Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][CH2:5][C:6]([NH:8][C@@H:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][C@H:10]1[NH:18][C:19]([C:21]1[NH:25][C:24]2[S:26][C:27]([Cl:29])=[CH:28][C:23]=2[CH:22]=1)=[O:20])=[O:7])(=O)C.CO.C([O-])([O-])=O.[K+].[K+].O>C1COCC1>[Cl:29][C:27]1[S:26][C:24]2[NH:25][C:21]([C:19]([NH:18][C@@H:10]3[CH2:11][C:12]4[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=4)[C@H:9]3[NH:8][C:6](=[O:7])[CH2:5][OH:4])=[O:20])=[CH:22][C:23]=2[CH:28]=1
Reactant: CC(=O)OCC(=O)N[C@@H]1c2ccccc2C[C@H]1NC(=O)c1cc2cc(Cl)sc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(CO)N[C@@H]1c2ccccc2C[C@H]1NC(=O)c1cc2cc(Cl)sc2[nH]1
Temperature: 25 °C
Reaction time: 4 h
Yield: 71.7 %

Procedure:
N-{(1R,2R)-1-[(2-Acetoxyacetyl)amino]-2,3-dihydro-1H-inden-2-yl}-2-chloro-6H-thieno[2,3-b]pyrrole-5-carboxamide (Example 39; 393 mg, 0.92 mmol) was dissolved in THF (5 mL), MeOH (5 mL) and K2CO3 (50 mg) were then added and the suspension stirred at ambient temperature for 4 hours. Water (10 mL) was added and the aqueous phase was extracted with EtOAc (3×10 mL). The combined organic phases were washed with water (50 mL), brine (50 mL) and dried (MgSO4). The solvent was removed by evaporation under reduced pressure, the crude product was triturated (EtOAc:isohexane, 1:5), filtered, washed with isohexane (5 mL) and dried to give the title compound (257 mg, 72%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([OH:11])[C:9]=1[OH:10])[CH:5]=[O:6].C(=O)([O-])[O-].[Li+].[Li+].[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH2:23]Cl>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([OH:11])[C:9]=1[O:10][CH2:23][C:22]1[CH:25]=[CH:26][CH:27]=[C:20]([O:19][CH3:18])[CH:21]=1)[CH:5]=[O:6]
Reactant: O=Cc1cc(O)c(O)c(Br)c1
Reactant: COc1cccc(CCl)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cccc(COc2c(O)cc(C=O)cc2Br)c1

Procedure:
A mixture of 3-bromo-4,5-dihydroxy-benzaldehyde (1 g), lithium carbonate (314 mg), 3-methoxybenzyl chloride (742 μl) and a catalytic amount of tetrabutylammonium iodide in DMF (5 ml) was stirred at 60° C. for 17 h. The mixture was diluted with ethyl acetate and washed with water. The organic layer was dried (MgSO4), filtered and concentrated in vacuo.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[CH:16][CH:15]=1)[O:9][CH2:8][CH2:7][CH:6]2[C:23]([O:25][CH3:26])=[O:24])#[N:2].C(Cl)(=O)C(Cl)=O.[C:33]1([C@@H:39]([CH3:42])[CH2:40][NH2:41])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.N1C=CC=CC=1>ClCCl.CN(C=O)C.CN(C)C1C=CN=CC=1>[C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][C:14]1[CH:22]=[CH:21][C:17]([C:18](=[O:20])[NH:41][CH2:40][C@@H:39]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH3:42])=[CH:16][CH:15]=1)[O:9][CH2:8][CH2:7][CH:6]2[C:23]([O:25][CH3:26])=[O:24])#[N:2]
Reactant: C[C@@H](CN)c1ccccc1
Reactant: COC(=O)C1CCOc2cc(Oc3ccc(C(=O)O)cc3)c(C#N)cc21
Agent: CN(C)c1ccncc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)C1CCOc2cc(Oc3ccc(C(=O)NC[C@H](C)c4ccccc4)cc3)c(C#N)cc21
Reaction time: 0.75 h
Yield: 97.6 %

