Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([Si:5](Cl)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([CH3:4])[CH3:3].[CH3:19][O:20][C:21]([C@@H:23]1[CH2:27][C@@H:26]([OH:28])[CH2:25][N:24]1[C:29](=[O:42])[NH:30][C:31]1[CH:36]=[CH:35][C:34]([O:37][C:38]([F:41])([F:40])[F:39])=[CH:33][CH:32]=1)=[O:22].N1C=CN=C1.O>CN(C=O)C>[CH3:19][O:20][C:21]([C@@H:23]1[CH2:27][C@@H:26]([O:28][Si:5]([C:2]([CH3:4])([CH3:3])[CH3:1])([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:25][N:24]1[C:29](=[O:42])[NH:30][C:31]1[CH:32]=[CH:33][C:34]([O:37][C:38]([F:39])([F:40])[F:41])=[CH:35][CH:36]=1)=[O:22]
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)Nc1ccc(OC(F)(F)F)cc1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)[C@@H]1C[C@@H](O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CN1C(=O)Nc1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 87 %

Procedure:
TBDPSCl (1.73 g, 6.3 mmol) was dropped into a solution of (2S,4R)-4-Hydroxy-1-(4-trifluoromethoxy-phenylcarbamoyl)-pyrrolidine-2-carboxylic acid methyl ester (1.0 g, 2.9 mmol) and imidazole (0.98 g, 14.4 mmol) in DMF (20 mL), the mixture was stirred at room temperature for 4 hours. Then the mixture was poured into water (50 mL), extracted with ethyl acetate (3×30 mL). The organic layers was combined, washed with water (2×30 mL), brine (30 mL), then dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether=1:5) to give compound 1.48 g (88%) of the title compound. 1H NMR (300 MHz, CDCl3): δ 7.67-7.62 (m, 4H), 7.47-7.37 (m, 8H), 7.13 (d, 2H, J=8.7 Hz), 6.37 (s, 1H), 4.68-4.55 (m, 2H), 3.71 (s, 3H), 3.54-3.42 (m, 2H), 2.33-2.25 (m, 1H), 2.05-1.97 (m, 1H), 1.06 (s, 9H); LC-MS: 587.2 [M+1]+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[OH-].[K+].[C:18]1([SH:24])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CCO.O>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][CH:3]=[C:2]2[S:24][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Sc1ccccc1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1cc2nccc(Sc3ccccc3)c2cc1OC
Temperature: 100 °C

Procedure:
To a solution of 4-chloro-6,7-dimethoxy-quinoline (214 mg, 0.96 mmol) in EtOH (10 mL) and H2O (10 mL), was added KOH (107 mg, 1.44 mmol). The solution was stirred in a 100° C. bath. Then thiophenol (148 μL, 1.44 mmol) was added. The reaction was stirred at 100° C. for 1 h. The solvent was removed by rotary evaporation. The resulting residue was worked up with water and extracted with EtOAc 3×. The combined organic layer was washed with water and brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude material was purified by silica gel prep-TLC with 100% EtOAc to give the titled compound. MS (ESI, pos. ion) m/z: 298.1 (M+1).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([O:15]CC2C=CC=CC=2)[C:12]([C:23]2[N:27]([CH2:28][CH2:29][CH2:30][CH3:31])[N:26]=[N:25][N:24]=2)=[CH:11][C:10]=1[C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38](O)=[O:39])[CH:33]=1)C1C=CC=CC=1.[CH2:41]([S:43]([N:46]1[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]1)(=[O:45])=[O:44])[CH3:42]>>[CH2:28]([N:27]1[C:23]([C:12]2[C:13]([OH:15])=[CH:14][C:9]([OH:8])=[C:10]([C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([C:38]([N:49]4[CH2:48][CH2:47][N:46]([S:43]([CH2:41][CH3:42])(=[O:45])=[O:44])[CH2:51][CH2:50]4)=[O:39])[CH:33]=3)[CH:11]=2)=[N:24][N:25]=[N:26]1)[CH2:29][CH2:30][CH3:31]
Reactant: CCS(=O)(=O)N1CCNCC1
Reactant: CCCCn1nnnc1-c1cc(-c2cccc(C(=O)O)c2)c(OCc2ccccc2)cc1OCc1ccccc1
Product: CCCCn1nnnc1-c1cc(-c2cccc(C(=O)N3CCN(S(=O)(=O)CC)CC3)c2)c(O)cc1O

