Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[N:17]1[CH2:22][CH2:21][CH:20]([CH2:23][N:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)[CH2:19][CH2:18]1.[F:29][C:30]1[CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:33]=[C:32]([O:45][CH3:46])[C:31]=1[OH:47]>>[CH:14]1([C:12]([C:6]2[CH:7]=[N:8][C:9]3[C:4]([C:5]=2[N:17]2[CH2:22][CH2:21][CH:20]([CH2:23][N:24]4[CH2:28][CH2:27][CH2:26][CH2:25]4)[CH2:19][CH2:18]2)=[CH:3][C:2]([C:34]2[CH:33]=[C:32]([O:45][CH3:46])[C:31]([OH:47])=[C:30]([F:29])[CH:35]=2)=[CH:11][CH:10]=3)=[O:13])[CH2:15][CH2:16]1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)cc(F)c1O
Reactant: O=C(c1cnc2ccc(Br)cc2c1N1CCC(CN2CCCC2)CC1)C1CC1
Product: COc1cc(-c2ccc3ncc(C(=O)C4CC4)c(N4CCC(CN5CCCC5)CC4)c3c2)cc(F)c1O
Yield: 51.8 %

Procedure:
Following general procedure D, {6-bromo-4-[4-(pyrrolidin-1-ylmethyl)piperidin-1-yl]quinolin-3-yl}(cyclopropyl)methanone (26 mg, 0.059 mmol) was reacted with 2-fluoro-6-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (32 mg, 0.118 mmol) to afford the desired product (15.4 mg, 52%) as a gray solid: 1H NMR (500 MHz, CD3OD) δ 8.78 (s, 1H), 8.27 (s, 1H), 8.03 (s, 2H), 7.23-7.04 (m, 2H), 3.99 (s, 3H), 3.54 (d, J=12.8 Hz, 2H), 3.28-3.11 (m, 6H), 3.05 (d, J=6.6 Hz, 2H), 2.63-2.51 (m, 1H), 2.20-1.89 (m, 7H), 1.80-1.58 (m, 2H), 1.41-1.16 (m, 4H).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]([C:9]1[N:10]([CH2:21][CH2:22][OH:23])[C:11]2[C:16]([CH:17]=1)=[CH:15][C:14]([N+:18]([O-:20])=[O:19])=[CH:13][CH:12]=2)([CH3:8])[CH3:7])C.CC(C[AlH]CC(C)C)C.O>C1COCC1>[OH:23][CH2:22][CH2:21][N:10]1[C:11]2[C:16](=[CH:15][C:14]([N+:18]([O-:20])=[O:19])=[CH:13][CH:12]=2)[CH:17]=[C:9]1[C:6]([CH3:8])([CH3:7])[CH2:5][CH2:4][OH:3]
Reactant: CCOC(=O)CC(C)(C)c1cc2cc([N+](=O)[O-])ccc2n1CCO
Agent: CC(C)C[AlH]CC(C)C
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(CCO)c1cc2cc([N+](=O)[O-])ccc2n1CCO
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.9 %

Procedure:
To a solution of 3-[1-(2-hydroxy-ethyl)-5-nitro-1H-indol-2-yl]-3-methyl-butyric acid ethyl ester (700 mg, 2.1 mmol) in THF (25 mL) was added DIBAL-H (1.0 M, 4.2 mL, 4.2 mmol) at −78° C. The mixture was stirred at room temperature for 1 h. Water (2 mL) was added and the resulting mixture was extracted with EtOAc (15 mL×3). The combined organic layers were dried over anhydrous Na2SO4 and evaporated under vacuum. The residue was purified by chromatography on silica gel (15% ethyl acetate/petroleum) to afford 3[1-(2-hydroxy-ethyl)-5-nitro-1H-indol-2-yl]-3-methyl-butan-1-ol (300 mg, 49%). 1H NMR (300 MHz, d-DMSO) δ 8.42 (d, J=1.5 Hz, 1 H), 7.95 (dd, J=1.2, 8.7 Hz, 1 H), 6.36 (d, J=9.3 Hz, 1 H), 6.50 (s, 1 H), 5.25 (br s, 1 H), 4.46-4.42 (m, 4 H), 3.69-3.66 (m, 2 H), 3.24-3.21 (m, 2 H), 1.42 (s, 6 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:9](Cl)(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1.[C:13]([NH2:17])([CH3:16])([CH3:15])[CH3:14]>O1CCCC1>[C:13]([NH:17][S:9]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)(=[O:11])=[O:10])([CH3:16])([CH3:15])[CH3:14]
Reactant: COc1cccc(S(=O)(=O)Cl)c1
Reactant: CC(C)(C)N
Solvent: C1CCOC1
Product: COc1cccc(S(=O)(=O)NC(C)(C)C)c1
Temperature: 60 °C
Reaction time: 7 h
Yield: 92.6 %

