Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([C:16]2[N:17]=[N:18][N:19]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)[CH:20]=2)[OH:15])=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:40]2[CH:45]=[CH:44][C:43]([C:46]3([C:49]([NH:51][S:52]([CH3:55])(=[O:54])=[O:53])=[O:50])[CH2:48][CH2:47]3)=[CH:42][CH:41]=2)O1>>[OH:15][CH:14]([C:16]1[N:17]=[N:18][N:19]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=2)[CH:20]=1)[C:9]1[C:10]([CH3:13])=[N:11][O:12][C:8]=1[C:5]1[CH:6]=[CH:7][C:2]([C:40]2[CH:41]=[CH:42][C:43]([C:46]3([C:49]([NH:51][S:52]([CH3:55])(=[O:54])=[O:53])=[O:50])[CH2:48][CH2:47]3)=[CH:44][CH:45]=2)=[CH:3][CH:4]=1
Reactant: CC1(C)OB(c2ccc(C3(C(=O)NS(C)(=O)=O)CC3)cc2)OC1(C)C
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(O)c1cn(Cc2cccc(C(F)(F)F)c2)nn1
Product: Cc1noc(-c2ccc(-c3ccc(C4(C(=O)NS(C)(=O)=O)CC4)cc3)cc2)c1C(O)c1cn(Cc2cccc(C(F)(F)F)c2)nn1

Procedure:
Prepared according to the procedure described in Example 166, Step 3, using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-[1-(3-trifluoromethyl-benzyl)-1H-[1,2,3]triazol-4-yl]-methanol and N-{1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarbonyl}-methanesulfonamide.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:13])[C@@H:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[NH2:6].[C:14](=O)([O-:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17].C(=O)([O-])[O:23]C(C)(C)C.C(N(CC)CC)C>O1CCCC1>[CH3:2][O:3][C:4](=[O:13])[C@H:5]([NH:6][C:14]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:20])[C:7]1[CH:12]=[CH:11][C:10]([OH:23])=[CH:9][CH:8]=1
Reactant: CC(C)(C)OC(=O)[O-]
Reactant: COC(=O)[C@H](N)c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)[C@H](NC(=O)OC(C)(C)C)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(R)-(−)-2-phenylglycine methyl ester hydrochloride (2.17 g, 10 mmol) and di-t-butyl di-carbonate (2.62 g, 12 mmol) were combined in tetrahydrofuran (100 ml). Triethylamine (1.60 ml, 22 mmol) was added to the mixture via syringe at room temperature. The reaction mixture was stirred at room temperature overnight. The THF in reaction mixture was then removed in vacuum. Saturated aqueous NH4Cl and ethyl acetate were added to the mixture in a separatory funnel. The aqueous layer was extracted with ethyl acetate (3×40 ml). The combined organic layer was washed with saturated aqueous NH4Cl, dried over MgSO4, filtered and concentrated to give a white solid (3.08 g, crude product): 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.20 (d, J=8.1 Hz, 2H), 6.77 (m, 2H), 5.73 (br. s., 1H), 5.56 (br. s., 1H), 5.25 (d, J=6.6 Hz, 1H), 3.73 (s, 3H), 1.46 (s, 9H) LCMS (ESI) m/e 282.1 [(M+H)+, calcd for C14H20NO5 282.3].
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1)#[N:2].[ClH:9].[CH:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1)=[CH2:11]>C(O)(C)C>[ClH:9].[Cl-:9].[N:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[CH2:10][CH2:11][N+:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1
Reactant: N#Cc1ccncc1
Reactant: C=Cc1ccccn1
Agent: Cl
Solvent: CC(C)O
Product: N#Cc1cc[n+](CCc2ccccn2)cc1
Product: [Cl-]
Temperature: 25 °C

