Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([OH:11])[N:5]=[C:4](SC)[N:3]=1.[NH:14]1[CH2:19][CH2:18][S:17][CH2:16][CH2:15]1>>[OH:11][C:6]1[C:7]([N+:8]([O-:10])=[O:9])=[C:2]([OH:1])[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][S:17][CH2:16][CH2:15]2)[N:5]=1
Reactant: CSc1nc(O)c([N+](=O)[O-])c(O)n1
Reactant: C1CSCCN1
Product: O=[N+]([O-])c1c(O)nc(N2CCSCC2)nc1O

Procedure:
4,6-Dihydroxy-5-nitro-2-thiomorpholino-pyrimidine was prepared in analogous manner from 4,6-dihydroxy-2-methylthio-5-nitro-pyrimidine and thiomorpholine. M.p. 220°-223°C.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([N:11]3[CH2:16][CH2:15][N:14](CC4C=CC=CC=4)[CH2:13][CH2:12]3)=[N:7][NH:8]2)=[CH:4][CH:3]=1.[H][H]>[Ni].[Pd].CO>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([N:11]3[CH2:12][CH2:13][NH:14][CH2:15][CH2:16]3)=[N:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: [H][H]
Reactant: Fc1ccc2c(N3CCN(Cc4ccccc4)CC3)n[nH]c2c1
Agent: [Ni]
Agent: [Pd]
Solvent: CO
Product: Fc1ccc2c(N3CCNCC3)n[nH]c2c1
Yield: 92 %

Procedure:
A mixture of 12 parts of 6-fluoro-3-[4-(phenylmethyl)-piperazinyl]-1H-indazole, 1 part of Raney nickel catalyst and 200 parts of methanol was hydrogenated in a Parr-apparatus at normal pressure and at 50° C. with 2 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off over diatomaceous earth and the filtrate was evaporated in vacuo. The residue was crystallized from acetonitrile. The product was filtered off and dried, yielding 7.7 parts (92.0%) of 6-fluoro-3-(1-piperazinyl)-1H-indazole (int. 8).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].Br[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH:5]([C:4]1[CH:3]=[C:2]([CH:9]=[CH:8][CH:7]=1)[O:1][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[O:6]
Reactant: CCOC(=O)CBr
Reactant: O=Cc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)COc1cccc(C=O)c1
Temperature: 60 °C
Reaction time: 15 h
Yield: 98 %

Procedure:
To a solution of 3-hydroxybenzaldehyde (10.0 g) and ethyl bromoacetate (15.0 g) in DMF (150 mL) was added potassium carbonate (17.0 g), and the mixture was stirred at 60° C. for 15 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (16.7 g) as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:14])[C:6](=[C:11]([CH3:13])[CH:12]=1)C(OC)=O.[OH-].[K+].Cl>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:14])[CH:6]=[C:11]([CH3:13])[CH:12]=1
Reactant: COC(=O)c1c(C)cc(OC)cc1O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Product: COc1cc(C)cc(O)c1
Yield: 70 %

Procedure:
1.0 g of the methyl 4-methoxy-6-methyl-salicylate thus obtained is boiled under reflux with 35 ml of aqueous potassium hydroxide solution (15% strength) for 8 hours. The reaction mixture is then acidified with dilute hydrochloric acid and extracted with ethyl acetate. 0.70 g (yield: 70%) of orcinyl (3-methoxy-5-methylphenol) is obtained.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:37])[C@@:5](C(NC(OC(C)(C)C)=O)C[C@@H](C)CC)([C@@H:7]([C:11]([CH:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH2:15][NH:14]1)=[O:12])[CH2:8][S:9][CH3:10])[NH2:6]>CCOC(C)=O>[CH3:2][O:3][C:4](=[O:37])[C@H:5]([C@@H:7]([C:11]([CH:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH2:15][NH:14]1)=[O:12])[CH2:8][S:9][CH3:10])[NH:6][CH2:4][C@@H:5]([NH2:6])[C@@H:7]([CH3:8])[CH2:11][CH3:13]
Reactant: CC[C@H](C)CC(NC(=O)OC(C)(C)C)[C@](N)(C(=O)OC)[C@H](CSC)C(=O)C1NCCc2ccccc21
Agent: Cl
Solvent: CCOC(C)=O
Product: CC[C@H](C)[C@H](N)CN[C@H](C(=O)OC)[C@H](CSC)C(=O)C1NCCc2ccccc21
Temperature: -20 °C
Reaction time: 0.5 h

