Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li]CCCC.C(NC(C)C)(C)C.N#N.[Br:15][C:16]1[CH:17]=[N:18][CH:19]=[C:20]([F:22])[CH:21]=1.CN([CH:26]=[O:27])C>C1COCC1>[Br:15][C:16]1[CH:17]=[N:18][CH:19]=[C:20]([F:22])[C:21]=1[CH:26]=[O:27]
Reactant: CN(C)C=O
Reactant: Fc1cncc(Br)c1
Agent: N#N
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: O=Cc1c(F)cncc1Br
Temperature: -50 °C
Reaction time: 0.17 h
Yield: 62.1 %

Procedure:
n-BuLi (1.6 M in hexanes, 2.250 mL, 3.60 mmol) was added dropwise to a solution of diisopropylamine (0.556 mL, 3.90 mmol) in THF (20 mL) at −78° C. under inert gas (N2). The resulting mixture was warmed up to ˜−50° C. and stirred for 10 min and cooled again to −78° C. A solution of 3-bromo-5-fluoropyridine (528 mg, 3 mmol) in THF (5 mL) was added dropwise at this temperature. The reaction mixture turned from clear light brown to heterogenous light brown. After 30 min, DMF (0.256 mL, 3.30 mmol) was added dropwise and the resulting mixture was stirred for 30 min. The reaction was quenched by MeOH then NH4Cl (saturated solution) and warmed up to room temperature. After concentration, the residue was dissolved in CH2Cl2 and washed with NaHCO3 (Saturated solution). After drying over Na2SO4, concentration, the residue was purified by column (Heptane to CH2Cl2) and yielded slightly yellow crystal (380 mg). 1H NMR (400.3 MHz, CDCl3): δ 8.58 (s, 1H), 8.72 (s, 1H), 10.33 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11]1[N:12]=[C:13]2[CH:18]=[CH:17][N:16](Cl)[CH2:15][N:14]2[CH:20]=1.[H][H].C(N(CC)CC)C>C(OCC)(=O)C.[Pd]>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11]1[N:12]=[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][N:14]2[CH:20]=1
Reactant: COc1ccc(-c2cn3c(n2)C=CN(Cl)C3)c(OC)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COc1ccc(-c2cn3cnccc3n2)c(OC)c1

Procedure:
A solution of 3 g. of 2-(2,4-dimethoxyphenyl)-6-chloro-imidazo[1,2-c]pyrimidine (free base) in ethyl acetate was treated with 1 g. of 5% palladium-on-carbon and subjected to hydrogenation until hydrogen uptake ceased. Two grams of triethylamine were added and hydrogenation was continued. When hydrogen uptake ceased, the catalyst was removed by filtration, and the ethyl acetate solution was washed with 300 ml. of a saturated sodium chloride solution. The organic solution was evaporated in vacuo, and the resulting residue was crystallized from ethyl acetate/ether to give 1.2 g. of the title product, M+ =255.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:10])=[CH:4][C:5]([Br:9])=[C:6]([OH:8])[CH:7]=1.[CH2:11](Br)[CH:12]=[CH2:13].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:13]([O:8][C:6]1[C:5]([Br:9])=[CH:4][C:3]([F:10])=[C:2]([CH:7]=1)[NH2:1])[CH:12]=[CH2:11]
Reactant: C=CCBr
Reactant: Nc1cc(O)c(Br)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C=CCOc1cc(N)c(F)cc1Br
Temperature: 25 °C
Reaction time: 12 h
Yield: 32.9 %

Procedure:
5-Amino-2-bromo-4-fluorophenol (30.9 g), allyl bromide (21.8 g) and potassium carbonate (22.77 g) were suspended in acetonitrile (300 ml), and the mixture was stirred at room temperature for 12 hours. After the reaction, the precipitates were filtered, the solvent was distilled off, and this was extracted with ethyl acetate. After washing with water, it was dried over anhydrous magnesium sulfate. Then, ethyl acetate was distilled off and the resulting oily substance was purified by chromatography on silica gel (ethyl acetate:n-hexane=1:3) to obtain the objective 5-allyloxy-4-bromo-2-fluoroaniline (12.14 g).
Reaction SMILES: [OH-].[Na+:2].O=O.[O:5]=[C:6]([OH:17])[C@@H:7]([C@H:9]([C@@H:11]([C@@H:13]([CH2:15][OH:16])[OH:14])[OH:12])[OH:10])[OH:8]>>[O:5]=[C:6]([O-:17])[C@@H:7]([C@H:9]([C@@H:11]([C@@H:13]([CH2:15][OH:16])[OH:14])[OH:12])[OH:10])[OH:8].[Na+:2]
Reactant: O=C(O)[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: O=O
Agent: [Na+]
Agent: [OH-]
Product: O=C([O-])[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO

