Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].C1([B:15]2[O:23][C:20]([CH3:22])([CH3:21])[C:17]([CH3:19])([CH3:18])[O:16]2)C=CC=CC=1>>[CH3:18][C:17]1([CH3:19])[C:20]([CH3:22])([CH3:21])[O:23][B:15]([C:7]2[CH:2]=[C:3]([OH:8])[CH:4]=[CH:5][CH:6]=2)[O:16]1
Reactant: CC1(C)OB(c2ccccc2)OC1(C)C
Reactant: Oc1ccccc1I
Product: CC1(C)OB(c2cccc(O)c2)OC1(C)C

Procedure:
The above reaction procedure used for 2-iodophenol was followed. The reaction was faster, being complete before the first sample for gc analysis was withdrawn after 1 h 50 min reaction time. The amount of phenylboronic acid pinacol ester was higher than in the 2-iodophenol reaction (around 7%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[F:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][P:15]([O-:24])[O:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)=[CH:10][CH:9]=1.[ClH:25]>C(Cl)Cl.CCOCC>[ClH:25].[NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[P:15]([O:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)(=[O:24])[O:14][C:11]1[CH:10]=[CH:9][C:8]([F:7])=[CH:13][CH:12]=1
Reactant: C1CCNCC1
Reactant: [O-]P(Oc1ccc(F)cc1)Oc1ccc(F)cc1
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: O=P(Oc1ccc(F)cc1)(Oc1ccc(F)cc1)C1CCCCN1
Yield: 54 %

Procedure:
A mixture of piperidine trimer (4.5 g, 54 mmole) and di(4-fluorophenyl)phosphite (14.8 g, 55 mmole) was heated at 90°-100° C. for 3 h under nitrogen. The resulted oil was cooled and dissolved in a mixture of 50 mL CH2Cl2 and 50 mL ether. The solution was saturated with dry HCl, the oil was separated and solidified after several hours. The solid was filtered, washed with ether and dried. The hygroscopic material was stirred in 200 mL dry ether for several hours and the yellowish solid was filtered and dried. The product was obtained in 54% yield (11.6 g) and used for subsequent reaction: mp. 155°-165° C. (dec); 1H NMR (D2O) δ7.2-6.8 (m, 8H), 3.6-2.9 (m, 3H), 2.2-1.4 (m, 6H); MS (FAB) m/e 354 (M-Cl)+. Anal. (exact mass, HRMS) calcd. for C17H19N1O3P1Cl2 m/e 354.1070, found 354.1098.
Reaction SMILES: C(N(CC)CC)C.C(Cl)Cl.[CH:11]1([CH2:14][N:15]2[C:23]([N:24]3[CH2:29][CH2:28][NH:27][C@H:26]([CH3:30])[CH2:25]3)=[N:22][C:21]3[C:16]2=[N:17][C:18]([C:37]2[CH:38]=[N:39][C:40]([NH2:43])=[N:41][CH:42]=2)=[N:19][C:20]=3[N:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)[CH2:13][CH2:12]1.[C:44](OC(=O)C)(=[O:46])[CH3:45]>C(Cl)Cl.CO>[C:44]([N:27]1[CH2:28][CH2:29][N:24]([C:23]2[N:15]([CH2:14][CH:11]3[CH2:13][CH2:12]3)[C:16]3[C:21]([N:22]=2)=[C:20]([N:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)[N:19]=[C:18]([C:37]2[CH:42]=[N:41][C:40]([NH2:43])=[N:39][CH:38]=2)[N:17]=3)[CH2:25][C@H:26]1[CH3:30])(=[O:46])[CH3:45]
Reactant: C[C@@H]1CN(c2nc3c(N4CCOCC4)nc(-c4cnc(N)nc4)nc3n2CC2CC2)CCN1
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CO
Product: CC(=O)N1CCN(c2nc3c(N4CCOCC4)nc(-c4cnc(N)nc4)nc3n2CC2CC2)C[C@H]1C
Temperature: 25 °C
Reaction time: 1.58 h
Yield: 100.9 %

