Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[O:3]1[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][NH:11][CH:12]([C:16]2([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)[CH2:19][CH2:18][CH2:17]2)[CH2:13][O:14][CH3:15])[CH2:5][CH2:4]1.[CH:27](O)=O.C=O>C(OCC)(=O)C>[CH3:27][N:11]([CH:12]([C:16]1([C:20]2[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=2)[CH2:17][CH2:18][CH2:19]1)[CH2:13][O:14][CH3:15])[CH2:10][CH2:9][N:6]1[CH2:5][CH2:4][O:3][CH2:8][CH2:7]1
Reactant: COCC(NCCN1CCOCC1)C1(c2ccc(Cl)cc2)CCC1
Reactant: O=CO
Agent: C=O
Agent: Cl
Solvent: CCOC(C)=O
Product: COCC(N(C)CCN1CCOCC1)C1(c2ccc(Cl)cc2)CCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of the product of Example 208 in the form of its free base (2.0 g), 98% formic acid (8 ml) and 37-40% aqueous formaldehyde solution (25 ml) was stirred at room temperature for 2 hours. The mixture was then heated at 95°-100° C. for 18 hours, cooled, basified and extracted with ether. The extract was washed with water and dried. Dry hydrogen chloride gas was passed into the ethereal solution. Evaporation of the solvent gave a residue which was heated with ethyl acetate (20 ml) to give a white solid which was partitioned between ether and water. The aqueous phase was basified and then extracted with ether. The extract was dried and evaporated to give a residue which was distilled using a Buchi Kugelrohr apparatus (200° C./0.5 mm) to give N-methyl-N-(2-morpholinoethyl)-1-[1-(4-chlorophenyl)cyclobutyl]-2-methoxyethylamine.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][C:6]1[NH:7][C:8]([CH3:28])=[C:9]([C:24]([O:26][CH3:27])=[O:25])[CH:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:23])[C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13].[N:29]1([C:35](Cl)=[O:36])[CH2:33][CH2:32][NH:31][C:30]1=[O:34]>C(Cl)(Cl)Cl.C(N(CC)CC)C>[Cl:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[CH:10]1[C:9]([C:24]([O:26][CH3:27])=[O:25])=[C:8]([CH3:28])[NH:7][C:6]([CH2:5][O:4][CH2:3][CH2:2][NH:1][C:35]([N:29]2[CH2:33][CH2:32][NH:31][C:30]2=[O:34])=[O:36])=[C:11]1[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: O=C(Cl)N1CCNC1=O
Reactant: CCOC(=O)C1=C(COCCN)NC(C)=C(C(=O)OC)C1c1ccccc1Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C1=C(COCCNC(=O)N2CCNC2=O)NC(C)=C(C(=O)OC)C1c1ccccc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 55.4 %

