Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:10])=[C:4]([C:7]([OH:9])=O)[S:5][CH:6]=1.S(Cl)(Cl)=O.CN(C=O)C.[NH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22](/[CH:29]=[CH:30]/[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[NH2:37])=[N:21]1.C(N(CC)CC)C>C1COCC1.ClCCl>[NH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22](/[CH:29]=[CH:30]/[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[NH:37][C:7]([C:4]2[S:5][CH:6]=[C:2]([Br:1])[C:3]=2[CH3:10])=[O:9])=[N:21]1
Reactant: Cc1c(Br)csc1C(=O)O
Reactant: Nc1ccccc1/C=C/c1n[nH]c2ccccc12
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Product: Cc1c(Br)csc1C(=O)Nc1ccccc1/C=C/c1n[nH]c2ccccc12
Yield: 23.3 %

Procedure:
In a similar manner to Example 29, 4-bromo-3-methylthiophene-2-carboxylic acid (0.10 g, 0.47 mmol) was treated with thionyl chloride (53 μL, 0.72 mmol), DMF (5.0 μL, 0.085 mmol) and dichloromethane (2.0 mL), followed by reacting with Compound 2 (0.10 g, 0.43 mmol), triethylamine (60 μL, 1.1 mmol) and THF (2.0 mL) to obtain Compound 353 (44 mg, 24%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.[C:11]1([CH3:19])[CH:16]=[CH:15][C:14]([Mg]Br)=[CH:13][CH:12]=1>O1CCCC1>[OH:10][C:8]([C:4]1[CH:3]=[C:2]([OH:1])[CH:7]=[CH:6][CH:5]=1)([C:14]1[CH:15]=[CH:16][C:11]([CH3:19])=[CH:12][CH:13]=1)[CH3:9]
Reactant: Cc1ccc([Mg]Br)cc1
Reactant: CC(=O)c1cccc(O)c1
Solvent: C1CCOC1
Product: Cc1ccc(C(C)(O)c2cccc(O)c2)cc1

Procedure:
By using 3′-hydroxyacetophenone (200 mg) and a 1 M solution of p-tolylmagnesium bromide in tetrahydrofuran (4.4 ml) as starting materials, the title compound (346.8 mg) was obtained in the same manner as that of Reference Example 69.
Reaction SMILES: C(OC([N:11]1[CH2:15][CH2:14][CH2:13][C@@H:12]1[CH2:16][C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([N:26](CC3C=CC=CC=3)CC3C=CC=CC=3)[CH:24]=2)[NH:19][CH:18]=1)=O)C1C=CC=CC=1>C(O)C.[OH-].[Pd+2].[OH-]>[NH2:26][C:23]1[CH:24]=[C:25]2[C:20](=[CH:21][CH:22]=1)[NH:19][CH:18]=[C:17]2[CH2:16][C@H:12]1[CH2:13][CH2:14][CH2:15][NH:11]1
Reactant: O=C(OCc1ccccc1)N1CCC[C@@H]1Cc1c[nH]c2ccc(N(Cc3ccccc3)Cc3ccccc3)cc12
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: Nc1ccc2[nH]cc(C[C@H]3CCCN3)c2c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 99.7 %

Procedure:
A mixture of (R)-3-(N-benzyloxycarbonylpyrrolidin-2-ylmethyl)-5-dibenzylamino-1H-indole (7.90 g, 14.91 mmol) and moist palladium (II) hydroxide on carbon (Pearlman's catalyst, 3.16 g) in absolute ethanol (100 mL) was shaken under a hydrogen atmosphere (3 atm) for 12 hours at room temperature. The resulting mixture was filtered through diatomaceous earth, and the filtrate was evaporated and dried under reduced pressure to afford the title compound as a white foam (3.20 g, 100%): 1H NMR (CD3OD) δ7.18 (d, J=8.5 Hz, 1H), 7.08 (s, 1H), 6.92 (d, J=2.0 Hz, 1H), 6.69 (dd, J=1.9 and 8.5 Hz, 1H), 3.81-3.69 (m, 1H), 3.30-2.95 (m, 4H), 2.09-1.55 (m, 4H); 13C NMR (CD3OD) δ140.1, 133.4, 129.1, 125.0, 114.6, 113.1, 109.8, 105.1, 62.1, 46.0, 31.1, 29.1, 24.3; LRMS (m/z, relative intensity) 215 (M+, 2), 198 (1) , 146 (100), 128 (7), 117 (9), 70 (60).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([O:16]CC2C=CC(OC)=CC=2)=[CH:12][C:11]=1[C:26](=O)[C:27]([CH3:32])([CH3:31])[CH2:28][CH2:29][CH3:30]>C1COCC1.C(O)(=O)C.[OH-].[OH-].[Pd+2]>[CH3:31][C:27]([CH3:32])([CH2:28][CH2:29][CH3:30])[CH2:26][C:11]1[CH:12]=[C:13]([OH:16])[CH:14]=[CH:15][C:10]=1[C:3]1[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=1[F:1]
Reactant: CCCC(C)(C)C(=O)c1cc(OCc2ccc(OC)cc2)ccc1-c1cc(OC)ccc1F
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCCC(C)(C)Cc1cc(O)ccc1-c1cc(OC)ccc1F
Reaction time: 17 h

