Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].C(=O)([O-])[O-].[K+].[K+].[C:21](#[N:24])[CH2:22][OH:23].O>C(#N)C>[N+:12]([C:3]1[CH:4]=[C:5]([N+:9]([O-:11])=[O:10])[C:6]([F:8])=[CH:7][C:2]=1[O:23][CH2:22][C:21]#[N:24])([O-:14])=[O:13]
Reactant: N#CCO
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])c(F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: N#CCOc1cc(F)c([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.1 %

Procedure:
To a suspension of 1,5-difluoro-2,4-dinitrobenzene (3.8 g) and anhydrous potassium carbonate (3.1 g) in acetonitrile (50 ml) kept at room temperature, a solution of glycolonitrile (1.5 g) in acetonitrile (10 ml) was dropwise added, followed by stirring at room temperature for 1 hour. The reaction mixture was heated and allowed to reflux for 30 minutes (inner temperature, 83° C.). After cooling, the resultant mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water and concentrated to give crystalline 2,4-dinitro-5-fluorophenoxyacetonitrile (4.0 g; yield, 89.1%).
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@H:6]([C:10]([OH:12])=O)[CH:7]([CH3:9])[CH3:8])=[O:4].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[S:27]1[CH:31]=[CH:30][N:29]=[C:28]1[C:32]1[CH:37]=[CH:36][C:35]([CH2:38][N:39]([NH:52][C:53]([O:55][C:56]([CH3:59])([CH3:58])[CH3:57])=[O:54])[CH2:40][C@H:41]([OH:51])[C@@H:42]([NH2:50])[CH2:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)=[CH:34][CH:33]=1>CN(C=O)C>[S:27]1[CH:31]=[CH:30][N:29]=[C:28]1[C:32]1[CH:37]=[CH:36][C:35]([CH2:38][N:39]([NH:52][C:53]([O:55][C:56]([CH3:59])([CH3:58])[CH3:57])=[O:54])[CH2:40][C@H:41]([OH:51])[C@@H:42]([NH:50][C:10](=[O:12])[C@H:6]([CH:7]([CH3:8])[CH3:9])[NH:5][C:3]([O:2][CH3:1])=[O:4])[CH2:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)=[CH:34][CH:33]=1
Reactant: COC(=O)N[C@H](C(=O)O)C(C)C
Reactant: CC(C)(C)OC(=O)NN(Cc1ccc(-c2nccs2)cc1)C[C@H](O)[C@@H](N)Cc1ccccc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)CN(Cc1ccc(-c2nccs2)cc1)NC(=O)OC(C)(C)C)C(C)C
Reaction time: 0.75 h

Procedure:
Under a nitrogen atmosphere, 1.4 g (8.0 mmol) of N-methoxycarbonyl-(L)-valine, 2.87 g (15 mmol) of EDC and 1.35 g (10 mmol) of HOBT are dissolved in 22 ml of DMF. After 45 min, 4.2 ml (30 mmol) of TEA are added and then a solution of 2.34 g (5.0 mmol) of 1-[4-(thiazol-2-yl)-phenyl]-4(S)-hydroxy-2-(tert-butoxycarbonyl)amino-5(S)-amino-6-phenyl-2-azahexane in 45 ml of DMF is added dropwise. After 1.5 hours, the reaction mixture is concentrated by evaporation; the residue is taken up in methylene chloride and washed with water, sat. NaHCO3 solution, water and brine. The aqueous phases are extracted 2× with methylene chloride; the combined organic phases are dried (Na2 SO4) and concentrated by evaporation. Column chromatography (SiO2 ; methylene chloride/ethyl acetate 2:1) and crystallisation from ethyl acetate/ether yield the title compound: m.p: 178°-179° C.; HPLC20-100 : tRet =15.8.
Reaction SMILES: [C:1]([O:9][C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([O:17][C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N(C(C)(C)C#N)=NC(C)(C)C#N.[Br:38]N1C(=O)CCC1=O>>[C:18]([O:17][C:12]1[CH:13]=[C:14]([CH2:16][Br:38])[CH:15]=[C:10]([O:9][C:1](=[O:8])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:11]=1)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Cc1cc(OC(=O)c2ccccc2)cc(OC(=O)c2ccccc2)c1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Product: O=C(Oc1cc(CBr)cc(OC(=O)c2ccccc2)c1)c1ccccc1

