Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][NH:8][C:9]1[CH:10]=[C:11]([O:20][CH3:21])[CH:12]=[C:13]2[C:18]=1[N:17]=[CH:16][CH:15]=[C:14]2[CH3:19].[N:22]1([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:21][O:20][C:11]1[CH:12]=[C:13]2[C:18](=[C:9]([NH:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:25]3[CH2:24][CH2:23][N:22]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:27][CH2:26]3)[CH:10]=1)[N:17]=[CH:16][CH:15]=[C:14]2[CH3:19]
Reactant: CCOC(=O)N1CCNCC1
Reactant: COc1cc(NCCCCCCCl)c2nccc(C)c2c1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCOC(=O)N1CCN(CCCCCCNc2cc(OC)cc3c(C)ccnc23)CC1
Yield: 21 %

Procedure:
A mixture of 6.0 g (0.0195 mole) of N-(6-chlorohexyl)-6-methoxy-4-methyl-8-quinolinamine and 6 ml of 1-piperazinecarboxylic acid, ethyl ester in 2 ml of toluene was heated in an oil bath at 135° for 3 hr, allowed to cool, diluted with ethyl acetate and toluene, washed with water, dried, and concentrated to dryness in vacuo. The residue was chromatographed over 700 g of silica gel first with 2 l of ethyl acetate and then with 2 l each of the following solutions of methanol in ethyl acetate: 2%, 5%, 10%, and 20%. The eluant containing product, Rf (silica--ethyl acetate)=0.16, was concentrated to dryness. The residue was taken up in ether, filtered to remove dark flocculent material, and then treated with 1.2 ml of 85% phosphoric acid in 30 ml of ethanol. The gum which settled was washed with ether and acetone and then dissolved in 2-propanol and water. The pH of the solution was adjusted to 8 with ammonium hydroxide. The solution was then heated on the steambath, diluted with water to the cloud point and chilled to afford 1.7 g (21%) of the title compound, mp. 59°-60°.
Reaction SMILES: [CH3:1][N:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[NH:6][C:5](=[O:13])[C:4]2=[CH:14][S:15][CH:16]=[C:3]12.[H-].[Na+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C)C=O>[CH2:19]([N:6]1[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N:2]([CH3:1])[C:3]2=[CH:16][S:15][CH:14]=[C:4]2[C:5]1=[O:13])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CN1c2ccccc2NC(=O)c2cscc21
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1c2cscc2C(=O)N(Cc2ccccc2)c2ccccc21

Procedure:
A mixture of 0.35 g. of 4,9-dihydro-4-methyl-10H-thieno[3,4-b] [1,5]benzodiazepin-10-one, 65 mg. of 57% sodium hydride-mineral oil dispersion and 0.3 ml. of benzylbromide in 10 ml. of dimethylformamide is stirred at room temperature for 3 hours, quenched by dropwise addition of water, diluted with 100 ml. of water and extracted several times with chloroform. The chloroform solution is dried over magnesium sulfate and concentrated under reduced pressure to give a yellow oil which is chromatographed on silica gel with benzene-methanol (19:1) to give an oil which crystallizes on trituration with acetonitrile. Recrystallization from methanol-water gives off-white crystals, m.p. 137°-138.5°C.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][O:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH:9]=[C:10]([C:16]1[CH2:20][CH2:19][CH2:18][CH:17]=1)[NH:11]2)C.[Li+].[BH4-]>C1COCC1>[C:16]1([C:10]2[NH:11][C:12]3[C:8]([CH:9]=2)=[C:7]([O:6][CH2:5][CH2:4][OH:3])[CH:15]=[CH:14][CH:13]=3)[CH2:20][CH2:19][CH2:18][CH:17]=1
Reactant: CCOC(=O)COc1cccc2[nH]c(C3=CCCC3)cc12
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCCOc1cccc2[nH]c(C3=CCCC3)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.6 %

