Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[N:5][CH:6]=[C:7]([C:9]2[CH:14]=[C:13]([O:15][CH3:16])[C:12]([O:17][CH3:18])=[C:11]([O:19][CH3:20])[CH:10]=2)[CH:8]=1.[NH:21]1[CH2:27][CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>>[CH3:20][O:19][C:11]1[CH:10]=[C:9]([C:7]2[CH:8]=[C:3]([CH2:2][N:21]3[CH2:27][CH2:26][CH2:25][N:24]([CH2:2][C:3]4[CH:4]=[N:5][CH:6]=[C:7]([C:9]5[CH:14]=[C:13]([O:15][CH3:16])[C:12]([O:17][CH3:18])=[C:11]([O:19][CH3:20])[CH:10]=5)[CH:8]=4)[CH2:23][CH2:22]3)[CH:4]=[N:5][CH:6]=2)[CH:14]=[C:13]([O:15][CH3:16])[C:12]=1[O:17][CH3:18]
Reactant: COc1cc(-c2cncc(CCl)c2)cc(OC)c1OC
Reactant: C1CNCCNC1
Product: COc1cc(-c2cncc(CN3CCCN(Cc4cncc(-c5cc(OC)c(OC)c(OC)c5)c4)CC3)c2)cc(OC)c1OC

Procedure:
3-Chloromethyl-5-(3,4,5-trimethoxyphenyl)pyridine (70 mg) and homopiperazine (12 mg) were reacted in the same manner as in Example 1 to obtain the title compound as a free base. Yield: 56 mg (76%). 1H-NMR (400 MHz, CDCl3) δ: 1.85 (br, 2H), 2.73 (br, 4H), 2.79 (t, 4H, J=5.9 Hz), 3.73 (s, 4H), 3.90 (s, 6H), 3.94 (s, 12H), 6.76 (s, 4H), 7.82 (s, 2H), 8.53 (d, 2H, J=2.0 Hz), 8.68 (d, 2H, J=2.1 Hz). m/z (EI): 614 [M+].
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH3:17])=[O:9])=[CH:6][N:5]=[C:4](S(CC)(=O)=O)[N:3]=1.[NH2:23][CH:24]1[CH2:29][CH2:28][N:27]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:26][CH2:25]1>C(O)(C)C>[CH2:33]([O:32][C:30]([N:27]1[CH2:26][CH2:25][CH:24]([NH:23][C:4]2[N:3]=[C:2]([NH2:1])[C:7]([C:8](=[O:9])[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[O:16][CH3:17])=[CH:6][N:5]=2)[CH2:29][CH2:28]1)=[O:31])[CH3:34]
Reactant: CCOC(=O)N1CCC(N)CC1
Reactant: CCS(=O)(=O)c1ncc(C(=O)c2ccccc2OC)c(N)n1
Solvent: CC(C)O
Product: CCOC(=O)N1CCC(Nc2ncc(C(=O)c3ccccc3OC)c(N)n2)CC1
Temperature: 105 °C
Yield: 85.1 %

Procedure:
A suspension of (4-amino-2-ethanesulfonylpyrimidin-5-yl)-(2-methoxyphenyl)-methanone (20.0 mg, 0.0650 mmol, Example 6) and ethyl 4-amino-1-piperidinecarboxylate (15.1 mg, 0.0876 mmol, Aldrich) in isopropanol (2.5 mL) was placed in a sealed tube and heated at ˜100-110° C. under microwave conditions for ˜1 hour and the resulting mixture was evaporated in vacuo. The crude product was purified on silica gel with 95:5 of dichloromethane/methanol to give 4-[4-amino-5-(2-methoxy-benzoyl)-pyrimidin-2-ylamino]-piperidine-1-carboxylic acid ethyl ester as a light yellow solid (22.1 mg, 89% yield). HRMS, observed: 400.1984; Calcd for (M+H)+: 400.1980.
Reaction SMILES: C[Si](C)(C)[O:3][C:4](=[CH:6][CH2:7][CH3:8])[CH3:5].[C:11](Cl)(=[O:16])[CH2:12][C:13](Cl)=[O:14]>CCOCC>[CH2:7]([C:6]1[C:11]([OH:16])=[CH:12][C:13](=[O:14])[O:3][C:4]=1[CH3:5])[CH3:8]
Reactant: CCC=C(C)O[Si](C)(C)C
Reactant: O=C(Cl)CC(=O)Cl
Solvent: CCOCC
Product: CCc1c(O)cc(=O)oc1C
Temperature: -78 °C
Yield: 42.3 %

