Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([O:10]C)=[O:9])[CH:5]=[CH:4][C:3]=1[CH2:12][N:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1.CO.[OH-].[Li+].Cl>O>[C:22]([O:21][C:19]([N:16]1[CH2:17][CH2:18][N:13]([CH2:12][C:3]2[CH:4]=[CH:5][C:6]([C:8]([OH:10])=[O:9])=[CH:7][C:2]=2[Cl:1])[CH2:14][CH2:15]1)=[O:20])([CH3:25])([CH3:23])[CH3:24]
Reactant: COC(=O)c1ccc(CN2CCN(C(=O)OC(C)(C)C)CC2)c(Cl)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccc(C(=O)O)cc2Cl)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.1 %

Procedure:
A 100 mL round-bottom flask was charged with tert-butyl 4-[[2-chloro-4-(methoxycarbonyl)phenyl]methyl]piperazine-1-carboxylate (3.54 g, 9.60 mmol, 1.00 equiv), methanol (20 mL), H2O (10 mL), lithium hydroxide (0.690 g, 28.8 mmol, 3.00 equiv). The resulting solution was stirred overnight at room temperature. The pH value of the solution was adjusted to 6 with hydrogen chloride (1 mol/L). The resulting solution was extracted with dichloromethane (3×20 mL) and the organic layers were combined, washed with brine (1×20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to provide 2.90 g (crude) of 4-([4-[(tert-butoxy)carbonyl]piperazin-1-yl]methyl)-3-chlorobenzoic acid as a white solid. 1H NMR 300 MHz (CDCl3) δ 7.89-8.06 (m, 3H), 3.88 (s, 2H), 3.56 (br, 4H), 2.68 (br, 4H), 1.46 (s, 9H). LCMS (ESI, m/z): 355 [M+H]+.
Reaction SMILES: C([O:3][C:4](=[O:46])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:23]=[C:24]([C:31]3[CH:36]=[CH:35][C:34]([F:37])=[C:33]([F:38])[CH:32]=3)[CH:25]=[C:26]([O:28][CH2:29][CH3:30])[CH:27]=2)[C:10]=1[CH2:39][CH2:40][C:41]([O:43]CC)=[O:42])C.[OH-].[Na+]>>[C:41]([CH2:40][CH2:39][C:10]1[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:23]=[C:24]([C:31]3[CH:36]=[CH:35][C:34]([F:37])=[C:33]([F:38])[CH:32]=3)[CH:25]=[C:26]([O:28][CH2:29][CH3:30])[CH:27]=2)=[CH:12][CH:13]=[CH:14][C:9]=1[O:8][CH2:7][CH2:6][CH2:5][C:4]([OH:46])=[O:3])([OH:43])=[O:42]
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(OCC)cc(-c3ccc(F)c(F)c3)c2)c1CCC(=O)OCC
Agent: [Na+]
Agent: [OH-]
Product: CCOc1cc(OCCCCCCc2cccc(OCCCC(=O)O)c2CCC(=O)O)cc(-c2ccc(F)c(F)c2)c1
Yield: 99.2 %

Procedure:
A similar procedure as described in Example 43, step 5 was used, starting from 4-[2-(2-ethoxycarbonyl-ethyl)-3-[6-(3′,4′-difluoro-5-ethoxy-biphenyl-3-yloxy)-hexyl]-phenoxy]-butyric acid ethyl ester (65 mg, 0.1 mmol) and 1.0 N aqueous sodium hydroxide (1.0 mL) to afford 4-[2-(2-carboxy-ethyl)-3-[6-(3′,4′-difluoro-5-ethoxy-biphenyl-3-yloxy)-hexyl]-phenoxy]-butyric acid (58 mg, 98%) as a light brown waxy solid: ES(+)-HRMS m/e calcd for C33H38F2O7 (M+Na)+ 607.2478. found 607.2481.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.[CH:21]1([NH:24][CH2:25][C@@H:26]2[C@H:30]([F:31])[CH2:29][NH:28][CH2:27]2)[CH2:23][CH2:22]1>>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11]([N:28]4[CH2:29][C@@H:30]([F:31])[C@@H:26]([CH2:25][NH:24][CH:21]5[CH2:22][CH2:23]5)[CH2:27]4)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Reactant: F[C@@H]1CNC[C@@H]1CNC1CC1
Product: O=C(O)c1cn(C2CC2)c2c(F)c(N3C[C@H](CNC4CC4)[C@H](F)C3)c(F)cc2c1=O
Yield: 49.8 %

