Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]([O:5]C(C)(C)C)=[O:4].[NH:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1.[ClH:15]>C1COCC1.O1CCOCC1>[ClH:15].[N:10]1([CH2:2][C:3]([OH:5])=[O:4])[CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: C1CCNC1
Reactant: CC(C)(C)OC(=O)CBr
Agent: Cl
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: O=C(O)CN1CCCC1
Reaction time: 2 h
Yield: 97.4 %

Procedure:
A solution of 19.6 g (101 mmol) of t-butyl bromoacetate in 150 mL of THF was cooled in an ice bath and treated dropwise over about 0.5 hour with a solution of 14.4 g (202 mmol) of pyrrolidine in 75 mL of THF, to produce a white precipitate. The bath was removed and the reaction slurry stirred for two hours. The solid was removed by filtration and the filtrate was concentrated under reduced pressure to yield a clear liquid over an orange-colored solid. The liquid was cooled in an ice bath, then treated with 40 mL (80 mmol) of 4N HCl in dioxane and stirred for 15 hours. The solvents were removed in vacuo, and the residue was triturated with diethyl ether, then filtered to yield 12.9 g of the desired acid as an off-white solid.
Reaction SMILES: Cl.C([NH:4][C:5]1[S:6][C:7]([Br:31])=[C:8]([C:10](=[N:28][O:29][CH3:30])[C:11]([NH:13][CH:14]2[C:26](=[O:27])[N:16]3[C:17]([C:23]([OH:25])=[O:24])=[CH:18][CH:19]([O:21][CH3:22])[S:20][C@H:15]23)=[O:12])[N:9]=1)=O.C.[OH-].[Na+]>CO.O>[NH2:4][C:5]1[S:6][C:7]([Br:31])=[C:8]([C:10](=[N:28][O:29][CH3:30])[C:11]([NH:13][CH:14]2[C:26](=[O:27])[N:16]3[C:17]([C:23]([OH:25])=[O:24])=[CH:18][CH:19]([O:21][CH3:22])[S:20][C@H:15]23)=[O:12])[N:9]=1
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CC(OC)S[C@H]12)c1nc(NC=O)sc1Br
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CC(OC)S[C@H]12)c1nc(N)sc1Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.6 %

Procedure:
Conc. hydrochloric acid (0.7 ml.) was added to a solution of 7-[2-(2-formamido-5-bromothiazol-4-yl)-2-methoxyiminoacetamido]-2-methoxy-3-cephem-4-carboxylic acid (syn isomer, 1.4 g.) in methanol (45 ml.) and stirred at room temperature for 2 hrs. and further for 3.5 hrs. under ice-cooling. The reaction mixture was treated with activated charcoal. Water (30 ml.) was added to the solution and adjusted to pH 6.5 with 1N-aqueous sodium hydroxide, and methanol was distilled off. Ethyl acetate was added to the residue and adjusted to pH 2.5 with 1N-hydrochloric acid. The ethyl acetate layer was separated and the aqueous layer was washed with ethyl acetate. The ethyl acetate solution obtained above and the washings were combined, dried over magnesium sulfate, treated with activated charcoal and evaporated in vacuo. The residue was pulverized with diethyl ether, and the precipitates were collected by filtration and dried to give 7-[2-(2-amino-5-bromothiazol-4-yl)-2-methoxyiminoacetamido]-2-methoxy-3 -cephem-4-carboxylic acid (syn isomer, 1.2 g.).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[CH:11][C:10]([C:16]#[N:17])=[C:9]2Cl)=[O:5])[CH3:2].[N:19]1[CH:24]=[CH:23][CH:22]=[C:21](B(O)O)[CH:20]=1.C(=O)([O-])[O-].[Na+].[Na+]>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>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[CH:11][C:10]([C:16]#[N:17])=[C:9]2[C:21]1[CH:20]=[N:19][CH:24]=[CH:23][CH:22]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc2ncc(C#N)c(Cl)c2c1
Reactant: OB(O)c1cccnc1
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+]
Product: CCOC(=O)c1ccc2ncc(C#N)c(-c3cccnc3)c2c1

