Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH2:5].[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1>>[F:1][C:2]([F:10])([F:11])[C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH:5][S:20]([C:17]1[CH:16]=[CH:15][C:14]([O:13][CH3:12])=[CH:19][CH:18]=1)(=[O:22])=[O:21]
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1ccccc1C(F)(F)F
Product: COc1ccc(S(=O)(=O)Nc2ccccc2C(F)(F)F)cc1
Yield: 75.5 %

Procedure:
Using 2-trifluoromethylaniline (1.39 g, 8.55 mmol) and 4-methoxybenzenesulfonyl chloride (1.78 g, 8.55 mmol), the procedure of Reference Example 2 was repeated to obtain 2.14 g (75.5%) of the title compound in the form of colorless solid.
Reaction SMILES: O1C2C=CC(O)=CC=2OC1.[O:11]1[C:15]2[CH:16]=[C:17]([OH:20])[CH:18]=[CH:19][C:14]=2[CH2:13][CH2:12]1.C1(CCN2C3C(=CC=CC=3)C(=O)C2=O)CC1.[Br:37][C:38]1[CH:46]=[CH:45][CH:44]=[C:43]2[C:39]=1[C:40](=[O:48])[C:41](=[O:47])[NH:42]2>>[Br:37][C:38]1[CH:46]=[CH:45][CH:44]=[C:43]2[C:39]=1[C:40]([OH:48])([C:18]1[C:17]([OH:20])=[CH:16][C:15]3[O:11][CH2:12][CH2:13][C:14]=3[CH:19]=1)[C:41](=[O:47])[NH:42]2
Reactant: Oc1ccc2c(c1)OCC2
Reactant: O=C1Nc2cccc(Br)c2C1=O
Agent: O=C1C(=O)N(CCC2CC2)c2ccccc21
Agent: Oc1ccc2c(c1)OCO2
Product: O=C1Nc2cccc(Br)c2C1(O)c1cc2c(cc1O)OCC2

Procedure:
Following the procedure as described in PREPARATION 2B, and making non-critical variations to replace 1,3-benzodioxol-5-ol with 2,3-dihydrobenzofuran-6-ol and 1-(2-cyclopropylethyl)-1H-indole-2,3-dione with 4-bromo-1H-indole-2,3-dione, the title compound was obtained (78%) as a white solid: 1H NMR (300 MHz, DMSO-d6) δ 10.36 (s, 1H), 9.15 (s, 1H), 7.49 (1H), 7.04 (t, 1H), 6.89 (d, 1H), 6.74 (d, 1H), 6.35 (br, 1H), 5.90 (s, 1H), 4.45 (t, 2H), 3.05 (t, 2H); 13C NMR (75 MHz, DMSO-d6) δ 178.4, 160.2, 154.0, 145.7, 131.6, 130.7, 125.5, 125.4, 118.9, 117.7, 116.1, 108.8, 96.8, 76.9, 71.8, 29.1; MS (ES−) m/z 344.4 (M−17), 360.4 (M−1).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:12])=[C:4]([C:13]([OH:15])=O)[N:3]=1.F[P-](F)(F)(F)(F)F.N1([O+]=C(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[C:40]([O:44][C:45](=[O:50])[NH:46][CH2:47][CH2:48][NH2:49])([CH3:43])([CH3:42])[CH3:41].C(N(C(C)C)C(C)C)C>ClCCl>[C:40]([O:44][C:45](=[O:50])[NH:46][CH2:47][CH2:48][NH:49][C:13]([C:4]1[N:3]=[C:2]([Cl:1])[C:11]2[C:6]([C:5]=1[OH:12])=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:15])([CH3:43])([CH3:41])[CH3:42]
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: O=C(O)c1nc(Cl)c2ccccc2c1O
Agent: CN(C)C(=[O+]n1nnc2ccccc21)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NCCNC(=O)c1nc(Cl)c2ccccc2c1O
Reaction time: 120 h
Yield: 10.9 %

