Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:21]=[CH:20][C:7]([O:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([OH:19])=[CH:16][CH:17]=3)[N:12]=[CH:11][CH:10]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[OH-].[K+].Br[CH2:25][CH2:26][OH:27]>CN(C=O)C>[N+:1]([C:4]1[CH:21]=[CH:20][C:7]([O:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:19][CH2:25][CH2:26][OH:27])=[CH:16][CH:17]=3)[N:12]=[CH:11][CH:10]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: OCCBr
Reactant: O=[N+]([O-])c1ccc(Oc2ccnc3cc(O)ccc23)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Oc2ccnc3cc(OCCO)ccc23)cc1
Temperature: 45 °C
Reaction time: 12 h
Yield: 12.8 %

Procedure:
To a solution of 4-(4-nitrophenoxy)quinolin-7-ol (2.82 g, 10 mmol) in DMF (20 mL) was added KOH pellets (1.12 g, 20 mmol) and 2-bromoethanol (1.87 g, 15 mmol) at room temperature. The reaction was then warmed up to 45° C. and stirred for 12 hours. The mixture was then concentrated in vacuo and the residue was purified by a column chromatography on silica gel (EtOAc/PE=1:1) to give the title compound as a pale yellow solid (417 mg, 12.8%).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH2:11][CH2:12][C:13]2([CH:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)[O:18][C:17](=[O:19])[CH2:16][C:15](=[O:20])[CH2:14]2)[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:26][C:27]1[CH:32]=[C:31]([CH3:33])[N:30]2[N:34]=[C:35]([CH:37]=O)[N:36]=[C:29]2[N:28]=1>>[C:1]([C:5]1[CH:6]=[C:7]([CH2:11][CH2:12][C:13]2([CH:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)[O:18][C:17](=[O:19])[C:16]([CH2:37][C:35]3[N:36]=[C:29]4[N:28]=[C:27]([CH3:26])[CH:32]=[C:31]([CH3:33])[N:30]4[N:34]=3)=[C:15]([OH:20])[CH2:14]2)[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cccc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)c1
Reactant: Cc1cc(C)n2nc(C=O)nc2n1
Product: Cc1cc(C)n2nc(CC3=C(O)CC(CCc4cccc(C(C)(C)C)c4)(C4CCCC4)OC3=O)nc2n1

Procedure:
The title compound was prepared by coupling the 6-[2-(3-tert-Butyl-phenyl)-ethyl]-6-cyclopentyl-dihydro-pyran-2,4-dione from Step 1 to 5,7-Dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde using the Me2NHBH3 method described in the synthesis of Example B(31). 1H NMR (DMSO-d6): d 1.29 (s, 9H), 1.46-1.76 (br m, 8H), 2.19 (m, 2H), 2.47 (s, 3 Hz), 2.56-2.70 (m, 7H), 2.87 (d, 1H, J=17.5 Hz), 3.80 (d, 1H, J=16.2 Hz), 3.90 (d, 1H, J=16.2 Hz), 7.12 (m, 2H), 7.28 (m, 3H), 10.92 (s, 1H). Anal. Calcd. For C30H38N4O3.0.4AcOH: C, 70.24; H, 7.58; N, 10.64. Found: C, 70.27; H, 7.42; N, 10.59.
Reaction SMILES: C[O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH:23]=[O:24])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.[OH-].[Na+].Cl>CO.C1COCC1>[CH:23]([C:14]1[CH:15]=[C:16]([C:19]([F:22])([F:21])[F:20])[CH:17]=[CH:18][C:13]=1[C:7]1[C:8]([O:11][CH3:12])=[CH:9][CH:10]=[C:5]([CH2:4][C:3]([OH:25])=[O:2])[CH:6]=1)=[O:24]
Reactant: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2C=O)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(CC(=O)O)cc1-c1ccc(C(F)(F)F)cc1C=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To (2′-formyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid methyl ester (0.301 g, 0.85 mmol) in MeOH (2.4 mL) and THF (3 mL) was added aqueous 1N NaOH (1.9 mL), and the solution was stirred overnight at room temperature. Once no starting material was seen by analytical LCMS, the reaction was neutralized with aqueous 1N HCl and extracted with CH2Cl2. The combined organic layers were dried over MgSO4, filtered, and concentrated, and the residue was purified by silica gel chromatography (50-100% EtOAc in hexanes, followed by 5% MeOH in CH2Cl2) to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][CH:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9]C2)=[CH:4][CH:3]=1.[N:22]1[CH:27]=[CH:26][CH:25]=[C:24]([N:28]2[CH2:32][CH2:31][C@H:30]([C:33](O)=[O:34])[CH2:29]2)[N:23]=1.C(OC(N1CC(C(O)=O)C1)=O)C1C=CC=CC=1>>[N:22]1[CH:27]=[CH:26][CH:25]=[C:24]([N:28]2[CH2:32][CH2:31][C@H:30]([C:33]([NH:1][C:2]3[CH:3]=[CH:4][C:5]([O:6][C@H:7]4[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])[CH2:9]4)=[CH:20][CH:21]=3)=[O:34])[CH2:29]2)[N:23]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(N)cc2)CC1
Reactant: O=C(O)[C@H]1CCN(c2cccnn2)C1
Agent: O=C(O)C1CN(C(=O)OCc2ccccc2)C1
Product: CC(C)(C)OC(=O)N1CC[C@H](Oc2ccc(NC(=O)[C@H]3CCN(c4cccnn4)C3)cc2)C1

