Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[CH2:12][CH:11]([C:13](Cl)=[O:14])[O:10][N:9]=2)[CH:3]=1.C(N(CC)CC)C.[OH:23][N:24]=[C:25]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:26]1[CH:31]=[CH:30][C:29]([NH2:32])=[CH:28][CH:27]=1.O>C1COCC1>[OH:23]/[N:24]=[C:25](\[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)/[C:26]1[CH:27]=[CH:28][C:29]([NH:32][C:13]([CH:11]2[O:10][N:9]=[C:8]([C:4]3[CH:3]=[N:2][CH:7]=[CH:6][CH:5]=3)[CH2:12]2)=[O:14])=[CH:30][CH:31]=1
Reactant: O=C(Cl)C1CC(c2cccnc2)=NO1
Reactant: Nc1ccc(C(=NO)c2ccccc2)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(/C(=N/O)c2ccccc2)cc1)C1CC(c2cccnc2)=NO1
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 12.9 %

Procedure:
To a cooled stirred suspension of (±)-4,5-dihydro-3-(3-pyridinyl)-5-isoxazole carbonylchloride monohydrochloride (0.016 mol) in dry THF (100 ml), triethylamine (0.040 mol) was added. The reaction mixture was cooled to 0° C. 4-[(Hydroxyimino)-phenylmethyl]benzenamine (0.018 mol) was added in one portion. Stirring was continued for 2.5 hours. Water was added to the reaction mixture and this mixture was extracted with CH2Cl2. The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated. The residue was stirred in CH3OH/CH2Cl2 5/95. The precipitate was filtered off, washed with CH3OH/CH2Cl2 5/95 and dried. The product (1.6 g) was stirred in boiling ethyl acetate (25 ml) and crystallized from ethyl acetate (150 ml). The volume was reduced to 75 ml. The precipitate was filtered off, washed with ethyl acetate and DIPE, then dried, yielding 0.8 g of (±)-(E)4,5-dihydro-N-[4-[(hydroxyimino)phenylmethyl]phenyl]-3-(3-pyridinyl)-5-isoxazolecarboxamide. (compound 301)
Reaction SMILES: [Cl:1][C:2]1[CH:41]=[CH:40][C:5]([CH2:6][CH2:7][NH:8][C:9]([C:11]2[CH:39]=[CH:38][C:14]([O:15][C:16]3[C:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([S:28]([CH3:31])(=[O:30])=[O:29])[CH:23]=4)=[CH:20][C:19]([CH2:32][C:33]([O:35]CC)=[O:34])=[CH:18][CH:17]=3)=[CH:13][CH:12]=2)=[O:10])=[CH:4][CH:3]=1.[OH-].[Na+].O>O1CCOCC1.C(OCC)(=O)C.Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH2:7][NH:8][C:9]([C:11]2[CH:12]=[CH:13][C:14]([O:15][C:16]3[C:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([S:28]([CH3:31])(=[O:30])=[O:29])[CH:23]=4)=[CH:20][C:19]([CH2:32][C:33]([OH:35])=[O:34])=[CH:18][CH:17]=3)=[CH:38][CH:39]=2)=[O:10])=[CH:40][CH:41]=1
Reactant: CCOC(=O)Cc1ccc(Oc2ccc(C(=O)NCCc3ccc(Cl)cc3)cc2)c(-c2cccc(S(C)(=O)=O)c2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: CS(=O)(=O)c1cccc(-c2cc(CC(=O)O)ccc2Oc2ccc(C(=O)NCCc3ccc(Cl)cc3)cc2)c1
Reaction time: 2 h
Yield: 6.6 %

