Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(S([O:16][S:17]([C:20]([F:32])([F:31])[C:21]([F:30])([F:29])[C:22]([F:28])([F:27])[C:23]([F:26])([F:25])[F:24])(=[O:19])=[O:18])(=O)=O)C(F)(F)C(F)(F)C(F)(F)F.[C:34]1([S:40]([N:43]2[C:47]3[CH:48]=[N:49][C:50]([C:53]#[N:54])=[C:51](O)[C:46]=3[C:45]3[CH:55]=[C:56]([C:59]4[CH:60]=[N:61][N:62]([CH3:64])[CH:63]=4)[CH:57]=[N:58][C:44]2=3)(=[O:42])=[O:41])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.N1C=CC=CC=1.Cl>C(Cl)Cl>[C:34]1([S:40]([N:43]2[C:47]3[CH:48]=[N:49][C:50]([C:53]#[N:54])=[C:51]([O:16][S:17]([C:20]([F:31])([F:32])[C:21]([F:30])([F:29])[C:22]([F:27])([F:28])[C:23]([F:24])([F:25])[F:26])(=[O:18])=[O:19])[C:46]=3[C:45]3[CH:55]=[C:56]([C:59]4[CH:60]=[N:61][N:62]([CH3:64])[CH:63]=4)[CH:57]=[N:58][C:44]2=3)(=[O:41])=[O:42])[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: Cn1cc(-c2cnc3c(c2)c2c(O)c(C#N)ncc2n3S(=O)(=O)c2ccccc2)cn1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cn1cc(-c2cnc3c(c2)c2c(OS(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)c(C#N)ncc2n3S(=O)(=O)c2ccccc2)cn1
Temperature: 25 °C
Reaction time: 4 h
Yield: 84.2 %

Procedure:
1,1,2,2,3,3,4,4,4-Nonafluorobutanesulfonic anhydride (0.75 g, 0.40 mL, 1.3 mmol) was added dropwise to a suspension of 9-benzenesulfonyl-5-hydroxy-3-(1-methyl-1H-pyrazol-4-yl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile (106 mg, 0.25 mmol) in pyridine (0.7 mL, 8.0 mmol) and dry DCM (7 mL) at 0° C. The reaction mixture was then allowed to warm to ambient temperature and stirred for 4 h. The reaction mixture was treated with 1N hydrochloric acid (6 mL) and the phases were separated. The aqueous phase was extracted with DCM (2×10 mL), the combined organic phase was dried over anhydrous magnesium sulfate and concentrated in vacuo. The resultant residue was purified by chromatography (silica, 2 g column, Si-SPE, gradient of DCM/EtOAc) and further trituration with pentane (2 mL) to afford the title compound as a white solid (150 mg, 84%). 1H NMR (CDCl3, 400 MHz): 9.95 (s, 1H), 8.99 (d, J=2.1 Hz, 1H), 8.74 (d, J=2.1 Hz, 1H), 8.35-8.32 (m, 2H), 7.86 (d, J=0.8 Hz, 1H), 7.74-7.68 (m, 2H), 7.61-7.56 (m, 2H), 4.04 (s, 3H). LCMS (Method G): RT=4.80 min, M+H+=713.
Reaction SMILES: C([S:4][CH2:5][CH2:6][CH2:7][C:8]([N:10]1[C@H:20]([C:21]([OH:23])=[O:22])[CH2:19][C:12]2([C:16](=[O:17])[CH2:15][CH2:14][C:13]2=[O:18])[CH2:11]1)=[O:9])(=O)C.N>>[SH:4][CH2:5][CH2:6][CH2:7][C:8]([N:10]1[C@H:20]([C:21]([OH:23])=[O:22])[CH2:19][C:12]2([C:16](=[O:17])[CH2:15][CH2:14][C:13]2=[O:18])[CH2:11]1)=[O:9]
Reactant: CC(=O)SCCCC(=O)N1CC2(C[C@H]1C(=O)O)C(=O)CCC2=O
Agent: N
Product: O=C(O)[C@@H]1CC2(CN1C(=O)CCCS)C(=O)CCC2=O

