Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:4][NH:5][C:6]2[N:14]=[CH:13][N:12]=[C:11]3[C:7]=2[N:8]=[CH:9][N:10]3[C@H:15]2[CH2:19][CH2:18][C@@H:17]([CH2:20][OH:21])[O:16]2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:29][O:30][CH2:31][C:32](Cl)=[O:33]>CN(C)C1C=CN=CC=1.C(#N)C>[CH:1]1([CH2:4][NH:5][C:6]2[N:14]=[CH:13][N:12]=[C:11]3[C:7]=2[N:8]=[CH:9][N:10]3[C@H:15]2[CH2:19][CH2:18][C@@H:17]([CH2:20][O:21][C:32](=[O:33])[CH2:31][O:30][CH3:29])[O:16]2)[CH2:2][CH2:3]1
Reactant: COCC(=O)Cl
Reactant: OC[C@@H]1CC[C@H](n2cnc3c(NCC4CC4)ncnc32)O1
Agent: CN(C)c1ccncc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COCC(=O)OC[C@@H]1CC[C@H](n2cnc3c(NCC4CC4)ncnc32)O1
Temperature: 25 °C
Reaction time: 6 h
Yield: 54.6 %

Procedure:
6-(Cyclopropylmethylamino)-9-[(2R,5S)-tetrahydro-5-(hydroxymethyl)-2-furyl]-9H-purine (0.319 g, 1.1 mmoles), 4-dimethylaminopyridine (10 mg, 0.1 mmoles, Aldrich Chemical Co., Madison, Wis.), and triethylamine (1.0 mL, 7 mmoles, Aldrich Chemical Co., Madison, Wis.) were dissolved in 50 mL acetonitrile. Methoxyacetyl chloride (460 μm, 5.0 mmoles, Aldrich Chemical Co., Madison, Wis.) was added and the reaction was stirred at room temperature for 6 hours. The reaction was quenched with methanol and solvents were evaporated in vacuo. The residue was dissolved in acetone and passed over a silica gel column (4.8×13 cm). The UV absorbing eluent was concentrated and separated on a Chromatotron (4 mm silica gel plate) with a mixture of chloroform:acetone (95:5). Solvents were removed in vacuo and the residue was further purified on a preparative silica gel plate (20×20×0.2 cm) developed in a mixture of chloroform:acetone (70:30). The product was scraped from the preparative plate and eluted from the silica gel with ethanol. Lyophilization afforded 0.217 g of 6-(cyclopropylmethylamino)-9-[(2R,5S)-5-[(methoxyacetoxy)methyl]-tetrahydro-2-furyl]-9H-purine as an oil (53% yield).
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:12]=1[Cl:18])C=C.O.CN1C[CH2:24][CH2:23][C:22]1=O>>[CH2:24]([C:10]1[CH:9]=[CH:8][CH:7]=[C:6]([C:11]2[C:12]([Cl:18])=[CH:13][CH:14]=[CH:15][C:16]=2[Cl:17])[C:5]=1[OH:4])[CH:23]=[CH2:22]
Reactant: CN1CCCC1=O
Reactant: C=CCOc1ccccc1-c1c(Cl)cccc1Cl
Solvent: O
Product: C=CCc1cccc(-c2c(Cl)cccc2Cl)c1O
Reaction time: 120 h
Yield: 83 %

