Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N[C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].N([O-])=[O:11].[Na+]>OS(O)(=O)=O.O>[OH:11][C@@H:2]([CH2:3][CH:4]([CH3:6])[CH3:5])[C:7]([OH:9])=[O:8]
Reactant: O=N[O-]
Reactant: CC(C)C[C@H](N)C(=O)O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: CC(C)C[C@H](O)C(=O)O
Temperature: 0 °C
Reaction time: 24 h
Yield: 28203.2 %

Procedure:
To a stirred solution of L-Leu-OH (5.0 g, 38.2 mmol) in 1 N H2SO4 (50 mL) at 0° C. was slowly added over 11/2 h a solution of sodium nitrite (NaNO2) (7.5 g, 0.11 mmol) in water (20 mL) while maintaining the temperature at 0° C. The reaction mixture was gradually warmed to R.T., stirred for 24 h, and concentrated to give a white solid. The solid was extracted with ether (5×50 mL). The combined organic layers were dried (MgSO4), filtered and concentrated to give (2S)-2-hydroxy-4-methylpentanoic acid as an oil (4.1 g, 81.2%): 1H NMR (CDCl3, 300 MHz) δ0.98 (d, 6 H, J=12.0 Hz), 1.57-1.67 (m, 2 H), 1.82-1.93 (m, 1 H), 4.36 (t, 1 H, J=6.0 Hz) ppm.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([N:11]2[CH2:20][CH2:19][C@@H:18]3[C@H:13]([O:14][CH2:15][C:16](=O)[NH:17]3)[CH2:12]2)[C:9]=1[Cl:10])[C:5]#[N:6].B.CSC>O1CCCC1>[NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([N:11]2[CH2:20][CH2:19][C@@H:18]3[C@H:13]([O:14][CH2:15][CH2:16][NH:17]3)[CH2:12]2)[C:9]=1[Cl:10])[C:5]#[N:6]
Reactant: N#Cc1cc(N)c(Cl)c(N2CC[C@H]3NC(=O)CO[C@@H]3C2)c1
Agent: B
Solvent: C1CCOC1
Solvent: CSC
Product: N#Cc1cc(N)c(Cl)c(N2CC[C@H]3NCCO[C@@H]3C2)c1
Temperature: 90 °C
Yield: 94.3 %

Procedure:
(+/−)-3-amino-4-chloro-5-((4aR,8aR)-2-oxohexahydro-1H-pyrido[3,4-b][1,4]oxazin-6(7H)-yl)benzonitrile (Example 370B) (144 mg, 0.469 mmol) was dissolved in Tetrahydrofuran (10 ml) in a 20 ml scintillation vial. Borane-methyl sulfide complex (2 M in THF) (0.493 ml, 0.986 mmol) was added, the vial was capped and the reaction mixture heated to 90° C. for 3 hours. The reaction mixture was partitioned between EtOAc and aq. NH4Cl solution. The organic layer was washed with brine, then dried over MgSO4, filtered and evaporated to dryness to give (+/−)-3-amino-4-chloro-5-((4aR,8aR)-hexahydro-1H-pyrido[3,4-b][1,4]oxazin-6(7H)-yl)benzonitrile (129.5 mg)
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:25])=[C:5]([C:16]([O:23][CH3:24])=[C:17]([O:21][CH3:22])[C:18]=1[O:19][CH3:20])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([OH:15])=[C:11]([CH:14]=1)[CH:12]=[O:13].C(=O)([O-])[O-].[Na+].[Na+].[CH2:32](Br)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>CC(C)=O>[CH3:1][O:2][C:3]1[C:4]([CH3:25])=[C:5]([C:16]([O:23][CH3:24])=[C:17]([O:21][CH3:22])[C:18]=1[O:19][CH3:20])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:15][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[C:11]([CH:14]=1)[CH:12]=[O:13]
Reactant: BrCc1ccccc1
Reactant: COc1c(C)c(Cc2ccc(O)c(C=O)c2)c(OC)c(OC)c1OC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: COc1c(C)c(Cc2ccc(OCc3ccccc3)c(C=O)c2)c(OC)c(OC)c1OC
Yield: 75.2 %

