Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5]2[CH:7]=[CH:8][C:9]([NH:11][C:12](=[O:16])[C:13]([OH:15])=O)=[CH:10][C:4]=2[O:3]1.[CH3:17][C:18]1[CH:19]=[C:20]([CH:28]=[CH:29][CH:30]=1)[CH2:21][CH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.C(OC(C)C)(C)C>>[CH3:17][C:18]1[CH:19]=[C:20]([CH:28]=[CH:29][CH:30]=1)[CH2:21][CH:22]1[CH2:27][CH2:26][N:25]([C:13](=[O:15])[C:12]([NH:11][C:9]2[CH:8]=[CH:7][C:5]3[NH:6][C:2](=[O:1])[O:3][C:4]=3[CH:10]=2)=[O:16])[CH2:24][CH2:23]1
Reactant: Cc1cccc(CC2CCNCC2)c1
Reactant: O=C(O)C(=O)Nc1ccc2[nH]c(=O)oc2c1
Solvent: CC(C)OC(C)C
Product: Cc1cccc(CC2CCN(C(=O)C(=O)Nc3ccc4[nH]c(=O)oc4c3)CC2)c1

Procedure:
The title compound is prepared from N-(2-oxo-2,3-dihydro-benzoxazol-6-yl)-oxalamic acid (Example 43e) and 4-(3-methyl-benzyl)-piperidine according to the method described in Example 2. Melting Point: 204-208° C. (diisopropylether)
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Al](C)C.C[O:14][C:15]([C:17]1[S:18][CH:19]=[CH:20][C:21]=1[NH:22][C:23]1[C:24]2[CH:31]=[CH:30][NH:29][C:25]=2[N:26]=[CH:27][N:28]=1)=O.O>C1(C)C=CC=CC=1.CO>[CH2:1]([NH:8][C:15]([C:17]1[S:18][CH:19]=[CH:20][C:21]=1[NH:22][C:23]1[C:24]2[CH:31]=[CH:30][NH:29][C:25]=2[N:26]=[CH:27][N:28]=1)=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1sccc1Nc1ncnc2[nH]ccc12
Reactant: NCc1ccccc1
Agent: C[Al](C)C
Solvent: CO
Solvent: O
Solvent: Cc1ccccc1
Product: O=C(NCc1ccccc1)c1sccc1Nc1ncnc2[nH]ccc12
Temperature: 105 °C
Reaction time: 2 h
Yield: 41.3 %

Procedure:
To a solution of benzylamine (99 μl; 98 mg; 0.91 mmol) in anhydrous toluene (3 mL) placed in a sealed tube under nitrogen was added a solution of trimethylaluminum (365 μl; 2 M; 0.73 mmol) in toluene. The colorless solution was stirred at 25° C. for 1 h, before 3-(7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-thiophene-2-carboxylic acid methyl ester (50 mg; 0.18 mmol) was added and the resulting yellow suspension was heated to 105° C. overnight. The reaction mixture was allowed to cool down before water (0.1 mL) was added. The resulting blue suspension was stirred at 25° C. for 2 h, diluted with methanol and purified by chromatography on a SP1 Biotage system, using dichloromethane and methanol as eluents to afford 3-(7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-thiophene-2-carboxylic acid benzylamide (26 mg, 39%) as a gray solid (HPLC: 95%, RT: 6.04 min). 1H NMR (DMSO-d6) 11.96 (br s, 1H), 11.39 (s, 1H), 8.82 (t, J=5.9 Hz, 1H), 8.50 (d, J=5.1 Hz, 1H), 8.38 (s, 1H), 7.79 (d, J=5.5 Hz, 1H), 7.36-7.33 (m, 5H), 7.27-7.22 (m, 1H), 6.43 (dd, J=3.3, 1.8 Hz, 1H), 4.50 (d, J=5.9 Hz, 2H); MS (m/z) 350 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH3:19])[C:5]([O:8][C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=2)=[N:6][CH:7]=1.[Cl:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:22]=1[C:28]1[C:32]([CH2:33]O)=[C:31]([CH:35]([CH3:37])[CH3:36])[O:30][N:29]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1C=CC=CC=1>[Cl:27][C:23]1[CH:24]=[CH:25][CH:26]=[C:21]([Cl:20])[C:22]=1[C:28]1[C:32]([CH2:33][O:1][C:2]2[CH:3]=[C:4]([CH3:19])[C:5]([O:8][C:9]3[CH:10]=[CH:11][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:17][CH:18]=3)=[N:6][CH:7]=2)=[C:31]([CH:35]([CH3:37])[CH3:36])[O:30][N:29]=1
Reactant: COC(=O)c1ccc(Oc2ncc(O)cc2C)cc1
Reactant: CC(C)c1onc(-c2c(Cl)cccc2Cl)c1CO
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: COC(=O)c1ccc(Oc2ncc(OCc3c(-c4c(Cl)cccc4Cl)noc3C(C)C)cc2C)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 70.2 %

