Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH3:7])=[CH:3][CH:2]=1.[CH:8](=O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(OC(=O)C)(=O)C>[C:9]1(/[CH:8]=[CH:7]/[C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Cc1ccncc1
Reactant: O=Cc1ccccc1
Solvent: CC(=O)OC(C)=O
Product: C(=C/c1ccncc1)\c1ccccc1
Yield: 32.9 %

Procedure:
A solution of 4-picoline (18.6 g, 0.2 mol) and benzaldehyde (21.2 g, 0.2mol) in acetic anhydride (125 ml) was stirred under reflux for 24 h. The resulting black solution was evaporated, the residue partitioned between ethyl acetate (100 ml) and aqueous sodium carbonate (100 ml) and the liquid phases decanted from the solid residue. The organic layer was washed with sodium carbonate (100 ml), dried (MgSO4), and evaporated to leave a black solid. The solid remaining from the earlier extraction was dissolved in dichloromethane (100 ml), the solution washed with sodium carbonate (75 ml), dried (MgSO4) and evaporated. The combined solid residues were dissolved in methanol (200ml), treated with charcoal, filtered and the filtrate evaporated to leave a brown solid which was triturated with cyclohexane, the suspension filtered and the solid recrystallised from cyclohexane to leave the product as a brown crystalline powder (11.94 g). The combined organic supernatants were chromatographed on silica gel eluting with ethyl acetate/hexanes (7:3) to give a further crop as a yellow solid (6.2 g).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:21].C(O)C>>[ClH:21].[CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccccc2)CC1
Agent: Cl
Solvent: CCO
Product: c1ccc(CN2CCNCC2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 97 %

Procedure:
To 1-benzyl-4-tert-butoxycarbonylpiperazine (3.12 g), saturated ethanol hydrochloride was added, followed by stirring for 90 minutes at room temperature. The solvent was distilled off under reduced pressure, followed by drying, whereby the title compound (2.73 g, 97%) was obtained as white powder.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:4]=[C:5]([O:18][S:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[S:28]([N:31]([CH2:39][CH2:40][C:41]([O:43]CC)=[O:42])[CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)(=[O:30])=[O:29])(=[O:21])=[O:20])[CH:6]=[C:7]([CH:17]=1)[O:8][CH2:9][CH2:10][CH2:11][O:12][NH:13][C:14]([NH2:16])=[NH:15].C(C(=CC1C=CC(O)=CC=1)C(O)=O)#N>>[CH3:2][C:3]1[CH:4]=[C:5]([O:18][S:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[S:28]([N:31]([CH2:39][CH2:40][C:41]([OH:43])=[O:42])[CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)(=[O:29])=[O:30])(=[O:20])=[O:21])[CH:6]=[C:7]([CH:17]=1)[O:8][CH2:9][CH2:10][CH2:11][O:12][NH:13][C:14]([NH2:16])=[NH:15]
Reactant: CCOC(=O)CCN(Cc1ccccc1)S(=O)(=O)c1ccccc1S(=O)(=O)Oc1cc(C)cc(OCCCONC(=N)N)c1
Agent: Cl
Agent: N#CC(=Cc1ccc(O)cc1)C(=O)O
Product: Cc1cc(OCCCONC(=N)N)cc(OS(=O)(=O)c2ccccc2S(=O)(=O)N(CCC(=O)O)Cc2ccccc2)c1
Yield: 97 %

