Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[Cl:12][C:13]([Cl:40])([Cl:39])[CH2:14][O:15][C:16]([CH:18]1[N:22]2[C:23](=[O:35])[CH:24]([NH:25][C:26](=[O:34])[CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C@H:21]2[S:20][C:19]1([CH2:37][Cl:38])[CH3:36])=[O:17]>C(Cl)(Cl)Cl>[Cl:38][CH2:37][C:19]1([CH3:36])[CH:18]([C:16]([O:15][CH2:14][C:13]([Cl:39])([Cl:12])[Cl:40])=[O:17])[N:22]2[C:23](=[O:35])[CH:24]([NH:25][C:26](=[O:34])[CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C@H:21]2[S:20]1=[O:9]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC1(CCl)S[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N2C1C(=O)OCC(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CC1(CCl)C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)C(NC(=O)Cc3ccccc3)[C@H]2S1=O
Yield: 79.5 %

Procedure:
A solution of m-chloroperbenzoic acid (2.03 g) in chloroform (30 ml) was added dropwise to a solution of 2,2,2-trichloroethyl-2-chloromethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate (5.0 g) in chloroform (40 ml) at -10° ~ -5°C under stirring, and then the mixture was stirred at -10° ~ -5°C for 1 hour. After the solid was filtered off, the filtrate was washed with a saturated sodium becarbonate aqueous solution and water, in turn, and then dried over magnesium sulfate. After removal of solvent, the residue was crystallized by adding ethanol. The crystal was filtered and recrystallized from ethanol to give 2,2,2-trichloroethyl 2-chloromethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate-1-oxide (4.10 g), mp 130° ~ 131°C.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][C:11]([N:14]3[CH2:19][CH2:18][N:17]([S:20]([CH2:23][C@H:24]([CH:29]([CH3:31])[CH3:30])[C:25]([NH:27][OH:28])=[O:26])(=[O:22])=[O:21])[CH2:16][CH2:15]3)=[N:12][CH:13]=2)=[CH:4][CH:3]=1.[C:32](C1C=CC(C2C=NC(N3CCN(S(C[C@H](C(C)C)C(O)=O)(=O)=O)CC3)=NC=2)=CC=1)#[N:33]>>[C:32]([C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][C:11]([N:14]3[CH2:19][CH2:18][N:17]([S:20]([CH2:23][C@H:24]([CH:29]([CH3:30])[CH3:31])[C:25]([NH:27][OH:28])=[O:26])(=[O:21])=[O:22])[CH2:16][CH2:15]3)=[N:12][CH:13]=2)=[CH:4][CH:3]=1)#[N:33]
Reactant: CC(C)[C@@H](CS(=O)(=O)N1CCN(c2ncc(-c3ccc(F)cc3)cn2)CC1)C(=O)NO
Reactant: CC(C)[C@@H](CS(=O)(=O)N1CCN(c2ncc(-c3ccc(C#N)cc3)cn2)CC1)C(=O)O
Product: CC(C)[C@@H](CS(=O)(=O)N1CCN(c2ncc(-c3ccc(C#N)cc3)cn2)CC1)C(=O)NO
Yield: 53 %

Procedure:
Prepared according to the method for the preparation of 2-(R)-{4-[5-(4-fluorophenyl)pyrimidin-2-yl]piperazine-1-sulfonylmethyl}-N-hydroxy-3-methylbutyramide, from 2-(R)-{4-[5-(4-cyanophenyl)pyrimidin-2-yl]piperazine-1-sulfonylmethyl}-3-methylbutyric acid (0.070 g), to provide the title compound as a white solid (0.039 g, 53%).
