Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [P:1]([O-:19])([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].C(Cl)(=O)C(Cl)=O.[CH2:26]1[N:31]([CH2:32][CH2:33][CH2:34][CH2:35][O:36][C:37]2[CH:42]=[CH:41][C:40]3[CH:43]=[CH:44][C:45]([NH:47][C:39]=3[CH:38]=2)=O)[CH2:30][CH2:29][N:28]([C:48]2[CH:53]=[CH:52][CH:51]=[C:50]([Cl:54])[C:49]=2[Cl:55])[CH2:27]1.CC(C)([O-])C.[K+]>ClCCl.CN(C)C=O.CC1CCCO1>[P:1]([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([O:19][C:45]1[CH:44]=[CH:43][C:40]2[C:39](=[CH:38][C:37]([O:36][CH2:35][CH2:34][CH2:33][CH2:32][N:31]3[CH2:30][CH2:29][N:28]([C:48]4[CH:53]=[CH:52][CH:51]=[C:50]([Cl:54])[C:49]=4[Cl:55])[CH2:27][CH2:26]3)=[CH:42][CH:41]=2)[N:47]=1)=[O:2]
Reactant: O=P([O-])(OCc1ccccc1)OCc1ccccc1
Reactant: O=c1ccc2ccc(OCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)cc2[nH]1
Agent: CC(C)(C)[O-]
Agent: O=C(Cl)C(=O)Cl
Agent: [K+]
Solvent: CC1CCCO1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=P(OCc1ccccc1)(OCc1ccccc1)Oc1ccc2ccc(OCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)cc2n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of dibenzyl phosphate (2.48 g, 8.91 mmol) in dichloromethane (25 ml) was added dimethyl formamide (1 drop) followed by oxalyl chloride (0.75 mL, 8.91 mmol). After 2 hours the reaction mixture was concentrated in vacuo. The residue was dissolved in 2-methyltetrahydrofuran (5 mL) and added to a suspension of dehydro-aripiprazole (1.66 g, 3.71 mmol) and potassium t-butoxide (0.92 g, 8.17 mmol) in 2-methyltetrahydrofuran (35 mL) at 0° C. under Ar (g) then allowed to gradually warm to room temperature. After stirring overnight the reaction was quenched with water (25 mL) and 28% aq NH3 (15 mL) and stirred for 10 minutes. The reaction mixture was then extracted with ethyl acetate (2×40 mL). The combined organics were washed with water (50 mL) and brine (50 mL) then dried (MgSO4) and concentrated in vacuo. The crude mixture was purified by column chromatography eluting with 5% methanol (1:1 ethyl acetate/dichloromethane) to give the product. The 1H-NMR showed minor impurities still present (impurities not observed by LCMS). Various further purifications were attempted but failed to remove these impurities.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[F:13][C:14]1[CH:15]=[C:16]([C:48]2[C:49]([C:54]#[N:55])=[CH:50][CH:51]=[CH:52][CH:53]=2)[CH:17]=[CH:18][C:19]=1[CH2:20][C:21]1[C:22](=[O:47])[N:23]([C@H:33]2[CH2:38][CH2:37][C@H:36]([O:39][CH:40]([C:42]3([OH:46])[CH2:45][CH2:44][CH2:43]3)[CH3:41])[CH2:35][CH2:34]2)[C:24]2[N:25]([N:30]=[CH:31][N:32]=2)[C:26]=1[CH2:27][CH2:28][CH3:29]>O.C(OCC)(=O)C>[F:13][C:14]1[CH:15]=[C:16]([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][C:49]=2[C:54]2[NH:3][C:4](=[O:7])[O:5][N:55]=2)[CH:17]=[CH:18][C:19]=1[CH2:20][C:21]1[C:22](=[O:47])[N:23]([C@H:33]2[CH2:38][CH2:37][C@H:36]([O:39][CH:40]([C:42]3([OH:46])[CH2:43][CH2:44][CH2:45]3)[CH3:41])[CH2:35][CH2:34]2)[C:24]2[N:25]([N:30]=[CH:31][N:32]=2)[C:26]=1[CH2:27][CH2:28][CH3:29]
Reactant: [NH3+]O
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n([C@H]2CC[C@H](OC(C)C3(O)CCC3)CC2)c2ncnn12
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2F)c(=O)n([C@H]2CC[C@H](OC(C)C3(O)CCC3)CC2)c2ncnn12
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
A mixture of hydroxylammonium chloride (2.7 g), sodium hydrogen carbonate (4.3 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C. for 30 min, 3′-fluoro-4′-[(4-{trans-4-[1-(1-hydroxycyclobutyl)ethoxy]cyclohexyl}-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile (1.5 g) was added, and the mixture was stirred at 90° C. for 16 hr. Ethyl acetate and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (15 mL). N,N′-Carbonyldiimidazole (0.50 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.46 mL) were added, and the mixture was stirred at room temperature for 2 hr. Ethyl acetate and water were added to the reaction mixture, and the mixture was acidified with 1 M hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (1.3 g, 81%).
