Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][CH2:15][C:16]2[C:17]3[N:24]([CH2:25][CH3:26])[C:23]([C:27]4[C:31]([NH2:32])=[N:30][O:29][N:28]=4)=[N:22][C:18]=3[CH:19]=[N:20][CH:21]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(=O)([O-])[O-].[K+].[K+].[C:39](Cl)(=[O:41])[CH3:40]>ClC1CC(C(C)C)CCC1(Cl)C>[NH2:32][C:31]1[C:27]([C:23]2[N:24]([CH2:25][CH3:26])[C:17]3[C:16]([CH2:15][N:14]([CH:11]4[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]4)[C:39](=[O:41])[CH3:40])=[CH:21][N:20]=[CH:19][C:18]=3[N:22]=2)=[N:28][O:29][N:30]=1
Reactant: CC(=O)Cl
Reactant: CCn1c(-c2nonc2N)nc2cncc(CNC3CCN(C(=O)OC(C)(C)C)CC3)c21
Agent: CC(C)C1CCC(C)(Cl)C(Cl)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCn1c(-c2nonc2N)nc2cncc(CN(C(C)=O)C3CCNCC3)c21
Temperature: 25 °C
Reaction time: 1 h
Yield: 59 %

Procedure:
The title compound from Example 191, Step 2 (145 mg, 0.3 mmol) in dichloromenthane at 0° C. was treated with potassium carbonate (90 mg, 0.66 mmol) followed by acetyl chloride (26 mg, 0.33 mL), and the mixture was stirred at room temperature for 1 hour. Purification of the residue by silica gel chromatography eluting with 10% methanol/dichloromethane afforded the title compound (68 mg, 10%). MS (ES+) m/e 484 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]2[CH2:15][C:14]([C:20]3[CH:25]=[C:24]([Cl:26])[CH:23]=[C:22]([Cl:27])[CH:21]=3)([C:16]([F:19])([F:18])[F:17])[S:13][N:12]=2)[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[CH3:28]OC(OC)N(C)C.Cl.[CH3:37][O:38][NH2:39].[OH-].[Na+]>O.C(O)(=O)C>[Cl:1][C:2]1[CH:10]=[C:9]([C:11]2[CH2:15][C:14]([C:20]3[CH:21]=[C:22]([Cl:27])[CH:23]=[C:24]([Cl:26])[CH:25]=3)([C:16]([F:19])([F:18])[F:17])[S:13][N:12]=2)[CH:8]=[CH:7][C:3]=1[C:4]([NH:6]/[CH:28]=[N:39]/[O:38][CH3:37])=[O:5]
Reactant: CON
Reactant: NC(=O)c1ccc(C2=NSC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1Cl
Reactant: COC(OC)N(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: CO/N=C/NC(=O)c1ccc(C2=NSC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 2-chloro-4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]benzamide (50 mg) and N,N-Dimethylformamide dimethylacetal (1 mL) was refluxed under Argon for 30 min then the solution was concentrated in vacuo. The residue was dissolved in 1,4-dioxane (0.48 mL) and a solution of O-methylhydroxylamine hydrochloride (2.8 eq.) and sodium hydroxide (6 eq.) in water (0.43 mL) and acetic acid (0.43 mL) was added. The solution was stirred at rt for one hour. It was then quenched by addition of water and extracted with methyl tert-butyl ether. The combined organic extracts were washed with brine, dried over sodium sulfate and evaporated. Flash Chromatography eluting with Cyclohexane:EtOAc afforded 30 mg of the title compound.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[CH2:5]Cl)[CH3:2].[CH3:10][C:11]1[CH:16]=[CH:15][C:14]([SH:17])=[CH:13][CH:12]=1.[Na]>CC(N(C)C)=O>[CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[CH2:5][S:17][C:14]1[CH:15]=[CH:16][C:11]([CH3:10])=[CH:12][CH:13]=1)[CH3:2]
Reactant: Cc1ccc(S)cc1
Reactant: CCOC(CCl)OCC
Agent: [Na]
Solvent: CC(=O)N(C)C
Product: CCOC(CSc1ccc(C)cc1)OCC

