Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH2:3]([SH:5])[CH3:4].[H][H].F[C:9]1[CH:16]=[C:15]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=2[Cl:24])[CH:14]=[CH:13][C:10]=1[C:11]#[N:12]>CN(C)C=O>[Cl:24][C:18]1[CH:19]=[C:20]([Cl:23])[CH:21]=[CH:22][C:17]=1[C:15]1[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[C:9]([S:5][CH2:3][CH3:4])[CH:16]=1
Reactant: [H][H]
Reactant: CCS
Reactant: N#Cc1ccc(-c2ccc(Cl)cc2Cl)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCSc1cc(-c2ccc(Cl)cc2Cl)ccc1C#N
Temperature: 60 °C
Reaction time: 6 h
Yield: 87.3 %

Procedure:
0.12 g (3.0 mmol) of 60% sodium hydride was stirred in 30 ml of N,N-dimethylformamide at room temperature while 0.2 g (3.2 mmol) of ethanethiol was added dropwise. After generation of hydrogen was over, 0.7 g (2.6 mmol) of 2-fluoro-4-(2,4-dichlorophenyl)benzonitrile was added, and the reaction mixture was stirred at 60° C. for 6 hours. The reaction mixture was poured into about 100 ml of ice-cold water and extracted with 50 ml of ethyl acetate twice. The ethyl acetate layer was washed with 50 ml of water twice and dried over anhydrous magnesium sulfate, and the ethyl acetate was distilled off under reduced pressure. Purification of the residue by silica gel column chromatography afforded 0.7 g of 4-(2,4-dichlorophenyl)-2-ethylthiobenzonitrile (yield 88.0%) as pale yellow crystals (m.p. 89-92° C.).
Reaction SMILES: [C:1]([CH2:5][C:6]([OH:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].C([N+](CCCC)(CCCC)CCCC)CCC.O.[C:28](=[O:35])([S:32][CH2:33][CH3:34])[O:29][CH2:30]Cl>CO.C(Cl)Cl>[CH2:33]([S:32][C:28]([O:29][CH2:30][O:7][C:6](=[O:8])[CH2:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:35])[CH3:34]
Reactant: CC(C)(C)CC(=O)O
Reactant: CCSC(=O)OCCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Solvent: O
Product: CCSC(=O)OCOC(=O)CC(C)(C)C
Reaction time: 1 h
Yield: 102.4 %

Procedure:
To a solution of t-butylacetic acid (0.025 mol, 3 g) in methanol is added tetrabutylammonium hydroxide (1M/methanol, 25 ml). The mixture is stirred for 1 h and the solvent removed to a residue. The residue is dissolved in 150 ml of methylene chloride and 150 ml of water and a solution of O-chloromethyl S-ethyl carbonothioate (0.025 mol, 3.85 f) in 50 ml of methylene chloride added. The mixture is stirred at room temperature for 24 h. The methylene chloride layer is separated, washed with water, brine and dried over sodium sulfate. The solvent is removed under vacuo and the residue stirred in 300 ml of ether for 24 h. The resulting white solid is filtered, the solid discarded and the solvent removed from the filtrate to give 6 g of a crude oil.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]1[C:9](=[O:10])[C@@H:8]([NH:11][C:12](=[O:21])[O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C@H:7]1[CH2:22][N:23]1C(C)=N[NH:25][NH:24]1.OP([O-])([O-])=O.[K+].[K+].[C:42](#[N:44])[CH3:43].O>>[CH3:43][C:42]1[N:25]=[N:24][N:23]([CH2:22][C@@H:7]2[C@H:8]([NH:11][C:12](=[O:21])[O:13][CH2:14][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:9](=[O:10])[NH:6]2)[N:44]=1
Reactant: COc1ccc(CN2C(=O)[C@@H](NC(=O)OCc3ccccc3)[C@H]2CN2NNN=C2C)c(OC)c1
Reactant: CC#N
Agent: O=P([O-])([O-])O
Agent: [K+]
Solvent: O
Product: Cc1nnn(C[C@H]2NC(=O)[C@H]2NC(=O)OCc2ccccc2)n1
Temperature: 25 °C
Yield: 81 %

