Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.Br[CH:22]([CH3:36])[CH2:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]#[C:32][CH2:33][CH2:34][OH:35])=[CH:27][CH:26]=1.CCN(CC)CC>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:15]2[CH2:16][CH2:17][N:18]([CH2:36][CH2:22][CH2:23][O:24][C:25]3[CH:30]=[CH:29][C:28]([C:31]#[C:32][CH2:33][CH2:34][OH:35])=[CH:27][CH:26]=3)[CH2:19][CH2:20]2)=[CH:4][CH:3]=1
Reactant: CC(Br)COc1ccc(C#CCCO)cc1
Reactant: Clc1ccc([C@@H](c2ccccc2)N2CCNCC2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: OCCC#Cc1ccc(OCCCN2CCN([C@H](c3ccccc3)c3ccc(Cl)cc3)CC2)cc1
Yield: 73 %

Procedure:
[(1R)(4-chlorophenyl)phenylmethyl]piperazine (1.6 g, 5.6 mmol) and 4-[4-(2-bromopropoxy)phenyl]but-3-yn-1-ol (2.0 g, 7.04 mmol) were dissolved in dichloromethane (10 mL). Et3N (1 mL, 7.04 mmol) was added dropwise, the solution was heated at reflux under Ar overnight. The solvent was evaporated and the compound was purified by silica gel chromatography, eluted with ethyl acetate. 2.0 g of the title compound were obtained as a white solid.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:19]=[CH:18][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH3:17])=[O:8])=[CH:5][CH:4]=1.[OH-].[Na+].CO.C1C[O:27][CH2:26]C1>>[CH3:26][O:27][CH2:2][C:3]1[CH:19]=[CH:18][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH3:17])=[O:8])=[CH:5][CH:4]=1
Reactant: COc1ccccc1NC(=O)c1ccc(CCl)cc1
Reactant: C1CCOC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COCc1ccc(C(=O)Nc2ccccc2OC)cc1
Reaction time: 14 h
Yield: 92.9 %

Procedure:
4-Chloromethyl-N-(2-methoxyphenyl)benzamide (138 mg, 0.50 mmol) was dissolved in a methanol-THF (1:1) mixture solution (6 ml) to which was subsequently added 10% sodium hydroxide aqueous solution (3 ml) at room temperature. After 14 hours of stirring at the same temperature, the reaction solution was subjected to 3 hours of ultrasonic treatment. After removing the organic solvent by evaporation, the resulting residue was extracted with methylene chloride and dried on anhydrous magnesium sulfate. After removing the solvent by evaporation, the resulting colorless oily material was purified by silica gel column chromatography (ether:hexane=1:2) to obtain 126 mg (92.9%) of the title compound in the form of colorless oil.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][N:14]([C:17](=[O:23])[CH2:18][CH2:19][C:20]([OH:22])=O)[CH2:13][CH2:12]1)([CH3:4])([CH3:3])[CH3:2].[CH:24]1([CH2:27][NH:28][S:29]([NH2:32])(=[O:31])=[O:30])[CH2:26][CH2:25]1.CC1C=CC=C([N+]([O-])=O)C=1C(OC(=O)C1C([N+]([O-])=O)=CC=CC=1C)=O.C(N(CC)CC)C>O.C(#N)C>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][N:14]([C:17](=[O:23])[CH2:18][CH2:19][C:20]([NH:32][S:29](=[O:31])(=[O:30])[NH:28][CH2:27][CH:24]2[CH2:26][CH2:25]2)=[O:22])[CH2:13][CH2:12]1)([CH3:3])([CH3:4])[CH3:2]
Reactant: NS(=O)(=O)NCC1CC1
Reactant: CC(C)(C)c1ccccc1N1CCN(C(=O)CCC(=O)O)CC1
Agent: Cc1cccc([N+](=O)[O-])c1C(=O)OC(=O)c1c(C)cccc1[N+](=O)[O-]
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)c1ccccc1N1CCN(C(=O)CCC(=O)NS(=O)(=O)NCC2CC2)CC1
Temperature: 25 °C
Yield: 20.9 %

