Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C:17]([OH:19])=O)=[CH:12][CH:11]=2)=[N:7][CH:8]=1.Cl.C(N=C=NCCCN(C)C)C.[NH2:34][C:35]1[CH:40]=[CH:39][N:38]=[C:37]([Cl:41])[CH:36]=1>ClCCl>[Cl:41][C:37]1[CH:36]=[C:35]([NH:34][C:17](=[O:19])[CH2:16][C:13]2[CH:12]=[CH:11][C:10]([O:9][C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:21])[F:20])=[CH:8][N:7]=3)=[CH:15][CH:14]=2)[CH:40]=[CH:39][N:38]=1
Reactant: Nc1ccnc(Cl)c1
Reactant: O=C(O)Cc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: O=C(Cc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1)Nc1ccnc(Cl)c1
Yield: 72.5 %

Procedure:
2.3 g (7.78 mmol) of 4-[(5-trifluoromethylpyridin-2-yl)oxy]phenylacetic acid was dissolved in 10 ml of dichloromethane and cooled to a temperature of from -10° to 0° C. Then, 1.94 g (10.1 mmol) of 1-ethyl3-(dimethylaminopropyl)carbodiimide hydrochloride was added thereto, and the mixture was stirred at a temperature of from -10° to 0° C. 20 minutes later, 1.0 g (7.78 mmol) of 4-amino-2-chloropyridine was added thereto, and the mixture was gradually returned to room temperature with stirring and further stirred over night at room temperature. Then, 10 ml of dichloromethane was added to the reaction solution. The organic layer was washed with water and then dried over anhydrous magnesium sulfate. Then, dichloromethane was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solvent: n-hexane/ethyl acetate) to obtain 2.3 g of the desired product as a slightly yellow powder (melting point: 49 to 53° C.).
Reaction SMILES: [CH:1]1([CH2:4][C:5]2[NH:9][C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[N:6]=2)[CH2:3][CH2:2]1.Br[CH2:15][C:16]1[CH:35]=[CH:34][C:19]2/[C:20](=[C:30](/[CH3:33])\[C:31]#[N:32])/[C:21]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:22]=3[O:23][CH2:24][C:18]=2[CH:17]=1>>[CH:1]1([CH2:4][C:5]2[N:6]([CH2:15][C:16]3[CH:35]=[CH:34][C:19]4/[C:20](=[C:30](/[CH3:33])\[C:31]#[N:32])/[C:21]5[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:22]=5[O:23][CH2:24][C:18]=4[CH:17]=3)[C:7]3[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=3[N:9]=2)[CH2:2][CH2:3]1
Reactant: C/C(C#N)=C1/c2ccc(CBr)cc2COc2cc(F)ccc21
Reactant: c1ccc2[nH]c(CC3CC3)nc2c1
Product: C/C(C#N)=C1/c2ccc(Cn3c(CC4CC4)nc4ccccc43)cc2COc2cc(F)ccc21
Yield: 92.9 %

Procedure:
Using 2-cyclopropylmethyl-1H-benzo[d]imidazole (72 mg, 0.419 mmol) and (E)-2-[8-(bromomethyl)-3-fluorodibenzo[b,e]oxepin-11(6H)-ylidene]propanenitrile (150 mg, 0.419 mmol) obtained in Reference Example 1, and in the same manner as in Reference Example 1A, the title compound (175 mg, 93%) was obtained.
Reaction SMILES: [BH4-].[Na+].[F:3][CH:4]([F:51])[C:5]([C:38]1[CH:43]=[CH:42][C:41]([C:44]2[CH:49]=[CH:48][C:47]([F:50])=[CH:46][N:45]=2)=[CH:40][CH:39]=1)([OH:37])[CH2:6][C:7]1[N:8]([C:18]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:9]=[C:10]([CH2:12][C:13]([CH3:17])([CH3:16])[CH:14]=[O:15])[N:11]=1>CO>[F:51][CH:4]([F:3])[C:5]([C:38]1[CH:39]=[CH:40][C:41]([C:44]2[CH:49]=[CH:48][C:47]([F:50])=[CH:46][N:45]=2)=[CH:42][CH:43]=1)([OH:37])[CH2:6][C:7]1[N:8]([C:18]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:9]=[C:10]([CH2:12][C:13]([CH3:17])([CH3:16])[CH2:14][OH:15])[N:11]=1
Reactant: CC(C)(C=O)Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(CC(O)(c2ccc(-c3ccc(F)cn3)cc2)C(F)F)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(CO)Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(CC(O)(c2ccc(-c3ccc(F)cn3)cc2)C(F)F)n1
Temperature: 25 °C

