Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:4]=[C:5]1[N:9]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)[CH:8]=[C:7]([CH3:20])[S:6]1)(=O)C.Cl>C(O)C.O>[NH:4]=[C:5]1[N:9]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:17])[F:18])[CH:11]=2)[CH:8]=[C:7]([CH3:20])[S:6]1
Reactant: CC(=O)N=c1sc(C)cn1-c1cccc(C(F)(F)F)c1
Agent: Cl
Solvent: CCO
Solvent: O
Product: Cc1cn(-c2cccc(C(F)(F)F)c2)c(=N)s1
Yield: 46.5 %

Procedure:
A mixture of 2-(acetylimino)-3-(3-trifluoromethylphenyl)-5-methylthiazoline (1 g) and hydrochloric acid (38%, 4 ml) in ethanol-water (1 : 2, 15 ml) was refluxed for 3 hours. Ethanol was removed by distillation under reduced pressure, and the residue was neutralized with potassium carbonate, extracted with ethyl acetate and dried over anhydrous magnesium sulfate. The solvenet was removed by distillation under reduced pressure to give 0.4 g of 2-imino-3-(3-trifluoromethylphenyl)-5-methylthiazoline (Compound (xi)).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[N:5][CH:6]=[C:7]3[CH2:12][CH2:11][CH:10]([OH:13])[C:8]3=2)[O:3][CH2:2]1.C[N+]1([O-])CCOCC1>C(#N)C>[CH2:1]1[C:9]2[C:4](=[N:5][CH:6]=[C:7]3[CH2:12][CH2:11][C:10](=[O:13])[C:8]3=2)[O:3][CH2:2]1
Reactant: OC1CCc2cnc3c(c21)CCO3
Agent: C[N+]1([O-])CCOCC1
Solvent: CC#N
Product: O=C1CCc2cnc3c(c21)CCO3
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 67.8 %

Procedure:
A suspension of 1,6,7,8-tetrahydro-2H-cyclopenta[d]furo[2,3-b]pyridin-8-ol (500 mg, 2.82 mmol), 4 Å molecular sieves (1 g), 4-methylmorpholine N-oxide (825 mg, 7.05 mmol) and tetra-n-propylammonium perruthenate(VII) (99 mg, 0.282 mmol) in acetonitrile (15 mL) was stirred at room temperature for 15 min. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate) to give the title compound (335 mg, yield 68%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH2:8]O.S(Cl)([Cl:12])=O.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH2:8][Cl:12]
Reactant: OCc1ccncc1Cl
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: ClCc1ccncc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.7 %

Procedure:
To a mixture of 0.70 g of (3-chloropyridin-4-yl)methanol and 8 ml of chloroform was added dropwise 0.70 g of thionyl chloride at room temperature, and the mixture was stirred at room temperature for 2 hours. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, and the mixture was extracted twice with chloroform. The organic layers were combined and dried over magnesium sulfate. The resulting mixture was concentrated under reduced pressure to obtain 0.78 g of 3-chloro-4-(chloromethyl)pyridine.
Reaction SMILES: C1COCC1.[CH2:6]([O:8][C:9]([CH:11]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[O:10])[CH3:7].[H-].[Na+].[Br:31][C:32]1[C:37]([CH2:38]Br)=[C:36]([O:40][CH3:41])[C:35]([O:42][CH3:43])=[C:34]([O:44][CH3:45])[C:33]=1[O:46][CH3:47]>[Cl-].[NH4+]>[Br:31][C:32]1[C:37]([CH2:38][C:11]([C:9]([O:8][CH2:6][CH3:7])=[O:10])([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:36]([O:40][CH3:41])[C:35]([O:42][CH3:43])=[C:34]([O:44][CH3:45])[C:33]=1[O:46][CH3:47]
Reactant: COc1c(Br)c(CBr)c(OC)c(OC)c1OC
Reactant: CCOC(=O)CCCCCCCC(C(=O)OCC)C(=O)OCC
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCOC(=O)CCCCCCCC(Cc1c(Br)c(OC)c(OC)c(OC)c1OC)(C(=O)OCC)C(=O)OCC
Reaction time: 2 h
Yield: 65.6 %

