Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)(=O)CC(CC(O)=O)(C(O)=O)[OH:4].N[C@@:15]1(C#N)[C@H:20]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=2)[CH2:19][C@@H:18]2[C@H:16]1[C@@:17]2([F:34])[C:31]([NH2:33])=[O:32].C(O)(=O)CC(CC(O)=O)(C(O)=O)O.N[C@]1(C#N)[C@H](OCC2C=CC(Cl)=C(Cl)C=2)C[C@@H]2[C@H]1[C@@]2(F)C(N)=O.O.C(OCC)(=O)C>CO.C(Cl)(Cl)Cl>[Cl:30][C:25]1[CH:24]=[C:23]([CH:28]=[CH:27][C:26]=1[Cl:29])[CH2:22][O:21][C@@H:20]1[CH2:19][C@@H:18]2[C@@H:16]([C@@:17]2([F:34])[C:31]([NH2:33])=[O:32])[C:15]1=[O:4]
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Reactant: N#C[C@@]1(N)[C@H]2[C@@H](C[C@H]1OCc1ccc(Cl)c(Cl)c1)[C@]2(F)C(N)=O
Agent: N#C[C@]1(N)[C@H]2[C@@H](C[C@H]1OCc1ccc(Cl)c(Cl)c1)[C@]2(F)C(N)=O
Solvent: O
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: NC(=O)[C@@]1(F)[C@@H]2C[C@@H](OCc3ccc(Cl)c(Cl)c3)C(=O)[C@@H]21
Temperature: 91.5 °C
Reaction time: 4.5 h
Yield: 977.1 %

Procedure:
174.84 g [containing 0.351 g of (1R,2S,3R,5R,6R)-2-amino-2-cyano-3-[(3,4-dichloro benzyl)oxy]-6-fluoro bicyclo[3.1.0]hexane-6-carboxamide citrate (6b) and 3.853 g of (1R,2R,3R,5R,6R)-2-amino-2-cyano-3-[(3,4-dichloro benzyl)oxy]-6-fluorobicyclo[3.1.0]hexane-6-carboxamide citrate (8b)] of the 190.36 g of the filtrate and washing solution (acetic acid solution) obtained from the Example 9 was added with 174 mL of water and stirred for 4.5 hrs under heating at 90 to 93° C. The reaction solution was cooled to room temperature, added with ethyl acetate and water, and extracted. The organic layer was washed with water, a saturated aqueous solution of sodium hydrogen carbonate, and a saturated aqueous solution of sodium chloride in order, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure to give a crude product, which was then subjected to silica gel column chromatography (eluent solution: chloroform:methanol=20:1). The concentrated residues obtained were crystallized with chloroform-hexane to obtain 2.07 g of (1R,3R,5R,6R)-3-[(3,4-dichloro benzyl)oxy]-6-fluoro-2-oxo bicyclo[3.1.0]hexane-6-carboxamide (5b) as a colorless solid.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[N:11]=[C:10]([CH:12]=[O:13])[CH:9]=[CH:8][CH:7]=1.S([CH2:24][N:25]=[C:26]=O)(C1C=CC(C)=CC=1)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CO>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:7]=[CH:8][CH:9]=[C:10]([C:12]2[O:13][CH:26]=[N:25][CH:24]=2)[N:11]=1
Reactant: Cc1ccc(S(=O)(=O)CN=C=O)cc1
Reactant: O=Cc1cccc(C2OCCO2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: c1cc(-c2cnco2)nc(C2OCCO2)c1

Procedure:
1 g of 6-[1,3]dioxolan-2-yl-pyridine-2-carbaldehyde (5.58 mmol), 1.10 g of tosylmethyl isocyanate (5.63 mmol) and 0.80 g of potassium carbonate (5.79 mmol) are mixed in 15 ml of methanol. The suspension is heated under reflux for 2 hours. The methanol is separated off, the residue is taken up in a saturated aqueous solution of sodium chloride and the mixture is extracted with ethyl acetate. The organic phase is dried over magnesium sulfate, filtered and then concentrated under vacuum. The title product is isolated by chromatography on a silica column (eluent: hexane/ethyl acetate; 50:50). 1.14 g of a yellow oil are obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[CH:14]([Br:20])[CH2:13][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCOCC.CO.[BH4-].[Na+].C(O)(=O)C>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH:15]([OH:19])[CH:14]([Br:20])[CH2:13][CH2:12]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1c2ccc(OCc3ccccc3)cc2CCC1Br
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCOCC
Solvent: CC(=O)O
Product: OC1c2ccc(OCc3ccccc3)cc2CCC1Br
Temperature: 3.5 °C
Reaction time: 1 h
Yield: 91.8 %

