Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[CH:7]=[O:8].O1CCCC1.C(N(CC)C(C)C)(C)C.[CH3:27][O:28][CH2:29][CH2:30][O:31][CH2:32]Cl>ClCCl>[CH3:27][O:28][CH2:29][CH2:30][O:31][CH2:32][O:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: COCCOCCl
Reactant: O=Cc1cc(O)ccc1[N+](=O)[O-]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COCCOCOc1ccc([N+](=O)[O-])c(C=O)c1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 96.7 %

Procedure:
A suspension of 5 g (30 mmol) of 5-hydroxy-2-nitrobenzaldehyde (1) in 100 mL of dichloromethane and 10 mL of freshly distilled tetrahydrofuran was cooled to 0° C. To this suspension 6.25 mL (57 mmol) of N,N-diisopropylethylamine was added, and the resulting reaction mixture was stirred for 5 minutes. To this reaction mixture 3.76 mL (33 mmol) of 2-methoxyethoxymethyl chloride was added, stirred for 10 minutes at 0° C., warmed up to room temperature, and allowed to stir at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure, and 150 mL of ethyl acetate were added. The resulting off-white precipitate was filtered off, and the filtrate was transferred into a separatory funnel. The organic layer was washed with 75 mL of 1N sodium hydroxide solution, 100 mL water, and 75 mL brine. The organic layer was dried over anhydrous potassium carbonate, filtered, and concentrated to give 7.4 g (29 mmol, 97%) of 2 [LC-MS; M+Na 278].
Reaction SMILES: C([O:3][CH:4](OCC)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([NH:26][C:27]([NH:29][C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([O:36][CH3:37])[CH:31]=2)=[O:28])([CH2:15][C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=2)=[O:17])[C:7]1=[O:38])C.O.Cl>CC(C)=O>[CH:4]([CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([NH:26][C:27]([NH:29][C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([O:36][CH3:37])[CH:31]=2)=[O:28])([CH2:15][C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=2)=[O:17])[C:7]1=[O:38])=[O:3]
Reactant: CCOC(CN1C(=O)C(CC(=O)Nc2ccc(C)cc2)(NC(=O)Nc2cccc(OC)c2)c2ccccc21)OCC
Agent: Cl
Solvent: CC(C)=O
Solvent: O
Product: COc1cccc(NC(=O)NC2(CC(=O)Nc3ccc(C)cc3)C(=O)N(CC=O)c3ccccc32)c1
Yield: 79.4 %

Procedure:
To a solution of 1.61 g of (RS)-1-(2,2-diethoxyethyl)-3-(N'-(3-methoxyphenyl)ureido)-3-((4-methylphenyl)aminocarbonylmethyl)indolin-2-one in 40 ml of acetone were added 10 ml of water and 1 ml of concentrated hydrochloric acid, and the mixture was heated under reflux for 2 hours. The reaction mixture was poured into water, and the thus formed precipitate was collected by filtration and washed with ethyl ether to obtain 1.11 g (79%) of the title compound.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[N:18]1[CH:23]=[CH:22][CH:21]=[C:20](B(O)O)[CH:19]=1>C1(C)C=CC=CC=1.C(O)C.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:2]2[CH:10]=[C:9]3[C:5]([CH2:6][C:7](=[O:11])[NH:8]3)=[CH:4][CH:3]=2)[CH:19]=1
Reactant: OB(O)c1cccnc1
Reactant: O=C1Cc2ccc(Br)cc2N1
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: CCO
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: O=C1Cc2ccc(-c3cccnc3)cc2N1
Temperature: 100 °C
Reaction time: 12 h
Yield: 42 %

