Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[C@@H:2]([C@H:4]1[CH2:8][O:7][C:6](=[O:9])[N:5]1[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)[CH3:3].C(N(CC)CC)C.[F:26]C(F)(S(F)(=O)=O)C(F)(F)C(F)(F)C(F)(F)F>CC#N.O>[F:26][C@H:2]([C@H:4]1[CH2:8][O:7][C:6](=[O:9])[N:5]1[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)[CH3:3]
Reactant: COc1ccc(CN2C(=O)OC[C@@H]2[C@@H](C)O)cc1
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Solvent: O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1ccc(CN2C(=O)OC[C@@H]2[C@H](C)F)cc1
Temperature: 0 °C
Reaction time: 1.17 h
Yield: 95.7 %

Procedure:
To a cooled (0° C.) solution of (R)-4-((R)-1-hydroxyethyl)-3-(4-methoxybenzyl)oxazolidin-2-one (2.27 g, 9.04 mmol) in 30 mL MeCN were added triethylamine (11.4 mL, 82 mmol) followed by perfluoro-1-butanesulfonyl fluoride (4.9 mL, 27.3 mmol) and NEt3(HF)3 (4.5 mL, 27.6 mmol) and the resulting mixture was stirred at 0° C. for 70 min. The reaction mixture was diluted with water (60 mL) and extracted with EtOAc (3×60 mL). Combined organics were washed with water (70 mL), brine (70 mL), dried over Na2SO4, filtered and concentrated. Flash column chromatography (EtOAc/heptane 5 to 70%) gave 2.19 g of the desired product. 1H NMR (400 MHz, CDCl3) δ 7.25-7.20 (m, 2H), 6.92-6.83 (m, 2H), 4.87 (d, J=15.1 Hz, 1H), 4.75 (dqd, J=47.6, 6.6, 2.1 Hz, 1H), 4.26 (td, J=9.2, 1.4 Hz, 1H), 4.17-4.05 (m, 2H), 3.81 (s, 3H), 3.71 (dddd, J=19.8, 9.5, 5.8, 2.1 Hz, 1H), 1.29 (dd, J=23.1, 6.2 Hz, 3H). MS m/z 254.5 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][C:10](=[O:18])[NH:9]2)[CH:5]=[CH:6][CH:7]=1.[S:19](Cl)([CH3:22])(=[O:21])=[O:20]>ClCCl.C(N(CC)CC)C>[OH2:18].[CH3:22][S:19]([NH:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][C:10](=[O:18])[NH:9]2)[CH:5]=[CH:6][CH:7]=1)(=[O:21])=[O:20].[CH3:22][S:19]([NH:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][C:10](=[O:18])[NH:9]2)[CH:5]=[CH:6][CH:7]=1)(=[O:21])=[O:20]
Reactant: Nc1cccc(C2NC(=O)Cc3ccccc32)c1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)Nc1cccc(C2NC(=O)Cc3ccccc32)c1
Product: O
Reaction time: 3 h
Yield: 48.7 %

Procedure:
A solution of 1-(3-aminophenyl)-1,4-dihydroisoquinol-3-one (8.0 g) in dichloromethane (500 ml) and triethylamine (50 ml) was treated dropwise, at room temperature, with a solution of mesyl chloride (9.7 g) in dichloromethane (20 ml). After stirring for 3 h, the resulting precipitate (m.p. 251°-253° C.) was collected, washed with dichloromethane, water, and air dried. The product was stirred with a mixture of 10% aqueous sodium hydroxide (200 ml) and methanol (20 ml) at 50° C. for 1 h. The mixture was filtered and the filtrate was evaporated to one third volume in vacuo. It was acidified with dilute hydrochloric acid, and the resulting precipitate was collected and washed with water. Recrystallisation from methanol-ether afforded the title compound (3.55 g)
Reaction SMILES: C(O[CH:4]=[C:5]([C:8]#[N:9])[C:6]#[N:7])C.Cl.[F:11][C:12]1[CH:13]=[CH:14][C:15]([CH3:20])=[C:16]([NH:18][NH2:19])[CH:17]=1.C(N(CC)C(C)C)(C)C>CO>[NH2:9][C:8]1[N:18]([C:16]2[CH:17]=[C:12]([F:11])[CH:13]=[CH:14][C:15]=2[CH3:20])[N:19]=[CH:4][C:5]=1[C:6]#[N:7]
Reactant: Cc1ccc(F)cc1NN
Reactant: CCOC=C(C#N)C#N
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: Cc1ccc(F)cc1-n1ncc(C#N)c1N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 19.11 %

