Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][C@@H:5]([C:8]([OH:10])=[O:9])[CH2:6][SH:7])(=[O:3])[CH3:2].F[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N+:18]([O-:20])=[O:19].C(=O)(O)[O-].[Na+].O>C(O)C>[N+:18]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[S:7][CH2:6][C@H:5]([C:8]([OH:10])=[O:9])[NH:4][C:1](=[O:3])[CH3:2])([O-:20])=[O:19]
Reactant: CC(=O)N[C@H](CS)C(=O)O
Reactant: O=[N+]([O-])c1ccccc1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(=O)N[C@H](CSc1ccccc1[N+](=O)[O-])C(=O)O
Temperature: 25 °C
Yield: 84.1 %

Procedure:
A mixture of 9.28 g (56.9 mmol) of (S)-N-acetyl-cysteine, 7.43 mL (70.5 mmol) of 1-fluoro-2-nitrobenzene and 13.66 g (163 mmol) of sodium bicarbonate was refluxed in 136 mL of ethanol and 41 mL of water for 3 hours. The mixture was cooled to room temperature and the solvent evaporated. The residue was dissolved in 136 mL of water and extracted with ether. The water solution was then acidified to pH=1with 12N hydrochloric acid (HCl). The resulting yellow precipitate was filtered to yield 13.6 g (84%) of product.
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[NH:7][CH2:8][C:9]1[N:10]([CH2:29][CH:30]([CH3:32])[CH3:31])[C:11](=[O:28])[C:12]2[C:17]([C:18]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[CH:16][C:15]([CH2:25][C:26]#N)=[CH:14][CH:13]=2)([CH3:4])([CH3:3])[CH3:2].[OH-:34].[K+].C(O)C.[OH-:39].[Na+]>>[C:1]([O:5][C:6]([NH:7][CH2:8][C:9]1[N:10]([CH2:29][CH:30]([CH3:31])[CH3:32])[C:11](=[O:28])[C:12]2[C:17]([C:18]=1[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[CH:16][C:15]([CH2:25][C:26]([OH:39])=[O:34])=[CH:14][CH:13]=2)=[O:33])([CH3:3])([CH3:2])[CH3:4]
Reactant: [OH-]
Reactant: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2ccccc2)c2cc(CC#N)ccc2c1=O
Agent: [K+]
Agent: [Na+]
Solvent: CCO
Product: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2ccccc2)c2cc(CC(=O)O)ccc2c1=O
Yield: 87 %

Procedure:
A mixture of tert-butyl[6-(cyanomethyl)-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl]methylcarbamate (0.13 g, 0.29 mmol), 2N potassium hydroxide solution (5 mL) and ethanol (5 mL) was refluxed for 4 h. The reaction mixture was diluted with 0.1N sodium hydroxide solution (100 mL) and washed with ethyl acetate (20 mL×2). The aqueous layer was separated, acidified with 1N hydrochloric acid and extracted with ethylacetate (100 mL×2). The organic layers were combined, washed with brine (20 mL), saturated aqueous sodium hydrogencarbonate (50 mL) and brine (50 mL), dried over, anhydrous magnesium sulfate and concentrated under reduced pressure to give (3-{[(tert-butoxycarbonyl)amino]methyl}-2-isobutyl-1-oxo-4-phenyl-1,2-dihydroisoquinolin-6-yl)acetic acid (0.36 g, 87%) as a pale yellow oil.
Reaction SMILES: C(N(CC)CC)C.Cl.[NH2:9][C@@H:10]([CH2:14][CH3:15])[C:11]([NH2:13])=[O:12].Br[CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]>C1(C)C=CC=CC=1>[NH2:13][C:11]([C@@H:10]([NH:9][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)CCCBr
Reactant: CC[C@H](N)C(N)=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOC(=O)CCCN[C@@H](CC)C(N)=O
Temperature: 80 °C

