Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]([OH:12])[CH2:4][CH2:3]1.[CH3:13][O:14]C(Cl)Cl.Cl>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[OH:1][CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]([OH:12])[CH2:4][CH:3]1[CH:13]=[O:14]
Reactant: OC1CCC(O)c2ccccc21
Reactant: COC(Cl)Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: Cl
Solvent: ClCCl
Product: O=CC1CC(O)c2ccccc2C1O
Yield: 60 %

Procedure:
To a solution of 1,4-dihydroxy-tetralin (1.640 g, 0.010 mol) in dichloromethane (50 ml) was added titanium tetrachloride (5.69 g, 0.03 mol). Then 1,1-dichlorodimethyl ether (1.73 g, 0.015 mol) was added dropwise under vigorous stirring and the reaction mixture stirred for another 3 h at room temperature. Finally 5% hydrochloric acid (10 ml) was added under ice-cooling. The organic phase was separated and the residual aqueous phase repeatedly extracted with ether. The combined organic phases are washed with saturated saline solution, dried over sodium sulfate and evaporated under vacuum. The residue was crystallized from benzene or alternatively submitted to flash chromatography on silica gel with benzene/ethylacetate 85:15 to afford pure title compound in about 60% yield (1.080 g), m.p. 145° C.
Reaction SMILES: [CH2:1]([C:4]1[C:12]([O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])=[C:11]2[C:7]([CH2:8][O:9][C:10]2=[O:20])=[C:6]([CH3:21])[C:5]=1[CH2:22][CH3:23])[CH:2]=C.NC(N)=S.C[OH:29]>C(Cl)Cl.N1C=CC=CC=1>[CH2:22]([C:5]1[C:6]([CH3:21])=[C:7]2[C:11]([C:10](=[O:20])[O:9][CH2:8]2)=[C:12]([O:13][CH2:14][CH2:15][Si:16]([CH3:18])([CH3:19])[CH3:17])[C:4]=1[CH2:1][CH:2]=[O:29])[CH3:23]
Reactant: C=CCc1c(CC)c(C)c2c(c1OCC[Si](C)(C)C)C(=O)OC2
Reactant: CO
Agent: NC(N)=S
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCc1c(C)c2c(c(OCC[Si](C)(C)C)c1CC=O)C(=O)OC2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 69 %

Procedure:
A solution of 6-allyl-5-ethyl-4-methyl-7-(2-trimethylsilanyl-ethoxy)-3H-isobenzofuran-1-one (261 mg, 0.788 mmol) in MeOH (5 mL), CH2Cl2 (5 mL) and pyridine (50 μL) was cooled to −78° C. using a dry ice/acetone bath according to the procedure of Smith, D. B. et al., J. Org. Chem., 1996, 61, 6, 2236. A stream of ozone was bubbled through the reaction via a gas dispersion tube until the reaction became blue in color (15 minutes). The ozone line was replaced with a stream of nitrogen and bubbling continued for another 15 minutes, by which time the blue color had disappeared. To this solution, at −78° C., was added thiourea (59.9 mg, 0.788 mmol) in one portion, and the cooling bath was removed. The reaction was allowed to warm to room temperature and stirred for 15 hours. The reaction mixture was filtered and then partitioned between CH2Cl2 and water. The aqueous layer was extracted with CH2Cl2 one more time and the organic extracts were combined, washed with aqueous 1N HCl, saturated NaHCO3 and brine and dried over sodium sulfate. Filtration and evaporation of solvents in vacuo yielded the crude product, which was purified by silica gel chromatography to afford 181 mg (69%) of the product as a white solid. 1H NMR (300 MHz, CDCl3): δ=0.04 (s, 9H), 1.11 (t, J=7.5 Hz, 3H), 1.19 (m, 2H), 2.21 (s, 3H), 2.66 (q, J=7.5 Hz, 2H), 3.90 (s, 2H), 4.36 (m, 2H), 5.18 (s, 2H), 9.71 (s, 1H) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([O:10]C)[C:7]([O:12][CH3:13])=[CH:6][C:3]=1[CH:4]=[O:5].ClCCl.[Cl-].[Cl-].[Cl-].[Al+3]>O>[Cl:1][C:2]1[CH:9]=[C:8]([OH:10])[C:7]([O:12][CH3:13])=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: COc1cc(Cl)c(C=O)cc1OC
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: COc1cc(C=O)c(Cl)cc1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Chloro-4,5-dimethoxy-benzaldehyde (135, 2.00 g, 0.00997 mol), dichloromethane (73.44 mL) and aluminum trichloride (2.50 g, 0.0187 mol) were combined under an atmosphere of nitrogen. The reaction was stirred at room temperature overnight. The reaction was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and washed with 5% ethyl acetate in hexane to provide an off-white solid (136, 757 mg, 41%). MS (ESI) [M−H+]−=185.0, 187.0.
Reaction SMILES: Cl.[C:2]([C:4]1[CH:12]=[CH:11][C:7]([CH2:8][O:9]N)=[C:6]([O:13][CH2:14][CH3:15])[CH:5]=1)#[N:3].[OH2:16].[NH3:17]>>[C:2]([C:4]1[CH:12]=[CH:11][C:7]([CH2:8][O:9][O:16][NH2:17])=[C:6]([O:13][CH2:14][CH3:15])[CH:5]=1)#[N:3]
Reactant: N
Reactant: CCOc1cc(C#N)ccc1CON
Reactant: O
Agent: Cl
Product: CCOc1cc(C#N)ccc1COON