Procedure:
To 166.4 parts of 4-cyanopyridine in 500 cc of isopropanol was added 170 parts of a 15.9% solution of hydrogen chloride in isopropanol. To this was added 292 parts of 2-vinylpyridine in 500 cc of isopropanol, and the resulting mixture heated to reflux for 5.5 hours. The reaction was cooled to 25° C. and 261 parts of 1-[2-(2-pyridyl)ethyl]-4-cyanopyridinium chloride hydrochloride isolated on filtration.
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH3:10])=[CH:6][C:5]([O:11][CH3:12])=[C:4]([O:13][CH3:14])[CH:3]=1.[CH2:15](Br)[C:16]#[CH:17].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.CC(C)=O>[CH2:17]([O:1][C:2]1[C:7]([CH2:8][CH2:9][CH3:10])=[CH:6][C:5]([O:11][CH3:12])=[C:4]([O:13][CH3:14])[CH:3]=1)[C:16]#[CH:15]
Reactant: C#CCBr
Reactant: CCCc1cc(OC)c(OC)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CC(C)=O
Product: C#CCOc1cc(OC)c(OC)cc1CCC

Procedure:
Following the same procedure as in Example 3 b), 3.92 g (0.02 moles) of 1-hydroxy-6-propyl-3,4-dimethoxybenzene were reacted with 3.0 g (0.02 moles) of a solution of propargyl bromide in toluene (80% w/w) and 2.8 g (0.02 moles) of anhydrous potassium carbonate in 20 ml of acetone.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][NH2:9])=[CH:4][CH:3]=1.[Br:10][C:11]1[CH:12]=[CH:13][C:14]([F:19])=[C:15]([CH:18]=1)[CH:16]=O.CCO>O>[Br:10][C:11]1[CH:12]=[CH:13][C:14]([F:19])=[C:15](/[CH:16]=[N:9]/[NH:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH:18]=1
Reactant: NNc1ccc(F)cc1
Reactant: O=Cc1cc(Br)ccc1F
Solvent: CCO
Solvent: O
Product: Fc1ccc(N/N=C/c2cc(Br)ccc2F)cc1
Temperature: 90 °C
Reaction time: 2 h
Yield: 96.7 %

Procedure:
A 1000 mL round bottom flask was charged with 20.0 g (123 mmol) of 4-fluorophenylhydrazine and 28.4 g (140 mmol) of 5-bromo-2-fluorobenzaldehyde and 400 mL of EtOH and warmed at 90° C. After 2 hours, the mixture was cooled to room temperature and then diluted with 200 mL of water and filtered. The solid were then dissolved in EtOAc and washed with brine. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was passed through a pad of silica gel to afford 37 g (97%) of N-[1-(5-bromo-2-fluorophenyl)meth-(E)-ylidene]-N′-(4-fluorophenyl)hydrazine. MS m/z 312.11 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][N:9]=[CH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.[CH:17](O)=[O:18].C(OC(=O)C)(=O)C>COCCOC>[CH:17]([N:8]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)[N:9]=[CH:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:18]
Reactant: Clc1ccc(NN=Cc2ccccc2)cc1
Reactant: O=CO
Solvent: COCCOC
Solvent: CC(=O)OC(C)=O
Product: O=CN(N=Cc1ccccc1)c1ccc(Cl)cc1
Reaction time: 4 h

Procedure:
6.91 g of 1A was dissolved in 37.5 ml of dry 1,2-dimethoxyethane and treated with 4.5 g of distilled mixed anhydride of formic acid and acetic acid prepared by mixing the appropriate amount of formic acid and acetic anhydride. The resulting mixture was left for 4 hours at room temperature and then heated up to boiling point and excess solvent removed in vacuo. The residue was triturated with 5% sodium bicarbonate solution, dried and crystallized from methanol to give 1, mp 122°-123° C.
Reaction SMILES: [Li+].[OH-].C[O:4][C:5]([C:7]1[C:8]([CH3:17])=[C:9]2[N:14]([CH:15]=1)[N:13]=[CH:12][NH:11][C:10]2=[O:16])=[O:6]>O.C1COCC1.CO>[CH3:17][C:8]1[C:7]([C:5]([OH:6])=[O:4])=[CH:15][N:14]2[C:9]=1[C:10](=[O:16])[NH:11][CH:12]=[N:13]2
Reactant: COC(=O)c1cn2nc[nH]c(=O)c2c1C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1c(C(=O)O)cn2nc[nH]c(=O)c12
Temperature: 65 °C
Yield: 90.6 %

