Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=S(Cl)Cl.[NH2:5][C:6]1[CH:7]=[C:8]([CH:27]=[CH:28][C:29]=1[NH2:30])[C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][N:20]2[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]2)=[CH:14][CH:13]=1)=[O:10].[OH:31][C:32]1[CH:39]=[CH:38][C:37]([C:40]2[CH:45]=[CH:44][CH:43]=[C:42]([O:46][CH3:47])[N:41]=2)=[CH:36][C:33]=1[CH:34]=O.CO>ClCCl>[CH3:26][N:23]1[CH2:24][CH2:25][N:20]([CH2:19][CH2:18][C:15]2[CH:14]=[CH:13][C:12]([NH:11][C:9]([C:8]3[CH:27]=[CH:28][C:29]4[NH:30][C:34]([C:33]5[CH:36]=[C:37]([C:40]6[CH:45]=[CH:44][CH:43]=[C:42]([O:46][CH3:47])[N:41]=6)[CH:38]=[CH:39][C:32]=5[OH:31])=[N:5][C:6]=4[CH:7]=3)=[O:10])=[CH:17][CH:16]=2)[CH2:21][CH2:22]1
Reactant: CN1CCN(CCc2ccc(NC(=O)c3ccc(N)c(N)c3)cc2)CC1
Reactant: COc1cccc(-c2ccc(O)c(C=O)c2)n1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Solvent: CO
Product: COc1cccc(-c2ccc(O)c(-c3nc4cc(C(=O)Nc5ccc(CCN6CCN(C)CC6)cc5)ccc4[nH]3)c2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.5 %

Procedure:
To a suspension of silica gel (0.8 g) in dichloromethane (5 mL) was added SOCl2 (0.6 mL) and the mixture was stirred at the room temperature for 1 h (gas was released from the reaction mixture). 3,4-Diamino-N-{4-[2-(4-methyl-piperazin-1-yl)-ethyl]-phenyl}-benzamide (178.2 mg, 0.5 mmol), 2-hydroxy-5-(6-methoxy-pyridin-2-yl)-benzaldehyde (114.6 mg, 0.5 mmol) and 2 mL dichloromethane were added, and the resulting reaction mixture was stirred at the room temperature for 4 h. After methanol (5 mL) was added, the reaction mixture was stirred at room temperature for another 1 h and was evaporated under reduced pressure. The residue on silica gel was purified by chromatography (250:10:1 CH2Cl2/MeOH/28% aqueous NH4OH) to afford the title compound (190 mg, 68%). 1H NMR (MeOH-d4) δ 2.26 (s, 3H), 2.37-2.72 (12H), 4.01 (s, 3H), 6.62 (d, J=9 Hz, 1H), 7.04 (d, J=9 Hz, 1H), 7.12 (d, J=9 Hz, 2H), 7.37 (d, J=6 Hz, 1H), 7.55 (d, J=9 Hz, 1H), 7.54-7.63 (2H), 7.76 (d, J=6 Hz, 1H), 8.04 (d, J=6 Hz, 1H), 8.13 (s, 1H), 8.53 (s, 1H). ESI-MS m/z 563 (MH+).
Reaction SMILES: [Li+].[N:2]1([CH2:7][C@@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13]([C:15]2[CH:31]=[CH:30][C:18]([O:19][CH2:20][C:21]3[CH:29]=[CH:28][C:24]([C:25]([O-])=[O:26])=[CH:23][CH:22]=3)=[CH:17][CH:16]=2)=[O:14])[CH2:6][CH2:5][CH2:4][CH2:3]1.[NH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1>>[N:32]1([C:25]([C:24]2[CH:28]=[CH:29][C:21]([CH2:20][O:19][C:18]3[CH:17]=[CH:16][C:15]([C:13]([N:9]4[CH2:10][CH2:11][CH2:12][C@H:8]4[CH2:7][N:2]4[CH2:6][CH2:5][CH2:4][CH2:3]4)=[O:14])=[CH:31][CH:30]=3)=[CH:22][CH:23]=2)=[O:26])[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: O=C([O-])c1ccc(COc2ccc(C(=O)N3CCC[C@H]3CN3CCCC3)cc2)cc1
Reactant: C1CCNCC1
Agent: [Li+]
Product: O=C(c1ccc(COc2ccc(C(=O)N3CCC[C@H]3CN3CCCC3)cc2)cc1)N1CCCCC1