Reaction SMILES: O1CCCCC1[N:7]1[CH:15]=[N:14][C:13]2[C:8]1=[N:9][CH:10]=[N:11][C:12]=2[C:16]1[C:17]([NH:22][C:23]2[CH:24]=[CH:25][C:26]([NH:29]C(=O)C)=[N:27][CH:28]=2)=[N:18][CH:19]=[CH:20][CH:21]=1>Cl>[N:11]1[C:12]([C:16]2[C:17]([NH:22][C:23]3[CH:28]=[N:27][C:26]([NH2:29])=[CH:25][CH:24]=3)=[N:18][CH:19]=[CH:20][CH:21]=2)=[C:13]2[C:8]([NH:7][CH:15]=[N:14]2)=[N:9][CH:10]=1
Reactant: CC(=O)Nc1ccc(Nc2ncccc2-c2ncnc3c2ncn3C2CCCCO2)cn1
Agent: Cl
Product: Nc1ccc(Nc2ncccc2-c2ncnc3[nH]cnc23)cn1

Procedure:
A solution of N-(5-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-ylamino)pyridin-2-yl)acetamide (18.8 mg, 44 μmol) in 5 N aqueous HCl (1 mL) was heated at 95° C. for 1 h, after which time LCMS indicated conversion to desired product. The solution was made slightly alkaline with 5 N aqueous NaOH (about pH 8) and the resulting precipitate was collected by filtration, washing with water, and dried to give N3-(3-(9H-purin-6-yl)pyridin-2-yl)pyridine-3,6-diamine (6.0 mg, 45% yield) as a dark solid. 1H NMR (d6-DMSO, 400 MHz) δ 12.17 (bs, 1H), 9.74 (d, 1H), 8.98 (s, 1H), 8.55 (s, 1H), 8.21 (m, 2H), 7.77 (dd, 1H), 6.89 (dd, 1H), 6.49 (d, 1H), 5.65 (bs, 3H); m/z (API-ES) 305, (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[CH2:6].C[N+]1([O-])CC[O:14]CC1.C1C=C(Cl)C=C(C(OO)=O)C=1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C@H:5]1[O:14][CH2:6]1
Reactant: C[N+]1([O-])CCOCC1
Reactant: C=Cc1cccc(Cl)c1
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Clc1cccc([C@@H]2CO2)c1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 86.3 %

Procedure:
A round-bottom flask equipped with a overhead stirrer was charged with 3-chlorostyrene (1.00 g, 7.22×10−3 mol), CH2Cl2 (78 mL), (R,R)4 (0.349 g, 3.61×10−4 mol and NMO (4.22 g, 3.62×10−2 mol). The solution was cooled to −78° C. before solid m-CPBA (2.51 g, 1.46×10−2 mol) was added in portions over 1.5 minutes. The reaction was monitored by GC. Upon completion (3 h), the reaction was quenched by the addition of a solution of dimethyl sulfide (6 mL) in CH2Cl2 (25 mL) precooled to −78° C. The solution was stirred for an additional 10 minutes at −78° C. before removal of the cold bath and addition of 2N NaOH (20 mL) and CH2Cl2 (20 mL). The phases were separated and the aqueous layer was washed with CH2Cl2 (2×50 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. Removal of the catalyst was effected by elution through a pad of SiO2 (10 g) using pentane and CH2Cl2 (1:1). The eluent was concentrated in vacuo, and subsequent bulb-to-bulb distillation from CaH2 afforded (R)-3-chlorostyrene oxide (0.963 g, 86%) as a colorless liquid in 81% ee.
