Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][NH2:6].[CH:7]1([NH:10][C:11]2[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[N:14]=[C:13](F)[N:12]=2)[CH2:9][CH2:8]1.ClCCl>O1CCCC1>[CH:7]1([NH:10][C:11]2[CH:16]=[C:15]([C:17]([F:19])([F:20])[F:18])[N:14]=[C:13]([NH:6][CH2:5][CH2:4][CH2:3][O:2][CH3:1])[N:12]=2)[CH2:8][CH2:9]1
Reactant: COCCCN
Reactant: Fc1nc(NC2CC2)cc(C(F)(F)F)n1
Solvent: C1CCOC1
Solvent: ClCCl
Product: COCCCNc1nc(NC2CC2)cc(C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 6 h
Yield: 977.9 %

Procedure:
6.1 g (0.068 mol) of 3-methoxypropylamine are added dropwise at room temperature to 7 g (0.0031 mol) of 4-cyclopropylamino-2-fluoro-6-trifluoromethylpyrimidine dissolved in 100 ml of tetrahydrofuran, and the mixture is stirred for 6 hours at room temperature. After addition of 2 l of ice-water, extraction with dichloromethane, drying of the organic phase and concentrating, 8.8 g (95.4% of theory) of the desired pyrimidine are obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:6]([CH2:7][NH:8][C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=[CH:5][CH:4]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Cl:26][C:27]1[C:36]2[C:31](=[CH:32][C:33]([S:38](Cl)(=[O:40])=[O:39])=[C:34]([CH3:37])[CH:35]=2)[N:30]=[CH:29][CH:28]=1.[NH4+].[Cl-]>C1COCC1>[Cl:26][C:27]1[C:36]2[C:31](=[CH:32][C:33]([S:38]([N:8]([CH2:7][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:15][CH:14]=3)[C:9]3[S:10][CH:11]=[CH:12][N:13]=3)(=[O:39])=[O:40])=[C:34]([CH3:37])[CH:35]=2)[N:30]=[CH:29][CH:28]=1
Reactant: COc1ccc(CNc2nccs2)cc1
Reactant: Cc1cc2c(Cl)ccnc2cc1S(=O)(=O)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(CN(c2nccs2)S(=O)(=O)c2cc3nccc(Cl)c3cc2C)cc1
Reaction time: 0.25 h
Yield: 55.5 %

Procedure:
To a flask containing ice cold suspension of N-(4-methoxybenzyl)thiazol-2-amine (147 mg, 0.665 mmol) in THF (2437 μl) was added lithium bis(trimethylsilyl)amide (1M in THF) (1267 μl, 1.267 mmol) faster than drop wise. The mixture was stirred for 15 min prior to the drop wise addition of a solution of 4-chloro-6-methylquinoline-7-sulfonyl chloride (175 mg, 0.634 mmol) in THF (2.0 ml, 0.5 ml wash). The solution was allowed to stir for 20 min (ice melt) providing a brown solution containing primarily product. The mixture was added to a flask containing sat. aq. NH4Cl and ice. The aqueous mixture was extracted 2× with EtOAc and the combined organics were dried with Na2SO4, filtered, and dried under reduced pressure. The crude material was purified with a 25 g HP Silicycle column ramping EtOAc in heptane (0-50%, 10% DCM throughout) to afford product, 4-chloro-N-(4-methoxybenzyl)-6-methyl-N-(thiazol-2-yl)quinoline-7-sulfonamide (162 mg, 0.352 mmol, 55.6% yield) as a yellow solid with about 15% impurity by LC-MS. m/z (ESI) 460.3 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]([C:11]([N:13]([CH2:31][CH:32]([CH3:34])[CH3:33])[C@@H:14]3[CH2:19][N:18]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:17][C@H:16]([C:27]([O:29][CH3:30])=[O:28])[CH2:15]3)=[O:12])[NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.CS(O[CH2:40][CH2:41][CH2:42][CH2:43][O:44][CH3:45])(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+]>CC(N(C)C)=O>[Cl:1][C:2]1[C:10]2[N:9]([CH2:40][CH2:41][CH2:42][CH2:43][O:44][CH3:45])[C:8]([C:11]([N:13]([CH2:31][CH:32]([CH3:34])[CH3:33])[C@@H:14]3[CH2:19][N:18]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:17][C@H:16]([C:27]([O:29][CH3:30])=[O:28])[CH2:15]3)=[O:12])=[N:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)[C@@H]1C[C@H](N(CC(C)C)C(=O)c2nc3c(Cl)cccc3[nH]2)CN(C(=O)OC(C)(C)C)C1
Reactant: COCCCCOS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: COCCCCn1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C(=O)OC)CN(C(=O)OC(C)(C)C)C2)nc2cccc(Cl)c21
Temperature: 70 °C
Reaction time: 12 h
Yield: 10 %

