Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH:8]=[C:7]([C:16]#[C:17][CH2:18][N:19]3[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][OH:27])[CH2:21][CH2:20]3)[C:6]=2[CH:28]=1.[C:29](OC(=O)C)(=[O:31])[CH3:30]>>[C:29]([O:27][CH2:26][CH2:25][N:22]1[CH2:21][CH2:20][N:19]([CH2:18][C:17]#[C:16][C:7]2[C:6]3[CH:28]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=3[S:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH:8]=2)[CH2:24][CH2:23]1)(=[O:31])[CH3:30]
Reactant: CC(=O)OC(C)=O
Reactant: OCCN1CCN(CC#CC2=Cc3ccccc3Sc3ccc(Cl)cc32)CC1
Product: CC(=O)OCCN1CCN(CC#CC2=Cc3ccccc3Sc3ccc(Cl)cc32)CC1

Procedure:
A solution of 5.0 g. of 2-{4-[3-(8-chloro-dibenzo[b,f]thiepin-10-yl)-2-propynyl]-1-piperazinyl}-ethanol in 50 ml. of acetic anhydride is heated for 15 minutes on a steam-bath. After evaporation of the excess acetic anhydride under greatly reduced pressure, the resulting oil is taken up in ether and washed with saturated sodium bicarbonate solution. By concentration of the ethereal phase, there is obtained 2-{4-[3-(8-chloro-dibenzo[b,f]thiepin-10-yl)-2-propynyl]-1-piperazinyl}-ethyl acetate which melts at 96°-99° C. after recrystallization from ethyl acetate/hexane.
Reaction SMILES: [ClH:1].[C:2]([C:5]1[CH:14]=[C:13]2[C:8]([CH:9]=[CH:10][C:11]([CH2:15][N:16]([C:20]3[CH:25]=[CH:24][C:23]([N:26]4[CH2:32][CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)=[CH:22][CH:21]=3)[SH:17](=[O:19])=[O:18])=[CH:12]2)=[CH:7][CH:6]=1)(=[NH:4])[NH2:3].Cl.[C:34](=[NH:39])(OCC)[CH3:35].[CH2:40](N(CC)CC)C>C(O)C>[ClH:1].[ClH:1].[C:34]([N:29]1[CH2:30][CH2:31][CH2:32][N:26]([C:23]2[CH:22]=[CH:21][C:20]([N:16]([CH2:15][C:11]3[CH:10]=[CH:9][C:8]4[C:13](=[CH:14][C:5]([C:2](=[NH:3])[NH2:4])=[CH:6][CH:7]=4)[CH:12]=3)[S:17]([CH3:40])(=[O:18])=[O:19])=[CH:25][CH:24]=2)[CH2:27][CH2:28]1)(=[NH:39])[CH3:35]
Reactant: N=C(N)c1ccc2ccc(CN(c3ccc(N4CCCNCC4)cc3)[SH](=O)=O)cc2c1
Reactant: CCN(CC)CC
Reactant: CCOC(C)=N
Agent: Cl
Solvent: CCO
Product: CC(=N)N1CCCN(c2ccc(N(Cc3ccc4ccc(C(=N)N)cc4c3)S(C)(=O)=O)cc2)CC1
Temperature: -20 °C

