Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:13])([CH3:12])[C:9]([OH:11])=O)=[CH:4][C:3]=1[F:14].S(Cl)(Cl)=O.[C:19]([O:27][CH2:28][CH3:29])(=[O:26])[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22].[Mg+2].[Cl-].[Cl-]>C(#N)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:13])([CH3:12])[C:9]([CH:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:19]([O:27][CH2:28][CH3:29])=[O:26])=[O:11])=[CH:4][C:3]=1[F:14]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CC(C)(C(=O)O)c1ccc(Cl)c(F)c1
Agent: [Cl-]
Agent: [Mg+2]
Solvent: O
Solvent: CC#N
Solvent: O=S(Cl)Cl
Product: CCOC(=O)C(C(=O)OCC)C(=O)C(C)(C)c1ccc(Cl)c(F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.9 %

Procedure:
A solution of 2-(4-chloro-3-fluorophenyl)-2-methylpropanoic acid (2.05 g, 9.46 mmol) in thionyl chloride (40.0 mL, 548 mmol) in a 500 mL round bottom flask was stirred at 95° C. for 2 hours. The reaction was concentrated in vacuo and azeotroped in toluene (50 mL) to give the crude acid chloride. A solution of diethyl malonate (1.43 mL, 9.46 mmol) in ACN (20 mL) was cooled to 0° C. MgCl2 (0.901 g, 9.46 mmol) and then TEA (2.76 mL, 19.9 mmol) were added, and the mixture was stirred at 25° C. for 2 hours. A solution of the acid chloride in ACN (30 mL) was added, and the mixture was stirred at 50° C. for 16 hours. The reaction was cooled, diluted with water (75 mL), and extracted with EtOAc (2×100 mL). The combined organic layers were washed with water (75 mL) and brine (75 mL). The organic layer was dried over MgSO4, concentrated, and dried in vacuo to give diethyl 2-(2-(4-chloro-3-fluorophenyl)-2-methylpropanoyl)malonate (2.95 g). MS m/e=359.4 (M+H)+.
Reaction SMILES: [Si]([O:8][C@@H:9]1[C@@:42]2([CH3:43])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:41]2[CH2:40][CH2:39][C@@:38]2([CH3:44])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@@H:21]([O:23][CH2:24][C:25]#[C:26][C:27]([CH3:37])([O:29][Si](CC)(CC)CC)[CH3:28])[CH3:22])[CH2:12][C@@H:11]([O:45][Si](C(C)(C)C)(C)C)[CH2:10]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[OH:8][C@@H:9]1[C@@:42]2([CH3:43])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:41]2[CH2:40][CH2:39][C@@:38]2([CH3:44])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@@H:21]([O:23][CH2:24][C:25]#[C:26][C:27]([OH:29])([CH3:28])[CH3:37])[CH3:22])[CH2:12][C@@H:11]([OH:45])[CH2:10]1
Reactant: CC[Si](CC)(CC)OC(C)(C)C#CCO[C@@H](C)C1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C[C@H](OCC#CC(C)(C)O)C1=CC[C@H]2C3=CC=C4C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C
Yield: 31.6 %

Procedure:
By the same procedure as in Example 9, 1α,3β-bis(tert-butyldimethylsilyloxy)-20(S)-(4-methyl-4-triethylsilyloxy-2-pentynyloxy)pregna-5,7,16-triene (80.0 mg, 0.104 mmol), tetrahydrofuran (3 ml) and 1M tetra-n-butylammonium fluoride solution in tetrahydrofuran (2 ml) were reacted (heating under reflux for 5.5 hours) and worked up, and then the residue was purified by preparative thin layer chromatography (0.5 mm×1, dichloromethane:ethyl acetate:ethanol 20:80:1, developed once) to give the title compound as a pale yellow oil (14.0 mg, 32%).
Reaction SMILES: [CH3:1][N:2]1[C:14]2[CH2:13][CH2:12][CH:11]([CH2:15][C:16]3[N:17]=[CH:18][N:19](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[C:20]=3[CH3:21])[C:10](=[O:41])[C:9]=2[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.C(O)(=O)C.C1COCC1.[OH-].[Na+]>O>[CH3:1][N:2]1[C:14]2[CH2:13][CH2:12][CH:11]([CH2:15][C:16]3[N:17]=[CH:18][NH:19][C:20]=3[CH3:21])[C:10](=[O:41])[C:9]=2[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2
Reactant: Cc1c(CC2CCc3c(c4ccccc4n3C)C2=O)ncn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: O
Product: Cc1[nH]cnc1CC1CCc2c(c3ccccc3n2C)C1=O
Yield: 77.7 %