Procedure:
To a suspension of methyl 4-(5-hydroxy-3-methylpyridin-2-yloxy)benzoate synthesised in step 3 (0.042 g, 0.162 mmol), [3-(2,6-dichloro-phenyl)-5-isopropyl-isoxazol-4-yl]methanol (0.046 g; 0.162 mmol) (for preparation refer to: P. Maloney et al. “Identification of a chemical tool for the orphan nuclear receptor FXR” J. Med. Chem. 2000, 43(16), 2971-2974) and triphenylphosphine (0.052 g, 0.2 mmol) in benzene (2 ml) was added diisopropyl azodicarboxylate (0.051 g, 0.25 mmol). The mixture was stirred at room temperature for 20 h, the solvent was removed in vacuo and the residue was purified by preparative HPLC to provide methyl 4-(5-((3-(2,6-dichlorophenyl)-5-isopropylisoxazol-4-yl)methoxy)-3-methylpyridin-2-yloxy)benzoate (0.06 g, 70% yield).
Reaction SMILES: [CH2:1]([N:4]([CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:5](=[O:15])[C:6]1[CH:11]=[CH:10][C:9]([NH:12][CH3:13])=[C:8]([NH2:14])[CH:7]=1)[CH2:2][CH3:3].C1(N(CCC(OCC)=O)C(=O)C2C=CC(NCC)=C(N)C=2)C=CC=CC=1.[Cl:49][CH2:50][C:51](O)=[O:52]>O1CCCC1>[CH2:1]([N:4]([CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:5](=[O:15])[C:6]1[CH:11]=[CH:10][C:9]([NH:12][CH3:13])=[C:8]([NH:14][C:51](=[O:52])[CH2:50][Cl:49])[CH:7]=1)[CH2:2][CH3:3]
Reactant: O=C(O)CCl
Reactant: CCCN(CCC(=O)OCC)C(=O)c1ccc(NC)c(N)c1
Agent: CCNc1ccc(C(=O)N(CCC(=O)OCC)c2ccccc2)cc1N
Solvent: C1CCOC1
Product: CCCN(CCC(=O)OCC)C(=O)c1ccc(NC)c(NC(=O)CCl)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 1.8 g (5.9 mmol) of 3-amino-4-methylaminobenzoic acid-N-(n-propyl)-N-(2-ethoxycarbonylethyl)amide [prepared analogously to 3-amino-4-ethylaminobenzoic acid-N-phenyl-N-(2-ethoxycarbonylethyl)amide], 1.1 g (6.8 mmol) of N,N′-carbonyldiimidazole, and 0.65 g (6.9 mmol) of chloroacetic acid in 75 mL tetrahydrofuran was stirred for 1 hour at room temperature. Then the solvent was distilled off in vacuo, and the crude product was purified by flash chromatography (silica gel; methylene chloride/ethanol=49:1). Yield: 1.7 g (77% of theory) yellow oil; Rf value: 0.58 (silica gel; ethyl acetate/ethanol/ammonia=90:10:1).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:12])[CH:8]=2)[N:3]=1.[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14]>>[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][N:23]([C:2]2[CH:11]=[CH:10][C:9]3[C:4](=[CH:5][CH:6]=[C:7]([Cl:12])[CH:8]=3)[N:3]=2)[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: Clc1ccc2nc(Cl)ccc2c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc3cc(Cl)ccc3n2)CC1