Procedure:
To a solution of 2-(2-aminoethoxymethyl)-4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine (1.0 g) in a mixture of chloroform (dried over alumina) (20 ml) and triethylamine (2 ml) was added imidazolidin-2-on-1-yl carbonyl chloride (0.36 g) in one portion and the mixture stirred at room temperature for 18 hours. After evaporation to dryness, the resultant oil was partitioned between 5% aqueous sodium carbonate and methylene chloride. The combined organic liquors were dried (MgSO4), filtered and evaporated to give 0.7 g of a yellow oil which crystallised from diisopropyl ether on standing to give pure title compound, (0.4 g), m.p. 145° C. Found: C, 54.94; H, 5.62; N, 10.62. C24H29ClN4O7 requires C, 55.33; H, 5.61; N, 10.76%.
Reaction SMILES: C[CH:2]1N(CC2C=CC=CC=2)C(=O)N(C2C=CC(Cl)=CC=2)[C:3]1=[O:4].[CH2:23]([O:25][C:26](=[O:53])[C@H:27]1[CH2:31][CH:30]([O:32]S(C2C=CC(C)=CC=2)(=O)=O)[CH2:29][N:28]1[S:43]([C:46]1[CH:51]=[CH:50][C:49]([CH3:52])=[CH:48][CH:47]=1)(=[O:45])=[O:44])[CH3:24]>C1(C)C=CC=CC=1.C([O-])(=O)C.C[N+](C)(C)C>[CH2:23]([O:25][C:26](=[O:53])[C@H:27]1[CH2:31][CH:30]([O:32][C:3](=[O:4])[CH3:2])[CH2:29][N:28]1[S:43]([C:46]1[CH:51]=[CH:50][C:49]([CH3:52])=[CH:48][CH:47]=1)(=[O:44])=[O:45])[CH3:24]
Reactant: CCOC(=O)[C@H]1CC(OS(=O)(=O)c2ccc(C)cc2)CN1S(=O)(=O)c1ccc(C)cc1
Reactant: CC1C(=O)N(c2ccc(Cl)cc2)C(=O)N1Cc1ccccc1
Agent: CC(=O)[O-]
Agent: C[N+](C)(C)C
Solvent: Cc1ccccc1
Product: CCOC(=O)[C@H]1CC(OC(C)=O)CN1S(=O)(=O)c1ccc(C)cc1
Yield: 72.8 %

Procedure:
To 218 g (466 mmol) of allo-1-(4-toluenesulfonyl)- 4-(4-toluenesulfonyloxy)-D-proline ethyl ester in 1500 ml of toluene was added 81 g (606 mmol) of tetramethyl ammonium acetate and the mixture was heated to reflux for 2 hours. The reaction was cooled, washed with 2x500 ml of water and dried over sodium sulfate. Evaporation of the solvent and drying the resulting solids in a vacuum oven overnight at 30° C. provided 120.6 g of product (72% yield). M.P.=82°-83° C.
Reaction SMILES: [C:1]1(/[C:7](/[C:17]2[CH:22]=[CH:21][C:20]([CH:23]=[CH:24][C:25](O)=[O:26])=[CH:19][CH:18]=2)=[C:8](/[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)\[CH2:9][CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:28][C:29]1[CH:30]=[C:31]([S:35]([NH2:38])(=[O:37])=[O:36])[CH:32]=[CH:33][CH:34]=1>>[Cl:28][C:29]1[CH:30]=[C:31]([S:35]([NH:38][C:25](=[O:26])[CH:24]=[CH:23][C:20]2[CH:21]=[CH:22][C:17]([C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[C:8]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:9][CH3:10])=[CH:18][CH:19]=2)(=[O:36])=[O:37])[CH:32]=[CH:33][CH:34]=1
Reactant: NS(=O)(=O)c1cccc(Cl)c1
Reactant: CC/C(=C(\c1ccccc1)c1ccc(C=CC(=O)O)cc1)c1ccccc1
Product: CCC(=C(c1ccccc1)c1ccc(C=CC(=O)NS(=O)(=O)c2cccc(Cl)c2)cc1)c1ccccc1

Procedure:
Prepared by coupling 1a and 3-chlorobenzenesulfonamide in accordance with Procedure 1, Method B described hereinabove. Yield (25%); 1H NMR (d6-DMSO) δ 12.36 (s, 1H), 7.88-7.76 (m, 3H), 7.63 (t, J=8.1 Hz, 1H), 7.42-7.07 (m, 13H), 6.84 (d, J=8.0 Hz, 2H), 6.40 (d, J=15.7 Hz, 1H), 2.36 (q, J=7.3 Hz, 2H), 0.82 (t, J=7.3 Hz, 3H); APcI m/z: 527 (M−H−).
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:18])[C:10]1[CH:15]=[C:14]([I:16])[CH:13]=[C:12]([OH:17])[CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:25]([O:27][C:28](=[O:53])[CH2:29][CH2:30][CH2:31][O:32][C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44]Br)[C:34]=1[CH2:46][CH2:47][C:48]([O:50][CH2:51][CH3:52])=[O:49])[CH3:26]>CC(C)=O.CN(C=O)C>[CH2:25]([O:27][C:28](=[O:53])[CH2:29][CH2:30][CH2:31][O:32][C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][O:17][C:12]2[CH:13]=[C:14]([I:16])[CH:15]=[C:10]([C:9](=[O:18])[NH:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:11]=2)[C:34]=1[CH2:46][CH2:47][C:48]([O:50][CH2:51][CH3:52])=[O:49])[CH3:26]
Reactant: O=C(NCc1ccccc1)c1cc(O)cc(I)c1
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCBr)c1CCC(=O)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(I)cc(C(=O)NCc3ccccc3)c2)c1CCC(=O)OCC
Temperature: 75 °C
Reaction time: 48 h
Yield: 100.8 %

