Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH2:2][C:3]1[C:4]([I:13])=[N:5][C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:33]N1C(=O)CCC1=O>CN(C=O)C>[Cl:33][CH2:2][C:3]1[C:4]([I:13])=[N:5][C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2
Reactant: OCc1cc2ccccc2nc1I
Reactant: O=C1CCC(=O)N1Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: ClCc1cc2ccccc2nc1I
Temperature: -23 °C
Reaction time: 1 h
Yield: 84 %

Procedure:
To a stirred mixture of 3-hydroxymethyl-2-iodoquinoline prepared in accordance with Example 10 above (350 mg, 1.23 mmol) and triphenylphosphine (483 mg, 1.84 mmol) in 10 mL of dry DMF at -23° C. was added N-chlorosuccinimide (246 mg, 1.84 mmol), and the mixture was stirred for 1 h at -23° C. After the addition of 40 mL of dilute aqueous NaHCO4, the mixture was extracted with ethyl acetate (20 mL) and then ether (2×15 mL). The combined organic extracts were washed successively with 20-mL portions of dilute NaHCO4, water and brine, and were dried over MgSO4. Concentration and purification of the residue by radial PLC (silica gel, 10% ethyl acetate/hexanes) afforded 312 mg (84%) of 3-chloromethyl-2-iodoquinoline as a white crystalline solid: mp 138°-140° C. Recrystallization from hexanes afforded an analytical sample as colorless needles: mp 139°-140° C. 1H NMR (300 MHz, CDCl3) δ 8.17 (s, 1H), 8.07 (d, 1H, J=9 Hz), 7.84 (d, 1H, J=9 Hz), 7.75 (t, 1H, J=9 Hz), 7.62 (t, 1H, J=9 Hz), 4.80 (s, 1H); IR (nujol) 1585, 1555, 1260, 1010, 780, 755, 710 cm-1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=O.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.C(=O)(O)[O-].[Na+].[NH:30]1[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=2[N:32]=[C:31]1[C:39]1[C:47]2[C:42](=[CH:43][CH:44]=[C:45]([NH2:48])[CH:46]=2)[N:41]([CH:49]2[CH2:54][CH2:53][CH2:52][CH2:51][O:50]2)[N:40]=1>CN(C=O)C>[NH:32]1[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[N:30]=[C:31]1[C:39]1[C:47]2[C:42](=[CH:43][CH:44]=[C:45]([NH:48][C:5](=[O:7])[C:4]3[CH:8]=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=3)[CH:46]=2)[N:41]([CH:49]2[CH2:54][CH2:53][CH2:52][CH2:51][O:50]2)[N:40]=1
Reactant: Nc1ccc2c(c1)c(-c1nc3ccccc3[nH]1)nn2C1CCCCO1
Reactant: O=C(O)c1cccc(F)c1
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: O=C(Nc1ccc2c(c1)c(-c1nc3ccccc3[nH]1)nn2C1CCCCO1)c1cccc(F)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 60.6 %

Procedure:
3-Fluorobenzoic acid (10 mg, 0.029 mmol), HOBt (6 mg, 0.044 mmol), EDC (9 mg, 0.045 mmol) and sodium bicarbonate (2.5 mg, 0.029 mmol) were added to a solution of 3-(1H-benzo[d]imidazol-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-amine (10 mg, 0.029 mmol) in DMF (6 mL). The reaction mixture was stirred at room temperature for 24 h, and then the solvent was removed in vacuo. Purification by flash chromatography (6% CH3OH/CH2Cl2) afforded the title compound (8 mg) as a off white solid. 1H NMR (400 MHz, CDCl3): δ 8.40 (d, 1H, J=1.6 Hz), 8.15-8.13 (m, 2H), 7.95 (s, 1H), 7.58 (m, 2H), 7.52 (d, 1H, J=9.6 Hz), 7.42-7.36 (m, 2H), 7.21 (m, 2H), 5.69 (dd, 1H, J=2.4 and 9.2 Hz), 3.99 (m, 1H), 3.72 (m, 1H), 2.55 (m, 1H), 2.06 (m, 2H), 1.67 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[N:12][C:11](Cl)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.O.[NH2:16][NH2:17]>C(O)CCC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[N:12][C:11]([NH:16][NH2:17])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: Clc1ccc(-c2ccc(Cl)nn2)cc1
Reactant: NN
Solvent: O
Solvent: CCCCO
Product: NNc1ccc(-c2ccc(Cl)cc2)nn1