Procedure:
152.5 Grams (1 mole) of chloroacetaldehyde-diethylacetal were heated at 100° C for 6 hours on the steam bath, together with 162 g (1 mole) of 4-methylthiophenol-sodium salt in 200 ml of dimethylacetamide (in a manner analogous to Comptes Rendus 194, 617 (1932)). After the precipitated sodium chloride had been suction-filtered, the solvent was removed by distillation under reduced pressure. 4-Methylthio-phenoxyacetaldehyde-diethylacetal was obtained as an oily residue which was directly further reacted.
Reaction SMILES: [CH3:1][CH:2]([OH:10])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:11][O:12][CH2:13][C:14]1([N:20]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:21](=[O:24])[CH2:22][CH3:23])[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.[C:31](=[O:34])([O-:33])[O-].[Na+].[Na+].CC(C)CC(=O)C>O>[C:2]([OH:10])(=[O:12])[C:31]([OH:33])=[O:34].[CH3:11][O:12][CH2:13][C:14]1([N:20]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:21](=[O:24])[CH2:22][CH3:23])[CH2:19][CH2:18][N:17]([CH:2]([CH3:1])[CH2:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:16][CH2:15]1
Reactant: CCC(=O)N(c1ccccc1)C1(COC)CCNCC1
Reactant: O=C([O-])[O-]
Reactant: CC(O)Cc1ccccc1
Agent: [Na+]
Solvent: O
Solvent: CC(=O)CC(C)C
Product: CCC(=O)N(c1ccccc1)C1(COC)CCN(C(C)Cc2ccccc2)CC1
Product: O=C(O)C(=O)O

Procedure:
A mixture of 3.54 parts of α-methylphenethyl alcohol, methanesulfonate ester, 4.1 parts of N-[4-(methoxymethyl)-4-piperidinyl]-N-phenylpropanamide, 3.97 parts of sodium carbonate and 160 parts of 4-methyl-2-pentanone is stirred and refluxed for 24 hours with water-separator. After cooling, water is added and the product is extracted with trichloromethane. The extract is washed with water, dried, filtered and evaporated. The residue is purified by column-chromatography over silica gel using a mixture of benzene and 10% of methanol as eluent. The pure fractions are collected and the eluent is evaporated. The residue is converted into the ethanediolate salt in 2-propanol. The salt is filtered off, washed with 2-propanol and dried, yielding N-[4-(methoxymethyl)-1-(1-methyl-2-phenylethyl)-4-piperidinyl]-N-phenylpropanamide ethanedioate; mp. 196.8° C.
Reaction SMILES: C1(CNCC2C=C(C3C=C4C(=C(C(N)=O)C=3)NC=C4C3CCN(S(CC)(=O)=O)CC3)C=NC=2)CC1.[CH3:36][C:37]1([CH3:52])[C:41]([CH3:43])([CH3:42])[O:40][B:39]([C:44]2[CH:45]=[C:46]([CH:50]=O)[CH:47]=[N:48][CH:49]=2)[O:38]1.[CH3:53][O:54][CH2:55][CH2:56][NH2:57].[BH3-]C#N.[Na+]>>[CH3:53][O:54][CH2:55][CH2:56][NH:57][CH2:50][C:46]1[CH:47]=[N:48][CH:49]=[C:44]([B:39]2[O:38][C:37]([CH3:52])([CH3:36])[C:41]([CH3:43])([CH3:42])[O:40]2)[CH:45]=1
Reactant: CC1(C)OB(c2cncc(C=O)c2)OC1(C)C
Reactant: COCCN
Agent: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cncc(CNCC5CC5)c4)cc23)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Product: COCCNCc1cncc(B2OC(C)(C)C(C)(C)O2)c1
Yield: 50.4 %

