Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:12]=3)=[C:9]([CH2:25][CH3:26])[N:8]([C@@H:27]3[CH2:30][C@H:29]([CH2:31]O)[CH2:28]3)[C:4]=2[N:5]=[CH:6][N:7]=1.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[NH:44]1[CH2:48][CH2:47][CH2:46][CH2:45]1>N1C=CC=CC=1>[CH2:18]([O:17][C:13]1[CH:12]=[C:11]([C:10]2[C:3]3[C:2]([NH2:1])=[N:7][CH:6]=[N:5][C:4]=3[N:8]([C@H:27]3[CH2:28][C@@H:29]([CH2:31][N:44]4[CH2:48][CH2:47][CH2:46][CH2:45]4)[CH2:30]3)[C:9]=2[CH2:25][CH3:26])[CH:16]=[CH:15][CH:14]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCc1c(-c2cccc(OCc3ccccc3)c2)c2c(N)ncnc2n1[C@H]1C[C@@H](CO)C1
Reactant: C1CCNC1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: CCc1c(-c2cccc(OCc3ccccc3)c2)c2c(N)ncnc2n1[C@H]1C[C@@H](CN2CCCC2)C1

Procedure:
The title compound is prepared in a one pot reaction in analogy to Example 116 starting from 0.2 g (0.46 mmol) cis-{3-[4-amino-5-(3-benzyloxy-phenyl)-6-ethyl-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutyl}-methanol of Example 124 and 0.18 g (0.92 mmol) p-toluenesulfonyl chloride in 2 ml dry pyridine followed by 2 ml pyrrolidine. The reaction is controlled by tlc. Analytical HPLC: tR=9.61 min (Grad 1); ES-MS: m/eo=482.0; NMR (DMSO-d6; not all signals reported): 8.12/s (1H); 6.9-7.5/several m's (6H), 7.05/“d” (1H); 6.95/s (1H); 6.92/“d” (1H); 5.4-6.0/b (NH2); 5.15/s (2H); 4.72/m (1H); 2.62/q (2H); 1.06/t (3H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].C1C(=O)N([Br:19])C(=O)C1>CC#N>[C:1]([C:5]1[CH:10]=[C:9]([Br:19])[CH:8]=[CH:7][C:6]=1[OH:11])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)c1ccccc1O
Solvent: CC#N
Product: CC(C)(C)c1cc(Br)ccc1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.3 %

Procedure:
To a solution of 2-tert-butylphenol (250 g, 1.67 mol) in CH3CN (1500 mL) was added NBS (300 g, 1.67 mol) at room temperature. After addition, the mixture was stirred at room temperature overnight and then the solvent was removed. Petroleum ether (1000 mL) was added, and the resulting white precipitate was filtered off. The filtrate was concentrated under reduced pressure to give the crude 2-tert-butyl-4-bromophenol (380 g), which was used without further purification.
