Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([N:7]2[C:10]3([CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)[CH2:9][C:8]2=[O:16])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:17]([OH:24])(=[O:23])/[CH:18]=[CH:19]/[C:20]([OH:22])=[O:21]>C(OCC)C>[C:17]([OH:24])(=[O:23])/[CH:18]=[CH:19]/[C:20]([OH:22])=[O:21].[CH:17]12[CH2:4][CH:3]([N:13]3[CH2:12][CH2:11][C:10]4([N:7]([C:1]5[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=5)[C:8](=[O:16])[CH2:9]4)[CH2:15][CH2:14]3)[CH:2]1[CH2:1][CH2:6][CH2:5][CH2:20][CH2:19][CH2:18]2
Reactant: O=C1CC2(CCNCC2)N1c1ccccc1
Agent: O=C(O)/C=C/C(=O)O
Solvent: CCOCC
Product: O=C1CC2(CCN(C3CC4CCCCCCC43)CC2)N1c1ccccc1

Procedure:
Reaction of (1RS,8RS)-bicyclo[6.2.0]dec-9-one and 1-phenyl-1,7-diaza-spiro[3.5]nonan-2-one in accordance with the general method of example 1 and treatment of the base with fumaric acid in diethyl ether yielded the title compound, pale brown solid, m.p. 158° C. and MS: m/e=353.4 (M+H+).
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:13])[C:4]1[CH:12]=[CH:11][C:10]2[O:9][CH2:8][O:7][C:6]=2[CH:5]=1.Br[CH2:15][CH2:16][CH2:17][CH3:18]>O1CCCC1>[CH2:15]([O:13][CH2:3][C:4]1[CH:12]=[CH:11][C:10]2[O:9][CH2:8][O:7][C:6]=2[CH:5]=1)[CH2:16][CH2:17][CH3:18]
Reactant: OCc1ccc2c(c1)OCO2
Reactant: CCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCOCc1ccc2c(c1)OCO2
Reaction time: 0.5 h
Yield: 38.4 %

Procedure:
4 g of sodium hydride (60%) and 100 ml of tetrahydrofuran (THF) were stirred in a nitrogen stream. Thereto was dropwise added, in 30 minutes, 15.2 g (0.1 mol) of piperonyl alcohol dissolved in 70 ml of THF, followed by stirring for 30 minutes. Thereto was dropwise added 13.7 g (0.1 mol) of 1-bromobutane dissolved in THF, followed by stirring for 12 hours. The stirring was stopped and the reaction mixture was concentrated. The concentrate was dropped into an excess amount of a 2 N aqueous hydrochloric acid solution. Heptane was added thereto for extraction. The extract was washed with water until the washings became neutral, and then concentrated. The concentrate was purified by silica gel column chromatography (hexane:ethyl acetate=30:1) to obtain 8.0 g of piperonyl butyl ether at a yield of 38.5% as a transparent oily substance.
Reaction SMILES: [CH3:1][N:2]1[CH2:14][CH2:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:15])[CH:10]=3)[NH:5][C:4]=2[CH2:3]1.N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].Br[C:39]#[C:40][C:41]1[CH:46]=[CH:45][C:44]([Cl:47])=[CH:43][CH:42]=1>C1(C)C=CC=CC=1>[Cl:47][C:44]1[CH:45]=[CH:46][C:41]([C:40]#[C:39][N:5]2[C:6]3[C:11](=[CH:10][C:9]([CH3:15])=[CH:8][CH:7]=3)[C:12]3[CH2:13][CH2:14][N:2]([CH3:1])[CH2:3][C:4]2=3)=[CH:42][CH:43]=1
Reactant: Cc1ccc2[nH]c3c(c2c1)CCN(C)C3
Reactant: Clc1ccc(C#CBr)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Agent: c1cnc2c(c1)ccc1cccnc12
Solvent: Cc1ccccc1
Product: Cc1ccc2c(c1)c1c(n2C#Cc2ccc(Cl)cc2)CN(C)CC1
Temperature: 80 °C
Yield: 7.2 %

