Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=3)[CH:10]([CH2:25][NH:26][CH:27]([CH3:29])[CH3:28])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[CH3:30][S:31]([NH:34][C:35]1[CH:43]=[CH:42][C:38]([C:39](Cl)=[O:40])=[CH:37][CH:36]=1)(=[O:33])=[O:32]>>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=3)[CH:10]([CH2:25][N:26]([CH:27]([CH3:29])[CH3:28])[C:39](=[O:40])[C:38]3[CH:42]=[CH:43][C:35]([NH:34][S:31]([CH3:30])(=[O:33])=[O:32])=[CH:36][CH:37]=3)[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(CN2CCN(c3cccc(Cl)c3)CC2CNC(C)C)cc1OC
Reactant: CS(=O)(=O)Nc1ccc(C(=O)Cl)cc1
Product: COc1ccc(CN2CCN(c3cccc(Cl)c3)CC2CN(C(=O)c2ccc(NS(C)(=O)=O)cc2)C(C)C)cc1OC

Procedure:
In a manner similar to Preparation 3, react 4-(3-chlorophenyl)-1-[(3,4-dimethoxyphenyl)methyl]-N-(1-methylethyl)-2-piperazinemethanamine with 4-[(methylsulfonyl)amino]benzoyl chloride to obtainthe title compound.
Reaction SMILES: [ClH:1].CCOC(C)=O.[C:8]1([C:14]2[N:19]=[C:18]3[N:20]4[C:26]([C:27]5[CH:32]=[N:31][CH:30]=[CH:29][N:28]=5)=[N:25][N:24]=[C:21]4[CH:22]=[CH:23][C:17]3=[N:16][C:15]=2[C:33]2[CH:38]=[CH:37][C:36]([C:39]3([NH:43]C(=O)OC(C)(C)C)[CH2:42][CH2:41][CH2:40]3)=[CH:35][CH:34]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>CO.C(Cl)Cl>[ClH:1].[C:8]1([C:14]2[N:19]=[C:18]3[N:20]4[C:26]([C:27]5[CH:32]=[N:31][CH:30]=[CH:29][N:28]=5)=[N:25][N:24]=[C:21]4[CH:22]=[CH:23][C:17]3=[N:16][C:15]=2[C:33]2[CH:34]=[CH:35][C:36]([C:39]3([NH2:43])[CH2:42][CH2:41][CH2:40]3)=[CH:37][CH:38]=2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4ccc5nnc(-c6cnccn6)n5c4nc3-c3ccccc3)cc2)CCC1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: NC1(c2ccc(-c3nc4ccc5nnc(-c6cnccn6)n5c4nc3-c3ccccc3)cc2)CCC1

Procedure:
A 4N solution of HCl in EtOAc (10 mL, 40 mmol) was added to stirred solution of tert-butyl {1-[4-(2-phenyl-9-pyrazin-2-yl[1,2,4]triazolo[4′,3′:1,6]pyrido[2,3-b]pyrazin-3-yl)phenyl]cyclobutyl}carbamate (8-7, 0.110 g, 0.193 mmol) in MeOH (2 mL) and DCM (2 mL). After 4 hours the reaction mixture was concentrated in vacuo to give 1-[4-(2-phenyl-9-pyrazin-2-yl[1,2,4]triazolo[4′,3′:1,6]pyrido[2,3-b]pyrazin-3-yl)phenyl]cyclobutanamine hydrochloride (8-8) as an orange/tan solid. HRMS (M+H)+: observed=471.2076, calculated=471.2040.
Reaction SMILES: C([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:33][O:34][CH2:35][CH2:36][NH:37]C(OC(C)(C)C)=O)[C:10]([NH:12][CH:13]2[C:31](=[O:32])[N:15]3[C:16]([C:28]([OH:30])=[O:29])=[C:17]([CH2:20][S:21][C:22]4[N:26]([CH3:27])[N:25]=[N:24][N:23]=4)[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=O.Cl>CO>[NH2:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:33][O:34][CH2:35][CH2:36][NH2:37])[C:10]([NH:12][CH:13]2[C:31](=[O:32])[N:15]3[C:16]([C:28]([OH:30])=[O:29])=[C:17]([CH2:20][S:21][C:22]4[N:26]([CH3:27])[N:25]=[N:24][N:23]=4)[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1
Reactant: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCCNC(=O)OC(C)(C)C)c3csc(NC=O)n3)[C@H]2SC1
Agent: Cl
Solvent: CO
Product: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCCN)c3csc(N)n3)[C@H]2SC1
Yield: 33.3 %