Procedure:
This product was synthesized using 2′,4′-bis-benzyloxy-5′-(1-butyl-1H-tetrazol-5-yl)-biphenyl-3-carboxylic acid and 1-ethylsulfonyl-piperazine as described in general procedure D. LCMS: 514 [M+H].
Reaction SMILES: [Mg].Br[C:3]1[CH:4]=[C:5]([O:11][CH3:12])[C:6]([O:9][CH3:10])=[CH:7][CH:8]=1.CO[C:15]1[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[CH:17][C:16]=1[C:25]1[O:26][CH2:27][C:28]([CH3:31])([CH3:30])[N:29]=1.[Cl-].[NH4+]>O1CCCC1>[CH3:12][O:11][C:5]1[CH:4]=[C:3]([C:15]2[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[CH:17][C:16]=2[C:25]2[O:26][CH2:27][C:28]([CH3:31])([CH3:30])[N:29]=2)[CH:8]=[CH:7][C:6]=1[O:9][CH3:10]
Reactant: COc1cc(OC)c(C2=NC(C)(C)CO2)cc1OC
Reactant: COc1ccc(Br)cc1OC
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccc(-c2cc(OC)c(OC)cc2C2=NC(C)(C)CO2)cc1OC
Temperature: 25 °C
Reaction time: 48 h
Yield: 92.8 %

Procedure:
In tetrahydrofuran (100 ml), magnesium (1.3 g) was reacted with 4-bromoveratrole (13 g) to prepare a Grignard reagent. While cooling in an ice-water bath, a solution of 2-(2,4,5-trimethoxyphenyl)-4,4-dimethyl-2-oxazoline (7.7 g) in tetrahydrofuran (100 ml) was added thereto. After stirring at room temperature for 48 hours, an aqueous saturated ammonium chloride solution (150 ml) was added and stirred for 15 minutes. Then, the mixed solution was separated to extract the aqueous layer with tetrahydrofuran (150 ml). The organic layers were combined each other and concentrated by an evaporator. The residue was dissolved in 10% hydrochloric acid (100 ml), which was washed with diethyl ether. The aqueous layer was cooled in an ice-water bath, then neutralized by adding a 20% aqueous sodium hydroxide solution. It was extracted with ethyl acetate, washed with a saturated saline solution and then dried over sodium sulfate. The solvent was distilled off to give 10 g of 2-[2-(3,4-dimethoxyphenyl)-4,5-dimethoxyphenyl]-4,4-dimethyl-2-oxazoline as a pale brown oil.
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Cl:11][C:12]1[C:13]([O:34][C:35](=[O:39])[N:36]([CH3:38])[CH3:37])=[CH:14][C:15]2[O:20][C:19](=[O:21])[C:18]([CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([N+:29]([O-:31])=[O:30])[CH:24]=3)=[C:17]([CH3:32])[C:16]=2[CH:33]=1.[C:40](Cl)(=[O:42])[CH3:41].O>C1COCC1>[Cl:11][C:12]1[C:13]([O:34][C:35](=[O:39])[N:36]([CH3:37])[CH3:38])=[CH:14][C:15]2[O:20][C:19](=[O:21])[C:18]([CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([N+:29]([O-:31])=[O:30])[CH:24]=3)=[C:17]([CH2:32][C:40](=[O:42])[CH3:41])[C:16]=2[CH:33]=1
Reactant: CC(=O)Cl
Reactant: Cc1c(Cc2cccc([N+](=O)[O-])c2)c(=O)oc2cc(OC(=O)N(C)C)c(Cl)cc12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)Cc1c(Cc2cccc([N+](=O)[O-])c2)c(=O)oc2cc(OC(=O)N(C)C)c(Cl)cc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 29.1 %