Procedure:
Ethyl 2-(6-(4-(4-chlorophenethylcarbamoyl)phenoxy)-3′-(methylsulfonyl)biphenyl-3-yl)acetate (80 mg, 0.135 mmol) was diluted with dioxane (1 mL) followed by the addition of NaOH (0.270 ml, 1.35 mmol) and 300 μL of water. After stirring for 2 hours, the reaction was diluted with ethyl acetate and 2N HCl. The layers were separated and the organic layer was dried over MgSO4, filtered and concentrated. The material was purified using a biotage 12i cartridge eluting with 1-4% methanol/DCM to yield 2-(6-(4-(4-chlorophenethylcarbamoyl)phenoxy)-3′-(methylsulfonyl)biphenyl-3-yl)acetic acid (5 mg, 6.56% yield). 1H NMR (400 MHz, CD3Cl3, CD3OD) 8.05 (s, 1H), 7.81 (d, 1H), 7.78 (d, 1H), 7.50-7.60 (m, 3H), 7.42 (s, 1H), 7.38 (d, 1H), 7.25 (d, 2H), 7.19 (d, 2H), 7.05 (d, 1H), 6.85 (d, 1H), 3.75 (s, 2H), 3.62 (q, 2H), 3.0 (s, 3H), 2.90 (t, 2H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4]Cl.[S:6]([O-:9])([O-:8])=[O:7].[Na+:10].[Na+]>O>[CH3:1][O:2][CH2:3][CH2:4][S:6]([O-:9])(=[O:8])=[O:7].[Na+:10]
Reactant: O=S([O-])[O-]
Reactant: COCCCl
Agent: [Na+]
Solvent: O
Product: COCCS(=O)(=O)[O-]
Temperature: 25 °C
Yield: 128 %

Procedure:
2-Chloroethyl methyl ether (10 g, 0.106 mol) was added at RT to a suspension of sodium sulfite (13.35 g, 0.106 mol) in 30 mL of H2O. The resulting biphasic mixture was stirred at reflux for 48 hours before being cooled to RT (clear monophasic solution), and evaporated. The white residue was turned into a powder and was then washed with 100 mL of an 8/2 mixture of Et2O and toluene, before being dried to give 22 g sodium 2-methoxy-ethanesulfonate (129% yield, contaminated with excess sodium sulfite). Used as is in step 2.
Reaction SMILES: N#N.[CH3:3][C:4]1([C:9]2[O:13][C:12]([CH2:14]O)=[N:11][CH:10]=2)[O:8][CH2:7][CH2:6][O:5]1.CCN(CC)CC.S([Cl:27])(C)(=O)=O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:27][CH2:14][C:12]1[O:13][C:9]([C:4]2([CH3:3])[O:8][CH2:7][CH2:6][O:5]2)=[CH:10][N:11]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC1(c2cnc(CO)o2)OCCO1
Agent: CN(C)c1ccncc1
Agent: N#N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(c2cnc(CCl)o2)OCCO1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of [5-(2-methyl-[1,3]dioxolan-2-yl)-oxazol-2-yl]-methanol (35 mg, 0.19 mmol) in dry CH2Cl2 (1.0 mL) was treated at 0° C. with Et3N (0.03 mL, 0.25 mmol) followed by DMAP (2.3 mg, 0.02 mmol) and Ms-Cl (0.02 mL, 0.23 mmol). After stirring at rt for 30 min, the reaction mixture was quenched with water (10 mL), extracted with CH2Cl2 (10 mL) and the combined org. extracts were dried over Na2SO4, filtered, and the solvents were removed under reduced pressure to give crude 2-chloromethyl-5-(2-methyl-[1,3]dioxolan-2-yl)-oxazole as a yellow oil. A solution of this crude 2-chloromethyl-5-(2-methyl-[1,3]dioxolan-2-yl)-oxazole (38 mg, 0.19 mmol) in acetone (1.0 mL) was treated with 5-nitro-1H-pyrazole (21 mg, 0.19 mmol) and TBA bromide (12 mg, 0.04 mmol) followed by K2CO3 (77 mg, 0.56 mmol). The reaction mixture was stirred at rt until completion. The solvent was removed under reduced pressure and water (10 mL) followed by EA (10 mL) were added. The aq. layer was extracted with EA (10 mL) and the combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (4:6 hept-EA) gave the title compound as a colorless oil. TLC: rf (4:6 hept-EA)=0.15. LC-MS-conditions 02: tR=0.83 min; [M+H]+=281.05.
Reaction SMILES: CO[C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:5]=1[CH2:11]Br.[CH2:14]([NH2:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1.CCCCCC>[CH2:14]([N:21]1[CH2:11][C:5]2[C:4](=[CH:9][CH:8]=[C:7]([Cl:10])[CH:6]=2)[C:3]1=[O:13])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COC(=O)c1ccc(Cl)cc1CBr
Reactant: NCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: O=C1c2ccc(Cl)cc2CN1Cc1ccccc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 39.6 %

