Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.C[Si]([C:15]#[N:16])(C)C.C(N(S(F)(F)[F:23])CC)C>C(Cl)Cl.[I-].[Zn+2].[I-]>[Br:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[CH:4]([F:23])[C:15]#[N:16]
Reactant: CCN(CC)S(F)(F)F
Reactant: O=Cc1ccc(Cl)cc1Br
Reactant: C[Si](C)(C)C#N
Agent: [I-]
Agent: [Zn+2]
Solvent: ClCCl
Product: N#CC(F)c1ccc(Cl)cc1Br
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60.4 %

Procedure:
Add 2-bromo-4-chloro-benzaldehyde (3.5 g, 16 mmol) in DCM (6 mL) to a flask that contains zinc iodide (8 mg). Stir the mixture at RT for 30 min. Cool the mixture to 0° C. with an ice-water bath. Add trimethylsilylcyanide (2.14 mL, 15.99 mmol) to the vigorously stirred mixture. Remove the cooling bath and stir at RT for 18 h. Add DCM (20 mL) and cool the mixture to 0° C. Add a solution of diethylaminosulfurtrifluoride (2.32 mL, 18 mmol) in DCM (8 mL) to the previous reaction mixture and stir the mixture overnight. Pour the reaction mixture into ice-water (50 mL) and separate the organic layer. Wash the organic layer with water, 0.5 N HCl, water, saturated NaHCO3, and water. Dry over magnesium sulfate. Remove the organic solvent to give the crude product. Purify by column chromatography (hexane/ethyl acetate, 10:1) to give the title compound (2.40 g, 74%). MS (GC) 249 [M]+.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:12])=[C:4]([CH:7]=[C:8]([F:11])[C:9]=1[OH:10])[CH:5]=[O:6].[C:13](=O)([O-])[O-].[K+].[K+].COS(OC)(=O)=O.C(OC(=O)C)C>CN(C=O)C>[Br:1][C:2]1[C:3]([F:12])=[C:4]([CH:7]=[C:8]([F:11])[C:9]=1[O:10][CH3:13])[CH:5]=[O:6]
Reactant: O=C([O-])[O-]
Reactant: O=Cc1cc(F)c(O)c(Br)c1F
Agent: [K+]
Solvent: CN(C)C=O
Solvent: COS(=O)(=O)OC
Solvent: CCOC(C)=O
Product: COc1c(F)cc(C=O)c(F)c1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 53666 %

Procedure:
To a solution of 3-bromo-2,5-difluoro-4-hydroxybenzaldehyde (48.4 g, 0.193 mmol) in DMF (200 mL) was added potassium carbonate (40.0 g) and dimethylsulfate (27.4 mL). The reaction mixture was stirred at room temperature overnight. The reaction was diluted wit ethylacetate and washed successively with water and brine, dried over magnesium sulfate, filtered and evaporated. The residue was triturated with hexane to afford 26 g of 3-bromo-2,5-difluoro-4-methoxy benzaldehyde. The mother liquor was evaporated and chromatographed on silica gel (0–10% ethyl acetate in hexane) to give 10.86 g of more product. (38% overall yield from 2,5-dinitrophenol).
Reaction SMILES: N[C:2]1[CH:3]=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[BrH:10].N([O-])=O.[Na+].[C:15]([O:19][CH3:20])(=[O:18])[CH:16]=[CH2:17]>O.CC(C)=O>[Br:10][CH:16]([CH2:17][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1)[C:15]([O:19][CH3:20])=[O:18]
Reactant: Br
Reactant: C=CC(=O)OC
Reactant: COc1ccc(N)cn1
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: COC(=O)C(Br)Cc1ccc(OC)nc1
Reaction time: 0.5 h
Yield: 58 %

