Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][N:9]1[C:14](=[O:15])[C:13]2[CH:16]=[C:17]([F:25])[C:18]([N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)=[N:19][C:12]=2[N:11]([CH2:26][CH3:27])[C:10]1=[O:28])C1C=CC=CC=1>CO.C(OCC)(=O)C.[Pd]>[CH2:26]([N:11]1[C:12]2[N:19]=[C:18]([N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[C:17]([F:25])=[CH:16][C:13]=2[C:14](=[O:15])[N:9]([OH:8])[C:10]1=[O:28])[CH3:27]
Reactant: CCn1c(=O)n(OCc2ccccc2)c(=O)c2cc(F)c(N3CCCC3)nc21
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCn1c(=O)n(O)c(=O)c2cc(F)c(N3CCCC3)nc21

Procedure:
Following the procedure of Example 32, hydrogenation of 3-benzyloxy-1-ethyl-6-fluoro-7-pyrrolidin-1-yl-1H-pyrido[2,3-d]pyrimidine-2,4-dione (Example X-2, 110 mg, 0.286 mmol) and 10% Pd/C (60 mg) in MeOH (2 mL) and ethyl acetate (3 mL) afforded 55 mg, of the title compound as a solid, mp 236-237° C. (decomp.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:9][CH:10]([CH2:14][CH3:15])[C:11]([OH:13])=O)[CH:5]=[N:6][C:7]=1[Cl:8].[NH2:16][C:17]([CH3:30])([CH3:29])[C:18]#[C:19][CH2:20][O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23]>>[Cl:1][C:2]1[CH:3]=[C:4]([O:9][CH:10]([CH2:14][CH3:15])[C:11]([NH:16][C:17]([CH3:30])([CH3:29])[C:18]#[C:19][CH2:20][O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:23])[CH3:24])=[O:13])[CH:5]=[N:6][C:7]=1[Cl:8]
Reactant: CC(C)(N)C#CCO[Si](C)(C)C(C)(C)C
Reactant: CCC(Oc1cnc(Cl)c(Cl)c1)C(=O)O
Product: CCC(Oc1cnc(Cl)c(Cl)c1)C(=O)NC(C)(C)C#CCO[Si](C)(C)C(C)(C)C

Procedure:
In a similar procedure to that described in Example 11 Stage 3, the product from Step 2 was reacted with 4-amino-1-tert-butyldimethylsilyloxy-4-methylpent-2-yne to give 2-(5,6-dichloro-3-pyridyloxy)-N-(1-tert-butyldimethylsilyloxy-4methylpent-2-yn-4-yl)butyramide as a yellow oil.
Reaction SMILES: [C:1]([CH:4]1[N:9]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([OH:25])([C:21]([F:24])([F:23])[F:22])[C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=2)[CH2:8][CH2:7][N:6]([S:26]([C:29]2[S:33][C:32]([NH:34]C(=O)C)=[N:31][N:30]=2)(=[O:28])=[O:27])[CH2:5]1)#[C:2][CH3:3].Cl.O1CCOCC1>CO>[NH2:34][C:32]1[S:33][C:29]([S:26]([N:6]2[CH2:7][CH2:8][N:9]([C:10]3[CH:11]=[CH:12][C:13]([C:16]([OH:25])([C:17]([F:19])([F:20])[F:18])[C:21]([F:23])([F:24])[F:22])=[CH:14][CH:15]=3)[CH:4]([C:1]#[C:2][CH3:3])[CH2:5]2)(=[O:27])=[O:28])=[N:30][N:31]=1
Reactant: CC#CC1CN(S(=O)(=O)c2nnc(NC(C)=O)s2)CCN1c1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CC#CC1CN(S(=O)(=O)c2nnc(N)s2)CCN1c1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Temperature: 100 °C
Yield: 46.7 %

