Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[Br:8][C:9]1[CH:17]=[C:16]2[C:12]([CH2:13][C:14]3([CH2:34][NH:33][CH2:32]3)[C:15]2([NH:22][S:23]([CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])(=[O:25])=[O:24])[C:18]([O:20][CH3:21])=[O:19])=[CH:11][CH:10]=1.Cl[C:36]1[N:41]=[CH:40][CH:39]=[CH:38][N:37]=1.CCN(CC)CC>CO>[Br:8][C:9]1[CH:17]=[C:16]2[C:12]([CH2:13][C:14]3([CH2:34][N:33]([C:36]4[N:41]=[CH:40][CH:39]=[CH:38][N:37]=4)[CH2:32]3)[C:15]2([NH:22][S:23]([CH2:26][CH2:27][Si:28]([CH3:30])([CH3:29])[CH3:31])(=[O:25])=[O:24])[C:18]([O:20][CH3:21])=[O:19])=[CH:11][CH:10]=1
Reactant: Clc1ncccn1
Reactant: COC(=O)C1(NS(=O)(=O)CC[Si](C)(C)C)c2cc(Br)ccc2CC12CNC2
Solvent: CO
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)C1(NS(=O)(=O)CC[Si](C)(C)C)c2cc(Br)ccc2CC12CN(c1ncccn1)C2
Temperature: 80 °C
Reaction time: 18 h
Yield: 39.2 %

Procedure:
To a solution of methyl 6′-bromo-1′-(2-(trimethylsilyl)ethylsulfonamido)-1′,3′-dihydrospiro[azetidine-3,2′-indene]-1′-carboxylate trifluoroacetate (0.2196 g, 0.37 mmol) and 2-chloropyrimidine (0.1080 g, 0.94 mmol) in MeOH (4 mL) was added Et3N (0.5 mL) at room temperature. The mixture was stirred at 80° C. for 18 h and then concentrated under reduced pressure. The residue was purified by reversed-phase HPLC (SunFire™ Prep C18 OBD™ 5 μm 19×50 mm column, 10%→90% MeOH/H2O, 0.1% CF3COOH over 8 min and then 90% MeOH/H2O, 0.1% CF3COOH over 2 min, flow rate 20 mL/min) to afford 0.0803 g (39%) of methyl 6′-bromo-1-(pyrimidin-2-yl)-1′-(2-(trimethylsilyl)ethylsulfonamido)-1′,3′-dihydrospiro[azetidine-3,2′-indene]-1′-carboxylate. LC-MS tR=1.87 min in 3 min chromatography, m/z 553, 555 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.[C:11]1([CH:17]2[CH2:21][CH2:20][NH:19][CH2:18]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:19]2[CH2:20][CH2:21][CH:17]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH2:18]2)=[O:8])=[CH:9][CH:10]=1
Reactant: O=C(O)c1ccc(Br)cc1
Reactant: c1ccc(C2CCNC2)cc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1ccc(Br)cc1)N1CCC(c2ccccc2)C1

Procedure:
The above compound could be made in the following manner analogous to Example 60: 1 equivalent of p-Bromobenzoic acid, 1 equivalent 3-Phenylpyrrolidine, 1.1 equivalents of EDC, 1.1 equivalents of HOBt and 1 equivalent of Hunig's Base in DMF would be stirred at room temperature overnight. The solution would then be diluted with water and extracted with ethyl acetate. The organic layers would be combined and washed with water, aqueous saturated sodium bicarbonate solution, 1N HCl and brine. The organic layers would be dried with sodium sulfate, filtered and concentrated. Purification would be done with flash chromatography to afford product.
Reaction SMILES: Cl.C(O[C:5](=[O:23])[CH2:6][CH2:7][C@H:8]([NH2:22])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)C.[CH2:24]([N:26]([CH2:29][CH3:30])[CH2:27]C)[CH3:25]>C(OC(C)C)(=O)C>[C:13]1([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:12]=[CH:11][C:10]([CH2:9][C@H:8]2[N:22]([CH2:27][N:26]3[CH2:29][CH2:30][CH2:25][CH2:24]3)[C:5](=[O:23])[CH2:6][CH2:7]2)=[CH:15][CH:14]=1
Reactant: CCN(CC)CC
Reactant: CCOC(=O)CC[C@H](N)Cc1ccc(-c2ccccc2)cc1
Agent: Cl
Solvent: CC(=O)OC(C)C
Product: O=C1CC[C@@H](Cc2ccc(-c3ccccc3)cc2)N1CN1CCCC1
Temperature: 55 °C
Reaction time: 1 h