Procedure:
A mixture of 10.0 g. of 6-(p-chlorophenyl)-3-chloropyridazine, 6.6 g. of hydrazine hydrate and 150 ml. of butanol is heated at reflux overnight. The reaction mixture is cooled and the precipitate is collected by filtration, washed with butanol and water and then dried yielding 6-(p-chlorophenyl)-3-hydrazinopyridazine.
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:15])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([F:14])([F:13])[F:12])[CH:6]=1)[CH3:2].[CH3:16][Si:17](Cl)([CH3:19])[CH3:18]>>[CH2:1]([NH:3][C:4](=[O:15])[C:5]1[CH:6]=[C:7]([C:11]([F:12])([F:14])[F:13])[CH:8]=[CH:9][C:10]=1[Si:17]([CH3:19])([CH3:18])[CH3:16])[CH3:2]
Reactant: CCNC(=O)c1cccc(C(F)(F)F)c1
Reactant: C[Si](C)(C)Cl
Product: CCNC(=O)c1cc(C(F)(F)F)ccc1[Si](C)(C)C

Procedure:
This amide was reacted with TMSCl (1.3 eq) as in Example 221 to afford the title compound. The crude product was purified by RC (ethyl acetate/hexanes) and recrystallization from pentane (-78° C.) to afford 0.14 g (5%) of the title compound as a white solid. m.p. 101°-102° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[S:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19].[C:23]([C:27]1[CH:31]=[C:30]([NH:32][C:33](=O)[O:34]C2C=CC=CC=2)[N:29]([C:42]2[CH:43]=[N:44][CH:45]=[C:46]([F:48])[CH:47]=2)[N:28]=1)([CH3:26])([CH3:25])[CH3:24]>C1COCC1.CN(C1C=CN=CC=1)C>[C:23]([C:27]1[CH:31]=[C:30]([NH:32][C:33]([NH:19][C:18]2[CH:20]=[CH:21][CH:22]=[C:16]([S:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][N:7]=3)[CH:17]=2)=[O:34])[N:29]([C:42]2[CH:43]=[N:44][CH:45]=[C:46]([F:48])[CH:47]=2)[N:28]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: COc1cc2ncnc(Sc3cccc(N)c3)c2cc1OC
Reactant: CC(C)(C)c1cc(NC(=O)Oc2ccccc2)n(-c2cncc(F)c2)n1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: COc1cc2ncnc(Sc3cccc(NC(=O)Nc4cc(C(C)(C)C)nn4-c4cncc(F)c4)c3)c2cc1OC
Yield: 62.2 %

Procedure:
Using the procedure described in Example 306A, to a solution of 3-(6,7-dimethoxyquinazolin-4-ylthio)aniline (94 mg, 0.3 mmol), prepared as described in Example 115B, in THF (3.3 ml) was added DMAP (20 mg, 0.16 mmol) and phenyl 3-tert-butyl-1-(5-fluoropyridin-3-yl)-1H-pyrazol-5-ylcarbamate (159 mg, 0.45 mmol) described in Example 326A to afford 1-(3-tert-butyl-1-(5-fluoropyridin-3-yl)-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl)urea (107 mg, 62%) as a solid. 1H NMR (300 MHz, DMSO-d6) δ 1.28 (s, 9H), 3.99 (m, 6H), 6.43 (s, 1H), 7.25 (d, J=7.5 Hz, 1H), 7.34 (d, J=4.5 Hz, 2H), 7.38-7.47 (m, 2H), 7.54 (s, 1H), 7.98 (d, J=9.9 Hz, 1H), 8.61-8.72 (m, 4H), 9.25 (s, 1H); LC-MS (ESI) m/z 574 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:10][CH2:11]I)[CH:5]=[CH:6][C:7]=1[Cl:8].[C-:21]#[N:22].[Na+].O>CS(C)=O>[C:21]([CH2:11][CH2:10][C@@H:9]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1)#[N:22]
Reactant: [C-]#N
Reactant: CC(C)(C)OC(=O)N[C@H](CCI)c1ccc(Cl)c(Cl)c1
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H](CCC#N)c1ccc(Cl)c(Cl)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 86.3 %