Procedure:
A solution of 7-[2-(2-formamidothiazol-4-yl)-2-(2-tert-butoxycarbonylaminoethoxyimino)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer, 2.6 g.), conc. hydrochloric acid (2 g.) and methanol (40 ml.) was stirred at room temperature for 3 hours. After evaporating the solvent in vacuo, methanol was added to the residue and mixture was evaporated in vacuo again. The residue was dissolved in water (30 ml.) and adjusted to pH 3.5 with a saturated sodium bicarbonate aqueous solution under ice-cooling. The solution was subjected to column chromatography on macroporous non-ionic adsorption resin "Diaion HP-20" [trademark, manufactured by Mitsubishi Chemical Industries Ltd.], and eluted with 30% aqueous isopropyl alcohol. The eluate was concentrated in vacuo and the residue was lyophilized to give 7-[2-(2-aminothiazol-4-yl)-2-(2-aminoethoxyimino)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer, 0.7 g.)
Reaction SMILES: [I-:1].[Na+].CNCCNC.Br[C:10]1[N:15]=[C:14]([O:16][CH3:17])[C:13]([NH2:18])=[CH:12][CH:11]=1.O>O1CCOCC1.[Cu](I)I.C(OCC)(=O)C>[I:1][C:10]1[N:15]=[C:14]([O:16][CH3:17])[C:13]([NH2:18])=[CH:12][CH:11]=1
Reactant: COc1nc(Br)ccc1N
Reactant: [I-]
Agent: I[Cu]I
Agent: CNCCNC
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COc1nc(I)ccc1N
Temperature: 120 °C
Reaction time: 14 h
Yield: 78.1 %

Procedure:
Sodium iodide (40 g), copper iodide (6.0 g) and N,N′-dimethylethylenediamine (7 mL) was added to a solution of 6-bromo-2-methoxypyridin-3-amine (26 g) in 1,4-dioxane (250 mL) in a nitrogen gas stream, and the mixture was stirred at 120° C. for 14 hours. The reaction solution was left to cool, and then water and ethyl acetate were added. Filtration through celite was followed by extraction. The organic layer was washed with a 20% sodium thiosulfate solution and brine, dried over anhydrous magnesium sulfate and filtered. The solvent was then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=85:15→70:30) to give 6-iodo-2-methoxypyridin-3-amine as a colorless powder (25 g, 75%).
Reaction SMILES: [CH3:1]/[CH:2]=[C:3]1/[CH2:4][CH2:5][C@@H:6]2[C@:20]/1([CH3:21])[CH2:19][CH2:18][C@H:17]1[C@H:7]2[CH2:8][CH:9]=[C:10]2[C@:15]1([CH3:16])[CH2:14][CH2:13][C@H:12]([OH:22])[CH2:11]2.[C:23]1([CH3:33])[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1.C(=O)(O)[O-:35].[Na+]>N1C=CC=CC=1>[CH3:1]/[CH:2]=[C:3]1/[CH2:4][CH2:5][C@@H:6]2[C@:20]/1([CH3:21])[CH2:19][CH2:18][C@H:17]1[C@H:7]2[CH2:8][CH:9]=[C:10]2[C@:15]1([CH3:16])[CH2:14][CH2:13][C@H:12]([OH:22])[CH2:11]2.[CH3:33][C:23]1[CH:28]=[CH:27][C:26]([S:29]([OH:35])(=[O:31])=[O:30])=[CH:25][CH:24]=1
Reactant: O=C([O-])O
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: C/C=C1/CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: [Na+]
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)O)cc1
Reaction time: 3 h

