Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:7]=[C:8]([NH:12][C:13](=[O:23])[C@@H:14]([NH2:22])[CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:9]=[CH:10][CH:11]=2)=[N:2]1.[S:24]1[CH:28]=[C:27]([CH:29]=O)[N:26]=[CH:25]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[NH:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:7]=[C:8]([NH:12][C:13](=[O:23])[C@@H:14]([NH:22][CH2:29][C:27]3[N:26]=[CH:25][S:24][CH:28]=3)[CH2:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:9]=[CH:10][CH:11]=2)=[N:2]1
Reactant: O=Cc1cscn1
Reactant: N[C@@H](Cc1ccccc1)C(=O)Nc1cccc(-c2cc[nH]n2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: O=C(Nc1cccc(-c2cc[nH]n2)c1)[C@H](Cc1ccccc1)NCc1cscn1
Reaction time: 1 h
Yield: 25.4 %

Procedure:
To a solution of (2S)—N-(3-(1H-pyrazol-3-yl)phenyl)-2-amino-3-phenylpropanamide 12.C (200 mg, 0.65 mmol) in DCM (5 mL) was added thiazole-4-carbaldehyde (73 mg, 0.65 mmol, available from Combi-Blocks). The mixture was stirred for 1 h, then sodium triacetoxyborohydride (207 mg, 0.98 mmol) was added and the mixture stirred for an additional hour at room temperature. The mixture was then concentrated and the crude product purified by reverse phase chromatography (0-100% CH3CN/water+0.5% TFA) to afford (2S)—N-(3-(1H-pyrazol-3-yl)phenyl)-3-phenyl-2-(thiazol-4-ylmethylamino)propanamide 12 as a white solid (66.7 mg, 25% yield). LCMS ESI (pos.) m/e: 404.0 (M+1): 1H NMR (500 MHz, MeOH-D4) δ ppm 9.11 (d, J=1.96 Hz, 1H), 7.82-7.87 (m, 1H), 7.80 (d, J=1.96 Hz, 1H), 7.74 (d, J=2.20 Hz, 1H), 7.51-7.60 (m, 1H), 7.21-7.38 (m, 7H), 6.68 (d, J=2.20 Hz, 1H), 4.50 (d, J=5.38 Hz, 2H), 4.29 (dd, J=9.29, 5.87 Hz, 1H), 3.43 (dd, J=13.45, 5.62 Hz, 1H), 3.27 (dd, J=13.45, 9.29 Hz, 1H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].FC(F)(F)S(O[C:13]1[CH:18]=[C:17]([CH3:19])[C:16]([Br:20])=[C:15]([CH3:21])[CH:14]=1)(=O)=O.[O:24]1[CH2:29][CH:28]=[C:27](B2OC(C)(C)C(C)(C)O2)[CH2:26][CH2:25]1>CN(C=O)C>[Br:20][C:16]1[C:17]([CH3:19])=[CH:18][C:13]([C:27]2[CH2:28][CH2:29][O:24][CH2:25][CH:26]=2)=[CH:14][C:15]=1[CH3:21]
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Reactant: Cc1cc(OS(=O)(=O)C(F)(F)F)cc(C)c1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(C2=CCOCC2)cc(C)c1Br
Temperature: 85 °C
Reaction time: 4 h

