Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:23][C:24]2[CH:25]=[CH:26][C:27]3[O:31][CH2:30][CH2:29][C:28]=3[CH:32]=2)[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11](Br)=[CH:10][CH:9]=2)=[O:4].CO.[H][H]>[C].[Pd].C1COCC1>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:23][C:24]2[CH:25]=[CH:26][C:27]3[O:31][CH2:30][CH2:29][C:28]=3[CH:32]=2)[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:4]
Reactant: COC(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc2c(c1)CCO2
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1c(-c2ccccc2)c2ccccc2c(=O)n1Cc1ccc2c(c1)CCO2
Yield: 92.4 %

Procedure:
A mixture of 6-bromo-2-(2,3-dihydrobenzofuran-5-ylmethyl)-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester (400 mg), 10% palladium carbon (150 mg), methanol (6 ml) and THF (6 ml) was stirred at room temperature under 1 atm hydrogen pressure for 12 hrs. Palladium carbon was filtered off, and the filtrate was concentrated. The obtained residue was crystallized from ethyl acetate-hexane to give the title compound (310 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[F:24])[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[N:14]=2)[N:11]=1.[F:25][C:26]([F:37])([F:36])[C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=1)[C:30](O)=[O:31].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O>[CH:18]1([C:16]([NH:15][C:13]2[N:14]=[C:9]3[CH:8]=[CH:7][C:6]([O:5][C:4]4[CH:21]=[CH:22][C:23]([F:24])=[C:2]([NH:1][C:30](=[O:31])[C:29]5[CH:33]=[CH:34][CH:35]=[C:27]([C:26]([F:25])([F:36])[F:37])[CH:28]=5)[CH:3]=4)=[N:11][N:10]3[CH:12]=2)=[O:17])[CH2:20][CH2:19]1
Reactant: Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)ccc1F
Reactant: O=C(O)c1cccc(C(F)(F)F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C(Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)ccc1F)c1cccc(C(F)(F)F)c1
Yield: 64.1 %

Procedure:
Using N-[6-(3-amino-4-fluorophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (163 mg, 0.50 mmol), 3-(trifluoromethyl)benzoic acid (950 mg, 5.00 mmol), 1-hydroxybenzotriazole (676 mg, 5.00 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (959 mg, 5.00 mmol) and N,N-dimethylformamide (5.0 mL) as starting materials and in the same manner as in Example 106, the title compound (160 mg, 64%) was obtained as a white powder.
Reaction SMILES: C[O:2][C:3](=[O:29])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:14]=[C:15]3[C:20](=[C:21]([CH2:23][CH3:24])[CH:22]=2)[O:19][C:18]([CH3:26])([CH3:25])[CH2:17][C:16]3([CH3:28])[CH3:27])=[CH:7][CH:6]=1.CO.[OH-].[Na+].O>C(#N)C>[CH2:23]([C:21]1[CH:22]=[C:13]([C:12]#[C:11][C:8]2[CH:9]=[CH:10][C:5]([CH2:4][C:3]([OH:29])=[O:2])=[CH:6][CH:7]=2)[CH:14]=[C:15]2[C:20]=1[O:19][C:18]([CH3:25])([CH3:26])[CH2:17][C:16]2([CH3:28])[CH3:27])[CH3:24]
Reactant: CCc1cc(C#Cc2ccc(CC(=O)OC)cc2)cc2c1OC(C)(C)CC2(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Solvent: CO
Product: CCc1cc(C#Cc2ccc(CC(=O)O)cc2)cc2c1OC(C)(C)CC2(C)C

Procedure:
Following general procedure L and using [4-(8-ethyl-2,2,4,4-tetramethyl-chroman-6-ylethynyl)phenyl] acetic acid methyl ester (Compound 55, 0.035 g, 0.1 mmol), 5 mL of methanol and 1M sodium hydroxide solution (1 mL) followed by preparative reverse phase HPLC using 10% water in acetonitrile as the mobile phase, the title compound was obtained as a solid (0.11 g, 25%).
Reaction SMILES: [OH:1][C:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH3:13])[C:4](=[O:14])[CH:3]=1.[N+:15]([O-])([OH:17])=[O:16]>C(Cl)(Cl)Cl>[OH:1][C:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH3:13])[C:4](=[O:14])[C:3]=1[N+:15]([O-:17])=[O:16]
Reactant: O=[N+]([O-])O
Reactant: Cc1cccc2c1C(=O)C(O)=CC2=O
Solvent: ClC(Cl)Cl
Product: Cc1cccc2c1C(=O)C(O)=C([N+](=O)[O-])C2=O
Yield: 43 %

