Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][Si](C)(C)[N-][Si](C)(C)C.[K+].[Br-].[CH2:12]([C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][C:15]=1[I:22])[CH3:13]>C1COCC1>[CH:18]([C:17]1[CH:20]=[CH:21][C:14]([CH2:12][CH3:13])=[C:15]([I:22])[CH:16]=1)=[CH2:1]
Reactant: CCc1ccc(C=O)cc1I
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=Cc1ccc(CC)c(I)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Potassium hexamethyldisilazide (0.5 M in THF) (46.1 mL, 23.07 mmol) was added dropwise to a stirred suspension of methyltriphenylphosphohonium bromide (8.24 g, 23.1 mmol) in dry THF (62 mL) at 0° C. and the mixture was stirred for 20 min. A solution of 4-ethyl-3-iodobenzaldehyde (2.40 g, 9.23 mmol) in dry THF (31 mL) was added via cannula. The reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction was quenched with satd NH4Cl (50 mL) and the resulting mixture was extracted with EtOAc (3×50 mL). The combined extracts were dried (MgSO4) and concentrated in vacuo to give the crude product. This was purified by flash chromatography (Biotage Horizon, 40M, Si, ˜30 mL/min, 100% hexanes for 2448 mL) to afford 4-ethenyl-1-ethyl-2-iodobenzene, as a colorless oil. Rf=0.79 (hexanes). 1H NMR (500 MHz, CDCl3): δ 7.37 (d, J=1.8 Hz, 1H); 6.83 (dd, J=7.9, 1.8 Hz, 1H); 6.68 (d, J=7.9 Hz, 1H); 6.11 (dd, J=17.6, 10.9 Hz, 1H); 5.21 (d, J=17.6 Hz, 1H); 4.72 (d, J=9.7 Hz, 1H); 2.23 (q, J=7.5 Hz, 2H); 0.72 (t, J=7.5 Hz, 3H).
Reaction SMILES: [CH2:1]([S:5][CH2:6][C:7]([O:9]C)=[O:8])[CH2:2][C:3]#[CH:4].[OH-].[Na+]>O>[CH2:1]([S:5][CH2:6][C:7]([OH:9])=[O:8])[CH2:2][C:3]#[CH:4]
Reactant: C#CCCSCC(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: C#CCCSCC(=O)O
Reaction time: 24 h

Procedure:
Thioglycollic acid (6.0 g) was added to a stirred solution of sodium hydroxide (8.0 g) in ethanol (50 ml). But-3-ynyl methanesulphonate (7.4 g) was added and the mixture was stirred at 20° for 24 hours. The reaction mixture was poured into water and the aqueous mixture was extracted with diethyl ether. The aqueous alkaline extracts were acidified with hydrochloric acid and the mixture was extracted with diethyl ether. The ethereal extracts were dried over anhydrous magnesium sulphate and evaporated in vacuo. The resulting oil was stirred in dry dimethylformamide (100 ml) and anhydrous sodium carbonate (15 g) was added. Methyl iodide (7.0 ml) was added and the reaction mixture was stirred at 20° for 3 days. Water was added and the aqueous mixture was extracted with diethyl ether. The ethereal extracts were washed with water and dried over anhydrous magnesium sulphate. The solvent was removed in vacuo and the residue was chromatographed on silica, eluting with 1:4 diethylether: hexane. Methyl 2-(but-3-ynylthio)acetate was obtained as a colourless oil (1.2 g) (a small amount of methyl 2-(but-3-yn-1-ylthio)propionate was present). A mixture of methyl 2-(but-3-ynylthio)acetate (0.6 g) and sodium hydroxide solution (20 ml, 2N, 1:1 methanol:water) was stirred for 24 hours at 20°. Water was added and the aqueous mixture was extracted with diethyl ether. The aqueous alkaline extracts were acidified with hydrochloric acid and the mixture was extracted with diethyl ether. The ethereal extracts were dried over anhydrous magnesium sulphate and the solvent was removed in vacuo. 2-(But-3-ynylthio)acetic acid was obtained as a colourless oil (0.5 g). (A small amount of 2-(but-3-ynylthio)propionic acid was present.
Reaction SMILES: OO.C(OC(C(F)(F)F)=O)(C(F)(F)F)=[O:4].[N:16]1([CH2:23][CH2:24][NH:25][C:26]2[N:27]=[N+:28]([O-:39])[C:29]3[CH:38]=[C:37]4[C:33]([CH2:34][CH2:35][CH2:36]4)=[CH:32][C:30]=3[N:31]=2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.C(O)(C(F)(F)F)=O>C(Cl)Cl.N>[N:16]1([CH2:23][CH2:24][NH:25][C:26]2[N:27]=[N+:28]([O-:39])[C:29]3[CH:38]=[C:37]4[C:33]([CH2:34][CH2:35][CH2:36]4)=[CH:32][C:30]=3[N+:31]=2[O-:4])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: [O-][n+]1nc(NCCN2CCCCCC2)nc2cc3c(cc21)CCC3
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Agent: N
Agent: OO
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: [O-][n+]1nc(NCCN2CCCCCC2)[n+]([O-])c2cc3c(cc21)CCC3
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 60.7 %