Procedure:
To a mixture of (S)-4-Amino-5-biphenyl-4-yl-pentanoic acid ethyl ester hydrochloride [10-a, R5=Et] (86 g) in isopropyl acetate (1 L) is added triethylamine (43 g). The mixture is then stirred at about 55° C. for 1 h and then filtered. The filtrate is heated at reflux for 24 hours. To the mixture is added saturated ammonium chloride solution and the phases are separated. The organic layer is concentrated to dryness and crystallized from isopropyl acetate to yield (S)-5-biphenyl-4-ylmethylpyrrolidin-2-one [Key Lactam (1-a, R1=H)]. Spectroscopic data agree with data provided above.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:20][CH3:21])[C:4]1[N:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][NH:11]2)=[CH:6][C:5]=1[CH:14]1[CH2:19][CH2:18][O:17][CH2:16]C1.O1CC=C(B2OC(C)(C)C(C)(C)O2)C1>>[CH3:21][O:20][CH:3]([O:2][CH3:1])[C:4]1[N:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][NH:11]2)=[CH:6][C:5]=1[CH:14]1[CH2:19][CH2:18][O:17][CH2:16]1
Reactant: COC(OC)c1nc2c(cc1C1CCOCC1)CCCN2
Agent: CC1(C)OB(C2=CCOC2)OC1(C)C
Product: COC(OC)c1nc2c(cc1C1CCOC1)CCCN2

Procedure:
The title compound was synthesized in an analogous manner to intermediate 312, by replacing 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1, 3,2-dioxaborolane with 2-(2,5-dihydrofuran-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane. The title compound was obtained as a viscous, turbid light yellow oil. (UPLC-MS 3) tR 0.50 min; ESI-MS 279.2 [M+H]+.
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH2:7][CH3:8])=[C:4]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:3]=1.[S:14]1[CH2:19][CH2:18][C:17](=[O:20])[CH2:16][CH2:15]1>>[CH2:7]([C:5]1[S:6][C:2]([C:17]2([OH:20])[CH2:18][CH2:19][S:14][CH2:15][CH2:16]2)=[CH:3][C:4]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH3:8]
Reactant: CCOC(=O)c1cc(Br)sc1CC
Reactant: O=C1CCSCC1
Product: CCOC(=O)c1cc(C2(O)CCSCC2)sc1CC
Yield: 72.9 %

Procedure:
An operation similar to that in Example 73 (1) was performed using ethyl 5-bromo-2-ethylthiophene-3-carboxylate (5.00 g) synthesized in Example 69 (4) and tetrahydro-4H-thiopyran-4-one (6.62 g) to give the title compound (4.16 g, 73%).
Reaction SMILES: [CH:1]1([N:7]([CH3:17])[C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([OH:16])=O)[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][N:23]=[CH:22]2>>[CH:1]1([N:7]([CH3:17])[C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([NH:18][C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[NH:24][N:23]=[CH:22]4)=[O:16])[CH:9]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Nc1ccc2[nH]ncc2c1
Reactant: CN(c1cc(C(=O)O)ncn1)C1CCCCC1
Product: CN(c1cc(C(=O)Nc2ccc3[nH]ncc3c2)ncn1)C1CCCCC1

