Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([C:8]1[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:9]=1[C:10](O)=[O:11])C1C=CC=CC=1.C[N:20](C=O)C.C(Cl)(=O)C(Cl)=O>C(Cl)Cl>[CH3:18][O:17][C:15]1[CH:14]=[CH:13][C:9]([C:10]([NH2:20])=[O:11])=[CH:8][CH:16]=1
Reactant: CN(C)C=O
Reactant: COc1ccc(C(=O)O)c(Cc2ccccc2)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: COc1ccc(C(N)=O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-benzyl-4-methoxybenzoic acid (14.2 g) in 600 mL CH2Cl2 was added a catalytic amount of DMF, followed by a solution of oxalyl chloride (8.7 g) in 100 mL of CH2Cl2. The reaction was stirred at room temp overnight, then concentrated and azeotroped with toluene (2×). The residue was dissolved in 700 mL CH2Cl2 and cooled to 0 C. Tert-butyl amine (13.9 g) was added, and the reaction was warmed to room temp. After 1.5 h, the reaction was quenched with 5% aqueous KHSO4. The organic solution was separated, washed once with saturated aqueous sodium bicarbonate, dried (Na2SO4) and concentrated to give 15.9 g of 2-benzyl-N-tert-butyl)-4-methoxybenzamide.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[C:9]2[N:10]=[C:11]([C:13]3[NH:22][C:16]4[CH2:17][CH2:18][NH:19][CH2:20][CH2:21][C:15]=4[N:14]=3)[S:12][C:8]=2[C:7]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[CH:6][CH:5]=1.C(N(C(C)C)C(C)C)C.[C:38]1([CH3:47])[C:39]([C:44](Cl)=[O:45])=[CH:40][CH:41]=[CH:42][CH:43]=1>O1CCCC1>[CH3:2][O:3][C:4]1[C:9]2[N:10]=[C:11]([C:13]3[NH:22][C:16]4[CH2:17][CH2:18][N:19]([C:44]([C:39]5[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=5[CH3:47])=[O:45])[CH2:20][CH2:21][C:15]=4[N:14]=3)[S:12][C:8]=2[C:7]([N:23]2[CH2:24][CH2:25][O:26][CH2:27][CH2:28]2)=[CH:6][CH:5]=1
Reactant: Cc1ccccc1C(=O)Cl
Reactant: COc1ccc(N2CCOCC2)c2sc(-c3nc4c([nH]3)CCNCC4)nc12
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1ccc(N2CCOCC2)c2sc(-c3nc4c([nH]3)CCN(C(=O)c3ccccc3C)CC4)nc12
Yield: 98.4 %

Procedure:
To a suspension of 0.04 g 2-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-1,4,5,6,7,8-hexahydro-imidazo[4,5-d]azepine hydrochloride in 3.4 ml tetrahydrofurane were added at 0–4° C. 0.07 ml N-ethyldiisopropylamine and 0.017 g o-toluoyl chloride. The mixture was refluxed for 17 hours, silicagel was added and the solvent was distilled off. The residue was transferred to a column prefilled with silicagel and was chromatographed with dichloromethane/methanol 96:4 to yield 0.047 g (94%) [2-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-4,5,7,8-tetrahydro-1H-imidazo[4,5-d]azepin-6-yl]-o-tolyl-methanone as yellow solid; M.p.: 194–196° C.; MS (ISP): m/e=504 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([OH:12])[CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:32][N:33]1[CH2:38][CH2:37][CH:36](O)[CH2:35][CH2:34]1.N(C(OCC)=O)=NC(OCC)=O>CO.C1C=CC=CC=1>[F:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([O:12][CH:36]2[CH2:37][CH2:38][N:33]([CH3:32])[CH2:34][CH2:35]2)[CH:3]=1
Reactant: CN1CCC(O)CC1
Reactant: COC(=O)c1ccc(F)cc1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Solvent: CO
Product: COC(=O)c1ccc(F)cc1OC1CCN(C)CC1
Temperature: 0 °C
Yield: 57.5 %