Procedure:
To a mixture of 45 mg (0.2 mmol) of 1-chloro-4-hydroxy-isoquinoline-3-carboxylic acid, 76 mg (0.2 mmol) of benzotriazol-1-yl-(bis-dimethylamino-methylene)-oxonium hexafluoro phosphate (HBTU), 32 μl (2-amino-ethyl)-carbamic acid tert-butyl ester (0.2 mmol), and 1 ml of dichloromethane was added 96 μl (0.55 mmol) of ethyl-diisopropyl-amine with stirring. Stirring was continued at ambient temperature for 5 days. The product was isolated from the reaction mixture by flash column chromatography on silica gel using hexanes:ethyl acetate (8:2) as the eluent to give a tan gum. 8 mg of the title compound were obtained; MS-(−)-ion: M−1=364.0.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([Br:16])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[C:24]([CH3:31])([CH3:30])[C:25]([O:27][CH2:28][CH3:29])=[O:26]>CN(C=O)C>[CH2:28]([O:27][C:25](=[O:26])[C:24]([O:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:10][C:11]=1[Br:16])([CH3:31])[CH3:30])[CH3:29]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: Oc1ccc(OCc2ccccc2)cc1Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)Oc1ccc(OCc2ccccc2)cc1Br
Temperature: 55 °C
Yield: 34.7 %

Procedure:
A mixture of 4-benzyloxy-2-bromo-phenol (9.37 g, 33.6 mmol) and Cs2CO3 (21.9 g, 67.2 mmol) in DMF (80 mL) was treated with ethyl bromoisobutyrate (15 mL, 100 mmol) and heated at 55° C. for 18 h. The reaction mixture was cooled and partitioned between ethyl acetate (250 mL) and H2O (100 mL). The organic layer was washed with brine (75 mL), dried (Na2SO4), and concentrated. The crude product was purified by flash chromatography using CH2Cl2:hexanes (2:3 to 3:2) to give a pale yellow oil (4.58 g, 35%): 1H NMR (400 MHz, CDCl3) δ 1.29 (t, 3H, J=7.1 Hz), 1.57 (s, 6H), 4.25 (q, 2H, J=7.1 Hz), 4.98 (s, 2H), 6.79 (dd, 1H, J 3.2, 9.1 Hz), 6.89 (d, 1H, J=8.8 Hz), 7.17 (d, 1H, J=3.4 Hz), 7.32-7.40 (m, 5H); MS (ES) m/e # [M+1].
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]([NH:10][C:11]2[CH:12]=[C:13]([N:20]3[CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22][CH2:21]3)[CH:14]=[CH:15][C:16]=2[N+:17]([O-:19])=[O:18])[CH3:9])[CH:5]=[CH:6][CH:7]=1.[ClH:33].CCOCC>ClCCl>[ClH:33].[Br:1][C:2]1[CH:3]=[C:4]([CH:8]([NH:10][C:11]2[CH:12]=[C:13]([N:20]3[CH2:21][CH2:22][NH:23][CH2:24][CH2:25]3)[CH:14]=[CH:15][C:16]=2[N+:17]([O-:19])=[O:18])[CH3:9])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(Nc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)ccc1[N+](=O)[O-])c1cccc(Br)c1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: CC(Nc1cc(N2CCNCC2)ccc1[N+](=O)[O-])c1cccc(Br)c1
Reaction time: 18 h
Yield: 33 %