Procedure:
The O-(4-cyano-2-ethoxybenzyl)hydroxyamine hydrochloride (19) and ammonia water were mixed, then, extracted with ethyl acetate to obtain O-(4-cyano-2-ethoxybenzyl)hydroxyamine (18) (80 mg, 0.42 mmol). This was dissolved in acetonitrile (12 ml), then, several drops of 85% phosphoric acid aqueous solution were dropped on this, and the produced white solid was filtrated by filtration under reduced pressure. The filtrated substance was washed with acetonitrile, then, the filtrated substance was recovered and dried by a vacuum pump to obtain 60 mg of a while solid.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]#[N:16])[CH2:11][CH2:10]1)(C)(C)C.C(O)(C(F)(F)F)=O.CC(=O)OCC>C(Cl)Cl>[NH2:16][CH2:15][C@H:12]1[CH2:13][CH2:14][C@H:9]([C:8]#[N:7])[CH2:10][CH2:11]1
Reactant: CC(C)(C)OC(=O)NC[C@H]1CC[C@H](C#N)CC1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: N#C[C@H]1CC[C@H](CN)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl((trans-4-cyanocyclohexyl)methyl)carbamate (1.4 g, 5.86 mmol) in CH2Cl2 (20 mL) was added TFA (20 mL) at r.t. The resulting mixture was stirred at room temperature for 1 h. TLC (PE:EA=5:1) showed the reaction was complete. The mixture was concentrated in vacuo to give trans-4-(aminomethyl)cyclohexanecarbonitrile (2.6 g, 319%) as TFA salts.
Reaction SMILES: N(C(OC(C)C)=O)=NC([O:5][CH:6]([CH3:8])C)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[C@@H:35]1[CH2:52][CH2:51][C@@:50]2([CH3:53])[C:37]([CH2:38][CH2:39][C@@H:40]3[C@@H:49]2[CH2:48][CH2:47][C@@:45]2([CH3:46])[C@H:41]3[CH2:42][CH2:43][C:44]2=[O:54])=[CH:36]1.[S:55]1C=CC=C1CC(O)=O>O1CCCC1>[C:6]([S:55][C@H:35]1[CH2:52][CH2:51][C@@:50]2([CH3:53])[C:37]([CH2:38][CH2:39][C@@H:40]3[C@@H:49]2[CH2:48][CH2:47][C@@:45]2([CH3:46])[C@H:41]3[CH2:42][CH2:43][C:44]2=[O:54])=[CH:36]1)(=[O:5])[CH3:8]
Reactant: O=C(O)Cc1cccs1
Reactant: CC(C)OC(=O)N=NC(=O)OC(C)C
Reactant: C[C@]12CC[C@@H](O)C=C1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=O)S[C@@H]1C=C2CC[C@@H]3[C@H](CC[C@]4(C)C(=O)CC[C@@H]34)[C@@]2(C)CC1