Procedure:
The title compound was prepared in 97% yield from 3-[5-methyl-3-(2-(N-(2-ethoxycarbonylethyl)-N-benzylaminosulfonyl)phenylsulfonyloxy)phenoxy]propoxyguanidine hydrochloride as prepared in step b of Example 53, in a manner analogous to Example 27. 1H-NMR (300 MHz, DMSO-d6) δ8.19 (t, J=7.9 Hz, 2H), 7.99 (t, J=7.7 Hz, 1H), 7.88 (t, J=7.8 Hz, 1H), 7.56 (br s, 4H), 7.34 (m, 5H), 6.74 (s, 1H), 6.54 (s, 1H), 6.51 (s, 1H), 4.63 (s, 2H), 3.97 (t, J=6.2 Hz, 2H), 3.89 (t, J=6.1 Hz, 2H), 3.51 (t, J=7.4 Hz, 2H), 2.28 (t, J=7.5 Hz, 4H), 2.22 (s, 3H), 1.99 (pentet, J=6.1 Hz, 2H). Mass spectrum (MALDI-TOF, α-cyano-4-hydroxycinnamic acid matrix) calcd. for C27H32N4O9S2: 621.2 (M+H), 643.2 (M+Na). Found: 621.0, 642.9.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:17]=[CH:16][C:6]([CH2:7][NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:5][CH:4]=1.[C:18]1(=[O:24])[O:23][C:21](=[O:22])[CH2:20][CH2:19]1>C(Cl)Cl.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[C:11]([O:10][C:9]([NH:8][CH2:7][C:6]1[CH:16]=[CH:17][C:3]([CH2:2][NH:1][C:18](=[O:24])[CH2:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:4][CH:5]=1)=[O:15])([CH3:12])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)NCc1ccc(CN)cc1
Reactant: O=C1CCC(=O)O1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCc1ccc(CNC(=O)CCC(=O)O)cc1
Temperature: 36 °C
Yield: 73.4 %

Procedure:
A mixture of the above compound (27) (2.0 g, 8.5 mmol) and succinic anhydride (0.85 g, 8.5 mmol) in DCM (50 mL) were stirred at 36° C. for several hours. The product was diluted with 5% citric acid and extracted with DCM (3×50 mL). The combined extracts were washed with brine and dried over MgSO4 to give 2.1 g (28) (72%) of the desired compound. MS (ESI−) m/z 335.23 (M−H+).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:24])[C:8]2[CH:9]=[C:10]3[CH:20]=[C:19]([F:21])[C:18](F)=[C:17]([F:23])[C:11]3=[N:12][C:13]=2[N:14]([CH3:16])[CH:15]=1)=[O:5])[CH3:2].[OH:25][CH2:26][CH2:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([CH:35]2[CH2:40][NH:39][CH2:38][CH2:37][NH:36]2)=[CH:31][CH:30]=1>>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:24])[C:8]2[CH:9]=[C:10]3[CH:20]=[C:19]([F:21])[C:18]([N:39]4[CH2:38][CH2:37][NH:36][CH:35]([C:32]5[CH:31]=[CH:30][C:29]([O:28][CH2:27][CH2:26][OH:25])=[CH:34][CH:33]=5)[CH2:40]4)=[C:17]([F:23])[C:11]3=[N:12][C:13]=2[N:14]([CH3:16])[CH:15]=1)=[O:5])[CH3:2]
Reactant: OCCOc1ccc(C2CNCCN2)cc1
Reactant: CCOC(=O)c1cn(C)c2nc3c(F)c(F)c(F)cc3cc2c1=O
Product: CCOC(=O)c1cn(C)c2nc3c(F)c(N4CCNC(c5ccc(OCCO)cc5)C4)c(F)cc3cc2c1=O

Procedure:
(RS)-3-Ethoxycarbonyl-7,9-difluoro-8-{3-[4-(2-hydroxyethoxy)phenyl]-1-piperazinyl}-1 -methyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine was prepared under the conditions of Example 39, but starting with 3-ethoxycarbonyl-7,8,9-trifluoro-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine (1.9 g) and (RS)-2-[4-(2-hydroxyethoxy)phenyl]piperazine (1.6 g). The expected product (2.2 g) is obtained in the form of a yellow solid, m.p. 183° C.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][N:15]2[C@@H:10]([CH2:11][O:12][CH2:13][C:14]2=[O:18])[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:11]1[C@H:10]2[CH2:9][NH:8][CH2:17][CH2:16][N:15]2[C:14](=[O:18])[CH2:13][O:12]1
Reactant: CC(C)(C)OC(=O)N1CCN2C(=O)COC[C@H]2C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1COC[C@H]2CNCCN12
Temperature: 25 °C
Reaction time: 2 h
Yield: 76 %