Procedure:
143.6 ml (1.035 mole) of triethylamine are added to a suspension of 47.75 g (0.345 mole) of (S)-2-amino-butanamide hydrochloride ([alpha]D25 : +26.1°; c=1, methanol) in 400 ml of toluene. The mixture is heated to 80° C. and 67.2 g (0.345 mole) of ethyl 4-bromobutyrate are introduced dropwise.
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][CH:15]=[CH:14][C:5]=1[CH2:6][CH2:7][CH2:8][NH:9][CH2:10][C:11]([OH:13])=[O:12])([O-])=O.[H][H]>[Pd].C(O)C>[NH2:1][C:4]1[CH:17]=[CH:16][CH:15]=[CH:14][C:5]=1[CH2:6][CH2:7][CH2:8][NH:9][CH2:10][C:11]([OH:13])=[O:12]
Reactant: [H][H]
Reactant: O=C(O)CNCCCc1ccccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: Nc1ccccc1CCCNCC(=O)O
Yield: 77 %

Procedure:
To a solution of 13.0 g. (5.46 × 10-2 moles) of N-(o-nitrobenzyl)ethyl glycine in 200 ml. of absolute ethyl alcohol was added slowly 0.76 g. (5% by weight) of 10% Pd/C catalyst and the mixture placed on a Paar hydrogenator. The mixture was shaken until theoretical hydrogen (16.4 × 10-2 moles) had been absorbed, removed from the Paar and the mixture filtered under suction. The catalyst was washed with ethyl alcohol and the solvent removed in vacuo affording a yellow oil. Purification of the oil was effected by distillation yielding 8.8 g. (77% yield) of a colorless oil; b.p. 124°-126° C. (0.03 mm).
Reaction SMILES: C[CH:2]([CH:6]1[C:10]2=[C:11]([S:20][C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)[C:12]3[C:13](Br)=[CH:14][C:15]([F:18])=[CH:16][C:17]=3[N:9]2[CH2:8][CH2:7]1)[C:3]([O-:5])=[O:4].[CH3:28][N:29]1[C:33]([Sn](CCCC)(CCCC)CCCC)=[CH:32][CH:31]=[N:30]1>>[Cl:27][C:24]1[CH:23]=[CH:22][C:21]([S:20][C:11]2[C:12]3[C:13]([C:33]4[N:29]([CH3:28])[N:30]=[CH:31][CH:32]=4)=[CH:14][C:15]([F:18])=[CH:16][C:17]=3[N:9]3[CH2:8][CH2:7][CH:6]([CH2:2][C:3]([OH:5])=[O:4])[C:10]=23)=[CH:26][CH:25]=1
Reactant: CC(C(=O)[O-])C1CCn2c1c(Sc1ccc(Cl)cc1)c1c(Br)cc(F)cc12
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccnn1C
Product: Cn1nccc1-c1cc(F)cc2c1c(Sc1ccc(Cl)cc1)c1n2CCC1CC(=O)O

Procedure:
Starting from (+/−)-methyl{8-bromo-9-[(4-chlorophenyl)thio]-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl}acetate (Example 7, Step 9, 200 mg, 0.43 mmol) and 1-methyl-5-(tributylstannyl)-1H-pyrazole (239 mg, 0.64 mmol), the title compound was synthesized following the procedures described in Example 42 and Step 10 of Example 7.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1([C:15]#[N:16])[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.[C:17]([O:21][C:22]([NH:24][CH2:25][CH2:26][CH2:27]Br)=[O:23])([CH3:20])([CH3:19])[CH3:18].[I-].[Na+]>CC(C)=O>[C:17]([O:21][C:22](=[O:23])[NH:24][CH2:25][CH2:26][CH2:27][N:12]1[CH2:13][CH2:14][C:9]([C:15]#[N:16])([C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[F:1])[CH2:10][CH2:11]1)([CH3:20])([CH3:19])[CH3:18]
Reactant: N#CC1(c2ccc(F)cc2F)CCNCC1
Reactant: CC(C)(C)OC(=O)NCCCBr
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)NCCCN1CCC(C#N)(c2ccc(F)cc2F)CC1
Temperature: 25 °C
Yield: 74.7 %