Procedure:
5-(3,4,5,6-Tetramethoxy-2-methylbenzyl)-2-hydroxybenzaldehyde (0.100 g, 0.290 mol) was dissolved in acetone (10 ml) and, after addition of anhydrous sodium carbonate (0.080 g, 0.579 mmol) and benzyl bromide (0.059 g, 0.347 mmol), the mixture was heated to reflux for 3 hours. The reaction solution was filtered and the residue obtained by concentration of the filtrate was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to give the title compound (0.114 g, 0.261 mmol, 90%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[Br:11]N1C(=O)CCC1=O>>[Br:11][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccccc1[N+](=O)[O-]
Product: O=[N+]([O-])c1ccccc1CBr

Procedure:
1-Methyl-2-nitro-benzene was reacted with N-bromosuccinimide as described in the synthesis of Example 1e to obtain the title compound.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:9]2[N:13]3[CH:14]=[CH:15][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[C:17]([F:18])[C:12]3=[N:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].[F:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[C:26]([O:33][CH3:34])[CH:25]=1>>[F:8][C:7]1[CH:6]=[CH:5][C:4]([C:9]2[N:13]3[CH:14]=[CH:15][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[C:17]([F:18])[C:12]3=[N:11][CH:10]=2)=[CH:3][C:2]=1[C:27]1[CH:28]=[CH:29][C:24]([F:23])=[CH:25][C:26]=1[O:33][CH3:34]
Reactant: COc1cc(F)ccc1B(O)O
Reactant: CC(C)(O)c1ccn2c(-c3ccc(F)c(Cl)c3)cnc2c1F
Product: COc1cc(F)ccc1-c1cc(-c2cnc3c(F)c(C(C)(C)O)ccn23)ccc1F
Yield: 4 %

Procedure:
2-[3-(3-Chloro-4-fluorophenyl)-8-fluoroimidazo[1,2-α]pyridin-7-yl]-propan-2-ol and 4-fluoro-2-methoxybenzeneboronic acid were coupled in the same way as in Example 30 to give 2-[3-(2,4′-difluoro-2′-methoxy-biphenyl-5-yl)-8-fluoroimidazo[1,2-α]pyridin-7-yl]propan-2-ol as an off-white solid (5 mg, 4%): m/z (ES+) 413 [MH+].
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH2:9])=[C:5](I)[CH:4]=1.[Br:11][C:12]1[CH:13]=[C:14](B(O)O)[C:15]([F:18])=[N:16][CH:17]=1>[F-].[K+].C(#N)C.O>[Br:11][C:12]1[CH:13]=[C:14]([C:5]2[CH:4]=[C:3]([O:2][CH3:1])[N:8]=[CH:7][C:6]=2[NH2:9])[C:15]([F:18])=[N:16][CH:17]=1
Reactant: OB(O)c1cc(Br)cnc1F
Reactant: COc1cc(I)c(N)cn1
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COc1cc(-c2cc(Br)cnc2F)c(N)cn1
Temperature: 95 °C
Yield: 70.6 %

Procedure:
A mixture of 6-methoxy-4-iodopyridin-3-amine (9.5 g, 38 mmol), 5-bromo-2-fluoropyridin-3-ylboronic acid (16.7 g, 76 mmol), and 1,1′-[bis(diphenylphosphino)ferrocene] dichloropalladium(II) (1.5 g, 2 mmol) in 1N aqueous potassium fluoride (95 mL) and acetonitrile (200 mL) was heated at 95° C. for 16 h. The cooled reaction mixture was diluted with water (100 mL) and extracted with DCM (3×100 mL). The combined organic layer was dried over sodium sulfate, filtered, and evaporated to afford a residue which was purified by flash chromotagraphy (silica, 120 g column, ISCO, 0-40% ethyl acetate in hexanes) to afford the title compound as a yellow/orange solid (8.0 g, 71%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH:14]2[N:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:10]([CH2:11][C:12]([C:39]3[S:40][CH:41]=[C:42]([CH2:44][CH2:45][CH2:46][OH:47])[N:43]=3)=[C:13]2[C:24](=[O:38])[N:25]([CH:35]2[CH2:37][CH2:36]2)[CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[C:28]=2[Cl:34])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:48][C:49]1[CH:54]=[CH:53][CH:52]=[C:51]([F:55])[C:50]=1O>>[C:1]([O:5][C:6]([N:8]1[CH2:15][CH:14]2[N:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:10]([CH2:11][C:12]([C:39]3[S:40][CH:41]=[C:42]([CH2:44][CH2:45][CH2:46][O:47][C:50]4[C:49]([F:48])=[CH:54][CH:53]=[CH:52][C:51]=4[F:55])[N:43]=3)=[C:13]2[C:24](=[O:38])[N:25]([CH:35]2[CH2:36][CH2:37]2)[CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[C:28]=2[Cl:34])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC2CC(c3nc(CCCO)cs3)=C(C(=O)N(Cc3cccc(Cl)c3Cl)C3CC3)C(C1)N2C(=O)OC(C)(C)C
Reactant: Oc1c(F)cccc1F
Product: CC(C)(C)OC(=O)N1CC2CC(c3nc(CCCOc4c(F)cccc4F)cs3)=C(C(=O)N(Cc3cccc(Cl)c3Cl)C3CC3)C(C1)N2C(=O)OC(C)(C)C