Procedure:
Triethylamine (77.3 μl, 0.55 mmol) was added to a methylene chloride solution (3.0 ml) of 5-{9-(cyclopropylmethyl)-8-[(3R)-3-methylpiperazin-1-yl]-6-morpholin-4-yl-9H-purin-2-yl}pyrimidin-2-amine (104.1 mg, 0.23 mmol) at room temperature followed by the addition of acetic anhydride (26.2 μl, 0.28 mmol) with ice cooling. The resulting mixture was stirred at room temperature for 95 minutes and the reaction mixture was poured into methylene chloride-methanol (10:1), washed with water, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and the resulting residue was purified by medium pressure silica gel column chromatography (methylene chloride:methanol=32:1 to 16:1) to give the title compound (114.3 mg, 100%) as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[NH:6][C:7]3[CH:8]=[C:9]([C:26]([O:28]C)=[O:27])[CH:10]=[C:11]([CH:25]=3)[O:12][CH2:13][CH2:14][S:15][C:16]3[CH:24]=[C:20]([NH:21][C:22]=1[N:23]=2)[CH:19]=[CH:18][CH:17]=3.[OH-].[Na+]>CO.O1CCCC1>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[NH:6][C:7]3[CH:8]=[C:9]([C:26]([OH:28])=[O:27])[CH:10]=[C:11]([CH:25]=3)[O:12][CH2:13][CH2:14][S:15][C:16]3[CH:24]=[C:20]([NH:21][C:22]=1[N:23]=2)[CH:19]=[CH:18][CH:17]=3
Reactant: COC(=O)c1cc2cc(c1)OCCSc1cccc(c1)Nc1nc(ncc1Cl)N2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1cc2cc(c1)OCCSc1cccc(c1)Nc1nc(ncc1Cl)N2
Temperature: 60 °C
Yield: 92 %

Procedure:
A solution of methyl 6-chloro-17-oxa-14-thia-2,4,8,24-tetraazatetracyclo[16.3.1.1(3,7).1(9,13)]tetracosa-1(22),3(24),4,6,9(23),10,12,18,20-nonaene-20-carboxylate (450 mg, 1.1 mmol) in methanol (2.3 mL) and tetrahydrofuran (4.5 mL) was treated with 1 M sodium hydroxide (2.1 mL, 2.1 mmol) dropwise and heated at 60° C. for 16 h. The reaction mixture was cooled to 0° C. and quenched with 1 M HCl (3.2 mL). The resultant suspension was diluted with a small amount of water, filtered, and washed with cold acetonitrile to give the desired product (420 mg, 97%) as a white solid. LCMS for C19H16ClN4O3S (M+H)+: m/z=414.9.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH2:19])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.[C:20](Cl)(=[O:24])/[CH:21]=[CH:22]/[CH3:23]>N1C=CC=CC=1.CCOCC>[Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH:19][C:20](=[O:24])/[CH:21]=[CH:22]/[CH3:23])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccc2ncnc(Nc3cccc(Br)c3)c2c1
Reactant: C/C=C/C(=O)Cl
Solvent: c1ccncc1
Solvent: CCOCC
Product: C/C=C/C(=O)Nc1ccc2ncnc(Nc3cccc(Br)c3)c2c1

Procedure:
A solution of 1.6 g of N-(3-bromophenyl)-4,6-quinazolindiamine in 15 ml of pyridine was cooled in an ice bath and a solution of 0.57 ml of trans-crotonoyl chloride in 6 ml of ether was added dropwise. After stirring and cooling for 2 hours, the solvents were removed at reduced pressure. The residue was treated with water and the resulting solid recrystallized from n-butanol to give 0.69 g of N-[4-[(3-bromophenyl)amino]-6-quinazolinyl]-(E)-2-butenamide: mp=153-160° C., mass spectrum (m/e): M+H 383, 385.
Reaction SMILES: [H-].[Na+].C(O[C:6](=O)[O:7][CH2:8][CH3:9])C.[Br:11][C:12]1[CH:13]=[CH:14][C:15]([O:21][CH2:22][O:23][CH3:24])=[C:16]([C:18](=[O:20])[CH3:19])[CH:17]=1.C1C[O:28]CC1>>[Br:11][C:12]1[CH:13]=[CH:14][C:15]([O:21][CH2:22][O:23][CH3:24])=[C:16]([C:18](=[O:20])[CH2:19][C:9](=[O:28])[CH2:8][O:7][CH3:6])[CH:17]=1
Reactant: CCOC(=O)OCC
Reactant: COCOc1ccc(Br)cc1C(C)=O
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Product: COCOc1ccc(Br)cc1C(=O)CC(=O)COC
Temperature: 80 °C
Reaction time: 5 h