Procedure:
H2O2 (70%, 0.37 mL, ca. 7.3 mmol) was added dropwise to a stirred solution of TFAA (1.0 mL, 7.3 mmol) in DCM (20 mL) at 0° C. The solution was stirred at 0° C. for 5 min, warmed to 20° C. for 10 min, then cooled to 0° C. and added to a stirred solution of 1-oxide 46 (240 mg, 0.7 mmol) and TFA (0.28 mL, 3.7 mmol) in DCM (20 mL) at 0° C. The solution was stirred at 20° C. for 6 h, diluted with dilute aqueous NH3 solution (10 mL) and extracted with CHCl3 (4×50 mL). The combined organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give 1,4-dioxide 47 (146 mg, 61%) as a red solid: mp (MeOH) 181-184° C.; 1H NMR δ 8.13 (s, 1H, H-9), 8.10 (s, 1H, H-5), 7.55 (br s, 1H, NH), 3.56-3.60 (m, 2H, CH2N), 3.03-3.07 (m, 4H, H-6, H-8), 2.81 (dd, J=6.1, 6.0 Hz, 2H, CH2N), 2.67-2.72 (m, 4H, 2×CH2N), 2.20 (p, J=7.5 Hz, 2H, H-7), 1.60-1.71 (m, 8H, 4×CH2); 13C NMR δ 155.6, 149.4, 145.7, 138.0, 129.6, 115.7, 111.5, 55.9, 55.1 (2), 39.0, 33.4, 32.3, 28.5 (2), 27.0 (2), 25.5. Anal. calcd for C18H25N5O2: C, 63.0; H, 7.3; N, 20.4. Found: C, 62.9; H, 7.2; N, 20.3%.
Reaction SMILES: [CH2:1]([N:3]([CH2:11]C)[C:4](=[O:10])[CH2:5][C:6]([CH2:8][Cl:9])=[O:7])C.Cl[C:14]#[N:15]>O.C1C=CC=CC=1.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:1][N:3]([CH3:11])[C:4](=[O:10])[CH:5]([C:14]#[N:15])[C:6]([CH2:8][Cl:9])=[O:7]
Reactant: CCN(CC)C(=O)CC(=O)CCl
Reactant: N#CCl
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: c1ccccc1
Product: CN(C)C(=O)C(C#N)C(=O)CCl
Yield: 75.3 %