Procedure:
A solution of 2′-(allyloxy)-2,6-dichloro-1,1′-biphenyl (5.7 g, 0.0204 mol) in anhydrous 1-methyl-2-pyrrolidinone (50 mL) was heated to 180° C. for 42 hours then at 190° C. for 5 days. The cooled reaction mixture was poured into water (300 mL), the mixture stirred vigorously for 15 minutes then the resulting oily suspension extracted with ethyl acetate (400 mL). The organic extract was washed with water (300 mL) and saturated brine (300 mL), dried over magnesium sulfate and concentrated under reduced pressure to afford a brown oil. Purification by flash chromatography using a solvent gradient of 2 to 4% ethyl acetate in hexane gave 4.71 g (83%) of 3-allyl-2′,6′-dichloro-1,1′-biphenyl-2-ol as a colorless oil. MS (ES) m/z 278.9 ([M+H]+).
Reaction SMILES: S1C=CC=C1.C([Li])CCC.Cl[Si:12]([CH2:15][Cl:16])([CH3:14])[CH3:13].[NH4+].[Cl-].[CH2:19]([O:21][CH2:22][CH3:23])[CH3:20]>>[Cl:16][CH2:15][Si:12]([CH3:14])([CH3:13])[C:19]1[O:21][CH:22]=[CH:23][CH:20]=1
Reactant: CCOCC
Reactant: C[Si](C)(Cl)CCl
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: c1ccsc1
Product: C[Si](C)(CCl)c1ccco1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Dissolve thiophene (4.76 g, 56.5 mmol) in dry diethyl ether. Add n-butyl lithium (62.2 mmol) at room temperature and stir overnight under nitrogen. Cool the mixture to 0° C., add chloro(chloromethyl)dimethylsilane (8.1 g, 56.5 mmol, in 2.5 mL diethyl ether) slowly and stir overnight under nitrogen. Add saturated NH4Cl solution to the reaction mixture. Drain off the aqueous phase and wash the organic phase with brine. Dry the organic phase over Na2SO4, filter and concentrate in vacuo. Distill the residue in a kugelrohr to afford chloromethyl(dimethyl)furylsilane (4.4 g).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([C:12]3[CH:17]=[C:16]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)[N:15]=[C:14]([NH2:25])[N:13]=3)[CH2:9]2)=[CH:4][CH:3]=1.[CH2:26]([O:28][C:29]1[CH:34]=[CH:33][C:32]([CH2:35][N:36]2[CH:40]=[C:39](B3OC(C)(C)C(C)(C)O3)[CH:38]=[N:37]2)=[CH:31][N:30]=1)[CH3:27]>>[CH2:26]([O:28][C:29]1[N:30]=[CH:31][C:32]([CH2:35][N:36]2[CH:40]=[C:39]([C:2]3[CH:11]=[C:10]4[C:5]([CH2:6][CH2:7][N:8]([C:12]5[CH:17]=[C:16]([N:18]6[CH2:19][CH2:20][N:21]([CH3:24])[CH2:22][CH2:23]6)[N:15]=[C:14]([NH2:25])[N:13]=5)[CH2:9]4)=[CH:4][CH:3]=3)[CH:38]=[N:37]2)=[CH:33][CH:34]=1)[CH3:27]
Reactant: CN1CCN(c2cc(N3CCc4ccc(Br)cc4C3)nc(N)n2)CC1
Reactant: CCOc1ccc(Cn2cc(B3OC(C)(C)C(C)(C)O3)cn2)cn1
Product: CCOc1ccc(Cn2cc(-c3ccc4c(c3)CN(c3cc(N5CCN(C)CC5)nc(N)n3)CC4)cn2)cn1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 2 starting from 4-(7-bromo-3,4-dihydroisoquinolin-2(1H)-yl)-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine and 2-ethoxy-5-{[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]methyl}pyridine. LCMS(M+H)+: m/z=526.4
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[NH:7][N:8]1[CH:12]=[CH:11][CH:10]=[CH:9]1)([CH3:4])([CH3:3])[CH3:2].[Cl:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19]Cl)=[CH:17][CH:16]=1.[H-].[Na+]>>[C:1]([O:5][C:6](=[O:13])[N:7]([CH2:19][C:18]1[CH:21]=[CH:22][C:15]([Cl:14])=[CH:16][CH:17]=1)[N:8]1[CH:12]=[CH:11][CH:10]=[CH:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: ClCc1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)Nn1cccc1
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)N(Cc1ccc(Cl)cc1)n1cccc1

