Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([O:21][C:22]([F:25])([F:24])[F:23])[CH:7]=[C:8]2[C:13]=1[O:12][CH:11]([C:14]([F:17])([F:16])[F:15])[C:10]([C:18]([OH:20])=[O:19])=[CH:9]2)(=[O:3])[CH3:2].CCO.[BH4-].[Na+]>C1COCC1>[OH:3][CH:1]([C:4]1[CH:5]=[C:6]([O:21][C:22]([F:25])([F:23])[F:24])[CH:7]=[C:8]2[C:13]=1[O:12][CH:11]([C:14]([F:17])([F:16])[F:15])[C:10]([C:18]([OH:20])=[O:19])=[CH:9]2)[CH3:2]
Reactant: CC(=O)c1cc(OC(F)(F)F)cc2c1OC(C(F)(F)F)C(C(=O)O)=C2
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(O)c1cc(OC(F)(F)F)cc2c1OC(C(F)(F)F)C(C(=O)O)=C2
Temperature: 25 °C
Reaction time: 2.75 h
Yield: 52 %

Procedure:
To a solution of 8-acetyl-6-(trifluoromethoxy)-2-(trifluoromethyl)-2H-chromene-3-carboxylic acid prepared as in Example 62 lb (0.980 g, 2.65 mmole) in a mixture of THF (25 mL) and absolute EtOH (25 mL) at 0° C. was added NaBH4 (0.100 g, 2.65 mmole) in portions under a N2 atmosphere. The ice bath was removed after 15 minutes and the mixture was stirred at room temperature for 2.75 hrs. The mixture was then poured into ice water (100 mL), which was then saturated with NaCI and extracted with EtOAc (2×200 mL). The extracts were combined, washed with brine, dried over MgSO4, filtered and concentrated in vacuo to give the crude product as a pale yellow solid. Purification by silica chromatography (0% to 25% EtOAc:hexanes gradient) gave the crude product, which was further purified by crystallization from acetonitrile to give 516 mg (52% yield) of the product as an off-white crystalline solid: ESHRMS m/z 371.0378 (M−H, C14H9F6O5, Calc'd 371.0354); 1H NMR (dmso-d6, 300 MHz) 13.42 (brs, 1H), 7.89 (s, 1H), 7.93 (d, 1H, J=2.6 Hz), 7.42 (s, 1H), 6.42 (q, 1H, J=7.3 Hz), 5.41 (m, 1H), 4.96 (d, 1H, J=3.4 Hz), 1.29 (d, 3H, J=6.2 Hz).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[C:14]=2[C:23]([O:25][CH:26]([CH3:28])[CH3:27])=[O:24])[CH:10]([C:29](N2C3CC4C(C)(C)C3(CC4)CS2(=O)=O)=[O:30])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-:45].[Li+].Cl>C1COCC1.O>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:20])[F:21])[C:14]=2[C:23]([O:25][CH:26]([CH3:28])[CH3:27])=[O:24])[C@@H:10]([C:29]([OH:30])=[O:45])[CH2:9]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)OC(=O)c1c(C2CN(C(=O)OC(C)(C)C)CC2C(=O)N2C3CC4CCC3(CS2(=O)=O)C4(C)C)cccc1C(F)(F)F
Reactant: [OH-]
Agent: Cl
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)OC(=O)c1c([C@@H]2CN(C(=O)OC(C)(C)C)C[C@@H]2C(=O)O)cccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 138.9 %

Procedure:
To a solution of 3-(10,10-Dimethyl-3,3-dioxo-3λ6-thia-4-aza-tricyclo[5.2.1.01,5]decane-4-carbonyl)-4-(2-isopropoxycarbonyl-3-trifluoromethyl-phenyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (625 mg, 0.97 mmol)) in 20 mL of 2:1 THF/H2O was added lithium hydroxide (70 mg, 2.91 mmol). The reaction mixture was allowed to stir at ambient temperature for 18 h. The reaction was acidified with 1 N HCl and extracted with EtOAc. The EtOAc layer was washed with brine, dried (MgSO4) and concentrated to afford 0.60 g of a mixture of the title compound and (1R)-(+)-2,10-camphorsultam, which was used without purification. LRMS (ES)+: 446.28 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:8])[CH2:7][NH:6][CH2:5][CH2:4][NH:3]1.C(N(CC)CC)C.[CH3:16][S:17](Cl)(=[O:19])=[O:18]>ClCCl>[CH3:16][S:17]([N:6]1[CH2:5][CH2:4][NH:3][C:2]([CH3:8])([CH3:1])[CH2:7]1)(=[O:19])=[O:18]
Reactant: CC1(C)CNCCN1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(C)CN(S(C)(=O)=O)CCN1
Temperature: 25 °C
Reaction time: 16 h
Yield: 61 %

