Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:13]=[CH:12][C:9]([CH:10]=O)=[CH:8][CH:7]=1.[NH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:13]=[CH:12][C:9]([CH2:10][NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:8][CH:7]=1
Reactant: O=Cc1ccc(C2OCCO2)cc1
Reactant: Nc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: c1ccc(NCc2ccc(C3OCCO3)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 45.9 %

Procedure:
To a tetrahydrofuran (200 mL) solution of 4-[1,3]dioxolane-2-ylbenzaldehyde (6.32 g, 35.5 mmol) described in Manufacturing Example 73-1-1, aniline (2.08 mL, 35.5 mmol) and acetic acid (10.2 mL, 178 mmol) was added sodium triacetoxyborohydride (15 g, 71 mmol). This mixture was stirred for 1 hour at room temperature. This mixture was partitioned into ethyl acetate and water. The organic layer was separated, washed with water, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by silica gel column chromatography (heptane:ethyl acetate=4:1) to obtain the title compound (4.16 g, 46%).
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]1([C:20]3=[CH:21][C:22]4[O:26][CH2:25][O:24][C:23]=4[CH:27]=[C:19]3[O:18][CH2:17]1)[C:5](=[O:16])[N:6]2[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].[F:28][C:29]([F:38])([F:37])[C:30]1[CH:31]=[C:32]([CH:34]=[CH:35][CH:36]=1)[NH2:33].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.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:11]([N:6]1[C:7]2[C:3](=[C:2]([NH:33][C:32]3[CH:34]=[CH:35][CH:36]=[C:30]([C:29]([F:28])([F:37])[F:38])[CH:31]=3)[CH:10]=[CH:9][CH:8]=2)[C:4]2([C:20]3=[CH:21][C:22]4[O:26][CH2:25][O:24][C:23]=4[CH:27]=[C:19]3[O:18][CH2:17]2)[C:5]1=[O:16])[CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: CCCCCN1C(=O)C2(COc3cc4c(cc32)OCO4)c2c(Br)cccc21
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: Cc1ccccc1
Product: CCCCCN1C(=O)C2(COc3cc4c(cc32)OCO4)c2c(Nc3cccc(C(F)(F)F)c3)cccc21
Temperature: 110 °C
Yield: 97.9 %

Procedure:
A mixture of 4′-bromo-1′-pentylspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one (0.05 g, 0.12 mmol), 3-(trifluoromethyl)aniline (0.03 g, 0.17 mmol), Pd2(dba)3 (0.02 g, 0.01 mmol), xanthphos (0.007 g, 0.01 mmol), and sodium tert-butoxide (0.02 g, 0.17 mmol) in toluene (5.00 mL) was heated at 110° C. for 4 days. After cooling down to ambient temperature, the mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to dryness. The residue was subjected to column chromatography eluting with ethyl acetate/hexane to give the title compound (0.06 g, 71%) as a solid: MS (ES+) m/z 511.5 (M+1).
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][C:9]1([C:22](O)=[O:23])[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]1)=[O:7])([CH3:4])[CH3:3].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[CH3:58][N:59]([CH3:70])[C:60](=[O:69])[O:61][C:62]1[CH:67]=[CH:66][CH:65]=[C:64]([NH2:68])[CH:63]=1>C(OC(C)C)(=O)C.CCOC(C)=O>[C:2]([O:5][C:6]([NH:8][C:9]1([C:22](=[O:23])[NH:68][C:64]2[CH:65]=[CH:66][CH:67]=[C:62]([O:61][C:60](=[O:69])[N:59]([CH3:70])[CH3:58])[CH:63]=2)[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:13][CH2:14]1)=[O:7])([CH3:4])([CH3:3])[CH3:1]
Reactant: CN(C)C(=O)Oc1cccc(N)c1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CCN(C(=O)OC(C)(C)C)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CC(=O)OC(C)C
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C(=O)Oc1cccc(NC(=O)C2(NC(=O)OC(C)(C)C)CCN(C(=O)OC(C)(C)C)CC2)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 44.9 %