Procedure:
The synthesis of this compound proceeded in the same fashion as in Example 11 using 24.93 g (0.075 mol) of 5-methyl-benzene-1,3-diol dibenzoate, a catalytic amount of 2,2'-azobisisobutyronitrile and 13.35 g (0.075 mol) of N-bromosuccinimide. Recrystallization of the crude material from ethyl acetate gave a product (m.p. 123°-126° C.) which was used directly in the next step.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][NH:8]2)=[CH:4][CH:3]=1.[CH:15](=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C([BH3-])#N.[Na+].C(=O)(O)[O-].[Na+]>C(O)(=O)C.CO>[CH2:15]([N:8]1[CH2:9][CH2:10][CH2:11][CH2:12][CH:7]1[CH2:6][C:5]1[CH:13]=[CH:14][C:2]([Br:1])=[CH:3][CH:4]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=Cc1ccccc1
Reactant: Brc1ccc(CC2CCCCN2)cc1
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: Brc1ccc(CC2CCCCN2Cc2ccccc2)cc1
Temperature: 25 °C
Yield: 51.7 %

Procedure:
To a 100 mL round-bottomed flask equipped with N2 inlet were added 250 mg (0.984 mmol) 2-(4-bromobenzyl)-piperidine (prepared as described in Tetrahedron Letters, 7, 631 (1977)), 110 uL (1.08 mmol) benzaldehyde, 7 mL methanol, 74 mg (1.18 mmol) sodium cyanoborohydride, and a few drops of acetic acid. The reaction was stirred at room temperature, followed by additional benzaldehyde, sodium cyanoborohydride, and acetic acid, for a total of 16 hours then poured into dilute aqueous sodium bicarbonate solution, and extracted into ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and evaporated. The residue was chromatographed on silica gel using methanol/methylene chloride as eluant, and the product further purified by conversion to the hydrochloride salt in ether followed by basification using aqueous sodium hydroxide solution to afford 175 mg (52%) of an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[N:10]=[CH:9][N:8]([CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][O:13]3)[C:7]=2[CH:6]=[CH:5][C:4]=1[CH:18]=CC1C=CC=CC=1.I([O-])(=O)(=O)=[O:27].[Na+]>O1CCOCC1.O.[Os](=O)(=O)(=O)=O>[CH3:1][O:2][C:3]1[C:11]2[N:10]=[CH:9][N:8]([CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][O:13]3)[C:7]=2[CH:6]=[CH:5][C:4]=1[CH:18]=[O:27]
Reactant: COc1c(C=Cc2ccccc2)ccc2c1ncn2C1CCCCO1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COc1c(C=O)ccc2c1ncn2C1CCCCO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.9 %

Procedure:
A 1 L three-necked round bottom flask fitted with an overhead stirrer was dried and cooled under a stream of nitrogen then charged with 4-methoxy-5-styryl-1-(tetrahydro-pyran-2-yl)-1H-benzoimidazole (25 g, 0.074 mol, 1.0 equiv.) in dioxane (250 mL) and water (80 mL). To this solution was added sodium periodate (36.77 g, 0.17 mol, 2.3 equiv.) and osmium tetroxide (15 mL, 4% aq. soln.) at 0° C., and the reaction mixture was stirred at RT overnight. The reaction mixture was quenched with ice cold water (1 L) and extracted with EtOAc (2×750 mL). The organic layers were combined, washed with brine (500 mL), dried (Na2SO4), filtered and concentrated in vacuo. The crude material was purified by SiO2 chromatography eluting with an EtOAc/hexane gradient (40-50% EtOAc) to afford 4-methoxy-1-(tetrahydro-pyran-2-yl)-1H-benzoimidazole-5-carbaldehyde (15 g, 77%) as a pale yellow solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:20]=[CH:19][C:18]3[CH2:17][N:16]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:15][CH2:14][C:13]=3[N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:28]([O:31][CH2:32][C:33]1[C:38](B2OC(C)(C)C(C)(C)O2)=[CH:37][CH:36]=[CH:35][C:34]=1[N:48]1[CH2:60][CH2:59][N:51]2[C:52]3[CH2:53][CH2:54][CH2:55][CH2:56][C:57]=3[CH:58]=[C:50]2[C:49]1=[O:61])(=[O:30])[CH3:29].C([O-])([O-])=O.[Na+].[Na+].COCCOC>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(Cl)Cl>[C:28]([O:31][CH2:32][C:33]1[C:34]([N:48]2[CH2:60][CH2:59][N:51]3[C:52]4[CH2:53][CH2:54][CH2:55][CH2:56][C:57]=4[CH:58]=[C:50]3[C:49]2=[O:61])=[CH:35][CH:36]=[CH:37][C:38]=1[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:20]=[CH:19][C:18]3[CH2:17][N:16]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:15][CH2:14][C:13]=3[N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1)(=[O:30])[CH3:29]
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cccc1N1CCn2c(cc3c2CCCC3)C1=O
Reactant: Cn1cc(Br)cc(Nc2ccc3c(n2)CCN(C(=O)OC(C)(C)C)C3)c1=O
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: ClCCl
Solvent: COCCOC
Product: CC(=O)OCc1c(-c2cc(Nc3ccc4c(n3)CCN(C(=O)OC(C)(C)C)C4)c(=O)n(C)c2)cccc1N1CCn2c(cc3c2CCCC3)C1=O

