Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH:12]([CH3:14])[CH3:13])[C:5](O)=[O:6].[Cl:15]CCl.C(Cl)(=O)C(Cl)=O>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH:12]([CH3:14])[CH3:13])[C:5]([Cl:15])=[O:6]
Reactant: CC(C)Oc1ccc(C(=O)O)cc1Cl
Reactant: ClCCl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc(C(=O)Cl)cc1Cl
Temperature: 0 °C

Procedure:
A round bottom flask was charged with 3-chloro-4-[(1-methylethyl)oxy]benzoic acid (available from Paragos Product List, 10.2 g, 47.5 mmol), dichloromethane (158 ml) and oxalyl chloride (8.29 ml, 95 mmol). The reaction mixture was cooled to 0° C. in an ice/water bath prior to the addition of N,N-dimethylformamide (0.158 ml). The solution was allowed to warm to ambient temperature overnight. The solvent was evaporated to yield the title compound as a cream solid (11.4 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C:5]1[CH:10]=[C:9]([F:11])[C:8](F)=[C:7]([Cl:13])[C:6]=1[F:14])[CH3:2].C(N(CC)CC)C.[C:23]([O:27][C:28](=[O:35])[NH:29][C@H:30]1[CH2:34][CH2:33][NH:32][CH2:31]1)([CH3:26])([CH3:25])[CH3:24]>C(#N)C.C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:15])[C:5]1[CH:10]=[C:9]([F:11])[C:8]([N:32]2[CH2:33][CH2:34][C@H:30]([NH:29][C:28]([O:27][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:35])[CH2:31]2)=[C:7]([Cl:13])[C:6]=1[F:14])[CH3:2]
Reactant: CCOC(=O)c1cc(F)c(F)c(Cl)c1F
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cc(F)c(N2CC[C@H](NC(=O)OC(C)(C)C)C2)c(Cl)c1F
Reaction time: 48 h
Yield: 100.1 %

Procedure:
To a solution of 3-chloro-2,4,5-trifluorobenzoic acid ethyl ester (Example 1c, 5.50 g, 23.05 mmol) in acetonitrile (25 mL) is added triethylamine (6.43 mL, 46.1 mmol) and (S)-pyrrolidin-3-ylcarbamic acid tert-butyl ester (4.72 g, 25.4 mmol). After 48 hours, the mixture is diluted with ethyl acetate and washed with saturated NaHCO3, water, and brine. The organic layer is dried over MgSO4, filtered, and the filtrate is concentrated to afford the title compound (9.34 g). MS CI: m/z 405 (MH+).
Reaction SMILES: C(O)C.[Cl-].[NH4+].[CH3:6][C:7]1[CH:12]=[C:11]([CH3:13])[CH:10]=[CH:9][C:8]=1[N:14]1[CH2:19][CH2:18][N:17]([C:20]([C:22]2[CH:27]=[CH:26][C:25]([N+:28]([O-])=O)=[CH:24][C:23]=2[NH:31][S:32]([CH3:35])(=[O:34])=[O:33])=[O:21])[CH2:16][CH2:15]1>[Fe].O>[NH2:28][C:25]1[CH:26]=[CH:27][C:22]([C:20]([N:17]2[CH2:16][CH2:15][N:14]([C:8]3[CH:9]=[CH:10][C:11]([CH3:13])=[CH:12][C:7]=3[CH3:6])[CH2:19][CH2:18]2)=[O:21])=[C:23]([NH:31][S:32]([CH3:35])(=[O:34])=[O:33])[CH:24]=1
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc([N+](=O)[O-])cc3NS(C)(=O)=O)CC2)c(C)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N)cc3NS(C)(=O)=O)CC2)c(C)c1
Temperature: 60 °C
Yield: 107.9 %