Procedure:
10.0 gm. (0.05 mole) of copper acetate was dissolved hot in 150 ml of H2O and added to a solution of 19.1 gm. (0.1 mole) of γ-chloroacetoacetic acid diethyl amide in 150 ml of benzene. After brief stirring the green benzene solution was separated and dried over MgSO4. Then 6.2 gm. (0.1 mole) of ClCN were introduced into the benzene solution -- the temperature was kept at 20° to 30° C. The precipitated CuCl2 was filtered off and the benzene solution was precipitated. 14.2 gm of α-cyano-γ-chloroacetoacetic acid dimethylamide was obtained, which corresponds to 65.6 percent of theoretical.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:7]=[C:8]([Cl:10])[CH:9]=1)(=[O:3])[CH3:2].[Br:16]Br.O>O1CCOCC1>[Br:16][CH2:2][C:1]([C:4]1[CH:5]=[C:6]([NH:11][S:12]([CH3:15])(=[O:13])=[O:14])[CH:7]=[C:8]([Cl:10])[CH:9]=1)=[O:3]
Reactant: CC(=O)c1cc(Cl)cc(NS(C)(=O)=O)c1
Reactant: BrBr
Solvent: O
Solvent: C1COCCO1
Product: CS(=O)(=O)Nc1cc(Cl)cc(C(=O)CBr)c1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
N-(3-acetyl-5-chlorophenyl)methanesulfonamide (500 mg) was dissolved in dioxane (10 mL). The temperature was maintained at 50° C. and bromine (0.11 mL) was added. After stirring for 30 minutes, water (50 mL) was added to the mixture, and the mixture was extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with water (50 mL) twice and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (1:2 ethyl acetate/hexane) to yield N-(3-bromoacetyl-5-chlorophenyl)methanesulfonamide (600 mg) as a colorless crystal.
Reaction SMILES: [K].[OH:2][N:3]1[CH:7]=[N:6][CH:5]=[N:4]1.Br[CH:9]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=1[Cl:20])[CH2:10][CH2:11][CH3:12].[I-].[K+]>CN(C)C=O>[Cl:20][C:14]1[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:13]=1[CH:9]([O:2][N:3]1[CH:7]=[N:6][CH:5]=[N:4]1)[CH2:10][CH2:11][CH3:12]
Reactant: On1cncn1
Reactant: CCCC(Br)c1ccc(Cl)cc1Cl
Agent: [I-]
Agent: [K+]
Agent: [K]
Solvent: CN(C)C=O
Product: CCCC(On1cncn1)c1ccc(Cl)cc1Cl

Procedure:
1.2 g (10 mmol) of the potassium salt of 1-hydroxy-1,2,4-triazole were dissolved in 100 ml of dimethylformamide and the solution was added at room temperature to a solution of 4.0 g (10 mmol) of 1-bromo-1-(2,4-dichlorophenyl)-butane in 50 ml of dimethylformamide. 0.1 g of potassium iodide was added to the mixture, which was refluxed for 10 minutes. Thereafter, the solvent was removed under reduced pressure, the residue was taken up in ether and the solution was washed three times with water. After the organic phase had been dried with Na2SO4, the solvent was removed under reduced pressure.
Reaction SMILES: [O:1]1[CH2:13][CH:2]1[CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][CH3:12].[F:14][C:15]1[CH:32]=[CH:31][C:18]([C:19]([NH:21][C:22]([NH:24][CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[O:23])=[O:20])=[CH:17][CH:16]=1>C(O)(C)C>[F:14][C:15]1[CH:16]=[CH:17][C:18]([C:19]([NH:21][C:22](=[O:23])[NH:24][CH:25]2[CH2:26][CH2:27][N:28]([CH2:13][CH:2]([OH:1])[CH2:3][O:4][C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[O:11][CH3:12])[CH2:29][CH2:30]2)=[O:20])=[CH:31][CH:32]=1
Reactant: O=C(NC(=O)c1ccc(F)cc1)NC1CCNCC1
Reactant: COc1ccccc1OCC1CO1
Solvent: CC(C)O
Product: COc1ccccc1OCC(O)CN1CCC(NC(=O)NC(=O)c2ccc(F)cc2)CC1

Procedure:
2-(2,3-Epoxypropoxy)anisole (0.99 g, 0.0055 m) and 1-(4-fluorobenzoyl)-3-(piperid-4-yl)urea (1.32 g, 0.005 m) in isopropyl alcohol (50 cm3) were refluxed for 24 hours. The solution was cooled and the product which crystallised was filtered off. This was dissolved in ethanol and acidified with ethanolic hydrogen chloride. The solution was heated on a water bath and ethyl acetate was added to replace the lost solvent. The product crystallised out and was recrystallised twice from ethanol giving the title compound as the hydrochloride, hemihydrate (0.44 g) m.p. 194°-195° C.
Reaction SMILES: [C:1]1([CH:7]([CH2:11][C:12]([OH:14])=[O:13])[C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C>C1(C)C=CC=CC=1>[C:1]1([CH:7]2[CH2:11][C:12](=[O:13])[O:14][C:8]2=[O:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)CC(C(=O)O)c1ccccc1
Solvent: CC(=O)Cl
Solvent: Cc1ccccc1
Product: O=C1CC(c2ccccc2)C(=O)O1
Temperature: 25 °C
Yield: 69.3 %