Procedure:
To 216 mg (0.758 mmol) of the ester from step 1 in 5 mL THF at 0° C. was added 455 μL (0.91 mmol, 1.2 eq) of LiBH4 solution (1M THF) and the reaction was stirred at room temperature overnight. The reaction was quenched with 1N HCl, extracted with EtOAc, washed with H2O, aqueous NaCl solution, dried (Mg SO4), and concentrated in vacuo to yield 167 mg (91%) of 2-(2-cyclopent-1-enyl-1H-indol-4-yloxy)-ethanol.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11](O)=[O:12])=[CH:10][C:5]=2[N:4]=[C:3]1[NH:14][C:15]1[S:16][C:17]2[CH:23]=[C:22]([O:24][C:25]([F:28])([F:27])[F:26])[CH:21]=[CH:20][C:18]=2[N:19]=1.[CH3:29][O:30][C:31](=[O:34])[CH2:32][NH2:33].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH3:29][O:30][C:31](=[O:34])[CH2:32][NH:33][C:11]([C:9]1[CH:8]=[CH:7][C:6]2[N:2]([CH3:1])[C:3]([NH:14][C:15]3[S:16][C:17]4[CH:23]=[C:22]([O:24][C:25]([F:28])([F:26])[F:27])[CH:21]=[CH:20][C:18]=4[N:19]=3)=[N:4][C:5]=2[CH:10]=1)=[O:12]
Reactant: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)O)ccc21
Reactant: COC(=O)CN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CNC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(OC(F)(F)F)cc3s1)n2C
Yield: 74.8 %

Procedure:
{[1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carbonyl]-amino}-acetic acid methyl ester (36 mg) was prepared by following General Procedure F using 1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzimidazole-5-carboxylic acid (41 mg), glycine methyl ester (27 mg), HBTU (38 mg), and DIEA (0.1 ml). LC/MS: m/z 481. 1H NMR (DMSO-d6, 400 MHz): δ 8.85 (br, 1H), 8.08 (s, 1H), 7.91 (m, 2H), 7.81-7.70 (m, 2H), 7.49 (d, 1H), 7.35 (d, 1H), 4.03 (d, 2H), 3.65 (s, 3H), and 3.62 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.[Li]N1C(C)(C)CCCC1(C)C.[Li]CCCC.CC1CCCN(C)C1(C)C.[C:41](=[O:43])=[O:42].[OH-].[Na+]>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:5]=[C:6]([F:8])[C:7]=1[C:41]([OH:43])=[O:42]
Reactant: Fc1cc(F)cc(-c2ccccc2)c1
Reactant: O=C=O
Agent: CC1CCCN(C)C1(C)C
Agent: [Li]CCCC
Agent: [Li]N1C(C)(C)CCCC1(C)C
Solvent: C1CCOC1
Product: O=C(O)c1c(F)cc(-c2ccccc2)cc1F
Temperature: -78 °C
Yield: 77 %