Reaction SMILES: CS([O:5][C@H:6]1[C@H:10]([NH:11][S:12]([CH:15]([CH3:17])[CH3:16])(=[O:14])=[O:13])[CH2:9][O:8][CH2:7]1)(=O)=O.[Br:18][C:19]1[CH:24]=[CH:23][C:22](O)=[CH:21][CH:20]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C(=O)(O)[O-].[Na+]>C(#N)C>[Br:18][C:19]1[CH:24]=[CH:23][C:22]([O:5][C@@H:6]2[CH2:7][O:8][CH2:9][C@H:10]2[NH:11][S:12]([CH:15]([CH3:17])[CH3:16])(=[O:14])=[O:13])=[CH:21][CH:20]=1
Reactant: CC(C)S(=O)(=O)N[C@@H]1COC[C@H]1OS(C)(=O)=O
Reactant: Oc1ccc(Br)cc1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CC(C)S(=O)(=O)N[C@@H]1COC[C@H]1Oc1ccc(Br)cc1
Temperature: 25 °C

Procedure:
In a microwave vial, a solution of trans-4-[(isopropylsulfonyl)amino]tetrahydrofuran-3-yl methanesulfonate (546 mg, 1.90 mmol) in acetonitrile (8 mL) was combined with 4-bromophenol (97%, 407 mg, 2.28 mmol) and cesium carbonate (929 mg, 2.85 mmol). The reaction was irradiated in a microwave reactor at 160° C. for 2 hours, then cooled to room temperature and treated with saturated aqueous sodium bicarbonate solution (10 mL). The reaction was extracted with ethyl acetate and the combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (Gradient: 20% to 50% ethyl acetate in heptane), to afford trans-N-[4-(4-bromophenoxy)tetrahydrofuran-3-yl]propane-2-sulfonamide. Yield: 626 mg, 1.72 mmol, 91%. LCMS m/z 361.9 (M−1). 1H NMR (400 MHz, CDCl3) δ 1.38 (d, J=6.9 Hz, 3H), 1.40 (d, J=6.8 Hz, 3H), 3.19 (septet, J=6.8 Hz, 1H), 3.82 (br d, J=8.0, 1H), 3.91 (dd, J=10.6, 1.7 Hz, 1H), 4.02-4.08 (m, 2H), 4.24 (dd, J=10.5, 4.7 Hz, 1H), 4.85 (br d, J=4.7 Hz, 1H), 4.95 (br d, J=8.3 Hz, 1H), 6.88 (d, J=9.0 Hz, 2H), 7.40 (d, J=9.0 Hz, 2H). 13C NMR (100 MHz, CDCl3) δ 16.45, 16.71, 54.14, 58.70, 71.45, 71.81, 82.07, 113.97, 117.20, 132.52, 155.75.
Reaction SMILES: [CH2:1]([O:3][CH:4]1[C:13](=[C:14]=[O:15])[N:12]([CH3:16])[C:11]2[N:10]=[C:9]3[CH:17]=[C:18](F)[C:19]([F:21])=[CH:20][C:8]3=[CH:7][C:6]=2[C:5]1=[O:23])[CH3:2].Cl.Cl.[CH2:26]([N:28]([CH2:33][CH3:34])[CH:29]1[CH2:32][NH:31][CH2:30]1)[CH3:27]>>[CH2:26]([N:28]([CH2:33][CH3:34])[CH:29]1[CH2:32][N:31]([C:18]2[C:19]([F:21])=[CH:20][C:8]3[C:9]([CH:17]=2)=[N:10][C:11]2[N:12]([CH3:16])[C:13](=[C:14]=[O:15])[CH:4]([O:3][CH2:1][CH3:2])[C:5](=[O:23])[C:6]=2[CH:7]=3)[CH2:30]1)[CH3:27]
Reactant: CCOC1C(=O)c2cc3cc(F)c(F)cc3nc2N(C)C1=C=O
Reactant: CCN(CC)C1CNC1
Agent: Cl
Product: CCOC1C(=O)c2cc3cc(F)c(N4CC(N(CC)CC)C4)cc3nc2N(C)C1=C=O

Procedure:
8-(3-Diethylamino-1-azetidinyl)-3-ethoxy-carbonyl-7-fluoro-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine was prepared under the conditions of Example 2, but starting with 2 g of 3-ethoxy-carbonyl-7,8-difluoro-1-methyl-4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine and 1.4 g of 3-(diethylamino)-azetidine dihydrochloride. After recrystallization of the crude product in 500 cm3 of methanol, 2.07 g of 8-(3-diethylamino-1-azetidinyl)-3-ethoxy-carbonyl-7-fluoro-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine are obtained in the form of a yellow solid, melting point 260° C.