Procedure:
1-tert-Butyl 3-methyl(3R,5S)-5-{[(4-chloro-1H-benzimidazol-2-yl)carbonyl](2-methylpropyl)amino}piperidine-1,3-dicarboxylate (1.7 g) and 4-methoxybutyl methanesulfonate (754 mg) were dissolved in DMA (50 ml), cesium carbonate (1.7 g) was added, and the mixture was stirred at 70° C. for 12 hr. The reaction mixture was poured into ice water (100 ml), and the mixture was extracted twice with ethyl acetate (100 ml). The extract was washed with brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a less polar fraction eluted with ethyl acetate-hexane (1:4-1:1) was concentrated under reduced pressure to give 1-tert-butyl 3-methyl(3R,5S)-5-[{[7-chloro-1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]piperidine-1,3-dicarboxylate (200 mg).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([OH:13])[C:7]([OH:14])=[N:6]2.N([O-])=O.[Na+].[N-:19]=[N+:20]=[N-].[Na+]>OS(O)(=O)=O.O>[N:2]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([OH:13])[C:7]([OH:14])=[N:6]2)=[N+:19]=[N-:20]
Reactant: [N-]=[N+]=[N-]
Reactant: Nc1ccc2nc(O)c(O)nc2c1
Agent: Cl
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Solvent: O
Product: [N-]=[N+]=Nc1ccc2nc(O)c(O)nc2c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 62.8 %

Procedure:
A solution of 5 g (23.5 mmol) 6-amino-2,3-dihydroxyquinoxaline hydrochloride in 250 ml 0.5 N H2SO4 is cooled to 0° C. and then a solution of 1.65 g (24 mmol) NaNO2 in 50 ml water is added. After stirring at 0° C. for 15 min., a solution of 1.5 g (24 mmol) NaN3 in 100 ml water is added. Stirring at 0° C. for 45 min. gives a precipitate of 3 g (67%) 6-azido-2,3-dihydroxyquinoxaline. IR: a peak at 2220 cm−1.
Reaction SMILES: [C:1]1([C:11]2[CH2:12][CH2:13][N:14]([CH2:17][CH2:18][CH2:19]O)[CH2:15][CH:16]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH2:21]([N:23](CC)CC)C.CS(Cl)(=O)=O.CN>C(Cl)(Cl)Cl.C(#N)C>[CH3:21][NH:23][CH2:19][CH2:18][CH2:17][N:14]1[CH2:15][CH:16]=[C:11]([C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)[CH2:12][CH2:13]1
Reactant: OCCCN1CC=C(c2cccc3ccccc23)CC1
Reactant: CCN(CC)CC
Agent: CN
Agent: CS(=O)(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CC#N
Product: CNCCCN1CC=C(c2cccc3ccccc23)CC1
Temperature: 0 °C
Yield: 95.3 %

