Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:14]1([NH2:21])[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>[Cu].O>[NH2:20][C:17]1[CH:18]=[CH:19][C:14]([NH:21][C:2]2[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=2[C:4]([OH:6])=[O:5])=[CH:15][CH:16]=1
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1Cl
Reactant: Nc1ccc(N)cc1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Nc1ccc(Nc2ccc([N+](=O)[O-])cc2C(=O)O)cc1
Reaction time: 5 h
Yield: 64.2 %

Procedure:
A mixture of 2-chloro-5-nitrobenzoic acid 9 (150 g, 0.744 mol), 1,4-phenylenediamine 8 (150.0 g, 1.387 mol), anhydrous potassium carbonate (309 g, 2.236 mol), copper powder (2.0 g, 31.5 mol), cupric sulfate (10 mg) and water (2.25 l) was heated to reflux with stirring for 5 hr. It was then filtered hot through a fluted paper and allowed to stand overnight at room temperature. The potassium salt of the product was collected on a glass sinter and washed with ice-cold water (2×250 mL) followed by ice-cold ethanol (250 mL). The product was dissolved in boiling water (1250 mL) and acetic acid was then added until there was no further precipitation. The mixture was cooled with an external ice water bath and the product collected. The product was washed with ice-cold water (3×500 mL) followed by ice-cold ethanol (2×500 mL), dry ether (250 mL) and finally hexane (2×500 mL). The product was dried over P2O5 under vacuum to yield a light brown solid 10 (130.52 g 64%).
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:5]2[CH2:6][CH2:7][CH2:8][C:9](=[O:13])[N:10]([CH2:11][CH3:12])[C:4]=2[CH:3]=1.[Br:16][C:17]1[C:18]([NH:24][C:25]2[C:34]([F:35])=[CH:33][CH:32]=[CH:31][C:26]=2[C:27]([NH:29][CH3:30])=[O:28])=[N:19][C:20](Cl)=[N:21][CH:22]=1>C(O)(C)C>[Br:16][C:17]1[C:18]([NH:24][C:25]2[C:34]([F:35])=[CH:33][CH:32]=[CH:31][C:26]=2[C:27]([NH:29][CH3:30])=[O:28])=[N:19][C:20]([NH:1][C:2]2[CH:15]=[CH:14][C:5]3[CH2:6][CH2:7][CH2:8][C:9](=[O:13])[N:10]([CH2:11][CH3:12])[C:4]=3[CH:3]=2)=[N:21][CH:22]=1
Reactant: CNC(=O)c1cccc(F)c1Nc1nc(Cl)ncc1Br
Reactant: CCN1C(=O)CCCc2ccc(N)cc21
Solvent: CC(C)O
Product: CCN1C(=O)CCCc2ccc(Nc3ncc(Br)c(Nc4c(F)cccc4C(=O)NC)n3)cc21
Temperature: 120 °C
Reaction time: 2 h
Yield: 49 %

Procedure:
A microwave vessel was charged with 8-amino-1-ethyl-1,3,4,5-tetrahydro-1-benzazepin-2-one (44.7 mg, 0.219 mmol), 2-(5-bromo-2-chloro-pyrimidin-4-ylamino)-3-fluoro-N-methyl-benzamide (65.6 mg, 0.182 mmol) 10-camphorsulfonic acid (4.2 mg, 0.018 mmol) and isopropyl alcohol (2.0 mL) and heated in a microwave at 120° C. for 60 minutes. The reaction mixture was quenched with a slurry of saturated, aqueous, NaHCO3 and stirred for 2 h. This mixture was diluted with water (10 mL) and extracted into DCM. The organic layer was dried by passing through a funnel filled with Na2SO4, and the filtrate was evaporated onto celite prior to purification by chromatography (amine modified silica gel, 25% EtOAc/hexane→80% EtOAc gradient). The appropriate fractions were combined, evaporated to afford a solid that was triturated with ether (2×2 mL) and yielded product (47 mg, 46%) as a pale yellow powder that had the following properties: m.p: 231-232° C.; LC/MS (ESI+): 528/530 (M+H); 1H-NMR (DMSO-d6, 400 MHz): δ 9.40 (s, 1H), 9.33 (s, 1H), 8.63 (m, 1H), 8.27 (s, 1H), 7.47 (d, J=7.0, 1H), 7.44 (s, 1H), 7.35-7.20 (m, 3H), 6.98 (d, J=8.2, 1H), 3.65 (br s, 2H), 2.75 (d, J=5.1, 3H), 2.50 (m, 2H), 2.10-1.85 (m, 4H), 0.93 (t, J=7.0, 3H).
Reaction SMILES: [OH-].[K+].[C:3]([C:7]1[C:8]([OH:16])=[CH:9][C:10]([CH3:15])=[C:11]([CH:14]=1)[CH:12]=[O:13])([CH3:6])([CH3:5])[CH3:4].[CH3:17][N:18]([CH3:22])[C:19](Cl)=[S:20].CN(C)C(Cl)=S.C1COCC1>O.C1COCC1>[C:3]([C:7]1[CH:14]=[C:11]([CH:12]=[O:13])[C:10]([CH3:15])=[CH:9][C:8]=1[O:16][C:19](=[S:20])[N:18]([CH3:22])[CH3:17])([CH3:6])([CH3:5])[CH3:4]
Reactant: Cc1cc(O)c(C(C)(C)C)cc1C=O
Reactant: CN(C)C(=S)Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(OC(=S)N(C)C)c(C(C)(C)C)cc1C=O
Temperature: 45 °C
Reaction time: 0.17 h