Procedure:
Similar procedure as described in example 61g was used, starting from 4-chloro-3-cyano-quinoline-6-carboxylic acid ethyl ester (example 46c), pyridine-3-boronic acid, tetrakis(triphenylphosphine)palladium(0), and sodium carbonate solution to give 3-cyano-4-pyridin-3-yl-quinoline-6-carboxylic acid ethyl ester. LC-MS m/e 304 (MH+).
Reaction SMILES: ClC1N=C(C2NC3C(C=2)=CC=CC=3)C(O)=CC=1.ClCI.C([O-])([O-])=O.[K+].[K+].[Cl:27][C:28]1[CH:29]=[CH:30][C:31]2[O:43][CH2:42][N:34]3[C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][C:40]=4[CH:41]=[C:33]3[C:32]=2[N:44]=1>CN(C=O)C.O>[Cl:27][C:28]1[CH:29]=[CH:30][C:31]2[O:43][CH2:42][C:41]3[C:40]4[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=4)[NH:34][C:33]=3[C:32]=2[N:44]=1
Reactant: Clc1ccc2c(n1)-c1cc3ccccc3n1CO2
Agent: ClCI
Agent: O=C([O-])[O-]
Agent: Oc1ccc(Cl)nc1-c1cc2ccccc2[nH]1
Solvent: CN(C)C=O
Solvent: O
Product: Clc1ccc2c(n1)-c1[nH]c3ccccc3c1CO2
Yield: 15.3 %

Procedure:
A solution of 6-chloro-2-(1H-indol-2-yl)pyridin-3-ol (500 mg, 3.05 mmol) in DMF (50 mL) was added dropwise to a mixture of chloroiodomethane (5.37 g, 30.5 mmol) and K2CO3 (1.26 g, 9.15 mmol) in DMF (50 mL) at 100° C. After addition, the mixture was diluted with water (100 mL) and extracted with EtOAc (50 mL*3). The organic layer was washed with brine (50 mL*3), dried over Na2SO4 and concentrated in vacuo. The resulting residue was purified using chromatography (petroleum ether:EtOAc=30:1) to provide the mixture of 2-chloro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indole and 2-chloro-6,11-dihydropyrido[2′,3′:5,6]pyrano[4,3-b]indole (ratio=3:1, 80 mg, yield: 15.3%), which was further purified with prep-HPLC to provide both of the isomers. MS (M+H)+: 257/259.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH:10]=[CH:9][S:8][C:6]=2[N:7]=1.[CH3:12][NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(O)C>[Cl:1][C:2]1[N:3]=[C:4]([N:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH3:12])[C:5]2[CH:10]=[CH:9][S:8][C:6]=2[N:7]=1
Reactant: CNc1ccccc1
Reactant: Clc1nc(Cl)c2ccsc2n1
Solvent: CCO
Product: CN(c1ccccc1)c1nc(Cl)nc2sccc12

