Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[F:2][C:3]([F:28])([F:27])[C:4]1[CH:17]=[CH:16][C:15]2[S:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]([CH2:18][CH2:19][CH2:20][N:21]3[CH2:25][CH2:24][CH:23]([OH:26])[CH2:22]3)[C:6]=2[CH:5]=1.[C:29](Cl)(=[O:35])[CH2:30][CH2:31][CH2:32][CH2:33][CH3:34].CO>ClC(Cl)C>[F:28][C:3]([F:27])([F:2])[C:4]1[CH:17]=[CH:16][C:15]2[S:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]([CH2:18][CH2:19][CH2:20][N:21]3[CH2:25][CH2:24][CH:23]([O:26][C:29](=[O:35])[CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH2:22]3)[C:6]=2[CH:5]=1
Reactant: OC1CCN(CCCN2c3ccccc3Sc3ccc(C(F)(F)F)cc32)C1
Reactant: CCCCCC(=O)Cl
Agent: Cl
Solvent: CC(Cl)Cl
Solvent: CO
Product: CCCCCC(=O)OC1CCN(CCCN2c3ccccc3Sc3ccc(C(F)(F)F)cc32)C1

Procedure:
8.6 G. of 2-trifluoromethyl-10-[3-(3-hydroxypyrrolidino)-propyl]-phenothiazine.hydrochloride were dissolved in 100 ml of dichloroethane. To the solution were added drop by drop 3.0 g of caproylchloride at a room temperature with stirring. This mixture was heated under reflux for two hours. After cooling, 20 ml of methanol were added to said mixture, and the whole was stirred for about 1 hour. The resulting reaction mixture was washed, in turn, with water, aqueous potasium carbonate solution and water respectively, and dried over sodium sulphate. The solvent was distilled off under a reduced pressure. The resulting pale brown oily material was purified by means of silicagel column chromatography (solvent for elution: the mixed solvent of n-hexan.ethylacetate), thereby obtaining the object as the free base, which was pale yellowish viscous liquid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH2:8][N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[N:6][CH:7]=1.[CH3:15][C:16]1C=CC(C#C)=CN=1>>[C:15]([C:2]1[CH:3]=[CH:4][C:5]([CH2:8][N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[N:6][CH:7]=1)#[CH:16]
Reactant: Brc1ccc(CN2CCOCC2)nc1
Reactant: C#Cc1ccc(C)nc1
Product: C#Cc1ccc(CN2CCOCC2)nc1

Procedure:
4-(5-Ethynyl-pyridin-2-ylmethyl)-morpholine was prepared from 4-(5-bromo-pyridine-2-ylmethyl)-morpholine (U.S. Pat. No. 6,358,945) in the same manner as 2-methyl-5-ethynyl pyridine (Example 7).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([CH2:28][O:29]S(C)(=O)=O)[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:18][CH:17]=2)=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[Cl:34][C:35]1[CH:40]=[CH:39][C:38](O)=[CH:37][CH:36]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([CH2:28][O:29][C:38]2[CH:39]=[CH:40][C:35]([Cl:34])=[CH:36][CH:37]=2)[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:18][CH:17]=2)=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: CCOC(=O)Cc1ccc(NC(=O)C(COS(C)(=O)=O)NS(=O)(=O)c2ccc(Cl)cc2)cc1
Product: CCOC(=O)Cc1ccc(NC(=O)C(COc2ccc(Cl)cc2)NS(=O)(=O)c2ccc(Cl)cc2)cc1
Yield: 64.8 %

Procedure:
The procedure described in Example 125 was repeated, except that (RS)-2-(4-chlorobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-3-methanesulfonyloxypropanamide (360 mg) was reacted with 4-chlorophenol (178.3 mg) to obtain (RS)-2-(4-chlorobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl)phenyl)-3-(4-chlorophenoxy) propanamide (248 mg).
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]([C:18]([NH2:20])=[O:19])[CH2:12]2.[C:21](Cl)(=[O:23])[CH3:22]>ClC(Cl)Cl>[C:21]([N:14]1[C:15]2[C:11](=[CH:10][C:9]([Cl:8])=[CH:17][CH:16]=2)[CH2:12][CH:13]1[C:18]([NH2:20])=[O:19])(=[O:23])[CH3:22]
Reactant: CC(=O)Cl
Reactant: NC(=O)C1Cc2cc(Cl)ccc2N1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(=O)N1c2ccc(Cl)cc2CC1C(N)=O
Temperature: 5 °C
Reaction time: 0.08 h
Yield: 85.7 %