Procedure:
The title compound was prepared as described in Example 1A, substituting (R)-tert-butyl 3-(4-aminophenoxy)pyrrolidine-1-carboxylate for tert-butyl 4-(4-aminophenoxy)piperidine-1-carboxylate and (S)-1-(pyridazin-3-yl)pyrrolidine-3-carboxylic acid for 1-(benzyloxycarbonyl)azetidine-3-carboxylic acid.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]([CH:31]([CH3:33])[CH3:32])[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([C:15]([N:17]1[CH2:23][CH2:22][CH2:21][N:20]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:19][CH2:18]1)=[O:16])=[CH:10][CH:9]=2)=[O:5])C.O.[OH-].[Li+]>O1CCCC1.CO.O>[C:27]([O:26][C:24]([N:20]1[CH2:21][CH2:22][CH2:23][N:17]([C:15]([C:11]2[CH:12]=[C:13]3[C:8](=[CH:9][CH:10]=2)[N:7]([CH:31]([CH3:32])[CH3:33])[C:6]([C:4]([OH:5])=[O:3])=[CH:14]3)=[O:16])[CH2:18][CH2:19]1)=[O:25])([CH3:28])([CH3:30])[CH3:29]
Reactant: CCOC(=O)c1cc2cc(C(=O)N3CCCN(C(=O)OC(C)(C)C)CC3)ccc2n1C(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)n1c(C(=O)O)cc2cc(C(=O)N3CCCN(C(=O)OC(C)(C)C)CC3)ccc21
Temperature: 25 °C
Reaction time: 48 h
Yield: 42.8 %

Procedure:
To a solution of 5-(4-tert-butoxycarbonyl-[1,4]diazepane-1-carbonyl)-1-isopropyl-1H-indole-2-carboxylic acid ethyl ester (1.60 g, 3.5 mmol) in tetrahydrofuran (10 ml), methanol (10 ml) and water (2 ml) was added lithium hydroxide monohydrate (2 eq., 168 mg). The mixture was stirred two days at room temperature. The solvent was removed under vacuum and the residue was quenched with 1M aq. dihydrogen potassium phosphate solution to pH 5. The aqueous phase was extracted with ethyl acetate (2×) and the combined organic phases washed with brine, dried over MgSO4 and filtered. The crude product was purified by column chromatography on silica gel (3:1 heptane/ethyl acetate eluant) to afford the product as an off-white powder (644 mg, 42%). MS (m/z): 430.3 (M+H)+.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1.[CH3:14][O:15][CH2:16][CH2:17][O:18][CH2:19]Cl.O>O1CCCC1.CN(C)C=O>[CH3:14][O:15][CH2:16][CH2:17][O:18][CH2:19][O:3][C:4]1[CH:5]=[CH:6][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:12][CH:13]=1
Reactant: COCCOCCl
Reactant: COC(=O)c1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COCCOCOc1ccc(C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 101.4 %

