Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:6]([NH:8][C:9]1[C:10]([CH3:21])=[CH:11][C:12]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N:13][C:14]=1I)=[O:7])(C)(C)C.[Cl:22][C:23]1[CH:29]=[C:28]([O:30][CH3:31])[C:27]([S:32][C:33]([CH3:41])([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH3:34])=[CH:26][C:24]=1[NH2:25].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.CC(C)([O-])C.[Na+]>O1CCCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(OCC)(=O)C>[Cl:22][C:23]1[CH:29]=[C:28]([O:30][CH3:31])[C:27]([S:32][C:33]([CH3:34])([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH3:41])=[CH:26][C:24]=1[N:25]1[C:14]2=[N:13][C:12]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:11][C:10]([CH3:21])=[C:9]2[NH:8][C:6]1=[O:7]
Reactant: CCOC(=O)c1cc(C)c(NC(=O)OC(C)(C)C)c(I)n1
Reactant: COc1cc(Cl)c(N)cc1SC(C)(C)c1ccccc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(C)c2[nH]c(=O)n(-c3cc(SC(C)(C)c4ccccc4)c(OC)cc3Cl)c2n1
Temperature: 25 °C
Yield: 36.1 %

Procedure:
A mixture of ethyl 5-(tert-butoxycarbonylamino)-6-iodo-4-methylpyridine-2-carboxylate (0.2 g), 2-chloro-4-methoxy-5-(1-methyl-1-phenylethylthio)aniline (0.15 g), tris(dibenzylideneacetone)dipalladium(0) (23 mg), 4,5-bis(diphenyl-phosphino)-9,9-dimethylxanthene (29 mg) and sodium tert-butoxide (66 mg) in tetrahydrofuran (4 mL) was heated at reflux under an argon atmosphere overnight. The reaction mixture was cooled to room temperature. To the reaction mixture was added ethyl acetate, and the insoluble material was removed by filtration. The filtrate was washed with 1 mol/L hydrochloric acid and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=2/1−1/1) to give the title compound (90 mg).
Reaction SMILES: [C:1]([NH:8][C@H:9]([C@H:17]1[O:21][C:20](=[O:22])[C@H:19]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]#[N:31])[CH:25]=2)[CH2:18]1)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[OH-:32].[Li+]>C(COC)OC.O>[C:1]([NH:8][C@@H:9]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C@@H:17]([OH:21])[CH2:18][C@@H:19]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]#[N:31])[CH:25]=1)[C:20]([OH:22])=[O:32])([O:3][C:4]([CH3:6])([CH3:5])[CH3:7])=[O:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H]1C[C@@H](Cc2cccc(C#N)c2)C(=O)O1
Reactant: [OH-]
Agent: [Li+]
Solvent: COCCOC
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H](O)C[C@@H](Cc1cccc(C#N)c1)C(=O)O

Procedure:
Analogously to Example 1i), 1.6 g (3.8 mmol) of 5(S)-[1(S)-(Boc-amino)-2-phenylethyl]-3(R)-(m-cyanophenylmethyl)-dihydrofuran-2-(3H)-one in 37 ml of dimethoxyethane and 20 ml of water are hydrolysed with 15.2 ml of 1M lithium hydroxide solution to yield the title compound: tRet (I)=13.8 min.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[C:11](=[N:12][C:13](Cl)=[N:14][CH:15]=3)[N:10]([C:18]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.CCN(C(C)C)C(C)C.[C:46]([O:50][C:51](=[O:60])[NH:52][CH:53]1[CH2:58][CH2:57][CH:56]([NH2:59])[CH2:55][CH2:54]1)([CH3:49])([CH3:48])[CH3:47].O>CN(C=O)C>[C:46]([O:50][C:51](=[O:60])[NH:52][CH:53]1[CH2:54][CH2:55][CH:56]([NH:59][C:13]2[N:12]=[C:11]3[N:10]([C:18]([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)([C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)[C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)[N:9]=[C:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=4)[C:16]3=[CH:15][N:14]=2)[CH2:57][CH2:58]1)([CH3:49])([CH3:47])[CH3:48]
Reactant: Clc1ncc2c(-c3cccc(Br)c3)nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c2n1
Reactant: CC(C)(C)OC(=O)NC1CCC(N)CC1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NC1CCC(Nc2ncc3c(-c4cccc(Br)c4)nn(C(c4ccccc4)(c4ccccc4)c4ccccc4)c3n2)CC1
Temperature: 120 °C
Reaction time: 12 h

