Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]1[C:10]([O:11][CH2:12][CH2:13][O:14][CH3:15])=[CH:9][C:6]([C:7]#[N:8])=[C:5]([N+:16]([O-:18])=[O:17])[CH:4]=1.[Al+3].[Cl-].[Cl-].[Cl-].CC(=O)OCC>C(Cl)Cl.Cl>[OH:2][C:3]1[C:10]([O:11][CH2:12][CH2:13][O:14][CH3:15])=[CH:9][C:6]([C:7]#[N:8])=[C:5]([N+:16]([O-:18])=[O:17])[CH:4]=1
Reactant: COCCOc1cc(C#N)c([N+](=O)[O-])cc1OC
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COCCOc1cc(C#N)c([N+](=O)[O-])cc1O
Yield: 56.5 %

Procedure:
To a solution of 4-methoxy-5-(2-methoxyethoxy)-2-nitrobenzonitrile (1.5 g) in anhydrous DCM (30 mL) was added anhydrous AlCl3 (6 g) at 0° C. The resulting mixture was heated to reflux for 1 h. After reaction finished, the mixture was diluted with 1N aqueous HCl (50 mL) and exacted with EA (3×50 mL). The combined organic layer was dried over Na2SO4, concentrated under reduced pressure, and purification by silica chromatography to give 0.8 g of 4-hydroxy-5-(2-methoxyethoxy)-2-nitrobenzonitrile.
Reaction SMILES: [C:1]([C:3]([CH3:16])([CH3:15])[CH2:4][C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][CH:14]=1)[C:8]([O:10]C)=[O:9])#[N:2].O1CCCC1.[OH-].[Na+].Cl>CO>[C:1]([C:3]([CH3:16])([CH3:15])[CH2:4][C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][CH:14]=1)[C:8]([OH:10])=[O:9])#[N:2]
Reactant: COC(=O)c1cccc(CC(C)(C)C#N)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C#N)Cc1cccc(C(=O)O)c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 94.3 %

Procedure:
To a solution of methyl 3-(2-cyano-2-methylpropyl)benzoate (260 mg, 1.20 mmol) in methanol (6 mL)/tetrahydrofuran (2 mL) was added 2N aqueous sodium hydroxide solution (1.20 mL, 2.39 mmol), and the mixture was stirred at 60° C. for 2 hr. The reaction mixture was neutralized with 6N hydrochloric acid (600 μL), 1N hydrochloric acid (30 mL) was added, and the mixture was extracted with ethyl acetate (30 mL, 10 mL). The combined organic layer was washed with saturated brine (5 mL), and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give the title compound (230 mg, 95%) as a white solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[CH2:12][CH2:11][C:10]3[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=3[S:8][C:7]=2[CH:17]=1)#N.Cl.CC[O:21]CC>>[CH:5]1[C:6]2[CH2:12][CH2:11][C:10]3[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=3[S:8][C:7]=2[CH:17]=[C:3]([CH:1]=[O:21])[CH:4]=1
Reactant: N#Cc1ccc2c(c1)Sc1ccccc1CC2
Reactant: CCOCC
Agent: Cl
Product: O=Cc1ccc2c(c1)Sc1ccccc1CC2
Temperature: 25 °C
Reaction time: 50 h