Procedure:
In 200 mL of ether, was dissolved 13.6 g (85.9 mmol) of 2-trimethylsilyloxy-2-pentene, and 4.6 mL (47.3 mmol) of malonyl chloride was added dropwise to the solution while stirring the solution at −78° C. After the addition of malonyl chloride, the solution was stirred for 1 hour at −78° C., and then, stirred over night while gradually heating the solution to room temperature. The precipitate was filtered and washed with ether. As a result, 3.08 g (20.0 mmol, 42.3%) of 5-ethyl-4-hydroxy-6-methyl-2-pyrone was obtained.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21](O)=[O:22])=[CH:19][NH:18][C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.CCN=C=NCCCN(C)C.[NH2:35][C:36]1([CH3:49])[CH2:41][CH2:40][N:39]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:38][CH2:37]1.O>CN(C=O)C.CN(C1C=CN=CC=1)C>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21]([NH:35][C:36]5([CH3:49])[CH2:37][CH2:38][N:39]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:40][CH2:41]5)=[O:22])=[CH:19][NH:18][C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1
Reactant: CC1(N)CCN(C(=O)OC(C)(C)C)CC1
Reactant: Cn1nc(-c2cnc3[nH]cc(C(=O)O)c3n2)c2ccc(F)cc21
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: O
Product: Cn1nc(-c2cnc3[nH]cc(C(=O)NC4(C)CCN(C(=O)OC(C)(C)C)CC4)c3n2)c2ccc(F)cc21
Reaction time: 16 h
Yield: 61.6 %

Procedure:
To a stirred solution of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (100 mg, 0.32 mmol) in 10 mL of DMF were added EDCI (122 mg, 0.64 mmol), tert-butyl 4-amino-4-methylpiperidine-1-carboxylate (103 mg, 0.48 mmol) and DMAP (78 mg, 0.64 mmol) in one portion at room temperature. Then the reaction mixture was stirred for 16 hours, then was poured into 50 mL of water and filtered. The filter cake was washed with water (10 mL) and passed through a pad of silica gel (200-300 mesh, eluting with a mixture of petroleum ether and ethyl acetate (1:2, v/v) to give tert-butyl 4-(2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamido)-4-methylpiperidine-1-carboxylate (100 mg, 61.6%) as a white solid which was used for the next step without further purification. MS: (M+H)+=508.2.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[NH:14][C:15]([C:18]2[CH:31]=[CH:30][C:29]3[C:28]4[C:23](=[CH:24][C:25](Br)=[CH:26][CH:27]=4)[CH2:22][CH2:21][C:20]=3[CH:19]=2)=[CH:16][N:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Sn](CCCC)(CCCC)[C:38]([O:40]CC)=[CH2:39])CCC.O.C1C(=O)N([Br:59])C(=O)C1>O1CCOCC1.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[NH:14][C:15]([C:18]2[CH:31]=[CH:30][C:29]3[C:28]4[C:23](=[CH:24][C:25]([C:38](=[O:39])[CH2:40][Br:59])=[CH:26][CH:27]=4)[CH2:22][CH2:21][C:20]=3[CH:19]=2)=[CH:16][N:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)OC(=O)N1CCCC1c1ncc(-c2ccc3c(c2)CCc2cc(Br)ccc2-3)[nH]1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCCC1c1ncc(-c2ccc3c(c2)CCc2cc(C(=O)CBr)ccc2-3)[nH]1
Temperature: 80 °C
Reaction time: 0.67 h

