Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: OCC1C=NC2N3CCC[C@H]3C(=O)NC=2C=1.Cl.Cl[C:19]1[CH:20]=[C:21]([CH:27]=[CH:28][C:29]=1N1CCNCC1)[C:22]([NH:24]CC)=[O:23].[I-].C(C[P+](C)(C)C)#N.C(N(CC)C(C)C)(C)C>C(#N)CC>[C:22]([NH2:24])(=[O:23])[C:21]1[CH:27]=[CH:28][CH:29]=[CH:19][CH:20]=1
Reactant: CCNC(=O)c1ccc(N2CCNCC2)c(Cl)c1
Agent: C[P+](C)(C)CC#N
Agent: Cl
Agent: O=C1Nc2cc(CO)cnc2N2CCC[C@@H]12
Solvent: CCC#N
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)c1ccccc1
Temperature: 105 °C
Yield: 35.3 %

Procedure:
(S)-3-(hydroxymethyl)-6a,7,8,9-tetrahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-6(5H)-one (100 mg, 0.456 mmol), 3-chloro-N-ethyl-4-(piperazin-1-yl)benzamide hydrochloride (139 mg, 0.456 mmol), (cyanomethyl)trimethylphosphonium iodide (166 mg, 0.684 mmol) and N,N-diisopropylethylamine (0.398 ml, 2.281 mmol) were suspended in propiononitrile (Volume: 1.370 ml) and heated in a closed vial at 90-120° C. for 4 h. The reaction mixture became a dark brown solution. It was cooled to room temperature, concentrated in vacuo, dissolved in DMSO (2 mL) and purified using HPLC (basic, 10-95% ACN in water). The fractions were concentrated in vacuo and the resulting solid was recrystallized from water-methanol (5:1, 6 mL) and dried in vacuum to afford (S)-3-chloro-N-ethyl-4-(44(6-oxo-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzamide (75.6 mg, 0.161 mmol, 35.3% yield) as a tan solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.03 (t, J=7.20 Hz, 3H) 1.76-1.93 (m, 3H) 2.06-2.17 (m, 1H) 2.44-2.51 (m, 4H) 2.96 (br. s., 4H) 3.14-3.23 (m, 2H) 3.28-3.38 (m, 3H) 3.46-3.58 (m, 1H) 3.88-3.97 (m, 1H) 6.92 (d, J=2.02 Hz, 1H) 7.10 (d, J=8.34 Hz, 1H) 7.56 (d, J=1.77 Hz, 1H) 7.70 (dd, J=8.34, 2.02 Hz, 1H) 7.81 (d, J=2.27 Hz, 1H) 8.37 (t, J=5.43 Hz, 1H) 10.38 (s, 1H). [M+H] calc'd for C24H29ClN6O2, 469; found, 469.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:12]=[CH:11][C:6]2[S:7][CH:8]=[C:9]([CH3:10])[C:5]=2[CH:4]=1.C([Li])CCC.[C:18](=[O:20])=[O:19]>CCOCC>[OH:1][CH2:2][C:3]1[CH:12]=[CH:11][C:6]2[S:7][C:8]([C:18]([OH:20])=[O:19])=[C:9]([CH3:10])[C:5]=2[CH:4]=1
Reactant: O=C=O
Reactant: Cc1csc2ccc(CO)cc12
Agent: [Li]CCCC
Solvent: CCOCC
Product: Cc1c(C(=O)O)sc2ccc(CO)cc12
Reaction time: 2 h

Procedure:
A solution of 5-hydroxymethyl-3-methylbenzo[b]thiophene (8.50 g.) in dry ether (120 ml.) was added dropwise to a stirred solution of n-butyl lithium (72 ml. of 1.6 M solution in hexane) in dry ether (120 ml.) at 0° under an atmosphere of dry nitrogen. The resulting mixture was stirred at 0° for 2 hours and then poured onto a mixture of crushed solid carbon dioxide and ether. When all the carbon dioxide had evaporated the mixture was shaken with water. The aqueous layer was separated and acidified with concentrated hydrochloric acid. The solid was filtered off, washed well with water and crystallized from ethanol to give 5-hydroxymethyl-3-methylbenzo[b]thiophene-2-carboxylic acid (4.80 g.), m.p. 260°-262°.
Reaction SMILES: [NH:1]([C:5]1[NH:6][CH2:7][CH2:8][N:9]=1)[N+]([O-])=O.N[CH2:11][CH:12]([OH:20])[C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1>C1(C)C(C)=CC=CC=1>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([CH:12]([OH:20])[CH2:11][NH:1][C:5]2[NH:6][CH2:7][CH2:8][N:9]=2)=[CH:14][CH:15]=1
Reactant: O=[N+]([O-])NC1=NCCN1
Reactant: NCC(O)c1ccc(Cl)cc1
Solvent: Cc1ccccc1C
Product: OC(CNC1=NCCN1)c1ccc(Cl)cc1