Procedure:
(Ethoxymethylene)malononitrile (CAS no. 123-06-8) (3.18 g, 26.04 mmol) was added portionwise to the stirred solution of (5-fluoro-2-methylphenyl)hydrazine hydrochloride (CAS no. 325-50-8) (4.6 g, 26.04 mmol) and N,N-diisopropylethylamine (5.90 mL, 33.86 mmol) in MeOH (50 mL), under nitrogen at 5° C. The resulting solution was allowed to stir for a further 30 minutes at this temperature. The reaction mixture was then heated to reflux and was stirred for 3 hours. The reaction mixture was allowed to cool to ambient temperature. The reaction mixture was evaporated to dryness, redissolved in EtOAc (200 mL), washed with water (50 mL), and saturated brine (50 mL). The organic layer was dried (MgSO4), filtered and evaporated to afford crude product. This was purified by flash silica chromatography, elution gradient 0 to 50% EtOAc in isohexane to afford the product (1.076 g, 19.11%). 1H NMR (400 MHz, DMSO) δ 2.00 (3H, s), 6.56 (2H, s), 7.20 (1H, dd), 7.29 (1H, td), 7.43 (1H, t), 7.75 (1H, s); m/z (ES+) (M+H)+=217; HPLC tR=1.61 min.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH2:10][C:9](O[Si](C)(C)C)=[C:8](O[Si](C)(C)C)[CH2:7][C:6]=1[C:21]([O:23][CH3:24])=[O:22])=[O:4].[CH2:25]([N:27]([C:30]1[CH:36]=[CH:35][C:33]([NH2:34])=[CH:32][CH:31]=1)[CH2:28][CH3:29])[CH3:26]>C(O)(=O)C>[CH3:1][O:2][C:3](=[O:4])[C:5]1[C:6](=[CH:7][C:8]([NH:34][C:33]2[CH:32]=[CH:31][C:30]([N:27]([CH2:28][CH3:29])[CH2:25][CH3:26])=[CH:36][CH:35]=2)=[C:9]([NH:34][C:33]2[CH:32]=[CH:31][C:30]([N:27]([CH2:28][CH3:29])[CH2:25][CH3:26])=[CH:36][CH:35]=2)[CH:10]=1)[C:21]([O:23][CH3:24])=[O:22]
Reactant: COC(=O)C1=C(C(=O)OC)CC(O[Si](C)(C)C)=C(O[Si](C)(C)C)C1
Reactant: CCN(CC)c1ccc(N)cc1
Solvent: CC(=O)O
Product: CCN(CC)c1ccc(Nc2cc(C(=O)OC)c(C(=O)OC)cc2Nc2ccc(N(CC)CC)cc2)cc1

Procedure:
A solution of 2.4 g (6 mmol) of 4,5-bis(trimethylsilyloxy)cyclohexa-1,4-diene-1,2-dicarboxylic acid dimethyl ester (Example 1a) and 3.94 g (24 mmol) of 4-(N,N-diethylamino)-aniline in 24 ml of glacial acetic acid is boiled under reflux for 2 hours. The reaction mixture is cooled, the solvent is evaporated off and the dark-brown residue is dissolved in dichloromethane and the solution is washed in succession with 50 ml of saturated NaHCO3 and twice with 20 ml of water, dried with sodium sulfate and concentrated by evaporation. The evaporation residue is chromatographed on silica gel with dichloromethane/methanol 400:15 and the product fractions are concentrated by evaporation and again chromatographed on silica gel with ethyl acetate/hexane 1:1. The product fractions are concentrated by evaporation, yielding the title compound in the form of green crystals, FAB-MS: 518 [M+ ], 519 [M+ +H].
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[NH2:7][NH2:8].[Cl:9][C:10]1[N:15]=[C:14](Cl)[C:13]([O:17][CH3:18])=[CH:12][N:11]=1>CO.O>[Cl:9][C:10]1[N:15]=[C:14]([NH:7][NH2:8])[C:13]([O:17][CH3:18])=[CH:12][N:11]=1
Reactant: NN
Reactant: COc1cnc(Cl)nc1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1cnc(Cl)nc1NN
Temperature: 43 °C
Reaction time: 4.5 h
Yield: 95.7 %