Procedure:
333 mg of N-[4-(4-t-butoxycarbonylhexahydro-1H-1,4-diazepin-1-yl)phenyl]-N-[(7-cyano-2-naphthyl)-methyl]methanesulfonamide obtained in Reference Example 24 was dissolved in 10 ml of ethanol, and the resulting solution was cooled to −20° C. with stirring, into which was introduced hydrogen chloride up to saturation. The reaction mixture was stirred at 5° C. for 15 hours, and then evaporated. The resulting residue was dissolved in a mixture of 10 ml of ethanol and 10 ml of methanol, to which was added 480 mg of ammonium acetate, and stirred at room temperature for 24 hours. The reaction mixture was evaporated, and the resulting residue was purified through ODS column chromatography. From the fraction having been eluted with an eluent solvent of methanol/water (5/95), obtained was 249 mg of a roughly-purified product of N-[(7-amidino-2-naphthyl)methyl]-N-[4-(hexahydro-1H-1,4-diazepin-1-yl)phenyl]sulfonamide. 224 mg of this product was dissolved in 10 ml of ethanol, to which were added 650 mg of ethyl acetimidate hydrochloride and 683 mg of triethylamine, and stirred at room temperature for 20 hours. The reaction mixture was evaporated, and the resulting residue was purified through ODS (YMC-GEL ODS-A 120-230/70) column chromatography using an eluent solvent of methanol/water (5/95). A small amount of 1 N hydrochloric acid was added to the thus-purified product, which was then freeze-dried to obtain 169 mg of N-[4-(4-acet-imidoylhexahydro-1H-1,4-diazepin-1-yl)phenyl]-N-[(7-amidino-2-naphthyl)methyl]methanesulfonamide dihydro-chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH:16]=[CH:15][C:14](=[O:17])[CH2:13][CH:12]2[C:18]([O:20][CH2:21][CH3:22])=[O:19])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:23][N:24]([CH:26](OC)OC)[CH3:25]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH:16]=[CH:15][C:14](=[O:17])[C:13](=[CH:23][N:24]([CH3:26])[CH3:25])[CH:12]2[C:18]([O:20][CH2:21][CH3:22])=[O:19])(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C1CC(=O)C=CN1S(=O)(=O)c1ccc(Cl)cc1
Reactant: COC(OC)N(C)C
Product: CCOC(=O)C1C(=CN(C)C)C(=O)C=CN1S(=O)(=O)c1ccc(Cl)cc1
Temperature: 100 °C

Procedure:
Compound 103 (5.0 g, 15 mmol) was dissolved in DMF-DMA (20 mL) and heated at 100° C. for 30 minutes. The reaction mixture was concentrated in vacuo to yield compound 104 as a yellow oil that was used without further purification.
Reaction SMILES: O[C:2]1[C:3]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:4]([CH3:7])[S:5][CH:6]=1.P(Cl)(Cl)([Cl:15])=O.C[C:19]([O-:21])=O.[Na+]>CN(C=O)C>[Cl:15][C:2]1[C:3]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:4]([CH3:7])[S:5][C:6]=1[CH:19]=[O:21]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1c(O)csc1C
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(C)sc(C=O)c1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of ethyl 4-hydroxy-2-methylthiophene-3-carboxylate (F-3) (20.0 g, 0.11 mol, 1.0 eq) in DMF (150 mL) at −20° C. under argon, phosphoryl chloride (49.4 g, 0.32 mol, 3.0 eq) is added dropwise while keeping the reaction temperature below 10° C. The resulting mixture is stirred at RT for 30 min and then at 80° C. for 1 h. The reaction mixture is cooled to RT and poured into ice-water (800 mL). The resulting mixture is neutralized with NaOAc to adjust the pH to 7-8. The precipitate is collected by filtration, rinsed with H2O (150 mL), and dried in vacuo. The product is purified by flash column chromatography on silica gel (5% ethyl acetate-petroether) to afford the product, ethyl 4-chloro-5-formyl-2-methylthiophene-3-carboxylate (F-4).
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH:9]([NH:12][C:13]2[N:18]=[C:17]([N:19]3[C:23]4[CH:24]=[CH:25][CH:26]=[C:27]([I:28])[C:22]=4[N:21]=[N:20]3)[CH:16]=[CH:15][N:14]=2)[CH2:8][CH2:7]1)=[O:5])C.O[Li].O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.CCO.O>[I:28][C:27]1[C:22]2[N:21]=[N:20][N:19]([C:17]3[CH:16]=[CH:15][N:14]=[C:13]([NH:12][CH:9]4[CH2:8][CH2:7][CH:6]([C:4]([OH:5])=[O:3])[CH2:11][CH2:10]4)[N:18]=3)[C:23]=2[CH:24]=[CH:25][CH:26]=1
Reactant: CCOC(=O)C1CCC(Nc2nccc(-n3nnc4c(I)cccc43)n2)CC1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li]O
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: O=C(O)C1CCC(Nc2nccc(-n3nnc4c(I)cccc43)n2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
To a mixture of 4-[4-(4-iodobenzotriazol-1-yl)-pyrimidin-2-ylamino]-cyclohexane-carboxylic acid ethyl ester (2.56 g) in THF (20 mL), EtOH (20 mL) and H2O (15 mL) was added LiOH.H2O (0.65 g), and the resulting mixture stirred at RT overnight. The reaction mixture was then acidified with citric acid (2.99 g) in H2O (10 mL), and the solvent removed in vacuo. The resulting light orange solid was stirred in H2O for 30 min, filtered, washed with H2O, and dried to obtain 4-[4-(4-iodobenzotriazol-1-yl)-pyrimidin-2-ylamino]-cyclohexanecarboxylic acid (2.1 g, 87%) as a light orange powder. Mp=252-254° C.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=2[Cl:18])[C:8]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)=[CH:7][N:6]=1)(=O)=O.[NH3:26]>CN(C=O)C>[NH2:26][C:5]1[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=2[Cl:18])[C:8]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)=[CH:7][N:6]=1
Reactant: CS(=O)(=O)c1ncc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1
Reactant: N
Solvent: CN(C)C=O
Product: Nc1ncc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1
Temperature: 120 °C

