Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[C:7]([S:19]C1C=CC=C(Cl)C=1)=[C:8]([CH3:18])[N:9]2[CH2:14][C:15]([OH:17])=[O:16])(=[O:3])[CH3:2].[Cl:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1S>>[C:1]([NH:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[C:7]([S:19][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=1[Cl:27])=[C:8]([CH3:18])[N:9]2[CH2:14][C:15]([OH:17])=[O:16])(=[O:3])[CH3:2]
Reactant: Sc1ccccc1Cl
Reactant: CC(=O)Nc1cccc2c1c(Sc1cccc(Cl)c1)c(C)n2CC(=O)O
Product: CC(=O)Nc1cccc2c1c(Sc1ccccc1Cl)c(C)n2CC(=O)O

Procedure:
The title compound was prepared by the method of Example 5 parts (iv) and using the product from Example 17 part (i) and 2-chlorothiophenol, and purified by column chromatography (33% EtOAc/hexane as eluent). The resulting product was treated as outlined in example 1 part (v) to give the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[C:3]=1[C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5].S(Cl)([Cl:22])(=O)=O.CC(N=NC(C#N)(C)C)(C#N)C.C([O-])(O)=O.[Na+]>C(Cl)(Cl)(Cl)Cl>[Cl:22][CH2:1][C:2]1[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[C:3]=1[C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5]
Reactant: Cc1cccc(C)c1C(=O)OCc1ccccc1
Reactant: O=S(=O)(Cl)Cl
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1cccc(CCl)c1C(=O)OCc1ccccc1

Procedure:
12.0 g of benzyl 2,6-dimethylbenzoate are initially charged into 50 ml of carbon tetrachloride admixed at room temperature with 5.4 g of sulfuryl chloride and 40 mg of AIBN. The mixture is stirred at reflux for 4–5 h. Afterwards, it is admixed with 40 ml of saturated NaHCO3 solution. After the phase separation, the organic phase is washed with 50 ml of 10% sodium sulfite solution, and the organic phase is then dried over magnesium sulfate. The product-containing solution is filtered trough silica gel and washed again with 20 ml of carbon tetrachloride. After distilling off the solvent in vacuo, the product obtained is a bright yellow oil. Yield: 8.0 g (73% of theory; 88.4 area %).
Reaction SMILES: [C:1]([OH:5])(=O)[CH:2]=[CH2:3].CN1CCOCC1.ClC(OCC(C)C)=O.[C:21]([O:25][C:26](=[O:35])[NH:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[NH2:34])([CH3:24])([CH3:23])[CH3:22]>ClCCl>[C:21]([O:25][C:26](=[O:35])[NH:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[NH:34][C:1](=[O:5])[CH:2]=[CH2:3])([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)OC(=O)Nc1ccccc1N
Reactant: C=CC(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: C=CC(=O)Nc1ccccc1NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 34.3 %

Procedure:
To a solution of acrylic acid (2.50 g, 34.7 mmol) in dichloromethane (80 mL) at 0 degrees Celcius was added N-methyl-morpholine (4.73 g, 46.8 mmol), followed by isobutyl chloroformate (6.37 g, 46.8 mmol). After 30 minutes, a solution of (2-amino-phenyl)-carbamic acid tertbutyl ester (5.80 g, 27.8 mmol) in dichloromethane (50 mL) was added dropwise to the refluxing reaction mixture over 30 min. After the reaction was completed (2 hours later), the reaction mixture was allowed to cool down to room temperature, poured into ice water, and extracted with dichloromethane (30 mL×3). The organic layer was washed with water, dilute sodium bicarbonate solution, 0.1M HCl, water, and brine in turn. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The crude solid was recrystallized from ethyl acetate/petroleum ether=1/4 (v/v) to obtain the desired product (2.5 g, 34%). MS: calc'd 263 (MH+), exp 263 (MH+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C:8](=[N:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[N:9]1[CH2:14][CH2:13][C:12](=O)[CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2].[CH3:25][C:26]1[C:27]([CH2:32][NH2:33])=[N:28][CH:29]=[CH:30][CH:31]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:24])[NH:7][C:8](=[N:16][C:17]([O:19][C:20]([CH3:22])([CH3:23])[CH3:21])=[O:18])[N:9]1[CH2:10][CH2:11][CH:12]([NH:33][CH2:32][C:27]2[C:26]([CH3:25])=[CH:31][CH:30]=[CH:29][N:28]=2)[CH2:13][CH2:14]1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)N1CCC(=O)CC1
Reactant: Cc1cccnc1CN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cccnc1CNC1CCN(C(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)CC1

