Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@H:18]4[CH2:22][CH2:21][N:20](S(C)(=O)=O)[CH2:19]4)[C:14]([F:27])=[CH:13][N:12]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH3:28][O:29][CH2:30][C:31](Cl)=[O:32]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@H:18]4[CH2:22][CH2:21][N:20]([C:31](=[O:32])[CH2:30][O:29][CH3:28])[CH2:19]4)[C:14]([F:27])=[CH:13][N:12]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CS(=O)(=O)N1CC[C@H](Nc2nc(-c3c[nH]c4ncc(Cl)cc34)ncc2F)C1
Reactant: COCC(=O)Cl
Product: COCC(=O)N1CC[C@H](Nc2nc(-c3c[nH]c4ncc(Cl)cc34)ncc2F)C1
Yield: 33 %

Procedure:
According to the procedure for compound 398 using methoxyacetyl chloride (50 mg, 0.46 mmol) afforded 8.6 mg (33% yield) of 481, as a solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][CH:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:16]=[CH:15][C:14](B3OC(C)(C)C(C)(C)O3)=[CH:13][CH:12]=2)[CH2:7][CH2:6]1.Br[C:28]1[CH:33]=[CH:32][C:31]([Br:34])=[CH:30][N:29]=1.C([O-])([O-])=O.[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1.C(O)C>[CH3:1][O:2][C:3](=[O:26])[CH2:4][CH:5]1[CH2:6][CH2:7][CH:8]([C:11]2[CH:12]=[CH:13][C:14]([C:28]3[CH:33]=[CH:32][C:31]([Br:34])=[CH:30][N:29]=3)=[CH:15][CH:16]=2)[CH2:9][CH2:10]1
Reactant: COC(=O)CC1CCC(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Brc1ccc(Br)nc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: COC(=O)CC1CCC(c2ccc(-c3ccc(Br)cn3)cc2)CC1
Temperature: 60 °C

Procedure:
To a solution of {4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclohexyl}-acetic acid methyl ester (4.0 g, 11.2 mmol, 1.0 equiv) and 2,5-dibromopyridine (3.2 g, 13.4 mmol, 1.2 equiv) in 50 Ml toluene/ethanol (1:1) was added 2 M Na2CO3 (16.8 Ml, 3 equiv) followed by Pd(PPh3)4 (0.38 g, 0.34 mmol, 0.03 equiv). The biphasic mixture was sparged with nitrogen for 10 min, then heated to 60° C. for 3 days. The reaction was cooled to room temperature and then partitioned between ethyl acetate and saturated ammonium chloride solution. The organic extracts were washed with brine, then dried over sodium sulphate and concentrated in vacuo. Purification by silica gel chromatography (7-40% EtOAc in hexanes) afforded the title compound as a yellow solid: 1H NMR (400 MHz, CDCl3) 1.11 (dd, J=13.01, 2.15 Hz, 2 H) 1.41-1.54 (m, 2 H) 1.76-1.90 (m, 5 H) 2.20 (d, J=6.57 Hz, 2 H) 2.46 (tt, J=12.09, 3.19 Hz, 1 H) 3.62 (s, 3 H) 7.23 (d, J=8.08 Hz, 2 H) 7.53 (dd, J=8.59, 0.76 Hz, 1 H) 7.77 (dd, J=8.46, 2.40 Hz, 1 H) 7.81 (q, J=3.87 Hz, 1 H) 7.81 (d, J=8.34 Hz, 1 H) 8.64 (d, J=1.77 Hz, 1 H); (M+H)+ 390.0.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.[F:9][C:10]([C:13]1[CH:18]=[CH:17][N:16]2[C:19]([Sn](CCCC)(CCCC)CCCC)=[CH:20][N:21]=[C:15]2[N:14]=1)([CH3:12])[CH3:11]>>[Br:8][C:4]1[N:3]=[C:2]([C:19]2[N:16]3[CH:17]=[CH:18][C:13]([C:10]([F:9])([CH3:11])[CH3:12])=[N:14][C:15]3=[N:21][CH:20]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: Brc1cccc(Br)n1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc2nc(C(C)(C)F)ccn12
Product: CC(C)(F)c1ccn2c(-c3cccc(Br)n3)cnc2n1
Yield: 68 %