Procedure:
1-(2′-Fluoro-5′-methoxy-4-((4-methoxybenzyl)oxy)-[1,1′-biphenyl]-2-yl)-2,2-dimethylpentan-1-one (43.3 mg) was dissolved in a mixed solution of THF (10 mL) and acetic acid (2 mL), and the reaction was performed in H-Cube having a 20% palladium hydroxide/carbon cartridge (70 mm) at 60° C., 40 atm, flow rate 1 ml/min for 17 hr. The solvent was evaporated under reduced pressure to give the title, compound. This compound was used for the next step without purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH2:9][S:10][CH2:11][CH2:12][NH2:13])=[N:5][CH:6]=[CH:7][CH:8]=1.[C:14]([N:22]=[C:23]=[S:24])(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(Cl)(Cl)Cl>[C:14]([NH:22][C:23]([NH:13][CH2:12][CH2:11][S:10][CH2:9][C:4]1[C:3]([O:2][CH3:1])=[CH:8][CH:7]=[CH:6][N:5]=1)=[S:24])(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COc1cccnc1CSCCN
Reactant: O=C(N=C=S)c1ccccc1
Solvent: ClC(Cl)Cl
Product: COc1cccnc1CSCCNC(=S)NC(=O)c1ccccc1

Procedure:
Treatment of 2-(3-methoxy-2-pyridylmethylthio)ethylamine with benzoyl isothiocyanate in refluxing chloroform yields N-benzoyl-N'-[2-(3-methoxy-2-pyridylmethylthio)ethyl]thiourea. The hydrobromide salt of this thiourea is refluxed with 1,3-dibromopropane in ethanol and the N-benzoyl groups removed by hydrolysis to yield 1,3-bis-[S-(N-(2-(3-methoxy-2-pyridylmethylthio)ethyl)isothioureido]propane tetrahydrobromide.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.[CH3:22][N:23]1[C:27]([CH3:28])=[CH:26][C:25]([C:29](Cl)=[O:30])=[N:24]1>>[CH3:22][N:23]1[C:27]([CH3:28])=[CH:26][C:25]([C:29]([N:1]2[CH2:2][CH2:3][C:4]3([O:11][C:10]4[C:12]5[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=4[S:8][CH2:7]3)=[CH:16][CH:15]=[CH:14][CH:13]=5)[CH2:5][CH2:6]2)=[O:30])=[N:24]1
Reactant: Cc1cc(C(=O)Cl)nn1C
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCNCC1)O2
Product: Cc1cc(C(=O)N2CCC3(CC2)CSC2=C(O3)c3ccccc3C(=O)C2=O)nn1C

Procedure:
Compound 45 was synthesized using spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, 1,5-dimethyl-1H-pyrazole-3-carbonyl chloride and conditions outlined in procedure N. M.p.=184-185° C.; 300 MHz 1H NMR (DMSO-d6) δ 8.04 (d, 1H), 7.80 (m, 1H), 7.65 (m, 1H), 7.46 (m, 1H), 6.42 (s, 1H), 3.80 (s, 3H), 3.47 (m, 2H), 2.98 (s, 2H), 2.26 (s, 3H), 2.18 (m, 2H), 1.90 (m 2H), 1.62 (brs, 2H); LCMS: 424 [M+H].
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[N:6][C:5](Br)=[CH:4][N:3]=1.[F:11][C:12]([F:27])([F:26])[C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:18]=1.C(=O)([O-])[O-].[K+].[K+].O>C1(C)C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd]>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[N:6][C:5]([C:15]2[CH:16]=[C:17]([C:19]([F:22])([F:20])[F:21])[CH:18]=[C:13]([C:12]([F:11])([F:27])[F:26])[CH:14]=2)=[CH:4][N:3]=1
Reactant: OB(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: N#Cc1nc(Br)cnc1N
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: N#Cc1nc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cnc1N