Procedure:
A solution of 3-hydroxy-5methyl-1,4-naphthoquinone (1.9g) in chloroform (200ml) was nitrated with fuming nitric acid according to example 1(a). A yield of 1.01g (43%) of material of m.p. 148°-149° C (d) was obtained. (Found; C, 56,69; H, 3.16; N, 5.73; C11H7NO5 requires; C, 56.66; H, 3.03; N, 6.01%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1.[C:17]1(=[O:23])[O:22][C:20](=[O:21])[CH2:19][CH2:18]1>CN(C)C1C=CN=CC=1.C(Cl)(Cl)Cl>[C:13]([O:12][C:10]([N:7]1[CH2:8][CH2:9][N:4]([CH2:3][CH2:2][O:1][C:17](=[O:23])[CH2:18][CH2:19][C:20]([OH:22])=[O:21])[CH2:5][CH2:6]1)=[O:11])([CH3:16])([CH3:15])[CH3:14]
Reactant: O=C1CCC(=O)O1
Reactant: CC(C)(C)OC(=O)N1CCN(CCO)CC1
Agent: CN(C)c1ccncc1
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCN(CCOC(=O)CCC(=O)O)CC1
Reaction time: 18 h

Procedure:
Compound 57 (5.3 g, 23.0 mmol), succinic anhydride (2.30 g, 23.0 mmol) and 4-dimethylaminopyridine (281 mg, 2.30 mmol) were dissolved in CHCl3 (14 mL) and stirred for 18 h. The solution was concentrated in vacuo and used without further purification. 1H NMR (400 MHz, CDCl3) δ 1.42 (s, 9H), 2.54-2.60 (m, 8H), 2.72 (t, J=5.6, 2H), 3.43-3.46 (m, 4H), 4.23 (t, J=5.5, 2H).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([Cl:10])[CH:3]=1.C1COCC1.C([O-])([O-])=O.[Na+].[Na+].[O:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]1[N:28]1[C:32](B2OC(C)(C)C(C)(C)O2)=[CH:31][CH:30]=[N:29]1>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O.C1(C)C=CC=CC=1>[Cl:10][C:4]1[CH:3]=[C:2]([C:32]2[N:28]([CH:23]3[CH2:24][CH2:25][CH2:26][CH2:27][O:22]3)[N:29]=[CH:30][CH:31]=2)[CH:9]=[CH:8][C:5]=1[C:6]#[N:7]
Reactant: CC1(C)OB(c2ccnn2C2CCCCO2)OC1(C)C
Reactant: N#Cc1ccc(Br)cc1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1ccc(-c2ccnn2C2CCCCO2)cc1Cl
Temperature: 42 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
4-Bromo-2-chlorobenzonitrile (30 g, 139 mmol), 90 ml of THF and 360 ml of toluene were placed in reaction vessel under nitrogen atmosphere. Bis(triphenylphosphine)-palladium(II) chloride (4.57 g, 6.51 mmol), Na2CO3 (33.1 g, 312 mmol), 180 ml of water and tetrabutylammonium bromide (0.894 g, 2.77 mmol) were added. The reaction mixture was heated up to 42° C. 1-(Tetrahydro-2H-pyran-2-yl)-1H-pyrazole-5-boronic acid pinacol ester (42.4 g; 152 mmol) was added in three portions within one hour. The reaction was agitated at 42° C. for one hour followed with addition of 180 ml of water and cool down. The reaction mixture was filtered and layers separated. Organic phase was washed with 400 ml of water. The layers were separated and the toluene phase was distilled close to dryness. 180 ml of ethanol was added to the warm residue and the mixture was cooled down to 5° C. for three hours. The precipitate was filtered and washed with cold ethanol. 36.4 g of the title compound was obtained after vacuum drying. 1H-NMR (400 MHz, DMSO-d6): δ 1.48-1.70 (m, 3H), 1.78-1.86 (m, 1H), 1.90-2.00 (m, 1H), 2.29-2.46 (m, 1H), 3.55-3.68 (m, 1H), 3.93-4.04 (m, 1H), 5.29 (dd, 1H), 6.72 (d, 1H), 7.65 (d, 1H), 7.72 (dd, 1H), 7.92 (d, 1H), 8.13 (d, 1H).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:16](=[O:17])[C:15]([C:18]([O:20]CC)=O)=[CH:14][N:6]3[CH2:7][C:8](=[O:13])[N:9]([CH3:12])[C:10]([CH:11]=1)=[C:5]23.[Cl:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][NH2:29])=[CH:26][CH:25]=1>C(#N)C>[Cl:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][NH:29][C:18]([C:15]2[C:16](=[O:17])[C:4]3[C:5]4[N:6]([CH:14]=2)[CH2:7][C:8](=[O:13])[N:9]([CH3:12])[C:10]=4[CH:11]=[C:2]([I:1])[CH:3]=3)=[O:20])=[CH:26][CH:25]=1
Reactant: CCOC(=O)c1cn2c3c(cc(I)cc3c1=O)N(C)C(=O)C2
Reactant: NCc1ccc(Cl)cc1
Solvent: CC#N
Product: CN1C(=O)Cn2cc(C(=O)NCc3ccc(Cl)cc3)c(=O)c3cc(I)cc1c32

