Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([NH:11][C:12]2[CH:13]=[C:14]([N:24]3[CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][CH2:25]3)[CH:15]=[CH:16][C:17]=2[C:18](=[O:23])[C:19]([F:22])([F:21])[F:20])[CH3:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1.Cl>ClCCl.C(OCC)C>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([NH:11][C:12]2[CH:13]=[C:14]([N:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)[CH:15]=[CH:16][C:17]=2[C:18](=[O:23])[C:19]([F:20])([F:22])[F:21])[CH3:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CC(Nc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)ccc1C(=O)C(F)(F)F)c1cc(Cl)cc(Cl)c1
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: CC(Nc1cc(N2CCNCC2)ccc1C(=O)C(F)(F)F)c1cc(Cl)cc(Cl)c1
Reaction time: 2 h
Yield: 193.3 %

Procedure:
To a solution of t-butyl 4-(3-(1-(3,5-dichlorophenyl)ethylamino)-4-(2,2,2-trifluoroacetyl)phenyl)piperazine-1-carboxylate (50.1 mg, 0.09 mmol) in dichloromethane (2.0 mL) was added a saturated solution of HCl in diethyl ether (15 mL). The reaction mixture was stirred for 2 hours. The solvent was removed by rotary evaporation to afford the title compound (42.0 mg, 95% yield). 1H NMR (400 MHz, CD3OD): δ 7.67 (d, 1H), 7.37 (s, 2H), 7.35 (s, 1H), 6.41 (d, 1H), 5.84 (s, 1H), 4.79 (m, 1H), 3.57 (m, 4H), 3.25 (m, 4H), 1.61 (d, 3H); MS (ESI) m/z: Calculated for C20H21Cl2F3N3O: 446.1; Observed: 446.5 (M++1) [corresponding to the free base].
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]1[S:11][N:10]=[C:9]([CH3:12])[CH:8]=1.[I-].[K+].[Cl:15][C:16]1[CH:21]=[C:20]([C:22]2[O:23][CH2:24][CH2:25][N:26]=2)[CH:19]=[C:18]([Cl:27])[C:17]=1[OH:28].[OH-].[K+]>C(#N)C>[Cl:15][C:16]1[CH:21]=[C:20]([C:22]2[O:23][CH2:24][CH2:25][N:26]=2)[CH:19]=[C:18]([Cl:27])[C:17]=1[O:28][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]1[S:11][N:10]=[C:9]([CH3:12])[CH:8]=1
Reactant: Oc1c(Cl)cc(C2=NCCO2)cc1Cl
Reactant: Cc1cc(CCCCCCl)sn1
Agent: [I-]
Agent: [K+]
Agent: [OH-]
Solvent: CC#N
Product: Cc1cc(CCCCCOc2c(Cl)cc(C3=NCCO3)cc2Cl)sn1
Yield: 76.9 %

Procedure:
A suspension of 6.5 g 5-(5-chloropentyl)-3-methylisothiazole, 5.3 g potassium iodide, 9.1 g 2,6-dichloro-4-(4,5-dihydro-2-oxazolyl)phenol and 3.9 g potassium hydroxide in 300 ml acetonitrile was heated at reflux for 40 hours. Filtration, concentration and flash filtration (silica gel; 1:1 hexane/ethyl acetate) gave 9.8 g of oily product which when crystallized from hexane at Dry Ice temperature gave 5.3 g 2-}3,5-dichloro-4-[(5-(3-methyl-5-isothiazolyl)pentyl)oxy]phenyl}-4,5-dihydro-oxazole as a colorless solid, m.p. 38°-39.5° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14]([OH:16])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1.[CH3:57][NH:58][O:59][CH3:60]>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14]([N:58]([O:59][CH3:60])[CH3:57])=[O:16])[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCCC(C(=O)O)C1
Reactant: CNOC
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON(C)C(=O)C1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 96 %