Procedure:
N-Boc-amino-(4-N-Boc-piperidinyl)carboxylic acid (0.114 g, 0.33 mmol), HATU (0.151 g, 0.40 mmol) and N,N-diisopropylethylamine (128 mg, 1.0 mmol) were combined in isopropyl acetate (2.3 mL) and stirred at room temperature for 15 minutes. 3-aminophenyl dimethylcarbamate (0.072 g, 0.40 mmol) was added, and the mixture heated at 80° C. for 1.5 hours. The reaction mixture was allowed to cool, diluted with EtOAc, washed with 2 N Na2CO3, 1 N HCl, and brine, and then dried over MgSO4 and concentrated. Purification by silica gel chromatography (60% EtOAc/hexanes) gave the title compound (0.075 g, 45%) as a white solid. MS (ES+) [M+NH4]+=524.
Reaction SMILES: [C:1]([NH:5][OH:6])([CH3:4])([CH3:3])[CH3:2].C(O)(=O)C.C(NO)(C)(C)C.C(=O)(O)[O-].[Na+].[H-].[Na+].[C:24]([C:28]1[S:32]/[C:31](=[N:33]\[C:34](=[O:46])[C:35]2[CH:40]=[C:39]([C:41]([F:44])([F:43])[F:42])[CH:38]=[CH:37][C:36]=2F)/[N:30]([CH2:47][C@H:48]2[CH2:52][CH2:51][CH2:50][O:49]2)[N:29]=1)([CH3:27])([CH3:26])[CH3:25]>C1COCC1>[C:1]([NH:5][O:6][C:36]1[CH:37]=[CH:38][C:39]([C:41]([F:42])([F:44])[F:43])=[CH:40][C:35]=1[C:34](/[N:33]=[C:31]1\[S:32][C:28]([C:24]([CH3:27])([CH3:25])[CH3:26])=[N:29][N:30]\1[CH2:47][C@H:48]1[CH2:52][CH2:51][CH2:50][O:49]1)=[O:46])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)NO
Reactant: CC(C)(C)c1nn(C[C@H]2CCCO2)/c(=N/C(=O)c2cc(C(F)(F)F)ccc2F)s1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(C)(C)NOc1ccc(C(F)(F)F)cc1C(=O)/N=c1\sc(C(C)(C)C)nn1C[C@H]1CCCO1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a solution of N-tert-butylhydroxylamine (145 mg, 1.62 mmol) (prepared from commercially available N-tert-butylhydroxylamine acetate (Aldrich) by adding saturated sodium bicarbonate solution and extracting the free base with ethyl ether) in anhydrous THF (10 mL) was added sodium hydride (58.4 mg, 1.46 mmol). The mixture was stirred at 0° C. for 20 minutes. A solution of Example 153A (350 mg, 0.81 mmol) in THF (4 mL) was added and the mixture was stirred at 0° C. for 3 hours. The solvent was removed under reduced pressure and the residue was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried with MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by chromatography on SiO2 using an Analogix® Intelliflash280™ (Hexanes-EtOAc: 0-50% gradient) to give the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 1.22 (s, 9H), 1.42 (s, 9H), 1.74-1.89 (m, 1H), 1.88-2.08 (m, 3H), 3.74-3.84 (m, 1 H), 3.89-4.00 (m, 1H), 4.29 (dd, J=12.0, 4.7 Hz, 1H), 4.45-4.63 (m, 2H), 5.73 (s, 1H), 7.59 (dd, J=8.8, 3.1 Hz, 1H), 7.80 (d, J=8.8 Hz, 1H), 8.33 (d, J=2.4 Hz, 1H); MS (ESI) m/z 501 (M+H)−.
Reaction SMILES: Br[CH:2](C)[C:3](OC)(OC)[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][CH:5]=1.[C:17]([O-:20])(=[O:19])C.[K+]>C(O)CCC>[CH3:11][O:10][C:7]1[CH:6]=[CH:5][C:4]([CH:3]([CH3:2])[C:17]([OH:20])=[O:19])=[CH:9][CH:8]=1
Reactant: CC(=O)[O-]
Reactant: COc1ccc(C(OC)(OC)C(C)Br)cc1
Agent: [K+]
Solvent: CCCCO
Product: COc1ccc(C(C)C(=O)O)cc1
Temperature: 115 °C
Yield: 89 %

Procedure:
A mixture of 2-bromo-1,1-dimethoxy-1-(4'-methoxyphenyl)-propane (2.89 g; 0.01 mol), potassium acetate (1.2 g; 0.012 mol) and n-butanol (40 ml) is heated to 115° C. for 32 hours. By following the procedure of Example 1a, there is obtained the title product (1.60 g; 0.0089 mol). Yield, 89%; m.p. 56°-57° C.
Reaction SMILES: [BH4-].[Na+].[C:3]1([CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=2)[CH:17]=[O:18])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>CO>[C:3]1([CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=2)[CH2:17][OH:18])[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=Cc1cccc(OCCCCc2ccccc2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OCc1cccc(OCCCCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.7 %

