Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:5][C:6]1[O:7][C:8]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[N:16]([S:20]([C:23]2[CH:29]=[CH:28][C:26]([CH3:27])=[CH:25][CH:24]=2)(=[O:22])=[O:21])[CH:15]=[C:14]3B2OC(C)(C)C(C)(C)O2)=[N:9][N:10]=1)([CH3:4])([CH3:3])[CH3:2].Cl[C:40]1[N:45]=[C:44]([CH2:46][CH3:47])[C:43]([F:48])=[CH:42][N:41]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>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].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>[C:1]([NH:5][C:6]1[O:7][C:8]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[N:16]([S:20]([C:23]2[CH:29]=[CH:28][C:26]([CH3:27])=[CH:25][CH:24]=2)(=[O:22])=[O:21])[CH:15]=[C:14]3[C:40]2[N:45]=[C:44]([CH2:46][CH3:47])[C:43]([F:48])=[CH:42][N:41]=2)=[N:9][N:10]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CCc1nc(Cl)ncc1F
Reactant: Cc1ccc(S(=O)(=O)n2cc(B3OC(C)(C)C(C)(C)O3)c3cc(-c4nnc(NC(C)(C)C)o4)ccc32)cc1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: CCc1nc(-c2cn(S(=O)(=O)c3ccc(C)cc3)c3ccc(-c4nnc(NC(C)(C)C)o4)cc23)ncc1F
Temperature: 130 °C
Yield: 75.1 %

Procedure:
To a 5 mL glass microwave tube containing N-tert-butyl-5-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-indol-5-yl)-1,3,4-oxadiazol-2-amine (166 mg, 0.309 mmol) was added 2-chloro-4-ethyl-5-fluoropyrimidine (78 mg, 0.402 mmol), potassium phosphate (197 mg, 0.928 mmol), dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (8.9 mg, 0.019 mmol), and Pd2(dba)3 (8.5 mg, 9.28 μmol). The tube was purged with argon, the solids were treated with dioxane (2.5 mL) and water (0.25 mL), the tube was sealed, and the contents were heated in an Initiator microwave reactor (Personal Chemistry, Biotage AB, Inc., Upssala, Sweden) at 130° C. for 30 min. The mixture was treated with H2O and extracted with EtOAc and the organic layer was washed with brine, dried over MgSO4, filtered and concentrated. The crude material was purified by flash chromatography (eluting with 5-60% EtOAc in Hex) affording N-tert-butyl-5-(3-(4-ethyl-5-fluoropyrimidin-2-yl)-1-tosyl-1H-indol-5-yl)-1,3,4-oxadiazol-2-amine (124 mg, 75%) as a light yellow foam. MS (ESI, pos. ion) m/z: 535.1 (M+1). 1H NMR (400 MHz, CDCl3) δ ppm 9.16 (1H, s), 8.46-8.53 (2H, m), 8.09 (1H, d, J=8.4 Hz), 7.94-8.00 (1H, m), 7.86 (2H, d, J=8.6 Hz), 7.25 (2H, d, J=8.6 Hz), 4.71 (1H, s), 2.89-2.99 (2H, m), 2.35 (3H, s), 1.50 (9H, s), 1.44 (3H, t, J=7.5 Hz).
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:16]=[N:17][C:18]([N:21]([CH3:23])[CH3:22])=[CH:19][CH:20]=3)[N:11]=2)[CH:5]=1.[Li+].[OH-]>O1CCOCC1>[CH3:22][N:21]([CH3:23])[C:18]1[N:17]=[CH:16][C:15]([C:12]2[N:11]=[C:10]([C:6]3[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=3)[C:3]([OH:24])=[O:2])[O:14][N:13]=2)=[CH:20][CH:19]=1
Reactant: COC(=O)c1cccc(-c2nc(-c3ccc(N(C)C)nc3)no2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CN(C)c1ccc(-c2noc(-c3cccc(C(=O)O)c3)n2)cn1
Reaction time: 20 h