Procedure:
A THF (10 ml) solution of ethyl 2,9-diethoxycarbonylnonanoate (8.86 g, 26.8 mmols) was dropwise added to a THF (90 ml) suspension of sodium hydride (60% oily, 1.29 g, 32.2 mmols) at room temperature. The reaction mixture was stirred for 2 hours, and then a THF (10 ml) solution of 1-bromo-6-bromomethyl-2,3,4,5-tetramethoxybenzene (10.9 g, 29.5 mmols) was dropwise added at room temperature, and stirring was continued for additional 2 hours. The reaction mixture was diluted with a saturated aqueous ammonium chloride solution and then concentrated in vacuo. The residue was extracted with ethyl acetate, and the resulting organic layer was washed with water and a saturated aqueous sodium chloride solution, then dried, and concentrated in vacuo. The crude product thus obtained was purified by silica gel column chromatography (hexane:ethyl acetate=10:1 to 4:1) to obtain the entitled compound (10.9 g) as an oil.
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:10]([NH2:13])[CH:11]=[CH2:12]>C1C=CC=CC=1>[C:1]1([NH:7][C:8]([NH:13][CH2:10][CH:11]=[CH2:12])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C=Nc1ccccc1
Reactant: C=CCN
Solvent: c1ccccc1
Product: C=CCNC(=O)Nc1ccccc1
Reaction time: 8 h
Yield: 81.1 %

Procedure:
A solution of 100 g (0.84 mole) phenylisocyanate in 50 ml of benzene was added dropwise over a period of 30 minutes to a stirring solution of 60 g (1.05 mole) allyl amine in 2 liters of benzene. The mixture was stirred overnight and suction filtered yielding 120 g (95% yield) of 1-phenyl-3-allyl urea with a melting point of 112°-113°. This material was also characterized by IR and nmr analysis.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[C:4](=[O:21])[C@@H:5]2[CH2:20][C@@:8]3([CH2:19][C:18]4[C:14]5[N:15]=[N:16][NH:17][C:13]=5[CH:12]=[CH:11][C:10]=4[C:9]=13)[CH2:7][CH2:6]2.[BH4-].[Na+]>C(O)C>[F:22][C:2]([F:1])([F:23])[C:3]1[C@H:4]([OH:21])[C@H:5]2[CH2:20][C@:8]3([CH2:19][C:18]4[C:14]5[N:15]=[N:16][NH:17][C:13]=5[CH:12]=[CH:11][C:10]=4[C:9]=13)[CH2:7][CH2:6]2
Reactant: O=C1C(C(F)(F)F)=C2c3ccc4[nH]nnc4c3C[C@]23CC[C@H]1C3
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: O[C@H]1C(C(F)(F)F)=C2c3ccc4[nH]nnc4c3C[C@@]23CC[C@@H]1C3
Reaction time: 1 h