Procedure:
A 20-mL microwave vial was charged with N-(5-((3-(1-propyn-1-yl)-4-(4-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)phenyl)-1-piperazinyl)sulfonyl)-1,3,4-thiadiazol-2-yl)acetamide (370 mg, 0.647 mmol), MeOH (2 mL), 1N aq. HCl (3 mL, 3.00 mmol) and 4N HCl in dioxane (3 mL, 12.00 mmol). The reaction vessel was sealed and the mixture heated to 100° C. for 4 h. The reaction was concentrated onto silica and purified via column chromatography on silica gel (0 to 10% MeOH in CH2Cl2) to give 2-(4-(4-((5-amino-1,3,4-thiadiazol-2-yl)sulfonyl)-2-(1-propyn-1-yl)-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol (160 mg) as a mixture of two isomers.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:19])[NH:4][C:5](=[O:18])[N:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[CH:7]=1.[C:20](=O)([O-])[O-].[K+].[K+].CI.[Cl-].[NH4+]>CN(C)C=O>[Br:1][C:2]1[C:3](=[O:19])[N:4]([CH3:20])[C:5](=[O:18])[N:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[CH:7]=1
Reactant: O=c1[nH]c(=O)n(-c2cccc(C(F)(F)F)c2)cc1Br
Reactant: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cn1c(=O)c(Br)cn(-c2cccc(C(F)(F)F)c2)c1=O
Yield: 98.3 %

Procedure:
To a solution of 5-bromo-1-(3-trifluoromethylphenyl)pyrimidin-2,4(1H,3H)-dione (prepared in Reference Example 97) (150.0 mg) and potassium carbonate (181.6 mg) in N,N-dimethy formamide (4.0 ml) was added at room temperature, methyl iodide (0.042 ml) and the resulting mixture was stirred at 70° C. for two and a half hours. To the reaction mixture was added saturated aqueous ammonium chloride solution (20.0 ml), and the resulting mixture was extracted with ethyl acetate (20 ml×2) and the organic layer was washed with water (20 ml×2) and saturated saline (20 ml), dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to afford 5-bromo-3-methyl-1-(3-trifluoromethylphenyl)pyrimidin-2,4(1H,3H)-dione (153.6 mg).
Reaction SMILES: Cl.[C:2]([NH2:10])(=[NH:9])[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.C(O)C.C[O-].[Na+].[C:17]1([N:23]=[N:24][CH:25]([C:28]#[N:29])[C:26]#[N:27])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>O>[C:17]1([N:23]=[N:24][C:25]2[C:26]([NH2:27])=[N:9][C:2]([C:3]3[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=3)=[N:10][C:28]=2[NH2:29])[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: N#CC(C#N)N=Nc1ccccc1
Reactant: N=C(N)c1ccncc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Nc1nc(-c2ccncc2)nc(N)c1N=Nc1ccccc1
Reaction time: 0.5 h
Yield: 61.2 %

Procedure:
The intermediate 5-(phenylazo)-2-(4-pyridinyl)-4,6-pyrimidinediamine was prepared as follows: a mixture containing 477 g of isonicotinamidine hydrochloride, 3 liters of ethanol and 170 g of sodium methoxide was stirred for 30 minutes and to the mixture was added 340 g of α-(phenylazo)malononitrile and the reaction mixture was stirred under reflux for 5 hours and then poured into 3 liters of water. The solid that separated was collected, washed with water and dried in a vacuum oven at 90°-95° C. to yield 356 g of 5-(phenylazo)-2-(4-pyridinyl)-4,6-pyrimidinediamine, m.p. 302°-305° C.
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:14]([O:16][CH3:17])=[O:15])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1.C(N(CC)CC)C.[F:25][C:26]1[CH:36]=[CH:35][C:29]([CH:30]=[CH:31][C:32](O)=[O:33])=[CH:28][CH:27]=1.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[F:25][C:26]1[CH:27]=[CH:28][C:29]([CH:30]=[CH:31][C:32]([NH:2][C@H:3]([C:14]([O:16][CH3:17])=[O:15])[CH2:4][C:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][CH:6]=2)=[O:33])=[CH:35][CH:36]=1
Reactant: COC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Reactant: O=C(O)C=Cc1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)C=Cc1ccc(F)cc1
Yield: 74.7 %