Procedure:
To a solution of N-benzyl-3-hydroxy-5-iodo-benzamide (4.1 g) in a mixture of acetone and DMF (2:1, 100 mL) were added potassium carbonate (16.0 g) and 4-[3-(6-bromo-hexyl)-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (6.0 g). The resulting mixture was stirred at 75° C. for 2 days. Then the insoluble material was filtered out and the filtrate was diluted with ethyl acetate and washed with water and brine. The organic extract was dried over anhydrous sodium sulfate, concentrated and purified on a silica gel column using ethyl acetate and hexanes to yield 8.7 g of yellow oil (100% yield).
Reaction SMILES: [F:1][C:2]1[C:11]([F:12])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:14]3[CH:15]=[N:16][C:17]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:18][CH:19]=3)[C:8]=2[F:13])[C:3]=1[OH:27].[F:28][C@@H:29]([CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH2:30]O>>[CH2:21]([O:20][C:17]1[CH:18]=[CH:19][C:14]([C:7]2[CH:6]=[CH:5][C:4]3[C:9](=[CH:10][C:11]([F:12])=[C:2]([F:1])[C:3]=3[O:27][CH2:30][CH:29]([F:28])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[C:8]=2[F:13])=[CH:15][N:16]=1)[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCCCCC[C@H](F)CO
Reactant: CCCCCCOc1ccc(-c2ccc3c(O)c(F)c(F)cc3c2F)cn1
Product: CCCCCCCCC(F)COc1c(F)c(F)cc2c(F)c(-c3ccc(OCCCCCC)nc3)ccc12

Procedure:
From 2,3,5-trifluoro-6-(6-hexyloxypyridin-3-yl)naphthalen-1-ol and 2-(S)-fluorodecan-1-ol by means of the Mitsunobu reaction.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[C@@H:11]1[O:28][C@H:27]([CH2:29][O:30][C:31](=[O:33])[CH3:32])[C@@H:22]([O:23][C:24](=[O:26])[CH3:25])[C@H:17]([O:18][C:19](=[O:21])[CH3:20])[C@H:12]1[O:13][C:14](=[O:16])[CH3:15].[O:34]1[CH:38]=[CH:37][C:36]2[CH:39]=[C:40]([C:43](Cl)=[O:44])[CH:41]=[CH:42][C:35]1=2>>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([C:43]([C:40]1[CH:41]=[CH:42][C:35]3[O:34][CH:38]=[CH:37][C:36]=3[CH:39]=1)=[O:44])=[CH:5][N:6]2[C@@H:11]1[O:28][C@H:27]([CH2:29][O:30][C:31](=[O:33])[CH3:32])[C@@H:22]([O:23][C:24](=[O:26])[CH3:25])[C@H:17]([O:18][C:19](=[O:21])[CH3:20])[C@H:12]1[O:13][C:14](=[O:16])[CH3:15]
Reactant: O=C(Cl)c1ccc2occc2c1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2ccc3c(F)cccc32)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Product: CC(=O)OC[C@H]1O[C@@H](n2cc(C(=O)c3ccc4occc4c3)c3c(F)cccc32)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O