Procedure:
Methyl 2-amino-4-nitrobenzoate (600 mg) and triethylamine (2.9 mL) were dissolved in tetrahydrofuran (11 mL), methanesulfonyl chloride (0.51 mL) was added under ice-cooling, and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, and the solvent was evaporated. Methanol (18 mL) and 1N aqueous sodium hydroxide solution (9.1 mL) were added to the obtained residue, and the mixture was stirred at 50° C.-60° C. After completion of the reaction, to the reaction mixture was added aqueous sodium hydroxide solution, and the mixture was partitioned with ethyl acetate. The aqueous layer was neutralized with diluted hydrochloric acid, and the precipitated solid was collected by filtration to give 2-methanesulfonylamino-4-nitrobenzoic acid (358 mg). Using the obtained 2-methanesulfonylamino-4-nitrobenzoic acid (358 mg) and 1-(2,4-dimethylphenyl)piperazine (262 mg) and by the reaction and treatment in the same manner as in Preparation Example 111, N-{2-[4-(2,4-dimethylphenyl)piperazine-1-carbonyl]-5-nitrophenyl}methanesulfonamide (330 mg) was obtained. Then, to a solution of ethanol (5.4 mL) and water (1.8 mL) were added ammonium chloride (528 mg) and iron (379 mg), and the obtained N-{2-[4-(2,4-dimethylphenyl)piperazine-1-carbonyl]-5-nitrophenyl}methanesulfonamide (267 mg) was added while stirring at 60° C. After completion of the reaction, the insoluble material was collected by filtration, and the filtrate was concentrated. To the obtained residue was added aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The solvent was evaporated from the organic layer to give the title compound (268 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([Cl:9])[C:6]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:5][C:3]=1[NH2:4].[C:15](Cl)(Cl)=[S:16]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:8]=[C:7]([Cl:9])[C:6]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:5][C:3]=1[N:4]=[C:15]=[S:16]
Reactant: CCOC(=O)c1cc(N)c(Cl)cc1Cl
Reactant: S=C(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cc(N=C=S)c(Cl)cc1Cl
Temperature: 10 °C
Reaction time: 2 h
Yield: 97.8 %

Procedure:
23.4 g (0.1 mol) of 2,4-dichloro-5-ethoxycarbonylaniline were dissolved in 80 ml of chloroform. The resulting solution was cooled to 10° C. or lower and 14.9 g (0.13 mol) of thiophosgene were added dropwise thereto. The mixture was stirred at room temperature for two hours, and then refluxed for three hours. The reaction mixture was concentrated to give 27 g (yield 97.7%) of the desired product as pale brown crystals with a melting point of 45°-46° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[C@@H:4](/[CH:5]=[CH:6]\[C:7](=[O:16])[O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C@H:3]1[C:17](Cl)=[O:18].CC1(C)[C@@H](/C=C\C(OCC(F)(F)F)=O)[C@H]1C([O:37][C@H:38]([C:52]#N)[C:39]1[CH:44]=[CH:43][CH:42]=[C:41]([O:45]C2C=CC=CC=2)[CH:40]=1)=O.[CH:55]1C=CC=CC=1.Cl>O.N1C=CC=CC=1>[CH3:1][C:2]1([CH3:20])[C@@H:4](/[CH:5]=[CH:6]\[C:7](=[O:16])[O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C@H:3]1[C:17]([O:45][C@H:41]1[CH2:52][C:38](=[O:37])[C:39]([CH2:44][CH:43]=[CH2:42])=[C:40]1[CH3:55])=[O:18]
Reactant: CC1(C)[C@H](C(=O)Cl)[C@@H]1/C=C\C(=O)OCc1ccccc1
Reactant: CC1(C)[C@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)[C@@H]1/C=C\C(=O)OCC(F)(F)F
Reactant: c1ccccc1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: C=CCC1=C(C)[C@@H](OC(=O)[C@@H]2[C@H](/C=C\C(=O)OCc3ccccc3)C2(C)C)CC1=O
Reaction time: 6 h