Procedure:
A solution of LiOH (25 gm, 10 equiv) in water (416 mL) was added to a solution of 5-methyl-4-oxo-3,4-dihydro-pyrrolo[2,1-f][1,2,4]triazine-6-carboxylic acid methyl ester (23.0 gm, 0.104 mol) in a mixture of THF (1.2 L) and MeOH (0.4 L). This was heated at 65° C. for 20 h and then concentrated in vacuo to about 200 mL. Water (400 mL) was added and the pH was adjusted to 4 using conc. aqueous HCl. The precipitate was collected, washed with water, and dried to give the acid (18.2 gm, 90%). 1H NMR (MeOH-D4) δ 2.67 (s, 3H), 7.63 (s, 1H), 7.84 (s, 1H). HPLC Ret Time: 0.97 min (YMC C18 S5, 4.6×50 mm column, 3 min gradient, 4 mL/min).
Reaction SMILES: [OH:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[O:14][CH3:15].[Cl:16][C:17]1[N:26]=[C:25]([CH3:27])[C:24]([Cl:28])=[C:23]([CH3:29])[C:18]=1/[C:19](=[N:21]/O)/[NH2:20].N1C=CC=CC=1.Cl>S(Cl)(Cl)=O>[Cl:16][C:17]1[C:18]([C:19]2[N:20]=[C:6]([C:5]3[CH:9]=[C:10]([N+:11]([O-:13])=[O:12])[C:2]([OH:1])=[C:3]([O:14][CH3:15])[CH:4]=3)[O:8][N:21]=2)=[C:23]([CH3:29])[C:24]([Cl:28])=[C:25]([CH3:27])[N:26]=1
Reactant: Cc1nc(Cl)c(/C(N)=N/O)c(C)c1Cl
Reactant: COc1cc(C(=O)O)cc([N+](=O)[O-])c1O
Agent: Cl
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: COc1cc(-c2nc(-c3c(Cl)nc(C)c(Cl)c3C)no2)cc([N+](=O)[O-])c1O
Temperature: 80 °C
Yield: 62.7 %

Procedure:
A stirred suspension of 4-hydroxy-3-methoxy-5-nitrobenzoic acid (2.00 g, 9.38 mmol) in thionyl chloride (8.2 mL) was heated at 80° C. for two hours. The excess of thionyl chloride was removed under vacuum. The resulting yellow solid was dissolved in DMA (15.4 mL), then (Z)-2,5-dichloro-N′-hydroxy-4,6-dimethylnicotinimidamide (2.636 g, 11.26 mmol) and pyridine (6.2 mL) were added. The red solution was heated to 120° C. for 2.5 hours. The reaction mixture was cooled to room temperature and poured into a mixture of cc HCl (10 ml) and ice (80 g), then stirred for thirty minutes. The yellow precipitate was filtered off, washed with water and dried under vacuum. Recrystallization from dichloromethane-isopropanol mixture afforded 2.42 g (62%) of 4-(3-(2,5-dichloro-4,6-dimethylpyridin-3-yl)-1,2,4-oxadiazol-5-yl)-2-methoxy-6-nitrophenol as yellow crystalline.
Reaction SMILES: [CH2:1]([C@@H:3]1[CH2:24][O:23][C:6]2=[C:7]3[C:12](=[CH:13][CH:14]=[C:5]2[NH:4]1)[N:11]=[C:10]([O:15][CH:16]([CH3:18])[CH3:17])[CH:9]=[C:8]3[C:19]([F:22])([F:21])[F:20])[CH3:2].[BH3-]C#N.[Na+].C(O[CH:32](O)[C:33]([F:36])([F:35])[F:34])C>C(O)(C(F)(F)F)=O>[CH2:1]([C@@H:3]1[CH2:24][O:23][C:6]2=[C:7]3[C:12](=[CH:13][CH:14]=[C:5]2[N:4]1[CH2:32][C:33]([F:36])([F:35])[F:34])[N:11]=[C:10]([O:15][CH:16]([CH3:18])[CH3:17])[CH:9]=[C:8]3[C:19]([F:21])([F:22])[F:20])[CH3:2]
Reactant: CC[C@@H]1COc2c(ccc3nc(OC(C)C)cc(C(F)(F)F)c23)N1
Reactant: CCOC(O)C(F)(F)F
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: CC[C@@H]1COc2c(ccc3nc(OC(C)C)cc(C(F)(F)F)c23)N1CC(F)(F)F
Yield: 167.7 %