Reaction SMILES: [CH:1]1([N:6]2[C:15]3[N:14]=[C:13]([NH:16][C:17]4[CH:18]=[CH:19][C:20]([C:26](O)=[O:27])=[C:21]5[C:25]=4[O:24][CH2:23][CH2:22]5)[N:12]=[CH:11][C:10]=3[N:9]([CH3:29])[C:8](=[O:30])[C@@H:7]2[CH2:31][CH3:32])[CH2:5][CH2:4][CH2:3][CH2:2]1.F[B-](F)(F)F.[N:38]1(OC(N(C)C)=[N+](C)C)[C:42]2[CH:43]=[CH:44]C=[CH:46][C:41]=2N=N1.[CH:55]([N:58](C(C)C)CC)(C)C.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[CH:1]1([N:6]2[C:15]3[N:14]=[C:13]([NH:16][C:17]4[CH:18]=[CH:19][C:20]([C:26]([NH:38][CH:42]5[CH2:41][CH2:46][N:58]([CH3:55])[CH2:44][CH2:43]5)=[O:27])=[C:21]5[C:25]=4[O:24][CH2:23][CH2:22]5)[N:12]=[CH:11][C:10]=3[N:9]([CH3:29])[C:8](=[O:30])[C@@H:7]2[CH2:31][CH3:32])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCN(C(C)C)C(C)C
Reactant: CC[C@H]1C(=O)N(C)c2cnc(Nc3ccc(C(=O)O)c4c3OCC4)nc2N1C1CCCC1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CC[C@H]1C(=O)N(C)c2cnc(Nc3ccc(C(=O)NC4CCN(C)CC4)c4c3OCC4)nc2N1C1CCCC1
Reaction time: 0.17 h
Yield: 66.1 %

Procedure:
7-[[(7S)-8-Cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]-2,3-dihydrobenzofuran-4-carboxylic acid 41g (150 mg, 0.34 mmol) and O-(benzotriazol-1-yl)-N,N,N′,N′-tetra methyluronium tetrafluoroborate (111 mg, 0.34 mmol) were dissolved in 30 mL of dichloromethane followed by the addition of diisopropylethylamine (0.13 mL, 0.76 mmol), stirred for 10 minute, then added with 1-methyl-piperidyl-4-yl-amine (40 mg, 0.34 mmol), stirred at room temperature for 1 hour. The reaction mixture was added with 20 mL of saturated sodium carbonate solution and extracted with dichloromethane (100 mL×2). The combined organic phase was washed with water (20 mL) and saturated sodium chloride solution (20 mL) successively, then dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography with elution system A to obtain the title compound 7-[[(7S)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]-N-(1-methyl-4-piperidyl)-2,3-dihydrobenzofuran-4-carboxamide 41 (120 mg, yield: 65.0%) as a white solid.
Reaction SMILES: COC1C=CC=CC=1C([O:18][CH2:19][C@H:20]1[O:24][C@@H:23]([N:25]2[C:48]3[N:47]=[CH:46][N:45]=[C:29]([NH:30][C:31]([O:33][CH2:34][CH2:35][C:36]4[CH:41]=[CH:40][C:39]([N+:42]([O-:44])=[O:43])=[CH:38][CH:37]=4)=[O:32])[C:28]=3[N:27]=[CH:26]2)[C@H:22]([O:49][C:50](=[O:72])[CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][NH:56][C:57](=[O:71])[CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH3:70])[CH2:21]1)(C1C=CC=CC=1)C1C=CC=CC=1.CC1C=CC(S(O)(=O)=O)=CC=1.O>C(Cl)Cl.CO.C(Cl)Cl>[N+:42]([C:39]1[CH:40]=[CH:41][C:36]([CH2:35][CH2:34][O:33][C:31]([NH:30][C:29]2[C:28]3[N:27]=[CH:26][N:25]([C:48]=3[N:47]=[CH:46][N:45]=2)[C@@H:23]2[O:24][C@H:20]([CH2:19][OH:18])[CH2:21][C@H:22]2[O:49][C:50](=[O:72])[CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][NH:56][C:57](=[O:71])[CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH3:70])=[O:32])=[CH:37][CH:38]=1)([O-:44])=[O:43]