Procedure:
To a solution of 2,2-dimethylpiperazine (400 mg) and triethylamine (0.59 mL) in dichloromethane (10 mL) at 0° C. was added dropwise methanesulfonyl chloride (0.30 mL). The reaction mixture was stirred at room temperature for 16 h and then quenched with water (10 mL) and extracted into dichloromethane (2×20 mL). The combined organic layers were washed with saturated aqueous brine solution (2×20 mL), dried (MgSO4) and concentrated to afford 1-methanesulfonyl-3,3-dimethyl-piperazine as a white solid (412 mg, 61%).
Reaction SMILES: [F:1][C:2]1[C:3]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([I:19])=[CH:15][C:14]=2[F:20])=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([OH:7])=O.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.Cl.[NH:55]1[CH2:58][CH:57]([OH:59])[CH2:56]1.CCN(C(C)C)C(C)C>CN(C=O)C>[F:1][C:2]1[C:3]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([I:19])=[CH:15][C:14]=2[F:20])=[C:4]([C:5]([N:55]2[CH2:58][CH:57]([OH:59])[CH2:56]2)=[O:7])[CH:8]=[CH:9][C:10]=1[F:11]
Reactant: O=C(O)c1ccc(F)c(F)c1Nc1ccc(I)cc1F
Reactant: OC1CNC1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1ccc(F)c(F)c1Nc1ccc(I)cc1F)N1CC(O)C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 88 %

Procedure:
3,4-Difluoro-2-[(2-fluoro-4-iodophenyl)amino]benzoic acid (2.1 g, 5.3 mmol), prepared using procedures similar to those in U.S. Pat. No. 7,019,033, was taken into DMF (10 mL) followed by addition of PyBOP (2.6 g, 5.3 mmol) and the mixture was allowed to stir at room temperature over 15 minutes. Azetidin-3-ol hydrochloride (870 mg, 8.0 mmol) and DIPEA (1.85 mL, 11.2 mmol) was then added and the mixture was allowed to stir an additional hour at room temperature. The mixture was then partitioned with ethyl acetate and 0.5 M aqueous sodium hydroxide solution. The organic layer was then washed with water (3×) then brine and dried over anhydrous sodium sulfate. Filtration and concentration followed by silica gel flash chromatography using ethyl acetate: hexanes (5:1) eluent afforded 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol (2.09 g, 87% yield) as a colorless amorphous solid. 1H NMR (400 MHz, CDCl3): 8.47 (s, 1H), 7.39 (dd, 1H), 7.32 (d, 1H), 7.13-7.09 (m, 1H), 6.84-6.78 (m, 1H), 6.63-6.57 (m, 1H), 4.74-4.67 (m, 1H), 4.43-4.39 (m, 2H), 4.20-3.96 (br d, 2H), 2.50 (d, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:18]2[CH:30]=[CH:29][C:21]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[C:20]([F:31])[CH:19]=2)=[N:4][C:5]([CH:8]2[CH2:17][CH2:16][C:11]3(OCC[O:12]3)[CH2:10][CH2:9]2)=[CH:6][N:7]=1.C(#N)C.Cl.[OH-].[Na+]>O>[NH2:1][C:2]1[C:3]([C:18]2[CH:30]=[CH:29][C:21]([C:22]([O:24][C:25]([CH3:27])([CH3:28])[CH3:26])=[O:23])=[C:20]([F:31])[CH:19]=2)=[N:4][C:5]([CH:8]2[CH2:17][CH2:16][C:11](=[O:12])[CH2:10][CH2:9]2)=[CH:6][N:7]=1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2nc(C3CCC4(CC3)OCCO4)cnc2N)cc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Product: CC(C)(C)OC(=O)c1ccc(-c2nc(C3CCC(=O)CC3)cnc2N)cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.1 %

