Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]([CH:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)O)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:17](#[N:21])[CH2:18][C:19]#[N:20].C(N(CC)CC)C>CN(C=O)C>[NH2:21][C:17]1[O:8][C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:18]=1[C:19]#[N:20]
Reactant: N#CCC#N
Reactant: O=C(c1ccccc1)C(O)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: N#Cc1c(N)oc(-c2ccccc2)c1-c1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Stir 100 g (470 mmol) of benzoin, 62.25 g (940 mmol) of malononitrile and 47.68 g (470 mmol) of triethylamine at RT in 1345 ml of DMF overnight. Add a further 41 g (620 mmol) of malononitrile and stir the mixture at RT for another 24 h. Then add ethyl acetate and water and extract the aqueous phase twice with ethyl acetate. Dry the combined organic phases over magnesium sulphate and concentrate them under reduced pressure. After column chromatography on silica gel (eluent: dichloromethane→dichloromethane/methanol 98:2), 120 g (97.9% of theory) of the title compound are obtained as yellowish solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:10]=[N:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=2)[C:5]([C:17]2[N:22]=[C:21]([CH3:23])[N:20]=[C:19]([S:24][CH3:25])[N:18]=2)=[CH:4][N:3]=1.[F:26][C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.[NH4+].[Cl-].[Pd+2].ClC1C=C[C-](P(C2C=CC=CC=2)C2C=CC=CC=2)C=1Cl.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[F:26][C:27]1[CH:32]=[CH:31][C:30]([C:2]2[N:7]=[C:6]([NH:8][C:9]3[CH:10]=[N:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=3)[C:5]([C:17]3[N:22]=[C:21]([CH3:23])[N:20]=[C:19]([S:24][CH3:25])[N:18]=3)=[CH:4][N:3]=2)=[CH:29][CH:28]=1
Reactant: COc1ccc(Nc2nc(Cl)ncc2-c2nc(C)nc(SC)n2)cn1
Reactant: OB(O)c1ccc(F)cc1
Agent: [Fe+2]
Agent: [Pd+2]
Agent: Clc1cc[c-](P(c2ccccc2)c2ccccc2)c1Cl
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(Nc2nc(-c3ccc(F)cc3)ncc2-c2nc(C)nc(SC)n2)cn1
Temperature: 100 °C
Reaction time: 1 h
Yield: 52.5 %

