Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:12][N:11]([C:13]([C:15]3[CH:16]=[CH:17][C:18]([CH3:40])=[C:19]([C:21]4[N:22]=[C:23]([CH:27]5[CH2:32][CH2:31][N:30]([C:33]([O:35]C(C)(C)C)=O)[CH2:29][CH2:28]5)[NH:24][C:25]=4[CH3:26])[CH:20]=3)=[O:14])[CH2:10]2)=[CH:5][CH:4]=1)#[N:2].F[C:42](F)(F)C(O)=O.CC1C=CC(C(N2CC(C3C=CC(C#N)=CC=3)C2)=O)=CC=1C1NC(C2CCNCC2)=NC=1C.C(OC(=O)C)(=O)C.C(N(CC)CC)C>C(Cl)Cl>[C:33]([N:30]1[CH2:31][CH2:32][CH:27]([C:23]2[NH:22][C:21]([C:19]3[CH:20]=[C:15]([CH:16]=[CH:17][C:18]=3[CH3:40])[C:13]([N:11]3[CH2:10][CH:9]([C:6]4[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=4)[CH2:12]3)=[O:14])=[C:25]([CH3:26])[N:24]=2)[CH2:28][CH2:29]1)(=[O:35])[CH3:42]
Reactant: O=C(O)C(F)(F)F
Reactant: Cc1ccc(C(=O)N2CC(c3ccc(C#N)cc3)C2)cc1-c1nc(C2CCN(C(=O)OC(C)(C)C)CC2)[nH]c1C
Agent: Cc1ccc(C(=O)N2CC(c3ccc(C#N)cc3)C2)cc1-c1[nH]c(C2CCNCC2)nc1C
Solvent: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CCC(c2nc(C)c(-c3cc(C(=O)N4CC(c5ccc(C#N)cc5)C4)ccc3C)[nH]2)CC1
Reaction time: 1.5 h

Procedure:
To a solution of tert-butyl 4-(4-(5-(3-(4-cyanophenyl)azetidine-1-carbonyl)-2-methylphenyl)-5-methyl-1H-imidazol-2-yl)piperidine-1-carboxylate (compound 182.3, 475 mg, 0.88 mmol) in 20 mL DCM, was added trifluoroacetic acid (4 mL). The reaction was stirred for 1.5 hours, concentrated under reduced pressure and neutralized with 10 mL Na2CO3 (1M) to obtain a crude product after lyophilization. A mixture of 4-(1-(4-methyl-3-(4-methyl-2-(piperidin-4-yl)-1H-imidazol-5-yl)benzoyl)azetidin-3-yl)benzonitrile (252 mg, 0.57 mmol), acetic anhydride (71 μL, 0.75 mmol) and triethylamine (120 μL, 0.86 mmol) was stirred at room temperature for 16 hours. The reaction was concentrated under reduced pressure, then diluted with saturated NaH2PO4 (20 mL) and extracted with EtOAc (3×20 mL). The organic phase was dried over MgSO4 and concentrated under reduced pressure. The residue was purified by preparative TLC with 10% methanol in dichloromethane and lyophilized to give 235 mg (80%-2 steps) of the title compound as a white solid. m/z (ES+) 482 (M+H)+.
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.F[C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN1CCCCC1=O>[C:1]1([CH:7]2[CH2:8][CH2:9][N:10]([C:14]3[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=3)[CH2:11][CH2:12]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc(C2CCNCC2)cc1
Reactant: N#Cc1ccc(F)cc1
Agent: CN1CCCCC1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: N#Cc1ccc(N2CCC(c3ccccc3)CC2)cc1
Temperature: 20 °C
Reaction time: 5 h
Yield: 48.7 %