Procedure:
4-(6-Cyano-4-(methoxycarbonyl)chroman-7-yloxy)benzoic acid (0.030 g, 0.0849 mmol) in 2 ml dry dichloromethane was treated with oxalyl chloride (0.0296 ml, 0.340 mmol) followed by 1 drop DMF at ambient temperature. After 45 minutes, the solution was concentrated under vacuum and the residue re-suspended in 2 ml DCM and treated with (R)-2-phenylpropan-1-amine (0.0182 ml, 0.127 mmol), 4-dimethylaminopyridine (0.00104 g, 0.00849 mmol), and pyridine (0.0137 ml, 0.170 mmol). After 12 hours, the reaction was diluted with dichloromethane and washed with 10% aqueous HCl. The dichloromethane layer was dried over sodium sulfate, filtered, concentrated, and purified on silica gel. Elution with a gradient of 30-50% ethyl acetate-hexanes provided the title compound (39 mg, 98%) as a solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10]Br)=[CH:4][CH:3]=1.[CH2:12]([N:19]1[C:23]([C:24]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)=[O:25])=[CH:22][N:21]=[CH:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH2:12]([N:19]1[C:23]([C:24]([C:26]2[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=2)([OH:25])[CH2:10][CH2:9][CH2:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[CH:22][N:21]=[CH:20]1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C(c1ccc(F)cc1)c1cncn1Cc1ccccc1
Reactant: Fc1ccc(CCCBr)cc1
Product: OC(CCCc1ccc(F)cc1)(c1ccc(F)cc1)c1cncn1Cc1ccccc1

Procedure:
1-benzyl-5-[1,4-bis(4-fluorophenyl)-1-hydroxybutyl]-1H-imidazole is prepared analogously to Example 7 a) starting from 3-(4-fluorophenyl)-1-bromopropane and 1-benzyl-5-[1-(4-fluorophenyl)-1-oxomethyl]-1H-imidazole. The product is purified by flash chromatography.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:13]=[CH:14][CH:15]=1)[CH2:7][N:8]1[CH:12]=[CH:11][N:10]=[CH:9]1)([O-])=O>[Pd].C(O)C>[NH2:1][C:4]1[CH:5]=[C:6]([CH:13]=[CH:14][CH:15]=1)[CH2:7][N:8]1[CH:12]=[CH:11][N:10]=[CH:9]1
Reactant: O=[N+]([O-])c1cccc(Cn2ccnc2)c1
Agent: [Pd]
Solvent: CCO
Product: Nc1cccc(Cn2ccnc2)c1
Reaction time: 0.25 h

Procedure:
A mixture of 1-(3-nitrobenzyl)imidazole (0.5 g, 0.0025 mol) and palladium on charcoal (0.05 g, 10%) in dry ethanol (20 ml) was stirred under an atmosphere of hydrogen for 0.25 h. The reaction mixture was then filtered through Hyflo-supercel, and the ethanol was evaporated under reduced pressure to give a colourless oil. The oil was distilled to yield 1-(3-aminobenzyl)imidazole, b.p. 160°/0.01 mm Hg, which solidified on cooling. Recrystallisation of the solid from toluene gave the product as a white solid, m.p. 75°-76°.
Reaction SMILES: [OH:1][CH2:2][C:3]#[C:4][C:5]1[CH:14]=[CH:13][CH:12]=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8].[H][H]>CO.[Pd]>[OH:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:14]=[CH:13][CH:12]=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8]
Reactant: [H][H]
Reactant: COC(=O)c1ccccc1C#CCO
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1ccccc1CCCO

Procedure:
Step 2--A mixture of methyl o-(1-hydroxy-2-propyn-3-yl)benzoate (CXIX, 5.91 g) in methanol (60 ml) is hydrogenated at 40 psi hydrogen for 9 hrs using a total of 900 mg. Palladium on carbon (10%) is added in equal portions three times during the course of the reaction. The reaction is filtered and concentrated to give the saturated ester, methyl o-(1-hydroxyprop-3-yl)benzoate (CXXI).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].OS(O)(=O)=O.[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][C:22]([C:32]#[N:33])([C:25]2[CH:30]=[CH:29][C:28]([I:31])=[CH:27][CH:26]=2)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13]>C1COCC1>[C:12]([O:16][C:17]([N:19]1[CH2:20][CH2:21][C:22]([CH2:32][NH2:33])([C:25]2[CH:30]=[CH:29][C:28]([I:31])=[CH:27][CH:26]=2)[CH2:23][CH2:24]1)=[O:18])([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)OC(=O)N1CCC(C#N)(c2ccc(I)cc2)CC1
Agent: O=S(=O)(O)O
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(CN)(c2ccc(I)cc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 25.7 %