Procedure:
To a solution of 3-(3-bromo-phenyl)-6-chloro-1-trityl-1H-pyrazolo[3,4-d]pyrimidine (from Example 42 supra) (1.10 g, 2.0 mmol) in DMF (20 mL) was add DIPEA (0.39 g, 2.8 mmol) and (4-amino-cyclohexyl)-carbamic acid tert-butyl ester (0.60 g, 2.8 mmol). This mixture was stirred at 120° C. for 12 hours. After cooling to room temperature, the reaction mixture was poured into water (100 mL) and the resulting precipitate was collected by filtration. The obtained yellow solid was purified by chromatography (silica gel, MeOH:dichloromethane, 1:100) to give a light solid which was washed with ether (4 mL) to give {4-[3-(3-bromo-phenyl)-1-trityl-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino]-cyclohexyl}-carbamic acid tert-butyl ester as a white solid. (Yield 730 mg, 50.1%).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:29]([O:31]CC)=[O:30])=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14](=[O:27])[NH:15][C@@H:16]([C:19]2[CH:24]=[C:23]([F:25])[CH:22]=[C:21]([Br:26])[CH:20]=2)[CH2:17][OH:18])=[C:10]([F:28])[CH:9]=1.O[Li].O>CO.C1COCC1.O>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:29]([OH:31])=[O:30])=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14](=[O:27])[NH:15][C@@H:16]([C:19]2[CH:24]=[C:23]([F:25])[CH:22]=[C:21]([Br:26])[CH:20]=2)[CH2:17][OH:18])=[C:10]([F:28])[CH:9]=1
Reactant: CCOC(=O)c1cnc(N)c(-c2ccc(C(=O)N[C@H](CO)c3cc(F)cc(Br)c3)c(F)c2)n1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Nc1ncc(C(=O)O)nc1-c1ccc(C(=O)N[C@H](CO)c2cc(F)cc(Br)c2)c(F)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
A mixture of (S)-ethyl 5-amino-6-(4-((1-(3-bromo-5-fluorophenyl)-2-hydroxyethyl)carbamoyl)-3-fluorophenyl)pyrazine-2-carboxylate (220 mg, 0.422 mmol) and LiOH.H2O (142 mg, 3.38 mmol) in MeOH (2 ml), THF (2 mL) and Water (2 mL) was stirred for 3 hours at RT. The mixture was concentrated, to the residue was added 2 ml of water, 3N HCl was then added under stirring until the final pH was about 4. The resultant mixture was then concentrated and further dried to afford the crude product was a light yellow solid. (208 mg, 0.422 mmol, 100% yield). LC-MS (m/z): 494.9 (MH+), 0.653 min.
Reaction SMILES: C1COCC1.[CH3:6][O:7][C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13](Br)[CH:14]=2)[N:9]=1.[F:19][C:20]([F:29])([F:28])[CH:21]1[CH2:26][CH2:25][C:24](=[O:27])[CH2:23][CH2:22]1>CCCCCC>[CH3:6][O:7][C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:24]3([OH:27])[CH2:23][CH2:22][CH:21]([C:20]([F:28])([F:29])[F:19])[CH2:26][CH2:25]3)[CH:14]=2)[N:9]=1
Reactant: COc1ccc2cc(Br)ccc2n1
Reactant: O=C1CCC(C(F)(F)F)CC1
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1ccc2cc(C3(O)CCC(C(F)(F)F)CC3)ccc2n1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a cold (−78° C.) anhydrous THF solution of 2-methoxy-6-bromoquinoline (1.16 g, 4.89 mmol) was added w-BuLi (2.05 mL of a 2.5 M solution in hexane, 5.13 mmol). The mixture was stirred at −78° C. under a nitrogen atmosphere for 15 min and 4-(trifluoromethyl)cyclohexanone (0.81 g, 4.89 mmol) was added slowly to the reaction. After addition was complete, the bath was allowed to warm to room temperature. The reaction mixture was quenched with saturated NH4Cl (aq) and extracted with EtOAc/hexanes. The organic layer was dried over Na2SO4 and evaporated in vacuo and the resultant residue was purified by flash chromatography on silica gel using gradient elution (0% to 20% EtOAc/hexanes, 150 mL; 20% to 35% EtOAc/hexanes, 204 mL; 35% to 75% EtOAc/hexanes, 381 mL) to provide Isomer A as the faster-moving isomer and Isomer B as the slower-moving isomer.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([NH:11][S:12]([C:15]3[S:16][CH:17]=[CH:18][CH:19]=3)(=[O:14])=[O:13])[CH:10]=1)[NH:7][C:6]([C:20](O)=[O:21])=[CH:5]2.[CH2:23]([S:30][C:31]([CH3:35])([CH3:34])[CH2:32][NH2:33])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.N1(O)C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>C(OCC)(=O)C.CN(C)C=O>[CH2:23]([S:30][C:31]([CH3:35])([CH3:34])[CH2:32][NH:33][C:20]([C:6]1[NH:7][C:8]2[C:4]([CH:5]=1)=[CH:3][C:2]([F:1])=[CH:10][C:9]=2[NH:11][S:12]([C:15]1[S:16][CH:17]=[CH:18][CH:19]=1)(=[O:14])=[O:13])=[O:21])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CC(C)(CN)SCc1ccccc1
Reactant: O=C(O)c1cc2cc(F)cc(NS(=O)(=O)c3cccs3)c2[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(CNC(=O)c1cc2cc(F)cc(NS(=O)(=O)c3cccs3)c2[nH]1)SCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 72.3 %