Procedure:
To a stirred solution of 366 (810 mg, 1.88 mmol) in DMSO (4 mL) at RT was added NaCN (102 mg, 2.07 mmol) and the resulting mixture was stirred at 80° C. overnight. The mixture was poured into water, extracted with EtOAc, washed with brine, dried (MgSO4), and concentrated. The product was purified by SiO2 chromatography eluting with 20% EtOAc/hexanes to afford 534 mgs (86%) of (R)-tert-butyl 3-cyano-1-(3,4-dichlorophenyl)propylcarbamate (368).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH3:9])[C:5]([OH:8])=[N:6][CH:7]=1.[C:10]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C>[I:1][C:2]1[CH:3]=[C:4]([CH3:9])[C:5](=[O:8])[N:6]([CH3:10])[CH:7]=1
Reactant: Cc1cc(I)cnc1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cc1cc(I)cn(C)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 79 %

Procedure:
To a stirred suspension of 5-iodo-3-methylpyridin-2-ol (Step 23.1) (1.67 g, 7.11 mmol) and K2CO3 (1.964 g, 14.21 mmol) in DMF (20 mL) was added MeI (0.666 mL, 10.66 mmol) at rt under Ar. The reaction mixture was stirred 1 hr at rt, concentrated, diluted with water, and extracted with EtOAc. The organic layers were combined and washed once with water, dried over Na2SO4 and evaporated. The crude material was purified by silica gel column chromatography (hexane/EtOAc 50-65) to afford the title product (1.40 g, 5.62 mmol, 79% yield) as a brown solid. tR: 3.31 min (HPLC 1); tR: 0.71 min (LC-MS 2); ESI-MS: 250 [M+H]+ (LC-MS 2); Rf=0.31 (hexane/EtOAc 1:1).
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[C:10]2[CH2:16][CH2:17][NH:18][C:19](=[O:21])[CH3:20].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:42]>C(#N)C>[Br:42][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[C:10]2[CH2:16][CH2:17][NH:18][C:19](=[O:21])[CH3:20]
Reactant: CC(=O)NCCc1c[nH]c2ccc(OCCCCO)cc12
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: CC(=O)NCCc1c[nH]c2ccc(OCCCCBr)cc12

Procedure:
3.92 g of the compound obtained in Step B are dissolved in 50 ml of acetonitrile, and then 5.31 g of triphenylphosphine and 6.71 g of carbon tetrabromide are added with stirring. After leaving at room temperature overnight, the acetonitrile is removed by evaporation in vacuo and the resulting residue is purified by chromatography over a column of silica gel (eluant: dichloromethane/methanol 96/4). Oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][CH3:14])[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C[N:16]1CCOCC1.ClC(OCC(C)C)=O.[NH4+].[OH-]>CN(C=O)C.CCCCCC>[C:10]([C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:13][CH3:14])(=[O:11])[NH2:16]
Reactant: CC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CN1CCOCC1
Agent: CC(C)COC(=O)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: CC[C@H](NC(=O)OC(C)(C)C)C(N)=O
Temperature: -20 °C
Reaction time: 0.17 h
Yield: 80.4 %

Procedure:
To a solution of (2S)-2-[(tert-butoxycarbonyl)amino]butanoic acid (1.01 g, 4.99 mmol) in DMF (5 mL) at −20° C. was added NMM (1.10 mL, 9.99 mmol) and isobutyl chloroformate (1.30 mL, 9.99 mmol). The reaction was stirred for 10 min at −20° C. The precipitate was removed by filtration. 26% NH4OH (aq) solution (0.39 mL, 9.99 mmol) was added and the reaction was stirred at −20° C. for 3 h. The volume was reduced under vacuum and hexane was added. A white precipitate was formed after a few minutes. The precipitate was collected in a filter and washed with additional hexane. The precipitate was recrystallised from EtOAc and hexane to give the title compound (0.811 g, 80%) as white solid.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH:10]([C:12]1[C:21]2[C:16](=[C:17]([C:22]([F:25])([F:24])[F:23])[CH:18]=[CH:19][CH:20]=2)[N:15]=[C:14]([C:26]([F:29])([F:28])[F:27])[CH:13]=1)[OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:30]=O>CO>[CH2:1]([N:8]1[CH2:9][CH:10]([C:12]2[C:21]3[C:16](=[C:17]([C:22]([F:23])([F:24])[F:25])[CH:18]=[CH:19][CH:20]=3)[N:15]=[C:14]([C:26]([F:28])([F:29])[F:27])[CH:13]=2)[O:11][CH2:30]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OC(CNCc1ccccc1)c1cc(C(F)(F)F)nc2c(C(F)(F)F)cccc12
Reactant: C=O
Solvent: CO
Product: FC(F)(F)c1cc(C2CN(Cc3ccccc3)CO2)c2cccc(C(F)(F)F)c2n1
Yield: 28 %