Procedure:
Triethylamine (0.02080 mole) was added to intermediate (7) (0.09632 mole) dissolved in trichloromethane (700 ml). The mixture was cooled to 5° C. Acetyl chloride (0.2480 mole) was added over 2 minutes with stirring. After 5 minutes, a precipitate formed. The ice bath was removed, and the container allowed to sit for 15 minutes. Ice water (250 ml) was added, and the mixture was stirred for 10 minutes. The sample was filtered, rinsed with water and trichloromethane. The solid was suspended in water (200 ml), and swirled for 10 minutes. Trichloromethane (200 ml) was added and the mixture was stirred, then filtered and rinsed with water and trichloromethane, and then dried to the air overnight, yielding 19.71 g of 1-acetyl-5-chloro-2,3-dihydro-1H-indole-2-carboxamide (intermediate 8).
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[CH:3]1[CH2:8][NH:7][CH2:6][CH2:5][NH:4]1.[CH:11]1([N:14]2[C:23]3[C:18](=[CH:19][C:20]([F:25])=[C:21](F)[CH:22]=3)[C:17](=[O:26])[C:16]([C:27]([OH:29])=[O:28])=[CH:15]2)[CH2:13][CH2:12]1>N1C=CC=CC=1>[CH:11]1([N:14]2[C:23]3[C:18](=[CH:19][C:20]([F:25])=[C:21]([N:7]4[CH2:6][CH2:5][NH:4][CH:3]([C:2]([F:10])([F:9])[F:1])[CH2:8]4)[CH:22]=3)[C:17](=[O:26])[C:16]([C:27]([OH:29])=[O:28])=[CH:15]2)[CH2:12][CH2:13]1
Reactant: FC(F)(F)C1CNCCN1
Reactant: O=C(O)c1cn(C2CC2)c2cc(F)c(F)cc2c1=O
Solvent: c1ccncc1
Product: O=C(O)c1cn(C2CC2)c2cc(N3CCNC(C(F)(F)F)C3)c(F)cc2c1=O
Temperature: 77 °C
Reaction time: 3 h

Procedure:
A 0.55 g portion of 2-(trifluoromethyl)piperazine was dissolved in 14 ml of pyridine. To this was added 265 mg of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid. The mixture was stirred for 3 hours at 77° C.. The pyridine was removed by repeated evaporation with toluene. The residue was triturated with hot methanol. The resulting solid was collected, washed with methanol and ether and dried, giving 105 mg of the desired product as a colorless solid.
Reaction SMILES: [Br:1][C:2]1[C:10]2[O:9][C:8](SC)=[N:7][C:6]=2[C:5]([O:13][CH3:14])=[CH:4][CH:3]=1.[NH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1>>[Br:1][C:2]1[C:10]2[O:9][C:8]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[N:7][C:6]=2[C:5]([O:13][CH3:14])=[CH:4][CH:3]=1
Reactant: C1COCCN1
Reactant: COc1ccc(Br)c2oc(SC)nc12
Product: COc1ccc(Br)c2oc(N3CCOCC3)nc12
Temperature: 80 °C

Procedure:
A mixture of 7-bromo-4-methoxy-2-methylsulfanylbenzooxazole (10.0 g) and morpholine (6.6 ml) were heated at 80° C. for 18 hours. Purification by chromatography on silica eluting with 20-100% ethyl acetate in heptane afforded the title compound as an off-white solid (11.6 g).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][N:12]([CH:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[Cl:26][C:27]1[CH:28]=[C:29]2[C:34](=[CH:35][CH:36]=1)[N:33]([CH2:37][CH:38]=O)[C:32](=[O:40])[CH:31]=[CH:30]2.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(O)(=O)C.C(Cl)(Cl)Cl>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][N:12]([CH:20]3[CH2:25][CH2:24][N:23]([CH2:38][CH2:37][N:33]4[C:34]5[C:29](=[CH:28][C:27]([Cl:26])=[CH:36][CH:35]=5)[CH:30]=[CH:31][C:32]4=[O:40])[CH2:22][CH2:21]3)[C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:16])[CH3:17])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCNCC1
Reactant: O=CCn1c(=O)ccc2cc(Cl)ccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCN(CCn2c(=O)ccc3cc(Cl)ccc32)CC1
Temperature: 25 °C
Yield: 60.1 %

