Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: B(F)(F)F.[Br:5][C:6]1[CH:26]=[CH:25][C:9]2[O:10][CH2:11][C:12]3([C:15]4[S:19][C:18]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[N:17][C:16]=4[C:8]=2[CH:7]=1)[CH2:14][O:13]3.[SiH](CC)(CC)CC>ClCCl.C([O-])(O)=O.[Na+]>[Br:5][C:6]1[CH:26]=[CH:25][C:9]2[O:10][CH2:11][CH:12]([CH2:14][OH:13])[C:15]3[S:19][C:18]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[N:17][C:16]=3[C:8]=2[CH:7]=1
Reactant: CCOC(=O)c1nc2c(s1)C1(COc3ccc(Br)cc3-2)CO1
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Agent: O=C([O-])O
Solvent: ClCCl
Product: CCOC(=O)c1nc2c(s1)C(CO)COc1ccc(Br)cc1-2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 67.5 %

Procedure:
Boron trifluoride diethleherate (0.16 mL, 1.00 equiv) was added dropwise to a stirred solution of ethyl 9-bromo-5H-spiro[benzo[2,3]oxepino[4,5-d]thiazole-4,2′-oxirane]-2-carboxylate (500 mg, 1.31 mmol, 1.00 equiv) and Et3SiH (227.5 mg, 1.96 mmol, 1.50 equiv) in dichloromethane (25 mL) at 0° C. After being stirred for 15 min at room temperature the reaction solution was diluted with 50 mL of aqueous NaHCO3, extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by a silica gel column with ethyl acetate/petroleum ether (1:3) to give 340 mg (68%) of the titled compound as a off-white solid; LC-MS (ES, m/z) 384,386 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:13]([CH2:14][CH2:15][CH2:16]O)[C:12]3[C:18]([C:23]([O:25][CH3:26])=[O:24])=[CH:19][CH:20]=[C:21]([Cl:22])[C:11]=3[N:10]=2)=[C:4]([Cl:27])[CH:3]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:9]3=[N:10][C:11]4[C:12](=[C:18]([C:23]([O:25][CH3:26])=[O:24])[CH:19]=[CH:20][C:21]=4[Cl:22])[N:13]3[CH2:14][CH2:15][CH2:16]2)=[C:4]([Cl:27])[CH:3]=1
Reactant: COC(=O)c1ccc(Cl)c2nc(Nc3ccc(Br)cc3Cl)n(CCCO)c12
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Br)cc1Cl
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 87 %

Procedure:
To a solution of methyl 2-[(4-bromo-2-chlorophenyl)amino]-4-chloro-1-(3-hydroxypropyl)-1H-benzimidazole-7-carboxylate (9.08 g, 19.20 mmol) in tetrahydrofuran (90.0 mL) were added triethylamine (13.4 mL, 96.00 mmol) and methanesulfonyl chloride (5.94 mL, 76.80 mmol) at 0° C. The reaction mixture was stirred at room temperature for 3.5 hrs. The mixture was quenched with aqueous sodium hydrogen carbonate and extracted with ethyl acetate (×3). The combined organic layer was washed with brine (×1), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The resulting mesylate was dissolved into N,N-dimethylformamide (50.0 mL) and to the solution was added potassium carbonate (5.31 g, 38.40 mmol). The mixture was stirred at 60° C. for 17 hrs. After cooling, the mixture was diluted with water. The generated precipitate was collected by filtration and washed with diisopropyl ether/ethyl acetate to give the title compound as a colorless solid (7.60 g, 16.70 mmol, 87%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[OH:12])[C:5]([O:7][CH3:8])=[O:6].C(N(CC)CC)C.[CH:20]([O:22]CCCC)=[CH2:21].Cl>C(O)C.C(OCC)C.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].C(O[Pd]OC(=O)C)(=O)C.C(Cl)Cl>[C:20]([C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[OH:12])[C:5]([O:7][CH3:8])=[O:6])(=[O:22])[CH3:21]
Reactant: C=COCCCC
Reactant: COC(=O)c1ccc(O)c(Br)c1
Agent: CC(=O)O[Pd]OC(C)=O
Agent: [Fe+2]
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: ClCCl
Product: COC(=O)c1ccc(O)c(C(C)=O)c1
Temperature: 70 °C
Yield: 81.6 %