Procedure:
A mixture of 2-chloro-N-(6-methoxypyridin-3-yl)-5-(4-methyl-6-(methylthio)-1,3,5-triazin-2-yl)pyrimidin-4-amine (38 mg, 0.101 mmol), 4-fluorobenzeneboronic acid (16.98 mg, 0.121 mmol), dichloro 1,1′-bis(diphenylphosphino)ferrocene palladium(II) (8.26 mg, 10.11 μmol) and cesium carbonate (66 mg, 0.202 mmol) in dioxane (3 mL) and water (0.5 mL) was stirred at 100° C. for 1 h. The mixture was cooled down to room temperature. The reaction mixture was diluted with saturated NH4Cl (5 mL) and extracted with EtOAc (2×30 mL). The organic extract was washed with saturated NaCl (5 mL) and dried over Na2SO4. The solution was filtered and concentrated in vacuo to give the crude material as an orange solid. The crude product was purified by silica gel chromatography eluting with 30% EtOAc/hexanes to give 2-(4-fluorophenyl)-N-(6-methoxypyridin-3-yl)-5-(4-methyl-6-(methylthio)-1,3,5-triazin-2-yl)pyrimidin-4-amine (23 mg, 0.053 mmol, 52.2% yield). 1H NMR (300 MHz, CDCl3) δ 11.64 (s, 1H); 9.73 (s, 1H); 8.39-8.50 (m, 3H); 8.11 (dd, J=8.77, 2.48 Hz, 1H); 7.16 (t, J=8.62 Hz, 2H); 6.87 (d, J=8.92 Hz, 1H); 4.00 (s, 3H); 2.67 (d, J=4.38 Hz, 6H). m/z (ESI, +ve ion) 436.1 (M+H)+.
Reaction SMILES: C([O:3][C:4](=[O:20])[C@@H:5]([O:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16]Br)=[CH:9][CH:8]=1)C.[CH3:21][N:22]([CH3:30])[C:23]1[CH:24]=[C:25]([OH:29])[CH:26]=[CH:27][CH:28]=1.CO[C@@H](CC1C=CC(OCCCOC2C=CC=CC=2)=CC=1)C(O)=O>>[CH3:21][N:22]([CH3:30])[C:23]1[CH:24]=[C:25]([CH:26]=[CH:27][CH:28]=1)[O:29][CH2:16][CH2:15][CH2:14][O:13][C:10]1[CH:9]=[CH:8][C:7]([CH2:6][C@H:5]([O:18][CH3:19])[C:4]([OH:3])=[O:20])=[CH:12][CH:11]=1
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCCBr)cc1)OC
Reactant: CN(C)c1cccc(O)c1
Agent: CO[C@@H](Cc1ccc(OCCCOc2ccccc2)cc1)C(=O)O
Product: CO[C@@H](Cc1ccc(OCCCOc2cccc(N(C)C)c2)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-[4-(3-bromo-propoxy)-phenyl]-2-methoxy-propionic acid ethyl ester (Example 284, Step 2) and 3-dimethylamino-phenol via the same procedure used for the preparation of (2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid (Example 285, Step 1), to produce a colorless oil.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=[O:6].[C:12](OC(=O)C)(=[O:14])[CH3:13]>>[C:12]([O:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=[O:6])(=[O:14])[CH3:13]
Reactant: Cc1ccc(C(=O)O)cc1O
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Oc1cc(C(=O)O)ccc1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A suspension of 3-hydroxy-4-methylbenzoic acid (10.73 g, 70.5 mmol, Lancaster) in acetic anhydride (25 mL, 265 mmol, Aldrich) was heated at reflux for 5 hours. After cooling to room temperature, the mixture was poured into an ice-water mixture (600 mL) and stirred overnight. Solid clumps were broken up and collected by filtration. The residue was washed with water and dried in a vacuum oven to give 3-acetoxy-4-methyl-benzoic acid as a tan solid. (Yield 11.82 g). 3-Acetoxy-4-methyl-benzoic acid (1.94 g, 10 mmol) was suspended in thionyl chloride (3 mL, 40 mmol, Aldrich) and N,N-dimethyl-formamide (3 drops) and heated at reflux for 2 hours. After cooling to room temperature, the mixture was diluted with toluene (30 mL) and concentrated under reduced pressure. The resulting oil was dissolved in dichloromethane (30 mL) and added dropwise to a solution of 4-chloroaniline (1.34 g, 10.5 mmol, Aldrich) and N,N-diisopropylethylamine (1.6 g, 12.5 mmol) in dichloromethane (50 mL). After stirring for another 2 hours, the mixture was diluted with water (50 mL) and stirred for another 30 minutes. The layers were separated. The organic layer was washed with water (50 mL). Aqueous layers were back washed with dichloromethane (50 mL). Organic layers were then combined and concentrated. The residue was dissolved in mixture of tetrahydrofuran (25 mL), methanol (25 mL) and 1 N aqueous sodium hydroxide (10 mL, 10 mmol). After stirring for 16 hours, the mixture was diluted with water (100 mL) and acetic acid (5 mL) and concentrated under reduced pressure to remove most of the organic solvent. Precipitate formed was collected by filtration and washed with water, and dried to give N-(4-chloro-phenyl)-3-hydroxy-4-methyl-benzamide as off-white crystals. (Yield 2.57 g).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][N:12]2[CH2:21][CH2:20][C:19]3[C:18]([C:22]([O:24]C)=[O:23])=[CH:17][CH:16]=[CH:15][C:14]=3[CH2:13]2)=[CH:3][CH:2]=1.O.[OH-].[Na+]>O1CCOCC1>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][N:12]2[CH2:21][CH2:20][C:19]3[C:18]([C:22]([OH:24])=[O:23])=[CH:17][CH:16]=[CH:15][C:14]=3[CH2:13]2)=[CH:3][CH:2]=1
Reactant: COC(=O)c1cccc2c1CCN(Cc1ccnc3ccccc13)C2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)c1cccc2c1CCN(Cc1ccnc3ccccc13)C2
Temperature: 25 °C
Reaction time: 48 h
Yield: 92.2 %

