Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[CH:19]=[CH:18][C:17]([N:20]([CH3:22])[CH3:21])=[CH:16][CH:15]=2)=[C:12]([CH3:23])[C:11]([C:24](O)=[O:25])=[N:10]1.[OH:27][C:28]1([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>O1CCCC1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[CH:15]=[CH:16][C:17]([N:20]([CH3:21])[CH3:22])=[CH:18][CH:19]=2)=[C:12]([CH3:23])[C:11]([C:24]([N:31]2[CH2:30][CH2:29][C:28]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)([OH:27])[CH2:33][CH2:32]2)=[O:25])=[N:10]1
Reactant: OC1(c2ccccc2)CCNCC1
Reactant: Cc1c(C(=O)O)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(N(C)C)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1c(C(=O)N2CCC(O)(c3ccccc3)CC2)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(N(C)C)cc1
Yield: 49 %

Procedure:
1-(2,4-dichlorophenyl)-5-[4-(dimethylamino)phenyl]-4-methyl-1H-pyrazole-3-carboxylic acid (1 eq, 10 mg, 0.026 mmol), 4-hydroxy-4-phenylpiperidine (1 eq, 4.5 mg, 0.026 mmol), benzotriazole-1-yl-oxytris(dimethylamino)phosphonium hexafluorophosphate (BOP) (1 eq., 11.3 mg, 0.026 mmol), and triethylamine (0.02 mL) were stirred in tetrahydrofuran (5 mL) for 16 h. The reaction was concentrated in vacuo. The crude reaction material was then purified by silica gel column chromatography using 0-100% ethyl acetate/hexane to yield pure 1-{[1-(2,4-dichlorophenyl)-5-[4-(dimethylamino)phenyl]-4-methyl-1H-pyrazol-3-yl]carbonyl}-4-phenylpiperidin-4-ol (7 mg, 50%). 1H NMR (300 MHz, CHLOROFORM-d) d ppm 1.73-1.95 (m, 2H) 2.09-2.29 (m, 5H) 2.85-3.04 (m, 3H) 3.34 (t, J=12.43 Hz, 1H) 3.66 (t, J=12.81 Hz, 1H) 4.34 (d, J=13.19 Hz, 1H) 4.74 (d, J=13.28 Hz, 1H) 6.61 (d, J=8.57 Hz, 2H) 6.99 (d, J=8.67 Hz, 2H) 7.09-7.57 (m, 8H).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[NH:7][C:6](=[O:8])[C:5]2[CH:9]=[C:10]([OH:13])[CH:11]=[CH:12][C:4]=2[O:3]1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:22][C:23](=[O:25])[CH3:24]>C(#N)C>[CH3:1][C:2]1([CH3:14])[NH:7][C:6](=[O:8])[C:5]2[CH:9]=[C:10]([O:13][CH2:22][C:23](=[O:25])[CH3:24])[CH:11]=[CH:12][C:4]=2[O:3]1
Reactant: CC1(C)NC(=O)c2cc(O)ccc2O1
Reactant: CC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(=O)COc1ccc2c(c1)C(=O)NC(C)(C)O2

Procedure:
70 g of 2,3-dihydro-2,2-dimethyl-6-hydroxy-4H-1,3-benzoxazine-4-one are refluxed for 30 hours, whilst stirring, in 400 ml of acetonitrile with 100 g of potassium carbonate and 32 ml of chloroacetone. After the addition of a further 3.2 ml of chloroacetone, the reaction mixture is heated for a further 15 to 20 hours. The still warm reaction mixture is filtered, the residue thoroughly washed with acetone and the combined filtrate is concentrated by evaporation. The crystalline residue is recrystallised from toluene and yields 2,3-dihydro-2,2-dimethyl-6-(2-oxopropoxy)-4H-1,3-benzoxazin-4-one having a melting point of 125°-126°.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([C:11]([F:14])([F:13])[F:12])[CH:3]=1.[CH2:15](O)[CH:16]=[CH2:17]>S(=O)(=O)(O)O>[OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH2:17][CH:16]=[CH2:15])=[O:7])=[C:4]([C:11]([F:12])([F:13])[F:14])[CH:3]=1
Reactant: C=CCO
Reactant: O=C(O)c1ccc(O)cc1C(F)(F)F
Agent: O=S(=O)(O)O
Product: C=CCOC(=O)c1ccc(O)cc1C(F)(F)F
Yield: 59 %

