Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[N:12]1[N:16]=[C:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:14]([O:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([O:29][C:30]([F:33])([F:32])[F:31])[CH:24]=2)=[N:13]1.S(=O)(=O)(O)O.N(OCCC(C)C)=O.OP=O>C(O)C.[Cl-].[Na+]>[F:33][C:30]([F:31])([F:32])[O:29][C:25]1[CH:24]=[C:23]([CH:28]=[CH:27][CH:26]=1)[O:22][C:14]1[C:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[N:16][N:12]([C:3]2[CH:4]=[CH:5][C:6]([C:8]([F:11])([F:10])[F:9])=[CH:7][CH:2]=2)[N:13]=1
Reactant: CCOC(=O)c1nn(-c2ccc(C(F)(F)F)cc2N)nc1Oc1cccc(OC(F)(F)F)c1
Agent: CC(C)CCON=O
Agent: O=PO
Agent: O=S(=O)(O)O
Solvent: CCO
Product: CCOC(=O)c1nn(-c2ccc(C(F)(F)F)cc2)nc1Oc1cccc(OC(F)(F)F)c1
Temperature: -20 °C
Reaction time: 1 h

Procedure:
To a solution of ethyl 2-[2-amino-4-(trifluoromethyl)phenyl]-5-[3-(trifluoromethoxy)phenoxy]-2H-1,2,3-triazole-4-carboxylate (i.e. the product of Step G, 0.70 g, 1.5 mmol) in ethanol (20 mL) was added concentrated sulfuric acid (2 mL). The stirring mixture was cooled to −20° C., and then isopentyl nitrite (0.91 g, 8.8 mmol) was added dropwise over 5 min. The reaction mixture was stirred at −20° C. for 1 h, after which an aqueous solution of hypophosphorus acid (3.9 g, 29.4 mmol, 50% in water) was added. The solution was stirred at 23° C. for 14 h. The reaction mixture was diluted with saturated aqueous sodium chloride solution (20 mL), extracted with ethyl acetate (2×40 mL), and washed with saturated aqueous sodium bicarbonate solution (2×20 mL). The organic layer was dried (MgSO4) and concentrated under reduced pressure to afford the crude residue which was purified by chromatography on silica gel eluting with 0 to 15% ethyl acetate in hexanes to obtain the title compound (0.55 g) as a colorless solid.
Reaction SMILES: [CH:1]1([N:7]2[C:15]3[C:14](=[O:16])[NH:13][C:12]([C:17]4[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][C:18]=4[O:27][CH2:28][CH3:29])=[N:11][C:10]=3[C:9]([CH3:30])=[N:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:31][N:32]1[CH2:38][CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>>[CH:1]1([N:7]2[C:15]3[C:14](=[O:16])[NH:13][C:12]([C:17]4[CH:22]=[CH:21][C:20]([S:23]([N:35]5[CH2:36][CH2:37][CH2:38][N:32]([CH3:31])[CH2:33][CH2:34]5)(=[O:25])=[O:24])=[CH:19][C:18]=4[O:27][CH2:28][CH3:29])=[N:11][C:10]=3[C:9]([CH3:30])=[N:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOc1cc(S(=O)(=O)Cl)ccc1-c1nc2c(C)nn(C3CCCCC3)c2c(=O)[nH]1
Reactant: CN1CCCNCC1
Product: CCOc1cc(S(=O)(=O)N2CCCN(C)CC2)ccc1-c1nc2c(C)nn(C3CCCCC3)c2c(=O)[nH]1
Yield: 83 %

