Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([Si:5]([O:8][C:9]1[C:14]([CH:15]=[CH2:16])=[CH:13][CH:12]=[CH:11][C:10]=1[F:17])([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].[H][H]>C(OCC)(=O)C.[Pd]>[C:1]([Si:5]([O:8][C:9]1[C:10]([F:17])=[CH:11][CH:12]=[CH:13][C:14]=1[CH2:15][CH3:16])([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=Cc1cccc(F)c1O[Si](C)(C)C(C)(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCc1cccc(F)c1O[Si](C)(C)C(C)(C)C
Reaction time: 4 h

Procedure:
To a stirred solution of tert-butyl(2-fluoro-6-vinylphenoxy)dimethylsilane (1.18 g, 4.67 mmol) in ethyl acetate (61 mL) under nitrogen, was added 497 mg of 10% palladium on carbon. The flask was then equipped with a hydrogen containing balloon and the reaction mixture stirred rapidly for 4 hours. The hydrogen balloon was removed, the reaction mixture sparged with nitrogen, and then filtered through a plug of Celite®, eluting with EtOAc. The filtrate was concentrated to dryness to afford the title compound that was used without further purification. 1H NMR (500 MHz, CDCl3) δ 6.94-6.85 (m, 2H), 6.85-6.77 (m, 1H), 2.65 (q, J=7.6, 2H), 1.19 (t, J=7.5, 3H), 1.02 (s, 9H), 0.21 (d, J=2.7, 6H).
Reaction SMILES: [CH3:1][C:2]1[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[C:3]=1[CH2:4][O:5][C:6]1[C:7]([O:14][CH3:15])=[C:8]([CH2:12][OH:13])[CH:9]=[CH:10][CH:11]=1.C(N(CC)CC)C.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>C(Cl)Cl>[CH3:28][S:29]([O:13][CH2:12][C:8]1[CH:9]=[CH:10][CH:11]=[C:6]([O:5][CH2:4][C:3]2[C:16]([CH3:20])=[CH:17][CH:18]=[CH:19][C:2]=2[CH3:1])[C:7]=1[O:14][CH3:15])(=[O:31])=[O:30]
Reactant: CS(=O)(=O)Cl
Reactant: COc1c(CO)cccc1OCc1c(C)cccc1C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1c(COS(C)(=O)=O)cccc1OCc1c(C)cccc1C
Temperature: 25 °C

Procedure:
To a solution of (3-(2,6-dimethylbenzyloxy)-2-methoxyphenyl)methanol (Step B, 9.5 g, 32.7 mmol) and triethylamine (5.80 g, 57.4 mmol) in dry CH2Cl2 (100 ml) was added drop wise methanesulfonyl chloride (3.5 ml, 45 mmol) at 0° C. under argon. The reaction mixture was warmed to room temperature for 6 hours or until all the starting material is consumed, neutralized with cooled 10% Na2CO3 and extracted with CH2Cl2. The organic layer was concentrated, and purified by flash chromatography on a silica gel column (hex:methylene chloride 2:1) to give the title compound as light yellow oil
Reaction SMILES: [C@H:1]([NH:5][C:6]1[C:7]([C:17]#[N:18])=[CH:8][C:9]([CH3:16])=[C:10]([CH:15]=1)[C:11]([O:13][CH3:14])=[O:12])([CH2:3][CH3:4])[CH3:2].OO.C(=O)([O-])[O-:22].[K+].[K+]>CS(C)=O>[C@H:1]([NH:5][C:6]1[C:7]([C:17]([NH2:18])=[O:22])=[CH:8][C:9]([CH3:16])=[C:10]([CH:15]=1)[C:11]([O:13][CH3:14])=[O:12])([CH2:3][CH3:4])[CH3:2]
Reactant: CC[C@@H](C)Nc1cc(C(=O)OC)c(C)cc1C#N
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Product: CC[C@@H](C)Nc1cc(C(=O)OC)c(C)cc1C(N)=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 282.3 %

