Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[CH:4]([O:13][C:14]1[C:22]3[N:21]=[C:20]([CH3:23])[NH:19][C:18]=3[CH:17]=[C:16]([C:24]([OH:26])=O)[CH:15]=1)[CH2:5][CH2:6][O:7]2.[NH:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1>>[F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[CH:4]([O:13][C:14]1[C:22]3[N:21]=[C:20]([CH3:23])[NH:19][C:18]=3[CH:17]=[C:16]([C:24]([N:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)=[O:26])[CH:15]=1)[CH2:5][CH2:6][O:7]2
Reactant: Cc1nc2c(OC3CCOc4cc(F)cc(F)c43)cc(C(=O)O)cc2[nH]1
Reactant: C1CCNC1
Product: Cc1nc2c(OC3CCOc4cc(F)cc(F)c43)cc(C(=O)N3CCCC3)cc2[nH]1
Yield: 56 %

Procedure:
The title compound was prepared as a white solid (70 mg, 56% yield for 3 steps) from 4-[(5,7-difluoro-3,4-dihydro-2H-chromen-4-yl)oxy]-2-methyl-1H-benzimidazole-6-carboxylic acid (100 mg, crude, STEP 4) and pyrrolidine (59 mg, 0.832 mmol) by the same manner in STEP 5 of Example 1.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]([CH3:9])[C:4](=[O:10])[C:3]=1[C:11](=[O:25])[CH:12]=[CH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[NH:20][C:21]([NH:23][CH3:24])=[S:22].[H-].[Na+].I[CH3:29]>CN(C)C=O>[OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]([CH3:9])[C:4](=[O:10])[C:3]=1[C:11](=[O:25])[CH:12]=[CH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[NH:20][C:21](=[N:23][CH3:24])[S:22][CH3:29]
Reactant: CNC(=S)Nc1ccccc1C=CC(=O)c1c(O)cc(C)n(C)c1=O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN=C(Nc1ccccc1C=CC(=O)c1c(O)cc(C)n(C)c1=O)SC
Reaction time: 1 h
Yield: 19 %

Procedure:
To a solution of 0.40 g of 4-hydroxy-3-[3-[(3-methylthioureido)phenyl]-1-oxo-2-propenyl]-1,6-dimethyl-2(1H)-pyridinone in 7 ml of dimethylformamide was added 0.044 g of sodium hydride (60% oily) at room temperature, and this was stirred for 1 hour. 0.26 g of iodomethane was added thereto, and this was stirred at room temperature overnight. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography to obtain 0.079 g of yellow oily 4-hydroxy-3-[3-[(2,3-dimethylisothioureido)phenyl]-1-oxo-2-propenyl]-1,6-dimethyl-2(1H)-pyridinone [Compound No. (115a)].
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:14])=[C:6]([CH:13]=1)[C:7]([O:9][CH2:10][CH2:11][CH3:12])=[O:8].C(N(CC)CC)C.[C:22]1([CH3:31])[C:23]([C:28](Cl)=[O:29])=[CH:24][CH:25]=[CH:26][CH:27]=1>C(Cl)Cl>[Cl:14][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:28](=[O:29])[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[CH3:31])=[CH:13][C:6]=1[C:7]([O:9][CH2:10][CH2:11][CH3:12])=[O:8]
Reactant: Cc1ccccc1C(=O)Cl
Reactant: CCCOC(=O)c1cc(N)ccc1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCOC(=O)c1cc(NC(=O)c2ccccc2C)ccc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 45 %