Procedure:
The pH of the solution is kept constant by continuously adding a solution containing 1 mol.liter-1 of sodium hydroxide, which has been saturated beforehand with oxygen at atmospheric pressure. The gluconic acid is thus neutralised to give sodium gluconate.
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([NH2:14])[CH2:11][CH2:10][N:9]1[C:15](=[O:24])[C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([Cl:23])[CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:25]1([CH2:31][C:32](Cl)=[O:33])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(N(CC)CC)C>>[CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([NH:14][C:32](=[O:33])[CH2:31][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:11][CH2:10][N:9]1[C:15](=[O:24])[C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([Cl:23])[CH:17]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N[C@H]1CCN(C(=O)c2cc(Cl)cc(Cl)c2)[C@H](Cc2ccccc2)C1
Reactant: O=C(Cl)Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=C(Cc1ccccc1)N[C@H]1CCN(C(=O)c2cc(Cl)cc(Cl)c2)[C@H](Cc2ccccc2)C1

Procedure:
200 mg (0.55 1 mmol) of (2R*,4S*)-2-benzyl-1-(3,5-dichlorobenzoyl)-4-piperidinamine are reacted in analogy to Example 39a with 88 μl (0.661 mmol) of phenylacetyl chloride and 108 μl (0.771 mmol) of triethylamine. The title compound ##STR90## is obtained (127 mg, 48% ) as white foam. TLC: methylene chloride/methanol/conc. ammonia (1000:50:1) Rf =0.56, FD-MS: M+ =480, 482; IR: 3660, 3405, 1665, 1630 cm-1
Reaction SMILES: C([Li])CCC.I[C:7]1[CH:12]=[CH:11][C:10]([I:13])=[CH:9][CH:8]=1.[CH3:14][CH:15]([CH3:19])[C:16](=[O:18])[CH3:17].Cl>C1COCC1>[I:13][C:10]1[CH:11]=[CH:12][C:7]([C:16]([OH:18])([CH:15]([CH3:19])[CH3:14])[CH3:17])=[CH:8][CH:9]=1
Reactant: CC(=O)C(C)C
Reactant: Ic1ccc(I)cc1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)C(C)(O)c1ccc(I)cc1
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
n-Butyllithium (37.0 mL of a 2.5 M solution in hexanes, 92.8 mmol) was added to a stirred solution of 1,4-diiodobenzene (30.0 g, 90.9 mmol) in THF (200 mL) at −78° C. After approximately 20 min, 3-methyl-2-butanone (10.2 mL, 95.5 mmol) was added, and the resulting mixture was allowed to stir at −78° C. for about 1 h. The reaction mixture was poured into aqueous 1N HCl and extracted twice with diethyl ether. The combined organic extracts were washed water and brine, dried (magnesium sulfate) and concentrated in vacuo to afford the title compound i-2a. m/z (ES) 273 (M-OH)+. 1HNMR (500 MHz, CDCl3): δ 7.67 (d, 2H, J=8.5 Hz), 7.20 (d, 2H, J=8.7 Hz), 2.00 (m, 1H), 1.52 (s, 3H), 0.92 (d, 3H, J=6.7 Hz), 0.81 (d, 3H, J=6.9 Hz).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:27]=[CH:26][C:8]2[N:9]=[C:10]([NH:12][C:13]3[N:17]([CH3:18])[C:16]4[CH:19]=[CH:20][C:21]([C:23]([OH:25])=O)=[CH:22][C:15]=4[N:14]=3)[S:11][C:7]=2[CH:6]=1)(=[O:4])=[O:3].CN.[CH3:30][N:31](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH3:30][NH:31][C:23]([C:21]1[CH:20]=[CH:19][C:16]2[N:17]([CH3:18])[C:13]([NH:12][C:10]3[S:11][C:7]4[CH:6]=[C:5]([S:2]([CH3:1])(=[O:3])=[O:4])[CH:27]=[CH:26][C:8]=4[N:9]=3)=[N:14][C:15]=2[CH:22]=1)=[O:25]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: Cn1c(Nc2nc3ccc(S(C)(=O)=O)cc3s2)nc2cc(C(=O)O)ccc21
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(S(C)(=O)=O)cc3s1)n2C
Yield: 82.3 %