Procedure:
A solution of phenylsuccinic acid (20.0 g, 0.10 mol), acetyl chloride, and 200 mL of toluene was stirred at reflux for 5.5 hours, removing H2O azeotropically during the reaction. After cooling to room temperature, toluene was evaporated in vacuo, and the residue was crystallized from ether to obtain 12.2 g of phenyl succinic anhydride as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[OH:21].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][CH2:10][C:11](=[O:13])[NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[OH:21])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NCCC(=O)O
Reactant: Nc1ccccc1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCC(=O)Nc1ccccc1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 3-tert-Butoxycarbonylamino-propionic acid (5-1) (1.0 g, 5.3 mmol) and 2-aminophenol (5-2) (578 mg, 5.3 mmol) in dichloromethane (10 mL) was added N,N′-dicyclo hexyl carbodiimide (1.3 g, 6.4 mmol). The resulting mixture was stirred at room temperature overnight. The volatile solvents were removed by rotovap evaporation then the reaction mixture was directly purified by silica gel chromatography (10-100% Hexane/Ethyl Acetate) to recover the desired product (5-3) as white solid: 1H-NMR (500 MHz, d4-CD3OD) δ7.43 (m, 1H), 6.88 (m, 1H), 6.76 (m, 1H), 6.70 (m, 1H), 3.29 (m, 2H), 2.48 (m, 2H), 1.29 (s, 9H).
Reaction SMILES: C(O[C:6](=O)[N:7]([CH:9]1[CH2:14][CH2:13][CH:12]([C:15]([N:17]2[CH2:21][CH:20]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=3)[CH:19]([CH:30]([O:32][C:33]3[CH:38]=[CH:37][C:36]([C:39]#[N:40])=[CH:35][N:34]=3)[CH3:31])[CH2:18]2)=[O:16])[CH2:11][CH2:10]1)C)(C)(C)C.C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:29][C:24]1[CH:23]=[C:22]([CH:20]2[CH2:21][N:17]([C:15]([CH:12]3[CH2:13][CH2:14][CH:9]([NH:7][CH3:6])[CH2:10][CH2:11]3)=[O:16])[CH2:18][CH:19]2[CH:30]([O:32][C:33]2[CH:38]=[CH:37][C:36]([C:39]#[N:40])=[CH:35][N:34]=2)[CH3:31])[CH:27]=[CH:26][C:25]=1[Cl:28]
Reactant: CC(Oc1ccc(C#N)cn1)C1CN(C(=O)C2CCC(N(C)C(=O)OC(C)(C)C)CC2)CC1c1ccc(Cl)c(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNC1CCC(C(=O)N2CC(c3ccc(Cl)c(Cl)c3)C(C(C)Oc3ccc(C#N)cn3)C2)CC1
Reaction time: 1 h
Yield: 98 %

Procedure:
To a stirred solution of {4-[(3RS,4SR)-3-[(SR)-1-(5-cyano-pyridin-2-yloxy)-ethyl]-4-(3,4-dichloro-phenyl)-pyrrolidine-1-carbonyl]-cyclohexyl}-methyl-carbamic acid tert-butyl ester described herein above (30 mg, 0.050 mmol) in CH2Cl2 (4 mL) was added TFA (1 mL). After 1 hour, aqueous NaHCO3 was added until ph=8, the product was extracted with CH2Cl2. The combined organic phases were dried over Na2SO4 to give the title product as a colorless oil (25 mg, 98%). ES-MS m/e: 500.9 (M+H+).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4](=[CH:7][C:8]2[CH:9]=[C:10]([CH:22]=[CH:23][CH:24]=2)[O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][N:13]=2)[CH2:3][CH2:2]1.[N:25]1[CH:30]=[CH:29][CH:28]=[C:27]([NH:31][C:32](=O)[O:33]C2C=CC=CC=2)[CH:26]=1.C(N(C(C)C)CC)(C)C>C(#N)C>[N:25]1[CH:30]=[CH:29][CH:28]=[C:27]([NH:31][C:32]([N:1]2[CH2:6][CH2:5][C:4](=[CH:7][C:8]3[CH:24]=[CH:23][CH:22]=[C:10]([O:11][C:12]4[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:19])[F:20])=[CH:14][N:13]=4)[CH:9]=3)[CH2:3][CH2:2]2)=[O:33])[CH:26]=1
Reactant: FC(F)(F)c1ccc(Oc2cccc(C=C3CCNCC3)c2)nc1
Reactant: O=C(Nc1cccnc1)Oc1ccccc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cccnc1)N1CCC(=Cc2cccc(Oc3ccc(C(F)(F)F)cn3)c2)CC1
Temperature: 50 °C
Reaction time: 4 h
Yield: 94.9 %