Procedure:
Methyl 2-(quinolin-4-ylmethyl)-1,2,3,4-tetrahydroisoquinoline-5-carboxylate (1.2 g, 3.61 mmol) was dissolved in dioxane (15 mL) and water (5 mL) then added a solution of 2N aqueous sodium hydroxide (1.90 mL, 3.80 mmol). The reaction mixture was stirred at room temperature for 2 days then concentrated under vacuum to remove the dioxane. The remaining aqueous solution was diluted with water then added 1N aqueous hydrochloric acid (3.8 mL) to bring the mixture to pH 7. A precipitate formed which was collected on a glass frit, washing with minimal water then dichloromethane. The solid was dried under high vacuum to afford 1.06 g of 2-(quinolin-4-ylmethyl)-1,2,3,4-tetrahydroisoquinoline-5-carboxylic acid as a white solid. MS (ESI, pos. ion) m/z: 319.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[C:6]([CH3:13])=[C:5]2[N:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20](I)[CH:21]=2)[C:16]([CH3:25])([CH3:24])[CH2:15]1.CC1(C)C(C)(C)OB([C:34]2[CH:35]=[N:36][NH:37][CH:38]=2)O1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[C:6]([CH3:13])=[C:5]2[N:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([C:34]3[CH:35]=[N:36][NH:37][CH:38]=3)[CH:21]=2)[C:16]([CH3:25])([CH3:24])[CH2:15]1
Reactant: Cc1nc2ccc(Cl)cc2c(N2CC(C)(C)c3ccc(I)cc32)c1C
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Product: Cc1nc2ccc(Cl)cc2c(N2CC(C)(C)c3ccc(-c4cn[nH]c4)cc32)c1C

Procedure:
Prepared according to procedure W using 6-chloro-4-(6-iodo-3,3-dimethylindolin-1-yl)-2,3-dimethylquinoline (0.15 g, 0.32 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.084 g, 0.432 mmol) to give 6-chloro-4-(3,3-dimethyl-6-(1H-pyrazol-4-yl)-2,3-dihydro-1H-indol-1-yl)-2,3-dimethylquinoline as a yellow solid: 1H NMR (500 MHz, DMSO-d6) δ ppm 12.73 (1H, br. s.), 8.01 (1H, d, J=9.0 Hz), 7.91 (1H, br. s.), 7.75 (1H, d, J=2.4 Hz), 7.62-7.71 (2H, m), 7.19 (1H, d, J=7.6 Hz), 6.94 (1H, d, J=7.6 Hz), 6.07 (1H, s), 3.56-3.78 (2H, m), 2.68 (3H, s), 2.21 (3H, s), 1.48 (3H, s), 1.43 (3H, s); Mass Spectrum (ESI) m/e=403.1 (M+1).
Reaction SMILES: C([Li])CCC.[S:6]([C:16]1[S:17][CH:18]=[CH:19][CH:20]=1)([C:9]1[CH:15]=[CH:14][C:12]([CH3:13])=[CH:11][CH:10]=1)(=[O:8])=[O:7].[Cl:21][C:22]1[N:27]=[CH:26][CH:25]=[CH:24][N:23]=1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl.[OH-].[Na+]>O1CCCC1>[Cl:21][C:22]1[N:27]=[C:26]([C:18]2[S:17][C:16]([S:6]([C:9]3[CH:10]=[CH:11][C:12]([CH3:13])=[CH:14][CH:15]=3)(=[O:7])=[O:8])=[CH:20][CH:19]=2)[CH:25]=[CH:24][N:23]=1
Reactant: Clc1ncccn1
Reactant: Cc1ccc(S(=O)(=O)c2cccs2)cc1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)c2ccc(-c3ccnc(Cl)n3)s2)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 49.1 %