Procedure:
Sodium borohydride (8 mg, 0.2 mmol) was added to a solution of 3-(2-{3,3-difluoro-2-[4-(5-fluoropyridin-2-yl)phenyl]-2-hydroxypropyl}-1-trityl-1H-imidazol-4-yl)-2,2-dimethylpropanal (70 mg, 0.1 mmol) in methanol (3 mL). After stirring at ambient temperature until the reaction was complete (LCMS), the reaction mixture was quenched with water and extracted with methylene chloride. The combined organic extracts were dried (magnesium sulfate) and concentrated in vacuo to afford 3-(2-{3,3-difluoro-2-[4-(5-fluoropyridin-2-yl)phenyl]-2-hydroxypropyl}-1-trityl-1H-imidazol-4-yl)-2,2-dimethylpropan-1-ol which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[N:13]([CH3:14])[C:12]([C:15]3[CH:19]=[CH:18][N:17]([CH2:20][CH3:21])[N:16]=3)=[N:11][C:10]=2[C:22]2[CH:27]=[CH:26][C:25]([C:28]3[N:32]=CON=3)=[CH:24][CH:23]=2)=[CH:4][CH:3]=1.[CH:33]1(B(O)O)CC1.C([O-])([O-])=O.[Cs+].[Cs+].N1C2C(=CC=C3C=2N=CC=C3)C=CC=1>O1CCOCC1.CN(C1C=CN=CC=1)C.CC([O-])=O.CC([O-])=O.[Cu+2].O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][C:9]2[N:13]([CH3:14])[C:12]([C:15]3[CH:19]=[CH:18][N:17]([CH:20]4[CH2:21][CH2:33]4)[N:16]=3)=[N:11][C:10]=2[C:22]2[CH:27]=[CH:26][C:25]([C:28]#[N:32])=[CH:24][CH:23]=2)=[CH:6][CH:7]=1
Reactant: OB(O)C1CC1
Reactant: CCn1ccc(-c2nc(-c3ccc(-c4ncon4)cc3)c(Sc3ccc(Cl)cc3)n2C)n1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: C1COCCO1
Product: Cn1c(-c2ccn(C3CC3)n2)nc(-c2ccc(C#N)cc2)c1Sc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 36.3 %

Procedure:
To a mixture of Step 2 product of Example 140 (150 mg, 0.383 mmol), cyclopropyl boronic acid (132 mg, 1.53 mmol) and Cu(II) acetate (139 mg, 0.766 mmol) in dioxane (2.0 ml) were added DMAP (187 mg, 1.53 mmol), Cs2CO3 (125 mg, 0.383 mmol) and 1,10-phenanthroline (276 mg, 1.53 mmol) in a sealed tube under N2, stirred at rt for 30 min and then heated at 90° C. for overnight. Reaction mixture was diluted water, extracted with EtOAc, washed with brine and dried over Na2SO4, filtered, concentrated, and separated by prep TLC (hex:EtOAc=2:1) to afford 4-{5-[(4-chlorophenyl)sulfanyl]-2-(1-cyclopropyl-1H-pyrazol-3-yl)-1-methyl-1H-imidazol-4-yl}benzonitrile (60 mg) as white solid. LCMS: [M+1]+=432.0.
Reaction SMILES: Cl.[Br:2][C:3]1[C:11]([Cl:12])=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[C:5]([NH:13]N)[CH:4]=1.O=[C:16]1[CH2:21][CH2:20][CH2:19][CH:18]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:17]1.C(O)(=O)C>C1(C)C=CC=CC=1>[Br:2][C:3]1[C:11]([Cl:12])=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[C:5]2[C:4]=1[C:21]1[CH2:20][CH2:19][CH:18]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:17][C:16]=1[NH:13]2
Reactant: CCOC(=O)C1CCCC(=O)C1
Reactant: NNc1cc(Br)c(Cl)cc1C(=O)O
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CCOC(=O)C1CCc2c([nH]c3c(C(=O)O)cc(Cl)c(Br)c23)C1
Temperature: 105 °C
Reaction time: 16 h
Yield: 73 %