Procedure:
In a 250 ml round flask, 7.0 g (21.6 mmol) of 3-[3-(6-dimethylamino-pyridin-3-yl)-[1,2,4]oxadiazol-5-yl]-benzoic acid methyl ester is dissolved in 150 ml of dioxane and treated with 32.4 ml (1M, 32.4 mmol, 1.5 eq.) of aqueous LiOH solution. After 20 h, the solvent is removed under vacuo and the residue suspended in 300 ml H2O. The pH value is then adjusted to 2 by addition of 1M HCl-solution. The precipitate is stirred for 30 minutes, then filtered, washed with 0.1 M HCl-solution and with diethyl-ether and dried. This yields the title compound as light yellow solid. Mass spectrum: m/z (M+H)+: 311.0
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[C:38]([O:42][C:43](=[O:51])[NH:44][CH:45]1[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1)([CH3:41])([CH3:40])[CH3:39]>>[C:38]([O:42][C:43](=[O:51])[NH:44][CH:45]1[CH2:50][CH2:49][N:48]([C:21]2[N:20]=[C:19]([O:18][C:11]3[C:12]4[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=4)[C:8]([NH:7][C:5](=[O:6])[C:4]4[CH:29]=[C:30]([N:32]5[CH2:37][CH2:36][O:35][CH2:34][CH2:33]5)[CH:31]=[C:2]([F:1])[CH:3]=4)=[CH:9][CH:10]=3)[CH:24]=[CH:23][N:22]=2)[CH2:47][CH2:46]1)([CH3:41])([CH3:39])[CH3:40]
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCOCC4)c3)c3ccccc23)n1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Product: CC(C)(C)OC(=O)NC1CCN(c2nccc(Oc3ccc(NC(=O)c4cc(F)cc(N5CCOCC5)c4)c4ccccc34)n2)CC1

Procedure:
Compound is prepared from 3-fluoro-N-(4-{[2-(methylsulfonyl)pyrimidin-4-yl]oxy}-1-naphthyl)-5-morpholin-4-ylbenzamide and piperidin-4-yl-carbamic acid t-butyl ester according to conditions described in general procedure C. Mp: 214-216° C.; 1H NMR (400 MHz, DMSO-d6) δ 1.33-1.41(m, 14 H), 2.47-3.41(m, 4H), 3.25-3.28(m, 4H), 3.75-3.78(m, 4 H), 4.20(s, 1 H), 6.20(d, J=5.5 Hz, 1H), 6.77-6.79(m, 1 H), 7.00-7.05(m, 1H), 7.18-7.26(m, 1H), 7.38-7.63(m, 5H), 7.85(d, J=9.2 Hz, 1 H), 8.00(d, J=8.4 Hz, 1H), 8.26(d, J=5.5 Hz, 1H), 10.47(s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([OH:7])=[O:6].S(Cl)(Cl)=O.[CH3:16][CH2:17]O>C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([O:7][CH2:16][CH3:17])=[O:6]
Reactant: CCO
Reactant: O=C(O)c1ccc(F)c(Br)c1
Solvent: O=S(Cl)Cl
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc(F)c(Br)c1
Yield: 90.3 %

Procedure:
To a solution of compound 3-bromo-4-fluoro-benzoic acid (430 g, 1.97 mol, 1 eq) in EtOH (2.3 L) was added dropwise thionyl chloride (287 mL, 3.94 mol, 2 eq) at 10° C. Then the mixture was heated to reflux overnight. The mixture was concentrated in vacuum to give a residue. The residue was dissolved in ethyl acetate (800 mL), washed with aqueous sodium hydrogen carbonate, brine (300 mL) and water (200 mL), then concentrated in vacuo to give title compound as a white solid (440 g, 1.78 mol, 90.3%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[CH:9][N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:7]=1[CH3:17])=[O:5])[CH3:2].C(O[C:21]([C:23]1C2C(=CC=CC=2)N[C:24]=1[CH3:32])=O)C>>[CH2:1]([O:3][C:4]([C:6]1[C:10]2[C:9](=[CH:21][CH:23]=[CH:24][CH:32]=2)[N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:7]=1[CH3:17])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(C)[nH]c2ccccc12
Reactant: CCOC(=O)c1ccn(-c2ccccc2)c1C
Product: CCOC(=O)c1c(C)n(-c2ccccc2)c2ccccc12

