Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:31])[N:4]([CH2:19][C:20]2[N:21]=[CH:22][C:23]([C:26]([O:28]CC)=[O:27])=[N:24][CH:25]=2)[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17].[OH-].[Na+]>>[Cl:1][C:2]1[C:3](=[O:31])[N:4]([CH2:19][C:20]2[N:21]=[CH:22][C:23]([C:26]([OH:28])=[O:27])=[N:24][CH:25]=2)[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17]
Reactant: CCOC(=O)c1cnc(Cn2c(C)cc(OCc3ccc(F)cc3F)c(Cl)c2=O)cn1
Agent: [Na+]
Agent: [OH-]
Product: Cc1cc(OCc2ccc(F)cc2F)c(Cl)c(=O)n1Cc1cnc(C(=O)O)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 104.2 %

Procedure:
A mixture of ethyl 5-{[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]methyl}pyrazine-2-carboxylate (1.03 g, 2.3 mmol) in 1N NaOH (3.4 ml, 3.45 mmol, EtOH/water 1:1 v/v) stirred at room temperature for 2 hours. The reaction mixture was quenched with 5% citric acid and filtered. The solid was washed with water and dried to afford the desired product (1.011 g, 100%) as a white solid. 1H NMR (CD3OD, 400 MHz) δ 9.02 (s, 1H), 8.60 (s, 1H), 7.60 (m, 1H), 7.04 (m, 2H), 6.55 (s, 1H), 5.50 (s, 2H), 5.30 (s, 2H), 2.52 (s, 3H); ES-HRMS m/z 422.0732 (M+H calculated for C19H15N3O4ClF2 requires 422.0714).
Reaction SMILES: [CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([CH2:33]Br)[CH:28]=4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:35]1[CH2:39][CH2:38][CH:37]([OH:40])[CH2:36]1.C(N(CC)CC)C>CN(C=O)C.[I-].[Na+]>[NH2:26][C:24]1[C:25]2=[C:17]([C:12]3[CH:11]=[CH:10][C:15]4[C:14]([CH:13]=3)=[N:9][N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:16]=4)[CH:18]=[C:19]([C:27]3[CH:28]=[C:29]([CH:30]=[CH:31][CH:32]=3)[CH2:33][N:35]3[CH2:39][CH2:38][CH:37]([OH:40])[CH2:36]3)[N:20]2[N:21]=[CH:22][N:23]=1
Reactant: OC1CCNC1
Reactant: Nc1ncnn2c(-c3cccc(CBr)c3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Nc1ncnn2c(-c3cccc(CN4CCC(O)C4)c3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Temperature: 55 °C
Yield: 22.1 %

Procedure:
To a solution of 5-(2-benzyl-2H-indazol-6-yl)-7-[3-(bromomethyl)phenyl]pyrrolo[2,1-f][1,2,4]triazin-4-amine (125 mg, 025 mmol) in DMF (1 mL) was added 3-pyrrolidinol (26 μL, 0.27 mmol), triethylamine (103 μl, 0.74 mmol), and sodium iodide (0.4 mg, 0.002 mmol). The reaction was heated (55° C.) for 17 h and then cooled to rt. The crude reaction mixture was purified via preparative HPLC using a gradient elution from 15% to 50% acetonitrile in water followed by filtration through an acidic resin, washing with MeOH. The product was eluted with 2M NH3 in MeOH and the filtrate was concentrated to provide 28 mg (22%) of the desired product. 1H NMR (400 MHz, DMSO-d6) δ 8.57 (s, 1 H), 7.92-8.00 (m, 3 H), 7.83 (d, 1 H), 7.69 (d, 1 H), 7.25-7.44 (m, 7 H), 7.22 (dd, 1 H), 7.14 (s, 1 H), 5.67 (s, 2 H), 4.68 (d, 1 H), 4.09-4.21 (m, 1 H), 3.60 (q, 2 H), 2.65-2.72 (m, 1 H), 2.58 (q, 1 H), 2.37-2.46 (m, 1 H), 2.32 (dd, 1 H), 1.93-2.03 (m, 1 H), 1.48-1.59 (m, 1 H); ES-MS m/z 516.20 [M+H]+, HPLC RT (min) 2.53.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[C:3]=1[NH2:4].[Br:10]N1C(=O)CCC1=O>CN(C)C=O>[Br:10][C:7]1[CH:8]=[C:2]([F:1])[C:3]([NH2:4])=[C:5]([F:9])[CH:6]=1
Reactant: Nc1c(F)cccc1F
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: Nc1c(F)cc(Br)cc1F
Yield: 61.9 %

