Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:2].[C:15]([C:19]1[CH:47]=[CH:46][C:22]([CH2:23][N:24]2[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[N:26]([CH2:33][C:34]3[CH:39]=[CH:38][C:37]([NH:40][S:41]([CH3:44])(=[O:43])=[O:42])=[CH:36][CH:35]=3)[C:25]2=O)=[CH:21][CH:20]=1)([CH3:18])([CH3:17])[CH3:16].[OH-].[Na+].[Na+].[Cl-]>C1(C)C=CC(C)=CC=1.O>[C:15]([C:19]1[CH:47]=[CH:46][C:22]([CH2:23][N:24]2[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[N:26]([CH2:33][C:34]3[CH:39]=[CH:38][C:37]([NH:40][S:41]([CH3:44])(=[O:43])=[O:42])=[CH:36][CH:35]=3)[C:25]2=[S:2])=[CH:21][CH:20]=1)([CH3:18])([CH3:17])[CH3:16]
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: CC(C)(C)c1ccc(Cn2c(=O)n(Cc3ccc(NS(C)(=O)=O)cc3)c3ccccc32)cc1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccc(C)cc1
Product: CC(C)(C)c1ccc(Cn2c(=S)n(Cc3ccc(NS(C)(=O)=O)cc3)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 40.5 %

Procedure:
Phosphorus pentasulfide (300 mg, 0.67 mmol) was added to a suspension of N-{4-[3-(4-tert-butylbenzyl)-2-oxo-2,3-dihydrobenzimidazol-1-ylmethyl]phenyl}methanesulfonamide (6) (235 mg, 0.51 mmol) in para-xylene (20 mL) under a blanket of argon. The reaction mixture was heated to the boil over a period of 5 h. Following cooling, there was added to the reaction mixture water (1 mL) followed by 2N NaOH solution in water (10 mL), and the mixture was stirred at RT for 30 min. To the reaction mixture there was added aqueous NaCl solution, and the resulting mixture was extracted with ethyl acetate (4×20 mL). The combined organic phases were dried over Na2SO4 and the solvent removed in vacuo. After purifying the residue by means of column chromatography (SiO2; cyclohexane/EtOAc 7:3), the desired product N-{4-[3-(4-tert-butylbenzyl)-2-thioxo-2,3-dihydrobenzoimidazol-1-ylmethyl]phenyl}methanesulfonamide (2) (99 mg, 40% of theory, mp: 176-178° C.) was obtained.
Reaction SMILES: C([O:8][C:9]1[C:17]2[N:16]=[C:15]([CH3:18])[N:14]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:13]=2[CH:12]=[CH:11][CH:10]=1)C1C=CC=CC=1.[H][H]>CCO.C1COCC1.[Pd]>[OH:8][C:9]1[C:17]2[N:16]=[C:15]([CH3:18])[N:14]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:13]=2[CH:12]=[CH:11][CH:10]=1
Reactant: [H][H]
Reactant: CCOC(=O)Cn1c(C)nc2c(OCc3ccccc3)cccc21
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)Cn1c(C)nc2c(O)cccc21
Yield: 93.2 %

Procedure:
To a solution of ethyl [4-(benzyloxy)-2-methyl-1H-benzimidazol-1-yl]acetate (2.57 g) in a mixture of EtOH (25.7 mL) and THF (12.9 mL) was added 10% palladium on carbon (50% wet, 0.78 g) at ambient temperature, and the resultant mixture was hydrogenated under atmospheric pressure of hydrogen for 2 hours. The catalyst was removed by filtration and evaporated in vacuo to give crude solid. The crude solid was recrystallized from solvent (EtOAc:n-hexane) to give ethyl (4-hydroxy-2-methyl-1H-benzimidazol-1-yl)acetate (1.73 g) as a white solid.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6](=[O:17])[NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=1)([CH3:4])[CH3:3].[N:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24]1[S:28][C:27]([S:29](Cl)(=[O:31])=[O:30])=[CH:26][CH:25]=1>>[CH3:4][C:2]([CH3:1])([O:5][C:6]([NH:7][CH2:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([NH:16][S:29]([C:27]2[S:28][C:24]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][N:18]=3)=[CH:25][CH:26]=2)(=[O:30])=[O:31])=[CH:14][CH:15]=1)=[O:17])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCc1ccc(N)cc1
Reactant: O=S(=O)(Cl)c1ccc(-c2ccccn2)s1
Product: CC(C)(C)OC(=O)NCCc1ccc(NS(=O)(=O)c2ccc(-c3ccccn3)s2)cc1