Procedure:
Following the general method as outlined in Example 1, starting from 6-[cyclohexyl(methyl)amino]pyrimidine-4-carboxylic acid (Intermediate 10) and 5-aminoindazole (Aldrich), the title compound was obtained as a white solid after purification by column chromatography (silica) eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: C([N:8]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C:24]([NH:26][C@@H:27]([CH2:31][CH2:32][CH2:33][NH:34][CH:35]2[C:44]3[N:43]=[CH:42][CH:41]=[CH:40][C:39]=3[CH2:38][CH2:37][CH2:36]2)[C:28]([OH:30])=[O:29])=[O:25])=[CH:19][CH:18]=1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1)(OC(C)(C)C)=O.[ClH:45].O1CCOCC1>CO>[ClH:45].[N:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[CH2:9][NH:8][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C:24]([NH:26][C@@H:27]([CH2:31][CH2:32][CH2:33][NH:34][CH:35]2[C:44]3[N:43]=[CH:42][CH:41]=[CH:40][C:39]=3[CH2:38][CH2:37][CH2:36]2)[C:28]([OH:30])=[O:29])=[O:25])=[CH:19][CH:18]=1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(CC(=O)N[C@@H](CCCNC2CCCc3cccnc32)C(=O)O)cc1)Cc1ccccn1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: O=C(Cc1ccc(CNCc2ccccn2)cc1)N[C@@H](CCCNC1CCCc2cccnc21)C(=O)O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
The compound obtained in Example 8-8 (18.0 mg) was dissolved in methanol (0.2 ml) and 4 mol/l hydrochloric acid/dioxane solution was added. The mixture was stirred for 1.5 hours at room temperature. After the reaction, the solvent was removed by distillation. The residue was purified by silica gel column chromatography (1.0 g, chloroform/methanol/water=7/3/0.5). The obtained product was added with an aqueous solution of hydrochloric acid, concentrated and then azeotropically distilled with water. The resulting solid was washed with ether to obtain a hydrochloride of the title compound (14.4 mg) as a white solid.
Reaction SMILES: C(OC(=O)[NH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([CH3:20])([CH3:19])[CH3:18])=[C:13]([NH:21][CH:22]=[O:23])[CH:12]=1)C1C=CC=CC=1.CO>[Pd].C(Cl)Cl>[NH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([CH3:20])([CH3:19])[CH3:18])=[C:13]([NH:21][CH:22]=[O:23])[CH:12]=1
Reactant: CC(C)(C)c1ccc(NC(=O)OCc2ccccc2)cc1NC=O
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)c1ccc(N)cc1NC=O
Reaction time: 20 h
Yield: 95.7 %

Procedure:
A 100 mL flask was charged with (4-tert-butyl-3-formylamino-phenyl)-carbamic acid benzyl ester (650 mg, 1.99 mmol), methanol (30 mL) and 10% Pd—C (50 mg), and stirred under H2 (1 atm) for 20 h. CH2Cl2 (5 mL) was added to quench the catalyst, and the mixture then filtered through Celite, and concentrated to afford N-(5-amino-2-tert-butyl-phenyl)-formamide as an off-white solid (366 mg, 96%). Rotameric by 1H and 13C NMR (DMSO-d6). 1H NMR (400 MHz, DMSO-d6, rotameric) δ 9.24 (d, J=10.4 Hz, 1H), 9.15 (s, 1H), 8.23 (d, J=1.5 Hz, 1H), 8.06 (d, J=10.4 Hz, 1H), 7.06 (d, J=8.5 Hz, 1H), 7.02 (d, J=8.5 Hz, 1H), 6.51 (d, J=2.5 Hz, 1H), 6.46 (dd, J=2.5, 8.5 Hz, 1H), 6.39 (dd, J=2.5, 8.5 Hz, 1H), 6.29 (d, J=2.5 Hz, 1H), 5.05 (s, 2H), 4.93 (s, 2H), 1.27 (s, 9H); 13C NMR (100 MHz, DMSO-d6, rotameric) δ 164.0, 160.4, 147.37, 146.74, 135.38, 135.72, 132.48, 131.59, 127.31, 126.69, 115.15, 115.01, 112.43, 112.00, 33.92, 33.57, 31.33, 30.92; ESI-MS 193.1 m/z (MH+).
Reaction SMILES: O[C:2]1[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[N:3]=1.P(Cl)(Cl)([Cl:19])=O>>[Cl:19][C:2]1[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1cc2c(nc1O)CCCC2
Product: CCOC(=O)c1cc2c(nc1Cl)CCCC2