Procedure:
The product from part (a) is hydrolyzed with concentrated ammonia according to the procedure of Example 2 to yield (8S)-7-(4-mercapto-1-oxobutyl)-1,4-dioxo-7-azaspiro[4.4]nonane-8-carboxylic acid.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[C:7]([CH:12]=[C:13]([O:18][CH:19]([CH3:21])[CH3:20])[C:14]=1[N+:15]([O-])=O)[C:8]([O:10][CH3:11])=[O:9])([CH3:3])[CH3:2]>CO.C(O)=O.[Pd]>[NH2:15][C:14]1[C:13]([O:18][CH:19]([CH3:21])[CH3:20])=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][C:5]=1[O:4][CH:1]([CH3:3])[CH3:2]
Reactant: COC(=O)c1cc(OC(C)C)c([N+](=O)[O-])c(OC(C)C)c1
Agent: [Pd]
Solvent: CO
Solvent: O=CO
Product: COC(=O)c1cc(OC(C)C)c(N)c(OC(C)C)c1
Yield: 74.4 %

Procedure:
Methyl 3,5-diisopropoxy-4-nitrobenzoate (3) (594 mg, 2.00 mmol) was dissolved in a mixture of MeOH (40 mL) and formic acid (5 mL) and was passed through a Thales ‘H-cube’ cartridge (10% Pd/C) at a flow rate of 1 mL/min at 40° C. under H2 (full H2 mode). The solvents were removed in vacuo to yield methyl 4-amino-3,5-diisopropoxybenzoate (4) (398 mg, 72%) as a pale yellow oil: 1H NMR (400 MHz, CDCl3) δ: 7.20 (2H, s), 4.59 (2H, sep), 4.23 (2H, br s), 3.83 (3H, s), 1.33 (12H, d).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]([C:10]([O:12][CH3:13])=[O:11])[CH2:7][C:6]=2[CH:14]=1.Cl[C:16]1[N:21]=[C:20]([NH:22][C:23]2[CH:28]=[C:27]3[O:29][CH2:30][O:31][C:24]=2[C:25]([F:33])=[C:26]3[F:32])[C:19]([F:34])=[CH:18][N:17]=1>>[CH3:13][O:12][C:10]([CH:8]1[CH2:7][C:6]2[CH:14]=[C:2]([NH:1][C:16]3[N:21]=[C:20]([NH:22][C:23]4[CH:28]=[C:27]5[O:29][CH2:30][O:31][C:24]=4[C:25]([F:33])=[C:26]5[F:32])[C:19]([F:34])=[CH:18][N:17]=3)[CH:3]=[CH:4][C:5]=2[O:9]1)=[O:11]
Reactant: Fc1cnc(Cl)nc1Nc1cc2c(F)c(F)c1OCO2
Reactant: COC(=O)C1Cc2cc(N)ccc2O1
Product: COC(=O)C1Cc2cc(Nc3ncc(F)c(Nc4cc5c(F)c(F)c4OCO5)n3)ccc2O1

