Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:6]([CH2:7][C:8]([NH:10][CH3:11])=O)[N:5]=[N:4][N:3]=1.C(Cl)Cl.C(Cl)(Cl)=O.[N-:19]=[N+:20]=[N-:21].CN(C)C(=[NH2+])N(C)C>N1C=CC=CC=1>[CH3:11][N:10]1[C:8]([CH2:7][N:6]2[C:2]([Cl:1])=[N:3][N:4]=[N:5]2)=[N:21][N:20]=[N:19]1
Reactant: [N-]=[N+]=[N-]
Reactant: CNC(=O)Cn1nnnc1Cl
Agent: CN(C)C(=[NH2+])N(C)C
Agent: O=C(Cl)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cn1nnnc1Cn1nnnc1Cl
Reaction time: 0.17 h

Procedure:
To a suspension of 1.75 g. (10 mmole) of 5-chloro-N-methyl-1H-tetrazol-1-acetamide, prepared as described under A above, in 50 ml. of methylene chloride containing 0.8 g. of pyridine and maintained at a temperature of about 0° C. was added with stirring excess phosgene. After addition was complete, the reaction mixture was stirred for 10 minutes without further cooling. The clear solution obtained on reaction was evaporated to dryness at a temperature of about 30° C. under reduced pressure. The residue containing the reaction product was suspended in 50 ml. of dioxane, and 2.4 g. (15.2 mmole) of tetramethylguanidinium azide were added to the suspension. The mixture was heated for 2 hours at the reflux temperature and after stirring overnight at room temperature, the reaction mixture was concentrated to near dryness under reduced pressure. The concentrate was dissolved in 30 ml. of water forming a pale yellow solution from which the product crystallized as colorless needles. The product was filtered and 0.4 g. of the crystalline product melting at about 138° C. to about 140° C. were obtained. A second crop of 0.5 g. of the product melting at about 136° C. to about 139° C. was isolated from the filtrate.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:4]3[C:8](=[C:9]([Cl:11])[CH:10]=1)[N:7]=[C:6](S)[C:5]=3[CH:13]=[CH:14][CH:15]=2.[N:16]1([CH2:21][CH2:22][CH2:23][NH2:24])[CH:20]=[CH:19][N:18]=[CH:17]1>CN(C)C=O>[Cl:1][C:2]1[C:3]2[C:4]3[C:8](=[C:9]([Cl:11])[CH:10]=1)[N:7]=[C:6]([NH:24][CH2:23][CH2:22][CH2:21][N:16]1[CH:20]=[CH:19][N:18]=[CH:17]1)[C:5]=3[CH:13]=[CH:14][CH:15]=2
Reactant: NCCCn1ccnc1
Reactant: SC1=Nc2c(Cl)cc(Cl)c3cccc1c23
Solvent: CN(C)C=O
Product: Clc1cc(Cl)c2cccc3c2c1N=C3NCCCn1ccnc1
Yield: 43.4 %

Procedure:
A mixture of 5.0 g of 6,8-dichloro-benz(cd) indole-2-thiol, 35 ml of dimethylformamide, 2.6 g of 3-(1H-imidazol-yl)propanamine and 6.3 g of mercuric acetate was reacted as described in Example 1, giving 2.95 g of the desired product, mp 182° C.-183° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C:10]1=[O:15].[Br:16]Br>C(Cl)(Cl)Cl>[Br:16][CH:11]1[CH2:12][CH2:13][CH2:14][CH:9]([C:3]2[CH:4]=[C:5]([Cl:8])[CH:6]=[CH:7][C:2]=2[Cl:1])[C:10]1=[O:15]
Reactant: BrBr
Reactant: O=C1CCCCC1c1cc(Cl)ccc1Cl
Solvent: ClC(Cl)Cl
Product: O=C1C(Br)CCCC1c1cc(Cl)ccc1Cl
Temperature: 25 °C
Yield: 115.3 %

