Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:4][CH:5]1[CH2:10][CH2:9][N:8](C(OC(C)(C)C)=O)[CH2:7][CH2:6]1)([OH:3])=O.[ClH:18].CN(CCCN=C=NCC)C.[F:30][C:31]([F:41])([F:40])[C:32]1[CH:39]=[CH:38][C:35]([CH2:36][NH2:37])=[CH:34][CH:33]=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[ClH:18].[F:30][C:31]([F:40])([F:41])[C:32]1[CH:39]=[CH:38][C:35]([CH2:36][NH:37][C:1]([CH2:4][CH:5]2[CH2:6][CH2:7][NH:8][CH2:9][CH2:10]2)=[O:3])=[CH:34][CH:33]=1
Reactant: NCc1ccc(C(F)(F)F)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(CC(=O)O)CC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: O=C(CC1CCNCC1)NCc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 77 %

Procedure:
4-Carboxymethyl-1-tert-butoxycarbonylpiperidine (207 mg, 0.85 mmol, commercially available from Neosystem), 1-(3-(N,N-dimethylamino)-prop-1-yl)-3-ethylcarbodiimide hydrochloride (EDC) (177 mg, 0.92 mmol) and 4-(N,N-dimethylamino)pyridine (2 mg, 0.02 mmol) were dissolved in 4 mL of CH2Cl2. (4-(Trifluoromethyl)benzyl)amine (0.114 mL, 0.8 mmol) was added and the reaction was stirred at rt for 14 h. The mixture was diluted with CH2Cl2, washed with 1 N NaOH, 1 N HCl and brine and dried over MgSO4. The solvent was removed, the residue was redissolved in 1% HCl/methanol and the solution was heated to 50° C. for 24 h. The solution was then concentrated to afford 208 mg (77%) of the title compound. ESI-MS: 301.1 (M+H); HPLC A: 1.66 min.
Reaction SMILES: [CH:1]12[N:8]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH:5]([CH2:6][CH2:7]1)[CH2:4][NH:3][CH2:2]2.C(N(CC)CC)C.[C:23](Cl)(=[O:39])[O:24][CH2:25][CH:26]1[C:38]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[C:32]2[C:27]1=[CH:28][CH:29]=[CH:30][CH:31]=2>ClCCl>[CH:1]12[N:8]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([C:23]([O:24][CH2:25][CH:26]1[C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:32]=3[C:33]3[C:38]1=[CH:37][CH:36]=[CH:35][CH:34]=3)=[O:39])[CH2:2]2
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Reactant: CC(C)(C)OC(=O)N1C2CCC1CNC2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C2CCC1CN(C(=O)OCC1c3ccccc3-c3ccccc31)C2
Reaction time: 1 h

Procedure:
A solution of tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (105 mg, 0.5 mmol) in dichloromethane (3 mL) and triethylamine (100 mg, 138 μL, 1.0 mmol) was treated with 9H-fluoren-9-ylmethyl carbonochloridate (128.0 mg, 0.5 mmol). The reaction mixture was stirred for 1 h. The reaction mixture was washed with 1 N HCl, water, 50% saturated bicarbonate and brine. The organic layer was dried over Na2SO4, filtered and concentrated to obtain a solution of 3-(9H-fluoren-9-yl)methyl 8-tert-butyl 3,8-diazabicyclo[3.2.1]octane-3,8-dicarboxylate in DCM (2 mL), which was used directly for the next step. LC/MS m/z 435.5 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]([NH:7][C:8]([C:10]2[C:15]([NH2:16])=[CH:14][CH:13]=[C:12]([CH3:17])[N:11]=2)=[O:9])[N:6]=1.Br[C:19]1[CH:20]=[N:21][CH:22]=[C:23]([F:25])[CH:24]=1>>[CH3:1][C:2]1[S:3][CH:4]=[C:5]([NH:7][C:8]([C:10]2[C:15]([NH:16][C:19]3[CH:20]=[N:21][CH:22]=[C:23]([F:25])[CH:24]=3)=[CH:14][CH:13]=[C:12]([CH3:17])[N:11]=2)=[O:9])[N:6]=1
Reactant: Fc1cncc(Br)c1
Reactant: Cc1ccc(N)c(C(=O)Nc2csc(C)n2)n1
Product: Cc1ccc(Nc2cncc(F)c2)c(C(=O)Nc2csc(C)n2)n1

