Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5]([NH:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:12]2)(=[O:7])=[O:6].[I-].[Na+].[NH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>C(#N)C.C(Cl)Cl>[N:25]1([CH2:2][CH2:3][CH2:4][S:5]([NH:8][C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:12]3)(=[O:7])=[O:6])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: C1CCNCC1
Reactant: CCOC(=O)c1cc2cc(NS(=O)(=O)CCCCl)ccc2[nH]1
Agent: [I-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC#N
Product: CCOC(=O)c1cc2cc(NS(=O)(=O)CCCN3CCCCC3)ccc2[nH]1
Reaction time: 8 h

Procedure:
Ethyl 5-[(3-chloropropyl)sulfonamido]indole-2-carboxylate (PREPARATION 82, 2.3 g) is dissolved in acetonitrile (10 ml) and piperadine (27 ml). Solid sodium iodide (1.0 g) is added and the reaction is stirred overnight at 20°-25°. The reaction is diluted with methylene chloride, washed with saturated aqueous sodium bicarbonate, dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification by flash column chromatography, eluting with a gradient of 5% methanol/methylene chloride to 10% methanol/methylene chloride, pooling and concentration of the appropriate fractions gives the title compound, NMR (300 MHz, d4 -CD3OD) 7.45, 7.32, 7.12, 7.03, 4.28, 2.96, 2.28, 1.18, 1.42, 1.33 and 1.30.
Reaction SMILES: [C:1]([CH:4]1[C:9](=O)[CH2:8][CH2:7][N:6]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:5]1)(=O)[CH3:2].[NH2:18][NH2:19].O>CCO>[CH3:2][C:1]1[C:4]2[CH2:5][N:6]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:8][C:9]=2[NH:19][N:18]=1
Reactant: CC(=O)C1CN(C(=O)OC(C)(C)C)CCC1=O
Reactant: NN
Solvent: CCO
Solvent: O
Product: Cc1n[nH]c2c1CN(C(=O)OC(C)(C)C)CC2
Temperature: 90 °C
Yield: 76.3 %

Procedure:
To a solution of tert-butyl 3-acetyl-4-oxopiperidine-1-carboxylate (10.00 g, 41.44 mmol, 1.0 eq) in EtOH was added 98% H2NNH2—H2O (3.11 mL, 62.16 mmol, 1.5 eq). The reaction mixture was heated to 90° C. and refluxed for 2.0 h. The resulted mixture was concentrated in vacuo to give two tautomers as yellow oil (7.5 g, 76.5%), and which were used for the next step without further purification. The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 238.31 (M+1);
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[C:3]=1[CH:9]=[O:10].[F:11][C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1.C(O)(=O)CCCCCCCCCCCCC.N1C(C)=CC=CC=1C>C1(C)C=CC=CC=1.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[F:11][C:12]1[CH:17]=[CH:16][C:15]([N:5]2[CH:6]=[CH:7][C:2]([I:1])=[C:3]([CH:9]=[O:10])[C:4]2=[O:8])=[CH:14][CH:13]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: O=Cc1c(I)cc[nH]c1=O
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: CCCCCCCCCCCCCC(=O)O
Solvent: Cc1cccc(C)n1
Solvent: Cc1ccccc1
Product: O=Cc1c(I)ccn(-c2ccc(F)cc2)c1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 48.3 %