Procedure:
49.5 gm (0.24 mol) of 3-methoxy-benzene sulfonic acid chloride were dissolved in 50 ml of tetrahydrofuran, and the solution was added dropwise over a period of 25 minutes to a solution of 40 gm (0.55 mol) of tert. butylamine in 200 ml of tetrahydrofuran. After stirring for 1 hour at room temperature and for 7 hours at 60° C., the reaction mixture was filtered, and the filtrate was evaporated in vacuo. The residue was treated with cyclohexane, yielded 54.1 gm (92.6% of theory) of N-tert. butyl-3-methoxy-benzenesulfonamide.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([S:8][CH2:9][C:10]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:11])[CH:7]=1.[Cl:19][S:20](O)(=[O:22])=[O:21]>ClC1C=CC=CC=1Cl>[Cl:1][C:2]1[C:3]([S:20]([Cl:19])(=[O:22])=[O:21])=[CH:4][CH:5]=[C:6]([S:8][CH2:9][C:10]([NH:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[O:11])[CH:7]=1
Reactant: O=S(=O)(O)Cl
Reactant: O=C(CSc1cccc(Cl)c1)Nc1ccccc1
Solvent: Clc1ccccc1Cl
Product: O=C(CSc1ccc(S(=O)(=O)Cl)c(Cl)c1)Nc1ccccc1

Procedure:
A mixture of 250 g. (0.9 mole) of 5-chloro-2-(phenylthio)acetanilide and 116.52 g. (1.0 mole) of chlorosulfonic acid in 2.5 liters of o-dichlorobenzene is heated at 150°-160°C for 2 hours in an oil bath. The reaction mixture is cooled, washed with 1 liter of cold sodium carbonate solution, washed with water and then dried using magnesium sulfate. Removal of the solvent by distillation under vacuum yields the product.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([S:17](=[O:21])(=[O:20])[NH:18][CH3:19])=[CH:13][CH:12]=2)=[O:9])=[C:6](Cl)[N:5]=[CH:4][N:3]=1.[NH3:23]>O1CCOCC1>[NH2:23][C:6]1[C:7]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([S:17](=[O:21])(=[O:20])[NH:18][CH3:19])=[CH:13][CH:12]=2)=[O:9])=[C:2]([Cl:1])[N:3]=[CH:4][N:5]=1
Reactant: N
Reactant: CNS(=O)(=O)c1ccc(NC(=O)c2c(Cl)ncnc2Cl)cc1
Solvent: C1COCCO1
Product: CNS(=O)(=O)c1ccc(NC(=O)c2c(N)ncnc2Cl)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 80.2 %

Procedure:
4,6-Dichloro-N-(4-(N-methylsulfamoyl)phenyl)pyrimidine-5-carboxamide (238 m g, 0.66 mmol) was dissolved in dioxane (3 ml) and cooled in an ice bath. Ammonia (0.47 ml, 7N in MeOH, 3.3 mmol) was dropwise added and the mixture was stirred at 0° C. for 6 h and at room temperature overnight. The solvent was removed and ethyl acetate added. The solid precipitate was filtered and washed with ethyl acetate to give 181 mg (80% yield) of the title compound. Purity 100%
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15](=[O:35])[CH2:16][CH2:17][CH2:18][C:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[C:20]=3[C:29]([O:31]CC=C)=[O:30])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1CCCCC1>ClCCl.Cl.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>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][C:12]([C:15](=[O:35])[CH2:16][CH2:17][CH2:18][C:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[C:20]=3[C:29]([OH:31])=[O:30])=[CH:13][CH:14]=2)=[CH:5][CH:4]=1
Reactant: C=CCOC(=O)c1c(CCCC(=O)c2ccc(-c3ccc(OC)cc3)cc2)ccc2ccccc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: C1CCNCC1
Product: COc1ccc(-c2ccc(C(=O)CCCc3ccc4ccccc4c3C(=O)O)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 107.7 %