Procedure:
Ten percent KOH (80 mL) was added to a mixture of 5-tert-butyl-4-hydroxy-2-methylbenzaldehyde (Example T 99.0 g, 515 mmol) in water (180 mL) and THF (135 mL.) The mixture was treated with a solution of N,N-dimethylthiocarbamoyl chloride (86.1 g) in THF (108 mL) over a 2-hour period with simultaneous addition of 10% KOH in order to hold the pH of the reaction mixture between 12.0 and 12.3. After approximately 70% of the dimethylthiocarbamoyl chloride-THF solution had been added, vacuum was applied to the reaction mixture to remove the THF; during this distillation, the simultaneous additions of 10% KOH and the dimethylthiocarbamoyl chloride-THF solution were continued while maintaining the pH range between 12.0 and 11.6 and the reaction temperature between 23° C. to 25° C. The distillation was continued for 10 minutes after all the dimethylthiocarbamoyl chloride solution had been added. Stirring at ambient pressure and temperature was continued for another 90 minutes, during which time the pH was stable between 11.6 and 1.75. A solution of EtOAc (150 mL) and heptane (150 mL) was added to the reaction mixture, and after stirring and settling, the layers were separated and the aqueous layer extracted with 1:1 heptane:EtOAc. The combined organic extracts were extracted with 10% KOH (2×100 mL) and water (2×90 mL) and concentrated. The residue was diluted with MeOH (120 mL). The solution was warmed to 45° C. and H2O (20 mL) was added. The solution was cooled to room temperature. 50% NaOH (170 mg) was added, and the solution was concentrated. This residue was redissolved in MeOH (120 mL) at 50° C. and H2O (15 mL) was added. The solution was cooled slowly to −5° C. with the addition of dimethylthiocarbamic acid O-(2-tert-butyl-4-formyl-5-methyl-phenyl)ester seed crystals to promote crystallization. The mixture was filtered and the solid washed with 4:1 MeOH:H2O to give the title compound, mp 80-81° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](/[CH:13]=[CH:14]/[C:15]3[S:16][C:17]([C:21](O)=[O:22])=[C:18]([CH3:20])[N:19]=3)=[C:11]([CH3:24])[N:10]=[N:9]2)=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:56][CH:57]1[CH2:62][CH2:61][O:60][CH2:59][CH2:58]1>CN(C=O)C>[O:60]1[CH2:61][CH2:62][CH:57]([NH:56][C:21]([C:17]2[S:16][C:15](/[CH:14]=[CH:13]/[C:12]3[N:8]([C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)[N:9]=[N:10][C:11]=3[CH3:24])=[N:19][C:18]=2[CH3:20])=[O:22])[CH2:58][CH2:59]1
Reactant: Cc1nc(/C=C/c2c(C)nnn2-c2ccc(F)cc2)sc1C(=O)O
Reactant: NC1CCOCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1nc(/C=C/c2c(C)nnn2-c2ccc(F)cc2)sc1C(=O)NC1CCOCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.7 %