Procedure:
A suspension of 4-bromo-5-chloro-2-hydrazinylbenzoic acid hydrochloride (12.89 g, 37.6 mmol), ethyl 3-oxocyclohexanecarboxylate (7.03 g, 41.3 mmol), and acetic acid (6.45 mL, 113 mmol) in toluene (188 mL) was heated at 105° C. overnight. After 16 h, more acetic acid (6 mL) and ethyl 3-oxocyclohexanecarboxylate (2.00 g) were added and the mixture was heated at 110° C. for 4.5 h. The mixture was concentrated, and the residue was combined with toluene (100 mL) and TFA (20 mL). The suspension was heated at 90° C. overnight. The cooled mixture was concentrated and the residue was suspended in EtOAc. The resulting solid was collected by filtration, washed with EtOAc and air-dried to give 5-bromo-6-chloro-2-(ethoxycarbonyl)-2,3,4,9-tetrahydro-1H-carbazole-8-carboxylic acid as a yellow solid (11.0 g, 73% yield). Mass spectrum m/z 400, 402 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 13.44 (br. s., 1H), 11.24 (s, 1H), 7.69 (s, 1H), 4.12 (qd, J=7.1, 2.3 Hz, 2H), 3.23-2.81 (m, 5H), 2.23-2.09 (m, 1H), 1.91-1.75 (m, 1H), 1.22 (t, J=7.0 Hz, 3H).
Reaction SMILES: O=[C:2]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([C:11]([OH:13])=[O:12])[C:5]=2[CH2:4][CH2:3]1.Cl.[F:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22]N)=[CH:18][CH:17]=1>>[F:15][C:16]1[CH:21]=[CH:20][C:19]2[NH:22][C:2]3[C:10]4[CH:9]=[CH:8][CH:7]=[C:6]([C:11]([OH:13])=[O:12])[C:5]=4[CH2:4][C:3]=3[C:18]=2[CH:17]=1
Reactant: O=C(O)c1cccc2c1CCC2=O
Reactant: NNc1ccc(F)cc1
Agent: Cl
Product: O=C(O)c1cccc2c1Cc1c-2[nH]c2ccc(F)cc12
Yield: 9.2 %

Procedure:
In a manner similar to Example 17, 1-oxo-indan-4-carboxylic acid (1.00 g, 5.68 mmol) and 4-fluorophenylhydrazine hydrochloride (0.923 g, 5.68 mmol) were converted to the title compound (0.140 g, 10%) as an off-white solid: mp>300° C.; 1H NMR (DMSO-d6): δ 3.98 (s, 2H), 6.93 (d of t, 1H), 7.38 (d of d, 1H), 7.44 (d of d, 1H), 7.50 (d, 1H), 7.77-7.80 (m, 2H), 11.72 (s, 1H), 13.43 (s, 1H); MS [EI, m/z]: 267 [M]+.
Reaction SMILES: C([O:8][C:9]1[N:14]=[C:13]2[NH:15][CH:16]=[N:17][C:12]2=[CH:11][CH:10]=1)C1C=CC=CC=1.[F:18][C:19]1[C:24]([CH3:25])=[CH:23][CH:22]=[CH:21][C:20]=1B(O)O>>[F:18][C:19]1[C:24]([CH3:25])=[CH:23][CH:22]=[CH:21][C:20]=1[N:15]1[C:13]2=[N:14][C:9]([OH:8])=[CH:10][CH:11]=[C:12]2[N:17]=[CH:16]1
Reactant: c1ccc(COc2ccc3nc[nH]c3n2)cc1
Reactant: Cc1cccc(B(O)O)c1F
Product: Cc1cccc(-n2cnc3ccc(O)nc32)c1F