Procedure:
Anhydrous sodium carbonate (29.15 g, 0.275 mole), methanol (300 mL), and 35% aqueous hydrazine (54.9 g, 0.60 mole) were loaded into a 1 L glass jacketed reactor equipped with a thermocouple temperature probe, overhead stirrer with glass agitator, condenser, and a programmable circulating bath. 2,4-Dichloro-5-methoxypyrimidine (89.50 g, 0.50 mole) was added as a solid in small increments over 70 min. During the addition, the reactor jacket was kept at 20° C., and the reaction temperature rose from 21° C. to 28° C. Upon completion of the addition, the reaction mixture was heated to 43° C. over 60 min, then held at 43° C. for 4.5 h. Water (300 mL) was then added, and a distillation head was attached to the reactor. Vacuum was applied to lower the pressure to 140 mmHg, and methanol was removed by distillation. Distillation continued for 1.5 h, at which point the rate of distillation had slowed greatly. The pressure as further decreased to 85 mmHg until water started to distill over, then vacuum was broken under a nitrogen flow. The reaction mixture was cooled from 43° C. to 25° C. over 60 min. The resulting slurry was stirred overnight at 25° C. The product was recovered by filtration through Whatman #52 filter paper using a Buchner funnel and aspirator vacuum. After washing the filter cake with water (221 g), the product was dried overnight in vacuo at 42° C., to give 83.5 g of white 2-chloro-4-hydrazino-5-methoxypyrimidine (purity 96.8%, yield=92.7%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=O)[CH:5]=[CH:6][CH:7]=1.[OH:12][C:13]1[C:19]([Br:20])=[CH:18][C:17]([Cl:21])=[CH:16][C:14]=1[NH2:15].C(N1C=CN=C1)(N1C=CN=C1)=O>>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([NH:15][C:14]2[CH:16]=[C:17]([Cl:21])[CH:18]=[C:19]([Br:20])[C:13]=2[OH:12])=[O:11])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1cccc(Cl)c1
Reactant: Nc1cc(Cl)cc(Br)c1O
Agent: O=C(n1ccnc1)n1ccnc1
Product: O=C(Cc1cccc(Cl)c1)Nc1cc(Cl)cc(Br)c1O
Yield: 67.5 %

Procedure:
Using the normal amide forming conditions, the condensation of 3-chlorophenylacetic acid (13.54 g, 0.079 mol) and 2-hydroxy-3-bromo-5-chloroaniline (17.7 g, 0.079 mol) with 1,1′-carbonyl diimidazole (13.5 g, 0.083 mol) gave the title compound (20 g).
Reaction SMILES: [N:1]([C:4]1[CH:5]=[CH:6][C:7]([CH3:30])=[C:8]([C:10]([C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19]3[CH:24]=[CH:23][C:22](C(F)(F)F)=[CH:21][CH:20]=3)=[CH:14][C:13]=2[Cl:29])=[O:11])[CH:9]=1)=[N+:2]=[N-:3].N[C:32]1C=CC(C)=C(C(C2C=CC(NC3C=C(C)C=CC=3)=CC=2Cl)=O)C=1>>[N:1]([C:4]1[CH:5]=[CH:6][C:7]([CH3:30])=[C:8]([C:10]([C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19]3[CH:20]=[C:21]([CH3:32])[CH:22]=[CH:23][CH:24]=3)=[CH:14][C:13]=2[Cl:29])=[O:11])[CH:9]=1)=[N+:2]=[N-:3]
Reactant: Cc1ccc(N=[N+]=[N-])cc1C(=O)c1ccc(Nc2ccc(C(F)(F)F)cc2)cc1Cl
Reactant: Cc1cccc(Nc2ccc(C(=O)c3cc(N)ccc3C)c(Cl)c2)c1
Product: Cc1cccc(Nc2ccc(C(=O)c3cc(N=[N+]=[N-])ccc3C)c(Cl)c2)c1