Procedure:
Pd(Ph3)4 (15 mg, 0.015 mmol) and PdCl2(Ph3)2 (10 mg, 0.015 mmol) were added to a mixture 2-[5-(7-bromo-9,10-dihydro-phenanthren-2-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester (180 mg, 0.37 mmol) and tributyl(1-ethoxyvinyl)tin (0.15 mL, 0.44 mL) in 5 mL dioxane. The reaction mixture was flushed with nitrogen, heated at 80° C. for 16 hours, then cooled to ambient temperature. Water (1.5 mL) and NBS (78 mg, 0.44 mmol) was added and the mixture was stirred at room temperature for 40 minutes, then diluted with ethyl acetate (100 mL). Washed with water and brine, dried over Na2SO4, filtered and concentrated in vacuo. The obtained residue was carried on to next step reaction without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][CH2:11][NH:10][CH2:9]2)=[CH:4][CH:3]=1.[CH:14](=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[BH3-]C#N.[Na+]>CO>[CH2:14]([N:10]1[CH2:11][CH2:12][CH2:13][CH:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[CH2:9]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=Cc1ccccc1
Reactant: Clc1ccc(C2CCCNC2)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: Clc1ccc(C2CCCN(Cc3ccccc3)C2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 62 %

Procedure:
To a solution of 3-(4-chlorophenyl)piperidine in MeOH (0.2 M), benzaldehyde (2.1 eq.) was added and the reaction mixture was stirred at RT for 1 h. Then, it was cooled to 0° C. and NaBH3CN (3 eq.) was added. The mixture was allowed to warm to RT and stirred for 1 h. Evaporation of the solvent gave a residue that was partitioned between sat. aq. NaHCO3 and EtOAc and the organic phase was separated and dried (Na2SO4). Evaporation of the solvent gave a crude that was purified by flash chromatography column on silica (Petroleum ether to EtOAc/Petroleum ether 1:19) yielding (62%) the title compound as a yellow powder. 1H NMR (300 MHz, DMSO-d6, 300K) δ 7.36-7.17 (9H, m), 3.48 (2H, s), 2.87-2.68 (3H, m), 2.05-1.91 (2H, m), 1.86-1.75 (1H, m), 1.74-1.50 (2H, m), 1.48-1.3 (1H, m). MS (ES+) C18H20ClN required: 285, found: 286 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:29]=[CH:28][C:6]2[NH:7][C:8](=[O:27])[N:9]([CH:12]3[CH2:17][CH2:16][N:15]([C:18]4[CH:23]=[C:22]([C:24]([OH:26])=O)C=[CH:20][N:19]=4)[CH2:14][CH2:13]3)[CH2:10][CH2:11][C:5]=2[CH:4]=1.[S:30]1[C:34]2[CH2:35][NH:36][CH:37]([CH2:39][OH:40])[CH2:38][C:33]=2[CH:32]=[CH:31]1.C[N:42](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[OH:40][CH2:39][CH:37]1[N:36]([C:24]([C:22]2[N:42]=[CH:20][N:19]=[C:18]([N:15]3[CH2:16][CH2:17][CH:12]([N:9]4[CH2:10][CH2:11][C:5]5[CH:4]=[C:3]([O:2][CH3:1])[CH:29]=[CH:28][C:6]=5[NH:7][C:8]4=[O:27])[CH2:13][CH2:14]3)[CH:23]=2)=[O:26])[CH2:35][C:34]2[S:30][CH:31]=[CH:32][C:33]=2[CH2:38]1
Reactant: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)O)ccn3)CC1)C(=O)N2
Reactant: OCC1Cc2ccsc2CN1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)N4Cc5sccc5CC4CO)ncn3)CC1)C(=O)N2
Temperature: 25 °C
Reaction time: 5 h