Procedure:
Sodium borohydride (200 mg) was added to a solution of 660 mg of m-(4-phenylbutoxy)benzaldehyde in 10 ml of methanol, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, 5% hydrochloric acid was added to the residue, and the product was extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 510 mg of m-(4-phenylbutoxy)benzyl alcohol.
Reaction SMILES: [S:1]1[CH2:7][C:5](=[O:6])[NH:4][C:2]1=[S:3].[CH:8]1[C:13]([CH:14]=O)=[CH:12][C:11]2[O:16][CH2:17][O:18][C:10]=2[CH:9]=1>COCCOC>[O:18]1[C:10]2[CH:9]=[CH:8][C:13]([CH:14]=[C:7]3[S:1][C:2](=[S:3])[NH:4][C:5]3=[O:6])=[CH:12][C:11]=2[O:16][CH2:17]1
Reactant: O=Cc1ccc2c(c1)OCO2
Reactant: O=C1CSC(=S)N1
Solvent: COCCOC
Product: O=C1NC(=S)SC1=Cc1ccc2c(c1)OCO2
Temperature: 120 °C
Reaction time: 5 h

Procedure:
In a 24 ml vial was placed 1 g of commercially available rhodanine, 1.3 g of piperonal and 0.5 ml of TEA in 10 ml of DME. The reaction was stirred for 5 h at 120° C. and then cooled to room temperature upon which the final product precipitated. The solid was filtered and washed with DME affording 1.6 g (80%) of orange powder.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[S:10][CH:9]=[C:8]([C:11]3[CH:12]=[C:13]([NH2:17])[CH:14]=[CH:15][CH:16]=3)[C:6]=2[N:7]=1.[Cl:18][CH2:19][CH2:20][CH2:21][S:22](Cl)(=[O:24])=[O:23]>>[Cl:18][CH2:19][CH2:20][CH2:21][S:22]([NH:17][C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([C:8]2[C:6]3[N:7]=[C:2]([Cl:1])[N:3]=[CH:4][C:5]=3[S:10][CH:9]=2)[CH:12]=1)(=[O:24])=[O:23]
Reactant: O=S(=O)(Cl)CCCCl
Reactant: Nc1cccc(-c2csc3cnc(Cl)nc23)c1
Product: O=S(=O)(CCCCl)Nc1cccc(-c2csc3cnc(Cl)nc23)c1
Yield: 78.5 %