Procedure:
This compound was prepared according to General Method 5 (EXAMPLE 2) from (3R)-3-ethyl-3,4-dihydro-8-isopropoxy-10-(trifluoromethyl)-2H-[1,4]oxazino[2,3-f]quinoline (0.008 g, 0.024 mmol), NaCNBH3 (0.007 g, 0.118 mmol) and trifluoroacetaldehyde ethyl hemiacetal (0.028 mL, 0.235 mmol) in TFA (0.8 mL) to afford 0.017 g of (3R)-3-ethyl-3,4-dihydro-8-isopropoxy-4-(2,2,2-trifluoroethyl)-10-(trifluoromethyl)-2H-[1,4]oxazino[2,3-f]quinoline, a brown-red solid. This material (0.017 g) was carried on according to General Method 4 (EXAMPLE 1) by treatment with conc. HCl (0.3 mL) in AcOH (0.6 mL) and heated at 95° C. for 2 h to afford 0.006 g (67% for the 2 steps) of Compound 110, a yellow solid. Rf0.4 (9:1 CH2Cl2;MeOH); 1H NMR (400 MHz, CDCl3) δ 12.47 (broad s, 1H), 7.15 (s, 1H), 7.14 (d, 1H, J=8.9), 7.02 (d, 1H, J=8.9), 4.38 (d, 1H, J=10.9), 3.98 (dd, 1H, J=10.8, 2.4) 3.93–3.65 (m, 2H), 3.27–3.22 (m, 1H), 1.68–1.51 (m, 2H), 0.98 (t, 3H, J=7.5).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][C:5]=1[C:6](Cl)=[O:7])([O-:3])=[O:2].[CH:17]1([C:20]([N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])=[CH2:21])[CH2:19][CH2:18]1.C(N(CC)CC)C.C>C1(C)C=CC=CC=1>[CH:17]1([C:20]([N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])=[CH:21][C:6]([C:5]2[CH:9]=[CH:10][C:11]([C:13]([F:16])([F:15])[F:14])=[CH:12][C:4]=2[N+:1]([O-:3])=[O:2])=[O:7])[CH2:19][CH2:18]1
Reactant: C=C(C1CC1)N(CC)CC
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCN(CC)C(=CC(=O)c1ccc(C(F)(F)F)cc1[N+](=O)[O-])C1CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 31.4 %

Procedure:
2-nitro-4-trifluoromethylbenzoyl chloride (9.4 g) was added dropwise to a cooled mixture of 1-cyclopropyl-1-diethylaminoethene (5.1 g) and triethylamine (3.7 g) in toluene (100 ml) whilst maintaining the temperature below 10° C. The mixture was then stirred at room temperature for 1 hour. The suspension was treated with decolourising charcoal and filtered. The filtrate was evaporated and the residue was purified by chromatography on silica gel eluted with a mixture of ethyl acetate and dichloromethane (1:9) to give 3-cyclopropyl-3-diethylamino-1-(2-nitro-4-trifluoromethylphenyl)-prop-2-en-1-one (4.1 g) as a red oil with its 1H NMR (in CDCl3) giving peaks at d=0.7-1.8(m, 11H), 3.5(q, 4H), 5.0(s, 1H), 7.5(d, 1H), 7.7(d, 1H),and 7.95(s, 1H).
Reaction SMILES: C[O:2][C:3](=[O:32])[CH2:4][CH:5]1[C:9]2=[C:10]([S:24][C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)[C:11]3[C:12]([CH:21]([CH3:23])[CH3:22])=[CH:13][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:15][C:16]=3[N:8]2[CH2:7][CH2:6]1.[Li+].[OH-].CC(O)=O>C1COCC1.CO>[Cl:31][C:28]1[CH:29]=[CH:30][C:25]([S:24][C:10]2[C:11]3[C:12]([CH:21]([CH3:23])[CH3:22])=[CH:13][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:15][C:16]=3[N:8]3[CH2:7][CH2:6][CH:5]([CH2:4][C:3]([OH:32])=[O:2])[C:9]=23)=[CH:26][CH:27]=1
Reactant: COC(=O)CC1CCn2c1c(Sc1ccc(Cl)cc1)c1c(C(C)C)cc(S(C)(=O)=O)cc12
Agent: [Li+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)c1cc(S(C)(=O)=O)cc2c1c(Sc1ccc(Cl)cc1)c1n2CCC1CC(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.5 %