Procedure:
A mixture of 4-[4-(2-tert-butylphenyl)piperazin-1-yl]-4-oxobutanoic acid obtained in Example 53 (500 mg), N-(cyclopropylmethyl)sulfamide (248 mg), 2-methyl-6-nitrobenzoic anhydride (692 mg), N,N-dimethylaminopyridine (192 mg), triethylamine (0.656 mL), and acetonitrile (10 mL) was stirred at room temperature for over-night. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to provide the title compound (148 mg, 21%) as a colorless solid.
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]1([S:13]([NH:16][C:17]2[CH:18]=[C:19]([C@@H:23]([OH:43])[CH2:24][NH:25][C:26]([CH3:42])([CH3:41])[CH2:27][CH2:28][N:29]3[C:37]4[C:32](=[CH:33][C:34]([C:38]([OH:40])=[O:39])=[CH:35][CH:36]=4)[CH:31]=[CH:30]3)[CH:20]=[CH:21][CH:22]=2)(=[O:15])=[O:14])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Cl.[CH:45]([N:48]([CH:52]([CH3:54])[CH3:53])[CH2:49][CH2:50]Cl)([CH3:47])[CH3:46]>CN(C=O)C.C(OCC)(=O)C>[C:7]1([S:13]([NH:16][C:17]2[CH:18]=[C:19]([C@@H:23]([OH:43])[CH2:24][NH:25][C:26]([CH3:41])([CH3:42])[CH2:27][CH2:28][N:29]3[C:37]4[C:32](=[CH:33][C:34]([C:38]([O:40][CH2:50][CH2:49][N:48]([CH:52]([CH3:54])[CH3:53])[CH:45]([CH3:47])[CH3:46])=[O:39])=[CH:35][CH:36]=4)[CH:31]=[CH:30]3)[CH:20]=[CH:21][CH:22]=2)(=[O:15])=[O:14])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CC(C)(CCn1ccc2cc(C(=O)O)ccc21)NC[C@H](O)c1cccc(NS(=O)(=O)c2ccccc2)c1
Reactant: CC(C)N(CCCl)C(C)C
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)N(CCOC(=O)c1ccc2c(ccn2CCC(C)(C)NC[C@H](O)c2cccc(NS(=O)(=O)c3ccccc3)c2)c1)C(C)C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Potassium tert. butoxide (58 mg, 0.58 mmol) is added to a solution of 1-{3-[(R)-2-[3-(phenylsulphonylamino)-phenyl]-2-hydroxy-ethylamino]-3-methyl-butyl}-1H-indole-5-carboxylic acid [free base (Zwitterion) of Example 6; 300 mg, 0.58 mmol] in 2 ml DMF. Then the reaction mixture is stirred for 10 minutes at RT and 2-diisopropylamino-ethyl chloride hydrochloride (115 mg, 0.58 mmol) is added. After 72 hours stirring at RT the reaction mixture is diluted with 30 ml of ethyl acetate and extracted four times with 15 ml ice water. The organic phase is dried on magnesium sulphate, acidified with about 0.5 ml TFA and the solvent is eliminated in vacuo. The crude product is chromatographed on Microsorb C18-reverse-phase [acetonitrile (0.1% TFA)/water (0.13% TFA)=10:90→100:0].
Reaction SMILES: [F:1][C:2]([C:12]1[CH:17]=[CH:16][C:15](I)=[CH:14][CH:13]=1)([CH3:11])[CH2:3][NH:4][S:5]([CH:8]([CH3:10])[CH3:9])(=[O:7])=[O:6].[C:19]([C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1)([OH:21])=[O:20].C(=O)([O-])[O-].[K+].[K+].O>O1CCOCC1.O>[F:1][C:2]([C:12]1[CH:17]=[CH:16][C:15]([C:25]2[CH:26]=[CH:27][C:22]([C:19]([OH:21])=[O:20])=[CH:23][CH:24]=2)=[CH:14][CH:13]=1)([CH3:11])[CH2:3][NH:4][S:5]([CH:8]([CH3:10])[CH3:9])(=[O:7])=[O:6]
Reactant: O=C(O)c1ccc(B(O)O)cc1
Reactant: CC(C)S(=O)(=O)NCC(C)(F)c1ccc(I)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)S(=O)(=O)NCC(C)(F)c1ccc(-c2ccc(C(=O)O)cc2)cc1
Temperature: 100 °C
Reaction time: 18 h
Yield: 30.7 %