Procedure:
To a solution of (R)-4-oxo-hexahydro-pyrazino[2,1-c][1,4]oxazine-8-carboxylic acid tert-butyl ester in DCM (5 mL) was added TFA (1 mL). The resulting mixture was stirred at RT for 2 h then concentrated in vacuo. The resulting residue was azeotroped with toluene then purified by SCX column to give the title compound as a colourless oil (60 mg, 76%).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH:8](I)[CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4].[N-:18]=[N+:19]=[N-:20].[Na+]>CN(C=O)C>[CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH:8]([N:18]=[N+:19]=[N-:20])[CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4]
Reactant: COC(=O)C1CC(I)CN1C(=O)OC(C)(C)C
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C1CC(N=[N+]=[N-])CN1C(=O)OC(C)(C)C
Reaction time: 8 h

Procedure:
To a solution of 4-iodo-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester in DMF is added NaN3, the resulting mixture is heated to about 65 centigrade and stirred overnight. The mixture is diluted, extracted and dried. After removal of solvent, the residue is purified to give 4-azido-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl (8).
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([OH:12])[CH:10]=2)[N:5]=[C:4]2[C:13]3[C:18]([O:19][CH2:20][C:3]=12)=[CH:17][C:16]([OH:21])=[CH:15][CH:14]=3.[Cl:22][C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][CH:28]=1>>[Cl:22][C:23]1[CH:28]=[C:27]([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([OH:12])[CH:10]=3)[N:5]=[C:4]3[C:13]4[C:18]([O:19][CH2:20][C:3]=23)=[CH:17][C:16]([OH:21])=[CH:15][CH:14]=4)[CH:26]=[CH:25][CH:24]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: Oc1ccc2c(c1)OCc1c-2nc2ccc(O)cc2c1Br
Product: Oc1ccc2c(c1)OCc1c-2nc2ccc(O)cc2c1-c1cccc(Cl)c1
Yield: 94 %

Procedure:
This compound was prepared from 7-bromo-3,9-dihydroxy-6H-chromeno[4,3-b]quinoline (7) using 3-chlorophenylboronic acid according to method M. Orange powder; Yield: 94%; mp 162-165° C. (dec.); 1H-NMR (400 MHz, DMSOd-6) δ 5.01 (s, 2H), 6.36 (d, J=2.3 Hz, 1H), 6.60 (dd, J=8.5, 2.2 Hz, 1H), 6.61 (d, J=2.6 Hz, 1H), 7.26 (dd, J=9.1, 2.6 Hz, 1H), 7.35 (m, 1H), 7.50 (d, J=1.0 Hz, 1H), 7.64 (dd, J=3.9, 1.6, Hz, 2H), 7.90 (d, J=9.1 Hz, 1H), 8.15 (d, J=8.8 Hz, 1H), 9.86 (s, 1H), 9.98 (s, 1H); MS (ESI) m/z 374/376 ([M−H]−), 376/378 ([M+H]+); HRMS (ESI+) calcd for C22H14ClNO3 376.0735 ([M+H]+). Found: 376.0721.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][C:5]2([CH3:14])[CH3:13].[CH3:15][Si:16]([C:19]#[CH:20])([CH3:18])[CH3:17]>C(N(CC)CC)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>[CH3:15][Si:16]([C:19]#[C:20][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][C:5]2([CH3:14])[CH3:13])([CH3:18])[CH3:17]
Reactant: CC1(C)CCC(=O)c2ccc(Br)cc21
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Product: CC1(C)CCC(=O)c2ccc(C#C[Si](C)(C)C)cc21
Reaction time: 24 h

Procedure:
To a solution (flushed for 15 minutes with a stream of argon) of 13.55 g (53.8 mmol) of 6-bromo-3,4-dihydro-4,4-dimethylnaphthalen-1(2H)-one (Compound H) in 280 ml of triethylamine was added 1.87 g (2.66 mmol) of bis(triphenylphosphine)palladium(II) chloride and 0.53 g (2.66 mmol) of cuprous iodide. The solution mixture was flushed with argon for 5 minutes and then 100 ml (938.7 mmol) of (trimethylsilyl)acetylene was added. The reaction mixture was sealed in a pressure tube and placed in a preheated oil bath (100° C.) for 24 hours. The reaction mixture was then filtered through Celite, washed with Et2O and the filtrate concentrated in vacuo to give crude 6-(trimethylsilyl)ethynyl-3,4-dihydro-4,4-dimethylnaphthalen-1(2H)-one. To a solution of this crude TMS-acetylenic compound in 50 ml of methanol was added 2.8 g (20.3 mmol) of K2CO3. The mixture was stirred for 8 hours at ambient temperature and then filtered. The filtrate was concentrated in vacuo, diluted with Et2O (100 ml), washed with water (10 ml), 10% HCl (10 ml) and brine (10 ml), dried over MgSO4 and concentrated in vacuo. Purification by column chromatography (silica, 10% EtOAc-hexane) yielded the title compound as a white solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH2:9])[CH:3]=1.[NH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1>>[CH3:8][C:6]1[N:5]=[C:4]([NH2:9])[CH:3]=[C:2]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH:7]=1
Reactant: C1COCCN1
Reactant: Cc1cc(Cl)cc(N)n1
Product: Cc1cc(N2CCOCC2)cc(N)n1
Temperature: 150 °C