Procedure:
2-(6-Methanesulfonyl-benzothiazol-2-ylamino)-1-methyl-1H-benzimidazole-5-carboxylic acid methylamide (34 mg) was prepared by following General Procedure F using 2-(6-methanesulfonyl-benzothiazol-2-ylamino)-1-methyl-1H-benzimidazole-5-carboxylic acid (40 mg), methylamine (0.2 ml, 2.0 M solution in THF), HBTU (38 mg), and DIEA (0.1 ml). LCMS: m/z 417; and 1H NMR (DMSO-d6, 400 MHz): δ 8.45 (m, 1H), 8.04 (br, 1H), 8.00 (m, 1H), 7.93 (s, 1H), 7.71 (t, 2H), 7.43 (d, 1H), 7.18 (t, 1H), 3.63 (s, 3H), 3H), 3.27 (s, 3H), and 2.87 (s, 3H).
Reaction SMILES: [CH3:1][CH:2]1[NH:7][CH2:6][CH:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+].[CH3:22][O:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Cl)=[CH:26][CH:25]=1.O>CN(C)C=O>[CH3:22][O:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][N:7]2[C@@H:2]([CH3:1])[CH2:3][CH2:4][C@@H:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:6]2)=[CH:26][CH:25]=1
Reactant: COc1ccc(CCl)cc1
Reactant: CC1CCC(NC(=O)OC(C)(C)C)CN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(CN2C[C@H](NC(=O)OC(C)(C)C)CC[C@@H]2C)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of tert-butyl (6-methylpiperidin-3-yl)carbamate (8.03 g) in dimethylformamide (90 ml) were added potassium carbonate (10.4 g) and 4-methoxybenzyl chloride (5.34 ml), and the mixture was stirred at room temperature for 6 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (the developing solvent: chloroform/methanol=100/3) to give the title compound (8.87 g) as a colorless oil.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:8]([F:9])=[CH:7][C:6]([C:10](=[O:16])[CH2:11][NH:12][CH:13]([CH3:15])[CH3:14])=[CH:5][C:4]=1[C:17]#[N:18]>>[NH2:2][C:3]1[C:8]([F:9])=[CH:7][C:6]([CH:10]([OH:16])[CH2:11][NH:12][CH:13]([CH3:15])[CH3:14])=[CH:5][C:4]=1[C:17]#[N:18]
Reactant: CC(C)NCC(=O)c1cc(F)c(N)c(C#N)c1
Agent: Cl
Product: CC(C)NCC(O)c1cc(F)c(N)c(C#N)c1

Procedure:
m.p. of the hydrochloride: 182°-184° C. (decomp.), was prepared from 4'-amino-3'-cyano-5'-fluoro-2-isopropylaminoacetophenone analogous to Example 49.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:6]([C:7](=O)[CH:8]=[CH:9][C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.[C:22]1([NH:28][NH2:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.Cl.[OH-].[Na+]>C(O)C.O>[CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:6]([C:7]2[CH2:8][CH:9]([C:10]3[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=3)[N:28]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:29]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C(=O)C=Cc2ccc([N+](=O)[O-])cc2)cc1
Reactant: NNc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1ccc(C2=NN(c3ccccc3)C(c3ccc([N+](=O)[O-])cc3)C2)cc1
Yield: 78.8 %

Procedure:
14.2 g of 4'-methoxy-4-nitrochalcone was reacted with 5.4 g of phenylhydrazine in 100 ml of ethanol in the presence of 5 ml of hydrochloric acid by refluxing while heating for 6 hours. After neutralizing the reaction mixture with 50 ml of 1N NaOH, 400 ml of water was added thereto. Decantation-water washing was repeated three times. Crystals formed were recrystallized from 200 ml of acetone to obtain 14.7 g of the desired compound. m.p. 168°-173° C.
Reaction SMILES: C(NCC)C.C([Li])CCC.[CH2:11]([Sn:15](Cl)([CH2:20][CH2:21][CH2:22][CH3:23])[CH2:16][CH2:17][CH2:18][CH3:19])[CH2:12][CH2:13][CH3:14].[O:25]1[CH2:29]C[CH2:27][CH2:26]1>>[CH2:11]([Sn:15]([CH2:20][CH2:21][CH2:22][CH3:23])([CH2:16][CH2:17][CH2:18][CH3:19])[C:27]#[C:26][O:25][CH3:29])[CH2:12][CH2:13][CH3:14]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: C1CCOC1
Agent: [Li]CCCC
Solvent: CCNCC
Product: CCCC[Sn](C#COC)(CCCC)CCCC
Temperature: 23 °C
Reaction time: 0.17 h
Yield: 78 %

