Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.Cl.[F:9][C:10]1[CH:15]=[C:14]([S:16]([CH3:19])(=[O:18])=[O:17])[CH:13]=[CH:12][C:11]=1[NH:20][C:21]1[C:22]2[O:29][CH:28]=[C:27]([CH:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)[C:23]=2[N:24]=[CH:25][N:26]=1.[N:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[C:42](O)=[O:43].Cl.C(N=C=NCCCN(C)C)C>O.C(Cl)Cl>[F:9][C:10]1[CH:15]=[C:14]([S:16]([CH3:19])(=[O:17])=[O:18])[CH:13]=[CH:12][C:11]=1[NH:20][C:21]1[C:22]2[O:29][CH:28]=[C:27]([CH:30]3[CH2:35][CH2:34][N:33]([C:42]([C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][N:36]=4)=[O:43])[CH2:32][CH2:31]3)[C:23]=2[N:24]=[CH:25][N:26]=1
Reactant: O=C(O)c1ccccn1
Reactant: CS(=O)(=O)c1ccc(Nc2ncnc3c(C4CCNCC4)coc23)c(F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(Nc2ncnc3c(C4CCN(C(=O)c5ccccn5)CC4)coc23)c(F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 29 %

Procedure:
Under an argon atmosphere, anhydrous methylene chloride (0.5 mL) and triethylamine (10 μL, 0.069 mmol) were added to N-[2-fluoro-4-(methylsulfonyl)phenyl]-7-(piperidin-4-yl)furo[3,2-d]pyrimidine-4-amine hydrochloride (10 mg, 0.023 mmol), picolinic acid (3.3 mg, 0.028 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (9 mg, 0.046 mmol) and N,N-dimethylaminopyridine (0.3 mg, 0.002 mmol), followed by stirring at room temperature for 2 hours. Water was added to the reaction liquid, the reaction liquid was extracted with chloroform, the organic layer was dried over anhydrous sodium sulfate and concentrated under a reduced pressure, and the obtained residue was purified by silica gel preparative thin layer chromatography (chloroform:methanol=20:1) to give the titled compound (3.3 mg, 35%) as a yellow oily substance.
Reaction SMILES: [C:1]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:6]=[CH:5][CH:4]=[C:3]([C:7]#[C:8][CH2:9][CH2:10][CH2:11][N:12]2C(=O)C3C(=CC=CC=3)C2=O)[CH:2]=1.O.NN>C(O)C>[C:1]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:6]=[CH:5][CH:4]=[C:3]([C:7]#[C:8][CH2:9][CH2:10][CH2:11][NH2:12])[CH:2]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCC#Cc1cccc(-c2ccccc2)c1
Agent: NN
Solvent: O
Solvent: CCO
Product: NCCCC#Cc1cccc(-c2ccccc2)c1
Temperature: 80 °C
Reaction time: 2.5 h

Procedure:
2-(5-(Biphenyl-3-yl)pent-4-ynyl)isoindoline-1,3-dione (0.11 g, 0.30 mmol) and hydrazine monohydrate (0.030 mL, 0.60 mmol) were taken up into ethanol (3 mL) and stirred at 80° C. for 2.5 hours. The resulting mixture was filtered and the solvent removed in vacuo to yield 5-(biphenyl-3-yl)pent-4-yn-1-amine, which was used in the next step without further purification. MH+ 236.2
Reaction SMILES: S(=O)(=O)(O)N.[CH2:6]([O:13][C:14]1[CH:28]=[CH:27][C:17]([O:18][C:19]2[CH:26]=[CH:25][C:22]([CH:23]=[O:24])=[CH:21][CH:20]=2)=[CH:16][CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Cl([O-])=[O:30].[Na+]>O.CC(C)=O>[CH2:6]([O:13][C:14]1[CH:28]=[CH:27][C:17]([O:18][C:19]2[CH:20]=[CH:21][C:22]([C:23]([OH:30])=[O:24])=[CH:25][CH:26]=2)=[CH:16][CH:15]=1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: [O-][Cl+][O-]
Reactant: O=Cc1ccc(Oc2ccc(OCc3ccccc3)cc2)cc1
Agent: NS(=O)(=O)O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: O=C(O)c1ccc(Oc2ccc(OCc3ccccc3)cc2)cc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 85.4 %