Procedure:
To a slurry of sodium hydride (60% oily dispersion; 1.49 g, 37 mmol) and diethylcarbonate (6.0 mL, 49 mmol) in anhydrous THF (70 mL), a solution of 1-(5-bromo-2-(methoxymethoxy)phenyl)ethanone (15, 4.435 g, 17.1 mmol) in anhydrous THF (30 mL) was added in one portion at rt under a nitrogen atmosphere. The mixture was stirred at 80° C. for 5 h. As the reaction was deemed complete by LC-MS, the mixture was cooled to room temperature and quenched by pouring it onto 1:1 ice/1N NaHSO4 (100 mL). Extractions with Et2O (2×150 mL) followed. The combined organic layers were washed with water (80 mL), brine (60 mL), and then dried over MgSO4. After purification by flash chromatography (9:1 to 8:2 hexane/EtOAc), the title compound (16) was obtained as colorless oil (4.403 g, 78% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([O:9][CH3:10])=[O:8].[OH-].[K+].ClC(Cl)([O:16]C(=O)OC(Cl)(Cl)Cl)Cl>O.C1(C)C=CC=CC=1>[NH:1]1[C:2]2[CH:6]=[CH:5][S:4][C:3]=2[C:7](=[O:8])[O:9][C:10]1=[O:16]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COC(=O)c1sccc1N
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: O=c1[nH]c2ccsc2c(=O)o1
Temperature: 90 °C
Reaction time: 2 h
Yield: 78.5 %

Procedure:
To a solution of methyl 3-aminothiophene-2-carboxylate 20.0 g (0.127 mol) in water 150 ml was added the aqueous solution of potassium hydroxide 10.7 g (0.191 mol). The resulting solution wad heated to 90° C. for 2 hrs. After being checked by TLC till the starting material was consumed, the reaction solution was cooled to 0° C. Then a solution of triphosgene 18.9 g (0.064 mol) in toluene 150 ml was added dropwise. The resulting solution was stirred at room temperature for 2 hrs. The residue was filtered, and the solid was recrystallized from tetrahydrofuran to obtain 1H-thieno[3,2-d][1,3]oxazine-2,4-dione 8.5 g (yield 40%).
Reaction SMILES: [NH2:1][C@@H:2]1[C@@H:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C@H:6]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@@H:5]([CH2:24][O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:4][C@H:3]1O.[CH3:34][N:35]=[C:36]=[S:37]>>[CH3:34][NH:35][C:36]1[S:37][C@H:3]2[CH2:4][C@H:5]([CH2:24][O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C@@H:6]([O:16][CH2:17][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[C@H:7]([O:8][CH2:9][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)[C@H:2]2[N:1]=1
Reactant: CN=C=S
Reactant: N[C@@H]1[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@@H](COCc2ccccc2)C[C@H]1O
Product: CNC1=N[C@@H]2[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@@H](COCc3ccccc3)C[C@@H]2S1

