Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1](Br)[CH3:2].[Mg].[F:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[CH:9]=[O:10]>C1COCC1>[F:5][C:6]1[CH:7]=[C:8]([CH:9]([OH:10])[CH2:1][CH3:2])[CH:11]=[CH:12][CH:13]=1
Reactant: O=Cc1cccc(F)c1
Reactant: CCBr
Agent: [Mg]
Solvent: C1CCOC1
Product: CCC(O)c1cccc(F)c1
Temperature: 5 °C
Reaction time: 2 h

Procedure:
18 L ethyl bromide were dissolved in 30 L of THF and added dropwise to a suspension of 6 kg of magnesium in 30 L of THF. The reaction solution was next stirred for two hours at 65° to 75° C. and then cooled to 0 to 10° C. 15 kg of 3-fluorobenzaldehyde in 60 L of THF were added while cooling with ice over a period of 6 hr and the reaction solution was stirred overnight at room temp. The reaction solution was quenched with saturated ammonium chloride solution at 0°-10° C. The reaction solution was stirred for one hour, organic layer separated and concentrated. The concentrate was extracted with 40 L of DCM and washed with 30 L of 5% HCl solution. The solvent was removed in vacuo. After drying, 20 kg of 1-(3-Fluoro -phenyl)-propan-1-ol were obtained as a brown oil and taken as such to the next step.
Reaction SMILES: N1C=CC=CC=1.[CH2:7]([Si:9]([CH2:13][CH3:14])([CH2:11][CH3:12])Cl)[CH3:8].[OH:15][C@@H:16]([C@@H:18]1[C@@H:21]([C@H:22]2[CH2:31][CH2:30][C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:23]2=[O:32])[NH:20][C:19]1=[O:33])[CH3:17]>C(Cl)Cl>[CH2:7]([Si:9]([CH2:13][CH3:14])([CH2:11][CH3:12])[O:15][C@@H:16]([C@@H:18]1[C@@H:21]([C@H:22]2[CH2:31][CH2:30][C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:23]2=[O:32])[NH:20][C:19]1=[O:33])[CH3:17])[CH3:8]
Reactant: CC[Si](Cl)(CC)CC
Reactant: C[C@@H](O)[C@H]1C(=O)N[C@@H]1[C@H]1CCc2ccccc2C1=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC[Si](CC)(CC)O[C@H](C)[C@H]1C(=O)N[C@@H]1[C@H]1CCc2ccccc2C1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
0.06 ml of pyridine and 0.1 ml of triethylchlorosilane were added successively at 0° C. to 100 mg (0.39 mmol) of the hydroxyethyl compound from step 1 in 3 ml of anhydrous methylene chloride and then stirred at room temperature for 3 h. The reaction mixture was diluted with 10 ml of methylene chloride and washed successively with dilute hydrochloric acid, saturated NaHCO3 solution and water. After drying over sodium sulfate and concentration in vacuo, the residue was chromatographed on silica gel (eluent: toluene/ethyl acetate=1:2). Yield: 122 mg (85%). -1H-NMR (200 MHz, CDCl3): δ=0.50-0.70 (2×m, 6H and 9H, SiCH3CH3); 1.28 (d, 3H, CH--CH3); 1.95-2.38 (m, 2H, CH--CH2 --CH2); 2.76 (dt, 1H, CH--CH2 --CH2) 3.02-3.16 (m, 3H, CH--CH2 --CH2 and H-3); 4.23 (mc, 1H, CH--CH3); 4.43 (dd, 1H, H-4); 5.8 (bs, 1H, NH); 7.22-7.38 and 7.45-7.57 (2×m, 3 H, aromatic H); 8.02 (dd, 1H, aromatic H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:14][C:15]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21]C=2)=[O:16])[CH2:10][C:11]([OH:13])=O)[CH:5]=[CH:6][C:7]=1[Cl:8].[C:25](N1C=CN=C1)(N1C=CN=C1)=O.[BH4-].[Na+]>CCOC(C)=O.O.CCOCC>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:10][CH2:11][OH:13])[CH2:14][C:15]([N:17]([CH3:25])[C:18]2[CH:19]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:16])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(O)CC(CC(=O)NCc1ccccc1)c1ccc(Cl)c(Cl)c1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: O
Product: CN(C(=O)CC(CCO)c1ccc(Cl)c(Cl)c1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 96.3 %

