Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I.[CH2:2]([NH:4][C:5](=[NH:8])SC)[CH3:3].[CH2:9]1[C:13]2([CH2:17][CH2:16][CH2:15][CH2:14]2)[CH2:12][N:11]=[N:10]1>N1C=CC=CC=1>[CH2:2]([NH:4][C:5]([N:10]1[N:11]=[CH:12][C:13]2([CH2:17][CH2:16][CH2:15][CH2:14]2)[CH2:9]1)=[NH:8])[CH3:3]
Reactant: C1CCC2(C1)CN=NC2
Reactant: CCNC(=N)SC
Agent: I
Solvent: c1ccncc1
Product: CCNC(=N)N1CC2(C=N1)CCCC2
Temperature: 60 °C
Reaction time: 8 h

Procedure:
40.89 g 1-Ethyl-2-methyl-isothiourea hydroiodide was dissolved in 150 mL pyridine at 40° C. Subsequently, 20.00 g 2,3-diaza-spiro[4.4]non-2-ene was added and the mixture was stirred overnight under reflux. The mixture was cooled to 60° C. and concentrated under reduced pressure, and the orange residue was taken up in DCM (250 mL). The organic phase was extracted 3 times with water, dried over Na2SO4 and evaporated under reduced pressure. Residual pyridine was removed by azeotropic destillation with water under reduced pressure at 60° C., and residual water was removed by azeotropic destillation with isopropanol under reduced pressure at 60° C. This yielded 31.5 g of a yellow/brown oil containing ˜80% of anticipated product which was used in subsequent steps without further purification. 1H NMR (400 MHz, CDCl3) δ 1.35 (t, J=7.22 Hz, 3H), 1.57-1.99 (m, 8H), 3.60 (q, J=7.22 Hz, 2H), 4.04 (s, 2H), 7.03 (s, 1H) [guanidine NH2 invisible].
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][N:37]([CH2:40][C:41](O)=[O:42])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:47]([O:49][CH2:50][CH2:51][NH:52][CH2:53][CH2:54][O:55][CH2:56][CH3:57])[CH3:48]>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][N:37]([CH2:40][C:41]([N:52]([CH2:53][CH2:54][O:55][CH2:56][CH3:57])[CH2:51][CH2:50][O:49][CH2:47][CH3:48])=[O:42])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[C@@:14]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)O)CC1
Reactant: CCOCCNCCOCC
Product: CCOCCN(CCOCC)C(=O)CN1CCN(C(=O)N2C(c3cnc(C(C)(C)C)cc3OCC)=N[C@@](C)(c3ccc(Cl)cc3)[C@@]2(C)c2ccc(Cl)cc2)CC1

Procedure:
In a manner analogous to the method described in example 99, {4-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-acetic acid was coupled with bis-(2-ethoxy-ethyl)-amine (TCI-US) to give the title compound. HR-MS (ES, m/z) calculated for C43H59Cl2N6O5 [(M+H)+] 809.3919, observed 809.3118.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([F:13])([F:12])[CH2:7][CH2:6][CH2:5]2.P([O-])(O)(O)=[O:15].[K+].O.O.O.O.O.O.O.P([O-])([O-])([O-])=O.[Na+].[Na+].[Na+].[Mn]([O-])(=O)(=O)=O.[K+]>C(O)(C)(C)C.O.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9]([C:8]([F:12])([F:13])[CH2:7][CH2:6][C:5]2=[O:15])=[CH:10][CH:11]=1
Reactant: FC1(F)CCCc2cc(Br)ccc21
Reactant: O=P([O-])(O)O
Agent: O=[Mn](=O)(=O)[O-]
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(C)(C)O
Product: O=C1CCC(F)(F)c2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 15 h
Yield: 70.5 %

