Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:12]([NH:15]C(=O)C)([CH3:14])[CH3:13])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1>Cl.O>[NH2:15][C:12]([C:4]1[CH:3]=[C:2]([CH:7]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:5]=1)[NH2:1])([CH3:14])[CH3:13]
Reactant: CC(=O)NC(C)(C)c1cc(N)cc(C(F)(F)F)c1
Agent: Cl
Solvent: O
Product: CC(C)(N)c1cc(N)cc(C(F)(F)F)c1
Temperature: 25 °C
Yield: 31.8 %

Procedure:
A solution of N-{1-[3-amino-5-(trifluoromethyl)phenyl]-1-methylethyl}acetamide (1.07 g, 4.11 mmol) in 6N HCl (20 mL) was heated at 110° C. for 18 h, then allowed to cool to rt and diluted with water. The mixture was washed with EtOAc and the aqueous solution was neutralized by the addition of 1N NaOH and washed again with EtOAc. The aqueous solution was further basified to pH 10-11 by addition of 1N NaOH and extracted with EtOAc (2×). The extracts were dried over Na2SO4, filtered and concentrated to give 3-(1-amino-1-methylethyl)-5-(trifluoromethyl)aniline as a brown oil (285 mg, 31.8%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([C@@H:21]([CH2:29][CH3:30])/[CH:22]=[CH:23]/[S:24]([CH2:27][CH3:28])(=[O:26])=[O:25])[C:11](=[O:31])[C@:10]([CH2:33][CH:34]3[CH2:38][O:37][C:36]([CH3:40])([CH3:39])[O:35]3)([CH3:32])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1>ClCCCl.C1CCC(P(C2CCCCC2)C2CCCCC2)CC1.C1CC=CCCC=C1.C1C=CN=CC=1.F[P-](F)(F)(F)(F)F.[Ir]>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=3)[N:12]([C@@H:21]([CH2:29][CH3:30])[CH2:22][CH2:23][S:24]([CH2:27][CH3:28])(=[O:25])=[O:26])[C:11](=[O:31])[C@:10]([CH2:33][CH:34]3[CH2:38][O:37][C:36]([CH3:40])([CH3:39])[O:35]3)([CH3:32])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC[C@@H](/C=C/S(=O)(=O)CC)N1C(=O)[C@@](C)(CC2COC(C)(C)O2)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Agent: [Ir]
Agent: C1=C\CC/C=C\CC/1
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Solvent: c1ccncc1
Solvent: ClCCCl
Solvent: C1=CCCC=CCC1
Product: CC[C@@H](CCS(=O)(=O)CC)N1C(=O)[C@@](C)(CC2COC(C)(C)O2)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of (3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-1-((S,E)-1-(ethylsulfonyl)pent-1-en-3-yl)-3-methylpiperidin-2-one (65.0 mg, 0.107 mmol; Example 205, Step B) in 1,2-dichloroethane (1.07 mL) at 25° C. was added Crabtree's catalyst (7.74 mg, 9.61 μmol). The reaction system (a hydrogenation bomb) was flushed with hydrogen gas 3×, pressurized with hydrogen at 3447.38 kilopascal, and the reaction was stirred at 25° C. for 24 hours. The reaction mixture was filtered through celite, washed with DCM, and concentrated under reduced pressure to yield the title compound as an off-white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[NH:24][CH:23]=[CH:22]4)[N:15]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].C(OC1C=C(C2ON=C(C3C=CC=C4C=3C=CN4)N=2)C=CC=1OCC)C>>[Cl:1][C:2]1[CH:3]=[C:4]([C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[NH:24][CH2:23][CH2:22]4)[N:15]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCOc1ccc(-c2nc(-c3ccc4[nH]ccc4c3)no2)cc1Cl
Agent: CCOc1ccc(-c2nc(-c3cccc4[nH]ccc34)no2)cc1OCC
Product: CCCCCOc1ccc(-c2nc(-c3ccc4c(c3)CCN4)no2)cc1Cl
Yield: 100 %

