Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([NH2:9])[C:3]=1[NH2:10].S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+].[CH3:20][C:21]1[C:26]([CH:27]=O)=[CH:25][N:24]=[C:23]([NH:29][CH2:30][CH2:31][CH2:32][CH:33]2[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]2)[N:22]=1.C(N(CC)CC)C>CN(C=O)C>[CH3:1][C:2]1[C:3]2[N:10]=[C:27]([C:26]3[C:21]([CH3:20])=[N:22][C:23]([NH:29][CH2:30][CH2:31][CH2:32][CH:33]4[CH2:34][CH2:35][N:36]([CH3:39])[CH2:37][CH2:38]4)=[N:24][CH:25]=3)[NH:9][C:4]=2[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cc(C)c(N)c(N)c1
Reactant: Cc1nc(NCCCC2CCN(C)CC2)ncc1C=O
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cc(C)c2nc(-c3cnc(NCCCC4CCN(C)CC4)nc3C)[nH]c2c1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
To a 2 L Erlenmeyer flask were added 3,5-dimethyl-benzene-1,2-diamine.2HCl (54.85 g, 262.3 mmol) and Na2S2O5 (64.82 g, 341.0 mmol), as well as 4-methyl-2-[3-(1-methyl-piperidin-4-yl)-propylamino]-pyrimidine-5-carbaldehyde (prepared as in Example 3 above) (72.5 g, 262.3 mmol) in DMF (725 mL). After addition of triethylamine (73.1 mL, 524.6 mmol), the resultant mixture was warmed on a hot plate with stirring to 90° C. and held at this temperature for 2 hours. The resultant mixture was then concentrated to near dryness and partitioned between dichloromethane (0.7 L) and 1 N NaOH (1 L). The resultant mixture was stirred for 1 hour and then filtered to isolate the voluminous solid which had formed. The solids were dried and then partitioned between chloroform (700 mL) and saturated aqueous NaHCO3 (700 mL). The layers were separated, the organic layer was dried over sodium sulfate and concentrated to a residue. The residue was recrystallized in hot heptane/ethyl acetate (1.8:1, 840 mL total volume) with initial hot filtration (˜1 g of oily residues removed) and final filter cake washing with heptane/ethyl acetate (3:1, 250 mL total volume) to yield the title compound as a crystalline solid.
Reaction SMILES: [N:1]1([C:7]([C:9]2[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[C:11]([N+:19]([O-])=O)[CH:10]=2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1>C(OCC)(=O)C.[Pd]>[N:1]1([C:7]([C:9]2[CH:10]=[C:11]([NH2:19])[CH:12]=[C:13]([C:15]([F:16])([F:18])[F:17])[CH:14]=2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: O=C(c1cc([N+](=O)[O-])cc(C(F)(F)F)c1)N1CCOCC1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1cc(C(=O)N2CCOCC2)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.5 %

Procedure:
Morpholin-4-yl-(3-nitro-5-trifluoromethyl-phenyl)-methanone (800 mg, 2.6 mmoles) from the previous step was dissolved in 40 mL of ethyl acetate. To this solution was added 10% palladium on carbon, the reaction was stirred under hydrogen at room temperature overnight. The solution filtered through celite and concentrated to give 3-(morpholine-4-carbonyl)-5-(trifluoromethyl)phenylamine (688 mg). 1H NMR (300 MHz, DMSO-d6) δ 6.90 (s, 1H), 6.75 (d, 2H), 5.6 (b, 6H).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][O:9][CH2:10][CH:11]2[CH2:13][O:12]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N-:14]=[N+:15]=[N-:16].[Na+].C(OC)=O.CO>O>[C:1]1([CH2:7][CH2:8][O:9][CH2:10][CH:11]([OH:12])[CH2:13][N:14]=[N+:15]=[N-:16])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [N-]=[N+]=[N-]
Reactant: c1ccc(CCOCC2CO2)cc1
Agent: [Na+]
Solvent: CO
Solvent: COC=O
Solvent: O
Product: [N-]=[N+]=NCC(O)COCCc1ccccc1
Yield: 98.3 %