Procedure:
A solution of 6-bromo-1,1-difluoro-1,2,3,4-tetrahydro-naphthalene (691 mg, 2.8 mmol) in tert-butanol (7 ml). A solution of potassium dihydrogenphosphate (769 mg, 5.59 mmol) in water (2 ml) and a solution of sodium phosphate heptahydrate (1.51 g, 5.59 mmol) in water (2 ml) were added. Thereafter, potassium permanganate (670 mg, 4.2 mmol) was added and the reaction mixture stirred at room temperature for 15 hours. For the workup, the mixture was diluted with ethyl acetate (200 ml), the organic layer separated, washed with water (10 ml) and brine (10 ml), finally dried over sodium sulphate and evaporated at reduced pressure. The crude product was purified by chromatography on silica gel using a gradient of heptane/ethyl acetate=100:0 to 80:20 as the eluent. The 7-bromo-4,4-difluoro-3,4-dihydro-2H-naphthalen-1-one (515 mg, 71% yield) was obtained as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH:23]=O)[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.[NH2:26][C@@H:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH2:29][CH2:28]1>>[CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:21])([F:20])[F:22])=[CH:15][C:14]=2[CH2:23][NH:26][C@@H:27]2[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH2:29][CH2:28]2)[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1
Reactant: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2C=O)c1
Reactant: N[C@H]1CCc2ccccc21
Product: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN[C@H]2CCc3ccccc32)c1

Procedure:
Prepared according to the procedure described in Example 4, Step 1, using the following starting materials: (2′-formyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid methyl ester and (S)-(+)-1-aminoindan.
Reaction SMILES: NC1C=CC(C2C=C(C)C=CC=2S(C2C=CC(C)=CC=2C2C=CC(N)=C([N+]([O-])=O)C=2)=O)=CC=1[N+]([O-])=O.[Cl:37][C:38]1[CH:43]=[CH:42][C:41]([S:44]([C:46]2[CH:51]=[CH:50][C:49]([C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)=[CH:48][CH:47]=2)=[O:45])=[CH:40][C:39]=1[N+:58]([O-])=O>>[NH2:58][C:39]1[CH:40]=[C:41]([S:44]([C:46]2[CH:51]=[CH:50][C:49]([C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)=[CH:48][CH:47]=2)=[O:45])[CH:42]=[CH:43][C:38]=1[Cl:37]
Reactant: O=[N+]([O-])c1cc(S(=O)c2ccc(-c3ccccc3)cc2)ccc1Cl
Agent: Cc1ccc(S(=O)c2ccc(C)cc2-c2ccc(N)c([N+](=O)[O-])c2)c(-c2ccc(N)c([N+](=O)[O-])c2)c1
Product: Nc1cc(S(=O)c2ccc(-c3ccccc3)cc2)ccc1Cl
Yield: 85 %

Procedure:
Following the procedure described in Example 2 but using as a starting material instead of (4-amino-3-nitrophenyl)-4-methylphenyl sulfoxide a corresponding amount of 4-(4-chloro-3-nitrophenylsulfinyl)-biphenyl, the title compound is obtained.
Reaction SMILES: [ClH:1].[CH:2]1([N:7]([CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[CH2:8][CH2:9][NH:10]C(=O)OC(C)(C)C)[CH2:6][CH2:5][CH2:4][CH2:3]1>ClCCl>[ClH:1].[CH:2]1([N:7]([CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[CH2:8][CH2:9][NH2:10])[CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(C)(C)OC(=O)NCCN(C1CCCC1)C1CCCC1
Agent: Cl
Solvent: ClCCl
Product: NCCN(C1CCCC1)C1CCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Hydrogen chloride gas was passed through a stirred ice cold solution of tert-butyl 2-(dicyclopentylamino)ethylcarbamate (0.22 g, 0.74 mmol) (Preparation 52) in dichloromethane (15 ml) until the solution was saturated. The reaction mixture was allowed to warm to room temperature and then stirred for 1 hour. The solvent was removed under reduced pressure to give the title compound (0.15 g) as a brown foam.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:19]([O:20][C:21](=[O:23])[CH3:22])[C@H:18]([O:24][C:25](=[O:27])[CH3:26])[CH2:17][S:16][C@H:6]1[O:7][C:8]1[C:9](Cl)=[N:10][CH:11]=[CH:12][C:13]=1[CH3:14])(=[O:3])[CH3:2].[O:28]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29]1>>[C:1]([O:4][C@@H:5]1[C@@H:19]([O:20][C:21](=[O:23])[CH3:22])[C@H:18]([O:24][C:25](=[O:27])[CH3:26])[CH2:17][S:16][C@H:6]1[O:7][C:8]1[C:9]([C:30]2[CH:31]=[CH:32][O:28][CH:29]=2)=[N:10][CH:11]=[CH:12][C:13]=1[CH3:14])(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1c(C)ccnc1Cl
Reactant: OB(O)c1ccoc1
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1c(C)ccnc1-c1ccoc1

