Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=O)[CH:5]=[CH:6][CH:7]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[Cl:22][C:23]1[CH:32]=[CH:31][C:26](C(OC)=O)=[CH:25][CH:24]=1>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([C:26]2[CH:31]=[CH:32][C:23]([Cl:22])=[CH:24][CH:25]=2)=[O:11])[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(Cl)cc1
Reactant: O=C(O)Cc1cccc(Cl)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(Cc1cccc(Cl)c1)c1ccc(Cl)cc1
Temperature: -78 °C
Reaction time: 0.67 h

Procedure:
To a solution of 2-(3-chlorophenyl)acetic acid (10 g, 58.6 mmol) in THF (58 ml) was added 117 mL of a 1M solution of sodium bis-(trimethylsilyl)amide in THF slowly over 1 h at −78° C. After being stirred at −78° C. for 40 min, a solution of methyl 4-chlorobenzoate (10 g, 58.6 mmol) in THF (35 ml) was added over a period of 10 min. The reaction was stirred at −78° C. for 3 h, then allowed to warm to 25° C., and stirred an additional 2 h until completion. The reaction was quenched with saturated aqueous NH4Cl solution and most of the THF was removed under reduced pressure. The residue was extracted with ethyl acetate (2×100 ml). The combined organic layers were washed with sat. NaCl solution, dried over Na2SO4, filtered and the filtrate was concentrated. The product was recrystallized from ether/pentane to provide the title compound as a white solid.
Reaction SMILES: [CH3:1][CH:2]([C:6]([NH:8][CH:9]1[C:15](=[O:16])[N:14]([CH3:17])[C:13]2[CH:18]=[CH:19][CH:20]=[CH:21][C:12]=2[C:11]2[CH:22]=[CH:23][CH:24]=[CH:25][C:10]1=2)=[O:7])[C:3]([OH:5])=O.[F:26][C:27]1[CH:34]=[CH:33][CH:32]=[CH:31][C:28]=1[CH2:29][NH2:30].[B-](F)(F)(F)F.CN(C(ON1C(=O)C=CC=C1)=[N+](C)C)C.CC#N>CN(C=O)C.C(O)(C(F)(F)F)=O>[F:26][C:27]1[CH:34]=[CH:33][CH:32]=[CH:31][C:28]=1[CH2:29][NH:30][C:3](=[O:5])[CH:2]([CH3:1])[C:6]([NH:8][CH:9]1[C:15](=[O:16])[N:14]([CH3:17])[C:13]2[CH:18]=[CH:19][CH:20]=[CH:21][C:12]=2[C:11]2[CH:22]=[CH:23][CH:24]=[CH:25][C:10]1=2)=[O:7]
Reactant: NCc1ccccc1F
Reactant: CC(C(=O)O)C(=O)NC1C(=O)N(C)c2ccccc2-c2ccccc21
Agent: CN(C)C(On1ccccc1=O)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: CC(C(=O)NCc1ccccc1F)C(=O)NC1C(=O)N(C)c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Methyl-N-(5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-malonamic acid (20 mg, 0.059 mmol) and 2-fluorobenzylamine (7.4 mg, 0.059 mmol) were placed in a disposable polypropylene tube and dissolved in DMF (2 ml). TPTU (2-(2-pyridon-1-yl)-1,1,3,3-tetramethyl uronium tetrafluoroborate, 19 mg, 0.065 mmol) was added, and the mixture was shaken overnight at r.t. The title compound, MS: m/e=446.2 (M+H+), was isolated from the reaction mixture by automated, preparative HPLC (YMC CombiPrep C18 column 50×20 mm, solvent gradient 5-95% CH3CN in 0.1% TFA(aq) over 6.0 min, λ=230 nm, flow rate 40 ml/min).