Procedure:
A mixture of methyl 4-fluoro-2-hydroxybenzoate (12 g, 70.5 mmol), triphenyl-phosphine (22.2 g, 84.6 mmol), N-methyl-4-hydroxypiperidine (8.1 g, 70.3 mmol) and benzene (25 mL) was heated until all the solids dissolved. The solution was cooled to 0° C., then sonicated while adding diethyl azodicarboxylate (14.7 g, 84.6 mmol) dropwise. After the addition was complete, the reaction was sonicated for an additional 60 minutes, and then purified by flash chromatography, eluting sequentially with 50% EtOAc in hexanes followed by 1%, 2%, 5% then 10% MeOH in CHCl3, to yield 10.8 g (40.4 mmol, 57%) of an oil.
Reaction SMILES: [CH:1]12[N:8]([C:9](Cl)=[O:10])[CH:5]([CH2:6][CH2:7]1)[CH2:4][CH2:3][CH2:2]2.[F:12][C:13]1[CH:14]=[CH:15][C:16]([NH:19][NH2:20])=[N:17][CH:18]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[F:12][C:13]1[CH:14]=[CH:15][C:16]([NH:19][NH:20][C:9]([N:8]2[CH:5]3[CH2:6][CH2:7][CH:1]2[CH2:2][CH2:3][CH2:4]3)=[O:10])=[N:17][CH:18]=1
Reactant: O=C(Cl)N1C2CCCC1CC2
Reactant: NNc1ccc(F)cn1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NNc1ccc(F)cn1)N1C2CCCC1CC2
Reaction time: 120 h
Yield: 46.6 %

Procedure:
To a solution of Intermediate 122a (240 mg, 1.38 mmol) and (5-fluoro-pyridin-2-yl)-hydrazine (176 mg, 1.38 mmol) in DCM (10 mL) was added DIPEA (721 μL, 4.15 mmol) and the reaction stirred for 5 days. The reaction was then partitioned between DCM and water. The aqueous phase was extracted with DCM (×3) and the combined organic layers were washed with brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was purified by FCC on silica, using a gradient of 0-10% MeOH in DCM to give the title compound (170 mg, 47%). LCMS (Method 3): Rt 2.31 min, m/z 265 [MH+].
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:37])=[C:7]2[C:12](=[C:13]([C:15]3[CH:16]=[N:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=3)[N:14]=1)[N:11]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:10](=[O:30])[C:9]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[CH:8]2)=[O:4].[NH2:38][CH2:39][CH2:40][C:41]([OH:43])=[O:42].C[O-].[Na+]>>[CH2:23]([N:11]1[C:12]2[C:7](=[C:6]([OH:37])[C:5]([C:3]([NH:38][CH2:39][CH2:40][C:41]([OH:43])=[O:42])=[O:4])=[N:14][C:13]=2[C:15]2[CH:16]=[N:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=2)[CH:8]=[C:9]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:10]1=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: COC(=O)c1nc(-c2ccc(OC)nc2)c2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Reactant: NCCC(=O)O
Agent: C[O-]
Agent: [Na+]
Product: COc1ccc(-c2nc(C(=O)NCCC(=O)O)c(O)c3cc(-c4ccccc4)c(=O)n(Cc4ccccc4)c23)cn1
Temperature: 25 °C
Yield: 68.8 %

