Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:12]([SH:13])=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].C1C(=O)N(Cl)C(=O)C1.[Cl:22][C:23]1[C:31]([F:32])=[C:30]2[C:26]([CH:27]=[C:28]([CH:40]3[CH2:42][CH2:41]3)[N:29]2[C:33]2[CH:34]=[N:35][N:36]([CH2:38][CH3:39])[CH:37]=2)=[CH:25][CH:24]=1>C(Cl)Cl.O>[Cl:22][C:23]1[C:31]([F:32])=[C:30]2[C:26]([C:27]([S:13][C:12]3[C:2]([F:1])=[C:3]([CH:9]=[CH:10][CH:11]=3)[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[C:28]([CH:40]3[CH2:42][CH2:41]3)[N:29]2[C:33]2[CH:34]=[N:35][N:36]([CH2:38][CH3:39])[CH:37]=2)=[CH:25][CH:24]=1
Reactant: CCn1cc(-n2c(C3CC3)cc3ccc(Cl)c(F)c32)cn1
Reactant: CCOC(=O)c1cccc(S)c1F
Agent: O=C1CCC(=O)N1Cl
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)c1cccc(Sc2c(C3CC3)n(-c3cnn(CC)c3)c3c(F)c(Cl)ccc23)c1F
Reaction time: 2 h
Yield: 80.9 %

Procedure:
To a stirred solution of ethyl 2-fluoro-3-mercaptobenzoate 6 (2.8 g, 14.0 mmol) in CH2Cl2 (30 mL) under inert atmosphere was added NCS (1.9 g, 14.0 mmol) at RT and allowed to stir for 2 h. To this, compound 5 (3.9 g, 12.8 mmol) in CH2Cl2 (10 mL) was added at RT and stirred for 16 h. After completion of the reaction by TLC, the reaction mixture was diluted with water (100 mL) and extracted with CH2Cl2 (2×80 mL). The combined organic extracts were washed with water (2×200 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to obtain the crude. The crude was purified by triturating with n-pentane (2×50 mL) to afford 7 (5.2 g, 81%) as a pale yellow solid. 1H NMR (400 MHz, CDCl3): δ 7.66-7.7.60 (m, 3H), 7.18 (d, J=8.4 Hz, 1H), 7.08 (dd, J=8.4, 6.5 Hz, 1H), 6.93 (t, J=8.4 Hz, 1H), 6.79-6.75 (m, 1H), 4.40 (q, J=7.2 Hz, 2H), 4.26 (q, J=7.6 Hz, 2H), 1.74-1.68 (m, 1H), 1.56 (t, J=7.2 Hz, 3H), 1.41 (t, J=7.6 Hz, 3H), 1.08-1.04 (m, 2H), 0.89-0.84 (m, 2H); MS (ESI): m/z 502.5 (M+H+); HPLC: 97.5%; (column: Acquity BEH C-18 (50×2.1 mm, 1.7μ); RT 3.44 min; ACN: 0.025% TFA (aq); 0.5 mL/min.
Reaction SMILES: [O:1]=[C:2]1[N:7]2[C:8]3[C:13]([C:14]([CH2:15][CH2:16][NH2:17])=[C:6]2[CH2:5][CH2:4][CH2:3]1)=[CH:12][CH:11]=[CH:10][CH:9]=3.[Cl-].C[NH2+]C.[CH2:22]([N:24]([CH2:27]C)[CH2:25][CH3:26])C>CN(C)C=O>[CH3:27][N:24]([CH2:25][CH2:26][CH2:5][CH2:4][CH2:3][C:2]([NH:17][CH2:16][CH2:15][C:14]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]2[C:2](=[O:1])[CH2:3][CH2:4][CH2:5][C:6]=12)=[O:1])[CH3:22]
Reactant: NCCc1c2n(c3ccccc13)C(=O)CCC2
Reactant: CCN(CC)CC
Agent: C[NH2+]C
Agent: [Cl-]
Solvent: CN(C)C=O
Product: CN(C)CCCCCC(=O)NCCc1c2n(c3ccccc13)C(=O)CCC2
Temperature: 90 °C

