Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C([N:5]1[CH2:11][CH:10]([CH3:12])[C:9]2[CH:13]=[C:14]([I:21])[C:15]([O:17][CH2:18][CH:19]=[CH2:20])=[CH:16][C:8]=2[CH2:7][CH2:6]1)=O.[OH-].[Na+]>CO.O>[CH2:18]([O:17][C:15]1[C:14]([I:21])=[CH:13][C:9]2[CH:10]([CH3:12])[CH2:11][NH:5][CH2:6][CH2:7][C:8]=2[CH:16]=1)[CH:19]=[CH2:20]
Reactant: C=CCOc1cc2c(cc1I)C(C)CN(C(=O)C(F)(F)F)CC2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: C=CCOc1cc2c(cc1I)C(C)CNCC2
Reaction time: 8 h
Yield: 90.4 %

Procedure:
A solution of N-trifluoroacetyl-7-allyloxy-8-iodo-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (23 mg, 0.058 mmol) in methanol (2 mL) was treated with 15% aqueous NaOH (2 mL), and stirred overnight at 20 C. The product mixture was diluted with water (5 mL), extracted twice with EtOAc (5 mL), the combined organic phases were washed with brine (5 mL), dried with Na2SO4 and concentrated to give 18 mg of a white solid. MS calculated for C14H18INO+H: 344, observed: 344.
Reaction SMILES: I[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9]2[N:10]=[C:11]([NH:14][C:15](=[O:22])[C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)[S:12][CH:13]=2)=[C:4]([CH3:23])[CH:3]=1.[CH3:24][O:25][CH2:26][CH2:27][O:28][C:29]1[N:30]=[CH:31][C:32]([SH:35])=[N:33][CH:34]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.[Cu](I)I>[CH3:24][O:25][CH2:26][CH2:27][O:28][C:29]1[N:30]=[CH:31][C:32]([S:35][C:2]2[CH:7]=[C:6]([CH3:8])[C:5]([C:9]3[N:10]=[C:11]([NH:14][C:15](=[O:22])[C:16]4[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=4)[S:12][CH:13]=3)=[C:4]([CH3:23])[CH:3]=2)=[N:33][CH:34]=1
Reactant: Cc1cc(I)cc(C)c1-c1csc(NC(=O)c2ccncc2)n1
Reactant: COCCOc1cnc(S)cn1
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCCOc1cnc(Sc2cc(C)c(-c3csc(NC(=O)c4ccncc4)n3)c(C)c2)cn1
Temperature: 100 °C
Reaction time: 7 h
Yield: 58.8 %

Procedure:
A mixture of 25-1 (3.00 g, 6.89 mmol), 5-(2-methoxyethoxy)pyrazine-2-thiol (27-2, 2.57 g, 13.8 mmol), copper iodide (66.0 mg, 0.35 mmol), and potassium carbonate (2.86 g, 20.7 mmol) in 13.8 mL of DMF was stirred at 100° C. for 7.0 h. The reaction mixture was concentrated under reduced pressure and purified by column chromatography on silica gel (EtOAc:hexnaes=2:1 as eluant) to give N-(4-{4-(5-(2-methoxyethoxy)pyrazin-2-ylthio)-2,6-dimethylphenyl}thiazol-2-yl)isonicotinamide (27, 2.00 g) as light yellow solids in 59% yield: 1H NMR (500 MHz, CDCl3) δ 8.75 (d, J=4.0 Hz, 2 H), 8.19 (d, J=1.0 Hz, 1 H), 8.00 (d, J=1.0 Hz, 1H), 7.63 (d, J=5.0 Hz, 2 H), 6.96 (s, 1 H), 6.79 (s, 2 H), 4.44 (t, J=4.5 Hz, 2 H), 3.72 (t, J=4.5 Hz, 2 H), 3.41 (s, 3 H), 1.95 (s, 6 H). ESI-MS: m/z 494.2 (M+H)+.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10](F)=[CH:9][CH:8]=1)=O.[NH:14]1[CH:18]=[CH:17][N:16]=[CH:15]1>>[N:14]1([C:10]2[CH:11]=[CH:12][C:7]([C:5]3[C:15]4[N:14]([CH:18]=[CH:17][N:16]=4)[CH2:2][CH2:3][CH:4]=3)=[CH:8][CH:9]=2)[CH:18]=[CH:17][N:16]=[CH:15]1
Reactant: O=C(CCCCl)c1ccc(F)cc1
Reactant: c1c[nH]cn1
Product: C1=C(c2ccc(-n3ccnc3)cc2)c2nccn2CC1

