Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](Cl)=[N:6][CH:7]=1.[N:9]1([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1>O1CCOCC1.O.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[N:4][C:5]([N:12]2[CH2:11][CH2:10][N:9]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:14][CH2:13]2)=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Clc1ncc(Br)cn1
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCN(c2ncc(Br)cn2)CC1
Temperature: 25 °C
Yield: 58 %

Procedure:
A mixture of 5-bromo-2-chloropyrimidine (5.17 mmol) and 1,1-dimethylethyl 1-piperazinecarboxylate (11.4 mmol) in 1,4-dioxane (10 ml) was heated at reflux for 2 hours. After cooling to room temperature, the reaction mixture was diluted with water (100 ml) and ethyl acetate (100 ml). Separation of the organic layer, drying (MgSO4), filtration and concentration in vacuo provided a residue which was purified by silica gel chromatography (40 g silica gel, CHCl3/EtOAc) to give the title compound as a white solid (58%). ESMS [M+H-Boc]+: 245.0/243.0.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5](Br)[CH:6]=[CH:7][CH:8]=1.[Mg].Br[CH:14]([CH3:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16].O>O1CCCC1.[Cl-].[Zn+2].[Cl-].CCOCC>[CH2:18]([O:17][C:15](=[O:16])[CH:14]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:11])([F:10])[F:1])[CH:4]=1)[CH3:20])[CH3:19]
Reactant: CCOC(=O)C(C)Br
Reactant: FC(F)(F)c1cccc(Br)c1
Agent: [Cl-]
Agent: [Mg]
Agent: [Zn+2]
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCOC(=O)C(C)c1cccc(C(F)(F)F)c1
Temperature: 55 °C

Procedure:
3-Trifluoromethylbromobenzene 50 (0.2 mol) was dissolved in dry tetrahydrofuran (100 mL). A small amount of magnesium metal was added and the mixture was warmed until reaction commenced. Additional magnesium (0.2 mol) was added. The mixture was maintained at reflux until the magnesium was consumed. A solution of anhydrous zinc chloride (0.2 mol) in tetrahydrofuran (50 mL) was added. The mixture was maintained at 55° C. for 2 hours, and then ethyl 2-bromopropionate (0.2 mol) was added. The mixture was maintained at 55° C. and the progress of the reaction was monitored by TLC. When the reaction was complete, the mixture was cooled and added to water and ether. The organic layer was dried and concentrated, and the residue was chromatographed to afford 2-(3-trifluoromethyl-phenyl)-propionic acid ethyl ester 51.
Reaction SMILES: CC(C)([O-])C.[K+].[CH2:7]([O:9][C:10](=[O:30])[CH2:11][CH2:12][N:13]([C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21])[CH2:14][C:15](OCC)=[O:16])[CH3:8].C(O)(=O)C>C1(C)C=CC=CC=1>[CH2:7]([O:9][C:10]([CH:11]1[C:15](=[O:16])[CH2:14][N:13]([C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:21])[CH2:12]1)=[O:30])[CH3:8]
Reactant: CCOC(=O)CCN(CC(=O)OCC)C(=O)OCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CCOC(=O)C1CN(C(=O)OCc2ccccc2)CC1=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a suspension of potassium t-butoxide (2.52 g, 22.4 mmol, 1.4 equiv.) in toluene (50 mL) at 0° C. under nitrogen, was added diester 70 (5.41 g, 16 mmol) in toluene (10 mL) over a 10 min period. The solution was stirred for 30 min at 0° C. and 2 mL of glacial acetic acid was added, immediately followed by 10 g of NaH2PO4.H2O in 100 mL of ice-cold water. The resultant mixture was extracted with chloroform (3×150 mL), and the combined organic extracts were washed twice with phosphate buffer (2×25 mL, pH=7.0), dried over anhydrous sodium sulfate and evaporated to dryness. The residue was dissolved in toluene (200 mL), cooled to 0° C., and extracted with cold pH 9.5 carbonate buffer (3×150 mL). The aqueous extracts were converted to pH 3 with phosphoric acid, and extracted with chloroform (5×125 mL) which were combined, dried, and evaporated to a afford keto ester 71 (2.2 g, 42%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=2)[C:5]([C:21](O)=[O:22])=[N:6][C:7]=1[C:8]([N:10]1[CH2:15][CH2:14][CH:13]([N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:12][CH2:11]1)=[O:9].[C:34]([O:38][C:39]([N:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1)=[O:40])([CH3:37])([CH3:36])[CH3:35].CCN(CC)CC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:34]([O:38][C:39]([N:41]1[CH2:46][CH2:45][N:44]([C:21]([C:5]2[C:4]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:32])([F:33])[F:31])[CH:25]=3)=[CH:3][C:2]([CH3:1])=[C:7]([C:8]([N:10]3[CH2:15][CH2:14][CH:13]([N:16]4[CH2:17][CH2:18][CH2:19][CH2:20]4)[CH2:12][CH2:11]3)=[O:9])[N:6]=2)=[O:22])[CH2:43][CH2:42]1)=[O:40])([CH3:37])([CH3:35])[CH3:36]
Reactant: Cc1cc(-c2cccc(C(F)(F)F)c2)c(C(=O)O)nc1C(=O)N1CCC(N2CCCC2)CC1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cc(-c2cccc(C(F)(F)F)c2)c(C(=O)N2CCN(C(=O)OC(C)(C)C)CC2)nc1C(=O)N1CCC(N2CCCC2)CC1

