Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=O)[CH:4]([C:6]1[N:7]=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[S:9][C:10]=1[CH3:11])[CH3:5].C[O:24][C:25](=O)[C:26]([CH3:44])([C:28]1[N:29]=[C:30]([C:34]2[CH:39]=[CH:38][C:37]([C:40]([F:43])([F:42])[F:41])=[CH:36][CH:35]=2)[S:31][C:32]=1[CH3:33])[CH3:27].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH3:11][C:10]1[S:9][C:8]([C:12]2[CH:13]=[CH:14][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:17]=2)=[N:7][C:6]=1[CH:4]([CH3:5])[CH2:3][OH:2].[CH3:44][C:26]([C:28]1[N:29]=[C:30]([C:34]2[CH:35]=[CH:36][C:37]([C:40]([F:42])([F:43])[F:41])=[CH:38][CH:39]=2)[S:31][C:32]=1[CH3:33])([CH3:27])[CH2:25][OH:24]
Reactant: COC(=O)C(C)c1nc(-c2ccc(C(F)(F)F)cc2)sc1C
Reactant: COC(=O)C(C)(C)c1nc(-c2ccc(C(F)(F)F)cc2)sc1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1sc(-c2ccc(C(F)(F)F)cc2)nc1C(C)(C)CO
Product: Cc1sc(-c2ccc(C(F)(F)F)cc2)nc1C(C)CO
Reaction time: 2 h

Procedure:
To a solution of 2-[5-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-4-yl]-propionic acid methyl ester and 2-Methyl-2-[5-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-4-yl]-propionic acid methyl ester (10.6 g) in THF (50 mL) is added a solution of lithium aluminum hydride in THF (1.0 M, 33 mL) at 0° C. After 2 hrs, the reaction is quenched by water and sodium hydroxide, filtered, concentrated. Chromatography on silica gel yields 2-[5-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-4-yl]-propan-1-ol (4.3 g) and 2-Methyl-2-[5-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-4-yl]-propan-1-ol (2.6 g).
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:18][C:17]([CH3:20])([CH3:19])[CH2:16][C:15]2[N:14]=[C:13]([CH:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[C:12]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[C:11](I)[C:10]1=2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[O:33]1[CH2:38][CH:37]=[C:36](B2OC(C)(C)C(C)(C)O2)[CH2:35][CH2:34]1.C(=O)([O-])[O-].[Cs+].[Cs+].[F-].[Cs+]>O.O1CCCC1.C1(C)C=CC=CC=1>[Si:1]([O:8][C@H:9]1[CH2:18][C:17]([CH3:20])([CH3:19])[CH2:16][C:15]2[N:14]=[C:13]([CH:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[C:12]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[C:11]([C:36]3[CH2:37][CH2:38][O:33][CH2:34][CH:35]=3)[C:10]1=2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Reactant: CCOC(=O)c1c(C2CCOCC2)nc2c(c1I)[C@@H](O[Si](C)(C)C(C)(C)C)CC(C)(C)C2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [F-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)c1c(C2CCOCC2)nc2c(c1C1=CCOCC1)[C@@H](O[Si](C)(C)C(C)(C)C)CC(C)(C)C2

Procedure:
Obtained by starting from (S)-ethyl 5-(tert-butyldimethylsilyloxy)-4-iodo-7,7-dimethyl-2-(tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydroquinoline-3-carboxylate and 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane. A 2 M solution of caesium carbonate in water is used instead caesium fluoride. The reaction is run in tetrahydrofurane/toluene 4:1.