Procedure:
The title compound is prepared in a manner substantially analogous to Procedure D from 4-[4-(2-(S)-Pyrrolidin-1-ylmethyl-pyrrolidine-1-carbonyl)-phenoxymethyl]-benzoic acid lithium salt and piperidine. MS (ES+) 476.2
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][CH:12]=[C:11](Cl)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:19]([Sn](CCCC)(CCCC)CCCC)=[CH2:20]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([O:8][C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][CH:12]=[C:11]([CH:19]=[CH2:20])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: O=[N+]([O-])c1ccc(Cl)nc1OCc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=Cc1ccc([N+](=O)[O-])c(OCc2ccccc2)n1
Temperature: 110 °C
Reaction time: 12 h

Procedure:
To a stirred mixture of (2-(benzyloxy)-6-chloro-3-nitropyridine (3.2 g, 0.0123 mol) in toluene (32.5 mL) in a 250 mL sealed tube, were added Pd(PPh3)4 (426 mg, 0.000369 mol, Aldrich) and vinyl tributyltin (3.90 g, 0.0123 mol). The tube was purged with the argon gas for 10 min, capped and stirred for 12 h at 110° C. After completion of the reaction (monitored by TLC, 10% EtOAc in hexane), the reaction mixture was quenched with water (20 mL) and extracted with EtOAc (50 mL×3). The organic layers were combined, dried over anhydrous sodium sulfate, and purified by column chromatography, silica gel (60-120 mesh) using 5-7% EtOAc in petroleum ether as an eluent to afford the title compound as a white solid. 1H NMR (400 MHz, DMSO-d6) δ: 8.47 (d, J=8.1 Hz, 1H), 7.52 (d, J=6.9 Hz, 1H), 7.43-7.27 (m, 3H), 7.20 (br. s., 2H), 6.92-6.83 (m, 1H), 6.49 (dd, J=17.4, 1.5 Hz, 1H), 5.74 (dd, J=10.5, 1.5 Hz, 1H), 5.59 (s, 2H). MS (ESI, positive ion) m/z: 257 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([C:16]([O:18]CC)=O)=[C:5]([C:11](OCC)=[O:12])[NH:6]2.O.[NH2:22][NH2:23]>C(O)C>[Br:1][C:2]1[C:3]2[C:4]3[C:16](=[O:18])[N:23]=[N:22][C:11](=[O:12])[C:5]=3[NH:6][C:7]=2[CH:8]=[CH:9][CH:10]=1
Reactant: NN
Reactant: CCOC(=O)c1[nH]c2cccc(Br)c2c1C(=O)OCC
Solvent: O
Solvent: CCO
Product: O=C1N=NC(=O)c2c1[nH]c1cccc(Br)c21
Temperature: 25 °C
Yield: 88 %

Procedure:
To a stirred solution of diethyl 4-bromoindole-2,3-dicarboxylate (0.4 g, 1.2 mM) in ethanol (3 mL) was added hydrazine hydrate (2.0 mL, 40 mM). The mixture was heated to reflux for 2 hours, cooled to room temperature, and the resulting solid was filtered. This was then suspended in glacial acetic acid (3 mL), heated to reflux for several minutes, and cooled to room temperature. The solid was then filtered and dried. This afforded the titled compound as a white solid (0.3 g, 88%), mp >260° C. NMR (d6 -DMSO): 12.8 (br s, 1H), 11.52 (br s, 2H), 7.60 (d, J=8 Hz, 1H), 7.52 (d, J=8 Hz, 1H), 7.52 (d, J=8 Hz, 1H), 7.32 (t, J=8 Hz, 1H). MS(CI): 280(M+1).
Reaction SMILES: [Li+].[OH-].C(OC([C:8]1[C:13]([Cl:14])=[CH:12][C:11](=[O:15])[N:10]([CH3:16])[C:9]=1[NH:17][CH3:18])=O)C.Cl>CO.C1COCC1>[Cl:14][C:13]1[CH:8]=[C:9]([NH:17][CH3:18])[N:10]([CH3:16])[C:11](=[O:15])[CH:12]=1
Reactant: CCOC(=O)c1c(Cl)cc(=O)n(C)c1NC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CNc1cc(Cl)cc(=O)n1C
Temperature: 25 °C
Reaction time: 43 h
Yield: 60.1 %