Procedure:
A mixture of 1-benzyl-5-hydroxy-8-(6-methoxy-pyridin-3-yl)-2-oxo-3-phenyl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (67 mg, 0.14 mmol), β-alanine (726 mg, 8.2 mmol) and NaOMe solution (12 mL, 6.1 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was partitioned between EtOAc and water. 1 M HCl was added with vigorous stirring until pH was about 3-4. The aqueous layer was extracted with additional EtOAc, and the organic layers were combined, dried over MgSO4 and concentrated. The residue was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH about 3-4, and the resulting precipitate was isolated by filtration to give 53 mg of the title compound as a light yellow solid. MS: (+) m/z 551.39 (M+1).
Reaction SMILES: ClS([N:5]=[C:6]=[O:7])(=O)=O.C1COCC1.[CH2:13]([O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:31]=[C:30]([CH2:32][OH:33])[O:29][N:28]=2)=[CH:23][CH:22]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>O>[CH2:13]([O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:31]=[C:30]([CH2:32][O:33][C:6](=[O:7])[NH2:5])[O:29][N:28]=2)=[CH:23][CH:22]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: OCc1cc(-c2ccc(OCc3ccccc3)cc2)no1
Reactant: O=C=NS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: O
Product: NC(=O)OCc1cc(-c2ccc(OCc3ccccc3)cc2)no1
Reaction time: 1 h
Yield: 84.6 %

Procedure:
4-Benzyloxybenzaldehyde (4.24 g, 20 mmol) was dissolved in a solvent mixture of ethanol and water (3:1, 100 ml) in the concentration of 0.2 M while stirring. NH2OH—HCl (2.78 g, 40 mmol) and sodium acetate (2.46 g, 30 mmol) were added thereto, which was then stirred for about 30 min at room temperature. The completion of reaction was confirmed by liquid chromatography, and water and ethanol were distilled off under reduced pressure to give a pale yellow solid compound. This solid compound was extracted three times with water and ethyl acetate, and the organic solvent layer was subjected to the condition of reduced pressure. The crude compound was recrystallized from hexane/ethyl acetate (10:1) to give a compound as a white solid. Thus obtained solid 4-benzyloxy-benzaldehydeoxime (2.27 g, 10 mmol; a compound of 92% purity) was dissolved in methylene chloride (40 ml, 0.25 M), and propargyl alcohol (1.77 ml, 30 mmol) was added thereto. To this solution was very slowly added in drops 10% NaOCl (13.7 ml, 20 mmol) at 0° C. by using a dropping funnel. After all NaOCl was added, the mixture was stirred for about 5 h during which the temperature was slowly raised to room temperature. After the completion of reaction was confirmed by liquid chromatography, the reaction mixture was distilled under reduced pressure to evaporate methylene chloride. Water (200 ml) was added to the residue, and the resulting solid was filtered. The compound thus filtered was washed with excess water and then finally washed with diethyl ether. The solid compound thus obtained was recrystallized from ethyl acetate/hexane (1:2) to give [3-(4-benzyloxy-phenyl)-isoxazol-5-yl]-methanol as a white solid (Yield: 2.5 g). Chlorosulfonyl isocyanate (1.04 ml, 12 mmol) was slowly added to the THF solution (50 ml, 0.2 M) containing [3-(4-benzyloxy-phenyl)-isoxazol-5-yl]-methanol (2.813 g, 10 mmol) in a 250 ml flask at −78° C. After disappearance of all the starting materials was confirmed by liquid chromatography, water was added to the reaction solution. After 1 h, distillation under reduced pressure was carried out to evaporate THF. Water (100 ml) was added thereto, and the resulting solid was filtered. Thus filtered solid was washed with 100 me of water and ethyl acetate/hexane (1:2) solution, and dried to give 3.4 g of the crude product (Purity: 95.9%). This crude product was recrystallized from ethyl acetate/hexane/methylene chloride (1:4:1) solution containing 1% methanol to give 2.743 g of carbamic acid 3-(4-benzyloxy-phenyl)-isoxazol-5-ylmethyl ester (CBI) in the purity of 99%.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([CH:8]([OH:25])[CH2:9][N:10]2[C:22]3[N:21]=[CH:20][C:19]([CH3:23])=[CH:18][C:17]=3[C:16]3[CH2:15][N:14]([CH3:24])[CH2:13][CH2:12][C:11]2=3)=[CH:4][CH:3]=1.[CH3:26][N:27](C=O)C>CCOC(C)=O.[C-]#N.[Zn+2].[C-]#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:23][C:19]1[CH:20]=[N:21][C:22]2[N:10]([CH2:9][CH:8]([C:5]3[CH:4]=[CH:3][C:2]([C:26]#[N:27])=[N:7][CH:6]=3)[OH:25])[C:11]3[CH2:12][CH2:13][N:14]([CH3:24])[CH2:15][C:16]=3[C:17]=2[CH:18]=1
Reactant: CN(C)C=O
Reactant: Cc1cnc2c(c1)c1c(n2CC(O)c2ccc(Br)nc2)CCN(C)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: Cc1cnc2c(c1)c1c(n2CC(O)c2ccc(C#N)nc2)CCN(C)C1
Temperature: 150 °C