Procedure:
3-Chloro-N-(3-(2-chloro thieno[3,2-d]pyrimidin-7-yl)phenyl)propane-1-sulfonamide (240 mg, 78% yield) was prepared in the same manner as Step 7 of Example 1 using 3-(2-chlorothieno[3,2-d]pyrimidin-7-yl)benzenamine (200 mg, 0.76 mmol) and 3-chloropropane-1-sulfonyl chloride (145 mg, 0.84 mmol).
Reaction SMILES: [NH2:1][C:2]1[CH:26]=[CH:25][CH:24]=[CH:23][C:3]=1[CH2:4][O:5][NH:6][C:7](=[O:22])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][CH2:15][C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1.C(N(CC)CC)C.[C:34]1([S:40](Cl)(=[O:42])=[O:41])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>ClCCl>[C:34]1([S:40]([NH:1][C:2]2[CH:26]=[CH:25][CH:24]=[CH:23][C:3]=2[CH2:4][O:5][NH:6][C:7](=[O:22])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[NH:14][CH2:15][C:16]2[CH:17]=[CH:18][N:19]=[CH:20][CH:21]=2)(=[O:42])=[O:41])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Nc1ccccc1CONC(=O)c1ccccc1NCc1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NOCc1ccccc1NS(=O)(=O)c1ccccc1)c1ccccc1NCc1ccncc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a stirred solution of N-(2-amino-benzyloxy)-2-[(pyridin-4-ylmethyl)-amino]-benzamide (see example 400) in dichloromethane at 0-5° C. was added triethylamine (1.2 eq.) followed by addition of benzensulfonyl chloride (1.1 eq.). The mixture was allowed to warm to room temperature and stirred for 20 hours. The solvent was evaporated under reduced pressure, and the residue was dissolved in EtOAc and washed with water and brine. The organic layer was dried (MgSO4) and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether/EtOAc, 2/1, v/v) and gave the title compound. 13C-NMR (DMSO-d6) δ 170.7, 149.6, 149.4, 149.1, 140.7, 138.3, 134.2, 132.5, 131.0, 130.7, 128.8, 127.4, 126.9, 125.3, 124.5, 123.0, 122.2, 115.7, 112.4, 111.1, 76.6, 46.0.
Reaction SMILES: Cl.[C:2]([C:6]1[O:10][N:9]=[C:8]([NH:11][C:12](=[O:35])[NH:13][C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:34])[C:22]3[CH:27]=[CH:26][C:25]([O:28][CH:29]4[CH2:33][CH2:32][NH:31][CH2:30]4)=[CH:24][N:23]=3)=[CH:16][CH:15]=2)[CH:7]=1)([CH3:5])([CH3:4])[CH3:3].[CH3:36][S:37]([CH:40]=[CH2:41])(=[O:39])=[O:38]>C1COCC1>[C:2]([C:6]1[O:10][N:9]=[C:8]([NH:11][C:12](=[O:35])[NH:13][C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:34])[C:22]3[CH:27]=[CH:26][C:25]([O:28][CH:29]4[CH2:33][CH2:32][N:31]([CH2:41][CH2:40][S:37]([CH3:36])(=[O:39])=[O:38])[CH2:30]4)=[CH:24][N:23]=3)=[CH:16][CH:15]=2)[CH:7]=1)([CH3:5])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1cc(NC(=O)Nc2ccc(NC(=O)c3ccc(OC4CCNC4)cn3)cc2)no1
Reactant: C=CS(C)(=O)=O
Agent: Cl
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(NC(=O)Nc2ccc(NC(=O)c3ccc(OC4CCN(CCS(C)(=O)=O)C4)cn3)cc2)no1
Temperature: 60 °C
Yield: 79.4 %

Procedure:
N-(4-(3-(5-tert-Butylisoxazol-3-yl)ureido)phenyl)-5-(pyrrolidin-3-yloxy)picolinamide hydrochloride (150 mg, 0.30 mmol) was suspended in 3 mL of THF at rt. Methylsulfonylethene (29 μL, 0.33 mmol) and TEA (126 μL, 0.90 mmol) were added sequentially. The resulting mixture was heated at 60° C. for 1 h, then heated at 52° C. for 60 h. LC-MS indicated the reaction was complete. The organic solvent was evaporated under reduced pressure and the residue was purified by reverse phase HPLC to give N-(4-(3-(5-tert-butylisoxazol-3-yl)ureido)phenyl)-5-(1-(2-(methylsulfonyl)ethyl)pyrrolidin-3-yloxy)picolinamide (136 mg, 79%). LC-MS (ESI) m/z 571 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:15]([CH3:19])([CH3:18])[CH:16]=[CH2:17])[C:10]([O:12]CC)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].[OH-].[K+]>CCO>[C:1]([O:5][C:6]([NH:8][CH:9]([C:15]([CH3:19])([CH3:18])[CH:16]=[CH2:17])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CC(C)(C)C(NC(=O)OC(C)(C)C)C(=O)OCC
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: C=CC(C)(C)C(NC(=O)OC(C)(C)C)C(=O)O
Temperature: 70 °C
Reaction time: 8 h
Yield: 95.7 %