Procedure:
To a warm, stirred solution of 6-bromo-2-oxindole (4 g, 26.3 mmol) in 60 mL toluene and 60 mL ethanol was added tetrakis(triphenylphosphine)palladium(0) (2.3 g, 1.9 mmol) followed by 2M aqueous sodium carbonate (50 mL, 100 mmol) and pyridine-3-boronic acid, propanediol ester (5 g, 30.7 mmol). The mixture was stirred at 100° C. in an oil bath for 12 hours. The reaction mixture was cooled, diluted with ethyl acetate (500 mL) and washed with saturated sodium bicarbonate (200 mL), water (200 mL) and brine (200 mL). The organic layer was separated, dried over anhydrous magnesium sulfate and concentrated to afford a brown solid. The solid was triturated with methylene chloride/diethyl ether to give 2.32 g (42%) of 6-pyridin-3-yl-1,3-dihydro-indol-2-one as a brown solid.
Reaction SMILES: C(OC([N:8]1[CH2:20][CH:19]2[CH:11]([C:12](=[O:29])[C:13]3[C:18]2=[CH:17][C:16]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[Cl:28])=[CH:15][CH:14]=3)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:28][C:22]1[CH:23]=[C:24]([Cl:27])[CH:25]=[CH:26][C:21]=1[C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][CH:15]=1)[C:12](=[O:29])[C@H:11]1[C@@H:19]2[CH2:20][NH:8][CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCC2C(=O)c3ccc(-c4ccc(Cl)cc4Cl)cc3C2C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1c2ccc(-c3ccc(Cl)cc3Cl)cc2[C@H]2CNCC[C@@H]12
Temperature: 20 °C
Reaction time: 2 h

Procedure:
To a solution of 6-(2,4-dichloro-phenyl)-9-oxo-1,2,4,4a,9,9a-hexahydro-3-aza-fluorene-3-carboxylic acid tert-butyl ester in CH2Cl2 (3.2 mL) was added trifluoroacetic acid (0.8 mL). The reaction mixture was stirred for 2 h at 20° C. then concentrated in vacuo. The residue was basified with NH4OH then extracted with CH2Cl2. The organic layer was dried over MgSO4, filtered and concentrated in vacuo to give the title compound (42 mg, 0.13 mmol): MS (ES) 332.1 (M+H).
Reaction SMILES: [CH:1]1([CH:7]([NH:19][C:20]2[N:25]=[CH:24][C:23]([C:26]([N:28]([CH3:36])[CH2:29][CH2:30][C:31]([O:33]CC)=[O:32])=[O:27])=[CH:22][CH:21]=2)[C:8]2[O:9][C:10]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:11]=3[C:12]=2[CH3:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O1CCCC1.[OH-].[Na+]>C(O)C>[CH:1]1([CH:7]([NH:19][C:20]2[N:25]=[CH:24][C:23]([C:26]([N:28]([CH3:36])[CH2:29][CH2:30][C:31]([OH:33])=[O:32])=[O:27])=[CH:22][CH:21]=2)[C:8]2[O:9][C:10]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:11]=3[C:12]=2[CH3:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(NC(c2oc3ccc(F)cc3c2C)C2CCCCC2)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1c(C(Nc2ccc(C(=O)N(C)CCC(=O)O)cn2)C2CCCCC2)oc2ccc(F)cc12
Temperature: 25 °C
Reaction time: 5 h
Yield: 64.2 %

Procedure:
To a mixture of ethyl 3-{[(6-{[cyclohexyl(5-fluoro-3-methyl-1-benzofuran-2-yl)methyl]amino}pyridin-3-yl)carbonyl](methyl)amino}propanoate (236 mg) synthesized above, tetrahydrofuran (5 mL) and ethanol (5 mL) was added 1N aqueous sodium hydroxide solution (1.00 mL), and the mixture was stirred at room temperature for 5 hr, and concentrated under reduced pressure. The residue was dissolved in water (10 mL), 1N hydrochloric acid (1.00 mL) was added at 0° C., and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give a pale-yellow solid. The obtained solid was recrystallized from ethyl acetate/hexane to give the title object compound (143 mg, 64%) as colorless crystals.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[C:6](=[O:15])[CH:7]=[CH:8][C:9]2=[O:14])([O-:3])=[O:2].[CH2:16]=[CH:17][CH:18]=[CH2:19]>C(O)C>[N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[C:6](=[O:15])[C:7]1[CH2:16][CH2:17][CH2:18][CH2:19][C:8]=1[C:9]2=[O:14])([O-:3])=[O:2]
Reactant: O=C1C=CC(=O)c2c1cccc2[N+](=O)[O-]
Reactant: C=CC=C
Solvent: CCO
Product: O=C1C2=C(CCCC2)C(=O)c2c1cccc2[N+](=O)[O-]
Reaction time: 2.5 h
Yield: 72.9 %

