Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1>>[C:3]1([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][S:22]([C:19]1[CH:18]=[CH:17][C:16]([O:15][CH3:14])=[CH:21][CH:20]=1)(=[O:24])=[O:23]
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1ccccc1-c1ccccc1
Product: COc1ccc(S(=O)(=O)Nc2ccccc2-c2ccccc2)cc1

Procedure:
The title compound was prepared from 2-aminobiphenyl (Aldrich) and 4-methoxy-benzenesulfonyl chloride according to the method described in Example 1b.
Reaction SMILES: C1(C)C=CC=CC=1.[C:8]([C:11]1[S:12][CH:13]=[CH:14][CH:15]=1)(=O)[CH3:9].C[OH:17].[C:18](=O)([O:21]C)[O:19][CH3:20]>>[O:17]=[CH:9][CH:8]([C:11]1[S:12][CH:13]=[CH:14][CH:15]=1)[C:18]([O:19][CH3:20])=[O:21]
Reactant: COC(=O)OC
Reactant: CC(=O)c1cccs1
Reactant: CO
Solvent: Cc1ccccc1
Product: COC(=O)C(C=O)c1cccs1

Procedure:
510 ml of dimethyl carbonate and 1 500 ml of toluene were heated to 100° C. in a 2 L flask and a solution of 257 g of 2-acetylthiophene in 510 ml of dimethyl carbonate was then added dropwise within the space of 4 hours. The methanol which was formed in the reaction was distilled off as an azeotrope. 120 ml of conc. sulphuric acid were introduced, in 900 g of ice, into a 4 L flask and the cooled reaction mixture was added such that 40° C. was not exceeded. The mixture was then stirred and the pH was adjusted to pH 1. The phases were separated and the organic phase was extracted three times by shaking with an aqueous solution of sodium sulphate and then concentrated in vacuo. Vacuum distillation of the crude product yielded 278 g of methyl 3-oxo-(2-thiophenyl)propanoate as a transparent, slightly yellowish liquid (98% pure according to GC, 74% of theory).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([NH:11][Si](C)(C)C)[CH:4]=1.C1(O[C:23](Cl)=[S:24])C=CC=CC=1>C(#N)C>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([N:11]=[C:23]=[S:24])[CH:4]=1
Reactant: S=C(Cl)Oc1ccccc1
Reactant: COc1cc(N[Si](C)(C)C)nc(OC)c1
Solvent: CC#N
Product: COc1cc(N=C=S)nc(OC)c1
Yield: 43.6 %

Procedure:
To 300 ml of acetonitrile are added 45.0 g of 4,6-dimethoxy-2trimethylsilylaminopyridine and 35.0 g of phenylchlorothiocarbonate, followed by refluxing for 10 hours. The reaction solution is concentrated under reduced pressure to remove acetonitrile, and to the residue is added 300 ml of toluene. Insoluble product is filtered off, and the filtrate is concentrated under reduced pressure. The residue is purified by silica gel chromatography (eluent: ethyl acetate-hexane) to give 17.0 g of the title Compound. mp. 85°-86° C.
Reaction SMILES: [C:1]1([CH3:21])[CH:6]=[CH:5][C:4]([N:7]([CH2:9][CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]([F:20])([F:19])[F:18])=[N:15][CH:16]=2)N)=[CH:3][CH:2]=1.Cl.O.[NH:24]1[CH2:29][CH2:28][C:27](=O)[CH2:26][CH2:25]1>O1CCOCC1.C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>[CH3:21][C:1]1[CH:6]=[CH:5][C:4]2[N:7]([CH2:9][CH2:10][C:11]3[CH:16]=[N:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=3)[C:27]3[CH2:28][CH2:29][NH:24][CH2:25][C:26]=3[C:3]=2[CH:2]=1
Reactant: O=C1CCNCC1
Reactant: Cc1ccc(N(N)CCc2ccc(C(F)(F)F)nc2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc2c(c1)c1c(n2CCc2ccc(C(F)(F)F)nc2)CCNC1
Temperature: 100 °C