Procedure:
A procedure similar to that described in Preparation 12 was repeated, except that 4.50 g of 2-phenylethoxymethyloxirane (prepared as described in Preparation 55), 8.20 g of sodium azide, 45 ml of methyl formate and 180 ml of an 8:1 by volume mixture of methanol and water were used, to give 5.49 g of the title compound as a colorless oil having an Rf value of 0.70 (on silica gel thin layer chromatography, using a 2:1 by volume mixture of hexane and ethyl acetate as the developing solvent).
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].Cl.[CH2:7]([NH2:16])[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:9]>CN(C)C=O>[CH2:7]([NH:16][C:3](=[O:4])[CH2:2][Cl:1])[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:9]
Reactant: O=C(Cl)CCl
Reactant: NCC(=O)c1ccccc1
Agent: Cl
Solvent: CN(C)C=O
Product: O=C(CCl)NCC(=O)c1ccccc1
Reaction time: 4 h

Procedure:
Chloroacetyl chloride (25 g; 0.226 mole) was added slowly to a stirred solution of phenacylamine hydrochloride (25.9 g; 0.151 mole) in anhydrous dimethylformamide (DMF) (80 ml) at room temperature. The internal temperature rose to ca. 40° C. The mixture was stirred for 4 hours after the addition and the bulk of the DMF evaporated under vacuum. The residue was treated with water (200 ml) and the crystalline precipitate collected, washed with water and dried. Yield 24.75 g (77%). m.p. 118°-119° C.
Reaction SMILES: Cl[CH2:2][Si:3]([O:8][CH3:9])([O:6][CH3:7])[O:4][CH3:5].[NH3:10]>>[CH3:5][O:4][Si:3]([CH2:2][NH:10][CH2:2][Si:3]([O:8][CH3:9])([O:6][CH3:7])[O:4][CH3:5])([O:8][CH3:9])[O:6][CH3:7]
Reactant: N
Reactant: CO[Si](CCl)(OC)OC
Product: CO[Si](CNC[Si](OC)(OC)OC)(OC)OC
Temperature: 100 °C

Procedure:
Chloromethyltrimethoxysilane (50.0 g., 0.29 mole) and ammonia (98.6 g., 5.80 mole) were charged to a 300 ml. stainless steel pressure vessel. The mixture was heated to 100° C. at 800 psi pressure for 8 hours and then cooled. The mixture was filtered. The crude product was distilled at 60° C. and 0.2 mm Hg pressure to produce N,N-bis-(trimethoxysilylmethyl)amine. The N,N-bis-(trimethoxysilylmethyl)amine so produced (3.0 g., 0.01 mole) was found to be greater than 95% pure by gas chromatography.
Reaction SMILES: S(Cl)(Cl)=O.[F:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]([OH:14])=[O:13])=[N:10][CH:11]=1.[CH3:15]O>>[CH3:15][O:13][C:12]([C:9]1[CH:8]=[CH:7][C:6]([F:5])=[CH:11][N:10]=1)=[O:14]
Reactant: CO
Reactant: O=C(O)c1ccc(F)cn1
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(F)cn1
Temperature: 65 °C
Reaction time: 2 h

Procedure:
2.7 mL Thionylchloride was dropped to 5 g 5-fluor-pyridine-2-carboxylic acid in 50 mL methanol. The reaction was stirred for 2 h at 65° C. in a sealed micro wave vial. The solvents were removed and the residue was desolved in a mixture of DCM and methanol and filtered over silica gel. The filtrate was evaporated to give 5.9 g of the desired product.
Reaction SMILES: [H-].[Na+].[CH2:3]1[O:18][C:6]2([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[S:9](=[O:17])(=[O:16])[NH:8][CH2:7]2)[O:5][CH2:4]1.Br[CH2:20][CH2:21][Cl:22]>CN(C=O)C>[CH2:3]1[O:18][C:6]2([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[S:9](=[O:17])(=[O:16])[N:8]([CH2:20][CH2:21][Cl:22])[CH2:7]2)[O:5][CH2:4]1
Reactant: O=S1(=O)NCC2(OCCO2)c2ccccc21
Reactant: ClCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=S1(=O)c2ccccc2C2(CN1CCCl)OCCO2
Reaction time: 1 h