Procedure:
In like manner to the preparation of (±)-N4-(3,4-difluorophenyl)-N2-(2,3-dihydro-2-methoxycarbonylbenzofuran-5-yl)-5-fluoro-2,4-pyrimidinediamine, the reaction of (±)-5-amino-2,3-dihydro-2-methoxycarbonylbenzofuran with 2-chloro-N4-(3,4-difluoromethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine gave (±)-N2-(2,3-dihydro-2-methoxycarbonylbenzofuran-5-yl)-N4-(3,4-difluoromethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine. 1H NMR (DMSO-d6): δ 10.36 (bs, 1H), 9.93 (bs, 1H), 8.22 (d, 1H, J=4.8 Hz), 7.91 (bs, 1H), 7.38 (m, 3H), 7.15 9bd, 1H, J=8.7 Hz), 6.79 (d, 1H, J=6.0 Hz), 5.33 (dd, 1H, J=6.3 and 6.6 Hz), 3.69 (s, 3H), 3.50 (dd, 1H, J=10.5 and 10.8 Hz), 3.22 (dd, 1H, J=6.0 Hz); LCMS: purity: 100%; MS (m/e): 461 (MH+).
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:9]([CH2:15][O:16][C:17](=[O:19])[CH3:18])[O:8][C@@H:7]([O:20][C@@H:21]2[C@H:30]([O:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C@@H:29]([O:39][CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[C@H:28]([CH3:47])[O:27][C@H:22]2[O:23]CC=C)[C@@H:6]1[NH:48][C:49](=[O:54])[C:50]([Cl:53])([Cl:52])[Cl:51])(=[O:3])[CH3:2]>O1CCCC1>[C:1]([O:4][C@H:5]1[C@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:9]([CH2:15][O:16][C:17](=[O:19])[CH3:18])[O:8][C@@H:7]([O:20][C@@H:21]2[C@H:30]([O:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C@@H:29]([O:39][CH2:40][C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=3)[C@H:28]([CH3:47])[O:27][C@H:22]2[OH:23])[C@@H:6]1[NH:48][C:49](=[O:54])[C:50]([Cl:53])([Cl:52])[Cl:51])(=[O:3])[CH3:2]
Reactant: C=CCO[C@@H]1O[C@@H](C)[C@H](OCc2ccccc2)[C@@H](OCc2ccccc2)[C@H]1O[C@@H]1O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1NC(=O)C(Cl)(Cl)Cl
Solvent: C1CCOC1
Product: CC(=O)OC[C@H]1O[C@@H](O[C@@H]2[C@H](OCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](C)O[C@H]2O)[C@H](NC(=O)C(Cl)(Cl)Cl)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.1 %

Procedure:
1,5-Cyclooctadiene-bis(methyldiphenylphosphine)iridium hexafluorophosphate (120 mg, 140 μmol) was dissolved tetrahydrofuran (10 mL), and the resulting red solution was degassed in an argon stream. Hydrogen was then bubbled through the solution, causing the colour to change to yellow. The solution was then degassed again in an argon stream. A solution of 317 (1.46 g, 1.75 mmol) in tetrahydrofuran (20 mL) was degassed and added. The mixture was stirred at rt overnight. The mixture was concentrated. The residue was taken up in acetone (27 mL), and water (3 mL) was added. Mercuric bromide (949 mg, 2.63 mmol) and mercuric oxide (761 mg, 3.5 mmol) were added to the mixture, protected from light. The mixture was stirred for 2 h at rt, then concentrated. The residue was taken up in CH2Cl2 and washed three times with sat. aq. KI, then with brine. The organic phase was dried and concentrated. The residue was purified by column chromatography (cyclohexane-EtOAc 4:1) to give 318 (1.13 g, 81%) as a white foam. [α]D+4° (c 1, CHCl3). 1H NMR: δ 7.35-7.05 (m, 10H, Ph), 6.74 (d, 1H, J2,NH=8.5 Hz, NHD), 5.10 (d, 1H, J1,2=1.1 Hz, H-1A), 5.02 (m, 2H, H-3D, 4D), 4.80-4.50 (m, 4H, CH2Ph), 4.61 (d, 1H, J1,2=8.5 Hz, H-1D), 4.15-4.08 (m, 2H, J5,6=4.5, J6a,6b=12.3 Hz, H-6aD, 6bD), 4.00 (m, 1H, H-2D), 3.90 (dd, 1H, J2,3=3.3, H-2A), 3.86 (dd, 1H, J3,4=9.5 Hz, H-3A), 3.85 (dq, 1H, J4,5=9.5, J5,6=6.2 Hz, H-5A), 3.50 (m, 1H, H-5D), 3.30 (pt, 1H, H-4A), 2.85 (d, 1H, J1,OH=3.5 Hz, OH), 2.02, 1.97, 1.94 (3s, 9H, OAc), 1.23 (d, 3H, H-6A); 13C NMR: δ 171.1, 170.0, 169.6, 162.1 (C═O), 138.5-127.1 (Ph), 101.7 (C-1D), 94.1 (C-1A), 92.6 (CCl3), 81.4 (C-4A), 79.9 (C-2A), 77.3 (C-3A), 75.9, 74.1 (2C, CH2Ph), 72.7 (C-3D), 72.5 (C-5D), 68.6 (C-4D), 68.4 (C-5A), 62.2 (C-6D), 56.1 (C-2D), 21.1, 21.0, 20.9 (3C, OAc), 18.3 (C-6A). FAB-MS for C34H40Cl3NO13 (M, 775), m/z 789 [M+Na]+. Anal. Calcd for C34H40Cl3NO13: C, 52.55; H, 5.19; N, 1.80%. Found: C, 52.48; H, 5.37; N, 1.67%.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:23])[CH2:6][CH2:7][N:8]([C:12](=[O:22])[C:13]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[C:15]([Cl:21])[CH:14]=1)[CH:9]([CH3:11])[CH3:10].Cl>O1CCOCC1>[Cl:21][C:15]1[CH:14]=[C:13]([CH:18]=[C:17]([O:19][CH3:20])[CH:16]=1)[C:12]([N:8]([CH:9]([CH3:11])[CH3:10])[CH2:7][CH2:6][C:5]([OH:23])=[O:4])=[O:22]
Reactant: COC(=O)CCN(C(=O)c1cc(Cl)cc(OC)c1)C(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COc1cc(Cl)cc(C(=O)N(CCC(=O)O)C(C)C)c1
Yield: 98.4 %