Procedure:
To a solution of freshly distilled diethylamine (9.6 mL, 92 mmol, 3.9 equiv) in tetrahydrofuran (300 mL) at 0° C. was added n-butyllithium (2.5 M in hexanes, 32 mL, 80 mmol 3.4 equiv). After stirring for 10 min, 1,1-dimethoxy-2-chloro-acetaldehyde (4.0 mL, 26 mmol, 1.1 equiv) was added dropwise to the reaction mixture. The reaction was stirred for 2 hours at 0° C. Tributyltin chloride (6.2 mL, 24 mmol, 1.0 equiv) was then added to the reaction mixture. The reaction was warmed to 23° C. over 1 hour and stirred for 8 hours. The volatiles were removed in vacuo and the reaction mixture was re-suspended in hexane (30 mL) and filtered through a glass frit under an argon atmosphere. The solution was then re-concentrated by rotary evaporation and distilled by Kugelrohr to yield 6.4 g (78%) of 10 as a colorless oil.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[C:3]=1[CH3:20].[O:21]1[CH2:26][CH2:25][N:24]([C:27]2[CH:33]=[CH:32][C:31]([N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)=[CH:30][C:28]=2[NH2:29])[CH2:23][CH2:22]1>C1(C)C=CC=CC=1>[N:24]1([C:27]2[CH:33]=[CH:32][C:31]([N:34]3[CH2:35][CH2:36][O:37][CH2:38][CH2:39]3)=[CH:30][C:28]=2[NH:29][C:2]2[C:11]3[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=3[F:12])[N:5]=[C:4]([N:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[C:3]=2[CH3:20])[CH2:25][CH2:26][O:21][CH2:22][CH2:23]1
Reactant: Nc1cc(N2CCOCC2)ccc1N1CCOCC1
Reactant: Cc1c(N2CCCCC2)nc2cc(F)cc(F)c2c1Cl
Solvent: Cc1ccccc1
Product: Cc1c(N2CCCCC2)nc2cc(F)cc(F)c2c1Nc1cc(N2CCOCC2)ccc1N1CCOCC1

Procedure:
Essentially prepared according to Procedure H using 4-chloro-5,7-difluoro-3-methyl-2-(piperidin-1-yl)quinoline (34.0 mg, 0.120 mmol) and 2,5-dimorpholinoaniline in toluene to give N-(2,5-di-4-morpholinylphenyl)-5,7-difluoro-3-methyl-2-(1-piperidinyl)-4-quinolinamine. 1H NMR (CDCl3) δ ppm 7.97 (1H, d, J=7.6 Hz), 7.08 (1H, d, J=8.6 Hz), 6.67-6.82 (1H, m), 6.45 (1H, d, J=9.6 Hz), 6.06 (1H, d, J=2.2 Hz), 3.88 (4H, t, J=4.3 Hz), 3.70-3.82 (4H, m), 3.36 (4H, br. s.), 2.96-3.24 (4H, m), 2.70-2.97 (4H, m), 2.11 (3H, s), 1.58-1.92 (7H, m). Mass Spectrum (ESI) m/e=524.3 (M+1).
Reaction SMILES: [F:1][C:2]1[C:3]([NH2:9])=[N:4][C:5](=[O:8])[NH:6][CH:7]=1.[CH3:10][O:11][C:12]1[CH:13]=[C:14]([CH:18]=[C:19]([O:23][CH3:24])[C:20]=1[O:21][CH3:22])[C:15](Cl)=[O:16].O>N1C=CC=CC=1>[F:1][C:2]1[C:3]([NH:9][C:15](=[O:16])[C:14]2[CH:13]=[C:12]([O:11][CH3:10])[C:20]([O:21][CH3:22])=[C:19]([O:23][CH3:24])[CH:18]=2)=[N:4][C:5](=[O:8])[NH:6][CH:7]=1
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Reactant: Nc1nc(=O)[nH]cc1F
Solvent: c1ccncc1
Solvent: O
Product: COc1cc(C(=O)Nc2nc(=O)[nH]cc2F)cc(OC)c1OC
Temperature: 100 °C
Reaction time: 5 h
Yield: 90.4 %