Procedure:
Scheme VI, Step A′: Into a 50 mL single neck flask [2-fluoro-2-(4-iodophenyl)propyl][(methylethyl)sulfonyl]amine (300 mg, 0.78 mmol, prepared in example 1), 4-carboxybenzene boronic acid (188 mg, 1.13 mmol), potassium carbonate (156 mg, 1.13 mmol) and tetrakis(triphenyl phosphine)palladium(0) (52 mg, 0.05 mmol) were combined in dioxane/water (30 mL, 3:1). The mixture was then heated at 100° C. with stirring for 18 hours. The reaction was cooled to room temperature and poured into H2O. The desired product was extracted with ethyl acetate and the organic layer was separated, washed twice with H2O, dried over K2CO3, and concentrated under reduced vacuum to yield the crude material (350 mg) as a tan solid. The crude material was purified via silica gel chromatography employing the Chromatotron using a 4000 micron rotor and eluting with a solvent of methylene chloride/methanol 9:1 to yield the title compound (91 mg, 31%) as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]=[N:7][NH:8][C:9]1[N:10]=[N:11][C:12]([Cl:15])=[CH:13][CH:14]=1)=[O:5])[CH3:2].C([O-])(=O)C.[Na+].[Br:21]Br>CC(O)=O.O>[Br:21][C:6](=[N:7][NH:8][C:9]1[N:10]=[N:11][C:12]([Cl:15])=[CH:13][CH:14]=1)[C:4]([O:3][CH2:1][CH3:2])=[O:5]
Reactant: CCOC(=O)C=NNc1ccc(Cl)nn1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)C(Br)=NNc1ccc(Cl)nn1
Reaction time: 3 h
Yield: 65 %

Procedure:
To a solution of compound 1-ethoxycarbonylmethylene-2-(6-chloro-3-pyridazinyl) hydrazine (11.4 g, 0.05 mol) and sodium acetate (11 g, 0.05 mol) in 50 mL of HOAc, bromine (8 g, 0.05 mol) in HOAc was added dropwise during 20 min. Stirring was continued for 3 h, the mixture was diluted with water (1 L), the precipitated crystals were filtered off, washed with water to give product ethyl 2-bromo-2-(2-(6-chloropyridazin-3-yl)hydrazono)acetate as a yellow solid (10 g, 66%). 1H NMR (300 MHz, d6-DMSO): δ 9.33 (br, 1H), 7.69-7.66 (d, J=9.0 Hz, 1H), 7.50-7.47 (d, J=9.0 Hz, 1H), 4.44-4.37 (q, 2H), 1.43-1.39 (t, 3H).
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][C:7]([O:8][CH3:9])=[C:5]([OH:6])[CH:4]=1.[C:12]1([CH3:22])[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1.N1C=CC=CC=1>O>[C:12]1([CH3:22])[CH:17]=[CH:16][C:15]([S:18]([O:6][C:5]2[CH:4]=[C:3]([CH:11]=[CH:10][C:7]=2[O:8][CH3:9])[CH:2]=[O:1])(=[O:20])=[O:19])=[CH:14][CH:13]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1ccc(C=O)cc1O
Solvent: O
Solvent: c1ccncc1
Product: COc1ccc(C=O)cc1OS(=O)(=O)c1ccc(C)cc1
Temperature: 75 °C
Reaction time: 0.08 h
Yield: 98 %