Procedure:
A mixture of 2-bromomethyl-4-chloro-benzoic acid methyl ester (0.120 g, 0.46 mmol), benzylamine (0.106 mL, 1.0 mmol), and K2CO3 (0.207 g, 1.5 mmol) in toluene (5 mL) was heated with stirring at 100° C. for 2 h. Workup and silica gel column chromatography using 30% ethyl acetate in hexane afforded 2-benzyl-5-chloro-2,3-dihydro-isoindol-1-one (0.047 g, 40%). 1H NMR (300 MHz, CDCl3): δ (ppm) 4.26 (m, 2H), 4.80 (m, 2H), 7.32 (m, 7H), 7.83 (m, 1H). GC-MS: m/z 257 (M)+, 180 (M−77)+.
Reaction SMILES: C(O)C.C([O-])(O)=O.[Na+].[OH:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][C:17]=1[OH:18])[CH:13]=O.Cl.[CH3:20][O:21][C:22](=[O:27])[C@H:23]([CH2:25][SH:26])[NH2:24]>O>[OH:9][C:10]1[CH:11]=[C:12]([CH:13]2[NH:24][C@H:23]([C:22]([O:21][CH3:20])=[O:27])[CH2:25][S:26]2)[CH:15]=[CH:16][C:17]=1[OH:18]
Reactant: O=Cc1ccc(O)c(O)c1
Reactant: COC(=O)[C@@H](N)CS
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COC(=O)[C@@H]1CSC(c2ccc(O)c(O)c2)N1
Temperature: 25 °C
Reaction time: 5 h
Yield: 83 %

Procedure:
In a co-solvent of ethanol (5 mL) and water (5 mL), a solution including NaHCO3 (486 mg, 5.79 mmol), 3,4-dihydroxybenzaldhehyde (3,4-dihydroxybenzaldehyde) (800 mg, 5.80 mmol), and L-cysteine methyl ester hydrochloride (1.0 g, 5.84 mmol) was stirred at room temperature for 5 hours. After ethanol was evaporated, the reaction mixture was distributed between ethyl acetate and water, and an organic layer was dried, filtered, and evaporated. The residual was purified by silica gel column chromatography using hexane and ethyl acetate (4:1) to obtain a solid Compound 104 (1.23 g, 83%).
Reaction SMILES: Cl.CO[C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1OCC1CCNCC1)[N:10]=[CH:9][N:8]([CH2:22][O:23][C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26])[C:7]2=[O:30].C(N(CC)CC)C.C(=O)([O-])[O-].[K+].[K+].C(S(C)(=O)=O)=C>CO.C(Cl)Cl>[C:24]([O:23][CH2:22][N:8]1[C:7](=[O:30])[C:6]2[C:11](=[CH:12][CH:13]=[CH:4][CH:5]=2)[N:10]=[CH:9]1)(=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26]
Reactant: COc1cc2c(=O)n(COC(=O)C(C)(C)C)cnc2cc1OCC1CCNCC1
Agent: C=CS(C)(=O)=O
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)OCn1cnc2ccccc2c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 105.7 %