Procedure:
Combine 50 g (0.25 mol) of 4-chloro-4'-fluorobutyrophenone with 120 g (1.76 mol) of imidazole, and heat to 175° C. for 18 hr. Isolation of the product from 500 g of silica gel, followed by crystallization from ethyl acetate, provides the title compound.
Reaction SMILES: [O-:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[K+].F[C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1>CN1CCCC1=O.O>[CH:5]1[CH:6]=[CH:7][C:2]([O:1][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)=[CH:3][CH:4]=1
Reactant: Fc1ccc(Cl)cc1
Reactant: [O-]c1ccccc1
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: Clc1ccc(Oc2ccccc2)cc1
Yield: 54.2 %

Procedure:
A stirred solution containing 14.8 g (0.112 mole) of potassium phenoxide and 13.1 g (0.10 mole) of p-fluorochlorobenzene in 100 ml of N-methyl-2-pyrrolidinone is heated at reflux for a period of time necessary to effect complete reaction, as determined by vapor phase chromotography techniques. The crude reaction mixture is cooled and diluted to a volume of 400 ml with water, whereupon it is extracted with several portions of ether. The combined organic extracts are washed with a 5% sodium hydroxide solution, water, and a saturated sodium chloride solution, dried (magnesium sulfate), and concentrated in vacuo. Distillation at reduced pressure affords 11.1 g (54%) of material, b(0.05 mm) 73.5°-75.5°, whose spectral properties are in agreement with the desired structure.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].O.[CH:8]([N:10]1[CH:15]=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:13]([CH2:22][C:23]([O:25]CC)=[O:24])[C:12](=[O:28])[CH:11]1[CH:29]([CH3:31])[CH3:30])=[O:9].C(OCC)(=O)C>C(O)C>[CH:8]([N:10]1[CH:15]=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:13]([CH2:22][C:23]([OH:25])=[O:24])[C:12](=[O:28])[CH:11]1[CH:29]([CH3:31])[CH3:30])=[O:9]
Reactant: CCOC(=O)CN1C(=O)C(C(C)C)N(C=O)C=C1c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(C)C1C(=O)N(CC(=O)O)C(c2ccccc2)=CN1C=O

Procedure:
Potassium carbonate (983 mg) and water (6 ml) are added to a solution of ethyl {(3RS)-4-formyl-3-isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}acetate (1.96 g, Reference compound No. 50-1) in ethanol (14 ml), and the mixture is stirred overnight. Ethyl acetate is added to reaction mixture, and the whole is extracted with water. A 10% aqueous citric acid solution is added to the extract to acidify the system, and the whole is extracted with ethyl acetate again. The extract is washed with water and dried over anhydrous magnesium sulfate. The extract is concentrated under reduced pressure to give the titled reference compound (0.90 g).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:25][C@@H:26]3[CH2:30][CH2:29][CH2:28][N:27]3[C:31](=[O:35])[CH2:32][C:33]#[N:34])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][C:12]=3[F:24])[C:3]=12.[CH:36]1([CH:39]=O)[CH2:38][CH2:37]1.N1CCCCC1>C(O)C>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:25][C@@H:26]3[CH2:30][CH2:29][CH2:28][N:27]3[C:31]([C:32](=[CH:39][CH:36]3[CH2:38][CH2:37]3)[C:33]#[N:34])=[O:35])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:13][C:12]=3[F:24])[C:3]=12
Reactant: N#CCC(=O)N1CCC[C@H]1Cn1nc(-c2ccc(Oc3ccccc3)cc2F)c2c(N)ncnc21
Reactant: O=CC1CC1
Solvent: C1CCNCC1
Solvent: CCO
Product: N#CC(=CC1CC1)C(=O)N1CCC[C@H]1Cn1nc(-c2ccc(Oc3ccccc3)cc2F)c2c(N)ncnc21
Temperature: 90 °C
Yield: 54.7 %