Procedure:
Diisopropyl azodicarboxylate (3.3 ml) was added to a solution of 4.5 g of triphenylphosphine in 90 ml of tetrahydrofuran at 0 ° C. and the mixture was stirred for 30'. To this mixture a solution of 2.1 g of 3α-hydroxy-androst-4-en-17-one (D'Incan E., Tetrahedron, 1982, 38, 1755) and 2.1 ml of thiolacetic acid in 90 ml of tetrahydrofuran was added dropwise and the residue was stirred for 1 hr at room temperature. The solvent was evaporated to dryness under reduced pressure and the crude product was purified by flash-chromatography (SiO2) using n-hexane/ethyl acetate 95/5 as eluant to give 1.4 g of the title compound (IV-a) as a white solid.
Reaction SMILES: C([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:58]/[O:59][CH:60]([C:75]([O:77]C(C2C=CC=CC=2)C2C=CC=CC=2)=[O:76])[C:61]2[CH:66]=[CH:65][C:64]([O:67][C:68](=[O:70])[CH3:69])=[C:63]([O:71][C:72](=[O:74])[CH3:73])[CH:62]=2)/[C:27]([NH:29][C@@H:30]2[C:56](=[O:57])[N:32]3[C:33]([C:44]([O:46]CC4C=CC(OC)=CC=4)=[O:45])=[C:34]([CH:37]=[CH:38][C:39]4[S:43][CH:42]=[N:41][CH:40]=4)[CH2:35][S:36][C@H:31]23)=[O:28])[N:25]=1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.FC(F)(F)C(O)=O>C(Cl)Cl.C1(OC)C=CC=CC=1>[NH2:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:58]/[O:59][CH:60]([C:75]([OH:77])=[O:76])[C:61]2[CH:66]=[CH:65][C:64]([O:67][C:68](=[O:70])[CH3:69])=[C:63]([O:71][C:72](=[O:74])[CH3:73])[CH:62]=2)/[C:27]([NH:29][C@@H:30]2[C:56](=[O:57])[N:32]3[C:33]([C:44]([OH:46])=[O:45])=[C:34]([CH:37]=[CH:38][C:39]4[S:43][CH:42]=[N:41][CH:40]=4)[CH2:35][S:36][C@H:31]23)=[O:28])[N:25]=1
Reactant: COc1ccc(COC(=O)C2=C(C=Cc3cncs3)CS[C@@H]3[C@H](NC(=O)/C(=N\OC(C(=O)OC(c4ccccc4)c4ccccc4)c4ccc(OC(C)=O)c(OC(C)=O)c4)c4csc(NC(c5ccccc5)(c5ccccc5)c5ccccc5)n4)C(=O)N23)cc1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)Oc1ccc(C(O/N=C(\C(=O)N[C@@H]2C(=O)N3C(C(=O)O)=C(C=Cc4cncs4)CS[C@H]23)c2csc(N)n2)C(=O)O)cc1OC(C)=O
Reaction time: 3 h
Yield: 80.3 %

Procedure:
After 870 mg (0.69 mmol) of p-methoxybenzyl 7β-[(Z)-2-(2-tritylamino-4-thiazolyl)-2-[[(R S)-(diphenylmethoxycarbonyl)(3,4-diacetoxyphenyl)methoxy]imino]acetamido]-3-[-2-(5-thiazolyl)vinyl]-3-cephem-4-carboxylate was dissolved in 9 ml of methylene chloride and 4 ml of anisole, 16 ml of trifluoroacetic acid was added therein under ice-cooling and the reaction solution was reacted for 90 min. as it was. The residue obtained by evaporating off trifluoroacetate under the reduced pressure was powdered with ethyl ether-hexane (1:1). The powder obtained by filtering off was further dissolved in 45 ml of trifluoroacetic acid under ice-cooling, and then, 11 ml of water was added therein, and the reaction was effected for 3 hrs. at the room temperature. The residue obtained by evaporating off trifluoroacetic acid and water under the reduced pressure was powdered by adding ethyl ether, and filtered off to give 404 mg of 7β-[(Z)-2-(2-amino-4-thiazolyl)-2-[[(R S)-(carboxy) (3,4 -diacetoxyphenyl)methoxy]imino]acetamido]-3-[-2-(5-thiazolyl)vinyl]-3-cephem-4-carboxylic acid.trifluoroacetate, a crude product.
Reaction SMILES: S(=O)(=O)(O)[OH:2].[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[C:8]=1[CH:14]([NH:17][C:18]1[CH:27]=[CH:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=1)[C:15]#[N:16]>>[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[C:8]=1[CH:14]([NH:17][C:18]1[CH:27]=[CH:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=1)[C:15]([NH2:16])=[O:2]
Reactant: O=S(=O)(O)O
Reactant: N#CC(Nc1ccc2ccccc2c1)c1c(Cl)cccc1Cl
Product: NC(=O)C(Nc1ccc2ccccc2c1)c1c(Cl)cccc1Cl
Reaction time: 8 h