Procedure:
To a cold (0° C.) solution of 1-(tert-butoxycarbonyl)-3-piperidine carboxylic acid (7.000 g, 30.531 mmol) in dichloromethane (200 mL) including triethylamine (4.681 mL, 33.584 mmol) were added benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate (15.885 g, 30.531 mmol), N,O-dimethylhydroxyamine (3.276 g, 33.584 mmol) and triethylamine (4.255 mL, 30.531 mmol) successively. The mixture was allowed to warm to room temperature, and the stirring was continued for 12 hrs. The reaction mixture was diluted with dichloromethane and washed with an aqueous 1N HCl solution, saturated aqueous NaHCO3 solution, and brine, successively. The organic phase was dried over Na2SO4, filtered, and concentrated. The resulting residue was purified by column chromatography on silica gel (chloroform/ethyl acetate=10/1-9/1) to give 3-{[methoxy(methyl)amino]carbonyl}-1-piperidine-carboxylic acid tert-butyl ester as a white solid. (8.050 g, yield;96%)
Reaction SMILES: [N:1]1([C:6]2[N:11]=[CH:10][C:9]([NH:12]C(OC(C)(C)C)=O)=[C:8]([C:20]([F:23])([F:22])[F:21])[CH:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(OCC)C.[ClH:29]>O1CCOCC1>[ClH:29].[N:1]1([C:6]2[N:11]=[CH:10][C:9]([NH2:12])=[C:8]([C:20]([F:23])([F:21])[F:22])[CH:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)Nc1cnc(N2CCCC2)cc1C(F)(F)F
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: Nc1cnc(N2CCCC2)cc1C(F)(F)F
Reaction time: 5 h

Procedure:
A solution of 1 g (3.02 mmol) of 6-(pyrrolidin-1-yl)-4-trifluoromethyl-3-(terbutoxycarbonylamino)pyridine, prepared in the preceding stage, in 11 mL of 4N hydrochloric acid in dioxane, is stirred for 5 hours under reflux. Then 200 mL of ethyl ether is added to the cooled reaction mixture. 0.8 g of a precipitate is collected by filtration.
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:9][CH2:8][C@H:7]([C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)[CH:19]=3)[CH2:14][C@@H:13]2[CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[O:11])[CH2:6]1)=[O:4].[Li+].[OH-]>>[CH2:32]([C@H:13]1[CH2:14][N:15]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH:27]3[CH2:28][CH2:29][CH2:30][CH2:31]3)[CH:19]=2)[CH2:16][CH2:17][N:12]1[C:10]([C@H:7]1[CH2:8][CH2:9][C@@H:5]([C:3]([OH:4])=[O:2])[CH2:6]1)=[O:11])[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: COC(=O)[C@@H]1CC[C@H](C(=O)N2CCN(c3ccc(OC)c(OC4CCCC4)c3)C[C@@H]2Cc2ccccc2)C1
Agent: [Li+]
Agent: [OH-]
Product: COc1ccc(N2CCN(C(=O)[C@H]3CC[C@@H](C(=O)O)C3)[C@@H](Cc3ccccc3)C2)cc1OC1CCCC1
Yield: 80 %

Procedure:
A solution of (S)-3-Benzyl-1-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazine (92 mg, 0.25 mmol) in CH2Cl2 (1 mL) at 0-5° C. was treated with a catalytic amount of DMAP and (1S,3R)-3-(methoxycarbonyl)cyclopentanecarboxylic acid (47 mg, 0.28 mmol) followed by DCC (57 mg, 0.28 mmol). The reaction mixture was allowed to warm to room temperature and stir 1 h. After this time the reaction mixture was evaporated and the residue purified by silica gel flash chromatography with 30% then 50% EtOAc/hexanes as eluant to afford intermediate (1R,3S)-3-[(S)-2-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazine-1-carbonyl]-cyclopentanecarboxylic acid methyl ester as an oil (109 mg, 84%). LC/MS (Method B) 4.14 min, [M+1]+ 521. The intermediate (1R,3S)-3-[(S)-2-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazine-1-carbonyl]-cyclopentanecarboxylic acid methyl ester was then hydrolyzed with LiOH as described in Example 121, to afford the title compound as a colorless solid (85 mg, 80%) LC/MS (Method B) 3.68 min, [M+1]+ 507.
Reaction SMILES: [CH3:1][N:2]([S:21]([C:24]1[S:25][CH:26]=[CH:27][CH:28]=1)(=[O:23])=[O:22])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:13][C:14]([CH2:17][C:18]([OH:20])=O)=[CH:15][N:16]=1)=[CH:8]2.[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1.N1(O)C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>O.CN(C)C=O>[CH3:1][N:2]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:13][C:14]([CH2:17][C:18]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)=[O:20])=[CH:15][N:16]=1)=[CH:8]2)[S:21]([C:24]1[S:25][CH:26]=[CH:27][CH:28]=1)(=[O:22])=[O:23]
Reactant: C1COCCN1
Reactant: CN(c1cccc2cc(-c3ncc(CC(=O)O)s3)[nH]c12)S(=O)(=O)c1cccs1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CN(c1cccc2cc(-c3ncc(CC(=O)N4CCOCC4)s3)[nH]c12)S(=O)(=O)c1cccs1
Temperature: 25 °C
Reaction time: 4 h
Yield: 84 %