Procedure:
To 4-chloro-6-methylpyridin-2-amine (150 mg, 1.05 mmol) in a nitrogen purged vial was added morpholine (0.917 mL, 10.5 mmol). The reaction mixture was sealed and heated at 150° C. for 1.5 hours. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in DCM (10 mL) and washed with aqueous saturated sodium bicarbonate solution. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-10% methanol/DCM with 1% ammonium hydroxide, linear gradient) to give 6-methyl-4-morpholinopyridin-2-amine. MS ESI calc'd. for C10H16N3O [M+H]+ 194. found 194. 1H NMR (500 MHz, DMSO-d6) δ 6.00 (s, 1H), 5.62 (s, 1H), 5.42 (s, 2H), 3.63 (m, 4H), 3.08 (m, 4H), 2.08 (s, 3H).
Reaction SMILES: [CH2:1]([C:5]1[N:10]=[C:9]([N:11]2C(C)=CC=C2C)[CH:8]=[C:7]([CH3:18])[CH:6]=1)[CH2:2][CH:3]=[CH2:4].Cl.NO.C(OCC)(=O)C.ClCCl>C(O)C.O.C(OCC)C>[NH2:11][C:9]1[CH:8]=[C:7]([CH3:18])[CH:6]=[C:5]([CH2:1][CH2:2][CH:3]=[CH2:4])[N:10]=1
Reactant: C=CCCc1cc(C)cc(-n2c(C)ccc2C)n1
Agent: Cl
Agent: NO
Solvent: O
Solvent: ClCCl
Solvent: CCOCC
Product: C=CCCc1cc(C)cc(N)n1
Temperature: 100 °C
Yield: 82.6 %

Procedure:
A mixture of 147 mg (0.612 mmol) of 6-(3-buten-1-yl)-4-methyl-2-(2,5-dimethylpyrrol-1-yl)pyridine and 215 mg (3.09 mmol) of hydroxylamine hydrochloride in 1.6 mL of 95% ethanol and 0.6 mL of water was heated overnight in a 100° C. oil bath. After cooling to room temperature, the solution was diluted with 25 mL of ethyl ether and washed with 15 mL of 2.5 N aqueous sodium hydroxide followed by 15 mL of saturated aqueous sodium chloride. The aqueous layers were extracted in succession with 25 mL of ethyl ether. The combined ethyl ether layers were dried (sodium sulfate), decanted, and evaporated. Flash column chromatography on 6 g of silica gel eluting with 100 mL of 1:1 ethyl acetate/dichloromethane gave 82 mg (83% yield) of 2-amino-6-(3-buten-1-yl)-4-methylpyridine as a pale yellow oil.
Reaction SMILES: CCN(C(C)C)C(C)C.[Br:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][C:19]=1[CH3:20])[C:14]([OH:16])=O.[N:21]1([CH2:26][CH2:27][C:28]2[CH:33]=[CH:32][C:31]([NH2:34])=[CH:30][CH:29]=2)[CH2:25][CH2:24][CH2:23][CH2:22]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C.CCOC(C)=O>[Br:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][C:19]=1[CH3:20])[C:14]([NH:34][C:31]1[CH:32]=[CH:33][C:28]([CH2:27][CH2:26][N:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:29][CH:30]=1)=[O:16]
Reactant: Nc1ccc(CCN2CCCC2)cc1
Reactant: Cc1ccc(C(=O)O)cc1Br
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1ccc(C(=O)Nc2ccc(CCN3CCCC3)cc2)cc1Br
Temperature: 25 °C
Reaction time: 8 h