Procedure:
A mixture of tert-butyl 4-(3-(1-(3-bromophenyl)ethylamino)-4-nitrophenyl)piperazine-1-carboxylate (0.45 g, 0.9 mmol), 2N HCl in ether (10 mL, 20.0 mmol) and dichloromethane (5 mL) was stirred for 18 h and concentrated in vacuo. The residue was dissolved in dichloromethane; this solution was washed with aqueous NaHCO3 solution, dried over Na2SO4 and concentrated in vacuo. The yellow solid residue was dissolved in dichloromethane (0.5 mL) and reacted with 1N HCl in ether (1 mL). The resulting precipitates were collected by vacuum filtration, washed with ether and air dried to yield the title compounds as a yellow solid (0.13 g, 33%). 1H NMR (400 MHz, CDCl3): δ 8.71 (d, 1 H), 8.05 (d, 1 H), 7.50 (s, 1 H), 7.39 (m, 1 H), 7.23 (m, 2 H), 6.19 (dd, 1 H), 5.60 (d, 1 H), 4.53 (m, 1 H), 3.21 (m, 2 H), 3.13 (m, 2 H), 2.88 (m, 4 H), 1.63 (d, 3 H). MS (ESI) m/z: Calculated: 404; Observed: 405 (M+H+).
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][O:16][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]2[C:26]=1[CH:25]([NH2:27])[CH2:24][CH2:23][CH2:22]2.[CH:28]([C:30]1[CH:38]=[CH:37][CH:36]=[C:35]2[C:31]=1[CH:32]=[CH:33][NH:34]2)=O>>[NH:34]1[C:35]2[C:31](=[C:30]([CH2:28][NH:1][C:4]3[C:5]4[CH:6]=[CH:7][C:8]([NH:27][CH:25]5[C:26]6[C:21](=[CH:20][CH:19]=[CH:18][C:17]=6[O:16][CH3:15])[CH2:22][CH2:23][CH2:24]5)=[N:9][C:10]=4[CH:11]=[CH:12][CH:13]=3)[CH:38]=[CH:37][CH:36]=2)[CH:32]=[CH:33]1
Reactant: O=[N+]([O-])c1cccc2nc(Cl)ccc12
Reactant: COc1cccc2c1C(N)CCC2
Reactant: O=Cc1cccc2[nH]ccc12
Product: COc1cccc2c1C(Nc1ccc3c(NCc4cccc5[nH]ccc45)cccc3n1)CCC2

Procedure:
The title compound, MS: m/e=449.3 (M+H+), was prepared in accordance with the general method of example 43 from 5-nitro-2-chloroquinoline, rac-8-methoxy-1,2,3,4-tetrahydronaphthalen-1-amine (CAS 535935-61-6) and 4-formylindole.
Reaction SMILES: [CH2:1]([C:3]1([CH2:21][CH3:22])[CH2:14][CH:13]=[CH:12][CH2:11][CH2:10][CH:9]=[CH:8][CH2:7][CH:6]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:5]=[CH:4]1)[CH3:2].Cl.Cl.[NH2:25][OH:26]>O>[CH2:1]([C:3]([CH2:21][CH3:22])([CH2:14][CH:13]=[CH:12][CH2:11][CH2:10][CH:9]=[CH:8][CH2:7][CH:6]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[NH2:5])[CH:4]=[N:25][OH:26])[CH3:2]
Reactant: NO
Reactant: CCC1(CC)C=NC(c2ccccc2)CC=CCCC=CC1
Agent: Cl
Solvent: O
Product: CCC(C=NO)(CC)CC=CCCC=CCC(N)c1ccccc1
Yield: 97.5 %

Procedure:
The procedure described in Example 1(b) is repeated, except that 95.3 g (0.323 mol) of 3,3-diethyl-12-phenyl-1-aza-1,5,9-cyclododecatriene, 20 g of 37% hydrochloric acid, 22.4 g (0.322 mol) of hydroxylamine hydrochloride and 250 ml of water are used. Working up yields 103.1 g (0.314 mol) of 2,2-diethyl-11-phenyl-11-amino-undeca-4,8-dienal oxime; yield 97.5% of theory.
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:17])[NH:5][C:6](=[O:16])[NH:7][C:8]=1[S:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:2].[Si:18]([O:25][CH2:26][CH:27]1[CH2:31][C:30]([CH2:32]Br)=[CH:29][CH2:28]1)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19].C(=O)(O)[O-].[Na+]>CN(C)C=O>[Si:18]([O:25][CH2:26][CH:27]1[CH2:31][C:30]([CH2:32][N:7]2[C:8]([S:9][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)=[C:3]([CH2:1][CH3:2])[C:4](=[O:17])[NH:5][C:6]2=[O:16])=[CH:29][CH2:28]1)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]
Reactant: CC(C)(C)[Si](C)(C)OCC1CC=C(CBr)C1
Reactant: CCc1c(Sc2ccccc2)[nH]c(=O)[nH]c1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1c(Sc2ccccc2)n(CC2=CCC(CO[Si](C)(C)C(C)(C)C)C2)c(=O)[nH]c1=O