Procedure:
To a round bottom flask was added ethyl 2-(tert-butoxycarbonylamino)-3,3-dimethylpent-4-enoate (280 mg, 1.03 mmol), EtOH (20 mL) and aqueous 1 N NaOH (5.16 mL, 5.16 mmol). The reaction was stirred at 70° C. overnight. The reaction was cooled to rt and KOH (232 mg, 4.13 mmol) was added and the reaction was stirred at rt for 3 days. The solvent was removed and the residue was dissolved in water (15 mL). The aqueous solution was washed with DCM (5 mL). The pH of the aqueous layer was then adjusted to <4 using aqueous 1 N HCl. Then, the aqueous solution was extracted with DCM (5×10 mL). The combined organic layers were washed with saturated aqueous NaCl (20 mL). The organic layer was separated, dried over MgSO4, filtered and concentrated to give 2-(tert-butoxycarbonylamino)-3,3-dimethylpent-4-enoic acid (240 mg, 0.986 mmol, 96% yield) as beige solid. 1H NMR (500 MHz, CDCl3) δ ppm 5.87 (dd, J=17.32, 10.72 Hz, 1H), 5.23-5.03 (m, 2H), 4.98 (d, J=8.25 Hz, 1H), 4.17 (d, J=8.80 Hz, 1H), 1.45 (s, 9H), 1.16 (d, J=4.40 Hz, 6H).
Reaction SMILES: C(NC1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(O)=O)C3=O)=CC=2)=CC=1)(=O)C1C=CC=CC=1.[Cl:33][C:34]1[CH:66]=[CH:65][CH:64]=[C:63]([Cl:67])[C:35]=1[C:36]([NH:38][C:39]1[CH:44]=[CH:43][C:42]([C:45]2[CH:53]=[C:52]3[C:48]([CH2:49][N:50]([C@@H:55]([CH:60]([CH3:62])[CH3:61])[C:56]([O:58]C)=[O:57])[C:51]3=[O:54])=[CH:47][CH:46]=2)=[CH:41][CH:40]=1)=[O:37]>>[Cl:33][C:34]1[CH:66]=[CH:65][CH:64]=[C:63]([Cl:67])[C:35]=1[C:36]([NH:38][C:39]1[CH:44]=[CH:43][C:42]([C:45]2[CH:53]=[C:52]3[C:48]([CH2:49][N:50]([C@@H:55]([CH:60]([CH3:62])[CH3:61])[C:56]([OH:58])=[O:57])[C:51]3=[O:54])=[CH:47][CH:46]=2)=[CH:41][CH:40]=1)=[O:37]
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4c(Cl)cccc4Cl)cc3)cc2C1=O
Agent: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)c4ccccc4)cc3)cc2C1=O
Product: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)c4c(Cl)cccc4Cl)cc3)cc2C1=O
Yield: 43 %

Procedure:
The compound of example 130 was prepared analogous to compound of example 98 by hydrolysis of compound of example 129.
Reaction SMILES: [C:1](=[O:34])(OC1C=CC([N+]([O-])=O)=CC=1)[O:2][C@H:3]1[C:17](=[O:18])[N:16]([CH2:19][C:20]([F:23])([F:22])[F:21])[CH2:15][C:6]2[C:7]3[CH:8]=[N:9][NH:10][C:11]=3[C:12]([Cl:14])=[CH:13][C:5]=2[CH2:4]1.[NH:35]1[CH2:40][CH2:39][CH:38]([N:41]2[CH2:47][CH2:46][C:45]3[CH:48]=[CH:49][CH:50]=[CH:51][C:44]=3[NH:43][C:42]2=[O:52])[CH2:37][CH2:36]1>ClCCl>[O:52]=[C:42]1[NH:43][C:44]2[CH:51]=[CH:50][CH:49]=[CH:48][C:45]=2[CH2:46][CH2:47][N:41]1[CH:38]1[CH2:39][CH2:40][N:35]([C:1]([O:2][C@H:3]2[C:17](=[O:18])[N:16]([CH2:19][C:20]([F:23])([F:22])[F:21])[CH2:15][C:6]3[C:7]4[CH:8]=[N:9][NH:10][C:11]=4[C:12]([Cl:14])=[CH:13][C:5]=3[CH2:4]2)=[O:34])[CH2:36][CH2:37]1
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)O[C@@H]1Cc2cc(Cl)c3[nH]ncc3c2CN(CC(F)(F)F)C1=O
Reactant: O=C1Nc2ccccc2CCN1C1CCNCC1
Solvent: ClCCl
Product: O=C(O[C@@H]1Cc2cc(Cl)c3[nH]ncc3c2CN(CC(F)(F)F)C1=O)N1CCC(N2CCc3ccccc3NC2=O)CC1
Reaction time: 2 h
Yield: 40 %

