Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:25])([F:24])[CH:21]([F:23])[F:22])[CH:14]=1)[CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[N:6]=1)[OH:4].[C:26]1([C:37](O)=[O:38])[CH:27]=[CH:28][CH:29]=[C:30]2[CH2:36][CH2:35][CH2:34][CH:33]=[CH:32][C:31]=12.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>C(#N)C.O>[F:11][C:7]1[N:6]=[C:5]([CH:3]([OH:4])[CH:2]([NH:1][C:37]([C:26]2[CH:27]=[CH:28][CH:29]=[C:30]3[CH2:36][CH2:35][CH2:34][CH:33]=[CH:32][C:31]=23)=[O:38])[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:24])([F:25])[CH:21]([F:22])[F:23])[CH:14]=2)[CH:10]=[CH:9][CH:8]=1
Reactant: O=C(O)c1cccc2c1C=CCCC2
Reactant: NC(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1cccc(F)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CC#N
Product: O=C(NC(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1cccc(F)n1)c1cccc2c1C=CCCC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.3 %

Procedure:
To a solution of (1RS,2RS)-2-amino-1-(6-fluoropyridin-2-yl)-3-(3-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-propanol (300 mg, 0.83 mmol) in acetonitrile (20 ml) were added 6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxylic acid (156 mg, 0.83 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (238 mg, 1.24 mmol) and 1-hydroxy-1H-benzotriazole (127 mg, 0.83 mmol), and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed successively with 1N hydrochloric acid, 1N aqueous sodium hydroxide solution and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. Recrystallization of the residue from ethyl acetate-hexane gave the title compound (293 mg, 66%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH:10]2[CH2:15][CH2:14][CH:13]([O:16][CH2:17][C:18]([N:20]3[CH2:25][CH2:24][N:23]([C:26]4[CH:35]=[CH:34][C:33]5[C:28](=[CH:29][CH:30]=[C:31]([C:36]([F:39])([F:38])[F:37])[CH:32]=5)[N:27]=4)[CH2:22][CH2:21]3)=[O:19])[CH2:12][CH2:11]2)=[CH:5][C:4]=1[C:40]([F:43])([F:42])[F:41])#[N:2].[H-].[Na+].I[CH3:47]>C1COCC1.O>[CH3:47][N:9]([C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[C:4]([C:40]([F:42])([F:43])[F:41])[CH:5]=1)[CH:10]1[CH2:15][CH2:14][CH:13]([O:16][CH2:17][C:18]([N:20]2[CH2:21][CH2:22][N:23]([C:26]3[CH:35]=[CH:34][C:33]4[C:28](=[CH:29][CH:30]=[C:31]([C:36]([F:37])([F:38])[F:39])[CH:32]=4)[N:27]=3)[CH2:24][CH2:25]2)=[O:19])[CH2:12][CH2:11]1
Reactant: CI
Reactant: N#Cc1ccc(NC2CCC(OCC(=O)N3CCN(c4ccc5cc(C(F)(F)F)ccc5n4)CC3)CC2)cc1C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CN(c1ccc(C#N)c(C(F)(F)F)c1)C1CCC(OCC(=O)N2CCN(c3ccc4cc(C(F)(F)F)ccc4n3)CC2)CC1
Reaction time: 0.5 h
Yield: 100.9 %

Procedure:
To a solution of 2-[(4-[[4-cyano-3-(trifluoromethyl)phenyl]amino]-cyclohexyl)oxy]-1-[4-[6-(trifluoromethyl)quinolin-2-yl]piperazin-1-yl]ethan-1-one (100 mg, 0.16 mmol) in THF (3 ml) was added sodium hydride (25 mg, 0.63 mmol, 3.9 eq.) and the mixture was stirred for 30 minutes. The mixture was then treated with iodomethane (100 mg, 0.7 mmol, 4 eq.) and stirred for 5 days. The resulting mixture was diluted with water (30 ml), and extracted with ethyl acetate (30 mL). The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give a residue from which the product was purified by silica gel column flash chromatography eluting with ethyl acetate/heptanes to afford 2-[(4-[methyl[4-cyano-3-(trifluoromethyl)phenyl]-amino]-cyclohexyl)oxy]-1-[4-[6-(trifluoromethyl)quinolin-2-yl)piperazin-1-yl]ethan-1-one as a yellow