Procedure:
A solution of LiAlH4 (8.5 mL of a 1.0M solution in THF, 8.5 mmol, 3.5 eq.) was cooled to 0° C. and concentrated H2SO4 (0.43 mL, 7.6 mmol, 3.2 eq.) was added in a drop-wise fashion. The resulting white slurry was stirred at room temperature for 0.5 h, then heated to 30° C. for 0.5 h. The reaction was cooled to room temperature and a solution of 4-cyano-4-(4-iodo-phenyl)-piperidine-1-carboxylic acid tert-butyl ester (1 g, 2.43 mmol, 1 eq.) in THF (3 mL) was added over 0.25 h. The mixture was heated to 55° C. and monitored by TLC. After 5 h the reaction was cooled to room temperature and quenched by careful addition of H2O (0.323 mL), 1N NaOH (0.646 mL) and H2O (0.97 mL). This mixture was diluted with CH2Cl2 (25 mL) and stirred vigorously for 1 h and then filtered through a pad of celite®. The salts were washed with CH2Cl2 (5×25 mL) and the combined washings were concentrated by rotary evaporation to give the crude product as a yellow solid (0.597 g) which was purified by flash column chromatography by eluting with 1% MeOH/1% TEA/CH2Cl2 to give the title compound 4-aminomethyl-4-(4-iodo-phenyl)-piperidine-1-carboxylic acid tert-butyl ester (0.26 g, 0.625 mmol, 26%) as a colorless oil. 1H NMR (CDCl3): δ 7.81 (d, 2H), 7.17 (d, 2H), 3.82 (m, 2H), 3.145 (m, 2H), 2.86 (s, 2H), 2.24 (m, 2H), 1.80 (m, 2H), 1.65 (br. m., 2H), 1.56 (s, 9H).
Reaction SMILES: [CH:1]([O:4][C:5]1[C:10]2[CH:11]=[C:12]([C:14]([O-:16])=[O:15])[O:13][C:9]=2[CH:8]=[CH:7][CH:6]=1)([CH3:3])[CH3:2].[OH-].[Na+]>CO.C1COCC1>[CH:1]([O:4][C:5]1[C:10]2[CH:11]=[C:12]([C:14]([OH:16])=[O:15])[O:13][C:9]=2[CH:8]=[CH:7][CH:6]=1)([CH3:3])[CH3:2]
Reactant: CC(C)Oc1cccc2oc(C(=O)[O-])cc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)Oc1cccc2oc(C(=O)O)cc12
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 95.2 %

Procedure:
To 0.15 g (0.62 mmole) of 4-isopropoxy-1-benzofuran-2-carboxylate in 2.5 mL of methanol and 2.5 mL of THF was added 3 mL of 1N sodium hydroxide solution. The solution was stirred at room temperature for 45 minutes. The reaction mixture was concentrated in vacuo, the residue was diluted with water and neutralized with 1N HCl to pH ˜3-4, and then extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate, filtered, and concentrated in vacuo to give 0.13 g of 4-isopropoxy-1-benzofuran-2-carboxylic acid. Yield 94%. m.p. 148-150° C. MS: 219.1(M−H)−.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:6][CH2:7][C:8](=O)[NH:9][C:10]=2[N:11]=1>C1COCC1.ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:6][CH2:7][CH2:8][NH:9][C:10]=2[N:11]=1
Reactant: O=C1COc2ccc(Br)nc2N1
Solvent: ClCCl
Solvent: C1CCOC1
Product: Brc1ccc2c(n1)NCCO2
Temperature: 70 °C