Procedure:
To a solution of 2-{(E)-2-[3-(4-fluoro-phenyl)-5-methyl-3H-[1,2,3]triazol-4-yl]-vinyl}-4-methyl-thiazole-5-carboxylic acid (72 mg, 0.21 mmol) and TBTU (74 mg, 0.23 mmol) in DMF (3 mL) was added DIPEA (178 μL, 1.05 mmol). Then 4-aminotetrahydropyran (23 mg, 0.23 mmol) was added and the mixture was stirred at room temperature under Ar for 2 h. The mixture was then evaporated and purification by chromatography (silica, 30 to 80% ethylacetate in heptane) afforded the title compound (68 mg, 76%) as a light yellow solid. MS: m/e=428.3 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][C:3]=1[NH2:4].C(O[CH:16]=[C:17]([C:20]#[N:21])[C:18]#[N:19])C>C(O)C>[C:18]([C:17]([C:20]#[N:21])=[CH:16][NH:4][C:3]1[CH:5]=[C:6]([C:9]([F:10])([F:11])[F:12])[CH:7]=[CH:8][C:2]=1[Cl:1])#[N:19]
Reactant: Nc1cc(C(F)(F)F)ccc1Cl
Reactant: CCOC=C(C#N)C#N
Solvent: CCO
Product: N#CC(C#N)=CNc1cc(C(F)(F)F)ccc1Cl
Yield: 70 %

Procedure:
19.6 Parts of 2-chloro-5-trifluoromethyl-aniline and 12.2 parts of ethoxymethylenemalononitrile are dissolved in 125 parts of ethanol and the mixture is refluxed for 48 hours. After cooling, the precipitated product is collected by filtration and washed with ethanol. Recrystallisation from ethanol affords the above product with a melting point of 166°-169° C. and in a 70% yield.
Reaction SMILES: C[O:2][C:3](=[O:21])[C@H:4]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)[NH:5]C(OC(C)(C)C)=O.[CH2:22]([C:24]1[O:28][C:27]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[N:26][C:25]=1[CH2:35]O)[CH3:23].C(O)(C(F)(F)F)=O.[OH-].[Na+]>O>[NH2:5][C@@H:4]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([O:20][CH2:35][C:25]2[N:26]=[C:27]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[O:28][C:24]=2[CH2:22][CH3:23])=[CH:18][CH:19]=1)[C:3]([OH:2])=[O:21]
Reactant: CCc1oc(-c2ccccc2)nc1CO
Reactant: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CCc1oc(-c2ccccc2)nc1COc1ccc(C[C@H](N)C(=O)O)cc1
Yield: 69 %

Procedure:
Intermediate 61 was prepared as described above for the preparation of intermediate 52. From 465 mg of N-(Boc)-L-Tyrosine methyl ester and 320 mg of Intermediate 8G was prepared 520 mg of BOC-protected intermediate methyl ester (69% yield; 1H NMR (CDCl3, 300 MHz) δ8.09-8.06 (m, 2H), 7.47-7.46 (m, 3H), 7.08 (d, 2H, J=8.7), 6.97 (d, 2H, J=8.7), 5.02 (s, 2H), 5.01 (s, 1H), 4.59-4.55 (m, 1H), 3.74 (s, 3H), 3.08-3.02 (m, 2H), 2.83 (q, 2H, J=7.5), 1.45 (s, 9H), 1.32 (t, 3H, J=7.5); From 510 mg of BOC-protected ester intermediate was prepared the crude TFA salt of intermediate 61. The TFA salt was suspended into water and the pH adjusted to ˜7.0 with 10% NaOH. The resulting solids were filtered and dried to yield 315 mg of intermediate 61; 1H NMR (DMSO-d6, 300 MHz) δ7.96-7.94 (m, 2H), 7.52-7.51 (m, 3H), 7.18 (d, 2H, J=8.4), 6.95 (d, 2H, J=8.4), 4.97 (s, 3H), 3.10-3.05 (m, 1H), 2.86-2.79 (m, 4H), 1.22 (t, 3H, J=7.5); low resolution MS (ES+)m/e 366.86 (MH+); TLC Rf=0.52 (4/1, DCM/MeOH).
Reaction SMILES: Br[C:2]1[C:3]([O:21][CH2:22][C:23]([F:26])([F:25])[F:24])=[N:4][CH:5]=[C:6]([CH:20]=1)[C:7]([NH:9][CH2:10][C:11]1[O:15][N:14]=[C:13]([C:16]([F:19])([F:18])[F:17])[N:12]=1)=[O:8].B(O)(O)[C:28]1[CH:29]=[CH:30][C:31]([CH3:34])=[CH:32][CH:33]=1.C([O-])([O-])=O.[Na+].[Na+].O1CCCC1>O>[C:31]1([CH3:34])[CH:32]=[CH:33][C:28]([C:2]2[C:3]([O:21][CH2:22][C:23]([F:26])([F:25])[F:24])=[N:4][CH:5]=[C:6]([CH:20]=2)[C:7]([NH:9][CH2:10][C:11]2[O:15][N:14]=[C:13]([C:16]([F:19])([F:18])[F:17])[N:12]=2)=[O:8])=[CH:29][CH:30]=1
Reactant: Cc1ccc(B(O)O)cc1
Reactant: O=C(NCc1nc(C(F)(F)F)no1)c1cnc(OCC(F)(F)F)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(-c2cc(C(=O)NCc3nc(C(F)(F)F)no3)cnc2OCC(F)(F)F)cc1
Temperature: 90 °C
Reaction time: 15 h
Yield: 46.8 %