Procedure:
LiHMDS (11.5 mL, 1.0 M in THF) was added under nitrogen atmosphere at −78° C. to a suspension of dimethylcarbamic acid 6-chloro-4-methyl-3-(3-nitrobenzyl)-2-oxo-2H-1-benzopyran-7-yl ester (compound 1g-1-3) (4.0 g, 9.60 mmol) in anhydrous THF (100 mL), and the mixture was stirred at −78° C. for 30 minutes and at 0° C. for 30 minutes. Acetyl chloride (1.36 mL, 19.2 mmol) was then added thereto, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was then poured into water and extracted with ethyl acetate. The organic extract was washed with saturated saline and dried over magnesium sulfate. A crude solid was obtained by vacuum concentration, and purified by column chromatography (ethyl acetate:hexane=1:3) to yield the title compound (1.28 g, 29%) as a white powder.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH2:4][CH:5]1[C:9](=[O:10])[N:8]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[C:14]([CH3:19])[CH:13]=2)[C:7](=[O:20])[NH:6]1.[H-].[Na+].[CH3:24][O:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30]Cl)=[CH:28][CH:27]=1>CN(C=O)C>[CH3:1][O:2][C:3](=[O:21])[CH2:4][CH:5]1[C:9](=[O:10])[N:8]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[C:14]([CH3:19])[CH:13]=2)[C:7](=[O:20])[N:6]1[CH2:30][C:29]1[CH:32]=[CH:33][C:26]([O:25][CH3:24])=[CH:27][CH:28]=1
Reactant: COC(=O)CC1NC(=O)N(Cc2ccc(C)c(C)c2)C1=O
Reactant: COc1ccc(CCl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)CC1C(=O)N(Cc2ccc(C)c(C)c2)C(=O)N1Cc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 102.1 %

Procedure:
A 0° C. solution of compound [1-(3,4-dimethyl-benzyl)-2,5-dioxo-imidazolidin-4-yl]-acetic acid methyl ester (2.24 g, 7.71 mmol) in DMF (30 mL) was treated with sodium hydride (60% dispersion, 0.37 g, 9.25 mmol) and warmed to room temperature and stirred under N2 for 20 minutes. The resultant mixture was cooled to 0° C. and then treated with 4-methoxybenzyl chloride (2.41 g, 15.4 mmol) and then warmed to room temperature and stirred for 16 h. The reaction was quenched with 25 mL of aqueous 1 N HCl and then worked up extractively with Et2O and water. The organic layer was dried (MgSO4) and the solvent removed in vacuo to give crude product that was purified by flash chromatography using a gradient of 5:1 hexanes:actetone to afford 3.23 g (100%) [1-(3,4-dimethyl-benzyl)-3-(4-methoxy-benzyl)-2,5-dioxo-imidazolidin-4-yl]-acetic acid methyl ester. MS (ES+) Calc'd for C23H26N2O5 (M+1) 411. Found m/z. 411 (100%). 1H NMR.
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([SH:15])(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH2:16]([O:19][C:20]([N:22]1[CH2:26][C@H:25](OS(C)(=O)=O)[CH2:24][C@H:23]1[CH2:32][CH2:33][N:34]1[CH:38]=[CH:37][N:36]=[C:35]1[C:39](=[O:41])[NH2:40])=[O:21])[CH:17]=[CH2:18]>CN(C)C=O>[CH2:16]([O:19][C:20]([N:22]1[CH2:26][C@@H:25]([S:15][C:7](=[O:14])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:24][C@H:23]1[CH2:32][CH2:33][N:34]1[CH:38]=[CH:37][N:36]=[C:35]1[C:39](=[O:41])[NH2:40])=[O:21])[CH:17]=[CH2:18]
Reactant: C=CCOC(=O)N1C[C@H](OS(C)(=O)=O)C[C@H]1CCn1ccnc1C(N)=O
Reactant: O=C(S)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCOC(=O)N1C[C@@H](SC(=O)c2ccccc2)C[C@H]1CCn1ccnc1C(N)=O
Temperature: 25 °C
Reaction time: 1.25 h