Procedure:
A mixture of ethyl 9-iodo-1-methyl-2,7-dioxo-2,3-dihydro-1H,7H-pyrido[1,2,3-de]quinoxaline-6-carboxylate (Preparation 22, 400 mg) is stirred at 180° C. in 4-chlorobenzylamine (2.0 mL) for 1 h. The mixture is cooled and diluted with acetonitrile to give 412 mg of the title compound. Physical characteristics: M.p. 278-283° C.; 1H NMR (DMSO-d6) δ3.38, 4.55, 5.21, 7.35, 7.39, 7.69, 8.18, 8.76, 10.12. Anal. Found: C, 47.43; H, 3.01; N, 8.32; Cl, 7.14.
Reaction SMILES: O[C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11].P(Cl)(Cl)([Cl:17])=O.[Cl-].C([N+](CC)(CC)CC)CCC>C(#N)C>[Cl:17][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)c1c(O)cc(C)[nH]c1=O
Reactant: O=P(Cl)(Cl)Cl
Agent: CCCC[N+](CC)(CC)CC
Agent: [Cl-]
Solvent: CC#N
Product: CCOC(=O)c1c(Cl)cc(C)[nH]c1=O
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 44 %

Procedure:
A mixture of ethyl 4-hydroxy-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxylate (3.00 g, 15.2 mmol), phosphorus oxychloride (7.75 mL), n-butyltriethylammonium chloride (13.8 g, 60.8 mmol) and acetonitrile (60 mL) was stirred at 40° C. for 30 min and under refluxing conditions for 30 min. After cooling, the reaction mixture was concentrated under reduced pressure, water was added to the residue and the mixture was extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was washed with ethyl acetate-hexane mixed solution, and dried under reduced pressure to give the title compound (1.45 g, 44%) as a white powder.
Reaction SMILES: [ClH:1].O1CCOCC1.[CH2:8]([O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[C:24]([CH2:29][C@H:30]([N:35]([C:37](=[O:61])[C@H:38]([NH:53]C(OC(C)(C)C)=O)[CH2:39][CH2:40][CH2:41][NH:42][C:43]([O:45][CH2:46][C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)=[O:44])[CH3:36])[C:31]([O:33][CH3:34])=[O:32])[CH:23]=2)=[CH:18][C:17]=1[CH2:62][C@H:63]([NH:78][C:79]([O:81][CH2:82][C:83]1[CH:88]=[CH:87][CH:86]=[CH:85][CH:84]=1)=[O:80])[C:64]([O:66][C:67]1[C:72]([F:73])=[C:71]([F:74])[C:70]([F:75])=[C:69]([F:76])[C:68]=1[F:77])=[O:65])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>O1CCOCC1>[ClH:1].[NH2:53][C@H:38]([CH2:39][CH2:40][CH2:41][NH:42][C:43]([O:45][CH2:46][C:47]1[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=1)=[O:44])[C:37]([N:35]([CH3:36])[C@@H:30]([CH2:29][C:24]1[CH:23]=[C:22]([C:19]2[CH:20]=[CH:21][C:16]([O:15][CH2:8][C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)=[C:17]([CH2:62][C@H:63]([NH:78][C:79]([O:81][CH2:82][C:83]3[CH:84]=[CH:85][CH:86]=[CH:87][CH:88]=3)=[O:80])[C:64](=[O:65])[O:66][C:67]3[C:68]([F:77])=[C:69]([F:76])[C:70]([F:75])=[C:71]([F:74])[C:72]=3[F:73])[CH:18]=2)[CH:27]=[CH:26][C:25]=1[F:28])[C:31]([O:33][CH3:34])=[O:32])=[O:61]
Reactant: COC(=O)[C@H](Cc1cc(-c2ccc(OCc3ccccc3)c(C[C@H](NC(=O)OCc3ccccc3)C(=O)Oc3c(F)c(F)c(F)c(F)c3F)c2)ccc1F)N(C)C(=O)[C@@H](CCCNC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)[C@H](Cc1cc(-c2ccc(OCc3ccccc3)c(C[C@H](NC(=O)OCc3ccccc3)C(=O)Oc3c(F)c(F)c(F)c(F)c3F)c2)ccc1F)N(C)C(=O)[C@H](N)CCCNC(=O)OCc1ccccc1
Reaction time: 1 h

