Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][C:7]2[N:11]([CH2:12][C:13]([N:15]3[CH2:20][CH2:19][CH:18]([NH:21][CH3:22])[CH2:17][CH2:16]3)=[O:14])[N:10]=[C:9]([C:23]3[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=3)[CH:8]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH:38]1([C:41](Cl)=[O:42])[CH2:40][CH2:39]1>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[N:11]([CH2:12][C:13]([N:15]3[CH2:16][CH2:17][CH:18]([N:21]([CH3:22])[C:41]([CH:38]4[CH2:40][CH2:39]4)=[O:42])[CH2:19][CH2:20]3)=[O:14])[N:10]=[C:9]([C:23]3[CH:24]=[CH:25][N:26]=[CH:27][CH:28]=3)[CH:8]=2)=[CH:29][CH:30]=1
Reactant: CNC1CCN(C(=O)Cn2nc(-c3ccncc3)cc2Cc2ccc(F)cc2)CC1
Reactant: O=C(Cl)C1CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C(=O)C1CC1)C1CCN(C(=O)Cn2nc(-c3ccncc3)cc2Cc2ccc(F)cc2)CC1
Reaction time: 0.17 h

Procedure:
To a solution of 1-{[5-(4-fluorobenzyl)-3-pyridin-4-yl-1H-pyrazol-1-yl]acetyl}-N-methylpiperidin-4-amine (150 mg, 0.37 mmol) in DCM (3 mL) at room temperature was added triethylamine (56 μL, 0.40 mmol) followed by cyclopropanecarbonyl chloride (34 μL, 0.37 mmol) and the solution stirred for 10 minutes. The solution was then loaded directly onto a pre-wetted Biotage 25M column for flash chromatography and eluted with 2-8% MeOH/DCM to yield the title compound as a white solid, 162 mg, 92%. 1H NMR (rotomers seen, 400 MHz, DMSO-D6) δ ppm 8.43-8.59 (2 H, m), 7.59-7.72 (2 H, m), 7.31 (2 H, dd, J=8.46, 5.68 Hz), 7.15 (2 H, t, J=8.84 Hz), 6.52 (1 H, s), 5.10-5.36 (2 H, m), 4.22-4.60 (2 H, m), 3.95 (3 H, s), 3.03-3.26 (1 H, m), 2.53-3.01 (4 H, m), 1.42-2.10 (5 H, m), 0.62-0.79 (4 H, m); m/z (APCI+) for C27H30N5O2F 476.2 (M+H)+.
Reaction SMILES: [CH3:1][C:2]#[C:3][CH2:4][CH2:5][CH2:6][CH3:7].B1C2CCCC1CCC2.B(O)O.Br[C:21]1[CH:54]=[CH:53][C:24]([CH2:25][C:26]2[N:27]([C:39]3[CH:40]=[C:41]([N:45]4[S:49](=[O:51])(=[O:50])[NH:48][C:47](=[O:52])[CH2:46]4)[CH:42]=[CH:43][CH:44]=3)[CH:28]=[C:29]([C:31]3[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][C:32]=3[Cl:38])[N:30]=2)=[CH:23][CH:22]=1>C1COCC1>[Cl:38][C:32]1[CH:33]=[C:34]([Cl:37])[CH:35]=[CH:36][C:31]=1[C:29]1[N:30]=[C:26]([CH2:25][C:24]2[CH:53]=[CH:54][C:21]([C:2]([CH3:1])=[CH:3][CH2:4][CH2:5][CH2:6][CH3:7])=[CH:22][CH:23]=2)[N:27]([C:39]2[CH:40]=[C:41]([N:45]3[S:49](=[O:50])(=[O:51])[NH:48][C:47](=[O:52])[CH2:46]3)[CH:42]=[CH:43][CH:44]=2)[CH:28]=1
Reactant: O=C1CN(c2cccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(Br)cc3)c2)S(=O)(=O)N1
Reactant: CC#CCCCC
Agent: B1C2CCCC1CCC2
Agent: OBO
Solvent: C1CCOC1
Product: CCCCC=C(C)c1ccc(Cc2nc(-c3ccc(Cl)cc3Cl)cn2-c2cccc(N3CC(=O)NS3(=O)=O)c2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 2-heptyne (129 μL, 1 mmol) in 2 mL dry THF at 0° C. was added 2 mL 0.5 M 9-BBN solution in THF. The resulting solution was stirred at room temperature under nitrogen for 4 hr. Then it was condensed under vacuum and used as boronic acid derivative according to general procedure G, reacting with 5-{3-[2-(4-bromo-benzyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide (119 mg, 0.2 mmol) to give 5-(3-{4-(2,4-dichloro-phenyl)-2-[4-(1-methyl-hex-1-enyl)-benzyl]-imidazol-1-yl}-phenyl)-1,2,5-thiadiazolidine-3-one-1,1-dioxide.
Reaction SMILES: Cl[C:2]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CN1CCCC1=O.C(N(C(C)C)CC)(C)C>CCOC(C)=O>[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:2]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: Nc1ccccc1
Reactant: N#Cc1ccc([N+](=O)[O-])cc1Cl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: N#Cc1ccc([N+](=O)[O-])cc1-c1ccccc1N
Yield: 88.4 %

