Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:11]1[CH2:14][CH:13]([C:15]2[O:16][CH:17]=[C:18]([CH3:20])[N:19]=2)[CH2:12]1)=O)C1C=CC=CC=1>C(O)C>[NH:11]1[CH2:14][CH:13]([C:15]2[O:16][CH:17]=[C:18]([CH3:20])[N:19]=2)[CH2:12]1
Reactant: Cc1coc(C2CN(C(=O)OCc3ccccc3)C2)n1
Solvent: CCO
Product: Cc1coc(C2CNC2)n1
Temperature: 30 °C
Reaction time: 18 h

Procedure:
To 40 mg (0.15 mmol) 3-(4-methyl-oxazol-2-yl)-azetidine-1-carboxylic acid benzyl ester in 2 mL ethanol was added 4 mg (20% w/w on carbon) palladium hydroxide, the reaction was purged 3 times with nitrogen then 3 times with hydrogen and was stirred at 30° C. under a balloon of hydrogen for 18 hours. The mixture was purged twice with nitrogen, then the solution was filtered through a pad of celite. The solvent was evaporated to give the desired product, which was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[NH2:9].CO.[CH3:12][S:13](Cl)(=[O:15])=[O:14].[OH-].[Na+]>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:13]([CH3:12])(=[O:15])=[O:14])=[CH:4][C:3]=1[NH2:9]
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ccc(Cl)c(N)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CS(=O)(=O)Nc1ccc(Cl)c(N)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
35.8 g of 4-chloro-1,3-diaminobenzene are stirred thoroughly into 250 ml of water and 50 ml of methanol. 23 ml of methanesulphonyl chloride are added dropwise at 0° C. in the course of about 2 hours; the pH is kept at 4 by dropwise addition of concentrated sodium hydroxide solution. The mixture is subsequently stirred at room temperature for about 2 hours and, if appropriate after diluting with water, the 1-chloro-2-amino-4-methanesulphonamido-benzene which has separated out is then filtered off. It is sufficiently pure for further reactions according to Example 59.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4](Cl)[N:3]=1.[Cl:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][CH2:17][CH2:16]2>C(O)CCC>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([N:18]2[C:19]3[C:15](=[CH:14][C:13]([Cl:12])=[CH:21][CH:20]=3)[CH2:16][CH2:17]2)[N:3]=1
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Reactant: Clc1ccc2c(c1)CCN2
Solvent: CCCCO
Product: Clc1ccc2c(c1)CCN2c1nc(Cl)nc2[nH]cnc12

Procedure:
The same procedure as in stage 1 of Example 1 is carried out, starting from 756 mg of 2,6-dichloro-purine, 12 ml of butanol and 737 mg of 5-chloro-2,3-dihydro-1H-indole.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4].COC(OC)CN>>[C:8]1([CH2:7][CH2:6][NH:5][C:3](=[O:4])[CH3:2])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C(CCl)NCCc1ccccc1
Agent: COC(CN)OC
Product: CC(=O)NCCc1ccccc1

Procedure:
Eur. J. Org. Chem. 2008, 895-913 describes a process comprising: a) reacting phenylethylamine with chloroacetyl chloride in presence of sodium bicarbonate to obtain 2-chloro-N-phenethylacetamide, b) treating 2-chloro-N-phenethylacetamide with aminoacetaldehyde dimethylacetal to give 2-[2,2-dimethoxyethyl)amino]-N-(2-phenylethyl)acetamide, c) making hydrochloride salt of 2-[(2,2-dimethoxyethyl)amino]-N-(2-phenylethyl)acetamide, and d) cyclising using sulphuric acid to form praziquanamine (i.e.4-oxo-1,2,3,6,7,11b-hexahydro-4H-pyrazino[2,1-a]isoquinoline).
Reaction SMILES: [C:1]([Si:5]([CH3:16])([CH3:15])[O:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH2:13])[C:8]=1[NH2:14])([CH3:4])([CH3:3])[CH3:2].CO[C:19]1C(OC)=C[C:22]2[NH:23][C:24](CCCNC)=N[C:21]=2[CH:20]=1>>[C:1]([Si:5]([CH3:16])([CH3:15])[O:6][C:7]1[C:8]2[N:14]=[C:19]([CH2:20][CH2:21][CH2:22][NH:23][CH3:24])[NH:13][C:9]=2[CH:10]=[CH:11][CH:12]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CNCCCc1nc2cc(OC)c(OC)cc2[nH]1
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc(N)c1N
Product: CNCCCc1nc2c(O[Si](C)(C)C(C)(C)C)cccc2[nH]1