Procedure:
The title compound, was prepared from 3-Amino-6-methyl-pyridine-2-carboxylic acid (2-methyl-thiazol-4-yl)-amide and 3-Bromo-5-fluoropyridine in accordance with the general method of example 20 to yield the final compound as an off-white solid, MS (ISP): m/e=344.3 (M+H+).
Reaction SMILES: [O:1]=[S@@:2]1[C@@H:7]2[C@H:8]([NH:11][C:12](=[O:20])[CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:9](=[O:10])[N:6]2[C:5]([C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)=[O:22])=[C:4](OS(C(F)(F)F)(=O)=O)[CH2:3]1.[CH2:41]=[CH:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1.C(N(C(C)C)CC)(C)C>ClCCl>[O:1]=[S@@:2]1[C@H:7]2[N:6]([C:9](=[O:10])[C@H:8]2[NH:11][C:12](=[O:20])[CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:5]([C:21]([O:23][CH2:24][C:25]2[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=2)=[O:22])=[C:4]2[C@@H:3]1[CH:42]([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[CH2:41]2
Reactant: C=Cc1ccccc1
Reactant: COc1ccc(COC(=O)C2=C(OS(=O)(=O)C(F)(F)F)C[S@](=O)[C@@H]3[C@H](NC(=O)Cc4ccccc4)C(=O)N23)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(COC(=O)C2=C3CC(c4ccccc4)[C@@H]3[S@](=O)[C@@H]3[C@H](NC(=O)Cc4ccccc4)C(=O)N23)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52.8 %

Procedure:
To a suspension of p-methoxybenzyl (1S,6R,7R)-1-oxo-7-phenylacetamido-3-trifluoromethanesulphonyloxyceph-3-em-4-carboxylate (30 mg, 0.05 mmol) and styrene (300 μl, 2.62 mmol) in dichloromethane (3 ml), was added diisopropyl-ethylamine (10 μl, 0.057 mmol). After stirring at room temperature for 30 min the mixture was chromatographed to give the title compounds (14.7 mg, 53%), νmax (CH2Cl2), 1790, 1728, 1689 cm-1 ; δH (CDCl3) 7.41-7.16 (12H, m) 6.89 (2H, m) 6.67 (0.4H, d, J 9.7 Hz), 6.52 (0.6H, d, J 9.8 Hz), 5.98 (0.4H, dd, J 9.7, 4.9 Hz), 5.86 (0.6H, dd, J 9.8, 4.9 Hz), 5.28 (ABq, J 11.9 Hz), 5.23 (0.8H, ABq, J 11.8 Hz), 4.38 (1H, m), 4.31 (0.6H, m), 4.0 (1.4H, m), 3.80 (3H, s), 3.73-3.82 (4H, m).
Reaction SMILES: ClC1N=C(Cl)C2SCCC=2N=1.[NH2:12][C:13]1([CH2:16][OH:17])[CH2:15][CH2:14]1.[Cl:18][C:19]1[N:20]=[C:21](NC2(CO)CC2)[C:22]2[S:27](=[O:28])[CH2:26][CH2:25][C:23]=2[N:24]=1>>[Cl:18][CH:19]1[N:24]([NH:12][C:13]2([CH2:16][OH:17])[CH2:15][CH2:14]2)[C:23]2[CH2:25][CH2:26][S:27](=[O:28])[C:22]=2[CH:21]=[N:20]1
Reactant: O=S1CCc2nc(Cl)nc(NC3(CO)CC3)c21
Reactant: NC1(CO)CC1
Agent: Clc1nc(Cl)c2c(n1)CCS2
Product: O=S1CCC2=C1C=NC(Cl)N2NC1(CO)CC1

