Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([NH2:4])(=O)C.[C:5]([C:9]1[CH:49]=[CH:48][C:12]([C:13]([NH:15][C@H:16]([C:44]([O:46][CH3:47])=[O:45])[CH2:17][C:18]2[CH:43]=[CH:42][C:21]([C:22]([O:24][CH2:25][C:26]([C:28]3[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])=[CH:30][CH:29]=3)=O)=O)=[CH:20][CH:19]=2)=[O:14])=[CH:11][CH:10]=1)([CH3:8])([CH3:7])[CH3:6]>CC(=O)OCC>[C:5]([C:9]1[CH:49]=[CH:48][C:12]([C:13]([NH:15][C@@H:16]([CH2:17][C:18]2[CH:43]=[CH:42][C:21]([C:22]3[O:24][CH:25]=[C:26]([C:28]4[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])=[CH:30][CH:29]=4)[N:4]=3)=[CH:20][CH:19]=2)[C:44]([O:46][CH3:47])=[O:45])=[O:14])=[CH:11][CH:10]=1)([CH3:8])([CH3:7])[CH3:6]
Reactant: CCCCCCCOc1ccc(C(=O)COC(=O)c2ccc(C[C@H](NC(=O)c3ccc(C(C)(C)C)cc3)C(=O)OC)cc2)cc1
Reactant: CC(N)=O
Solvent: CCOC(C)=O
Product: CCCCCCCOc1ccc(-c2coc(-c3ccc(C[C@H](NC(=O)c4ccc(C(C)(C)C)cc4)C(=O)OC)cc3)n2)cc1
Temperature: 140 °C
Reaction time: 1 h
Yield: 35.4 %

Procedure:
To borontrifluoride diethyl etherate (33.3 μl, 0.27 mmol) was added a mixture of acetamide (763 mg, 12.9 mmol) and (S)-2-(4-(heptyloxy)phenyl)-2-oxoethyl 4-(2-(4-(tert-butyl)benzamido)-3-methoxy-3-oxopropyl)benzoate (159 mg, 0.26 mmol). The reaction mixture was stirred at 140° C. for 1 h. The reaction mixture was allowed to cool to RT, diluted with EA (15 mL) and extracted with NaHCO3 (3×15 mL) and brine (15 mL). The combined organics were dried over MgSO4, filtered and concentrated. The residue was recrystallised from Et2O (5 mL), filtered and rinsed with Et2O. The filtrate was concentrated to afford 55 mg (16%) of (S)-methyl 2-(4-(tert-butyl)benzamido)-3-(4-(4-(4-(heptyloxy)phenyl)oxazol-2-yl)phenyl)propanoate as an orange oil. LCMS-ESI (m/z) calculated for C37H44N2O5: 596.8; found 597.0 [M+H]+, tR=3.11 min. (Method 4).
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([C:13]2([C:30]([F:33])([F:32])[F:31])[CH2:17][CH2:16][N:15]([C:18]3[N:23]=[CH:22][C:21]([CH2:24]O)=[C:20]([C:26]([F:29])([F:28])[F:27])[CH:19]=3)[CH2:14]2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[C:36]1(=[O:46])[NH:40][C:39](=[O:41])[C:38]2=[CH:42][CH:43]=[CH:44][CH:45]=[C:37]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[F:35][C:2]([F:1])([F:34])[C:3]1[CH:4]=[C:5]([C:13]2([C:30]([F:31])([F:32])[F:33])[CH2:17][CH2:16][N:15]([C:18]3[N:23]=[CH:22][C:21]([CH2:24][N:40]4[C:36](=[O:46])[C:37]5[C:38](=[CH:42][CH:43]=[CH:44][CH:45]=5)[C:39]4=[O:41])=[C:20]([C:26]([F:27])([F:28])[F:29])[CH:19]=3)[CH2:14]2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: OCc1cnc(N2CCC(c3cc(C(F)(F)F)cc(C(F)(F)F)c3)(C(F)(F)F)C2)cc1C(F)(F)F
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1Cc1cnc(N2CCC(c3cc(C(F)(F)F)cc(C(F)(F)F)c3)(C(F)(F)F)C2)cc1C(F)(F)F
Reaction time: 3 h
Yield: 49.2 %