Procedure:
5-(2-(1-p-Tolylhydrazinyl)ethyl)-2-(trifluoromethyl)pyridine (88 mg, 0.29 mmol) was dissolved in 1,4-dioxane (2 mL) and 4-piperidone hydrate hydrochloride was added with one drop of TFA. The reaction mixture became acidic. The mixture was heated at 100° C. for 2 h. The reaction was monitored by TLC and LCMS. After completion of reaction, the mixture was diluted with sat. NaHCO3 solution and extracted with EtOAc. The organic extracts were dried over anhydrous sodium sulfate and concentrated. The compound was purified by reverse phase chromatography. 1HNMR (CD3OD, TFA salt) d (ppm): 8.20 (s, 1H), 7.60 (m, 2H), 7.25 (d, 1H), 7.18 (d, 1H), 6.98 (d, 1H), 4.40 (m, 4H), 3.50 (t, 2H), 3.20 (m, 2H), 2.82 (t, 2H), 2.40 (s, 3H).
Reaction SMILES: Cl[C:2]1[C:7]2[N:8]=[C:9]([CH3:11])[S:10][C:6]=2[C:5](B(O)O)=[CH:4][N:3]=1.Br[C:16]1[CH:17]=[N:18][CH:19]=[C:20]([CH3:22])[CH:21]=1.[NH2:23][C:24]1[N:25]=[C:26]([CH3:29])[S:27][CH:28]=1>>[CH3:11][C:9]1[S:10][C:6]2[C:5]([C:16]3[CH:17]=[N:18][CH:19]=[C:20]([CH3:22])[CH:21]=3)=[CH:4][N:3]=[C:2]([NH:23][C:24]3[N:25]=[C:26]([CH3:29])[S:27][CH:28]=3)[C:7]=2[N:8]=1
Reactant: Cc1nc2c(Cl)ncc(B(O)O)c2s1
Reactant: Cc1cncc(Br)c1
Reactant: Cc1nc(N)cs1
Product: Cc1cncc(-c2cnc(Nc3csc(C)n3)c3nc(C)sc23)c1

Procedure:
The title compound, MS: m/e=354.3 (M+H+), was prepared in accordance with the general method of example 2, step 1 and step 2 from 4-chloro-2-methyl-thiazolo[4,5-c]pyridine-7-boronic acid (Example D), 3-bromo-5-methylpyridine and 4-amino-2-methylthiazole (Example C).
Reaction SMILES: S(Cl)(Cl)=O.[N+:5]([C:8]1[CH:13]=[CH:12][C:11]([CH:14]=[CH:15][C:16]([OH:18])=[O:17])=[CH:10][CH:9]=1)([O-:7])=[O:6].[CH3:19]O>>[CH3:19][O:17][C:16](=[O:18])[CH:15]=[CH:14][C:11]1[CH:10]=[CH:9][C:8]([N+:5]([O-:7])=[O:6])=[CH:13][CH:12]=1
Reactant: CO
Reactant: O=C(O)C=Cc1ccc([N+](=O)[O-])cc1
Solvent: O=S(Cl)Cl
Product: COC(=O)C=Cc1ccc([N+](=O)[O-])cc1
Temperature: 40 °C
Reaction time: 1 h

Procedure:
Thionyl chloride (28.8 ml, 0.4 mol) was added dropwise to methanol (450 ml) at −10° C. temperature. To the obtained solution was added 3-(4-nitrophenyl)-acrylic acid (71) (38.63 g, 0.2 mol) and the reaction mixture was stirred at 0° C. for 3 hours, at ambient temperature for 24 hours and at 40° C. for 1 hour. The resulting precipitate was filtered, washed with methanol (2×10 ml) and dried affording the title compound in a form of yellow crystals (39.55 g, 96%). 1H NMR (DMSO-d6, HMDSO), δ: 3.69 (2H, br s); 3.77 (3H, s); 6.87 (1H, d, J=16.0 Hz); 7.67-8.39 (5H, m).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]1[N:11]=[CH:10][C:9]([C@@H:12]([NH:15][C:16]([C@H:18]2[CH2:20][C@@H:19]2[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:17])[CH2:13][OH:14])=[CH:8][CH:7]=1)[CH3:4].[CH3:27]I>CN(C=O)C.[Cl-].[Na+].O>[CH2:3]([O:5][C:6]1[N:11]=[CH:10][C:9]([C@@H:12]([NH:15][C:16]([C@H:18]2[CH2:20][C@@H:19]2[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:17])[CH2:13][O:14][CH3:27])=[CH:8][CH:7]=1)[CH3:4]
Reactant: CCOc1ccc([C@H](CO)NC(=O)[C@H]2C[C@@H]2c2ccccc2)cn1
Reactant: CI
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1ccc([C@H](COC)NC(=O)[C@H]2C[C@@H]2c2ccccc2)cn1
Reaction time: 0.5 h