Procedure:
A solution of Example 11F (200 mg, 0.431 mmol) in dichloromethane (5 mL) at room temperature was treated with tetrakis(triphenylphosphine)palladium (43 mg, 0.0375 mmol), triphenylphosphine (19.6 mg, 0.075 mmol), piperidine (0.0447 mL, 0.452 mmol), and allowed to stir at room temperature for 30 minutes. The reaction mixture was diluted with 0.5 N HCl, and extracted with dichloromethane. The organic layer was dried (Na2SO4), filtered, concentrated, and purified on silica gel with 10% methanol/CH2Cl2 to provide 197 mg (100%) of the desired compound as an white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH:12]3[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH2:23][CH2:24][NH:25][S:26]([CH2:29][CH2:30][CH3:31])(=[O:28])=[O:27])[CH:20]=4)[CH2:15][CH2:14][NH:13]3)[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.CS[C:34]([NH:46][C:47](=[O:56])[O:48][CH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)=[N:35][C:36](=[O:45])[O:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.C(N(CC)CC)C>CN(C)C=O.FC(F)(F)S([O-])(=O)=O.[Ag+]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH:12]3[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH2:23][CH2:24][NH:25][S:26]([CH2:29][CH2:30][CH3:31])(=[O:27])=[O:28])[CH:20]=4)[CH2:15][CH2:14][N:13]3/[C:34](/[NH:46][C:47](=[O:56])[O:48][CH2:49][C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)=[N:35]/[C:36](=[O:45])[O:37][CH2:38][C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=3)[CH2:9][CH2:10][CH2:11]2)=[CH:4][CH:3]=1
Reactant: CCCS(=O)(=O)NCCOc1ccc2c(c1)C(C1(c3ccc(F)cc3)CCC1)NCC2
Reactant: CSC(=NC(=O)OCc1ccccc1)NC(=O)OCc1ccccc1
Agent: [Ag+]
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCS(=O)(=O)NCCOc1ccc2c(c1)C(C1(c3ccc(F)cc3)CCC1)N(/C(=N/C(=O)OCc1ccccc1)NC(=O)OCc1ccccc1)CC2
Reaction time: 3 h

Procedure:
N-[2-({1-[1-(4-Fluorophenyl)cyclobutyl]-1,2,3,4-tetrahydroisoquinolin-7-yl}oxy)ethyl]propane-1-sulfonamide (100 mg, 0.224 mmol, cf. example 65) and dibenzyl [(methylsulfanyl)methylylidene]biscarbamate (104 mg, 0.291 mmol) were dissolved in dry dimethylformamide (1 mL). Triethylamine (0.094 mL, 0.672 mmol) was added followed by silver trifluoromethanesulfonate (81 mg, 0.313 mmol). A yellow precipitate was formed and the reaction mixture turned dark brown. Stirring was continued at room temperature for 3 h. The solvent was evaporated in vacuo. Dichloromethane (15 mL) was added, the solid was removed by filtration and washed with dichloromethane. The combined dichloromethane phases were concentrated in vacuo and the crude product was purified by flash chromatography (silica, dichloromethane then dichlorometane:methanol=100:1). Yield: 100 mg (0.132 mmol, 59%).
Reaction SMILES: [NH2:1][C@H:2]([C:6]1[CH:11]=[CH:10][C:9]([Br:12])=[CH:8][CH:7]=1)[CH2:3][CH2:4][OH:5].[C:13]([O:17][C:18]([NH:20][C:21]1([C:36](O)=[O:37])[CH2:26][CH2:25][N:24]([C:27]2[C:28]3[CH:35]=[CH:34][NH:33][C:29]=3[N:30]=[CH:31][N:32]=2)[CH2:23][CH2:22]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CC(N(C)C)=O>[Br:12][C:9]1[CH:8]=[CH:7][C:6]([C@@H:2]([NH:1][C:36]([C:21]2([NH:20][C:18](=[O:19])[O:17][C:13]([CH3:15])([CH3:14])[CH3:16])[CH2:22][CH2:23][N:24]([C:27]3[C:28]4[CH:35]=[CH:34][NH:33][C:29]=4[N:30]=[CH:31][N:32]=3)[CH2:25][CH2:26]2)=[O:37])[CH2:3][CH2:4][OH:5])=[CH:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CCN(c2ncnc3[nH]ccc23)CC1
Reactant: N[C@@H](CCO)c1ccc(Br)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NC1(C(=O)N[C@@H](CCO)c2ccc(Br)cc2)CCN(c2ncnc3[nH]ccc23)CC1
Temperature: 20 °C
Reaction time: 24 h
Yield: 44.5 %