Procedure:
To a mixture of (2-{7-[methyl(2-thienylsulfonyl)amino]-1H-indol-2-yl}-1,3-thiazol-5-yl)acetic acid (0.38 g), morpholine (0.16 g), 1H-1,2,3-benzotriazol-1-ol (0.18 g) and N,N-dimethylformamide (10 mL) was added N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide-hydrochloride (0.26 g) at 0° C., and the mixture was stirred at room temperature for 4 hr. Water was added to the reaction mixture, and the obtained crystals were filtrated, washed with water and dried. A solution of the obtained crystals in tetrahydrofuran was treated with activated carbon and concentrated to give the title compound (0.37 g, yield 83%) as colorless crystals. The crystals were recrystallized from ethyl acetate. melting point 199-200° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]([N:18]3[C:27]4[C:22](=[CH:23][C:24]([O:28][CH3:29])=[CH:25][CH:26]=4)[CH2:21][CH2:20][CH2:19]3)=[N:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:30]([O:32]C)=[O:31])[CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.[OH-].[Na+]>O.CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]([N:18]3[C:27]4[C:22](=[CH:23][C:24]([O:28][CH3:29])=[CH:25][CH:26]=4)[CH2:21][CH2:20][CH2:19]3)=[N:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:30]([OH:32])=[O:31])[CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(N3CCCc4cc(OC)ccc43)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1ccc2c(c1)CCCN2c1nc2cc(C(=O)O)ccc2nc1-c1ccc(F)cc1
Reaction time: 8 h
Yield: 64.7 %

Procedure:
To a solution of methyl 2-(4-fluorophenyl)-3-(6-methoxy-1,2,3,4-tetrahydroquinolin-1-yl)quinoxaline-6-carboxylate (80 mg, 0.18 mmol) in water (1 mL) and MeOH (15 mL) was added sodium hydroxide (29 mg, 0.72 mmol) with stifling overnight at room temperature. The reaction mixture was concentrated under vacuum, dissolved in water (30 mL), adjusted to pH 5 with hydrogen chloride (3 N) to give the precipitation, which was collected by filtration to afford 2-(4-fluorophenyl)-3-(6-methoxy-1,2,3,4-tetrahydroquinolin-1-yl)quinoxaline-6-carboxylic acid as a light yellow solid (50 mg, 64.6%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([F:16])[CH:9]=2)[CH:5]=[C:4]([N:17]2[CH2:22][C@@H:21]([NH2:23])[CH2:20][CH2:19][C@H:18]2[CH3:24])[N:3]=1.[C:25]([O-:28])(O)=[O:26].[Na+]>C1COCC1.O>[C:8]1([CH2:6][O:28][C:25](=[O:26])[NH:23][C@H:21]2[CH2:20][CH2:19][C@@H:18]([CH3:24])[N:17]([C:4]3[CH:5]=[C:6]([C:8]4[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([F:16])[CH:9]=4)[N:7]=[C:2]([NH2:1])[N:3]=3)[CH2:22]2)[CH:15]=[CH:14][CH:11]=[CH:10][CH:9]=1
Reactant: C[C@@H]1CC[C@H](N)CN1c1cc(-c2ccc(C#N)c(F)c2)nc(N)n1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H]1CC[C@H](NC(=O)OCc2ccccc2)CN1c1cc(-c2ccc(C#N)c(F)c2)nc(N)n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 4-{2-amino-6-[(2R,5S)-5-amino-2-methyl-1-piperidinyl]-4-pyrimidinyl}-2-fluorobenzonitrile (170 mg, 0.426 mmol) in THF (4 mL) was added saturated aqueous NaHCO3 (2 mL) followed by phenylmethyl chloridocarbonate (0.07 mL, 0.47 mmol), and the reaction mixture was stirred at room temperature for 4 hours. The mixture was diluted with 3 mL of water and then extracted with EtOAc (3×30 mL). The organic was then washed with brine, dried over MgSO4, filtered and concentrated. The resulting yellow oil was purified on a Biotage SNAP 10 g column with gradient of 0 to 50% EtOAc in hexane over 30 minutes to afford the title compound (57 mg) as a yellow oil. LC-MS (ES) m/z=327 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[CH3:11].CI.[C:14](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:14][O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[CH3:11]
Reactant: CC(=O)c1ccc(O)c(C)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COc1ccc(C(C)=O)cc1C
Yield: 96.9 %