Procedure:
Following the general procedure of 5-(5-{[(cyclopropylmethyl)amino]methyl}-3-pyridinyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide, 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinecarbaldehyde (30 mg, 0.129 mmol), [2-(methyloxy)ethyl]amine (0.011 mL, 0.129 mmol), and NaCNBH3 (16 mg, 0.258 mmol) were reacted to give 19 mg of crude [2-(methyloxy)ethyl]{[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinyl]methyl}amine. The crude [2-(methyloxy)ethyl]{[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinyl]methyl}amine was then reacted with 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (30 mg, 0.0723 mmol), potassium carbonate (60 mg, 0.434 mmol), and chloro-2-(dimethylaminomethyl)-ferrocen-1-yl-(dinorbornylphosphine)palladium(11) (4.4 mg, 0.00723 mmol) to give 15 mg of the title compound (46%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([OH:15])([CH3:14])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:16].O1CCOCC1>C(Cl)Cl>[ClH:16].[CH3:14][C:11]1([OH:15])[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: CC1(O)CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC1(O)CCNCC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 4-hydroxy-4-methyl-piperidine-1-carboxylic acid tert-butyl ester (1.08 g, 4.87 mmol) in DCM (25 mL) is added 4M HCl in 1,4-dioxane (20 mL, 80 mmol) and the reaction stirred at about 25° C. for 18 hours. The reaction is concentrated, suspended in Et2O and heptane, and filtered to afford the title compound (R) as a white powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.C(N(CC)CC)C.[C:30](Cl)(Cl)=[S:31].[N:34]1([CH2:39][CH2:40][NH2:41])[CH2:38][CH2:37][CH2:36][CH2:35]1>CN(C)C=O.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:30]([NH:41][CH2:40][CH2:39][N:34]2[CH2:38][CH2:37][CH2:36][CH2:35]2)=[S:31])=[CH:18][CH:17]=1
Reactant: NCCN1CCCC1
Reactant: S=C(Cl)Cl
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc2ncnc(Oc3ccc(NC(=S)NCCN4CCCC4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 5 h
Yield: 20.6 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (51 mg) was dissolved in N,N-dimethylformamide (2 ml) and triethylamine (1 ml) to prepare a solution. Thiophosgene (50 mg) was then added to the solution, and the mixture was stirred at room temperature for 5 hr. Next, 2-(1-pyrrolidyl)ethylamine (50 mg) was added thereto, and the mixture was further stirred at room temperature for 16 hr. Ethyl acetate was added to the reaction solution, followed by washing with water and saturated brine in that order. The organic layer was then dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by HPLC using chloroform/methanol for development to give the title compound (16 mg, yield 21%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([O:19][CH3:20])[C@H:13]([OH:14])[C@@H:12]([OH:15])[C@H:11]([OH:16])[C@@H:10]([CH2:17][OH:18])[O:9]2)=[CH:4][C:3]=1[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH3:30])=[C:24]([F:31])[C:23]=1[F:32].[Si:33](Cl)([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34].N1C=CN=C1>ClCCl>[Si:33]([O:18][CH2:17][C@H:10]1[O:9][C@:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH3:30])=[C:24]([F:31])[C:23]=3[F:32])[CH:4]=2)([O:19][CH3:20])[C@H:13]([OH:14])[C@@H:12]([OH:15])[C@@H:11]1[OH:16])([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCOc1ccc(Cc2cc([C@]3(OC)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)ccc2Cl)c(F)c1F
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CCOc1ccc(Cc2cc([C@]3(OC)O[C@H](CO[Si](C)(C)C(C)(C)C)[C@@H](O)[C@H](O)[C@H]3O)ccc2Cl)c(F)c1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 107.5 %