Procedure:
24.8 g of crude 5-nitronaphthoquinone (comprised of 82 wt% of 5-nitronaphthoquinone and 10 wt% of 6-nitronaphthoquinone), 12.1 g of 1,3-butadiene, and 124 g of ethanol were introduced into an autoclave. The autoclave was hermetically sealed and the reaction was effected at about 80°C for 2.5 hours. The resultant reaction solution was cooled to 25°-30°C to crystalize 5-nitrotetrahydroanthraquinone, and filtered. The cake was washed with 40 g of ethanol and dried to obtain 22.9 g of 5-nitrotetrahydroanthraquinone. The yield was 89.0%.
Reaction SMILES: [CH3:1][CH:2]([OH:6])[CH2:3][CH2:4][CH3:5].[S:7](Cl)([C:10]1[CH:16]=[CH:15][C:13]([CH3:14])=[CH:12][CH:11]=1)(=[O:9])=[O:8].CCN(CC)CC>CN(C1C=CN=CC=1)C>[S:7]([C:10]1[CH:16]=[CH:15][C:13]([CH3:14])=[CH:12][CH:11]=1)([O:6][CH:2]([CH2:3][CH2:4][CH3:5])[CH3:1])(=[O:9])=[O:8]
Reactant: CCCC(C)O
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Product: CCCC(C)OS(=O)(=O)c1ccc(C)cc1
Yield: 92 %

Procedure:
This compound was synthesized as a colorless oil from 2-pentanol (122.0 mg, 1.384 mmol), TsCl (316.6 mg, 1.66 mmol), Et3N (280.3 mg, 2.77 mmol), and DMAP (169.0 mg, 1.384 mmol) in 92% yield by following general procedure 1.1: 1H NMR (400 MHz, CDCl3; δH) 7.75 (d, J=8.3 Hz, 2H), 7.30 (d, J=8.3 Hz, 2H), 4.63-4.51 (m, 1H), 2.40 (s, 3H), 1.56 (dddd, J=14.0, 10.0, 7.2, 5.4 Hz, 1H), 1.49-1.35 (m, 1H), 1.35-1.04 (m, 5H), 0.77 (t, J=1A Hz, 3H); 13C NMR (100 MHz, CDCl3, δC) 144.57, 134.63, 129.84, 127.78, 80.55, 38.70, 21.73, 20.90, 18.28, 13.74. ESI-MS: 243.1 (M+H+), 265.1 (M+Na+).
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13](=[O:15])[CH3:14])=[CH:10][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].CO[CH:18](OC)[N:19]([CH3:21])[CH3:20]>>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13](=[O:15])/[CH:14]=[CH:18]/[N:19]([CH3:21])[CH3:20])=[CH:10][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: COC(OC)N(C)C
Reactant: CC(=O)c1ccc2c(c1)CCN2C(C)=O
Product: CC(=O)N1CCc2cc(C(=O)/C=C/N(C)C)ccc21
Temperature: 110 °C
Yield: 97 %

Procedure:
A mixture of 1-(1-acetyl-2,3-dihydro-1H-indol-5-yl)ethanone (6.0 g) and N,N-dimethylformamide dimethylacetal (14.2 g) was refluxed at 110° C. for 4 hours and evaporated in vacuo. The residue was triturated with diisopropylether, collected by filtration, and dried in vacuo to afford crude (2E)-1-(1-acetyl-2,3-dihydro-1H-indol-5-yl)-3-(dimethylamino)prop-2-en-1-one (7.4 g). To a solution of crude product in methanol (100 mL) were added guanidine hydrochloride (3.56 g) and potassium tert-butoxide (3.86 g) and the mixture was stirred at 100° C. for 3 hours.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][CH:3]=1.[C:11]([OH:14])(=[O:13])[CH3:12]>>[C:11]([O:14][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][CH:3]=1)(=[O:13])[CH3:12]
Reactant: Ic1c[nH]c2ccccc12
Reactant: CC(=O)O
Product: CC(=O)Oc1c[nH]c2ccccc12
Temperature: 90 °C
Reaction time: 1 h