Procedure:
To a solution of 6-methoxy-7-((piperidin-4-yl)methoxy)-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one hydrochloride (0.88 g, 2 mmol) and triethylamine (0.3 ml, 2.1 mmol) in methanol (10 ml) and methylene chloride (10 ml) was added potassium carbonate (280 mg, 2 mmol) and methyl vinyl sulfone (0.4 ml, 2.1 mmol). After stirring for 2 hours at ambient temperature, the volatiles were removed under vacuum. The residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried (MgSO4) and evaporated to give 6-methoxy-7-41-(2-methylsulphonylethyl)piperidin-4-yl)methoxy)-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one (0.55 g, 54%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C@H:11]([N:24]2[C:32](=[O:33])[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][C:30]=3[N:34]3[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]3)[C:25]2=[O:40])[CH2:12][CH2:13][CH2:14][NH:15][S:16]([C:19]2[S:20][CH:21]=[CH:22][CH:23]=2)(=[O:18])=[O:17])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].ClC(Cl)C.C(N(CC)CC)C.[C:52]1(=O)[CH2:56][CH2:55][CH2:54][CH2:53]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[CH:52]1([N:37]2[CH2:38][CH2:39][N:34]([C:30]3[CH:29]=[CH:28][CH:27]=[C:26]4[C:31]=3[C:32](=[O:33])[N:24]([C@@H:11]([C:5]3[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=3)[CH2:12][CH2:13][CH2:14][NH:15][S:16]([C:19]3[S:20][CH:21]=[CH:22][CH:23]=3)(=[O:18])=[O:17])[C:25]4=[O:40])[CH2:35][CH2:36]2)[CH2:56][CH2:55][CH2:54][CH2:53]1
Reactant: O=C1CCCC1
Reactant: COc1ccc([C@@H](CCCNS(=O)(=O)c2cccs2)N2C(=O)c3cccc(N4CCNCC4)c3C2=O)cc1OC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC(Cl)Cl
Product: COc1ccc([C@@H](CCCNS(=O)(=O)c2cccs2)N2C(=O)c3cccc(N4CCN(C5CCCC5)CC4)c3C2=O)cc1OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 48.8 %

Procedure:
A 50-mL round bottom flask was charged with Compound 167 (10.0 mg, 0.016 mmol) and dichloroethane (2.3 mL). Triethylamine (2.5 μL, 0.018 mmol) was added followed by cyclopentanone (7.1 μL, 0.06 mmol) and sodium triacetoxyborohydride (4.7 mg, 0.022 mmol). The mixture was stirred at room temperature for 3 h. The mixture was quenched with saturated aqueous sodium bicarbonate (10 mL) and extracted with dichloromethane (50 mL). The organic layer was dried using Na2SO4, filtered through Celite®, and concentrated in vacuo. The crude oil was purified on a on a Gilson HPLC with a reversed phase Kromasil column (10 u, 100 Å C18, column length 250×50 mm, gradient 75:25-0:100 H2O:MeCN) to give 5.1 mg of Compound 193 as a yellow solid. 1H NMR (300 MHz, CDCl3) δ 7.53-7.64 (m, 3 H), 7.44 (d, J=7.2 Hz, 1 H), 7.14 (d, J=8.2 Hz, 1 H), 6.91-7.06 (m, 3 H), 6.79 (d, J=8.0 Hz, 1 H), 6.56 (s, 1 H), 5.13-5.19 (m, 1 H), 4.51-4.64 (m, 1 H), 3.88 (s, 3 H), 3.85 (s, 3 H), 3.73-3.83 (m, 2 H), 3.42-3.64 (m, 2 H), 2.78-3.22 (m, 6 H), 2.48-2.61 (m, 1 H), 1.88-2.31 (m, 4 H), 1.47-1.69 (m, 4 H), and 1.27-1.33 (m, 4 H); MS (ES+) 653 (M+1).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][C:11](=[O:12])[C:5]=2[CH:4]=[N:3]1.[H-].[Na+].[CH3:15][O:16][C:17](=O)[O:18]C>>[CH3:1][N:2]1[C:6]2[CH2:7][CH2:8][CH2:9][CH:10]([C:17]([O:16][CH3:15])=[O:18])[C:11](=[O:12])[C:5]=2[CH:4]=[N:3]1
Reactant: COC(=O)OC
Reactant: Cn1ncc2c1CCCCC2=O
Agent: [H-]
Agent: [Na+]
Product: COC(=O)C1CCCc2c(cnn2C)C1=O

Procedure:
A solution of 1-methyl-5,6,7,8-tetrahydro-1H-cycloheptapyrazol-4-one (0.75 g, 4.6 mmol) in dimethylcarbonate (3 mL) is treated with 60% dispersion of sodium hydride in oil (0.4 g, 10 mmol) as described in Example 1A to yield the title compound: MS (DCI/NH3) m/z 223 (M+H)+.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](Cl)(=[O:7])[CH3:6].[CH2:9]1[C:20]2=[C:21]3[C:16](=[CH:17][CH:18]=[CH:19]2)[CH2:15][CH2:14][CH2:13][CH:12]3[CH2:11][CH2:10]1>C(=S)=S>[C:19]1([C:5](=[O:7])[CH3:6])[C:20]2=[C:21]3[CH:12]([CH2:11][CH2:10][CH2:9]2)[CH2:13][CH2:14][CH2:15][C:16]3=[CH:17][CH:18]=1
Reactant: CC(=O)Cl
Reactant: c1cc2c3c(c1)CCCC3CCC2
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CC(=O)c1ccc2c3c1CCCC3CCC2
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 45 %