Procedure:
A stirred solution of 1.6 grams (0.008 mole) of 2-amino-3-cyano-5-bromopyrazine [prepared by the method of Taylor and Ray--JOC, 52, 3997 (1987)], 3.2 grams (0.012 mole) of 3,5-di(trifluoromethyl)phenylboronic acid [commercially available or prepared by the method of Thompson and Gaudino--JOC, 49, 5237 (1984)], 4.3 grams (0,031 mole) of potassium carbonate and 0.3 gram of tetrakis(triphenylphosphine)palladium(O) in 150 mL of toluene is heated at 90° C. for about 20 hours. After this time, the reaction mixture is stirred with 100 mL of water, and the organic layer is separated. The organic layer is concentrated under reduced pressure to a residue. The residue is subjected to column chromatography on silica gel. The product-containing fractions are combined and concentrated under reduced pressure, yielding 2-amino-3-cyano-5-[3,5-di(trifluoromethyl)phenyl]pyrazine.
Reaction SMILES: Cl[CH2:2]/[CH:3]=[CH:4]\[CH2:5]Cl.C[Si](C)(C)CCOC[N:13]1[C:17]2=[N:18][CH:19]=[CH:20][CH:21]=[C:16]2[CH2:15][C:14]1=[O:22].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[NH:13]1[C:17]2=[N:18][CH:19]=[CH:20][CH:21]=[C:16]2[C:15]2([CH2:5][CH:4]=[CH:3][CH2:2]2)[C:14]1=[O:22]
Reactant: ClC/C=C\CCl
Reactant: C[Si](C)(C)CCOCN1C(=O)Cc2cccnc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=C1Nc2ncccc2C12CC=CC2
Temperature: 45 °C
Reaction time: 1 h
Yield: 25.2 %

Procedure:
To a solution of cis-1,4-dichloro-2-butene (1.98 g, 15.8 mmol) and 1-{[2-(trimethylsilyl)ethoxy]methyl}-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one (3.49 g, 13.2 mmol) in DMF (175 mL) was added cesium carbonate (10.7 g, 32.9 mmol). After 24 h the reaction mixture was partitioned between Et2O (200 mL) and H2O (200 mL). The aqueous layer was extracted further with Et2O (2×200 mL). The combined organic layers were washed with H2O (2×100 mL), then brine (100 mL), dried over MgSO4, filtered, and concentrated under reduced pressure. To a solution of this material in dichloromethane (150 mL) was added trifluoroacetic acid (150 mL). After 1 h, the reaction was concentrated, dissolved in EtOH (150 mL) and 2N HCl (150 mL) was added. This mixture was heated at 45° C. for 48 h. The mixture was concentrated, diluted with saturated aqueous NaHCO3, and extracted with dichloromethane (2×). The combined organic layers were dried and concentrated. The crude product was purified by silica gel chromatography, eluting with a gradient of 0 to 5% methanol:dichloromethane to give the title compound (0.62 g). MS: m/z=187.1 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][NH:6][C:7]1[C:12]([NH:13][C:14](=O)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:11][CH:10]=[CH:9][N:8]=1)[CH3:2].[O-][Si]([O-])=O.[Mg+2]>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:22])[CH2:5][N:6]1[C:7]2=[N:8][CH:9]=[CH:10][CH:11]=[C:12]2[N:13]=[C:14]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH3:2]
Reactant: CCOC(=O)CNc1ncccc1NC(=O)c1ccccc1
Agent: O=[Si]([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCl
Product: CCOC(=O)Cn1c(-c2ccccc2)nc2cccnc21
Reaction time: 0.12 h
Yield: 38 %

