Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2](F)(F)[C:3]([O-])=[O:4].[Cl:8][C:9]1[CH:17]=[C:16]2[C:12]([CH:13]=[C:14]([C:20](=[O:37])[NH:21][CH:22]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=3)[C:23]([F:26])([F:25])[F:24])[N:15]2[CH2:18][CH3:19])=[CH:11][C:10]=1[CH2:38][NH3+:39].C(N(CC)CC)C.C(OC(=O)C)(=O)C.C(OCC)(=O)C>CN(C)C1C=CN=CC=1.ClCCl>[C:3]([NH:39][CH2:38][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][C:9]=1[Cl:8])[N:15]([CH2:18][CH3:19])[C:14]([C:20]([NH:21][CH:22]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:34])([F:35])[F:36])[CH:28]=1)[C:23]([F:25])([F:24])[F:26])=[O:37])=[CH:13]2)(=[O:4])[CH3:2]
Reactant: O=C([O-])C(F)(F)F
Reactant: CCn1c(C(=O)NC(c2cccc(C(F)(F)F)c2)C(F)(F)F)cc2cc(C[NH3+])c(Cl)cc21
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CC(=O)OC(C)=O
Solvent: CCOC(C)=O
Product: CCn1c(C(=O)NC(c2cccc(C(F)(F)F)c2)C(F)(F)F)cc2cc(CNC(C)=O)c(Cl)cc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 76.9 %

Procedure:
At 0° C., [6-chloro-1-ethyl-2-({2,2,2-trifluoro-1-[3-(trifluoromethyl)phenyl]ethyl}carbamoyl)-1H-indol-5-yl]methanaminium trifluoroacetate (0.07 g, 0.15 mmol), triethylamine (0.036 g, 0.36 mmol) and N,N-dimethylpyridin-4-amine (0.002 g, 0.12 mmol) were initially charged in dichloromethane (1 ml). Acetic anhydride (0.021 g, 0.21 mmol) was added dropwise and the reaction mixture was stirred at room temperature for 16 h. Ethyl acetate was added and the organic phase was washed successively with water, saturated ammonium chloride solution and saturated sodium hydrogencarbonate solution. The organic phase was dried over sodium sulphate and the solvent was removed under reduced pressure. 0.06 g (98% of theory) of 5-(acetamidomethyl)-6-chloro-1-ethyl-N-{2,2,2-trifluoro-1-[3-(trifluoromethyl)phenyl]ethyl}-1H-indole-2-carboxamide was obtained.
Reaction SMILES: [C:1]([O:4][C:5]1[C:6]([CH2:35][CH2:36][CH3:37])=[C:7]([CH:29]=[CH:30][C:31]=1[C:32](=[O:34])[CH3:33])[O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:27]=[CH:26][C:16]([C:17]([O:19]C2CCCCO2)=[O:18])=[CH:15][C:14]=1[Br:28])(=[O:3])[CH3:2].Cl.C(Cl)(Cl)Cl>O1CCCC1>[C:1]([O:4][C:5]1[C:6]([CH2:35][CH2:36][CH3:37])=[C:7]([CH:29]=[CH:30][C:31]=1[C:32](=[O:34])[CH3:33])[O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:27]=[CH:26][C:16]([C:17]([OH:19])=[O:18])=[CH:15][C:14]=1[Br:28])(=[O:3])[CH3:2]
Reactant: CCCc1c(OCCCOc2ccc(C(=O)OC3CCCCO3)cc2Br)ccc(C(C)=O)c1OC(C)=O
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: CCCc1c(OCCCOc2ccc(C(=O)O)cc2Br)ccc(C(C)=O)c1OC(C)=O
Reaction time: 1 h
Yield: 63 %