Procedure:
(R)-4-chloro-8-oxo-9-(2,2,2-trifluoroethyl)-3,6,7,8,9,10-hexahydroazepino [3,4-e]indazol-7-yl 4-nitrophenyl carbonate (60 mg, 0.120 mmol) in dichloromethane (15 mL) was added 3-(piperidin-4-yl)-4,5-dihydro-1H-benzo[d][1,3]diazepin-2(3H)-one (32.5 mg, 0.132 mmol). The reaction mixture was stirred for 2 h. LC-MS analysis suggested formation of product (Rf=2.473, 605.22 (M+H)). The reaction mixture was washed with aqueous NaHCO3 followed by 1.0 M HCl. THe crude product was purified by flash chromatography using 5% MeOH in dichloromethane to give (R)-4-chloro-8-oxo-9-(2,2,2-trifluoroethyl)-3,6,7,8,9,10-hexahydroazepino [3,4-e]indazol-7-yl 4-(2-oxo-4,5-dihydro-1H-benzo[d][1,3]diazepin-3 (2H)-yl)piperidine-1-carboxylate (29.00 mg, 0.048 mmol, 40% yield). 1H NMR (500 MHz, CD3OD): in δ 8.30 (s, 1H), 7.32 (s, 1H), 7.09 (m, 3H), 6.93-6.87 (m, 3H), 6.09-6.05 (m, 1H), 5.50 (s, 2H), 5.44 (m, 1H), 4.68-4.54 (m, 1H), 4.39-4.35 (m, 2H), 4.32-4.19 (m, 1H), 4.16-4.05 (m, 3H), 3.55-3.50 (m, 3H), 3.12-2.92 (m, 2H), 1.87-1.74 (m, 4H); MS (ESI) 605 (M+H); Rf=2.47.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([NH2:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[C:17](O)(=[O:28])[CH2:18][NH:19][C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:21]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([NH:16][C:17]([CH2:18][NH:19][C:20](=[O:21])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:28])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(O)CNC(=O)c1ccccc1
Reactant: NC(c1ccccc1)c1ccc(Cl)cc1Cl
Product: O=C(CNC(=O)c1ccccc1)NC(c1ccccc1)c1ccc(Cl)cc1Cl

Procedure:
Prepared in analogy to example 1.1 from rac-C-(2,4-dichloro-phenyl)-C-phenyl-methylamine (example 4.2) and hippuric acid.
Reaction SMILES: FC1(F)CC(C([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=O)C1.C[Si](C)(C)[N-][Si](C)(C)C.[Na+].[Cl:24][C:25]1[C:26]([O:39][C:40]2[CH:41]=[N:42][C:43](F)=[C:44]([Cl:46])[CH:45]=2)=[CH:27][C:28]([F:38])=[C:29]([CH:37]=1)[C:30]([NH:32][S:33]([CH3:36])(=[O:35])=[O:34])=[O:31]>C1(C)C=CC=CC=1>[C:9]([O:8][C:43]1[N:42]=[CH:41][C:40]([O:39][C:26]2[C:25]([Cl:24])=[CH:37][C:29]([C:30]([NH:32][S:33]([CH3:36])(=[O:35])=[O:34])=[O:31])=[C:28]([F:38])[CH:27]=2)=[CH:45][C:44]=1[Cl:46])([CH3:12])([CH3:11])[CH3:10]
Reactant: CS(=O)(=O)NC(=O)c1cc(Cl)c(Oc2cnc(F)c(Cl)c2)cc1F
Reactant: CC(C)(C)OC(=O)C1CC(F)(F)C1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)(C)Oc1ncc(Oc2cc(F)c(C(=O)NS(C)(=O)=O)cc2Cl)cc1Cl
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 44.8 %

Procedure:
To a solution of tert-butyl 3,3-difluorocyclobutanecarboxylate (Preparation 227, 126 mg, 0.66 mmol) in toluene (2 mL) was added a solution of sodium 1,1,1,3,3,3-hexamethyldisilazan-2-ide (1M solution in THF, 1.6 mL, 1.6 mmol) at 0° C. The resulting solution was stirred for 10 minutes at the same temperature, then 5-chloro-4-[(5-chloro-6-fluoropyridin-3-yl)oxy]-2-fluoro-N-(methylsulfonyl)benzamide (Example 19, 200 mg, 0.50 mmol) was added. The resulting mixture was warmed up to room temperature and stirred for 36 hours. The reaction was quenched with saturated aqueous NH4Cl solution and extracted with EtOAc. The organic phase was washed with aqueous 1N citric acid solution, then brine, dried over Na2SO4, filtered, and concentrated in vacuo to give a crude product as a yellow oil. The crude product was purified by silica gel column chromatography eluting with 0-100% EtOAc in heptane to give a yellow foam. The foam was triturated with heptane to give the title compound (101 mg, 44%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9](Cl)[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][NH2:8].[Cl:14]C1C(Cl)=CC=CC=1O.ClC1C=CC=C(Cl)C=1O>>[Cl:1][C:2]1[C:12]([Cl:14])=[CH:11][CH:10]=[CH:9][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][NH2:8]
Reactant: Oc1cccc(Cl)c1Cl
Reactant: NCCCOc1c(Cl)cccc1Cl
Agent: Oc1c(Cl)cccc1Cl
Product: NCCCOc1cccc(Cl)c1Cl
Yield: 88 %