Procedure:
To a mixture of 5-amino-2-methoxypyridine (5.00 g), 47% hydrobromic acid (8.75 g) and acetone (50 ml) was added dropwise a solution of sodium nitrite (3.06 g) in water (5 ml) at 5-10° C. After stirring for 30 minutes, methyl acrylate (20.8 g) was added, to which cuprous oxide (50 mg) was added while stirring vigorously at 15° C. After stirring for one hour at room temperature, the reaction mixture was concentrated, concentrated aqueous ammonia was added, and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4), and concentrated under reduce pressure. The residue was subjected to a silica gel chromatography. From the fraction eluted with ethyl acetate-hexane (1:9, v/v), methyl 2-bromo-3-(2-methoxy-5-pyridyl)propionate (6.40 g, 58%) was obtained. Oily substance.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[S:13][C:12]([CH3:14])=[N:11][C:10]=2[C:15]([OH:17])=O)[CH:6]=[CH:7][CH:8]=1.[NH:18]1[CH2:23][CH2:22][CH2:21][C@@H:20]([NH:24][C:25]([C:27]2[N:34]3[C:30]([S:31][CH:32]=[CH:33]3)=[N:29][C:28]=2[CH3:35])=[O:26])[CH2:19]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[S:13][C:12]([CH3:14])=[N:11][C:10]=2[C:15]([N:18]2[CH2:23][CH2:22][CH2:21][C@@H:20]([NH:24][C:25]([C:27]3[N:34]4[C:30]([S:31][CH:32]=[CH:33]4)=[N:29][C:28]=3[CH3:35])=[O:26])[CH2:19]2)=[O:17])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(-c2sc(C)nc2C(=O)O)c1
Reactant: Cc1nc2sccn2c1C(=O)N[C@@H]1CCCNC1
Product: COc1cccc(-c2sc(C)nc2C(=O)N2CCC[C@@H](NC(=O)c3c(C)nc4sccn34)C2)c1

Procedure:
prepared by reaction of 5-(3-methoxy-phenyl)-2-methyl-thiazole-4-carboxylic acid with (R)-6-methyl-imidazo[2,1-b]-thiazole-5-carboxylic acid-piperidin-3-ylamide.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C@@H:3]([OH:32])[CH2:4][C@@H:5]([NH:19][C:20]([C@@H:22]([NH:27][C:28](=[O:31])[O:29][CH3:30])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1.[CH3:40][O:41][C:42]([NH:44][C@@H:45]([C:49]([CH3:53])([S:51][CH3:52])[CH3:50])[C:46](O)=[O:47])=[O:43].CCOP(ON1N=NC2C=CC=CC=2C1=O)(OCC)=O.C(N(CC)C(C)C)(C)C>C1COCC1>[CH3:40][O:41][C:42](=[O:43])[NH:44][C@@H:45]([C:49]([CH3:50])([S:51][CH3:52])[CH3:53])[C:46](=[O:47])[NH:1][C@@H:2]([CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[C@@H:3]([OH:32])[CH2:4][C@H:5]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1)[NH:19][C:20](=[O:21])[C@H:22]([C:23]([CH3:26])([CH3:25])[CH3:24])[NH:27][C:28](=[O:31])[O:29][CH3:30]
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@@H](N)Cc1ccccc1)C(C)(C)C
Reactant: COC(=O)N[C@H](C(=O)O)C(C)(C)SC
Agent: CCOP(=O)(OCC)On1nnc2ccccc2c1=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](NC(=O)OC)C(C)(C)SC)C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 39.3 %