Procedure:
Into a 500 mL round bottom flask was placed a solution of 3-iodo-1H-indole (23 g, 94.65 mmol) in acetic acid (300 mL). To the mixture was added CH3COOAg (31.6 g, 189.22 mmol). The resulting solution was allowed to react, with stirring, for 1 hour while the temperature was maintained at 90° C. in a bath of oil. The reaction progress was monitored by TLC (ethyl acetate/petroleum ether=1:1). A filtration was performed. The filtrate was concentrated by evaporation under vacuum using a rotary evaporator. The resulting solution was dissolved with 100 mL of ethyl acetate. The resulting mixture was washed 2 times with 100 mL of NaCl(aq.). The final product was purified by recrystallization from MeOH/H2O in the ratio 2:3. This resulted in 8.5 g (41%) of 1H-indol-3-yl acetate as a dark purple solid.
Reaction SMILES: [CH3:1][CH:2]1[CH2:9][C@H:8]2[C@H:4]([CH2:5][NH:6][C@@H:7]2[CH2:10][NH:11][C:12]([C:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[S:16][N:15]=2)=[O:13])[CH2:3]1.[CH3:23][C:24]1[S:25][C:26]([C:32]2[CH:33]=[C:34]([CH3:38])[CH:35]=[CH:36][CH:37]=2)=[C:27]([C:29](O)=[O:30])[N:28]=1>>[CH3:1][CH:2]1[CH2:9][C@H:8]2[C@H:4]([CH2:5][N:6]([C:29]([C:27]3[N:28]=[C:24]([CH3:23])[S:25][C:26]=3[C:32]3[CH:33]=[C:34]([CH3:38])[CH:35]=[CH:36][CH:37]=3)=[O:30])[C@@H:7]2[CH2:10][NH:11][C:12]([C:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[S:16][N:15]=2)=[O:13])[CH2:3]1
Reactant: CC1C[C@H]2CN[C@H](CNC(=O)c3nsc4ccccc34)[C@H]2C1
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)O)c1
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3CC(C)C[C@@H]3[C@H]2CNC(=O)c2nsc3ccccc23)c1

Procedure:
prepared by reaction of benzo[d]isothiazole-3-carboxylic acid-[(1S,2S,5R)-7-methyl-3-aza-bicyclo[3.3.0]oct-2-ylmethyl]-amide with 2-methyl-5-m-tolyl-thiazole-4-carboxylic acid.
Reaction SMILES: C(OC(N1CC2C(=CC=CC=2)C1C1C=C(Cl)C=CC=1OCC(OCC)=O)=O)(C)(C)C.[CH2:31]([O:38][C:39]([N:41]1[CH2:49][C:48]2[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=2)[CH:42]1[C:50]1[CH:55]=[C:54]([Cl:56])[CH:53]=[CH:52][C:51]=1[O:57][CH2:58][C:59]([O:61][CH2:62][CH3:63])=[O:60])=[O:40])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[CH2:31]([O:38][C:39]([N:41]1[CH2:49][C:48]2[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=2)[C@H:42]1[C:50]1[CH:55]=[C:54]([Cl:56])[CH:53]=[CH:52][C:51]=1[O:57][CH2:58][C:59]([O:61][CH2:62][CH3:63])=[O:60])=[O:40])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CCOC(=O)COc1ccc(Cl)cc1C1c2ccccc2CN1C(=O)OCc1ccccc1
Agent: CCOC(=O)COc1ccc(Cl)cc1C1c2ccccc2CN1C(=O)OC(C)(C)C
Product: CCOC(=O)COc1ccc(Cl)cc1[C@@H]1c2ccccc2CN1C(=O)OCc1ccccc1

Procedure:
Following the same procedure, but starting from (±)-1-(5-chloro-2-ethoxycarbonylmethoxy-phenyl)-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester, (±)-1-(5-chloro-2-ethoxycarbonylmethoxy-phenyl)-1,3-dihydro-isoindole-2-carboxylic acid benzyl ester was prepared.
Reaction SMILES: O[C@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1.C(N(C(C)C)CC)(C)C.FC(F)(F)S(O)(=O)=O.[CH3:31][O:32][C:33]1[CH:34]=[C:35]([C@H:39]([NH2:41])[CH3:40])[CH:36]=[CH:37][CH:38]=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(Cl)(Cl)Cl>[CH3:31][O:32][C:33]1[CH:34]=[C:35]([C@H:39]([NH:41][CH:2]2[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]2)[CH3:40])[CH:36]=[CH:37][CH:38]=1
Reactant: COc1cccc([C@@H](C)N)c1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](O)C1
Agent: O=C([O-])O
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: COc1cccc([C@@H](C)NC2CCN(C(=O)OC(C)(C)C)C2)c1
Temperature: -20 °C
Reaction time: 0.25 h
Yield: 45.2 %

