Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](Cl)=[N:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:22][C:23]1[C:31]([OH:32])=[CH:30][CH:29]=[C:28]2[C:24]=1[CH:25]=[C:26]([CH3:33])[NH:27]2.C(=O)([O-])[O-].[K+].[K+]>CN1C(=O)CCC1>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([O:32][C:31]3[C:23]([F:22])=[C:24]4[C:28](=[CH:29][CH:30]=3)[NH:27][C:26]([CH3:33])=[CH:25]4)=[N:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc2c(F)c(O)ccc2[nH]1
Reactant: COc1cc2c(Cl)ncnc2cc1OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ncnc2cc1OCc1ccccc1
Temperature: 95 °C
Reaction time: 1 h
Yield: 57.5 %

Procedure:
A suspension of 7-benzyloxy-4-chloro-6-methoxyquinazoline free base (10 g, 33.2 mmol), 4-fluoro-5-hydroxy-2-methylindole (5.9 g, 35.7 mmol), (prepared as described for the starting material in Example 1), and potassium carbonate (9.2 g, 66.6 mmol) in NMP (100 ml) was stirred at 95° C. for 1 hour. After cooling, the mixture was partitioned between ethyl acetate and aqueous sodium hydrogen carbonate. The organic layer was separated, washed with brine and dried over magnesium sulphate and evaporated under vacuum. The residue was triturated under acetonitrile and the suspension was cooled. The precipitate was filtered and dried under vacuum to give 7-benzyloxy-4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxyquinazoline (8.2 g, 57%).
Reaction SMILES: [CH2:1]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][N:13]=2)[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=2)=[C:7]([NH:23][C:24]([NH:26][C:27]2[C:32]([CH:33]([CH3:35])[CH3:34])=[CH:31][CH:30]=[C:29]([NH2:36])[C:28]=2[CH:37]([CH3:39])[CH3:38])=[O:25])[C:6]1=[O:40])[CH2:2][CH2:3][CH3:4].[C:41](O)(=[O:48])[C:42]1[CH:47]=[CH:46][CH:45]=[N:44][CH:43]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.CCN(CC)CC>CN(C=O)C.O>[CH2:1]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][N:13]=2)[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=2)=[C:7]([NH:23][C:24]([NH:26][C:27]2[C:32]([CH:33]([CH3:35])[CH3:34])=[CH:31][CH:30]=[C:29]([NH:36][C:41]([C:42]3[CH:43]=[N:44][CH:45]=[CH:46][CH:47]=3)=[O:48])[C:28]=2[CH:37]([CH3:39])[CH3:38])=[O:25])[C:6]1=[O:40])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1c(=O)c(NC(=O)Nc2c(C(C)C)ccc(N)c2C(C)C)c(-c2cccc(OC)c2)c2cccnc21
Reactant: O=C(O)c1cccnc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCCn1c(=O)c(NC(=O)Nc2c(C(C)C)ccc(NC(=O)c3cccnc3)c2C(C)C)c(-c2cccc(OC)c2)c2cccnc21
Yield: 76.9 %