Procedure:
This compound is prepared from compound E4 and 2,6-difluorophenol, according to the above-described procedure A. LC-MS: tR=1.24 min, ES+: 819.40.
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)(C)=O.[CH2:9]([O:16][C:17]1[N:18]=[N:19][C:20]([C:31]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[CH2:32])=[CH:21][C:22]=1[O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>CS(C)=O.O1CCCC1>[CH2:9]([O:16][C:17]1[N:18]=[N:19][C:20]([C:31]2([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH2:4][CH2:32]2)=[CH:21][C:22]=1[O:23][CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: C=C(c1ccccc1)c1cc(OCc2ccccc2)c(OCc2ccccc2)nn1
Reactant: C[S+](C)(C)=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: c1ccc(COc2cc(C3(c4ccccc4)CC3)nnc2OCc2ccccc2)cc1
Yield: 23 %

Procedure:
To a suspension of sodium hydride (0.487 g, 12.17 mmol, 60% in mineral oil) in DMSO (33.8 ml) stirring under nitrogen was added trimethyl sulfoxonium iodide (2.68 g, 12.17 mmol) in 4 portions over 20 minutes. A solution of 3,4-bis(benzyloxy)-6-(1-phenylethenyl)pyridazine (Intermediate 25; 3.2 g, 8.11 mmol) in tetrahydrofuran (50.7 ml) was added via a dropping funnel over 90 minutes before the reaction was left to stir at room temperature for 18 hours. The resulting mixture was concentrated, poured into ice water and extracted with ethyl acetate (×3). The organics portion was dried (MgSO4), filtered and concentrated to give a brown oil. The crude oil was purified by silica chromatography (eluting with 0-50% ethyl acetate in petrol) to yield 3,4-bis(benzyloxy)-6-(1-phenylcyclopropyl)pyridazine as a yellow oil (yield=23%).
Reaction SMILES: [CH2:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH2:5][CH2:4][N:3]([C:12](=[O:14])[CH3:13])[CH2:2]1.[N+:15]([O-])([OH:17])=[O:16]>C(O)(=O)C.S(=O)(=O)(O)O>[N+:15]([C:10]1[CH:9]=[CH:8][C:7]2[CH2:1][CH2:2][N:3]([C:12](=[O:14])[CH3:13])[CH2:4][CH2:5][C:6]=2[CH:11]=1)([O-:17])=[O:16]
Reactant: CC(=O)N1CCc2ccccc2CC1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: CC(=O)N1CCc2ccc([N+](=O)[O-])cc2CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 85 %

Procedure:
1-(1,2,4,5-Tetrahydrobenzo[d]azepin-3-yl)ethanone (3.8 g) was dissolved in a 2:1 mixture of acetic acid and 96% sulphuric acid (15 ml), then the mixture was cooled to 0° C. and a 3:2 mixture of 65% nitric acid and 96% sulphuric acid (2.5 ml) was added dropwise, while the temperature was maintained below 5° C. The mixture was stirred for additional 30 min, then poured into crushed ice (300 g) and extracted with ethyl acetate. The organic phase was washed with 5% aqueous NaHCO3, dried over Na2SO4 and concentrated to afford a crude material (4.3 g). Filtration through a silica gel pad (DCM/MeOH, 98/2) yielded the title compound as a yellow solid (4.0 g, 85% yield).
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[C:10]2[C:5](=[CH:6][C:7]([N+:15]([O-:17])=[O:16])=[C:8]([NH:11]C(=O)C)[CH:9]=2)[NH:4][C:3]1=[O:18].[CH2:20](I)[CH2:21][CH2:22][CH2:23][CH3:24].C([O-])([O-])=O.[K+].[K+].CC#N>CC(O)C.Cl>[NH2:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][C:7]=1[N+:15]([O-:17])=[O:16])[N:4]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[C:3](=[O:18])[C:2]2([CH3:1])[CH3:19]
Reactant: CCCCCI
Reactant: CC(=O)Nc1cc2c(cc1[N+](=O)[O-])NC(=O)C2(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CC(C)O
Product: CCCCCN1C(=O)C(C)(C)c2cc(N)c([N+](=O)[O-])cc21
Yield: 73.6 %