Procedure:
In analogy to the procedure described for the preparation of example 1, 5-methyl-6-(4-pyrrolidin-1-yl-piperidine-1-carbonyl)-3-(3-trifluoromethyl-phenyl)-pyridine-2-carboxylic acid (example 47) was reacted with piperazine-1-carboxylic acid tert-butyl ester, Et3N and HATU in DMF to give the title compound as light yellow solid. MS: 630.3 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]([O:19][CH3:20])([C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:17][CH3:18])[CH:13]=2)[CH:8]=1)[CH:4]([OH:6])[CH3:5].[C:21]1([CH3:31])[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1>N1C=CC=CC=1>[C:21]1([CH3:31])[CH:26]=[CH:25][C:24]([S:27]([O:6][CH:4]([CH3:5])[C:3]([O:19][CH3:20])([O:2][CH3:1])[C:7]2[CH:16]=[CH:15][C:14]3[C:9](=[CH:10][CH:11]=[C:12]([O:17][CH3:18])[CH:13]=3)[CH:8]=2)(=[O:29])=[O:28])=[CH:23][CH:22]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1ccc2cc(C(OC)(OC)C(C)O)ccc2c1
Solvent: c1ccncc1
Product: COc1ccc2cc(C(OC)(OC)C(C)OS(=O)(=O)c3ccc(C)cc3)ccc2c1
Temperature: 10 °C
Reaction time: 8 h

Procedure:
The oil, 1,1-dimethoxy-1-(6-methoxy-2-naphthyl) propan-2-ol, prepared in Example 29 is dissolved in 60 ml of pyridine and cooled to 10° C. Then 13 g of p-toluenesulfonyl chloride is added and the reaction mixture is stirred to dissolve the p-toluenesulfonyl chloride. The reaction mixture is allowed to stand overnight and the precipitation of pyridine hydrochloride is observed. The reaction mixture is poured into 7 volumes of water and extracted with ethyl ether. The ethereal layer is washed with dilute hydrochloric acid and then with dilute sodium hydroxide. The ethereal extract is dried over magnesium sulfate and evaporated to yield 1,1-dimethoxy-1-(6-methoxy-2-naphthyl)prop-2-yl p-toluenesulfonate, as an oil, [which is characterized by an NMR spectra in duterochloroform of τ=8.86 (doublet, J=2.5), 7.57, 6.82, 6.74, 6.09, 4.87 (quartet, J=2.5), 2.2-3.0 (multiplet)].
Reaction SMILES: [F:1][C:2]1[C:3]2[O:28][N:27]=[C:26]([C:29]3[N:30]([CH3:34])[CH:31]=[CH:32][N:33]=3)[C:4]=2[CH:5]=[C:6]2[C:19]=1[N:18]1[CH2:20][C@@H:21]([CH3:25])[O:22][C@@H:23]([CH3:24])[C@H:17]1[C:8]1([C:13](=[O:14])[NH:12][C:11](=[O:15])[NH:10][C:9]1=[O:16])[CH2:7]2>C(O)C>[F:1][C:2]1[C:3]2[O:28][N:27]=[C:26]([C:29]3[N:30]([CH3:34])[CH:31]=[CH:32][N:33]=3)[C:4]=2[CH:5]=[C:6]2[C:19]=1[N:18]1[CH2:20][C@@H:21]([CH3:25])[O:22][C@@H:23]([CH3:24])[C@@H:17]1[C:8]1([C:13](=[O:14])[NH:12][C:11](=[O:15])[NH:10][C:9]1=[O:16])[CH2:7]2
Reactant: C[C@@H]1CN2c3c(cc4c(-c5nccn5C)noc4c3F)CC3(C(=O)NC(=O)NC3=O)[C@@H]2[C@H](C)O1
Solvent: CCO
Product: C[C@@H]1CN2c3c(cc4c(-c5nccn5C)noc4c3F)CC3(C(=O)NC(=O)NC3=O)[C@H]2[C@H](C)O1
Yield: 85.4 %