Procedure:
[6-{3-[3,5-Bis(trifluoromethyl)phenyl]-3-(trifluoromethyl)pyrrolidin-1-yl}-4-(trifluoromethyl)pyridin-3-yl]methanol (0.98 g), phthalimide (0.30 g, 2.04 mmol) and triphenylphosphine (0.58 g) were dissolved in tetrahydrofuran (50 ml), and to the solution was added diethyl azodicarboxylate (40% toluene solution, 1.0 ml) at room temperature. After stirring the mixture for 3 hours, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain the target compound (0.60 g).
Reaction SMILES: B(F)(F)F.CCOCC.Cl[C:11](Cl)(Cl)[C:12](=N)[O:13][C@H:14]1[S:31][CH2:30][C@@H:25]([O:26][C:27](=[O:29])[CH3:28])[C@H:20]([O:21][C:22](=[O:24])[CH3:23])[C@H:15]1[O:16][C:17](=[O:19])[CH3:18].OC1C=[CH:42][C:39]([C:40]#[N:41])=[CH:38][CH:37]=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[C:17]([O:16][C@@H:15]1[C@@H:20]([O:21][C:22](=[O:24])[CH3:23])[C@H:25]([O:26][C:27](=[O:29])[CH3:28])[CH2:30][S:31][C@H:14]1[O:13][C:12]1[CH:37]=[CH:38][C:39]([C:40]#[N:41])=[CH:42][CH:11]=1)(=[O:19])[CH3:18]
Reactant: N#Cc1ccc(O)cc1
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@@H](OC(=N)C(Cl)(Cl)Cl)SC[C@H]1OC(C)=O
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: ClCCl
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1ccc(C#N)cc1
Yield: 80 %

Procedure:
1 ml of a 0.1M solution of boron trifluoride etherate in methylene chloride is added at -15° C., under an inert atmosphere, to a suspension of 250 mg (0.57.10-3 mol) of 2,3,4-tri-O-acetyl-5-thio-α-D-xylopyranosyl trichloroacetimidate, 57 mg (0.48.10-3 mol) of 4-hydroxybenzonitrile and a molecular sieve (1 nm) in 10 ml of methylene chloride. The reaction medium is allowed to return gradually to 0° C. and, after a reaction time of 3 h, is neutralized with sodium bicarbonate. The reaction mixture is then washed with water and dried over magnesium sulfate, MgSO4, and the solvent is evaporated off under reduced pressure. 150 mg (yield: 80%) of the expected product are obtained after purification by chromatography on silica gel using a hexane/ethyl acetate mixture (2/1 v/v) as the eluent.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:9]3[CH:10]=[CH:11]C(C#N)=[CH:13][C:8]=3[N:7]=[C:6]2[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH3:25])=[CH:19][N:18]=2)[CH2:3][CH2:2]1.[CH3:26][CH2:27][OH:28].[OH-:29].[K+].Cl>O>[CH:1]1([CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][C:26]([C:27]([OH:29])=[O:28])=[CH:13][C:8]=3[N:7]=[C:6]2[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH3:25])=[CH:19][N:18]=2)[CH2:3][CH2:2]1
Reactant: [OH-]
Reactant: CCO
Reactant: CCOc1ccc(Cc2nc3cc(C#N)ccc3n2CC2CC2)nc1
Agent: Cl
Agent: [K+]
Solvent: O
Product: CCOc1ccc(Cc2nc3cc(C(=O)O)ccc3n2CC2CC2)nc1

Procedure:
To a solution 1-(cyclopropylmethyl)-2-[(5-ethoxy-2-pyridinyl)methyl]-1H-benzimidazole-5-carbonitrile (400 mg, 1.203 mmol) in 1:1 EtOH:H2O (12 mL) was added KOH (269 mg, 4.81 mmol). The resulting mixture was refluxed for 36 h. The mixture was acidified with 1 N HCl to pH˜6.0. The precipitate (397 mg, 94%) was used in the subsequent step without further purification. MS (ESI) (M+H)+=352.
Reaction SMILES: [CH3:1][CH2:2][N:3]([CH:7]([CH3:9])[CH3:8])[CH:4]([CH3:6])[CH3:5].CC#[N:12]>>[NH2:12][CH2:9][CH:7]1[CH2:8][CH2:6][CH2:4][N:3]1[CH2:2][CH3:1].[CH3:1][CH2:2][N:3]([CH:7]([CH3:9])[CH3:8])[CH:4]([CH3:6])[CH3:5]
Reactant: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCN1CCCC1CN
Temperature: 80 °C
Reaction time: 15 h