Procedure:
8.9 g (0.022 mole) D4, 3.2 g (0.44 mole) dimethylammonium chloride and 6 g triethylamine were dissolved in 150 ml N,N-dimethylformamide and heated for 6 h at 90° C. The solvent was evaporated in vacuo and the residue extracted with 100 ml chloroform and 100 ml water. The organic layer was separated and dried. The solvent was evaporated and the residue crystallised from ethyl acetate.
Reaction SMILES: [Br:1][CH2:2][CH2:3]Br.[Cl:5][C:6]1[CH:7]=[C:8]([CH:11]=[C:12]([O:15][CH3:16])[C:13]=1[OH:14])[CH:9]=[O:10].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Br:1][CH2:2][CH2:3][O:14][C:13]1[C:12]([O:15][CH3:16])=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][C:6]=1[Cl:5]
Reactant: BrCCBr
Reactant: COc1cc(C=O)cc(Cl)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C=O)cc(Cl)c1OCCBr
Temperature: 25 °C
Reaction time: 16 h
Yield: 58.9 %

Procedure:
1,2-Dibromoethane (46 mL, 0.54 moles) was added to a mixture of 3-chloro-4-hydroxy-5-methoxybenzaldehyde (10 g, 54 mmoles) and potassium carbonate (37 g, 0.27 moles) in DMF (180 ml) and the resulting mixture was stirred vigorously at room temperature for 16 hours. The mixture was poured into water (100 mL) and extracted with ethyl acetate (2×100 mL). The combined organic phases were washed with saturated sodium chloride (150 mL), dried over MgSO4 and evaporated in vacuo to afford 9.33 g (59%) of 4-(2-bromoethoxy)-3-chloro-5-methoxybenzaldehyde. M.p. 52-54° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[NH:14][C:13](=[O:15])[CH:12]3[CH:8]([CH2:9][CH2:10][CH2:11]3)[N:7]([CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[C:6]=2[N:21]=1.[CH3:22]N(C)C=O.C(=O)([O-])[O-].[Cs+].[Cs+].IC>C(OCC)(=O)C.O>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[N:14]([CH3:22])[C:13](=[O:15])[CH:12]3[CH:8]([CH2:9][CH2:10][CH2:11]3)[N:7]([CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[C:6]=2[N:21]=1
Reactant: O=C1Nc2cnc(Cl)nc2N(C2CCCC2)C2CCCC12
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CI
Product: CN1C(=O)C2CCCC2N(C2CCCC2)c2nc(Cl)ncc21
Reaction time: 0.33 h