Procedure:
Sulphamic acid (0.526 g, 5.43 mmol) in 2 mL water was added at 0° C. to 4-(4-benzyloxy-phenoxy)-benzaldehyde (0.55 g, 1.81 mmol) in acetone (8 mL). After 5 minutes, sodium chlorite (0.654 g, 7.24 mmol) was added and the mixture was stirred at 0° C. for three hours. Water was added and the resulting solid was isolated by filtration to afford 495 mg (85% yield) of 4-(4-benzyloxy-phenoxy)-benzoic acid.
Reaction SMILES: Cl.[NH2:2][C:3]1([CH3:22])[CH2:7][CH2:6][CH2:5][CH:4]1[NH:8][C:9](=[O:21])[O:10][C@@H:11]1[CH2:16][C@H:15]([CH3:17])[CH2:14][CH2:13][C@H:12]1[CH:18]([CH3:20])[CH3:19].Cl[C:24]1[CH:29]=[N:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][N:25]=1.CCN(C(C)C)C(C)C>CS(C)=O.O>[CH3:22][C@:3]1([NH:2][C:24]2[CH:29]=[N:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][N:25]=2)[CH2:7][CH2:6][CH2:5][C@@H:4]1[NH:8][C:9](=[O:21])[O:10][C@@H:11]1[CH2:16][C@H:15]([CH3:17])[CH2:14][CH2:13][C@H:12]1[CH:18]([CH3:19])[CH3:20]
Reactant: CC(C)[C@@H]1CC[C@@H](C)C[C@H]1OC(=O)NC1CCCC1(C)N
Reactant: FC(F)(F)c1cnc(Cl)cn1
Agent: Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC(C)[C@@H]1CC[C@@H](C)C[C@H]1OC(=O)N[C@H]1CCC[C@]1(C)Nc1cnc(C(F)(F)F)cn1

Procedure:
A solution of (1R,2S,5R)-5-methyl-2-(propan-2-yl)cyclohexyl N-(2-amino-2-methylcyclopentyl)carbamate hydrochloride (5.14 g, 15.44 mmol), 2-chloro-5-(trifluoromethyl)pyrazine (CAS number 799557-87-2; 2.097 ml, 16.98 mmol) and DIPEA (8.10 ml, 46.32 mmol) in DMSO (51.5 ml) was heated to 140° C. for 17 hours. The reaction mixture was diluted with water (200 ml) and extracted with ethyl acetate (2×200 ml). The combined organics were washed with brine (3×200 ml), dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography (silica, 0-15% ethyl acetate/petrol) to afford the title compound as a single diastereomer.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].O[C:13]1[CH:18]=CC(C(C2C=CC(O)=CC=2)(C)C)=C[CH:14]=1.B(F)(F)F.CCOCC>C1(C)C=CC=CC=1>[OH:11][C:8]1[CH:7]=[C:6]2[C:5](=[CH:10][CH:9]=1)[C:1]([CH3:4])([CH3:2])[CH2:3][C:13]2([CH3:18])[CH3:14]
Reactant: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Reactant: CC(C)(C)c1ccc(O)cc1
Agent: FB(F)F
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CC1(C)CC(C)(C)c2cc(O)ccc21
Yield: 37.2 %

Procedure:
172 g (1.15 mol) of 4-tert.-butylphenol, 57.5 g (0.25 mol) of 2,2-bis-(4- hydroxyphenyl)-propane and 5 g of boron trifluoride etherate are stirred in an autoclave for 6 hours at around 150° C. The reaction mixture is then diluted with 400 ml of toluene and the catalyst washed out with 900 ml of water used in several portions. The solvent is then distilled off. 17.6 g (0.093 mol) of 5-hydroxy-1,1,3,3-tetramethyl indane were isolated from the 216.7 g reaction product by fractional distillation.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=O.[S:12]([C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1)(=[O:15])(=[O:14])[NH2:13]>>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=[N:20][C:19]1[CH:21]=[CH:22][C:16]([S:12](=[O:15])(=[O:14])[NH2:13])=[CH:17][CH:18]=1
Reactant: COc1ccc(C=O)cc1F
Reactant: Nc1ccc(S(N)(=O)=O)cc1
Product: COc1ccc(C=Nc2ccc(S(N)(=O)=O)cc2)cc1F