Procedure:
Prepared in analogy to example 1.18 (a) from 2,6-dichloroquinoline and piperazine-1-carboxylic acid tert-butyl ester. Crystallisation from methanol yields the title compound as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:33]2[CH:38]=[CH:37][C:36]([C:39]([OH:41])=O)=[CH:35][CH:34]=2)[CH:5]=[C:6]([Cl:32])[C:7]=1[CH2:8][C@@H:9]1[CH2:13][CH2:12][N:11]([N:14]2[CH2:19][CH2:18][CH:17]([O:20][Si:21]([CH:28]([CH3:30])[CH3:29])([CH:25]([CH3:27])[CH3:26])[CH:22]([CH3:24])[CH3:23])[CH2:16][CH2:15]2)[C:10]1=[O:31].C(N1C=CN=C1)(N1C=CN=C1)=O.[NH:54]1[CH2:59][CH2:58][O:57][CH2:56][CH2:55]1.C(OCC)(=O)C>C(Cl)Cl>[Cl:32][C:6]1[CH:5]=[C:4]([C:33]2[CH:34]=[CH:35][C:36]([C:39]([N:54]3[CH2:59][CH2:58][O:57][CH2:56][CH2:55]3)=[O:41])=[CH:37][CH:38]=2)[CH:3]=[C:2]([Cl:1])[C:7]=1[CH2:8][C@@H:9]1[CH2:13][CH2:12][N:11]([N:14]2[CH2:15][CH2:16][CH:17]([O:20][Si:21]([CH:25]([CH3:26])[CH3:27])([CH:22]([CH3:24])[CH3:23])[CH:28]([CH3:29])[CH3:30])[CH2:18][CH2:19]2)[C:10]1=[O:31]
Reactant: CC(C)[Si](OC1CCN(N2CC[C@@H](Cc3c(Cl)cc(-c4ccc(C(=O)O)cc4)cc3Cl)C2=O)CC1)(C(C)C)C(C)C
Reactant: C1COCCN1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)[Si](OC1CCN(N2CC[C@@H](Cc3c(Cl)cc(-c4ccc(C(=O)N5CCOCC5)cc4)cc3Cl)C2=O)CC1)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.7 %

Procedure:
Treat a solution of (R)-3′,5′-dichloro-4′-[2-oxo-1-(4-triisopropylsilanyloxy-piperidin-1-yl)-pyrrolidin-3-ylmethyl]-biphenyl-4-carboxylic acid (0.2 g, 0.32 mmol) in CH2Cl2 (15 mL) with 1,1′-carbonyldiimidazole (0.10 g, 0.65 mmol) and stir for 1 hour at room temperature. Treat the reaction with morpholine (0.06 g, 0.65 mmol) and stir for 12 hours at room temperature. Load the mixture on silica gel column and flash with 25% to 35% ethyl acetate in hexanes to afford 0.20 g (90%) of the title compound. MS (m/z): 688 (M+).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]2[CH:22]=[C:21]([C:23]#[N:24])[CH:20]=[CH:19][N:18]=2)=[CH:12][CH:11]=1)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]2[CH:22]=[C:21]([CH:20]=[CH:19][N:18]=2)[C:23]#[N:24])=[CH:12][CH:11]=1
Reactant: CC(C)(C)OC(=O)NCCc1ccc(Oc2cc(C#N)ccn2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccnc(Oc2ccc(CCN)cc2)c1
Reaction time: 3 h
Yield: 179.4 %