Procedure:
To a solution of α-benzylaminomethyl-2,8-bis(trifluoromethyl)-4-quinolinemethanol (142 mg, 0.34 mmol) in MeOH (3 mL) was added formaldehyde (0.2 mL, 37% in water), the mixture was refluxed for 30 mins, cooled, concentrated in vacuo, and the residue was suspended in heptane and filtered to give the title compound (41 mg, 28%) as a white solid: mp 108.5-108.9° C.; IR νmax (Nujol)/cm−1 2924, 2854, 1602, 1586, 1458, 1378, 1306, 1271, 1184, 1153, 1139, 1127, 1105, 775 and 726; NMR δH (400 MHz, CDCl3) 2.85 (1H, dd, J 11.7, 7.0 Hz), 3.77 (1H, dd, J 11.7, 7.4 Hz), 3.85 (1H, d, J 13.1 Hz), 3.90 (1H, d, 13.1 Hz), 4.71 (1H, d, J 5.8 Hz), 4.74 (1H, d, J 5.8 Hz), 5.72 (1H, t, J 7.0 Hz), 7.21-7.43 (5H, m), 7.72 (1H, t, J 7.9 Hz), 8.17 (1H, d, J 7.5 Hz), 8.11 (1H, s) and 8.03 (1H, d, J 8.1 Hz).
Reaction SMILES: [C:1]([C:5]1[CH:31]=[CH:30][C:8]([C:9]([NH:11][C:12]2[CH:28]=[C:27]([NH2:29])[CH:26]=[CH:25][C:13]=2[C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)=[O:15])=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:32]([S:34](Cl)(=[O:36])=[O:35])[CH3:33]>>[C:1]([C:5]1[CH:31]=[CH:30][C:8]([C:9]([NH:11][C:12]2[CH:28]=[C:27]([NH:29][S:34]([CH2:32][CH3:33])(=[O:36])=[O:35])[CH:26]=[CH:25][C:13]=2[C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)=[O:15])=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCS(=O)(=O)Cl
Reactant: COc1ccc(NC(=O)c2ccc(N)cc2NC(=O)c2ccc(C(C)(C)C)cc2)cc1
Product: CCS(=O)(=O)Nc1ccc(C(=O)Nc2ccc(OC)cc2)c(NC(=O)c2ccc(C(C)(C)C)cc2)c1
Yield: 52 %

Procedure:
Using the procedure described in Example 59, Part E, 2-(4-tert-butylbenzoylamino)-4-amino-N-(4-methoxyphenyl)benzamide was reacted with ethanesulfonyl chloride (0.47 mmol) to yield 127 mg (52%) of the title compound as a solid.
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][CH3:11])=[C:2]=[S:3].[CH:12]1([CH2:15][N:16]2[C:20]3[CH:21]=[CH:22][C:23]([NH:25][CH3:26])=[CH:24][C:19]=3[N:18]=[C:17]2[CH2:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH3:36])=[CH:30][CH:29]=2)[CH2:14][CH2:13]1>CN(C=O)C>[CH:12]1([CH2:15][N:16]2[C:20]3[CH:21]=[CH:22][C:23]([N:25]([CH3:26])[C:2]([NH:1][C:4]4[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=4[O:10][CH3:11])=[S:3])=[CH:24][C:19]=3[N:18]=[C:17]2[CH2:27][C:28]2[CH:29]=[CH:30][C:31]([O:34][CH2:35][CH3:36])=[CH:32][CH:33]=2)[CH2:14][CH2:13]1
Reactant: COc1ccccc1N=C=S
Reactant: CCOc1ccc(Cc2nc3cc(NC)ccc3n2CC2CC2)cc1
Solvent: CN(C)C=O
Product: CCOc1ccc(Cc2nc3cc(N(C)C(=S)Nc4ccccc4OC)ccc3n2CC2CC2)cc1
Temperature: 50 °C
Yield: 27.8 %