Procedure:
n-Butyllithium in hexanes (0.92 mL, 2.5 M, 2.30 mmol) was added dropwise to a solution of 2-tosylthiophene (0.5 g, 2.09 mmol) in anhydrous tetrahydrofuran (30 mL) at −78° C. The resulting mixture was stirred at −78° C. for 1 h and a solution of 2-chloropyrimidine (0.26 g, 2.30 mmol) in 3 mL of tetrahydrofuran was added slowly. The mixture was stirred at −78° C. for 1 h and then at −40° C. for 2 h. The reaction was quenched with a solution (0.22 mL) of acetic acid and methanol (1:1) at −40° C. and a solution of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (0.57 g, 2.51 mmol) was added. After complete addition the reaction was stirred for 1 h, and then warmed to rt and stirred for an additional 15 h. 20 mL of aqueous sodium hydroxide (2 M) was added and the mixture was extracted with ethyl acetate (3×50 mL). The combined organic layer was washed with brine (80 mL), dried over anhydrous sodium sulfate and filtered. The solvent was evaporated in vacuo and the product was purified by flash chromatography eluting with ethyl acetate/hexane (1:3) to afford the title compound as a white solid (0.36 g, 49%).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([Cl:42])=[C:9]([N:11]2[C:15](=[O:16])[N:14]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]4[CH:29]=[C:28]([CH2:30][CH2:31][CH3:32])[CH:27]=[CH:26][C:25]=4[S:33](=[O:36])(=[O:35])[NH2:34])=[CH:20][C:19]=3[F:37])[C:13]([CH2:38][CH2:39][CH2:40][CH3:41])=[N:12]2)[CH:10]=1)(=[O:3])[CH3:2].[Cl:43][C:44]1[CH:52]=[CH:51][CH:50]=[CH:49][C:45]=1[C:46](O)=[O:47].C1N=CN(C(N2C=NC=C2)=O)C=1.C1CCN2C(=NCCC2)CC1>>[C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([Cl:42])=[C:9]([N:11]2[C:15](=[O:16])[N:14]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]4[CH:29]=[C:28]([CH2:30][CH2:31][CH3:32])[CH:27]=[CH:26][C:25]=4[S:33](=[O:36])(=[O:35])[NH:34][C:46](=[O:47])[C:45]4[CH:49]=[CH:50][CH:51]=[CH:52][C:44]=4[Cl:43])=[CH:20][C:19]=3[F:37])[C:13]([CH2:38][CH2:39][CH2:40][CH3:41])=[N:12]2)[CH:10]=1)(=[O:3])[CH3:2]
Reactant: O=C(O)c1ccccc1Cl
Reactant: CCCCc1nn(-c2cc(NC(C)=O)ccc2Cl)c(=O)n1Cc1ccc(-c2cc(CCC)ccc2S(N)(=O)=O)cc1F
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Product: CCCCc1nn(-c2cc(NC(C)=O)ccc2Cl)c(=O)n1Cc1ccc(-c2cc(CCC)ccc2S(=O)(=O)NC(=O)c2ccccc2Cl)cc1F
Yield: 56 %

Procedure:
Reaction of 2-[5-(acetylamino)-2-chlorophenyl]-5-n-butyl-2,4-dihydro-4-[(3-fluoro-5'-n-propyl-2'-sulfamoylbiphenyl-4-yl)methyl]-3H-1,2,4-triazol-3-one (from Step E) with 2-chlorobenzoic acid (2 equivalents), CDI (2 equiv), and DBU (2 equiv) according to the procedure of Example 69 gave a 56% yield of the title compound as a white, glassy solid, mp 144°-146° C.; homogeneous by TLC (95:5 CH2Cl2 --MeOH); mass spectrum (FAB) m/e 752 (M+1)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[C:18]=2F)=[N:15][OH:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(C)([O-])C.[K+]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[C:18]=3[O:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=NO)c2cccc(C(F)(F)F)c2F)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(c2noc3c(C(F)(F)F)cccc23)CC1
Temperature: 60 °C
Reaction time: 8 h
Yield: 73 %