Procedure:
To 4 mL of a chloroform solution containing 0.68 g of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(piperidin-4-yl)carbamate, 0.44 g of (6-chloro-2-oxoquinolin-1(2H)-yl)acetaldehyde and 40 μL of acetic acid were added, then, to the reaction mixture, 0.62 g of sodium triacetoxyborohydride was added and stirred at room temperature for 2 nights. Aqueous saturated sodium hydrogen carbonate solution was added, the organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and extracts were combined, washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [Silica Gel; Kanto Chemical Co., Inc., Silica Gel 60, eluent; ethyl acetate], to give 0.65 g of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(6-chloro-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate as a white foam.
Reaction SMILES: C1(C)C=CC(S([O-])(=O)=O)=CC=1.[CH3:12][N+:13]1[C:17]2[CH2:18][CH2:19][CH2:20][CH2:21][C:16]=2[S:15][C:14]=1SC.[CH2:24]([NH:26][C:27]1[CH:34]=[CH:33][C:30]([C:31]#[N:32])=[CH:29][C:28]=1[N:35]=[C:36]1[N:40]([CH2:41][C:42]2[CH:43]=[N:44][CH:45]=[CH:46][CH:47]=2)[C:39](=[O:48])[CH2:38][S:37]1)[CH3:25]>>[CH2:24]([NH:26][C:27]1[CH:34]=[CH:33][C:30]([C:31]#[N:32])=[CH:29][C:28]=1[N:35]=[C:36]1[N:40]([CH2:41][C:42]2[CH:43]=[N:44][CH:45]=[CH:46][CH:47]=2)[C:39](=[O:48])[C:38](=[C:14]2[N:13]([CH3:12])[C:17]3[CH2:18][CH2:19][CH2:20][CH2:21][C:16]=3[S:15]2)[S:37]1)[CH3:25]
Reactant: CCNc1ccc(C#N)cc1N=C1SCC(=O)N1Cc1cccnc1
Reactant: CSc1sc2c([n+]1C)CCCC2
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Product: CCNc1ccc(C#N)cc1N=C1SC(=C2SC3=C(CCCC3)N2C)C(=O)N1Cc1cccnc1

Procedure:
The title compound was prepared in a manner similar to Example 168 by condensing intermediate 3-methyl-2-methylthio-4,5,6,7-tetrahydro-benzothiazol-3-ium p-toluenesulfonate with 4-ethylamino-3-(4-oxo-3-pyridin-3-ylmethylthiazolidin-2-ylideneamino)benzonitrile. MS(ESI): 503 (MH+).
Reaction SMILES: [C:1]12C[CH:5]([C:6]1(C)C)[CH2:4][CH:3]([C:10]1([CH:20]3CC4CC(C4(C)C)=C3C)[CH2:15]C3CC(C3(C)C)=[C:11]1C)[C:2]=2C.C(OC1C(OC(=O)C)=C(I)C=CC=1)(=[O:33])C>C(Cl)(Cl)(Cl)Cl>[C:10]([CH:3]1[CH2:4][CH2:5][C:6](=[O:33])[CH2:1][CH2:2]1)([CH3:20])([CH3:15])[CH3:11]
Reactant: CC(=O)Oc1cccc(I)c1OC(C)=O
Reactant: CC1=C2CC(CC1C1(C3CC4CC(=C3C)C4(C)C)CC3CC(=C1C)C3(C)C)C2(C)C
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)C1CCC(=O)CC1
Reaction time: 0.5 h

Procedure:
To a 4-t-butylcyclohexane-1,1-dihydroperoxide and terpinene (trapping reagent) in a stirred room temperature solution of carbon tetrachloride was added, over a period of five to ten minutes, a solution of bisacetoxyiodobenzene (BAIB) in carbon tetrachloride. Rapid bubbling commenced upon addition of the BAIB solution and ceased within a few minutes after addition was completed. Stirring was continued for 0.5 h, after which the solution was filtered through a plug of silica, which was washed with CH2Cl2. The residue obtained upon concentration was purified by column chromatography on silica gel to give 4-t-butyl cyclohexanone and the trapping product ascaridole (endoperoxide of terpinene).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.C[C:13]1[CH:17]=[C:16](C)[NH:15][C:14]=1[CH:19]=O.N1CCCCC1>CCO>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:19][C:14]1[NH:15][CH:16]=[CH:17][CH:13]=1
Reactant: Cc1cc(C)c(C=O)[nH]1
Reactant: O=C1Cc2cc(Cl)ccc2N1
Solvent: CCO
Solvent: C1CCNCC1
Product: O=C1Nc2ccc(Cl)cc2C1=Cc1ccc[nH]1
Temperature: 25 °C
Yield: 44.2 %