Procedure:
A stock solution of 2-(aminomethyl)-1-ethylpyrrolidine (1.08 M) and DIEA (1.19 M) in CH3CN was prepared and 0.5 mL (containing 69 mg/79 μL, 0.542 mmol amine and 77 mg/104 μL, 0.596 mmol DIEA) was dispensed into each of the 40 mL vials from the second step. The vials were shaken on the J-KEM block at about 80° C. for about 15 h. The solutions were cooled to room temperature and concentrated in vacuo. The residues were then extracted with ethyl acetate and the extract washed with brine. The aqueous layers were extracted a second time with ethyl acetate and the combined organic layers were dried over Na2SO4 and passed through a plug of Celite™ into barcoded, tared vials. After concentration in vacuo, masses were calculated and the compounds were sampled for LC/MS analysis.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]2([C:13]#[N:14])[CH2:12][CH2:11]2)=[CH:2]1.[H-].[Na+].[CH3:17]I.O>CN(C)C=O>[CH3:17][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]2([C:13]#[N:14])[CH2:11][CH2:12]2)=[CH:2]1
Reactant: N#CC1(c2c[nH]c3ccccc23)CC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1cc(C2(C#N)CC2)c2ccccc21
Reaction time: 0.08 h

Procedure:
1-(1H-indole-3-yl)cyclopropanecarbonitrile (183 mg) was dissolved in N,N-dimethylformamide (2 mL) and sodium hydride (60% in oil, 45 mg) was added under ice cooling, followed by stirring for 5 minutes. To the reaction solution, methyl iodide (0.07 mL) was added, followed by stirring at room temperature for one hour. To the reaction solution, water was added, followed by extraction with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate and then concentrated. The residue was purified by silica gel column chromatography (parallel separation purification system) to obtain the titled compound having the following physical properties (196 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]3[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=3[CH:10]=2)=[CH:5][CH:4]=1.Cl.[N:19]1([CH2:24][CH2:25][O:26][C:27]2[CH:35]=[CH:34][C:30]([C:31](O)=[O:32])=[CH:29][CH:28]=2)[CH2:23][CH2:22][CH2:21][CH2:20]1.CO>C(Cl)Cl>[N:19]1([CH2:24][CH2:25][O:26][C:27]2[CH:28]=[CH:29][C:30]([C:31]([C:10]3[C:11]4[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=4[S:13][C:9]=3[C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)=[O:32])=[CH:34][CH:35]=2)[CH2:20][CH2:21][CH2:22][CH2:23]1
Reactant: O=C(O)c1ccc(OCCN2CCCC2)cc1
Reactant: COc1ccc(-c2cc3ccccc3s2)cc1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: COc1ccc(-c2sc3ccccc3c2C(=O)c2ccc(OCCN3CCCC3)cc2)cc1
Yield: 59 %

Procedure:
By essentially following the procedure detailed in Example 1, Part C, the title compound was prepared from 2-(4-methoxyphenyl)benzo[b]thiophene (Example 3, Part A) and 4-[2-(1-pyrrolidinyl)ethoxy]benzoic acid hydrochloride in 59% yield as an oil following radial chromatography (SiO2; gradient of 2-5% MeOH in CH2Cl2).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9](=O)[CH3:10])[CH:5]=[CH:6][CH:7]=1.Cl.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21]N)=[CH:17][CH:16]=1.Cl.O1CCOCC1.C(OCC)(=O)C>C1(C)C=CC=CC=1>[CH3:13][O:14][C:15]1[CH:20]=[C:19]2[C:18](=[CH:17][CH:16]=1)[NH:21][C:9]([CH3:10])=[C:8]2[C:4]1[CH:3]=[C:2]([Br:1])[CH:7]=[CH:6][CH:5]=1
Reactant: COc1ccc(NN)cc1
Reactant: CC(=O)Cc1cccc(Br)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COc1ccc2[nH]c(C)c(-c3cccc(Br)c3)c2c1
Temperature: 60 °C
Reaction time: 1 h
Yield: 27.4 %