Procedure:
37 ml of a 4M hydrogen chloride-dioxane solution are added to a solution of 1.038 g (crude product, about 0.92 mmol) of pentafluorophenyl (2S)-3-(4-(benzyloxy)-3′-{(2S)-2-[{(2R)-5-{[(benzyloxy)carbonyl]amino}-2-[(tert-butoxycarbonyl)amino]-pentanoyl}(methyl)amino]-3-methoxy-3-oxopropyl}-4′-fluorobiphenyl-3-yl)-2-{[(benzyloxy)carbonyl]amino}propanoate (Example 21O) in 19 ml of anhydrous dioxane at 0° C. After 1 h at 0° C., the reaction solution is concentrated in vacuo, coevaporated several times with dichloromethane and dried under high vacuum. The crude product is reacted without further purification.
Reaction SMILES: C([O:3][C:4]([CH2:6][CH2:7][CH2:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]1)=O)C.C([NH2:24])=O.[O-]CC.[Na+]>CN(C)C=O>[C:4]([CH2:6][CH2:7][CH2:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]1)(=[O:3])[NH2:24]
Reactant: NC=O
Reactant: CCOC(=O)CCCC1CCN(C(=O)OC(C)(C)C)CC1
Agent: CC[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(CCCC(N)=O)CC1
Temperature: 100 °C

Procedure:
tert-Butyl 4-(3-ethoxycarbonylpropyl)piperidine-1-carboxylate (0.60 g, 2.0 mmol, the product of Production example 43-1) and formamide (0.27 ml, 6.7 mmol) were dissolved in N,N-dimethylformamide (1.0 ml); sodium ethoxide (0.095 g, 1.4 mmol) was added thereto while stirred and heated at 100° C.; the reaction mixture was stirred for 2 hours under nitrogen atmosphere. After cooled to room temperature, the reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (eluent; hexane-ethyl acetate=95:5 to 85:15). The title compound was obtained as a colorless oil (0.38 g, 1.4 mmol, 70%).
Reaction SMILES: [CH:1]1([NH:5][N:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([OH:16])=[C:8]([C:17]3[NH:22][C:21]4[CH:23]=[CH:24][C:25]([NH:27][S:28](=[O:41])(=[O:40])[NH:29]C(OCC5C=CC=CC=5)=O)=[CH:26][C:20]=4[S:19](=[O:43])(=[O:42])[N:18]=3)[C:7]2=[O:44])[CH2:4][CH2:3][CH2:2]1>O1CCCC1.CO.[Pd]>[CH:1]1([NH:5][N:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([OH:16])=[C:8]([C:17]3[NH:22][C:21]4[CH:23]=[CH:24][C:25]([NH:27][S:28]([NH2:29])(=[O:40])=[O:41])=[CH:26][C:20]=4[S:19](=[O:42])(=[O:43])[N:18]=3)[C:7]2=[O:44])[CH2:2][CH2:3][CH2:4]1
Reactant: O=C(NS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(c1c(O)c3ccccc3n(NC3CCC3)c1=O)N2)OCc1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: NS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(c1c(O)c3ccccc3n(NC3CCC3)c1=O)N2
Temperature: 25 °C
Reaction time: 24 h
Yield: 82.6 %