Procedure:
Following a procedure similar to that described in Example 1(i), but using 3-fluoro-4-methoxybenzaldehyde and 4-sulfamoylaniline as starting materials, the title compound was obtained as a slightly yellow powder (yield 57%).
Reaction SMILES: O[C:2]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH3:20])[C:13]2[CH:12]=[CH:11][S:10][C:9]=2[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.S(Cl)([Cl:23])=O>C1C=CC=CC=1>[Cl:23][C:2]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH3:20])[C:13]2[CH:12]=[CH:11][S:10][C:9]=2[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2
Reactant: Cc1ccccc1C1(O)c2ccccc2-c2sccc21
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: Cc1ccccc1C1(Cl)c2ccccc2-c2sccc21

Procedure:
5.6 g (20 mmoles) of 4-hydroxy-4-(2-methyl-phenyl)-4H-indeno[1,2-b]thiophene were dissolved in 40 ml of absolute benzene, and 34 ml of thionyl chloride were added. The mixture was heated under reflux for 5 hours. The reaction solution was then evaporated in vacuo, the oily residue was taken up in cyclohexane, the insoluble material was filtered off and the clear filtrate was evaporated again in vacuo. 6.1 g of crude 4-chloro-4-(2-methyl-phenyl)-4H-indeno[1,2-b]thiophene were obtained as a viscous oil, which was further reacted directly. ##STR11##
Reaction SMILES: CC([O-])(C)C.[K+].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[CH:10][CH:9]=1.Br[CH:23]([C:27]1[CH:36]=[CH:35][C:30]([C:31]([O:33][CH3:34])=[O:32])=[CH:29][CH:28]=1)[CH2:24][CH2:25][CH3:26].O>CN(C=O)C>[C:18]([O:17][C:15](=[O:16])[CH:14]([CH:23]([C:27]1[CH:36]=[CH:35][C:30]([C:31]([O:33][CH3:34])=[O:32])=[CH:29][CH:28]=1)[CH2:24][CH2:25][CH3:26])[C:11]1[CH:10]=[CH:9][C:8]([Cl:7])=[CH:13][CH:12]=1)([CH3:21])([CH3:20])[CH3:19]
Reactant: CCCC(Br)c1ccc(C(=O)OC)cc1
Reactant: CC(C)(C)OC(=O)Cc1ccc(Cl)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCC(c1ccc(C(=O)OC)cc1)C(C(=O)OC(C)(C)C)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.03 h

Procedure:
To a suspension of KOtBu (980 mg, 8.73 mmol) in anhydrous DMF (15 mL) at 0° C. was added tert-butyl 4-chlorophenylacetate (1.80 g, 7.94 mmol). After stirring for two minutes, a solution of methyl 4-(1-bromobutyl)benzoate in DMF (5 mL) was added dropwise. The mixture was allowed to warm to room temperature. After stirring for 20 minutes, water was added then the solution was extracted with CH2Cl2 (2×100 mL). The combined organic layers were washed with saturated NH4Cl (aq) (20 mL) then saturated NaCl (aq) (20 mL), dried over Na2SO4, filtered, then concentrated. The residue was purified by silica gel chromatography eluting with 2% EtOAc/petroleum ether to afford the title compound: 1H NMR (300 MHz, CD3OD) δ 7.98-8.02 (m, 2 H), 7.77-7.81 (m, 2 H), 7.38-7.44 (m, 2 H), 7.09-7.13 (m, 2 H), 3.91 (s, 3 H), 3.79-3.81 (m, 1 H), 3.34-3.40 (m, 1 H), 1.20-1.30 (m, 2 H), 1.03 (s, 9 H), 0.91-1.02 (m, 2 H), 0.68 (t, J=7.4 Hz, 3 H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH:8][CH3:9])=[N:6][C:5]([Br:10])=[CH:4][N:3]=1.Cl[CH2:12][C:13]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=O>CN(C)C=O>[Br:10][C:5]1[N:6]=[C:7]([NH:8][CH3:9])[C:2]2[N:3]([CH:12]=[C:13]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:1]=2)[CH:4]=1
Reactant: CCOC(=O)CC(=O)CCl
Reactant: CNc1nc(Br)cnc1N
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1cn2cc(Br)nc(NC)c2n1
Yield: 12.8 %