Procedure:
To 5.2 parts of 2-(nitramino)-2-imidazoline is added a solution of 7.5 parts of α-(aminomethyl)-p-chlorobenzyl alcohol in 40 parts of xylene while heating. Upon completion, stirring is continued while heating in an oil-bath at 150°-160°C. and while the xylene is partly distilled off (till gas evolution ceases). The residue is cooled and after the addition of a few parts of acetone, the produce is allowed to crystallize. It is filtered off, washed successively with acetone and diisopropylether, dried and the product is recrystallized from 4-methyl-2-pentanone, yielding p-chloro-α-(2-imidazolin-2-ylaminomethyl)benzyl alcohol; m.p. 156°-158°C.
Reaction SMILES: C[O:2][C:3]([CH2:5][CH2:6][C:7]1([CH2:48][CH2:49][C:50](OC)=[O:51])[C:19]2[CH:18]=[C:17]([N:20]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:21]3[CH:22]=[C:23]([CH3:27])[CH:24]=[CH:25][CH:26]=3)[CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][C:10]([N:34]([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[C:35]1[CH:36]=[C:37]([CH3:41])[CH:38]=[CH:39][CH:40]=1)=[CH:11][CH:12]=2)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+]>O1CCCC1>[OH:51][CH2:50][CH2:49][CH2:48][C:7]1([CH2:6][CH2:5][CH2:3][OH:2])[C:8]2[CH:9]=[C:10]([N:34]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[C:35]3[CH:36]=[C:37]([CH3:41])[CH:38]=[CH:39][CH:40]=3)[CH:11]=[CH:12][C:13]=2[C:14]2[C:19]1=[CH:18][C:17]([N:20]([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[C:21]1[CH:22]=[C:23]([CH3:27])[CH:24]=[CH:25][CH:26]=1)=[CH:16][CH:15]=2
Reactant: COC(=O)CCC1(CCC(=O)OC)c2cc(N(c3ccccc3)c3cccc(C)c3)ccc2-c2ccc(N(c3ccccc3)c3cccc(C)c3)cc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cccc(N(c2ccccc2)c2ccc3c(c2)C(CCCO)(CCCO)c2cc(N(c4ccccc4)c4cccc(C)c4)ccc2-3)c1
Temperature: 25 °C
Yield: 96.3 %