Procedure:
The ketone from Step 1 (1.065 g, 5 mmol) and 4-methoxyphenylhydrazine hydrochloride (870 mg, 5 mmol) in toluene (20 is mL) were gently warmed up to 60° C. After 1 h, 4M HCl/dioxane (2 mL) was added and the mixture was heated at 60° C. for 1 h. It was then cooled, poured over ice water and ethyl acetate. The organic layer was separated, washed with dilute NaHCO3. Removal of the solvents left a residue which was purified by chromatography over SiO2 to afford the product (433 mg).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:10]3[CH2:11][CH2:12][CH:13]([C:15]([OH:17])=O)[CH2:14][C:9]=3[S:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:18][O:19][CH2:20][CH2:21][NH:22][CH2:23][CH2:24][O:25][CH3:26]>>[Cl:1][C:2]1[C:3]2[C:10]3[CH2:11][CH2:12][CH:13]([C:15]([N:22]([CH2:23][CH2:24][O:25][CH3:26])[CH2:21][CH2:20][O:19][CH3:18])=[O:17])[CH2:14][C:9]=3[S:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: COCCNCCOC
Reactant: O=C(O)C1CCc2c(sc3ncnc(Cl)c23)C1
Product: COCCN(CCOC)C(=O)C1CCc2c(sc3ncnc(Cl)c23)C1

Procedure:
300 mg (1.12 mmol) (RS)-4-chloro-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidine-7-carboxylic acid (prepared according to intermediate example 31b) were transformed in analogy to example 3 using 2-methoxy-N-(2-methoxyethyl)ethanamine to give after working up and purification 340 mg (79%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.Cl.[CH3:12][NH:13][CH3:14].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:12][N:13]([CH3:14])[C:8]([C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][N:6]=1)=[O:10]
Reactant: O=C(O)c1ccc(Br)cn1
Reactant: CNC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN(C)C(=O)c1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.9 %

Procedure:
To a solution of 5-bromopyridine-2-caboxylic acid (3.00 g, 14.85 mmol), dimethyl amine hydrochloride (1.82 g, 22.30 mmol) and triethylamine (6.21 ml, 44.60 mmol) in 20 mL of DMF was added HATU (8.47 g, 22.30 mmol). The mixture was stirred at room temperature overnight, quenched with water, extracted with 3×EtOAc. The combined organic layer was washed with 2×H2O, dried with Na2SO4, concentrated and purified by Biotage column chromatography with 60-70% EtOAc in hexanes to give a yellow oil (1.56 g, 46% yield). 1H NMR (400 MHz, CDCl3) δ 8.59 (d, J=1.77 Hz, 1 H) 7.88 (dd, J=8.34, 2.27 Hz, 1 H) 7.52 (d, J=8.34 Hz, 1 H) 3.06 (d, J=14.15 Hz, 6 H); LCMS for C8H9BrN2O m/z 229.00 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:8])[CH:5]=[N:6][CH:7]=1.C(N(CC)CC)C.[CH2:16]([S:18](Cl)(=[O:20])=[O:19])[CH3:17].[OH-].[Na+]>ClCCl.CO>[Br:1][C:2]1[CH:3]=[C:4]([NH:8][S:18]([CH2:16][CH3:17])(=[O:20])=[O:19])[CH:5]=[N:6][CH:7]=1
Reactant: CCS(=O)(=O)Cl
Reactant: Nc1cncc(Br)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCS(=O)(=O)Nc1cncc(Br)c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a stirred solution of 5-bromo-3-pyridinamine (0.8 g, 4.62 mmol), triethylamine (2.6 mL, 18.48 mmol) in dichloromethane (20 mL) at 0° C. under inert atmosphere. The reaction mixture was stirred for 15 min and then ethyl sulfonyl chloride (0.88 mL, 9.24 mmol) was added slowly. The reaction mixture was stirred for 2 h at room temperature. Diluted with dichloromethane and then washed with saturated aqueous sodium chloride solution, separated the organic layer, dried over sodium sulphate, concentrated under high vacuum, light yellow solid obtained. The solid was dissolved in methanol (10 mL), cooled to 0° C., added 10N aqueous sodium hydroxide (10 mL) solution. The reaction mixture was stirred for 1 h and then methanol was evaporated completely and extracted with ethyl acetate. The combined organic layer was washed with saturated aqueous sodium chloride solution, dried over sodium sulphate and concentrated under vacuum to obtain the title compound. MS (M+1): 266.9.
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][CH3:15])(=[O:13])=[O:12])=[CH:7][CH:6]=1)=[N+]=[N-].C1CCC=CC=1>CO.[OH-].[Pd+2].[OH-]>[NH2:1][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([S:11]([NH:14][CH3:15])(=[O:13])=[O:12])=[CH:9][CH:10]=1
Reactant: CNS(=O)(=O)c1ccc(CN=[N+]=[N-])cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: C1=CCCC=C1
Product: CNS(=O)(=O)c1ccc(CN)cc1
Temperature: 65 °C