Procedure:
When the product of Step C was substituted for 5-(3,4-diethoxyphenyl)-3-(1H-indol-4-yl)-1,2,4-oxadiazole in Example 34, Step C, the identical process afforded the title compound in 100% yield. 1H-NMR (CDCl3) 0.94 (tr, 3H, J=7.11 Hz); 1.44-1.54 (m, 4H); 1.66-2.03 (m, 2H); 3.45 (tr, 2H, J=8.16 Hz); 3.65 (tr, 2H, J=7.83 Hz); 4.11 (tr, 2H, J=6.51 Hz); 6.75 (d, 1H, J=7.68 Hz); 7.00 (d, 1H, J=8.67 Hz); 7.20 (tr, 1H, J=6.24 Hz); 7.51 (broad d, 1H, J=7.77 Hz); 8.04 (dd, 1H, J=2.13, 8.64 Hz); 8.21 (d, 1H, J=2.1 Hz).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]2)[CH:3]=1.[C:26]1([NH2:33])[CH:31]=[CH:30][CH:29]=[C:28]([NH2:32])[CH:27]=1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O1CCOCC1>[O:24]=[S:16]1(=[O:25])[C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[CH2:19][N:13]([C:4]2[CH:3]=[C:2]([NH:32][C:28]3[CH:29]=[CH:30][CH:31]=[C:26]([NH2:33])[CH:27]=3)[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=3)[N:5]=2)[CH2:14][CH2:15]1
Reactant: Nc1cccc(N)c1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(Cl)c2c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(Nc3cccc(N)c3)c2c1
Temperature: 140 °C

Procedure:
A mixture of 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (150 mg, 0.40 mmol, prepared in analogy to the one in Example 2-1), benzene-1,3-diamine (86 mg, 0.80 mmol), palladium acetate (18 mg, 0.04 mmol), 2,2′-bis(diphenylphosphino)-1,1′-binaphthalene (50 mg, 0.04 mmol), potassium phosphate (169.6 mg, 0.8 mmol) and 1,4-dioxane (3 mL) in a 2-5 mL of process vial was heated at 140° C. under microwave irradiation for 1.5 hours. After being cooled to room temperature, the mixture was filtered and washed with ethyl acetate. The filtrate was washed with brine, dried over sodium sulfate, and concentrated in vacuo. The residue was purified by preparative HPLC to afford the pure product as a solid. MS obsd. (ESI+) [(M+H)+] 445, 1H NMR (400 MHz, DMSO-d6) δ ppm 8.31 (s, 1 H), 7.88 (dd, J=6.06, 1.52 Hz, 2 H), 7.63 (td, J=7.52, 1.14 Hz, 1 H), 7.54-7.46 (m, 1 H), 7.42-7.33 (m, 2 H), 7.33-7.27 (m, 1 H), 7.16 (t, J=7.83 Hz, 1 H), 6.52 (t, J=1.89 Hz, 1 H), 6.49-6.34 (m, 3 H), 5.23 (s, 2 H), 4.86 (s, 2 H), 3.60 (brs, 2 H), 2.38 (s, 3 H).
Reaction SMILES: [CH2:1](C([Sn])=C(CCCC)CCCC)[CH2:2]CC.[CH2:16]([O:18][C:19]([C:21]1[CH:22]=[N:23][C:24]2[C:29]([C:30]=1Cl)=[CH:28][CH:27]=[CH:26][C:25]=2[Cl:32])=[O:20])[CH3:17]>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.C1(C)C=CC=CC=1>[CH2:16]([O:18][C:19]([C:21]1[CH:22]=[N:23][C:24]2[C:29]([C:30]=1[CH:1]=[CH2:2])=[CH:28][CH:27]=[CH:26][C:25]=2[Cl:32])=[O:20])[CH3:17]
Reactant: CCOC(=O)c1cnc2c(Cl)cccc2c1Cl
Reactant: CCCCC([Sn])=C(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=Cc1c(C(=O)OCC)cnc2c(Cl)cccc12
Reaction time: 2 h