Procedure:
2,6-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (200 mg, 1 mmol) was mixed with CuSO4.5H2O (50 mg, 0.2 mmol), 1,10-phenanthroline (72 mg, 0.4 mmol), K3PO4 (425 mg, 2 mmol) and 1-(bromoethynyl)-4-chlorobenzene (237 mg, 1.1 mmol) in toluene (8-10 ml). The reaction mixture was flushed with nitrogen and heated at 80° C. for 16 h. The reaction mixture was filtered through Celite, and the Celite bed was rinsed with dichloromethane. Combined organic layer was concentrated under reduced pressure and the residue was purified by silica gel chromatography (100-200 mesh) eluting with 60-80% ethyl acetate in hexane to obtain 9-((4-chlorophenyl)ethynyl)-2,6-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (24 mg) as brown semi solid. 1H NMR (CDCl3) FREE BASE 7.42 (m, 3H), 7.36 (m, 3H), 7.10 (d, 1H), 3.70 (s, 2H), 2.80 (m, 4H), 2.60 (s, 3H), 2.42 (s, 3H).
Reaction SMILES: [CH:1]1CCCC=1.C1C=CC=CC=1.S([O-])([O-])(=O)=O.[Ba+2].[C:18]([CH:22]1[C:26](=[O:27])[CH2:25][CH:24]([O:28][C:29](=[O:31])[CH3:30])[CH:23]1[CH2:32][C:33]([OH:35])=[O:34])([O:20][CH3:21])=[O:19]>C(Cl)(Cl)Cl>[CH3:1][O:34][C:33](=[O:35])[CH2:32][CH:23]1[CH:24]([O:28][C:29](=[O:31])[CH3:30])[CH2:25][C:26](=[O:27])[CH:22]1[C:18]([O:20][CH3:21])=[O:19]
Reactant: C1=CCCC1
Reactant: COC(=O)C1C(=O)CC(OC(C)=O)C1CC(=O)O
Agent: O=S(=O)([O-])[O-]
Agent: [Ba+2]
Solvent: c1ccccc1
Solvent: ClC(Cl)Cl
Product: COC(=O)CC1C(OC(C)=O)CC(=O)C1C(=O)OC

Procedure:
The cyclopentene acid, V, (9.5 g.) is dissolved in 180 ml. of benzene and the solution is hydrogenated at room temperature and atmospheric pressure in the presence of 0.5 g. of palladiated barium sulfate. When the theoretical amount of hydrogen is absorbed, catalyst is filtered off and the solution is evaporated to dryness under vacuum, yielding 9 g. (95%) of the methy ester of 2-carbomethoxy-3-oxo-5-acetoxycyclopentaneacetic acid with the required stereochemical configuration. The compound is a rather unstable solid, melting at 54° C; [α]d25 :- 17.8 (C=1.017% in CHCl3).
Reaction SMILES: [Na+:1].[Na+].[C:3]([O-:12])(=[O:11])[C@@H:4]([C@H:6]([C:8]([O-:10])=[O:9])[OH:7])[OH:5].[C:13]([C@@H:16]([C@H:18]([C:20]([O-:22])=[O:21])[OH:19])[OH:17])([O-:15])=[O:14].C(O)(=O)[C@@H]([C@H](C(O)=O)O)[OH:25].[OH-].[Na+].[Na+].[Na+].C([O-])(=O)C(C(C([O-])=O)O)O>>[C:3]([OH:12])(=[O:11])[CH:4]([CH:6]([C:8]([OH:10])=[O:9])[OH:7])[OH:5].[Na+:1].[C:20]([O-:22])(=[O:21])[CH:18]([CH:16]([C:13]([OH:15])=[O:14])[OH:17])[OH:19].[OH-:25].[Na+:1]
Reactant: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Reactant: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)C(O)C(O)C(=O)O
Product: O=C([O-])C(O)C(O)C(=O)O

