Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][CH2:2][CH2:3][C:4]#[C:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][CH2:14][CH3:15])=[CH:8][CH:7]=1.[N:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=1>C(#N)C>[Br-:1].[CH2:12]([C:9]1[CH:10]=[CH:11][C:6]([C:5]#[C:4][CH2:3][CH2:2][N+:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)=[CH:7][CH:8]=1)[CH2:13][CH2:14][CH3:15]
Reactant: CCCCc1ccc(C#CCCBr)cc1
Reactant: Cc1ccncc1
Solvent: CC#N
Product: CCCCc1ccc(C#CCC[n+]2ccc(C)cc2)cc1
Product: [Br-]
Yield: 67 %

Procedure:
1-(4-Bromo-but-1-ynyl)-4-butyl-benzene (1 mmol) was added to a solution of 4-picoline (3 mmol) in acetonitrile, and the solution was refluxed for 24 hours. The acetonitrile was removed in vacuum, and the resulting residue was partitioned between ether and water. The aqueous layer was washed extensively with ether until no picoline was left in the aqueous layer. The resulting aqueous solution of the product was extracted with chloroform. The chloroform was removed to afford the product (67%). 1HNMR (300 MHz, CDCl3, ppm), 9.40 (d, J=6.9, 1H), 7.80 (d, 1H), 7.17 (d, J=7.8, 2H), 7.06 (d, J=7.8, 2H), 5.2 (t, 2H), 3.23 (t, 2H), 2.65 (s, 3H), 2.56 (t, J=7.8, 2H), 1.49-1.57 (m, 2H), 1.27-1.35 (m, 2H), 0.90 (t, J=7.5, 3H).
Reaction SMILES: [CH2:1]([N:8](C)[C:9]1([C:20]([NH:22][CH3:23])=[O:21])[CH2:12][N:11]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:10]1)C1C=CC=CC=1.[H][H]>[Pd].C(OCC)(=O)C.C(O)C.Cl.ClCCl>[CH3:1][NH:8][C:9]1([C:20]([NH:22][CH3:23])=[O:21])[CH2:10][N:11]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:12]1
Reactant: CNC(=O)C1(N(C)Cc2ccccc2)CN(C(=O)OC(C)(C)C)C1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CNC(=O)C1(NC)CN(C(=O)OC(C)(C)C)C1
Yield: 93.3 %

Procedure:
10% wt Palladium on charcoal (160 mg) in ethyl acetate (2 ml) was added to a solution of tert-butyl 3-[benzyl(methyl)amino]-3-[(methylamino)carbonyl]azetidine-1-carboxylate (580 mg, 1.74 mmol) in ethanol (45 ml). After the addition of a few drops of saturated hydrogen chloride in dichloromethane, the reaction mixture was stirred at room temperature under 3 bars of hydrogen for 3 hours. Filtration of the catalyst and concentration under reduced pressure gave tert-butyl 3-(methylamino)-3-[(methylamino)carbonyl]azetidine-1-carboxylate (395 mg, 93%) as a white solid, which was used without further purification in the next step. 1H NMR Spectrum: (CDCl3) 1.43 (s, 9H), 2.30 (s, 3H), 2.84 (s, 3H), 3.68 (d, 2H), 4.27 (brs, 2H), 7.05 (brs, 1H).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[NH2:10][C:11]1[CH:15]=[CH:14][NH:13][N:12]=1.[F:16][C:17]([F:27])([F:26])[C:18](=O)[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]>>[F:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]1[C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:18]([C:17]([F:16])([F:26])[F:27])[NH:10][C:11]2=[N:12][NH:13][CH:14]=[C:15]12
Reactant: Nc1cc[nH]n1
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Reactant: O=Cc1ccccc1F
Product: CCOC(=O)C1=C(C(F)(F)F)Nc2n[nH]cc2C1c1ccccc1F