Procedure:
A solution of (2R,4S,4aR)-rel-11-fluoro-2,4-dimethyl-8-(1-methyl-1H-imidazol-2-yl)-2,4,4a,6-tetrahydro-1H,1′H-spiro[isoxazolo[4,5-g][1,4]oxazino[4,3-a]quinoline-5,5′-pyrimidine]-2′,4′,6′(3′H)-trione (Example 68, 50 mg, 0.11 mmol) in ethanol (40 ml) was heated to reflux for 4 days. The solvent was removed and the residue was triturated with methanol. The resulting solid was filtered, washed with methanol, and dried to give 44 mg of product.
Reaction SMILES: C([Li])CCC.[CH2:6]([N:8]([CH2:11][C:12]#[CH:13])[CH2:9][CH3:10])[CH3:7].[CH3:14][N:15]1[C:23]2[N:22]=[CH:21][N:20]([CH2:24][CH2:25][CH3:26])[C:19]=2[C:18](=[O:27])[N:17]([CH2:28][CH2:29][CH2:30][CH2:31][C:32](=[O:34])[CH3:33])[C:16]1=[O:35].Cl>CCCCCC.O1CCCC1>[CH2:6]([N:8]([CH2:9][CH3:10])[CH2:11][C:12]#[C:13][C:32]([OH:34])([CH3:33])[CH2:31][CH2:30][CH2:29][CH2:28][N:17]1[C:18](=[O:27])[C:19]2[N:20]([CH2:24][CH2:25][CH3:26])[CH:21]=[N:22][C:23]=2[N:15]([CH3:14])[C:16]1=[O:35])[CH3:7]
Reactant: CCCn1cnc2c1c(=O)n(CCCCC(C)=O)c(=O)n2C
Reactant: C#CCN(CC)CC
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCn1cnc2c1c(=O)n(CCCCC(C)(O)C#CCN(CC)CC)c(=O)n2C
Temperature: -70 °C
Reaction time: 1 h

Procedure:
32.4 ml (52 mmol) of a 1.6 M solution of n-butyllithium in n-hexane was added dropwise in 30 minutes to 5.8 g (52 mmol) of N,N-diethyl-2-propynylamine from stage C1) dissolved in 40 ml of tetrahydrofuran at between -60° C. and -65° C. The mixture was stirred at -70° C. for one hour and then warmed to room temperature, and a solution of 12.3 g (40 mmol) of 3-methyl-1-(5-oxohexyl)-7-propylxanthine in 60 ml of tetrahydrofuran was added dropwise over the course of 20 minutes, during which the temperature of the reaction mixture rose to 35° C. After stirring at room temperature for four hours, 100 ml of cold 1 N hydrochloric acid were added, the mixture was extracted by shaking several times with dichloromethane, the aqueous phase was made alkaline with sodium carbonate, the reaction product was extracted with dichloromethane, and drying of the sodium sulfate was followed by concentration under reduced pressure. The oily residue was purified by filtration through a silica gel column in chloroform/methanol (19:1) as eluent.
Reaction SMILES: Cl.[NH:2]1[CH2:8][CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C([O-])(=O)C.[Na+].Cl[C:15]([O:17][CH2:18][CH3:19])=[O:16]>O>[N:2]1([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:8][CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1
Reactant: CCOC(=O)Cl
Reactant: C1CNCCNC1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CCOC(=O)N1CCCNCC1
Yield: 67.1 %