Procedure:
In a 75 mL stainless steel pressure vessel was added 5 mL DMF and 2-methylsulfonyl-4-(2,4-dichlorophenyl)-5-(4-chlorophenyl)pyrimidine (420 mg, 1.0 mmol). Then excess ammonia gas was introduced into the vessel, and the vessel was sealed with a stainless steel nut. The vessel was heated at 120° C. for 18 h. The solvent was removed under high vacuum and product was obtained. HPLC/MS: m/e=351 (M+1); Rt=3.42 min; 1H-NMR 500 MHz (CDCl3): δ 4.8 (bs, 2H), 7.42 (d, J=9 Hz, 1H), 7.5-7.6 (m, 3H), 7.8 (m, 2H), 8.18 (s, 1H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[O:7][CH:8]([C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=1)[CH:9]1[CH2:14][CH2:13][N:12]([CH:15]([CH3:19])[CH2:16][CH2:17][NH2:18])[CH2:11][CH2:10]1.[CH3:30][C:31]1[CH:39]=[C:38]([C:40]2[CH:45]=[CH:44][N:43]=[CH:42][CH:41]=2)[CH:37]=[C:36]([CH3:46])[C:32]=1[C:33](O)=[O:34]>>[CH3:46][C:36]1[CH:37]=[C:38]([C:40]2[CH:45]=[CH:44][N:43]=[CH:42][CH:41]=2)[CH:39]=[C:31]([CH3:30])[C:32]=1[C:33]([NH:18][CH2:17][CH2:16][CH:15]([N:12]1[CH2:11][CH2:10][CH:9]([CH:8]([O:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:27])[F:28])=[CH:22][CH:21]=2)[CH2:14][CH2:13]1)[CH3:19])=[O:34]
Reactant: Cc1cc(-c2ccncc2)cc(C)c1C(=O)O
Reactant: CC(CCN)N1CCC(C(Oc2ccccn2)c2ccc(C(F)(F)F)cc2)CC1
Product: Cc1cc(-c2ccncc2)cc(C)c1C(=O)NCCC(C)N1CCC(C(Oc2ccccn2)c2ccc(C(F)(F)F)cc2)CC1
Yield: 50.4 %