Procedure:
A mixture of 5-ethyl-6-phenylthio-2,4-pyrimidinedione (0.16 g, 0.66 mmol) and (4-t-butyldimethylsilyloxymethylcyclopent-1-en-1-yl)methyl bromide (0.20 g, 0.66 mmol) in dimethylformamide (10 mmol) were heated at 50° C. for overnight in the presence of sodium bicarbonate (66 mg, 0.79 mmol). After the concentration of dimethylformamide, [(4-t-butyldimethylsilyloxymethyl cyclopent-1-en-1-yl)methyl]-5-ethyl-6-phenylthio-2,4-pyrimidinedione was obtained by the separation of the column chromatography. And then, this compound in THF (10 ml) was reacted with n-tetrabutylammoniumfluoride at room temperature for 1 hr. After the concentration of THF, the residue was separated by column chromatography to give a desirable product (35 mg).
Reaction SMILES: [F:1][C:2]([F:45])([F:44])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([C:26]4[CH:27]=[C:28]([CH2:34][CH2:35][C:36]([O:38][CH3:39])=[O:37])[CH:29]=[CH:30][C:31]=4[O:32][CH3:33])=[C:24]([CH3:40])[N:23]=[C:22](SC)[N:21]=3)[C@H:14]2[CH3:43])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C1C=C(Cl)C=C(C(OO)=O)C=1.[F:57][C:58]1([F:62])[CH2:61][NH:60][CH2:59]1.CCN(CC)CC>C(Cl)Cl.C1COCC1>[F:1][C:2]([F:45])([F:44])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([C:26]4[CH:27]=[C:28]([CH2:34][CH2:35][C:36]([O:38][CH3:39])=[O:37])[CH:29]=[CH:30][C:31]=4[O:32][CH3:33])=[C:24]([CH3:40])[N:23]=[C:22]([N:60]4[CH2:61][C:58]([F:62])([F:57])[CH2:59]4)[N:21]=3)[C@H:14]2[CH3:43])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: COC(=O)CCc1ccc(OC)c(-c2c(C)nc(SC)nc2CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)c1
Reactant: FC1(F)CNC1
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)CCc1ccc(OC)c(-c2c(C)nc(N3CC(F)(F)C3)nc2CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of the title compound from Step A (20 mg, 0.030 mmol) and mCPBA (10.50 mg, 0.061 mmol) in CH2Cl2 (2 mL) was stirred at room temperature for 1 h. TLC showed no SM. The mixture was diluted with CH2Cl2 (10 mL) and washed with Na2S2O3 and Na2HCO3, and dried over Na2SO4. The solvent was removed. A mixture of the residue, 3,3-difluoro-azetidine (19.70 mg, 0.152 mmol) and Et3N (3.08 mg, 0.030 mmol) in THF was heated at 140° C. under microwave for 4 h. The solvent was removed and the title compound was purified by preparative TLC plate as a white solid using EtOAc/hexane as the elute (2/8). LCMS=703.4 (M+H)+. The final compound was a mixture of two separable atropisomers, which could be separated by chiral OD column using EtOH/heptane as the elute.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:14]([CH3:15])=[CH:13][CH:12]=[C:11]([NH:16][C:17]([C:19]3([C:22]4[CH:30]=[CH:29][C:25]5[O:26][CH2:27][O:28][C:24]=5[CH:23]=4)[CH2:21][CH2:20]3)=[O:18])[CH:10]=2)=[CH:5][CH:4]=1.[CH2:31]([S:34](Cl)(=[O:36])=[O:35])[CH2:32][CH3:33].CCN(CC)CC>ClCCl>[O:26]1[C:25]2[CH:29]=[CH:30][C:22]([C:19]3([C:17]([NH:16][C:11]4[CH:10]=[C:9]([C:6]5[CH:5]=[CH:4][C:3]([CH2:2][NH:1][S:34]([CH2:31][CH2:32][CH3:33])(=[O:36])=[O:35])=[CH:8][CH:7]=5)[C:14]([CH3:15])=[CH:13][CH:12]=4)=[O:18])[CH2:20][CH2:21]3)=[CH:23][C:24]=2[O:28][CH2:27]1
Reactant: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)cc1-c1ccc(CN)cc1
Reactant: CCCS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCS(=O)(=O)NCc1ccc(-c2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)ccc2C)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 10.5 %