Procedure:
To a degassed solution of methyl 3-bromo-4-hydroxybenzoate (350 g, 1514.87 mmol) in ethanol (3 L) were added triethylamine (0.528 L, 3787.17 mmol), 1-(vinyloxy)butane (0.588 L, 4544.60 mmol), 1,1′-bis(diphenylphosphino)ferrocene (33.1 g, 60.6 mmol) and diacetoxypalladium (8.50 g, 37.9 mmol) under nitrogen. The mixture was heated at 70° C. overnight. The reaction was cooled down, filtered and the filtrate concentrated. The resulting solid was solubilized with DCM (2 L) and HCl 4N (1.14 L, 4544 mmol) was added under stirring. Stirring was maintained for 2 hrs, the organic phase was separated, dried over magnesium sulfate, filtered and concentrated to afford a solid which was stirred in diethyl ether (5 L) for 2 hrs. The solid was filtered off and the filtrate concentrated to dryness to afford methyl 3-acetyl-4-hydroxybenzoate (240 g, 82%) as a beige powder. Mass spectrum: [M−H]− 193.
Reaction SMILES: [Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]2[N:23]=[C:22]([N:24]3[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]3)[N:21]=[C:20]([C:31]([O:33]C)=[O:32])[CH:19]=2)[CH2:14][CH2:13]1)=[O:10].[OH-].[Li+]>>[Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][CH:12]1[CH2:13][CH2:14][N:15]([C:18]2[N:23]=[C:22]([N:24]3[CH2:25][CH2:26][N:27]([CH3:30])[CH2:28][CH2:29]3)[N:21]=[C:20]([C:31]([OH:33])=[O:32])[CH:19]=2)[CH2:16][CH2:17]1)=[O:10]
Reactant: COC(=O)c1cc(N2CCC(NC(=O)c3[nH]c(C)c(Cl)c3Cl)CC2)nc(N2CCN(C)CC2)n1
Agent: [Li+]
Agent: [OH-]
Product: Cc1[nH]c(C(=O)NC2CCN(c3cc(C(=O)O)nc(N4CCN(C)CC4)n3)CC2)c(Cl)c1Cl

Procedure:
The title compound was synthesized by an analogous method to Example 310 starting from methyl 6-(4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}piperidin-1-yl)-2-(4-methylpiperazin-1-yl)pyrimidine-4-carboxylate (Example 318) and 2 N lithium hydroxide.
Reaction SMILES: S(Cl)(Cl)=O.[Cl:5][C:6]1[C:15]([CH:16]=[N:17]O)=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:19][CH3:20])[CH:12]=2)[N:7]=1>CN(C)C=O>[Cl:5][C:6]1[C:15]([C:16]#[N:17])=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:19][CH3:20])[CH:12]=2)[N:7]=1
Reactant: COc1ccc2nc(Cl)c(C=NO)cc2c1
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: COc1ccc2nc(Cl)c(C#N)cc2c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 98.3 %