Procedure:
Fifty grams (0.39 mole) of 2,6-difluoroaniline was treated with 71.0 g (0.39 mole) of N-bromosuccinimide in 250 ml of dimethylformamide by the procedure of Mitchell, Lai and Williams, J. Org. Chem., 44, 4733 (1979) to give a total yield of 50.2 g (62%) of 4-bromo-2,6-difluoroaniline, m.p.: 64°-66° C.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][CH:3]=1.[CH:10]([B-](F)(F)F)=[CH2:11].[K+].C(Cl)Cl>C(O)(C)C>[CH:10]([C:2]1[N:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][CH:3]=1)=[CH2:11]
Reactant: C=C[B-](F)(F)F
Reactant: OCc1ccc(Cl)nc1
Agent: [K+]
Solvent: CC(C)O
Solvent: ClCCl
Product: C=Cc1ccc(CO)cn1
Temperature: 80 °C
Yield: 54.4 %

Procedure:
A 100 mL sealed tube was charged with a solution of (6-chloropyridin-3-yl)methanol (0.5 g, 3.4 mmol, Org. Lett. 2005, p 2965-2967) dissolved in isopropanol (10 mL), potassium vinyltrifluoroborate (1 g, 7.63 mmol, Aldrich), [1,1,-bis(diphenyl phosphino)ferrocine]dichloro palladium(II) complex with DCM (0.277 g, 0.34 mmol, Aldrich) and TEA (0.92 mL, 6.8 mmol). The mixture was degassed with nitrogen then heated at about 80° C. for about 12 h. The reaction mixture was cooled to RT, filtered and washed with isopropanol (10 mL). The filtrate was evaporated to dryness under reduced pressure and the crude material obtained was purified by silica gel column chromatography using 30 to 40% of EtOAc in hexane as an eluent. Relevant fractions containing the target compound were combined and evaporated to dryness under reduced pressure to afford (6-vinylpyridin-3-yl)methanol as a dark brown liquid 0.25 g (53%), 1H NMR (400 MHz, DMSO): δ 8.479 (s, 1H), 7.704-7.688 (d, J=6.4 Hz, 1H), 7.471-7.456 (d, J=6.0 Hz, 1H), 6.827-6.806 (m, 1H), 6.212-6.177 (d, J=14 Hz, 1H), 5.439-5.417 (d, J=8.8 Hz, 1H), 5.300 (m, 1H), 4.524 (d, J=4.4 Hz, 2H), MS m/z: 136 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13](Br)=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>CC1C=CC=CC=1C>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([N:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1ccc2c(ccn2Cc2ccccc2)c1
Reactant: C1CNCCN1
Solvent: Cc1ccccc1C
Product: c1ccc(Cn2ccc3cc(N4CCNCC4)ccc32)cc1
Temperature: 110 °C
Yield: 89 %