Procedure:
A mixture of 3-hydroxy-4-methoxybenzaldehyde 12 (5.0 g, 32 mmol) and p-toluenesulfonyl chloride (10.0 g, 52.5 mmol) was dissolved in pyridine (12.5 mL, 154 mmol). The reaction mixture stirred for 5 min and maintained at 70-80° C. The clear reaction mixture becomes turbid and becomes slurry. The stirring was continued for a period of 2 h at 70-80° C. The reaction completion was determined by TLC and the contents of the flask were cooled to room temperature and poured in to cold water. The white crystalline solid formed was filtered, washed successively with 5 mL 1:1 HCl:H2O, 5 mL of 5% NaOH solution and water till the filtrate is free from pyridine, dried to constant weight to get the desired product 21. Yield: 98%; white solid mp 148-151° C. 1H NMR: δ 2.40 (s, 3H, CH3), 3.71 (S, 3H, OCH3), 6.91-7.83 (m, 7H, Ar—H), 9.83 (s, 1H, CHO). Anal. Calcd for C15H14O5S: C, 58.81, H, 4.61. Found: C, 58.79, H, 4.59.
Reaction SMILES: C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH3:38][O:39][C:40](=[O:50])[CH2:41][C:42]1[CH:47]=[CH:46][C:45](Cl)=[CH:44][C:43]=1[F:49].[CH2:51]([C:53]([OH:86])([CH2:84][CH3:85])[CH2:54][CH2:55][C:56]1[CH:61]=[CH:60][C:59]([C:62]([CH2:81][CH3:82])([C:65]2[CH:70]=[CH:69][C:68](B3OC(C)(C)C(C)(C)O3)=[C:67]([CH3:80])[CH:66]=2)[CH2:63][CH3:64])=[CH:58][C:57]=1[CH3:83])[CH3:52]>O.C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:38][O:39][C:40](=[O:50])[CH2:41][C:42]1[CH:47]=[CH:46][C:45]([C:68]2[CH:69]=[CH:70][C:65]([C:62]([CH2:63][CH3:64])([C:59]3[CH:60]=[CH:61][C:56]([CH2:55][CH2:54][C:53]([CH2:84][CH3:85])([OH:86])[CH2:51][CH3:52])=[C:57]([CH3:83])[CH:58]=3)[CH2:81][CH3:82])=[CH:66][C:67]=2[CH3:80])=[CH:44][C:43]=1[F:49]
Reactant: COC(=O)Cc1ccc(Cl)cc1F
Reactant: CCC(O)(CC)CCc1ccc(C(CC)(CC)c2ccc(B3OC(C)(C)C(C)(C)O3)c(C)c2)cc1C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: O
Solvent: Cc1ccccc1
Product: CCC(O)(CC)CCc1ccc(C(CC)(CC)c2ccc(-c3ccc(CC(=O)OC)c(F)c3)c(C)c2)cc1C
Temperature: 100 °C
Reaction time: 3 h
Yield: 70.5 %

Procedure:
A solution of palladium acetate (3.1 mg, 0.0139 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (11.4 mg, 0.0279 mmol) and potassium phosphate (59.3 mg, 0.0279 mmol) in water (0.050 mL) and toluene (0.200 mL) was stirred for three minutes. A solution of (4-chloro-2-fluoro-phenyl)acetic acid methyl ester (Example 40; 30.3 mg, 0.14 mmol) and 3-ethyl-1-(4-{1-ethyl-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-propyl}-2-methyl-phenyl)-pentan-3-ol (Example 29; 49.2 mg, 0.0998 mmol) in toluene (0.250 mL) was added, and the mixture was stirred in a nitrogen atmosphere at 100° C. for three hours. After filtration through cotton plug, the filtrate was concentrated under reduced pressure. The residue was purified by thin layer silica gel chromatography (15% ethyl acetate/hexane) to give the title compound (37.5 mg, 70%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@@H:12]([CH3:14])[N:11]([C:15]2[CH:16]=[C:17]3[C:26](=[CH:27][C:28]=2[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[F:35])[O:25][CH2:24][C:23]2[N:18]3[CH:19]([CH3:45])[C:20](=[O:44])[N:21](COCC[Si](C)(C)C)[N:22]=2)[CH2:10][C@@H:9]1[CH3:46])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O>[C:1]([O:5][C:6]([N:8]1[CH2:13][C@@H:12]([CH3:14])[N:11]([C:15]2[CH:16]=[C:17]3[C:26](=[CH:27][C:28]=2[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[F:35])[O:25][CH2:24][C:23]2[N:18]3[CH:19]([CH3:45])[C:20](=[O:44])[NH:21][N:22]=2)[CH2:10][C@@H:9]1[CH3:46])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC1C(=O)N(COCC[Si](C)(C)C)N=C2COc3cc(-c4ccccc4F)c(N4C[C@H](C)N(C(=O)OC(C)(C)C)C[C@H]4C)cc3N21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Product: CC1C(=O)NN=C2COc3cc(-c4ccccc4F)c(N4C[C@H](C)N(C(=O)OC(C)(C)C)C[C@H]4C)cc3N21
Temperature: 80 °C
Yield: 69.9 %

