Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:4][NH:5][N:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([OH:16])=[C:8]([C:17]3[NH:22][C:21]4[CH:23]=[CH:24][C:25]([OH:30])=[C:26]([N+:27]([O-])=O)[C:20]=4[S:19](=[O:32])(=[O:31])[N:18]=3)[C:7]2=[O:33])[CH2:3][CH2:2]1.[Cl-].[NH4+]>CO.O1CCCC1.O.[Fe]>[NH2:27][C:26]1[C:20]2[S:19](=[O:31])(=[O:32])[N:18]=[C:17]([C:8]3[C:7](=[O:33])[N:6]([NH:5][CH2:4][CH:1]4[CH2:2][CH2:3]4)[C:15]4[C:10]([C:9]=3[OH:16])=[CH:11][CH:12]=[CH:13][CH:14]=4)[NH:22][C:21]=2[CH:23]=[CH:24][C:25]=1[OH:30]
Reactant: O=c1c(C2=NS(=O)(=O)c3c(ccc(O)c3[N+](=O)[O-])N2)c(O)c2ccccc2n1NCC1CC1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Nc1c(O)ccc2c1S(=O)(=O)N=C(c1c(O)c3ccccc3n(NCC3CC3)c1=O)N2
Temperature: 60 °C
Yield: 53.9 %

Procedure:
A mixture of the product of Example 381 (10 mg, 0.021 mmol), iron powder (5.9 mg, 0.105 mmol), and ammonium chloride (1.3 mg, 0.024 mmol) in methanol:tetrahydrofuran:water (2:2:1, 2 mL) was heated at 60° C. for 1 hour. The solution filtered through Celite® and washed with tetrahydrofuran. The solution was evaporated under reduced pressure and the residue was triturated with ethyl acetate, filtered and washed with water and dried to give title compound (5 mg, 53%). 1H NMR (300 MHz, DMSO-d6) δ 0.13 (d, J=3.68 Hz, 2 H) 0.40 (d, J=7.72 Hz, 2 H) 1.02 (m, 1 H) 2.85 (d, J=5.52 Hz, 2 H) 5.40 (s, 2 H) 6.46 (s, 1 H) 6.65 (d, J=8.46 Hz, 1 H) 7.00 (d, J=8.09 Hz, 1 H) 7.45 (t, J=7.35 Hz, 1 H) 7.89 (t, J=7.17 Hz, 1 H) 8.10 (d, J=8.46 Hz, 1 H) 8.17 (d, J=8.82 Hz, 1 H) 10.13 (s, 1 H) 13.82 (s, 1 H) 15.17 (s, 1 H). MS (ESI−) m/z 440 (M−H)−.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]([CH2:13][CH2:14][O:15][CH3:16])[C:6]1[C:7]([NH2:12])=[CH:8][CH:9]=[CH:10][CH:11]=1.[C:17](Cl)(Cl)=[S:18].O>O1CCOCC1>[CH3:1][O:2][CH2:3][CH2:4][N:5]([CH2:13][CH2:14][O:15][CH3:16])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:12]=[C:17]=[S:18]
Reactant: S=C(Cl)Cl
Reactant: COCCN(CCOC)c1ccccc1N
Solvent: O
Solvent: C1COCCO1
Product: COCCN(CCOC)c1ccccc1N=C=S
Temperature: 0 °C
Reaction time: 4 h