Procedure:
To a suspension of 440 mg (11 mmol) of 60% sodium hydride in 20 ml of DMF, a solution of 2.41 g (10 mmol) of 3,4-dihydro-2H-1,2-benzothiazin-4-one 1,1-dioxide ethylene acetal in 10 ml of DMF was added under ice cooling and stirring. The reaction mixture was stirred for one hour at 0° C. and then for further one hour at room temperature. Under ice cooling, a solution of 2.86 g (20 mmol) of 1-bromo-2-chloroethane in 10 ml of DMF was added to the reaction mixture, followed by stirring for 16 hours at room temperature.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[CH:3]([C:10]([F:13])([F:12])[F:11])[C@@H:4]([C:6]([O:8][CH3:9])=[O:7])[NH2:5].N1C=CC=CC=1.[Br:22][C:23]1[CH:24]=[C:25]([S:29](Cl)(=[O:31])=[O:30])[S:26][C:27]=1[Cl:28].CCOC(C)=O.CCCCCC>C(Cl)Cl>[Br:22][C:23]1[CH:24]=[C:25]([S:29]([NH:5][CH:4]([C:6]([O:8][CH3:9])=[O:7])[CH:3]([C:10]([F:12])([F:11])[F:13])[C:2]([F:14])([F:15])[F:1])(=[O:31])=[O:30])[S:26][C:27]=1[Cl:28]
Reactant: O=S(=O)(Cl)c1cc(Br)c(Cl)s1
Reactant: COC(=O)[C@@H](N)C(C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)C(NS(=O)(=O)c1cc(Br)c(Cl)s1)C(C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 19 h
Yield: 77.7 %

Procedure:
A solution of methyl 4,4,4,4′,4′,4′-hexafluorovalinate (1.0 g, 4.18 mmol) in CH2Cl2 (10 mL) was stirred under N2 atmosphere at 25° C. Pyridine (0.81 mL, 10.04 mmol) was added dropwise followed by 4-bromo-5-chlorothiophene-2-sulfonyl chloride (1.486 g, 5.05 mmol) in one portion and the resulting solution stirred for 19 h at 25° C. After this time period, the reaction was complete by TLC (1:4 EtOAc-hexane). After quenching with water (1.0 mL), the mixture was diluted with CH2Cl2 (30 mL). The organic layer was washed sequentially with 1N aqueous HCl (10 mL), saturated aqueous NaHCO3 (10 mL) and brine (15 mL), then dried over MgSO4, filtered and concentrated to obtain a crude oil (2.1 g). The crude product was purified by the Biotage Flash™ 40 chromatography system, eluent: 1:6 EtOAc-hexanes, to afford methyl N-[(4-bromo-5-chloro-thien-2-yl)sulfonyl]-4,4,4,4′,4′,4′-hexafluoro-dl-valinate as a white solid (1.62 g, 83.07%). Mass Spectrum (−ESI): 497 (M−H)−.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]2[N:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:14]=[CH:15][C:3]=12.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([S:30]([NH:33][CH2:34][C:35]2[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=2)(=[O:32])=[O:31])=[CH:26][CH:25]=1.[H-].[Na+]>>[CH3:22][O:23][C:24]1[CH:25]=[CH:26][C:27]([S:30]([N:33]([CH2:34][C:35]2[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=2)[C:2]2[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]3[N:13]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[N:14]=[CH:15][C:3]=23)(=[O:31])=[O:32])=[CH:28][CH:29]=1
Reactant: CCOC(=O)c1cnc2c(cnn2-c2ccccc2)c1Cl
Reactant: COc1ccc(S(=O)(=O)NCc2cccnc2)cc1
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)c1cnc2c(cnn2-c2ccccc2)c1N(Cc1cccnc1)S(=O)(=O)c1ccc(OC)cc1