Procedure:
Prepared from 3-(tert.-butyl-dimethyl-silanyloxy)-benzene-1,2-diamine in analogy to the methods described for [3-(5,6-dimethoxy-1H-benzoimidazol-2-yl)-propyl]-methyl-amine.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:11]=[CH:10][S:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.S(Cl)([Cl:15])(=O)=O>ClCCl>[Cl:15][C:8]1[S:9][CH:10]=[CH:11][C:7]=1[O:6][CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: c1cc(OC2CCCC2)cs1
Reactant: O=S(=O)(Cl)Cl
Solvent: ClCCl
Product: Clc1sccc1OC1CCCC1
Reaction time: 1 h
Yield: 57.2 %

Procedure:
2-Chloro-3-cyclopentyloxythiophene was prepared according to the procedures described in P. Stanetty and E. Puschautz, Monatshefte Chemie, 1989, 120, 65. Thus, to a solution of 3-cyclopentyloxythiophene (3.98 g, 23.7 mmol) in dichloromethane (35 mL) was added sulfuryl chloride (2 mL, 24.9 mmol) at 15° C. under argon. The mixture was stirred for 1 hour, then concentrated to dryness. Purification by flash chromatography (silica, 100% hexane) gave 2-chloro-3-cyclopentyloxythiophen (2.75 g, 59%) as a pale yellow oil; 1HNMR (300 MHz, CDCl3) δ 6.99 (d, J=6.0 Hz, 1H), 6.75 (d, J=6.0 Hz, 1H), 4.69–4.74 (m, 1H), 1.7–1.93 (m, 6H), 1.5–1.7 (m, 2H). MS m/e (%): 202 (M+; 6).
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([O:8][CH2:9][CH:10]([CH2:13][O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[CH2:11]O)=[CH:4][CH:3]=1.[I:22]I.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N1C=CN=C1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH2:9][CH:10]([CH2:11][I:22])[CH2:13][O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])=[CH:6][N:7]=1
Reactant: II
Reactant: CC(C)(C)[Si](C)(C)OCC(CO)COc1ccc(Br)nc1
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(C)(C)[Si](C)(C)OCC(CI)COc1ccc(Br)nc1
Yield: 97 %

Procedure:
Iodination of alcohol 187 with I2, PPh3 and imidazole as in Example 2GGG above for 18 h, followed by chromatography of the product on silica gel, eluting with petroleum ether and pentane (foreruns) and then with 5-25% Et2O/pentane, gave 2-bromo-5-[3-{[tert-butyl(dimethyl)silyl]oxy}-2-(iodomethyl)propoxy]pyridine (188) (97%) as a colourless oil; 1H NMR (CDCl3) δ 8.07 (d, J=3.0 Hz, 1H), 7.37 (dd, J=8.7, 0.3 Hz, 1H), 7.11 (dd, J=8.7, 3.2 Hz, 1H), 4.06 (dd, J=9.2, 5.7 Hz, 1H), 3.99 (dd, J=9.2, 6.1 Hz, 1H), 3.74 (dd, J=10.1, 5.6 Hz, 1H), 3.70 (dd, J=10.1, 5.5 Hz, 1H), 3.36 (d, J=6.0 Hz, 2H), 2.12 (sept, J=5.8 Hz, 1H), 0.89 (s, 9H), 0.06 (2 s, 6H); HRESIMS calcd for C15H26BrINO2Si m/z [M+H]+ 487.9935, 485.9955. found 487.9931, 485.9952.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:16])=[CH:4][C:5]2[O:10][CH2:9][C:8](=[O:11])[N:7]([O:12][CH2:13][CH3:14])[C:6]=2[CH:15]=1.[C:17]1([CH3:24])[C:18]([CH3:23])=[CH:19][CH:20]=[CH:21][CH:22]=1>>[CH2:13]([O:12][N:7]1[C:6]2[CH:15]=[C:2]([N:1]3[CH:23]=[C:18]4[C:17]([CH2:22][CH2:21][CH2:20][CH2:19]4)=[CH:24]3)[C:3]([F:16])=[CH:4][C:5]=2[O:10][CH2:9][C:8]1=[O:11])[CH3:14]
Reactant: CCON1C(=O)COc2cc(F)c(N)cc21
Reactant: Cc1ccccc1C
Product: CCON1C(=O)COc2cc(F)c(-n3cc4c(c3)CCCC4)cc21
Reaction time: 0.25 h