Procedure:
6-Benzyloxy-2-bromo-3,4-dihydro-2H-naphthalen-1-one (32.9 g, 0.0964 mol) was dissolved in ether (200 mL, 2 mol) and methanol (30.0 mL, 0.740 mol), cooled with ice bath to internal temperature of 3° C. Sodium tetrahydroborate (1.82 g, 0.0482 mol) was added portionwise over 15 min at 3° C.-8° C. (internal). The mixture was stirred at 2-5° C. for 1 hour. Acetic acid (2.74 mL, 0.0482 mol) was added and the mixture was quenched with water, extracted with EtOAc (100 mL), washed with water (2×), brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude intermediate, 6-(benzyloxy)-2-bromo-1,2,3,4-tetrahydronaphthalen-1-ol (29.5 g).
Reaction SMILES: [C:1]([O:7][OH:8])([CH2:4][CH2:5][CH3:6])([CH3:3])[CH3:2].[C:9](OC)([CH2:12][CH2:13][CH3:14])([CH3:11])[CH3:10]>>[C:1]([O:7][O:8][C:9]([CH2:12][CH2:13][CH3:14])([CH3:11])[CH3:10])([CH2:4][CH2:5][CH3:6])([CH3:3])[CH3:2]
Reactant: CCCC(C)(C)OC
Reactant: CCCC(C)(C)OO
Product: CCCC(C)(C)OOC(C)(C)CCC

Procedure:
In similar manner, although optimal conditions may vary, hydrogen peroxide may be reacted with methyl t-amyl ether to provide t-amyl hydroperoxide or di-t-amyl peroxide; with methyl t-hexyl ether to provide t-hexyl hydroperoxide or di-t-hexyl peroxide; with ethyl t-butyl ether to provide t-butyl hydroperoxide or di-t-butyl peroxide; with ethyl t-amyl ether to provide t-amyl hydroperoxide or di-t-amyl peroxide; with ethyl t-hexyl ether to provide t-hexyl hydroperoxide or di-t-hexyl peroxide; with n-propyl t-butyl ether to provide t-butyl hydroperoxide or di-t-butyl peroxide; with n-propyl t-amyl ether to provide t-amyl hydroperoxide or di t-amyl peroxide; or with n-propyl t-hexyl ether to provide t-hexyl hydroperoxide or di-t-hexyl peroxide. Illustrative of reactions employing hydroperoxide reactants are the reaction of t-butyl hydroperoxide with methyl t-butyl ether to provide di-t-butyl peroxide; the reaction of t-hexyl hydroperoxide with methyl t-hexyl ether to provide di-t-hexyl peroxide; the reaction of t-butyl hydroperoxide with methyl t-amyl ether to provide t-butyl t-amyl peroxide; the reaction of t-butyl hydroperoxide with methyl t-hexyl ether to provide t-butyl t-hexyl peroxide; and the reaction of t-amyl hydroperoxide with ethyl t-hexyl ether to provide t-amyl t-hexyl peroxide.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[N:6][C:7]([S:10]([CH2:13]P(OCC)(=O)OCC)(=[O:12])=[O:11])=[N:8][CH:9]=1.[CH:22](=O)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.O>C1C=CC=CC=1>[CH:13](/[S:10]([C:7]1[N:8]=[CH:9][C:4]([Cl:3])=[CH:5][N:6]=1)(=[O:11])=[O:12])=[CH:22]\[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CCOP(=O)(CS(=O)(=O)c1ncc(Cl)cn1)OCC
Reactant: O=Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Product: O=S(=O)(/C=C/c1ccccc1)c1ncc(Cl)cn1