Procedure:
A flask was charged with 75 ml of o-xylene, 6.21 g of N-benzyl-5-bromoindole, 11.2 g of piperazine and 2.85 g of NaOBut. The flask was flushed with nitrogen for 10 minutes, and then, 6.0 mg of palladium acetate (the ratio of palladium atom/N-benzyl-5-bromoindole=0.10% by mole) and 0.07 ml of a solution in toluene of tri-tert.-butylphosphine having a concentration of 0.25 g/ml were added into the flask. Then the content was heated to 110° C. and maintained at that temperature for 3 hours. Extraction, drying and concentration were conducted, and finally recrystallization was conducted from toluene to give N-benzyl-5-(1-piperazinyl)indole. The yield was 89% by mole on the basis of N-benzyl-5-bromoindole.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:10][OH:11])=[N:4][C:5]([CH3:8])=[CH:6][N:7]=1.Br[CH2:19][C:20]1[N:25]=[C:24]([N:26]2[C:34](=[O:35])[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:27]2=[O:36])[CH:23]=[CH:22][CH:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[K+]>C(#N)C>[CH3:1][C:2]1[C:3]([C:9](=[N:10][O:11][CH2:19][C:20]2[N:25]=[C:24]([N:26]3[C:27](=[O:36])[C:28]4[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:34]3=[O:35])[CH:23]=[CH:22][CH:21]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:4][C:5]([CH3:8])=[CH:6][N:7]=1
Reactant: Cc1cnc(C)c(C(=NO)c2ccccc2)n1
Reactant: O=C1c2ccccc2C(=O)N1c1cccc(CBr)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CC#N
Product: Cc1cnc(C)c(C(=NOCc2cccc(N3C(=O)c4ccccc4C3=O)n2)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 7 h
Yield: 40.4 %

Procedure:
To a solution of 1-(3,6-dimethylpyrazin-2-yl)-N-hydroxy-1-phenylmethanimine (3.38 g, 14.9 mmol) and 2-[6-(bromomethyl)pyridin-2-yl]-1H-isoindole-1,3(2H)-dione (5.19 g, 16.4 mmol) in acetonitrile (50 mL) were added cesium carbonate (10.2 g, 31.2 mmol) and potassium iodide (3.70 mg, 22.3 mmol). After stirring at room temperature for 7 h, the reaction mixture was filtered, the insolubles washed with ethyl acetate, and the combined filtrates concentrated in vacuo, diluted in ethyl acetate (150 mL), washed with water (2×150 mL), dried over MgSO4 and concentrated to dryness in vacuo. Purification on silica gel afforded 2-{6-[({[(3,6-dimethylpyrazin-2-yl)(phenyl)methylene]amino}oxy)methyl]pyridin-2-yl}-1H-isoindole-1,3(2H)-dione [2.79 g, yield 41%; HPLC/MS: m/z=464 (M+H); log P(HCOOH)=3.35].
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[C:32]([O:36][C:37]([N:39]1[CH2:43][CH2:42][CH2:41][C@H:40]1[CH2:44][OH:45])=[O:38])([CH3:35])([CH3:34])[CH3:33].O[C:47]1[CH:48]=[N:49][CH:50]=[CH:51][CH:52]=1>O1CCCC1>[C:32]([O:36][C:37]([N:39]1[CH2:43][CH2:42][CH2:41][C@H:40]1[CH2:44][O:45][C:47]1[CH:48]=[N:49][CH:50]=[CH:51][CH:52]=1)=[O:38])([CH3:35])([CH3:34])[CH3:33]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CO
Reactant: Oc1cccnc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@H]1COc1cccnc1
Yield: 143.7 %

Procedure:
To a solution of triphenylphosphine (1.97 g, 7.5 mmol) in 30 mL of tetrahydrofuran at room temperature was added diethyl azodicarboxylate (DEAD) (1.13 mL, 7.5 mmol) dropwise with stirring. After stirring at room temperature for 30 minutes, (S)-1-t-butoxycarbonyl-2-pyrrolidinemethanol (from Example 15a below, 1 g, 5.0 mmol) and 3-hydroxypyridine (713 mg, 7.5 mmol) were added to the reaction mixture. The resultant solution was stirred at room temperature for 16 hr. After all the starting material was consumed, the organic solvent was evaporated in vacuo. The residue was purified by silica gel column chromatography. Elution with chloroform:methanol (10:1) provided 2 g of the title compound. MS (DCI/NH3) m/e 279 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[CH:7][C:8]([NH2:12])=[N:9]2)=[CH:4][CH:3]=1.[F:19][C:20]([F:26])([F:25])[CH2:21][N:22]=[C:23]=[S:24].C(N(C(C)C)CC)(C)C>>[NH2:12][C:8]1[CH:7]=[C:6]([N:13]2[CH2:18][CH2:17][N:16]([C:23](=[S:24])[NH:22][CH2:21][C:20]([F:26])([F:25])[F:19])[CH2:15][CH2:14]2)[C:5]2[C:10](=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:9]=1
Reactant: FC(F)(F)CN=C=S
Reactant: Nc1cc(N2CCNCC2)c2ccc(Cl)cc2n1
Solvent: CCN(C(C)C)C(C)C
Product: Nc1cc(N2CCN(C(=S)NCC(F)(F)F)CC2)c2ccc(Cl)cc2n1