Procedure:
3,6-Dihydro-4-(1-naphthalenyl)-1(2H)-pyridinepropanol (Ex. 4: 1.20 g, 4.49 mmol) was dissolved in chloroform (50 mL) followed by the addition of triethylamine (0.94 mL, 6.73 mmol) and cooled to 0° C. Methanesulfonyl chloride (0.42 mL, 5.39 mmol) was added dropwise and the reaction was allowed to stir for thirty minutes while warming to room temperature. Solvent was then removed in vacuo yielding a crude solid (IV). This material was then dissolved in a solution of acetonitrile (60 mL) containing 40 wt. % aqueous methylamine (60 mL) and heated at reflux for three hours. The reaction was cooled to room temperature and concentrated in vacuo. The crude residue was diluted with chloroform (500 mL) and washed with aqueous 10% potassium carbonate (200 mL) followed by saturated aqueous sodium chloride (200 mL). The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated yielding 1.20 g (98%) of the title compound as a viscous golden oil: 1H NMR (CDCl3): δ 1.80 (m, 2H), 2.05 (br s, 1H), 2.43 (s, 3H), 2.57 (m, 2H), 2.70 (t, J=Hz, 2H), 2.79 (t, J=Hz, 2H), 3.20 (m, 2H), 5.73 (m, 1H), 7.25 (d, J=1.58, 1H), 7.39-7.48 (m, 3H), 7.75 (d, J=8.19, 1H), 7.83 (m, 1H), 7.96 (m, 1H)
Reaction SMILES: [Br:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[C:5]([NH:18][C:19](=[O:26])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:4][CH:3]=1.[OH-].[K+].[CH3:29]I>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.ClC1C=CC=CC=1>[Br:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[C:5]([N:18]([CH3:29])[C:19](=[O:26])[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[CH:4][CH:3]=1
Reactant: CI
Reactant: O=C(Nc1ccc(Br)c2c1C(=O)c1ccccc1C2=O)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: Clc1ccccc1
Product: CN(C(=O)c1ccccc1)c1ccc(Br)c2c1C(=O)c1ccccc1C2=O
Temperature: 30 °C
Reaction time: 1 h
Yield: 98.1 %

Procedure:
A mixture of 4-bromo-1-benzoylaminoanthraquinone (purity 98.5%, 41.2 g), monochlorobenzene (500 g), tetra-n-butyl ammonium bromide (0.3 g) and 96% potassium hydroxide (12.0 g) was stirred for one hour at 30° C., and methyl iodide (28.4 g) was added thereto at 30° C. over 2 hours. A mixture was stirred at 30° C. for 30 minutes and 40° C. for 3 hours, successively. Then, the same aftertreatment as in Example 3 was conducted to obtain 4-bromo-N-benzoyl-1-methylaminoanthraquinone (41.8 g, purity 94.5%, yield 94.0%).
Reaction SMILES: OC(C(F)(F)F)=O.OC(C(F)(F)F)=O.[CH:15]12[O:22][CH:19]([CH2:20][CH2:21]1)[CH2:18][N:17]([C:23]1[N:28]=[C:27]([N:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)[N:26]=[C:25]([C:35]3[CH:40]=[CH:39][C:38]([NH:41][C:42]([NH:44][C:45]4[CH:50]=[CH:49][N:48]=[CH:47][CH:46]=4)=[O:43])=[CH:37][CH:36]=3)[N:24]=1)[CH2:16]2.[CH:51](=O)[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.C(N(CC)CC)C>[CH2:51]([N:32]1[CH2:33][CH2:34][N:29]([C:27]2[N:28]=[C:23]([N:17]3[CH2:16][CH:15]4[O:22][CH:19]([CH2:20][CH2:21]4)[CH2:18]3)[N:24]=[C:25]([C:35]3[CH:36]=[CH:37][C:38]([NH:41][C:42]([NH:44][C:45]4[CH:46]=[CH:47][N:48]=[CH:49][CH:50]=4)=[O:43])=[CH:39][CH:40]=3)[N:26]=2)[CH2:30][CH2:31]1)[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1
Reactant: O=Cc1ccccc1
Reactant: O=C(Nc1ccncc1)Nc1ccc(-c2nc(N3CCNCC3)nc(N3CC4CCC(C3)O4)n2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: O=C(Nc1ccncc1)Nc1ccc(-c2nc(N3CCN(Cc4ccccc4)CC3)nc(N3CC4CCC(C3)O4)n2)cc1