Procedure:
To a stirred solution of 4-(2,4-difluorophenyl)-piperidine-4-carbonitrile (0.203 g, 0.914 mmol) in acetone (20 ml), N-(tert-butoxycarbonyl)-3-bromopropylamine (0.239 g, 1.00 mmol) potassium carbonate (0.505 g, 3.65 mmol) and sodium iodide (0.274 g, 1.82 mmol) were added and the solution refluxed for 24 hours. The reaction mixture was cooled to room temperature, concentrated and partitioned between chloroform (20 mL) and water (5 mL). The organic layer was dried over sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography (ethyl acetate) to yield 0.259 g (75%) of the required product as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:29]=[CH:28][C:6]([CH2:7][N:8]2[CH2:12][CH:11]([CH2:13][CH2:14][O:15]S(C3C=CC(C)=CC=3)(=O)=O)[N:10]([CH3:26])[C:9]2=[O:27])=[CH:5][CH:4]=1.[CH2:30]([O:32][C:33](=[O:45])[C:34]([O:37][C:38]1[CH:43]=[CH:42][C:41](O)=[CH:40][CH:39]=1)([CH3:36])[CH3:35])[CH3:31].N#N>CN(C=O)C>[CH2:30]([O:32][C:33](=[O:45])[C:34]([O:37][C:38]1[CH:43]=[CH:42][C:41]([O:15][CH2:14][CH2:13][CH:11]2[CH2:12][N:8]([CH2:7][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:29][CH:28]=3)[C:9](=[O:27])[N:10]2[CH3:26])=[CH:40][CH:39]=1)([CH3:36])[CH3:35])[CH3:31]
Reactant: COc1ccc(CN2CC(CCOS(=O)(=O)c3ccc(C)cc3)N(C)C2=O)cc1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(O)cc1
Agent: N#N
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)Oc1ccc(OCCC2CN(Cc3ccc(OC)cc3)C(=O)N2C)cc1
Temperature: 25 °C
Yield: 92.8 %

Procedure:
A mixture of toluene-4-sulfonic acid 2-[1-(4-methoxy-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-ethyl ester (3.10 g, 7.41 mmol), 2-(4-hydroxy-phenoxy)-2-methyl-propionic acid ethyl ester (1.50 g, 6.69 mmol) and CS2CO3 (2.62 g, 8.04 mmol) in DMF (70 mL) was heated at 65° C. for under N2 for 16 h. The reaction mixture was cooled to room temperature, quenched with aqueous 1 N HCl (25 mL), and worked up extractively with EtOAc and water. The organic layer was dried (MgSO4) and the solvent removed in vacuo to afford crude product that was purified by flash chromatography using 5:1 hexanes:acetone to afford 2.92 g (93%) 2-(4-{2-[1-(4-methoxy-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-ethoxy}-phenoxy)-2-methyl-propionic acid ethyl ester. MS (ES+) Calc'd for C36H47N2O6 (M+1) 603. Found m/z 603 (100%). 1H NMR.
Reaction SMILES: [OH:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[O:5][C:4](=[O:12])[C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[CH2:19]([N:21]([CH2:25][CH3:26])[CH2:22][CH2:23]Cl)[CH3:20]>>[CH2:19]([N:21]([CH2:25][CH3:26])[CH2:22][CH2:23][O:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[O:5][C:4](=[O:12])[C:3]=1[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[CH3:20]
Reactant: CCN(CC)CCCl
Reactant: O=c1oc2c(c(O)c1-c1ccccc1)CCCC2
Product: CCN(CC)CCOc1c2c(oc(=O)c1-c1ccccc1)CCCC2
Yield: 68.7 %