Procedure:
2,4-Dichlorothieno[2,3-d]pyrimidine (4.5 g, 0.022 mol) and N-methylaniline (4.7 g, 0.044 mol) in ethanol (50 ml) were stirred at room temperature for 72 hours. The solid obtained was collected by filtration, washed with ethanol and dried, 5.15 g. Recrystallization from ethyl acetate gave the title compound, m.p. 167°-168°.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=[C:12]([CH3:20])[N:11]=2)[CH3:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:28](OC(=O)C)(=[O:30])[CH3:29].C(OCC)(=O)C>ClCCl.CN(C)C1C=CN=CC=1>[C:28]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=[C:12]([CH3:20])[N:11]=2)[CH3:9])=[CH:4][CH:3]=1)(=[O:30])[CH3:29]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1nc(N(C)c2ccc(N)cc2)c2ccccc2n1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ccc(N(C)c2nc(C)nc3ccccc23)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
To a solution of (4-amino-phenyl)-(2-methyl-quinazolin-4-yl)-methylamine (28 mg, 0.11 mmol) in 2 mL of dichloromethane with triethylamine (50 uL, 0.36 mmol) cooled at 0° C. was added acetic anhydride (50 uL, 0.53 mmol), followed by a few crystals of 4-dimethylaminopyridine, and the mixture was allowed to warm to room temperature. The reaction mixture was stirred for 0.5 h and 25 mL of ethyl acetate was added. The solution was washed with saturated NaHCO3, dried over anhydrous Na2SO4, filtered and concentrated. The crude was purified by column chromatography (80% ethyl acetate/hexane) to give the title compound (32.5 mg, 0.11 mmol, 100%). 1H NMR (CDCl3): 7.75 (d, J=8.1, 1H), 7.5-7.57 (m, 3H), 6.94-7.12 (m, 4H), 3.60 (s, 3H), 2.72 (s, 3H), 2.42 (s, 3H).
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][N:6]1[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:21]=[CH:20][C:16]([C:17]([OH:19])=O)=[CH:15][CH:14]=2)[CH2:8][CH2:7]1.[CH3:22][C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][C:24]=1[N+:30]([O-:32])=[O:31].N1C=CC=CC=1>C1(C)C=CC=CC=1>[CH3:22][C:23]1[CH:29]=[CH:28][C:26]([NH:27][C:17](=[O:19])[C:16]2[CH:15]=[CH:14][C:13]([CH2:12][N:9]3[CH2:8][CH2:7][N:6]([CH3:5])[CH2:11][CH2:10]3)=[CH:21][CH:20]=2)=[CH:25][C:24]=1[N+:30]([O-:32])=[O:31]
Reactant: CN1CCN(Cc2ccc(C(=O)O)cc2)CC1
Reactant: Cc1ccc(N)cc1[N+](=O)[O-]
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: Cc1ccc(NC(=O)c2ccc(CN3CCN(C)CC3)cc2)cc1[N+](=O)[O-]
Temperature: 23 °C
Reaction time: 6 h
Yield: 96 %

Procedure:
Thionyl chloride (53.3 g, 448 mmol) Is added over a period of 15 min to a suspension of 4-(4-methyl-piperazin-1-ylmethyl)-benzoic acid (70.0 g, 299 mmol) in toluene (300 ml) at 0° C. At the end of the addition, the reaction mixture is heated at 23° C. over a period of 45 min. The excess of SOCl2 is removed by co-distillation with toluene under reduced pressure at 40° C. At the end of the distillation, the resulting suspension id cooled down to 0° C. and the benzoyl chloride is filtered off, washed with toluene (2×50 ml) and dried in vacuo at 45° C. overnight. Yield: 55.0 g, 79% of theory based on the di-hydrochloride salt of the benzoylchloride, white solid. The dried benzoyl chloride (55 g) is then resuspended in toluene (100 ml). A solution of 4-methyl-3-nitroaniline (22.75 g, 145 mmol) and pyridine (34.4 g, 435 mmol) in toluene (60 ml) is added dropwise at 23° C. over a period of 15 min. The resulting orange-brown reaction mixture is heated at 45° C. and is stirred for 6 hrs. The suspension is filtrated and the filtercake is washed successively with toluene (300 ml) and acetone (350 ml), and is then suspended in water (350 ml). Aqueous NaOH (30%) is added until the pH of the suspension reaches 11 and remains stable. The suspension is further stirred for 1 h at 40° C. before being filtrated. The filtercake is washed with water (5×50 ml) and dried in vacuo to give 51.3 g of the title compound (96%) as beige crystals, (98.7% area by HPLC).
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11](B(O)O)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:18]1[C:19]([NH2:24])=[N:20][CH:21]=[CH:22][CH:23]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.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>[O:1]([C:8]1[CH:13]=[CH:12][C:11]([C:18]2[C:19]([NH2:24])=[N:20][CH:21]=[CH:22][CH:23]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ncccc1Br
Reactant: OB(O)c1ccc(Oc2ccccc2)cc1
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: COCCOC
Solvent: O
Product: Nc1ncccc1-c1ccc(Oc2ccccc2)cc1
Temperature: 80 °C
Reaction time: 20 h
Yield: 89.2 %