Procedure:
To a solution of 1.80 g (6.0 mmol) (Z)-pregna-5,17(20)-dien-3β-ol in 8 ml of pyridine under a nitrogen atmosphere was added 1.26 g (6.6 mmol) of p-toluenesulfonyl chloride. Precipitation (pyridinium hydrochloride) began after 3 hr. After 19 hr., an additional 1.03 g (5.4 mmol) of p-toluenesulfonyl chloride was added. The reaction was left stirring for 5 days and then was poured into a stirred solution of 150 ml of 5% aqueous sodium bicarbonate cooled to 7°. After 30 min., the precipitate was removed by filtration, the filter cake washed with 2×15 ml of water and then dried over night to a vacuum dessicator (Drierite) at about 1 mm Hg to afford 2.50 g (92%) of crude product suitable for the next step. (Unstable to chromatography). An analytical sample was recrystallized from hexane to give (Z)-pregna-5,17(20)-dien-3β-ol-p-toluenesulfonate as white crystals, mp 119°-119.3°.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[O:3]1.I[CH2:18][CH2:19][O:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][O:26][CH2:27][CH2:28]I>>[O:20]([CH2:21][CH2:22][O:23][CH2:24][CH2:25][O:26][C:27]1[CH:28]=[CH:14][C:9]([B:4]2[O:5][C:6]([CH3:8])([CH3:7])[C:2]([CH3:1])([CH3:16])[O:3]2)=[CH:10][CH:11]=1)[CH2:19][CH2:18][O:15][CH2:12][CH2:13][O:15][C:12]1[CH:13]=[CH:14][C:9]([B:4]2[O:3][C:2]([CH3:16])([CH3:1])[C:6]([CH3:7])([CH3:8])[O:5]2)=[CH:10][CH:11]=1
Reactant: ICCOCCOCCOCCI
Reactant: CC1(C)OB(c2ccc(O)cc2)OC1(C)C
Product: CC1(C)OB(c2ccc(OCCOCCOCCOCCOc3ccc(B4OC(C)(C)C(C)(C)O4)cc3)cc2)OC1(C)C

Procedure:
By following the process described in Example R65, Example R66 is prepared by dimerization of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol with 1-iodo-2-{2-[2-(2-iodoethoxy)ethoxy]ethoxy}ethane (Example R4). A white powder is obtained.
Reaction SMILES: [CH:1]1([N:7]2[CH2:13][C:12]([F:16])([CH:14]=[CH2:15])[C:11](=[O:17])[N:10]([CH3:18])[C:9]3[CH:19]=[N:20][C:21]([NH:23][C:24]4[CH:32]=[CH:31][C:27]([C:28](O)=[O:29])=[CH:26][C:25]=4[O:33][CH3:34])=[N:22][C:8]2=3)C[CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=[N:50][C:45]2[CH:46]=C[CH:48]=[N:49][C:44]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.Cl.CN1CC(N)C1>>[CH:1]1([N:7]2[CH2:13][C:12]([F:16])([CH:14]=[CH2:15])[C:11](=[O:17])[N:10]([CH3:18])[C:9]3[CH:19]=[N:20][C:21]([NH:23][C:24]4[CH:32]=[CH:31][C:27]([C:28]([NH:50][CH:45]5[CH2:44][N:49]([CH3:48])[CH2:46]5)=[O:29])=[CH:26][C:25]=4[O:33][CH3:34])=[N:22][C:8]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: C=CC1(F)CN(C2CCCCC2)c2nc(Nc3ccc(C(=O)O)cc3OC)ncc2N(C)C1=O
Agent: CN1CC(N)C1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Product: C=CC1(F)CN(C2CCCC2)c2nc(Nc3ccc(C(=O)NC4CN(C)C4)cc3OC)ncc2N(C)C1=O