Procedure:
Sodium hydride dispersion (55-60%, 2 mmol) was further dispersed in benzene (4 ml) and added gradually to a solution of diethyl (5-chloropyrimidin-2-sulfonyl)methanephosphonate (0.66 g, 2 mmol) in benzene (4 ml). The mixture was stirred for 10 min before a solution of benzaldehyde (0.21 g, 2 mmol) in benzene (2 ml) was added. The resultant mixture was stirred at room temperature overnight before extraction with water. Evaporation of the dried (MgSO4) benzene solution left the product which was recrystallised from ethanol; yield 0.20 g 35%, m.p. 150° C. 1H NMR (CDCl3): δ7.24 and 7.90 (2H-vinyl, Jvic 16 Hz), 7.60 (Ph, m.), 8.90 (2H-4,6).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][C:3]=1[N+:14]([O-:16])=[O:15].Br[CH2:18][CH2:19][CH3:20]>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:9][CH2:10][N:11]([CH2:18][CH2:19][CH3:20])[CH2:12][CH2:13]2)=[CH:4][C:3]=1[N+:14]([O-:16])=[O:15]
Reactant: Cc1ccc(N2CCNCC2)cc1[N+](=O)[O-]
Reactant: CCCBr
Product: CCCN1CCN(c2ccc(C)c([N+](=O)[O-])c2)CC1

Procedure:
Beginning with 1-(4-methyl-3-nitro-phenyl)-piperazine and 1-bromopropane, the title compound was recovered by the procedure described in Example 2. MS m/z (rel. intensity, 70 eV) 263 (M+, 26), 234 (bp), 191 (19), 70 (84), 56 (40).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:25][CH2:26][C:27]1[C:28]([F:44])=[C:29]([O:34][C:35]2[CH:36]=[C:37]([CH:40]=[C:41]([Cl:43])[CH:42]=2)[C:38]#[N:39])[C:30]([Cl:33])=[CH:31][CH:32]=1.[Cl:45][C:46]1[CH:50]=[CH:49][NH:48][C:47]=1[C:51](O)=[O:52].CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:45][C:46]1[CH:50]=[CH:49][NH:48][C:47]=1[C:51]([NH:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[C:29]([O:34][C:35]2[CH:36]=[C:37]([C:38]#[N:39])[CH:40]=[C:41]([Cl:43])[CH:42]=2)[C:28]=1[F:44])=[O:52]
Reactant: O=C(O)c1[nH]ccc1Cl
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CN)c2F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CNC(=O)c3[nH]ccc3Cl)c2F)c1
Reaction time: 2 h
Yield: 26.6 %

Procedure:
HATU (0.061 g, 0.16 mmole) was added to a DMF (2 ml) solution of 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-chlorobenzonitrile (0.050 g, 0.16 mmole) and 3-chloro-1H-pyrrole-2-carboxylic acid (0.023 g, 0.16 mmole) in DMF. DIPEA (0.021 g, 0.16 mmole) was added and the solution stirred for 2 h. The mixture was partitioned between EtOAc and water. The organic layer was separated and washed with 15% NaHCO3 and dried over MgSO4 and the EtOAc evaporated. The residue was purified on silica with EtOAc and Hexanes to afford the title compound (0.0187 g, 26%) as a white solid. 1H NMR (400 MHz, Acetone-d6): δ ppm 10.93 (br. s., 1H), 7.62-7.67 (m, 1H), 7.56-7.62 (m, 1H), 7.37-7.48 (m, 4H), 7.02 (t, 1H), 6.23 (t, 1H), 4.72 (d, 2H). MS: m/z 438.1 (M+1).
Reaction SMILES: C(O[C:6](=O)[N:7]([CH2:9][CH2:10][CH2:11][NH:12][C:13]([O:15][CH2:16][CH:17]1[C:29]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[C:23]2[C:18]1=[CH:19][CH:20]=[CH:21][CH:22]=2)=[O:14])C)(C)(C)C.[ClH:31]>CCOC(C)=O>[ClH:31].[CH:19]1[C:18]2[CH:17]([CH2:16][O:15][C:13](=[O:14])[NH:12][CH2:11][CH2:10][CH2:9][NH:7][CH3:6])[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:23]=2[CH:22]=[CH:21][CH:20]=1
Reactant: CN(CCCNC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: CNCCCNC(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.9 %