Procedure:
Intermediate 12 (55 mg, 0.250 mmol, 88% yield) was prepared as a white powder following the procedure described for Intermediate 9 using 2,3-dichlorophenol and 2,6-dichlorophenol as starting materials. LC-MS (ESI) 221 (M+H), RT=1.48 min (Method B).
Reaction SMILES: [CH3:1][N:2]([CH:21]([CH3:23])[CH3:22])[C:3]1[CH:20]=[N:19][C:6]2[CH2:7][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:9][CH2:10][O:11][C:5]=2[N:4]=1.[Br:24]N1C(=O)CCC1=O.C(#N)C>O>[Br:24][C:20]1[C:3]([N:2]([CH3:1])[CH:21]([CH3:23])[CH3:22])=[N:4][C:5]2[O:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:16])[CH3:17])=[O:13])[CH2:7][C:6]=2[N:19]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)N(C)c1cnc2c(n1)OCCN(C(=O)OC(C)(C)C)C2
Solvent: O
Solvent: CC#N
Product: CC(C)N(C)c1nc2c(nc1Br)CN(C(=O)OC(C)(C)C)CCO2
Temperature: 25 °C
Reaction time: 16 h
Yield: 73.5 %

Procedure:
A mixture of tert-butyl 3-[methyl(1-methylethyl)amino]-6,7-dihydropyrazino[2,3-f][1,4]oxazepine-8(9H)-carboxylate (1.0 g), N-bromosuccinimide (608 mg) and acetonitrile (20 mL) was stirred at room temperature for 16 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: 3→30% ethyl acetate/hexane) to give the title compound (915 mg, 74%) as a colorless oil.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[CH:13]([N:16]1[CH2:21][CH2:20][CH:19]([OH:22])[CH2:18][CH2:17]1)([CH3:15])[CH3:14].O[C:24]1[CH:25]=[C:26]([CH:32]=[CH:33][CH:34]=1)[C:27]([O:29][CH2:30][CH3:31])=[O:28].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[CH:13]([N:16]1[CH2:21][CH2:20][CH:19]([O:22][C:24]2[CH:25]=[C:26]([CH:32]=[CH:33][CH:34]=2)[C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:18][CH2:17]1)([CH3:15])[CH3:14]
Reactant: CCOC(=O)c1cccc(O)c1
Reactant: CC(C)N1CCC(O)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1cccc(OC2CCN(C(C)C)CC2)c1
Temperature: 0 °C
Reaction time: 42 h
Yield: 52.6 %

Procedure:
Diethyl azodicarboxylate (2.26 g) was added dropwise to a stirred mixture of N-isopropyl-4-hydroxypiperidine (Helv. Chim. Acta, 1966, 46, 693; 1.57 g), ethyl 3-hydroxybenzoate (1.66 g), triphenylphosphine (3.4 g) and THF (40 ml) which had been cooled to 0° C. The mixture was stirred at ambient temperature for 42 hours. The solvent was evaporated and the residue was partitioned between ethyl acetate and 2N aqueous hydrochloric acid. The aqueous phase was washed with ethyl acetate, basified to pH10 by the addition of solid potassium carbonate and extracted with diethyl ether. The organic extract was dried over magnesium sulphate and evaporated to give ethyl 3-(N-isopropypiperidin-4-yloxy)benzoate as an oil (1.53 g); NMR Spectrum: (CDCl3) 1.06 (d, 6H), 1.38 (t, 3H), 1.8 (m, 2H), 2.07 (m, 2H), 2.41 (m, 2H), 2.72 (m, 1H), 2.78 (m, 2H), 4.38 (m, 2H), 7.08 (m, 1H), 7.32 (t, 1H), 7.57 (d, 1H), 7.62 (d, 1H). The oil so obtained was dissolved in diethyl ether (20 ml) and a 1M solution of hydrogen chloride in diethyl ether (12 ml) was added. The resultant precipitate was isolated to give ethyl 3-(N-isopropypiperidin-4-yloxy)benzoate hydrochloride salt (1.55 g).