Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Zn:1].[O-2].[Zn+2].[N+:4]([O-:7])([OH:6])=[O:5]>O>[N+:4]([O-:7])([O-:6])=[O:5].[Zn+2:1].[N+:4]([O-:7])([O-:6])=[O:5]
Reactant: O=[N+]([O-])O
Reactant: [Zn]
Agent: [O-2]
Agent: [Zn+2]
Solvent: O
Product: O=[N+]([O-])[O-]
Reaction time: 0.62 h

Procedure:
For use in preparing the aforementioned 15-0-0-5Zn solution, zinc nitrate solution containing about 16.5% zinc may be obtained commercially or prepared by reaction of metallic zinc or zinc oxide with nitric acid and introducing sufficient water to the reaction mixture to provide a zinc nitrate product solution containing about 16.5% zinc (47.8% zinc nitrate). This is accomplished by adding commercially available granular zinc oxide (containing about 80% zinc ) to a mixture of water and commercial strength (about 55%) nitric acid solution in a vessel provided with agitation and means for temperature control, e.g., coil(s) for steam heating and water cooling, together with a temperature sensing device. Typically, a 10 part batch of said zinc nitrate solution is prepared by adding to the reaction vessel about 5.8 parts of 55% nitric acid and 2.1 parts of water. After thorough mixing, granular zinc oxide is added over a period of about 15 to 30 minutes, accompanied by vigorous agitation. Once vigorous reaction has begun and during the period that it is self-sustaining, cooling is employed to maintain a reaction mix temperature of around 140° to 180° F. The rate of addition of zinc oxide granules is governed by the ability to maintain such temperature. The total reaction, generally requiring around 30-45 minutes, is usually deemed complete when substantially no particles of unreacted zinc oxide remain in the reaction mixture and the pH of said mixture has risen from about 0 to about 2 to 3.
Reaction SMILES: [C:1]([C:5]1N=C(N2CCC(F)(F)C2)[C:8]2[N:13]=[N:12][N:11](CC)[C:9]=2[N:10]=1)([CH3:4])(C)C.[C:23]([C:27]1[N:28]=[C:29]([N:36]2[CH2:42][C:38]3([CH2:41][O:40][CH2:39]3)[CH2:37]2)[C:30]2[N:35]=[N:34][NH:33][C:31]=2[N:32]=1)([CH3:26])([CH3:25])[CH3:24].ClCC1N(C2CC2)N=NN=1>>[C:23]([C:27]1[N:28]=[C:29]([N:36]2[CH2:37][C:38]3([CH2:39][O:40][CH2:41]3)[CH2:42]2)[C:30]2[N:35]=[N:34][N:33]([CH2:8][C:9]3[N:10]([CH:5]4[CH2:1][CH2:4]4)[N:13]=[N:12][N:11]=3)[C:31]=2[N:32]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)c1nc(N2CC3(COC3)C2)c2nn[nH]c2n1
Reactant: CCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21
Agent: ClCc1nnnn1C1CC1
Product: CC(C)(C)c1nc(N2CC3(COC3)C2)c2nnn(Cc3nnnn3C3CC3)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-Butyl-7-(2-oxa-6-aza-spiro[3.3]hept-6-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 5-(chloromethyl)-1-cyclopropyl-1H-tetrazole and isolated as white solid. MS (m/e): 397.3 (MH+).
Reaction SMILES: N#N.Cl[C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:14][CH3:15])[CH:12]=2)[C:7]([CH2:16][C:17]2[C:22]([Cl:23])=[CH:21][N:20]=[CH:19][C:18]=2[Cl:24])=[N:6][N:5]=1.[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1.CCCCCC.C(OCC)(=O)C>CN(C=O)C>[Cl:24][C:18]1[CH:19]=[N:20][CH:21]=[C:22]([Cl:23])[C:17]=1[CH2:16][C:7]1[C:8]2[C:13](=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)[C:4]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)=[N:5][N:6]=1
Reactant: COc1ccc2c(Cc3c(Cl)cncc3Cl)nnc(Cl)c2c1
Reactant: C1COCCN1
Agent: N#N
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc2c(Cc3c(Cl)cncc3Cl)nnc(N3CCOCC3)c2c1
Temperature: 100 °C
Reaction time: 14 h
Yield: 78.7 %