Reaction SMILES: [NH:1]([C:3]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[NH:5][N:4]=1)[NH2:2].[CH:13]([O:16][C:17](Cl)=[O:18])([CH3:15])[CH3:14]>N1C=CC=CC=1>[CH:13]([O:16][C:17]([NH:2][NH:1][C:3]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[NH:5][N:4]=1)=[O:18])([CH3:15])[CH3:14]
Reactant: NNc1n[nH]c2cc(Cl)ccc12
Reactant: CC(C)OC(=O)Cl
Solvent: c1ccncc1
Product: CC(C)OC(=O)NNc1n[nH]c2cc(Cl)ccc12
Yield: 68 %

Procedure:
Analogously to Example 1, 0.05 mol of 3-hydrazino-6-chloro-indazole and 0.05 mol of chlorocarbonic acid isopropyl ester in 30 ml of pyridine at 0° - 5° C, followed by 3 hours at room temperature, give 3-isopropoxycarbonylhydrazino-6-chloroindazole (melting point 184° - 185° C after recrystallisation from isopropanol: yield, 68% of theory).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](=[O:12])C(=O)[NH:8]2)=[C:4]([F:13])[CH:3]=1.[OH:14]O>[OH-].[Na+]>[NH2:8][C:9]1[CH:10]=[C:2]([Br:1])[CH:3]=[C:4]([F:13])[C:5]=1[C:6]([OH:12])=[O:14]
Reactant: O=C1Nc2cc(Br)cc(F)c2C1=O
Reactant: OO
Agent: [Na+]
Agent: [OH-]
Product: Nc1cc(Br)cc(F)c1C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 6-bromo-4-fluoroindoline-2,3-dione (7.4 g, 31.8 mmol) in 1 M NaOH (100 mL) was added 38% H2O2 (13 mL) dropwise. The resulting solution was stirred at rt for 2 h. The mixture was filtered and the filtrate was acidified using hydrochloric acid (2 N) till pH became around 2. The precipitate was formed and filtered, washed with water, dried under vacuum to give 2.8 g of the desired product. MS (ESI): 232, 234 (MH−).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl[C:15]1[N:20]=[C:19](Cl)[C:18]([CH3:22])=[CH:17][N:16]=1>>[C:8]1([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[NH:1][C:15]2[N:20]=[C:19]([NH:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:18]([CH3:22])=[CH:17][N:16]=2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: Cc1cnc(Cl)nc1Cl
Reactant: Nc1ccccc1-c1ccccc1
Product: Cc1cnc(Nc2ccccc2-c2ccccc2)nc1Nc1ccccc1-c1ccccc1

Procedure:
In like manner to the preparation of 5-fluoro-N2,N4-bis(3-hydroxyphenyl)-2,4-pyrimidinediamine, 2-aminobiphenyl and 2,4-dichloro-5-methylpyrimidine were reacted to provide N2,N4-bis(2-phenylphenyl)-5-methyl-2,4-pyrimidinediamine. LCMS: ret. time: 30.47 min.; purity: 91%; MS (m/e): 429 (MH+).
Reaction SMILES: [N:1]([CH:4]([C:6]1[N:7]=[C:8]2[S:16][CH:15]=[C:14]([CH3:17])[N:9]2[C:10](=[O:13])[C:11]=1Br)[CH3:5])=[N+:2]=[N-:3].[F:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].O>O1CCOCC1.C(OCC)(=O)C.Cl[Pd](Cl)(P(C(C)(C)C)(C(C)(C)C)C1C=CC(N(C)C)=CC=1)P(C1C=CC(N(C)C)=CC=1)(C(C)(C)C)C(C)(C)C>[N:1]([CH:4]([C:6]1[N:7]=[C:8]2[S:16][CH:15]=[C:14]([CH3:17])[N:9]2[C:10](=[O:13])[C:11]=1[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[F:18])[CH3:5])=[N+:2]=[N-:3]
Reactant: OB(O)c1ccccc1F
Reactant: Cc1csc2nc(C(C)N=[N+]=[N-])c(Br)c(=O)n12
Agent: CN(C)c1ccc([PH](C(C)(C)C)(C(C)(C)C)[Pd](Cl)(Cl)[PH](c2ccc(N(C)C)cc2)(C(C)(C)C)C(C)(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: Cc1csc2nc(C(C)N=[N+]=[N-])c(-c3ccccc3F)c(=O)n12
Temperature: 100 °C
Reaction time: 8 h
Yield: 69.5 %

Procedure:
To a mixture of 7-(1-azidoethyl)-6-bromo-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one (0.12 g, 0.38 mmol) and (2-fluorophenyl)boronic acid (0.064 g, 0.46 mmol) in 1,4-dioxane (4 mL) was added a 1 N solution of sodium carbonate in water (0.8 mL, 0.8 mmol) and dichloro(bis{di-tert-butyl[4-(dimethylamino)phenyl]phosphoranyl})palladium (0.014 g, 0.019 mmol). The mixture was stirred at 100° C. overnight. After cooling, the mixture was diluted with ethyl acetate, washed with water, dried over Na2SO4, concentrated, and purified on silica gel (0-35% ethyl acetate/hexane) to give the desired product (87 mg). LCMS calculated for C15H13FN5OS (M+H)+: m/z=330.1. Found: 330.0.