Procedure:
Using general procedure E, 3-{4-[(pyridin-2-yloxy)-(4-trifluoromethyl-phenyl)-methyl]-piperidin-1-yl}-butylamine (75 mg, 0.18 mmol) (see EXAMPLE 22) and 2,6-dimethyl-4-pyridin-4-yl-benzoic acid (46 mg, 0.20 mmol) gave COMPOUND 49 as a white solid (56 mg, 50%). 1H NMR (CDCl3) δ 0.46-1.09 (m, 2H), 0.94 (dd, 3H, J=6.6, 3.6 Hz), 1.44-2.05 (m, 5H), 2.24-2.46 (m, 1H), 2.40 (s, 3H), 2.41 (s, 3H), 2.54-2.89 (m, 4H), 3.23-3.40 (m, 1H), 3.77-3.94 (m, 1H), 5.23-5.31 (m, 1H), 6.60 (dd, 1H, J=8.4, 3.6 Hz), 6.54 (dd, 1H, J=11.7, 4.8 Hz), 7.17 (d, 2H, J=8.1 Hz), 7.36-7.44 (m, 5H), 5.54-5.57 (m, 2H), 7.84, 7.79 (dd, 1H, J=4.8, 1.2 Hz), 8.57, 8.73 (d, 1H, J=5.7 Hz), 8.61, 8.63 (s, 2H). 13C NMR (CDCl3) δ 13.22, 13.39, 19.40 (2 carbons), 28.23, 28.80, 29.09, 29.77, 30.52, 31.09, 39.72, 39.85, 42.21, 43.98, 51.97, 52.14, 60.25, 60.55, 79.55, 79.63, 111.01, 116.96, 121.67, 124.05 (q, J=272 Hz), 124.91, 124.95, 126.05, 126.07, 127.25, 129.46 (q, J=32 Hz), 135.18, 138.06, 138.16, 138.54, 139.39, 144.59, 144.67, 146.64, 147.88, 150.27, 162.79, 162.82, 169.26, 169.52. ES-MS m/z 617 (M+H). Anal. Calcd. for C36H39F3N4O2: C, 68.76; H, 6.36; N, 8.88; F, 9.04. Found. C, 68.54; H, 6.31; N, 8.75; F, 9.26.
Reaction SMILES: COC(C1C(C2C=CC([C@H](NC([C:23]3([NH2:27])[CH2:26][O:25][CH2:24]3)=O)C)=C(F)C=2)=CC=CC=1Cl)=O.C(O[C:34](=[O:59])[NH:35][C@@H:36]([C:38]1[CH:43]=[CH:42][C:41]([C:44]2[CH:49]=[C:48]([Cl:50])[CH:47]=[C:46]([F:51])[C:45]=2[C:52]2[N:53]=[N:54][N:55]([CH3:57])[N:56]=2)=[CH:40][C:39]=1[F:58])[CH3:37])(C)(C)C>>[Cl:50][C:48]1[CH:47]=[C:46]([F:51])[C:45]([C:52]2[N:53]=[N:54][N:55]([CH3:57])[N:56]=2)=[C:44]([C:41]2[CH:42]=[CH:43][C:38]([C@H:36]([NH:35][C:34]([C:23]3([NH2:27])[CH2:26][O:25][CH2:24]3)=[O:59])[CH3:37])=[C:39]([F:58])[CH:40]=2)[CH:49]=1
Reactant: C[C@@H](NC(=O)OC(C)(C)C)c1ccc(-c2cc(Cl)cc(F)c2-c2nnn(C)n2)cc1F
Reactant: COC(=O)c1c(Cl)cccc1-c1ccc([C@@H](C)NC(=O)C2(N)COC2)c(F)c1
Product: C[C@@H](NC(=O)C1(N)COC1)c1ccc(-c2cc(Cl)cc(F)c2-c2nnn(C)n2)cc1F