Procedure:
Following the procedure of Example 53, the product of Example 47 is reacted with (4-methoxybenzenesulfonyl) (3-pyridinylmethyl) amine and sodium hydride to provide ethyl 4-[(4-methoxybenzenesulfonyl)pyridin-3-ylmethylamino]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate. m.p. 89°-91° C.
Reaction SMILES: [CH2:1]([OH:7])[CH2:2][C:3]#[C:4][CH2:5][CH3:6].[S:8](Cl)([C:11]1[CH:17]=[CH:16][C:14]([CH3:15])=[CH:13][CH:12]=1)(=[O:10])=[O:9].CCN(CC)CC>CN(C1C=CN=CC=1)C>[CH3:15][C:14]1[CH:16]=[CH:17][C:11]([S:8]([O:7][CH2:1][CH2:2][C:3]#[C:4][CH2:5][CH3:6])(=[O:10])=[O:9])=[CH:12][CH:13]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCC#CCCO
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Product: CCC#CCCOS(=O)(=O)c1ccc(C)cc1
Yield: 98 %

Procedure:
This compound was synthesized as a colorless oil from hex-3-yn-1-ol (117.0 mg, 1.19 mmol), TsCl (295.5 mg, 1.55 mmol), Et3N (181.3 mg, 1.79 mmol), and DMAP (145.6 mg, 1.19 mmol) in 98% yield by following general procedure 1.1: ESI-MS: 253.1 (M+H+), 275.1 (M+Na+).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:13]([OH:15])=O)=[N:4][C:5]([Br:12])=[C:6]([C:8]([F:11])([F:10])[F:9])[N:7]=1.[NH2:16][C:17]1[C:25]2[C:20](=[N:21][CH:22]=[CH:23][CH:24]=2)[NH:19][N:18]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C=O)C.O>[NH2:1][C:2]1[C:3]([C:13]([NH:16][C:17]2[C:25]3[C:20](=[N:21][CH:22]=[CH:23][CH:24]=3)[NH:19][N:18]=2)=[O:15])=[N:4][C:5]([Br:12])=[C:6]([C:8]([F:9])([F:10])[F:11])[N:7]=1
Reactant: Nc1nc(C(F)(F)F)c(Br)nc1C(=O)O
Reactant: Nc1n[nH]c2ncccc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CN1CCOCC1
Product: Nc1nc(C(F)(F)F)c(Br)nc1C(=O)Nc1n[nH]c2ncccc12
Temperature: 80 °C
Reaction time: 8 h

Procedure:
A mixture comprising 3-amino-6-bromo-5-trifluoromethyl-pyrazine-2-carboxylic acid (Intermediate 2) (0.320 g, 1.118 mmol), 3-aminopyrazolo[3,4-b]pyridine (0.150 g, 1.118 mmol) and HATU (0.425 g, 1.118 mmol) in DMF (5 ml) was treated with N-methylmorpholine (0.111 ml, 1.118 mmol) and stirred at 80° C. overnight. After cooling to RT, the mixture was diluted with water (25 ml) and the resulting yellow precipitate was filtered under vacuum and washed with water. The crude material was purified by chromatography on silica eluting with iso-hexane:EtOAc (gradient of 0 to 100 EtOAc) to give the title compound as a yellow solid.
Reaction SMILES: [C:1]([Cl:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]([NH:21][NH2:22])=[N:13][N:12]=1.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>C1(C)C(C)=CC=CC=1>[Cl:9][C:1]1[C:2]2[C:7](=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:14]2=[N:13][N:12]=[C:11]([C:20]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:21]2[N:22]=1
Reactant: NNc1nnc(Cl)c2ccccc12
Reactant: O=C(Cl)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1C
Product: Clc1nn2c(-c3ccccc3)nnc2c2ccccc12
Reaction time: 8 h
Yield: 74.1 %