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3]C.[I-].CC([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C.[CH3:29][C:30]([C:33]1[N:38]=[CH:37][C:36](/[CH:39]=[CH:40]/[C:41]([O:43][CH2:44][CH3:45])=[O:42])=[CH:35][N:34]=1)([CH3:32])[CH3:31]>CCCCCC.O1CCCC1>[CH3:1][C:2]1([CH3:3])[C@@H:39]([C:36]2[CH:35]=[N:34][C:33]([C:30]([CH3:29])([CH3:31])[CH3:32])=[N:38][CH:37]=2)[C@@H:40]1[C:41]([O:43][CH2:44][CH3:45])=[O:42]
Reactant: CCOC(=O)/C=C/c1cnc(C(C)(C)C)nc1
Reactant: [Li]CCCC
Agent: CC(C)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [I-]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOC(=O)[C@H]1[C@H](c2cnc(C(C)(C)C)nc2)C1(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of n-butyllithium (10.6 cm3 of a 1.55M solution in hexane) was added slowly to a stirred solution of prop-2-yl triphenyl phosphonium iodide (7.1 g) in dry tetrahydrofuran (20 cm3) at the ambient temperature under a nitrogen atmosphere and the resultant mixture stirred for a further 15 minutes after which a solution of ethyl trans 3-[2-(2-methylprop-2-yl)pyrimidin-5-yl]propenoate (3.2 g) in dry tetrahydrofuran (25 cm3) was added dropwise at -5° C. After stirring for a further period of 30 minutes during which time the mixture warmed to the ambient temperature it was kept at the ambient temperature for 16 hours. The mixture was partitioned between water (300 cm3) and diethyl ether (200 cm3) and the aqueous phase extracted with ether (2×200 cm3) and the extracts combined with the ethereal phase. After washing with water (2×100 cm3) and drying over anhydrous magnesium sulphate, the ether was removed by evaporation under reduced pressure to yield a residual oil which was subjected to dry column chromatography using a silica column eluted first with dichloromethane (to remove triphenyl phosphine) and then with a mixture of dichloromethane (100 parts by volume) and ethyl acetate (5 parts by volume) to yield ethyl trans-2,2-dimethyl-3-[2-(2-methylprop-2-yl)pyrimidin-5-yl]cyclopropane carboxylate (2.8 g), the identity of which was confirmed by infra red and n.m.r. spectroscopy.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14](=[O:15])[N:13]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]([F:29])([F:28])[CH:25]([F:27])[F:26])=[CH:18][CH:17]=3)[CH:12]=[N:11]2)=[CH:6][CH:5]=1)([O-])=O.CO.[H][H]>[C].[Pd].ClCCl>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[C:14](=[O:15])[N:13]([C:16]3[CH:17]=[CH:18][C:19]([O:22][CH2:23][C:24]([F:28])([F:29])[CH:25]([F:26])[F:27])=[CH:20][CH:21]=3)[CH:12]=[N:11]2)=[CH:8][CH:9]=1
Reactant: [H][H]
Reactant: O=c1n(-c2ccc(OCC(F)(F)C(F)F)cc2)cnn1-c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Product: Nc1ccc(-n2ncn(-c3ccc(OCC(F)(F)C(F)F)cc3)c2=O)cc1
Yield: 90.2 %

Procedure:
2-(4—Nitrophenyl)-4-[4-(2,2,3,3-tetrafluoropropoxy)-phenyl]-3(2H,4H)-1,2,4-triazolone (5.5 g) and 10% palladium-carbon (50% wet, 0.5 g) were added to methanol (200 ml). The mixture was subjected to catalytic hydrogenation at ordinary temperature under ordinary pressure. When hydrogen absoption stopped, dichloromethane (200 ml) was added thereto and the catalyst was removed by filtration. The catalyst was washed with dichloroethane (50 ml). The washings and the filtrate were combined and distilled under reduced pressure to give 2-(4-aminophenyl)-4-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-3(2H,4H)-1,2,4-triazolone (4.6 g, 90%) as a white solid. This compound was used for next process without purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:9][NH2:10])[CH:5]=[CH:6][C:7]=1[F:8].[CH3:11][C:12]([O:15][C:16]([N:18]1[CH2:23][CH2:22][CH:21]([CH2:24][C:25]2[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=2)[C:28](O)=[O:29])[CH2:20][CH2:19]1)=[O:17])([CH3:14])[CH3:13].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([CH2:9][NH:10][C:28]([C:27]2[CH:26]=[C:25]([CH2:24][CH:21]3[CH2:22][CH2:23][N:18]([C:16]([O:15][C:12]([CH3:14])([CH3:13])[CH3:11])=[O:17])[CH2:19][CH2:20]3)[CH:33]=[CH:32][CH:31]=2)=[O:29])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: NCc1ccc(F)c(Br)c1