Procedure:
1-(6-Bromo-pyridin-3-yl)-2-(3,6-dimethyl-5,6,7,8-tetrahydro-1,6,9-triaza-fluoren-9-yl)-ethanol (2 g, 4.9 mmol) was dissolved in DMF (20 mL), and the mixture was purged with nitrogen. Zinc cyanide (1.16 g, 9.9 mmol) and Pd(PPh3)4 (339 mg, 0.294 mmol) were added, and the mixture heated at 150° C. for 2 h. The reaction was monitored by LCMS. The reaction mixture was allowed to cool at RT, diluted with EtOAc (250 mL) and filtered. The filtrate was washed with water (3×100 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated to obtain the crude that was purified by reverse phase chromatography to obtain 100 mg of 5-[2-(3,6-dimethyl-5,6,7,8-tetrahydro-1,6,9-triaza-fluoren-9-yl)-1-hydroxy-ethyl]-pyridine-2-carbonitrile. This was followed by chiral separation. 1H NMR (CDCl3, Free base) δ (ppm): 8.62 (s, 1H), 8.03 (s, 1H), 7.73 (d, 1H), 7.6 (d, 1H), 7.5 (s, 1H), 5.25 (d, 1H), 4.45 (d, 1H), 4.3 (dd, 1H), 3.55 (dd, 2H), 2.8 (m, 1H), 2.7 (m, 2H), 2.5 (s, 3H), 2.45 (s, 3H), 2.4 (m, 1H). Separation by chiral HPLC provided enantiomers II-114a-b.
Reaction SMILES: CO[C:3](=[O:34])[N:4]=[C:5](SC)[C:6]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]#[N:29])=[C:22]([O:30][CH3:31])[CH:21]=1)=[N:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:18]=[C:17]([CH3:19])[O:16][N:15]=2)=[CH:10][CH:9]=1.[NH:35]([C:37]1[N:42]=[CH:41][CH:40]=[CH:39][N:38]=1)[NH2:36].C(N(CC)CC)C>CN(C=O)C>[CH3:31][O:30][C:22]1[CH:21]=[C:20]([CH:6]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[N:18]=[C:17]([CH3:19])[O:16][N:15]=3)=[CH:10][CH:9]=2)[C:5]2[NH:4][C:3](=[O:34])[N:35]([C:37]3[N:42]=[CH:41][CH:40]=[CH:39][N:38]=3)[N:36]=2)[CH:25]=[CH:24][C:23]=1[O:26][CH2:27][C:28]#[N:29]
Reactant: COC(=O)N=C(SC)C(=Nc1ccc(-c2noc(C)n2)cc1)c1ccc(OCC#N)c(OC)c1
Reactant: NNc1ncccn1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc(C(Nc2ccc(-c3noc(C)n3)cc2)c2nn(-c3ncccn3)c(=O)[nH]2)ccc1OCC#N
Temperature: 85 °C
Reaction time: 16 h