Procedure:
A solution of N,N-bis(2-methoxyethyl)benzene-1,2-diamine (7.5 g) in dioxane (10 ml) was added to a mixture of thiophosgene (4 ml) and water (60 ml) which had been cooled to 0° C. The temperature of the mixture was allowed to rise to ambient and the mixture was stirred for 4 hours. Ice water (50 ml) was added and the mixture extracted with ether (3×20 ml). The extract was washed with water (50 ml) and brine (50 ml), dried and evaporated to give a residue which was heated at 45° C. under vacuum (100 mm/Hg) to give 2-[bis(2-methoxyethyl)amino]phenyl isothiocyanate as an oil.
Reaction SMILES: [CH3:1][C:2]([CH3:5])([O-])[CH3:3].[K+].[C:7]1([N:13]2[C:26]3[CH:25]=[CH:24][C:23]([CH:27]=O)=[CH:22][C:21]=3[S:20][C:19]3[C:14]2=[CH:15][CH:16]=[C:17]([CH:29]=O)[CH:18]=3)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH:31](P(=O)(OCC)OCC)([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[C:2]1([C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:27][C:23]2[CH:24]=[CH:25][C:26]3[N:13]([C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=4)[C:14]4[C:19]([S:20][C:21]=3[CH:22]=2)=[CH:18][C:17]([CH:29]=[C:31]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)=[CH:16][CH:15]=4)[CH:3]=[CH:19][CH:14]=[CH:15][CH:1]=1
Reactant: CC(C)(C)[O-]
Reactant: CCOP(=O)(OCC)C(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccc2c(c1)Sc1cc(C=O)ccc1N2c1ccccc1
Agent: [K+]
Product: C(=C(c1ccccc1)c1ccccc1)c1ccc2c(c1)Sc1cc(C=C(c3ccccc3)c3ccccc3)ccc1N2c1ccccc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
6.63 g (58.1 mmol) of potassium tert-butoxide and then 8.50 g (25.7 mmol) of 10-phenylphenothiazine-3,7-dicarbaldehyde were added at room temperature with stirring to a solution of 15.61 g (51.3 mmol) of diethyl benzhydrylphosphonate (prepared analogously to Example 13 in U.S. Pat. No. 5,130,603) in 121 ml of dimethyl sulfoxide dried over molecular sieve. After stirring at room temperature for 5 hours, the reaction solution was diluted with 1500 ml of methanol and stirred for a further 15 min. The precipitate was filtered off, washed with methanol and dried at 80° C. under reduced pressure. 6.92 g (43% of theory) of yellowish solid having a melting point of 232-237° C. were obtained.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([OH:14])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[NH:15]1[CH2:20][CH2:19][CH:18](O)[CH2:17][CH2:16]1>>[CH:1]1[C:13]2[CH:12]([O:14][CH:18]3[CH2:19][CH2:20][NH:15][CH2:16][CH2:17]3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: OC1c2ccccc2-c2ccccc21
Reactant: OC1CCNCC1
Product: c1ccc2c(c1)-c1ccccc1C2OC1CCNCC1
Yield: 38 %

Procedure:
Using 9-fluorenol and 4-piperidinol, the procedure of Reference Example 23 was otherwise repeated to provide the title compound. Yield 38%.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([OH:16])[CH:14]=[CH:15][C:7]1=2)[CH3:2].[H-].[Na+].[C:20]([O:24][C:25](=[O:31])[NH:26][CH2:27][CH2:28][CH2:29]Br)([CH3:23])([CH3:22])[CH3:21].[CH3:32]N(C=O)C>>[CH2:1]([O:3][C:4](=[O:17])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([O:16][CH2:29][CH2:28][CH2:27][NH:26][C:25]([O:24][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:31])[CH:14]=[C:15]([CH3:32])[C:7]1=2)[CH3:2]
Reactant: CCOC(=O)CC1OB(O)c2cc(O)ccc21
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)NCCCBr
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)CC1OB(O)c2cc(OCCCNC(=O)OC(C)(C)C)cc(C)c21
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 40 %

Procedure:
To a solution of (1,6-dihydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl)-acetic acid ethyl ester (0.500 g, 1.99 mmol) in DMF (20 mL) was added NaH (0.176 g, 4.40 mmol) and the mixture was stirred at 0° C. for 45 minutes. A solution of (3-bromo-propyl)-carbamic acid tert-butyl ester (1.04 g, 4.38 mmol) in DMF (5 mL) was added and the mixture was stirred at room temperature for 18 hours. The reaction mixture was quenched with H2O and extracted with EtOAc (3×50 mL). The organic extracts were washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel flash column chromatography (33-66% EtOAc/Hexane) to give [6-(3-tert-butoxycarbonylamino-propoxy)-1-hydroxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl]-acetic acid ethyl ester (0.325 g, 40%). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.00 (s, 1H), 6.87 (br. s., 1H), 6.81 (s, 1H), 5.43 (d, J=7.42 Hz, 1H), 3.97-4.10 (m, 2H), 3.93 (t, J=6.06 Hz, 2H), 2.99-3.08 (m, 3H), 2.23 (s, 3H), 2.14-2.22 (m, 1H), 1.72-1.85 (m, 2H), 1.35 (s, 9H), 1.08-1.19 (m, 3H).
Reaction SMILES: [CH3:1][N:2]([CH3:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1.ClC(N(C)C)=C(C)C.[Br:21][C:22]1[C:23]([CH3:29])=[C:24]([CH:26]=[CH:27][CH:28]=1)[NH2:25].CCN(C(C)C)C(C)C>C(Cl)Cl.C([O-])(O)=O.[Na+]>[Br:21][C:22]1[C:23]([CH3:29])=[C:24]([NH:25][C:7](=[O:9])[C:6]2[CH:5]=[CH:4][C:3]([N:2]([CH3:1])[CH3:12])=[CH:11][CH:10]=2)[CH:26]=[CH:27][CH:28]=1
Reactant: CN(C)c1ccc(C(=O)O)cc1
Reactant: Cc1c(N)cccc1Br
Agent: CC(C)=C(Cl)N(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(Br)cccc1NC(=O)c1ccc(N(C)C)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 53.5 %

