Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[Si](C)(C)C.[O:6]1[CH2:10][CH2:9][O:8][CH:7]1[CH2:11][CH2:12][CH2:13][C@H:14]([NH2:18])[C:15]([OH:17])=[O:16].S(OC)(O[CH3:22])=O.C[O-].[K+]>CO.C(OCC)(=O)C>[NH2:18][C@@H:14]([CH2:13][CH2:12][CH2:11][CH:7]([O:8][CH3:9])[O:6][CH3:10])[C:15]([O:17][CH3:22])=[O:16]
Reactant: N[C@@H](CCCC1OCCO1)C(=O)O
Reactant: COS(=O)OC
Agent: C[O-]
Agent: C[Si](C)(C)Cl
Agent: [K+]
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)[C@@H](N)CCCC(OC)OC
Temperature: 42.5 °C
Reaction time: 72 h
Yield: 80.2 %

Procedure:
Under nitrogen, chlorotrimethyl silane (28.0 g) was added to a slurry of 5-(1,3-dioxolan-2-yl)-(S)-2-amino-pentanoic acid (20.0 g) and dimethyl sulfite (12.0 g) in methanol (240 mL) to afford a homogeneous solution. Following the observation of an exotherm to 29° C., the solution was heated to 40-45° C., stirred at that temperature for 8 h and at ˜22° C. for up to 72 hours. In-process HPLC analysis showed that the reaction was complete (˜93 M % conversion to product) and the resulting solution was cooled to −5 to −10° C. With stirring, the apparent pH of the mixture was adjusted to 11.7 to 11.9 by the slow careful addition of 32% (or 4.45 M) methanolic potassium methoxide solution (70 mL) maintaining the temperature in the range −5 to 0° C. Analysis of the product slurry (NMR) indicated that the neutralization was complete (chemical shift of the alpha proton of BMS-205787 was <3.36 ppm). The solvent of the product slurry was exchanged with ethyl acetate by first concentrating the thin slurry under vacuum at <30° C. to 300 mL volume followed by the addition of ethyl acetate until the removal of methanol was completed as judged by in-process GC analysis (<1 AP). Upon completion of the solvent exchange, the batch volume was adjusted to ˜400 mL with ethyl acetate and the resulting slurry was filtered. Poly(acrylic acid co-acrylamide), potassium salt (3.0 to 3.2 g) and water (30-32 mL) were added to the filtrate. The mixture was stirred for ˜35 minutes and filtered. Optionally, the Poly(acrylic acid co-acrylamide), potassium salt treatment can be repeated on the filtrate if the quantity of ethylene glycol exceeds 0.15 equivalents, as judged by in-process GC analysis. Following in-process HPLC analysis, (S)-2-Amino-6,6-dimethoxyhexanoic acid, methyl ester (17.4 g) was obtained as an ethyl acetate solution in 80.8 M % yield.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6](=[O:23])[NH:7][C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11](Br)=[CH:10][C:9]=2[CH3:22])=[O:4].[Cu][C:25]#[N:26].O>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[C:6](=[O:23])[NH:7][C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([C:25]#[N:26])=[CH:10][C:9]=2[CH3:22])=[O:4]
Reactant: N#C[Cu]
Reactant: COC(=O)c1c(-c2ccccc2)c2cc(Br)cc(C)c2[nH]c1=O
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1c(-c2ccccc2)c2cc(C#N)cc(C)c2[nH]c1=O
Temperature: 130 °C
Yield: 100.3 %

Procedure:
A suspension of 6-bromo-8-methyl-2-oxo-4-phenyl-1,2-dihydro-quinoline-3-carboxylic acid methyl ester (prepared as described in example 54 step C) (140 mg, 376 μmol, Eq: 1.00) and copper(I) cyanide (121 mg, 41.5 μl, 1.35 mmol, Eq: 3.6) in DMF (2.8 ml) was heated to 130° C. for 2 d. Then water was added and the mixture was extracted with DCM (3×). The combined extracts were washed with water and brine, dried with Na2SO4 and evaporated to give the title compound as off-white solid (120 mg). MS (ESI): 317.2 (M−H)−
Reaction SMILES: [Cl:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[F:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16]Cl)=[CH:14][CH:13]=1>O.[OH-].[Na+]>[Cl:1][C:2]1[N:6]([CH2:16][C:15]2[CH:18]=[CH:19][C:12]([F:11])=[CH:13][CH:14]=2)[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1
Reactant: Clc1nc2ccccc2[nH]1
Reactant: Fc1ccc(CCl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Fc1ccc(Cn2c(Cl)nc3ccccc32)cc1
Temperature: 82 °C