Procedure:
In tetrahydrofuran (10 ml) was dissolved tetrahydropyranyl 4-[3-(3-acetoxy-4-acetyl-2-propylphenoxy)propoxy]-3-bromobenzoate (1.3 g). To the solution was added 1N HCl (1 ml), which was left standing at room temperature for one hour, followed by addition of chloroform (60 ml). The mixture was washed with water sufficiently and dried with sodium sulfate. Then, the solvent was evaporated off. The residue was crystallized with isopropyl ether, followed by recrystallization from aqueous alcohol to give 0.7 g of 4-[3-(3-acetoxy-4-acetyl-2-propylphenoxy)propoxy]-3-bromobenzoic acid as crystals, m.p. 155°-156° C.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:3]=1[NH:4][CH2:5][C:6]1[C:7](=O)[NH:8][C:9]([S:12][CH3:13])=[N:10][CH:11]=1.C(N(CC)C1C=CC=CC=1)C.P(Cl)(Cl)([Cl:33])=O>>[Cl:33][C:7]1[C:6]([CH2:5][NH:4][C:3]2[CH:15]=[CH:16][C:17]([Cl:19])=[CH:18][C:2]=2[Cl:1])=[CH:11][N:10]=[C:9]([S:12][CH3:13])[N:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CSc1ncc(CNc2ccc(Cl)cc2Cl)c(=O)[nH]1
Solvent: CCN(CC)c1ccccc1
Product: CSc1ncc(CNc2ccc(Cl)cc2Cl)c(Cl)n1
Temperature: 110 °C
Yield: 87 %

Procedure:
A solution of 1.2 g (3.8 mmol) of 5-[2,4-dichloroanilinomethyl]-2-methylthio-3H-pyrimidin-4-one in 40 ml of phosphorus oxychloride was treated with 0.6 ml (3.7 mmol) of N,N-diethylaniline and the mixture was heated at 110° C. for 1 hour, cooled and evaporated. The residue was cautiously partitioned between 40 ml of ice/water and 30 ml of diethyl ether. The aqueous phase was extracted with a further 30 ml of diethyl ether and the combined organic phases were dried over magnesium sulfate, filtered and evaporated to give 1.1 g (87%) of 4-chloro-5-(2,4-dichloroanilinomethyl)-2-methylthiopyrimidine as an oil which slowly solidified to a white solid. [Mass spectrum (ESI) MH+ =334].
Reaction SMILES: Br.C(OC([N:12]1[C@H:17]([CH3:18])[CH2:16][N:15]([CH2:19][C:20]2[CH:29]=[C:28]3[C:23]([C:24]([Cl:30])=[CH:25][CH:26]=[N:27]3)=[CH:22][CH:21]=2)[C:14](=[O:31])[C@@H:13]1[CH3:32])=O)C1C=CC=CC=1.C(N(CC)CC)C>C(O)(=O)C.C(OCC)(=O)C>[Cl:30][C:24]1[C:23]2[C:28](=[CH:29][C:20]([CH2:19][N:15]3[CH2:16][C@@H:17]([CH3:18])[NH:12][C@@H:13]([CH3:32])[C:14]3=[O:31])=[CH:21][CH:22]=2)[N:27]=[CH:26][CH:25]=1
Reactant: C[C@@H]1CN(Cc2ccc3c(Cl)ccnc3c2)C(=O)[C@H](C)N1C(=O)OCc1ccccc1
Agent: Br
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: C[C@@H]1CN(Cc2ccc3c(Cl)ccnc3c2)C(=O)[C@H](C)N1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.5 %

Procedure:
A 33% solution of hydrogen bromide in acetic acid (10 mL) is added to (2S,6R)-4-(4-chloro-quinolin-7-ylmethyl)-2,6-dimethyl-3-oxo-piperazine-1-carboxylic acid benzyl ester (1.04 g, 2.38 mmol). The reaction is left to stir at room temperature for one hour. The reaction mixture is diluted with ethyl acetate and stirred vigorously to force the product to precipitate out of solution. The ethyl acetate is decanted off and the precipitate is purified on a silica gel column (1% triethylamine/3% methanol/methylene chloride) to 582 mg (81% yield) of (3S,5R)-1-(4-chloro-quinolin-7-ylmethyl)-3,5-dimethyl-piperazin-2-one as a white solid.
Reaction SMILES: [CH2:1]([NH2:11])[C:2]1[CH:10]=[CH:9][C:8]2[O:7][CH2:6][O:5][C:4]=2[CH:3]=1.[CH3:12][O:13][C:14]1[N:23]=[C:22](OC)[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([O:26][CH3:27])[CH:20]=2)[N:15]=1>CS(C)=O>[CH3:12][O:13][C:14]1[N:23]=[C:22]([NH:11][CH2:1][C:2]2[CH:10]=[CH:9][C:8]3[O:7][CH2:6][O:5][C:4]=3[CH:3]=2)[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([O:26][CH3:27])[CH:20]=2)[N:15]=1
Reactant: COc1ccc2nc(OC)nc(OC)c2c1
Reactant: NCc1ccc2c(c1)OCO2
Solvent: CS(C)=O
Product: COc1ccc2nc(OC)nc(NCc3ccc4c(c3)OCO4)c2c1
Reaction time: 1 h
Yield: 17.8 %