Procedure:
A solution under stirring and dry N2 of 4-chloro-1-(3,5-dichloro-pyridin-4-ylmethyl)-6-methoxy-phthalazine (1 g, 2.82 mmoles), prepared as described in example 45, in DMF (25 ml), at room temperature, was added with morpholine (0.73 g, 8.46 mmoles) and the temperature was raised to 100° C. After 14 hours the whole was brought to dryness and the solid partitioned between water and CH2Cl2. The organic phase was washed with water, anhydrified and brought to dryness to give a solid which was flash chromatographed (eluent: hexane/ethyl acetate 6:4, then in gradient up to 3:7) to give 0.9 g of the title compound (yield: 79%). m.p.: 179-180° C.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][N:3]=[C:2]1[C:6]1([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:20][CH2:19][C:18]4[C:21]([C:32]([F:35])([F:34])[F:33])=[N:22][N:23]([C:24]5[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=5)[C:17]=4[C:16]3=[O:36])=[CH:11][CH:10]=2)[CH2:8][CH2:7]1.[O-][Mn](=O)(=O)=O.[K+].[CH3:43]CN(CC)CC.CO.C(Cl)Cl>O1CCOCC1.CO>[CH3:31][O:30][C:27]1[CH:28]=[CH:29][C:24]([N:23]2[C:17]3[C:16](=[O:36])[N:15]([C:12]4[CH:11]=[CH:10][C:9]([C:6]5([C:2]6[N:1]([CH3:43])[CH:5]=[CH:4][N:3]=6)[CH2:7][CH2:8]5)=[CH:14][CH:13]=4)[CH2:20][CH2:19][C:18]=3[C:21]([C:32]([F:33])([F:34])[F:35])=[N:22]2)=[CH:25][CH:26]=1
Reactant: CCN(CC)CC
Reactant: COc1ccc(-n2nc(C(F)(F)F)c3c2C(=O)N(c2ccc(C4(C5=NCCN5)CC4)cc2)CC3)cc1
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: CO
Solvent: ClCCl
Solvent: C1COCCO1
Product: COc1ccc(-n2nc(C(F)(F)F)c3c2C(=O)N(c2ccc(C4(c5nccn5C)CC4)cc2)CC3)cc1
Temperature: 80 °C
Yield: 72 %

Procedure:
The product from Example 144 (0.08 g, 0.18 mmol) was dissolved in 1,4-dioxane (2.0 mL) and KMnO4 (spatula tip) was added. The reaction was heated to 80° C. for 12 h at rt. The reaction was filtered, concentrated, and purified via flash chromatography (silica, 100% EtOAc then 0.5% Et3N:10% MeOH/CH2Cl2 then 100% MeOH) to yield the title compound (0.06 g, yield: 72%). 1H NMR δ 7.44 (d, J=9.1 Hz, 2H), 7.24 (d, J=8.7 Hz, 2H), 6.98 (m, 4H), 4.07 (dd, J=2.9, 3.7 Hz, 2H), 3.81 (s, 3H), 3.48 (s, 2H), 3.12 (t, J=6.2 Hz, 2H), 1.44 (m, 2H), 1.21 (t, J=7.3 Hz, 2H) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH3:35])[C:6]=1[C:7]1[CH:21]=[C:20]([NH:22][C:23](=[O:34])[C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=2)[CH:19]=[CH:18][C:8]=1[O:9][CH2:10][C:11]([O:13]C(C)(C)C)=[O:12].O.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH3:35])[C:6]=1[C:7]1[CH:21]=[C:20]([NH:22][C:23](=[O:34])[C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:32])([F:33])[F:31])[CH:25]=2)[CH:19]=[CH:18][C:8]=1[O:9][CH2:10][C:11]([OH:13])=[O:12]
Reactant: Cn1ncc(Cl)c1-c1cc(NC(=O)c2cccc(C(F)(F)F)c2)ccc1OCC(=O)OC(C)(C)C
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1ncc(Cl)c1-c1cc(NC(=O)c2cccc(C(F)(F)F)c2)ccc1OCC(=O)O
Reaction time: 18 h
Yield: 70.8 %