Procedure:
To a solution of the ester of Step 4 (140 mg) in THF/MeOH (3/1) mixture at r.t. was added 1 M LiOH (aqueous solution). The reaction mixture was stirred at r.t. for 2 hours and AcOH was added and the solvent was evaporated. The residue was taken up in EtOAc/H2O and the organic phase was washed with brine, dried (MgSO4), filtered and evaporated. The residue was purified by silica gel chromatography eluting with 1% AcOH in EtOAc to give 100 mg of the title compound.
Reaction SMILES: [C:1]1([O:7][CH3:8])[CH:6]=[CH:5]C=[CH:3][CH:2]=1.[Br:9]Br.[C:11]([Cl:15])(Cl)(Cl)Cl>[Fe]>[Br:9][C:2]1[CH:3]=[C:11]([Cl:15])[CH:5]=[CH:6][C:1]=1[O:7][CH3:8]
Reactant: COc1ccccc1
Reactant: BrBr
Reactant: ClC(Cl)(Cl)Cl
Agent: [Fe]
Product: COc1ccc(Cl)cc1Br

Procedure:
Anisole (10 g, 70.1 mmol) was dissolved in carbon tetrachloride (200 ml) and iron powder (6.0 g, 105 mmol Fe)was added. Bromine (4 ml, 77.1 mmol) was added at 0° C. The temperature was allowed rise to room temperature over one hour. Washing with aqueous sodium sulfite three times was followed by washing with aqueous sodium hydroxide (4 M). Drying over magnesium sulfate and evaporation gave the title compound. Yield 5.63 g, 36%.
Reaction SMILES: [N+:1]([CH:4]=[C:5](SC)[NH:6][CH2:7][CH2:8][S:9][CH2:10][C:11]1[CH:15]=[CH:14][O:13][N:12]=1)([O-:3])=[O:2].[CH2:18]([NH2:20])[CH3:19]>>[N+:1]([CH:4]=[C:5]([NH:20][CH2:18][CH3:19])[NH:6][CH2:7][CH2:8][S:9][CH2:10][C:11]1[CH:15]=[CH:14][O:13][N:12]=1)([O-:3])=[O:2]
Reactant: CSC(=C[N+](=O)[O-])NCCSCc1ccon1
Reactant: CCN
Product: CCNC(=C[N+](=O)[O-])NCCSCc1ccon1

Procedure:
Reaction of 1-nitro-2-methylthio-2-[2-(3-isoxazolylmethylthio)ethylamino]ethylene (see Example 31 (ii)) with ethylamine by the procedure of Example 8(ii) gives the title product.
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][C@@H:13]2[C@H:9]1[CH2:10][CH2:11][NH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1.CC(C)([O-])C.[Na+]>>[CH2:1]([N:8]1[CH2:14][C@@H:13]2[C@H:9]1[CH2:10][CH2:11][N:12]2[C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(CN2C[C@H]3NCC[C@H]32)cc1
Reactant: Brc1cccnc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Product: c1ccc(CN2C[C@@H]3[C@H]2CCN3c2cccnc2)cc1
Yield: 98 %