Procedure:
1 g of (1R,cis) 2,2-dimethyl-3-[(Z) 3-oxo-3-benzyloxy-1-propenyl]-cyclopropane-carboxylic acid chloride was added to a mixture of 450 mg of (S) 3-(2-propenyl)-1-hydroxy-2-methyl-4-oxo-cyclopent-2-en-1-yl, 20 ml of benzene and 0.6 ml of pyridine and the mixture was stirred for 6 hours and was then poured into a mixture of iced water and N hydrochloric acid. The mixture was extracted with benzene and the combined benzene phases was washed with water, dried and evaporated to dryness. The 1.5 g of residue was chromatographed over silica gel and was eluted with an 8-2 cyclohexane-ethyl acetate mixture to obtain (1S) 2-methyl-4-oxo-3-(2-propenyl)-2-cyclopenten-1-yl (1R,cis) 2,2-dimethyl-3-[(Z) 3-oxo-3-benzyloxy-1-propenyl]-cyclopropane-carboxylate having a specific rotation of [α]D20 =+37°±2.5 (c=0.5% in benzene).
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(CC)CC)C>C(#N)C>[CH2:14]([N:4]1[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: BrCc1ccccc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
In acetonitrile (80 ml), tert-butyl 1-piperazine carboxylate (2.50 g) was dissolved. Under ice cooling, benzyl bromide (1.59 ml) and triethylamine (1.87 ml) were added dropwise to the resulting solution, followed by stirring at room temperature for 90 minutes. After the solvent was distilled off under reduced pressure, distilled water and dichloromethane were added to the residue to separate the organic layer. The organic layer was washed with saturated aqueous NaCl solution and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by chromatography on a silica gel column (ethyl acetate:hexane=1:20 to 1:5), whereby the title compound (3.12 g, 84%) was obtained as colorless powder.
Reaction SMILES: [CH3:1][S:2](Br)(=[O:4])=[O:3].[CH2:6]([O:9][CH3:10])[CH:7]=[CH2:8].OO.C(N(CC)CC)C>C1C=CC=CC=1.[Cl-].[Zn+2].[Cl-]>[CH3:1][S:2]([CH:8]=[CH:7][CH2:6][O:9][CH3:10])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Br
Reactant: C=CCOC
Agent: OO
Agent: [Cl-]
Agent: [Zn+2]
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: COCC=CS(C)(=O)=O
Reaction time: 0.5 h
Yield: 83.2 %

Procedure:
159 g (1 mole) of methanesulfonyl bromide are slowly added dropwise, at 45° C., to a mixture of 78 g (1.07 moles) of methyl allyl ether, 7.5 g of zinc chloride and 3.3 ml of 50% strength hydrogen peroxide. After the exothermic reaction has subsided, the mixture is stirred for a further 30 minutes and is diluted with 450 ml of benzene, and 135 g (1.33 moles) of triethylamine are added at room temperature, whilst cooling. After 2 hours, the precipitate is filtered off and the solvent is distilled off. Distillation of the residue gives 125 g of 1-methylsulfonyl-3-methoxy-prop-1-ene, boiling point 114°-115° C./0.3 mm Hg. According to the NMR spectrum, the product is a mixture of cis and trans isomers in the ratio of 15:85.
Reaction SMILES: [O:1]=[C:2]1[C:8](=[CH:9][OH:10])[C:7](=[O:11])[N:6]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:5]=[CH:4][N:3]1[CH2:18][C:19]([N:21]([CH:30]([CH3:32])[CH3:31])[C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1)=[O:20].[CH3:33][S:34](Cl)(=[O:36])=[O:35].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[O:1]=[C:2]1[C:8](=[CH:9][O:10][S:34]([CH3:33])(=[O:36])=[O:35])[C:7](=[O:11])[N:6]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:5]=[CH:4][N:3]1[CH2:18][C:19]([N:21]([CH:30]([CH3:32])[CH3:31])[C:22]1[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=1)=[O:20]
Reactant: COc1ccc(N(C(=O)CN2C=CN(c3ccccc3)C(=O)C(=CO)C2=O)C(C)C)cc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(N(C(=O)CN2C=CN(c3ccccc3)C(=O)C(=COS(C)(=O)=O)C2=O)C(C)C)cc1