Procedure:
A mixture consisting of 6-amino-4-ethoxy-7-fluoro-1,4-benzoxazin -3(4H)-one (1.06 g), 1,2-cyclohexanedicarboxyaldehyde (0.7 g) and xylene (50 ml) was stirred for 15 minutes under heat-refluxing. After the solvent had been distilled off under reduced pressure, the residue was purified through silica-gel chromatography (eluent: hexane/ethyl acetate=19/1) to obtain the aimed 4-ethoxy-7-fluoro-6-(4,5,6,7-tetrahydroisoindole-2-yl)1,4-benzoxazin-3(4H)-one (1.37 g). nD20 1.5797
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:11]1[C:40]([CH3:41])=[C:39](Br)[C:38]2=[N:43][C:35]3=[C:36](Br)[N:37]2[C:12]=1[N:13]1[CH2:49][CH2:48][C:16]([CH3:50])([O:17][CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]([CH3:47])[O:23][C:24]2[CH:25]=[CH:26][C:27]([F:46])=[CH:28][C:29]=2[C:30]2[CH:45]=[C:34]3[CH:33]=[CH:32][CH:31]=2)[CH2:15][CH2:14]1)[C:7]([O:9][CH3:10])=[O:8])([CH3:4])([CH3:3])[CH3:2].[C:51]([Zn]C#N)#[N:52]>[Zn].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].CC(N(C)C)=O>[C:1]([O:5][C@@H:6]([C:11]1[C:40]([CH3:41])=[C:39]([C:51]#[N:52])[C:38]2=[N:43][C:35]3=[CH:36][N:37]2[C:12]=1[N:13]1[CH2:49][CH2:48][C:16]([CH3:50])([O:17][CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]([CH3:47])[O:23][C:24]2[CH:25]=[CH:26][C:27]([F:46])=[CH:28][C:29]=2[C:30]2[CH:45]=[C:34]3[CH:33]=[CH:32][CH:31]=2)[CH2:15][CH2:14]1)[C:7]([O:9][CH3:10])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)c(Br)c2nc3c(Br)n2c1N1CCC(C)(CC1)OCCCC[C@H](C)Oc1ccc(F)cc1-c1cccc-3c1
Reactant: N#C[Zn]C#N
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Zn]
Solvent: CC(=O)N(C)C
Product: COC(=O)[C@@H](OC(C)(C)C)c1c(C)c(C#N)c2nc3cn2c1N1CCC(C)(CC1)OCCCC[C@H](C)Oc1ccc(F)cc1-c1cccc-3c1
Temperature: 150 °C
Reaction time: 2 h

Procedure:
Methyl(2S)-2-(tert-butoxy)-2-[(22S)-5,8-dibromo-17-fluoro-4,22,28-trimethyl-21,27-dioxa-1,7,34-triazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18-decaen-3-yl]acetate (50 mg, 0.061 mmol, 1.0 equiv) was placed in a microwave tube, followed by zinc (0.401 mg, 6.13 μmol, 0.1 equiv), dicyanozinc (14.40 mg, 0.123 mmol, 2.0 equiv), and Pd(dppf)Cl2 (50.1 mg, 0.061 mmol, 1.0 equiv). To this mixture was added DMAC (681 μl) and degassed, sealed, placed in microwave, and stirred for 2 hours at 150° C. Then it was diluted by 10 mL EA, washed by NaHCO3, dried over MgSO4, concentrated to give the pure enough product. LCMS (ESI, M+1): 683.4.
Reaction SMILES: [CH3:1][C:2]([CH3:15])([CH3:14])[CH2:3][N:4]1[C:8]2[CH:9]=[CH:10][C:11](N)=[CH:12][C:7]=2[N:6]=[N:5]1.N([O-])=[O:17].[Na+]>OS(O)(=O)=O.O>[CH3:1][C:2]([CH3:15])([CH3:14])[CH2:3][N:4]1[C:8]2[CH:9]=[CH:10][C:11]([OH:17])=[CH:12][C:7]=2[N:6]=[N:5]1
Reactant: CC(C)(C)Cn1nnc2cc(N)ccc21
Reactant: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: CC(C)(C)Cn1nnc2cc(O)ccc21
Temperature: 25 °C