Procedure:
(2S,5R)-4-[7-(2-Fluoro-phenyl)-4-methyl-3-oxo-2-(2-trimethylsilanyl-ethoxymethyl)-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-yl]-2,5-dimethyl-piperazine-1-carboxylic acid tert-butyl ester (0.2 g, 0.306 mmol) was dissolved in tetrabutylammonium fluoride (1M in THF, 3.06 mL, 3.06 mmol) and the reaction mixture was heated at 80° C. overnight. The reaction mixture was cooled to ambient temperature and water (10 mL) was added. The reaction mixture was extracted with EtOAc (3×10 mL). The combined organic phase was washed with brine (3×10 mL) and concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluting with 0-40% EtOAc in petroleum ether) to give (2S,5R)-4-[7-(2-fluoro-phenyl)-4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-yl]-2,5-dimethyl-piperazine-1-carboxylic acid tert-butyl ester (0.112 g, 70%) as a solid. LC/MS (Table 1, Method 25) Rt=0.959 min.; MS m/z: 524 [M+H]+. 1H NMR (400 MHz, CDCl3): δ 8.15-8.08 (m, 1H), 7.42 (m, 1H), 7.35-7.29 (m, 1H), 7.22-7.10 (m, 2H), 6.95-6.91 (m, 1H), 6.52-6.46 (m, 1H), 4.76-4.72 (m, 1H), 4.65-4.54 (m, 2H), 4.35 (m, 1H), 3.45 (m, 1H), 3.33 (m, 1H), 2.85 (m, 1H), 2.69 (m, 1H), 2.60 (m, 1H), 1.52 (m, 3H), 1.49-1.32 (m, 9H), 1.24 (m, 3H), 0.81 (m, 3H).
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[C:9]([O:10][CH3:11])=[CH:8][C:7]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[C:6]([F:18])[CH:5]=1.[NH:19]1[CH:23]=[CH:22][N:21]=[C:20]1[C:24]1[C:32]2[C:27](=[N:28][CH:29]=[CH:30][CH:31]=2)[N:26]([CH2:33][C:34](O)=[O:35])[N:25]=1>>[Cl:3][C:4]1[C:9]([O:10][CH3:11])=[CH:8][C:7]([N:12]2[CH2:13][CH2:14][N:15]([C:34](=[O:35])[CH2:33][N:26]3[C:27]4=[N:28][CH:29]=[CH:30][CH:31]=[C:32]4[C:24]([C:20]4[NH:19][CH:23]=[CH:22][N:21]=4)=[N:25]3)[CH2:16][CH2:17]2)=[C:6]([F:18])[CH:5]=1
Reactant: COc1cc(N2CCNCC2)c(F)cc1Cl
Reactant: O=C(O)Cn1nc(-c2ncc[nH]2)c2cccnc21
Agent: Cl
Product: COc1cc(N2CCN(C(=O)Cn3nc(-c4ncc[nH]4)c4cccnc43)CC2)c(F)cc1Cl