Procedure:
4-Fluoro-1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-indole obtained in Example 2-(3) and benzo[b]furan-5-carbonyl chloride were treated in a manner similar to Example 2-(4) to give benzo[b]furan-5-yl 4-fluoro-1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)indol-3-yl ketone as a colorless powder. APCI-Mass m/Z 627 (M+NH4), 610 (M+H). 1H-NMR (DMSO-d6) δ 1.73 (s, 3H), 1.96 (s, 3H), 1.98 (s, 3H), 2.03 (s, 3H), 4.10 (d, J=4.0 Hz, 2H), 4.28-4.31 (m, 1H), 5.28 (t, J=9.8 Hz, 1H), 5.54 (t, J=9.6 Hz, 1H), 5.77 (t, J=9.3 Hz, 1H), 6.35 (d, J=9.2 Hz, 1H), 7.04 (dd, J=10.8, 8.0 Hz, 1H), 7.09 (d, J=1.4 Hz, 1H), 7.39 (td, J=8.1, 4.7 Hz, 1H), 7.64 (d, J=8.3 Hz, 1H), 7.75-7.77 (m, 1H), 7.82-7.84 (m, 1H), 8.14-8.15 (m, 2H), 8.17 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.[O:23]1[CH:27]=[CH:26][CH:25]=[C:24]1[C:28](O)=[O:29].Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:17]=[CH:18][C:19]([NH:22][C:28]([C:24]2[O:23][CH:27]=[CH:26][CH:25]=2)=[O:29])=[CH:20][CH:21]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: O=C(O)c1ccco1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: COc1cc2nccc(Oc3ccc(NC(=O)c4ccco4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 22 h
Yield: 48.3 %

Procedure:
6,7-Dimethoxy-4-(4-aminophenoxy)quinoline (55 mg) and commercially available 2-furancarboxylic acid (32 mg) were dissolved in N,N-dimethylformamide (2 ml), 1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide hydrochloride (91 mg) was added, and the admixture was stirred at room temperature for 22 hours. The reaction mixture was then purified in the same manner as described in Example 51 to obtain 35 mg of the title compound (yield: 48%).
Reaction SMILES: [C:1]([C:4]1[CH:26]=[CH:25][C:7]([O:8][CH2:9][C:10]2[CH:11]=[C:12]([NH:16][C:17]3[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=3)[C:20]#[N:21])[CH:13]=[CH:14][CH:15]=2)=[C:6]([CH2:27][CH2:28][CH3:29])[C:5]=1[OH:30])(=[O:3])[CH3:2].[N-:31]=[N+:32]=[N-:33].[Na+].Cl.C(N(CC)CC)C>>[OH:30][C:5]1[C:6]([CH2:27][CH2:28][CH3:29])=[C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([NH:16][C:17]3[CH:24]=[CH:23][CH:22]=[C:19]([C:20]4[N:31]=[N:32][NH:33][N:21]=4)[CH:18]=3)[CH:11]=2)[CH:25]=[CH:26][C:4]=1[C:1](=[O:3])[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CCCc1c(OCc2cccc(Nc3cccc(C#N)c3)c2)ccc(C(C)=O)c1O
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Product: CCCc1c(OCc2cccc(Nc3cccc(-c4nn[nH]n4)c3)c2)ccc(C(C)=O)c1O
Yield: 20.8 %

