Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[NH:10][C:11]([C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][C:20]=2[O:22]CC2C=CC=CC=2)[NH:15][CH:14]=1)=[O:12].CO.[H][H]>[Pd].C(O)C>[F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[NH:10][C:11]([C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][C:20]=2[OH:22])[NH:15][CH:14]=1)=[O:12]
Reactant: [H][H]
Reactant: COc1ccc(NC(=O)c2c[nH]c3cccc(OCc4ccccc4)c23)c(F)c1
Agent: [Pd]
Solvent: CCO
Solvent: CO
Product: COc1ccc(NC(=O)c2c[nH]c3cccc(O)c23)c(F)c1

Procedure:
N-(2-Fluoro-4-methoxyphenyl)-4-benzyloxy-1H-indole-3-carboxamide (1.34 g, 3.4 mmol), prepared using the method above, was slurried with 10% palladium on carbon (134 mg) in ethanol (35 mL) in a Parr bottle and placed under a hydrogen atmosphere (50 psi) for 5 h. Methanol (5 ml) was added and the mixture returned to the Hydrogen atmosphere for an additional 18 h. The solution was filtered through Celite, concentrated in vacuo, and the residue purified by flash chromatography to afford N-(2-fluoro-4-methoxyphenyl)-4-hydroxy-1H-indole-3-carboxamide (Compound 2) as a beige solid; mp 259-261° C. (d).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.C(N(C(C)C)CC)(C)C.[NH2:18][C:19]1[CH:20]=[N:21][N:22]([CH2:24][C@H:25]2[O:30][CH2:29][CH2:28][N:27]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:26]2)[CH:23]=1>O1CCOCC1>[Cl:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:18][C:19]2[CH:20]=[N:21][N:22]([CH2:24][C@H:25]3[O:30][CH2:29][CH2:28][N:27]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:26]3)[CH:23]=2)[N:7]=1
Reactant: Clc1ncnc(Cl)n1
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](Cn2cc(N)cn2)C1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCO[C@H](Cn2cc(Nc3ncnc(Cl)n3)cn2)C1
Temperature: 110 °C
Reaction time: 1 h
Yield: 71.1 %

Procedure:
To a solution of 2,4-dichloro-1,3,5-triazine (1.8 g, 6.4 mmol) in dioxane (20 mL) was added diisopropylethylamine (4 mL), followed by the addition of (S)-tert-butyl 2-((4-amino-1H-pyrazol-1-yl)methyl)morpholine-4-carboxylate (1.2 g, 7.2 mmol). The reaction mixture was stirred at 110° C. for 1 hour, and LCMS (liquid chromatography-mass spectrometry) showed the reaction was completed. The solvents were removed under reduced pressure, and the residue was purified by silica gel chromatography, eluting with petroleum ether:ethyl acetate=5:1, to afford (S)-tert-butyl 2-((4-(4-chloro-1,3,5-triazin-2-ylamino)-1H-pyrazol-1-yl)methyl)morpholine-4-carboxylate as a yellow solid (1.8 g, 70%). MS (ES+) C16H22ClN7O3 requires: 395, 396, found: 396, 397 [M+H]+.
Reaction SMILES: [CH3:1][Si:2]([CH3:49])([CH3:48])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:40][O:41][CH2:42][CH2:43][Si:44]([CH3:47])([CH3:46])[CH3:45])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]4[C:25]([CH:26]=3)=[CH:24][CH:23]=[CH:22][CH:21]=4)=[C:12]2[N:11]=[C:10]([CH:27]2[CH2:32][CH2:31][CH2:30][N:29]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:28]2)[CH:9]=1.C1C(=O)N([Br:57])C(=O)C1>CC#N>[CH3:47][Si:44]([CH3:46])([CH3:45])[CH2:43][CH2:42][O:41][CH2:40][N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:1])([CH3:48])[CH3:49])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20]4[C:25]([CH:26]=3)=[CH:24][CH:23]=[CH:22][CH:21]=4)=[C:12]2[N:11]=[C:10]([CH:27]2[CH2:32][CH2:31][CH2:30][N:29]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:28]2)[C:9]=1[Br:57]
Reactant: CC(C)(C)OC(=O)N1CCCC(c2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(-c4cnc5ccccc5c4)c3n2)C1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCCC(c2nc3c(-c4cnc5ccccc5c4)cnn3c(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)c2Br)C1
Reaction time: 3 h