Procedure:
A solution of N-[1-butyl-4-(3-methoxyphenyl)-1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl]-N′-(2,6-diisopropyl-3-aminophenyl)urea (300 mg, 0.485 mmol), nicotinic acid (66 mg, 0.533 mmol), 1-hydroxybenzotriazole (131 mg, 0.97 mmol), 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (93 mg, 0.485 mmol) and Et3N (0.06 ml, 0.485 mmol) in DMF (10 ml) is stirred at room temperature overnight. To the reaction solution is added water, and the mixture is extracted with ethyl acetate. The organic layer is washed twice with an aqueous ammonium chloride solution, and washed twice with an aqueous sodium hydrogen carbonate solution. The solvent is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography to give the title compound (243 mg, 0.373 mmol) as white crystals.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][N:18]2[CH:22]=[N:21][C:20]([C:23]([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)[OH:24])=[N:19]2)[CH2:13][CH2:12]1.[CH2:37]([O:44][C:45]1[CH:46]=[CH:47][C:48]([C@@H:56]([O:59][Si:60]([C:63]([CH3:66])([CH3:65])[CH3:64])([CH3:62])[CH3:61])[CH2:57]Br)=[C:49]2[C:54]=1[NH:53][C:52](=[O:55])[CH:51]=[CH:50]2)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.CS(C)=O.C(N(C(C)C)CC)(C)C>ClCCl>[NH3:1].[CH2:37]([O:44][C:45]1[CH:46]=[CH:47][C:48]([C@@H:56]([O:59][Si:60]([C:63]([CH3:64])([CH3:66])[CH3:65])([CH3:62])[CH3:61])[CH2:57][NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([CH2:17][N:18]3[CH:22]=[N:21][C:20]([C:23]([OH:24])([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)[C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)=[N:19]3)[CH2:13][CH2:12]2)=[C:49]2[C:54]=1[NH:53][C:52](=[O:55])[CH:51]=[CH:50]2)[C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CBr)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Reactant: NCCCCCCCCCN1CCC(Cn2cnc(C(O)(c3ccccc3)c3ccccc3)n2)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)O[C@@H](CNCCCCCCCCCN1CCC(Cn2cnc(C(O)(c3ccccc3)c3ccccc3)n2)CC1)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Product: N
Temperature: 95 °C
Reaction time: 48 h

Procedure:
(1-{[1-(9-aminononyl)piperidin-4-yl]methyl}-1H-1,2,4-triazol-3-yl)(diphenyl)methanol (Preparation 28, 710 mg, 1.45 mmol) and 8-(benzyloxy)-5-[(1R)-2-bromo-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl]quinolin-2(1H)-one (WO200509286, 708 mg, 1.45 mmol) were dissolved in dichloromethane (5 ml) and dimethylsulphoxide (100 μl) and diisopropylethylamine (253 μl) added. After stirring in a sealed vessel at 95° C. for 48 hours the solvent was removed in vacuo. The residue was purified by column chromatography on silica gel eluting with dichloromethane:methanol:880 ammonia (90:10:1, by volume) to furnish the title compound as a clear oil, in 38% yield, 500 mg.
Reaction SMILES: [C:1]([N:9]1[CH2:22][CH2:21][C:20]2[C:19]3[CH:18]=[C:17](Br)[CH:16]=[CH:15][C:14]=3[NH:13][C:12]=2[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:24]1([OH:30])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CC1C=CC=CC=1C.[Cu-]=O>[C:1]([N:9]1[CH2:22][CH2:21][C:20]2[C:19]3[CH:18]=[C:17]([O:30][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH:16]=[CH:15][C:14]=3[NH:13][C:12]=2[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Oc1ccccc1
Reactant: O=C(c1ccccc1)N1CCc2[nH]c3ccc(Br)cc3c2CC1
Agent: O=[Cu-]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1C
Product: O=C(c1ccccc1)N1CCc2[nH]c3ccc(Oc4ccccc4)cc3c2CC1
Temperature: 25 °C
Yield: 10.6 %

Procedure:
A mixture of 3-benzoyl-9-bromo-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (1.00 g, 2.71 mmol), phenol (0.51 g, 5.42 mmol), copper (I) oxide (0.019 g, 0.14 mmol), and cesium carbonate (2.65 g, 8.12 mmol) in o-xylene was refluxed for 24 h. After cooling to room temperature, the mixture was filtered and washed with ethyl acetate. The filtrate was concentrated in vacuo to dryness, and the residue was subjected to column chromatography (silica gel, 60% EtOAc/hexane) to afford 0.11 g (10%) of a colorless solid as the title compound: 1H NMR (300 MHz, CDCl3) δ 7.42, 7.29-7.19, 7.03-6.86, 4.12-3.91, 3.72-3.61, 3.20-3.04, 2.90-2.76; MS (ESI+) m/z 383 (M++1).
Reaction SMILES: [NH:1]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C@H:2]([C:18]([OH:20])=O)[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9].[NH2:28][C@H:29]([C:33]([O:35][CH3:36])=[O:34])[C@@H:30]([CH3:32])[OH:31].Cl.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>C1COCC1>[NH:1]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C@H:2]([C:18]([NH:28][C@H:29]([C:33]([O:35][CH3:36])=[O:34])[C@@H:30]([CH3:32])[OH:31])=[O:20])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:9]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)O
Reactant: COC(=O)[C@@H](N)[C@@H](C)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: COC(=O)[C@@H](NC(=O)[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C)[C@@H](C)O
Temperature: 25 °C
Reaction time: 15 h
Yield: 91.5 %