Procedure:
A solution of propyl 5-amino-2-chlorobenzoate (10.7 g, 0.050 mole) and triethylamine (6 g, 0.059 mole) in methylene chloride (50 ml) was added dropwise over 1 hour to an ice-cooled solution of o-toluoyl chloride (7.8 g, 0.50 mole) in methylene chloride (50 ml). The mixture was then stirred at room temperature for 3 hours and worked up by washing sequentially with water, dilute hydrochloric acid, water, 2% aqueous sodium hydroxide and water. The residue from evaporation of the methylene chloride was recrystallized from ethanol (100 ml) to give the title compound, m.p. 103°-105° C. (7.5 g, 45% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:10])=[C:6]([CH:9]=1)[CH2:7]O.S(Cl)([Cl:13])=O>C1(C)C=CC=CC=1.N1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:10])=[C:6]([CH:9]=1)[CH2:7][Cl:13]
Reactant: OCc1cc(Br)ccc1Cl
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: ClCc1cc(Br)ccc1Cl
Temperature: 100 °C

Procedure:
To a solution of 5-bromo-2-chlorobenzyl alcohol (10.66 g) in toluene (100 ml) solution were added thionyl chloride (10 ml), and pyridine (2 drops), and the mixture was stirred under heating at 100° C. overnight. The solvent was evaporated under reduced pressure, and the residue was dissolved in ethyl acetate. The solution was washed successively with water, a 10% aqueous hydrochloric acid solution, a saturated aqueous sodium hydrogen carbonate solution and brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure to give 5-bromo-2-chlorobenzyl chloride as pale yellow crystals, which was used in the subsequent step without further purification. (2) The above 5-bromo-2-chlorobenzyl chloride was dissolved in acetonitrile (100 ml), and the mixture was cooled to 0° C. Added thereto was tetraethylammonium cyanide (8.8 g), and the mixture was stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure, and the residue was dissolved in ethyl acetate. The solution was washed successively with water, 10% aqueous hydrochloric acid solution, a saturated aqueous sodium hydrogen carbonate solution and brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure to give 5-bromo-2-chlorophenylacetonitrile as a pale yellow solid, which was used in the subsequent step without further purification. (3) The above 5-bromo-2-chlorophenylacetonitrile was added to water (90 ml)-sulfuric acid (75 ml), and the mixture was stirred under heating at 160° C. overnight. The mixture was further diluted with water, and cooled to 0° C. The solvent was removed by decant, and the residue was dissolved in diethyl ether. The solution was washed with water and brine, and extracted with 10% sodium hydroxide. To the extract was added concentrated hydrochloric acid to make the solution acidic. The precipitates were collected by filtration, and purified by silica gel column chromatography (chloroform) to give 5-bromo-2-chlorophenylacetic acid (6.67 g) as colorless crystals. ESI-Mass m/Z 247/249 (M−H). (4) The above 5-bromo-2-chlorophenylacetic acid was treated in a manner similar to Reference Example 118-(4) and (5) to give the desired 5-bromo-2-chloro-1-(2-(5-phenyl-2-thienyl)ethyl)benzene as a pale yellow solid. APCI-Mass m/Z 377/379 (M+H).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[CH:8]([CH2:14][N:15](C)[CH2:16][CH2:17][C:18]([N:20]1[CH2:26][CH2:25][C:24]3[CH:27]=[C:28]([O:33][CH3:34])[C:29]([O:31][CH3:32])=[CH:30][C:23]=3[CH2:22][CH2:21]1)=[O:19])[CH2:7]2.[CH3:36][O:37][C:38]1[CH:39]=[C:40]2[C:43](=[CH:44][C:45]=1[O:46][CH3:47])[CH:42]([CH2:48][NH:49][CH3:50])[CH2:41]2.[C:51]([OH:58])(=[O:57])/[CH:52]=[CH:53]/[C:54]([OH:56])=[O:55]>>[C:51]([OH:58])(=[O:57])/[CH:52]=[CH:53]/[C:54]([OH:56])=[O:55].[CH3:54][O:55][C:39]1[C:38]([O:37][CH3:36])=[C:45]([O:46][CH3:47])[CH:44]=[C:43]2[C:40]=1[CH2:41][CH:42]2[CH2:48][NH:49][CH2:50][CH2:17][C:18]([N:20]1[CH2:26][CH2:25][C:24]2[CH:27]=[C:28]([O:33][CH3:34])[C:29]([O:31][CH3:32])=[CH:30][C:23]=2[CH2:22][CH2:21]1)=[O:19].[CH3:36][O:37][C:5]1[C:4]([O:3][CH3:2])=[C:11]([O:12][CH3:13])[CH:10]=[C:9]2[C:6]=1[CH2:7][CH:8]2[CH2:14][NH:15][CH2:16][CH2:17][C:18](=[O:19])[N:20]1[CH2:21][CH2:22][C:23]2[CH:30]=[C:29]([O:31][CH3:32])[C:28]([O:33][CH3:34])=[CH:27][C:24]=2[CH2:25][CH2:26]1
Reactant: CNCC1Cc2cc(OC)c(OC)cc21
Reactant: COc1cc2c(cc1OC)CCN(C(=O)CCN(C)CC1Cc3cc(OC)c(OC)cc31)CC2
Agent: Cl
Agent: O=C(O)/C=C/C(=O)O
Product: COc1cc2c(cc1OC)CCN(C(=O)CCNCC1Cc3c1cc(OC)c(OC)c3OC)CC2