Procedure:
Prepared in analogy to that of 2-methyl-1-phenyl-1H-pyrrole-3-carboxylic acid ethyl ester from 2-Methyl-1H-indole-3-carboxylic acid ethyl ester. The title compound, 1H NMR (200 MHz, CDCl3): δ (ppm)=8.15 (d, 1H, J=7.4 Hz), 7.6-6.9 (m, 8H), 4.43 (q, 2H, J=7.4 Hz), 2.59 (s, 3H), 1.47 (t, 3H, J=7.4 Hz).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.Br[C:12]1[C:13]2[N:14]([CH:18]=[CH:19][N:20]=2)[CH:15]=[CH:16][CH:17]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>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>[N:20]1[CH:19]=[CH:18][N:14]2[CH:15]=[CH:16][CH:17]=[C:12]([C:5]3[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=3)[C:13]=12
Reactant: Brc1cccn2ccnc12
Reactant: OB(O)c1ccc(O)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: Oc1ccc(-c2cccn3ccnc23)cc1
Yield: 75 %

Procedure:
A mixture of 4-hydroxyphenylboronic acid (0.77 g), 8-bromoimidazo[1,2-a]pyridine (1.1 g), tetrakis(triphenylphosphine)palladium(0) (0.19 g), sodium carbonate (2.1 g), DME (30 ml) and water (6 ml) was heated under reflux overnight under an argon atmosphere. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) and recrystallized from ethyl acetate to give the title compound (0.88 g).
Reaction SMILES: [C:1]1([CH:11]=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C([O-])(=O)C.[NH4+].[N+:18]([CH3:21])([O-:20])=[O:19].C(OC(=O)C)C>CCCCCC>[N+:18](/[CH:21]=[CH:11]/[C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1)([O-:20])=[O:19]
Reactant: C[N+](=O)[O-]
Reactant: O=Cc1cccc2ccccc12
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: O=[N+]([O-])/C=C/c1cccc2ccccc12
Yield: 62 %

Procedure:
7.81 g (50 mmol) of 1-naphthaldehyde and 1.54 g (20 mmol) of ammonium acetate were added to 70 ml of nitromethane and heated under reflux for 3 hours (see: J. Org. Chem., 1984, 49, 4761). 100 ml of ethylacetate was added and the resulting mixture was washed with 50 ml of water and 50 ml of brine. The organic layer was collected and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure and the residue was subjected to column chromatography (eluent: hexane/ethylacete=90/10, v/v) to give 6.27 g( 0.031 mmol, Yield 62%) of the title compound.
Reaction SMILES: [OH-].[Na+].[OH:3][C:4]1[CH:5]=[CH:6][C:7]([CH3:10])=[N:8][CH:9]=1.[CH3:11]I>CCCCCC.CN(C)C=O>[CH3:11][O:3][C:4]1[CH:5]=[CH:6][C:7]([CH3:10])=[N:8][CH:9]=1
Reactant: CI
Reactant: Cc1ccc(O)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: COc1ccc(C)nc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To sodium hydroxide (50% oil dispersion, 43.2 g, 21.6 g of active NaH, 900 mmol), prewashed in dry hexane, in 800 ml of dimethylformamide (DMF) is added 5-hydroxy-2-methylpyridine (98.8 g, 906 mmol) in 700 ml of DMF at 15° and over 0.75 hour. The reaction is allowed to warm to RT and is stirred for 2 hours. It is then cooled to 10°, and methyliodide is added over 0.5 hour. The reaction is again allowed to warm to RT and is stirred overnight. It is then filtered through celite, and the solid is washed with chloroform, filtered and rotoevaporated. The resulting solid is washed with chloroform 3×, and is stirred with chloroform overnight. It is filtered and rotoevaporated, after which ether is added, followed by 10% sodium hydroxide and water. The mixture is extracted with ether (3×). The combined ether extracts are washed with water and with brine, dried over calcium sulfate, filtered and rotoevaporated to give 5 -methoxy-2-methylpyridine.
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=2)[N:6]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].CCOC(C)=O.O>C1COCC1>[CH3:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:14]=[CH:13][C:10]([CH2:11][NH2:12])=[CH:9][CH:8]=2)[N:6]=1
Reactant: Cc1nc(-c2ccc(C#N)cc2)cs1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1nc(-c2ccc(CN)cc2)cs1
Temperature: 0 °C
Yield: 38.6 %