Procedure:
In a manner analogous to that of Example 5, the title compound was prepared from the Boc amine from Example 4 and 5-(pyridin-2-yl)-2-thiophenesulfonyl chloride: 1H NMR (400 MHz, CD3OD) 8.48 (d, 1, H, J=5.2 Hz), 7.81 (m, 2H), 7.54 (d, 1H, J=4.1 Hz), 7.41 (m, 1H), 7.30 (m, 1H), 7.11 (s, 4H), 3.18 (t, 2H, J=7.1 Hz), 2.67 (t, 2H, J=7.1 Hz), 1.38 (s, 9H). FAB MS m/z 460 (M+1).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][N:3]=1.[NH:11]1[CH2:16][CH2:15][CH:14]([N:17]2[C:25]3[C:20](=[N:21][CH:22]=[CH:23][CH:24]=3)[NH:19][C:18]2=[O:26])[CH2:13][CH2:12]1.N>O>[O:26]=[C:18]1[NH:19][C:20]2=[N:21][CH:22]=[CH:23][CH:24]=[C:25]2[N:17]1[CH:14]1[CH2:15][CH2:16][N:11]([C:2]2[CH:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][N:3]=2)[CH2:12][CH2:13]1
Reactant: O=c1[nH]c2ncccc2n1C1CCNCC1
Reactant: O=C(O)c1ccnc(Br)c1
Agent: N
Solvent: O
Product: O=C(O)c1ccnc(N2CCC(n3c(=O)[nH]c4ncccc43)CC2)c1
Reaction time: 0.17 h

Procedure:
0.50 g (2.4 mmol) 2-bromopyridine-4-carboxylic acid and 1.1 g (5.0 mmol) 1-piperidin-4-yl-1,3-dihydro-imidazo[4,5-b]pyridin-2-one were mixed and melted for 10 min using the hot air blower. The reaction mixture was cooled, mixed with water and made basic with ammonia. It was extracted with EtOAc. The aqueous phase was concentrated and purified by HPLC. The product-containing fractions were combined and concentrated to dryness by rotary evaporation.
Reaction SMILES: [ClH:1].Cl.Cl.[NH2:4][C:5]1[C:6]([NH:28][CH3:29])=[C:7]([O:11][CH2:12][CH:13]([OH:27])[CH2:14][NH:15][CH2:16][CH2:17][NH:18][C:19]2[C:24]([CH3:25])=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:26])[CH:8]=[CH:9][CH:10]=1.[CH:30](O)=O>>[ClH:1].[ClH:1].[CH3:29][N:28]1[C:6]2[C:7]([O:11][CH2:12][CH:13]([OH:27])[CH2:14][NH:15][CH2:16][CH2:17][NH:18][C:19]3[C:24]([CH3:25])=[CH:23][CH:22]=[CH:21][C:20]=3[CH3:26])=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[CH:30]1
Reactant: CNc1c(N)cccc1OCC(O)CNCCNc1c(C)cccc1C
Reactant: O=CO
Agent: Cl
Product: Cc1cccc(C)c1NCCNCC(O)COc1cccc2ncn(C)c12