Procedure:
An aqueous solution of LiOH (2N, 400 mmol, 200 mL) was slowly added at 0° C. to a stirring solution of example 31c (16.0 g, 65.6 mmol) in MeOH/THF (200 mL/100 mL). The reaction mixture was allowed to warm to room temperature and stirred for 43 h. The solution was adjusted to neutral pH with 1N HCl and extracted with EtOAc. The combined organic extracts were dried (MgSO4) and concentrated under reduced pressure to give 6.8 g (60%) of clean desired product as an off-white solid. 1H NMR (400 MHz, DMSO-d6): δ 6.87 (q, 1H, J=4.4 Hz), 5.63 (s, 1H), 5.35 (s, 1H), 3.25 (s, 3H), 2.72 (d, 3H, J=4.4 Hz). MS (ES) [m+H] calc'd for C7H9ClN2O, 173, 175; found 173, 175.
Reaction SMILES: F[C:2]1[CH:11]=[CH:10][C:9]2[NH:8][CH:7]=[C:6]3[C:12](=[O:21])[N:13]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[N:14]=[C:5]3[C:4]=2[CH:3]=1.[CH:22]([N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)([CH3:24])[CH3:23]>>[CH:22]([N:25]1[CH2:30][CH2:29][N:28]([C:2]2[CH:11]=[CH:10][C:9]3[NH:8][CH:7]=[C:6]4[C:12](=[O:21])[N:13]([C:15]5[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=5)[N:14]=[C:5]4[C:4]=3[CH:3]=2)[CH2:27][CH2:26]1)([CH3:24])[CH3:23]
Reactant: O=c1c2c[nH]c3ccc(F)cc3c-2nn1-c1ccccc1
Reactant: CC(C)N1CCNCC1
Product: CC(C)N1CCN(c2ccc3[nH]cc4c(=O)n(-c5ccccc5)nc-4c3c2)CC1
Yield: 84 %

Procedure:
23a was stirred with excess of N-isopropylpiperazine at 175° C. for 72 hours. The precipitates were collected by filtration and washed with ethyl acetate and purified using column chromatography to obtain title compound in 84% yield. 1H-NMR (DMSO-d6) δ (ppm): 1.01 (6H, d, J=6.03 Hz), 2.63 (4H, br), 2.70 (1H, m), 3.22 (4H, br), 7.13 (2H, brt, J=7.32 Hz), 7.42 (3H, m), 7.58 (1H, d, J=9.32 Hz), 8.23 (2H, d, J=8.54 Hz), 8.54 (1H, s). m/z 388.5 (MH+).
Reaction SMILES: [NH:1]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C@H:2]([C:4]([NH:6][C@H:7]([C:11]([O:13]C)=[O:12])[CH:8]([CH3:10])[CH3:9])=[O:5])[CH3:3].[OH-].[Na+]>CC(C)=O>[NH:1]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C@H:2]([C:4]([NH:6][C@H:7]([C:11]([OH:13])=[O:12])[CH:8]([CH3:10])[CH3:9])=[O:5])[CH3:3]
Reactant: COC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)OC(C)(C)C)C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: CC(C)[C@H](NC(=O)[C@H](C)NC(=O)OC(C)(C)C)C(=O)O
Temperature: 23 °C
Reaction time: 2 h
Yield: 93.5 %