Procedure:
Dissolve 4-(2-methylthiazol-4-yl)-benzonitrile (305 mg, 1.52 mmol) in anhydrous THF (50 mL). Add a 1M solution of lithium aluminum hydride in THF (3.05 mL, 3.05 mmol). Heat the mixture overnight under reflux. Cool the reaction mixture with ice/water and work-up sequentially with EtOAc and water. Filter the mixture over Celite®. Separate the organic phase, and extract the aqueous phase with chloroform. Dry the combined organic extracts over Na2SO4, filter and concentrate to obtain the title compound as an oil (120 mg) that was used without further purification. GC-MS m/z: 204 (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:13])=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[CH2:8][CH2:7]2.C(=O)([O-])[O-].[K+].[K+].[CH2:20]([CH:22]1[O:24][CH2:23]1)Cl>C(O)(C)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:13][CH2:20][CH:22]2[O:24][CH2:23]2)=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[CH2:8][CH2:7]2
Reactant: O=C1CCc2c(O)ccc(Cl)c2N1
Reactant: ClCC1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Product: O=C1CCc2c(OCC3CO3)ccc(Cl)c2N1
Reaction time: 6 h

Procedure:
20.0 Grams of 8-chloro-5-hydroxy-3,4-dihydrocarbostyril and 18 g of potassium carbonate are suspended in 160 ml of isopropyl alcohol, then 40 ml of epichlorohydrin are added and the reaction is carried out at 70°-80° C. for 6 hours. The reaction mixture is concentrated under reduced pressure and the thus-obtained residue is stirred with 100 ml of 2N-sodium hydroxide under cooling conditions. The insoluble matter is separated by filtration, washed with water and dried. The crude crystals are recrystallized from isopropanol to obtain 18.5 g of 8-chloro-5-(2,3-epoxypropoxy)-3,4-dihydrocarbostyril in the form of colorless needle-like crystals with a melting point of 161°-165° C.
Reaction SMILES: [ClH:1].C[O:3][C:4]([C:6]1([NH:12][C:13]([C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][CH3:29])[CH2:23][CH2:22]3)=[CH:17][CH:16]=2)=[O:14])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:5]>>[ClH:1].[CH2:27]([N:24]1[CH2:23][CH2:22][N:21]([C:18]2[CH:17]=[CH:16][C:15]([C:13]([NH:12][C:6]3([C:4]([OH:5])=[O:3])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]3)=[O:14])=[CH:20][CH:19]=2)[CH2:26][CH2:25]1)[CH2:28][CH3:29]
Reactant: CCCN1CCN(c2ccc(C(=O)NC3(C(=O)OC)CCCCC3)cc2)CC1
Agent: Cl
Product: CCCN1CCN(c2ccc(C(=O)NC3(C(=O)O)CCCCC3)cc2)CC1
Temperature: 25 °C
Yield: 41 %

Procedure:
3 ml of 4N hydrochloric acid was added to 600 mg (1.55 mmol) of 1-[[[4-(4-propylpiperazin-1-yl)phenyl]carbonyl]amino]cyclohexanecarboxylic acid methyl ester, and the mixture was heated under reflux for 6 hours. The mixture was cooled to room temperature and the precipitated crystal was collected by filtration to obtain 258 mg (41%) of the title compound.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[NH:12]1[CH2:16][CH2:15][CH2:14][CH:13]1[C:17]([OH:19])=[O:18].Cl>[OH-].[Na+]>[CH2:5]([O:4][C:2]([N:12]1[CH2:16][CH2:15][CH2:14][CH:13]1[C:17]([OH:19])=[O:18])=[O:3])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(O)C1CCCN1
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)C1CCCN1C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 93.1 %