Procedure:
Ethyl 2-hydroxy-5,6,7,8-tetrahydroquinoline-3-carboxylate (3.40 g) was dissolved in phosphorus oxychloride (30 ml), and the mixture was stirred with heating to reflux for 10 hr. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (50:50-100:0) was concentrated under reduced pressure to give the object compound (3.68 g).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([CH2:8][NH:9][C:10]2[C:15]([C:16]([F:19])([F:18])[F:17])=[CH:14][N:13]=[C:12]([NH:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][C:29]([F:32])([F:31])[F:30])[N:11]=2)[CH2:4][CH2:3]1.Br[CH2:34][CH2:35][CH2:36][CH2:37]Br.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[N:1]1([C@H:2]2[CH2:3][CH2:4][C@H:5]([CH2:8][NH:9][C:10]3[C:15]([C:16]([F:17])([F:18])[F:19])=[CH:14][N:13]=[C:12]([NH:20][CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[O:28][C:29]([F:31])([F:32])[F:30])[N:11]=3)[CH2:6][CH2:7]2)[CH2:37][CH2:36][CH2:35][CH2:34]1
Reactant: BrCCCCBr
Reactant: N[C@H]1CC[C@H](CNc2nc(NCc3ccccc3OC(F)(F)F)ncc2C(F)(F)F)CC1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: FC(F)(F)Oc1ccccc1CNc1ncc(C(F)(F)F)c(NC[C@H]2CC[C@H](N3CCCC3)CC2)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of N4-[(trans-4-aminocyclohexyl)methyl]-N2-[2-(trifluoromethoxy)benzyl]-5-(trifluoromethyl)pyrimidine-2,4-diamine (100 mg, 0.22 mmol) in DMF (2 mL) were added 1,4-dibromobutane (140 mg, 0.65 mmol) and DIPEA (113 μL, 0.65 mmol). The reaction mixture was stirred at room temperature for 16 h and then heated at 65° C. for another 2 h. The reaction mixture was then diluted with EtOAc and washed with water (×4). The organic phase was dried over anhydrous Na2SO4 and concentrated in vacuo. The resulting residue was purified by silica gel preparative TLC using 10:1 CH2Cl2:MeOH as an eluent to afford 49 mg of the title compound as a while solid, m/z 518.6 [M+1]+.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([S:26]CC4C=CC(OC)=CC=4)[C:10]([F:25])=[C:11]([NH:15][CH2:16][CH2:17][NH:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=4)[C:12]=3[F:14])[C:7](=[O:36])[C:6]([C:37]([OH:39])=[O:38])=[CH:5]2)[CH2:3][CH2:2]1.FC(F)(F)C(O)=O>C1(OC)C=CC=CC=1>[CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([SH:26])[C:10]([F:25])=[C:11]([NH:15][CH2:16][CH2:17][NH:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=4)[C:12]=3[F:14])[C:7](=[O:36])[C:6]([C:37]([OH:39])=[O:38])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: COc1ccc(CSc2c(F)c(NCCNc3ccccn3)c(F)c3c2c(=O)c(C(=O)O)cn3C2CC2)cc1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1cn(C2CC2)c2c(F)c(NCCNc3ccccn3)c(F)c(S)c2c1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 68.3 %