Procedure:
To a mixture of 5-fluoro-7-[(2-thienylsulfonyl)amino]-1H-indole-2-carboxylic acid (0.20 g), 2-(benzylthio)-2-methylpropylamine (0.13 g), 1H-1,2,3-benzotriazol-1-ol (0.11 g) and N,N-dimethylformamide (10 mL) was added N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (0.14 g) at 4° C., and the mixture was stirred at room temperature for 18 hr. The reaction solution was diluted with ethyl acetate, washed with aqueous citric acid solution, aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate:hexane=2:8-4:6) to give the title compound (220 mg, crude yield 72%) as pale-purple crystals.
Reaction SMILES: C([O:8][C:9]1[C:14]2[NH:15][C:16](=[O:19])[CH2:17][O:18][C:13]=2[C:12]([C:20](=[O:24])[CH:21](O)O)=[CH:11][CH:10]=1)C1C=CC=CC=1.[F:25][C:26]([F:39])([F:38])[C:27]1[CH:37]=[CH:36][C:30]([CH2:31][C:32]2([NH2:35])[CH2:34][CH2:33]2)=[CH:29][CH:28]=1.FC(F)(F)C([O-])=O>>[OH:8][C:9]1[C:14]2[NH:15][C:16](=[O:19])[CH2:17][O:18][C:13]=2[C:12]([CH:20]([OH:24])[CH2:21][NH:35][C:32]2([CH2:31][C:30]3[CH:36]=[CH:37][C:27]([C:26]([F:25])([F:38])[F:39])=[CH:28][CH:29]=3)[CH2:33][CH2:34]2)=[CH:11][CH:10]=1
Reactant: NC1(Cc2ccc(C(F)(F)F)cc2)CC1
Reactant: O=C1COc2c(C(=O)C(O)O)ccc(OCc3ccccc3)c2N1
Agent: O=C([O-])C(F)(F)F
Product: O=C1COc2c(C(O)CNC3(Cc4ccc(C(F)(F)F)cc4)CC3)ccc(O)c2N1

