Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:58])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[C:26]([C:31]4[CH:36]=[CH:35][C:34]([C:37]5[NH:38][C:39]([CH:42]6[CH2:46][CH2:45][CH2:44][N:43]6[C:47](=[O:57])[CH:48]([NH:52][C:53]([O:55][CH3:56])=[O:54])[CH:49]([CH3:51])[CH3:50])=[N:40][CH:41]=5)=[CH:33][CH:32]=4)[CH:27]=3)[CH:22]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7].CO[C:61](=O)[NH:62]C(C(N1CCCC1C1NC(C2C=CC3C(=CC=C(B4OC(C)(C)C(C)(C)O4)C=3)C=2)=CN=1)=O)C(C)C>>[CH3:1][O:2][C:3](=[O:58])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[C:26]([C:31]4[CH:32]=[CH:33][C:34]([C:37]5[NH:38][C:39]([CH:42]6[CH2:46][CH:45]([C:61]#[N:62])[CH2:44][N:43]6[C:47](=[O:57])[CH:48]([NH:52][C:53]([O:55][CH3:56])=[O:54])[CH:49]([CH3:51])[CH3:50])=[N:40][CH:41]=5)=[CH:35][CH:36]=4)[CH:27]=3)[CH:22]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7]
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc3cc(B4OC(C)(C)C(C)(C)O4)ccc3c2)[nH]1)C(C)C
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(-c3ccc4cc(-c5cnc(C6CCCN6C(=O)C(NC(=O)OC)C(C)C)[nH]5)ccc4c3)cc2)[nH]1)C(C)C
Product: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc3cc(-c4ccc(-c5cnc(C6CC(C#N)CN6C(=O)C(NC(=O)OC)C(C)C)[nH]5)cc4)ccc3c2)[nH]1)C(C)C

Procedure:
Title compound was prepared according to the method employed to prepare [1-(2-{5-[6-(4-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester (Example AZ), substituting (1-{2-[5-(4-Bromo-phenyl)-1H-imidazol-2-yl]-4-cyano-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester for [2-methyl-1-(2-{5-[6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-propyl]-carbamic acid methyl ester. NMR (MeOH-d4, 400 MHz) δ: 8.12-8.03 (m, 2H), 7.89-7.74 (m, 6H), 7.48-7.36 (m, 2H), 5.20 (m, 2H), 4.60 (m, 1H), 4.28-3.88 (m, 6H), 3.66 (s, 6H), 2.86 (m, 1H), 2.60 (m, 1H), 2.40-2.19 (m, 3H), 2.11-1.97 (m, 3H), 1.00-0.88 (m, 12H); MS (ESI) m/z 814 [M+H]+.
Reaction SMILES: C(OC([NH:11][C:12]1[CH:21]=[CH:20][C:19]2[N:18]3[CH2:22][CH2:23][C@@H:17]3[CH2:16][O:15][C:14]=2[C:13]=1[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=O)C1C=CC=CC=1>C(O)C.[Pd]>[NH2:11][C:12]1[CH:21]=[CH:20][C:19]2[N:18]3[CH2:22][CH2:23][C@@H:17]3[CH2:16][O:15][C:14]=2[C:13]=1[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25]
Reactant: CC(C)(C)OC(=O)c1c(NC(=O)OCc2ccccc2)ccc2c1OC[C@H]1CCN21
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)c1c(N)ccc2c1OC[C@H]1CCN21
Yield: 99 %