Procedure:
The title compound was prepared following Protocol A. 1-(4-Chloro-2-fluoro-5-methoxyphenyl)piperazine dihydrochloride and [3-(1H-imidazol-2-yl)-pyrazolo[3,4-b]pyridin-1-yl]-acetic acid were used as the coupling components. The crude product was purified by silica gel chromatography (1% to 10% MeOH in CH2Cl2) to provide 1-[4-(4-chloro-2-fluoro-5-methoxyphenyl)piperazin-1-yl]-2-[3-(1H-imidazol-2-yl)-pyrazolo[3,4-b]pyridin-1-yl]ethanone as a tan solid (27 mg): 1H NMR (CDCl3, 400 MHz) δ 8.79 (dd, 0.6H), 8.67 (dd, 0.4H), 8.57-8.55 (m, 1H), 7.31-7.20 (m, 2H), 7.12-7.06 (m, 2H), 6.49-6.45 (m, 1H), 5.45 (s, 0.6H), 5.43 (s, 1.4H), 3.86 (s, 0.9H), 3.85 (s, 2.1; H), 3.81-3.75 (m, 4H), 3.15-3.08 (m, 4H); LC/MS m/z (M+H)+ 470.4.
Reaction SMILES: [CH:1]1C=CC2NC=C(CCO)C=2C=1.[Li].[H-].[CH2:15]([O:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][CH:27]=[C:26]2[C:32](=O)[C:33]([O:35][CH2:36][CH3:37])=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CC(C)=O>[CH2:15]([O:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][C:27]1[C:36]([CH3:37])([CH3:1])[O:35][CH2:33][CH2:32][C:26]2=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CCOC(=O)C(=O)c1c[nH]c2ccc(OCc3ccccc3)cc12
Reactant: OCCc1c[nH]c2ccccc12
Agent: [H-]
Agent: [Li]
Solvent: CC(C)=O
Product: CC1(C)OCCc2c1[nH]c1ccc(OCc3ccccc3)cc21

Procedure:
5-Benzyloxy-3-tryptophol (II; R2, R3, R4 and R5 = H, R6 = 5-benzyloxy and X1 = OH), m.p. 93° - 95° C., is prepared by lithium aluinum hydride reduction of ethyl 5-benzyloxy-3-indoleglyoxalate (British Patent 778,823) according to the procedure of Example 309. Subsequent treatment of 5-benzyloxy-3-tryptophol with the ketone, acetone, according to the procedure of Example 785 affords 6-benzyloxy-1,1-dimethyl-1,3,4,9-tetrahydropyrano[3,4-b]indole (VIIl R1M CH3), nmr (CDCl3) δ1.53 (6H), 2.73 (t, 2H), 4.03 (t, 2H), 5.10 (2H), 6.67 - 7.83 (9H). The latter compound is then N-alkylated with the organic halide, dimethylaminoethyl chloride, according to the procedure of Example 838 to afford 6-benzyloxy-1,1-dimethyl-9-[2-(dimethylamino)ethyl]-1,3,4,9-tetrahydropyrano[3,4-b]indole, which on treatment with hydrochloric acid gives the corresponding hydrochloric acid addition salt thereof, m.p. 209° C.
Reaction SMILES: [H-].[Na+].[OH:3][CH:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1.[Br:10][C:11]1[CH:16]=[CH:15][N:14]=[C:13](Cl)[CH:12]=1>C1COCC1>[Br:10][C:11]1[CH:16]=[CH:15][N:14]=[C:13]([O:3][CH:4]2[CH2:9][CH2:8][O:7][CH2:6][CH2:5]2)[CH:12]=1
Reactant: Clc1cc(Br)ccn1
Reactant: OC1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Brc1ccnc(OC2CCOCC2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a suspension of NaH (0.4 g, 10 mmol) in THF (20 ml) at 0° C. was added 4-hydroxytetrahydropyran (1.02 ml, 10 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 30 mins before 4-bromo-2-chloropyridine (0.89 ml, 8.0 mmol) was added dropwise. The reaction mixture was stirred for 18 h before being quenched with EtOH (1 ml), partitioned between CH2Cl2 and H2O and extracted CH2Cl2 (×2). The organics were combined, dried (MgSO4), filtered and the solvent removed in vacuo. Purified by column chromatography to afford 4-Bromo-2-(tetrahydro-pyran-4-yloxy)-pyridine MS: [MH]+ 258, 260
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([Cl:10])[CH:3]=1.COC1C=CC([B:19]([OH:21])[OH:20])=C(C(F)(F)F)C=1>>[Cl:10][C:4]1[CH:3]=[C:2]([B:19]([OH:21])[OH:20])[CH:7]=[CH:6][C:5]=1[O:8][CH3:9]
Reactant: COc1ccc(Br)cc1Cl
Reactant: COc1ccc(B(O)O)c(C(F)(F)F)c1
Product: COc1ccc(B(O)O)cc1Cl
Yield: 62 %