Procedure:
3.75 g (24.8 mmol) of piperonylamine was added to a solution of 2.00 g (8.26 mmol) of the 2,4,6-trimethoxyquinazoline prepared in Example 88 in dimethyl sulfoxide (15 ml). The obtained mixture was stirred under heating at 150° to 160° C. After one hour, the reaction mixture was purified by silica gel column chromatography (ethyl acetate/n-hexane) and recrystallized from ethyl acetate/n-hexane to give 0.50 g of the title compound as a pale-yellow crystal.
Reaction SMILES: [OH:1][C:2]1[CH:16]=[CH:15][C:5]([C:6](=[N:13]O)[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.C([O-])(=O)C.[NH4+].C([BH3-])#N.[Na+].C(=O)([O-])O.[Na+].[OH-].[Na+]>[Cl-].[Cl-].[Cl-].[Ti+3].C(OCC)(=O)C>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH:6]([NH2:13])[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:15][CH:16]=1
Reactant: ON=C(c1ccccc1)c1ccc(O)cc1
Agent: [Ti+3]
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Solvent: CCOC(C)=O
Product: NC(c1ccccc1)c1ccc(O)cc1

Procedure:
A procedure similar to that described in Preparation 12 was repeated, but using 86 ml of a methanolic solution containing 4.28 g of 4-hydroxybenzophenone oxime, 17.03 g of ammonium acetate, 3.79 g of sodium cyanoborohydride, and 40.1 ml of a 17-19% by volume aqueous solution of titanium trichloride, and using a dilute aqueous solution of sodium hydrogencarbonate instead of the aqueous solution of sodium hydroxide, and using ethyl acetate as the extracting solvent. The residue obtained was subjected to silica gel column chromatography and eluted with a 80% by volume solution of ethyl acetate in hexane, with ethyl acetate itself and with a 3% by volume solution of methanol in ethyl acetate, to give 2.74 g of the title compound as crystals, melting at 113°-115° C. (after recrystallization from methylene chloride).
Reaction SMILES: C(OC([N:6]1[C:14]([NH2:15])=[C:13]2[C:8]([C:9]([NH:20]C(OCC)=O)=[CH:10][C:11]([C:16]([F:19])([F:18])[F:17])=[CH:12]2)=[N:7]1)=O)C>C(OC(OC(OCC)=O)=O)C>[NH2:15][C:14]1[C:13]2[C:8](=[C:9]([NH2:20])[CH:10]=[C:11]([C:16]([F:18])([F:17])[F:19])[CH:12]=2)[NH:7][N:6]=1
Reactant: CCOC(=O)Nc1cc(C(F)(F)F)cc2c(N)n(C(=O)OCC)nc12
Agent: CCOC(=O)OC(=O)OCC
Product: Nc1n[nH]c2c(N)cc(C(F)(F)F)cc12

Procedure:
Analogously to Example 1, 0.1 mol of 3,7-diamino-5-trifluoromethylindazole in 70 ml of pyrocarbonic acid diethyl ester gives 3-amino-5-trifluoromethyl-7-ethoxycarbonylaminoindazole-2-carboxylic acid ethyl ester (melting point: 229°-230° C; 89% of theory) in 20 minutes at 70° C.
Reaction SMILES: [CH3:1][N:2]([CH2:12][CH2:13][OH:14])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][CH:6]=1)=[O:4].[C:15](Cl)(=[O:27])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>>[CH3:1][N:2]([CH2:12][CH2:13][O:14][C:15](=[O:27])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][CH:6]=1)=[O:4]
Reactant: Cc1ccc(C(=O)N(C)CCO)cc1
Reactant: CCCCCCCCCCCC(=O)Cl
Product: CCCCCCCCCCCC(=O)OCCN(C)C(=O)c1ccc(C)cc1