Procedure:
A suspension of 4-(dimethylamino)benzoic acid (100 mg, 0.605 mmol) in DCM (3 mL) was treated with 1-chloro-N,N,2-trimethylprop-1-en-1-amine (0.120 mL, 0.908 mmol) and the resulting solution was stirred at rt for 1.5 h. 3-Bromo-2-methylaniline (0.053 mL, 0.432 mmol) was added, followed by DIEA (0.264 mL, 1.513 mmol). The mixture was stirred at rt for 1 h, then was diluted with DCM and NaHCO3 (aq). The layers were separated and the organic phase was washed with brine, dried and concentrated. The residue was purified by column chromatography (eluting with a gradient from 85:15 to 65:35 hexane-EtOAc) to provide N-(3-bromo-2-methylphenyl)-4-(dimethylamino)benzamide as a light yellow solid (77 mg, 53%). 1H NMR (400 MHz, DMSO-d6) δ 9.75 (s, 1H) 7.85 (d, J=9.0 Hz, 2H) 7.49 (dd, J=8.0, 1.0 Hz, 1H) 7.30 (dd, J=7.9, 0.9 Hz, 1H) 7.15 (t, J=7.9 Hz, 1H) 6.75 (d, J=9.0 Hz, 2H) 2.99 (s, 6H) 2.25 (s, 3H). Mass spectrum m/z 331, 333 (M−H)−.
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.CN1CCOCC1.CCN=C=NCCCN(C)C.Cl.[CH3:29][O:30][C:31](=[O:38])[C@H:32]([C@H:34]([CH2:36][CH3:37])[CH3:35])[NH2:33]>C(Cl)Cl>[CH3:29][O:30][C:31](=[O:38])[CH:32]([NH:33][C:1]([C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1)=[O:9])[CH:34]([CH3:35])[CH2:36][CH3:37]
Reactant: CC[C@H](C)[C@H](N)C(=O)OC
Reactant: O=C(O)c1cccnc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CCC(C)C(NC(=O)c1cccnc1)C(=O)OC
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 70.2 %

Procedure:
To a solution of nicotinic acid (2.0 g, 16.5 mmol) in DCM (20 mL), was added N-methylmorpholine (6.9 mL, 49.5 mmol), EDCI.HCl (6.3 g, 33.0 mmol) and isoleucine methyl ester (3.0 g, 16.5 mmol). The mixture was allowed to stir at room temperature (25° C.) over 2.5 h under nitrogen atmosphere. The resulting mixture was diluted with DCM (200 mL), washed with water (3×100 mL) and dried over sodium sulphate. The crude product obtained upon evaporation of the solvent was further purified by silica gel column chromatography to obtain product as yellow solid (2.9 g, 72%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:20]3[C:19]([CH3:22])([CH3:21])[CH2:18][CH2:17][C:16]([CH3:24])([CH3:23])[C:15]=3[CH:14]=[C:13]([CH:25]([OH:28])[C:26]#[CH:27])[CH:12]=2)=[CH:7][CH:6]=1)(C)(C)C.I[C:30]1[CH:38]=[CH:37][C:33]([C:34]([OH:36])=[O:35])=[CH:32][CH:31]=1>[Cu](I)I.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>[OH:28][CH:25]([C:13]1[CH:12]=[C:11]([C:8]2[CH:7]=[CH:6][C:5]([CH3:1])=[CH:10][CH:9]=2)[C:20]2[C:19]([CH3:22])([CH3:21])[CH2:18][CH2:17][C:16]([CH3:24])([CH3:23])[C:15]=2[CH:14]=1)[C:26]#[C:27][C:30]1[CH:38]=[CH:37][C:33]([C:34]([OH:36])=[O:35])=[CH:32][CH:31]=1
Reactant: C#CC(O)c1cc(-c2ccc(C(C)(C)C)cc2)c2c(c1)C(C)(C)CCC2(C)C
Reactant: O=C(O)c1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Product: Cc1ccc(-c2cc(C(O)C#Cc3ccc(C(=O)O)cc3)cc3c2C(C)(C)CCC3(C)C)cc1
Yield: 72 %