Procedure:
To a solution of potassium t-butoxide (8.42 g) in dimethylformamide (70 ml) was added thiobenzoic S-acid (9.27 ml) dropwise at -20° C. under dry ice--acetone bath. After the addition, the solution was warmed to room temperature, and then stirred for 75 minutes. To the solution was added a solution of (2R,4R)-1-allyloxycarbonyl-2-[2-(2-carbamoylimidazol-1-yl)ethyl]-4-methylsulfonyloxypyrrolidine (14.5 g) in dimethylformamide (70 ml) and the mixture was heated to 85° C. and stirred for 2 hours. After cooling to room temperature, the mixture was quenched by the addition of water (280 ml) and extracted with ethyl acetate (140 ml×3). The combined extract was washed with aqueous saturated sodium bicarbonate solution (140 ml×2), water (200 ml×2), and brine (200 ml×2), and then dried over magnesium sulfate. The solvent was evaporated and the residue was chromatographed on a 150 g of silica gel eluting with a mixture of chloroform and methanol (95:5, V/V) to give (2R,4S)-1-allyloxycarbonyl-4-benzoylthio-2-[2-(2-carbamoylimidazol-1-yl) ethyl]pyrrolidine (11.2 g) as a yellow paste.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[CH:12][C:6]([O:7][CH2:8][C:9]([OH:11])=O)=[CH:5][CH:4]=1.[NH2:14][CH2:15][CH:16]([OH:28])[CH2:17][N:18]1[CH2:27][CH2:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19]1.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:19]1[C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:26][CH2:27][N:18]1[CH2:17][CH:16]([OH:28])[CH2:15][NH:14][C:9](=[O:11])[CH2:8][O:7][C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:13][CH:12]=1
Reactant: NCC(O)CN1CCc2ccccc2C1
Reactant: COc1ccc(OCC(=O)O)cc1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(OCC(=O)NCC(O)CN2CCc3ccccc3C2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 6.5 %

Procedure:
A mixture of compound 2-(4-methoxyphenoxy)acetic acid (100 mg, 0.55 mmol), 1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol (113.7 mg, 0.55 mmol), BOP-Cl (177.2 mg, 0.696 mmol) and DIPEA (1 mL) in DCM (10 mL) was stirred at room temperature for 4 h. The solvent was removed by concentration and the crude product was purified by pre-HPLC to give the title compound (13.3 mg, yield 6.5%). 1H NMR (500 MHz, MeOD): δ 7.11-7.06 (m, 3H), 7.02-7.00 (m, 1H), 6.90-6.60 (m, 4H), 4.45 (s, 2H), 4.01-3.98 (m, 1H), 3.73 (s, 3H), 3.66 (s, 1H), 3.41-3.39 (m, 2H), 2.90-2.87 (m, 2H), 2.81-2.76 (m, 2H), 2.55 (d, J=6.0 Hz, 2H) ppm; ESI-MS (m/z): 371.2 [M+1]+.
Reaction SMILES: [CH:1]1([CH:7]2[CH2:12][CH2:11][CH:10](O)[CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.S(=O)(=O)(O)O.S([O-])([O-])(=O)=O.[Na+].[Na+]>O>[CH:1]1([CH:7]2[CH2:12][CH2:11][CH:10]=[CH:9][CH2:8]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: OC1CCC(C2CCCCC2)CC1
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: O
Product: C1=CCC(C2CCCCC2)CC1
Yield: 89.9 %

Procedure:
A 1 L four-necked flask equipped with a mechanical stirrer, a thermometer, and a Dean-Stark water separator was charged with 4-cyclohexyl-1-cyclohexanol (0.549 mol), sulfuric acid (0.055 mol), sodium sulfate (0.055 mol), distilled water (40 g), and xylene (100 g), and they were heated and refluxed for 3 hours. After completion of the reaction, the reaction mixture was filtered with a glass filter, the solvent was removed by vacuum distillation, and purification was carried out by silica gel column chromatography (silica gel 60 (70-230 mesh), manufactured by Merck Ltd., elution solvent: n-hexane). The reaction product thus obtained was subjected to vacuum distillation using a kugelrohr distillation apparatus at 120° C./666 Pa to give 81.04 g (90% yield) of 4-cyclohexyl-1-cyclohexene (Formula (18) below). The results of 1H-NMR of this product are shown below.
Reaction SMILES: [N:1]1([S:5]([C:8]2[C:13]([Cl:14])=[CH:12][CH:11]=[C:10]([N+:15]([O-])=O)[C:9]=2[OH:18])(=[O:7])=[O:6])[CH2:4][CH2:3][CH2:2]1.[H][H]>[Pd]>[N:1]1([S:5]([C:8]2[C:9]([OH:18])=[C:10]([CH:11]=[CH:12][C:13]=2[Cl:14])[NH2:15])(=[O:7])=[O:6])[CH2:4][CH2:3][CH2:2]1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)N2CCC2)c1O
Agent: [Pd]
Product: Nc1ccc(Cl)c(S(=O)(=O)N2CCC2)c1O
Yield: 99.8 %