Procedure:
Potassium carbonate (1.99 g) and Pd(dppf)Cl2-DCM complex (196 mg) were added to a solution of 4-bromo-3,5-dimethylphenyl trifluoromethanesulfonate (1.6 g) and 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester (CAS No. 287944-16-5) (1.11 g) in DMF (16 mL). The reaction mixture was stirred at 85° C. for four hours. The reaction mixture was returned to room temperature, and the reaction mixture was then concentrated under reduced pressure. MTBE, water and brine were added to the residue, and the organic layer was separated. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate/n-heptane, 2%) to give the title compound (747 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:23]=[C:22]2[C:12]([NH:13][CH:14]=[C:15]2[CH2:16][CH:17]([C:19]([OH:21])=[O:20])[NH2:18])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:24]([O:28][C:29]1[CH:34]=[CH:33][C:32]([S:35](Cl)(=[O:37])=[O:36])=[CH:31][CH:30]=1)[C:25]#[C:26][CH3:27]>>[CH2:24]([O:28][C:29]1[CH:34]=[CH:33][C:32]([S:35]([NH:18][CH:17]([CH2:16][C:15]2[C:22]3[C:12](=[CH:11][CH:10]=[C:9]([O:8][CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[CH:23]=3)[NH:13][CH:14]=2)[C:19]([OH:21])=[O:20])(=[O:37])=[O:36])=[CH:31][CH:30]=1)[C:25]#[C:26][CH3:27]
Reactant: NC(Cc1c[nH]c2ccc(OCc3ccccc3)cc12)C(=O)O
Reactant: CC#CCOc1ccc(S(=O)(=O)Cl)cc1
Product: CC#CCOc1ccc(S(=O)(=O)NC(Cc2c[nH]c3ccc(OCc4ccccc4)cc23)C(=O)O)cc1

Procedure:
The title compound was prepared by the method of Example 6, using 5-benzyloxy-DL-tryptophan and 4-but-2-ynyloxy-benzenesulfonyl chloride as starting materials. 1H NMR (DMSO-d6): 400 MHz δ 12.55 (bs, 1H), 10.64 (s, 1H), 8.05 (d, J=8.0 Hz, 1H), 7.50-7.33 (m, 7H), 7.19 (d, J=12.0 Hz, 1H), 7.03 (d, J=4.0 Hz, 1H), 6.97 (d, J=4.0 Hz, 1H), 6.87 (d, J=8.0 Hz, 2H), 6.76 (dd, J=8.0, 4.0 Hz, 1H), 5.04 (s, 2H), 4.74 (q, J=2.4 Hz, 2H), 3.86 (q, J=8.0 Hz, 1H), 3.00 (dd J=14.4, 6.4 Hz, 1H), 2.83 (dd J=14.4, 8.0 Hz, 1H), 1.82 (t, J=2.4 Hz, 3H); HRMS: calcd for C28H27N2O6S (ESI+, [M+H]1+), 519.1584; found 519.1588; LCMS m/z (ESI) [M+H] 519, retention time=2.99 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([CH:13]=O)=[CH:5][CH:4]=1.[CH3:15][N:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[NH2:17]>Cl.C(O)C>[CH3:15][N:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[N:17]=[CH:13][C:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]([O:2][CH3:1])=[CH:4][CH:5]=1
Reactant: COc1ccc(C=O)c2ccccc12
Reactant: CN(N)c1ccccc1
Agent: Cl
Solvent: CCO
Product: COc1ccc(C=NN(C)c2ccccc2)c2ccccc12

Procedure:
3.7 g of 4-methoxy-1-naphthaldehyde and 2.4 g of 1-methyl-1-phenylhydrazine were added to 50 ml of ethanol. To the mixture, two or three drops of 1 N hydrochloric acid were added. The mixture was heated and refluxed for about an hour. The reaction mixture was cooled and the crystals then separated, which were then collected on a suction funnel. The thus obtained crude 4-methoxy-1-naphthaldehyde 1-methyl-1-phenylhydrazone was recrystallized from ethanol. The yield was 4.0 g (69.0%) of light yellow needle-like crystals which melt at 119.5°-120.5° C.
Reaction SMILES: [CH3:1][N:2]([CH3:27])[S:3]([NH:6][C:7]1[CH:8]=[CH:9][C:10]2[CH:24]=[CH:23][C:14]3=[N:15][CH:16]=[C:17]([C:19]([O:21]C)=[O:20])[CH:18]=[C:13]3[C:12](=[O:25])[C:11]=2[CH:26]=1)(=[O:5])=[O:4]>C1COCC1.[OH-].[Na+]>[CH3:1][N:2]([CH3:27])[S:3]([NH:6][C:7]1[CH:8]=[CH:9][C:10]2[CH:24]=[CH:23][C:14]3=[N:15][CH:16]=[C:17]([C:19]([OH:21])=[O:20])[CH:18]=[C:13]3[C:12](=[O:25])[C:11]=2[CH:26]=1)(=[O:4])=[O:5]
Reactant: COC(=O)c1cnc2ccc3ccc(NS(=O)(=O)N(C)C)cc3c(=O)c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CN(C)S(=O)(=O)Nc1ccc2ccc3ncc(C(=O)O)cc3c(=O)c2c1