Procedure:
Tributylvinyltin (2.8 ml) and tetrakistriphenylphosphinepalladium (171 mg) were added to a toluene solution (20 ml) containing 2.0 g (7.4 mmol) of ethyl-4,8-dichloroquinoline-3-carboxylate obtained in the same manner as in Production Example 4b, followed by stirring for 2 hours under heating under reflux. The reaction solution was filtered through Celite and the filtrate was concentrated. Then, the residue was purified by silica gel chromatography, to give 1.92 g of the title compound.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[Cl:13][C:14]1[C:15]([CH3:31])=[N:16][O:17][C:18]=1[NH:19][S:20]([C:23]1[CH:27]=[CH:26][S:25][C:24]=1[C:28]([OH:30])=O)(=[O:22])=[O:21].N1C=CN=C1.Cl.CNOC.Cl[CH2:43][C:44]1[C:52]([CH3:53])=[CH:51][C:47]2[O:48][CH2:49][O:50][C:46]=2[CH:45]=1.[Mg]>O1CCCC1>[Cl:13][C:14]1[C:15]([CH3:31])=[N:16][O:17][C:18]=1[NH:19][S:20]([C:23]1[CH:27]=[CH:26][S:25][C:24]=1[C:28](=[O:30])[CH2:53][C:52]1[C:44]([CH3:43])=[CH:45][C:46]2[O:50][CH2:49][O:48][C:47]=2[CH:51]=1)(=[O:21])=[O:22]
Reactant: Cc1noc(NS(=O)(=O)c2ccsc2C(=O)O)c1Cl
Reactant: Cc1cc2c(cc1CCl)OCO2
Agent: CNOC
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: Cc1cc2c(cc1CC(=O)c1sccc1S(=O)(=O)Nc1onc(C)c1Cl)OCO2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 11.8 %

Procedure:
1,1′-carbonyldiimidazole (600 mg) was added to a solution of 3-[(4-chloro-3-methyl-5-isoxazolyl)sulfamoyl]-2-thiophenecarboxylic acid (900 mg, 2.79 mmol) in anhydrous tetrahydrofuran (20 mL). The mixture was stirred at ambient temperature for about 15 minutes and then sequentially treated with imidazole (380 mg, 5.58 mmol) and N,O-dimethylhydroxylamine hydrochloride (420 mg, 4.3 mmol). Under continuous stirring, the mixture was maintained at ambient temperature for about 4 hours. The solvent was removed in vacuo and the residue was partitioned between ethyl acetate (100 mL) and 1 N hydrochloric acid (30 mL). The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated. The resulting residue was treated with toluene and re-concentrated. The resulting red oil was dissolved in anhydrous tetrahydrofuran (20 mL), cooled to about 0° C., and then treated with a Grignard reagent prepared from 5-chloromethyl-6-methyl-benzo[1,3]dioxole (800 mg, 4.36 mmol) and magnesium turnings (826 mg, 34.4 mmol) in tetrahydrofuran (50 mL). Under continuous stirring, the mixture was maintained at about 0° C. for about 1 hour and then at ambient temperature for about 2 hours. At about 0° C., the reaction mixture was quenched with a mixture of concentrated hydrochloric acid (20 mL) and methanol (50 mL). The mixture was stirred at about 0° C. for about 10 minutes, and then concentrated in vacuo. The aqueous residue was partitioned between ethyl acetate (100 mL) and 1 N hydrochloric acid (30 mL). The crude product was isolated using standard extractive work up and purified by prep-TLC (eluted with CH2Cl2:MeOH=7:1) to give 2-[2-(6-methyl-benzo[1,3]dioxol-5-yl)-acetyl]-thiophene-3-sulfonic acid (4-chloro-3-methyl-isoxazol-5-yl) amide (150 mg, 30%) as a yellow solid. 1H NMR (300 MHz, CD3OD) δ 7.77 (d, J=5.1 Hz, 1H), 7.40 (d, J=5.1 Hz, 1H), 6.74 (d, J=4.2 Hz, 2H), 5.94 (s, 3H), 4.76 (s, 2H), 2.04 (s, 3H), 1.99 (s, 3H); ESI-MS: m/z=455 (MH)+; HPLC purity: 95%.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][CH2:40]O)=[CH:33][C:32]=2[CH3:42])=[C:28]([CH:43]([CH3:45])[CH3:44])[NH:27][N:26]=1)(=O)C.[NH2:46][C:47]([CH3:53])([CH3:52])[CH2:48][C:49]([NH2:51])=[O:50].NC(C)(C)C(NCCO)=O>>[C:49]([CH2:48][C:47]([NH:46][CH2:40][CH2:39][CH2:38][O:37][C:34]1[CH:35]=[CH:36][C:31]([CH2:30][C:29]2[C:25]([O:24][C@@H:6]3[O:7][C@H:8]([CH2:19][OH:20])[C@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]3[OH:4])=[N:26][NH:27][C:28]=2[CH:43]([CH3:45])[CH3:44])=[C:32]([CH3:42])[CH:33]=1)([CH3:53])[CH3:52])(=[O:50])[NH2:51]
Reactant: CC(C)(N)CC(N)=O
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(OCCCO)cc2C)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Agent: CC(C)(N)C(=O)NCCO
Product: Cc1cc(OCCCNC(C)(C)CC(N)=O)ccc1Cc1c(O[C@@H]2O[C@H](CO)[C@H](O)[C@H](O)[C@H]2O)n[nH]c1C(C)C