Procedure:
In a manner analogous to Example 1(a) starting with 2 g (9.7 mmoles) of 4-hydroxy-2-trifluoromethylbenzoic acid treated at 100° C. for 12 hours with 20 ml of allyl alcohol and 260 μl of concentrated sulfuric acid, give 1.4 g (59% yield) of the expected ester having a melting point of 82°-83°.
Reaction SMILES: [N:1]1[CH:6]=[C:5]([C:7]([NH:9][C:10]2([C:13]([OH:15])=O)[CH2:12][CH2:11]2)=[O:8])[CH:4]=[N:3][CH:2]=1.[CH:16]([C:19]1[CH:33]=[CH:32][CH:31]=[CH:30][C:20]=1[O:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][NH2:27])=[CH:24][CH:23]=1)([CH3:18])[CH3:17]>>[CH:16]([C:19]1[CH:33]=[CH:32][CH:31]=[CH:30][C:20]=1[O:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][NH:27][C:13]([C:10]2([NH:9][C:7]([C:5]3[CH:4]=[N:3][CH:2]=[N:1][CH:6]=3)=[O:8])[CH2:11][CH2:12]2)=[O:15])=[CH:24][CH:23]=1)([CH3:18])[CH3:17]
Reactant: CC(C)c1ccccc1Oc1ccc(CN)cc1
Reactant: O=C(NC1(C(=O)O)CC1)c1cncnc1
Product: CC(C)c1ccccc1Oc1ccc(CNC(=O)C2(NC(=O)c3cncnc3)CC2)cc1
Yield: 89 %

Procedure:
Analogously to Example (7c) the title compound was prepared from 1-[(pyrimidine-5-carbonyl)-amino]-cyclopropanecarboxylic acid and 4-(2-isopropyl-phenoxy)-benzylamine.
Reaction SMILES: Br[C:2]1[C:10]2[C:6](=[N:7][S:8][N:9]=2)[CH:5]=[CH:4][CH:3]=1.C(NC(C)C)(C)C.[CH3:18][Si:19]([C:22]#[CH:23])([CH3:21])[CH3:20]>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.[Cu]I.C1COCC1>[CH3:18][Si:19]([C:22]#[C:23][C:2]1[C:10]2[C:6](=[N:7][S:8][N:9]=2)[CH:5]=[CH:4][CH:3]=1)([CH3:21])[CH3:20]
Reactant: Brc1cccc2nsnc12
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: C[Si](C)(C)C#Cc1cccc2nsnc12
Temperature: 45 °C
Reaction time: 20 h

Procedure:
4-Bromobenzo[c][1,2,5]thiadiazole (0.378 g, 1.76×10−3 mol), Pd(PPh3)4 (0.125 g, 1.68×10−4 mol), CuI (0.014 g, 7.4×10−5 mol), THF (20 ml), diisopropylamine (1.00 ml), and (trimethylsilyl)acetylene (1.00 ml, 7.1×10−3 mol) were added to a 50-ml Schlenk tube. N2 was bubbled through the mixture for 5 min, following which the reaction was stirred at 45° C. for 20 h. After cooling, the solvent was evaporated and the residue was chromatographed on silica gel using 1:1 hexanes:CHCl3 as the eluent. Yield=0.398 g (97.3% based on 0.378 g of 4-bromobenzothiadiazole). 1H NMR (500 MHz, CDCl3): δ 7.88 (m, 1H, Ph-H), 7.67 (m, 1H, Ph-H), 7.45 (m, 1H, Ph-H), 0.33 (s, 9H, —Si—CH3).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]=[C:4]([NH2:9])[N:3]=1.[CH3:10][O-:11].[Na+]>CO>[Cl:1][C:2]1[CH:7]=[C:6]([O:11][CH3:10])[N:5]=[C:4]([NH2:9])[N:3]=1
Reactant: C[O-]
Reactant: Nc1nc(Cl)cc(Cl)n1
Agent: [Na+]
Solvent: CO
Product: COc1cc(Cl)nc(N)n1
Yield: 90.4 %