Procedure:
To a stirred solution of [3-(9H-fluoren-9-ylmethoxycarbonylamino)propyl]-methylcarbamic acid tert-butyl ester (4.24 g, 10.3 mmol) in EtOAc (8 mL) was slowly added concentrated hydrochloric acid (2 mL, 60 mmol) and the resulting mixture was stirred at room temperature overnight. The mixture was concentrated under reduced pressure to give the title compound (3.21 g, 78% yield) as a white solid.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])[C:4](=[O:17])[C:3]=1[C:18]1[NH:23][C:22]2[CH:24]=[CH:25][C:26]([NH:28][S:29]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[N+:38]([O-])=O)(=[O:31])=[O:30])=[CH:27][C:21]=2[S:20](=[O:42])(=[O:41])[N:19]=1.[NH4+].[Cl-]>CO.O1CCCC1.O.[Fe]>[NH2:38][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=1[S:29]([NH:28][C:26]1[CH:25]=[CH:24][C:22]2[NH:23][C:18]([C:3]3[C:4](=[O:17])[N:5]([CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])[C:6]4[C:11]([C:2]=3[OH:1])=[CH:10][CH:9]=[CH:8][N:7]=4)=[N:19][S:20](=[O:42])(=[O:41])[C:21]=2[CH:27]=1)(=[O:31])=[O:30]
Reactant: CC(C)CCn1c(=O)c(C2=NS(=O)(=O)c3cc(NS(=O)(=O)c4ccccc4[N+](=O)[O-])ccc3N2)c(O)c2cccnc21
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC(C)CCn1c(=O)c(C2=NS(=O)(=O)c3cc(NS(=O)(=O)c4ccccc4N)ccc3N2)c(O)c2cccnc21
Temperature: 60 °C
Yield: 92.4 %

Procedure:
A mixture of the product of Example 409A (8 mg, 0.013 mmol), iron powder (5.0 mg, 0.089 mmol), and NH4Cl (1Mg, 0.019 mmol) in methanol:tetrahydrofuran:water (2:2:1,10 mL) was heated at 60° C. for 2 hour. The solution filtered through Celite® and washed with THF. The solution was concentrated and the residue was diluted with water, and extracted with ethyl acetate. The organic layer was washed with water, dried with MgSO4, filtered and concentrated to give title compound (7 mg, 92%). 1H NMR (300 MHz, DMSO-d6) δ 0.97 (d, J=6.62 Hz, 6 H) 1.54 (m, 2 H) 1.68 (m, 1 H) 4.46 (m, 2 H) 6.06 (s, 2 H) 6.59 (t, J=7.17 Hz, 1 H) 6.78 (d, J=8.46 Hz, 1 H) 7.23 (m, 1 H) 7.46 (m, 4 H) 7.63 (d, J=8.82 Hz, 1 H) 8.53 (dd, J=8.09, 1.84 Hz, 1 H) 8.87 (dd, J=4.41, 1.84 Hz, 1 H) 10.79 (s, 1 H) 14.00 (s, 1 H). (ESI−) m/z 581 (M−H)−.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][CH2:11][CH2:12]Br)=[CH:4][CH:3]=1.C[O-].[Na+].O.[C:18](OCC)(=[O:20])C>CO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][O:20][CH3:18])=[CH:4][CH:3]=1
Reactant: BrCCCCOc1ccc(Br)cc1
Reactant: CCOC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COCCCCOc1ccc(Br)cc1

Procedure:
A solution of 1-bromo-4-(4-bromobutoxy)benzene (3.05 g) in methanol (30 ml) was treated with 28% sodium methoxide in methanol (2.43 ml), and the solution was refluxed for 5 hours. After cooling, the reaction mixture was added to a mixture of water and ethyl acetate. The organic layer was washed with brine. The organic layer was taken and dried over magnesium sulfate. The magnesium sulfate was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (10:1 hexane-ethyl acetate elution) to give 1-bromo-4-(4-methoxybutoxy)benzene (1.95 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][C:7]=1[Cl:8].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+].[OH:37][C@H:38]([C:60]1[CH:61]=[N:62][CH:63]=[CH:64][CH:65]=1)[CH2:39][N:40]([CH2:48][C@H:49]1[CH2:58][CH2:57][C:56]2[C:51](=[CH:52][CH:53]=[C:54](I)[CH:55]=2)[O:50]1)C(=O)OC(C)(C)C>C1(C)C=CC=CC=1.ClCCl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:54]2[CH:55]=[C:56]3[C:51](=[CH:52][CH:53]=2)[O:50][C@@H:49]([CH2:48][NH:40][CH2:39][C@@H:38]([C:60]2[CH:61]=[N:62][CH:63]=[CH:64][CH:65]=2)[OH:37])[CH2:58][CH2:57]3)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)(C)OC(=O)N(C[C@H]1CCc2cc(I)ccc2O1)C[C@H](O)c1cccnc1
Reactant: OB(O)c1ccc(Cl)c(Cl)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: O[C@@H](CNC[C@H]1CCc2cc(-c3ccc(Cl)c(Cl)c3)ccc2O1)c1cccnc1
Temperature: 80 °C
Reaction time: 16 h
Yield: 20 %