Procedure:
Using 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (212 mg) and (3R,4S)-3-cyclopropylaminomethyl-4-fluoropyrrolidine (142 mg), the same procedure was followed as in Example 23 to give 1-cyclopropyl-7-[(3S,4S)-3-cyclopropylaminomethyl-4-fluoro-1-pyrrolidinyl]-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid as a pale yellow crystals (157 mg).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8](C)=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]([F:22])([F:21])[C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[N:3]=1.FC(F)(C1C=CC(F)=CC=1)C1N=[C:33]([OH:35])C2C(=CC(C)=CC=2)N=1.FC(F)(C1C=CC(F)=CC=1)C1N=C(O)C2C(=CC(OC)=CC=2)N=1>>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:35][CH3:33])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]([F:22])([F:21])[C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[N:3]=1
Reactant: Cc1ccc2c(O)nc(C(F)(F)c3ccc(F)cc3)nc2c1
Reactant: Cc1ccc2c(Cl)nc(C(F)(F)c3ccc(F)cc3)nc2c1
Agent: COc1ccc2c(O)nc(C(F)(F)c3ccc(F)cc3)nc2c1
Product: COc1ccc2c(Cl)nc(C(F)(F)c3ccc(F)cc3)nc2c1

Procedure:
4-Chloro-2-(difluoro(4-fluorophenyl)methyl)-7-methoxyquinazoline was obtained according to the procedure described in Example 26 for synthesis of 4-chloro-2-(difluoro(4-fluorophenyl)methyl)-7-methylquinazoline, substituting 2-(difluoro(4-fluorophenyl)methyl)-7-methylquinazolin-4-ol in Example 26 with 2-(difluoro(4-fluorophenyl)methyl)-7-methoxyquinazolin-4-ol. 4-Chloro-2-(difluoro(4-fluorophenyl)methyl)-7-methoxyquinazoline was isolated as a light yellow solid (0.290 g, 89%). LC-MS (ESI) m/z 339 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[S:10](Cl)(=[O:12])=[O:11].[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([S:21]([CH:24]=[CH:25][C:26]#[N:27])(=[O:23])=[O:22])=[CH:17][CH:16]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[S:10]([NH:14][C:15]1[CH:16]=[CH:17][C:18]([S:21]([CH:24]=[CH:25][C:26]#[N:27])(=[O:23])=[O:22])=[CH:19][CH:20]=1)(=[O:12])=[O:11]
Reactant: Cc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Reactant: N#CC=CS(=O)(=O)c1ccc(N)cc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: Cc1cc(C)c(S(=O)(=O)Nc2ccc(S(=O)(=O)C=CC#N)cc2)c(C)c1
Reaction time: 0.08 h