Procedure:
The same reaction procedure as in Example 49 was performed, except that the compound obtained in Example 255 was used in place of the compound obtained in Example 48, and N-methyl-1,4-diazacycloheptane was used in place of N-methylpiperazine. In this manner, 145 mg (83%) of the captioned compound was obtained.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[O:6][C@@H:5]([CH2:7][CH:8]([CH3:10])[CH3:9])[C@@H:4]([CH:11]=C)[O:3]1.[O:14]=[O+][O-]>ClCCl>[CH3:13][C:2]1([CH3:1])[O:6][C@@H:5]([CH2:7][CH:8]([CH3:9])[CH3:10])[C@H:4]([CH:11]=[O:14])[O:3]1
Reactant: O=[O+][O-]
Reactant: C=C[C@H]1OC(C)(C)O[C@H]1CC(C)C
Solvent: ClCCl
Product: CC(C)C[C@@H]1OC(C)(C)O[C@H]1C=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A dichloromethane solution of the product of Example 16B (1 g) is cooled to -78° C. and a stream of ozone is passed through the solution until a blue color persists. Excess ozone is removed with nitrogen ebullition and dimethyl sulfide (1 mL) is added. The reaction is allowed to warm to room temperature and stirred overnight. The solvents are removed under reduced pressure, and the title compound is obtained following purification by silica gel chromatography.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]=[C:7]([CH2:15][CH2:16][S:17][CH3:18])[C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:4].[Li+].[OH-].C1COCC1>CO>[CH3:18][S:17][CH2:16][CH2:15][C:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:14]=[C:5]([C:3]([OH:4])=[O:2])[N:6]=1
Reactant: COC(=O)c1cc2ccccc2c(CCSC)n1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CSCCc1nc(C(=O)O)cc2ccccc12
Yield: 91.7 %

Procedure:
1-(2-methylsulfanyl-ethyl)-isoquinoline-3-carboxylic acid was prepared according to General Procedure B using 49 mg (0.187 mmol) of 1-(2-methylsulfanyl-ethyl)-isoquinoline-3-carboxylic acid methyl ester, 0.28 mL of 2 N aq. LiOH, 2 mL of THF and 0.5 mL of methanol stirring at room temperature for 1 h. 42.4 mg (91%) of 1-(2-methylsulfanyl-ethyl)-isoquinoline-3-carboxylic acid was obtained. LCMS: 248 (M+1)+.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][C:6]=1[C:7]([OH:9])=O)([CH3:3])[CH3:2].Cl.[F:19][C:20]([F:33])([F:32])[C:21]1[S:25][C:24]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[N:23][CH:22]=1>>[CH:1]([O:4][C:5]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][C:6]=1[C:7]([N:29]1[CH2:30][CH2:31][N:26]([C:24]2[S:25][C:21]([C:20]([F:33])([F:19])[F:32])=[CH:22][N:23]=2)[CH2:27][CH2:28]1)=[O:9])([CH3:2])[CH3:3]
Reactant: FC(F)(F)c1cnc(N2CCNCC2)s1
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)O
Agent: Cl
Product: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCN(c2ncc(C(F)(F)F)s2)CC1
Yield: 28 %

Procedure:
Prepared in analogy to example 1 (b) from 2-isopropoxy-5-methanesulfonyl-benzoic acid (Example A1) and 1-(5-trifluoromethyl-thiazol-2-yl)-piperazine hydrochloride. The crude material was purified by chromatography (SiO2, ethyl acetate/heptane) followed by trituration in pentane to yield the title compound as a white crystalline solid (yield 28%). MS (m/e): 478.3 (M+H+, 100%).
Reaction SMILES: [C:1]1([NH:7][S:8]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][C:15](=[O:20])[CH2:14]3)(=[O:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:21]1([CH2:26][CH2:27][O:28][C:29]2[CH:30]=[C:31]3[C:35](=[CH:36][CH:37]=2)[NH:34][C:33]([CH:38]=O)=[CH:32]3)[CH2:25][CH2:24][CH2:23][CH2:22]1>>[C:1]1([NH:7][S:8]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][C:15](=[O:20])[C:14]3=[CH:38][C:33]2[NH:34][C:35]3[C:31]([CH:32]=2)=[CH:30][C:29]([O:28][CH2:27][CH2:26][N:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:37][CH:36]=3)(=[O:10])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1Cc2cc(S(=O)(=O)Nc3ccccc3)ccc2N1
Reactant: O=Cc1cc2cc(OCCN3CCCC3)ccc2[nH]1
Product: O=C1Nc2ccc(S(=O)(=O)Nc3ccccc3)cc2C1=Cc1cc2cc(OCCN3CCCC3)ccc2[nH]1