Procedure:
Analogously to general procedure (I) N-(3,3-dimethyl-6-nitro-2-oxo-2,3-dihydro-1H-indol-5-yl)-acetamide (50 g) is alkylated using pentyliodide (76.8 g; 0.38 mol) and K2CO3 (53.6 g; 0.38 mol) at 60° C. for 24 h. After aqueous work-up the crude material is de-acetylated under reflux in 2-propanol (500 ml) and hydrochloric acid (6 N; 300 ml). After aqueous work-up pure 5-amino-3,3-dimethyl-6-nitro-1-pentyl-1,3-dihydro-indol-2-one (40.7 g) is obtained by re-crystallization from MeCN.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[N:8]([CH2:13][CH2:14][O:15][CH3:16])[C:9](=[O:12])[CH2:10][NH:11][C:5]2=[N:4][CH:3]=1.C[Sn](C)(C)[C:19]1[CH:20]=[CH:21][C:22]([C:25]([OH:28])([CH3:27])[CH3:26])=[N:23][CH:24]=1>CN(C)C=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[OH:28][C:25]([C:22]1[N:23]=[CH:24][C:19]([C:2]2[N:7]=[C:6]3[N:8]([CH2:13][CH2:14][O:15][CH3:16])[C:9](=[O:12])[CH2:10][NH:11][C:5]3=[N:4][CH:3]=2)=[CH:20][CH:21]=1)([CH3:27])[CH3:26]
Reactant: COCCN1C(=O)CNc2ncc(Br)nc21
Reactant: CC(C)(O)c1ccc([Sn](C)(C)C)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: COCCN1C(=O)CNc2ncc(-c3ccc(C(C)(C)O)nc3)nc21
Temperature: 140 °C
Yield: 38 %

Procedure:
7-Bromo-1-(2-methoxyethyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one (1 equiv), 2-(5-(trimethylstannyl)pyridin-2-yl)propan-2-ol (See Example 5.E) (1 equiv) and dichlorobis(triphenylphosphine)-palladium(II) (0.2 equiv) were suspended in dimethylformamide. The reaction was purged with nitrogen and was heated to 140° C. for 2 h. The reaction was cooled to room temperature, filtered through Celite and washed with ethyl acetate. Volatiles were removed under reduced pressure and the resulting purple slurry was purified using silica gel column chromatography (0-100% (5% methanol in ethyl acetate) in hexanes). The desired fractions were combined and organic volatiles removed under reduced pressure. The solid was triturated in 5% ethyl acetate in hexanes and washed with hexanes to afford the desired product in 38% yield. 1H NMR (400 MHz, DMSO-d6) δ (ppm) 9.02 (d, J=1.6 Hz, 1H), 8.27 (s, 1H), 8.24 (dd, J=8.6, 2.3 Hz, 1H), 7.71 (d, J=0.8 Hz, 1H), 7.69 (s, 1H), 5.25 (s, 1H), 4.28 (t, J=6.2 Hz, 2H), 4.20 (d, 2H), 3.60 (t, J=6.2 Hz, 2H), 3.26 (s, 3H), 1.46 (s, 6H); MS (ESI) m/z 344.3 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:3]=1[NH:4][C:5](=O)[CH2:6][CH2:7][O:8][CH2:9][CH2:10][CH3:11].C(N(CC)CC)C.C(Cl)(Cl)=O.[NH:29]1[CH:33]=[CH:32][N:31]=[CH:30]1>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:3]=1[N:4]=[C:5]([N:29]1[CH:33]=[CH:32][N:31]=[CH:30]1)[CH2:6][CH2:7][O:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCOCCC(=O)Nc1ccc(Cl)cc1Cl
Reactant: c1c[nH]cn1
Agent: O=C(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCCOCCC(=Nc1ccc(Cl)cc1Cl)n1ccnc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.5 %