Reaction SMILES: [NH2:1][CH:2]([C:4]1[N:5]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:6](=[O:15])[C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][C:8]=2[CH3:14])[CH3:3].CCN(C(C)C)C(C)C.[F:31][C:32]1[N:40]=[C:39]2[C:35]([N:36]=[C:37]([NH:47][CH:48]([C:50]3[N:51]([C:62]4[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=4)[C:52](=[O:61])[C:53]4[C:58]([CH:59]=3)=[CH:57][CH:56]=[CH:55][C:54]=4[CH3:60])[CH3:49])[N:38]2[CH:41]2[CH2:46][CH2:45][CH2:44][CH2:43][O:42]2)=[CH:34][N:33]=1>CCCCO>[F:31][C:32]1[N:40]=[C:39]2[C:35]([N:36]=[CH:37][NH:38]2)=[C:34]([NH:1][C@H:2]([C:4]2[N:5]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:6](=[O:15])[C:7]3[C:12]([CH:13]=2)=[CH:11][CH:10]=[CH:9][C:8]=3[CH3:14])[CH3:3])[N:33]=1.[F:31][C:32]1[N:40]=[C:39]2[C:35]([N:36]=[C:37]([NH:47][CH:48]([C:50]3[N:51]([C:62]4[CH:63]=[CH:64][CH:65]=[CH:66][CH:67]=4)[C:52](=[O:61])[C:53]4[C:58]([CH:59]=3)=[CH:57][CH:56]=[CH:55][C:54]=4[CH3:60])[CH3:49])[N:38]2[CH:41]2[CH2:46][CH2:45][CH2:44][CH2:43][O:42]2)=[CH:34][N:33]=1
Reactant: Cc1cccc2cc(C(C)N)n(-c3ccccc3)c(=O)c12
Agent: Cc1cccc2cc(C(C)Nc3nc4cnc(F)nc4n3C3CCCCO3)n(-c3ccccc3)c(=O)c12
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc2cc([C@H](C)Nc3nc(F)nc4[nH]cnc34)n(-c3ccccc3)c(=O)c12
Temperature: 120 °C
Reaction time: 16 h

Procedure:
3-(1-Aminoethyl)-8-methyl-2-phenylisoquinolin-1(2H)-one (200 mg, 0.72 mol) 6-chloro-2fluoro-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (compound 5202) (369 mg, 1.44 mmol) and DIPEA (279 mg, 2.16 mmol) were dissolved in n-BuOH (20 mL) in a sealed tube, and the resulting mixture was stirred at 120° C. for 16 h. The reaction mixture was concentrated in vacuo and the residue was purified by flash column chromatography on silica gel (eluting with 30% to 50% Hex/EA) to afford the desired product, 3-(1-(2-fluoro-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-ylamino)ethyl)-8-methyl-2-phenylisoquinolin-1(2H)-one (compound 5203) (167 mg, 47% yield) as a white solid.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[N:7]12[CH2:16][CH:11]3[CH2:12][CH:13]([CH2:15][CH:9]([CH:10]3[C:17](OCC)=[O:18])[CH2:8]1)[CH2:14]2.O.[OH-].[Na+]>C1COCC1>[N:7]12[CH2:16][CH:11]3[CH2:12][CH:13]([CH2:15][CH:9]([CH:10]3[CH2:17][OH:18])[CH2:8]1)[CH2:14]2
Reactant: CCOC(=O)C1C2CC3CC1CN(C3)C2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: OCC1C2CC3CC1CN(C3)C2
Reaction time: 1 h

Procedure:
To a suspension of LAH in THF was added dropwise a solution of ethyl 1-azatricyclo[3.3.1.13,7]decane-4-carboxylate in THF at 0 to 5° C., followed by stirring at the same temperature for 1 hour. Under ice-cooling, to the reaction mixture were added water, a 15% aqueous NaOH solution, and then water in this order. The insolubles were removed by filtration through Celite, followed by washing with EtOAc. The filtrate was dried over MgSO4 and then concentrated under reduced pressure to obtain 1-azatricyclo[3.3.1.13,7]decan-4-yl methanol as a colorless oily substance.