Procedure:
To a solution of tert-butyl 3-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-(quinolin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)piperidine-1-carboxylate (350 mg, 0.50 mmol) in CH3CN (5.0 mL) was added NBS (90 mg, 0.50 mmol). The mixture was stirred at it for 3 h and concentrated in vacuo. The residue was purified by Biotage (CH2Cl2/EtOAc, 100:1 to 10:1) to give the title compound as light yellow solid. LC/MS RT=2.49 min. Mass calculated for, M+H 768.29, observed 389.17.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH:11]=O)=[CH:3][CH:2]=1.N1(C2C=C[C:21]([CH:22]=[O:23])=CC=2)C=CC=N1>>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH:11]=[CH:21][CH:22]=[O:23])=[CH:3][CH:2]=1
Reactant: O=Cc1ccc(-n2cccn2)cc1
Reactant: O=Cc1ccnc2ccccc12
Product: O=CC=Cc1ccnc2ccccc12

Procedure:
The title compound was prepared by a procedure analogous to Reference Example 30 by substituting 4-quinolinecarboxaldehyde for the 4-(1H-pyrazol-1-yl)-benzaldehyde of Reference Example 30. MS 184 (M+H)+.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([N:14]1[CH2:19][CH2:18][C:17]3([C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[N:21](C(OC(C)(C)C)=O)[CH2:20]3)[CH2:16][CH2:15]1)=[O:13])[CH2:8]2.FC(F)(F)C(O)=O>C(Cl)Cl>[CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([N:14]1[CH2:15][CH2:16][C:17]3([C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[NH:21][CH2:20]3)[CH2:18][CH2:19]1)=[O:13])[CH2:8]2
Reactant: CC(C)(C)OC(=O)N1CC2(CCN(C(=O)NC3C4CC5CC(C4)CC3C5)CC2)c2ccccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(NC1C2CC3CC(C2)CC1C3)N1CCC2(CC1)CNc1ccccc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 25.6 %

Procedure:
A 10-mL round-bottomed flask was charged with tert-butyl 1′-((2-adamantyl)carbamoyl)spiro[indoline-3,4′-piperidine]-1-carboxylate (50 mg, 0.107 mmol) and 20% trifluoroacetic acid in CH2Cl2 (2 mL). The mixture was stirred for 1 h at 0° C. The solution was concentrated under vacuum and the crude product was purified by preparative HPLC to provide N-(2-adamantyl)spiro[indoline-3,4′-piperidine]-1′-carboxamide (10 mg, 25%). 1H NMR (CD3OD, 400 MHz): δ=1.60˜2.00 (m, 18H), 3.00 (t, 2H), 3.86 (d, 3H), 4.08 (d, 2H), 7.40˜7.50 (m, 4H); LC-MS (4 min) tR=1.93 min, m/z=366 (M++1).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]1[O:17][C@@H:14]([O:15][CH3:16])[C@H:13]([O:18]CC2C=CC(I)=CC=2)[C@@H:12]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][C:32]([Br:35])=[CH:31][CH:30]=2)[C@@H:11]1[O:36][CH2:37][C:38]1[CH:43]=[CH:42][C:41]([Cl:44])=[CH:40][CH:39]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CNC1C=CC=CC=1.CC([O-])(C)C.[Na+]>C1COCC1.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]>[CH2:1]([O:8][CH2:9][C@H:10]1[O:17][C@@H:14]([O:15][CH3:16])[C@H:13]([OH:18])[C@@H:12]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][C:32]([Br:35])=[CH:31][CH:30]=2)[C@@H:11]1[O:36][CH2:37][C:38]1[CH:43]=[CH:42][C:41]([Cl:44])=[CH:40][CH:39]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CO[C@@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccc(Cl)cc2)[C@H](OCc2ccc(Br)cc2)[C@H]1OCc1ccc(I)cc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CNc1ccccc1
Solvent: C1CCOC1
Product: CO[C@@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccc(Cl)cc2)[C@H](OCc2ccc(Br)cc2)[C@H]1O
Temperature: 25 °C
Reaction time: 4 h
Yield: 83.5 %