Procedure:
To tert-butyl 4-(3-amino-6-(1,4-dioxaspiro[4.5]decan-8-yl)pyrazin-2-yl)-2-fluorobenzoate (14.34 g, 33.4 mmol) were added acetonitrile (250 mL), water (160 mL) and then 3 M aqueous solutionueous HCl (55.6 mL, 167 mmol). The reaction mixture was stirred at 25° C. for 30 min which was monitored by LCMS. The mixture was basified with 2 M NaOH aqueous solution under stirring to pH 9. Light yellow solid was precipitated out. Acetonitrile was removed under reduced pressure at room temperature. The solid was filtered and washed with water (2×30 mL), and dried under high vacuum overnight to afford tert-butyl 4-(3-amino-6-(4-oxocyclohexyl)pyrazin-2-yl)-2-fluorobenzoate (12 g, 31.1 mmol, 93%) as a light yellow solid. LCMS (m/z): 386.1 (MH+), 0.89 min; 1H NMR (400 MHz, ACETONITRILE-d3) δ ppm 8.05-7.89 (m, 2H) 7.73-7.51 (m, 2H), 5.14 (br. s., 2H), 3.30-3.08 (m, 1H), 2.64-2.48 (m, 2H), 2.40 (br. s., 2H), 2.30-2.17 (m, 2H), 2.12-1.99 (m, 2H), 1.96 (dt, J=4.99, 2.40 Hz, 4H), 1.61 (s, 9H).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[CH:7][CH:6]=1)(=[O:4])=[O:3].C[Al](C)C.[Cl:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][C:24]=1[CH3:25])[C:20]#[N:21]>C1(C)C=CC=CC=1.C(Cl)(Cl)Cl>[Cl:16][C:17]1[CH:18]=[C:19]([C:20](=[NH:21])[NH:9][C:8]2[CH:10]=[CH:11][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:6][CH:7]=2)[CH:22]=[CH:23][C:24]=1[CH3:25]
Reactant: CS(=O)(=O)c1ccc(N)cc1
Reactant: Cc1ccc(C#N)cc1Cl
Agent: C[Al](C)C
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: Cc1ccc(C(=N)Nc2ccc(S(C)(=O)=O)cc2)cc1Cl
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a suspension of 4-(methylsulfonyl)aniline (2.82 g, 16.5 mmol) in toluene (150 mL), trimethylaluminum (2M solution in toluene, 12.5 mL, 24.7 mmol) was added over 15 minutes. The reaction mixture was warmed to room temperature and stirred for 2.5 hours. A solution of 3-chloro-4-methylbenzonitrile (5 g, 33 mmol) in toluene (100 mL) was added over 10 minutes and the reaction mixture was heated to 90–95° C. After 20 hours, the reaction mixture was cooled to room temperature and poured over a slurry of silica gel in chloroform. After filtration, the residue was washed with a mixture of methylene chloride/methanol (2/1). The combined filtrates were concentrated in vacuo and the resulting yellowish solid was stirred with a mixture of hexane/ether (2/1, 700 mL). The intermediate was filtered and washed with more of hexane/ether (2/1). The pale yellow solid 3-chloro-4-methyl-N-[4-(methylsulfonyl)phenyl]benzenecarboximidamide (4.7 g, 88%) was used in the next reaction without further purification: mp (DSC) 179° C. Anal. Calc'd. for C15H15N2SO2Cl: C, 55.81; H, 4.68; N, 8.68. Found: C, 55.65; H. 4.63; N, 8.59.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:17](=[O:18])[C:16]3[C:15]4[C:10](=[CH:11][C:12]([C:19]#[N:20])=[CH:13][CH:14]=4)[NH:9][C:8]=3[C:7]([CH3:22])([CH3:21])[C:6]=2[CH:23]=1.[CH3:24][O:25][CH2:26][CH2:27]O>>[CH3:24][O:25][CH2:26][CH2:27][O:1][C:2]1[CH:3]=[CH:4][C:5]2[C:17](=[O:18])[C:16]3[C:15]4[C:10](=[CH:11][C:12]([C:19]#[N:20])=[CH:13][CH:14]=4)[NH:9][C:8]=3[C:7]([CH3:21])([CH3:22])[C:6]=2[CH:23]=1
Reactant: CC1(C)c2cc(O)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Reactant: COCCO
Product: COCCOc1ccc2c(c1)C(C)(C)c1[nH]c3cc(C#N)ccc3c1C2=O