Procedure:
The title compound was prepared from 2-fluorobenzaldehyde, 3-aminopyrazole and ethyl trifluoroacetoacetate in the same manner as in Example 1.
Reaction SMILES: [Na:1].[CH3:2][C:3]1[C:4]([CH2:22][S:23]([C:25]2[NH:29][C:28]3[CH:30]=[CH:31][CH:32]=[CH:33][C:27]=3[N:26]=2)=[O:24])=[N:5][CH:6]=[CH:7][C:8]=1[O:9][CH2:10]C1(C)OCC2(OCCO2)CO1.[CH3:34][C:35]1([CH2:45]CO)[O:44][CH2:43][C:38]2([O:42][CH2:41][CH2:40][O:39]2)[CH2:37][O:36]1.N1C2C=[C:54]3[O:60]CC[O:57][C:55]3=CC=2N=C1S>>[Na:1].[CH3:2][C:3]1[C:4]([CH2:22][S:23]([C:25]2[NH:29][C:28]3[CH:30]=[C:31]4[O:60][CH2:54][CH2:55][O:57][C:32]4=[CH:33][C:27]=3[N:26]=2)=[O:24])=[N:5][CH:6]=[CH:7][C:8]=1[O:9][CH2:10][CH2:45][C:35]1([CH3:34])[O:36][CH2:37][C:38]2([O:39][CH2:40][CH2:41][O:42]2)[CH2:43][O:44]1
Reactant: Cc1c(OCC2(C)OCC3(CO2)OCCO3)ccnc1CS(=O)c1nc2ccccc2[nH]1
Reactant: Sc1nc2cc3c(cc2[nH]1)OCCO3
Reactant: CC1(CCO)OCC2(CO1)OCCO2
Agent: [Na]
Product: Cc1c(OCCC2(C)OCC3(CO2)OCCO3)ccnc1CS(=O)c1nc2cc3c(cc2[nH]1)OCCO3
Yield: 9.2 %