Procedure:
1.14 g (3 mmol) of Boc-Lys(Z)-OH, 0.51 g (3 mmol) of H-Thr-OMe.HCl, 0.68 g of (3.6 mmol) of EDCI, 0.58 g (3.6 mmol) of HOBT and 0.66 ml (6 mmol) of NMM are dissolved at -10° C. in 10 ml THF and stirred at room temperature for 15 hours. The THF is distilled off under vacuum, the residue dissolved in 50 ml ethyl acetate and the organic phase washed three times with 10 ml 0.5 N HCl, 10% NaHCO3 solution and water respectively. The organic phase is dried with MgSO4 and the solvent distilled off under vacuum. 1.36 g (92%) of thin-layer chromatographically identical Boc-Lys(Z)-Thr-OMe are obtained as a colourless foam.
Reaction SMILES: [O:1]1[C:7]2[CH:8]=[C:9]([CH:12]=O)[CH:10]=[CH:11][C:6]=2[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:14]([NH2:18])[CH:15]([CH3:17])[CH3:16].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(OCC)(=O)C>[CH3:16][CH:15]([CH3:17])[CH2:14][NH:18][CH2:12][C:9]1[CH:10]=[CH:11][C:6]2[CH2:5][CH2:4][CH2:3][CH2:2][O:1][C:7]=2[CH:8]=1
Reactant: O=Cc1ccc2c(c1)OCCCC2
Reactant: CC(C)CN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: CC(C)CNCc1ccc2c(c1)OCCCC2
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 106.3 %

Procedure:
To a mixture of 0.48 g (2.7 mmol) of 2,3,4,5-tetrahydro-1-benzoxepine-8-carbaldehyde and 1.33 mL (13.5 mmol, 5 equiv) of isobutylamine in 22 mL of 1,2-dichloroethane was added 0.86 mL (15.0 mmol, 5.5 equiv) of acetic acid. The mixture was stirred under nitrogen at ambient temperature for 20 minutes and 0.64 g (3.0 mmol, 1.1 equiv) of sodium triacetoxyborohydride was added. The mixture was stirred overnight then diluted with 125 mL of ethyl acetate and washed with 60 mL each of saturated sodium bicarbonate solution, water and brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give 0.67 g of a yellow oil. Purification by flash chromatography (0-10% methanol in ethyl acetate) gave the product as a colorless oil. MS (m+1)=234.2; 1H NMR (400 MHz, CDCl3) 7.07 (d, 1H, J 8 Hz), 7.09 (d, 1H, J 1.5 Hz), 6.99 (m, 1H), 3.99 (m, 2H), 3.72 (s, 2H), 2.70 (m, 2H), 2.43 (d, 2H, J 7 Hz), 1.95 (m, 2H), 1.77 (m, 1H), 1.71 (m, 2H), 1.5 (br s, 1H), 0.91 (d, 6H, J 7 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:8]=[C:9]([NH2:11])[CH:10]=1)=[O:4].N1C=CC=CC=1.[C:24](Cl)(Cl)=[O:25].[C:28]1([C:34]2[CH:35]=[CH:36][C:37]3[O:41][C:40]([CH2:42][OH:43])=[CH:39][C:38]=3[CH:44]=2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C1(C)C=CC=CC=1.CN(C1C=CN=CC=1)C>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:8]=[C:9]([NH:11][C:24]([O:43][CH2:42][C:40]2[O:41][C:37]3[CH:36]=[CH:35][C:34]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)=[CH:44][C:38]=3[CH:39]=2)=[O:25])[CH:10]=1)=[O:4]
Reactant: OCc1cc2cc(-c3ccccc3)ccc2o1
Reactant: O=C(Cl)Cl
Reactant: COC(=O)c1cc(N)cc(-c2ccccc2)c1
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: COC(=O)c1cc(NC(=O)OCc2cc3cc(-c4ccccc4)ccc3o2)cc(-c2ccccc2)c1
Temperature: 90 °C