Procedure:
Using General Procedure B, reaction of [tert-butoxycarbonylimino-(4-oxo-piperidin-1-yl)-methyl]-carbamic acid tert-butyl ester, C-(3-methylpyridin-2-yl)-methylamine and NaBH(OAc)3 in CH2Cl2 gave (tert-butoxycarbonylimino-{4-[(3-methyl-pyridin-2-ylmethyl)-amino]-piperidin-1-yl}-methyl)-carbamic acid tert-butyl ester as a white solid.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([CH2:19][C:20]4[S:21][CH:22]=[C:23]([C:25]([O:27]CC)=[O:26])[N:24]=4)=[CH:15][C:13]=3[CH:14]=2)[S:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>O.CO>[C:1]([C:5]1[N:6]=[C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([CH2:19][C:20]4[S:21][CH:22]=[C:23]([C:25]([OH:27])=[O:26])[N:24]=4)=[CH:15][C:13]=3[CH:14]=2)[S:8][CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1csc(Cc2ccc3oc(-c4nc(C(C)(C)C)cs4)cc3c2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C)c1csc(-c2cc3cc(Cc4nc(C(=O)O)cs4)ccc3o2)n1
Yield: 93.5 %

Procedure:
A mixture of 4-tert-butyl-2-{5-{[4-(ethoxycarbonyl)-thiazol-2-yl]methyl}benzofuran-2-yl}thiazole (0.79 g) and sodium hydroxide (0.17 g) in a mixture of water (2 ml) and methanol (6 ml) was stirred under reflux for 3 hours. After being cooled, the resulting solution was concentrated under reduced pressure. The residue was dissolved in water and neutralized with diluted hydrochloric acid. The resulting mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and concentrated in reduced pressure. The residue was washed with a small amount of ethyl acetate to give 4-tert-butyl-2-{5-{[4-carboxythiazol-2-yl]methyl}benzofuran-2-yl}thiazole (0.69 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[C:5]([NH:7][C:8]1[CH:9]=[CH:10][C:11]([Br:18])=[C:12]2[C:17]=1[N:16]=[CH:15][CH:14]=[CH:13]2)=[O:6])[CH3:2].[N+:20]([O-])([OH:22])=[O:21]>FC(F)(F)C(O)=O>[CH2:1]([O:3][C:4](=[O:19])[C:5]([NH:7][C:8]1[C:9]([N+:20]([O-:22])=[O:21])=[CH:10][C:11]([Br:18])=[C:12]2[C:17]=1[N:16]=[CH:15][CH:14]=[CH:13]2)=[O:6])[CH3:2]
Reactant: CCOC(=O)C(=O)Nc1ccc(Br)c2cccnc12
Reactant: O=[N+]([O-])O
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C(=O)Nc1c([N+](=O)[O-])cc(Br)c2cccnc12
Yield: 45 %