Procedure:
{2-[4-(4-Cyanopyridin-2-yloxy)-phenyl]-ethyl}-carbamic acid tert-butyl ester (5.57 g, 8.2 mmol) was dissolved with magnetic stirring in CH2Cl2 (100 mL) in a 250 mL round bottom flask equipped with a dry nitrogen line at 25° C. To this solution was added trifluoroacetic acid (10 mL), and the reaction mixture was kept at 25° C. for 3 h. The solution was concentrated in vacuo. The residue was taken up in H2O (50 mL) and EtOAc (75 mL) and treated with conc. ammonium hydroxide (NH4OH) to adjust the pH to 9-10. The layers were separated, and the aqueous fraction was extracted twice with EtOAc. The pooled organic fractions were filtered and concentrated in vacuo to afford 2-[4-(2-aminoethyl)-phenoxy]-isonicotinonitrile (3.52 g, 89%) as a beige waxy solid: 1H NMR (400 MHz, CDCl3) δ 8.32 (d, J=5.1 Hz, 1H), 7.27 (m, 2H), 7.19 (d, J=5.1 Hz, 1H), 7.15 (s, 1H), 7.07 (d, J=8.4 Hz, 2H), 3.00 (t, J=6.9 Hz, 2H), 2.78 (t, J=6.9 Hz, 2H), 1.63 (s, 2H); ESIMS m/z 240.1 ([M+H]+).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:15]([N:17]3[CH2:22][CH2:21][N:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[F:29])[CH2:19][CH2:18]3)=[O:16])=[CH:7][N:8]2[CH2:11][C:12](O)=[O:13])=[CH:4][CH:3]=1.C(OC(=O)[NH:36][CH2:37][CH2:38][NH2:39])(C)(C)C.Cl>>[NH2:36][CH2:37][CH2:38][NH:39][C:12](=[O:13])[CH2:11][N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:10]=2)[C:6]([C:15]([N:17]2[CH2:18][CH2:19][N:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[F:29])[CH2:21][CH2:22]2)=[O:16])=[CH:7]1
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: O=C(O)Cn1cc(C(=O)N2CCN(c3ccccc3F)CC2)c2ccc(Cl)cc21
Agent: Cl
Product: NCCNC(=O)Cn1cc(C(=O)N2CCN(c3ccccc3F)CC2)c2ccc(Cl)cc21

Procedure:
Following general procedure I, the coupling of {6-chloro-3-[4-(2-fluoro-phenyl)-piperazine-1-carbonyl]-indol-1-yl}-acetic acid (preparation described herein), with (commercially available) (2-amino-ethyl)-carbamic acid tert-butyl ester gave, after treatment with HCl and neutralisation, the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][C:10]([CH3:15])([CH3:14])[C:11](O)=[O:12])[CH:6]=[CH:7][CH:8]=1.C(N(CC)CC)C.ClC(OC)=O.[N-:28]=[N+:29]=[N-:30].[Na+]>CC(C)=O.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][C:10]([CH3:15])([CH3:14])[C:11]([N:28]=[N+:29]=[N-:30])=[O:12])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(CC(C)(C)C(=O)O)c1
Reactant: [N-]=[N+]=[N-]
Agent: COC(=O)Cl
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: COc1cccc(CC(C)(C)C(=O)N=[N+]=[N-])c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 26.8 %

Procedure:
A mixture of 3-(3-methoxyphenyl)-2,2-dimethylpropanoic acid (200 mg, 0.96 mmol) in acetone (40 mL) and water (4 mL) was cooled to 0° C. Triethyl amine (0.18 mL, 1.3 mmol) was added to the reaction mixture followed by methyl chloroformate (118 mg, 1.25 mmol). The mixture was stirred for 1 hour at 0° C. and then another solution of sodium azide (94 mg, 1.45 mmol) in water (1 mL) was added dropwise. The reaction mixture was stirred at room temperature for another 1 hour. The mixture was diluted with water and extracted with ethyl acetate. The combined organic fractions were washed with water, dried over sodium sulfate and concentrated to give 3-(3-methoxyphenyl)-2,2-dimethylpropanoyl azide (60 mg) as a crude yellow oil, which was used without further purification.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[CH:6][N:7]=[CH:8][CH:9]=2)[NH:4][CH:3]=1.[O:11](C(OC(C)(C)C)=O)[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=O>CN(C1C=CN=CC=1)C.O1CCOCC1>[C:15]([O:14][C:12]([N:4]1[C:5]2=[CH:6][N:7]=[CH:8][CH:9]=[C:10]2[C:2]([Br:1])=[CH:3]1)=[O:11])([CH3:18])([CH3:17])[CH3:16]
Reactant: Brc1c[nH]c2cnccc12
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)n1cc(Br)c2ccncc21
Yield: 74.8 %