Procedure:
2,6-Dibromopyridine was coupled with 7-(1-fluoro-1-methylethyl)-3-tributylstannylimidazo[1,2-α]pyrimidine by the method of Example 1 to afford 3-(6-bromopyridin-2-yl)-7-(1-fluoro-1-methylethyl)imidazo[1,2-α]pyrimidine (1.0 g, 68%) as a pale yellow solid: δH (360 MHz, CDCl3) 1.81 (6H, d, J 22), 7.37 (1H, d, J 8), 7.42 (1H, dd, J 7 and 2), 7.61 (1H, dd, J 8 and 8), 7.71 (1H, dd, J 8 and 1), 8.33 (1H, s), 10.09 (1H, d, J 7).
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2Cl)[C:7]([CH2:10][CH:11]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:12]([O:14][CH3:15])=[O:13])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4].[H][H]>CO.[Pt]=O>[CH2:1]([C:5]1[N:6]([CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:7]([CH2:10][CH:11]([CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:12]([O:14][CH3:15])=[O:13])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ncc(CC(Cc2ccccc2)C(=O)OC)n1Cc1ccccc1Cl
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CO
Product: CCCCc1ncc(CC(Cc2ccccc2)C(=O)OC)n1Cc1ccccc1
Yield: 18.1 %

Procedure:
A solution of methyl 3-[2-n-butyl-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]-2-benzylpropanoate [Example 9] (0.75 g) in methanol (25 mL) was stirred with platinum oxide (0.07 g) at room temperature under one atmosphere of hydrogen for 18 hours. Column chromatographic separation of the crude product over silica gel with 10% methanol in ethyl acetate gave 0.52 g of the crude de-chlorinated product. This was further purified on a prep silica gel plate using 30% acetone in hexane to provide 0.125 g of methyl 3-[2-n-butyl-1-benzyl-1H-imidazol-5-yl]-2-benzylpropanoate as a syrup.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.N1C=CN=C1.[Si:14](Cl)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15].O>C1COCC1>[Si:14]([O:8][C:5]1[CH:6]=[CH:7][C:2]([NH2:1])=[CH:3][CH:4]=1)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]
Reactant: Nc1ccc(O)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)[Si](C)(C)Oc1ccc(N)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 67.1 %

Procedure:
To a solution of 4-aminophenol (11 g, 100 mmol) and imidazole (10 g, 150 mmol) in THF (250 mL) was added tert-butyldimethylsilyl chloride (18 g, 120 mmol) and the reaction was stirred at room temperature for 18 h. The reaction mixture was poured into water and extracted with diethyl ether. The combined organic layers were dried over Na2SO4, filtered, concentrated and the residue was purified by column chromatography to afford the desired product (15 g, 67%): ESI MS m/z 224 [C12H21NOSi+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[F:29])[CH2:5][NH:6][C:7]1[S:8][C:9](=[CH:13][C:14]2[N:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[N:20]=[CH:19][C:18](C#N)=[CH:17]3)[C:10](=[O:12])[N:11]=1.C(O[Na])(C)=O.[CH:35]([O:38]C1C=CN=C2C=1N=C(C=C1SC(NC3CC3C3C=CC=CC=3)=NC1=O)C=C2)([CH3:37])[CH3:36]>CC(O)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[F:29])[CH2:5][NH:6][C:7]1[S:8][C:9](=[CH:13][C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[C:17]([O:38][CH:35]([CH3:37])[CH3:36])[CH:18]=[CH:19][N:20]=3)[N:15]=2)[C:10](=[O:12])[N:11]=1
Reactant: N#Cc1cnc2ccc(C=C3SC(NCc4ccc(F)c(Cl)c4)=NC3=O)nc2c1
Reactant: CC(C)Oc1ccnc2ccc(C=C3SC(NC4CC4c4ccccc4)=NC3=O)nc12
Agent: CC(=O)O[Na]
Solvent: CC(=O)O
Product: CC(C)Oc1ccnc2ccc(C=C3SC(NCc4ccc(F)c(Cl)c4)=NC3=O)nc12
Temperature: 100 °C
Yield: 86.9 %