Procedure:
L(+)-tartaric acid disodium salt, also denoted as bisodium L-tartrate, is commercially available, e.g. from Sigma-Aldrich (CAS Number 6106-24-7). It is noted that instead of using L(+)-tartaric acid disodium salt, it is also possible to use L(+)-tartaric acid (commercially available from e.g. Sigma-Aldrich, CAS Number 87-69-4) and prepare the L(+)-tartaric acid disodium salt in situ, by addition of additional NaOH. The same holds for the other potential starting material, DL-tartaric acid disodium salt: it may be purchased from e.g. Sigma-Aldrich or produced in situ from DL-tartaric acid (CAS Number 133-37-9) or DL-tartaric acid monosodium salt and NaOH. In fact any tartaric acid source, containing D, L, meso in any proportion and in the acidic or salt form can be used for this process. D-tartaric acid can also be used as starting material, but this is less preferred because it is relatively expensive. The use of L-tartaric acid disodium salt (either produced in situ by addition of NaOH or used as such) is preferred because these starting materials are relatively cheap and the process to prepare a composition with between 55 and 90% by weight of meso-tartaric acid is faster than when a mixture of D- and L-tartaric acid is used as starting material. Obviously, it is also possible to use a mixture of D-, L-, and meso-tartaric acid.
Reaction SMILES: [N+](=[CH:3][C:4](=[O:11])[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])=[N-].[N+:12]([C:15]1[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=1[C:17]([NH2:19])=[O:18])([O-:14])=[O:13].O.C(OCC)(=O)C>C(Cl)Cl>[CH2:9]([O:8][C:6](=[O:7])[CH:5]([NH:19][C:17](=[O:18])[C:16]1[CH:20]=[CH:21][CH:22]=[CH:23][C:15]=1[N+:12]([O-:14])=[O:13])[C:4](=[O:11])[CH3:3])[CH3:10]
Reactant: CCOC(=O)CC(=O)C=[N+]=[N-]
Reactant: NC(=O)c1ccccc1[N+](=O)[O-]
Solvent: O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOC(=O)C(NC(=O)c1ccccc1[N+](=O)[O-])C(C)=O
Temperature: 40 °C
Yield: 76.4 %

Procedure:
Rh2(OAc)4 (30 mg, 0.063 mmol) was added to a solution of ethyl diazoacetoacetate (1.0 g, 6.32 mmol) and 2-nitrobenzamide (1.05 g, 6.32 mmol) in methylene chloride (15 mL), and the mixture was stirred at 40° C. for a day and a night. Water was then added to the reaction mixture, extraction was performed with ethyl acetate, and the organic extract was washed with water and saturated saline. After drying over magnesium sulfate, it was concentrated under reduced pressure to yield a crude product, which was then purified by column chromatography to yield the title compound (1.42 g, 77%) as a yellow oil.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([S:8]([NH:11][C:12]2[O:16][N:15]=[C:14]([CH3:17])[C:13]=2[Br:18])(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.NC1C=CC=CC=1S(N[C:30]1[O:34]N=C(C)C=1Br)(=O)=O.[N+](C1C=CC=CC=1S(N[C:50]1[O:54]N=C(C)C=1Br)(=O)=O)([O-])=O>>[CH3:50][O:54][C:5]1[CH:6]=[CH:7][C:2]([O:34][CH3:30])=[CH:3][C:4]=1[S:8]([NH:11][C:12]1[O:16][N:15]=[C:14]([CH3:17])[C:13]=1[Br:18])(=[O:10])=[O:9]
Reactant: Cc1noc(NS(=O)(=O)c2ccccc2[N+](=O)[O-])c1Br
Reactant: Cc1noc(NS(=O)(=O)c2cccc(N)c2)c1Br
Reactant: Cc1noc(NS(=O)(=O)c2ccccc2N)c1Br
Product: COc1ccc(OC)c(S(=O)(=O)Nc2onc(C)c2Br)c1

Procedure:
3-Amino-N-(4-bromo-3-methyl-5-isoxazolyl)benzenesulfonamide and 2-amino-N-(4-bromo-3-methyl-5-isoxazolyl)benzenesulfonamide can be prepared by hydrogenation of corresponding nitro-N-(4-bromo-3-methyl-5-isoxazolyl)benzenesulfonamide, which is prepared as described above.
Reaction SMILES: [H-].[Na+].[NH:3]1[C:7]2C=[CH:9][CH:10]=[CH:11][C:6]=2N[S:4]1(=[O:13])=[O:12].[CH3:14]I.O.C[N:18]([CH3:21])[CH:19]=O>>[CH3:21][N:18]1[C:19]2[CH:9]=[CH:10][CH:11]=[CH:6][C:7]=2[N:3]([CH3:14])[S:4]1(=[O:13])=[O:12]
Reactant: O=S1(=O)Nc2ccccc2N1
Reactant: CI
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CN1c2ccccc2N(C)S1(=O)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium hydride (5 g) was added to a solution of 1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (10 g) obtained in Reference Example 126 in dimethylformamide (100 ml), the mixture was stirred at room temperature for 1 hour, methyl iodide was added, and the mixture was stirred at room temperature for 18 hours. Water (200 g) was poured into the reaction mixture, extracted with ethyl acetate, and washed with brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give a reddish brown solid (9.9 g). Further recrystallization from water-ethyl acetate afforded the title compound as colorless crystals (9.0 g).
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[Br:11][C:12]1[S:13][C:14]([Cl:19])=[CH:15][C:16]=1[CH2:17][OH:18].C(N(CC)CC)C>ClCCl>[Br:11][C:12]1[S:13][C:14]([Cl:19])=[CH:15][C:16]=1[CH:17]=[O:18]
Reactant: OCc1cc(Cl)sc1Br
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=Cc1cc(Cl)sc1Br
Reaction time: 0.5 h