Procedure:
A suspension of aluminum chloride (0.250 g) in carbon disulfide (3 ml) was added with acetyl chloride (0.16 ml). The mixture was stirred at room temperature for 5 minutes, and then slowly added with 2,3,3a,4,5,6-hexahydro-1H-phenalene (0.250 g) dissolved in carbon disulfide (2 ml) at 0° C. The reaction mixture was stirred at 0° C. for 1 hour and at room temperature for 1 hour, and then poured into ice water, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (developing solvent: ethyl acetate:n-hexane=1:500) to obtain (±)-1-(5,6,6a,7,8,9-hexahydro-4H-1-phenalenyl)ethanone (0.139 g, yield: 45%) and the title compound (0.135 g, yield: 43%).
Reaction SMILES: [CH:1]([S:4]([CH:6]([CH3:8])[CH3:7])=O)([CH3:3])[CH3:2].FC(F)(F)C(OC(=O)C(F)(F)F)=O.[Cl:22][C:23]1[C:28]2[O:29][CH2:30][O:31][C:27]=2[CH:26]=[C:25]([C:32]2[C:36]([C:37]([F:40])([F:39])[F:38])=[N:35][N:34]([C:41]3[N:46]=[CH:45][CH:44]=[CH:43][N:42]=3)[C:33]=2[NH2:47])[CH:24]=1>ClCCl.N>[Cl:22][C:23]1[C:28]2[O:29][CH2:30][O:31][C:27]=2[CH:26]=[C:25]([C:32]2[C:36]([C:37]([F:39])([F:40])[F:38])=[N:35][N:34]([C:41]3[N:46]=[CH:45][CH:44]=[CH:43][N:42]=3)[C:33]=2[N:47]=[S:4]([CH:6]([CH3:8])[CH3:7])[CH:1]([CH3:3])[CH3:2])[CH:24]=1
Reactant: Nc1c(-c2cc(Cl)c3c(c2)OCO3)c(C(F)(F)F)nn1-c1ncccn1
Reactant: CC(C)S(=O)C(C)C
Agent: N
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: CC(C)S(=Nc1c(-c2cc(Cl)c3c(c2)OCO3)c(C(F)(F)F)nn1-c1ncccn1)C(C)C
Reaction time: 0.33 h
Yield: 6.4 %

Procedure:
To a solution of diisopropyl sulfoxide (0.75 g, 5.6 mmo) in dichloromethane at −60° C. under argon was added dropwise trifluoroacetic anhydride (1.18 g, 5.6 mmol). The solution was stirred for 20 min at this temperature. Then the 4-(7-chloro-1,3-benzodioxol-5-yl)-2-pyrimidin-2-yl-5-(trifluoromethyl)pyrazol-3-amine (0.97 g, 2.5 mmol) was added and the solution stirred at −60° C. for 1 h. The reaction was diluted with aqueous ammonia; the organic layer separated and further washed with water and then dried and concentrated. The residue was re-crystallized with a mixture of ethyl acetate and petrole ether to give the title compound (80 mg; 8%).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([CH:12]=[CH:13][C:14]([O:16][CH3:17])=[O:15])[CH:3]=1.[H][H]>CO.[Pd]>[Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])[CH:3]=1
Reactant: COC(=O)C=Cc1cc(Cl)ccc1C(=O)OC
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COC(=O)CCc1cc(Cl)ccc1C(=O)OC
Yield: 79.8 %