Procedure:
Prepared in an analogous manner to example 4, step 2 using benzyl ((2R,3S)-1-(2,4-dimethoxybenzyl)-2-((5-methyl-2H-tetrazol-1-yl)methyl)-4-oxoazetidin-3-yl)carbamate (202 mg, 0.433 mmol), K2S2O8 (164 mg, 0.606 mmol) and K2HPO4 (98 mg, 0.563 mmol) in ACN:water (2:1, 7.4 mL) at 90° C. for 1.5 h. More K2S2O8 (35 mg, 0.13 mmol) and K2HPO4 (20 mg, 0.11 mmol) were added and it was heated for an additional 30 min then cooled to rt then concentrated in vacuo. The mixture was diluted with EtOAc, washed with brine, dried over Na2SO4 and concentrated in vacuo. The crude residue was purified via silica gel chromatography (MeOH-DCM, 0-10%), to afford the title compound (111 mg, 81%). LCMS: Rt=0.58 min, m/z=317.2 (M+1) Method 2m_acidic; 1H NMR (400 MHz, CDCl3) δ 7.43-7.30 (m, 5H), 6.34 (br s, 1H), 6.01 (br s, 1H), 5.28-5.21 (m, 1H), 5.20-5.12 (m, 3H), 4.92 (dd, J=14.3, 3.9 Hz, 1H), 4.68 (dd, J=14.2, 7.9 Hz, 1H), 4.48-4.27 (m, 2H), 2.53 (s, 3H).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([CH2:8][NH:9][C:10]2[C:15]([C:16]#[N:17])=[CH:14][N:13]=[C:12]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][C:27]([F:30])([F:29])[F:28])[N:11]=2)[CH2:4][CH2:3]1.Br[CH2:32][CH2:33][CH2:34]Br.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[N:1]1([C@H:2]2[CH2:3][CH2:4][C@H:5]([CH2:8][NH:9][C:10]3[C:15]([C:16]#[N:17])=[CH:14][N:13]=[C:12]([NH:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[O:26][C:27]([F:29])([F:30])[F:28])[N:11]=3)[CH2:6][CH2:7]2)[CH2:34][CH2:33][CH2:32]1
Reactant: N#Cc1cnc(NCc2ccccc2OC(F)(F)F)nc1NC[C@H]1CC[C@H](N)CC1
Reactant: BrCCCBr
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: N#Cc1cnc(NCc2ccccc2OC(F)(F)F)nc1NC[C@H]1CC[C@H](N2CCC2)CC1
Temperature: 50 °C
Reaction time: 24 h

Procedure:
To a solution of 4-{[(trans-4-aminocyclohexyl)methyl]amino}-2-{[2-(trifluoromethoxy)benzyl]-amino}pyrimidine-5-carbonitrile (150 mg, 0.36 mmol) in DMF (1 mL) were added 1,3-dibromo-propane (86 mg, 0.43 mmol) and DIPEA (124 μL, 0.71 mmol). The reaction mixture was stirred at 50° C. for 24 h. The reaction mixture was then diluted with EtOAc and washed with NaHCO3 (×1) and water (×4). The organic phase was dried over anhydrous Na2SO4 and concentrated in vacuo. The resulting residue was purified by silica gel preparative TLC using 10:1:0.2 CH2Cl2:MeOH:NH4OH as an eluent to afford 54 mg (33%) of the title compound as a white solid, m/z 461.6 (M+1)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:23]=[C:22]([O:24][CH3:25])[C:21]([F:26])=[CH:20][C:11]=1[C:12]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:13].[CH3:27]OC(OC)N(C)C.C(OCC)C>C1C=CC=CC=1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:10]2[C:11](=[CH:20][C:21]([F:26])=[C:22]([O:24][CH3:25])[N:23]=2)[C:12](=[O:13])[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:27]1
Reactant: CCOC(=O)CC(=O)c1cc(F)c(OC)nc1Nc1ccc(F)cc1F
Reactant: COC(OC)N(C)C
Solvent: CCOCC
Solvent: c1ccccc1
Product: CCOC(=O)c1cn(-c2ccc(F)cc2F)c2nc(OC)c(F)cc2c1=O
Yield: 63.3 %