Procedure:
A mixture of 1-cyclopropyl-6,8-difluoro-1,4-dihydro-5-(4-methoxybenzylthio)-4-oxo-7-[2-(2-pyridylamino)ethylamino]quinoline-3-carboxylic acid (290 mg, 0.525 mmol) and trifluoroacetic acid (1.5 mL) in anisole (1.5 mL) was stirred at room temperature for 24 h. The mixture was concentrated in vacuo. The residue was dissolved in water (5 mL), then added saturated aq. NaHCO3 until pH=7. The resulting precipitate was combined by filtration. Recrystallization of the cake from MeOH (30 mL) gave 1-cyclopropyl-6,8-difluoro-1,4-dihydro-5-mercapto-4-oxo-7-[2-(2-pyridylamino)ethylamino]quinoline-3-carboxylic acid as a pale yellow solid (155 mg, 68%).
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[CH2:16]([O:23][C:24]1[CH:35]=[CH:34][C:27]([CH2:28][C@@H:29]([C:31]([OH:33])=[O:32])[NH2:30])=[CH:26][CH:25]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:16]([O:23][C:24]1[CH:35]=[CH:34][C:27]([CH2:28][C@H:29]([NH:30][C:2]2[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]3[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=3)[N:3]=2)[C:31]([OH:33])=[O:32])=[CH:26][CH:25]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: N[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)O
Reactant: O=C(O)c1cc2cc(Cl)ccc2nc1Cl
Product: O=C(O)c1cc2cc(Cl)ccc2nc1N[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)O
Yield: 32 %

Procedure:
In close analogy to the procedure described in Example 1, 2,6-dichloroquinoline-3-carboxylic acid is reacted with O-benzyl-L-tyrosine to provide the title compound in 32% yield as yellow needles (recrystallization from acetone/EtOH).
Reaction SMILES: Cl[C:2]1[C:7]2[C:8]([CH3:16])=[CH:9][N:10]([CH2:11][CH2:12][CH2:13][O:14][CH3:15])[C:6]=2[CH:5]=[C:4]([C:17](=[O:19])[CH3:18])[N:3]=1.[CH3:20]B1OB(C)OB(C)O1.C(=O)([O-])[O-].[Cs+].[Cs+].O>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>[CH3:15][O:14][CH2:13][CH2:12][CH2:11][N:10]1[C:6]2[CH:5]=[C:4]([C:17](=[O:19])[CH3:18])[N:3]=[C:2]([CH3:20])[C:7]=2[C:8]([CH3:16])=[CH:9]1
Reactant: CB1OB(C)OB(C)O1
Reactant: COCCCn1cc(C)c2c(Cl)nc(C(C)=O)cc21
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: COCCCn1cc(C)c2c(C)nc(C(C)=O)cc21
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a solution of 1-[4-chloro-1-(3-methoxypropyl)-3-methyl-1H-pyrrolo[3,2-c]pyridin-6-yl]ethanone (50 mg) in 1,4-dioxane (2 mL) were added trimethylboroxine (50 μL), cesium carbonate (174 mg), 2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl (X-Phos) (17 mg) and tris(dibenzylideneacetone)dipalladium (8 mg) under argon, and the mixture was stirred at 80° C. for 2 hours. The reaction solution was cooled, and then thereto was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane→n-hexane/ethyl acetate=1/1) to give 1-[1-(3-methoxypropyl)-3,4-dimethyl-1H-pyrrolo[3,2-c]pyridin-6-yl]ethanone [REx(105-9)] (105 mg) as a colorless oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[N:14]=[CH:13][C:12]([NH2:15])=[CH:11][N:10]=2)=[CH:4][C:3]=1[O:16][C:17]([F:20])([F:19])[F:18].[O-]P([O-])([O-])=O.[K+].[K+].[K+].[CH3:29]B(O)O>CN(C=O)C.O>[CH3:29][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[N:14]=[CH:13][C:12]([NH2:15])=[CH:11][N:10]=2)=[CH:4][C:3]=1[O:16][C:17]([F:20])([F:19])[F:18]
Reactant: CB(O)O
Reactant: Nc1cnc(Oc2ccc(Br)c(OC(F)(F)F)c2)nc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(Oc2ncc(N)cn2)cc1OC(F)(F)F
Temperature: 110 °C
Reaction time: 0.5 h
Yield: 61.4 %