Procedure:
Following the general hydrogenation procedure outlined in example 15, 1-(azetidin-1-yl)sulfonyl-6-chloro-2-hydroxy-3-nitrobenzene (240 mg, 0.82 mmol) was reduced with hydrogen and 10% Pd/C (110 mg) to form the desired product (215 mg, 100%). 1H NMR (MeOD-d4): δ 6.91 (m, 2H), 4.01 (t, 4H), 2.23 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][OH:19])=[CH:12][CH:11]=2)=[O:9])=[CH:4][CH:3]=1.[O:20]1[CH:25]=[CH:24][CH2:23][CH2:22][CH2:21]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][O:19][CH:21]3[CH2:22][CH2:23][CH2:24][CH2:25][O:20]3)=[CH:12][CH:11]=2)=[O:9])=[CH:6][CH:7]=1
Reactant: C1=COCCC1
Reactant: O=C(c1ccc(F)cc1)c1ccc(OCCO)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: O=C(c1ccc(F)cc1)c1ccc(OCCOC2CCCCO2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In an oven-dried flask placed under a nitrogen atmosphere, the product of Step 1 (121 g) and 3,4-dihydro-2H-pyran (106 mL) were stirred in dichloromethane (1100 mL). To this was added p-toluenesulfonic acid (4.4 g). The reaction mixture was stirred at room temperature for 2 hours. It was then transferred to a separatory funnel and washed with a saturated aqueous solution of sodium bicarbonate (1 L), dried over sodium sulfate and concentrated by rotary evaporation to yield an oil. 160 grams of 4-fluorophenyl-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)phenyl methanone was isolated. It was used in the next reaction as is without further purification.
Reaction SMILES: [F:1][C:2]1[C:11]2[CH2:10][N:9]([C@H:12]([CH:16]([CH3:18])[CH3:17])[C:13]([OH:15])=O)[C:8](=[O:19])[C:7]3=[CH:20][NH:21][C:5]([C:6]=23)=[N:4][CH:3]=1.Cl.[CH:23]1([CH2:26][O:27][NH2:28])[CH2:25][CH2:24]1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C)C1C=CN=CC=1.CN(C=O)C>[CH:23]1([CH2:26][O:27][NH:28][C:13](=[O:15])[C@H:12]([N:9]2[C:8](=[O:19])[C:7]3=[CH:20][NH:21][C:5]4[C:6]3=[C:11]([C:2]([F:1])=[CH:3][N:4]=4)[CH2:10]2)[CH:16]([CH3:18])[CH3:17])[CH2:25][CH2:24]1
Reactant: CC(C)[C@H](C(=O)O)N1Cc2c(F)cnc3[nH]cc(c23)C1=O
Reactant: NOCC1CC1
Agent: CN(C)c1ccncc1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC(C)[C@H](C(=O)NOCC1CC1)N1Cc2c(F)cnc3[nH]cc(c23)C1=O
Yield: 27.2 %