Procedure:
To a well-stirred solution of 8.8 grams of 9,9-bis[2-(methoxycarbonyl)ethyl]-2,7-bis(phenyl-m-tolylamino)fluorene in 150 milliliters of dried tetrahydrofuran under a nitrogen atmosphere was added in small portions, 0.52 gram, of lithium aluminum hydride over a period of 15 to 30 minutes. The reaction mixture was stirred at room temperature for two hous. Ten percent aqueous sodium hydroxide solution was then slowly added to the reaction mixture. The organic layer was separated and evaporated to dryness under reduced pressure. The residue as dissolved in methylene chloride, and washed several times with water. Evaporation of the dry methylene chloride solution provided a white solid, which was recrystallized from isopropanol and water to yield 7.8 grams of the above fluorene pure product, melting point, 216° to 217° C.
Reaction SMILES: C(OP([CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])(OCC)=O)C.[H-].[Na+].[Si:19]([O:26][C:27]1[CH:34]=[CH:33][C:30]([CH:31]=O)=[CH:29][C:28]=1[CH:35]1[CH2:39][CH2:38][CH2:37][CH2:36]1)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20].CCCCCC>CCOCC.CCOC(C)=O>[Si:19]([O:26][C:27]1[CH:34]=[CH:33][C:30](/[CH:31]=[CH:9]/[C:10]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:11])=[CH:29][C:28]=1[CH:35]1[CH2:39][CH2:38][CH2:37][CH2:36]1)([C:22]([CH3:24])([CH3:25])[CH3:23])([CH3:21])[CH3:20]
Reactant: CCOP(=O)(CC(=O)OC(C)(C)C)OCC
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(C=O)cc1C1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)/C=C/c1ccc(O[Si](C)(C)C(C)(C)C)c(C2CCCC2)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a 100 mL 3-necked flask equipped with a magnetic stirrer, a nitrogen inlet and a reflux condenser were added 1.57 g of tert-butyl diethylphosphonoacetate (Aldrich) and 20 mL of anhydrous ethyl ether. This was followed by addition of 0.40 g of 60% NaH mineral oil dispersion. The resulting cloudy solution was heated at reflux for 25 min, cooled to 0° C. and treated with a solution of 1.52 g of 4((tert-butyldimethylsilyl)oxy)-3-cyclopentylbenzaldehyde in 10 mL of ether. A thick yellow gel resulted which was broken up with a spatula. The mixture was allowed to warm to RT and stirring was continued for an additional 1 h Analysis by tic (SiO2, 95:5 hexane:EtOAc) indicated a major new component at Rf=0.48 and minor components at Rf=0.06, 0.41 and 0.98. The mixture was diluted with 70 mL of ether, washed with saturated brine, and dried over anhydrous MgSO4. The drying agent was removed by filtration and the filtrate concentrated to give a yellow oil. This material was purified by flash chromatography on silica gel (97:3 hexaneEtOAc) to afford 1.53 g (77%) of tert-butyl trans-4-((tert-butyldimethylsilyl)oxy)-3-cyclopentylcinramate as a clear oil.
Reaction SMILES: C(OCC)(=O)C=C.[N+](CCC(OCC)=O)([O-])=O.Cl.[H][H].[C:21]([CH2:26][CH2:27][C:28]1([CH2:34][C:35]([O:37]CC)=[O:36])[NH:32][C:31](=[O:33])[CH2:30][CH2:29]1)([O:23]CC)=[O:22].C(CC1(CCC(O)=O)NC(=O)CC1)(OCC)=O.C(CCC1(CC(O)=O)NC(=O)CC1)(OCC)=O.[OH-].[Na+]>C(O)(C)(C)C.O.C(O)C.[Pd]>[C:21]([CH2:26][CH2:27][C:28]1([CH2:34][C:35]([OH:37])=[O:36])[NH:32][C:31](=[O:33])[CH2:30][CH2:29]1)([OH:23])=[O:22]
Reactant: [H][H]
Reactant: CCOC(=O)CCC1(CC(=O)OCC)CCC(=O)N1
Agent: [Pd]
Agent: C=CC(=O)OCC
Agent: CCOC(=O)CC1(CCC(=O)O)CCC(=O)N1
Solvent: O
Solvent: CC(C)(C)O
Solvent: CCO
Product: O=C(O)CCC1(CC(=O)O)CCC(=O)N1