Procedure:
methyl 7-{[(dimethylamino)sulfonyl]amino}-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridine-3-carboxylate (17 mg, 0.044 mmol) was dissolved in 1 mL of THF and 1 mL of 1 M aqueous sodium hydroxide. After 2 h the mixture was quenched by the addition of 1.1 mL of 1M HCl and the organics were removed in vacuo. The material was freeze dried to afford 7-{[(dimethylamino)sulfonyl]amino}-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridine-3-carboxylic acid.
Reaction SMILES: [CH2:1]([N:8]1[C@H:12]([C:13]([O:15][CH2:16][CH2:17][CH2:18][CH3:19])=[O:14])[C@H:11]([C:20]([O:22]CCCC)=[O:21])[N:10]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:9]1=[O:34])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>P([O-])([O-])([O-])=O>[CH2:1]([N:8]1[C@@H:12]([C:13]([O:15][CH2:16][CH2:17][CH2:18][CH3:19])=[O:14])[C@@H:11]([C:20]([OH:22])=[O:21])[N:10]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:9]1=[O:34])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCOC(=O)[C@@H]1[C@H](C(=O)OCCCC)N(Cc2ccccc2)C(=O)N1Cc1ccccc1
Agent: O=P([O-])([O-])[O-]
Product: CCCCOC(=O)[C@H]1[C@@H](C(=O)O)N(Cc2ccccc2)C(=O)N1Cc1ccccc1

Procedure:
A suspension of di-n-butyl cis-1,3-dibenzyl-2-oxoimidazolidine-4,5-dicarboxylate (500 mg) in 0.1M phosphate buffer (pH 8.0, 45 ml) was treated with Pig Liver Esterase (manufactured by Sigma Lab., 1600 units, 10 mg) in a manner similar to that in Example 1 (1) to give (4S,5R)-1,3-dibenzyl-5-n-butyloxycarbonyl-2-oxoimidazolidine-4-carboxylic acid as an oily product. [α]D20 =+4.1° (c=1.55, CHCl3).
Reaction SMILES: Cl.C1OC2C=CC(C([NH:9][CH2:10][CH:11]([OH:25])[CH2:12][N:13]([C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=O)=CC=2O1.C1OC2C=CC(C(Cl)=O)=CC=2O1>>[NH2:9][CH2:10][CH:11]([OH:25])[CH2:12][N:13]([C:21]([CH3:23])([CH3:22])[CH3:24])[CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CC(C)(C)N(Cc1ccccc1)CC(O)CNC(=O)c1ccc2c(c1)OCO2
Agent: Cl
Agent: O=C(Cl)c1ccc2c(c1)OCO2
Product: CC(C)(C)N(Cc1ccccc1)CC(O)CN
Yield: 80 %

Procedure:
1-(3,4-methylenedioxy benzamido)-3-(N-benzyl tert-butylamino)-2- propanol hydrochloride, starting from 6.3 g (0.034 mole) of 3,4-methylenedioxy benzoyl chloride and 8 g (0.034 mole) of 1-amino-3-(N-benzyl tert-butylamino)-2- propanol (yield 80 %).
Reaction SMILES: C([C:4]1[CH:15]=[CH:14][C:7]([O:8][CH:9]([CH3:13])[C:10]([OH:12])=[O:11])=[CH:6][CH:5]=1)(=O)C.[C:16]([O:19]O)(=[O:18])[CH3:17]>C(O)(=O)C>[C:16]([O:19][C:4]1[CH:5]=[CH:6][C:7]([O:8][CH:9]([CH3:13])[C:10]([OH:12])=[O:11])=[CH:14][CH:15]=1)(=[O:18])[CH3:17]
Reactant: CC(=O)OO
Reactant: CC(=O)c1ccc(OC(C)C(=O)O)cc1
Solvent: CC(=O)O
Product: CC(=O)Oc1ccc(OC(C)C(=O)O)cc1
Reaction time: 9 h
Yield: 91.4 %