Procedure:
To a solution of 3-[(2S)-2-[[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]methyl]pyrrolidin-1-yl]-3-oxo-propanenitrile (2173 mg, 4.61 mmol) in ethanol (36 mL) was added cyclopropanecarbaldehyde (0.53 mL, 6.91 mmol) and piperidine (0.23 mL, 2.3 mmol). The reaction was heated to 90° C. for 75 minutes, then cooled and concentrated. The residue was dissolved in ethyl acetate (200 mL) and washed with water and then brine. The organic layer was dried (MgSO4), filtered and concentrated. The residue was purified by Isolera (100 g column, 1%-7% MeOH/DCM) to provided 1.32 g (55% yield) of the title compound. LCMS m/z 524 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:5]=[CH:4][N:3]=1.[NH:14]1[CH2:19][CH2:18][CH:17]([NH:20][S:21]([CH3:24])(=[O:23])=[O:22])[CH2:16][CH2:15]1.CCN(CC)CC.CCOC(C)=O>CC#N>[N:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:6]1[CH:5]=[CH:4][N:3]=[C:2]([N:14]2[CH2:15][CH2:16][CH:17]([NH:20][S:21]([CH3:24])(=[O:22])=[O:23])[CH2:18][CH2:19]2)[N:7]=1
Reactant: Clc1nccc(-c2ccccn2)n1
Reactant: CS(=O)(=O)NC1CCNCC1
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)NC1CCN(c2nccc(-c3ccccn3)n2)CC1
Yield: 78 %

Procedure:
A solution of 2-chloro-4-(pyridin-2-yl)pyrimidine (0.576 g, 3 mmol), N-(piperidin-4-yl)methanesulfonamide (0.64 g, 3.6 mmol) and Et3N (0.77 mL, 6 mmol) in CH3CN (15 mL) was refluxed for 2 h and TLC (petroleum:EtOAc=5:1) showed the reaction was complete. The reaction mixture was concentrated and purified by chromatography, eluted with CH2Cl2:MeOH (10:1 to 5:1) to give the title compound (0.78 g, 78%) as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[C:9](N1C=CN=C1)(N1C=CN=C1)=[S:10].[NH2:21][C:22]1[N:23]=[CH:24][C:25]([C:32]2[CH:42]=[CH:41][C:35]([C:36]([N:38]([CH3:40])[CH3:39])=[O:37])=[CH:34][CH:33]=2)=[N:26][C:27]=1[C:28]([NH:30][NH2:31])=[O:29]>ClCCl.O>[NH2:21][C:22]1[N:23]=[CH:24][C:25]([C:32]2[CH:33]=[CH:34][C:35]([C:36]([N:38]([CH3:39])[CH3:40])=[O:37])=[CH:41][CH:42]=2)=[N:26][C:27]=1[C:28](=[O:29])[NH:30][NH:31][C:9](=[S:10])[NH:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[Cl:1]
Reactant: CN(C)C(=O)c1ccc(-c2cnc(N)c(C(=O)NN)n2)cc1
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: Nc1ccccc1Cl
Solvent: O
Solvent: ClCCl
Product: CN(C)C(=O)c1ccc(-c2cnc(N)c(C(=O)NNC(=S)Nc3ccccc3Cl)n2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 2-chloroaniline (31.85 mg, 41.15 μL, 0.2497 mmol) in dichloromethane (2 mL) was slowly added dropwise to a solution of 1,1′-thiocarbonyldiimidazole (53.39 mg, 0.2996 mmol) in dichloromethane (1.5 mL) and the resulting solution stirred at room temperature for 1 h. Additional 1,1′-thiocarbonyldiimidazole (8.9 mg, 0.05 mmol) was added, and the reaction mixture stirred at room temperature overnight. The reaction mixture diluted with water and extracted with dichloromethane (3×5 mL). The organic extracts were dried over MgSO4, filtered and evaporated to dryness to leave a yellow solid. The solid was re-dissolved in dichloromethane (1.5 mL) and 4-(5-amino-6-(hydrazinecarbonyl)pyrazin-2-yl)-N,N-dimethylbenzamide (75 mg, 0.2497 mmol) added and the reaction mixture stirred at room temperature for 48 h. The reaction mixture was evaporated to drymess and then triturated with EtOAc/Petrol/Ether to give a yellow solid, 4-[5-amino-6-[[(2 chlorophenyl)carbamothioylamino]carbamoyl]pyrazin-2-yl]-N,N-dimethyl-benzamide. This was re-dissolved in dichloromethane (1.5 mL) and EDC (71.81 mg, 0.3746 mmol) added and the resulting solution heated at 40° C. for 3 h. The reaction mixture was cooled to room temperature and concentrated in vacuo and the solid triturated with EtOAc and petroleum ether to yield the product as a yellow solid (28.9 mg, 26% yield); 1H NMR (400.0 MHz, DMSO) d 2.96 (s, 3H), 3.01 (s, 3H), 7.15-7.25 (m, 1H), 7.40-7.49 (m, 1H), 7.53 (d, 3H), 7.70 (br s, 2H), 8.11 (d, 3H), 8.89 (s, 1H) and 10.45 (s, 1H) ppm; MS (ES+) 436.11
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=2)[CH:7]=1.[CH3:15][Si:16]([C:19]#[CH:20])([CH3:18])[CH3:17]>>[C:11]([C:9]1[CH:10]=[C:5]2[N:4]=[CH:3][C:2]([C:20]#[C:19][Si:16]([CH3:18])([CH3:17])[CH3:15])=[CH:7][N:6]2[N:8]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: C#C[Si](C)(C)C
Reactant: CC(C)(C)c1cc2ncc(Br)cn2n1
Product: CC(C)(C)c1cc2ncc(C#C[Si](C)(C)C)cn2n1