Procedure:
A mixture of 1 (4 hydroxy-3-methylphenyl)-ethanone 5.0 g, methyl iodide 5.70 g, potassium carbonate 20.0 g and acetone 200 ml was stirred with heating under reflux for six hours. The reaction mixture was filtered and was extracted with ethyl acetate. The organic layer was washed with water and was dried over anhydrous magnesium sulfate, and was then concentrated under reduced pressure to give 1-(4-methoxy-3-methylphenyl)-ethanone 5.3 g.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[CH:9])=[CH:4][CH:3]=1.[Cl:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][SH:16])=[CH:13][CH:12]=1.[Na]>>[F:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]\[CH:15]([S:16][CH:15](/[CH:9]=[CH:8]\[C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[C:14]2[CH:17]=[CH:18][C:11]([Cl:10])=[CH:12][CH:13]=2)[C:14]2[CH:17]=[CH:18][C:11]([Cl:10])=[CH:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: SCc1ccc(Cl)cc1
Reactant: C#Cc1ccc(F)cc1
Agent: [Na]
Product: Fc1ccc(/C=C\C(SC(/C=C\c2ccc(F)cc2)c2ccc(Cl)cc2)c2ccc(Cl)cc2)cc1

Procedure:
A solution of 4-fluorophenylacetylene (0.02 mol) and 4-chlorobenzyl mercaptan (0.02 mol) and metallic sodium (0.02 g atom) was subjected to Procedure 2 to form (Z)-4-fluorostyryl 4-chlorobenzylsulfide. The title compound was obtained in 82% yield following oxidation. 1HNMR (CDC13) δ4.60 (2H, s), 6.68 (1H, d, JH,H=11.84), 7.18-7.60 (8H aromatic+1H ethylenic).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([C:16]3[S:25][C:19]4[N:20]=[CH:21][NH:22][C:23](=[O:24])[C:18]=4[C:17]=3[CH3:26])=[O:15])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:34][C:35]([N:37]([CH2:43][CH3:44])[CH2:38][C:39]([F:42])([F:41])[F:40])=[O:36]>CC#N>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([C:16]3[S:25][C:19]4[N:20]=[CH:21][N:22]([CH2:34][C:35]([N:37]([CH2:43][CH3:44])[CH2:38][C:39]([F:40])([F:41])[F:42])=[O:36])[C:23](=[O:24])[C:18]=4[C:17]=3[CH3:26])=[O:15])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(C(=O)N2CCN(c3cccc(Cl)c3)CC2)sc2nc[nH]c(=O)c12
Reactant: CCN(CC(F)(F)F)C(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCN(CC(F)(F)F)C(=O)Cn1cnc2sc(C(=O)N3CCN(c4cccc(Cl)c4)CC3)c(C)c2c1=O
Yield: 20.8 %