Procedure:
Glycoside 10 (0.138 g, 0.174 mmol) was loaded into a round-bottom flask and azeotropically dried with toluene (3×3 mL) followed by additional drying for 1 h under vacuum. The flask was purged with argon, N-methylaniline (20 μL, 0.182 mmol) was added and the residue dissolved in THF (0.60 mL). An oven-dried resealable Schlenk flask was evacuated and backfilled with argon. The flask was charged with Pd2dba3 (1.0 mol % Pd, 0.7 mg, 0.0008 mmol), 1-(N,N-dimethylamino)-1′-(dicyclohexylphosphino)biphenyl (1.0 mol %, 0.7 mg, 0.0017 mmol), NaOtBu (23.4 mg, 0.244 mmol), evacuated and backfilled with argon. A rubber septum was installed and glycoside/amine solution was added via cannula. The flask was sealed using a teflon screwcap and the reaction mixture was stirred at room temperature. After 4 h, the reaction solution was diluted with diethyl ether, filtered through a pad of celite and concentrated in vacuo. The aminated product was taken up in CH2Cl2 (1 mL) and treated with 2% dichloroacetic acid/CH2Cl2 (v/v) (1 mL). After stirring at room temperature for 30 min, the reaction mixture was diluted with CH2Cl2, washed with brine, saturated NaHCO3(aq), dried over Na2SO4, filtered and concentrated in vacuo. Purification by flash column chromatography on silica gel (20% EtOAc/Hexanes) gave 84.0 mg 11 (84%) as a white solid. [α]24D: −29.2° (c 2.19, CH2Cl2); IR (thin film) 3450, 2866, 1490, 1452, 1061 cm−1; 1H-NMR (CDCl3) δ 7.43 (d, J=8.2 Hz, 2H), 7.34-7.23 (m, 7H), 7.20 (d, J=8.2 Hz, 2H), 7.02 (d, J=8.5 Hz, 2H), 4.89 (d, J=11.6 Hz, 1H), 4.72 (d, J=11.6 Hz, 1H), 4.71 (d, J=11.0 Hz, 1H), 4.65 (d, J=12.2 Hz, 1H), 4.53 (d, J=12.2 Hz, 1H), 4.46 (d, J=11.0 Hz, 1H), 4.17 (d, J=7.6 Hz, 1H), 3.75-3.67 (m, 2H), 3.61-3.53 (m, 6H), 3.48-3.44 (m, 1H), 2.41 (d, J=1.5 Hz, 1H); 13C-NMR (CDCl3) δ 138.1, 137.7, 136.7, 133.7, 131.7, 129.6, 129.2, 128.7, 128.6, 128.1, 127.9, 121.7, 103.9, 84.5, 77.5, 75.2, 75.0, 74.4, 74.3, 73.7, 68.7, 57.4; FAB MS m/z (M+Na)+: calcd 599.0812, obsd 599.0795.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[NH2:15][C:16]1[C:21]2[C:22]([C:25]3[CH:26]=[C:27]4[C:31](=[CH:32][CH:33]=3)[N:30]([C:34](=[O:42])[CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[CH2:29][CH2:28]4)=[CH:23][S:24][C:20]=2[C:19]([C:43]2[CH:44]=[C:45]([CH:48]=[CH:49][CH:50]=2)[CH:46]=O)=[CH:18][N:17]=1.[CH3:51][NH:52][CH3:53].C1COCC1.CC(O)=O>ClCCCl>[CH3:51][N:52]([CH2:46][C:45]1[CH:44]=[C:43]([C:19]2[C:20]3[S:24][CH:23]=[C:22]([C:25]4[CH:26]=[C:27]5[C:31](=[CH:32][CH:33]=4)[N:30]([C:34](=[O:42])[CH2:35][C:36]4[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=4)[CH2:29][CH2:28]5)[C:21]=3[C:16]([NH2:15])=[N:17][CH:18]=2)[CH:50]=[CH:49][CH:48]=1)[CH3:53]
Reactant: CNC
Reactant: Nc1ncc(-c2cccc(C=O)c2)c2scc(-c3ccc4c(c3)CCN4C(=O)Cc3ccccc3)c12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: ClCCCl
Product: CN(C)Cc1cccc(-c2cnc(N)c3c(-c4ccc5c(c4)CCN5C(=O)Cc4ccccc4)csc23)c1
Reaction time: 3.5 h