Procedure:
4-Phenylpiperidine (0.5 g), p-fluorobenzonitrile (0.37 g) and potassium carbonate (0.78 g) are dissolved in N-methylpiperidone (5 ml), and the mixture is stirred at 1 20° C. for five hours. To the reaction solution is added ethyl acetate (50 ml), and the mixture is washed with water, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. To the resulting residue is added methanol, and the insoluble crystals are collected by filtration, dried under reduced pressure to give 4-phenyl-1-(4-cyanophenyl)-piperidine (0.39 g) as white needles.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][CH:20](SC)[NH:19][C:18]4=[O:24])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:27]([F:30])([F:29])[F:28])[CH:3]=1.[OH:31][C@H:32]([C:36]1[CH:41]=[CH:40][C:39]([OH:42])=[CH:38][CH:37]=1)[CH2:33][NH:34][CH3:35]>>[Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:34]([CH2:33][C@H:32]([OH:31])[C:36]5[CH:41]=[CH:40][C:39]([OH:42])=[CH:38][CH:37]=5)[CH3:35])=[N:19][C:18]4=[O:24])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:27]([F:30])([F:29])[F:28])[CH:3]=1
Reactant: CNC[C@H](O)c1ccc(O)cc1
Reactant: CSC1NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Product: CN(C[C@H](O)c1ccc(O)cc1)C1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1

Procedure:
(R)-5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-{[2-hydroxy-2-(4-hydroxy-phenyl)-ethyl]-methyl-amino}-thiazol-4-one was prepared from 5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazolidin-4-one and (R)-4-(1-Hydroxy-2-methylamino-ethyl)-phenol following General Procedure B.
Reaction SMILES: [C:1]([NH:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:17])[NH:13][C:14](=[O:16])[CH3:15])=[CH:8][C:7]=1[N+:18]([O-])=O)(=[O:3])[CH3:2].S(S([O-])=O)([O-])=O.[Na+].[Na+].C(O)C.O>O1CCCC1>[C:1]([NH:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:17])[NH:13][C:14](=[O:16])[CH3:15])=[CH:8][C:7]=1[NH2:18])(=[O:3])[CH3:2]
Reactant: CC(=O)NCc1ccc(C(=O)NC(C)=O)cc1[N+](=O)[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: CC(=O)NCc1ccc(C(=O)NC(C)=O)cc1N
Yield: 118.8 %

Procedure:
2-((N-Acetyl)aminomethyl)-5-((N-acetyl)carbamoyl)-1-nitrobenzene (1.00 g) and sodium hydrosulfite (7.0 g) in a mixture of tetrahydrofuran (5 ml), ethanol (5 ml) and water (20 ml) were heated under reflux for 1 hr. After cooling, the organic layer was separated, dried over sodium sulfate and concentrated. The residue was purified by silica gel column chromatography to give the objective compound (1.06 g).
Reaction SMILES: [CH3:1][N:2]1[CH2:10][C:9]2[C:4](=[C:5]([N+:21]([O-])=O)[CH:6]=[CH:7][C:8]=2[N:11]2[CH2:16][CH2:15][CH:14]([C:17]([O:19][CH3:20])=[O:18])[CH2:13][CH2:12]2)[C:3]1=[O:24].[H][H]>CO.[Pd]>[NH2:21][C:5]1[CH:6]=[CH:7][C:8]([N:11]2[CH2:12][CH2:13][CH:14]([C:17]([O:19][CH3:20])=[O:18])[CH2:15][CH2:16]2)=[C:9]2[C:4]=1[C:3](=[O:24])[N:2]([CH3:1])[CH2:10]2
Reactant: [H][H]
Reactant: COC(=O)C1CCN(c2ccc([N+](=O)[O-])c3c2CN(C)C3=O)CC1
Agent: [Pd]
Solvent: CO
Product: COC(=O)C1CCN(c2ccc(N)c3c2CN(C)C3=O)CC1
Yield: 72 %