Procedure:
A solution of 1,2,3,9-tetrahydro-9-methyl-3-[[5-methyl(triphenylmethyl)-1H-imidazol-4-yl]methyl]carbazol-4-one (268 mg) in a mixture of glacial acetic acid (5 ml), THF (5 ml), and water (5 ml) was heated at 100°-110° for 8 h. After cooling, 2N sodium hydroxide solution (50 ml) was added and the resulting suspension was extracted with dichloromethane (2×50 ml). The combined, dried organic extracts were concentrated to give a foam which was purified by FCC eluting with System A (100:8:1) to give the title compound (114 mg) as a solid. The 1H-n.m.r. and t.l.c. of this material were consistent with those obtained for the product of Example 8.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:20])[CH:5]=[C:6]([F:19])[C:7]=1[O:8][C:9]1[CH:10]=[N:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2.[Cl:21][C:22]1[CH:27]=[C:26]([Cl:28])[C:25]([CH3:29])=[CH:24][C:23]=1[S:30](Cl)(=[O:32])=[O:31]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:20][S:30]([C:23]2[CH:24]=[C:25]([CH3:29])[C:26]([Cl:28])=[CH:27][C:22]=2[Cl:21])(=[O:32])=[O:31])[CH:5]=[C:6]([F:19])[C:7]=1[O:8][C:9]1[CH:10]=[N:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2
Reactant: Cc1cc(S(=O)(=O)Cl)c(Cl)cc1Cl
Reactant: Nc1cc(F)c(Oc2cnc3ccccc3c2)c(Cl)c1
Solvent: c1ccncc1
Product: Cc1cc(S(=O)(=O)Nc2cc(F)c(Oc3cnc4ccccc4c3)c(Cl)c2)c(Cl)cc1Cl
Reaction time: 1 h
Yield: 73.5 %

Procedure:
To a solution of 3-chloro-5-fluoro-4-(quinolin-3-yloxy)phenylamine (186.2) (0.420 g) in pyridine (2.2 ml), was added 2,4-dichloro-5-methylbenzenesulfonylchloride 0.360 g. The mixture was stirred at room for 1 hr. The reaction mixture was purified directly by column chromatography (silicagel, AcOEt:Hexane=1:3). The product was triturated by hexane to give title compound (0.522 g). (73%) as a solid.
Reaction SMILES: [CH3:1][CH:2]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH3:14])[C:3]([O:5]C)=[O:4].[OH-].[Na+]>CO>[CH3:1][CH:2]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH3:14])[C:3]([OH:5])=[O:4]
Reactant: COC(=O)C(C)Cc1ccccc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1ccccc1CC(C)C(=O)O