Procedure:
To a solution of 25 g of tert-butyl (S)-3-hydroxypyrrolidine-1-carboxylate and 25.9 g of diisopropylethylamine dissolved in 500 ml of methylene chloride was added dropwise 100 ml of a solution of 49 g of anhydrous trifluoromethanesulfonic acid in methylene chloride at −20° C. or lower. The reaction mixture was stirred for 15 minutes while maintaining it to −20° C., and then, to the mixture was added dropwise 100 ml of a solution of 24.2 g of (R)-1-(3-methoxyphenyl)ethylamine in methylene chloride at −20° C. or lower, and the reaction mixture was stirred at room temperature for 16 hours. To the reaction mixture were added a saturated aqueous sodium bicarbonate solution and chloroform, the mixture was stirred and the liquids were separated. The organic layer was dried and the solvent was evaporated, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1→1:2) to obtain 19.32 g of tert-butyl 3-[(R)-1-(3-methoxyphenyl)ethylamino]pyrrolidine-1-carboxylate. (2) To a solution of 19.32 g of tert-butyl 3-[(R)-1-(3-methoxyphenyl)ethylamino]pyrrolidine-1-carboxylate dissolved in 30 ml of chloroform was added 300 ml of a solution of 4M hydrochloric acid in dioxane, and the mixture was stirred at room temperature for 16 hours. The resulting precipitates were collected by filtration, washed with ethyl acetate, and recrystallized from methanol and tetrahydrofuran twice to obtain 8.54 g of (R)-3-[(R)-1-(3-methoxyphenyl)ethylamino]pyrrolidine dihydrochloride (the following Reference example Table, Reference example 1.003).
Reaction SMILES: C(OC([NH:8][CH2:9][CH:10]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1)[C:11]([O:13][CH3:14])=[O:12])=O)(C)(C)C.Cl>O1CCOCC1.CCOCC>[ClH:21].[NH2:8][CH2:9][CH:10]([C:15]1[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=1)[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)C(CNC(=O)OC(C)(C)C)c1ccc(Cl)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: COC(=O)C(CN)c1ccc(Cl)cc1
Reaction time: 18 h
Yield: 178.2 %

Procedure:
A solution of methyl 3-(tert-butoxycarbonylamino)-2-(4-chlorophenyl)propanoate (4 mg, 1.44 mmol) in dioxane (6.0 mL) was treated with 4M HCl in dioxane (about 6.0 mL, 23.0 mmol) at room temperature. The mixture was stirred for 18 hours to completion, after which the reaction mixture was diluted with ether to afford a precipitate. The slurry was filtered under nitrogen to afford a white solid, which was washed with ether. The solid was dried under vacuum to afford the methyl 3-amino-2-(4-chlorophenyl)propanoate hydrochloride as a white solid (321 mg, 89%). LCMS (APCI+) m/z 214.0 [M+H]+.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])[CH2:2]1.CCN(CC)CC.[CH3:20][C:21](OC(C)=O)=[O:22]>C(Cl)Cl>[C:21]([N:1]1[CH2:4][CH:3]([NH:5][C:6](=[O:12])[O:7][C:8]([CH3:9])([CH3:11])[CH3:10])[CH2:2]1)(=[O:22])[CH3:20]
Reactant: CC(C)(C)OC(=O)NC1CNC1
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1CC(NC(=O)OC(C)(C)C)C1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl azetidin-3-ylcarbamate (100 g, 0.58 mol) and Et3N (88 g, 0.87 mol) in DCM (1500 mL) was added Ac2O (59.6 g, 0.88 mol) dropwise at 0° C. The mixture was then stirred at 0° C. for 2 h, at which time TLC showed the completion of the reaction. The reaction was quenched by addition of water (1000 mL) and then stirred at 20° C. for 30 min. The organic phase was separated, dried (Na2SO4) and concentrated to give the crude product. Seven batches were run in parallel and produced a combined crude product weight of 530 g. This crude was used in next step without the further purification. LCMS (m/z): 215.1 (M+1).
Reaction SMILES: [C:1]1(=[O:8])[O:7][C:5](=[O:6])[CH2:4][CH2:3][CH2:2]1.[Cl-].[Al+3].[Cl-].[Cl-].[C:13]([O:16][CH2:17][CH3:18])(=O)C>C1(OC)C=CC=CC=1>[CH3:13][O:16][C:17]1[CH:18]=[CH:4][C:3]([C:5](=[O:6])[CH2:4][CH2:3][CH2:2][C:1]([OH:7])=[O:8])=[CH:2][CH:1]=1
Reactant: CCOC(C)=O
Reactant: O=C1CCCC(=O)O1
Agent: [Al+3]
Agent: [Cl-]
Solvent: COc1ccccc1
Product: COc1ccc(C(=O)CCCC(=O)O)cc1
Reaction time: 3 h
Yield: 59 %