Procedure:
From 5-(benzyloxy)-3H-imidazo[4,5-b]pyridine and 2-fluoro-3-methylphenylboronic acid, prepared in a similar manner as the one described in Example 1.26, the title compound was obtained. LCMS m/z=244.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[NH:12][C:11]3[CH:15]=[C:16]([O:19][CH3:20])[CH:17]=[CH:18][C:10]=3[S:9]2(=[O:22])=[O:21])=[CH:4][CH:3]=1.[H-].[Na+].[CH3:25]I>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[N:12]([CH3:25])[C:11]3[CH:15]=[C:16]([O:19][CH3:20])[CH:17]=[CH:18][C:10]=3[S:9]2(=[O:21])=[O:22])=[CH:4][CH:3]=1
Reactant: CI
Reactant: COc1ccc2c(c1)NC(=O)N(c1ccc(Cl)cc1)S2(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)N(C)C(=O)N(c1ccc(Cl)cc1)S2(=O)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-(4-chlorophenyl)-6-methoxy-2H-1,2,4-benzothiadiazine-3(4H)-one 1,1-dioxide (23.50 g) in dried N,N-dimethylformamide (150 ml) was added sodium hydride (60% oil dispersion) in one portion at 0° C. The suspension was stirred for one hour at ambient temperature and then methyl iodide (5.18 ml) was added therein at the same temperature. The reaction mixture was stirred for one and half hours a ambient temperature and then poured into ice water. The separated solid was filtered, dried and recrystrallized from ethanol to yield 2-(4-chlorophenyl)-6-methoxy-4-methyl-2H-1,2,4-benzothiadiazine-3(4H)-one 1,1-dioxide (21.07 g) as a white needle crystal.
Reaction SMILES: Br[CH2:2][C:3]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:4]=1[C:5]#[N:6].[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1.C(N(CC)CC)C>C(Cl)Cl>[O:17]1[CH2:18][CH2:19][N:14]([CH2:2][C:3]2[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:4]=2[C:5]#[N:6])[CH2:15][CH2:16]1
Reactant: N#Cc1cccc([N+](=O)[O-])c1CBr
Reactant: C1COCCN1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#Cc1cccc([N+](=O)[O-])c1CN1CCOCC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 90.5 %

Procedure:
To a stirred solution of 2-(bromomethyl)-3-nitrobenzonitrile (1.10 g, 4.56 mmol) and morpholine (0.80 g, 9.13 mmol) in CH2Cl2 (15 mL) was added triethylamine (1.85 g, 18.25 mmol) dropwise at 0° C. The mixture was stirred at room temperature for 1.5 h and evaporated to dryness under reduced pressure. The residue was diluted with water (10 mL) and extracted with CH2Cl2 (3×50 mL). The CH2Cl2 solution was dried over anhydrous Na2SO4, filtered, and evaporated to dryness under reduced pressure. The residue was purified by MPLC on silica gel using a mixture of EtOAc and hexane as eluent to give 2-(morpholinomethyl)-3-nitrobenzonitrile (1.02 g, 90%) as a yellow solid. 1H NMR (400 MHz, CDCl3): δ 7.90 (br d, 1H, J=8.0 Hz), 7.84 (dd, 1H, J=8.0, 1.2 Hz), 7.56 (t, 1H, J=8.0 Hz), 3.99 (s, 2H), 3.60 (br t, 4H, J=4.4 Hz), 2.46 (br s, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][C:3]=1[C:4]([N:6]1[CH2:12][CH2:11][CH2:10][C:9](=[O:13])[C:8]2[S:14][CH:15]=[CH:16][C:7]1=2)=[O:5].C(O[CH:29](N(C)C)[N:30]([CH3:32])[CH3:31])(C)(C)C>C(Cl)Cl>[CH3:29][N:30]([CH:32]=[C:10]1[CH2:11][CH2:12][N:6]([C:4](=[O:5])[C:3]2[CH:17]=[CH:18][C:19]([N+:21]([O-:23])=[O:22])=[CH:20][C:2]=2[Cl:1])[C:7]2[CH:16]=[CH:15][S:14][C:8]=2[C:9]1=[O:13])[CH3:31]
Reactant: O=C1CCCN(C(=O)c2ccc([N+](=O)[O-])cc2Cl)c2ccsc21
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Solvent: ClCCl
Product: CN(C)C=C1CCN(C(=O)c2ccc([N+](=O)[O-])cc2Cl)c2ccsc2C1=O