Procedure:
N-[3-(benzoylamino)-2-pyridinyl]glycine ethyl ester, 10.32 g (0.034 mole) in two divided portions was heated in glass in a Wood's metal bath at 190° C. under a flow of nitrogen, one portion for 15 min and the other for 7 min. The green glassy residues were dissolved in methylene chloride, combined, and stirred together with 90 g of Florisil® for 1 hr. The mixture was filtered, and the filtrate evaporated to an oil, which crystallized. The solid was recrystallized from hexanes to give a crystalline solid, which was dried under high vacuum at room temperature overnight to give 3.67 g (38%) of crystals, m.p. 93°-95° C.
Reaction SMILES: [NH:1]([C:8]1[CH:9]=[C:10]2[C:15]3=[C:16]([CH2:18][CH2:19][CH2:20][N:14]3[CH2:13][C@@H:12]3[CH2:21][N:22](C(OC(C)(C)C)=O)[CH2:23][C@H:11]23)[CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[C:2]1([NH:1][C:8]2[CH:9]=[C:10]3[C:15]4=[C:16]([CH2:18][CH2:19][CH2:20][N:14]4[CH2:13][C@@H:12]4[CH2:21][NH:22][CH2:23][C@H:11]34)[CH:17]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1C[C@H]2CN3CCCc4cc(Nc5ccccc5)cc(c43)[C@H]2C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: c1ccc(Nc2cc3c4c(c2)[C@H]2CNC[C@H]2CN4CCC3)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 24.6 %

Procedure:
To a solution of (±)-cis-tert-butyl 2-anilino-5,6,8a,9,11,11a-hexahydro-4H-pyrido[3,2,1-ij]pyrrolo[3,4-c]quinoline-10(8H)-carboxylate (80 mg, 0.20 mmol) in 5 ml of CH2Cl2 was added 1 ml of trifluoroacetic acid and the reaction was stirred at room temperature for 3 h. The volatiles were removed under reduced pressure and the residue was purified by prep HPLC (C18 reverse phase column, elution with a H2O/CH3CN gradient with 0.5% TFA). Product-containing fractions were combined, concentrated and partitioned between chloroform and saturated aqueous sodium carbonate. The organics were washed with brine, dried (K2CO3) and concentrated in vacuo to afford 15 mg (23%) of the title compound of EXAMPLE 17. 1H NMR (CDCl3): δ 7.18 (app t, 2H, J=7.8 Hz), 6.84 (app d, 2H, J=8.0 Hz), 6.78-6.72 (m, 1H), 6.67 (s, 1H), 6.65 (s, 1H), 5.46 (s, 1H), 3.45-3.30 (m, 2H), 3.24-3.17 (m, 1H), 3.08-3.00 (m, 2H), 2.97-2.85 (m, 1H), 2.78-2.55 (broad m, 6H), 2.05-1.93 (m, 2H). LRMS (ES)+: 306.3 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:10]([I:11])=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:12][O:13][C:14]([C@H:16]1[CH2:19][C@@H:18](O)[CH2:17]1)=[O:15].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH3:12][O:13][C:14]([C@H:16]1[CH2:19][C@H:18]([N:8]2[C:4]3[N:5]=[CH:6][N:7]=[C:2]([Cl:1])[C:3]=3[C:10]([I:11])=[CH:9]2)[CH2:17]1)=[O:15]
Reactant: COC(=O)[C@H]1C[C@@H](O)C1
Reactant: Clc1ncnc2[nH]cc(I)c12
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)[C@H]1C[C@H](n2cc(I)c3c(Cl)ncnc32)C1
Temperature: 75 °C