solid (100 mg, 98%). (CI, m/z): [M+H]+ 620; 1H NMR (400 MHz, DMSO-d6): δ 8.24 (d, J=9.3 Hz, 1H), 8.17 (s, 1H), 7.76 (d, J=8.7 Hz, 2H), 7.70 (d, J=8.7 Hz, 1H), 7.40 (d, J=9.3 Hz, 1H), 7.13-7.07 (m, 2H), 4.23 (s, 2H), 3.94-3.76 (m, 5H), 3.63-3.57 (m, 4H), 3.41-3.32 (m, 1H), 2.85 (s, 3H), 2.14-2.05 (m, 2H), 1.69-1.57 (m, 4H), 1.50-1.38 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[CH:12](OC)(OC)OC.OS(O)(=O)=O>CO.CCOC(C)=O>[CH3:12][O:10][C:9](=[O:11])[CH2:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1]
Reactant: O=C(O)Cc1ccccc1Cl
Reactant: COC(OC)OC
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)Cc1ccccc1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 97.3 %

Procedure:
To a solution of 10.0 g (59 mmol) (2-chlorophenyl)acetic acid in MeOH (10 mL) was added 9.6 mL (88 mmol) of trimethyl orthoformate and 0.32 mL (6.0 mmol) of H2SO4. The reaction was stirred at room temperature for 4 h then diluted with EtOAc and washed with H2O followed by a saturated aqueous solution of NaHCO3. The organic phase was dried over anhydrous Na2SO4 and concentrated under reduced pressure to provide 10.6 g (97%) of (2-chlorophenyl)-acetic acid methyl ester as a clear oil. The crude reaction product was not purified but used immediately.
Reaction SMILES: [C:1]1([CH:7]([C:13]([O:15]CC)=O)[C:8]([O:10]CC)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][N:23]=[C:22]2[NH2:28].C(N(CCCC)CCCC)CCC.[OH-].[Na+]>O>[F:18][C:19]1[CH:27]=[CH:26][C:25]2[C:21](=[C:22]3[N:28]=[C:8]([OH:10])[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)=[C:13]([OH:15])[N:23]3[N:24]=2)[CH:20]=1
Reactant: Nc1n[nH]c2ccc(F)cc12
Reactant: CCOC(=O)C(C(=O)OCC)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCCCN(CCCC)CCCC
Product: Oc1nc2c3cc(F)ccc3nn2c(O)c1-c1ccccc1
Yield: 78.8 %

Procedure:
14.3 g (60.2 mmol) Diethyl phenylmalonate, 9.1 g (60.2 mol) 5-fluoro-1H-indazol-3-ylamine and 25.3 mL tributyl amine were heated for 15 h at 180° C. The reaction mixture was treated with 2M sodium hydroxide and water and extracted with tert-butyl methyl ether. The organic phase was discarded and the aqueous phase was acidified with conc. hydrochloric acid. The precipitate was collected by filtration and washed with water to obtain 14 g of the desired product which is 90% pure. MS (Cl, M+1): 296
Reaction SMILES: C(OC([NH:8][C:9]([NH:24]C(OC(C)(C)C)=O)=[N:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]2[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][N:18]=2)[CH:12]=1)=O)(C)(C)C.[ClH:32]>ClCCl.O1CCOCC1>[ClH:32].[ClH:32].[CH3:23][C:21]1[CH:20]=[CH:19][N:18]=[C:17]([C:13]2[CH:12]=[C:11]([NH:10][C:9]([NH2:24])=[NH:8])[CH:16]=[CH:15][CH:14]=2)[CH:22]=1
Reactant: Cc1ccnc(-c2cccc(N=C(NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)c2)c1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cc1ccnc(-c2cccc(NC(=N)N)c2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of N,N′-bis(tert-butoxycarbonyl)-N″-(3-(4-methylpyridin-2-yl)phenyl)guanidine (300 mg) in dichloromethane (3 ml) was added a solution of hydrogen chloride in 1,4-dioxane (4N, 6 ml), and the mixture was stirred at room temperature for 18 hours. The solvent was evaporated under reduced pressure. To the residue was added 5% ethanol in ethyl acetate (100 ml), and the precipitate was collected by filtration and dried under reduced pressure to give (3-(4-methylpyridin-2-yl)phenyl)guanidine dihydrochloride (119 mg).