Procedure:
By carrying out the operation analogously to example 1, starting from 2-chloro-4-methyl-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside obtained according to preparation VI, and 3-furanboronic acid, the desired product is obtained in the form of an ecru solid (yield=77%).
Reaction SMILES: [C:1]([C:4]1([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14](=[O:28])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]2([C:25]([OH:27])=[O:26])[CH2:24][CH2:23][CH2:22][CH2:21]2)[CH2:8][CH2:7][CH2:6][CH2:5]1)([OH:3])=[O:2].[OH-].[Na+].[BH4-].[Na+]>CC(O)C.O>[C:25]([C:20]1([CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH:14]([OH:28])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][C:4]2([C:1]([OH:3])=[O:2])[CH2:8][CH2:7][CH2:6][CH2:5]2)[CH2:21][CH2:22][CH2:23][CH2:24]1)([OH:27])=[O:26]
Reactant: O=C(CCCCCC1(C(=O)O)CCCC1)CCCCCC1(C(=O)O)CCCC1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: O=C(O)C1(CCCCCC(O)CCCCCC2(C(=O)O)CCCC2)CCCC1
Reaction time: 19 h
Yield: 102.9 %

Procedure:
To a mixture of 1-[11-(1-carboxycyclopentyl)-6-oxoundecyl]-1-cyclopentanecarboxylic acid (5.00 g, 12.7 mmol) in iPrOH (30 mL) and H2O (30 mL) was added NaOH (1.07 g, 26.3 mmol). To the resulting clear solution, NaBH4 (0.38 g, 10.0 mmol) was added. After 19 h, the reaction mixture was concentrated in vacuo. The remaining residue was dissolved in H2O (50 mL) and acidified with aqueous HCl (6M, 15 mL). The resulting mixture was extracted with Et2O (100 mL, 2×50 mL), and the combined organic layers were washed with brine (2×50 mL), dried (Na2SO4) and concentrated in vacuo to give 1-[11-(1-carboxycyclopentyl)-6-hydroxyundecyl]-1-cyclopentanecarboxylic acid (5.18 g, 99%, contains 4% (w/w) Et2O) as a thick, light yellow oil that slowly crystallized on standing. mp=: 76-77° C. 1H NMR (CDCl3); δ=3.56 (br s, 1H), 2.16-2.11 (m, 4H), 1.64-1.61 (m, 12H), 1.51-1.18 (m, 20H). 13C NMR (CDCl3): δ=184.3 (2×), 71.4, 54.2 (2×), 39.2 (2×), 36.9 (2×), 36.2 (2×), 35.7 (2×), 29.5 (2×), 25.9 (2×), 25.2 (2×), 25.1 (2×), 25.0 (2×).
Reaction SMILES: Cl.[NH2:2][OH:3].[OH-].[Na+].[Br:6][C:7]1[CH:8]=[C:9]([C:13](=O)[CH:14]=[C:15]([C:20]2[CH:25]=[C:24]([Cl:26])[CH:23]=[C:22]([Cl:27])[CH:21]=2)[C:16]([F:19])([F:18])[F:17])[S:10][C:11]=1[CH3:12]>CCO>[Br:6][C:7]1[CH:8]=[C:9]([C:13]2[CH2:14][C:15]([C:20]3[CH:25]=[C:24]([Cl:26])[CH:23]=[C:22]([Cl:27])[CH:21]=3)([C:16]([F:19])([F:18])[F:17])[O:3][N:2]=2)[S:10][C:11]=1[CH3:12]
Reactant: Cc1sc(C(=O)C=C(c2cc(Cl)cc(Cl)c2)C(F)(F)F)cc1Br
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1sc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1Br
Reaction time: 12 h
Yield: 54.7 %