Procedure:
N-methyl-N-(2-lauroyloxyethyl)-p-toluamide was prepared by the procedure of example 1 from 19 gms. (0.1 mole) of N-methyl-N-(2-hydroxyethyl)-p-toluamide and 22 gms. (0.1 mole) of lauroyl chloride. The structure of the final product was characterized on the basis of IR and NMR spectral analyses as described in example 1.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([S:12]([CH3:15])(=[O:14])=[O:13])=[CH:8][C:7]=2B2OC(C)(C)C(C)(C)O2)[CH2:3][CH2:2]1.Br[C:26]1[C:27]2[CH:36]=[C:35]([Cl:37])[O:34][C:28]=2[C:29](=[O:33])[N:30]([CH3:32])[CH:31]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:37][C:35]1[O:34][C:28]2[C:29](=[O:33])[N:30]([CH3:32])[CH:31]=[C:26]([C:7]3[CH:8]=[C:9]([S:12]([CH3:15])(=[O:13])=[O:14])[CH:10]=[CH:11][C:6]=3[O:5][CH2:4][CH:1]3[CH2:2][CH2:3]3)[C:27]=2[CH:36]=1
Reactant: Cn1cc(Br)c2cc(Cl)oc2c1=O
Reactant: CC1(C)OB(c2cc(S(C)(=O)=O)ccc2OCC2CC2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: Cn1cc(-c2cc(S(C)(=O)=O)ccc2OCC2CC2)c2cc(Cl)oc2c1=O
Temperature: 70 °C
Reaction time: 1.5 h
Yield: 73.6 %

Procedure:
A mixture of 2-[2-(cyclopropylmethoxy)-5-methylsulfonylphenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (33 mg, 0.09 mmol), 4-bromo-2-chloro-6-methylfuro[2,3-c]pyridin-7-one (25 mg, 0.09 mmol), K3PO4 (50 mg, 0.24 mmol), Pd(dppf)Cl2 (7 mg, 10%) in dioxane/H2O (700 uL/70 uL) was bubbled with nitrogen for 5 min. The sealed vial was stirred at 70° C. for 90 min. The reaction mixture was filtered through a short plug of celite; the celite plug was washed with EtOAc (10 mL). The filtrate was washed with water and brine; the organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to afford a tan residue. The resulting residue was purified by prep-HPLC to afford the title compound (27 mg, 69%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.23-0.34 (m, 2H) 0.44-0.55 (m, 2H) 1.00-1.13 (m, 1H) 3.19-3.24 (m, 3H) 3.61 (s, 3H) 3.94-4.05 (m, 2H) 6.82-6.89 (m, 1H) 7.10-7.16 (m, 1H) 7.26-7.35 (m, 1H) 7.70-7.78 (m, 1H) 7.87-7.94 (m, 1H). LCMS (M+H)+=409.
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:11]([CH3:12])=[C:10]([O:13][CH2:14][CH2:15][CH3:16])[CH:9]=[CH:8][N:7]=1)(=O)C.[OH-].[Na+]>C1(C)C=CC=CC=1>[OH:4][CH2:5][C:6]1[C:11]([CH3:12])=[C:10]([O:13][CH2:14][CH2:15][CH3:16])[CH:9]=[CH:8][N:7]=1
Reactant: CCCOc1ccnc(COC(C)=O)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CCCOc1ccnc(CO)c1C
Yield: 48.7 %

Procedure:
27.8 g of 2-acetoxymethyl-3-methyl-4-propoxy-pyridine was added dropwise into a 25% aqueous solution of sodium hydroxide, and the mixture was allowed to react for one hour at room temperature. Subsequently, the reaction liquid was diluted with toluene, and then the toluene phase was washed with water, dried over anhydrous magnesium sulfate, and then concentrated to dryness, to obtain 11.0 g of 2-hydroxymethyl-3-methyl-4-propoxy-pyridine as an oily matter.
Reaction SMILES: [C:1]1([CH3:26])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C@H:7]([O:9][C:10](=[O:25])[NH:11][C:12]1[C:13]([CH3:24])=[N:14][O:15][C:16]=1[C:17]1[CH:22]=[CH:21][C:20](Br)=[CH:19][CH:18]=1)[CH3:8].[CH2:27]([O:29][C:30](=[O:47])[CH2:31][C:32]1[CH:37]=[CH:36][C:35](B2OC(C)(C)C(C)(C)O2)=[CH:34][CH:33]=1)[CH3:28]>>[CH2:27]([O:29][C:30](=[O:47])[CH2:31][C:32]1[CH:37]=[CH:36][C:35]([C:20]2[CH:21]=[CH:22][C:17]([C:16]3[O:15][N:14]=[C:13]([CH3:24])[C:12]=3[NH:11][C:10]([O:9][C@@H:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=3[CH3:26])[CH3:8])=[O:25])=[CH:18][CH:19]=2)=[CH:34][CH:33]=1)[CH3:28]
Reactant: CCOC(=O)Cc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: Cc1ccccc1[C@@H](C)OC(=O)Nc1c(C)noc1-c1ccc(Br)cc1
Product: CCOC(=O)Cc1ccc(-c2ccc(-c3onc(C)c3NC(=O)O[C@H](C)c3ccccc3C)cc2)cc1