Procedure:
Thionyl chloride (7.9 ml) was added dropwise over a 12 min period to a stirred solution of 16.3 g 2-chloro-6-methoxy-3-quinolinecarboxaldehyde oxime in 160 ml dimethylformamide at 0° C. The reaction mixture was stirred for 15 min longer at 0° C. and then at room temperature overnight. The mixture was then quenched in ice-water, and the yellow solid product was collected, washed with water and dried in vacuo at 75° C. to give 14.8 g 2-chloro-6-methoxy-3-quinolinecarbonitrile, m.p. 201°-202° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:12])[C:6](=[CH:10][CH:11]=1)[C:7]([OH:9])=[O:8].[CH3:13][Si](C=[N+]=[N-])(C)C>CO.O1CCCC1>[NH2:12][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[CH:11]=[CH:10][C:6]=1[C:7]([O:9][CH3:13])=[O:8]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: COc1ccc(C(=O)O)c(N)c1
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1ccc(OC)cc1N
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4-methoxyanthranilic acid (5.0 g, 30.0 mmol) in a mixture of 10% methanol in tetrahydrofuran (100 mL) was added dropwise (trimethylsilyl)diazomethane (2.0 M solution in diethyl ether, 18.0 mL, 36.0 mmol) at 0° C. The reaction mixture was stirred for 16 hours at room temperature then quenched by the addition of glacial acetic acid (0.1 mL). The reaction mixture was concentrated and the residue was partitioned between saturated sodium bicarbonate (50 mL) and ethyl acetate (250 mL). The organic layer was separated and washed with water (50 mL), saturated sodium bicarbonate (50 mL) and brine (50 mL), dried over sodium sulfate, filtered and concentrated to give methyl 2-amino-4-methoxybenzoate as an oil (5.4 g, quantitative). MS (EI) for C9H11NO3: 182 (MH+).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([N+:14]([O-:16])=[O:15])[C:5]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[N:6][CH:7]=1.[CH3:17][C:18]1([CH3:24])[O:23][CH2:22][CH2:21][NH:20][CH2:19]1.C1(P(C2CCCCC2)C2(C(C)C)CC(C(C)C)=CC(C(C)C)=C2C2C=CC=CC=2)CCCCC1.CC([O-])(C)C.[Na+]>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].C1(C)C=CC=CC=1>[CH3:17][C:18]1([CH3:24])[O:23][CH2:22][CH2:21][N:20]([C:2]2[CH:7]=[N:6][C:5]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)=[C:4]([N+:14]([O-:16])=[O:15])[CH:3]=2)[CH2:19]1
Reactant: O=[N+]([O-])c1cc(Cl)cnc1N1CCOCC1
Reactant: CC1(C)CNCCO1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)C1=CC(C(C)C)=C(c2ccccc2)C(C(C)C)(P(C2CCCCC2)C2CCCCC2)C1
Solvent: Cc1ccccc1
Product: CC1(C)CN(c2cnc(N3CCOCC3)c([N+](=O)[O-])c2)CCO1
Temperature: 25 °C

Procedure:
A solution of 4-(5-chloro-3-nitropyridin-2-yl)morpholine (850 mg, 3.49 mmol; described herein), 2,2-dimethylmorpholine (480 μL, 4180 μmol), tris(dibenzylideneacetone)dipalladium(o) (224 mg, 0.244 mmol), 2-(dicyclohexylphosphino)-2,4,6,-tri-i-propyl-1,1-biphenyl (249 mg, 0.523 mmol), sodium 2-methylpropan-2-olate (671 mg, 6.98 mmol), and toluene (517 mL) was refluxed overnight, then cooled to rt and concentrated. The resulting residue was taken up in EtOAc, washed with satd aq. sodium bicarbonate and brine, then the organic layer dried (magnesium sulfate) and concentrated. Column chromatography afforded 2,2-dimethyl-4-(6-morpholino-5-nitropyridin-3-yl)morpholine as a red solid. Mass Spectrum (ESI) m/e=323.2 (M+1).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([CH:12]=O)[CH2:8][CH2:7]1.[CH:24]1([NH:27][C:28](=[O:37])[CH2:29][NH:30][C:31]2[CH2:35][S:34][C:33](=[O:36])[N:32]=2)[CH2:26][CH2:25]1.C([O-])(=O)C.[NH2+]1CCCCC1>CC(O)C>[F:23][C:2]([F:1])([F:22])[C:3]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][CH:9](/[CH:12]=[C:35]2/[C:31]([NH:30][CH2:29][C:28]([NH:27][CH:24]3[CH2:25][CH2:26]3)=[O:37])=[N:32][C:33](=[O:36])[S:34]/2)[CH2:8][CH2:7]1
Reactant: O=C(CNC1=NC(=O)SC1)NC1CC1
Reactant: O=CC1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: CC(C)O
Product: O=C(CNC1=NC(=O)S/C1=C\C1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1)NC1CC1
Temperature: 80 °C
Reaction time: 3.5 h
Yield: 63.2 %