Procedure:
To a solution of 2-(4-acetylphenoxy)propanoic acid (5.08 g, 24.4 mmol) in acetic acid (20 mL) is added purified peracetic acid (16%, 15.80 g, 33.3 mmol) over 30 minutes. The reaction mixture is stirred under reflux at 55° C. to 60° C. and 60-64 mm Hg for 9 hours. The solution is rotovapped and vacuumed to remove the acetic acid. The product obtained is 5.0 g of 2-(4-acetoxyphenoxy)propanoic acid (yield 91%): m.p. 102° C., 1H NMR (CDCl3, delta 1.63 (d, J=7.0 Hz, 3H), 2.26 (s, 3H), 4.85 (q, J=7.0 Hz, 1H), 7.10 (m, 4H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:24])=[C:8]2[C:15]([Cl:16])=[CH:14][N:13]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:9]2=[C:10](Cl)[N:11]=1)=[O:5])[CH3:2].C[C:26]([N:28](C)C)=O>[C-]#N.[C-]#N.[Zn+2].[Zn].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2]>[CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:24])=[C:8]2[C:15]([Cl:16])=[CH:14][N:13]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:9]2=[C:10]([C:26]#[N:28])[N:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(Cl)c2c(c(Cl)cn2Cc2ccccc2)c1O
Reactant: CC(=O)N(C)C
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: CCOC(=O)c1nc(C#N)c2c(c(Cl)cn2Cc2ccccc2)c1O
Temperature: 120 °C

Procedure:
A mixture of 1-benzyl-3,7-dichloro-4-hydroxy-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester (155 mg), Zn(CN)2 (30 mg), Zn dust (3.3 mg), Pd2(dba)3 (19.4 mg), dppf (23.5 mg) in DMA (1.5 mL) was heated to 120° C. for 90 min; then the mixture was partitioned between EtOAc and water, the organic phase was then washed with sat. NaCl solution, dried over anhydrous sodium sulfate, filtered and concentrated sequentially to give a residue, which was purified with column to give desired title compound (100 mg). 1H NMR (200 MHz, CDCl3): δ(ppm)=12.16 (s, 1H), 7.4-7.1 (m, 6H), 5.71 (s, 2H), 4.53 (q, 2H, J=7.1 Hz), 1.49 (t, 3H, J=7.1 Hz).
Reaction SMILES: CC(C[AlH]CC(C)C)C.[CH:10]([C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][C:22](/[C:25](/[CH3:32])=[CH:26]/[C:27](OCC)=[O:28])=[CH:21][CH:20]=2)=[CH:15][CH:14]=1)([CH3:12])[CH3:11]>>[CH:10]([C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:20]=[CH:21][C:22](/[C:25](/[CH3:32])=[CH:26]/[CH2:27][OH:28])=[CH:23][CH:24]=2)=[CH:15][CH:14]=1)([CH3:12])[CH3:11]
Reactant: CCOC(=O)/C=C(\C)c1ccc(-c2ccc(C(C)C)cc2)cc1
Agent: CC(C)C[AlH]CC(C)C
Product: C/C(=C\CO)c1ccc(-c2ccc(C(C)C)cc2)cc1