Procedure:
11 g 2-chlorobenzimidazole are dissolved in 74 ml water and 17.35 ml 30% sodium hydroxide. The mixture is heated to 82° C. and to this they are slowly added 23.76 g 4-fluorobenzyl chloride within 5 hours. When the reaction is achieved, the solution is cooled to 20° C. and extracted with methylene chloride. The compound is recrystallized from ethyl acetate.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Br:11])=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:12]([NH2:14])=[O:13].[O:15]=[C:16](Cl)OC(Cl)(Cl)Cl.O>O1CCOCC1>[Br:11][C:7]1[CH:8]=[CH:9][C:10]2[C:2]3[NH:1][C:16](=[O:15])[NH:14][C:12](=[O:13])[C:3]=3[NH:4][C:5]=2[CH:6]=1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: NC(=O)c1[nH]c2cc(Br)ccc2c1N
Solvent: C1COCCO1
Solvent: O
Product: O=c1[nH]c(=O)c2[nH]c3cc(Br)ccc3c2[nH]1
Temperature: 25 °C
Yield: 82.5 %

Procedure:
12.2 g (58 mmol) 3-amino-6-bromo-1H-indole-2-carboxylic acid amide was suspended in 50 ml dioxan, and, after the addition of 11.7 ml (96 mmol) diphosgene, the suspension was refluxed for 2 h. Having cooled down to room temperature, 20 ml water was carefully added and the precipitate was subsequently sucked off. 13.4 g (99%) 7-bromo-1H-pyrimido[5,4-b]indole-2,4(3H,5H)-dione was obtained. ESI-MS [m/z]: 278, 280 [M−H]−
Reaction SMILES: [CH2:1]([C:7]1([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:11][CH2:10][CH2:9][CH:8]1[OH:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].N1C=CC=CC=1.[CH3:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][CH:26]=1>C(Cl)Cl>[CH2:1]([C:7]1([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:11][CH2:10][CH2:9][CH:8]1[O:12][C:29](=[O:30])[C:28]1[CH:32]=[CH:33][C:25]([CH3:24])=[CH:26][CH:27]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: CCCCCCC1(C(=O)OCC)CCCC1O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCCCC1(C(=O)OCC)CCCC1OC(=O)c1ccc(C)cc1

Procedure:
7.44 grams of ethyl 1-n-hexyl-2-hydroxy-cyclopentane carboxylate obtained in Example 17 were diluted with 60 ml of methylene chloride. At room temperature and with magnetic stirring, 3.66 ml of pyridine was slowly added, then 6.12 ml of 4-methyl-benzoyl chloride was dropwise added. Then the procedure as described in Example 23 was followed, to give 12.53 g of yellow liquid. MS: m/e 360(M+′), 315(M+—OCH2CH3), 287(M+—CO2CH2CH3), 276, 241(M+−CH3C6H4CO), 225(M+—CH3C6H4CO2), 195, 185, 151, 140, 119 (base), 91, 77.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[C:10](=[O:11])[CH2:9][CH2:8][N:7]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6]1)=[O:4].CCN(C(C)C)C(C)C.[CH3:28][O:29][CH2:30]Cl>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[CH2:6][N:7]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:9][C:10]=1[O:11][CH2:28][O:29][CH3:30])=[O:4]
Reactant: COC(=O)C1CN(C(=O)OC(C)(C)C)CCC1=O
Reactant: COCCl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCOC1=C(C(=O)OC)CN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred mixture of 4-oxo-piperidine-1,3-dicarboxylic acid 1-tert-butylester 3-methyl ester (10 mmol, 2.71 g) and DIEA (1 mL) in DCM was added methoxymethyl chloride (1.3 mL) drop-wise and continued stirring for 16 h at room temperature. Volatiles were removed under reduced pressure, the resultant residue was taken up in ethyl acetate (50 mL), washed with water (25 mL), dried the organic layer, filtered and concentrated under reduced pressure. The resultant residue was purified by flash column chromatography using mixture of hexanes and ethyl acetate to provide 4-methoxymethoxy-5,6-dihydro-2H-pyridine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester.
Reaction SMILES: Br[CH2:2][C:3]1[C:11]2[O:10][CH2:9][CH2:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.[N-:12]=[N+:13]=[N-:14].[Na+].O>CN(C)C=O>[N:12]([CH2:2][C:3]1[C:11]2[O:10][CH2:9][CH2:8][C:7]=2[CH:6]=[CH:5][CH:4]=1)=[N+:13]=[N-:14]
Reactant: BrCc1cccc2c1OCC2
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: [N-]=[N+]=NCc1cccc2c1OCC2
Reaction time: 3 h