Procedure:
2-Oxo-2,3-dihydro-1H-indole-5-sulfonic acid phenylamide was condensed with 5-(2-pyrrolidin-1-yl-ethoxy)-1H-indole-2-carbaldehyde to give the title compound.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:4]2[C:14]([O:15][CH2:16][C@H:17]3[CH2:22][CH2:21][CH2:20][CH2:19][NH2+:18]3)=[CH:13][CH:12]=[CH:11][C:5]=2[NH:6][S:7](=[O:10])(=[O:9])[N:8]=1.[N:23]1[CH:28]=[CH:27][C:26]([C:29](O)=[O:30])=[CH:25][N:24]=1>>[NH2:2][C:3]1[C:4]2[C:14]([O:15][CH2:16][C@H:17]3[CH2:22][CH2:21][CH2:20][CH2:19][N:18]3[C:29]([C:26]3[CH:27]=[CH:28][N:23]=[N:24][CH:25]=3)=[O:30])=[CH:13][CH:12]=[CH:11][C:5]=2[NH:6][S:7](=[O:9])(=[O:10])[N:8]=1
Reactant: O=C(O)c1ccnnc1
Reactant: NC1=NS(=O)(=O)Nc2cccc(OC[C@H]3CCCC[NH2+]3)c21
Agent: Cl
Product: NC1=NS(=O)(=O)Nc2cccc(OC[C@H]3CCCCN3C(=O)c3ccnnc3)c21

Procedure:
Prepared as in Example 15 from (R)-2-(((4-amino-2,2-dioxido-1H-benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidinium hydrochloride (Example 15a) and pyridazine-4-carboxylic acid. 1H NMR (400 MHz, DMSO-d6) δ 1.46-1.89 (m, 6H), 2.24 (s, 3H), 3.28 (m, 2H), 4.26 (m, 1H), 4.64 (t, 1H, J=10.1 Hz), 5.29 (m, 1H), 6.62 (d, 1H, J=8.2 Hz), 6.87 (d, 1H, J=8.2 Hz), 7.46 (t, 1H, J=8.2 Hz), 7.69 (dd, 1H, J=5.0, 1.8 Hz), 7.77 (br s, 1H), 8.37 (br s, 1H), 9.26 (m, 1H), 9.35 (d, 1H, J=5.0 Hz), 10.94 (s, 1H). MS 417 (MH+).
Reaction SMILES: COC1C=CC(C2CCC3C(=CC=C(OC)C=3)C2)=C(N)C=1.Cl.[CH:23]([N:26]([CH:40]([CH3:42])[CH3:41])[CH2:27][CH2:28][O:29][C:30]1[CH:38]=[CH:37][C:33]([C:34](O)=O)=[CH:32][C:31]=1[F:39])([CH3:25])[CH3:24].C(N(C(C)C)CCOC1C=C[C:53]([CH2:54][NH:55][C:56]2[CH:61]=[C:60]([O:62][CH3:63])[CH:59]=[CH:58][C:57]=2[CH:64]2[CH2:73][CH2:72][C:71]3[C:66](=[CH:67][CH:68]=[C:69]([O:74][CH3:75])[CH:70]=3)[CH2:65]2)=CC=1F)(C)C>>[CH:23]([N:26]([CH:40]([CH3:42])[CH3:41])[CH2:27][CH2:28][O:29][C:30]1[CH:38]=[CH:37][C:33]([CH2:34][N:55]([CH2:54][CH3:53])[C:56]2[CH:61]=[C:60]([O:62][CH3:63])[CH:59]=[CH:58][C:57]=2[CH:64]2[CH2:73][CH2:72][C:71]3[C:66](=[CH:67][CH:68]=[C:69]([O:74][CH3:75])[CH:70]=3)[CH2:65]2)=[CH:32][C:31]=1[F:39])([CH3:25])[CH3:24]
Reactant: CC(C)N(CCOc1ccc(C(=O)O)cc1F)C(C)C
Reactant: COc1ccc2c(c1)CCC(c1ccc(OC)cc1NCc1ccc(OCCN(C(C)C)C(C)C)c(F)c1)C2
Agent: COc1ccc(C2CCc3cc(OC)ccc3C2)c(N)c1
Agent: Cl
Product: CCN(Cc1ccc(OCCN(C(C)C)C(C)C)c(F)c1)c1cc(OC)ccc1C1CCc2cc(OC)ccc2C1