Procedure:
A mixture of 4-iodo-2-oxo-1,2-dihydropyridine-3-carbaldehyde (12.0 g, 48.3 mmol), 4-fluorophenylboronic acid (20.1 g, 144.7 mmol), copper(II) acetate (17.55 g, 96.75 mmol), and myristic acid (44 g, 193 mmol) in toluene (700 mL) was treated with 2,6-lutidine (45 mL, 385.5 mmol) and stirred vigorously at RT for 1 day. Additional 4-fluorophenylboronic acid (5 g) was added and the reaction was stirred vigorously for an additional 3 days. The reaction mixture was concentrated to dryness, suspended in 10% MeOH/EtOAc and the solids removed via filtration through diatomaceous earth. The filtrate was concentrated to dryness, the residue treated with EtOAc and water and again filtered through diatomaceous earth. The filtrate was washed with 1N HCl, dried over Na2SO4 and concentrated to dryness. The material was treated with EtOAc and the resulting solid was collected via filtration to afford 1-(4-fluorophenyl)-4-iodo-2-oxo-1,2-dihydropyridine-3-carbaldehyde (8.0 g, 42%) as a yellow solid.
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH2:5][OH:6])[CH2:3][OH:4].[C:8](=O)(OCC)[O:9]CC.O(C)[Na]>>[CH3:1][C:2]1([CH3:7])[CH2:5][O:6][C:8](=[O:9])[O:4][CH2:3]1
Reactant: CC(C)(CO)CO
Reactant: CCOC(=O)OCC
Agent: CO[Na]
Product: CC1(C)COC(=O)OC1
Temperature: 130 °C

Procedure:
A mixture of 208 grams (2 moles) 2,2-dimethyl-1,3-propanediol (neopentyl glycol), 295 grams diethyl carbonate, and 4.3 grams NaOCH3 was placed in a flask equipped with an 18-inch vigreux column and heated gradually to 130° C. About 230 ml ethanol was distilled. When the pot temperature reached 150°-160° C. excess diethyl carbonate was removed under reduced pressure. The resulting product was dissolved in benzene, washed with water, and concentrated. This product was recrystallized from ether and isolated as pure 5,5-dimethyl-1,3-dioxan-2-one. A 75 gram sample had a melting point of 108° C., very nearly matching that in the literature (109° C.).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:3][C@H:4]([OH:32])[C@@H:5]([NH:19][C:20]([C@@H:22]([NH:27][C:28](=[O:31])[O:29][CH3:30])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1.[CH3:40][C:41]([CH3:62])([CH3:61])[C@H:42]([N:46]1[CH2:50][C:49](=[O:51])[N:48]([CH2:52][C:53]2[CH:58]=[CH:57][CH:56]=[C:55]([CH3:59])[N:54]=2)[C:47]1=[O:60])[C:43](O)=[O:44].CCOP(ON1N=NC2C=CC=CC=2C1=O)(OCC)=O.C(N(CC)C(C)C)(C)C>C1COCC1>[CH3:40][C:41]([CH3:62])([CH3:61])[C@H:42]([N:46]1[CH2:50][C:49](=[O:51])[N:48]([CH2:52][C:53]2[CH:58]=[CH:57][CH:56]=[C:55]([CH3:59])[N:54]=2)[C:47]1=[O:60])[C:43]([NH:1][C@@H:2]([CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[CH2:3][C@H:4]([OH:32])[C@@H:5]([NH:19][C:20]([C@@H:22]([NH:27][C:28](=[O:31])[O:29][CH3:30])[C:23]([CH3:25])([CH3:26])[CH3:24])=[O:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1)=[O:44]
Reactant: Cc1cccc(CN2C(=O)CN([C@H](C(=O)O)C(C)(C)C)C2=O)n1
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)[C@@H](O)C[C@@H](N)Cc1ccccc1)C(C)(C)C
Agent: CCOP(=O)(OCC)On1nnc2ccccc2c1=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)[C@@H](O)C[C@H](Cc1ccccc1)NC(=O)[C@@H](N1CC(=O)N(Cc2cccc(C)n2)C1=O)C(C)(C)C)C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.3 %