Procedure:
To a mixture of 2-(3-chloro-4-fluoro-benzylamino)-thiazol-4-one (41.4 mg, 0.16 mmol) (see Example 19), AcONa (160 mg, 1.95 mmol), and 8-isopropoxy-[1,5]naphthyridine-2-carbaldehyde (38.9 mg, 0.18 mmol) (see Example 20) in a sealed tube was added AcOH(0.3 mL). The reaction mixture was heated to 100° C. (oil bath) for 2 hrs. The reaction mixture was then cooled to r.t. and triturated with water. The solid was collected by filtration and washed with water, acetone and ether to give 2-(3-chloro-4-fluoro-benzylamino)-5-(8-isopropoxy-[1,5]naphthyridin-2-ylmethylene)-thiazol-4-one as a light brown solid (63.5 mg, 86.9%). HR-ES (+) m/e calcd for C22H18FClN4O2S (M+H)+ 457.0896. found 457.0897.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:25]=[CH:26][C:27]=1[N+:28]([O-:30])=[O:29])[CH2:12][CH:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH2:15][C:14]1=[N:23]O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)(Cl)Cl.[OH2:37]>C(Cl)(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:25]=[CH:26][C:27]=1[N+:28]([O-:30])=[O:29])[CH2:12][CH:13]1[C:22]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH2:16][CH2:15][C:14](=[O:37])[NH:23]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(CC2C(=NO)CCc3ccccc32)cc1OCc1ccccc1
Reactant: O
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: O=C1CCc2ccccc2C(Cc2ccc([N+](=O)[O-])c(OCc3ccccc3)c2)N1
Temperature: 25 °C

Procedure:
A solution of 1-(3-benzyloxy-4-nitrobenzyl)-3,4-dihydro-1H-naphthalen-2-one oxime (600 mg, 1.49 mmol) in 10 mL CHCl3 is cooled to −50° C. PCl5 (310 mg, 1.49 mmol) is added portionwise over 10 minutes to maintain the temperature below −30° C. The suspension is stirred until it becomes a solution then is warmed to RT and stirred for 2 hours. Water is added and the solution is extracted with CH2Cl2. The organic layer is washed with water, 5% NaOH and brine then is dried over MgSO4. The solvent is removed under reduced pressure and the residue is purified by flash chromatography using a gradient of 14-100% EtOAc/hexane as eluent to give the title compound as a yellow solid. 1H NMR (CDCl3): 7.85-7.83 (d, J=8.59 Hz, 1H), 7.45-7.20 (m, 8H), 7.09-7.07 (d, J=7.58 Hz, 1H), 6.88-6.86 (dd, J=1.52 Hz, 8.34 Hz, 2 H), 5.80-5.79 (d, J=4.80 Hz, 1H), 5.22-5.14 (q, J=12.12, 2H), 4.74-4.69 (m, 1H), 3.37-3.32 (q, J=5.56 Hz, 1H), 3.19-3.08 (m, 2H), 3.04-2.97 (m, 1H), 2.81-2.65 (m, 2H). (M−1)−=401.
Reaction SMILES: [N:1]1([CH2:6][C@@H:7]([O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:21](=[O:25])[CH2:20][CH2:19][CH2:18][C:17]=3[C:16]=2[CH2:26][S:27][C:28]2[CH:36]=[CH:35][CH:34]=[CH:33][C:29]=2[C:30]([OH:32])=O)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[CH3:37][N:38]([CH3:42])[CH2:39][CH2:40][NH2:41]>>[CH3:37][N:38]([CH3:42])[CH2:39][CH2:40][NH:41][C:30](=[O:32])[C:29]1[CH:33]=[CH:34][CH:35]=[CH:36][C:28]=1[S:27][CH2:26][C:16]1[C:17]2[CH2:18][CH2:19][CH2:20][C:21](=[O:25])[C:22]=2[CH:23]=[CH:24][C:15]=1[O:14][C@@H:7]([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[CH2:6][N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CN(C)CCN
Reactant: O=C(O)c1ccccc1SCc1c(O[C@H](Cn2ccnc2)c2ccccc2)ccc2c1CCCC2=O
Product: CN(C)CCNC(=O)c1ccccc1SCc1c(O[C@H](Cn2ccnc2)c2ccccc2)ccc2c1CCCC2=O
Yield: 47.5 %