Procedure:
HCl gas was bubbled into a solution of N-[2(S)-(t-butyloxycarbonylamino-3(S)-methylpentyl]-1,2,3,4-tetrahydro-3(S)-isoquinolinecarbonyl-methionine methyl ester (0.37 g, 0.71 mmol) in EtOAc (25 mL) with stirring at -20° C. over 0.5 h. The solution was purged with argon for 0.5 h, then concentrated to give the title compound as a white solid which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][CH:10]([C:12]([OH:14])=O)[CH3:11])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[C:15]1([C@@H:21]([CH2:23][OH:24])[NH2:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[Cl:8][C:6]1[CH:5]=[C:4]([NH:9][CH:10]([C:12]([NH:22][C@@H:21]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:23][OH:24])=[O:14])[CH3:11])[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: CC(Nc1cc(Cl)cc(Cl)c1)C(=O)O
Reactant: N[C@H](CO)c1ccccc1
Product: CC(Nc1cc(Cl)cc(Cl)c1)C(=O)N[C@H](CO)c1ccccc1

Procedure:
Following General Procedure E and using N-(3,5-dichlorophenyl)-D,L-alanine (from Example B above) and (S)-(+)-2-phenylglycinol (Aldrich), the title compound could be prepared.
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[CH2:3][CH2:4][CH2:5][OH:6].[C:9]1([CH3:19])[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:10]=1>C(Cl)Cl.N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[CH3:19][C:9]1[CH:14]=[CH:13][C:12]([S:15]([O:6][CH2:5][CH2:4][CH2:3][C:2]([F:8])([F:7])[F:1])(=[O:17])=[O:16])=[CH:11][CH:10]=1
Reactant: OCCCC(F)(F)F
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCCC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 45.4 %

Procedure:
To a solution of 4,4,4-trifluorobutan-1-ol (5.0 g, 39.0 mmol) in CH2Cl2 (30 mL) and pyridine (20 mL) was added 4-(dimethylamino)pyridine (0.24 g, 2.0 mmol) followed by p-toluenesulfonyl chloride (7.4 g, 39.0 mmol). The mixture was allowed to stir at ambient temperature for 20 hours then was quenched with 5% aqueous HCl (20 mL) and the layers were separated. The aqueous phase was extracted with CH2Cl2 (3×5 mL). The combined organic extracts were dried over Na2SO4, filtered and concentrated under reduced pressure. Purification by column chromatography (SiO2, 75% hexanes in EtOAc) afforded the title compound (5.0 g, 17.7 mmol, 45% yield). 1H NMR (300 MHz, CDCl3) δ ppm 1.86-1.98 (m, 2H) 2.06-2.24 (m, 2H) 2.46 (s, 3H) 4.09 (t, J=5.9 Hz, 2H) 7.37 (d, J=7.8 Hz, 2H) 7.79 (d, J=8.5 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[C:10]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:15]=[CH:14][C:13]([C:16](=[O:18])[CH3:17])=[CH:12][CH:11]=1>>[C:10]1([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:11]=[CH:12][C:13]([C:16](=[O:18])[CH:17]=[CH:6][C:5]2[CH:8]=[CH:9][C:2]([Cl:1])=[CH:3][CH:4]=2)=[CH:14][CH:15]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: CC(=O)c1ccc(-c2ccccc2)cc1
Product: O=C(C=Cc1ccc(Cl)cc1)c1ccc(-c2ccccc2)cc1