Procedure:
Dissolve crude 3,5-difluorobiphenyl (1.3 g, 6.83 mmol) in THF (14 mL) and cool to −78° C. Prepare LiTMP from the addition of BuLi (1.6 M soln in hexanes, 5.33 mL) to tetramethyl piperidine (1.4 mL, 1.25 equiv) at −78° C. in THF (14 mL). Cannulate the cooled LiTMP into the cooled 3,5-difluorobiphenyl and stir the reaction at −78° C. for 1 hour. Bubble carbon dioxide gas through the solution for 5 minutes, warn the reaction to room temperature, pour into 50 mL of 1M NaOH, and extract with 50 mL EtOAc. Discard the organic layer. Acidify the remaining aqueous layer with conc. HCl and extract twice with EtOAc. Dry the organics over MgSO4, filter, and evaporate to give 1.22 g of the title compound as a white solid (77%). MS (ES): m/z 233.1 (M−H).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.[C:15]([N:19]=[C:20]=[S:21])([CH3:18])([CH3:17])[CH3:16].O>ClCCl>[CH2:8]([N:5]1[CH2:6][CH2:7][CH:2]([NH:1][C:20]([NH:19][C:15]([CH3:18])([CH3:17])[CH3:16])=[S:21])[CH2:3][CH2:4]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC(C)(C)N=C=S
Reactant: NC1CCN(Cc2ccccc2)CC1
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)NC(=S)NC1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
24.93 g of 4-amino-1-benzylpiperidine are dissolved in 300 ml of dichloromethane and then 16.7 ml of tert-butylisothiocyanate are added dropwise and at room temperature. The reaction mixture is stirred at room temperature for 5 hours and then water is added and the mixture is allowed to settle. The organic phase is separated, dried over sodium sulphate and evaporated. The residue obtained is crystallized from petroleum ether in order to give white crystals which melt at 137° C.; yield: 88%.
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][C:13]2[N:15]=[CH:16][C:17]([N:19]([CH3:23])[CH:20]([CH3:22])[CH3:21])=[N:18][C:12]=2[O:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:24]N1C(=O)CCC1=O.C(#N)C>O>[CH2:1]([N:8]1[CH2:14][C:13]2[N:15]=[C:16]([Br:24])[C:17]([N:19]([CH3:23])[CH:20]([CH3:21])[CH3:22])=[N:18][C:12]=2[O:11][CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)N(C)c1cnc2c(n1)OCCN(Cc1ccccc1)C2
Solvent: O
Solvent: CC#N
Product: CC(C)N(C)c1nc2c(nc1Br)CN(Cc1ccccc1)CCO2
Temperature: 50 °C
Reaction time: 24 h
Yield: 19.5 %

Procedure:
A mixture of 8-benzyl-N-methyl-N-(1-methylethyl)-6,7,8,9-tetrahydropyrazino[2,3-f][1,4]oxazepin-3-amine (500 mg), N-bromosuccinimide (342 mg) and acetonitrile (10 mL) was stirred at room temperature for 16 hr and at 50° C. for 24 hr. Water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient: 0→40% ethyl acetate/hexane) to give the title compound (122 mg, 20%) as a colorless oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:25])[C@@H:13]([NH:17][C:18]([O:20][C:21]([CH3:24])(C)C)=[O:19])[CH2:14][CH:15]=[CH2:16])[CH2:8][CH2:7]1)=[O:5])[CH3:2]>ClCCl.C(O)(C(F)(F)F)=O>[CH2:1]([O:3][C:4]([N:6]1[CH2:7][CH2:8][N:9]([C:12](=[O:25])[C@@H:13]([NH:17][C:18]([O:20][CH2:21][C:24]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:19])[CH2:14][CH:15]=[CH2:16])[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: C=CC[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCN(C(=O)OCC)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C=CC[C@H](NC(=O)OCc1ccccc1)C(=O)N1CCN(C(=O)OCC)CC1

Procedure:
A solution of 767 mg 4-((S)-2-tert-Butoxycarbonylamino-pent-4-enoyl)-piperazine-1-carboxylic acid ethyl ester in 5 ml dichloromethane and 1.6 ml TFA was stirred for 2 h. The reaction mixture was concentrated, the residue dissolved in 4 ml dioxane/water (1:1) and 661 mg NaHCO3 and 688 mg N-(Benzyloxycarbonyloxy)succinimide were added. After 12 h the reaction mixture was diluted with ethyl acetate and washed with water, 0.1 M HCl and half-saturated aqueous NaHCO3 solution. The crude product obtained after evaporation of the solvent was purified by chromatography on silica using ethyl acetate/heptane 1:2 to 2:1 as eluent. Yield: 640 mg.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[C:19]([Cl:21])[CH:20]=1)[CH2:5][C:6]1[C:7]([CH2:16][CH3:17])=[N:8][N:9]([CH2:13][CH2:14][NH2:15])[C:10]=1[CH2:11][CH3:12].C(N(CC)CC)C.[O:29]=[C:30]1[NH:35][C:34](=[O:36])[C:33]([S:37](Cl)(=[O:39])=[O:38])=[CH:32][NH:31]1>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[C:19]([Cl:21])[CH:20]=1)[CH2:5][C:6]1[C:7]([CH2:16][CH3:17])=[N:8][N:9]([CH2:13][CH2:14][NH:15][S:37]([C:33]2[C:34](=[O:36])[NH:35][C:30](=[O:29])[NH:31][CH:32]=2)(=[O:38])=[O:39])[C:10]=1[CH2:11][CH3:12]
Reactant: CCc1nn(CCN)c(CC)c1Cc1cc(Cl)cc(Cl)c1
Reactant: O=c1[nH]cc(S(=O)(=O)Cl)c(=O)[nH]1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCc1nn(CCNS(=O)(=O)c2c[nH]c(=O)[nH]c2=O)c(CC)c1Cc1cc(Cl)cc(Cl)c1
Reaction time: 18 h