Procedure:
To a mixture of 2-(3-piperidin-4-ylidenemethyl-phenoxy)-5-trifluoromethyl-pyridine (80.0 g, 0.216 mol) and phenyl pyridin-3-ylcarbamate (48.6 g, 0.227 mol) in acetonitrile (650 mL) was added dropwise diisopropylethyl amine (55.8 g, 0.432 mol). A solution formed after ˜45 min of stirring. The slightly turbid solution was stirred at ambient temperature for 18 h. TLC showed a prominent product spot with traces of both starting materials and two other fast moving spots. The solution was concentrated in vacuo to a viscous oil. This was partitioned between dichloromethane (600 mL) and water (500 mL). The aqueous layer was extracted with 200 mL of dichloromethane. The combined organic layers were washed with successive portions of 500 mL of 5% sodium hydroxide, and 200 mL of water, then dried over magnesium sulfate and concentrated in vacuo to 139.5 g of a viscous oil. This was dissolved in 350 mL of warm (50° C.) methyl t-butyl ether. Soon after a solution formed, solid began separating. The crystallizing mixture was kept at −10° C. for 4 h and filtered. The solid was rinsed with 60 mL of methyl t-butyl ether and pressed dry under suction. Further drying in vacuo at 28° C. for 16 h and then at 35° C. for 6 h provided 93.2 g (95%) of product.
Reaction SMILES: [CH:1]([O:8][CH2:9][CH3:10])(OCC)OCC.C(O[C@@H:15]1[C@H:21]2[C@H:22]3[C@H:31]([CH2:32][CH2:33][C@:18]2([CH2:19][CH3:20])[C:17](=[O:35])[CH2:16]1)[C@@H:30]1[C:25](=[CH:26]C(=O)[CH2:28][CH2:29]1)[CH2:24][CH2:23]3)(=O)C.C(=O)([O-])[O-].[K+].[K+]>C(O)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:9]([O:8][C:1]1[CH2:28][CH2:29][C@H:30]2[C:25](=[CH:24][CH2:23][C@@H:22]3[C@@H:31]2[CH2:32][CH2:33][C@@:18]2([CH2:19][CH3:20])[C@H:21]3[CH:15]=[CH:16][C:17]2=[O:35])[CH:26]=1)[CH3:10]
Reactant: CC[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1[C@@H](OC(C)=O)CC2=O
Reactant: CCOC(OCC)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CCOC1=CC2=CC[C@@H]3[C@H](CC[C@]4(CC)C(=O)C=C[C@@H]34)[C@H]2CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.6 %

Procedure:
Triethyl orthoformate (2 ml, 12 mmol) and p-Toluenesulfonic acid (20 mg, 0.10 mmol) were added to a suspension of 15α-acetoxy-18-methyl-estr-4-en-3,17-dione (2 g, 5.81 mmol) in ethanol (20 ml). The mixture was stirred at room temperature for 1 h. Potassium carbonate (1.1 g, 8.06 mmol) in solution in water (20 ml) was added and the mixture was heated under reflux for 2 h, cooled to 10° C. and water (20 ml) was then added. The precipitate was filtered, washed with water and dried under vacuum, to afford 3-ethoxy-18-methyl-estra-3,5,15-trien-17-one (1.3 g, yield: 78%). mp and 1H-NMR were in accordance with those obtained for example 2. HPLC analysis was as shown in FIG. 1b.
Reaction SMILES: [CH2:1]([C:5](=[CH:8][C:9]1[CH:14]=[CH:13][C:12]2[O:15][CH2:16][O:17][C:11]=2[CH:10]=1)[CH:6]=[O:7])[CH2:2][CH2:3][CH3:4].Cl.[CH3:19]O>>[CH2:1]([C:5]1[CH2:8][C:9]2[C:14]([C:6]=1[O:7][CH3:19])=[CH:13][C:12]1[O:15][CH2:16][O:17][C:11]=1[CH:10]=2)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC(C=O)=Cc1ccc2c(c1)OCO2
Reactant: CO
Agent: Cl
Product: CCCCC1=C(OC)c2cc3c(cc2C1)OCO3
Yield: 90 %