Procedure:
5-Bromo-6-(2,2,2-trifluoroethoxy)-N-((3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl)methyl)nicotinamide (example BP; 100 mg, 223 μmol), p-tolylboronic acid (CAN 5720-05-8; 33 mg, 243 μmol), 1,1′-bis(diphenylphosphino)-ferrocene-palladium(II)dichloride dichloromethane complex (4 mg, 5.27 μmol) and Na2CO3 (35 mg, 330 μmol) were combined with tetrahydrofuran (5 mL) and water (1.5 mL). The reaction mixture was heated to 90° C., stirred for 15 h, cooled down and poured into 25 mL H2O. The mixture was extracted with ethyl acetate (2×25 mL). The organic layers were combined, washed with brine (1×25 mL), dried with MgSO4 and concentrated in vacuo. The crude material was purified twice by flash chromatography (silica gel, 20 g, 0% to 40% ethyl acetate in hexanes) to give 48 mg (46%) of the title compound as a light yellow solid; MS (ESI): 459.090 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:16][O:17][C:18]2[CH:27]=[C:26]3[C:21]([CH2:22][CH2:23][C:24]([CH3:29])([CH3:28])[O:25]3)=[CH:20][CH:19]=2)=[CH:4][C:5]([F:15])=[C:6]([CH:14]=1)[C:7]([O:9]C(C)(C)C)=[O:8].FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:1][C:2]1[C:3]([CH2:16][O:17][C:18]2[CH:27]=[C:26]3[C:21]([CH2:22][CH2:23][C:24]([CH3:29])([CH3:28])[O:25]3)=[CH:20][CH:19]=2)=[CH:4][C:5]([F:15])=[C:6]([CH:14]=1)[C:7]([OH:9])=[O:8]
Reactant: CC(C)(C)OC(=O)c1cc(Cl)c(COc2ccc3c(c2)OC(C)(C)CC3)cc1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1(C)CCc2ccc(OCc3cc(F)c(C(=O)O)cc3Cl)cc2O1
Temperature: 25 °C
Reaction time: 16 h
Yield: 39.8 %

Procedure:
A mixture of tert-butyl 5-chloro-4-((2,2-dimethylchroman-7-yloxy)methyl)-2-fluorobenzoate (290 mg, 0.689 mmol) and trifluoroacetic acid (10 mL) in DCM (10 mL) was stirred at room temperature for 16 hrs. The solvents were removed and the residue was extracted with EtOAc (150×3 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by reverse phase combiflash (15%-19% MeCN in 0.5% NH4HCO3) to give target product of 5-chloro-4-((2,2-dimethylchroman-7-yloxy)methyl)-2-fluorobenzoic acid (100 mg, 49%) as a white solid. LCMS (ESI) m/z: 364.9 [M+H].
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([C:11]2[CH:16]=[N:15][CH:14]=[C:13](Cl)[N:12]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2].[C:18]([C:22]1[N:23]=[C:24]([NH2:27])[S:25][CH:26]=1)([CH3:21])([CH3:20])[CH3:19].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1>[C:18]([C:22]1[N:23]=[C:24]([NH:27][C:13]2[N:12]=[C:11]([C:7]3[CH:6]=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[CH:10]=[CH:9][CH:8]=3)[CH:16]=[N:15][CH:14]=2)[S:25][CH:26]=1)([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)c1csc(N)n1
Reactant: CC(=O)Nc1cccc(-c2cncc(Cl)n2)c1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Product: CC(=O)Nc1cccc(-c2cncc(Nc3nc(C(C)(C)C)cs3)n2)c1
Yield: 21 %