Procedure:
Benzyl chloroformate (29.7 g, 174 mmol) was added dropwise to a 0° C. solution of Pyrrolidine-2-carboxylic acid (20.0 g, 174 mmol) dissolved in 1N NaOH (350 mL). The solution was stirred at 0° C. for 30 mins. The solution was allowed to equilibrate to room temperature while stirring overnight. The solution was acidified to pH=3 by addition of 1M HCl. The resulting solution was extracted with ethyl acetate (3×300 mL). The organic layers were combined, dried over MgSO4 and concentrated under vacuo to afford 40.4 g (89%) of the crude product, pyrrolidine-1,2-dicarboxylic acid 1-benzyl ester, as a colorless oil.
Reaction SMILES: O[CH2:2][CH2:3][N:4]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]([O:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])[C:8]=2[O:7][CH2:6][CH2:5]1.[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)([SH:29])[CH3:28])=[CH:23][CH:22]=1>>[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([C:30]2[CH:31]=[CH:32][C:33]([F:36])=[CH:34][CH:35]=2)([S:29][CH2:2][CH2:3][N:4]2[C:9]3[CH:10]=[CH:11][CH:12]=[C:13]([O:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])[C:8]=3[O:7][CH2:6][CH2:5]2)[CH3:28])=[CH:23][CH:22]=1
Reactant: CC(S)(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: COC(=O)COc1cccc2c1OCCN2CCO
Product: COC(=O)COc1cccc2c1OCCN2CCSC(C)(c1ccc(F)cc1)c1ccc(F)cc1
Yield: 83.2 %

Procedure:
The same process as Example 1 was repeated except that methyl (4-(2-hydroxyethyl)-3,4-dihydro-2H-1,4-benzoxazin-8-yloxy)acetate (200 mg) and 1,1-bis-(4-fluorophenyl)ethanethiol (450 mg) were used to obtain the colorless oily object compound (311 mg, yield 83%).
Reaction SMILES: [Cl:1][C:2]1[S:6][CH:5]=[C:4]([C:7]([NH2:9])=[O:8])[C:3]=1[O:10][CH2:11][CH3:12].C(Cl)Cl.N[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(N(CC)CC)C>[Cl:1][C:2]1[S:6][CH:5]=[C:4]([C:7]([NH:9][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:8])[C:3]=1[O:10][CH2:11][CH3:12]
Reactant: Nc1ccccc1
Reactant: CCOc1c(C(N)=O)csc1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOc1c(C(=O)Nc2ccccc2)csc1Cl