Procedure:
The colourless solid (E)-3-(4′-isopropyl-biphenyl-4-yl)-but-2-en-1-ol was prepared by DIBAL-H reduction of (E)-ethyl 3-(4′-isopropyl-biphenyl-4-yl)-but-2-enoate by a procedure analogous to that described in example 50b.
Reaction SMILES: [NH2:1][C:2]12[CH2:9][CH:8]3[CH2:10][C:4]([C:11]([NH2:13])=[O:12])([CH2:5][CH:6]1[CH2:7]3)[CH2:3]2.[Br:14][C:15]1[CH:33]=[CH:32][C:18]([CH2:19][CH:20]2[C:25]([CH3:27])([CH3:26])[O:24][C:23](OC)=[N:22][S:21]2(=[O:31])=[O:30])=[C:17]([F:34])[CH:16]=1>C(Cl)Cl>[Br:14][C:15]1[CH:33]=[CH:32][C:18]([CH2:19][C@@H:20]2[C:25]([CH3:27])([CH3:26])[O:24][C:23]([NH:1][C:2]34[CH2:9][CH:8]5[CH2:10][C:4]([C:11]([NH2:13])=[O:12])([CH2:5][CH:6]3[CH2:7]5)[CH2:3]4)=[N:22][S:21]2(=[O:31])=[O:30])=[C:17]([F:34])[CH:16]=1
Reactant: COC1=NS(=O)(=O)C(Cc2ccc(Br)cc2F)C(C)(C)O1
Reactant: NC(=O)C12CC3CC(C1)C(N)(C3)C2
Solvent: ClCCl
Product: CC1(C)OC(NC23CC4CC2CC(C(N)=O)(C4)C3)=NS(=O)(=O)[C@@H]1Cc1ccc(Br)cc1F
Temperature: 35 °C
Reaction time: 16 h
Yield: 54.9 %

Procedure:
3a-Aminohexahydro-2,5-methanopentalene-2-carboxamide (58 mg) and 5-(4-bromo-2-fluorobenzyl)-2-methoxy-6,6-dimethyl-5,6-dihydro-[1,4,3]oxathiazine 4,4-dioxide (110 mg) were dissolved in methylene chloride and stirred at 35° C. for 16 h. In the course of this, the solvent was evaporated. Purification was effected by preparative HPLC. This gave the product (84 mg) with a molecular weight of 528.5 g/mol (C22H27BrFN3O4S), MS (ESI): (M+H+) 529.5 g/mol.
Reaction SMILES: C[O:2][C:3]1[C:4]2[C:9]([C:10]([C:17]3[C:19](=[O:20])[C:18]=3[C:21]3[C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[C:28]([O:35]C)=[C:27]4[C:22]=3[CH:23]=[CH:24][CH:25]=[CH:26]4)=[C:11]3[C:16]=1[CH:15]=[CH:14][CH:13]=[CH:12]3)=[CH:8][CH:7]=[CH:6][CH:5]=2.[Al+3].[Cl-].[Cl-].[Cl-].C(N(CC)CC)C>ClC1C=CC=CC=1>[OH:2][C:3]1[C:16]2[C:11]([C:10]([C:17]3[C:19](=[O:20])[C:18]=3[C:21]3[C:22]4[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:28]([OH:35])=[C:29]4[C:34]=3[CH:33]=[CH:32][CH:31]=[CH:30]4)=[C:9]3[C:4]=1[CH:5]=[CH:6][CH:7]=[CH:8]3)=[CH:12][CH:13]=[CH:14][CH:15]=2
Reactant: COc1c2ccccc2c(-c2c(-c3c4ccccc4c(OC)c4ccccc34)c2=O)c2ccccc12
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: Clc1ccccc1
Product: O=c1c(-c2c3ccccc3c(O)c3ccccc23)c1-c1c2ccccc2c(O)c2ccccc12
Temperature: 0 °C
Yield: 83.7 %

Procedure:
1.17 g of bis(9-methoxy-10-anthracenyl)cyclopropenone was dissolved in chlorobenzene, and refluxed for 12 hours with 250 mg of AlCl3. When disappearance of starting materials was complete, the cooled mixture was poured into ice water with a small amount of triethylamine therein, and the organic layer separated. The water layer was washed twice with CHCl3, and the combined organics washed with water, dried with CaCl2, and evaporated to give 0.92 g bis(9-hydroxy-10-anthracenyl)cyclopropenone as a maroon solid, i.r. 1810, 1600 cm. ##STR7##
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[C:5]([CH:9]2[C:18]3[C:13](=[CH:14][C:15]([O:19]C)=[CH:16][CH:17]=3)[C:12](=[O:21])[CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1>C(O)(=O)C.Br>[F:1][C:2]([F:22])([F:23])[C:3]1[CH:4]=[C:5]([CH:9]2[C:18]3[C:13](=[CH:14][C:15]([OH:19])=[CH:16][CH:17]=3)[C:12](=[O:21])[CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1ccc2c(c1)C(=O)CCC2c1cccc(C(F)(F)F)c1
Agent: Br
Solvent: CC(=O)O
Product: O=C1CCC(c2cccc(C(F)(F)F)c2)c2ccc(O)cc21