Procedure:
Following the procedure described in Example 36, Step 6, [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-carbamic acid (R)-1-o-tolyl-ethyl ester and [4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetic acid ethyl ester were reacted to provide {4′-[3-methyl-4-((R)-1-o-tolyl-ethoxycarbonylamino)-isoxazol-5-yl]-biphenyl-4-yl}-acetic acid ethyl ester, which was hydrolyzed to the acid as described in Example 34, Step 2.
Reaction SMILES: C([O:3][C:4](=[O:12])[C:5]([NH:7][NH:8][C:9](=[NH:11])[NH2:10])=O)C>O>[NH2:10][C:9]1[NH:8][N:7]=[C:5]([C:4]([OH:3])=[O:12])[N:11]=1
Reactant: CCOC(=O)C(=O)NNC(=N)N
Solvent: O
Product: Nc1nc(C(=O)O)n[nH]1
Yield: 24.1 %

Procedure:
A solution of ethyl 2-(2-carbamimidoylhydrazinyl)-2-oxoacetic acid (2 g, 35.60 mmol) in water (100 ml) was stirred for 12 h at 100° C. The resulting mixture was concentrated under vacuum to give a residue, which was precipitated from water (10 ml) to afford 5-amino-1H-1,2,4-triazole-3-carboxylic acid as a white solid (1.1 g, 63%).
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.[H-].[Na+].[CH2:8]([O:10][C:11](=[O:39])[CH2:12][C:13]1[CH:14]=[C:15]([C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][C:22]=2[CH2:31][N:32]([C:35](=[O:38])[CH2:36]Cl)[CH2:33][CH3:34])[C:16]([O:19][CH3:20])=[CH:17][CH:18]=1)[CH3:9]>CN(C=O)C.[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CCOC(C)=O.O>[CH2:8]([O:10][C:11](=[O:39])[CH2:12][C:13]1[CH:14]=[C:15]([C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:29])([F:30])[F:28])=[CH:23][C:22]=2[CH2:31][N:32]([CH2:33][CH3:34])[C:35](=[O:38])[CH2:36][N:1]2[CH:5]=[N:4][CH:3]=[N:2]2)[C:16]([O:19][CH3:20])=[CH:17][CH:18]=1)[CH3:9]
Reactant: CCOC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN(CC)C(=O)CCl)c1
Reactant: c1nc[nH]n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Agent: [I-]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN(CC)C(=O)Cn2cncn2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1,2,4-triazole (0.042 g, 0.61 mmol) in DMF at 0° C. was added sodium hydride (60% in mineral oil; 0.044 g, 1.1 mmol), and the mixture was stirred for 30 minutes. (2′-{[(2-Chloro-acetyl)-ethyl-amino]-methyl}-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid ethyl ester (0.55 mmol) in DMF was added, followed by tetrabutylammonium iodide (0.1022 g, 0.06 mmol), and the reaction was warmed to room temperature and stirred for 1.5 hours. The mixture was diluted with EtOAc and H2O, and the aqueous layer was extracted twice with EtOAc. The combined organic layers were washed three times with H2O, and then dried and concentrated, and the residue was purified by silica gel chromatography (40-90% EtOAc in hexanes) to give the title compound.
Reaction SMILES: [C:1]([Si:5]([O:18][C@@H:19]1[C@H:26]2[C@H:22]([O:23][C:24]([CH3:28])([CH3:27])[O:25]2)[C:21]([CH2:29][O:30][C:31]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[C:20]1I)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([CH3:4])([CH3:3])[CH3:2].C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:61])(=O)=O)=CC=1.CCCCC.[Li]CCCC>C1COCC1.CCOCC>[C:1]([Si:5]([O:18][C@@H:19]1[C@H:26]2[C@H:22]([O:23][C:24]([CH3:28])([CH3:27])[O:25]2)[C:21]([CH2:29][O:30][C:31]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[C:20]1[F:61])([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC1(C)O[C@@H]2[C@H](O1)C(COC(c1ccccc1)(c1ccccc1)c1ccccc1)=C(I)[C@@H]2O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CCCCC
Product: CC1(C)O[C@@H]2[C@H](O1)C(COC(c1ccccc1)(c1ccccc1)c1ccccc1)=C(F)[C@@H]2O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: -78 °C
Yield: 332.8 %

