Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[O:25][CH2:26][CH:27]4[CH2:29][CH2:28]4)[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:3][CH2:2]1.Cl[C:31]([C@@H:33]([O:35]C(=O)C)[CH3:34])=[O:32]>>[OH:35][C@@H:33]([CH3:34])[C:31]([N:1]1[CH2:2][CH2:3][CH:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[O:25][CH2:26][CH:27]4[CH2:28][CH2:29]4)[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:5][CH2:6]1)=[O:32]
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Reactant: O=C(NC1CCNCC1)c1c[nH]c2c(-c3ccccc3OCC3CC3)ncnc12
Product: C[C@H](O)C(=O)N1CCC(NC(=O)c2c[nH]c3c(-c4ccccc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from 4-(2-cyclopropylmethoxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid piperidin-4-ylamide (example A162) and acetic acid (S)-1-chlorocarbonyl-ethyl ester the title compound is obtained as colorless solid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:15]([O:17]CC)=[O:16])[CH:7]=[C:8]2[C:12]=1[NH:11][N:10]=[C:9]2[CH2:13][CH3:14])[CH3:2].[Li+].[OH-].C(O)C>C1COCC1>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:15]([OH:17])=[O:16])[CH:7]=[C:8]2[C:12]=1[NH:11][N:10]=[C:9]2[CH2:13][CH3:14])[CH3:2]
Reactant: CCOC(=O)c1cc(OCC)c2[nH]nc(CC)c2c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOc1cc(C(=O)O)cc2c(CC)n[nH]c12
Temperature: 25 °C
Yield: 100.1 %

Procedure:
To a solution of ethyl 7-ethoxy-3-ethyl-1H-indazole-5-carboxylate (389 mg, 1.48 mmol) in THF (13 mL) was added 1 M LiOH (3.0 mL, 3.0 mmol). The mixture was heated at reflux overnight. To the reaction was added trace amounts of ethanol to aid in solubilizing materials. Continue heating at reflux for an additional 2 hours. The reaction was cooled to room temperature, concentrated, triturated with 1 N HCl, the filtered solids were then washed with water and air dried to provide the title compound (347 mg, 97%).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5](I)=[CH:4][CH:3]=1.[CH2:10]([O:17][CH2:18][CH:19]=[O:20])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[NH4+].[Cl-]>C1COCC1>[CH2:10]([O:17][CH2:18][CH:19]([C:5]1[C:6]([Cl:8])=[N:7][C:2]([Br:1])=[CH:3][CH:4]=1)[OH:20])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Clc1nc(Br)ccc1I
Reactant: O=CCOCc1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: OC(COCc1ccccc1)c1ccc(Br)nc1Cl
Temperature: -78 °C
Reaction time: 1 h
Yield: 95.4 %

Procedure:
6-Bromo-2-chloro-3-iodopyridine (1.50 g, 4.71 mmol) was dissolved in THF (15 mL) and cooled to −78° C., followed by addition of isopropylmagnesium chloride-lithium chloride complex (3.99 mL, 5.18 mmol). The mixture was stirred at −78° C. for 1 h. 2-(benzyloxy)acetaldehyde (0.849 g, 5.65 mmol) was added and the resulting mixture warmed to 0° C. and stirred for 2 h. The mixture was treated with saturated NH4Cl and extracted with ethyl acetate. The organic layer was washed with brine, dried (Na2SO4), filtered and concentrated in vacuo to gave 2-(benzyloxy)-1-(6-bromo-2-chloropyridin-3-yl)ethanol (1.54 g, yield: 95%). MS (M+H)+: 344.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=1[C:6](=[O:12])[NH:7]2.[C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH3:25])#[CH:18]>>[CH3:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[C:17]#[C:18][C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=1[C:6](=[O:12])[NH:7]2
Reactant: C#Cc1ccccc1C
Reactant: O=c1[nH]c2nccc(Cl)c2c2ccccc12
Product: Cc1ccccc1C#Cc1ccnc2[nH]c(=O)c3ccccc3c12
Yield: 65.9 %