Procedure:
A solution of 4-(3-trifluoromethylphenyl)-7-methoxy-1-tetralone (3.1 g) in acetic acid (25 ml) and hydrobromic acid (48%, 25 ml) was heated under reflux for 16 hr. The solution was concentrated in vacuo, water was added and the mixture extracted with ethyl acetate, the extracts washed well with water and sodium bicarbonate solution, dried (MgSO4) and the solvent removed to leave 4-(3-trifluoromethylphenyl)-7-hydroxy-1-tetralone as a dark green oil, used without purification. The oil was taken up in dry toluene (50 ml), sodium hydride (80%) dispersion in oil, 0.45 g) added and the mixture heated to the point of reflux. Dimethylaminoethyl chloride (1.2 g) was added to the cooled mixture, which was then heated under reflux for 5 hr. The solvent was removed, ethyl acetate-water added and the organic layer separated, washed with sodium bicarbonate solution, dried (K2CO3), passed through a short alumina column, and the solvent removed to give impure 4-(3-trifluoromethylphenyl)-7-(2-dimethylaminoethoxy)-1 -tetralone. The pure hydrochloride was obtained as off-white prisms after two recrystallisations from ether-ethanol (0.9 g, 22%), m.p. 203°-207°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:13])[CH2:9][C:10](=[O:12])[CH3:11])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([CH:9]([C:10](=[O:12])[CH3:11])[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[O:13])=[CH:6][CH:7]=1
Reactant: CCOC(=O)CBr
Reactant: CC(=O)CC(=O)c1ccc(F)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: Cc1ccccc1
Product: CCOC(=O)CC(C(C)=O)C(=O)c1ccc(F)cc1
Temperature: 20 °C
Reaction time: 8 h

Procedure:
A mixture of 1-(4-fluorophenyl)butane-1,3-dione (1.0 g), potassium carbonate (3.42 g), and tetrabutylammonium bromide (20 mg) in toluene (10 ml) was refluxed for 3 hours. After cooling to 20° C., ethyl bromoacetate (0.74 ml) was added to the mixture. After being allowed to stand at 20° C. overnight, the mixture was partitioned between ethyl acetate and 0.5N hydrochloric acid. The organic layer was separated, washed with water and brine, dried over magnesium sulfate, and evaporated. The residue was chromatographed on silica gel eluting with a mixture of ethyl acetate and hexane (1:5) to give ethyl 3-(4-fluorobenzoyl)-4-oxopentanoate (964 mg) as an oil.
Reaction SMILES: [C:1]([O:9][C@@H:10]1[CH2:15][C@@H:14]([CH2:16][CH3:17])[O:13][C@@:12]([O:33]C)([C@@H:18]2[CH2:22][S:21][C:20](=[O:23])[N:19]2CC2C=CC(OC)=CC=2)[CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO[C@]1([C@@H]2CSC(=O)N2CC2C=CC(OC)=CC=2)C[C@H]2C[C@@H](CCCC=CCCC(C)=CC(=O)O2)O1>>[C:1]([O:9][C@@H:10]1[CH2:15][C@@H:14]([CH2:16][CH3:17])[O:13][C@@:12]([OH:33])([C@@H:18]2[CH2:22][S:21][C:20](=[O:23])[NH:19]2)[CH2:11]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC[C@@H]1C[C@@H](OC(=O)c2ccccc2)C[C@](OC)([C@@H]2CSC(=O)N2Cc2ccc(OC)cc2)O1
Agent: COc1ccc(CN2C(=O)SC[C@H]2[C@@]2(OC)C[C@H]3C[C@@H](CCC/C=C\CC/C(C)=C\C(=O)O3)O2)cc1
Agent: COc1ccc(CN2C(=O)SC[C@H]2[C@@]2(OC)C[C@H]3C[C@@H](CCCC=CCCC(C)=CC(=O)O3)O2)cc1
Product: CC[C@@H]1C[C@@H](OC(=O)c2ccccc2)C[C@](O)([C@@H]2CSC(=O)N2)O1