Procedure:
Synthesized from 5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenylamine and 4-(2-diisopropylaminoethoxy)-3-fluorobenzoic acid hydrochloride according to an analogous synthetic method to Example 152, [4-(2-diisopropylaminoethoxy)-3-fluorobenzyl][5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]amine (459 mg) was used according to an analogous synthetic method to Example 36 to provide [4-(2-diisopropylaminoethoxy)-3-fluorobenzyl]ethyl[5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]amine (429 mg). This compound (427 mg) was used according to an analogous synthetic method to Example 111 to provide the title compound (303 mg).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([C:12]3([OH:18])[CH2:17]COCC3)[N:8]2[CH3:11])=[C:4]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][C@@H:20]2[CH3:25])[N:3]=1.[O:26]1CC(=O)[CH2:27]1>>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([C:12]3([OH:18])[CH2:17][O:26][CH2:27]3)[N:8]2[CH3:11])=[C:4]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][C@@H:20]2[CH3:25])[N:3]=1
Reactant: C[C@H]1COCCN1c1nc(Cl)nc2c1nc(C1(O)CCOCC1)n2C
Reactant: O=C1COC1
Product: C[C@H]1COCCN1c1nc(Cl)nc2c1nc(C1(O)COC1)n2C

Procedure:
This compound was prepared in an analogous fashion to (S)-4-(2-chloro-9-methyl-6-(3-methylmorpholino)-9H-purin-8-yl)tetrahydro-2H-pyran-4-ol, using 3-oxetanone as the starting material. 1H NMR (CDCl3, 400 MHz) δ ppm 5.35 (broad s, 2H), 5.15 (t, J=6.9 Hz, 2H), 4.96 (d, J=7.2 Hz, 2H), 4.00 (dd, J=11.2, 3 Hz, 1H), 3.84 (s, 3H), 3.81 to 3.71 (m, 2H), 3.59 (td, J=11.6, 2.7 Hz, 1H), 3.47 (broad s, 1H), 1.39 (d, J=6.8 Hz, 3H); LC-MS m/z (method B2)=340/342 [M+H]+, RT=1.59 min.
Reaction SMILES: [OH-].[K+].C([OH:7])(C)(C)C.[CH3:8][C:9]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][C:10]=1[O:11][CH2:12][C:13]1[CH:23]=[CH:22][CH:21]=[CH:20][C:14]=1[C:15]([C:18]#[N:19])=[N:16][OH:17].Cl>O>[CH3:8][C:9]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][C:10]=1[O:11][CH2:12][C:13]1[CH:23]=[CH:22][CH:21]=[CH:20][C:14]=1[C:15](=[N:16][OH:17])[C:18]([NH2:19])=[O:7]
Reactant: CC(C)(C)O
Reactant: Cc1ccc(C)c(OCc2ccccc2C(C#N)=NO)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: Cc1ccc(C)c(OCc2ccccc2C(=NO)C(N)=O)c1
Yield: 60 %

Procedure:
85% Potassium hydroxide (6.12 g, 92.8 mmol) and tert-butyl alcohol (15 ml) were added to 2-(2,5-dimethylphenoxymethyl)-α-hydroxyiminobenzyl cyanide(E/Z=15/85)(1.30 g, 4.64 mmol). The mixture was heated under reflux for 5 hours. After completion of the reaction, the reaction mixture was neutralized with 6N hydrochloric acid, and water (100 ml) was added. The resulting mixture was extracted with ether (100 ml), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting crystals were recrystallized from n-hexane/ethyl acetate to give 2-[2-(2,5dimethylphenoxymethyl)phenyl]-2-hydroxyiminoacetamide (0.83 g, Yield: 60.0%, Z=at least 98%) as colorless crystals.
Reaction SMILES: [CH3:1][CH2:2][C@@:3]1([OH:26])[C:8](=[O:9])[O:7][CH2:6][C:5]2[C:10]([N:12]3[C:24](=[CH:25][C:4]1=2)[C:23]1[N:22]=[C:21]2[C:16]([CH:17]=[CH:18][CH:19]=[CH:20]2)=[CH:15][C:14]=1[CH2:13]3)=[O:11].C(O)(=O)[CH2:28][OH:29].S(OOS([O-])(=O)=O)([O-])(=O)=O.[NH4+].[NH4+]>S(=O)(=O)(O)O.[N+]([O-])([O-])=O.[Ag+]>[CH3:1][CH2:2][C@@:3]1([OH:26])[C:8](=[O:9])[O:7][CH2:6][C:5]2[C:10]([N:12]3[C:24](=[CH:25][C:4]1=2)[C:23]1[C:14](=[C:15]([CH2:28][OH:29])[C:16]2[C:21]([N:22]=1)=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:13]3)=[O:11]
Reactant: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2cc3ccccc3nc2-1
Reactant: O=C(O)CO
Agent: [Ag+]
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Product: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2c-1nc1ccccc1c2CO
Temperature: 0 °C