Procedure:
(S)-3-Amino-3-(4-bromophenyl)propan-1-ol (Intermediate 51) (191 mg, 0.83 mmol) was added in one portion to 4-(tert-butoxycarbonylamino)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxylic acid (Intermediate 1) (300 mg, 0.83 mmol) and DIPEA (0.435 mL, 2.49 mmol) in DMA (5 mL). O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (347 mg, 0.91 mmol) was added and the resulting solution was stirred at 20° C. for 24 hours. The reaction mixture was evaporated to dryness then diluted with EtOAc (300 mL), and washed sequentially with water (50 mL) and saturated brine (50 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 2 to 6% MeOH with ammonia in DCM. Fractions were evaporated to afford (S)-tert-butyl 4-(1-(4-bromophenyl)-3-hydroxypropylcarbamoyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-ylcarbamate (212 mg, 44.5%) as a white solid. The product (212 mg, 0.36 mmol) was suspended in dioxane (5.00 mL) and 4M hydrogen chloride in dioxane (0.577 mL, 16.6 mmol) added. The reaction was stirred at ambient temperature for 2 hours. The crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 3.5N ammonia/MeOH and pure fractions were evaporated to dryness. The product was then purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5 μm silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% ammonia) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford (S)-4-amino-N-(1-(4-bromophenyl)-3-hydroxypropyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamide (51.0 mg, 13.0%) as a white solid.
Reaction SMILES: CCO.[Na].[C:5]([O:12][CH2:13][CH3:14])(=[O:11])[C:6]([O:8]CC)=O.[CH3:15][C:16]([CH3:18])=[O:17]>>[O:8]=[C:6]([CH2:15][C:16](=[O:17])[CH3:18])[C:5]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CC(C)=O
Reactant: CCOC(=O)C(=O)OCC
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(=O)CC(C)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59.2 %