Procedure:
To a microwave tube equipped with a stirring bar, tert-butyl 2-(5-bromo-1-methyl-2-oxo-1,2-dihydropyridin-3-ylamino)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate 158c (300 mg, mmol), 2-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl acetate 114a (352 mg, 0.758 mmol), Pd(PPh3)4 (39.8 mg, 0.035 mmol), Na2CO3 aqueous solution (1.0 N, 2.27 mL, 2.27 mmol), and 1,2-dimethoxyethane (3.5 mL) were added. The mixture was reacted in microwave at 130° C. for 10 min. methylene chloride (200 mL) was added and the resulting mixture was washed with water (30 mL×3), brine (30 mL×1), dried over MgSO4, filtered, and removed solvent in vacuo. Silica gel column chromatography (methanol:methylene chloride=5:95) gave 166a.
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[NH:7][C:8]1[O:9][CH2:10][C@@:11]2([C:21]3[C:16](=[CH:17][CH:18]=[C:19]([NH2:22])[CH:20]=3)[O:15][C:14]([CH3:24])([CH3:23])[C:13]32[CH2:26][CH2:25]3)[N:12]=1)([CH3:4])([CH3:3])[CH3:2].[F:28][CH:29]([F:39])[C:30]1[N:31]=[CH:32][C:33]([C:36](O)=[O:37])=[N:34][CH:35]=1.N1(O)C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>C(Cl)(Cl)Cl>[C:1]([O:5][C:6](=[O:27])[NH:7][C:8]1[O:9][CH2:10][C@@:11]2([C:21]3[C:16](=[CH:17][CH:18]=[C:19]([NH:22][C:36]([C:33]4[CH:32]=[N:31][C:30]([CH:29]([F:39])[F:28])=[CH:35][N:34]=4)=[O:37])[CH:20]=3)[O:15][C:14]([CH3:24])([CH3:23])[C:13]32[CH2:25][CH2:26]3)[N:12]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1=N[C@@]2(CO1)c1cc(N)ccc1OC(C)(C)C21CC1
Reactant: O=C(O)c1cnc(C(F)F)cn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)NC1=N[C@@]2(CO1)c1cc(NC(=O)c3cnc(C(F)F)cn3)ccc1OC(C)(C)C21CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.3 %