Procedure:
To 360 parts of concentrated sulfuric acid are added portionwise 30 parts of 2,6-dichloro-α-[(2-naphthalenyl)amino]benzeneacetonitrile and the whole is stirred till all solid enters solution. The reaction solution is allowed to stand overnight at room temperature and then poured onto 1000 parts of crushed ice. The precipitated product is filtered off and extracted with 1500 parts of chloroform. The organic phase is washed with water, dried, filtered and evaporated. The oily residue solidifies on triturating in 2-propanol. The solid product is filtered off and crystallized from 200 parts of 2-propanol at 0° C., yielding 11.3 parts of 2,6-dichloro-α-[(2-naphthalenyl)amino]benzeneacetamide; mp. 157.9° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:12]1[CH2:17][CH2:16][N:15]([C:18]([C:20]2[CH:25]=[C:24]([S:26]([CH3:29])(=[O:28])=[O:27])[CH:23]=[CH:22][C:21]=2I)=[O:19])[CH2:14][CH2:13]1.[CH3:31][C:32]1[CH:33]=[N:34][NH:35][CH:36]=1>>[F:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:12]1[CH2:17][CH2:16][N:15]([C:18]([C:20]2[CH:25]=[C:24]([S:26]([CH3:29])(=[O:28])=[O:27])[CH:23]=[CH:22][C:21]=2[N:34]2[CH:33]=[C:32]([CH3:31])[CH:36]=[N:35]2)=[O:19])[CH2:14][CH2:13]1
Reactant: Cc1cn[nH]c1
Reactant: CS(=O)(=O)c1ccc(N2CCN(C(=O)c3cc(S(C)(=O)=O)ccc3I)CC2)c(F)c1
Product: Cc1cnn(-c2ccc(S(C)(=O)=O)cc2C(=O)N2CCN(c3ccc(S(C)(=O)=O)cc3F)CC2)c1
Yield: 29 %

Procedure:
The title compound was prepared according to the procedure described for example 294 from [4-(2-Fluoro-4-methanesulfonyl-phenyl)-piperazin-1-yl]-(2-iodo-5-methanesulfonyl-phenyl)-methanone (compound CM) and 4-Methyl-1H-pyrazole (29% yield, yellow foam, MS (m/e): 521.3 (M+H, 100%)
Reaction SMILES: C[O-].[Na+].[CH3:4][O:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]=[C:9]2[CH2:15][C:16]#[N:17].[CH3:18][N:19]1[CH:23]=[C:22](C=O)[CH:21]=[N:20]1.[CH2:26](OCC)C>C(O)C>[CH3:4][O:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]=[C:9]2/[C:15](=[CH:26]/[C:21]1[CH:22]=[CH:23][N:19]([CH3:18])[N:20]=1)/[C:16]#[N:17]
Reactant: COc1ccc2[nH]cc(CC#N)c2c1
Reactant: CCOCC
Reactant: Cn1cc(C=O)cn1
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccc2[nH]cc(/C(C#N)=C/c3ccn(C)n3)c2c1
Temperature: 50 °C