Procedure:
The same procedure as in the steps (5d) to (5h) was repeated using the 2-(8-methyl-1,4,7,9-tetraoxaspiro[4.5]dec-8-yl)ethanol and 6,7-dihydro-1H-[1,4]dioxino[2′,3′:4,5]benzo[d]imidazole-2-thiol obtained in Example (73b) to obtain the title compound (110 mg, content: 93.5%, total 9.2% yield) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:21]([NH:23][C:24]2[CH:25]=[C:26]([C:36]([F:39])([F:38])[F:37])[CH:27]=[C:28]([N:30]3[CH:34]=[N:33][C:32]([CH3:35])=[CH:31]3)[CH:29]=2)=[O:22])=[CH:6][C:7]=1[NH:8][C:9]1[N:10]=[CH:11][CH:12]=[C:13]([C:15]2[CH:16]=[CH:17][CH:18]=[N:19][CH:20]=2)[N:14]=1.CC(OC)(C)C.[C:46]([OH:55])(=[O:54])[C@@H:47]([C@H:49]([C:51]([OH:53])=[O:52])[OH:50])[OH:48]>CCO>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:21]([NH:23][C:24]2[CH:25]=[C:26]([C:36]([F:38])([F:39])[F:37])[CH:27]=[C:28]([N:30]3[CH:34]=[N:33][C:32]([CH3:35])=[CH:31]3)[CH:29]=2)=[O:22])=[CH:6][C:7]=1[NH:8][C:9]1[N:10]=[CH:11][CH:12]=[C:13]([C:15]2[CH:16]=[CH:17][CH:18]=[N:19][CH:20]=2)[N:14]=1.[C:51]([C@@H:49]([C@H:47]([C:46]([O-:55])=[O:54])[OH:48])[OH:50])([O-:53])=[O:52]
Reactant: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Agent: Cc1cn(-c2cc(NC(=O)c3ccc(C)c(Nc4nccc(-c5cccnc5)n4)c3)cc(C(F)(F)F)c2)cn1
Solvent: CCO
Solvent: COC(C)(C)C
Product: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
Nilotinib base form A (4.00 g, 7.55 mmol) was mixed with ethanol absolute (40 mL, 10V) in a 250 mL reactor equipped with a mechanical stirrer and a reflux condenser to obtain a suspension. The suspension was heated to 80° C. and stirred at the same temperature for 30 min. To the suspension was added a solution of L-tartaric acid (1.25 g, 8.31 mmol, 1.1 mol eq) in ethanol absolute (10 mL, 2.5V) in one portion. The resulting mixture was stirred at 80° C. for 1 hour. Then the heating source was removed and the mixture was allowed to cool to room temperature. The stirring was continued at ambient temperature over a period of 6 h, during which time the mixture became viscous. To the viscous mixture was added another 80 mL ethanol. The mixture was then transferred to the refrigerator and was kept at about 5° C. for 5 days (in a closed vessel) A yellow precipitate formed and was isolated by vacuum filtration to give Nilotinib L-tartrate form IV as indicated by XRD (wet sample). The obtained Nilotinib L-tartrate form IV was dried in a vacuum oven (35 mmHg) at 60° C. for 16 h. The sample was then analyzed by PXRD using a Bruker X-Ray powder diffractometer model D8 and was found to be Nilotinib L-tartrate form IV (4.7 g).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:16](=[O:32])[C:17]1[CH:22]=[CH:21][C:20](B2OC(C)(C)C(C)(C)O2)=[CH:19][CH:18]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:34]1[S:38][C:37]([C:39]2[CH:44]=[CH:43][N:42]=[C:41]([S:45][CH3:46])[N:40]=2)=[CH:36][CH:35]=1>C(OCC)(=O)C.O>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:16](=[O:32])[C:17]1[CH:18]=[CH:19][C:20]([C:34]2[S:38][C:37]([C:39]3[CH:44]=[CH:43][N:42]=[C:41]([S:45][CH3:46])[N:40]=3)=[CH:36][CH:35]=2)=[CH:21][CH:22]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: CSc1nccc(-c2ccc(Br)s2)n1
Solvent: O
Solvent: CCOC(C)=O
Product: CSc1nccc(-c2ccc(-c3ccc(C(=O)Nc4ccccc4NC(=O)OC(C)(C)C)cc3)s2)n1

Procedure:
Using an analogous procedure to that described in Method 4, N-(2-t-butoxycarbonylaminophenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (Method 13, 219 mg, 0.5 mmol) was reacted with 4-(5-bromothien-2-yl)-2-(methylthio)pyrimidine (145 mg, 0.5 mmol). The crude residue stirred in ethyl acetate/water for 1 hour before being filtered, and the aqueous removed using a Varian Chem Elut Column (CE1010). The resulting solution was concentrated and recrystallised from methanol to give the title compound; Mass Spectrum: M+H+-Boc 463.
Reaction SMILES: C[O:2][C:3](=O)[CH:4]([CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14])[N:5]([S:7]([NH2:10])(=[O:9])=[O:8])[CH3:6].C[O-].[Na+]>CO>[CH3:14][CH:13]([CH3:15])[CH2:12][CH2:11][CH:4]1[N:5]([CH3:6])[S:7](=[O:9])(=[O:8])[NH:10][C:3]1=[O:2]
Reactant: COC(=O)C(CCC(C)C)N(C)S(N)(=O)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CC(C)CCC1C(=O)NS(=O)(=O)N1C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 99.8 %