Procedure:
2-(2,5-Dichloro-phenyl)-cyclohexanone (50 mg, 0.21 mmol) was dissolved in chloroform (1 mL). To this solution bromine (34.5 mg, 0.22 mmol) in chloroform (0.5 mL) was added drop wise at room temperature. The reaction was stirred for 1½ hours at room temperature. The solvent was removed under reduced pressure to yield the crude title compound (78 mg) which was used directly in the next step without further purification.
Reaction SMILES: [OH:1][C:2]1([CH2:15][N:16]([CH:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:27]O)[CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.CS(OS(C)(=O)=O)(=O)=O>C1COCC1>[CH3:25][O:24][C:21]1[CH:22]=[CH:23][C:18]([CH2:17][N:16]2[CH:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:27][O:1][C:2]3([CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:12])[CH3:13])=[O:9])[CH2:4][CH2:3]3)[CH2:15]2)=[CH:19][CH:20]=1
Reactant: COc1ccc(CN(CC2(O)CCN(C(=O)OC(C)(C)C)CC2)C(CO)c2ccccc2)cc1
Agent: CS(=O)(=O)OS(C)(=O)=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CN2CC3(CCN(C(=O)OC(C)(C)C)CC3)OCC2c2ccccc2)cc1
Temperature: 25 °C
Yield: 51.9 %

Procedure:
To a solution of tert-butyl 4-hydroxy-4-[[(2-hydroxy-1-phenyl-ethyl)-[(4-methoxyphenyl)methyl]amino]methyl]piperidine-1-carboxylate (1.0 g, 2.13 mmol) in THF (10 mL) was added DIEA (1.1 mL, 6.38 mmol) followed by an addition of a solution of methylsulfonyl methanesulfonate (1.1 g, 6.38 mmol) in THF (2 mL) under an atmosphere of nitrogen at 0° C. The reaction mixture was warmed to room temperature and then heated at 40° C. for 16 hours. The reaction mixture was quenched with water and the aqueous layer was extracted with DCM. The organic layer was washed with a sat. solution of NaHCO3, followed by washing with water. The organic layer was dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography using 0 to 100% DCM in hexanes as eluent to obtain tert-butyl 8-[(4-methoxyphenyl)methyl]-9-phenyl-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylate (0.5 g, 51%). ESI-MS m/z calc. 452.6. Found 453.5 (M+1)+; Retention time: 1.62 minutes (3 min run).
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21](O)[N:20]=[CH:19][C:16]=43)[CH:10]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].[NH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>>[CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[C:16]4[CH:19]=[N:20][C:21]([N:24]5[CH2:29][CH2:28][O:27][CH2:26][CH2:25]5)=[CH:22][C:15]=4[O:14][CH2:13][CH2:12][N:11]3[CH:10]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1cnc(O)cc1OCC2
Reactant: C1COCCN1
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1cnc(N3CCOCC3)cc1OCC2
Yield: 44 %

Procedure:
Following the procedures of Example 339, 2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulen-8-ol from Example 93 and morpholine, the crude product was recrystallised from methanol to give 341 as a white solid (107 mg, 44%). LCMS: RT=3.12 min, [M+H]+ 382. 1H NMR 400 MHz (DMSO-d) δ: 9.14 (1H, s), 7.90 (1H, d, J=0.63 Hz), 7.86 (1H, s), 6.36 (1H, s), 5.93-5.92 (1H, m), 4.57-4.48 (4H, m), 3.70 (4H, t, J=4.74 Hz), 3.50 (4H, t, J=4.74 Hz), 1.49 (6H, d, J=6.60 Hz)
Reaction SMILES: C[O-].[Na+].Cl.[CH3:5][O:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([NH2:13])=[NH:12])=[CH:9][CH:8]=1.[C:16](OCC)(=[O:23])[CH2:17][C:18](OCC)=[O:19]>CO.C(O)C>[CH3:5][O:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]2[N:13]=[C:18]([OH:19])[CH:17]=[C:16]([OH:23])[N:12]=2)=[CH:9][CH:8]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: COc1ccc(C(=N)N)cc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: CO
Product: COc1ccc(-c2nc(O)cc(O)n2)cc1
Yield: 83.9 %