Procedure:
A solution of 6.6 g (0.03 mol) of 2,4,6-trimethylbenzenesulfonyl chloride in 50 ml chloroform is added at room temperature to a stirred slurry of 6.3 g (0.03 mol) of 3-(4-aminobenzenesulfonyl)acrylonitrile in 100 ml chloroform, the slurry additionally containing 4 ml (0.03 mol) triethylamine, portionwise over a five minute period. After 3 hours stirring the reaction mixture is filtered. The chloroform solution is thereafter washed with water, dilute hydrochloric acid, and water, in that order, separated from the water layer, dried over anhydrous magnesium sulfate and evaporated. The recovered 3-[4-(2,4,6-trimethylbenzenesulfonamido)benzenesulfonyl]acrylonitrile has the formula: ##SPC18##
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7](=[O:9])[CH3:8])=[CH:4][CH:3]=1.[Br:10]Br>C(O)(=O)C>[Br:10][CH2:8][C:7]([C:5]1[S:6][C:2]([Br:1])=[CH:3][CH:4]=1)=[O:9]
Reactant: CC(=O)c1ccc(Br)s1
Reactant: BrBr
Solvent: CC(=O)O
Product: O=C(CBr)c1ccc(Br)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-(5-Bromothiophen-2-yl)ethanone (1 g, 4.87 mmol) was dissolved in glacial acetic acid (5 mL) and treated with bromine (0.25 mL) in acetic acid (2 mL) added dropwise. The reaction was stirred at ambient temperature overnight. The volatiles were removed in vacuo while care was taken so as to keep the bath temperature under 40° C. The residue was dissolved in dichloromethane, washed with saturated aqueous sodium bicarbonate, water and brine. The organic layer was then dried with sodium sulfate, concentrated and purified by flash chromatography using a gradient of 10 to 30% of ethyl acetate in hexanes to yield a off-white solid (0.85 g).
Reaction SMILES: [C:1]1([CH3:26])[CH:6]=[CH:5][C:4]([S:7]([N:10]2[CH2:14][CH2:13][CH:12](OS(C3C=CC(C)=CC=3)(=O)=O)[CH2:11]2)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH3:27][O:28][C:29]1[CH:30]=[C:31]([SH:35])[CH:32]=[CH:33][CH:34]=1>>[CH3:27][O:28][C:29]1[CH:30]=[C:31]([S:35][CH:12]2[CH2:13][CH2:14][N:10]([S:7]([C:4]3[CH:3]=[CH:2][C:1]([CH3:26])=[CH:6][CH:5]=3)(=[O:8])=[O:9])[CH2:11]2)[CH:32]=[CH:33][CH:34]=1
Reactant: Cc1ccc(S(=O)(=O)OC2CCN(S(=O)(=O)c3ccc(C)cc3)C2)cc1
Reactant: COc1cccc(S)c1
Product: COc1cccc(SC2CCN(S(=O)(=O)c3ccc(C)cc3)C2)c1

Procedure:
The title compound, MS: m/e=363.1 (M+) was prepared from (RS)-toluene-4-sulfonic acid 1-(toluene-4-sulfonyl)-pyrrolidin-3-yl ester and 3-methoxythiophenol and by using DMF as solvent instead of acetonitrile.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][C:13]([N:15]([CH3:17])[CH3:16])=O.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][CH2:13][N:15]([CH3:17])[CH3:16]
Reactant: CN(C)C(=O)CCc1c[nH]c2ccc(Br)cc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN(C)CCCc1c[nH]c2ccc(Br)cc12
Temperature: 65 °C
Reaction time: 16 h

Procedure:
To an argon purged 250 mL round bottom flask fitted with condenser and magnetic stirbar containing 53 (1.283 g, 4.35 mmol) was added lithium aluminum hydride (412 mg, 10.86 mmol). Anhydrous tetrahydrofuran (15 mL) was added resulting in gas formation. The flask was placed in an oil bath and heated to 65° C. and stirred for 16 hours under argon. The reaction was cooled to room temperature and quenched with water (1.1 mL), 3N sodium hydroxide (1.7 mL) and water (3.3 mL) sequentially. The mixture was filtered to remove the white solid and the pale yellow filtrate concentrated to afford a pale yellow oil. Drying under high vacuum afforded a pale yellow solid, compound 54. Yield: 1.193 g of pale yellow solid (97.5%). 1H NMR (DMSO) δ 7.65-7.64 (d, 1H, J=1.5), 7.30-7.27 (d, 1H, J=8.7 Hz), 7.167 (s, 1 H), 7.14-7.09 (q, 1H, J=6.9, 8.4 Hz), 2.67-2.62 (t, J=7.5, 2H), 2.25-2.20 (t, J=7.5 Hz, 2H), 2.12 (s, 8 H).
Reaction SMILES: OS(O)(=O)=O.[Br:6][C:7]1[N:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9]([OH:11])=[O:10].[CH3:16]O>>[CH3:16][O:10][C:9](=[O:11])[C:8]1[CH:12]=[CH:13][CH:14]=[N:15][C:7]=1[Br:6]
Reactant: O=C(O)c1cccnc1Br
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cccnc1Br
Temperature: 25 °C
Reaction time: 5 h