Procedure:
A solution of N-(aminosulfonyl)-2-(3-methylbutyl)-sarcosine methyl ester (12.28 g, 48.67 mmol) in methanol (150 ml) was added under nitrogen to a solution of sodium methoxide (Na=2.1 g, 95.71 mmol) ) in 150 ml of ice-cold methanol. The resulting reaction mixture was stirred at room temperature under nitrogen for 1.5 hours, and the mixture was treated with 25 g of ion-exchange resin (BIO-RAD 50W-x8 H+) for 40 minutes, and filtered. The filtrate was concentrated in vacuo to afford 10.7 g (99.8%) of 4-(3-methylbutyl)-5-methyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide (Formula IV: R1 =H; R2= (CH2)2CH (CH3)2 ; R3 =CH3) as a solid, m.p. 212°-214° C.
Reaction SMILES: CC(C(CCC[CH2:15][N:16]1[C:20]([CH:21]([CH3:23])[CH3:22])=[C:19]([C:24]([NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:25])[C:18]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[C:17]1[C:39]1[CH:44]=[CH:43][C:42]([F:45])=[CH:41][CH:40]=1)C(O)(O)C([O-])=O)(C)C.[OH-].[Na+].[C:48]([O:51]CC)(=[O:50])[CH3:49].[C:54]([O-:57])(=O)[CH3:55].[Ca+2].[C:59]([O-])(=[O:61])[CH3:60]>C(#N)C.O.C1CCCCC1>[CH3:23][CH:21]([C:20]1[N:16]([CH2:15][CH2:60][C@@H:59]([OH:61])[CH2:55][C@@H:54]([OH:57])[CH2:49][C:48]([OH:51])=[O:50])[C:17]([C:39]2[CH:40]=[CH:41][C:42]([F:45])=[CH:43][CH:44]=2)=[C:18]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:19]=1[C:24]([NH:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:25])[CH3:22]
Reactant: CC(=O)[O-]
Reactant: CC(C)c1c(C(=O)Nc2ccccc2)c(-c2ccccc2)c(-c2ccc(F)cc2)n1CCCCC(C(C)(C)C)C(O)(O)C(=O)[O-]
Reactant: CCOC(C)=O
Agent: [Ca+2]
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Solvent: C1CCCCC1
Product: CC(C)c1c(C(=O)Nc2ccccc2)c(-c2ccccc2)c(-c2ccc(F)cc2)n1CC[C@@H](O)C[C@@H](O)CC(=O)O
Reaction time: 0.5 h

Procedure:
20 gm of R—(R*,R*)]-1,1-dimethylethyl-2-(4-fluorophenyl)-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoate was taken in 400 mL of acetonitrile to obtain clear solution at 40° C. to 45° C. The reaction mixture was cooled to 25° C. to 30° C. and 2.60 gm of NaOH solution in 100 mL of water was added within 15 min and stirred for 30 min. Acetonitrile was distilled under vacuum to obtain white slurry or solid. The compound thus obtained was further cooled at 10° C. to 15° C. 400 mL of water was added followed by slow addition of 400 mL of ethyl acetate to dissolve the solution. 10.46 gm of calcium acetate solution in 244 mL of water was added to obtain hazzy solution at 10° C. to 15° C. The reaction mixture was stirred for 2 hrs at 35° C. to 40° C. and cooled to 30° C. to 35° C. The organic layer was separated and washed with water and filtered through hyflow bed followed by washing with ethyl acetate. Ethyl acetate was taken in another RBF and was treated with 30 mg of L-lysine or L-argenine. The organic layer was further treated with butylated hydroxy toluene. The organic phase was then distilled to remove ethyl acetate completely till powder or lump of material was obtained. The solid thus obtained was treated with 100 mL of cyclohexane and stirred for 30 min. The product was filtered, washed with cyclohexane and dried at 30° C. to 35° C. The partially dried wet cake was treated with diethyl ether to obtain slurry. The slurry was filtered and dried to get atorvastatin amorphous. The product thus obtained was humidified under nitrogen atmosphere to obtain stable atorvastatin amorphous calcium with 5-6% water w/w.
Reaction SMILES: O.[CH3:2][C:3]1[NH:4][C:5]([CH3:32])=[C:6]([C:21]([O:23][CH2:24][O:25][C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28])=[O:22])[CH:7]([CH3:20])[C:8]=1[C:9]([O:11]COC(=O)C(C)(C)C)=[O:10]>C(OC(C)C)(C)C>[CH3:2][C:3]1[NH:4][C:5]([CH3:32])=[C:6]([C:21]([O:23][CH2:24][O:25][C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28])=[O:22])[CH:7]([CH3:20])[C:8]=1[C:9]([OH:11])=[O:10]
Reactant: CC1=C(C(=O)OCOC(=O)C(C)(C)C)C(C)C(C(=O)OCOC(=O)C(C)(C)C)=C(C)N1
Solvent: CC(C)OC(C)C
Solvent: O
Product: CC1=C(C(=O)O)C(C)C(C(=O)OCOC(=O)C(C)(C)C)=C(C)N1
Temperature: 25 °C
Yield: 75.8 %