Reaction SMILES: [CH2:1]([N:4]([CH2:28][CH2:29][CH3:30])[CH2:5][CH2:6][CH2:7][CH2:8][N:9]([CH3:27])[S:10]([C:13]1[CH:18]=[CH:17][C:16]([CH2:19][NH:20][CH2:21][C:22]2[NH:23][CH:24]=[CH:25][N:26]=2)=[CH:15][CH:14]=1)(=[O:12])=[O:11])[CH2:2][CH3:3].[CH3:31][N:32]1[CH:36]=[CH:35][N:34]=[C:33]1[CH:37]=O.C([BH3-])#N.[Na+].C(O)(=O)C>CO>[CH2:28]([N:4]([CH2:1][CH2:2][CH3:3])[CH2:5][CH2:6][CH2:7][CH2:8][N:9]([CH3:27])[S:10]([C:13]1[CH:18]=[CH:17][C:16]([CH2:19][N:20]([CH2:21][C:22]2[NH:26][CH:25]=[CH:24][N:23]=2)[CH2:37][C:33]2[N:32]([CH3:31])[CH:36]=[CH:35][N:34]=2)=[CH:15][CH:14]=1)(=[O:11])=[O:12])[CH2:29][CH3:30]
Reactant: Cn1ccnc1C=O
Reactant: CCCN(CCC)CCCCN(C)S(=O)(=O)c1ccc(CNCc2ncc[nH]2)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCCN(CCC)CCCCN(C)S(=O)(=O)c1ccc(CN(Cc2ncc[nH]2)Cc2nccn2C)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
The compound (171.8 mg) obtained in Example 112-2 was dissolved in anhydrous methanol (7.0 ml). The solution was added with 1-methyl-2-imidazole carboxaldehyde (65.0 mg) and sodium cyanoborohydride (49.0 mg). Then, the solution was adjusted to pH 5 with acetic acid and then stirred at room temperature for 2 days. After the reaction, the solvent was distilled off. The residue was added with a 1 mol/l sodium hydroxide aqueous solution and extracted with chloroform. The extract was dried with magnesium sulfate, and the solvent was distilled off. Then, the residue was purified through silica gel column chromatography (chloroform/methanol) and treated with hydrochloric acid, thereby obtaining hydrochloride (184.8 mg) of the subject compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11](=[O:18])[NH:10][N:9]=2)=[CH:4][CH:3]=1.CC([O-])(C)C.[K+].C1(P(O[NH2:40])(C2C=CC=CC=2)=O)C=CC=CC=1.CN(C=O)C>C1COCC1.CCOC(C)=O>[NH2:40][N:10]1[N:9]=[C:8]([C:5]2[CH:6]=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]1=[O:18]
Reactant: O=c1[nH]nc(-c2ccc(Cl)nc2)c2ccccc12
Reactant: NOP(=O)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Nn1nc(-c2ccc(Cl)nc2)c2ccccc2c1=O
Reaction time: 1 h
Yield: 42.2 %

Procedure:
A mixture of the product from Example 4A (0.527 g, 2.04 mmol) and potassium 2-methylpropan-2-olate (0.299 g, 2.66 mmol) in THF (6 mL) was stirred for 1 h, and O-(diphenylphosphoryl)hydroxylamine (0.621 g, 2.66 mmol) and DMF (2 mL) were added, stirred at room temperature for 2 hours, diluted with EtOAc, washed with 1N NaOH and brine, dried (Na2SO4), filtered, and chromatographed (20-60% EtOAc/DCM) to give 235 mg of title compound as a white solid: 1H NMR (300 MHz, DMSO-d6) δ 8.67 (dd, J=2.4, 0.5, 1H), 8.38 (s, 1H), 8.14 (dd, J=8.2, 2.5, 1H), 8.02-7.82 (m, 2H), 7.81-7.65 (m, 2H), 6.54 (s, 2H).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([S:9][CH3:10])[S:5][C:6]=1[C:7]#[N:8].S(=O)(=O)(O)O.[OH2:16].[CH:17](O)=O>>[CH3:10][S:9][C:4]1[S:5][C:6]2[C:7](=[O:16])[NH:8][CH:17]=[N:1][C:2]=2[N:3]=1