Procedure:
To a solution of 4,6-dichloro-2-amino pyrimidine (5.0 g, 30.5 mmol) in methanol (100 mL) was added 25% sodium methoxide (6.59 g, 30.5 mmol). The solution was refluxed for 20 hours, at which time the methanol was removed in vacuo. The residue was dissolved in EtOAc (350 mL), washed with H2O (100 mL) and with NaCl(sat.) (100 mL), dried over Na2SO4, filtered and concentrated yielding 4.4 g (90%) of 4-chloro-6-methoxypyrimidine-2-ylamine.
Reaction SMILES: O[CH2:2][CH2:3][NH:4][C:5]1[CH2:9][S:8][C:7](=[O:10])[N:6]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[N:4]1[CH2:3][CH2:2][N:6]2[C:5]=1[CH2:9][S:8][C:7]2=[O:10]
Reactant: O=C1N=C(NCCO)CS1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: O=C1SCC2=NCCN12
Temperature: 40 °C
Reaction time: 8 h
Yield: 45.7 %

Procedure:
To a solution of 4-[(2-hydroxyethyl)amino]-1,3-thiazol-2(5H)-one (641 mg) and triphenylphosphine (1570 mg) in THF (10 mL) was added 1.9M diisopropyl azodicarboxylate toluene solution (3.16 mL) at room temperature. The reaction mixture was stirred overnight at 40° C. The solvent was evaporated, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (260 mg).
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH2:13][O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH:10]([CH3:12])[CH3:11])=O)(C)(C)C>C(O)=O>[CH2:15]([O:14][CH2:13][C@@H:9]([CH:10]([CH3:12])[CH3:11])[NH2:8])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)[C@H](COCc1ccccc1)NC(=O)OC(C)(C)C
Solvent: O=CO
Product: CC(C)[C@@H](N)COCc1ccccc1

Procedure:
A solution of N-tert-butoxycarbonyl-O-benzyl-D-valinol (9.95 g, 34 mmol) in formic acid (50 ml) was stirred for 4 hours at room temperature. After removal of the formic acid in vacuo, the sticky residue was dissolved in water (100 ml), neutralized with a saturated solution of sodium bicarbonate (100 ml) and the organic material extracted twice with ethyl acetate (2×200 ml). The organic phases were washed until neutral with water (2×200 ml) and the combined organic layers were dried on sodium sulfate. Filtration and evaporation of the solvent in vacuo afforded the title amine as a slightly yellowish oil (5.20 g, 79%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C@H:4]([CH2:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][CH:8]=1)[NH2:5].[OH:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[CH:21]=O>>[OH:17][C:18]1[CH:19]=[C:20]([CH:21]2[C:8]3[NH:9][C:10]4[C:15]([C:7]=3[CH2:6][CH:4]([C:3]([O:2][CH3:1])=[O:16])[NH:5]2)=[CH:14][CH:13]=[CH:12][CH:11]=4)[CH:23]=[CH:24][C:25]=1[O:26][CH3:27]
Reactant: COc1ccc(C=O)cc1O
Reactant: COC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Product: COC(=O)C1Cc2c([nH]c3ccccc23)C(c2ccc(OC)c(O)c2)N1

Procedure:
The same method but starting from racemic tryptophan methyl ester and 3-hydroxy-4-methoxybenzaldehyde gave the title compound as a yellow solid m.p.: 140-148° C.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([NH:6][OH:7])=[CH:4][CH:3]=1.[N:10]([C:13]1[N:18]=[C:17]([O:19][CH2:20][C:21]([F:24])([F:23])[F:22])[CH:16]=[C:15]([O:25][CH2:26][C:27]([F:30])([F:29])[F:28])[N:14]=1)=[C:11]=[O:12]>C1COCC1>[F:24][C:21]([F:22])([F:23])[CH2:20][O:19][C:17]1[CH:16]=[C:15]([O:25][CH2:26][C:27]([F:28])([F:29])[F:30])[N:14]=[C:13]([NH:10][C:11](=[O:12])[N:6]([C:5]2[CH:8]=[CH:9][C:2]([Cl:1])=[CH:3][CH:4]=2)[OH:7])[N:18]=1
Reactant: O=C=Nc1nc(OCC(F)(F)F)cc(OCC(F)(F)F)n1
Reactant: ONc1ccc(Cl)cc1
Solvent: C1CCOC1
Product: O=C(Nc1nc(OCC(F)(F)F)cc(OCC(F)(F)F)n1)N(O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 36 %