Procedure:
A mixture of methyl 1-(2-methyl-7-nitro-1-oxo-2,3-dihydro-1H-isoindol-4-yl)piperidine-4-carboxylate (Compound 256B, 33 mg, 0.099 mmol) and palladium/C in methanol (1.0 mL) was stirred under 1 atmosphere of hydrogen at room temperature overnight. The reaction mixture was filtered through celite, concentrated in vacuo and used directly in next step without further purification (20 mg, 72% yield). MS (ES+): m/z 304.20 (100) [MH+]; HPLC: tR=0.58 min (UPLC, Analytical).
Reaction SMILES: [Br:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][CH2:7][CH2:8][CH2:9][C:10]([O:12]CC)=[O:11])=[CH:4][C:3]=1[F:17].[Li+].[OH-].O1CCCC1.Cl>O>[Br:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:4][C:3]=1[F:17]
Reactant: CCOC(=O)CCCOc1ccc(Br)c(F)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CCCOc1ccc(Br)c(F)c1
Temperature: 50 °C
Reaction time: 8 h
Yield: 68.3 %

Procedure:
Into a 2000-mL 4-necked round-bottom flask purged and maintained with an inert atmosphere of argon was placed ethyl 4-(4-bromo-3-fluorophenoxy)butanoate (80.6 g, 264.14 mmol, 1.00 equiv), LiOH (12.7 g, 530.27 mmol, 2.00 equiv), tetrahydrofuran (250 mL), and water (240 mL). The resulting solution was stirred at 50° C. overnight, cooled to 0° C. with a water/ice bath, adjusted to pH=3-4 with hydrochloric acid (2 N) and extracted with 3×100 mL of ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was triturated in 30 mL of EA to afford 50 g (68%) of 4-(4-bromo-3-fluorophenoxy)butanoic acid as a white solid.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1.[Br:14][C:15]1[CH:19]=[CH:18][S:17][C:16]=1[C:20](=[N:22]O)[NH2:21]>>[Br:14][C:15]1[CH:19]=[CH:18][S:17][C:16]=1[C:20]1[N:22]=[C:7]([C:6]2[CH:10]=[CH:11][C:3]([C:2]([F:13])([F:12])[F:1])=[CH:4][CH:5]=2)[O:8][N:21]=1
Reactant: NC(=NO)c1sccc1Br
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Product: FC(F)(F)c1ccc(-c2nc(-c3sccc3Br)no2)cc1

Procedure:
The title compound was prepared from 4-trifluoromethyl-benzoyl chloride (66 μL, 0.44 mmol) and 3-bromo-thiophene-2-amidoxime (98 mg, 0.44 mmol) similar to Example 16, and yielded 130 mg (78%) of white solid. 1H NMR (CDCl3): 8.34 (d, J=8.24 Hz, 2H), 7.83 (d, J=8.51 Hz, 2H), 7.52 (d, J=5.22 Hz, 1H), 7.19 (d, J=5.21 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9](=[O:28])[N:10]([C:20]2[CH:25]=[CH:24][C:23]([O:26]C)=[CH:22][CH:21]=2)[CH:11]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[CH:13]=1>Br.C(=O)(O)[O-].[Na+]>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9](=[O:28])[N:10]([C:20]2[CH:21]=[CH:22][C:23]([OH:26])=[CH:24][CH:25]=2)[CH:11]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[CH:13]=1
Reactant: COc1ccc(-n2cc(-c3ccccn3)cc(-c3ccccc3Cl)c2=O)cc1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Product: O=c1c(-c2ccccc2Cl)cc(-c2ccccn2)cn1-c1ccc(O)cc1
Temperature: 25 °C
Yield: 68.8 %