Procedure:
2.03 g (10 mmol) of 2-amino-5-bromo-3-methylaminopyrazine are dissolved in 5 ml of dimethylformamide (DMF). A solution of 1.645 g(10 mmol) of ethyl (chloroacetyl)acetate in 5 ml of DMF is added dropwise with stirring. The mixture is maintained with stirring and under gentle reflux for 3 hours. The DMF is then evaporated off under reduced pressure and the residue, dissolved in 50 ml of anhydrous ethanol, is brought to reflux for one hour. After removal of the solvent, the residue is taken up with water, alkalinized and extracted with dichloromethane. After dehydration over anhydrous calcium chloride, the solvent is evaporated off under reduced pressure. The crude product is purified by chromatography on a silica column (eluant=dichloromethane to which 5% of methanol has been added). 0.4 g (Yld=30%) of ethyl 6-bromo-8-methylaminoimidazo[1,2-a]pyrazine-2-acetate (m.p. 104° C.) is obtained.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH2:9])[CH:6]=[CH:7][CH:8]=1)#[CH:2].[CH3:10][O:11][CH2:12][C:13](Cl)=[O:14]>C(Cl)Cl>[C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:13](=[O:14])[CH2:12][O:11][CH3:10])[CH:6]=[CH:7][CH:8]=1)#[CH:2]
Reactant: C#Cc1cccc(N)c1
Reactant: COCC(=O)Cl
Solvent: ClCCl
Product: C#Cc1cccc(NC(=O)COC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.8 %

Procedure:
To a cooled solution of 3-ethynylphenylamine (7.02 g, 60 mmol) in methylene chloride is added a solution of methoxyacetyl chloride (7.8 g, 72 mmol) in methylene chloride (10 mL) dropwise over a period of 30 min at 0° C. After addition, the reaction mixture is allowed to warm-up to room temperature and stirred overnight. The solvent is evaporated and the residue is partitioned between water and ethyl acetate. The organic phase is washed with saturated NaHCO3, H2O, dried (MgSO4) and concentrated to afford the title compound as a colorless oil 10.2 g (90%). 1HNMR (CDCl3): δ (ppm) 3.04 (s, 1H,), 3.48 (s, 3H), 3.98 (s, 2H), 7.24 (m, 2H), 7.61 (d, 1H), 7.66 (s, 1H), 8.21 (s, b, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[CH2:10][C:11]([OH:13])=[O:12].OS(O)(=O)=O.[CH3:19]O>>[CH3:19][O:12][C:11](=[O:13])[CH2:10][C:3]1[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=1[Cl:1]
Reactant: CO
Reactant: COc1ccc(Cl)c(CC(=O)O)c1
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1cc(OC)ccc1Cl

Procedure:
2-Chloro-5-methoxy-benzeneacetic acid (10 g, CAS Reg. No. 91367-10−1) was dissolved in MeOH (210 mL) and H2SO4 (0.7 mL) was added. The mixture was then refluxed over night. Methanol was removed in vacuo and the residue was dissolved in ethyl acetate. The organic layer was washed with sat. NaHCO3 and brine, dried over Na2SO4 and evaporated. The title compound was obtained as a light brown oil (10.16 g) and was used without further purification. 1H-NMR, (CDCl3): 7.27 (d, 1H), 6.83 (d, 1H), 6.77 (dd, 1H), 3.79 (s, 3H), 3.74 (s, 2H), 3.72 (s, 3H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:12])[CH:10]=2)[N:5]=[C:4]([C:13]([F:16])([F:15])[F:14])[CH:3]=1.[NH3:17]>C(O)CO>[NH2:17][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:12])[CH:10]=2)[N:5]=[C:4]([C:13]([F:16])([F:15])[F:14])[CH:3]=1
Reactant: Fc1ccc2nc(C(F)(F)F)cc(Cl)c2c1
Reactant: N
Solvent: OCCO
Product: Nc1cc(C(F)(F)F)nc2ccc(F)cc12
Temperature: 25 °C