Procedure:
Prepared as indicated in Example 14, Stage B, from 12.1 g. (0.05 mol) of 4-hydroxy-3-phenyl-5,6,7,8-tetrahydrocoumarin (Example 14, Stage A) and 8.8 g. (0.065 mol) of 2-diethylamino-1-chloroethane. 13.2 g. of an oil are obtained, which cannot be crystallised. Yield 68.7% (theoretical yield 19.2 g.).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].C(NC(C)C)(C)C.C([Li])CCC.[C:21]1([CH3:30])[C:22]([C:27]([OH:29])=[O:28])=[CH:23][CH:24]=[CH:25][CH:26]=1.[CH2:31](Br)[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41]>O1CCCC1>[CH2:30]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]([OH:29])=[O:28])[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH3:31]
Reactant: Cc1ccccc1C(=O)O
Reactant: CCCCCCCCCCCBr
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCCCCCCCCCCCc1ccccc1C(=O)O
Reaction time: 0.08 h

Procedure:
A solution containing lithium diisopropylamide (0.1 mole) was prepared by treating a solution of diisopropylamine (14.1 ml, 0.1 mole) in tetrahydrofuran (200 ml) at 0° C. with n-butyl lithium (41.2 ml of a 2.43M solution, 0.1 mole), and stirring for 5 minutes. To this was added a solution of o-toluic acid (6.8 g, 0.05 mole) in tetrahydrofuran (50 ml). The ice bath was removed and the intense red solution was stirred for 30 minutes. This solution was slowly pipetted into a solution of undecylbromide (11.8 g, 0.05 mole) in tetrahydrofuran (50 ml) at -20° C. After the addition, the cooling bath was removed and the solution stirred for 30 minutes. A small amount of water was added and most of the tetrahydrofuran was removed under reduced pressure. The residue was poured into water, acidified with 3N hydrochloric acid and extracted with ether. The ether was dried, evaporated and the residue was recrystallized from acetonitrile, then from hexane, to give the product.
Reaction SMILES: [C:1]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=1)([O:3][CH3:4])=[O:2].[C:30]([OH:35])(=[O:34])[CH:31]([CH3:33])O.C1(C)C(S(O)(=O)=O)=CC=CC=1>C1(C)C=CC=CC=1>[C:1]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:21]1[CH:22]=[CH:23][C:24]([C:25]([O:27][CH:31]([C:30]([OH:35])=[O:34])[CH3:33])=[O:26])=[CH:28][CH:29]=1)([O:3][CH3:4])=[O:2]
Reactant: COC(=O)CCCCCCCCCCCCCCCNc1ccc(C(=O)O)cc1
Reactant: CC(O)C(=O)O
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: Cc1ccccc1
Product: COC(=O)CCCCCCCCCCCCCCCNc1ccc(C(=O)OC(C)C(=O)O)cc1

Procedure:
A flask containing 10.0 g. 4-(15-carbomethoxypentadecylamino)benzoic acid, 3.3 g. lactic acid, 500 mg. toluene-sulfonic acid and 500 ml. toluene is equipped with a Soxhlet extractor charged with activated 4A Linde molecular sieves. The solution is refluxed for 4 hours, during which time the Soxhlet extractor is charged twice more with fresh sieves. The hot solution is filtered and left to cool, whereupon the product separates as off-white crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([CH3:12])=[C:10]2[C:6]([C:7](=[O:13])[O:8][CH2:9]2)=[C:5]([O:14][S:15]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)(=[O:17])=[O:16])[C:4]=1[CH2:25][C:26]1[CH2:30][CH2:29][CH:28]([CH2:31][CH:32]=[O:33])[C:27]=1[CH3:34].C1(C=CC=C(O)C=1)[OH:36].Cl([O-])=O.[Na+].Cl>O1CCOCC1.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[C:11]([CH3:12])=[C:10]2[C:6]([C:7](=[O:13])[O:8][CH2:9]2)=[C:5]([O:14][S:15]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)(=[O:17])=[O:16])[C:4]=1[CH2:25][C:26]1[CH2:30][CH2:29][CH:28]([CH2:31][C:32]([OH:36])=[O:33])[C:27]=1[CH3:34]
Reactant: Oc1cccc(O)c1
Reactant: COc1c(C)c2c(c(OS(=O)(=O)c3ccc(C)cc3)c1CC1=C(C)C(CC=O)CC1)C(=O)OC2
Agent: Cl
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COc1c(C)c2c(c(OS(=O)(=O)c3ccc(C)cc3)c1CC1=C(C)C(CC(=O)O)CC1)C(=O)OC2
Reaction time: 0.03 h