Procedure:
H2SO4 (0.6 mL) was added to a solution of 2-bromonicotinic acid (1.5 g, 7.43 mmol, 1.00 eq.) in MeOH (20 mL). The resulting solution was stirred for 5 hours while the temperature was maintained at reflux in an oil bath. The mixture was cooled to room temperature and concentrated under vacuum. The resulting solution was diluted with EtOAc (50 mL) and the pH of the solution was adjusted to 10 with Na2CO3 (20%). The resulting organic layer was washed with water (1×50 mL) and saturated aqueous NaCl (2×100 mL), dried over anhydrous Na2SO4, and concentrated under vacuum to yield 2-bromonicotinic acid methyl ester (1.1 g) as a yellow liquid.
Reaction SMILES: [C:1]([C:3]1[C@@H:8]([C:9]2[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][C:10]=2[S:17]([CH3:20])(=[O:19])=[O:18])[N:7]([C:21](OC2C=CC([N+]([O-])=O)=CC=2)=[O:22])[C:6](=[O:33])[N:5]([C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([C:40]([F:43])([F:42])[F:41])[CH:35]=2)[C:4]=1[CH3:44])#[N:2].[CH3:45][O:46][CH2:47][CH2:48][NH2:49]>C(#N)C>[C:1]([C:3]1[C@@H:8]([C:9]2[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][C:10]=2[S:17]([CH3:20])(=[O:19])=[O:18])[N:7]([C:21]([NH:49][CH2:48][CH2:47][O:46][CH3:45])=[O:22])[C:6](=[O:33])[N:5]([C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([C:40]([F:42])([F:43])[F:41])[CH:35]=2)[C:4]=1[CH3:44])#[N:2]
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(C)(=O)=O)N(C(=O)Oc2ccc([N+](=O)[O-])cc2)C(=O)N1c1cccc(C(F)(F)F)c1
Reactant: COCCN
Solvent: CC#N
Product: COCCNC(=O)N1C(=O)N(c2cccc(C(F)(F)F)c2)C(C)=C(C#N)[C@H]1c1ccc(C#N)cc1S(C)(=O)=O

Procedure:
According to the General Procedure 1, 4-nitrophenyl (6S)-5-cyano-6-[4-cyano-2-(methylsulfonyl)phenyl]-4-methyl-2-oxo-3-[3-(trifluoromethyl)phenyl]-3,6-dihydropyrimidine-1(2H)-carboxylate (78.0 mg, 0.125 mmol; Example 6A) was reacted with 2-methoxyethylamine (28.1 mg, 0.374 mmol) in acetonitrile (1 ml) to give the target compound (55 mg, 78% of theory).
Reaction SMILES: S1C=CC=C1.C(O)C.[F:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]([C:43]2[CH:48]=[CH:47][C:46]([F:49])=[CH:45][CH:44]=2)[CH2:17][CH2:18][CH2:19][N:20]2[CH2:25][CH2:24][N:23]([CH2:26][C:27]([NH:29][C:30]3[C:35]([CH3:36])=[CH:34][C:33]([N+:37]([O-])=O)=[CH:32][C:31]=3[CH3:40])=[O:28])[CH:22]([CH2:41][OH:42])[CH2:21]2)=[CH:12][CH:11]=1.[H][H]>[Pt].CO>[NH2:37][C:33]1[CH:32]=[C:31]([CH3:40])[C:30]([NH:29][C:27](=[O:28])[CH2:26][N:23]2[CH2:24][CH2:25][N:20]([CH2:19][CH2:18][CH2:17][CH:16]([C:13]3[CH:12]=[CH:11][C:10]([F:9])=[CH:15][CH:14]=3)[C:43]3[CH:48]=[CH:47][C:46]([F:49])=[CH:45][CH:44]=3)[CH2:21][CH:22]2[CH2:41][OH:42])=[C:35]([CH3:36])[CH:34]=1
Reactant: Cc1cc([N+](=O)[O-])cc(C)c1NC(=O)CN1CCN(CCCC(c2ccc(F)cc2)c2ccc(F)cc2)CC1CO
Reactant: [H][H]
Agent: [Pt]
Solvent: CCO
Solvent: CO
Solvent: c1ccsc1
Product: Cc1cc(N)cc(C)c1NC(=O)CN1CCN(CCCC(c2ccc(F)cc2)c2ccc(F)cc2)CC1CO
Yield: 54 %