Procedure:
A solution of the amine of Example 43 (6.5 mg, 20 μmol) and triethylamine (6 μl, 40 μmol) in dimethylformamide (250 μL) was treated with 2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinesulfonyl chloride (J. Am. Chem. Soc., 1956, 78, 401) (0.8 mg, 4.0 μmol) and the mixture was shaken for 18 hours. The reaction mixture was filtered and the filtrate was purified by HPLC (Hypersil Thermoquest Luna C8 150×10 mm column; a gradient mobile phase was used, 10:90 (by volume)→95:5 (by volume) acetonitrile:(water, 95% by volume/trifluoroacetic acid, 0.1% by volume/acetonitrile 5%, by volume)).
Reaction SMILES: [Br:1][C:2]1[CH:15]=[C:14]2[C:5]([CH2:6][C:7]3([C:13]2=O)[CH2:12][CH2:11][O:10][CH2:9][CH2:8]3)=[CH:4][CH:3]=1.[CH3:17][C:18]([S:21]([NH2:23])=[O:22])([CH3:20])[CH3:19].CO.C([O-])(O)=O.[Na+]>CC1CCCO1.[O-]CC.[Ti+4].[O-]CC.[O-]CC.[O-]CC.CCOC(C)=O>[Br:1][C:2]1[CH:15]=[C:14]2[C:5](=[CH:4][CH:3]=1)[CH2:6][C:7]1([CH2:12][CH2:11][O:10][CH2:9][CH2:8]1)[C:13]2=[N:23][S:21]([C:18]([CH3:20])([CH3:19])[CH3:17])=[O:22]
Reactant: CC(C)(C)S(N)=O
Reactant: O=C1c2cc(Br)ccc2CC12CCOCC2
Agent: [Ti+4]
Agent: CC[O-]
Agent: O=C([O-])O
Solvent: CO
Solvent: CC1CCCO1
Solvent: CCOC(C)=O
Product: CC(C)(C)S(=O)N=C1c2cc(Br)ccc2CC12CCOCC2
Temperature: 70 °C
Reaction time: 8 h
Yield: 35 %