Procedure:
The title compound, brown solid, MS: m/e=272.3 (M+H+), can be prepared in accordance with the general method of example 1 from 6-bromo-2-tert-butyl-pyrazolo[1,5-a]pyrimidine (example 9, step 1) and trimethylsilylacetylene.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:15](=[O:16])[N:14]2[C:9]([C:10]([CH3:19])=[C:11](Cl)[C:12]([F:17])=[CH:13]2)=[C:8]([CH:20]2[CH2:22][CH2:21]2)[CH:7]=1)=[O:5])C.[N:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>C(#N)C>[N:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N:29]1[CH2:30][CH2:31][N:32]([C:11]2[C:12]([F:17])=[CH:13][N:14]3[C:9]([C:10]=2[CH3:19])=[C:8]([CH:20]2[CH2:22][CH2:21]2)[CH:7]=[C:6]([C:4]([OH:3])=[O:5])[C:15]3=[O:16])[CH2:33][CH2:34]1
Reactant: c1ccc(N2CCNCC2)nc1
Reactant: CCOC(=O)c1cc(C2CC2)c2c(C)c(Cl)c(F)cn2c1=O
Solvent: CC#N
Product: Cc1c(N2CCN(c3ccccn3)CC2)c(F)cn2c(=O)c(C(=O)O)cc(C3CC3)c12

Procedure:
A 60 mg sample of 8-chloro-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid ethyl ester, from Example 253i above, was dissolved in 2 mL of anhydrous acetonitrile, reacted with 4-(2-pyridyl)piperazine (63.5 mg, 0.39 mmol, Aldrich Chem. Co.), and carried forward as described in Example 253j-k to give the title product. MS 423 (M+H)+ ; 1H NMR (CDCl3) ∂: 0.71 (m, 2H), 1.05 (m, 2H), 2.30 (m, 1H), 2.86 (s, 3H), 3.59 (m, 4H), 3.78 (m, 4H), 6.76 (m, 2H), 7.57 (m, 1H), 8.25 (m, 1H), 8.40 (s, 1H), 8.25 (d, 1H), 13,83 (bs, 1H). Anal. Calcd for C23H23N4O3F.1.5 H2O: C, 61.46; H, 5.83; N, 12.46; Found: C, 61.76; H, 5.54; N, 11.64.
Reaction SMILES: O.[OH-].[Li+].[F:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[N:12]=[N:13][N:14]([CH3:31])[C:15]=1[C:16]1[N:17]=[CH:18][N:19]([C:21]2[CH:30]=[CH:29][C:24]([C:25]([O:27]C)=[O:26])=[CH:23][N:22]=2)[CH:20]=1>O.C1COCC1.CO>[F:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[N:12]=[N:13][N:14]([CH3:31])[C:15]=1[C:16]1[N:17]=[CH:18][N:19]([C:21]2[CH:30]=[CH:29][C:24]([C:25]([OH:27])=[O:26])=[CH:23][N:22]=2)[CH:20]=1
Reactant: COC(=O)c1ccc(-n2cnc(-c3c(-c4ccccc4F)nnn3C)c2)nc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Cn1nnc(-c2ccccc2F)c1-c1cn(-c2ccc(C(=O)O)cn2)cn1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 89.9 %