Procedure:
To a solution of 1-[2,4-bis(trifluoromethyl)benzyl]piperidine-4-carbaldehyde (2.65 g) and N-cyclopropyl-N2-(2-oxo-2,5-dihydro-1,3-thiazol-4-yl)glycinamide (2 g) in 2-propanol (20 mL) was added piperidinium acetate (1.14 g). The reaction mixture was stirred at 80° C. for 3.5 hr and concentrated. Water and THF were added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (methanol/ethyl acetate) and recrystallized from ethyl acetate/water/heptane to give the title compound (2.64 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([OH:19])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23].C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[CH2:25]([O:24][C:22](=[O:23])[CH2:21][O:19][C:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:10][CH:11]=1)[CH3:26]
Reactant: Oc1ccc(OCc2ccccc2)c2ccccc12
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCOC(=O)COc1ccc(OCc2ccccc2)c2ccccc12
Yield: 82.9 %

Procedure:
A mixture of 2 g (8 mmol) of 4-benzyloxy-naphthalen-1-ol [Journal of Medicinal Chemistry (1985), 28(6), 822-41, of 2.67 g (16 mmol) of ethyl bromoacetate and of 3.12 g (9.6 mmol) of cesium carbonate in 30 ml of acetonitrile was stirred at 60° C. for 3 hours. Subsequently, the reaction mixture was evaporated to dryness and the residue was partitioned between water and tert.-butyl methyl ether. The organic phase was separated, washed with water and brine, dried over anhydrous sodium sulfate and finally evaporated. 2.23 g of the title compound were obtained as white crystals after crystallization from n-heptane.
Reaction SMILES: [Mg].O1CCCC1.Cl[CH2:8][C:9]([CH3:11])=[CH2:10].[CH:12]([C:15](=[CH2:18])[CH:16]=[O:17])([CH3:14])[CH3:13]>C1(C)C=CC=CC=1>[CH3:11][C:9]([CH2:8][CH:16]([OH:17])[C:15](=[CH2:18])[CH:12]([CH3:14])[CH3:13])=[CH2:10]
Reactant: C=C(C)CCl
Reactant: C=C(C=O)C(C)C
Agent: [Mg]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: C=C(C)CC(O)C(=C)C(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 73.8 %

Procedure:
A mixture of magnesium turnings (146 grams) and tetrahydrofuran (2,000 grams) is heated to reflux with vigorous agitation. To this mixture is added a mixture of 3-chloro-2-methylpropene (500 grams), toluene (75 grams), and 3-methyl-2-methylenebutanal (500 grams prepared according to Example I), at such a rate as to maintain reflux. The addition requires approximately four hours. The mass is stirred at reflux for 30 minutes and is then cooled to room temperature and quenched into excess ice cold 10% aqueous acetic acid mixture. The organic layer is washed successively with an equal volume of water, saturated sodium carbonate solution and saturated salt solution. Rapid distillation at 3-12 mm/Hg pressure using a short column followed by careful redistillation (after bulking) through a 12"×1" Goodloe packed column yields 580 grams of 2,6-dimethyl-5-methylene-1-hepten-4-ol, boiling point range 73°-78° C. at 9 mm/Hg pressure.
Reaction SMILES: FC1C=CC([C:8]2[C:9]([NH2:37])=[N:10][CH:11]=[N:12][C:13]=2[N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[N:21]([CH3:36])[CH:22]=[C:23]([C:25]4[CH:30]=[CH:29][C:28]([F:31])=[C:27]([C:32]([F:35])([F:34])[F:33])[CH:26]=4)[N:24]=3)[CH2:16][CH2:15]2)=CC=1.[C:38]([C:40]1[CH:45]=[CH:44][C:43](B(O)O)=[CH:42][C:41]=1[F:49])#[N:39]>>[NH2:37][C:9]1[C:8]([C:43]2[CH:44]=[CH:45][C:40]([C:38]#[N:39])=[C:41]([F:49])[CH:42]=2)=[C:13]([N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[N:21]([CH3:36])[CH:22]=[C:23]([C:25]4[CH:30]=[CH:29][C:28]([F:31])=[C:27]([C:32]([F:34])([F:33])[F:35])[CH:26]=4)[N:24]=3)[CH2:16][CH2:15]2)[N:12]=[CH:11][N:10]=1
Reactant: N#Cc1ccc(B(O)O)cc1F
Reactant: Cn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2-c2ccc(F)cc2)CC1
Product: Cn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2-c2ccc(C#N)c(F)c2)CC1