Procedure:
The product of Example 48B (4.40 g) in N,N-dimethylformamide (60 mL) at room temperature was treated in one portion with sodium azide (5.37 g), stirred for 3 hours, poured into water and extracted with diethylether (2×100 mL). The organics were dried (sodium sulfate), filtered, and the filtrate concentrated under reduced pressure. The residue was purified by flash chromatography (5% ethyl acetate/hexane) to provide the title compound. 1H NMR (CDCl3) δ 3.23 (t, 2H), 4.31 (s, 2H), 4.60 (t, 2H), 6.85 (t, 1H), 7.06 (d, 1H), 7.19 (dd, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:5]=[CH:6][C:7]=1[OH:8].C([O-])([O-])=O.[K+].[K+].[Cl:20][C:21]1[CH:41]=[CH:40][C:24]([CH2:25][CH2:26][NH:27][C:28](=[O:39])[C:29]2[CH:34]=[CH:33][C:32](Cl)=[C:31]([N+:36]([O-:38])=[O:37])[CH:30]=2)=[CH:23][CH:22]=1>CS(C)=O.C(Cl)Cl>[Cl:20][C:21]1[CH:22]=[CH:23][C:24]([CH2:25][CH2:26][NH:27][C:28]([C:29]2[CH:34]=[CH:33][C:32]([O:8][C:7]3[CH:6]=[CH:5][C:4]([CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:3][C:2]=3[Cl:1])=[C:31]([N+:36]([O-:38])=[O:37])[CH:30]=2)=[O:39])=[CH:40][CH:41]=1
Reactant: O=C(NCCc1ccc(Cl)cc1)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: COC(=O)Cc1ccc(O)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CS(C)=O
Product: COC(=O)Cc1ccc(Oc2ccc(C(=O)NCCc3ccc(Cl)cc3)cc2[N+](=O)[O-])c(Cl)c1
Temperature: 85 °C
Reaction time: 12 h
Yield: 46.2 %

Procedure:
Methyl 2-(3-chloro-4-hydroxyphenyl)acetate (177 mg, 0.885 mmol) was diluted with DMSO (3 mL) followed by the addition of K2CO3 (122 mg, 0.885 mmol) and N-(4-chlorophenethyl)-4-chloro-3-nitrobenzamide (300 mg, 0.885 mmol) (synthesized in step C). The reaction was heated to 85° C. and stirred for 12 hours. The reaction was cooled, diluted with DCM and washed with 10% aq. sodium carbonate, water and brine. The layers were separated and the organic layer was dried over H2SO4, filtered and concentrated. The material was purified using a biotage 40S cartridge eluting with DCM:MeOH (99:1) to yield methyl 2-(4-(4-((4-chlorophenethyl)carbamoyl)-2-nitrophenoxy)-3-chlorophenyl)acetate (206 mg, 46.3% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]2[C:17]3[C:12](=[CH:13][N:14]=[C:15]([C:18]4[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=4)[CH:16]=3)[N:11]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[N:10]=2)=[N:6][C:7]=1F.Cl.[NH:33]1[CH2:39][CH2:38][CH2:37][C@@H:36]([NH:40][C:41](=[O:50])[O:42][CH2:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH2:35][CH2:34]1>>[Br:1][C:2]1[C:7]([N:33]2[CH2:39][CH2:38][CH2:37][C@@H:36]([NH:40][C:41](=[O:50])[O:42][CH2:43][C:44]3[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=3)[CH2:35][CH2:34]2)=[N:6][C:5]([C:9]2[C:17]3[C:12](=[CH:13][N:14]=[C:15]([C:18]4[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=4)[CH:16]=3)[N:11]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[N:10]=2)=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)CCOCn1nc(-c2ccc(Br)c(F)n2)c2cc(-c3cccnc3)ncc21
Reactant: O=C(N[C@@H]1CCCNCC1)OCc1ccccc1
Agent: Cl
Product: C[Si](C)(C)CCOCn1nc(-c2ccc(Br)c(N3CCC[C@@H](NC(=O)OCc4ccccc4)CC3)n2)c2cc(-c3cccnc3)ncc21