Procedure:
A mixture of 3.0 g of 4,5,6,7-tetrahydro-4-(2-chloro-4-nitrobenzoyl)-8H-thieno[3,2-b]azepin-8-one and 20 ml of tert-butoxy-bis(dimethylamino)methane is heated on a steam bath 2 hours followed by the addition of 10 ml of methylene chloride. The reaction mixture is refluxed for 1 hour. The reaction mixture is evaporated in vacuo to a residue which is diluted with 100 ml of methylene chloride and filtered through a pad of hydrous magnesium silicate. The filtrate is filtered through a short column of silica gel to give 2.45 g of the desired product as a yellow foam.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@@H:8]([CH2:14][O:15][C:16](=[O:18])[CH3:17])[O:7][CH:6]1Cl)(=[O:3])[CH3:2].C(O[C@@H]1O[C@H](COC(=O)C)[C@@H](OC(=O)C)[C@H]1OC(=O)C)(=O)C.[C:42]([C:45]1[N+:49]([CH2:50][C:51]2[CH:56]=[CH:55][C:54]([N+:57]([O-:59])=[O:58])=[CH:53][CH:52]=2)=[CH:48][NH:47][C:46]=1[O-:60])(=[O:44])[NH2:43]>>[N+:57]([C:54]1[CH:53]=[CH:52][C:51]([CH2:50][N:49]2[C:45]([C:42]([NH2:43])=[O:44])=[C:46]([O:60][C@@H:6]3[O:7][C@H:8]([CH2:14][O:15][C:16](=[O:18])[CH3:17])[C@@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@H:5]3[O:4][C:1](=[O:3])[CH3:2])[N:47]=[CH:48]2)=[CH:56][CH:55]=1)([O-:59])=[O:58]
Reactant: NC(=O)c1c([O-])[nH]c[n+]1Cc1ccc([N+](=O)[O-])cc1
Reactant: CC(=O)OC[C@H]1OC(Cl)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Product: CC(=O)OC[C@H]1O[C@@H](Oc2ncn(Cc3ccc([N+](=O)[O-])cc3)c2C(N)=O)[C@H](OC(C)=O)[C@@H]1OC(C)=O

Procedure:
Following a procedure similar to that of Example 1 but using 2,3,5-tri-O-acetyl-D-ribofuranosyl chloride prepared from 2.50 g of 1,2,3,5-tetra-O-acetyl-β-D-ribofuranose and 1.022 g of 5-carbamoyl-1-(4-nitrobenzyl)imidazolium-4-olate there was obtained 0.986 g of 1-(4-nitrobenzyl)-4-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)oxy-1H-imidazole-5-carboxamide which was recrystallized from ethanol. m.p. 155.5°-156.5° C.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10](=[O:16])[C@H:11]1[CH2:15][CH2:14][CH2:13][NH:12]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[OH:17][C:18]1[CH:23]=[C:22]([CH2:24][C:25]([OH:27])=O)[C:21]([OH:28])=[CH:20][C:19]=1[CH2:29][C:30]([OH:32])=O>CCOC(C)=O.CCCCCC>[CH2:2]([O:9][C:10]([C@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:30](=[O:32])[CH2:29][C:19]1[CH:20]=[C:21]([OH:28])[C:22]([CH2:24][C:25]([N:12]2[CH2:13][CH2:14][CH2:15][C@@H:11]2[C:10]([O:9][CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)=[O:16])=[O:27])=[CH:23][C:18]=1[OH:17])=[O:16])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=C(O)Cc1cc(O)c(CC(=O)O)cc1O
Reactant: O=C(OCc1ccccc1)[C@H]1CCCN1
Agent: Cl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: O=C(OCc1ccccc1)[C@H]1CCCN1C(=O)Cc1cc(O)c(CC(=O)N2CCC[C@@H]2C(=O)OCc2ccccc2)cc1O
Yield: 23.9 %

