Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC[O:22]C(/N=N/C(OCC)=O)=O.C([O:34][C:35](=[O:52])[C@@H:36]([O:50][CH3:51])[CH2:37][C:38]1[CH:43]=[CH:42][C:41]([C:44]#[C:45][CH2:46][CH2:47][CH2:48][OH:49])=[CH:40][CH:39]=1)C.[O:53]([C:60]1[CH:65]=[CH:64][C:63](O)=[CH:62][CH:61]=1)[C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1>C1COCC1>[CH3:51][O:50][C@@H:36]([CH2:37][C:38]1[CH:39]=[CH:40][C:41]([C:44](=[O:22])[CH2:45][CH2:46][CH2:47][CH2:48][O:49][C:63]2[CH:62]=[CH:61][C:60]([O:53][C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=3)=[CH:65][CH:64]=2)=[CH:42][CH:43]=1)[C:35]([OH:34])=[O:52]
Reactant: CCOC(=O)[C@H](Cc1ccc(C#CCCCO)cc1)OC
Reactant: Oc1ccc(Oc2ccccc2)cc1
Reactant: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CO[C@@H](Cc1ccc(C(=O)CCCCOc2ccc(Oc3ccccc3)cc2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A solution of triphenylphosphine (0.915 mmol) in 5 mL of dry THF was treated at 0° C. with diethylazodicarboxylate (0.915 mmol) and stirred for 20 min. A solution of (2S)-3-[4-(5-hydroxy-pent-1-ynyl)-phenyl]-2-methoxy-propionic acid ethyl ester (Example 21, Step A) (0.61 mmol) and 4-phenoxyphenol (0.915 mmol) in 2 mL of dry THF was added, and the mixture was stirred at room temperature overnight. The mixture was concentrated under vacuum and purified by silica gel chromatography (silica gel, hexanes/ethyl acetate 10:1 to 3:1). Fractions with Rfs 0.48 and 0.45 (hexanes/ethyl acetate 2:1) corresponding to the coupled compound and starting phenol, respectively, were combined and concentrated. The mixture was dissolved in 5 mL of methanol and was treated with a mire of 75 mg of mercury (II) oxide and 4% sulfuric acid in water. The solution was stirred at 55° C. for 3 hours, cooled to room temperature, diluted with saturated aqueous NaHCO3 (20 mL), and extracted with dichloromethane (4×20 mL). The combined organic layers were washed with brine (20 mL), dried (MgSO4), and concentrated. The residue was dissolved in 6 mL of methanol and 2 mL of 1N NaOH and stirred for 2 hours. The methanol was evaporated under vacuum, and the aqueous solution was diluted with brine (6 mL) and washed with diethyl ether (3×15 mL). The aqueous layer was acidified with 1N HCl (pH 1–2) and extracted with ethyl acetate (3×15 mL) then concentrated to give the title compound. 1H-NMR (CDCl3, 200.15 MHz): 7.91 (d, 2H, J=8.3), 7.36–7.27 (m, 4H), 7.07–6.83 (m, 7H), 4.08–3.96 (m, 3H), 3.41 (s, 3H), 3.22 (dd, 1H, J=14.0, 4.3), 3.14–3.01 (m, 4H), 1.26 (s, 1H).
Reaction SMILES: COC(C1C=C(OC2C=CC(C(N3CCC3)=O)=CC=2)C2CC(C)(C)OC=2C=1)=O.[CH3:29][O:30][C:31]([C:33]1[CH:43]=[C:42]([OH:44])[C:36]2[CH2:37][C:38]([CH3:41])([CH3:40])[O:39][C:35]=2[CH:34]=1)=[O:32].[C:45]([O:49][C:50](=[O:60])[C:51]1[C:56]([F:57])=[CH:55][C:54](Br)=[CH:53][C:52]=1[F:59])([CH3:48])([CH3:47])[CH3:46]>>[CH3:29][O:30][C:31]([C:33]1[CH:43]=[C:42]([O:44][C:54]2[CH:53]=[C:52]([F:59])[C:51]([C:50]([O:49][C:45]([CH3:47])([CH3:46])[CH3:48])=[O:60])=[C:56]([F:57])[CH:55]=2)[C:36]2[CH2:37][C:38]([CH3:41])([CH3:40])[O:39][C:35]=2[CH:34]=1)=[O:32]
Reactant: COC(=O)c1cc(O)c2c(c1)OC(C)(C)C2
Reactant: CC(C)(C)OC(=O)c1c(F)cc(Br)cc1F
Agent: COC(=O)c1cc(Oc2ccc(C(=O)N3CCC3)cc2)c2c(c1)OC(C)(C)C2
Product: COC(=O)c1cc(Oc2cc(F)c(C(=O)OC(C)(C)C)c(F)c2)c2c(c1)OC(C)(C)C2