Procedure:
The same procedures as in Example 2 were carried out from methyl L-tryptophanate hydrochloride (4.0 g), triethylamine (4.8 mL), 4-fluorocinnamic acid (2.9 g), WSC.HCl (3.3 g), and methylene chloride (150 mL), to give the captioned compound (4.3 g, 74%) as an oily product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-])=O)[C:5]([NH2:8])=[N:6][CH:7]=1.C(OCC)(=O)C.O.O.[Sn](Cl)(Cl)(Cl)Cl.[BH4-].[Na+]>CC(O)(C)C>[Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[N:6][CH:7]=1
Reactant: Nc1ncc(Br)cc1[N+](=O)[O-]
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Solvent: CCOC(C)=O
Product: Nc1cc(Br)cnc1N
Temperature: 60 °C
Reaction time: 2 h
Yield: 38 %

Procedure:
Commercially-available 5-bromo-3-nitro-pyridin-2-ylamine (20.0g, 92 mmol) was suspended in a 9:1 ethyl acetate:t-BuOH solution (470 ml). Tin chloride dihydrate (104 g, 460 mmol) was added, and the suspension was stirred under nitrogen for 2 h at 60° C. NaBH4 (1.75 g, 46 mmol) was added slowly, and the suspension was allowed to stir for another 3 hours. The reaction mixture was then cooled and filtered. The filtrate was extracted with 3 N HCl three times, and the collected acid washes were washed with ethyl acetate. The acidic solution was made basic by the careful addition of solid sodium carbonate. This aqueous solution was extracted with ethyl acetate three times, and the organic fractions were combined. The ethyl acetate solution was washed with brine, dried over MgSO4 and concentrated to yield the title product (6.5 g (38%), 35 mmol). 1H NMR (DMSO-d6): δ=11.99 (bs, 2H), 7.31 (d,1H, J=2.1 Hz), 6.84 (d, 1H, J=2.1 Hz), 5.90 (bs, 2H). Calculated mass=188.03, [M+H]+=189.
Reaction SMILES: FC(F)(F)C(O)=O.C[O:9][C:10](=[O:40])[C@H:11]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH2:28][CH2:29][C:30]2[CH:39]=[CH:38][C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:31]=2)[CH:22]=1)[NH:12]C(OC(C)(C)C)=O.O.[OH-].[Li+].Cl>C(Cl)Cl.O>[CH:31]1[C:32]2[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:38]=[CH:39][C:30]=1[CH2:29][CH2:28][O:27][C:23]1[CH:22]=[C:21]([CH:26]=[CH:25][CH:24]=1)[CH2:20][C@@H:11]([C:10]([OH:40])=[O:9])[NH2:12]
Reactant: COC(=O)[C@H](Cc1cccc(OCCc2ccc3ccccc3c2)c1)NC(=O)OC(C)(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: N[C@@H](Cc1cccc(OCCc2ccc3ccccc3c2)c1)C(=O)O
Reaction time: 0.5 h
Yield: 59 %