Procedure:
To a solution of 4-chloro-N-hydroxyaniline (0.423 g, 2.95 mmol (prepared according to the procedure of Rondestwedt Jr., C. S, and Johnson, T. A. Synthesis 1977, p 850-851) in THF (10 mL) was added the 2-isocyanato-4,6-bis(2,2,2-trifluoroethoxy)pyrimidine (2.0 g, 6.3 mmol) in THF (10 mL) and the mixture stirred at room temperature for 12 h. The mixture was concentrated in vacuo to give a brown solid. This solid was purified by reverse phase column chromatography (CH3CN/H2O) to afford 64 as a dark brown gum (448 mg, 36% yield): ESI/MS 461 (M+H), 459 (M−H); 1H NMR (DMSO-d6): δ 11.04 (S, 1H, 9.51 (S, 1H), 7.63 (d, 2H, J=6.6 Hz), 7.41 (d, 2H, J=6.6 Hz), 6.30 (s, 1H), 5.05 (m, 4H).
Reaction SMILES: [C:1]1(=[O:12])[O:7][C:5](=[O:6])[C:4]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:3]2[CH2:2]1.[C:13]1([C@@H:19]([NH2:22])[CH2:20][CH3:21])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(#N)C>[C:13]1([C@@H:19]([NH:22][C:1]([CH2:2][C:3]2[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=2[C:5]([OH:7])=[O:6])=[O:12])[CH2:20][CH3:21])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC[C@H](N)c1ccccc1
Reactant: O=C1Cc2ccccc2C(=O)O1
Solvent: CC#N
Product: CC[C@H](NC(=O)Cc1ccccc1C(=O)O)c1ccccc1
Yield: 72 %

Procedure:
A mixture of homophthalic anhydride (810 mg, 5 mmol) and (S)-(−)-1-phenylpropylamine (676 mg, 5 mmol) in acetonitrile (15 ml) was heated under microwave irradiation at +150° C. for 15 min. White precipitate was collected by filtration, washed with heptane and dried in vacuo to give pure title compound in 72% yield (1.065 g). Alternatively, to a stirred solution of homophthalic anhydride (16.214 g, 0.1 mol) in acetonitrile (100 ml) (S)-(−)-1-phenylpropylamine (13.83 g, 0.102 mol) was added dropwise (exothermic reaction) and the obtained reaction mixture was refluxed for 5 min. It was allowed to cool and the product was isolated by filtration as above to give 23.4 g of colourless solid, 79% yield. LC-MS (m/z) 298.5 (MH+); tR=1.11. 1H NMR (500 MHz, DMSO-d6): 0.84 (t, J=7.3 Hz, 3H), 1.67 (quintet, J=7.3 Hz, 2H), 3.85 (d of AB system, J=15.1 Hz, 1H), 3.95 (d of AB system, J=15.1 Hz, 1H), 4.66 (q, J=7.6 Hz, 1H), 7.2 (unres. m, 1H), 7.25-7.34 (m, 5H), 7.45 (t, J=7.3 Hz, 1H), 7.8 (d, J=7.8 Hz, 1H), 8.39 (br. d, J=7.7 Hz, 1H, NH).
Reaction SMILES: C([O:3][C:4]([C@@H:6]([NH:10][C@H:11]([C:13]([OH:15])=[O:14])[CH3:12])[CH2:7][CH2:8][CH3:9])=O)C.[NH3:16]>>[C:4]([C@@H:6]([NH:10][C@H:11]([C:13]([OH:15])=[O:14])[CH3:12])[CH2:7][CH2:8][CH3:9])(=[O:3])[NH2:16]
Reactant: CCC[C@H](N[C@@H](C)C(=O)O)C(=O)OCC
Reactant: N
Product: CCC[C@H](N[C@@H](C)C(=O)O)C(N)=O
Yield: 95 %

Procedure:
10 g of (S)-N-[(S)-1-(ethoxycarbonyl)butyl]alanine are placed in 100 ml of 28% strength aqueous ammonia solution at 100° C. for 18 hours. After evaporation of the solvent, the residue is taken up with 50 ml of water. The solution is evaporated to dryness, then taken up with 100 ml of isopropanol and evaporated. The expected product is obtained after drying under vacuum.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].[OH-].[K+].O.C1(C)C=CC(S(O[CH2:22][CH:23]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH3:24])(=O)=O)=CC=1>C(O)C>[CH2:26]([O:25][CH:23]([CH3:22])[CH2:24][O:2][C:1]1[CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: CCCCCCCCOC(C)COS(=O)(=O)c1ccc(C)cc1
Reactant: Oc1ccc(O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCCCCCCOC(C)COc1ccc(O)cc1

