Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=[CH:2][CH2:3][CH:4]1[CH2:12][C:11]2[C:6](=[CH:7][C:8]([O:13][CH2:14][CH3:15])=[CH:9][CH:10]=2)[C:5]1=O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O.[NH2:29][CH2:30][C@H:31]([OH:33])[CH3:32]>C1(C)C=CC=CC=1>[CH2:14]([O:13][C:8]1[CH:7]=[C:6]2[C:11]([CH2:12][C:4]3[CH:3]=[CH:2][N:29]([CH2:30][C@H:31]([OH:33])[CH3:32])[C:5]=32)=[CH:10][CH:9]=1)[CH3:15]
Reactant: C[C@@H](O)CN
Reactant: CCOc1ccc2c(c1)C(=O)C(CC=O)C2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCOc1ccc2c(c1)-c1c(ccn1C[C@@H](C)O)C2
Reaction time: 0.75 h
Yield: 54.6 %

Procedure:
A solution of 1.6 g of (RS)-2-(2-oxoethyl)-6-ethoxy-1-indanone and 70 mg of p-toluenesulfonic acid in 70 ml of anhydrous toluene was heated on a water separator. A solution of 2.2 g of (R)-1-amino-2-propanol in 20 ml of anhydrous toluene was added dropwise to the boiling solution over a period of 5 minutes. Subsequently, the mixture was boiled for an additional 45 minutes, during which the solvent was reduced to a volume of 20 ml. The cooled reaction mixture was purified by column chromatography on silica gel (ethyl acetate/hexane 4:1). 1.03 g (52%) of (R)-1-(7-ethoxy-1,4-dihydro-indeno[1,2-b]pyrrol-1-yl)-propan-2-ol were obtained as a brown oil.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[C:11]([CH2:15][OH:16])=[CH:12][O:13][CH:14]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].N1C=NN=N1.[CH2:22]([O:25][P:26]([O:34][CH2:35][CH:36]=[CH2:37])N(C(C)C)C(C)C)[CH:23]=[CH2:24].C([O:42]O)(C)(C)C>ClCCl.CCCCCC.C(OCC)(=O)C>[P:26]([O:16][CH2:15][C:11]1[C:10]([CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])=[CH:14][O:13][CH:12]=1)([O:25][CH2:22][CH:23]=[CH2:24])([O:34][CH2:35][CH:36]=[CH2:37])=[O:42]
Reactant: C=CCOP(OCC=C)N(C(C)C)C(C)C
Reactant: CC(C)(C)[Si](C)(C)OCc1cocc1CO
Reactant: CC(C)(C)OO
Agent: c1nnn[nH]1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: C=CCOP(=O)(OCC=C)OCc1cocc1CO[Si](C)(C)C(C)(C)C
Yield: 94.2 %