Procedure:
Using the general procedure for formation of tetrazole (Et3NHCl method) of Example 1 using 3-[3-(4-acetyl-3-hydroxy-2-propyl-phenoxymethyl)-phenylamino]-benzonitrile (1.36 g, 3.39 mmol), sodium azide (662 mg, 10.2 mmol), and triethylamine hydrochloride (1.40 g, 10.2 mmol) to yield the title product as a yellow solid (313 mg, 21%): 1H NMR (DMSO-d6) δ 0.791 (t, 3H), 1.43 (sextuplet, 2H), 2.57 (m, 5H), 5.24 (s, 2H), 6.72 (d, 1H), 6.98 (d, 1H), 7.08 (d, 1H), 7.24 (m, 2H), 7.32 (t, 1H), 7.44 (m, 2H), 7.79 (m, 2H), 8.55 (s, 1H), 12.84 (s, 1H); MS (esi negative) m/z (rel intensity) 442 (100).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([CH2:15][C:16]([OH:18])=O)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1.Cl.[CH3:20][NH:21][O:22][CH3:23].C(N1C=CN=C1)(N1C=CN=C1)=O.Cl>ClCCl.O>[CH3:23][O:22][N:21]([CH3:20])[C:16](=[O:18])[CH2:15][C:9]1([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]1
Reactant: CNOC
Reactant: COc1ccc(C2(CC(=O)O)CCCCC2)cc1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: ClCCl
Product: COc1ccc(C2(CC(=O)N(C)OC)CCCCC2)cc1
Temperature: 0 °C
Reaction time: 48 h
Yield: 80.2 %

Procedure:
To a solution of [1-(4-methoxy-phenyl)-cyclohexyl]-acetic acid (1.2 g) in dichloromethane (9.7 ml) was added N,O-dimethylhydroxylamine hydrochloride (577 mg). The mixture was cooled in an ice bath. 1,1′-Carbonyldiimidazole (1.01 g) was added. The mixture was stirred for 5 min at 0° C. and for 2 days at room temperature. A mixture of water and 1 M HCl was added and the mixture was extracted with ethyl acetate. The organic phase was washed with brine, dried (MgSO4), filtered and concentrated to dryness. The product was purified by chromatography (20 g NH3-modified SiO2, cyclohexane/ethyl acetate 1:0 to 3:2) to give the title compound (1.13 g) as a colorless oil, MS (ESI+): m/z=292.2 [M+H]+.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:3]=1.[CH2:14]([NH2:17])[CH:15]=[CH2:16]>>[CH2:14]([NH:17][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:3]=1)[CH:15]=[CH2:16]
Reactant: C=CCN
Reactant: N#Cc1ccc(F)cc1C(F)(F)F
Product: C=CCNc1ccc(C#N)c(C(F)(F)F)c1

Procedure:
Synthesized as described in Example 1A from 4-fluoro-2-(trifluoromethyl)benzonitrile and allylamine: MS (APCI) m/z 249 ([M+Na]+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]=[C:9]([CH3:15])[C:10]([O:12]CC)=[O:11].[OH-].[Na+].Cl>O1CCCC1>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]=[C:9]([CH3:15])[C:10]([OH:12])=[O:11]
Reactant: CCOC(=O)C(C)=Cc1ccccc1N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(=Cc1ccccc1N)C(=O)O

Procedure:
Into 10 ml of tetrahydrofuran (THF), 1.50 g (7.31 mmol) of (E) ethyl 3-(2-aminophenyl)-2-methyl-2-propenate were dissolved; and, with 10 ml of a 1-N aqueous sodium hydroxide solution being added thereto, the mixture was reacted at 40° C. for 4 hours. After the completion of the reaction was verified by TLC, the mixture was cooled with 10 ml of 1-N hydrochloric acid being added thereto. The precipitated crystal was filtered out, whereby 1.30 g of the aimed compound were obtained (quantitatively).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:6]([NH:9][C:10]1[C:11](Cl)=[C:12]2[CH:21]=[CH:20][CH:19]=[C:18]3[C:13]2=[C:14]([CH:29]=1)[C:15](=[O:28])[N:16]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:17]3=[O:22])(=[O:8])[CH3:7]>O>[C:6]([NH:9][C:10]1[C:11]([N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[C:12]2[CH:21]=[CH:20][CH:19]=[C:18]3[C:13]2=[C:14]([CH:29]=1)[C:15](=[O:28])[N:16]([O:23][C:24]([CH3:26])([CH3:25])[CH3:27])[C:17]3=[O:22])(=[O:8])[CH3:7]
Reactant: C1CCNC1
Reactant: CC(=O)Nc1cc2c3c(cccc3c1Cl)C(=O)N(OC(C)(C)C)C2=O
Solvent: O
Product: CC(=O)Nc1cc2c3c(cccc3c1N1CCCC1)C(=O)N(OC(C)(C)C)C2=O
Temperature: 100 °C
Yield: 94.8 %