Procedure:
A solution of the product from Example 82 (23.5 g, 58 mmol) in 30 mL fuming nitric acid and 150 mL trifluoroacetic acid was heated at 80° C. for 18 hours. The solvent was removed and the residue was treated with water to give a solid. The solid was collected by filtration and washed with ether and dried to give the title compound (9.5 g, 45% yield).
Reaction SMILES: [H-].[Na+].Cl[CH2:4][C:5]1[N:9]([CH3:10])[N:8]=[C:7]([CH3:11])[CH:6]=1.[Br:12][C:13]1[N:18]=[C:17]([CH2:19][OH:20])[CH:16]=[CH:15][CH:14]=1>C1COCC1.O.C(Cl)Cl>[Br:12][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]([CH2:19][O:20][CH2:4][C:5]2[N:9]([CH3:10])[N:8]=[C:7]([CH3:11])[CH:6]=2)[N:18]=1
Reactant: OCc1cccc(Br)n1
Reactant: Cc1cc(CCl)n(C)n1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(COCc2cccc(Br)n2)n(C)n1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a suspension of NaH (64 mg, 1.59 mmol) in THF (4 mL) at 0° C. under argon was added 5-(chloromethyl)-1,3-dimethyl-1H-pyrazole (230 mg, 1.59 mmol) and allowed to stir for 20 minutes. (6-Bromopyridin-2-yl)methanol (150 mg, 0.80 mmol) was then added and the mixture was allowed to warm to room temperature and then heated to 55° C. overnight. The reaction was then cooled to ambient temperature and quenched by the addition of water. The quenched reaction mixture was diluted with water (10 mL) and DCM (10 mL) and shaken. The suspensions were passed through disposable phase separators and the DCM eluent was captured and evaporated to dryness to afford the title compound which was used without further purification.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([C:14]2[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][N:15]=2)[C:3]=1[CH3:21].[O:22]1[CH2:27][CH2:26][N:25]([C:28]2[CH:29]=[C:30]3[NH:36][CH2:35][C:34]4([CH2:41][CH2:40][O:39][CH2:38][CH2:37]4)[C:31]3=[N:32][CH:33]=2)[CH2:24][CH2:23]1.CC(C)([O-])C.[Na+]>CC(C1C=C(C(C)C)C(C2C(P(C3CCCCC3)C3CCCCC3)=CC=CC=2)=C(C(C)C)C=1)C.C1C=[C-]C(CCN)=CC=1.Cl[Pd+].C1(C)C=CC=CC=1>[F:12][C:10]1[CH:9]=[C:8]([F:13])[CH:7]=[C:6]2[C:11]=1[C:2]([N:36]1[C:30]3[C:31](=[N:32][CH:33]=[C:28]([N:25]4[CH2:26][CH2:27][O:22][CH2:23][CH2:24]4)[CH:29]=3)[C:34]3([CH2:41][CH2:40][O:39][CH2:38][CH2:37]3)[CH2:35]1)=[C:3]([CH3:21])[C:4]([C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][N:15]=1)=[N:5]2
Reactant: Cc1ccnc(-c2nc3cc(F)cc(F)c3c(Cl)c2C)c1
Reactant: c1nc2c(cc1N1CCOCC1)NCC21CCOCC1
Agent: Cl[Pd+]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Product: Cc1ccnc(-c2nc3cc(F)cc(F)c3c(N3CC4(CCOCC4)c4ncc(N5CCOCC5)cc43)c2C)c1