Procedure:
The product from Example 18E (260 mg, 1.0 mmol) and 3-bromopyridine were processed as described in Example 1E, except that a larger amount of sodium tert-butoxide (384 mg, 4.0 mmol) was used to neutralize the salt. The crude product was purified by chromatography (SiO2, CH2Cl2:MeOH, 95:5, Rf 0.3) to provide the title compound (0.26 g, 98% yield). 1H NMR (CD3OD, 300 MHz) δ 2.40 (m, 2H), 3.20 (m, 2H), 3.503.80 (m, 4H), 4.10 (m, 1H), 4.50 (m, 1H), 7.00-7.60 (m, 9H); MS (DCI/NH3) m/z 266 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([S:9][C:10]2[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=2)[C:13](O)=[O:14])=[N:7][CH:8]=1)#[N:2].[BH4-].[Na+].O>S(Cl)(Cl)=O.O1CCOCC1>[OH:14][CH2:13][C:12]1[CH:11]=[C:10]([S:9][C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][N:7]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: N#Cc1ccc(Sc2cccc(C(=O)O)c2)nc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Solvent: O=S(Cl)Cl
Product: N#Cc1ccc(Sc2cccc(CO)c2)nc1
Temperature: 50 °C
Reaction time: 2 h
Yield: 56.7 %

Procedure:
Dissolve 3-(5-cyano-pyridin-2-ylsulfanyl)-benzoic acid (1.25 g, 4.88 mmol) in thionyl chloride (50 mL) and stir. Heat to reflux. After 2 hours, concentrate under reduced pressure to give a residue. Dissolve residue in dioxane (100 mL) and add sodium borohydride (1.85 g, 48.8 mmol). Heat to 50° C. After 2 hours, cool to ambient temperature and add water. Extract with ethyl acetate, combine organic layers, dry with sodium sulfate, filter and concentrate to give the title compound as a yellow oil (670 mg, 57%): 1H NMR (DMSO-d6) δ 4.56 (d, 2H), 5.33 (t, 1H), 7.06 (d, 1H), 7.49 (m, 3H), 7.57 (m, 1H), 8.08 (dd, 1H), 8.82 (dd, 1H).
Reaction SMILES: [CH3:1][CH2:2][O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][OH:9].O=[C:11]1O[C@H:16]([C@H:18]([CH2:20]O)[OH:19])[C:14](O)=[C:12]1O>CS(C)=O>[CH3:1][CH2:2][O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][OH:9].[CH:11]1[C:12]([C@H:4]2[CH2:5][O:6][C:7]3[CH:8]=[C:18]([OH:19])[CH:16]=[CH:14][C:12]=3[CH2:11]2)=[CH:14][CH:16]=[C:18]([OH:19])[CH:20]=1
Reactant: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Solvent: CS(C)=O
Solvent: CCOCCOCCO
Product: Oc1ccc([C@H]2COc3cc(O)ccc3C2)cc1
Temperature: 37 °C

Procedure:
Approximately 20 to 40 mg of the test material was weighed into pre-tared sterile glass vials and the precise weight was recorded. Vehicle volume was then calculated to give a 50% w/v solution, and the vehicle was added. Two different vehicles were used, as indicated in Examples. DMSO vehicle was prepared from 100% DMSO (EMD Biosciences Cat. #MX1458-6, Lot #42364321). Transcutol vehicle was prepared from 100% transcutol (Gattefosse a.s.a., Cedex, France). Samples were then vortexed vigorously until the dry powder was visually brought into solution. In some cases, samples need to be briefly warmed to 37° C. Stock solution aliquots can be frozen in small aliquots and maintained at approximately −20° C., or used immediately after preparation. Racemic mixtures of equol were prepared for testing at concentrations of 0 (control), 0.3, 1.0, and 5.0%. A positive control was prepared using ascorbic acid at a concentration of 50 μg/ml in DMEM/F-12. After stock solutions were diluted for use they were then discarded.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:9]=[C:8]([S:10][CH3:11])[C:7]([S:12][CH3:13])=[CH:6][C:4]=1[NH2:5].[C:14](OC(=O)C)(=[O:16])[CH3:15]>>[C:14]([NH:5][C:4]1[CH:6]=[C:7]([S:12][CH3:13])[C:8]([S:10][CH3:11])=[CH:9][C:3]=1[S:2][CH3:1])(=[O:16])[CH3:15]
Reactant: CSc1cc(SC)c(SC)cc1N
Reactant: CC(=O)OC(C)=O
Product: CSc1cc(SC)c(SC)cc1NC(C)=O
Yield: 62 %