Procedure:
26.1 g of the methyl 4-chloro-2-(3-methoxy-3-oxo-1-propenyl)-benzoate prepared according to Example 1 are taken up in 300 ml of methanol and transferred into an autoclave and then hydrogenated at 30° C. and a hydrogen pressure of 30 bar for 5 h, until the theoretical amount of hydrogen has been taken up. The substance contains the palladium catalyst required for the Heck coupling, so that separate addition of a hydrogenation catalyst can be dispensed with. The pressure is reduced to 1 bar, and insoluble components are then filtered off. Solvent is then removed under reduced pressure until the hydrogenation product precipitates. Recrystallization gives 21 g of methyl 4-chloro-2-(3-methoxy-3-oxo-1-propanyl)-benzoate.
Reaction SMILES: FC(F)(F)S([O:6][S:7]([C:10]([F:13])([F:12])[F:11])(=[O:9])=[O:8])(=O)=O.O[C:17]1[CH:18]=[CH:19][C:20]2[O:24][C:23]([C:25]3[S:26][CH:27]=[C:28]([C:30]([CH3:33])([CH3:32])[CH3:31])[N:29]=3)=[CH:22][C:21]=2[CH:34]=1.N1C(C)=CC=CC=1C>ClCCl>[F:13][C:10]([F:11])([F:12])[S:7]([O:6][C:17]1[CH:18]=[CH:19][C:20]2[O:24][C:23]([C:25]3[S:26][CH:27]=[C:28]([C:30]([CH3:32])([CH3:31])[CH3:33])[N:29]=3)=[CH:22][C:21]=2[CH:34]=1)(=[O:8])=[O:9]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: CC(C)(C)c1csc(-c2cc3cc(O)ccc3o2)n1
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: CC(C)(C)c1csc(-c2cc3cc(OS(=O)(=O)C(F)(F)F)ccc3o2)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Trifluoromethanesulfonic anhydride (0.74 ml) was added dropwise to an ice-cooled mixture of 2-(5-hydroxy-benzofuran-2-yl)-4-tert-butylthiazole (1.0 g), N,N-dimethylaminopyridine (67 mg) and 2,6-lutidine (0.52 ml, 4.39 mmol) in dry dichloromethane (10 ml) below 10° C. After being stirred at room temperature for 2 hours, the reaction mixture was washed with diluted hydrochloric acid, then dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using n-hexane-ethyl acetate (4:1) as eluent to give 2-(4-tert-butylthiazol-2-yl)-benzofuran-5-yl trifluoromethanesulfonate as a colorless oil (1.39 g).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:6][C:5]([NH:14][C:15](=[O:21])[C:16]([O:18]CC)=[O:17])=[CH:4][C:3]=1[NH:22][C:23](=[O:29])[C:24]([O:26]CC)=[O:25].C(Cl)(Cl)Cl.[OH-].[Na+]>O>[Cl:1][C:2]1[C:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:6][C:5]([NH:14][C:15](=[O:21])[C:16]([OH:18])=[O:17])=[CH:4][C:3]=1[NH:22][C:23](=[O:29])[C:24]([OH:26])=[O:25]
Reactant: CCOC(=O)C(=O)Nc1cc(NC(=O)C(=O)OCC)c(Cl)c(-c2ccccc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=C(O)C(=O)Nc1cc(NC(=O)C(=O)O)c(Cl)c(-c2ccccc2)c1

Procedure:
To a solution of 5.0 g (0.014 mole) of diethyl N,N'-(4-Chloro-5-phenyl-m-phenylene)dioxamate in 125 ml. of chloroform in a separatory funnel is added 29 ml. of 1 M sodium hydroxide solution. Water is added to the mixture until the solid that forms on shaking redissolves. The mixture is allowed to stand with occasional shaking for fifteen minutes. The aqueous layer is drawn off, filtered and the filtrate acidified by the addition of 1N hydrochloric acid. The precipitate that forms is removed by filtration. There is obtained 3.89 g. of material melting above 310°.
Reaction SMILES: [BH3-]C#N.[Na+].[F:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[C:7]=1[C:13]1[C:14]2[C:15]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22][C:16]=3[NH:17][C:18]=2[CH:19]=[CH:20][CH:21]=1>C(C(O)=O)(F)(F)F>[F:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[C:7]=1[C:13]1[C:14]2[CH:15]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22][CH:16]3[NH:17][C:18]=2[CH:19]=[CH:20][CH:21]=1
Reactant: Fc1cccc(F)c1-c1cccc2[nH]c3c(c12)CCNCC3
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: Fc1cccc(F)c1-c1cccc2c1C1CCNCCC1N2
Reaction time: 4 h
Yield: 68.4 %