Reaction SMILES: [F:1][C:2]1[CH:31]=[CH:30][CH:29]=[CH:28][C:3]=1[CH2:4][NH:5][C:6]1[C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=[C:8]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)=[CH:18][CH:17]=2)[CH:7]=1.Cl.CCN(C(C)C)C(C)C.[CH3:42][S:43]([Cl:46])(=[O:45])=[O:44]>CN1C(=O)CCC1>[F:1][C:2]1[CH:31]=[CH:30][CH:29]=[CH:28][C:3]=1[CH2:4][NH:5][C:6]1[C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=[C:8]([NH:15][C:16]2[CH:17]=[CH:18][C:19]([CH:22]3[CH2:27][CH2:26][N:25]([S:43]([CH3:42])(=[O:45])=[O:44])[CH2:24][CH2:23]3)=[CH:20][CH:21]=2)[CH:7]=1.[ClH:46]
Reactant: CS(=O)(=O)Cl
Reactant: NC(=O)c1cnc(Nc2ccc(C3CCNCC3)cc2)cc1NCc1ccccc1F
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CS(=O)(=O)N1CCC(c2ccc(Nc3cc(NCc4ccccc4F)c(C(N)=O)cn3)cc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Compound 4-(2-fluorobenzylamino)-6-(4-(piperidin-4-yl)phenylamino)nicotinamide (Example 106) HCl salt (100 mg, 0.2 mmol) was stirred in 5 mL NMP. To the solution were added DIEA (0.18 mL, 1.0 mmol) and MsCl (0.047 mL, 0.6 mmol). The mixture was stirred at RT for 30 min and quenched with Me2NH. The mixture was concentrated in vacuo and subjected to reverse phase prep HPLC to isolate the title compound as HCl salt. UV=259 nm. M+H found for C25H28FN5O3S: 498.5. NMR (CD3OD): 8.13 (1H, s), 7.39-7.34 (3H, m), 7.29 (1H, td, J=8.0; 2.0 Hz), 7.19-7.10 (4H, m), 5.88 (1H, s), 4.51 (2H, s), 3.86 (2H, m), 2.88 (2H, m), 2.85 (3H, s), 2.75 (1H, m), 1.97 (2H, m), 1.79 (2H, m) ppm.
Reaction SMILES: [C:1](=[O:4])([O-])[O-].[K+].[K+].CI.[Br:9][C:10]1[CH:15]=[CH:14][C:13](O)=[C:12]([CH2:17][CH3:18])[CH:11]=1>CN(C=O)C>[Br:9][C:10]1[CH:15]=[CH:14][C:13]([O:4][CH3:1])=[C:12]([CH2:17][CH3:18])[CH:11]=1
Reactant: O=C([O-])[O-]
Reactant: CCc1cc(Br)ccc1O
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CCc1cc(Br)ccc1OC
Reaction time: 16 h
Yield: 67.5 %

Procedure:
Potassium carbonate (3.9 g, 28.3 mmol) and methyl iodide (0.59 mL, 9.43 mmol) were added to a solution of 4-Bromo-2-ethyl-phenol (1.9 g, 9.43 mmol, from step 1 of Example A(22)) dissolved in DMF (10 mL). The mixture was stirred for 16 h under N2 and then partitioned between 1N HCl and EtOAc. The organic layer was washed with saturated NaHCO3, brine, dried over Na2SO4 and concentrated to a yellow oil. The oil was purifed by silica gel chromatography to give the title compound as a clear oil (1.37 g, 68%).