Procedure:
338 g of a 30% solution of sodium methylate in methanol are added over 10 minutes to a suspension of 112 g of p-methoxybenzamidine hydrochloride and 101 g of diethyl malonate in 520 ml of ethanol, and the mixture is subsequently refluxed for 5 hours. The reaction mixture is then concentrated by rotary evaporation and the residue is dissolved in 1000 ml of warm water of 80° C. The solution is filtered and the filtrate is acidified to pH 1. The precipitate is isolated by filtration and vacuum dried at 80° C., affording 109.8 g of 2-p-methoxyphenyl-4,6-dihydroxypyrimidine with a melting point of 318° C. (decompos.).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[CH:6]=[CH:5][C:4]=1[N+:15]([O-])=O.[H][H]>CCOC(C)=O.CCO.[Pd]>[CH3:1][O:2][C:3]1[C:4]([NH2:15])=[CH:5][CH:6]=[C:7]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[N:8]=1
Reactant: [H][H]
Reactant: COc1nc(N2CCOCC2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1nc(N2CCOCC2)ccc1N
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.1 %

Procedure:
To a solution of 4-(6-methoxy-5-nitropyridin-2-yl)morpholine (Preparation 81, 280 mg, 1.170 mmol) in EtOAc/EtOH (1:1, 10 ml) was added palladium on charcoal (10%, 100 mg). The flask was charged with hydrogen and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was filtered through Celite® and concentrated in vacuo to give the title compound (245 mg, 99%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:11]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:14][S:13][C:12]=2[C:22]([O:24][CH3:25])=[O:23])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:10])=O.[C:26]([O-:29])(=[O:28])[CH3:27].[Na+].C(OCC)C>C(OC(=O)C)(=O)C>[C:26]([O:29][CH2:10][S:8][C:7]1[CH:6]=[CH:5][C:4]([C:11]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:14][S:13][C:12]=2[C:22]([O:24][CH3:25])=[O:23])=[CH:3][C:2]=1[F:1])(=[O:28])[CH3:27]
Reactant: COC(=O)c1scc(-c2ccccc2)c1-c1ccc(S(C)=O)c(F)c1
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: CCOCC
Product: COC(=O)c1scc(-c2ccccc2)c1-c1ccc(SCOC(C)=O)c(F)c1
Yield: 62.5 %

Procedure:
The methyl 3-[3-fluoro-4-(methylsulfinyl)phenyl]-4-phenyl-2-thiophenecarboxylate (4.13 g, 11.04 mmol) was dissolved in acetic anhydride (45.0 mL). Powdered sodium acetate (4.0 g, 48.7 mmol) was added and the solution was refluxed for 8 hours. The solution was poured into a 500 mL round bottom flask and solvent removed at reduced pressure. The residue was taken up in ethyl acetate (200 ml) and dichloromethane (20 mL). The solution was extracted with saturated sodium bicarbonate (3×100 mL) followed by saturated ammonium chloride (2×100 mL). The solvent was removed at reduce pressure and residue taken up in ether, dried over sodium sulfate and solvent removed at reduced pressure. Methyl 3-[4-[[(acetyloxy)methyl]thio]-3-fluorophenyl]-4-phenyl-2-thiophenecarboxylate (2.9 g, 6.90 mmol) was isolated by crystallization from diethyl ether and hexanes as white crystals. (62% yield). Mp 102.9-103.7° C. 1H NMR (CDCl3/300 MHz) 7.53 (s, 1H), 7.43 (t, 1H, J=7.8 Hz), 7.22-7.28 (m, 3H), 7.04-7.08 (m, 2H), 6.92-6.98 (m, 2H), 5.42 (s, 2H), 3.81 (s, 3H), 2.11 (s, 3H). ESHRMS m/z 434.0898 (calcd for M+NH4+, 434.0896)
Reaction SMILES: C[Si]([N:5]=[N+:6]=[N-:7])(C)C.[C:8]([C:10]1[N:15]=[C:14]([O:16][CH3:17])[C:13]([N+:18]([O-:20])=[O:19])=[CH:12][CH:11]=1)#[CH:9]>C1(C)C=CC=CC=1.O>[CH3:17][O:16][C:14]1[C:13]([N+:18]([O-:20])=[O:19])=[CH:12][CH:11]=[C:10]([C:8]2[CH:9]=[N:7][NH:6][N:5]=2)[N:15]=1
Reactant: C#Cc1ccc([N+](=O)[O-])c(OC)n1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Solvent: O
Solvent: Cc1ccccc1
Product: COc1nc(-c2cn[nH]n2)ccc1[N+](=O)[O-]
Temperature: 130 °C
Reaction time: 48 h
Yield: 231 %