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([CH2:31][CH:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)[C:14](=O)[CH2:15][CH2:16][C:17]([C:19]3[N:20]=[CH:21][N:22]([CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH:23]=3)=O)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.C([O-])(=O)C.[NH4+:42].[OH-].[Na+]>C(O)(=O)C>[CH:1]1([S:4]([C:7]2[CH:8]=[CH:9][C:10]([CH:13]([C:14]3[NH:42][C:17]([C:19]4[N:20]=[CH:21][N:22]([CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH:23]=4)=[CH:16][CH:15]=3)[CH2:31][CH:32]3[CH2:33][CH2:34][O:35][CH2:36][CH2:37]3)=[CH:11][CH:12]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1
Reactant: [NH4+]
Reactant: CCOC(=O)Cn1cnc(C(=O)CCC(=O)C(CC2CCOCC2)c2ccc(S(=O)(=O)C3CC3)cc2)c1
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CCOC(=O)Cn1cnc(-c2ccc(C(CC3CCOCC3)c3ccc(S(=O)(=O)C4CC4)cc3)[nH]2)c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 43.5 %

Procedure:
A mixture of ethyl (4-{5-[4-(cyclopropylsulfonyl)phenyl]-4-oxo-6-(tetrahydro-2H-pyran-4-yl)hexanoyl}-1H-imidazol-1-yl)acetate (1.05 g), ammonium acetate (0.70 g) and acetic acid (5 mL) was stirred at 80° C. for 3 hr. The reaction mixture was neutralized with 8M aqueous sodium hydroxide solution, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to basic silica gel column chromatography, and the fraction eluted with ethyl acetate was concentrated. The obtained residue was subjected to silica gel column chromatography, and the title compound (0.44 g, yield 51%) was obtained as a pale-yellow amorphous solid from a fraction eluted with tetrahydrofuran-hexane (5:1, volume ratio). MS: 512 (MH+).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH3:21])=[CH:16][CH:15]=2)=[CH:10][C:9]=1[NH2:22])(C)(C)C.CC1(C)O[C:29]([C:31]2[CH:32]=[C:33]([CH:36]=[CH:37][CH:38]=2)[C:34]#[N:35])=[CH:28][C:27](=[O:39])O1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:20]([C:17]1[CH:16]=[CH:15][C:14]([C:11]2[CH:12]=[CH:13][C:8]3[N:7]=[C:29]([C:31]4[CH:32]=[C:33]([CH:36]=[CH:37][CH:38]=4)[C:34]#[N:35])[CH2:28][C:27](=[O:39])[NH:22][C:9]=3[CH:10]=2)=[CH:19][CH:18]=1)[CH3:21]
Reactant: CC1(C)OC(=O)C=C(c2cccc(C#N)c2)O1
Reactant: CCc1ccc(-c2ccc(NC(=O)OC(C)(C)C)c(N)c2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCc1ccc(-c2ccc3c(c2)NC(=O)CC(c2cccc(C#N)c2)=N3)cc1

Procedure:
Prepared from (3-amino-4′-ethyl-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example G8) and 3-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-benzonitrile (Example J4) according to the general procedure K. The obtained material was deprotected and cyclized by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a beige solid (67 mg).
Reaction SMILES: O.NN.[NH2:4][C:5]1[C:14]2[N:15]=[C:16]([CH2:29][O:30][N:31]3C(=O)C4C(=CC=CC=4)C3=O)[N:17]([CH2:18][CH2:19][CH2:20][NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:13]=2[C:12]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[N:6]=1>C(O)C>[C:24]([O:23][C:22](=[O:28])[NH:21][CH2:20][CH2:19][CH2:18][N:17]1[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[N:6]=[C:5]([NH2:4])[C:14]=2[N:15]=[C:16]1[CH2:29][O:30][NH2:31])([CH3:27])([CH3:25])[CH3:26]
Reactant: CC(C)(C)OC(=O)NCCCn1c(CON2C(=O)c3ccccc3C2=O)nc2c(N)nc3ccccc3c21