Procedure:
A solution of the product of Example 465 (0.790 g, 1.2 mmol) in tetrahydrofuran (80 mL) and methanol (20 mL) was treated with 10% palladium on carbon (200 mg) and stirred for 24 hours at 25° C. under a hydrogen atmosphere. The reaction was filtered through Celite® (diatomaceous earth) and the filtrate concentrated under reduced pressure to provide the title compound (0.500 g, 83% yield). 1H NMR (300 MHz, DMSO-d6) δ 1.58 (m, 1 H) 1.67 (m, 1 H) 2.03 (m, 4 H) 3.78 (m, 1 H) 6.56 (s, 1 H) 7.39 (s, 2 H) 7.44 (t, J=7.54 Hz, 1 H) 7.52 (m, 1 H) 7.64 (m, 2 H) 7.89 (t, J=7.91 Hz, 1 H) 8.07 (d, J=8.82 Hz, 1 H) 8.17 (d, J=8.46 Hz, 1 H) 10.06 (s, 1 H) 14.09 (s, 1 H) 15.14(s, 1 H). MS (ESI−) m/z 503 (M−H)−.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@H:10]1[O:18][C@H:17]2[C@H:13]([N:14]=[C:15]([N:19]([CH3:23])[C:20](=[O:22])[O-:21])[S:16]2)[C@@H:12]([OH:24])[C@@H:11]1[OH:25])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=1>CN(C=O)C>[Si:1]([O:8][CH2:9][C@H:10]1[O:18][C@H:17]2[C@H:13]([N:14]=[C:15]([N:19]([CH3:23])[C:20](=[O:21])[O:22][C:4]([CH3:7])([CH3:6])[CH3:5])[S:16]2)[C@@H:12]([O:24][CH2:29][C:30]2[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=2)[C@@H:11]1[O:25][CH2:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3]
Reactant: CN(C(=O)[O-])C1=N[C@@H]2[C@@H](O)[C@H](O)[C@@H](CO[Si](C)(C)C(C)(C)C)O[C@@H]2S1
Reactant: COc1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(CO[C@@H]2[C@H]3N=C(N(C)C(=O)OC(C)(C)C)S[C@H]3O[C@H](CO[Si](C)(C)C(C)(C)C)[C@H]2OCc2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 135.5 %

Procedure:
To a solution of (3aR,5R,6S,7R,7aR)-5-((tert-butyldimethylsilyloxy)methyl)-6,7-dihydroxy-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-2-yl(methyl)carbamate (20 g, 45 mmol) in DMF (150 mL) was added sodium hydride (10.7 g, 446 mmol) in portion at 0° C., and followed by addition of 1-(bromomethyl)-4-methoxybenzene (36 g, 179 mmol). The resulting solution was stirred for 2 h at room temperature, quenched with cold water (200 mL), and extracted with ethyl acetate (3×500 mL). The combined organic layers were washed with brine (5×200 mL), dried over anhydrous magnesium sulfate, and concentrated under vacuum to afford a residue, which was purified by silica gel column, eluted with 10% ethyl acetate in petroleum ether to give compound 27 as a yellow liquid (21 g, 68%). (ES, m/z): [M+H]+ 689.1. 1H NMR (300 MHz, CDCl3) δ 7.31-7.37 (m, 2H), 7.22-7.28 (m, 2H), 6.10-6.12 (d, J=6.9 Hz, 1H), 4.60-4.74 (m, 4H), 4.20-4.47 (m, 4H), 3.82 (s, 6H), 3.69 (s, 3H), 3.33-3.37 (m, 2H), 1.56 (s, 9H), 0.89 (s, 9H), 0.05 (s, 6H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[N+:21]([O-])=O)([CH3:4])([CH3:3])[CH3:2]>[Pd]>[C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH2:21])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOc1cc(NC(=O)OC(C)(C)C)c([N+](=O)[O-])cc1C(F)(F)F
Agent: [Pd]
Product: CCOc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F