Procedure:
To a solution of DMSO (2.10 mL, 29.7 mmol) in dichloromethane (50 mL) at −78° C. was added oxalyl chloride (1.90 mL, 26.8 mmol) dropwise and the mixture was stirred for 30 min. at the temperature. To it was then added (2-bromo-5-chloro-3-thienyl)methanol from Example 1, Step 2 (4.50 g, 19.8 mmol, crude) in dichloromethane (25 mL) via a cannula and the resultant solution was stirred for 30 min. Triethylamine (6.40 mL, 45.5 mmol) was added in one portion and the mixture was stirred at −78° C. for 30 min. and allowed to warm slowly in air. The mixture was concentrated in vacuo and then resuspended in ether and then filtered. The filtrate was concentrated in vacuo to give the desired product. The crude was used directly without further purification.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]2[CH:15]=[CH:14][C:13]([C@H:16]([C:27]3[CH:32]=[CH:31][C:30](Cl)=[CH:29][C:28]=3[CH3:34])[CH2:17][C:18]([C:20]3[CH:25]=[CH:24][N:23]=[C:22]([CH3:26])[CH:21]=3)=O)=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[ClH:35].[NH2:36][OH:37].C(=O)([O-])O.[Na+]>>[Cl:35][C:30]1[CH:31]=[CH:32][C:27]([C@@H:16]([C:13]2[CH:14]=[CH:15][C:10]([CH:7]3[CH2:8][CH2:9][N:4]([C:1](=[O:3])[CH3:2])[CH2:5][CH2:6]3)=[CH:11][CH:12]=2)[CH2:17]/[C:18](=[N:36]\[OH:37])/[C:20]2[CH:25]=[CH:24][N:23]=[C:22]([CH3:26])[CH:21]=2)=[C:28]([CH3:34])[CH:29]=1
Reactant: CC(=O)N1CCC(c2ccc([C@@H](CC(=O)c3ccnc(C)c3)c3ccc(Cl)cc3C)cc2)CC1
Reactant: Cl
Reactant: NO
Agent: O=C([O-])O
Agent: [Na+]
Product: CC(=O)N1CCC(c2ccc([C@@H](C/C(=N\O)c3ccnc(C)c3)c3ccc(Cl)cc3C)cc2)CC1

Procedure:
In analogy to example 132, step 6, from (R)-3-(4-(1-acetylpiperidin-4-yl)phenyl)-3-(4-chloro-2-methylphenyl)-1-(2-methylpyridin-4-yl)propan-1-one and hydroxylamine hydrochloride in the presence of sodium hydrogencarbonate was prepared the title compound as a white foam, MS (ESI+): m/z=490.0 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:3]=1[C:4](=O)[CH2:5]Cl.[CH2:13]([NH:15][C:16](=[S:19])[NH:17][NH2:18])[CH3:14]>CO>[ClH:1].[Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:3]=1[C:4]1[CH2:5][S:19][C:16]([NH:15][CH2:13][CH3:14])=[N:17][N:18]=1
Reactant: CCNC(=S)NN
Reactant: O=C(CCl)c1ccc(Cl)cc1Cl
Solvent: CO
Product: CCNC1=NN=C(c2ccc(Cl)cc2Cl)CS1
Product: Cl
Yield: 100.1 %