Procedure:
Hydroxylamine hydrochloride (13 g) and NaOH (18 g) are added to a solution of 1-(4-bromo-5-methyl-thiophen-2-yl)-3-(3,5-dichloro-phenyl)-4,4,4-trifluoro-but-2-en-1-one (84 g, 71% purity) in EtOH (1000 ml) at room temperature. After 12 hours at room, the reaction mixture is concentrated in vacuo, diluted with diethylether and water. The aqueous phase is separated and further extracted two times with diethylether. The organic phases are combined, washed with a saturated aqueous solution of NaCl, dried over MgSO4 and concentrated in vacuo. The crude product is purified by chromatography on silica gel (1800 g) eluting with a mixture of heptane and dichloromethane (4:1) to yield 3-(4-bromo-5-methyl-thiophen-2-yl)-5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazole (47 g) as a light brown crystals.
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][C:4]([C:7](Cl)=[O:8])=[CH:3][CH:2]=1.[Cl-].[Al+3].[Cl-].[Cl-].[CH2:15]([O:17][C:18]([C:20]1[C:24]([CH3:25])=[CH:23][N:22]([CH3:26])[C:21]=1[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[O:19])[CH3:16]>ClCCCl>[CH3:26][N:22]1[C:23]([C:7]([C:4]2[CH:5]=[CH:6][C:1]([CH3:10])=[CH:2][CH:3]=2)=[O:8])=[C:24]([CH3:25])[C:20]([C:18]([O:17][CH2:15][CH3:16])=[O:19])=[C:21]1[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29]
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: CCOC(=O)Cc1c(C(=O)OCC)c(C)cn1C
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CCOC(=O)Cc1c(C(=O)OCC)c(C)c(C(=O)c2ccc(C)cc2)n1C

Procedure:
A solution of 30.8 g. p-toluoyl chloride and 26.6 g. (0.2 mole) of aluminum chloride in 250 ml. of 1,2-dichloroethane is added to a refluxing solution of 50.6 g. (0.2 mole) of ethyl 3-ethoxycarbonyl-1,4-dimethylpyrrole-2-acetate in 250 ml. of 1,2-dichloroethane over 30 min. The mixture is heated under reflux for 90 min. and poured into ice-diluted hydrochloric acid. The organic solution is separated, washed with brine, and dried over magnesium sulfate. The solvent is evaporated in vacuo and the residue is recrystallized from methanol to give ethyl 1,4-dimethyl-3-ethoxycarbonyl-5-(p-toluoyl)-pyrrole-2-acetate as a white solid, m.p. 108°-111° C.
Reaction SMILES: [O:1]1[CH2:6][CH:5]=[C:4]([C:7]2[CH:8]=[C:9]([C:13]3[CH:14]=[C:15]4[C:20](=[N:21][CH:22]=3)[N:19]([C:23]([NH2:25])=[O:24])[CH2:18][CH2:17][CH2:16]4)[CH:10]=[N:11][CH:12]=2)[CH2:3][CH2:2]1.C([O-])=O.[NH4+]>[Pd].CO>[O:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:8]=[C:9]([C:13]3[CH:14]=[C:15]4[C:20](=[N:21][CH:22]=3)[N:19]([C:23]([NH2:25])=[O:24])[CH2:18][CH2:17][CH2:16]4)[CH:10]=[N:11][CH:12]=2)[CH2:3][CH2:2]1
Reactant: NC(=O)N1CCCc2cc(-c3cncc(C4=CCOCC4)c3)cnc21
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: NC(=O)N1CCCc2cc(-c3cncc(C4CCOCC4)c3)cnc21
Temperature: 80 °C
Reaction time: 26 h
Yield: 70.7 %