Procedure:
NaH (60% suspension in mineral oil) (2.06 g, 51.5 mmol) was suspended in DMF and the reaction vessel was cooled in an ice bath. (1S,2S)-2-Phenyl-cyclopropanecarboxylic acid [(R)-1-(6-ethoxy-pyridin-3-yl)-2-hydroxy-ethyl]-amide (Compound 33) (15 g, 48 mmol) was dissolved in DMF (50 ml) and added drop wise to the sodium hydride suspension at 5-8 C over 20 minutes. The solution was stirred 30 minutes. Methyl iodide (3.30 ml, 53.0 mmol) dissolved in DMF (25 ml) was added drop wise at 5-12 C over 10 minutes and the mixture was stirred at 7-8 C for 30 minutes. The mixture was added to a brine solution and extracted with EtOAc. The organic layer was washed with more brine, dried (MgSO4) filtered and the solvent was evaporated off. The crude product was purified by silica gel chromatography (eluent EtOAc in heptanes 4:1). The fractions that contained the product was collected and the solvent was removed in vac. The residue was redissolved in THF (50 ml) EtOAc (100 ml) and heptanes (25 ml). The mixture was concentrated until 40 ml remained and cooled in ice. A white solid precipitated and was collected by filtration. Yield: 6.75 g (43%) of Compound 46. LC-MS (m/z) 341.2 (MH+). tR=0.64 min (method B).
Reaction SMILES: [CH3:1][N:2]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)[S:3]([C:6]1[CH:11]=[CH:10][C:9](Br)=[CH:8][CH:7]=1)(=[O:5])=[O:4].C(N(CC)CC)C.[C:29]([O:33][CH3:34])(=[O:32])[CH:30]=[CH2:31]>CC([O-])=O.CC([O-])=O.[Pd+2].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(#N)C>[CH3:1][N:2]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)[S:3]([C:6]1[CH:11]=[CH:10][C:9]([CH:31]=[CH:30][C:29]([O:33][CH3:34])=[O:32])=[CH:8][CH:7]=1)(=[O:5])=[O:4]
Reactant: C=CC(=O)OC
Reactant: COc1ccc(CN(C)S(=O)(=O)c2ccc(Br)cc2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)C=Cc1ccc(S(=O)(=O)N(C)Cc2ccc(OC)cc2)cc1
Temperature: 120 °C
Yield: 123.2 %

Procedure:
A mixture of N-methyl-N-(4-methoxybenzyl)-4-bromophenylsulfonamide (1.68 g, 4.54 mmol), Pd(OAc)2 (20 mg, 0.091 mmol), tri-o-tolylphosphine (55 mg, 0.18 mmol), triethylamine (1.25 mL), acetonitrile (2.5 mL) and methyl acrylate (0.83 mL, 9.08 mmol) were placed in a stainless steel bomb and heated to about 120° C. for 4 hours. The mixture was cooled to 0° C., the bomb was vented, and the solid reaction mixture was collected, washed with ether and dried to afford 2.1 g of crude product which was used directly in the next step without further purification.
Reaction SMILES: [O:1]=[C:2]1[N:6]2[CH2:7][S:8][CH2:9][CH:5]2[C:4](=[O:10])[N:3]1[C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]([C:21]#[N:22])=[CH:13][CH:12]=1.ClC1C=C(C=CC=1)C(OO)=[O:28]>C(Cl)Cl>[O:28]=[S:8]1[CH2:9][CH:5]2[C:4](=[O:10])[N:3]([C:11]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[C:14]([C:21]#[N:22])=[CH:13][CH:12]=3)[C:2](=[O:1])[N:6]2[CH2:7]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: N#Cc1ccc(N2C(=O)C3CSCN3C2=O)c2ccccc12
Solvent: ClCCl
Product: N#Cc1ccc(N2C(=O)C3CS(=O)CN3C2=O)c2ccccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 9.2 %