Procedure:
To a cooled (0° C.) solution of (R)-methyl 5-(sec-butylamino)-4-cyano-2-methylbenzoate (300 mg, 1.22 mmol) in DMSO (1.5 mL) was added 30% hydrogen peroxide solution (258 μL, 8.96 mmol) and potassium carbonate (56 mg, 0.402 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 4 h, at which time it was concentrated in vacuo. The residue was purified by flash chromatography (100% hexanes to 10% ethyl acetate in hexanes) to afford (R)-methyl 5-(sec-butylamino)-4-(aminocarbonyl)-2-methylbenzoate (300 mg, 93%) as yellow crystals. MS (EI) for C14H20N2O3: 265 (MH+).
Reaction SMILES: [CH:1]12[C:10](=[O:11])O[C:7](=[O:8])[CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6]2.[NH3:12]>>[CH:1]12[C:10](=[O:11])[NH:12][C:7](=[O:8])[CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6]2
Reactant: O=C1OC(=O)C2CCCCC12
Reactant: N
Product: O=C1NC(=O)C2CCCCC12
Reaction time: 2 h

Procedure:
A mixture of cyclohexane-1,2-dicarboxylic anhydride (3 g; 19.5 mmol) and 29% aqueous ammonia (3.4 g) was heated to and kept at an inner temperature of 180° to 190° C. for 2 hours to give the objective compound quantitatively. M.P., 132°-136° C.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][NH:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]([C:17]2[S:27][C:26]3[N:28]4[C:19](=[CH:20][N:21]=[C:22]4[CH:23]=[CH:24][CH:25]=3)[CH:18]=2)=[O:16])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:29].[CH3:30]O>C(O)C>[ClH:29].[ClH:29].[CH3:30][N:10]([CH2:11][CH2:12][CH2:13][NH:14][C:15]([C:17]1[S:27][C:26]2[N:28]3[C:19](=[CH:20][N:21]=[C:22]3[CH:23]=[CH:24][CH:25]=2)[CH:18]=1)=[O:16])[CH2:9][CH2:8][CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CO
Reactant: O=C(NCCCNCCCc1ccccc1)C1=Cc2cnc3cccc(n23)S1
Agent: Cl
Solvent: CCO
Product: CN(CCCNC(=O)C1=Cc2cnc3cccc(n23)S1)CCCc1ccccc1

Procedure:
To a solution of 577.3 mg (1.42 mM) of N-[3-(N-(3-phenylpropan-1-yl)amino)propan-1-yl]-5-thia-1,8b-diazaacenaphthylene-4-carboxamide in ethanol (6 ml) was added 2.0 ml (8.0 mM) of 4N-HCl/methanol at room temperature and the mixture was stirred for several minutes. The solvent was then distilled off under reduced pressure to provide the title compound.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1>C(N(CC)CC)C.C(O)=O.[C].[Pd]>[NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH2:3][CH2:2]1
Reactant: c1cnc2[nH]ccc2c1
Agent: [Pd]
Solvent: O=CO
Solvent: CCN(CC)CC
Product: c1cnc2c(c1)CCN2
Temperature: 80 °C
Reaction time: 96 h
Yield: 24.1 %

Procedure:
1H-Pyrrolo[2,3-b]pyridine (8.78 g, 74.3 mmol) and 5% palladium-carbon in a mixture of triethylamine (5 mL) and formic acid (30 mL) was stirred at 80° C. for 4 days. The reaction mixture was allowed to cool to room temperature and filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was adjusted to pH 12 with 6 M aqueous sodium hydroxide and stirred at 65° C. for 5 hours. The reaction mixture was allowed to cool to room temperature and extracted with chloroform, and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/2-ethyl acetate/methanol=20/1 (v/v)) to give the title compound as a pale yellow solid (2.15 g, yield 24%).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C:11]3[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=3)[N:9]=[CH:10][C:3]=12.[C:21]([O:25][C:26](=[O:35])[NH:27][CH:28]1[CH2:33][CH2:32][CH:31]([NH2:34])[CH2:30][CH2:29]1)([CH3:24])([CH3:23])[CH3:22].C(=O)([O-])[O-].[K+].[K+]>C1COCC1>[C:21]([O:25][C:26](=[O:35])[NH:27][CH:28]1[CH2:29][CH2:30][CH:31]([NH:34][C:2]2[N:7]=[CH:6][N:5]=[C:4]3[N:8]([C:11]4[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=4)[N:9]=[CH:10][C:3]=23)[CH2:32][CH2:33]1)([CH3:24])([CH3:22])[CH3:23]
Reactant: CS(=O)(=O)c1ccc(-n2ncc3c(Cl)ncnc32)cc1
Reactant: CC(C)(C)OC(=O)NC1CCC(N)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1CCC(Nc2ncnc3c2cnn3-c2ccc(S(C)(=O)=O)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76 %