Procedure:
[4-[(tert-Butyldimethylsilyl)oxymethyl]-3-furyl]methanol (174 mg, 0.72 mmol) obtained from Example 35-(1) was reacted in dichloromethane (3 ml) with tetrazole (61 mg, 0.87 mmol), bis(allyloxy)(diisopropylamino)phosphine (265 mg, 1.08 mmol), and tert-butyl hydroperoxide (80% di-tert-butyl peroxide solution; Merck; 135 mg, 1.2 mmol) according to a similar procedure to that described in Example 1-(10). The oily residue obtained by extraction was subjected to chromatography on a silica gel (5 g) column (eluent; ethyl acetate:hexane=1:4) to afford the title compound (273 mg, 93% yield) as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]3([CH2:15][CH2:14][C:13]4[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=4[CH2:11][CH2:10]3)[C:7](=O)[C:6]=2[CH:21]=1.C[Si](C)(C)[N:24]=[C:25]=[N:26][Si](C)(C)C>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]3([CH2:15][CH2:14][C:13]4[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=4[CH2:11][CH2:10]3)[C:7](=[N:26][C:25]#[N:24])[C:6]=2[CH:21]=1
Reactant: C[Si](C)(C)N=C=N[Si](C)(C)C
Reactant: O=C1c2cc(Br)ccc2OC12CCc1ccccc1CC2
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: N#CN=C1c2cc(Br)ccc2OC12CCc1ccccc1CC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 5′-bromo-5,6,8,9-tetrahydro-3′H-spiro[benzo[7]annulene-7,2′-benzofuran]-3′-one (0.1660 g, 0.48 mmol) in CH2Cl2 (5 mL) was added TiCl4 (1.0 M in CH2Cl2, 1.0 mL, 1.0 mmol) dropwise at room temperature. The reaction mixture was turned into orange precipitates in a few minutes. After 1 h, 1,3-bis(trimethylsilyl)carbodiimide (0.30 mL, 1.32 mmol) was added via a syringe. The precipitates were disappeared and the reaction mixture was turned into a red solution. The mixture was stirred at room temperature for 15 h and then quenched with ice, extracted with CH2Cl2, dried over Na2SO4. After the solvent was removed under reduced pressure, the crude product was directly used in the next step without further purification. LC-MS tR=2.27 min in 3 min chromatography, m/z 367, 369 (MH+).
Reaction SMILES: [CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[O:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[N:8]=1)=[O:2].[Cl:16]N1C(=O)N(Cl)C(=O)N(Cl)C1=O>CN(C)C=O>[CH:1]([NH:3][C:4]1[S:5][C:6]([Cl:16])=[C:7]([C:9](=[O:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[N:8]=1)=[O:2]
Reactant: O=c1n(Cl)c(=O)n(Cl)c(=O)n1Cl
Reactant: CCOC(=O)C(=O)c1csc(NC=O)n1
Agent: CCOC(=O)C(=O)c1csc(=NC=O)[nH]1
Solvent: CN(C)C=O
Product: CCOC(=O)C(=O)c1nc(NC=O)sc1Cl
Temperature: 60 °C

Procedure:
A suspension of ethyl 2-(2-formylamino-1,3-thiazol-4-yl)glyoxylate, which can be represented as ethyl 2-(2formylimino-2,3-dihydro-1,3-thiazol-4-yl)glyoxylate, (6.9 g.) in dimethylformamide (40 ml.) was heated at 60° C. to produce a solution, and to the solution was dropwise added a solution of trichloroisocyanuric acid (2.8 g.) in dimethylformamide (10 ml.) over 15 minutes at the same temperature with stirring and then the mixture was further stirred for 1 hours at the same temperature. After the reaction, the reaction mixture was poured into ice-water (400 g.). The precipitates were collected by filtration, washed with water and then dried to give ethyl 2-(2-formylamino-5-chloro-1,3-thiazol-4-yl)glyoxylate, which can be represented as ethyl 2-(2-formylimino-5-chloro-2,3-dihydro-1,3-thiazol-4-yl)glyoxylate, (7.1 g.), mp. 151° to 153° C. The remaining filtrate was extracted with ethyl acetate, and the extract was washed with water and then dried over magnesium sulfate. The solvent was distilled off from the extract to give further the same object compound (0.75 g.).
Reaction SMILES: BrC1C=C(C)C=CC=1N(C)[C:10]1[N:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[N:11]=1.[Br:19][C:20]1[CH:26]=[C:25]([CH:27]([CH3:29])[CH3:28])[CH:24]=[CH:23][C:21]=1[NH2:22]>C(O)CO>[Br:19][C:20]1[CH:26]=[C:25]([CH:27]([CH3:29])[CH3:28])[CH:24]=[CH:23][C:21]=1[NH:22][C:10]1[N:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[N:11]=1
Reactant: CC(C)c1ccc(N)c(Br)c1
Reactant: Cc1ccc(N(C)c2nc(C)cc(C)n2)c(Br)c1
Solvent: OCCO
Product: Cc1cc(C)nc(Nc2ccc(C(C)C)cc2Br)n1
Temperature: 25 °C