Procedure:
A solution of tert-butyl (R)-6-benzyloxycarbonylamino-1,2,2a,3-tetrahydro-4-oxa-8b-aza-cyclobuta[a]naphthalene-5-carboxylate (Intermediate 45, 0.138 g) in ethanol (20 mL) was treated with 10% palladium on carbon (0.05 g) and the resultant mixture was stirred under an atmosphere of hydrogen for 30 minutes. The mixture was filtered and the filtrate was concentrated in vacuo to give tert-butyl (R)-6-amino-1,2,2a,3-tetrahydro-4-oxa-8b-azacyclobuta[a]naphthalene-5-carboxylate (0.092 g) as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21]([OH:23])=O)=[CH:19][N:18]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.Cl.Cl.[CH3:34][N:35]1[CH:39]=[CH:38][N:37]=[C:36]1[CH:40]([NH2:42])[CH3:41].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CCOC(C)=O.CN(C=O)C>[CH3:34][N:35]1[CH:39]=[CH:38][N:37]=[C:36]1[CH:40]([NH:42][C:21]([C:20]1[C:14]2[C:15](=[N:16][CH:17]=[C:12]([C:6]3[C:5]4[C:9](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=4)[N:8]([CH3:11])[N:7]=3)[N:13]=2)[N:18]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[CH:19]=1)=[O:23])[CH3:41]
Reactant: CC(N)c1nccn1C
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)O)cn3COCC[Si](C)(C)C)c2ccc(Cl)cc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(Cl)ccc34)nc12)c1nccn1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 61 %

Procedure:
In a 20 mL scintillation vial, 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (400 mg, 0.87 mmol), 1-(1-methyl-1H-imidazol-2-yl)-ethylamine dihydrochloride (219 mg, 1.75 mmol), HBTU (431 mg, 1.14 mmol), HOBt (153 mg, 1.14 mmol) and DIPEA (0.31 ml, 1.75 mmol) were combined with DMF (6 ml) to give a light yellow solution. After stirring at room temperature overnight, the reaction mixture was diluted with EtOAc (50 mL) and washed with sat NaHCO3 (3×25 mL) and H2O (3×25 mL). The organic layer was dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 4 g, 0% to 10% MeOH in DCM with 0.1% NH4OH) to provide 300 mg (61%) of 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [1-(1-methyl-1H-imidazol-2-yl)-ethyl]-amide. MS: (M+H)+=566.
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][N:10]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=3)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:22]1[C:31]2[C:26](=[CH:27][C:28]([C:32]([F:35])([F:34])[F:33])=[CH:29][CH:30]=2)[N:25]=[CH:24][CH:23]=1>>[C:1]1([N:7]2[CH2:8][CH2:9][N:10]([CH2:13][C:14]3[CH:15]=[CH:16][C:17]([NH:20][C:22]4[C:31]5[C:26](=[CH:27][C:28]([C:32]([F:35])([F:33])[F:34])=[CH:29][CH:30]=5)[N:25]=[CH:24][CH:23]=4)=[CH:18][CH:19]=3)[CH2:11][CH2:12]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: FC(F)(F)c1ccc2c(Cl)ccnc2c1
Reactant: Nc1ccc(CN2CCN(c3ccccc3)CC2)cc1
Product: FC(F)(F)c1ccc2c(Nc3ccc(CN4CCN(c5ccccc5)CC4)cc3)ccnc2c1

Procedure:
In the manner given in Example 1C, 1-phenyl-4-[(4-aminophenyl)methyl]piperazine and 4-chloro-7-(trifluoromethyl)quinoline are reacted together at reflux to give 4-[[4-[[4-phenyl-1-piperazinyl]methyl]phenyl]amino]-7-(trifluoromethyl)quinoline.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:13])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[C:14](OC(=O)C)(=[O:16])[CH3:15]>>[C:14]([O:13][C:5]1[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)(=[O:16])[CH3:15]
Reactant: COc1cc(O)cc(OC)c1OC
Reactant: CC(=O)OC(C)=O
Product: COc1cc(OC(C)=O)cc(OC)c1OC
Temperature: 0 °C
Yield: 93 %