Procedure:
100 mg (0.25 mmol) 4-(7-methoxy-2-oxo-1,2,4,5-tetrahydro-benzo[d][1,3]diazepin-3-yl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4′-carboxylic acid and 50 mg (0.28 mmol) (4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-5-yl)-methanol in 50 μL (0.36 mmol) TEA and 0.90 mL DMF were combined with 85 mg (0.27 mmol) TBTU and the mixture was stirred for 5 h at RT. Then the reaction mixture was purified by preparative HPLC-MS. The product-containing fractions were combined and evaporated down roughly by half. The precipitate formed was suction filtered and dried.
Reaction SMILES: CN(C)C=O.I[C:7]1[C:12]([O:13][C:14]2[C:23]3[C:18](=[CH:19][C:20]([O:26][CH3:27])=[C:21]([O:24][CH3:25])[CH:22]=3)[N:17]=[CH:16][CH:15]=2)=[CH:11][CH:10]=[C:9]([CH3:28])[N:8]=1.C([Sn](CCCC)(CCCC)[C:34]1[S:35][CH:36]=[CH:37][N:38]=1)CCC>[Cu]=O.O>[CH3:25][O:24][C:21]1[CH:22]=[C:23]2[C:18](=[CH:19][C:20]=1[O:26][CH3:27])[N:17]=[CH:16][CH:15]=[C:14]2[O:13][C:12]1[C:7]([C:34]2[S:35][CH:36]=[CH:37][N:38]=2)=[N:8][C:9]([CH3:28])=[CH:10][CH:11]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccs1
Reactant: COc1cc2nccc(Oc3ccc(C)nc3I)c2cc1OC
Agent: O=[Cu]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2nccc(Oc3ccc(C)nc3-c3nccs3)c2cc1OC
Temperature: 70 °C
Reaction time: 8 h
Yield: 11.6 %

Procedure:
N,N-Dimethylformamide (1 ml) was added to 4-(2-iodo-6-methyl-pyridin-3-yloxy)-6,7-dimethoxy-quinoline (compound 116) (50 mg), tetrakistriphenylphosphine palladium (14 mg), tri-n-butyl-(thiazol-2-yl)-tin (132 mg), and copper(II) oxide (1.9 mg) under an argon atmosphere, and the mixture was stirred at 70° C. overnight. The reaction solution was cooled to room temperature, water was then added thereto, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using hexane-acetone to give the title compound (5.2 mg, yield 12%).
Reaction SMILES: C[O:2][C:3]([C@H:5]1[NH:24][C:23](=[O:25])[C:22]2=[CH:26][C:18](=[C:19]([CH3:28])[CH:20]=[C:21]2[CH3:27])[C:17]2=[CH:29][C:13](=[N:14][C:15]([NH2:30])=[N:16]2)[S:12][CH2:11][CH2:10][C:9](=[O:31])[NH:8][CH2:7][CH2:6]1)=[O:4].[OH-].[Na+].O>CO>[NH2:30][C:15]1[N:14]=[C:13]2[CH:29]=[C:17]([C:18]3[CH:26]=[C:22]([C:23](=[O:25])[NH:24][C@H:5]([C:3]([OH:4])=[O:2])[CH2:6][CH2:7][NH:8][C:9](=[O:31])[CH2:10][CH2:11][S:12]2)[C:21]([CH3:27])=[CH:20][C:19]=3[CH3:28])[N:16]=1
Reactant: COC(=O)[C@@H]1CCNC(=O)CCSc2cc(nc(N)n2)-c2cc(c(C)cc2C)C(=O)N1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1cc(C)c2cc1C(=O)N[C@H](C(=O)O)CCNC(=O)CCSc1cc-2nc(N)n1
Temperature: 25 °C
Reaction time: 6 h
Yield: 86.4 %