Procedure:
To a mixture of 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (prepared according to: L. B. Townsend et al., J. Med. Chem. 1990, 33 (7), 1984-92) (280 mg, 1.00 mmol), cis-3-hydroxycyclobutanecarboxylic acid methyl ester (trans/cis=1:5) (180 mg, 1.38 mmol), and PS—PPh3 (loading 2.02 mmol/g; 951 mg, 2.02 mmol) in dry THF (10 mL), cooled by ice/water, was added DIAD (295 μL, 303 mg, 1.50 mmol), then the cooling bath was removed, and the mixture was vortexed (220 rpm) for 2 d. The resin was filtered off and washed thoroughly with THF (7480 mL), the filtrate and washings were combined, concentrated, and chromatographed on silica gel [Jones Flashmaster, 20 g/70 mL cartridge, eluting with CH2Cl2 (1-14)→5% EtOAc in CH2Cl2 (15-30)], fractions containing product were combined and chromatographed again under the same conditions. This material was suspended in iPrOH (≈1.5 mL), heated to 75° C. for 10 min and cooled to −20° C. for 2 h. The solid was filtered off, washed with cold (−20° C.) iPrOH, and dried in vacuo, giving the title compound as white solid, trans/cis=5:1. 1H NMR (CDCl3, 400 MHz) δ 2.83-2.97 (m, 4H), 3.23-3.32 (m, 1H), 3.79 (s, 3H), 5.50 (quint, J=8.7 Hz, 1H), 7.51 (s, 1H), 8.61 (s, 1H). MS (ES+): m/z 391.9/393.9 (100/35) [MH+]. HPLC: tR=3.5 min (OpenLynx, polar—5 min).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[CH2:11][C:10]([CH:13]3[CH2:15][CH2:14]3)([F:12])[CH2:9]2)[CH:5]=[C:4]([Cl:16])[N:3]=1.[CH3:17][C:18]1[NH:22][N:21]=[C:20]([NH2:23])[CH:19]=1.CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.C([O-])([O-])=O.[Na+].[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[Cl:16][C:4]1[N:3]=[C:2]([NH:23][C:20]2[NH:21][N:22]=[C:18]([CH3:17])[CH:19]=2)[CH:7]=[C:6]([N:8]2[CH2:11][C:10]([CH:13]3[CH2:15][CH2:14]3)([F:12])[CH2:9]2)[CH:5]=1
Reactant: FC1(C2CC2)CN(c2cc(Cl)nc(Cl)c2)C1
Reactant: Cc1cc(N)n[nH]1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Cc1cc(Nc2cc(N3CC(F)(C4CC4)C3)cc(Cl)n2)[nH]n1
Temperature: 140 °C
Reaction time: 0.25 h
Yield: 36.5 %

Procedure:
Nitrogen was bubbled through a mixture of 2,6-Dichloro-4-(3-cyclopropyl-3-fluoroazetidine-1-yl)pyridine (1.0 g, 3.83 mmol), 5-methyl-1H-pyrazol-3-amine (0.7 g, 3.85 mmol), tris-(dibenzylideneacetone)dipalladium(0) (Pd2dba2, 180 mg, 0.2 mmol), 9,9-dimethyl-4,5-bis(diphenyl-phosphino)xanthene (xantphos, 220 mg, 0.38 mmol), Na2CO3 (570 mg, 5.4 mmol), and 1,4-dioxane (12 mL) for about 15 minutes in a microwave vial. The vial was capped and heated in the microwave to 140° C. for 45 minutes and then to 170° C. for 15 minutes. The reaction mixture was filtered through Celite and rinsed with 1,4-dioxane. The solvent was removed under reduced pressure and the residue was dissolved in methanol/CH2Cl2 (1:1, 50 mL). Silica (2.5 g) was added and the solvents were removed under reduced pressure and the residue was brought on a column (100 mL silica in CH2Cl2/3% 2-propanol). The column was eluted with a gradient of 2-propanol (3-5%) in CH2Cl2. The fractions that contained the product (running with TLC RF=0.4 (SiO2, CH2Cl2/5% 2-propanol)) were pooled and concentrated to yield 450 mg (37%) of the title compound with 84/90% purity (HPLC, 215/254 nm). 1H-NMR (300 MHz, DMSO-d6): δ 11.74 (s, 1H); 9.02 (s, 1H); 6.38 (s, 1H); 5.88 (s, 1H); 5.84 (s, 1H); 3.94-3.78 (m, 4H); 2.15 (s, 3H); 1.42-1.03 (m, 1H); 0.62-0.57 (m, 2H); 0.44-0.40 (m, 2H) ppm.
Reaction SMILES: [Br:1][C:2]1[C:6]([N+:7]([O-:9])=[O:8])=[C:5](Br)[N:4]([CH2:11][CH2:12][CH2:13][OH:14])[N:3]=1.[CH2:15]([NH2:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CCO>[CH2:15]([NH:22][C:5]1[N:4]([CH2:11][CH2:12][CH2:13][OH:14])[N:3]=[C:2]([Br:1])[C:6]=1[N+:7]([O-:9])=[O:8])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: NCc1ccccc1
Reactant: O=[N+]([O-])c1c(Br)nn(CCCO)c1Br
Solvent: CCO
Product: O=[N+]([O-])c1c(Br)nn(CCCO)c1NCc1ccccc1