Procedure:
Under the same conditions as the method for synthesizing Compound A7-1, the title compound was prepared from Compound A6 and 2-methoxyethanol.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:12][CH2:11][C:10]2[C:13]([Br:22])=[C:14]([C:16](=O)[C:17]([F:20])([F:19])[F:18])[S:15][C:9]=2[CH2:8][CH2:7]1)=[O:5])[CH3:2].[BH4-].[Na+].Cl[Sn]Cl>CCO.O>[CH2:1]([O:3][C:4]([N:6]1[CH2:12][CH2:11][C:10]2[C:13]([Br:22])=[C:14]([CH2:16][C:17]([F:20])([F:18])[F:19])[S:15][C:9]=2[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCc2sc(C(=O)C(F)(F)F)c(Br)c2CC1
Agent: Cl[Sn]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)N1CCc2sc(CC(F)(F)F)c(Br)c2CC1
Temperature: 80 °C
Reaction time: 0.33 h

Procedure:
The product of step (a) (73 mg, 0.18 mmol) was stirred in 3 mL EtOH and treated with NaBH4 (20 mg, 0.5 mmol). After stirring for 20 minutes, the reaction was quenched with HOAc until no bubbling was observed. The reaction was diluted with water (5 mL) and the crude product was extracted into DCM (3×5 mL). The combined organic extracts were concentrated and the residue was dissolved in HOAc (2 mL) and concentrated HCl (1 mL). SnCl2 (225 mg, 1 mmol) was added and the reaction was heated to 80° C. for 2 hours. The crude reaction was diluted with water (10 mL) and the product was extracted into DCM (3×5 mL). The combined organic extracts were concentrated to dryness and used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH2:10][CH2:11][O:12][CH3:13])=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:14][C:15]#[N:16].[C:17](OCC)(=[O:19])[CH3:18]>O1CCCC1>[CH3:1][O:2][C:3]1[C:8]([O:9][CH2:10][CH2:11][O:12][CH3:13])=[CH:7][CH:6]=[CH:5][C:4]=1[CH:14]([C:17](=[O:19])[CH3:18])[C:15]#[N:16]
Reactant: CCOC(C)=O
Reactant: COCCOc1cccc(CC#N)c1OC
Solvent: C1CCOC1
Product: COCCOc1cccc(C(C#N)C(C)=O)c1OC
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 171.1 %