Procedure:
N-(4′-(Aminomethyl)-6-methylbiphenyl-3-yl)-1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (40 mg, 0.10 mmol), 1-propanesulfonyl chloride (11 μL, 0.10 mmol) and Et3N (28 μL, 0.20 mmol) were dissolved in dichloromethane (1.0 mL) and allowed to stir at 25° C. for 16 hours. Volatiles were removed in vacuo and crude product was purified by reverse phase HPLC to afford 1-(benzo[d][1,3]dioxol-5-yl)-N-(6-methyl-4′-(propylsulfonamidomethyl)biphenyl-3-yl)cyclopropanecarboxamide (5.3 mg, 10%). ESI-MS m/z calc. 506.6, found 507.3 (M+1)+; retention time 3.48 minutes.
Reaction SMILES: Cl.Cl.Cl.[Cl:4][C:5]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:6]=1[N:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]2[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]2)[CH2:14][CH2:13]1.C(N(CC)CC)C.[CH3:34][N:35]([CH3:39])[C:36](Cl)=[O:37]>ClCCl>[Cl:4][C:5]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:6]=1[N:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]2[CH2:25][CH2:24][C@H:23]([NH:26][C:36]([N:35]([CH3:39])[CH3:34])=[O:37])[CH2:22][CH2:21]2)[CH2:14][CH2:13]1
Reactant: CN(C)C(=O)Cl
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3cccc(Cl)c3Cl)CC2)CC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)C(=O)N[C@H]1CC[C@H](CCN2CCN(c3cccc(Cl)c3Cl)CC2)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
1.39 g (3 mmol) trans-4-{2-[4-(2,3-dichlorophenyl)-piperazin-1-yl]-ethyl}-cyclohexyl-amine trihydrochloride was suspended in dichloromethane (100 ml), triethylamine (2.1 ml, 15 mmol) was added followed by 0.30 ml (3.3 mmol) N,N-dimethylcarbamoylchloride. The reaction mixture was stirred for 48 hours at room temperature, filtered. The filtrate was washed with water (2×20 ml), dried and evaporated in vacuo. Recrystallizing from methanol gave the title compound (0.83 g, 65%), melting at 212-4° C.
Reaction SMILES: [CH:1]([C:4]1([CH3:22])[C:8](=[O:9])[NH:7][C:6]([C:10]2[N:15]=[C:14]3[O:16][CH:17]=[CH:18][C:13]3=[CH:12][C:11]=2[C:19]([OH:21])=[O:20])=[N:5]1)([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].C(O)C.[H][H]>[Pd].O>[CH:1]([C:4]1([CH3:22])[C:8](=[O:9])[NH:7][C:6]([C:10]2[N:15]=[C:14]3[O:16][CH2:17][CH2:18][C:13]3=[CH:12][C:11]=2[C:19]([OH:21])=[O:20])=[N:5]1)([CH3:3])[CH3:2]
Reactant: [H][H]
Reactant: CC(C)C1(C)N=C(c2nc3occc3cc2C(=O)O)NC1=O
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CC(C)C1(C)N=C(c2nc3c(cc2C(=O)O)CCO3)NC1=O
Temperature: 25 °C
Reaction time: 10 h
Yield: 5.9 %