Procedure:
Mix 4.74 g (20 mmole) of 3-cyano-10,11-dihydro-dibenzo[b,f]thiepin with 7.56 g (40 mmole) anhydrous stannous chloride and 150 ml ether saturated with anhydrous hydrogen chloride. Stir the mixture at 25° C. for approximately 50 hours to produce a crystalline solid suspended in the reaction mixture. Shake the crystalline solid with 200 ml ice water, and extract with 150 ml ethyl acetate using methanol to dissolve any residual lumpy yellow solid. Separate the ethyl acetate layer containing the product, and after washing with water/saturated chloride solution and drying, the ethyl acetate is removed by evaporation to produce as a residue an amber-colored oil, which crystallizes overnight. Distill the crystalline residue under reduced pressure at 145° C. at 0.04 mm. The distilled product crystallizes, m.p. 55.5°-56.5° C.
Reaction SMILES: C(OC([N:8]1[CH2:12][C@@H:11]([CH2:13][N:14]([CH:31]([CH3:33])[CH3:32])[C:15](=[O:30])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH2:25][CH2:26][CH2:27][O:28][CH3:29])[CH:17]=2)[C@H:10]([CH:34]=O)[CH2:9]1)=O)(C)(C)C.[CH2:36]([NH2:40])[CH:37]([CH3:39])[CH3:38].[BH4-].[Na+]>C(Cl)Cl.CO>[CH2:36]([NH:40][CH2:34][C@@H:10]1[CH2:9][NH:8][CH2:12][C@H:11]1[CH2:13][N:14]([CH:31]([CH3:33])[CH3:32])[C:15](=[O:30])[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH2:25][CH2:26][CH2:27][O:28][CH3:29])[CH:17]=1)[CH:37]([CH3:39])[CH3:38]
Reactant: CC(C)CN
Reactant: COCCCOc1cc(C(=O)N(C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2C=O)C(C)C)ccc1OC
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COCCCOc1cc(C(=O)N(C[C@@H]2CNC[C@H]2CNCC(C)C)C(C)C)ccc1OC

Procedure:
from (3S*,4R*)-3-formyl-4-({isopropyl-[4-methoxy-3-(3-methoxy-propoxy)-benzoyl]-amino}-methyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (0.75 g, 1.52 mmol), isobutylamine (0.756 mL, 7.61 mmol) and NaBH4 (0.115 g, 3.04 mmol) and purification by flash chromatography on silica gel (CH2Cl2/MeOH 96:4, then CH2Cl2/MeOH (10% NH3 conc.) gradient from 9:1 to 8:2) to give the title compound as colorless oil. MS: 550.4 [M+H]+. tR (HPLC, Nucleosil C18HD column, 5-100% CH3CN/H2O/6 min, 100% CH3CN/2 min, CH3CN and H2O containing 0.1% TFA, flow: 1 mL/min): 4.74 min.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].Br[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([O:7][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:6]
Reactant: O=C(O)c1cccc(I)c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)c1cccc(I)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.9 %

Procedure:
Into a 500-mL round-bottom flask, was placed a solution of 3-iodobenzoic acid (9.92 g, 40.00 mmol, 1.00 equiv) in DMF (100 mL), 1-(bromomethyl)benzene (6.84 g, 40.00 mmol, 1.00 equiv), potassium carbonate (11.04 g, 80.00 mmol, 2.00 equiv). The resulting solution was stirred for 2 h at room temperature. The solids were filtered out and the filtrate was concentrated under vacuum. The residue was diluted with 50 mL of water and extracted with 2×50 mL of ethyl acetate. The combined organic layers were washed with 2×50 mL of sodium chloride, dried over anhydrous sodium sulfate and concentrated under vacuum to give 13.1 g (97%) of benzyl 3-iodobenzoate as light brown oil
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9](O)[CH2:10][CH3:11].P(Br)(Br)[Br:14]>>[Br:14][CH:9]([C:3]1[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=1[F:1])[CH2:10][CH3:11]
Reactant: BrP(Br)Br
Reactant: CCC(O)c1cc(F)ccc1F
Product: CCC(Br)c1cc(F)ccc1F

Procedure:
rac-2-(1-Bromo-propyl)-1,4-difluoro-benzene was prepared from rac-1-(2,5-difluoro-phenyl)-propan-1-ol and phosphorus tribromide in analogy to Example 23 b): colourless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][NH:10][C:11]2[N:16]=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][N:24]([CH2:31][CH3:32])[CH:25]4[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]4)[CH:18]=3)[CH:14]=[CH:13][N:12]=2)[CH:5]=[CH:4][C:3]=1[OH:33].[CH:34](=O)[CH3:35]>>[Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][NH:10][C:11]2[N:16]=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][N:24]([CH2:31][CH3:32])[CH:25]4[CH2:30][CH2:29][N:28]([CH2:34][CH3:35])[CH2:27][CH2:26]4)[CH:18]=3)[CH:14]=[CH:13][N:12]=2)[CH:5]=[CH:4][C:3]=1[OH:33]
Reactant: CC=O
Reactant: CCN(Cc1cccc(-c2ccnc(NCCc3ccc(O)c(Cl)c3)n2)c1)C1CCNCC1
Product: CCN1CCC(N(CC)Cc2cccc(-c3ccnc(NCCc4ccc(O)c(Cl)c4)n3)c2)CC1