Reactant: O
Reactant: CSc1nc(N)c(C#N)s1
Reactant: O=CO
Agent: O=S(=O)(O)O
Product: CSc1nc2nc[nH]c(=O)c2s1
Temperature: 95 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
To a solution of 4-amino-2-(methylthio)thiazole-5-carbonitrile (800 mg) in formic acid (8 mL) was added concentrated sulfuric acid (3.2 mL) dropwise for 15 min. The reaction mixture was stirred at 90-100° C. for 1 h and allowed to rt. The reaction mixture was poured into ice cooled water and stirred for 15 min. The precipitated solid was filtered, washed with water and dried to give the product as a white color solid (820 mg, 88%), mp 260-262° C. 1H NMR (400 MHz, DMSO-d6): δ 12.83 (1H, br s), 8.25 (1H, s), 2.80 (3H, s); LC-MS (negative ion mode): m/z 198 (M−H)−.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][CH2:15][CH2:14][CH2:13][CH:9]1[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OC([NH:23][CH:24]1[CH:28]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[O:27][C:26](=[O:37])[CH2:25]1)=O)C=C>>[C:1]([O:5][C:6]([N:8]1[CH2:16][CH2:15][CH2:14][CH2:13][CH:9]1[C:10]([NH:23][CH:24]1[CH:28]([O:29][CH2:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[O:27][C:26](=[O:37])[CH2:25]1)=[O:12])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCCCC1C(=O)O
Reactant: C=CCOC(=O)NC1CC(=O)OC1OCc1ccccc1
Product: CC(C)(C)OC(=O)N1CCCCC1C(=O)NC1CC(=O)OC1OCc1ccccc1
Yield: 85.9 %

Procedure:
Reaction of N-tert-butoxycarbonylpipecolic acid (460 mg, 2.0 mmol) and N-allyloxycarbonyl-4-amino-5-benzyloxy-2-oxotetrahydrofuran (530 mg, 1.82 mmol) was carried out by a method analogous to that reported by Chapman (Bioorg. & Med. Chem. Lett. 2, pp. 613-618, (1992)) to give 654 mg of the title compound.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[NH:10]([C:14]1[CH:19]=[CH:18][C:17](I)=[CH:16][CH:15]=1)[C:11]([CH3:13])=[O:12]>CC([O-])=O.CC([O-])=O.[Pd+2].C(N(CC)CC)C>[C:11]([NH:10][C:14]1[CH:19]=[CH:18][C:17]([C:2]2[CH2:3][C:4]3[C:9]([CH:1]=2)=[CH:8][CH:7]=[CH:6][CH:5]=3)=[CH:16][CH:15]=1)(=[O:12])[CH3:13]
Reactant: CC(=O)Nc1ccc(I)cc1
Reactant: C1=Cc2ccccc2C1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ccc(C2=Cc3ccccc3C2)cc1

Procedure:
20 ml of triethylamine, 2.2 g (20 mmol) of indene, 5.22 , (20 mmol) of para-acetamino-iodo-benzene and 0.134 g (0.6 mmol) of Pd(OAc)2 were stirred under reflux for 10 h. After that all triethylamine was removed under reduced pressure. The residue was treated with the mixture 50 ml of dichloromethane and 50 ml of water. Organic layer was separated, washed twice with water, filtered and dried over Na2SO4. Dichloromethane was removed and the residue was recrystallized from 20 ml of EtOH. The yield of product was 13%.