Procedure:
A solution containing the product from Example 23S (0.020 g, 0.038 mmol) in THF (0.4 mL) was treated with the product from Example 46E (0.020 g, 0.046 mmol), DEPBT (0.017 g, 0.057 mmol), and N,N-diisopropylethylamine (0.035 mL, 0.201 mmol), stirred at 25° C. for 1 hour, and partitioned between ethyl acetate and 10% Na2CO3 solution. The organic phase was washed with additional 10% Na2CO3 solution and brine, dried over MgSO4, filtered and concentrated. The residue was chromatographed on silica gel eluting with 0-100% ethyl acetate/dichloromethane to give the title compound (0.021 g, 67% yield). 1H NMR (300 MHz, DMSO-d6), δ ppm 0.80 (s, 9 H), 0.88 (s, 9 H), 1.55 (m, 2 H), 2.29 (m, 1 H), 2.39 (s, 3H), 2.75 (m, 3 H), 3.15 (d, J=18.38 Hz, 1 H), 3.52 (s, 3 H), 3.61 (m, 1 H), 3.94 (m, 2 H), 4.19 (m, 3 H), 4.68 (d, J=10.30 Hz, 2 H), 4.89 (d, J=5.52 Hz, 1 H), 6.83 (d, J=9.93 Hz, 1 H), 7.00 (m, 6 H), 7.13 (d, J=7.72 Hz, 1 H), 7.31 (m, 3 H), 7.64 (m, 2 H), 7.88 (m, 4 H), 8.09 (d, J=9.19 Hz, 1 H), 8.63 (d, J=4.78 Hz, 1 H).
Reaction SMILES: [F:1][C:2]1[C:3]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)=[C:4]([CH:10]=[C:11](I)[CH:12]=1)[C:5]([N:7]([CH3:9])[CH3:8])=[O:6].[CH3:22][O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:30]1[C:38]2[C:33](=[N:34][CH:35]=[C:36](B3OC(C)(C)C(C)(C)O3)[CH:37]=2)[N:32]([S:48]([C:51]2[CH:56]=[CH:55][C:54]([CH3:57])=[CH:53][CH:52]=2)(=[O:50])=[O:49])[CH:31]=1.ClCCl.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C>[F:1][C:2]1[C:3]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)=[C:4]([CH:10]=[C:11]([C:36]2[CH:37]=[C:38]3[C:30]([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=4[O:23][CH3:22])=[CH:31][N:32]([S:48]([C:51]4[CH:52]=[CH:53][C:54]([CH3:57])=[CH:55][CH:56]=4)(=[O:50])=[O:49])[C:33]3=[N:34][CH:35]=2)[CH:12]=1)[C:5]([N:7]([CH3:9])[CH3:8])=[O:6]
Reactant: CN(C)C(=O)c1cc(I)cc(F)c1NCc1ccncc1
Reactant: COc1ccccc1-c1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(B3OC(C)(C)C(C)(C)O3)cc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: ClCCl
Product: COc1ccccc1-c1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(-c3cc(F)c(NCc4ccncc4)c(C(=O)N(C)C)c3)cc12
Yield: 22.3 %

Procedure:
Crude 3-fluoro-5-iodo-N,N-dimethyl-2-[(pyridin-4-ylmethyl)-amino]-benzamide (˜1.63 mmol) from the previous step and 3-(2-methoxy-phenyl)-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine (822 mg, 1.63), [1,1′-bis(diphenylphosphino)-ferrocene]dichloropalladium(II) complex with dichloromethane (1:1, 133 mg, 0.16 mmol), acetonitrile (8 ml) and 2 M aqueous sodium carbonate solution (4 ml) were placed in a microwave reactor and irradiated to 100° C. for 10 minutes. The reaction mixture was concentrated in vacuo and the residue partitioned between dichloromethane and water. The organic layer was dried over sodium sulfate, and concentrated. The crude product was purified by flash chromatography on silica gel (0 to 100% [10% methanol in ethyl acetate] in hexanes) to afford 236 mg (22% for 2 steps) of 3-fluoro-5-[3-(2-methoxy-phenyl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-N,N-dimethyl-2-[(pyridin-4-ylmethyl)-amino]-benzamide. MS: m/z 650.3 (M+H+).
Reaction SMILES: [CH3:1][Si:2]([CH3:26])([C:22]([CH3:25])([CH3:24])[CH3:23])[O:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[C:9]([OH:11])[CH:10]=1.Cl[CH2:28][C:29](Cl)=[O:30].S(=O)(=O)(O)[O-].[Na+]>ClCCl.C(N(CC)CC)C.CN(C1C=CC=CN=1)C>[CH3:26][Si:2]([CH3:1])([C:22]([CH3:23])([CH3:25])[CH3:24])[O:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]2[N:12]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[C:29](=[O:30])[CH2:28][O:11][C:9]=2[CH:10]=1
Reactant: COc1ccc(CNc2ccc(CO[Si](C)(C)C(C)(C)C)cc2O)cc1
Reactant: O=C(Cl)CCl
Agent: CN(C)c1ccccn1
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(CN2C(=O)COc3cc(CO[Si](C)(C)C(C)(C)C)ccc32)cc1