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:17]=[CH:16][C:12](C(O)=O)=[CH:11][CH:10]=2)[O:3]1.C(Cl)CCl.[CH3:23][NH:24][CH3:25].C1C[O:29]CC1>CN(C1C=CN=CC=1)C.CN(C=O)C.C(OCC)(=O)C>[CH3:23][NH:24][C:25](=[O:29])[C:17]1[CH:16]=[CH:12][CH:11]=[CH:10][C:9]=1[B:4]1[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:1])([CH3:18])[O:3]1
Reactant: CNC
Reactant: CC1(C)OB(c2ccc(C(=O)O)cc2)OC1(C)C
Reactant: C1CCOC1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CNC(=O)c1ccccc1B1OC(C)(C)C(C)(C)O1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (1.0 g, 4.03 mmol), EDC (0.81 g, 4.23 mmol), and DMAP (catalytic amount) in 3 mL of DMF was stirred at room temperature for 1 hr, and then 2 mL of a 2M solution of N,N-dimethylamine in THF (4 mmol) was added into the reaction mixture. The resulting mixture was stirred at room temperature for 16 h. Ethyl acetate (100 mL) was added and the mixture was washed with saturated sodium bicarbonate and brine. The organic layer was dried over Na2SO4, filtered and the filtrate was concentrated. The solvent was removed to give the title compound which was used without further purification for the next step. Mass Spectrum (ESI) m/e=262 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:12]=[C:13]([N+:23]([O-:25])=[O:24])[CH:14]=[C:15]3[C:20]=2[N:19]=[C:18](Cl)[N:17]=[C:16]3[OH:22])=[O:10])=[CH:4][CH:3]=1.[F:26][C:27]1[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][C:28]=1[C:34]([F:37])([F:36])[F:35]>CN1CCCC1=O.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:12]=[C:13]([N+:23]([O-:25])=[O:24])[CH:14]=[C:15]3[C:20]=2[N:19]=[C:18]([NH:31][C:30]2[CH:32]=[CH:33][C:27]([F:26])=[C:28]([C:34]([F:37])([F:35])[F:36])[CH:29]=2)[N:17]=[C:16]3[OH:22])=[O:10])=[CH:4][CH:3]=1
Reactant: Nc1ccc(F)c(C(F)(F)F)c1
Reactant: O=C(Nc1ccc(F)cc1)c1cc([N+](=O)[O-])cc2c(O)nc(Cl)nc12
Solvent: O
Solvent: CN1CCCC1=O
Product: O=C(Nc1ccc(F)cc1)c1cc([N+](=O)[O-])cc2c(O)nc(Nc3ccc(F)c(C(F)(F)F)c3)nc12
Temperature: 130 °C

Procedure:
To a solution of N-(4-fluorophenyl)-2-chloro-4-hydroxy-6-nitroquinazoline-8-carboxamide (0.050 g) in 1-methyl-2-pyrrolidinone (1 mL) was added 4-fluoro-3-(trifluoromethyl)aniline (0.053 mL). The reaction mixture was heated at 130° C. for 4.5 h, then cooled to room temperature and diluted with water. The resulting mixture was cooled at 5° C. for 3 h and the precipitate which formed was isolated by filtration, washed with water and dried to afford the title compound as a grey solid (0.054 g). 1H NMR (300 MHz, DMSO-d6): 12.31 (s, 1H), 11.87 (s, 1H), 9.64 (s, 1H), 9.00 (d, J=2.9 Hz, 1H), 8.8. (d, J=2.9 Hz, 1H), 7.95-7.87 (m, 2H), 7.39-7.32 (m, 1H), 7.15-6.95 (m, 4H); HPLC (Method E): 4.3 min.; MS (APCI−): m/z 504.