Procedure:
3.2 g (78.9 mmol) of 60% sodium hydride are added to a solution of 10 g (65.7 mmol) of methyl 4 hydroxybenzoate in 50 ml of tetrahydrofuran and 50 ml of dimethylformamide. The reaction medium is stirred at ambient temperature for 20 minutes then 8.3 g (72.3 mmol) of 2-methoxyethoxymethyl chloride are added. After stirring for 24 h at ambient temperature, the mixture is poured over water then extracted with ethyl acetate. The organic phase is washed with water then with a saturated aqueous solution of sodium chloride, dried over magnesium sulphate, filtered and concentrated. 16 g (100%) of methyl 4-(2-methoxyethoxymethoxy)benzoate are obtained in the form of a colourless oil.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:8])C(Cl)(Cl)Cl.[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([O:37][CH3:38])=[C:14]([CH:36]=1)[C:15]([NH:17][CH:18]1[CH2:27][C:26]2[C:21](=[CH:22][C:23]([O:32][CH3:33])=[C:24]([S:28](=[O:31])(=[O:30])[NH2:29])[CH:25]=2)[O:20][C:19]1([CH3:35])[CH3:34])=[O:16].[OH-].[Na+].C>>[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([O:37][CH3:38])=[C:14]([CH:36]=1)[C:15]([NH:17][CH:18]1[CH2:27][C:26]2[C:21](=[CH:22][C:23]([O:32][CH3:33])=[C:24]([S:28]([NH:29][C:3]([NH:2][CH3:1])=[O:8])(=[O:30])=[O:31])[CH:25]=2)[O:20][C:19]1([CH3:35])[CH3:34])=[O:16]
Reactant: COc1ccc(Cl)cc1C(=O)NC1Cc2cc(S(N)(=O)=O)c(OC)cc2OC1(C)C
Reactant: CNC(=O)C(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Product: CNC(=O)NS(=O)(=O)c1cc2c(cc1OC)OC(C)(C)C(NC(=O)c1cc(Cl)ccc1OC)C2
Temperature: 80 °C

Procedure:
1.23 g (7.5 mmol) of N-methyltrichloroacetamide were added to 2.27 g (5 mmol) of 3-(5-chloro-2-methoxybenzamido)-2,2-dimethyl-6-sulfamoyl-7-methoxychroman and 0.5 g (12.5 mmol) of finely powdered sodium hydroxide. After the mixture had been stirred at 80° C. for half an hour, it was introduced into ice/water, clarified with charcoal and acidified to pH 1. The precipitate was filtered off with suction, dried and recrystallized from ethanol/DMF. The product had a melting point of 248° C.
Reaction SMILES: [C:1](=[O:18])(ON1C(=O)CCC1=O)[O:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:19][NH:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([N+:28]([O-:30])=[O:29])[CH:23]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:19][N:20]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([N+:28]([O-:30])=[O:29])[CH:23]=1)[C:1](=[O:18])[O:2][CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Reactant: CNCc1cccc([N+](=O)[O-])c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(Cc1cccc([N+](=O)[O-])c1)C(=O)OCc1ccccc1
Reaction time: 1 h
Yield: 97.1 %

Procedure:
Benzyl 2,5-dioxopyrrolidin-1-yl carbonate (1.65 g, 6.6 mmol) was added to a solution of N-methyl-1-(3-nitrophenyl)methanamine (1 g, 6 mmol) in CH2Cl2 (24 mL) and DIEA (2.7 mL, 15 mmol) and the reaction mixture was stirred for 1 h. The mixture was diluted with CH2Cl2 (100 mL), washed with NH4Cl, NaHCO3, brine, dried over Na2SO4 and concentrated in vacuo to yield 60A (1.75 g, 99%) as a white solid. MS (ESI) m/z 301.03 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[C:12]([O:16][C:17](=[O:20])[CH:18]=[CH2:19])([CH3:15])([CH3:14])[CH3:13].C(N(CC)CC)C>C(#N)C.C(Cl)Cl.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:12]([O:16][C:17](=[O:20])[CH:18]=[CH:19][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2)([CH3:15])([CH3:14])[CH3:13]
Reactant: Brc1cnc2ccccc2c1
Reactant: C=CC(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CC#N
Product: CC(C)(C)OC(=O)C=Cc1cnc2ccccc2c1