Procedure:
Part A: A mixture of the product from Example 1, Part A (2.01 g, 14.01 mmoles), 2-bromo-4-(1-methylethyl)aniline (3 g, 14.10 mmoles) in ethylene glycol (20 mL) was heated to reflux for 1.5 hours. Following cooling to room temperature and partitioning between ethyl acetate (200 mL) and aqueous sodium hydroxide (1 M, 50 mL), the organic layer was washed with brine, dried, and concentrated in vacuo. The residue was chromatographed on silica gel using 5% ethyl acetate in hexanes to give 2-N-(2-bromo-4-(1-methylethyl)phenyl)-4,6-dimethylpyrimidinamine (3.28 g).
Reaction SMILES: [C:1]([N:8]1[CH2:12][C@@H:11]([N:13]([CH:20]2[CH2:25][CH2:24][C:23]([CH3:27])([CH3:26])[CH2:22][CH2:21]2)[C:14](=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:10][C@@H:9]1[C:28](N(OC)C)=[O:29])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH3:34][Mg]Br.CCOCC>C1COCC1>[C:1]([N:8]1[CH2:12][C@@H:11]([N:13]([CH:20]2[CH2:25][CH2:24][C:23]([CH3:26])([CH3:27])[CH2:22][CH2:21]2)[C:14](=[O:19])[C:15]([CH3:16])([CH3:18])[CH3:17])[CH2:10][C@@H:9]1[C:28](=[O:29])[CH3:34])([O:3][C:4]([CH3:5])([CH3:7])[CH3:6])=[O:2]
Reactant: CON(C)C(=O)[C@H]1C[C@H](N(C(=O)C(C)(C)C)C2CCC(C)(C)CC2)CN1C(=O)OC(C)(C)C
Reactant: C[Mg]Br
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(=O)[C@H]1C[C@H](N(C(=O)C(C)(C)C)C2CCC(C)(C)CC2)CN1C(=O)OC(C)(C)C
Reaction time: 3 h
Yield: 46 %

Procedure:
To a solution of BOC (2R,4S)-4-[(4,4-dimethylcyclohexyl)(2,2-dimethylpropanoyl)amino]-2-{[methoxy(methyl)amino]carbonyl}pyrrolidine (670 mg, 1.44 mmol) prepared in Step B in THF (5 ml) was added methylmagnesium bromide 3M in ether solution (1.2 ml, 3.66 mmol), and the solution was stirred for 3 h. After the reaction finished, the solution was concentrated in vacuo. The residue was diluted with EtOAc, and washed with water and brine. The organic solution was dried over MgSO4, and concentrated in vacuo. The residue was purified by column chromatography (eluent: EtOAc:Hex=3/1) to give the title compound (280 mg, 46%).
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)[NH2:2].[F:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17](=O)[CH3:18])=[CH:12][CH:11]=1.C1(C)C=CC=CC=1>O>[N:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[NH:1][N:2]=[C:17]([CH3:18])[CH2:16][C:13]1[CH:14]=[CH:15][C:10]([F:9])=[CH:11][CH:12]=1
Reactant: CC(=O)Cc1ccc(F)cc1
Reactant: NNc1ccccn1
Solvent: O
Solvent: Cc1ccccc1
Product: CC(Cc1ccc(F)cc1)=NNc1ccccn1

Procedure:
In a vessel fitted with a condenser under nitrogen, 21.8 g (0.2M) of 2-hydrazinopyridine and 30.4 g (0.2M) of (4-fluorophenyl)acetone are heated at 80°-90° for about 30 to 60 mins. Toluene is then added and the mixture refluxed until all water is azeotropically distilled off. The mixture is then evaporated to dryness yielding crude product of this step as a yellow gum. The gum is distilled under reduced pressure (150°-160° at about 50 microns) to obtain the product of this step (as a yellow gum).
Reaction SMILES: [OH:1][C@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@:3]1([CH2:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([OH:27])=O)=[CH:23][CH:22]=1)[C:11]1[CH2:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2.CCN(CC)CC.[NH2:37][CH2:38][CH2:39][OH:40].C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>C(Cl)Cl>[OH:1][C@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@:3]1([CH2:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([NH:37][CH2:38][CH2:39][OH:40])=[O:27])=[CH:23][CH:22]=1)[C:11]1[CH2:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2
Reactant: O=C(O)c1ccc(C[C@]2(C3=Cc4ccccc4C3)Cc3ccccc3[C@@H]2O)cc1
Reactant: NCCO
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCCO)c1ccc(C[C@]2(C3=Cc4ccccc4C3)Cc3ccccc3[C@@H]2O)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 72.3 %