Procedure:
Synthesised according to example 1.59.1 using 4-chlorobenzaldehyde (3.58 g, 25.48 mmol) and 1-(biphenyl-4-yl)ethanone (5.00 g, 25.48 mmol); pale yellow solid; yield: 7.74 g (95%);
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH:15]3[CH:20]([O:21][CH2:22][C:23]4[CH:24]=[CH:25][C:26]5[O:31][CH2:30][CH2:29][N:28]([CH2:32][CH2:33][CH2:34][O:35][CH3:36])[C:27]=5[CH:37]=4)[CH2:19][N:18](C(OCC4C=CC=CC=4)=O)[CH2:17][CH:16]3[OH:48])=[CH:11][CH:10]=2)=[N:6][CH:7]=1.B(F)(F)F.CCOCC.C(S)C>ClCCl>[Br:1][C:2]1[CH:7]=[N:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH:15]3[CH:20]([O:21][CH2:22][C:23]4[CH:24]=[CH:25][C:26]5[O:31][CH2:30][CH2:29][N:28]([CH2:32][CH2:33][CH2:34][O:35][CH3:36])[C:27]=5[CH:37]=4)[CH2:19][NH:18][CH2:17][CH:16]3[OH:48])=[CH:11][CH:10]=2)=[N:4][CH:3]=1
Reactant: COCCCN1CCOc2ccc(COC3CN(C(=O)OCc4ccccc4)CC(O)C3c3ccc(Oc4ncc(Br)cn4)cc3)cc21
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Solvent: CCS
Product: COCCCN1CCOc2ccc(COC3CNCC(O)C3c3ccc(Oc4ncc(Br)cn4)cc3)cc21
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of 139.8 mg of benzyl 4-[4-(5-bromopyrimidin-2-yloxy)phenyl]-3-hydroxy-5-[4 -(3-methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidine-1-carboxylate in 0.5 ml of dichloromethane is added to a mixture of 0.232 ml of boron trifiuoride etherate and 0.4 ml of ethanethiol. The reaction mixture is stirred at room temperature under argon for 20 hours. The solvent is then evaporated off, and 2 ml of water are added to the residue. The aqueous phase is extracted three times with 5 ml of ethyl acetate each time. The combined organic phases are dried with sodium sulphate, filtered and evaporated. The title compound is obtained as a beige wax from the residue by flash chromatography (SiO2 60F).
Reaction SMILES: [CH2:1]([C@:8]([OH:42])([CH2:22][CH2:23][O:24][Si:25]([C:38]([CH3:41])([CH3:40])[CH3:39])([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:9]([NH:11][C@H:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][C@H:13]1[OH:21])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:43]1(C)[CH:48]=CC(S(O)(=O)=O)=C[CH:44]=1.[NH+]1C=CC=CC=1.COC(C)=C.C([O-])(O)=O.[Na+]>ClCCl>[CH2:1]([C@:8]([OH:42])([CH2:22][CH2:23][O:24][Si:25]([C:38]([CH3:39])([CH3:41])[CH3:40])([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:9]([N:11]1[C@H:12]2[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[CH2:14][C@H:13]2[O:21][C:43]1([CH3:48])[CH3:44])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CC(C)(C)[Si](OCC[C@@](O)(Cc1ccccc1)C(=O)N[C@H]1c2ccccc2C[C@H]1O)(c1ccccc1)c1ccccc1
Agent: C=C(C)OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC1(C)O[C@@H]2Cc3ccccc3[C@@H]2N1C(=O)[C@@](O)(CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)Cc1ccccc1
Reaction time: 6 h