Procedure:
3-(2-Chlorophenyl)-5-(2-pyridyl)-1-(4-methoxyphenyl)-1,2-dihydropyridin-2-one (440 mg) was dissolved in 5 ml of 48% hydrobromic acid and heated to reflux for 1 hours. After the reaction solution was allowed to cool at room temperature, it was diluted with a saturated aqueous solution of sodium bicarbonate and extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate. The drying agent was filtered off and the filtrate was concentrated in vacuo and purified by a silica gel column chromatography (hexane-ethyl acetate system) to give 292 mg of the title compound.
Reaction SMILES: Cl.Cl.[NH2:3][C@@H:4]1[CH2:6][C@H:5]1[C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:27])[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[CH:16]=2)=[CH:9][CH:8]=1.[CH:28](=O)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(=O)([O-])O.[Na+].[BH4-].[Na+]>CO.O>[CH2:28]([NH:3][C@@H:4]1[CH2:6][C@H:5]1[C:7]1[CH:8]=[CH:9][C:10]([NH:13][C:14](=[O:27])[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[CH:16]=2)=[CH:11][CH:12]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: N[C@@H]1C[C@H]1c1ccc(NC(=O)c2cccc(N3CCCCC3)c2)cc1
Reactant: O=Cc1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [BH4-]
Solvent: CO
Solvent: O
Product: O=C(Nc1ccc([C@@H]2C[C@H]2NCc2ccccc2)cc1)c1cccc(N2CCCCC2)c1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
To a solution of N-{4-[trans-2-aminocyclopropyl]phenyl}-3-(piperidin-1-yl)benzamide dihydrochloride (64.2 mg) in methanol (2 mL) were added benzaldehyde (16 μL) and sodium hydrogen carbonate (19.8 mg). The reaction mixture was stirred at 70° C. for 1 hr, and ice-cooled to 0° C. and sodium borohydride (8.9 mg) was added. The mixture was stirred for 1 hr and water was added. The mixture was extracted with ethyl acetate, and the extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (51.0 mg).
Reaction SMILES: [CH3:1][C:2]([CH3:12])([CH2:9][CH:10]=O)[CH2:3][C:4]([O:6]CC)=[O:5].P(Cl)(Cl)(Cl)=O>S1(CCCC1)(=O)=O>[CH3:12][C:2]1([CH3:1])[CH:9]=[CH:10][O:6][C:4](=[O:5])[CH2:3]1
Reactant: CCOC(=O)CC(C)(C)CC=O
Solvent: O=S1(=O)CCCC1
Solvent: O=P(Cl)(Cl)Cl
Product: CC1(C)C=COC(=O)C1
Temperature: 200 °C
Reaction time: 1 h
Yield: 77 %

Procedure:
A solution of 16.98 g (0.10 mole at 93% purity) of ethyl 3,3-dimethyl-5-oxopentanoate and 9.44 g (0.062 mole) of phosphoryl chloride in 10 g of sulfolane was added to 250 g of sulfolane and the whole heated to 200° C. in an oil bath during 50 minutes. The reaction mixture was stirred at 200° C. for 1 hour, then subjected to distillation to give 9.71 g of 3,4-dihydro-4,4-dimethyl-2H-pyran-2-one in 2 fractions: fraction 1, 7.49 g, bp 55° C./400 Pa (3 mm Hg), 95.9% purity (glpc); fraction 2, 2.22 g, bp 55°-120° C./400 Pa, 71.1% purity (glpc).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH2:6][C:7]2[C:8](=[CH:12][CH:13]=1)[N:9]=[N:10][N:11]=2)=[O:4].[H-].[Na+].[CH3:16]I>CN(C)C=O>[CH3:1][O:2][C:3]([C:5]1[CH:13]=[CH:12][C:8]2[N:9]([CH3:16])[N:10]=[N:11][C:7]=2[CH:6]=1)=[O:4]
Reactant: CI
Reactant: COC(=O)C1=CC=C2N=NN=C2C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(c1)nnn2C
Reaction time: 0.33 h