Procedure:
Following Method L, 2-(3-acetamidophenyl)-6-chloropyrazine (4a) (60 mg, 0.24 mmol), 4-(tert-butyl)-1,3-thiazol-2-amine (54.7 mg, 0.35 mmol), Pd(0)2 dba3 (9 mg, 0.01 mmol), BINAP (50 mg, 0.04 mmol), sodium tert-butoxide (33 mg, 0.34 mmol) and toluene (5 mL) were reacted at 85° C. for 16 hours. The same workup as is Method L produced a solid that was washed with 50 mL dichloromethane and filtered. The dichloromethane slowly evaporated to produce white crystals that were removed by filtration and washing with dichloromethane (10 mL). The dichloromethane was then evaporated and the resulting crude was chromatographed in silica gel using ethyl acetate: dichloromethane, 2:1, as eluent to furnish 18.5 mg of title compound. Yield: 21.0%. 1 H NMR (250 MHz, DMSO-d6) δ 1.30 (s, 9H), 2.10 (s, 3 H), 6.69 (s, 1 H), 7.47 (t, 1 H, 7.9 Hz), 7.69 (d, 1 H, 8.0 Hz), 7.89 (d, 1 H, 7.8 Hz), 8.38 (s, 1 H), 8.45 (bs, 1 H), 8.58 (s, 1 H), 10.11 (s, 1 H), 11.78 (bs, 1 H);
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][N:3]=1.C[Al](C)C.C([O:15][C:16]([C:18]1[N:19]=[C:20]([CH3:34])[S:21][C:22]=1[NH:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([S:30](=[O:33])(=[O:32])[NH2:31])[CH:25]=1)=O)C.S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCOCC1.O>[F:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:16]([C:18]2[N:19]=[C:20]([CH3:34])[S:21][C:22]=2[NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([S:30](=[O:33])(=[O:32])[NH2:31])[CH:25]=2)=[O:15])=[N:3][CH:4]=1
Reactant: CCOC(=O)c1nc(C)sc1Nc1cccc(S(N)(=O)=O)c1
Reactant: Nc1ccc(F)cn1
Agent: C[Al](C)C
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1nc(C(=O)Nc2ccc(F)cn2)c(Nc2cccc(S(N)(=O)=O)c2)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 2.8 %

Procedure:
A solution of 2-amino-5-fluoro pyridine (0.15 g, 1.38 mmol) in 10 ml dry dioxane was treated at 0° C. with trimethylaluminium (2M in hexane, 0.69 ml, 1.38 mmol). The mixture was stirred at room temperature for 1 h. 2-Methyl-5-(3-sulfamoyl-phenylamino)-thiazole-4-carboxylic acid ethyl ester (0.12 g, 0.35 mmol) was added and the reaction mixture was refluxed for 4 h. 1 ml water and 2 g sodium sulfate were sequentially added and filtered. The filtrate was evaporated and the residue purified by flash chromatography (hetane, ethyl acetate) to yield 2-methyl-5-(3-sulfamoyl-phenylamino)-thiazole-4-carboxylic acid (5-fluoro-pyridin-2-yl)-amide (0.004 g, 3%) as an off-white solid, MS (ISP): m/e=408.4 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([B:9]2[O:13][C:12]([CH3:15])([CH3:14])[C:11]([CH3:17])([CH3:16])[O:10]2)[CH:8]=1)[NH2:5].Cl[C:19]1[N:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[CH:21][N:20]=1.O1CCOCC1.CS(O)(=O)=O>C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([NH:5][C:19]2[N:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[CH:21][N:20]=2)[CH:6]=[C:7]([B:9]2[O:13][C:12]([CH3:15])([CH3:14])[C:11]([CH3:17])([CH3:16])[O:10]2)[CH:8]=1
Reactant: CC1(C)OB(c2cc(N)cc(F)c2)OC1(C)C
Reactant: FC(F)(F)c1ccnc(Cl)n1
Agent: CS(=O)(=O)O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC1(C)OB(c2cc(F)cc(Nc3nccc(C(F)(F)F)n3)c2)OC1(C)C
Temperature: 100 °C
Yield: 76.4 %