Procedure:
2M Aqueous sodium hydroxide (4.5 ml) was added to a stirred solution of 3-[(3-chloro-5-methoxy-benzoyl)-isopropyl-amino]-propionic acid methyl ester (1.50 g) in 1,4-dioxan (30 ml). 2M aqueous hydrochloric acid (4.5 ml) was added after 20 h. The reaction mixture was evaporated and the residue partitioned between ethyl acetate and water. The aqueous layer was removed and the organic phase was dried with brine and over sodium sulphate and then concentrated under reduced pressure to give the title compound (1.41 g) as a brown solid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1)#[N:2].C(O)(=O)[CH2:10][CH:11]([CH3:13])[CH3:12].FC(F)(F)C(O)=O.[OH-].[Na+]>[N+]([O-])([O-])=O.[Ag+].ClC1C=CC=CC=1.O>[C:1]([C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH2:10][CH:11]([CH3:13])[CH3:12])[CH:4]=1)#[N:2]
Reactant: N#Cc1ccncc1
Reactant: CC(C)CC(=O)O
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Agent: [Na+]
Solvent: Clc1ccccc1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)Cc1cc(C#N)ccn1
Temperature: 0 °C
Yield: 53.1 %

Procedure:
p-cyanopyridine (8.00 g, 76.8 mmol) was added to a 1:1 mixture of chlorobenzene/water (1.5 L) in a 2 L round-bottom flask. Isovaleric acid (21.74 g, 212.8 mmol), (NH4)2S2O8 (34.40 g, 150.7 mmol), trifluoroacetic acid (8.78 g, 77.0 mmol) and AgNO3 (1.040 g, 6.1 mmol) were added and the heterogeneous mixture was vigorously stirred and refluxed for 2 h. The reaction was cooled down to 0° C. and 8 M NaOH was added slowly until pH 9-10. The mixture was filtered through Celite and extracted with EtOAc (×3). The combined organic extracts were dried with MgSO4 and the solvent removed in vacuo. The dark-brown oil was purified via flash chromatography (1:4 EtOAc/Hexane) to give a brown oil (6.538 g, 54%);
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:16]2[CH2:15][CH2:14][N:13]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)[CH:12]([CH2:26][N:27]3C(=O)C4C(=CC=CC=4)C3=O)[C:11]=2[S:10][C:9]=1[NH2:38])=[O:7])([CH3:4])([CH3:3])[CH3:2].NN>C(O)C>[C:1]([O:5][C:6]([C:8]1[C:16]2[CH2:15][CH2:14][N:13]([CH2:17][C:18]3[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=3)[CH:12]([CH2:26][NH2:27])[C:11]=2[S:10][C:9]=1[NH2:38])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(CN2CCc3c(sc(N)c3C(=O)OC(C)(C)C)C2CN2C(=O)c3ccccc3C2=O)cc1
Agent: NN
Solvent: CCO
Product: COc1ccc(CN2CCc3c(sc(N)c3C(=O)OC(C)(C)C)C2CN)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 84.4 %