Procedure:
To a solution of (2S,3R,4S,5S,6R)-2-[4-chloro-3-[ (4-ethoxy-2,3-difluoro-phenyl)methyl]phenyl]-6-(hydroxymethyl)-2-methoxy-tetrahydropyran-3,4,5-triol 23g (9.02 g, 18.95 mmol) in dichloromethane (150 mL) were added tert-butyldimethylsilyl chloride (4.29 g, 28.43 mmol), imidazole (2.58 g, 37.9 mmol) and N,N-dimethylaminopyridine (0.23 g, 1.9 mmol) in turn at 0° C. The mixture was stirred at room temperature for 3 hours, and then washed with water (100 mL×3) and saturated aqueous sodium chloride (100 mL) in turn. The resulting mixture was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to give the title compound 23h as a yellow solid (12.0 g, 100%). This material was not further purified.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:11]2[S:10](=[O:13])(=[O:12])[N:9]=[C:8]([C:14]3[C:15](=[O:34])[N:16]([CH2:26][C:27]4[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=4)[C@@H:17]4[C@H:22]([C:23]=3[OH:24])[C@@H:21]3[CH2:25][C@H:18]4[CH2:19][CH2:20]3)[NH:7][C:6]=2[S:5][CH:4]=1.C(N(CC)CC)C.[CH:42]1([S:45](Cl)(=[O:47])=[O:46])[CH2:44][CH2:43]1>ClCCl>[F:33][C:30]1[CH:29]=[CH:28][C:27]([CH2:26][N:16]2[C:15](=[O:34])[C:14]([C:8]3[NH:7][C:6]4[S:5][CH:4]=[C:3]([CH2:2][NH:1][S:45]([CH:42]5[CH2:44][CH2:43]5)(=[O:47])=[O:46])[C:11]=4[S:10](=[O:12])(=[O:13])[N:9]=3)=[C:23]([OH:24])[C@H:22]3[C@@H:17]2[C@H:18]2[CH2:25][C@@H:21]3[CH2:20][CH2:19]2)=[CH:32][CH:31]=1
Reactant: NCc1csc2c1S(=O)(=O)N=C(C1=C(O)[C@@H]3[C@H]4CC[C@H](C4)[C@@H]3N(Cc3ccc(F)cc3)C1=O)N2
Reactant: O=S(=O)(Cl)C1CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1C(C2=NS(=O)(=O)c3c(CNS(=O)(=O)C4CC4)csc3N2)=C(O)[C@@H]2[C@H]3CC[C@H](C3)[C@@H]2N1Cc1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 85 %

Procedure:
To a solution of (1R,2S,7R,8S)-5-(7-aminomethyl-1,1-dioxo-1,4-dihydro-1λ6-thieno[2,3-e][1,2,4]thiadiazin-3-yl)-3-(4-fluoro-benzyl)-6-hydroxy-3-aza-tricyclo[6.2.1.02,7]undec-5-en-4-one (0.10 g, 0.20 mmol) in dichloromethane (3 mL) at 0° C. was added triethylamine (56 μl, 0.40 mmol) and cyclopropanesulfonyl chloride (23 μl, 0.22 mmol). The reaction was stirred at 0° C. for 30 min, then at 25° C. for 2 h. The reaction was quenched with water (10 mL). The resulting mixture was extracted with ethyl acetate (3×10 mL). The organic layers were combined, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified via flash column chromatography (Teledyne Isco RediSep column; 0-1% methanol in dichloromethane) to afford the desired product, cyclopropanesulfonic acid {3-[(1R,2S,7R,8S)-3-(4-fluoro-benzyl)-6-hydroxy-4-oxo-3-aza-tricyclo[6.2.1.02,7]undec-5-en-5-yl]-1,1-dioxo-1,4-dihydro-1λ6-thieno[2,3-e][1,2,4]thiadiazin-7-ylmethyl}-amide (0.10 g, 0.17 mmol, 84%), as a white solid. 1H NMR (400 MHz, CDCl3) δ: 1.15-1.78 (10H, m), 2.32-2.38 (1H, m), 2.56-2.58 (1H, m), 2.84-2.88 (2H, m), 3.48 (1H, d, J=9.2 Hz), 4.21 (1H, d, J=15.6 Hz), 4.51 (2H, d, J=6.4 Hz), 5.15 (1H, d, J=14.8 Hz), 5.35 (1H, t, J=6.4 Hz), 7.02-7.07 (3H, m), 7.19-7.22 (2H, m). LC-MS (ESI) calculated for C26H27FN4O6S3 606.71. found 607.2 [M+H+].
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([Cl:9])[CH:6]=[C:5]([Cl:10])[C:3]=1[NH2:4].[CH2:11](N1[C@H](C)CN([C@H](C2C=C(C=CC=2)C(Cl)=O)C2C=CC=C(O[Si](C(C)(C)C)(C)C)C=2)[C@@H](C)C1)C=C>>[CH3:11][NH:4][C:3]1[C:2]([Cl:1])=[CH:8][C:7]([Cl:9])=[CH:6][C:5]=1[Cl:10]
Reactant: Nc1c(Cl)cc(Cl)cc1Cl
Reactant: C=CCN1C[C@H](C)N([C@@H](c2cccc(O[Si](C)(C)C(C)(C)C)c2)c2cccc(C(=O)Cl)c2)C[C@H]1C
Product: CNc1c(Cl)cc(Cl)cc1Cl