Procedure:
To a solution of 4-(((1R,2R)-1-hydroxy-2,3-dihydro-1H,1′H-[2,2′-biinden]-2-yl)methyl)benzoic acid (100 mg, 0.26 mmol), Et3N (157 mg, 1.56 mmol) and 2-amino ethanol (40 mg, 0.65 mmol) in DCM (5 mL), was added T3P (0.33 mL, 50 wt % solution in ethyl acetate, 0.52 mmol) and then stirred at room temperature for 12 h. The reaction mixture was quenched with water (25 mL) and extracted with DCM (3×25 mL). The organic layer was washed with brine (25 mL), dried over anhydrous Na2SO4 and evaporated under reduced pressure. The residue was purified by CombiFlash using 20% ethyl acetate in chloroform as an eluent to yield 80 mg (72%) of the title compound as an off white solid.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([S:8](Cl)(=[O:10])=[O:9])=[C:5]([CH3:7])[N:6]=1.[OH-].[NH4+:13]>>[Cl:1][C:2]1[S:3][C:4]([S:8]([NH2:13])(=[O:10])=[O:9])=[C:5]([CH3:7])[N:6]=1
Reactant: [NH4+]
Reactant: Cc1nc(Cl)sc1S(=O)(=O)Cl
Agent: [OH-]
Product: Cc1nc(Cl)sc1S(N)(=O)=O
Yield: 88.2 %

Procedure:
Prepared by general procedure III from 2-Chloro-4-methyl-thiazole-5-sulfonyl chloride (1.0 g, 4 mmol,) and ammonium hydroxide (0.32 mL, 4 mmol) to give 2-Chloro-4-methyl-thiazole-5-sulfonic acid amide (0.75 g, 81%) as a white solid. MS (ISP) 213.0 [(M+H)+], 215.1[(M+2+H)+].
Reaction SMILES: [CH3:1][C:2]1[C:9]([C:10]([F:21])([F:20])[C:11]([F:19])([F:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4]Br.[C:22]1(=[O:32])[NH:26][C:25](=[O:27])[C:24]2=[CH:28][CH:29]=[CH:30][CH:31]=[C:23]12.[K].CN(C)C=O>C(Cl)(Cl)Cl>[CH3:1][C:2]1[C:9]([C:10]([F:21])([F:20])[C:11]([F:19])([F:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][N:26]1[C:25](=[O:27])[C:24]2=[CH:28][CH:29]=[CH:30][CH:31]=[C:23]2[C:22]1=[O:32]
Reactant: Cc1c(CBr)cccc1C(F)(F)C(F)(F)c1ccccc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: Cc1c(CN2C(=O)c3ccccc3C2=O)cccc1C(F)(F)C(F)(F)c1ccccc1

Procedure:
A mixture of 8.02 g. (0.022 mole) of 2-methyl-3-(α,α,β,β-tetrafluorophenethyl)-benzyl bromide, 4.10 g. (0.022 mole) of potassium phthalimide, and 40 ml. of dimethylformamide is stirred 30 minutes at room temperature, 4 hours at 95° C., and 3 hours at reflux. The cooled mixture is diluted with 100 ml of chloroform and washed with 150 ml. of water. After re-extraction of the aqueous layer with chloroform, the combined organic extracts are washed with 0.1 N. sodium hydroxide, water, dried over anhydrous magnesium sulfate, and evaporated to dryness in vacuo. Recrystallization of the residual solid from isopropyl alcohol affords the white crystalline product, m.p. 135°-137° C.
Reaction SMILES: CC(C)([O-:4])C.[K+].BrCC1N=C([C:19]2[CH:24]=[CH:23][C:22](C(F)(F)F)=[CH:21][CH:20]=2)SC=1C(OCC)=O.[CH2:29]([O:31][C:32](=[O:37])[C:33](Br)([CH3:35])[CH3:34])[CH3:30]>C1COCC1>[CH3:34][C:33]([O:4][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)([CH3:35])[C:32]([O:31][CH2:29][CH3:30])=[O:37]
Reactant: CC(C)(C)[O-]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: CCOC(=O)c1sc(-c2ccc(C(F)(F)F)cc2)nc1CBr
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)C(C)(C)Oc1ccccc1
Temperature: 25 °C