Procedure:
2N Hydrochloric acid was added to a solution of 1.10 g of homopiperazine in 15 ml of water at room temperature until a pH of 2 was attained. Then, 40% aqueous sodium acetate and 1.28 g of ethyl chloroformate were added alternately in portions within the pH range of 2.0 to 3.5, and the resultant mixture was stirred at room temperature for 2 hours. The reaction mixture was washed with ethyl acetate, and the aqueous layer was saturated with potassium carbonate and extracted with ethyl acetate. The organic layer was washed with saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 1.27 g of ethyl 1-homopiperazinecarboxylate.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:33][CH2:34][C:35]([O:37]CC)=[O:36])[C:9]([C:11]1[CH:32]=[CH:31][C:14]2[N:15]([CH3:30])[C:16]([CH2:18][N:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27](=[NH:29])[NH2:28])=[CH:23][CH:22]=3)[CH3:20])=[N:17][C:13]=2[CH:12]=1)=[O:10].[OH-].[Na+]>>[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:33][CH2:34][C:35]([OH:37])=[O:36])[C:9]([C:11]1[CH:32]=[CH:31][C:14]2[N:15]([CH3:30])[C:16]([CH2:18][N:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27](=[NH:28])[NH2:29])=[CH:23][CH:22]=3)[CH3:20])=[N:17][C:13]=2[CH:12]=1)=[O:10]
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CN(C)c1ccc(C(=N)N)cc1)n2C)c1ccccn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CN(Cc1nc2cc(C(=O)N(CCC(=O)O)c3ccccn3)ccc2n1C)c1ccc(C(=N)N)cc1

Procedure:
Prepared analogously to Example 26 from 1-methyl-2-[N-(4-amidinophenyl)-N-methyl-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide-hydrochloride and sodium hydroxide solution.
Reaction SMILES: [N:1]1([CH:5]2[CH:14]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:13]3[CH:12]=[C:11]([C:22]#[N:23])[CH:10]=[CH:9][C:8]=3[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.ClCCl>CO.[Ni]>[N:1]1([CH:5]2[CH:14]([CH2:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:13]3[CH:12]=[C:11]([CH2:22][NH2:23])[CH:10]=[CH:9][C:8]=3[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1
Reactant: N#Cc1ccc2c(c1)C(Cc1ccccc1)C(N1CCC1)CC2
Agent: [Ni]
Solvent: CO
Solvent: ClCCl
Product: NCc1ccc2c(c1)C(Cc1ccccc1)C(N1CCC1)CC2
Temperature: 25 °C
Reaction time: 48 h

Procedure:
7-(Azetidin-1-yl)-8-benzyl-5,6,7,8-tetrahydronaphthalene-2-carbonitrile (340 mg, 1.12 mmol) was dissolved in dry methanol (20 mL) under a nitrogen atmosphere. Raney nickel (900 mg, 3.36 mmol) was added under nitrogen and the reaction mixture stirred at room temperature for 48 h under an atmosphere of hydrogen. Methanol (20 mL) and dichloromethane (30 mL) were added. After stirring at room temperature for 20 minutes the catalyst was removed by filtration and the solvent evaporated in vacuo. Yield: 338 mg (1.10 mmol, 98%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][CH2:14][C:13]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])(O)[CH2:12][CH2:11]2)=[C:6]([F:22])[C:5]=1[F:23])[CH3:2].O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][CH2:14][C:13]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:12][CH2:11]2)=[C:6]([F:22])[C:5]=1[F:23])[CH3:2]
Reactant: CCCCCC1(O)CCC(c2ccc(OCC)c(F)c2F)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCCC1=CCC(c2ccc(OCC)c(F)c2F)CC1