Procedure:
2-Chloro-4-nitro-benzonitrile (Aldrich) (3.64 g, 20 mmol), aniline (2 mL, 22 mmol), 1-methyl-2-pyrollidinone (10 mL) and diisopropylethylamine (4 mL) were combined and heated to 120° under Ar for 18 h, cooler poured into EtOAc (150 mL), washed with H20 (3×50 mL) and satd aq NaCl (50 mL), dried (Na2SO4), concentrated, and the residue was triturated with hexane, filtered and the solid was washed with hexane and dried in vacuo to afford 4.23 g (88%) of the title compound as a light green solid. 1H NMR (400) MHz, δ: 8.45 (finely split doublet, 1), 8.19 (dd, 1), 7.48 (m,3), 7.28 (d,2), 7.06 (d,1), 6.96 (br s,1).
Reaction SMILES: ClC1C=C(C(OCC2(C3C=CC(F)=CC=3)CCN(C)CC2)C)[C:5]2N(COCC[Si](C)(C)C)C(=O)[N:7](COCC[Si](C)(C)C)[C:6]=2C=1.[C:46]([OH:52])([C:48]([F:51])([F:50])[F:49])=[O:47]>>[C:6](#[N:7])[CH3:5].[C:46]([OH:52])([C:48]([F:51])([F:50])[F:49])=[O:47]
Reactant: CC(OCC1(c2ccc(F)cc2)CCN(C)CC1)c1cc(Cl)cc2c1n(COCC[Si](C)(C)C)c(=O)n2COCC[Si](C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: CC#N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
6-Chloro-4-(1-((4-(4-fluorophenyl)-1-methylpiperidin-4-yl)methoxy)ethyl)-1,3-bis((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2(3H)-one (58 mg, 0.085 mmol) was dissolved in TFA (40% in dichloromethane, 1 mL) and stirred at room temperature for 1 h. The reaction was concentrated, loaded onto a strong cation exchange cartridge, and flushed with several volumes of methanol which were discarded. The crude product was eluted with 2M ammonia in methanol and concentrated. preparative HPLC (29% B, isocratic method, ACN/TFA) gave 12.5 mg (27%) as a colorless film. 1H-NMR (CD3OD, 500 MHz) δ 7.30-7.60 (m, 2H), 7.00-7.25 (m, 2H), 6.92 (s, 1H), 6.60-6.70 (m, 1H), 4.49 (q, J=6.4 Hz, 1H), 3.46 (m, 2.4H), 3.23 (m, 1H), 2.40-3.00 (m, 7H), 1.90-2.25 (m, 2H), 1.38 (d, J=6.1 Hz, 3H). Mass spec.: 418.15 (MH)+.
Reaction SMILES: C[O:2][C:3](=[O:26])[C@H:4]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:14](=[O:25])[N:15]([CH3:24])[C:16]([C:20]([F:23])([F:22])[F:21])=[CH:17][C:18]=2[CH3:19])=[CH:9][CH:8]=1)[NH2:5].[Cl:27][C:28]1[CH:36]=[CH:35][CH:34]=[C:33]([CH3:37])[C:29]=1[C:30](Cl)=[O:31]>>[Cl:27][C:28]1[CH:36]=[CH:35][CH:34]=[C:33]([CH3:37])[C:29]=1[C:30]([NH:5][C@H:4]([C:3]([OH:26])=[O:2])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[C:14](=[O:25])[N:15]([CH3:24])[C:16]([C:20]([F:23])([F:22])[F:21])=[CH:17][C:18]=2[CH3:19])=[CH:11][CH:12]=1)=[O:31]
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2c(C)cc(C(F)(F)F)n(C)c2=O)cc1
Reactant: Cc1cccc(Cl)c1C(=O)Cl
Product: Cc1cccc(Cl)c1C(=O)N[C@@H](Cc1ccc(-c2c(C)cc(C(F)(F)F)n(C)c2=O)cc1)C(=O)O