Procedure:
To a solution of 5-amino-biphenyl-3-carboxylic acid methyl ester (crude from Step 4; 1.00 g, 4.40 mmol) and pyridine (0.711 mL, 8.80 mmol) in toluene (15 mL) at room temperature under argon was added 20% phosgene in toluene (3.3 mL, 6.3 mmol) and the mixture was heated at 90° C. for 1 h. The mixture was filtered, and the filtrate was concentrated to dryness (0.373 g). The crude material was dissolved in toluene (4 mL), (5-phenyl-benzofuran-2-yl)-methanol (0.300 g, 1.38 mmol) and DMAP (0.016 g, 0.137 mmol) were added and the mixture was heated at 90° C. for 18 h. The solvent was evaporated to dryness. Purification by flash chromatography gave 0.125 g of a white solid.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[S:10][CH:9]=[C:8]([CH3:11])[C:6]=2[N:7]=1.C(N(CC)CC)C.Cl.[C:21]([NH:25][NH2:26])([CH3:24])([CH3:23])[CH3:22]>CN(C=O)C>[C:21]([NH:25][NH:26][C:4]1[C:5]2[S:10][CH:9]=[C:8]([CH3:11])[C:6]=2[N:7]=[C:2]([Cl:1])[N:3]=1)([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)NN
Reactant: Cc1csc2c(Cl)nc(Cl)nc12
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1csc2c(NNC(C)(C)C)nc(Cl)nc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 58 %

Procedure:
To 6 ml of a solution of 438 mg (2.0 mol) of 2,4-dichloro-7-metylthieno[3,2-d]pyrimidine and 445 mg (4.4 mmol) of triethylamine in DMF was added 249 mg (2.0 mmol) of t-butylhydrazine hydrochloride under ice cooling. The reaction mixture was stirred at the same temperature for one hour and then allowed to resume room temperature, followed by stirring for further 16 hours. After completion of the reaction, ice water was added to the reaction mixture, followed by extraction with ethyl acetate (50 ml×3). After the organic layer was washed successively with 1N hydrochloric acid, water and brine and dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (eluent: ethyl acetate-hexane=1:2) to give 314 mg (yield: 58.0%) of the title compound.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]#[CH:5].[F:6][C:7]1[C:8](I)=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:16])/[C:10]/2=[CH:17]\[C:18]1[NH:19][CH:20]=[CH:21][CH:22]=1>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.CN(C=O)C.CCN(CC)CC>[F:6][C:7]1[C:8]([C:5]#[C:4][CH2:3][NH:2][CH3:1])=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:16])/[C:10]/2=[CH:17]\[C:18]1[NH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=C1Nc2ccc(F)c(I)c2/C1=C/c1ccc[nH]1
Reactant: C#CCNC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CNCC#Cc1c(F)ccc2c1/C(=C/c1ccc[nH]1)C(=O)N2