Procedure:
Obtained in the same manner as the product of Example 1, but with replacement of the [(3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl)methyl]methylamine in Step 4 by the product of Preparation 11. Conversion to a salt is carried out in the presence of fumaric acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:57]=[CH:56][C:6]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:18]4[CH:23]=[CH:22][C:21]([NH:24][C:25]([C:27]5[C:32](=[O:33])[N:31]([C:34]6[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=6)[N:30]=[CH:29][CH:28]=5)=[O:26])=[CH:20][C:19]=4[F:41])=[C:11]3[C:10]([N:42]3[CH2:48][CH2:47][CH2:46][N:45](C(OC(C)(C)C)=O)[CH2:44][CH2:43]3)=[N:9]2)=[CH:5][CH:4]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[N:42]1([C:10]2[C:11]3[C:12](=[N:13][CH:14]=[CH:15][C:16]=3[O:17][C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:25]([C:27]4[C:32](=[O:33])[N:31]([C:34]5[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=5)[N:30]=[CH:29][CH:28]=4)=[O:26])=[CH:20][C:19]=3[F:41])[N:8]([CH2:7][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:57][CH:56]=3)[N:9]=2)[CH2:48][CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1
Reactant: COc1ccc(Cn2nc(N3CCCN(C(=O)OC(C)(C)C)CC3)c3c(Oc4ccc(NC(=O)c5ccnn(-c6ccc(F)cc6)c5=O)cc4F)ccnc32)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(Cn2nc(N3CCCNCC3)c3c(Oc4ccc(NC(=O)c5ccnn(-c6ccc(F)cc6)c5=O)cc4F)ccnc32)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.9 %

Procedure:
A round-bottomed flask was charged with tert-butyl 4-(1-(4-methoxybenzyl)-4-(2-fluoro-4-(1-(4-fluorophenyl)-6-oxo-1,6-dihydropyridazine-5-carboxamido)phenoxy)-1H-pyrazolo[3,4-b]pyridin-3-yl)-1,4-diazepane-1-carboxylate (118.3 mg, 0.1519 mmol), 2,2,2-trifluoroacetic acid (346.4 mg, 3.038 mmol) and CH2Cl2 (10 mL). The reaction mixture was stirred at room temperature for one hour. The solvent was removed and the residue was purified by silica gel chromatography (DCM/7 M NH3 in MeOH from 50/1 to 10/1, v/v) to give product (60.7 mg, 58.88%). LRMS (APCI pos): m/e 679 (M+1).
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C:5]2[CH:15]=[CH:16][CH:17]=[CH:18][C:4]=2[NH:3]1.Br[C:20]1[S:21][CH:22]=[C:23]([Br:25])[N:24]=1>>[C:11]([O:10][C:8](=[O:9])[CH2:7][N:6]1[C:5]2[CH:15]=[CH:16][CH:17]=[CH:18][C:4]=2[N:3]([C:20]2[S:21][CH:22]=[C:23]([Br:25])[N:24]=2)[C:2]1=[O:1])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)Cn1c(=O)[nH]c2ccccc21
Reactant: Brc1csc(Br)n1
Product: CC(C)(C)OC(=O)Cn1c(=O)n(-c2nc(Br)cs2)c2ccccc21