Procedure:
To an 8 mL scintillation vial equipped for stirring was added (R)-2-(6-fluoro-3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-3-methylbutanoic acid (15 mg, 0.051 mmol). DMF (0.5 mL), O-(cyclopropylmethyl)hydroxylamine hydrochloride (6.4 mg, 0.051 mmol), HOBt (11.83 mg, 0.077 mmol), EDC (14.81 mg, 0.077 mmol) and N,N-dimethylpyridin-4-amine (9.44 mg, 0.077 mmol) were added and the solution was stirred at 25° C. for 4 h. The reaction mixture was purified via preparative mass trigger LC-MS (AcCN/H2O, 20-50%). The fractions were collected and lyophilized to afford the title compound as a white solid (5 mg, 23%). 1H NMR (400 MHz, CD3OD) δ 0.16-0.24 (m, 2 H) 0.39-0.55 (m, 2 H) 0.93 (d, J=6.57 Hz, 3 H) 1.05 (d, J=6.32 Hz, 3 H) 1.06-1.15 (m, 1 H) 2.53 (dt, J=11.24, 6.51 Hz, 1 H) 3.55-3.73 (m, 2 H) 4.94 (d, J=11.37 Hz, 1 H) 5.07 (d, J=19.20 Hz, 1 H) 5.46 (d, J=18.44 Hz, 1 H) 7.86 (s, 1 H) 8.17 (d, J=3.28 Hz, 1 H). [M+H] calc'd for C18H21FN4O3, 361; found, 361.4.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6]2[CH:10]=[CH:9][NH:8][C:7]=12.[NH:13]1[CH:17]=[N:16][C:15]([C:18]#[N:19])=[N:14]1>N1C=CC=CC=1.CCOC(C)=O.[Cu]I>[CH3:12][O:11][C:5]1[CH:4]=[N:3][C:2]([N:13]2[CH:17]=[N:16][C:15]([C:18]#[N:19])=[N:14]2)=[C:7]2[NH:8][CH:9]=[CH:10][C:6]=12
Reactant: COc1cnc(Cl)c2[nH]ccc12
Reactant: N#Cc1nc[nH]n1
Agent: [Cu]I
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: COc1cnc(-n2cnc(C#N)n2)c2[nH]ccc12
Temperature: 150 °C
Yield: 38 %

Procedure:
7-Chloro-4-methoxy-1H-pyrrolo[2,3-c]pyridine (4 g, 21.90 mmol), 1H-1,2,4-triazole-3-carbonitrile (6.18 g, 65.7 mmol) and copper (I) iodide (1.252 g, 6.57 mmol) were combined in pyridine (6 mL) in a sealed tube. The mixture was heated to 150° C. for 6 hrs. After cooling to room temperature, the mixture was diluted with EtOAc (3000 mL), washed with 5% NaHCO3 (100 mL), brine (100 mL) and concentrated. The residue was purified by silica gel column using 30% EtOAc in hexanes mixture to give 1-(4-methoxy-1H-pyrrolo[2,3-c]pyridin-7-yl)-1H-1,2,4-triazole-3-carbonitrile (2 g, 8.33 mmol, 38.0% yield). LCMS: m/z 241.1 (M+H), 1.67 min (method 8).
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)=[O:4].[BH4-].[Na+].C(O)(=O)C.[C:18]([NH2:22])([CH3:21])([CH3:20])[CH3:19]>CO>[F:11][C:8]1[CH:9]=[CH:10][C:5]([CH:3]([OH:4])[CH2:2][NH:22][C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:6][CH:7]=1
Reactant: CC(C)(C)N
Reactant: O=C(CCl)c1ccc(F)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)NCC(O)c1ccc(F)cc1
Temperature: -5 °C
Reaction time: 1 h
Yield: 63 %

Procedure:
50 g (0.289 mol) of α-chloro-p-fluoroacetophenone are dissolved in 900 ml of methanol. The mixture is cooled to -5° C. and 5.80 g of NaBH4 are added. It is left in contact for 1 hour then 10 ml of acetic acid are added. 151 ml of tertiary-butylamine are added and the mixture is refluxed for 12 hours. It is evaporated to dryness and the residue of evaporation is taken up in distilled water. The free base which has crystallised is filtered off and, by recrystallisation in hexane, 39 g (yield 63%) of 1-(4-fluorophenyl)-2-tertiary-butylamino-1-ethanol are obtained. m.p. 117° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[C:8]([CH:17]=O)[N:9]2[CH:12](CC)CC)=[CH:5][CH:4]=1.[C:19]([CH:23]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:21][CH3:22])=[O:20]>ClCCl>[CH3:22][O:21][C:19](=[O:20])/[CH:23]=[CH:17]/[C:8]1[N:9]([CH3:12])[C:10]2[C:6]([C:7]=1[CH2:5][CH2:4][CH2:3][CH2:11][CH3:10])=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:11]=2
Reactant: CCC(CC)n1c(C=O)cc2ccc(OC)cc21
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: CCCCCc1c(/C=C/C(=O)OC)n(C)c2cc(OC)ccc12
Yield: 207.4 %