Procedure:
To an ice-water cooled mixture of tert-butyl[(4′R)-6′-amino-2′,2′-dimethyldispiro[cyclopropane-1,3′-chromene-4′,4″-[1,3]oxazol]-2″-yl]carbamate (430 mg, 1.15 mmol), 5-(difluoromethyl)pyrazine-2-carboxylic acid (221 mg, 1.27 mmol) and 1H-benzotriazol-1-ol (170 mg, 1.26 mmol) in chloroform (8.6 ml) was added N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (244 mg, 1.28 mmol). The mixture was stirred at room temperature overnight and directly purified by silica gel column chromatography (precolumn: basic silica gel, main column: neutral silica gel, hexane/ethyl acetate=2:1-1:1-0:100) to afford tert-butyl[(4′R)-6′-({[5-(difluoromethyl)pyrazin-2-yl]carbonyl}amino)-2′,2′-dimethyldispiro[cyclopropane-1,3′-chromene-4′,4″-[1,3]oxazol]-2″-yl]carbamate (373 mg).
Reaction SMILES: FC1C=CC=CC=1C1C2C=C(N[C:20](NCCO)=[O:21])C=CC=2N2C=NN=C2CN=1.[NH2:29][C:30]1[CH:31]=[CH:32][C:33]2[N:39]3[C:40]([CH3:43])=[N:41][N:42]=[C:38]3[CH2:37][N:36]=[C:35]([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=3[Cl:50])[C:34]=2[CH:51]=1>C(Cl)Cl>[Cl:50][C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=1[C:35]1[C:34]2[CH:51]=[C:30]([N:29]=[C:20]=[O:21])[CH:31]=[CH:32][C:33]=2[N:39]2[C:40]([CH3:43])=[N:41][N:42]=[C:38]2[CH2:37][N:36]=1
Reactant: Cc1nnc2n1-c1ccc(N)cc1C(c1ccccc1Cl)=NC2
Reactant: O=C(NCCO)Nc1ccc2c(c1)C(c1ccccc1F)=NCc1nncn1-2
Solvent: ClCCl
Product: Cc1nnc2n1-c1ccc(N=C=O)cc1C(c1ccccc1Cl)=NC2

Procedure:
A solution of [6-(o-chlorophenyl)-1-methyl-4H-s-triazolo[4,3-a][1,4]benzodiazepin-8-yl]isocyanate is prepared as described in paragraph (a) of Example 1 from 7.0 g (21.6 mmol) of 8-amino-6-(o-chlorophenyl)-1-methyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine, but using methylene chloride in place of 1,2-dichloroethane.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[C:4]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[N:5][CH:6]=[CH:7][CH:8]=1.[CH:17]1([CH2:23][C:24](O)=[O:25])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C)C=O>[CH:17]1([CH2:23][C:24]([N:12]2[CH2:11][CH2:10][N:9]([C:4]3[C:3]([C:2]([F:1])([F:15])[F:16])=[CH:8][CH:7]=[CH:6][N:5]=3)[CH2:14][CH2:13]2)=[O:25])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: O=C(O)CC1CCCCC1
Reactant: FC(F)(F)c1cccnc1N1CCNCC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: O=C(CC1CCCCC1)N1CCN(c2ncccc2C(F)(F)F)CC1
Yield: 56 %

Procedure:
Coupling of 1-(3-(trifluoromethyl)pyridin-2-yl)piperazine (271 mg, 1.17 mmol) with 2-cyclohexylacetic acid (100 mg, 0.70 mmol) was carried out according to a similar procedure described for example 19A using N,N-dimethylformamide (1 mL) as solvent and benzotriazole-1 yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate (700 mg, 1.56 mmol) as coupling agent. 1-(cyclohexylacetyl)-4-[3-(trifluoromethyl)pyridin-2-yl]piperazine was obtained in 56% yield (140 mg) as colorless oil.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10]CC)=O)=[CH:6][N:5]=[CH:4][C:3]=1[CH2:13][CH2:14][CH3:15].[C:16]1([NH:22][NH2:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(O)CCC>[C:16]1([N:22]2[C:8](=[O:10])[C:7]3=[CH:6][NH:5][CH:4]=[C:3]([CH2:13][CH2:14][CH3:15])[C:2]3=[N:23]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: NNc1ccccc1
Reactant: CCCc1cncc(C(=O)OCC)c1Cl
Solvent: CCCCO
Product: CCCc1c[nH]cc2c(=O)n(-c3ccccc3)nc1-2
Yield: 83.6 %