Procedure:
A solution containing the product from Example 2C (0.10 g, 0.18 mmol) in THF (2 mL) was treated with the product from Example 30A (0.05 g, 0.226 mmol), DEPBT (0.085 g, 0.28 mmol), and N,N-diisopropylethylamine (0.165 mL, 0.947 mmol), stirred at 25° C. for 1 hour, and partitioned between ethyl acetate and 10% Na2CO3 solution. The organic phase was washed with additional 10% Na2CO3 solution and brine, dried over MgSO4, filtered and concentrated. The residue was chromatographed on silica gel eluting with 0-100% ethyl acetate/dichloromethane to give the title compound (0.052 g, 38% yield). 1H NMR (300 MHz, DMSO-d6), δ ppm 0.80 (s, 9 H), 1.10 (s, 3 H), 1.21 (s, 3 H), 1.54 (m, 2 H), 1.98 (s, 3 H), 2.57 (m, 1 H), 2.75 (m, 3 H), 3.49 (s, 3 H), 3.56 (s, 3 H), 3.64 (m, 1 H), 3.82 (d, J=9.56 Hz, 1 H), 4.17 (m, 3 H), 4.83 (d, J=5.88 Hz, 1 H), 6.61 (d, J=9.56 Hz, 1 H), 6.90 (d, J=9.56 Hz, 1 H), 7.15 (m, 7 H), 7.31 (m, 1 H), 7.84 (m, 6 H), 8.63 (d, J=4.78 Hz, 1 H).
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[N:6][CH:7]=[C:8]3[C:13]=2[CH:12]=[CH:11][CH:10]=[CH:9]3)[CH:4]=[CH:3][CH:2]=1.[CH2:15]([Li])[CH3:16].[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][C:21]=1[CH3:30]>C(OCC)C>[CH2:15]([CH:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:14]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=2[N:6]1[S:26]([C:23]1[CH:24]=[CH:25][C:20]([O:19][CH3:18])=[C:21]([CH3:30])[CH:22]=1)(=[O:28])=[O:27])[CH3:16]
Reactant: c1ccc2c(c1)cnc1ccccc12
Reactant: [Li]CC
Reactant: COc1ccc(S(=O)(=O)Cl)cc1C
Solvent: CCOCC
Product: CCC1c2ccccc2-c2ccccc2N1S(=O)(=O)c1ccc(OC)c(C)c1

Procedure:
The title compound was prepared from phenanthridine, 0.62 M ethyllithium in diethyl ether, and 4-methoxy-3-methylbenzenesulfonyl chloride according to the procedure and in the same manner as described in Example 18, step a and yielded, after chromatographic purification and crystallization from diethyl ether, 6-ethyl-5-[(4-methoxy-3-methylphenyl)sulfonyl]-5,6-dihydrophenanthridine as a colorless, crystalline, solid, which was characterized by LCMS (ES+, FA, CV=5) and 1H NMR.
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[CH:8][C:9]([C:11]([F:14])([F:13])[F:12])=[N:10][C:5]2=[N:4][CH:3]=1.CC1(C)COB([C:22]2[CH:23]=[CH:24][C:25]([F:37])=[C:26]([C:28]3[C:29]([C:35]#[N:36])=[CH:30][CH:31]=[C:32]([F:34])[CH:33]=3)[CH:27]=2)OC1>>[F:34][C:32]1[CH:33]=[C:28]([C:26]2[CH:27]=[C:22]([C:2]3[N:6]4[N:7]=[CH:8][C:9]([C:11]([F:14])([F:13])[F:12])=[N:10][C:5]4=[N:4][CH:3]=3)[CH:23]=[CH:24][C:25]=2[F:37])[C:29]([C:35]#[N:36])=[CH:30][CH:31]=1
Reactant: FC(F)(F)c1cnn2c(Br)cnc2n1
Reactant: CC1(C)COB(c2ccc(F)c(-c3cc(F)ccc3C#N)c2)OC1
Product: N#Cc1ccc(F)cc1-c1cc(-c2cnc3nc(C(F)(F)F)cnn23)ccc1F
Yield: 46 %

Procedure:
7-Bromo-3-trifluoromethylimidazo[1,2-b][1,2,4]triazine was coupled with 5′-(5,5-dimethyl-[1,3,2]dioxaborinan-2-yl)-5,2′-difluorobiphenyl-2-carbonitrile as described in Example 3 to give 68.7 mg (46%) of 5,2′-difluoro-5′-(3-trifluoromethylimidazo[1,2-b][1,2,4]triazin-7-yl)biphenyl-2-carbonitrile as a yellow solid: mp 200-201° C.; 1H NMR (360 MHz, CDCl3) δ 7.25-7.34 (2H, m), 7.44 (1H, t, J 8.9 Hz), 7.87 (1H, dd, J 5.4, 8.6 Hz), 8.18-8.26 (2H, m), 8.63 (1H, s), 8.82 (1H, s); MS (ES+) m/z 401. Anal. Found: C, 55.98; H, 2.13; N, 17.49%. Required for C19H8F5N5.0.3H2O: C, 56.11; H, 2.13; N, 17.22%.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:11]=[CH:10][C:7]([CH2:8][OH:9])=[CH:6][CH:5]=1.Cl[C:13]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH3:32])[CH:24]=1)=[CH:14][C:15]([N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)=[O:16]>O1CCCC1.CN(C)C=O>[Cl:3][C:4]1[CH:11]=[CH:10][C:7]([CH2:8][O:9][C:13]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH3:32])[CH:24]=2)=[CH:14][C:15]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[O:16])=[CH:6][CH:5]=1
Reactant: COc1ccc(C(Cl)=CC(=O)N2CCOCC2)cc1OC
Reactant: OCc1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1ccc(C(=CC(=O)N2CCOCC2)OCc2ccc(Cl)cc2)cc1OC
Temperature: 90 °C
Reaction time: 20 h