Procedure:
To a cooled (0° C.) solution of (S)-2-benzyl-4-(tert-butyl-diphenyl-silanyloxy)-2-hydroxy-N-((1S,2R)-2-hydroxy-indan-1-yl)-butyramide (21e) (0.325 g, 0.56 mmol) and pyridinium p-toluenesulphonic acid (15 mg, 0.05 mmol) in dry dichloromethane (20 mL), 2-methoxypropene (0.4 g, 5.6 mmol) was added and stirred for 6 h at the same temperature. Saturated NaHCO3 solution was added, organic layer and washed with sat. NaHCO3, brine, dried over anhydrous MgSO4 and evaporated under reduced pressure. The crude title product [(0.33 g), MS (ESI+): 620 (M+)] was used as such for the next reaction.
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]([CH3:7])[N:6]=1.C([Li])CCC.[C:13](OCC)(=[O:15])[CH3:14]>C1COCC1>[CH3:7][C:5]1[N:6]=[C:2]([CH2:1][C:13]([CH3:14])=[O:15])[S:3][CH:4]=1
Reactant: Cc1csc(C)n1
Reactant: CCOC(C)=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(=O)Cc1nc(C)cs1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
5.00 g (44.2 mmol) of 2,4-dimethylthiazole are dissolved in 50 ml of THF and, at −78° C., 19.4 ml (48.6 mmol) of n-butyllithium (2.5 M solution in hexane) are added dropwise. After stirring at −78° C. for 2 hours, 6.62 g (75.1 mmol) of ethyl acetate are added as solution in 25 ml of abs. THF. The mixture is stirred at −78° C. for 1 h and then warmed to room temperature. It is then hydrolyzed with sodium bicarbonate solution, and the mixture is extracted three times with diethyl ether. The combined organic phases are dried with magnesium sulfate, and the solvent is removed in a rotary evaporator. The crude product is purified by column chromatography (silica gel, mobile phase, cyclohexane/ethyl acetate 5:1). 3.2 g (47% of theory) of the title compound are obtained.
Reaction SMILES: N1C=CC=CC=1.[CH3:7][O:8][C:9](=[O:28])[CH:10]([C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1)[CH:11]([C:13]1[CH:18]=[CH:17][N:16]=[C:15]([S:19][CH3:20])[N:14]=1)[OH:12]>C(Cl)Cl.CCOCC.[Cr]>[CH3:7][O:8][C:9](=[O:28])[CH:10]([C:21]1[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=1)[C:11]([C:13]1[CH:18]=[CH:17][N:16]=[C:15]([S:19][CH3:20])[N:14]=1)=[O:12]
Reactant: COC(=O)C(c1ccc(F)cc1)C(O)c1ccnc(SC)n1
Agent: [Cr]
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CCOCC
Product: COC(=O)C(C(=O)c1ccnc(SC)n1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 43 %

Procedure:
To a suspension of CrO3 in CH2Cl2 (300 mL) is added pyridine. The mixture is stirred vigorously for 1 hour at room temp. A solution of the crude 2-(4-fluorophenyl)-3-(2-methylsulfanyl-pyrimidin-4-yl)-3-hydroxypropionic acid methyl ester, 2, prepared above in CH2Cl2 (50 mL) is added dropwise to the chromium suspension. The reaction mixture is stirred at room temperature for 16 hours, diluted with ether (1 L) and filtered through a pad of Celite. The filtrate is concentrated in vacuo and the resulting residue is purified over silica (25% EtOAc/hexanes) to afford 3.7 g (43% yield) of the desired product as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][C:5]([Br:11])=[CH:4][C:3]=1[C:12]([F:15])([F:14])[F:13].Cl[Sn]Cl.C([O-])(O)=O.[Na+]>C(O)C>[NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][C:5]([Br:11])=[CH:4][C:3]=1[C:12]([F:15])([F:13])[F:14]
Reactant: Nc1c([N+](=O)[O-])cc(Br)cc1C(F)(F)F
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Nc1cc(Br)cc(C(F)(F)F)c1N
Temperature: 90 °C
Yield: 62 %