Procedure:
N-[(2-chloro-6-methylphenyl)carbonyl]-4-(1,4-dimethyl-6-(trifluoromethyl)-2-oxo-3-pyridinyl)-L-phenylalanine was prepared from 4-[1,4-dimethyl-6-(trifluoromethyl)-2-oxo-3-pyridinyl]-L-phenylalanine methyl ester and 2-chloro-6-methylbenzoyl chloride using the general procedures described in example 44. ES-LRMS m/z 507.1 (M+H), 529.1 (M+Na).
Reaction SMILES: [OH-].[Na+].C([O:5][C:6]([C:8]1[C:9]2[S:17][CH:16]=[C:15]([CH2:18][O:19][C:20]3[CH:25]=[C:24]([C:26]4[O:30][N:29]=[C:28]([CH3:31])[N:27]=4)[CH:23]=[CH:22][C:21]=3[CH3:32])[C:10]=2[C:11]([NH2:14])=[N:12][CH:13]=1)=[O:7])C>O1CCCC1.CO>[NH2:14][C:11]1[C:10]2[C:15]([CH2:18][O:19][C:20]3[CH:25]=[C:24]([C:26]4[O:30][N:29]=[C:28]([CH3:31])[N:27]=4)[CH:23]=[CH:22][C:21]=3[CH3:32])=[CH:16][S:17][C:9]=2[C:8]([C:6]([OH:7])=[O:5])=[CH:13][N:12]=1
Reactant: CCOC(=O)c1cnc(N)c2c(COc3cc(-c4nc(C)no4)ccc3C)csc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1noc(-c2ccc(C)c(OCc3csc4c(C(=O)O)cnc(N)c34)c2)n1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
An aqueous solution of sodium hydroxide (2 N, 3.0 mL, 1.5 mmol) was added to a solution of 4-amino-3-[2-methyl-5-(3-methyl-[1,2,4]oxadiazol-5-yl)-phenoxymethyl]-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (0.33 g, 0.78 mmol) (from Example 54 supra) in tetrahydrofuran/methanol (3:1, 8 mL) and the mixture was heated at 50° C. for 1 day. The reaction mixture was concentrated and azeotroped with toluene. The solid residue was triturated with ethyl acetate. The solid was then suspended in water and treated with hydrochloric acid (1N). After stirring 30 minutes, the solid was collected, washed with water and dried to 4-amino-3-[2-methyl-5-(3-methyl-[1,2,4]oxadiazol-5-yl)-phenoxymethyl]-thieno[3,2-c]pyridine-7-carboxylic acid. (Yield 0.29 g, 94%).
Reaction SMILES: [Si]([O:8][C@H:9]([C@H:17]([O:42][Si](C(C)(C)C)(C)C)[CH:18]=[CH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH:26]=[CH:27][C@H:28]([O:34][Si](C(C)(C)C)(C)C)[CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH2:10][CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[OH:8][C@H:9]([C@H:17]([OH:42])[CH:18]=[CH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH:26]=[CH:27][C@H:28]([OH:34])[CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH2:10][CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14]
Reactant: CCCCC[C@H](C=Cc1ccccc1C=C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H](CCCC(=O)OC)O[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C
Agent: CCCCC[C@@H](O)/C=C/c1ccccc1/C=C/[C@@H](O)[C@@H](O)CCCC(=O)OC
Agent: CCCCC[C@H](/C=C/c1ccccc1/C=C/[C@@H](O[Si](C)(C)C(C)(C)C)[C@H](CCCC(=O)OC)O[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: C1CCOC1
Product: CCCCC[C@@H](O)C=Cc1ccccc1C=C[C@@H](O)[C@@H](O)CCCC(=O)OC
Temperature: 0 °C
Reaction time: 8 h