Procedure:
A solution of 3,4,5-trimethoxyphenol (5.52 g, 30 mmol) in acetic anhydride (15 mL) was refluxed for 4 h. The reaction mixture was poured onto crushed ice (50 g). The resulting precipitate was collected and washed with water. The residue was dried in vacuum at 50° C. for 24 h to afford white crystals (6.31 g, 93%), 74-75° C.; 1H NMR (CDCl3, 200 M Hz) δ 6.34 (s, 2H), 3.83 (s, 6H), 3.82 (s, 3H), 2.29 (s, 3H); 13C NMR (CDCl3, 50 M Hz) δ 169.6 (s), 153.5 (s, 2C), 146.7 (s), 135.8 (s), 99.1 (d, 2C), 60.9 (q), 56.1 (q, 2C), 21.1 (q).
Reaction SMILES: [BH4-].[Na+].FC(F)(F)C(O)=O.[Cl:10][C:11]1[CH:12]=[C:13]([CH2:18][C:19]#[N:20])[CH:14]=[CH:15][C:16]=1[Cl:17]>O1CCCC1.ClCCl>[Cl:10][C:11]1[CH:12]=[C:13]([CH2:18][CH2:19][NH2:20])[CH:14]=[CH:15][C:16]=1[Cl:17]
Reactant: N#CCc1ccc(Cl)c(Cl)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCCc1ccc(Cl)c(Cl)c1
Temperature: 10 °C
Reaction time: 0.17 h
Yield: 63 %

Procedure:
To a stirred suspension of sodium borohydride (10.17 g, 0.2688 mol) in anhydrous tetrahydrofuran (160 ml) under N2 at 0° C. was added a solution of trifluoroacetic acid (30.65 g, 20.71 ml, 0.2688 mol) in anhydrous tetrahydrofuran (25 ml) dropwise over 30 minutes. The mixture was stirred at 10° C. for 10 minutes. A solution of 2-(3,4-dichlorophenyl)acetonitrile (50 g, 0.268 mol) in anhydrous tetrahydrofuran (50 ml) was added dropwise over 30 minutes. The mixture was stirred at room temperature for 1 hour and then poured slowly onto 500 g of crushed ice. The mixture was extracted three times with dichloromethane (300 ml). The organic phases were combined, washed three times with aqueous saturated NaHCO3 (250 ml) and once with water (250 ml), dried over sodium sulfate and concentrated under reduced pressure to provide a yellow oil as the crude product (56 g). This crude product was dissolved in dichloromethane (560 ml, 10 ml/g) and extracted three times with 2 M HCl solution (300 ml). The combined aqueous layers were washed with dichloromethane (300 ml), basified to pH 10 by addition of 1 M NaOH at 0° C. then extracted three times with dichloromethane (500 ml). The combined organic phases containing the product were dried over sodium sulfate, filtered, and concentrated under reduced pressure to provide the desired 2-(3,4-dichlorophenyl)ethylamine free base as a light yellow oil (32.07 g, 62% yield).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:5]=2[N:6]=1.Br[CH2:13][CH2:14][CH2:15][Cl:16].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([O:11][CH2:13][CH2:14][CH2:15][Cl:16])=[CH:7][C:5]=2[N:6]=1
Reactant: Cc1nc2cc(O)ccc2s1
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1nc2cc(OCCCCl)ccc2s1
Temperature: 60 °C
Reaction time: 18 h

Procedure:
A mixture of 2-methyl-5-benzothiazolol (8 g, 48.4 mmol), 1-bromo-3-chloropropane (23 g, 146 mmol), and potassium carbonate (33.6 g, 240 mmol) in 50 ml of acetonitrile was stirred at 60° C. for 18 hr. The mixture was cooled, evaporated under reduced pressure, diluted with water and ethyl acetate. The organic phase was separated, dried over sodium sulfate, and concentrated under vacuum to give 2-methyl-5-(3-chloropropoxyl)-benzothiazole (IV) as a tan crystalline solid (10 g, 85%, mp 63-65° C., MS (CI) m+1=242).
Reaction SMILES: C([N:8]1[C:12]2[N:13]=[C:14]([NH:28][C:29]3[CH:34]=[CH:33][C:32]([C:35]#[N:36])=[CH:31][CH:30]=3)[N:15]=[C:16]([O:17][C:18]3[C:25]([CH3:26])=[CH:24][C:21]([C:22]#[N:23])=[CH:20][C:19]=3[CH3:27])[C:11]=2[CH:10]=[CH:9]1)C1C=CC=CC=1.[Cl-].[Al+3].[Cl-].[Cl-]>ClC1C=CC=CC=1Cl>[C:35]([C:32]1[CH:33]=[CH:34][C:29]([NH:28][C:14]2[N:15]=[C:16]([O:17][C:18]3[C:19]([CH3:27])=[CH:20][C:21]([C:22]#[N:23])=[CH:24][C:25]=3[CH3:26])[C:11]3[CH:10]=[CH:9][NH:8][C:12]=3[N:13]=2)=[CH:30][CH:31]=1)#[N:36]
Reactant: Cc1cc(C#N)cc(C)c1Oc1nc(Nc2ccc(C#N)cc2)nc2c1ccn2Cc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: Clc1ccccc1Cl
Product: Cc1cc(C#N)cc(C)c1Oc1nc(Nc2ccc(C#N)cc2)nc2[nH]ccc12
Temperature: 160 °C
Reaction time: 0.75 h
Yield: 26.3 %