Procedure:
1-Isothiocyanato-2-methoxybenzene (100 mg, 0.61 mmol) was added to a solution of 1-(cyclopropylmethyl)-2-(4-ethoxybenzyl)-N-methyl-1H-benzimidazol-5-amine (100 mmol, 0.30 mmol) in DMF (5 mL). The reaction mixture was heated at 50° C. overnight. The crude product isolated following removal of the solvent was purified by chromatography on silica gel (EtOAc/CH2Cl2 1:1) giving the desired product (85 mg, 57%) 1HNMR (CDCl3): free base δ 8.26 (dd, J=2.0, 8.4 Hz, 1H), 7.74 (d, J=2.0 Hz, 1H), 7.50 (s, 1H), 7.43 (d, J=8.4 Hz, 1H), 7.20 (dd, J=1.6, 8.4 Hz, 1H), 7.15 (d, J=8.4 Hz, 2H), 7.08–7.02 (m, 1H), 6.98–6.92 (m, 1H), 6.83 (d, J=8.4 Hz, 2H), 6.75 (d, J=8.4 Hz, 1H), 4.29 (s, 2H), 4.00 (q, J=7.0 Hz, 2H), 3.96 (d, J=6.8 Hz, 2H), 3.80 (s, 3H), 3.58 (s, 3H), 1.37 (t, J=7.0 Hz, 3H), 1.10–1.00 (m, 1H), 0.59–0.52 (m, 2H), 0.32–0.25 (m, 2H). MS (ESI) (M+H)+=501.
Reaction SMILES: I[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:19]=[CH:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[N:7][N:8]2[CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])=[CH:4][CH:3]=1.[C:27]1(B(O)O)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.C(OCC)(=O)C.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>[C:27]1([C:2]2[CH:10]=[C:9]3[C:5]([C:6]([CH:19]=[CH:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[N:7][N:8]3[CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])=[CH:4][CH:3]=2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: C[Si](C)(C)CCOCn1nc(C=Cc2ccccc2)c2ccc(I)cc21
Reactant: OB(O)c1ccccc1
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: C1COCCO1
Product: C[Si](C)(C)CCOCn1nc(C=Cc2ccccc2)c2ccc(-c3ccccc3)cc21
Temperature: 90 °C
Yield: 80.9 %