Procedure:
3,4-Dichloro-beta-[2-[(phenyl)methylamino]-2-oxoethyl]benzenepropanoic acid (0.98 g) in EtOAc (25 mL) was treated with carbonyldiimidazole (0.653 g) and N,N-dimethylaminopyridine (trace). The resulting solution was stirred at room temperature for 15 minutes and then heated at 50° C. for two hours. The reaction mixture was cooled to 0° C. and treated with a solution of NaBH4 (0.668 g) in H2O (10 mL), warmed slowly to room temperature and stirred for 12 hours. The reaction mixture was then diluted with Et2O and washed with 1N HCl (20 mL), sat. NaHCO3 (20 mL) and water (20 mL). The organic phase was dried over MgSO4, filtered and concentrated under reduced pressure to yield the title compound (0.908 g). Mass spectrum (CI): 352.
Reaction SMILES: C(O)(C(F)(F)F)=O.[NH2:8][CH2:9][CH2:10][CH2:11][CH:12]([C@@H:20]1[CH2:25][CH2:24][CH2:23][N:22]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:21]1)[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=1.CCN(C(C)C)C(C)C.Cl[C:43]([O:45][CH3:46])=[O:44]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[F:19][C:15]1[CH:14]=[C:13]([CH:12]([C@@H:20]2[CH2:25][CH2:24][CH2:23][N:22]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:21]2)[CH2:11][CH2:10][CH2:9][NH:8][C:43]([O:45][CH3:46])=[O:44])[CH:18]=[CH:17][CH:16]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](C(CCCN)c2cccc(F)c2)C1
Reactant: COC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)NCCCC(c1cccc(F)c1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 38 %

Procedure:
A 100 mL round bottom flask was charged with 0.092 g of TFA salt of (3S)-tert-butyl 3-(4-amino-1-(3-fluorophenyl)butyl)piperidine-1-carboxylate, 0.152 g of DMAP, 10 mL of CH2Cl2, and 2 mL of DIPEA. The mixture was cooled with an ice bath and then a solution of methyl chloroformate (0.280 g) in CH2Cl2 (3 mL) was added. The reaction mixture was allowed to slowly warm to rt while stirring overnight. After the reaction mixture was evaporated under reduced pressure, the crude product was purified by reversed-phase HPLC (Phenomenex® Luna 5μ C18(2) 100 A, 250×21.20 mm, 5 micron, 70%→90% CH3CN/H2O, 0.1% CF3COOH over 8 min and then 90% CH3CN/H2O, 0.1% CF3COOH over 2 min, flow rate 25 mL/min) to afford 0.0306 g (38%) of (3S)-tert-butyl 3-(1-(3-fluorophenyl)-4-(methoxycarbonylamino)butyl)piperidine-1-carboxylate. Isomer 1 and 2, MS ESI +ve m/z 431 (MNa+), 409 (MH+), tR=1.91, 1.98 min in 3 min chromatography.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([C:10]#[CH:11])[C:7]([CH:12]([CH3:14])[CH3:13])=[CH:6][C:5]=1[NH2:15].[N:17]1[CH:22]=[CH:21]N=N[N:18]=1>ClCCCl>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([C:10]2[CH:21]=[CH:22][N:17]=[N:18][CH:11]=2)[C:7]([CH:12]([CH3:14])[CH3:13])=[CH:6][C:5]=1[NH2:15]
Reactant: C#Cc1cc(C(=O)OC)c(N)cc1C(C)C
Reactant: c1cnnnn1
Solvent: ClCCCl
Product: COC(=O)c1cc(-c2ccnnc2)c(C(C)C)cc1N
Yield: 26.4 %