Procedure:
To a solution of sodium methanolate (204 mg, 3.8 mmol, 1.4 eq.) in anhydrous ethanol (30 mL) were added, under an argon atmosphere, (5-methoxy-1H-indol-3-yl)-acetonitrile (500 mg, 2.7 mmol, 1.0 eq.) and, after 30 minutes stirring, 1-methyl-1H-pyrazole-4-carbaldehyde (326 mg, 3.0 mmol, 1.1 eq.). The reaction apparatus was protected from light and the mixture heated at 50° C. for 18 hours. The reaction was allowed to cool to room temperature and then, the solvent was removed under reduced pressure and the crude taken up in ethyl acetate. The organic layer was washed with water and brine, dried over MgSO4 and then, evaporated. The residue was purified by silica gel flash-column chromatography (eluent: CH2Cl2/EtOH, 99/1 to 98/2) to afford, after trituration with diethyl ether, the compound (51) as a beige powder (640 mg, 85%). mp: 178° C.; 1H NMR (DMSO, 300 MHz) δ (ppm): 3.81 (3H, s, 5′-methoxy), 3.92 (3H, s, N-methyl), 6.90 (1H, dd, J6′-7′=8.7 Hz, J6′-4′=2.3 Hz, H6′), 7.37 (1H, d, J7′-6′=8.7 Hz, H7′), 7.38 (1H, m, H4′), 7.55 (1H, s, H3), 7.61 (1H, s, H2′), 8.00 (1H, s, H3″), 8.24 (1H, s, H5″), 11.43 (1H, s, indolic H); 13C NMR (DMSO, 75.5 MHz) δ (ppm): 38.8 (N-methyl), 55.6 (5′-methoxy), 101.5 (C2), 101.5 (C4′), 109.8 (C3′), 111.9 (C6′), 112.9 (C7′), 117.4 (C4″), 119.3 (C1), 124.0 (C3a′), 125.6 (C2′), 128.5 (C3), 131.0 (C5″), 132.1 (C7a′), 138.8 (C3″), 154.1 (C5′); MS: ESI-MS: m/z 264.1 ([M+H]+), 286.1 ([M+Na]+); HRESI-MS: m/z 301.1060 (calcd for C16H14N4ONa+, 301.1065); Anal. Calcd for C19H14N4O, 0.1H2O: C, 68.61; H, 5.11; N, 20.00; O, 6.55. Found: C, 68.73; H, 5.33; N, 19.69.
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:20])[C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:8]=[CH:7]2.[Cl:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][C:30]=1[O:31][CH:32]([CH3:34])[CH3:33])[C:25](O)=O.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C)C=O.CCOC(C)=O>[Cl:21][C:22]1[CH:23]=[C:24]([C:25]2[O:1][N:2]=[C:3]([C:4]3[CH:5]=[C:6]4[C:10](=[CH:11][CH:12]=3)[N:9]([CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:8]=[CH:7]4)[N:20]=2)[CH:28]=[CH:29][C:30]=1[O:31][CH:32]([CH3:33])[CH3:34]
Reactant: CCOC(=O)CCn1ncc2cc(C(=N)NO)ccc21
Reactant: CC(C)Oc1ccc(C(=O)O)cc1Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: CCOC(=O)CCn1ncc2cc(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)ccc21
Temperature: 120 °C
Yield: 58.1 %