Procedure:
Intermediate 85 was coupled with acetaldehyde following procedure E. The product was purified by HPLC. LC-MS showed the product had the expected M+H+ of 494. 1H NMR (Varian 300 MHz, DMSO, shifts relative to the solvent peak at 2.50 ppm) δ 8.3 (d, 1H), 7.9 (d, 1H), 7.5-7.4 (m, 3H), 7.2 (d, 1H), 7.1 (d, 1H), 7.0 (d, 1H), 6.8 (d, 1H), 3.6 (s, 2H), 3.5 (d, 2H), 3.1 (d, 2H), 2.7 (q, 2H), 2.6 (m, 3H), 2.3 (m, 4H), 1.7-1.6 (m, 4H), 1.0 (t, 3H), 0.94 (t, 3H).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:40])=[C:5]([C:21]([O:23][CH2:24][CH2:25][O:26][CH2:27][CH2:28][N:29]2C(=O)C3=CC=CC=C3C2=O)=[O:22])[CH:6]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)[C:7]=1[C:8]([O:10][CH3:11])=[O:9].O.NN>C(O)C>[CH3:40][C:4]1[NH:3][C:2]([CH3:1])=[C:7]([C:8]([O:10][CH3:11])=[O:9])[CH:6]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)[C:5]=1[C:21]([O:23][CH2:24][CH2:25][O:26][CH2:27][CH2:28][NH2:29])=[O:22]
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCOCCN2C(=O)c3ccccc3C2=O)C1c1cccc([N+](=O)[O-])c1
Agent: NN
Solvent: O
Solvent: CCO
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCOCCN)C1c1cccc([N+](=O)[O-])c1
Yield: 68.8 %

Procedure:
A solution of 9.14 g of methyl 2-(2-phthalimidoethoxy)ethyl 2,6-dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate and 4,2 g of hydrazine monohydrate in 100 ml of ethanol was refluxed for 2 hours under heating. After cooling the reaction solution with ice and then adding thereto 100 ml of chloroform, precipitates were removed by filtration. The filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography. The product was eluted with chloroform-methanol (8:2 v/v) and 4.8 g of 2-(2-aminoethoxy)ethyl methyl 2,6-dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate was obtained as liquid.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[Cl:23][C:24]1[C:25]([CH2:71][C:72]2[CH:77]=[CH:76][C:75]([CH2:78][CH3:79])=[CH:74][CH:73]=2)=[CH:26][C:27]([C@H:32]2[C@H:37]([O:38][CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[C@@H:36]([O:46][CH2:47][C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)[C@H:35]([O:54][CH2:55][C:56]3[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=3)[C@@H:34]([CH2:62][O:63][CH2:64][C:65]3[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=3)[O:33]2)=[C:28]([CH2:30][OH:31])[CH:29]=1>ClCCl>[Cl:23][C:24]1[C:25]([CH2:71][C:72]2[CH:73]=[CH:74][C:75]([CH2:78][CH3:79])=[CH:76][CH:77]=2)=[CH:26][C:27]([C@H:32]2[C@H:37]([O:38][CH2:39][C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=3)[C@@H:36]([O:46][CH2:47][C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)[C@H:35]([O:54][CH2:55][C:56]3[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=3)[C@@H:34]([CH2:62][O:63][CH2:64][C:65]3[CH:66]=[CH:67][CH:68]=[CH:69][CH:70]=3)[O:33]2)=[C:28]([CH:29]=1)[CH:30]=[O:31]
Reactant: CCc1ccc(Cc2cc([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c(CO)cc2Cl)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CCc1ccc(Cc2cc([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c(C=O)cc2Cl)cc1
Temperature: 0 °C
Yield: 49.5 %