Procedure:
Using the method in Example 172, 2-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzoic acid (50 mg, 0.10 mmol, 0.20M in DMF) and 2-dimethylaminoethylamine (27 mg, 0.30 mmol, 0.60M in DMF) were combined to give 27 mg of the desired compound: Low resolution mass spectrum (LC-MS, APCI) m/z 569 [M+H]+.
Reaction SMILES: [OH:1][C:2]1([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[CH:17]=2)[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[C:4](=[O:11])N1CCCC.Cl.[OH2:26]>>[OH:26][C:2]1([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[CH:17]=2)[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[C:4](=[O:11])[O:1]1
Reactant: O
Reactant: CCCCN1C(=O)c2cccnc2C1(O)c1cccc([N+](=O)[O-])c1
Agent: Cl
Product: O=C1OC(O)(c2cccc([N+](=O)[O-])c2)c2ncccc21

Procedure:
The 7-hydroxy-7-(3-nitrophenyl)-6-(n-butyl)-6,7-dihydropyrrolo[3,4-b]pyridin-5-one was mixed with 500 mL of water and 250 mL of concentrated hydrochloric acid was added. The mixture was heated under reflux for 20 hours. After cooling the mixture was diluted with 500 mL of water and the solid was removed by filtration. After washing the solid with water (500 mL) and methanol (200 mL) the material was dried to give 39.85 of 7-hydroxy-7-(3-nitrophenyl)-7H-furo[3,4-b]pyridin-5-one.
Reaction SMILES: [C:1]1([C:7](=[CH:11][CH2:12][CH3:13])[CH:8]=[N:9][OH:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br.[CH2:15]([O:17][C:18]([C@@H:20]1[CH2:25][CH2:24][CH2:23][N:22]([CH2:26][CH2:27]Br)[CH2:21]1)=[O:19])[CH3:16].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:15]([O:17][C:18]([C@@H:20]1[CH2:25][CH2:24][CH2:23][N:22]([CH2:26][CH2:27][O:10][N:9]=[CH:8][C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:11][CH2:12][CH3:13])[CH2:21]1)=[O:19])[CH3:16]
Reactant: CCOC(=O)[C@@H]1CCCN(CCBr)C1
Reactant: CCC=C(C=NO)c1ccccc1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCC=C(C=NOCCN1CCC[C@@H](C(=O)OCC)C1)c1ccccc1
Temperature: 25 °C
Reaction time: 96 h
Yield: 52.7 %

Procedure:
A mixture of the above oxime (2.0 g, 11 mmol), (R)-1-(2-bromoethyl)-3-piperidinecarboxylic acid ethyl ester hydrobromide (3.94 g, 11 mmol), potassium carbonate (4.73 g, 34 mmol) and acetone (25 ml) was stirred at room temperature for 4 days. The mixture was filtered and the solvent was evaporated from the filtrate in vacuo. The residue was purified by column chromatography on silica gel (75 g, cyclohexane/ethyl acetate 3/1) to give 2.08 g of (R)-1-(2-(((2-phenyl-2-penten-1-ylidene)amino)oxy)ethyl)-3-piperidinecarboxylic acid ethyl ester.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([O:10][CH3:11])=[O:9])=[CH:4][C:3]=1[SH:12].[CH3:13][C:14]1([CH3:29])[CH2:23][CH2:22][C:21]([CH3:25])([CH3:24])[C:20]2[CH:19]=[C:18]([C:26](Cl)=[O:27])[CH:17]=[CH:16][C:15]1=2>C(N(CC)CC)C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([O:10][CH3:11])=[O:9])=[CH:4][C:3]=1[S:12][C:26]([C:18]1[CH:17]=[CH:16][C:15]2[C:14]([CH3:29])([CH3:13])[CH2:23][CH2:22][C:21]([CH3:25])([CH3:24])[C:20]=2[CH:19]=1)=[O:27]
Reactant: COC(=O)c1ccc(C)c(S)c1
Reactant: CC1(C)CCC(C)(C)c2cc(C(=O)Cl)ccc21
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(C)c(SC(=O)c2ccc3c(c2)C(C)(C)CCC3(C)C)c1
Yield: 88.3 %