Procedure:
To a solution of 4-[7-benzyl-2-(4-cyano-phenylamino)-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy]-3,5-dimethyl-benzonitrile (28 mg, 0.060 mmol) in 1,2-dichlorobenzene (1 mL) was added aluminum chloride (40 mg, 0.30 mmol). The reaction mixture was stirred at 160° C. for 45 min and cooled to room temperature. The mixture was poured into ice water and extracted with CH2Cl2 (2×10 mL). The combined organic solution was washed with brine (10 mL), dried with Na2SO4, and concentrated to dryness. Silica gel chromatography (Hexanes:EtOAc=50:50) yielded 6 mg (27%) of 4-[2-(4-cyano-phenylamino)-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy]-3,5-dimethyl-benzonitrile as a tan solid.
Reaction SMILES: [CH:1](NC(C)C)(C)C.C([Li])CCC.[CH2:13]([C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]2[C:24](=[O:54])[CH:25]([CH2:28][C:29]3[N:30]=[CH:31][N:32]([C:35]([C:48]4[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=4)([C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)[C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[C:33]=3[CH3:34])[CH2:26][CH2:27][C:16]=12)[CH3:14].CI>O1CCCC1.CCCCCC.O>[CH2:13]([C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]2[C:24](=[O:54])[C:25]([CH3:1])([CH2:28][C:29]3[N:30]=[CH:31][N:32]([C:35]([C:48]4[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=4)([C:36]4[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=4)[C:42]4[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=4)[C:33]=3[CH3:34])[CH2:26][CH2:27][C:16]=12)[CH3:14]
Reactant: CC(C)NC(C)C
Reactant: CCc1c2n(c3ccccc13)C(=O)C(Cc1ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c1C)CC2
Agent: [Li]CCCC
Solvent: CI
Solvent: O
Solvent: C1CCOC1
Product: CCc1c2n(c3ccccc13)C(=O)C(C)(Cc1ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c1C)CC2
Reaction time: 0.5 h