Procedure:
A suspension of 116 g (0.97 mole) β-nitropropanoic acid (CAS number 504-88-1) in chloroform (1 l) is stirred and treated with 127.5 g (1.07 mole) thionyl chloride. A rapid evolution of gas takes place and the mixture is stirred one hour at room temperature. Ethanol (50 g, 1.07 mole) is added dropwise followed by rapid gas evolution. The mixture is stirred 72 hours, concentrated and distilled to yield ethyl β-nitropropanoate, bp 95°-105° C. at 15 mm. A solution of 182 g (1.84 mole) ethyl acrylate [CAS number 140-88-5] in t-butanol (150 ml) and 10 ml of Triton B is treated at 40° C. with 135.5 g (0.92 mole) of ethyl β-nitropropanoate. Additional portions of Triton B (2 ml×3) and ethyl acrylate (25 g×3) are added over a five-hour period. The mixture is cooled and poured into a solution of 100 ml of concentrated hydrochloric acid in water (1 l). The diethyl-γ-nitro-γ-carboethoxymethylpimelate is extracted using dichloromethane (4×500 ml). The combined extracts are dried over anhydrous magnesium sulfate, filtered, and concentrated to yield an oil. The oil (160 g) is dissolved in ethanol (1.5 l) and treated with hydrogen in the presence of 7 g 20% Pd/C. The mixture is filtered through filter aid and concentrated to yield a mixture of 5-carboethoxyethyl-5carboethoxymethyl-2-pyrrolidinone (major product), 5-carboethoxymethyl-5-carboxyethyl-2-pyrrolidinone, and 5-carboethoxyethyl-5-carboxymethyl-2-pyrrolidinone as an oil. The oil dissolved in 1 l of 50% ethanol is titrated with a solution of 50% sodium hydroxide with stirring at reflux accompanied by removal of ethanol. The hydrolyzed mixture is neutralized with concentrated hydrochloric acid to yield 5-carboxyethyl-5-carboxymethyl-2-pyrrolidinone in water. The water is removed at reduced pressure and the resulting solid is added to acetic anhydride (1 kg) with stirring. The mixture is heated at 100° C. for 16 hours. The mixture is filtered through filter aid and concentrated at reduced pressure to yield tetrahydro-3,5-dioxo-1H-pyrrolizine-7a(5H)acetic acid anhydride with acetic acid as an oil. The oil is dissolved in a minimum amount of acetonitrile, an equivalent amount of water is added, and the mixture is stirred 16 hours. The mixture is concentrated at reduced pressure to yield a solid. The solid is recrystallized from acetonitrile to yield tetrahydro-3,5 -dioxo-1H-pyrrolizine-7a(5H)-acetic acid with a melting point of 177°-180° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:5]([Br:14])=[CH:4][N:3]=1.C1COCC1.[C:20]([N:28]=[C:29]=[S:30])(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(OCC)(=O)C.CCCCCC>[C:20]([NH:28][C:29](=[S:30])[NH:1][C:2]1[CH:7]=[C:6]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:5]([Br:14])=[CH:4][N:3]=1)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CCOC(=O)Cc1cc(N)ncc1Br
Reactant: O=C(N=C=S)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOC(=O)Cc1cc(NC(=S)NC(=O)c2ccccc2)ncc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.2 %

Procedure:
A flask was charged with ethyl 2-(2-amino-5-bromopyridin-4-yl)acetate (2.700 g, 10.42 mmol) and THF (20 mL), and benzoyl isothiocyanate (1.546 mL, 11.46 mmol) was added. The mixture was stirred overnight at ambient temperature. The thick slurry was diluted with 50 mL of 10% ethyl acetate/hexane and filtered. The filter cake was washed with 10% ethyl acetate/hexane and dried to afford the desired product (3.75 g, 85.22%) as a pale yellow fluffy solid.
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[ClH:15].[OH:16][C:17]1[CH:26]=[CH:25][C:20]([S:21][CH2:22][CH:23]=O)=[CH:19][CH:18]=1>CO>[ClH:15].[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH:7]2[CH2:8][CH2:9][N:10]([CH2:23][CH2:22][S:21][C:20]3[CH:25]=[CH:26][C:17]([OH:16])=[CH:18][CH:19]=3)[CH2:11][CH2:12]2)=[CH:13][CH:14]=1
Reactant: O=CCSc1ccc(O)cc1
Reactant: Fc1ccc(CC2CCNCC2)cc1
Agent: Cl
Solvent: CO
Product: Oc1ccc(SCCN2CCC(Cc3ccc(F)cc3)CC2)cc1

Procedure:
The title compound was prepared from 4-(4-fluorobenzyl)piperidine (from 804 mg of the hydrochloride), 4-hydroxythiophenoxyacetaldehyde (560 mg, 3.33 mmol) and NaCNH3B (416 mg, 6.66 mmol) in MeOH (100 mL) as a colorless crystalline solid (430 mg): mp 177-178° C.; 1H NMR (CD3OD) 1.40-1.60 (m, 2H), 1.76-1.92 (m, 3H), 2.59 (d, J=6.3 Hz, 2H), 2.81-3.00 (m, 2H), 3.08-3.26 (m, 4H), 3.42-3.58 (m, 2H), 6.78 (d, J=8.7 Hz, 2H), 6.96-7.22 (m, 4 H), 7.36 (d, J=8.7 Hz, 2H).
Reaction SMILES: Cl[C:2]1[S:6][N:5]=[C:4]([CH2:7][Cl:8])[N:3]=1.CCN(C(C)C)C(C)C.[CH3:18][O:19][C:20]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:21]=1[CH2:22][NH2:23]>C(Cl)Cl>[Cl:8][CH2:7][C:4]1[N:3]=[C:2]([NH:23][CH2:22][C:21]2[CH:24]=[CH:25][C:26]([O:28][CH3:29])=[CH:27][C:20]=2[O:19][CH3:18])[S:6][N:5]=1
Reactant: COc1ccc(CN)c(OC)c1
Reactant: ClCc1nsc(Cl)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(CNc2nc(CCl)ns2)c(OC)c1
Reaction time: 8 h