Procedure:
A mixture of 4-phenoxyphenylboronic acid (40.2 g), 3-bromopyridin-2-amine (25 g), tetrakis(triphenylphosphine)palladium(0) (5.01 g) and sodium carbonate (30.6 g) in DME (722 mL) and water (145 mL) was stirred at 80° C. under N2 for 20 hr. NH silica gel was added and the mixture was concentrated in vacuo. The residue was purified by column chromatography (NH silica gel, eluted with EtOAc in hexane) to give a white solid. The solid was crystallized from EtOAc and hexane to give the title compound (33.8 g) as a white solid.
Reaction SMILES: I[C:2]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=2[Cl:22])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH2:23]([SH:25])[CH3:24].[H-].[Na+].Cl>CN(C)C=O>[CH2:23]([S:25][C:2]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=2[Cl:22])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5])[CH3:24]
Reactant: CCS
Reactant: O=C(O)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1I
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCSc1ccc(Oc2ccc(C(F)(F)F)cc2Cl)cc1C(=O)O

Procedure:
2-Iodo-5-(2-chloro-4-trifluoromethylphenoxy)benzoic acid (0.1 mole) in dimethylformamide (500 ml) was cooled to 0°. Cuprous oxide (0.11 mole) was added, followed by ethyl mercaptan (0.1 mole). The mixture was stirred while sodium hydride (0.25 mole) was added in portions. After 15 minutes the temperature was raised to 80° for 6 hours. The mixture was cooled and poured into hydrochloric acid (2 molar). The mixture was twice extracted with ether. The ether extract was washed with water, dried (Na2SO4) and evaporated. The residue was recrystallised from ether to give 2-ethylthio-5-(2-chloro-4-trifluoromethylphenoxy)benzoic acid, with a melting point of 153°-155°.
Reaction SMILES: [C:1]([C:3]1[C:7]([S:8]([C:11]([F:14])([F:13])[F:12])(=[O:10])=[O:9])=[C:6]([NH:15][NH2:16])[N:5]([C:17]2[C:22]([Cl:23])=[CH:21][C:20]([C:24]([F:27])([F:26])[F:25])=[CH:19][C:18]=2[Cl:28])[N:4]=1)#[N:2].CO[CH:31](OC)[CH2:32][CH:33](OC)OC.Cl>C(O)C>[C:1]([C:3]1[C:7]([S:8]([C:11]([F:12])([F:13])[F:14])(=[O:10])=[O:9])=[C:6]([N:15]2[CH:33]=[CH:32][CH:31]=[N:16]2)[N:5]([C:17]2[C:22]([Cl:23])=[CH:21][C:20]([C:24]([F:26])([F:25])[F:27])=[CH:19][C:18]=2[Cl:28])[N:4]=1)#[N:2]
Reactant: COC(CC(OC)OC)OC
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(NN)c1S(=O)(=O)C(F)(F)F
Agent: Cl
Solvent: CCO
Product: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(-n2cccn2)c1S(=O)(=O)C(F)(F)F
Yield: 34.8 %

Procedure:
A mixture of 3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-5-hydrazino-4-trifluoromethylsulphonylpyrazole (1.6 g), 1,1,3,3-tetramethoxypropane (0.58 g), ethanol (10 ml) and concentrated hydrochloric acid (1 ml) was heated under reflux for 4 hours. After evaporation in vacuo the residue was dissolved in dichloromethane (200 ml) and washed in turn with sodium bicarbonate solution (2×50 ml) and with water (50 ml). Filtration (phase separating paper), followed by evaporation gave a red solid, which was purified by chromatography on silica, eluting with dichloromethane/hexane (1:1). The product was recrystallised from toluene giving 3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-5-pyrazol-1-yl-4-trifluoromethylsulphonylpyrazole (0.6 g) as a white solid, m.p. 191°-193° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][CH3:10])=[N+:4]([O-])[C:3]=1[C:12]([O:14][CH3:15])=[O:13].P(Cl)(Cl)([Cl:18])=O>C(#N)C>[Cl:1][C:2]1[C:3]([C:12]([O:14][CH3:15])=[O:13])=[N:4][C:5]([CH2:8][O:9][CH3:10])=[CH:6][C:7]=1[Cl:18]
Reactant: COCc1ccc(Cl)c(C(=O)OC)[n+]1[O-]
Reactant: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: COCc1cc(Cl)c(Cl)c(C(=O)OC)n1
Temperature: 25 °C
Yield: 98.3 %