Procedure:
The title compound was prepared in analogy to intermediate 4 using a modified procedure in step A for the synthesis of {(R)-1-[5′-chloro-3,3′-difluoro-2′-(2-methyl-2H-tetrazol-5-yl)-biphenyl-4-yl]-ethyl}-carbamic acid tert-butyl ester:
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]2[C:8]([NH:30][CH2:31][CH3:32])=[N:9][N:10]([C:11]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:4]=2[CH:3]=1.[C:33]1([C@H:39]([NH:41][C:42]([NH2:44])=[O:43])[CH3:40])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.CC(C)([O-])C.[Na+]>CC(C1C=C(C(C)C)C(C2C(P(C3CCCCC3)C3CCCCC3)=C(OC)C=CC=2OC)=C(C(C)C)C=1)C.C1COCC1>[CH2:31]([NH:30][C:8]1[C:5]2[CH:6]=[N:7][C:2]([NH:44][C:42]([NH:41][C@@H:39]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH3:40])=[O:43])=[CH:3][C:4]=2[N:10]([C:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=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)[N:9]=1)[CH3:32]
Reactant: C[C@@H](NC(N)=O)c1ccccc1
Reactant: CCNc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(Cl)ncc12
Agent: CC(C)(C)[O-]
Agent: COc1ccc(OC)c(P(C2CCCCC2)C2CCCCC2)c1-c1c(C(C)C)cc(C(C)C)cc1C(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CCNc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(NC(=O)N[C@H](C)c3ccccc3)ncc12
Temperature: 50 °C

Procedure:
6-Chloro-N-ethyl-1-trityl-1H-pyrazolo[4,3-c]pyridin-3-amine (3 g, 6.83 mmol), (R)-1-(1-phenylethyl)urea (1.68 g, 10.25 mmol), and BrettPhos pre-catalyst (546 mg, 0.68 mmol) were taken up in THF (13 mL). The resulting mixture was degassed for 5 min followed by addition of sodium tert-butoxide (6834 μL, 13.67 mmol) at room temperature. After the mixture was degassed again for 5 min, the reaction was heated to 50° C. under N2 for 6 h, Room temperature was attained, sat NH4Cl was added, and the mixture was extracted with EtOAc. The organic layer was washed with water, dried, filtered, and concentrated in vacuo. Purification of the residue by flash chromatography (0-100% EtOAc/Hexanes) gave (R)-1-(3-(ethylamino)-1-trityl-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(1-phenylethyl)urea. MS ESI calc'd. For C36H34N6O [M+1]+ 567. found 567.
Reaction SMILES: [C:1]1([C:11]([OH:13])=O)[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH2:14]([O:16][C:17]([C:19]1([NH2:29])[CH2:27][C:26]2[C:21](=[CH:22][CH:23]=[C:24]([F:28])[CH:25]=2)[CH2:20]1)=[O:18])[CH3:15].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:14]([O:16][C:17]([C:19]1([NH:29][C:11]([C:1]2[C:10]3[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=3[CH:4]=[CH:3][CH:2]=2)=[O:13])[CH2:27][C:26]2[C:21](=[CH:22][CH:23]=[C:24]([F:28])[CH:25]=2)[CH2:20]1)=[O:18])[CH3:15]
Reactant: CCOC(=O)C1(N)Cc2ccc(F)cc2C1
Reactant: O=C(O)c1cccc2c1CCCC2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)C1(NC(=O)c2cccc3c2CCCC3)Cc2ccc(F)cc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.8 %