Procedure:
To a suspension of (2-(methyloxy)-3-{[2-(methyloxy)ethyl]oxy}phenyl)acetonitrile (0.17 g, 0.76 mmol) sodium hydride (40% oil dispersion, 93 mg, 2.3 mmol) in tetrahydrofuran (5 mL), was added ethyl acetate (0.37 mL, 0.38 mmol), and the resulting mixture was stirred at 60° C. for 1.5 hours. Then it was cooled to room temperature, and poured into a mixture of ice-water (50 mL). This aqueous mixture was washed with dichloromethane (3×20 mL) then acidified to pH 2. The acidified mixture was extracted with ethyl acetate (3×30 mL). The combined extract was washed with saturated sodium bicarbonate solution, brine, dried over sodium sulfate, filtered and concentrated to give 2-(2-(methyloxy)-3-{[2-(methyloxy)ethyl]oxy}phenyl)-3-oxobutanenitrile (0.17 g, 0.65 mmol, 85% yield). MS (EI) for C14H17NO4: 264 (MH+).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([Mg]Br)=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CON(C)[C:19]([C:21]1[C:26]([NH2:27])=[N:25][CH:24]=[C:23]([C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[C:30]([Cl:35])[CH:29]=2)[N:22]=1)=[O:20].Cl>C1COCC1>[NH2:27][C:26]1[C:21]([C:19]([C:11]2[CH:12]=[CH:13][C:8]([CH2:7][N:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)=[CH:9][CH:10]=2)=[O:20])=[N:22][C:23]([C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[C:30]([Cl:35])[CH:29]=2)=[CH:24][N:25]=1
Reactant: CON(C)C(=O)c1nc(-c2ccc(Cl)c(Cl)c2)cnc1N
Reactant: Br[Mg]c1ccc(CN2CCCCC2)cc1
Agent: Cl
Solvent: C1CCOC1
Product: Nc1ncc(-c2ccc(Cl)c(Cl)c2)nc1C(=O)c1ccc(CN2CCCCC2)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of 0.25 M [4-(1-piperidinyl-methyl)phenyl]magnesium bromide in THF (5.51 ml, 1.37 mmol) is added dropwise to a solution of 3-amino-6-(3,4-dichloro-phenyl)-pyrazine-2-carboxylic acid methoxy-methyl amide (Intermediate B) (0.09 g, 0.27 mmol) in THF (5 ml) and the resulting solution is stirred for 2 hours. The solution is cooled to 0° C., and 2M HCl (10 ml) is added. The solution is washed with EtOAc (20 ml) and then the pH is adjusted to 11 using 2M NaOH. Extraction with EtOAc (50 ml), drying (MgSO4) and removal of solvent in vacuo affords a yellow oil. Purification by flash chromatography (SiO2, 50-100% EtOAc in iso-hexane) followed by trituration with methanol affords the title compound as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 9.04 (1H, s), 8.12 (1H, d), 7.97 (2H, bs), 7.93-7.88 (3H, m), 7.71 (1H, d), 7.47 (2H, d), 3.54 (2H, s), 2.36 (4H, bs), 1.52-1.51 (4H, m), 1.43-1.37 (2H, m); MS m/z 441, 443 [M+H]+
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([O:10][CH:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)[N:7]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH2:23])[N:18]=3)[C:6]=2[CH:24]=1.[CH3:25][C:26]1[O:30][N:29]=[C:28]([C:31]([OH:35])([C:33]#[CH:34])[CH3:32])[CH:27]=1.C(N(CC)CC)C>CS(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:23][C:19]1[N:18]=[C:17]([N:7]2[C:6]3[CH:24]=[C:2]([C:34]#[C:33][C:31]([C:28]4[CH:27]=[C:26]([CH3:25])[O:30][N:29]=4)([OH:35])[CH3:32])[CH:3]=[CH:4][C:5]=3[N:9]=[C:8]2[O:10][CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[CH:22]=[CH:21][N:20]=1
Reactant: C#CC(C)(O)c1cc(C)on1
Reactant: Nc1nccc(-n2c(OC3CCOCC3)nc3ccc(Br)cc32)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: Cc1cc(C(C)(O)C#Cc2ccc3nc(OC4CCOCC4)n(-c4ccnc(N)n4)c3c2)no1
Temperature: 70 °C
Reaction time: 5 h
Yield: 24.1 %

Procedure:
A mixture of 4-[6-bromo-2-(oxan-4-yloxy)-1H-1,3-benzodiazol-1-yl]pyrimidin-2-amine (150 mg, 0.27 mmol, 70%), 2-(5-methyl-1,2-oxazol-3-yl)but-3-yn-2-ol (200 mg, 1.32 mmol), bis(triphenylphosphine)palladium(II) dichloride (220 mg, 0.31 mmol) and triethylamine (1 mL) in dimethylsulfoxide (2 mL) was stirred under nitrogen atmosphere for 5 hr at 70° C. The reaction mixture was cooled to room temperature then filtered through a frit filter to remove the catalyst. The filtrate was purified by preparative HPLC to give 30 mg (24%) of 4-[1-(2-aminopyrimidin-4-yl)-2-(oxan-4-yloxy)-1H-1,3-benzodiazol-6-yl]-2-(5-methyl-1,2-oxazol-3-yl)but-3-yn-2-ol as a white solid. 1H NMR (400 MHz, DMSO) delta 8.41 (d, J=5.6 Hz, 1H), 8.15 (s, 1H), 7.46 (d, J=8.0 Hz, 1H), 7.28-7.07 (m, 1H), 7.08 (s, 2H), 6.99 (d, J=5.6 Hz, 1H), 6.46 (s, 1H), 6.37 (s, 1H), 5.39-5.35 (m, 1H), 3.88-3.82 (m, 2H), 3.06-3.55 (m, 2H), 2.51 (s, 3H), 2.24-2.16 (m, 2H), 1.88-1.82 (m, 5H); LC-MS: m/z=+461 (M+H)+.
Reaction SMILES: S(=O)(=O)(O)O.[F:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]([OH:16])=[O:15])=[CH:9][CH:8]=1.[CH3:17]O>CCOCC.C(OCC)(=O)C>[F:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:13][C:14]([O:16][CH3:17])=[O:15])=[CH:11][CH:12]=1
Reactant: CO
Reactant: O=C(O)Cc1ccc(F)cc1
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: COC(=O)Cc1ccc(F)cc1