Procedure:
To 1 part of a solution of 2 parts of thiophene in 40 parts of ethanol were added 3.4 parts of 4-[4,4-bis(4-fluorophenyl)butyl]-N-(2,6-dimethyl-4-nitrophenyl)-2-(hydroxymethyl)-1-piperazineacetamide and 120 parts of methanol. The whole is hydrogenated at normal pressure and at room temperature with 2 parts of platinum-on-charcoal catalyst 5%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated. The oily residue was purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (90:10 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The oily residue solidified on cooling in a 2-propanone/CO2 -bath. The product was dried, yielding 1.73 parts (54%) of N-(4-amino-2,6-dimethylphenyl)-4-[4,4-bis(4-fluorophenyl)butyl]-2-(hydroxymethyl)-1-piperazineacetamide; mp. 85.2° C. (compound 156).
Reaction SMILES: [N:1]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]=[CH:6][CH:5]=1)=[C:2]=[S:3].[NH2:14][CH:15]([C:19]#[N:20])[C:16]([NH2:18])=[O:17]>CCOC(C)=O>[NH2:20][C:19]1[S:3][C:2]([NH:1][C:4]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]=[CH:6][CH:5]=2)=[N:14][C:15]=1[C:16]([NH2:18])=[O:17]
Reactant: N#CC(N)C(N)=O
Reactant: S=C=Nc1ccnc2ccccc12
Solvent: CCOC(C)=O
Product: NC(=O)c1nc(Nc2ccnc3ccccc23)sc1N

Procedure:
A mixture of 4-isothiocyanatoquinoline (0.3 g, 1.6 mmol) and 2-amino-cyanoacetamide (0.26g, 2.68 mmol) in EtOAc (20 mL) was refluxed for 90 min. The reaction mixture was concentrated in vacuo, and the resulting solids were collected and washed with EtOAc to give 0.33 g (contained impurities) of the titled compound which was used in the next step without further purification.
Reaction SMILES: Cl[C:2]1[NH:14][C:5]2=[N:6][CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=[C:4]2[N:3]=1.[NH:15]1[CH2:20][CH2:19][C:18]2([C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22](=[O:29])[O:21]2)[CH2:17][CH2:16]1.O>CN1C(=O)CCC1>[F:11][C:10]([F:13])([F:12])[C:8]1[CH:9]=[C:4]2[N:3]=[C:2]([N:15]3[CH2:20][CH2:19][C:18]4([C:28]5[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=5)[C:22](=[O:29])[O:21]4)[CH2:17][CH2:16]3)[NH:14][C:5]2=[N:6][CH:7]=1
Reactant: O=C1OC2(CCNCC2)c2ccccc21
Reactant: FC(F)(F)c1cnc2[nH]c(Cl)nc2c1
Solvent: CN1CCCC1=O
Solvent: O
Product: O=C1OC2(CCN(c3nc4cc(C(F)(F)F)cnc4[nH]3)CC2)c2ccccc21

Procedure:
Heat a solution of 2-chloro-6-trifluoromethyl-3-H-imidazo[4,5-b]pyridine (0.1 g, 0.45 mmol) and spiro[isobenzofuran-1,4′-piperidin]-3-one (0.2 g, 0.90 mmol) in dry NMP (5 mL) at 100° C. for 10 hours. Pour the cooled mixture into water (20 mL) and extract twice with EtOAc (20 mL). Wash the combined extracts with brine (20 mL), dry, and evaporate in vacuo. Purify by preparative TLC (4% MeOH-CH2Cl2) to obtain 1′-(6-trifluoromethyl-3-H-imidazo[4,5-b]pyridine-2-yl)-spiro[isobenzofuran-1,4′-piperidin]-3-one as a yellow solid.
Reaction SMILES: [OH:1][C:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH:11]1[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]1)([CH3:4])[CH3:3].[OH-].[K+]>C(O)(C)C.O>[NH:14]1[CH2:15][CH2:16][CH:11]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:2]([OH:1])([CH3:3])[CH3:4])[CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccccc2C(C)(C)O)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: CC(C)(O)c1ccccc1C1CCNCC1
Temperature: 25 °C

Procedure:
A solution of intermediate D40 (27 g, 5.636 mmol) and KOH (2.433 g, 43.357 mmol) in isopropyl alcohol (13.5 ml) and water (27 ml) was heated at 180° C. under microwave irradiation for 60 min. After cooling to r.t., the mixture was washed with water and NaCl (aqueous saturated solution). The organic phase was dried (Na2SO4) and the solvent evaporated in vacuo. The crude product was purified by column chromatography (silica gel; DCM/7M solution of NH3 in MeOH up to 10% as eluent). The desired fractions were collected and concentrated in vacuo to yield intermediate compound D41 as a yellow solid (1.041. g, 84%). M.P. 219.5° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][OH:11])=[CH:4][CH:3]=1.Br[CH2:13][CH2:14][CH3:15].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:13]([O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][OH:11])=[CH:6][CH:7]=1)[CH2:14][CH3:15]
Reactant: OCCCc1ccc(O)cc1
Reactant: CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCOc1ccc(CCCO)cc1