Procedure:
Starting from 2,4-dichloro-6,7-dihydro-thieno[3,2-d]pyrimidine and 1-amino-cyclopropanmethanol the two enantiomers of [1-(2-chloro-5-oxo-6,7-dihydro-5H-5λ4-thieno[3,2-d]pyrimidin-4-ylamino)-cyclopropyl]-methanol may be prepared as described in Example 28 (cf 2.1.2). The enantiomers may be separated by chiral HPLC (column Diacel IA, 250×4.6 mm, 5 m, eluant: (hexane+cyclohexylamine (0.2%))/ethanol (80/20), flow rate: 1 ml/min): enantiomer 1: RT=11.1 min; enantiomer 2: RT=16.5 min.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[Si:11]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]([OH:32])[CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[C:22]([O:33][CH3:34])[CH:21]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12].C(N(CC)CC)C>C(Cl)Cl>[Si:11]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26](=[O:32])[CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[C:22]([O:33][CH3:34])[CH:21]=1)([C:14]([CH3:15])([CH3:17])[CH3:16])([CH3:12])[CH3:13]
Reactant: CCCCCC(O)c1ccc(CO[Si](C)(C)C(C)(C)C)cc1OC
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: CCCCCC(=O)c1ccc(CO[Si](C)(C)C(C)(C)C)cc1OC
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 91.4 %

Procedure:
A solution of 14.0 ml (0.20 mol) of dimethyl sulfoxide in 50 ml of methylene chloride was added dropwise over a period of 35 minutes to a solution of 9.0 ml (0.10 mol) of oxalyl chloride in 100 ml of methylene chloride cooled to -78° C., whilst the internal temperature of the mixture was kept below -60° C. The resulting mixture was then stirred at -78° C. for 30 minutes, after which a solution of 30.65 g (86.9 mmol) of 1-(4-t-butyldimethylsilyloxymethyl-2-methoxyphenyl)hexyl alcohol [prepared as described in step (i) above] in 60 ml of methylene chloride was added dropwise at the same temperature over a period of 35 minutes. The mixture was then stirred for 30 minutes. 60 ml (0.43 mol) of triethylamine were added dropwise to the mixture at the same temperature over a period of 17 minutes, and then the reaction mixture was stirred for 10 minutes, after which the dry ice-acetone bath was removed and the mixture was stirred for a further 50 minutes. At the end of this time, the reaction was terminated by adding water. The reaction mixture was then diluted with methylene chloride, and the organic phase was separated and then washed with 2 N aqueous hydrochloric acid, with water and with a saturated aqueous solution of sodium hydrogencarbonate, in that order, after which it was dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under reduced pressure, and the resulting residue was purified by column chromatography through 250 g of silica gel, using a 1:9 by volume mixture of ethyl acetate and hexane as the eluent, to give 27.84 g (yield 91%) of the title compound as an oily substance.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C.[CH3:43][CH:44]1[C:49]2[CH:50]=[CH:51][S:52][C:48]=2[CH2:47][CH2:46][NH:45]1>C(#N)C.O>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:45]3[CH2:46][CH2:47][C:48]4[S:52][CH:51]=[CH:50][C:49]=4[CH:44]3[CH3:43])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Reactant: CC1NCCc2sccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: O
Product: CC1c2ccsc2CCN1C(=O)c1cc2ncc(Br)cn2n1
Temperature: 50 °C
Reaction time: 2 h
Yield: 47.9 %