Procedure:
17.0 g of hydroquinone, 11.4 g of 85% KOH, 7.5 ml of water and 200 ml of ethanol were added into a four-necked flask, and after the reaction for 5 hours, the mixture was elevated in temperature to 50° C. and 33 g of (2'-octyloxypropyl) p-toluenesulfonate was added dropwise thereto. After the reaction for 5 hours, the mixture was heated at reflux for 11 hours and thereafter ethanol was evaporated. The residue was added into 600 ml of water and acidified with hydrochloric acid. The mixture was extracted with 500 ml of hexane and the extract was dried over anhydrous Na2SO4, followed by recrystallization. Yield: 4.2 g (16%). Optical rotation [α]D26.2° =-11.3°.
Reaction SMILES: [C:1](#[N:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[K+].[NH2:14][C:15]1[N:20]=[C:19]([C:21]2[O:22][C:23](Br)=[CH:24][CH:25]=2)[C:18]([C:27]#[N:28])=[C:17]([S:29][CH2:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=2)[N:16]=1>C1COCC1>[NH2:14][C:15]1[N:20]=[C:19]([C:21]2[O:22][C:23]([CH2:2][C:1]#[N:3])=[CH:24][CH:25]=2)[C:18]([C:27]#[N:28])=[C:17]([S:29][CH2:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=2)[N:16]=1
Reactant: N#Cc1c(SCCc2ccccn2)nc(N)nc1-c1ccc(Br)o1
Reactant: CC#N
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: N#CCc1ccc(-c2nc(N)nc(SCCc3ccccn3)c2C#N)o1
Reaction time: 1 h
Yield: 8.1 %

Procedure:
To a stirred solution of 0.2 ml (3.72 mmol) acetonitrile in 25 ml dry THF under argon at −78° C. was added dropwise 3.3 ml (1,65 mmol) potassium bis(trimethylsilyl)amide solution (0.5M in toluene) and stirring continued for 1 hour. The solution was then transferred dropwise via cannula to a solution of 300 mg (0.75 mmol) 2-amino-4-(5-bromo-furan-2-yl)-6-(2-pyridin-2-yl-ethylsulfanyl)-pyrimidine-5-carbonitrile in 25 ml THF at −78° C. and stirring continued for 5 h at −78° C. and 1 h at −40° C. The reaction mixture was then quenched by addition of saturated aqueous ammonium chloride solution. The mixtured was extracted twice with ethyl acetate and the combined organic phases dried over sodium sulfate and concentrated in vacuo. Chromatography (ethyl acetate/hexane 4/1 then ethyl acetate) afforded 22 mg (8%) 2-amino-4-(5-cyanomethyl-furan-2-yl)-6-(2-pyridin-2-yl-ethylsulfanyl)-pyrimidine-5-carbonitrile as a brown crystalline solid. ES-MS m/e (%): 385 (M+Na+, 45), 363 (M+H+, 100).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=[O:11])=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:31][C:32]([F:37])([F:36])[CH2:33][CH2:34]O.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[F:31][C:32]([F:37])([F:36])[CH2:33][CH2:34][O:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=[O:11])=[CH:4][CH:3]=1
Reactant: OCCC(F)(F)F
Reactant: O=C1CCc2ccc(O)cc21
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1CCc2ccc(OCCC(F)(F)F)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 21.8 %