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 160 using 83 (100 mg, 0.43 mmol) and 2-ethynyltoluene (0.08 mL, 0.65 mmol) to provide 257 (88 mg, 65% yield) as a tan solid. LC-MS (M+H=311 obsd.=311). 1H NMR (400 MHz, d6-DMSO): δ 9.79 (d, 1H), 8.48 (d, 1H), 8.42 (dd, 1H), 7.95 (m, 1H), 7.75 (m, 2H), 7.46 (m, 3H), 7.36 (m, 1H), 2.61 (s, 3H).
Reaction SMILES: CC1C=C(C)C=C(C)C=1S([O-])(=O)=O.[NH2:14][N+:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:16]=1.CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].[Br:37][C:38]1[CH:43]=[CH:42][C:41]([C:44](=[O:51])[C:45]#[C:46][CH2:47][CH2:48][CH2:49][CH3:50])=[CH:40][CH:39]=1>O>[CH2:24]([O:23][C:21]([C:17]1[CH:18]=[CH:19][C:20]2[N:15]([N:14]=[C:46]([CH2:47][CH2:48][CH2:49][CH3:50])[C:45]=2[C:44](=[O:51])[C:41]2[CH:42]=[CH:43][C:38]([Br:37])=[CH:39][CH:40]=2)[CH:16]=1)=[O:22])[CH3:25]
Reactant: CCOC(=O)c1ccc[n+](N)c1
Reactant: CCCCC#CC(=O)c1ccc(Br)cc1
Agent: Cc1cc(C)c(S(=O)(=O)[O-])c(C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCc1nn2cc(C(=O)OCC)ccc2c1C(=O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 45.6 %

Procedure:
A mixture of 13.8 g of ethyl 1-aminopyridinium 3-carboxylate 2,4,6-trimethylbenzenesulphonate (compound A) (Synthesis 1977, page 1, TAMURA, et al.), 150 ml of dimethylformamide, 5.7 g of potassium carbonate and 10 g of the product of Step A of Example 1 were stirred for 3 hours at room temperature and then 6.9 g of compound A and 2.85 g of potassium carbonate were added. The mixture was stirred for 2 hours. Then 6.9 g of compound A and 2.85 g of potassium carbonate were added and the mixture was stirred for 2 hours at ambient temperature. The mixture was taken up in water and extracted with ethyl acetate. Separation was carried out by chromatography on silica (essence G: 80/ethyl acetate: 20) to obtain 7.38 g of the expected product (M.p.≤50° C.) and 8.25 g of the corresponding isomer of Example 16.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.Cl.[OH:12][NH2:13].C([O-])(=O)C.[Na+]>C(O)C.O>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[N:13][OH:12])=[CH:5][CH:4]=1
Reactant: COc1ccc(C=O)cc1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1ccc(C=NO)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 115.4 %

Procedure:
4-Methoxybenzaldehyde (10.0 g, 73.4 mmol) was dissolved in 200 mL of ethanol. A solution of hydroxyamine hydrochloride (6.38 g, 91.8 mmol) in 50 mL of H2O was added followed by a solution of sodium acetate (12.1 g, 146.8 mmol) in 50 mL of H2O. The mixture was stirred at room temperature under N2 for 12 h. The ethanol was removed in vacuo and the aqueous mixture was extracted with EtOAc. The EtOAc solution was washed with brine, dried over MgSO4, and concentrated to afford 12.8 g of light yellow oil. 1H NMR showed it was 80% pure (92% yield). This material was taken into the next step without further purification. (CDCl3): δ2.15 (s, 1H); 3.83 (s, 3H); 6.92 (d, 2H); 7.50 (d, 2H); 8.10 (s, 1H).
Reaction SMILES: [C:1]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[NH2:17][C:18]1[O:22][N:21]=[C:20]([CH3:23])[C:19]=1[CH3:24]>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[CH3:23][C:20]1[C:19]([CH3:24])=[C:18]([NH:17][S:7]([C:4]2[CH:5]=[CH:6][C:1]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:2][CH:3]=2)(=[O:9])=[O:8])[O:22][N:21]=1
Reactant: Cc1noc(N)c1C
Reactant: O=S(=O)(Cl)c1ccc(-c2ccccc2)cc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: Cc1noc(NS(=O)(=O)c2ccc(-c3ccccc3)cc2)c1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 45 %