Procedure:
N-Methyl-2,4,6-trichloroaniline [NMR (200 MHz, CDCl3): δ 2.82 (s, 3H); 5.11 (s, 1H); 7.46 (s, 2H)] was prepared from 2,4,6-trichloroaniline, coupled with 3-((αR)-α-((2S, 5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-(tert-butyldimethylsilyloxy)benzyl)benzoyl chloride, deprotected and purified by the methods described in Example 10 to give (+)-3-((αR)-α-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-methyl-N-(2,4,6-trichlorophenyl) as an off-white powder.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]([CH2:15][CH2:16][O:17][CH3:18])[C:13]3[C:19]([O:31][CH3:32])=[CH:20][C:21]([CH:23]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=4)[OH:24])=[CH:22][C:12]=3[N:11]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].C(N(C(C)C)C(C)C)C.[CH3:42][S:43](Cl)(=[O:45])=[O:44]>>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]([CH2:15][CH2:16][O:17][CH3:18])[C:13]3[C:19]([O:31][CH3:32])=[CH:20][C:21]([CH:23]([O:24][S:43]([CH3:42])(=[O:45])=[O:44])[C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=4)=[CH:22][C:12]=3[N:11]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: COCCn1c(-c2ccc(C(C)C)cc2)nc2cc(C(O)c3ccccn3)cc(OC)c21
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Product: COCCn1c(-c2ccc(C(C)C)cc2)nc2cc(C(OS(C)(=O)=O)c3ccccn3)cc(OC)c21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A mixture of 330 mg (0.76 mmol) [2-(4-isopropyl-phenyl)-7-methoxy-1-(2-methoxy-ethyl)-1H-benzoimidazol-5-yl]-pyridin-2-yl-methanol, 0.6 ml ethyl-diisopropyl-amine and 0.25 ml methanesulfonyl chloride is stirred at 0° C. for 1 h. Then the reaction mixture is poured on water and extracted (3×) with ethyl acetate. The combined organic layers are washed with water and brine, dried over MgSO4, filtered and concentrated in vacuo to afford the title product as an oil that is used directly in the next step.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:10][C:11]([OH:13])=[O:12])[CH:6]=[C:7]([CH3:9])[CH:8]=1.OS(O)(=O)=O.[CH3:19][CH2:20]O>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:10][C:11]([O:13][CH2:19][CH3:20])=[O:12])[CH:6]=[C:7]([CH3:9])[CH:8]=1
Reactant: COc1cc(C)cc(CC(=O)O)c1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)Cc1cc(C)cc(OC)c1
Reaction time: 40 h
Yield: 85 %

Procedure:
To a solution 3-methoxy-5-methylphenylacetic acid of (8.1 g; 0.045 mol; from step (iii) above) in EtOH (100 mL) was added H2SO4 (conc.), and the solution was left to stand for 40 hours. The reaction mixture was concentrated, and the crude product was partitioned between water and ether. The organic layer was washed with NaHCO3/aq and water, dried (Na2SO4), and evaporated to yield 8.0 g (85%) of the sub-title compound as a brown oil.
Reaction SMILES: F[C:2]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:3]=1N.[CH3:12][NH2:13].C1COCC1.C(=O)([O-])[O-].[K+].[K+].C[N:26]1CCCC1=O>>[CH3:12][NH:13][C:3]1[C:2]([NH2:26])=[CH:8][CH:7]=[C:6]([N+:9]([O-:11])=[O:10])[CH:5]=1
Reactant: CN1CCCC1=O
Reactant: Nc1cc([N+](=O)[O-])ccc1F
Reactant: CN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CNc1cc([N+](=O)[O-])ccc1N
Temperature: 120 °C