Procedure:
To a mixture of 0.68 g (0.0022 mole) of (rac)-6-chloro-4-cyclopentyl-2,3,3a,4,9,10a-hexahydro-1H-4,5,7,9-tetraaza-benzo[f]azulen-10-one (VI-68), 20 mL of dimethylformamide and 1.83 g (0.0056 mole) of cesium carbonate was added 1.254 g (0.0088 mole) of iodomethane. The mixture was stirred for 20 minutes, then diluted with ethyl acetate and water. The water layer was extracted twice with ethyl acetate and the combined ethyl acetate layers washed successively with water, then brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give 0.580 g of (rac)-6-chloro-4-cyclopentyl-9-methyl-2,3,3a,4,9,10a-hexahydro-1H-4,5,7,9-tetraazabenzo[f]azulen-10-one (VII-68), which was used in the next step without further purification.
Reaction SMILES: [CH2:1]([CH:3]1[CH:20]([OH:21])[CH:19]([CH3:22])[CH:18]=[C:17]([CH3:23])[CH:16]=[C:15]([O:24][CH3:25])[C:14](=[O:26])[O:13][CH:12]([CH:27]([CH:29]([OH:48])[CH:30]([CH3:47])/[C:31](=[N:41]\[O:42][CH2:43][C:44](O)=[O:45])/[CH:32]=[CH:33]/[CH:34]([CH3:40])[CH:35]([OH:39])/[CH:36]=[CH:37]/[CH3:38])[CH3:28])[CH:11]([O:49][CH3:50])[CH:10]=[CH:9][CH:8]=[C:7]([CH3:51])[CH2:6][CH:5]([CH3:52])[CH:4]1[OH:53])[CH3:2].C1C=CC2N(O)N=NC=2C=1.[N:64]1([CH:70]2[CH2:75][CH2:74][NH:73][CH2:72][CH2:71]2)[CH2:69][CH2:68][CH2:67][CH2:66][CH2:65]1.O>ClCCl>[N:64]1([CH:70]2[CH2:75][CH2:74][N:73]([C:44](=[O:45])[CH2:43][O:42]/[N:41]=[C:31](/[CH:32]=[CH:33]/[CH:34]([CH3:40])[CH:35]([OH:39])/[CH:36]=[CH:37]/[CH3:38])\[CH:30]([CH3:47])[CH:29]([OH:48])[CH:27]([CH:12]3[O:13][C:14](=[O:26])[C:15]([O:24][CH3:25])=[CH:16][C:17]([CH3:23])=[CH:18][CH:19]([CH3:22])[CH:20]([OH:21])[CH:3]([CH2:1][CH3:2])[CH:4]([OH:53])[CH:5]([CH3:52])[CH2:6][C:7]([CH3:51])=[CH:8][CH:9]=[CH:10][CH:11]3[O:49][CH3:50])[CH3:28])[CH2:72][CH2:71]2)[CH2:69][CH2:68][CH2:67][CH2:66][CH2:65]1
Reactant: C/C=C/C(O)C(C)/C=C/C(=N/OCC(=O)O)C(C)C(O)C(C)C1OC(=O)C(OC)=CC(C)=CC(C)C(O)C(CC)C(O)C(C)CC(C)=CC=CC1OC
Reactant: C1CCN(C2CCNCC2)CC1
Agent: C/C=C/C(O)C(C)/C=C/C(=N/OCC(=O)N1CCC(N2CCCCC2)CC1)C(C)C(O)C(C)C1OC(=O)/C(OC)=C/C(C)=C/C(C)C(O)C(CC)C(O)C(C)C/C(C)=C/C=C/C1OC
Agent: C/C=C/C(O)C(C)/C=C/C(=N/OCC(=O)O)C(C)C(O)C(C)C1OC(=O)/C(OC)=C/C(C)=C/C(C)C(O)C(CC)C(O)C(C)C/C(C)=C/C=C/C1OC
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Product: C/C=C/C(O)C(C)/C=C/C(=N/OCC(=O)N1CCC(N2CCCCC2)CC1)C(C)C(O)C(C)C1OC(=O)C(OC)=CC(C)=CC(C)C(O)C(CC)C(O)C(C)CC(C)=CC=CC1OC
Reaction time: 0.33 h

Procedure:
To a solution of compound of example 10 (10 mg) in dichloromethane (2 mL) dicyclohexylcarbodiimide (3 mg), and HOBT (2 mg) were added. After 20 min, 4-piperidino-piperidine 2.5 mg) was added. The reaction mixture was stirred for 18 h under nitrogen atmosphere. Cold water was added to the reaction mixture, the organic layer was separated; Reaction mixture was extracted with dichloromethane (3×5 mL). The combined organic layer was washed with water (2×5 mL). The organic layer was dried over sodium sulphate, and was concentrated. The crude product was purified by preparative HPLC [Eurospere-100, C18 column (250 mm×8 mm), mobile phase: acetonitrile-water (1:1 isocratic)] to obtain the title compound.
Reaction SMILES: [CH3:1][C:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][NH:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=2)=[CH:12][CH:11]=1)([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].Br[C:31]1[CH:36]=[CH:35][C:34]([Br:37])=[CH:33][N:32]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[Br:37][C:34]1[CH:35]=[CH:36][C:31]([N:18]([CH2:19][C:20]2[CH:21]=[CH:22][C:23]([C:26]([F:27])([F:28])[F:29])=[CH:24][CH:25]=2)[CH2:17][CH2:16][C:13]2[CH:14]=[CH:15][C:10]([O:9][C:2]([CH3:1])([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4])=[CH:11][CH:12]=2)=[N:32][CH:33]=1
Reactant: Brc1ccc(Br)nc1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(CCNCc2ccc(C(F)(F)F)cc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CCOC(=O)C(C)(C)Oc1ccc(CCN(Cc2ccc(C(F)(F)F)cc2)c2ccc(Br)cn2)cc1
Yield: 18.2 %