Procedure:
To a solution of potassium t-butoxide (1M in THF, 531ml, 0.531moles, 1eq) precooled to 0° C. (ice bath) was added phenol (50g, 0.531moles, 1eq) in dry THF (50ml) dropwise via an addition funnel over 20minutes maintaining the internal temperature of the reaction below 5degrees centigrade. Ethyl-2-bromoisobutyrate (70.14ml, 0.9eq, 0.478moles) in dry THF (20ml) was added dropwise over 10minutes maintaining the internal reaction temperature below 5° C. After the addition was complete, the ice bath was removed and the reaction was allowed to warm to room temperature. The reaction was brought to reflux and maintained at this reflux temperature for 8hours. Following the cooling of the reaction to 0° C. the volatiles were removed in vacuo. The residue was then partitioned between EtOAc and 1N NaOH. The phases were separated and the organic phase washed with 1N NaOH, H2O, brine and dried over Na2SO4. After filtration the solution was concentrated under reduced pressure to yield 83g (75%) of clean title compound.
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH2:24]C2CCCCC2)[C:4](=[O:23])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13](Br)[CH:14]=3)[O:9][CH:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:7]2)[N:6]=1.[CH3:31][N:32]([CH3:44])[C:33]([C:35]1[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=1)=[O:34]>O1CCOCC1.C([O-])([O-])=O.[Cs+].[Cs+].Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1[N:3]([CH3:24])[C:4](=[O:23])[C:5]2([C:15]3[C:14](=[CH:13][CH:12]=[C:11]([C:38]4[CH:39]=[CH:40][C:35]([C:33]([N:32]([CH3:44])[CH3:31])=[O:34])=[CH:36][CH:37]=4)[CH:10]=3)[O:9][CH:8]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:7]2)[N:6]=1
Reactant: NC1=NC2(CC(c3ccccc3)Oc3ccc(Br)cc32)C(=O)N1CC1CCCCC1
Reactant: CN(C)C(=O)c1ccc(B(O)O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CN(C)C(=O)c1ccc(-c2ccc3c(c2)C2(CC(c4ccccc4)O3)N=C(N)N(C)C2=O)cc1
Temperature: 120 °C
Yield: 33.7 %

Procedure:
Pd(PPh3)2Cl2 (10 mg) in a 10 mL tube under Ar was treated sequentially with 2′-amino-6-bromo-1′-(cyclohexylmethyl)-2-phenylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (20 mg, 0.052 mmol) in 1,4-dioxane (1 mL), Cs2CO3 (2 N, 0.3 mL) and 4-(dimethylcarbamoyl)phenylboronic acid (20.1 mg, 0.104 mmol). The mixture was heated at 120° C. in a microwave reactor for 0.5 h. The reaction mixture was concentrated in vacuo to give the residue, which was purified by preparative TLC to give pure 4-(2′-amino-1′-methyl-5′-oxo-2-phenyl-1′,5′-dihydrospiro[chroman-4,4′-imidazole]-6-yl)-N,N-dimethylbenzamide (7.97 mg, 34%). 1H-NMR (MeOD): 2.07 (m, 1H), 2.24 (m, 1H), 3.00 (m, 6H), 3.11 (m, 3H), 5.22 (d, 0.3H), 5.86 (d, 0.7H), 6.97 (m, 1H), 7.18 (m, 1H), 7.28 (m, 1H), 7.34 (m, 2H), 7.39 (m, 4H), 7.46 (m, 1H), 7.54 (m, 2H).
Reaction SMILES: C([Mg]Br)C.I[C:6]1[N:7]=[C:8]([CH3:30])[N:9]([C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:10]=1.[CH2:31]([Sn:35](Cl)([CH2:40][CH2:41][CH2:42][CH3:43])[CH2:36][CH2:37][CH2:38][CH3:39])[CH2:32][CH2:33][CH3:34]>C1COCC1.O>[CH3:30][C:8]1[N:9]([C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:10]=[C:6]([Sn:35]([CH2:40][CH2:41][CH2:42][CH3:43])([CH2:36][CH2:37][CH2:38][CH3:39])[CH2:31][CH2:32][CH2:33][CH3:34])[N:7]=1
Reactant: Cc1nc(I)cn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: CC[Mg]Br
Solvent: O
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(C)n1
Reaction time: 2 h
Yield: 117.3 %