Procedure:
To a solution of 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid (0.7 g, 2.9 mmol, 1.0 equiv) and TBTU (1.0 g, 3.1 mmol, 1.1 equiv) in dry acetonitrile (20 mL), triethylamine (1 mL, 7.25 mmol, 2.5 equiv) and 4-methyl-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine (0.45 g, 2.9 mmol, 1 equiv) are added. The reaction mixture is stirred at 50° C. for 2 h and then at room temperature for 8 h. The reaction mixture is diluted with water (10 ml). The precipitate is filtered, washed sequentially with 50% aqueous ethanol, water, 5% aqueous ammonia, and diethyl ether, and then dried to provide 0.524 g of the title compound.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([CH2:16][N:17]2[CH2:20][C:19]([F:22])([F:21])[CH2:18]2)=[C:12]([CH:15]=1)[C:13]#[N:14].O.[OH-].[Na+]>CCOCC>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([CH2:16][N:17]2[CH2:18][C:19]([F:22])([F:21])[CH2:20]2)=[C:12]([CH:15]=1)[CH2:13][NH2:14]
Reactant: N#Cc1cc(Cl)ccc1CN1CC(F)(F)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: NCc1cc(Cl)ccc1CN1CC(F)(F)C1
Reaction time: 0.25 h
Yield: 88.3 %

Procedure:
1M LAH in ether (0.42 mL, 0.42 mmol) was added to a stirred solution of 5-chloro-2-[(3,3-difluoroazetidin-1-yl)methyl]benzonitrile (67.8 mg, 0.28 mmol) in ether (5 ml) at 0° C. After 1 h the reaction was treated successively with water (16 μL), 15% NaOH (16 μL), and water (32 μL). After stirring for 15 min the mixture was filtered and the filtrate was evaporated. The residue was partitioned between 1N HCl and ether. The aqueous layer was made neutral with NaHCO3 and was extracted with CH2Cl2. The organic layer was dried with Na2SO4 and evaporated to give 5-chloro-2-[(3,3-difluoroazetidin-1-yl)methyl]benzylamine (61 mg) as a glass: 1H NMR (CDCl3, 400 MHz) δ 3.56 (t, J=11.9 Hz, 4H), 3.73 (s, 2H), 3.85 (s, 2H), 7.26 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([NH:9][NH:10][C:11](=[O:19])[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[N:14][CH:13]=1)=O.ClC1C=CC(C(Cl)=O)=CN=1.C(=O)(O)[O-].[Na+]>ClCCl>[Cl:18][C:15]1[N:14]=[CH:13][C:12]([C:11]2[O:19][C:7]([C:3]3[S:4][CH:5]=[CH:6][C:2]=3[Cl:1])=[N:9][N:10]=2)=[CH:17][CH:16]=1
Reactant: O=C(NNC(=O)c1sccc1Cl)c1ccc(Cl)nc1
Agent: O=C(Cl)c1ccc(Cl)nc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Clc1ccc(-c2nnc(-c3sccc3Cl)o2)cn1
Reaction time: 0.08 h
Yield: 96 %

Procedure:
6-Chloro-nicotinic acid N′-(3-chloro-thiophene-2-carbonyl)-hydrazide: A solution of 3-chloro-thiophene-2-carbonyl hydrazide (70 mg, 0.40 mmol), 6-chloronicotinoyl chloride (76 mg, 0.43 mmol) and dichloromethane (10 mL) was stirred for 5 min. To the solution was added saturated sodium bicarbonate solution (10 mL) and it was stirred for 5 min. The layers were separated and the aqueous phase was extracted with dichloromethane (8×10 mL). Ethyl acetate (50 mL) was added to the combined organic phases, which were dried over anhydrous sodium sulfate, decanted, and concentrated to yield 120 mg (96%) of the title compound as a white powder. 1H NMR (DMSO-d6): 10.89 (s, 1H), 10.37 (s, 1H), 8.89 (d, J=2.19 Hz, 1H), 8.30 (dd, J=8.52, 2.48 Hz, 1H), 7.93 (d, J=5.22 Hz, 1H), 7.72 (d, J=8.25 Hz, 1H), 7.22 (d, J=5.22 Hz, 1H).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1.CCO.[C:17]([O:21][CH2:22][CH3:23])(=[O:20])[CH:18]=O.N#N>C1(C)C=CC=CC=1>[CH2:22]([O:21][C:17]([CH:18]1[C:6]2[NH:7][C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:5]=2[CH2:4][CH2:3][NH:2]1)=[O:20])[CH3:23]
Reactant: CCOC(=O)C=O
Reactant: NCCc1c[nH]c2ccccc12
Agent: Cl
Agent: N#N
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCOC(=O)C1NCCc2c1[nH]c1ccccc21
Yield: 66.6 %