Procedure:
The 3-(1,3-dihydro-6-methoxy-7methyl-3-oxo-4-p-toluenesulfonyloxy-5-isobenzofuranylmethyl)-2-methylcyclopent-2-en-1-ylacetaldehyde was dissolved in dioxane (8 mL) and pH 5 buffer (3 mL) and treated with resorcinol (0.10 g). To this mixture was then added sodium chlorite (0.080 g). After 2 minutes, the reaction was diluted with ethyl acetate and made acidic with 5% hydrochloric acid. After two extractions with ethyl acetate, the combined organic layers were dried over magnesium sulfate. The residue, 3-(1,3-dihydro-6-methoxy-7-methyl-3-oxo-4-p-toluenesulfonyloxy-5-isobenzofuranylmethyl)-2-methylcyclopent-2-en-1-ylacetic acid obtained after solvent removal was carried on without further purification.
Reaction SMILES: N1C=CC=CC=1.P(Cl)(Cl)(Cl)(Cl)[Cl:8].[C:13]([CH:15]1[CH2:20][CH:19]2[CH2:21][CH2:22][CH:16]1[CH:17]=[CH:18]2)#[N:14]>C(Cl)(Cl)Cl>[Cl:8][C:15]1([C:13]#[N:14])[CH2:20][CH:19]2[CH2:21][CH2:22][CH:16]1[CH:17]=[CH:18]2
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: N#CC1CC2C=CC1CC2
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: N#CC1(Cl)CC2C=CC1CC2
Yield: 94.8 %