Procedure:
The title compound was prepared in a similar manner to that described in Example 72 using 3-(2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyloxy)-4-{[4-(3-hydroxypropoxy)-2-methylphenyl]methyl}-5-isopropyl-1H-pyrazole and 3-amino-3-methylbutyramide instead of 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-{[4-(3-hydroxypropoxy)phenyl]-methyl}-5-isopropyl-1H-pyrazole and 2-[2-amino-2-(methyl)-propionylamino]ethanol, respectively.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH2:6][CH2:7][Cl:8])=[O:3].[NH2:9][C:10]1[N:42]=[C:13]2[C:14]([C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([C:38]([F:41])([F:40])[F:39])[CH:33]=3)=[C:15]([CH3:31])[C:16]([C:18]3[N:22]([C:23]4[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=4)[N:21]=[CH:20][CH:19]=3)=[CH:17][N:12]2[N:11]=1.N1C=CC=CC=1>C1COCC1>[Cl:8][CH2:7][CH2:6][CH2:5][O:4][C:2](=[O:3])[NH:9][C:10]1[N:42]=[C:13]2[C:14]([C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([C:38]([F:40])([F:41])[F:39])[CH:33]=3)=[C:15]([CH3:31])[C:16]([C:18]3[N:22]([C:23]4[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=4)[N:21]=[CH:20][CH:19]=3)=[CH:17][N:12]2[N:11]=1
Reactant: O=C(Cl)OCCCCl
Reactant: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)cn2nc(N)nc2c1-c1cccc(C(F)(F)F)c1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)cn2nc(NC(=O)OCCCCl)nc2c1-c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 98.9 %

Procedure:
3-Chloropropyl chloroformate (133 μL, 1.089 mmol) was added to a mixture of 4-{5-[2-amino-7-methyl-8-(3-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-6-yl]-pyrazol-1-yl}-benzonitrile (Ex. 1, 100 mg, 0.218 mmol) and pyridine (107 μL, 1.308 mmol) in THF (3 mL) and the mixture was stirred rapidly for 20 mins at RT then heated at 60° C. 20 mins using microwave irradiation. The reaction mixture was concentrated in vacuo to give the title compound (125 mg of impure product contains chloroformate).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6](F)[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([NH2:12])=O.[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:15]=1[CH2:21][C:22]([NH2:24])=[O:23]>>[C:9]1([C@H:21]2[C@H:21]([C:15]3[C:14]([Cl:13])=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:20])[C:22](=[O:23])[NH:24][C:22]2=[O:23])[C:3]2=[C:4]3[C:5](=[CH:6][CH:7]=[CH:2]2)[CH2:19][CH2:14][CH2:15][N:12]3[CH:10]=1
Reactant: NC(=O)Cc1ccc(F)cc1Cl
Reactant: NC(=O)Cc1c(Cl)cccc1Cl
Product: O=C1NC(=O)[C@@H](c2cn3c4c(cccc24)CCC3)[C@@H]1c1c(Cl)cccc1Cl

Procedure:
(±)-Trans-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1yl)-4-(2,6-dichlorophenyl)pyrrolidine-2,5-dione was prepared according to Example 40 replacing 2-chloro-4-fluorophenylacetamide with 2,6-dichlorophenylacetamide. Yield 52.2 mg, 13.0%. 1H NMR (DMSO-d6) 400 MHz δ: 11.82 (s, 1H), 7.34 (m, 3H), 7.10 (d, 1H, J=7.2 Hz), 6.87 (m, 2H), 5.16 (d, 1H J=7.6 Hz), 5.10 (d, 1H, J=7.6 Hz), 2.91 (t, 2H, J=6.0 Hz) 2.10 (m, 2H).
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][OH:7])(=[O:3])[CH3:2].[Si:8](Cl)([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9].N1C=CN=C1.O>CN(C=O)C>[C:11]([Si:8]([CH3:10])([CH3:9])[O:7][CH2:6][CH2:5][CH2:4][C:1](=[O:3])[CH3:2])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(=O)CCCO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)CCCO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 66 h
Yield: 58.6 %