Procedure:
Trifluoroacetic acid (3 ml) was added to a solution of N-t-butoxycarbonyl-3-[2-(2-naphthyl)ethoxy]-L-phenylalanine methyl ester (125 mg, 0.278 mmol) in methylene chloride (3 ml) under ice cooling and the mixture was stirred at the same temperature for 30 min. The solvent of the reaction mixture was distilled off at room temperature under reduced pressure. The residue was triturated with n-hexane and collected by filtration. The resultant solid was dissolved in tetrahydrofuran (1.2 ml)-water (0.6 ml). Lithium hydroxide mono-hydrate (41 mg, 0.973 mmol) was added to the solution with stirring under ice cooling and the mixture was reacted at the same temperature for 12 hrs. The reaction mixture was diluted with water (2 ml) and adjusted to pH 3-4 with 1N HCl. After the addition of water (25 ml), the mixture was stirred at room temperature for 1 hr. The precipitates were collected by filtration, washed with water and then dried under reduced pressure to give 3-[2-(2-naphthyl)ethoxy]-L-phenylalanine (55 mg, 59%) as colorless crystals.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]([CH2:15][CH2:16][P:17]([CH:22]([O:26][CH2:27][CH3:28])[O:23][CH2:24][CH3:25])(=[O:21])[O:18][CH2:19][CH3:20])#[N:14].[CH2:29](Br)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.[Cl-].[NH4+]>O1CCCC1.CCCCCC>[CH2:29]([CH:15]([C:13]#[N:14])[CH2:16][P:17]([CH:22]([O:23][CH2:24][CH3:25])[O:26][CH2:27][CH3:28])(=[O:21])[O:18][CH2:19][CH3:20])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CCOC(OCC)P(=O)(CCC#N)OCC
Reactant: BrCc1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCOC(OCC)P(=O)(CC(C#N)Cc1ccccc1)OCC
Reaction time: 0.17 h

Procedure:
To a solution of 0.97 g of diisopropylamine in 40 ml of tetrahydrofuran at -78° C. under an atmosphere of nitrogen are added 6.0 ml of a 1.6M solution of n-butyllithium in hexane. This solution is then stirred for a period of 10 minutes at this temperature, after which time a solution of 2.0 g of ethyl 2-cyanoethyl(diethoxymethyl)phosphinate in 10 ml of tetrahydrofuran is added. This mixture is then stirred for a period of 1 hour at -78° C. after which time a solution of 1.4 g of benzyl bromide in 10 ml of tetrahydrofuran is introduced. This mixture is then allowed to warm to room temperature when 40 ml of a saturated ammonium chloride solution is added. The aqueous layer is then extracted with 2×25 ml of diethyl ether and the organic extracts are combined and dried over magnesium sulphate. The solvent is then evaporated under reduced pressure and the crude product chromatographed on silica gel using ethyl acetate as an eluent to give ethyl 2-benzyl-2-cyanoethyl(diethoxymethyl)phosphinate as a viscous oil, 31 p=+40.7 and +40.5 ppm (CDCl3).
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([NH:19][C:20](=[O:28])[C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)[CH:14]=2)[CH2:8][CH2:7]1)=[O:5])C.O.[OH-].[Li+].Cl>C1COCC1.CO>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([C:20]([NH:19][C:15]2[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=2)[CH2:12][N:9]2[CH2:10][CH2:11][CH:6]([C:4]([OH:5])=[O:3])[CH2:7][CH2:8]2)=[O:28])=[CH:22][CH:23]=1
Reactant: CCOC(=O)C1CCN(Cc2cccc(NC(=O)c3ccc(Cl)cc3)c2)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(Nc1cccc(CN2CCC(C(=O)O)CC2)c1)c1ccc(Cl)cc1
Yield: 91.8 %

Procedure:
A solution of 1-[3-(4-chloro-benzoylamino)-benzyl]-piperidine-4-carboxylic acid ethyl ester (1.65 g, 4.12 mmol) in a mixture of THF (20 mL) water (10 mL) and MeOH (10 mL) is treated with lithium hydroxide monohydrate (190 mg, 4.53 mmol) at RT for 2 h. Aq. 2N HCl (2.3 mL) is added and the resulting solution is lyophilized to yield the crude title compound (1.41 g) containing one equivalent LiCl. LC-MS A: tR=0.64 min; [M+H]+=372.93.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1.B.Cl.O1CCOCC1>O1CCCC1.CCOCC>[I:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH2:10])=[CH:4][CH:3]=1
Reactant: N#CCc1ccc(I)cc1
Agent: B
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: C1COCCO1
Product: NCCc1ccc(I)cc1
Yield: 92.9 %