Procedure:
6-Bromo-4H-pyrido[3,2-b][1,4]oxazin-3-one (1.35 g, 5.89 mmol) was dissolved in THF (40 mL). Boranedimethylsulphide complex (2.0 M in THF, 5.89 mL, 11.79 mmol) was added and the resulting mixture heated to 70° C. under nitrogen for 15 minutes. Next, the reaction mixture was cooled to room temperature, quenched with methanol (˜5 mL), and then dried under vacuum to obtain a white solid. The crude material was dissolved in dichloromethane and washed with H2O. The aqueous phase was discarded and the organic phase was dried under vacuum to give 6-bromo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine. Yield: 1.1 g (87%). LCMS (ESI): calc. C7H7BrN2O=214, 216; obs. M+H=215, 217.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([NH2:25])=[C:8](C(OC(C)(C)C)=O)[N:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=2)[CH:10]=1)=[O:5])[CH3:2].[CH:26]([N:29]=[C:30]=[O:31])([CH3:28])[CH3:27]>>[CH2:1]([O:3][C:4]([C:6]1[C:7]([NH:25][C:30]([NH:29][CH:26]([CH3:28])[CH3:27])=[O:31])=[CH:8][N:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=2)[CH:10]=1)=[O:5])[CH3:2]
Reactant: CC(C)N=C=O
Reactant: CCOC(=O)c1cn(-c2cccc(F)c2)c(C(=O)OC(C)(C)C)c1N
Product: CCOC(=O)c1cn(-c2cccc(F)c2)cc1NC(=O)NC(C)C
Yield: 55 %

Procedure:
Following general method 4, employing 3-amino-1-(3-fluorophenyl)-1H-pyrrole-2,4-dicarboxylic acid 2-tert-butyl ester 4-ethyl ester and isopropyl isocyanate, afforded the title compound as an off-white solid (0.150 g, 55%); LCMS (method B): RT=3.77 min, M+H+=334; 1H NMR (CDCl3, 300 MHz): 8.35 (s, 1H), 7.62 (d, J=2.7 Hz, 1H), 7.45 (d, J=2.7 Hz, 1H), 7.38 (dt, J=8.2, 6.2 Hz, 1H), 7.22 (ddd, J=8.2, 2.3, 0.9 Hz, 1H), 7.15 (dt, J=9.9, 2.3 Hz, 1H), 6.98 (tdd, J=8.2, 2.3, 0.9 Hz, 1H), 4.52 (br. s, 1H), 4.31 (q, J=7.1 Hz, 2H), 3.94 (br. s, 1H), 1.37 (t, J=7.1 Hz, 3H), 1.22 (d, J=6.5 Hz, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([Cl:9])=[CH:4][C:3]=1[CH3:10].[Br:11]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([Cl:9])=[CH:4][C:3]=1[CH2:10][Br:11]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(Cl)c(Cl)cc1Cl
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1cc(Cl)c(CBr)cc1Cl
Temperature: 25 °C
Yield: 37.8 %

Procedure:
Under a nitrogen atmosphere, a stirred solution of 5.0 grams (0.026 mole) of 2,4,5-trichlorotoluene and 5.3 grams (0.030 mole) of N-bromosuccinimide in 30 ml of carbon tetrachloride was heated to reflux and then was irradiated with a sun lamp during a 10 minute period. The reaction mixture was allowed to cool to ambient temperature at which time it was filtered to remove excess succinimide. The filtrate was concentrated under reduced pressure to a residual oil. The oil was distilled under vacuum, yielding four fractions in the boiling point range of 130°-152° C./5 mm Hg. NMR analysis of the fractions indicated that two fractions, boiling point 140°-150° C./5 mm Hg., contained the majority of the reaction product. The two fractions were combined and diluted with 1 ml of petroleum ether. The mixture was filtered to remove unreacted starting material. The filtrate was diluted with 12 ml of petroleum ether, and the solution was cooled in dry-ice. The solvent was removed from the resultant solid by pipette. The solid was dried under reduced pressure, yielding 2.7 grams of 80% pure 2,4,5-trichlorophenylmethyl bromide. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [Cl:1][C:2]1[CH:37]=[CH:36][CH:35]=[CH:34][C:3]=1[CH2:4][N:5]1[C:13]2[C:12](=[O:14])[N:11]([CH3:15])[C:10](=[O:16])[N:9]([CH3:17])[C:8]=2[C:7]([CH:18]=[O:19])=[C:6]1[N:20]1[CH2:25][CH2:24][CH2:23][C@@H:22]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:21]1.[CH3:38][Mg]Br.[Cl-].[NH4+]>O1CCCC1>[Cl:1][C:2]1[CH:37]=[CH:36][CH:35]=[CH:34][C:3]=1[CH2:4][N:5]1[C:13]2[C:12](=[O:14])[N:11]([CH3:15])[C:10](=[O:16])[N:9]([CH3:17])[C:8]=2[C:7]([CH:18]([OH:19])[CH3:38])=[C:6]1[N:20]1[CH2:25][CH2:24][CH2:23][C@@H:22]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:30])([CH3:31])[CH3:32])[CH2:21]1
Reactant: Cn1c(=O)c2c(c(C=O)c(N3CCC[C@@H](NC(=O)OC(C)(C)C)C3)n2Cc2ccccc2Cl)n(C)c1=O
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(O)c1c(N2CCC[C@@H](NC(=O)OC(C)(C)C)C2)n(Cc2ccccc2Cl)c2c(=O)n(C)c(=O)n(C)c12