Procedure:
To a solution of 2-({4-bromo-3-[(trifluoromethyl)oxy]phenyl}oxy)-5-pyrimidinamine (Intermediate 162, 270 mg) in DMF (4 mL) were added K3PO4 (490 mg, 2.31 mmol), Pd(tBu3)2 (197 mg, 0.385 mmol) and methyl boronic acid (276 mg, 4.62 mmol) and the reaction mixture was stirred for 30 minutes at 110° C. under microwave irradiation. After cooling the reaction was diluted with water (10 mL) and extracted with ethyl acetate (3×10 mL). The organic layer was washed with ice cold brine (2×5 mL), dried (Na2SO4), filtered and evaporated and the residue was purified by flash chromatography on silica gel (SNAP 10 g) eluting from 80:20 to 50:50 cyclohexane/ethyl acetate to afford the title compound as white solid (135 mg).
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[CH2:9]2)(=[O:5])=[O:4].[NH:16]1[C:24]2[C:19](=[CH:20][C:21]([CH:25]=O)=[CH:22][CH:23]=2)[CH:18]=[CH:17]1>>[CH3:1][NH:2][S:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[C:9]2=[CH:25][C:21]1[CH:20]=[C:19]2[C:24](=[CH:23][CH:22]=1)[NH:16][CH:17]=[CH:18]2)(=[O:5])=[O:4]
Reactant: O=Cc1ccc2[nH]ccc2c1
Reactant: CNS(=O)(=O)c1ccc2c(c1)CC(=O)N2
Product: CNS(=O)(=O)c1ccc2c(c1)C(=Cc1ccc3[nH]ccc3c1)C(=O)N2

Procedure:
5-Methylaminosulfonyl-2-oxindole was condensed with indole-5-carbaldehyde to give the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:29])[NH:8][C:9]2[C:14]([C:15]=1[N:16]1[CH2:21][CH2:20][N:19]([C:22]([C:24]3[S:25][CH:26]=[CH:27][CH:28]=3)=[O:23])[CH2:18][CH2:17]1)=[CH:13][N:12]=[CH:11][CH:10]=2)=[O:5])[CH3:2].Br[CH2:31][C:32]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:33]>>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:29])[N:8]([CH2:31][C:32](=[O:33])[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:9]2[C:14]([C:15]=1[N:16]1[CH2:21][CH2:20][N:19]([C:22]([C:24]3[S:25][CH:26]=[CH:27][CH:28]=3)=[O:23])[CH2:18][CH2:17]1)=[CH:13][N:12]=[CH:11][CH:10]=2)=[O:5])[CH3:2]
Reactant: O=C(CBr)c1ccccc1
Reactant: CCOC(=O)c1c(N2CCN(C(=O)c3cccs3)CC2)c2cnccc2[nH]c1=O
Product: CCOC(=O)c1c(N2CCN(C(=O)c3cccs3)CC2)c2cnccc2n(CC(=O)c2ccccc2)c1=O