Procedure:
To a solution of diisopropylamine (202.4 mg) in tetrahydrofuran (5 ml) at -50° C. under nitrogen atmosphere was added 1.64M-butyllithium in hexane (1.23 ml). After being stirred at -60~-70° C. for 30 minutes, the mixture was treated with a solution of 8,9-dihydro-10-ethyl-7-[(5-methyl-1-trityl-1H-imidazol-4-yl)methyl]pyrido[1,2-a]indol-6(7H)-one (549 mg) in tetrahydrofuran (10 ml) over 20 minutes. The mixture was stirred at -60~-70° C. stirred for 60 minutes and a solution of methyl iodide (213 mg) in tetrahydrofuran (1 ml) was added dropwise at -60° C. over 10 minutes. After the mixture was stirred at -65° C. for 30 minutes and at -20° C. for 1 hour, it was diluted with water and extracted twice with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and evaporated in vacuo to give 8,9-dihydro-10-ethyl-7-methyl-7[(5-methyl-1-trityl-1H-imidazol-4-yl)methyl]pyrido[1,2-a]indol-6(7H)-one, which was dissolved with 80% aqueous acetic acid (6 ml) and stirred at 60° C. for 2 hours. After evaporation of the solvent, the residue was diluted with water, neutralized with an aqueous sodium bicarbonate solution, and extracted twice with 10%-methanol-chloroform. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and evaporated in vacuo. The residue was purified by silica gel column chromatography (5% methanol-chloroform). The obtained 8,9-dihydro-10-ethyl-7methyl-7-[(5-methyl-1H-imidazol-4-yl)methyl]pyrido[1,2-a]indol-6(7H)-one was dissolved in 12N-hydrogenchloride in ethanol (1 ml) and evaporated in vacuo. Tritulation of the residue with ether gave 8,9-dihydro-10-ethyl-7-methyl-7-[(5-methyl-1H-imidazol-4-yl)methyl]pyrido[1,2-a]indol- 6(7H)-one hydrochloride (202.56 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][C:9]2[N:13]([CH3:14])[CH:12]=[N:11][C:10]=2[C:15]2[CH:20]=[CH:19][C:18]([C@H:21]3[CH2:23][C@@H:22]3[C:24]3[O:28][C:27](=[O:29])[NH:26][N:25]=3)=[CH:17][CH:16]=2)=[N:6][CH:7]=1.[C:30](=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.IC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][C:9]2[N:13]([CH3:14])[CH:12]=[N:11][C:10]=2[C:15]2[CH:20]=[CH:19][C:18]([C@H:21]3[CH2:23][C@@H:22]3[C:24]3[O:28][C:27](=[O:29])[N:26]([CH3:30])[N:25]=3)=[CH:17][CH:16]=2)=[N:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: Cn1cnc(-c2ccc([C@H]3C[C@@H]3c3n[nH]c(=O)o3)cc2)c1Sc1ccc(Cl)cn1
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cn1cnc(-c2ccc([C@H]3C[C@@H]3c3nn(C)c(=O)o3)cc2)c1Sc1ccc(Cl)cn1
Reaction time: 16 h

Procedure:
To a solution of Example 17 (5 mg, 0.012 mmol) and excess cesium carbonate in 0.5 mL DMF was added 2 drops of iodomethane. The reaction was stirred at it for 16 h before filtering and subjecting to purification via reverse phase HPLC. The fractions containing the product were collected, diluted with ethyl acetate, and washed with aqueous sodium bicarbonate, water, and brine. The organic layer was dried (MgSO4), filtered, and concentrated to afford the title compound. 1H NMR (500 MHz), [(CD3)2CO]: 8.43 (s, 1H), 8.13 (s, 1H), 7.96 (d, 2H), 7.75 (d, 1H), 7.24 (d, 2H), 7.02 (d, 1H), 3.75 (s, 3H), 3.30 (s, 3H) 2.56 (m, 1H), 2.20 (m, 1H), 1.60 (br, 2H). LCMS: [M+1]+=440. Human FAAH lysate assay: IC50=170.6 DM.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([N+:13]([O-:15])=[O:14])[CH:6]=1.[CH2:16]([NH:18][CH2:19][CH3:20])[CH3:17]>C(#N)C.ClCCl>[CH2:16]([N:18]([CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([N+:13]([O-:15])=[O:14])[CH:6]=1)[CH2:19][CH3:20])[CH3:17]
Reactant: CCNCC
Reactant: COc1ccc(OCCCl)cc1[N+](=O)[O-]
Solvent: ClCCl
Solvent: CC#N
Product: CCN(CC)CCOc1ccc(OC)c([N+](=O)[O-])c1
Temperature: 120 °C