Procedure:
Compound 8 (0.48 kg) and NFSI (N-fluorobenzenesulfonimide) (0.29 kg) was dissolved in THF (3 L) and ether (1 L). To the solution was added 1.5 L of n-pentane, and the mixture was cooled to −78° C. in a dry-ice bath. A solution of n-BuLi in THF (2.5 M, 0.72 L) was added drop wise to the reaction mixture within 4 hours, while keeping the reaction temperature below −70° C. The reaction mixture was stirred another hour until HPLC indicated complete consumption of compound 8. Saturated ammonium chloride solution (aqueous, 2 L) was added drop wise to the reaction mixture. It was then allowed to warm to ambient temperature. Eight such reactions were combined and diluted with 30 L of ethyl acetate. The mixture was stirred for 30 minutes, then the organic phase separated and the aqueous layer was extracted with 20 L of ethyl acetate. The combined organic phase was washed with brine (10 L), dried over sodium sulfate, and concentrated to dryness. HPLC indicated ratio of compound 9 to its corresponding de-fluoro side product was about 3/1. The residue was loaded on a silica gel column (300˜400 mesh) and eluted with petroleum ether/dichloromethane/ethyl acetate (first 100/0/0, then 200/10/1 to remove the front impurities, then changed to 200/15/1 to collect the desired product 9, (then 200/20/1 to collect the side product). Altogether 1.38 kg of compound 9 (yield 36%, purity˜95%) was obtained. 1H-NMR (300 MHz, CDCl3) δ 7.25-7.92 (m, 25H), 5.04 (t, J=7.2 Hz, 1H), 4.45 (m, 1H), 4.33 (m, 1H), 3.98 (d, J=12.0 Hz, 1H), 3.86 (d, J=12.0 Hz, 1H), 1.55 (s, 3H), 1.48 (s, 3H), 1.18 (s, 9H); 13C-NMR DEPT-135 (75 MHz, CDCl3, δ<100) δ 78.70, 75.35, 71.10, 56.39, 28.04, 27.25, 26.82.
Reaction SMILES: CCOC1N(CC2C=CC(C3C=CC=CC=3C3N=NNN=3)=CC=2)C2[C:10]([C:31]([O:33][CH:34]([O:36]C(OC3CCCCC3)=O)[CH3:35])=O)=[CH:9][CH:8]=CC=2N=1.[CH2:46](Cl)Cl>>[C:34]([O:33][CH2:31][CH2:10][CH:9]([CH3:8])[CH3:46])(=[O:36])[CH3:35]
Reactant: ClCCl
Reactant: CCOc1nc2cccc(C(=O)OC(C)OC(=O)OC3CCCCC3)c2n1Cc1ccc(-c2ccccc2-c2nn[nH]n2)cc1
Product: CC(=O)OCCC(C)C

Procedure:
Candesartan cilexetil Form I (C) (2.5 g) was dissolved in DCM (3.5 ml) at about 25° C. to form a solution, and isoamyl acetate (35 ml) was added dropwise. The solution was cooled in an ice bath and stirred for about 3 hours to obtain a precipitate. The precipitate was collected by filtration and dried under reduced pressure (30 mbar) at 50° C. for about 7.5 hours to obtain Form XIII.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([OH:11])[C:3]=1[C:4](O)=[O:5]>C1COCC1>[Cl:1][C:2]1[C:3]([CH2:4][OH:5])=[C:7]([OH:11])[CH:8]=[CH:9][CH:10]=1
Reactant: O=C(O)c1c(O)cccc1Cl
Solvent: C1CCOC1
Product: OCc1c(O)cccc1Cl
Temperature: 25 °C
Reaction time: 0.21 h