Procedure:
Prepared according to general method 3 from 329 mg (1 mmol) 5-benzyloxy-8-(2,2-dihydroxy-acetyl)-4H-benzo[1,4]oxazin-3-one and 215 mg (1 mmol) 1-(4-trifluoromethyl-benzyl)-cyclopropylamine. Yield: 18 mg (3%, trifluoroacetate); mass spectroscopy: [M+H]+=423.
Reaction SMILES: [N:1]([CH:4]1[CH2:10][CH2:9][C:8]2[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=2[N:6]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:5]1=[O:21])=[N+]=[N-].[H][H]>[Pd].C(O)C>[NH2:1][CH:4]1[CH2:10][CH2:9][C:8]2[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=2[N:6]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:5]1=[O:21]
Reactant: CCOC(=O)CN1C(=O)C(N=[N+]=[N-])CCc2ccccc21
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CN1C(=O)C(N)CCc2ccccc21

Procedure:
The reaction mixture of 3-azido-1-ethoxycarbonylmethyl-2,3,4,5-tetrahydro-1H[1]-benzazepin-2-one (13.98 kg) and 5% palladium on carbon (1.3 kg) in anhydrous ethanol (57 liters) was hydrogenated under 3 atmospheres pressure of hydrogen for 5 hours. The pressure reactor was vented at hourly intervals to remove the accumulated nitrogen. The catalyst was removed by filtration and washed with ethyl alcohol. The solution was evaporated to dryness to give 3-amino-1-ethoxycarbonylmethyl-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one.
Reaction SMILES: C(OC([N:6]1[C:25]([NH2:26])=[C:9]2[CH2:10][N:11]([S:14]([C:17]3[CH:22]=[C:21]([F:23])[CH:20]=[C:19]([F:24])[CH:18]=3)(=[O:16])=[O:15])[CH2:12][CH2:13][C:8]2=[N:7]1)=O)C.C(N(CC)CC)C>ClCCl.CO>[F:23][C:21]1[CH:22]=[C:17]([S:14]([N:11]2[CH2:12][CH2:13][C:8]3=[N:7][NH:6][C:25]([NH2:26])=[C:9]3[CH2:10]2)(=[O:16])=[O:15])[CH:18]=[C:19]([F:24])[CH:20]=1
Reactant: CCOC(=O)n1nc2c(c1N)CN(S(=O)(=O)c1cc(F)cc(F)c1)CC2
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CO
Product: Nc1[nH]nc2c1CN(S(=O)(=O)c1cc(F)cc(F)c1)CC2
Temperature: 25 °C
Reaction time: 48 h
Yield: 93.9 %

Procedure:
3-Amino-5-(3,5-difluoro-benzenesulfonyl)-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-2-carboxylic acid ethyl ester (45.4 g, 117.5 mmol) was dissolved in a mixture of dichloromethane (200 mL) and methanol (900 mL) then triethylamine (200 mL) was added. The solution was stirred at room temperature for 2 days and then evaporated to dryness. The solid was treated with diethylether (1 L), stirred for 1 hour, filtered and washed with diethylether. After drying in vacuo the title compound was obtained as white solid (34.68 g, 94%).
Reaction SMILES: C[O:2][C:3]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[C:9]([O:14][CH3:15])[CH:8]=2)=[O:4].Br[CH2:17][C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1>>[CH3:15][O:14][C:9]1[CH:8]=[C:7]2[C:12]([CH:13]=[C:5]([C:3]([OH:2])=[O:4])[N:6]2[CH2:17][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=[CH:20][CH:19]=2)=[CH:11][CH:10]=1
Reactant: COC(=O)c1cc2ccc(OC)cc2[nH]1
Reactant: BrCc1cccc2ccccc12
Product: COc1ccc2cc(C(=O)O)n(Cc3cccc4ccccc34)c2c1