Procedure:
A solution of tert-butyl {(3R)-1-[5-(2-chlorobenzyl)-7-formyl-1,3-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidin-6-yl]piperidin-3-yl}carbamate (132 mg) in tetrahydrofuran (4 ml) was cooled to 0° C., followed by adding thereto methylmagnesium bromide (417 μl), and the resulting mixture was stirred at 0° C. for 2 hours. A saturated aqueous ammonium chloride solution was added to the reaction solution, followed by two runs of extraction with chloroform (50 ml). The organic layer was dried over sodium sulfate and filtered and the filtrate was concentrated under reduced pressure to obtain a crude product of the title compound (167 mg).
Reaction SMILES: [C:1]1([C:7]([C:9]2[CH:10]=[N:11][N:12]3[C:17]([C:18]4[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=4)=[CH:16][CH:15]=[N:14][C:13]=23)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([BH3-])#N.[Na+].CC(OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=O>C(O)(=O)C>[C:1]1([C:7]([C:9]2[CH:10]=[N:11][N:12]3[CH:17]([C:18]4[CH:19]=[CH:20][N:21]=[CH:22][CH:23]=4)[CH2:16][CH2:15][NH:14][C:13]=23)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(c1ccccc1)c1cnn2c(-c3ccncc3)ccnc12
Agent: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C(c1ccccc1)c1cnn2c1NCCC2c1ccncc1

Procedure:
To a 20.0 g portion of phenyl[7-(4-pyridinyl)pyrazolo[1,5-a]pyrimidin-3-yl]methanone (prepared as described in Ex. 9) suspended and stirred in 100 ml of glacial acetic acid under nitrogen was added in portions 8.5 g of sodium cyanoborohydride, during this addition another 50 ml of glacial acetic was also added. After 3 hours the solution was evaporated to dryness in vacuo. The residue was dissolved in dichloromethane and treated with saturated sodium bicarbonate until basic. The organic layer was separated and dried over anhydrous sodium sulfate. Evaporation gave a gummy solid. The solid was recrystallized from isopropyl alcohol and gave the desired product as a light yellow solid, mp 186°-189° C.
Reaction SMILES: Cl[C:2]1[C:31]([O:32][CH2:33][CH3:34])=[CH:30][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([NH:13][C:14](=[O:29])[C:15]3[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[C:17]([O:23][CH2:24][CH:25]([OH:28])[CH2:26][OH:27])[CH:16]=3)[CH2:9][CH2:8]2)=[CH:4][C:3]=1[O:35][CH2:36][CH3:37].C(OC1C=C(C=O)C=C(OCC)C=1[C:52]1[CH:57]=[CH:56][C:55]([F:58])=[CH:54][CH:53]=1)C.C([BH3-])#N.[Na+].C(N(C(C)C)C(C)C)C>C(O)C.C(O)(=O)C>[CH2:36]([O:35][C:3]1[CH:4]=[C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([NH:13][C:14](=[O:29])[C:15]3[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[C:17]([O:23][CH2:24][CH:25]([OH:28])[CH2:26][OH:27])[CH:16]=3)[CH2:9][CH2:8]2)[CH:30]=[C:31]([O:32][CH2:33][CH3:34])[C:2]=1[C:52]1[CH:57]=[CH:56][C:55]([F:58])=[CH:54][CH:53]=1)[CH3:37]
Reactant: CCOc1cc(CN2CCC(NC(=O)c3cc(OC)cc(OCC(O)CO)c3)CC2)cc(OCC)c1Cl
Reactant: CCOc1cc(C=O)cc(OCC)c1-c1ccc(F)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)O
Product: CCOc1cc(CN2CCC(NC(=O)c3cc(OC)cc(OCC(O)CO)c3)CC2)cc(OCC)c1-c1ccc(F)cc1