Procedure:
DIEA (473 μL, 2.72 mmol) was added into a solution of 3-bromo-4-methylbenzoic acid (189 mL, 0.881 mmol), 4-(2-(pyrrolidin-1-yl)ethyl)benzenamine (140 mg, 0.734 mmol), BOP (487 mg, 1.01 mmol) in DMF. The reaction mixture was stirred at rt under argon atmosphere overnight. The reaction mixture was diluted with AcOEt, and then washed with 1N NaOH aqueous solution three times. Organic phase was dried with anhydrous Na2SO4, and then evaporated to remove organic solvents. The obtained residue was further dried under high vacuum overnight to give crude product, which was used directly for the next step synthesis without further purification. MS (ESI+) m/z 387.0 [M+H]+.
Reaction SMILES: [Si:1]([O:8][CH:9]([C@H:11]1[C@H:14]([C:15]#[C:16][Si](C)(C)C)[NH:13][C:12]1=[O:21])[CH3:10])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].S(=O)(=O)(O)[OH:23].C(OCC)(=O)C>O1CCCC1.O.S([O-])([O-])(=O)=O.[Hg+2]>[C:15]([C@@H:14]1[NH:13][C:12](=[O:21])[C@H:11]1[CH:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[CH3:10])(=[O:23])[CH3:16]
Reactant: CC(O[Si](C)(C)C(C)(C)C)[C@@H]1C(=O)N[C@H]1C#C[Si](C)(C)C
Reactant: O=S(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Agent: [Hg+2]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)[C@@H]1NC(=O)[C@H]1C(C)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 15 h

Procedure:
trans-3-[1-(tert-Butyldimethylsilyloxy)ethyl]-4-trimethylsilylethynyl-2-azetidinone (1.2 g) is dissolved in a mixture of tetrahydrofuran (20 ml) and water (2 ml), and mercury sulfate (0.07 g) and concentrated sulfuric acid (catalytic amount) are added, followed by stirring at room temperature for 15 hours. The reaction mixture is poured into a mixture of ethyl acetate (150 ml) and water (100 ml) and the organic layer is separated, washed with aqueous sodium chloride, dried over magnesium sulfate and concentrated under reduced pressure to give 0.60 g of trans-4-acetyl-3-[1-(tert-butyldimethylsilyloxy)ethyl]-2-azetidinone.
Reaction SMILES: [C:1]1(=[O:7])O[C:4](=[O:5])[CH:3]=[CH:2]1.[NH2:8][C:9]1[CH:10]=[C:11]([C:15]#[CH:16])[CH:12]=[CH:13][CH:14]=1.C(OC(=O)C)(=O)C>O.O.O.O.O.C([O-])(=O)C.[Ni+2].C([O-])(=O)C>[C:15]([C:11]1[CH:10]=[C:9]([N:8]2[C:4](=[O:5])[CH:3]=[CH:2][C:1]2=[O:7])[CH:14]=[CH:13][CH:12]=1)#[CH:16]
Reactant: O=C1C=CC(=O)O1
Reactant: C#Cc1cccc(N)c1
Agent: [Ni+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: C#Cc1cccc(N2C(=O)C=CC2=O)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.1 %