Reaction SMILES: S(Cl)([Cl:3])=O.[F:5][C:6]([F:23])([F:22])[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:14]([C:19](O)=[O:20])=[CH:15][CH:16]=[CH:17][CH:18]=2)=[CH:9][CH:8]=1>CN(C=O)C.C(Cl)Cl>[F:5][C:6]([F:23])([F:22])[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:14]([C:19]([Cl:3])=[O:20])=[CH:15][CH:16]=[CH:17][CH:18]=2)=[CH:9][CH:8]=1
Reactant: O=C(O)c1ccccc1-c1ccc(C(F)(F)F)cc1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1ccccc1-c1ccc(C(F)(F)F)cc1

Procedure:
Thionyl chloride (3.6 ml) was added to a clear solution of 4′-(trifluoromethyl)-[1,1′-biphenyl]-2-carboxylic acid (0.025 mol) in DMF (1 ml) and DCM (100 ml). The mixture was stirred and refluxed for one hour. The solvent was evaporated. DCM (50 ml) was added to the residue, then evaporated, yielding 4′-(trifluoromethyl)-[1,1′-biphenyl]-2-carbonyl chloride (intermediate 5).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:35])[NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:18]=[C:19]4[C:23](=[CH:24][CH:25]=3)[C:22](=[O:26])[N:21]([C@@H:27]([CH:32]([CH3:34])[CH3:33])[C:28]([O:30][CH3:31])=[O:29])[CH2:20]4)=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.[NH2:36][C:37]1C=CC(C2C=C3C(=CC=2)C(=O)N([C@@H](C(C)C)C(OC)=O)C3)=CC=1.C(C1C=C(N=C=O)C=CC=1)#N>>[C:37]([C:7]1[CH:6]=[C:5]([NH:8][C:9](=[O:35])[NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:18]=[C:19]4[C:23](=[CH:24][CH:25]=3)[C:22](=[O:26])[N:21]([C@@H:27]([CH:32]([CH3:33])[CH3:34])[C:28]([O:30][CH3:31])=[O:29])[CH2:20]4)=[CH:13][CH:12]=2)[CH:4]=[CH:3][CH:2]=1)#[N:36]
Reactant: COC(=O)[C@H](C(C)C)N1Cc2cc(-c3ccc(N)cc3)ccc2C1=O
Reactant: COC(=O)[C@H](C(C)C)N1Cc2cc(-c3ccc(NC(=O)Nc4ccc(F)cc4)cc3)ccc2C1=O
Agent: N#Cc1cccc(N=C=O)c1
Product: COC(=O)[C@H](C(C)C)N1Cc2cc(-c3ccc(NC(=O)Nc4cccc(C#N)c4)cc3)ccc2C1=O

Procedure:
The compound of example 254 was prepared analogous to compound of example 224 by reaction of compound of example 223 with 3-cyanophenyl isocyanate. The compound of example 254 was used directly without isolation for the preparation of compound of example 255.