Procedure:
Essentially following the procedures described for Intermediate 7, but using 2,4-dibromothiazole in place of 2-bromopyridine, the title compound was prepared. MS: m/z=412 (M+1).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([C:22]2[CH:31]=[CH:30][C:25]([C:26]([NH:28][NH2:29])=[O:27])=[CH:24][CH:23]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH:39]1([C:43](Cl)=[O:44])[CH2:42][CH2:41][CH2:40]1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([C:22]2[CH:23]=[CH:24][C:25]([C:26]([NH:28][NH:29][C:43]([CH:39]3[CH2:42][CH2:41][CH2:40]3)=[O:44])=[O:27])=[CH:30][CH:31]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cccc(C2(c3ccc(C(=O)NN)cc3)CCN(Cc3ccccc3)CC2)c1
Reactant: O=C(Cl)C1CCC1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cccc(C2(c3ccc(C(=O)NNC(=O)C4CCC4)cc3)CCN(Cc3ccccc3)CC2)c1
Temperature: 0 °C
Reaction time: 5 h
Yield: 74.9 %

Procedure:
To a solution of 4-[1-Benzyl-4-(3-methoxy-phenyl)-piperidin-4-yl]-benzoic acid hydrazide (0.7 g, 1.69 mmol) in CH2Cl2 (10 mL) at 0° C. was added triethylamine (0.35 mL, 2.5 mmol) was catalytic DMAP (20 mg) and cyclobutane carbonyl chloride (0.19 mL, 1.69 mmol). The mixture was stirred at 0° C. for 1 hour and at room temperature for 5 hours. The solution was washed with brine (5 mL), dried (MgSO4) and concentrated. Purification by flash chromatography with hexanes/EtOAc (6:4) afforded 0.63 g (75% yield) of cyclobutanecarboxylic acid N′-{4-[1-benzyl-4-(3-methoxy-phenyl)-piperidin-4-yl]-benzoyl}-hydrazide. 1HNMR (400 MHz, CDCl3) δ 8.59 (s, 1H), 7.67 (d, 2H), 7.41-7.08 (comp, 8H), 6.82-6.61 (comp, 3H), 3.79 (s, 3H), 2.41 (s, 2H), 3.09-3.02 (m, 1H), 2.41-2.23 (comp, 8H), 2.19-1.67 (comp, 6H); MS (M+1) 498.2.
Reaction SMILES: Br[C:2]1[CH:21]=[N:20][C:5]2[NH:6][CH2:7][CH2:8][N:9]([CH2:10][C:11]3[C:16]([F:17])=[CH:15][CH:14]=[C:13]([F:18])[C:12]=3[Cl:19])[C:4]=2[C:3]=1[CH3:22].[O:23]1[CH2:28][CH2:27][N:26]([CH2:29][CH2:30][NH:31][C:32]2[CH:37]=[CH:36][C:35](B3OC(C)(C)C(C)(C)O3)=[CH:34][N:33]=2)[CH2:25][CH2:24]1>>[Cl:19][C:12]1[C:13]([F:18])=[CH:14][CH:15]=[C:16]([F:17])[C:11]=1[CH2:10][N:9]1[CH2:8][CH2:7][NH:6][C:5]2[N:20]=[CH:21][C:2]([C:35]3[CH:36]=[CH:37][C:32]([NH:31][CH2:30][CH2:29][N:26]4[CH2:27][CH2:28][O:23][CH2:24][CH2:25]4)=[N:33][CH:34]=3)=[C:3]([CH3:22])[C:4]1=2
Reactant: Cc1c(Br)cnc2c1N(Cc1c(F)ccc(F)c1Cl)CCN2
Reactant: CC1(C)OB(c2ccc(NCCN3CCOCC3)nc2)OC1(C)C
Product: Cc1c(-c2ccc(NCCN3CCOCC3)nc2)cnc2c1N(Cc1c(F)ccc(F)c1Cl)CCN2