Procedure:
12.9 g of 5-fluorocytosine was suspended in 78 ml of pyridine, followed by addition of 23.1 g of 3,4,5-trimethoxybenzoyl chloride and stirring at 100° C. for 5 hours. The reaction mixture was cooled down to room temperature and then poured into 310 ml of water at room temperature over a period of 20 minutes. The precipitated crystals were collected by filtration to obtain 29.2 g (90.4%) of 5-fluro-N4 -(3,4,5-trimethoxybenzoyl)cytosine.
Reaction SMILES: Cl.[CH3:2][N:3]1[CH2:8][CH2:7][CH:6]([CH2:9][CH2:10][C:11]([OH:13])=O)[CH2:5][CH2:4]1.C(Cl)(=O)C([Cl:17])=O>ClCCl.CN(C)C=O>[CH3:2][N:3]1[CH2:8][CH2:7][CH:6]([CH2:9][CH2:10][C:11]([Cl:17])=[O:13])[CH2:5][CH2:4]1
Reactant: CN1CCC(CCC(=O)O)CC1
Reactant: O=C(Cl)C(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CN1CCC(CCC(=O)Cl)CC1

Procedure:
A suspension of 3-(1-methylpiperid-4-yl)propionic acid hydrochloride (WO 9620173 A1, Example 1)(0.33 g, 0.00159 mole) in dry dichloromethane (10 ml) was treated with dimethylformamide (1 drop) and oxalyl chloride (0.416 ml, 0.605 g, 0.00477 mole) under an atmosphere of argon. After stirring for 3½ hours the mixture was concentrated in vacuo. The residue was dissolved in dry dichloromethane and concentrated in vacuo to give the title compound as a white solid.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:41]=[CH:40][C:8]2[NH:9][C:10]([C:12]3[N:13]=[C:14]([C:36]([F:39])([F:38])[F:37])[S:15][C:16]=3[N:17]3[CH2:22][CH2:21][N:20]([C:23](=[O:34])[CH2:24][N:25]4[C:29]5=[N:30][CH:31]=[CH:32][CH:33]=[C:28]5[N:27]=[CH:26]4)[C@H:19]([CH3:35])[CH2:18]3)=[N:11][C:7]=2[CH:6]=1)=O.[CH2:42]([Mg]Br)[CH3:43]>C1COCC1.C(Cl)Cl.C([O-])(O)=O.[Na+].CC(O[Ti](OC(C)C)(OC(C)C)OC(C)C)C>[OH:2][C:3]1([C:5]2[CH:41]=[CH:40][C:8]3[NH:9][C:10]([C:12]4[N:13]=[C:14]([C:36]([F:37])([F:38])[F:39])[S:15][C:16]=4[N:17]4[CH2:22][CH2:21][N:20]([C:23](=[O:34])[CH2:24][N:25]5[C:29]6=[N:30][CH:31]=[CH:32][CH:33]=[C:28]6[N:27]=[CH:26]5)[C@H:19]([CH3:35])[CH2:18]4)=[N:11][C:7]=3[CH:6]=2)[CH2:43][CH2:42]1
Reactant: COC(=O)c1ccc2[nH]c(-c3nc(C(F)(F)F)sc3N3CCN(C(=O)Cn4cnc5cccnc54)[C@H](C)C3)nc2c1
Reactant: CC[Mg]Br
Agent: CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: C[C@@H]1CN(c2sc(C(F)(F)F)nc2-c2nc3cc(C4(O)CC4)ccc3[nH]2)CCN1C(=O)Cn1cnc2cccnc21
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of Example 167 (25 mg) in THF (1.15 mL) was added Ti(OiPr)4 (0.0126 mL). Ethylmagnesium bromide (1M in THF, 0.513 mL) was added dropwise over 30 min at RT. The reaction mixture was stirred at RT for 20 h and diluted with DCM and 1M NaHCO3. The phases were separated. The org. phase was washed with water, dried (Na2SO4), filtered off and evaporated in vacuo. The residue was purified by preparative LC-MS (III) to afford 1 mg of pale yellow solid. LC-MS (B): tR=0.65 min; [M+H]+: 583.18.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:4]=[C:5]2[CH:11]=[C:10]([CH:12]=[O:13])[NH:9][C:6]2=[N:7][CH:8]=1.[H-].[Na+].[F:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Br)=[CH:19][CH:18]=1.[Cl-].[NH4+]>CN(C)C=O>[F:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][N:9]2[C:6]3=[N:7][CH:8]=[C:3]([S:2][CH3:1])[N:4]=[C:5]3[CH:11]=[C:10]2[CH:12]=[O:13])=[CH:19][CH:18]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: CSc1cnc2[nH]c(C=O)cc2n1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CSc1cnc2c(cc(C=O)n2Cc2ccc(F)cc2)n1
Reaction time: 0.33 h
Yield: 96.2 %