Procedure:
A mixture of Example 695J (0.32 g, 1.62 mmol), (BOC)2O (0.43 g, 1.94 mmol) and DMAP (50 mg) in 10 mL of dioxane was stirred overnight at room temperature. The reaction mixture was partitioned between water and EtOAc. The aqueous layer was extracted with additional EtOAc. The combined organic layers were washed with water, brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel eluting with 7:3 hexanes/ethyl acetate to provide 0.36 g (75%) of the desired product. MS (APCI) m/e 298 (M+H)+, 1H NMR (500 MHz, DMSO-d6): □ 9.29 (s, 1H), 8.28 (d, J=5.09 Hz, 1H), 8.16 (s, 1H), 7.55 (d, J=5.43 Hz, 1H), 1.65 (s, 9H).
Reaction SMILES: [CH:1]([C@H:4]1[CH2:8][O:7][C:6](=[O:9])[N:5]1[C:10]1[CH:15]=[CH:14][N:13]2[N:16]=[CH:17][C:18]([C:19]3[CH:24]=[CH:23][C:22]([C:25]4[O:29][C:28](=[O:30])[NH:27][N:26]=4)=[CH:21][CH:20]=3)=[C:12]2[N:11]=1)([CH3:3])[CH3:2].[NH2:31][CH2:32][CH2:33][OH:34]>CCO>[OH:34][CH2:33][CH2:32][NH:31][C:28]([NH:27][NH:26][C:25](=[O:29])[C:22]1[CH:21]=[CH:20][C:19]([C:18]2[CH:17]=[N:16][N:13]3[CH:14]=[CH:15][C:10]([N:5]4[C@@H:4]([CH:1]([CH3:2])[CH3:3])[CH2:8][O:7][C:6]4=[O:9])=[N:11][C:12]=23)=[CH:24][CH:23]=1)=[O:30]
Reactant: NCCO
Reactant: CC(C)[C@H]1COC(=O)N1c1ccn2ncc(-c3ccc(-c4n[nH]c(=O)o4)cc3)c2n1
Solvent: CCO
Product: CC(C)[C@H]1COC(=O)N1c1ccn2ncc(-c3ccc(C(=O)NNC(=O)NCCO)cc3)c2n1
Temperature: 25 °C
Yield: 29.3 %

Procedure:
A suspension of (S)-5-(4-(5-(4-isopropyl-2-oxooxazolidin-3-yl)pyrazolo[1,5-a]pyrimidin-3-yl)phenyl)-1,3,4-oxadiazol-2(3H)-one (42.8 mg, 0.105 mmol) and 2-aminoethanol (19.1 μL, 0.316 mmol) in EtOH (2 mL) was heated to reflux for 22 hours. After the reaction mixture was cooled to ambient temperature, the solvent was removed under reduced pressure. The crude product was flash chromatographed (0-10% MeOH in dichloromethane) to afford 14.4 mg (29%) of (S)—N-(2-hydroxyethyl)-2-(4-(5-(4-isopropyl-2-oxooxazolidin-3-yl)pyrazolo[1,5-a]pyrimidin-3-yl)benzoyl)hydrazinecarboxamide. LCMS (APCI−) m/z 466.5 [M−H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:19]=[CH:18][C:12]([CH:13]=[CH:14][C:15]([OH:17])=O)=[CH:11][C:10]=1[N+:20]([O-:22])=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>>[CH2:1]([O:8][C:9]1[CH:19]=[CH:18][C:12]([CH:13]=[CH:14][C:15]([N:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[O:17])=[CH:11][C:10]=1[N+:20]([O-:22])=[O:21])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C=Cc1ccc(OCc2ccccc2)c([N+](=O)[O-])c1
Reactant: C1CCNCC1
Product: O=C(C=Cc1ccc(OCc2ccccc2)c([N+](=O)[O-])c1)N1CCCCC1
Yield: 65.3 %