Procedure:
To a flask containing 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (3.3 g, 14.00 mmol) and 2-chloro-4-(trifluoromethyl)pyrimidine (2.94 g, 16.10 mmol) were added dioxane (44 mL) and methanesulfonic acid (1.55 g, 16.10 mmol) and the reaction was heated at 100° C. overnight. The reaction was cooled, diluted with ethyl acetate, washed with water, dried over magnesium sulfate, filtered and concentrated. Flash chromatography was used for purification to yield. N-[3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-4-(trifluoromethyl)pyrimidin-2-amine (4.10 g, 10.70 mmol, 76% yield). MS ESI: [M+H]+ m/z 384. 1H NMR (500 MHz, DMSO-d6) δ 10.41 (s, 1H), 8.85 (d, J=4.9, 1H), 7.92 (dt, J=2.3, 12.1, 1H), 7.77 (d, J=1.5, 1H), 7.32 (d, J=4.9, 1H), 6.98 (dd, J=2.2, 8.4, 1H), 1.28 (s, 12H).
Reaction SMILES: [Cl-].[CH2:2]([NH2+:9][CH2:10][CH2:11]Cl)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Cl:13][C:14]1[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:15]=1[N:21]=[C:22]=[S:23]>>[Cl:13][C:14]1[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:15]=1[N:21]=[C:22]1[N:9]([CH2:2][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:10][CH2:11][S:23]1
Reactant: ClCC[NH2+]Cc1ccccc1
Reactant: S=C=Nc1cccc(Cl)c1Cl
Agent: [Cl-]
Product: Clc1cccc(N=C2SCCN2Cc2ccccc2)c1Cl

Procedure:
2-Hydroxyethylamine was reacted with benzyl bromide according to Method B2a to give N-benzyl-N-(2-hydroxyethyl)amine. The alcohol was reacted with SOCl2 according to Method B7c to give N-benzyl-N-(2-chloroethyl)ammonium chloride. The chloroethylamine was reacted with 2,3-dichlorophenyl isothiocyanate to give 2-(2,3-dichlorophenylimino)-3-benzyl-1,3-thiazolidine.
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:12]2=[N:13][C:14]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH:27]([F:29])[F:28])[CH:24]=4)[N:19]([CH2:30][CH2:31][CH:32]([OH:34])[CH3:33])[N:18]=3)=[CH:15][N:16]=[C:11]2[N:10](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[C:1]([NH:5][C:6]([C:8]1[C:12]2=[N:13][C:14]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH:27]([F:28])[F:29])[CH:24]=4)[N:19]([CH2:30][CH2:31][CH:32]([OH:34])[CH3:33])[N:18]=3)=[CH:15][N:16]=[C:11]2[NH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(O)CCn1nc(-c2cnc3c(n2)c(C(=O)NC(C)(C)C)cn3C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(OC(F)F)ccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(O)CCn1nc(-c2cnc3[nH]cc(C(=O)NC(C)(C)C)c3n2)c2cc(OC(F)F)ccc21
Reaction time: 1.5 h
Yield: 30 %