Procedure:
Starting from 4-bromo-2-chloroanisole (5.0 g, 23 mmol) in place of 4-bromo-3-trifluoromethylanisole, the title compound (2.6 g, 62%) was synthesized in essentially the same manner as described above for 4-methoxy-2-trifluoromethylphenylboronic acid in Step 2, Scheme 1.
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[CH2:27][CH2:26][C@:7]2([O:11][CH2:10][C:9]([C:12]3[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:13]=3[C:22]([F:25])([F:24])[F:23])=[CH:8]2)[C@@H:6]1[C:28]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=1)=[O:4]>C(O)(=O)C>[CH3:1][O:2][C:3]([C@H:5]1[CH2:27][CH2:26][C@:7]2([O:11][CH2:10][C@H:9]([C:12]3[CH:17]=[C:16]([C:18]([F:19])([F:20])[F:21])[CH:15]=[CH:14][C:13]=3[C:22]([F:25])([F:23])[F:24])[CH2:8]2)[C@@H:6]1[C:28]1[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=1)=[O:4]
Reactant: COC(=O)[C@H]1CC[C@@]2(C=C(c3cc(C(F)(F)F)ccc3C(F)(F)F)CO2)[C@@H]1c1ccc(F)cc1
Solvent: CC(=O)O
Product: COC(=O)[C@H]1CC[C@@]2(C[C@@H](c3cc(C(F)(F)F)ccc3C(F)(F)F)CO2)[C@@H]1c1ccc(F)cc1

Procedure:
The title compound was prepared by the procedure given in Example 6, Step G, employing (5R,6S,7S)-6-(4-fluorophenyl)-3-(2,5-bis-(trifluoromethyl)phenyl)-1-oxaspiro[4.4]non-3-ene-7-carboxylic acid methyl ester in place of methyl[5-(RS),6-(SR),7-(SR)]-6-(4-fluorophenyl)-3-(2-methoxy-5-((5-trifluoromethyl)tetrazol-1-yl)phenyl)-1-oxaspiro[4.4]non-3-ene-7-carboxylate, except that acetic acid was not used as a cosolvent and the reaction time was extended to between 2 and 16 hr. MS (NH3 /CI): m/e=491 (M+1).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:6].[C:13]([NH:21][CH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C([O-])([O-])=O.[K+].[K+].O>C(Cl)(Cl)Cl>[C:5]([CH2:4][CH2:3][CH2:2][N:25]1[CH2:26][CH2:27][CH:22]([NH:21][C:13](=[O:20])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:23][CH2:24]1)(=[O:6])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C(CCCCl)c1ccccc1
Reactant: O=C(NC1CCNCC1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=C(CCCN1CCC(NC(=O)c2ccccc2)CC1)c1ccccc1
Yield: 9.1 %

Procedure:
A mixture of 4-chlorobutyrophenone (447 mg, 2.45 mmol), 4-benzamidopiperidine (500 mg, 2.45 mmol) and K2CO3 (338 mg, 2.45 mmol) was heated up in boiling water bath for 1 hour. The reaction mixture was portioned between water and CHCl3. The organic layer was separated and dried over Na2SO4. After filtration and removal of solvent, the residue was purified by chromatography (SiO2, MeOH:CHCl3, 5:95). Recrystallization from AcOEt/hexane gave a white powder (78 mg, 8.2%). mp 143°-144° C.; 1H NMR (CD3OD, 400 MHz) δ 1.65 (dq, J1 =3.16 Hz, J2 =11.9 Hz, 2H) , 1.90-2.00 (m, 4H), 2.18 (t, J=11.9 Hz, 2H), 2.48 (m, 2H), 3.00-3.10 (m, 4H), 3.88 (m, 1H) , 7.40-8.00 (m, 10H); Mass spectrum (M+1)+ at m/z 351.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[CH2:10][C:11]#[N:12].[CH2:13](N)[CH2:14][NH2:15]>>[Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[CH2:10][C:11]1[NH:15][CH2:14][CH2:13][N:12]=1
Reactant: NCCN
Reactant: Cc1ccc(F)c(CC#N)c1Cl
Product: Cc1ccc(F)c(CC2=NCCN2)c1Cl