Procedure:
Pyrrolidine (0.85 g, 12.0 mmol) was added to 5-acetamido-2-tert-butyloxy-6-chloro benzo[de]isoquinoline-1,3-dione (0.30 g, 0.8 mmol, from Example P2). The solution was heated at 100° C. overnight followed by addition of water (10 mL). The precipitate was filtered to give 0.30 g of the title compound.
Reaction SMILES: [CH3:1]CN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.[CH:24]1([N:28]2[CH2:33][CH2:32][N:31]([C:34]([C@@H:36]3[CH2:38][C@H:37]3[C:39]3[CH:47]=[CH:46][C:42]([C:43]([NH2:45])=[O:44])=[CH:41][CH:40]=3)=[O:35])[CH2:30][C@H:29]2[CH3:48])[CH2:27][CH2:26][CH2:25]1>CN(C=O)C>[CH:24]1([N:28]2[CH2:33][CH2:32][N:31]([C:34]([C@@H:36]3[CH2:38][C@H:37]3[C:39]3[CH:40]=[CH:41][C:42]([C:43]([NH2:45])=[O:44])=[CH:46][CH:47]=3)=[O:35])[CH2:30][C:29]2([CH3:1])[CH3:48])[CH2:25][CH2:26][CH2:27]1
Reactant: C[C@@H]1CN(C(=O)[C@@H]2C[C@H]2c2ccc(C(N)=O)cc2)CCN1C1CCC1
Reactant: CCN(C(C)C)C(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC1(C)CN(C(=O)[C@@H]2C[C@H]2c2ccc(C(N)=O)cc2)CCN1C1CCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 25.7 %

Procedure:
Intermediate 14 (282 mg, 1.38 mmol) was dissolved in DMF (15 mL). DIPEA (1.201 mL, 6.88 mmol) was added, followed by HOBT (279 mg, 2.06 mmol), EDC (395 mg, 2.06 mmol) and Intermediate 2 (278 mg, 1.65 mmol). The reaction mixture was stirred at rt for 2 h and concentrated under reduced pressure. The residue was redissolved in DCM, washed with sat NaHCO3, dried over MgSO4, filtered and concentrated under reduced pressure to give 632 mg of crude as an orange oil. The crude material was purified on preparative HPLC UV using the long high pH shallow gradient method (Mobile phase: 20-40% B; A: H2O with 10 mM NH4CO3 and 0.375% NH4OH v/v, B: CH3CN, 30 min run) on XBridge Prep C18 OBD, 50×250 mm, 10μ, Waters reverse phase column, providing 151 mg title compound (30.9%) as a solid (enantiomeric mixture). 1H NMR (400 MHz, CD3OD) δ ppm 1.01 (s, 2H) 1.08 (s, 4H) 1.34-1.43 (m, 1H) 1.55-1.70 (m, 4H) 1.96-2.12 (m, 5H) 2.25-2.37 (m, 1H) 2.40-2.48 (m, 1H) 2.61 (br. s., 2H) 3.45 (br. s., 2H) 3.75 (br. s., 1H) 7.26 (dd, J=8.20, 5.08 Hz, 2H) 7.80 (dd, J=8.40, 2.93 Hz, 2H); HRMS m/z calcd for C21H30N3O2 356.23325 [M+H]+, found 356.23286.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([N+:9]([O-:11])=[O:10])[C:3]=1[O:12][CH3:13].[C:14]([C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][CH:22]=1)([OH:16])=[O:15]>C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:8][C:6]1[CH:5]=[C:4]([N+:9]([O-:11])=[O:10])[C:3]([O:12][CH3:13])=[C:2]([C:21]2[CH:20]=[CH:19][CH:18]=[C:17]([C:14]([OH:16])=[O:15])[CH:22]=2)[CH:7]=1
Reactant: O=C(O)c1cccc(B(O)O)c1
Reactant: COc1c(Br)cc(F)cc1[N+](=O)[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COc1c(-c2cccc(C(=O)O)c2)cc(F)cc1[N+](=O)[O-]
Temperature: 120 °C
Yield: 41.7 %