Procedure:
To a solution of 5,6,7,8-tetrahydro-naphthalene-1-carboxylic acid (400 mg, 2.27 mmol), 2-amino-5-fluoro-indan-2-carboxylic acid ethyl ester (610 mg, 2.72 mmol), HATU (1.30 g, 3.41 mmol) in anhydrous DMF (15 mL) is added DIPEA (563 μL, 3.41 mmol). The resulting solution is stirred at RT overnight. After the removal of DMF in vacuo, the residue is dissolved in EtOAc (70 mL) and washed with water (1×10 mL) and brine (2×10 mL). The organic layer is dried over anhydrous Na2SO4 and concentrated in vacuo. The residue is purified by flash column chromatography (115 g silica gel, gradient elution: 5%-40% EtOAc in heptane) to give a pure product (86) as white solid (345 mg, 40%).
Reaction SMILES: C([Mg]Cl)(C)C.[CH:6]1([NH2:9])[CH2:8][CH2:7]1.[F:10][C:11]1[CH:20]=[C:19]([CH3:21])[C:18]([N:22]2[CH:27]=[CH:26][N:25]=[C:24]([NH:28][C:29]3([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=4[OH:38])[CH2:31][CH2:30]3)[C:23]2=[O:39])=[CH:17][C:12]=1[C:13](OC)=[O:14].Cl>C1COCC1.O>[CH:6]1([NH:9][C:13](=[O:14])[C:12]2[CH:17]=[C:18]([N:22]3[CH:27]=[CH:26][N:25]=[C:24]([NH:28][C:29]4([C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=5[OH:38])[CH2:31][CH2:30]4)[C:23]3=[O:39])[C:19]([CH3:21])=[CH:20][C:11]=2[F:10])[CH2:8][CH2:7]1
Reactant: COC(=O)c1cc(-n2ccnc(NC3(c4ccccc4O)CC3)c2=O)c(C)cc1F
Reactant: NC1CC1
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(F)c(C(=O)NC2CC2)cc1-n1ccnc(NC2(c3ccccc3O)CC2)c1=O
Temperature: 25 °C

Procedure:
Isopropylmagnesium chloride (5.19 mL of a 2.0 M solution in THF) was added over 20 min ot a solution of cyclopropylamine (1.830 mL) and methyl 2-fluoro-5-[3-{[1-(2-hydroxyphenyl)cyclopropyl]amino}-2-oxopyrazin-1(2H)-yl]-4-methylbenzoate (Example 318f, 1.063 g) in THF (20 mL) stirring at room temperature under nitrogen. The reaction mixture was stirred for 1 h. Water and 2 M HCl were cautiously added and the volatiles removed in vacuo. The residue was basified with saturated aqueous sodium bicarbonate solution and extracted into DCM. The organics were combined, dried (MgSO4) and evaporated to give the subtitle compound (1.189 g).
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19](SCC)=[N:18][C:17]3=[O:24])=[CH:12][CH:13]=2)[CH:8]=[N:7]1.[CH3:35][N:36]1[CH2:41][CH2:40][NH:39][CH:38]([CH3:42])[C:37]1=[O:43]>>[F:34][C:2]([F:1])([F:33])[C:3]1[CH:28]=[C:27]([C:29]([F:30])([F:32])[F:31])[CH:26]=[CH:25][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19]([N:39]4[CH2:40][CH2:41][N:36]([CH3:35])[C:37](=[O:43])[CH:38]4[CH3:42])=[N:18][C:17]3=[O:24])=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: CC1NCCN(C)C1=O
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)S1
Product: CC1C(=O)N(C)CCN1C1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)S1

Procedure:
4-{5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-1,3-dimethyl-piperazin-2-one was prepared from 5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-one and 1,3-Dimethyl-piperazin-2-one following General Procedure B.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][CH:3]=1.[Mg].[Cl:10][CH2:11][C:12]([O:14]CC)=O.[ClH:17]>CCOCC>[Br-:1].[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([C:12]([C:2]2[CH:7]=[CH:6][C:5]([Cl:17])=[CH:4][CH:3]=2)([OH:14])[CH2:11][Cl:10])=[CH:3][CH:4]=1
Reactant: CCOC(=O)CCl
Reactant: Clc1ccc(Br)cc1
Reactant: Cl
Agent: [Mg]
Solvent: CCOCC
Product: OC(CCl)(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Product: [Br-]
Yield: 71 %