Procedure:
To a solution of 535 mg of {2-(4-cyanomethoxy-3-methoxyphenyl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene}carbamic acid methyl ester in 8 ml of DMF there were added 123 mg of 2-hydrazinopyrimidine and 312 μl of triethylamine, and the mixture was stirred at 85° C. for 16 hours under a nitrogen atmosphere. The reaction mixture was concentrated, and the residue was dissolved in 6 ml of a methanol:THF=1:1 mixed solvent. Next, 229 μl of acetic acid and 357 mg of sodium cyanotrihydroborate were added to the solution and the mixture was stirred at room temperature for 3 hours and 30 minutes. After adding ethyl acetate to the reaction mixture, it was filtered through a small amount of NAM silica gel, and the silica gel was washed with ethyl acetate-methanol. The filtrate was concentrated under reduced pressure, and the residue was crudely purified by NAM silica gel column chromatography (methanol-ethyl acetate), to give (2-methoxy-4-{[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylamino]-(5-oxo-1-pyrimidin-2-yl-4,5-dihydro-1H-[1,2,4]triazol-3-yl)methyl}phenoxy)acetonitrile.
Reaction SMILES: CO[CH:3](OC)[CH2:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][CH2:15][CH2:16][N:17]([CH3:19])[CH3:18])[CH:7]=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O>FC(F)(F)C(O)=O>[CH3:18][N:17]([CH3:19])[CH2:16][CH2:15][O:14][C:8]1[CH:7]=[C:6]2[C:11]([CH:3]=[CH:4][NH:5]2)=[CH:10][C:9]=1[O:12][CH3:13]
Reactant: COc1ccc(NCC(OC)OC)cc1OCCN(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: COc1cc2cc[nH]c2cc1OCCN(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 83 %

Procedure:
A stirred solution of N-[3-(2-dimethylaminoethoxy)-4-methoxyphenyl]aminoacetaldehyde dimethyl acetal (D15, 5.3 g, 0.018 mole) in trifluoroacetic acid (22 ml) at -5° C. under argon was treated dropwise over 40 minutes with trifluoroacetic anhydride (22 ml). After a further 30 minutes the dark solution was treated with more trifluoroacetic acid (33 ml) and then heated under reflux for 7 hours. The solution was concentrated in vacuo and the residue basified with 10% Na2CO3 solution and extracted with ethyl acetate. The extract was dried (Na2SO4), concentrated in vacuo and the residue dissolved in methanol (100 ml), treated with potassium carbonate (10 g) and stirred at room temperature for 3 hours. The mixture was concentrated in vacuo, the residue treated with water (60 ml) and extracted with ethyl acetate (2×70 ml). The combined extract was dried (Na2SO4) and concentrated in vacuo to afford the title compound as a brown solid (3.5 g, 83%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH2:9])=[C:4]([NH2:10])[CH:3]=1.[CH:11]([C:13]1[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=1)=O>[N+](C1C=CC=CC=1)([O-])=O.CCCCCC>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]2[N:9]=[C:11]([C:13]3[CH:14]=[CH:15][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:21][CH:22]=3)[NH:10][C:4]=2[CH:3]=1
Reactant: Nc1cc(Cl)c(Cl)cc1N
Reactant: COC(=O)c1ccc(C=O)cc1
Solvent: O=[N+]([O-])c1ccccc1
Solvent: CCCCCC
Product: COC(=O)c1ccc(-c2nc3cc(Cl)c(Cl)cc3[nH]2)cc1
Temperature: 140 °C
Reaction time: 1 h
Yield: 68.9 %

Procedure:
A mixture of 4,5-dichlorophenylendiamine (4 g, 22.6 mmol) and methyl 4-formylbenzoate (3.68, 22.6 mmol) in nitrobenzene (35 ml) was heated at 140° C. for 30 h. After cooling, the mixture was diluted with n-hexane (150 ml) and stirred for 1 h. The solid was filtered obtaining 5 g of the title compound (yield 68.9%) as a brown powder, mp=240–250° C.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].[OH-].[Na+].[O:12](C(OC(C)(C)C)=O)[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=O.Cl>C1COCC1>[C:13]([NH:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5])([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:12]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: CC(C)C[C@H](N)C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 4 h
Yield: 115.3 %