Procedure:
Maleic anhydride (79.6 g, 0.81 mole) was added to a solution of distilled 3-aminophenylacetylene (95.1 g, 0.81 mole) dissolved in 500 mL of dry N,N'-dimethylacetamide (DMAc) at 5°-10° C. After addition, another 300 mL of DMAc was added and the mixture stirred at room temperature for two hours. Nickel acetate tetrahydrate (0.8 g) and acetic anhydride (300 mL) were added to the reaction mixture and stirring was continued for 12 hours at room temperature to affect cyclodehydration. The crude product was isolated by precipitation in water and recrystallized from methanol to provide N-(3-ethynylphenyl)maleimide (128 g, 80% yield) as a yellow crystalline solid, mp 129°-131° C. Elemental analysis calculated for C12H7NO2 : C, 73.09%; H, 3.58%; N, 7.10%. Found: C, 72.94%; H, 3.61%; N, 7.04%.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[OH:7][C:8]1[C:13]2[O:14][C:15]([CH3:20])([CH3:19])[O:16][C:17](=[O:18])[C:12]=2[CH:11]=[CH:10][CH:9]=1.I[CH:22]([CH3:24])[CH3:23]>CN(C)C=O>[CH3:19][C:15]1([CH3:20])[O:14][C:13]2[C:8]([O:7][CH:22]([CH3:24])[CH3:23])=[CH:9][CH:10]=[CH:11][C:12]=2[C:17](=[O:18])[O:16]1
Reactant: CC(C)I
Reactant: CC1(C)OC(=O)c2cccc(O)c2O1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)Oc1cccc2c1OC(C)(C)OC2=O
Temperature: 25 °C
Reaction time: 1.33 h
Yield: 77.2 %

Procedure:
Cesium carbonate (5.46 g, 16.6 mmol) was added to a solution of 8-hydroxy-2,2-dimethyl-4H-1,3-benzodioxin-4-one (123a, 1.50 g, 7.73 mmol) in N,N-dimethylformamide (31 mL) and the mixture stirred at room temperature for five minutes before 2-iodopropane (1.00 mL, 10.0 mmol) was added. The mixture was stirred at room temperature for 80 minutes, then partitioned between deionized water (30 mL) and ethyl acetate (2×75 mL). The combined organic extracts were dried over magnesium sulfate, filtered, concentrated under vacuum, and purified by column chromatography (ethyl acetate/heptane) to give 2,2-dimethyl-8-(propan-2-yloxy)-4H-1,3-benzodioxin-4-one (123b, 1.41 g, 77% yield) as a colorless gel which slowly crystallized to a white solid.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[F:7][C:8]([F:22])([F:21])[O:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14](=O)[C:13]2=O.[O-]S([O-])(=O)=O.[Na+].[Na+].C(OCC)(=O)C>C1COCC1>[F:22][C:8]([F:7])([F:21])[O:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][CH:14]=[CH:13]2
Reactant: O=C1Nc2ccc(OC(F)(F)F)cc2C1=O
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: FC(F)(F)Oc1ccc2[nH]ccc2c1
Yield: 23.3 %

Procedure:
Lithium aluminum hydride (10.4 mL, 1M in THF, 10.4 mmol) was added to a solution of 5-trifluoromethoxyisatin (0.8 g, 3.45 mmol) in THF at room temperature and the mixture was refluxed overnight. The reaction mixture was cooled, and Na2SO4 10H2O was added very carefully portionwise, followed by ethyl acetate. The reaction mixture was then filtered, and the filtrate was evaporated. The residual oil was purifed by column chromatography with ethyl acetate in hexanes (2:98) to yield 5-trifluoromethoxy-1H-indole (0.162 g, 23%).
Reaction SMILES: [C:1]([C:9]1[CH:10]=[C:11]([CH:15]([CH3:19])[C:16]([OH:18])=[O:17])[CH:12]=[CH:13][CH:14]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.COC(C)(C)C.CC(C)[C@@H](C1C=CC=CC=1)CN>O>[C:1]([C:9]1[CH:10]=[C:11]([C@H:15]([CH3:19])[C:16]([OH:18])=[O:17])[CH:12]=[CH:13][CH:14]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C(=O)O)c1cccc(C(=O)c2ccccc2)c1
Agent: CC(C)[C@H](CN)c1ccccc1
Solvent: COC(C)(C)C
Solvent: O
Product: C[C@H](C(=O)O)c1cccc(C(=O)c2ccccc2)c1
Temperature: 10 °C
Yield: 37.6 %