Procedure:
A catalytic amount (0.5 mL) of concentrated sulfuric acid was added to a solution of 4-fluorophenylacetic acid (30.8 g, 0.20 mol) in 500 mL of methanol. The solution was stirred at reflux for 4 hours. The volatile materials were removed under reduced pressure to furnish a colorless oil which was dissolved in ether/ethyl acetate and washed with 2 N aqueous Na2CO3, brine, dried over MgSO4, and filtered. The filtrate was concentrated under reduced pressure to provide an oil which was dried overnight under high vacuum (yield: 33.6 g; 95%). 1H NMR (300 MHz, CDCl3) δ 3.59 (s, 2H), 3.65 (s, 3H), 7.01 (t, J=9 Hz, 2H), 7.20-7.28 (m, 2H). MS (DCI/NH3) m/z 186 (M+NH4)+.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]([CH3:23])([CH3:22])[C:12](OCC3C=CC=CC=3)=[O:13])[NH:8]2)=[CH:4][C:3]=1[N+:24]([O-:26])=[O:25].CC(C[AlH]CC(C)C)C>C(Cl)Cl>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]([CH3:23])([CH3:22])[CH2:12][OH:13])[NH:8]2)=[CH:4][C:3]=1[N+:24]([O-:26])=[O:25]
Reactant: CC(C)(C(=O)OCc1ccccc1)c1cc2cc([N+](=O)[O-])c(F)cc2[nH]1
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Product: CC(C)(CO)c1cc2cc([N+](=O)[O-])c(F)cc2[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.3 %

Procedure:
To a solution of benzyl 2-(6-fluoro-5-nitro-1H-indol-2-yl)-2-methylpropanoate (18.0 g, 0.05 mol) in CH2Cl2 (100 mL) was added DIBAL-H (12 mL) at −78° C. The mixture was stirred for 1 h at that temperature and was warmed to room temperature. The reaction was quenched with water and the aqueous layer was extracted with EtOAc (100 mL×3). The combined organic layers were dried over anhydrous Na2SO4, the solvent was evaporated in vacuo. The residue was purified by chromatography on silica gel (10% EtOAc in petroleum ether) to give 2-(6-fluoro-5-nitro-1H-indol-2-yl)-2-methylpropan-1-ol (10.0 g, 77%). 1H NMR (300 MHz, CDCl3) 9.37 (s, 1 H), 8.32 (d, J=7.2 Hz, 1 H), 7.11 (d, J=11.7 Hz, 1 H), 6.36 (s, 1 H), 3.73 (d, J=5.1 Hz 2 H), 1.97 (t, J=5.1 Hz, 1 H), 1.39 (s, 6 H).
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([S:7]([N:10]2[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C:17]([OH:19])=O)=[CH:11]2)(=[O:9])=[O:8])=[CH:4][CH:3]=1.CN(C=O)C.[C:25]([O:29][C:30](=[O:39])[NH:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[NH2:38])([CH3:28])([CH3:27])[CH3:26]>C(N(CC)CC)C>[C:25]([O:29][C:30](=[O:39])[NH:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[NH:38][C:17](=[O:19])/[CH:16]=[CH:15]/[C:12]1[CH:13]=[CH:14][N:10]([S:7]([C:5]2[S:6][C:2]([Br:1])=[CH:3][CH:4]=2)(=[O:8])=[O:9])[CH:11]=1)([CH3:28])([CH3:26])[CH3:27]
Reactant: O=C(O)/C=C/c1ccn(S(=O)(=O)c2ccc(Br)s2)c1
Reactant: CC(C)(C)OC(=O)Nc1ccccc1N
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)/C=C/c1ccn(S(=O)(=O)c2ccc(Br)s2)c1
Reaction time: 0.5 h