Procedure:
In 30 ml of isopropyl ether saturated with water was dissovled 1.32 g of the bis(pivaloyloxymethyl) 1,4-dihydro -2,4,6-trimethyl-3,5-pyridinedicarboxylate obtained in Example 18, and 300 mg of Lipase B was added thereto, followed by stirring at room temperature for 8 horus. Any insoluble matter was removed by filtration and washed with acetone. The filtrate was concentrated under reduce dpressure. The residue was subjected to silica gel column chromatography (ethyl acetate/hexane=1/3) to obtain 741 mg (yield: 76%) of (+)-1,4-dihydro -2,4,6-trimethyl-5-pivaloyloxymethoxycarbonyl -3-pyridinecarboxylic acid as a pale yellow crystal.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[CH2:13]Br)[C:6]([O:8][CH3:9])=[O:7].[Cl:15][C:16]1[C:17]2[CH2:24][C:23](=[O:25])[NH:22][C:18]=2[N:19]=[CH:20][N:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O>[Cl:15][C:16]1[C:17]2[C@@:24]3([CH2:2][C:3]4[C:12](=[CH:11][CH:10]=[C:5]([C:6]([O:8][CH3:9])=[O:7])[CH:4]=4)[CH2:13]3)[C:23](=[O:25])[NH:22][C:18]=2[N:19]=[CH:20][N:21]=1
Reactant: O=C1Cc2c(Cl)ncnc2N1
Reactant: COC(=O)c1ccc(CBr)c(CBr)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc2c(c1)C[C@@]1(C2)C(=O)Nc2ncnc(Cl)c21
Reaction time: 0.17 h

Procedure:
To a solution of methyl 3,4-bis(bromomethyl)benzoate (5.0 g, 15.5 mmol) and 4-chloro-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one (5.3 g, 31.1 mmol) in N,N-dimethylformamide (150 mL) was added cesium carbonate (10.1 g, 31.1 mmol). After 10 min, water was added and the mixture was extracted with ethyl acetate. The combined organic extracts were washed with water, brine, dried over magnesium sulfate, filtered and concentrated. Purification by silica gel chromatography (1% methanol/dichloromethane→5% methanol/dichloromethane) then a second silica gel purification (100% dichloromethane→75% dichloromethane/EtOAc gave the title compound as a racemic mixture (2.1 g). Chiral separation of the individual enantiomers was accomplished by use of HPLC using a 10 cm Chiral Pak® AD® column (60% EtOH/hexanes with 0.1% diethylamine to give the title compound (1st eluting enantiomer, 0.9 g). MS 330.2 (M).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[CH:5][C:6]2[N:11]=[C:10]([N:12]=[C:13](SC)SC)[S:9][C:7]=2[N:8]=1.Cl.Cl.[NH2:20][CH2:21][C@@:22]1([OH:30])[CH:27]2[CH2:28][CH2:29][N:24]([CH2:25][CH2:26]2)[CH2:23]1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[CH3:1][O:2][C:3]1[N:4]=[CH:5][C:6]2[N:11]=[C:10]([NH:12][C:13]3[O:30][C@:22]4([CH2:21][N:20]=3)[CH:27]3[CH2:28][CH2:29][N:24]([CH2:25][CH2:26]3)[CH2:23]4)[S:9][C:7]=2[N:8]=1
Reactant: COc1ncc2nc(N=C(SC)SC)sc2n1
Reactant: NC[C@]1(O)CN2CCC1CC2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ncc2nc(NC3=NC[C@@]4(CN5CCC4CC5)O3)sc2n1
Temperature: 100 °C
Yield: 64.5 %