Reactant: CC(C)(C)OC(=O)N1CCC(Cc2cccc(C(=O)O)c2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(Cc2cccc(C(=O)NCc3ccc(F)c(Br)c3)c2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.2 %

Procedure:
To a solution of [(3-bromo-4-fluorophenyl)methyl]amine (0.802 g, 3.33 mmol) in DMF (12.0 mL) was added 3-[(1-{[(1,1-dimethylethyl)oxy]carbonyl}-4-piperidinyl)methyl]benzoic acid (1.060 g, 3.32 mmol), HATU (1.389 g, 3.65 mmol), and diisopropylethylamine (2.9 mL, 16.6 mmol). The reaction was allowed to stir at room temperature overnight. The reaction was diluted with EtOAc (300 mL), washed with 1N HCl (2×75 mL), then saturated NaHCO3 (3×75 mL), then brine (2×75 mL). The organic layer was dried over MgSO4, filtered, and concentrated under vacuum to give the desired product (1.58 g, 94.2%). EI-MS m/z 506(M−H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:37][CH:38]2[CH:43]3[CH2:44][CH2:45][CH:40]([CH2:41][CH2:42]3)[CH:39]2[C:46]([O:48][CH3:49])=[O:47])=[N:4][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[C:14]([F:17])[CH:15]=3)[N:10](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:9]=2)=[N:6][CH:7]=1.[SiH](CC)(CC)CC.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:1][C:2]1[C:3]([NH:37][CH:38]2[CH:43]3[CH2:42][CH2:41][CH:40]([CH2:45][CH2:44]3)[CH:39]2[C:46]([O:48][CH3:49])=[O:47])=[N:4][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[C:14]([F:17])[CH:15]=3)[NH:10][N:9]=2)=[N:6][CH:7]=1
Reactant: COC(=O)C1C2CCC(CC2)C1Nc1nc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3ncc(F)cc23)ncc1Cl
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)C1C2CCC(CC2)C1Nc1nc(-c2n[nH]c3ncc(F)cc23)ncc1Cl
Temperature: 25 °C
Yield: 66 %

Procedure:
To a solution of (+/−)-trans-(2,3)-methyl 3-((5-chloro-2-(5-fluoro-1-trityl-1H-pyrazolo[3,4-b]pyridin-3-yl)pyrimidin-4-yl)amino)bicyclo[2.2.2]octane-2-carboxylate, 38, (0.85 g, 1.26 mmol) in CH2Cl2 (42.5 mL) at room temperature was added Et3SiH (1.00 mL, 6.32 mmol) followed by trifluoroacetic acid (0.97 mL, 12.60 mmol). The reaction was stirred at room temperature. After the reaction was complete, as judged by LC-MS, the solution was concentrated in vacuo. Careful flash chromatography (SiO2, 0-7% MeOH—CH2Cl2, gradient elution) provided the desired product (373 mg, 66% yield)L 1H NMR (400 MHz, MeOD) δ 8.66 (dd, J=8.3, 2.5 Hz, 1H), 8.53 (s, 1H), 8.28 (s, 1H), 5.05 (d, J=6.5 Hz, 1H), 3.69 (s, 3H), 2.95 (d, J=6.8 Hz, 1H), 2.09 (s, 1H), 1.98 (s, 1H), 1.96-1.79 (m, 3H), 1.77-1.61 (m, 3H), 1.61-1.45 (m, 2H); LC/MS Gradient 10-90%, 0.1% formic 5 min, C18/ACN, RT=2.55 min, (M+H) 431.14.
Reaction SMILES: [F:1][C:2]1([F:36])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14]([NH:16][C:17]4[N:18]=[C:19]([C:27]5[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=5)[C:30](O)=[O:31])[C:20]5[C:25]([CH:26]=4)=[CH:24][CH:23]=[CH:22][CH:21]=5)=[O:15])[CH2:13][CH2:12]3)=[CH:10][C:4]=2[O:3]1.S(Cl)([Cl:39])=O.CN(C)C=O>ClCCl>[F:1][C:2]1([F:36])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14]([NH:16][C:17]4[N:18]=[C:19]([C:27]5[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=5)[C:30]([Cl:39])=[O:31])[C:20]5[C:25]([CH:26]=4)=[CH:24][CH:23]=[CH:22][CH:21]=5)=[O:15])[CH2:13][CH2:12]3)=[CH:10][C:4]=2[O:3]1
Reactant: O=C(O)c1cccc(-c2nc(NC(=O)C3(c4ccc5c(c4)OC(F)(F)O5)CC3)cc3ccccc23)c1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1cccc(-c2nc(NC(=O)C3(c4ccc5c(c4)OC(F)(F)O5)CC3)cc3ccccc23)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 3-(3-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)isoquinolin-1-yl)benzoic acid (1.26 g, 2.58 mmol) in dichloromethane (5 mL) was added thionyl chloride (922 mg, 564 μL, 7.75 mmol) and N,N-dimethyl formamide (20 μL). The reaction mixture was stirred at room temperature for 30 minutes before it was evaporated to dryness to yield 3-(3-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)isoquinolin-1-yl)benzoyl chloride as a yellow solid.