Procedure:
0.3 g (10 mmol) of sodium hydride (80%) are stirred in 15 ml of tetrahydrofuran and 1.42 g (10 mmol) of 4-chlorobenzyl alcohol in 10 ml of tetrahydrofuran are added dropwise. The resulting clear solution is evaporated to dryness and a solution of 2.02 g (6.5 mmol) of 3-chloro-3-(3,4-dimethoxyphenyl)-1-morpholin-4-ylprop-2-en-1-one in 25 ml of dimethylformamide is added. The mixture is stirred at 90° C. for 20 hours. The solvent is then evaporated and the residue shaken with toluene/water. The organic phase is separated, washed with water, dried and purified over a flash column with 40 g of silicagel. Elution is carried out with toluene containing 10, 20 and 30% of acetone. The fractions with the TLC Rf-values 0.45 and 0.31 (toluene/acetone 7:3) are collected and evaporated.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][N:6]1[C:14]2[C:13]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([O:29][C:30]([F:33])([F:32])[F:31])[CH:24]=4)=[C:18]([Cl:34])[CH:17]=3)=[N:12][CH:11]=[N:10][C:9]=2[CH:8]=[CH:7]1.[CH3:35][S:36]([CH2:39][C:40](O)=[O:41])(=[O:38])=[O:37].Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1>O.CN(C)C=O.C(N(CC)CC)C>[Cl:34][C:18]1[CH:17]=[C:16]([NH:15][C:13]2[C:14]3[N:6]([CH2:5][CH2:4][NH:3][C:40](=[O:41])[CH2:39][S:36]([CH3:35])(=[O:38])=[O:37])[CH:7]=[CH:8][C:9]=3[N:10]=[CH:11][N:12]=2)[CH:21]=[CH:20][C:19]=1[O:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([O:29][C:30]([F:33])([F:32])[F:31])[CH:24]=1
Reactant: CS(=O)(=O)CC(=O)O
Reactant: NCCn1ccc2ncnc(Nc3ccc(Oc4cccc(OC(F)(F)F)c4)c(Cl)c3)c21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CS(=O)(=O)CC(=O)NCCn1ccc2ncnc(Nc3ccc(Oc4cccc(OC(F)(F)F)c4)c(Cl)c3)c21
Temperature: 25 °C
Reaction time: 20 h
Yield: 64.3 %

Procedure:
A mixture of 5-(2-aminoethyl)-N-{3-chloro-4-[3-(trifluoromethoxy)phenoxy]phenyl}-5H-pyrrolo[3,2-d]pyrimidin-4-amine dihydrochloride (160 mg), 2-(methylsulfonyl)acetic acid (82.3 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (171 mg), 1-hydroxybenzotriazole monohydrate (137 mg), triethylamine (0.42 mL) and N,N-dimethylformamide (5.0 mL) was stirred at room temperature for 20 hrs. Water was added to the reaction system and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by basic silica gel column chromatography (eluent, ethyl acetate→ethyl acetate:methanol=4:1) and crystallization from ethanol-ethyl acetate-diisopropyl ether to give the title compound (112 mg) as pale-yellow crystals.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:23])[C@@H:10]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11][C:12](=[S:14])[NH2:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:24](OC(OCC)([O-])CBr)[CH3:25]>C(COC)OC>[CH2:1]([O:8][C:9](=[O:23])[C@@H:10]([NH:15][C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17])[CH2:11][C:12]1[S:14][CH:24]=[CH:25][N:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC([O-])(CBr)OCC
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(N)=S)C(=O)OCc1ccccc1
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N[C@@H](Cc1nccs1)C(=O)OCc1ccccc1