Procedure:
38.45 g (200 mmol) of ester f2, 850 ml of 5% strength NaOH and 850 ml of MeOH were refluxed for 4.5 hours, the MeOH was distilled off, the product was acidified, and the ether extract was dried with MgSO4 and distilled (107°-109° C./high vacuum).
Reaction SMILES: [CH3:1][C:2]([O:11][Si:12]([CH3:15])([CH3:14])[CH3:13])([C:6](=[CH2:10])[CH2:7][CH2:8][CH3:9])[CH2:3][C:4]#[CH:5].[CH2:16]([SnH:20]([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:21][CH2:22][CH2:23][CH3:24])[CH2:17][CH2:18][CH3:19]>>[CH3:1][C:2]([O:11][Si:12]([CH3:13])([CH3:14])[CH3:15])([C:6](=[CH2:10])[CH2:7][CH2:8][CH3:9])[CH2:3]/[CH:4]=[CH:5]/[Sn:20]([CH2:21][CH2:22][CH2:23][CH3:24])([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: C#CCC(C)(O[Si](C)(C)C)C(=C)CCC
Reactant: CCCC[SnH](CCCC)CCCC
Product: C=C(CCC)C(C)(C/C=C/[Sn](CCCC)(CCCC)CCCC)O[Si](C)(C)C
Reaction time: 1 h

Procedure:
A mixture of 26 g. of 4-methyl-5-methylene-4-trimethylsilyloxy-1-octyne, 200 mg. of azoisobutyrylnitrile and 41.1 g. of tri-n-butylstannane is stirred under argon in an oil bath at 140° C. The mixture is stirred at 140°-150° C. for one hour under argon, then at 140°-150° C. for 1.5 hours under vacuum to remove excess tri-n-butylstannane. The residue is distilled via a Kugelrohr (150° C., 0.05 mm.) giving the desired product as a colorless liquid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C@H:10]([OH:17])/[CH:11]=[CH:12]/[C:13]([O:15][CH3:16])=[O:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.[CH3:34][S:35](Cl)(=[O:37])=[O:36].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>ClCCl>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[C@H:10]([O:17][S:35]([CH3:34])(=[O:37])=[O:36])/[CH:11]=[CH:12]/[C:13]([O:15][CH3:16])=[O:14])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)/C=C/[C@@H](O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)/C=C/[C@@H](OS(C)(=O)=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Reaction time: 0.33 h

Procedure:
A solution of 0.44 g (1.3 mmol) of the resultant compound of Example 6 and 0.91 ml (5.2 mmol) of diisopropylethylamine in 20 ml of anhydrous dichloromethane was cooled under N2 atmosphere to -20° C. and treated with 0.2 ml (2.6 mmol) of methanesulfonyl chloride. After 20 minutes, the mixture was treated with 10 % aqueous citric acid, extracted with methylene chloride, dried over sodium sulfate and concentrated in vacuo. Silica gel chromatography provided the desired product. 1H NMR (CDCl3) δ 1.36 (s, 9 H), 2.73 (m, 1 H), 2.93 (dd, J=14, 5 Hz, 1 H), 3.06 (S, 3 H), 3.77 (s, 3 H), 4.18 (m, 1 H), 4.62 (s, 1 H), 5.47 (m, 1 H), 6.17 (dd, J=16, 2 Hz, 1 H), 6.90 (dd, J=16, 6 Hz, 1 H), 7.15-7.35 (m, 5 H).
Reaction SMILES: [O:1]([C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14]C)=[O:13])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>O.O1CCOCC1>[O:1]([C:8]1[CH:17]=[CH:16][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(Oc2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)c1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl 4-phenoxybenzoate (0.144 g; 0.630 mmol) was added to a mixture of NaOH in water (1 mL; 2M) and dioxane (1 mL) and stirred vigorously at room temperature overnight. The resulting mixture was concentrated in vacuo and extracted with dichloromethane. The aqueous layer was acidified with a 6N solution of hydrochloric acid in water. The precipitated product was collected by filtration to yield 0.136 g (quantitative) of the title compound as a white solid which was used without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[C:5]([O:21][CH2:22][CH3:23])=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13]CC2C=CC=CC=2)=[CH:9][CH:8]=1)[CH3:2]>C(OCC)(=O)C.[Pd]>[CH2:22]([O:21][CH:5]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([OH:13])=[CH:11][CH:12]=1)[C:4]([O:3][CH2:1][CH3:2])=[O:24])[CH3:23]
Reactant: CCOC(=O)C(=Cc1ccc(OCc2ccccc2)cc1)OCC
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)C(Cc1ccc(O)cc1)OCC
Yield: 100.7 %