Agent: NN
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)NCCCn1c(CON)nc2c(N)nc3ccccc3c21
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 114.1 %

Procedure:
Hydrazine hydrate (8 mL of 55%) was added to a suspension of tert-butyl (3-{4-amino-2-[(1,3-dioxo-1,3-dihydroisoindol-2-yl)oxymethyl]-1H-imidazo[4,5-c]quinolin-1-yl}propyl)carbamate (4.25 g, 8.23 mmol) in ethanol (70 mL). The reaction became homogeneous after about 2 minutes. A precipitate started forming after about 1 hour. After stirring at ambient temperature for a total of 2 hours the reaction mixture was filtered and the filter cake was washed with dichloromethane. The filtrate was concentrated under reduced pressure. The residue was azeotroped twice with toluene to provide 3.63 g of tert-butyl[3-(4-amino-2-aminooxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl]carbamate as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:34])[N:10]([CH2:31][CH:32]=[CH2:33])[C:11]1[C:16](=[O:17])[N:15]2[C@H:18]([C:22](=[O:30])[NH:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:19][CH:20]([CH3:21])[C:14]2=[N:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.CC(C1C=C(C(C)C)C(S([N:60]=[N+:61]=[N-:62])(=O)=O)=C(C(C)C)C=1)C.CC(O)=O>C1COCC1.CCOC(C)=O>[CH2:1]([O:8][C:9](=[O:34])[N:10]([CH2:31][CH:32]=[CH2:33])[C:11]1[C:16](=[O:17])[N:15]2[C@H:18]([C:22](=[O:30])[NH:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:19][C@:20]([N:60]=[N+:61]=[N-:62])([CH3:21])[C:14]2=[N:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CCN(C(=O)OCc1ccccc1)c1cnc2n(c1=O)[C@H](C(=O)Nc1ccccc1)CC2C
Reactant: CC(C)c1cc(C(C)C)c(S(=O)(=O)N=[N+]=[N-])c(C(C)C)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=CCN(C(=O)OCc1ccccc1)c1cnc2n(c1=O)[C@H](C(=O)Nc1ccccc1)C[C@@]2(C)N=[N+]=[N-]
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 65 %

Procedure:
To a solution of the methyl diastereomers (18c) (3.90 g, 8.51 mmol) in 40 mL THF at −78° C., was added LiHMDS (IM in THF, 17.9 mL, 17.9 mmol). The red solution was stirred at −78° C. for 5 min, then a solution of trisyl azide (2.90 g, 9.36 mmol) in 8 mL THF was added. The reaction was stirred at −78° C. for 1.5 h, then was quenched with the addition of AcOH (2.19 mL, 38.3 mmol). The mixture was stirred at rt for 1 h, then was diluted with EtOAc. The organic phase was washed with 1N HCl, H2O and brine, dried (Na2SO4), and concentrated. The product was purified by flash chromatography (35 to 40% EtOAc/hexanes) to afford 2.764 g (65%) of azide 18d. MS (ESI) 500.4 (M+H+), 522.4 (M+Na+).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([OH:8])[C:5]([S:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16]Cl)=[CH:12][CH:11]=2)=[C:4]([CH3:18])[N:3]=1.[C-:19]#[N:20].[K+].O>CN(C=O)C.CS(C)=O>[NH2:1][C:2]1[N:7]=[C:6]([OH:8])[C:5]([S:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C:19]#[N:20])=[CH:12][CH:11]=2)=[C:4]([CH3:18])[N:3]=1
Reactant: [C-]#N
Reactant: Cc1nc(N)nc(O)c1Sc1ccc(CCl)cc1
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Solvent: CN(C)C=O