Procedure:
6.9 g of 2',4'-dichloro-3-(propoxy)propionanilide and 8 g of triethylamine were dissolved in 30 ml of chloroform and 3.7 g of phosgene were introduced thereto at 0° to 10° C. under cooling with ice. After raising the temperature of the solution to room temperature, the solution was stirred for 2 hours, and then, 2 g of imidazole were added thereto. The mixture was heated under reflux for 2 hours. After completion of the reaction, the resulting reaction solution was cooled to room temperature, washed with water and dried over anhydrous magnesium sulfate. Removal of chloroform from the solution by distillation gave 7.7 g of the desired compound. (nD29 1.5688)
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]2[CH:8]=[C:9]([C:18]3[CH:19]=[N:20][N:21]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH:22]=3)[N:10]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:4]=2[CH:3]=1.[CH3:30][O:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[NH2:38]>>[C:26]([O:25][C:23]([N:21]1[CH:22]=[C:18]([C:9]2[N:10]([C:11]([O:13][C:14]([CH3:16])([CH3:15])[CH3:17])=[O:12])[C:4]3[CH:3]=[C:2]([NH:38][C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=4[O:31][CH3:30])[N:7]=[CH:6][C:5]=3[CH:8]=2)[CH:19]=[N:20]1)=[O:24])([CH3:28])([CH3:27])[CH3:29]
Reactant: CC(C)(C)OC(=O)n1cc(-c2cc3cnc(Br)cc3n2C(=O)OC(C)(C)C)cn1
Reactant: COc1ccccc1N
Product: COc1ccccc1Nc1cc2c(cn1)cc(-c1cnn(C(=O)OC(C)(C)C)c1)n2C(=O)OC(C)(C)C
Yield: 48 %

Procedure:
The title compound was prepared in 48% yield from compound 10 and 2-methoxyphenyl amine using the method described for Preparation 35. 1H-NMR (CDCl3, 500 MHz): δ 1.53 (s, 9H), 1.69 (s, 9H), 3.92 (s, 3H), 6.58 (d, J=0.95 Hz, 1H), 6.91-6.99 (m, 3H), 7.08 (br s, 1H), 7.66 (m, 1H), 7.83 (d, J=0.95 Hz, 1H), 7.92-7.95 (m, 1H), 8.33 (d, J=0.63 Hz, 1H), 8.49 (d, J=0.95 Hz, 1H).
Reaction SMILES: [N:1]1([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=O.[CH2:19]([NH2:23])[CH2:20][CH2:21][CH3:22]>>[N:1]1([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([NH:23][CH2:19][CH2:20][CH2:21][CH3:22])=[O:5]
Reactant: CCCCN
Reactant: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Product: CCCCNC(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1

Procedure:
12.5 g. (0.05 M) of Z-Pro-OH is converted to active ester as in Example 3 (a) and, with the addition of 5.7 ml. (0.06 M) of n-butylamine, it is stirred for 12 hours. The dioxane is distilled off under reduced pressure and the residue is dissolved in ethyl acetate. The ethyl acetate layer is washed with 5% NaHCO3 and 1N-HCl, followed by drying. The ethyl acetate is distilled off under reduced pressure and, following the addition of petroleum benzin, the residue is filtered. The crude product is recrystallized from ethyl acetate. Yield 14.0 g. (92.7%); melting point: 94.0°-95.0° C, optical rotation [α]D21 -39.6° (c=0.54, in N,N-dimethylformamide)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[C:17]([CH3:18])=[CH:16][CH:15]=[C:14]1[CH3:19].[Cl:20][C:21]([Cl:25])([F:24])[S:22]Cl>ClCCl>[Cl:12][C:4]1[CH:5]=[C:6]([C:8]([F:10])([F:11])[F:9])[CH:7]=[C:2]([Cl:1])[C:3]=1[N:13]1[C:14]([CH3:19])=[CH:15][C:16]([S:22][C:21]([Cl:25])([Cl:20])[F:24])=[C:17]1[CH3:18]
Reactant: FC(Cl)(Cl)SCl
Reactant: Cc1ccc(C)n1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Solvent: ClCCl
Product: Cc1cc(SC(F)(Cl)Cl)c(C)n1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Temperature: 0 °C
Yield: 89.6 %