Procedure:
Boc-Ala-Val-OMe 53 (1.750 g, 5.79 mmol) was stirred in 40 mL acetone. NaOH solution (8.7 mL of 2.0 M aqueous solution) was added and stirred 2 h at 23° C. Acetone was removed under reduced pressure and the resulting solution was diluted with EtOAc (20 mL). The organic fraction was washed with water (2×20 mL), dried over sodium sulfate, and concentrated in vacuo to yield 1.561 g (99%) product. 1H NMR (CDCl3, 300 MHz) δ 12.28 (br s, 1H), 7.69 (d, J=8.7 Hz, 1H), 6.98 (d, J=7.5 Hz, 1H), 4.15 (dd, J=5.4, 8.4 Hz, 1H), 4.04 (quintet, J=7.2 Hz, 1H), 3.35 (br s, 2H), 2.04 (octet, J=6.6 Hz, 1H), 1.37 (s, 9H), 1.16 (d, J=7.2 Hz, 3H), 0.87 (d, J=7.2 Hz, 3H); 13C NMR (CDCl3, 75 MHz) δ 172.9, 155.1, 78.1, 56.8, 30.2, 28.2, 19.0, 18.0, 17.8.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][CH:9]2[CH2:11][CH2:10]2)[N:5]2[N:12]=[CH:13][C:14]([CH:15]=[O:16])=[C:4]2[N:3]=1.[CH3:17][S-:18].[Na+].O>CN(C)C=O>[CH:9]1([NH:8][C:6]2[N:5]3[N:12]=[CH:13][C:14]([CH:15]=[O:16])=[C:4]3[N:3]=[C:2]([S:18][CH3:17])[CH:7]=2)[CH2:11][CH2:10]1
Reactant: C[S-]
Reactant: O=Cc1cnn2c(NC3CC3)cc(Cl)nc12
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CSc1cc(NC2CC2)n2ncc(C=O)c2n1
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 85.9 %

Procedure:
To 5-chloro-7-(cyclopropylamino)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde (4.0 g, 16.87 mmol) in dimethylformamide was added sodium thiomethoxide (3.54 g, 50.5 mmol) and the reaction mixture was heated to 80° C. for 2 hrs. Cooled the reaction mixture, added water, stirred for 15 minutes and filtered white precipitate, dried to yield 7-(cyclopropylamino)-5-(methylthio)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde (3.60 g, 86% yield). LCMS (M+1=249)
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([N:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3][CH2:2]1.[CH2:17]([N:19](CC)CC)[CH3:18].ClCC#N>CN1CCCC1=O>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([N:11]3[CH2:16][CH2:15][N:14]([CH2:18][C:17]#[N:19])[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: CCN(CC)CC
Reactant: c1cc2c(c(N3CCNCC3)c1)OCCO2
Agent: N#CCCl
Solvent: CN1CCCC1=O
Product: N#CCN1CCN(c2cccc3c2OCCO3)CC1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
A solution of 1-(1,4-benzodioxan-5-yl)piperazin (11 g) and triethylamine (7 ml) in N-methyl-2-pyrrolidinone was treated dropwise with chloroacetonitrile (4.5 g). After stirring for 2 h at 100° C. the mixture was poured onto ice and extracted with ethyl acetate. The organic phase was washed with water, dried over magnesium sulfate, filtered, and concentrated in vacuo. The product, 1-(1,4-benzodioxan-5-yl)-4-cyanomethylpiperazine, was obtained as an oil (17.4 g) which was sufficiently pure for use in the next step.
Reaction SMILES: [O-]CC.[Na+].[CH3:5][C:6]([C:9]1[CH:14]=[C:13]([SH:15])[CH:12]=[C:11]([C:16]([CH3:19])([CH3:18])[CH3:17])[C:10]=1[OH:20])([CH3:8])[CH3:7].Cl[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].O>C(O)C>[CH3:17][C:16]([C:11]1[CH:12]=[C:13]([S:15][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH:14]=[C:9]([C:6]([CH3:5])([CH3:7])[CH3:8])[C:10]=1[OH:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Reactant: CCCCCCl
Agent: CC[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCCCCSc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of freshly prepared sodium ethoxide (ca. 17 mmole) in ethanol (12 ml) was added with stirring 2,6-bis(1,1-dimethylethyl)-4-mercaptophenol (4.0 g, 17 mmole). After one hour, 1-chloropentane (4 ml, ca. 34 mmole) was added and the reaction mixture was stirred at room temperature for 20 hours. Water was added, and the mixture was extracted with diethyl ether. The ether layer was dried over magnesium sulfate, filtered, and concentrated in vacuo to an oil. Chromatography on silica gel and recrystallization from pentane gave the title compound, m.p. 54°-55°.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]1[NH:11][CH:12]=[C:13]([C:15]2[C:16]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[N:17][O:18][C:19]=2[CH3:20])[N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:28][C:29]1[CH:33]=[C:32]([CH3:34])[O:31][N:30]=1>>[CH2:1]([O:8][CH2:9][C:10]1[N:11]([CH2:28][C:29]2[CH:33]=[C:32]([CH3:34])[O:31][N:30]=2)[CH:12]=[C:13]([C:15]2[C:16]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[N:17][O:18][C:19]=2[CH3:20])[N:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1onc(-c2ccccc2)c1-c1c[nH]c(COCc2ccccc2)n1
Reactant: Cc1cc(CCl)no1
Product: Cc1cc(Cn2cc(-c3c(-c4ccccc4)noc3C)nc2COCc2ccccc2)no1
Yield: 63 %