Procedure:
Prepared according to the benzylation condition used in Example 1 step b) from pyrrol-1-yl-carbamic acid tert-butyl ester (1.0 eq.), 4-chlorobenzyl chloride (1.03 eq.) and sodium hydride (1.3 eq.). ESI (m/z): 307 (M+H)+.
Reaction SMILES: [CH:1]1([N:7]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[C:8]([NH:10][C:11]2[S:12][C:13]([CH:16]=O)=[CH:14][N:15]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[O:25]=[S:26]1(=[O:32])[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[CH:1]1([N:7]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[C:8]([NH:10][C:11]2[S:12][C:13]([CH2:16][N:29]3[CH2:30][CH2:31][S:26](=[O:32])(=[O:25])[CH2:27][CH2:28]3)=[CH:14][N:15]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=S1(=O)CCNCC1
Reactant: O=Cc1cnc(NC(=O)N(C2CCCCC2)C2CCCCC2)s1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Product: O=C(Nc1ncc(CN2CCS(=O)(=O)CC2)s1)N(C1CCCCC1)C1CCCCC1
Yield: 17.6 %

Procedure:
Prepared as described in general procedure (P) using 1,1-dicyclohexyl-3-(5-formyl-thiazol-2-yl)-urea (67 mg. 0.20 mmol), 1,1-dioxo-thiomorpholine hydrochloride (52 mg, 0.30 mmol) and sodium triacetoxyborohydride (51 mg, 0.24 mmol) to afford 16 mg (18%) of the desired product after purification.
Reaction SMILES: [CH2:1]([Sn:5]([CH2:23][CH2:24][CH2:25][CH3:26])([CH2:19][CH2:20][CH2:21][CH3:22])[C:6]1[CH:7]=[C:8]([C:12]2[O:16][C:15]([CH:17]=O)=[CH:14][CH:13]=2)[CH:9]=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH3:4].[CH2:27]([O:29][C:30](=[O:39])[CH2:31][N:32]1[C:36](=[O:37])[CH2:35][NH:34][C:33]1=[S:38])[CH3:28].N1CCCCC1>ClCCl>[CH2:27]([O:29][C:30](=[O:39])[CH2:31][N:32]1[C:36](=[O:37])/[C:35](=[CH:17]/[C:15]2[O:16][C:12]([C:8]3[CH:9]=[CH:10][CH:11]=[C:6]([Sn:5]([CH2:1][CH2:2][CH2:3][CH3:4])([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:19][CH2:20][CH2:21][CH3:22])[CH:7]=3)=[CH:13][CH:14]=2)/[NH:34][C:33]1=[S:38])[CH3:28]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccc(-c2ccc(C=O)o2)c1
Reactant: CCOC(=O)CN1C(=O)CNC1=S
Solvent: ClCCl
Solvent: C1CCNCC1
Product: CCCC[Sn](CCCC)(CCCC)c1cccc(-c2ccc(/C=C3\NC(=S)N(CC(=O)OCC)C3=O)o2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-(3-(Tributylstannyl)phenyl)furan-2-carbaldehyde (10 mg, 0.022 mmol) synthesized by the same method as in Example 4 and ethyl-2-(5-oxo-2-thioxoimidazolidin-1-yl)acetate (4.4 mg, 0.022 mmol) synthesized by the same method as in Example 2 were dissolved in dichloromethane (3 mL), piperidine (5 μL) was added thereto, and the mixture was stirred at room temperature (25° C.) overnight. After the reaction was completed the solvent was removed by evaporation under reduced pressure, and the residue was subjected to silica gel column chromatography using ethyl acetate/hexane (3/7 (volume ratio)) as an eluent, to give labeling precursor 2 in a yield of 11 mg (74.0%).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][C:5]=1[C:6](O)=[O:7])([O-:3])=[O:2].[CH3:17][NH:18][O:19][CH3:20].CN1CCOCC1.C[N+]1(C2N=C(OC)N=C(OC)N=2)CCOCC1.[Cl-]>C1COCC1>[CH3:20][O:19][N:18]([CH3:17])[C:6](=[O:7])[C:5]1[CH:9]=[CH:10][C:11]([C:13]([F:16])([F:15])[F:14])=[CH:12][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: CNOC
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CON(C)C(=O)c1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Yield: 87.3 %