Procedure:
The title compound was prepared in a similar manner as described for Intermediate 35b, from 4-hydroxy-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester (3e) and 4-bromo-2,6-difluoro-benzoic acid tert-butyl ester. 1H NMR (400 MHz, CDCl3) δ 7.29 (s, 1 H) 7.23 (s, 1 H) 6.48 (d, J=8.84 Hz, 2 H) 3.89 (s, 3 H) 2.88 (s, 2 H) 1.59 (s, 9 H) 1.49 (s, 6 H); LCMS for C23H24F2O6 m/z 457.20 (M+Na)+.
Reaction SMILES: S(OS(C(F)(F)F)(=O)=O)(C(F)(F)F)(=O)=O.[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH:25]=[CH:26][C:27]=1[N+:28]([O-:30])=[O:29])[C:21]([NH:23][CH3:24])=O.[N-:31]=[N+:32]=[N-:33].[Na+].C([O-])(O)=O.[Na+]>CC#N>[CH3:16][O:17][C:18]1[CH:19]=[C:20]([C:21]2[N:23]([CH3:24])[N:33]=[N:32][N:31]=2)[CH:25]=[CH:26][C:27]=1[N+:28]([O-:30])=[O:29]
Reactant: CNC(=O)c1ccc([N+](=O)[O-])c(OC)c1
Reactant: [N-]=[N+]=[N-]
Agent: O=C([O-])O
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [Na+]
Solvent: CC#N
Product: COc1cc(-c2nnnn2C)ccc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 69.4 %

Procedure:
Triflic anhydride (0.27 mL, 1.580 mmol) was added dropwise to a solution of 3-methoxy-N-methyl-4-nitrobenzamide (Preparation 196, 0.166 g, 0.790 mmol) and sodium azide (0.205 g, 3.16 mmol) in MeCN (4.0 mL) at −10° C. The reaction mixture was warmed up to room temperature over 3 hours. The reaction was neutralised with saturated aqueous NaHCO3. The mixture was extracted with EtOAc and the organic layer washed with saturated aqueous NaHCO3, brine, dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by Biotage silica gel column chromatography eluting with cyclohexane/EtOAc 70/30 to 50/50 to afford the title compound as a white solid (129 mg, 69%).
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[CH:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]1.C1C(=O)N([Br:27])C(=O)C1>C(#N)C>[Br:27][C:4]1[S:3][C:2]([CH3:1])=[C:6]([CH:7]2[CH2:8][CH2:9][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:11][CH2:12]2)[CH:5]=1
Reactant: Cc1sccc1C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: Cc1sc(Br)cc1C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 57 %

Procedure:
To a solution of Compound 1059 (810 mg; 2.89 mmol) in 15 mL of acetonitrile was added NBS portionwise (505 mg; 2.83 mmol). The reaction mixture was stirred at room temperature for 10 minutes, quenched with saturated Na2SO3 solution, and extracted with EtOAc (3×). The combined organics were dried (Na2SO4), filtered, and concentrated in vacuo to give a crude light yellow semi-solid. The residue was purified by medium pressure silica gel chromatography, eluting with 0-20% EtOAc/hexanes over 25 minutes, to give tert-butyl 4-(5-bromo-2-methylthiophen-3-yl)piperidine-1-carboxylate (Compound 1060, 590 mg, 57%); 1H NMR (CDCl3): δ 6.7 (s, 1H), 4.2 (m, 2H), 2.6 (m, 3H), 2.2 (s, 3H), 1.6 (m, 2H), 1.5 (m, 2H), 1.45 (s, 9H).
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][C:15]=2[C:17]([N:19]2[CH2:23][C@@H:22]([C:24]3[CH:28]=[CH:27][S:26][CH:25]=3)[C@H:21]([CH2:29][N:30]3[CH2:35][CH2:34][CH:33]([C:36]4[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=4)[CH2:32][CH2:31]3)[CH2:20]2)=[O:18])[CH:10]=[C:9]1C)=O)(C)(C)C.[C:44]([C:48]([OH:50])=[O:49])(F)(F)F>O>[NH3:8].[C:48]([CH2:44][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][C:15]=2[C:17]([N:19]2[CH2:23][C@@H:22]([C:24]3[CH:28]=[CH:27][S:26][CH:25]=3)[C@H:21]([CH2:29][N:30]3[CH2:35][CH2:34][CH:33]([C:36]4[CH:37]=[CH:38][C:39]([F:42])=[CH:40][CH:41]=4)[CH2:32][CH2:31]3)[CH2:20]2)=[O:18])[CH:10]=[CH:9]1)([OH:50])=[O:49]
Reactant: O=C(O)C(F)(F)F
Reactant: Cc1cc2cccc(C(=O)N3C[C@@H](CN4CCC(c5ccc(F)cc5)CC4)[C@H](c4ccsc4)C3)c2n1C(=O)OC(C)(C)C
Solvent: O
Product: N
Product: O=C(O)Cn1ccc2cccc(C(=O)N3C[C@@H](CN4CCC(c5ccc(F)cc5)CC4)[C@H](c4ccsc4)C3)c21