Procedure:
A mixture of 4-azidomethyl-N-methyl-benzenesulfonamide (2.20 g, 10.0 mmol), cyclohexadiene (8.90 mL, 90.0 mmol) and palladium hydroxide (20% on carbon, 1.4 g, 2.0 mmol) in MeOH (20 mL) was warmed at 65° C. for 2 hours. The solution was cooled to room temperature and filtered through diatomaceous earth. The solvent was removed in vacuo to afford 4-aminomethyl-N-methyl-benzenesulfonamide.
Reaction SMILES: C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O.C(OC(=O)[NH:22][CH2:23][CH2:24][C:25]1[C:33]2[C:28](=[CH:29][CH:30]=[C:31]([C:34]([CH3:45])([CH3:44])[C:35]([N:37]3[CH:41]4[CH2:42][CH2:43][CH:38]3[CH2:39][CH2:40]4)=[O:36])[CH:32]=2)[NH:27][C:26]=1[C:46]1[CH:51]=[C:50]([CH3:52])[CH:49]=[C:48]([CH3:53])[CH:47]=1)(C)(C)C>>[NH2:22][CH2:23][CH2:24][C:25]1[C:33]2[C:28](=[CH:29][CH:30]=[C:31]([C:34]([CH3:45])([CH3:44])[C:35]([N:37]3[CH:38]4[CH2:39][CH2:40][CH:41]3[CH2:42][CH2:43]4)=[O:36])[CH:32]=2)[NH:27][C:26]=1[C:46]1[CH:51]=[C:50]([CH3:52])[CH:49]=[C:48]([CH3:53])[CH:47]=1
Reactant: Cc1cc(C)cc(-c2[nH]c3ccc(C(C)(C)C(=O)N4C5CCC4CC5)cc3c2CCNC(=O)OC(C)(C)C)c1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C)cc(-c2[nH]c3ccc(C(C)(C)C(=O)N4C5CCC4CC5)cc3c2CCN)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 106.2 %

Procedure:
To a solution of {2-[5-[2-(7-azabicyclo[2.2.1]hept-7-yl)-1,1-dimethyl-2-oxo-ethyl]-2-(3,5-dimethylphenyl)-1H-indol-3-yl]ethyl} carbamic acid tert-butyl ester (728 mg in 30 mL methylene chloride) at 0° C. was added 1.5 mL anisole followed by 10.5 mL trifluoroacetic acid and the mixture stirred at 0° C. After 2 hours, the mixture was concentrated in vacuo and the residual acid quenched by the addition of 10% ammonium hydroxide in methanol. The concentrated was then purified by flash chromatography on silica gel (methylene chloride:10% ammonium hydroxide in methanol, 95:5; then 92:8) to give the title compound (627 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17]3[C:12](=[CH:13][C:14]([OH:18])=[CH:15][CH:16]=3)[C:11](=[O:19])[C:10]([CH3:21])([CH3:20])[CH2:9]2)=[CH:4][CH:3]=1.[H-].[Na+].[CH3:24][N:25]([CH3:29])[CH2:26][CH2:27]Cl>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17]3[C:12](=[CH:13][C:14]([O:18][CH2:27][CH2:26][N:25]([CH3:29])[CH3:24])=[CH:15][CH:16]=3)[C:11](=[O:19])[C:10]([CH3:21])([CH3:20])[CH2:9]2)=[CH:4][CH:3]=1
Reactant: CN(C)CCCl
Reactant: CC1(C)CC(c2ccc(Cl)cc2)c2ccc(O)cc2C1=O
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CN(C)CCOc1ccc2c(c1)C(=O)C(C)(C)CC2c1ccc(Cl)cc1
Yield: 93.5 %