Procedure:
(S)-4-Amino-18,20-dimethyl-10,16-dioxo-7-thia-3,5,11,15-tetraazatricyclo[15.3.1.12,6]docosa-1(20),2(22),3,5,17(21),18-hexaene-14-carboxylic acid methyl ester (1.1 g) obtained in Example 2-12 was dissolved in methanol (24.8 ml), and then a 1N aqueous sodium hydroxide solution (2.7 ml) was added thereto at room temperature. The resulting mixture was stirred at room temperature for six hours, and then water (80 ml) was added thereto. The precipitate was collected by filtration, washed with water, and then dried under reduced pressure to yield (S)-4-amino-18,20-dimethyl-10,16-dioxo-7-thia-3,5,11,15-tetraazatricyclo[15.3.1.12,6]docosa-1(20),2(22),3,5,17(21),18-hexaene-14-carboxylic acid (Compound 64) (0.92 g) as a white solid material.
Reaction SMILES: [C:1]([C:3]1[C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]=O)[CH:10]=2)=[CH:7][C:6]([CH2:17][NH:18][C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([NH:29][CH2:30][C:31]3[C:32]([NH:44][CH:45]4[CH2:50][CH2:49][O:48][CH2:47][CH2:46]4)=[C:33]4[CH:41]=[N:40][N:39]([CH2:42][CH3:43])[C:34]4=[N:35][C:36]=3[CH2:37][CH3:38])=[O:28])[CH:22]=2)=[O:20])=[CH:5][CH:4]=1)#[N:2].[C@H:51]12[CH2:57][C@H:54]([NH:55][CH2:56]1)[CH2:53][N:52]2C(OC(C)(C)C)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CC(O)=O>C(Cl)Cl>[C:1]([C:3]1[C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:52]3[CH2:53][C@@H:54]4[CH2:57][C@H:51]3[CH2:56][NH:55]4)[CH:10]=2)=[CH:7][C:6]([CH2:17][NH:18][C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([NH:29][CH2:30][C:31]3[C:32]([NH:44][CH:45]4[CH2:50][CH2:49][O:48][CH2:47][CH2:46]4)=[C:33]4[CH:41]=[N:40][N:39]([CH2:42][CH3:43])[C:34]4=[N:35][C:36]=3[CH2:37][CH3:38])=[O:28])[CH:22]=2)=[O:20])=[CH:5][CH:4]=1)#[N:2]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2ccc(C#N)c(-c3cccc(C=O)c3)c2)c1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2ccc(C#N)c(-c3cccc(CN4C[C@@H]5C[C@H]4CN5)c3)c2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N-[(6-Cyano-3′-formyl-3-biphenylyl)methyl]-N′-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-1,3-benzenedicarboxamide (108 mg, 0.000161 mol) in DCM (4 mL) and 1,1-dimethylethyl (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (46 mg, 0.00023 mol) were mixed with sodium triacetoxyborohydride (68.3 mg, 0.00032 mol) and AcOH (11.6 mg, 11 μL). The solution was stirred overnight at room temperature. LC-MS showed that the reaction was complete. The reaction was quenched with sat. aq. NaHCO3, then extracted with DCM (2×). The combined organic extracts were washed with sat. aq. NaCl and dried (Na2SO4) and concentrated to a glassy foam (227.5 mg). The glassy foam was taken up in DCM (10 mL) containing 25% TFA and allowed to stand at room temperature for 3 h. LC-MS showed the reaction to be complete. Solvent was stripped off. Purification was carried out on Gilson instrument with acetonitrile-water (0.1% TFA) gradient on a C18-RP column. Fractions containing the clean desired product were combined; diluted with EtOAc; washed with sat. aq. NaHCO3; and the aq. phase back-extracted with EtOAc. Combined organic layers were washed with sat. aq. NaCl and dried (Na2SO4) and concentrated to a residue. It was taken up in a small amount of DCM and transferred to a vial and pumped down to afford the title compound as a chalky, white solid [71.5 mg (59%)]. LC-MS m/z 752.3 (M+H)+.
Reaction SMILES: C([O-])(=O)C.C([O-])(=O)C.[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([IH+:17])=[CH:13][CH:12]=1.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([IH+])=[CH:22][CH:21]=1.[F:27][C:28]([F:33])([F:32])[C:29]([OH:31])=[O:30].C1(OC)C=CC=CC=1>ClCCl>[F:27][C:28]([F:33])([F:32])[C:29]([O-:31])=[O:30].[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([I+:17][C:23]2[CH:24]=[CH:25][C:20]([O:19][CH3:18])=[CH:21][CH:22]=2)=[CH:13][CH:12]=1
Reactant: O=C(O)C(F)(F)F
Reactant: COc1ccc([IH+])cc1
Agent: CC(=O)[O-]
Solvent: COc1ccccc1
Solvent: ClCCl
Product: COc1ccc([I+]c2ccc(OC)cc2)cc1
Product: O=C([O-])C(F)(F)F
Temperature: -30 °C
Reaction time: 0.5 h
Yield: 84.2 %