Procedure:
To a solution of tert-butyl 2-(2-(4-chloro-1-methyl-1H-pyrazol-5-yl)-4-(3-(trifluoromethyl)benzamido)phenoxy)acetate (0.460 g, 0.902 mmol) in CH2Cl2 (5 mL) was added water (0.5 mL) and trifluoroacetic acid (5 mL, 56 mmol). The resulting solution was stirred for 18 hours, reduced under vacuum, azeotroped with toluene, and triturated in ether to give the title compound as a white solid (0.290 g, 70.8%). LCMS m/z (%)=454 (M+H, 35Cl, 100), 456(M+H, 37Cl, 30). 1H NMR (400 MHz, DMSO-d6) δ 3.72 (s, 3H) 4.70-4.84 (m, 2H) 7.11 (d, J=9.09 Hz, 1H) 7.63 (s, 1H) 7.72 (d, J=2.53 Hz, 1H) 7.79 (t, J=7.83 Hz, 1H) 7.87 (dd, J=9.22, 2.65 Hz, 1H) 7.97 (d, J=8.34 Hz, 1H) 8.26 (d, J=8.08 Hz, 1H) 8.29 (s, 1H) 10.52 (s, 1H) 13.10 (br. s., 1H).
Reaction SMILES: [CH3:1][C:2]1[C:7]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+].I[CH2:25][CH3:26]>C(#N)C>[CH3:1][C:2]1[C:7]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:12]1[CH2:17][CH2:16][N:15]([CH2:25][CH3:26])[CH2:14][CH2:13]1
Reactant: CCI
Reactant: Cc1c(C2CCNCC2)cccc1S(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCN1CCC(c2cccc(S(C)(=O)=O)c2C)CC1

Procedure:
Preparation according to Example 1: 4-[2-methyl-3-(methyl-sulfonyl)phenyl]piperidine (0.17 g, 0.67 mmol), acetonitrile (20 ml), potassium carbonate (0.23 g, 1.67 mmol) and 1-iodoethane (0.065 ml, 0.74 mmol). Yield: 0.12 g (64%). MS m/z (relative intensity, 70 eV) 281 (M+, 22), 267 (17), 266 (bp), 129 (12), 115 (24).
Reaction SMILES: [OH-].[K+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:11](=[C:12]([O:14][CH3:15])[CH:13]=1)[N:10]([CH3:16])[CH:9]=[C:8]2[C:17]1[N:25](S(C2C=CC(C)=CC=2)(=O)=O)[C:20]2=[N:21][CH:22]=[CH:23][CH:24]=[C:19]2[CH:18]=1.O>CO>[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:11](=[C:12]([O:14][CH3:15])[CH:13]=1)[N:10]([CH3:16])[CH:9]=[C:8]2[C:17]1[NH:25][C:20]2=[N:21][CH:22]=[CH:23][CH:24]=[C:19]2[CH:18]=1
Reactant: COc1cc(OC)c2c(c1)c(-c1cc3cccnc3n1S(=O)(=O)c1ccc(C)cc1)cn2C
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1cc(OC)c2c(c1)c(-c1cc3cccnc3[nH]1)cn2C
Temperature: 80 °C
Yield: 35.4 %