Procedure:
A solution of (8S,10aR)-6-(trifluoromethyl)-3,9,10,11-tetrahydro-8,10a-methanocyclohepta[1,2]indeno[4,5-d][1,2,3]triazol-7(8H)-one (6.0 mg, 0.019 mmol) in ethanol (0.5 mL) was cooled to 0° C. and solid sodium borohydride (2.8 mg, 0.075 mmol) was added. After 1 hour, the reaction was quenched by addition of water and was directly loaded onto a reverse phase HPLC column eluting with MeCN/water (10:90 to 90:10). The fraction containing the desired product was concentrated under vacuum and then partitioned between ethyl acetate and pH 7 phosphate buffer. The organic phase was washed with brine and dried over MgSO4. The solution was filtered and evaporated under vacuum and the residue was lyophilized from benzene to give (7R,8R,10aS)-6-(trifluoromethyl)-3,7,8,9,10,11-hexahydro-8,10a-methanocyclohepta[1,2]indeno[4,5-d][1,2,3]triazol-7-ol as a white solid.
Reaction SMILES: [NH:1]=[C:2]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([NH:19][C:20]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([S:29](=[O:43])(=[O:42])[NH:30][CH2:31][C:32]3[CH:37]=[CH:36][C:35]([S:38](=[O:41])(=[O:40])[NH2:39])=[CH:34][CH:33]=3)=[CH:25][CH:24]=2)=[O:21])[CH:14]=1)[N:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][CH3:12])=[O:10])[CH2:5][CH2:4]1.CCN(C(C)C)C(C)C.[C:53](Cl)(=[O:55])[CH3:54].O>C(Cl)Cl.CN(C=O)C>[C:53]([N:1]=[C:2]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([NH:19][C:20]([NH:22][C:23]2[CH:24]=[CH:25][C:26]([S:29](=[O:42])(=[O:43])[NH:30][CH2:31][C:32]3[CH:37]=[CH:36][C:35]([S:38](=[O:41])(=[O:40])[NH2:39])=[CH:34][CH:33]=3)=[CH:27][CH:28]=2)=[O:21])[CH:14]=1)[N:3]1[CH2:4][CH2:5][N:6]([C:9]([O:11][CH3:12])=[O:10])[CH2:7][CH2:8]1)(=[O:55])[CH3:54]
Reactant: CC(=O)Cl
Reactant: COC(=O)N1CCN(C(=N)c2cccc(NC(=O)Nc3ccc(S(=O)(=O)NCc4ccc(S(N)(=O)=O)cc4)cc3)c2)CC1
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCl
Product: COC(=O)N1CCN(C(=NC(C)=O)c2cccc(NC(=O)Nc3ccc(S(=O)(=O)NCc4ccc(S(N)(=O)=O)cc4)cc3)c2)CC1
Temperature: 0 °C
Yield: 19 %

Procedure:
100 mg of compound 60 were dissolved in 2 ml of DCM/DMF 1:1 solution, containing 2 eq of DIEA. Under stirring and at 0° C., 6 eq of acetylchloride were added portionwise during 30 minutes. The solution was stirred overnight at rt, then water was added and a precipitate formed. The precipitate was separated and the title compound was obtained after preparative HPLC purification.
Reaction SMILES: Br[C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[CH:8]([OH:18])[CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[CH2:19]([O:21][C:22](=[O:48])[CH2:23][C:24]1([C:27]2[CH:32]=[CH:31][C:30]([C:33]3[CH:38]=[CH:37][C:36](B4OC(C)(C)C(C)(C)O4)=[CH:35][CH:34]=3)=[CH:29][CH:28]=2)[CH2:26][CH2:25]1)[CH3:20]>>[CH2:19]([O:21][C:22](=[O:48])[CH2:23][C:24]1([C:27]2[CH:28]=[CH:29][C:30]([C:33]3[CH:38]=[CH:37][C:36]([C:2]4[CH:6]=[N:5][N:4]([CH3:7])[C:3]=4[CH:8]([OH:18])[CH2:9][CH2:10][CH2:11][C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)=[CH:35][CH:34]=3)=[CH:31][CH:32]=2)[CH2:25][CH2:26]1)[CH3:20]
Reactant: Cn1ncc(Br)c1C(O)CCCc1ccccc1
Reactant: CCOC(=O)CC1(c2ccc(-c3ccc(B4OC(C)(C)C(C)(C)O4)cc3)cc2)CC1
Product: CCOC(=O)CC1(c2ccc(-c3ccc(-c4cnn(C)c4C(O)CCCc4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 5, Step 2, using the following starting materials: 1-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-phenyl-butan-1-ol and {1-[4′-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-biphenyl-4-yl]-cyclopropyl}-acetic acid ethyl ester.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4](Cl)[C:5]([C:8]#[N:9])=[N:6][CH:7]=1.[CH3:11][O-:12].[Na+].CO>CO.O>[NH2:1][C:2]1[N:3]=[C:4]([O:12][CH3:11])[C:5]([C:8]#[N:9])=[N:6][CH:7]=1
Reactant: N#Cc1ncc(N)nc1Cl
Reactant: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1nc(N)cnc1C#N
Temperature: 80 °C
Yield: 58 %