Procedure:
Under N2 protection, 1.41 g (4 mmol) p-methoxyphenyliodonium diacetate was dissolved in 30 mL of dry dichloromethane and the solution was cooled to −30° C. 0.61 mL (8 mmol) of trifluoroacetic acid was added and the solution was slowly brought back to room temperature and stirred for 30 minutes. The solution was, again, cooled to −30° C. and 0.44 mL (4 mmol) anisole was added slowly and the mixture was warmed back up to room temperature and stirred for 1 hour. The solvent was evaporated and the residual solid was recrystallized from diethylether/dichloromethane to give 1.53 g bis(p-methoxyphenyl)iodonium trifluoroacetate (71%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]2[N:14]=[C:15]([NH:17][C:18]3[NH:22][C:21]4[CH:23]=[C:24]([C:27](=[O:38])[NH:28][C:29]5[CH:37]=[C:36]6[C:32]([CH:33]=[N:34][NH:35]6)=[CH:31][CH:30]=5)[CH:25]=[CH:26][C:20]=4[N:19]=3)[S:16][C:10]=2[CH2:9]1)=O)(C)(C)C>CO.Cl.O1CCOCC1.CCOCC>[NH:35]1[C:36]2[C:32](=[CH:31][CH:30]=[C:29]([NH:28][C:27]([C:24]3[CH:25]=[CH:26][C:20]4[N:19]=[C:18]([NH:17][C:15]5[S:16][C:10]6[CH2:9][NH:8][CH2:13][CH2:12][C:11]=6[N:14]=5)[NH:22][C:21]=4[CH:23]=3)=[O:38])[CH:37]=2)[CH:33]=[N:34]1
Reactant: CC(C)(C)OC(=O)N1CCc2nc(Nc3nc4ccc(C(=O)Nc5ccc6cn[nH]c6c5)cc4[nH]3)sc2C1
Agent: Cl
Solvent: CO
Solvent: CCOCC
Solvent: C1COCCO1
Product: O=C(Nc1ccc2cn[nH]c2c1)c1ccc2nc(Nc3nc4c(s3)CNCC4)[nH]c2c1
Temperature: 25 °C
Reaction time: 5.5 h