Procedure:
In a 500 ml round-bottom flask, a suspension of 2-amino-7-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-6-(4-methoxy-benzyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester (5.00 g, 9.4 mmol) in absolute ethanol (200 ml) was flushed with nitrogen. The reaction mixture was stirred at room temperature and hydrazine (1.5 ml, 47.8 mmol) was added. The reaction mixture was heated to 80° C. for 6 hours and then cooled to room temperature. After 14 hours at room temperature, the precipitate was filtered off and washed with absolute ethanol. The mother liquid was concentrated in vacuo and the residue was dissolved in dichloromethane (75 ml) and refiltered to remove an additional precipitate. Concentration of the mother liquid afforded 3.2 g (85%) of 2-amino-7-aminomethyl-6-(4-methoxy-benzyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester as a solid.
Reaction SMILES: [O-]S(S([O-])=O)=O.[Na+].[Na+].[Br:9][C:10]1[CH:46]=[C:45]([CH3:47])[C:13]([O:14][C:15]2[C:20]([N+]([O-])=O)=[C:19](/[CH:24]=[CH:25]/[N:26](C)C)[N:18]=[C:17]([N:29]([C:37]3[CH:42]=[CH:41][C:40]([C:43]#[N:44])=[CH:39][CH:38]=3)[C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[N:16]=2)=[C:12]([CH3:48])[CH:11]=1>O.C1COCC1>[Br:9][C:10]1[CH:46]=[C:45]([CH3:47])[C:13]([O:14][C:15]2[C:20]3[NH:26][CH:25]=[CH:24][C:19]=3[N:18]=[C:17]([N:29]([C:37]3[CH:42]=[CH:41][C:40]([C:43]#[N:44])=[CH:39][CH:38]=3)[C:30](=[O:36])[O:31][C:32]([CH3:34])([CH3:33])[CH3:35])[N:16]=2)=[C:12]([CH3:48])[CH:11]=1
Reactant: Cc1cc(Br)cc(C)c1Oc1nc(N(C(=O)OC(C)(C)C)c2ccc(C#N)cc2)nc(/C=C/N(C)C)c1[N+](=O)[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(Br)cc(C)c1Oc1nc(N(C(=O)OC(C)(C)C)c2ccc(C#N)cc2)nc2cc[nH]c12
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of Na2S2O4 (40.04 g, 230 mmol) in water (100 ml) was added to a solution of (E)-tert-butyl 4-(4-bromo-2,6-dimethylphenoxy)-6-(2-(dimethylamino)vinyl)-5-nitropyrimidin-2-yl(4-cyanophenyl)carbamate (28.0 g, 45.9 mmol) in THF (300 ml). The mixture was stirred at room temperature of 2 days. The reaction mixture was concentrated. The residue was washed with water and extracted with ethyl acetate. The organic layer was concentrated and the product was obtained by crystallization from a mixture of water and methanol (18.15 g (mmol, 74%). 1H NMR (CDCl3, 400 MHz) δ 1.33 (s, 9H), 2.05 (s, 6H), 6.73 (d, J=3.8 Hz, 1H), 7.18 (d, J=8.8 Hz, 2H), 7.21 (s, 2H), 7.49 (d, J=8.8, 2H), 7.55 (d, J=3.8 Hz, 1H), 9.09 (s, 1H).
Reaction SMILES: C([O:3][C:4](=[O:19])[CH:5]([O:16][CH2:17][CH3:18])[CH2:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[CH:10]2)C.Cl[CH2:21][C:22]1[N:23]=[C:24]([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)[O:25][C:26]=1[CH3:27]>>[CH2:17]([O:16][CH:5]([CH2:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH2:21][C:22]1[N:23]=[C:24]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)[O:25][C:26]=1[CH3:27])[CH:11]=[CH:10]2)[C:4]([OH:3])=[O:19])[CH3:18]
Reactant: Cc1oc(-c2ccc(F)cc2)nc1CCl
Reactant: CCOC(=O)C(Cc1ccc2[nH]ccc2c1)OCC
Product: CCOC(Cc1ccc2c(ccn2Cc2nc(-c3ccc(F)cc3)oc2C)c1)C(=O)O
Yield: 39 %