Procedure:
In a manner analogous to the preceding Example, by reacting 3-amino-2-methylamino-1-(2-hydroxy-3-[2-(2,6-dimethylphenylamino)-ethylamino]-propoxy)-benzene trihydrochloride with formic acid, there are obtained 2.1 g. (14% of theory) of the desired compound; m.p. 94°-96° C. (after recrystallization from ethanol/diethyl ether).
Reaction SMILES: C1(C)C=CC(S([N:10]2[CH:14]=[C:13]([C@@H:15]([NH:18]S(C(C)(C)C)=O)[CH2:16][CH3:17])[CH:12]=[N:11]2)(=O)=O)=CC=1.Cl>CO.O1CCOCC1>[NH:10]1[CH:14]=[C:13]([C@@H:15]([NH2:18])[CH2:16][CH3:17])[CH:12]=[N:11]1
Reactant: CC[C@H](NS(=O)C(C)(C)C)c1cnn(S(=O)(=O)c2ccc(C)cc2)c1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CC[C@H](N)c1cn[nH]c1
Reaction time: 12 h

Procedure:
To a solution of 2-methyl-propane-2-sulfinic acid {(S)-1-[1-(toluene-4-sulfonyl)-1H-pyrazol-4-yl]-propyl}-amide (2.00 g, 5.22 mmol) in MeOH was added a 4 M solution of HCl (5.0 mL, 20 mmol) in dioxane. After 12 hours, the solvent was concentrated in vacuo. The residue was made basic with saturated aqueous NaHCO3 and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo to afford the title compound.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][CH:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][N:25]=2)[CH2:6][C@@H:5]1[CH3:32])(=[O:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:66][CH2:67][CH2:68][NH:69][C:70](=[O:76])[O:71][C:72]([CH3:75])([CH3:74])[CH3:73]>CN(C=O)C>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:22]=[CH:21][C:17]([C:18]([NH:66][CH2:67][CH2:68][NH:69][C:70](=[O:76])[O:71][C:72]([CH3:74])([CH3:73])[CH3:75])=[O:19])=[CH:16][CH:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][N:25]=2)[CH2:6][C@@H:5]1[CH3:32])(=[O:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: CC(=O)N1c2ccc(-c3ccc(C(=O)O)cc3)cc2[C@H](Nc2ccc(C#N)cn2)C[C@@H]1C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(=O)N1c2ccc(-c3ccc(C(=O)NCCNC(=O)OC(C)(C)C)cc3)cc2[C@H](Nc2ccc(C#N)cn2)C[C@@H]1C
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a flask charged with 4-((2S,4R)-1-acetyl-4-((5-cyanopyridin-2-yl)amino)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)benzoic acid (for a preparation see Intermediate 4)((70 mg, 0.164 mmol) and HATU (74.9 mg, 0.197 mmol) was added DMF (3 mL) and the resulting mixture was treated with DIPEA (0.086 mL, 0.492 mmol). After 5 min, tert-butyl (2-aminoethyl)carbamate (52.6 mg, 0.328 mmol) was added and the mixture was stirred at room temperature for 1 h and then concentrated in vacuo. The residue was partitioned between EtOAc and water and the layers were separated. The aqueous phase was extracted with EtOAc (×2) and the combined organic layers were washed with saturated aqueous NaHCO3 (×3), then brine, dried over MgSO4 and concentrated in vacuo to give tert-butyl (2-(4-((2S,4R)-1-acetyl-4-((5-cyanopyridin-2-yl)amino)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)benzamido)ethyl)carbamate as a brown foam which was further purified by MDAP (HpH). to give tert-butyl (2-(4-((2S,4R)-1-acetyl-4-((5-cyanopyridin-2-yl)amino)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)benzamido)ethyl)carbamate (65 mg, 0.114 mmol, 69.6% yield) as a white solid. LCMS (HpH, 2 min), Rt=1.00 min, MH+=569.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:10][C:11]1[C:19]([CH3:20])=[C:18]([CH3:21])[C:17]([CH3:22])=[C:16]2[C:12]=1[CH2:13][C:14](=[N:24]O)[C:15]2=[O:23].C(N(CC)CC)C>ClCCl>[CH3:10][C:11]1[C:19]([CH3:20])=[C:18]([CH3:21])[C:17]([CH3:22])=[C:16]2[C:12]=1[CH2:13][CH:14]([NH:24][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:15]2=[O:23]
Reactant: O=C(Cl)c1ccccc1
Reactant: Cc1c(C)c(C)c2c(c1C)CC(=NO)C2=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1c(C)c(C)c2c(c1C)CC(NC(=O)c1ccccc1)C2=O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Benzoyl chloride (1.635 g) is added dropwise to 4,5,6,7-tetramethyl-indan-1,2-dione 2-oxime (2.53 g) and triethylamine (2.25 g) in anhydrous dichloromethane (60 ml) at 0° C. The reaction mixture is stirred at room temperature for 1.5 hours after which the solid product is filtered off and allowed to stir with water (150 ml), refiltered and dried. The organic filtrate is washed with 1M HCl, 10% brine, saturated sodium bicarbonate solution, 10% brine and treated with magnesium sulphate. After filtration, the solvent is removed in vacuo and the product triterated with diethyl ether, filtered and dried.
Reaction SMILES: [ClH:1].[N+:2]([C:5]1[CH:28]=[CH:27][C:8]([C:9]([N:11]2[CH2:26][CH2:25][C:14]3([N:23]=[C:22]([NH2:24])[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[NH:15]3)[CH2:13][CH2:12]2)=[O:10])=[CH:7][CH:6]=1)([O-])=O.[H][H]>[Pd].C(O)C>[ClH:1].[ClH:1].[NH2:2][C:5]1[CH:6]=[CH:7][C:8]([C:9]([N:11]2[CH2:26][CH2:25][C:14]3([N:23]=[C:22]([NH2:24])[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[NH:15]3)[CH2:13][CH2:12]2)=[O:10])=[CH:27][CH:28]=1
Reactant: NC1=NC2(CCN(C(=O)c3ccc([N+](=O)[O-])cc3)CC2)Nc2ccccc21
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: NC1=NC2(CCN(C(=O)c3ccc(N)cc3)CC2)Nc2ccccc21