Procedure:
A solution of ethyl 2-methyl-2-[4-(2-{[4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]propanoate (3 g; 7.3 mmol) in 7 ml of dioxane was treated under nitrogen with 2,5-dibromopyridine (1.9 g; 8.1 mmol) and DIEA (1.4 ml; 8.1 mmol) and heated in a pressure tube for 2 days at 210C. Upon cooling, additional DIEA (1.4 ml) was added and heated 2 more days. Upon cooling, the reaction mixture was partitioned between ethyl acetate and 0.5N HCl. The organic phase was washed with 0.5N HCl and saturated brine, dried over sodium sulfate and concentrated. Purification by silica gel chromatography using an ethyl acetate-hexane gradient (5–60%) afforded the title compound (0.75 g; 18% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:15]([O:17][CH3:18])=[O:16])[C:5]2[O:9][C:8]([CH3:11])([CH3:10])[CH2:7][C:6]=2[C:12]=1[NH:13][CH3:14].[Cl:19][C:20]1[CH:21]=[N:22][CH:23]=[C:24]([Cl:29])[C:25]=1[N:26]=[C:27]=S>C(#N)C>[Cl:19][C:20]1[CH:21]=[N:22][CH:23]=[C:24]([Cl:29])[C:25]=1[NH:26][C:27]1[N:13]([CH3:14])[C:12]2[C:6]3[CH2:7][C:8]([CH3:11])([CH3:10])[O:9][C:5]=3[C:4]([C:15]([O:17][CH3:18])=[O:16])=[CH:3][C:2]=2[N:1]=1
Reactant: S=C=Nc1c(Cl)cncc1Cl
Reactant: CNc1c(N)cc(C(=O)OC)c2c1CC(C)(C)O2
Solvent: CC#N
Product: COC(=O)c1cc2nc(Nc3c(Cl)cncc3Cl)n(C)c2c2c1OC(C)(C)C2
Yield: 59.3 %

Procedure:
The title compound was prepared following the procedure described for step-1 of Intermediate-3 using methyl 5-amino-2,2-dimethyl-4-(methylamino)-2,3-dihydrobenzofuran-7-carboxylate (step-6 of Intermediate-49, 2.00 g, 8.0 mmol), 3,5-dichloro-4-isothiocyanatopyridine (Intermediate-2, 1.96 g, 9.6 mmol), N,N-di-isopropyl carbodimide (0.5 mL) and acetonitrile (10.0 mL) to afford 2.0 g of the desired product. 1HNMR (DMSO-d6): 1.47 (s, 6H), 3.49 (s, 2H), 3.56 (s, 3H), 3.73 (s, 3H), 7.10 (s, 1H), 8.46 (s, 2H), 10.79 (s, 1H).
Reaction SMILES: [CH2:1]=[O:2].[OH-].[K+].[NH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.O[C:13]1C=CC(C(C2C=CC(O)=CC=2)(C)C)=CC=1>C1(C)C=CC=CC=1.CO>[O:2]1[C:1]2[CH:13]=[CH:7][CH:8]=[CH:9][C:10]=2[CH2:11][CH2:6][NH:5]1
Reactant: C=O
Reactant: Nc1ccccc1
Reactant: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: Cc1ccccc1
Product: c1ccc2c(c1)CCNO2
Reaction time: 1 h

Procedure:
To a reactor are charged 66 parts of paraformaldehyde, 66 parts of methanol and 1 part of potassium hydroxide. The mixture is warmed and stirred until the paraform dissolves. While the temperature is maintained in the 25°-35° C. range, 93 parts of aniline are added to the paraform solution. Upon completion of the aniline addition the reaction is stirred for 15 minutes and then 114 parts of bisphenol A are added. The reaction is heated to atmospheric reflux and refluxed for 1 hour. After 1 hour, toluene (100 parts) is added to the reaction mixture while it is being cooled. A water layer forms which is removed. The toluene is removed by heating and applying reduced pressure until a temperature of 90° C. at 7 kPa pressure is reached. The appropriate solvent is added at this point. The devolitilized resin has a % closed dihydrobenzoxazine ring of 87%, and a calculated equivalent weight of 262.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([CH2:12][C:13]2[CH:30]=[CH:29][C:16]([C:17]([NH:19][C@@H:20]3[CH2:24][NH:23][CH2:22][C@@H:21]3[C:25]([O:27][CH3:28])=[O:26])=[O:18])=[CH:15][CH:14]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.C(N(C(C)C)CC)(C)C.[CH:40](=O)[CH:41]([CH3:43])[CH3:42].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCl.C(OCC)(=O)C>[CH2:40]([N:23]1[CH2:24][C@@H:20]([NH:19][C:17](=[O:18])[C:16]2[CH:15]=[CH:14][C:13]([CH2:12][C:10]3[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[N:3]=[C:2]([CH3:1])[CH:11]=3)=[CH:30][CH:29]=2)[C@@H:21]([C:25]([O:27][CH3:28])=[O:26])[CH2:22]1)[CH:41]([CH3:43])[CH3:42]
Reactant: COC(=O)[C@H]1CNC[C@H]1NC(=O)c1ccc(Cc2cc(C)nc3ccccc23)cc1
Reactant: CC(C)C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: COC(=O)[C@H]1CN(CC(C)C)C[C@H]1NC(=O)c1ccc(Cc2cc(C)nc3ccccc23)cc1
Yield: 79.1 %