Procedure:
A solution of 128.0 g of 4-(4-ethoxy-2,3-difluorophenyl)-1-pentylcyclohexanol in 1 l of toluene was refluxed in a water separator with addition of 5.0 g of toluene-4-sulphonic acid monohydrate. When all the water had been removed, the mixture was subjected to conventional work-up, giving 1-ethoxy-2,3-difluoro-4-(4-pentylcyclohex-3-enyl)benzene.
Reaction SMILES: C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[C:11]([O:15][C:16]([C@@:18]1([CH2:33][CH2:34]Br)[CH:22]([CH3:23])[C:21](=[O:24])[N:20]([C@@H:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH3:26])[CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C(O)(=O)CC(CC(O)=O)(C(O)=O)O.C(OCC)(=O)C>O1CCCC1>[C:11]([O:15][C:16]([C@@:18]12[CH2:33][CH2:34][C@:22]1([CH3:23])[C:21](=[O:24])[N:20]([C@@H:25]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH3:26])[CH2:19]2)=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC1C(=O)N([C@H](C)c2ccccc2)C[C@@]1(CCBr)C(=O)OC(C)(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C[C@H](c1ccccc1)N1C[C@]2(C(=O)OC(C)(C)C)CC[C@]2(C)C1=O
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 80.9 %

Procedure:
A 1.0 M solution of lithium hexamethyldisilazide in tetrahydrofuran (3.8 mL, 3.80 mmol) was added dropwise to a solution of (3S)-3-(2-bromoethyl)-4-methyl-5-oxo-1-[(1R)-1-phenylethyl]pyrrolidine-3-carboxylic acid tert-butyl ester (1.30 g, 3.17 mmol) in tetrahydrofuran (20 mL) in a nitrogen atmosphere at −72° C. over seven minutes. The mixture was stirred at the same temperature for 30 minutes. After heating to −10° C. and stirring for 1.5 hours, a 1.0 M solution of lithium hexamethyldisilazide in tetrahydrofuran (4.0 mL, 4.0 mmol) was added over two minutes, and the mixture was stirred at 0° C. for 20 hours. A 10% citric acid solution (20 mL) was added at the same temperature. The reaction solution was poured into a mixture of ethyl acetate (100 mL) and a 10% citric acid solution (10 mL). After extraction with ethyl acetate (150 mL), the organic layer was washed with brine (30 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1→1:1) to give 0.845 g (81%) of the title compound as a white solid.
Reaction SMILES: [CH3:1][C:2]([CH3:36])([CH3:35])[CH2:3][CH2:4][C@:5]1([CH3:34])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([OH:15])=[C:7]([C:16]2[NH:21][C:20]3[CH:22]=[CH:23][C:24]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])=[CH:25][C:19]=3[S:18](=[O:32])(=[O:31])[N:17]=2)[C:6]1=[O:33].[OH-].[K+:38]>C(O)C.O>[CH3:1][C:2]([CH3:36])([CH3:35])[CH2:3][CH2:4][C@:5]1([CH3:34])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([O-:15])=[C:7]([C:16]2[NH:21][C:20]3[CH:22]=[CH:23][C:24]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])=[CH:25][C:19]=3[S:18](=[O:32])(=[O:31])[N:17]=2)[C:6]1=[O:33].[K+:38]
Reactant: CC(C)(C)CC[C@@]1(C)C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C(O)c2ccccc21
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)(C)CC[C@@]1(C)C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C([O-])c2ccccc21
Temperature: 55 °C
Reaction time: 8 h

Procedure:
Placed 245.12 mg of the product of Example 49-7 into a 10 mL receiver flask. Added 6 mL of 50/50 ethanol/water. Warmed to in an oil bath on a hot-plate set to 90° C. and added 29.02 mg of potassium hydroxide. Solution clarified. Cooled in 10° C. increments to 55° C. Solid precipitated. Cooled to 40° C. and held for -1 hour. Cooled to ambient temperature and stirred overnight. Collected solid via vacuum filtration the next morning and dried the solid at 50° C./vacuum for 3 days.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[F:9][C:10]1[CH:11]=[C:12]([CH2:16][NH2:17])[CH:13]=[CH:14][CH:15]=1>CS(C)=O>[Cl:8][C:4]1[N:3]=[C:2]([NH:17][CH2:16][C:12]2[CH:13]=[CH:14][CH:15]=[C:10]([F:9])[CH:11]=2)[CH:7]=[N:6][CH:5]=1
Reactant: Clc1cncc(Cl)n1
Reactant: NCc1cccc(F)c1
Solvent: CS(C)=O
Product: Fc1cccc(CNc2cncc(Cl)n2)c1
Temperature: 90 °C
Yield: 57.3 %