Procedure:
As described for example 159, 7-chloro-4-(1-piperazinyl)-2-quinolinamine, 1,1,1-trifluoro-2-isothiocyanato-ethane, and diisopropylethyl amine, are reacted to give the product. LC-MS: 466 (M++1). 1H NMR (DMSO-TFA-d6) δ 1.0–1.3 (m, 1H), 3.0–3.14 (d, 1H), 3.18–3.38 (m, 6), 3.38–3.7 (m, 7H), 4.6–4.8 (m, 1H), 6.2–6.4 (s, 1H), 6.7–7.0 (m, 1H), 7.28–7.44 (m, 1H), 7.6–7.7 (s, 1H), 7.8–8.0 (m, 1H), 8.1–8.2 (m, 1H).
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[CH3:5][O:6][C:7]1[C:8]([NH2:13])=[CH:9][CH:10]=[CH:11][CH:12]=1>ClC1C=CC=CC=1>[CH3:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]=[C:1]=[O:2]
Reactant: COc1ccccc1N
Reactant: O=C(Cl)Cl
Solvent: Clc1ccccc1
Product: COc1ccccc1N=C=O
Temperature: 125 °C
Yield: 89 %

Procedure:
Into a 2 liter three-necked flask equipped with a dry ice condenser and an overhead stirrer, was condensed 100 ml of phosgene. At - 5° C., was added a solution of 25 g (0.2032 moles) of o-anisidine in 350 ml of chlorobenzene and a heavy white precipitate was observed. The mixture was then heated at 125° C. for three and a half hours while passing phosgene slowly through the solution for the first hour and a half, and then nitrogen for the last two hours. The solution was then distilled to afford 27.0 g (89%) of o-methoxyphenyl isocyanate, bp 74°-76° C. at 3 mm Hg. 'H NMR (δ,CDCL3) 6.7-7.1 (multiplet, 4H) and 3.80 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([NH2:9])=[CH:7][CH:6]=[CH:5][N:4]=1.C(N(CC)C(C)C)(C)C.[Cl:19][C:20]1[N:25]=[C:24](Cl)[C:23]([Cl:27])=[CH:22][N:21]=1>C(O)(C)C>[Cl:19][C:20]1[N:25]=[C:24]([NH:9][C:8]2[C:3]([O:2][CH3:1])=[N:4][CH:5]=[CH:6][CH:7]=2)[C:23]([Cl:27])=[CH:22][N:21]=1
Reactant: Clc1ncc(Cl)c(Cl)n1
Reactant: COc1ncccc1N
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: COc1ncccc1Nc1nc(Cl)ncc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.3 %

Procedure:
To a suspension of 2-methoxy-pyridin-3-ylamine (1.00 g, 0.00806 mol) and N,N-diisopropylethylamine (2.1 mL, 0.012 mol) in isopropyl alcohol (20 mL) was added 2,4,5-trichloropyrimidine (1.0 mL, 0.0089 mol). The mixture was stirred at room temperature overnight. The suspension was filtered, the solid was washed with isopropanol (10 mL) then hexane (20 mL). The solids were dried under vacuum to provide (2,5-dichloro-pyrimidin-4-yl)-(2-methoxy-pyridin-3-yl)-amine (1.23 g, 56%) as a white solid. LC/MS (ESI+): 271.40 (M+H).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH:8]2[O:9][CH:5]([CH2:6][CH2:7]2)[CH:4]1[CH2:10][C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=1[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.CC(C)=[O:28].OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O.[O-2].[Cr+3].[O-2].[O-2].[Cr+3]>[C:2]([CH:3]1[CH:8]2[O:9][CH:5]([CH2:6][CH2:7]2)[CH:4]1[CH2:10][C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=1[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([OH:28])=[O:1]
Reactant: CC(C)=O
Reactant: OCC1C2CCC(O2)C1Cc1cc(F)ccc1OCc1ccccc1
Agent: O=[Cr](=O)=O
Agent: [Cr+3]
Agent: O=S(=O)(O)O
Product: O=C(O)C1C2CCC(O2)C1Cc1cc(F)ccc1OCc1ccccc1
Reaction time: 0.17 h