Procedure:
The TFA salt (403a) (70 mg, 0.11 mmol) was dissolved in 1 mL of dichloromethane. Diisopropylethylamine (43 mg, 60 μL, 0.33 mmol), isobutyraldehyde (12 mg, 5 μL) and NaBH(OAc)3 (35 mg, 0.17 mmol) were added. The whole mixture was stirred until the reaction went to completion. The solution was diluted with ethyl acetate and washed with saturated NaHCO3, H2O and brine. The organic layer was dried over MgSO4. After filtration and concentration, the residue was purified on silica gel to provide methyl (3S,4S)-1-isobutyl-4-({4-[(2-methyl-4-quinolinyl)methyl]benzoyl}amino)-3-pyrrolidinecarboxylate (40 mg, 78%). MS (ES+): 460 (M+1).
Reaction SMILES: [C:1](Cl)(=[O:4])[CH2:2][CH3:3].[CH3:6][O:7][C:8](=[O:40])[CH2:9][C@H:10]1[C:14]2[CH:15]=[CH:16][C:17]([O:19][C@H:20]3[C:28]4[C:23](=[C:24]([CH2:33][N:34]5[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]5)[C:25]([C:29]([F:32])([F:31])[F:30])=[CH:26][CH:27]=4)[CH2:22][CH2:21]3)=[CH:18][C:13]=2[O:12][CH2:11]1>N1C=CC=CC=1>[CH3:6][O:7][C:8](=[O:40])[CH2:9][C@H:10]1[C:14]2[CH:15]=[CH:16][C:17]([O:19][C@H:20]3[C:28]4[C:23](=[C:24]([CH2:33][N:34]5[CH2:35][CH2:36][N:37]([C:1](=[O:4])[CH2:2][CH3:3])[CH2:38][CH2:39]5)[C:25]([C:29]([F:30])([F:31])[F:32])=[CH:26][CH:27]=4)[CH2:22][CH2:21]3)=[CH:18][C:13]=2[O:12][CH2:11]1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C(F)(F)F)c4CN3CCNCC3)ccc21
Reactant: CCC(=O)Cl
Solvent: c1ccncc1
Product: CCC(=O)N1CCN(Cc2c(C(F)(F)F)ccc3c2CC[C@H]3Oc2ccc3c(c2)OC[C@H]3CC(=O)OC)CC1