Procedure:
A mixture of 4-chloro-6-fluoro-2-(trifluoromethyl)quinoline (1 g, 4.01 mmol) and NH3 (3 mL) in ethylene glycol (20 mL) is prepared at −78° C. in a sealed tube. After warming up to room temperature, the sealed tube is gradually heated to 100° C. overnight. After cooling to −78° C., the sealed tube is opened and the contents are concentrated by rotary evaporator. The residue is purified by flash chromatography on silica gel (1:3 EtOAc/hexanes) to give 4-amino-6-fluoro-2-(trifluoromethyl)quinoline as a light yellow solid.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.[CH2:21]1[C:24]2([CH2:28][CH2:27][CH2:26][NH:25]2)[CH2:23][CH2:22]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH2:23]1[C:24]2([CH2:28][CH2:27][CH2:26][N:25]2[C:12]([C:10]2[CH:9]=[CH:8][C:7]([N:15]3[CH2:18][C:17]([F:20])([F:19])[CH2:16]3)=[C:6]([O:5][CH2:4][CH:1]3[CH2:2][CH2:3]3)[N:11]=2)=[O:14])[CH2:21][CH2:22]1
Reactant: C1CNC2(C1)CCC2
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1)N1CCCC12CCC2

Procedure:
In analogy to the procedure described in Example 47 b), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1 b)) was reacted with 5-azaspiro[3.4]octane (52876-78-5) in the presence of TBTU and DIEA to obtain the title compound as colorless oil; MS (EI): m/e=378.5 [MH+].
Reaction SMILES: [SH:1][C:2]1[N:3]([CH3:12])[C:4](=[O:11])[C:5]2[S:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[OH-].[Na+].O.[Cl:16][C:17]1[CH:32]=[CH:31][C:20]([C:21]([C:23]2[CH:30]=[CH:29][C:26]([CH2:27]Br)=[CH:25][CH:24]=2)=[O:22])=[CH:19][N:18]=1>C(O)C.O>[Cl:16][C:17]1[CH:32]=[CH:31][C:20]([C:21]([C:23]2[CH:30]=[CH:29][C:26]([CH2:27][S:1][C:2]3[N:3]([CH3:12])[C:4](=[O:11])[C:5]4[S:10][CH:9]=[CH:8][C:6]=4[N:7]=3)=[CH:25][CH:24]=2)=[O:22])=[CH:19][N:18]=1
Reactant: O=C(c1ccc(CBr)cc1)c1ccc(Cl)nc1
Reactant: Cn1c(S)nc2ccsc2c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cn1c(SCc2ccc(C(=O)c3ccc(Cl)nc3)cc2)nc2ccsc2c1=O
Temperature: 60 °C
Reaction time: 1 h
Yield: 74.7 %

Procedure:
To a solution of 2-mercapto-3-methylthieno[3,2-d]-pyrimidin-4(3H)-one (1.98 g) and 1N-sodium hydroxide/water (10.5 ml) in ethanol (30 ml) was added 4-(6-chloronicotinoyl)benzyl bromide (3.35 g) and the mixture was stirred at 60° C. fro 1 hour. This reaction mixture was poured in water and the resulting crystals were collected by filtration, rinsed with water, and recrystallized from ethyl acetate to provide the title compound as light-yellow solid (3.194 g).
Reaction SMILES: [Mg].[CH2:2](Br)[CH:3]=[CH2:4].[CH:6](=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>CCCCCC>[C:7]1([CH:6]([OH:13])[CH2:4][CH:3]=[CH2:2])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=Cc1ccccc1
Reactant: C=CCBr
Agent: [Mg]
Solvent: CCCCCC
Product: C=CCC(O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
The following procedure for the preparation of allylpinacolboronate ester is representative. A 25-mL round-bottom flask equipped with a magnetic stir bar was charged with magnesium turnings (0.04 g, 1.65 mmol) and fitted with a rubber septum. The flask was purged with argon and charged with dry THF (2.3 mL) followed by PinBH (0.199 mL, 1.37 mmol). To the reaction mixture allylbromide (0.116 mL, 1.37 mmol) was added drop wise with constant stirring over five minutes at 25° C. After stirring for 30 min at 25° C., a second equivalent of allylbromide (0.116 mL, 1.37 mmol) was added. After 90 min of stirring at 25° C. the magnesium turnings were fully consumed and 11B NMR analysis confirmed the complete formation of allylpinacolboronate. Benzaldehyde (0.138 mL, 1.37 mmol) was then added and the reaction mixture was stirred for addition 12 h at 25° C. The reaction mixture was then diluted with hexane (5 mL), quenched with aqueous 1 M HCl (5 mL) and transferred to a separatory funnel. The organic layer was washed with aqueous 1 M NaOH (2×5 mL) and DI water (2×3 mL). The combined organic layers were dried over anhydrous MgSO4, filtered, and dried under vacuo (25° C., 1 Torr) to afford 1-phenyl-3-buten-1-ol as a clear colorless oil; 94.5% (0.190 g). The results for the other allylpinacolborane esters prepared by this method are summarized in Table 3.
Reaction SMILES: [CH2:1]=[CH:2]/[CH:3]=[CH:4]/C.[C:6]1(=[O:12])[O:11][C:9](=[O:10])[CH:8]=[CH:7]1.C(C1C=C(O)C(=CC=1)O)(C)(C)C.S(CCC(OCCCCCCCCCCCC)=O)CCC(OCCCCCCCCCCCC)=O.O=O>>[CH2:1]1[CH:7]2[C:6]([O:11][C:9](=[O:10])[CH:8]2[CH2:4][CH:3]=[CH:2]1)=[O:12]
Reactant: O=C1C=CC(=O)O1
Reactant: C=C/C=C/C
Agent: CC(C)(C)c1ccc(O)c(O)c1
Agent: CCCCCCCCCCCCOC(=O)CCSCCC(=O)OCCCCCCCCCCCC
Agent: O=O
Product: O=C1OC(=O)C2CC=CCC12
Reaction time: 0.5 h

