2.5 Hz, CHACHBHCCHDCHEHFCONHPh), 3.73 (1H, m, CHACHBHCCHDCHEHFCONHPh), 3.98 (1H, dd, J=12.4 and 3.3 Hz, CHACHBHCCHDCHEHFCONHPh), 4.72 (1H, br, s, ArNHCHA), 6.50 (1H, d, J=2.0 Hz, 6-H or 8-H), 6.70 (1H, d, J=2.0 Hz, 6-H or 8-H), 7.15 (2H, m, p-proton and PhNH), 7.33 (2H, t, J=7.5 Hz, m protons), 7.50 (2H, d, J=7.5 Hz, o protons); m/e (FAB) 379 (M+1).
Reaction SMILES: C(N(C(C)C)CC)(C)C.[C:10]([O:14][C:15]([NH:17][CH2:18][CH2:19][CH2:20][CH2:21][NH2:22])=[O:16])([CH3:13])([CH3:12])[CH3:11].[CH2:23]([O:25][C:26]([C:28]1[CH:29]=[C:30]([NH:34][C:35]2[N:40]=[C:39]([C:41]3[S:45][C:44](Cl)=[N:43][C:42]=3[C:47]([F:50])([F:49])[F:48])[CH:38]=[CH:37][N:36]=2)[CH:31]=[CH:32][CH:33]=1)=[O:27])[CH3:24]>C(#N)C>[CH2:23]([O:25][C:26]([C:28]1[CH:29]=[C:30]([NH:34][C:35]2[N:40]=[C:39]([C:41]3[S:45][C:44]([NH:22][CH2:21][CH2:20][CH2:19][CH2:18][NH:17][C:15]([O:14][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:16])=[N:43][C:42]=3[C:47]([F:49])([F:50])[F:48])[CH:38]=[CH:37][N:36]=2)[CH:31]=[CH:32][CH:33]=1)=[O:27])[CH3:24]
Reactant: CC(C)(C)OC(=O)NCCCCN
Reactant: CCOC(=O)c1cccc(Nc2nccc(-c3sc(Cl)nc3C(F)(F)F)n2)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCOC(=O)c1cccc(Nc2nccc(-c3sc(NCCCCNC(=O)OC(C)(C)C)nc3C(F)(F)F)n2)c1
Temperature: 25 °C

Procedure:
Diisopropylethylamine (0.1 mL, 0.6 mmol) and 4-t-butoxycarbonylamino-butylamine (25 mg, 1.4 mmol) are added to a solution of N-[3-ethoxycarbonyl-phenyl]-4-[2-chloro-4-trifluoromethyl-5-thiazolyl]-2-pyrimidineamine (52 mg, 0.12 mmol) in 50 mL anhydrous acetonitrile. The mixture is then heated to reflux overnight. The reaction is stopped, cooled to room temperature and concentrated. Water (30 mL) is added and the reaction mixture is extracted with ethyl acetate (3×100 mL). The combined organic layers are dried over MgSO4, filtered and concentrated. The residue is used in the next step without further purification; ESI-MS (m/z): 567.2 (M++H).
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:27][CH2:26][C:25]([C:29]#[N:30])([CH3:28])[CH2:24][CH2:23]2)=[C:4]([C@H:10]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:11]([O:13][CH:14]([CH3:16])[CH3:15])=[O:12])[C:5]([CH3:9])=[N:6][C:7]=1[CH3:8].[F:31][C:32]1[CH:57]=[CH:56][C:35]([CH2:36][CH2:37][O:38][C:39]2[CH:44]=[CH:43][C:42](B3OC(=O)CN(C)CC(=O)O3)=[CH:41][CH:40]=2)=[CH:34][CH:33]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.CCOC(C)=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>[C:18]([O:17][C@@H:10]([C:4]1[C:5]([CH3:9])=[N:6][C:7]([CH3:8])=[C:2]([C:42]2[CH:41]=[CH:40][C:39]([O:38][CH2:37][CH2:36][C:35]3[CH:34]=[CH:33][C:32]([F:31])=[CH:57][CH:56]=3)=[CH:44][CH:43]=2)[C:3]=1[N:22]1[CH2:27][CH2:26][C:25]([C:29]#[N:30])([CH3:28])[CH2:24][CH2:23]1)[C:11]([O:13][CH:14]([CH3:15])[CH3:16])=[O:12])([CH3:20])([CH3:19])[CH3:21]
Reactant: CN1CC(=O)OB(c2ccc(OCCc3ccc(F)cc3)cc2)OC(=O)C1
Reactant: Cc1nc(C)c([C@H](OC(C)(C)C)C(=O)OC(C)C)c(N2CCC(C)(C#N)CC2)c1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1nc(C)c([C@H](OC(C)(C)C)C(=O)OC(C)C)c(N2CCC(C)(C#N)CC2)c1-c1ccc(OCCc2ccc(F)cc2)cc1
Temperature: 90 °C
Reaction time: 16 h
Yield: 75.7 %