Procedure:
A mixture of 3-bromoquinoline 3-1(25 g, 120 mmol), acrylic acid tert-butyl ester (100 mL, 672 mmol), triethylamine (50 mL, 300 mmol) and Pd(OAc)2 (1.61 g, 7.2 mmol) in acetonitrile (100 mL) was refluxed for 18 hr. It is then cooled, diluted with 500 mL CH2Cl2 and filtered. The solution was washed with 10% NaHCO3, dried and concentrated. The residue was dissolved in 50 ml hot CH2Cl2 and diluted with 300 mL hexane. After standing, the desired product 3-2 was obtained as a crystalline compound.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([NH:12][C:13]1[NH:21][C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[N:19]=2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11].Br[CH2:26][CH2:27][CH2:28][CH2:29][CH:30]1[CH2:34][CH2:33][O:32][CH2:31]1>>[CH2:8]([NH:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[N:19]2[CH2:26][CH2:27][CH2:28][CH2:29][CH:30]2[CH2:34][CH2:33][O:32][CH2:31]2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11]
Reactant: CCCCNc1nc(N)c2nc(OC)nc-2[nH]1
Reactant: BrCCCCC1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: CCCCNc1nc(N)c2nc(OC)n(CCCCC3CCOC3)c2n1

Procedure:
Prepared similarly to Intermediate 216 from N2-butyl-8-(methyloxy)-3H-purine-2,6-diamine trifluoroacetate and 3-(4-bromobutyl)tetrahydrofuran.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([Mg]Br)=[CH:5][CH:4]=1.[Mg].Br[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1.[N:21]1[C:28](Cl)=[N:27][C:25](Cl)=[N:24][C:22]=1[Cl:23].Cl>C1COCC1>[Cl:23][C:22]1[N:24]=[C:25]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[N:27]=[C:28]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[N:21]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: COc1ccc([Mg]Br)cc1
Reactant: COc1ccc(Br)cc1
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Product: COc1ccc(-c2nc(Cl)nc(-c3ccc(OC)cc3)n2)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A Grignard solution of p-methoxyphenylmagnesium bromide (prepared from 12.2 g (0.05 mol) of magnesium and 93.5 g (0.5 mol) of p-bromoanisole in 130 ml of anhydrous THF) is added to a solution of 31.3 g (0.17 mol) of cyanuric chloride in 100 ml of THF over the course of 1.5 hours, while maintaining the temperature in the range from 0 to 20 C. After addition is complete, the mixture is stirred at room temperature for 1.5 hours and then poured into 150 ml of 12% hydrogen chloride solution in an icebath. The beige suspension is filtered off, washed neutral with water and then washed with methanol. The crude product is recrystallized from 350 ml of toluene to give the compound of the formula ##STR21##
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([CH2:9][C:10](O)=[O:11])=[C:4]([F:13])[CH:3]=1.S(Cl)([Cl:16])=O.CN(C=O)C>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([CH2:9][C:10]([Cl:16])=[O:11])=[C:4]([F:13])[CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)Cc1c(F)cc(Br)cc1F
Solvent: CN(C)C=O
Product: O=C(Cl)Cc1c(F)cc(Br)cc1F
Temperature: 60 °C
Reaction time: 2 h
Yield: 69.6 %