Procedure:
A solution of 0.185 g (0.307 mmol) of 1-(1-t-butoxycarbonyl methyl-7-indolecarbonyl)-3-(R)-(4-(4-fluorophenyl)piperidinylmethyl)-4-(R)-(3-thienyl)pyrrolidine in 6 mL of CF3CO2H and 5 drops of H2O was stirred at rt for 1.5 h. The reaction mixture was concentrated and purified by chromatography (silica, CH2Cl2: ethyl acetate: NH3 (2M in MeOH), 10:10:1, then CH2Cl2: MeOH: NH3 (2M in MeOH) 100:8:4) to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[C:16](Cl)[N:15]=[C:14]([NH:19][CH3:20])[N:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH:21]([NH2:24])([CH3:23])[CH3:22]>C(O)C>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[C:16]([NH:24][CH:21]([CH3:23])[CH3:22])[N:15]=[C:14]([NH:19][CH3:20])[N:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CC(C)N
Reactant: CNc1nc(Cl)cc(NS(=O)(=O)c2ccc(N)cc2)n1
Solvent: CCO
Product: CNc1nc(NC(C)C)cc(NS(=O)(=O)c2ccc(N)cc2)n1
Yield: 35.7 %

Procedure:
0.314 g (0.001 mol) of 4-amino-N-(6-chloro-2-methylamino-pyrimidin-4-yl)-benzenesulfonamide and 8.6 ml (0.1 mol) of isopropylamine were stirred in 15 ml of ethanol in an autoclave at 130° C. for 3 hours. The reaction mixture was freed from solvent, the residue was suspended in 8 ml of ethanol and treated in an ultra sound bath for 15 minutes. The precipitate was filtered off, dissolved in 10 ml of 0.1N NaOH and filtered. The filtrate was adjusted to pH 6 with 0.1N HCl. The precipitate was filtered off under suction, washed with water and dried. There was obtained 0.12 g (36%) of 4-amino-N-(6-isopropylamino-2-methylamino-pyrimidin-4-yl)-benzenesulfonamide as beige crystals; m.p. 240° C. (dec.).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][S:7]([N:10]1[CH2:15][CH:14]=[C:13]([C:16]2[CH:40]=[CH:39][C:19]3[N:20]=[C:21]([O:23][CH:24]4[CH2:29][CH2:28][N:27]([C:30]5[N:35]=[CH:34][C:33]([CH2:36][CH2:37][CH3:38])=[CH:32][N:31]=5)[CH2:26][CH2:25]4)[S:22][C:18]=3[CH:17]=2)[CH2:12][CH2:11]1)(=[O:9])=[O:8].CCO[CH2:44][CH3:45]>CCO.CCN(CC)CC>[Br-:1].[CH2:11]([N+:10]([CH2:44][CH3:45])([CH2:15][CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][S:7]([N:10]1[CH2:11][CH2:12][C:13]([C:16]2[CH:40]=[CH:39][C:19]3[N:20]=[C:21]([O:23][CH:24]4[CH2:29][CH2:28][N:27]([C:30]5[N:35]=[CH:34][C:33]([CH2:36][CH2:37][CH3:38])=[CH:32][N:31]=5)[CH2:26][CH2:25]4)[S:22][C:18]=3[CH:17]=2)=[CH:14][CH2:15]1)(=[O:9])=[O:8])[CH3:12]
Reactant: CCOCC
Reactant: CCCc1cnc(N2CCC(Oc3nc4ccc(C5=CCN(S(=O)(=O)CCCCCBr)CC5)cc4s3)CC2)nc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCCc1cnc(N2CCC(Oc3nc4ccc(C5=CCN(S(=O)(=O)CCCCC[N+](CC)(CC)CC)CC5)cc4s3)CC2)nc1
Product: [Br-]
Temperature: 120 °C
Yield: 51 %