Procedure:
Using general procedure B, 6-methoxy-1H-indole-2-carboxylic acid methyl ester was coupled with 1-bromomethyl-naphthalene and the product obtained was hydrolyzed to give the title compound as a white solid. MS: 330.1 ([M−H]−).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][N:17]3[C:21](=[O:22])[CH2:20][O:19][C:18]3=[O:23])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[CH3:24][NH2:25]>O1CCCC1.CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][NH:17][C:18](=[O:23])[O:19][CH2:20][C:21]([NH:25][CH3:24])=[O:22])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: O=C1COC(=O)N1CCc1ccc(Oc2ccc(Cl)cc2)cc1
Reactant: CN
Solvent: C1CCOC1
Solvent: CO
Product: CNC(=O)COC(=O)NCCc1ccc(Oc2ccc(Cl)cc2)cc1
Yield: 79.3 %

Procedure:
0.46 g (1.39 mmol) of 3-(2-(4-[(4-chlorophenyl)oxy]phenyl)ethyl)-1,3-oxazolidine-2,4-dione, prepared in step 14.2., is redissolved in a mixture of 3 ml of tetrahydrofuran and 6 ml of methanol. 3 ml of a 2M solution of methylamine (6 mmol) in tetrahydrofuran are added. The mixture is left to react at ambient temperature overnight and then 2 g of silica are added and the mixture is evaporated to dryness. The residue is purified by chromatography on silica gel, eluting with a 98/2 then 96/4 and 94/6 mixture of dichloromethane and methanol. The product is recrystallized from a mixture of ethyl acetate and diisopropyl ether, to give 0.40 g of product in the form of a white powder.
Reaction SMILES: [CH3:1][C:2]1[NH:10][C:9]2[C:8]([O:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1.[C:18]([O:26][CH2:27][CH2:28][O:29][CH2:30][CH2:31]OS(C)(=O)=O)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:18]([O:26][CH2:27][CH2:28][O:29][CH2:30][CH2:31][N:10]1[C:9]2[C:8]([O:11][C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=[C:2]1[CH3:1])(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Cc1cc2ncnc(Oc3ccccc3)c2[nH]1
Reactant: CS(=O)(=O)OCCOCCOC(=O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc2ncnc(Oc3ccccc3)c2n1CCOCCOC(=O)c1ccccc1
Temperature: 60 °C
Reaction time: 21 h
Yield: 93.2 %

Procedure:
6-Methyl-4-phenoxy-5H-pyrrolo[3,2-d]pyrimidine (299.9 mg) and 2-{2-[(methylsulfonyl)oxy]ethoxy}ethyl benzoate (464.1 mg) were dissolved in N,N-dimethylformamide (7 mL), potassium carbonate (431 mg) was added, and the mixture was stirred at 60° C. for 21 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent, hexane:ethyl acetate=80:20→20:80) to give the title compound (517.8 mg) as a yellow oil.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]([NH:7][C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])[C:4]([OH:6])=[O:5].N#N.[CH3:20][C:21](=[CH2:23])[CH3:22].C([O-])(O)=O.[Na+]>O1CCOCC1.C(OCC)C>[NH2:1][CH2:2][C@H:3]([NH:7][C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])[C:4]([O:6][C:21]([CH3:23])([CH3:22])[CH3:20])=[O:5]
Reactant: C=C(C)C
Reactant: NC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: N#N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)[C@H](CN)NC(=O)OCc1ccccc1