Product: Cc1nc(N)nc(O)c1Sc1ccc(CC#N)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of the product from step (ii) (8.7 g) and KCN (8.28 g) in DMF (20 ml) and DMSO (20 ml) was stirred at rt for 2 h then 50° C. for 2 h. Water (150 ml) was added and stirred for 30 min. The solid obtained was filtered off and added to MeOH (150 ml), heated to reflux for 5 min then hot filtered and allowed to cool to rt. The precipitate was filtered and dried under high vacuum at 45° C., to give the subtitle compound as a brown solid, 23 g.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[N:8]=[CH:7][C:6]([C:9]([OH:11])=O)=[CH:5][N:4]=1.C(Cl)(=O)C(Cl)=O.[F:20][C:21]([F:34])([F:33])[C:22]1[NH:23][C:24]2[C:29]([CH:30]=1)=[CH:28][C:27]([CH2:31][NH2:32])=[CH:26][CH:25]=2.C(N(CC)CC)C>ClCCl.CN(C=O)C>[F:12][C:2]([F:1])([F:13])[C:3]1[N:4]=[CH:5][C:6]([C:9]([NH:32][CH2:31][C:27]2[CH:28]=[C:29]3[C:24](=[CH:25][CH:26]=2)[NH:23][C:22]([C:21]([F:34])([F:20])[F:33])=[CH:30]3)=[O:11])=[CH:7][N:8]=1
Reactant: NCc1ccc2[nH]c(C(F)(F)F)cc2c1
Reactant: O=C(O)c1cnc(C(F)(F)F)nc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(NCc1ccc2[nH]c(C(F)(F)F)cc2c1)c1cnc(C(F)(F)F)nc1
Reaction time: 2 h
Yield: 57.9 %

Procedure:
2-(Trifluoromethyl)-5-pyrimidinecarboxylic acid (Bio-Farma) (108 mg, 0.560 mmol) was stirred in dichloromethane (10 ml). Oxalyl chloride (0.082 ml, 0.934 mmol) then DMF (1.808 μl, 0.023 mmol) was added. The reaction mixture was then left to stir for 2 h under Argon gas. The reaction mixture was then evaporated to dryness and the resulting residues were then dissolved in dichloromethane (10 ml). A solution of {[2-(trifluoromethyl)-1H-indol-5-yl]methyl}amine (Intermediate 4, 100 mg, 0.467 mmol) in DCM (10 mL) was added then triethylamine (0.130 ml, 0.934 mmol) was added. The reaction mixture was then left to stir at room temperature for 1 h. The reaction mixture was evaporated to dryness. The resulting residues where then purified on the MDAP to give the title compound (105 mg). m/z (ES+) 389 (M+1); 1H NMR (400 MHz, d6-DMSO): δ 12.24 (1H, s), 9.57 (1H, t), 9.43 (2H, s), 7.68 (1H, s), 7.45 (1H, d), 7.32 (1H, dd), 7.00 (1H, s), 4.63 (2H, d).
Reaction SMILES: [CH2:1]([C@H:3]1[CH:20]=[C:19]2[C@:14]([CH3:22])([CH2:15][CH2:16][C:17](=[O:21])[CH2:18]2)[C@@H:13]2[C@@H:4]1[C@H:5]1[C@@:9]([CH2:11][CH2:12]2)([CH3:10])[C@@H:8]([O:23][Si](C(C)(C)C)(C)C)[CH2:7][CH2:6]1)[CH3:2].N12CCCN=C1CCCCC2.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.CCOC(C)=O>[CH2:1]([C@H:3]1[CH2:20][C:19]2[C@:14]([CH3:22])([CH2:15][CH2:16][C:17](=[O:21])[CH:18]=2)[C@@H:13]2[C@@H:4]1[C@H:5]1[C@@:9]([CH2:11][CH2:12]2)([CH3:10])[C@@H:8]([OH:23])[CH2:7][CH2:6]1)[CH3:2]
Reactant: CC[C@H]1C=C2CC(=O)CC[C@]2(C)[C@H]2CC[C@]3(C)[C@@H](O[Si](C)(C)C(C)(C)C)CC[C@H]3[C@H]12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: C1CCC2=NCCCN2CC1
Product: CC[C@H]1CC2=CC(=O)CC[C@]2(C)[C@H]2CC[C@]3(C)[C@@H](O)CC[C@H]3[C@H]12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