Procedure:
A mixture of 5-chlorooxindole (6.98 g, 41.6 mmol), 3,5-dimethyl-1H-pyrrole-2-carboxaldehyde (5.12 g, 41.6 mmol) and piperidine (410 μL, 4.16 mmol) in 200 mL of EtOH was heated at reflux for 8 h. The reaction mixture was cooled to room temperature and filtered to give the title compound (4.50 g, 40%) as a red/orange solid.
Reaction SMILES: [Na].[C:2]([NH:5][CH:6]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:4])[CH3:3].Cl.[N:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24]Cl)[CH:19]=1>CCO>[N:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][C:6]([NH:5][C:2](=[O:4])[CH3:3])([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH:19]=1
Reactant: ClCc1cccnc1
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(Cc1cccnc1)(NC(C)=O)C(=O)OCC
Yield: 30.2 %

Procedure:
Sodium metal (1.40 g, 61 mmol) was dissolved in EtOH (100 mL) and diethyl acetamidomalonate (6.62 g, 30.5 mmol) and 3-picolylchloride hydrochloride (5.00 g, 30.5 mmol) were added. The mixture was heated to reflux for 6 hours, and then cooled and filtered to remove NaCl (washed with EtOH). The solvent was removed in vacuo and the mixture was taken up into saturated aqueous NaHCO3 (100 mL) and extracted with EtOAc (3×100 mL). The solvent was removed and the residue purified by silica gel flash chromatography (95:5 CH2Cl2/MeOH) to give diethyl 2-(3-pyridylmethyl)-2-acetamidomalonate (2.84 g, 30%).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([S:12][CH3:13])[CH:10]=2)[N:5]=[C:4]([C:14]([F:17])([F:16])[F:15])[N:3]=1.ClC1C=CC=C(C(OO)=[O:26])C=1>C(Cl)(Cl)Cl>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([S:12]([CH3:13])=[O:26])[CH:10]=2)[N:5]=[C:4]([C:14]([F:15])([F:17])[F:16])[N:3]=1
Reactant: CSc1ccc2nc(C(F)(F)F)nc(Cl)c2c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: CS(=O)c1ccc2nc(C(F)(F)F)nc(Cl)c2c1
Yield: 48.5 %

Procedure:
A solution of 4-chloro-6-methylthio-2-trifluoromethylquinazoline (0.4 g, 1.4 mmol) and m-chloroperbenzoic acid (0.3 g, 1.4 mmol) in chloroform (14 mL) was stirred at 0° C. for 0.5 h. The reaction mixture was washed with saturated sodium bisulfite solution, 1M sodium bicarbonate solution, and brine. The solution was dried (Na2SO4), filtered, and concentrated to give the title compound (0.2 g, 49%); m.p. 105-107° C.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[CH:10]=[CH:9][C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:7][C:5]=2[N:6]=1.[Br:17]N1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[Br:17][CH2:1][C:2]1[O:3][C:4]2[CH:10]=[CH:9][C:8]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)=[CH:7][C:5]=2[N:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1nc2cc(-c3ccccc3)ccc2o1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1nc2cc(-c3ccccc3)ccc2o1
Yield: 32.3 %