Procedure:
A 250 mL round bottom flask was charged with 2-(S)-tert-butoxycarbonylamino-3-thiocarbamoyl-propionic acid benzyl ester (1.0 g, 2.96 mmol), dimethoxyethane (66 mL), and bromoacetate diethylacetal (2.4 mL, 15.5 mmol). The flask containing the resulting mixture was fit with a reflux condenser and the mixture refluxed for 3 h. The resulting mixture was then concentrated in vacuo and the residue purified via flash silica gel chromatography (Analogix IF-280, SF65-400 g column, gradient 100:0-90:10 CH2Cl2:MeOH) to yield 2-(S)-tert-butoxycarbonylamino-3-thiazol-2-yl-propionic acid benzyl ester. 1H NMR (300 MHz, CDCl3) δ 7.67 (d, J=3.3 Hz, 1H), 7.29-7.44 (m, 5H), 7.20 (d, J=3.3 Hz, 1H), 5.15 (s, 2H), 5.75 (t, J=5.5 Hz, 1H), 73.15 (d, J=7.4 Hz, 1H), and 1.44 (s, 9H); MS (ES+) 363 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[CH:5]2.O1CCCC1.[F:16][C:17]1[CH:18]=[C:19]([S:23](Cl)(=[O:25])=[O:24])[CH:20]=[CH:21][CH:22]=1>C(N(CC)CC)C>[F:16][C:17]1[CH:18]=[C:19]([S:23]([NH:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][N:6]=[CH:5]3)(=[O:25])=[O:24])[CH:20]=[CH:21][CH:22]=1
Reactant: Nc1ccc2[nH]ncc2c1
Reactant: O=S(=O)(Cl)c1cccc(F)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=S(=O)(Nc1ccc2[nH]ncc2c1)c1cccc(F)c1
Yield: 36.6 %

Procedure:
3-Fluoro-N-(1H-indazol-5-yl)benzenesulfonamide can be obtained as described in Example 1 from 0.4 g of 5-amino-1H-indazole, 20 ml of tetrahydrofuran, 0.83 ml of triethylamine and 0.88 g of 3-fluorobenzenesulfonyl chloride. 0.32 g of 3-fluoro-N-(1H-indazol-5-yl)-benzenesulfonamide is thus obtained in the form of a cream solid.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([O:8][CH3:9])=[O:7])[C:3]([C:10]([O:12][CH3:13])=[O:11])=[N:2]1.[CH3:14][O:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20]O)=[CH:18][CH:17]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.CCOC(C)=O>[CH3:14][O:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][N:2]2[C:3]([C:10]([O:12][CH3:13])=[O:11])=[C:4]([C:6]([O:8][CH3:9])=[O:7])[CH:5]=[N:1]2)=[CH:18][CH:17]=1.[CH3:14][O:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][N:1]2[CH:5]=[C:4]([C:6]([O:8][CH3:9])=[O:7])[C:3]([C:10]([O:12][CH3:13])=[O:11])=[N:2]2)=[CH:18][CH:17]=1
Reactant: COc1ccc(CO)cc1
Reactant: COC(=O)c1c[nH]nc1C(=O)OC
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)c1cn(Cc2ccc(OC)cc2)nc1C(=O)OC
Product: COC(=O)c1cnn(Cc2ccc(OC)cc2)c1C(=O)OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 32 %
Yield: 29 %