Procedure:
N-Acetyl 2,4,5 trimethylthioaniline was prepared by dissolving 2,4,5 trimethylthioaniline (33 g, 0.143 mol) in 200 mL of acetic anhydride at room temperature. Ligroin (800 mL) was added and the mixture was stirred and cooled until the product precipitated. The solid was collected and dried (24 g, 62% yield), mp 87-89° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].C([O-])([O-])=O.[Cs+].[Cs+].[Br-].[CH:19]1([CH3:22])[CH2:21][CH2:20]1.O>CN(C=O)C>[CH:19]1([CH2:22][O:8][C:5]2[CH:6]=[CH:7][C:2]([NH2:1])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=2)[CH2:21][CH2:20]1
Reactant: CC1CC1
Reactant: Nc1ccc(O)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ccc(OCC2CC2)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 91.5 %

Procedure:
4-Amino-3-nitrophenol (26.00 g, 165.5 mMol) was dissolved in 200 mL of anhydrous DMF under an atmosphere of dry N2. The reaction mixture was then cooled to 0° C. and to this mixture was added Cs2CO3 (64.7 g, 199 mMol), and cyclopropyl methane bromide (17.7 mL, 182 mMol). After stirring for 15 minutes, the reaction mixture was then warmed up to ambient temperature and then stirred overnight. The reaction mixture is then poured into 800 mL of water. The precipitate was collected via suction filtration and partitioned between DCM and aqueous 0.1 N NaOH. The DCM layer was saved and washed again aqueous 0.1 N NaOH, then with brine, dried over Na2SO4, filtered and concentrated under vacuum to give 31.52 g of 4-cyclopropylmethoxy-2-nitro-phenylamine 133A as an orange solid.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[C:5]([NH:16][CH2:17][CH2:18][NH:19][C:20](=[O:22])[CH3:21])=[N:6][C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([O:14][CH3:15])=[CH:9][CH:8]=2.[CH3:23][O:24][C:25]1[CH:26]=[C:27]2[C:32](=[CH:33][C:34]=1[O:35][CH3:36])[C:31]([CH2:37][CH2:38][CH3:39])=[N:30][C:29]([OH:40])=[CH:28]2.[Li+].[OH-]>C1COCC1.C(Cl)Cl>[OH:40][C:29]1[N:30]=[C:31]([CH2:37][CH2:38][CH3:39])[C:32]2[C:27]([C:28]=1[CH2:3][C:4]1[C:5]([NH:16][CH2:17][CH2:18][NH:19][C:20](=[O:22])[CH3:21])=[N:6][C:7]3[C:12]([CH:13]=1)=[CH:11][C:10]([O:14][CH3:15])=[CH:9][CH:8]=3)=[CH:26][C:25]([O:24][CH3:23])=[C:34]([O:35][CH3:36])[CH:33]=2
Reactant: COc1ccc2nc(NCCNC(C)=O)c(CCl)cc2c1
Reactant: CCCc1nc(O)cc2cc(OC)c(OC)cc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCCc1nc(O)c(Cc2cc3cc(OC)ccc3nc2NCCNC(C)=O)c2cc(OC)c(OC)cc12
Temperature: 150 °C
Reaction time: 1.5 h