Procedure:
A mixture of 4-chloro-1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidine (308 mg, 1 mmol), (4-amino-cyclohexyl)-carbamic acid tert-butyl ester (257 mg, 1.2 mmol) and potassium carbonate (166 mg, 1.2 mmol) in THF (10 mL) was stirred at rt overnight. The mixture was purified by column chromatography to provide Compound A35 as a solid (76%). 1H NMR (CDCl3, 400 MHz) δ 1.46 (s, 9H), 1.74–2.04 (m, 8H), 3.09 (s, 3H), 3.73 (s, 1H), 4.62 (s, 1H), 8.07–8.09 (m, 3H), 8.49 (s, 1H), 8.57–8.59 (m, 2H). Exact mass calculated for C23H30N6O4S 486.2, found 487.2 (MH+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[N:13]([CH2:16][C:17]([O:19]C)=O)[C:12](S(C)(=O)=O)=[N:11][C:10]=1[C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.Cl.[CH3:32][NH:33][NH:34][CH3:35].C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH2:1]([O:8][C:9]1[C:14](=[O:15])[N:13]2[C:12]([N:33]([CH3:32])[N:34]([CH3:35])[C:17](=[O:19])[CH2:16]2)=[N:11][C:10]=1[C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CNNC
Reactant: CCOC(=O)c1nc(S(C)(=O)=O)n(CC(=O)OC)c(=O)c1OCc1ccccc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)c1nc2n(c(=O)c1OCc1ccccc1)CC(=O)N(C)N2C
Temperature: 22 °C
Reaction time: 4 h
Yield: 68.7 %

Procedure:
A mixture of intermediate 3, ethyl 5-benzyloxy-1-(methoxycarbonylmethyl)-2-(methylsulfonyl)-6-oxo-1,6-dihydropyrimidine-4-carboxylate, (0.487 g, 1.15 mmol) in N,N-dimethylformamide (25 ml) was treated with 1,2-dimethylhydrazine dihydrochloride (1.56 g, 11.7 mmol) followed by N,N-diisopropylethylamine (4.1 ml, 11.7 mmol) and the resulting mixture stirred at 22° C. for 4 h. The solvent was then removed in vacuo and the residue diluted with ethyl acetate, washed successively with saturated sodium bicarbonate and brine then dried over anhydrous magnesium sulfate. Evaporation of the solvent followed by chromatography on silica gel (elution with a gradient of ethyl acetate 0–50% in toluene) gave 0.294 g (69% yield) of the title ester as a clear syrup.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][N:9]2[CH2:14][CH2:13][C:12](=O)[CH2:11][CH2:10]2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl.[NH2:17][OH:18]>>[N:1]1([CH2:7][CH2:8][N:9]2[CH2:14][CH2:13][C:12](=[N:17][OH:18])[CH2:11][CH2:10]2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: NO
Reactant: O=C1CCN(CCN2CCOCC2)CC1
Agent: Cl
Product: ON=C1CCN(CCN2CCOCC2)CC1

Procedure:
1-(2-(4-Morpholinyl)ethyl)-4-piperidone oxime is prepared from 1-(2-(4-morpholinyl)ethyl)-4-piperidone and hydroxylamine hydrochloride essentially as described above in Example 38, Scheme C, step b.
Reaction SMILES: [O:1]=[O+][O-].[CH3:4][C:5]1([CH3:27])[CH:7]([CH:8]=C(C)C)[CH:6]1[C:12]([O:14][CH2:15][C:16]1[C:21]([F:22])=[C:20]([F:23])[C:19]([F:24])=[C:18]([F:25])[C:17]=1[F:26])=[O:13]>C(OCC)(=O)C>[CH3:4][C:5]1([CH3:27])[CH:7]([CH:8]=[O:1])[CH:6]1[C:12]([O:14][CH2:15][C:16]1[C:21]([F:22])=[C:20]([F:23])[C:19]([F:24])=[C:18]([F:25])[C:17]=1[F:26])=[O:13]
Reactant: CC(C)=CC1C(C(=O)OCc2c(F)c(F)c(F)c(F)c2F)C1(C)C
Reactant: O=[O+][O-]
Solvent: CCOC(C)=O
Product: CC1(C)C(C=O)C1C(=O)OCc1c(F)c(F)c(F)c(F)c1F
Yield: 89 %