Procedure:
A solution of 2-[2,4-dioxo-3-(hydroxymethylene)-5-phenyl-2,3,4,5-tetrahydro-1H-1,5-diazepin-1-yl]-N-isopropyl-N-(4-methoxyphenyl)acetamide (−12r, 0.500 g) in CH2Cl2 (10 mL) under argon was treated with methanesulfonyl chloride (0.266 mL) and diisopropylethylamine (0.598 mL). After several minutes, the reaction was transferred to a separatory funnel and washed with aqueous 1N NaHSO4. The aqueous layer was back-extracted with CH2Cl2. The combined organic layers were dried over anhydrous MgSO4, filtered and evaporated in vacuo. The residue was purified on flash grade silica gel eluting with 2:3 ethyl acetate/hexane. Fractions containing the product were combined, evaporated in vacuo and triturated with hexane. Hexane was removed in vacuo and the residual solid was dried under high vacuum to provide 2-[2,4-dioxo-3-(methanesulfonyloxymethylene)-5-phenyl-2,3,4,5-tetrahydro-1H-1,5-diazepin-1-yl]-N-isopropyl-N-(4-methoxyphenyl)acetamide (12s, 0.502 g) as a solid. The product was contaminated with approximately 40% of 2-[2,4-dioxo-3-methylene-5-phenyl-2,3,4,5-tetrahydro-1H-1,5-diazepin-1-yl]-N-isopropyl-N-(4-methoxyphenyl)acetamide which reacted equally well in the subsequent steps. 1H NMR (300 MHz, CDCl3) 1.10 (d, J=7 Hz, 6H), 3.15 (s, 3H), 3.89 (s, 3H), 3.96 (d, J=2 Hz, 2H), 4.92 (m, 4H), 6.03 (m, 2H), 7.00 (m, 2H), 7.18 (m, 2H), 7.40 (m, 5H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8](I)=[C:9]([CH2:11][S:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[N:10]=2)[CH:7]=1.[C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=1)#[CH:21].C(N(CC)CC)C>CN(C=O)C.[Cu](I)I.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:21]#[C:20][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:29])([F:30])[F:31])[CH:23]=3)=[C:9]([CH2:11][S:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[N:10]=2)[CH:7]=1
Reactant: C#Cc1cccc(C(F)(F)F)c1
Reactant: CCOC(=O)CSCc1nc2ccc(Cl)cn2c1I
Agent: I[Cu]I
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)CSCc1nc2ccc(Cl)cn2c1C#Cc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.7 %