Procedure:
Compound (a) (62 g; 0.19 mole) was hydrogenated in ethyl acetate (400 ml) at atmospheric pressure using Pd/C (10%) as catalyst. The mixture was filtered through celite and evaporated in vacuo to give 45.6 g (yield 100%) of the desired product.
Reaction SMILES: [OH-].[Na+].[CH2:3]([NH:10][C:11](=[O:34])[N:12]([C:14]1[CH:15]=[C:16]([C:20]2[CH:25]=[CH:24][C:23](/[CH:26]=[C:27](\[O:32][CH3:33])/[C:28]([O:30]C)=[O:29])=[CH:22][CH:21]=2)[CH:17]=[CH:18][CH:19]=1)[CH3:13])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].C(O)(=O)C>O1CCCC1>[CH2:3]([NH:10][C:11](=[O:34])[N:12]([C:14]1[CH:15]=[C:16]([C:20]2[CH:21]=[CH:22][C:23](/[CH:26]=[C:27](\[O:32][CH3:33])/[C:28]([OH:30])=[O:29])=[CH:24][CH:25]=2)[CH:17]=[CH:18][CH:19]=1)[CH3:13])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(/C=C(\OC)C(=O)OC)cc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(/C=C(\OC)C(=O)O)cc2)c1
Temperature: 68 °C
Reaction time: 4 h
Yield: 85.7 %

Procedure:
3.3 mL (3.3 mmol) of aqueous 1 N sodium hydroxide solution are added to a solution of 1 g (2.2 mmol) of methyl (Z)-3-[3′-(3-heptyl-1-methylureido)biphenyl-4-yl]-2-methoxyacrylate in 16 mL of tetrahydrofuran. The reaction medium is heated at 68° C. and stirred for 4 hours. The reaction medium is acidified with 3.5 mL of 1 N acetic acid solution and extracted with ethyl acetate. The organic phase is washed with water, dried over magnesium sulfate, filtered and evaporated. The residue obtained is recrystallized from a hot heptane/ethyl acetate mixture. 800 mg (86%) of (Z)-3-[3′-(3-heptyl-1-methylureido)biphenyl-4-yl]-2-methoxyacrylic acid are obtained in the form of a white solid with a melting point of 114° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][CH2:15][O:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([Cl:36])=[C:24]([CH2:27][CH2:28][C:29](=[O:35])[N:30]3[CH2:34][CH2:33][CH2:32][CH2:31]3)[CH:25]=2)[NH:20][C:19](=[O:37])[C:18]=1[C:38]1[CH:43]=[C:42]([CH3:44])[CH:41]=[C:40]([CH3:45])[CH:39]=1)=O)(C)(C)C.FC(F)(F)C(O)=O>C1(OC)C=CC=CC=1>[Cl:36][C:23]1[CH:22]=[C:21]2[C:26]([C:17]([O:16][CH2:15][CH2:14][CH:9]3[CH2:10][CH2:11][CH2:12][CH2:13][NH:8]3)=[C:18]([C:38]3[CH:39]=[C:40]([CH3:45])[CH:41]=[C:42]([CH3:44])[CH:43]=3)[C:19](=[O:37])[NH:20]2)=[CH:25][C:24]=1[CH2:27][CH2:28][C:29](=[O:35])[N:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: Cc1cc(C)cc(-c2c(OCCC3CCCCN3C(=O)OC(C)(C)C)c3cc(CCC(=O)N4CCCC4)c(Cl)cc3[nH]c2=O)c1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: Cc1cc(C)cc(-c2c(OCCC3CCCCN3)c3cc(CCC(=O)N4CCCC4)c(Cl)cc3[nH]c2=O)c1
Temperature: 25 °C
Yield: 92.3 %