Procedure:
Ozone gas was bubbled at -78° C. into a solution of 3.48 g (10.0 mmol) of pentafluorophenylmethyl 2,2-dimethyl-3-(2-methyl-1-propenyl)cyclopropanecarboxylate obtained in Reference Example 4, in 20 ml of ethyl acetate. The subsequent operation was conducted in the same manner as in Reference Example 5, whereby 2.87 g of pentafluorophenylmethyl 2,2-dimethyl-3-formylcyclopropanecarboxylate was obtained as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][O:4][C:3]=1[C:7]([OH:9])=[O:8].[Li]CCCC.CN([CH:18]=[O:19])C>C1COCC1>[CH:18]([C:5]1[O:4][C:3]([C:7]([OH:9])=[O:8])=[C:2]([CH3:1])[CH:6]=1)=[O:19]
Reactant: CN(C)C=O
Reactant: Cc1ccoc1C(=O)O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1cc(C=O)oc1C(=O)O
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 36.7 %

Procedure:
Under N2, a solution of 3-methyl-2-furoic acid (2.0 g, 15.9 mmol) in THF (80 mL) was cooled to −78° C. and n-BuLi (1.6 M in hexane) (20.8 mL, 33.3 mmol, 2.1 equiv) was added dropwise. The mixture was kept for 30 min at −78° C., then a solution of DMF (6.11 mL, 79.4 mmol, 5 equiv) in THF (20 mL) was added. After being stirred for 3 h at −78° C., the reaction mixture was allowed to warm to rt. The reaction was quenched with saturated aqueous ammonium chloride then the reaction mixture was partitioned between water and ether. The ether layer was washed with water, and then dried over sodium sulfate, filtered, and the solvent was evaporated. The residue was purified by chromatography over silica gel (0 to 30% EtOAc in heptane over 30 min) to give 5-formyl-3-methyl-2-furoic acid (0.9 g, 37%). 1H NMR (400 MHz, CD3OD) δ ppm 2.39 (s, 3H) 7.29 (s, 1H) 9.67 (s, 1H).
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:18]=[CH:17][C:13]([C:14](O)=[O:15])=[CH:12][CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].S(Cl)([Cl:21])=O>>[Si:1]([O:8][CH2:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([Cl:21])=[O:15])=[CH:12][CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CC(C)(C)[Si](C)(C)OCc1ccc(C(=O)O)cc1
Product: CC(C)(C)[Si](C)(C)OCc1ccc(C(=O)Cl)cc1
Temperature: 80 °C

Procedure:
4-[[t-Butyl(dimethyl)silyl]oxymethyl]benzoic acid (1.44 g) was suspended in thionyl chloride and the mixture was heated to 80° C. for 45 minutes. The resulting solution was concentrated in vacuo. Residual thionyl chloride and HCl were removed by subsequent concentration from toluene (twice). The crude residue was carried on to the next reaction step without purification.
Reaction SMILES: Cl[C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4]2[NH:9][C:10]([CH:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]3)=[CH:11][C:3]=12.[F:25][C:26]1[CH:27]=[CH:28][C:29]([O:35][CH3:36])=[C:30](B(O)O)[CH:31]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCCC1.O>[F:8][C:7]1[C:2]([C:28]2[CH:27]=[C:26]([F:25])[CH:31]=[CH:30][C:29]=2[O:35][CH3:36])=[C:3]2[CH:11]=[C:10]([CH:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]3)[NH:9][C:4]2=[N:5][CH:6]=1
Reactant: COc1ccc(F)cc1B(O)O
Reactant: CC(C)(C)OC(=O)N1CCC(c2cc3c(Cl)c(F)cnc3[nH]2)CC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(F)cc1-c1c(F)cnc2[nH]c(C3CCN(C(=O)OC(C)(C)C)CC3)cc12
Temperature: 120 °C