Reaction SMILES: [N+:1]([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])#[C-:2].CO[CH:11]([N:14]([CH3:16])[CH3:15])OC>C(O)C>[CH2:7]([O:6][C:4](=[O:5])/[C:3](/[N+:1]#[C-:2])=[CH:11]/[N:14]([CH3:16])[CH3:15])[CH3:8]
Reactant: [C-]#[N+]CC(=O)OCC
Reactant: COC(OC)N(C)C
Solvent: CCO
Product: [C-]#[N+]/C(=C\N(C)C)C(=O)OCC
Reaction time: 12 h
Yield: 78 %

Procedure:
To a solution of ethyl iso-cyanoacetate (8) (10 g, 88.4 mmol) in absolute ethanol (100 mL) at 0° C. under N2 atmosphere was added dimethoxymethyl dimethyl-amine (9) (23.4 mL, 176.8 mmol.) dropwise while stirring was continued at room temperature for 12 h. The reaction mixture was concentrated under reduced pressure to remove ethanol. The residue (crude mass, brown color) was purified by column chromatography over neutral alumina using 3 to 4% ethyl acetate in hexane as eluant. Solvent fractions were concentrated under reduced pressure and low temperature (to avoid polymerization of compound) to furnish compound 5 (11.6 g, 78%) as pale orange liquid which was solidified on cooling at 4° C.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][N:10]([C:40]1[CH:45]=[C:44]([CH3:46])[CH:43]=[C:42]([CH3:47])[CH:41]=1)[CH2:11][C:12]1[CH:39]=[CH:38][C:15]2[N:16]=[C:17]([NH:28][CH2:29][CH2:30][CH2:31][N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)[N:18]([CH2:19][C:20]3[C:25]([OH:26])=[CH:24][CH:23]=[C:22]([CH3:27])[N:21]=3)[C:14]=2[CH:13]=1)(C)(C)C.Cl>O.O1CCCC1>[NH2:7][CH2:8][CH2:9][N:10]([CH2:11][C:12]1[CH:39]=[CH:38][C:15]2[N:16]=[C:17]([NH:28][CH2:29][CH2:30][CH2:31][N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)[N:18]([CH2:19][C:20]3[C:25]([OH:26])=[CH:24][CH:23]=[C:22]([CH3:27])[N:21]=3)[C:14]=2[CH:13]=1)[C:40]1[CH:41]=[C:42]([CH3:47])[CH:43]=[C:44]([CH3:46])[CH:45]=1
Reactant: Cc1cc(C)cc(N(CCNC(=O)OC(C)(C)C)Cc2ccc3nc(NCCCN4CCOCC4)n(Cc4nc(C)ccc4O)c3c2)c1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(C)cc(N(CCN)Cc2ccc3nc(NCCCN4CCOCC4)n(Cc4nc(C)ccc4O)c3c2)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 44 %

Procedure:
A mixture of (2-{(3,5-dimethyl-phenyl)-[3-(3-hydroxy-6-methyl-pyridin-2-ylmethyl)-2-(3-morpholin-4-yl-propylamino)-3H-benzoimidazol-5-ylmethyl]-amino}-ethyl)-carbamic acid tert-butyl ester, prepared as described for compounds n-4, (0.00012 mol) in a 3N solution of HCl in water (10 ml) and tetrahydrofuran (10 ml) was stirred at room temperature for 12 hours. The precipitate was filtered off and taken up in a 10% solution of K2CO3 in water. The solution was saturated with K2CO3 (powder) and extracted with CH2Cl2/CH3OH (95/5). The organic layer was separated, dried (over MgSO4), filtered and the solvent was evaporated until dryness. The residue (0.07 g) was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH/NH4OH 92/8/1; 10 μm). The pure fractions were collected and the solvent was evaporated. The residue was crystallized from CH3CN/CH3OH/diisopropylether, yielding 0.03 g of 2-[6-{[(2-amino-ethyl)-(3,5-dimethyl-phenyl)-amino]-methyl}-2-(3-morpholin-4-yl-propylamino)-benzoimidazol-1-ylmethyl]-6-methyl-pyridin-3-ol (Compound 66, 44%, melting point: 196° C.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[C:13](=[CH:14][N:15]([CH3:18])[N:16]=3)[CH:12]=[CH:11][CH:10]=2)=[C:5]([CH3:19])[CH:4]=1.[Li]CCCC.[CH3:25][O:26][CH2:27][C:28](=[O:33])[CH2:29][CH2:30][O:31][CH3:32]>C1COCC1.CCOC(C)=O>[CH3:25][O:26][CH2:27][C:28]([C:14]1[N:15]([CH3:18])[N:16]=[C:17]2[C:13]=1[CH:12]=[CH:11][CH:10]=[C:9]2[C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][C:5]=1[CH3:19])([OH:33])[CH2:29][CH2:30][O:31][CH3:32]
Reactant: COCCC(=O)COC
Reactant: COc1ccc(-c2cccc3cn(C)nc23)c(C)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COCCC(O)(COC)c1c2cccc(-c3ccc(OC)cc3C)c2nn1C
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 64.5 %

Procedure:
Indazole 4c (0.29 g, 0.79 mMol) was dissolved in 5 mL dry THF under a nitrogen atmosphere and cooled to −78° C. n-BuLi (0.4 mL of 2.5 M hexane solution, 1 mMol) was added dropwise via syringe, and stirred at −78° C. for 10 minutes. 1,4-dimethoxy-2-butanone (0.16 g, 1.18 mMol) was added dropwise at −78° C. and then the reaction mixture was allowed to warm to rt. The reaction mixture was diluted with EtOAc (50 mL) and washed successively with saturated ammonium chloride solution, brine and dried over magnesium sulfate. Evaporation of the solvent afforded crude material which was flash chromatographed on silica and eluted with hexane:EtOAc (3:1) which afforded 27c as an oil (0.196 g; 65%).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C@@H:15]([OH:36])[C@H:16]([O:32][CH:33]([CH3:35])[CH3:34])[C:17]([N:19]2[C@@H:23]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:22][O:21][C:20]2=[O:31])=[O:18])[CH:10]=1)(C)(C)C.[CH3:38][S:39](Cl)(=[O:41])=[O:40]>N1C=CC=CC=1.C(OCC)(=O)C>[NH2:7][CH2:8][C:9]1[CH:10]=[C:11]([C@@H:15]([O:36][S:39]([CH3:38])(=[O:41])=[O:40])[C@H:16]([O:32][CH:33]([CH3:35])[CH3:34])[C:17]([N:19]2[C@@H:23]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:22][O:21][C:20]2=[O:31])=[O:18])[CH:12]=[CH:13][CH:14]=1
Reactant: CC(C)O[C@H](C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1)[C@H](O)c1cccc(CNC(=O)OC(C)(C)C)c1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(C)O[C@H](C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1)[C@H](OS(C)(=O)=O)c1cccc(CN)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
19.2 g of {3-[3-(4 (S)-Benzyl-2-oxooxazolidin-3-yl)-1-(R)-hydroxy-2(S)-isopropoxy-3-oxopropyl]benzyl}-carbamic acid t-butyl ester was dissolved in 100 ml of pyridine, and 4.35 ml of methanesulfonyl chloride was added dropwise under ice-cooling. After stirring was continued for 2 hours under ice-cooling and for 3 hours at room temperature, the reaction solution was diluted with ethyl acetate and washed successively with 1N hydrochloric acid and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, filtered, and the solvent was concentrated, to give methanesulfonic acid 1 (R)-(3-aminomethylphenyl)-3-(4 (S)-benzyl-2-oxooxazolidin-3-yl)-2(S)-isopropoxy-3-oxopropyl ester. This product was dissolved in 500 ml of ethanol, and 10 g of 10% palladium carbon and 5 g of potassium acetate were added, and the mixture was stirred overnight at room temperature under hydrogen atmosphere. The reaction solution was filtered and the filtrate was concentrated. The residue was diluted with ethyl acetate and washed with saturated aqueous sodium hydrogencarbonate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography, to give 15.3 g of the title compound as a white solid in the 2:1→3:2 hexane-ethyl acetate fraction.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Br[C:6]1([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:9][CH2:8][CH2:7]1.O.C(OCC)C>CS(C)=O>[N:1]([C:6]1([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:9][CH2:8][CH2:7]1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(=O)C1(Br)CCC1
Agent: [Na+]
Solvent: CCOCC
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)C1(N=[N+]=[N-])CCC1
Temperature: 40 °C
Reaction time: 8 h
Yield: 97.7 %

Procedure:
Sodium azide (3.14 g, 48.3 mmol) was partially dissolved in dry DMSO (50 mL), under nitrogen at ambient temperature. Ethyl 1-bromocyclobutanecarboxylate (3.91 mL, 24.2 mmol, Aldrich) was then added via syringe. After heating to 40° C. for 7 hours, the homogenous solution was allowed to cool to ambient temperature and stirring was continued overnight. The reaction mixture was then poured into water (700 mL), along with diethyl ether (200 mL). The ether layer was washed three times with half brine and then once with brine. The organic layer was dried over sodium sulfate, filtered and then evaporated under reduced pressure to provide ethyl 1-azidocyclobutanecarboxylate (4.00 g) as a clear oil.