Procedure:
Application of the method shown in Example 46, with the modification that (2R,4R,6R)-6-ethyl-2-methoxy-2-((R)-3-(4-methoxybenzyl)-2-oxothiazolidin-4-yl)-tetrahydro-2H-pyran-4-yl benzoate was substituted for (R)-4-((1R,4Z,8Z,13R,15R)-15-methoxy-5-methyl-3-oxo-2,14-dioxa-bicyclo[11.3.1]heptadeca-4,8-dien-15-yl)-3-(4-methoxybenzyl)thiazolidin-2-one, afforded the title compound.
Reaction SMILES: [CH3:1][S-:2].[Na+].[CH3:4][C:5]1[S:13][C:12]2[C:11](Cl)=[N:10][CH:9]=[N:8][C:7]=2[CH:6]=1>C(#N)C>[CH3:4][C:5]1[S:13][C:12]2[C:11]([S:2][CH3:1])=[N:10][CH:9]=[N:8][C:7]=2[CH:6]=1
Reactant: C[S-]
Reactant: Cc1cc2ncnc(Cl)c2s1
Agent: [Na+]
Solvent: CC#N
Product: CSc1ncnc2cc(C)sc12
Yield: 97 %

Procedure:
A solution of sodium thiomethoxide (24S mg) and 6-methyl-4-chlorothieno[3,2-d]pyrimidine (Acta Pol. Pharm. (1986), 43(2), 97-100) (650 mg) in acetonitrile (50 mL) was stirred overnight. The mixture was filtered and the solid was washed with acetonitrile. The combined filtrate and washes were evaporated to give the title compound as a white solid (665 mg, 97%);
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[CH2:11]([N:18]1[C:25](=O)[CH2:24][CH:23]2[CH2:27][CH:19]1[CH2:20][CH2:21][CH:22]2[O:28]C(=O)C)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1(C)C=CC=CC=1>[CH2:11]([N:18]1[CH2:25][CH2:24][CH:23]2[CH2:27][CH:19]1[CH2:20][CH2:21][CH:22]2[OH:28])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CC(=O)OC1CCC2CC1CC(=O)N2Cc1ccccc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Product: OC1CCC2CC1CCN2Cc1ccccc1
Temperature: -70 °C
Reaction time: 8 h

Procedure:
Diisobutylaluminum hydride (1.5 mol/L in toluene, 21 mL) is added to a solution of acetic acid 2-benzyl-3-oxo-2-aza-bicyclo[3.3.1]non-6-yl ester (1.50 g, for synthesis see J. Chem. Soc. Perkin Trans. 1 1999, 1157-1162) in toluene (30 mL) cooled to −70° C. The cooling bath is removed and the solution is stirred at ambient temperature overnight. Then, another portion of diisobutylaluminum hydride (1.5 mol/L in toluene, 20 mL) is added and the solution is stirred for additional 4 h at room temperature. Then, the solution is poured into ice-cold water and the resulting mixture is extracted with ethyl acetate. The aqueous phase is acidified using 4 M hydrochloric acid and extracted one more time with ethyl acetate. The combined organic extracts are dried (Na2SO4) and the solvent is removed. The residue is purified by chromatography on silica gel (dichloromethane/methanol 1:0→2:1).
Reaction SMILES: C1(C(=[N:14][C:15]2[CH:20]=[CH:19][C:18]([C@H:21]3[O:26][CH2:25][CH2:24][N:23]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:22]3)=[C:17]([F:34])[CH:16]=2)C2C=CC=CC=2)C=CC=CC=1.C([O-])(=O)C.[Na+].Cl.NO>CO>[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([C@H:21]2[O:26][CH2:25][CH2:24][N:23]([C:27]([O:29][C:30]([CH3:32])([CH3:31])[CH3:33])=[O:28])[CH2:22]2)=[C:17]([F:34])[CH:16]=1
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](c2ccc(N=C(c3ccccc3)c3ccccc3)cc2F)C1
Agent: CC(=O)[O-]
Agent: Cl
Agent: NO
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCO[C@H](c2ccc(N)cc2F)C1
Temperature: 50 °C
Reaction time: 8 h
Yield: 78.4 %