Procedure:
To a solution of 2-{2-[7-chloro-3-(3,5-dimethylphenyl)-2-oxo-6-(3-oxo-3-pyrrolidin-1-yl-propyl)-1,2-dihydroquinolin-4-yloxy]-ethyl}-piperidine-1-carboxylic acid tert-butyl ester (9.0 mg in 2.0 dry methylene chloride) was added a few drops of anisole followed by 1.0 mL of trifluoroacetic acid and the mixture stirred at room temperature. After 30 minutes the solvents were removed in vacuo and the resulting residue purified by flash chromatography on silica gel (methylene chloride:10% ammonium hydroxide in methanol, 9:1) to give the title compound (7.0 mg). MASS: 536 (M+H)
Reaction SMILES: [CH3:1][C:2]([Si:5]([CH3:30])([CH3:29])[O:6][CH2:7][C@@H:8]([O:10][C:11]1[CH:12]=[C:13]([CH:25]=[C:26]([OH:28])[CH:27]=1)[C:14]([NH:16][C:17]1[CH:21]=[CH:20][N:19]([CH:22]([CH3:24])[CH3:23])[N:18]=1)=[O:15])[CH3:9])([CH3:4])[CH3:3].[N:31]1([C:35]([C:37]2[CH:38]=[C:39]([Cl:44])[C:40](Cl)=[N:41][CH:42]=2)=[O:36])[CH2:34][CH2:33][CH2:32]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[N:31]1([C:35]([C:37]2[CH:38]=[C:39]([Cl:44])[C:40]([O:28][C:26]3[CH:25]=[C:13]([CH:12]=[C:11]([O:10][C@@H:8]([CH3:9])[CH2:7][O:6][Si:5]([C:2]([CH3:4])([CH3:3])[CH3:1])([CH3:30])[CH3:29])[CH:27]=3)[C:14]([NH:16][C:17]3[CH:21]=[CH:20][N:19]([CH:22]([CH3:24])[CH3:23])[N:18]=3)=[O:15])=[N:41][CH:42]=2)=[O:36])[CH2:34][CH2:33][CH2:32]1
Reactant: CC(C)n1ccc(NC(=O)c2cc(O)cc(O[C@@H](C)CO[Si](C)(C)C(C)(C)C)c2)n1
Reactant: O=C(c1cnc(Cl)c(Cl)c1)N1CCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)n1ccc(NC(=O)c2cc(Oc3ncc(C(=O)N4CCC4)cc3Cl)cc(O[C@@H](C)CO[Si](C)(C)C(C)(C)C)c2)n1
Temperature: 160 °C
Yield: 94.2 %

Procedure:
A solution of 3-[((1S)-2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-1-methylethyl)oxy]-5-hydroxy-N-[1-(1-methylethyl)-1H-pyrazol-3-yl]benzamide (103 mg, 0.24 mmol) and 5-(azetidin-1-ylcarbonyl)-2,3-dichloropyridine (66 mg, 0.29 mmol) in acetonitrile (2 mL), containing potassium carbonate (66 mg, 0.48 mmol), was heated in a microwave reactor at 160° C. for 6 hours. The reaction mixture was filtered and the filtrate evaporated to dryness under reduced pressure and purified by chromatography on silica, eluting with 50-100% ethyl acetate in hexane, to give the required product as a white foam (142 mg). m/z 628 (M+H)+
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][O:5][C:4]2[CH:13]=[CH:14][C:15]([CH2:17][CH2:18][N:19]([O:23]CC3C=CC=CC=3)[C:20](=[O:22])[CH3:21])=[CH:16][C:3]1=2.C([O-])=O.[NH4+]>C(O)C.[Pd]>[O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][O:5][C:4]2[CH:13]=[CH:14][C:15]([CH2:17][CH2:18][N:19]([OH:23])[C:20](=[O:22])[CH3:21])=[CH:16][C:3]1=2
Reactant: CC(=O)N(CCc1ccc2c(c1)C(=O)c1ccccc1CO2)OCc1ccccc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: CC(=O)N(O)CCc1ccc2c(c1)C(=O)c1ccccc1CO2
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 41.2 %