Procedure:
4-Iodophenylacetonitrile (4.80 g, 19.7 mmol) was dissolved in tetrahydrofuran (25 mL) under nitrogen, and 1.0 M borane in tetrahydrofuran (29.6 mL, 29.6 mmol) was added via syringe. The reaction was heated at reflux for 1 hour, then cooled in ice and the excess borane was quenched by the addition of methanol (100 mL). When hydrogen evolution ceased, the solvents were removed under reduced pressure. The residue was dissolved in tetrahydrofuran (25 mL) and 4N HCl in dioxane (6.0 mL, 24 mmol) was added, followed by ether (75 mL). The hydrochloride salt of 4-iodophenethylamine was collected on a Buchner funnel, washed with ether (2×50 mL) and dried under reduced pressure. To generate the free base, the solid was partitioned between dichloromethane (200 mL) and 1N NaOH (100 mL). The aqueous layer was extracted with dichloromethane (2×100 mL). The combined organic layers were dried (Na2SO4) and concentrated to give 4-iodophenethylamine (4.52 g) as a colorless oil.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:15]=[C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:17]=1[OH:18])[O:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]#[N:14])([CH3:4])([CH3:3])[CH3:2].[Cl-].C([NH+](CC)CC)C.[N-:31]=[N+:32]=[N-:33].[Na+].Cl>O.CN1CCCC1=O>[C:1]([C:5]1[CH:6]=[C:7]([CH:15]=[C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:17]=1[OH:18])[O:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[NH:33][N:32]=[N:31][N:14]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc(OCCCCC#N)cc(C(C)(C)C)c1O
Reactant: [N-]=[N+]=[N-]
Agent: CC[NH+](CC)CC
Agent: Cl
Agent: [Cl-]
Solvent: CN1CCCC1=O
Solvent: O
Product: CC(C)(C)c1cc(OCCCCc2nnn[nH]2)cc(C(C)(C)C)c1O
Temperature: 150 °C
Yield: 41.4 %

Procedure:
Under a nitrogen atmosphere, a mixture of 7.00 g (0.023 mole) of 5-(3,5-di-t-butyl-4-hydroxyphenoxy)-valeronitrile, 4.73 g (0.034 mole) of triethylammonium chloride, 4,47 g (0.069 mole) of sodium azide and 200 ml of 1-methylpyrrolidone was heated at 150° C. for about 60 hours. The reaction mixture was cooled and then poured into 200 ml of water. The aqueous mixture was acidified to pH 1 with 10% hydrochloric acid and then extracted five times with 100 ml portions of diethyl ether. The diethyl ether extracts were combined, washed with brine, dried over magnesium sulfate and evaporated to provide an oil. The oil was purified by silica gel chromatography eluting with 2:1 hexane:acetone containing 3 ml of acetic acid per 1600 ml of solvent followed by recrystallization of the isolated material from a mixture of ethyl acetate and hexane to provide 3.3 g of 5-[4-(3,5-di-t-butyl-4-hydroxyphenoxy)butyl]tetrazole as a white solid, m.p. 141°-141.5° C. Analysis: Calculated for C19H30N4O2 : %C, 65.9; %H, 8.7; %N, 16.2; Found: %C, 65.7; %H, 8.6; %N, 16.2.
Reaction SMILES: [I-].[Na+].Cl[Si](C)(C)C.S(=O)(=O)(O)O.[CH3:13][O:14][C:15](=[O:34])[C@H:16]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[Cl:33])[N:17]1[CH2:22][CH:21](O)[C:20]2[S:24][CH:25]=[CH:26][C:19]=2[CH2:18]1.C(=O)(O)[O-].[Na+]>C(#N)C>[CH3:13][O:14][C:15]([C@@H:16]([N:17]1[CH2:18][C:19]2[CH:26]=[CH:25][S:24][C:20]=2[CH2:21][CH2:22]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[Cl:33])=[O:34]
Reactant: COC(=O)[C@H](c1ccccc1Cl)N1Cc2ccsc2C(O)C1
Agent: C[Si](C)(C)Cl
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Solvent: CC#N
Product: COC(=O)[C@H](c1ccccc1Cl)N1CCc2sccc2C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of sodium iodide in acetonitrile is added chlorotrimethylsilane. The mixture is stirred at room temperature under nitrogen for 1 hour. (αS,7RS)-methyl-α-(7-hydroxy-4,5,6,7-tetrahydro-5-thieno[3,2-c]pyridyl)-o-chlorophenylacetate bisulfate salt (30.0 g, 68.9 mmol) is added to the mixture at 0–5° C. After the addition is complete the mixture is warmed to room temperature and stirred for 8 hours. The reaction mixture is then basified with aqueous sodium bicarbonate solution. The organic layer is then washed with aqueous sodium thiosulfate solution, followed by water, then brine. The organic layer is then dried, filtered and concentrated to provide clopidogrel free base as an oily product (21.4 g). The product obtained was found to be identical to the product obtained in Example 1 by 1H-NMR.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[OH:11][C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([O:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: Oc1cccnc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc(Oc2cccnc2)cc1
Temperature: 35 °C
Reaction time: 2 h
Yield: 31.1 %