Procedure:
To a stirred solution of (R)-tert-butyl 2-(4-(diphenylmethyleneamino)-2-fluorophenyl)morpholine-4-carboxylate (5.95 g) in methanol (50 ml) were added sodium acetate (2.93 g) and hydroxylamine hydrochloride (1.82 g). The reaction mixture was stirred at 50° C. overnight. The reaction mixture was then filtered through sintered glass and the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography (silica gel; gradient: 0% to 60% EtOAc in hexanes) to afford (R)-tert-butyl 2-(4-amino-2-fluorophenyl)morpholine-4-carboxylate (3.0 g, 85%) as a yellow solid. MS (ISP): 296 ([M]+), 240 ([M-C4H8]+), 195 ([M+H—C4H8—CO2H]+).
Reaction SMILES: Br[CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[CH2:10]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH:23]([OH:26])[CH2:22][CH2:21]1)=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[OH-].[Na+]>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.O.C1(C)C=CC=CC=1>[CH2:10]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH:23]([O:26][CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])[CH2:22][CH2:21]1)=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(OCc1ccccc1)N1CCC(O)CC1
Reactant: CC(C)(C)OC(=O)CBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)OC(=O)COC1CCN(C(=O)OCc2ccccc2)CC1
Reaction time: 8 h

Procedure:
28 ml of t-butyl bromoacetate and 1.4 g of tetra-n-butylammonium hydrogen sulphate in 10 ml of water are added to a solution of 30.1 g of N-benzyloxycarbonyl-4-hydroxy-piperidine in 300 ml of toluene. Thereafter, a solution of 125 g of sodium hydroxide in 125 ml of water is added dropwise thereto. After stirring overnight, the organic extracts are separated, dried and concentrated. After drying there are obtained 34.1 g of N-benzyloxycarbonyl-4-[(t-butoxy carbonyl) methoxy]-piperidine, Rf =0.76 (ethyl acetate). MS (EI): 293 (M-C4H8)+.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:17][CH:18]2[CH2:23][CH2:22][N:21]([CH:24]([CH3:26])[CH3:25])[CH2:20][CH2:19]2)=[CH:4][C:5]2[CH:6]=[C:7]3[C:14](=[O:15])[NH:13][CH2:12][C@@H:11]([CH3:16])[N:8]3[C:9]=2[CH:10]=1.[H-].[Na+].Br[CH2:30][CH:31]1[CH2:33][CH2:32]1>>[Br:1][C:2]1[C:3]([O:17][CH:18]2[CH2:23][CH2:22][N:21]([CH:24]([CH3:26])[CH3:25])[CH2:20][CH2:19]2)=[CH:4][C:5]2[CH:6]=[C:7]3[C:14](=[O:15])[N:13]([CH2:30][CH:31]4[CH2:33][CH2:32]4)[CH2:12][C@@H:11]([CH3:16])[N:8]3[C:9]=2[CH:10]=1
Reactant: BrCC1CC1
Reactant: CC(C)N1CCC(Oc2cc3cc4n(c3cc2Br)[C@H](C)CNC4=O)CC1
Agent: [H-]
Agent: [Na+]
Product: CC(C)N1CCC(Oc2cc3cc4n(c3cc2Br)[C@H](C)CN(CC2CC2)C4=O)CC1

Procedure:
The title compound was synthesized in analogy to example 17, from (R)-7-bromo-8-(1-isopropyl-piperidin-4-yloxy)-4-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (example 93), sodium hydride and 1-(bromomethyl)cyclopropane, to give the product as a white solid (55%).