Procedure:
A solution of N-[2-(6,11-dihydro-11-oxodibenz[b,e]oxepin-2-yl)ethyl]-N-(phenylmethoxy)acetamide (4.07 g) in absolute ethanol was treated with ammonium formate (3.2 g) and 700 mg 5% palladium on carbon. The mixture was stirred at room temperature for 1.5 hours then filtered through a short pad of celite. The filtrate was evaporated and the residue purified by flash chromatography (silica gel, 2:1 ethyl acetate-hexane) to give an oil. This oil crystallized from ethyl acetate-hexane to give 1.3 g of N-[2-(6,11-dihydro-11-oxodibenz[b,e]oxepin-2-yl)ethyl]-N-hydroxyacetamide, as crystals, m.p. 113°-115° C.
Reaction SMILES: [Br:1][C:2]1[NH:3][C:4]2[CH:5]=[CH:6][CH:7]=[C:8]3[C:14](=[O:15])[NH:13][CH2:12][CH2:11][C:10]=1[C:9]=23.[F:16]C1C=CC(C)=C(C=1)C(O)=O>>[Br:1][C:2]1[NH:3][C:4]2[CH:5]=[C:6]([F:16])[CH:7]=[C:8]3[C:14](=[O:15])[NH:13][CH2:12][CH2:11][C:10]=1[C:9]=23
Reactant: Cc1ccc(F)cc1C(=O)O
Reactant: O=C1NCCc2c(Br)[nH]c3cccc1c23
Product: O=C1NCCc2c(Br)[nH]c3cc(F)cc1c23

Procedure:
The title compound was prepared in a manner similar to that used for 2-bromo-1,3,4,5-tetrahydro-azepino[5,4,3-cd]indol-6-one, starting from 5-fluoro-2-methylbenzoic acid. 2-Bromo-8-fluoro-1,3,4,5-tetrahydro-azepino[5,4,3-cd]indol-6-one was isolated as an orange solid: m.p. 203-204° C. (dec); 1H NMR (300 MHz, d6-DMSO) δ 2.79 (m, 2H), 3.41 (m, 2H), 7.29 (dd, J=8.7, 1.2 Hz, 1H), 7.74 (dd, J=10.8, 1.5 Hz, 1H), 8.23 (br t, 1H), 12.12 (br s, 1H). MS (electrospray, [M+Na]+) 305/307.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][N:13]([C:15]([N:17]3[CH2:22][CH2:21][S:20][CH2:19][CH2:18]3)=[O:16])[CH2:12][CH:11]([C:23]([OH:25])=O)[CH2:10]2)=[CH:5][CH:4]=1)[CH3:2].[CH2:26]([O:28][CH2:29][CH2:30][C:31](=[N:33]O)[NH2:32])[CH3:27]>>[CH2:26]([O:28][CH2:29][CH2:30][C:31]1[N:33]=[C:23]([CH:11]2[CH2:10][CH:9]([C:6]3[CH:5]=[CH:4][C:3]([CH2:1][CH3:2])=[CH:8][CH:7]=3)[CH2:14][N:13]([C:15]([N:17]3[CH2:22][CH2:21][S:20][CH2:19][CH2:18]3)=[O:16])[CH2:12]2)[O:25][N:32]=1)[CH3:27]
Reactant: CCOCCC(N)=NO
Reactant: CCc1ccc(C2CC(C(=O)O)CN(C(=O)N3CCSCC3)C2)cc1
Product: CCOCCc1noc(C2CC(c3ccc(CC)cc3)CN(C(=O)N3CCSCC3)C2)n1