Procedure:
To a solution of 17B (62 mg, 0.2 mmol) in CH2Cl2 (1.5 mL) was added 3chloroperoxybenzoic acid (46 mg, 0.2 mmol). The reaction was stirred at RT for 2 h, then quenched with 5% aqueous Na2S2O3 and extracted with CH2Cl2 (2×) and EtOAc (2×). The combined organic extracts were washed with saturated aqueous NaHCO3, brine, dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give a crude product, which was chromatographed (silica gel) eluting with EtOAc/hexane (2:3) to give 6 mg of the title compound (reacemate) as a white solid. HPLC: 97% at 4.0 min (retention time) (Conditions: Zorbax SB C18 (4.6×75 mm); Eluted with 0% to 100% B, 8 min gradient. (A=90% H2O-10% MeOH-0.1% H3PO4 and B=10% H2O-90% MeOH-0.1% H3PO4); Flow rate at 2.5 mL/min. UV detection at 220 nm). MS (ES): m/z 326 [M+1]+.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:15]3[CH:16]=[N:17][N:18]([CH:20]4[CH2:22][CH2:21]4)[CH:19]=3)=[C:11](N)[CH:12]=2)[N:7]([C:23]([O:25][CH:26]([CH3:28])[CH3:27])=[O:24])[CH2:6][C@@H:5]1[CH3:29])(=[O:3])[CH3:2].C(N1C2C(=CC(C3C=CC(S(C)(=O)=O)=CC=3)=C([F:43])C=2)N(C(OC(C)C)=O)C[C@@H]1C)(=O)C>>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:15]3[CH:16]=[N:17][N:18]([CH:20]4[CH2:22][CH2:21]4)[CH:19]=3)=[C:11]([F:43])[CH:12]=2)[N:7]([C:23]([O:25][CH:26]([CH3:28])[CH3:27])=[O:24])[CH2:6][C@@H:5]1[CH3:29])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2cc(N)c(-c3cnn(C4CC4)c3)cc2N(C(=O)OC(C)C)C[C@@H]1C
Reactant: CC(=O)N1c2cc(F)c(-c3ccc(S(C)(=O)=O)cc3)cc2N(C(=O)OC(C)C)C[C@@H]1C
Product: CC(=O)N1c2cc(F)c(-c3cnn(C4CC4)c3)cc2N(C(=O)OC(C)C)C[C@@H]1C

Procedure:
Isopropyl (S)-4-acetyl-7-(1-cyclopropyl-1H-pyrazol-4-yl)-6-fluoro-3-methyl-3,4-dihydroquinoxaline-1(2H)-carboxylate was synthesized from isopropyl (S)-4-acetyl-6-amino-7-(1-cyclopropyl-1H-pyrazol-4-yl)-3-methyl-3,4-dihydroquinoxaline-1 (2H)-carboxylate according to the procedure described above for isopropyl (S)-4-acetyl-6-fluoro-3-methyl-7-(4-(methylsulfonyl)phenyl)-3,4-dihydroquinoxaline-1(2H)-carboxylate (Example 241). MS (ESI, pos. ion) m/z 401 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:11][N:10]=[C:9](O)[C:8]=2[CH:13]=1)([O-:3])=[O:2].P(Cl)(Cl)([Cl:16])=O>>[Cl:16][C:9]1[C:8]2[CH:13]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[CH:6][C:7]=2[O:11][N:10]=1
Reactant: O=[N+]([O-])c1ccc2onc(O)c2c1
Reactant: O=P(Cl)(Cl)Cl
Product: O=[N+]([O-])c1ccc2onc(Cl)c2c1
Temperature: 152.5 °C

Procedure:
A mixture of 5-nitro-1,2-benzisoxazol-3-ol (4.00 g, 0.0220 mol) and phosphorus oxychloride (40.0 mL, 65.8 g, 0.429 mol) is placed in a glass bomb, heated at 150-155° C. for two hours, cooled overnight, concentrated in vacuo, diluted with methylene chloride, and brought to about pH 8 with sodium hydrogen carbonate solution. The phases are separated. The organic phase is washed sequentially with water and brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo to obtain a residue. Column chromatography of the residue using silica gel and a methylene chloride/hexanes solution (1:1) gives the title product as an amber oil which is identified by NMR spectral analysis.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:17])[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[BH4-].[Na+].O>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:17])[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1
Reactant: O=C(Cc1ccc(Cl)cc1)c1ccc(Cl)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: OC(Cc1ccc(Cl)cc1)c1ccc(Cl)cc1
Temperature: 0 °C