Procedure:
To a 100 mL two neck RB flask fitted with magnetic stirrer was charged with 25 mL of ethanol. To the stirred solvent was added sodium metal pieces (0.86 g, 37 mmol) slowly at 0° C. under nitrogen atmosphere and stirred for 30 minutes at room temperature. After 30 minutes, diethyl oxalate (5 g, 34.2 mmol) in acetone (10 mL) was added drop wise. During addition, the reaction mixture was changed to yellow color. After addition, thick mass was observed, was added ethanol (10 mL) to the reaction mixture and stirred at room temperature for 1 h. Then, the reaction mixture was filtered; the solids were dissolved in ice-cold water (50 mL), acidified with concentrated sulfuric acid and extracted with ethyl acetate (100 mL). The organic layer was concentrated under reduced pressure and the solvent traces were removed by triturated with n-hexane. The product was obtained as brown liquid (3.2 g, yield: 59.2%). 1H NMR (300 MHz, DMSO-d6): δ 5.46 (s, 2H), 4.02-4.09 (q, 2H), 1.89 (s, 3H), 1.18-1.22 (t, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[SH:9].C(O)C.C[O-].[Na+].Br[CH2:17][C:18]([OH:20])=[O:19]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[S:9][CH2:17][C:18]([OH:20])=[O:19]
Reactant: Sc1c(Cl)cccc1Cl
Reactant: O=C(O)CBr
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCO
Product: O=C(O)CSc1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2,6-dichlorothiophenol, 50.0 gm, was added to 250 ml of ethanol. 63.8 ml of a 25% solution of sodium methoxide (2 equivalents) in methanol was then added to the system. The system was stirred at room temperature for approximately 3 hours. Afterwards, 20 ml of bromoacetic acid was added and the system was then heated to reflux. The system was continued at reflux for 16 hours. The reaction was then stopped and the solvent removed by stripping. The resulting material was dissolved with a basic aqueous solution and then washed with methylene chloride. Concentrated HCl was next added to the aqueous solution to acidify it. The product was extracted with methylene chloride. The methylene chloride solution was stripped and then triturated with hexane. The product was then filtered, washed with water and air dried to yield 55.3 gm of the 2,6-dichlorothiophenoxyacetic acid.
Reaction SMILES: [CH2:1]([OH:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[H-].[Na+:15]>>[CH2:1]([O:13][Na:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: [Na+]
Reactant: CCCCCCCCCCCCO
Agent: [H-]
Product: CCCCCCCCCCCCO[Na]
Temperature: 100 °C
Reaction time: 2 h
Yield: 96.5 %

Procedure:
A 500 ml round bottom flask equipped with a condenser, thermometer (with controller) and overhead stirrer was charged with 93 g (0.5 moles) of C12H25OH and (0.25 moles) of NaH. The mixture exothermed to 70° C. After the exotherm began to subside, the mixture was heated to 100° C. with stirring. After about two hours, a light grey paste was formed. This paste was subjected to a Kugelrohr distillation at 180° C. The non-volatile residue was 54.6% of the charge (theory for C12H24ONa=53.0%). The hard, dry, white powder residue was recovered. Analysis by titration showed the yield was 96.5% of theory for the named compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH3:25][C:26]([OH:30])([C:28]#[CH:29])[CH3:27].C(NC(C)C)(C)C>C1COCC1.[Cu]I.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:15]([O:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]2[CH:6]=[CH:7][C:2]([C:29]#[C:28][C:26]([OH:30])([CH3:27])[CH3:25])=[CH:3][CH:4]=2)=[CH:9][CH:10]=1)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: C#CC(C)(C)O
Reactant: CCCCCCCCCCOc1ccc(-c2ccc(Br)cc2)cc1
Agent: [Cu]I
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCCCCCCCCCOc1ccc(-c2ccc(C#CC(C)(C)O)cc2)cc1

Procedure:
A stirred mixture of compound 68 (15.00 g, 0.039 mol), 2-methylbut-3-yn-2-ol (7.15 g, 0.085 mol), copper(I) iodide (0.34 g, 1.80 mmol), tetrakis (triphenylphosphine) palladium(0) (2.89 g, 2.50 mmol) and diisopropylamine (150 ml) was heated under reflux in a dry nitrogen atmosphere for 24 h. The resultant mass was dissolved in THF and filtered over hyflo filter aid to remove inorganic materials. Volatile materials were removed in vacuo and the brown solid was recrystallised from ethanol to give a white, fluffy solid.
Reaction SMILES: C([O:14][C:15]([C:17]1[O:18][C@@H:19]([C:35](=[O:41])[N:36]([CH3:40])[CH2:37][CH2:38][CH3:39])[C@H:20]([NH:31][C:32](=[O:34])[CH3:33])[C@@H:21]([NH:23]C(OC(C)(C)C)=O)[CH:22]=1)=[O:16])(C1C=CC=CC=1)C1C=CC=CC=1.[F:42][C:43]([F:48])([F:47])[C:44]([OH:46])=[O:45]>ClCCl>[F:42][C:43]([F:48])([F:47])[C:44]([OH:46])=[O:45].[C:32]([NH:31][C@H:20]1[C@H:19]([C:35](=[O:41])[N:36]([CH3:40])[CH2:37][CH2:38][CH3:39])[O:18][C:17]([C:15]([OH:16])=[O:14])=[CH:22][C@@H:21]1[NH2:23])(=[O:34])[CH3:33]
Reactant: CCCN(C)C(=O)[C@@H]1OC(C(=O)OC(c2ccccc2)c2ccccc2)=C[C@H](NC(=O)OC(C)(C)C)[C@H]1NC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCN(C)C(=O)[C@@H]1OC(C(=O)O)=C[C@H](N)[C@H]1NC(C)=O
Reaction time: 3 h