Procedure:
A solution of 5-chloro-3-chloromethyl-[1,2,4]thiadiazole (3 g, 18 mmol, [74461-64-6]) in DCM (20 mL) was treated with DIPEA (1 eq), followed by 2,4-dimethoxybenzylamine (1 eq). After stirring overnight, the mixture was concentrated and purified by silica gel chromatography (10% MeOH/EtOAc) to afford (3-chloromethyl-[1,2,4]thiadiazol-5-yl)-(2,4-dimethoxy-benzyl)-amine, which was used directly in the next step.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[CH2:9][O:10][CH2:11][CH2:12][CH:13]=2)=[N:6][CH:5]=[CH:4][N:3]=1.[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[O:10]1[CH2:11][CH2:12][CH:13]=[C:8]([C:7]2[C:2]([O:21][C:18]3[CH:19]=[CH:20][C:15]([NH2:14])=[CH:16][CH:17]=3)=[N:3][CH:4]=[CH:5][N:6]=2)[CH2:9]1
Reactant: Clc1nccnc1C1=CCCOC1
Reactant: Nc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ccc(Oc2nccnc2C2=CCCOC2)cc1
Temperature: 120 °C
Reaction time: 2.5 h

Procedure:
2-Chloro-3-(5,6-dihydro-2H-pyran-3-yl)pyrazine (0.13 g, 0.68 mmol), 4-aminophenol (0.15 g, 1.35 mmol), and cesium carbonate (0.44 g, 1.35 mmol) were mixed in DMF (2 mL) in a microwave tube. The tube was sealed and placed under a nitrogen atmosphere. The reaction mixture was stirred at 120° C. for 2.5 h. The reaction mixture was cooled to room temperature and diluted with water. The resulting precipitate was filtered and washed with water to give 4-(3-(5,6-dihydro-2H-pyran-3-yl)pyrazin-2-yloxy)aniline. [M+1]=270.1.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[O:6][C:5]2[CH:7]=[CH:8][C:9]([NH:11][C:12]([CH3:14])=[O:13])=[CH:10][C:4]=2[O:3]1.[N+:16]([O-])([OH:18])=[O:17]>C(O)(=O)C>[CH3:1][C:2]1([CH3:15])[O:6][C:5]2[CH:7]=[C:8]([N+:16]([O-:18])=[O:17])[C:9]([NH:11][C:12]([CH3:14])=[O:13])=[CH:10][C:4]=2[O:3]1
Reactant: CC(=O)Nc1ccc2c(c1)OC(C)(C)O2
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: CC(=O)Nc1cc2c(cc1[N+](=O)[O-])OC(C)(C)O2
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.2 %

Procedure:
18.4 g of 2,2-dimethyl-5-acetamino-1,3-benzodioxole were nitrated at 15°-25° C. in 90 ml of glacial acetic acid by the dropwise addition of 9.5 ml of nitric acid (d=1.4) in 30 ml of glacial acetic acid. After stirring at room temperature for 3 hours, the suspension was poured into ice/water and the crystals were removed by filtration under suction. These were made into a paste with methanol and again suction filtered. There were obtained 22.0 g (98.2% of theory) of 2,2-dimethyl-5-acetamino-6-nitro-1,3-benzodioxole of melting point 173°-174° C.
Reaction SMILES: [C:1]1([CH3:28])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N:13]=[C:12]([N:17]1[CH:21]=[C:20]([C:22]([O:24]CC)=[O:23])[CH:19]=[N:18]1)[NH:11][C:10]2=O.[CH2:29]([NH:31][CH3:32])[CH3:30]>>[CH2:29]([N:31]([CH3:32])[C:10]1[C:9]2[C:14](=[CH:15][CH:16]=[C:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=3[CH3:28])[CH:8]=2)[N:13]=[C:12]([N:17]2[CH:21]=[C:20]([C:22]([OH:24])=[O:23])[CH:19]=[N:18]2)[N:11]=1)[CH3:30]
Reactant: CCOC(=O)c1cnn(-c2nc3ccc(-c4ccccc4C)cc3c(=O)[nH]2)c1
Reactant: CCNC
Product: CCN(C)c1nc(-n2cc(C(=O)O)cn2)nc2ccc(-c3ccccc3C)cc12