Procedure:
As described for Example 67, 4-(2-benzyloxymethyl-1H-imidazol-4-yl)-5-methyl-3-phenyl-isoxazole (100 mg, 0.29 mmol) using 3-(chloromethyl)-5-methylisoxazole instead of benzyl bromide was converted to the title compound (80 mg, 63%) which was obtained as a light yellow gum. MS: m/e=441.4 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2([C:25]3[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=3[F:32])[CH2:16][CH2:15][CH:14]([NH:17][S:18]([CH2:21][C:22]([NH2:24])=O)(=[O:20])=[O:19])[CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.S(Cl)(Cl)=O.CN(C)C=O>C1(C)C=CC=CC=1.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2([C:25]3[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=3[F:32])[CH2:12][CH2:13][CH:14]([NH:17][S:18]([CH2:21][C:22]#[N:24])(=[O:20])=[O:19])[CH2:15][CH2:16]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: NC(=O)CS(=O)(=O)NC1CCC(c2cc(F)ccc2F)(S(=O)(=O)c2ccc(Cl)cc2)CC1
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: O
Product: N#CCS(=O)(=O)NC1CCC(c2cc(F)ccc2F)(S(=O)(=O)c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Yield: 99.7 %

Procedure:
To a solution of the amide of Example 44 (80 mg, 0.16 mmol) in toluene (10 ml) under nitrogen was added thionyl chloride (23 μL, 0.32 mmol) and a catalytic amount of dimethylformamide. After refluxing for 16 h, the reaction was cooled to ambient temperature, diluted with water and extracted with ethyl acetate The combined organic layers were washed with brine, dried (MgSO4) and evaporated to give a residue (78 mg) which was purified using preparative thin layer chromatography eluting with ethyl acetate:hexane 1:2 to give the desired product (42 mg). 1H NMR (CDCl3) 7.39-7.31 (4H, m), 7.08-7.04 (2H, m), 6.88-6.84 (1H, m), 6.24 (1H, d, J=6.1 Hz), 4.12 (2H, s), 3.09-3.07 (1H, m), 2.62-2.46 (4H, m), 2.11-2.04 (2H, m), 1.65-1.57 (2H, m). M/z(ES−)=487/489
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[F:22])[CH2:5][N:6]1[C:10]2=[N:11][C:12]([CH3:18])=[C:13]([CH:16]=[O:17])[C:14]([I:15])=[C:9]2[CH:8]=[CH:7]1.[Si](C#N)(C)(C)C.S(=O)(=O)(O)O.[C:34]([O-:37])(O)=[O:35].[Na+].O.[C:40]([O-])(O)=O.[Na+]>C(Cl)Cl.[I-].[Zn+2].[I-]>[F:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[F:22])[CH2:5][N:6]1[C:10]2=[N:11][C:12]([CH3:18])=[C:13]([CH:16]([OH:17])[C:34]([O:37][CH3:40])=[O:35])[C:14]([I:15])=[C:9]2[CH:8]=[CH:7]1
Reactant: Cc1nc2c(ccn2Cc2ccc(F)c(F)c2)c(I)c1C=O
Reactant: O=C([O-])O
Agent: C[Si](C)(C)C#N
Agent: O=S(=O)(O)O
Agent: [I-]
Solvent: ClCCl
Solvent: O
Product: COC(=O)C(O)c1c(C)nc2c(ccn2Cc2ccc(F)c(F)c2)c1I
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 99 %