Procedure:
To a mixture of 6-[5-(3,6-dihydro-2H-pyran-4-yl)-pyridin-3-yl]-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid amide (42.0 mg, 0.13 mmol) and 10% Pd/C (42 mg) under Argon is added 2 mL of MeOH. Then ammonium formate (10 eq) is as added and the mixture stirred for 26 hrs at 80° C. The mixture is filtered, concentrated and purified by Preparative HPLC system (10%-80% CH3CN/H2O) to give 31.1 mg of the titled product.
Reaction SMILES: [CH3:1][CH:2]([NH:4][CH2:5][CH:6]([OH:19])[CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][C:16]([NH2:18])=[O:17])=[CH:13][CH:14]=1)[CH3:3].[CH3:20][C:21]1[CH:22]=[CH:23][C:24]([C:27]([OH:29])=[O:28])=[CH:25][CH:26]=1>CC(C)=O>[CH3:3][CH:2]([NH:4][CH2:5][CH:6]([OH:19])[CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][C:16]([NH2:18])=[O:17])=[CH:13][CH:14]=1)[CH3:1].[C:21]1([CH3:20])[CH:26]=[CH:25][C:24]([C:27]([O-:29])=[O:28])=[CH:23][CH:22]=1
Reactant: Cc1ccc(C(=O)O)cc1
Agent: CC(C)NCC(O)COc1ccc(CC(N)=O)cc1
Solvent: CC(C)=O
Product: Cc1ccc(C(=O)[O-])cc1
Reaction time: 14.5 h

Procedure:
The atenolol having low optical purity (1 mole) and p-toluic acid (1 mole) are dissolved in acetone (5 to 50 liters) with heating and the mixture is stirred at 0° to 15° C. for 5 to 24 hours. The precipitated crystals are removed by filtration, and the mother liquor is concentrated to give an optically active atenolol p-toluate with having higher optical purity, for example a salt having an optical purity of 98% ee or more from a salt having an optical purity of 91% ee in a yield of 50to 80%. In this method, when benzoic acid is used instead of p-toluic acid and chloroform is used instead of acetone, similar result is obtained. When p-t-butylbenzoic acid is used instead of p-toluic acid in the above method, the produced salt is hardly soluble in a solvent, and hence, it is necessary to use a solvent having higher solubility such as ethanol or 2-propanol instead of acetone.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][CH3:20])=[C:6]([C:8]([CH3:18])([CH3:17])[CH2:9][C@:10]2([C:13]([F:16])([F:15])[F:14])[CH2:12][O:11]2)[CH:7]=1.C(#N)C.[NH2:24][C:25]1[CH:33]=[C:32]([CH3:34])[CH:31]=[C:30]2[C:26]=1[CH:27]=[N:28][N:29]2[C:35]1[CH:36]=[C:37]([CH:42]=[CH:43][CH:44]=1)[C:38]([O:40][CH3:41])=[O:39]>C(OCC)(=O)C.FC(F)(F)S([O-])(=O)=O.[Y+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][CH3:20])=[C:6]([C:8]([CH3:18])([CH3:17])[CH2:9][C@:10]([OH:11])([C:13]([F:16])([F:15])[F:14])[CH2:12][NH:24][C:25]2[CH:33]=[C:32]([CH3:34])[CH:31]=[C:30]3[C:26]=2[CH:27]=[N:28][N:29]3[C:35]2[CH:36]=[C:37]([CH:42]=[CH:43][CH:44]=2)[C:38]([O:40][CH3:41])=[O:39])[CH:7]=1
Reactant: COc1ccc(F)cc1C(C)(C)C[C@]1(C(F)(F)F)CO1
Reactant: COC(=O)c1cccc(-n2ncc3c(N)cc(C)cc32)c1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Y+3]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COC(=O)c1cccc(-n2ncc3c(NC[C@](O)(CC(C)(C)c4cc(F)ccc4OC)C(F)(F)F)cc(C)cc32)c1
Temperature: 83 °C

Procedure:
(2R)-2-{2-[5-Fluoro-2-(methyloxy)phenyl]-2-methylpropyl}-2-(trifluoromethyl)oxirane (530 mg, 1.81 mmol) was added to acetonitrile (2.5 mL), followed by the addition of methyl 3-(4-amino-6-methyl-1H-indazol-1-yl)benzoate (590 mg, 2.1 mmol) and yttrium trifluoromethanesulfonate (197 mg, 0.37 mmol) at room temperature under a nitrogen atmosphere. The resulting mixture was then heated to reflux (83° C.) overnight, then allowed to cool down to room temperature and diluted with ethyl acetate (7 mL). The mixture was washed successively with saturated sodium bicarbonate (10 mL) and water (10 mL), dried and concentrated. The residue was then purified by column chromatography (10% ethyl acetate in cyclohexane) to give, after concentration, the title compound (540 mg).
Reaction SMILES: [CH2:1]=[CH:2][CH:3]=[CH2:4].[OH2:5]>>[CH:1]([OH:5])=[CH:2][CH:3]=[CH:4][CH2:1][CH2:2][CH2:3][CH3:4]
Reactant: O
Reactant: C=CC=C
Product: CCCCC=CC=CO