Procedure:
Pd(Ph3P)4 (144 mg, 0.125 mmol) was added to an argon-degassed solution (S)-isopropyl 2-(5-bromo-4-(4-cyano-4-methylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-(tert-butoxy)acetate (300 mg, 0.624 mmol), 2-(4-(4-fluorophenethoxy)phenyl)-6-methyl-1,3,6,2-dioxazaborocane-4,8-dione (179 mg, 0.687 mmol), potassium phosphate tribasic (994 mg, 4.68 mmol) in dioxane (4 ml) and water (0.8 ml) stirred in a screw-capped pressure vessel for 16 h at 90° C. The reaction was allowed to cool, diluted with EtOAc, and the organic layer was washed with brine and dried (MgSO4). The crude product was charged (DCM) to a 40 g ISCO silica gel cartridge and gradient elution (0-70% EtOAc/hexanes) using an Isolera chromatography station gave (S)-isopropyl 2-(tert-butoxy)-2-(4-(4-cyano-4-methylpiperidin-1-yl)-5-(4-(4-fluorophenethoxy)phenyl)-2,6-dimethylpyridin-3-yl)acetate 291 mg (76%) as a mixture of diastereomers. 1H NMR (500 MHz, DMSO-d6) δ 7.38-7.3 (m, 2H), 7.19 (br. s, 1H), 7.13 (d, J=8.4 Hz, 2H), 7.08-7.06 (m, 1H), 7.02-7.00 (m, 2H), 5.91 (br. s, 1H), 4.94 (br. s, 1H), 4.28-4.23 (m, 1H), 4.19-4.15 (m, 1H), 3.44-3.40 (m, 4H), 3.05 (t, J=6.2 Hz, 2H), 2.45 (s, 3H), 2.06 (s, 3H), 1.80 (br. s, 1H), 1.69 (br. s, 1H), 1.55 (br. s, 1H), 1.34-1.32 (m, 1H), 1.29 (s, 3H), 1.18 (d, J=6.2 Hz, 3H), 1.15-1.1 (m, 12H). UPLC (M+H)=616.6.
Reaction SMILES: [C:1]([O:5][C:6](=[O:11])[NH:7][CH:8]1[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.F[B-](F)(F)F.[N:23]#[O+:24]>C(#N)C>[C:1]([O:5][C:6](=[O:11])[N:7]([N:23]=[O:24])[CH:8]1[CH2:9][CH2:10]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1CC1
Reactant: N#[O+]
Agent: F[B-](F)(F)F
Solvent: CC#N
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N(N=O)C1CC1
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 26.4 %

Procedure:
A solution of cyclopropyl-carbamic acid tert-butyl ester (4.8 g, 30.5 mmol) and pyridine (5.9 mL, 73 mmol) in acetonitrile (75 mL) was cooled to approximately −25° C. in a carbon tetrachloride/dry ice bath. Nitrosonium tetrafluoroborate (4.7 g, 40.2 mmol) was added over a period of 20 min. The cooling bath was removed and the reaction mixture was stirred in an ice-bath at 0° C. for 2.5 h. Water (100 mL) and ethyl acetate (500 mL) were added and the organic layer was washed with water (100 mL), 2 M aqueous HCl (50 mL) and brine (100 mL), dried (magnesium sulfate), filtered, evaporated, and purified in two batches using an ISCO 120 g column, eluting with 10-30% ethyl acetate, to give N-nitroso-N-cyclopropyl-carbamic acid tert-butyl ester (1.5 g, 26%) as a yellow oil.
Reaction SMILES: [CH3:1][CH:2]([O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]=[C:16]([NH2:19])[CH:15]=[CH:14]2)[CH2:3][C:4]([CH3:7])([CH3:6])[CH3:5].CCN(CC)CC.[CH3:27][C:28]([CH3:33])([CH3:32])[C:29](Cl)=[O:30]>C1COCC1>[CH3:27][C:28]([CH3:33])([CH3:32])[C:29]([NH:19][C:16]1[CH:15]=[CH:14][C:13]2[C:18](=[C:9]([O:8][CH:2]([CH3:1])[CH2:3][C:4]([CH3:7])([CH3:6])[CH3:5])[CH:10]=[CH:11][CH:12]=2)[N:17]=1)=[O:30]
Reactant: CC(CC(C)(C)C)Oc1cccc2ccc(N)nc12
Reactant: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(CC(C)(C)C)Oc1cccc2ccc(NC(=O)C(C)(C)C)nc12
Reaction time: 8 h

Procedure:
To a 20 mL scintillation vial was added a stir bar, the title compound from Example 16 (161 mg, 0.624 mmol) and 1.5 mL of THF. To the resultant solution was added Et3N (0.174 mL, 2 equiv) and trimethylacetylchloride (93 μL, 1.2 equiv). The solution was allowed to stir overnight, after which time the mixture placed directly on a silica column and eluted with EtOAc/hexanes to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.27 (m, 1H), 7.96–8.18 (m, 1H), 7.42 (m, 2H), 7.21 (m, 1H), 4.64–4.90 (m, 1H), 1.90 (m, 1H), 1.53 (m, 1H), 1.31 (m, 12H), 0.83–1.05 (m, 9H); MS (DCI/NH3) m/z 343 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:22]=[CH:21][C:5]([NH:6][C:7]2[S:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[C:8]=2[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:4]([N+:23]([O-])=O)[CH:3]=1.[H][H]>[C].[Pd].C(OCC)(=O)C>[NH2:23][C:4]1[CH:3]=[C:2]([Br:1])[CH:22]=[CH:21][C:5]=1[NH:6][C:7]1[S:11][C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[C:8]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: [H][H]
Reactant: CCOC(=O)c1c(Nc2ccc(Br)cc2[N+](=O)[O-])sc2ccccc12
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(Nc2ccc(Br)cc2N)sc2ccccc12

Procedure:
In the same manner as in Starting Material Synthesis Example 19 and using ethyl 2-(4-bromo-2-nitroanilino)benzo[b]thiophene-3-carboxylate, ethyl acetate, 10% palladium-carbon and hydrogen (60 atm kg/cm2), ethyl 2-(2-amino-4-bromoanilino)benzo[b]thiophene-3-carboxylate is obtained.