Procedure:
To a room temperature mixture of 4-[(2-fluoro-3-trifluoromethyl-phenyl)-hydroxyimino-methyl]-piperidine-1-carboxylic acid tert-butyl ester (1.40 g, 3.59 mmol) in THF (20 mL) under nitrogen was added potassium tert-butoxide (3.60 mL of a 1M THF solution, 3.60 mmol) in one portion and the reaction heated at 60° C. for 1.5 h. After standing at room temperature overnight, the solvent was removed and the residue diluted with ethyl acetate (60 mL). The organics were washed with water (30 mL) and brine (30 mL) successively, dried over magnesium sulfate, filtered, and concentrated to give an amber solid. The crude product was chromatographed on silica using 40% ethyl acetate/heptane as eluent to afford 0.97 g (73%) of the desired product as a white solid, mp:111-113° C.
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([CH3:5])=O.[NH:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1>C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[NH:9]1[CH2:13][CH2:12][CH2:11][CH:10]1[C:3]([CH3:5])=[CH:2][C:1]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)CC(C)=O
Reactant: C1CCNC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)C=C(C)C1CCCN1
Temperature: 140 °C
Yield: 99.5 %

Procedure:
Methyl acetoacetate (20 g, 172.23 mmol) was dissolved in 250 mL of toluene, and then pyrrolidine (43 ml, 516.70 mmol) and p-toluenesulfonic acid hydrate (about 100 mg) were added dropwise. After installing a Dean-Stark separator to the reactor, the reaction mixture was refluxed 140° C. for two days, and then solvent was removed by concentrating the resulting mixture under a reduced pressure, thereby to obtain the desired product (29 g, 99%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1.[CH3:9][N:10](C=O)C>[C-]#N.[Zn+2].[C-]#N.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>[C:9]([C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1)#[N:10]
Reactant: Cc1ccnc(Cl)n1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: Cc1ccnc(C#N)n1
Temperature: 180 °C
Yield: 54 %

Procedure:
To a solution of 2-chloro-4-methylpyrimidine (1 g, 7.78 mmol) and zinc cyanide (475 mg, 4.04 mmol) in anhydrous DMF (10 ml) was added Pd(PPh3)4 (449 mg, 0.366 mmol) and nitrogen flushed through the mixture for 5 min. The mixture was heated at 180° C. for 30 min in a microwave reactor. The reaction was repeated on the same scale and the reaction mixtures were combined. The mixture was partitioned between EtOAc and water (filtered through celite to remove some insolubles), and the organic layer washed with sat. NaCl, dried over MgSO4, filtered and evaporated. The residue was purified by MPLC (Biotage Horizon: FLASH 25+M) eluent: 100% Hexanes (90 ml), gradient rising from 100% Hexanes to 15% EtOAc in Hexanes (900 ml), then 15% EtOAc in Hexanes (500 ml) to give 1 g of the title compound (54%) as an off-white solid. 1H NMR (CDCl3): 2.62 (s, 3H), 7.42 (d, J5.1 Hz, 1H), 8.69 (d, J5.1 Hz, 1H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][Si:5]([O:16][Si:17]([CH3:20])([CH3:19])[CH3:18])([O:11][Si:12]([CH3:15])([CH3:14])[CH3:13])[O:6][Si:7]([CH3:10])([CH3:9])[CH3:8].[I-:21].[Na+]>CC(C)=O>[I:21][CH2:2][CH2:3][CH2:4][Si:5]([O:16][Si:17]([CH3:20])([CH3:19])[CH3:18])([O:11][Si:12]([CH3:15])([CH3:14])[CH3:13])[O:6][Si:7]([CH3:10])([CH3:9])[CH3:8]
Reactant: [I-]
Reactant: C[Si](C)(C)O[Si](CCCCl)(O[Si](C)(C)C)O[Si](C)(C)C
Agent: [Na+]
Solvent: CC(C)=O
Product: C[Si](C)(C)O[Si](CCCI)(O[Si](C)(C)C)O[Si](C)(C)C
Reaction time: 24 h
Yield: 79.4 %

Procedure:
90 g of 3-chloropropyltris(trimethylsiloxy)silane (27) (Chem. Abstracts No. 18077-31-1) and 105.22 g of sodium iodide are added to 250 ml of acetone and stirred for 24 hours at reflux. The acetone is evaporated and the residue taken up in methylene chloride. The organic phase is washed with water, dried and evaporated. 89 g of the desired 3-iodopropyl-tris(trimethylsiloxy)silane (28) are obtained; 1H-NMR (ppm, CDCl3): 3.12 2H t, 1.75 2H txt, 0.43 2H t, 0 27H s.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH:3]([C:6]([OH:8])=O)[CH2:2]1.CN([C:12]([O:16][N:17]1N=NC2C=CC=C[C:18]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.CNOC.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:12][O:16][N:17]([CH3:18])[C:6]([CH:3]1[CH2:4][CH2:5][O:1][CH2:2]1)=[O:8]
Reactant: O=C(O)C1CCOC1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CNOC
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)C1CCOC1
Reaction time: 1 h
Yield: 161.8 %