Procedure:
19.7 g (0.15 mole) L-Leucine 4 was suspended in 200 mlH2O and 6.75 g (0.17 mole) NaOH was added. The clear solution was cooled to <10° C. and a solution of 36 g (0.165 mole) (BOC)2O in 100 ml THF was added dropwise keeping T<10° C. (30 minutes). After stirring for 4 hours at room temperature the mixture was acidified to pH2 by adding 1N HCl. The mixture was extracted with EtOAc (250, 100 and 100 ml), the combined organic layers were dried on Na2SO4 and evaporated, yielding 40 g (>100%) 5 as a colorless oil which contained some THF but was used as such.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:12]3[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH2:23][CH2:24][NH:25]C(=O)OC(C)(C)C)[CH:20]=4)[CH2:15][CH2:14][N:13]=3)[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.NC1C=CC=CN=1.[CH3:40][S:41](Cl)(=[O:43])=[O:42].O>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:12]3[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH2:23][CH2:24][NH:25][S:41]([CH3:40])(=[O:43])=[O:42])[CH:20]=4)[CH2:15][CH2:14][N:13]=3)[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)NCCOc1ccc2c(c1)C(C1(c3ccc(Cl)cc3)CCC1)=NCC2
Agent: Nc1ccccn1
Solvent: O
Solvent: C1CCOC1
Product: CS(=O)(=O)NCCOc1ccc2c(c1)C(C1(c3ccc(Cl)cc3)CCC1)=NCC2
Temperature: 25 °C
Reaction time: 14 h
Yield: 80.8 %

Procedure:
2-(1-(1-(4-chlorophenyl)cyclobutyl)-3,4-dihydroisoquinolin-7-yloxy)ethanamine (example 1, 100 mg, 0.26 mmol), aminopyridine (34.0 mg, 0.28 mmol), and methanesulfonyl chloride (31.9 mg, 0.28 mmol) were dissolved in THF (5 ml) and stirred for 14 h at RT. Water was added and the mixture was extracted with ethyl acetate. The organic layers were washed with water and saturated NaCl solution, dried with MgSO4, and the solvent was removed. The residue was purified by flash chromatography on silica gel using methylenehloride/MeOH 98:2→95:5 to give N-(2-{1-[1-(4-Chloro-phenyl)-cyclobutyl]-3,4-dihydro-isoquinolin-7-yloxy}-ethyl)-methanesulfonamide (90.0 mg, 0.21 mmol, 78%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][N:5]1[C:14]2[C:15]3[CH:16]=[C:17]4[O:25][CH2:24][O:23][C:18]4=[CH:19][C:20]=3[C:21](=[O:22])[C:13]=2[C:12]2[C:7](=[CH:8][C:9]([O:28][CH3:29])=[C:10]([O:26][CH3:27])[CH:11]=2)[C:6]1=[O:30].[H-].[Na+].[NH:33]1[CH:37]=[CH:36][CH:35]=[N:34]1>CN(C=O)C.O>[NH:33]1[CH:37]=[CH:36][C:35]([CH2:2][CH2:3][CH2:4][N:5]2[C:14]3[C:15]4[CH:16]=[C:17]5[O:25][CH2:24][O:23][C:18]5=[CH:19][C:20]=4[C:21](=[O:22])[C:13]=3[C:12]3[C:7](=[CH:8][C:9]([O:28][CH3:29])=[C:10]([O:26][CH3:27])[CH:11]=3)[C:6]2=[O:30])=[N:34]1
Reactant: COc1cc2c3c(n(CCCBr)c(=O)c2cc1OC)-c1cc2c(cc1C3=O)OCO2
Reactant: c1cn[nH]c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c3c(n(CCCc4cc[nH]n4)c(=O)c2cc1OC)-c1cc2c(cc1C3=O)OCO2
Temperature: 60 °C
Yield: 57.6 %