Procedure:
In an argon atmosphere, 27 g (59.8 mmol) of ethyl 2-((6-chloro-3-iodoimidazo[1,2-a]-pyridin-2-yl)methylthio)acetate, 9.51 ml (65.8 mmol) of 1-ethynyl-3-(trifluoromethyl)benzene, 1.139 g (5.98 mmol) of copper iodide and 125 ml (897 mmol) of triethylamine are loaded in 100 ml of DMF. Argon was bubbled in the solution for 10 min, and then 2.74 g (2.99 mmol) of Pd2(dba)3 were added. The mixture was stirred for 1 h at r.t. The catalyst was filtered on folded paper, the solution was poured onto 300 ml of water, extracted with 2×200 ml of ethyl acetate, the collected organic phases were washed with 3×150 ml of water and once with 150 ml of brine, dried on Na2SO4 which was then removed by filtration and the obtained filtrate was concentrated in vacuo. The residue was purified on a silica cake, and eluted with a heptane/ethyl acetate mixture. 23.21 g (yield=85%) of ethyl 2-((6-chloro-3-((3-(trifluoromethyl)phenyl)ethynyl)-imidazo[1,2-a]pyridin-2-yl)methylthio)acetate were obtained as a yellow solid. LC-MS: m/z=453 (MH+) UV purity at 254 nm=99%. 1H NMR (300 MHz, DMSO) δ 8.91 (dd, J=1.9, 0.6 Hz, 1H), 8.14 (s, 1H), 8.01 (d, J=7.6 Hz, 1H), 7.71 (ddd, J=14.3, 9.4, 4.3 Hz, 3H), 7.47 (dd, J=9.5, 2.0 Hz, 1H), 4.18-3.93 (m, 4H), 3.46 (s, 2H), 1.11 (t, J=7.1 Hz, 3H).
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]([CH:19]([CH3:21])[CH3:20])[C:3]1=[O:22].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C([NH:44][C@@H:45]([C:53](O)=[O:54])[CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)(OC(C)(C)C)=O>CN(C)C=O.C(=O)([O-])O.[Na+].C(OCC)(=O)C>[NH2:44][C@H:45]([CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)[C:53]([NH:1][CH:2]1[C:3](=[O:22])[N:4]([CH:19]([CH3:20])[CH3:21])[C:5]2[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=2[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:8]1)=[O:54]
Reactant: CC(C)N1C(=O)C(N)N=C(c2ccccc2)c2ccccc21
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)C(=O)O
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)N1C(=O)C(NC(=O)[C@H](N)Cc2ccccc2)N=C(c2ccccc2)c2ccccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirring solution of (+)-3-amino-2,3-dihydro-1-(2-propyl)-2-oxo-5-phenyl-1H-1,4-benzodiazepine (40.8 g, 139 mmol) in dimethylformamide (140 mL) was added EDC (32.0 g, 167 mmol), HOBT (22.6 g, 167 mmol) and N-BOC-D-phenylalanine (44.3 g, 167 mmol). This was stirred at ambient temperature for 2 h. The reaction was diluted with saturated aqueous sodium hydrogen carbonate (1.5 L) and extracted with ethyl acetate (3×1 L). The organic layers were combined, dried with brine, anhydrous magnesium sulfate, filtered, and evaporated under reduced pressure to give a yellow oil which was dissolved in ethyl acetate (700 mL), cooled in an ice/water bath. Hydrogen chloride gas was bubbled into the solution for 3 h. The reaction mixture was concentrated under reduced pressure and the resulting foam was dissolved in ethyl acetate (1 L) and saturated aqueous sodium hydrogen carbonate (1 L). The layers were separated and the aqueous layer was extracted with ethyl acetate again (2×1 L). The organic layers were combined, dried with brine, anhydrous magnesium sulfate, filtered, and evaporated under reduced pressure to give a white solid, which was chromatographed over silica (2.5 kg) with ethyl acetate. The faster running diastereomer was recovered as a white solid (22.0 g, 72%). 1H NMR, CDCl3, δ 9.02 (d, J=8.6 Hz, 1H), 7.64-7.25 (m, 14H), 5.50 (d, J=8.6 Hz, 1H), 4.54 (septet, J=7.0 Hz, 1H), 3.70 (dd, J=3.9, 9.8 Hz, 1H), 3.34 (dd, J=3.9, 13.8 Hz, 1H), 2.82 (dd, J=9.8, 13.8 Hz, 1H), 1.51-1.40 (m, 5H), 1.27 (d, J=7.0 Hz, 1H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:9])[CH2:4][CH2:3]1.[BH4-].[Na+]>CO>[CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([CH:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[OH:9])[CH2:4][CH2:3]1
Reactant: CN1CCC(C(=O)c2ccccc2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CN1CCC(C(O)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.4 %

Procedure:
To a solution of 1-methylpiperidin-4-yl phenyl methanone 1.02 g (5 mmol) in 30ml methanol was added in small portions sodium borohydride 0.378 g (10 mmol). The reaction mixture was stirred at room temperature for two hours, concentrated, added water and extracted with methylene chloride 2×50 ml. The combined organic solution was dried over sodium sulfate and concentrated to give 1 g of the title compound in 98% yield.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[OH:11])[C:5]([OH:7])=[O:6].Cl[C:13]([O:15][CH3:16])=[O:14].[OH-].[Na+]>O>[CH3:16][O:15][C:13]([O:11][C:10]1[CH:9]=[CH:8][C:4]([C:5]([OH:7])=[O:6])=[CH:3][C:2]=1[F:1])=[O:14]
Reactant: COC(=O)Cl
Reactant: O=C(O)c1ccc(O)c(F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COC(=O)Oc1ccc(C(=O)O)cc1F
Temperature: -20 °C
Reaction time: 4 h