Procedure:
To a solution of 2-(4-bromo-2,6-difluorophenyl)acetic acid (0.3 g, 1.195 mmol) in sulfurous dichloride (5 mL, 1.195 mmol) was added DMF (9.25 μL, 0.120 mmol). The resulting mixture was stirred at 60° C. After 2 h, LCMS analysis showed the starting material had disappeared and the solvent was removed in vacuo to give 2-(4-bromo-2,6-difluorophenyl)acetyl chloride (0.35 g, 0.832 mmol, 69.6% yield). To a solution of 4-(2-(benzyloxy)ethoxy)-3-(trifluoromethyl)aniline (0.347 g, 1.113 mmol) and Et3N (0.225 g, 2.227 mmol) in DCM (30 mL) was added 2-(4-bromo-2,6-difluorophenyl)acetyl chloride (0.3 g, 1.113 mmol). The resulting mixture was stirred at 25° C. After LCMS analysis showed the starting material had disappeared, the mixture was washed with H2O (20 mL) and brine (20 mL). The organic layer was dried over Na2SO4, filtered, concentrated, and purified by preparative TLC (PE/EA=3/1) to give N-(4-(2-(benzyloxy)ethoxy)-3-(trifluoromethyl)phenyl)-2-(4-bromo-2,6-difluorophenyl)acetamide (110 mg, 0.196 mmol, 17.6% yield): 1H NMR (400 MHz, CD3OD) δ 7.81 (d, J=2.8 Hz, 1H), 7.68 (d, J=2.4 Hz, 1H), 7.32-7.25 (m, 7H), 7.15 (d, J=8.8 Hz, 1H), 4.61 (s, 2H), 4.23 (t, J=4.6 Hz, 2H), 3.84 (t, J=4.6 Hz, 2H), 3.77 (s, 2H); ES-LCMS m/z 546.0 (M+H).
Reaction SMILES: Cl[C:2]1[C:7]2[C:8]([O:30][CH3:31])=[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:6]=2[CH:5]=[C:4]([Cl:32])[N:3]=1.[CH3:33][O-:34].[Na+]>C1COCC1.C(Cl)Cl>[Cl:32][C:4]1[N:3]=[C:2]([O:34][CH3:33])[C:7]2[C:8]([O:30][CH3:31])=[N:9][N:10]([C:11]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:6]=2[CH:5]=1
Reactant: C[O-]
Reactant: COc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(Cl)nc(Cl)c12
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1nc(Cl)cc2c1c(OC)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 40 °C
Reaction time: 1 h
Yield: 87.1 %

Procedure:
4,6-dichloro-3-methoxy-1-trityl-1H-pyrazolo[4,3-c]pyridine (Intermediate 37B, 100 mg, 0.217 mmol) in THF (1086 μl) was treated with sodium methoxide (4.6 N in MeOH) (51.9 μl, 0.239 mmol) and stirred @ 40° C. for 1 h. Reaction was diluted in with DCM and concentrated in vacuo on silica. Material was purified by normal phase column chromotography eluting with Hex/EtOAc (0-10%) affording 6-chloro-3,4-dimethoxy-1-trityl-1H-pyrazolo[4,3-c]pyridine (56B, 86 mg, 0.189 mmol, 87% yield) as a white foam. MS: [M+H]+ m/z 456.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]([NH:29][C:30]([CH2:32][CH:33]2[CH2:38][CH2:37][N:36](C(OC(C)(C)C)=O)[CH2:35][CH2:34]2)=[O:31])[C:10]([N:12]2[CH2:17][CH2:16][CH:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[NH:24][S:25]([CH3:28])(=[O:27])=[O:26])[CH2:14][CH2:13]2)=[O:11])=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]([NH:29][C:30](=[O:31])[CH2:32][CH:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[C:10]([N:12]2[CH2:17][CH2:16][CH:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[NH:24][S:25]([CH3:28])(=[O:26])=[O:27])[CH2:14][CH2:13]2)=[O:11])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CC(=O)N[C@H](Cc2ccc(Cl)cc2)C(=O)N2CCC(c3ccccc3NS(C)(=O)=O)CC2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)Nc1ccccc1C1CCN(C(=O)[C@@H](Cc2ccc(Cl)cc2)NC(=O)CC2CCNCC2)CC1
Reaction time: 0.5 h