Reaction SMILES: C([O:4][C@@H:5]1[CH2:24][CH2:23][C@@:22]2([CH3:25])[C@@H:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:21]2[CH2:20][CH2:19][C@@:18]2([CH3:26])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[C:15](=[O:17])[CH3:16])[CH2:6]1)(=O)C.Cl(O)(=O)(=O)=O>CO>[OH:4][C@@H:5]1[CH2:24][CH2:23][C@@:22]2([CH3:25])[C@@H:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:21]2[CH2:20][CH2:19][C@@:18]2([CH3:26])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[C:15](=[O:17])[CH3:16])[CH2:6]1
Reactant: CC(=O)O[C@@H]1CC[C@@]2(C)[C@@H](CC[C@@H]3[C@@H]2CC[C@]2(C)[C@@H](C(C)=O)CC[C@@H]32)C1
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CO
Product: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Yield: 107.8 %

Procedure:
3α-acetoxy-5α-pregnan-20-one (4.8 g) in 150 mL of methanol was cooled to 0° C. with an ice bath and 15.0 mL of perchloric acid was added dropwise. After 30 m of stirring, the ice bath was removed and the reaction mixture was left stirring for three days. The reaction mixture was poured into water and extracted with chloroform three times. The chloroform extracts were combined, dried over magnesium sulfate, and the solvent evaporated to give 4.57 g of crude product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:10](=[N:22][O:23][CH2:24][C:25]2[N:30]=[C:29]([N:31]3C(=O)C4C(=CC=CC=4)C3=O)[CH:28]=[CH:27][CH:26]=2)[C:11]2[C:16]([Cl:17])=[CH:15][C:14]([C:18]([F:21])([F:20])[F:19])=[CH:13][N:12]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].O.NN>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]([C:10](=[N:22][O:23][CH2:24][C:25]2[N:30]=[C:29]([NH2:31])[CH:28]=[CH:27][CH:26]=2)[C:11]2[C:16]([Cl:17])=[CH:15][C:14]([C:18]([F:20])([F:21])[F:19])=[CH:13][N:12]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(C(=NOCc2cccc(N3C(=O)c4ccccc4C3=O)n2)c2ncc(C(F)(F)F)cc2Cl)cc1Br
Agent: NN
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(C(=NOCc2cccc(N)n2)c2ncc(C(F)(F)F)cc2Cl)cc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
To a solution of 2-(6-{[({(3-bromo-4-methoxyphenyl)[3-chloro-5-(trifluoromethyl)pyridin-2-yl]methylene}amino)oxy]methyl}pyridin-2-yl)-1H-isoindole-1,3(2H)-dione (7.00 g, 9.75 mmol) in tetrahydrofuran (150 mL) was added hydrazine hydrate (2.37 mL, 48.7 mmol) dropwise. After stirring overnight at room temperature, the reaction mixture was filtered, and the filtrate concentrated in vacuo. Purification on silica gel afforded 6-{[({(3-bromo-4-methoxyphenyl)[3-chloro-5-(trifluoromethyl)pyridin-2-yl]methylene}amino)oxy]methyl}pyridin-2-amine as an oil [4.00 g, yield 75%; HPLC/MS: m/z=516 (M+H); log P(HCOOH)=2.54].