Procedure:
In a similar manner to that of Example 1g, by reacting 300 mg (0.8 mmol) of 1-[4-(4-tert-butylphenyl)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl]prop-2-yn-1-ol with 166 mg (0.7 mmol) of 4-iodobenzoic acid in the presence of 7 mg of copper iodide and 12 mg of bis(triphenylphosphine)dichloropalladium. The desired product is obtained in the form of white crystals (m=280 mg; yield=72%; m.p.=180° C.).
Reaction SMILES: CS(C)=O.[OH-].[K+].[NH:7]1[CH:11]=[CH:10][N:9]=[CH:8]1.[Br:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17]Br)=[CH:15][CH:14]=1>O>[Br:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][N:7]2[CH:11]=[CH:10][N:9]=[CH:8]2)=[CH:15][CH:14]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: c1c[nH]cn1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: Brc1ccc(Cn2ccnc2)cc1
Reaction time: 0.08 h
Yield: 64 %

Procedure:
Dimethyl sulphoxide (20 mL, dried over 4 Å molecular sieves) was added to potassium hydroxide (2.24 g, 0.04 mol, crushed pellets) and the mixture was stirred for 5 min. Imidazole (0.5718 g, 0.0084 mol) was then added and the mixture was stirred for 2 hours. 4-Bromobenzyl bromide (3.25 g, 0.013 mol) was added and the mixture was cooled briefly and stirred for a further hour before adding water (20 mL). The mixture was extracted with ether (3×100 mL) and each extract was washed with water (3×50 mL). The combined ether layers were dried over CaCl2 and the solvent was removed in vacuo. The residue was chromatographed on silica gel with CHCl3/MeOH (30:1) plus 0.05% formic acid as eluent yielding the sub-title compound (1.275 g, yield: 53%).
Reaction SMILES: [NH2:1][C:2]1[C:17]([Cl:18])=[CH:16][C:5]([C:6]([NH:8][CH2:9][CH2:10][N:11]([CH2:14][CH3:15])[CH2:12][CH3:13])=[O:7])=[C:4]([O:19][CH:20]([CH3:24])[C:21](=[O:23])[CH3:22])[CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[BH4-].[Na+]>C(O)C>[NH2:1][C:2]1[C:17]([Cl:18])=[CH:16][C:5]([C:6]([NH:8][CH2:9][CH2:10][N:11]([CH2:14][CH3:15])[CH2:12][CH3:13])=[O:7])=[C:4]([O:19][CH:20]([CH3:24])[CH:21]([OH:23])[CH3:22])[CH:3]=1
Reactant: CCN(CC)CCNC(=O)c1cc(Cl)c(N)cc1OC(C)C(C)=O
Agent: O=C([O-])[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCN(CC)CCNC(=O)c1cc(Cl)c(N)cc1OC(C)C(C)O