Procedure:
A solution of lithium hydroxide monohydrate (63 mg, 1.49 mmol) in water (3.0 mL) was added dropwise to a suspension of methyl 6-(4-(4-(2-fluorophenyl)-1-methyl-1H-1,2,3-triazol-5-yl)-1H-imidazol-1-yl)nicotinate (282 mg, 0.745 mmol) in THF (6.0 mL) and methanol (1 mL). The reaction mixture was then stirred at room temperature for 1.5 h and was then evaporated and the residue dissolved in water, acidified with HCl (1 N), and the resulting precipitate filtered off to afford the title product (244 mg, 90%) as a white solid. MS: m/e=363.3 [M−H]−.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([N:13]([C:22]2[CH:27]=[CH:26][C:25](Br)=[CH:24][N:23]=2)[C:14]2[CH:19]=[CH:18][C:17]([F:20])=[C:16]([Cl:21])[CH:15]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:29][C:30]1[CH:35]=[CH:34][C:33](OB(O)O)=[CH:32][CH:31]=1.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([N:13]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[C:16]([Cl:21])[CH:15]=2)[C:22]2[CH:27]=[CH:26][C:25]([C:33]3[CH:34]=[CH:35][C:30]([F:29])=[CH:31][CH:32]=3)=[CH:24][N:23]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)Oc1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N(c2ccc(F)c(Cl)c2)c2ccc(Br)cn2)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)OC(=O)N1CC[C@H](N(c2ccc(F)c(Cl)c2)c2ccc(-c3ccc(F)cc3)cn2)C1
Temperature: 100 °C
Reaction time: 10 h
Yield: 0.8 %

Procedure:
3(S)-[(5-bromopyridin-2-yl)-(3-chloro-4-fluorophenyl)amino]pyrrolidine-1-carboxylic acid tert-butyl ester (300 mg, 0.64 mmol), 4-fluorophenylboric acid (98 mg, 0.7 mmol), tetrakis(triphenylphosphine)palladium (23 mg, 0.02 mmol) and a 2 M aqueous sodium carbonate solution (0.83 ml) were added to toluene (3 ml), followed by stirring under a nitrogen atmosphere at 100° C. for 10 hours. After cooling to room temperature, ethyl acetate and water were added to the reaction solution to separate the reaction solution into layers. The organic layer was washed with saturated saline, followed by drying over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=5:1). The solvent was distilled off from the purified product under reduced pressure to thereby obtain 2.55 mg of white solid 3(S)-{(3-chloro-4-fluorophenyl)-[5-(4-fluorophenyl)pyridin-2-yl]amino}pyrrolidine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [NH2:1][C:2]1[N:7]2[O:8][C:9](=[O:11])[N:10]=[C:6]2[N:5]=[C:4]([N:12]([CH2:16][CH:17]=[CH2:18])[CH2:13][CH:14]=[CH2:15])[N:3]=1.[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.Cl>O.C(Cl)Cl.C(N(CC)CC)C>[CH2:13]([N:12]([CH2:16][CH:17]=[CH2:18])[C:4]1[N:3]=[C:2]([NH:1][C:19](=[O:26])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:7]2[O:8][C:9](=[O:11])[N:10]=[C:6]2[N:5]=1)[CH:14]=[CH2:15]
Reactant: C=CCN(CC=C)c1nc(N)n2oc(=O)nc2n1
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: C=CCN(CC=C)c1nc(NC(=O)c2ccccc2)n2oc(=O)nc2n1
Temperature: 0 °C