Procedure:
A mixture of ethyl 4-chloro-3-propyl-5-pyridinecarboxylate (0.5123 g, 2.25 mmol) and phenylhydrazine (0.32 ml, 3.25 mmol) in anhydrous 1-butanol (18 ml) was stirred at reflux under nitrogen for 50 h. The solvent was removed in vacuo and the residue was purified by flash chromatography (silica gel, 5-10% MeOH/CH2Cl2) to give 0.4767 g (84%) of the title compound as a yellow solid; mp 221-224° C. (CH2Cl2-EtOAc-hexane); 1H NMR (360 MHz, DMSO-d6) δ0.95 (3H, t, J 7.3 Hz), 1.77 (2H, m), 2.63 (2H, t, J 7.3 Hz), 7.15 (1H, t, J 7.4 Hz), 7.36 (1H, s), 7.42 (2H, t, J 7.4 Hz), 8.19 (2H, d, J 7.5 Hz), 8.47 (1H, s), 12.14 (1H, br s); MS (ES+) m/z 254 [MH]+. Anal. found: C, 71.22; H, 5.59; N, 16.45. C15H15N3O requires: C, 71.13; H, 5.97; N, 16.59%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[CH:26][C:4]=1[CH2:5][N:6]([C:21]1[S:22][CH:23]=[CH:24][N:25]=1)[S:7]([C:10]1[CH:19]=[C:18]2[C:13]([C:14](=O)[NH:15][CH:16]=[N:17]2)=[CH:12][CH:11]=1)(=[O:9])=[O:8].O=P(Cl)(Cl)[Cl:34]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Cl:34][C:14]1[C:13]2[C:18](=[CH:19][C:10]([S:7]([N:6]([CH2:5][C:4]3[CH:26]=[CH:27][C:28]([O:30][CH3:31])=[CH:29][C:3]=3[O:2][CH3:1])[C:21]3[S:22][CH:23]=[CH:24][N:25]=3)(=[O:9])=[O:8])=[CH:11][CH:12]=2)[N:17]=[CH:16][N:15]=1
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(=O)[nH]cnc3c2)c(OC)c1
Reactant: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(Cl)ncnc3c2)c(OC)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
N-(2,4-dimethoxybenzyl)-4-oxo-N-(thiazol-2-yl)-3,4-dihydroquinazoline-7-sulfonamide (0.990 g, 2.159 mmol) was dissolved in toluene (10.80 ml) and POCl3 (0.403 ml, 4.32 mmol) was added. The reaction was stirred for 90 minutes at room temperature, then heated to 90° C. and stirred for four hours. The reaction was diluted with ethyl acetate and washed with saturated sodium bicarbonate solution. The aqueous layer was extracted twice with ethyl acetate, and the combined organic layers were dried with sodium sulfate, filtered, and concentrated to afford a brown oily solid. The solid was triturated in heptane, stirred for 30 minutes, and filtered. The resulting material was vacuum dried to afford crude 4-chloro-N-(2,4-dimethoxybenzyl)-N-(thiazol-2-yl)quinazoline-7-sulfonamide as a free flowing tan solid. (ESI) 499.1 (M+Na)+.
Reaction SMILES: [CH3:1][NH2:2].[CH:3](=O)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>C1(C)C=CC=CC=1>[CH:3](=[CH:1][NH2:2])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CN
Reactant: O=Cc1ccccc1
Solvent: Cc1ccccc1
Product: NC=Cc1ccccc1
Temperature: 0 °C
Yield: 88 %

Procedure:
Anhydrous monomethylamine (about 1-1.5 eq,) was introduced below the surface of a stirred solution of benzaldehyde (1062 g, 10.0 mol) in toluene (2000 ml) cooled to 0° C. The rate of addition of monomethylamine was adjusted so as to maintain the reaction temperature between 25°-30° C.; after 45 minutes the addition of monomethylamine was terminated. The organic phase was separated and concentrated in vacuo. Distillation of the residual oil afforded N-benzylidenemethylamine (1047g, 8.79 mol) in 88% yield. The product had a boiling point of 79° C. at 20 mm. [This N-benzylidinemethylamine starting material is reported by R. B. Moffett et al, Org. Syn. Coll. Vol. IV, 605-608 (1963)].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:6]([CH2:7][O:8][NH:9][S:10]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)(=[O:12])=[O:11])=[CH:5][CH:4]=1.[O-]CC.[Na+].[Br:26][CH2:27][CH2:28][CH2:29]Br>C(O)C>[Br:26][CH2:27][CH2:28][CH2:29][N:9]([O:8][CH2:7][C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:21][CH:20]=1)[S:10]([C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1)(=[O:11])=[O:12]
Reactant: COc1ccc(CONS(=O)(=O)c2ccc(C)cc2)cc1
Reactant: BrCCCBr
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(CON(CCCBr)S(=O)(=O)c2ccc(C)cc2)cc1
Temperature: 70 °C
Reaction time: 1.5 h
Yield: 87.8 %