Reactant: CCCCCCCCCCCCCC(=O)NCCCCCC(=O)O[C@@H]1C[C@@H](COC(c2ccccc2)(c2ccccc2)c2ccccc2OC)O[C@H]1n1cnc2c(NC(=O)OCCc3ccc([N+](=O)[O-])cc3)ncnc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: CCCCCCCCCCCCCC(=O)NCCCCCC(=O)O[C@@H]1C[C@@H](CO)O[C@H]1n1cnc2c(NC(=O)OCCc3ccc([N+](=O)[O-])cc3)ncnc21
Yield: 88.3 %

Procedure:
Compound 8 (330 mg, 0.317 mmol) was stirred at r.t. in CH2Cl2/MeOH 4:1 (6 ml) containing 2% of TsOH.H2O for 15 min. Then the mixture was diluted with CH2Cl2 (70 ml) and washed with sat. NaHCO3 soln. (2×40 ml), the aq. phase reextracted with CH2Cl2, the combined org. layer dried (MgSO4) and evaporated, and the residue purified by FC (silica gel, 12×2 cm, CHCl3, CHCl3+5% MeOH). The obtained oily substance was treated with small amounts of Et2O/MeCN 2:1 to give 215 mg (88%) of 10. Amorphous solid. UV (CH2Cl2); 272 (sh, 4.36), 267 (4.41). 1H-NMR (CDCl3):8.71, 8.21-8.15 (2m, H—C(8), H—C(2), 2 H o to NO2,NH(ade)); 7.45 (d, 2 H m to NO2); 6.03 (d, H—C(1′)); 5.58 (m, H—C(2′)); 5.55 (br., NH(CH2)5CO); 5.0 (br., OH—C(5′)); 4.65-4.50 (m, t, H—C(4′), OCH2CH2); 4.12, 3,75 (2m, 2 H—C(5′)); 3.25(q, 1 CH2 of NH(CH2)5CO); 3.15 (t, OCH2CH2);2.9, 2.25 (2m, 2 H—C(3′)); 2.35, 2.15 (2t, 2 CH2 of NH(CH2)5CO), 2 H of Me(CH2)12CO); 1.7-1.15 (m, 28 H, 2 CH2 of NH(CH2)5CO, Me(CH2)12CO); 0.87 (t, Me(CH2)12CO)12 Anal. calc. for C39H57N7O9 ½ H2O (782.02): C 59.90, H 7.41, N 12.54; found: C 60.27, H 7.66, N 12.06.
Reaction SMILES: C([O:5][C:6](=[O:18])[CH2:7][CH:8]([NH:11][C:12]([O:14][CH2:15][CH:16]=[CH2:17])=[O:13])[CH2:9][OH:10])(C)(C)C.[CH2:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:21][CH:20]1O>>[CH2:15]([O:14][C:12](=[O:13])[NH:11][CH:8]1[CH2:7][C:6](=[O:5])[O:18][CH:9]1[O:10][CH:20]1[CH2:19][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:21]1)[CH:16]=[CH2:17]
Reactant: OC1Cc2ccccc2C1
Reactant: C=CCOC(=O)NC(CO)CC(=O)OC(C)(C)C
Product: C=CCOC(=O)NC1CC(=O)OC1OC1Cc2ccccc2C1
Yield: 64.6 %

Procedure:
Prepared from 3-allyloxycarbonylamino-4-hydroxy-butyric acid tert-butyl ester (5.2 gram, 20 mmol) as described for 40 using 2-indanol (8.05 gram, 60 mmol) to afford 4.10 grams (65% yield) of the title compound as a mixture of epimers. Purification provided 1.76 gram (28% yield ) of the 4(S), 5(R) epimer as a yellow oil. 1H NMR (500 MHz, CDCl3) δ 2.42 (dd, J=17.2, 10.5 Hz, 1H), 2.79 (dd, J=17.2, 8.4 Hz, 1H), 2.99 (dd, J=16.7, 4.1 Hz, 1H), 3.04 (dd, J=16.7, 4.1 Hz, 1H), 3.22 (dd, J=17.2, 6.6 Hz, 1H), 3.26 (dd, J=17.2, 6.6 Hz, 1H), 4.53 (m, 3H), 4.70 (m, 1H), 5.20 (m, 2H), 5.60 (d, J=5.3 Hz, 1H), 5.87 (m, 1H), 7.17 (m, 4H) ppm. LC-MS (ES+): m/e=318 (M+H). Analytical HPLC (C18 column): 17.094 min.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[N:8]=[CH:7][C:6]([OH:9])=[CH:5][N:4]=1.F[C:13]1[CH:20]=[CH:19][C:18]([CH:21]=[O:22])=[CH:17][C:14]=1[C:15]#[N:16]>>[CH:21]([C:18]1[CH:19]=[CH:20][C:13]([O:9][C:6]2[CH:7]=[N:8][C:3]([C:2]([F:1])([F:10])[F:11])=[N:4][CH:5]=2)=[C:14]([CH:17]=1)[C:15]#[N:16])=[O:22]
Reactant: N#Cc1cc(C=O)ccc1F
Reactant: Oc1cnc(C(F)(F)F)nc1
Product: N#Cc1cc(C=O)ccc1Oc1cnc(C(F)(F)F)nc1

Procedure:
The title compound was prepared by a procedure similar to that described for D4 starting from 2-(trifluoromethyl)pyrimidin-5-ol and 2-fluoro-5-formylbenzonitrile.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8](Cl)=[N:9]2)([O-])=O.[CH3:15][C:16]1[O:17][C:18]2[C:24]([NH2:25])=[CH:23][CH:22]=[CH:21][C:19]=2[CH:20]=1.[CH3:26][C:27]1[N:28]=[CH:29][NH:30][C:31]=1[CH:32]=O>>[CH3:15][C:16]1[O:17][C:18]2[C:24]([NH:25][C:8]3[CH:7]=[CH:6][C:5]4[C:4]([NH:1][CH2:26][C:27]5[NH:28][CH:29]=[N:30][C:31]=5[CH3:32])=[CH:13][CH:12]=[CH:11][C:10]=4[N:9]=3)=[CH:23][CH:22]=[CH:21][C:19]=2[CH:20]=1
Reactant: O=[N+]([O-])c1cccc2nc(Cl)ccc12
Reactant: Cc1nc[nH]c1C=O
Reactant: Cc1cc2cccc(N)c2o1
Product: Cc1cc2cccc(Nc3ccc4c(NCc5[nH]cnc5C)cccc4n3)c2o1

Procedure:
The title compound, MS: m/e=384.1 (M+H+), was prepared from 5-nitro-2-chloroquinoline, (2-methyl-1-benzofuran-7-yl)amine and 4-methyl-1H-imidazole-5-carbaldehyde as described in example 26.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([Br:11])[CH:8]=[CH:7][C:6]=1[OH:12])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.Cl[C:21]([O:23][CH3:24])=[O:22]>ClCCl>[C:21](=[O:22])([O:12][C:6]1[CH:7]=[CH:8][C:9]([Br:11])=[CH:10][C:5]=1[C:1]([CH3:4])([CH3:2])[CH3:3])[O:23][CH3:24]
Reactant: CC(C)(C)c1cc(Br)ccc1O
Reactant: COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)Oc1ccc(Br)cc1C(C)(C)C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 2-t-butyl-4-bromophenol (380 g, 1.67 mol) in dichloromethane (1000 mL) was added Et3N (202 g, 2 mol) at room temperature. Methyl chloroformate (155 mL) was added dropwise to the above solution at 0° C. After addition, the mixture was stirred at 0° C. for 2 h., quenched with saturated ammonium chloride solution and diluted with water. The organic layer was separated and washed with water and brine, dried over Na2SO4, and concentrated to provide the crude methyl (2-tert-butyl-4-bromophenyl) carbonate (470 g), which was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:18]=[C:12]2[CH:13]=[C:14]([NH2:17])[CH:15]=[CH:16][N:11]2[N:10]=1.[CH2:19]([O:21][C:22]([C:24]1[CH:25]=[N:26][N:27]([CH3:32])[C:28]=1[C:29](O)=[O:30])=[O:23])[CH3:20]>>[CH2:19]([O:21][C:22]([C:24]1[CH:25]=[N:26][N:27]([CH3:32])[C:28]=1[C:29](=[O:30])[NH:17][C:14]1[CH:15]=[CH:16][N:11]2[N:10]=[C:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[O:2][CH3:1])[N:18]=[C:12]2[CH:13]=1)=[O:23])[CH3:20]
Reactant: CCOC(=O)c1cnn(C)c1C(=O)O
Reactant: COc1ccccc1-c1nc2cc(N)ccn2n1
Product: CCOC(=O)c1cnn(C)c1C(=O)Nc1ccn2nc(-c3ccccc3OC)nc2c1
Yield: 64.2 %

Procedure:
The product was prepared in the same manner as described in example 28 using 2-(2-methoxyphenyl)-[1,2,4]triazolo[1,5-a]pyridin-7-amine (365 mg, 1.52 mmol) and 4-(ethoxycarbonyl)-1-methyl-1H-pyrazole-5-carboxylic acid (331 mg, 1.67 mmol) as starting material. The reaction affords 5-[2-(2-methoxy-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl]-1-methyl-1H-pyrazole-4-carboxylic acid ethyl ester (410 mg, 64.2%) as white solid. MS: m/z=421.1 