Procedure:
1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(piperazin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea-2TFA (130 mg) in dichloromethane (4 mL) and triethylamine (0.10 mL) was treated with benzaldehyde (0.10 mL), followed by sodium triacetoxyborohydride (80 mg). The mixture was concentrated to dryness and purified on HPLC to give the title compound as its di-TFA salt; MS (ES+) 578.3 (M+H)+.
Reaction SMILES: [F:1][CH:2]([F:37])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:6]=1[C:15]1[C:16]2[N:17]([N:21]=[C:22]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([CH:31]4[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]4)=[CH:27][CH:26]=3)[N:23]=2)[CH:18]=[CH:19][CH:20]=1.Cl[CH2:39][C:40]([N:42]([CH3:44])[CH3:43])=[O:41]>>[F:37][CH:2]([F:1])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:12])([F:13])[F:14])=[CH:7][C:6]=1[C:15]1[C:16]2[N:17]([N:21]=[C:22]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([CH:31]4[CH2:32][CH2:33][N:34]([CH2:39][C:40]([N:42]([CH3:44])[CH3:43])=[O:41])[CH2:35][CH2:36]4)=[CH:27][CH:26]=3)[N:23]=2)[CH:18]=[CH:19][CH:20]=1
Reactant: CN(C)C(=O)CCl
Reactant: FC(F)COc1ccc(C(F)(F)F)cc1-c1cccn2nc(Nc3ccc(C4CCNCC4)cc3)nc12
Product: CN(C)C(=O)CN1CCC(c2ccc(Nc3nc4c(-c5cc(C(F)(F)F)ccc5OCC(F)F)cccn4n3)cc2)CC1

Procedure:
2-[4-(4-{8-[2-(2,2-Difluoro-ethoxy)-5-trifluoromethyl-phenyl]-[1,2,4]-triazolo[1,5-a]pyridin-2-ylamino}-phenyl)-piperidin-1-yl]-N,N-dimethyl-acetamide was prepared from {8-[2-(2,2-difluoro-ethoxy)-5-trifluoromethyl-phenyl]-[1,2,4]-triazolo[1,5-a]pyridin-2-yl}-(4-piperidin-4-yl-phenyl)-amine (0.067 g, 0.130 mmol) and 2-chloro-N,N-dimethyl-acetamide (0.020 mL, 0.190 mmol) in a manner analogous to Example 313 to give product (0.020 g, 26%). MP=98-101° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.54 (s, 1H), 8.80 (d, 1H), 8.08 (s, 1H), 7.82 (d, 1H), 7.68 (d, 1H), 7.58 (m, 2H), 7.45 (d, 1H), 7.10 (m, 3H), 6.30 (br m, 1H), 4.49 (m, 2H), 3.15 (s, 2H), 3.05 (s, 3H), 2.95 (m, 2H), 2.82 (s, 3H), 2.38 (m, 1H), 2.12 (m, 2H), 1.55-1.72 (br m, 4H): MS=603 (MH)+.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.Br[C:15]1[CH:20]=[CH:19][C:18]([C:21](=[O:28])[CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.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:28]=[C:21]([C:18]1[CH:19]=[CH:20][C:15]([C:6]2[CH:7]=[CH:8][C:3]([C:2]([F:13])([F:12])[F:1])=[CH:4][CH:5]=2)=[CH:16][CH:17]=1)[CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25]
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: COC(=O)CCC(=O)c1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COC(=O)CCC(=O)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Yield: 84.4 %

Procedure:
In a manner similar to Example 12, Step (b), (4-trifluoromethyl-phenyl)boronic acid (1.285 g, 0.00676 mol) was allowed to react with 4-(4-bromo-phenyl)-4-oxo-butyric acid, methyl ester (1.356 g, 0.00500 mol) in the presence of tetrakis(triphenylphosphine)palladium(0) (0.173 g, 0.000150 mol) and 2.0 M aqueous sodium carbonate (5.0 mL, 0.010 mol) in toluene (10 mL) to give, after chromatography on silica gel (270 g, 230-400 mesh), eluting with chloroform to give 1.42 g of 4-oxo-4-(4′-trifluoromethyl-biphenyl-4-yl)-butyric acid, methyl ester as a white solid; mp 140-142° C.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([N-]C(C)C)(C)C.[Li+].C([Li])CCC.CCCCCC.C(NC(C)C)(C)C.[O:45]1[CH2:49][CH2:48][CH2:47][CH:46]1[CH2:50][CH:51]=[O:52]>O1CCCC1>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[C:11]2[CH:51]([OH:52])[CH2:50][CH:46]2[CH2:47][CH2:48][CH2:49][O:45]2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=CCC1CCCO1
Reactant: O=S(=O)(c1ccccc1)n1ccc2cccnc21
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Product: O=S(=O)(c1ccccc1)n1c(C(O)CC2CCCO2)cc2cccnc21
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 10.1 %