Procedure:
The title compound was prepared via a synthetic sequence as described above Intermediate Example 7, starting form (1R,2S,3R,4R,5R)-2-amino-3,4-bis(benzyloxy)-5-((benzyloxy)methyl)cyclohexanol (0.150 g, 0.336 mmol) and methyl isothiocyanate (MeNCS) (0.049 g, 0.67 mmol). The crude product was purified on silica gel by automatic flash column chromatography (EtOAc/hexanes, 1:20 to 1:3), affording (3aR,4R,5R,6R,7aS)-2-(mthylamino)-4,5-bisbenzyloxy-6-(benzyloxymethyl)-3a,4,5,6,7,7a-hexahydrobenzo[d]thiazole as a colorless oil (0.16 g, impure).
Reaction SMILES: CS(O[CH2:6][C:7]1[C:8]2[CH:16]=[C:15]([CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[S:14][C:9]=2[N:10]=[C:11]([CH3:13])[N:12]=1)(=O)=O.CC#N.[CH:26]1([NH2:31])[CH2:30][CH2:29][CH2:28][CH2:27]1>O>[CH:17]1([C:15]2[S:14][C:9]3[N:10]=[C:11]([CH3:13])[N:12]=[C:7]([CH2:6][NH:31][CH:26]4[CH2:30][CH2:29][CH2:28][CH2:27]4)[C:8]=3[CH:16]=2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: NC1CCCC1
Reactant: Cc1nc(COS(C)(=O)=O)c2cc(C3CCCCC3)sc2n1
Solvent: O
Solvent: CC#N
Product: Cc1nc(CNC2CCCC2)c2cc(C3CCCCC3)sc2n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of (6-cyclohexyl-2-methylthieno[2,3-d]pyrimidin-4-yl)methyl methanesulfonate (500 mg) and CH3CN (10 mL) was added cyclopentylamine (1.0 mL), followed by stirring at room temperature for 3 hours. To the reaction mixture was added water, followed by extraction with EtOAc. The organic layer was dried over MgSO4 and then concentrated under reduced pressure. The residue was purified by basic silica gel column (hexane/EtOAc) and silica gel column (hexane/EtOAc) to obtain N-[(6-cyclohexyl-2-methylthieno[2,3-d]pyrimidin-4-yl)methyl]cyclopentaneamine (326 mg).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[C:7]([O:10][C:11]3[CH:16]=[CH:15][C:14]([C:17]4[C:22]5=[N:23][S:24](=[O:28])(=[O:27])[CH2:25][CH2:26][N:21]5[CH:20]=[CH:19][CH:18]=4)=[CH:13][CH:12]=3)[CH:8]=[CH:9][C:4]=2[CH2:3][CH2:2]1>C1COCC1.CO.[Pt](=O)=O>[O:1]1[C:5]2[CH:6]=[C:7]([O:10][C:11]3[CH:16]=[CH:15][C:14]([CH:17]4[C:22]5=[N:23][S:24](=[O:27])(=[O:28])[CH2:25][CH2:26][N:21]5[CH2:20][CH2:19][CH2:18]4)=[CH:13][CH:12]=3)[CH:8]=[CH:9][C:4]=2[CH2:3][CH2:2]1
Reactant: O=S1(=O)CCN2C=CC=C(c3ccc(Oc4ccc5c(c4)OCC5)cc3)C2=N1
Agent: O=[Pt]=O
Solvent: C1CCOC1
Solvent: CO
Product: O=S1(=O)CCN2CCCC(c3ccc(Oc4ccc5c(c4)OCC5)cc3)C2=N1
Temperature: 25 °C
Reaction time: 3 h
Yield: 68.1 %

Procedure:
Platinum(IV) oxide (20 mg) was added to a solution of 9-[4-(2,3-dihydro-1-benzofuran-6-yloxy)phenyl]-3,4-dihydropyrido[2,1-c][1,2,4]thiadiazine 2,2-dioxide (100 mg) in THF (dry) (50 mL) and MeOH (50 mL). The mixture was stirred at room temperature under hydrogen for 3 hr. Activated carbon was added and the insoluble solid was removed by filtration through NH-silica gel/Celite pad (eluted with EtOAc). Platinum(IV) oxide (20 mg) was added and the mixture was stirred at room temperature under hydrogen overnight. Activated carbon was added and the insoluble solid was removed by filtration through NH-silica gel/Celite pad (eluted with EtOAc) and the filtrate was concentrated in vacuo. The residue was crystallized from THF/IPE to give the title compound (68.8 mg) as colorless crystals.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][N:7]([C:10]3[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=3[F:17])[C:6]=2[CH:18]=1.[F:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]2[C:30](B(O)O)=[CH:29][CH:28]=[N:27]2)=[CH:22][CH:21]=1>>[Cl:16][C:13]1[CH:14]=[CH:15][C:10]([N:7]2[C:6]3[CH:18]=[C:2]([C:30]4[N:26]([C:23]5[CH:24]=[CH:25][C:20]([F:19])=[CH:21][CH:22]=5)[N:27]=[CH:28][CH:29]=4)[CH:3]=[CH:4][C:5]=3[N:9]=[CH:8]2)=[C:11]([F:17])[CH:12]=1
Reactant: Fc1cc(Cl)ccc1-n1cnc2ccc(Br)cc21
Reactant: OB(O)c1ccnn1-c1ccc(F)cc1
Product: Fc1ccc(-n2nccc2-c2ccc3ncn(-c4ccc(Cl)cc4F)c3c2)cc1