Procedure:
The reaction was carried out similarly as described in the preparation of compound 416, using compound 464 (1.17 mmol). The crude product was purified by flash chromatography using EtOAc/petroleum ether (40-60) 1:9 and 1:6 as the eluent to afford the title compound as yellow syrup.
Reaction SMILES: [CH3:1][N:2]1[CH2:10][C:9]2[C:8]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][C@@H:12]3[CH3:17])=[N:7][C:6]([C:18]3[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=3)=[N:5][C:4]=2[CH2:3]1.C([O-])(O)=O.[Na+].Cl[C:31]([O:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:32]>C1COCC1>[CH3:1][N:2]1[CH2:10][C:9]2[C:8]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][C@@H:12]3[CH3:17])=[N:7][C:6]([C:18]3[CH:24]=[CH:23][C:21]([NH:22][C:31](=[O:32])[O:33][C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)=[CH:20][CH:19]=3)=[N:5][C:4]=2[CH2:3]1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: C[C@H]1COCCN1c1nc(-c2ccc(N)cc2)nc2c1CN(C)C2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: C[C@H]1COCCN1c1nc(-c2ccc(NC(=O)Oc3ccccc3)cc2)nc2c1CN(C)C2
Temperature: 20 °C
Reaction time: 2 h
Yield: 99.4 %

Procedure:
To a stirring solution of (S)-4-(6-methyl-4-(3-methylmorpholino)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)aniline (intermediate 9) (311 mg, 0.96 mmol) and NaHCO3 (120 mg, 1.43 mmol) in dry THF, was added phenyl chloroformate (133 μL, 1.05 mmol) dropwise. The reaction mixture was stirred at room temperature (20° C.) for 2 hours, before partitioning the crude reaction mixture between water and EtOAc. The phases were separated and the organic layer dried over magnesium sulphate, filtered and then reduced in vacuo, affording the title compound as a pink solid (425 mg, 100%).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13](=[O:29])[N:14]([CH2:25][C:26](O)=[O:27])[CH:15]=[C:16]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:17]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:30][CH:31]([CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[CH:32]([OH:37])[C:33]([F:36])([F:35])[F:34].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13](=[O:29])[N:14]([CH2:25][C:26]([NH:30][CH:31]([CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH:32]([OH:37])[C:33]([F:34])([F:35])[F:36])=[O:27])[CH:15]=[C:16]([CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:17]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13](=[O:29])[N:14]([CH2:25][C:26]([NH:30][CH:31]([CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:32](=[O:37])[C:33]([F:35])([F:36])[F:34])=[O:27])[CH:15]=[C:16]([CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:17]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)Cn1cc(Cc2ccccc2)cc(NC(=O)OCc2ccccc2)c1=O
Reactant: NC(Cc1ccccc1)C(O)C(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C(Cn1cc(Cc2ccccc2)cc(NC(=O)OCc2ccccc2)c1=O)NC(Cc1ccccc1)C(=O)C(F)(F)F
Product: O=C(Cn1cc(Cc2ccccc2)cc(NC(=O)OCc2ccccc2)c1=O)NC(Cc1ccccc1)C(O)C(F)(F)F

Procedure:
2-(3-Benzyloxycarbonylamino-5-benzyl-2-oxo-1,2-dihydro-1-pyridyl)-N-(1-benzyl-3,3,3-trifluoro-2-hydroxypropyl)acetamide was synthesized in the same manner as in Example 1. That is, 2-(3-benzyloxycarbonylamino-5-benzyl-2-oxo-1,2-dihydro-1-pyridyl)acetic acid (title compound in Reference Example 7, 380 mg, 0.968 mmol) was treated with 3-amino-1,1,1-trifluoro-4-phenyl-2-butanol (title compound in Reference Example 1, 249 mg, 1.14 mmol), WSCI hydrochloride (277 mg, 1.45 mmol) and HOBT (158 mg, 1.17 mmol) in DMF (10 mL) to give 428 mg (74%) of the target compound as a slightly yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:13])[CH2:9][C:10](O)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.Cl.[CH3:16][O:17][C:18]1[CH:19]=[C:20]([NH2:25])[C:21]([NH2:24])=[CH:22][CH:23]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CCOC(C)=O.CN(C=O)C>[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]2[NH:24][C:10]([CH2:9][N:8]([CH3:13])[C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[N:25][C:20]=2[CH:19]=1
Reactant: COc1ccc(N)c(N)c1
Reactant: CN(CC(=O)O)C(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2[nH]c(CN(C)C(=O)OC(C)(C)C)nc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.2 %