Procedure:
To a stirred mixture of 2-amino-5-bromo-3-nitrobenzotrifluoride (261 mg, 0.949 mmol) in ethanol (4 mL) was added SnCl2 ·2H2O (1.076 g, 4.745 mmol) in one portion. The mixture was refluxed at 80° C. (oil bath 90° C.) for 1 h. The solution was cooled to room temperature and ice water (20 g) was added. It was adjusted to pH=7 with NaHCO3 and extracted by ethyl acetate (2×4 mL). The extract was dried over Mg2SO4 and evaporated to give 150 mg (64.6%) of 2,3-diamino-5-bromobenzotrifluoride as a brown solid. 1H NMR (CDCl3): δ3.503 (s, 2H); 3.898 (s, 2H); 6.987 (d, 1H, J=1.8 Hz); 7.123 (d, 1H, J=1.8 Hz).
Reaction SMILES: [CH2:1]([OH:5])[C:2]#[C:3][CH3:4].O[C:7]1[CH:8]=[CH:9][C:10]([C:13]([O:15][CH3:16])=[O:14])=[N:11][CH:12]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[CH2:1]([O:5][C:7]1[CH:8]=[CH:9][C:10]([C:13]([O:15][CH3:16])=[O:14])=[N:11][CH:12]=1)[C:2]#[C:3][CH3:4]
Reactant: COC(=O)c1ccc(O)cn1
Reactant: CC#CCO
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC#CCOc1ccc(C(=O)OC)nc1
Reaction time: 48 h
Yield: 81.5 %

Procedure:
To a solution of but-2-yn-1-ol (0.635 mL, 8.49 mmol) in THF (30 mL) were added methyl 5-hydroxypicolinate (1.3 g, 8.49 mmol), triphenylphosphine (3.34 g, 12.73 mmol) and diisopropyl azodicarboxylate (2.507 mL, 12.73 mmol) at 0° C. The reaction mixture was then allowed to reach r.t and stirred for 2 days. The reaction mixture was concentrated and the product was purified by flash chromatography using a heptane/EtOAc gradient to give 1.42 g (82% yield) of the title compound. 1H NMR (400 MHz, CDCl3) δ ppm 1.87 (t, 3 H), 4.00 (s, 3 H), 4.79 (q, 2 H), 7.41 (dd, 1 H), 8.11-8.20 (m, 1 H), 8.49 (d, 1 H).
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([CH2:11][OH:12])[CH2:7][CH2:6]1)=[O:4].CCN(CC)CC.S(=O)(=O)=O.N1C=CC=CC=1>C(Cl)Cl.CS(C)=O>[CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][CH:8]([CH:11]=[O:12])[CH2:7][CH2:6]1)=[O:4]
Reactant: COC(=O)[C@H]1CC[C@H](CO)CC1
Agent: O=S(=O)=O
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: COC(=O)C1CCC(C=O)CC1
Reaction time: 1.17 h

Procedure:
The title intermediate (700 mg, 1.87 mmol, 40%) was obtained as a white solid from 4-formyl-cyclohexanecarboxylic acid methyl ester (800 mg, 4.7 mmol) and 4-iodoaniline (601 mg, 2.74 mmol) analogously to Intermediate 75.7. HPLC: GtRet=7.874 min; LC-MS: m/z 374.2 [M+H]+. 4-Formyl-cyclohexanecarboxylic acid methyl ester was prepared by the following method. To a solution of trans-4-hydroxymethyl-cyclohexanecarboxylic acid methyl ester (which is reported in Synthesis Comm. (1982) page 42-43) (861 mg, 5.0 mmol) and Et3N (2.1 mL, 15.0 mmol) in DCM (16 mL) was slowly added a solution of pyridine sulfur trioxide (2.39 g, 15 mmol) in DMSO (10 mL) at 0° C. (ice bath). After 70 min stirring, it was then diluted into DCM and washed with water. The organic layer was dried over Na2SO4, filtered and evaporated to dryness. This crude material (0.8 g, 4.7 mmol) was used for the next step without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([OH:13])=[O:12])=[CH:6][CH:5]=1)([O-])=O.[OH-].[Na+]>O.[Ni]>[NH2:1][C@H:4]1[CH2:5][CH2:6][C@H:7]([CH2:10][C:11]([OH:13])=[O:12])[CH2:8][CH2:9]1
Reactant: O=C(O)Cc1ccc([N+](=O)[O-])cc1
Agent: [Ni]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: N[C@H]1CC[C@H](CC(=O)O)CC1
Temperature: 125 °C