Procedure:
Camptothecin (50 mg, 0.143 m-mol) was dissolved in 75% sulfuric acid (3 ml). To this solution were added glycolic acid (500 mg, 6.57 m-mol) and silver nitrate (250 mg, 1.31 m-mol) and then was added dropwise under heating (100°-110° C.) and agitation and aqueous solution (15 ml) of ammonium persulfate (3.00 g, 0.0131 m-mol) over 2 hours. After the reaction mixture was allowed to cool, ice water (100 ml) was poured into the reaction mixture which was then extracted with chloroform (100 ml×3). The chloroform layers were combined, washed with a 7% aqueous solution of sodium bicarbonate (300 ml) and then with a saturated edible salt solution (100 ml), dried with anhydrous magnesium sulfate, filtered and evaporated until dryness under reduced pressure. The residue was subjected to thin layer chromatography (5% methanol-chloroform) to effect separation and purification of 7-hydroxymethylcamptothecin whereupon 10.3 mg (19.0%) of pure 7-hydroxymethylcamptothecin were obtained. Besides this, 10.7 mg of camptothecin were recovered.
Reaction SMILES: Br[CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[F:10][C:11]([F:15])([F:14])[CH2:12][NH2:13]>>[F:10][C:11]([F:15])([F:14])[CH2:12][NH:13][CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4]
Reactant: NCC(F)(F)F
Reactant: CC(C)(C)OC(=O)CBr
Product: CC(C)(C)OC(=O)CNCC(F)(F)F
Yield: 74 %

Procedure:
The subtitled compound was synthesized by the method of example 15 step (i) from tert-butyl bromoacetate (13.6 g) and 2,2,2-trifluoroethylamine (8.9 g). The sub-title compound (11 g) was obtained as a colourless oil; 1H NMR (300 MHz, CDCl3); 3.39 (2H, s), 3.20 (2H, q, J=9.4 Hz), 1.44 (9H, s).
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:20]=[CH:19][C:18](/[C:21](/[CH3:28])=[CH:22]/[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:17][CH:16]=3)=[N:11]2)=[CH:6][CH:5]=1>[Pd].C(OCC)(=O)C>[F:30][C:2]([F:1])([F:29])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([CH:21]([CH3:28])[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:17][CH:16]=3)=[N:11]2)=[CH:6][CH:5]=1
Reactant: CCOC(=O)/C=C(\C)c1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)CC(C)c1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
A flask containing (E)-ethyl 3-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)but-2-enoate (C26) (1.80 g, 4.31 mmol) and palladium on carbon (10 wt %, 0.46 g, 0.43 mmol) in ethyl acetate (14.5 mL) was evacuated and backfilled with nitrogen, and then evacuated and placed under hydrogen by balloon (˜1 atm). The reaction was stirred at room temperature overnight, and then filtered through Celite® and concentrated to afford the title compound as a tan liquid (1.79 g, 98%): 1H NMR (400 MHz, CDCl3) δ 8.55 (s, 1H), 8.17-8.07 (m, 2H), 7.87-7.75 (m, 2H), 7.38 (d, J=9.1 Hz, 2H), 7.36-7.31 (m, 2H), 4.08 (qd, J=7.1, 0.8 Hz, 2H), 3.35 (dd, J=14.6, 7.2 Hz, 1H), 2.62 (qd, J=15.1, 7.6 Hz, 2H), 1.34 (d, J=7.0 Hz, 3H), 1.19 (t, J=7.1 Hz, 3H); 19F NMR (376 MHz, CDCl3) δ −58.03; ESIMS m/z 420 ([M+H]+).
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][CH:5]=1.[C:11]([C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)#[CH:12].N>>[N:6]1[CH:7]=[CH:8][CH:9]=[C:4]([C:3]2[CH:12]=[C:11]([C:13]3[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=3)[O:1][N:2]=2)[CH:5]=1
Reactant: C#Cc1cccnc1
Reactant: ON=C(Cl)c1cccnc1
Agent: N
Product: c1cncc(-c2cc(-c3cccnc3)on2)c1