Procedure:
The product of Step 4 was dissolved in THF (1 mL) and cooled to 0° C. Tetra-butyl ammonium fluoride (10 μL, 0.078 mmol) was added and the reaction mixture was warmed to RT and allowed to stir overnight. The reaction mixture was quenched with saturated ammonium chloride, extracted with ether, dried and concentrated. Purification by preparatory TLC (silica plate, 5% MeOH/Ethyl acetate) afforded 6.1 mg (96.8%) of (5S,6R,E)-methyl 5,6-dihydroxy-8-(2-((R,E)-3-hydroxyoct-1-enyl)phenyl)oct-7-enoate. 1H NMR (250 Hz, CDCl3): δ 7.38 (m, 2H), 7.22 (m, 2H), 6.86 (t, J=15.4 Hz, 1H), 6.07 (m, 1H), 4.27 (m, 1H), 3.77 (m, 1H), 3.63 (m, 1H), 3.46 (q, J=14 Hz, 6.9 Hz, 1H), 2.35 (t, J=7.5 Hz, 2H), 1.81-1.53 (m, 4H), 1.32-1.16 (m, 7H), 0.915-0.789 (m, 4H). 13C (500 NMR C6D6): δ 173.79, 136.18, 136.12, 135.98, 131.59, 130.34, 136.18, 131.59, 130.34, 128.53, 128.20, 127.81, 127.68, 127.62, 127.47, 127.13, 76.02, 74.36, 72.65, 51.01, 37.92, 33.83, 32.22, 30.15, 25.58, 23.05, 21.57, 14.24.
Reaction SMILES: [NH3:1].C[O:3][C:4]([C:6]1[N:7]([CH3:12])[CH:8]=[C:9]([Br:11])[N:10]=1)=O>CO>[Br:11][C:9]1[N:10]=[C:6]([C:4]([NH2:1])=[O:3])[N:7]([CH3:12])[CH:8]=1
Reactant: N
Reactant: COC(=O)c1nc(Br)cn1C
Solvent: CO
Product: Cn1cc(Br)nc1C(N)=O
Temperature: 20 °C
Reaction time: 16 h
Yield: 100 %

Procedure:
To the saturated solution of ammonia in MeOH was added 165 mg of 4-bromo-1-methyl-1H-imidazole-2-carboxylic acid methyl ester and the resulting mixture was stirred at 20° C. for 16 h. The solution was evaporated to give 4-bromo-1-methyl-1H-imidazole-2-carboxylic acid amide (154 mg, yield 100%). LC-MS calcd for C5H6BrN3O (m/e) 202.97, obsd 204 and 206 [M+1]+.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][CH:6]=[CH:5][C:4]=2[C:3]=1[C:12]([OH:14])=[O:13].[Cl:15][C:16]1[C:17]([N:22]2[C:26]([C:27](O)=O)=[CH:25][C:24]([C:30]([F:33])([F:32])[F:31])=[N:23]2)=[N:18][CH:19]=[CH:20][CH:21]=1.N1C=CC=CC=1.CS(Cl)(=O)=O>O1CCCC1>[Cl:15][C:16]1[C:17]([N:22]2[C:26]([C:27]3[O:13][C:12](=[O:14])[C:3]4[C:4]5[C:9](=[N:8][CH:7]=[CH:6][CH:5]=5)[CH:10]=[CH:11][C:2]=4[N:1]=3)=[CH:25][C:24]([C:30]([F:33])([F:31])[F:32])=[N:23]2)=[N:18][CH:19]=[CH:20][CH:21]=1
Reactant: Nc1ccc2ncccc2c1C(=O)O
Reactant: O=C(O)c1cc(C(F)(F)F)nn1-c1ncccc1Cl
Agent: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: O=c1oc(-c2cc(C(F)(F)F)nn2-c2ncccc2Cl)nc2ccc3ncccc3c12
Temperature: 0 °C
Reaction time: 48 h