Procedure:
A mixture of 3-(3,5-dibromo-4-nitropyrazol-1-yl)propan-1-ol (3-2) (17.1 g, 52 mmol), EtOH (100 ml) and benzylamine (27.9 g, 260 mmol) was refluxed for 15 hours. The reaction medium was concentrated to the maximum under reduced pressure. The highly viscous residue was suspended in EtOAc (100 ml) and EtOH (100 ml). The organic phase was washed with NaCl solution (10%, 100 ml) and then dried over Na2SO4. After evaporating off the solvent under reduced pressure, an orange-colored oil was obtained (13.6 g), which was subsequently purified by column chromatography (gradient: 10%/90% EtOAc/hexane to 40%/60% EtOAc/hexane) in order to obtain, after evaporating off the solvent, the 3-(5-benzylamino-3-bromo-4-nitropyrazol-1-yl)propan-1-ol in the form of a yellow solid (8.8 g, 48%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([P:9]([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12])=[CH:5][CH:4]=1.[C:16]1(O)[CH:21]=CC=[CH:18][CH:17]=1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([P:9]([O:13][C:14]2[CH:18]=[CH:17][CH:16]=[CH:21][CH:15]=2)[O:10][CH2:11][CH3:12])=[CH:7][CH:8]=1
Reactant: Oc1ccccc1
Reactant: CCOP(OCC)c1ccc(OC)cc1
Product: CCOP(Oc1ccccc1)c1ccc(OC)cc1
Temperature: 110 °C

Procedure:
113 g (0.496 mol) of diethyl 4-methoxyphenylphosphonite and 46.6 g (0.496 mol) of phenol were mixed and heated with stirring to 110° C. at 350-400 mbar. Ethanol distilled off during this via a small column. The temperature was then increased stepwise to 150° C., and the vacuum was simultaneously increased to 100 mbar. After completion of the reaction, the batch was cooled and distilled. 105 g were obtained having a boiling point of 159° C. at 0.4 mbar. The yield was thus 77% of theory.
Reaction SMILES: [C:1]([Si:5]([CH3:21])([CH3:20])[O:6][CH2:7][CH2:8][N:9]1[C:17]2[C:12](=[CH:13][C:14]([CH3:19])=[C:15]([NH2:18])[CH:16]=2)[CH:11]=[CH:10]1)([CH3:4])([CH3:3])[CH3:2].[F:22][C:23]1[CH:28]=[CH:27][C:26]([C@@H:29]2[CH2:34][C:33](=[O:35])[NH:32][CH:31]=[C:30]2[C:36](Cl)=[O:37])=[CH:25][CH:24]=1>ClCCl.C(N(CC)CC)C.CN(C1C=CN=CC=1)C>[C:1]([Si:5]([CH3:21])([CH3:20])[O:6][CH2:7][CH2:8][N:9]1[C:17]2[C:12](=[CH:13][C:14]([CH3:19])=[C:15]([NH:18][C:36]([C:30]3[C@H:29]([C:26]4[CH:27]=[CH:28][C:23]([F:22])=[CH:24][CH:25]=4)[CH2:34][C:33](=[O:35])[NH:32][CH:31]=3)=[O:37])[CH:16]=2)[CH:11]=[CH:10]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C1C[C@@H](c2ccc(F)cc2)C(C(=O)Cl)=CN1
Reactant: Cc1cc2ccn(CCO[Si](C)(C)C(C)(C)C)c2cc1N
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc2ccn(CCO[Si](C)(C)C(C)(C)C)c2cc1NC(=O)C1=CNC(=O)C[C@H]1c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
1-[2-(tert-Butyl-dimethyl-silanyloxy)-ethyl]-5-methyl-1H-indol-6-ylamine was dissolved in 10 ml dichloromethane and 0.25 ml triethylamine. The solution was cooled to 0° C. and 150 mg of (S)-4-(4-fluoro-phenyl)-6-oxo-1,4,5,6-tetrahydro-pyridine-3-carboxylic acid chloride in 1.5 ml dichloromethane was added. The resulting mixture was stirred at 0° C. for one hour, then at room temperature for two hours. DMAP (100 mg) was added and the mixture stirred for another hour. The reaction mixture was then partitioned between pH 7 phosphate buffer and ethyl acetate. The organic layer was dried over sodium sulfate, filtered, concentrated under reduced pressure, and the residue purified by flash chromatography to give 70 mg of (S)-4-(4-fluoro-phenyl)-6-oxo-1,4,5,6-tetrahydro-pyridine-3-carboxylic acid {1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-5-methyl-1H-indol-6-yl}-amide e/z 522 (M+H).
Reaction SMILES: [K].[O-][CH2:3][CH2:4]CC.[CH3:7][S:8][C:9]1[N:10]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:11](=[O:20])[CH:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:13]=1.C(I)C>O1CCCC1.C(OCC)(=O)C>[CH2:3]([C:12]1([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:11](=[O:20])[N:10]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:9]([S:8][CH3:7])=[N:13]1)[CH3:4]
Reactant: CSC1=NC(c2ccccc2)C(=O)N1Nc1ccccc1
Reactant: CCCC[O-]
Agent: [K]
Solvent: C1CCOC1
Solvent: CCI
Solvent: CCOC(C)=O
Product: CCC1(c2ccccc2)N=C(SC)N(Nc2ccccc2)C1=O