Procedure:
3 M Ethyl magnesium bromide in THF (6.0 ml, 18.0 mmol) was added dropwise to a solution of 4-iodo-2-methyl-1-trityl-1H-imidazole (5.30 g, 11.8 mmol) in THF (100 ml) at −78° C. After stirring for 2 h, tributyltin chloride (5.0 ml, 18.4 mmol) was added. After stirring for an additional 2 h, the solution was diluted with water and extracted with methylene chloride. The combined organic extracts were dried over magnesium sulfate, filtered and concentrated under reduced pressure to yield 8.49 g of impure 2-methyl-4-(tributylstannyl)-1-trityl-1H-imidazole as a orange liquid. Method [7]Retention time 11.32 min by HPLC (MH+ 615).
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].[C:11]1([CH3:17])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[CH2:18](O)CCCCC(C)C>>[C:1]([O:10][CH2:18][CH:14]([CH2:13][CH3:12])[CH2:15][CH2:16][CH2:11][CH3:17])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4]
Reactant: CC(C)CCCCCO
Reactant: O=C(O)c1ccccc1S
Reactant: Cc1ccccc1
Product: CCCCC(CC)COC(=O)c1ccccc1S

Procedure:
77.1 g (0.5 mol) of thiosalicylic acid are dissolved, with stirring, in 250 ml of hot isooctanol. After the addition of 100 ml of toluene and a catalytic amount of paratoluenesulfonic acid, the reaction mixture is heated under reflux. Under azeotropic conditions, 8.5 ml of water (calculated: 9 ml) separate off after 25 hours. The residue is extracted by shaking with a bicarbonate solution, then washed with water and dried. The volatile constituents are removed in vacuo. The product is obtained after rectification with a mercury diffusion pump.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[O:4][CH2:5][CH2:6][OH:7].[N+](=[CH:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[N-].CO>ClCCl.CC(O)=O.CC(O)=O.CC(O)=O.CC(O)=O.[Rh].[Rh]>[CH2:18]([O:17][C:15](=[O:16])[CH2:14][O:7][CH2:6][CH2:5][O:4][C:3]1[CH:8]=[CH:9][CH:10]=[CH:11][C:2]=1[Cl:1])[CH3:19]
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: OCCOc1ccccc1Cl
Agent: [Rh]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CO
Product: CCOC(=O)COCCOc1ccccc1Cl
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 52.6 %

Procedure:
To a solution of 2-(2-chlorophenoxy)ethanol (1.73 mL, 10.0 mmol) in dichloromethane (20 mL) is added rhodium (II) acetate dimer (11 mg) followed by ethyl diazoacetate (1.05 mL, 10.0 mmol). The reaction mixture is stirred at rt for 20 min. To the reaction mixture is added MeOH followed by rotary evaporated, and the residue is purified by chromatography on silica gel; elution with EtOAc:heptane (25:75) gives 1.36 g of the product 436. 1H NMR (CDCl3) δ 7.35 (d, 1 H), 7.19 (d, 1 H), 6.95-6.90 (m, 2 H), 4.30 (s, 2 H), 4.25-4.15 (m, 4 H), 4.0 (t, 2 H), 1.2 (t, 3 H); MS: m/z 259 (M++1).
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[O:9][C:7](=[O:8])[CH2:6][C:4](=[O:5])[O:3]1.[CH:11](OC)(OC)OC.[CH3:18][O:19][C:20]1[N:25]=[CH:24][C:23]([NH2:26])=[CH:22][CH:21]=1>CCCCCC>[CH3:18][O:19][C:20]1[N:25]=[CH:24][C:23]([NH:26][CH:11]=[C:6]2[C:7](=[O:8])[O:9][C:2]([CH3:10])([CH3:1])[O:3][C:4]2=[O:5])=[CH:22][CH:21]=1
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: COC(OC)OC
Reactant: COc1ccc(N)cn1
Solvent: CCCCCC
Product: COc1ccc(NC=C2C(=O)OC(C)(C)OC2=O)cn1
Temperature: 105 °C