Procedure:
The title compound was synthesized from 4-(9-cyclohexyl-7-fluoro-7-vinyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid as described in the General procedure for amide bond synthesis using HATU and 1-methylazetidin-3-amine bis-hydrochloride. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.48-2.10 (m, 8H) 2.32 (br. s., 3H) 3.08 (t, J=6.82 Hz, 2H) 3.29 (br. s., 3H) 3.62 (t, J=6.95 Hz, 2H) 3.82 (m, 2H) 3.94 (br. s., 3H) 4.44 (m, 1H) 4.88 (m, 1H) 5.38 (d, J=12.13 Hz, 2H) 5.99 (m, 1H) 7.50 (br. s., 2H) 7.84 (br. s., 1H) 8.13 (br. s., 1H)) 8.31 (d, J=8.0 Hz, 1H) 8.65 (d, J=7.83 Hz, 1H). [M+H] calculated for C27H34FN7O3, 524. found 524.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:14][S:15]([C:17]2[NH:21][C:20]3[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=3[N:18]=2)=[O:16])=[N:4][CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].C(N(CC)CC)C.Cl[S:34]([C:37]1[CH:53]=[CH:52][C:40]([O:41][CH2:42][C:43]([NH:45][C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][N:47]=2)=[O:44])=[CH:39][CH:38]=1)(=[O:36])=[O:35]>ClCCl>[CH3:1][C:2]1[C:3]([CH2:14][S:15]([C:17]2[N:18]([S:34]([C:37]3[CH:53]=[CH:52][C:40]([O:41][CH2:42][C:43]([NH:45][C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][N:47]=4)=[O:44])=[CH:39][CH:38]=3)(=[O:35])=[O:36])[C:19]3[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=3[N:21]=2)=[O:16])=[N:4][CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:11])[F:12]
Reactant: O=C(COc1ccc(S(=O)(=O)Cl)cc1)Nc1ccccn1
Reactant: Cc1c(OCC(F)(F)F)ccnc1CS(=O)c1nc2ccccc2[nH]1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1c(OCC(F)(F)F)ccnc1CS(=O)c1nc2ccccc2n1S(=O)(=O)c1ccc(OCC(=O)Nc2ccccn2)cc1
Yield: 71.7 %

Procedure:
2-[[ [3-Methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole (185 mg) dissolved in 20 ml of dichloromethane and 0.2 ml of triethylamine was added to 170 mg of 2-[p-(chlorosulfonyl)phenoxy]-N-(2-pyridyl)acetamide. The reaction mixture was washed with water. Organic layer was dried over anhydrous magnesium sulfate, and evaporated. Residual material was lyophilized to give 237 mg of the titled product. M.P. 78-81° C.
Reaction SMILES: [CH3:1][S:2]([C:5]1[N:10]=[CH:9][C:8]([O:11][C:12]2[CH:13]=[C:14]3[C:18](=[C:19]([O:21][CH:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:20]=2)[NH:17][C:16]([C:28]([NH2:30])=O)=[CH:15]3)=[CH:7][CH:6]=1)(=[O:4])=[O:3].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:40])=CC=1.C(OCC)(=O)C.CCCCCC>O1CCCC1>[CH3:1][S:2]([C:5]1[N:10]=[CH:9][C:8]([O:11][C:12]2[CH:13]=[C:14]3[C:18](=[C:19]([O:21][CH:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:20]=2)[NH:17][C:16]([C:28](=[S:40])[NH2:30])=[CH:15]3)=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CS(=O)(=O)c1ccc(Oc2cc(OC3CCOCC3)c3[nH]c(C(N)=O)cc3c2)cn1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc(Oc2cc(OC3CCOCC3)c3[nH]c(C(N)=S)cc3c2)cn1
Yield: 100 %

Procedure:
To a solution of 5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-7-(tetrahydro-2H-pyran-4-yloxy)-1H-indole-2-carboxamide (1.35 g) in tetrahydrofuran (20 mL) was added a Lawesson's reagent (1.4 g), and the mixture was stirred with heating under reflux for 1 hr. The reaction mixture was cooled, and concentrated under reduced pressure. The obtained crude product was subjected to silica gel column chromatography (ethyl acetate:hexane=0:100 to 100:0, volume ratio) to give the title compound (1.4 g, yield 100%) as a yellow amorphous solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[CH2:9][S:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[N+:12]=1[O-:18].OO.[OH2:21].C(O)(=[O:24])C>[O-][W]([O-])(=O)=O.[Na+].[Na+]>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[CH2:9][S:10]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[N+:12]=1[O-:18])(=[O:24])=[O:21]
Reactant: CC(=O)O
Reactant: O
Reactant: Cc1ccc(C)c(CSc2cccc(C)[n+]2[O-])c1
Agent: O=[W](=O)([O-])[O-]
Agent: OO
Agent: [Na+]
Product: Cc1ccc(C)c(CS(=O)(=O)c2cccc(C)[n+]2[O-])c1
Temperature: 40 °C