Procedure:
To a suspension of 1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridine (6.16 g, 24 mmol) in dry tetrahydrofuran (150 mL) at −78° C. was added freshly prepared lithium diisopropylamide [prepared by adding 1.6 M n-butyllithium in n-hexane (22.5 mL, 36 mmol) to a 0° C. solution of diisopropylamine (5.4 mL, 38 mmol) in dry tetrahydrofuran (20 mL)] dropwise. The mixture was stirred at −78° C. for 15 min and then treated with (tetrahydro-furan-2-yl)-acetaldehyde (4.9 g, 43 mmol) dropwise. The resulting mixture was stirred at −78° C. for 1 h and quenched with brine. The mixture was extracted with ethyl acetate (2×150 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. Purification by flash column chromatography (QingDao silica gel, 200-300 mesh, 30% ethyl acetate/hexanes) afforded 1-(1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-(tetrahydro-furan-2-yl)-ethanol as a colorless oil (0.9 g, 31%): LC/MS m/e calcd for C19H20N2O4S [M+H]+ 373.45, observed 373.3.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2.[Cl:12][C:13]([Cl:18])([Cl:17])[C:14](Cl)=[O:15]>ClCCl.CCN(CC)CC>[Cl:12][C:13]([Cl:18])([Cl:17])[C:14]([NH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2)=[O:15]
Reactant: Nc1cccc2cnccc12
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1cccc2cnccc12)C(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 14 h
Yield: 65.1 %

Procedure:
A solution of 5-aminoisoquinoline (1.0 g, 6.9 mmol) in dichloromethane (40 mL) and Et3N (1 mL) at 5° C. was treated with trichloroacetyl chloride (1.38 g, 7.6 mmol) dropwise. The reaction mixture was stirred at ambient temperature for 14 hours, concentrated, diluted with ethyl acetate and washed with 1N HCl. The aqueous layer was treated with aqueous NaHCO3 and extracted with ethyl acetate. The organic layer the was washed with water and concentrated. The solid residue was suspended in ethyl acetate (5 mL) and filtered to obtain 1.3 g (65%) of the title compound as a tan solid. 1H NMR (300 MHz, d6-DMSO) δ 11.20 (broad s, 1H), 9.41, (s, 1H), 8.60 (d, 1H), 8.18 (m, 1H), 7.77 (m, 2H), 7.66 (d, 1H); MS (DCI/NH3) m/z 289 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([C:9]([F:12])([F:11])[F:10])[N:3]=1.Cl.[CH:14]12[O:21][CH:18]([CH2:19][CH2:20]1)[CH2:17][NH:16][CH2:15]2.C(N(CC)CC)C>C(OCC)C.C(O)C>[Cl:1][C:2]1[N:7]=[C:6]([N:16]2[CH2:15][CH:14]3[O:21][CH:18]([CH2:19][CH2:20]3)[CH2:17]2)[CH:5]=[C:4]([C:9]([F:12])([F:11])[F:10])[N:3]=1
Reactant: FC(F)(F)c1cc(Cl)nc(Cl)n1
Reactant: C1CC2CNCC1O2
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: CCO
Product: FC(F)(F)c1cc(N2CC3CCC(C2)O3)nc(Cl)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 120.2 %