Procedure:
2-Nitro-4-trifluoromethyl-benzoic acid (2.753 mg, 11.7 mmol) in THF was reacted with N,O-dimethylhydroxy amine (1.277 g, 13.1 mmol), NMM (3 ml) and DMTMM (3.34 g) at room temperature overnight. The reaction mixture was quenched by adding H2O. The mixture was extracted with ethyl acetate (50 ml×3). The combined organic layer was washed 1M NaHCO3 (50 ml×2), 3% HCl (50 ml×2) and brine (50 ml), and then dried over MgSO4. The filterate was concentrated in vacuo to yield the title compound (2.84 g, 87%).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.Br[CH:17]([CH3:21])[C:18](=O)[CH3:19]>>[CH3:21][C:17]1[N:1]=[C:2]2[C:7]([O:8][CH2:9][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)=[CH:6][CH:5]=[N:4][N:3]2[C:18]=1[CH3:19]
Reactant: CC(=O)C(C)Br
Reactant: Nc1nnccc1OCc1ccccc1
Product: Cc1nc2c(OCc3ccccc3)ccnn2c1C

Procedure:
Similarly, condensation of the 3-amino-4-phenylmethoxypyridazine with 3-bromo-2-butanone gives the 2,3-dimethyl-8-phenylmethoxyimidazo[1,2-b]pyridazine as shown in the following reaction Scheme IV: ##STR16##
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([S:8]([NH:11][C:12](=[O:14])[CH3:13])(=[O:10])=[O:9])[CH:5]=[CH:4][CH:3]=1.[S:15]1[CH:19]=[CH:18][N:17]=[C:16]1[C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.Cl[Pd](Cl)(P(C(C)(C)C)(C(C)(C)C)O)P(O)(C(C)(C)C)C(C)(C)C>[N:22]1[CH:23]=[CH:24][CH:25]=[C:20]([C:16]2[S:15][C:19]([C:2]3[N:7]=[C:6]([S:8]([NH:11][C:12](=[O:14])[CH3:13])(=[O:10])=[O:9])[CH:5]=[CH:4][CH:3]=3)=[CH:18][N:17]=2)[CH:21]=1
Reactant: CC(=O)NS(=O)(=O)c1cccc(Br)n1
Reactant: c1cncc(-c2nccs2)c1
Agent: CC(C)(C)[PH](O)(C(C)(C)C)[Pd](Cl)(Cl)[PH](O)(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(=O)NS(=O)(=O)c1cccc(-c2cnc(-c3cccnc3)s2)n1

Procedure:
N-[(6-Bromopyridin-2-yl)sulphonyl]acetamide (0.112 g, 0.4 mmol), 3-(1,3-thiazol-2-yl)pyridine (0.065 g, 0.4 mmol, prepared by the methods described in WO 2010/006713), dichloro{bis[di-tert-butyl(hydroxy)phosphoranyl]}palladium (0.006 g, 0.012 mmol) and caesium carbonate (0.26 g, 0.8 mmol) were stirred in 10 ml of N,N-dimethylformamide at 120° C. under argon for 16 h. After cooling, the solvent was removed under reduced pressure and the residue was chromatographed (silica gel, dichloromethane/methanol eluent). This gave 0.024 g (15% of theory) of N-({6-[2-(pyridin-3-yl)-1,3-thiazol-5-yl]pyridin-2-yl}sulphonyl)acetamide.
Reaction SMILES: [C@@H:1]12[N:8]([C:9]3[CH:18]=[N:17][C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[N:10]=3)[CH2:7][C@@H:6]1[CH2:5][CH2:4][NH:3][CH2:2]2.C1(C2C=CN=C(N3C4C(CCNC4)C3)N=2)C=CC=CC=1.[CH3:39][C:40]1[CH:45]=[C:44]([CH3:46])[CH:43]=[CH:42][C:41]=1[S:47](Cl)(=[O:49])=[O:48].CC1C=CC(C)=CC=1S(Cl)(=O)=O>>[CH3:39][C:40]1[CH:45]=[C:44]([CH3:46])[CH:43]=[CH:42][C:41]=1[S:47]([N:3]1[CH2:4][CH2:5][C@@H:6]2[C@@H:1]([N:8]([C:9]3[CH:18]=[N:17][C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[N:10]=3)[CH2:7]2)[CH2:2]1)(=[O:48])=[O:49]
Reactant: Cc1ccc(S(=O)(=O)Cl)c(C)c1
Reactant: c1ccc2nc(N3C[C@@H]4CCNC[C@@H]43)cnc2c1
Agent: Cc1ccc(C)c(S(=O)(=O)Cl)c1
Agent: c1ccc(-c2ccnc(N3CC4CCNCC43)n2)cc1
Product: Cc1ccc(S(=O)(=O)N2CC[C@H]3CN(c4cnc5ccccc5n4)[C@H]3C2)c(C)c1