Procedure:
The entitled compound can be prepared from 7-bromo-1-(2-chloro-3,6-difluorobenzyl)-8-methyl-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine and 2-(2-morpholinoethylamino)pyridine-5-boronic acid pinacol ester as described in example 25.
Reaction SMILES: [NH2:1][C@@H:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:3][OH:4].[N:11]([C:14]1[CH:19]=[CH:18][C:17]([C:20]2[N:24]=[CH:23][N:22]([C:25]3[CH:30]=[CH:29][C:28]([O:31][C:32]([F:35])([F:34])[F:33])=[CH:27][CH:26]=3)[N:21]=2)=[CH:16][CH:15]=1)=[C:12]=[S:13]>>[OH:4][CH2:3][C@@H:2]([NH:1][C:12]([NH:11][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[N:24]=[CH:23][N:22]([C:25]3[CH:30]=[CH:29][C:28]([O:31][C:32]([F:35])([F:33])[F:34])=[CH:27][CH:26]=3)[N:21]=2)=[CH:18][CH:19]=1)=[S:13])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: N[C@H](CO)c1ccccc1
Reactant: FC(F)(F)Oc1ccc(-n2cnc(-c3ccc(N=C=S)cc3)n2)cc1
Product: OC[C@@H](NC(=S)Nc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1)c1ccccc1

Procedure:
The title compound was prepared with (S)-2-amino-2-phenylethanol and 3-(4-isothiocyanato-phenyl)-1-(4-trifluoromethoxy-phenyl)-1H-1,2,4-triazole and isolated as an off-white solid (0.300 g, 73%): mp 125-128° C.; 1H NMR (400 MHz, CD3OD) δ 9.14 (s, 1H), 8.13 (d, J=8.3 Hz, 2H), 8.04 (d, J=8.8 Hz, 2H), 7.64 (d, J=8.3 Hz, 2H), 7.51 (d, J=8.7 Hz, 2H), 7.43-7.35 (m, 4H), 7.30-7.27 (m, 1H), 5.64 (s, 1H), 3.94-3.86 (m, 2H) (NH, OH not observed); ESIMS m/z 500 ([M+H]+).
Reaction SMILES: CON(C)[C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Br:24])[N:19]=2)[CH:7]=1)=[O:5].[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([Mg]Br)=[CH:29][C:28]=1[F:35]>C1COCC1>[Br:24][C:20]1[N:19]=[C:18]([CH2:17][N:8]2[C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:15](=[O:16])[C:6]([C:4](=[O:5])[C:30]3[CH:31]=[CH:32][C:27]([Cl:26])=[C:28]([F:35])[CH:29]=3)=[CH:7]2)[CH:23]=[CH:22][CH:21]=1
Reactant: Fc1cc([Mg]Br)ccc1Cl
Reactant: CON(C)C(=O)c1cn(Cc2cccc(Br)n2)c2ccccc2c1=O
Solvent: C1CCOC1
Product: O=C(c1ccc(Cl)c(F)c1)c1cn(Cc2cccc(Br)n2)c2ccccc2c1=O

Procedure:
Experimental conditions analogous to those described for Step 6 of Example 60 from 90 mg (0.22 mmol) of 1-(6-bromo-pyridin-2-ylmethyl)-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid methoxy-methyl-amide in 1.5 mL THF and 0.98 mL 0.5M 4-chloro-3-fluorophenylmagnesium bromide. Yield: 52 mg of a white solid. LC-MSD, m/z for C22H13BrClFN2O2 [M+H]+=471.0, 473.0; HPLC retention time: 2.6 min.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][NH:4][N:3]=1.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1B(O)O.N1C=CC=CC=1>CN(C)C(=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N:4]1[CH:5]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[C:2]([CH3:1])=[N:3]1
Reactant: COC(=O)c1c[nH]nc1C
Reactant: COc1ccccc1B(O)O
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CC(=O)N(C)C
Solvent: c1ccncc1
Product: COC(=O)c1cn(-c2ccccc2OC)nc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.3 %