Procedure:
A mixture of 4.1 g (E)-3-[1-(5-bromo-thiophene-2-sulfonyl)-1H-pyrrol-3-yl]-acrylic acid with 200 ml DMF and 1.8 g HOBtxH2O and 16.0 ml triethylamine is stirred for 0.5 h. Then it is added 6.6 g EDCxHCL and stirred for 0.5 h. After that 2.4 g (2-amino-phenyl)-carbamic acid tert-butyl ester are added and the suspension is stirred at ambient temperature for 24 h. The DMF is evaporated and the residue is extracted with ethyl acetate and water. The organic layer is dried over sodium sulfate and evaporated. The title product is isolated by flash chromatography. By this method 3.7 g of a colorless solid is obtained.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:12]=1[O:13][CH3:14])[CH2:8][OH:9].[Br:15][C:16]1[CH:21]=[C:20](F)[CH:19]=[C:18]([F:23])[CH:17]=1.O>CN(C=O)C>[Br:15][C:16]1[CH:17]=[C:18]([F:23])[CH:19]=[C:20]([O:9][CH2:8][C:7]2[CH:10]=[CH:11][C:12]([O:13][CH3:14])=[C:5]([O:4][CH3:3])[CH:6]=2)[CH:21]=1
Reactant: COc1ccc(CO)cc1OC
Reactant: Fc1cc(F)cc(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(COc2cc(F)cc(Br)c2)cc1OC
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 82.8 %

Procedure:
Sodium hydride (80% disp. in oil; 933 mg, 31.1 mmol) was added, all at once to 3,4-dimethoxybenzyl alcohol (3.48 g, 20.7 mmol) in DMF (40 mL) at 0° C. and under Ar. After 5 min., the mixture was allowed to warm to r.t. After 1 h, 1-bromo-3,5-difluorobenzene (4 g, 20.7 mmol) in DMF (5 mL) was added dropwise at r.t. The resulting mixture was kept at this temperature for 16 h and slowly poured into H2O (500 mL). It was extracted with EtOAc (3×) and the combined organics were washed with 25% NH4OAc buffer (1×), H2O (2×) and brine. The solution was dried (MgSO4) and concentrated to give a pale yellow solid that was purified by column chromatography on silica gel (EtOAc:hexane, 10:90-15:85) to afford the title compound as a white solid (5.85 g, 83%).
Reaction SMILES: [NH2:1][CH2:2][C:3]1([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[N:17]=2)[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1.[Cl:23][C:24]1[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:25]=1[C:26](Cl)=[O:27]>>[Cl:23][C:24]1[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:25]=1[C:26]([NH:1][CH2:2][C:3]1([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[N:17]=2)[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:14])([CH3:15])[CH3:13])=[O:10])[CH2:5][CH2:4]1)=[O:27]
Reactant: CC(C)(C)OC(=O)N1CCC(CN)(c2cccc(F)n2)CC1
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Product: CC(C)(C)OC(=O)N1CCC(CNC(=O)c2ccc(Cl)cc2Cl)(c2cccc(F)n2)CC1

Procedure:
tert-Butyl 4-(aminomethyl)-4-(6-fluoropyridin-2-yl)piperidine-1-carboxylate (0.82 mmol) was acylated with 2,4-dichlorobenzoyl chloride (0.12 mL, 0.82 mmol) using the method described in example 8-1 to afford the desired product: tert-butyl 4-{[(2,4-dichlorobenzoyl)amino]methyl}-4-(6-fluoropyridin-2-yl)piperidine-1-carboxylate: 1H NMR δ (ppm)(CDCl3): 7.81 (1 H, q, J=8.0 Hz), 7.61 (1 H, d, J=8.3 Hz), 7.38 (1 H, d, J=1.9 Hz), 7.29 (1 H, dd, J=8.0, 2.0 Hz), 7.24 (1 H, dd, J=7.7, 2.7) 6.82 (1 H, dd, J=3.0, 8.1 Hz), 6.69 (1 H, m), 3.80 (1 H, br s) 3.68-3.62 (2 H, m), 3.40-3.34 (2 H, m), 2.22-2.16 (2 H, m), 1.87-1.81 (2 H, m), 1.45 (9 H, s).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([CH3:12])[CH:9]=[CH:8][C:3]=1[C:4](=[N:6][OH:7])[NH2:5].N1C=CC=CC=1.Cl[C:20](OCC)=[O:21]>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:11]=[C:10]([CH3:12])[CH:9]=[CH:8][C:3]=1[C:4]1[NH:5][C:20](=[O:21])[O:7][N:6]=1
Reactant: Cc1ccc(C(N)=NO)c(C)c1
Reactant: CCOC(=O)Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: Cc1ccc(-c2noc(=O)[nH]2)c(C)c1

Procedure:
Under an inert atmosphere, 10.5 g of 2,4-dimethyl benzamidoxime are dissolved in 40 ml of anhydrous toluene; 6.5 ml of pyridine and 7.6 g of ethyl chloroformate are added.