Procedure:
To a solution of 2-[6-(1H-indazol-6-ylcarbamoyl)-1H-benzimidazol-2-ylamino]-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylic acid tert-butyl ester (0.25 mmol; see Example 79) in methanol (1 mL), 4M HCl in dioxane (0.5 mL) was added. The resulting mixture was stirred at room temperature for 5-6 h. The volatiles were removed in vacuo, the residue obtained was suspended in ether. The solid obtained was collected by filtration, washed with ether and dried in vacuo to afford 2-(4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-ylamino)-3H-benzimidazole-5-carboxylic acid (1H-indazol-6-yl)-amide as a hydrochloride salt. MS: m/z 431 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]([CH3:21])[CH2:3][CH2:4][NH:5][C:6]1[S:7][CH:8]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[N:10]=1.[H-].[Na+].Br[CH2:25][C:26]1[CH:35]=[CH:34][C:29]([C:30]([O:32][CH3:33])=[O:31])=[CH:28][CH:27]=1.O>CN(C)C=O>[CH3:1][CH:2]([CH3:21])[CH2:3][CH2:4][N:5]([CH2:25][C:26]1[CH:35]=[CH:34][C:29]([C:30]([O:32][CH3:33])=[O:31])=[CH:28][CH:27]=1)[C:6]1[S:7][CH:8]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:18])([F:20])[F:19])=[CH:13][CH:12]=2)[N:10]=1
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: CC(C)CCNc1nc(-c2ccc(C(F)(F)F)cc2)cs1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(CN(CCC(C)C)c2nc(-c3ccc(C(F)(F)F)cc3)cs2)cc1
Reaction time: 0.5 h
Yield: 75.8 %

Procedure:
To a solution of N-(3-methylbutyl)-4-[4-(trifluoromethyl)phenyl]-1,3-thiazole-2-amine (1.20 g, 3.82 mmol) in N,N-dimethylformamide (20 mL) was added sodium hydride (60% in oil, 229 mg, 5.73 mmol) and the mixture was stirred for 30 min. Methyl 4-(bromomethyl)benzoate (1.05 g, 4.58 mmol) was added and the mixture was stirred at 60° C. for 1.5 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=97/3-hexane/ethyl acetate=60/40) to give the title compound (1.34 g, yield 76%) as a yellow oil.
Reaction SMILES: [CH:1]#[C:2][CH:3]([OH:9])[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[Si:10](Cl)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11].N1C=CN=C1>CN(C=O)C.CCOCC>[C:13]([Si:10]([CH3:12])([CH3:11])[O:9][CH:3]([CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[C:2]#[CH:1])([CH3:16])([CH3:15])[CH3:14]
Reactant: C#CC(O)CCCCC
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: C#CC(CCCCC)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 96 %

Procedure:
To a solution of 1-octyn-3-ol (5.0 g, 0.039 mol) in DMF (50 mL) were added tert-butyldimethylsilyl chloride (7.16 g, 0.0475 mol) and imidazole (3.2 g, 0.0475 mol). The resulting solution was stirred at RT for 18 h then diluted with ether (200 mL) and washed with water (2×200 mL), saturated solution of NH4Cl (200 mL), and brine (200 mL). The organic solution was dried over sodium sulfate and concentrated in vacuo to afford the desired compound (9.0 g, 95%) as a colorless oil used in the next step without further purification. Rf 0.9 (EtOAc/hexanes 1/9); 1H NMR (CDCl3) δ 0.09 (s, 3H), 0.12 (s, 3H), 0.89 (s, 9H), 0.85-1.00 (t, 3H), 1.20-1.70 (m, 8H), 2.35 (s, 1H), 4.30-4.35 (m, 1H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][CH:4]=1)#[CH:2].Br[C:12]1[S:13][CH:14]=[CH:15][N:16]=1.C(N(CC)CC)C>C(#N)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[S:13]1[CH:14]=[CH:15][N:16]=[C:12]1[C:8]1[CH:7]=[C:6]([O:9][CH3:10])[CH:5]=[CH:4][C:3]=1[C:1]#[CH:2]
Reactant: Brc1nccs1
Reactant: C#Cc1ccc(OC)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CC#N
Product: C#Cc1ccc(OC)cc1-c1nccs1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 70 %