Procedure:
To a mixture of N-(tert-butoxycarbonyl)-N-methylglycine (1.00 g), 4-methoxybenzene-1,2-diamine dihydrochloride (1.16 g) and DMF (25 mL) were added HATU (2.41 g) and DIPEA (4.5 mL), followed by stirring at room temperature overnight. The reaction mixture was diluted with EtOAc, and washed with water and brine in this order. The organic layer was dried over Na2SO4 and then concentrated under reduced pressure. To the residue was added acetic acid (20 mL), followed by heating and stirring at 80° C. for 3 hours, and then concentrating under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent: Hex/EtOAc=80/20-20/80) to obtain tert-butyl [(5-methoxy-1H-benzimidazol-2-yl)methyl]methylcarbamate (1.22 g).
Reaction SMILES: [OH:1][CH:2]([CH:13]([OH:24])[C:14]([O:16]N1C(=O)CCC1=O)=O)[C:3]([O:5]N1C(=O)CCC1=O)=O.[NH2:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][O:31][CH2:32][CH2:33][O:34][CH2:35][CH2:36][NH:37][S:38]([C:41]1[CH:46]=[CH:45][C:44]([CH:47]2[C:56]3[C:51](=[C:52]([Cl:58])[CH:53]=[C:54]([Cl:57])[CH:55]=3)[CH2:50][N:49]([CH3:59])[CH2:48]2)=[CH:43][CH:42]=1)(=[O:40])=[O:39]>>[Cl:57][C:54]1[CH:55]=[C:56]2[C:51](=[C:52]([Cl:58])[CH:53]=1)[CH2:50][N:49]([CH3:59])[CH2:48][CH:47]2[C:44]1[CH:43]=[CH:42][C:41]([S:38]([NH:37][CH2:36][CH2:35][O:34][CH2:33][CH2:32][O:31][CH2:30][CH2:29][O:28][CH2:27][CH2:26][NH:25][C:3](=[O:5])[CH:2]([OH:1])[CH:13]([OH:24])[C:14]([NH:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][O:31][CH2:32][CH2:33][O:34][CH2:35][CH2:36][NH:37][S:38]([C:41]2[CH:42]=[CH:43][C:44]([CH:47]3[C:56]4[C:51](=[C:52]([Cl:58])[CH:53]=[C:54]([Cl:57])[CH:55]=4)[CH2:50][N:49]([CH3:59])[CH2:48]3)=[CH:45][CH:46]=2)(=[O:40])=[O:39])=[O:16])(=[O:40])=[O:39])=[CH:46][CH:45]=1
Reactant: O=C(ON1C(=O)CCC1=O)C(O)C(O)C(=O)ON1C(=O)CCC1=O
Reactant: CN1Cc2c(Cl)cc(Cl)cc2C(c2ccc(S(=O)(=O)NCCOCCOCCOCCN)cc2)C1
Product: CN1Cc2c(Cl)cc(Cl)cc2C(c2ccc(S(=O)(=O)NCCOCCOCCOCCNC(=O)C(O)C(O)C(=O)NCCOCCOCCOCCNS(=O)(=O)c3ccc(C4CN(C)Cc5c(Cl)cc(Cl)cc54)cc3)cc2)C1
Yield: 19.8 %