Procedure:
To a stirred solution of N-(2-((3-(chloromethyl)-6-methoxyquinolin-2-yl)amino)ethyl)acetamide hydrochloride SLA 41090 (128 mg, 0.372 mmol) in THF (10 mL) in a 20 mL microwave vial equipped with a magnetic stirrer was added 6,7-dimethoxy-1-propylisoquinolin-3-ol RBO 35134 (103 mg, 0.417 mmol) followed by a 2 N aq. LiOH solution (0.21 mL, 0.42 mmol) and the mixture was stirred at 150° C. for 1.5 h under microwave irradiation. After cooling to RT, the mixture was diluted with CH2Cl2:MeOH=9:1 (150 mL) and washed with brine (20 mL), dried over Na2SO4, filtered and concentrated at 40° C. under vacuum. Purification by column chromatography (SiO2, eluent CH2Cl2:MeOH=100:0 to 92:8) provided 19.4 mg of N-(2-(3-((3-hydroxy-6,7-dimethoxy-1-propylisoquinolin-4-yl)methyl)-6-methoxyquinolin-2-ylamino)ethyl)acetamide. This free base was dissolved in CH2Cl2 (2 mL) in a 10 mL round-bottomed flask equipped with a magnetic stirrer before addition of a 0.49 M HCl solution in MeOH (1.0 mL). The reaction mixture was stirred for 5 min at RT then concentrated at 40° C. under vacuum to afforded N-(2-((3-((3-hydroxy-6,7-dimethoxy-1-propylisoquinolin-4-yl)methyl)-6-methoxyquinolin-2-yl)amino)ethyl)acetamide dihydrochloride 55 as a yellow solid (20 mg, 9% yield).
Reaction SMILES: [CH3:1][CH:2]([S:4]([CH2:7][C:8]1[CH:9]=[C:10]([NH:14]C(=O)C)[CH:11]=[CH:12][CH:13]=1)(=[O:6])=[O:5])[CH3:3].[ClH:18].C(O)C.C(OCC)(=O)C>C(O)C>[Cl-:18].[CH3:3][CH:2]([S:4]([CH2:7][C:8]1[CH:9]=[C:10]([CH:11]=[CH:12][CH:13]=1)[NH3+:14])(=[O:6])=[O:5])[CH3:1]
Reactant: Cl
Reactant: CC(=O)Nc1cccc(CS(=O)(=O)C(C)C)c1
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(C)S(=O)(=O)Cc1cccc([NH3+])c1
Product: [Cl-]

Procedure:
A solution of N-{3-[(propan-2-ylsulfonyl)methyl]phenyl}acetamide (5.4 g) in ethanol (29.6 mL) was treated with concentrated hydrochloric acid (35.5 mL) and refluxed for 24 hours. The reaction mixture was condensed to dryness. The title compound (3.5 g) was obtained by crystallization from ethanol/ethyl acetate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[O:13][C:12]2[CH:14]=[C:15]([F:21])[C:16]([C:18](O)=[O:19])=[CH:17][C:11]=2[O:10]1.[C:29](C1NC=CN=1)([C:31]1[NH:32][CH:33]=CN=1)=O.C(NC)C>CN(C)C=O>[CH2:31]([N:32]([CH3:33])[C:18]([C:16]1[C:15]([F:21])=[CH:14][C:12]2[O:13][C:9]([C:3]3[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=3[Cl:1])([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[O:10][C:11]=2[CH:17]=1)=[O:19])[CH3:29]
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Reactant: O=C(O)c1cc2c(cc1F)OC(c1ccc(F)cc1)(c1ccc(Cl)cc1Cl)O2
Agent: CCNC
Solvent: CN(C)C=O
Product: CCN(C)C(=O)c1cc2c(cc1F)OC(c1ccc(F)cc1)(c1ccc(Cl)cc1Cl)O2
Temperature: 20 °C
Reaction time: 2 h

Procedure:
To a solution of [2-(2,4-dichloro-phenyl)-6-fluoro-2-(4-fluoro-phenyl)-benzo[1,3]dioxole-5-carboxylic acid (Example 108d, 220 mg; 0.52 mmol; 1 eq.) in N,N-dimethylformamide (5 mL), was added carbonyl diimidazole (110 mg; 0.68 mmol; 1.3 eq.) and the mixture stirred 2 h at 20° C. A solution of ethyl-methylamine in N,N-dimethylformamide (1M, 1 mL; 1.3 mmol; 2.5 eq.) was added and the reaction mixture stirred 4 days at 20° C. Purification by preparative HPLC (YMC pro C18) afforded the title compound as 10 mM DMSO stock solution.