Procedure:
A solution of 3-acetyl-1-propanol (3.000 g, 29.37 mmol), tert-butyldimethylsilyl chloride (4.522 g, 30.00 mmol), and imidazole (5.004 g, 73.5 mmol) in DMF (40 mL) was heated at 40° C. for 5 h and was stirred at room temperature for 66 h. Water (60 mL) was added and the product was extracted into EtOAc (4×50 mL). The combined organic extracts were washed with water (2×50 mL), dried over MgSO4, filtered, and concentrated. Purification by flash chromatography (hexanes:EtOAc 9:1) provided the title compound (3.722 g). 1H NMR (400 MHz, CDCl3) δ 3.59 (t, 2H), 2.49 (t, 2H), 2.13 (s, 3H), 1.76 (m, 2H), 0.86 (s, 9H), 0.02 (s, 6H); MS 217 (M+1).
Reaction SMILES: C(OC([N:8]1[C:12]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)=[C:11]([CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[C:10]2[S:26][C:27]([C:29]([O:31]C)=[O:30])=[CH:28][C:9]1=2)=O)(C)(C)C.[OH-].[Na+]>C(Cl)Cl.C(O)(C(F)(F)F)=O.CO>[Cl:19][C:16]1[CH:15]=[CH:14][C:13]([C:12]2[NH:8][C:9]3[CH:28]=[C:27]([C:29]([OH:31])=[O:30])[S:26][C:10]=3[C:11]=2[CH:20]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]2)=[CH:18][CH:17]=1
Reactant: COC(=O)c1cc2c(s1)c(C1CCCCC1)c(-c1ccc(Cl)cc1)n2C(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CO
Product: O=C(O)c1cc2[nH]c(-c3ccc(Cl)cc3)c(C3CCCCC3)c2s1
Reaction time: 0.17 h
Yield: 53 %

Procedure:
A solution (0.5 M) of methyl 4-(tert-butoxycarbonyl)-5-(4-chlorophenyl)-6-cyclohexyl-4H-thieno[3,2-b]pyrrole-2-carboxylate in DCM/TFA (1:1) was stirred at RT for 1 h. Evaporation of the solvent gave a solid that was dissolved in MeOH. The resulting solution (0.1N) was treated with aqueous NaOH (1 N solution, 12 eq.). The mixture was heated to reflux for 3 h then concentrated and acidified to pH 1 with aqueous HCl (1 N), the aqueous solution was diluted with MeCN and purified by RP-HPLC (Conditions: Waters X-TERRA MS C18, 5 micron, 19×150 mm; flow: 15 mL/min; Gradient: A: H2O+0.05% TFA; B: MeCN+0.05% TFA; 60% A isocratic for 2 min then linear to 0% A in 10 min) to afford the title compound (53%) as a solid.
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[O:2].[Br:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21]2[C:22]([C:30]([NH:32][NH2:33])=[O:31])=[CH:23][N:24]([CH3:29])[C:25](=[O:28])[C:26]=2[CH3:27])=[C:16]([F:34])[CH:15]=1>CN(C=O)C.C(OCC)(=O)C>[Br:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21]2[C:22]([C:30]3[O:31][C:1](=[O:2])[NH:33][N:32]=3)=[CH:23][N:24]([CH3:29])[C:25](=[O:28])[C:26]=2[CH3:27])=[C:16]([F:34])[CH:15]=1
Reactant: Cc1c(Nc2ccc(Br)cc2F)c(C(=O)NN)cn(C)c1=O
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1c(Nc2ccc(Br)cc2F)c(-c2n[nH]c(=O)o2)cn(C)c1=O
Reaction time: 1 h