Procedure:
The title compound was prepared in an analogous manner as 5-(4-Fluoro-phenyl)-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine using 4-cyano-3-fluorophenylboronic acid instead of 4-fluorophenylboronic acid. LC-MS: (M+1=540, obsd.=540).
Reaction SMILES: [CH2:1]([N:5]([CH2:35][CH2:36][CH2:37][CH3:38])[C:6]([C:8]1[N:9]=[C:10]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][C:14]=2[C:23]([N:25]2[CH2:34][CH2:33][C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH2:26]2)=[O:24])[NH:11][CH:12]=1)=[O:7])[CH2:2][CH2:3][CH3:4].C([O-])([O-])=O.[K+].[K+].Br[CH2:46][CH2:47][CH2:48][OH:49]>CN(C=O)C.CC(OC)(C)C>[CH2:35]([N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:6]([C:8]1[N:9]=[C:10]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][C:14]=2[C:23]([N:25]2[CH2:34][CH2:33][C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH2:26]2)=[O:24])[N:11]([CH2:46][CH2:47][CH2:48][OH:49])[CH:12]=1)=[O:7])[CH2:36][CH2:37][CH3:38]
Reactant: OCCCBr
Reactant: CCCCN(CCCC)C(=O)c1c[nH]c(-c2ccc(C(=O)OC)cc2C(=O)N2CCc3ccccc3C2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COC(C)(C)C
Solvent: CN(C)C=O
Product: CCCCN(CCCC)C(=O)c1cn(CCCO)c(-c2ccc(C(=O)OC)cc2C(=O)N2CCc3ccccc3C2)n1
Temperature: 40 °C
Yield: 30.7 %

Procedure:
To a stirred solution of methyl 4-(4-(dibutylcarbamoyl)-1H-imidazol-2-yl)-3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)benzoate (200 mg, 0.38 mmol) in DMF (8 mL) was added K2CO3 (107 mg, 0.77 mmol) and 3-bromopropanol (54 mg, 0.38 mmol). The reaction mixture was heated at 40° C. for 4 h, cooled to room temperature, diluted with MTBE, and quenched with water. The organic layer was separated and the aqueous layer was extracted with MTBE (3×). The combined organic layer was dried over Na2SO4 and concentrated in vacuo to provide crude product. The crude material was purified by flash chromatography (gradient from 10 to 50% EtOAc/hexanes) to provide the title compound (67 mg, 32%). 1H NMR (CDCl3, 1:1 mixture of amide rotamers) δ 8.19-8.15 (m, 1H), 8.04 (dd, J=11.2, 1.6 Hz, 1H), 7.62 (s, 0.5H), 7.55 (s, 0.5H), 7.50-7.46 (m, 1H), 7.25-7.14 (m, 3.5H), 6.94 (d, J=7.2 Hz, 0.5H), 4.84-4.59 (m, 2H), 4.29-4.13 (m, 2H), 3.96 (s, 3H), 3.82-3.70 (m, 2H), 3.50-3.35 (m, 4H), 3.31-2.88 (m, 4H), 1.89-1.87 (m, 2H), 1.55-1.49 (m, 2H), 1.40-1.05 (m, 6H), 0.93-0.88 (m, 3H), 0.74 (t, J=7.2 Hz, 1.5H), 0.65 (t, J=7.2 Hz, 1.5H); MS(ESI+) m/z 575.6 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([OH:13])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[Cl:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Br)=[CH:19][CH:18]=1>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([O:13][CH2:21][C:20]2[CH:23]=[CH:24][C:17]([Cl:16])=[CH:18][CH:19]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Clc1ccc(CBr)cc1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@@H](OCc2ccc(Cl)cc2)C1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
A solution of (R)-3-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester (1.14 mmol, 1.0 eq) in THF (2.5 mL) was added to a suspension of sodium hydride (1.15 eq) in THF (2.5 mL) cooled at 0° C. and the resulting mixture was stirred for 45 min. A solution of 4-chlorobenzyl bromide (1.31 mmol, 1.15 eq) in THF (2.0 mL) was then added drop wise and reaction mixture was slowly warmed to room temperature and stirred for 18 h. The reaction mixture was quenched with water (1.0 ml) and diluted with ethyl acetate. The combined organics were dried over sodium sulfate. The crude product was purified on silica using gradient elution from hexane/ethyl acetate (10%) to hexane/ethyl acetate (30%). 1H-NMR (CDCL3) δ: 1.45 (9H, s), 1.80-2.05 (2H, m), 3.30-3.55 (4H, m), 4.05 (1H, m), 4.45 (2H, s), 7.15-7.30 (4H, m). ESI-MS m/z: 311 (M+1), UV retention time: 2.94 min.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([Cl:9])=[CH:4][N:3]=1.[NH2:10][NH2:11]>O1CCOCC1>[Cl:8][C:7]1[C:2]([NH:10][NH2:11])=[N:3][CH:4]=[C:5]([Cl:9])[CH:6]=1
Reactant: Clc1cnc(Cl)c(Cl)c1
Reactant: NN
Solvent: C1COCCO1
Product: NNc1ncc(Cl)cc1Cl
Temperature: 25 °C
Yield: 71.5 %