Procedure:
A mixture of Example 255B (600 mg, 1.696 mmol), (5-fluoro-2-methoxyphenyl)boronic acid (403 mg, 2.374 mmol), phenylallylchloro[1,3-bis(diisopropylphenyl)-2-imidazol-2-ylidene]palladium(II) (110 mg, 0.170 mmol), and potassium phosphate (1080 mg, 5.09 mmol) in 12 mL tetrahydrofuran and 3 mL water was degassed with nitrogen and heated in a Biotage microwave for 40 minutes at 120° C. The mixture was extracted with ethyl acetate and purified by silica gel column chromatography eluting with 0-5% methanol in dichloromethane to afford the title compound. MS (ESI(+)) m/e 444 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]=[C:12]=[O:13])(=[O:10])=[O:9].[NH2:14][C:15]1[C:20]([C:21]#[N:22])=[C:19]([CH3:23])[N:18]=[C:17]([CH3:24])[N:16]=1.N12CCN(CC1)CC2>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]([NH:14][C:15]1[C:20]([C:21]#[N:22])=[C:19]([CH3:23])[N:18]=[C:17]([CH3:24])[N:16]=1)=[O:13])(=[O:10])=[O:9]
Reactant: O=C=NS(=O)(=O)c1ccccc1Cl
Reactant: Cc1nc(C)c(C#N)c(N)n1
Agent: C1CN2CCN1CC2
Solvent: ClCCl
Product: Cc1nc(C)c(C#N)c(NC(=O)NS(=O)(=O)c2ccccc2Cl)n1
Reaction time: 72 h
Yield: 71.2 %

Procedure:
4.35 g of 2-Chlorobenzenesulfonyl isocyanate was dissolved in 10 ml xylenes and 25 ml methylene chloride. To this was added 2.96 g of 4-amino-2,6-dimethyl-5-pyrimidine carbonitrile and a catalytic amount of 1,4-diazabicyclo-[2.2.2]octane. The reaction was stirred under a CaSO4 drying tube for three days. The reaction was filtered to remove unreacted pyrimidine, and then the desired product was precipitated by addition of 1-chlorobutane, filtered off, rinsed well with 1-chlorobutane and dried in vacuo giving 5.2 g of the desired product, m.p. 125°-127°. IR: 2240 cm-1 (C≡N), 1730 cm-1 (C=O); NMR (DMSO-d6)δ: 2.6 (s, 6H), 7.4-8.1 (m, 4H) ppm indicating the title compound.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].Cl[C:14]1[C:15]([O:20][CH2:21][CH2:22][O:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([Br:30])[CH:25]=2)=[N:16][CH:17]=[CH:18][N:19]=1>C(#N)C>[N:1]1([C:14]2[C:15]([O:20][CH2:21][CH2:22][O:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([Br:30])[CH:25]=3)=[N:16][CH:17]=[CH:18][N:19]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1
Reactant: Clc1nccnc1OCCOc1cccc(Br)c1
Reactant: C1CNCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Brc1cccc(OCCOc2nccnc2N2CCNCC2)c1
Yield: 84.9 %

Procedure:
Piperazine (1.29 g, 15.0 mmol) and K2CO3 (0.69 g, 5.0 mmol) were added to a solution of 2-(3-bromophenoxy)ethyl 3-chloro-2-pyrazinyl ether (1.65 g, 5.00 mmol) in acetonitrile (25 mL) at room temperature. The mixture was heated at reflux for 21 h, allowed to cool, concentrated and the residue was partitioned between water and EtOAc. The layers were separated and the organic phase was washed with water and brine, and dried over MgSO4. Purification by chromatography on silica gel (gradient: PhMe to PhMe/MeOH/Et3N, 8:1:1) gave 1.61 g (85%) of the title compound as a pale yellow oil that slowly solidified on standing: mp 62-63° C. Anal. (C16H19BrN4O2) C, H, N.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]2=1.Cl[C:19]([O:21][CH3:22])=[O:20]>ClCCl>[CH3:22][O:21][C:19]([NH:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]2=1)=[O:20]
Reactant: CN(C)C1CCc2[nH]c3ccc(N)cc3c2C1
Reactant: COC(=O)Cl
Solvent: ClCCl
Product: COC(=O)Nc1ccc2[nH]c3c(c2c1)CC(N(C)C)CC3
Yield: 53.5 %