Procedure:
The 4-biphenylsulfonyl chloride from step (a) was added to a solution of 5-amino-3,4-dimethylisoxazole (250 mg, 2.2 mmol) and 4-(dimethyl)aminopyridine (5 mg) in dry pyridine (2.0 ml). The reaction mixture was stirred at room temperature for 4 h. Pyridine was removed under reduced pressure and the residue was partitioned between water and ethyl acetate. The organic layer was washed with 1N HCl (2×25 ml), brine (25 ml) and dried over anhydrous magnesium sulfate. Evaporation of the solvents left an oily residue that, after purification by column chromatography over silica gel (1% methanol in chloroform as eluent), yielded 337 mg (45%) of a white solid. Recrystallization from ethyl acetate/hexanes gave white crystals, m.p. 154-155° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH3:18])=[C:6]([CH:17]=1)[CH2:7][N:8]1[C:12]([O:13][CH3:14])=[N:11][N:10]([CH3:15])[C:9]1=[O:16].[C:19]([C:23]#[CH:24])([CH3:22])([CH3:21])[CH3:20].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>C(#N)C.C(OCC)(=O)C.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.[Cu]I>[CH3:20][C:19]([CH3:22])([CH3:21])[C:23]#[C:24][C:2]1[CH:3]=[CH:4][C:5]([CH3:18])=[C:6]([CH:17]=1)[CH2:7][N:8]1[C:12]([O:13][CH3:14])=[N:11][N:10]([CH3:15])[C:9]1=[O:16]
Reactant: C#CC(C)(C)C
Reactant: COc1nn(C)c(=O)n1Cc1cc(Br)ccc1C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COc1nn(C)c(=O)n1Cc1cc(C#CC(C)(C)C)ccc1C
Temperature: 25 °C
Reaction time: 31 h
Yield: 33 %

Procedure:
A mixture of 624 mg (2.0 mmol) of 4-(5-bromo-2-methylbenzyl)-5-methoxy-2-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one (the compound 299 of the present invention), 1.50 g (18.3 mmol) of tert-butyl acetylene, 67 mg (0.095 irmmol) of PdCl2(PPh3)2, 33 mg (0.17 mmol) of copper (I) iodide, 106 mg (0.40 mmol) of triphenylphosphine and 1.5 g of triethylamine in 8 ml of acetonitrile was stirred at room temperature under an atmosphere of nitrogen for 31 hours. The reaction mixture was diluted with ethyl acetate, washed with water, dried and concentrated. The residue was subjected to silica gel column chromatography (eluted with hexane:ethyl acetate=6:1) to obtain 0.21 g (0.66 mmol) of 4-{5-(3,3-dimethyl-1-butynyl)-2-methylbenzyl}-5-methoxy-2-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one (the compound 526 of the present invention).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6](I)[C:5]([O:9][CH3:10])=[CH:4][C:3]=1[Cl:11].[NH2:12][C@@H:13]([CH3:17])[C:14]([OH:16])=[O:15].C1(NN=CC2C=CC=CC=2O)C=CC=CC=1.O>CN(C=O)C.[Cu]I.CCOCC>[Br:1][C:2]1[C:3]([Cl:11])=[CH:4][C:5]([O:9][CH3:10])=[C:6]([NH:12][C@@H:13]([CH3:17])[C:14]([OH:16])=[O:15])[CH:7]=1
Reactant: C[C@H](N)C(=O)O
Reactant: COc1cc(Cl)c(Br)cc1I
Agent: [Cu]I
Agent: Oc1ccccc1C=NNc1ccccc1
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: O
Product: COc1cc(Cl)c(Br)cc1N[C@@H](C)C(=O)O
Temperature: 80 °C
Reaction time: 16 h
Yield: 63.8 %