Procedure:
To a 500 mL flask, 2,3,5-trichloropyridine (20.00 g, 0.110 mol), 80% hydrazine (34.30 g, 0.550 mol) and dioxane (200 mL) were added sequentially. The reaction mixture was heated to reflux for 20 hours. Then the reaction mixture was cooled down to room temperature overnight and white crystal was precipitated. The white crystal was isolated via filtration and dried to give the product (14.0 g) as a white solid in 72% yield. Melting point: 187-189° C.
Reaction SMILES: [N:1]1[C:10]2[NH:9][C:8]3[CH:11]=[C:12]([CH2:15][NH:16][C:17]([NH2:19])=[S:18])[CH:13]=[CH:14][C:7]=3[S:6][C:5]=2[N:4]=[CH:3][CH:2]=1.[CH3:20]N(C)C=O.CI.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.C(OCC)(=O)C>[N:1]1[C:10]2[NH:9][C:8]3[CH:11]=[C:12]([CH2:15][NH:16][C:17](=[NH:19])[S:18][CH3:20])[CH:13]=[CH:14][C:7]=3[S:6][C:5]=2[N:4]=[CH:3][CH:2]=1
Reactant: CN(C)C=O
Reactant: NC(=S)NCc1ccc2c(c1)Nc1nccnc1S2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Solvent: CCOC(C)=O
Product: CSC(=N)NCc1ccc2c(c1)Nc1nccnc1S2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1.0 g of N-(10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)thiourea in acetone (10 ml)/N,N-dimethylformamide (10 ml) was added 1.0 ml of methyl iodide and the resulting mixture was stirred at room temperature for 0.5 hour. Next, the reaction mixture was distributed into an aqueous solution of potassium carbonate and ethyl acetate. The organic layer was extracted and washed with water. After distilling off the solvent under reduced pressure, the crystals thus precipitated were taken up by filtration and washed with ethyl acetate to thereby give 0.900 g of the title compound as yellow crystals.
Reaction SMILES: [CH3:1][Si:2]([C:5]#[C:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][OH:14])=[CH:9][CH:8]=1)([CH3:4])[CH3:3].N1C=CN=C1.[CH3:20][C:21]([Si:24](Cl)([CH3:26])[CH3:25])([CH3:23])[CH3:22].S([O-])([O-])(=O)=O.[Mg+2]>C1COCC1>[C:21]([Si:24]([CH3:26])([CH3:25])[O:14][CH2:13][C:10]1[CH:9]=[CH:8][C:7]([C:6]#[C:5][Si:2]([CH3:3])([CH3:4])[CH3:1])=[CH:12][CH:11]=1)([CH3:23])([CH3:22])[CH3:20]
Reactant: C[Si](C)(C)C#Cc1ccc(CO)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCc1ccc(C#C[Si](C)(C)C)cc1
Temperature: 0 °C
Reaction time: 15 h
Yield: 95.2 %