Procedure:
A mixture of dimethyl 5-methoxythiazolo[5,4-d]pyrimidin-2-ylcarbonimidodithioate (100 mg, 0.349 mmol), (S)-3-(aminomethyl)quinuclidin-3-ol dihydrochloride (80 mg, 0.349 mmol) and cesium carbonate (228 mg, 0.698 mmol) in DMF (1.7 mL) was heated to 100° C. for 2 hours. The reaction mixture was cooled to ambient temperature, poured into water and the solids were collected by filtration to afford (R)—N-(5-methoxythiazolo[5,4-d]pyrimidin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine (78 mg, 64% yield). 1H NMR (500 MHz, CDCl3) δ ppm 9.12 (br. s., 1 H) 8.63 (s, 1 H) 3.95-4.18 (m, 4 H) 3.71 (d, J=9.77 Hz, 1 H) 3.41 (d, J=15.26 Hz, 1 H) 2.74-3.10 (m, 5 H) 2.11-2.27 (m, 2 H) 1.71-1.86 (m, 1 H) 1.50-1.70 (m, 2 H). MS (LC/MS) R.T.=1.66; [M+H]+=347.0.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[N:13]([CH3:14])[C:12](I)=[N:11][C:10]=2[C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=2)=[CH:4][CH:3]=1.C[C:27]1[C:28](B(O)O)=[N:29][NH:30][CH:31]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].O1CCOC[CH2:44]1>CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[N:13]([CH3:14])[C:12]([C:27]3[CH:28]=[N:29][N:30]([CH3:44])[CH:31]=3)=[N:11][C:10]=2[C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=2)=[CH:4][CH:3]=1
Reactant: Cc1c[nH]nc1B(O)O
Reactant: Cn1c(I)nc(-c2ccc(S(C)(=O)=O)cc2)c1Sc1ccc(Cl)cc1
Reactant: C1COCCO1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: Cn1cc(-c2nc(-c3ccc(S(C)(=O)=O)cc3)c(Sc3ccc(Cl)cc3)n2C)cn1
Temperature: 110 °C

Procedure:
A mixture of Example 133 compound (60 mg, 0.119 mmol), methylpyrazole boronic acid (29.7 mg, 0.143 mmol), Pd(PPh3)4 (13.7 mg, 0.012 mmol), K3PO4 (50.5 mg, 0.238 mmol, aq) in dioxane (2 ml) was vacuumed and purged to N2 for 3 times, then reaction mixture was heated at 110° C. for 3 hrs. Reaction mixture was diluted with EtOAc, washed with brine dried and concentrated. Separated by prep TLC (hex:EtOAc:CH3OH=6:5:1) to give 4-{5-[(4-chlorophenyl)sulfanyl]-1-methyl-4-[4-(methylsulfonyl)phenyl]-1H-imidazol-2-yl}-1-methyl-1H-pyrazole (25 mg) 1H NMR (500 MHz), [(CDCl3]: 8.35 (m, 1H), 7.95 (m, 3H), 7.25 (m, 3H), 7.01 (m, 2H), 4.10 (s, 3H), 3.78 (s, 3H), 3.10 (s, 3H). LCMS: [M+1]+=459.0. Human FAAH lysate assay: IC50=13.9 nM.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[C:7]([NH:9][C:10]([NH:12][C:4]2=[CH:3][CH:2]=1)=[O:11])=[O:8].[CH:13]([CH:15]=[CH2:16])=[O:14]>CO.C(OCC)(=O)C.O>[O:11]=[C:10]1[N:9]([CH2:16][CH2:15][CH:13]=[O:14])[C:7](=[O:8])[C:5]2[C:4](=[CH:3][CH:2]=[CH:1][CH:6]=2)[NH:12]1
Reactant: O=c1[nH]c(=O)c2ccccc2[nH]1
Reactant: C=CC=O
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: O=CCCn1c(=O)[nH]c2ccccc2c1=O
Temperature: 55 °C
Reaction time: 0.25 h
Yield: 59.4 %