Procedure:
A mixture of 3-(4-hydroxyphenyl)-1-propanol (1.33 g), 1-bromopropane (1.2 ml) and potassium carbonate (2.25 g) and acetone (100 ml) was heated at reflux for 2 days. After concentration under reduced pressure, the residue was mixed with water and was extracted with ethyl acetate. The organic layer was washed with a 1 N aqueous solution of sodium hydroxide and an aqueous saturated solution of sodium chloride, and was dried with magnesium sulfate. The resulting organic layer was evaporated under reduced pressure to remove the solvent to obtain 3-(4-propoxyphenyl)-1-propanol (1.61 g) as a colorless oily substance.
Reaction SMILES: C(OC(=O)[N:7]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=1)[C:8]1[N:13]=[C:12]([N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[CH:11]=[N:10][CH:9]=1)(C)(C)C.Cl.O1CCOCC1.Cl>CO>[Cl:27][C:23]1[CH:22]=[C:21]([CH:26]=[CH:25][CH:24]=1)[CH2:20][NH:7][C:8]1[N:13]=[C:12]([N:14]2[CH2:15][CH2:16][NH:17][CH2:18][CH2:19]2)[CH:11]=[N:10][CH:9]=1
Reactant: CC(C)(C)OC(=O)N(Cc1cccc(Cl)c1)c1cncc(N2CCNCC2)n1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Clc1cccc(CNc2cncc(N3CCNCC3)n2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.2 %

Procedure:
(3-Chloro-benzyl)-(3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-6′-yl)-carbamic acid tert-butyl ester I-4f (37.5 mg, 0.09 mmol) was treated with 4.0M HCl/Dioxane (2 mL, 8 mmol). Methanol was added until a clear solution is formed and the mixture was stirred overnight at ambient temperature. The reaction mixture was poured into 1N HCl and extracted with ethyl acetate. The aqueous phase was brought to pH 14 with 5N KOH and extracted with Ethyl Acetate. The organic layers were washed with brine, dried (Na2SO4), and concentrated to afford the title compound 4-M (23.3 mg).
Reaction SMILES: C(OC([NH:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[C:21]([Cl:22])=[CH:20][N:19]=[C:18](Cl)[N:17]=2)=[CH:11][C:10]=1[CH2:24][CH2:25][C:26]1[CH:27]=[C:28]([NH:32]C(=O)OC(C)(C)C)[CH:29]=[CH:30][CH:31]=1)=O)(C)(C)C.[ClH:40].O1CCOCC1>C(#N)C.O.CC(O)CC>[ClH:22].[ClH:40].[Cl:22][C:21]1[CH:20]=[N:19][C:18]2[NH:32][C:28]3[CH:29]=[CH:30][CH:31]=[C:26]([CH:27]=3)[CH2:25][CH2:24][C:10]3[CH:11]=[C:12]([NH:15][C:16]=1[N:17]=2)[CH:13]=[CH:14][C:9]=3[NH2:8]
Reactant: CC(C)(C)OC(=O)Nc1cccc(CCc2cc(Nc3nc(Cl)ncc3Cl)ccc2NC(=O)OC(C)(C)C)c1
Agent: Cl
Solvent: CC#N
Solvent: CCC(C)O
Solvent: C1COCCO1
Product: Nc1ccc2cc1CCc1cccc(c1)Nc1ncc(Cl)c(n1)N2
Yield: 84 %