Procedure:
Following the procedures of Examples 241 and 287, 3-(5-bromo-6-fluoropyridin-2-yl)-5-(pyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridine and (R)-benzyl azepan-4-ylcarbamate hydrochloride were reacted to give (R)-benzyl 1-(3-bromo-6-(5-(pyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)pyridin-2-yl)azepan-4-ylcarbamate, which was dissolved in Trifluoroacetic Acid (5 mL) and Methylene chloride (5 mL), and treated with Trifluoromethanesulfonic acid (5 eq.) and Triethylsilane (5 eq.). The resulting mixture was stirred at room temperature for 2 days. The mixture was then concentrated, and the residue was purified by reverse phase HPLC to afford 313 as an off-white solid (14.2 mg, 25.5%) over two steps. 1H NMR (400 MHz, DMSO) δ 9.24 (s, 2H), 8.91 (s, 1H), 8.61 (d, J=3.6 Hz, 1H), 8.42 (d, J=8.0 Hz, 1H), 8.35 (s, 1H), 8.03 (d, J=8.0 Hz, 1H), 7.62-7.51 (m, 2H), 4.00 (d, J=14.6 Hz, 2H), 3.90-3.81 (m, 2H), 3.77 (dd, J=11.4, 6.7 Hz, 2H), 3.67-3.59 (m, 3H), 2.18 (s, 1H), 1.98 (dd, J=31.3, 18.3 Hz, 4H), 1.75-1.59 (m, 1H); ESI MS m/z=464.01 (M+1)
Reaction SMILES: F[C:2]1[C:7]([C:8]#[N:9])=[CH:6][CH:5]=[C:4]([OH:10])[CH:3]=1.[CH3:11][NH:12][NH2:13]>>[NH2:9][C:8]1[C:7]2[C:2](=[CH:3][C:4]([OH:10])=[CH:5][CH:6]=2)[N:12]([CH3:11])[N:13]=1
Reactant: CNN
Reactant: N#Cc1ccc(O)cc1F
Product: Cn1nc(N)c2ccc(O)cc21
Temperature: 25 °C

Procedure:
A solution of 6-fluoro-4-hydroxy benzonitrile (Aldrich, 10.1 g, 73.9 mmol) in methyl hydrazine (Aldrich, 20.0 mL, 379 mmol) was stirred at 80° C. for 16 h. After cooling to RT, the volatile portion was removed in vacuo. The residue was triturated with DCM and MeOH. The title compound was obtained by filtration as an off-white solid. The filtrate was concentrated in vacuo and purified by silica gel chromatography (DCM/MeOH: 100/0 to 95/5) to give an additional amount of the title compound as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([N+:13]([O-:15])=[O:14])[CH:12]=1)[C:7]([OH:9])=[O:8])([O-:3])=[O:2].[CH2:16](O)C>CO>[N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([N+:13]([O-:15])=[O:14])[CH:12]=1)[C:7]([O:9][CH3:16])=[O:8])([O-:3])=[O:2]
Reactant: CCO
Reactant: O=C(O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Solvent: CO
Product: COC(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Yield: 96 %