Procedure:
To a solution of 1-(2,2-dimethylpropyl)-1H-1,2,3-benzotriazol-5-amine (2-4, 150 mg, 0.734 mmol, 1.0 equv.) in 20% H2SO4 (5 mL), was slowly added sodium nitrite (70.8 mg, 1.026 mmol, 1.4 equiv.). The reaction mixture was stirred at room temperature until LCMS showed complete conversion to diazonium ion. The reaction solution was transferred to a microwave vial, and then irradiated at 120° C. for 50 minutes. LCMS showed complete hydrolysis of the diazonium salt. The reaction mixture was diluted with water, then extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered and concentrated to give the crude product, which was purified with normal phase silica gel chromatography (EtOAc/hexane gradient from 0 to 100%) to yield 1-(2,2-dimethylpropyl)-1H-1,2,3-benzotriazol-5-ol (2-5 LRMS m/z (M+H) 206.0 found, 206.1 required.
Reaction SMILES: [CH3:1][CH:2]([NH:11][C:12]1[S:13][CH:14]=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:16]=1)[C:3]1[CH:10]=[CH:9][C:6]([CH2:7][OH:8])=[CH:5][CH:4]=1.O[C:24]1[CH:29]=[CH:28][C:27]([CH2:30][C:31]([O:33][CH3:34])=[O:32])=[CH:26][CH:25]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1>[CH3:1][CH:2]([NH:11][C:12]1[S:13][CH:14]=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:16]=1)[C:3]1[CH:4]=[CH:5][C:6]([CH2:7][O:8][C:24]2[CH:29]=[CH:28][C:27]([CH2:30][C:31]([O:33][CH3:34])=[O:32])=[CH:26][CH:25]=2)=[CH:9][CH:10]=1
Reactant: COC(=O)Cc1ccc(O)cc1
Reactant: CC(Nc1nc(-c2ccccc2)cs1)c1ccc(CO)cc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: COC(=O)Cc1ccc(OCc2ccc(C(C)Nc3nc(-c4ccccc4)cs3)cc2)cc1
Reaction time: 16 h
Yield: 100.2 %

Procedure:
To a mixture of 4-[methyl(4-phenyl-2-thiazolyl)aminomethyl]benzyl alcohol (1.00 g), methyl 2-(4-hydroxyphenyl)acetate (643 mg), tributylphosphine (1.30 g) and tetrahydrofuran (30 mL) was added 1,1′-(azodicarbonyl)dipiperidine (1.62 g) at room temperature and the mixture was stirred for 16 hrs. The precipitated crystals were filtered off. The filtrate was concentrated and the residue was subjected to silica gel column chromatography to give methyl 4-[4-[methyl(4-phenyl-2-thiazolyl)aminomethyl]benzyloxy]phenylacetate (1.48 g, quantitative) as a yellow oil from a fraction eluted with ethyl acetate-hexane (1:4, v/v).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH:8](O)[CH3:9])=[CH:6][CH:5]=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[N:3]=1.O=S(Cl)[Cl:23]>C(Cl)Cl>[Cl:23][CH:8]([C:7]1[C:2]([CH3:1])=[N:3][C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)=[CH:5][CH:6]=1)[CH3:9]
Reactant: Cc1nc(-c2cccc(C(F)(F)F)c2)ccc1C(C)O
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: Cc1nc(-c2cccc(C(F)(F)F)c2)ccc1C(C)Cl

Procedure:
0.530 g (1.89 mmol) of the above prepared [rac]-1-[2-methyl-6-(3-trifluoromethyl-phenyl)-pyridin-3-yl]-ethanol was dissolved in 9.5 ml of CH2Cl2 and treated dropwise at 0° C. with 0.275 ml (2 eq.) of SOCl2. The reaction mixture was kept at 0° C. for 5 Min. and at RT for 30 Min. Pouring onto crashed ice/NaHCO3, twofold extraction with EtOEt, washing with water, drying over sodium sulfate and evaporation of the solvents yielded 0.586 g of pure title compound as light yellow oil.
Reaction SMILES: [CH2:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1)(=[O:8])=[O:7])[CH2:2][CH2:3][CH3:4].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:35](O)[CH2:36][OH:37].N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH2:1]([N:5]([CH2:35][CH2:36][OH:37])[S:6]([C:9]1[CH:10]=[CH:11][C:12]([CH3:15])=[CH:13][CH:14]=1)(=[O:7])=[O:8])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNS(=O)(=O)c1ccc(C)cc1
Reactant: OCCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCCN(CCO)S(=O)(=O)c1ccc(C)cc1