Procedure:
To 2,6-dichloropyrazine (175 mg, 1.175 mmol) was added DMSO (1.5 ml), TEA (0.196 ml, 1.410 mmol) and (3-fluorophenyl)methanamine (368 mg, 2.94 mmol) l. The reaction mixture then was stirred at 90° C. until completion as indicated by LCMS, about 1 hour. To the reaction mixture was added 3 ml of DMSO, filtered and the residue was purified by prep LC. After lyphilization, 160 mg of the title compound was obtained as a TFA. LCMS (m/z): 238.1 (MH+), retention time=0.96 min.
Reaction SMILES: [N:1]1[C:6]2[C:7]3[CH2:13][CH2:12][CH2:11][CH2:10][C:8]=3[O:9][C:5]=2[C:4](O)=[N:3][CH:2]=1.O=P(Cl)(Cl)[Cl:17]>>[Cl:17][C:4]1[C:5]2[O:9][C:8]3[CH2:10][CH2:11][CH2:12][CH2:13][C:7]=3[C:6]=2[N:1]=[CH:2][N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1ncnc2c3c(oc12)CCCC3
Product: Clc1ncnc2c3c(oc12)CCCC3
Temperature: 110 °C
Reaction time: 0.5 h

Procedure:
A 15 mL sealed tube was charged with 6,7,8,9-tetrahydro-benzo[4,5]furo[3,2-d]pyrimidin-4-ol (0.31 g, 1.6 mmol) and POCl3 (3 mL), sealed, and heated to 110° C. After 30 min, POCl3 was removed under reduced pressure and the resultant residue was purified by FCC (40% EtOAc/hexanes) to afford the desired product as a white solid (0.27 g). MS: 189.0 (negative mode). 1H NMR (400 MHz, d6-DMSO) δ ppm 8.00 (s, 1H), 2.74-2.67 (m, 2H), 2.57-2.51 (m, 2H), 1.90-1.82 (m, 2H), 1.80-1.70 (m, 2H).
Reaction SMILES: C[O:2][C:3]([C:5]1[N:17]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[C:8]2=[N:9][CH:10]=[C:11]([S:13]([CH3:16])(=[O:15])=[O:14])[CH:12]=[C:7]2[CH:6]=1)=O.O1CCCC1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[Na+].[Cl-]>C(OCC)(=O)C>[F:25][C:22]1[CH:21]=[CH:20][C:19]([CH2:18][N:17]2[C:8]3=[N:9][CH:10]=[C:11]([S:13]([CH3:16])(=[O:15])=[O:14])[CH:12]=[C:7]3[CH:6]=[C:5]2[CH2:3][OH:2])=[CH:24][CH:23]=1
Reactant: COC(=O)c1cc2cc(S(C)(=O)=O)cnc2n1Cc1ccc(F)cc1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CS(=O)(=O)c1cnc2c(c1)cc(CO)n2Cc1ccc(F)cc1
Reaction time: 0.25 h
Yield: 86.3 %