Procedure:
To a solution of methyl 3-chloro-6-(methoxymethyl)pyridine-2-carboxylate 1-oxide (1.64 g, 7.08 mmol) in acetonitrile (28 mL) was added phosphorus oxychloride (1.32 mL, 14.16 mmol) and the mixture stirred at reflux for 4 hours. After cooling to room temperature the mixture was concentrated to dryness in vacuo. The residue was diluted with ethyl ether and carefully washed with saturated NaHCO3 solution. The organic layer was separated and the aqueous layer was extracted with ethyl ether. After the organic layers were combined, the solution was dried (MgSO4), filtered and concentrated to dryness to give crude methyl 3,4-dichloro-6-(methoxymethyl)pyridine-2-carboxylate (1.74 g) as a yellow oil; 1H NMR (CDCl3): δ 7.70 (s, 1H), 4.60 (s, 2H), 4.00 (s, 3H), 3.40 (s, 3H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:8]=[C:9]([CH:14]=[CH:15][CH:16]=2)[C:10](OC)=[O:11])[CH2:3][CH2:2]1.[NH2:17][NH2:18]>CO>[O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:8]=[C:9]([CH:14]=[CH:15][CH:16]=2)[C:10]([NH:17][NH2:18])=[O:11])[CH2:3][CH2:2]1
Reactant: NN
Reactant: COC(=O)c1cccc(N2CCOCC2)c1
Solvent: CO
Product: NNC(=O)c1cccc(N2CCOCC2)c1
Temperature: 65 °C
Yield: 52 %

Procedure:
Methyl 3-morpholinobenzoate (100 mg, 0.452 mmol) was added to hydrazine (14.48 mg, 0.452 mmol) in methanol (10 mL) and refluxed for 12 h at 65° C. The reaction was monitored by TLC. Upon completion of the reaction and following cooling, the solvent was removed by vacuum and the compound was purified by column chromatography (2% CH3OH/CH2Cl2) affording the title compound as a solid (52 mg). 1H NMR (400 MHz, DMSO-d6): δ 9.69 (s, 1H), 7.35 (s, 1H), 7.27 (m, 2H), 7.07 (m, 1H), 4.45 (bs, 2H), 3.74 (m, 4H), 3.14 (m, 4H). ESI-MS: 222.1 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][N:3]=1.Br[CH2:10][C:11](=O)[C:12]([O:14][CH2:15][CH3:16])=[O:13]>C(#N)C>[Br:8][C:6]1[CH:5]=[CH:4][N:3]2[CH:10]=[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:1]=[C:2]2[CH:7]=1
Reactant: Nc1cc(Br)ccn1
Reactant: CCOC(=O)C(=O)CBr
Solvent: CC#N
Product: CCOC(=O)c1cn2ccc(Br)cc2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 56.8 %

Procedure:
0.6 g (3.47 mmol) of 2-amino-4-bromopyridine, 1.55 g (7.15 mmol) of ethyl bromopyruvate and 4 mL of acetonitrile are placed in a 20 mL screw-topped tube equipped with a magnetic bar. The top is then screwed on and the tube is stirred at room temperature for 1 hour, and then heated at 150° C. with stirring for 30 minutes. After this time and cooling to room temperature, the precipitate obtained is filtered off, rinsed with acetonitrile and dried. The filtrate is concentrated to dryness and then purified by chromatography on a column of silica gel, eluting with a mixture of dichloromethane and methanol. The solid obtained after evaporating off the solvent is dried under reduced pressure. 530 mg of the expected product are obtained in total.
Reaction SMILES: [C:1]([CH2:3][C:4]([C:6]1[S:7][CH:8]=[CH:9][N:10]=1)=[O:5])#[N:2].CO[CH:13](OC)[N:14]([CH3:16])[CH3:15]>>[C:1]([C:3](=[CH:13][N:14]([CH3:16])[CH3:15])[C:4]([C:6]1[S:7][CH:8]=[CH:9][N:10]=1)=[O:5])#[N:2]
Reactant: COC(OC)N(C)C
Reactant: N#CCC(=O)c1nccs1
Product: CN(C)C=C(C#N)C(=O)c1nccs1