Procedure:
Dissolve N-butyl-4-methyl-benzenesulfonamide (10 mmol) in tetrahydrofuran (50 mL) and add triphenylphosphine (10 mmol). Treat this with ethylene glycol (10 mmol) followed by addition of diethyl azodicarboxylate (10 mmol). Stir the reaction at 25° C. for 18 hours. Concentrate the reaction under vacuum. Purify the residue by flash chromatography (silica gel, toluene/ethyl acetate) to provide N-butyl-N-(2-hydroxy-ethyl)-4-methyl-benzenesulfonamide.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([C:11]2[C:15]3[S:16][CH:17]=[CH:18][C:14]=3[O:13][N:12]=2)[CH:8]=[CH:9][CH:10]=1.C(=O)([O-])[O-].[K+].[K+].[F:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][C:33]=1[F:34])[CH2:29][NH2:30]>C(#N)C>[F:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][C:33]=1[F:34])[CH2:29][NH:30][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]2[C:15]3[S:16][CH:17]=[CH:18][C:14]=3[O:13][N:12]=2)[CH:6]=1
Reactant: NCc1ccc(F)c(F)c1
Reactant: BrCCOc1cccc(-c2noc3ccsc23)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Fc1ccc(CNCCOc2cccc(-c3noc4ccsc34)c2)cc1F

Procedure:
The title compound is prepared from 3-[3-(2-bromo-ethoxy)-phenyl]-thieno[2,3-d]isoxazole, potassium carbonate, 3,4-difluorobenzylamine and acetonitrile essentially as described above in example 35. Purity by LC/MS (APCI)=100%, [M+H]+=387.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[O:9][C:10]2[CH:17]=[CH:16][CH:15]=[C:14](OS(C(F)(F)F)(=O)=O)[C:11]=2[C:12]=1[CH3:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].[C:32]1(B(O)O)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.COCCOC>O>[C:1]([O:5][C:6]([C:8]1[O:9][C:10]2[CH:17]=[CH:16][CH:15]=[C:14]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:11]=2[C:12]=1[CH3:13])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1ccccc1
Reactant: Cc1c(C(=O)OC(C)(C)C)oc2cccc(OS(=O)(=O)C(F)(F)F)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: Cc1c(C(=O)OC(C)(C)C)oc2cccc(-c3ccccc3)c12
Temperature: 85 °C
Reaction time: 2 h
Yield: 68.7 %

Procedure:
3-Methyl-4-trifluoromethanesulfonyloxy-benzofuran-2-carboxylic acid tert-butyl ester (85 mg, 0.25 mmol) was mixed with K2CO3 (68 mg, 0.5 mmol), phenylboronic acid (31 mg, 0.25 mmol), Pd(Ph3)4 (14 mg, 0.01 mmol), 1 mL of 1,2-dimethoxyethane and 2 drops of water. The mixture was heated and stirred in an 85° C. oil bath for 2 h. The reaction mixture was poured into water and was extracted with ethyl acetate. The organic extract was washed with water and dried over sodium sulfate. Filtration followed by removal of the solvent in vacuo gave the crude product (71 mg), which was purified by column chromatography to give 53 mg (77% yield) of 3-methyl-4-phenyl-benzofuran-2-carboxylic acid tert-butyl ester, obtained as white solid.
Reaction SMILES: S(OS(C(F)(F)F)(=O)=O)(C(F)(F)F)(=O)=O.[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH:25]=[CH:26][C:27]=1[N+:28]([O-:30])=[O:29])[C:21]([NH:23][CH3:24])=O.[N-:31]=[N+:32]=[N-:33].[Na+].C([O-])(O)=O.[Na+]>CC#N>[CH3:16][O:17][C:18]1[CH:19]=[C:20]([C:21]2[N:23]([CH3:24])[N:33]=[N:32][N:31]=2)[CH:25]=[CH:26][C:27]=1[N+:28]([O-:30])=[O:29]
Reactant: [N-]=[N+]=[N-]
Reactant: CNC(=O)c1ccc([N+](=O)[O-])c(OC)c1
Agent: O=C([O-])O
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [Na+]
Solvent: CC#N
Product: COc1cc(-c2nnnn2C)ccc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 69.4 %