Procedure:
Following Example 11 but replacing the 1-(H)-tetrazolylacetic acid with 3,5-dinitrobenzoic acid, 3.39 g (1.6 cmoles) and the ethanol with methanol, 0.64 ml (1.6 cmoles), the ester was obtained with a yield of 96% (2.17 g), m.p.=108° C.
Reaction SMILES: [H-].[Na+].Cl[C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[CH:12]=2)[N:7]=[CH:6][N:5]=1.[CH2:21]([OH:23])[CH3:22]>>[CH2:21]([O:23][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[CH:12]=2)[N:7]=[CH:6][N:5]=1)[CH3:22]
Reactant: Fc1ccc(-c2ccc3ncnc(Cl)c3c2)cc1
Reactant: CCO
Agent: [H-]
Agent: [Na+]
Product: CCOc1ncnc2ccc(-c3ccc(F)cc3)cc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 88 %

Procedure:
To absolute ethanol (10 ml) was added NaH (80 mg of a 60% dispersion in mineral oil, 2.0 mmol). The mixture was stirred at room temperature for 10 minutes. Then, 4-chloro-6-(4-fluorophenyl)-quinazoline (52 mg, 0.2 mmol) was added to this solution. The resulting mixture was stirred at room temperature for another 30 minutes. The solvents were evaporated in vacuo and the crude residue was purified by silica gel flash chromatography, the mobile phase being a mixture of ethanol and dichloromethane in a volume ratio of 1:100), yielding the title compound as a white solid (46 mg, yield: 88%) was characterized by its mass spectrum as follows: MS (m/z): 269 ([M+H]+, 100).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH2:2]1.[CH3:25][N:26]([CH3:31])[CH2:27][C:28](O)=[O:29].Cl.CN(C)CCCN=C=NCC>C(Cl)Cl.CCOC(C)=O>[CH3:25][N:26]([CH2:27][C:28]([N:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH2:2]1)=[O:29])[CH3:31]
Reactant: CN(C)CC(=O)O
Reactant: CC(Nc1nccc(-n2cnc3ccccc32)n1)C1CCCNC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(Nc1nccc(-n2cnc3ccccc32)n1)C1CCCN(C(=O)CN(C)C)C1
Reaction time: 4.5 h

Procedure:
To a solution of 2-[1-(piperidin-3-yl)-ethylamino]-4-[benziniidazol-1-yl]pyrimidine (EXAMPLE 18) (21 mg, 0.065 mmol) in CH2Cl2 (0.6 mL) was added N,N-dimethylglycine (10 mg, 0.098 mmol) followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (19 mg, 0.098 mmol) at room temperature. After stirring for 4.5 h, the reaction mixture was diluted with EtOAc (5 mL) and was washed with H2O (2×2 mL) and brine. The organic layer was dried over Na2SO4. After removal of the solvent, the crude product was purified by preparative thin layer chromatography (1:9 2M NH3 in MeOH:CH2Cl2) to obtain the title compound. Presence of rotamers in Partial 1H NMR (500 MHz, CDCl3): δ 8.6 (s, 1H); 8.35 (br s, 1H); 8.12 (d, J=7.5 Hz, 1H); 7.82 (br s, 1H); 7.35 (br s, 2H); 6.75 (two d, J=5.3 Hz, 1H); 4.54 (m, 1H); 2.24 (s, 3H); 2.19 (s, 3H); 1.28 (br s, 3H). Mass spectrum 408.4 (ESI, M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:20]=[C:19]([CH2:21]O)[CH:18]=[C:17]([CH3:23])[C:3]=1[O:4][CH:5]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=1)[C:6]([O:8][CH3:9])=[O:7].P(Br)(Br)[Br:25]>C(Cl)(Cl)(Cl)Cl>[Br:25][CH2:21][C:19]1[CH:20]=[C:2]([CH3:1])[C:3]([O:4][CH:5]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C:6]([O:8][CH3:9])=[O:7])=[C:17]([CH3:23])[CH:18]=1
Reactant: BrP(Br)Br
Reactant: COC(=O)C(Oc1c(C)cc(CO)cc1C)c1cccc(Cl)c1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)C(Oc1c(C)cc(CBr)cc1C)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 81.2 %