Procedure:
Utilizing the reaction conditions of Example 2, 9.3 g (0.04 mole) of 2,4-dichlorophenacyl chloride and 4.77 g (0.04 mole) of 4-ethylthiosemicarbazide are reacted in 200 ml of methanol to produce 6.5 g of 5-(2,4-dichlorophenyl)-N-ethyl-6H-1,3,4-thiadiazin-2-amine monohydrochloride after recrystallization which, in this case, was from methanol/ethyl acetate. m.p. 197°-198° C.
Reaction SMILES: O1CCCC1.[Cl:6][CH2:7][CH2:8][CH2:9][S:10](Cl)(=[O:12])=[O:11].[NH2:14][CH:15]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(CC)CC)C>O>[CH:15]([NH:14][S:10]([CH2:9][CH2:8][CH2:7][Cl:6])(=[O:12])=[O:11])([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=S(=O)(Cl)CCCCl
Reactant: NC(c1ccccc1)c1ccccc1
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=S(=O)(CCCCl)NC(c1ccccc1)c1ccccc1
Temperature: 0 °C
Yield: 118.6 %

Procedure:
In a three-neck round bottom flask equipped with argon inlet was charged with anhydrous tetrahydrofuran and 3-chloropropane sulfonyl chloride (500 mg, 2.82 mmol, Aldrich). The flask was cooled down to 0° C., and aminodiphenylmethane (0.49 mL, 2.82 mmol, Fluka) was added, followed by triethylamine (0.59 mL, 4.23 mmol). The reaction mixture was stirred at 0° C. and monitored by the thin layer chromatography. Upon completion, water was added the reaction mixture. It was concentrated then diluted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated to give 3-chloro-propane-1-sulfonic acid benzhydryl-amide (1.083 g, light brown solid). The crude product was used without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][CH:10]=[CH:11][C:12]=2[C:13]#[N:14])=[CH:4][CH:3]=1.[Br:15]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[C:13]([C:12]1[CH:11]=[CH:10][S:9][C:8]=1[C:5]1[CH:4]=[CH:3][C:2]([CH2:1][Br:15])=[CH:7][CH:6]=1)#[N:14]
Reactant: Cc1ccc(-c2sccc2C#N)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1ccsc1-c1ccc(CBr)cc1
Reaction time: 24 h
Yield: 40.9 %

Procedure:
24.5 g of 2-(4-methylphenyl)-3-cyanothiophene, prepared in E), are dissolved in 200 ml of carbon tetrachloride. 21.9 g of N-bromosuccinimide are added, as well as 0.1 g of benzoyl peroxide. The mixture is heated to reflux for 24 hours. The crystals of succinimide are filtered off and the solvent is evaporated off under vacuum. The residue is taken up in a mixture of hexane and ethyl acetate and the solution is kept in a freezer for 24 hours. The crystals formed are drained to give 14 g of 4-(3-cyano-2-thienyl)benzyl bromide in the form of crystals of melting point 80° C.
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([SH:16])=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].C(=O)([O-])[O-].[K+].[K+].Cl[C:26]1[N:31]=[CH:30][CH:29]=[CH:28][N:27]=1.CN(C)C=O>C(OCC)(=O)C>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([S:16][C:26]4[N:31]=[CH:30][CH:29]=[CH:28][N:27]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: Clc1ncccn1
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(S)cc3CC[C@@H]12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN1C(=O)CC[C@]2(C)c3ccc(Sc4ncccn4)cc3CC[C@@H]12
Yield: 23.3 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-mercapto-10b-methyl-1,2,3,4,4a,-5,6,10b-octahydrobenzo[f]quinolin-3-one (100 mg, 0.38 mmol), potassium carbonate (158 mg, 1.14 mmol), 2-chloropyrimidine (53 mg, 0.46 mmol) and 1 mL of anhydrous dimethylformamide, fitted with a reflux condenser, and the stirred mixture was heated at 60°, under nitrogen, for 18 h. The mixture was cooled, diluted with ethyl acetate (75 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (ethyl acetate eluent) to give 30 mg (23%) of the title compound as an oil. FDMS: m/e=339.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[N:10]=[C:9]([S:11][CH2:12][CH2:13][NH:14][C:15](SC)=[CH:16][N+:17]([O-:19])=[O:18])[CH:8]=[CH:7][CH:6]=1)[CH3:3].[CH3:22][NH2:23]>C(O)C>[CH3:1][N:2]([CH2:4][C:5]1[N:10]=[C:9]([S:11][CH2:12][CH2:13][NH:14][C:15]([NH:23][CH3:22])=[CH:16][N+:17]([O-:19])=[O:18])[CH:8]=[CH:7][CH:6]=1)[CH3:3]
Reactant: CSC(=C[N+](=O)[O-])NCCSc1cccc(CN(C)C)n1
Reactant: CN
Solvent: CCO
Product: CNC(=C[N+](=O)[O-])NCCSc1cccc(CN(C)C)n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
1-[2-(6-Dimethylaminomethyl-2-pyridylthio)ethylamino]-1-methylthio-2-nitroethene (0.45 g, 0.0014 mol) is added to ethanol (8 ml) saturated with monomethylamine gas at ice bath temperature and is allowed to stir at ambient temperature for 18 hours. Evaporation of the solvent yielded a glassy product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([Mg]Br)=[CH:5][CH:4]=1.[Mg].[Br-].[CH3:13][O:14]C1C=CC=CC=1.[C:21]1([Mg]Br)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1COCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:13]([OH:14])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc([Mg]Br)cc1
Reactant: Br[Mg]c1ccccc1
Reactant: COc1ccccc1
Agent: [Br-]
Agent: [Mg]
Solvent: C1CCOC1
Product: COc1ccc([C@@H](O)c2ccccc2)cc1