Procedure:
A mixture of 1-bromo-2-chloro-5-iodo-4-methoxybenzene (3 g, 8.64 mmol), (S)-2-aminopropanoic acid (769 mg, 8.64 mmol), CuI (164 mg, 0.864 mmol), 2-hydroxybenzaldehyde phenylhydrazone (366 mg, 1.73 mmol), K3PO4.3H2O (4.6 g, 17.28 mmol) in DMF (10 mL) was stirred under argon at 80° C. for 16 h. The mixture was allowed to cool to RT, H2O and Et2O were added to the solution. The resulting solution was partitioned into two phases, the aqueous phase was separated, and the organic layer was extracted with 5% NaOH. The combined aqueous phase was acidified to pH 4 with 20% HCl, and then extracted with Et2O. The resulting organic layer was dried over MgSO4 and concentrated in vacuo to afford the desired product (1.7 g, 64% yield). ESI-MS m/z: 306.1[M+H]−
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[C:5]([CH3:11])([CH3:10])[C@:4]([C:13]2[CH:18]=[C:17]([NH2:19])[CH:16]=[CH:15][C:14]=2[F:20])([CH3:12])[N:3]=1.[F:21][C:22]([F:26])([F:25])[CH:23]=O.[B][B][B][B][B][B][B][B][B][B]>>[NH2:1][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[C:5]([CH3:10])([CH3:11])[C@:4]([C:13]2[CH:18]=[C:17]([NH:19][CH2:23][C:22]([F:26])([F:25])[F:21])[CH:16]=[CH:15][C:14]=2[F:20])([CH3:12])[N:3]=1
Reactant: CN1C(=O)C(C)(C)[C@@](C)(c2cc(N)ccc2F)N=C1N
Reactant: O=CC(F)(F)F
Agent: [B][B][B][B][B][B][B][B][B][B]
Product: CN1C(=O)C(C)(C)[C@@](C)(c2cc(NCC(F)(F)F)ccc2F)N=C1N

Procedure:
The reductive amination of (S)-2-amino-6-(5-amino-2-fluoro-phenyl)-3,5,5,6-tetramethyl-5,6-dihydro-3H-pyrimidin-4-one (intermediate J) and trifluoro-acetaldehyde using decaborane yielded the title compound as a colorless waxy solid. MS (ESI): m/z=361.3 [M+H]+.
Reaction SMILES: C[Si]([NH-])(C)C.C[Si]([NH-])(C)C.[Li+].[Li+].[CH3:13][S:14][CH:15]1[NH:18][C:17](=[O:19])[CH:16]1[CH:20]([O:22][C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=1)=[O:24])[CH3:21].Br[CH2:37][C:38]([O:40][CH2:41][C:42]1[CH:47]=[CH:46][C:45]([N+:48]([O-:50])=[O:49])=[CH:44][CH:43]=1)=[O:39]>O1CCCC1.CN(C=O)C.C(OCC)(=O)C.C1(C)C=CC=CC=1>[CH3:13][S:14][CH:15]1[N:18]([CH2:37][C:38]([O:40][CH2:41][C:42]2[CH:47]=[CH:46][C:45]([N+:48]([O-:50])=[O:49])=[CH:44][CH:43]=2)=[O:39])[C:17](=[O:19])[CH:16]1[CH:20]([O:22][C:23]([O:25][CH2:26][C:27]1[CH:28]=[CH:29][C:30]([N+:33]([O-:35])=[O:34])=[CH:31][CH:32]=1)=[O:24])[CH3:21]
Reactant: CSC1NC(=O)C1C(C)OC(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: O=C(CBr)OCc1ccc([N+](=O)[O-])cc1
Agent: C[Si](C)(C)[NH-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CSC1C(C(C)OC(=O)OCc2ccc([N+](=O)[O-])cc2)C(=O)N1CC(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 48.7 %