Procedure:
Sodium triacetoxyborohydride (76 mg, 0.359 mmol) was added to a solution of 3-{4-amino-3-[1-(phenylacetyl)-2,3-dihydro-1H-indol-5-yl]thieno[3,2-c]pyridin-7-yl}benzaldehyde (66 mg, 0.135 mmol), dimethylamine, 2.0 M in THF (0.10 mL, 0.200 mmol), and acetic acid (8 μL, 0.140 mmol) in 1,2-Dichloroethane (DCE) (7 mL), and the mixture was stirred at room temperature under Nitrogen for 3 days. LCMS showed only starting material, so another portion each of dimethylamine, 2.0 M in THF (0.20 mL, 0.400 mmol) and sodium triacetoxyborohydride (162 mg, 0.764 mmol) were added. Stirring continued at room temperature for another 3.5 hr, when LCMS showed complete conversion to the desired product. The mixture was poured into saturated aqueous NaHCO3 (15 mL) and extracted with methylene chloride (2×15 mL). The extracts were dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by reverse phase HPLC (Gilson, C18, 5% to 45% CH3CN in water with 0.1% TFA, 8 minute gradient). The product fractions were combined and concentrated in vacuo, and the residue was taken up in MeOH and passed through a PL-HCO3 MP-resin cartridge, rinsing with more MeOH. The filtrate was concentrated in vacuo and dried in the vacuum oven overnight to give 7-{3-[(dimethylamino)methyl]phenyl}-3-[1-(phenylacetyl)-2,3-dihydro-1H-indol-5-yl]thieno[3,2-c]pyridin-4-amine (50 mg, 0.092 mmol, 67.9% yield) as a white solid. LC/MS (ES) m/z=519 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 2.20 (s, 6H), 3.24 (t, J=8.34 Hz, 2H), 3.47 (s, 2H), 3.90 (s, 2H), 4.26 (t, J=8.46 Hz, 2H), 5.53 (br. s., 2H), 7.23-7.30 (m, 2H), 7.30-7.39 (m, 6H), 7.43-7.50 (m, 2H), 7.51-7.56 (m, 1H), 7.60 (s, 1H), 7.90 (s, 1H), 8.18 (d, J=8.34 Hz, 1H).
Reaction SMILES: [C:1]([C:4]12[CH2:13][CH:8]([C:9]([CH3:12])=[CH:10][CH2:11]1)[C:7](=[O:14])[CH2:6][CH:5]2[CH3:15])([CH3:3])=[CH2:2].[Li]C.[CH3:18]COCC.[NH4+].[Cl-]>C1COCC1>[C:1]([C:4]12[CH2:13][CH:8]([C:9]([CH3:12])=[CH:10][CH2:11]1)[C:7]([CH3:18])([OH:14])[CH2:6][CH:5]2[CH3:15])([CH3:3])=[CH2:2]
Reactant: C=C(C)C12CC=C(C)C(C1)C(=O)CC2C
Reactant: CCOCC
Agent: [Cl-]
Agent: [Li]C
Agent: [NH4+]
Solvent: C1CCOC1
Product: C=C(C)C12CC=C(C)C(C1)C(C)(O)CC2C
Temperature: 5 °C
Reaction time: 5 h