Procedure:
To a solution of 6-hydroxy-2,3-dihydro-1H-inden-1-one (3.0 g, 20.3 mmol) in THF (140 mL) were triphenylphosphine (7.97 g, 30.4 mmol) and 3,3,3-trifluoropropan-1-ol (1.96 mL, 22.3 mmol) added. Diisopropyl azodicarboxylate (5.98 mL, 30.4 mmol) was added dropwise and the mixture was left stirring at r.t. overnight. Since there was starting material remaining, 3,3,3-trifluoro-1-propanol (0.892 mL, 10.1 mmol) was added dropwise and stirring was continued. After 30 min the mixture was heated to 40° C. and after 1 h the mixture was concentrated. The product was purified by flash chromatography (0-12% EtOAc in heptane as eluent) to afford 1.08 g (22% yield) of the title compound (containing some diisopropyl azodicarboxylate): 1H NMR (500 MHz, CDCl3) δ 2.65 (qt, 2 H), 2.71-2.77 (m, 2 H), 3.05-3.13 (m, 2 H), 4.23 (t, 2 H), 7.17-7.23 (m, 2 H), 7.40 (d, 1 H); MS (ES+) m/z 245 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]2[S:19][C:20]([C:23]#[N:24])=[CH:21][N:22]=2)[CH2:14][CH2:13]1)=[O:10].[N-:25]=[N+:26]=[N-:27].[Na+].[Cl-].[NH4+]>CN(C=O)C>[Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]2[S:19][C:20]([C:23]3[NH:27][N:26]=[N:25][N:24]=3)=[CH:21][N:22]=2)[CH2:14][CH2:13]1)=[O:10]
Reactant: Cc1[nH]c(C(=O)NC2CCN(c3ncc(C#N)s3)CC2)c(Cl)c1Cl
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1[nH]c(C(=O)NC2CCN(c3ncc(-c4nnn[nH]4)s3)CC2)c(Cl)c1Cl
Temperature: 120 °C
Reaction time: 3 h

Procedure:
To a solution of 3,4-dichloro-N-[1-(5-cyano-1,3-thiazol-2-yl)piperidin-4-yl]-5-methyl-1H-pyrrole-2-carboxamide (Example 321, 0.100 g, 0.26 mmol) in DMF (3 ml) was added sodium azide (0.169 g, 2.60 mmol) followed by the addition of ammonium chloride (0.139 g, 2.60 mmol) at room temperature. The reaction was stirred at 120° C. for 3 hrs. The reaction mixture was cooled to room temperature, filtered and purified by reverse phase HPLC eluting with acetonitrile/water (0.1% TFA) (0.025 g).
Reaction SMILES: C[O:2][B:3]([O:6]C)OC.[Cl-].[Mg+2].[Cl:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1.[Cl-]>C(OCC)C>[Cl:10][C:11]1[CH:16]=[C:15]([B:3]([OH:6])[OH:2])[CH:14]=[CH:13][CH:12]=1
Reactant: COB(OC)OC
Reactant: Clc1ccccc1
Agent: [Cl-]
Agent: [Mg+2]
Solvent: CCOCC
Product: OB(O)c1cccc(Cl)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of trimethylborate in 200 mL of ethyl ether was cooled to -65° C. 3-Chlorobenzene magnesium chloride (0.8M, 60 mL), i.e., a grignard reagent, was added to the solution in a dropwise manner over 20 minutes. The mixture was kept in the temperature range of -60° C. to -70° C. and stirred. After 30 minutes, the mixture was allowed to warm to 0° C. and stirred for 1 hour. The mixture was quenched with H2O (25 mL) and stirred at room temperature for 1 hour. The solvent was removed and the remaining mass was extracted with ethyl ether (3×100 mL). The organic layers were combined and washed with H2O (2×50 mL), dilute HCl (2×100 mL), H2O (2×50 mL) and brine 1×50 mL). The organic layer was dried with MgSO4 and concentrated, and 100 mL of hexanes was added, and the mixture stirred for 1 hour. The resultant white precipitate was filtered off and allowed to air dry, yielding 4.6 g of 3-chlorobenzene boronic acid, a compound of Formula 4 where R4 is 3-chlorophenyl, as a white solid.
Reaction SMILES: [Si]([O:8][CH2:9][C@H:10]1[CH2:21][CH2:20][C:19]2[S:18][C:17]3[N:16]=[CH:15][N:14]=[C:13]([O:22][CH:23]4[CH2:28][CH2:27][CH:26]([N:29]([CH3:37])[C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:25][CH2:24]4)[C:12]=3[C:11]1=2)(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.O>[OH:8][CH2:9][C@H:10]1[CH2:21][CH2:20][C:19]2[S:18][C:17]3[N:16]=[CH:15][N:14]=[C:13]([O:22][CH:23]4[CH2:24][CH2:25][CH:26]([N:29]([CH3:37])[C:30](=[O:36])[O:31][C:32]([CH3:33])([CH3:34])[CH3:35])[CH2:27][CH2:28]4)[C:12]=3[C:11]1=2
Reactant: CN(C(=O)OC(C)(C)C)C1CCC(Oc2ncnc3sc4c(c23)[C@@H](CO[Si](C)(C)C(C)(C)C)CC4)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: CN(C(=O)OC(C)(C)C)C1CCC(Oc2ncnc3sc4c(c23)[C@@H](CO)CC4)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.6 %