Procedure:
The sulfide isolated in step (a) above was dissolved in 15 ml of glacial acetic acid and then 2 ml of 30% hydrogen peroxide was added along with 50 mg of sodium tungstate. The reaction mixture was heated at 40° C. for two hours, cooled, and poured into water to percipitate the product. Yield, 1.53 g.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]1[N:18]=[CH:17][C:16]2[C:19](/[CH:28]=[CH:29]/[C:30]3[CH:31]=[N:32][N:33]([CH3:35])[CH:34]=3)=[N:20][N:21](C3CCCCO3)[C:15]=2[CH:14]=1.Cl.C(Cl)(=O)C>CO>[Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]1[N:18]=[CH:17][C:16]2[C:19](/[CH:28]=[CH:29]/[C:30]3[CH:31]=[N:32][N:33]([CH3:35])[CH:34]=3)=[N:20][NH:21][C:15]=2[CH:14]=1
Reactant: COc1cc(OC)c(Cl)c(-c2cc3c(cn2)c(/C=C/c2cnn(C)c2)nn3C2CCCCO2)c1Cl
Agent: Cl
Solvent: CC(=O)Cl
Solvent: CO
Product: COc1cc(OC)c(Cl)c(-c2cc3[nH]nc(/C=C/c4cnn(C)c4)c3cn2)c1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
6-(2,6-Dichloro-3,5-dimethoxyphenyl)-3-[(E)-2-(1-methyl-1H-pyrazol-4-yl)vinyl]-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine was dissolved in methanol (0.8 mL). To the solution was added HCl solution previously prepared from acetyl chloride (0.5 mL) and methanol (0.5 mL). The mixture was stirred at r.t. for 2 h. The solvent was removed. The residue was dissolved in methanol, and purified by RP-HPLC (pH=10) to afford the desired product (4.9 mg). LCMS (M+H)+=430.1.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][C:12]([N:18]3[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]3)=[CH:13][CH:14]=2)[C:9]1=[O:31].[F:32][C:33]([F:58])([F:57])[CH2:34][NH:35][C:36]([C:38]1([CH2:52][CH2:53][CH2:54][CH2:55]Br)[C:51]2[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=2[O:45][C:44]2[C:39]1=[CH:40][CH:41]=[CH:42][CH:43]=2)=[O:37]>>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][C:12]([N:18]3[CH2:19][CH2:20][N:21]([CH2:55][CH2:54][CH2:53][CH2:52][C:38]4([C:36](=[O:37])[NH:35][CH2:34][C:33]([F:58])([F:57])[F:32])[C:51]5[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=5[O:45][C:44]5[C:39]4=[CH:40][CH:41]=[CH:42][CH:43]=5)[CH2:22][CH2:23]3)=[CH:13][CH:14]=2)[C:9]1=[O:31]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc3c(c2)C(=O)N(CC2CCCCO2)CC3)CC1
Reactant: O=C(NCC(F)(F)F)C1(CCCCBr)c2ccccc2Oc2ccccc21
Product: O=C1c2cc(N3CCN(CCCCC4(C(=O)NCC(F)(F)F)c5ccccc5Oc5ccccc54)CC3)ccc2CCN1CC1CCCCO1

Procedure:
Step (b) of Example 97 was repeated, except that the compound prepared in step (a) of Example 99 and the compound prepared in step (a) of Example 96 were used as the starting compounds. Thus, the title compound was prepared.
Reaction SMILES: [OH:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[N:9]([C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]([O:21]C)=[O:20])=[CH:14][CH:13]=1)=[C:10]=[O:11]>>[OH:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4][C:10](=[O:11])[NH:9][C:12]1[CH:13]=[CH:14][C:15]([CH2:18][C:19]([OH:21])=[O:20])=[CH:16][CH:17]=1
Reactant: Nc1ccccc1O
Reactant: COC(=O)Cc1ccc(N=C=O)cc1
Product: O=C(O)Cc1ccc(NC(=O)Nc2ccccc2O)cc1

Procedure:
4-(2-Hydroxyphenylureido)phenylacetic acid was prepared using procedure C with 2-hydroxyaniline and KCl: 1H NMR (CD3SOCD3, 300 MHz, ppm) 9.90 (s, 1H), 9.25 (s, 1H), 8.12 (s, 1H), 8.02 (bd, 1H), 7.37 (d, 2H), 7.13 (d, 2H), 6.70-6.97 (m, 3H), 3.48 (s, 2H).
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[C:11]([C:16]([O:18][CH2:19]C)=[O:17])[C:10]([CH3:21])=[CH:9]2)(=O)C.C(=O)([O-])[O-].[K+].[K+]>CO>[OH:4][CH2:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[C:11]([C:16]([O:18][CH3:19])=[O:17])[C:10]([CH3:21])=[CH:9]2
Reactant: CCOC(=O)c1nc2ccc(COC(C)=O)cc2cc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COC(=O)c1nc2ccc(CO)cc2cc1C
Reaction time: 0.5 h
Yield: 5.9 %