Procedure:
In 4 ml of benzene was suspended 200 mg of ethyl 2-[2-(2,4-difluorophenylamino)-5-fluoro-6-methoxynicotinoyl]acetate, and 71 mg of N,N-dimethylformamide dimethylacetal was added thereto, after which the resulting mixture was subjected to reaction under reflux for 9 hours. The solvent was removed by distillation under reduced pressure, and to the residue thus obtained was added 2 ml of diethyl ether, after which the crystals thus deposited were collected by filtration to obtain 130 mg (yield 63.3%) of ethyl 1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-7-methoxy-4-oxo-1,8-naphthyridine-3-carboxylate having a melting point of 190°-192° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]=[C:4]([S:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:12]=2[F:18])[N:3]=1.[H-].[Na+].[OH2:21].[CH3:22]O>>[Cl:1][C:2]1[CH:7]=[C:6]([O:21][CH3:22])[N:5]=[C:4]([S:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:12]=2[F:18])[N:3]=1
Reactant: Fc1cccc(CSc2nc(Cl)cc(Cl)n2)c1F
Reactant: O
Reactant: CO
Agent: [H-]
Agent: [Na+]
Product: COc1cc(Cl)nc(SCc2cccc(F)c2F)n1
Reaction time: 5 h

Procedure:
To a stirred solution of 4,6-Dichloro-2-[(2,3-difluorobenzyl)thio]pyrimidine (the product of Example 1, step ii) (5 g) in dry methanol (40 mL) was added 60% sodium hydride (0.68 g) batchwise over 5 min. The reaction mixture was stirred for 5 h, H2O added and the solvents were partially evaporated. The residue was extracted with EtOAc which was washed with H2O, dried (MgSO4) and the solvent evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel, eluting with Et2O/iso-hexane (5:95) to give the subtitle compound as a white solid. Yield: 4.05 g.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[C:7]=1Cl.O.[NH2:13][NH2:14]>C(O)C>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[C:7]=1[NH:13][NH2:14]
Reactant: O=[N+]([O-])c1cncc(Br)c1Cl
Reactant: NN
Solvent: O
Solvent: CCO
Product: NNc1c(Br)cncc1[N+](=O)[O-]
Yield: 79.5 %

Procedure:
A solution of 3-bromo-4-chloro-5-nitro-pyridine (500 mg, 2.106 mmol), hydrazine hydrate (158.1 mg, 153.6 μL, 3.159 mmol) in ethanol (5.000 mL) was stirred at RT for 1 h. The bright yellow precipitate was filtered, washed with methanol and dried under vacuum to leave 3-bromo-4-hydrazinyl-5-nitropyridine (390 mg, 79.5%). MS (ES−) 232.8.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][N:18]=[C:17]([C:21](O)=[O:22])[CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[NH2:46][C:47]1[CH:52]=[CH:51][C:50]([NH:53][C:54]([NH:56][C:57]2[CH:61]=[C:60]([C:62]([CH3:65])([CH3:64])[CH3:63])[O:59][N:58]=2)=[O:55])=[CH:49][CH:48]=1.O>CN(C=O)C>[C:62]([C:60]1[O:59][N:58]=[C:57]([NH:56][C:54](=[O:55])[NH:53][C:50]2[CH:49]=[CH:48][C:47]([NH:46][C:21]([C:17]3[CH:16]=[C:15]([O:14][CH:11]4[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH2:10]4)[CH:20]=[CH:19][N:18]=3)=[O:22])=[CH:52][CH:51]=2)[CH:61]=1)([CH3:65])([CH3:63])[CH3:64]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccnc(C(=O)O)c2)CC1
Reactant: CC(C)(C)c1cc(NC(=O)Nc2ccc(N)cc2)no1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccnc(C(=O)Nc3ccc(NC(=O)Nc4cc(C(C)(C)C)on4)cc3)c2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 83.4 %