Procedure:
To a suspension of 6-(4-(3-chlorophenyl)piperazine-1-carbonyl)-5-methylthieno[2,3-d]pyrimidin-4(3H)-one, (0.1 g, 0.26 mmol) in CH3CN (5 mL) was added K2CO3 (36 mg, 0.26 mmol), KI (43 mg, 0.26 mmol), and 2-chloro-N-ethyl-N-(2,2,2-trifluoroethyl)acetamide, (52 mg, 0.26 mmol). The reaction mixture was refluxed overnight and then quenched with H2O (20 mL). The resultant precipitate was filtered and dried to provide a crude solid which was purified by flash chromatography (Et2O:DCM, 1:1) providing 30 mg of pure 2-(6-(4-(3-chlorophenyl)piperazine-1-carbonyl)-5-methyl-4-oxothieno[2,3-d]pyrimidin-3 (4H)-yl)-N-ethyl-N-(2,2,2-trifluoroethyl)acetamide, (yield: 21%).
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([C:12]([N:14]2[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15]2)=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:23]3[CH:28]=[C:27]([F:29])[C:26]([F:30])=[CH:25][C:24]=3[CH2:31]Cl)[CH:8]=2)[N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:39][N:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1>C(#N)C>[NH2:1][C:2]1[N:11]=[C:10]([C:12]([N:14]2[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15]2)=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:23]3[CH:28]=[C:27]([F:29])[C:26]([F:30])=[CH:25][C:24]=3[CH2:31][N:43]3[CH2:44][CH2:45][N:40]([CH3:39])[CH2:41][CH2:42]3)[CH:8]=2)[N:3]=1
Reactant: CN1CCNCC1
Reactant: Nc1nc(C(=O)N2Cc3ccccc3C2)c2cc(-c3cc(F)c(F)cc3CCl)ccc2n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CN1CCN(Cc2cc(F)c(F)cc2-c2ccc3nc(N)nc(C(=O)N4Cc5ccccc5C4)c3c2)CC1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
200 mg of [2-amino-6-(2-chloromethyl-4,5-difluorophenyl)quinazolin-4-yl]-(1,3-dihydroisoindol-2-yl)methanone are dissolved in 5 ml of acetonitrile. 289 mg of caesium carbonate and 84 μl of methylpiperazine are added, and the mixture is stirred at 80° C. for 16 h. After cooling to 25° C., the mixture is filtered, and the filtrate is evaporated to dryness. The residue is taken up in 5 ml of ethyl acetate, the solution is washed with 5 ml of 2N sodium hydroxide solution, and the combined organic phases are dried over sodium sulfate. After filtration, the filtrate is evaporated to dryness and purified by chromatography (reversed phase HPLC).
Reaction SMILES: C([CH:4]1[CH:8]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[CH:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[NH:6][C:5]1=[O:22])(O)=O.C1(C)C(C)=CC=CC=1.C(=O)=O>CCCCCC>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([CH:8]2[CH:7]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:6][C:5](=[O:22])[CH2:4]2)=[CH:10][CH:11]=1
Reactant: O=C(O)C1C(=O)NC(c2ccccc2)C1c1ccc(Cl)cc1
Agent: O=C=O
Solvent: Cc1ccccc1C
Solvent: CCCCCC
Product: O=C1CC(c2ccc(Cl)cc2)C(c2ccccc2)N1

Procedure:
12 g. of 3-carboxy-4-p-chlorophenyl-5-phenyl-2-pyrrolidinone in 200 ml. of xylene are refluxed until evolution of CO2 ceased (about 20 minutes). The solution is cooled, 200 ml. of hexane are added and the reaction product crystallizes out. 8 g. of 4-p-chlorophenyl-5-phenyl-2-pyrrolidinone are obtained. M.P. : 159°-160°C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][C:10]=1[OH:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C)C=O.[H-].[Na+].Cl[CH2:26][O:27][CH3:28]>O>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][C:10]=1[O:17][CH2:26][O:27][CH3:28])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COCCl
Reactant: O=Cc1ccc(OCc2ccccc2)c(O)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCOc1cc(C=O)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.1 %