Procedure:
2.2 ml of 1M solution of lithium bis(trimethylsilylamide) are added over the course of 5 minutes to a stirred mixture, at 70° C., of 680 mg (2 mmol) of 4-methylthio-3-[1-(p-nitrobenzyloxycarbonyloxy)-ethyl]-azetidin-2-one and 602 mg (2.2 mmol) of p-nitrobenzyl bromoacetate in 2 ml of dry tetrahydrofuran and 2 ml of dry DMF. The reaction mixture is stirred at -70° C. for 30 minutes, diluted with 30 ml of ethyl acetate and 70 ml of toluene and washed twice with dilute NaCl solution. The organic phase is dried over MgSO4 and filtered, and the solvent is evaporated in vacuo. The residue is chromatographed over 65 g of silica gel using toluene:ethyl acetate 4:1, to give 520 mg of a yellow oil. IR spectrum in CH2Cl2 : 2920, 2850, 1765, 1750, 1605, 1520, 1355, 1345 cm-1.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([NH:6][CH2:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:5].[C:14]1([C:20]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:21][C:22](O)=[O:23])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)(Cl)Cl.C(OCC)(=O)C.C(N(CC)CC)C>[C:31]1([C:20]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:21][C:22]([NH:2][CH2:3][C:4]([NH:6][CH2:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:5])=[O:23])[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: CCOC(=O)CCNC(=O)CN
Reactant: O=C(O)CC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)CCNC(=O)CNC(=O)CC(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 2 h
Yield: 51.4 %

Procedure:
To a solution of 1.52 g of ethyl 3-{(2-aminoacetyl)amino}-propionate monohydrochloride and 2.18 g of 3,3,3-triphenylpropionic acid in 20 ml of chloroform, 1.46 g of 1-hydroxybenzotriazole monohydrate, 2.07 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide monohydrochloride and 2.0 ml of triethylamine were successively added at room temperature by the order stated, followed by 2 hours' stirring at the same temperature. The reaction liquid was diluted with ethyl acetate and washed successively with aqueous saturated sodium bicarbonate solution, 1N-hydrochloric acid and water, and filtered through cerite. The filtrate was dried on anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resultant residue was purified by means of silica gel column chromatography (eluting solvent: hexane/ethyl acetate=4/1-chloroform/methanol=10/1) to provide 1.7 g of the title compound.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][CH2:10][C:11]([O:13]C)=[O:12])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[ClH:15]>O>[ClH:15].[N:1]1([CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)CCCCN1CCCCC1
Agent: Cl
Solvent: O
Product: O=C(O)CCCCN1CCCCC1
Reaction time: 16 h

Procedure:
23.5 g. (0.117 mole) of methyl δ-piperidinovalerate was dissolved in a combination of 125 ml. of concentrated hydrochloric acid and 125 ml. of water and refluxed with stirring for 16 hours. The excess water was removed using reduced pressure (water aspirator) to give a semi-solid residue which was triturated with acetone, filtered and dried. 21.0 g. (79%) of colorless crystals of δ-piperidinovaleric acid hydrochloride was obtained with a m.p. of 202°-204° C.
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([NH:28][CH2:29][CH:30]1[CH2:35][CH2:34][CH:33]([C:36]([OH:38])=[O:37])[CH2:32][CH2:31]1)=[O:27])=[O:7])([CH3:4])([CH3:3])[CH3:2].[B-](F)(F)(F)F.CN(C(O[N:52]1[C:57](=[O:58])[CH2:56][CH2:55][C:53]1=[O:54])=[N+](C)C)C>C1COCC1.C(#N)C>[O:54]=[C:53]1[CH2:55][CH2:56][C:57](=[O:58])[N:52]1[O:37][C:36]([CH:33]1[CH2:34][CH2:35][CH:30]([CH2:29][NH:28][C:26](=[O:27])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:31][CH2:32]1)=[O:38]
Reactant: CC(C)(C)OC(=O)CCCCCCCCCCCCCCCCCCC(=O)NCC1CCC(C(=O)O)CC1
Reactant: CN(C)C(ON1C(=O)CCC1=O)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: CC#N
Product: CC(C)(C)OC(=O)CCCCCCCCCCCCCCCCCCC(=O)NCC1CCC(C(=O)ON2C(=O)CCC2=O)CC1
Yield: 87.8 %