Procedure:
This compound was prepared from 2-oxo-4-[4-(thiophene-2-carbonyl)-piperazin-1-yl]-1,2-dihydro-[1,6]-naphthyridin-3-carboxylic acid ethyl ester (121) and 2-bromoacetophenone according to General Procedure B. Yield 127 mg (24%), MP 157° C.; 1H-NMR (DMSO-d6): δ 1.27 (t, J=6.8 Hz, 3H), 3.24 (m, 4H), 3.93 (m, 4H), 4.26 (q, J=7.2 Hz, 2H), 5.85 (s, 2H), 7.15 (dd, J=3.6, 5.2 Hz, 1H), 7.47 (m, 2H), 7.62 (m, 2H), 7.74 (m, 1H), 7.80 (d, J=5.2 Hz, 1H), 8.13 (d, J=5.2 Hz, 1H), 8.32 (d, J=7.2 Hz, 2H), 8.56 (d, J=6.0 Hz, 1H), 9.12 (s, 1H); EIMS: 531 (M+1). Anal. (C28H26N4O5S) C, H, N.
Reaction SMILES: [CH2:1]([C@@:8]12[CH2:21][C:20](=[O:22])[C@:19]([OH:29])([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:18][C@H:17]1[CH2:16][CH2:15][C:14]1[CH:13]=[C:12]([C:30]([NH:32][C:33]3[C:34]([CH3:39])=[N:35][CH:36]=[CH:37][CH:38]=3)=[O:31])[CH:11]=[CH:10][C:9]2=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:40]1COCC1.[Li]C.[NH4+].[Cl-]>C(#N)C.O>[CH2:1]([C@@:8]12[CH2:21][C@:20]([OH:22])([CH3:40])[C@:19]([OH:29])([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:18][C@H:17]1[CH2:16][CH2:15][C:14]1[CH:13]=[C:12]([C:30]([NH:32][C:33]3[C:34]([CH3:39])=[N:35][CH:36]=[CH:37][CH:38]=3)=[O:31])[CH:11]=[CH:10][C:9]2=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C1CCOC1
Reactant: Cc1ncccc1NC(=O)c1ccc2c(c1)CC[C@@H]1C[C@@](O)(c3ccccc3)C(=O)C[C@@]21Cc1ccccc1
Agent: [Cl-]
Agent: [Li]C
Agent: [NH4+]
Solvent: O
Solvent: CC#N
Product: Cc1ncccc1NC(=O)c1ccc2c(c1)CC[C@@H]1C[C@@](O)(c3ccccc3)[C@](C)(O)C[C@@]21Cc1ccccc1
Temperature: -17 °C
Reaction time: 1 h
Yield: 73 %