Procedure:
4-(2-chloroethoxy)-1-methoxy-2-nitrobenzene (0.15 g, 0.67 mmol) was dissolved in acetonitrile (1 ml). Excess diethylamine (1.5 ml, 17.7 mmol) was added and the reaction heated in the microwave (T=120° C., 40 min) to complete conversion. The reaction mixture was diluted with dichloromethane, then washed with 5M sodium hydroxide and brine, then dried over sodium sulfate. Evaporation of the solvent under reduced pressure gave the title compound as an orange oil.
Reaction SMILES: [CH:1]1([C:4]2[N:8]([CH:9]3[CH2:12][CH:11]([CH2:13][CH:14]([CH3:16])[CH3:15])[CH2:10]3)[N:7]=[N:6][C:5]=2[CH:17]([CH2:26][CH2:27][OH:28])[CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:3][CH2:2]1.C(Cl)(Cl)Cl.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[CH:1]1([C:4]2[N:8]([CH:9]3[CH2:10][CH:11]([CH2:13][CH:14]([CH3:16])[CH3:15])[CH2:12]3)[N:7]=[N:6][C:5]=2[CH:17]([CH2:26][CH:27]=[O:28])[CH2:18][C:19]([O:21][C:22]([CH3:24])([CH3:23])[CH3:25])=[O:20])[CH2:2][CH2:3]1
Reactant: CC(C)CC1CC(n2nnc(C(CCO)CC(=O)OC(C)(C)C)c2C2CC2)C1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: CC(C)CC1CC(n2nnc(C(CC=O)CC(=O)OC(C)(C)C)c2C2CC2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.5 %

Procedure:
tert-Butyl 3-[5-cyclopropyl-1-(3-isobutylcyclobutyl)-1H-[1,2,3]triazol-4-yl]-5-hydroxyvalerate (106 mg) and chloroform (1 mL) were mixed. To the mixture was added Dess-Martin reagent (130 mg) at ice temperature. After stirring at RT for 1 hr, saturated aqueous sodium bicarbonate and ethyl acetate were added to the mixture at ice temperature. The mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate, water and brine, then dried over magnesium sulfate. The magnesium sulfate was filtered off and the filtrate was concentrated in vacuo to give the title compound (106 mg) as a crude product.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[N:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]#[C:18][CH2:19][CH2:20]O.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH2:20][CH2:19][C:18]#[C:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][N:11]=1)=[O:5]
Reactant: OCCC#Cc1ccccn1
Reactant: O=C(O)c1ccccc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: O=C(OCCC#Cc1ccccn1)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To solution of 2-chlorobenzoic acid (330 mg, 2.10 mmol), 4-(pyridin-2-yl)but-3-yn-1-ol (310 mg, 2.1 mmol), in DCM (7 mL), was successively added EDCI.HCl (600 mg, 3.2 mmol) and DMAP (13 mg, 0.105 mmol). The resulting mixture was then stirred overnight at ambient temperature. The reaction mixture was concentrated.
Reaction SMILES: [OH:1][C:2]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[C:16]([O:22][CH3:23])[C:3]=1[C:4](=[O:15])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1.[C:24](Cl)(=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26].Cl>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[CH3:23][O:22][C:16]1[CH:17]=[C:18]([O:20][CH3:21])[CH:19]=[C:2]([O:1][C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26])[C:3]=1[C:4](=[O:15])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: COc1ccc(C=CC(=O)c2c(O)cc(OC)cc2OC)cc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Product: COc1ccc(C=CC(=O)c2c(OC)cc(OC)cc2OC(=O)C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 115.7 %