Procedure:
To a stirred solution of N-tert-butyl-2-(5-(difluoromethoxy)-1-(3-hydroxybutyl)-1H-indazol-3-yl)-5-trityl-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide in dichloromethane (2 mL) was added drop-wise trifluoroacetic acid (1 mL) at room temperature. Then the reaction mixture was stirred for 1.5 hours. The solvent was removed under reduced pressure and the residue was purified by preparative-TLC (silica gel, petroleum ether:EtOAc=1:1) to give N-tert-butyl-2-(5-(difluoromethoxy)-1-(3-hydroxybutyl)-1H-indazol-3-yl)-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (22 mg, 30% over three steps) as a white solid. MS: (M+H)+=473.2; 1H NMR (300 MHz, DMSO): δ 12.86 (s, 1H), 9.11 (s, 1H), 8.42 (s, 1H), 8.24 (d, 1H, J=1.8 Hz), 7.92-7.89 (m, 2H), 7.47-7.42 (m, 1H), 7.23 (t, 1H, J=74.4 Hz), 4.75-4.61 (m, 3H), 3.65 (brs, 1H), 2.06-1.92 (m, 2H), 1.53 (s, 9H), 1.15 (d, 3H, J=6.3 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C@H:10]([CH2:11][CH2:12][OH:13])[O:9][CH2:8][CH2:7][C:6]=2[CH:14]=1.N1C=CN=C1.Cl[Si:21]([C:34]([CH3:37])([CH3:36])[CH3:35])([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(OCC)C>C1COCC1>[Si:21]([O:13][CH2:12][CH2:11][C@H:10]1[C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:14][C:6]=2[CH2:7][CH2:8][O:9]1)([C:34]([CH3:37])([CH3:36])[CH3:35])([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: OCC[C@@H]1OCCc2cc(Br)ccc21
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)[Si](OCC[C@@H]1OCCc2cc(Br)ccc21)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 2-((1S)-6-bromo-3,4-dihydro-1H-2-benzopyran-1-yl)ethanol (3.0 g, 11.7 mmol) in dry THF (100 mL) was added imidazole (3.97 g, 58.4 mmol) and chloro-tert-butyl(diphenyl)silane (6.42 g, 23.4 mmol), and the mixture stirred under nitrogen at room temperature for 20 h. Diethyl ether was added and the mixture filtered through a pad of silica. The filtrate was evaporated in vacuo and the crude product purified by flash chromatography on silica, eluting with ethyl acetate/heptane (0:10 to 2:8), to yield the title compound.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:14]([CH2:17][CH2:18][CH2:19][CH3:20])[C:15]#[N:16])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:21][CH2:22]Br.[OH-].[Na+].O>CS(C)=O>[C:15]([C:14]([C:10]1[CH:11]=[CH:12][CH:13]=[C:8]([O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:9]=1)([CH2:17][CH2:18][CH2:19][CH3:20])[CH2:22][Br:21])#[N:16]
Reactant: BrCBr
Reactant: CCCCC(C#N)c1cccc(Oc2ccccc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CCCCC(C#N)(CBr)c1cccc(Oc2ccccc2)c1
Reaction time: 1 h
Yield: 88.1 %

Procedure:
To a solution of 10 g (0.038 mole) of 2-(3-phenoxyphenyl)hexanenitrile, 6.6 g (0.038 mole) of dibromomethane in 50 ml of dimethyl sulfoxide is added 3.2 g (0.04 mole) of 50% sodium hydroxide solution dropwise. The reaction mixture is stirred at 60° for one hour, poured into water and extracted with ether. The combined ether extracts are washed with water and dried over MgSO4. Solvent is evaporated to give 12 g of product.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](Br)[N:3]=1.[CH3:9][NH:10][NH2:11]>>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N:10]([CH3:9])[NH2:11])[N:3]=1
Reactant: CNN
Reactant: Brc1cccc(Br)n1
Product: CN(N)c1cccc(Br)n1
Temperature: 100 °C
Yield: 66 %

Procedure:
A suspension of 2,6-dibromopyridine (10.0 g, 42.0 mmol) in anhydrous methylhydrazine (10 mL) was heated at 100° C. for 2 h. The mixture was cooled to room temperature and washed with water (3×20 mL). The organic layer was separated, dried over sodium sulfate, filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica gel, hexanes/EtOAc, 80:20) gave the title compound (5.70 g, 66%) as white solid: 1H NMR (500 MHz, CDCl3) δ 7.30-7.26 (dd, J=8.5, 7.8Hz, 1H), 6.83 (d, J=8.0 Hz, 1H), 6.73 (d, J=7.0 Hz, 1H), 4.03 (br s, 2H), 3.36 (s, 3H).
Reaction SMILES: [CH3:1][CH:2]1[CH2:4][CH:3]1[CH2:5][O:6][C:7]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-])=O)[C:8]=1[C:9]#[N:10]>CCOC(C)=O.CCO.[Pd]>[NH2:15][C:11]1[CH:12]=[CH:13][CH:14]=[C:7]([O:6][CH2:5][CH:3]2[CH2:4][CH:2]2[CH3:1])[C:8]=1[C:9]#[N:10]
Reactant: CC1CC1COc1cccc([N+](=O)[O-])c1C#N
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC1CC1COc1cccc(N)c1C#N
Yield: 79.1 %

Procedure:
A solution of 2-((2-methylcyclopropyl)methoxy)-6-nitrobenzonitrile (example 254c) (0.29 g, 1.25 mmol) in EtOAc/EtOH 1:1 (30 mL) was hydrogenated in an H-cube apparatus using 10% Pd/C as catalyst. The solution was evaporated to give 2-amino-6-((2-methylcyclopropyl)methoxy)benzonitrile (0.20 g, 79%) as a yellow oil. MS 203 (MH+).