Procedure:
Using General Procedure A with 10.7 g (44.2 mmol) D-Proline benzyl ester hydrochloride and 5.0 g (22.1 mmol) 2,5-dihydroxy-1,4-phenylenediacetic acid afforded, after flash chromatography (gradient: 70-100% EtOAc/hexane), 3.17 g (24%) of the title compound as a colorless foam.
Reaction SMILES: [C:1]([C:4]12[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]3[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]3[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]1)[CH2:6][CH2:5]2)([OH:3])=O.[Cl:24][C:25]1[CH:31]=[CH:30][C:28]([NH2:29])=[CH:27][CH:26]=1>>[Cl:24][C:25]1[CH:31]=[CH:30][C:28]([NH:29][C:1]([C:4]23[CH2:9][CH2:8][C:7]([NH:12][CH2:13][C:14]([N:16]4[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]4[C:22]#[N:23])=[O:15])([CH2:6][CH2:5]2)[CH2:10][CH2:11]3)=[O:3])=[CH:27][CH:26]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)O)(CC1)CC2
Product: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)Nc3ccc(Cl)cc3)(CC1)CC2
Yield: 38.2 %

Procedure:
In a similar manner to Example 63, (2S,4S)-1-[[N-(4-carboxybicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (50.0 mg) and 4-chloroaniline (43.0 mg) were used to obtain (2S,4S)-1-[[N-[4-[N-(4-chlorophenyl)amino]carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (25.6 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:4]=1[CH2:5][NH:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][N:8]=1.[F:19][C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=1[S:27](Cl)(=[O:29])=[O:28].N12CCN(CC1)CC2>C(#N)C>[CH3:1][O:2][C:3]1[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:4]=1[CH2:5][N:6]([C:7]1[CH:12]=[CH:11][N:10]=[CH:9][N:8]=1)[S:27]([C:21]1[CH:22]=[CH:23][C:24]([F:26])=[CH:25][C:20]=1[F:19])(=[O:29])=[O:28]
Reactant: COc1ccc(CNc2ccncn2)c(OC)c1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1F
Agent: C1CN2CCN1CC2
Solvent: CC#N
Product: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2ccc(F)cc2F)c(OC)c1
Yield: 58.8 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 14b by using the N-(2,4-dimethoxybenzyl)pyrimidine-4-amine (0.40 g, 1.63 mmol) prepared in Example 14a, 2,4-difluorobenzenesulfonyl chloride (0.69 g, 3.26 mmol), 1,4-diazabicyclo[2.2.2]octane (0.37 g, 3.26 mmol) and acetonitrile (11 mL), to yield the title compound (403.8 mg, 59%) as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:25]#[N:26])=[C:6]([S:8][C@@H:9]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH:7]=1.[H-].[Na+].I[CH3:30].O>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:25]#[N:26])=[C:6]([S:8][C@@H:9]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:10][N:11]([CH3:30])[C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:15])[CH3:16])[CH:7]=1
Reactant: CI
Reactant: CC(C)(C)OC(=O)NC[C@@H](Sc1cc(Cl)ccc1C#N)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CN(C[C@@H](Sc1cc(Cl)ccc1C#N)c1ccccc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of the product from Example 4 step (a) (92 mg) in THF (5 ml) was added sodium hydride (60% in oil; 10 mg) followed by iodomethane (60 μl). The mixture was stirred at room temperature for 2 days then poured into water and extracted with diethyl ether (three times). The combined organic layers were washed with brine and dried (MgSO4). The solvent was evaporated off to give the sub-title compound (100 mg) as an oil.
Reaction SMILES: [CH2:1]([N:8]([CH3:25])[C:9]1[CH:14]=[C:13]([CH2:15][N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[CH:12]=[CH:11][C:10]=1[N+:22]([O-])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>C(OCC)(=O)C.[Pd]>[CH2:1]([N:8]([CH3:25])[C:9]1[C:10]([NH2:22])=[CH:11][CH:12]=[C:13]([CH2:15][N:16]2[CH2:17][CH2:18][O:19][CH2:20][CH2:21]2)[CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: CN(Cc1ccccc1)c1cc(CN2CCOCC2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CN(Cc1ccccc1)c1cc(CN2CCOCC2)ccc1N
Yield: 102.6 %