Procedure:
A suspension of 1-(4-Nitrobenzoyl)spiro[piperidine-4,2'(1'H)-quinazoline]4'-amine hydrochloride (Example 57)(181 mg, 0.45 mnmol) and 10% palladium on charcoal (18 mg, 10 mol%) in ethanol (20 ml) was stirred under 3 atrmospheres pressure of hydrogen for 20 h. The mixture was filtered and concentrated in vacuo. Purification by RP-HPLC eluting is with trifluoroacetic acid/water/methanol (1:90:10, increasing the gradient to 1:5:95) gave a yellow foam, MS (+FAB) 336 ([M+H]+), 1H NMR (d6 -DMSO) 10.64 (1H, s), 9.30 (1H, s), 8.75 (1H, s), 7.86 (1H, d, J 8.0 Hz), 7.78 (1H, s), 7.48 (1H, t, J 7.7 Hz), 7.42 (2H, d, J 8.2 Hz), 7.23 (2H, d, J 8.1 Hz), 6.94 (1H, d, J 8.3 Hz), 6.81 (1H, t, J 7.6 Hz), 4.05 (2H, br. s), 3.75 (2H, br. s), 3.63 (2H, br. s), 1.97 (2H, br. s), 1.84 (2H, br. s).
Reaction SMILES: [NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[C:2]1=[O:3].[H-].[Na+].[CH3:14]I.Cl>CN(C)C=O>[CH3:14][N:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[C:2]1=[O:3]
Reactant: O=C1Nc2ccccc2C1=O
Reactant: CI
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1C(=O)C(=O)c2ccccc21
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 84.4 %