Procedure:
7.0 g. of 7-amino-5-diallylamino-2H-[1,2,4]oxadiazolo[2,3-a]-s-triazin-2-one are suspended in 250 ml. of methylene chloride and 10 ml. of triethylamine, cooled while stirring to 0° C. and treated with 4.5 ml. of benzoyl chloride in 35 ml. of methylene chloride. The mixture is subsequently stirred at 0° C. for 1 hour, then diluted with water and adjusted to pH 4 with hydrochloric acid. The two phases are separated and the aqueous phase is extracted twice with methylene chloride. The organic extracts are combined, dried over magnesium sulfate and evaporated at 20° C. under reduced pressure. The residue is recrystallized from methylene chloride and diethyl ether, there being obtained pure N-{5-diallylamino-2-oxo-2H-[1,2,4]oxadiazolo[2,3-a]-s-triazin-7-yl}benzamide having a melting point of 182°-183° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([CH3:10])=[CH:4][N:3]=1.B1(C=C)OB([CH:17]=[CH2:18])OB(C=C)O1.C1C=CN=CC=1.C([O-])([O-])=O.[K+].[K+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:9][O:8][C:6]1[C:5]([CH3:10])=[CH:4][N:3]=[C:2]([CH:17]=[CH2:18])[CH:7]=1
Reactant: C=CB1OB(C=C)OB(C=C)O1
Reactant: COc1cc(Cl)ncc1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Solvent: O
Solvent: COCCOC
Product: C=Cc1cc(OC)c(C)cn1
Temperature: 80 °C
Reaction time: 15 h
Yield: 62.9 %

Procedure:
To a solution of 2-chloro-4-methoxy-5-methyl-pyridine (2.91 g, 18.5 mmol) in DME (75 mL), 2,4,6-trivinylcyclotriboroxane pyridine complex (3.13 g, 13.0 mmol) followed by 2 M aq. K2CO3 solution (25 mL) is added. The mixture is degassed and put under argon before Pd(PPh3)4 (384 mg, 0.332 mmol) is added. The mixture is stirred at 80° C. for 15 h before it is cooled to rt, diluted with water and extracted with diethyl ether. The org. extract is washed with sat. aq. NaHCO3 solution, dried over MgSO4, filtered and concentrated. The crude product is purified by CC on silica gel eluting with heptane:EA 4:1 to give 4-methoxy-5-methyl-2-vinyl-pyridine (1.22 g) as a white solid; LC-MS: tR=0.52 min, [M+1]+=150.08.
Reaction SMILES: [NH2:1][CH:2]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([S:12]([C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]([NH:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[O:23])=[CH:17][CH:16]=2)(=[O:14])=[O:13])[CH2:3]1.Cl[C:32]1[N:37]=[C:36]([NH2:38])[N:35]=[C:34]2[NH:39][N:40]=[CH:41][C:33]=12.C(N(C(C)C)CC)(C)C.O>CC(N(C)C)=O>[NH2:38][C:36]1[N:35]=[C:34]2[NH:39][N:40]=[CH:41][C:33]2=[C:32]([NH:1][CH:2]2[CH2:11][C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[N:4]([S:12]([C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:22]([NH:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[O:23])=[CH:17][CH:16]=3)(=[O:13])=[O:14])[CH2:3]2)[N:37]=1
Reactant: Nc1nc(Cl)c2cn[nH]c2n1
Reactant: NC1Cc2ccccc2N(S(=O)(=O)c2ccc(NC(=O)Nc3ccccc3)cc2)C1
Solvent: CC(=O)N(C)C
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1nc(NC2Cc3ccccc3N(S(=O)(=O)c3ccc(NC(=O)Nc4ccccc4)cc3)C2)c2cn[nH]c2n1
Temperature: 120 °C
Reaction time: 20 h