Procedure:
To a mixture of 4-benzyloxy-3-hydroxybenzaldehyde (27.30 g) and N,N-dimethylformamide (300 mL) was added sodium hydride (60% in oil, 5.28 g) at 0° C., and the mixture was stirred at room temperature for 1 hr. Chloromethylmethyl ether (16.10 g) was added to the reaction mixture and the mixture was further stirred at room temperature for 15 hrs. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give 4-benzyloxy-3-methoxymethoxybenzaldehyde as a colorless oil (32.60 g, yield 100%) from a fraction eluted with ethyl acetate-hexane (1:3, v/v).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([O:10][CH2:11][CH2:12][CH2:13]Cl)=[CH:9][C:4]=2[O:3][CH2:2]1.[CH3:15][NH2:16]>CO>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([O:10][CH2:11][CH2:12][CH2:13][NH:16][CH3:15])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CN
Reactant: ClCCCOc1ccc2c(c1)OCO2
Solvent: CO
Product: CNCCCOc1ccc2c(c1)OCO2
Temperature: 100 °C

Procedure:
Crude 1-benzo[3,4-d]1,3-dioxolan-5-yloxy-3-chloropropane (1.95 g, 9.1 mmol) was dissolved in methanol (25 mL) and added to a 40 wt % aqueous solution of methylamine (25 mL) in a heavy-walled glass pressure-tube apparatus. The tube was sealed and the mixture was stirred and heated at 100° C. (oil bath temperature) for 4 h. After cooling, the solution was concentrated by rotary evaporation, and saturated NaCl solution (50 mL) was added. The mixture was acidified to pH 1 with 10% HCl solution, and extracted with CHCl3 (4×25 mL) to remove impurities. The pH of the aqueous phase was adjusted to 7 with 10% NaOH solution, and the mixture was extracted with ether (4×30 mL) to remove impurities. The aqueous phase was basified with 10% NaOH solution to pH 11. The mixture was extracted with ether (4×50 mL). The combined ether extracts were dried (MgSO4), filtered and concentrated by rotary evaporation to give a residue. The residue was briefly dried under high vacuum producing a light-brown oil (0.286 g). The oil was purified by column chromatography on silica gel (20 g) eluting with CHCl3—CH3OH (1:1, v/v) to remove impurities, followed by CHCl3—CH3OH—Et3N (50:50:2, v/v/v) to collect the product (Rf 0.14). Selected fractions containing the product were combined and concentrated by rotary evaporation. The resulting brown oil was dissolved in CHCl3 and the CHCl3 solution was dried (MgSO4), filtered and concentrated by rotary evaporation to a residue. The residue was dried under vacuum at 40° C. to give 0.274 g (14.4%) of a brown oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10]2[C:15]([C:16]3[N:21]=[C:20]([CH3:22])[N:19]=[C:18](SC)[N:17]=3)=[CH:14][N:13]=[CH:12][N:11]=2)=[CH:5][CH:4]=1.[OH-].[NH4+:26]>O1CCOCC1>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10]2[C:15]([C:16]3[N:21]=[C:20]([CH3:22])[N:19]=[C:18]([NH2:26])[N:17]=3)=[CH:14][N:13]=[CH:12][N:11]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(Nc2ncncc2-c2nc(C)nc(SC)n2)cn1
Reactant: [NH4+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COc1ccc(Nc2ncncc2-c2nc(C)nc(N)n2)cn1
Yield: 79 %