Procedure:
Starting from rac-2-ethoxy-3-(1H-indol-5-yl)-propionic acid ethyl ester and 4-chloromethyl-2-(4-fluoro-phenyl)-5-methyl-oxazole, the title compound was obtained in 39% yield as a colourless solid. MS: (M+H)30 423.3.
Reaction SMILES: O=[C:2]([C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][CH2:17][N:18]2[CH2:23][CH2:22][N:21]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=3)[CH2:20][CH2:19]2)=[CH:10][CH:9]=1)[CH2:3][CH2:4][C:5](O)=[O:6].[CH2:34]([NH2:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>>[CH2:34]([N:41]1[CH:2]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][N:21]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:31])([F:33])[F:32])[CH:25]=4)[CH2:20][CH2:19]3)=[CH:10][CH:9]=2)[CH2:3][CH2:4][C:5]1=[O:6])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: NCc1ccccc1
Reactant: O=C(O)CCC(=O)c1ccc(CCCCN2CCN(c3cccc(C(F)(F)F)c3)CC2)cc1
Product: O=C1CCC(c2ccc(CCCCN3CCN(c4cccc(C(F)(F)F)c4)CC3)cc2)N1Cc1ccccc1

Procedure:
4-Oxo-4-[4-(4-(4-(3-trifluoromethylphenyl)piperazin-1-yl)butyl)phenyl]butyric acid and benzylamine are reacted together to give N-benzyl-5-[4-(4-(4-(3-trifluoromethylphenyl)piperazin-1-yl)butyl)phenyl ]pyrrolidin-2-one.
Reaction SMILES: [CH3:1][N:2]([CH3:20])[CH2:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][C:11]([O:18][CH3:19])=[C:12]([N+:15]([O-])=O)[CH:13]=2)[CH2:8][CH2:7]1)=[O:5].O.NN>CO.[Fe](Cl)(Cl)Cl>[CH3:20][N:2]([CH2:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][C:11]([O:18][CH3:19])=[C:12]([NH2:15])[CH:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:1]
Reactant: COc1cc2c(cc1[N+](=O)[O-])N(C(=O)CN(C)C)CC2
Agent: Cl[Fe](Cl)Cl
Agent: NN
Solvent: CO
Solvent: O
Product: COc1cc2c(cc1N)N(C(=O)CN(C)C)CC2
Temperature: 60 °C
Yield: 62 %