Reaction SMILES: [O:1]=[O+][O-].[F:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][C@H:12]([CH3:15])[CH2:13][CH3:14])=[CH:7][C:6]=1[CH:16]=C.[BH4-].[Na+]>ClCCl.CO>[F:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][C@H:12]([CH3:15])[CH2:13][CH3:14])=[CH:7][C:6]=1[CH2:16][OH:1]
Reactant: C=Cc1cc(O[C@H](C)CC)ccc1F
Reactant: O=[O+][O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CC[C@@H](C)Oc1ccc(F)c(CO)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Ozone was bubbled through a −78° C. solution of 1-fluoro-4-{[(1R)-1-methylpropyl]oxy}-2-vinylbenzene (0.81 g, 4.17 mmol) in dichloromethane (27.8 ml) and MeOH (13.90 ml) until the reaction color remained blue. The reaction stirred 10 min, and then was purged with N2 for 10 min. MeOH (25 mL) was added, followed by sodium borohydride (0.237 g, 6.25 mmol). The reaction warmed to rt. After 1 h, the reaction mixture was concentrated in vacuo. The residue was purified by column chromatography on a silica gel cartridge (12% EtOAc/hexanes) to give the desired product.
Reaction SMILES: [OH:1][C@H:2]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C@H:3]1[CH2:7][CH2:6][C@@H:5]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([N:17]3[CH:23]4[CH2:24][CH2:25][CH:18]3[CH:19]3[N:26]([CH2:27][C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=5)[CH:22]4[CH2:21][CH2:20]3)=[O:16])=[CH:11][CH:10]=2)[N:4]1C(OC(C)(C)C)=O.O>Cl.O1CCOCC1>[C:41]1([C@H:2]([C@H:3]2[CH2:7][CH2:6][C@@H:5]([CH2:8][C:9]3[CH:14]=[CH:13][C:12]([C:15]([N:17]4[CH:18]5[CH2:25][CH2:24][CH:23]4[CH:22]4[N:26]([CH2:27][C:28]6[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=6)[CH:19]5[CH2:20][CH2:21]4)=[O:16])=[CH:11][CH:10]=3)[NH:4]2)[OH:1])[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: CC(C)(C)OC(=O)N1[C@H](Cc2ccc(C(=O)N3C4CCC3C3CCC4N3Cc3ccccn3)cc2)CC[C@@H]1[C@H](O)c1ccccc1
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: O=C(c1ccc(C[C@@H]2CC[C@H]([C@H](O)c3ccccc3)N2)cc1)N1C2CCC1C1CCC2N1Cc1ccccn1

Procedure:
The title compound from Step C above (30 mg, 0.06 mmol was dissolved in 4 M HCl in dioxane plus 10% water (v/v) (2 mL) and stirred at RT for 2 h. The mixture was concentrated under reduced pressure and dried under high vacuum to give the title compound. ESI-MS calculated for both is C33H36N4O2: Exact Mass: 522.32. Found 523.30.
Reaction SMILES: C1(N(C2CCCCC2)C(=O)NC2SC(S(NC[C:20](O)=[O:21])(=O)=O)=CN=2)CCCCC1.[CH:30]1([NH:36][C@H:37]2[CH2:42][CH2:41][C@H:40]([O:43][CH2:44][CH2:45][CH3:46])[CH2:39][CH2:38]2)[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1.C1(N([C@H]2CC[C@H](OC)CC2)C(=O)NC2SC(SCC(O)=O)=CN=2)CCCC1.O[C@H]1CC[C@H](C2C=CC=C3C=2C(=O)NC3=O)CC1.BrCCC.C1(=O)CCCCC1.C[O:104][C:105](=[O:119])[C:106]([NH:109][S:110]([C:113]1[S:117][C:116]([NH2:118])=[N:115][CH:114]=1)(=[O:112])=[O:111])([CH3:108])[CH3:107]>>[CH:30]1([N:36]([C@H:37]2[CH2:42][CH2:41][C@H:40]([O:43][CH2:44][CH2:45][CH3:46])[CH2:39][CH2:38]2)[C:20](=[O:21])[NH:118][C:116]2[S:117][C:113]([S:110]([NH:109][C:106]([CH3:108])([CH3:107])[C:105]([OH:104])=[O:119])(=[O:112])=[O:111])=[CH:114][N:115]=2)[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]1
Reactant: COC(=O)C(C)(C)NS(=O)(=O)c1cnc(N)s1
Reactant: CCCO[C@H]1CC[C@H](NC2CCCCC2)CC1
Reactant: O=C(O)CNS(=O)(=O)c1cnc(NC(=O)N(C2CCCCC2)C2CCCCC2)s1