Procedure:
A solution of 1,2-di(4-chlorophenyl)ethan-1-one (known compound) and sodium borohydride in methanol is stirred at ambient temperature for about three hours. After this time, the reaction mixture is cooled, and water is carefully added to destroy excess sodium borohydride. The mixture is cooled to 0° C. and neutralized with concentrated hydrochloric acid. The mixture is concentrated under reduced pressure to remove some of the methanol. The concentrate is taken up in ethyl acetate and washed with an aqueous solution saturated with sodium chloride. The organic layer is dried with sodium sulfate, filtered, and concentrated under reduced pressure, yielding the subject compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[CH:17])([CH3:4])([CH3:3])[CH3:2].[CH3:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)(=[O:28])=[O:27])=[CH:22][C:21]=1Br>>[C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[C:17][C:21]1[CH:22]=[C:23]([S:26]([N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)(=[O:28])=[O:27])[CH:24]=[CH:25][C:20]=1[CH3:19])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)N2CCOCC2)cc1Br
Reactant: C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Product: Cc1ccc(S(=O)(=O)N2CCOCC2)cc1C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Yield: 81 %

Procedure:
Following the general method as outlined in Intermediate 20, starting from (4-chloro-2-ethynyl-phenoxy)-acetic acid tert-butyl ester (Intermediate 3) and 1-(3-bromo-4-methylphenylsulfonyl)morpholine (Combiblocks), the title compound was obtained as a yellow sticky solid in 81% yield after purification by flash column chromatography (silica), eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([S:14]([CH3:17])(=[O:16])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Cl:28][C:29]1[CH:30]=[C:31]([CH2:35][CH2:36][C:37](OCC)=[O:38])[CH:32]=[N:33][CH:34]=1.C(OCC)(=O)C>C1COCC1.CCCCCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([S:14]([CH2:17][C:37](=[O:38])[CH2:36][CH2:35][C:31]3[CH:32]=[N:33][CH:34]=[C:29]([Cl:28])[CH:30]=3)(=[O:15])=[O:16])[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)CCc1cncc(Cl)c1
Reactant: CS(=O)(=O)N1CCN(c2ccc(Cl)cc2)CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C(CCc1cncc(Cl)c1)CS(=O)(=O)N1CCN(c2ccc(Cl)cc2)CC1
Reaction time: 0.67 h
Yield: 61.2 %

Procedure:
To a stirred solution of 1-(4-chlorophenyl)-4-(methylsulfonyl)piperazine (235 mg, 0.85 mmol) in dry THF (7.5 mL) at −10° C. under an argon atmosphere was added dropwise over 4 minutes a solution of LiHMDS (1.71 mL of a 1.0 M solution in THF, 1.71 mmol). The solution was then stirred at this temperature for 40 minutes. A solution of ethyl 3-(5-chloropyridin-3-yl)propanoate (201 mg, 0.94 mmol) in THF (1 mL) was then added dropwise via cannula over a period of 5 minutes. The reaction was stirred at −10° C. for an additional 30 minutes before being quenched with saturated aqueous ammonium chloride solution (5 mL). Volatiles were removed in vacuo, and the residue was extracted with CH2Cl2 (3×5 mL). The combined organic extracts were washed with water (10 mL) and brine (10 mL) before being dried, (MgSO4), filtered and concentrated in vacuo. Flash chromatography (silica gel, 50% ethyl acetate in hexane) gave the title compound (228 mg, 0.52 mmol) and recovered ethyl 3-(5-chloropyridin-3-yl)propanoate (74 mg, 0.35 mmol).
Reaction SMILES: Cl[C@@:2]([C:5]([OH:7])=[O:6])([CH3:4])[NH2:3].C(Cl)([Cl:10])=O.[O:12]1[CH2:16]CCC1>C1(C)C=CC=CC=1>[Cl:10][CH2:4][CH:2]1[C:5](=[O:6])[O:7][C:16](=[O:12])[NH:3]1
Reactant: C[C@@](N)(Cl)C(=O)O
Reactant: C1CCOC1
Reactant: O=C(Cl)Cl
Solvent: Cc1ccccc1
Product: O=C1NC(CCl)C(=O)O1