Procedure:
In a manner analogous to Example 1(a), starting with 1.83 g (10 mmol) of methyl 3-mercapto-4-methyl benzoate, 1.5 ml of triethylamine and 2.76 g (11 mmol) of 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphtoyl chloride, methyl 4-methyl-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphtoylthio)benzoate (3.50 g; 88%) is produced.
Reaction SMILES: O([C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:18]([F:21])([F:20])[F:19])[CH:16]=2)[CH:11]=[CH:10][N:9]=1)C1C=CC=CC=1.C([O-])(=O)C.[NH4+:26].[OH-].[Na+]>O>[F:19][C:18]([F:21])([F:20])[C:15]1[CH:16]=[C:17]2[C:12]([CH:11]=[CH:10][N:9]=[C:8]2[NH2:26])=[CH:13][CH:14]=1
Reactant: FC(F)(F)c1ccc2ccnc(Oc3ccccc3)c2c1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1nccc2ccc(C(F)(F)F)cc12
Temperature: 25 °C

Procedure:
A mixture of 1-phenoxy-7-(trifluoromethyl)isoquinoline (670 mg, 2.3 mmol), from above step D, and ammonium acetate (1.8 g, 23 mmol) was heated at 160° C. for 4 h. The mixture was cooled to room temperature and dissolved in water. Sodium hydroxide (1N solution) was added until the solution was basic and extracted with EtOAc (×4). The combined organic fractions were washed with saturated NaCl, dried over Na2SO4 and evaporated under vacuum to give the title compound.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]([CH3:8])[CH2:5][CH2:6][OH:7].F[C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=1>O1CCCC1>[CH3:3][N:4]([CH3:8])[CH2:5][CH2:6][O:7][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CN(C)CCO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(C)CCOc1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Sodium hydride (60% in oil, 1.04 g, 26 mmol) was placed in a round bottom flask and washed with hexanes and then was suspended in tetrahydrofuran and cooled to 0° C. A solution of 2-dimethylamino-ethanol (Aldrich, 1.78g, 20 mmol) in tetrahydrofuran was added and the suspension was stirred at 0° C. for 30 minutes and at room temperature for 1 hour. Then, the suspension was cooled to −20° C. and a solution of 4-fluoro nitrobenzene (Aldrich, 3.95g, 28 mmol) in tetrahydrofuran was added. The mixture was stirred for 2 hours by gradually increasing the temperature to around 5° C. The reaction was quenched by addition of 1N HCl and the mixture was washed with ether and basified with 1 N NaOH and extracted with diethyl ether. The extract was dried (Na2SO4) and concentrated to give a light yellow oil. 2.8 g, 66%. MS (ES) MH+=211.
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][C@H:10]([NH:13][C:14]([C:16]23[CH2:25][CH:20]4[CH2:21][CH:22]([CH2:24][CH:18]([CH2:19]4)[CH2:17]2)[CH2:23]3)=[O:15])[CH2:9]1)C1C=CC=CC=1.O.NN>C(O)C.[C].[Pd]>[NH:8]1[CH2:12][CH2:11][C@H:10]([NH:13][C:14]([C:16]23[CH2:25][CH:20]4[CH2:21][CH:22]([CH2:24][CH:18]([CH2:19]4)[CH2:17]2)[CH2:23]3)=[O:15])[CH2:9]1
Reactant: O=C(N[C@H]1CCN(Cc2ccccc2)C1)C12CC3CC(CC(C3)C1)C2
Agent: [Pd]
Agent: NN
Solvent: O
Solvent: CCO
Product: O=C(N[C@H]1CCNC1)C12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Yield: 93.5 %