Procedure:
10 g (42 mmol) of (2S)-3-amino-2-benzyloxycarbonylaminopropionic acid were shaken in an autoclave at 20 atm. N2 pressure for 3 days in a mixture of 100 ml of dioxane, 100 ml of isobutylene and 8 ml of conc. H2SO4Excess isobutylene was blown out and 150 ml of diethyl ether and 150 ml of saturated NaHCO3 solution were added to the remaining solution. The phases were separated and the aqueous phase was extracted twice using 100 ml of diethyl ether each time. The combined organic phases were washed with 2×100 ml of H2O and dried over Na2SO4. After removing the solvent in vacuo, (1.1) were obtained as a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[S:13])[O:10][CH2:11][CH3:12])[CH:5]=[CH:6][CH:7]=1.C(O)C.[OH-].[Na+]>O.[C-]#N.[C-]#N.[C-]#N.[C-]#N.[C-]#N.[C-]#N.[K+].[K+].[K+].[Fe+3]>[Cl:1][C:2]1[C:3]2[S:13][C:9]([O:10][CH2:11][CH3:12])=[N:8][C:4]=2[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=S)Nc1cccc(Cl)c1
Agent: [Fe+3]
Agent: [C-]#N
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CCOc1nc2cccc(Cl)c2s1
Temperature: 90 °C

Procedure:
20 ml-portions of a mixture of 49.5 gm (0.24 mol) of O-ethyl (3-chlorophenyl)-thiocarbamate, 60 ml of ethanol, 350 ml of an aqueous 30% sodium hydroxide solution, and 300 ml of water were added at intervals of 5 minutes to a solution of 494 gm (1.5 mol) of potassium hexacyanoferrate (III) in 600 ml of water at 80°-90° C. After heating the mixture for 2 hours at 90° C., 200 gm (0.61 mol) of potassium hexacyanoferrate (III) were added again, and the mixture was heated for another 3 hours at 90° C. After cooling, the mixture was diluted with 3 liters of water, extracted exhaustively with ether, and the separated organic phase was washed with water and dried over sodium sulfate. The residue remaining after evaporation of the solvent was purified by chromatography on 500 gm of silica gel, using dichloromethane/petroleum ether (volume ratio of 1:1) for elution. The fractions containing the two principal products were combined and evaporated. The residual crystal sludge yielded, after two successive recrystallizations from petroleum ether, 7.5 gm of colorless crystals having a melting point of 74°-75° C., which consisted according to spectroscopic examination of 5-chloro-2-ethoxy-benzothiazole. For the purpose of isolating the desired 7-chloro-2-ethoxybenzothiazole, i.e. the substance with the lower Rf value, the combined mother liquors were chromatographed on 500 gm of silica gel, using petroleum ether/dichloromethane as the eluant. The 7-chloro-2-ethoxy-benzothiazole, a light yellow oil obtained after evaporation of the corresponding eluates, was used in the next step without further purification. Yield: 15.5 gm (32% of theory).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].CI.C(O[C:14]([N:16]1[CH2:21][CH2:20][O:19][CH:18]([CH2:22][O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH2:30][CH2:31][CH2:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:17]1)=O)(C)(C)C>CC(N(C)C)=O>[CH3:14][N:16]1[CH2:21][CH2:20][O:19][CH:18]([CH2:22][O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH2:30][CH2:31][CH2:32][CH2:33][C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:17]1
Reactant: CC(C)(C)OC(=O)N1CCOC(COc2ccccc2CCCCc2ccccc2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: CI
Product: CN1CCOC(COc2ccccc2CCCCc2ccccc2)C1
Yield: 76.5 %