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][N:14]([CH:31]([CH3:33])[CH3:32])[C:15](=[O:30])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH2:25][CH2:26][CH2:27][O:28][CH3:29])[CH:17]=2)[C@H:10]([C:34](O)=[O:35])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CSC.B.CO>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][N:14]([CH:31]([CH3:32])[CH3:33])[C:15](=[O:30])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH2:25][CH2:26][CH2:27][O:28][CH3:29])[CH:17]=2)[C@H:10]([CH2:34][OH:35])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COCCCOc1cc(C(=O)N(C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2C(=O)O)C(C)C)ccc1OC
Agent: B
Solvent: C1CCOC1
Solvent: CSC
Solvent: CO
Product: COCCCOc1cc(C(=O)N(C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2CO)C(C)C)ccc1OC
Temperature: -10 °C
Reaction time: 0.33 h

Procedure:
To a solution of (3S*,4R*)-4-({isopropyl-[4-methoxy-3-(3-methoxy-propoxy)-benzoyl]-amino}-methyl)-pyrrolidine-1,3-dicarboxylic acid 1-tert-butyl ester (1.29 g, 2.54 mmol) (Example 1 G) in THF (25 mL), a solution of borane dimethylsulfide complex (2M in THF, 2.80 mL, 5.58 mmol) is slowly added at −10° C. The mixture is stirred for 20 min at −10° C., then allowed to reach RT and further stirred overnight. MeOH is carefully added (exothermic!), and the mixture is concentrated under reduced pressure. MeOH is again added, and the mixture is concentrated. This operation is repeated 3 times, and the mixture is finally taken up into a saturated aqueous solution of NaHCO3 and extracted 3 times with CH2Cl2. The combined organic extracts are dried over Na2SO4, filtered and concentrated. The crude material is purified by flash chromatography on silica gel (eluent: CH2Cl2/MeOH from 100:0 to 95:5) to give the desired product. TLC, Rf (CH2Cl2/MeOH 95:5)=0.3. MS (LC-MS): 395.1 [M+H-Boc]+; tR (HPLC, C18 column, 10-100% CH3CN/H2O/5 min, 100% CH3CN/3 min, CH3CN and H2O containing 0.1% TFA, flow: 1.5 mL/min): 5.01 min.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5]([OH:7])=[O:6].CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].[CH2:23](Br)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]>O.C(OCC)(=O)C>[NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5]([O:7][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH3:23])=[O:6]
Reactant: Nc1cc(C(=O)O)ccc1Cl
Reactant: CCCCCCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCCCCCCCCCCCOC(=O)c1ccc(Cl)c(N)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95 %

Procedure:
17.2 g (0.1 mol) of 3-amino-4-chlorobenzoic acid was added to 50 ml of N,N-dimethylformamide. Then 13.8 g (0.1 mol) of potassium carbonate was added to the solution obtained above, and the resulting mixture was stirred in the temperature range of from 20 to 30° C. for 30 min. 27.4 g (0.11 mol) of dodecyl bromide was poured into the solution thus obtained, and the resulting solution was heated to 80° C., and allowed to react at the temperature for 1 hour. After completing the reaction, 50 ml of ethyl acetate, and 50 ml of water were added to the reaction mixture, and the organic layer was separated, concentrated, diluted with 100 ml of methanol, and then cooled to precipitate crystals. The crystals were separated by filtration, and then dried to obtain 32.3 g (yield 95%) of the desired product. Purity 99% or higher. Melting point 58.3-59.5° C. A result of the elemental analysis of this sample is as follows:
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]([O:13][CH3:14])[C:3]=1[C:4]([NH2:6])=[O:5].[CH:15]([C:17]1[CH:27]=[CH:26][C:20]([O:21][CH2:22][C:23]([OH:25])=[O:24])=[C:19](C)[CH:18]=1)=O.S([O-])(O)=O.[Na+].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.CN(C)[C:48](=[O:50])C>>[CH3:14][O:13][C:7]1[CH:8]=[C:9]([O:11][CH3:12])[CH:10]=[C:2]2[C:3]=1[C:4](=[O:5])[NH:6][C:15]([C:17]1[CH:27]=[CH:26][C:20]([O:21][CH2:22][C:23]([OH:25])=[O:24])=[C:19]([O:50][CH3:48])[CH:18]=1)=[N:1]2
Reactant: CC(=O)N(C)C
Reactant: COc1cc(N)c(C(N)=O)c(OC)c1
Reactant: Cc1cc(C=O)ccc1OCC(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Product: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(OCC(=O)O)c(OC)c3)nc2c1
Yield: 8.1 %

Procedure:
A mixture of NaOH (1.8 g, 0.045 mol) and 4-hydroxy-3-methoxylbenzalde (3.10 g, 0.0203 mol) in water (20 mL) was mixed with bromoacetic acid (2.82 g, 0.0203 mol) and heated to reflux for 6 h. The reaction mixture was adjusted to pH 3.0 by adding a HCl solution. The solid was filtered off and further washed with cold water and ethyl acetate (2×30 mL) to yield (4-formyl-2-methyl-phenoxy)-acetic acid (2.89 g, 67.7%). 2-Amino-4,6-dimethoxy-benzamide (150 mg, 0.764 mmol) with (4-formyl-2-methyl-phenoxy)-acetic acid (160 mg, 0.764 mmol), sodium hydrogen sulfite (150 mg, 58.5%) and p-toluenesulfonic acid monohydrate (15 mg) in N,N-dimethyl acetamide (10 mL) were heated to 150° C. for 16 h. N,N-dimethyl acetamide was removed under vacuum and the residue was poured into water (50 mL). The solid was filtered off and further purified by base/acid extractions/washes to yield 2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2-methoxyphenoxy)acetic acid (25 mg, 8.1%). Selected data: MS (ES) m/z: 387.1; MP 275-277° C.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])(C)(C)C.[N:19]([CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=C=O.[O:27]1[C:31]2[CH:32]=[CH:33][C:34]([CH2:36][N:37]3[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]3)=[CH:35][C:30]=2[O:29][CH2:28]1>>[O:27]1[C:31]2[CH:32]=[CH:33][C:34]([CH2:36][N:37]3[CH2:38][CH2:39][N:40]([C:16]([C@@H:9]4[CH2:10][C:11](=[N:13][O:14][CH3:15])[CH2:12][N:8]4[C:6]([NH:19][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[O:7])=[O:18])[CH2:41][CH2:42]3)=[CH:35][C:30]=2[O:29][CH2:28]1
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: c1cc2c(cc1CN1CCNCC1)OCO2
Reactant: CCCCCN=C=O
Product: CCCCCNC(=O)N1CC(=NOC)C[C@H]1C(=O)N1CCN(Cc2ccc3c(c2)OCO3)CC1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, 1-isocyanatopentane, and 1-(1,3-benzodioxol-5-ylmethyl)piperazine the title compound was obtained in 72% purity by LC/MS. MS(ESI+): m/z=474.4.