Procedure:
3Me--THPA was produced by the gas phase aeration method. Thus, the air in a 300-ml four-necked flask equipped with a stirrer, thermometer, condenser, a dropping funnel for feeding crude trans-1,3-pentadiene, and an unreactive fraction recovery vessel was replaced with nitrogen and, then, the flask was charged with 98 g of maleic anhydride, 500 ppm of p-tert-butylcatechol by way of radical polymerization inhibitor and 1000 ppm of dilauryl thiodipropionate as auxiliary polymerization inhibitor. The charge was melted at 50° to 55° C. and after the internal atmosphere was replaced with nitrogen gas, nitrogen gas containing 4% of oxygen was passed through the gas phase at a rate of 10 ml/min throughout the reaction period. Under this atmosphere, 374 g of crude trans-1,3-pentadiene of the same composition as that used in Example 1 was continuously added at 50° to 55° C. over a period of 4 hours. During the reaction, major portion of unreactive fractions was distilled off from the reaction system. After completion of addition, the reaction was conducted at 70° C. for 30 minutes. After completion of the reaction, the reaction mixture was distilled at 85° C. under atmospheric pressure and, then, under reduced pressure to remove the volatile fraction. In this manner, 164 g of 3Me--THPA was obtained. The investigation revealed no gels in the product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:8][CH3:9])[CH:5]=[CH:6][CH:7]=1.C1C=C(Cl)C=C(C(OO)=[O:18])C=1>CCOC(C)=O.O>[CH3:9][S:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=1)=[O:18]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1cccc(Br)c1
Solvent: CCOC(C)=O
Solvent: O
Product: CS(=O)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 69393.7 %

Procedure:
A mixture of 3-bromothioanisole (4.9687 g, 0.0245 mmol) and MCPBA (5.066 g, %) was stirred at room temperature. After 4 h, extractive EtOAc/H2O workup followed by flash chromatography (EtOAc/Hexanes, 50:50) provided the title compound (3.725 g, 69%) as an oil. 1H NMR (DMSO, 400 MHz): 7.80 (br s, 1H), 7.61 (d, J=8.01 Hz, 1H), 7.53 (d, J=8.01 Hz, 1H), 7.39 (t, J=8.01 Hz, 1H), 2.72 (s, 3H).
Reaction SMILES: [ClH:1].[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][Cl:9])[CH:3]=1.Cl.[C:11]1([C:17]2[CH2:18][CH2:19][N:20]([CH2:23][CH2:24][SH:25])[CH2:21][CH:22]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C>CN(C)C=O>[ClH:9].[ClH:1].[C:11]1([C:17]2[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][S:25][CH2:8][C:4]3[CH:3]=[N:2][CH:7]=[CH:6][CH:5]=3)[CH2:19][CH:18]=2)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: ClCc1cccnc1
Reactant: SCCN1CC=C(c2ccccc2)CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C1=C(c2ccccc2)CCN(CCSCc2cccnc2)C1
Temperature: 80 °C
Yield: 29.1 %