Procedure:
The title compound, white solid (46 mg, 37%), MS (ISP) m/z=407.5 [(M+H)+], mp 153° C., was prepared in accordance with the general method of example 1 from 6-bromo-1-(4-chloro-2-fluoro-phenyl)-1H-benzo[d]imidazole (intermediate M) (100 mg, 307 μmol) and 1-(4-fluoro-phenyl)-1H-pyrazol-5-ylboronic acid (intermediate A) (76.0 mg, 369 μmol).
Reaction SMILES: O[C@H:2]([CH2:22][CH3:23])[C@@H:3]([NH:7][C:8]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:9])[C:4]([OH:6])=[O:5].O[C@@H](CC)[C@@H](NC(OCCCCCC1C=CC=CC=1)=O)C(O)=O.CCN(CC)CC.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(Cl)Cl>[C:16]1([CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][O:10][C:8](=[O:9])[NH:7][C@H:3]2[C:4](=[O:6])[O:5][C@@H:2]2[CH2:22][CH3:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC[C@@H](O)[C@@H](NC(=O)OCCCCCc1ccccc1)C(=O)O
Agent: CC[C@H](O)[C@@H](NC(=O)OCCCCCc1ccccc1)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC[C@H]1OC(=O)[C@@H]1NC(=O)OCCCCCc1ccccc1
Temperature: 0 °C
Reaction time: 15 h
Yield: 57 %

Procedure:
Under nitrogen atmosphere, to a stirred mixture of (2R*,3R*)-3-hydroxy-2-(5-phenylpentoxy-carbonylamino)-pentanoic acid and (2R*,3S*)-3-hydroxy-2-(5-phenylpentoxy-carbonylamino)-pentanoic acid (0.155 g, 0.48 mmol) in dry CH2Cl2, (20.0 mL), at 0° C., Et3N (0.2 mL, 1.44 mmol) and subsequently TBTU (0.185 g, 0.58 mmol) were added. The mixture was left stirring at 0° C. for 1 h and at rt for 15 h. The organics were then removed under reduced pressure, and the resulting crude product purified by column chromatography, using a Teledyne ISCO apparatus, eluting with Cy:AcOEt (from 100:0 to 80:20) to afford the title compound (0.075 g, 57%), as pure anti diastereoisomer, as white solid. MS (ESI) m/z: 323 [M−NH4]+; (ESI) m/z: 304 [M−H]−. 1H NMR (DMSO-d6) δ 0.90 (t, J=7.41 Hz, 3H), 1.26-1.38 (m, 2H), 1.58 (p, J=7.71, 8.27 Hz, 4H), 1.67-1.90 (m, 2H), 2.57 (t, J=7.65 Hz, 2H), 3.98 (t, J=6.60 Hz, 2H), 4.51 (td, J=4.28, 6.84 Hz, 1H), 4.69 (dd, J=4.32, 8.12 Hz, 1H), 7.09-7.32 (m, 5H), 8.06 (d, J=8.09 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([NH:13][NH2:14])=O)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[Si:15]([O:22][CH2:23][C:24]1([CH3:33])[S:30][CH2:29][CH2:28][N:27]=[C:26](SC)[CH2:25]1)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]>C(O)CCC>[Si:15]([O:22][CH2:23][C:24]1([CH3:33])[S:30][CH2:29][CH2:28][N:27]2[C:11]([C:8]3([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)[CH2:10][CH2:9]3)=[N:13][N:14]=[C:26]2[CH2:25]1)([C:18]([CH3:21])([CH3:19])[CH3:20])([CH3:16])[CH3:17]
Reactant: NNC(=O)C1(c2ccc(Cl)cc2)CC1
Reactant: CSC1=NCCSC(C)(CO[Si](C)(C)C(C)(C)C)C1
Solvent: CCCCO
Product: CC1(CO[Si](C)(C)C(C)(C)C)Cc2nnc(C3(c4ccc(Cl)cc4)CC3)n2CCS1
Temperature: 25 °C
Yield: 48.9 %