Procedure:
1,1′-Carbonyldiimidazole (275 mg, 1.70 mmol) was added to a stirred solution of 4-(4-bromo-2-fluorophenylamino)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid hydrazide (728 mg, 1.62 mmol (82% pure material)) in DMF (2 mL). After 1 hour, the reaction mixture was diluted with ethyl acetate and washed with brine. Some of the product precipitated and was collected by filtration. The filtrate was diluted with 1 N HCl and the layers separated. The aqueous layer was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (MgSO4) and concentrated under reduced pressure. The resulting residue was triturated with diethyl ether to give the desired product which was combined with the earlier obtained product. The combined yield of clean desired product was 482 mg (75%); MS APCI (−) m/z 393, 395 (M−, Br pattern) detected; 1H NMR (400 MHz, DMSO-d6) δ 8.22 (s, 1H), 7.88 (s, 1H), 7.50 (dd, 1H), 7.21 (d, 1H), 6.59 (t, 1H), 3.52 (s, 3H), 1.76 (s, 3H).
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH3:18]O>>[C:1]1([NH:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([O:14][CH3:18])=[O:13])=[CH:10][CH:9]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CO
Reactant: O=C(O)c1ccc(Nc2ccccc2)cc1
Agent: Cl
Product: COC(=O)c1ccc(Nc2ccccc2)cc1

Procedure:
30 ml of 10% hydrogen chloride-methanol was added to 1.59 g (7.46 mmol) of 4-(phenylamino)benzoic acid and the mixture was refluxed overnight under heating. After the reaction mixture was concentrated under reduced pressure, the residue was dissolved in ethyl acetate, washed with a sodium hydrogencarbonate aqueous solution and brine, and dried (MgSO4). The solvent was distilled off and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=5:1 (v/v)) to obtain 1.66 g (7.30 mmol) of methyl 4-(phenylamino)benzoate as a pale yellow solid. Its spectroscopic data are as follows:
Reaction SMILES: C[O:2][C:3](=[O:32])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12][CH2:13][CH:14]=[C:15]([C:23]2[CH:28]=[CH:27][C:26]([Br:29])=[CH:25][CH:24]=2)[C:16]2[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][CH:17]=2)=[CH:8][C:7]=1[CH2:30][CH3:31].[OH-].[Na+].Cl>C(O)C>[Br:29][C:26]1[CH:25]=[CH:24][C:23]([C:15]([C:16]2[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][CH:17]=2)=[CH:14][CH2:13][S:12][C:9]2[CH:10]=[CH:11][C:6]([O:5][CH2:4][C:3]([OH:32])=[O:2])=[C:7]([CH2:30][CH3:31])[CH:8]=2)=[CH:28][CH:27]=1
Reactant: CCc1cc(SCC=C(c2ccc(Br)cc2)c2ccc(Br)cc2)ccc1OCC(=O)OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCc1cc(SCC=C(c2ccc(Br)cc2)c2ccc(Br)cc2)ccc1OCC(=O)O
Temperature: 5 °C
Reaction time: 18 h

Procedure:
{4-[3,3-Bis-(4-bromo-phenyl)-allylsulfanyl]-2-ethyl-phenoxy}-acetic acid methyl ester (350 mg, 0.6 mmol, example 21) was dissolved in ethanol (10 ml). 1N NaOH (3 ml, 3 mmol) was added at room temperature and the reaction mixture was stirred for 18 h at 5° C. after which it was treated with 1N HCl (15 ml) and extracted with dichloromethane (2×20 ml). The combined organic phases were dried and evaporated to give the title compound in 130 mg (68%) yield.
Reaction SMILES: [Cl:1][C:2]1[C:12]([Cl:13])=[CH:11][CH:10]=[C:9]([Si:14]([CH3:17])([CH3:16])[CH3:15])[C:3]=1[C:4]([NH:6]CC)=[O:5].[CH2:18]([O:21]N)[CH:19]=[CH2:20]>>[Cl:1][C:2]1[C:12]([Cl:13])=[CH:11][CH:10]=[C:9]([Si:14]([CH3:15])([CH3:16])[CH3:17])[C:3]=1[C:4]([NH:6][O:21][CH2:18][CH:19]=[CH2:20])=[O:5]
Reactant: C=CCON
Reactant: CCNC(=O)c1c([Si](C)(C)C)ccc(Cl)c1Cl
Product: C=CCONC(=O)c1c([Si](C)(C)C)ccc(Cl)c1Cl
Yield: 86 %