Procedure:
At 5° C., a soln. of 1 g of 5-isopropenyl-4,8-dimethylbicyclo[3.3.1]non-7-en-2-one (4.9 mmol) in 15 ml THF was treated dropwise with 21 ml 1.4M MeLi in Et2O (29.4 mmol, 6 eq.). The reaction mixture was stirred 5 h at 5° C., warmed to 25° C. overnight, poured into aq. sat. NH4Cl soln., and extracted with Et2O. The org. phase was washed with aq. sat. NaCl soln., dried, and concentrated. FC (SiO2, hexane/Et2O 9:1) of the crude (1.2 g, starting material/OH exo/OH endo 17:65:18)gave 0.2 g of starting material (20%), 0.5 g 8A (46%), 0.25 g 8A/8B (1:1, 23%), and 0.1 g 8B (9%).
Reaction SMILES: [CH:1]1[C:14]2[C:13](=[O:15])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6](=[O:16])[C:5]=2[CH:4]=[CH:3][CH:2]=1.[N+:17]([O-])([OH:19])=[O:18]>S1(CCCC1)(=O)=O>[N+:17]([C:8]1[C:7]2[C:6](=[O:16])[C:5]3[C:14](=[CH:1][CH:2]=[CH:3][CH:4]=3)[C:13](=[O:15])[C:12]=2[CH:11]=[CH:10][CH:9]=1)([O-:19])=[O:18]
Reactant: O=[N+]([O-])O
Reactant: O=C1c2ccccc2C(=O)c2ccccc21
Solvent: O=S1(=O)CCCC1
Product: O=C1c2ccccc2C(=O)c2c1cccc2[N+](=O)[O-]
Reaction time: 0.13 h

Procedure:
21 g of anthraquinone are introduced into 100 ml of 98 % HNO3 at 20° and the mixture is stirred at this temperature for 8 minutes. 50 ml of sulpholan are then added, the temperature rising to 53°. 40 ml of 98 % HNO3 are distilled off at 35°/10 mm, a further 50 ml of sulpholan are added, the reaction mixture is filtered at 40° and the precipitate is washed with a small quantity of sulpholan and then with water. After drying, 13.9 g of 1-nitro-anthraquinone are obtained, having the following composition:
Reaction SMILES: [Br:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]=[C:7](Cl)[C:8]3[C:13]([C:4]=2[CH:3]=1)=[C:12]([Cl:14])[N:11]=[CH:10][CH:9]=3.[NH2:18][C:19]1[C:24]([Cl:25])=[CH:23][C:22]([S:26]([NH:29][CH2:30][C:31]2[N:32]([CH3:36])[CH:33]=[CH:34][N:35]=2)(=[O:28])=[O:27])=[CH:21][C:20]=1[Cl:37].C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>CC(N(C)C)=O>[Br:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]=[C:7]([NH:18][C:19]3[C:24]([Cl:25])=[CH:23][C:22]([S:26]([NH:29][CH2:30][C:31]4[N:32]([CH3:36])[CH:33]=[CH:34][N:35]=4)(=[O:27])=[O:28])=[CH:21][C:20]=3[Cl:37])[C:8]3[C:13]([C:4]=2[CH:3]=1)=[C:12]([Cl:14])[N:11]=[CH:10][CH:9]=3
Reactant: Clc1nc2ccc(Br)cc2c2c(Cl)nccc12
Reactant: Cn1ccnc1CNS(=O)(=O)c1cc(Cl)c(N)c(Cl)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: Cn1ccnc1CNS(=O)(=O)c1cc(Cl)c(Nc2nc3ccc(Br)cc3c3c(Cl)nccc23)c(Cl)c1
Temperature: 25 °C