Procedure:
A dimethylformamide (hereinafter referred to as DMF) (500 ml) solution of isatin (14.70 g, 100 mmol, purity 98%; manufactured by SIGMA-ALDRICH) was cooled to 0° C. in an ice bath, and sodium hydride (4.73 g, 118 mmol, 60% in oil; manufactured by Tokyo Chemical Industry Co., Ltd.) was added by portions with a spatula over a period of 10 min. After stirring for 15 min, methyl iodide (7.5 mL, 120 mmol) was added by portions with a Komagome pipette over a period of 10 min. The mixture was stirred at 0° C. for 1 hr and was then poured into 1 L of an aqueous hydrochloric acid solution. The mixture was extracted with ethyl acetate, and an ethyl acetate phase was washed twice with water. The ethyl acetate phase was concentrated to obtain 13.6 g of a crude product of N-methylisatin (HPLC assay: 79 area %). The HPLC assay was carried out in the same manner as described above.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:19])[CH:5]=[N:6][C:7]=1[O:8][C:9]1[N:10]=[CH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2.[CH3:20][C:21]1[CH:26]=[C:25]([CH3:27])[CH:24]=[C:23]([CH3:28])[C:22]=1[S:29](Cl)(=[O:31])=[O:30]>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:19][S:29]([C:22]2[C:23]([CH3:28])=[CH:24][C:25]([CH3:27])=[CH:26][C:21]=2[CH3:20])(=[O:31])=[O:30])[CH:5]=[N:6][C:7]=1[O:8][C:9]1[N:10]=[CH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2
Reactant: Nc1cnc(Oc2cc3ccccc3cn2)c(Cl)c1
Reactant: Cc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Product: Cc1cc(C)c(S(=O)(=O)Nc2cnc(Oc3cc4ccccc4cn3)c(Cl)c2)c(C)c1

Procedure:
The title compound was prepared by reacting 5-chloro-6-(isoquinolin-3-yloxy)pyridin-3-amine (obtained as per procedure described in preparation 2) and 2,4,6-trimethylbenzene-1-sulfonyl chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:14]#[N:15])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[Cl:16][C:17]1[C:18]([C:27]([F:30])([F:29])[F:28])=[N:19][N:20]([CH2:23][C:24](O)=[O:25])[C:21]=1[CH3:22].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN1C(=O)CCC1>[Cl:16][C:17]1[C:18]([C:27]([F:29])([F:28])[F:30])=[N:19][N:20]([CH2:23][C:24]([N:11]2[CH2:12][CH2:13][C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)([C:14]#[N:15])[CH2:9][CH2:10]2)=[O:25])[C:21]=1[CH3:22]
Reactant: N#CC1(c2ccc(Cl)cc2)CCNCC1
Reactant: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCCC1=O
Product: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)N1CCC(C#N)(c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 25 mL flask was added 455 mg of 4-(4-chloro-phenyl)-piperidine-4-carbonitrile (2.06 mmol, 1.0 equiv), 500 mg of (4-chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid (2.06 mmol, 1.00 equiv), 1.10 g of BOP (2.47 mmol, 1.2 equiv), 1.15 mL TEA (8.24 mmol, 4.00 equiv) and 6 mL NMP. A stir bar was placed in the flask and the reaction solution was stirred overnight at room temperature under N2 atmosphere. The crude product was purified by normal phase HPLC (EtOAc-hexane as the eluent) to yield 1-[2-(4-chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetyl]-4-(4-chloro-phenyl)-piperidine-4-carbonitrile: MS (ES) M+H expected=445.3, found=445.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][OH:10])[C:4]=1[CH2:11][OH:12].N1C=CN=C1.[C:18]([Si:22](Cl)([CH3:24])[CH3:23])([CH3:21])([CH3:20])[CH3:19].O>O1CCCC1>[Si:22]([O:10][CH2:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[C:4]=1[CH2:11][OH:12])([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:24])[CH3:23]
Reactant: COc1cccc(CO)c1CO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Solvent: O
Product: COc1cccc(CO[Si](C)(C)C(C)(C)C)c1CO
Temperature: 0 °C
Yield: 52.9 %

Procedure:
3-Methoxy-1,2-benzenedimethanol (1.30 g, 7.73 mmol) obtained from Example 21-(1) was dissolved in tetrahydrofuran (15 ml), and imidazole (526.2 mg, 7.73 mmol) and tert-butylchlorodimethylsilane (1.165 g, 7.73 mmol) were added thereto at 0° C. with stirring. The mixture was stirred at room temperature for 2 hours, then water was added thereto, and the product was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, and the solvent was distilled off under reduced pressure. The residue was subjected to chromatography on a silica gel (60 g) column (eluent; ethyl acetate:hexane=1:4) to afford the title compound (1.156 g, 53% yield) as an oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([NH:13][CH3:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:22][S:23](O)(=[O:25])=[O:24]>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([N:13]([S:23]([CH3:22])(=[O:25])=[O:24])[CH3:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CNC1CCN(C(=O)OC(C)(C)C)C1
Reactant: CS(=O)(=O)O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C1CCN(C(=O)OC(C)(C)C)C1)S(C)(=O)=O
Reaction time: 24 h