Procedure:
Tetrahydro-3-furoic acid (412 μL, 4.31 mmol) was dissolved in DMF (18 mL) and HBTU (1.96 g, 5.17 mmol) was added. The reaction mixture was stirred for 1 h and N,O-dimethylhydroxylamine hydrochloride (504 mg, 5.17 mmol) and DIPEA (2.25 mL, 12.9 mmol) were added. The reaction mixture was stirred overnight and concentrated in vacuo. The residue was diluted with DCM (40 mL) and washed with sat aq NH4Cl (20 mL) and sat aq Na2CO3 (20 mL), dried (MgSO4) and concentrated in vacuo. The residue was purified by normal phase column chromatography to give the crude title compound as a yellow gum (1.11 g). LCMS (ES+): 160.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([N:8](C)[C:9](=O)OC(C)(C)C)=[C:4]([I:17])[CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][CH3:9])=[C:4]([I:17])[CH:3]=1
Reactant: CN(C(=O)OC(C)(C)C)c1cnc(Cl)cc1I
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNc1cnc(Cl)cc1I
Temperature: 25 °C
Reaction time: 4 h
Yield: 97.7 %

Procedure:
To the solution of tert-butyl (6-chloro-4-iodopyridin-3-yl)(methyl)carbamate (62.5 g, 0.172 mol) in 500 mL of anhydrous DCM was added 180 mL of TFA. Then the solution was stirred at room temperature for 4 hrs. Concentrated to remove the solvent, and purified by flash chromatography to afford 45.1 g 6-chloro-4-iodo-N-methylpyridin-3-amine as a yellow solid (Yield: 97.3%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([O:12]C(C)(C)C)=[O:11])=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.[ClH:24]>C(Cl)Cl.O1CCOCC1>[ClH:24].[NH2:1][C:2]1[N:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)/C=C/c1ccc(N)nc1
Agent: Cl
Solvent: C1COCCO1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1ccc(/C=C/C(=O)O)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76 %

Procedure:
To a solution of tert-butyl (2E)-3-(6-aminopyridin-3-yl)acrylate (380 mg, 1.73 mmol; which may be prepared as described in Step 1) in DCM (3.45 mL) under Argon was added trifluoroacetic acid (3.45 mL). The mixture was stirred at room temperature for 1 h, then HCl 4N in dioxane (6.9 mL) was added. A beige solid started precipitating at the half of the addition. After concentration, the solid was triturated in Et2O, filtered, rinsed with Et2O and dried under vacuum to give the title compound as a beige solid (265 mg, 76%).
Reaction SMILES: [CH3:1][CH:2]([NH:11][CH3:12])[CH:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.CN.C[C@H](NC)[C@H](O)C1C=CC=CC=1>>[CH3:1][C@H:2]([NH:11][CH3:12])[C@@H:3]([OH:10])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CNC(C)C(O)c1ccccc1
Agent: CN
Agent: CN[C@@H](C)[C@H](O)c1ccccc1
Product: CN[C@@H](C)[C@@H](O)c1ccccc1