Procedure:
Triflic anhydride (0.27 mL, 1.580 mmol) was added dropwise to a solution of 3-methoxy-N-methyl-4-nitrobenzamide (Preparation 196, 0.166 g, 0.790 mmol) and sodium azide (0.205 g, 3.16 mmol) in MeCN (4.0 mL) at −10° C. The reaction mixture was warmed up to room temperature over 3 hours. The reaction was neutralised with saturated aqueous NaHCO3. The mixture was extracted with EtOAc and the organic layer washed with saturated aqueous NaHCO3, brine, dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by Biotage silica gel column chromatography eluting with cyclohexane/EtOAc 70/30 to 50/50 to afford the title compound as a white solid (129 mg, 69%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:13]([C:14]([OH:16])=O)=[C:12]([C:17]2[CH:18]=[N:19][N:20]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[CH:27]=3)[C:21]=2[C:22]([F:25])([F:24])[F:23])[O:11][N:10]=1.[CH3:33][NH:34][O:35][CH3:36].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(OC(=O)C)C>CN(C)O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:13]([C:14]([N:34]([O:35][CH3:36])[CH3:33])=[O:16])=[C:12]([C:17]2[CH:18]=[N:19][N:20]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[CH:27]=3)[C:21]=2[C:22]([F:24])([F:25])[F:23])[O:11][N:10]=1
Reactant: O=C(O)c1c(-c2c(F)cccc2Cl)noc1-c1cnn(-c2cccc(Cl)c2)c1C(F)(F)F
Reactant: CNOC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CN(C)O
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Product: CON(C)C(=O)c1c(-c2c(F)cccc2Cl)noc1-c1cnn(-c2cccc(Cl)c2)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 10.8 g (22.2 mmol) 3-(2-chloro-6-fluorophenyl)-5-(1-(3-chlorophenyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl)isoxazole-4-carboxylic acid, 2.17 g (1 eq) N,O-Dimethylhydroxylamine and 8.42 g (1 eq) HBTU in dimethylhydroxylamine 3.68 mL DIPEA were added. The mixture was stirred overnight at r.t. The solvent was removed in the vacuum. The residue was resolved in ethylacetate and extracted with sodium hydrogen carbonate (5%, aq) and citric acid (5%, aq). The organic layer was dried over anhydrous magnesium sulfate and the solvent was removed in the vacuum. TLC (6:4 petrolether:ethylacetate) showed residual educt. The product was isolated by column chromatoghraphy (6:4) petrolether:ethylacetate). The product (example 63) was dried under vacuum to yield 2.28 g (19%). Result of LC/MS MH+: 528.8; 1H NMR (DMSO-d6; CCl4): 3.08 (3H, s, CH3), 3.36 (3H, s, CH3), 7.40-7.81 (7H, m, CH-arom.), 8.39 (1H, s, CH-pyraz.)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[H-].[Na+].CS(O[CH2:16][CH2:17][CH2:18][NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])(=O)=O>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:16][CH2:17][CH2:18][NH:19][C:20](=[O:21])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:4][CH:3]=1
Reactant: Sc1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)NCCCOS(C)(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCCSc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 4-chlorothiophenol (91 mg) in 6 mL of DMF was cooled to 0° C. under N2. Sodium hydride (60%, 30 mg) was added and the reaction stirred for 30 minutes. The product from Step A above in 3 mL of DMF was added and the reaction allowed to warm to room temperature while stirring overnight. This was diluted with EtOAc, washed with saturated NaHCO3 and brine and dried over Na2SO4. Concentrating in vacuo gave the titled compound. ESI+ MS: 202 [MH-Boc]+.
Reaction SMILES: [N:1]1([C:7]2[C:8]3[N:16]=[C:15]([C:17]4[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=4)[S:14][C:9]=3[N:10]=[C:11]([NH2:13])[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Cl:24][C:25]1[CH:35]=[CH:34][C:28]([O:29][CH2:30][C:31](O)=[O:32])=[CH:27][CH:26]=1>>[NH2:13][C:11]1[N:12]=[C:7]([N:1]2[CH2:2][CH2:3][N:4]([C:31](=[O:32])[CH2:30][O:29][C:28]3[CH:34]=[CH:35][C:25]([Cl:24])=[CH:26][CH:27]=3)[CH2:5][CH2:6]2)[C:8]2[N:16]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)[S:14][C:9]=2[N:10]=1
Reactant: O=C(O)COc1ccc(Cl)cc1
Reactant: Cc1ccc(-c2nc3c(N4CCNCC4)nc(N)nc3s2)cc1
Product: Cc1ccc(-c2nc3c(N4CCN(C(=O)COc5ccc(Cl)cc5)CC4)nc(N)nc3s2)cc1
Yield: 32 %