Procedure:
4-(1-(tert-Butoxycarbonyl)piperidin-4-yloxy)picolinic acid from Step 2 (188 mg, 0.58 mmol) was stirred in 3 mL of DMF. TBTU (244 mg, 0.76 mmol) was added, followed by TEA (82 μL, 0.058 mmol). After 10 min, 1-(4-aminophenyl)-3-(5-tert-butylisoxazol-3-yl)urea (Ref: Milanov, Zdravko V. et al. WO2005/48948 A2, 2005 Jun. 2) (160 mg, 0.58 mmol) was added, followed by TEA (82 μL, 0.058 mmol). The resulting mixture was stirred at rt for 3 h. LC-MS indicated that the reaction was complete. Water (20 mL) was then added, the precipitates were collected by filtration and washed with cold water, dried in vacuum oven to give tert-butyl 4-(2-(4-(3-(5-tert-butylisoxazol-3-yl)ureido)phenylcarbamoyl)pyridin-4-yloxy)piperidine-1-carboxylate (280 mg, 83%) as an off-white solid. LC-MS (ESI) m/z 579 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:19]([O:21]C)=[O:20])[C:10]([S:13][CH2:14][CH2:15][CH2:16][CH:17]=[CH2:18])([CH3:12])[CH3:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[OH-].[Li+].Cl>O1CCCC1.O.C(OCC)C>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:19]([OH:21])=[O:20])[C:10]([S:13][CH2:14][CH2:15][CH2:16][CH:17]=[CH2:18])([CH3:11])[CH3:12])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C=CCCCSC(C)(C)[C@H](NC(=O)OC(C)(C)C)C(=O)OC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: C=CCCCSC(C)(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 65 h
Yield: 99.3 %

Procedure:
To a solution of 8.52 g (25.7 mmol) of N-tert-butoxycarbonyl-3-(4-pentenylthio)-L-valine, methyl ester in 200 mL of tetrahydrofuran at room temperature was added a solution of 1.10 g (26.2 mmol) of lithium hydroxide monohydrate in 50 mL of water. The resulting mixture was stirred at room temperature for 65 hours. To the reaction mixture then was added 28 mL of 1.00N hydrochloric acid. The mixture was diluted with diethyl ether, washed with water (3×) and brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to afford 8.10 g of N-tert-butoxycarbonyl-3-(4-pentenylthio)-L-valine as a colorless oil. NMR (300 MHz, CDCl3): δ 5.75 (d of d of t, 1 H, J=17.2, 10.3, 6.6 Hz), 5.40 (br s, 1 H), 5.05-4.94 (m, 2 H), 4.28 (br s, 1 H), 2.56 (m, 2 H), 2.13 (quart., 2H, J=7.3 Hz), 1.63 (quint., 2H, J=7.3 Hz), 1.44 (s, 9 H), 1.39 (s, 3 H), 1.37 (s, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][CH:10]=1)C1C=CC=CC=1.Cl.[C:18]([O:22][C:23](=[O:26])[CH2:24][NH2:25])([CH3:21])([CH3:20])[CH3:19].Cl.COC(=O)CN>>[C:18]([O:22][C:23](=[O:26])[CH2:24][NH:25][CH2:13][C:12]1[CH:11]=[CH:10][C:9]([O:8][CH3:1])=[CH:16][CH:15]=1)([CH3:21])([CH3:20])[CH3:19]
Reactant: O=Cc1ccc(OCc2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)CN
Agent: COC(=O)CN
Agent: Cl
Product: COc1ccc(CNCC(=O)OC(C)(C)C)cc1

Procedure:
According to Example 1, Step 1, by substituting 4-methoxybenzaldehyde for 4-benzyloxybenzaldehyde and glycine tert-butyl ester hydrochloride for glycine methyl ester hydrochloride, the title compound was obtained as a yellow oil (80% yield).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([O:10][CH2:11][CH2:12]Cl)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[F:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][C:19](NCCC)=[CH:18]2.O>CS(C)=O>[F:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][CH:19]=[C:18]2[CH2:4][CH2:3][CH2:2][NH:1][CH2:12][CH2:11][O:10][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:4]=1[CH:3]=[CH:2][NH:1]2
Reactant: CCCNc1cc2cc(F)ccc2[nH]1
Reactant: ClCCOc1cccc2[nH]ccc12
Solvent: O
Solvent: CS(C)=O
Product: Fc1ccc2[nH]cc(CCCNCCOc3cccc4[nH]ccc34)c2c1
Temperature: 90 °C
Reaction time: 12 h
Yield: 85.4 %