Procedure:
In analogy to the procedure described in example 50k), rac-3-(2,3-dihydroxy-propoxy)-5-methoxy-N-piperidin-4-yl-benzamide hydrochloride (example 248) was reacted with 2,6-diethoxy-4′-fluoro-biphenyl-4-carbaldehyde (example 102), sodium cyanoborohydride, N-ethyl-diisopropylamine and acetic acid in ethanol at 50° C. to yield the title compound as colorless solid. MS: 597.3 (MH+).
Reaction SMILES: N[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][N:10]=2)[N:5]=[C:4]([CH2:12][O:13][CH:14]([CH3:16])[CH3:15])[N:3]=1.C([OH:19])C>[OH-].[Na+]>[CH:14]([O:13][CH2:12][C:4]1[NH:3][C:2](=[O:19])[C:11]2[C:6](=[N:7][CH:8]=[CH:9][N:10]=2)[N:5]=1)([CH3:16])[CH3:15]
Reactant: CCO
Reactant: CC(C)OCc1nc(N)c2nccnc2n1
Agent: [Na+]
Agent: [OH-]
Product: CC(C)OCc1nc2nccnc2c(=O)[nH]1

Procedure:
Obtained using the procedure described in section d of Example 2, starting with 4.5 g (0.0205 mole) of 4-amino-2-(isopropoxymethyl)pteridine in 150 ml of 5% aqueous sodium hydroxide. Heating time: 2 hours at 80° C. Yld: 3.0 g (66%), m.p. 198°-199° C. (ethanol).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH2:8][C:9]#[N:10])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:11]([OH:13])[CH3:12].[ClH:14]>C(Cl)Cl>[ClH:14].[CH3:1][C:2]1[C:7]([CH2:8][C:9](=[NH:10])[O:13][CH2:11][CH3:12])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Cc1ncccc1CC#N
Reactant: CCO
Agent: Cl
Solvent: ClCCl
Product: CCOC(=N)Cc1cccnc1C
Reaction time: 8 h

Procedure:
Through a stirred solution of Example 20A (1.7 g, 12.86 mmol) in absolute ethanol (0.89 g, 19.35 mmol) and anhydrous methylene chloride (25 ml) was bubbled with hydrogen chloride gas for 20 min. The mixture was allowed to stand overnight in the refrigerator. The product was precipitated with anhydrous ether and filtered to obtain the title compound, which was immediately used in the next step. MS (ESI+) m/z 180 (M+H)+.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:9])[CH:5]([CH2:7][OH:8])[NH2:6].CCN(CC)CC.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1>ClCCl.CN(C)C1C=CN=CC=1>[OH:8][CH2:7][CH:5]([NH:6][S:25]([C:22]1[CH:21]=[CH:20][C:19]([O:18][CH3:17])=[CH:24][CH:23]=1)(=[O:27])=[O:26])[C:4]([O:3][CH3:2])=[O:9]
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)C(N)CO
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C(CO)NS(=O)(=O)c1ccc(OC)cc1
Temperature: 0 °C
Reaction time: 20 h
Yield: 97.7 %