Procedure:
Using Method C above, N-methylpropargyl amine (48.4 mg, 0.7 mmol) was coupled with (Z)-1,3-dihydro-5-fluoro-4-iodo-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one (100 mg, 0.28 mmol) (Starting Material 5, supra) using (Ph3P)4Pd (32 mg) and Cul (5.3 mg) as catalyst in DMF (5 mL) and Et3N (5 mL) as solvent at 85° C. for 18 h to yield (Z)-1,3-Dihydro-5-fluoro-4-[3-(N-methylamino)-1-propynyl]-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one. (Yield 10 mg, 12%).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]([CH:31]=O)[CH:8]=[C:9]2[C:17]=1[CH:16]([CH2:18][O:19][C:20](=[O:22])[NH2:21])[C:15]1([O:24][C:25](=[O:27])[CH3:26])[O:23][N:10]2[CH2:11][CH:12]2[CH:14]1[N:13]2[C:28](=[O:30])[CH3:29])(=[O:3])[CH3:2].Cl.[NH2:34][OH:35].C(=O)(O)[O-].[Na+]>CO>[C:1]([O:4][C:5]1[CH:6]=[C:7]([CH:31]=[N:34][OH:35])[CH:8]=[C:9]2[C:17]=1[CH:16]([CH2:18][O:19][C:20](=[O:22])[NH2:21])[C:15]1([O:24][C:25](=[O:27])[CH3:26])[O:23][N:10]2[CH2:11][CH:12]2[CH:14]1[N:13]2[C:28](=[O:30])[CH3:29])(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1cc(C=O)cc2c1C(COC(N)=O)C1(OC(C)=O)ON2CC2C1N2C(C)=O
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CC(=O)Oc1cc(C=NO)cc2c1C(COC(N)=O)C1(OC(C)=O)ON2CC2C1N2C(C)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 31.4 %

Procedure:
To a solution of 11-acetyl-8-carbamoyloxymethyl-4-formyl-14-oxa-1,11-diazatetracyclo[7.4.1.02,7.010,12 ]tetradeca-2,4,6-trien-6,9-diyl diacetate (40 mg) in methanol (2 ml) were added hydroxylamine hydrochloride (10 mg) and sodium bicarbonate (8 mg). The mixture was stirred for 2 hours at ambient temperature and evaporated in vacuo. The residue was subjected to preparative thin layer chromatography, which was developed with a mixture of chloroform and methanol (10:1, v/v) to afford 11-acetyl-8-carbamoyloxymethyl-4-hydroxyiminomethyl-14-oxa-1,11-diazatetracyclo[7.4.1.02,7.010,12 ]tetradeca-2,4,6-trien-6,9-diyl diacetate (13 mg).
Reaction SMILES: [O:1]=[S:2]1(=[O:30])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:26][CH2:25][N:24]([CH:27]([CH3:29])[CH3:28])[CH2:23][CH2:22]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[CH3:31][S:32]([C:35]1[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=1)(=[O:34])=[O:33].N1C=CC=CC=1>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.C(Cl)(Cl)Cl>[O:30]=[S:2]1(=[O:1])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[N:11]([C:38]3[CH:39]=[CH:40][C:35]([S:32]([CH3:31])(=[O:34])=[O:33])=[CH:36][CH:37]=3)[C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:22][CH2:23][N:24]([CH:27]([CH3:28])[CH3:29])[CH2:25][CH2:26]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCS(=O)(=O)CC4)cc3c2)CC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CC(C)N1CCN(C(=O)c2ccc3c(c2)cc(C(=O)N2CCS(=O)(=O)CC2)n3-c2ccc(S(C)(=O)=O)cc2)CC1
Yield: 25 %

Procedure:
The title compound was synthesized in analogy to example 66, from [2-(1,1-dioxo-thiomorpholine-4-carbonyl)-1H-indol-5-yl]-(4-isopropyl-piperazin-1-yl)-methanone (example 1), 4-methylsulfonylphenylboronic acid, copper(II) acetate, pyridine and using chloroforme instead of dichloromethane as solvent, to give the desired product as a colorless solid (25%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][C@@H:13]2[O:18][C:17]3[C:19]([NH2:24])=[C:20]([NH2:23])[CH:21]=[CH:22][C:16]=3[O:15][CH2:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:25][CH2:26][C:27](=O)[C:28](=O)[CH2:29][CH3:30]>O.C(O)C.C(=O)([O-])O.[Na+]>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[O:18][C:17]3=[C:19]4[C:20](=[CH:21][CH:22]=[C:16]3[O:15][CH2:14]2)[N:23]=[C:28]([CH2:29][CH3:30])[C:27]([CH2:26][CH3:25])=[N:24]4)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CCC(=O)C(=O)CC
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc(N)c(N)c3O2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCc1nc2ccc3c(c2nc1CC)OC(COS(=O)(=O)c1ccc(C)cc1)CO3
Temperature: 60 °C