Procedure:
A solution of 6-(4-isopropyl-4-methyl-5-oxo-2-imidazolin-2-yl)furo[2,3-b]pyridine-5-carboxylic acid (1.7 g 0.056 mol) and 1.0 g (0.0072 mol) potassium carbonate in 200 mL 9:1 ethanol:water is added to 100 mg 5% palladium on carbon catalyst in a 500 mL pressure bottle. The bottle is fitted to a Parr hydrogenation apparatus, pressurized to 30 psi, with hydrogen, then shaken at room temperature for 10 hours. The catalyst is removed by filtration through a sintered glass funnel, and the filtrate concentrated in vacuo to 10 mL. Acidification of the residue to pH 2 gives a white precipitate which is removed by filtration, washed with water and air dried to give 1.0 g (63%) of 2,3-dihydro-6-(4-isopropyl-4-methyl-5-oxo-2-imidazolin-2-yl)furo[2,3-b]pyridine-5-carboxylic acid as an off-white solid, mp 189°-192° C.
Reaction SMILES: [Li+].[OH-].C[O:4][C:5]([C@@H:7]1[CH2:12][N:11]([CH3:13])[CH2:10][CH2:9][N:8]1[C:14](=[O:24])[C@H:15]([O:20]C(=O)C)[C:16]([CH3:19])([CH3:18])[CH3:17])=[O:6].C1COCC1.CO>O>[OH:20][C@H:15]([C:16]([CH3:19])([CH3:18])[CH3:17])[C:14]([N:8]1[CH2:9][CH2:10][N:11]([CH3:13])[CH2:12][C@H:7]1[C:5]([OH:6])=[O:4])=[O:24]
Reactant: COC(=O)[C@@H]1CN(C)CCN1C(=O)[C@H](OC(C)=O)C(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CN1CCN(C(=O)[C@H](O)C(C)(C)C)[C@H](C(=O)O)C1
Yield: 59.8 %

Procedure:
A solution of LiOH (0.016 g, 0.66 mmol) in water (2 mL) was added to a stirred solution of (S)-methyl-1-{(R)-2-acetoxy-3,3-dimethylbutanoyl}-4-methylpiperazine-2-carboxylate (0.07 g, 0.22 mmol) in a 1:1 THF:MeOH mixture (3 mL) and the reaction mixture was stirred at room temperature for 2 h. The solvent was removed under reduced pressure and the residue was dissolved in water (10 mL), acidified with 1M aqueous HCl to pH 2-3 and extracted with EtOAc (2×20 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to afford the title compound (0.034 g) as a colorless oil.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C@@:10]([NH:14][C:15]2[CH:16]=[C:17]3[C:26](=[CH:27][C:28]=2/[CH:29]=[CH:30]/OCC)[O:25][CH2:24][C:23]2[N:18]3[C@@H:19]([CH3:35])[C:20](=[O:34])[NH:21][N:22]=2)([CH3:13])[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:35][C@H:19]1[C:20](=[O:34])[NH:21][N:22]=[C:23]2[N:18]1[C:17]1[CH:16]=[C:15]3[N:14]([C@@:10]4([CH3:13])[CH2:11][CH2:12][NH:8][CH2:9]4)[CH:30]=[CH:29][C:28]3=[CH:27][C:26]=1[O:25][CH2:24]2
Reactant: CCO/C=C/c1cc2c(cc1N[C@@]1(C)CCN(C(=O)OC(C)(C)C)C1)N1C(=NNC(=O)[C@@H]1C)CO2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@H]1C(=O)NN=C2COc3cc4ccn([C@@]5(C)CCNC5)c4cc3N21
Temperature: 25 °C
Reaction time: 1 h
Yield: 21.6 %