Procedure:
To a cold (0° C.) stirred suspension of Dess-Martin periodinane (1.24 g, 2.92 mmol) in dichloromethane (20 mL) was added (5-chloro-4-(4-ethylbenzyl)-2-((2S,3S,4R,5R,6R)-3,4,5-tris(benzyloxy)-6-(benzyloxymethyl)tetrahydro-2H-pyran-2-yl)phenyl)methanol (1.76 g, 2.25 mmol) (prepared as described in U.S. Ser. No. 12/060,767) in dichloromethane (3 mL). The mixture was stirred for 2 hours at 0° C., and the reaction was quenched with 2N sodium hydroxide (5 mL). The organic phase was separated, and the aqueous phase was extracted with ethyl acetate. The organic phases were combined, washed with saturated sodium bicarbonate, then with water and then with brine, and then dried over anhydrous sodium sulfate. The combined filtrate was concentrated under reduced pressure. The residue was purified by column chromatography to give 0.87 g of white solid. MS ESI+ (m/z): 798 (M+18)+.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([CH:13]1[C:17](O)([CH3:18])[CH:16]=[CH:15][C:14]1=[O:20])[CH2:9][CH2:10][CH2:11][CH3:12].[SH2:21]>C1(C)C=CC=CC=1>[CH2:8]([C:13]1[C:14](=[O:20])[CH2:15][CH:16]([SH:21])[C:17]=1[CH3:18])[CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: S
Reactant: CCCCCC1C(=O)C=CC1(C)O
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCCCCC1=C(C)C(S)CC1=O
Reaction time: 4 h
Yield: 90.9 %

Procedure:
Into the same flask as used in Example 1, triethylamine (5 g), 2-n-pentyl-3-hydroxy-3-methyl-4-cyclopentenone (18.2 g) and toluene (30 g) were charged, and hydrogen sulfide (8 g) was introduced into the mixture at a temperature of 15° to 30° C. Thereafter, the reaction mixture was stirred at a temperature of 50° to 70° C. for 4 hours. After completion of the reaction, the mixture was washed with an acid and water in order. The organic layer was separated and concentrated to obtain 2-n-pentyl-3-methyl-4-mercapto-2-cyclopentenone (18.0 g). Yield, 91%. nD20 1.5212.
Reaction SMILES: [CH3:1][N:2]([CH3:25])[CH2:3][CH2:4][O:5][CH2:6][CH2:7][CH2:8][CH:9]1[S:13][C:12]2[C:14]([CH3:24])=[C:15]([O:20]COC)[C:16]([CH3:19])=[C:17]([CH3:18])[C:11]=2[O:10]1.S(=O)(=O)(O)O>C(O)(=O)C>[CH3:25][N:2]([CH3:1])[CH2:3][CH2:4][O:5][CH2:6][CH2:7][CH2:8][CH:9]1[S:13][C:12]2[C:14]([CH3:24])=[C:15]([OH:20])[C:16]([CH3:19])=[C:17]([CH3:18])[C:11]=2[O:10]1
Reactant: COCOc1c(C)c(C)c2c(c1C)SC(CCCOCCN(C)C)O2
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: Cc1c(C)c2c(c(C)c1O)SC(CCCOCCN(C)C)O2