Procedure:
The title compound was prepared from (5-ethoxy-2-nitro-4-trifluoromethyl-phenyl)-carbamic acid tert.-butyl ester (Example A9) (5.52 g, 15.8 mmol) by hydrogenation with 10% Pd/C according to the general procedure J (method a). Obtained as a yellow solid (3.84 g).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([OH:9])=O.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Br.[Br:42][CH2:43][CH2:44][NH2:45]>ClCCl.O>[Br:42][CH2:43][CH2:44][NH:45][C:7]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)=[O:9]
Reactant: O=C(O)c1ccccn1
Reactant: NCCBr
Agent: Br
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: O=C(NCCBr)c1ccccn1
Reaction time: 0.17 h
Yield: 52.5 %

Procedure:
Picolinic acid (0.99 g) in dichloromethane (30 mL) was treated with triethylamine (1.27 mL) and HATU (3.6 g). The mixture was stirred for 10 minutes then a solution of 2-bromoethylamine hydrobromide (1.5 g) and triethylamine (1.27 mL) in dichloromethane (20 mL) was added. The reaction mixture was stirred for 3h. Water (50 mL) was added and the layers were separated. The organic layer was washed with water (3×50 mL), dried over magnesium sulphate and evaporated to afford the crude product which was purified by silica gel chromatography eluting with 0-100% EtOAc/dichloromethane. The relevant fractions were combined and evaporated, dissolved up in EtOAc (40 mL) and washed with saturated sodium hydrogen carbonate solution, ensuring the aqueous layer remained basic. The organic layer was dried over magnesium sulphate and evaporated to give the sub-titled compound (0.88 g) as a white solid.
Reaction SMILES: [C:1]1([C:7]#[CH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:9]1([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[C:17](I)[CH:16]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[C:1]1([C:7]2[O:21][C:18]3[CH:19]=[CH:20][C:15]([C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=4)=[CH:16][C:17]=3[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C#Cc1ccccc1
Reactant: Oc1ccc(-c2ccccc2)cc1I
Product: c1ccc(-c2ccc3oc(-c4ccccc4)cc3c2)cc1

Procedure:
The general procedure was used to convert phenylacetylene and 4-phenyl-2-iodophenol to the title product. Purification by flash chromatography (10% CH2Cl2 in hexanes as the eluent) gave the analytically pure product as a white solid (427 mg, 79% yield). 1H NMR (300 MHz, CDCl3) δ 7.88 (d, J=7.53, 2H), 7.78-7.75 (m, 1H), 7.67-7.33 (m, 10H), 7.07 (s, 1H). 13C NMR (75 MHz, CDCl3) δ 156.56, 154.49, 141.63, 136.61, 130.37, 129.74, 128.79, 128.73, 128.62, 127.41, 126.86, 124.93, 123.98, 119.36, 111.25, 101.45. Anal. Calcd. For C20H14O: C, 88.86; H, 5.22. Found C, 88.99; H, 5.28. m.p.: 166-167° C. (lit., 8166-168° C.).
Reaction SMILES: [S:1](=[N:4][C:5]1[CH:6]=[C:7]([CH:13](C(NC)=S)[C:14]([OH:16])=[O:15])[CH:8]=[CH:9][C:10]=1[O:11][CH3:12])(=[O:3])=[O:2].S(=N[C:25]1C=C(CC(O)=O)C=CC=1OC)(=O)=O.[OH-].[Na+].CN=C=S.Cl>CN(C=O)C>[S:1](=[N:4][C:5]1[CH:6]=[C:7]([CH2:13][C:14]([OH:16])=[O:15])[CH:8]=[CH:9][C:10]=1[O:11][CH2:12][CH3:25])(=[O:3])=[O:2]
Reactant: COc1ccc(CC(=O)O)cc1N=S(=O)=O
Reactant: CNC(=S)C(C(=O)O)c1ccc(OC)c(N=S(=O)=O)c1
Agent: CN=C=S
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOc1ccc(CC(=O)O)cc1N=S(=O)=O
Temperature: 70 °C
Reaction time: 2 h