7β-Ethyl-17β-tert-butyl-dimethylsilyloxy-androst-5-en-3-one (15.000 g, 34.824 mmol) from Example 16E or otherwise obtained is dissolved in THF (100 mL). To the solution is added 1,8-diazabicyclo[5.4.0]undec-7-ene (1.20 mL, 8.024 mmol) and the reaction mixture is heated to reflux under nitrogen. After 1 hour, the reaction mixture is cooled to room temperature and tetrabutylammonium fluoride (1.0 M in THF; 36.0 mL, 36.00 mmol) is added. The desilylation reaction is allowed to occur over 90 minutes at room temperature with stirring. At the end of this time, the reaction mixture is diluted with EtOAc (500 mL) and washed with saturated aqueous NH4Cl (3×200 mL) and brine (200 mL), then dried over MgSO4, filtered, and evaporated to dryness. The residue is recrystalized from ethanol to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([CH2:30][C:31](O)=[O:32])[C:25]=1[CH3:34])(=[O:12])=[O:11].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.[CH:49]1([NH:52][C:53]([C@@H:55]2[CH2:59][C@@H:58]([OH:60])[CH2:57][NH:56]2)=[O:54])[CH2:51][CH2:50]1>CN(C=O)C.C(Cl)Cl>[CH:49]1([NH:52][C:53]([C@@H:55]2[CH2:59][C@@H:58]([OH:60])[CH2:57][N:56]2[C:31](=[O:32])[CH2:30][C:26]2[C:25]([CH3:34])=[C:24](/[CH:23]=[C:16]3\[C:17](=[O:22])[NH:18][C:19]4[C:15]\3=[CH:14][C:13]([S:10]([CH2:9][C:3]3[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])(=[O:11])=[O:12])=[CH:21][CH:20]=4)[NH:28][C:27]=2[CH3:29])=[O:54])[CH2:51][CH2:50]1
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1CC(=O)O
Reactant: O=C(NC1CC1)[C@@H]1C[C@@H](O)CN1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: ClCCl
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1CC(=O)N1C[C@H](O)C[C@H]1C(=O)NC1CC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a mixture of {5-[5-(2,6-dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrol-3-yl}-acetic acid (238 mg, 0.46 mmol), HOBt (68 mg, 0.51 mmol) and EDC (105 mg, 0.55 mmol) in DMF 98 mL) was added (2S,4R)-4-hydroxy-pyrrolidine-2-carboxylic acid cyclopropylamide (excess) and TEA (0. 95 mL, 0.6 mmol). The mixture was stirred at rt for 3 days. The reaction was diluted with DCM (200 mL), washed with NH4Cl, NaHCO3, brine, dried and concentrated. The residue was purified on a silica gel column to give 120 mg of the titled compound. MS m/z 655 [M−1].
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:3]=1[O:4][C:5]1[N:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=O.[CH3:19][N:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[NH:23][CH2:22][CH2:21]1.C(N(C(C)C)C(C)C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Cl:1][C:2]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:3]=1[O:4][C:5]1[C:6]([C:7]([N:23]2[C:24]3[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=3)[N:20]([CH3:19])[CH2:21][CH2:22]2)=[O:9])=[CH:10][CH:11]=[CH:12][N:13]=1
Reactant: CN1CCNc2ccccc21
Reactant: O=C(O)c1cccnc1Oc1cc(Cl)ccc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCN(C(=O)c2cccnc2Oc2cc(Cl)ccc2Cl)c2ccccc21
Temperature: 100 °C
Yield: 25.1 %

Procedure:
To a solution of 2-(2,5-dichloro-phenoxy)-nicotinic acid (42.6 mg, 0.15 mmol, 1.0 equiv; Example 31, Step 1) in anhydrous DMF (1 mL) was added 1-methyl-1,2,3,4-tetrahydro-quinoxaline (26.7 mg, 0.18 mmol, 1.2 equiv; [CAS RN 36438-97-8]), N-ethyldiisopropylamine (97 mg, 131 μL, 0.75 mmol, 5.0 equiv; [CAS RN 7087-68-5]) and HATU (68 mg, 0.18 mmol, 1.2 equiv; [CAS RN 148893-10-1]). The reaction mixture was heated by microwave irradiation to 100° C. for 30 min. Removal of the solvent mixture under reduced pressure and purification by preparative HPLC on reversed phase (Xterra® PrepMSC 18, 5 μm, 19×50 mm column equipped with a Gilson Liquid Handler 215 autosampler, two Rainin Dynamax® SD-300 pumps, a Sedex ELSD 75 lightscatter and a Dionex UVD 340S UV detector) eluting with a gradient of acetonitrile/water provided 15.6 mg (25%) of the title compound. MS (ISP): 413.9 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1([CH2:14][CH3:15])[CH2:11][CH:10]([CH2:12][CH3:13])[CH:9]2[CH:4]([CH2:5][CH2:6][CH2:7][CH2:8]2)[NH:3]1.