Procedure:
A solution of crude 2,4-dichloro-6-(trifluoromethyl)pyrimidine (62, 6.7 mmol) in diethyl ether (10 mL) was diluted with ethanol (25 mL) and cooled in an ice-water bath. 8-Oxa-3-azabicyclo[3.2.1]octane hydrochloride (2, 3.4 mmol) was added, followed by triethylamine (2 mL). Two additional portions of 8-oxa-3-azabicyclo[3.2.1]octane hydrochloride (2, 100 mg each) were added, the mixture was slowly warmed to room temperature and stirred overnight. Additional triethylamine (4 mL) was added to the mixture, which was then concentrated to dryness under reduced pressure. The residue was purified via flash silica gel chromatography (40% ethyl acetate/hexanes) to provide the title compound as a light colored solid (1.2 g, 61%). MS (ES+): 294.2 (M+H)+.
Reaction SMILES: Cl.[CH3:2][C:3]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH2:18][CH2:19][CH3:20])[C:13]([CH3:21])=[C:12]2[C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1)([CH3:7])[C:4](O)=[O:5].[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+]>O1CCCC1>[CH3:2][C:3]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH2:18][CH2:19][CH3:20])[C:13]([CH3:21])=[C:12]2[C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1)([CH3:7])[CH2:4][OH:5]
Reactant: CCCn1c(C)c(-c2ccncc2)c2cc(OC(C)(C)C(=O)O)ccc21
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: CCCn1c(C)c(-c2ccncc2)c2cc(OC(C)(C)CO)ccc21

Procedure:
A suspension of 1.0 g (2.6 m mole) of 2-methyl-2-[2-methyl-1-propyl-3-(4-pyridyl)-1H-indole-5-yloxy]propanoic acid hydrochloride was added dropwise to 1.0 g (26 m mole) of lithiumaluminium hydride in 50 ml of absolute tetrahydrofurane under stirring. After the mixture was stirred for one hour at 60° C., 2 N sodium hydroxide solution was added. The sodium aluminate precipitate was filtered off, and the residue was evaporated and purified on silicagel by colunn chromatography (eluant: ethyl acetate).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[CH:11][CH2:12][OH:13])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N(CC)CC)C.[C:21]([SiH2:25][O:26][C:27]([CH3:49])([CH3:48])[CH:28]1[CH2:32][CH2:31][CH2:30][N:29]1[C:33]([C:35]1[CH:40]=[C:39]([O:41][CH3:42])[C:38]([O:43][CH3:44])=[CH:37][C:36]=1[N:45]=[C:46]=[O:47])=[O:34])([CH3:24])([CH3:23])[CH3:22].NC1C=C(OC)C(OC)=CC=1C(N1CCCC1C(C)(C)O[SiH2]C(C)(C)C)=O.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl.C1(C)C=CC=CC=1.CCOC(C)=O>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH:10]=[CH:11][CH2:12][O:13][C:46](=[O:47])[NH:45][C:36]2[CH:37]=[C:38]([O:43][CH3:44])[C:39]([O:41][CH3:42])=[CH:40][C:35]=2[C:33]([N:29]2[CH2:30][CH2:31][CH2:32][CH:28]2[C:27]([CH3:49])([CH3:48])[O:26][SiH2:25][C:21]([CH3:23])([CH3:22])[CH3:24])=[O:34])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: COc1cc(N=C=O)c(C(=O)N2CCCC2C(C)(C)O[SiH2]C(C)(C)C)cc1OC
Reactant: O=[N+]([O-])c1ccc(C=CCO)cc1
Agent: COc1cc(N)c(C(=O)N2CCCC2C(C)(C)O[SiH2]C(C)(C)C)cc1OC
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1cc(NC(=O)OCC=Cc2ccc([N+](=O)[O-])cc2)c(C(=O)N2CCCC2C(C)(C)O[SiH2]C(C)(C)C)cc1OC
Reaction time: 20 h