Procedure:
To a solution of 3-methylamino-pyrrolidine-1-carboxylic acid tert-butyl ester (0.50 g) in dichloromethane (10 ml) was added triethylamine (0.38 ml) followed by methanesulfonic acid (0.21 ml). After stirring for 24 hours, the reaction mixture was diluted with dichloromethane, washed with sodium bicarbonate solution, dried (MgSO4) and the solvent removed in vacuo. The residue was purified by flash chromatography to yield 3-(methanesulfonyl-methyl-amino)-pyrrolidine-1-carboxylic acid tert-butyl ester (0.52 g). Treatment of this compound with HCl in dichloromethane/methanol yielded N-Methyl-N-pyrrolidin-3-yl-methanesulfonamide hydrochloride salt (0.41 g).
Reaction SMILES: [C:1]([O:14][C@H:15]([CH2:41][O:42][C:43](=[O:55])[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54])[CH2:16][S:17][CH2:18][C@@H:19]([C:38](O)=[O:39])[NH:20][C:21](=[O:37])[O:22][CH2:23][CH:24]1[C:36]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:30]2[C:25]1=[CH:26][CH:27]=[CH:28][CH:29]=2)(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].Cl.[NH2:57][CH2:58][CH2:59][O:60][CH2:61][CH2:62][O:63][CH2:64][CH2:65][C:66]([P:69](=[O:76])([O:73][CH2:74][CH3:75])[O:70][CH2:71][CH3:72])([F:68])[F:67].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[CH:35]1[C:36]2[CH:24]([CH2:23][O:22][C:21]([NH:20][C@@H:19]([CH2:18][S:17][CH2:16][C@H:15]([O:14][C:1](=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH2:41][O:42][C:43](=[O:55])[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54])[C:38](=[O:39])[NH:57][CH2:58][CH2:59][O:60][CH2:61][CH2:62][O:63][CH2:64][CH2:65][C:66]([P:69](=[O:76])([O:73][CH2:74][CH3:75])[O:70][CH2:71][CH3:72])([F:68])[F:67])=[O:37])[C:25]3[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:31]=2[CH:32]=[CH:33][CH:34]=1
Reactant: CCOP(=O)(OCC)C(F)(F)CCOCCOCCN
Reactant: CCCCCCCCCCCC(=O)OC[C@H](CSC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O)OC(=O)CCCCCCCCCCC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCCCCCCCCCC(=O)OC[C@H](CSC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)NCCOCCOCCC(F)(F)P(=O)(OCC)OCC)OC(=O)CCCCCCCCCCC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (5R,9R)-9-(dodecanoyloxy)-1-(9H-fluoren-9-yl)-3,12-dioxo-2,11-dioxa-7-thia-4-azatricosane-5-carboxylic acid (6, 1 eq) in DCM (0.1M) was added diethyl 3-(2-(2-aminoethoxy)ethoxy)-1,1-difluoropropylphosphonate hydrochloride (1.3 eq), DIEA (3.5 eq) and HBTU (1.2 eq). The reaction mixture was then stirred at room temperature for 2 hours. The mixture was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 30-80% EtOAc/Hex to give the product.
Reaction SMILES: [CH2:1]([N:3]([CH2:37][CH3:38])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][C:35]=2[CH3:36])[C:30]([OH:32])=O)[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[C:12]=2[N:13]=1)[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[CH3:70][NH:71][C:72](=[O:75])[CH2:73][NH2:74]>CN(C=O)C>[CH2:1]([N:3]([CH2:37][CH3:38])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][C:35]=2[CH3:36])[C:30]([NH:74][CH2:73][C:72]([NH:71][CH3:70])=[O:75])=[O:32])[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[C:12]=2[N:13]=1)[CH3:2]
Reactant: CCN(CC)CCCNc1nc(-c2cc(C(=O)O)ccc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Reactant: CNC(=O)CN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCN(CC)CCCNc1nc(-c2cc(C(=O)NCC(=O)NC)ccc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 30.4 %