Procedure:
A solution of the compound (2.03 g, 10 mmol) obtained in Example 1-1) and 7-({[tert-butyl(dimethyl)silyl]oxy}methyl)-7-methyl-5-(methylthio)-2,3,6,7-tetrahydro-1,4-thiazepine (WO2008078725) (3.2 g, 10 mmol) in n-butanol (50 mL) was stirred at 140° C. for 7 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Isco Combiflash, 40 g, hexane:ethyl acetate=0:100 to 100:0, gradient) to obtain the title compound (2.27 g, 49%) as a light yellow oily substance.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:4].[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.C(N(CC)C(C)C)(C)C>C1(C)C=CC=CC=1>[C:6]1([NH:5][C:3](=[O:4])[CH2:2][N:21]2[CH2:22][CH2:23][N:18]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][N:12]=3)[CH2:19][CH2:20]2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(CCl)Nc1ccccc1
Reactant: c1ccc(N2CCNCC2)nc1
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: O=C(CN1CCN(c2ccccn2)CC1)Nc1ccccc1
Temperature: 25 °C
Yield: 45.8 %

Procedure:
N-Chloroacetylaniline (0.5 g, 2.95 mmol), 1-(2-pyridinyl)piperazine (0.72 g, 4.42 mmol), and N,N-diisopropylethylamine (1.03 mL, 5.9 mmol) were combined in toluene and heated at reflux overnight. The mixture was allowed to cool to room temperature, filtered, and the filtrate concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (elution with 60% ethyl acetate:hexanes) to provide 400 mg (46% yield) of the title compound as a hygroscopic white solid. 1H NMR (300 MHz, CDCl3) δ 2.60 (m, 4H), 3.18 (s, 2H), 3.55 (m, 4H), 6.65 (dd, 1H, J=12, 6 Hz), 6.85 (d, 1H, J=9 Hz), 7.05 (t, 1H, J=6 Hz), 7.3 (t, 2H, J=9 Hz), 7.51 (ddd, 1H, J=9, 7.5, 3 Hz) 7.68 (d, 2H, J=9 Hz) 8.1 (dd, 1H, J=6, 3 Hz) 9.75 (br s, 1H); MS (DCI/NH3) m/e 297 (M+H)+; Anal. calcd for C17H20N4O: C, 68.89; H, 6.80; N, 18.90. Found: C, 68.97; H, 6.87; N, 19.01.
Reaction SMILES: [F:1][C:2]1[C:3]([OH:16])=[C:4]([C:11]([O:13]CC)=O)[C:5](=[O:10])[N:6]([CH3:9])[C:7]=1[CH3:8].[NH2:17][C:18]1[N:19]=[N:20][C:21]([Cl:24])=[CH:22][CH:23]=1.BrC1C=CC=CC=1.C(Cl)(Cl)Cl>CO>[Cl:24][C:21]1[N:20]=[N:19][C:18]([NH:17][C:11]([C:4]2[C:5](=[O:10])[N:6]([CH3:9])[C:7]([CH3:8])=[C:2]([F:1])[C:3]=2[OH:16])=[O:13])=[CH:23][CH:22]=1
Reactant: Nc1ccc(Cl)nn1
Reactant: CCOC(=O)c1c(O)c(F)c(C)n(C)c1=O
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: Brc1ccccc1
Product: Cc1c(F)c(O)c(C(=O)Nc2ccc(Cl)nn2)c(=O)n1C
Temperature: 160 °C
Reaction time: 4 h
Yield: 66.4 %