Procedure:
To a suspension of 240 mg (1.28 mmol) of 6-amino-quinoline-5-carboxylic acid in 9.60 mL of anhydrous tetrahydrofuran at 10° C., is added 372 mg (1.28 mmol) of 2-(3-chloro-pyridin-2-yl)-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid followed by 5134 (6.38 mmol) of pyridine. Then the suspension is cooled to 0° C. and 398 μL (5.10 mmol) of methanesulfonyl chloride are added dropwise. The mixture is stirred at ambient temperature for 48 hours. Then the solvent is evaporated and the residue is precipitated with a minimum of ethyl acetate and washed with ethyl acetate. After filtration, water is added to the filtrate and the new suspension formed is filtrated again. After drying on high vacuum pump 303 mg (54%) of solid are obtained; LC/MS:444/446 (M+H)+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[CH:10](O)=[O:11].O>C1(C)C=CC=CC=1>[CH:10]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1)=[O:11]
Reactant: O=CO
Reactant: c1ccc2c(c1)CCN2
Solvent: O
Solvent: Cc1ccccc1
Product: O=CN1CCc2ccccc21
Temperature: 25 °C
Yield: 91.7 %

Procedure:
A mixture of indoline (145 g, 1.2 mol) and formic acid (90%, 92 g, 1.8 mol) was brought to reflux in toluene with removal of water via a Dean-Stark apparatus. After 6 hours the reaction mixture was cooled to room temperature, washed with water and concentrated in vacuo. N-formylindoline (158 g, 1.1 mol, 88% yield) was isolated as an off-white solid and used in the next step without further purification. Mixture of rotamers: 1H-NMR (CDCl3) δ 8.92 (s, 0.85H), 8.51 (s, 0.15H), 8.06 (d, J=8.3 Hz, 0.15H), 7.26-7.16 (m, 3.85H), 7.16-7.02 (m, 1H), 4.13-4.02 (m, 2H), 3.21-3.12 (dt, 2H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([O:23][CH3:24])=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14](C(OC)=O)[CH:13]=[C:12]2[CH3:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC1C(OC)=CC=C2C=1C(C)=CN2)C1C=CC=CC=1>>[CH2:1]([O:8][C:9]1[C:10]([O:23][CH3:24])=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[C:12]2[CH3:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)n1cc(C)c2c(OC)c(OCc3ccccc3)ccc21
Agent: COc1ccc2[nH]cc(C)c2c1OCc1ccccc1
Product: COc1c(OCc2ccccc2)ccc2[nH]cc(C)c12
Yield: 92 %

Procedure:
The 5-benzyloxy-4-methoxy-1-methoxycarbonyl-3-methylindole (4.5 g) was hydrolyzed in the same manner as in the preparation of 4-benzyloxy-5-methoxy-3-methylindole in Experimental Example 4 to give 5-benzyloxy-4-methoxy-3-methylindole (3.4 g).
Reaction SMILES: [CH3:1][C:2](=[O:5])[C:3]#[CH:4].[N+:6](=[CH:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[N-:7]>CCOCC>[CH2:12]([O:11][C:9]([C:8]1[CH:4]=[C:3]([C:2](=[O:5])[CH3:1])[NH:7][N:6]=1)=[O:10])[CH3:13]
Reactant: C#CC(C)=O
Reactant: CCOC(=O)C=[N+]=[N-]
Solvent: CCOCC
Product: CCOC(=O)c1cc(C(C)=O)[nH]n1
Temperature: 0 °C
Yield: 42.6 %