Procedure:
A solution of 2-(1H-indol-4-yloxy)ethylchloride (0.7 g, 3.6 mmol), 5-fluoro-indolyl-3-propylamine (1.0 g, 5.4 mmol) in dimethylsulfoxide (20 ml) was allowed to stir for 12 hours at 90° C. The reaction mixture was poured into water (100 ml) and extracted with methylene chloride (3×100 ml). The organic layer was washed with water (3×150 ml), dried over anhydrous sodium sulfate, filtered and the solvent was removed under vacuum. Chromatography (5%-10% methanol-methylene chloride) afforded 0.54 g (43%) of product as a white solid: mp 70-73° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](Cl)=[N:8][C:9]([S:12][CH3:13])=[N:10][CH:11]=1)=[O:5])[CH3:2].C(N(CC)CC)C.[CH:22]1([NH2:27])[CH2:26][CH2:25][CH2:24][CH2:23]1>C1COCC1.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[C:7]([NH:27][CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)=[N:8][C:9]([S:12][CH3:13])=[N:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: NC1CCCC1
Reactant: CCOC(=O)c1cnc(SC)nc1Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cnc(SC)nc1NC1CCCC1
Temperature: 25 °C
Yield: 77.4 %

Procedure:
Commercially available 4-chloro-2-methylsulfanyl-pyrimidine-5-carboxylic acid ethyl ester (6) (25 g, 107 mmol) was dissolved in THF. Subsequently, triethylamine (32.6 g, 322 mmol) and cyclopentylamine (10 g, 117 mmol) were added to the reaction mixture. The combination was stirred over night at room temperature. Precipitated salts were filtered away from solvent and discarded. The collected solvent was then evaporated in vacuo to give an oil. The resultant oil was dissolved in ethyl acetate, washed with sodium bicarbonate, and then dried over Na2SO4. The drying aid was filtered away and the resultant solvent was evaporated under vacuum to give 23.3 g of product (7). 1H NMR (300 MHz, CDCl3), δ 8.60 (s, 1H), 8.25 (br s, 1H), 4.49-4.54 (m, 1H), 4.30 (q, 2H), 2.52 (s, 3H), 2.00-2.10 (m, 2H), 1.50-1.79 (m, 6H), 1.35 (t, 3H).
Reaction SMILES: [H-].[Na+].[C:3]([O:11][CH2:12][CH3:13])(=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].Br[CH2:15][C:16]1[CH:29]=[CH:28][C:19]([C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:21])=[CH:18][CH:17]=1.[Br-]>CN(C=O)C.O>[C:20]([C:19]1[CH:18]=[CH:17][C:16]([CH2:15][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:3]([O:11][CH2:12][CH3:13])=[O:10])=[CH:29][CH:28]=1)(=[O:21])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: O=C(c1ccccc1)c1ccc(CBr)cc1
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(Cc1ccc(C(=O)c2ccccc2)cc1)C(=O)OCC
Temperature: 0 °C
Yield: 84.8 %

Procedure:
60% mineral oil suspension of sodium hydride (1.454 g; 36.3 mmol) was added into anhydrous DMF (50 mL) under nitrogen at 0° C. Diethyl malonate (5.82 g; 36.3 mmol) was added to the stirred suspension over 10 min and the mixture was then stirred rapidly at 0° C. until a clear pale yellow solution was obtained. 4-(bromomethyl)benzophenone (5.00 g; 18.2 mmol) in DMF (15 mL) was added dropwise over 5 min and the reaction mixture was stirred for 16 h at ambient temperature. Complete conversion of the starting bromide was confirmed by TLC. The reaction was diluted with water (400 mL) and extracted with dichloromethane (3×50 mL). The organic phase was separated, dried and evaporated to an oily residue. Chromatography on silicagel (eluent hexane/2-butanone 10:1→5:1) provided the desired 1,3-diethyl 2-[(4-benzoylphenyl)methyl]propanedioate (5.47 g; 86%) as a colourless oil.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:9][C@H:8]([OH:10])[CH2:7][C@H:6]1[C:11]([O:13]C)=O)=[O:4].[CH2:15]([NH2:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(CC)CC)C>C(OCCO)C>[CH2:15]([N:22]1[CH2:2][C:3](=[O:4])[N:5]2[CH2:9][C@H:8]([OH:10])[CH2:7][C@H:6]2[C:11]1=[O:13])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: NCc1ccccc1
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)CCl
Solvent: CCN(CC)CC
Solvent: CCOCCO
Product: O=C1[C@@H]2C[C@@H](O)CN2C(=O)CN1Cc1ccccc1