Procedure:
Benzoylene urea (4.0 9, 24.7 mmol), Triton B (40 wt % in methanol) (11.0 mL, 24.7 mmol), water (80 mL) and methanol (400 mL) were combined at ambient temperature and stirred vigorously for 15 minutes. (until all the solids had gone into solution). To this colorless solution, acrolein (1.7 mL, 24.7 mmol) in methanol (20 mL) was added dropwise over 5 minutes. to give a yellow solution. The reaction was then heated to 55° C. and stirred for 2 hours. and then at room temperature for approximately 16 hours. The yellow solution was concentrated to give a yellow oil which was taken up in ethyl acetate (25 mL) and water (50 mL). The aqueous layer was extracted again with ethyl acetate (25 mL). The organic layers were combined, washed with 1N HCl (20 mL), water (20 mL), saturated sodium bicarbonate solution (20 mL) and brine (20 mL), the organic layer was dried over magnesium sulfate and concentrated to give 3-[2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl]propionaldehyde as a yellow foam (3.2 g, 59%) which was used without further purification. The NMR data showed a purity of ˜70%. NMR CDCl3 δ9.85 (s, 1H), 8.10-8.06 (m, 1H), 7.63-7.57 (m, 1H), 7.24-7.19 (m, 1H), 7.13-7.07 (m, 1H), 4.44-4.40 (m, 2H), 2.85 (dt, 2H, J1,2=2 Hz, J1,3=7 Hz); MS=219 (p+1).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:11][C:12]2[C:17]([CH3:18])=[CH:16][C:15]([CH3:19])=[CH:14][C:13]=2[CH3:20])[C:5]2[S:10][CH:9]=[CH:8][C:6]=2[N:7]=1.C(O)(C(F)(F)F)=O.[NH2:28][C:29]1[CH:36]=[CH:35][C:32]([C:33]#[N:34])=[CH:31][CH:30]=1>C(OCC)(=O)C>[C:13]1([CH3:20])[CH:14]=[C:15]([CH3:19])[CH:16]=[C:17]([CH3:18])[C:12]=1[NH:11][C:4]1[C:5]2[S:10][CH:9]=[CH:8][C:6]=2[N:7]=[C:2]([NH:28][C:29]2[CH:36]=[CH:35][C:32]([C:33]#[N:34])=[CH:31][CH:30]=2)[N:3]=1
Reactant: Cc1cc(C)c(Nc2nc(Cl)nc3ccsc23)c(C)c1
Reactant: N#Cc1ccc(N)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: Cc1cc(C)c(Nc2nc(Nc3ccc(C#N)cc3)nc3ccsc23)c(C)c1
Temperature: 90 °C
Reaction time: 15 h
Yield: 19.8 %

Procedure:
To a solution of 2-Chloro-N-mesitylthieno[3,2-d]pyrimidin-4-amine (51.4 mg, 0.17 mmol), TFA (0.11 mL, 1.36 mmol) in TFE (1 mL) was added 4-aminobenzonitrile (80.2 mg, 0.68 mmol) in a sealed tube. The reaction was stirred at 90° C. for 15 h. Reaction mixture was diluted with ethyl acetate and washed with saturated NaHCO3 (3×10 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by prep HPLC to afford the product as a white solid (13 mg, 20%): 1H NMR (DMSO, 300 MHz) δ 2.09 (s, 6H), 2.31 (s, 3H), 7.00 (s, 2H), 7.28 (d, J=5.7 Hz, 1H), 7.66 (d, J=8.4 Hz, 2H), 8.06-8.08 (m, 3H), 9.60 (bs, 1H), 9.72 (bs, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]3[CH2:14][CH2:15][CH2:16][C:11]3=[C:10]([NH:17][C:18]3[CH:27]=[CH:26][C:21]([C:22]([O:24]C)=[O:23])=[CH:20][CH:19]=3)[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[Li+].[OH-].O.C1COCC1.Cl>CO.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]3[CH2:14][CH2:15][CH2:16][C:11]3=[C:10]([NH:17][C:18]3[CH:19]=[CH:20][C:21]([C:22]([OH:24])=[O:23])=[CH:26][CH:27]=3)[CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(Nc2cc(-c3cccc(Cl)c3)nc3c2CCC3)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc(Nc2cc(-c3cccc(Cl)c3)nc3c2CCC3)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 24.8 %