Procedure:
5-Amino-3-chloropyrazine-2-carbonitrile (52 mg, 0.34 mmol) was suspended in NaOMe/MeOH (2M, 2 mL). The reaction mixture was heated at 80° C. for 30 min using microwave irradiation. After cooling, the mixture was diluted with MeOH (3 mL) and water (2 mL). The solvents were concentrated and the resulting precipitate was filtered off, washed with water (3 mL) and dried in vacuo to give the title compound as a yellow solid (33 mg, 58%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.CO[C:9]1[C:10](=[O:16])[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1>CO>[N:1]1([C:11]2[C:10](=[O:16])[CH:9]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:6][CH2:5][N:4]([C:9]2[C:10](=[O:16])[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:3][CH2:2]1
Reactant: COc1cccccc1=O
Reactant: C1CNCCN1
Solvent: CO
Product: O=c1cccccc1N1CCN(c2cccccc2=O)CC1
Temperature: 95 °C
Yield: 32.9 %

Procedure:
To a solution of piperazine (7.74 g) in methanol (10 ml) at 70° C., a solution of 2-methoxy-2,4,6-cycloheptatrien-1-one (8.16 g) in methanol (50 ml) was added drop by drop. The reaction mixture was heated at 95° C. for 5 hr, cooled and evaporated. The residue was dissolved in chloroform and water. The organic extract was separated, dried and evaporated. The residue was chromatographed on silica gel (250 g) using chloroform then 5% methanol in chloroform, increasing gradually the concentration of methanol up to 20%. The product was recrystallized from methanol to yield 2.9 g of the title compound: mp 184°-186° C.; ir(CHCl3) 1565 cm-1 ; uv max(MeOH) 355 (ε=19075), 256 (ε=29080) and 223 nm (ε=22460); nmr(CDCl3) δ3.55 (m, 8H) and 7.0 (m, 10H); and Anal. Calcd for C 18 H18N2O2 : C, 73.45% H, 6.16% N, 9.52% and Found: C, 73.76% H, 6.17% N, 9.45%.
Reaction SMILES: [CH3:1][O:2][C@@H:3]1[O:8][C@H:7]([CH2:9][OH:10])[C@H:6]([OH:11])[C@H:5]([OH:12])[C@H:4]1[OH:13].CC1C=C(C(C)(C)C)C(O)=C(C(C)(C)C)C=1.[OH-].[Na+].[C:32]([O:36][CH2:37]CO)(=[O:35])[CH:33]=[CH2:34]>OP(O)=O.O[Mo](O)(=O)=O>[CH:3]1([O:2][CH2:1][CH2:37][O:36][C:32](=[O:35])[CH:33]=[CH2:34])[O:8][C@H:7]([CH2:9][OH:10])[C@H:6]([OH:11])[C@H:5]([OH:12])[C@H:4]1[OH:13]
Reactant: CO[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Reactant: C=CC(=O)OCCO
Agent: O=[Mo](=O)(O)O
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: O=[PH](O)O
Product: C=CC(=O)OCCOC1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O

Procedure:
A 20.0 g quantity of methyl β-D-galactoside (product of Nacalai Co., Ltd., a guaranteed reagent)was suspended in 150 ml of 2-hydroxyethyl acrylate. To the suspension were added 1.0 g of butylhydroxytoluene and 1.0 g of phosphomolybdic acid, and the mixture was stirred well and gradually heated. After heating to a temperature of 60° to 70° C., the mixture was further stirred for about 2 hours while maintaining the same temperature, and was neutralized with 2N sodium hydroxide. The obtained reaction mixture was purified in the same manner as in Example 1. A fraction (Rf =0.2) of the reaction mixture was concentrated, giving 15.8 g of galactosyloxyethylacrylate (HEA-Gal) as an oily product (yield 55%).
Reaction SMILES: C[O:2][C:3](=O)[N:4]=[C:5](SC)[C:6]([C:20]1[CH:25]=[C:24]([CH2:26][O:27][CH3:28])[C:23]([O:29][CH3:30])=[C:22]([O:31][CH3:32])[CH:21]=1)=[N:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:18]=[C:17]([CH3:19])[O:16][N:15]=2)=[CH:10][CH:9]=1.[NH:36]([C:38]1[N:43]=[CH:42][CH:41]=[CH:40][N:39]=1)[NH2:37].C(N(CC)CC)C>CN(C=O)C>[CH3:32][O:31][C:22]1[CH:21]=[C:20]([CH:6]([NH:7][C:8]2[CH:9]=[CH:10][C:11]([C:14]3[N:18]=[C:17]([CH3:19])[O:16][N:15]=3)=[CH:12][CH:13]=2)[C:5]2[NH:4][C:3](=[O:2])[N:36]([C:38]3[N:43]=[CH:42][CH:41]=[CH:40][N:39]=3)[N:37]=2)[CH:25]=[C:24]([CH2:26][O:27][CH3:28])[C:23]=1[O:29][CH3:30]
Reactant: NNc1ncccn1
Reactant: COCc1cc(C(=Nc2ccc(-c3noc(C)n3)cc2)C(=NC(=O)OC)SC)cc(OC)c1OC
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COCc1cc(C(Nc2ccc(-c3noc(C)n3)cc2)c2nn(-c3ncccn3)c(=O)[nH]2)cc(OC)c1OC
Temperature: 85 °C
Reaction time: 8 h
Yield: 49.5 %