Procedure:
The above compound may be made analogous to Example 1 using ethyl 1-(6-(o-tolyl)-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylate in step D and N-ethyl-N-methylamine in step E. MS (ESI/CI): predicted mass C22H21N5O2, 387.2.
Reaction SMILES: S(Cl)([Cl:3])=O.CN(C)C=O.[Cl:10][C:11]1[CH:12]=[CH:13][C:14]([N+:20]([O-:22])=[O:21])=[C:15]([CH:19]=1)[C:16](O)=[O:17]>C1(C)C=CC=CC=1>[Cl:10][C:11]1[CH:12]=[CH:13][C:14]([N+:20]([O-:22])=[O:21])=[C:15]([CH:19]=1)[C:16]([Cl:3])=[O:17]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cc(Cl)ccc1[N+](=O)[O-]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: O=C(Cl)c1cc(Cl)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of thionyl chloride (7.25 mL, 99.5 mmol) and N,N-dimethylformamide is added to a mixture of 5-chloro-2-nitrobenzoic acid in toluene. The reaction mixture is heated to and held at 80° C. for 16 hours, cooled to room temperature, concentrated in vacuo, diluted with toluene, concentrated in vacuo and diluted with toluene to obtain the title product as a 1 molar solution in toluene.
Reaction SMILES: Cl[C:2](=[CH2:5])[C:3]#[N:4].N12CCCCC1C=NCCC2.Cl.[Cl:18][CH2:19][C:20]([NH2:22])=[NH:21].O>C(#N)C.C(OCC)(=O)C>[NH2:4][C:3]1[CH:2]=[CH:5][N:22]=[C:20]([CH2:19][Cl:18])[N:21]=1
Reactant: N=C(N)CCl
Reactant: C=C(Cl)C#N
Agent: C1=NCCCN2CCCCC12
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC#N
Product: Nc1ccnc(CCl)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 67.8 %

Procedure:
Solutions of 2-chloroacrylonitrile (15.7 g.) in acetonitrile (20 ml.) and 1,5-diazabicyclo[5,4,0]undec-5-ene (27 g.) in acetonitrile (20 ml.) were added simultaneously over 30 minutes to a stirred, ice-cooled solution of 2-chloroacetamidine hydrochloride (19.2 g.) and 1,5-diazabicyclo[5,4,0]undec-5-ene (22.5 g.) in acetonitrile (200 ml.), keeping the temperature below 30° and the mixture stirred a further 4 hours at room temperature after the addition was complete. The resulting mixture was stirred with a mixture of water (100 ml.) and ethyl acetate (200 ml.) and then filtered through a pad of diatomaceous earth and the ethyl acetate phase separated. The aqueous phase was further extracted with ethyl acetate (2×100 ml.) and the combined ethyl acetate extracts dried and evaporated to dryness to give 4-amino-2-chloromethylpyrimidine (14.5 g.) which was used without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](=[S:19])[CH:14]=[CH:15][NH:16]2)=[CH:11][C:10]=1[O:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:23]1[S:24][C:25]([N+:28]([O-:30])=[O:29])=[CH:26][CH:27]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([S:19][C:23]3[S:24][C:25]([N+:28]([O-:30])=[O:29])=[CH:26][CH:27]=3)=[CH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:20][CH3:21])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc2c(=S)cc[nH]c2cc1OCc1ccccc1
Reactant: O=[N+]([O-])c1ccc(Br)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(Sc3ccc([N+](=O)[O-])s3)ccnc2cc1OCc1ccccc1
Yield: 76.9 %