Procedure:
The title compound was prepared in a manner analogous to Example 19, substituting (1R,6S)-2-(3,8-diaza-bicyclo[4.2.0]oct-8-yl)-quinoxaline (Intermediate 3) for 8-(4-phenyl-pyrimidin-2-yl)-3,8-diaza-bicyclo[4.2.0]octane and 2,4-dimethyl-benzenesulfonyl chloride for 2,5-dimethyl-benzenesulfonyl chloride. MS (ESI) mass calcd. for C22H24N4O2S, 408.52; m/z found 409.2 [M+H]+. 1H NMR (400 MHz, CDCl3): 7.96 (s, 1H), 7.86 (dd, J=8.2, 1.3, 1H), 7.66 (d, J=1.2, 1H), 7.58-7.52 (m, 1H), 7.49 (dd, J=8.4, 1.1, 1H), 7.43-7.37 (m, 1H), 6.62-6.48 (m, 2H), 4.69-4.61 (m, 1H), 4.22-3.95 (m, 4H), 3.85-3.74 (m, 1H), 3.69-3.59 (m, 1H), 3.41 (dd, J=14.0, 2.8, 1H), 3.05-2.89 (m, 1H), 2.42 (s, 3H), 2.30-2.14 (m, 1H), 2.09 (s, 3H), 2.05-1.92 (m, 1H).
Reaction SMILES: [C:1]([N:11]1[CH2:16][CH2:15][NH:14][CH:13]([C:17]([OH:19])=[O:18])[CH2:12]1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[F:20][C:21]1[CH:26]=[C:25]([N+:27]([O-:29])=[O:28])[C:24](F)=[CH:23][C:22]=1[F:31]>>[C:1]([N:11]1[CH2:16][CH2:15][N:14]([C:24]2[CH:23]=[C:22]([F:31])[C:21]([F:20])=[CH:26][C:25]=2[N+:27]([O-:29])=[O:28])[CH:13]([C:17]([OH:19])=[O:18])[CH2:12]1)([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2]
Reactant: O=[N+]([O-])c1cc(F)c(F)cc1F
Reactant: O=C(O)C1CN(C(=O)OCc2ccccc2)CCN1
Product: O=C(O)C1CN(C(=O)OCc2ccccc2)CCN1c1cc(F)c(F)cc1[N+](=O)[O-]
Yield: 16.7 %