Reaction SMILES: [C:1]([C:4]1[O:5][C:6]2[CH:16]=[C:15]([NH2:17])[C:14]([Br:18])=[CH:13][C:7]=2[C:8]=1[C:9]([NH:11][CH3:12])=[O:10])(=[O:3])[CH3:2].C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28].[Li+].[OH-].O>C1COCC1.O>[C:1]([C:4]1[O:5][C:6]2[CH:16]=[C:15]([NH:17][S:27]([CH3:26])(=[O:29])=[O:28])[C:14]([Br:18])=[CH:13][C:7]=2[C:8]=1[C:9]([NH:11][CH3:12])=[O:10])(=[O:3])[CH3:2]
Reactant: CNC(=O)c1c(C(C)=O)oc2cc(N)c(Br)cc12
Reactant: CS(=O)(=O)Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CNC(=O)c1c(C(C)=O)oc2cc(NS(C)(=O)=O)c(Br)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 44.7 %

Procedure:
To a mixture of 2-acetyl-6-amino-5-bromo-N-methylbenzofuran-3-carboxamide (500 mg, 1.61 mmol) and triethylamine (650 mg, 6.43 mmol) in THF (20 mL) was added MsCl (406 mg, 3.54 mmol) dropwise at 0° C. under N2. The mixture was stirred at room temperature for 1 hour. The mixture was quenched with H2O and extracted with EtOAc, and then the combined organic layers were washed with brine, dried over Na2SO4, and concentrated in vacuo to give the crude product. The crude product was dissolved in THF (20 mL) and then a solution of LiOH/H2O (200 mg/6 mL) was added. The mixture was stirred at room temperature for 1 hour, then water was added to the mixture and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated in vacuo to give the crude product. The crude product was purified by column chromatography to give compound 2-acetyl-5-bromo-N-methyl-6-(methylsulfonamido)benzofuran-3-carboxamide (280 mg, yield: 44.8%). 1H-NMR (CDCl3, 400 MHz) δ 9.83 (s, 1H), 8.97 (s, 1H).7.91 (s, 1H), 7.07 (s, 1H), 3.06 (s, 3H), 3.02 (d, J=4.8 Hz, 3H), 2.77 (s, 3H). MS (M+H)+: 389/391.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[O:6][C@@H:5]([CH:7]=O)[C:4]([CH3:10])([CH3:9])[O:3]1.[OH2:12].Cl.[NH2:14]O.C([O-])([O-])=O.[Na+].[Na+]>CO>[CH3:1][C:2]1([CH3:11])[O:6][C@@H:5]([CH:7]=[N:14][OH:12])[C:4]([CH3:10])([CH3:9])[O:3]1
Reactant: CC1(C)O[C@@H](C=O)C(C)(C)O1
Reactant: O
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: CC1(C)O[C@@H](C=NO)C(C)(C)O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 74 %

Procedure:
(R)-2,2,5,5-Tetramethyl-1,3-dioxolane-4-carbaldehyde (16 g, 101 mmol) [Burger, A. Synthesis 1989, (2) 93-97] was dissolved in 1:1 methanol:water (250 mL) and hydroxylamine hydrochloride (7.0 g, 101 mmol), and Na2CO3 (5.4 g, 51 mmol) was added. The reaction was stirred at ambient temperature for 2 hours. The methanol was partially removed in vacuo and the aqueous layer was extracted with CH2Cl2, dried, filtered and concentrated to afford (S)-2,2,5,5-tetramethyl-1,3-dioxolane-4-carbaldehyde oxime (13 g, 75 mmol, 74% yield) as an amber oil.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH:9]=[C:8]([C:11]2[CH:12]=[C:13]3[CH2:27][C:18]4([CH2:26][C:20]5([CH2:25][CH2:24][NH:23][CH2:22][CH2:21]5)[CH2:19]4)[O:17][C:14]3=[CH:15][N:16]=2)[CH2:7][CH2:6]1)(=[O:4])=[O:3].[F:28][C:29]([F:46])([F:45])[C@H:30]([O:32][C:33](=O)[O:34]C1C=CC([N+]([O-])=O)=CC=1)[CH3:31]>>[CH3:1][S:2]([N:5]1[CH2:6][CH:7]=[C:8]([C:11]2[CH:12]=[C:13]3[CH2:27][C:18]4([CH2:19][C:20]5([CH2:21][CH2:22][N:23]([C:33]([O:32][C@H:30]([CH3:31])[C:29]([F:46])([F:45])[F:28])=[O:34])[CH2:24][CH2:25]5)[CH2:26]4)[O:17][C:14]3=[CH:15][N:16]=2)[CH2:9][CH2:10]1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)N1CC=C(c2cc3c(cn2)OC2(C3)CC3(CCNCC3)C2)CC1
Reactant: C[C@@H](OC(=O)Oc1ccc([N+](=O)[O-])cc1)C(F)(F)F
Product: C[C@@H](OC(=O)N1CCC2(CC1)CC1(Cc3cc(C4=CCN(S(C)(=O)=O)CC4)ncc3O1)C2)C(F)(F)F

Procedure:
The title compound is prepared from 5-(1-methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-dispiro[2,3-dihydrofuro[2,3-c]pyridine-2,1′-cyclobutane-3′,4″-piperidine] (HCl salt) and (R)-carbonic acid 4-nitro-phenyl ester 2,2,2-trifluoro-1-methyl-ethyl ester following a procedure analogous to that described for Example 12. LC (method 6): tR=1.00 min; Mass spectrum (ESI+): m/z=530 [M+H]+.
Reaction SMILES: C([C:3]1[C:8]2[N:9]=[C:10](/[CH:12]=[CH:13]/[C:14]3[CH:19]=[C:18]([NH2:20])[CH:17]=[CH:16][C:15]=3[Cl:21])[NH:11][C:7]=2[CH:6]=[CH:5][CH:4]=1)C.[CH3:22][C:23]1C=CC2SC(/C=C/C3C=C(N)C(Cl)=CC=3Cl)=NC=2C=1.NN>CO.B#[Ni]>[Cl-:21].[NH2:20][C:18]1[CH:17]=[CH:16][C:15]2[N:9]3[C:8]4[CH:3]=[CH:4][CH:5]=[CH:6][C:7]=4[N+:11]([CH2:22][CH3:23])=[C:10]3[CH:12]=[CH:13][C:14]=2[CH:19]=1
Reactant: CCc1cccc2[nH]c(/C=C/c3cc(N)ccc3Cl)nc12
Reactant: Cc1ccc2sc(/C=C/c3cc(N)c(Cl)cc3Cl)nc2c1
Agent: B#[Ni]
Agent: NN
Solvent: CO
Product: CC[n+]1c2ccccc2n2c3ccc(N)cc3ccc21
Product: [Cl-]

Procedure:
The amino precursors of ABQ-38 and ABQ-95, (E)-7-ethyl-2-(5-amino-2-chlorostyryl)benzimidazole IIv and (E)-5-methyl-2-(5-amino-2,4-dichlorostyryl)benzothiazole IId, respectively, were prepared by the reduction of the corresponding nitro derivatives with hydrazine in the presence of nickel boride in dry methanol, see FIG. 3. (E)-7-ethyl-2-(5-amino-2-chlorostyryl)benzimidazole IIv was photocyclized as described (BQS