Procedure:
A mixture of ethyl 6-acetoxymethyl-3-methylquinoline-2-carboxylate (420 mg) and potassium carbonate in methanol was stirred for 30 minutes under ice-cooling. After filtration the filtrate was concentrated and partitioned between ethyl acetate and water. The organic layer was washed with water, dried over magnesium sulfate and concentrated to give methyl 6-hydroxymethyl-3-methylquinoline-2-carboxylate (20 mg).
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([N:8]=[C:9]([NH:11][C:12]([CH:14]3[CH2:16][CH2:15]3)=[O:13])[CH:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH:17]([C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1)=[O:18].C([O-])([O-])=O.[Na+].[Na+].O>O1CCOCC1>[CH:17]([C:19]1[CH:24]=[CH:23][C:22]([C:2]2[C:3]3[N:4]([N:8]=[C:9]([NH:11][C:12]([CH:14]4[CH2:16][CH2:15]4)=[O:13])[CH:10]=3)[CH:5]=[CH:6][CH:7]=2)=[CH:21][CH:20]=1)=[O:18]
Reactant: O=C(Nc1cc2c(Br)cccn2n1)C1CC1
Reactant: O=Cc1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: O=Cc1ccc(-c2cccn3nc(NC(=O)C4CC4)cc23)cc1
Temperature: 25 °C

Procedure:
N-(4-Bromopyrazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamide (4.66 g, 17 mmol), 4-formylphenyl boronic acid (3.06 g, 20.4 mmol), PdCl2dppf (0.37 g, 0.45 mmol) and Na2CO3 (3.6 g, 34 mmol) were stirred in 1,4-dioxane (140 mL) and water (28 mL) at 100° C. for 3 h. The reaction mixture was cooled to room temperature, filtered through celite, washed through with DCM and concentrated in vacuo. The residue was triturated with EtOAc and dried in vacuo to afford N-(4-(4-formylphenyl)pyrazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamide.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:13]=[C:12]2[C:7]([C:8]([C:25]([O:27][CH3:28])=[O:26])=[C:9]([CH3:24])[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=3)=[N:11]2)=[CH:6][C:5]=1[S:29]([CH2:32][CH3:33])(=[O:31])=[O:30])[CH3:2].[Br:34]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:34][CH2:24][C:9]1[C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:21])[F:22])[CH:15]=2)=[N:11][C:12]2[C:7]([C:8]=1[C:25]([O:27][CH3:28])=[O:26])=[CH:6][C:5]([S:29]([CH2:32][CH3:33])(=[O:31])=[O:30])=[C:4]([O:3][CH2:1][CH3:2])[CH:13]=2
Reactant: CCOc1cc2nc(-c3cccc(C(F)(F)F)c3)c(C)c(C(=O)OC)c2cc1S(=O)(=O)CC
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: CCOc1cc2nc(-c3cccc(C(F)(F)F)c3)c(CBr)c(C(=O)OC)c2cc1S(=O)(=O)CC
Temperature: 100 °C

Procedure:
A mixture of methyl 7-(ethyloxy)-6-(ethylsulfonyl)-3-methyl-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate (9.11 g, 18.92 mmol), N-bromosuccinimide (4.38 g, 24.60 mmol) and diphenylperoxyanhydride (0.458 g, 1.892 mmol) in carbon tetrachloride (100 mL) was heated to 100° C. overnight. The mixture was cooled to room temperature and the solvent was removed under reduced pressure to afford methyl 3-(bromomethyl)-7-(ethyloxy)-6-(ethylsulfonyl)-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate. This material was used without further purification. MS (m/z) 562.0 (M+H+).
Reaction SMILES: FC(F)(F)C(OC(=O)C(F)(F)F)=O.[CH3:14][O:15][C:16]1[CH:24]=[C:23]([NH:25][C:26]2[S:27][C:28]3[CH2:34][CH2:33][CH2:32][CH:31]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[C:29]=3[N:30]=2)[CH:22]=[CH:21][C:17]=1[C:18]([NH2:20])=O.N1C=CC=CC=1>O1CCOCC1>[CH3:14][O:15][C:16]1[CH:24]=[C:23]([NH:25][C:26]2[S:27][C:28]3[CH2:34][CH2:33][CH2:32][CH:31]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[C:29]=3[N:30]=2)[CH:22]=[CH:21][C:17]=1[C:18]#[N:20]
Reactant: COc1cc(Nc2nc3c(s2)CCCC3c2ccccc2)ccc1C(N)=O
Solvent: C1COCCO1
Solvent: c1ccncc1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: COc1cc(Nc2nc3c(s2)CCCC3c2ccccc2)ccc1C#N
Reaction time: 0.5 h
Yield: 39.6 %