Procedure:
(4-Nitro-phenyl)-acetic acid (50 g, 276 mmol) was added to a stirred solution of 22.08 g of 50% sodium hydroxide solution in 450 mL deionizated water. The clear yellow solution is transferred into a high-pressure autoclave that it charged with 30 g (511 mmol) of water-wet sponge nickel catalyst. The autoclave is sealed, flushed with nitrogen and then pressurized to 115 bar with hydrogen. The reaction mixture is stirred and heated to 125° C. for 48 h. At that time the autoclave is cooled, vented and charged under nitrogen with another 30 g (511 mmol) of the sponge nickel catalyst. The autoclave is flushed again with nitrogen and then pressurized to 115 bar and the vessel is heated to 130° C. while stirring (a maximum pressure of 130 bars is observed). Hydrogenation is continued for 5 days to 130° C. The autoclave is then cooled, vented and flushed with nitrogen and the contents are removed and filtered through filter aid to remove catalyst. After removal of the solvent 74 g of crude material was obtained. The intermediated is used directly in the next step without purification. MS (m/e): 158.3 (M+H+).
Reaction SMILES: [N+]([O-])(O)=O.[N+:5]([C:8]1[CH:18]=[CH:17][C:11]2[CH2:12][CH2:13][NH:14][CH2:15][CH2:16][C:10]=2[CH:9]=1)([O-:7])=[O:6].C(=O)([O-])[O-].[K+].[K+].I[CH2:26][CH3:27]>CC(C)=O>[CH2:26]([N:14]1[CH2:15][CH2:16][C:10]2[CH:9]=[C:8]([N+:5]([O-:7])=[O:6])[CH:18]=[CH:17][C:11]=2[CH2:12][CH2:13]1)[CH3:27]
Reactant: CCI
Reactant: O=[N+]([O-])c1ccc2c(c1)CCNCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=[N+]([O-])O
Solvent: CC(C)=O
Product: CCN1CCc2ccc([N+](=O)[O-])cc2CC1
Reaction time: 2 h

Procedure:
7-Nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepine nitrate salt (1.03 g/4 mmol) was suspended in acetone (10 mL). Potassium carbonate and iodoethane were added sequentially and the suspension was heated to reflux with vigorous stirring for 2 hours. The mixture was then filtered through a pad of celite (rinsing with acetone) and the filtrate concentrated onto silica gel. 3-Ethyl-7-nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepine was isolated by column chromatography on silica gel (eluting with 0→10% methanol/methylene chloride) as a yellow/orange oil (600 mg/72%). 1H NMR (400 MHz, CDCl3) δ 7.98 (m, 2H), 7.28 (m, 1H), 3.15 (s, 4H), 2.91 (s, 4H), 2.79 (q, J=7.1 Hz, 2H), 1.20 (t, J=7.1 Hz, 3H).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C@@:9]3([CH3:14])[C:11]([CH3:13])([CH3:12])[C@H:6]([CH2:7][CH2:8]3)[C:5]=2[C:4](=[O:15])[NH:3]1.[F:16][C:17]([F:27])([F:26])[C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[CH2:21]Br>CN(C)C=O>[F:16][C:17]([F:26])([F:27])[C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[CH2:21][N:3]1[C:4](=[O:15])[C:5]2[C@@H:6]3[C:11]([CH3:12])([CH3:13])[C@@:9]([CH3:14])([CH2:8][CH2:7]3)[C:10]=2[N:2]1[CH3:1]
Reactant: FC(F)(F)c1cccc(CBr)c1
Reactant: Cn1[nH]c(=O)c2c1[C@]1(C)CC[C@H]2C1(C)C
Solvent: CN(C)C=O
Product: Cn1c2c(c(=O)n1Cc1cccc(C(F)(F)F)c1)[C@H]1CC[C@]2(C)C1(C)C
Temperature: 100 °C
Yield: 35.8 %