Procedure:
7-(Benzyloxy)-6-methoxy-1,4-dihydro-4-quinolinethione (14.3 g), 2-bromo-5-nitrothiophene (10 g), potassium carbonate (9.9 g) and dimethylformamide (150 ml) were stirred together at room temperature for 6 hours. Water was added, and the precipitated solid was filtered out and washed with water and then ethyl acetate to obtain 15.7 g of a yellow powder.
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[C:29]([Cl:31])[CH:28]=[CH:27][C:3]=1[C:4]([C:6]1[O:7][C:8]2[CH:18]=[C:17](OS(C(F)(F)F)(=O)=O)[CH:16]=[CH:15][C:9]=2[C:10]=1[C:11]([F:14])([F:13])[F:12])=[O:5].[C:32]([NH:35][C:36]1[CH:37]=[C:38](B(O)O)[CH:39]=[CH:40][CH:41]=1)(=[O:34])[CH3:33].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=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>[Cl:1][C:2]1[CH:30]=[C:29]([Cl:31])[CH:28]=[CH:27][C:3]=1[C:4]([C:6]1[O:7][C:8]2[CH:18]=[C:17]([C:40]3[CH:41]=[C:36]([NH:35][C:32](=[O:34])[CH3:33])[CH:37]=[CH:38][CH:39]=3)[CH:16]=[CH:15][C:9]=2[C:10]=1[C:11]([F:12])([F:13])[F:14])=[O:5]
Reactant: CC(=O)Nc1cccc(B(O)O)c1
Reactant: O=C(c1ccc(Cl)cc1Cl)c1oc2cc(OS(=O)(=O)C(F)(F)F)ccc2c1C(F)(F)F
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: [K+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1cccc(-c2ccc3c(C(F)(F)F)c(C(=O)c4ccc(Cl)cc4Cl)oc3c2)c1
Temperature: 80 °C
Reaction time: 6 h
Yield: 18.3 %

Procedure:
To a solution of trifluoro-methanesulfo4nic acid 2-(2,4-dichloro-benzoyl)-3-trifluoromethyl-benzofuran-6-yl ester from step 2 (110 mg, 0.217 mmol) in anhydrous N,N-dimethylformamide (2 mL) were added 3-acetamidobenzene boronic acid (58.2 mg, 0.325 mmol, 1.5 eq), potassium carbonate (60.0 mg, 0.434 mmol, 2 eq) and tetrakis(triphenylphosphine)palladium(0) (50 mg, 0.043 mmol, 0.2 eq) under argon. The resulting reaction mixture was degassed for 5 min. and then the reaction was then stirred at 80° C. for 6 h. The mixture was cooled to room temperature then poured into ethyl acetate (10 mL) and water (10 mL). The aqueous layer was extracted with ethyl acetate (2×10 mL), and the combined organic layers were washed with water (2×10 mL), dried over Na2SO4, filtrated, and evaporated in vacuo. The residue was purified by pre-HPLC to afford an yellow solid (19.5 mg, 18.3%) as product. 1H-NMR (DMSO-d6): 10.08 (s, 1H), 8.10 to 7.99 (m, 3H), 7.91 (d, J=2.0 Hz, 1H), 7.88 (d, J=8.5 Hz, 1H), 7.81 (dd, J=8.5, 1.7 Hz, 1H), 7.70 (dd, J=8.4, 2.3 Hz, 1H), 7.59 (dt, J=7.6, 2.0 Hz, 1H), 7.47 to 7.37 (m, 2H), 2.06 (s, 3H); LC-MS (MH+=492/494).
Reaction SMILES: [C:1]1([C:7]2[S:8][CH:9]=[C:10]([C:12]([C:14]3[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=3)=O)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[NH2:27][NH2:28]>C(Cl)Cl.C(O)C>[N:27](=[C:12](/[C:14]1[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=1)\[C:10]1[N:11]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[S:8][CH:9]=1)\[NH2:28]
Reactant: NN
Reactant: COc1cc(C(=O)c2csc(-c3ccccc3)n2)cc(OC)c1OC
Solvent: CCO
Solvent: O
Solvent: ClCCl
Product: COc1cc(/C(=N/N)c2csc(-c3ccccc3)n2)cc(OC)c1OC

Procedure:
To a mixture of 1h (230 mg, 0.65 mmol) in 3 mL CH2Cl2 and 3 mL ethanol was added hydrazine hydrate (2 mL). Then the mixture was refluxed for overnight. After completion of the reaction, the residue was absorbed on silica gel and purified by column chromatography to give compounds 2d-cis (80 mg) and 2d-trans (56 mg). NMR (300 MHz, CDCl3) δ 8.01-7.98 (m, 2H), 7.49-7.46 (m, 5H), 7.33 (s, 1H), 6.82 (s, 2H), 3.87 (s, 3H), 3.85 (s, 6H). MS (ESI) m/z 370.1 (M+H)+.