Procedure:
2,3,4,9-Tetrahydro-1H-betacarboline-1-carboxylic acid ethyl ester was prepared by the addition of tryptamine-HCl (1.33 g, 6.76 mmol), EtOH (12 mL), and a 50% toluene solution of ethyl glyoxylate (1.66 g, 8.11 mmol) to a 50 mL flask purged with N2. The reaction solution was allowed to reflux 16 hours. The reaction solution was concentrated under reduced pressure, and the resulting crude material was chromatographed (SiO2, 100% DCM to 4% MeOH) to provide 1.10 g (68% yield) of 2,3,4,9-tetrahydro-1H-betacarboline-1-carboxylic acid ethyl ester; 1H NMR (CDCl3) δ 8.59 (1H, br s), 7.46 (1H, d), 7.39 (1H, d), 7.23 (1H, t), 7.14 (1H, t), 5.40 (1H, s), 4.24 (2H, q), 3.51 (1H, m), 3.07 (1H, m), 2.86 (1H, d), 1.30 (3H, t); 13C NMR (CDCl3) δ 166, 137, 126, 123, 122, 120, 119, 112, 108, 64, 60, 53, 41, 14; MS (ESI): 245 (MH+).
Reaction SMILES: [O:1]=[C:2]1[C:6]([CH2:13][CH2:14][CH2:15][N:16]([CH3:18])[CH3:17])([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:5]2[CH2:19][CH:20]=[CH:21][CH:22]=[C:4]2[O:3]1.[H-].[H-].[H-].[H-].[Li+].[Al+3].[C:29]([OH:34])(=[O:33])[C:30]([OH:32])=[O:31]>C1COCC1.CCOCC.C(Cl)Cl>[C:29]([OH:34])(=[O:33])[C:30]([OH:32])=[O:31].[CH3:18][N:16]([CH3:17])[CH2:15][CH2:14][CH2:13][C:6]([C:5]1[CH:19]=[CH:20][CH:21]=[CH:22][C:4]=1[OH:3])([C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)[CH2:2][OH:1]
Reactant: CN(C)CCCC1(c2ccccc2)C(=O)OC2=CC=CCC21
Agent: O=C(O)C(=O)O
Agent: [Al+3]
Agent: [H-]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCOCC
Product: CN(C)CCCC(CO)(c1ccccc1)c1ccccc1O
Reaction time: 2 h
Yield: 52.3 %