Procedure:
Dissolved in 80 ml of methanol was 12 g of 2-n-butyl-3-(3,4-methylenedioxyphenyl)acrylaldehyde, into which hydrogen chloride qas was blown under ice-salt cooling. Upon confirmation of full consumption of the raw material by thin-layer chromatography (eluent: a 5:1 mixture of n-hexane and ether), the bubbling of hydrogen chloride gas was stopped. Water was added to the reaction mixture, followed by extraction of the resultant mixture with ether. After the resultant ether solution was washed with water, a saturated aqueous solution of sodium hydrogencarbonate and water successively, the ether solution was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: a 10:1 mixture of n-hexane and ether) to give 11.4 g of 2-n-butyl-3-methoxy-5,6-methylenedioxyindene as an oily substance (yield: 90%).
Reaction SMILES: Cl[N:2]1[CH:11]=[C:10]([Cl:12])[C:9]2[C:4](=[CH:5][C:6]([O:13][CH3:14])=[CH:7][CH:8]=2)[CH2:3]1.[CH:15]([O:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1)([CH3:17])[CH3:16].C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O>[Cl:12][C:10]1[C:9]2[C:4](=[CH:5][C:6]([O:13][CH3:14])=[CH:7][CH:8]=2)[CH2:3][N:2]([C:22]2[CH:23]=[CH:24][C:19]([O:18][CH:15]([CH3:17])[CH3:16])=[CH:20][CH:21]=2)[CH:11]=1
Reactant: CC(C)Oc1ccc(B(O)O)cc1
Reactant: COc1ccc2c(c1)CN(Cl)C=C2Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc2c(c1)CN(c1ccc(OC(C)C)cc1)C=C2Cl
Temperature: 90 °C
Reaction time: 0.33 h
Yield: 83.9 %

Procedure:
To a solution of 2,4-dichloro-7-methoxyisoquinolin (0.7 g, 3.07 mmol), 4-isopropoxyphenylboronic acid (0.60 g, 3.38 mmol) in 1,4-Dioxane (15 ml) and water (10 ml) was added K2CO3 (0.84 g, 6.14 mmol). The reaction mass was degasified for 20 min. Pd (Ph3P)4 (0.17 g, 0.15 mmol) was added to the above reaction mass and degasified again for 5 min at room temperature. The reaction vessel (Pressure tube) was sealed and heated at 90° C. for 18 h. The reaction mass was evaporated under reduced pressure. The residue was diluted with water and extracted with ethyl acetate. The combined organic layer was dried over anhydrous Na2SO4 and evaporated under reduced pressure to get crude compound. The crude compound was purified by silica gel chromatography to get desired compound (0.85 g, 84%) as white solid. 1HNMR (400 MHz, CDCl3): δ ppm 8.25-8.22 (d, J=8 Hz, 1H), 8.13 (s, 1H), 8.07-8.05 (d, J=8 Hz, 1H), 7.48-7.47 (d, J=4 Hz, 1H), 7.34-7.32 (d, J=8 Hz, 1H), 7.07-7.05 (m, 2H), 4.77-4.71 (m, 1H), 4.15 (s, 3H), 1.32-1.31 (d, J=4 Hz, 6H); MS: MS m/z 328.20 (M++1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=2[CH3:27])[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)=O)=[CH:4][CH:3]=1.Cl.[NH2:29][OH:30].C([O-])(O)=O.[Na+]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=2[CH3:27])[CH2:9]/[C:10](/[C:12]2[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)=[N:29]\[OH:30])=[CH:4][CH:3]=1
Reactant: NO
Reactant: Cc1cc(F)ccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(Br)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc(F)ccc1C(C/C(=N\O)c1ccc(=O)n(C)c1)c1ccc(Br)cc1