Procedure:
N-(p-methoxybenzyloxy)-p-toluenesulfonamide (61.4 g) was added to a solution of sodium ethoxide in absolute ethanol (Na:4.6 g, absolute C2H5OH:540 ml) and stirred at 70° C. for 1.5 hours. After cooling at ambient temperature, 1,3-dibromopropane (121.2 g) was added to the mixture, and then the mixture was refluxed with stirring for 2 hours and filtered. The filtrate was concentrated under reduced pressure. To the residue was added a mixture of ethyl acetate and water, and the organic layer was separated, dried over magnesium sulfate and evaporated to dryness under reduced pressure to give an oil, which was crystallized from a mixture of ethyl acetate and n-hexane to give N-(3-bromopropyl)-N-(p-methoxybenzyloxy)-p-toluenesulfonamide (75.1 g).
Reaction SMILES: [NH:1]1[CH2:10][CH2:9][CH2:8][NH:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.CN(C)[P:13](N(C)C)N(C)C>C1(C)C=CC=CC=1>[N:1]12[P:13]3[N:4]([CH2:5][CH2:6][N:7]3[CH2:8][CH2:9][CH2:10]1)[CH2:3][CH2:2]2
Reactant: CN(C)P(N(C)C)N(C)C
Reactant: C1CNCCNCCNC1
Solvent: Cc1ccccc1
Product: C1CN2CCN3CCN(C1)P23
Yield: 88.9 %

Procedure:
A solution of 5.00 g of 1,4,7-triazacyclodecane and 5.70 g of hexamethylphosphorous triamide in 50 ml. of toluene is refluxed for 48 hours. The toluene is removed under reduced pressure, and the residue is distilled through a short-path column, to give 5.31 g (89%) of 1,4,7-triaza-11-phosphatricyclo[5.3.1.04,11 ]undecane as a clear, colorless liquid having a boiling point of 96°-98° C at 0.70 mm. The product solidifies on standing at room temperature.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][NH2:17])[CH2:11][CH2:10]1.[CH3:18][C:19]1[N:23]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:22]=[C:21]([CH:30]=O)[CH:20]=1>>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][NH:17][CH2:30][C:21]2[CH:20]=[C:19]([CH3:18])[N:23]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[N:22]=2)[CH2:13][CH2:14]1
Reactant: Cc1cc(C=O)nn1-c1ccccc1
Reactant: Cc1cccc(N2CCN(CCN)CC2)c1C
Product: Cc1cccc(N2CCN(CCNCc3cc(C)n(-c4ccccc4)n3)CC2)c1C
Yield: 85.6 %

Procedure:
Compound 14 was prepared using the same method as that of Example 1 except that 4-(2,3-dimethylphenyl)piperazin-1-ylethylamine and 5-methyl-1-phenylpyrazole-3-carbaldehyde were used.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].C(N(CC)CC)C.Cl.[N:17]1([CH2:23][CH2:24][C:25]2[N:29]3[CH:30]=[CH:31][CH:32]=[CH:33][C:28]3=[C:27]([C:34](Cl)=[O:35])[N:26]=2)[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][C:34]([C:27]2[N:26]=[C:25]([CH2:24][CH2:23][N:17]3[CH2:18][CH2:19][O:20][CH2:21][CH2:22]3)[N:29]3[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=23)=[O:35])[CH:6]=[CH:7][CH:8]=1
Reactant: O=C(Cl)c1nc(CCN2CCOCC2)n2ccccc12
Reactant: Nc1cccc(Cl)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1cccc(Cl)c1)c1nc(CCN2CCOCC2)n2ccccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 35.2 %