Procedure:
To a stirred solution of 5-(dimethyl-t-butylsilyl)oxymethyl-2-(4-methoxybenzylamino) phenol in anhydrous dichloromethane, triethylamine and dimethylaminopyridine at 0° C. and under nitrogen atmosphere, chloroacetyl-chloride is added. The mixture is refluxed for 10 h, poured into aqueous sodium bisulfate, extracted with dichloromethane and the product isolated by flash chromatography.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:5]=[C:6]([O:10][CH3:11])[C:7]=1[C:8]#[N:9].[NH3:18]>>[NH2:18][C:2]1[CH:3]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:5]=[C:6]([O:10][CH3:11])[C:7]=1[C:8]#[N:9]
Reactant: N
Reactant: COc1cc(-c2ccccc2)cc(F)c1C#N
Product: COc1cc(-c2ccccc2)cc(N)c1C#N
Temperature: 25 °C
Yield: 52 %

Procedure:
A solution of 3-fluoro-5-methoxy-[1,1′-biphenyl]-4-carbonitrile (3, 4.0 g, 17.6 mmol) in ammonia saturated DMSO (100 mL) was heated in an autoclave at 150° C. for 18 h. After this time, the mixture was cooled to room temperature, concentrated and purified by silica gel chromatography eluting with ethyl acetate in hexane (0-100%) to afford the title compound (2.06 g, 52%) as a light yellow solid: 1H NMR (500 MHz, CDCl3) δ7.54-7.52 (m, 2H), 7.46-7.43 (m, 2H), 7.41-7.38 (m, 1H), 6.52 (d, J=1.0 Hz, 1H), 6.43 (d, J=1.0 Hz, 1H), 4.43 (br s, 2H), 3.93 (s, 3H).
Reaction SMILES: CCCCC.Cl[SiH](Cl)Cl.[CH3:10][NH:11][CH3:12].[CH2:13]([O:15][SiH:16]([O:18][CH2:19][CH3:20])Cl)[CH3:14]>C(O)C>[CH2:13]([O:15][SiH:16]([O:18][CH2:19][CH3:20])[N:11]([CH3:12])[CH3:10])[CH3:14]
Reactant: CNC
Reactant: CCO[SiH](Cl)OCC
Agent: Cl[SiH](Cl)Cl
Solvent: CCCCC
Solvent: CCO
Product: CCO[SiH](OCC)N(C)C

Procedure:
Following the same general procedure described in Example 1, 2 liters of pentane and 404 mls of trichlorosilane were charged in a 5 L flask. During reflux, 464 mls of anhydrous ethanol was added dropwise. After the alcoholysis was completed, 550 mls of dimethylamine was added to the unisolated diethoxychlorosilane. Distillation yielded 290 g of diethoxy(dimethylamino)silane (b.p. 138°-139° C.).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([OH:9])=O.C(Cl)(=O)C(Cl)=O.[Sn](Cl)(Cl)(Cl)Cl.[N:21]1([N:26]2[C:34](=[O:35])[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:27]2=[O:36])[CH:25]=[CH:24][CH:23]=[CH:22]1>C(Cl)Cl.O>[CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([C:22]1[N:21]([N:26]2[C:34](=[O:35])[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:27]2=[O:36])[CH:25]=[CH:24][CH:23]=1)=[O:9]
Reactant: O=C1c2ccccc2C(=O)N1n1cccc1
Reactant: Cc1ccsc1C(=O)O
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: O
Product: Cc1ccsc1C(=O)c1cccn1N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 25.2 %