Procedure:
To a stirred, cold (0° C.) solution of 1,2,3-benzotriazole-5-carboxylic acid methyl ester (2.51 g) in dimethylformamide was added 60% sodium hydride (370 mg) portion wise. After 20 minutes, methyl iodide (0.87 mL) was added. The reaction was quenched by the addition of water after 30 minutes. The mixture was extracted with ethyl acetate; the extracts were washed with water, and brine, and dried (sodium sulfate). Filtration and concentration of the filtrate gave a residue from which 716 mg of 1-methyl-1H-benzotriazole-5-carboxylic acid methyl ester crystallized (hot ethyl acetate). The mother liquor was purified by flash chromatography (eluting with 3:2 hexanes/ethyl acetate) to give 890 mg of 2-methyl-2H-benzotriazole-5-carboxylic acid methyl ester and 490 mg of 3-methyl-3H-benzotriazole-5-carboxylic acid methyl ester. Structural assignments were made on the basis of proton NMR and nOe experiments.
Reaction SMILES: CCN(C(C)C)C(C)C.[N:10]1[CH:15]=[CH:14][CH:13]=[C:12]([N:16]2[CH:20]=[C:19]([C:21]([NH:23][CH2:24][C:25]([OH:27])=O)=[O:22])[N:18]=[N:17]2)[CH:11]=1.NC1C=NC=CC=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[CH3:57][C:58]1[CH:65]=[CH:64][C:61]([C:62]#[N:63])=[CH:60][C:59]=1[O:66][CH:67]1[CH2:72][CH2:71][NH:70][CH2:69][CH2:68]1>CN(C=O)C.O>[C:62]([C:61]1[CH:64]=[CH:65][C:58]([CH3:57])=[C:59]([CH:60]=1)[O:66][CH:67]1[CH2:68][CH2:69][N:70]([C:25](=[O:27])[CH2:24][NH:23][C:21]([C:19]2[N:18]=[N:17][N:16]([C:12]3[CH:11]=[N:10][CH:15]=[CH:14][CH:13]=3)[CH:20]=2)=[O:22])[CH2:71][CH2:72]1)#[N:63]
Reactant: Cc1ccc(C#N)cc1OC1CCNCC1
Reactant: O=C(O)CNC(=O)c1cn(-c2cccnc2)nn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Nc1cccnc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cc1ccc(C#N)cc1OC1CCN(C(=O)CNC(=O)c2cn(-c3cccnc3)nn2)CC1
Reaction time: 0.03 h
Yield: 49.2 %

Procedure:
DIPEA (94.1 mg, 0.72 mmol) was added to a stirred solution of [(1-pyridin-3-yl-1H-[1,2,3]triazole-4-carbonyl)-amino]-acetic acid (45 mg, 0.18 mmol) (prepared by the method used for the synthesis of Intermediate 64, starting from 3-aminopyridine, and subsequently, application of Step 3 of the General Scheme) in DMF (2 mL) followed by HOBt (27 mg, 0.2 mmol) and EDCI (69.8 mg, 0.366 mmol). After 2 minutes of stirring, 4-methyl-3-(piperidin-4-yloxy)-benzonitrile hydrochloride (prepared by the method used for the synthesis of Intermediate 15) (50.6 mg, 0.2 mmol) was added and the resulting mixture was stirred at room temperature overnight. Cold water was added and the precipitate was collected. The solid was purified by stirring in mixture of DCM in hexane to afford 40 mg (49.2% Yield) of 1-pyridin-3-yl-1H-[1,2,3]triazole-4-carboxylic acid {2-[4-(5-cyano-2-methyl-phenoxy)-piperidin-1-yl]-2-oxo-ethyl}-amide. LC/MS [M+H]+: 446.19, 96.84%. 1H NMR (300 MHz, DMSO-d6): δ 9.45 (s, 1H), 9.2 (d, 1H), 8.75 (d, 1H), 8.55-8.45 (t, 1H), 8.4 (m, 1H), 7.72-7.64 (m, 1H), 7.55 (s, 1H), 7.4-7.3 (q, 2H), 4.8 (m, 1H), 4.25 (d, 2H), 3.8-3.6 (m, 2H), 3.5-3.4 (m, 2H), 2.25 (s, 3H), 2.1-1.8 (m, 2H), 1.8-1.5 (m, 2H).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:9]2[O:13][C:12]([C:14]([OH:16])=O)=[CH:11][CH:10]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH2:17]([O:19][C:20](=[O:30])[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([NH2:29])[CH:24]=1)[CH3:18]>>[CH2:17]([O:19][C:20](=[O:30])[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([NH:29][C:14]([C:12]2[O:13][C:9]([C:4]3[CH:3]=[CH:2][CH:7]=[C:6]([Cl:8])[CH:5]=3)=[CH:10][CH:11]=2)=[O:16])[CH:24]=1)[CH3:18]
Reactant: CCOC(=O)CCc1cccc(N)c1
Reactant: O=C(O)c1ccc(-c2cc(Cl)cc(Cl)c2)o1
Product: CCOC(=O)CCc1cccc(NC(=O)c2ccc(-c3cccc(Cl)c3)o2)c1