Procedure:
A suspension of 6-(1-(5-bromopentylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-2-(1-(5-propylpyrimidin-2-yl)piperidin-4-yloxy)benzo[d]thiazole (Example 30C, 22.8 mg, 0.035 mmol) in EtOH (1.5 mL) and Et3N (0.75 mL) was heated in microwave at 120° C. for 40 min. It was cooled to rt, Et2O (2 mL) was added. The solid was collected via filtering. The solid was dissolved in hot EtOH (0.5 mL), the vial was sealed and slowly cooled to rt. The precipitate was collected via filtering to afford the desired product as a white solid (15 mg, 51% yield). LCMS (m/z)=669 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([N+:9]([O-])=O)[C:3]=1[NH2:4].N1[CH:17]=[CH:16][CH:15]=[CH:14]C=1.C1(C(Cl)=O)CC1.N>CC(N(C)C)=O.O.CO>[Cl:1][C:2]1[C:3]2[NH:4][C:14]([CH:15]3[CH2:17][CH2:16]3)=[N:9][C:5]=2[CH:6]=[CH:7][CH:8]=1
Reactant: Nc1c(Cl)cccc1[N+](=O)[O-]
Reactant: c1ccncc1
Agent: N
Agent: O=C(Cl)C1CC1
Solvent: CC(=O)N(C)C
Solvent: CO
Solvent: O
Product: Clc1cccc2nc(C3CC3)[nH]c12
Temperature: 50 °C
Reaction time: 3 h
Yield: 35.8 %

Procedure:
2-Chloro-6-nitroaniline (3.00 g, 17.4 mmol) and pyridine (7.0 mL, 86.9 mmol) were dissolved in DMA (17 mL), cyclopropanecarbonyl chloride (4.0 mL, 43.5) was added and the mixture was stirred at 50° C. for 3 hr. To the mixture were added methanol (10 mL) and aqueous ammonia (9 mL), and the mixture was stirred at room temperature for 30 min. Water (10 mL) was added, and the precipitated solid was collected by filtration. The solid was suspended in ethanol (38 mL) and water (38 mL), ferrous sulfate 7 hydrate (13.86 g, 49.9 mmol) and aqueous ammonia (19 mL) were added, and the mixture was stirred at 50° C. for 4 hr. The mixture was filtered, and the filtrate was extracted with ethyl acetate, washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Acetic acid (8 mL) was added to the residue, and the mixture was stirred at 90° C. for 1 hr. The mixture was concentrated under reduced pressure, neutralized with aqueous sodium hydroxide solution, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Ethyl acetate (5 mL) and diisopropyl ether (5 mL) were added to the residue, and the precipitated solid was collected by filtration to give the title compound (1.20 g, 36%).
Reaction SMILES: [C:1]1([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:21](O)([CH3:23])[CH3:22])[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1>O>[CH3:22][C:21]1([CH3:23])[C:2]2[CH:3]=[CH:4][C:5]3[C:6]4[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=4[NH:12][C:13]=3[C:1]=2[NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]1=2
Reactant: CC(C)(O)c1ccccc1Nc1cccc2c1[nH]c1ccccc12
Solvent: O
Product: CC1(C)c2ccccc2Nc2c1ccc1c2[nH]c2ccccc21
Temperature: 0 °C
Reaction time: 3 h