Procedure:
To a solution of N,N-dimethyl-2-[5-(methyloxy)-6-nitro-2,3-dihydro-1H-indol-1-yl]-2-oxoethanamine (1.0 g, 3.58 mmol) in methanol (30 mL) was added activated carbon (1.0 g), iron (III) chloride (0.120 mg, 0.2 equiv.) and hydrazine hydrate (0.800 mL, 25 mmol, 7.0 equiv.). The resulting slurry was warmed to 60° C. and maintained overnight. The next morning the reaction was filtered, taken to a residue under reduced pressure, and partitioned between ethyl acetate and brine. The organic layer was dried over sodium sulfate. Volatiles were removed and the derived 1-[(dimethylamino)acetyl]-5-(methyloxy)-2,3-dihydro-1H-indol-6-amine was isolated as a white solid of sufficient purity for use in subsequent transformations (0.550 g, 2.20 mmol, 62% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.23 (s, 6 H), 2.95 (t, J=8.43 Hz, 2 H), 3.11 (s, 2 H), 3.68 (s, 3 H), 4.05 (t, J=8.25 Hz, 2 H), 4.61 (s, 2 H), 6.68 (s, 1 H), 7.53 (s, 1 H).
Reaction SMILES: C(O[C:6]([C:8]1[N:9]=[C:10]([Br:26])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[C:13]([S:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH:12]=2)=[O:7])CCC.[NH2:27][CH2:28][C:29]([OH:31])=[O:30].C[O-].[Na+]>>[Br:26][C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[C:13]([S:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:12]=2)[C:17]([OH:18])=[C:8]([C:6]([NH:27][CH2:28][C:29]([OH:31])=[O:30])=[O:7])[N:9]=1
Reactant: CCCCOC(=O)c1nc(Br)c2cc(Sc3ccccc3)ccc2c1O
Reactant: NCC(=O)O
Agent: C[O-]
Agent: [Na+]
Product: O=C(O)CNC(=O)c1nc(Br)c2cc(Sc3ccccc3)ccc2c1O

Procedure:
216 mg of 1-bromo-4-hydroxy-7-phenylsulfanyl-isoquinoline-3-carboxylic acid butyl ester (0.5 mmol) from Example D-1 e) were reacted with glycine and sodium methylate analogously to Example D-1 g). 192 mg of the title compound were obtained; 1H NMR (DMSO-d6): δ=9.15 (t, 1H), 8.22 (d, 1H), 7.52 to 7.74 (m, 7H), 4.01 (d, 2H).
Reaction SMILES: C[O-].[Na+].[CH3:4][O:5][CH2:6][CH2:7][CH2:8][NH:9][C:10]([NH2:12])=[S:11].[C:13]([CH2:15][C:16](OCC)=[O:17])#[N:14]>C(O)C>[NH2:14][C:13]1[N:9]([CH2:8][CH2:7][CH2:6][O:5][CH3:4])[C:10](=[S:11])[NH:12][C:16](=[O:17])[CH:15]=1
Reactant: CCOC(=O)CC#N
Reactant: COCCCNC(N)=S
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Product: COCCCn1c(N)cc(=O)[nH]c1=S
Yield: 48.3 %

Procedure:
Sodium methoxide (0.81 g, 21.2 mmol, 1.05 eq.) was added to a solution of 3-methoxypropylthiourea (3.00 g, 20.2 mmol) in ethanol (10 mL). Ethyl cyanoacetate (2.18 mL, 20.2 mmol) in ethanol (10 mL) was added and the resulting white slurry was heated to reflux for 2.5 h. The solvent was evaporated and the remaining pale brown oil was treated with 2M acetic acid (15 mL,). The white crystals were filtered off and washed with acetic acid to give the title compound (2.10 g, 48%).
Reaction SMILES: CC1C=CC(S(O[C:12]2[CH:21]=[CH:20][C:19]3[C:18](=[O:22])[CH2:17][CH2:16][CH2:15][C:14]=3[CH:13]=2)(=O)=O)=CC=1.[NH:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26][CH2:25][CH2:24]1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1COCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[N:23]1([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[C:18](=[O:22])[CH2:17][CH2:16][CH2:15]3)[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26][CH2:25][CH2:24]1
Reactant: Cc1ccc(S(=O)(=O)Oc2ccc3c(c2)CCCC3=O)cc1
Reactant: c1ccc2c(c1)CCCN2
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Product: O=C1CCCc2cc(N3CCCc4ccccc43)ccc21
Yield: 76.4 %