Agent: CO[C@H]1CC[C@H](N(C(=O)Nc2ncc(SCC(=O)O)s2)C2CCCC2)CC1
Agent: O=C1NC(=O)c2c1cccc2[C@H]1CC[C@H](O)CC1
Solvent: CCCBr
Solvent: O=C1CCCCC1
Product: CCCO[C@H]1CC[C@H](N(C(=O)Nc2ncc(S(=O)(=O)NC(C)(C)C(=O)O)s2)C2CCCCC2)CC1

Procedure:
Prepared in a similar manner to [2-(3,3-dicyclohexyl-ureido)-thiazole-5-sulfonylamino]-acetic acid via cyclohexyl-(trans-4-propoxy-cyclohexyl)-amine (prepared according to the procedure described for the synthesis of {2-[3-cyclopentyl-3-(trans-4-methoxy-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid (Step 1) using (trans-4-hydroxy-cyclohexyl)-isoindole-1,3-dione, 1-bromopropane and cyclohexanone) and 2-(2-amino-thiazole-5-sulfonylamino)-2-methyl-propionic acid methyl ester to give the title compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH:10]([C:14]3[NH:18][C:17]4[CH2:19][CH2:20][CH2:21][CH2:22][C:16]=4[N:15]=3)[CH2:9]2)[N:5]=[C:4]([NH2:23])[N:3]=1.[F:24][C:25]1[CH:32]=[C:31](B2OC(C)(C)C(C)(C)O2)[CH:30]=[CH:29][C:26]=1[C:27]#[N:28].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:23][C:4]1[N:3]=[C:2]([C:31]2[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[C:25]([F:24])[CH:32]=2)[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH:10]([C:14]3[NH:18][C:17]4[CH2:19][CH2:20][CH2:21][CH2:22][C:16]=4[N:15]=3)[CH2:9]2)[N:5]=1
Reactant: CC1(C)OB(c2ccc(C#N)c(F)c2)OC1(C)C
Reactant: Nc1nc(Cl)cc(N2CCOC(c3nc4c([nH]3)CCCC4)C2)n1
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: C1COCCO1
Solvent: O
Product: N#Cc1ccc(-c2cc(N3CCOC(c4nc5c([nH]4)CCCC5)C3)nc(N)n2)cc1F
Temperature: 140 °C
Reaction time: 1 h
Yield: 57.4 %

Procedure:
A mixture of 4-chloro-6-[2-(4,5,6,7-tetrahydro-1H-benzimidazol-2-yl)-4-morpholinyl]-2-pyrimidinamine (208 mg, 0.623 mmol), 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (200 mg, 0.809 mmol), Na2CO3 (165 mg, 1.557 mmol) and Pd(PPh3)4 (72 mg, 0.062 mmol) in 1,4-dioxane (6 mL) and water (2 mL) was heated at 140° C. under microwave condition with stirring for 1 hour. The mixture was filtered, washed by EtOAc (150 mL), evaporated, and chromatographed (PE-EtOAc, 3:1) to afford the title compound (150 mg) as a yellow solid. LC-MS (ES) m/z=420 [M+H]+.
Reaction SMILES: N[C:2]1[NH:3][C:4](=[O:18])[C:5]2[N:6]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:7]=[N:8][C:9]=2[N:10]=1.C(=O)([O-])[O-:20].[K+].[K+].[CH3:25][Si:26]([CH3:33])([CH3:32])[CH2:27][CH2:28][O:29][CH2:30]Cl>CN(C=O)C.O>[CH2:11]([N:6]1[C:5]2[C:4](=[O:18])[NH:3][C:2](=[O:20])[N:10]([CH2:30][O:29][CH2:28][CH2:27][Si:26]([CH3:33])([CH3:32])[CH3:25])[C:9]=2[N:8]=[CH:7]1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C([O-])[O-]
Reactant: C[Si](C)(C)CCOCCl
Reactant: Nc1nc2ncn(Cc3ccccc3)c2c(=O)[nH]1
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1c(=O)[nH]c(=O)c2c1ncn2Cc1ccccc1
Temperature: 60 °C
Reaction time: 16 h
Yield: 107.9 %

Procedure:
To a solution of 2-amino-7-benzyl-1H-purin-6(7H)-one (6.5 g, 26.86 mmol) in DMF (50 mL) was added potassium carbonate (5.6 g, 40.58 mmol), followed by 2-(trimethylsilyl)ethoxymethyl chloride (4.45 g, 27.08 mmol) at 0° C. The resulting mixture was stirred at 60° C. for 16 h. The mixture was diluted with water and filtered. The filter cake was washed with water twice, dried in vacuo to give 7-benzyl-3-((2-(trimethylsilyl)ethoxy)methyl)-1H-purine-2,6(3H,7H)-dione (10.8 g, 100% yield) as yellow oil. LCMS retention time 1.523 min; LCMS MH+-58 315.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:15]3[CH:16]=[N:17][CH:18]=[C:14]3[CH:13]=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)([OH:3])=O.C(Cl)(=O)C(Cl)=O.[C:25]([NH2:29])([CH3:28])([CH3:27])[CH3:26].C(=O)(O)[O-].[Na+]>C(Cl)Cl.CN(C)C=O>[C:25]([NH:29][C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:15]3[CH:16]=[N:17][CH:18]=[C:14]3[CH:13]=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)=[O:3])([CH3:28])([CH3:27])[CH3:26]
Reactant: O=C(O)c1ccc(-c2cccc3cncn23)cc1
Reactant: CC(C)(C)N
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)NC(=O)c1ccc(-c2cccc3cncn23)cc1
Reaction time: 1.5 h

Procedure:
To a slurry of 0.4 g of 5-(p-carboxyphenyl)imidazo[1,5-a]pyridine in 40 ml of methylene chloride under nitrogen at room temperature, is added 30 μl of N,N-dimethylformamide followed by 0.16 ml of oxalyl chloride. The reaction mixture is stirred until gas evolution is complete and 0.46 ml of tert-butylamine is added dropwise. Stirring is discontinued after 90 min and 10 ml of saturated sodium bicarbonate solution is added. The organic layer is separated, dried over sodium sulfate and evaporated to yield the title compound, m.p. 128°-131°.
Reaction SMILES: Cl.[C:2]([O:6][C:7](=[O:11])[C@H:8]([CH3:10])[NH2:9])([CH3:5])([CH3:4])[CH3:3].Cl[C:13]1C=CC(S(Cl)(=O)=O)=CC=1.[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[C:26]([N+:34]([O-:36])=[O:35])[CH:25]=1>>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([S:30]([NH:9][C@H:8]([CH2:10][CH3:13])[C:7]([O:6][C:2]([CH3:5])([CH3:4])[CH3:3])=[O:11])(=[O:32])=[O:31])=[C:26]([N+:34]([O-:36])=[O:35])[CH:25]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: O=[N+]([O-])c1cc(Cl)ccc1S(=O)(=O)Cl
Reactant: C[C@H](N)C(=O)OC(C)(C)C
Agent: Cl
Product: CC[C@@H](NS(=O)(=O)c1ccc(Cl)cc1[N+](=O)[O-])C(=O)OC(C)(C)C

Procedure:
Instead of the starting material compound of Reference Example 166, that is, L-alanine tert-butyl ester hydrochloride, D-2-amino-n-butyric acid tert-butyl ester hydrochloride was used, further, instead of 4-chlorobenzenesulfonyl chloride, 4-chloro-2-nitrobenzenesulfonyl chloride was used for the similar procedure as with Reference Example 167 to obtain the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([CH3:21])[O:20][CH2:19][CH2:18][O:17]3)=[CH:12][CH:11]=2)[CH:5]=[C:6](Br)[CH:7]=1.[CH2:22]([O:24][C:25]([N:27]1[CH2:31][CH2:30][C:29](=[O:32])[CH2:28]1)=[O:26])[CH3:23]>>[CH2:22]([O:24][C:25]([N:27]1[CH2:31][CH2:30][C:29]([C:6]2[CH:7]=[C:2]([F:1])[CH:3]=[C:4]([S:9][C:10]3[CH:15]=[CH:14][C:13]([C:16]4([CH3:21])[O:20][CH2:19][CH2:18][O:17]4)=[CH:12][CH:11]=3)[CH:5]=2)([OH:32])[CH2:28]1)=[O:26])[CH3:23]
Reactant: CC1(c2ccc(Sc3cc(F)cc(Br)c3)cc2)OCCO1
Reactant: CCOC(=O)N1CCC(=O)C1
Product: CCOC(=O)N1CCC(O)(c2cc(F)cc(Sc3ccc(C4(C)OCCO4)cc3)c2)C1
Yield: 50 %

Procedure:
Using an analogous procedure to that described in the fourth paragraph of the portion of Example 28 which is concerned with the preparation of starting materials, 5-fluoro-3-[4-(2-methyl-1,3-dioxolan-2-yl)phenylthio]bromobenzene was reacted with 1-ethoxycarbonylpyrrolidin-3-one to give 1-ethoxycarbonyl-3-{5-fluoro-3-[4-(2-methyl1,3-dioxolan-2-yl)phenylthio]phenyl}-3-hydroxypyrrolidine as a gum in 50% yield.