Procedure:
The acid prepared in Example 203 was converted to the acid chloride by the procedure of example b. The acid chloride was reacted with aq O-allylhydroxylamine using General Method E1 to afford the title compound. Purification by recrystallization from ether/hexanes gave 0.68 g of the title compound as a white solid in 86% yield. m.p. 92°-94° C.
Reaction SMILES: II.[Mg].Br[C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:7]([F:17])[CH:6]=1.[C:18](=[O:20])=[O:19].Cl>O1CCCC1>[F:17][C:7]1[CH:6]=[C:5]([C:18]([OH:20])=[O:19])[CH:10]=[CH:9][C:8]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Fc1cc(Br)ccc1-c1ccccc1
Reactant: O=C=O
Agent: Cl
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: O=C(O)c1ccc(-c2ccccc2)c(F)c1
Temperature: 65 °C

Procedure:
Few crystals of iodine are added to tetrahydrofuran (1400 mL) containing magnesium turnings (25.17 g, 1.035 mol). The mixture is heated at 60-70° C. A solution of 4-bromo-2-fluorobiphenyl (200 g, 0.797 mol) in tetrahydrofuran (600 mL) is added dropwise to the reaction mixture and refluxed for 1 hr. Reaction mixture is brought to room temperature and then cooled to −20° C. Carbon dioxide gas is passed through the reaction mixture for 45 minutes. The reaction mixture is treated with 3N HCl (500 mL) and extracted with ethyl acetate (2×500 mL). Combined organic layer is dried over sodium sulphate. Removal of solvent under reduced pressure gives a solid which is washed with diethyl ether (2×200 mL) and then dried to furnish 2-fluorobiphenyl-4-carboxylic acid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH2:9][O:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)[N:3]=1.[CH3:17][O:18][C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[S:27]([N:30]=[C:31]=[O:32])(=[O:29])=[O:28])=[O:20]>CCOCC>[CH3:8][C:6]1[CH:5]=[C:4]([CH2:9][O:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)[N:3]=[C:2]([NH:1][C:31]([NH:30][S:27]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[C:19]([O:18][CH3:17])=[O:20])(=[O:29])=[O:28])=[O:32])[N:7]=1
Reactant: COC(=O)c1ccccc1S(=O)(=O)N=C=O
Reactant: Cc1cc(COC2CCCCO2)nc(N)n1
Solvent: CCOCC
Product: COC(=O)c1ccccc1S(=O)(=O)NC(=O)Nc1nc(C)cc(COC2CCCCO2)n1
Reaction time: 3 h
Yield: 88.7 %

Procedure:
To a solution of 3.25 g of the product from Example 3 in 50 ml of ether was added 3.75 g of 2-methoxycarbonylbenzenesulfonyl isocyanate and the mixture was stirred for 3 hours under nitrogen. The precipitated product was filtered and washed with ether to afford 6.0 g of the title compound, m.p. 126°-128° (d).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[N:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]=O)[CH:10]=1.[BH4-].[Na+]>CO>[Br:1][C:2]1[CH:3]=[C:4]([NH:5][CH2:15][C:11]2[CH:10]=[N:9][CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: O=Cc1cccnc1
Reactant: Nc1cccc(Br)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Brc1cccc(NCc2cccnc2)c1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A solution of 3-bromoaniline (Aldrich; 1.3 equiv.) in methanol (0.4 M) was treated with 3-pyridinecarboxaldehyde (Aldrich; 1.0 equiv.). The solution was heated to reflux for 2 hours. The reaction was cooled to 0° C. and treated slowly with sodium borohydride (3.4 equiv.). After 1 hour the cooling bath was removed and stirring continued overnight. The reaction was concentrated in vacuo. The residue was partitioned between DCM and water. The aqueous phase was back-extracted once with DCM. The combined organics were washed with water and brine. The organic layer was concentrated to a white solid, which was purified via column chromatography eluting with 90:10 DCM/ethyl acetate to give N-(3-bromophenyl)pyridin-3-ylmethylamine. Anal Calcd for C12H11BrN2: C, 54.77; H, 4.21; N, 10.64. Found: C, 54.67; H, 4.19; N, 10.57. MS found 262.99, 264.99 [M+H]+