Procedure:
3.3 ml of a 5N aqueous potassium hydroxide solution are added to a solution of 0.31 g of 2-(5,7-dimethoxy-1-methyl-1H-indol-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine in 20 ml of methanol. The mixture is heated at around 80° C. for approximately 18 hours. The reaction medium is run into a mixture of 100 ml of ice plus water, and extracted with three times 75 ml of ethyl acetate. The combined organic phases are washed with 100 ml of water and then with 100 ml of a saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (13 kPa). The residue is purified by flash chromatography on a silica column [eluent: dichloromethane]. 0.073 g of 2-(5,7-dimethoxy-1-methyl-1H-indol-3-yl)-1H-pyrrolo[2,3-b]pyridine is obtained in the form of a solid, the characteristics of which are as follows:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH:17]3[CH2:22][CH2:21][N:20]([CH:23]4[CH2:26][O:25][CH2:24]4)[CH2:19][CH2:18]3)=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:27]([O:30][CH2:31][C:32]1[C:37]([N:38]2[CH2:50][CH2:49][N:41]3[C:42]4[CH2:43][CH2:44][CH2:45][CH2:46][C:47]=4[CH:48]=[C:40]3[C:39]2=[O:51])=[CH:36][C:35]([F:52])=[CH:34][C:33]=1B1OC(C)(C)C(C)(C)O1)(=[O:29])[CH3:28].C(=O)([O-])[O-].[Na+].[Na+].COCCOC>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.C(Cl)Cl.CO>[C:27]([O:30][CH2:31][C:32]1[C:37]([N:38]2[CH2:50][CH2:49][N:41]3[C:42]4[CH2:43][CH2:44][CH2:45][CH2:46][C:47]=4[CH:48]=[C:40]3[C:39]2=[O:51])=[CH:36][C:35]([F:52])=[CH:34][C:33]=1[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH:17]3[CH2:22][CH2:21][N:20]([CH:23]4[CH2:26][O:25][CH2:24]4)[CH2:19][CH2:18]3)=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1)(=[O:29])[CH3:28]
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cc(F)cc1N1CCn2c(cc3c2CCCC3)C1=O
Reactant: Cn1cc(Br)cc(Nc2ccc(C3CCN(C4COC4)CC3)cn2)c1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: COCCOC
Solvent: CO
Product: CC(=O)OCc1c(-c2cc(Nc3ccc(C4CCN(C5COC5)CC4)cn3)c(=O)n(C)c2)cc(F)cc1N1CCn2c(cc3c2CCCC3)C1=O
Temperature: 130 °C
Yield: 69.1 %

Procedure:
Following Example 121b, 264c (210 mg, 0.5 mmol), 4-fluoro-2-(1-oxo-3,4,6,7,8,9-hexahydro-pyrazino[1,2-a]indol-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl acetate 210d (242 mg, 0.5 mmol), 1M sodium carbonate solution (2 mL, 2 mmol), tetrakis(triphenylphosphine)palladium(0) (29 mg, 0.025 mmol) and 1,2-dimethoxyethane (5 mL) were heated at 130° C. for 15 minutes in the microwave reactor. Work-up and flash column chromatography (silica, 9:1 methylene chloride/methanol) gave a 69% yield (240 mg) of 265a as brown oil: MS (ESI+) m/z 695.5 (M+H).
Reaction SMILES: C1(CC(CC(=O)NCCC2C=CC=CC=2)C([N:15](C(=O)[C@H](CC2N=CNC=2)N)N)=O)C2C(=CC=CC=2)C=CC=1.Cl.[C:40]1([CH2:50][CH:51]([CH2:67][C:68](=[O:78])[NH:69][CH2:70][CH2:71][C:72]2[CH:77]=[CH:76][CH:75]=[CH:74][CH:73]=2)[C:52]([NH:54][C@H:55]([C:62](N=[N+]=[N-])=[O:63])[CH2:56][C:57]2[N:61]=[CH:60][NH:59][CH:58]=2)=[O:53])[C:49]2[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=2)[CH:43]=[CH:42][CH:41]=1.[N-]=[N+]=[N-].Cl.[CH3:83][O:84][CH2:85][CH:86]([OH:93])[C@@H:87](N)[CH2:88][CH:89]([CH3:91])[CH3:90]>CN(C)C=O.N(OCCC(C)C)=O.C(N(CC)CC)C>[CH3:83][O:84][CH:85]([NH2:15])[CH:86]([OH:93])[C@@H:87]([C:62](=[O:63])[C@H:55]([CH2:56][C:57]1[N:61]=[CH:60][NH:59][CH:58]=1)[NH:54][C:52](=[O:53])[CH:51]([CH2:50][C:40]1[C:49]2[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=2)[CH:43]=[CH:42][CH:41]=1)[CH2:67][C:68](=[O:78])[NH:69][CH2:70][CH2:71][C:72]1[CH:73]=[CH:74][CH:75]=[CH:76][CH:77]=1)[CH2:88][CH:89]([CH3:91])[CH3:90]
Reactant: [N-]=[N+]=NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)C(CC(=O)NCCc1ccccc1)Cc1cccc2ccccc12
Reactant: COCC(O)[C@@H](N)CC(C)C
Reactant: N[C@@H](Cc1c[nH]cn1)C(=O)N(N)C(=O)C(CC(=O)NCCc1ccccc1)Cc1cccc2ccccc12
Agent: CC(C)CCON=O
Agent: Cl
Agent: [N-]=[N+]=[N-]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(N)C(O)[C@H](CC(C)C)C(=O)[C@H](Cc1c[nH]cn1)NC(=O)C(CC(=O)NCCc1ccccc1)Cc1cccc2ccccc12
Reaction time: 16 h