Procedure:
By the same procedure described for example 2 method 2B, from 1.5 g of racemic 4-carbobenzyloxypiperazine-2-carboxylic acid and 1,2,4-trifluoro-5-nitro-benzene, there was obtained 0.4 g (16.7%) of title compound as an orange-red residue.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:8]([NH2:9])=[CH:7][S:6][CH:5]=1.C(N(C(C)C)C(C)C)C.[CH3:19][C:20]1[C:21]([N:25]=[C:26]=[S:27])=[CH:22][S:23][CH:24]=1>O1CCCC1>[NH2:3][C:4]1[C:8]([NH:9][C:26]([NH:25][C:21]2[C:20]([CH3:19])=[CH:24][S:23][CH:22]=2)=[S:27])=[CH:7][S:6][CH:5]=1
Reactant: Nc1cscc1N
Reactant: Cc1cscc1N=C=S
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1cscc1NC(=S)Nc1cscc1N
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 1.87 g of 3,4-diaminothiophene dihydrochloride, 60 ml of anhydrous tetrahydrofuran (THF) and 2.58 g of N-ethyl-N,N-diisopropylamine was stirred at room temperature for 30 minutes and then admixed with 1.5 g of 4-methyl-3-thienyl isothiocyanate. After stirring over approx. 18 hours, the solvent was distilled off, the residue admixed with water and extracted repeatedly with ethyl acetate. After the combined organic phases had been treated with activated carbon, they were dried over sodium sulfate and the solvent was once again distilled off. The N-(3-amino-4-thienyl)-N′-(4-methyl-3-thienyl)thiourea was obtained as an amorphous foamy solid.
Reaction SMILES: S([O-])([O-])(=O)=O.N[C:7]1[CH:14]=[CH:13][C:10]([CH:11]=[O:12])=[CH:9][CH:8]=1.S(=O)(=O)(O)[OH:16]>>[OH:16][C:7]1[CH:14]=[CH:13][C:10]([CH:11]=[O:12])=[CH:9][CH:8]=1
Reactant: O=S(=O)(O)O
Reactant: Nc1ccc(C=O)cc1
Agent: O=S(=O)([O-])[O-]
Product: O=Cc1ccc(O)cc1
Reaction time: 1 h

Procedure:
The procedure of Example 8 was followed except that the production of the sulphate of p-aminobenzaldehyde by reaction with sulphuric acid in 40% aqueous solution was effected at 40° C. for one hour, to obtain 2.0 g (0.016 mol) of p-hydroxybenzaldehyde. The yield thereof was 41%, based on the weight of p-aminobenzaldehyde used.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:6][CH:5]=1.CN(CCN(C)C)C.C([Li])(CC)C.C1CCCCC1.C1C[O:42][CH2:41]C1>CN(C)C=O>[CH:41]([C:6]1[CH:5]=[C:4]([O:3][C:2]([F:18])([F:19])[F:1])[CH:9]=[CH:8][C:7]=1[NH:10][C:11](=[O:17])[O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:42]
Reactant: CC(C)(C)OC(=O)Nc1ccc(OC(F)(F)F)cc1
Reactant: C1CCOC1
Agent: CN(C)CCN(C)C
Agent: [Li]C(C)CC
Solvent: C1CCCCC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1ccc(OC(F)(F)F)cc1C=O
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A magnetically stirred solution of tert-butyl 4-(trifluoromethoxy)phenylcarbamate (19.95 g, 72 mmol) and TMEDA (16.7 g, 144 mmol) in THF (300 mL) at −78° C. was treated with the dropwise addition of a 1.4M solution of sec-butyllithium in cyclohexane (170 mL, 237 mmol), at a rate which maintained the internal temperature below −60° C. The mixture was stirred for 1 h at −78° C., then allowed to warm to −50° C. and stirred an additional 30 min. The solution was returned to −78° C., treated with the dropwise addition of N,N-dimethylformamide, at a rate which maintained the internal temperature below −60° C. The reaction was stirred at −78° C. for 30 min, allowed to warm to −20° C., then quenched with the addition of saturated ammonium chloride solution (200 mL). The mixture was transferred to a 1 L seperatory funnel, diluted with diethyl ether (400 mL), and the layers were separated. The organic phase was washed successively with saturated ammonium chloride solution (100 mL), water (100 mL), and brine (100 mL), dried over sodium sulfate, and concentrated in-vacuo to a yellow solid. The solid was purified over silica gel, eluting with 5% ethyl acetate/hexanes, to yield 18.36 g of a colorless solid as product. 1H NMR (400 MHz, CDCl3) δ ppm 1.55 (m, 9 H) 7.26 (s, 4 H) 7.43 (dd, J=9.23, 2.64 Hz, 6 H) 7.48 (s, 1 H) 8.54 (d, J=9.23 Hz, 1 H) 9.88 (s, 1 H) 10.33 (s, 1 H).
Reaction SMILES: Cl.[NH2:2][OH:3].C([O-])(O)=O.[Na+].[CH:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][C:10]=1[NH:19][S:20]([C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][C:31](Cl)=[O:32])[CH:26]=[CH:27][CH:28]=1)(=[O:22])=[O:21]>O1CCCC1>[OH:3][NH:2][C:31](=[O:32])[CH:30]=[CH:29][C:25]1[CH:26]=[CH:27][CH:28]=[C:23]([S:20](=[O:22])(=[O:21])[NH:19][C:10]2[CH:11]=[CH:12][C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:9]=2)[CH:24]=1
Reactant: NO
Reactant: O=C(Cl)C=Cc1cccc(S(=O)(=O)Nc2ccc3ccccc3c2)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(C=Cc1cccc(S(=O)(=O)Nc2ccc3ccccc3c2)c1)NO
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.3 %