Procedure:
1-Bromo-5-fluoro-2-methoxy-3-nitro-benzene 2c (16.18 g, 64.7 mmol), 3-carboxyphenylboronic acid (13.88 g, 77.7 mmol) and tetrakis(triphenylphosphine)palladium (3.73 g, 3.2 mmol) were dissolved in the solvent mixture of 65 mL of aqueous sodium carbonate (2 N) and 300 mL of 1,4-dioxane. The reaction mixture was heated to reflux at 120° C. for 24 hours. The reaction was monitored by TLC until the disappearance of the starting materials. The mixture was concentrated under reduced pressure and diluted with 150 mL of hydrochloric acid (6 N) and 200 mL of ethyl acetate. The aqueous layer was extracted with ethyl acetate (100 mL×2). The combined organic extracts were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to obtain the title compound 5′-fluoro-2′-methoxy-3′-nitro-biphenyl-3-carboxylic acid 2d (7.86 g, yield 41.7%) as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][CH2:5][CH2:6][O:7][C:8]1[C:17]([N:18]2[CH2:24][CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)=[C:16]2[C:11]([CH:12]=[CH:13][CH:14]=[N:15]2)=[CH:10][C:9]=1[CH3:25].[OH:27][CH:28]1[CH2:33][CH2:32][N:31]([C:34]2[S:35][CH:36]=[C:37]([CH:39]=O)[N:38]=2)[CH2:30][CH2:29]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl.C(Cl)Cl>[CH3:1][O:2][C:3](=[O:26])[CH2:4][CH2:5][CH2:6][O:7][C:8]1[C:17]([N:18]2[CH2:24][CH2:23][CH2:22][N:21]([CH2:39][C:37]3[N:38]=[C:34]([N:31]4[CH2:30][CH2:29][CH:28]([OH:27])[CH2:33][CH2:32]4)[S:35][CH:36]=3)[CH2:20][CH2:19]2)=[C:16]2[C:11]([CH:12]=[CH:13][CH:14]=[N:15]2)=[CH:10][C:9]=1[CH3:25]
Reactant: O=Cc1csc(N2CCC(O)CC2)n1
Reactant: COC(=O)CCCOc1c(C)cc2cccnc2c1N1CCCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: ClCCl
Product: COC(=O)CCCOc1c(C)cc2cccnc2c1N1CCCN(Cc2csc(N3CCC(O)CC3)n2)CC1
Reaction time: 1 h

Procedure:
The product from step 2 (3.63 mmol) was dissolved in 1,2-dichloroethane (7.26 mL), and 2-(4-Hydroxy-piperidin-1-yl)-thiazole-4-carbaldehyde (771 mg, 3.63 mmol) was then added. This solution was stirred for 1 h, then NaBH(OAc)3 (1.54 g, 7.26 mmol) was added. The solution was stirred for 2 h, then diluted with CH2Cl2. The solution was washed with sat. aq. NaHCO3, then brine. The organic was dried over MgSO4, filtered, and concentrated to give the crude product. This was carried on without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]O)=[CH:4][C:3]=1[C:10]([F:13])([F:12])[F:11].S(Cl)([Cl:16])=O>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][Cl:16])=[CH:4][C:3]=1[C:10]([F:13])([F:12])[F:11]
Reactant: OCc1ccc(Cl)c(C(F)(F)F)c1
Reactant: O=S(Cl)Cl
Product: FC(F)(F)c1cc(CCl)ccc1Cl
Temperature: 50 °C
Reaction time: 18 h
Yield: 97.5 %