Procedure:
To a solution of 0.560 g (1.62 mmol) of the product of Step B dissolved in 5.0 mL of carbon tetrachloride was added 154 μL (1.62 mmol) of phosphorous tribromide and the reaction mixture was stirred at room temperature for 5 minutes. Carbon tetrachloride was evaporated from the reaction mixture several times to remove the hydrogen bromide, then the residue was purified on a silica gel flash chromatography column eluted with 5% EtOAc-hexane. The purified fractions were evaporated in vacuo affording 0.523 g (81%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](B2OC(C)(C)C(C)(C)O2)=[CH:4][N:3]=1.C(N1C=CN=C1)CCC.[OH:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][CH:35]([NH:37][C:38](=[O:40])[CH3:39])[CH3:36])=[CH:29][CH:28]=1.N1C=CC=CC=1>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.C1(C)C=CC=CC=1>[F:1][C:2]1[N:3]=[CH:4][C:5]([O:26][C:27]2[CH:28]=[CH:29][C:30]([CH2:33][CH2:34][CH:35]([NH:37][C:38](=[O:40])[CH3:39])[CH3:36])=[CH:31][CH:32]=2)=[CH:6][CH:7]=1
Reactant: CC(=O)NC(C)CCc1ccc(O)cc1
Reactant: CC1(C)OB(c2ccc(F)nc2)OC1(C)C
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: CCCCn1ccnc1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CC(=O)NC(C)CCc1ccc(Oc2ccc(F)nc2)cc1
Temperature: 100 °C
Reaction time: 15 h

Procedure:
2-Fluoro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine (900 mg, 4.03 mmol), anhydrous copper acetate (550 mg, 3.03 mmol), 1-butylimidazole (175 mg, 1.41 mmol), N-[3-(4-hydroxyphenyl)-1-methylpropyl]acetamide (418 mg, 2.02 mmol) and pyridine (0.326 ml, 4.03 mmol) were admixed with 25 ml of toluene, and stirred at 100° C. for 15 h, under argon. The reaction mixture was filtered and the filtrate was concentrated and purified by preparative HPLC (PR18, acetonitrile/water 0.1% TFA). Yield: 394 mg (32%), M+H+: 303.0.
Reaction SMILES: C(OC([NH:8][CH:9]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:10]1[CH:11]=[C:12]([CH:25]=[CH:26][CH:27]=1)[O:13][CH2:14][C:15]1[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=1)=O)(C)(C)C.[ClH:34].O1CCOCC1>CO>[ClH:34].[NH2:8][C@@H:9]([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[C:10]1[CH:11]=[C:12]([CH:25]=[CH:26][CH:27]=1)[O:13][CH2:14][C:15]1[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=1
Reactant: COC(=O)c1ccc(COc2cccc(C(NC(=O)OC(C)(C)C)c3ccccc3)c2)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: COC(=O)c1ccc(COc2cccc([C@@H](N)c3ccccc3)c2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 95 %

Procedure:
To a solution of methyl 4-((3-(((tert-butoxycarbonyl)amino)(phenyl)methyl)-phenoxy)methyl)benzoate (3.21 g, 7.20 mmol) in methanol (36 mL) was added hydrogen chloride in dioxane (4 M, 9.0 mL, 36 mmol). The reaction mixture was stirred at RT for 16 hours. The solvent was removed at reduced pressure to afford the title compound (2.65 g, >95%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([O:12][CH3:13])=[CH:10][C:6]2[N:7]=[CH:8][NH:9][C:5]=2[CH:4]=1.Cl[C:15]1[S:16][C:17]([C:26]#[N:27])=[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:19]=1.N1C2=CC3COCOC=3C=C2N=C1>>[CH3:13][O:12][C:11]1[C:3]([O:2][CH3:1])=[CH:4][C:5]2[N:9]([C:15]3[S:16][C:17]([C:26]#[N:27])=[C:18]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[N:19]=3)[CH:8]=[N:7][C:6]=2[CH:10]=1
Reactant: COc1cc2nc[nH]c2cc1OC
Reactant: N#Cc1sc(Cl)nc1-c1ccccc1
Agent: c1nc2cc3c(cc2[nH]1)COCO3
Product: COc1cc2ncn(-c3nc(-c4ccccc4)c(C#N)s3)c2cc1OC
Yield: 47 %