Procedure:
Glutaric anhydride (10.0 g) was dissolved in anisole (100 mL), aluminum chloride (25.7 g) was added, then stirred for three hours on ice. Ethyl acetate (300 mL) was added to the reaction solution, and the organic layer was washed with water (100 mL) and a saturated sodium chloride solution (100 mL). After drying on anhydrous sodium sulfate, filtration and vacuum condensation, the residue was washed with n-hexane to give the above-identified compound (11.5 g, yield 59%) as a colorless solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:18]=[C:17]([N:19]([CH2:24][C:25]4[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=4)[S:20]([CH3:23])(=[O:22])=[O:21])[C:16]([O:33][CH:34]([CH3:36])[CH3:35])=[CH:15][C:11]=3[C:12]=2[CH2:13][OH:14])=[CH:4][CH:3]=1.C[N+]1([O-])CCOCC1>ClCCl.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:18]=[C:17]([N:19]([CH2:24][C:25]4[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=4)[S:20]([CH3:23])(=[O:22])=[O:21])[C:16]([O:33][CH:34]([CH3:36])[CH3:35])=[CH:15][C:11]=3[C:12]=2[CH:13]=[O:14])=[CH:4][CH:3]=1
Reactant: COc1ccc(CN(c2cc3oc(-c4ccc(F)cc4)c(CO)c3cc2OC(C)C)S(C)(=O)=O)cc1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Product: COc1ccc(CN(c2cc3oc(-c4ccc(F)cc4)c(C=O)c3cc2OC(C)C)S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
N-(2-(4-fluorophenyl)-3-(hydroxymethyl)-5-isopropoxybenzofuran-6-yl)-N-(4-methoxybenzyl)methanesulfonamide (0.68 g, 1.32 mmol) was dissolved in dichloromethane. N-methyl morpholine oxide (0.23 g, 1.99 mmol), 4 A molecular sieves (0.7 g) and finally tetrapropylammonium perruthenate (0.023 g, 0.066 mmol) were added. The resulting black slurry was stirred for 60 minutes at room temperature. The reaction mixture was filtered through a pad of diatomaceous earth, and the solid was washed with dichloromethane until the washes were clear. The combined dichloromethane washes were applied to a dry 10 g silica gel cartridge and the column was eluted with ethyl acetate until no more product was eluted. The solvent was removed in vacuo leaving a tan solid, 0.65 g, 96%.
Reaction SMILES: [ClH:1].Cl.[F:3][C:4]1[CH:5]=[CH:6][C:7]2[N:16]=[C:15]([N:17]3[CH2:22][CH2:21][N:20]([CH3:23])[C@@H:19]([CH2:24][CH2:25][O:26][CH3:27])[CH2:18]3)[C:14]3[CH:13]=[C:12]([CH2:28]C)[S:11][C:10]=3[NH:9][C:8]=2[CH:30]=1.Cl.[F:32]C1C(F)=CC2N=C(N)C3C=C(C)SC=3NC=2C=1>>[ClH:1].[ClH:1].[F:3][C:4]1[C:5]([F:32])=[CH:6][C:7]2[N:16]=[C:15]([N:17]3[CH2:22][CH2:21][N:20]([CH3:23])[C@@H:19]([CH2:24][CH2:25][O:26][CH3:27])[CH2:18]3)[C:14]3[CH:13]=[C:12]([CH3:28])[S:11][C:10]=3[NH:9][C:8]=2[CH:30]=1
Reactant: CCc1cc2c(s1)Nc1cc(F)ccc1N=C2N1CCN(C)[C@@H](CCOC)C1
Reactant: Cc1cc2c(s1)Nc1cc(F)c(F)cc1N=C2N
Agent: Cl
Product: COCC[C@H]1CN(C2=Nc3cc(F)c(F)cc3Nc3sc(C)cc32)CCN1C