Procedure:
To a solution of [(2R)-7,8-diamino-2,3-dihydro-1,4-benzodioxin-2-yl]-methyl 4-methylbenzenesulfonate (2.226 g, 5.258 mmole) in water (50 mL) was added a solution of 3,4-hexanedione (0.750 g, 6.572 mmole) in ethyl alcohol (50 mL) and the reaction mixture was heated at 60° C. for 3 hours. The reaction mixture was allowed to cool to room temperature and was diluted with aqueous sodium hydrogen carbonate (250 mL) and extracted with ethyl acetate (2×100 mL). The combined organic extracts were washed with water (100 mL), aqueous sodium chloride (100 mL), dried (magnesium sulfate) and the solvent was removed in vacuo to give a crude solid. Purification by flash column chromatography (silica, ethyl acetate:hexanes 7:3) gave 1.796 g (80%) of the (R)-enantiomer of the title compound as a tan crystalline solid. Rf=0.85 (silica, ethyl acetate:hexanes 7:3); mp 132-135° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:17]([O:18][CH3:19])=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[C:11]([I:20])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I[CH2:22][CH3:23].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:1]([O:8][C:9]1[C:17]([O:18][CH3:19])=[CH:16][C:12]([C:13]([O:15][CH2:22][CH3:23])=[O:14])=[C:11]([I:20])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCI
Reactant: COc1cc(C(=O)O)c(I)cc1OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cc(OC)c(OCc2ccccc2)cc1I
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 4-benzyloxy-2-iodo-5-methoxybenzoic acid (reference example 5-1) (2 g), 2-iodoethane (0.5 mL), potassium carbonate (1.08 g) and N,N-dimethylformamide (17 mL) was stirred at room temperature for 2 hours. Water was added to the mixture. Insoluble materials were collected by filtration to give the title compound (2.07 g).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]([S:10][CH3:11])[N:3]=1.[CH3:12][C:13](OC(C)=O)=[O:14]>N1C=CC=CC=1>[C:8]([C:7]1[C:2]([NH:1][C:13](=[O:14])[CH3:12])=[N:3][C:4]([S:10][CH3:11])=[N:5][CH:6]=1)#[N:9]
Reactant: CC(=O)OC(C)=O
Reactant: CSc1ncc(C#N)c(N)n1
Solvent: c1ccncc1
Product: CSc1ncc(C#N)c(NC(C)=O)n1
Temperature: 80 °C
Reaction time: 23 h
Yield: 48 %

Procedure:
To a suspension of 4-amino-2-methylsulfanyl-pyrimidine-5-carbonitrile (5.45 g) in pyridine (66 mL) was added Ac2O (31 mL) at RT. The reaction mixture was stirred at 80° C. for 23 h, then was cooled to RT and evaporated under reduced pressure. The residue was dissolved in DCM (150 mL) and washed with NaHCO3 (sat'd aq) and brine. The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The crude residue was purified by flash chromatography (from 0 to >50% EtOAc/Hexane in 20 min.) to give 3.25 g (48% yield) of N-(5-cyano-2-methylsulfanyl-pyrimidin-4-yl)-acetamide as a yellow solid. MS=167 [M−C2H3O+1]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:13])[C:6](=[CH:11][CH:12]=1)[C:7]([O:9][CH3:10])=[O:8].C([O-])([O-])=O.[K+].[K+].[C:20]([O:24][C:25]([NH:27][CH2:28][CH2:29][CH2:30]Br)=[O:26])([CH3:23])([CH3:22])[CH3:21].[I-].[K+]>CN(C)C=O.O>[C:20]([O:24][C:25]([NH:27][CH2:28][CH2:29][CH2:30][O:13][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[CH:12]=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8])=[O:26])([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)OC(=O)NCCCBr
Reactant: COC(=O)c1ccc(OC)cc1O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(OC)cc1OCCCNC(=O)OC(C)(C)C
Reaction time: 60 h
Yield: 93.2 %