Procedure:
A solution of Ethyl 3-{5-[(hydroxyamino)(imino)methyl]-1H-indazol-1-yl}propanoate (D52) (2.04 g, 7.38 mmol), 3-chloro-4-[(1-methylethyl)oxy]benzoic acid (D3) (1.743 g, 8.12 mmol), EDC (2.123 g, 11.08 mmol) and HOBT (1.357 g, 8.86 mmol) in N,N-Dimethylformamide (DMF) (25 ml) was stirred overnight then heated at 120° C. during 4 hours. The mixture was dissolved in EtOAc then washed with water and NaHCO3 and purified by flash chromatography, eluting with EtOAc/iso-Hexane 10-90% then 10-30%. The solvent was evaporated to give (1.95 g) of white solid. MS (ES): C23H2335ClN4O4 requires 454; found (MH+) 455.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[C:4]([C:9]([F:12])([F:11])[F:10])[N:3]=1.[N:13]1([S:19]([C:22]2[CH:27]=[CH:26][C:25]([SH:28])=[CH:24][CH:23]=2)(=[O:21])=[O:20])[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.[Cl:29][C:30]1[CH:35]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:33]=[CH:32][C:31]=1[S:40](Cl)(=[O:42])=[O:41]>>[Cl:29][C:30]1[CH:35]=[C:34]([C:36]([F:38])([F:37])[F:39])[CH:33]=[CH:32][C:31]=1[S:40]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([S:28][C:25]2[CH:24]=[CH:23][C:22]([S:19]([N:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)(=[O:21])=[O:20])=[CH:27][CH:26]=2)=[C:4]([C:9]([F:12])([F:11])[F:10])[N:3]=1)(=[O:42])=[O:41]
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1Cl
Reactant: Nc1ccc(Br)c(C(F)(F)F)n1
Reactant: O=S(=O)(c1ccc(S)cc1)N1CCOCC1
Product: O=S(=O)(Nc1ccc(Sc2ccc(S(=O)(=O)N3CCOCC3)cc2)c(C(F)(F)F)n1)c1ccc(C(F)(F)F)cc1Cl

Procedure:
Prepared from 2-amino-5-bromo-6-trifluoromethylpyridine and 4-(N-morpholinylsulfonyl)thiophenol according to General Method 11 step 1 followed by reaction with 2-chloro-4-trifluoromethylphenylsulfonyl chloride according to General Method 11 step 2. 1H NMR (CDCl3): 8.31 (1H, d, J 10 Hz, A-ring CH ortho to SO2NH), 7.45 (1H, s, A ring CH ortho to CF3 & Cl), 7.65-7.50 & 7.26-7.15 (4H & 3H, 2×m, Ar CH's), 3.71-3.61 (4H, m, CH2OCH2), 2.95-2.86 (4H, m, CH2NCH2). Hplc (Luna 2, Gradient 5): rt=6.53 minutes. LC/MS rt=7.06 minutes, 662 (MH+).
Reaction SMILES: C(NC1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(OC)=O)C3=O)=CC=2)=CC=1)(=O)C1C=CC=CC=1.[NH2:34][C:35]1[CH:40]=[CH:39][C:38]([C:41]2[CH:49]=[C:48]3[C:44]([CH2:45][N:46]([C:51]4([C:55]([O:57][CH3:58])=[O:56])[CH2:54][CH2:53][CH2:52]4)[C:47]3=[O:50])=[CH:43][CH:42]=2)=[CH:37][CH:36]=1.[Cl:59][C:60]1[CH:68]=[CH:67][C:63]([C:64](Cl)=[O:65])=[CH:62][CH:61]=1>>[Cl:59][C:60]1[CH:68]=[CH:67][C:63]([C:64]([NH:34][C:35]2[CH:36]=[CH:37][C:38]([C:41]3[CH:49]=[C:48]4[C:44]([CH2:45][N:46]([C:51]5([C:55]([O:57][CH3:58])=[O:56])[CH2:52][CH2:53][CH2:54]5)[C:47]4=[O:50])=[CH:43][CH:42]=3)=[CH:39][CH:40]=2)=[O:65])=[CH:62][CH:61]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: COC(=O)C1(N2Cc3ccc(-c4ccc(N)cc4)cc3C2=O)CCC1
Agent: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ccccc4)cc3)cc2C1=O
Product: COC(=O)C1(N2Cc3ccc(-c4ccc(NC(=O)c5ccc(Cl)cc5)cc4)cc3C2=O)CCC1
Yield: 96 %

Procedure:
The compound of example 577 was prepared analogous to compound of example 97 by reaction of compound of example 574 with 4-chloro benzoyl chloride.
Reaction SMILES: B(Br)(Br)[Br:2].CO[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14](=[CH:19][CH3:20])[C:15]([O:17][CH3:18])=[O:16].CO.O>C(Cl)Cl>[Br:2][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14](=[CH:19][CH3:20])[C:15]([O:17][CH3:18])=[O:16]
Reactant: CC=C(C(=O)OC)c1ccccc1COC
Reactant: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: CC=C(C(=O)OC)c1ccccc1CBr