Procedure:
A mixture of 4-(4-chlorophenyl)-7-hydroxy-2,2-dimethyl-1-tetralone (14.7 g), sodium hydride (80% oil dispersion, 1.65 g) and 2-dimethylaminoethyl chloride (5.8 g) was heated under reflux in toluene (150 ml) for 6 hr. The solvent was removed and the residue shaken with ether-dilute hydrochloric acid. The aqueous layer was separated, basified, extracted with ether and the extract dried (MgSO4). Evaporation gave 4-(4-chlorophenyl)-2,2-dimethyl-7-(2-dimethylaminoethoxy)-1-tetralone as a yellow oil (17 g, 91%) which was contaminated with ether. A portion was converted to the hydrochloride salt (64%), which crystallised as white prisms from ethanol-ether, m.p. 209°-211°.
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][CH:11]2[C:28](=[O:29])[N:13]3[CH:14]([C:20]([O:22][CH:23]([CH:25]4[CH2:27][CH2:26]4)[CH3:24])=[O:21])[C:15]([CH3:19])([CH2:17]Br)[S:16][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1>C1C=CC=CC=1>[C:1]1([CH2:7][C:8]([NH:10][CH:11]2[C:28](=[O:29])[N:13]3[C:14]([C:20]([O:22][CH:23]([CH:25]4[CH2:26][CH2:27]4)[CH3:24])=[O:21])=[C:15]([CH3:19])[CH2:17][S:16][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(OC(=O)C1N2C(=O)C(NC(=O)Cc3ccccc3)[C@H]2SC1(C)CBr)C1CC1
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: CC1=C(C(=O)OC(C)C2CC2)N2C(=O)C(NC(=O)Cc3ccccc3)[C@H]2SC1
Yield: 62.5 %

Procedure:
A solution of 1-cyclopropylethyl 6-(2-phenylacetamido)-2-methyl-2-bromomethylpenam-3-carboxylate (0.5 g.) and pyridine (0.20 g.) in benzene (12 cc) was heated under reflux for 3 hours. After cooling, the benzene layer was washed with water, dried and then concentrated. The residue was subjected to chromatography on silica gel to yield crystals (0.26 g.) of 1-cyclopropylethyl 7-(2-phenylacetamido)-3-methyl-3-cephem-4-carboxylate, m.p. 108°-112° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:15]3([CH:19]([CH2:20][O:21][CH3:22])[S:18][C:17]([NH2:23])=[N:16]3)[C:14]3[CH:13]=[C:12]([Cl:24])[N:11]=[CH:10][C:9]=3[O:8][C:5]2=[CH:6][CH:7]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[F:33][C:34]1[C:39](B(O)O)=[CH:38][CH:37]=[CH:36][N:35]=1.O1CCOCC1>O.C(C1C(C(C)(C)C)=C([Pd]Cl)C=CC=1N(C)C)(C)(C)C>[Cl:24][C:12]1[N:11]=[CH:10][C:9]2[O:8][C:5]3[C:4]([C:15]4([CH:19]([CH2:20][O:21][CH3:22])[S:18][C:17]([NH2:23])=[N:16]4)[C:14]=2[CH:13]=1)=[CH:3][C:2]([C:39]1[C:34]([F:33])=[N:35][CH:36]=[CH:37][CH:38]=1)=[CH:7][CH:6]=3
Reactant: OB(O)c1cccnc1F
Reactant: COCC1SC(N)=NC12c1cc(Br)ccc1Oc1cnc(Cl)cc12
Agent: CN(C)c1ccc([Pd]Cl)c(C(C)(C)C)c1C(C)(C)C
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COCC1SC(N)=NC12c1cc(-c3cccnc3F)ccc1Oc1cnc(Cl)cc12
Temperature: 100 °C
Yield: 66.8 %

Procedure:
To a microwave vessel was added 7-bromo-3-chloro-5′-(methoxymethyl)-5′H-spiro[chromeno[2,3-c]pyridine-5,4′-thiazol]-2′-amine (1.50 g, 3.52 mmol, prepared as described in Method CC27), potassium phosphate (2.24 g, 10.55 mmol), (2-fluoropyridin-3-yl)boronic acid (1.14 g, 8.09 mmol), 1,1-bis[(di-t-butyl-p-dimethylaminophenyl]palladium(ii) chloride (0.25 g, 0.35 mmol), dioxane (13.2 mL), and water (4.4 mL). The resulting mixture was then heated at 100° C. in a microwave for 10 min. The reaction mixture was diluted with water and extracted with EtOAc. The organic extract was washed with brine, dried over MgSO4, filtered and concentrated in vacuo to give the crude material as an orange solid. The crude material was absorbed onto a plug of silica gel and purified by chromatography through a gold Redi-Sep pre-packed silica gel column (80 g), eluting with a gradient of 30% to 45% to 60% DCM/MeOH/NH4OH (90/10/1) in 40% EtOAc in Heptane, to provide 3-chloro-7-(2-fluoropyridin-3-yl)-5′-(methoxymethyl)-5′H-spiro[chromeno[2,3-c]pyridine-5,4′-thiazol]-2′-amine (1.04 g, 2.35 mmol, 66.8% yield) as off-white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH3:16])=[CH:9][C:5]=1[C:6]([NH2:8])=[O:7])([O-])=O.[NH4+].[Cl-]>CO.O.[Fe]>[NH2:1][C:4]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH3:16])=[CH:9][C:5]=1[C:6]([NH2:8])=[O:7]
Reactant: CCCOc1ccc([N+](=O)[O-])c(C(N)=O)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: CCCOc1ccc(N)c(C(N)=O)c1
Temperature: 60 °C
Reaction time: 3 h
Yield: 98 %