Procedure:
To a mixture of 6.0 mg (0.026 mMol) 6-amino-3-(dimethyl)amino-1,2,3,4-tetrahydro-9H-carbazole and 8.0 mg (0.07 mMol) polyvinylpyridine in 3.0 mL dichloromethane were added 2.4 mg (0.0273 mMol) methyl chloroformate. The reaction mixture was mixed for 2 days at ambient temperature. To this mixture were then added 90 mg (0.073 mMol) aminomethylated polystyrene and the reaction mixed for an additional 18 hours. The reaction mixture was then filtered and the volatiles evaporated to give 4.0 mg (53%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[C:3]([N:11]2[CH2:16][CH2:15][N:14]([C:17](=[O:38])[C@@H:18]([C:31]3[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=3)[CH2:19][N:20]([CH:28]([CH3:30])[CH3:29])C(=O)OC(C)(C)C)[CH2:13][CH2:12]2)=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.C(O)(C(F)(F)F)=O.C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>C(Cl)Cl>[Br:1][C:2]1[C:3]([N:11]2[CH2:12][CH2:13][N:14]([C:17](=[O:38])[C@@H:18]([C:31]3[CH:32]=[CH:33][C:34]([Cl:37])=[CH:35][CH:36]=3)[CH2:19][NH:20][CH:28]([CH3:30])[CH3:29])[CH2:15][CH2:16]2)=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CC(C)N(C[C@@H](C(=O)N1CCN(c2c(Br)cnc3[nH]ccc23)CC1)c1ccc(Cl)cc1)C(=O)OC(C)(C)C
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)NC[C@@H](C(=O)N1CCN(c2c(Br)cnc3[nH]ccc23)CC1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
(S)-tert-Butyl 3-(4-(5-bromo-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazin-1-yl)-2-(4-chlorophenyl)-3-oxopropyl(isopropyl)carbamate (0.040 g, 0.066 mmol) was placed in DCM (3 mL). TFA (0.3 mL) was then added. The reaction was stirred at room temperature for 1 hour. The reaction was then concentrated to dryness, dissolved in minimal DCM, and added dropwise to a stirring solution of 1M HCl in ether. The solid product was filtered, washed with ether, and dried to give (S)-1-(4-(5-bromo-1H-pyrrolo[2,3-b]pyri din-4-yl)piperazin-1-yl)-2-(4-chlorophenyl)-3-(isopropylamino)propan-1-one (0.03 g, 90% yield) as the dihydrochloride salt. MS ESI (+) m/z 505 detected.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][N:15]=2)[C:10]([CH2:17]O)=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:39]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][N:15]=2)[C:10]([CH2:17][Cl:39])=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: ClC(Cl)(Cl)Cl
Reactant: CC(C)(C)OC(=O)n1cc(CO)c2cccnc21
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)n1cc(CCl)c2cccnc21
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 1-(tert-butyloxycarbonyl)-3-(hydroxymethyl)-7-azaindole (Int-17, 8.4 g, 34 mmol), triphenylphosphine (9.9 g, 37 mmol), dry CCl4 (50 mL) in dry DMF (35 mL) were stirred at room temperature for 48 h. Solvents were removed and the residue was purified by flash column chromatography to give chloride Int-14 (3.45 g, 38%).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[CH:8]=[C:9]([CH2:13][C:14]([OH:16])=[O:15])[CH:10]=[CH:11][CH:12]=1.C(=O)([O-])[O-].[Na+].[Na+].Cl>O>[CH3:1][S:2]([NH:6][C:7]1[CH:8]=[C:9]([CH2:13][C:14]([OH:16])=[O:15])[CH:10]=[CH:11][CH:12]=1)(=[O:4])=[O:3]
Reactant: Nc1cccc(CC(=O)O)c1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CS(=O)(=O)Nc1cccc(CC(=O)O)c1
Temperature: 85 °C
Reaction time: 4 h

Procedure:
Methanesulphonylchloride (1.70 ml) was added to a stirred mixture of 3-aminophenylacetic acid (3.2 g) and sodium carbonate (5.44 g) in water (36 ml), and the mixture was heated at 85° C. with stirring for 4 h, allowed to cool and acidified with conc. hydrochloric acid to pH 2. After leaving to stand at approximately 4° C. for 18 h, a solid was filtered off, and the residue washed with water and ether. The aqueous and ether filtrates were combined and evaporated in vacuo to give a solid, which was dissolved in hot water, the solution was filtered whilst still hot and the filtrate left to cool before standing at 4° C. for 18 h. The precipitated solid was filtered, washed with a small quantity of cold water and dried in vacuo to give the title compound as a pale yellow solid (0.417 g).
Reaction SMILES: [C:1]1([C:7]2[CH:14]=[CH:13][C:10]([CH:11]=[O:12])=[CH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:15][Mg]Br>>[C:1]1([C:7]2[N:8]=[CH:9][C:10]([CH:11]([OH:12])[CH3:15])=[CH:13][CH:14]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=Cc1ccc(-c2ccccc2)nc1
Reactant: C[Mg]Br
Product: CC(O)c1ccc(-c2ccccc2)nc1