Procedure:
A 4.50 g. portion of 5-chloro-4-ethoxy-3-thiophenecarbonyl chloride (prepared as in Example 4) was dissolved in 40 ml. of methylene chloride and stirred overnight with 2.8 ml. of triethylamine and 1.86 g. of aniline. The mixture was filtered and the filtrate extracted with 3 N hydrochloric acid. The methylene chloride layer was treated with activated charcoal, dried over anhydrous sodium sulfate and diluted with petroleum ether to give 3.62 g. of the product of the example as a white crystalline solid, m.p. 69° C.
Reaction SMILES: C([O:5][C:6](=[O:16])[C@@H:7]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[NH2:8])(C)(C)C.C(N(CC)CC)C.[Cl:24][C:25]1[C:26]2[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][C:27]=2[S:28][C:29]=1[C:30](Cl)=[O:31]>ClCCl>[Cl:24][C:25]1[C:26]2[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][C:27]=2[S:28][C:29]=1[C:30]([NH:8][C@H:7]([CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:6]([OH:5])=[O:16])=[O:31]
Reactant: O=C(Cl)c1sc2cc(C(F)(F)F)ccc2c1Cl
Reactant: CC(C)(C)OC(=O)[C@H](N)Cc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(N[C@H](Cc1ccccc1)C(=O)O)c1sc2cc(C(F)(F)F)ccc2c1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Following general method B, to a solution of A1 (55.33 mg, 0.25 mmol) in dry dichloromethane (2 mL) at 0° C. was added triethylamine (0.043 mL, 0.28 mmol) and 5 (74.78 mg, 0.25 mmol). The reaction mixture was stirred at room temperature overnight and concentrated under reduced pressure. Then dissolved the oil mixture in 2 mL CH2Cl2 and 2 mL TFA was add under argon. The reaction mixture was stirred at room temperature for 12 h (TLC monitor). The solvent was removed under reduce pressure and the crude compound was purified by flash chromatography on silica gel, using HOAc/ethyl acetate (1:100) as the eluent, gave 5a; (100.64 mg, 94.1%). [α]D25: −21.1 (c=0.30, CHCl3); 1H-NMR (300 MHz, CDCl3): δ 8.12 (s, 1H), 7.93 (d, J=8.7 Hz, 1H), 7.71-7.61 (m, 2H), 7.37-7.26 (m, 5H), 6.83 (s, 1H), 5.17-5.15 (m, 1H), 3.45-3.30 (m, 2H); 13C NMR (300 MHz, CDCl3): δ 175.31, 160.07, 139.09, 137.76, 135.24, 135.13, 129.90, 129.46, 128.84, 127.56, 125.63, 123.89, 122.16, 120.45, 120.40, 119.49, 54.09, 39.26, 29.70; HRMS (ESI): calcd for: C19H13ClF3NO3S [M−H]−=426.0184, obsd [M−H]−=426.0170.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:13][C:14]2[N:15]=[N:16][C:17]([CH:20]([NH:22][C:23]([C:25]3[CH:33]=[CH:32][C:28]4[O:29][CH2:30][O:31][C:27]=4[CH:26]=3)=O)[CH3:21])=[CH:18][N:19]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].N1C=NC=N1.P(Cl)(Cl)(Cl)=O>N1C=CC=CC=1>[O:29]1[C:28]2[CH:32]=[CH:33][C:25]([C:23]3[N:16]4[C:17]([CH:18]=[N:19][C:14]([NH:13][C:5]5[CH:4]=[C:3]([O:2][CH3:1])[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=5)=[N:15]4)=[C:20]([CH3:21])[N:22]=3)=[CH:26][C:27]=2[O:31][CH2:30]1
Reactant: COc1cc(Nc2ncc(C(C)NC(=O)c3ccc4c(c3)OCO4)nn2)cc(OC)c1OC
Agent: c1nc[nH]n1
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: COc1cc(Nc2ncc3c(C)nc(-c4ccc5c(c4)OCO5)n3n2)cc(OC)c1OC
Yield: 42.8 %

Procedure:
In a similar manner as described for Example 9, N-(1-{3-[(3,4,5-trimethoxyphenyl)amino]-1,2,4-triazin-6-yl}ethyl)-1,3-benzodioxole-5-carboxamide (Intermediate 29) (61 mg, 0.134 mmol), and 1,2,4-triazole (55 mg, 0.80 mmol) in pyridine (2 mL) and phosphorous oxychloride (0.037 mL, 0.40 mmol) gave 7-(1,3-benzodioxol-5-yl)-5-methyl-N-(3,4,5-trimethoxy-phenyl)imidazo[5,1-f][1,2,4]triazin-2-amine (25 mg, 43%) as a yellow solid. 1H NMR (CD3OD): δ8.99 (s, 1H), 7.87 (s, 1H), 7.84 (d, J=1.65 Hz, 1H), 7.04 (s, 2H), 6.95 (d, J=7.87 Hz, 1H), 6.04 (s, 2H), 3.80 (s, 6H), 3.74 (s, 3H), 2.56 (s, 3H). MS m/z 435 (M+1).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5](=[O:8])[CH2:4][CH2:3]1.CCN(CC)CC.Cl[Si:17]([CH3:20])([CH3:19])[CH3:18]>O1CCOCC1>[CH3:1][N:2]1[CH2:7][CH:6]=[C:5]([O:8][Si:17]([CH3:20])([CH3:19])[CH3:18])[CH2:4][CH2:3]1
Reactant: CN1CCC(=O)CC1
Reactant: C[Si](C)(C)Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CN1CC=C(O[Si](C)(C)C)CC1
Temperature: 110 °C
Reaction time: 24 h