Procedure:
2-Methyl-5-phenyl-benzoxazole 48 (1.05 g, 5.0 mmol), N-bromosuccinimide (89 mg, 5.0 mmol) and azodilsobutyronitrile (AIBN) (41 mg, 0.25 mmol) in 10 ml of CCl4 was heated to reflux. After 5 hrs an additional 50 mg AIBN were added and the mixture was refluxed overnight. The mixture was diluted, washed with water, dried and concentrated. The crude product was chromatographed to give about 465 mg 2-bromomethyl-5-phenyl-benzoxazole 49.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH:8]2[CH2:12][CH2:11][CH2:10][NH:9]2)[CH:5]=[CH:4][C:3]=1[C:13]1[NH:17][C:16]2[CH:18]=[CH:19][CH:20]=[C:21]([C:22]([NH2:24])=[O:23])[C:15]=2[N:14]=1.[CH2:25](N(CC)CC)[CH3:26].C(=O)C.C([BH3-])#N.[Na+]>CO.O>[CH2:25]([N:9]1[CH2:10][CH2:11][CH2:12][CH:8]1[C:6]1[CH:5]=[CH:4][C:3]([C:13]2[NH:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21]([C:22]([NH2:24])=[O:23])[C:15]=3[N:14]=2)=[C:2]([F:1])[CH:7]=1)[CH3:26]
Reactant: NC(=O)c1cccc2[nH]c(-c3ccc(C4CCCN4)cc3F)nc12
Reactant: CCN(CC)CC
Agent: CC=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCN1CCCC1c1ccc(-c2nc3c(C(N)=O)cccc3[nH]2)c(F)c1
Reaction time: 1 h

Procedure:
To a solution of EXAMPLE 50F (150 mg) in methanol (6 mL) was added triethylamine (125 mL) and 32 wt/v % acetaldehyde in water (210 mL). The solution was stirred for 1 hour, treated with sodium cyanoborohydride (95 mg), stirred for 3 hours at ambient temperature and at 50° C. for 18 hours and concentrated. The concentrate was purified by HPLC (Zorbax, C-18, 250×2.54 column, mobile phase A: 0.1% TFA in water; B: 0.1% TFA in CH3CN; 0-100% gradient). 1H NMR (CD3OD) δ 1.31-1.36 (m, 3H), 2.30-2.42 (m, 2H), 2.61-2.70 (m, 1H), 3.17-3.29 (m, 2H), 3.34-3.41 (m, 1H), 3.52-3.62 (m, 1H), 3.94-4.01 (m, 1H), 4.64-4.73 (m, 1H), 7.75 (t, J=7.98 Hz, 1H), 7.87 (d, J=7.67 Hz, 1H), 7.93 (d, J=11.35 Hz, 1H), 8.07 (d, J=7.98 Hz, 1H), 8.13 (d, J=7.67 Hz, 1H), 8.28 (t, J=7.52 Hz, 1H).
Reaction SMILES: [CH3:1]/[C:2](=[CH:6]\[CH3:7])/[C:3]([OH:5])=[O:4].[Cl:8][GeH:9]([Cl:11])[Cl:10]>C(OCC)C>[CH3:1][CH:2]([CH:6]([Ge:9]([Cl:11])([Cl:10])[Cl:8])[CH3:7])[C:3]([OH:5])=[O:4]
Reactant: Cl[GeH](Cl)Cl
Reactant: C/C=C(\C)C(=O)O
Solvent: CCOCC
Product: CC(C(=O)O)C(C)[Ge](Cl)(Cl)Cl
Reaction time: 2 h
Yield: 76.5 %

Procedure:
20.02 g (0.2 mol) of (E)-2-methyl-2-butenoic acid was dissolved in 100 ml of dry ethyl ether. 36.0 g (0.2 mol) of trichlorogermane was added to the solution and stirred for 2 hrs. Crystals thus formed were recrystallized from n-hexane to obtain 42.86 g (yield: 76.5%) of 2-methyl-3-(trichlorogermyl)butanoic acid in the form of colorless plate.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:20]=[CH:19][C:7]2[NH:8][C:9](=[O:18])[N:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])[C:6]=2[CH:5]=1.[CH2:21]([N:23]([CH2:37][CH3:38])[C:24](=[O:36])[NH:25][C:26]1[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1)[CH3:22].O>CN(C=O)C>[Cl:3][C:4]1[CH:20]=[CH:19][C:7]2[N:8]([S:32]([C:29]3[CH:28]=[CH:27][C:26]([NH:25][C:24]([N:23]([CH2:37][CH3:38])[CH2:21][CH3:22])=[O:36])=[CH:31][CH:30]=3)(=[O:34])=[O:33])[C:9](=[O:18])[N:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])[C:6]=2[CH:5]=1
Reactant: O=c1[nH]c2ccc(Cl)cc2n1-c1ccccc1Cl
Reactant: CCN(CC)C(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCN(CC)C(=O)Nc1ccc(S(=O)(=O)n2c(=O)n(-c3ccccc3Cl)c3cc(Cl)ccc32)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 47.1 %