Procedure:
Trimethylsilylazide (1.2 mL, 9.21 mmol) was added to a solution of 6-ethynyl-2-methoxy-3-nitropyridine (Preparation 200, 0.082 g, 0.460 mmol) in toluene (10.2 mL). The reaction mixture was stirred at 130° C. for 48 hours. The reaction was diluted with water and concentrated in vacuo. The residue was purified using Biotage silica gel column chromatography eluting with cyclohexane/EtOAc 70/30 to 50/50 to afford the title compound as a beige solid (235 mg, 77%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=O.[NH2:12][CH:13]([CH2:21][CH3:22])[C:14]([O:16][CH2:17][CH:18]([CH3:20])[CH3:19])=[O:15]>>[CH2:17]([O:16][C:14](=[O:15])[CH:13]([NH:12][C:9](=[O:11])[CH2:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[CH3:1])[CH2:21][CH3:22])[CH:18]([CH3:19])[CH3:20]
Reactant: Cc1ccccc1CC(=O)O
Reactant: CCC(N)C(=O)OCC(C)C
Product: CCC(NC(=O)Cc1ccccc1C)C(=O)OCC(C)C

Procedure:
Following General Procedure BI above and using 2-methylphenylacetic acid (Aldrich) and iso-butyl 2-aminobutyrate (prepared following General Procedure BJ above), the title compound was prepared. The reaction was monitored by tlc on silica gel and purification was by filtration as described in the general procedure.
Reaction SMILES: [CH2:1]([C:3]1[N:4]([CH2:9][CH2:10][NH2:11])[CH:5]=[C:6]([I:8])[N:7]=1)[CH3:2].[F:12][C:13]1[C:18]([CH3:19])=[C:17]([F:20])[CH:16]=[CH:15][C:14]=1[CH2:21][CH2:22][CH:23]=O>>[F:12][C:13]1[C:18]([CH3:19])=[C:17]([F:20])[CH:16]=[CH:15][C:14]=1[CH2:21][CH2:22][CH:23]1[NH:11][CH2:10][CH2:9][N:4]2[C:3]([CH2:1][CH3:2])=[N:7][C:6]([I:8])=[C:5]12
Reactant: Cc1c(F)ccc(CCC=O)c1F
Reactant: CCc1nc(I)cn1CCN
Product: CCc1nc(I)c2n1CCNC2CCc1ccc(F)c(C)c1F

Procedure:
According to the general procedure (GP10), the microwave-assisted Pictet-Spengler reaction (60 W; 100° C.; 8 bars; 10 min.) between 2-(2-ethyl-4-iodo-imidazol-1-yl)-ethylamine (334.0 mg; 1.260 mmol) and 3-(2,4-difluoro-3-methyl-phenyl)-propionaldehyde (232.7 mg; 1.260 mmol) afforded 8-[2-(2,4-difluoro-3-methyl-phenyl)-ethyl]-3-ethyl-1-iodo-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine which was Boc-protected and finally purified by HPLC.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[C:7]1[CH:12]=[C:11]([C:13]2[CH:18]=[C:17](Cl)[N:16]=[C:15]([NH2:20])[N:14]=2)[C:10]([CH3:21])=[CH:9][C:8]=1[CH3:22])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[NH2:30][CH2:31][CH2:32][SH:33]>CN(C)C=O.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:23])[C:7]1[CH:12]=[C:11]([C:13]2[CH:18]=[C:17]([S:33][CH2:32][CH2:31][NH2:30])[N:16]=[C:15]([NH2:20])[N:14]=2)[C:10]([CH3:21])=[CH:9][C:8]=1[CH3:22])([CH3:4])([CH3:3])[CH3:2]
Reactant: NCCS
Reactant: Cc1cc(C)c(-c2cc(Cl)nc(N)n2)cc1C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cc(C)c(-c2cc(SCCN)nc(N)n2)cc1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 78.3 %