Procedure:
To a solution of dimethyl 1H-pyrazole-3,4-dicarboxylate (2.5 g, 13.6 mmol) in THF (100 mL) was added 4-methoxybenzyl alcohol (1.78 mL, 14.2 mmol) and triphenylphosphine 3.74 g, 14.2 mmol) followed by dropwise addition of DIAD (2.8 mL, 14.2 mmol) and the mixture was stirred at ambient temperature under nitrogen atmosphere for 3 h. The mixture was diluted with EtOAc and washed with saturated sodium bicarbonate/water. The organic phase was dried over sodium sulfate, concentrated and purified on silica using EtOAc/hexanes 0-50% to provide the title compound (1.4 g, 32%) and isomer dimethyl 1{{4-(methyloxy)phenyl]methyl}-1H-pyrazole-3,4-dicarboxylate (1.3 g, 29%). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.98 (s, 1H), 7.18 (d, 2H), 6.9 (d, 2H), 5.4 (s, 2H), 3.92 (s, 3H), 3.89 (s, 3H), 3.87 (s, 3H); ES-LCMS: 305.28 (M+1).
Reaction SMILES: I[C:2]1[C:11]([CH3:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[C:7]2[O:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=1.[CH3:24][NH:25][C:26]1[N:35]=[CH:34][C:33]2[C:28](=[CH:29][CH:30]=[C:31](B3OC(C)(C)C(C)(C)O3)[CH:32]=2)[N:27]=1.C(=O)([O-])[O-].[Na+].[Na+].CN(C=O)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>[CH3:24][NH:25][C:26]1[N:35]=[CH:34][C:33]2[C:28](=[CH:29][CH:30]=[C:31]([C:2]3[C:11]([CH3:12])=[CH:10][CH:9]=[C:8]4[C:3]=3[CH:4]=[CH:5][N:6]=[C:7]4[O:13][C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=3)[CH:32]=2)[N:27]=1
Reactant: Cc1ccc2c(Oc3cccc(C(F)(F)F)c3)nccc2c1I
Reactant: CNc1ncc2cc(B3OC(C)(C)C(C)(C)O3)ccc2n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CNc1ncc2cc(-c3c(C)ccc4c(Oc5cccc(C(F)(F)F)c5)nccc34)ccc2n1
Temperature: 150 °C

Procedure:
5-Iodo-6-methyl-1-(3-(trifluoromethyl)phenoxy)isoquinoline (0.170 g, 0.396 mmol), N-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-2-amine (0.124 g, 0.436 mmol), dichlorobis(triphenyl-phosphine)palladium (II) (0.0139 g, 0.0198 mmol), and sodium carbonate (0.0840 g, 0.792 mmol) were all placed in a clear microwave vial along with 5 ml of 9:1 DMF:water. The vial was capped and heated in a Personal Chemistry SmithSynthesizer to 150° C. for 10 minutes. The reaction was diluted with water and extracted with EtAOc. The organic layer was washed (2×) with an aqueous saturated solution of sodium bicarbonate, then with water and then brine. The organic layer was then dried with sodium sulfate and purified by column chromatography on silica gel using a gradient of 30-70% EtOAc in hexanes. The clean fractions were reduced in vacuo and the residue triturated with ether to give N-methyl-6-(6-methyl-1-(3-(trifluoromethyl)phenoxy)isoquinolin-5-yl)quinazolin-2-amine as a light yellow solid. MS (M+H)+ 461.
Reaction SMILES: Cl.[C:2]1([C:8]#[C:9][C:10]2[S:14][C:13]([C:15]3[N:16]=[C:17]4[CH:22]=[N:21][CH:20]=[CH:19][N:18]4C=3N)=[CH:12][CH:11]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].CI.CC(=O)OCC.[CH3:35][N:36]([CH:38]=O)[CH3:37]>>[CH3:35][N:36]([CH3:37])[C:38]1[N:18]2[CH:19]=[CH:20][N:21]=[CH:22][C:17]2=[N:16][C:15]=1[C:13]1[S:14][C:10]([C:9]#[C:8][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:11][CH:12]=1
Reactant: CN(C)C=O
Reactant: Nc1c(-c2ccc(C#Cc3ccccc3)s2)nc2cnccn12
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CI
Product: CN(C)c1c(-c2ccc(C#Cc3ccccc3)s2)nc2cnccn12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 40 %