Procedure:
Titanium(IV) ethoxide (2.119 mL, 10.14 mmol) was added to a solution of 6-bromo-2′,3′,5′,6′-tetrahydrospiro[indene-2,4′-pyran]-1(3H)-one (Intermediate 10, 1.14 g, 4.05 mmol) and 2-methyl-2-propanesulfinamide (0.688 g, 5.68 mmol) in 2-methyl-tetrahydrofuran (12 mL) and the resulting mixture was stirred at 70° C. overnight. When cooled to r.t., MeOH (1.5 mL), sat. aq. NaHCO3 (5 mL) and EtOAc (10 mL) were added. The mixture was stirred for 1 h, then filtered through diatomaceous earth. The filter cake was washed with EtOAc (3×10 mL). The combined organics were washed with brine (30 mL), dried over MgSO4, filtered, concentrated and purified on a silica gel column eluted with 0-40% EtOAc in heptane to give 545 mg (35% yield) of the title compound; 1H NMR (400 MHz, DMSO-d6) δ ppm 8.54 (br. s., 1H), 7.80 (dd, 1H), 7.51 (d, 1H), 3.88 (dd, 2H), 3.51 (m, 2H), 3.14 (s, 2H), 1.38 (m, 2H), 1.24 (m, 11H), MS (ES+) m/z 384 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][C:33]=1Cl)[C:5]([NH:7][CH2:8][C:9]([NH:11][C@@H:12]1[CH2:16][CH2:15][N:14]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=3)[CH2:19][CH2:18]2)[CH2:13]1)=[O:10])=[O:6].ClC1C=C(C=CC=1Cl)C(Cl)=O>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][CH:33]=1)[C:5]([NH:7][CH2:8][C:9]([NH:11][C@@H:12]1[CH2:16][CH2:15][N:14]([CH:17]2[CH2:18][CH2:19][N:20]([C:23]3[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=3)[CH2:21][CH2:22]2)[CH2:13]1)=[O:10])=[O:6]
Reactant: COc1ccc(N2CCC(N3CC[C@@H](NC(=O)CNC(=O)c4ccc(Cl)c(Cl)c4)C3)CC2)cc1
Agent: O=C(Cl)c1ccc(Cl)c(Cl)c1
Product: COc1ccc(N2CCC(N3CC[C@@H](NC(=O)CNC(=O)c4cccc(Cl)c4)C3)CC2)cc1

Procedure:
The title compound was synthesized in similar fashion to 3,4-Dichloro-N-[2-({(3R)-1-[1-(4-methoxyphenyl)piperidin-4-yl]pyrrolidin-3-yl}amino)-2-oxoethyl]benzamide, substituting 3-chlorobenzoylchloride for 3,4-dichlorobenzoylchloride, and was isolated as a white solid. 1H-NMR (CDCl3) δ: 1.63-1.64 (m, 3H), 1.86-1.90 (m, 2H), 2.01-2.44 (m, 3H), 2.56-2.74 (m, 4H), 2.92-3.00 (m, 1H), 3.43 (d, J=11.1 Hz, 2H), 3.70 (s, 3H), 4.04 (d, J=4.2 Hz, 2H), 4.43 (b, 1H), 6.55 (d, J=6.0 Hz, 1H), 6.74-6.85 (m, 4H), 7.06 (b, 1H), 7.30 (t, J=8.5 Hz, 1H), 7.42 (d, J=7.5 Hz, 2H), 7.63 (d, J=8.1 Hz, 1H), 7.27 (s, 1H). MS m/z: 471 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[C:4]([F:19])[CH:5]=[C:6]2[C:11]=1[N:10]([CH:12]1[CH2:14][CH2:13]1)[CH:9]=[C:8]([C:15]([OH:17])=[O:16])[C:7]2=[O:18].[CH3:21][N:22]1[CH2:29][CH2:28][CH:27]2[CH:23]1[CH2:24][NH:25][CH2:26]2>>[Cl:1][C:2]1[C:3]([N:25]2[CH2:24][CH:23]3[CH:27]([CH2:28][CH2:29][N:22]3[CH3:21])[CH2:26]2)=[C:4]([F:19])[CH:5]=[C:6]2[C:11]=1[N:10]([CH:12]1[CH2:14][CH2:13]1)[CH:9]=[C:8]([C:15]([OH:17])=[O:16])[C:7]2=[O:18]
Reactant: CN1CCC2CNCC21
Reactant: O=C(O)c1cn(C2CC2)c2c(Cl)c(F)c(F)cc2c1=O
Product: CN1CCC2CN(c3c(F)cc4c(=O)c(C(=O)O)cn(C5CC5)c4c3Cl)CC21