Procedure:
To a solution of [1S-(1α, 2α, 3α, 4α)]-2-[[3-[hydroxymethyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]-4-fluoro-1-phenylmethoxy-benzene (0.812 g, 2.37 mmol) in acetone (20 mL) was added Jones reagent (1 mL) (The Jones reagent was prepared by dissolving 534 mg of Chromium oxide in 0.46 mL of acid sulphuric concentrated and 1.54 mL of water) and the resulting mixture was stirred for 10 min. Then, more Jones reagent (1 mL) was added and the mixture was stirred for 1 h. After, 2-propanol (0.6 mL) was added and the reaction was stirred for 5 min. Then the reaction was stopped, the chromium salts were filtered and the solvent was evaporated under vacuum. The crude product was partitioned between chloroform (30 mL) and 2 M HCl (15 mL). The organic phase was separated; it was washed with brine (15 mL), dried (Na2SO4), filtered and the solvent was evaporated “under vacuum” to give the titled compound as a dark solid which was used in the next step without any additional purification. 1H-NMR (CDCl3, 300 MHz) δ 7.35 (m, 5H, ArH), 6.86 (m, 3H, ArH), 5.05 (s, 2H, —OCH2Ph), 4.84 (bs, 1H, —CH—O—), 4.33 (bs, 1H, —CH—O—), 2.87 (m, 2H, —CH—), 2.57 (m, 2H, —CH2—), 1.72 (m, 2H, —CH2—CH2—), 1.34 (m, 2H, —CH2—CH2—).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=O)[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][N:13]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].B.O1CCCC1>C1COCC1>[CH3:1][C:2]1[CH:3]=[C:4]([NH:9][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][N:13]=2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1ccc(CC(=O)Nc2ccc(C)c(C)c2)nc1
Agent: B
Solvent: C1CCOC1
Product: Cc1ccc(CCNc2ccc(C)c(C)c2)nc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 10.5 %

Procedure:
To a solution of 390 mg (1.5 mmol) N-(3,4-dimethyl-phenyl)-2-(5-methyl-pyridin-2-yl)-acetamide in 8 mL THF under argon at ambient temperature, was added dropwise 3.1 mL (3.1 mmol) of a 1 M borane-tetrahydrofuran solution. The solution was refluxed for 5 hours, cooled to 0° C. and quenched with 7 mL of a 20% NH4Cl solution. The solution was acidified with HCl 5N and stirred at ambient temperature for 1.5 hours. The residue was basified with a sat. NaHCO3 solution, and concentrated. The residue was dissolved in ethylacetate, the aqueous phase was extracted 2 times with ethyl acetate. The combined extracts were dried over Na2SO4, filtered and concentrated in vacuo. The crude oil was purified with flash column chromatography on silica eluting with a gradient formed from heptane and ethylacetate to provide 0.038 g (10%) of the title compound as a yellow oil. MS (m/e): 241.3 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[C:4]([SH:13])[N:3]=1.[OH-].[Na+].[CH2:16](Cl)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(O)C>[CH2:16]([S:13][C:4]1[N:3]=[C:2]([OH:1])[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Oc1nc(S)nn1-c1ccccc1
Reactant: ClCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Oc1nc(SCc2ccccc2)nn1-c1ccccc1
Reaction time: 24 h