Procedure:
To a stirred solution consisting of 3-methyl-2-thiophenecarboxylic acid (21.0 g) in dry DCM (1.5 l) was added oxalyl chloride (21.0 ml) at room temperature under nitrogen. After stirring for 1 hour at room temperature, the reaction mixture was cooled to -10° C. and tin (IV) chloride (17.3 ml) was added. The resulting solution was stirred for 10 minutes (-10° C.) at which time 2-(1H-pyrrol-1-yl)-1H-isoindole-1,3(2H)dione (31.3 g) was added in three portions. After stirring for 1 hour in the cooling bath, the reaction mixture was poured into cold water and the layers separated. The organic phase was washed twice with 5% HCl (aq.) and dried (MgSO4). Filtration and concentration gave the crude product. Purification via preparative HPLC (silica gel, DCM) afforded 12.5 g of the product as a solid, m.p. 221°-223° C.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][NH:6][CH2:5][CH:4]([CH3:8])[NH:3]1.[Cl:9][C:10]1[C:14](Cl)=[N:13][S:12][N:11]=1.O>CN(C=O)C>[Cl:9][C:10]1[C:14]([N:6]2[CH2:5][CH:4]([CH3:8])[NH:3][CH:2]([CH3:1])[CH2:7]2)=[N:13][S:12][N:11]=1
Reactant: Clc1nsnc1Cl
Reactant: CC1CNCC(C)N1
Solvent: CN(C)C=O
Solvent: O
Product: CC1CN(c2nsnc2Cl)CC(C)N1
Temperature: 100 °C
Reaction time: 3.5 h
Yield: 97 %

Procedure:
2,6-Dimethyl-piperazine (8.1 g, 71 mmol) was heated to 100° C. in DMF (8.0 ml). 3,4-Dichloro-1,2,5-thiadiazole (3.3 ml, 35 mmol) was added and the mixture stirred at 100° C. for 3-4 h. The reaction mixture was poured into H2O and extracted with EtOAc (4×). The combined EtOAc extractions were washed with sat'd NaHCO3 (1×), sat'd NaCl (1×), dried (Na2SO4), and concentrated in vacuo to give 7.9 g (97%) of 1-(4-chloro-[1,2,5]thiadiazol-3-yl)-3,5-dimethyl-piperazine which was used without further purification. 1H NMR (CDCl3) 3.90-3.86 (m, 2H), 3.05 (m, 2H), 2.52 (m, 2H), 1.12 (d, 6H) ppm. LC-MS (MH+)=233.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([F:12])[C:9]([CH3:13])=[C:8]2[C:3]=1[C:4](=[O:23])[C:5]([C:18]([O:20]CC)=[O:19])=[CH:6][N:7]2[C@@H:14]1[CH2:16][C@@H:15]1[F:17].O.S(=O)(=O)(O)O>C(O)(=O)C>[NH2:1][C:2]1[CH:11]=[C:10]([F:12])[C:9]([CH3:13])=[C:8]2[C:3]=1[C:4](=[O:23])[C:5]([C:18]([OH:20])=[O:19])=[CH:6][N:7]2[C@@H:14]1[CH2:16][C@@H:15]1[F:17]
Reactant: CCOC(=O)c1cn([C@@H]2C[C@@H]2F)c2c(C)c(F)cc(N)c2c1=O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: Cc1c(F)cc(N)c2c(=O)c(C(=O)O)cn([C@@H]3C[C@@H]3F)c12
Temperature: 120 °C
Reaction time: 4 h
Yield: 82.3 %