Procedure:
To a solution of (S)-3-[(S)-7-((E)-2-ethoxy-vinyl)-4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-ylamino]-3-methyl-pyrrolidine-1-carboxylic acid tert-butyl ester (0.115 g, 0.273 mmol) in DCM (2 mL) was added TFA (1 mL) and the reaction mixture was stirred at ambient temperature for 1 h. The solvent was removed in vacuo and the residue was purified by prep-TLC (eluting with 15% MeOH in DCM) to give (S)-1-methyl-10-((S)-3-methyl-pyrrolidin-3-yl)-3,5-dihydro-10H-6-oxa-3,4,10,11b-tetraaza-cyclopenta[b]phenanthren-2-one (0.020 g, 25%, SFC (Table 1, Method 53) Rt=1.81 min) as a white solid. 1H-NMR (400 MHz, methanol-d4) δ 7.41 (d, J=3.2 Hz, 1H), 7.25 (s, 1H), 7.22 (s, 1H), 6.49 (d, J=3.2 Hz, 1H), 5.11 (q J=6.8 Hz, 1H), 4.62-4.54 (d, J=13.6 Hz, 2H), 4.16-4.09 (m, 1H), 3.88-3.82 (m, 1H), 3.67-3.47 (m, 2H), 3.10-2.97 (m, 1H), 2.71-2.59 (m, 1H), 1.78 (s, 3H), 1.49 (d, J=6.8 Hz, 3H). LC/MS (Table 1, Method 5) Rt=1.916 min; MS m/z: 340 [M+1]+.
Reaction SMILES: [CH3:1][P:2]([CH2:5][N:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)([CH3:4])=[O:3].C(N(CC)CC)C.Br[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][C:22]=1[C:30]([F:33])([F:32])[F:31]>ClCCl>[CH3:4][P:2]([CH2:5][N:6]1[CH2:7][CH2:8][N:9]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][C:22]=2[C:30]([F:31])([F:32])[F:33])[CH2:10][CH2:11]1)([CH3:1])=[O:3]
Reactant: O=[N+]([O-])c1ccc(CBr)c(C(F)(F)F)c1
Reactant: CP(C)(=O)CN1CCNCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CP(C)(=O)CN1CCN(Cc2ccc([N+](=O)[O-])cc2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 54.2 %

Procedure:
1-[(dimethylphosphoryl)methyl]piperazine (3.6 mmol) was dissolved in 20 mL of anhydrous dichloromethane. Triethylamine (4.04 g, 11 eq.) was carefully added. The reaction solution temperature rose to 30° C. before cooling down to room temperature after 5 minutes. After 1-(bromomethyl)-4-nitro-2-(trifluoromethyl)benzene (60 weight %, 3.88 g, 7.9 mmol, 2.2 eq) was added in one portion, the reaction mixture was stirred at room temperature for 30 minutes under N2 protection. After the volatile components were evaporated, the reaction mixture was purified via column chromatography to give title compound as light yellow solid (740 mg). MS (LC/MS): 378.3 [M−]. 31P-NMR (300 MHz, CDCl3): 42.8.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([C:14]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[C:27]([CH3:28])=[CH:26][C:25]([CH3:29])=[CH:24][N:23]=3)[CH2:18][CH2:17]2)=[O:15])=[C:6]([N:8]2[CH2:12][CH2:11][CH2:10][C:9]2=[O:13])[CH:7]=1.[O:30]1[CH2:34][CH2:33][NH:32][C:31]1=[O:35]>>[CH3:28][C:27]1[C:22]([N:19]2[CH2:20][CH2:21][N:16]([C:14]([C:5]3[CH:4]=[CH:3][C:2]([N:32]4[CH2:33][CH2:34][O:30][C:31]4=[O:35])=[CH:7][C:6]=3[N:8]3[CH2:12][CH2:11][CH2:10][C:9]3=[O:13])=[O:15])[CH2:17][CH2:18]2)=[N:23][CH:24]=[C:25]([CH3:29])[CH:26]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Cl)cc3N3CCCC3=O)CC2)c(C)c1
Reactant: O=C1NCCO1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCOC4=O)cc3N3CCCC3=O)CC2)c(C)c1
Yield: 10.4 %