Procedure:
To a solution of Example 19B (75 g, 0.34 mol, 1 equivalent) in 2-ethoxyethanol (1.2 L), benzylamine (44 mL, 0.41 mol, 1.2 equivalents) was added. Triethylamine (60 mL, 0.43 mol, 1.28 equivalents) was then added, and the resultant mixture was refluxed for 12 hours. The reaction mixture was cooled and concentrated under reduced pressure. This crude material was purified by column chromatography on silica gel using a gradient of 0-10% methanol-ethyl acetate to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.93-2.03 (m, 1H), 2.1-2.17 (m, 1H), 3.23 (d, 1H, J=12.3 Hz), 3.55 (d, 1H, J=4.2 Hz), 3.63 (d, 1H, J=16.5 Hz), 4.15 (m, 1H), 4.32 (bs, 1H), 4.47-4.59 (m, 3H), 5.16 (s, 1H), 7.24-7.37 (m, 5H).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[C:7]1([C:27]3[C:18](=[CH:19][C:20]4[O:25][CH2:24][CH2:23][O:22][C:21]=4[CH:26]=3)[O:17][CH2:16]1)[C:8](=[O:15])[N:9]2[CH3:14])=O.[NH2:28][C:29]([NH2:31])=[S:30]>C(O)C>[NH2:31][C:29]1[S:30][CH:2]=[C:3]([C:5]2[CH:13]=[CH:12][CH:11]=[C:10]3[C:6]=2[C:7]2([C:27]4[C:18](=[CH:19][C:20]5[O:25][CH2:24][CH2:23][O:22][C:21]=5[CH:26]=4)[O:17][CH2:16]2)[C:8](=[O:15])[N:9]3[CH3:14])[N:28]=1
Reactant: NC(N)=S
Reactant: CN1C(=O)C2(COc3cc4c(cc32)OCCO4)c2c(C(=O)CBr)cccc21
Solvent: CCO
Product: CN1C(=O)C2(COc3cc4c(cc32)OCCO4)c2c(-c3csc(N)n3)cccc21
Temperature: 25 °C
Yield: 83 %

Procedure:
To a solution of 4′-(bromoacetyl)-1′-methyl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one (0.20 g, 0.47 mmol) in anhydrous ethanol (10 mL) was added thiourea (0.039 g, 0.51 mmol) and the reaction mixture was heated at reflux for 1 h. The reaction mixture was allowed to cool to ambient temperature and was concentrated to dryness in vacuo. The crude product was purified by column chromatography and eluted with a 0% to 10% gradient of methanol in dichloromethane to afford 4′-(2-amino-1,3-thiazol-4-yl)-1′-methyl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one (0.159 g, 84%) as a pale yellow solid: mp 233-234° C. (dec.) (dichloromethane/methanol); 1H NMR (300 MHz, CDCl3) δ7.44-7.37 (m, 1H), 7.23 (d, J=7.9 Hz, 1H), 6.95 (d, J=7.9 Hz, 1H), 6.57-6.42 (br m, 2H), 6.37 (s, 1H), 6.22 (s, 1H), 5.80 (s, 1H), 4.80-4.73 (m, 2H), 4.22-4.07 (m, 4H), 3.28 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 178.0, 168.2, 155.7, 144.8, 144.4, 138.1, 129.7, 129.4, 124.3, 121.9, 111.4, 109.4, 105.9, 99.2, 78.4, 77.4, 64.7, 64.0, 58.6, 27.1; MS (ES+) m/z 408.3 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:9]([O:10][CH3:11])=[CH:8][CH:7]=[C:6](I)[N:5]=1)[CH3:2].[Cu](C#N)[C:14]#[N:15]>CN(C=O)C>[CH2:1]([O:3][C:4]1[N:5]=[C:6]([C:14]#[N:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2]
Reactant: CCOc1nc(I)ccc1OC
Reactant: N#C[Cu]C#N
Solvent: CN(C)C=O
Product: CCOc1nc(C#N)ccc1OC
Temperature: 150 °C