Procedure:
The title compound was prepared according to the procedure described in Example 3, Step (b) from tert-butyl 4-({N-[(1R)-1-[(4-chlorophenyl)methyl]-2-(4-(2-[(methylsulfonyl)-amino]phenyl}piperidyl)-2-oxoethyl]-carbamoyl)methyl)-piperidinecarboxylate (Step a) (330 mg, 0.5 mmol) and 50% TFA in CH2Cl2 (20 mL). Purification by preparative reverse phase HPLC [Phenomenex; 5 μm 250×21.2 mm, 5% to 95% CH3CN (0.1% TFA) in H2O (0.1% TFA) over 30 min, then 100% CH3CN (0.1% TFA) for 2 min] provided the title compound (TFA salt) as a white foam (242 mg). MS (EST, pos. ion) m/z: 561 (M+1); (ESI, neg. ion) m/z: 559 (M−1). Calc'd for C28H37ClN4O4S: 560.22. Anal. Calcd for C28H37ClN4O4S.1.6C2HF3O2: C, 50.40; H, 5.23; N, 7.53. Found: C, 50.54; H, 5.53; N, 7.75.
Reaction SMILES: [Na].[NH2:2][C:3]1[N:8]=[C:7]([NH2:9])[CH:6]=[C:5](Cl)[N:4]=1.[Na+].[Cl-].[CH2:13]([OH:18])[CH2:14][CH:15]([CH3:17])[CH3:16]>>[CH3:16][CH:15]([CH3:17])[CH2:14][CH2:13][O:18][C:5]1[N:4]=[C:3]([NH2:2])[N:8]=[C:7]([NH2:9])[CH:6]=1
Reactant: CC(C)CCO
Reactant: Nc1cc(Cl)nc(N)n1
Agent: [Cl-]
Agent: [Na+]
Agent: [Na]
Product: CC(C)CCOc1cc(N)nc(N)n1
Reaction time: 11 h
Yield: 88 %

Procedure:
To a solution of 6.9 g (0.30 mol) sodium in 200 ml isopentyl alcohol were added 43.4 g (0.30 mol) 2,4-diamino-6-chloropyrimidine. The mixture was heated under reflux with stirring for 11 h. The reaction mixture was then stirred at 80° C. for a further 36 h. After the reaction was ended the precipitated NaCl was separated off and the solution was concentrated to dryness. The residue was repeatedly taken up in ethanol and again concentrated in order to remove residual isopentyl alcohol. After drying, 6-(3-Methylbutoxy)-2,4-diaminopyrimidine (51.8 g, 88%) was obtained as a yellow oil.
Reaction SMILES: Br.[Br:2][CH2:3][CH2:4][NH2:5].Cl[C:7]([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:8].C(N(CC)CC)C.O>ClCCl>[Br:2][CH2:3][CH2:4][NH:5][C:7](=[O:8])[O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: NCCBr
Agent: Br
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(NCCBr)Oc1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 89.5 %

Procedure:
To an ice-cooled suspension of 5.0 g of 2-bromoethylamine hydrobromide and 3.91 g of phenyl chloroformate in 50 ml of dichloromethane, 5.1 g of triethylamine was added. The mixture was stirred for 2 hours, and water was added thereto. The organic phase separated was concentrated to dryness under reduced pressure. The residue was crystallized with hexane to give 5.33 g of the entitled compound as colorless crystals.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13](Cl)=[O:14])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:18][C:19]([F:29])([F:28])[C@H:20]([OH:27])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].C(N(CC)CC)C>C(Cl)Cl>[F:18][C:19]([F:28])([F:29])[C@H:20]([O:27][C:13](=[O:14])[C:12]1[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:17][CH:16]=1)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: O=C(Cl)c1ccc(OCc2ccccc2)cc1
Reactant: CCCCCC[C@@H](O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCC[C@@H](OC(=O)c1ccc(OCc2ccccc2)cc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 12 h
Yield: 65.1 %