Procedure:
To a solution of the compound obtained in Example 34 (5) (10 mg) in N,N-dimethylformamide (0.5 ml), 60% sodium hydride (3 mg) was added at 0° C. and the mixture was stirred for 20 minutes. To the resulting mixture was added dropwise 4-fluorobenzyl bromide (15 mg) and the mixture was stirred at 15 to 30° C. for 30 minutes. The reaction solution was poured into a saturated aqueous ammonium chloride solution, extracted with chloroform, washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The resulting residue was separated using silica gel preparative thin-layer chromatography (hexane:ethyl acetate=5:1) to obtain 15 mg (99.6%) of the desired product as an orange powder.
Reaction SMILES: Br[C:2]1[C:7](=[O:8])[N:6]([CH3:9])[C:5]2[N:10]([C:13]3[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:14]=3[F:20])[N:11]=[CH:12][C:4]=2[CH:3]=1.[CH:21]1([NH:24][C:25](=[O:43])[C:26]2[CH:31]=[C:30](B3OC(C)(C)C(C)(C)O3)[C:29]([CH3:41])=[C:28]([F:42])[CH:27]=2)[CH2:23][CH2:22]1>O1CCOCC1.C([O-])([O-])=O.[Na+].[Na+].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>[CH:21]1([NH:24][C:25](=[O:43])[C:26]2[CH:27]=[C:28]([F:42])[C:29]([CH3:41])=[C:30]([C:2]3[C:7](=[O:8])[N:6]([CH3:9])[C:5]4[N:10]([C:13]5[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:14]=5[F:20])[N:11]=[CH:12][C:4]=4[CH:3]=3)[CH:31]=2)[CH2:22][CH2:23]1
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1B1OC(C)(C)C(C)(C)O1
Reactant: Cn1c(=O)c(Br)cc2cnn(-c3c(F)cccc3F)c21
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: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1cc2cnn(-c3c(F)cccc3F)c2n(C)c1=O
Temperature: 130 °C
Yield: 66.3 %

Procedure:
A mixture of 5-bromo-1-(2,6-difluorophenyl)-7-methyl-1H-pyrazolo[3,4-b]pyridin-6(7H)-one (110 mg, 0.32 mmol), N-cyclopropyl-3-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (122 mg, 0.38 mmol) and 15 mg of Pd(PPh3)4 in 2.0 mL dioxane and 0.8 mL of 1 M Na2CO3 in a sealed glass tube was heated at 130° C. for 30 min. The reaction mixture was diluted in EtOAc, washed with 1 N NaOH solution. The organic phase was dried over MgSO4, filtered and concentrated. Purification of the brown residue on an ISCO 12 g column (40-80% EtOAc in Hexanes) afforded the title compound (96 mg) as an off white amorphous solid. MS (ESI, pos.ion) m/z: 453.1 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][CH:9]=[CH:10][C:3]=12.[H-].[Na+].[CH3:13][S:14](Cl)(=[O:16])=[O:15]>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([S:14]([CH3:13])(=[O:16])=[O:15])[CH:9]=[CH:10][C:3]=12
Reactant: CS(=O)(=O)Cl
Reactant: Brc1ccnc2[nH]ccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)n1ccc2c(Br)ccnc21
Reaction time: 0.25 h