Procedure:
To a solution of 1-(4-(3-amino-3,4-dihydroquinolin-1(2H)-ylsulfonyl)phenyl)-3-phenylurea in dimethyl acetamide (1 mL) was added 4-chloro-1H-pyrazolo[3,4-d]pyrimidin-6-amine (135 mg, 1.0 mmol) and diisopropylethylamine (0.4 mL, 0.30 g, 2.30 mmol). The reaction mixture was stirred at 120° C. for 20 hours. After cooling to room temperature the mixture was poured into water (10 ml) and extracted with ethyl acetate (3×10 ml). The combined organics were dried over sodium sulfate and concentrated to give a residue that was purified by reverse phase chromatography on a preparative LC/UV/MS system using a mass triggered fractionation. Compounds were eluted from the HPLC column (Maccel 120-10-C18 SH 10 μm 20 mmID×50 mm) at 88 ml/min with 5-95 acetonitrile/water gradient using 0.1% TFA as modifier to yield 1-(4-(3-(6-amino-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino)-3,4-dihydroquinolin-1(2H)-ylsulfonyl)phenyl)-3-phenylurea (47.6 mg).
Reaction SMILES: [OH:1][C@H:2]([C@H:4]([N:14]1[CH:18]=[C:17]([C:19]([NH2:21])=[O:20])[N:16]=[CH:15]1)[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[OH:13])[CH3:3].Br[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][N:29]1[C:33](=[O:34])[C:32]2=[CH:35][CH:36]=[CH:37][CH:38]=[C:31]2[C:30]1=[O:39].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[OH:1][C@H:2]([C@H:4]([N:14]1[CH:18]=[C:17]([C:19]([NH2:21])=[O:20])[N:16]=[CH:15]1)[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][N:29]1[C:33](=[O:34])[C:32]2=[CH:35][CH:36]=[CH:37][CH:38]=[C:31]2[C:30]1=[O:39])[CH3:3]
Reactant: O=C1c2ccccc2C(=O)N1CCCCCCBr
Reactant: C[C@H](O)[C@@H](CCc1ccccc1O)n1cnc(C(N)=O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[C@H](O)[C@@H](CCc1ccccc1OCCCCCCN1C(=O)c2ccccc2C1=O)n1cnc(C(N)=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 111.1 %

Procedure:
A mixture of 1-[(2S,3R)-2-hydroxy-5-(2-hydroxyphenyl)-3-pentyl]imidazole-4-carboxamide (0.11 g), 1-bromo-6-phthalimidohexane (0.47 g) and potassium carbonate (0.42 g) in N,N-dimethylformamide (5 ml) was stirred overnight at room temperature. The mixture was taken up in ethyl acetate, washed three times with water, dried, and evaporated. The residue was purified by column chromatography on silica gel, eluting with a mixture of dichloromethane and methanol (20:1) to give a white powder of 1-{(2S,3R)-2-hydroxy-5-[2-(6-phthalimidohexyloxy)phenyl]-3-pentyl}imidazole-4-carboxamide (6-1) (219 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11](B1OC(C)(C)C(C)(C)O1)=[CH:10][CH:9]=2)=[O:5])[CH3:2].Br[C:25]1[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][N:26]=1.C(=O)([O-])[O-].[Na+].[Na+].CCO>CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([C:25]1[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][N:26]=1)=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: FC(F)(F)c1ccc(Br)nc1
Reactant: CCOC(=O)c1cc2cc(B3OC(C)(C)C(C)(C)O3)ccc2[nH]1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc2cc(-c3ccc(C(F)(F)F)cn3)ccc2[nH]1
Temperature: 80 °C
Reaction time: 16 h
Yield: 77.8 %

Procedure:
A stirred mixture of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indole-2-carboxylic acid ethyl ester (300 mg, 0.95 mmol; see step (a)), 2-bromo-5-(trifluoromethyl)pyridine (323 mg, 1.43 mmol), sodium carbonate (2M, 1.43 mL, 2.85 mmol), Pd(PPh3)4 (54 mg, 0.05 mmol), EtOH (5 mL) and toluene (20 mL) was heated at 80° C. for 2 h. Another portion of Pd(PPh3)4 (54 mg, 0.05 mmol) was added and the heating continued for 16 h. The mixture was diluted with EtOAc, washed with brine, dried over MgSO4, concentrated and purified by chromatography to give the sub-title compound (247 mg, 77%).