Procedure:
An operation was carried out in the same manner as in Example 14, except that 0.22 mL (0.375 mmol) of 4-methoxyphenylmagnesium bromide (1.7 mol/L) prepared from magnesium and 4-methoxybenzene bromide was used instead of the anhydrous THF solution of phenylmagnesium bromide. Thus, (S)-4-methoxybenzhydrol was obtained. The conversion rate of the raw material was 98%, while the enantiomeric excess was 92% ee.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[C:11]2[C:16]3=[C:17]([C@@H:19]4[CH2:24][NH:23][CH2:22][CH2:21][C@@H:20]4[N:15]3[CH2:14][CH2:13][CH2:12]2)[CH:18]=1.Br[CH2:26][CH2:27][CH2:28][CH:29]=[CH2:30].N>>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[C:11]2[C:16]3=[C:17]([C@@H:19]4[CH2:24][N:23]([CH2:30][CH2:29][CH2:28][CH:27]=[CH2:26])[CH2:22][CH2:21][C@@H:20]4[N:15]3[CH2:14][CH2:13][CH2:12]2)[CH:18]=1
Reactant: C=CCCCBr
Reactant: Clc1cccc(-c2cc3c4c(c2)[C@@H]2CNCC[C@@H]2N4CCC3)c1Cl
Agent: N
Product: C=CCCCN1CC[C@H]2[C@@H](C1)c1cc(-c3cccc(Cl)c3Cl)cc3c1N2CCC3

Procedure:
The title compound was prepared by the method of Example 382 as a yellow oil (22 mg, 62%) from (7aS,11aR)-2-(2,3-dichlorophenyl)-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3′,4′:4,5]pyrrolo[3,2,1-ij]quinoline (30 mg, 0.083 mmol) and 5-bromo-1-pentene (25 mg, 0.17 mmol). 1H NMR (CDCl3, 300 MHz) δ1.62-1.75 (br, 2H), 2.01-2.22 (m, 7H), 2.35-2.53 (br, 3H), 2.58-2.65 (m, 1H), 2.74 (t, J=6.6 Hz, 2H), 2.75-2.85 (br, 1H), 2.88-3.05 (br, 1H), 3.28-3.41 (m, 3H), 4.97 (d, J=13.5 Hz, 1H), 5.02 (dd, J=17.6, 1.5 Hz, 1H), 5.73-5.83 (m, 1H), 6.93 (s, 1H), 6.98 (s, 1H), 7.15-7.21 (m, 2H), 7.36-7.40 (m, 1H) ppm. MS (CI, NH3): 427.1 (base, M+H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8]3=[C:9]([CH2:11][CH2:12][N:7]3[C@H:6]3[CH2:13][CH2:14][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][C@@H:5]23)[CH:10]=1.[CH:24]([C:26]1[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:27]=1B(O)O)=[O:25].O.O.O.O.O.O.O.O.[OH-].[Ba+2].[OH-]>COCCOC.O.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>[CH:24]([C:26]1[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:27]=1[C:2]1[CH:3]=[C:4]2[C:8]3=[C:9]([CH2:11][CH2:12][N:7]3[C@H:6]3[CH2:13][CH2:14][N:15]([C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[CH2:16][C@@H:5]23)[CH:10]=1)=[O:25]
Reactant: CC(C)(C)OC(=O)N1CC[C@H]2[C@@H](C1)c1cc(Br)cc3c1N2CC3
Reactant: COc1ccc(B(O)O)c(C=O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Ba+2]
Agent: [OH-]
Solvent: O
Solvent: COCCOC
Product: COc1ccc(-c2cc3c4c(c2)[C@@H]2CN(C(=O)OC(C)(C)C)CC[C@@H]2N4CC3)c(C=O)c1
Yield: 40.5 %