Procedure:
To (±)-2-(3-benzoylphenyl)propionic acid (1200 g, 4.719 mol) were added methyl-t-butyl ether (hereinafter abbreviated to "MTBE") (4.8 L) and water (600 g, water/KET=0.50) and the mixture was dissolved with heating. Then, (S)-(+)-3-methyl-2-phenylbutylamine (388 g, 2.377 mol) was added dropwise with stirring at 50° C. to 55° C. This reaction solution was cooled to precipitate a crystal and then reheated from 35° C. to 50° C. This solution was again cooled and then reheated from 40° C. to 45° C. This solution was cooled slowly to 10° C. and stirred at 5° C. to 10° C. for one hour. Then, the crystal precipitated was filtered, and the filter cake was washed three times with cold MTBE (1 L) and dried. In this manner, a diastereomer salt (741 g, 1.775 mol) of (S)-(+)-2-(3-benzoylphenyl)propionic acid with (S)-(+)-3-methyl-2-phenylbutylamine was obtained. The yield of the product based on (S)-(+)-2-(3-benzoylphenyl)propionic acid contained in the starting material was 75.2% and the optical purity was 99.1% e.e.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH:19][C:20](=[O:37])[CH2:21][C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]2[CH:35]=[CH:34][N:33]=[C:32]([CH3:36])[CH:31]=2)[CH:25]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:36][C:32]1[CH:31]=[C:30]([C:26]2[CH:25]=[C:24]([C:22]3[CH2:21][C:20](=[O:37])[NH:19][C:9]4[CH:10]=[C:11]([O:14][C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:13][C:8]=4[N:7]=3)[CH:29]=[CH:28][CH:27]=2)[CH:35]=[CH:34][N:33]=1
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(OC(F)(F)F)ccc3NC(=O)OC(C)(C)C)c2)ccn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(-c2cccc(C3=Nc4ccc(OC(F)(F)F)cc4NC(=O)C3)c2)ccn1

Procedure:
The title compound was prepared from (2-{3-[3-(2-methyl-pyridin-4-yl)-phenyl]-3-oxo-propionylamino}-4-trifluoromethoxy-phenyl)-carbamic acid tert-butyl ester (Example M168) (236 mg, 0.45 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as an off-white solid (72 mg, 39%).
Reaction SMILES: [OH:1][C:2]1[CH:27]=[C:26]([C:28]2[S:29][C:30]3[CH2:36][CH2:35][CH2:34][CH2:33][C:31]=3[N:32]=2)[CH:25]=[CH:24][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[C@H:14]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:13][CH2:12]2.C([O-])([O-])=O.[Cs+].[Cs+].I[CH2:44][CH2:45][CH3:46]>CN(C=O)C.O>[CH2:44]([O:1][C:2]1[CH:27]=[C:26]([C:28]2[S:29][C:30]3[CH2:36][CH2:35][CH2:34][CH2:33][C:31]=3[N:32]=2)[CH:25]=[CH:24][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[C@H:14]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:13][CH2:12]2)[CH2:45][CH3:46]
Reactant: CCCI
Reactant: CCOC(=O)C[C@@H]1CCc2cc(OCCCOc3ccc(-c4nc5c(s4)CCCC5)cc3O)ccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCOc1cc(-c2nc3c(s2)CCCC3)ccc1OCCCOc1ccc2c(c1)CC[C@H]2CC(=O)OCC
Temperature: 25 °C
Reaction time: 18 h
Yield: 91.2 %

Procedure:
Ethyl ((1S)-5-{3-[2-hydroxy-4-(4,5,6,7-tetrahydro-1,3-benzothiazol-2-yl)-phenoxy]-propoxy}-2,3-dihydro-1H-inden-1-yl)acetate (Example 165, 90 mg, 0.177 mmol) was dissolved in DMF (3 mL) after which Cs2CO3 (69.3 mg, 0.213 mmol) and water (3 drops) were added. Iodopropane (0.02 mL, 0.213 mmol) was added to the flask, and the reaction mixture was stirred at room temperature for 18 h. The mixture was then filtered and the filtrate purified by preparative HPLC giving the desired ester as a white solid (88.7 mg, 91%). 1H NMR (400 MHz, CD2Cl2): δ 7.47 (s, 1H), 7.37 (dd, 1H), 7.05 (d, 1H), 6.93 (d, 1H), 6.79 (s, 1H), 6.71 (dd, 1H), 4.23 (t, 2H), 4.19-4.13 (m, 4H), 4.03 (t, 2H), 3.50 (m, 1H), 2.94-2.78 (m, 6H), 2.70 (dd, 1H), 2.44-2.25 (m, 4H), 1.92-1.70 (m, 7H), 1.28 (t, 3H), 1.07 (t, 3H).