Procedure:
2-Cyano-3-dimethylamino-1-thiazol-2-ylpropen-1-one was prepared from 2-cyanoacetyl thiazole (400 mg,2.94 mmol) and dimethylformamide dimethylacetal (1.5 mL) as a yellow solid, m.p. 126° δH (CDCl3) 8.89 (1H, s), 7.96 (1H, d, J 3.3 Hz), 7.60 (1H, d, J 3.1 Hz), 3.54 (3H, s) and 3.35 (3H, s).
Reaction SMILES: O[N:2]=[C:3]([C:11](=O)[C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].[CH2:19]([NH2:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(#N)C>[C:20]1([C:19]2[NH:26][C:11]([C:12]3[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=3)=[C:3]([C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])[N:2]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: NCc1ccccc1
Reactant: CC(C)(C)OC(=O)C(=NO)C(=O)c1cccnc1
Solvent: CC#N
Product: CC(C)(C)OC(=O)c1nc(-c2ccccc2)[nH]c1-c1cccnc1
Yield: 41.8 %

Procedure:
tert-Butyl 2-hydroxyimino-3-oxo-3-(3-pyridyl)propionate (4.1 g), benzylamine (3.5 g) and acetonitrile (80 ml) were reacted and treated in the same manner as in Starting Material Synthetic Example 5 to give tert-butyl 2-phenyl-5-(3-pyridyl)imidazole-4-carboxylate (2.2 g), melting point 196-197° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[OH:9].C(=O)([O-])[O-].[K+].[K+].I[CH2:17][CH2:18][CH3:19].O>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[O:9][CH2:17][CH2:18][CH3:19]
Reactant: Oc1cc(F)ccc1Br
Reactant: CCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCOc1cc(F)ccc1Br
Temperature: 25 °C
Reaction time: 10 h

Procedure:
A total of 5 g of 2-bromo-5-fluoro-phenol was dissolved in 66 ml of N,N-dimethylformamide. Under ice-cooling, 5.42 g of potassium carbonate and 3.07 ml of iodopropane were added, and the mixture was stirred at room temperature for 10 hours. Water was added to the reaction mixture, followed by extracting with diethyl ether. The resulting organic layer was washed with brine, dried over magnesium sulfate and the solvent was evaporated, to give 8.29 g of the title compound as a yellow oil.
Reaction SMILES: [H-].[Na+].C([O:5][CH2:6][CH3:7])=O.[CH2:8]([N:15]1[C:19]2[CH2:20]C[C:22](=[O:23])[C:18]=2[CH:17]=[N:16]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(O)C.O1CCCC1.O>[CH2:8]([N:15]1[C:19]2[CH2:20][C:7](=[CH:6][OH:5])[C:22](=[O:23])[C:18]=2[CH:17]=[N:16]1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: O=C1CCc2c1cnn2Cc1ccccc1
Reactant: CCOC=O
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: O=C1C(=CO)Cc2c1cnn2Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (1.44 grams of a 60% suspension in mineral oil), 1.46 ml of ethyl formate and 3 drops of ethanol were combined in 150 ml of anhydrous tetrahydrofuran and stirred at room temperature for 30 minutes. A solution of 4 grams of 1-benzyl-5,6-dihydro-4(1H)-cyclopentapyrazolone in 50 ml of anhydrous tetrahydrofuran was added dropwise and the reaction mixture was heated at reflux for 16 hours. An additional 1.44 grams of sodium hydride suspension and 1.46 ml of ethyl formate were then added and the reaction mixture was heated at reflux for 2 hours. The mixture was cooled, diluted with 150 ml of water, and washed with ethyl ether. The aqueous layer was acidified with aqueous hydrochloric acid and the solid which formed was collected by filtration to give 1-benzyl-5,6-dihydro-5-hydroxymethylene-4(1H)-cyclopentapyrazolone as a tan solid melting at about 171°-172° C.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH:15]=[C:14]([C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:20]=[CH:19][N:18]=2)[CH2:13][CH2:12]1)=O)C1C=CC=CC=1>CO.[Pd]>[NH:11]1[CH2:12][CH:13]=[C:14]([C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:20]=[CH:19][N:18]=2)[CH2:15][CH2:16]1
Reactant: O=C(OCc1ccccc1)N1CC=C(c2ncnc3ccccc23)CC1
Agent: [Pd]
Solvent: CO
Product: C1=C(c2ncnc3ccccc23)CCNC1
Yield: 64.4 %