Procedure:
A solution of 3-(2-oxo-3-phenyl-3-dihydrobenzofuranyl)-N,N-dimethylpropylamine (103 g, 349 mmol) in anhydrous THF (400 ml) was added to a suspension of LiAlH4 (15.3 g, 384 mmol) in Et2O (300 ml) at ice bath temperature and this mixture stirred for 2 hours. After further stirring 1 hour at room temperature the reaction mixture was quenched with saturated Na2SO4, filtered and the solids washed with EtOAc (4×500 ml). The combined organic phases were washed with saturated Na2CO3 (500 ml) and saturated NaCl (500 ml), and dried over Na2SO4. Filtration and evaporation gave 66 g of a crude oil which solidified on standing. A solution of 40 g of this material in CH2Cl2 (60 ml) was added to a stirred solution of anhydrous oxalic acid (19 g) in anhydrous Et2O (600 ml). Filtration of the precipitated salt gave 43 g of a solid. Recrystallization of the oxalate (6.0 g) from boiling EtOH (300 ml) yielded 4.3 g (38%) of crystals, m.p. 182.0°-182.5°.
Reaction SMILES: Br[CH2:2][CH2:3][N:4]1[C:29](=[O:30])[N:7]2[CH:8]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([OH:28])[CH:23]=3)[C:9]3[NH:10][C:11]4[C:16]([C:17]=3[CH2:18][C:6]2([CH3:31])[C:5]1=[O:32])=[CH:15][C:14]([O:19][CH2:20][CH3:21])=[CH:13][CH:12]=4.[CH3:33][NH2:34]>O1CCCC1>[CH2:20]([O:19][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9]1[CH:8]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([OH:28])[CH:23]=3)[N:7]3[C:29](=[O:30])[N:4]([CH2:3][CH2:2][NH:34][CH3:33])[C:5](=[O:32])[C:6]3([CH3:31])[CH2:18][C:17]2=1)[CH3:21]
Reactant: CCOc1ccc2[nH]c3c(c2c1)CC1(C)C(=O)N(CCBr)C(=O)N1C3c1cccc(O)c1
Reactant: CN
Solvent: C1CCOC1
Product: CCOc1ccc2[nH]c3c(c2c1)CC1(C)C(=O)N(CCNC)C(=O)N1C3c1cccc(O)c1

Procedure:
The title compound is prepared similarly as described for example 29 using (3aSR,10RS)-2-(2-Bromoethyl)-6-ethoxy-10-(3-hydroxy-phenyl)-3a-methyl-3a,4,9,10-tetrahydro-2,9,10a-triaza-cyclopenta[b]-fluorene-1,3-dione (example 22) and a 2 M solution of methyl amine in tetrahydrofurane instead of azetidine as starting materials. MS: m/z (MH+)=449.1
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].C([N:15]1[CH2:24][CH2:23][C:22]2[C:17](=[N:18][C:19]([N:29]3[CH2:34][CH2:33][CH:32]([O:35][C:36]4[CH:43]=[CH:42][C:39]([C:40]#[N:41])=[CH:38][C:37]=4[F:44])[CH2:31][CH2:30]3)=[C:20]([NH:25][CH:26]([CH3:28])[CH3:27])[N:21]=2)[CH2:16]1)C1C=CC=CC=1>C1COCC1.[OH-].[OH-].[Pd+2]>[F:44][C:37]1[CH:38]=[C:39]([CH:42]=[CH:43][C:36]=1[O:35][CH:32]1[CH2:31][CH2:30][N:29]([C:19]2[N:18]=[C:17]3[CH2:16][NH:15][CH2:24][CH2:23][C:22]3=[N:21][C:20]=2[NH:25][CH:26]([CH3:28])[CH3:27])[CH2:34][CH2:33]1)[C:40]#[N:41].[C:3]([OH:5])([C:2]([F:7])([F:6])[F:1])=[O:4]
Reactant: CC(C)Nc1nc2c(nc1N1CCC(Oc3ccc(C#N)cc3F)CC1)CN(Cc1ccccc1)CC2
Agent: [Pd+2]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: CC(C)Nc1nc2c(nc1N1CCC(Oc3ccc(C#N)cc3F)CC1)CNCC2
Temperature: 23 °C
Reaction time: 4 h