Procedure:
A mixture of (4S,7R)-1,7,8,8-tetramethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 19; 100 mg, 0.49 mmol) and 3-trifluoromethyl-benzyl bromide (75 μL, 0.49 mmol) in N,N-dimethylformamide (5 mL) was heated at 100° C. overnight. The reaction mixture was evaporated and the residue was purified using a Biotage 40S system, eluting with 0-1% methanol/chloroform, followed by drying under high vacuum to give (4S,7R)-2-(3-trifluoromethyl-benzyl)-1,7,8,8-tetramethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (64 mg, 36%) as an off-white solid. APCI-MS (M+H) 365.
Reaction SMILES: CN([CH:4]=[O:5])C.O=P(Cl)(Cl)Cl.[CH2:11]([O:18][C:19]1[CH:28]=[C:27]2[C:22]([C:23]([CH3:29])=[CH:24][CH2:25][O:26]2)=[CH:21][CH:20]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(Cl)Cl>[CH2:11]([O:18][C:19]1[CH:28]=[C:27]2[C:22]([C:23]([CH3:29])=[C:24]([CH:4]=[O:5])[CH2:25][O:26]2)=[CH:21][CH:20]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CC1=CCOc2cc(OCc3ccccc3)ccc21
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Product: CC1=C(C=O)COc2cc(OCc3ccccc3)ccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To DMF (1 mL) was added dropwise POCl3 (0.25 mL) at 0° C., followed by stirring at room temperature for 30 minutes. To the reaction mixture was added dropwise a solution of 7-(benzyloxy)-4-methyl 2H-chromene (280 mg) in DCM (1 mL), followed by stirring at room temperature for 3 hours. The reaction liquid was poured into ice-water, followed by extraction with EtOAc three times. The organic layer was combined, washed with water and brine in this order, dried over MgSO4, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (automatic purification device, hexane:EtOAc=85:15 to 70:30) to obtain 7-(benzyloxy)-4-methyl-2H-chromene-3-carbaldehyde (234 mg) as a pale yellow powder.
Reaction SMILES: C([O:8][C:9]1[CH:36]=[CH:35][C:34]([N:37]([CH3:39])[CH3:38])=[CH:33][C:10]=1[C:11]([NH:13][C:14]1[CH:26]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:24]=[CH:23][C:15]=1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:12])C1C=CC=CC=1>CO.C(OCC)(=O)C.[C].[Pd]>[CH3:39][N:37]([CH3:38])[C:34]1[CH:35]=[CH:36][C:9]([OH:8])=[C:10]([CH:33]=1)[C:11]([NH:13][C:14]1[CH:26]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:24]=[CH:23][C:15]=1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:12]
Reactant: CN(C)c1ccc(OCc2ccccc2)c(C(=O)Nc2cc(-c3ccccc3)ccc2C(=O)OC(C)(C)C)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CN(C)c1ccc(O)c(C(=O)Nc2cc(-c3ccccc3)ccc2C(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 69 %

Procedure:
To a solution mixture of the obtained tert-butyl 2-(2-(benzyloxy)-5-(dimethylamino)benzamido)-4-phenylbenzoate (0.063 g) in methanol (1.5 mL) and ethyl acetate (2.5 mL), 10% palladium-carbon (32 mg) was added, followed by stirring under a hydrogen atmosphere at room temperature for 2 hours. To the reaction mixture, 10% palladium-carbon (13 mg) was added, followed by stirring under a hydrogen atmosphere at room temperature for 1 hour and 30 minutes. Ethyl acetate was added to the reaction mixture. The insoluble substance was removed by filtration, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: 95-85% hexane/ethyl acetate] to obtain 0.036 g of tert-butyl 2-(5-(dimethylamino)-2-hydroxybenzamido)-4-phenylbenzoate.