Procedure:
128 μl (1.1 mmol) of benzoyl chloride was added to a xylene solution (10 ml) of 194 mg (1.0 mmol) of (4-chloro-phthalazin-1-yl)-hydrazine and 182 μl (1.3 mmol) of triethylamine, and stirred overnight under reflux. Aqueous saturated sodium hydrogencarbonate solution was added to the reaction liquid, and extracted with chloroform. The organic layer was washed with saturated saline solution, dried and concentrated under reduced pressure to obtain 208 mg (yield: 74%) of 6-chloro-3-phenyl-[1,2,4]triazolo[3,4-a]phthalazine as a yellow solid.
Reaction SMILES: [ClH:1].Cl.[NH2:3][CH2:4][CH2:5][CH2:6][C:7]1[N:8]=[C:9]([NH2:12])[NH:10][CH:11]=1.CS(C)=[O:15]>C(OCC)C>[ClH:1].[ClH:1].[NH2:12][C:9]1[NH:8][C:7](=[CH:6][CH2:5][CH2:4][NH2:3])[C:11](=[O:15])[N:10]=1
Reactant: CS(C)=O
Reactant: NCCCc1c[nH]c(N)n1
Agent: Cl
Solvent: CCOCC
Product: NCCC=C1NC(N)=NC1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-(3-amino-propyl)-1H-imidazol-2-ylamine 16 (0.200 g, 0.930 mmol) was dissolved in anhydrous dimethyl sulfoxide (6 mL) Bromine (0.047 mL, 0.930 mmol) was added drop-wise and the solution was stirred at room temperature for 1 h. Diethyl ether (7 mL) was added and the organics were then decanted. The residue was purified by column chromatography (MeOH sat. with NH3) to yield the desired product as its free base. Addition of concentrated hydrochloric acid to a methanol solution (8 mL) of the free base followed by evaporation under reduced pressure afforded the target compound ((Z)-isomer exclusively) (0.141 g, 67%) as a tan solid: 1H NMR (300 MHz, DMSO-d6) δ 12.10 (br s, 1H), 9.20 (br s, 2H), 8.18 (br s, 2H), 5.92 (t, 1H, J=7.8 Hz), 2.96 (m, 2H), 2.66 (m, 2H); 13C NMR (100 MHz, DMSO-d6) δ 164.13, 156.63, 130.88, 113.70, 37.57, 24.94; HRMS (FAB) calcd for C6H10N4O (MH+) 155.0933, found 155.0943.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH:6]=[C:5]2[N:18]1[CH2:23][CH2:22][CH:21]([C:24](Cl)=[O:25])[CH2:20][CH2:19]1.[CH2:27]([NH2:30])[CH2:28][CH3:29]>>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH:6]=[C:5]2[N:18]1[CH2:23][CH2:22][CH:21]([C:24]([NH:30][CH2:27][CH2:28][CH3:29])=[O:25])[CH2:20][CH2:19]1
Reactant: CCCN
Reactant: O=C(Cl)C1CCN(c2cc(-c3ccccc3)nc3ccc(F)cc23)CC1
Product: CCCNC(=O)C1CCN(c2cc(-c3ccccc3)nc3ccc(F)cc23)CC1

Procedure:
In a manner analogous to that of Example 1(e) but using 1-[6-Fluoro-2-phenyl-4-quinolinyl]-4-piperidinecarbonyl chloride and propylamine as starting materials the named compound was obtained as off-white needles, mp 196°-198° dec. after recrystallization from methanol.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[CH2:12]([CH2:14][NH2:15])[OH:13]>CO>[Cl:1][C:2]1[N:7]=[C:6]([NH:15][CH2:14][CH2:12][OH:13])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Reactant: NCCO
Solvent: CO
Product: O=[N+]([O-])c1cnc(Cl)nc1NCCO
Reaction time: 18 h
Yield: 85 %

Procedure:
19.40 g (0.1 mole) of 2,4-dichloro-5-nitropyrimidine was completely dissolved in 60 ml of methanol and maintained below 15° C. To this solution, a solution of 12.22 g (0.2 mole) of ethanolamine in 20 ml of methanol was added slowly while maintaining the temperature of a reactor below 20° C. The mixture was stirred below 15° C. for 18 hours. After completion of the reaction, the reaction product was maintained below 5° C., and the resulting crystal was filtered, washed and dried, thereby giving 18.58 g (85% yield) of light yellow-colored 2-chloro-4-(2-hydroxyethylamino)-5-nitropyrimidine.
Reaction SMILES: [H-].[Na+].P(=O)([O-])O[C:5]([CH2:17][CH3:18])(CC)[C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1.[CH:21]1[C:31]2C=C[C:28]3[CH:32]=[CH:33][CH:34]=[CH:35][C:27]=3[C:26](=O)[C:25]=2[CH:24]=[CH:23][CH:22]=1.CO>CS(C)=O.[Cl-].[Na+].O>[N+:12]([C:9]1[CH:8]=[CH:7][C:6]([CH:5]=[C:17]2[C:18]3[CH:35]=[CH:34][CH:33]=[CH:32][C:28]=3[CH:27]=[CH:26][C:25]3[CH:31]=[CH:21][CH:22]=[CH:23][C:24]2=3)=[CH:11][CH:10]=1)([O-:14])=[O:13]
Reactant: O=c1c2ccccc2ccc2ccccc12
Reactant: CCC(CC)(O[PH](=O)[O-])c1ccc([N+](=O)[O-])cc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Solvent: CO
Product: O=[N+]([O-])c1ccc(C=C2c3ccccc3C=Cc3ccccc32)cc1
Temperature: 70 °C
Reaction time: 1 h
Yield: 69.2 %