Procedure:
5-(2-Amino-6-chloropyrimidin-4-yl)-2,4-dimethylbenzoic acid tert-butyl ester (Compound 1-1) (5.0 g, 15.0 mmol) obtained in Example 1-1 was dissolved in N,N-dimethylformamide (125 ml), and then cesium carbonate (11.5 g, 150.0 mmol) and 2-aminoethanethiol (48.8 g, 150.0 mmol) were added thereto at room temperature. The resulting mixture was stirred at room temperature for three hours, and then diluted with ethyl acetate (500 ml). The solution was sequentially washed with water (500 ml, three times) and a saturated aqueous sodium chloride solution (500 ml). The washed organic layer was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The resulting crude product was dissolved in ethyl acetate (20 ml) while heating, and n-hexane (60 ml) was added thereto. The mixture was stirred at room temperature for one hour. The precipitated crystals were collected by filtration. After washing with n-hexane (60 ml), the crystals were dried under reduced pressure to yield 5-[2-amino-6-(2-aminoethylsulfanyl)pyrimidin-4-yl]-2,4-dimethylbenzoic acid tert-butyl ester (4.4 g) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11]([NH:13][CH2:14][CH:15]2[CH2:42][CH2:41][C:18]3[N:19](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[CH:20]=[N:21][C:17]=3[CH2:16]2)=[O:12])=[CH:4][CH:3]=1.ClC1C=CC(CCCC(NCC2CCC3N=CN(C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)C=3C2)=O)=CC=1>C(O)(=O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][C:11]([NH:13][CH2:14][CH:15]2[CH2:42][CH2:41][C:18]3[NH:19][CH:20]=[N:21][C:17]=3[CH2:16]2)=[O:12])=[CH:6][CH:7]=1
Reactant: O=C(CCCc1ccc(Cl)cc1)NCC1CCc2c(ncn2C(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Agent: O=C(CCCc1ccc(Cl)cc1)NCC1CCc2ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c2C1
Solvent: CC(=O)O
Solvent: O
Product: O=C(CCCc1ccc(Cl)cc1)NCC1CCc2[nH]cnc2C1
Temperature: 90 °C

Procedure:
A solution of a mixture of 4-(4-chlorophenyl)-N-((1-triphenylmethyl-4,5,6,7-tetrahydro-1H-benzimidazol-5-yl)methyl)butyramide and 4-(4-chlorophenyl)-N-((3-triphenylmethyl-4,5,6,7-tetrahydro-3H-benzimidazol-5-yl)methyl)butyramide (0.43 g, 0.72 mmol) in acetic acid (5 ml) and water (0.6 ml) was heated to 90° C. for 2 hours. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (40 g), using DCM/methanol/25% aqueous ammonia (100:10:1) as eluent, to give 0.21 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH3:27])[C:10]([C:16]1[CH:17]=[CH:18][C:19]2[O:23][C:22](=[O:24])[N:21]([CH3:25])[C:20]=2[CH:26]=1)([OH:15])[C:11]([F:14])([F:13])[F:12].[Cl:28][C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][C:34]=1[C:35]([O:37][CH3:38])=[O:36].N1C=CC=CC=1.Cl>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:38][O:37][C:35](=[O:36])[C:34]1[CH:33]=[CH:32][C:31]([O:8][C:6]2[CH:5]=[CH:4][C:3]([CH:9]([CH3:27])[C:10]([OH:15])([C:16]3[CH:17]=[CH:18][C:19]4[O:23][C:22](=[O:24])[N:21]([CH3:25])[C:20]=4[CH:26]=3)[C:11]([F:12])([F:13])[F:14])=[C:2]([Cl:1])[CH:7]=2)=[CH:30][C:29]=1[Cl:28]
Reactant: CC(c1ccc(O)cc1Cl)C(O)(c1ccc2oc(=O)n(C)c2c1)C(F)(F)F
Reactant: COC(=O)c1ccc(B(O)O)cc1Cl
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1ccc(Oc2ccc(C(C)C(O)(c3ccc4oc(=O)n(C)c4c3)C(F)(F)F)c(Cl)c2)cc1Cl
Temperature: 25 °C
Yield: 27 %