Procedure:
Prepared according to procedure Y by stirring 4-chloro-5,7-difluoro-3-methyl-2-(4-methylpyridin-2-yl)quinoline (45 mg, 0.148 mmol), 6′-morpholino-1′,2,2′,3,5,6-hexahydrospiro[pyran-4,3′-pyrrolo[3,2-b]pyridine] (48.8 mg, 0.177 mmol), XPhos precatalyst (10.9 mg, 0.015 mmol), sodium tert-butoxide (28.4 mg, 0.295 mmol), and toluene (1.6 mL) at 95° C. for 24 h. Purification by column chromatography (basic alumina, 0-30% EtOAc in hexanes) gave 1′-(5,7-difluoro-3-methyl-2-(4-methyl-2-pyridinyl)-4-quinolinyl)-6′-(4-morpholinyl)-1′,2,2′,3,5,6-hexahydrospiro[pyran-4,3′-pyrrolo[3,2-b]pyridine]. 1H NMR (400 MHz, chloroform-d) δ ppm 8.60 (1H, d, J=5.1 Hz), 7.68-7.74 (2H, m), 7.54-7.58 (1H, m), 7.21-7.27 (1H, m), 7.02 (1H, t, J=3.1 Hz), 5.78 (1H, s), 4.14 (2H, td, J=11.6, 3.9 Hz), 3.92-4.00 (1H, m), 3.71-3.84 (5H, m), 3.49-3.62 (2H, m), 2.98-3.08 (4H, m), 2.51 (3H, s), 2.37-2.42 (3H, m), 1.83 (1H, d, J=13.9 Hz), 1.68-1.78 (1H, m), 1.28-1.34 (2H, m). Mass Spectrum (ESI) m/e=544.1 (M+1).
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([C:9]2([N:19]([CH3:21])[CH3:20])[CH2:18][CH2:17][C:12]3(OCC[O:13]3)[CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.Cl>O>[CH3:20][N:19]([CH3:21])[C:9]1([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([F:2])[CH:4]=2)[CH2:18][CH2:17][C:12](=[O:13])[CH2:11][CH2:10]1
Reactant: CN(C)C1(c2cccc(F)c2)CCC2(CC1)OCCO2
Agent: Cl
Solvent: O
Product: CN(C)C1(c2cccc(F)c2)CCC(=O)CC1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
[8-(3-Fluoro-phenyl)-1,4-dioxa-spiro[4.5]dec-8-yl]-dimethyl-amine hydrochloride (2.80 g, 8.86 mmol) was dissolved in water (3.7 ml), concentrated hydrochloric acid (5.5 ml) was added and the mixture was stirred at RT for 4 d. When the hydrolysis had ended, the reaction mixture was extracted with ether (2×10 ml) and the aqueous solution was rendered alkaline with 5 N sodium hydroxide solution, while cooling with ice, the reaction mixture was extracted with methylene chloride (3×50 ml) and the organic phase was dried over sodium sulfate and concentrated i. vac. The crude product was purified by flash chromatography with CHCl3/MeOH (20:1).
Reaction SMILES: [CH3:1][C:2]1([C:7]2[S:11][C:10]([CH2:12][N:13]3[N:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[Cl:19][C:20]1[CH:21]=[C:22]([C:26]2[O:30][CH:29]=[N:28][C:27]=2[C:31](O)=[O:32])[CH:23]=[CH:24][CH:25]=1>>[C:2]([C:7]1[S:11][C:10]([CH2:12][N:13]2[N:17]=[C:16]([NH:18][C:31]([C:27]3[N:28]=[CH:29][O:30][C:26]=3[C:22]3[CH:23]=[CH:24][CH:25]=[C:20]([Cl:19])[CH:21]=3)=[O:32])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2ccc(Cn3ncc(N)n3)s2)OCCO1
Reactant: O=C(O)c1ncoc1-c1cccc(Cl)c1
Product: CC(=O)c1ccc(Cn2ncc(NC(=O)c3ncoc3-c3cccc(Cl)c3)n2)s1

Procedure:
Following general procedure A followed by B, starting from 2-[5-(2-methyl-[1,3]dioxolan-2-yl)-thiophen-2-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and 5-(3-chloro-phenyl)-oxazole-4-carboxylic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]2[N:9]=[CH:10][CH:11]=[C:4]2[N:3]=1.[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[C:6]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[N:5]2[N:9]=[CH:10][CH:11]=[C:4]2[N:3]=1
Reactant: C1COCCN1
Reactant: Clc1cc(Cl)n2nccc2n1
Solvent: C1COCCO1
Product: Clc1cc(N2CCOCC2)n2nccc2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91 %

Procedure:
5,7-Dichloro-pyrazolo[1,5-a]pyrimidine (400 mg, 2.13 mM) was dissolved in 1,4-dioxane (8 mL), then morpholine (372 μL, 4.26 mM) was added to the solution and the mixture was stirred at room temperature for 30 minutes. The solvent was distilled off from the reaction mixture, the resulting residue was diluted with water and extracted with methylene chloride. The extracts thus obtained were combined, dried over anhydrous sodium sulfate and the solvent was then distilled off to give the title compound (461 mg, yield: 91%).
Reaction SMILES: C(O[C:6](=O)[N:7](C)[C@@H:8]([C:15](=[O:18])[NH:16][CH3:17])[CH2:9][C:10]1[S:11][CH:12]=[CH:13][CH:14]=1)(C)(C)C.FC(F)(F)C(O)=O.O.C(=O)([O-])O.[Na+]>C(Cl)Cl>[CH3:17][NH:16][C:15](=[O:18])[C@H:8]([NH:7][CH3:6])[CH2:9][C:10]1[S:11][CH:12]=[CH:13][CH:14]=1
Reactant: CNC(=O)[C@@H](Cc1cccs1)N(C)C(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: O
Product: CNC(=O)[C@@H](Cc1cccs1)NC
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 90.1 %