Procedure:
In a 350 mL pressure flask, 2-fluoro-5-nitroaniline (10 g, 0.064 mol), methylamine as a 2M solution in THF (65 mL, 0.13 mol) and potassium carbonate (18 g, 0.13 mol) in 1-Methyl-2-pyrrolidinone (80 mL) were combined. The flask was sealed and heated to 120 degrees C. overnight. The reaction was monitored by TLC. When reaction was judged to be complete based upon consumption of 2-fluoro-5-nitroaniline, it was cooled to room temperature and poured into 2–3 times the total reaction volume of water. When a precipitate was formed, it was filtered and dried. The product was carried on without purification. 1H NMR (300 MHz, d6DMSO) δ 7.54 (dd, J=8.79, 2.64 Hz, 1H), 7.39 (d, J=2.64 Hz, 1H), 6.41 (d, J=8.79 Hz, 1H), 6.11 (d, J=4.39 Hz, 1H), 5.07 (s, 2H), 2.83 (d, J=4.83 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:12])=[CH:4][N:3]=1.C1C=C(Cl)C=C(C(OO)=O)C=1.COC1C2C(=CC=CC=2)[CH:29]=[N:28][CH:27]=1>>[Cl:1][C:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[O:12][CH2:29][N:28]=[CH:27][C:4]=2[N:3]=1.[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:12])=[CH:4][N:3]=1
Reactant: COc1cncc2ccccc12
Agent: O=C(OO)c1cccc(Cl)c1
Agent: Oc1cnc(Cl)c2ccccc12
Product: Clc1nc2c(c3ccccc13)OCN=C2

Procedure:
6-Chloro-1,3-Oxazino[5,6-c]isoquinoline was prepared by the procedure of Miyoko Toyama and Hirotaka Otomasu starting from 1-chloro-4-hydroxy isoquinoline. The starting material: 1-chloro-4-hydroxy isoquinoline (Example 226c) was prepared by the synthetic sequence shown above. MCPBA oxidation of 4-methoxy isoquinoline (Example 222a) was carried as usual to give 79.1% of the corresponding N-oxide (Example 226a). The material was converted into the 1-chloro derivative immediately afterward in POCl3 to give the chloride (Example 226b) in essentially quantitative yield. The crude 1-chloro-4-methoxy isoquinoline was de-methylated in BBr3 at room temperature to give the corresponding 1-chloro-4-hydroxy isoquinoline (Example 226c) after treating the crude BBr3 mixture with anhydrous methanol at room temperature, followed by evaporation to get rid of excess of borate residues. The reaction of Miyoko Toyama and Hirotaka Otomasu gave 266 mg of 6-chloro-1,3-oxazino[5,6-c]isoquinoline (Example 226d, 62.3%) overall yield from 300 mg of 4-methoxy isoquinoline in 4 steps. LC/MS Rt-min ([M−HCHO]H+) [method D]: 2.45 (192). 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 5.02 (s, 2 H) 5.41 (s, 2 H) 7.68 (m, 1 H) 7.77 (ddd, J=8.25, 6.91, 1.22 Hz, 1 H) 8.10 (d, J=8.31 Hz, 1 H) 8.26 (d, J=8.56 Hz, 1 H).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:3]=1[CH:4]=O.[N+:11]([CH2:14][CH2:15][CH2:16][C:17]([O:19]C)=O)([O-:13])=[O:12].C([O-])(=O)C.[NH4+:25]>C(O)C>[F:1][C:2]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:3]=1[C@@H:4]1[NH:25][C:17](=[O:19])[CH2:16][CH2:15][C@H:14]1[N+:11]([O-:13])=[O:12]
Reactant: [NH4+]
Reactant: COC(=O)CCC[N+](=O)[O-]
Reactant: O=Cc1cc(F)ccc1F
Agent: CC(=O)[O-]
Solvent: CCO
Product: O=C1CC[C@@H]([N+](=O)[O-])[C@H](c2cc(F)ccc2F)N1
Reaction time: 0.08 h