Procedure:
To a cooled (0° C.) solution of 3.00 g (9.74 mmoles) of the 1-(2,6-dichloro-4-trifluoromethylphenyl)-2,5-dimethylpyrrole prepared above in 60 mL of dichloromethane was added dropwise 1.03 mL (1.67 g, 9.86 mmoles) of dichlorofluoromethanesulfenyl chloride in 5 mL of dichloromethane solution. The mixture was maintained at 0° C. for 3 hours and then washed with a saturated aqueous solution of NaHCO3. Removal of solvent under reduced pressure afforded a black oil which was chromatographed on silica gel with a 1% EtOAc in hexane eluent to give 3.85 g (90%) of 1-(2,6-dichloro-4-trifluoromethylphenyl)-2,5-dimethyl-3-(dichlorofluoromethylthio)pyrrole as a yellow oil: 1H NMR (CDCl3): δ2.00 (s, 3H), 2.10 (s, 3H), 6.27 (s, 1H), 7.80 (s, 2H).
Reaction SMILES: C(OC([N:8]([C:10](=[O:23])[CH:11]=[CH:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=1)[NH2:9])=O)(C)(C)C.Cl>C(O)C>[CH:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:21]=[CH:22][C:13]=1[CH:12]=[CH:11][C:10]([NH:8][NH2:9])=[O:23]
Reactant: CC(C)(C)OC(=O)N(N)C(=O)C=Cc1ccc2ccccc2c1
Agent: Cl
Solvent: CCO
Product: NNC(=O)C=Cc1ccc2ccccc2c1
Yield: 91.6 %

Procedure:
To a solution of the above hydrazine carboxylic acid tert butyl ester (4.5 g, 14.4 mmol) in ethanol (25 ml) was added 2N hydrochloric acid and the mixture was refluxed for 1 h. The solvent was evaporated in vacuo and the residue was dissolved in water (100 ml) and made alkaline to pH=9 with 1N sodium hydroxide. The precipitated was filtered off and washed with water (2×30 ml) and heptane (2×30 ml) and dried in vacuo at 50° C. which afforded 2.8 g (92%) of 3-naphthalen-2-yl-acrylic acid hydrazide as a solid.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[F:22])=[CH:10][C:9]=1[NH:23][C:24](=[O:36])[CH2:25][C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([C:34]#[N:35])[CH:29]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[C:15]#[C:14][C:11]1[CH:12]=[CH:13][C:8]2[N:7]=[C:26]([C:28]3[CH:29]=[C:30]([CH:31]=[CH:32][CH:33]=3)[C:34]#[N:35])[CH2:25][C:24](=[O:36])[NH:23][C:9]=2[CH:10]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C#Cc2ccccc2F)cc1NC(=O)CC(=O)c1cccc(C#N)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1cccc(C2=Nc3ccc(C#Cc4ccccc4F)cc3NC(=O)C2)c1

Procedure:
Prepared from [2-[3-(3-cyano-phenyl)-3-oxo-propionylamino]-4-(2-fluoro-phenylethynyl)-phenyl]-carbamic acid tert.-butyl ester (Example K97) by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a yellow solid (82 mg).
Reaction SMILES: [H-].[Na+].[H][H].[Br-].[C:6]1([P+:12]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)CCCCC(O)=O)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>CS(C)=O>[P:12]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: O=C(O)CCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: [H][H]
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: c1ccc(P(c2ccccc2)c2ccccc2)cc1