Procedure:
To a solution of 9-bromo-1,5-dichlorobenzo[c]-2,6-naphthyridine (100 mg, 0.31 mmol) (Example 1, Step 5) and 4-amino-3,5-dichloro-N-[(1-methyl-1H-imidazol-2-yl)methyl]benzenesulfonamide (123 mg, 0.37 mmol) in DMA (1.2 mL) was added NaHMDS (0.7 mL, 1 M in THF, 0.7 mmol). The reaction was stirred at room temperature for ten minutes and then heated in the microwave to 100° C. for 15 minutes. The reaction was then quenched by the addition of sat. aq. NaHCO3 solution. The mixture was extracted with EtOAc and the organic extracts were dried over Na2SO4 and concentrated in vacuo. Purification of the residue by silica gel column chromatography (0-10% MeOH/DCM) afforded the title compound.
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[F:15])[C:6]2[CH:16]=[CH:17][CH:18]=[CH:19][C:5]=2[NH:4][C:3]1=[O:20].[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]=[C:29]=[O:30])=[CH:24][CH:23]=1>O1CCCC1>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29]([NH:1][CH:2]2[N:8]=[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[F:15])[C:6]3[CH:16]=[CH:17][CH:18]=[CH:19][C:5]=3[NH:4][C:3]2=[O:20])=[O:30])=[CH:24][CH:23]=1
Reactant: NC1N=C(c2ccccc2F)c2ccccc2NC1=O
Reactant: O=C=Nc1ccc(Cl)cc1
Solvent: C1CCOC1
Product: O=C(Nc1ccc(Cl)cc1)NC1N=C(c2ccccc2F)c2ccccc2NC1=O
Reaction time: 8 h

Procedure:
To a solution of 85 mg (0.315 mmole) of 1,3-dihydro-3(RS)-amino-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one in 8 ml of dry tetrahydrofuran was added 4-chlorophenylisocyanate (40 μl, 0.315 mmole) at room temperature. Within 15 minutes a flocculant, white precipitate formed. Stirring was continued for 8 hours more and the reaction mixture was filtered. The collected solids were washed with hot methanol and dried in vacuo to give the analytical product: m.p. 278° C.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][N:6]=1.C(N(CC)CC)C.[Cl:14][C:15]1[CH:16]=[N:17][CH:18]=[C:19]([C:21]#[CH:22])[CH:20]=1>COCCOC.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:14][C:15]1[CH:16]=[N:17][CH:18]=[C:19]([C:21]#[C:22][C:2]2[S:3][CH:4]=[CH:5][N:6]=2)[CH:20]=1
Reactant: Brc1nccs1
Reactant: C#Cc1cncc(Cl)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: COCCOC
Product: Clc1cncc(C#Cc2nccs2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2-Bromo-1,3-thiazole (980 mg, 6.0 mmol) and CuI (230 mg, 1.2 mmol) were combined in DME (15 mL) and argon gas was bubbled through the suspension for several minutes to deoxygenate the mixture. Triethylamine (4.2 mL, 30 mmol) and PdCl2(PPh3)2 (420 mg, 0.60 mmol) were added, then 3-chloro-5-ethynylpyridine (820 mg, 19 mmol) was added dropwise. After stirring at ambient temperature for 16 h, GC/MS analysis showed starting material remaining. The reaction mixture was heated at reflux for 2 h. The mixture was filtered through Celite.™, the filter pad was washed thoroughly with ethyl acetate, and the combined filtrates were concentrated in vacuo. The residue was dissolved in ethyl acetate (100 mL), and washed with water (100 mL), brine (100 mL), dried over Na2SO4 filtered and concentrated in vacuo. The residue was purified by column chromatography eluting with hexane then 9:1 hexane:ethyl acetate to afford 3-chloro-5-(1,3-thiazol-2-ylethynyl)pyridi-ne which contained some dimer. This material was crystallized from hot ethyl acetate to afford 3-chloro-5-(1,3-thiazol-2-ylethynyl)pyridine (300 mg 23% yield) as light orange crystals M.p. 124-125° C. 1H NMR (CDCl3, 300 MHz) Δ8.70 (d, J=1.5 Hz, 1H), 8.59 (d, J=3.0Hz, 1H), 7.93 (d, J=3.0 Hz, 1H), 7.88 (t, J=2.0 Hz, 1H), 7.48 (d, J=3.0 Hz, 2H). MS (ESI) 221.1 (M++H).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[F:26]N(S(C1C=CC=CC=1)(=O)=O)S(C1C=CC=CC=1)(=O)=O.C([O-])(O)=O.[Na+]>C1COCC1>[F:26][C:8]1([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:9][CH2:10][C:5]2([O:4][CH2:3][CH2:2][O:1]2)[CH2:6][CH2:7]1
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Reactant: CCOC(=O)C1CCC2(CC1)OCCO2
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C([O-])O
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C1(F)CCC2(CC1)OCCO2
Temperature: 0 °C
Reaction time: 1 h
Yield: 102.6 %