Procedure:
A solution of 476 mg (1.0 mmol) of 6-iodo-3-styryl-1-[2-(trimethyl-silanyl)ethoxymethyl]-1H-indazole, from Example 14 step (i), in dioxane (3 ml, degassed by sonication and bubbling argon), Pd(PPh3)4 (23 mg, 0.05 mmol), phenylboronic acid (362 mg, 2.5 mmol), and Na2CO3 (1.25 ml of a 2M aqueous solution, degassed as above) was heated at 90° C. for 2 h. The solution was then diluted with ethyl acetate (100 ml) and washed with brine (2×20 ml). The organic layer was dried over MgSO4, and concentrated under reduced pressure. Purification by silica gel chromatography gave of 6-phenyl-3-styryl-1-[2-(trimethyl-silanyl)-ethoxymethyl]-1H-indazole as a brown oil (345 mg, 81%). 1H NMR (300 MHz, CDCl3) δ 8.09 (dd, 1H, J=8.5, 0.7 Hz), 7.75 (s, 1H), 7.70 (d, 1H, J=7.0 Hz), 7.64-7.58 (m, 2H), 7.56-751 (m, 2H), 7.50-7.45 (m, 2H), 7.45-7.36 (m, 4H), 7.34-7.27 (m, 1H), 5.80 (s, 2H), 3.73 (t, 2H, J=8.3 Hz), 1.12 (t, 2H, J=8.3 Hz).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][O:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([O:25]C)[N:6]2[CH2:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[C:20]#[N:21].Cl.[C:28](#N)[CH3:29]>>[NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][O:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]([CH2:28][CH3:29])[C:5](=[O:25])[N:6]2[CH2:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[C:20]#[N:21]
Reactant: CC#N
Reactant: COCCOc1nc(N)c2nc(OC)n(Cc3cccc(C#N)c3)c2n1
Agent: Cl
Product: CCn1c(=O)n(Cc2cccc(C#N)c2)c2nc(OCCOC)nc(N)c21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-((6-Amino-8-methoxy-2-(2-methoxyethoxy)-9H-purin-9-yl)methyl)benzonitrile (9) (50 mg) was dissolved in acetonitrile (2 mL). A 6N aqueous HCl solution (2 mL) was added and the mixture was stirred at ambient temperature overnight. After evaporation to dryness, the residue was dissolved in DMF (1 mL). Potassium carbonate (100 mg) and ethyl iodide (0.02 mL) were added and the mixture was stirred at ambient temperature for 5 hours. After dilution with water (20 mL) the product was extracted with dichloromethane. The combined organic layers were washed with water and brine, dried with Na2SO4 and evaporated under vacuum. Purification by flash chromatography on silica gel (eluent: 0-10% MeOH in ethyl acetate) gave 3-((6-amino-7-ethyl-2-(2-methoxyethoxy)-8-oxo-7,8-dihydropurin-9-yl)methyl)benzonitrile (10) (35 mg) as a colorless glass.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:28][CH2:27][C:12]2=[C:13]([N:20]3[CH2:23][CH:22]([C:24](O)=[O:25])[CH2:21]3)[N:14]3[C:18]([N:19]=[C:11]2[CH2:10][CH2:9]1)=[CH:17][CH:16]=[N:15]3)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.FC(F)(F)C([O-])=O.[C:67]([CH:69]1[CH2:73][CH2:72][NH2+:71][CH2:70]1)#[CH:68]>CN1C(=O)CCC1>[C:1]([O:5][C:6]([N:8]1[CH2:28][CH2:27][C:12]2=[C:13]([N:20]3[CH2:21][CH:22]([C:24]([N:71]4[CH2:72][CH2:73][CH:69]([C:67]#[CH:68])[CH2:70]4)=[O:25])[CH2:23]3)[N:14]3[C:18]([N:19]=[C:11]2[CH2:10][CH2:9]1)=[CH:17][CH:16]=[N:15]3)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCc2nc3ccnn3c(N3CC(C(=O)O)C3)c2CC1
Reactant: C#CC1CC[NH2+]C1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: O=C([O-])C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: C#CC1CCN(C(=O)C2CN(c3c4c(nc5ccnn35)CCN(C(=O)OC(C)(C)C)CC4)C2)C1
Reaction time: 1 h

Procedure:
To 150 mg (0.29 mmol) of 10-(3-Carboxy-azetidin-1-yl)-5,6,8,9-tetrahydro-1,4,7,10a-tetraaza-cyclohept[f]indene-7-carboxylic acid tert-butyl ester (as DIPEA salt) in 1.0 mL NMP was added 105 mg (0.33 mmol) TBTU and 120 μL (0.70 mmol) DIPEA and stirring was continued at room temperature for 1 h. Then 60.7 mg (0.29 mmol) of 3-Ethynyl-pyrrolidinium trifluoro-acetate was added and the reaction mixture was stirred overnight. The reaction mixture was filtered and the purified by HPLC.
Reaction SMILES: [N+:1]([C:4]1[CH:21]=[CH:20][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:19][CH2:18][CH2:17][C@H:13]2[C:14]([OH:16])=O)=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].C1N=CN(C(N2C=NC=C2)=O)C=1.[NH2:34][CH:35]1[CH2:38][N:37]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:36]1>C(#N)C>[C:42]([O:41][C:39]([N:37]1[CH2:38][CH:35]([NH:34][C:14](=[O:16])[C@@H:13]2[CH2:17][CH2:18][CH2:19][N:12]2[C:10]([O:9][CH2:8][C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:21][CH:20]=2)=[O:11])[CH2:36]1)=[O:40])([CH3:45])([CH3:43])[CH3:44]
Reactant: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)OC(=O)N1CC(N)C1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CC(NC(=O)[C@@H]2CCCN2C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reaction time: 1 h
Yield: 80.3 %