Procedure:
Ethyl 5-amino-7-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylate (735 mg, 2.28 mmol) was dissolved in a 1:1 mixed solution (8 ml) of acetic acid:water, and after adding concentrated sulfuric acid (90 μl) thereto, it was stirred for 4 hours in an oil bath of 120° C. After cooling the reaction solution with ice, water (20 ml) was poured therein, and the mixed reaction solution was stirred at room temperature for 2 hours. The precipitated crystals were filtered out, washed with excess water, a small amount of cold ethanol and excess diethyl ether in that order, and then dried under a reduced pressure at 80° C. for 17 hours. 552 mg (82%) of the title compound was thereby obtained in the form of yellow crystals.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:10][C:9]=2[C:19]2[C:20]([F:35])=[C:21]([NH:25][S:26]([C:29]3[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=3)(=[O:28])=[O:27])[CH:22]=[CH:23][CH:24]=2)[CH:5]=[CH:4][N:3]=1.[CH2:36]([NH2:40])[CH:37]([CH3:39])[CH3:38]>>[F:35][C:20]1[C:19]([C:9]2[N:10]=[C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[S:12][C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:40][CH2:36][CH:37]([CH3:39])[CH3:38])[N:7]=2)=[CH:24][CH:23]=[CH:22][C:21]=1[NH:25][S:26]([C:29]1[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=1)(=[O:28])=[O:27]
Reactant: O=S(=O)(Nc1cccc(-c2nc(N3CCOCC3)sc2-c2ccnc(Cl)n2)c1F)c1cccnc1
Reactant: CC(C)CN
Product: CC(C)CNc1nccc(-c2sc(N3CCOCC3)nc2-c2cccc(NS(=O)(=O)c3cccnc3)c2F)n1

Procedure:
Following a procedure analogous to the procedure described in Example 18, Step B, using N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-3-pyridinesulfonamide (155 mg, 0.291 mmol) and isobutylamine (0.292 mL, 2.91 mmol) the title compound was obtained as a yellow foam (83 mg, 50% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.53 (s, 1H), 8.83 (d, J=2.3 Hz, 1H), 8.73 (dd, 1H), 8.03-8.13 (m, 1H), 7.83 (d, J=5.2 Hz, 1H), 7.53 (dd, J=8.1, 4.9 Hz, 1H), 7.31-7.44 (m, 1H), 7.17-7.34 (m, 2H), 7.09 (d, J=1.4 Hz, 1H), 5.39-5.65 (m, 1H), 3.66 (t, J=4.6 Hz, 4H), 3.36-3.49 (m, 4H), 2.82-3.14 (m, 2H), 1.77 (dt, J=13.3, 6.7 Hz, 1H), 0.82 (d, J=6.6 Hz, 6H). MS (ESI): 570.1 [M+H]+.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:11]=[C:10]2[N:12]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[C:30]4[NH:34][N:33]=[N:32][N:31]=4)=[CH:20][CH:19]=3)[C:13]([CH2:15][CH3:16])=[N:14][C:9]2=[C:8]([CH3:35])[CH:7]=1)=O)C.[NH:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1.[H-].[Na+].CC(O)=O>C1COCC1>[CH2:15]([C:13]1[N:12]([CH2:17][C:18]2[CH:19]=[CH:20][C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]3[NH:34][N:33]=[N:32][N:31]=3)=[CH:22][CH:23]=2)[C:10]2=[N:11][C:6]([C:4]([N:36]3[CH2:41][CH2:40][O:39][CH2:38][CH2:37]3)=[O:3])=[CH:7][C:8]([CH3:35])=[C:9]2[N:14]=1)[CH3:16]
Reactant: C1COCCN1
Reactant: CCOC(=O)c1cc(C)c2nc(CC)n(Cc3ccc(-c4ccccc4-c4nnn[nH]4)cc3)c2n1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCc1nc2c(C)cc(C(=O)N3CCOCC3)nc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Reaction time: 16 h

Procedure:
To 5-(ethoxycarbonyl)-2-ethyl-7-methyl-3-(2'-(tetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine (30 mg) in THF (1 mL) at RT was added 0.25 mL of morpholine and NaH (20 mg of an 80% dispersion). After stirring for 16 hours, 1% aqueous HOAc (2 mL) was added. Extractive workup (EtOAc), and purification (SiO2, 75/25/1 CH2Cl2 /MeOH/NH4OH) gave 10 mg of a solid.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][C:3]=1[NH2:4].[S:10](=O)(=[O:13])([OH:12])[OH:11].[OH-].[K+]>>[CH3:9][C:6]1[CH:5]=[C:3]([NH2:4])[C:2]([CH3:1])=[CH:8][C:7]=1[S:10]([OH:13])(=[O:12])=[O:11]
Reactant: O=S(=O)(O)O
Reactant: Cc1ccc(C)c(N)c1
Agent: [K+]
Agent: [OH-]
Product: Cc1cc(S(=O)(=O)O)c(C)cc1N