Procedure:
A solution of 3-picolyl chloride hydrochloride (2.50 g) and 3,6-dihydro-4 phenyl-1(2H)-pyridineethanethiol hydrochloride (3.90 g) (Example A) in 100 mL of dimethylformamide is treated with triethylamine (7.4 ml) and the mixture is heated at 80° C. for 8 hours. The solvent is evaporated in vacuo, and the residue is partitioned into chloroform/sodium bicarbonate solution. The organic extract is dried over magnesium sulfate, filtered and concentrated. The crude product is purified by column chromatography (silica gel; 2% methanol in chloroform) to yield 1.7 g of the title compound as an oil, which is converted into its hydrochloride salt (hydrogen chloride gas in diethyl ether) and recrystallized from ethanol/acetonitrile; mp 218°-220° C. (dec).
Reaction SMILES: [CH3:1][N:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C:6](=O)[N:5]2[CH2:14][CH2:15][CH2:16][CH:4]2[C:3]1=[O:17].CN1C(=O)OC(=O)C2=CC=CC=C12.N1CCC[C@@H]1C(O)=O.B>O1CCCC1.CO>[CH3:1][N:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][N:5]2[CH2:14][CH2:15][CH2:16][CH:4]2[C:3]1=[O:17]
Reactant: CN1C(=O)C2CCCN2C(=O)c2ccccc21
Agent: B
Agent: Cn1c(=O)oc(=O)c2ccccc21
Agent: O=C(O)[C@H]1CCCN1
Solvent: C1CCOC1
Solvent: CO
Product: CN1C(=O)C2CCCN2Cc2ccccc21

Procedure:
The above compound is obtained when (-)-1,2,3,11 a-tetrahydro-10-methyl-5H-pyrrolo[2,1-c] [1,4] benzodiazepin- 5,11(10H)-dione, melting point 120-122°C. [α]D 25 - 477°, (1.24%, methanol) and (prepared from N-methylisatoic anhydride and D-proline as described in Example 1) is treated with borane in tetrahydrofuran as described in Example 1.
Reaction SMILES: [C:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[S:13]1[C:17]([C:18]2[C:19]([O:28][CH3:29])=[CH:20][C:21]([O:26][CH3:27])=[C:22]([CH:25]=2)[CH:23]=O)=[CH:16][C:15]2[CH:30]=[CH:31][CH:32]=[CH:33][C:14]1=2.[OH-].[Na+]>CN(C)C=O.O>[S:13]1[C:17]([C:18]2[C:19]([O:28][CH3:29])=[CH:20][C:21]([O:26][CH3:27])=[C:22](/[CH:23]=[CH:2]/[C:1]([C:4]3[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=3)=[O:3])[CH:25]=2)=[CH:16][C:15]2[CH:30]=[CH:31][CH:32]=[CH:33][C:14]1=2
Reactant: CC(=O)c1ccc(C(=O)O)cc1
Reactant: COc1cc(OC)c(-c2cc3ccccc3s2)cc1C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(OC)c(-c2cc3ccccc3s2)cc1/C=C/C(=O)c1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 54 %

Procedure:
To a solution of 4-acetylbenzoic acid (1.50 g, 9.1 mmol) and 5-(benzo[b]thien-2-yl)-2,4-dimethoxybenzaldehyde from Ex-3A (3.27 g, 11.0 mmol) in N,N-dimethylformamide (76 mL) was added a solution of sodium hydroxide (5 M, 7.3 mL, 36.5 mmol). The reaction mixture was allowed to stir at room temperature for 2 h and was then diluted with water to a volume of 150 mL. The solution was washed with dichloromethane and acidified with concentrated sulfuric acid to pH=3. The resulting solution was then extracted with dichloromethane. The dichloromethane extract was washed with brine, dried over sodium sulfate and concentrated. The resulting oily product solidified in ethanol. The solid was further stirred in ethanol for one day and collected by filtration. The solid was washed with ethanol, then dried in vacuo to afford the title compound as a yellow solid (2.2 g, 54%). 1H NMR (300 MHz, DMSO-d6) δ 8.36 (s, 1H), 8.21 (d, 2H), 8.07 (m, 3H), 7.93 (m, 3H), 7.82 (d, 1H), 7.32 (m, 2H), 6.86 (s, 1H), 4.08 (s, 3H), 4.00 (s, 3H). Anal. Calculated for C26H20O5S·1/6H2O: C, 69.78; H, 4.58; S, 7.17; found: C, 69.95; H, 4.69; S, 7.15. HPLC purity: 97.9% (area percentage).