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:23]([O:25][CH3:26])=[O:24])[C:5]2[O:9][C:8]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[O:7][C:6]=2[CH:22]=1.[C-:27]#[N:28].[K+].C1OCCOCCOCCOCCOCCOC1.CCOC(C)=O>C1C=CC=CC=1.CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[C:27]([C:2]1[CH:3]=[C:4]([C:23]([O:25][CH3:26])=[O:24])[C:5]2[O:9][C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[O:7][C:6]=2[CH:22]=1)#[N:28]
Reactant: COC(=O)c1cc(Br)cc2c1OC(c1ccccc1)(c1ccccc1)O2
Reactant: [C-]#N
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: c1ccccc1
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(C#N)cc2c1OC(c1ccccc1)(c1ccccc1)O2
Temperature: 100 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 6-bromo-2,2-diphenyl-1,3-benzodioxole-4-carboxylate (800 mg, 1.95 mmol, 1 eq.) in a mixture of 15 mL benzene and 5 mL DMF, Pd(PPh3)4 (225 mg, 0.195 mmol, 0.1 eq.), KCN (127 mg, 1.95 mmol, 1 eq.) and 18-crown-6 (415 mg, 1.56 mmol, 0.8 eq.) was added and the reaction mixture was stirred at 100° C. overnight. Then the reaction mixture was poured into a separatory funnel containing EtOAc and H2O and the aqueous phase was extracted with EtOAc (2×20 mL). The combined organic phases were washed with H2O, then saturated aqueous NaCl solution, dried over MgSO4, and evaporated under reduced pressure. Flash chromatography on silica gel (hexane/EtOAc=20:1→9:1) afforded the desired compound as a colorless solid.
Reaction SMILES: CO[C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1Br)=[O:4].Cl.[NH2:12][C:13]1[CH:18]=[C:17]([C:19]#[N:20])[CH:16]=[CH:15][C:14]=1B(O)O.C(=O)([O-])[O-].[Cs+].[Cs+].O>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[O:4]=[C:3]1[C:5]2[S:6][CH:7]=[CH:8][C:9]=2[C:14]2[CH:15]=[CH:16][C:17]([C:19]#[N:20])=[CH:18][C:13]=2[NH:12]1
Reactant: COC(=O)c1sccc1Br
Reactant: N#Cc1ccc(B(O)O)c(N)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: N#Cc1ccc2c(c1)[nH]c(=O)c1sccc12

Procedure:
Methyl-3-bromothiophene carboxylate (1.0 eq, 2.42 g, 10.95 mmol), 2-amino-4-cyanophenylboronic acid hydrochloride (1.05 eq, 2.28 g, 11.49 mmol) and cesium carbonate (2.0 eq, 7.13 g, 21.9 mmol) were suspended in dioxane (25 ml) containing 5% water. The mixture was degassed by bubbling nitrogen for 10 minutes. PdCl2(dppf) (0.05 eq, 400 mg, 0.55 mmol) was added and the mixture was stirred at reflux for 1.5 hours. The mixture was cooled down, the solid filtered, washed with dioxane, water and methanol. After drying in vacuo, 4-oxo-4,5-dihydrothieno[2,3-c]quinoline-7-carbonitrile was isolated as a solid (1.81 g, 73% yield). LCMS (ES) m/z 227 [M+1]+.
Reaction SMILES: [Sn](Cl)(Cl)(Cl)Cl.[CH3:6][O:7][CH:8](Cl)Cl.C[O:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[CH:18]([CH2:22][C:23]1[N:24]=[CH:25][NH:26][CH:27]=1)[CH2:17][CH2:16]2.[OH-].[NH4+]>C(Cl)Cl.O>[NH:26]1[CH:27]=[C:23]([CH2:22][CH:18]2[C:19]3[C:15](=[CH:14][C:8]([O:7][CH3:6])=[C:21]([CH:13]=[O:12])[CH:20]=3)[CH2:16][CH2:17]2)[N:24]=[CH:25]1
Reactant: COc1ccc2c(c1)CCC2Cc1c[nH]cn1
Reactant: COC(Cl)Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: COc1cc2c(cc1C=O)C(Cc1c[nH]cn1)CC2