Procedure:
A solution of 2-amino-5-ethynyl-4-isopropyl-benzoic acid methyl ester (718 mg, 3.3 mmol) and tetrazine (406.8 mg, 5.0 mmol) in 1,2-dichloroethane (15 mL) in a sealed tube was heated in the microwave at 130° C. for 45 min. The reaction mixture was then concentrated in vacuo and the residue was purified by flash chromatography (50 g silica gel, hexanes→EtOAc:hexanes (1:1)) to provide the title compound (236 mg, 26%). API-ES: m/z 272 [M+H]+, rt 3.38 min.
Reaction SMILES: C(OC([N:6]1[C:10]([NH:11][C:12](=[O:50])[C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[CH:15][C:14]=2[NH:25][C:26]([C@@H:28]2[CH2:32][CH2:31][CH2:30][N:29]2C(OCC2C3C=CC=CC=3C3C2=CC=CC=3)=O)=[O:27])=[C:9]2[CH:51](CC)[N:52]([S:56]([C:59]3[CH:64]=[C:63]([F:65])[CH:62]=[C:61]([F:66])[CH:60]=3)(=[O:58])=[O:57])[C:53]([CH3:55])([CH3:54])[C:8]2=[N:7]1)=O)C>CO.ClCCl.N1CCCCC1>[F:66][C:61]1[CH:60]=[C:59]([S:56]([N:52]2[CH2:51][C:9]3[C:10]([NH:11][C:12]([C:13]4[CH:18]=[CH:17][C:16]([N:19]5[CH2:24][CH2:23][O:22][CH2:21][CH2:20]5)=[CH:15][C:14]=4[NH:25][C:26]([C@@H:28]4[CH2:32][CH2:31][CH2:30][NH:29]4)=[O:27])=[O:50])=[N:6][NH:7][C:8]=3[C:53]2([CH3:55])[CH3:54])(=[O:58])=[O:57])[CH:64]=[C:63]([F:65])[CH:62]=1
Reactant: CCOC(=O)n1nc2c(c1NC(=O)c1ccc(N3CCOCC3)cc1NC(=O)[C@@H]1CCCN1C(=O)OCC1c3ccccc3-c3ccccc31)C(CC)N(S(=O)(=O)c1cc(F)cc(F)c1)C2(C)C
Solvent: CO
Solvent: ClCCl
Solvent: C1CCNCC1
Product: CC1(C)c2[nH]nc(NC(=O)c3ccc(N4CCOCC4)cc3NC(=O)[C@@H]3CCCN3)c2CN1S(=O)(=O)c1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 74.4 %

Procedure:
To a solution of ethyl 5-(3,5-difluoro-benzenesulfonyl)-3-(2-{[(S)-1-(9H-fluoren-9-ylmethoxycarbonyl)-pyrrolidine-2-carbonyl]-amino}-4-morpholin-4-yl-benzoylamino)-6,6-dimethyl-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole-2-carboxylic acid ethyl ester (0.3 g, 0.32 mmol) in MeOH (10 mL) and dichloromethane (3 mL), piperidine (1 mL) was added and the reaction mixture stirred at room temperature for 12 hours. After evaporation to dryness, the residue was washed with petroleum ether and purified by flash chromatography on silica gel, using a mixture dichloromethane-MeOH 95:5 as the eluant, affording the title compound as pale yellow powder (0.15 g).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1.[OH-].[K+].[CH3:18][C:19]1[CH:24]=[N:23][C:22]([CH:25]=[CH2:26])=[CH:21][N:20]=1>CN1CCCC1=O.O>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:26][CH2:25][C:22]3[CH:21]=[N:20][C:19]([CH3:18])=[CH:24][N:23]=3)[C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1
Reactant: CN1CCc2[nH]c3ccc(Cl)cc3c2C1
Reactant: C=Cc1cnc(C)cn1
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1cnc(CCn2c3c(c4cc(Cl)ccc42)CN(C)CC3)cn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 48 %