Method 1) to give 3-amino-7-ethylbenzimidazo[3,2-a]quinolinium chloride (ABQ-38) as a yellow solid: 1H NMR (500.13 MHz, DMSO-d6): δ ppm 9.05 (d, 1H, J=8.50 Hz), 8.88 (d, 1H, J=9.0 Hz), 8.56 (d, 1H, J=9.5 Hz, 8.27 (d, 1H, J=8.5 Hz), 8.23 (d, 1H, J=9.50 Hz), 7.90 (t, 1H, J=7.5 Hz), 7.81 (t, 1H, J=7.5 Hz), 7.43 (dd, 1H, J=8.5, 2.5), 7.27 (d, 1H, J=2.5 Hz), 4.83 (q, 2H, J=7.0 Hz), 1.48 (t, 3H, J=7.0 Hz); UV-vis (95% EtOH) λmax/nm (e): 409 (1410), 351 (8104), 336 (9815) and 271 (20866); HRMS calcd for C17H16N3 (compound without the chloride counter ion) 262.1, found by ESI at m/z 261.9. (E)-5-methyl-2-(5-amino-2,4-dichlorostyryl)benzothiazole IId was photocyclized as described (BQS Method 1) to give 3-amino-2-chloro-10-methylbenzothiazolo[3,2-a]quinolinium chloride (ABQ-95) as a yellow solid: 1H NMR (500.13 MHz, DMSO-d6): δ ppm 9.17 (s, 1H), 8.92 (s, 1H), 8.63(AB quartet, 2H, J=9.5 Hz), 8.48 (d, 1H, J=8.5 Hz), 7.76 (d, 1H, J=8.5 Hz), 7.53 (s, 1H), 6.50 (m, 2H), 2.70 (s, 3H); UV-vis (95% EtOH) λmax/nm (e): 429 (4417), 380 (10 387), 282 (22 568) and 214(2650); HRMS calcd for C16H12ClN2S 299.0 (without the chloride counter ion), found by ESI at m/z 299.0 M+.
Reaction SMILES: [C:1]([C:3]1[C@@H:8]([C:9]2[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][C:10]=2[S:17]([CH3:20])(=[O:19])=[O:18])[N:7]([C:21](OC2C=CC([N+]([O-])=O)=CC=2)=[O:22])[C:6](=[O:33])[N:5]([C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([C:40]([F:43])([F:42])[F:41])[CH:35]=2)[C:4]=1[CH3:44])#[N:2].[CH3:45][O:46][CH2:47][CH2:48][NH2:49]>C(#N)C>[C:1]([C:3]1[C@@H:8]([C:9]2[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][C:10]=2[S:17]([CH3:20])(=[O:19])=[O:18])[N:7]([C:21]([NH:49][CH2:48][CH2:47][O:46][CH3:45])=[O:22])[C:6](=[O:33])[N:5]([C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([C:40]([F:42])([F:43])[F:41])[CH:35]=2)[C:4]=1[CH3:44])#[N:2]
Reactant: COCCN
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(C)(=O)=O)N(C(=O)Oc2ccc([N+](=O)[O-])cc2)C(=O)N1c1cccc(C(F)(F)F)c1
Solvent: CC#N
Product: COCCNC(=O)N1C(=O)N(c2cccc(C(F)(F)F)c2)C(C)=C(C#N)[C@H]1c1ccc(C#N)cc1S(C)(=O)=O

Procedure:
According to the General Procedure 1, 4-nitrophenyl (6S)-5-cyano-6-[4-cyano-2-(methylsulfonyl)phenyl]-4-methyl-2-oxo-3-[3-(trifluoromethyl)phenyl]-3,6-dihydropyrimidine-1(2H)-carboxylate (78.0 mg, 0.125 mmol; Example 6A) was reacted with 2-methoxyethylamine (28.1 mg, 0.374 mmol) in acetonitrile (1 ml) to give the target compound (55 mg, 78% of theory).