Procedure:
By reaction and treatment in the same manner as in Example 201 and using 1-{5-chloro-2-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]phenyl}pyrrolidin-2-one (206 mg) described in Preparation Example 121 and oxazolidin-2-one (43.5 mg), the title compound (24.1 mg) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][C:7]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:8]=2[C:9]2[C:10]([CH2:23][O:24][CH3:25])=[C:11]([CH:20]=[N:21][OH:22])[N:12]=[CH:13][C:14]=2[NH:15]3)=[CH:4][CH:3]=1.[Cl:28][O-].[Na+].[CH3:31][O:32][CH2:33][C:34]#[CH:35]>O1CCCC1.C(OCC)(=O)C>[Cl:28][C:19]1[C:7]([CH2:6][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:27][CH:26]=2)=[C:8]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14]1[CH:13]=[N:12][C:11]([C:20]3[CH:35]=[C:34]([CH2:33][O:32][CH3:31])[O:22][N:21]=3)=[C:10]([CH2:23][O:24][CH3:25])[C:9]2=1
Reactant: COCc1c(C=NO)ncc2[nH]c3cccc(Cc4ccc(Cl)cc4)c3c12
Reactant: C#CCOC
Reactant: [O-]Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COCc1cc(-c2ncc3[nH]c4ccc(Cl)c(Cc5ccc(Cl)cc5)c4c3c2COC)no1
Reaction time: 0.33 h
Yield: 5 %

Procedure:
0.5 g (0.0013 mol) 5-(4-chlorobenzyl)-4-methoxymethyl-β-carboline-3-carbaldehyde-oxime is suspended in 25 ml of tetrahydrofuran and mixed with 5 ml of sodium hypochlorite solution under protective gas (argon). After 20 minutes no more initial material can be detected by thin-layer chromatography. 0.7 ml of methylpropargylether is instilled over 2.5 hours then the mixture is stirred for another hour. After it is left standing overnight it is diluted with ethyl acetate, washed neutral with water, dried and concentrated by evaporation. From the evaporation residue 0.031 g (5% of theory) of 6-chloro-5-(4-chlorobenzyl)-4-methoxymethyl-3-(5-methoxymethylisoxazol-3-yl)-β-carboline, melting point 198°-200° C., is obtained by chromatography on silica gel and recrystallization from ethanol/ether.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([O:13][CH3:14])=[CH:11][C:6]2=[N:7][C:8](=[S:10])[N:9]=[C:5]2[CH:4]=1.Cl[C:16]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:17]=1[N+:24]([O-:26])=[O:25].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:1][O:2][C:3]1[C:12]([O:13][CH3:14])=[CH:11][C:6]2[NH:7][C:8]([S:10][C:16]3[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:17]=3[N+:24]([O-:26])=[O:25])=[N:9][C:5]=2[CH:4]=1
Reactant: COc1ccc([N+](=O)[O-])c(Cl)c1
Reactant: COc1cc2c(cc1OC)=NC(=S)N=2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc([N+](=O)[O-])c(Sc2nc3cc(OC)c(OC)cc3[nH]2)c1

Procedure:
5,6-Dimethoxy benzimidazole-2-thione (4.0 g), 2-chloro-4-methoxy nitrobenzene (3.6 g) and potassium carbonate (2.65 g) were stirred together in dry dimethyl formamide (30 ml) at 95° for 3 days. The cooled mixture was poured onto water (300 ml) and the precipitate collected. The solid was washed with water and dried to leave the sub-title compound as a pale yellow solid, MS 361 bp 207.
Reaction SMILES: C([N:11]1[CH2:18][C@@H:17]([O:19][CH3:20])[CH2:16][C@H:12]1[C:13]([OH:15])=[O:14])(OCC1C=CC=CC=1)=O.CO.[H][H]>[Pd].O>[CH3:20][O:19][C@@H:17]1[CH2:18][NH:11][C@H:12]([C:13]([OH:15])=[O:14])[CH2:16]1
Reactant: CO[C@H]1C[C@@H](C(=O)O)N(C(=O)OCc2ccccc2)C1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: O
Product: CO[C@@H]1CN[C@H](C(=O)O)C1

Procedure:
A mixture of 6.8 g. of N-carbobenzyloxy-cis-4-methoxy-L-proline, 210 ml. of 2:1 methanol and water, and 2.3 g. of 5% Pd-C is placed on a hydrogenator at 3 atmospheres of hydrogen for four hours. The mixture is filtered to remove the catalyst and the filtrate evaporated to give 3.15 g. of a grayish solid; m.p. 218°-220° (dec.). A sample is crystallized from methanol-ether to yield colorless cis-4-methoxy-L-proline, m.p. 224°-226° (dec.), [α]D25 -42° (c, 1% in methanol).