Procedure:
To a solution of ethyl 1,4-dioxaspiro[4.5]decane-8-carboxylate (15 g, 70.0 mmol, 1 equiv) in THF (200 mL) at 0° C. (ice water bath), was added LiHMDS (98 mL of a 1 M solution in THF, 98 mmol, 1.4 equiv) in 4 portions over ˜2 min. After stirring 1 h, N-fluoro-di(benzenesulfonyl)-amine (26.5 g, 84 mmol, 1.2 equiv) was added. The reaction was stirred 20 min then poured into a saturated aqueous solution of NaHCO3. The aqueous solution was extracted with ether (×3). The combined ether layers were dried (MgSO4) and concentrated in vacuo. Crude residue was stirred with hexane (˜600 mL) and filtered. The filtrate was concentrated in vacuo to give 16.68 g of the crude product as a yellow oil. ˜4:1 product:sm. Taken on as is to the ester reduction. 1H NMR (400 MHz, CDCl3) δ ppm 4.25 (q, J=7.11 Hz, 2H), 3.94-4.00 (m, 4H), 2.02-2.26 (m, 4H), 1.92 (td, J=13.30, 4.77 Hz, 2H), 1.66-1.77 (m, 2H), 1.31 (t, J=7.03 Hz, 3H); 19F NMR (376 MHz, CDCl3) δ ppm −168.50 (br. s., 1F).
Reaction SMILES: C([N:5]1[C:9](=[O:10])[C:8]2=[CH:11][CH:12]=[CH:13][CH:14]=[C:7]2[C:6]1=[O:15])CC#C.O1CCCC1.[I-].C1C=CC=CC=1>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu](I)I.C(N(CC)CC)C>[C:9]1(=[O:10])[NH:5][C:6](=[O:15])[C:7]2=[CH:14][CH:13]=[CH:12][CH:11]=[C:8]12
Reactant: C#CCCN1C(=O)c2ccccc2C1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Agent: [I-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: O=C1NC(=O)c2ccccc21
Temperature: 25 °C
Yield: 167 %

Procedure:
To 535 mg of dichlorobis(triphenylphosphine)palladium, 145 mg of copper iodide, and 3.00 g of N-(3-butynyl)phthalimide were added 35 ml of tetrahydrofuran, 3.06 g of benzene iodide, and 9.0 ml of triethylamine in a nitrogen atmosphere, and the mixture was stirred under reflux for 4 hours. After the stirring, the reaction mixture was cooled to room temperature and the solids were filtered. After concentrating the filtrate, the residue was purified by column chromatography (Wakogel C-200; toluene:ethyl acetate=4:1) to give 3.70 g of a phthalimide compound.
Reaction SMILES: [OH-].[K+].[OH:3][C:4]1[C:9]2[C:10]([CH3:15])=[CH:11][C:12](=[O:14])[O:13][C:8]=2[CH:7]=[CH:6][CH:5]=1.[CH3:16][N:17]([CH3:21])[C:18](Cl)=[S:19]>O.CC(C)=O>[CH3:16][N:17]([CH3:21])[C:18](=[S:19])[O:3][C:4]1[C:9]2[C:10]([CH3:15])=[CH:11][C:12](=[O:14])[O:13][C:8]=2[CH:7]=[CH:6][CH:5]=1
Reactant: CN(C)C(=S)Cl
Reactant: Cc1cc(=O)oc2cccc(O)c12
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: Cc1cc(=O)oc2cccc(OC(=S)N(C)C)c12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 90.3 %