Procedure:
A 500 ml Erlenmeyer flask was charged with 25.0 g of 3-butyne-2-one and ethyl ether (200 ml). To the resulting solution, 41.9 g of ethyl diazoacetate were added slowly with stirring. After 30 minutes of stirring, the ether solution began refluxing by itself. After stirring for 1 hour, the mixture was chilled at 0° C. for 1 hour and filtered to yield 28.5 g of 5-acetylpyrazole-3-carboxylic acid ethyl ester as white solids, mp 114°-115° C. NMR: 1.42 (t, 3H), 2.62 (s, 3H), 4.44 (q, 2H), 7.36 (s, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:26]=[CH:27][C:28]=1[O:29][CH2:30][CH2:31][O:32][CH2:33][CH2:34][CH3:35])[CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]2[S:18](=[O:20])(=[O:19])[CH2:17][CH2:16][C:15]([C:21]([O:23]C)=[O:22])=[CH:14][C:13]=2[CH:25]=1)[CH3:2].C(=O)([O-])[O-].[K+].[K+]>C1COCC1.CO>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:26]=[CH:27][C:28]=1[O:29][CH2:30][CH2:31][O:32][CH2:33][CH2:34][CH3:35])[CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]2[S:18](=[O:20])(=[O:19])[CH2:17][CH2:16][C:15]([C:21]([OH:23])=[O:22])=[CH:14][C:13]=2[CH:25]=1)[CH3:2]
Reactant: CCCOCCOc1ccc(COc2ccc3c(c2)C=C(C(=O)OC)CCS3(=O)=O)cc1OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: C1CCOC1
Product: CCCOCCOc1ccc(COc2ccc3c(c2)C=C(C(=O)O)CCS3(=O)=O)cc1OCC
Temperature: 65 °C
Reaction time: 20 h
Yield: 24.1 %

Procedure:
Into a solution of methyl 7-[[3-ethoxy-4-(propoxyethoxy)benzyl]oxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (0.76 g) in THF-methanol (10-5 ml) was added at room temperature a 1 M aqueous solution of potassium carbonate (3.0 ml), and the resulting mixture was stirred at 65° C. for 20 hours. After cooling to room temperature, the reaction mixture was extracted with ethyl acetate. To the aqueous layer was added 1 N hydrochloric acid (10 ml), and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous saturated solution of sodium chloride and was dried with magnesium sulfate. After concentration under reduced pressure, the precipitated crystals were collected by filtration. The crystals were washed with diisopropyl ether to obtain 7-[[3-ethoxy-4-(2-propoxyethoxy)benzyl]oxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylic acid (178 mg) as yellow crystals.
Reaction SMILES: F[P-](F)(F)(F)(F)F.[N:8]1(O[P+](N(C)C)(N(C)C)N(C)C)[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2N=N1.C1(C[C@H](N2CC3C(=CC=CC=3)C2=O)C(O)=O)CCCCC1.NC1SC2C=CC=CC=2N=1.[CH:59]1([CH2:65][C@H:66]([N:75]2[CH2:83][C:82]3[C:77](=[CH:78][CH:79]=[CH:80][CH:81]=3)[C:76]2=[O:84])[C:67]([NH:69][C:70]2[S:71]C=CN=2)=[O:68])[CH2:64][CH2:63][CH2:62][CH2:61][CH2:60]1>>[S:71]1[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:8]=[C:70]1[NH:69][C:67](=[O:68])[CH:66]([N:75]1[CH2:83][C:82]2[C:77](=[CH:78][CH:79]=[CH:80][CH:81]=2)[C:76]1=[O:84])[CH2:65][CH:59]1[CH2:60][CH2:61][CH2:62][CH2:63][CH2:64]1
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Reactant: O=C(Nc1nccs1)[C@H](CC1CCCCC1)N1Cc2ccccc2C1=O
Agent: F[P-](F)(F)(F)(F)F
Agent: Nc1nc2ccccc2s1
Agent: O=C(O)[C@H](CC1CCCCC1)N1Cc2ccccc2C1=O
Product: O=C(Nc1nc2ccccc2s1)C(CC1CCCCC1)N1Cc2ccccc2C1=O
Yield: 44 %