Procedure:
0.55 g of potassium ten-butoxide is added to a solution of 1.5 g (5.05 mmol of 2-methylthio-4-phenyl-1-phenylamino-2-imidazolin-5-one (Compound 5) in 50 ml of anhydrous tetrahydrofuran. The mixture is left to react for 30 minutes at more temperature and then 0.8 g (5.05 mmol) of ethyl iodide is added. The mixture is left to react for 1 hour at room temperature. The mixture is diluted with 150 ml of ethyl acetate. The solution is washed with water and then concentrated under reduced pressure. The product is purified by chromatography on a silica column (Merck 60H silica; eluent: 25% ethyl acetate/75% heptane). 0.65 g of Compound 48 is obtained in the form of a beige powder melting at 147° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][C:7](=O)[O:8]2.CO[CH2:16][N:17](CC1C=CC=CC=1)[CH2:18][Si](C)(C)C>>[CH3:1][O:2][C:3]1[C:4]2[C@@H:5]3[CH2:18][NH:17][CH2:16][C@@H:6]3[CH2:7][O:8][C:9]=2[CH:10]=[CH:11][CH:12]=1
Reactant: COc1cccc2oc(=O)ccc12
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Product: COc1cccc2c1[C@@H]1CNC[C@@H]1CO2

Procedure:
From 5-methoxycoumarin and N-methoxymethyl-N-trimethylsilylmethyl-benzylamine in an analogous manner as described in Examples 1A-C. 1H NMR (300 MHz, CDCl3) δ 2.55 (m, 1H), 2.67 (dd, 1H), 2.80 (dd, 1H), 3.21 (q, 1H), 3.32 (dd, 1H), 3.62 (dd, 1H), 3.70 (m, 1H), 3.81 (s, 3H), 4.10 (dd, 1H), 6.46 (d, 1H), 6.55 (d, 1H), 7.17 (t, 1H).
Reaction SMILES: [C:1]([OH:9])(=O)/[C:2](=[C:4](\[CH:6]=[O:7])/[Cl:5])/[Cl:3].[C:10]([CH2:12][C:13]([NH2:15])=[O:14])#[N:11].[OH-].[Na+].Cl>CO>[C:10]([CH:12]([CH:1]1[C:2]([Cl:3])=[C:4]([Cl:5])[C:6](=[O:7])[O:9]1)[C:13]([NH2:15])=[O:14])#[N:11]
Reactant: O=C/C(Cl)=C(/Cl)C(=O)O
Reactant: N#CCC(N)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: N#CC(C(N)=O)C1OC(=O)C(Cl)=C1Cl
Temperature: 25 °C
Yield: 17.8 %

Procedure:
Mucochloric acid (15.1 g) and 2-cyanoacetamide (7.53 g) were dissolved in methanol (53.6 ml), and 2.5N aqueous sodium hydroxide solution (53.6 ml) was added dropwise with stirring under ice-cooling. The mixture was allowed to warm to room temperature, and further stirred at room temperature for 3 hr. The reaction mixture was poured into 1N hydrochloric acid containing ice water, methanol was evaporated under reduced pressure, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was crystallized from ethanol-diisopropyl ether to give the title compound (3.74 g) as pale-brown crystals.