Procedure:
Synthesized using compound 43b (210 mg, 1.15 mmol) and methylmagnesium bromide (2.29 mL, 2.29 mmol, 1 M in THF) according to Method D. Crude product was purified by flash chromatography on silica-gel using a mixture of hexane/ethyl acetate (2:1) as eluent. Light yellow solid. Yield: 201 mg, 88%. 1H NMR (CDCl3, 500 MHz): δH (ppm)=1.51 (d, J=6.6 Hz, 3H), 3.05 (br, s, 1H), 4.92 (q, J=6.6 Hz, 1H), 7.38-7.50 (m, 3H), 7.65 (d, J=7.9 Hz, 1H), 7.74 (dd, J=8.2, 2.2 Hz, 1H), 7.91-7.97 (m, 2H), 8.58 (d, J=2.2 Hz, 1H); 13C NMR (CDCl3, 125 MHz): δC (ppm)=25.0, 67.8, 120.4, 126.9, 128.7, 128.9, 134.0, 139.0, 139.5, 147.2, 156.6; MS (ESI): m/z=200.32 [M+H]+.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[C:10]([O:14][CH3:15])=[CH:9][C:8]=2[C:16]2[C:17]3[NH:25][C:24]([CH3:26])=[C:23]([C:27]([NH:29][CH:30]4[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]4)=[O:28])[C:18]=3[N:19]=[C:20]([CH3:22])[N:21]=2)[CH2:4][CH2:3]1.[CH3:36][O:37][CH2:38][C:39](Cl)=[O:40]>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[C:10]([O:14][CH3:15])=[CH:9][C:8]=2[C:16]2[C:17]3[NH:25][C:24]([CH3:26])=[C:23]([C:27]([NH:29][CH:30]4[CH2:31][CH2:32][N:33]([C:39](=[O:40])[CH2:38][O:37][CH3:36])[CH2:34][CH2:35]4)=[O:28])[C:18]=3[N:19]=[C:20]([CH3:22])[N:21]=2)[CH2:4][CH2:3]1
Reactant: COc1cc(-c2nc(C)nc3c(C(=O)NC4CCNCC4)c(C)[nH]c23)c(OCC2CC2)cc1F
Reactant: COCC(=O)Cl
Agent: Cl
Product: COCC(=O)N1CCC(NC(=O)c2c(C)[nH]c3c(-c4cc(OC)c(F)cc4OCC4CC4)nc(C)nc23)CC1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-4-fluoro-5-methoxyphenyl]-2,6-dimethyl-N-(piperidin-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f59) and commercially available available methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [Br:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([C@@H:8]2[CH2:11][CH2:10][C@H:9]2[C:12]([OH:14])=[O:13])=[O:7])=[CH:4][CH:3]=1.[CH3:17]OC(OC)(C)C.Cl>CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C@@H:8]2[CH2:11][CH2:10][C@H:9]2[C:12]([O:14][CH3:17])=[O:13])=[O:7])=[CH:15][CH:16]=1
Reactant: COC(C)(C)OC
Reactant: O=C(O)[C@@H]1CC[C@H]1C(=O)c1ccc(Br)cc1
Agent: Cl
Solvent: CO
Product: COC(=O)[C@@H]1CC[C@H]1C(=O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 72.2 %

Procedure:
Step 2 To a solution of trans-2-(4-bromobenzoyl)cyclobutanecarboxylic acid (8.2 g, 28.94 mmol) in MeOH (250 mL) was added 2,2-dimethoxypropane (3.65 g, 35.02 mmol) and HCl (4.0 M in dioxane) (2.0 mL). The resulting solution was stirred at rt for 3 days, and then evaporated to dryness. The resulting residue was purified with flash chromatography (Biotage Flash 40M) using 4 to 11% ethyl acetate in hexanes to afford methyl trans-2-(4-bromobenzoyl)cyclobutanecarboxylate (6.21 g, 78%). 1H NMR (400 MHz, CD2Cl2) δ 2.14-2.39 (m, 4H), 3.62 (m, 1H), 3.68 (s, 3H), 4.24 (m, 1H), 7.63 (m, 2H), 7.80 (m, 2H).