Procedure:
Thus, for example, 8-chloro-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylicacid can be reacted with 2-methyl-2,7-diazabicyclo[3.3.0]octane to give 8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-7-(2-methyl-2,7-diazabicyclo[3.3.0]oct-7-yl)-4-oxo-3-quinolinecarboxylic acid, which has a high antibacterial activity.
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.[Li].[Cl:11][C:12]1[CH:35]=[CH:34][C:15]([O:16][C:17]2[CH:25]=[CH:24][C:20]([C:21]([NH2:23])=[O:22])=[CH:19][C:18]=2[C:26]2[C:31]([O:32][CH3:33])=[CH:30][CH:29]=[CH:28][N:27]=2)=[CH:14][CH:13]=1.[CH3:36][S:37](Cl)(=[O:39])=[O:38]>C1COCC1>[Cl:11][C:12]1[CH:35]=[CH:34][C:15]([O:16][C:17]2[CH:25]=[CH:24][C:20]([C:21]([NH:23][S:37]([CH3:36])(=[O:39])=[O:38])=[O:22])=[CH:19][C:18]=2[C:26]2[C:31]([O:32][CH3:33])=[CH:30][CH:29]=[CH:28][N:27]=2)=[CH:14][CH:13]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1cccnc1-c1cc(C(N)=O)ccc1Oc1ccc(Cl)cc1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Li]
Solvent: C1CCOC1
Product: COc1cccnc1-c1cc(C(=O)NS(C)(=O)=O)ccc1Oc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 5.4 %

Procedure:
Lithium hexamethyldisilazane (1.5 mL, 1.55 mmol) was added to a solution of 4-(4-chlorophenoxy)-3-(3-methoxypyridin-2-yl)benzamide (Preparation 11, 0.184 g, 0.52 mmol) in THF (10 mL) and then the mixture was stirred at room temperature for 10 minutes. Methansulfonyl chloride (0.14 mL, 1.81 mmol) was added to the yellow solution and the mixture was stirred at room temperature for 18 hours. The reaction was quenched by the addition of aqueous ammonium chloride (10 mL) and extracted with DCM (3×30 mL). The organic layer was washed with water (2×30 mL), dried over magnesium sulfate, and concentrated in vacuo to afford the crude product (0.294 g). The crude material was purified by preparative A-HPLC to afford the title compound (12.2 mg).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][N:8](C(OCC3C=CC=CC=3)=O)[CH:7]([C:21]([O:23][CH3:24])=[O:22])[CH2:6]2)[O:4][CH2:3][CH2:2]1>C(OCC)(=O)C.[Pd]>[O:1]1[C:5]2([CH2:10][CH2:9][NH:8][CH:7]([C:21]([O:23][CH3:24])=[O:22])[CH2:6]2)[O:4][CH2:3][CH2:2]1
Reactant: COC(=O)C1CC2(CCN1C(=O)OCc1ccccc1)OCCO2
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)C1CC2(CCN1)OCCO2
Yield: 90.9 %

Procedure:
A solution of the product of stage (iii) (5.50 g) in ethyl acetate (60 ml) was hydrogenated over 10% palladium on carbon (0.50 g) for 4 h. The catalyst was filtered off and the filtrate evaporated in vacuo to give the title compound as an oil (3.0 g).
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[C:5]1(=[O:15])[O:10][C:8](=[O:9])[C:7]2=[CH:11][CH:12]=[CH:13][CH:14]=[C:6]12.[Cl:16][C:17]1[CH:23]=[CH:22][C:20]([OH:21])=[CH:19][C:18]=1[OH:24]>[N+](C1C=CC=CC=1)([O-])=O>[C:8]([C:7]1[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=1[C:5](=[O:15])[C:22]1[CH:23]=[C:17]([Cl:16])[C:18]([OH:24])=[CH:19][C:20]=1[OH:21])([OH:10])=[O:9]
Reactant: Oc1ccc(Cl)c(O)c1
Reactant: O=C1OC(=O)c2ccccc21
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Product: O=C(O)c1ccccc1C(=O)c1cc(Cl)c(O)cc1O
Reaction time: 8 h