Procedure:
To a stirred solution of 4-Quinazolin-4-yl-3,6-dihydro-2H-pyridine-1-carboxylic acid benzyl ester (0.907 g, 2.63 mmol) in MeOH (30 mL) under N2 was cautiously added 10% Pd on carbon (100 mg). The reaction was hydrogenated at 50 psi using a parr shaker for 3 days. The catalyst was removed by filtration. The filtrate was evaporated under vacuum. The resulting residue was purified by column chromatography (DCM:MeOH, 20:1 to DCM:MeOH:Et3N, 100:10:1) to give 4-(1,2,3,6-Tetrahydro-pyridin-4-yl)-quinazoline (0.358 g, 64%) as a white waxy solid. 1H NMR (CDCl3, 400 MHz) δ 9.27 (s, 1H), 8.19 (d, J=8.4 Hz, 1H), 8.06 (d, J=8.4 Hz, 1H), 7.88 (t, J=8.4 Hz, 1H), 7.65 (t, J=8.4 Hz, 1H), 3.71 (m, 1H), 3.31 (m, 2H), 2.90 (m, 2H), 1.99 (m, 4H). LCMS (APCI+) m/z 214 [M+H]+; Rt=1.60 min.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]2[N:15]([C:16]=1[C:17]1[CH:18]=[N:19][C:20]([NH:23][NH2:24])=[CH:21][CH:22]=1)[CH:14]=[CH:13][O:12]2.F[C:26]1C=CC(C2N=C3N(C=2)C=CO3)=CC=1.C1C(=O)N(I)C(=O)C1.FC1C=CC(B(O)O)=CN=1.NN.O=CC(OCC)=O.C(O)(=O)C.C(O)(=O)C.IC1C=CC=CC=1.[Li+].[OH-]>CO.O>[N:23]1[N:24]=[CH:26][N:19]2[CH:18]=[C:17]([C:16]3[N:15]4[C:11]([O:12][CH:13]=[CH:14]4)=[N:10][C:9]=3[C:3]3[CH:4]=[CH:5][C:6]([F:8])=[CH:7][CH:2]=3)[CH:22]=[CH:21][C:20]=12
Reactant: Fc1ccc(-c2cn3ccoc3n2)cc1
Reactant: NNc1ccc(-c2c(-c3ccc(F)cc3F)nc3occn23)cn1
Agent: CCOC(=O)C=O
Agent: NN
Agent: O=C1CCC(=O)N1I
Solvent: Ic1ccccc1
Solvent: CC(=O)O
Solvent: O
Product: Fc1ccc(-c2nc3occn3c2-c2ccc3nncn3c2)cc1
Temperature: 65 °C
Reaction time: 0.25 h
Yield: 80 %

Procedure:
The 6-(2,4-difluorophenyl)-5-(6-hydrazinylpyridin-3-yl)imidazo[2,1-b]oxazole (0.20 g, 0.65 mmol; prepared using A from 6-(4-fluorophenyl)-imidazo[2,1-b]oxazole [prepared according to WO2004110990A2, Example 1, Steps 1-3] with NIS, C with 2-fluoropyridine-5-boronic acid [Asymchem], D with hydrazine) and ethyl 2-oxoacetate (0.65 mL, 9.7 mmol) were dissolved in MeOH (5.0 mL) and heated to about 65° C. for about 1 h. The MeOH was evaporated and then DCM (5 mL) was added followed by iodobenzene diacetate (0.53 g, 1.6 mmol). The reaction was stirred for about 15 min then the DCM was evaporated and the resulting solid was triturated with Et2O. The solid was dissolved in 1,4-dioxane (10 mL) and LiOH (0.060 g, 2.4 mmol) dissolved in water (2 mL) was added drop-wise followed by heating to about 50° C. for about 30 min. The 1,4-dioxane was evaporated and the pH was adjusted to about 1 with 1N HCl. The resulting precipitate was filtered and washed with water (about 10 mL) and dried in a vacuum oven to give the title compound (0.31 g, 80%): LC/MS (Table 1, Method a) Rt=1.88 min; MS m/z: 320.1 (M+H)+.