Procedure:
0.075 g of sodium hydride as a 60% dispersion in oil is added to a solution of 0.5 g of 5-chloro-3-(2-chlorophenyl)-1,3-dihydro-2H-benzimidazol-2-one in 40 ml of DMF and the mixture is stirred for 30 minutes at RT. 0.6 g of 4-(N',N'-diethylureido)benzenesulfonyl chloride is then added and the mixture is stirred for 4 hours at RT. The reaction mixture is poured into iced water, extracted with AcOEt, washed with water and dried over Na2SO4 and the solvent is evaporated off under vacuum. The residue is chromatographed on silica using a DCM/AcOEt mixture (95/5; v/v) as the eluent to give 0.45 g of the expected product. M.p.=222° C.
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].O.[OH-].[Na+].[CH2:8](Br)[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:10]>C(O)(=O)C.C(O)C>[C:1]([O:4][CH2:8][C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:10])(=[O:3])[CH3:2]
Reactant: O=C(CBr)c1ccccc1
Reactant: CC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(=O)OCC(=O)c1ccccc1

Procedure:
Five grams of acetic acid are added to 25 mls. of water in a suitable vessel and carefully neutralized with 10% aqueous sodium hydroxide. A few drops of acetic acid are then added until the solution is just acid to litmus paper. Fifty milliliters of ethanol and 5 grams of phenacyl bromide are then added and the mixture is refluxed for 1 hour. If a solid separates during refluxing additional ethanol is added to dissolve the same. The solution is allowed to cool and the phenacyl acetate is recovered by filtration and purified by recrystallization from ethanol, m.p. 47°-48° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]=1[O:14][CH3:15])[CH:6]=[CH:7][C:8](O)=[O:9].C(Cl)(=O)C([Cl:19])=O>CN(C=O)C.O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]=1[O:14][CH3:15])[CH:6]=[CH:7][C:8]([Cl:19])=[O:9]
Reactant: COc1ccc(C=CC(=O)O)cc1OC
Reactant: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1ccc(C=CC(=O)Cl)cc1OC
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a mixture of 3,4-dimethoxycinnamic acid (540 mg), DMF (2 drops) and tetrahydrofuran (10 ml) was added oxalyl chloride (0.27 ml) dropwise. The mixture was stirred at room temperature for 40 minutes, at the end of which time the solvent was distilled off to give 3,4-dimethoxycinnamoyl chloride. The chloride was dissolved in dichloromethane (10 ml) followed by addition of 3-amino-4-(2-methylphenyl)-7,8-dihydrocyclopenta [g] [1]benzopyran-2(6H)-one (582 mg) and N,N-dimethylaniline (0.25 ml). The mixture was then stirred at room temperature for 20 hours, after which it was washed with water, dried (MgSO4) and distilled to remove the solvent. The residue was chromatographed on silica gel and eluted with benzene-acetone (9:1) to give 3-(3,4-dimethoxycinnamoylamino) -4-(2-methylphenyl)-7,8-dihydrocyclopenta[g] 1benzopyran-2(6H)-one as oil. The oil was crystallized from ethanol-isopropyl ether (648 mg, 67.4%). Recrystallization from acetone gave colorless needles, m.p. 159°-160° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([NH:8]C(=O)OC(C)(C)C)=[C:4]([NH:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][CH3:22])[CH:3]=1.Cl>O1CCOCC1>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([NH2:8])=[C:4]([NH:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][CH3:22])[CH:3]=1
Reactant: CCCOCCNc1cc(Cl)ncc1NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CCCOCCNc1cc(Cl)ncc1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
A solution of tert-butyl 6-chloro-4-[(2-propoxyethyl)amino]pyridin-3-ylcarbamate (7.08 g, 21.4 mmol) in 1,4-dioxane (20 mL) was treated with 4N HCl in 1,4-dioxane (100 mL) and stirred at room temperature for one hour. The reaction was partitioned between ethyl acetate and saturated sodium bicarbonate solution. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, and solvent was removed at reduced pressure to give 6-chloro-N4-(2-propoxyethyl)pyridine-3,4-diamine as a brown oil. (4.93 g, 100% yield). 1H NMR (CDCl3) δ 7.63 (1H), 6.45 (1H), 4.67 (1H), 3.67 (2H), 3.43 (2H), 3.32-3.27 (2H), 2.92 (2H), 1.64-1.55 (2H), 0.93 (3H).
Reaction SMILES: [NH2:1][NH:2][C:3]([NH2:5])=[S:4].O=[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]1[CH2:13][CH2:14][NH:15][C:16](=[O:20])[CH:17]([CH3:19])[CH3:18].Cl.O>CO>[NH2:5][C:3]([NH:2][N:1]=[C:13]([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:7]=1)[CH2:14][NH:15][C:16](=[O:20])[CH:17]([CH3:19])[CH3:18])=[S:4]
Reactant: NNC(N)=S
Reactant: CC(C)C(=O)NCCC1C=CC=CC1=O
Agent: Cl
Solvent: O
Solvent: CO
Product: CC(C)C(=O)NCC(=NNC(N)=S)c1ccccc1
Yield: 60.7 %