Procedure:
(4S,5R,6R)-5-Acetylamino-4-(tert-butoxycarbonylamino)-6-(methyl-propylcarbamoyl)-5,6-dihydro-4H-pyran-2-carboxylic acid benzhydryl ester (0.10 g) was dissolved in dichloromethane (1 ml) and trifluoroacetic acid (1 ml) and left to stand at 23° C. for 3 hours. The solvent was removed in vacuo and the residue was triturated using diethyl ether (30 ml). The resulting solid was collected by filtration and dried to give the title compound as a white solid. (0.064 g): 1H NMR (250MHz, D2O) 5.99 (1H, m), 5.24 (1H, m), 4.52 (1H, m), 4.25 (1H, m), 3.59-3.18 (2H, m), 3.18+2.97 (3H, s), 2.02 (3H, s), 1.72-1.46 (2H, m), 0.87 (3H, m); Mass Analysis: C15H22F3N3O7. 0.25H2O. Required C, 43.12; H, 5.43; N, 10.06; Found C, 42.99; H, 5.60; N, 10.17; Mass Spec. (Low Resolution) MH+ =300.
Reaction SMILES: [CH3:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[C:4]([NH:6][C:7]1[CH:15]=[CH:14][C:10]([C:11](Cl)=[O:12])=[CH:9][CH:8]=1)=[O:5].[CH:20]1[C:30]2[CH2:29][C:28]3[CH:31]=[CH:32][CH:33]=[CH:34][C:27]=3[CH2:26][NH:25][C:24]=2[CH:23]=[CH:22][CH:21]=1.C(N(CC)CC)C>O1CCCC1>[CH:20]1[C:30]2[CH2:29][C:28]3[CH:31]=[CH:32][CH:33]=[CH:34][C:27]=3[CH2:26][N:25]([C:11]([C:10]3[CH:14]=[CH:15][C:7]([NH:6][C:4](=[O:5])[C:3]4[CH:16]=[CH:17][CH:18]=[CH:19][C:2]=4[CH3:1])=[CH:8][CH:9]=3)=[O:12])[C:24]=2[CH:23]=[CH:22][CH:21]=1
Reactant: c1ccc2c(c1)CNc1ccccc1C2
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)Cl)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 108.7 %