[CH2:16]1[O:18][CH2:17]1>C(O)CO>[OH:18][CH2:17][CH2:16][N:3]1[CH:4]2[CH:9]([CH2:8][CH2:7][CH2:6][CH2:5]2)[CH:10]([CH2:12][CH3:13])[CH2:11][C:2]1([CH3:1])[CH2:14][CH3:15]
Reactant: CCC1CC(C)(CC)NC2CCCCC12
Reactant: C1CO1
Solvent: OCCO
Product: CCC1CC(C)(CC)N(CCO)C2CCCCC12

Procedure:
Following the procedure given in E above, 75 grams of 2-methyl-2,4-diethyl decahydroquinoline were reacted with ethylene oxide in the presence of 50 milliliters of ethylene glycol at 200° C. for 10 hours to yield 1-(2'-hydroxyethyl)-2-methyl-2,4-diethyl decahydroquinoline, which had a boiling point of 140° C. at 0.8 mm Hg. The NMR and infrared spectra were consistent with the desired product. For formula of C16H31NO, the calculated carbon, hydrogen, nitrogen contents are 75.83% carbon, 12.33% hydrogen, and 5.53% nitrogen and the analyzed contents were 74.69% carbon, 12.24% hydrogen, and 5.14% nitrogen.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:22]([CH3:24])[CH3:23])[C:6]2[O:10][C:9]([C:11]3[CH:20]=[CH:19][C:14]([C:15]([O:17]C)=[O:16])=[CH:13][CH:12]=3)=[N:8][C:7]=2[CH:21]=1)#[N:2].O1CCCC1.CO.O.[OH-].[Li+]>O>[C:1]([C:3]1[CH:4]=[C:5]([CH:22]([CH3:24])[CH3:23])[C:6]2[O:10][C:9]([C:11]3[CH:12]=[CH:13][C:14]([C:15]([OH:17])=[O:16])=[CH:19][CH:20]=3)=[N:8][C:7]=2[CH:21]=1)#[N:2]
Reactant: COC(=O)c1ccc(-c2nc3cc(C#N)cc(C(C)C)c3o2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)c1cc(C#N)cc2nc(-c3ccc(C(=O)O)cc3)oc12
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To a 5-l, round-bottom flask fitted with a stir bar and a Claisen adapter fitted with a thermocouple and a nitrogen line was added was added methyl 4-(5-cyano-7-isopropyl-1,3-benzoxazol-2-yl)benzoate (40.5 g, Step B) tetrahydrofuran (1.25 l), methanol (630 ml), water (315 ml), and lithium hydroxide monohydrate (10.7 g). The mixture was heated to 50° C. and stirred at this temperature for 1 h. The mixture was then cooled and concentrated to a thick slurry. 1N HCl (3.2 l) was added and an off-white solid formed. The mixture was stirred for 5 min and then filtered, washing with water (2×500 ml). The solid was transferred to a 2-l round-bottom flask, concentrated from toluene (1 l) and then dried in vacuo. Mass spectrum (ESI) 307.0 (M+1). 1H NMR (500 MHz, DMSO-d6): δ 8.69 (d, J=7.5 Hz, 2H), 8.28 (s, 1H), 8.16 (d, J=8.0 Hz, 2H), 7.81 (s, 1H), 3.46 (septet, J=6.5 Hz, 1H), 1.40 (d, H=7.0 Hz, 6H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]2[CH:8]=[N:9][NH:10][C:4]=2[CH:3]=1.C1COCC1.CS(O)(=O)=O.[O:21]1[CH:26]=[CH:25][CH2:24][CH2:23][CH2:22]1>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[CH:6][C:5]2[CH:8]=[N:9][N:10]([CH:22]3[CH2:23][CH2:24][CH2:25][CH2:26][O:21]3)[C:4]=2[CH:3]=1
Reactant: Clc1cc2[nH]ncc2cn1
Reactant: C1=COCCC1
Agent: CS(=O)(=O)O
Solvent: C1CCOC1
Solvent: ClCCl
Product: Clc1cc2c(cn1)cnn2C1CCCCO1