Procedure:
The titled compound was prepared as the bishydrochloride salt according to Method CA using the product of Example 1A (0.78 g, 5.0 mmol) and 3-ethynylpyridine (Aldrich, 0.52 g, 5.0 mmol). 1H NMR (300 MHz, DMSO-d6) δ 7.76 (dd, J=8.1, 5.1 Hz, 1H), 7.79-7.86 (m, 1H), 7.98 (s, 1H), 8.44 (dt, J=8.0, 2.0, 1.9 Hz, 1H), 8.55 (dt, J=8.1, 1.9 Hz, 1H), 8.80 (dd, J=4.9, 1.5 Hz, 1H), 8.86 (dd, J=5.1, 1.7 Hz, 1H), 9.21 (d, J=2.0 Hz, 1H), 9.23 (d, J=2.0 Hz, 1H) ppm; MS (DCI/NH3) m/z 224 (M+H)+.
Reaction SMILES: [O:1]=[C:2]([C:9]#[C:10][Si](C)(C)C)[CH2:3][CH2:4][CH2:5][C:6]([OH:8])=[O:7]>CO.O>[O:1]=[C:2]([C:9]#[CH:10])[CH2:3][CH2:4][CH2:5][C:6]([OH:8])=[O:7]
Reactant: C[Si](C)(C)C#CC(=O)CCCC(=O)O
Solvent: CO
Solvent: O
Product: C#CC(=O)CCCC(=O)O
Temperature: 45 °C
Reaction time: 18 h

Procedure:
The known 5-oxo-7-(trimethylsilyl)hept-6-ynoic acid (1.15 g, 2; prepared using the procedure described in J. Org. Chem., Vol. 62, No. 4, 1997, p. 982-991) was dissolved in methanol (40 ml) and a solution of Borax (Na2B4O7×10H2O, 2.7 g) in water (6 ml) was added. The resulting reaction mixture was stirred for 18 h at 45° C. under argon. The reaction mixture was then quenched by the addition of 1 M HCl (20 ml) and methanol removed in vacuo. The remaining aqueous solution was then extracted with ethyl acetate (4×35 ml). After washing the pooled organic extracts with brine (2×40 ml), drying with MgSO4 and then filtering, volatiles were removed in vacuo. The crude orange oil remaining was purified by flash chromatography (5% ethyl acetate→10%→15% ethyl acetate/hexane) yielding a pale yellow oil product, 5-oxohept-6-ynoic acid (328 mg, 3), which crystallized under storage. 1H NMR (400 MHz, CDCl3): δ1.75 (m, 2H), 2.22 (t, 2H), 2.63 (t, 2H), 4.8 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]2[C:9]([C:13]3[NH:30][C:16]4=[N:17][CH:18]=[CH:19][C:20](/[CH:21]=[N:22]/[C:23]5[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=5)=[C:15]4[CH:14]=3)=[CH:10][N:11]([CH3:12])[C:6]2=[CH:5][C:4]=1[O:31][CH3:32].C([BH3-])#N.[Na+].[OH-].[Na+]>CO.O.ClCCl.[Cl-].[Zn+2].[Cl-]>[CH3:1][O:2][C:3]1[N:8]=[C:7]2[C:9]([C:13]3[NH:30][C:16]4=[N:17][CH:18]=[CH:19][C:20]([CH2:21][NH:22][C:23]5[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=5)=[C:15]4[CH:14]=3)=[CH:10][N:11]([CH3:12])[C:6]2=[CH:5][C:4]=1[O:31][CH3:32]
Reactant: COc1cc2c(nc1OC)c(-c1cc3c(/C=N/c4ccc(O)cc4)ccnc3[nH]1)cn2C
Agent: [BH3-]C#N
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: COc1cc2c(nc1OC)c(-c1cc3c(CNc4ccc(O)cc4)ccnc3[nH]1)cn2C
Reaction time: 4 h
Yield: 46.8 %