Procedure:
According to General Method 6A, 600 mg (1.655 mmol) of the compound from Example 7A and 355 mg (approx. 2.152 mmol) of 3-Ethoxy-N′-hydroxypropanimidamide were reacted Yield: 389 mg (49% of theory)
Reaction SMILES: [NH2:1][CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C:6](=[CH2:13])[C:5]2[CH:14]=[CH:15][CH:16]=[CH:17][C:4]=2[CH2:3]1.[OH-].[Na+].O.[C:21](=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)Cl.[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1>[N+:1]([CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C:6](=[CH2:13])[C:5]2[CH:14]=[CH:15][CH:16]=[CH:17][C:4]=2[CH2:3]1)#[C-:21]
Reactant: C=C1c2ccccc2CC(N)c2ccccc21
Reactant: O=C([O-])[O-]
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: [C-]#[N+]C1Cc2ccccc2C(=C)c2ccccc21
Reaction time: 8 h

Procedure:
To a solution of 10-amino-5-methylene-10,11-dihydro-5H-dibenzo[a,d]cycloheptene (8.1 g, 36.6 mmole) in chloroform (180 ml) was added sodium hydroxide pellets (4.42 g, 0.11 mole) benzyltriethylammonium chloride (0.42 g, 1.8 mmole) and water (0.5 ml). The mixture was stirred under nitrogen until the sodium hydroxide pellets dissolved (ca 4 hours), treated with anhydrous potassium carbonate, filtered, and evaporated to dryness in vacuo. The resulting oil was dissolved in chloroform (180 ml), treated with another 1.5 g (37.5 mmole) of sodium hydroxide and 0.2 g (0.86 mmole) of benzyltriethylammonium chloride, and stirred overnight under nitrogen. The mixture was again dried over potassium carbonate, filtered, and evaporated to dryness in vacuo. The resulting oil was chromatographed on 120 g of silica gel, and eluted with methylene chloride. The combined product fractions were evaporated to dryness in vacuo and the resulting solid was recrystallized from ether to give 4 g of solid, m.p. 96°-98°.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Cl:7][C:8]1[C:16]([F:17])=[CH:15][C:11]([C:12]([OH:14])=O)=[C:10]([F:18])[CH:9]=1.C(=O)([O-])[O-].[K+].[K+].[CH:25]1([C@H:28]([NH2:30])[CH3:29])[CH2:27][CH2:26]1>O.C(Cl)Cl.CN(C=O)C>[Cl:7][C:8]1[C:16]([F:17])=[CH:15][C:11]([C:12]([NH:30][C@@H:28]([CH:25]2[CH2:27][CH2:26]2)[CH3:29])=[O:14])=[C:10]([F:18])[CH:9]=1
Reactant: O=C(O)c1cc(F)c(Cl)cc1F
Reactant: C[C@@H](N)C1CC1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O
Product: C[C@@H](NC(=O)c1cc(F)c(Cl)cc1F)C1CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.3 %