Procedure:
600 mg of ethyl 5-fluoro-1,6-dimethyl-4-hydroxy-2-oxo-1,2-dihydropyridine-3-carboxylate and 194 mg of 3-amino-6-chloropyridazine were added to 5 ml of bromobenzene, and the mixture was stirred at 160° C. for 4 hours. The reaction mixture was cooled to room temperature, and subjected to silica gel chromatography (chloroform:methanol=20:1). The resulting crude product was washed with a mixture of t-butyl methyl ether and n-hexane, and dried to obtain 311 mg of N-(6-chloro-3-pyridazinyl)-5-fluoro-1,6-dimethyl-4-hydroxy-2-oxo-1,2-dihydropyridine-3-carboxamide (hereinafter, referred to as present compound 19) represented by the formula:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][C:4]=1[CH3:12].[CH3:13][CH2:14][CH:15]([NH2:18])[CH2:16][CH3:17]>>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH:18][CH:15]([CH2:16][CH3:17])[CH2:14][CH3:13])=[O:9])=[CH:5][C:4]=1[CH3:12]
Reactant: CCC(N)CC
Reactant: COc1ccc(C(=O)O)cc1C
Product: CCC(CC)NC(=O)c1ccc(OC)c(C)c1

Procedure:
Prepared in a similar manner as described in example 4 from 4-methoxy-3-methylbenzoic acid and pentan-3-amine. MS (M+H, 236)
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11]2([CH:17]([C:18]3[CH:23]=[CH:22][C:21]([CH:24]([CH3:26])[CH3:25])=[CH:20][CH:19]=3)[C:16]3[C:27]([CH3:34])=[C:28]([OH:33])[C:29]([CH3:32])=[C:30]([CH3:31])[C:15]=3[O:14]2)[CH2:10][CH2:9]1)C1C=CC=CC=1.C(N(CC)CC)C.C(Cl)(Cl)[Cl:43]>>[ClH:43].[CH:24]([C:21]1[CH:20]=[CH:19][C:18]([CH:17]2[C:11]3([CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[O:14][C:15]3[C:30]([CH3:31])=[C:29]([CH3:32])[C:28]([OH:33])=[C:27]([CH3:34])[C:16]2=3)=[CH:23][CH:22]=1)([CH3:26])[CH3:25]
Reactant: ClC(Cl)Cl
Reactant: Cc1c(C)c2c(c(C)c1O)C(c1ccc(C(C)C)cc1)C1(CCN(Cc3ccccc3)CC1)O2
Solvent: CCN(CC)CC
Product: Cc1c(C)c2c(c(C)c1O)C(c1ccc(C(C)C)cc1)C1(CCNCC1)O2
Product: Cl
Yield: 90.5 %