Procedure:
To a solution of 0.085 g of 4-{[1-[2-(5,6-dimethoxy-1-methyl-1H-pyrrolo[3,2-b]pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl]meth-(E)-ylidene]amino}phenol in 20 cm3 of methanol, at a temperature in the region of 20° C., are added 0.013 g of zinc chloride and 0.013 g of sodium cyanoborohydride. The reaction medium is stirred at the same temperature for 4 hours. The reaction medium is concentrated under reduced pressure. The residue obtained is taken up in 10 cm3 of water and 25 cm3 of dichloromethane, and then basified with 0.1N sodium hydroxide. After separation of the phases by settling, the organic phase is dried over magnesium sulfate, filtered and then concentrated under reduced pressure to give 0.04 g of 4-{[2-(5,6-dimethoxy-1-methyl-1H-pyrrolo[3,2-b]pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridin-4-ylmethyl]amino}phenol with the following characteristics:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=1)[CH:10]=O.N1C=CC=CC=1C1C=C[C:24]([CH:25]=[O:26])=CC=1>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:8]=[C:9](/[CH:10]=[CH:24]/[CH:25]=[O:26])[CH:12]=[CH:13][CH:14]=1
Reactant: O=Cc1cccc(-c2ccccn2)c1
Reactant: O=Cc1ccc(-c2ccccn2)cc1
Product: O=C/C=C/c1cccc(-c2ccccn2)c1

Procedure:
The title compound was prepared by a procedure analogous to Reference Example 31 by substituting 3-(2-pyridinyl)benzaldehyde (prepared as described in Reference Example 23) for the 4-(2-pyridinyl)-benzaldehyde of Reference Example 31. MS 210 (M+H)+.
Reaction SMILES: [C:1]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][C:4]([SH:7])=[CH:3][CH:2]=1.Cl[C:15]([O:17][CH2:18][CH:19]([CH3:21])[CH3:20])=[O:16].[OH-].[Na+]>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.ClCCl>[C:15](=[O:16])([O:17][CH2:18][CH:19]([CH3:21])[CH3:20])[S:7][C:4]1[CH:3]=[CH:2][C:1]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:6][CH:5]=1
Reactant: Sc1ccc(-c2ccccc2)cc1
Reactant: CC(C)COC(=O)Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)COC(=O)Sc1ccc(-c2ccccc2)cc1
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 90.2 %

Procedure:
A mixture of 9.3 g of [1,1'-biphenyl]-4-thiol (alternatively named 4'-mercapto-1,1'-biphenyl), 40 mL of dichloromethane, 0.21 g of tetrabutylammonium hydrogen sulfate, and 7.2 g of isobutyl chloroformate was cooled to 5° C. and 10.2 g of 20% aqueous NaOH was added over 10 min. The mixture was allowed to stir for 30 min at 15° C. the phases were separated, and the organic phase was concentrated to dryness. The residue was slurried in 100 mL of cold isopropanol, filtered, and suction-dried to afford 12.9 g (92% yield) of product, m.p. 78-79° C. 1H NMR (CDCl3): δ0.90 (d, 6H), 2.00 (s, 1H), 4.05 (d, 7.35-7.50 (m, 3H), 7.60 (d, 2H), 7.60 (s, 4H).
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16]([C:21](O)=[O:22])=[CH:15]3)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].Cl.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[NH:47]1[CH2:52][CH2:51][S:50][CH2:49][CH2:48]1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16]([C:21]([N:47]2[CH2:52][CH2:51][S:50][CH2:49][CH2:48]2)=[O:22])=[CH:15]3)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)O)cc3c2)CC1
Reactant: C1CSCCN1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCSCC4)cc3c2)CC1

Procedure:
The title compound was synthesized in analogy to example 1, from 5-(4-isopropyl-piperazine-1-carbonyl)-1H-indole-2-carboxylic acid 1:1 hydrochloride, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (commercially available), thiomorpholine (commercially available) and N,N-diisopropylethylamine in N,N-dimethylformamide to give the desired product after purification by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile/water/formic acid.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)=[CH:2][CH3:3].[H][H]>[Pd].C1COCC1>[CH2:1]([C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)[CH2:2][CH3:3]
Reactant: CC=Cc1cccc(O)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: CCCc1cccc(O)c1
Temperature: 25 °C
Yield: 100 %

Procedure:
To a mixture of Part B (1) compound (3 g, 22.4 mmol) and 10% palladium on carbon (150 mg) in THF (25 mL) was connected a hydrogen balloon. Hydrogenation was maintained at RT overnight. The mixture of reaction was filtered through Celite. The resulting clear solution was evaporated to give the title compound (2.97 g, 100%) as a yellowish oil.