Procedure:
To a solution of methyl 4-methoxysalicylate (11.48 g, 63 mmol) in dimethylformamide (30 mL) was added solid K2CO3 (13.06 g, 94.5 mmol), 1-tert-butoxycarbonylamino-3-bromopropane (22.5 g, 94.5 mmol), and freshly ground potassium iodide (1.5 g). The resulting slurry was placed under a nitrogen atmosphere and stirred for 2.5 days. The slurry was diluted with water (250 mL), washed with 1 N NaOH (2×250 mL), water (250 mL), and brine (250 mL), then dried over sodium sulfate and concentrated in vacuo. The crude mixture was purified on a preparative (Waters Prep LC™) 500 A chromatography apparatus using two silica columns and a hexanes through 1:1 hexanes:EtOAc gradient to provide methyl 2-(3-tert-butoxycarbonylaminopropoxy)-4-methoxybenzoate (19.93 g, 93.3%) as a colorless oil.
Reaction SMILES: [CH2:1]([C:4]1([C:10]([O:12][CH3:13])=[O:11])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1)[CH:2]=C.I(O)(=O)(=O)=[O:15].[Na].O>O1CCCC1.[Os](=O)(=O)(=O)=O>[CH:2]([CH2:1][C:4]1([C:10]([O:12][CH3:13])=[O:11])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1)=[O:15]
Reactant: [O-][I+3]([O-])([O-])O
Reactant: C=CCC1(C(=O)OC)CCCCC1
Agent: O=[Os](=O)(=O)=O
Agent: [Na]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)C1(CC=O)CCCCC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 72.7 %

Procedure:
To a solution of methyl 1-allylcyclohexanecarboxylate (340 mg) in tetrahydrofuran (7 mL) were added an aqueous solution of sodium periodic acid (3.4 g, 16.0 mmol) and osmium tetraoxide (100 mg) successively under ice cooling. The solution was stirred at room temperature for 20 hours. Water was added to the reaction solution and insolubles were filtered off. The filtrate was extracted with ethyl acetate, and it was washed in turn with water, sodium thiosulfate and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give the title compound (250 mg). This product was subjected to the subsequent step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][CH:28]=1)[C:5](=[O:25])[CH2:6][CH2:7][NH:8][C:9]1[C:17]2[C:12](=[CH:13][C:14]([Cl:19])=[CH:15][C:16]=2[Cl:18])[NH:11][C:10]=1[C:20]([O:22]CC)=[O:21].[OH-].[Li+].O1CCCC1.O>C(OC(=O)C)C>[F:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][CH:28]=1)[C:5](=[O:25])[CH2:6][CH2:7][NH:8][C:9]1[C:17]2[C:12](=[CH:13][C:14]([Cl:19])=[CH:15][C:16]=2[Cl:18])[NH:11][C:10]=1[C:20]([OH:22])=[O:21]
Reactant: CCOC(=O)c1[nH]c2cc(Cl)cc(Cl)c2c1NCCC(=O)c1cccc(F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(CCNc1c(C(=O)O)[nH]c2cc(Cl)cc(Cl)c12)c1cccc(F)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 87.8 %

Procedure:
Mix 3-[(m-fluorophenacyl)methylamino]-2-carbethoxy-4,6-dichloroindole (700 mg, 1.7 mmol), lithium hydroxide (210 mg, 5 mmol), tetrahydrofuran (10 mL)and water (10 mL). Stir for 24 hours at room temperature. Dilute with ethylacetate (40 mL). Acidify while stirring and separate the layers. Dry the organic phase over magnesium sulfate, filter and concentrate in vacuo. Recrystallize the residue (ethyl acetate/hexane) to yield the title compound as a white powder (590 mg, 91%); mp 270°-280° C.