Procedure:
To a suspension of 130 mg of N-[(+)-2-(1-naphthylmethyl)-3-(phenethylcarbamoyl)propionyl]-L-histidine hydrazide in 6 ml of dry N,N-dimethylformamide were added successively dropwise 0.19 ml of a dry 5.1N-hydrogen chloride in N,N-dimethylformamide solution and 0.05 ml of isoamyl nitrite, and the mixture was stirred. After disappearance of hydrazide compound, the reaction mixture was cooled to -30° C., and neutralized by adding 0.14 ml of triethylamine to prepare a solution of N-[(+)-2-(1-naphthylmethyl)-3-(phenethylcarbamoyl)propionyl]-L-histidine azide. The azide solution prepared was added drowise to a solution of 52 mg of (2RS, 3S)-3-amino-2-hydroxy-5-methylhexyl methyl ether hydrochloride and 0.05 ml of triethylamine in 2 ml of dry N,N-dimethylformamide under ice-cooling, and the mixture was stirred for 16 hours under ice-cooling. The reaction mixture was evaporated under reduced pressure, and a 5% aqueous sodium bicarbonate solution was added to the residue. The mixture was extracted with ethyl acetate, and the ethyl acetate layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue was purified by preparative silica gel thin layer chromatography (developing solvent: lower layer of chloroform/methanol/water32 8/3/1 by volume) to obtain 55 mg of (2RS, 3S)-3-{N-[(+)-2-(1-naphthylmethyl)-3-(phenethylcarbamoyl)propionyl]-L-histidyl}-amino-2-hydroxy-5-methylhexyl methyl ether as a white powder.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.N1C=CC=CC=1.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1>O>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([S:23]([NH:1][C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=2)(=[O:25])=[O:24])=[CH:19][CH:18]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: N#Cc1ccc(N)cc1
Solvent: c1ccncc1
Solvent: O
Product: N#Cc1ccc(NS(=O)(=O)c2ccc(Cl)cc2)cc1
Temperature: 15 °C
Reaction time: 18 h
Yield: 76 %