Procedure:
6-(3-Bromo-1-propyl)-5,6-dihydro-2,3-dimethoxy-8,9-methylenedioxy-5,11-dioxo-11H-indeno[1,2-c]isoquinoline (5y) (0.2113 g, 0.448 mmol) was added to sodium hydride (86.8 mg of a 60% suspension in mineral oil, 2.17 mmol) and pyrazole (0.1749 g, 2.57 mmol) in DMF (50 mL) and the reaction mixture was heated at 60° C. for 4 h. The reaction mixture was diluted with water (200 mL) and extracted with chloroform (200 mL). The organic layer was washed with water (7×200 mL) and concentrated. Benzene was added (2×30 mL) and the mixture was concentrated again. The residue was dissolved in chloroform (4 mL) and diethyl ether (50 mL) was added. The precipitate was washed with diethyl ether (100 mL) and a dark red solid (118.5 mg, 57.6%) was obtained: mp 262-264° C. (dec). IR (film) 3462, 3104, 2918, 1693, 1640, 1557, 1495, 1488, 1430, 1394, 1308, 1284, 1251, 1205, 868, 785, 769 cm−1; 1H NMR (DMSO-d6) δ 7.97 (s, 1H), 7.65 (d, J=1.5 Hz, 1H), 7.61 (s, 1H), 6.57 (s, 1H), 6.97 (s, 1H), 6.68 (s, 1H), 6.33 (s, 1H), 6.05 (s, 2H), 4.40 (m, 4H), 4.01 (s, 3H), 3.96 (s, 3H), 2.45 (m, 2H); ESIMS m/z (rel intensity) 460 (MH+, 100). Anal. (C25H21N3O6.0.75H2O) C, H, N.
Reaction SMILES: [CH3:1][C@@:2]12[O:9][C@@H:6]([CH2:7][CH2:8]1)[C:5](=[O:10])[CH2:4][C:3]2=[O:11].C(Cl)(Cl)Cl.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Br:28][C:29]1[CH:34]=[C:33]([CH3:35])[C:32]([Pb+3])=[C:31]([CH3:37])[CH:30]=1.Cl>CN(C)C1C=CN=CC=1.C1(C)C=CC=CC=1>[Br:28][C:29]1[CH:34]=[C:33]([CH3:35])[C:32]([CH:4]2[C:5](=[O:10])[C@H:6]3[O:9][C@:2]([CH3:1])([CH2:8][CH2:7]3)[C:3]2=[O:11])=[C:31]([CH3:37])[CH:30]=1
Reactant: Cc1cc(Br)cc(C)c1[Pb+3]
Reactant: C[C@]12CC[C@H](O1)C(=O)CC2=O
Agent: CC(=O)[O-]
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: Cc1cc(Br)cc(C)c1C1C(=O)[C@@H]2CC[C@@](C)(O2)C1=O
Temperature: 80 °C
Yield: 7.6 %

Procedure:
(1R*,5S*)-1-Methyl-8-oxabicyclo[3.2.1]octane-2,4-dione (6 g, 0.039 mol) and 4-dimethylaminopyridine (24 g, 0.196 mol) are added to a mixture of chloroform (120 ml) and toluene (30 ml). The reaction mixture is flushed with nitrogen for 15 minutes at ambient temperature. 4-Bromo-2,6-dimethylphenyllead triacetate (24 g, 0.042 mol) is added in one portion and the reaction mixture is stirred and heated to 80° C. (pre-heated oil bath) under an atmosphere of nitrogen for 1 hour. The reaction mixture is cooled to room temperature, acidified to pH 1 with 2N aqueous hydrochloric acid, filtered through a plug of diatomaceous earth and the two phases are separated. The aqueous phase is extracted with dichloromethane (2×100 ml), the organic phases are combined, washed with water, and dried over anhydrous sodium sulfate. The mixture is filtered, and the filtrate is evaporated under reduced pressure. The residue is purified by column chromatography on silica gel to give (1R*,5S*)-3-(4-bromo-2,6-dimethylphenyl)-1-methyl-8-oxabicyclo[3.2.1]octane-2,4-dione as a white solid (1 g).