Procedure:
5-[2-(2-Chloro-4-hydroxy-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-3-methyl-3H-benzooxazol-2-one (90 mg, obtained in Example 172), 3-chloro-4-methoxycarbonylphenyl-boronic acid (144 mg, [CAS Reg. No. 603122-82-3]), copper(II)-acetate (122 mg) and pyridine (0.090 mL) were dissolved in CH2Cl2 (3 mL). The mixture was stirred over night at r.t. The reaction mixture was poured into ice/water and acified with 1M aqueous HCl. The aqueous layer was extracted three times with ethylacetate. The combined organic layers were washed with brine, dried over Na2SO4, filtered and the solvent was evaporated. The residue was purified by flash chromatography (silica gel, gradient of heptane in ethyl acetate) to give the title compound as a colorless foam (35 mg, 27%). MS (m/e)=570.1 [M+H+].
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:21]([CH3:23])[CH3:22])[C:6]2[O:10][C:9]([C:11]3[CH:19]=[CH:18][C:14]([C:15](O)=[O:16])=[CH:13][CH:12]=3)=[N:8][C:7]=2[CH:20]=1)#[N:2].[CH3:24][O:25][C:26]([CH:28]([NH2:37])[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=1)=[O:27].Cl.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[CH3:24][O:25][C:26](=[O:27])[CH:28]([NH:37][C:15](=[O:16])[C:14]1[CH:13]=[CH:12][C:11]([C:9]2[O:10][C:6]3[C:5]([CH:21]([CH3:23])[CH3:22])=[CH:4][C:3]([C:1]#[N:2])=[CH:20][C:7]=3[N:8]=2)=[CH:19][CH:18]=1)[CH2:29][C:30]1[CH:31]=[CH:32][C:33]([Cl:36])=[CH:34][CH:35]=1
Reactant: CC(C)c1cc(C#N)cc2nc(-c3ccc(C(=O)O)cc3)oc12
Reactant: COC(=O)C(N)Cc1ccc(Cl)cc1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C(Cc1ccc(Cl)cc1)NC(=O)c1ccc(-c2nc3cc(C#N)cc(C(C)C)c3o2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 59.8 %

Procedure:
At room temperature, a 2-dram vial, equipped with a magnetic stirrer was charged with 4-(5-cyano-7-isopropyl-1,3-benzoxazol-2-yl)benzoic acid (153 mg, 0.5 mmol, INTERMEDIATE 2), DL-4-chlorophenylalanine methyl ester hydrochloride (125 mg, 0.5 mmol), bromotrispyrrolidinophosphonium hexafluorophosphate (233 mg, 0.5 mmol) and 5 ml of dimethylformamide. To this was added diisopropylethylamine (524 μl, 3 mmol) dropwise, during which addition the reaction turned a reddish-orange. After a few minutes the reaction mixture faded to a pale yellow clear solution. The reaction mixture was allowed to stir at room temperature for 3 d. The residue was purified by chromatography using a Biotage SP1, 40M silica cartridge, eluting with a linear gradient of hexanes in ethyl acetate from 20% to 100% over 15 column volumes to provide the title compound as a white solid (150 mg). Mass spectrum (ESI) 502.2 (M+1). 1H NMR (600 MHz, CDCl3): δ 8.31 (d, J=8.2 Hz, 2H), 7.93 (d, J=1.2 Hz, 1H), 7.89 (d, J=8.4 Hz, 2H), 7.5 (s, 1H), 7.26 (d, J=8.2 Hz, 2H), 7.1 (d, J=8.3 Hz, 2H), 6.66 (d, J=7.3 Hz, 1H), 3.79 (s, 1H), 3.46 (m, 1H), 3.3 (dd, J=5.9, 5.9 Hz, 1H), 3.21 (dd, J=5.2, 5.0 Hz, 1H), 1.44 (J=6.9 Hz, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([S:11](=[O:15])(=[O:14])[NH:12][CH3:13])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl[C:17]1[CH:25]=CC(S(O)=O)=C[C:18]=1C(O)=O.N1CCCC1>>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([S:11]([N:12]2[CH2:25][CH2:17][CH2:18][CH2:13]2)(=[O:15])=[O:14])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1cc(S(=O)O)ccc1Cl
Reactant: CNS(=O)(=O)c1ccc(Cl)c(C(=O)O)c1
Solvent: C1CCNC1
Product: O=C(O)c1cc(S(=O)(=O)N2CCCC2)ccc1Cl
Yield: 91 %