Procedure:
A mixture of 4-amino-2-(2-butanon-3-yl)oxy-5-chloro-N-[2-(diethylamino)ethyl]benzamide (obtained by treating 1.2 g, 3.1 mmole, of the corresponding hydrochloride salt, prepared in Example 7C, with saturated sodium carbonate solution) and sodium borohydride (100 mg) in ethanol (20 ml) was heated under reflux for one hour. The solution was concentrated, diluted with water, acidified with 2N hydrochloride acid, and basified with saturated sodium carbonate solution. The mixture was extracted with methylene chloride to yield 1.16 g of foam. This material was chromatographed over deactivated silica using methylene chloride (100), methanol (2), ammonia (0.5) as the solvent system. The appropriate fractions were combined to yield the title compound (470 mg) as a foamy mixture of diastereoisomers. The NMR spectrum (90 MHz) in CDCl3 gave the following resonances: δ 8.54 (bd, 1H); 8.2, 8.15 (2s, 1H); 6.32, 6.35 (2s, 1H); 4.36 (s, 2H); 4.24-4 (m, 1H); 4-2.12 (m, 3H); 2.8-2.52 (m, 6H); 1.41-0.96 (m, 12H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([NH2:8])=[CH:4][CH:3]=1.Br[C:10]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][C:11]=1[C:12]([OH:14])=[O:13].C([O-])([O-])=O.[K+].[K+].O>COCCOC>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][C:10]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][C:11]=2[C:12]([OH:14])=[O:13])=[CH:4][CH:3]=1
Reactant: Nc1ccc(Cl)nc1
Reactant: Cc1ccc(Br)c(C(=O)O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: Cc1ccc(Nc2ccc(Cl)nc2)c(C(=O)O)c1
Temperature: 130 °C
Yield: 46 %

Procedure:
A mixture of 6-chloropyridin-3-amine (11.67 mmol, 1.5 g) and 2-bromo-5-methylbenzoic acid (23.34 mmol, 5.02 g), Cu (1.17 mmol, 0.1 g), Cu2O (0.58 mmol, 0.1 g) and K2CO3 (23.34 mmol, 3.2 g) in 1,2-dimethoxyethane (15 ml) was heated at 130° C. for 16 hours, under argon atmosphere. Water was added and the mixture was filtered through celite. HCl 2N aqueous solution was added until pH 6 and the solid formed was filtered off. The crude was purified by chromatography eluting with DCM/MeOH mixtures affording 1.40 g (yield 46%).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:26])([CH3:25])[C@@H:11]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)[C:12]([OH:14])=[O:13])(=[O:7])=[O:6].C(Cl)(=O)C(Cl)=O.[C:33]1([C@H:39](O)[CH3:40])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.N1C=CC=CC=1>ClCCl>[Cl:1][CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:26])([CH3:25])[C@@H:11]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)[C:12]([O:14][C@@H:39]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH3:40])=[O:13])(=[O:7])=[O:6]
Reactant: COc1ccc(CO[C@@H](C(=O)O)C(C)(C)COS(=O)(=O)CCCCl)cc1
Reactant: C[C@@H](O)c1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(CO[C@@H](C(=O)O[C@H](C)c2ccccc2)C(C)(C)COS(=O)(=O)CCCCl)cc1
Yield: 68.2 %