Procedure:
To a solution of 2,5-difluorobenzaldehyde (3.82 mL, 35.2 mmol) in ethanol (70 mL) was added methyl 4-nitrobutyrate (4.51 mL, 35.2 mmol) and the mixture was stirred for 5 minutes. To the reaction mixture was added ammonium acetate (5.42 g, 70.4 mmol) and the mixture stirred for 10 minutes at ambient temperature and then heated at reflux temperature for 16 h. The solvent was removed in vacuo and to the yellow oil was added saturated aqueous sodium hydrogen carbonate (100 mL) and the aqueous phase extracted with ethyl acetate (3×50 mL). The combined organic phases were washed with saturated aqueous brine (1×50 mL), dried with anhydrous sodium sulfate, filtered and the solvent removed in vacuo. The yellow racemic product was purified by preparative HPLC on a Berger SFC using ChiralPak AS-H™ column, eluting with 20% MeOH/CO2 to give (5R,6S)-6-(2,5-difluorophenyl)-5-nitropiperidin-2-one [LC/MS 257.1 (M+1)] as the second eluting isomer and the title compound as the first eluting isomer. LC/MS 257.1 (M+1).
Reaction SMILES: [N+](=[CH:3]C(C=[N+]=[N-])=O)=[N-].[CH2:9]([O:16][C:17]([NH:19][C@H:20]([C:25]([NH:27][C@H:28]([C:36](O)=[O:37])[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:26])[CH2:21][CH:22]([CH3:24])[CH3:23])=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[CH2:39]([OH:45])[C:40]1[O:44][CH:43]=[CH:42][CH:41]=1>C(Cl)Cl.C([O-])(=O)C.[Rh+3].C([O-])(=O)C.C([O-])(=O)C>[CH2:9]([O:16][C:17]([NH:19][C@@H:20]([CH2:21][CH:22]([CH3:24])[CH3:23])[C:25]([NH:27][C@@H:28]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:36](=[O:37])[CH2:3][O:45][CH2:39][C:40]1[O:44][CH:43]=[CH:42][CH:41]=1)=[O:26])=[O:18])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: [N-]=[N+]=CC(=O)C=[N+]=[N-]
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: OCc1ccco1
Agent: [Rh+3]
Agent: CC(=O)[O-]
Solvent: ClCCl
Product: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)C(=O)COCc1ccco1
Temperature: 25 °C
Reaction time: 1 h
Yield: 7.4 %

Procedure:
N-Benzyloxycarbonyl-L-leucyl-L-phenylalanine diazomethylketone (314 mg) was dissolved in furfuryl alcohol (2 ml) and methylene chloride (1 ml). To the solution was added rhodium acetate (II) dimer (10 mg). After the mixture was stirred at room temperature for 1 hour, the solvents was removed in vacuo and the residue was chromatographed on a silica gel column, eluting with hexane-ethyl acetate to give the titled product (27 mg).
Reaction SMILES: [C:1]1([CH3:16])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[NH:9][CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.Br[CH2:18][CH2:19][C:20]1([CH2:26][C:27]([O:29][CH3:30])=[O:28])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.C(=O)([O-])[O-].[K+].[K+].C(Cl)(Cl)Cl>CN(C)C=O>[C:3]1([CH3:8])[CH:4]=[C:5]([CH3:7])[CH:6]=[C:1]([CH3:16])[C:2]=1[NH:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:18][CH2:19][C:20]2([CH2:26][C:27]([O:29][CH3:30])=[O:28])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[CH2:12][CH2:11]1
Reactant: COC(=O)CC1(CCBr)CCCCC1
Reactant: Cc1cc(C)c(NC2CCNCC2)c(C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: COC(=O)CC1(CCN2CCC(Nc3c(C)cc(C)cc3C)CC2)CCCCC1
Temperature: 80 °C
Reaction time: 10 h
Yield: 52.7 %

Procedure:
A suspension of 4-(mesitylamino)piperidine (250 mg, 1.15 mmol), methyl [1-(2-bromoethyl)cyclohexyl]acetate (371 mg, 1.38 mmol) and potassium carbonate (318 mg, 2.3 mmol) in N,N-dimethylformamide (3 mL) was stirred at 80° C. for 10 hours. Chloroform (10 mL) was added to the reaction mixture, the insoluble portion was filtered out, and the filtrate was concentrated under reduced pressure. The residue was dissolved in xylene (10 mL) and concentrated under reduced pressure. The residue was then purified by silica gel column chromatography (10 g Merck Art 9385, hexane:ethyl acetate=7:3-chloroform:methanol=10:1) to obtain the title compound as a brown oil (243 mg) (53% yield).