Procedure:
The title compound is prepared from propionyl chloride and {(S)-6-[(R)-4-piperazin-1-ylmethyl-5-trifluoromethyl-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester following a procedure analogous to that described for Intermediate 27; pyridine instead of triethylamine is used. LC (method 4): tR=0.97 min; Mass spectrum (ESI+): m/z=547 [M+H]+.
Reaction SMILES: C(O[C:6]([NH:8][C@H:9]([C:14]([OH:16])=O)[CH2:10][CH:11]([CH3:13])C)=O)(C)(C)C.[F:17][C:18]([F:38])([F:37])[C:19]1[CH:24]=[CH:23][C:22]([S:25]([N:28]2[CH2:32][C@H:31]3[C@H:33]([NH2:36])[CH2:34][CH2:35][C@H:30]3[CH2:29]2)(=[O:27])=[O:26])=[CH:21][CH:20]=1.[CH2:39](N1C[C@@H]2[C@@H](N)CC[C@@H]2C1)[C:40]1[CH:45]=CC=C[CH:41]=1>>[CH2:6]([NH:8][C@H:9]([C:14]([NH:36][C@H:33]1[C@H:31]2[C@H:30]([CH2:29][N:28]([S:25]([C:22]3[CH:21]=[CH:20][C:19]([C:18]([F:17])([F:37])[F:38])=[CH:24][CH:23]=3)(=[O:26])=[O:27])[CH2:32]2)[CH2:35][CH2:34]1)=[O:16])[CH2:10][CH2:11][CH3:13])[C:40]([CH3:45])([CH3:41])[CH3:39]
Reactant: N[C@H]1CC[C@@H]2CN(Cc3ccccc3)C[C@@H]21
Reactant: N[C@@H]1CC[C@H]2CN(S(=O)(=O)c3ccc(C(F)(F)F)cc3)C[C@H]21
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Product: CCC[C@H](NCC(C)(C)C)C(=O)N[C@@H]1CC[C@H]2CN(S(=O)(=O)c3ccc(C(F)(F)F)cc3)C[C@H]21

Procedure:
The title compound was prepared by substituting (S)-2-(neopentylamino)pentanoic acid from Step A of Example 246 for N-(tert-butoxycarbonyl)-L-leucine and (3aS,4R,6aR)-2-(4-(trifluoromethyl)phenylsulfonyl)octahydrocyclopenta[c]pyrrol-4-amine from Step A for (3aR,4S,6aS)-2-benzyloctahydrocyclopenta[c]pyrrol-4-amine in the procedure described in Example 221: 1H NMR (500 MHz, pyridine-d5) δ ppm 8.09-8.14 (m, 3H), 7.88-7.91 (m, 2H), 4.20-4.26 (m, 1H), 3.88 (dd, J=9.9, 2.9 Hz, 1H), 3.13-3.21 (m, 3H), 2.98 (dd, J=9.6, 7.4 Hz, 1H), 2.49-2.64 (m, 2H), 2.38 (d, J=11.2 Hz, 1H), 2.33 (d, J=11.2 Hz, 1H), 1.91-1.99 (m, 1H), 1.76-1.90 (m, 2H), 1.66-1.95 (m, 1H), 1.62-1.71 (m, 1H), 1.41-1.58 (m, 3H), 1.33 (ddt, J=9.5, 13.0, 6.5 Hz, 1H), 0.92 (s, 9H), 0.86 (t, J=7.3 Hz, 3H); MS (ESI+) m/z 504 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]([CH3:11])[C:3]1=[O:12].[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20][CH2:21][N:22]([CH3:31])[CH:23]([CH3:30])[CH2:24][CH2:25][CH2:26][C:27](O)=[O:28]>>[ClH:13].[CH3:11][N:4]1[C:5]2[CH:10]=[CH:9][C:8]([C:27](=[O:28])[CH2:26][CH2:25][CH2:24][CH:23]([N:22]([CH2:21][CH2:20][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[Cl:13])[CH3:31])[CH3:30])=[CH:7][C:6]=2[N:2]([CH3:1])[C:3]1=[O:12]
Reactant: CC(CCCC(=O)O)N(C)CCc1ccccc1Cl
Reactant: Cn1c(=O)n(C)c2ccccc21
Product: CC(CCCC(=O)c1ccc2c(c1)n(C)c(=O)n2C)N(C)CCc1ccccc1Cl
Product: Cl
Yield: 112.2 %

Procedure:
Using 484 mg (3 mmol) of 1,3-dimethyl-1,3-dihydro-2H-benzimidazol-2-one and 850 mg (3.3 mmol) of (±)-5-[[2-(2-chlorophenyl)ethyl](methyl)amino]hexanoic acid obtained in Reference Example 202 according to the same method as that of Example, a free base compound of the title compound (860 mg) was obtained as a pale yellow oil.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8]O)[CH:5]=[N:4][CH:3]=[N:2]1.S(Cl)([Cl:12])=O>>[Cl:12][CH2:8][CH2:7][CH2:6][N:1]1[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: OCCCn1cncn1
Reactant: O=S(Cl)Cl
Product: ClCCCn1cncn1