Procedure:
To a solution of 4-[(19-tert-butoxycarbonylnonadecanoylamino)methyl]cyclohexanecarboxylic acid (5.56 g) in THF (100 ml) was added a solution of TSTU (3.42 g) in acetonitrile (25 ml). The mixture was concentrated in vacuo after stirring over night. The solid residue was recrystallized from acetonitrile to give 4-[(19-tert-butoxycarbonylnonadecanoylamino)methyl]cyclohexanecarboxylic acid 2,5-dioxopyrrolidin-1-yl ester (5.76 g, 88%).
Reaction SMILES: [C:1]1([S:7]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH2:19][C:20]([OH:22])=O)=[CH:13][CH:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.CN(C)CCCN=C=NCC.O.[OH:36][N:37]1C2C=CC=CC=2N=N1.NOC1CCCCO1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>CN(C=O)C>[OH:36][NH:37][C:20](=[O:22])[CH2:19][CH2:18][CH2:17][C:14]1[CH:15]=[CH:16][C:11]([NH:10][S:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:9])=[O:8])=[CH:12][CH:13]=1
Reactant: O=C(O)CCCc1ccc(NS(=O)(=O)c2ccccc2)cc1
Reactant: On1nnc2ccccc21
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: O=C(CCCc1ccc(NS(=O)(=O)c2ccccc2)cc1)NO
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 13.3 %

Procedure:
To a solution 41 (800 mg, 2.59 mmol) in DMF (20 mL) at room temperature were added 1-(3-Dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (EDC, 593 mg, 3.12 mmol), and 1-Hydroxybenzotriazole hydrate (HOBT, 524 mg, 3.89 mmol). The mixture was stirred 20 min. at room temperature then NH2OTHP (455 mg, 3.89 mmol) was added. The resulting mixture was heated at 50° C. for 24 h then the DMF solvent was evaporated under reduced pressure and the residue was dissolved in CH2Cl2, washed with a saturated aqueous solution of NaHCO3. The combined organic extracts were dried over (MgSO4) then evaporated. The crude compound was purified by flash chromatography using Hexane/acetone (7:3) as solvent mixture. The residue was then dissolved in MeOH (30 mL) then 10-camphorsulfonic acid (CSA, 300 mg, 1.30 mmol) was added. The mixture was stirred 2 h at 50° C. then the solvents were condensed under reduced pressure at room temperature to avoid thermal decomposition. The crude was purified by flash chromatography using CH2Cl2/MeOH (9:1) as solvent mixture giving the title compound 42 (115 mg, 13%) as a yellowish solid.
Reaction SMILES: [C:1]1([CH:9]=[CH:8][CH:7]=[C:5]([OH:6])[C:3]=1[OH:4])[OH:2].[CH:10](OC)(OC)[O:11][CH3:12].ClC(Cl)C>ClCCCl>[OH:2][C:1]1[C:3]2[O:4][CH:10]([O:11][CH3:12])[O:6][C:5]=2[CH:7]=[CH:8][CH:9]=1
Reactant: COC(OC)OC
Reactant: Oc1cccc(O)c1O
Solvent: CC(Cl)Cl
Solvent: ClCCCl
Product: COC1Oc2cccc(O)c2O1