Procedure:
To a refluxing mixture of pyridine (14.2 g, 0.180 mol), phosphorus pentachloride (28.0 g, 0.135 mol), and chloroform (100 mL) was added drop-wise a solution of 5-cyanobicyclo[2,2,2]oct-2-ene (12 g, 90 mmol) in chloroform (50 mL). The resulting mixture was heated at reflux for 15 h, cooled, and poured onto ice. The organic layer was concentrated, and the residue was purified by chromatography on silica gel, eluting with mixtures of ethyl acetate (0.5% to 1%) in petroleum ether, to give 5-chloro-5-cyanobicyclo[2,2,2]oct-2-ene (14.3 g, 95% yield) as a white semisolid, 1H NMR (300 MHz, CDCl3) δ 1.3-1.5 (m, 3H), 2.02-2.18 (m, 2H), 2.51 (m, 1H), 2.72 (m, 1H), 3.12 (m, 1H), 6.22 (m, 1H), 6.41 (m, 1H); GCMS (m/z); 167.
Reaction SMILES: [C:1]([Si:5]([CH3:8])([CH3:7])Cl)([CH3:4])([CH3:3])[CH3:2].[CH3:9][C:10]([CH:14]1[NH:17][C:16](=[O:18])[CH2:15]1)([CH3:13])[CH:11]=[CH2:12].C(N(CC)CC)C>CN(C)C=O>[Si:5]([N:17]1[CH:14]([C:10]([CH3:13])([CH3:9])[CH:11]=[CH2:12])[CH2:15][C:16]1=[O:18])([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:8])[CH3:7]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C=CC(C)(C)C1CC(=O)N1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C=CC(C)(C)C1CC(=O)N1[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
t-Butyldimethylchlorosilane (7.51 g) is added in one portion to an ice-cold, stirred solution of 4-(1,1-dimethyl-prop-2-enyl)-azetidin-2-one (6.54 g) and triethylamine (5.04 g) in anhydrous dimethylformamide (100 ml). The reaction mixture is stirred at 0°-5° C. for 1 hour and then allowed to warm to room temperature. Most of the solvent is removed under vacuum to give a residue which is partitioned between diethyl ether (250 ml) and water. The ethereal phase is washed with 2.5N hydrochloric acid (50 ml), water (3×50 ml), and brine, dried with magnesium sulfate, filtered and evaporated under vacuum to provide crude product which is purified by chromatography on silica gel (20% ether in petroleum ether) to yield 2.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:25][CH2:26][C:27]1[C:28]([F:44])=[C:29]([O:34][C:35]2[CH:36]=[C:37]([CH:40]=[C:41]([Cl:43])[CH:42]=2)[C:38]#[N:39])[C:30]([Cl:33])=[CH:31][CH:32]=1.[Cl:45][C:46]1[CH:50]=[C:49]([CH2:51][CH2:52][OH:53])[NH:48][C:47]=1[C:54](O)=[O:55].CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:45][C:46]1[CH:50]=[C:49]([CH2:51][CH2:52][OH:53])[NH:48][C:47]=1[C:54]([NH:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[C:29]([O:34][C:35]2[CH:36]=[C:37]([C:38]#[N:39])[CH:40]=[C:41]([Cl:43])[CH:42]=2)[C:28]=1[F:44])=[O:55]
Reactant: O=C(O)c1[nH]c(CCO)cc1Cl
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CN)c2F)c1
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
Product: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CNC(=O)c3[nH]c(CCO)cc3Cl)c2F)c1
Reaction time: 2 h
Yield: 2.2 %

Procedure:
HATU (0.057 g, 0.15 mmol) was added to a solution of 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-chlorobenzonitrile (0.047 g, 0.15 mmol), 3-chloro-5-(2-hydroxyethyl)-1H-pyrrole-2-carboxylic acid (0.028 g, 0.15 mmol) and DIPEA (0.026 mL, 0.150 mmol) in DMF (2 mL). The resulting solution was stirred for 2 hours then partitioned between water and EtOAc. The organic layer was separated, dried over MgSO4 and evaporated to a residue. The residue was purified by reverse-phase HPLC (water/acetonitrile with 0.1% TFA) to afford the title compound (0.0016 g, 2%) as a film. 1H NMR (400 MHz, Acetone-d6) δ ppm 7.60-7.68 (m, 1H), 7.48-7.53 (m, 1H), 7.41-7.45 (m, 2H), 7.37-7.40 (m, 2H), 6.03 (d, 1H), 4.69 (d, 2H), 3.78 (t, 2 H), 2.82 (t, 2H). LCMS: m/z=479.9 (M−1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:19][OH:20])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:10]=[N:11][C:12]([C:15]([F:18])([F:17])[F:16])=[N:13][CH:14]=1.C(OC([N:28]1[C:36]2[N:31]([C:32](=[O:38])[N:33]=[C:34](Cl)[CH:35]=2)[CH2:30][C:29]1([CH3:40])[CH3:39])=O)(C)(C)C>>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[N:13][C:12]([C:15]([F:17])([F:18])[F:16])=[N:11][CH:10]=1)[CH2:19][O:20][C:34]1[CH:35]=[C:36]2[NH:28][C:29]([CH3:40])([CH3:39])[CH2:30][N:31]2[C:32](=[O:38])[N:33]=1
Reactant: CC(C)(C)OC(=O)N1c2cc(Cl)nc(=O)n2CC1(C)C
Reactant: OCc1ccc(Oc2cnc(C(F)(F)F)nc2)c(F)c1
Product: CC1(C)Cn2c(cc(OCc3ccc(Oc4cnc(C(F)(F)F)nc4)c(F)c3)nc2=O)N1