Procedure:
Part A. A solution of 4-chlorobenzenemagnesium bromide was prepared in ether (800 mL) from 4-bromochlorobenzene (114.9 g, 0.6 mole) and magnesium chips (15.1 g, 0.62 mole). This mixture was cooled to 0°, and a solution of ethyl chloroacetate (24.5 g, 0.2 mole) was added dropwise. When addition was complete, stirring was continued at 0° for an additional hour. 1 N hydrochloric acid was then added, and the mixture extracted with dichloromethane. The organic phase was washed with water, dried (MgSO4) and concentrated under reduced pressure. The residue was distilled in a kugelrohr apparatus at 0.1 torr and 180°-200° to provide 1,1-bis(4-chlorophenyl)-2-chloroethanol (43.1 g, 71%) as an oil. NMR(CDCl3) 7.33(8H,m) 4.11(2H,s) 3.17(1H,s). IR (neat film) 3551 cm-1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:25])=[C:6]([CH:24]=1)[CH2:7][N:8]([C:11]1[N:16]=[N:15][C:14]([C:17]([O:19]CCCC)=[O:18])=[CH:13][CH:12]=1)[CH2:9][CH3:10].[OH-].[Na+]>C1COCC1.CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:25])=[C:6]([CH:24]=1)[CH2:7][N:8]([C:11]1[N:16]=[N:15][C:14]([C:17]([OH:19])=[O:18])=[CH:13][CH:12]=1)[CH2:9][CH3:10]
Reactant: CCCCOC(=O)c1ccc(N(CC)Cc2cc(Br)ccc2O)nn1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCN(Cc1cc(Br)ccc1O)c1ccc(C(=O)O)nn1
Reaction time: 1.5 h
Yield: 73.8 %

Procedure:
A solution of butyl 6-[N-(5-bromo-2-hydroxybenzyl)-N-ethylamino]pyridazine-3-carboxylate (reference example 3) (0.36 g, 1.0 mmol) in THF (4 ml) and methanol (4 ml) was treated with aqueous sodium hydroxide 1N (4 ml) and allowed to stand at ambient temperature for 1.5 hours. The reaction was evaporated to a small volume, diluted with water and acidified with acetic acid. After standing for 18 hours, the precipitate was filtered, washed with water and ether, and dried (MgSO4) to give the title compound as a white solid (0.26 g, 71%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH2:8][OH:9])[CH:7]=1.[O:13]1[CH:18]=[CH:17][CH2:16][CH2:15][CH2:14]1.CC1C=CC(S(O)(=O)=O)=CC=1.C([O-])([O-])=O.[Na+].[Na+]>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH2:8][O:9][CH:14]2[CH2:15][CH2:16][CH2:17][CH2:18][O:13]2)[CH:7]=1
Reactant: C1=COCCC1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(Cl)cc1COC1CCCCO1
Reaction time: 2 h
Yield: 99.6 %

Procedure:
A mixture of 25 parts of 5-chloro-2-nitrobenzenemethanol, 13.3 parts of 3,4-dihydro-2H-pyran, 0.28 parts of dichloromethane and 300 parts of 4-methylbenzenesulfonic acid was stirred and for 2 hours at reflux temperature. After cooling, there was added Na2CO3 and the whole was stirred for 10 min. The reaction mixture was filtered and the filtrate was evaporated. The residue was co-evaporated with methylbenzene and was further purified by column chromatography (silica gel; CHCl3). The eluent of the desired fraction was evaporated and the residue was co-evaporated with methylbenzene, yielding 36 parts (99.6%) of 2-[(5-chloro-2-nitrophenyl)methoxy]-tetrahydro-2H-pyran (interm. 54).
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[C:11]2[C:6](=[CH:7][C:8](OS(C(F)(F)F)(=O)=O)=[CH:9][CH:10]=2)[N:5]([C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=2)[C:4](=[O:27])[CH2:3]1.C(N(CC)CC)C.[CH3:36][Si:37]([C:40]#[CH:41])([CH3:39])[CH3:38]>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.C(Cl)Cl>[CH3:1][C:2]1([CH3:28])[C:11]2[C:6](=[CH:7][C:8]([C:41]#[C:40][Si:37]([CH3:39])([CH3:38])[CH3:36])=[CH:9][CH:10]=2)[N:5]([C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=2)[C:4](=[O:27])[CH2:3]1
Reactant: C#C[Si](C)(C)C
Reactant: Cc1ccc(N2C(=O)CC(C)(C)c3ccc(OS(=O)(=O)C(F)(F)F)cc32)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(N2C(=O)CC(C)(C)c3ccc(C#C[Si](C)(C)C)cc32)cc1
Temperature: 85 °C