Procedure:
Following a procedure similar to that described in Example 1, but using 1 g of 4-benzyloxy-3-nitrocinnamic acid and 400 mg of piperidine, 0.8 g of the title compound were obtained, melting at 155°-156° C.
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]([N:11]1[C:15]([C:16]2[N:17]=[C:18]3[C:24]4[CH:25]=[CH:26][C:27]([N:29]5[CH2:33][CH2:32][CH2:31][C@H:30]5[C:34]([O:36]C(C)(C)C)=[O:35])=[CH:28][C:23]=4[O:22][CH2:21][CH2:20][N:19]3[CH:41]=2)=[N:14][CH:13]=[N:12]1)([CH3:10])[CH3:9].C([SiH](CC)CC)C>ClCCl>[CH:8]([N:11]1[C:15]([C:16]2[N:17]=[C:18]3[C:24]4[CH:25]=[CH:26][C:27]([N:29]5[CH2:33][CH2:32][CH2:31][C@H:30]5[C:34]([OH:36])=[O:35])=[CH:28][C:23]=4[O:22][CH2:21][CH2:20][N:19]3[CH:41]=2)=[N:14][CH:13]=[N:12]1)([CH3:10])[CH3:9]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(N3CCC[C@H]3C(=O)OC(C)(C)C)cc1OCC2
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(N3CCC[C@H]3C(=O)O)cc1OCC2
Reaction time: 3 h

Procedure:
Trifluoroacetic acid (3 ml) was added to a mixture of 153 mg of (S)-tert-butyl 1-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)pyrrolidine-2-carboxylate and 0.2 ml of triethylsilane in 5 ml of dichloromethane. The reaction mixture was stirred for 3 hours. The mixture was concentrated, the residue partitioned between 1 M aq. Na2CO3 and ethyl ether. The aqueous layer was extracted with ethyl acetate two more times. The organic layers were discarded, the aqueous solution neutralized to pH 6. A precipitate was collected, washed with water, dried in high vacuum for 36 hours to give (S)-1-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)pyrrolidine-2-carboxylic acid. Yield 55 mg. M/z 409.3, calc. 408.19.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[CH:13]=[C:14]([Cl:18])[C:15]([I:17])=[CH:16][C:11]=2[N:10]=[C:9]1S(C)(=O)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:23]([O:25][P:26]([C:31]1[CH:36]=[C:35]([OH:37])[CH:34]=[CH:33][C:32]=1[CH3:38])(=[O:30])[O:27][CH2:28][CH3:29])[CH3:24].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:28]([O:27][P:26]([C:31]1[CH:36]=[C:35]([O:37][C:9]2[N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:12]3[CH:13]=[C:14]([Cl:18])[C:15]([I:17])=[CH:16][C:11]=3[N:10]=2)[CH:34]=[CH:33][C:32]=1[CH3:38])(=[O:30])[O:25][CH2:23][CH3:24])[CH3:29]
Reactant: CS(=O)(=O)c1nc2cc(I)c(Cl)cc2n1Cc1ccccc1
Reactant: CCOP(=O)(OCC)c1cc(O)ccc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOP(=O)(OCC)c1cc(Oc2nc3cc(I)c(Cl)cc3n2Cc2ccccc2)ccc1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-benzyl-6-chloro-5-iodo-2-methanesulfonyl-1H-benzoimidazole (2.7 g, 6.0 mmol) in DMF (30 ml) was added (5-hydroxy-2-methyl-phenyl)-phosphonic acid diethyl ester (1.9 g, 8.4 mmol), followed by potassium carbonate (1.7 g, 12 mmol). After stirring overnight at rt the volatiles were removed by rotary evaporation. The residue thus obtained was partitioned between EtOAc and half-saturated ammonium chloride solution. The EtOAc layer was washed with H2O, brine, and then dried with MgSO4. The crude oil was then purified by flash chromatrography (SiO2, 80 g) using a gradient up to 65% EtOAc in hexane to yield the title compound.
Reaction SMILES: Cl[C:2]1[CH:21]=[CH:20][C:5]([C:6]([NH:8][C:9]2[CH:17]=[C:16]3[C:12]([CH:13]=[CH:14][N:15]3[CH2:18][CH3:19])=[CH:11][CH:10]=2)=[O:7])=[CH:4][N:3]=1.[CH2:22]([O:29][C:30](=[O:43])[C:31]1[CH:36]=[CH:35][C:34]([N:37]2[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]2)=[CH:33][CH:32]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(OC(=O)C1C=CC(N2CCN(C3C=CC(C(=O)NC4C=CC(C)=C(I)C=4)=CN=3)CC2)=CC=1)C>CCOC(C)=O>[CH2:22]([O:29][C:30](=[O:43])[C:31]1[CH:36]=[CH:35][C:34]([N:37]2[CH2:42][CH2:41][N:40]([C:2]3[CH:21]=[CH:20][C:5]([C:6](=[O:7])[NH:8][C:9]4[CH:17]=[C:16]5[C:12]([CH:13]=[CH:14][N:15]5[CH2:18][CH3:19])=[CH:11][CH:10]=4)=[CH:4][N:3]=3)[CH2:39][CH2:38]2)=[CH:33][CH:32]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CCn1ccc2ccc(NC(=O)c3ccc(Cl)nc3)cc21
Reactant: O=C(OCc1ccccc1)c1ccc(N2CCNCC2)cc1
Agent: CCOC(=O)c1ccc(N2CCN(c3ccc(C(=O)Nc4ccc(C)c(I)c4)cn3)CC2)cc1
Solvent: CCOC(C)=O
Product: CCn1ccc2ccc(NC(=O)c3ccc(N4CCN(c5ccc(C(=O)OCc6ccccc6)cc5)CC4)nc3)cc21