Procedure:
This compound was prepared via BOP coupling of (S)-3-cyclohexyl-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-propionic acid (prepared in Example 1, Step A, 144 mg; 0.5 mmol) and 2-amino-benzothiazole (81 mg; 0.55 mmol) in a manner similar to that used for the preparation of (S)-3-cyclohexyl-2-( 1-oxo-1,3-dihydro-isoindol-2-yl)-N-thiazol-2-yl-propionamide (outlined in Example 9, Step B) to provide crude N-Benzothiazol-2-yl-3-cyclohexyl-2-( 1-oxo-1,3-dihydro-isoindol-2-yl)-propionamide. The crude product was purified by flash chromatography (Merck Silica gel 60, 230-400 mesh, eluent: 35% ethyl acetate/hexanes) to give 185 mg (44%) of N-Benzothiazol-2-yl-3-cyclohexyl-2-( 1-oxo-1,3-dihydro-isoindol-2-yl)-propionamide as a white solid: EI-HRMS m/e calcd for C24H25N3O2S (M+) 419.1667, found 419.1661.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][O:11][CH:10]([CH:14]([O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[O:28][CH3:29])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:9]1)C1C=CC=CC=1>CCO.Cl.[Pd]>[CH3:29][O:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[O:21][CH:14]([CH:10]1[O:11][CH2:12][CH2:13][NH:8][CH2:9]1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: COc1ccccc1OC(c1ccccc1)C1CN(Cc2ccccc2)CCO1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: COc1ccccc1OC(c1ccccc1)C1CNCCO1
Yield: 54.6 %

Procedure:
A solution of 4-benzyl-2-[α-(2-methoxy-phenoxy)-benzyl]-morpholine (5 g) in 99% EtOH (150 ml) and HCl (6 ml) was reduced (palladium-charcoal catalyst) for 4 hours at room temperature. The mixture was then filtered, dried under vacuum and separated on a silica gel column (mobile phase: CHCl3 :MeOH:NH4OH=170:30:2) to obtain 2-[α-(2-methoxy-phenoxy)-benzyl]-morpholine (2.1 g; yield 54.7%) as a transparent oil .HCl m.p. 140°-170° C.
Reaction SMILES: [Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].[C:6]1([C:12]2[CH:17]=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:15]=[CH:14][S+:13]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[NH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(O)C>[Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].[NH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:14]2[CH:15]=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:17]=[C:12]([C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=3)[S+:13]=2)=[CH:27][CH:26]=1
Reactant: c1ccc(-c2cc[s+]c(-c3ccccc3)c2)cc1
Reactant: Nc1ccccc1
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CCO
Product: Nc1ccc(-c2cc(-c3ccccc3)cc(-c3ccccc3)[s+]2)cc1
Reaction time: 2 h
Yield: 52 %

Procedure:
2,4-diphenylthiopyrylium perchlorate (1 g, 2.87 mmole) and aniline (0.54 g, 5.74 mmole) were heated in 10 ml of ethanol at 40° to 45° C. The reaction mixture was immediately colored deep blue. After stirring was continued for two hours, the reaction mixture was allowed to stand at room temperature to give blue needles of 2-(4-aminophenyl)-4,6-diphenylthiopyrylium perchlorate. This compound was recrystallized from a mixture of ethanol-chloroform.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH2:21][C:22]([CH2:45][CH3:46])=[CH:23][CH2:24][C:25]1[C:33]([O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])=[C:32]2[C:28]([CH2:29][O:30][C:31]2=[O:41])=[C:27]([CH3:42])[C:26]=1[O:43][CH3:44].C(Br)(Br)(Br)[Br:48]>ClCCl>[Br:48][CH2:21][C:22]([CH2:45][CH3:46])=[CH:23][CH2:24][C:25]1[C:33]([O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])=[C:32]2[C:28]([CH2:29][O:30][C:31]2=[O:41])=[C:27]([CH3:42])[C:26]=1[O:43][CH3:44]
Reactant: CCC(=CCc1c(OC)c(C)c2c(c1OCC[Si](C)(C)C)C(=O)OC2)CO
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCC(=CCc1c(OC)c(C)c2c(c1OCC[Si](C)(C)C)C(=O)OC2)CBr
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.5 %