Procedure:
To a solution of 1-(3,4-difluorobenzyl)-4-iodo-6-methyl-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde (3.05 g, 6.29 mmol) in DCM (85 mL) at 0° C. was added zinc iodide (4.02 g, 12.58 mmol) followed by TMSCN (3.37 mL, 25.2 mmol) and the mixture was stirred at 0° C. for 5 min and then at RT for 30 min. The mixture was diluted with DCM and washed with cold water, dried (Na2SO4) and concentrated. The residue was cooled to 0° C. and MeOH (85 mL) was added followed by dropwise addition of sulfuric acid (16.09 mL, 302 mmol). The mixture was stirred at 80° C. for 26 h, cooled to 0° C. and saturated NaHCO3/water was added slowly followed by solid NaHCO3. The mixture extracted with EtOAc and washed with water, brine, dried (Na2 SO4), concentrated, dried in vacuo to provide methyl 2-(1-(3,4-difluorobenzyl)-4-iodo-6-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-hydroxyacetate (3.68 g, 6.23 mmol, 99% yield) as a thick yellowish oil. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.70 (s, 3 H), 3.47 (br s, 1 H), 3.81 (s, 3 H), 5.42-5.59 (m, 2H), 5.91 (s, 1 H), 6.41 (d, J=3.52 Hz, 1H), 6.93-7.22 (m, 3 H); LCMS (m/z) ES+=473 (M+1).
Reaction SMILES: [CH2:1]([N:8]1[C:12]([C:13]([F:16])([F:15])[F:14])=[C:11]([CH3:17])[C:10]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[C:9]1[C:25]([N:27]([CH2:31][C:32]([O:34]C(C)(C)C)=O)[CH2:28][CH2:29][OH:30])=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([N:8]1[C:12]([C:13]([F:14])([F:15])[F:16])=[C:11]([CH3:17])[C:10]([C:18]2[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=2)=[C:9]1[C:25]([N:27]1[CH2:31][CH2:32][O:34][C:29](=[O:30])[CH2:28]1)=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1c(-c2ccc(Cl)cc2)c(C(=O)N(CCO)CC(=O)OC(C)(C)C)n(Cc2ccccc2)c1C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(-c2ccc(Cl)cc2)c(C(=O)N2CCOC(=O)C2)n(Cc2ccccc2)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
tert-Butyl 2-(1-benzyl-3-(4-chlorophenyl)-N-(2-hydroxyethyl)-4-methyl-5-(trifluoromethyl)-1H-pyrrole-2-carboxamido)acetate (171 mg, 0.310 mmol) was dissolved in DCM (18 mL). TFA (2 mL) was added and the reaction mixture was stirred at room temperature for 3 h. The solvent was removed under reduced pressure and the residue co-evaporated with DCM (2×). The product was purified by flash chromategraphy (silica, gradient heptane/EtOAc, 1:0→2:1), to give 97 mg (66%) of SC-50.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([CH2:12][CH2:13][C:14]2[CH:15]=[C:16]([NH:19][C:20]([C:22]3[N:23]=[CH:24][C:25]([N:28]4[CH2:32][CH2:31][CH:30]([N:33](C)[C:34](=O)OC(C)(C)C)[CH2:29]4)=[N:26][CH:27]=3)=[O:21])[NH:17][N:18]=2)[CH:7]=[C:8]([O:10][CH3:11])[CH:9]=1>CO>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([CH2:12][CH2:13][C:14]2[CH:15]=[C:16]([NH:19][C:20]([C:22]3[CH:27]=[N:26][C:25]([N:28]4[CH2:32][CH2:31][CH:30]([NH:33][CH3:34])[CH2:29]4)=[CH:24][N:23]=3)=[O:21])[NH:17][N:18]=2)[CH:7]=[C:8]([O:10][CH3:11])[CH:9]=1
Reactant: COc1cc(CCc2cc(NC(=O)c3cnc(N4CCC(N(C)C(=O)OC(C)(C)C)C4)cn3)[nH]n2)cc(OC)c1
Agent: Cl
Solvent: CO
Product: CNC1CCN(c2cnc(C(=O)Nc3cc(CCc4cc(OC)cc(OC)c4)n[nH]3)cn2)C1
Temperature: 25 °C
Reaction time: 48 h
Yield: 39.2 %