Procedure:
Thiosemicarbazide (2.22 g, 24.4 mmol) was added to a solution of N-(2-oxo-phenyl-ethyl)-2-methyl-propanamide (5.0 g, 24.4 mmol), prepared in the previous step, in 70 ml of methanol plus 6.75 ml of 1N HCl plus 6.25 ml of water and the reaction stirred at room temperature overnight. The solid formed was collected by filtration, rinsed with isopropyl alcohol and hexane, and then dried to give 4.12 g of a white solid. Recrystallization of this solid from isopropyl alcohol gave the title compound (3.15 g, 46%) as a white solid, mp 183-185° C.
Reaction SMILES: [C:1]([Si:3]([CH3:6])([CH3:5])[CH3:4])#[CH:2].C([Mg]Br)C.[CH3:11][O:12][C:13]1[CH:14]=[C:15]([CH:18]=[C:19]([O:21][CH3:22])[CH:20]=1)[CH2:16]Br>C1COCC1.CCOCC>[CH3:22][O:21][C:19]1[CH:18]=[C:15]([CH2:16][C:2]#[C:1][Si:3]([CH3:6])([CH3:5])[CH3:4])[CH:14]=[C:13]([O:12][CH3:11])[CH:20]=1
Reactant: COc1cc(CBr)cc(OC)c1
Reactant: C#C[Si](C)(C)C
Agent: CC[Mg]Br
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1cc(CC#C[Si](C)(C)C)cc(OC)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100.1 %

Procedure:
To a stirred solution of ethynyl trimethylsilane (39.1 mL, 277 mmol, 4 equiv) in THF (120 mL) at 0° C. was added ethylmagnesium bromide (3.16 M in Et2O; 87.6 mL, 277 mmol, 4 equiv). The reaction was allowed to warm to room temperature and stirred for 30 min. After 30 min at room temperature, CuBr (9.93 g, 69.2 mmol, 1 equiv) was added and the reaction was allowed to stir at room temperature for an additional 15 min prior to addition of 3,5-dimethoxybenzylbromide (16.0 g, 69.2 mmol, 1 equiv). The resulting mixture was heated to reflux overnight (20 h). The reaction was diluted with Et2O, cautiously quenched with brine, and extracted with Et2O (×2). The combined organic layers were washed with a saturated aqueous solution of NH4Cl, brine, dried (MgSO4), filtered, and concentrated under reduced pressure. The crude mixture was purified by chromatography on SiO2 (EtOAc/hexanes, 1:10) to give 17.2 g (100% yield) of 7 as a pale yellow oil: Rf 0.41 (EtOAc/hexanes, 1:20); IR (neat) 2956, 2898, 2175, 1754, 1596, 1459, 1428, 1204, 1156, 1122, 1101, 839 cm−1; 1H NMR (400 MHz, CDCl3) δ 6.53 (d, 2H, J=2.4 Hz), 6.34 (t, 1 H, J=2.4 Hz), 3.79 (s, 6 H), 3.60 (s, 2H), 0.19 (s, 9 H); 13C NMR (100 MHz, CDCl3) δ 160.8, 138.7, 105.9, 104.0, 98.7, 87.1, 55.3, 26.3, 0.1; HRMS (ESI+) m/z calcd for C14H21O2Si 249.1311, found 249.1287.