Procedure:
An 18-mL vial was charged with methyl 4-[[2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl]amino]benzoate (20 mg, 0.053 mmol, 1 eq.) and LiOH/H2O (47.4 mg, 1.13 mmol, 21 eq.). THF (1 ml), H2O (0.3 ml) and MeOH (0.2 ml) was added to the vial. The resulting mixture was stirred at room temperature overnight. 2 N HCl aq. (0.5 ml) was added and the volatile material was removed under reduced pressure. The residue was purified by chromatography on silica gel using 5% of methanol in dichloromethane as eluent to give 4-[[2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl]amino]benzoic acid (4.8 mg, 25% yield). MW=364.82. 1H NMR (DMSO-D6, 360 MHz) δ 8.65 (s, 1H), 7.96 (s, 1H), 7.86 (m, 3H), 7.42 (m, 3H), 7.25 (d, J=8.31 Hz, 2H), 2.92 (t, J=7.86, 2H), 2.82 (t, J=6.93, 2H), 2.06 (m, 2H).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[C:5]([NH2:10])[CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[C:11](OC(=O)C)(=[O:13])[CH3:12]>>[CH2:1]1[C:9]2[C:4](=[C:5]([NH:10][C:11](=[O:13])[CH3:12])[CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cccc2c1CCC2
Product: CC(=O)Nc1cccc2c1CCC2
Temperature: 70 °C
Reaction time: 16 h

Procedure:
226 mg (1.7 mmol) indan-4-ylamine are combined with 5 ml acetic anhydride. The suspension is stirred for 16 h at 70° C. The resulting solution is stirred into 40 ml distilled water, adjusted to pH 7 with sodium carbonate and extracted three times with 30 ml of ethyl acetate. Then the organic phase is dried with MgSO4, the solvent is eliminated in vacuo and the crude product is purified by chromatography. The carrier used is silica gel and the eluant used is a mixture of cyclohexane:ethyl acetate (70:30).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[S:8][C:9]3[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=3[C:11](=[O:13])[N:12]=2)=[CH:3][CH:2]=1.ClC1C=CC=C(C(OO)=[O:26])C=1>C(Cl)(Cl)Cl>[N:1]1[CH:6]=[CH:5][C:4]([C:7]2[S:8][C:9]3[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=3[C:11](=[O:13])[N+:12]=2[O-:26])=[CH:3][CH:2]=1
Reactant: O=c1nc(-c2ccncc2)sc2ccccc12
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: O=c1c2ccccc2sc(-c2ccncc2)[n+]1[O-]
Temperature: 25 °C
Reaction time: 24 h
Yield: 17.1 %

Procedure:
2-(4-pyridyl)-4H-1,3-benzothiazine-4-one (1.00 g, 4.1 mmol) was dissolved in chloroform (20 ml). To the mixture was added 3-chloroperbenzoic acid (ca. 77%, 0.92 g, 4.1 mmol). The reaction mixture was stirred at room temperature for 24 hr and concentrated under reduced pressure. The residue was subjected to a silica gel column chromatography and eluted with ethyl acetate-methanol (20:1, v/v) and recrystallized from diisopropylether-methanol to give the titled compound (0.18 g, 16%) as crystals.