Procedure:
4-methoxycarbonyloxy-3-fluorobenzoic acid (VI) was synthesized from 3-fluoro-4-hydroxybenzoic acid (V) by reaction of the latter with methyl chloroformate. NaOH (90 mmol) and 3-fluoro-4-hydroxybenzoic acid (30 mmol) were dissolved in water (80 ml) and cooled to -20° C. Methyl chloroformate (45 mmol) was added dropwise to the mixture. The mixture was then stirred with a magnetic stir bar at 5° C. for four hours and left overnight in the refrigerator. The mixture was then acidified to pH 5 to precipitate 4-methoxycarbonyloxy-3-fluorobenzoic acid. The precipitates were filtered and crystallized from acetonitrile to afford the clean product, 4-methoxycarbonyloxy -3-fluorobenzoic acid (VI), in a 77% yield.
Reaction SMILES: [F:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([NH:11][CH2:12][C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[N:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH:26]([CH3:28])[CH3:27].C(Cl)(Cl)Cl>CC(N(C)C)=O.CO>[F:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:26]([CH3:28])[CH3:27])=[C:4]([NH:11][CH2:12][C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[N:3]=1
Reactant: CC(C)Br
Reactant: Fc1nc(NCc2cccnc2)c2nc[nH]c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CC(=O)N(C)C
Solvent: ClC(Cl)Cl
Product: CC(C)n1cnc2c(NCc3cccnc3)nc(F)nc21
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a stirred solution of (2-fluoro-9H-purin-6-yl)-pyridin-3-ylmethyl-amine (1.00 g, 1 eq, 4.10 mmol) in DMA (12 mL) under an argon atmosphere, at RT, was added K2CO3 (powdered, anhydrous, 2.75 g, 4.85 eq, 19.90 mmol) followed 2-bromopropane (3.75 mL, 9.75 eq, 39.93 mmol). The reaction mixture was stirred at RT for 48 h, when TLC (CHCl3:MeOH; 90:10) indicated that the reaction had gone to completion. The solvent was evaporated in vacuo and the residue partitioned between water (200 mL) and EtOAc (100 mL), the aqueous phase was separated and extracted with more EtOAc (2×50 mL). The bulked organic phase was washed with brine (50 mL), dried (MgSO4) and evaporated in vacuo, and the residue was purified by gradient column chromatography on silica gel, eluted with CHCl3:MeOH (100:0→95:5), to afford the title compound as a white solid. Yield: 0.73 g (62%). Mp 131-133° C. 1H-NMR (d6-DMSO, 250 MHz): δ 1.49 (2×s, 6H, —CH(CH3)2), 4.63 (m, 3H, —CH(CH3)2 & —HNCH2-Pyr), 7.34, 7.24, 8.44, 8.58 (4×m, 4H, Pyr), 8.26 (s, 1H, —N═CH—N—), 8.95 (bs, 1H, —HNCH2-Pyr). FABMS m/z (relative intensity): 287 ([M+H]+, 100), 245 (8), 154 (23), 136 (18). Accurate Mass (M+H): Actual: 287.1420, Measured: 287.1412. Microanalysis (Expected: Measured) C14H15N6F: C, 58.73; 58.57; H, 5.28; 5.21; N, 29.35; 29.27.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]2[N:7]([C:9]([CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[N:10][N:11]=2)[N:8]=1)=O.Cl.[NH2:22][OH:23].[OH-].[Na+]>C1COCC1>[OH:23]/[N:22]=[CH:1]/[C:3]1[CH:4]=[CH:5][C:6]2[N:7]([C:9]([CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[N:10][N:11]=2)[N:8]=1
Reactant: CC(C)(C)OC(=O)NCc1nnc2ccc(C=O)nn12
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCc1nnc2ccc(/C=N/O)nn12
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.5 %

Procedure:
Tert-butyl (6-formyl-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methylcarbamate (400 mg, 1.44 mmol) and hydroxylamine hydrochloride (200 mg, 2.86 mmol) were combined in a flask with 25 mL of THF and 25 mL of 1 N NaOH solution. Stirred at rt for 1 h. Then added dichloromethane (50 mL) and extracted the aqueous layer 3 times with DCM (50 mL), dried over Na2SO4 and concentrated. Purified the oxime via MPLC (DCM/MeOH+1% NH4OH) to give title compound (200 mg, 47% yield) as a tan solid.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([CH2:6][CH2:7][N:8]1[C:13]([CH3:14])=[CH:12][N:11]=[C:10](O)[C:9]1=[O:16])=[O:5].[F:17][C:18]([F:27])([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:19][NH2:20]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[F:17][C:18]([F:27])([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[CH2:19][NH:20][C:10]1[C:9](=[O:16])[N:8]([CH2:7][CH2:6][C:4]([O:3][CH2:2][CH3:1])=[O:5])[C:13]([CH3:14])=[CH:12][N:11]=1
Reactant: NCC(F)(F)c1ccccc1
Reactant: CCOC(=O)CCn1c(C)cnc(O)c1=O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCOC(=O)CCn1c(C)cnc(NCC(F)(F)c2ccccc2)c1=O
Temperature: 110 °C
Reaction time: 24 h
Yield: 78.7 %