Procedure:
To a solution of 169 mg of [2-(3,4-dimethoxy-5-methoxymethylphenyl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene]carbamic acid methyl ester in 2 ml of DMF there were added 40 mg of 2-hydrazinopyrimidine and 50 μl of triethylamine, and the mixture was stirred overnight at 85° C. under a nitrogen atmosphere. The reaction mixture was concentrated, and the residue was dissolved in 3 ml of methanol and 0.3 ml of acetic acid. After adding 100 mg of sodium cyanotrihydroborate to the solution, the mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by NAM silica gel column chromatography (methanol-ethyl acetate) to give 5-{(3,4-dimethoxy-5-methoxymethylphenyl)-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylamino]methyl}-2-pyrimidin-2-yl-2,4-dihydro-[1,2,4]triazol-3-one (89 mg) as a light brown solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH2:12])(=[O:11])=[O:10])=[CH:5][CH:4]=1.[Br:13][CH2:14][CH2:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[CH:18][CH:17]=1>C1(C)C=CC=CC=1>[Br:13][CH2:14][CH2:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([NH:12][S:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)(=[O:11])=[O:10])=[O:21])=[CH:18][CH:17]=1
Reactant: O=C(Cl)c1ccc(CCBr)cc1
Reactant: COc1ccc(S(N)(=O)=O)cc1
Solvent: Cc1ccccc1
Product: COc1ccc(S(=O)(=O)NC(=O)c2ccc(CCBr)cc2)cc1

Procedure:
A mixture of 18.72 g (0.10 mol) of 4-methoxybenzenesulfonamide, 24.75 g (0.10 mol) of 4-(2-bromoethyl)benzoyl chloride and 200 ml of toluene was stirred and heated to reflux at which time solution was achieved. The solution was heated at reflux for 16.5 hrs. The vapors emitted from the condenser were acidic during reaction. After this time, the solution was cooled and concentrated to an oil. The oil was dissolved in 3:7 heptane:toluene and cooled. Solid crystallized and was collected, washed with ligroine and dried.
Reaction SMILES: CCCCCC.[H-].[Na+].[C:9]([CH2:11]P(=O)(OCC)OCC)#[N:10].[CH2:20]1[C:29](=O)[CH2:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:21]1>C1COCC1.O>[C:21]1([CH2:11][C:9]#[N:10])[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:28][CH2:29][CH:20]=1
Reactant: CCOP(=O)(CC#N)OCC
Reactant: O=C1CCc2ccccc2C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: N#CCC1=CCCc2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.7 %