Procedure:
Under a nitrogen atmosphere a suspension of 1.49 g of NaH (80% dispersion in mineral oil) in 40 ml of DMSO was warmed to 60°-65° C., with stirring and with exclusion of humidity for 3 hours, until no more hydrogen was evolved. It was cooled to 5°-8° C. and 10.93 g of triphenyl-(4-carboxybutyl)-phosphonium bromide was added all at once. The material was kept at 15° C. and stirred until all the reagent was dissolved, giving a DMSO solution of the ylide (C6H5)3P-CH(-) -(CH2)3COO(-).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([C:11]2[CH2:12][CH2:13][N:14]([CH2:17][CH2:18][CH2:19][NH:20][C:21]([N:23]3[C@@H:28]([C:29]4[CH:34]=[CH:33][C:32]([F:35])=[C:31]([F:36])[CH:30]=4)[C:27]([C:37]([O:39][CH3:40])=[O:38])=[C:26]([CH2:41][O:42][CH3:43])[NH:25][C:24]3=[O:44])=[O:22])[CH2:15][CH:16]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2]>[Pd]>[C:1]([NH:4][C:5]1[CH:6]=[C:7]([CH:11]2[CH2:12][CH2:13][N:14]([CH2:17][CH2:18][CH2:19][NH:20][C:21]([N:23]3[C@@H:28]([C:29]4[CH:34]=[CH:33][C:32]([F:35])=[C:31]([F:36])[CH:30]=4)[C:27]([C:37]([O:39][CH3:40])=[O:38])=[C:26]([CH2:41][O:42][CH3:43])[NH:25][C:24]3=[O:44])=[O:22])[CH2:15][CH2:16]2)[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: COCC1=C(C(=O)OC)[C@H](c2ccc(F)c(F)c2)N(C(=O)NCCCN2CC=C(c3cccc(NC(C)=O)c3)CC2)C(=O)N1
Agent: [Pd]
Product: COCC1=C(C(=O)OC)[C@H](c2ccc(F)c(F)c2)N(C(=O)NCCCN2CCC(c3cccc(NC(C)=O)c3)CC2)C(=O)N1
Reaction time: 8 h

Procedure:
This radiochemical synthesis was carried out by Amersham Pharmacia Biotech, Cardiff, Wales. A methanolic solution of methyl (4S)-3-({[3-(4-[3-(acetylamino)phenyl]-3,6-dihydro-1(2H)-pyridinyl)propyl]amino}carbonyl)-4-(3,4-difluorophenyl)-6-(methoxymethyl)-2-oxo-1,2,3,4-tetrahydro-5-pyrimidinecarboxylate was exposed to tritium gas at 1 atmosphere pressure in the presence of 5% palladium on carbon with stirring overnight to give the tritiated methyl (4S)-3-{[(3-{4-[3-(acetylamino)phenyl]-1-piperidinyl}propyl)amino]carbonyl}-4-(3,4-difluorophenyl)-6-(methoxymethyl)-2-oxo-1,2,3,4-tetrahydro-5-pyrimidinecarboxylate ((+)-isomer). After purification by reverse phase HPLC (Hypersil ODS, 4.6×100 mm, methanol:H2O:Et3N 10:90:1 to 100:0:1 in 15 min at 1.0 mL/min, with radiochemical and UV detection), this product was used as a radioligand in the MCH1 binding assays. The same procedure was carried out with H2 gas in place of 3H2 to afford the non-radioactive version of Compound A.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[C:8]1([CH2:14][C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]=2[OH:25])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O>N1C=CC=CC=1>[C:1]([O:25][C:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:23]=[CH:24][C:15]=1[CH2:14][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)(=[O:3])[CH3:2]
Reactant: Oc1c(Cc2ccccc2)ccc2ccccc12
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)Oc1c(Cc2ccccc2)ccc2ccccc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 81.9 %

Procedure:
A solution of acetic anhydride (3.27, 0.032 mol) in pyridine (50 mL) was stirred at 0°. 2-Phenylmethyl-1-naphthol (5.00 g, 0.021 mol) was added and the mixture was stirred while warming to room temperature. After 18 h, water was added and the mixture was extracted with ether. The ether phase was washed with dilute hydrochloric acid, then with water, then with brine and was dried over MgSO4. Concentration afforded a brown oil which was flash chromatographed (5% ethyl acetate/hexane). The resulting oil crystallized on standing and was recrystallized (hexane) to provide the title compound (4.75 g, 82%) as white needles: mp 67°-69°; NMR (CDCl3) 7.9-7.6 (m, 3H), 7.45 (m, 2H), 7.20 (m, 6H), 4.01 (s, 2H), 2.40 (s, 3H); IR (mull) 1760; Mass Spec (EI) 276 (9), 234 (100), 156 (20); Calcd. for C19H16O2;C-82.57 H-5.84., Found: C-82.66 H-5.93