Temperature: 25 °C
Reaction time: 2 h
Yield: 112.2 %

Procedure:
At r.t. to a suspension of 6-chloro-1H-pyrazolo[4,3-c]pyridine (0.5 g, 3 mmol) (Frontier Cat. No. Z13659) in methylene chloride (3 mL) and THF (1 mL) was added methanesulfonic acid (42 μL, 0.65 mmol), followed by dihydropyran (0.89 mL, 9.8 mmol). The mixture was stirred at r.t. for 2 h., and then at 50° C. overnight. After cooling the mixture was concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column with ethyl acetate in hexanes (0-50%) to afford the desired product (0.8 g). LCMS (M+H)+=238.0; LCMS (M-84+H)+=154.0/156.0.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:25]=[CH:24][CH:23]=[CH:22][C:5]=1[O:6][C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13]2[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][N:14]=2)[CH2:8]1)[CH3:2].[NH2:26][CH2:27][C:28]1[CH:29]=[C:30]([CH:35]=[CH:36][CH:37]=1)[C:31]([O:33]C)=[O:32].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Li+].[OH-]>>[CH2:1]([O:3][C:4]1[CH:25]=[CH:24][CH:23]=[CH:22][C:5]=1[O:6][C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13]2[CH:21]=[CH:20][C:16]([C:17]([NH:26][CH2:27][C:28]3[CH:29]=[C:30]([CH:35]=[CH:36][CH:37]=3)[C:31]([OH:33])=[O:32])=[O:18])=[CH:15][N:14]=2)[CH2:8]1)[CH3:2]
Reactant: COC(=O)c1cccc(CN)c1
Reactant: CCOc1ccccc1O[C@@H]1CCCN(c2ccc(C(=O)O)cn2)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Li+]
Product: CCOc1ccccc1O[C@@H]1CCCN(c2ccc(C(=O)NCc3cccc(C(=O)O)c3)cn2)C1

Procedure:
(R)-3-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)nicotinamido)methyl)benzoic acid was prepared from (R)-6-(3-(2-ethoxyphenoxy)piperidin-1-yl)nicotinic acid and methyl 3-(aminomethyl)benzoate using Amidation Method 1 (HATU) and Ester Hydrolysis Method 1 (LiOH). 1H NMR (500 MHz, CD3OD) δ 8.84 (app t, 1H), 8.58 (d, 1H), 8.02 (s, 1H), 7.92 (dd, 2H), 7.58 (d, 1H), 7.44 (t, 1H), 7.01 (d, 1H), 6.92 (m, 2H), 6.87 (m, 1H), 6.73 (d, 1H), 4.60 (m, 2H), 4.37 (m, 1H), 4.05 (dd, 1H), 3.93 (m, 2H), 3.72 (m, 3H), 2.07 (m, 1H), 1.95 (m, 2H), 1.59 (m, 1H), 1.28 (t, 3H). MS (ES+) 476.3 (M+H).
Reaction SMILES: [OH:1][CH:2]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:10][CH:9]=1)[CH2:3][C:4]([OH:6])=[O:5].C(N(CC)CC)C.Br[CH:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:30](=[O:31])[O:29]1>C(Cl)(Cl)Cl>[OH:1][CH:2]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:10][CH:9]=1)[CH2:3][C:4]([O:6][CH:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:30](=[O:31])[O:29]1)=[O:5]
Reactant: O=C1OC(Br)c2ccccc21
Reactant: O=C(O)CC(O)Cc1ccc(-c2ccccc2)cc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C(CC(O)Cc1ccc(-c2ccccc2)cc1)OC1OC(=O)c2ccccc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 71 %

Procedure:
To a solution of 7.7 g of 3-hydroxy-4-(4-biphenylyl)butyric acid in 40 ml of chloroform and 3.4 g of triethylamine is added a solution of 6.2 g of 3-bromophtalide in 20 ml of chloroform. The solution thus obtained is stirred for 24 hours at room temperature, the organic phase is washed with an aqueous solution of sodium bicarbonate, then with water and finally it is dried on anhydrous sodium sulfate and evaporated to yield the phthalidyl 3-hydroxy-4-(4-biphenylyl)butyrate; yield 71%.