Procedure:
To a mechanically stirred mixture of hexane washed sodium hydride (8.98 g, 0.187 mol, 50%/mineral oil) in THF (400 mL) was added diethyl cyanomethylphosphonate (33.13 g, 0.187 mol) dropwise. The reaction was stirred at room temperature for 1/2 hour. β-Tetralone (24.8 g, 0.170 mol) in THF (100 mL) was added dropwise at 0° C., and the reaction was stirred at room temperature for 1 hour. The reaction was diluted with water (600 mL) and extracted with ether (3×400 mL). The organic phase was washed with brine, dried (MgSO4), and concentrated under reduced pressure to give an orange oil. Distillation from bulb to bulb under high vacuum yielded 22.65 g (79%) of product as a pale yellow oil.
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.C([Li])CCC.Cl[CH2:22][CH2:23][N:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1>O1CCCC1.CCCCCC>[CH:12]1[C:8]2[CH2:9][CH2:10][C:11]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=3[CH:6]([CH2:22][CH2:23][N:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)[C:7]=2[CH:15]=[CH:14][CH:13]=1
Reactant: ClCCN1CCCC1
Reactant: c1ccc2c(c1)CCc1ccccc1C2
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: c1ccc2c(c1)CCc1ccccc1C2CCN1CCCC1
Reaction time: 1 h

Procedure:
1.0 g of 10,11-dihydro-5H-dibenzo[a,d]cycloheptene in 25 ml of dry tetrahydrofuran is treated dropwise at -70° with 6.8 ml of an about 1.14M solution of n-butyl lithium in hexane. The mixture is stirred at -70° for 60 minutes. There are subsequently added dropwise thereto at -30° 1.1 g of 2-chloroethylpyrrolidine in 2.5 ml of dry tetrahydrofuran and the mixture is stirred at -30° for 1 hour and at 0° to 5° for 3 hours. After evaporation of the mixture, the residue remaining is dissolved in toluene and washed with water. The organic phase is filtered over 10 g of aluminum oxide (activity grade II, neutral) using toluene for the elution. Crude 1-[2-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-yl)ethyl]pyrrolidine is obtained as a yellow oil.
Reaction SMILES: O[CH2:2][CH2:3][N:4]([CH3:17])[C:5]([NH:7][C:8]1[S:12][C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[N:10][N:9]=1)=[O:6].S(Cl)([Cl:20])=O>C1C=CC=CC=1>[Cl:20][CH2:2][CH2:3][N:4]([CH3:17])[C:5]([NH:7][C:8]1[S:12][C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[N:10][N:9]=1)=[O:6]
Reactant: O=S(Cl)Cl
Reactant: CN(CCO)C(=O)Nc1nnc(C(C)(C)C)s1
Solvent: c1ccccc1
Product: CN(CCCl)C(=O)Nc1nnc(C(C)(C)C)s1
Reaction time: 1 h

Procedure:
The N-(β-hydroxyethyl)-N-methyl-N'-(2-t-butyl-1,3,4-thiadiazol-5-yl)urea prepared in Example 2, thionyl chloride (5 ml) and benzene (100 ml) were charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture was heated at reflux, with stirring, for a period of about one hour. After this time the benzene and unreacted thionyl chloride were stripped from the reaction mixture under reduced pressure to yield the desired product N-(β-chloroethyl)-N-methyl-N'-(2-t-butyl-1,3,4-thiadiazol-5-yl)urea as the residue.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[CH2:11][C@H:10]2[C:12]([O:14]C(C)(C)C)=[O:13])=[CH:5][CH:4]=1)#[N:2].CO>O.[OH-].[Na+]>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C@@H:9]2[CH2:11][C@H:10]2[C:12]([OH:14])=[O:13])=[CH:7][CH:8]=1)#[N:2]
Reactant: CC(C)(C)OC(=O)[C@@H]1C[C@H]1c1ccc(C#N)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: N#Cc1ccc([C@@H]2C[C@H]2C(=O)O)cc1
Temperature: 70 °C
Yield: 34.7 %