Procedure:
Preparation of 3-sulfonylamino-N-methylaminothiocarbonyl-4-methoxyphenylacetic acid ##STR18## 5 g of 3-sulfonylamino-4-methoxyphenylacetic acid were dissolved in 3 ml of DMF and stirred at 40° C. for 30 minutes with 245 mg of sodium hydroxide. 328 mg of methyl isothiocyanate were added thereto and the mixture was stirred for a further 2 h at 70° C. 2N hydrochloric acid was added to the cooled solution and the product was filtered off with suction. M.p. 174° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:26])=[C:8]2[C:14](Br)=[C:13](Br)[N:12]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:24][CH3:25])[C:9]2=[CH:10][N:11]=1)=[O:5])[CH3:2].C([O-])=O.[NH4+]>[Pd]>[CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:26])=[C:8]2[CH:14]=[CH:13][N:12]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:24][CH3:25])[C:9]2=[CH:10][N:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ncc2c(c1O)c(Br)c(Br)n2Cc1ccccc1OC
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Product: CCOC(=O)c1ncc2c(ccn2Cc2ccccc2OC)c1O

Procedure:
Prepared in analogy to that of Example 6(a) from 2,3-dibromo-1-(2-methoxy-benzyl)-4-hydroxy-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester, ammonium formate and Pd/C. The title compound, ESI MS (m/z): 327 (M+H)+.
Reaction SMILES: F[C:2]1[C:7]([C:8]2[N:13]=[C:12]([CH3:14])[N:11]=[C:10]([N:15]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=3)[CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[N:9]=2)=[CH:6][C:5]([CH:34]2[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)=[CH:4][N:3]=1.[F:40][C:41]1[CH:42]=[C:43]([NH2:49])[CH:44]=[N:45][C:46]=1[O:47][CH3:48].C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1>[F:40][C:41]1[CH:42]=[C:43]([NH:49][C:2]2[C:7]([C:8]3[N:13]=[C:12]([CH3:14])[N:11]=[C:10]([N:15]([CH2:25][C:26]4[CH:27]=[CH:28][C:29]([O:32][CH3:33])=[CH:30][CH:31]=4)[CH2:16][C:17]4[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=4)[N:9]=3)=[CH:6][C:5]([CH:34]3[CH2:35][CH2:36][O:37][CH2:38][CH2:39]3)=[CH:4][N:3]=2)[CH:44]=[N:45][C:46]=1[O:47][CH3:48]
Reactant: COc1ncc(N)cc1F
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C4CCOCC4)cnc3F)n2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C4CCOCC4)cnc3Nc3cnc(OC)c(F)c3)n2)cc1
Reaction time: 0.25 h
Yield: 85 %

Procedure:
A mixture of 4-(2-fluoro-5-(tetrahydro-2H-pyran-4-yl)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (210 mg, 0.397 mmol) and 5-fluoro-6-methoxypyridin-3-amine (85 mg, 0.595 mmol) in 1.5 mL of THF at 0° C. was treated with sodium bis(trimethylsilyl)amide (0.99 mL of 1.0 M solution in tetrahydrofuran, 0.99 mmol). It was stirred at this temperature for 15 min, then quenched with sat NH4Cl (5 mL) and extracted with 2×10 mL of EtOAc. The combined organic solution was dried with sodium sulfate and concentrated. The residue was purified on a silica gel column and eluted with 10-30% EtOAc in DCM to give the title compound (220 mg, 85% yield) as a brown amorphous solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.65 (s, 1H), 8.56 (d, J=2.6 Hz, 1H), 8.26 (d, J=2.4Hz, 1H), 8.07 (m, 2H), 7.29 (d, J=8.6 Hz, 2H), 7.22 (d, J=8.4 Hz, 2H), 6.91 (d, J=8.6Hz, 2H), 6.85 (d, J=8.6 Hz, 2H), 4.87 (s, 2H), 4.80 (s, 2H), 3.96 (m, 2H), 3.91 (s, 3H), 3.74 (s, 3H), 3.69 (s, 3H), 3.45 (m, 2H), 2.78 (m, 1H), 2.57 (s, 3H), 1.67 (m, 4H). m/z (ESI, positive ion) 652.0 (M+H)+.