Procedure:
To a solution of 0.27 g (1 mmol) of 4-[(2-methylbenzoyl)amino]benzoyl chloride in 2 ml of tetrahydrofuran is added 0.20 g (1 mmol) of 6,11-dihydro-5H-dibenz[b,e]azepine and 0.20 g of triethylamine. The mixture is stirred at room temperature for 3 hours and the solvent removed under vacuum. To the residue is added 1N HCl and the mixture extracted with ethyl acetate (20 ml) and the extract washed with saturated NaHCO3, brine and dried (Na2SO4). The solution is filtered through a thin pad of hydrous magnesium silicate and the filtrate evaporated. The residue is triturated with ether-hexane and filtered to give 0.47 g of a white solid: Mass Spectrum; EI 433(M+1); EI-high resolution 432.1842.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]([OH:9])=[O:8].[F:10][C:11]1[CH:12]=[C:13]([N:30]2[CH2:34][C@H:33]([CH2:35][N:36]3[CH:40]=[CH:39][N:38]=[N:37]3)[O:32][C:31]2=[O:41])[CH:14]=[CH:15][C:16]=1[C:17]1[CH:18]=[N:19][C:20]([C:23]2[CH2:27][C@@H:26]([CH2:28]O)[O:25][N:24]=2)=[CH:21][CH:22]=1.CN(C=O)C.C(N=C=NC(C)C)(C)C>CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[F:10][C:11]1[CH:12]=[C:13]([N:30]2[CH2:34][C@H:33]([CH2:35][N:36]3[CH:40]=[CH:39][N:38]=[N:37]3)[O:32][C:31]2=[O:41])[CH:14]=[CH:15][C:16]=1[C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH2:27][C@@H:26]([CH2:28][O:8][C:7]([C:2]3[CH:3]=[N:4][CH:5]=[CH:6][N:1]=3)=[O:9])[O:25][N:24]=2)=[N:19][CH:18]=1
Reactant: O=C(O)c1cnccn1
Reactant: O=C1O[C@@H](Cn2ccnn2)CN1c1ccc(-c2ccc(C3=NO[C@H](CO)C3)nc2)c(F)c1
Agent: CC(C)N=C=NC(C)C
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(OC[C@@H]1CC(c2ccc(-c3ccc(N4C[C@H](Cn5ccnn5)OC4=O)cc3F)cn2)=NO1)c1cnccn1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Pyrazine-2-carboxylic acid (118 mg, 0.95 mMol), (5R)-3-(3-fluoro-4-{6-[(5S)-5-(hydroxymethyl)-4,5-dihydroisoxazol-3-yl]pyridin-3-yl}phenyl)-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-one (Example 1: 200 mg, 0.46 mMol), 4-(dimethylamino)pyridine (5 mg, 0.041 mmol) and DMF (2 ml) were combined and warmed to give a clear solution. The solution was allowed to cool to room temperature, and then diisopropylcarbodiimide (0.15 ml, 0.96 mmol) was added. The mixture was stirred for 18 hours, ethyl acetate was added, followed by washing with saturated NaCl. The organic layer was dried over sodium sulfate, evaporated, triturated with 1:5 ether:hexane, dissolved in 1:1 acetonitrile:methanol, adsorbed on silica gel and purified by chromatography (silica gel; elution with 1 to 10% methanol in dichloromethane). The product containing fractions were pooled and evaporated to give the title compound as a white solid, 159 mg.
Reaction SMILES: [ClH:1].[C:2](=[NH:10])(OC)[CH2:3][CH2:4][CH2:5][CH:6]=[CH2:7].[NH3:11]>>[ClH:1].[C:2](=[NH:10])([NH2:11])[CH2:3][CH2:4][CH2:5][CH:6]=[CH2:7]
Reactant: N
Reactant: C=CCCCC(=N)OC
Agent: Cl
Product: C=CCCCC(=N)N

Procedure:
Methyl 5-hexenimidoate hydrochloride (P3, 1.5 g) was dissolved in NH3 (2M in MeOH, 46 mL) and the mixture was heated to reflux for 2 h. Volatiles were evaporated in vacuo to give 1.45 g of the title compound as brown solid, which was used in the subsequent step without further purification.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[CH3:19][C:20]1[O:21][C:22]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=2)=[C:23]([C:25](O)=[O:26])[N:24]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[C:16]([NH:18][C:25]([C:23]3[N:24]=[C:20]([CH3:19])[O:21][C:22]=3[C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:35])[F:36])[CH:29]=3)=[O:26])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: Cc1nc(C(=O)O)c(-c2cccc(C(F)(F)F)c2)o1
Reactant: CC1(c2ccc(Cn3cc(N)cn3)o2)OCCO1
Product: CC(=O)c1ccc(Cn2cc(NC(=O)c3nc(C)oc3-c3cccc(C(F)(F)F)c3)cn2)o1

Procedure:
Following general procedure B followed by T, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-4-ylamine and 2-methyl-5-(3-trifluoromethyl-phenyl)-oxazole-4-carboxylic acid. LC-MS-conditions 05b: tR=1.12 min; [M+H]+=459.1.