Procedure:
410 mg (7.3.10-3 mol) of potassium hydroxide are added under an inert atmosphere to a suspension of 1 g (5.7.10-3 mol) of 5-hydroxy-4-methyl-2H-1-benzopyran-2-one in 10 ml of water and 10 ml of acetone. After 10 minutes at room temperature, 770 mg (6.2.10-3 mol) of dimethylthiocarbamoyl chloride in 10 ml of acetone are added at 0° C. The reaction mixture is stirred for 2 hours at room temperature and then, after evaporation of the acetone, the expected derivative is precipitated in water to give 1.35 g (yield: 90%) of the expected product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:29]=[C:30]([O:34][CH3:35])[C:31]=1[O:32][CH3:33])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=2)([CH2:13][CH2:14]S(C)(=O)=O)[CH2:9]1)=[O:7].[F:36][C:37]1[CH:60]=[CH:59][C:40]([CH2:41][N:42]2[C:46]3[CH:47]=[CH:48][CH:49]=[CH:50][C:45]=3[N:44]=[C:43]2[C:51]([CH:53]2[CH2:58][CH2:57][NH:56][CH2:55][CH2:54]2)=[O:52])=[CH:39][CH:38]=1.C(N(C(C)C)CC)(C)C.C(OCC)(=O)C.CO>C(#N)C.C(OCC)(=O)C.ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:29]=[C:30]([O:34][CH3:35])[C:31]=1[O:32][CH3:33])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:13][CH2:14][N:56]2[CH2:57][CH2:58][CH:53]([C:51]([C:43]3[N:42]([CH2:41][C:40]4[CH:39]=[CH:38][C:37]([F:36])=[CH:60][CH:59]=4)[C:46]4[CH:47]=[CH:48][CH:49]=[CH:50][C:45]=4[N:44]=3)=[O:52])[CH2:54][CH2:55]2)([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=2)[CH2:9]1)=[O:7]
Reactant: O=C(c1nc2ccccc2n1Cc1ccc(F)cc1)C1CCNCC1
Reactant: COc1ccc(C2(CCS(C)(=O)=O)CCN(C(=O)c3cc(OC)c(OC)c(OC)c3)C2)cc1OC
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1ccc(C2(CCN3CCC(C(=O)c4nc5ccccc5n4Cc4ccc(F)cc4)CC3)CCN(C(=O)c3cc(OC)c(OC)c(OC)c3)C2)cc1OC
Reaction time: 18 h

Procedure:
Combine 1-(3,4,5-trimethoxy-benzoyl)-3-(3,4-dimethoxy-phenyl)-3-(2-methanesulfonyl-ethyl)-pyrrolidine (0.5 g, 0.96 mmol) and 4-[1-(4-fluoro-benzyl)-1 H-benzoimidazole-2-carbonyl]-piperidine (0.49 g, 1.44 mmol), and diisopropylethylamine (0.33 mL, 1.92 mmol) in acetonitrile (5 mL). Heat to reflux. After 18 hours, cool and dilute with ethyl acetate. Extract twice with 5% sodium bicarbonate solution, twice with water, and with saturated sodium chloride solution. Dry the organic layer over Na2SO4, filter, and concentrate in vacuo to obtain a residue. Chromatograph the residue on silica gel eluting with 5/1 ethyl acetate/methanol to give an oil. Combine the oil with dichloromethane and extract with 5% sodium bicarbonate solution. Dry the organic layer over Na2SO4, filter, and concentrate in vacuo to obtain a residue. Dry the residue in vacuo at 65° C. to give the title compound: Rf=0.27 (silica gel, 5/1 ethyl acetate/methanol).