Procedure:
Compound 227 was prepared following the procedure outlined in Example 168 using bis(2,5-dioxopyrrolidin-1-yl) 2,3-dihydroxysuccinate (49.6 mg, 0.144 mmol) and N-(2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethyl)-4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide (Compound 82, 157 mg, 0.288 mmol). Purification by preparative HPLC gave the title compound (34.5 mg) as a TFA salt. 1H-NMR (400 MHz, CD3OD): δ 7.89 (d, 4H), 7.53 (s, 2H), 7.45 (d, 4H), 6.83 (s, 2H), 4.77-4.74 (m, 6H), 4.46 (d, 2H), 4.43 (t, 2H), 3.89-3.84 (m, 2H), 3.62-3.53 (m, 19H), 3.49-3.41 (m, 13H), 3.14 (s, 6H), 3.08 (t, 4H). MS (m/z): 1206.94 [M+H]+.
Reaction SMILES: [C:1]([N:9]1[C:17]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:18](=O)[CH:19](Br)[CH2:20][CH:11]([C:12]=23)[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCOCC.[BH4-].[Na+].CO>O>[C:1]([N:9]1[C:17]2[CH:16]=[CH:15][CH:14]=[C:13]3[CH:18]=[CH:19][CH2:20][CH:11]([C:12]=23)[CH2:10]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1c2cccc3c2C(CC1Br)CN3C(=O)c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: CO
Product: O=C(c1ccccc1)N1CC2CC=Cc3cccc1c32
Reaction time: 0.58 h

Procedure:
A suspension of 5 g. of 1-benzoyl-4-bromo-5-keto-1,2,2a,3,4,5-hexahydrobenz[cd]indole was prepared in 200 ml. of ether. 2 g. of sodium borohydride and 50 ml. of methanol were added and the reaction mixture stirred for 35 minutes. The reaction mixture was then diluted with water and the aqueous layer extracted with ethyl acetate. The ethyl acetate layer was separated, washed with water and with saturated aqueous sodium chloride. The organic layer was dried and the solvent removed by evaporation to dryness. Thin layer chromatography indicated that the resulting residue was a single spot material and consisted of 1-benzoyl-4-bromo-5-hydroxy-1,2,2a,3,4,5-hexahydrobenz[cd]indole. The residue was dissolved in 50 ml. of acetic acid. 10 g. of zinc dust were added and the resulting mixture refluxed for 13/4 hours under a nitrogen atmosphere. Thin layer chromatography of an aliquot indicated that one major spot was present. The reaction mixture was filtered and the filtrate poured over ice. The resulting aqueous mixture was made basic with 14 N aqueous ammonium hydroxide. The alkaline layer was then extracted with ethyl acetate. The ethyl acetate extract was separated, washed with water and with saturated aqueous sodium chloride and then dried. Evaporation of the solvent yielded a residue which was shown by thin layer chromatography to consist of one major spot with a small spot corresponding to starting material. A chloroform solution of the residue was filtered through florisil and the residue obtained after the evaporation of chloroform in vacuo was crystallized from methanol to yield crystalline 1-benzoyl-1,2,2a,3-tetrahydrobenz[cd]indole melting at 89°-91° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[C:10](Cl)[N:9]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[F:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][C:23]=1[C:29]([F:32])([F:31])[F:30].C(OCC)(=O)C>CN(C)C=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:28][C:25]3[CH:26]=[CH:27][C:22]([F:21])=[C:23]([C:29]([F:32])([F:30])[F:31])[CH:24]=3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: Fc1ccc(-c2ccnc(Cl)n2)cc1
Reactant: Oc1ccc(F)c(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Fc1ccc(-c2ccnc(Oc3ccc(F)c(C(F)(F)F)c3)n2)cc1
Temperature: 75 °C
Yield: 192.9 %

Procedure:
To a solution of 0.60 g (2.87 mmol) of 2B in 15 ml of dimethylformamide was added 0.46 g of K2CO3 (3.3 mmol) and 0.60 g (3.3 mmol) of 4-fluoro-3-trifluoromethyl-phenol and the resulting mixture heated at 50° C. for 15 hr and 75° C. for 24 hrs. The cooled reaction mixture was poured into a separatory funnel containing 100 mL of ethyl acetate and washed with 2×50 mL water, 3×15 mL 2.5% NaOH solution, 1×30 mL brine, dried and evaporated in vacuuo to yield 1.95 g of a mobile yellow liquid. This material was filtered through a pad of silica and re-crystallized from heptane/ethyl acetate to give 0.49 g white crystalline solid (m.p. 69-74° C.; 48%).
Reaction SMILES: Br[C:2]1[S:3][C:4]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][N:6]=1.[F:11][C:12]([F:27])([F:26])[C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:18]=1>>[F:11][C:12]([F:26])([F:27])[C:13]1[CH:14]=[C:15]([C:2]2[S:3][C:4]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][N:6]=2)[CH:16]=[C:17]([C:19]([F:20])([F:21])[F:22])[CH:18]=1
Reactant: COC(=O)c1cnc(Br)s1
Reactant: OB(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: COC(=O)c1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)s1