Procedure:
4-{4-[5-(1-Ethyl-1H-indol-6-ylcarbamoyl)-pyridin-2-yl]-piperazin-1-yl}-benzoic acid benzyl ester was prepared from 6-chloro-N-(1-ethyl-1H-indol-6-yl)-nicotinamide and 4-piperazin-1-yl-benzoic acid benzyl ester following a method similar to the one described in the synthesis of 4-{4-[5-(3-iodo-4-methyl-phenylcarbamoyl)-pyridin-2-yl}-piperazin-1-yl]-benzoic acid ethyl ester above. The product was isolated after silica gel column chromatography with 20-60% EtOAc in hexanes gradient. HRMS m/z calcd for C34H33N5O3 [M+H]+: 560.2656. Found: 560.2656.
Reaction SMILES: [CH2:1]([S:3](Cl)(=[O:5])=[O:4])[CH3:2].[F:7][C:8]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:9]=1[O:10][C:11]1[N:16]=[CH:15][C:14]([NH2:17])=[CH:13][C:12]=1[B:18]1[O:22][C:21]([CH3:24])([CH3:23])[C:20]([CH3:26])([CH3:25])[O:19]1.N1C=CC=CC=1.O>C(Cl)Cl>[F:7][C:8]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:9]=1[O:10][C:11]1[N:16]=[CH:15][C:14]([NH:17][S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])=[CH:13][C:12]=1[B:18]1[O:22][C:21]([CH3:23])([CH3:24])[C:20]([CH3:25])([CH3:26])[O:19]1
Reactant: CC1(C)OB(c2cc(N)cnc2Oc2ccc(F)cc2F)OC1(C)C
Reactant: CCS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: CCS(=O)(=O)Nc1cnc(Oc2ccc(F)cc2F)c(B2OC(C)(C)C(C)(C)O2)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 82.2 %

Procedure:
Ethylsulfonyl chloride (50 uL, 52 mmol) was added to a stirred solution of 6-(2,4-difluorophenoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-amine (163 mg, 0.5 mmol) and pyridine (113 uL) in DCM (2.4 mL) at 0° C. under nitrogen. After the mixture was allowed to warm to rt and stir for 12 h, it was treated with water (15 mL) and extracted with DCM (3×15 mL); the combined organic extracts were washed with saturated bicarbonate solution (aq), dried over sodium sulfate, filtered and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography using a gradient of EtOAc (0 to 100%) in DCM to afford the title compound (181 mg, 88%) as a tan solid. LCMS (M+H)+=441.
Reaction SMILES: [CH3:1][O:2][CH:3]1[C:7]2([CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9][CH2:8]2)[C:6](=[O:20])[N:5]([C:21]2[CH2:22][O:23][C:24](=[O:27])[C:25]=2[CH3:26])[CH2:4]1.OC1C2(CCN(C(OC(C)(C)C)=O)CC2)C(=O)N(C2COC(=O)C=2C)C1.IC.[Al]>C(#N)C.[Ag]=O>[CH3:1][O:2][CH:3]1[C:7]2([CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[C:6](=[O:20])[N:5]([C:21]2[CH2:22][O:23][C:24](=[O:27])[C:25]=2[CH3:26])[CH2:4]1
Reactant: COC1CN(C2=C(C)C(=O)OC2)C(=O)C12CCN(C(=O)OC(C)(C)C)CC2
Agent: O=[Ag]
Agent: CC1=C(N2CC(O)C3(CCN(C(=O)OC(C)(C)C)CC3)C2=O)COC1=O
Agent: [Al]
Solvent: CI
Solvent: CC#N
Product: COC1CN(C2=C(C)C(=O)OC2)C(=O)C12CCNCC2
Temperature: 58 °C
Reaction time: 15 h