Procedure:
Carboxylic acid (67)(58 mg, 0.26 mmol) was coupled to aniline (124)(50 mg, 0.26 mmol) using Method C. The residue was purified by column chromatography eluting with 10% EtOAc in heptane to give the title compound.
Reaction SMILES: [C:1]([NH:8][CH2:9][C:10]1[S:11][C:12]([C:19]#[N:20])=[C:13]([C:15]([F:18])([F:17])[F:16])[N:14]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N(CC)CC)C.[SH2:28]>N1C=CC=CC=1>[C:1]([NH:8][CH2:9][C:10]1[S:11][C:12]([C:19](=[S:28])[NH2:20])=[C:13]([C:15]([F:17])([F:18])[F:16])[N:14]=1)([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)NCc1nc(C(F)(F)F)c(C#N)s1
Reactant: S
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCc1nc(C(F)(F)F)c(C(N)=S)s1
Reaction time: 48 h

Procedure:
2-(N-BOC-Aminomethyl)-5-cyano-4-trifluoromethylthiazole [sic] (4.6 g, 14.97 mmol) was dissolved in pyridine (20 ml), triethylamine (24 ml) was added, and the solution was saturated with hydrogen sulfide. After two days at room temperature, the solvent was removed on a rotary evaporator. The crude product was taken up in ethyl acetate and washed in succession with 20% strength sodium hydrogen sulfate solution and water. After drying (MgSO4), the solvent was removed on a rotary evaporator. The crude product was purified by flash chromatography. Yield: 2.5 g (7.32 mmol, 49%).
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([CH3:27])[C:24]([F:28])=[CH:23][C:22]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:15]=3[NH:14][C:13]=2[CH3:34])=[O:11])[CH2:5][CH2:4]1.C([O:38][C@@H:39]([CH3:43])[C:40](Cl)=[O:41])(=O)C>>[CH:31]1([CH2:30][O:29][C:22]2[CH:23]=[C:24]([F:28])[C:25]([CH3:27])=[CH:26][C:21]=2[C:20]2[C:15]3[NH:14][C:13]([CH3:34])=[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@@H:3]([NH:2][C:40](=[O:41])[C@@H:39]([OH:38])[CH3:43])[CH2:4][CH2:5]4)=[O:11])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:32][CH2:33]1
Reactant: Cc1cc(-c2ncnc3c(C(=O)N[C@H]4CC[C@@H](N)CC4)c(C)[nH]c23)c(OCC2CC2)cc1F
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Agent: Cl
Product: Cc1cc(-c2ncnc3c(C(=O)N[C@H]4CC[C@@H](NC(=O)[C@H](C)O)CC4)c(C)[nH]c23)c(OCC2CC2)cc1F