Procedure:
A solution of tert-butyl N-(4-[[(3S)-3-[[(tert-butyldimethylsilyl)oxy]methyl]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]oxy]cyclohexyl)-N-methylcarbamate (963 mg, 1.76 mmol, 1.00 equiv) in 5 mL of THF was added TBAF (919 mg, 3.51 mmol, 2.00 equiv) at room temperature. The resulting solution was stirred overnight at 25° C. and diluted with water, extracted with 3×50 mL of ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:1) to afford the tert-butyl N-(4-[[(3S)-3-(hydroxymethyl)-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]oxy]cyclohexyl)-N-methylcarbamate (691 mg, 91%) as a white solid. MS: m/z 434 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]2[C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:9]([CH3:11])[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][NH2:26])=[CH:20][CH:19]=1.C(N(CC)C(C)C)(C)C>C(#N)C>[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][NH:26][C:2]2[N:7]3[C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:9]([CH3:11])[N:10]=[C:6]3[CH:5]=[CH:4][CH:3]=2)=[CH:20][CH:19]=1
Reactant: CCOC(=O)c1c(C)nc2cccc(Cl)n12
Reactant: NCCc1ccc(N)cc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1c(C)nc2cccc(NCCc3ccc(N)cc3)n12
Yield: 75.5 %

Procedure:
A mixture of 4.07 g (17.1 mmol) of 5-chloro-3-ethoxycarbonyl-2-methylimidazo[1,2-a)pyridine, 3.48 g (25.6 mmol) of 2-(4-aminophenyl)ethylamine and 4.41 g (34.1 mmol) of N,N-diisopropylethylamine in 60 ml of acetonitrile was heated for 64 hours under reflux with stirring. After cooling, the solvent was distilled off. To the residue was added chloroform. The residue was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off. The residue was purified by column chromatography (eluent: chloroform/methanol=30:1) and recrystallized from ethyl acetate-n-hexane to give 4.37 g of the desired compound (75.7%, pale brown crystals).
Reaction SMILES: [CH2:1](OC1C=CC=CC=1)[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1>>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:1][CH:2]=[CH:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)=[CH:20][CH:19]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: C(=Cc1ccccc1)COc1ccccc1
Product: Clc1ccc(CC=Cc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 75.2 %

Procedure:
Following the general procedure using cinnamyloxybenzene (53 mg, 0.25 mmol), 4-chlorophenylboronic acid (58 mg, 0.38 mmol) and PdCl2(D-t-BPF) (0.015 mmol, 9.8 mg), the reaction was stirred for 20 h at rt. Column chromatography on silica gel (eluting with 3% EtOAc/hexanes) afforded the product as a colorless liquid (43 mg, 75%).
Reaction SMILES: [C:1](O)(=O)[CH:2]([CH3:4])[CH3:3].C(=O)(O)O.[NH:11]([C:13](=[NH:15])[NH2:14])[NH2:12].[N+]([O-])(O)=O>O>[CH:2]([C:1]1[N:14]=[C:13]([NH2:15])[NH:11][N:12]=1)([CH3:4])[CH3:3]
Reactant: CC(C)C(=O)O
Reactant: N=C(N)NN
Agent: O=C(O)O
Solvent: O
Solvent: O=[N+]([O-])O
Product: CC(C)c1n[nH]c(N)n1
Temperature: 110 °C
Reaction time: 75 h
Yield: 64.7 %

Procedure:
To a solution of isobutyric acid (25 g, 283.75 mmol) in water (25 mL) was added hydrazinecarboximidamide carbonic acid salt (15 g, 110.29 mmol) and HNO3 (0.3 mL), and the reaction mixture was stirred for 75 h at 110° C. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column (dichloromethane/methanol (15:1)) to afford 3-isopropyl-1H-1,2,4-triazol-5-amine as a white solid (9 g, 65%).