Procedure:
Oxalyl chloride (250.0 μL, 2.954 mmol) was added to a solution of 4-chloro-2,5-difluorobenzoic acid (0.0578 g, 0.300 mmol) in dichloromethylene (3 mL), followed by 15 μL of DMF. The mixture was stirred at room temperature for 1 hour. The volatiles were removed under reduced pressure. The residue was diluted with dichloromethylene (5 mL). To the solution was added potassium carbonate (82.9 mg, 0.600 mmol) in water (1 mL), and (1R)-1-cyclopropylethanamine (41.6 μL, 0.450 mmol). The mixture was stirred at room temperature for 30 minutes, and diluted with DCM, washed with water and brine. The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure to afford the desired product (0.075 g, 96%) which was directly used in the next step reaction without further purification. LCMS (M+H)+: m/z=260.0.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[O:7]1[C@H:9]2[C:10](=[O:37])[CH2:11][C@H:12]3[C@:34]([CH3:35])([C@@H:8]12)[C@@H:33]1[C@H:15]([C@H:16]2[C@:30]([CH3:36])([CH2:31][CH2:32]1)[C@H:19]1[C@@H:20]([C@:22]4([O:29][CH2:28][C@H:26]([CH3:27])[CH2:25][CH2:24]4)[O:23][C@H:18]1[CH2:17]2)[CH3:21])[CH2:14][CH2:13]3>C1COCC1>[OH:7][C@@H:8]1[C@@:34]2([CH3:35])[C@@H:12]([CH2:13][CH2:14][C@@H:15]3[C@@H:33]2[CH2:32][CH2:31][C@@:30]2([CH3:36])[C@H:16]3[CH2:17][C@@H:18]3[O:23][C@@:22]4([O:29][CH2:28][C@H:26]([CH3:27])[CH2:25][CH2:24]4)[C@@H:20]([CH3:21])[C@@H:19]32)[CH2:11][C@@H:10]([OH:37])[CH2:9]1
Reactant: C[C@@H]1CC[C@@]2(OC1)O[C@H]1C[C@H]3[C@@H]4CC[C@H]5CC(=O)[C@@H]6O[C@@H]6[C@]5(C)[C@H]4CC[C@]3(C)[C@H]1[C@@H]2C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C[C@@H]1CC[C@@]2(OC1)O[C@H]1C[C@H]3[C@@H]4CC[C@H]5C[C@@H](O)C[C@H](O)[C@]5(C)[C@H]4CC[C@]3(C)[C@H]1[C@@H]2C
Temperature: 25 °C
Reaction time: 1 h
Yield: 34 %

Procedure:
Lithium aluminum hydride (0.43 g, 15.38 mmol) was added to a solution of (1α,2α,5α,25R)-1,2-epoxy-spirostan-3-one in THF (20 mL) at 0° C. The reaction was gradually warmed to room temperature and after 3 hours, additional lithium aluminum hydride (0.10 g, 3.58 mmol) was added. After 1 hour, the reaction was cooled to 0° C. and quenched by the sequential addition of H2O (0.75 mL), 15% NaOH (0.75 mL), and H2O (1.50 mL). The mixture was dried with MgSO4, filtered, and concentrated in vacuo. The product was purified by flash chromatography (50% EtOAc/50% hexane to 95% EtOAc/5%MeOH) to afford 0.460 g, (34%) of the title compound.
Reaction SMILES: [CH3:1][N:2]1[C:7]2[CH:8]=[CH:9][N:10]=[CH:11][C:6]=2[S:5](=[O:13])(=[O:12])[NH:4][CH2:3]1.[C:14](=O)([O-])[O-].[K+].[K+].C1(C)C=CC(S(OC)(=O)=O)=CC=1>C(#N)C>[CH3:14][N:4]1[CH2:3][N:2]([CH3:1])[C:7]2[CH:8]=[CH:9][N:10]=[CH:11][C:6]=2[S:5]1(=[O:13])=[O:12]
Reactant: O=C([O-])[O-]
Reactant: CN1CNS(=O)(=O)c2cnccc21
Agent: COS(=O)(=O)c1ccc(C)cc1
Agent: [K+]
Solvent: CC#N
Product: CN1CN(C)S(=O)(=O)c2cnccc21

Procedure:
A solution of 0.25 g of 4-methyl-2,3-dihydro-4H- pyrido[4,3e][1,2,4]thiadiazine 1,1-dioxide (Example 5) in 8 cm3 of acetonitrile is treated with 0.5 g of potassium carbonate (±3 eq.) and then with 0.26 g of methyl p-toluenesulfonate (1.1 eq.). The suspension obtained is brought to reflux for 2 hours. The solvent is then removed by evaporation under reduced pressure and the residue is distributed between 10 cm3 of water and 100 ml of chloroform. The aqueous phase is then extracted twice with 50 cm3 of chloroform. The combined organic fractions are dried over MgSO4, filtered and then concentrated to dryness. The residue is dissolved in the minimum amount of chloroform. The addition of an excess of petroleum ether (40°-60° C.) causes precipitation of the crystals of the title product. They are collected on the filter, washed with petroleum ether (40°-60° C.) and dried. Yd. : 60-65%