Procedure:
3-(1H-1,2,4-triazol-1-yl)-1-propanol (0.160 g, 1.3 mmol) was refluxed in thionylchloride (3 ml) for 2 h. The recation mixture was evaporated yielding the title product.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([CH3:9])[CH:5]=[C:4]([CH3:10])[N:3]=1.[C:11](O)(=O)[CH3:12].C(=O)([O-])[O-].[Na+].[Na+].[NH4+]>>[CH3:11][C:12]1[NH:1][C:2]2=[N:3][C:4]([CH3:10])=[CH:5][C:6]([CH3:9])=[C:7]2[N:8]=1
Reactant: Cc1cc(C)c(N)c(N)n1
Reactant: CC(=O)O
Agent: O=C([O-])[O-]
Agent: [NH4+]
Agent: [Na+]
Product: Cc1cc(C)c2nc(C)[nH]c2n1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
2,3-Diamino-4,6-dimethylpyridine (25.0 g, 0.182 mol) was suspended in polyphosphoric acid (465 g), and acetic acid (31.3 mL, 0.547 mol) was added to the suspention, followed by stirring at 100° C. for 3 hours. The reaction mixture was moved to ice water and sodium carbonate (345 g) was added in a little portion while stirring. Then, 28% aqueous ammonium solution was added to the residue to control the pH to 9 and the mixture was stirred for 1 hour. Precipitated crystals were collected by filtration, and was washed with water, and the obtained crystals were dried under reduced pressure at 40° C. overnight to obtain Compound P11 (26.2 g, 0.162 mol, 89%).
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[CH3:10][C:11]1[NH:15][N:14]=[C:13]([NH2:16])[CH:12]=1.C(N(CC)CC)C>CCO>[Br:1][C:2]1[C:3]([NH:16][C:13]2[CH:12]=[C:11]([CH3:10])[NH:15][N:14]=2)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: Cc1cc(N)n[nH]1
Reactant: Clc1ncc(Br)c(Cl)n1
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1cc(Nc2nc(Cl)ncc2Br)n[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.8 %

Procedure:
To a solution of 5-bromo-2,4-dichloropyrimidine (1.29 g, 5.66 mmol) in EtOH (15 ml) at room temperature was added a solution of 5-methyl-1H-pyrazol-3-amine (549 mg, 5.66 mmol) in EtOH (3 ml) and triethylamine (628 mg, 6.22 mmol) and the reaction mixture was stirred at room temperature overnight. The suspension was filtered and washed with water and dried to give the desired product as a white solid (1.27 g, 78%). NMR (CDCl3) 2.24 (s, 3H), 6.24 (s, 1H), 8.41 (s, 1H), 9.29 (s, 1H), 12.32 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:9](=[O:31])[CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]3[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=3)[CH2:15][CH2:14]2)[CH:5]=[CH:6][C:7]=1[CH3:8].CI.[CH3:34]C([O-])(C)C.[Na+].C1COCC1>O>[CH3:1][C:2]1[CH:3]=[C:4]([C:9](=[O:31])[CH2:10][CH2:11][CH2:12][N:13]2[CH2:14][CH2:15][CH:16]([C:19]3[CH:20]=[C:21]([N:25]([CH3:34])[C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=3)[CH2:17][CH2:18]2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1ccc(C(=O)CCCN2CCC(c3cccc(NC(=O)C(C)C)c3)CC2)cc1C
Reactant: CC(C)(C)[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CI
Product: Cc1ccc(C(=O)CCCN2CCC(c3cccc(N(C)C(=O)C(C)C)c3)CC2)cc1C
Temperature: 25 °C
Reaction time: 5 h
Yield: 88.9 %