Procedure:
To a solution of 8-Chloro-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.11 g, 5.0 mmol) in N-methyl 2-pyrolidone (2.0 mL) was added powdered potassium hydroxide (0.224 g, 4.0 mmol) and allowed to stir for 10 min at RT. 2-methyl-5-vinyl pyrazine (0.065 g, 0.55 mmol) was added and stirred for further 2 h at 60 deg C. After completion (TLC), reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (3×100 mL). The organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude was purified through column chromatography (6% MeOH:DCM in silica 100-200 mesh, Diameter of column—2.5 cm, Height of silica—approx. 5 inch) to provide the desired compound as yellow oil (0.09 g, 54% yield). 8-Chloro-2-methyl-5-[2-(5-methyl-pyrazin-2-yl)-ethyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.09 g, 0.26 mmol) was dissolved in THF (1.0 mL). A solution of oxalic acid dihydrate (0.034 g, 0.26 mmol) in THF (1.0 mL) was added and stirred for 30 min at RT, Precipitate obtained was filtered and dried to give oxalate salt as white solid (0.08 g, 68% yield).
Reaction SMILES: ClC(OCC(C)C)=O.[NH:9]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C@H:10]([C:26]([OH:28])=O)[CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17].CN1CCOCC1.[NH2:43][C@H:44]([C:49]([NH:51][C@H:52]([C:57]([O:59][CH3:60])=[O:58])[CH2:53][CH:54]([CH3:56])[CH3:55])=[O:50])[CH2:45][CH:46]([CH3:48])[CH3:47].Cl>C(OCC)(=O)C>[NH:9]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C@H:10]([C:26]([NH:43][C@H:44]([C:49]([NH:51][C@H:52]([C:57]([O:59][CH3:60])=[O:58])[CH2:53][CH:54]([CH3:55])[CH3:56])=[O:50])[CH2:45][CH:46]([CH3:47])[CH3:48])=[O:28])[CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]([O:18][CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)=[O:17]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)O
Reactant: COC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CC(C)C
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Product: COC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C
Reaction time: 0.25 h
Yield: 90 %

Procedure:
Isobutyl chloroformate (13.66 g, 100 mmol) was added dropwise over 15 min at -15 to -10° C. to a solution of Boc-Lys(Z)-OH (38.04 9, 100 mmol) in ethyl acetate (200 g). Another portion of ethyl acetate was added (10 g) and the mixture was stirred for 15 min. 4-Methylmorpholine (10.12 g, 100 mmol) was added dropwise over 15 min at -15 to -10° C., followed by an additional portion of ethyl acetate (10.0 g) and the resulting mixture was stirred for 2 h. In a separate reaction vessel 4-methylmorpholine (10.12 g, 100 mmol) was added dropwise over 15 min, to a solution of H-Leu-Leu-OMe·HCl (29.48 g, 100 mmol) in ethyl acetate (200.0 g) at -23 to -10° C. An additional portion of ethyl acetate (10.0 g) was added followed by the addition of the formed anhydride over 30 to 45 min at a temperature of -8 to -10° C. Another portion of ethyl acetate (30.0 g) was added and the resulting mixture was stirred for 1.5 h. Ethyl acetate (50.00 g) was added, the solution was filtered and the resulting organic filtrate was concentrated in vacuo. The resulting solid was recrystallized from petroleum ether (bp 100 to 125) to give Boc-Lys(Z)-Leu-Leu-OMe (55.9 g, 90.2%).
Reaction SMILES: [O-:1][C:2]#[N:3].[K+].[NH2:5][C:6]1[CH:11]=[CH:10][C:9](/[C:12](/[C:19]2[NH:24][C:23](=[O:25])[C:22]([Cl:26])=[CH:21][CH:20]=2)=[CH:13]\[CH:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:8][CH:7]=1.C(=O)(O)[O-].[Na+].C(OCC)(=O)C>O.C(O)(=O)C>[Cl:26][C:22]1[C:23](=[O:25])[NH:24][C:19](/[C:12](/[C:9]2[CH:10]=[CH:11][C:6]([NH:5][C:2]([NH2:3])=[O:1])=[CH:7][CH:8]=2)=[CH:13]/[CH:14]2[CH2:15][CH2:16][CH2:17][CH2:18]2)=[CH:20][CH:21]=1
Reactant: Nc1ccc(/C(=C\C2CCCC2)c2ccc(Cl)c(=O)[nH]2)cc1
Reactant: N#C[O-]
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: NC(=O)Nc1ccc(/C(=C\C2CCCC2)c2ccc(Cl)c(=O)[nH]2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 21.3 %