Procedure:
NaCNBH3 (0.223 g, 3.54 mmol) was added to a solution of 10-(2,6-difluorophenyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (0.336 g, 1.13 mmol) in CF3CO2H (6 mL), which was cooled in an ice-water bath. After stirring for 4 h, the reaction mixture was quenched by adding 6N HCl (6 mL). The resulting mixture was refluxed for 0.45 h. The mixture was cooled and made basic by the addition of 6N NaOH (25 mL). The basic mixture was combined with CHCl3 (30 mL) and H2O (5 mL) and the layers were separated. The aqueous layer was extracted with CHCl3 (2×50 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated. The crude product (0.78 g) was chromatographed (SiO2 35 g, eluted with 90:10:2 CH2Cl2:CH3OH:conc. NH4OH) to yield 10-(2,6-difluorophenyl)-1,2,3,4,5,5a,6,10b-octahydroazepino[4,5-b]indole (0.232 g) in 69% yield. 1H NMR (400 MHz, CD3OD) δ 1.37, 1.61, 1.94, 2.05, 2.44, 2.65-2.73, 3.05, 3.54, 4.19, 6.52, 6.63, 7.03-7.09, 7.41: MS (ESI+) for C18H18F2N2 m/z 301.2 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[C:5](=[O:14])[N:6]([CH3:13])[N:7]=[CH:8][C:9]=1[N:10](C)C)(=O)[CH3:2].[NH2:15]N>C(O)C>[CH3:2][C:1]1[C:4]2[C:5](=[O:14])[N:6]([CH3:13])[N:7]=[CH:8][C:9]=2[NH:10][N:15]=1
Reactant: CC(=O)c1c(N(C)C)cnn(C)c1=O
Reactant: NN
Solvent: CCO
Product: Cc1n[nH]c2cnn(C)c(=O)c12
Reaction time: 6 h

Procedure:
4-Acetyl-5-dimethylamino-2-methyl-3(2H)-pyridazinone (137 mg) was added to hydrazine (224 mg)/ethanol (5 ml) and the mixture was refluxed with stirring for 6 hours. After the ethanol-hydrazine was distilled off, the residue was washed with diethyl ether and dried. White powder, 114 g. 1H-NMR (CDCl3) 8: 2.57(3H,s), 3.64(3H,s), 8.30(1H,s).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.Cl[S:16]([C:19]1[CH:20]=[C:21]([C:25]2[C:34]([CH3:36])([CH3:35])[CH2:33][C:32]3[C:27](=[CH:28][CH:29]=[C:30]([C:37]([O:39][CH3:40])=[O:38])[CH:31]=3)[N:26]=2)[CH:22]=[CH:23][CH:24]=1)(=[O:18])=[O:17]>ClCCl>[CH3:35][C:34]1([CH3:36])[CH2:33][C:32]2[C:27](=[CH:28][CH:29]=[C:30]([C:37]([O:39][CH3:40])=[O:38])[CH:31]=2)[N:26]=[C:25]1[C:21]1[CH:22]=[CH:23][CH:24]=[C:19]([S:16]([N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)(=[O:18])=[O:17])[CH:20]=1
Reactant: C1CCNC1
Reactant: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(S(=O)(=O)Cl)c1)=N2
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(S(=O)(=O)N3CCCC3)c1)=N2
Temperature: 25 °C
Reaction time: 3 h
Yield: 84.9 %

Procedure:
To a stirred solution of pyrrolidine (38 mg, 0.54 mmol) and N,N-diisopropylethylamine (116 mg, 0.90 mmol) in dichloromethane (4 mL) was added methyl 2-(3-(chlorosulfonyl)phenyl)-3,3-dimethyl-3,4-dihydroquinoline-6-carboxylate (175 mg, 0.45 mmol) portionwise. The resultant yellow solution was stirred for 3 h at room temperature. The mixture was purified on preparative Thin layer chromatography to afford 163 mg of methyl 3,3-dimethyl-2-(3-(pyrrolidin-1-ylsulfonyl)phenyl)-3,4-dihydroquinoline-6-carboxylate, which was used directly.