Procedure:
A mixture of N-(3-{1-[4-(3,4-dimethylphenyl)-4-oxobutyl]-4-piperidinyl}phenyl)-2-methylpropanamide (15.0 mg, 0.0357 mmol), MeI (5.07 mg, 0.0357 mmol), NaOtBu (6.86 mg, 0.0714 mmol) and THF (1.00 mL) was stirred for 5 h at 25° C. The resulting crude mixture was diluted with water (10 mL), the aqueous layer was extracted with CH2Cl2 (3×20 mL). The combined organic layers were concentrated in vacuo and the residue was purified by preparative TLC using 4.0% of NH3 (2.0 M in methanol) in CH2Cl2 to afford the desired product N-(3-{1-[4-(3,4-dimethylphenyl)-4-oxobutyl]-4-piperidinyl}phenyl)-N,2-dimethylpropanamide (13.8 mg, 89.1%): 1H NMR (400 MHz, CDCl3) 7.76 (s, 1H), 7.72 (dd, 1H, J=1.8, 7.7 Hz), 7.33 (t, 1H, J=8.8 Hz), 7.22 (d, 1H, J=7.8 Hz), 7.18 (d, 1H, J=8.8 Hz), 7.01 (m, 2H), 3.24 (s, 3H), 3.10 (d, 1H, J=10.6 Hz), 3.00 (t, 1H, J=7.6 Hz), 2.49–2.44 (m, 4H), 2.33 (s, 6H), 2.112.10 (m, 2H), 1.99 (m, 1H), 1.79–1.77 (m, 4H), 1.26 (t, 2H, J=7.6 Hz), 1.02 (d, 6H, J=7.6 Hz); ESMS m/e: 435.2 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]([C:6]([CH2:8][CH2:9][C:10]([N:12]2[CH2:19][CH2:18][CH2:17][C@H:13]2[C:14]([OH:16])=[O:15])=[O:11])=[O:7])=[CH:4][CH:3]=1.[Br:22]Br>Br.C(O)(=O)C.C(OCC)(=O)C.CCCCCC.C(O)(=O)C>[Br:22][CH:8]([C:6](=[O:7])[C:5]1[CH:20]=[CH:21][C:2]([F:1])=[CH:3][CH:4]=1)[CH2:9][C:10]([N:12]1[CH2:19][CH2:18][CH2:17][C@H:13]1[C:14]([OH:16])=[O:15])=[O:11]
Reactant: BrBr
Reactant: O=C(CCC(=O)N1CCC[C@H]1C(=O)O)c1ccc(F)cc1
Agent: Br
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: O=C(c1ccc(F)cc1)C(Br)CC(=O)N1CCC[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 10.26 g. of 1-[3-(4-fluorobenzoyl)propionyl]-L-proline (Example 17) in 100 ml. of acetic acid is added 3 drops of 30% hydrogen bromide in acetic acid. A solution of 5.6 g. of bromine in 20 ml. of acetic acid is then added dropwise and the mixture is stirred at room temperature overnight. The mixture is evaporated to 1/3 its volume, poured into ice and water and extracted with dichloromethane. The organic extract is washed twice with water and then with saline, dried over magnesium sulfate and evaporated to dryness in vacuo with moderate heat, giving a white glass. This glass is scraped from the flask giving 12.2 g. of white powder. This powder is dissolved in ethyl acetate-hexane-acetic acid (75:25:2), placed on a 11/2"×20" silica gel column and eluted with the same solvent system, taking 100 ml. cuts with a 300 ml. fore-cut and a 400 ml. hold back volume. Cuts 2, 5 and 6 are combined and re-columned in the same manner. Cut 2 gives the desired product as 2.0 g. of a white glass.
Reaction SMILES: C(C(OC1C=C(C)C=CC=1C)C1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1/[C:11](=[CH:16]\[CH3:17])/[C:12]([O:14][CH3:15])=[O:13])(=O)C.O1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>>[C:12]([C:11]1[C:16]([CH3:17])=[CH:28][C:29]([O:30][CH2:31][C:32]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2/[C:11](=[CH:16]\[CH3:17])/[C:12]([O:14][CH3:15])=[O:13])=[C:7]([CH3:8])[CH:6]=1)([OH:14])=[O:13]
Reactant: C1COCCO1
Reactant: C/C=C(/C(=O)OC)c1ccccc1C(Oc1cc(C)ccc1C)C(C)=O
Product: C/C=C(/C(=O)OC)c1ccccc1COc1cc(C)c(C(=O)O)cc1C

Procedure:
In a similar manner to the process for precursor δ), 9.6 g of methyl 2-[2-(acetyl-2,5-dimethylphenoxymethyl)phenyl]E-but-2-enoate in 60 ml of dioxane were reacted to give the carboxylic acid. After concentrating on a rotary evaporator a yellow oil remained which in addition to 70% of the title compound contained a further 30% of the diacid formed by hydrolysis of the methyl butanoate.