Procedure:
This compound was prepared from 7-(piperazin-1-yl)-2-p-tolylthiazolo[5,4-d]pyrimidin-5-amine using 4-chlorophenoxyacetic acid in a yield of 32%, according to the procedure for the synthesis of example 50.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][O:3][CH:2]1[CH2:7][CH2:8][CH2:9][C:10]([OH:12])=O.CN.Cl.[CH3:16][N:17](C)CCCN=C=NCC.OC1C2N=NNC=2C=CC=1>ClCCl>[O:1]1[CH2:6][CH2:5][CH2:4][O:3][CH:2]1[CH2:7][CH2:8][CH2:9][C:10]([NH:17][CH3:16])=[O:12]
Reactant: CCN=C=NCCCN(C)C
Reactant: O=C(O)CCCC1OCCCO1
Agent: CN
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: ClCCl
Product: CNC(=O)CCCC1OCCCO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 113.9 %

Procedure:
To 4-[1,3]dioxan-2-yl-butyric acid (2.55 g, 0.015 mol) in dichloromethane (200 ml) was added methylamine (2M in THF, 8.1 ml, 0.016 mol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (3.09 g, 0.016 mol) and hydroxybenzotriazole (2.16 g, 0.016 mol) and the mixture stirred at room temperature overnight. The organic layer was washed with saturated sodium bicarbonate solution (200 ml) and the aqueous layer extracted with dichloromethane (4×50 ml). The combined organics were dried (Na2SO4) and evaporated to give a colourless oil (3.2 g)
Reaction SMILES: [C:1]([C:3]1[C:7](I)=[CH:6][N:5]([C:9]2[C:14]([Cl:15])=[CH:13][C:12]([C:16]([F:19])([F:18])[F:17])=[CH:11][C:10]=2[Cl:20])[N:4]=1)#[N:2].C([Li])CCC.[F:26][C:27]([F:39])([F:38])[C:28]([F:37])([F:36])[C:29]([F:35])([F:34])[C:30](OC)=[O:31].O>O1CCCC1>[C:1]([C:3]1[C:7]([C:30](=[O:31])[C:29]([F:34])([F:35])[C:28]([F:36])([F:37])[C:27]([F:39])([F:38])[F:26])=[CH:6][N:5]([C:9]2[C:14]([Cl:15])=[CH:13][C:12]([C:16]([F:19])([F:18])[F:17])=[CH:11][C:10]=2[Cl:20])[N:4]=1)#[N:2]
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)cc1I
Reactant: COC(=O)C(F)(F)C(F)(F)C(F)(F)F
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)cc1C(=O)C(F)(F)C(F)(F)C(F)(F)F
Temperature: -73 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of 3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-iodopyrazole (3.0 g) in tetrahydrofuran (80 ml) at -80° C. under an atmosphere of nitrogen was added, at such a rate that the temperature of the reaction mixture did not exceed -73° C., n-butyllithium (2.78 ml of a 2.5M solution in hexanes). The mixture was stirred at -73° C. for 10 minutes and then a solution of methyl heptafluorobutyrate (1.07 ml) in tetrahydrofuran (5 ml) was then added at such a rate that the temperature of the reaction mixture did not exceed -75° C. Upon completion of the addition the mixture allowed to warm to room temperature over a period of 1.5 hours. Water (100 ml) was added and the mixture extracted twice with ethyl acetate (50 ml). The combined organic layers were dried (Na2SO4) and evaporated to give a pale yellow solid which was purified by column chromatography on silica gel (150 g) eluted with ether:hexane (3:2). Combination and evaporation of suitable fractions gave a yellow oil which was further purified by column chromatography on silica gel (150 g) eluted initially with hexane:ether (19:1), then hexane:ether (9:1) and finally hexane:ether (1:1). Combination and evaporation of suitable fractions gave the title compound as a pale yellow solid, m.p. 102-103° C.