Procedure:
115 mg of potassium carbonate and 118 mg of methyl iodide were added to a solution of 300 mg of 2-[2-(4-phenylbutyl)phenoxymethyl]morpholine hydrochloride (prepared as described in Example 7) in 6 ml of dimethylacetamide, and the resulting mixture was allowed to react at room temperature for 3 hours. At the end of this time, the reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated by evaporation under reduced pressure. The resulting yellow oily residue was purified by column chromatography through silica gel, using ethyl acetate as the eluent, to give 183 mg (yield 65%) of the title compound as a colorless oil.
Reaction SMILES: [C:1]([C:5]1[C:10]2[O:11][CH2:12][C:13]([CH3:15])([CH3:14])[C:9]=2[CH:8]=[C:7]([C:16](=[O:21])[CH:17]=[C:18]([CH3:20])[CH3:19])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].O.[ClH:23]>>[C:1]([C:5]1[C:10]2[O:11][CH2:12][C:13]([CH3:14])([CH3:15])[C:9]=2[CH:8]=[C:7]([C:16](=[O:21])[CH2:17][C:18]([Cl:23])([CH3:20])[CH3:19])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cl
Reactant: CC(C)=CC(=O)c1cc(C(C)(C)C)c2c(c1)C(C)(C)CO2
Solvent: O
Product: CC(C)(Cl)CC(=O)c1cc(C(C)(C)C)c2c(c1)C(C)(C)CO2

Procedure:
A solution of 1-(7-tert-butyl-3,3-dimethyl-2,3-dihydrobenzo[b]furan-5-yl)-3-methyl-2-buten-1-one (Example 12) (2.0 g, 6.2 mmol) in HCl-saturated Et2O (30 mL) is stirred at 25° C. overnight. The solution is treated with H2O (20 mL), and partitioned against CH2Cl2 (3×20 mL). The combined organic layers are dried (MgSO4), filtered, and evaporated to a cream-colored solid which is crystallized from hexane to give 1-(7-tert-butyl-3,3-dimethyl-2,3-dihydrobenzo[b]furan-5-yl)-3-chloro-3-methylbutan-1-one.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH2:10][O:9][CH2:8][C:7]2=C.C[OH:14].C(Cl)Cl>N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH2:10][O:9][CH2:8][C:7]2=[O:14]
Reactant: C=C1COCc2c(F)cccc21
Reactant: CO
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C1COCc2c(F)cccc21
Temperature: -78 °C

Procedure:
8-Fluoro-4-methylene-3,4-dihydro-1H-isochromene (400 mg) was dissolved in a solution of 1:1 MeOH/DCM (50 mL) and 1 mL of pyridine added. The mixture was chilled to −78° C. and ozone was bubbled through the mixture for 40 min. The reaction monitored by TLC. The mixture was purged with nitrogen at −78° C. for 10 min and then treated with PPh3. After concentration, the resulting residue was purified by preparative TLC to offer 300 mg of the title compound.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)=[C:5]2[C:15](=[O:31])[N:16]([CH2:19][CH2:20][C:21]3[CH:30]=[CH:29][C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[N:22]=3)[C:17](=S)[C:4]2=[CH:3]1>[Ni].CCO>[CH3:1][N:2]1[C:7](=[O:8])[C:6]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)=[C:5]2[C:15](=[O:31])[N:16]([CH2:19][CH2:20][C:21]3[CH:30]=[CH:29][C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[N:22]=3)[CH2:17][C:4]2=[CH:3]1
Reactant: Cn1cc2c(c(-c3ccncc3)c1=O)C(=O)N(CCc1ccc3ccccc3n1)C2=S
Agent: [Ni]
Solvent: CCO
Product: Cn1cc2c(c(-c3ccncc3)c1=O)C(=O)N(CCc1ccc3ccccc3n1)C2
Temperature: 25 °C
Reaction time: 3 h
Yield: 28 %

Procedure:
To a mixture of 5-methyl-7-pyridin-4-yl-2-(2-quinolin-2-yl-ethyl)-1,6-dioxo-5H-pyrrolo[3,4-c]pyridine-3-thione (40 mg, 0.09 mmol, see Example 11.1), Raney nickel (about 400 mg) in EtOH (12 ml) was stirred at r.t. under nitrogen for 3 hours. The Raney nickel was filtered off and the filtrate was concentrated and purified by preparative thin-layer chromatography (EA:MeOH=5:1) to give the title compound as a white solid (10 mg, 26%).