Procedure:
330 mg of 2-[3-(2-dimethylaminoethoxy)propyl]-5-methoxymethoxy-4,6,7-trimethyl-1,3-benzoxathiole (prepared as described in Example 88) were dissolved in 5 ml of acetic acid, and then 5 drops of 10% v/v aqueous sulfuric acid was added using a Komagome pipette; the mixture was then heated for 5 hours at 70°-75° C. The acetic acid solution was then condensed by evaporation under reduced pressure, and the condensate was poured into ice-water, neutralized with potassium carbonate and extracted with ethyl acetate. The ethyl acetate solution was washed with water and then dried over anhydrous sodium sulfate. The ethyl acetate was then distilled off under reduced pressure. The resulting residue was then subjected to silica gel column chromatography, and the title compound was obtained from the fraction eluted with a 20:1 by volume mixture of ethyl acetate and triethylamine.
Reaction SMILES: [C:1]1([CH:7]2[NH:12][CH2:11][CH2:10][N:9]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[C:24]([CH3:26])[CH:23]=[CH:22][C:21]=4[Cl:27])=[CH:16][CH:15]=3)[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:28][N:29]=[C:30]=[O:31]>ClCCl>[C:28]1([NH:29][C:30]([N:12]2[CH2:11][CH2:10][N:9]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[C:24]([CH3:26])[CH:23]=[CH:22][C:21]=4[Cl:27])=[CH:16][CH:15]=3)[CH2:8][CH:7]2[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[O:31])[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=1
Reactant: CN=C=O
Reactant: Cc1ccc(Cl)c(-c2ccc(CN3CCNC(c4ccccc4)C3)cc2)c1
Solvent: ClCCl
Product: Cc1ccc(Cl)c(-c2ccc(CN3CCN(C(=O)Nc4ccccc4)C(c4ccccc4)C3)cc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
55 mg of 3-phenyl-1-(2′-chloro-5′-methyl-biphenyl-4-ylmethyl)-piperazine were dissolved in dichloromethane, 2 equiv. methylisocyanate were added. The reaction was shaken at room temperature overnight. The reaction was concentrated in vacuo. The residue was diluted with DCM, washed with 1M aqueous sodium hydroxide solution, then dried over sodium sulfate, filtered and concentrated in vacuo. The crude residue was purified by column chromatography to afford the title compound as free base. Addition of 1 equiv. of 1M HCl in dioxane and concentratation in vacuo afforded the title compound as hydrochloride salt. Yield 33%, ES MS m/z 496.
Reaction SMILES: [C:1]1([C:7]2([NH:10][C:11](=[O:13])[CH3:12])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO[CH2:16][Cl:17]>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[Cl:17][CH2:16][C:4]1[CH:5]=[CH:6][C:1]([C:7]2([NH:10][C:11](=[O:13])[CH3:12])[CH2:8][CH2:9]2)=[CH:2][CH:3]=1
Reactant: CC(=O)NC1(c2ccccc2)CC1
Reactant: COCCl
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: CC(=O)NC1(c2ccc(CCl)cc2)CC1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a solution of N-(1-phenylcyclopropyl)acetamide (5.0 g) in methylene chloride (35 ml) was added titanium tetrachloride (6.26 ml) under ice-cooling and to this solution was added dropwise a solution of methoxymethyl chloride (4.33 ml) in methylene chloride (15 ml) over 10 min under ice-cooling. The mixture was stirred at room temperature for 14 hr. The reaction mixture was poured into ice water and extracted with chloroform (50 ml). The extract was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the obtained residue was purified by silica gel column chromatography (developing solvent; ethyl acetate) to give the title compound (3.71 g) as white crystals, m.p.=124-127° C.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]=[C:11]=[S:12])=[CH:6][CH:5]=1)(O)=[O:2].S(Cl)([Cl:15])=O>>[N:10]([C:7]1[CH:8]=[CH:9][C:4]([C:1]([Cl:15])=[O:2])=[CH:5][CH:6]=1)=[C:11]=[S:12]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc(N=C=S)cc1
Product: O=C(Cl)c1ccc(N=C=S)cc1
Yield: 93 %

Procedure:
A mixture of 500 mg (2.79 mmol) of 4-carboxyphenylisothiocyanate and 5 ml of thionyl chloride was refluxed for 6 hours. The reaction mixture was concentrated at reduced pressure and the resulting tan solid was pumped at high vacuum overnight. The solid was triturated with a small amount of hexane and collected by suction filtration to yield 516 mg (93%) of product as an off-white solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:8])[O:7][CH2:6][CH2:5][NH:4][CH2:3]1.[Cl:9][C:10]1[CH:15]=[C:14](Cl)[N:13]=[C:12]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[N:11]=1.C(N(CC)CC)C>CCO>[Cl:9][C:10]1[N:11]=[C:12]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[N:13]=[C:14]([N:4]2[CH2:5][CH2:6][O:7][C:2]([CH3:8])([CH3:1])[CH2:3]2)[CH:15]=1
Reactant: Clc1cc(Cl)nc(N2CCOCC2)n1
Reactant: CC1(C)CNCCO1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC1(C)CN(c2cc(Cl)nc(N3CCOCC3)n2)CCO1
Temperature: 110 °C