Procedure:
To a solution of 1-fluoro-4-nitrobenzene (50.00 g, 354.36 mmol) in DMF (450 ml) was added 3-hydroxypyridine (33.70 g, 354.36 mmol) under nitrogen. The reaction mixture was heated to 35° C. and then potassium carbonate (102.85 g, 744.15 mmol) was added in one portion. The reaction was very exothermic, and the temperature rapidly increased to 115° C., then gradually increased to 125° C. The mixture was then cooled to 90° C. and stirred at 90° C. for 2 h. The mixture was cooled to room temperature and poured into 2.5 L of water. The mixture was extracted with ethyl acetate (3×), and the combined organic phases were washed with water (3×) and brine (1×), dried over sodium sulfate, and evaporated at reduced pressure. The brown solid residue was stirred in MTBE at reflux, then filtered, and the filtrate was concentrated at reduced pressure to give a yellow crystalline solid that was triturated with ether to give 23.79 g (31%) of the desired product. The brown solids that did not dissolve in MTBE (43.89 g, 57%) were also of sufficient purity for use in the next step (i.e., total yield 88%). 1H-NMR (DMSO-d6) δ 8.50 (m, 2H), 8.24 (d, J=9.1 Hz, 2H), 7.67 (ddd, J=8.4, 2.9, 1.3 Hz, 1H), 7.52 (dd, J=8.3, 4.7 Hz, 1H), 7.18 (d, J=9.0 Hz, 2H); MS LC-MS [M+H]+=217, RT=1.67 min. In a subsequent experiment, the potassium carbonate was added to the 1-fluoro-4-nitrobenzene in DMF under nitrogen. To this stirred solution was dropwise added a solution of the 3-hydroxypyridine in DMF, and the exotherm caused the mixture to gradually warm up to 38° C. The reaction mixture was then heated to 60° C. for 2 h. Reaction work up as described above gave the desired product.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@H:6]1[CH2:15][C@@H:14]([NH2:16])[C:13]2[C:8](=[CH:9][C:10]([O:19][CH3:20])=[C:11]([O:17][CH3:18])[CH:12]=2)[N:7]1[C:21]([O:23][CH:24]([CH2:26][CH3:27])[CH3:25])=[O:22])=[O:5])[CH3:2].C(O)(=O)C.[F:32][C:33]([F:47])([F:46])[C:34]1[CH:35]=[C:36]([CH:39]=[C:40]([C:42]([F:45])([F:44])[F:43])[CH:41]=1)[CH:37]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C.C(Cl)(Cl)Cl>[CH2:1]([O:3][C:4]([C@H:6]1[CH2:15][C@@H:14]([NH:16][CH2:37][C:36]2[CH:39]=[C:40]([C:42]([F:44])([F:45])[F:43])[CH:41]=[C:34]([C:33]([F:32])([F:46])[F:47])[CH:35]=2)[C:13]2[C:8](=[CH:9][C:10]([O:19][CH3:20])=[C:11]([O:17][CH3:18])[CH:12]=2)[N:7]1[C:21]([O:23][CH:24]([CH2:26][CH3:27])[CH3:25])=[O:22])=[O:5])[CH3:2]
Reactant: O=Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CCOC(=O)[C@H]1C[C@@H](N)c2cc(OC)c(OC)cc2N1C(=O)OC(C)CC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: CCOC(=O)[C@H]1C[C@@H](NCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2cc(OC)c(OC)cc2N1C(=O)OC(C)CC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63.4 %