Reaction SMILES: [CH3:1][CH:2]([C:4](=O)[CH2:5][CH:6]([CH3:8])[CH3:7])[CH3:3].[C:10](O)(=O)C.[CH:14]([NH2:16])=[NH:15]>C(O)CCC>[CH:2]([C:4]1[C:5]([CH:6]([CH3:8])[CH3:7])=[CH:10][N:16]=[CH:14][N:15]=1)([CH3:3])[CH3:1]
Reactant: CC(C)CC(=O)C(C)C
Reactant: CC(=O)O
Reactant: N=CN
Solvent: CCCCO
Product: CC(C)c1cncnc1C(C)C
Temperature: 130 °C
Reaction time: 24 h
Yield: 38.1 %

Procedure:
A 100 mL reaction flask is charged with 2,5-dimethyl-hexan-3-one (10 g, 0.08 mol), formamidine acetate (40 g, 0.4 mol), and butanol (50 mL). The reaction mixture is heated to 130° C. and stirred for 24 hours. The crude mass is washed once with aqueous sulfuric acid (10%, 100 mL) followed by twice with brine (30 mL). Butanol is recovered by roto-evaporation. The crude product is further purified with liquid chromatography (Biotage® system) and then crystallized. Product 4,5-diisopropyl-pyrimidine (˜5 g) is obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[C:18]([Cl:20])[C:5]([O:6][C:7]2[CH:8]=[C:9]([CH:15]([CH3:17])[CH3:16])[C:10](=[O:14])[N:11]([CH3:13])[N:12]=2)=[C:4]([Cl:21])[CH:3]=1.[N:22]([O-])=O.[Na+].[C:26]([CH2:28][C:29]([NH:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])=[O:30])#[N:27].C([O-])(=O)C.[Na+]>C(O)(=O)C.Cl.O>[CH2:35]([O:34][C:32](=[O:33])[NH:31][C:29](=[O:30])[C:28]([C:26]#[N:27])=[N:22][NH:1][C:2]1[CH:19]=[C:18]([Cl:20])[C:5]([O:6][C:7]2[CH:8]=[C:9]([CH:15]([CH3:16])[CH3:17])[C:10](=[O:14])[N:11]([CH3:13])[N:12]=2)=[C:4]([Cl:21])[CH:3]=1)[CH3:36]
Reactant: CCOC(=O)NC(=O)CC#N
Reactant: CC(C)c1cc(Oc2c(Cl)cc(N)cc2Cl)nn(C)c1=O
Reactant: O=N[O-]
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)NC(=O)C(C#N)=NNc1cc(Cl)c(Oc2cc(C(C)C)c(=O)n(C)n2)c(Cl)c1
Temperature: 7.5 °C
Reaction time: 0.5 h
Yield: 99.7 %

Procedure:
A mixture of 6-(4-amino-2,6-dichloro-phenoxy)-4-isopropyl-2-methyl-2H-pyridazin-3-one (67) (10 g, 30.47 mmol) in glacial acetic acid (60 mL) and concentrated hydrochloric acid (9.06 mL) cooled to 5-10° C. was treated dropwise with a solution of sodium nitrite (2.3 g, 32.3 mmol) in water (6 mL). The reaction was stirred at 5-10° C. for 30 min. At this time, the reaction was treated with N-cyanoacetylurethane (5.34 g, 33.52 mmol) followed by a solution of sodium acetate (7.5 g, 91.41 mmol) in water (22.5 mL). The reaction was stirred at 5-10° C. for 30 min and then was diluted with water (50 mL). The resulting solids were collected by filtration, washed with a 1:1 mixture of glacial acetic acid:water (40 mL) followed by water (2×60 mL), dried under house vacuum, and then dried under vacuum at 50° C. to afford (2-cyano-2-{[3,5-dichloro-4-(5-isopropyl-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yloxy)-phenyl]-hydrazono}-acetyl)-carbamic acid ethyl ester (68) (15.04 g, 95%) as an orange solid; ES(+)-LRMS for C20H20Cl2N6O5 (M+H)+ at m/z=495. Exact Mass=494.0872; Molecular Weight=495.33.