Procedure:
N-Methyl-N-((1R)-1-(methylcarbamoyl)-2-(thiophen-2-yl)ethyl)carbamic acid tert-butylester (1.17 g; 3.92 mmol) was dissolved in methylene chloride (4 ml). The reaction was cooled to 0° C. and triflouroacetic acid was added. The mixture was stirred at room temperature for 1.5 hour. Water (30 ml) and solid sodium hydrogencarbonate were added to pH 8. The phases were separated. The aqueous phase was extracted with methylene chloride (4×20 ml). The combined organic phases were dried over magnesium sulfate and the solvent was removed over vacuo to afford 0.70 g of (2R)-N-methyl-2-methylamino-3-(thiophen-2-yl)propionamide.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]2[N:15]([C:16]=1[C:17]1[CH:18]=[CH:19][C:20]3[N:21]([C:23]([C:26]([OH:29])([CH3:28])[CH3:27])=[N:24][N:25]=3)[N:22]=1)[CH:14]=[CH:13][O:12]2.N1C=CC=CC=1.[C:36](OC(=O)C)(=[O:38])[CH3:37].C(Cl)(=O)C>CN(C=O)C.C(Cl)Cl>[C:36]([O:29][C:26]([C:23]1[N:21]2[N:22]=[C:17]([C:16]3[N:15]4[C:11]([O:12][CH:13]=[CH:14]4)=[N:10][C:9]=3[C:3]3[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=3[F:1])[CH:18]=[CH:19][C:20]2=[N:25][N:24]=1)([CH3:27])[CH3:28])(=[O:38])[CH3:37]
Reactant: CC(C)(O)c1nnc2ccc(-c3c(-c4ccc(F)cc4F)nc4occn34)nn12
Reactant: CC(=O)OC(C)=O
Solvent: CN(C)C=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)OC(C)(C)c1nnc2ccc(-c3c(-c4ccc(F)cc4F)nc4occn34)nn12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 54.3 %

Procedure:
2-(6-(6-(2,4-Difluorophenyl)imidazo[2,1-b]oxazol-5-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)propan-2-ol (0.125 g, 0.315 mmol, Example #37) was added to DCM (2 mL). Pyridine (0.077 mL, 0.95 mmol) and acetic anhydride (0.045 mL, 0.47 mmol) were added and the suspension was stirred at ambient temperature for about 15 min. Acetyl chloride (0.027 mL, 0.38 mmol) was added and the mixture was stirred at ambient temperature for about 30 min. DMF (1 mL), pyridine (0.077 mL, 0.95 mmol) and acetyl chloride (0.027 mL, 0.38 mmol) were added then the mixture was heated at about 85° C. for about 90 min. The mixture was cooled to ambient temperature, concentrated under reduced pressure then purified by RP-HPLC (Table 1, Method f). Concentration under reduced pressure resulted in a precipitate that was collected by filtration and dried to give the title compound (0.075 g, 54%): LC/MS (Table 1, Method g) Rt=1.96 min; MS m/z: 438.9 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH2:11])(=[O:10])=[O:9].C(N(CC)CC)C.[CH3:19][N:20]([CH3:25])[S:21](Cl)(=[O:23])=[O:22]>C(Cl)Cl>[CH3:19][N:20]([CH3:25])[S:21]([O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH2:11])(=[O:9])=[O:10])(=[O:23])=[O:22]
Reactant: NS(=O)(=O)c1ccccc1O
Reactant: CN(C)S(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)S(=O)(=O)Oc1ccccc1S(N)(=O)=O
Temperature: 25 °C
Reaction time: 72 h
Yield: 54.4 %

Procedure:
To 6.8 g (0.04 mole) 2-hydroxybenzenesulfonamide in 100 ml methylene chloride was added 4.4 g (0.044 mole) triethylamine and 6.3 g (0.044 mole) dimethylsulfamoyl chloride in 5 ml methylene chloride, keeping the reaction temperature <10° C. The mixture was then warmed to room temperature and stirred 72 hours. The reaction mixture was then diluted with 100 ml methylene chloride washed with 100 ml water, 100 ml 1% HCl and dried over MgSO4. The solvent was evaporated to give a crude yellow oil that slowly solidified on standing. The solids were then triturated with hexanes and filtered to give 6.1 g of a tan solid, m.p. 88°-89° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]2=[O:14])[CH:5]=[CH:4][C:3]=1[NH:15][C:16]([CH:18]1[CH:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:19]1[C:27]([OH:29])=[O:28])=[O:17].S(Cl)(Cl)=O.[CH3:34]O>>[CH3:34][O:28][C:27]([CH:19]1[CH:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:18]1[C:16](=[O:17])[NH:15][C:3]1[CH:4]=[CH:5][C:6]([N:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]2=[O:14])=[CH:7][C:2]=1[F:1])=[O:29]
Reactant: CO
Reactant: O=C(O)C1C(C(=O)Nc2ccc(-n3ccccc3=O)cc2F)C1c1ccccc1
Solvent: O=S(Cl)Cl
Product: COC(=O)C1C(C(=O)Nc2ccc(-n3ccccc3=O)cc2F)C1c1ccccc1
Reaction time: 8 h