Procedure:
To a suspension of hydroxylamine hydrochloride (0.2 g, 2.85 mmol) in tetrahydrofuran (3.5 ml) a saturated NaHCO3 solution (2.3 ml) was added and the resultant mixture was stirred at ambient temperature for 10 min. To the reaction mixture a solution of crude 3-[3-(naphthalen-2-ylsulfamoyl)-phenyl]-acryloyl chloride (16e) (0.21 g) in tetrahydrofuran (2.5 ml) was added and the mixture was stirred at ambient temperature for one hour. The reaction mixture was partitioned between ethyl acetate and 2N HCl. The organic layer was washed successively with water and saturated NaCl, then the solvent was removed. The residue was washed with diethyl ether and potroleum ether-ethyl acetate (3:1) affording the title compound (0.14 g, 68%). M.p. 164° C. 1H NMR (DMSO-d6, HMDSO) δ: 6.49 (1H, d, J=16.0 Hz); 7.16-7.89 (12H, m); 7.98 (1H, br s); 10.52 (1H, s); 10.76 (1H, br s). HPLC analysis on Symmetry C18 column: impurities 5% (column size 3.9×150 mm; mobile phase acetonitrile-0.1M phosphate buffer (pH 2.5), 50:50; sample concentration 0.5 mg/ml; flow rate 0.8 ml/min; detector UV 220 nm). Anal. Calcd for C19H16N2O4S, %: C, 61.94; H, 4.38; N, 7.60. Found %: C, 61.44; H, 4.39; N, 7.48.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]2[CH:8]=[N:9][NH:10][C:4]=2[CH:3]=1.C1COCC1.CS(O)(=O)=O.[O:21]1[CH:26]=[CH:25][CH2:24][CH2:23][CH2:22]1>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[CH:6][C:5]2[CH:8]=[N:9][N:10]([CH:22]3[CH2:23][CH2:24][CH2:25][CH2:26][O:21]3)[C:4]=2[CH:3]=1
Reactant: C1=COCCC1
Reactant: Clc1cc2[nH]ncc2cn1
Agent: CS(=O)(=O)O
Solvent: ClCCl
Solvent: C1CCOC1
Product: Clc1cc2c(cn1)cnn2C1CCCCO1
Temperature: 25 °C
Reaction time: 2 h
Yield: 112.2 %