Procedure:
A mixture of N-benzyl-N-methyl-5-(4-morpholinylmethyl)-2-nitroaniline (3.3 g, 9.7 mmol) and 10% palladium charcoal (0.25 g) in ethyl acetate (100 mL) is hydrogenated (50 psi initial hydrogen pressure) until HPLC shows that reaction is complete (40 min). The solvent is evaporated to give 3.1 g of the title compound as an oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4](=O)[CH:5](Cl)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH3:12].[C:16]([NH2:19])(=[S:18])[CH3:17]>>[CH3:1][O:2][C:3]([C:4]1[N:19]=[C:16]([CH3:17])[S:18][C:5]=1[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH3:12])=[O:15]
Reactant: CC(N)=S
Reactant: COC(=O)C(=O)C(Cl)c1ccccc1C
Product: COC(=O)c1nc(C)sc1-c1ccccc1C

Procedure:
prepared by reaction of 3-chloro-2-oxo-3-o-tolyl-propionic acid methyl ester with thioacetamide. LC-MS: tR=0.92 min; [M+H]+=248.1.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([C:18]([OH:20])=O)=[C:13]2[N:12]=[CH:11][C:10]=1[C:21]([N:23]1[CH2:28][CH2:27][CH:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:25][CH2:24]1)=[O:22].[CH3:35][C:36]1[C:40]([S:41]([NH2:44])(=[O:43])=[O:42])=[C:39]([CH3:45])[O:38][N:37]=1>>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([C:18]([NH:44][S:41]([C:40]3[C:36]([CH3:35])=[N:37][O:38][C:39]=3[CH3:45])(=[O:42])=[O:43])=[O:20])=[C:13]2[N:12]=[CH:11][C:10]=1[C:21]([N:23]1[CH2:24][CH2:25][CH:26]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH2:27][CH2:28]1)=[O:22]
Reactant: Cc1noc(C)c1S(N)(=O)=O
Reactant: Cc1ccccc1Nc1c(C(=O)N2CCC(c3ccccc3)CC2)cnc2c(C(=O)O)cnn12
Product: Cc1ccccc1Nc1c(C(=O)N2CCC(c3ccccc3)CC2)cnc2c(C(=O)NS(=O)(=O)c3c(C)noc3C)cnn12
Yield: 63.4 %

Procedure:
In the same manner as in Example 1, step 6 and using 7-(2-methylphenylamino)-6-(4-phenylpiperidine-1-carbonyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0.08 g, 0.18 mmol) obtained in Example 39, step 2 and 3,5-dimethylisoxazole-4-sulfonamide (0.16 g, 0.88 mmol), the title compound (0.07 g, 66%) was obtained.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8]2[NH:12][C:11]3[CH:13]=[CH:14][CH:15]=[C:16]([F:17])[C:10]=3[N:9]=2)[C:5]([O:18]C)=[CH:4][CH:3]=1.[Li+].[Cl-]>CN(C=O)C>[Br:1][C:2]1[N:7]=[C:6]([C:8]2[NH:12][C:11]3[CH:13]=[CH:14][CH:15]=[C:16]([F:17])[C:10]=3[N:9]=2)[C:5]([OH:18])=[CH:4][CH:3]=1
Reactant: COc1ccc(Br)nc1-c1nc2c(F)cccc2[nH]1
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: Oc1ccc(Br)nc1-c1nc2c(F)cccc2[nH]1
Temperature: 100 °C
Reaction time: 8 h
Yield: 58 %