Procedure:
The product of stage (b) (20 g), ethanol (300 ml) and sodium hydroxide (5 g) were stirred together for 10 minutes. Benzyl chloride (12.3 ml) was added, and the mixture was heated under reflux with stirring for 24 hours. The solvent was removed in vacuo, and the residue was treated with water. The pH was adjusted to 1.0 with concentrated hydrochloric acid, and the solid was filtered, washed with water and recrystallises from ethanol to give 21.75 g of the desired product.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[O:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[N:16]([CH2:20][CH3:21])[C:15]([CH2:22][OH:23])=[CH:14]2>C(Cl)(Cl)Cl.O=[Mn]=O>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[O:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[N:16]([CH2:20][CH3:21])[C:15]([CH:22]=[O:23])=[CH:14]2
Reactant: CCn1c(CO)cc2cc(Oc3nc4ccccc4s3)ccc21
Agent: O=[Mn]=O
Solvent: ClC(Cl)Cl
Product: CCn1c(C=O)cc2cc(Oc3nc4ccccc4s3)ccc21
Temperature: 80 °C
Yield: 58.2 %

Procedure:
To a solution [5-(benzothiazol-2-yloxy)-1-ethyl-1H-indol-2-yl]-methanol (0.5 g, 1.6 mmol) in CHCl3 (16 mL) was added MnO2 (1.4 g, 16 mmol) and heated (80° C., 3 h). The reaction mixture was cooled (rt), filtered (Celite®) and washed with EtOAc (100 mL). The organic layer was washed with brine (50 mL), dried, filtered and concentrated in vacuo. The resulting residue was recrystallized using EtOAc:hexane (1:3) to provide the title compound as beige solid (0.3 g, 59%). MS (ESI): mass calcd. for C18H14N2O2S, 322.1; m/z found, 323.1 [M+H]+. 1H NMR (500 MHz, CDCl3): 9.91 (s, 1H), 7.78-7.68 (m, 2H), 7.66 (dd, J=8.0, 0.7, 1H), 7.49 (d, J=9.1, 1H), 7.43-7.34 (m, 2H), 7.30-7.23 (m, 2H), 4.63 (q, J=7.1, 2H), 1.42 (t, J=7.1, 3H).
Reaction SMILES: [CH3:1][CH2:2][C@:3]12[CH2:21][C:20]([C:22]([O:24][CH3:25])=[O:23])=[C:19]3[C@@:9]4([C:12]5[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=5[NH:18]3)[CH2:10][CH2:11][N:7]([C@@H:8]14)[CH2:6][CH2:5][CH2:4]2.[H-].[Na+].[CH3:28]I.O>CN(C=O)C.CCOCC>[CH3:1][CH2:2][C:3]12[CH2:21][C:20]([C:22]([O:24][CH3:25])=[O:23])=[C:19]3[C:9]4([C:12]5[C:17]([N:18]3[CH3:28])=[CH:16][CH:15]=[CH:14][CH:13]=5)[CH2:10][CH2:11][N:7]([CH:8]14)[CH2:6][CH2:5][CH2:4]2
Reactant: CC[C@]12CCCN3CC[C@]4(C(=C(C(=O)OC)C1)Nc1ccccc14)[C@@H]32
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: O
Product: CCC12CCCN3CCC4(C(=C(C(=O)OC)C1)N(C)c1ccccc14)C32
Yield: 85 %

Procedure:
A solution of 34 mg (0.1 m mol) of ±vincadifformine in 1 ml of DMF was added at 20° C. to a mixture of 10 mg (0.2 m mol) of 50% NaH-mineral oil in 1 ml of DMF. After 20 min 20 μL (0.3 m mol) of methyl iodide was added to the brown solution. After 10 min 5 ml of water was added resulting in deposition of a gummy product. Decantation of the solvent, addition of ether, filtration of the ether solution through phase separating paper and concentration under vacuum gave 30 mg (85%) of minovine which showed no indolic NH singlet at δ 8.9 and the presence of the N-CH3 singlet at 3.24, integrating for 3 protons. A picrate was prepared with mp 194°-197° C., regeneration of the free base gave minovine, mp 119°-121° C., reported 120°-122° C.8MS (80eV) m/e (vel. intensity %): 124 (100), 168 (7), 228 (4) 267 (7), 352 (55) M+.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:13])[CH3:12])=[CH:7][C:6]=1[CH3:14])([CH3:3])[CH3:2].O1CCCC1.[C:20](=O)([O:24]CC)[O:21][CH2:22][CH3:23].Cl>C1OCCOC2C(=CC=CC=2)OCCOCCOC2C(=CC=CC=2)OC1.O.C(O)C>[CH2:22]([O:21][C:20](=[O:24])[CH2:12][C:11]([C:8]1[CH:9]=[CH:10][C:5]([O:4][CH:1]([CH3:3])[CH3:2])=[C:6]([CH3:14])[CH:7]=1)=[O:13])[CH3:23]
Reactant: CC(=O)c1ccc(OC(C)C)c(C)c1
Reactant: CCOC(=O)OCC
Agent: Cl
Agent: c1ccc2c(c1)OCCOCCOc1ccccc1OCCOCCO2
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)c1ccc(OC(C)C)c(C)c1
Yield: 93.6 %