Procedure:
To a solution of 3-chloroaniline (0.060 mL, 0.54 mmol) and triethylamine (0.16 mL, 1.14 mmol) in CH2Cl2 (10 mL) was added 3-(2-morpholin-4-yl-ethyl)-imidazo[1,5-a]pyridine-1-carbonyl chloride hydrochloride (150 mg, 0.45 mmol). The mixture was stirred at ambient temperature for 1 h then washed with sat. aq. NaHCO3 (20 mL). The organic layer was separated and the aqueous layer was extracted with dichloromethane (20 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was chromatographed on silica to yield the title compound (61 mg, 35%). 1H NMR (DMSO-d6) δ 10.0 (1H), 8.45 (1H), 8.15 (2H), 7.81 (1H), 7.35 (1H), 7.20 (1H), 7.10 (1H), 6.94 (1H), 3.49 (4H), 3.26 (2H), 2.81 (2H), 2.44 (4H); m/z (M+H)=385.18.
Reaction SMILES: Cl[C:2]1[CH:12]=[C:6]2[N:7]([CH3:11])[CH2:8][CH2:9][CH2:10][N:5]2[C:4](=[O:13])[N:3]=1.[OH:14][CH2:15][C:16]1[CH:17]=[CH:18][C:19]([O:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][N:26]=2)=[C:20]([CH:23]=1)[C:21]#[N:22].[H-].[Na+]>CN(C)C=O>[CH3:11][N:7]1[CH2:8][CH2:9][CH2:10][N:5]2[C:4](=[O:13])[N:3]=[C:2]([O:14][CH2:15][C:16]3[CH:17]=[CH:18][C:19]([O:24][C:25]4[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:32])[F:33])=[CH:27][N:26]=4)=[C:20]([CH:23]=3)[C:21]#[N:22])[CH:12]=[C:6]12
Reactant: CN1CCCn2c1cc(Cl)nc2=O
Reactant: N#Cc1cc(CO)ccc1Oc1ccc(C(F)(F)F)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCCn2c1cc(OCc1ccc(Oc3ccc(C(F)(F)F)cn3)c(C#N)c1)nc2=O
Reaction time: 0.17 h

Procedure:
The title compound was prepared by a procedure similar to that described for E1 starting from 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido[1,6-a]pyrimidin-6(2H)-one and 5-(hydroxymethyl)-2-5 ((5-(trifluoromethyl)pyridin-2-yl)oxy)benzonitrile. An exemplary process is shown as below: To a solution of 5-(hydroxymethyl)-2-((5-(trifluoromethyl)pyridin-2-yl)oxy)benzonitrile (0.108 mL, 0.601 mmol) in N,N-dimethylformamide (DMF) (5 mL) was added NaH (48.1 mg, 1.202 mmol) and stirred for 10 mins. Then 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido[1,6-a]pyrimidin-6(2H)-one (80 mg, 0.401 mmol) was charged and stirred for 45 mins at rt. The resulting solution was 10 quenched by addition of 1 mL aq. NH4Cl and the solution was filtered. The resulting solution was submitted for MDAP to afford the desired product as a white solid.
Reaction SMILES: C([O:5][C:6](=[O:33])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][N:18]([C:26]2[N:31]=[CH:30][C:29](Br)=[CH:28][N:27]=2)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[N:15]=1)([CH3:9])[CH3:8])(C)(C)C.[CH3:34][N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1.[F:41][C:42]([F:47])([F:46])[C:43]([OH:45])=[O:44]>ClCCl>[F:41][C:42]([F:47])([F:46])[C:43]([OH:45])=[O:44].[CH2:19]([N:18]([C:26]1[N:27]=[CH:28][C:29]([N:38]2[CH2:39][CH2:40][N:35]([CH3:34])[CH2:36][CH2:37]2)=[CH:30][N:31]=1)[CH2:17][CH2:16][C:14]1[N:15]=[C:11]([S:10][C:7]([CH3:9])([CH3:8])[C:6]([OH:5])=[O:33])[S:12][CH:13]=1)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CN1CCNCC1
Reactant: CCCCCCCN(CCc1csc(SC(C)(C)C(=O)OC(C)(C)C)n1)c1ncc(Br)cn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCCN(CCc1csc(SC(C)(C)C(=O)O)n1)c1ncc(N2CCN(C)CC2)cn1

Procedure:
A compound obtained using 2-[(4-{2-[(5-bromopyrimidin-2-yl)(heptyl)amino]ethyl}-1,3-thiazol-2-yl)thio]-2-methylpropionic acid tert-butyl ester synthesized in Example 442-1 and 1-methylpiperazine as starting materials and by an operation similar to that of Example 442-2 was treated with dichloromethane and trifluoroacetic acid. The reaction solution was concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography (elution solvent; 0.05% trifluoroacetic acid-water:0.05% trifluoroacetic acid-acetonitrile=65:35 to 15:85) to give the title compound.