Procedure:
To a solution of 2-(6-bromo-3-methoxypyridin-2-yl)-4-fluoro-1H-benzo[d]imidazole (350 mg, 1.12 mmol) in DMF (10 mL) was added LiCl (650 mg, 15.5 mmol) under N2 protection. The mixture was stirred on a pre-heated oil-bath at 100° C. overnight. After extracted with EtOAc, the organic phase was dried over Na2SO4 and concentrated. The residue was purified by prep-TLC (PE:EA=5:1) to give the product of 6-bromo-2-(4-fluoro-1H-benzo[d]imidazol-2-yl)pyridin-3-ol (200 mg, yield: 60%). 1H-NMR (DMSO-d6, 400 MHz) δ 13.75 (s, 1H), 12.70 (s, 1H), 7.64 (d, J=8.4 Hz, 1H), 7.50 (d, J=8.4 Hz, 1H), 7.41 (s, 1H), 7.30 (s, 1H), 7.12 (s, 1H). MS (M+H)+: 308/310.
Reaction SMILES: C(Cl)(C(Cl)=O)=O.CS(C)=O.[C:11]([Si:15]([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)[O:16][C:17]1[CH:18]=[C:19]([CH:29]=[CH:30][CH:31]=1)[CH2:20][C@:21]1([OH:28])[CH2:26][CH2:25][CH2:24][CH2:23][C@H:22]1[OH:27])([CH3:14])([CH3:13])[CH3:12].N1C=CN=C1>C(Cl)Cl.CN(C=O)C.C(N(CC)CC)C>[C:11]([Si:15]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)([C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[O:16][C:17]1[CH:18]=[C:19]([CH:29]=[CH:30][CH:31]=1)[CH2:20][C@:21]1([O:28][Si:15]([CH3:38])([CH3:32])[CH3:11])[CH2:26][CH2:25][CH2:24][CH2:23][C:22]1=[O:27])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)[Si](Oc1cccc(C[C@]2(O)CCCC[C@H]2O)c1)(c1ccccc1)c1ccccc1
Agent: O=C(Cl)C(=O)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[Si](Oc1cccc(C[C@]2(O[Si](C)(C)C)CCCCC2=O)c1)(c1ccccc1)c1ccccc1
Reaction time: 0.17 h
Yield: 16.6 %

Procedure:
To a solution of (COCl)2 (3.4 ml) in CH2Cl2 (100 ml) was dropwise added DMSO (3.7 ml) at −78° C. After 10minutes, a solution of (1R,2R)-1-[3-(tertbutyldiphenylsilyloxy)benzyl]-1,2-dihydroxycyclohexane (12 g) in CH2Cl2(50 ml) was added to the above mixture at the same temperature. After 10 minutes, the mixture was added with triethylamine (15 ml) and allowed to stand at room temperature. After evaporating the solvent, the residue was partitioned between EtOAc and water. The organic layer was washed with water and brine. The organic solvent was evaporated in vacuo to give an oily compound. The oily compound was dissolved in DMF (50 ml) and then added with trimethylsilychloride (6.6 ml) and imidazole(7.0 g) at room temperature. After stirring for 5 hours, the mixture was partitioned between EtOAc and water. The organic solvent was evaporated in vacuo. The residue was purified by chromatography on silica gel to give (R)-1-[3-(tertbutyldiphenylsilyloxy)benzyl]-1-trimethylsilyoxy-2-cyclohexanone (1.15 g).