Procedure:
The title compound was synthesised according to the procedure described for 2-Chloro-5-methylsulfamoyl-benzoic acid from 2-Chloro-5-sulfino-benzoic acid and pyrrolidine and obtained in 91% yield. MS (m/e): 288.0 (MH−, 100%).
Reaction SMILES: [Cl:1][CH2:2][O:3][C:4](F)(F)[CH:5]([C:10]([F:13])([F:12])[F:11])[C:6]([F:9])([F:8])[F:7].[Si](=O)=[O:17].S(F)(=O)(=O)O>>[F:7][C:6]([F:9])([F:8])[CH:5]([C:10]([F:13])([F:12])[F:11])[C:4]([O:3][CH2:2][Cl:1])=[O:17]
Reactant: O=[Si]=O
Reactant: FC(F)(F)C(C(F)(F)F)C(F)(F)OCCl
Agent: O=S(=O)(O)F
Product: O=C(OCCl)C(C(F)(F)F)C(F)(F)F
Reaction time: 21 h

Procedure:
In a four necked 1 liter flask equipped with a thermometer, a condenser and a stirrer, 1-chloromethoxy-1,1-difluoro-2-trifluoromethyl-3,3,3-trifluoropropane (276.6 g, 1.04 mol), silicon dioxide and fluorosulfuric acid (70.0 g, 0.70 mol) were charged. The reaction was continued at 110° C. for 21 hours. Then, the reaction mixture was distilled to give monochloromethyl 2-trifluoromethyl-3,3,3-trifluoropropanoate (190.3 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([C:13]([OH:15])=O)=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2.C1N=CN(C(N2C=NC=C2)=O)C=1.[NH2:28][C:29]1[NH:33][N:32]=[N:31][N:30]=1>O1CCCC1.CN(C)C=O>[CH3:1][O:2][C:3]1[C:4]([C:13]([NH:28][C:29]2[NH:33][N:32]=[N:31][N:30]=2)=[O:15])=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2
Reactant: COc1nc2ccccc2nc1C(=O)O
Reactant: Nc1nnn[nH]1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1nc2ccccc2nc1C(=O)Nc1nnn[nH]1

Procedure:
3Methoxy-2-quinoxalinecarboxylic acid (1.5 g) and N,N-carbonyldiimidazole (1.2 g) in tetrahydrofuran (50 ml) were heated under reflux for 15 minutes. 5-Amino-1H-tetrazole (0.7 g) in dimethylformamide (5 ml) was added and the solution was heated under reflux for 1 hour. The crystalline solid was collected and stirred with dilute hydrochloric acid (25 ml., 2N) and the solid was filtered off and dried. It had m.p. 260° (d) (45%).
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[NH:4][N:3]=1.[F:12][C:13]1([F:27])[CH2:17][N:16]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C@H:15]([CH2:25]O)[CH2:14]1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[NH2:11][C:9]1[N:8]=[CH:7][N:6]=[C:5]2[N:4]([CH2:25][C@@H:15]3[CH2:14][C:13]([F:27])([F:12])[CH2:17][N:16]3[C:18]([O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[O:19])[N:3]=[C:2]([I:1])[C:10]=12
Reactant: Nc1ncnc2[nH]nc(I)c12
Reactant: CC(C)(C)OC(=O)N1CC(F)(F)C[C@H]1CO
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(F)(F)C[C@H]1Cn1nc(I)c2c(N)ncnc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 20.8 %

Procedure:
Under nitrogen, to a solution of 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (2.61 g, 10.00 mmol, 1.00 equiv), tert-butyl (2S)-4,4-difluoro-2-(hydroxymethyl)pyrrolidine-1-carboxylate (2.37 g, 9.99 mmol, 1.00 equiv) and TPP (4 g, 15.2 mmol, 1.50 equiv) in THF was DIAD (3.00 g, 15.0 mmol, 1.50 equiv) at 0° C. in 30 min. The resulting solution was stirred overnight at room temperature. The mixture was then concentrated under vacuum and the residue was applied onto a silica gel column with dichloromethane/ethyl acetate (3/1) to give 1 g of tert-butyl (2S)-2-([4-amino-3-iodo-1H-pyrazolo[3,4-d]-pyrimidin-1-yl]methyl)-4,4-difluoropyrrolidine-1-carboxylate as reddish oil.