Reaction SMILES: C[O:2][C:3](=[O:53])[C@@H:4]([NH:20][C:21]([C@@H:23]1[CH2:32][C:31]2[CH:30]=[C:29]3[O:33][CH2:34][C@H:35]([C:37]4[CH:42]=[CH:41][C:40]([O:43][CH2:44][C:45]5[CH:50]=[CH:49][C:48]([Cl:51])=[C:47]([Cl:52])[CH:46]=5)=[CH:39][CH:38]=4)[O:36][C:28]3=[CH:27][C:26]=2[CH2:25][NH:24]1)=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.[N:54]([C@@H:57]([C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1)[CH3:58])=[C:55]=[O:56]>>[C:18]([C:15]1[CH:14]=[CH:13][C:12]([C:9]2[CH:10]=[CH:11][C:6]([CH2:5][C@H:4]([NH:20][C:21]([C@@H:23]3[CH2:32][C:31]4[CH:30]=[C:29]5[O:33][CH2:34][C@H:35]([C:37]6[CH:38]=[CH:39][C:40]([O:43][CH2:44][C:45]7[CH:50]=[CH:49][C:48]([Cl:51])=[C:47]([Cl:52])[CH:46]=7)=[CH:41][CH:42]=6)[O:36][C:28]5=[CH:27][C:26]=4[CH2:25][N:24]3[C:55](=[O:56])[NH:54][C@@H:57]([C:59]3[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=3)[CH3:58])=[O:22])[C:3]([OH:2])=[O:53])=[CH:7][CH:8]=2)=[CH:17][CH:16]=1)#[N:19]
Reactant: C[C@@H](N=C=O)c1ccccc1
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3
Product: C[C@@H](NC(=O)N1Cc2cc3c(cc2C[C@H]1C(=O)N[C@@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)C(=O)O)OC[C@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)O3)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (S)-3-(4′-Cyano-biphenyl-4-yl)-2-({(3S,8S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino [2,3-g]isoquinoline-8-carbonyl}-amino)-propionic acid methyl ester (20 mg) was added ((R)-1-isocyanato-ethyl)-benzene (5 equiv) and the reaction stirred at room temperature for 1 hour. The reaction mixture was directly purified over silica (hexanes to 1:1 hexanes EtOAc to 1:1 hexanes EtOAc+1% MeOH to 1:1 hexanes EtOAc+2% MeOH to 1:1 hexanes EtOAc+3% MeOH). The resulting compound was hydrolyzed according to General Procedure B to give the title compound (26 mg). LCMS (m/z): 884.
Reaction SMILES: C1(P([N:15]=[N+:16]=[N-:17])(C2C=CC=CC=2)=O)C=CC=CC=1.N12CCCN=C1CCCCC2.[NH2:29][C:30]([NH:32][C:33]1[NH:34][C:35]2[C:40]([C:41]=1[C:42]([NH2:44])=[O:43])=[CH:39][CH:38]=[C:37]([CH2:45]O)[CH:36]=2)=[O:31].O>O1CCCC1>[NH2:29][C:30]([NH:32][C:33]1[NH:34][C:35]2[C:40]([C:41]=1[C:42]([NH2:44])=[O:43])=[CH:39][CH:38]=[C:37]([CH2:45][N:15]=[N+:16]=[N-:17])[CH:36]=2)=[O:31]
Reactant: NC(=O)Nc1[nH]c2cc(CO)ccc2c1C(N)=O
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: O
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: [N-]=[N+]=NCc1ccc2c(C(N)=O)c(NC(N)=O)[nH]c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 11.4 %

Procedure:
Diphenylphosphoryl azide (42 μL, 0.19 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (29 μL, 0.19 mmol) were added to a solution of 2-aminocarbonylamino-6-hydroxymethylindole-3-carboxamide (Compound 16-1, 40 mg, 0.16 mmol) in anhydrous tetrahydrofuran (5 mL) under ice-cooling, the mixture was stirred at room temperature overnight. Water (10 mL) was added to the reaction mixture, and the whole was extracted with ethyl acetate (10 mL). The organic layer was washed with brine (20 mL) and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound (5.0 mg) as a yellow solid (yield 11%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([F:23])[CH:17]=1.ClC(Cl)(O[C:28](=[O:34])OC(Cl)(Cl)Cl)Cl.[CH3:36][NH:37][NH2:38].C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:28]([NH:38][NH:37][CH3:36])=[O:34])=[C:18]([F:23])[CH:17]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2nccc(Oc3ccc(N)c(F)c3)c2cc1OC
Reactant: CNN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CNNC(=O)Nc1ccc(Oc2ccnc3cc(OC)c(OC)cc23)cc1F
Yield: 76.5 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-fluoroaniline (50 mg) was added to toluene (5 ml), and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (50 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, methylhydrazine (50 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to the reaction solution to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with water and saturated brine in that order. The organic layer was then dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by HPLC using chloroform/methanol for development to give the title compound (47 mg, yield 76%).