Procedure:
The alkyne of the current example, 2-(2-thiazolyl)-4-methoxyphenylacetylene was prepared by adding to a degassed solution of 4 mmol of 4-ethynylanisole, 4 mmol of 2-bromothiazole, and 1 ml of triethylamine in 10 ml of acetonitrile, 140 mg (0.2 mmol) of PdCl2(PPh3)2 and 19 mg(0.1 mmol) of CuI. The mixture was degassed and stirred for 5 minutes at RT and heated to 90° C. for 12 hours. The reaction mixture was concentrated in vacuo and purified by silica column to afford 0.61 g of brown liquid in a 70% yield.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]([CH3:15])[S:9]([N:12]([CH3:14])[CH3:13])(=[O:11])=[O:10])[CH:5]=[C:4](Cl)[N:3]=1.[CH3:17][C:18]1[NH:22][N:21]=[C:20]([NH2:23])[CH:19]=1.CCN(C(C)C)C(C)C>CCCCO>[Cl:1][C:2]1[N:7]=[C:6]([N:8]([CH3:15])[S:9]([N:12]([CH3:14])[CH3:13])(=[O:11])=[O:10])[CH:5]=[C:4]([NH:23][C:20]2[CH:19]=[C:18]([CH3:17])[NH:22][N:21]=2)[N:3]=1
Reactant: CN(C)S(=O)(=O)N(C)c1cc(Cl)nc(Cl)n1
Reactant: Cc1cc(N)n[nH]1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: Cc1cc(Nc2cc(N(C)S(=O)(=O)N(C)C)nc(Cl)n2)n[nH]1
Temperature: 70 °C
Yield: 9.7 %

Procedure:
To a solution of N-(2,6-dichloropyrimidin-4-yl)-N,N′,N′-trimethylsulfamide (Method 27, 1.72 g, 6.05 mmol) in n-BuOH (6 ml) was added 5-methyl-1H-pyrazol-3-amine (0.605 g, 6.05 mmol) and DIPEA (1.6 mL, 9.09 mmol). The mixture was heated at 70° C. overnight. The reaction mixture was filtered; the solid was washed by MeOH three times to give pure white solid. (0.205 g, 9.7% yield). LC-MS, 346 (M+1). NMR (DMSO-d6, 400 MHz, 80° C.) δ 11.89 (s, 1H), 9.82 (s, 1H), 7.22 (s, 1H), 5.97 (s, 1H), 3.32 (s, 3H), 2.87 (s, 6H), 2.21 (s, 3H).
Reaction SMILES: [CH3:1][O:2][CH:3]([C:8]([O:10]C)=O)[C:4]([O:6]C)=O.Cl.[CH2:13]([O:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([NH2:27])=[NH:26])=[CH:23][CH:22]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[OH:6][C:4]1[C:3]([O:2][CH3:1])=[C:8]([OH:10])[N:27]=[C:25]([C:24]2[CH:28]=[CH:29][C:21]([O:20][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:22][CH:23]=2)[N:26]=1
Reactant: COC(=O)C(OC)C(=O)OC
Reactant: N=C(N)c1ccc(OCc2ccccc2)cc1
Agent: Cl
Product: COc1c(O)nc(-c2ccc(OCc3ccccc3)cc2)nc1O

Procedure:
In process (A), dimethyl methoxymalonate and 4-benzyloxybenzamidine hydrochloride are reacted to obtain 4,6-dihydroxy-5-methoxy-2-(4-benzyloxyphenyl)pyrimidine (1), which is then chlorinated with phosphorus oxychloride to obtain a dichloro derivative (2). The compound (2) is debenzylated by hydrogenation using palladium-on-carbon to obtain 5-methoxy-2-(4-hydroxyphenyl)pyrimidine (3), which is again protected with a benzyl group [(3)→(4)], followed by demethylation [(4)→(5)]. Compound (5) is reacted with an optically active 3-fluoroalkyl mesylate to obtain compound (6). After removing the benzyl protective group by hydrogenation with palladium-on-carbon [(6)→(7)], compound (7) is reacted with an optically active 3-fluoroalkyl mesylate to obtain compound (8).