Procedure:
Trifluoroacetic acid anhydride (257 uL, 1.83 mmol) was added slowly to a cooled suspension of 2-methoxy-4-(4-phenyl-4,5,6,7-tetrahydro-benzothiazol-2-ylamino)-benzamide (625 mg, 1.65 mmol) in dioxane (2 mL) and pyridine (292 uL, 3.6 mmol). The white suspension was stirred for 30 minutes under cooling and then for 2 hours at 50° C. and for 3 hours at 80° C. Additional trifluoroacetic acid anhydride (300 uL), pyridine (400 uL) and dioxane (5 mL) were added and the reaction was stirred at 80° C. for 2 hours resulting in a clear brown solution. The solvent was removed under reduced pressure and the residue was partitioned between ethyl acetate and water. The organic layer was washed twice with saturated aqueous sodium hydrogen carbonate, brine, dried over magnesium sulfate, filtered and the solvent was removed under reduced pressure. The residue was purified on silica gel using dichloromethane with 4% methanol as eluent to yield the title compound (236 mg, 40%) as a beige foam. MS ISP (m/e): 362.3 (100) [(M+H)+].
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]([O:18][CH:19]2[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]2)[C:9]2S[C:11]3[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=3[N:13]=2)[CH:5]=[CH:6][CH:7]=1.[Cu][C:27]#[N:28].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C[N:72](C)C=O>O>[NH:13]1[C:12]2[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=2[N:72]=[C:9]1[CH:8]([O:18][CH:19]1[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]1)[C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=1)[C:27]#[N:28]
Reactant: CN1CCC(OC(c2cccc(Br)c2)c2nc3ccccc3s2)CC1
Reactant: CN(C)C=O
Reactant: N#C[Cu]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: O
Product: CN1CCC(OC(c2cccc(C#N)c2)c2nc3ccccc3[nH]2)CC1
Temperature: 120 °C
Reaction time: 48 h

Procedure:
To a solution of 2-[(3-bromophenyl)(1-methylpiperidin-4-yloxy)methyl]benzothiazole (200 mg) in N,N-dimethylformamide (2.5 mL) and water (0.2 mL) are added copper(I) cyanide (180 mg), bis(dibenzylidenacetone)palladium (14.3 mg) and Xantphos (14.4 mg). The tube is evacuated, filled with argon and sealed. After stirring at 120° C. for 48 h, the mixture is diluted with water then extracted with ethyl acetate. The pooled organic extracts are washed with water, brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified by chromatography (gradient dichloromethane/methanol/ammonia from 100/0/0 to 92.5/7.5/0.75) to afford 3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]benzonitrile
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[C:4]2[C:11](=[O:15])[NH:12][CH2:13][CH2:14][C:3]1=2>[Pd]=O>[CH3:1][N:2]1[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[C:4]2[C:11](=[O:15])[NH:12][CH:13]=[CH:14][C:3]1=2
Reactant: Cn1c2c(c3ccccc31)C(=O)NCC2
Agent: O=[Pd]
Product: Cn1c2ccccc2c2c(=O)[nH]ccc21
Yield: 95 %

Procedure:
A mixture of 2,3,4,5-tetrahydro-5-methyl-1H-pyrido[4,3-b]indol-1-one (500 mg) and 10% palladium oxide on carbon catalyst (50% aqueous paste; 250 mg) was heated at 320° for 10 min. The cooled solid was triturated with ethanol (ca. 100 ml), filtered and the resulting filtrate was evaporated to give the title compound (470 mg), m.p. 242.5°.