Procedure:
AlCl3 (40.0 g, 300 mmol) was added to a solution of phthalic anhydride (20.0 g, 135 mmol) and 4-chlororesorcinol (18.8 g, 130 mmol) in 225 ml nitrobenzene and purged with N2. After stirring overnight, the solution was poured into a vigorously stirred biphasic solution of 750 ml hexanes and 1.0 L 0.5 M aqueous HCl. The solution was allowed to stir for 2 h and the light tan precipitate that formed was filtered and washed with 200 ml aqueous 0.1 M HCl and 300 ml hexanes. The crude product was crystallized from hot MeOH/H2O (12.1 g, 32%). 1H NMR (CD3OD) δ 6.48 (1 H, s), 6.95 (1 H, s), 7.39 (1 H, dd, J=7.2 1.5), 7.62-7.52 (2 H, m), 8.12 (1 H, dd, J=1.2, 7.8). FTIR (KBr, cm−1) 1691, 1615, 1571, 1488, 1453, 1419, 1288, 1219, 1155, 1141, 925, 894, 862, 772, 738, 709, 682, 649, 615, 590, 538.
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1)=[N+]=[N-]>[Pd]>[N:14]1[CH:15]=[CH:16][C:11]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH2:4][NH2:1])=[CH:12][CH:13]=1
Reactant: [N-]=[N+]=NCc1ccccc1-c1ccncc1
Agent: [Pd]
Product: NCc1ccccc1-c1ccncc1

Procedure:
The product of Example 120B and Pd/C were processed according to the method of Example 115B to provide the product. MS (ESI+) m/z 186 (M+H)+;
Reaction SMILES: [C:1]1([C@@H:13]2[CH2:18][CH2:17][C@H:16]([CH:19]=O)[CH2:15][CH2:14]2)[N:2]=[N:3][N:4]2[C:9]=1[C:8]1[CH:10]=[CH:11][NH:12][C:7]=1[N:6]=[CH:5]2.Cl.[OH:22][CH:23]1[CH2:26][NH:25][CH2:24]1.B.N1C=CC=CC=1C.O>CO.O1CCCC1.C(O)(=O)C>[C:1]1([C@@H:13]2[CH2:18][CH2:17][C@H:16]([CH2:19][N:25]3[CH2:26][CH:23]([OH:22])[CH2:24]3)[CH2:15][CH2:14]2)[N:2]=[N:3][N:4]2[C:9]=1[C:8]1[CH:10]=[CH:11][NH:12][C:7]=1[N:6]=[CH:5]2
Reactant: OC1CNC1
Reactant: O=C[C@H]1CC[C@@H](c2nnn3cnc4[nH]ccc4c23)CC1
Agent: B
Agent: Cl
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: Cc1ccccn1
Product: OC1CN(C[C@H]2CC[C@@H](c3nnn4cnc5[nH]ccc5c34)CC2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 20.4 %

Procedure:
cis-4-(7H-Pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)cyclohexanecarbaldehyde (30.0 mg, 0.111 mmol) in methanol (2 mL), tetrahydrofuran (1 mL) and acetic acid (100 μL) was mixed with 3-hydroxyazetidine hydrochloride (41.3 mg, 0.334 mmol) and stirred at room temperature for 1 hour. The reaction mixture was mixed with 2-picoline borane (23.8 mg, 0.334 mmol) and stirred at room temperature for 14 hours. After addition of water, the reaction mixture was extracted with ethyl acetate. The aqueous layer was adjusted to pH 10 with 1 M aqueous sodium hydroxide, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was washed with hexane/ethyl acetate (5/1 (v/v)) to give the title compound as a colorless solid (7.40 mg, yield 31%).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:21]=[CH:20][C:19]([CH3:22])=[C:18](B5OC(C)(C)C(C)(C)O5)[CH:17]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.Br[C:33]1[CH:40]=[CH:39][C:36]([C:37]#[N:38])=[C:35]([Cl:41])[CH:34]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[C:18]([C:33]5[CH:40]=[CH:39][C:36]([C:37]#[N:38])=[C:35]([Cl:41])[CH:34]=5)[C:19]([CH3:22])=[CH:20][CH:21]=4)=[O:14])[CH2:11][CH2:12]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)cc1B1OC(C)(C)C(C)(C)O1
Reactant: N#Cc1ccc(Br)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)cc1-c1ccc(C#N)c(Cl)c1
Temperature: 80 °C