Procedure:
Methyl 3-methyl-1H-pyrazole-4-carboxylate (7.3 g) synthesized in Example 1(3) was dissolved in N,N-dimethylacetamide (150 mL), 2-methoxyphenylboronic acid (15.9 g), copper acetate (18.2 g) and pyridine (16.2 mL) were added, and the mixture was stirred at room temperature overnight. The reaction mixture was filtered through celite, 1N hydrochloric acid (100 mL) was added to the filtrate, and the mixture was extracted with diethyl ether. The extract was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:4, volume ratio) to give the title object compound (10.3 g, 80%) as a pale-yellow oil.
Reaction SMILES: S(Cl)([Cl:3])=O.[N:5]([C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][C:16]=1[C@H:17]([NH:19][C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21])[CH3:18])[C:11](O)=[O:12])=[N+:6]=[N-:7]>CN(C)C=O.ClCCl>[N:5]([C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][C:16]=1[C@H:17]([NH:19][C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21])[CH3:18])[C:11]([Cl:3])=[O:12])=[N+:6]=[N-:7]
Reactant: C[C@@H](NC(=O)OCc1ccccc1)c1ccc(C(=O)O)cc1N=[N+]=[N-]
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: C[C@@H](NC(=O)OCc1ccccc1)c1ccc(C(=O)Cl)cc1N=[N+]=[N-]

Procedure:
Thionyl chloride (4 ml) and dimethylformamide (1 drop) were added to a solution of (R)-3-azido-4-(1-benzyloxycarbonylaminoethyl)benzoic acid in dichloromethane (20 ml), and the mixture was refluxed under heating for 2 hours. After the reaction, the solvent was evaporated under reduced pressure. The obtained residue was boiled with benzene to give 1.65 g of (R)-3-azido-4-(1-benzyloxycarbonylaminoethyl)benzoyl chloride as yellow crystals.
Reaction SMILES: [CH2:1]([C:3]1[N:4]=[C:5]([OH:20])[C:6]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[CH:10]=[CH:9][C:7]=2[N:8]=1)[CH3:2].CC1N=[C:24]([O:39][CH2:40]COC)[C:25]2N=C(C3C=CC(F)=CC=3)C=CC=2N=1>COCCO>[CH2:1]([C:3]1[N:4]=[C:5]([O:20][CH2:25][CH2:24][O:39][CH3:40])[C:6]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[CH:10]=[CH:9][C:7]=2[N:8]=1)[CH3:2]
Reactant: CCc1nc(O)c2nc(-c3ccc(F)cc3)ccc2n1
Reactant: COCCOc1nc(C)nc2ccc(-c3ccc(F)cc3)nc12
Solvent: COCCO
Product: CCc1nc(OCCOC)c2nc(-c3ccc(F)cc3)ccc2n1
Yield: 46 %

Procedure:
was synthesized from 2-ethyl-6-(4-fluorophenyl)-4-hydroxyl pyrido[3,2-d]pyrimidine and 2-methoxyethanol in 46% yield, using the procedure described for the synthesis of 2-methyl-4-(2-methoxyethoxy)-6-(4-fluorophenyl)-pyrido[3,2-d]pyrimidine. The mass spectrum was as follows: MS (m/z): 328 ([M+H]+, 100).
Reaction SMILES: [O:1]([Si:9]([CH:16]([CH3:18])[CH3:17])([CH:13]([CH3:15])[CH3:14])[CH:10]([CH3:12])[CH3:11])S(C(F)(F)F)(=O)=O.[Br:19][CH2:20][C@H:21]([CH3:25])[CH2:22][CH2:23]O.N1C(C)=CC=CC=1C.Cl>C(Cl)Cl>[CH:10]([Si:9]([CH:16]([CH3:18])[CH3:17])([CH:13]([CH3:15])[CH3:14])[O:1][CH2:23][CH2:22][C@@H:21]([CH3:25])[CH2:20][Br:19])([CH3:12])[CH3:11]
Reactant: CC(C)[Si](OS(=O)(=O)C(F)(F)F)(C(C)C)C(C)C
Reactant: C[C@@H](CBr)CCO
Agent: Cl
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: CC(C)[Si](OCC[C@@H](C)CBr)(C(C)C)C(C)C
Temperature: 0 °C