Procedure:
To a stirred solution of 1-methyl-piperidin-4-one (6.0 g, 53 mmol, 6.52 mL) and Et3N (14.16 g, 140 mmol, 19.5 mL) in 1,4-dioxane (20 mL) was added chlorotrimethylsilane (7.6 g, 70 mmol, 8.88 mL) drop wise during 30 min. The resultant reaction mixture was slowly heated to reflux at 110° C., stirred at the same temperature for 24 h, an additional amount of chlorotrimethylsilane (4.44 mL), heated for 24 h (take aliquot of it and run 1H NMR), cooled to room temp, filtered off the solid, solid was washed with n-pentane. The filtrate was concentrated on rotavaporator, and then diluted with n-pentane and filtered off the solid. The resultant solution was concentrated on rotavaporator followed by high vacuum furnished the 1-methyl-4-trimethylsilanyloxy-1,2,3,6-tetrahydro-pyridine (9.68 g, 1H NMR showed about 10:1 ratio of silylenolether and the starting material). The crude product was as such used in the next step without further purification.
Reaction SMILES: [CH:1](O)=[O:2].C(OC(=O)C)(=O)C.[OH:11][NH:12][CH:13]([CH2:36][CH2:37][CH2:38][C:39]1[N:44]=[CH:43][CH:42]=[CH:41][N:40]=1)[CH2:14][S:15]([N:18]1[CH2:23][CH2:22][N:21]([C:24]2[N:29]=[CH:28][C:27]([O:30][CH2:31][C:32]([F:35])([F:34])[F:33])=[CH:26][N:25]=2)[CH2:20][CH2:19]1)(=[O:17])=[O:16]>C1COCC1>[OH:11][N:12]([C@H:13]([CH2:14][S:15]([N:18]1[CH2:23][CH2:22][N:21]([C:24]2[N:29]=[CH:28][C:27]([O:30][CH2:31][C:32]([F:33])([F:34])[F:35])=[CH:26][N:25]=2)[CH2:20][CH2:19]1)(=[O:17])=[O:16])[CH2:36][CH2:37][CH2:38][C:39]1[N:44]=[CH:43][CH:42]=[CH:41][N:40]=1)[CH:1]=[O:2]
Reactant: O=CO
Reactant: O=S(=O)(CC(CCCc1ncccn1)NO)N1CCN(c2ncc(OCC(F)(F)F)cn2)CC1
Solvent: CC(=O)OC(C)=O
Solvent: C1CCOC1
Product: O=CN(O)[C@@H](CCCc1ncccn1)CS(=O)(=O)N1CCN(c2ncc(OCC(F)(F)F)cn2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 71.1 %

Procedure:
To formic acid (114 mL, 3.03 mol) at 0° C. was added acetic anhydride (28.6 mL, 0.303 mol) and the mixture was stirred at RT for 10 minutes. The reaction was then recooled to 0° C., and added to a solution of 2-(4-{[2-(hydroxyamino)-5-pyrimidin-2-ylpentyl]sulfonyl}piperazin-1-yl)-5-(2,2,2-trifluoroethoxy)pyrimidine (30.6 g, 60.5 mmol) and formic acid (114 mL, 3.03 mol) in THF (600 mL). The reaction was brought to room temperature and stirred for one hour. Volatiles were then removed in vacuo, and the residue azeotroped with toluene (2×300 mL). The residue was then dissolved in methanol (300 mL) and heated to 40° C. for one hour. The solution was then cooled to room temperature and concentrated in vacuo. The residue was then purified by flash chromatography (silica gel, 10% MeOH in EtOAc) to give the racemic compound as a pale orange foam (22.94 g, 43 mmol, 71%).