Procedure:
The combination of yeast transformation of benzaldehyde to produce PAC and chemical conversion of the PAC to make 1-ephedrine is described in U.S. Pat. No. 1,956,950. The PAC can be converted by a chemical reductive amination with methylamine to optically pure L-ephedrine as follows: ##STR2## The 1-ephedrine can then converted in high yield to d-pseudoephedrine as follows: ##STR3## It is apparent from this reaction scheme that microbial transformation of benzaldehyde by yeast to form L-(-)phenyl acetyl carbinol in high yield and purity is of prime importance for successful commercial operation of the synthetic route.
Reaction SMILES: [CH2:1]([N:5]([CH2:23][CH2:24][CH2:25][CH3:26])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][C:14]2[S:18][C:17]([CH:19]=O)=[CH:16][CH:15]=2)=[C:8]([O:21][CH3:22])[CH:7]=1)[CH2:2][CH2:3][CH3:4].[C:27]([C:29]1[C:30](=[C:37]([C:40]#[N:41])[C:38]#[N:39])[O:31][C:32]([CH3:36])([CH3:35])[C:33]=1[CH3:34])#[N:28].C([O-])(=O)C.[NH4+]>C(O)C.O1CCCC1>[CH2:23]([N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][C:14]2[S:18][C:17]([CH:19]=[CH:34][C:33]3[C:32]([CH3:35])([CH3:36])[O:31][C:30](=[C:37]([C:38]#[N:39])[C:40]#[N:41])[C:29]=3[C:27]#[N:28])=[CH:16][CH:15]=2)=[C:8]([O:21][CH3:22])[CH:7]=1)[CH2:24][CH2:25][CH3:26]
Reactant: CCCCN(CCCC)c1ccc(C=Cc2ccc(C=O)s2)c(OC)c1
Reactant: CC1=C(C#N)C(=C(C#N)C#N)OC1(C)C
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CCO
Solvent: C1CCOC1
Product: CCCCN(CCCC)c1ccc(C=Cc2ccc(C=CC3=C(C#N)C(=C(C#N)C#N)OC3(C)C)s2)c(OC)c1
Temperature: 50 °C
Reaction time: 2.5 h
Yield: 74.8 %

Procedure:
In 10 ml of ethanol and 3 ml of tetrahydrofuran were dissolved 300 mg (0.81 mmol) of 5-[2-(4-dibutylamino-2-methoxyphenyl)vinyl]thiophene-2-carboaldehyde and 177 mg (0.89 mmol) of 2-(3-cyano-4,5,5-trimethyl-2(5H)-furanylidene)propanedinitrile. To this mixture was added 63 mg of ammonium acetate, and the mixture was stirred at room temperature for 24 hours and further at 50° C. for 2.5 hours. The solvent was evaporated off and the residue was washed with ethanol to give 335 mg of a brown powdered crystal (yield: 75.1%; mp: 191-192° C.)
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4]1.C(N(C(C)C)CC)(C)C.[Br:24][C:25]1[CH:26]=[N:27][C:28]([O:31][CH2:32][C:33](O)=[O:34])=[N:29][CH:30]=1.O.ON1C2C=CC=CC=2N=N1>ClC(Cl)C.O1CCCC1.C(OCC)(=O)C>[C:11]([O:10][C:8]([N:5]1[CH2:6][CH2:7][CH:3]([CH2:2][NH:1][C:33](=[O:34])[CH2:32][O:31][C:28]2[N:27]=[CH:26][C:25]([Br:24])=[CH:30][N:29]=2)[CH2:4]1)=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: O=C(O)COc1ncc(Br)cn1
Reactant: CC(C)(C)OC(=O)N1CCC(CN)C1
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(CNC(=O)COc2ncc(Br)cn2)C1
Reaction time: 8 h

Procedure:
To a solution of 3-(RS)-aminomethyl-1-tert-butoxycarbonylpyrrolidine in dichloroethane (17 mL) were sequentially added diisopropylethylamine (5.1 mL), a solution of 2-(5-bromopyrimidin-2-yloxy)acetic acid (2.9 g, 12.2 mmol, 1.1 equiv.) in tetrahydrofuran (43 mL), 1-hydroxybenzotriazole hydrate (2.4 g, 17.5 mmol, 1.5 equiv.) and 1-(3-dimethyl-aminopropyl)-3-ethylcarbodiimide hydrochloride (3.4 g, 17.6 mmol, 1.5 equiv.). The solution was stirred under N2 overnight. The reaction mixture was diluted with ethyl acetate, washed with 1 M aqueous sodium hydroxide, 1 M hydrochloric acid, water and brine, then dried over sodium sulfate and concentrated. The residue was subjected to flash chromatography to afford clean N-(1-tert-butoxycarbonylpyrrolidin-3-(RS)-ylmethyl)-2-(5-bromopyrimidin-2-yloxy)acetamide (4.2 g).