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Tin(IV)chloride (800 mg) is added dropwise to a stirred solution of dichloromethyl methyl ether (343 mg) in methylene chloride (8 ml) with ice cooling under a nitrogen atmosphere. The solution is stirred at 0° C. for one hour before adding a solution of 4-(5-methoxyindan-1-ylmethyl)-1H-imidazole (300 mg) in methylene chloride (4 ml). The resulting mixture is allowed to warm to ambient temperature while being stirred for 4 hours. The mixture is then poured into cold water and is made basic with ammonium hydroxide solution. Work-up of the mixture gives the crude product which is purified by flash chromatography and recrystallized from ethyl acetate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([C:17]([OH:19])=O)=[C:10]2[O:13][CH:14]([CH3:16])[CH3:15])=[CH:5][CH:4]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[CH2:32]([NH2:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C1COCC1.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([C:17]([NH:39][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[O:19])=[C:10]2[O:13][CH:14]([CH3:15])[CH3:16])=[CH:5][CH:4]=1
Reactant: COc1ccc2ccc(C(=O)O)c(OC(C)C)c2c1
Reactant: NCc1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc2ccc(C(=O)NCc3ccccc3)c(OC(C)C)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73 %

Procedure:
To a room temperature solution of 7-methoxy-1-(1-methylethoxy)-2-naphthalenecarboxylic acid (200 mg, 0.77 mmol) in 5 mL of THF is added N,N-carbonyldiimidazole (162 mg, 1.00 mmol). The solution is heated at reflux for 1 hour and cooled slightly. Benzylamine (0.50 mn) is added and the reaction mixture is stirred at room temperature overnight. The mixture is diluted with ethyl acetate and washed with brine. The organic layer is dried over MgSO4, filtered, and concentrated in vacuo. The crude product is chromatographed on silica gel eluting with hexane:ethyl acetate (2:1) to provide 7-methoxy-1-(1-methylethoxy)-N-(phenylmethyl)-2-naphthalene-carboxamide in 73% yield; mp 88°-90° C.
Reaction SMILES: [OH:1]/[N:2]=[C:3](/[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([N:14]2[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15]2)=[O:13])=[CH:7][CH:6]=1)\[NH2:4].[C:23](O)(=O)[CH2:24][CH2:25][CH3:26].O.ON1C2C=CC=CC=2N=N1.CN1CCOCC1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O.C(OCC)(=O)C>[CH2:24]([C:23]1[O:1][N:2]=[C:3]([C:5]2[CH:10]=[CH:9][C:8]([NH:11][C:12]([N:14]3[CH2:15][C:16]4[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH2:22]3)=[O:13])=[CH:7][CH:6]=2)[N:4]=1)[CH2:25][CH3:26]
Reactant: CCCC(=O)O
Reactant: N/C(=N\O)c1ccc(NC(=O)N2Cc3ccccc3C2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Product: CCCc1nc(-c2ccc(NC(=O)N3Cc4ccccc4C3)cc2)no1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 4 mL vial was mixed (Z)—N-(4-(N′-hydroxycarbamimidoyl)phenyl)isoindoline-2-carboxamide (50 mg, 0.169 mmol), butyric acid (0.017 ml, 0.186 mmol), 1-hydroxybenzotriazole hydrate (12.92 mg, 0.084 mmol), and N-methylmorpholine (0.056 ml, 0.506 mmol) in anhydrous dimethylformamide (2 ml). To this solution was added N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (48.5 mg, 0.253 mmol) and the mixture was stirred overnight at ambient temperature. The solution was diluted with ethyl acetate and washed with water, saturated aqueous sodium bicarbonate, and brine. The organic layer was dried with sodium sulfate, decanted, and concentrated. The residue was taken up in anhydrous toluene (1 ml), and the mixture was heated at 110° C. for 2 days. The reaction was diluted with water; and the solids that formed were filtered and washed with water and ether to provide the title compound. 1H NMR (500 MHz, DMSO-d6) δ ppm 8.68 (s, 1H), 7.89-7.91 (m, 2H), 7.78-7.80 (m, 2H), 7.36-7.40 (m, 2H), 7.30-7.34 (m, 2H), 4.76-4.85 (m, 4H), 2.96 (t, J=7.4 Hz, 2H), 1.81 (hex, J=7.4 Hz, 2H), 0.99 (t, J=7.4 Hz, 3H); MS (ESI(−)) m/e347 (M−H)−.