Procedure:
To a solution of 4-amino-6,7-dimethoxy-3,4-dihydro-2H-quinoline-1,2-dicarboxylic acid 2-butyl ester 1-ethyl ester (Example 3) (500 mg, 1.30 mmol) in anhydrous dichloroethane (30 mL) was added acetic acid (79 mg, 1.30 mmol), followed by 3,5-bis(trifluoromethyl)benzaldehyde (318 mg, 1.30 mmol) and sodium triacetoxyborohydride (418 mg, 1.97 mmol). The reaction was stirred at room temperature for 30 min. The reaction mixture was then diluted with chloroform and washed with 1N NaOH. The organic layer was separated, dried over magnesium sulfate, filtered and concentrated in vacuo to afford the crude title compound (approximately 500 mg) which was used directly in Example 5.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[CH:8]=[C:7]([CH3:9])[N:6]([CH3:10])[N:5]=1.[I:11][C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][C:19]=2[N+:21]([O-:23])=[O:22])[NH:14][N:13]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:10][N:6]1[C:7]([CH3:9])=[CH:8][C:4]([CH2:3][N:14]2[C:15]3[C:20](=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][CH:16]=3)[C:12]([I:11])=[N:13]2)=[N:5]1
Reactant: O=[N+]([O-])c1cccc2[nH]nc(I)c12
Reactant: Cc1cc(CCl)nn1C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(Cn2nc(I)c3c([N+](=O)[O-])cccc32)nn1C
Reaction time: 20 h
Yield: 75.9 %

Procedure:
To 3-(chloromethyl)-1,5-dimethyl-1H-pyrazole hydrochloride (5.01 g, 27.7 mmol) in DMF (50 mL) was added 3-iodo-4-nitro-1H-indazole (8.00 g, 27.7 mmol) and K2CO3 (15.3 g, 111 mmol). The reaction mixture was stirred for 20 hours. The mixture was concentrated under reduced pressure to remove most of the DMF. The residue was diluted with DCM (100 mL) and washed with H2O. The organic phase was dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by silica gel chromatography (EtOAc/Hexane 1:3) to provide the product (8.35 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:36])[C@@H:4]([NH:11][C:12](=[O:35])[CH:13]([C:25](=[O:34])[NH:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21](=[NH:24])[NH:22]O)=[CH:17][CH:16]=1)[CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1>C(O)(=O)C.[Pd]>[CH3:1][O:2][C:3](=[O:36])[C@@H:4]([NH:11][C:12](=[O:35])[CH:13]([C:25](=[O:34])[NH:26][CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[CH2:14][C:15]1[CH:16]=[CH:17][C:18]([C:21](=[NH:22])[NH2:24])=[CH:19][CH:20]=1)[CH:5]1[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]1
Reactant: COC(=O)[C@@H](NC(=O)C(Cc1ccc(C(=N)NO)cc1)C(=O)NCc1ccccc1)C1CCCCC1
Agent: [Pd]
Solvent: CC(=O)O
Product: COC(=O)[C@@H](NC(=O)C(Cc1ccc(C(=N)N)cc1)C(=O)NCc1ccccc1)C1CCCCC1

Procedure:
{2-(R,S)-Benzylcarbamoyl-3-[4-(N-hydroxycarbamimidoyl)-phenyl]-propionylamino}-(S)-cyclohexyl-acetic acid methyl ester (7.6 g, 15.4 mmol) was hydrogenated in acetic acid with palladium/charcoal to give the desired product which was used without further purification in the next step. mp.: 101-104° C., MS m/z: 479 (M+H)+.