Reaction SMILES: C([Li])CCC.[F:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1Br.[OH:14][CH2:15][CH:16]1[CH2:24][CH:23]2[CH:19]([CH2:20][N:21]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:22]2)[C:18](=[O:32])[CH2:17]1.[Cl-].[NH4+]>CCCCCC.O1CCCC1>[OH:14][CH2:15][CH:16]1[CH2:24][CH:23]2[CH:19]([CH2:20][N:21]([C:25]([O:27][C:28]([CH3:30])([CH3:29])[CH3:31])=[O:26])[CH2:22]2)[C:18]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[F:6])([OH:32])[CH2:17]1
Reactant: CC(C)(C)OC(=O)N1CC2CC(CO)CC(=O)C2C1
Reactant: Fc1ccccc1Br
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC2CC(CO)CC(O)(c3ccccc3F)C2C1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
94.4 cm3 of a 1.6M solution of butyllithium in hexane are added dropwise to a solution of 16.5 cm3 of 2-fluorobromobenzene in 200 cm3 of tetrahydrofuran, cooled to -78° C. The reaction mixture is stirred at -78° C. for 2 hours, and then a solution of 8.1 g of (3aRS,6SR,7aSR)-6-hydroxymethyl-2-tert-butyloxycarbonylperhydroisoindol-4-one in 20 cm3 of tetrahydrofuran is added. The reaction mixture is subsequently stirred at room temperature for 48 hours, then treated with 50 cm3 of saturated aqueous ammonium chloride solution and subjected to extraction with 200 cm3 of ethyl acetate, and the organic phase is washed with 100 cm3 of saturated sodium chloride solution, dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a silica gel column (particle size 0.04-0.06 mm, diameter 6 cm, height 35 cm), eluting under a pressure of 0.5 bar of nitrogen with a mixture of cyclohexane and ethyl acetate (50:50 by volume) and collecting fractions of 75 cm3. Fractions 21 to 45 are combined and then concentrated to dryness under reduced pressure (2.7 kPa). 6.35 g of (3aRS,4RS,6SR,7aSR)-6-hydroxymethyl-4-(2-fluorophenyl)-2-tert-butyloxycarbonylperhydroisoindol 4-ol are obtained in the form of a thick white foam.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C@@:15]3([CH2:19][O:18][C:17]([NH2:20])=[N:16]3)[C:14]3[CH:13]=[C:12]([Cl:21])[N:11]=[C:10](F)[C:9]=3[O:8][C:5]2=[CH:6][CH:7]=1.[CH3:23][O-:24].[Na+]>CO>[Br:1][C:2]1[CH:3]=[C:4]2[C@@:15]3([CH2:19][O:18][C:17]([NH2:20])=[N:16]3)[C:14]3[CH:13]=[C:12]([Cl:21])[N:11]=[C:10]([O:24][CH3:23])[C:9]=3[O:8][C:5]2=[CH:6][CH:7]=1
Reactant: NC1=N[C@@]2(CO1)c1cc(Br)ccc1Oc1c2cc(Cl)nc1F
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1nc(Cl)cc2c1Oc1ccc(Br)cc1[C@@]21COC(N)=N1
Temperature: 65 °C

Procedure:
A 100 mL RBF containing a solution of (S)-7-bromo-3-chloro-1-fluoro-5′H-spiro[chromeno[2,3-c]pyridine-5,4′-oxazol]-2′-amine (0.50 g, 1.30 mmol, prepared as described in Method BB33) in methanol (13 mL) was treated with sodium methoxide (0.36 mL, 6.50 mmol) and the resulting suspension was heated to 65° C. for 3 h on a hot-plate. The reaction was cooled to RT and concentrated to dryness under high vacuum. The resulting yellowish residue was taken up in dichloromethane (75 mL), water (25 mL), and the organic layer was separated. The organic layer was dried over sodium sulfate and concentrated to yield the crude product. The crude product was purified by silica gel flash column chromatography and eluted using DCM/MeOH gradient to provide (S)-7-bromo-3-chloro-1-methoxy-5′H-spiro[chromeno[2,3-c]pyridine-5,4′-oxazol]-2′-amine as an amorphous off-white solid. [MS: m/z=395.9 (M+H)].