Procedure:
63 g (200 mmol) of 2-[2-(9H-carbazol-1-ylamino)phenyl]propan-2-ol are initially introduced in 268 g (2734 mmol) of polyphosphoric acid under protective gas and cooled to 0° C. The mixture is subsequently stirred at 100° C. for 3 h and then cooled to room temperature. Water is added to the mixture with ice cooling, the mixture is extracted with ethyl acetate, and the solvent is removed in vacuo. The content of product according to 1H-NMR is about 96% with an overall yield of 53 g (90%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[CH:11]([CH2:14][CH3:15])[CH2:12][OH:13].[CH3:16]OCOC>CCOCC>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[C:5]2[C:4]=1[CH:11]([CH2:14][CH3:15])[CH2:12][O:13][CH2:16]2
Reactant: COCOC
Reactant: CCC(CO)c1cc(OC)ccc1OC
Solvent: CCOCC
Product: CCC1COCc2c(OC)ccc(OC)c21
Reaction time: 8 h

Procedure:
Under argon atmosphere, the product from step 2 herein, 2.74 g (13.03 mmol) was dissolved in 55 ml of dry ether. Dimethoxy methane 1.65 ml (19.55 mmol) and boron trifluoro etherate 4.9 ml (39.09 mmol) were then added to this solution. The obtained reaction mixture was left stirring overnight. The reaction mixture was quenched using aqueous NaHCO3 and extractions were done using ether. The combined organic extracts were dried over Na2SO4, filtered, and the solvent was removed. The residue was purified by flash chromatography using hexanes-ethyl acetate (80:20) and (70:30) as eluent. The isolated titled product was a white solid (1.56 g; 54%).
Reaction SMILES: [OH-].[K+].O.O.NN.[Br:7][C:8]1[CH:9]=[CH:10][C:11]2[O:15][C:14]([C:16](=O)[C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)=[CH:13][C:12]=2[CH:26]=1>C(O)COCCO>[Br:7][C:8]1[CH:9]=[CH:10][C:11]2[O:15][C:14]([CH2:16][C:17]3[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=3)=[CH:13][C:12]=2[CH:26]=1
Reactant: COc1ccc(C(=O)c2cc3cc(Br)ccc3o2)cc1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: OCCOCCO
Solvent: O
Product: COc1ccc(Cc2cc3cc(Br)ccc3o2)cc1
Yield: 82.5 %

Procedure:
5.07 g of potassium hydroxide was added to 30 ml of diethylene glycol, and the mixture was stirred at room temperature during which 5.5 g of 80% hydrazine dihydrate.2H2O and 5.0 g of 5-bromo-2-(4-methoxybenzoyl)-benzofuran were further added. The thus prepared mixture was refluxed under heating. After cooling, the resulting reaction solution was adjusted to pH 4-5, extracted with benzene, and then dried. After distilling off the solvent, the resulting residue was purified by subjecting it to silica gel column chromatography using a n-hexane/iso-propanol mixture as an elution solvent, thereby obtaining 3.95 g of 5-bromo-2-(4-methoxybenzyl)benzofuran as a brown oily material.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[N:11][OH:12])[C:3](=[O:13])[O:2]1.[C:14](=O)([O-])[O-].[K+].[K+].COS(OC)(=O)=O.O>C1(C)C=CC=CC=1>[CH3:14][O:12][N:11]=[C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:1][O:2][C:3]1=[O:13]
Reactant: O=C1OCc2ccccc2C1=NO
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: COS(=O)(=O)OC
Product: CON=C1C(=O)OCc2ccccc21
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A suspension of isochroman-3,4-dione 4-oxime (90.4 HPLC-area %, 145.8 g, 0.74 mol) and potassium carbonate (153.4 g, 1.11 mol) in toluene (1000 mL) was stirred at ambient temperature for 1 h before dimethylsulfate (141.4 g, 1.11 mol) was added dropwise at 26° C. over a period of 2.5 h. The resulting mixture was stirred for 24 h at ambient temperature. After completion of the reaction, dist. water (1000 mL) was added to the mixture under stirring. The organic layer was separated, washed with dist. water (500 mL) and dried in vacuo at 30-50 mbar and max. 50° C. Isochroman-3,4-dione 4-(O-methyl-oxime) was obtained as a light orange solid (160.1 g, 88.7 HPLC-area %, quant. yield, diastereomeric ratio=58:42).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[CH2:8][OH:9].[H-].[Na+].[S:12](Cl)([C:15]1[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=1)(=[O:14])=[O:13]>CN(C=O)C>[CH3:19][C:18]1[CH:20]=[CH:21][C:15]([S:12]([O:9][CH2:8][CH:3]2[CH2:4][CH2:5][CH2:6][CH2:7][N:2]2[CH3:1])(=[O:14])=[O:13])=[CH:16][CH:17]=1
Reactant: CN1CCCCC1CO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)OCC2CCCCN2C)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 36.4 %