Procedure:
A mixture of 4-((1-(6-benzyl-2-(isopropylamino)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-yl)piperidin-4-yl)oxy)-3-fluorobenzonitrile 2,2,2-trifluoroacetate (579 mg, 0.942 mmol) and Pd(OH)2 (20 wt % Pd (dry basis) on carbon, wet, Degussa Type E101 NEW, 198 mg, 0.283 mmol) in THF (10 mL) was stirred under H2 (1.899 mg, 0.942 mmol) at 23° C. for 4 h. The mixture was filtered, rinsed with THF, concentrated via rotary evaporation, and dried in vacuo to give the title compound as a TFA salt (494 mg, 100%) as a brown oil. ESI-MS m/z [M+H]+ 411.4.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C@:8]2([CH3:17])[C:13]([F:15])([F:14])[CH2:12][O:11][C:10]([NH2:16])=[N:9]2)[CH:7]=1.[CH3:19][C:20]1[C:21]([C:25](O)=[O:26])=[N:22][O:23][CH:24]=1>>[NH2:16][C:10]1[O:11][CH2:12][C:13]([F:14])([F:15])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:25]([C:21]3[C:20]([CH3:19])=[CH:24][O:23][N:22]=3)=[O:26])[CH:3]=[CH:4][C:5]=2[F:18])([CH3:17])[N:9]=1
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)OCC1(F)F
Reactant: Cc1conc1C(=O)O
Product: Cc1conc1C(=O)Nc1ccc(F)c([C@@]2(C)N=C(N)OCC2(F)F)c1

Procedure:
The condensation of (R)-4-(5-amino-2-fluoro-phenyl)-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate XI-1) and 4-methyl-isoxazole-3-carboxylic acid following procedure I yielded the title compound as a white solid. MS (ISP): m/z=369.2 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)[N:11]([CH3:21])[C:12]=2[S:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:33]1[S:34][CH:35]=[CH:36][N:37]=1)CCC>C1(C)C=CC=CC=1.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:20][C:17]1[CH:18]=[CH:19][C:14]([S:13][C:12]2[N:11]([CH3:21])[C:10]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)=[N:9][C:8]=2[C:5]2[CH:6]=[CH:7][C:2]([C:33]3[S:34][CH:35]=[CH:36][N:37]=3)=[CH:3][CH:4]=2)=[CH:15][CH:16]=1
Reactant: Cn1c(-c2ccccn2)nc(-c2ccc(Br)cc2)c1Sc1ccc(Cl)cc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccs1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Cn1c(-c2ccccn2)nc(-c2ccc(-c3nccs3)cc2)c1Sc1ccc(Cl)cc1
Temperature: 150 °C

Procedure:
A mixture of 2-{4-(4-bromophenyl)-5-[(4-chlorophenyl)thio]-1-methyl-1H-imidazol-2-yl}pyridine (Example 15, 200 mg, 0.438 mmol), 2-(tributylstannyl)-1,3-thiazole (0.138 mL, 0.438 mmol), and tetrakis (50 mg, 0.044 mmol) was dissolved in toluene and heated at 150° C. for 20 min via microwave irradiation. The solvent was evaporated and the residue purified via column chromatography to afford the title compound. 1H NMR (500 MHz, (CD3)2CO): δ 8.71 (d, 1H), 8.40 (d, 1H), 8.40 (d, 2H), 8.32 (d, 2H), 8.00 (m, 1H), 7.90 (d, 1H), 7.63 (d, 1H), 7.46 (m, 1H), 7.36 (d, 2H), 7.20 (d, 2H), 4.18 (s, 3H). LCMS: m/z 461.0 (M+H)+. Human FAAH lysate assay: IC50=14.3 nM.
Reaction SMILES: [CH:1]([C:5]1[C:6]([OH:15])=[C:7]([CH:13]=[O:14])[CH:8]=[C:9]([CH:12]=1)[CH:10]=O)([CH2:3][CH3:4])[CH3:2].[CH3:16][C:17]1[CH:22]=[CH:21][C:20]([C:23](=[O:25])[CH3:24])=[CH:19][CH:18]=1.Cl>O1CCOCC1>[CH:1]([C:5]1[C:6]([OH:15])=[C:7]([CH:8]=[C:9](/[CH:10]=[CH:24]/[C:23](=[O:25])[C:20]2[CH:21]=[CH:22][C:17]([CH3:16])=[CH:18][CH:19]=2)[CH:12]=1)[CH:13]=[O:14])([CH2:3][CH3:4])[CH3:2]
Reactant: CCC(C)c1cc(C=O)cc(C=O)c1O
Reactant: CC(=O)c1ccc(C)cc1
Agent: Cl
Solvent: C1COCCO1
Product: CCC(C)c1cc(/C=C/C(=O)c2ccc(C)cc2)cc(C=O)c1O
Temperature: 80 °C
Reaction time: 2.5 h