Procedure:
A mixture of 2,2-dimethylmorpholine (2.0 equiv.), 4-(4,6-dichloropyrimidin-2-yl)morpholine (1 equiv.) and triethylamine (6 equiv.) in EtOH (0.2 M) were heated to 110° C. for 25 min in the microwave. The reaction mixture was partitioned between EtOAc and water. The organic phase was dried over sodium sulfate. The resulting solution was concentrated and dried under vacuo to give 4-(6-chloro-2-morpholinopyrimidin-4-yl)-2,2-dimethylmorpholine and was used in the next step without further purification. LCMS (m/z) (M+H)=313.2, Rt=0.86 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([CH3:9])=[CH:4][CH:3]=1.[Br:10]Br>C(Cl)(Cl)(Cl)Cl.C(Cl)Cl>[Br:10][C:4]1[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[C:5]=1[CH3:9]
Reactant: BrBr
Reactant: Cc1ccc(Cl)cc1Cl
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1c(Cl)cc(Cl)cc1Br
Yield: 213.1 %

Procedure:
To a mixture of 32 g of 4,6-dichlorotoluene and 0.3 g of anhydrous FeCl3, add, with stirring, 10 g of bromine in 1 g portions while maintaining a temperature of 20°-25° C. Add thereto a solution of 22 g of bromine in 100 mL of CCl4 slowly while maintaining a temperature of 20°-25° C. After the addition of bromine is complete, stir the mixture so formed for 15 min, and dilute the reaction mixture with 200 mL of CH2Cl2, and wash the organic solution with 5% aqueous sodium thiosulfate. Dry the organic layer over anhydrous K2CO3, filter, and evaporate to a residue. Recrystallize the residue from CH3CN to give 32 g of 2-bromo-4,6-dichlorotoluene, mp 84°-5° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)[CH:6]=[CH:5]2.[O:18]1[CH2:20][C@H:19]1[CH2:21][O:22][C:23]1[C:31]2[CH:30]=[CH:29][O:28][C:27]=2[CH:26]=[CH:25][CH:24]=1>CO>[O:28]1[CH:29]=[CH:30][C:31]2[C:23]([O:22][CH2:21][C@@H:19]([OH:18])[CH2:20][N:15]3[CH2:14][CH2:13][CH:12]([C:7]4[CH:6]=[CH:5][C:4]5[C:9](=[CH:10][CH:11]=[C:2]([F:1])[CH:3]=5)[CH:8]=4)[CH2:17][CH2:16]3)=[CH:24][CH:25]=[CH:26][C:27]1=2
Reactant: c1cc(OC[C@@H]2CO2)c2ccoc2c1
Reactant: Fc1ccc2cc(C3CCNCC3)ccc2c1
Solvent: CO
Product: O[C@H](COc1cccc2occc12)CN1CCC(c2ccc3cc(F)ccc3c2)CC1
Yield: 36.5 %

Procedure:
A solution 4-(6-fluoronaphth-2-yl)piperidine (0.075 g, 0.327 mmol) and (S)-(+)-4-(oxiranylmethoxy)benzo[b]furan (0.062 g, 0.327 mmol) in methanol (3 mL) was heated at reflux for 18 hours and then cooled and evaporated. The residue was purified using silica gel chromatography (dichloromethane/5% methanol in dichloromethane gradient elution) to give the final title compound as a white amorphous solid (0.050 g, 37%). FDMS m/e=420 (M++1). [α]D=11.31 (c 0.531, methanol). C26H26FNO3.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].Cl.[NH2:8][OH:9].[CH2:10]([C:22]1[CH:29]=[CH:28][C:25]([CH2:26]Cl)=[CH:24][CH:23]=1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>CN(C)C=O>[CH2:10]([C:22]1[CH:29]=[CH:28][C:25]([CH2:26][N:8]([CH2:26][C:25]2[CH:28]=[CH:29][C:22]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:23][CH:24]=2)[OH:9])=[CH:24][CH:23]=1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCCCCCCCCc1ccc(CCl)cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCc1ccc(CN(O)Cc2ccc(CCCCCCCCCCCC)cc2)cc1
Reaction time: 8 h