Procedure:
At 0° C., 105.3 ml (140 mmol) of a 1.33 M boron tribromide solution in methylene chloride was dripped into 31 g (140 mmol) of methyl α-(2-methoxymethylphenyl)-β-methylacrylate in 500 ml of CH2Cl2, and the mixture was refluxed for 2 hours. 25 ml of methanol was then added, the mixture was stirred for a further 90 minutes at room temperature, hydrolyzed with water while cooling with ice, and washed neutral with 3% strength caustic solution, and the aqueous phase was extracted with methylene chloride. The combined organic phases were washed with water, dried and evaporated down. The crystals which precipitated were separated off, washed with a small amount of n-hexane and dried. The filtrates were evaporated down and purified chromatographically in a silica gel column (cyclohexane/MTBE: 8/1). A total of 31 g of product was obtained in the form of pale yellow crystals.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][N:5]1[C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][C:7]([C:14]([O:16][CH3:17])=[O:15])=[N:6]1.[N-:18]=[N+:19]=[N-:20].[Na+]>CS(C)=O.O>[N:18]([CH2:2][CH2:3][CH2:4][N:5]1[C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][C:7]([C:14]([O:16][CH3:17])=[O:15])=[N:6]1)=[N+:19]=[N-:20]
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)c1cc(C(=O)OC)n(CCCBr)n1
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)c1cc(C(=O)OC)n(CCCN=[N+]=[N-])n1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of 5-1 (1.0 g, 3.45 mmol) in 10 ml DMSO was treated with NaN3 (0.883 g, 13.8 mmol) and mixture stirred at 25° C. for 5 h. Next, the reaction mixture was diluted with 100 ml of H2O and then extracted with ethyl acetate (3×100 ml). The combined organic extracts were washed with water (2×100 ml) and brine (1×100 ml), dried over Na2SO4 and evaporated to give 5-2 as a colorless oil.
Reaction SMILES: [CH:1]1([N:7]=[C:8]=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:10][C:11]1[C:20]2[N:21]=[C:22]([CH2:29][CH2:30][CH2:31][CH3:32])[N:23]([CH2:24][CH2:25][CH2:26][CH2:27][NH2:28])[C:19]=2[C:18]2[N:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:12]=1>>[NH2:10][C:11]1[C:20]2[N:21]=[C:22]([CH2:29][CH2:30][CH2:31][CH3:32])[N:23]([CH2:24][CH2:25][CH2:26][CH2:27][NH:28][C:8]([NH:7][CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)=[O:9])[C:19]=2[C:18]2[N:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:12]=1
Reactant: O=C=NC1CCCCC1
Reactant: CCCCc1nc2c(N)nc3cccnc3c2n1CCCCN
Product: CCCCc1nc2c(N)nc3cccnc3c2n1CCCCNC(=O)NC1CCCCC1
Yield: 66.7 %

Procedure:
Using the general method of Example 47, cyclohexyl isocyanate (61 μL, 0.48 mmol) was reacted with 4-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butaneamine (0.15 g, 0.48 mmole) to provide 0.14 g of N-[4-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butyl]-N′-cyclohexylurea as a white solid. Analysis: Calculated for C24H35N7O: %C, 65.88; %H, 8.06; %N, 22.41. 1H NMR (300 MHz, CDCl3) δ 8.60 (dd, J=4.4, 1.4 Hz, 1H), 8.08 (d, J=8.5 Hz, 1H), 7.44 (dd, J=8.5, 4.4 Hz, 1H), 5.55 (br s, 2H), 4.92 (t, J=5.8 Hz, 1H), 4.82 (apparent t, J=7.8 Hz, 2H), 4.13 (d, J=8.6 Hz, 1H), 3.48 (m, 1H), 3.35 (apparent q, J=6.4 Hz, 2H), 2.93 (apparent t, J=7.8 Hz, 2H), 1.80-2.05 (m, 4H), 1.45-1.75 (m, 6H), 1.2-1.4 (m 2H), 1.0-1.2 (m, 2H), 1.03 (t, 7.4 Hz, 3H); HRMS (EI) calcd for C24H35N7O (M+) 437.2903, found 437.2903.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][C:9](=[O:11])[CH2:10][C:3]=12.[N:12]1([CH2:18][CH2:19][NH:20][C:21]([C:23]2[NH:24][C:25]([CH:29]=O)=[C:26]([CH3:28])[CH:27]=2)=[O:22])[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.N1CCCCC1>C(O)C>[N:12]1([CH2:18][CH2:19][NH:20][C:21]([C:23]2[NH:24][C:25]([CH:29]=[C:10]3[C:3]4[C:4](=[N:5][CH:6]=[CH:7][C:2]=4[Cl:1])[NH:8][C:9]3=[O:11])=[C:26]([CH3:28])[CH:27]=2)=[O:22])[CH2:13][CH2:14][O:15][CH2:16][CH2:17]1
Reactant: Cc1cc(C(=O)NCCN2CCOCC2)[nH]c1C=O
Reactant: O=C1Cc2c(Cl)ccnc2N1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1cc(C(=O)NCCN2CCOCC2)[nH]c1C=C1C(=O)Nc2nccc(Cl)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 89 %