Procedure:
A mixture of pyrogallol (25 parts), trimethyl orthoformate (32 parts) and 1,2-dichloroethane (250 parts) was heated with continuous distillation of the solvent for 4 hours. The volume of solvent was kept constant by simultaneous addition of dichloroethane. The mixture was then washed three times with water and dried over sodium sulphate. Removal of the solvent under reduced pressure and distillation of the residue gave 4-hydroxy-2-methoxy-1,3-benzodioxole, boiling point 104°-105° C/1 mmHg.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([O:8][CH:9]2[CH2:14][CH2:13][C:12](=O)[CH2:11][CH2:10]2)[CH:3]=1.[NH:16]1[CH2:19][CH:18]([NH:20][C:21]([CH2:23][NH:24][C:25](=[O:36])[C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=2)=[O:22])[CH2:17]1>>[CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([O:8][CH:9]2[CH2:14][CH2:13][CH:12]([N:16]3[CH2:19][CH:18]([NH:20][C:21]([CH2:23][NH:24][C:25](=[O:36])[C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:33])[F:34])[CH:27]=4)=[O:22])[CH2:17]3)[CH2:11][CH2:10]2)[CH:3]=1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Reactant: Cc1ccnc(OC2CCC(=O)CC2)c1
Product: Cc1ccnc(OC2CCC(N3CC(NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)c1

Procedure:
The title compounds were prepared as white solids from the reductive amination of 4-(4-methyl-pyridin-2-yloxy)-cyclohexanone (as prepared in the previous step) and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide (as prepared in Example 2 Step C) using the procedure described in Step D of Example 1.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][C:9]1[N:13]([C@@H:14]2[CH2:19][CH2:18][N:17]([CH2:20][C@@H:21]3[CH2:29][C:28]4[C:23](=[CH:24][CH:25]=[C:26]([NH:30][C:31](=[O:35])[CH:32]([CH3:34])[CH3:33])[CH:27]=4)[CH2:22]3)[CH2:16][C@H:15]2[OH:36])[C:12]2[CH:37]=[CH:38][C:39]([CH3:41])=[CH:40][C:11]=2[N:10]=1.C(N(C(C)C)CC)(C)C.[CH3:51][S:52](Cl)(=[O:54])=[O:53].C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:8][C:9]1[N:13]([CH:14]2[CH2:19][CH2:18][N:17]([CH2:20][C@H:21]3[CH2:29][C:28]4[C:23](=[CH:24][CH:25]=[C:26]([NH:30][C:31](=[O:35])[CH:32]([CH3:34])[CH3:33])[CH:27]=4)[CH2:22]3)[CH2:16][CH:15]2[O:36][S:52]([CH3:51])(=[O:54])=[O:53])[C:12]2[CH:37]=[CH:38][C:39]([CH3:41])=[CH:40][C:11]=2[N:10]=1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1ccc2c(c1)nc(C)n2[C@@H]1CCN(C[C@H]2Cc3ccc(NC(=O)C(C)C)cc3C2)C[C@H]1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc2c(c1)nc(C)n2C1CCN(C[C@@H]2Cc3ccc(NC(=O)C(C)C)cc3C2)CC1OS(C)(=O)=O
Reaction time: 1 h

Procedure:
A solution of N-{(S)-2-[(3R,4R)-4-(2,5-Dimethyl-benzoimidazol-1-yl)-3-hydroxy-piperidin-1-ylmethyl]-indan-5-yl}-isobutyramide; compound with trifluoro-acetic acid (235 mg; 0.51 mmol) and diisopropylethylamine (122 mL; 0.7 mmol) in CH2Cl2 was treated with methanesulfonyl chloride (47 mL; 0.6 mmol). The reaction mixture was stirred for 1 h and then poured into saturated NaHCO3. The aqueous phase was extracted three times with CH2Cl2 and the combined organic layers were dried over Na2SO4. Filtration and removal of volatiles under reduced pressure gave a brown solid from which the methanesulfonic acid 4-(2,5-dimethyl-benzoimidazol-1-yl)-1-((R)-5-isobutyrylamino-indan-2-ylmethyl)-piperidin-3-yl ester was isolated by flash chromatography (0-10% CH3OH in EtOAc) as a waxy solid (171 mg; 62%)