Procedure:
A solution of potassium cyanate (41 mg) in water (2 mL) was added to a solution of 6-[(E)-1-(4-aminophenyl)-2-cyclopentylethenyl]-3-chloropyridin-2(1H)-one obtained in Example 1-105(1) (153 mg) in acetic acid (2 mL)-water (1 mL), and the mixture was stirred at room temperature for 30 minutes. Saturated aqueous sodium bicarbonate and ethyl acetate were sequentially added to the reaction solution. The organic layer was separated, washed with saturated aqueous sodium bicarbonate and brine and dried over sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform:methanol=9:1→8:2). This was powdered with ethyl acetate, and filtration operation gave the title compound as a light yellow powder (37 mg, 21%).
Reaction SMILES: [CH2:1]([P:5]([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4].[Cl:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][Cl:23])=[CH:18][CH:17]=1>C1(C)C=CC=CC=1>[Cl-:14].[Cl:23][CH2:22][C:19]1[CH:20]=[CH:21][C:16]([CH2:15][P+:5]([CH2:6][CH2:7][CH2:8][CH3:9])([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:1][CH2:2][CH2:3][CH3:4])=[CH:17][CH:18]=1
Reactant: ClCc1ccc(CCl)cc1
Reactant: CCCCP(CCCC)CCCC
Solvent: Cc1ccccc1
Product: CCCC[P+](CCCC)(CCCC)Cc1ccc(CCl)cc1
Product: [Cl-]
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of tri-n-butylphosphine (7 g, 34.6 mmol, leq.) in toluene (50 mL) was added dropwise to a mixture of α,α'-dichloro-p-xylene (12.1 g, 69.8 mmol, 2 eq.) in toluene (200 mL) under argon gas. The reaction mixture was allowed to stir for 12 hours at room temperature under argon, after which time the tri-n-butylphosphonium chloride salt had crystallized out of solution. The crystals were filtered and washed several times with toluene and hexanes, then air dried: 1H NMR (CDCl3) δ0.92 (t, 9H), 1.44 (m, 12H), 2.39 (m, 6H), 4.35-4.40 (d, 2H), 4.56 (s, 2H), 7.36-7.39 (d, 2H) , 7.47-7.51 (dd, 2H).
Reaction SMILES: P([C:9]#[N:10])(OCC)(OCC)=O.[CH3:11][Si]([N-][Si](C)(C)C)(C)C.[Na+].[C:21]([O:25][C:26](=[O:40])[NH:27][CH:28]1[C:37]2[C:32](=[CH:33][C:34]([CH:38]=O)=[CH:35][CH:36]=2)[CH2:31][CH2:30][CH2:29]1)([CH3:24])([CH3:23])[CH3:22]>C1COCC1>[C:21]([O:25][C:26](=[O:40])[NH:27][CH:28]1[C:37]2[C:32](=[CH:33][C:34]([CH:38]=[CH:11][C:9]#[N:10])=[CH:35][CH:36]=2)[CH2:31][CH2:30][CH2:29]1)([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)OC(=O)NC1CCCc2cc(C=O)ccc21
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CCOP(=O)(C#N)OCC
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1CCCc2cc(C=CC#N)ccc21
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of diethyl cyanophosphate (6.62 g, 37.36 mmol) in dry THF (25 mL) at 0° C. was added sodium bis(trimethylsilyl)amide (32 mL, 32.03 mmol) dropwise via the addition funnel. The temp. was kept between 0° C. to 5° C. for 30 min. The resulting mixture was then cooled to −78° C. followed by adding (6-formyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-carbamic acid tert-butyl ester (2.94 g, 10.67 mmol) in THF (40 mL) dropwise via the addition funnel. After the addition, it was stirred for 18 h and slowly warmed to RT. The reaction mixture was quenched with sat. NH4Cl. Solvent was removed. The residue was partitioned between EtOAc and water. The organic layer was washed with water, brine, dried over MgSO4 and evaporated in vacuo. The crude product was purified by chromatography on silica gel. Elution with Hex:EtOAc mixture (85:15) gave final compound MS m/z: 299.12 (M+H). Calc'd. for C18H22N2O2-298.38.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH:9]([NH:11][CH2:12][CH:13]([OH:16])[CH2:14][OH:15])[CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:17](=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(O)(=O)C1C=CC=CC=1>C1(C)C=CC=CC=1>[C:18]1([CH:17]2[N:11]([CH:9]([CH3:10])[CH2:8][CH2:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:12][CH:13]([CH2:14][OH:15])[O:16]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=Cc1ccccc1
Reactant: CC(CCc1ccccc1)NCC(O)CO
Agent: O=C(O)c1ccccc1
Solvent: Cc1ccccc1
Product: CC(CCc1ccccc1)N1CC(CO)OC1c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
A solution of 94 (24 g, 0.108 mol), toluene, benzaldehyde (40 ml) and benzoic acid (0.5 g) was heated at reflux with a Dean-Stark trap. After 1 hour, the theoretical amount of H2O was collected, the reaction cooled to room temperature and saturated Na2CO3 added. The aqueous layer was separated and washed with CHCl3 (3X). The combined extracts were dried, filtered and concentrated to dryness to yield 34 g (100%) of 95.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]3[C:23]4([CH2:27][O:26][C:25]([N:28](C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)=[N:24]4)[C:19]4([CH2:22][O:21][CH2:20]4)[C:15]4([CH2:18][CH2:17][CH2:16]4)[O:14][C:11]3=[CH:12][CH:13]=2)[CH:5]=[N:6][CH:7]=1.[C:43]([CH:45]1[CH2:47][CH2:46]1)#[CH:44]>CCN(CC)CC.C1(C)C=CC=CC=1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH:45]1([C:43]#[C:44][C:2]2[CH:3]=[C:4]([C:8]3[CH:9]=[C:10]4[C:23]5([CH2:27][O:26][C:25]([NH2:28])=[N:24]5)[C:19]5([CH2:20][O:21][CH2:22]5)[C:15]5([CH2:16][CH2:17][CH2:18]5)[O:14][C:11]4=[CH:12][CH:13]=3)[CH:5]=[N:6][CH:7]=2)[CH2:47][CH2:46]1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)C1=NC2(CO1)c1cc(-c3cncc(Br)c3)ccc1OC1(CCC1)C21COC1
Reactant: C#CC1CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: NC1=NC2(CO1)c1cc(-c3cncc(C#CC4CC4)c3)ccc1OC1(CCC1)C21COC1
Reaction time: 1 h
Yield: 15.6 %