Procedure:
At r.t. to a suspension of 6-chloro-1H-pyrazolo[4,3-c]pyridine (0.5 g, 3 mmol) (Frontier Cat. No. Z13659) in methylene chloride (3 mL) and THF (1 mL) was added methanesulfonic acid (42 μL, 0.65 mmol), followed by dihydropyran (0.89 mL, 9.8 mmol). The mixture was stirred at r.t. for 2 h., and then at 50° C. overnight. After cooling the mixture was concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column with ethyl acetate in hexanes (0-50%) to afford the desired product (0.8 g). LCMS (M+H)+=238.0; LCMS (M-84+H)+=154.0/156.0.
Reaction SMILES: [C:1]1([CH3:12])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8]([O:10][CH3:11])=[O:9].C[O-].[Na+].[CH:16](OC)=[O:17].C1(C)C=CC=CC=1>C1(C)C=CC=CC=1.O>[OH:17][CH:16]=[C:7]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[CH3:12])[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)Cc1ccccc1C
Reactant: COC=O
Agent: C[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)C(=CO)c1ccccc1C
Temperature: 25 °C
Reaction time: 12 h
Yield: 95 %

Procedure:
To a three neck flask (1000 mL), 50 g of methyl 2-o-tolylacetate and 600 mg of toluene were added, and then 54.3 g of sodium methoxide was further added with stiffing. The mixture was cooled with an ice-water bath to less than 10° C., and then a mixture of methyl formate (65 mL) and toluene (50 mL) was dripped. After that, the ice-water bath was removed and the temperature was raised slowly to room temperature. The solution was allowed to react with stirring for 12 hrs, and then dumped into 1000 mL of water, shaken, standed for demix. The organic layer was extracted with 500 mL of water twice. The water layer was combined, acidized with 6M hydrochloric acid to pH value of 4-5, extracted with ethyl acetate, dried with anhydrous magnesium sulfate, and distilled under vacuum condition to yield 55.9 g of light red oily product with a yield of 95%.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[CH:7][NH:8]2)([O-:3])=[O:2].[Cl-].[Cl:14][C:15]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:16]=1[CH:17]=[N+:18]([CH3:20])[CH3:19].ClC1C=C(F)C=CC=1C=O.CNC>>[Cl:14][C:15]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:16]=1[CH:17]([N:18]([CH3:20])[CH3:19])[C:6]1[C:5]2[C:9](=[CH:10][CH:11]=[CH:12][C:4]=2[N+:1]([O-:3])=[O:2])[NH:8][CH:7]=1
Reactant: O=[N+]([O-])c1cccc2[nH]ccc12
Reactant: C[N+](C)=Cc1ccc(F)cc1Cl
Agent: CNC
Agent: O=Cc1ccc(F)cc1Cl
Agent: [Cl-]
Product: CN(C)C(c1ccc(F)cc1Cl)c1c[nH]c2cccc([N+](=O)[O-])c12

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 4-nitroindole and (2-chloro-4-fluoro-benzylidene)-dimethyl-ammonium chloride, which had been prepared in accordance with example 24 from 2-chloro-4-fluoro-benzaldehyde and dimethylamine.
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][NH2:5].C([O-])([O-])=O.[K+].[K+].[C:12]([C:16]1[CH:21]=[CH:20][C:19]([SH:22])=[CH:18][CH:17]=1)([CH3:15])([CH3:14])[CH3:13]>C(Cl)(Cl)Cl>[C:12]([C:16]1[CH:17]=[CH:18][C:19]([S:22][CH2:3][CH2:4][NH2:5])=[CH:20][CH:21]=1)([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)c1ccc(S)cc1
Reactant: NCCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: CC(C)(C)c1ccc(SCCN)cc1
Temperature: 50 °C
Reaction time: 8 h
Yield: 74.1 %

Procedure:
To a stirring mixture of 4.36 g (38.0 mmol) of 2-chloroethylamine hydrochloride and 12.00 g (87.0 mmol) of K2CO3 in 30 mL of CHCl3 was added 4.82 g (29.0 mmol) of 4-t-butylbenzenethiol. The mixture was stirred at 50° C. in a sealed vial overnight. The mixture was washed three times with distilled water, dried with MgSO4 and filtered. Volatiles were removed in vacuo leaving 4.50 g (74%) of clear oil. 1H NMR (300 MHz, CDCl3): δ=7.32, m, 4H, 2.93, m, 4H, 1.42, broad singlet, 2H, 1.30, s, 9H.