Procedure:
To a stirred solution of 300 mg of 2'-hydroxy-4,4',6'-trimethoxychalcone in 12 ml of pyridine were added 65 mg of p-(dimethylamino)-pyridine and 165 mg of pivaloyl chloride. After being stirred at room temperature for 4 hours, the reaction mixture was poured into 30 ml of ice-water. The mixture was acidified with hydrochloric acid and then extracted with 50 ml of ethyl acetate. The ethyl acetate extract was successively washed with 0.2N hydrochloric acid, 10% aqueous sodium carbonate and water, dried over sodium sulfate and then evaporated to give 440 mg of 2',4,4'-trimethoxy-6'-(pivaloyloxy)-chalcone;
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([F:12])=[C:7]([CH2:9][CH2:10][OH:11])[CH:8]=1.FC(F)(F)C(O)=O.[CH2:20]([C:22]1[S:26][CH:25]=[C:24]([C:27]([N:29]2[CH2:34][C:33]3([CH2:39][CH2:38][NH:37][CH2:36][CH2:35]3)[O:32][CH2:31][CH2:30]2)=[O:28])[CH:23]=1)[CH3:21].C(N(CC)CC)C>C(#N)C>[CH2:20]([C:22]1[S:26][CH:25]=[C:24]([C:27]([N:29]2[CH2:34][C:33]3([CH2:39][CH2:38][N:37]([CH2:2][C:3]4[CH:4]=[CH:5][C:6]([F:12])=[C:7]([CH2:9][CH2:10][OH:11])[CH:8]=4)[CH2:36][CH2:35]3)[O:32][CH2:31][CH2:30]2)=[O:28])[CH:23]=1)[CH3:21]
Reactant: OCCc1cc(CBr)ccc1F
Reactant: CCc1cc(C(=O)N2CCOC3(CCNCC3)C2)cs1
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: CCc1cc(C(=O)N2CCOC3(CCN(Cc4ccc(F)c(CCO)c4)CC3)C2)cs1
Temperature: 20 °C
Reaction time: 2 h

Procedure:
2-(5-(Bromomethyl)-2-fluorophenyl)ethanol (example 47, step a) (0.171 g) was added to a solution of (5-ethylthiophen-3-yl)(1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)methanone trifluoroacetate (example 99, step a) (0.3 g) and triethylamine (0.410 ml) in acetonitrile (15 mL) and the mixture stirred at 20° C. for 2 hours. The solvent was evaporated under reduced pressure and the residue partitioned between ethyl acetate and saturated sodium bicarbonate solution. The organic layer was dried over sodium sulphate, filtered and the solvent evaporated under reduced pressure. The crude product was purified by flash silica chromatography using 1% triethylamine and 2% methanol in dichloromethane as solvent. Pure fractions were evaporated to dryness to afford the subtitled compound. Yield 0.2 g.
Reaction SMILES: [C:1]([O:6][CH2:7][CH:8]([OH:10])C)(=[O:5])[C:2]([CH3:4])=[CH2:3].[C:11](OCCCO)(=O)C(C)=C>>[C:1]([O:6][CH:7]([CH3:11])[CH2:8][OH:10])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C=C(C)C(=O)OCC(C)O
Reactant: C=C(C)C(=O)OCCCO
Product: C=C(C)C(=O)OC(C)CO

Procedure:
2-hydroxypropyl methacrylate; 3-hydroxypropyl methacrylate;
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][CH:11]=2)=[O:9])[CH2:4][CH2:3]1.CO.[H][H]>[Pd]>[NH2:16][C:13]1[CH:12]=[CH:11][C:10]([C:8]([N:5]2[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]2)=[O:9])=[CH:15][CH:14]=1
Reactant: [H][H]
Reactant: CN1CCN(C(=O)c2ccc([N+](=O)[O-])cc2)CC1
Agent: [Pd]
Solvent: CO
Product: CN1CCN(C(=O)c2ccc(N)cc2)CC1
Yield: 99.7 %

Procedure:
(4-Methyl-piperazin-1-yl)-(4-nitro-phenyl)-methanone (2.12 g, 8.51 mmol) was dissolved in Methanol (35 mL, 860 mmol) and the solution was carefully added to a Parr vessel containing 10% Palladium on Carbon (0.650 g, 48.7 mmol) under nitrogen. The mixture was then placed on a Parr hydrogenation apparatus and was allowed to shake at 55 psi until uptake of hydrogen ceased. The catalyst was then filtered to afford 1.86 g of (4-Amino-phenyl)-(4-methyl-piperazin-1-yl)-methanone without further purification. (M+H)=220.6. 1H NMR (400 MHz, DMSO, d6) δ 7.09 (d, 2H, J=8.41 Hz), 6.53 (d, 2H J=8.41 Hz), 5.48 (s, 2H), 3.46 (m, 4H), 2.28 (m, 4H), 2.17 (s, 3H).