Procedure:
A glass microwave reaction vessel was charged with N-(6-methoxypyridin-3-yl)-5-(4-methyl-6-(methylthio)-1,3,5-triazin-2-yl)pyrimidin-4-amine (14 mg, 0.041 mmol), ammonium hydroxide, 28.0-30.0% (0.5 mL, 12.84 mmol) and dioxane (1 mL). The reaction mixture was stirred and heated at reflux in an oil bath for 1 h. The solid formed was filtered off and washed with EtOAc to give 4-(4-(6-methoxypyridin-3-ylamino)pyrimidin-5-yl)-6-methyl-1,3,5-triazin-2-amine (10 mg, 0.032 mmol, 79% yield). 1H NMR (300 MHz, d6-DMSO) δ 11.78 (s, 1H); 9.37 (s, 1H); 8.65 (s, 1H); 8.48 (s, 1H); 8.10 (d, J=8.33 Hz, 1H); 7.94 (s, 1H); 7.79 (s, 1H); 6.88 (d, J=8.77 Hz, 1H); 3.87 (s, 3H); 2.43 (s, 3H). m/z (ESI, +ve ion) 311.1 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][NH2:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:12]1([C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][O:14]1)=[O:13].CCOCC>C(#N)C>[OH:14][CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=1[C:12]([NH:11][NH:10][C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=1)=[O:13]
Reactant: O=C1OCc2ccccc21
Reactant: NNc1ccc([N+](=O)[O-])cc1
Solvent: CC#N
Solvent: CCOCC
Product: O=C(NNc1ccc([N+](=O)[O-])cc1)c1ccccc1CO
Temperature: 20 °C
Yield: 10.2 %

Procedure:
To prepare compound I-24 identified above, 38.3 g of p-nitrophenylhydrazine and 33 g of phthalide were heated in acetonitrile for 3 hours at 70°-80° C. After cooling to 20° C., the solid product was stirred together with ether and then the product was collected by filtration and washed with ether to obtain 7.2 g of 1-(2'-hydroxymethylbenzoyl)-2-(p-nitrophenyl)hydrazine.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][CH:10]=1)[NH2:7])([O-:3])=[O:2].[Br:11]Br>C(O)(=O)C>[Br:11][C:8]1[CH:9]=[CH:10][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]=1[NH2:7]
Reactant: BrBr
Reactant: Nc1cccc([N+](=O)[O-])c1
Solvent: CC(=O)O
Product: Nc1cc([N+](=O)[O-])ccc1Br
Temperature: 0 °C
Reaction time: 1 h
Yield: 41 %

Procedure:
To a solution of 3-nitroaniline (0.5 g, 3.6 mmol) in 10 ml acetic acid added bromine (0.2 ml, 4.0 mmol) and stirred at 0° C. for 1 hour. The solution was filtered after recovering to room temperature to obtain 2-bromo-5-nitrobenzenamine (0.32 g, 40%) as a powder. A solution of 2-bromo-5-nitrobenzenamine (0.4 g, 1.8 mmol), sodium hydroxide (0.14 g, 3.6 mmol) and benzoyl chloride (0.24 ml, 2.0 mmol) in 20 ml THF was stirred for 2 hours in icy water bath. The reaction was quenched and washed with water (3×20 ml). The mixture was dried over anhydrous sodium sulfate. The crude N-(2-bromo-5-nitrophenyl)benzamide (0.3 g, 50%) was obtained after evaporation of the solvents. 1H NMR (500 MHz, CDCl3) δ (ppm) 7.65 (m, 2H), 7.68 (m, 1H), 7.80 (d, J=8.8 Hz, 1H), 7.94 (dd, J=8.8, 2.7 Hz, 1H), 8.00 (m, 2H), 8.62 (s, 1H), 9.55 (d, J=2.7 Hz, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]([OH:15])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:16](O)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29].C1CCC(N=C=NC2CCCCC2)CC1>C(OCC)(=O)C>[CH2:29]([O:14][C:13](=[O:15])[CH2:12][NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH3:16]
Reactant: CCCCCCCCCCCCCCO
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCCCCOC(=O)CNC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 59.7 %

Procedure:
To a solution of N-benzyloxycarbonyl glycine (3 g, 14.3 mmol), tetradecylalcohol (3.07 g, 14.3 mmol) an N,N-dimethylaminopyridine (87 mg, 10.3 mmol) in ethyl acetate (100 ml) was added DCC (2.98 g, 2.34 mmol) and the resulting mixture was stirred for 2 h at room temperature. After the precipitation which appeared was filtered off, the filtrate was concentrated in vacuo. The residue was washed with ethanol to give N-benzyloxycarbonylglycine tetradecyl ester (7) (3.46 g, 59.5%) as crystal.