Procedure:
At room temperature, to a mixture of 1-(4-isopropoxy-3-methyl-phenyl)-ethanone (described in Reference Preparation example 93) 9.4 g and tetrahydrofuran 150 ml was added diethyl carbonate 11.6 g, 55% sodium hydride 4.5 g, dibenzo-18-crown-6 0.04 g and ethanol 3 mL, and the resulting mixture was stirred with heating under reflux for nine hours. To the reaction mixture was added water, and the resulting mixture was acidified with 10% aqueous hydrochloric acid solution and was extracted with ethyl acetate. The organic layer was washed with water and was dried over anhydrous magnesium sulfate, and was then concentrated under reduced pressure. The resulting residue was subjected to a silica gel column chromatography to give 3-(4-isopropoxy-3-methyl-phenyl)-3-oxo-propionic acid ethyl ester 12.1 g.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[CH:4]=1.[Li]CCCC.[B:16](OC)([O:19]C)[O:17]C.O>C1COCC1.C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[B:16]([OH:19])[OH:17]
Reactant: COB(OC)OC
Reactant: COc1cccc(OC)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: COc1cccc(OC)c1B(O)O
Temperature: -78 °C
Reaction time: 1 h

Procedure:
1,3-Dimethoxybenzene (4 g) was dissolved in freshly distilled THF (10 mL). This solution was cooled to −78° C. and n-BuLi (24 mL, 1.6 M solution in hexanes) was added dropwise to the cold solution. The mixture was stirred at −78° C. for 1 h, then warmed to room temperature and stirred for 1 h. The resulting mixture was cooled again to −78° C. and (MeO)3B (6.7 mL) was added. The mixture was allowed to warm to room temperature and stirred overnight. Water (10 mL) was added, and the mixture was stirred for 0.5 h, acidified to pH 4 with acetic acid and extracted with EtOAc. The extract was dried (MgSO4) and evaporated to give 2,6-dimethoxybenzeneboronic acid, which was used without further purification.
Reaction SMILES: ON1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2N=N1.C(Cl)CCl.C(OCC)(=O)C.C[N:22](C)[CH:23]=[O:24]>>[C:23]([NH2:22])(=[O:24])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: On1nnc2ccccc21
Reactant: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: NC(=O)c1ccccc1
Reaction time: 0.33 h

Procedure:
To a solution of 175 mg (1.15 mmol) of 3-hydroxy-2-1methylbenzoic acid and 203 mg (1.5 mmol) of N-hydroxybenzotriazole in 6 mL of anhydrous N,N-dimethylformamide at 0° C., was added 220 mg (1.15 mmol) of EDC. After 20 minutes of activation at 0° C. and 1 hour at room temperature, 392 mg (1.0 mmol) of 2R-hydroxy-3-[(2-methylpropyl)(4-aminophenyl)sulfonyl]amino-1S-(phenylmethyl)propylamine was added. After 15 hours at room temperature, ethyl acetate was added, washed with 5% citric acid, saturated sodium bicarbonate, brine, dried, filtered and concentrated to afford 590 mg of crude material. This was chromatographed on silica gel using 50-80% ethyl acetate/methylene chloride as eluent to afford 255 mg of pure benzamide, N-[2R-hydroxy-3-[[(4-aminophenyl)sulfonyl](2-methylpropyl)amino)-1S-(phenylmethyl)propyl]-3-hydroxy-2-methyl, m/e=526(M+H).