Procedure:
(S)-N-(1-Benzylpyrrolidin-3-yl)-1-adamantanecarboxamide (10.5 g, described in Example 13) was dissolved in ethanol (100 ml), and 10% palladium-carbon (5 g) was added thereto. The mixture was stirred at room temperature, and to the reaction mixture was added hydrazine monohydrate (1.5 ml). The mixture was stirred under heating for 1 hour. The reaction mixture was cooled to room temperature, and 10% palladium-carbon was filtered off with celite. The filtrate was concentrated, and IPE (isopropyl ether) was added to the obtained residue. The precipitated crystals were collected by filtration to give (S)-N-(pyrrolidin-3-yl)-1-adamantanecarboxamide (7.2 g), melting point 186-188° C.
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:40])[C@@H:15]([O:32][C:33]1[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=1)[C@@H:16]([C:18]1[CH:23]=[CH:22][C:21]([O:24]CC2C=CC=CC=2)=[CH:20][CH:19]=1)[OH:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>C(O)C.[Pd]>[CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:40])[C@@H:15]([O:32][C:33]1[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=1)[C@H:16]([OH:17])[C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [H][H]
Reactant: Cc1ccc(O[C@H](C(=O)N2C(=O)OC[C@@H]2Cc2ccccc2)[C@H](O)c2ccc(OCc3ccccc3)cc2)cc1
Agent: [Pd]
Solvent: CCO
Product: Cc1ccc(O[C@H](C(=O)N2C(=O)OC[C@@H]2Cc2ccccc2)[C@H](O)c2ccc(O)cc2)cc1
Yield: 111.6 %

Procedure:
To a solution of (S)-4-benzyl-3-[(2S,3R)-3-(4-benzyloxyphenyl)-3-hydroxy-2-(4-methylphenoxy)propionyl]oxazolidin-2-one (9.80 g) obtained from Reference example 20(b) in ethanol (150 ml) was added 5% palladium-charcoal (1.00 g), and the reaction solution was stirred at 50° C. for 4 hours in an atmosphere of hydrogen. After the catalyst was removed by filtration, the filtrate was concentrated under reduced pressure. Water was added to the residue, and the resulting solution was extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous magnesium sulfate, and then the target compound (9.10 g) was obtained as a foam.
Reaction SMILES: FC(F)(F)C(O)=O.FC(F)(F)C(O)=O.[NH2:15][CH2:16][C@H:17]1[CH2:22][CH2:21][C@H:20]([N:23]2[C:27]3=[C:28]4[S:34][CH:33]=[CH:32][C:29]4=[N:30][CH:31]=[C:26]3[N:25]=[C:24]2[C@H:35]([OH:37])[CH3:36])[CH2:19][CH2:18]1.C(N(CC)CC)C.Cl[C:46]([O:48][CH:49]([CH3:51])[CH3:50])=[O:47]>C(Cl)Cl.C1(C)C=CC=CC=1>[OH:37][C@@H:35]([C:24]1[N:23]([C@H:20]2[CH2:21][CH2:22][C@H:17]([CH2:16][NH:15][C:46](=[O:47])[O:48][CH:49]([CH3:51])[CH3:50])[CH2:18][CH2:19]2)[C:27]2=[C:28]3[S:34][CH:33]=[CH:32][C:29]3=[N:30][CH:31]=[C:26]2[N:25]=1)[CH3:36]
Reactant: C[C@@H](O)c1nc2cnc3ccsc3c2n1[C@H]1CC[C@H](CN)CC1
Reactant: CC(C)OC(=O)Cl
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)OC(=O)NC[C@H]1CC[C@H](n2c([C@@H](C)O)nc3cnc4ccsc4c32)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (1R)-1-{1-[trans-4-(aminomethyl)cyclohexyl]-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-2-yl}ethanol bis(trifluoroacetate) (18 mg, 0.032 mmol) and triethylamine (22 μL, 0.16 mmol) in methylene chloride (1 mL) was added 1.0 M isopropyl chloroformate in toluene (39 μL). The mixture was stirred at room temperature for 1 h, then stripped to dryness and purified on prep-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min) to give the desired product (0.9 mg, 7%). LCMS calculated for C21H29N4O3S (M+H)+: m/z=417.2. Found: 417.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@H:13]([CH2:21][CH:22]([CH3:24])[CH3:23])[C:14]([O:16]C(C)(C)C)=[O:15])(=[O:11])=[O:10])=[CH:5][CH:4]=1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([S:9]([N:12]([CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C@H:13]([CH2:21][CH:22]([CH3:24])[CH3:23])[C:14]([OH:16])=[O:15])(=[O:11])=[O:10])=[CH:7][CH:8]=1
Reactant: COc1ccc(S(=O)(=O)N(Cc2ccccc2)[C@H](CC(C)C)C(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)N(Cc2ccccc2)[C@H](CC(C)C)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
t-Butyl 2(R)-[[4-methoxybenzenesulfonyl](benzyl)amino]-4-methylpentan oate (5.38 g, 12.02 mmol) is dissolved in methylene chloride (100.0 mL). Hydrochloric acid gas (from a lecture bottle) is bubbled through the solution for 20 minutes. The reaction is sealed and stirred overnight at room temperature. The solvent is then evaporated to give 2(R)-[[4-methoxybenzenesulfonyl](benzyl)amino]-4-methylpentanoic acid.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH:32]([CH3:34])[CH3:33])=[CH:27][CH:26]=2)[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([C:15]1[CH:20]=[CH:19][C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:17][CH:16]=1)=[CH:10][CH:9]=2)=[O:5])C.[OH-].[Na+].O.Cl>O1CCOCC1>[C:21]([C:18]1[CH:19]=[CH:20][C:15]([C:11]2[CH:12]=[C:13]3[C:8](=[CH:9][CH:10]=2)[N:7]([C:25]2[CH:26]=[CH:27][C:28]([O:31][CH:32]([CH3:33])[CH3:34])=[CH:29][CH:30]=2)[C:6]([C:4]([OH:5])=[O:3])=[CH:14]3)=[CH:16][CH:17]=1)([CH3:22])([CH3:24])[CH3:23]
Reactant: CCOC(=O)c1cc2cc(-c3ccc(C(C)(C)C)cc3)ccc2n1-c1ccc(OC(C)C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)Oc1ccc(-n2c(C(=O)O)cc3cc(-c4ccc(C(C)(C)C)cc4)ccc32)cc1
Reaction time: 0.5 h
Yield: 67.7 %