Procedure:
Polymer-supported triphenylphosphine (3 mmol/g, 0.66 g) was soaked in dichloromethane (6 mL) for 1 hour 6-(3-Hydroxymethyl-pent-2-enyl)-5-methoxy-4-methyl-7-(2-trimethylsilanyl-ethoxy)-3H-isobenzofuran-1-one (260 mg, 0.66 mmol) and carbon tetrabromide (657 mg, 1.98 mmol) were added sequentially and the mixture was shaken for 1 hour at room temperature. The mixture was filtered and the filtrate was concentrated. The residue was purified by silica gel chromatography to provide 233 mg (77%) of the product as a white solid. 1H NMR (300 MHz, CDCl3) δ 0.00 (s, 9H), 1.08 (t, 3H), 1.20 (dd, 2H, J=7, 8 Hz), 2.14 (s, 3H), 2.35-2.43 (m, 2H), 3.44 (d, J=7.2, 2H), 3.73 (s, 3H), 3.95 (s, 2H), 4.27 (dd, 2H, J=7, 8 Hz), 5.08 (s, 2H), 5.53 (t, J=7.2 Hz, 1H) ppm.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5][C:6]1[N:7]([CH3:18])[C:8]([C:11]2[S:15][C:14]([CH3:16])=[N:13][C:12]=2[CH3:17])=[N:9][N:10]=1.C([O-])([O-])=O.[K+].[K+].Cl.[F:26][C:27]1[CH:28]=[C:29]2[C:37](=[CH:38][CH:39]=1)[C:32]1([CH2:36][CH2:35][NH:34][CH2:33]1)[CH2:31][CH2:30]2.[Na+].[I-]>CN1C(=O)CCC1.O>[F:26][C:27]1[CH:28]=[C:29]2[C:37](=[CH:38][CH:39]=1)[C:32]1([CH2:36][CH2:35][N:34]([CH2:2][CH2:3][CH2:4][S:5][C:6]3[N:7]([CH3:18])[C:8]([C:11]4[S:15][C:14]([CH3:16])=[N:13][C:12]=4[CH3:17])=[N:9][N:10]=3)[CH2:33]1)[CH2:31][CH2:30]2
Reactant: Fc1ccc2c(c1)CCC21CCNC1
Reactant: Cc1nc(C)c(-c2nnc(SCCCCl)n2C)s1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1nc(C)c(-c2nnc(SCCCN3CCC4(CCc5cc(F)ccc54)C3)n2C)s1
Reaction time: 0.17 h
Yield: 36.1 %

Procedure:
To a solution of 5-(5-(3-chloropropylthio)-4-methyl-4H-1,2,4-triazol-3-yl)-2,4-dimethylthiazole (Prep28, 70 mg, 0.23 mmol) in dry NMP (1 ml), K2CO3 (0.145 g, 1.05 mmol) was added and stirred for 10 min. Then 5-fluoro-2,3-dihydrospiro[indene-1,3′-pyrrolidine]hydrochloride salt (Prep14, 88 mg, 0.39 mmol) and NaI (0.07 g, 0.47 mmol) were added and stirred overnight at 65° C. Water was then added and the solution was extracted with ethyl acetate (2×10 ml). The organic phase was washed with brine, dried over Na2SO4 and concentrated in vacuo. The crude product was purified by P-HPLC to give 38 mg of the title compound (y=36%).