Procedure:
Synthesized as described in Example 310D using methyl 2-bromo-1,3-thiazole-5-carboxylate and [3,5-bis(trifluoromethyl)phenyl]boronic acid: 1H NMR (400 MHz, CDCl3) δ 8.51 (s, 1H), 8.44 (s, 2H), 7.99 (s, 1H), 3.98 (s, 3H).
Reaction SMILES: [CH3:1][O:2][CH:3]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+].[C:29]12([O:44][CH2:43][CH2:42][O:41]1)[C:38]1[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=1)[CH2:32][C@@H:31]([CH:39]=O)[CH2:30]2>O1CCCC1>[CH3:1][O:2][CH:3]=[CH:39][C@@H:31]1[CH2:32][C:33]2[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:29]2([O:44][CH2:43][CH2:42][O:41]2)[CH2:30]1
Reactant: COC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C[C@@H]1Cc2ccccc2C2(C1)OCCO2
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC=C[C@@H]1Cc2ccccc2C2(C1)OCCO2
Reaction time: 0.5 h
Yield: 77.5 %

Procedure:
To a stirred solution of (methoxymethylene)triphenylphosphorane (6.74 g, 21.99 mmol) in tetrahydrofuran (30 mL) was added drop-wise a solution of potassium tert-butoxide (3.08 g, 27.5 mmol) in THF at −30° C. under argon, and the mixture was stirred for 30 min. Then a solution of (R)-3′,4′-dihydro-2′H-spiro[[1,3]dioxolane-2,1′-naphthalene]-3′-carbaldehyde (4.0 g, 18.33 mmol) in THF was added drop-wise and reaction was stirred for 1 h at −30° C. Reaction was monitored by TLC. Reaction mixture quenched with water at −30° C. and allowed to RT, diluted with water (25 mL) and extracted with ethyl acetate (2×50 mL), dried over Na2SO4, filtered and concentrated to give crude product (8 g). The crude compound was purified with silica gel flash column chromatography (Biotage) to give (R)-3′-(2-methoxyvinyl)-3′,4′-dihydro-2′H-spiro[[1,3]dioxolane-2,1′-naphthalene] (3.5 g, 14.21 mmol, 78% yield) as colourless liquid; m/z 246.6.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH2:8][CH2:9][NH:10]2)=[CH:6][CH:5]=1)([O-])=O.C(=O)([O-])O.[Na+].Br[CH2:19][C:20]([O:22][CH3:23])=[O:21]>CN(C=O)C.CO.[Pd]>[NH2:1][C:4]1[CH:12]=[C:11]2[C:7]([CH2:8][CH2:9][N:10]2[CH2:19][C:20]([O:22][CH3:23])=[O:21])=[CH:6][CH:5]=1
Reactant: COC(=O)CBr
Reactant: O=[N+]([O-])c1ccc2c(c1)NCC2
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: COC(=O)CN1CCc2ccc(N)cc21
Temperature: 25 °C
Yield: 75.5 %

Procedure:
A suspension of 6-nitroindoline (1.0 g, 6.1 mmol) and sodium hydrogen carbonate (0.6 g, 7.1 mmol) in DMF (60 ml) was stirred at room temperature. Methyl bromoacetate (0.68 mL, 1.09 g, 7.1 mmol) was added slowly and the mixture was heated at 90° C. for 1 hour. The mixture was cooled, the solvents evaporated under reduced pressure, and the residue partitioned between ethyl acetate (40 mL) and water (20 mL). The organic layer was dried over MgSO4 and then evaporated to give an orange solid. The solid was dissolved in methanol (100 ml), 5% Pd/C (50 mg, cat.) was added and the suspension was stirred under an atmosphere of hydrogen for 2 hours, during which time the yellow colour disappeared. The catalyst was removed by filtration through celite and the solvent was evaporated to give the amine as a brown oil (0.95 g, 75%).