Procedure:
To a solution of 4-aminobenzonitrile (2.36 g (20.0 mmol))in pyridine (10 ml), 4-chlorobenzenesulfonyl chloride (4.35 g (20.6 mmol)) was added under cooling in a water bath (15° C.). After 18 hours' stirring at room temperature, water (100 ml) was added to the reaction mixture and the stirring was continued to bring about separation of crystals, which were then collected by filtration and washed with water to give 4.45 g (76%) of 4-chloro-4′-cyanobenzenesulfonanilide as pale orange crystals.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][CH2:13][S:14](=[O:18])(=[O:17])[CH2:15][CH2:16][C:5]=3[C:4]=2[CH:3]=1.[H-].[Na+].[CH3:21][N:22]([CH3:27])[CH2:23][CH2:24][CH2:25]Cl>>[CH3:21][N:22]([CH3:27])[CH2:23][CH2:24][CH2:25][N:7]1[C:8]2[CH:9]=[CH:10][C:2]([Br:1])=[CH:3][C:4]=2[C:5]2[CH2:16][CH2:15][S:14](=[O:17])(=[O:18])[CH2:13][CH2:12][CH2:11][C:6]1=2
Reactant: O=S1(=O)CCCc2[nH]c3ccc(Br)cc3c2CC1
Reactant: CN(C)CCCCl
Agent: [H-]
Agent: [Na+]
Product: CN(C)CCCn1c2c(c3cc(Br)ccc31)CCS(=O)(=O)CCC2

Procedure:
A mixture of 9.0g (0.0276 mole) of 1,2,4,5,6,7-hexahydro-10-bromothiocino[5,4-b]indole 3,3-dioxide, 1.3g (0.03 mole) of 57% dispersion sodium hydride and 3.36g (0.0276 mole) of 3-dimethylaminopropyl chloride is treated according to the procedure in Example 6. After recrystallization from ethyl acetate, there is obtained 6.0g (52%) of an analytical sample, m.p. 135°-137° C.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[CH:7][CH:6]=1)=[O:4].[CH3:17][NH2:18].[C:19](=[O:30])(OC(C)(C)C)[O:20][C:21]([CH3:24])([CH3:23])[CH3:22]>C1COCC1>[O:4]=[C:3]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[CH:7][CH:6]=1)[CH2:2][N:18]([CH3:17])[C:19](=[O:30])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22]
Reactant: CN
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Reactant: O=C(CBr)c1ccc(N2CCOCC2)cc1
Solvent: C1CCOC1
Product: CN(CC(=O)c1ccc(N2CCOCC2)cc1)C(=O)OC(C)(C)C
Reaction time: 1 h
Yield: 38 %

Procedure:
2-Bromo-1-(4-morpholin-4-ylphenyl)ethanone (Tetrahedron Letters; 39, (1998), 4987-4990)(3.40 g, 11.97 mmol) was dissolved in dry THF (30 ml) under N2 and cooled in ice. A 2M solution of methylamine in THF (12 ml, 24 mmol) was added and the reaction stirred for 1 hr. The mixture was filtered and the filtrate treated with di-t-butyl carbonate (2.61 g, 12 mmol) at ice temperature. Stirring was continued for 24 hr then the solvent evaporated. Chromatography of the residue over silica gel (500 g) eluting with 1% MeOH-1% Et3N-EtOAc gave the product as a pale yellow solid (1.53 g, 38%): mp87-89°.
Reaction SMILES: N1C2C(=CC=CN=2)C(C(=O)C([O-])=O)=C1.[K+:15].[CH3:16][O:17][C:18]1[CH:26]=[N:25][C:24]([O:27][CH3:28])=[C:23]2[C:19]=1[C:20]([C:29](=[O:35])[C:30]([O:32]CC)=[O:31])=[CH:21][NH:22]2>>[CH3:16][O:17][C:18]1[CH:26]=[N:25][C:24]([O:27][CH3:28])=[C:23]2[C:19]=1[C:20]([C:29](=[O:35])[C:30]([O-:32])=[O:31])=[CH:21][NH:22]2.[K+:15]
Reactant: CCOC(=O)C(=O)c1c[nH]c2c(OC)ncc(OC)c12
Agent: O=C([O-])C(=O)c1c[nH]c2ncccc12
Agent: [K+]
Product: COc1ncc(OC)c2c(C(=O)C(=O)[O-])c[nH]c12