Procedure:
Using a method similar to the example (S)-6-fluoro 10-[3-(2-methoxy-ethyl)-4-methyl-piperazin-1-yl]-2-ethyl-4H-3-thia-4,9-diaza-benzo[f]azulene dihydrochloride, using 6,7-difluoro-2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulen-10-ylamine hydrochloride and (S)-2-(2-methoxy)ethylpiperazine: 1H NMR (DMSO-d6): δ 11.7110 (2H, bs), 9.3793 (1H, bs), 7.3795 (1H, bs), 7.0701 (1H, bt), 6.6326 (1H, bs), 4.1000 (3H, bm), 3.6041 (3H, bs), 3.4347 (3H, bs), 3.2081 (3H, bs), 2.8371 (3H, bs), 2.3319 (3H, bs), 2.2842 (1H, bm), 1.8410 (1H, bs); Mass Spectrum M+H=407.1.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([C:17]3[C:18]4[CH:33]=[CH:32][CH:31]=[CH:30][C:19]=4[S:20][C:21]=3[C:22]3[CH:27]=[CH:26][C:25]([O:28]C)=[CH:24][CH:23]=3)=[O:16])=[CH:11][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.N1C=CC=CC=1.CCOC(C)=O>O>[N:1]1([CH2:6][CH2:7][CH2:8][C:9]2[CH:10]=[CH:11][C:12]([C:15]([C:17]3[C:18]4[CH:33]=[CH:32][CH:31]=[CH:30][C:19]=4[S:20][C:21]=3[C:22]3[CH:23]=[CH:24][C:25]([OH:28])=[CH:26][CH:27]=3)=[O:16])=[CH:13][CH:14]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc(-c2sc3ccccc3c2C(=O)c2ccc(CCCN3CCCC3)cc2)cc1
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: O=C(c1ccc(CCCN2CCCC2)cc1)c1c(-c2ccc(O)cc2)sc2ccccc12
Temperature: 160 °C
Reaction time: 16 h
Yield: 111.5 %

Procedure:
A 100 mL round bottom flask containing 300 mg (0.66 mmol) of 2-(4-methoxyphenyl)benzo[b]thiophen-3-yl 4-[3-(1-pyrrolidinyl)propyl]phenyl ketone (Part A) was filled with 20 g of pyridine hydrochloride. The flask was heated to 160° C. to melt the solid. After 16 h, the reaction was cooled to warm temperature, diluted with 50 mL of H2O, and transferred to separatory funnel containing 50 mL H2O and 50 mL of EtOAc. The two layers were separated and the aqueous layer was extracted with EtOAc (2×50 mL). The combined EtOAc layers were dried over Na2SO4 and concentrated in vacuo to give 325 mg of a yellow oil. Purification by radial chromatography (SiO2; gradient of 2-10% MeOH in CH2Cl2) afforded 200 mg (0.45 mmol; 69%) of the title compound as a viscous yellow oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[C@H:7]2[CH2:8][C@@H:3]1[CH2:4][CH2:5][C:6]2=[O:9].[CH3:11][Si]([N-][Si](C)(C)C)(C)C.[Li+].C=O>O1CCCC1>[CH3:1][C:2]1([CH3:10])[C@H:7]2[CH2:8][C@@H:3]1[CH2:4][C:5](=[CH2:11])[C:6]2=[O:9]
Reactant: CC1(C)[C@H]2CCC(=O)[C@@H]1C2
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: C=O
Agent: [Li+]
Solvent: C1CCOC1
Product: C=C1C[C@H]2C[C@@H](C1=O)C2(C)C
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
(1R,5S)-6,6-Dimethylbicyclo[3.1.1]heptan-2-one (0.938 mL, 920 mg) was added to tetrahydrofuran (50 mL) and the mixture was cooled to −78° C. using an isopropanol/dry ice bath. Lithium bis(trimethylsilyl)amide (1M in tetrahydrofuran, 7.99 mL) was added, and the solution was stirred at −78° C. for 15 minutes. The solution was allowed to warm to 0° C. in a water/ice bath and the mixture was stirred for 45 minutes. Paraformaldehyde (2000 mg) was added. The solution was stirred at 0° C. for 15 minutes, allowed to warm to room temperature and stir for an additional four hours. The reaction was quenched with saturated aqueous ammonium chloride, extracted with diethyl ether, washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by flash column chromatography on silica gel using 5% ethyl acetate in hexanes.