Procedure:
Following the general procedure for the preparation of carboxylic esters from carboxylic acids of Description 15, (2R)-4-[(3-chloropropyl)sulfonyloxy]-2-[(4-methoxyphenyl)methoxy]-3,3-dimethylbutanoic acid (13) (0.50 g, 1.2 mmol) dissolved in 20 mL of anhydrous dichloromethane (DCM) was reacted with 0.7 mL (1.4 mmol) of oxalyl chloride (2.0 M in DCM). After completion of the reaction, a solution of 0.28 mL of (R)-(+)-1-phenylethanol (0.40 g, 3.3 mmol) and 0.28 mL of pyridine (0.26 g, 3.3 mmol) in 10 mL of anhydrous dichloromethane was added to the acid chloride. After work-up, the crude material was purified by silica gel column chromatography using a mixture of ethyl acetate (EtOAc) and hexane (Hxn) as eluent (EtOAc/Hxn=1:2) to provide 0.42 g (67% yield) of the title compound (34a) as a colorless oil. Rf=0.54 (EtOAc/Hxn=1:2). 1H NMR (400 MHz, CDCl3): δ=0.98 (s, 3H), 0.99 (s, 3H), 1.61 (d, J=6.4 Hz, 3H), 2.23-2.30 (m, 2H), 3.18-3.22 (m, 2H), 3.63-3.66 (m, 2H), 3.81-3.82 (m, 4H), 3.92 (d, J=9.2 Hz, 1H), 4.19 (d, J=9.2 Hz, 1H), 4.26 (d, J=11.2 Hz, 1H), 4.49 (d, J=11.2 Hz, 1H), 6.01 (q, J=6.4 Hz, 1H), 6.85 (d, J=8.8 Hz, 2H), 7.20 (d, J=8.4 Hz, 2H), 7.35-7.39 (m, 5H) ppm. D.e.>98% (by 1H NMR-spectroscopy, 400 MHz, CDCl3). MS (ESI) m/z 535.18 (M+Na)+. The analytical data was consistant with the proposed structure.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[F:26])[C:4]=2[N:5]=[C:6]([NH:8][CH:9]([CH2:12][OH:13])[CH2:10][OH:11])[N:7]=1.[CH3:27][S:28][C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][CH:34]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.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>[CH3:27][S:28][C:29]1[CH:34]=[C:33]([C:2]2[C:3]3[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]4[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=4[F:26])[C:4]=3[N:5]=[C:6]([NH:8][CH:9]([CH2:12][OH:13])[CH2:10][OH:11])[N:7]=2)[CH:32]=[CH:31][CH:30]=1
Reactant: O=c1ccc2c(Cl)nc(NC(CO)CO)nc2n1-c1ccc(F)cc1F
Reactant: CSc1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CSc1cccc(-c2nc(NC(CO)CO)nc3c2ccc(=O)n3-c2ccc(F)cc2F)c1
Temperature: 150 °C
Yield: 90 %

Procedure:
A solution of 4-Chloro-2-(2-hydroxy-1-hydroxymethyl-ethylamino)-8-(2, 4-difluoro-phenyl)-8H-pyrido[2,3-d]pyrimidin-7-one (50 mg, 0.13 mmol) in dioxane/H2O (3:1, 4.8 mL) was mixed with 3-methylthiophenyl boronic acid (33.8 mg, 0.20 mmol) and K2CO3 (54.3 mg, 0.39 mmol). The resultant mixture was bubbled with argon for 5 minutes follwoed by the addition of Pd(PPh3)4 (3.0 mg, 0.0026 mmol). The reaction tube was sealed and heated with “Smith Creator” (microwave, 150° C.) for 15 minutes. The mixture was concentrated under vaco. Flash chromatography (EtOAc/Hexane, 3:1) then provided the title compound (90%): MS (ES) m/z 471 (M+H)+; 1H-NMR(CDCl3) δ 2.40 (s, br, 2H), 2.40 (s, 3H), 3.90 (m, br, 5H), 6.00 (m, br, 1H), 6.45 (m, 1H), 7.15 (m, 2H), 7.40 (m, 5H), 7.85 (m, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]([O:19][CH:20]2[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]2)[C:9]2[NH:13][C:12]3[CH:14]=[CH:15][C:16]([F:18])=[CH:17][C:11]=3[N:10]=2)[CH:5]=[CH:6][CH:7]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.[C:69]([O:73][C:74](=[O:79])[NH:75][CH2:76][CH2:77][SH:78])([CH3:72])([CH3:71])[CH3:70].C(N(C(C)C)CC)(C)C>C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.[Pd].O1CCOCC1>[C:69]([O:73][C:74](=[O:79])[NH:75][CH2:76][CH2:77][S:78][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH:8]([C:9]2[NH:13][C:12]3[CH:14]=[CH:15][C:16]([F:18])=[CH:17][C:11]=3[N:10]=2)[O:19][CH:20]2[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]2)[CH:3]=1)([CH3:72])([CH3:70])[CH3:71]
Reactant: CC(C)(C)OC(=O)NCCS
Reactant: CN1CCC(OC(c2cccc(Br)c2)c2nc3cc(F)ccc3[nH]2)CC1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CN1CCC(OC(c2cccc(SCCNC(=O)OC(C)(C)C)c2)c2nc3cc(F)ccc3[nH]2)CC1
Temperature: 120 °C
Reaction time: 8 h