Procedure:
Compound 3ao (Potassium (4,7-dimethoxy-6-azaindol-3-yl)-oxoacetate) was prepared (as a yellow solid), by the same method used to prepare compound 3a except Ethyl (4,7-dimethoxy-6-azaindol-3-yl)-oxoacetate was employed as the starting material. MS m/z: (M+H)+ of the corresponding acid of compound 3ao (M-K+H)+ calcd for C11H11N2O5: 251.07; found 251.09. HPLC retention time: 0.69 minutes (column B).
Reaction SMILES: Cl[C:2]([O:4][C:5](Cl)(Cl)Cl)=[O:3].[Cl:9][C:10]1[CH:11]=[CH:12][C:13]2[O:17][N:16]=[C:15]([O:18][CH2:19][CH:20]([OH:23])CO)[C:14]=2[CH:24]=1.C([N:27](CC)CC)C>C1C=CC=CC=1>[C:2]([O:4][CH2:5][CH:20]([OH:23])[CH2:19][O:18][C:15]1[C:14]2[CH:24]=[C:10]([Cl:9])[CH:11]=[CH:12][C:13]=2[O:17][N:16]=1)(=[O:3])[NH2:27]
Reactant: CCN(CC)CC
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: OCC(O)COc1noc2ccc(Cl)cc12
Solvent: c1ccccc1
Product: NC(=O)OCC(O)COc1noc2ccc(Cl)cc12
Temperature: 10 °C
Reaction time: 0.5 h
Yield: 135.8 %

Procedure:
5.9 g (29.8 mmoles) of trichloromethyl chloroformate were added dropwise at 10° C. to a solution of 16.0 g (55.8 mmoles) of 5-chloro-3-(2,3-dihydroxypropoxy)-1,2-benzisoxazole [prepared as described in step (a) above] in 500 ml of dry benzene; the mixture was then stirred at the same temperature for 30 minutes, after which 6.1 g (60.3 mmoles) of triethylamine were added dropwise at 10°-15° C. The mixture was then stirred for a further 1 hour at 5°-10° C., after which insoluble materials were removed by filtration and washed with 100 ml of dry benzene. The filtrate and washings were combined, and cooled to 10° C., and then 38.0 ml (304.0 mmoles) of 28% v/v aqueous ammonia were added thereto at one time. The mixture was then stirred at room temperature for 2 hours, after which it was heated under reflux for an additional 2 hours. The reaction mixture was then concentrated by evaporation under reduced pressure, and 38.0 ml (304.0 mmoles) of 28% v/v aqueous ammonia and 200 ml of ethanol were added to the residue. The resulting mixture was then heated under reflux for a further 2 hours. At the end of this time, the reaction mixture was cooled by allowing it to stand, and the cooled mixture was then concentrated by evaporation under reduced pressure. The residue was purified by column chromatography through silica gel, eluted with a 1:2 by volume mixture of benzene and ethyl acetate, followed by recrystallization from ethyl acetate, to give 11.6 g (72.5%) of the title compound as a colorless amorphous powder, melting at 123°-124° C.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:21]=[CH:20][C:6]([NH:7][CH:8]=[C:9]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:5]([I:22])[CH:4]=1.[C:23](OC(=O)C)(=[O:25])[CH3:24].O>C(O)(=O)C>[C:23]([O:1][CH2:2][C:3]1[CH:21]=[CH:20][C:6]([NH:7][CH:8]=[C:9]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:5]([I:22])[CH:4]=1)(=[O:25])[CH3:24]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)C(=CNc1ccc(CO)cc1I)C(=O)OCC
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)C(=CNc1ccc(COC(C)=O)cc1I)C(=O)OCC
Temperature: 25 °C
Yield: 87 %