Procedure:
The procedure of Example 1 is repeated using 16.0 g of sodium carbonate, 2.57 g of hydroxylamine hydrochloride and 21.83 g of p-dodecylbenzyl chloride in 75 ml of dimethylformamide kept at 50°-55° C. overnight under nitrogen. The product is isolated as a light brown oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([O:23][CH3:24])=[CH:11][C:12]([C:17]2[N:21]=[C:20]([CH3:22])[O:19][N:18]=2)=[C:13]([CH:16]=1)[CH:14]=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CS(C)=[O:27].S(=O)(=O)(O)O.Cl([O-])=O.[Na+]>O.C(#N)C>[CH2:1]([O:8][C:9]1[C:10]([O:23][CH3:24])=[CH:11][C:12]([C:17]2[N:21]=[C:20]([CH3:22])[O:19][N:18]=2)=[C:13]([CH:16]=1)[C:14]([OH:27])=[O:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(-c2noc(C)n2)c(C=O)cc1OCc1ccccc1
Reactant: CS(C)=O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: CC#N
Product: COc1cc(-c2noc(C)n2)c(C(=O)O)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 5-benzyloxy-4-methoxy-2-(5-methyl-[1,2,4]oxadiazol-3-yl)benzaldehyde (reference example 15-1) (5.38 g), dimethyl sulfoxide (5.89 mL), concentrated sulfuric acid (0.506 mL), water (8 mL) and acetonitrile (41 mL) was added a mixture of sodium chlorite (2.25 g) and water (10 mL). After stirring at room temperature for 30 minutes, water was added to the mixture. The solid was collected by filtration to give the title compound (3.58 g).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([OH:19])([CH3:18])[CH3:17])=[CH:12][C:11]=2[F:20])=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].Br[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]2[CH:29]=[N:30][NH:31][CH:32]=2)[N:23]=1>>[F:20][C:11]1[CH:12]=[C:13]([C:16]([OH:19])([CH3:17])[CH3:18])[CH:14]=[CH:15][C:10]=1[C:4]1[S:3][C:2]([NH:1][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]3[CH:29]=[N:30][NH:31][CH:32]=3)[N:23]=2)=[C:6]([C:7]([NH2:9])=[O:8])[CH:5]=1
Reactant: Brc1cccc(-c2cn[nH]c2)n1
Reactant: CC(C)(O)c1ccc(-c2cc(C(N)=O)c(N)s2)c(F)c1
Product: CC(C)(O)c1ccc(-c2cc(C(N)=O)c(Nc3cccc(-c4cn[nH]c4)n3)s2)c(F)c1

Procedure:
The title compound was prepared as described in Example 1 using 2-amino-5-[2-fluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (77 mg, 0.26 mmol) and 2-bromo-6-(1H-pyrazol-4-yl)pyridine (59 mg, 0.262 mmol) as starting materials.
Reaction SMILES: [C-]#N.[Na+].[CH3:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([CH:12]=[O:13])=[CH:10][CH:11]=1.[CH2:14]([N:16](CC)CC)C.Cl>C(O)C>[CH3:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]([OH:13])[C:14]#[N:16])=[CH:8][CH:7]=1
Reactant: CCN(CC)CC
Reactant: COc1ccc(C=O)cc1
Agent: Cl
Agent: [C-]#N
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(C(O)C#N)cc1
Reaction time: 6 h

Procedure:
To 49 g (1 mole) of sodium cyanide and 136 g (1 mole) anisaldehyde in ethyl alcohol 800 ml), containing triethylamine (5 mol %, 5.1 g) is added HCl gas (1 mol, 36.5 g) over 30 minutes at 5°-10° C. The resulting slurry is stirred at that temperature for 6 hours. In situ sampling of the reaction mixture shows the reaction to be complete. Additional HCl (0.2 moles) is added to quench the reaction. tHE solution is filtered and used in the next step without further purification. Yield, ca. 80%.