Procedure:
Starting from N-(cis-4-aminocyclohexyl)-4-[2-(cyclopropylmethoxy)-4-fluoro-5-methylphenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f42) and commercially available (2S)-1-chloro-1-oxopropan-2-yl acetate the title compound is obtained as colorless solid.
Reaction SMILES: [N:1]1([C:6]2[CH:7]=[C:8]([CH:41]=[CH:42][CH:43]=2)[CH2:9][N:10]2[C:14]3[CH:15]=[CH:16][C:17]([O:19][CH2:20][C:21]4[CH:30]=[CH:29][C:28]5[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=5)[N:22]=4)=[CH:18][C:13]=3[N:12]=[C:11]2[CH2:31][C:32]2([C:37]([O:39]C)=[O:38])[CH2:36][CH2:35][CH2:34][CH2:33]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C1COCC1.[Li+].[OH-].Cl>C(Cl)Cl.O.CO>[N:1]1([C:6]2[CH:7]=[C:8]([CH:41]=[CH:42][CH:43]=2)[CH2:9][N:10]2[C:14]3[CH:15]=[CH:16][C:17]([O:19][CH2:20][C:21]4[CH:30]=[CH:29][C:28]5[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=5)[N:22]=4)=[CH:18][C:13]=3[N:12]=[C:11]2[CH2:31][C:32]2([C:37]([OH:39])=[O:38])[CH2:36][CH2:35][CH2:34][CH2:33]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)C1(Cc2nc3cc(OCc4ccc5ccccc5n4)ccc3n2Cc2cccc(N3CCCC3)c2)CCCC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)C1(Cc2nc3cc(OCc4ccc5ccccc5n4)ccc3n2Cc2cccc(N3CCCC3)c2)CCCC1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
To a 20 mL vial were added methyl 1-((1-(3-(pyrrolidin-1-yl)benzyl)-5-(quinolin-2-ylmethoxy)-1H-benzo[d]imidazol-2-yl)methyl)cyclopentanecarboxylate (20.7 mg, 0.04 mmol), THF (1 mL) and MeOH (1 mL) followed by treatment with LiOH (1 mL, 1 M). The reaction mixture was capped and heated to 80° C. for 3 h. The mixture was cooled to RT, water (5 mL) was added and the pH was adjusted to ˜4 using 1 M HCl. To the mixture was added DCM (5 mL) and the mixture was stirred for 1 h at RT. The organic layer was separated then concentrated to dryness. The resulting residue was purified using FCC to provide the title compound. MS (ESI): mass calcd. for C35H36N4O3, 560.28; m/z found, 561.1 [M+H]+.
Reaction SMILES: O.[C:2]1(C)C=CC(S(O)(=O)=O)=CC=1.[F:13][C:14]([F:23])([CH:18]([OH:22])[CH2:19][CH2:20][CH3:21])[C:15]([OH:17])=[O:16].C(=O)([O-])O.[Na+]>CO>[F:13][C:14]([F:23])([CH:18]([OH:22])[CH2:19][CH2:20][CH3:21])[C:15]([O:17][CH3:2])=[O:16]
Reactant: CCCC(O)C(F)(F)C(=O)O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCCC(O)C(F)(F)C(=O)OC
Yield: 58 %