Procedure:
To a solution of 1′-benzyl-3-(4-isopropylphenyl)-4,6,7-trimethylspiro[benzofuran-2(3H),4′-piperidine]-5-ol (3.51 g, 7.70 mmol) and triethylamine (1.1 mL, 7.9 mmol) in chloroform (40 mL) α-chloroethyl chloroformate (2.30 g, 16.1 mmol) was added at 0° C. The mixture was refluxed for 1 hour and concentrated under reduced pressure. The residue was refluxed in methanol (20 mL) for 1 hour and concentrated under reduced pressure. The residue was crystallized from ethanol-ethyl acetate to obtain the title compound (2.80 g, yield 90%).
Reaction SMILES: [Cl-].[NH4+].C(O)C.O1CCCC1.[CH2:11]([O:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[N:44]([CH2:45][O:46][CH2:47][CH2:48][Si:49]([CH3:52])([CH3:51])[CH3:50])[C:28]3[N:29]=[CH:30][N:31]=[C:32]([O:33][C:34]4[CH:39]=[CH:38][C:37]([N+:40]([O-])=O)=[C:36]([F:43])[CH:35]=4)[C:27]=3[CH:26]=2)=[CH:21][CH:20]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>[Fe].O>[CH2:11]([O:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[N:44]([CH2:45][O:46][CH2:47][CH2:48][Si:49]([CH3:52])([CH3:51])[CH3:50])[C:28]3[N:29]=[CH:30][N:31]=[C:32]([O:33][C:34]4[CH:39]=[CH:38][C:37]([NH2:40])=[C:36]([F:43])[CH:35]=4)[C:27]=3[CH:26]=2)=[CH:21][CH:20]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: C[Si](C)(C)CCOCn1c(-c2ccc(OCc3ccccc3)cc2)cc2c(Oc3ccc([N+](=O)[O-])c(F)c3)ncnc21
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: C[Si](C)(C)CCOCn1c(-c2ccc(OCc3ccccc3)cc2)cc2c(Oc3ccc(N)c(F)c3)ncnc21
Temperature: 85 °C
Reaction time: 3 h
Yield: 59 %

Procedure:
After adding 400 mg of iron powder, 1 g of ammonium chloride, 20 ml of ethanol, 10 ml of tetrahydrofuran and 10 ml of water to 470 mg of 6-(4-benzyloxyphenyl)-4-(3-fluoro-4-nitrophenoxy)-7-(trimethylsilanylethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidine, the mixture was stirred at 85° C. for 3 hours. After returning it to room temperature, it was filtered with celite, and ethyl acetate and water were added to the filtrate for liquid separation and extraction. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered with plug cotton, concentrated and subjected to NH silica gel column chromatography (hexane-ethyl acetate) to obtain 263 mg of the title compound.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[NH:4][N:3]=1.Br[CH:13]([C:15]1[O:16][C:17](=[O:31])[C:18]2[C:23]([C:24]=1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH3:14].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[NH2:11][C:9]1[N:8]=[CH:7][N:6]=[C:5]2[N:4]([CH:13]([C:15]3[O:16][C:17](=[O:31])[C:18]4[C:23]([C:24]=3[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH3:14])[N:3]=[C:2]([I:1])[C:10]=12.[NH2:11][C:9]1[C:10]2[C:5](=[N:4][N:3]([CH:13]([C:15]3[O:16][C:17](=[O:31])[C:18]4[C:23]([C:24]=3[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH3:14])[C:2]=2[I:1])[N:6]=[CH:7][N:8]=1
Reactant: CC(Br)c1oc(=O)c2ccccc2c1-c1ccccc1
Reactant: Nc1ncnc2[nH]nc(I)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(c1oc(=O)c2ccccc2c1-c1ccccc1)n1nc(I)c2c(N)ncnc21
Product: CC(c1oc(=O)c2ccccc2c1-c1ccccc1)n1nc2ncnc(N)c2c1I
Temperature: 80 °C
Reaction time: 1 h
Yield: 10 %
Yield: 2.6 %

Procedure:
Commercially available 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (270 mg, 1.033 mmol) and 3-(1-bromoethyl)-4-phenyl-1H-isochromen-1-one (intermediate C7, 500 mg, 1.519 mmol) were dissolved in DMF (4 mL). K2CO3 (315 mg, 2.278 mmol) was added and the resulting mixture was stirred at 80° C. for 1 hr. The mixture was poured into water (50 ml) and extracted with AcOEt (10 ml×3). Organic phases were dried and evaporated under reduced pressure. The crude was purified via reverse phase chromatography with a Biotage C18 SNAP 60 g column (Phase A, water 95%, ACN 4.9%, formic acid 0.1%); Phase B ACN 95%, water 5%, formic acid 0.1%) to give 3-(1-(4-Amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-4-phenyl-1H-isochromen-1-one (intermediate D2a, 78 mg, 10%) and 3-(1-(4-amino-3-iodo-2H-pyrazolo[3,4-d]pyrimidin-2-yl)ethyl)-4-phenyl-1H-isochromen-1-one (intermediate D2b, 20 mg, 2.6%).