Procedure:
U.S. Pat. Nos. 4,356,333 and 4,417,079 and EP-A 436 226 describe a two-phase system for the telomerization of butadiene with water to give octadienol. The reaction is carried out in a water/sulfolane mixture from which the octadienols formed precipitate. The palladium catalyst is retained in the sulfolane phase by means of monosulfonated triphenylphosphine (TPPMS).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[S:9][C:10]([C:13]#[C:14][Si](C)(C)C)=[CH:11][N:12]=1)([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].O.C(OCC)(=O)C>CO>[C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[S:9][C:10]([C:13]#[CH:14])=[CH:11][N:12]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1ncc(C#C[Si](C)(C)C)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O
Product: C#Cc1cnc(NC(=O)OC(C)(C)C)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
To a solution of (5-trimethylsilanylethynyl-thiazol-2-yl)-carbamic acid tert-butyl ester (1.67 g, 5.633 mmol) was dissolved in methanol (20 ml) was added K2CO3 (0.389 g, 2.816 mmol) and stirred at room temperature overnight. Then the reaction was heated at 50° C. for 2 hrs. Methanol was removed under reduced pressure. The residue obtained was partioned between water (50 ml) and ethyl acetate (50 ml). The layers were separated. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to provide (5-ethynyl-thiazol-2-yl)-carbamic acid tert-butyl ester (1.2 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:6].[C:19]([N:27]=[C:28]=[S:29])(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH3:18][O:17][C:16]1[CH:15]=[CH:14][C:4]([C:5]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:6])=[CH:3][C:2]=1[NH:1][C:28]([NH:27][C:19](=[O:26])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)=[S:29]
Reactant: COc1ccc(C(=O)Nc2ccccc2)cc1N
Reactant: O=C(N=C=S)c1ccccc1
Product: COc1ccc(C(=O)Nc2ccccc2)cc1NC(=S)NC(=O)c1ccccc1
Yield: 91.5 %

Procedure:
Prepared according to the procedure described for Example 60 using 3-amino-4-methoxy-N-phenyl-benzamide (0.243 g, 1.0 mmol) and benzoyl isothiocyanate (0.171 g, 1.04 mmol) to afford the product (0.371 g); m.p. 219-222° C.
Reaction SMILES: [CH:1]1([C:4]2[O:8][C:7]([C:9]3[CH:14]=[CH:13][C:12]([CH:15]([O:22][CH3:23])[C:16](N(OC)C)=[O:17])=[CH:11][CH:10]=3)=[N:6][N:5]=2)[CH2:3][CH2:2]1.[Br:24][C:25]1[C:30]([O:31][CH3:32])=[CH:29][C:28]([C:33]2[O:34][CH:35]=[CH:36][CH:37]=2)=[CH:27][C:26]=1[O:38][CH3:39]>>[Br:24][C:25]1[C:26]([O:38][CH3:39])=[CH:27][C:28]([C:33]2[O:34][C:35]([C:16](=[O:17])[CH:15]([C:12]3[CH:11]=[CH:10][C:9]([C:7]4[O:8][C:4]([CH:1]5[CH2:2][CH2:3]5)=[N:5][N:6]=4)=[CH:14][CH:13]=3)[O:22][CH3:23])=[CH:36][CH:37]=2)=[CH:29][C:30]=1[O:31][CH3:32]
Reactant: COC(C(=O)N(C)OC)c1ccc(-c2nnc(C3CC3)o2)cc1
Reactant: COc1cc(-c2ccco2)cc(OC)c1Br
Product: COc1cc(-c2ccc(C(=O)C(OC)c3ccc(-c4nnc(C5CC5)o4)cc3)o2)cc(OC)c1Br
Yield: 31 %