Procedure:
2-(5,6-Dimethoxy-benzoimidazol-1-yl)-4-phenyl-thiazole-5-carbonitrile (48.8 mg, yield 47%) was prepared from 5,6-dimethoxybenzimidazole (76 mg, 0.43 mmol) and 2-chloro-4-phenyl-thiazole-5-carbonitrile as described in Example 1 (63 mg, 0.28 mmol). MS M/z 363 (M+1)
Reaction SMILES: C(OC(=O)[NH:7][C:8]([CH3:39])([CH2:36][CH2:37][CH3:38])[CH2:9][NH:10][C:11]([C:13]1[C:14]([CH3:35])=[N:15][N:16]2[C:21]([O:22][CH2:23][C:24]3[C:29]([F:30])=[CH:28][CH:27]=[C:26]([C:31]#[N:32])[C:25]=3[F:33])=[CH:20][C:19]([CH3:34])=[CH:18][C:17]=12)=[O:12])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:7][C:8]([CH3:39])([CH2:36][CH2:37][CH3:38])[CH2:9][NH:10][C:11]([C:13]1[C:14]([CH3:35])=[N:15][N:16]2[C:21]([O:22][CH2:23][C:24]3[C:29]([F:30])=[CH:28][CH:27]=[C:26]([C:31]#[N:32])[C:25]=3[F:33])=[CH:20][C:19]([CH3:34])=[CH:18][C:17]=12)=[O:12]
Reactant: CCCC(C)(CNC(=O)c1c(C)nn2c(OCc3c(F)ccc(C#N)c3F)cc(C)cc12)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCC(C)(N)CNC(=O)c1c(C)nn2c(OCc3c(F)ccc(C#N)c3F)cc(C)cc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Crude rac-{1-[({7-[(3-cyano-2,6-difluorobenzyl)oxy]-2,5-dimethylpyrazolo[1,5-a]pyridin-3-yl}carbonyl)amino]-2-methylpentan-2-yl}carbamic acid tert-butyl ester (Example 126A) in 4 ml of dichloromethane was admixed with 2 ml of trifluoroacetic acid. The resulting solution was stirred at room temperature for 3 h. The solvent was drawn off under reduced pressure and the residue was purified by preparative HPLC chromatography (Method 21), which gave 4.5 mg (5% of theory over 2 stages) of the target compound.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=[CH2:10])[C:7](O)=[O:8].S(Cl)([Cl:13])=O>>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=[CH2:10])[C:7]([Cl:13])=[O:8]
Reactant: C=C(C(=O)O)c1ccco1
Reactant: O=S(Cl)Cl
Product: C=C(C(=O)Cl)c1ccco1

Procedure:
Furylacrylic acid (marketed by Aldrich) and excess thionyl chloride, SOCl2, are first reacted together at reflux for several hours in order to obtain furylacrylic acid chloride.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6]Cl)#[N:2].[C:11]1(=[O:21])[NH:15][C:14](=[O:16])[C:13]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:12]12.[K].O>CN(C)C=O>[C:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6][N:15]1[C:14](=[O:16])[C:13]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:12]2[C:11]1=[O:21])#[N:2]
Reactant: N#Cc1cccc(CCl)c1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1cccc(CN2C(=O)c3ccccc3C2=O)c1
Yield: 76.4 %

Procedure:
A solution of 3-cyanobenzyl chloride (13.3 g) in N,N-dimethylformamide (30 ml) was added dropwise to a suspension of potassium phthalimide (15.9 g) in N,N-dimethylformamide (160 ml) at ambient temperature under stirring and the resultant mixture was stirred for 12 hours at ambient temperature. The reaction mixture was poured into water and the precipitate was collected by filtration. The precipitate was dissolved in a mixture of ethyl acetate and tetrahydrofuran and the resultant solution was washed with brine and dried over magnesium sulfate. The solvent was concentrated in vacuo and the precipitate was collected by filtration to give N-(3-cyanobenzyl)phthalimide (17.1 g).