Procedure:
To a solution of tert-butyl(6aS,10aR)-2-bromo-4,5,7,8,10,10a-hexahydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH)-carboxylate (0.600 g, 1.59 mmol) in DME (35 mL) was added 2-formyl-4-methoxybenzeneboronic acid (0.344 g, 1.91 mmol), tetrakis(triphenylphosphine)palladium(0) (0.110 g), barium hydroxide octahydrate (0.753 g, 2.39 mmol), and H2O (10 mL). The combined mixture was refluxed for 20 h. Once at room temperature, the mixture was taken up in H2O (300 mL) and extracted with EtOAc (3×100 mL). The combined extracts were dried over MgSO4 and stripped of solvent under reduced pressure. Purification by normal phase HPLC using 25% EtOAc in hexanes afforded 0.280 g (41%) of tert-butyl (6aS,10aR)-2-(2-formyl-4-methoxyphenyl)-4,5,7,8,10,10a-hexahydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH)-carboxylate.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([C:15]([N:17]1[CH2:23][CH2:22][CH2:21][N:20]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:19][CH2:18]1)=[O:16])=[CH:10][CH:9]=2)=[O:5])[CH3:2].[CH:31](CS([O-])(=O)=O)([CH3:33])[CH3:32]>>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH:31]([CH3:33])[CH3:32])[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([C:15]([N:17]1[CH2:23][CH2:22][CH2:21][N:20]([C:24]([O:26][C:27]([CH3:29])([CH3:28])[CH3:30])=[O:25])[CH2:19][CH2:18]1)=[O:16])=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2cc(C(=O)N3CCCN(C(=O)OC(C)(C)C)CC3)ccc2[nH]1
Reactant: CC(C)CS(=O)(=O)[O-]
Product: CCOC(=O)c1cc2cc(C(=O)N3CCCN(C(=O)OC(C)(C)C)CC3)ccc2n1C(C)C

Procedure:
The title compound was synthesized in analogy to example 239, Intermediate a), from 5-(4-tert-butoxycarbonyl-[1,4]diazepane-1-carbonyl)-1H-indole-2-carboxylic acid ethyl ester and isopropylmethanesulfonate, to afford the product as a yellow oil (62%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9](=[O:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[CH:6][C:7]=1[F:8]>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[F:8])[C:9]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[C:7]([F:8])[CH:6]=1)([OH:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)C(=O)c1ccc(F)c(F)c1
Solvent: C1CCOC1
Product: CCOC(=O)C(O)(c1ccc(F)c(F)c1)c1ccc(F)c(F)c1
Temperature: 5 °C
Reaction time: 2 h

Procedure:
The Grignard reagent is prepared from 2.24 g (0.092 mol) of magnesium chips, a few granules of iodine, and 17.80 g (0.092 mol) of 1-bromo-3,4-difluorobenzene in 100 ml of THF at 50° C. After the halide has all been added, the mixture is stirred for another hour. The Grignard reagent thus obtained is added dropwise to 18.81 g (0.088 mol) of ethyl 3,4-difluorophenylglyoxylate in 80 ml of THF at 10° C.-15° C. and the mixture obtained is stirred for 2 hours at 5° C. The white suspension is poured onto ice/sulfuric acid for working up, extracted with ethyl acetate, the organic phase is washed with water, dried over MgSO4 and evaporated to dryness. The crude product is purified by column chromatography (eluant: toluene). Yield: 10.80 g (38% of theory).