Procedure:
To a mixture of (1-methylpiperidin-2-yl)methanol (1.00 g, 7.75 mmol) in dry DMF (5.0 mL) at 0° C. was added NaH (620 mg, 15.5 mmol, 60% in mineral oil). After being stirred for 1 h, TsCl (2.96 g, 15.5 mmol) in DMF (1.0 mL) was added. The resulting mixture was further stirred at room temperature for 10 h and then poured into the ice-water (20 mL). The resulting mixture was extracted with EtOAc (2×50 mL). The organic layers were dried over Na2SO4 and evaporated to dryness to afford the crude product, which was purified by silica gel chromatography eluting with a 20% gradient of EtOAc in petroleum ether to afford (1-methylpiperidin-2-yl)methyl 4-methylbenzenesulfonate (800 mg, 36.5% yield). LCMS (ESI) m/z: 284.2 [M+H+]
Reaction SMILES: [CH3:1][O:2][C:3](=[O:32])[N:4]=[C:5]([S:30][CH3:31])[C:6]([C:20]1[CH:25]=[C:24]([O:26][CH3:27])[C:23]([OH:28])=[CH:22][C:21]=1[F:29])=[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.Br[CH2:34][CH2:35][O:36][Si:37]([C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:39])[CH3:38].COC(=O)N=C(SC)C(C1C=C(OC)C=C(O)C=1F)=NC1C=CC(C2N=C(C)ON=2)=CC=1.FCCI>>[CH3:1][O:2][C:3](=[O:32])[N:4]=[C:5]([S:30][CH3:31])[C:6]([C:20]1[CH:25]=[C:24]([O:26][CH3:27])[C:23]([O:28][CH2:34][CH2:35][O:36][Si:37]([C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:39])[CH3:38])=[CH:22][C:21]=1[F:29])=[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
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Reactant: COC(=O)N=C(SC)C(=Nc1ccc(-c2noc(C)n2)cc1)c1cc(OC)c(O)cc1F
Agent: COC(=O)N=C(SC)C(=Nc1ccc(-c2noc(C)n2)cc1)c1cc(OC)cc(O)c1F
Agent: FCCI
Product: COC(=O)N=C(SC)C(=Nc1ccc(-c2noc(C)n2)cc1)c1cc(OC)c(OCCO[Si](C)(C)C(C)(C)C)cc1F