Procedure:
To a solution of 1-(4-nitrobenzyloxycarbonyl)-L-proline (2.81 g) in anhydrous acetonitrile (40 ml), N,N-carbonyldiimidazole (1.42 g) was added at room temperature, followed by stirring for one hour. The reaction mixture was allowed to react under ice cooling with a solution of 3-amino-1-(tert-butoxycarbonyl)azetidine (1.31 g) in anhydrous acetonitrile (10 ml) in a similar manner to that described in Referential Example 1-(1), whereby 2.74 g of 1-(tert-butoxycarbonyl)-3-[1-(4-nitrobenzyloxycarbonyl)-L-prolylamino]azetidine were obtained.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][C:5]([S:8][CH3:9])=[N:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:16](Br)[CH:17]=[CH2:18]>CC(C)=O>[CH2:18]([O:1][C:2]1[CH:3]=[N:4][C:5]([S:8][CH3:9])=[N:6][CH:7]=1)[CH:17]=[CH2:16]
Reactant: C=CCBr
Reactant: CSc1ncc(O)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1cnc(SC)nc1
Reaction time: 2 h

Procedure:
4.5 g of 5-hydroxy-2-methylthiopyrimidine, 9.0 g of potassium carbonate and 3.9 g of allyl bromide are together refluxed in 50 ml of acetone, with stirring, for 41/2 hours. The inorganic salts are removed by filtration, and the filtrate is concentrated under reduced pressure. The oil remaining yields, from petroleum ether, 5-allyloxy-2-methylthiopyrimidine, m.p. 41°-42°.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[O:5][C:6]1[CH:18]=[CH:17][C:9]2[N:10]=[C:11]([NH:13][C:14](=[O:16])[CH3:15])[S:12][C:8]=2[C:7]=1[C:19]#[N:20].[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][C:26]=1[N:35]=[C:36]=[O:37]>CN(C)C=O.C(OCC)(=O)C>[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][C:26]=1[NH:35][C:36]([NH:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[O:5][C:6]1[CH:18]=[CH:17][C:9]2[N:10]=[C:11]([NH:13][C:14](=[O:16])[CH3:15])[S:12][C:8]=2[C:7]=1[C:19]#[N:20])=[O:37]
Reactant: CC(=O)Nc1nc2ccc(Oc3cccc(N)c3)c(C#N)c2s1
Reactant: O=C=Nc1cc(C(F)(F)F)ccc1Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)Nc1nc2ccc(Oc3cccc(NC(=O)Nc4cc(C(F)(F)F)ccc4Cl)c3)c(C#N)c2s1
Temperature: 25 °C
Reaction time: 12 h
Yield: 73.7 %

Procedure:
N-[6-(3-Aminophenoxy)-7-cyano-1,3-benzothiazol-2-yl]acetamide (150 mg, 0.462 mmol) produced in Example 12(ii) was dissolved in N,N-dimethylformamide (2 mL), 1-chloro-2-isocyanato-4-(trifluoromethyl)benzene (90 μL, 0.60 mmol) was added, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was diluted with ethyl acetate (10 mL), washed successively with 5% aqueous sodium hydrogen carbonate solution (5 mL) and saturated brine (5 mL), and dried over anhydrous sodium sulfate. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/n-hexane=40/60→100/0), and the obtained solution was concentrated under reduced pressure. The residue was crystallized from ethanol to give the title compound (186 mg, 74%) as a white powder.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[C:20](Cl)([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21].C([O-])(O)=O.[Na+]>>[N:10]1[CH:9]=[CH:8][C:7]([CH:4]2[CH2:5][CH2:6][N:1]([C:20]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:21])[CH2:2][CH2:3]2)=[CH:12][CH:11]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: c1cc(C2CCNCC2)ccn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Product: O=C(OCc1ccccc1)N1CCC(c2ccncc2)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A 10 mL round bottom flask was charged with piperidine 32 (500 mg, 3.08 mmol), and then triethylamine (314 mg, 3.10 mmol), and then CbzCl (529 mg, 3.10 mmol), and the reaction mixture was allowed to stir at room temperature for 12 hours. The reaction mixture was then poured into 50 mL of an aqueous solution saturated with NaHCO3 and extracted with 3×50 mL of methylene chloride. The organic fractions were pooled, dried over Na2SO4, filtered, concentrated under reduced pressure, and not purified further. Crude yield of 33: 900 mg (99%). 1H NMR (500 MHz, CDCl3) δ 1.87 (m, 2H), 2.30 (m, 2H), 2.69 (m, 1H), 2.91 (bs, 2H), 4.37 (bs, 2H), 5.17 (m, 2H), 7.13 (d, J=6.3 Hz, 2H), 7.39 (m, 5H), 8.54 (d, J=6.3 Hz, 2H).