Procedure:
790 mg (2.5 mmol) of 2-(5-phenylethynyl-thiophen-2-yl)-imidazo[1,2-a]pyrazin-3-ylamine hydrochloride (Example 83) were dissolved in DMF (8 ml). After addition of 300 mg (7.5 mmol) of sodium hydride (60% dispersion in mineral oil) in portions, the mixture was stirred at RT for 30 min. 0.3 ml (5.0 mmol) of methyl iodide dissolved in DMF (2 ml) was then added dropwise. The reaction solution was stirred at RT for a further 4 h and then quenched with water (20 ml) and extracted with EA (2×50 ml). The combined organic phases were dried over MgSO4, filtered and evaporated under a vacuum. 351 mg (1.0 mmol, 40% of theoretical) of dimethyl-[2-(5-phenylethynyl-thiophen-2-yl)-imidazo[1,2-a]pyrazin-3-yl]-amine were obtained from the group by crystallisation (EA).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[C:16](Cl)[N:15]=[C:14]([N:19]3[CH2:22][CH2:21][CH2:20]3)[N:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH2:23]([NH2:25])[CH3:24]>C(O)C>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[C:16]([NH:25][CH2:23][CH3:24])[N:15]=[C:14]([N:19]3[CH2:22][CH2:21][CH2:20]3)[N:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CCN
Reactant: Nc1ccc(S(=O)(=O)Nc2cc(Cl)nc(N3CCC3)n2)cc1
Solvent: CCO
Product: CCNc1cc(NS(=O)(=O)c2ccc(N)cc2)nc(N2CCC2)n1
Temperature: 130 °C
Reaction time: 12 h
Yield: 42.3 %

Procedure:
0.2 g (0.00061 mol) of 4-amino-N-(2-azetidin-1-yl-6-chloro-pyrimidin-4-yl)-benzenesulfonamide was dissolved in 20 ml of ethanol, treated with 3.9 ml (0.061 mol) of ethylamine and stirred in an autoclave at 130° C. for 12 hours. The reaction mixture was free from solvent, the residue was suspended in 5 ml of ethanol and treated in an ultrasound bath for 15 minutes. The precipitate was filtered off, dissolved in 10 ml of 0.1N NaOH and filtered. The filtrate was adjusted to pH 6 with 0.1N HCl. The precipitate was filtered off under suction, washed with water and dried. There was obtained 0.090 g (44%) of 4-amino-N-(2-azetidin-1-yl-6-ethylamino-pyrimidin-4-yl)-benzenesulfonamide as beige crystals; m.p.: 260-262° C.
Reaction SMILES: CC1(C)C[O:5][C:4]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:8]=2[C:15](=O)[CH2:16][CH2:17][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:3]1.OS(O)(=O)=O.O.[NH2:34]N.[OH-].[Na+]>C(O)(=O)C.O.C(O)C>[CH3:14][O:13][C:10]1[CH:9]=[C:8]2[C:7](=[CH:12][CH:11]=1)[C:4](=[O:5])[NH:3][N:34]=[C:15]2[CH2:16][CH2:17][CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: NN
Reactant: COc1ccc(C2=NC(C)(C)CO2)c(C(=O)CCCCc2ccccc2)c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Solvent: CCO
Product: COc1ccc2c(=O)[nH]nc(CCCCc3ccccc3)c2c1
Reaction time: 5 h
Yield: 29.2 %

Procedure:
A solution of 1-[2-(4,4-dimethyl-4,5-dihydro-oxazol-2-yl)-5-methoxy-phenyl]-5-phenyl-pentan-1-one (0.37 g, 1 mmole), prepared as described in example 18, in 5 ml of a mixture of water (0.5 ml), ethanol (5 ml), concentrated H2SO4 (0.4 ml) up to 10 ml with ethanol, was stirred at reflux for 20 hours, then concentrated to small volume, taken up in water, extracted with ethyl ether and the ethereal phase was washed with water, anhydrified and brought to dryness. The resultant oil was dissolved in acetic acid (10 ml) and dropwise added, under N2, with a solution of hydrazine monohydrate (0.45 ml, 3 mmoles) in acetic acid (2 ml). The mixture was stirred for 3 hours at 80° C., then overnight at room temperature and at 80° C. for further 5 hours, cooled, almost brought to dryness, taken up in water, basified with NaOH, extracted more times with ethyl acetate. The organic phases were washed with water/NaCl, anhydrified and concentrated. The residue was flash chromatographed (eluent: petroleum/ethyl acetate 6:4) to give 0.09 g of the title compound (yield: 29%).