Procedure:
To a solution of 5-oxo-5,6,7,8-tetrahydronaphthalen-2-yl 4-methylbenzene-1-sulfonate (1.0 g, 3.4 mmol) in THF (20 mL) was added 1,2,3,4-tetrahydroquinoline (0.55 g, 4.1 mmol), Pd(OAc)2 (92 mg, 0.41 mmol), BINAP (383 mg, 0.61 mmol) and Cs2CO3 (1.7 g, 5.1 mmol). The mixture was heated to reflux under nitrogen overnight. The mixture was filtered and concentrated, and the residue was purified by silica gel chromatography (10% EtOAc/hexanes) to give 0.72 g (76%) of the title compound as a brown oil. 1H NMR (400 MHz, CDCl3): δ 7.94 (d, J=8.4 Hz, 1H), 7.18-7.04 (m, 4H), 6.97 (d, J=2.4 Hz, 1H), 6.90 (dt, J=7.6 Hz, 1.2 Hz, 1H), 3.69 (t, J=6.0 Hz, 2H), 2.87 (t, J=6.0 Hz, 2H), 2.77 (t, J=6.4 Hz, 2H), 2.61 (t, J=6.4 Hz, 2H), 2.14-2.08 (m, 2H), 2.05-1.98 (m, 2H). [M+H] calc'd for C19H19NO, 278. found 278.
Reaction SMILES: [NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([O:12][CH3:13])[CH:3]=1.C(N(CC)CC)C.ClC(OCC)=O.[CH3:27][N:28]([CH2:30][CH:31]1[CH:36]([NH2:37])[CH:35]2[CH2:38][CH2:39][N:32]1[CH2:33][CH2:34]2)[CH3:29]>C(Cl)Cl>[NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([NH:37][CH:36]2[CH:35]3[CH2:38][CH2:39][N:32]([CH2:33][CH2:34]3)[CH:31]2[CH2:30][N:28]([CH3:29])[CH3:27])=[O:8])=[C:4]([O:12][CH3:13])[CH:3]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Reactant: CN(C)CC1C(N)C2CCN1CC2
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(N)c(Cl)cc1C(=O)NC1C2CCN(CC2)C1CN(C)C
Temperature: -55 °C
Reaction time: 0.75 h
Yield: 72.8 %

Procedure:
A solution of 4-amino-5-chloro-2-methoxybenzoic acid (2.22 g, 11 mmoles) and triethylamine (1.12 g, 11 mmoles) in anhydrous methylene chloride (35 ml) under nitrogen was cooled (0° C.) and treated dropwise with ethyl chloroformate (1.2 g, 11 mmoles). After 45 minutes at 0° C., the solution was cooled (-55° C.) and treated dropwise with 2-(dimethylaminomethyl)-1-azabicyclo[2.2.2]octan-3-amine (2.11 g, 11.5 mmoles) in 7 ml of methylene chloride. The solution was warmed to 25° C. over one hour, stirred for one hour, and diluted with methylene chloride to a total volume of 100 ml. The organic solution was washed with 1.0N sodium hydroxide (2×35 ml), saturated aqueous sodium bicarbonate (35 ml), and brine (35 ml), dried (Na2SO4), and concentrated in vacuo to provide 2.94 g (73%) of an oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([N+:29]([O-:31])=[O:30])[CH:24]=1)[CH2:10][CH2:11]OS(C1C=CC(C)=CC=1)(=O)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C-:32]#[N:33].[Na+].O>CN(C=O)C>[C:1]([O:5][C:6](=[O:7])[NH:8][CH:9]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([N+:29]([O-:31])=[O:30])[CH:24]=1)[CH2:10][CH2:11][C:32]#[N:33])([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1ccc(S(=O)(=O)OCCC(NC(=O)OC(C)(C)C)c2cccc([N+](=O)[O-])c2)cc1
Reactant: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC(CCC#N)c1cccc([N+](=O)[O-])c1
Temperature: 60 °C
Reaction time: 5 h

Procedure:
1.88 g (4.16 mmol) Toluene-4-sulfonic acid 3-tert-butoxycarbonylamino-3-(3-nitro-phenyl)-propyl ester were dissolved in 5 ml DMF and 306 mg (6.24 mmol) sodium cyanide were added. The mixture was stirred for 5 h at 60° C. The reaction mixture was poured into 50 ml water, the precipitate was filtered, washed with water and dried in vacuo. The crude product was used without further purification.