Procedure:
To a mixture of 2-nitro-5-propoxy-benzamide (1.20 g, 5.36 mmol) in MeOH-H2O (v/v, 3:1, 60 mL) was added NH4Cl (2.84 g, 53.6 mmol) and Fe (2.99 g, 53.6 mmol). The resulting mixture was stirred at 60° C. for 3 h. After the reaction was completed, the mixture was cooled to room temperature and the iron was filtered off. The filtrate was concentrated to 15 mL and the formed precipitate was collected and dried in vacuo to give 1.02 g of ii-a as a pale yellow solid (98%). LCMS m/z=1781 (M−16), 195.1 (M+1) (Method B) (retention time=1.46 min).
Reaction SMILES: Br[CH2:2][C:3]1[C:13]([Cl:14])=[N:12][CH:11]=[CH:10][C:4]=1[C:5]([O:7]CC)=O.Cl.[Cl:16][C:17]1[CH:18]=[C:19]([CH:29]([NH2:31])[CH3:30])[CH:20]=[CH:21][C:22]=1[O:23][CH2:24][C:25]([F:28])([F:27])[CH3:26]>>[Cl:14][C:13]1[C:3]2[CH2:2][N:31]([CH:29]([C:19]3[CH:20]=[CH:21][C:22]([O:23][CH2:24][C:25]([F:27])([F:28])[CH3:26])=[C:17]([Cl:16])[CH:18]=3)[CH3:30])[C:5](=[O:7])[C:4]=2[CH:10]=[CH:11][N:12]=1
Reactant: CCOC(=O)c1ccnc(Cl)c1CBr
Reactant: CC(N)c1ccc(OCC(C)(F)F)c(Cl)c1
Agent: Cl
Product: CC(c1ccc(OCC(C)(F)F)c(Cl)c1)N1Cc2c(ccnc2Cl)C1=O
Yield: 59 %

Procedure:
The title compound is prepared in 59% yield (331 mg, colorless oil) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (389 mg, 1.40 mmol, Step-1 of Intermediate-1) and 1-(3-chloro-4-(2,2-difluoropropoxy)phenyl)ethanamine hydrochloride (400 mg, 1.40 mmol, Amine-85, single enantiomer) in a similar manner to Intermediate-2.
Reaction SMILES: O.NN.[Si:4]([O:11][C:12]1[CH:30]=[CH:29][C:15]([CH2:16][O:17][N:18]2C(=O)C3=CC=CC=C3C2=O)=[CH:14][CH:13]=1)([C:7]([CH3:10])([CH3:9])[CH3:8])([CH3:6])[CH3:5].O1CCCC1.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[Si:4]([O:11][C:12]1[CH:13]=[CH:14][C:15]([CH2:16][O:17][NH2:18])=[CH:29][CH:30]=1)([C:7]([CH3:10])([CH3:9])[CH3:8])([CH3:6])[CH3:5]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(CON2C(=O)c3ccccc3C2=O)cc1
Agent: NN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)(C)[Si](C)(C)Oc1ccc(CON)cc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 95.3 %

Procedure:
Hydrazine monohydrate (1.25 ml) was added to a solution of N-[4-(tert-butyldimethylsilyloxy)benzyloxy]phthalimide (5.00 g) in ethanol (10 ml)-tetrahydrofuran (40 ml) and stirred at 60° C. for 1 hour. The reaction mixture was cooled to room temperature, an aqueous solution of potassium carbonate was added and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated to obtain 4-(tert-butyldimethylsilyloxy)benzyloxyamine (3.15 g, yield 95%) as a colorless oil.