Procedure:
To a stirred solution of di-tert-butyl [6′-(5-bromopyridin-3-yl)trispiro[cyclobutane-1,2′-chromene-4′,4″-[1,3]oxazole-3′,3′″-oxetan]-2″-yl]imidodicarbonate (48 mg, 0.075 mmol) in Et3N (0.67 ml) were added ethynylcyclopropane (0.063 mL, 0.75 mmol), PdCl2(PPh3)2 (10 mg, 0.015 mmol) and CuI (5.7 mg, 0.030 mmol) at room temperature and the mixture was sealed and irradiated with microwave at 150° C. for 1 hour. To this mixture was added activated carbon (ca. 100 mg) and the mixture was stirred for 1 hour to remove palladium residues. The mixture was passed through a pad of Celite. The filtrate was evaporated to give a residue. To the solution of the residue in toluene (3 ml) was added silica gel (500 mg) and the mixture was refluxed for 2 hours. The mixture was passed through a pad of Celite and the filtrate was evaporated to give a crude product, which was purified with column chromatography (MeOH in CHCl3=0 to 10%) to give 6′-[5-(cyclopropylethynyl)pyridin-3-yl]trispiro[cyclobutane-1,2′ chromene-4′,4″-[1,3]oxazole-3′,3′″-o xetan]-2″-amine (5 mg).
Reaction SMILES: [C:1]([O:4][CH2:5][CH3:6])(=[O:3])[CH3:2].[C:7]1(C)[CH:12]=[CH:11]C=[CH:9][CH:8]=1.C1(C)C(C)=CC=CC=1.C(C1C=CC=CC=1)C>C(Cl)Cl>[CH2:5]1[C:6]2[C:9](=[CH:8][CH:7]=[CH:12][CH:11]=2)[CH2:2][C:1](=[O:3])[O:4]1
Reactant: Cc1ccccc1
Reactant: CCOC(C)=O
Solvent: Cc1ccccc1C
Solvent: CCc1ccccc1
Solvent: ClCCl
Product: O=C1Cc2ccccc2CO1