Procedure:
To 5 ml of a methylene chloride solution containing 0.56 g of 4-benzyloxybenzoic acid chloride was slowly added a solution of 0.38 g of (R)-(+)-1-trifluoromethylheptanol and 0.23 g of triethylamine in 5 ml of methylene chloride under ice-cooling. The mixture was allowed to warm to room temperature and stirred at that temperature for 12 hours. The reaction mixture was poured into ice-water and extracted with methylene chloride. The methylene chloride phase was washed successively with diluted hydrochloric acid, water, an aqueous 1N sodium carbonate solution, and water and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and the residual crude product was purified by silica gel column chromatography to obtain 0.53 g of (R)-(+)-4-benzyloxybenzoic acid 1-trifluoromethylheptyl ester.
Reaction SMILES: [C:1]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:6]=[CH:5][C:4]([C:7]2([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[O:11][C:10](=[O:12])[C:9]([O:13]CC3C=CC=CC=3)=[C:8]2[OH:21])=[CH:3][CH:2]=1.OC1C(=O)OC(C)(C2C=CC=CC=2)C=1O>>[C:1]1([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:6]=[CH:5][C:4]([C:7]2([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[O:11][C:10](=[O:12])[C:9]([OH:13])=[C:8]2[OH:21])=[CH:3][CH:2]=1
Reactant: O=C1OC(c2ccccc2)(c2ccc(-c3ccccc3)cc2)C(O)=C1OCc1ccccc1
Agent: CC1(c2ccccc2)OC(=O)C(O)=C1O
Product: O=C1OC(c2ccccc2)(c2ccc(-c3ccccc3)cc2)C(O)=C1O
Yield: 37.9 %

Procedure:
Hydrogenolysis of 500 mg of 5-[(1,1′-biphenyl)-4-yl]-4-hydroxy-3-phenylmethoxy-5-phenyl-2(5H)-furanone was performed in a similar manner as described in the preparation of 3,4-dihydroxy-5-methyl-5-phenyl-2(5H)-furanone to provide 150 mg (38% yield) of 5-[(1,1′-biphenyl)-4-yl]-3,4-dihydroxy-5-phenyl-2(5H)-furanone as colorless needles: mp 188-191° C. dec.(CHCl3/hexanes). 1H NMR (acetone-d6) δ 7.75-7.36 (m, 14H). 13C NMR (acetone-d6) δ 168.34, 154.84, 141.50, 140.66, 140.30, 139.42, 129.18, 128.74, 128.59, 127.92, 127.40, 127.25, 127.07, 119.45, 84.59. Anal Calcd for C22H16O4: C, 76.73; H, 4.68. Found: C, 76.44; H, 4.50.
Reaction SMILES: C([Li])CCC.[CH3:6][C:7]1([CH3:19])[CH:9]([CH:10]=[CH:11][C:12]([O:14]C)=[O:13])[CH:8]1[C:16]([OH:18])=[O:17].[CH3:20][C:21]1(C)[CH:23](C=C(Br)Br)[CH:22]1C([O-])=O.O1CCCC1>C1CCCCC1>[CH3:6][C:7]1([CH3:19])[C@@H:9]([C:10]#[C:11][C:12]([OH:14])=[O:13])[C@H:8]1[C:16]([O:18][C:21]([CH3:23])([CH3:22])[CH3:20])=[O:17]
Reactant: CC1(C)C(C=C(Br)Br)C1C(=O)[O-]
Reactant: COC(=O)C=CC1C(C(=O)O)C1(C)C
Agent: [Li]CCCC
Solvent: C1CCCCC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)[C@@H]1[C@H](C#CC(=O)O)C1(C)C
Temperature: -60 °C
Reaction time: 1 h

Procedure:
60 ml of a 20% solution of butyllithium in cyclohexane were added at -65° C. to a mixture of 26 g of tert.-butyl (1R, cis) 2,2-dimethyl-3-(2,2-dibromovinyl)-cyclopropane-carboxylate and 175 ml of anhydrous tetrahydrofuran and the mixture was stirred at -60° C. for one hour. A current of carbon dioxide was bubbled through the mixture for 90 minutes and the mixture was poured into an ice-water mixture containing N sodium hydroxide. The alkaline aqueous phase was acidified to a pH of 4 and was extracted with ether. The organic phase was dried and evaporated to dryness under reduced pressure. The residue was crystallized from petroleum ether (b.p.=60°-80° C. to obtain 8.3 g of tert.-butyl (1R,cis) 2,2-dimethyl-3-(3-hydroxy-3-oxo-1-propynyl)-cyclopropane-1-carboxylate melting at 144° C.