Procedure:
A solution of 140 mg (0.36 mmol) of (1RS,2SR,3SR)-2-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-3-phenyl-cyclopropanecarboxylic acid in 5 ml of methanol was treated at 0° C. with ca. 0.1 ml of thionylchloride and left to stirr overnight at RT. Evaporation of the solvent gave 160 mg of (1RS,2SR,3SR)-2-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-3-phenyl-cyclopropanecarboxylic acid methylester. Light yellow oil. MS: 405 (M−H)−.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:6]([N+:18]([O-:20])=[O:19])[CH:5]=1)=[O:3].[Br:21]Br>C(Cl)(Cl)Cl>[CH:15]1[CH:16]=[CH:17][C:12]([CH2:11][O:10][C:7]2[CH:8]=[CH:9][C:4]([C:2]([CH2:1][Br:21])=[O:3])=[CH:5][C:6]=2[N+:18]([O-:20])=[O:19])=[CH:13][CH:14]=1
Reactant: CC(=O)c1ccc(OCc2ccccc2)c([N+](=O)[O-])c1
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: O=C(CBr)c1ccc(OCc2ccccc2)c([N+](=O)[O-])c1
Reaction time: 0.5 h
Yield: 78.9 %

Procedure:
In 60 ml of chloroform there was dissolved 5.4 g of 4-benzyloxy-3-nitroacetophenone and after adding dropwise to the solution a mixture of 3.2 g of bromine and 5 ml. of chloroform, with stirring, the mixture was further stirred for 30 minutes. The reaction product was concentrated under a reduced pressure and the crystalline residue thus obtained was washed with 20 ml. of benzene and dried to give 5.5 g of 4-benzyloxy-3-nitro-α-bromoacetophenone melting at 135°-136° C.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[OH:11].[CH2:12]([C:21]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=1)(O)[C:22]#[CH:23])[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1>C1(C)C=CC=CC=1>[CH2:12]([C:21]1([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)[O:11][C:2]2[CH:3]=[CH:4][C:5]3[C:10]([C:1]=2[CH:23]=[CH:22]1)=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:13]1[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=1
Reactant: C#CC(O)(Cc1ccc(OC)cc1)Cc1ccc(OC)cc1
Reactant: Oc1ccc2ccccc2c1
Solvent: Cc1ccccc1
Product: COc1ccc(CC2(Cc3ccc(OC)cc3)C=Cc3c(ccc4ccccc34)O2)cc1
Reaction time: 1.5 h
Yield: 66 %

Procedure:
A mixture of 2-naphthol (3.23 g;0.0224 mol), 1,1-dianisylprop-2-yn-1-ol (6.00 g;0.0224 mol), acidic alumina Brockmann 1(6 g) and toluene (250 ml) was heated and stirred for 1.5 h, cooled, filtered and the solid washed with toluene. The filtrate was evaporated to give a pale purple tacky solid which was washed with pet. ether (40-60)/diethyl ether to yield crude product (7.07 g). Purification of the solid by crystallisation from ethylacetate gave 3,3-dianisyl-3H-naphtho[2,1-b]pyran as a white solid (5.52 g;66% yield), m.pt 176°-177° C. ##STR24##
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][CH3:9])=[C:6](I)[CH:5]=[CH:4][N:3]=1.[F:11][C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[C:14]([O:21][CH3:22])[CH:13]=1>>[Cl:1][C:2]1[C:7]([NH:8][CH3:9])=[C:6]([C:15]2[CH:16]=[CH:17][C:12]([F:11])=[CH:13][C:14]=2[O:21][CH3:22])[CH:5]=[CH:4][N:3]=1
Reactant: CNc1c(I)ccnc1Cl
Reactant: COc1cc(F)ccc1B(O)O
Product: CNc1c(-c2ccc(F)cc2OC)ccnc1Cl