Procedure:
DL-serine methylester HCl (14,6 g, 93,8 mmol) of the Chemical Formula 5 was suspended in 400 mL of dichloromethane, and Et3N (29 Ml, 206 mmol). and a catalytic amount of 4-dimethylaminopyridine were introduced therein while maintaining the temperature at 0° C., and 4-methoxybenzene-sulfonyl chloride (19.2 g 94 mmol) was add dropwise. They were stirred at room temperature for 20 hours, washed with 200 mL of distilled water, dried, and concentrated under reduced pressure to obtain a yellow solid title compound (26.5 g, yield 97%).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][N:3]=1.[F:11][C:12]1[CH:31]=[CH:30][C:15]([CH2:16][NH:17][C:18]([C:20]2[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=2)=[O:19])=[CH:14][CH:13]=1.CCN(CC)CC>C(Cl)Cl>[Cl:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([S:26]([C:23]2[CH:22]=[CH:21][C:20]([C:18]([NH:17][CH2:16][C:15]3[CH:30]=[CH:31][C:12]([F:11])=[CH:13][CH:14]=3)=[O:19])=[CH:25][CH:24]=2)(=[O:27])=[O:28])[N:3]=1
Reactant: O=C(NCc1ccc(F)cc1)c1ccc(S(=O)(=O)Cl)cc1
Reactant: Clc1n[nH]c2ccccc12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCc1ccc(F)cc1)c1ccc(S(=O)(=O)n2nc(Cl)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
Dissolve 3-chloro-1H-indazole (120 mg, 0.79 mmol) and 4-(4-fluoro-benzylcarbamoyl)-benzenesulfonyl chloride (114 mg, 0.35 mmol) in CH2Cl2 (2.0 mL) and treat with Et3N (50 L, 0.36 mmol). Stir the solution for 1 h at RT, then dilute with additional CH2Cl2 (20.0 mL) and wash with satd aq. NaHCO3 (15 mL). Dry, filter, and concentrate the organic phase and purify the crude material by flash chromatography (100% hexanes to 50% EtOAc/hexanes linear gradient) to give the title compound (129 mg, 83%) as a white foam. MS (ES+) 443.9 (M+1)+, (ES−) 442.0 (M−1)−. 1H NMR (400 MHz, CDCl3): δ 8.17 (d, 1H, J=8.3), 8.03 (d, 2H, J=8.2), 7.83 (d, 2H, J=8.9), 7.64 (m, 2H), 7.41 (t, 1H, J=7.4), 7.27 (m, 2H), 7.01 (t, 2H, J=8.9), 6.31 (br s, 1H), 4.57 (d, 2H, J=5.9).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.F[C:10]1[CH:17]=[CH:16][C:13]([CH:14]=[O:15])=[CH:12][CH:11]=1.C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:12]2[CH:11]=[CH:10][CH:17]=[CH:16][C:13]=2[CH:14]=[O:15])=[CH:4][CH:3]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: O=Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1ccccc1Oc1ccc(Cl)cc1
Temperature: 90 °C
Reaction time: 6 h

Procedure:
A heterogeneous mixture of 4-chlorophenol (14.1 g, 0.11 mmol), 4-fluorobenzaldehyde 12.4 g, 0.1 mmol) and Cs2CO3 (65.0 g, 0.20 mmol) in DMF (400 mL) was stirred at 90° C. for 6 h. The reaction mixture was poured into water (1.2 L) and extracted with ethyl acetate (2×200 mL). The organic phase was washed with water (2×100 mL), dried and concentrated to give essentially pure 4-chlorophenoxybenzaldehyde, which was used directly for the next step.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH:9]([P:18]([O:23][CH2:24][CH3:25])([O:20][CH2:21][CH3:22])=[O:19])[CH2:10][C:11]([O:13]C(C)(C)C)=[O:12])([O:6][CH2:7][CH3:8])=[O:5])[CH3:2]>C(O)(C(F)(F)F)=O>[CH2:21]([O:20][P:18]([CH:9]([P:4]([O:6][CH2:7][CH3:8])([O:3][CH2:1][CH3:2])=[O:5])[CH2:10][C:11]([OH:13])=[O:12])([O:23][CH2:24][CH3:25])=[O:19])[CH3:22]
Reactant: CCOP(=O)(OCC)C(CC(=O)OC(C)(C)C)P(=O)(OCC)OCC
Solvent: O=C(O)C(F)(F)F
Product: CCOP(=O)(OCC)C(CC(=O)O)P(=O)(OCC)OCC

Procedure:
Ester 40 (2.1 g, 5.2 mmol) was stirred in TFA (12 mL) for 2.5 min and concentrated under reduced pressure. Crude acid 41 was purified by flash chromatography (gradient elution 100% ethyl acetate-10% methanol/ethyl acetate). Acid 41 was obtained as a white solid (1.35 g, 75%). 1H NMR (400 MHz, CDCl3) δ 1.28-1.39 (m, 12H), 2.86 (dt, J=16.1, 6.3, 2H), 3.12 (tt, J=24.0, 6.3, 1H), 4.13-4.26 (m, 8H).