Procedure:
15.4 ml of triisopropylsilyl triflate are added to a solution of 8.7 g of (R)-4-bromo-3-methylbutan-1-ol in 320 ml of methylene chloride at 0° C., and 6.6 ml of 2,6-lutidine are then added in the course of 30 min. The reaction mixture is subsequently poured onto 100 ml of ice-water and the aqueous phase is acidified by addition of 2N hydrochloric acid (pH 3). It is extracted with methylene chloride and the organic phase is washed with a 5% sodium bicarbonate solution and saturated sodium chloride solution and dried over sodium sulfate. After purification of the crude product by FC over 200 g of silica gel (mobile phase J), the title compound is obtained: Rf (J)=0.48.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH2:6][CH:7]([O:9][CH:10]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:11]([OH:13])=O)[CH3:8])[CH3:5].Cl.[C:21]1([C:27]2([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[CH2:35][CH2:34][C@@H:33]([F:36])[C@@H:32]3[C@H:28]2[CH2:29][NH:30][CH2:31]3)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[OH:1][CH2:2][CH2:3][N:4]([CH2:6][CH:7]([O:9][CH:10]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:11]([N:30]1[CH2:29][C@@H:28]2[C@@H:32]([C@H:33]([F:36])[CH2:34][CH2:35][C:27]2([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH2:31]1)=[O:13])[CH3:8])[CH3:5]
Reactant: CC(CN(C)CCO)OC(C(=O)O)c1ccccc1
Reactant: F[C@@H]1CCC(c2ccccc2)(c2ccccc2)[C@@H]2CNC[C@H]12
Agent: Cl
Product: CC(CN(C)CCO)OC(C(=O)N1C[C@@H]2[C@H](F)CCC(c3ccccc3)(c3ccccc3)[C@@H]2C1)c1ccccc1
Yield: 43.7 %

Procedure:
By carrying out the procedure as in Example 2, but using 1.37 g of {3-[N-(2-hydroxyethyl)-N-methylamino]-2-propoxy}phenylacetic acid and 1.2 g of (3aR, 7R, 7aR)-4,4-diphenyl-7-fluoroperhydroisoindole hydrochloride, 0.86 g of (3aR,7R,7aR)-2-{{3-[N-(2-hydroxyethyl)-N-methylamino]-2-propoxy}phenylacetyl}-4,4-diphenyl-7-fluoroperhydroisoindole is obtained, after purification by chromatography on a silica gel column, in the form of a white meringue.
Reaction SMILES: [C:1]([C:4]1[CH:26]=[CH:25][C:7]([O:8][CH2:9][CH2:10][CH2:11][S:12][CH2:13][CH:14]2[CH2:18][O:17][C:16]([CH3:24])([CH2:19][CH2:20][C:21]([OH:23])=[O:22])[S:15]2)=[C:6]([CH2:27][CH2:28][CH3:29])[C:5]=1[OH:30])(=[O:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:39])C=1>>[C:1]([C:4]1[CH:26]=[CH:25][C:7]([O:8][CH2:9][CH2:10][CH2:11][S:12]([CH2:13][CH:14]2[CH2:18][O:17][C:16]([CH3:24])([CH2:19][CH2:20][C:21]([OH:23])=[O:22])[S:15]2)=[O:39])=[C:6]([CH2:27][CH2:28][CH3:29])[C:5]=1[OH:30])(=[O:3])[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCc1c(OCCCSCC2COC(C)(CCC(=O)O)S2)ccc(C(C)=O)c1O
Product: CCCc1c(OCCCS(=O)CC2COC(C)(CCC(=O)O)S2)ccc(C(C)=O)c1O
Yield: 50.3 %