Procedure:
The title compound is prepared by the procedure of Example 50 using 1.24 g of 2-chloro-L-alanine, 16 ml of 1.93M phosgene in toluene and 55 ml of tetrahydrofuran to give 0.150 g of the desired product.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:17]=[CH:16][C:11]([C:12](OC)=[O:13])=[CH:10][CH:9]=2)=[CH:4][C:3]=1[C:18]1[N:19]=[CH:20][C:21]2[C:26]([CH:27]=1)=[C:25]([Cl:28])[CH:24]=[CH:23][C:22]=2F.[OH-:30].[Na+].[CH3:32][OH:33]>O>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([OH:30])=[O:13])=[CH:10][CH:9]=2)=[CH:4][C:3]=1[C:18]1[N:19]=[CH:20][C:21]2[C:26]([CH:27]=1)=[C:25]([Cl:28])[CH:24]=[CH:23][C:22]=2[O:33][CH3:32]
Reactant: [OH-]
Reactant: COC(=O)c1ccc(-c2cnc(N)c(-c3cc4c(Cl)ccc(F)c4cn3)c2)cc1
Reactant: CO
Agent: [Na+]
Solvent: O
Product: COc1ccc(Cl)c2cc(-c3cc(-c4ccc(C(=O)O)cc4)cnc3N)ncc12
Temperature: 50 °C

Procedure:
To a solution of methyl 4-[6-amino-5-(5-chloro-8-fluoroisoquinolin-3-yl)-pyridin-3-yl]-benzoate (0.13 g, 0.32 mmol) in methanol (5 mL) and water (0.5 mL) was added NaOH (0.24 g, 6 mmol), and the mixture was heated at 50° C. for 16 h. The solvents were evaporated at reduced pressure, and the residue was neutralized with acetic acid. The solid formed was filtered off and dried in vacuo to give the title compound. 1H NMR (400 MHz, DMSO-d6): δ=12.82 (very brs, 1H), 9.63 (s, 1H), 8.51 (d, J=2.4 Hz, 1H), 8.35 (s, 1H), 8.31 (d, J=2.4 Hz, 1H), 8.03-7.98 & 7.90-7.85 (AA′BB′, 4H), 7.92 (d, J=8.0 Hz, 1H), 7.27 (brs, 2H), 7.15 (d, J=8.0 Hz, 1H), 4.07 (s, 3H). MS(ES+): m/z=406.08/408.03 (100/53) [MH+]. HPLC: tR=3.00 min (polar—5 min, ZQ3).
Reaction SMILES: [NH2:1][C:2]1[S:6][CH:5]=[N:4][C:3]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].[CH3:12][C:13](=O)[CH2:14][CH2:15][C:16](=O)[CH3:17]>[O-]S(C(F)(F)F)(=O)=O.[Sc+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O>[CH3:17][C:16]1[N:1]([C:2]2[S:6][CH:5]=[N:4][C:3]=2[C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:13]([CH3:12])=[CH:14][CH:15]=1
Reactant: CCOC(=O)c1ncsc1N
Reactant: CC(=O)CCC(C)=O
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Sc+3]
Product: CCOC(=O)c1ncsc1-n1c(C)ccc1C
Temperature: 180 °C

Procedure:
A mixture of ethyl 5-aminothiazole-4-carboxylate (91.3 mg, 0.53 mmol), scandium (III) triflate (2.61 mg, 0.005 mmol) and 2,5-hexanedione (1.5 mL) was heated up to 180° C. for 1 h by microwave. The reaction was then concentrated and purified with silica gel chromatography to give a tan solid of ethyl 5-(2,5-dimethyl-1H-pyrrol-1-yl)thiazole-4-carboxylate (104 mg). 1H NMR (400 MHz, CDCl3) δ 8.82 (s, 1H), 5.92 (s, 2H), 4.25 (q, 2H), 2.01 (s, 6H), 1.20 (t, 3H). MS m/z 251.3 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[O:15][C:14]([C:17]([NH:19][C@@H:20]4[CH:25]5[CH2:26][CH2:27][N:22]([CH2:23][CH2:24]5)[CH2:21]4)=[O:18])=[CH:13][C:12]=3[CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH:28]1([C:32]([Cl:34])=[O:33])[CH2:31][CH2:30][CH2:29]1.C(N(CC)CC)C.O>C1COCC1>[ClH:34].[N:22]12[CH2:23][CH2:24][CH:25]([CH2:26][CH2:27]1)[C@@H:20]([NH:19][C:17]([C:14]1[O:15][C:16]3[C:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][C:32]([CH:28]5[CH2:31][CH2:30][CH2:29]5)=[O:33])[CH:3]=4)=[CH:9][CH:10]=[CH:11][C:12]=3[CH:13]=1)=[O:18])[CH2:21]2
Reactant: Nc1cccc(-c2cccc3cc(C(=O)N[C@H]4CN5CCC4CC5)oc23)c1
Reactant: O=C(Cl)C1CCC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: Cl
Product: O=C(N[C@H]1CN2CCC1CC2)c1cc2cccc(-c3cccc(NC(=O)C4CCC4)c3)c2o1