Procedure:
A solution of diethyl 2-{[4-(hydroxymethyl)-2-iodoanilino]methylene}malonate (0.20 g) and acetic anhydride (0.054 mL) in acetic acid (0.24 mL) is heated at 80° C. overnight. The reaction is cooled to room temperature and poured into 50 mL of water. The resulting solid is filtered and dried to yield 0.19 g (87%) of diethyl 2-({4-[(acetyloxy)methyl]-2-iodoanilino}methylene)malonate as a white solid, m.p. 128-131° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[C:19]2[C:10](=[C:11]3[C:16](=[CH:17][CH:18]=2)[CH:15]=[CH:14][CH:13]=[N:12]3)[N:9]=[C:8]([CH3:20])[CH:7]=1.[O:21]1CCOCC1>O>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[C:19]2[C:10](=[C:11]3[C:16](=[CH:17][CH:18]=2)[CH:15]=[CH:14][CH:13]=[N:12]3)[N:9]=[C:8]([CH:20]=[O:21])[CH:7]=1
Reactant: C1COCCO1
Reactant: COCCOc1cc(C)nc2c1ccc1cccnc12
Solvent: O
Product: COCCOc1cc(C=O)nc2c1ccc1cccnc12
Yield: 53 %

Procedure:
A solution of SeO2 (1.19 g, 10.8 mmol) in a mixture of dioxane (50 mL) and water (2 mL) was heated to reflux in a two-neck 250 mL round-bottomed flask. A solution of 4-(2-methoxy-ethoxy)-2-methyl-[1,10]phenanthroline (1.16 g, 4.3 mmol) in hot dioxane (30 mL) was added through an addition funnel over a period of 10 minutes and the reaction mixture was refluxed for 30 minutes. The solvent was evaporated in vacuo and the residue was treated with methylene chloride (200 mL) and saturated NaHCO3 (200 mL). The aqueous layer was extracted several times with methylene chloride (3×100 mL) and the combined organic layers were washed with brine, dried (Na2SO4), filtered and evaporated. The crude product was purified by flash chromatography (SiO2, MeOH/DCM, 1:40 to 1:20) to afford the pure product as a pale solid (0.65 g, 53%).
Reaction SMILES: [F:1][CH:2]([F:36])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]3[CH:14]=[C:15]([O:18]C)[CH:16]=[CH:17][C:11]=3[C:10]=2[O:20][C:21]2[CH:26]=[CH:25][C:24](/[CH:27]=[CH:28]/[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[CH:23][CH:22]=2)=[CH:5][CH:4]=1.C1(S)C=CC=CC=1.C([O-])([O-])=O.[K+].[K+]>CN1CCCC1=O>[F:36][CH:2]([F:1])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[S:13][C:12]3[CH:14]=[C:15]([OH:18])[CH:16]=[CH:17][C:11]=3[C:10]=2[O:20][C:21]2[CH:26]=[CH:25][C:24](/[CH:27]=[CH:28]/[C:29]([O:31][C:32]([CH3:34])([CH3:33])[CH3:35])=[O:30])=[CH:23][CH:22]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc2c(Oc3ccc(/C=C/C(=O)OC(C)(C)C)cc3)c(-c3ccc(C(F)F)cc3)sc2c1
Agent: O=C([O-])[O-]
Agent: Sc1ccccc1
Agent: [K+]
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)/C=C/c1ccc(Oc2c(-c3ccc(C(F)F)cc3)sc3cc(O)ccc23)cc1
Yield: 62.2 %

Procedure:
To a microwave vial containing (E)-tert-butyl 3-(4-((2-(4-(difluoromethyl)phenyl)-6-methoxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylate (50 mg, 0.098 mmol) in N-methyl-2-pyrrolidone (1.0 mL) was added thiophenol (0.015 mL, 0.147 mmol) followed by K2CO3 (14 mg, 0.098 mmol). The resulting mixture was subjected to microwave irradiation for 1 h at 200° C. after which time the reaction was quenched with brine and extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the crude material which was purified by column chromatography (SiO2, 0-30% EtOAc/Heptane) to afford (E)-tert-butyl 3-(4-((2-(4-(difluoromethyl)phenyl)-6-hydroxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylate (30 mg, 0.061 mmol, 62% yield). LC/MS (m/z, M−H): 493.5