Procedure:
After the reaction, recovery of isochromanones can be carried out by concentration of reaction mixture or extraction with an organic solvent such as ethyl acetate, toluene, xylene, ethylbenzene, or methylene chloride. When the reaction mixture is separated into two layers, i.e., a water layer and a product layer, depending on the target isochromanones, it is possible to separate and remove the water layer. In particular, when the product is 3-isochromanone, the product layer is liquid at 85° C. or higher, so that solubility in water is low and the target compound can be recovered by separation operation. Further, distillation and purification under reduced pressure can give rise to highly pure 3-isochromanone.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[OH:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:16][S:17](Cl)(=[O:19])=[O:18]>C(Cl)Cl>[CH3:16][S:17]([O:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)(=[O:19])=[O:18]
Reactant: CS(=O)(=O)Cl
Reactant: Oc1ccccc1OCc1ccccc1
Solvent: ClCCl
Product: CS(=O)(=O)Oc1ccccc1OCc1ccccc1
Yield: 96.9 %

Procedure:
2-(Benzyloxy)phenol (3.00 g, 14.98 mmol) was dissolved in dry DCM (70 mL) under nitrogen atmosphere and cooled on an ice-water bath. Methanesulfonyl chloride (2.06 g, 17.98 mmol) was added during stirring followed by TEA (2.27 g, 22.47 mmol). The reaction mixture was stirred at rt for 2 h and then washed with aqueous saturated NaHCO3, dried (MgSO4), filtered and evaporated affording the title compound (4.04 g, 96.9%). 1H NMR (500 MHz, CDCl3): δ 3.09 (s, 3H), 5.15 (s, 2H), 7.02 (dt, 1H), 7.09 (dd, 1H), 7.27 (dt, 1H), 7.34-7.48 (m, 6H); 13C NMR (125 MHz, CDCl3): δ 38.72, 71.37, 114.67, 121.79, 125.06, 127.95, 128.50, 128.68, 129.00, 136.20, 138.96, 150.91.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:17]=2)[N:10]=1.[Cl:27][C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=1)[CH2:31][OH:32]>>[Cl:27][C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=1)[CH2:31][O:32][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:17]=2)[N:10]=1
Reactant: CS(=O)(=O)Cc1cccc(Nc2ncnc(-c3ccc(F)cc3F)n2)c1
Reactant: OCc1cccc(Cl)c1
Product: CS(=O)(=O)Cc1cccc(Nc2ncnc(-c3ccc(F)cc3OCc3cccc(Cl)c3)n2)c1

Procedure:
Starting with 4-(2,4-difluorophenyl)-N-{3-[(methylsulfonyl)methyl]phenyl}-1,3,5-triazin-2-amine (75 mg; 0.197 mmol), intermediate 42.1, and 3-chlorobenzyl alcohol (115 mg; 0.789 mmol), example 85 was prepared analogously to the procedure for the preparation of example 42.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:18][CH2:17][C:16]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([N+:19]([O-])=O)[CH:14]=3)[NH:9][C:8]=2[CH2:7]1)=[O:5])[CH3:2].[H][H]>[Ni].C(O)C>[CH2:1]([O:3][C:4]([CH:6]1[CH2:18][CH2:17][C:16]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([NH2:19])[CH:14]=3)[NH:9][C:8]=2[CH2:7]1)=[O:5])[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)C1CCc2c([nH]c3ccc([N+](=O)[O-])cc23)C1
Agent: [Ni]
Solvent: CCO
Product: CCOC(=O)C1CCc2c([nH]c3ccc(N)cc23)C1

Procedure:
A mixture of 1.3 g. of 6-nitro-1,2,3,4-tetrahydrocarbazole-2-carboxylic acid ethyl ester, 0.5 teaspoonful of Raney nickel and 100 ml. of ethanol was shaken in a Parr hydrogenation apparatus under 3.7 atmospheres of hydrogen at room temperature. After 2 hours of shaking the uptake of hydrogen had stopped. The catalyst was removed by filtration and the filtrate was concentrated to dryness, yielding 1.2 g. of product. Following recrystallization from a mixture of hexane and ethyl acetate, a yield of 0.8 g. of 6-amino-1,2,3,4-tetrahydrocarbazole-2-carboxylic acid ethyl ester, m.p. 123°-124° was obtained.