Procedure:
To a flame dried 50 mL round bottom flask was added the (4bR,7R,8aR)-4b-benzyl-7-hydroxy-N-(2-methylpyridin-3-yl)-6-oxo-7-phenyl-4b,5,6,7,8,8a,9,10-octahydrophenanthrene-2-carboxamide (0.28 g, 0.54 mmol) in a THF (5 mL). The solution was cooled to −17° C. in an ice/acetone bath. To the reaction was added MeLi*LiBr (0.1 mL). After 1 hour the LCMS indicated that starting material remained so an additional 0.15 mL was added. The reaction stirred to room temperature over 2 hours. By HPLC, 2.5% of the starting material remained. To the reaction was added NH4Cl slowly and off gassing was observed. The reaction was diluted to 125 mL with acetonitrile and water. The reaction was purified by reverse phase chromatography then was lyophilized. The resulting dried powder was dissolved in acetonitrile and water again with two drops of concentrated HCl. The solution was lyophilized to dryness. This afforded the title product (231.4 mg) as the HCl salt in 73% yield. LRMS ES+ 533.1 1H NMR (300 MHz, METHANOL-d4) δ ppm 1.23-1.28 (m, 3H) 1.53-1.62 (m, 1H) 1.90-2.20 (m, 3H) 2.70-2.74 (m, 3H) J=8.26 Hz, 2H) 6.84-6.92 (m, 2H) 6.99-7.10 (m, 3H) 7.13-7.29 (m, 3H) 7.45 (dd, J=8.15, 1.91 Hz, 1 H) 7.56-7.65 (m, 2H) 7.77 (d, J=1.81 Hz, 1H) 7.88 (dd, J=8.26, 5.84 Hz, 1H) 8.51-8.63 (m, 2H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([O:8][CH3:9])[CH2:5][CH2:6][OH:7].C(N(CC)CC)C.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>O1CCCC1>[CH3:17][S:18]([O:1][CH2:2][CH2:3][N:4]([O:8][CH3:9])[CH2:5][CH2:6][O:7][S:18]([CH3:17])(=[O:20])=[O:19])(=[O:20])=[O:19]
Reactant: CS(=O)(=O)Cl
Reactant: CON(CCO)CCO
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CON(CCOS(C)(=O)=O)CCOS(C)(=O)=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 2-[(2-hydroxy-ethyl)-methoxy-amino]-ethanol (20.0 g, 148.0 mmol) and triethylamine (41.3 ml, 30.0 g, 296.3 mmol) in tetrahydrofuran (855 ml) under argon was added methanesulfonyl chloride (25.2 ml, 37.3 g, 325.6 mmol) dropwise, keeping the temperature below 20° C. with an ice bath. The reaction mixture was stirred at room temperature for 4 hours, the resulting precipitate filtered off and the filtrate concentrated. The residue was diluted with ethyl acetate, washed with water, dried over sodium sulfate and concentrated. Yield: 40.0 g of methanesulfonic acid 2-[(2-methanesulfonyloxy-ethyl)-methoxy-amino]-ethyl ester as a pale yellow oil, this material was used without further purification.
Reaction SMILES: [N+]([C:4]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:5]=1[C:6]#[N:7])([O-])=O.[OH:15][CH2:16][C@H:17]1[CH2:21][CH2:20][CH2:19][N:18]1[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23]>>[C:6]([C:5]1[C:8]([N+:12]([O-:14])=[O:13])=[CH:9][CH:10]=[CH:11][C:4]=1[O:15][CH2:16][C@H:17]1[CH2:21][CH2:20][CH2:19][N:18]1[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])#[N:7]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1CO
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1cccc([N+](=O)[O-])c1C#N
Yield: 87 %

Procedure:
Prepared as in Example 166d from 2,6-dinitrobenzonitrile and (R)-tert-butyl 2-(hydroxymethyl)pyrrolidine-1-carboxylate in 87% yield as a tan solid. 1H NMR (400 MHz, DMSO-d6) δ 1.39 (s, 9H), 1.82 (m, 1H), 2.02 (m, 3H), 3.32 (m, 2H), 4.08 (m, 1H), 4.32 (m, 2H), 7.79 (d, J=8.0 Hz, 1H), 7.91 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]=[C:7]([C:9](=[C:12](OC)[CH3:13])[C:10]#[N:11])[S:8][C:4]=2[CH:3]=1.O.[NH2:19][NH2:20]>CO>[Br:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]=[C:7]([C:9]3[C:12]([CH3:13])=[N:20][NH:19][C:10]=3[NH2:11])[S:8][C:4]=2[CH:3]=1
Reactant: COC(C)=C(C#N)c1nc2ccc(Br)cc2s1
Reactant: NN
Solvent: O
Solvent: CO
Product: Cc1n[nH]c(N)c1-c1nc2ccc(Br)cc2s1
Temperature: 25 °C
Yield: 5 %

Procedure:
A solution of 2-(6-bromobenzothiazol-2-yl)-3-methoxybut-2-enenitrile (0.96 g, 3.1 mmol) and hydrazine hydrate (0.3 mL, 5.4 mmol) in methanol (30 mL) was heated to reflux overnight. The reaction was then cooled to room temperature. The resulting solid was isolated by filtration and was purified by flash chromatography to yield the title product. MS (m/z, ES+): 308.9 (Br79M+1, 100%), 310.9 (Br81M+1, 100%). Yield=5%.