Procedure:
2-(4-(5-Cyclopropyl-1,3,4-oxadiazol-2-yl)phenyl)-N,2-dimethoxy-N-methylacetamide was reacted with 2-(4-bromo-3,5-dimethoxyphenyl)furan according to the procedure for the synthesis of Example 12. Purification by chromatography (EtOAc-hexanes) gave 1-(5-(4-bromo-3,5-dimethoxyphenyl)furan-2-yl)-2-(4-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)phenyl)-2-methoxyethanone as a yellow foam (0.126 g, 31% yield). MS: m/z 539.2 [M+H]+.
Reaction SMILES: [C:1]1([NH2:8])[C:2]([NH2:7])=[CH:3][CH:4]=[CH:5][CH:6]=1.[O:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[CH:11]=[C:10]1[S:18](Cl)(=[O:20])=[O:19]>C(Cl)Cl.N1C=CC=CC=1>[O:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[CH:11]=[C:10]1[S:18]([NH:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[NH:8][S:18]([C:10]1[O:9][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[CH:11]=1)(=[O:19])=[O:20])(=[O:20])=[O:19]
Reactant: Nc1ccccc1N
Reactant: O=S(=O)(Cl)c1cc2ccccc2o1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=S(=O)(Nc1ccccc1NS(=O)(=O)c1cc2ccccc2o1)c1cc2ccccc2o1
Temperature: 25 °C
Reaction time: 6 h
Yield: 49.9 %

Procedure:
To a solution of benzene-1,2-diamine (0.5 mmol) in DCM (2 mL) and pyridine (0.5 mL) at 0° C., benzofuran-2-sulfonyl chloride (1.1 mmol; prepared as in Example 12) was added at 0° C. in small portions over 10-15 min. The reaction mixture was then gradually warmed to RT with stirring continued for 6 h. The reaction mixture was then diluted with DCM (5 mL). The organic phase was washed with 10% aqueous HCl (5 mL), water (5 mL), and brine (5 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue obtained was purified by flash column chromatography eluting with DCM followed by EtOAc/DCM (1% to 3%) to give 117 mg of N-{2-[(1-benzofuran-2-ylsulfonyl)amino]phenyl}-1-benzofuran-2-sulfonamide. Tr 1.18 min; MS: 469.7 (M+1)+.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:9])[CH2:5][CH2:6][CH2:7][NH2:8].[Cl:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=1)[CH:14]=O.[O-]S([O-])(=O)=O.[Mg+2].[BH4-].[Na+]>C1COCC1.CO>[ClH:10].[CH3:2][O:3][C:4](=[O:9])[CH2:5][CH2:6][CH2:7][NH:8][CH2:14][C:13]1[CH:16]=[CH:17][CH:18]=[C:11]([Cl:10])[CH:12]=1
Reactant: O=Cc1cccc(Cl)c1
Reactant: COC(=O)CCCN
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [BH4-]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)CCCNCc1cccc(Cl)c1
Temperature: 20 °C
Reaction time: 15 h
Yield: 65 %

Procedure:
To a solution of 4-amino-butyric acid methyl ester hydrochloride (30 g, 1 eq.) in 360 mL of THF were added TEA (67.7 mL, 2.5 eq.), then 3-chlorobenzaldehyde (19 mL, 0.9 eq.) and MgSO4 (35 g, 1.5 eq.). The reaction was stirred at 20° C. for 15 h under nitrogen. 360 mL of MeOH was added then the reaction was cooled to −20° C. NaBH4 (14.75 g, 2 eq.) was added portionwise. The reaction was stirred for 1 h at 0° C. The crude was partially concentrated under reduced pressure at 20° C., filtered and washed with DCM. The filtrate was washed with water and brine. The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure at 20° C. The residue, in solution in 1600 mL of Et2O, was treated with 87 mL of HCl 2N in Et2O. A solid was formed, filtrated, washed with Et2O, then pentane and dried to afford 4-(3-chloro-benzylamino)-butyric acid methyl ester hydrochloride (32 g, yield=65%).