Procedure:
To a solution of 0.20 g (0.57 mmol) of 4,4-dimethyl-3,4-dihydro-N-(4-methylphenyl)-7-[(trifluoromethanesulfonyl)oxy]-2(1H)-quinolinone (Compound 18) in 1.45 g (2.0 mL, 14 mmol) of triethylamine were added 0.70 g (1.0 mL, 7.1 mmol) of (trimethylsilyl)acetylene and 94 mg (0.13 mmol) of bis(triphenylphosphine)palladium(II) chloride. The resulting mixture was heated at 85° C. for 16 h. The reaction mixture was cooled, methylene chloride was added and the mixture adsorbed onto silica gel. The mixture was purified by flash chromatography (25% ethyl acetate in hexanes) to give the title compound as a foam. PNMR (300 MHz, CDCl3) d 0.19 (9 H, s), 1.40 (6 H, s), 2.44 (3 H, s), 2.66 (2 H, s), 6.53 (1 H, d, J=1.4 Hz), 7.09 (2 H, d, J=8.4 Hz), 7.15 (1 H, dd, J=7.9, 1.4 Hz), 7.25 (1 H, d, J=7.9 Hz), 7.33 (2 H, d, J=8.4 Hz).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]1[O:10][CH2:9][N:8]([CH:11]([C:19]([O:21][CH3:22])=[O:20])C2C=CC=CC=2Cl)[CH2:7]1.[ClH:23].C[N:25]([CH:27]=O)C>>[OH:10][CH:6]1[CH2:7][N:8]([CH:11]([C:19]([O:21][CH3:22])=[O:20])[NH:25][C:27]2[CH:7]=[CH:6][CH:2]=[CH:3][C:4]=2[Cl:23])[CH2:9][C:3]2[CH:4]=[CH:5][S:1][C:2]1=2
Reactant: Cl
Reactant: CN(C)C=O
Reactant: COC(=O)C(c1ccccc1Cl)N1COC(c2cccs2)C1
Product: COC(=O)C(Nc1ccccc1Cl)N1Cc2ccsc2C(O)C1

Procedure:
The reduction of the methyl N-(2-(2-thienyl)-2-oxoethyl)-o-chlorophenylglycinate 20 to the corresponding alcohol results in a mixture of diastereoisomeric alcohols methyl N-(2-(2-thienyl)-2-hydroxyethyl)-o-chlorophenylglycinate 21. Reaction with formaline provides the 5-(2-thienyl)-3-(methoxycarbonyl-o-chlorobenzyl)-1,3-oxazolidine 22. Rearrangement of the 5-(2-thienyl)oxazolidine 22 derivative occurs in dry HCl/DMF solution to produce the desired methyl α-(7-hydroxy-4,5,6,7-tetrahydro-5-thieno[3,2-c]pyridyl)-o-chlorophenylglycinate 23. Finally, the alcohol is reduced to the racemic 24 or dextrorotatory clopidogrel 2 by direct dehydroxylation, e.g. treatment with stannous chloride under acidic conditions. Alternatively, derivatization of hydroxyl group to a leaving group followed by reduction or stepwise elimination/reduction of the corresponding 4,5-dihydropyridyl intermediate is conducive to the synthesis of racemic 24 or dextrorotatory clopidogrel 2. Treatment with carbonyl diimidazole, heating, followed by sodium borohydride reduction is provided as a non-limiting example.