Procedure:
To the compound 3-[2-{[3-(diethylamino)propyl]amino}-8-(2,6-difluorophenyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methylbenzoic acid (26 mg, 0.05 mmol) in DMF (0.5 mL) were added HBTU (28 mg, 0.075 mmol), triethylamine (21.1 uL, 0.15 mmol) and N1-methylglycinamide (12.5 mg, 0.1 mmol). The mixture was stirred at rt overnight. Separation by HPLC with TFA, followed by neutralization with SPE amine cartridge afforded the title compound (9 mg, 30%). LC-MS m/z 592 (M+H)+.
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](=[N:30][OH:31])[NH2:29])=[CH:24][CH:23]=2)=[CH:4][CH:3]=1.[CH:32](OCC)(OCC)OCC.B(F)(F)F>CCOC(C)=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]([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:29]=[CH:32][O:31][N:30]=3)=[CH:24][CH:23]=2)=[CH:6][CH:7]=1
Reactant: CCn1ccc(-c2nc(-c3ccc(C(N)=NO)cc3)c(Sc3ccc(Cl)cc3)n2C)n1
Reactant: CCOC(OCC)OCC
Agent: FB(F)F
Solvent: CCOC(C)=O
Product: CCn1ccc(-c2nc(-c3ccc(-c4ncon4)cc3)c(Sc3ccc(Cl)cc3)n2C)n1
Temperature: 110 °C
Reaction time: 8 h

Procedure:
To a suspension of step 4 product (250 mg, 0.552 mmol) in triethyl orthoformate (9.09 ml, 55.2 mmol) was added BF3 etherate (0.699 μl, 5.52 μmol) and the mixture stirred at 110° C. for overnight. The reaction mixture was diluted with EtOAc and washed with NaHCO3 (aq), organic layer was dried, and concentrated. The residue was purified on silica gel column eluting a gradient of 8-70% EtOAc in hexane to afford 3-(4-{5-[(4-chlorophenyl)sulfanyl]-2-(1-ethyl-1H-pyrazol-3-yl)-1-methyl-1H-imidazol-4-yl}phenyl)-1,2,4-oxadiazole (130 mg; more polar; the major regioisomer. There was also a minor regioisomer that was the subject of the next example). 1H NMR (500 MHz), [CDCl3]: 8.78 (s, 1H), 8.28 (m, 2H), 8.15 (m, 2H), 7.55 (m, 1H), 7.22 (m, 2H), 7.06 (m, 2H), 6.95 (m, 1H), 4.28 (q, 2H), 4.00 (s, 3H), 1.60 (t, 3H). LCMS: [M+1]+=463.1 (rt=1.16 min). Human FAAH lysate assay: IC50=28.7 nM.
Reaction SMILES: C([NH:4][C:5]1[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][C:8]([C:9]([O:11]CC)=[O:10])=[C:7]([O:19][CH3:20])[CH:6]=1)(=O)C.[OH-].[Na+].O.Cl>CCO>[NH2:4][C:5]1[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][C:8]([C:9]([OH:11])=[O:10])=[C:7]([O:19][CH3:20])[CH:6]=1
Reactant: CCOC(=O)c1cc([N+](=O)[O-])c(NC(C)=O)cc1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1cc(N)c([N+](=O)[O-])cc1C(=O)O
Temperature: 25 °C

Procedure:
A mixture of ethyl 4-acetamido-2-methoxy-5-nitrobenzoate (4.0 g; 14.9 mmol) and NaOH (40 mL, 1 M aq; 40 mmol) in EtOH (80 mL) was refluxed for 2 h. The mixture was cooled to rt and water (20 mL) was added. The mixture was acidified by HCl (6 M aq) and the sub-title compound was filtered off. Yield: 3.0 g (95%).