Procedure:
tert-Butyl 4-methoxy-2-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-1-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate (Enantiomer A and Enantiomer B): To a solution of tert-butyl 4-hydroxy-2-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-1-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate (100 mg, 0.273 mmol) in acetonitrile (1 mL) was added iodomethane (171 μL, 2.73 mmol) and silver oxide (69.6 mg, 0.300 mmol). The vial was sealed, wrapped with aluminum foil, and stirred at 58° C. for 15 h. The reaction mixture was filtered through CELITE®, concentrated to give the crude product, which was purified by column chromatography (0-10% MeOH/DCM) to afford the title compound as a mixture of enantiomers. LC/MS: [(M+1)]+=381. The racemic mixture was separated by SFC-HPLC, using the following conditions: chiralcel AD-H, 2×25 cm, 15% MeOH, 60 mL/min to afford faster eluting Enantiomer A: LC/MS: [(M+1)]+=381; and slower eluting Enantiomer B: LC/MS: [(M+1)]+=381
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[Cl:15][C:16]1[N:17]=[C:18]([N:31]2[CH2:36][CH2:35][CH:34]([CH:37]=O)[CH2:33][CH2:32]2)[C:19]2[C:24]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:23][S:22][C:20]=2[N:21]=1.[CH3:39][NH:40][CH:41]1[CH2:45][N:44]([CH3:46])[CH2:43][CH2:42]1.C(O)(=O)C>ClCCl.O>[Cl:15][C:16]1[N:17]=[C:18]([N:31]2[CH2:36][CH2:35][CH:34]([CH2:37][N:40]([CH3:39])[CH:41]3[CH2:42][CH2:43][N:44]([CH3:46])[CH2:45]3)[CH2:33][CH2:32]2)[C:19]2[C:24]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:23][S:22][C:20]=2[N:21]=1
Reactant: CNC1CCN(C)C1
Reactant: O=CC1CCN(c2nc(Cl)nc3scc(-c4ccccc4)c23)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: ClCCl
Product: CN1CCC(N(C)CC2CCN(c3nc(Cl)nc4scc(-c5ccccc5)c34)CC2)C1
Reaction time: 2 h

Procedure:
Sodium triacetoxyborohydride (1.54 g, 7.28 mmol) was added to a stirred solution of 1-(2-chloro-5-phenyl-thieno[2,3-d]pyrimidin-4-yl)piperidine-4-carbaldehyde (1.3 g, 3.64 mmol), N,N′-dimethyl-3-aminopyrrolidine (519 ul, 4.00 mmol) and acetic acid (240 ul, 4.00 mmol) in dry dichloromethane (20 ml) at room temperature. The solution was stirred for ˜2 h, after which time the reaction had reached completion. Water (20 ml) was added and the organic layer separated, the aqueous phase was extracted with dichloromethane (×3) and the combined organics washed with brine, then dried (MgSO4) and evaporated. The crude residue was purified by flash column chromatography (0 to 5% 7.0M NH3/MeOH in dichloromethane). N—[[1-(2-chloro-5-phenyl-thieno[2,3-d]pyrimidin-4-yl)-4-piperidyl]methyl]-N,1-dimethyl-pyrrolidin-3-amine was isolated as a pale yellow oil (1.25 g, 76%). LCMS: (M+H)+ 456.2, RT=2.99.