Procedure:
The title compound was prepared in analogy to example 72, from (2-chloro-4-iodo-pyridin-3-yl)-methyl-amine and 4-fluoro-2-methoxyphenylboronic acid (CAS RN 179899-07-1). The compound was purified by silica gel chromatography on a 20 g column using a MPLC system eluting with a gradient of n-heptane:EtOAc (100:0 to 60:40). Light yellow solid (78%). MS (ESI): m/z=267.07 [M+H]+.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([C:29]1[CH:30]=[N:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=1)[CH2:23][C:24]1[CH:25]=[N:26][NH:27][CH:28]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[CH2:39][C:40]1[C:45]([CH3:46])=[CH:44][CH:43]=[CH:42][N:41]=1>>[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([C:29]1[CH:30]=[N:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=1)[CH2:23][C:24]1[CH:25]=[N:26][N:27]([CH2:39][C:40]2[C:45]([CH3:46])=[CH:44][CH:43]=[CH:42][N:41]=2)[CH:28]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(C)c1ccc(N(Cc2cn[nH]c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1
Reactant: Cc1cccnc1CCl
Agent: Cl
Product: Cc1cccnc1Cn1cc(CN(C(=O)C2CCCc3c(OCc4ccccc4)cccc32)c2ccc(C(C)C)nc2)cn1
Yield: 84.9 %

Procedure:
By the reaction and treatment in the same manner as in Example 271 using 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.78 g) and 2-chloromethyl-3-methylpyridine (0.53 g) as starting materials, 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-({1-[(3-methylpyridin-2-yl)methyl]pyrazol-4-yl}methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.75 g) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]3[N:16]=[C:15]4[C:17]([C:20](O)=[O:21])=[CH:18][NH:19][C:14]4=[N:13][CH:12]=3)=[N:7][NH:8]2)=[CH:4][CH:3]=1.[NH2:23][C@@H:24]([CH3:27])[CH2:25][OH:26].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C.O>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]3[N:16]=[C:15]4[C:17]([C:20]([NH:23][C@@H:24]([CH3:27])[CH2:25][OH:26])=[O:21])=[CH:18][NH:19][C:14]4=[N:13][CH:12]=3)=[N:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: O=C(O)c1c[nH]c2ncc(-c3n[nH]c4cc(Cl)ccc34)nc12
Reactant: C[C@H](N)CO
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](CO)NC(=O)c1c[nH]c2ncc(-c3n[nH]c4cc(Cl)ccc34)nc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 19.4 %

Procedure:
A mixture of 2-(6-chloro-1H-indazol-3-yl)-5H-pyrrolo[3,2-b]pyrazine-7-carboxylic acid (200 mg, 0.638 mmol), (S)-2-aminopropan-1-ol (57 mg, 0.765 mmol), EDCI (366 mg, 1.914 mmol), HOBt (258 mg, 1.914 mmol) and DIPEA (247 mg, 1.914 mmol) in dry DMF (10 mL) was stirred for 16 hours at room temperature. Water (10 mL) was added, the formed precipitate was separated by filtration, washed with methanol (1 mL) then was purified by preparative-HPLC (Gemini 5u C18 150×21.2 mm; inject volume: 3 mL/inj, flow rate: 20 mL/min; wavelength: 214 nm and 254 nm; the gradient conditions are: 30% acetonitrile/70% water (0.1% trifluoroacetic acid V/V) initially, and then proceed to 60% acetonitrile/40% water (0.1% trifluoroacetic acid V/V) in a linear fashion after just 9 min.) to afford (S)-2-(6-chloro-1H-indazol-3-yl)-N-(1-hydroxypropan-2-yl)-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (46 mg, 26% for two steps) as a yellow solid. LCMS: (M+H)+=371; 1H NMR (300 MHz, DMSO+D2O): δ 9.14 (s, 1H), 8.59 (d, 1H, J=8.7 Hz), 8.36 (s, 1H), 7.72 (s, 1H), 7.27 (dd, 1H, J1=8.4 Hz, J2=1.8 Hz), 4.23-4.18 (m, 1H), 3.55 (d, 1H, J=4.2 Hz), 1.25 (d, 1H, J=6.6 Hz).