Procedure:
The same procedure was carried out as in Example (3e), except that {2-(2-fluoro-4-hydroxy-5-methoxyphenyl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene}carbamic acid methyl ester and (2-bromoethoxy)-t-butyldimethylsilane were used instead of respectively the [2-(2-fluoro-3-hydroxy-5-methoxyphenyl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene]carbamic acid methyl ester and 1-fluoro-2-iodoethane, to give the title compound as a yellow solid.
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:10][C:11]([C:15]#[N:16])=[N:12]2)=[CH:7][CH:6]=1)=[N+:2]=[N-:3].[N+:23]([C:26]1[CH:43]=[CH:42][C:29]([C:30]([O:32][C:33]([CH2:40][CH3:41])([C:36]([F:39])([F:38])[F:37])[C:34]#[CH:35])=[O:31])=[CH:28][CH:27]=1)([O-:25])=[O:24].C(N(C(C)C)CC)(C)C>C1COCC1.[Cu](I)I>[N+:23]([C:26]1[CH:27]=[CH:28][C:29]([C:30]([O:32][C@@:33]([C:34]2[N:3]=[N:2][N:1]([CH2:4][C:5]3[CH:14]=[C:13]4[C:8]([C:9]([C:17]5[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=5)=[CH:10][C:11]([C:15]#[N:16])=[N:12]4)=[CH:7][CH:6]=3)[CH:35]=2)([C:36]([F:37])([F:38])[F:39])[CH2:40][CH3:41])=[O:31])=[CH:42][CH:43]=1)([O-:25])=[O:24]
Reactant: C#CC(CC)(OC(=O)c1ccc([N+](=O)[O-])cc1)C(F)(F)F
Reactant: N#Cc1cc(-c2ccccc2)c2ccc(CN=[N+]=[N-])cc2n1
Agent: I[Cu]I
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC[C@](OC(=O)c1ccc([N+](=O)[O-])cc1)(c1cn(Cc2ccc3c(-c4ccccc4)cc(C#N)nc3c2)nn1)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 7-(azidomethyl)-4-phenylquinoline-2-carbonitrile (120 mg, 0.42 mmol) and 1-ethyl-1-(trifluoromethyl)prop-2-yn-1-yl 4-nitrobenzoate (139 mg, 0.46 mmol, slower eluting enantiomer described in Example 1, step 2) in THF (5 mL) was added diisopropylethylamine (0.37 mL, 2.1 mmol) followed by copper iodide (120 mg, 0.63 mmol). The reaction was stirred at room temperature overnight and quenched with saturated aqueous NH4Cl and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. Purification on silica gel (eluting with EtOAc/hexanes, 4:6) gave the title compound. MS (+ESI): 587 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:16](=[O:17])[C:12]3([CH2:15][CH2:14][CH2:13]3)[N:11]([C:18]3[CH:23]=[CH:22][C:21]([CH2:24]OS(C)(=O)=O)=[CH:20][CH:19]=3)[C:10]2=[S:30])=[CH:5][C:4]=1[C:31]([F:34])([F:33])[F:32])#[N:2].[CH3:35][NH:36][CH3:37]>C1COCC1>[CH3:35][N:36]([CH2:24][C:21]1[CH:20]=[CH:19][C:18]([N:11]2[C:10](=[S:30])[N:9]([C:6]3[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[C:4]([C:31]([F:32])([F:34])[F:33])[CH:5]=3)[C:16](=[O:17])[C:12]32[CH2:15][CH2:14][CH2:13]3)=[CH:23][CH:22]=1)[CH3:37]
Reactant: CNC
Reactant: CS(=O)(=O)OCc1ccc(N2C(=S)N(c3ccc(C#N)c(C(F)(F)F)c3)C(=O)C23CCC3)cc1
Solvent: C1CCOC1
Product: CN(C)Cc1ccc(N2C(=S)N(c3ccc(C#N)c(C(F)(F)F)c3)C(=O)C23CCC3)cc1
Temperature: -78 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
A mixture of Methanesulfonic acid 4-[7-(4-cyano-3-trifluoromethylphenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]oct-5-yl]phenylmethyl ester (50a) (0.02 g, 0.039 mmol) and dimethylamine (0.5 ml; distilled from its 40% aqueous solution) in THF (1 ml) was stirred for 2 hours at −78° C. The mixture was concentrated and chromatographed (dichloromethane:acetone, 95:5; acetone) to yield 4-[5-(4-dimethylaminomethylphenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]oct-7-yl]-2-trifluoromethylbenzonitrile (50c) [RD156] (0.017 g, 0.037 mmol, 95%), the structure of which is illustrated in Formula 24, as a white powder.
Reaction SMILES: Br[C:2]1[C:3]([F:23])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([C:18]([NH:20][CH3:21])=[O:19])=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:22]=1.[N:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C@@:30]([OH:34])([C:32]#[CH:33])[CH3:31]>>[F:23][C:3]1[C:2]([C:33]#[C:32][C@:30]([OH:34])([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][N:24]=2)[CH3:31])=[CH:22][C:6]2[C:7]3[N:8]([C:12]([C:18]([NH:20][CH3:21])=[O:19])=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=3)[CH2:9][CH2:10][O:11][C:5]=2[CH:4]=1
Reactant: CNC(=O)c1c(C(N)=O)nc2n1CCOc1cc(F)c(Br)cc1-2
Reactant: C#C[C@](C)(O)c1ccccn1
Product: CNC(=O)c1c(C(N)=O)nc2n1CCOc1cc(F)c(C#C[C@](C)(O)c3ccccn3)cc1-2
Yield: 9 %

Procedure:
10-bromo-9-fluoro-N3-methyl-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2,3-dicarboxamide was reacted (2S)-2-(2-pyridyl)but-3-yn-2-ol via General Procedure E to afford 7.7 mg (9%) of 9-fluoro-10-[(3S)-3-hydroxy-3-(2-pyridyl)but-1-ynyl]-N3-methyl-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2,3-dicarboxamide. M+1=450.