Procedure:
A mixture of 5-(4-tert-butylphenyl)-1-(4-isopropoxyphenyl)indole-2-carboxylic acid ethyl ester (259 mg, 0.57 mmol; see step (b)), NaOH (114 mg, 2.85 mmol), water (0.6 mL) and dioxane (3 mL) was heated using microwave irradiation for 1 h at 120° C. An additional portion of NaOH (100 mg) was added and heating was continued for another 30 min at 120° C. After cooling, the reaction was acidified with HCl (1M) to pH 2 and extracted with EtOAc. The combined extracts were washed with water, brine and dried over Na2SO4 and purified by chromatography to give the title compound (165 mg, 60%).
Reaction SMILES: S(Cl)([Cl:3])=O.[C:5]([C:8]12[CH2:17][CH:13]([CH2:14][CH2:15][CH2:16]1)[CH:12]1[CH2:18][CH:9]2[CH2:10][CH2:11]1)(O)=[O:6]>C1C=CC=CC=1>[Cl:3][C:5]([C:8]12[CH2:17][CH:13]([CH2:14][CH2:15][CH2:16]1)[CH:12]1[CH2:18][CH:9]2[CH2:10][CH2:11]1)=[O:6]
Reactant: O=C(O)C12CCCC(C1)C1CCC2C1
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: O=C(Cl)C12CCCC(C1)C1CCC2C1
Yield: 92 %

Procedure:
68 ml of thionyl chloride was added dropwise to 46.0 g (0.24 mole) of 1-carboxytricyclo[4.3.1.12,5 ]undecane dissolved in 200 ml of benzene at room temperature. The resulting mixture was refluxed for 1.5 hours, and the excess thionyl chloride and benzene were distilled off under reduced pressure. The residue obtained was fractionally distilled under reduced pressure to afford 47.0 g (yield: 92%) of 1-chorocarbonyltricyclo[4.3.1.12,5 ]undecane having a boiling point of 101° c. (1 mmHg).