Procedure:
To a solution of 2-chloro-6-hydroxybenzoic acid (for a preparation see Intermediate 5)(1.45 g, 8.39 mmol) in THF (20 ml) at ambient temperature under nitrogen was added 1 M borane-tetrahydrofuran complex (16 ml, 16.0 mmol, Aldrich). The solution was stirred at ambient temperature for 10-15 min and then heated to 80° C. for 1 h. The resulting suspension was allowed to cool to ambient temperature and quenched with methanol (10 ml). The resulting solution was heated to 80° C. for 30 min and at ambient temperature overnight. The solvent was removed in vacuo and the oil dried under high vacuum to give the title compound as a solid (1.36 g); LCMS: (System 1) (M-H)−=157, tRET=2.22 min.
Reaction SMILES: [CH:1]1([N:4]2[C:9](=[O:10])[CH:8]=[C:7]([NH:11][CH3:12])[N:6]([C:13]3[CH:18]=[CH:17][C:16]([I:19])=[CH:15][C:14]=3[F:20])[C:5]2=[O:21])[CH2:3][CH2:2]1.[CH3:22][CH:23]([C:27]([OH:29])=O)[C:24]([OH:26])=O.C(OC(=O)C)(=O)C.CC(C)=O>O>[CH:1]1([N:4]2[C:9](=[O:10])[C:8]3[C:27]([OH:29])=[C:23]([CH3:22])[C:24](=[O:26])[N:11]([CH3:12])[C:7]=3[N:6]([C:13]3[CH:18]=[CH:17][C:16]([I:19])=[CH:15][C:14]=3[F:20])[C:5]2=[O:21])[CH2:2][CH2:3]1
Reactant: CC(C(=O)O)C(=O)O
Reactant: CNc1cc(=O)n(C2CC2)c(=O)n1-c1ccc(I)cc1F
Solvent: O
Solvent: CC(=O)OC(C)=O
Solvent: CC(C)=O
Product: Cc1c(O)c2c(=O)n(C3CC3)c(=O)n(-c3ccc(I)cc3F)c2n(C)c1=O
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 91 %

Procedure:
Under a nitrogen atmosphere, to 3-cyclopropyl-1-(2-fluoro-4-iodo-phenyl)-6-methylamino-1H-pyrimidine-2,4-dione 52 (34.4 g) and 2-methyl-malonic acid 54 (15.2 g) was added acetic anhydride (34.4 ml), and the mixture was stirred with heating at 100° C. for 3 hrs. After allowing to cool to 50° C., acetone (68.8 ml) was added dropwise, and the mixture was stirred as it was for 30 min. Water (172 ml) was further added dropwise, and the mixture was stirred for 1 hr. After allowing to cool to room temperature with stirring, the precipitated crystals were collected by filtration and dried to give crude crystals (37.7 g, LC purity 91%) of 3-cyclopropyl-1-(2-fluoro-4-iodo-phenyl)-5-hydroxy-6,8-dimethyl-1H,8H-pyrido[2,3-d]pyrimidine-2,4,7-trione 55. Isopropanol (92.0 ml) was added to the obtained crude crystals (30.7 g), and the mixture was stirred at room temperature for 4 hrs. The crystals were collected by filtration and dried to give 3-cyclopropyl-1-(2-fluoro-4-iodo-phenyl)-5-hydroxy-6,8-dimethyl-1H,8H-pyrido[2,3-d]pyrimidine-2,4,7-trione 55 (25.9 g, yield from 76, 58%) as pale-yellow crystals.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:24]=[CH:23][C:12]([C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][N:17]=2)=O)=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.Cl>C1COCC1>[CH2:1]([NH:8][C:9]1[CH:24]=[CH:23][C:12]([CH2:13][NH:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][N:17]=2)=[CH:11][N:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Nc1ccc(F)cn1)c1ccc(NCc2ccccc2)nc1
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: Fc1ccc(NCc2ccc(NCc3ccccc3)nc2)nc1
Temperature: 25 °C

Procedure:
BMS (400 μL) was added to a solution of 6-(benzylamino)-N-(5-fluoropyridin-2-yl)nicotinamide 4 in THF (20 mL). The reaction mixture was refluxed for 16 hrs. Then the reaction mixture was cooled to RT. MeOH (2 mL), followed by conc. HCl were added. The reaction mixture was refluxed for 8 hrs, concentrated and diluted with water (2 mL). The pH was adjusted to 14 and the reaction mixture was extracted with chloroform (50 mL×2). All organic phases were washed with brine and dried over Na2SO4. Evaporation of the solvent gave a crude product which was purified on silica gel (1:1, EtOAc: Pet-ether) to give N-benzyl-5-((5-fluoropyridin-2-ylamino)methyl)pyridin-2-amine 5. This was treated with HCl/MeOH to give the corresponding salt (50 mg 13%) as a white solid. Mp. 166-168° C.