Procedure:
4-Bromo-1H-pyrrolo[2,3-b]pyridine (250 mg, 1.27 mmol) was dissolved in 5 ml N—N, dimethylformamide. Sodium hydride was slowly added and the mixture was stirred for 15 minutes. Methanesulfonyl chloride (66 μl, 0.85 mmol) was added and the reaction mixture was stirred at room temperature overnight. The reaction was extracted with ethyl acetate and washed with water. The organic phase was dried over sodium sulphate, filtered and evaporated under reduced pressure. The residue (200 mg) was used in the next synthetic step without further purification.
Reaction SMILES: C([O:4][C:5]([C@@H:7]1[C@@H:12]2[C@H:8]1[CH2:9][C@H:10]([F:23])[C@@:11]2([NH:16]C(OCC=C)=O)[C:13]([OH:15])=[O:14])=[O:6])C=C.[C:24](=[O:36])([O:29][CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1)[O:25][CH:26](Cl)[CH3:27]>>[NH2:16][C@@:11]1([C:13]([O:15][CH:26]([O:25][C:24]([O:29][CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)=[O:36])[CH3:27])=[O:14])[C@@H:10]([F:23])[CH2:9][C@@H:8]2[C@H:12]1[C@H:7]2[C:5]([OH:4])=[O:6]
Reactant: C=CCOC(=O)N[C@]1(C(=O)O)[C@H]2[C@@H](C[C@@H]1F)[C@@H]2C(=O)OCC=C
Reactant: CC(Cl)OC(=O)OC1CCCCC1
Product: CC(OC(=O)OC1CCCCC1)OC(=O)[C@@]1(N)[C@H]2[C@@H](C[C@@H]1F)[C@@H]2C(=O)O
Yield: 14.4 %

Procedure:
(1S,2S,3S,5R,6S)-6-((Allyloxy)carbonyl) 2-(((allyloxy)carbonyl)amino)-3-fluorobicyclo[3.1.0]hexane-2-carboxylic acid (B-1-1, 701 mg) and 1-chloroethyl cyclohexyl carbonate (664 mg) were treated in the same manner as in Example A-8 (1), (2) to give the title compound (B-1, 115 mg) as a yellow solid.
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].[CH2:5]1[CH2:11][S:8](=[O:10])(=[O:9])[O:7][CH2:6]1.CCCCCC>ClCCl.CCOCC>[CH:1]([NH:4][CH2:6][CH2:5][CH2:11][S:8]([OH:10])(=[O:9])=[O:7])([CH3:3])[CH3:2]
Reactant: O=S1(=O)CCCO1
Reactant: CC(C)N
Solvent: ClCCl
Solvent: CCCCCC
Solvent: CCOCC
Product: CC(C)NCCCS(=O)(=O)O
Temperature: 25 °C
Yield: 65.8 %

Procedure:
Isopropylamine (2.5 mL, 29 mmol) was added to a solution of 1,3-propane sultone (3.05 g, 25 mmol) in a mixture of dichloromethane/ether (40 mL, 1:1). The mixture was heated at reflux for 3 hours. The reaction mixture was cooled to room temperature and hexane (10 mL) was added. The solid material was collected by filtration, rinsed with ether (10 mL), and dried in vacuo. Compound CG was obtained as a fine white powder (2.98 g, 65.6% yield). m.p. 240-43° C. 1H NMR (500 MHz, D2O) δ 1.06 (d, J=6.3 Hz, 6H), 1.86 (qt, J=7.6 Hz, 2H), 2.76 (t, J=7.6 Hz, 2H), 3.14 (t, J=7.8 Hz, 2H), 3.13-3.21 (m, J=6.6 Hz, 1H). 13C NMR (125 MHz, D2O) δ 18.2, 21.5, 25.8, 43.4, 47.9, 50.8.
Reaction SMILES: [OH-].[Na+].[C:3]1([C:9]2[O:10][CH:11]=[C:12]([C:14]3[N:24]=[CH:23][CH:22]=[CH:21][C:15]=3[C:16]([O:18]CC)=[O:17])[N:13]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>CCO>[C:3]1([C:9]2[O:10][CH:11]=[C:12]([C:14]3[N:24]=[CH:23][CH:22]=[CH:21][C:15]=3[C:16]([OH:18])=[O:17])[N:13]=2)[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(=O)c1cccnc1-c1coc(-c2ccccc2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1cccnc1-c1coc(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
An aqueous solution of NaOH (0.27 mL, 2M in water, 0.54 mmol) was added to a solution of ethyl 2-(2-phenyloxazol-4-yl)nicotinate (80 mg, 0.27 mmol) in EtOH (2.7 mL). After stirring overnight at room temperature the solvent was removed in vacuo, the residue was dissolved in water and HCl (2M in water) was added until pH ˜1 was obtained. The solvent was removed in vacuo and the crude product obtained was used without further purification; ESI-MS [M+H+]=267.1.