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([N:11]2[CH2:17][C:16]3[CH:18]=[C:19]([C:22]4[CH:27]=[CH:26][C:25]([C:28]5[N:29](C(OCC(C)C)=O)[CH:30]=[CH:31][N:32]=5)=[CH:24][CH:23]=4)[CH:20]=[CH:21][C:15]=3[O:14][CH2:13][CH2:12]2)=[O:10])[CH2:5][CH2:4]1)#[N:2].CO.C1COCC1.C(=O)([O-])[O-].[K+].[K+]>O>[NH:29]1[CH:30]=[CH:31][N:32]=[C:28]1[C:25]1[CH:26]=[CH:27][C:22]([C:19]2[CH:20]=[CH:21][C:15]3[O:14][CH2:13][CH2:12][N:11]([C:9]([N:6]4[CH2:7][CH2:8][CH:3]([C:1]#[N:2])[CH2:4][CH2:5]4)=[O:10])[CH2:17][C:16]=3[CH:18]=2)=[CH:23][CH:24]=1
Reactant: CC(C)COC(=O)n1ccnc1-c1ccc(-c2ccc3c(c2)CN(C(=O)N2CCC(C#N)CC2)CCO3)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: N#CC1CCN(C(=O)N2CCOc3ccc(-c4ccc(-c5ncc[nH]5)cc4)cc3C2)CC1
Yield: 64.7 %

Procedure:
2-Methylpropyl 2-(4-{4-[(4-cyanopiperidin-1-yl)carbonyl]-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl}phenyl)-1H-imidazole-1-carboxylate (296 mg, 0.56 mmol) was taken into methanol (10 mL), THF (2 mL) and water (0.5 mL) then warmed to give a homogeneous solution. Potassium carbonate (160 mg, 1.15 mmol) and the mixture was stirred for 30 minutes. The mixture was then concentrated and partitioned with ethyl acetate and 10% aqueous citric acid. The organic solution was washed with brine, dried over anhydrous sodium sulfate then filtered and concentrated. The residue was purified by silica gel chromatography (10% ethanol in ethyl acetate) to give 1-({7-[4-(1H-imidazol-2-yl)phenyl]-2,3-dihydro-1,4-benzoxazepin-4(5H)-yl}carbonyl)piperidine-4-carbonitrile (155 mg, 65% yield). 1H NMR (400 MHz, d4-methanol): 7.92 (d, 2H), 7.69 (d, 2H), 7.56 (d, 1H), 7.51 (dd, 1H), 7.15 (s, 2H), 7.04 (d, 1H), 4.51 (s, 2H), 4.21 (tr, 2H), 3.70 (tr, 2H), 3.49-3.43 (m, 2H), 3.13 (m, 2H), 2.97 (m, 1H), 1.98-1.93 (m, 2H), 1.86-1.78 (m, 2H). MS (EI) for C25H25N5O2: 429 (MH+).
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:27]([O:29][CH3:30])=[O:28])=[CH:12][C:13]=3[N:14]3[CH2:21][CH2:20][NH:19][CH2:18][C:17]4[CH:22]=[C:23]([F:26])[CH:24]=[CH:25][C:16]=4[C:15]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.[CH3:40][N:41]([CH3:46])[CH2:42][C:43](O)=[O:44].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl.Cl>[CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:27]([O:29][CH3:30])=[O:28])=[CH:12][C:13]=3[N:14]3[CH2:21][CH2:20][N:19]([C:43](=[O:44])[CH2:42][N:41]([CH3:46])[CH3:40])[CH2:18][C:17]4[CH:22]=[C:23]([F:26])[CH:24]=[CH:25][C:16]=4[C:15]=23)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CCNCc1cc(F)ccc1-3
Reactant: CN(C)CC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CCN(C(=O)CN(C)C)Cc1cc(F)ccc1-3
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 14-cyclohexyl-3-fluoro-5,6,7,8-tetrahydroindolo[2,1-a][2,5]benzodiazocine-11-carboxylate (from Step 5) in DCM (0.15 M), DIPEA (4 eq.), dimethylglycine (3 eq.) and HATU (2 eq.) were added and the mixture stirred at RT overnight. The solution was diluted with DCM and HCl (1N) and the 2 phases separated. The aqueous phase was extracted with DCM (twice). The combined organic phases were then washed with a saturated aqueous solution of NaHCO3 and brine before being dried (Na2SO4), filtered and concentrated in vacuo. The crude was used in the next step without further purification; MS (ES+) m/z 492 (M+H)+.