Procedure:
To a solution of 1-[(2-ethoxycarbonyl)ethyl]-3-bromo-6-methylpyrazinone (2-6) (0.441 g, 1.6 mmol) in toluene (15 mL) was added 2,2-difluoro-2-phenylethylamine (2-10) (0.51 g, 3.2 mmol). The resulting mixture was stirred at 110° C. for 24 hours. The mixture was diluted with ethyl acetate (100 mL) and washed with 10% hydrochloric acid (20 mL) and brine (20 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography using ethyl acetate/n-hexane (1:1) as eluent to afford the title compound (0.46 g, 81%) as a pale yellow solid. Rf 0.19 (ethyl acetate/hexane 1/1); 1H-NMR (CDCl3): δ 1.26 (t, J=7.2 Hz, 3H), 2.18 (d, J=1.2 Hz, 3H), 2.66 (t, J=6.8 Hz, 2H), 4.06 (dt, J=6.8, 14.4 Hz, 2H), 4.12 (q, J=6.8 Hz, 2H), 4.18 (t, J=7.6 Hz, 2H), 6.11 (t, J=6.4 Hz, 1H), 6.61(d, J=0.8 Hz, 1H), 7.37-7.41 (m, 3H), 7.49-7.53 (m, 2H).
Reaction SMILES: [Br:1][CH:2]([CH3:15])[C:3]([C:5]1[S:9][C:8]2[CH:10]=[CH:11][CH:12]=[C:13]([Cl:14])[C:7]=2[CH:6]=1)=O.[N:16]1[CH2:21][CH2:20][CH2:19][NH:18][C:17]=1[SH:22].C(O)C>C(O)(=O)C>[BrH:1].[Cl:14][C:13]1[C:7]2[CH:6]=[C:5]([C:3]3[N:18]4[CH2:19][CH2:20][CH2:21][N:16]=[C:17]4[S:22][C:2]=3[CH3:15])[S:9][C:8]=2[CH:10]=[CH:11][CH:12]=1
Reactant: CC(Br)C(=O)c1cc2c(Cl)cccc2s1
Reactant: SC1=NCCCN1
Solvent: CCO
Solvent: CC(=O)O
Product: Br
Product: CC1=C(c2cc3c(Cl)cccc3s2)N2CCCN=C2S1
Temperature: 95 °C
Yield: 40.2 %

Procedure:
A mixture of 2-bromo-1-(4-chlorobenzo[b]thiophen-2-yl)propan-1-one (0.5 g), 3,4,5,6-tetrahydro-2-pyrimidinethiol (0.144 g) and ethanol (8 ml) was heated under reflux for 20 minutes. Acetic acid (4 ml) was added, the mixture was heated under reflux for 18 hours then the solvents were removed in vacuo. 2.5M Sulphuric acid (10 ml) was added, the mixture was heated at 95° C. for 4.5 hours, then water (30 ml) was added and the mixture was basified to pH 7 by the addition of 5M aqueous sodium hydroxide solution. The product was extracted into dichloromethane (3×25 ml), the combined extracts were dried (MgSO4), and the solvent was removed in vacuo. The residue was dissolved in ethanol (20 ml) and hydrogen bromide (30% solution in acetic acid; 0.5 ml) was added. The solution was added dropwise to stirred ether (50 ml) and the resulting solid was collected by filtration and recrystallised from propan-2-ol (35 ml) to give 3-(4-chlorobenzo[b]thiophen-2-yl)-2-methyl-6,7-dihydro-5H-thiazolo[3,2-a]pyrimidine hydrobromide (0.2 g) as a white solid, m.p. 236-238° C.