Procedure:
The title compound was prepared by a procedure similar to that described for E9 starting from (3-fluoro-4-((2-(trifluoromethyl)pyrimidin-5-yl)oxy)phenyl)methanol and tert-buty-7-chloro-2,2-dimethyl-5-oxo-2,3-dihydroimidazo[1,2-c]pyrimidine-1(5H)-carboxylate.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[C:19]([O:20][CH3:21])=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][NH:14][CH2:15]2)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH:22](N)=[O:23]>C(O)=O>[CH2:2]([O:9][C:10]1[C:19]([O:20][CH3:21])=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][N:14]([CH:22]=[O:23])[CH2:15]2)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: COc1ccc2c(c1OCc1ccccc1)CCNC2
Reactant: NC=O
Agent: Cl
Solvent: O=CO
Product: COc1ccc2c(c1OCc1ccccc1)CCN(C=O)C2
Temperature: 0 °C

Procedure:
122.3 g of 5-benzyloxy-1,2,3,4-tetrahydro-6-methoxy-isoquinoline-hydrochloride, 140 ml of formic acid, and 700 ml of formamide are heated for 2.5 hours under reflux. The mixture is then poured over 2 kg of ice and extracted with methylene chloride. After evaporation to dryness of the methylene chloride solution under reduced pressure, the residue is recrystallized from methanol-water. 102.3 g of 5-benzyloxy-2-formyl-1,2,3,4-tetrahydro-6-methoxy-isoquinoline are obtained. m.p. = 117.5° - 118.5° C.
Reaction SMILES: O=P(Cl)(Cl)Cl.[CH3:6][C:7]1[O:11][N:10]=[C:9]([C:12]2[NH:13][C:14]3[C:19]([CH:20]=2)=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:8]=1.CN(C)[CH:23]=[O:24]>>[CH3:6][C:7]1[O:11][N:10]=[C:9]([C:12]2[NH:13][C:14]3[C:19]([C:20]=2[CH:23]=[O:24])=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:8]=1
Reactant: Cc1cc(-c2cc3ccccc3[nH]2)no1
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1cc(-c2[nH]c3ccccc3c2C=O)no1
Reaction time: 4 h

Procedure:
With vigorous stirring, POCl3 (1.4 mL, 15 mmol) was added slowly to dimethylformamide (2 mL) at 0° C. 2-(5-Methyl-isoxazol-3-yl)-1H-indole (1.0 g, 5.04 mmol) dissolved in N,N-dimethylformamide (8 mL) was added. The reaction mixture was allowed to come to room temperature, stirred for 4 h, and quenched with ice cold water followed by a 10% sodium hydroxide solution. The resulting precipitate was washed with water, dried in vacuo, and purified via silica gel column chromatography (30% ethyl acetate in petroleum ether) to obtain 2-(5-methyl-isoxazol-3-yl)-1H-indole-3-carbaldehyde (0.6 g, 2.65 mmol) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][C:5]([CH2:14][N:15](C)[C@@H:16]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:17]([OH:19])=O)=[C:6]([CH:12]=[O:13])[O:7]2.[NH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1.ON1C2C=CC=CC=2N=N1>C(Cl)Cl.O>[N:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[NH:25][C:17](=[O:19])[CH:16]([N:15]1[CH2:14][C:5]2[CH2:4][C:3]3[C:2]([Cl:1])=[CH:11][CH:10]=[CH:9][C:8]=3[O:7][C:6]=2[C:12]1=[O:13])[CH2:20][CH:21]([CH3:22])[CH3:23]
Reactant: CC(C)C[C@@H](C(=O)O)N(C)CC1=C(C=O)Oc2cccc(Cl)c2C1
Reactant: Nc1ccccn1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Product: CC(C)CC(C(=O)Nc1ccccn1)N1CC2=C(Oc3cccc(Cl)c3C2)C1=O
Yield: 220.1 %