Procedure:
(4-Chloro-3-(trifluoromethyl)phenyl)methanol (5.1 g, 24.22 mmol) was added in small portions to thionyl chloride (20 mL, 275 mmol). The reaction mixture was stirred at 50° C. for 18 h and heated under reflux for 23 h. The mixture was concentrated and dried under high vacuum to give the title compound as a colorless liquid (5.41 g). 1H NMR (400 MHz, CDCl3) δ ppm 4.58 (s, 2H), 7.50-7.51 (m, 2H), 7.71 (s, 1H).
Reaction SMILES: C(O[CH:4](OCC)[CH2:5][NH2:6])C.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N:18]=[C:19]=[S:20].Cl>C1(C)C=CC=CC=1>[CH3:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N:18]1[CH2:4][CH2:5][NH:6][C:19]1=[S:20]
Reactant: COc1ccccc1N=C=S
Reactant: CCOC(CN)OCC
Agent: Cl
Solvent: Cc1ccccc1
Product: COc1ccccc1N1CCNC1=S
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60.4 %

Procedure:
8.8 ml (0.065 mol) of aminoacetaldehyde-diethylacetal diluted in 15 ml of toluene are added, under nitrogen, to a solution of 10 g (0.065 mol) of 2-methoxyphenylisothiocyanate in 105 ml of toluene. The reaction mixture is stirred for 1 h 30 min at room temperature. 2.75 ml (0.030 mol) of hydrochloric acid at 35% are added and the mixture is stirred for 2 hours under reflux. The mixture is concentrated and water is added and the precipitate is triturated. The product is drained, washed with an ether/n-heptane mixture and dried over P2O5 overnight. 8.18 g of 1-(2-methoxyphenyl)imidazoline-2-thione are thus obtained.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][N:7]=[C:6]([CH3:10])[CH:5]=1.O.[NH2:13][NH2:14]>CO>[CH3:10][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][N:7]=1)[C:3]([NH:13][NH2:14])=[O:2]
Reactant: NN
Reactant: COC(=O)c1ccnc(C)c1
Solvent: O
Solvent: CO
Product: Cc1cc(C(=O)NN)ccn1
Temperature: 25 °C
Yield: 85.9 %

Procedure:
2-Methyl-isonicotinic acid methyl ester (316.5 mg, 2.093 mmol) was dissolved in MeOH (7 mL) under Argon and hydrazine monohydrate 98% (1 mL, 20.93 mmol) was added. The reaction was allowed to stir under Argon at room temperature for eighteen hours. The reaction was concentrated to give the title compound (271.9 mg, 86%) as a white solid. 1HNMR CDCl3 □(ppm): 8.59 (d, 1H), 7.50 (s, 1H), 7.38 (d, 1H), 3.09 (br. s, 3H), 2.60 (s, 3H).
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[O:3]1.C(O)C>C1S(=O)(=O)CCC1.[Pd]>[CH3:1][NH:2][CH2:6][CH2:5][CH:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[OH:3]
Reactant: CN1CCC(c2ccccc2)O1
Agent: [Pd]
Solvent: CCO
Solvent: O=S1(=O)CCCC1
Product: CNCCC(O)c1ccccc1
Temperature: 50 °C
Reaction time: 48 h

Procedure:
2-Methyl-5-phenylisoxazolidine (38.1 g, 234 mmol) dissolved in tetramethylene sulfone (38.1 g) is mixed with 5% Pd/C (1.9 g) in a glass pressure reactor. The reactor is warmed to 50° C. and the pressure is maintained at 40 psig with H2 for 24 hours. Ethanol (38.1 g) is added and heating is continued for 48 hours. After cooling, the mixture is filtered and the EtOH is removed to give a solution of N-methyl-3-phenyl-3-hydroxypropylamine in tetramethylene sulfone.