Procedure:
A solution of tert-butyl [3-(2-{2-[(tert-butoxycarbonyl)amino]-5-[(2,5-dichloropyrimidin-4-yl)amino]phenyl}ethyl)phenyl]carbamate (4.70 g, 8.18 mmol) in acetonitrile (750 mL), water (75 mL) and 2-butanol (1.0 mL) was treated with 4.0 M of hydrogen chloride in 1,4-dioxane (7.2 mL, 28.6 mmol) and refluxed for 20 hours. The reaction mixture was concentrated and the tan solid was triturated with dichloromethane and methanol to give the desired product (2.83 g, 84%). LCMS calculated for C18H17ClN5(M+H)+: m/z=338.1. 1H NMR (400 MHz, DMSO-d6): δ 8.37 (s, 1H), 7.89 (s, 1H), 7.79 (s, 1H), 7.59 (m, 1H), 7.43 (m, 3H), 7.36 (d, 1H), 7.17 (m, 2H), 6.91 (dd, 2H), 3.08 (d, 4H).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=3[OH:22])[N:9]=2)[CH:5]=[CH:4][CH:3]=1.[CH2:23]([C:29]1[C:30]([OH:38])=[C:31](B(O)O)[CH:32]=[CH:33][CH:34]=1)[CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]>>[CH2:23]([C:29]1[C:30]([OH:38])=[C:31]([C:2]2[N:7]=[C:6]([C:8]3[CH:13]=[CH:12][CH:11]=[C:10]([C:14]4[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=4[OH:22])[N:9]=3)[CH:5]=[CH:4][CH:3]=2)[CH:32]=[CH:33][CH:34]=1)[CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCCCCCc1cccc(B(O)O)c1O
Reactant: COc1ccc(O)c(-c2cccc(-c3cccc(Br)n3)n2)c1
Product: CCCCCCc1cccc(-c2cccc(-c3cccc(-c4cc(OC)ccc4O)n3)n2)c1O
Yield: 57 %

Procedure:
6-(3-Hexyl-2-hydroxyphenyl)-6′-(2-hydroxy-5-methoxyphenyl)-2,2′-bipyridine was prepared from 6-bromo-6′-(2-hydroxy-5-methoxyphenyl)-2,2′-bipyridine and 3-hexyl-2-hydroxyphenylboronic acid in 57% yield using method F; δH [2H6]-DMSO 12.40,(1H, s), 8.36,(2H, m), 8.25,(2H, t), 8.18,(1H, d), 8.09,(1H, d), 7.96,(1H, d), 7.65,(1H, s), 7.25,(1H, d), 6.99,(1H, d), 6.96-6.8,(2H, m), 3.81,(3H, s), 2.67,(2H, t), 1.60,(2H, m), 1.42-1.25,(6H, m), 0.88,(3H, t); MS 455 (MH)+; HPLC retention time (system 1) 4.96 minutes.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([OH:16])([C:14]#[N:15])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>O1CCCC1>[NH2:15][CH2:14][C:11]1([OH:16])[CH2:12][CH2:13][N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:9][CH2:10]1
Reactant: N#CC1(O)CCN(Cc2ccccc2)CC1
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: NCC1(O)CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.3 %

Procedure:
A suspension of the compound prepared in Example 248 (4.00 g) in tetrahydrofuran (90 mL) was treated with lithium aluminum hydride (1.75 g) slowly at 0° C. The mixture was allowed to stir at room temperature overnight, cooled to 0° C. and treated with Rochelle's salt (sodium potassium tartrate; 400 g). After stirring at room temperature for 3 hours, the organic phase was separated and the aqueous layer extracted with ethyl acetate. The combined organic extracts were dried and evaporated in vacuo to obtain the title compound (3.76 g) having the following physical data.
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([CH2:9]P(=O)(OCC)OCC)#[N:8].[CH:18]([CH:20]1[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]1)=O>O1CCCC1>[C:7]([CH:9]=[CH:18][CH:20]1[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]1)#[N:8]
Reactant: CCOP(=O)(CC#N)OCC
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(C=CC#N)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.8 %

Procedure:
To a solution of 1.0 M of potassium tert-butoxide in tetrahydrofuran (24.6 mL) at 0° C. was added dropwise a solution of diethyl cyanomethylphosphonate (4.18 mL, 0.0258 mol) in tetrahydrofuran (31.40 mL). The reaction was warmed to room temperature and then cooled to 0° C. again. To the reaction mixture was added a solution of tert-butyl 4-formylpiperidine-1-carboxylate (5.0 g, 0.023 mol) in tetrahydrofuran (6.28 mL). The reaction was allowed to warm up to room temperature and stirred at room temperature overnight. After being quenched with water, the mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried and evaporated to dryness. The crude mixture was purified on silica gel, eluting with 0 to 50% EtOAc in hexanes, to give the desired product (5.10 g, 92%). LCMS (M+Na) 259.0.