Procedure:
To 150 ml of dimethylsulfoxide, 3.60 g (about 90 mmol) of oily sodium hydride (about 60%) was added at room temperature. After the addition, the mixture was heated to the inner temperature of around 70° C. in an oil bath, and stirred under the same conditions for 1 hour. Thereafter, the reaction solution was cooled to room temperature, and then a solution of 25.1 g (92 mmol) of the diethyl-4-nitrobenzyl phosphonate and 10.0 g (48.6 mmol) of 5H-dibenzo[a,d]cyclohepten-5-one in 50 ml dimethyl sulfoxide was added dropwise thereto. After the addition was completed, the resulting mixture was stirred for 15 minutes at room temperature, and thereafter heated and stirred for 2 hours in an oil bath while keeping its internal temperature at 70 to 80° C. After the reaction was completed, the reaction mixture was cooled to room temperature, and then poured in about 1 liter of saturated brine, followed by extraction with ethyl acetate. The organic layer was dried with anhydrous sodium sulfate, and the solvent was removed under reduced pressure. To the residue thus obtained was added methanol, and the precipitated crystals were collected by filtration. The crystals were then recrystallized using a methanol/acetone mixed solvent to obtain 10.94 g of 5-(4-nitrobenzylidene)-5H-dibenzo[a,d]cycloheptene. Yield: 69.3%; m.p.: 151.5 to 152.5° C.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[C:5]([NH2:6])=[C:4]([N+:12]([O-])=O)[CH:3]=1>C(O)C.O>[CH3:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[C:5]([NH2:6])=[C:4]([NH2:12])[CH:3]=1
Reactant: Cc1cc([N+](=O)[O-])c(N)c([N+](=O)[O-])c1
Solvent: CCO
Solvent: O
Product: Cc1cc(N)c(N)c([N+](=O)[O-])c1
Temperature: 28 °C
Yield: 76.8 %

Procedure:
The procedure of Gillespie et al., J. Org. Chem. 25:942 (1960) was adopted as follows. A dark black solution of 4-methyl-2,6-dinitroaniline (0.100 g, 0.561 mmol, Aldrich, used as received) in 6.66% aq. (NH4)2S (3.3 mL, prepared from 20% aq.(NH4)2S solution supplied by Aldrich) and ethanol (3.5 mL) was refluxed for 45 min. It was then cooled to 28° C. and the solvents were removed as much as possible under vacuum (inside the hood to avoid the stench of ammonium sulfide). The slurry so obtained was diluted with water (10 mL) and the resulting red solid was filtered and dried under vacuum to obtain 0.072 g (85%) solid as a red powder, which was used as such for the next reaction. 1H NMR (acetone-d6): 2.205 (s, 3H), 6.342 (br s, 2H), 6.622 (s, 1H), 7.571 (s, 1H).
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])C=C1.N[C:9]1[CH:14]=[CH:13][CH:12]=CN=1>C(O)(=O)C>[CH3:12][C:13]1=[C:14]([CH3:9])[C:4]([O:6][C:1]1=[O:7])=[O:5]
Reactant: O=C1C=CC(=O)O1
Reactant: Nc1ccccn1
Solvent: CC(=O)O
Product: CC1=C(C)C(=O)OC1=O
Yield: 269.6 %