Procedure:
A reaction mixture of 4-chloro-1,3-dihydro-pyrrolo[2,3-b]pyridin-2-one (85 mg, 0.5 mmol), 5-formyl-4-methyl-1H-pyrrole-2-carboxylic acid (2-morpholin-4-yl-ethyl)-amide (125 mg, 0.5 mmol), 0.1 mL of piperidine and 10 mL of ethanol was stirred at room temperature overnight. The yellow precipitate was filtered after cooled with an ice bath, washed with cold ethanol and dried to give 185 mg (92%) of 5-(4-chloro-2-oxo-1,2-dihydro-pyrrolo[2,3-b]pyridin-3-ylidenemethyl)-4-methyl-1H-pyrrole-2-carboxylic acid (2-morpholin-4-yl-ethyl)-amide.
Reaction SMILES: [C:1]([C:3]1[CH:28]=[CH:27][C:6]([CH2:7][O:8][C:9]2[CH:10]=[C:11]([CH:15]=[C:16]([O:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=3)[CH:17]=2)[C:12]([OH:14])=O)=[CH:5][CH:4]=1)#[N:2].[C:29]([O:33][C:34](=[O:44])[NH:35][CH2:36][CH2:37][CH:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1)([CH3:32])([CH3:31])[CH3:30]>>[C:29]([O:33][C:34](=[O:44])[NH:35][CH2:36][CH2:37][CH:38]1[CH2:39][CH2:40][N:41]([C:12](=[O:14])[C:11]2[CH:15]=[C:16]([O:18][C:19]3[CH:20]=[CH:21][C:22]([C:25]#[N:26])=[CH:23][CH:24]=3)[CH:17]=[C:9]([O:8][CH2:7][C:6]3[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:28][CH:27]=3)[CH:10]=2)[CH2:42][CH2:43]1)([CH3:32])([CH3:30])[CH3:31]
Reactant: CC(C)(C)OC(=O)NCCC1CCNCC1
Reactant: N#Cc1ccc(COc2cc(Oc3ccc(C#N)cc3)cc(C(=O)O)c2)cc1
Product: CC(C)(C)OC(=O)NCCC1CCN(C(=O)c2cc(OCc3ccc(C#N)cc3)cc(Oc3ccc(C#N)cc3)c2)CC1
Yield: 73.4 %

Procedure:
Following the procedure of Example 5(c) 3-(4-cyano-benzyloxy)-5-(4-cyano-phenoxy)-benzoic acid 0.8 g (2.16 mmol) and (2-piperidin-4-yl-ethyl)-carbamic acid tert-butyl ester (0.49 g, 2.16 mmol) were used to afford 0.92 g of the required product. 1H NMR (DMSO-d6): δ 1.10 (2H, m), 1.30 (2H, m), 1.4 (9H, s), 1.50 (2H, m), 1.75 (1H, m), 2.70 (1H, m), 2.8 (3H, m), 3.5 (1H, m), 4.4 (1H, m), 5.2 (2H, s), 6.65 (1H, s), 6.78 (1H, m), 6.88 (2H, m), 7.16 (2H, s), 7.64 (2H, d), 7.88 (4H, m).