Procedure:
To a mixture of 1-(4-fluorobenzyl)-5-methanesulfonyl-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid methyl ester (0.49 g) and tetrahydrofuran (14 ml), lithium aluminum hydride (77 mg) was added at 0° C. and the mixture was stirred at the same temperature for 15 minutes. The mixture was diluted with ethyl acetate and a saturated aqueous NaCl solution was added thereto. The mixture was dried over sodium sulfate and concentrated under reduced pressure. The resulting residue was separated using silica gel column chromatography (hexane:ethyl acetate=1:1) to obtain the desired product (0.39 g) as a white powder.
Reaction SMILES: C([O:3][C:4](=[O:24])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]#[C:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH3:23])=[CH:17][CH:16]=2)=[CH:9][CH:8]=1)C.[OH-].[Na+].Cl>CO.O>[CH2:22]([O:21][C:18]1[CH:17]=[CH:16][C:15]([C:14]#[C:13][C:10]2[CH:9]=[CH:8][C:7]([CH2:6][CH2:5][C:4]([OH:24])=[O:3])=[CH:12][CH:11]=2)=[CH:20][CH:19]=1)[CH3:23]
Reactant: CCOC(=O)CCc1ccc(C#Cc2ccc(OCC)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCOc1ccc(C#Cc2ccc(CCC(=O)O)cc2)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To 750 mg (2.33 mmol) 3-[4-(4-ethoxy-phenylethynyl)-phenyl]-propionic acid ethyl ester (XIII.1) in 15 mL MeOH are added 3.49 mL (6.98 mmol) 2N NaOH solution and the mixture is stirred at rt for 12 h. After that time, 7.0 mL 2N HCl are added and the mixture is diluted with water. The precipitate is filtered off, washed with water and dried at 45° C. to yield the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:9][C:10]([CH:24]([CH3:26])[CH3:25])=[C:11]([CH2:13][CH2:14][CH:15]([C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)O)[N:12]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:9][C:10]([CH:24]([CH3:26])[CH3:25])=[C:11]([CH2:13][CH:14]=[CH:15][C:17]2[CH:18]=[CH:19][C:20]([OH:23])=[CH:21][CH:22]=2)[N:12]=1
Reactant: CC(C)c1oc(-c2ccccc2Cl)nc1CCC(O)c1ccc(O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)c1oc(-c2ccccc2Cl)nc1CC=Cc1ccc(O)cc1
Yield: 28.6 %

Procedure:
4-[3-[2-(2-chlorophenyl)-5-isopropyl-4-oxazolyl]-1-hydroxypropyl]phenol (110 mg, 0.296 mmol) and p-toluene-sulfonic acid monohydrate (17 mg, 0.092 mmol) were refluxed in toluene (2 mL) for 20 hours. After the starting compounds diminished, the reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was collected, washed with water, dried over anhydrous sodium sulfate, and filtered. The ethyl acetate was removed under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=5/1), to give the desired compound (30 mg) as white crystalline product (yield 28%).
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([C:6]1[N:7]([S:18]([C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=2)(=[O:20])=[O:19])[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([C:15]([OH:17])=[O:16])=[CH:10][CH:9]=2)=[O:5]>C(OC(OC(C)(C)C)N(C)C)(C)(C)C.C(OCC)(=O)C.O>[CH3:1][CH2:2][O:3][C:4]([C:6]1[N:7]([S:18]([C:21]2[CH:22]=[CH:23][C:24]([CH3:27])=[CH:25][CH:26]=2)(=[O:20])=[O:19])[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([C:15]([O:17][C:11]([CH3:15])([CH3:12])[CH3:10])=[O:16])=[CH:10][CH:9]=2)=[O:5]
Reactant: CCOC(=O)c1cc2cc(C(=O)O)ccc2n1S(=O)(=O)c1ccc(C)cc1
Agent: CN(C)C(OC(C)(C)C)OC(C)(C)C
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)c1cc2cc(C(=O)OC(C)(C)C)ccc2n1S(=O)(=O)c1ccc(C)cc1
Temperature: 80 °C
Yield: 134.3 %

Procedure:
1-(Toluene-4-sulfonyl)-1H-indole-2,5-dicarboxylic acid 2-ethyl ester (690 mg, 1.85 mmol) was dissolved in N,N-dimethylformamide di-tert-butyl acetal (3.0 ml), and stirred at 80° C. for two and half hours. N,N-dimethylformamide di-tert-butyl acetal (2.0 ml) was further added thereto and stirred at 80° C. for three hours. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (150 ml) and water (75 ml). The organic layer was isolated, washed with water and a saturated aqueous solution of sodium chloride, and then dried over anhydrous sodium sulfate. The desiccant was removed by filtration. The filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate=25/1 to 5/1) to give 1-(toluene-4-sulfonyl)-1H-indole-2,5-dicarboxylic acid 5-tert-butyl ester 2-ethyl ester (551 mg, 69%).