Procedure:
A round bottom flask was charged with 21B (11.6 g, 47.7 mmol, 1 eq) and MeOH (55 mL). With moderate stirring, a solution was formed. To the solution was added a solution of NaOH (5.7 g, 143.1 mmol, 3 eqs) in H2O (30 mL). The resulting mixture was heated in an oil bath at a temperature of 70° C. for 4 h. The reaction mixture was analyzed for completion using 1H NMR. After confirming completion of the reaction, the reaction mixture was concentrated to one-third its volume and the rest of the reaction mixture was diluted by the addition of 50 mL of a NaOH (0.5 M) solution. The resulting mixture was washed with 2×25 mL of MTBE. The aq. layer was separated and acidified by the dropwise addition of conc. HCl until the pH of the mixture was ˜1. The acidified mixture was extracted with 2×50 mL of EtOAc. The combined organic extracts were dried over MgSO4 and evaporated to dryness on a rotary evaporator to give crude product. The crude product was purified by flash chromatography, eluting with 1-10% MeOH in DCM. The product was isolated as a single spot on TLC. However, 1H NMR analysis of this product indicated a small amount of impurities were present. This material was then dissolved in a 1 M solution of NaOH (30 mL) and washed with 2×25 mL of EtOAc. The aq. layer was separated and re-acidified to pH ˜1 by the dropwise addition of conc. HCl. The mixture formed was extracted with EtOAc (50 mL). The organic extract was evaporated to dryness to give 3.1 g 21C as a white solid (36.4% yield). Note: a very small amount of impurities were still present in the material, as revealed by 1H NMR. 1H NMR (400 MHz, CDCl3-d) δ ppm 1.37-1.46 (m, 1H) 1.47-1.55 (m, 1H) 1.87-1.96 (m, 1H) 2.43-2.49 (m, 1H) 7.38 (d, 2H) 7.74 (d, 2H) 12.43 (s, 1H).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Cl:5][C:6]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:7]=1[C:8](Cl)=[O:9].[CH3:16][O:17][C:18]([C:20]1[CH:29]=[CH:28][C:23]2[O:24][C:25]([CH3:27])=[CH:26][C:22]=2[CH:21]=1)=[O:19]>C(Cl)Cl>[Cl:5][C:6]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:7]=1[C:8]([C:26]1[C:22]2[CH:21]=[C:20]([C:18]([O:17][CH3:16])=[O:19])[CH:29]=[CH:28][C:23]=2[O:24][C:25]=1[CH3:27])=[O:9]
Reactant: COC(=O)c1ccc2oc(C)cc2c1
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COC(=O)c1ccc2oc(C)c(C(=O)c3ccc(Cl)cc3Cl)c2c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Aluminum chloride (2.52 g, 18.9 mmol) was suspended in methylene chloride (25 ml) and 2,4-dichlorobenzoyl chloride (1.98 g, 9.5 mmol) was added. Then, 5-(methoxycarbonyl)-2-methylbenzo[b]furan (1.5 g, 7.9 mmol) was added and the mixture was stirred at room temperature for 1.5 hr. The reaction mixture was poured into ice water and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate (twice) and then saturated brine, and dried over anhydrous sodium sulfate. The desiccant was filtered off and the filtrate was concentrated under reduced pressure to give the objective compound (2.9 g, quantitative) as colorless crystals.
Reaction SMILES: [CH:1]1([Mg]Cl)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:9]([C:11]1[S:12][C:13](SC)=[C:14]2[C:19](=[O:20])[CH2:18][C:17]([CH3:22])([CH3:21])[CH2:16][C:15]=12)#[N:10]>>[C:9]([C:11]1[S:12][C:13]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[C:14]2[C:19](=[O:20])[CH2:18][C:17]([CH3:22])([CH3:21])[CH2:16][C:15]=12)#[N:10]
Reactant: CSc1sc(C#N)c2c1C(=O)CC(C)(C)C2
Reactant: Cl[Mg]C1CCCCC1
Product: CC1(C)CC(=O)c2c(C3CCCCC3)sc(C#N)c2C1
Yield: 28 %

Procedure:
In the same way as described in Example 6, Step 1, using cyclohexylmagnesium chloride and 1-cyano-6,6-dimethyl-3-methylthio-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one, the title compound (0.63 g, 28%) was isolated as a cream solid. mp 129-132° C. 1HNMR (360 MHz, CDCl3) δ 1.07 (6H, s), 1.20-1.55 (5H, m), 1.75-1.85 (3H, m), 2.01-2.06 (2H, m), 2.42 (2H, s), 2.84 (2H, s), 3.85-3.94 (1H, M).