Procedure:
A solution of 3-(4-nitrophenyl)-prop-2-en-1-ol (0.222 g, 1.24 mmol) and triethylamine (0.138 g, 0.19 mL, 1.37 mmol) in anhydrous CH2Cl2 (10 mL) was added to a solution of the isocyanate 7 prepared from the amine 5 (0.491 g, 1.24 mmol), triphosgene (0.132 g, 0.45 mmol) and triethylamine (0.17 g, 0.23 mL, 1.68 mmol) in anhydrous toluene (20 mL). The reaction was complete in 20 hours. The product was obtained (flash column chromatography 50% EtOAc/50% n-hexane) as a yellow oil which crystallised (0.432 g, 58%): νmax/cm−1 (film) (C=0, carbamate); [α]D25.3−65.0° (c=0.24, CHCl3), 1H NMR (CDCl3) δ 9.39 (bs, 1H), 7.89 ((s, 1H), 8.19 (d, J=8.8 Hz, 2H), 7.53 (d, J=9 Hz, 2H), 6.85 (s, 1H), 6.73 (d, J=15.9 Hz, 1H), 6.52 (dt, J=5.8, 15.9 Hz, 1H) 4.86 (m, 2H) 4.38 (m, 1H), 4.01 (m, 1H), 3.94 (s, 3H), 3.83 (s, 3H), 3.70 (m, 1H), 3.52 (m, 2H), 2.06 (m, 2H), 1.95 (m, 1H), 1.72 (m, 1H), 0.9 (s, 9H), 0.08 (s, 6H). IR (neat) 3340, 2930, 1729, 1597, 1519 cm−1. HRMS m/z calcd for C30H31N3O8SiNa 622.2561 (M+Na), found 622.2542.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:4]=1B(O)O.[Br:16][C:17]1[CH:18]=[CH:19][C:20]([CH:27]=[O:28])=[C:21]([CH:26]=1)[C:22]([O:24]C)=O.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1CC=CCCC=C1.C1CC=CCCC=C1.[Cl-].[Cl-].[Rh].[Rh].C1COCC1>[Br:16][C:17]1[CH:26]=[C:21]2[C:20]([CH:27]([C:4]3[CH:5]=[CH:6][C:7]([C:9]([F:12])([F:11])[F:10])=[CH:8][C:3]=3[O:2][CH3:1])[O:28][C:22]2=[O:24])=[CH:19][CH:18]=1
Reactant: COC(=O)c1cc(Br)ccc1C=O
Reactant: COc1cc(C(F)(F)F)ccc1B(O)O
Agent: [Rh]
Agent: C1=C\CC/C=C\CC/1
Agent: O=P([O-])([O-])[O-]
Solvent: C1=CCCC=CCC1
Solvent: C1CCOC1
Product: COc1cc(C(F)(F)F)ccc1C1OC(=O)c2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.7 %

Procedure:
2-Methoxy-4-(trifluoromethyl)phenyl boronic acid (2.05 g, 9.32 mmol; Combi-Blocks, San Diego, Calif.), methyl 5-bromo-2-formylbenzoate (1.51 g, 6.21 mmol; GLSyntech, LLC, Hatfield, Pa.), tripotassium phosphate (5.27 g, 24.9 mmol; freshly ground) and THF (31.1 mL) was added to a vial. The vial was purged with argon. Then chloro(1,5-cyclooctadiene)rhodium(i) dimer (0.153 g, 0.311 mmol; Strem Chemicals, Inc., Newburyport, Mass.) was added. The vial was sealed and stirred at RT. After 1 h, the reaction was filtered and the filtrate was concentrated under a vacuum. The crude material was absorbed onto a plug of silica gel and purified by chromatography through a silica gel column (80 g), eluting with a gradient of 0% to 10% EtOAc in heptane, to provide 6-bromo-3-(2-methoxy-4-(trifluoromethyl)phenyl)isobenzofuran-1(3H)-one (2.06 g, 86% yield) as a brown solid. 1H NMR (400 MHz, CDCl3) δ ppm 3.92 (s, 3H), 6.72 (s, 1H), 7.11-7.17 (m, 3H), 7.25 (dt, J=8.2, 0.7 Hz, 1H), 7.65 (dd, J=8.3, 1.7 Hz, 1H), 8.00 (d, J=1.8 Hz, 1H). m/z (ESI) 405.0 (M+H)+. This lactone was not stable on MS.