Procedure:
1-(Benzo[d][1,3]dioxol-5-yl)-N-(4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclopropanecarboxamide (0.084 g, 0.20 mmol), 4-bromo-2-chlorobenzonitrile (0.043 g, 0.20 mmol), aqueous potassium carbonate (520 μL, 1M), FibreCat 1007 (7 mg), and DMF (1 mL) were combined. The mixture was heated at 80° C. for 18 hours. After cooling, the mixture was filtered and purified by preparative HPLC to provide 1-(benzo[d][1,3]dioxol-5-yl)-N-(3′-chloro-4′-cyano-6-methylbiphenyl-3-yl)cyclopropanecarboxamide.
Reaction SMILES: [ClH:1].O1CCOCC1.C(OC([N:15]1[CH2:20][CH2:19][CH:18]([O:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:25]([NH:32][C:33]([NH:35][C:36]3[N:37]([C:45]4[CH:50]=[CH:49][C:48]([CH3:51])=[CH:47][CH:46]=4)[N:38]=[C:39]([C:41]4([CH3:44])[CH2:43][CH2:42]4)[CH:40]=3)=[O:34])=[CH:24][N:23]=2)[CH2:17][CH2:16]1)=O)(C)(C)C>ClCCl>[ClH:1].[ClH:1].[CH3:44][C:41]1([C:39]2[CH:40]=[C:36]([NH:35][C:33]([NH:32][C:25]3[C:26]4[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=4)[C:22]([O:21][CH:18]4[CH2:19][CH2:20][NH:15][CH2:16][CH2:17]4)=[N:23][CH:24]=3)=[O:34])[N:37]([C:45]3[CH:50]=[CH:49][C:48]([CH3:51])=[CH:47][CH:46]=3)[N:38]=2)[CH2:43][CH2:42]1
Reactant: Cc1ccc(-n2nc(C3(C)CC3)cc2NC(=O)Nc2cnc(OC3CCN(C(=O)OC(C)(C)C)CC3)c3ccccc23)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: Cc1ccc(-n2nc(C3(C)CC3)cc2NC(=O)Nc2cnc(OC3CCNCC3)c3ccccc23)cc1
Reaction time: 8 h

Procedure:
Add HCl 4 M in dioxane (2.4 mL, 9.36 mmol) to 4-(4-{3-[5-(1-methyl-cyclopropyl)-2-p-tolyl-2H-pyrazol-3-yl]-ureido}-isoquinolin-1-yloxy)-piperidine-1-carboxylic acid tert-butyl ester (1.4 g, 2.34 mmol) in dichloromethane (20 mL) at room temperature and stir overnight. Evaporate the solvent under reduced pressure to give the title compound (1.3 g) as a white solid (quantitative). ES+ (m/z): 497.4 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([O:12][CH3:13])[CH:11]=1)[C:6]([NH2:8])=[O:7].[Cl:14][CH2:15][C:16]([CH2:18]Cl)=O>>[Cl:14][CH2:15][C:16]1[N:8]=[C:6]([C:5]2[CH:9]=[C:10]([O:12][CH3:13])[CH:11]=[C:3]([O:2][CH3:1])[CH:4]=2)[O:7][CH:18]=1
Reactant: COc1cc(OC)cc(C(N)=O)c1
Reactant: O=C(CCl)CCl
Product: COc1cc(OC)cc(-c2nc(CCl)co2)c1
Yield: 59 %

Procedure:
In substantially the same manner as in Reference Example 31, 3,5-dimethoxybenzamide was allowed to react with 1,3-dichloroacetone to give 4-chloromethyl-2-(3,5-dimethoxyphenyl)oxazole. The yield was 59%. Recrystallization from ethyl acetate-hexane gave colorless needles, mp 85-86° C.