Procedure:
A mixture of Meldrum's acid (34.8 g, 0.42 mol) and trimethyl orthoformate (285 mL, 2.05 mol) was heated to 105° C. for 2 h. To the solution 6-methoxypyridin-3-amine (30 g, 0.242 mol) was added and continued the stirring overnight at the same temperature. The mixture was allowed to cool to RT and diluted with hexane. The solid precipitated was filtered and washed with hexane to afford 5-((6-methoxypyridin-3-ylamino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione as a pale yellow solid.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][C:3]=1[CH2:10][S:11]([CH3:14])(=[O:13])=[O:12].C(C1C=NC=C(CCC(C)C)C=1)#N>>[CH3:1][C:2]1[N:7]=[C:6]([CH2:8][NH2:9])[CH:5]=[CH:4][C:3]=1[CH2:10][S:11]([CH3:14])(=[O:13])=[O:12]
Reactant: Cc1nc(C#N)ccc1CS(C)(=O)=O
Agent: CC(C)CCc1cncc(C#N)c1
Product: Cc1nc(CN)ccc1CS(C)(=O)=O

Procedure:
(6-methyl-5-(methylsulfonylmethyl)pyridin-2-yl)methanamine was synthesized from 6-methyl-5-(methylsulfonylmethyl)picolinonitrile following the general procedure as described above for the 3-cyano-5-isopentylpyridine.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:12])[C:8](Br)=[CH:9][N:10]=1)=[O:5])[CH3:2].[CH3:13][Si:14]([C:17]#[CH:18])([CH3:16])[CH3:15]>CCN(CC)CC.C1COCC1.[Cu]I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:12])[C:8]([C:18]#[C:17][Si:14]([CH3:16])([CH3:15])[CH3:13])=[CH:9][N:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ncc(Br)n1C
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ncc(C#C[Si](C)(C)C)n1C
Temperature: 70 °C
Reaction time: 12 h
Yield: 24.1 %

Procedure:
To a solution of 800 mg (3.43 mmol) of 5-bromo-1-methyl-1H-imidazole-2-carboxylic acid ethyl ester in Et3N (10 mL) and THF (10 mL) was added 33 mg (0.17 mmol) of CuI and 120 mg (0.10 mmol) of Pd(PPh3)4. Trimethylsilylacetylene (0.48 mL, 3.4 mmol) was then added and the reaction was heated at 70° C. under N2. After 12 h, the mixture was cooled and filtered though a pad of celite, and then concentrated and chromatographed (0-50% EtOAc in hexanes) to give 1-methyl-5-trimethylsilanylethynyl-1H-imidazole-2-carboxylic acid ethyl ester as a brown oil (205 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:12][CH2:11][C:10]([O:13][Si](C)(C)C)=[CH:9]2)=[CH:4][N:3]=1.Cl>C1COCC1.CCOC(C)=O.C([O-])(O)=O.[Na+]>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([CH:8]2[CH2:12][CH2:11][C:10](=[O:13])[CH2:9]2)=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)OC1=CC(c2ccc(Cl)nc2)CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C1CCC(c2ccc(Cl)nc2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 37.2 %

Procedure:
2-Chloro-5-(3-trimethylsilanyloxycyclopent-2-enyl)pyridine (0.58 g, 2.2 mmol) was dissolved in THF (10 mL) in a 100 mL round bottom flask and treated with 1N HCl (2 mL) with stirring at room temperature. After 1 h, the mixture was diluted with EtOAc and sat. NaHCO3 and the layers separated. The aqueous phase was extracted with EtOAc and the combined organic layers dried (Na2SO4), filtered, concentrated, and purified by flash silica gel chromatography (hexanes: EtOAc/2:1) to give 3-(6-chloropyridin-3-yl)cyclopentanone (0.16 g, 37%) as a dark oil: LC/MS (ESI) m/z 195, 1H NMR (300 MHz, CDCl3) δ 8.31 (d, 1H, J=2.7 Hz), 7.54 (dd, 1H, J=8.4, 2.7 Hz), 7.31 (d, 1H, J=8.4 Hz), 3.43 (m, 1H), 2.70 (m, 1H), 2.56-2.22 (m, 4H), 1.97 (m, 1H).