Procedure:
Hydrogen chloride (4M in dioxane, 0.57 mL, 2.26 mmol) was added to tert-butyl N-[1-[5-[[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]carbamoyl]pyrazin-2-yl]pyrrolidin-3-yl]-N-methylcarbamate (312 mg, 0.57 mmol) in methanol (2.80 mL) at 25° C. The resulting solution was stirred at room temperature for 48 h. The reaction was incomplete and further hydrogen chloride (4M in dioxane, 0.28 mL, 1.12 mmol) was added and the solution was stirred at room temperature for a further 16 h. The reaction mixture was diluted with MeOH (5 ml) and the crude product was purified by ion exchange chromatography, using a SCX column. The desired product was eluted from the column using 7M NH3/MeOH and fractions were evaporated to dryness to afford impure product. The crude product was purified by preparative HPLC, using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford the title compound (101 mg, 39%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([CH2:11][C:12]#[N:13])[CH:8]=[CH:9][CH:10]=1)=[O:4].[C:14](=O)(OC)OC.C([O-])([O-])=O.[K+].[K+].N#N>>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([CH:11]([CH3:14])[C:12]#[N:13])[CH:8]=[CH:9][CH:10]=1)=[O:4]
Reactant: COC(=O)c1cccc(CC#N)c1
Reactant: COC(=O)OC
Agent: N#N
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COC(=O)c1cccc(C(C)C#N)c1
Temperature: 180 °C
Reaction time: 6 h
Yield: 78 %

Procedure:
The reaction for the selective methylation is carried out placing into a 250 ml (φi =45 mm) stainless steel autoclave a mixture of (3-methoxycarbonylphenyl)acetonitrile (10 g, 96% purity), dimethyl carbonate (86 ml) and K2CO3 (12 g), in the 1:18:2 molar ratio. Air is replaced by a N2 stream; then the mixture is heated at a temperature of 180° C., with stirring. During the reaction, which is completed within 6 hours, the pressure raises from 7 bars, reached at the working temperature, to about 12 bars after 5 hours of isothermal heating. After cooling K2CO3 is filtered off, DMC is recovered and the residue is distilled (b.p. 0.078=109°-110° C.) to obtain 8.3 g of 2-(3-methoxycarbonyl-phenyl)propionitrile which is 99,5% pure (78% yield) (>99% selectivity in monomethylation).
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[C:9]([OH:18])=[C:10]2[CH:17]=[CH:16][S:15][C:11]2=[C:12](Br)[N:13]=1)=[O:7])[CH2:2][CH2:3][CH3:4].[CH3:19]B1OB(C)OB(C)O1.C(=O)([O-])[O-].[K+].[K+]>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O1CCOCC1>[CH2:1]([O:5][C:6]([C:8]1[C:9]([OH:18])=[C:10]2[CH:17]=[CH:16][S:15][C:11]2=[C:12]([CH3:19])[N:13]=1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CB1OB(C)OB(C)O1
Reactant: CCCCOC(=O)c1nc(Br)c2sccc2c1O
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CCCCOC(=O)c1nc(C)c2sccc2c1O
Temperature: 140 °C