Procedure:
To a solution of 2-ethoxy-6-iodo-3-methoxypyridine (16-2, 100 mg, 0.36 mmol, 1 equiv) in DMF (675 uL) was added copper cyanide (39 mg, 0.43, mmol, 1.2 equiv). The reaction mixture was heated in a microwave reactor at 150° C. for 20 minutes, and then was partitioned between DCM (50mL) and water (50 mL). The aqueous layer was extracted with DCM (3×25 mL), and the organic phase was dried over Mg2SO4, concentrated and purified by normal phase column chromatography (20-50% EtOAc in hexanes) to yield the title compound (16-3) as a white solid. ESI+MS [M+H]+ C9H11N2O2: 179.1 found, 179.2 required.
Reaction SMILES: S1C=CC=C1B(O)[OH:7].Br[C:10]1[CH:15]=[CH:14][C:13]([N:16]2[C:25](=[O:26])[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]=[C:17]2[CH:27]([N:29]([CH3:43])[S:30]([C:33]2[CH:38]=[CH:37][C:36]([C:39]([CH3:42])([CH3:41])[CH3:40])=[CH:35][CH:34]=2)(=[O:32])=[O:31])[CH3:28])=[CH:12][CH:11]=1.BrC1C=C2[C:52](=[CH:53]C=1)[N:51]=[C:50]([CH:55](N(C)S(C1C=CC(C(C)(C)C)=CC=1)(=O)=O)C)N(C1C=CC(C)=CC=1)C2=O>>[C:39]([C:36]1[CH:35]=[CH:34][C:33]([S:30]([N:29]([CH3:43])[CH:27]([C:17]2[N:16]([C:13]3[CH:14]=[CH:15][C:10]([N:51]4[CH2:50][CH2:55][O:7][CH2:53][CH2:52]4)=[CH:11][CH:12]=3)[C:25](=[O:26])[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]=2)[CH3:28])(=[O:31])=[O:32])=[CH:38][CH:37]=1)([CH3:40])([CH3:41])[CH3:42]
Reactant: CC(c1nc2ccccc2c(=O)n1-c1ccc(Br)cc1)N(C)S(=O)(=O)c1ccc(C(C)(C)C)cc1
Reactant: OB(O)c1cccs1
Reactant: Cc1ccc(-n2c(C(C)N(C)S(=O)(=O)c3ccc(C(C)(C)C)cc3)nc3ccc(Br)cc3c2=O)cc1
Product: CC(c1nc2ccccc2c(=O)n1-c1ccc(N2CCOCC2)cc1)N(C)S(=O)(=O)c1ccc(C(C)(C)C)cc1

Procedure:
In a similar manner as described above in Paragraph A, but replacing phenyl boronic acid with thiophene-2-boronic acid and N-{1-[3-(4-bromophenyl)-4-oxo-3,4-dihydroquinazolin-2-yl]ethyl}-4-tert-butyl-N-methylbenzenesulfonamide with N-[1-(6-bromo-4-oxo-3-p-tolyl-3,4-dihydroquinazolin-2-yl)ethyl]-4-tert-butyl-N-methylbenzenesulfonamide, the following compound was made:
Reaction SMILES: C(O)C.[OH-].[K+].C([O:9][C:10]1[CH:15]=[C:14]([O:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH:13]=[CH:12][C:11]=1[O:21][CH2:22][CH2:23][CH2:24][CH3:25])(=O)C>O>[CH2:22]([O:21][C:11]1[CH:12]=[CH:13][C:14]([O:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:15][C:10]=1[OH:9])[CH2:23][CH2:24][CH3:25]
Reactant: CCCCOc1ccc(OCCCC)c(OC(C)=O)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCCOc1ccc(OCCCC)c(O)c1
Reaction time: 1 h

Procedure:
23 [ml] of ethanol, 51.1 [g] of potassium hydroxide and 53.0 [g] of 2-acetoxy-1,4-di-n-butoxybenzene were added to 255 [ml] of water, and the mixture was reacted at 80° C. while stirring for 1 hour. After cooling the reaction liquor, it was neutralized and extracted twice with 200 [ml] of ethyl acetate. The extraction solution (i.e. the ethyl acetate solution) was washed with water, and concentrated by evaporating off the ethyl acetate as solvent under reduced pressure. Concentration of the extraction solution was continued until there was effectively no further evaporation of ethyl acetate (i.e., effectively no further ethyl acetate remained in the extraction solution). The separated crystals were filtered using filter paper, washed with a small amount of ethyl acetate, and dried to obtain 35.1 [g] of 2,5-di-n-butoxyphenol.