Procedure:
A catalytic amount of p-toluenesulfonic acid monohydrate was added to a mixture of 75.5 g of Intermediate 4 in Example 4 and 200 g of methanol. With stirring in a nitrogen atmosphere, the reaction mixture was heated under reflux for 10 hours. After cooling, the reaction mixture was poured into a saturated sodium hydrogen carbonate aqueous solution and extracted with ethyl acetate. The ethyl acetate solution was washed, dried and concentrated, obtaining 63.0 g (yield 58%) of methyl 2,2-difluoro-3-hydroxyhexanoate. This crude product had a sufficient purity as an intermediate and was ready for use in the subsequent step.
Reaction SMILES: [CH2:1]([O:8][C:9]1(O)[CH:18]=[C:17]2[C:12]([CH:13]=[C:14]([N+:19]([O-])=O)[CH:15]=[N:16]2)=[CH:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:23].CN(C)C=[O:27]>[Pt]>[ClH:23].[NH2:19][C:14]1[CH:15]=[N:16][C:17]2[C:12]([C:13]=1[OH:27])=[CH:11][CH:10]=[C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH:18]=2
Reactant: O=[N+]([O-])c1cnc2c(c1)=CCC(O)(OCc1ccccc1)C=2
Reactant: CN(C)C=O
Agent: [Pt]
Agent: Cl
Product: Nc1cnc2cc(OCc3ccccc3)ccc2c1O
Reaction time: 8 h

Procedure:
A 1 L glass Parr bottle was charged with 7-benzyloxy-3-nitroquinolin-7-ol, anhydrous N,N-dimethylformamide (DMF, 500 mL) and 5% Pt/C catalyst (5.0 g). The vessel was placed on Parr apparatus, evacuated and charged with hydrogen gas (˜45 psi, 3.1×105 Pa). The reaction mixture was shaken overnight. The reaction mixture was filtered through glass fiber filters to remove catalyst. To the resulting dark colored solution was added concentrated hydrochloric acid (12 N HCl, 14 ml, 168.8 mmol). The product precipitated as the hydrochloride salt. The reaction mixture was stirred over the weekend. A solid was collected by vacuum filtration, washed with diethyl ether (100 mL), and air dried overnight to provide 44 g of 3-amino-7-benzyloxyquinolin-4-ol hydrochloride. This material was carried on without further purification.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[N:22]([C:26]([CH:28]2[CH2:30][CH2:29]2)=[O:27])[CH2:21][CH2:20]3)(=[O:16])=[O:15])[CH2:10][CH2:9]1)(C)(C)C.Cl>O1CCOCC1>[NH2:7][CH:8]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[N:22]([C:26]([CH:28]2[CH2:29][CH2:30]2)=[O:27])[CH2:21][CH2:20]3)(=[O:16])=[O:15])[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)NC1CCN(S(=O)(=O)c2ccc3c(c2)CCN3C(=O)C2CC2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: NC1CCN(S(=O)(=O)c2ccc3c(c2)CCN3C(=O)C2CC2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 32.2 %

Procedure:
[1-(1-Cyclopropanecarbonyl-2,3-dihydro-1H-indole-5-sulfonyl)-piperidin-4-yl]-carbamic acid tert-butyl ester (0.36 g, 0.8 mmol) was suspended in a 4M solution of HCl in Dioxane (10 ml). The resulting suspension was stirred at room temperature for 3 hours. After this time the solution was concentrated under vacuum, then azeotroped with methanol and suspended in diethyl ether. The resulting solid precipitate was then collected by filtration, washed with diethyl ether and dried under vacuum to afford the title compound (0.09 g, 32% yield) as a white solid. Tr=1.36 min, m/z (ES+) (M+H)+ 350.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:11]([OH:13])=O)[C:5](=[CH:9][CH:10]=1)[C:6]([OH:8])=O.[NH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O>>[OH:1][C:2]1[CH:3]=[C:4]2[C:11](=[O:13])[N:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:6](=[O:8])[C:5]2=[CH:9][CH:10]=1
Reactant: O=C(O)c1ccc(O)cc1C(=O)O
Reactant: Nc1ccccc1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Product: O=C1c2ccc(O)cc2C(=O)N1c1ccccc1

Procedure:
4-Hydroxy-N-phenylphthalimide was synthesized from 4-hydroxyphthalic acid and aniline in the same manner as in Example 1, a). By the reaction of the synthesized compound with trifluoromethanesulfonic anhydride, 4-(N-phenylphthalimide)-yl-triflate (NPhITf) was synthesized.