Procedure:
As in Example 111, 6-methoxy-1-3-pentyl-2-indolecarboxaldehyde (1.5 g) and (carbomethoxymethylene)triphenylphosphorane (2.13 g) in dichloromethane (25 mL) was stirred at room temperature for 17 hours. Work up of the reaction in the usual way afforded 2 g of (E)-3-(6-methoxy-1-methyl-3-pentylindol-2-yl)-2-propenoic acid methyl ester as an oil.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][C:7]([CH3:14])([CH3:13])[CH2:8][C:9]2=[O:12])=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.O[C@@H:49]1[CH2:53][CH2:52][O:51][CH2:50]1.Cl>>[CH3:13][C:7]1([CH3:14])[CH2:6][C:5]2[C:10](=[CH:11][C:2]([O:1][C@H:49]3[CH2:53][CH2:52][O:51][CH2:50]3)=[CH:3][CH:4]=2)[C:9](=[O:12])[CH2:8]1
Reactant: CC1(C)CC(=O)c2cc(O)ccc2C1
Reactant: O[C@@H]1CCOC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC1(C)CC(=O)c2cc(O[C@H]3CCOC3)ccc2C1

Procedure:
7-Hydroxy-3,3-dimethyl-3,4-dihydronaphthalen-1(2H)-one (0.95 g, 4.99 mmol) was dissolved in 30 ml DCMand triphenylphosphine (1.96 g, 7.49 mmol) and diisopropyl azodicarboxylate (1.23 ml, 6.24 mmol) and (r)-(−)-3-hydroxytetrahydrofuran (0.600 ml, 7.49 mmol) was added. The mixture was stirred over night. 0.5M HCl (aq.) was added and the mixture was extracted 3 times with EtOAc. Glass col. Chrom. (5-30% EtOAc in Hex.) provided (S)-3,3-dimethyl-7-(tetrahydrofuran-3-yloxy)-3,4-dihydronaphthalen-1(2H)-one as a yellow oil. MS m/z: 261.1 (M+1).
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:15]=[C:16]([NH:20][C:21]([C:23]4[N:24]([CH3:29])[N:25]=[C:26]([CH3:28])[CH:27]=4)=[O:22])[CH:17]=[CH:18][CH:19]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:30].[CH3:31][N:32]([CH3:42])[CH2:33][CH2:34][C:35]1[CH:40]=[CH:39][C:38]([NH2:41])=[CH:37][CH:36]=1>C1COCC1>[CH3:42][N:32]([CH3:31])[CH2:33][CH2:34][C:35]1[CH:40]=[CH:39][C:38]([NH:41][CH:2]=[C:3]2[C:11]3[C:6](=[CH:7][C:8]([C:12]([C:14]4[CH:15]=[C:16]([NH:20][C:21]([C:23]5[N:24]([CH3:29])[N:25]=[C:26]([CH3:28])[CH:27]=5)=[O:22])[CH:17]=[CH:18][CH:19]=4)=[O:13])=[CH:9][CH:10]=3)[NH:5][C:4]2=[O:30])=[CH:37][CH:36]=1
Reactant: CN(C)CCc1ccc(N)cc1
Reactant: Cc1cc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CO)c2)n(C)n1
Solvent: C1CCOC1
Product: Cc1cc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CNc3ccc(CCN(C)C)cc3)c2)n(C)n1
Temperature: 65 °C
Reaction time: 24 h
Yield: 11.6 %

Procedure:
test tube was charged with 2,5-Dimethyl-2H-pyrazole-3-carboxylic acid [3-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (as prepared in Example 60, 100 mg, 0.249 mmol) and THF (2 mL). To the resulting solution was added 4-(2-Dimethylamino-ethyl)-phenylamine (40.9 mg, 0.249 mmol), and the mixture was stirred for 24 h at 65° C. The reaction mixture was cooled to room temperature. Hexanes were added to the reaction mixture causing a black precipitate to form. The precipitate was vacuum filtered and the filtrate was then concentrated in vacuo and redissolved into ˜3 mL of EtOAc. Hexanes were added causing a light brown precipitate to form. The precipitate was then filtered and washed with ˜1 mL of i-prOH yielding 12% (0.016 g, 0.029 mmol) of the title compound.