Procedure:
Under argon condition, (4-((trimethylsilyl)ethynyl)phenyl) methanol (258 mg, 1.26 mmol) was dissolved in 5 mL of dry THF and then cooled to 0° C., and imidazole (103 mg, 1.52 mmol) and TBSCl (228 mg, 1.52 mmol) dissolved in 3 mL of dry THF were added thereto. Thereafter, the temperature was raised to room temperature, and the reaction mixture was stirred for 15 hours at room temperature. Upon completion of the reaction, the reaction was terminated by adding 10 mL of aqueous saturated ammonium chloride solution. The reaction mixture was extracted with ethyl acetate (10 mL×4), and the organic layer thus obtained was treated with anhydrous magnesium sulfate to remove water. The precipitate was filtered out and the resulting solution was concentrated by distillation under reduced pressure, and purified by column chromatography to obtain 383 mg (1.20 mmol, 95%) of the desired compound.
Reaction SMILES: [CH3:1][C:2]([C:6]1[NH:7][C:8](=[O:12])[CH:9]=[CH:10][CH:11]=1)([CH3:5])[C:3]#[N:4].Cl[C:14]([F:20])([F:19])C(OC)=O.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[F:19][CH:14]([F:20])[O:12][C:8]1[N:7]=[C:6]([C:2]([CH3:1])([CH3:5])[C:3]#[N:4])[CH:11]=[CH:10][CH:9]=1
Reactant: COC(=O)C(F)(F)Cl
Reactant: CC(C)(C#N)c1cccc(=O)[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C#N)c1cccc(OC(F)F)n1
Temperature: 95 °C
Reaction time: 3 h
Yield: 57.3 %

Procedure:
To a 100 mL round bottom flask was added 2-methyl-2-(6-oxo-1,6-dihydropyridin-2-yl)propanenitrile (8.2 g, 51 mmol, 1.0 equiv), methyl chlorodifluoroacetate (14.9 g, 103 mmol, 2.0 equiv), cesium carbonate (23.3 g, 71 mmol, 1.4 equiv), and DMF (100 mL). The reaction was heated to 95° C. and stirred for 3 hours. The reaction was then quenched with water (100 mL) and diluted with EtOAc (500 mL). The organic layer was separated from the aqueous layer. The aqueous layer was extracted with EtOAc (100 mL), and the combined organic phases were washed with saturated brine solution (3×200 mL), dried over Na2SO4, concentrated, and chromatographed with silica gel (2-5% EtOAc/hex) to give 2-(6-(difluoromethoxy)pyridin-2-yl)-2-methylpropanenitrile (6.2 g, 57%) as a clear oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:12][CH3:13])[C:9]=1[O:10][CH3:11])[CH:5]=O.C([O-])=O.[Na+].Cl.[NH2:19]O.[Cl-].[Na+]>C(O)=O>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:12][CH3:13])[C:9]=1[O:10][CH3:11])[C:5]#[N:19]
Reactant: NO
Reactant: COc1cc(C=O)cc(Br)c1OC
Agent: Cl
Agent: O=C[O-]
Agent: [Cl-]
Solvent: O=CO
Product: COc1cc(C#N)cc(Br)c1OC
Temperature: 95 °C

Procedure:
11 g 3-Bromo-4,5-dimethoxybenzaldehyde, 6.5 g sodium formate were dissolved in 50 mL of formic acid and stirred at 95° C. 3.6 g Hydroxylamine hydrochloride was added in portions and the mixture stirred for 4 h at 95° C., 2 days at 50° C. and 3 h at 120° C. The mixture was poured on to 700 mL of an almost saturated sodium chloride solution/ice mixture and the precipitate isolated, washed with water and dried to provide 3-bromo-4,5 dimethoxybenzonitrile.