Procedure:
A solution of 5-sec-butyl-4-hydroxyisophthalaldehyde of formula I (0.50 g, 3.05 mmol) and p-methyl acetophenone (0.41 g, 3.05 mmol) in dioxane (25 mL) was treated with conc.HCl (0.5 mL). The solution was heated at 80° C. for 2.5 h. Further, 0.5 mL of conc.HCl was added and reaction was continued for 2.5 h more. Most of the excess reagent was evaporated under reduced pressure, and the residue was suspended in water (50 mL) and extracted 3-fold with CHCl3 (50 mL). The combined organic layers were dried on Na2SO4, filtered, and concentrated to dryness under reduced pressure. The residue was chromatographed over silica gel (SiO2, 230-400 flash), eluting with a gradient of 4% ethyl acetate in hexane, which upon concentration provides (E)-3-sec-butyl-2-hydroxy-5-(3-oxo-3-p-tolylprop-1-enyl)benzaldehyde (General Formula III).
Reaction SMILES: [N:1]([CH:4]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[O:14])[CH2:5]1)=[C:2]=[O:3].[CH2:15]([OH:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.N1C=CC=CC=1>C1C=CC=CC=1>[CH2:15]([O:22][C:2]([NH:1][CH:4]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[O:14])[CH2:5]1)=[O:3])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C=NC1CC(=O)c2ccccc2C1
Reactant: OCc1ccccc1
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: O=C(NC1CC(=O)c2ccccc2C1)OCc1ccccc1
Temperature: 25 °C
Yield: 41.8 %

Procedure:
A solution of 3-isocyanato-1-oxo-1,2,3,4-tetrahydronaphthalene (10 g), benzyl alcohol (7.3 g), dry pyridine (3 mL), and benzene (50 mL) was refluxed for 90 min. At the conclusion of this period, the solution was cooled to room temperature, diluted with benzene (150 mL), and then washed with 5% aqueous hydrochloric acid solution (60 mL twice). The organic layer was dried and evaporated under vacuum to yield a residue. The residue was crystallized by dissolving in benzene (35 mL) and diluting with petroleum ether (25 mL). Crystals thus obtained were recrystallized in the same manner to obtain the title compound (6.6 g, mp 79.5–81.5° C.).
Reaction SMILES: [N:1]1([CH2:8][C:9]2[CH:10]=[C:11]([CH:17]=[CH:18][CH:19]=2)[O:12][CH2:13][CH2:14][CH2:15][NH2:16])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[C:21]1[S:25][C:24]([NH2:26])=[N:23][N:22]=1>>[N:1]1([CH2:8][C:9]2[CH:10]=[C:11]([CH:17]=[CH:18][CH:19]=2)[O:12][CH2:13][CH2:14][CH2:15][NH:16][C:21]2[S:25][C:24]([NH2:26])=[N:23][N:22]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Nc1nnc(Br)s1
Reactant: NCCCOc1cccc(CN2CCCCCC2)c1
Product: Nc1nnc(NCCCOc2cccc(CN3CCCCCC3)c2)s1

Procedure:
The compound is prepared by a method analogous to that of Example 51 from 3-[3-[(hexahydro-1H-azepin-1-yl) methyl]phenoxy]-1-propanamine and 5-bromo-1,3,4-thiadiazole-2-amine.