Procedure:
75 mg (0.21 mmol) of 7-(3-aminophenyl)-N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzofuran-2-carboxamide (Example 114), 37 mg (0.31 mmol) of cyclobutanecarbonyl chloride and 87 μl (0.62 mmol) of triethylamine are stirred in 2 ml of THF at RT overnight. After addition of water, the solvent is removed under reduced pressure. Purification takes place by preparative HPLC. The product is dissolved in methanol, and an excess of 1N hydrochloric acid is added. Removal of the solvent under reduced pressure and drying under high vacuum result in 57 mg (57% of theory) of the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH2:15][C:16]([OH:18])=O)[C:7]2[NH:8][C:9]3[C:14]([C:6]=2[CH2:5][CH2:4][O:3]1)=[CH:13][CH:12]=[CH:11][CH:10]=3.[CH2:19]([N:21](CC)[CH2:22]C)C.ClC(OCC)=O.CNC>O1CCCC1>[CH3:19][N:21]([CH3:22])[C:16](=[O:18])[CH2:15][C:2]1([CH3:1])[C:7]2[NH:8][C:9]3[C:14]([C:6]=2[CH2:5][CH2:4][O:3]1)=[CH:13][CH:12]=[CH:11][CH:10]=3
Reactant: CC1(CC(=O)O)OCCc2c1[nH]c1ccccc21
Reactant: CCN(CC)CC
Agent: CCOC(=O)Cl
Agent: CNC
Solvent: C1CCOC1
Product: CN(C)C(=O)CC1(C)OCCc2c1[nH]c1ccccc21
Temperature: -5 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid (15 g, 0.061 mole), prepared as described In Example 1, in dry tetrahydrofuran (300 ml), cooled to -5° C., is added triethylamine (18.5 g, 0.183 mole), followed by ethyl chloroformate (16.6 g, 0.153 mole). The mixture is stirred at -5° C. for 2 hr. This mixture, which now contains the mixed anhydride of the above starting material, is added dropwise to a cooled 40% aqueous solution of the amine, dimethylamine (225 ml). The resulting mixture is stirred at room temperature for one-half hour. Most of the tetrahydrofuran is evaporated, and the residue partitioned between chloroform and water. The organic phase is washed with water, dried over sodium sulfate, and evaporated under reduced pressure. The residue is subjected to chromatography on silica gel. Elution with 20% ethyl acetate in benzene, followed by crystallization of the eluate from ethyl acetate affords the title compound, m.p. 149°-151° C., νmaxCHCl3 3375, 1634 cm-1.
Reaction SMILES: S(Cl)(Cl)=O.O[CH:6]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:7][NH:8][C:9]1[NH:10][CH2:11][CH2:12][N:13]=1>>[C:14]1([CH:6]2[N:13]3[CH2:12][CH2:11][NH:10][C:9]3=[N:8][CH2:7]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: OC(CNC1=NCCN1)c1ccccc1
Solvent: O=S(Cl)Cl
Product: c1ccc(C2CN=C3NCCN32)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 80 parts thionylchloride (previously cooled to 0°C.) are added 10.15 parts 2-(β-hydroxy-phenethyl-amino)-2-imidazoline. After the addition is complete, the whole is stirred for 30 minutes at room temperature and further stirred and refluxed for 15 minutes. The solvent is evaporated. The residue is dissolved in 40 parts toluene and evaporated again. This treatment is repeated by using 40 parts methanol. The residue is then dissolved in 40 parts 2-propanol. To this solution is added a solution of 1.15 parts sodium metal in 40 parts 2-propanol. The whole is stirred and refluxed for one hour. The solvent is evaporated. The residue is dissolved in 150 parts water. The solution is filtered. The filtrate is alkalized with ammonium hydroxide and extracted three times with 40 parts ether and three times with 75 parts chloroform. The combined extracts are dried over potassium carbonate and evaporated. The solid residue is recrystallized from a mixture of 16 parts acetone and 16 parts 4-methyl-2-pentanone, yielding 2,3,5,6-tetrahydro-5-phenyl-1H-imidazo[1,2-a]imidazole; m.p. 167°-169.5°C.