Procedure:
2-(2-Chloro-6-fluoro-3-methyl-benzyl)-4,5-dihydro-1H-imidazole was prepared from (2-chloro-6-fluoro-3-methylphenyl)-acetonitrile and ethylene diamine in analogy to Example 19 b): off-white solid; MS (ISP): 227.0 ((M+H)+.).
Reaction SMILES: [CH:1]1([C:7]([C:10]2[CH:15]=[C:14]([O:16]C)[CH:13]=[C:12]([O:18]C)[CH:11]=2)([CH3:9])[CH3:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(C1(C2C=C(O)C=C(O)C=2)SCCS1)CCC>CCCCCC.C(OCC)C>[CH:1]1([C:7]([C:10]2[CH:15]=[C:14]([OH:16])[CH:13]=[C:12]([OH:18])[CH:11]=2)([CH3:9])[CH3:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1cc(OC)cc(C(C)(C)C2CCCCC2)c1
Agent: CCCCC1(c2cc(O)cc(O)c2)SCCS1
Solvent: CCCCCC
Solvent: CCOCC
Product: CC(C)(c1cc(O)cc(O)c1)C1CCCCC1

Procedure:
Compound 21 was prepared from Compound 14 using the same procedure as described above for Compound 16. Yield 1.11 g (61.9%) as a viscous oil. Rf=0.28 (hexane:diethyl ether 6:4); 1H NMR δ 6.38 (d, J=2 Hz, 2H), 6.17 (t, J=2.25 Hz, 1H), 4.82 (br s, 2H), 1.71–1.68 (m, 2H), 1.63–1.60 (m, 1H), 1.53–1.51 (m, 2H), 1.42–1.36 (m, 1H), 1.17 (s, 6H), 1.16–1.03(m, 3H), 0.94–0.86 (m, 2H); 13C NMR δ 156.32, 154.45, 106.56, 100.02, 49.21, 40.85, 28.12, 27.39, 26.91, 25.39, 14.40; MS: (ESI, Neg.) m/z 233 ([M−H]−).
Reaction SMILES: [CH3:1][C:2]([CH3:45])([CH3:44])[C@H:3]([NH:14][C:15]([C@H:17]([CH2:26]/[CH:27]=[CH:28]/[C:29]1[CH:34]=[C:33]([CH3:35])[C:32]([C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([O:42][CH3:43])[CH:37]=2)=[CH:31][CH:30]=1)[CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[O:16])[C:4]([O:6]CC1C=CC=CC=1)=[O:5]>[Pd]>[CH3:1][C:2]([CH3:45])([CH3:44])[C@H:3]([NH:14][C:15]([C@H:17]([CH2:26][CH2:27][CH2:28][C:29]1[CH:34]=[C:33]([CH3:35])[C:32]([C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([O:42][CH3:43])[CH:37]=2)=[CH:31][CH:30]=1)[CH2:18][C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])=[O:16])[C:4]([OH:6])=[O:5]
Reactant: COc1cccc(-c2ccc(/C=C/C[C@H](CC(=O)OC(C)(C)C)C(=O)N[C@H](C(=O)OCc3ccccc3)C(C)(C)C)cc2C)c1
Agent: [Pd]
Product: COc1cccc(-c2ccc(CCC[C@H](CC(=O)OC(C)(C)C)C(=O)N[C@H](C(=O)O)C(C)(C)C)cc2C)c1
Yield: 74741.7 %

Procedure:
According to the method of Preparation 19 c), tert-butyl (3R,5E)-3-({[(1S)-2,2-dimethyl-1-(benzyloxycarbonyl)propyl]amino}carbonyl)-6-(3′-methoxy-2-methylbiphen-4-yl]hex-5-enoate (1.040 g, 1.69 mmol) was hydrogenated over 10% palladium on charcoal to give tert-butyl (3R)-3-({[(1S)-2,2-dimethyl-1-(carboxy)propyl]amino}carbonyl)-6-(3′-methoxy-2-methylbiphen-4-yl)hexanoate (664 g, 75%) as a colourless foam.