Procedure:
In analogy to example 151, step 3, 5-(3-(4-bromophenyl)-3-(4-fluoro-2-methylphenyl)propanoyl)-1-methylpyridin-2(1H)-one was reacted with hydroxylamine hydrochloride in the presence of NaHCO3 to give the title compound containing 10% of the corresponding Z isomer as a colorless foam, MS (ESI+): m/z=443.08 [M+H]+.
Reaction SMILES: Cl.[S:2]1[CH:6]=[CH:5][N:4]=[C:3]1[C:7]([NH2:9])=[NH:8].[CH:10]1(C2N=C(C#N)SC=2)[CH2:12][CH2:11]1>>[CH:10]1([C:5]2[N:4]=[C:3]([C:7]([NH2:9])=[NH:8])[S:2][CH:6]=2)[CH2:12][CH2:11]1
Reactant: N#Cc1nc(C2CC2)cs1
Reactant: N=C(N)c1nccs1
Agent: Cl
Product: N=C(N)c1nc(C2CC2)cs1

Procedure:
Compound M was prepared in analogy to thiazole-2-carboxamidine (Compound A1) with the procedure shown in Scheme 5 by using 4-cyclopropyl-thiazole-2-carbonitrile instead of thiazole-2-carbonitrile. 1H NMR (CDCl3-d, 400 MHz): δ 9.68 (br, 1H), 9.56 (br, 1H), 2.23-2.19 (m, 1H), 1.01-0.92 (m, 4H).
Reaction SMILES: CS(O[CH2:6][CH2:7][O:8][CH:9]1[CH2:26][CH2:25][C:12]2([CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]2)[CH2:11][CH2:10]1)(=O)=O.[H-].[Na+].[NH:29]1[CH:33]=[CH:32][N:31]=[CH:30]1>CN(C=O)C.C(OCC)(=O)C>[N:29]1([CH2:6][CH2:7][O:8][CH:9]2[CH2:10][CH2:11][C:12]3([CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:23])([CH3:24])[CH3:22])=[O:19])[CH2:14][CH2:13]3)[CH2:25][CH2:26]2)[CH:33]=[CH:32][N:31]=[CH:30]1
Reactant: c1c[nH]cn1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCC(OCCOS(C)(=O)=O)CC2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC2(CCC(OCCn3ccnc3)CC2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 84 %

Procedure:
A solution of tert-butyl 9-(2-(methylsulfonyloxy)ethoxy)-3-azaspiro[5.5]undecane-3-carboxylate (2.68 mmol, 1.0 eq.) in DMF (10 ml) was added dropwise to a stirred mixture of NaH (8.04 mmol, 3.0 eq.) and imidazole (5.36 mmol, 2.0 eq.) in DMF (15 ml) at 0° C. and the resulting mixture was stirred at 25° C. for 16 h. The reaction mixture was diluted with ethyl acetate (300 ml) and washed with water (200 ml) and brine (200 ml). The organic layer was dried over sodium sulfate and concentrated under reduce pressure to give the crude product which was purified by silica gel column chromatography eluting with 2% MeOH in MC to afford the desired product as a yellow oil. Yield: 84%
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[S:11](=[O:14])(=[O:13])[NH2:12].[Br:15]Br.Br>C(OCC)(=O)C>[Br:15][CH2:9][C:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([S:11](=[O:13])(=[O:14])[NH2:12])[CH:4]=1)=[O:10]
Reactant: CC(=O)c1ccc(Cl)c(S(N)(=O)=O)c1
Reactant: BrBr
Agent: Br
Solvent: CCOC(C)=O
Product: NS(=O)(=O)c1cc(C(=O)CBr)ccc1Cl

Procedure:
4.7 g of 4'-chloro-3'-sulfamoylacetophenone were suspended in 50 ml of ethyl acetate and to that suspension, some drops of a solution of 3.2 g of bromine were added until the mixture was distinctly brown. The suspension was heated to about 60°-70° C. until the color changed (addition of a drop of 48% hydrobromic acid possible), cooled and the residual amount of the bromine solution was added dropwise at room temperature, while stirring. After distilling off the solvent, 2-bromo-4'-chloro-3'-sulfamoylacetophenone was obtained which melted at 169° C. (from n-butanol).