Procedure:
A solution of (S)-2-[(5-chloro-2-formyl-4H-chromen-3-ylmethyl)-methyl-amino]-4-methyl-pentanoic acid (300 mg, 2.1 mmol), commercially available 2-aminopyridine (101 mg, 1.07 mmol), N-ethyl-N-dimethyaminopropyl carbodiimide hydrochloride (EDCI. HCl) (190 mg, 0.98 mmol), and N-hydroxybenzotriazole (HOBt) (132 mg, 0.982 mmol) in methylene chloride (15 mL) was stirred for 16 hours at 25° C. The reaction mixture was diluted with water and extracted with ethyl acetate (3×). The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting residue, upon silica gel flash chromatography using hexane-ethyl acetate gradiant elution, to afford S)-2-(8-Chloro-3-oxo-3,9-dihydro-1H-chromeno[2,3-c]pyrrol-2-yl)-4-methyl-pentanoic acid pyridin-2-ylamide (970 mg, 26.4%), as a white solid. 1H NMR (DMSO-d6) δ: 10.89 (s, 1H), 8.34 (d, J=3.9 Hz, 1H), 8.01 (d, J=7.8 Hz, 1H), 7.77 (t, J=7.3 Hz, 1H), 7.21-7.42 (m, 2H), 7.02-7.17 (m, 2H), 5.07 (d, J=4.9 Hz, 1H), 4.44 (d, J=18.6 Hz, 1H), 4.07 (d, J=18.6 Hz, 1H), 3.75 (s, 2H), 1.75-1.90 (m, 1H), 1.61-1.74 (m, 1H), 1.46 (br. s., 1H), 1.24 (s, 1H), 0.93 (t, J=5.9 Hz, 6H).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][O:15]S(C1C=CC(C)=CC=1)(=O)=O.[CH2:26]([O:28][C:29](=[O:43])[C:30]([O:33][C:34]1[CH:39]=[CH:38][C:37](O)=[CH:36][C:35]=1[CH2:41][OH:42])([CH3:32])[CH3:31])[CH3:27].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH2:26]([O:28][C:29](=[O:43])[C:30]([O:33][C:34]1[CH:39]=[CH:38][C:37]([O:15][CH2:14][CH2:13][C:3]2[N:4]=[C:5]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)[O:6][C:2]=2[CH3:1])=[CH:36][C:35]=1[CH2:41][OH:42])([CH3:32])[CH3:31])[CH3:27]
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3ccccc3)oc2C)cc1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(O)cc1CO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1CO
Temperature: 80 °C
Yield: 19.6 %

Procedure:
To a 25 mL round bottom flask under a nitrogen atmosphere were charged 0.77 g (2.17 mmol) of toluene-4-sulfonic acid 2-(5-methyl-2-phenyloxazol-4-yl)ethyl ester, and 0.5 g (1.97 mmol) of 2-(4-hydroxy-2-hydroxymethylphenoxy)-2-methylpropionic acid ethyl ester dissolved in 10 mL of absolute ethanol. Next, 0.54 g (3.94 mmol) of potassium carbonate (325 mesh) was added and the reaction was heated to 80° C. for 12 h. The volatiles were removed in vacuo and the crude residue was dissolved in 75 mL EtOAc and washed twice with brine, dried over Na2SO4, and removed in vacuo to give a crude oil. This crude residue was purified using radial chromatography with a 2 mm normal phase silica gel plate, eluting with a step gradient of 5:95 EtOAc:Hex to 35:65 EtOAc:Hex to give a colorless oil (0.17 g, 20%). MS (ES) m/e 452 (M+1).