Procedure:
To 121 g of 2,5-dimethylaniline, 100 g of sulfuric acid (d=1.84) was gradually added dropwise and the mixture was heated at 220° to 230° C. on an oil bath for 5 hours. To the reaction mixture, 2 l of an 1 N aqueous potasium hydroxide solution was added and the mixture was stirred with heating. After filtering the mixture while hot, 1 kg of hydrochloric acid (d=1.18) was added to the filtrate. The crystals thus precipitated were collected by filtration and washed with 1 l of acetone.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:33])[C@H:4]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[S:29](=[O:32])(=[O:31])[NH2:30])=[CH:19][CH:18]=1)[NH:5][C:6](=[O:15])[C:7]1[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][C:8]=1[Cl:14].[C:34](Cl)(=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.CCOC(C)=O.C([O-])(O)=O.[Na+]>N1C=CC=CC=1>[CH3:1][O:2][C:3](=[O:33])[C@H:4]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[S:29](=[O:32])(=[O:31])[NH:30][C:34](=[O:41])[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[CH:19][CH:18]=1)[NH:5][C:6](=[O:15])[C:7]1[C:8]([Cl:14])=[CH:9][CH:10]=[CH:11][C:12]=1[Cl:13]
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccccc2S(N)(=O)=O)cc1)NC(=O)c1c(Cl)cccc1Cl
Reactant: O=C(Cl)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](Cc1ccc(-c2ccccc2S(=O)(=O)NC(=O)c2ccccc2)cc1)NC(=O)c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 12 h

Procedure:
N-(2,6-Dichlorobenzoyl)-4-(2-sulfamoylphenyl)-L-phenylalanine methyl ester (100 mg) was dissolved in anhydrous pyridine (5 mL). To this solution was added benzoyl chloride (50 μL) and the mixture was stirred for 12 h at room temperature under N2. EtOAc and satd. NaHCO3 were added to the mixture and the EtOAc phase was washed with 1 N HCl, dried (MgSO4) and evaporated. The residue was purified by flash column chromatography (silica gel; eluent: EtOAc/hexanes 1:2) to give N-(2,6-dichlorobenzoyl)-4-[2-(N-benzoylsulfamoyl)phenyl]-L-phenylalanine methyl ester.
Reaction SMILES: NC(N)=O.C=O.[NH2:7][CH2:8][C:9]([OH:11])=[O:10].[C:12]([OH:15])(=[O:14])[CH3:13]>>[NH:7]([CH2:13][C:12]([OH:15])=[O:14])[CH2:8][C:9]([OH:11])=[O:10]
Reactant: CC(=O)O
Reactant: NCC(=O)O
Agent: C=O
Agent: NC(N)=O
Product: O=C(O)CNCC(=O)O
Temperature: 130 °C
Reaction time: 1 h
Yield: 13 %

Procedure:
A 2 L autoclave was charged with urea (V) (60 g, 1.0 mole), Co(OAc) 2.4H2O (66 g, 0.26 mole), and acetic acid (1 L). After sealing the autoclave, 2200 psi (15,172 kPa) of CO:H2 (70:30) was established at 25° C. with stirring at 2000 rpm. The contents of the autoclave were heated to 130° C. and 3200 psi (22,069 kPa) CO:H2 (70:30) was established. After approximately one hour, rapid gas uptake was observed. The reaction mass was cooled to 85° C. and the feed gas was changed to a CO:H2 (90:10) composition. Under a constant 3200 psi (22,069 kPa), 47 Wt. % formalin (320 mL, 5.28 mole) was delivered at 16 mL/min. The reaction was stirred at 85° C. for 90 min. after the formalin addition was complete. Then the reaction was cooled to 25° C., removed from the autoclave, and concentrated to an oil under reduced pressure. The oil was treated with 2 L of 10% HCl at 100° C. for two hours. This resulted in a 13% yield of (XIV) and 5% glycine.