Procedure:
A screw-capped tube is charged with 2-[(3-bromophenyl)(1-methylpiperidin-4-yloxy)methyl]-5-fluoro-1H-benzimidazole (example 437D, 418 mg), palladium bis(dibenzylideneacetone) (30 mg), Xantphos (30 mg), (2-mercaptoethyl)carbamic acid tert-butyl ester (1 equivalent), diisopropylethylamine (180 μL) and 1,4-dioxane (6 mL). The tube is evacuated, filled with argon and sealed. After stirring at 120° C. overnight, the mixture is diluted with ethyl acetate and water and the aqueous phase is extracted with ethyl acetate. The pooled organic extracts are dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified by chromatography (gradient dichloromethane/methanol from 98/2 to 95/5) to afford (2-{3-[(5-fluoro-1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]phenylsulfanyl}ethyl)carbamic acid tert-butyl ester. 1H NMR: 11.07 (sl, 1H), 7.69-7.59 (m, 1H), 7.39-7.36 (m, 1H), 7.30-7.15 (m, 2H), 7.04-6.91 (m, 2H), 5.83 (s, 1H), 5.30 (sl, 1H), 4.20 (s, 2H), 3.65-3.40 (m, 3H), 3.30-3.05 (m, 2H), 2.80-2.65 (m, 2H), 2.27 (s, 3H), 2.25-1.75 (m, 6H), 1.55 (s, 9H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:12]=[CH:11][N:10]3[C:13]([C:16]4[CH:25]=[CH:24][C:23]5[C:18](=[C:19]([OH:26])[CH:20]=[CH:21][CH:22]=5)[N:17]=4)=[CH:14][N:15]=[C:9]3[CH:8]=2)[CH:2]=1.[F:27][C@H:28]1[C@@H:33](OS(C)(=O)=O)[CH2:32][CH2:31][N:30]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:29]1.C([O-])([O-])=O.[Cs+].[Cs+].CC(N(C)C)=O>O.CCOC(C)=O>[F:27][C@H:28]1[C@H:33]([O:26][C:19]2[CH:20]=[CH:21][CH:22]=[C:23]3[C:18]=2[N:17]=[C:16]([C:13]2[N:10]4[CH:11]=[CH:12][C:7]([C:3]5[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=5)=[CH:8][C:9]4=[N:15][CH:14]=2)[CH:25]=[CH:24]3)[CH2:32][CH2:31][N:30]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:29]1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](OS(C)(=O)=O)[C@H](F)C1
Reactant: Oc1cccc2ccc(-c3cnc4cc(-c5cccnc5)ccn34)nc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CC[C@@H](Oc2cccc3ccc(-c4cnc5cc(-c6cccnc6)ccn45)nc23)[C@H](F)C1
Temperature: 100 °C
Yield: 45.8 %

Procedure:
A mixture of 2-(7-(pyridin-3-yl)imidazo[1,2-a]pyridin-3-yl)quinolin-8-ol (30.2 mg, 0.089 mmol), tert-butyl cis-3-fluoro-4-(methylsulfonyloxy)piperidine-1-carboxylate (39.8 mg, 0.134 mmol) and Cs2CO3 (43.6 mg, 0.134 mmol) in DMA (7.78 mg, 0.089 mmol) was heated to 100° C. for 1 hour. The reaction mixture was cooled to ambient temperature and diluted with water and EtOAc. The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by preparative TLC, eluting with 10% MeOH 0.5% NH4OH in DCM to provide the desired product (22 mg, 46% yield).
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][C:6]1=[O:18].[CH2:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][CH2:21][NH:20]1>CCO>[CH2:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][CH2:21][N:20]1[CH2:3][CH:2]([OH:1])[CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][C:6]1=[O:18]
Reactant: c1ccc2c(c1)CCNC2
Reactant: CC(C)(C)OC(=O)N1CCN(CC2CO2)C(=O)C1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(CC(O)CN2CCc3ccccc3C2)C(=O)C1
Temperature: 120 °C
Yield: 98 %

Procedure:
To a solution of tert-butyl 4-(oxiran-2-ylmethyl)-3-oxopiperazine-1-carboxylate (400 mg, 1.56 mmol) in EtOH (1 mL) was added 1,2,3,4-tetrahydroisoquinoline (207 mg, 1.56 mmol). The mixture was heated under microwave conditions at 120° C. for 0.5 h and concentrated. The crude product was used without further purification. (600 mg, yield 98%) MS (ESI+) e/z: 390.2 [M+1]+.