Procedure:
58.0 g (0.5 mol) of maleic anhydride and 4.7 g (0.05 mol) of 2-aminopyridine are boiled under reflux for 48 hours in 200 ml of glacial acetic acid. Working up as in Example 1 affords 17.0 g (54%) of dimethylmaleic anhydride with a melting point of 91°-93° C.
Reaction SMILES: [H-].[Na+].[I:3][C:4]1[CH:12]=[CH:11][C:7]([CH2:8][CH2:9][OH:10])=[CH:6][CH:5]=1.I[CH3:14].[NH4+].[Cl-]>C1COCC1>[I:3][C:4]1[CH:12]=[CH:11][C:7]([CH2:8][CH2:9][O:10][CH3:14])=[CH:6][CH:5]=1
Reactant: OCCc1ccc(I)cc1
Reactant: CI
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COCCc1ccc(I)cc1
Temperature: 60 °C
Yield: 89.4 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 612 mg, 15.3 mmol) was slowly added to a solution of 4-iodophenethyl alcohol (2.53 g, 10.2 mmol) in THF (12 mL) at room temperature and with stirring. At the end of the addition, the solution had become cloudy. The reaction mixture was heated to 60° C. for 2 h and then cooled to 0° C. Iodomethane (952 μL, 15.3 mmol) was slowly added to the solution and the reaction mixture was stirred overnight. Upon the completion of the reaction, the mixture was cooled to 0° C., neutralized with aq. sat. NH4Cl (25 mL) and extracted with EtOAc (3×25 mL). The combined extracts were sequentially washed with aq. sat. NH4Cl (3×20 mL), brine (20 mL) and dried (Na2SO4). The crude product was concentrated and dried over high vacuum. Chromatography of the residue (EtOAc/hexanes=1/5) gave 2.39 g (9.12 mmol) of the title product. Yield: 89%, pale yellow oil. 1H NMR (300 MHz, CDCl3): δ 7.61 (d, J=8.2 Hz, 2H), 6.98 (d, J=8.2 Hz, 2H), 3.57 (t, J=6.8 Hz, 2H), 3.34 (s, 3H), 2.82 (t, J=6.8 Hz, 2H) ppm. 13C NMR (75 MHz, CDCl3): δ 138.9, 137.5, 131.1, 91.6, 73.3, 58.9, 35.9 ppm.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:4].[H-].[Na+].[CH2:14](Br)[C:15]#[CH:16].O>CN(C)C=O>[CH2:16]([N:5]([C:3]([O:2][CH3:1])=[O:4])[CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:15]#[CH:14]
Reactant: CCOC(=O)CNC(=O)OC
Reactant: C#CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C#CCN(CC(=O)OCC)C(=O)OC
Reaction time: 2 h
Yield: 64.6 %

Procedure:
100 g of ethyl N-methoxycarbonylglycinate were dissolved in 600 ml of N,N-dimethylformamide. Then ice-cooling the mixture, 25 g of sodium hydride (60% oil dispersion) were added thereto under a nitrogen atmosphere. After the reaction mixture was stirred for 2 hours, 81.3 g of propargyl bromide were dropped thereto over 2 hours. After the mixture was further stirred for an hour, the reaction product was poured into water and the aqueous layer was washed with hexane. Then it was subjected to three times of extraction with 100 ml of ether. The ether layers were combined together and dried over anhydrous magnesium sulfate and the solvent was evaporated off to obtain 79.8 g of ethyl N-propargyl-N-methoxycarbonylglycinate.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][CH2:5][S:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[O:18][N:17]=[CH:16][C:15]=2[C:19]([O:21]C(C)(C)C)=[O:20])=[CH:10][CH:9]=1.Cl>O1CCOCC1>[CH3:1][O:2][C:3](=[O:26])[CH2:4][CH2:5][S:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[O:18][N:17]=[CH:16][C:15]=2[C:19]([OH:21])=[O:20])=[CH:10][CH:9]=1
Reactant: COC(=O)CCSCc1ccc(-c2oncc2C(=O)OC(C)(C)C)cc1
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)CCSCc1ccc(-c2oncc2C(=O)O)cc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 97.2 %

Procedure:
To tert-butyl 5-(4-{[(3-methoxy-3-oxopropyl)thio]methyl}phenyl)isoxazole-4-carboxylate (300 mg, 0.80 mmol) was added 4N hydrogen chloride in 1,4-dioxane (10 ml), and the mixture was stirred overnight at 100° C. The solvent was evaporated under reduced pressure to give the title compound (250 mg, 98%).