Procedure:
A mixture of 7-bromo-4-hydroxy-thieno[2,3-c]pyridine-5-carboxylic acid butyl ester (example 43a, 165 mg, 0.5 mmol), trimethylboroxine (70 μl, 0.5 mmol), tetrakis(triphenylphosphine) palladium(0) (118 mg, 0.1 mmol), potassium carbonate (208 mg, 1.5 mmol), and anhydrous 1,4-dioxane (3 ml) was heated in a microwave oven at 140° C. for 15 min. Then silica gel was added and the mixture concentrated in vacuo. The residue was added on top of a short column filled with silica gel. Elution with ethyl acetate:hexanes=9:1 and in vacuo concentration gave the title compound as a yellowish oil; MS-(+)-ion: MS-(+)-ion: M+1=266.0.
Reaction SMILES: [C:1]([C:4]1[C:9]([OH:10])=[C:8]([CH3:11])[C:7]([CH3:12])=[C:6]([OH:13])[C:5]=1[CH3:14])(=[O:3])[CH3:2].[CH3:15][O:16][CH:17]([O:21][CH3:22])[C:18](=O)[CH3:19].N1CCCC1>C1(C)C=CC=CC=1>[CH3:15][O:16][CH:17]([O:21][CH3:22])[C:18]1([CH3:19])[CH2:2][C:1](=[O:3])[C:4]2[C:9](=[C:8]([CH3:11])[C:7]([CH3:12])=[C:6]([OH:13])[C:5]=2[CH3:14])[O:10]1
Reactant: CC(=O)c1c(C)c(O)c(C)c(C)c1O
Reactant: COC(OC)C(C)=O
Solvent: C1CCNC1
Solvent: Cc1ccccc1
Product: COC(OC)C1(C)CC(=O)c2c(C)c(O)c(C)c(C)c2O1
Yield: 70 %

Procedure:
15.0 g (77 mmoles) of acetyl-trimethylhydroquinone, 10.5 g (89 mmoles) of 1,1-dimethoxy-propan-2-one and 9.30 g (131 mmoles) of pyrrolidine were reacted in toluene solution by a method similar to that of Example 1 to give the above product. Boiling point: 165°-170° C./6.10-5 mbar (bulb tube); yield: 70%.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([S:21]([NH2:24])(=[O:23])=[O:22])[CH:6]=[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([NH:17][C:18]([NH2:20])=[O:19])[CH:12]=2)[C:8]=1[O:9][CH3:10])=[O:2].[N:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH2:31][CH2:32][C:33](Cl)=[O:34])[CH:26]=1>>[CH:1]([C:3]1[CH:4]=[C:5]([S:21]([NH:24][C:33](=[O:34])[CH2:32][CH2:31][C:27]2[CH:26]=[N:25][CH:30]=[CH:29][CH:28]=2)(=[O:23])=[O:22])[CH:6]=[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([NH:17][C:18]([NH2:20])=[O:19])[CH:12]=2)[C:8]=1[O:9][CH3:10])=[O:2]
Reactant: O=C(Cl)CCc1cccnc1
Reactant: COc1c(C=O)cc(S(N)(=O)=O)cc1-c1cccc(NC(N)=O)c1
Product: COc1c(C=O)cc(S(=O)(=O)NC(=O)CCc2cccnc2)cc1-c1cccc(NC(N)=O)c1

Procedure:
Proceeding as in Reference 21, but substituting 5-formyl-6-methoxy-3′-ureido-biphenyl-3-sulfonamide and 3-pyridin-3-ylpropanoyl chloride, gave 5-formyl-6-methoxy-N-(3-pyridin-3-ylpropanoyl)-3′-ureido-biphenyl-3-sulfonamide.