Procedure:
The title compound was prepared according to the procedure of Example 46 using the sulfide obtained in Example 38 (0.30 g, 0.00066 mol) and m-chloroperbenzoic acid (0.113 g, 0.00066 mol). The crude product was chromatographed on silica gel using ethyl acetate containing 0.5% acetic acid to give 0.157 g (50%) of the desired product as an oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]([C:17]2[C:21]([N+:22]([O-])=O)=[CH:20][NH:19][N:18]=2)=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)C.CN(C=O)C.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]([C:17]2[C:21]([NH2:22])=[CH:20][NH:19][N:18]=2)=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)c2n[nH]cc2[N+](=O)[O-])CC1
Agent: [Pd]
Solvent: CCO
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(NC(=O)c2n[nH]cc2N)CC1
Yield: 73.8 %

Procedure:
4-[(4-Nitro-1H-pyrazole-3-carbonyl)-amino]-piperidine-1-carboxylic acid tert-butyl ester (13.05 g) was dissolved in ethanol/DMF (300 ml/75 ml), treated with 10% palladium on carbon (500 mg) then hydrogenated at room temperature and pressure overnight. The catalyst was removed by filtration through Celite and the filtrate evaporated and re-evaporated with toluene. The crude material was purified by flash column chromatography eluting with EtOAc then 2% MeOH I EtOAc then 5% MeOH/EtOAc. Product containing fractions were combined and evaporated to give 8.78 g of 4-[(4-amino-1H-pyrazole-3-carbonyl)-amino]-piperidine-1-carboxylic acid tert-butyl ester as a brown foam. (LC/MS: Rt 1.91, [M+H]+ 310).
Reaction SMILES: [C:1]1(=[CH:7][CH2:8][C:9]2([CH3:38])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([OH:19])=[C:11]([C:20]3[NH:25][C:24]4[CH:26]=[CH:27][C:28]([NH:30][S:31]([CH3:34])(=[O:33])=[O:32])=[CH:29][C:23]=4[S:22](=[O:36])(=[O:35])[N:21]=3)[C:10]2=[O:37])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H][H]>[Pd].CO.O1CCCC1>[CH:1]1([CH2:7][CH2:8][C:9]2([CH3:38])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([OH:19])=[C:11]([C:20]3[NH:25][C:24]4[CH:26]=[CH:27][C:28]([NH:30][S:31]([CH3:34])(=[O:33])=[O:32])=[CH:29][C:23]=4[S:22](=[O:35])(=[O:36])[N:21]=3)[C:10]2=[O:37])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: [H][H]
Reactant: CC1(CC=C2CCCCC2)C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C(O)c2ccccc21
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CC1(CCC2CCCCC2)C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C(O)c2ccccc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 100.9 %

Procedure:
To a solution of Example 147 (18 mg, 0.032 mmol), 10% palladium on carbon (5 mg) in methanol (5 mL) and tetrahydrofuran (5 mL) was added a hydrogen balloon. After evacuating the solution two times the mixture was stirred under the hydrogen atmosphere at room temperature for 24 hours. The solution was then filtered through celite and the filtrate concentrated to provide the title compound (18 mg, 100%). MS (ESI+) m/z=558 (M+H)+. 1H NMR (300 MHz, DMSO-d6): δ 0.42 (m, 1H), 0.62 (m, 2H), 0.78 (m, 2H), 1.03 (m, 4H), 1.50 (m, 4H), 1.54 (s, 3H), 2.12 (m, 2H), 3.08 (s, 3H), 7.56 (m, 3H), 7.73 (m, 3H), 8.16 (d, J=8.1 Hz, 1H), 10.26 (s, 1H), 13.74 (s, 1H).