Procedure:
3,4-Dichlorophenylboronic acid (34 mg, 0.18 mmol), a solution of palladium acetate (3 mg, 0.01 mmol) and triphenylphosphine (12 mg, 0.05 mmol) in toluene (1 mL), and 2 M aqueous sodium carbonate (1 mL) were added successively to a solution of tert-butyl (2R)-2-hydroxy-2-(3-pyridinyl)ethyl{[(2R)-6-iodo-3,4-dihydro-2H-chromen-2-yl]methyl}carbamate (Example 37, 60 mg, 0.12 mmol) in toluene (2 mL). The mixture was heated (80° C.) and stirred for 16 hours. After cooling the reaction was diluted with dichloromethane (5 mL) and the layers were separated. The organic layer was concentrated in vacuo and the residue was dissolved in a solution of 4 M hydrogen chloride in dioxane (4 mL). The solution was stirred for 16 hours and then concentrated in vacuo. Preparative reverse phase HPLC of the residue using acetonitrile/water afforded 10.3 mg (20%) of the desired product (retention time=2.19 min.): 1H NMR (CD3OD, δ): 8.71 (d, J=2.2 Hz, 1 H), 8.59 (dd, J=5.1, 1.5 Hz, 1 H), 8.11 (ddd, J=7.9, 1.7, 1.7 Hz, 1 H), 7.71 (d, J=2.3 Hz, 1 H), 7.61 (dd, J=7.9, 5.1 Hz, 1 H), 7.37-7.56 (m, 4 H), 6.99 (d, 9.2 Hz, 1 H), 5.22 (dd, J=10.5, 2.9 Hz, 1 H), 4.43-4.54 (m, 1 H), 3.26-3.55 (m, 4 H), 2.87-3.10 (m, 2 H), 2.11-2.22 (m, 1 H), 1.76-1.92 (m, 1 H); mass spectroscopy gave m/z=429.2 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:23]=[CH:22][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[CH:10]=2)=[O:7])=[C:4]([CH3:24])[N:3]=1.[CH3:25][C@@H:26]([OH:29])[CH2:27][NH2:28]>C(O)CCC>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:6](=[O:7])[C:5]2[CH:22]=[CH:23][C:2]([NH:28][CH2:27][C@H:26]([OH:29])[CH3:25])=[N:3][C:4]=2[CH3:24])=[CH:10][C:11]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1
Reactant: Cc1nc(Cl)ccc1C(=O)Nc1ccc(Cl)c(-c2ccccn2)c1
Reactant: C[C@@H](O)CN
Solvent: CCCCO
Product: Cc1nc(NC[C@@H](C)O)ccc1C(=O)Nc1ccc(Cl)c(-c2ccccn2)c1

Procedure:
Procedure F was performed using 60 mg of 6-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-2-methylnicotinamide and 116 μL of R-(−)-1-amino-2-propanol in 0.5 mL of BuOH. Purified by reverse phase HPLC to yield (R)—N-(4-chloro-3-(pyridin-2-yl)phenyl)-6-(2-hydroxypropylamino)-2-methylnicotinamide. MS (Q1) 397.4 (M)+.
Reaction SMILES: C(=O)(OC(C)(C)C)N.[CH3:9][O:10][C:11]([C:13]1[CH:18]=[CH:17][C:16]([C@@H:19]([NH:21][C:22]([C:24]2([CH3:39])[N:31](C(OC(C)(C)C)=O)[CH2:30][CH2:29][C:26]3([CH2:28][CH2:27]3)[CH2:25]2)=[O:23])[CH3:20])=[CH:15][CH:14]=1)=[O:12]>>[CH3:39][C:24]1([C:22]([NH:21][C@H:19]([C:16]2[CH:15]=[CH:14][C:13]([C:11]([O:10][CH3:9])=[O:12])=[CH:18][CH:17]=2)[CH3:20])=[O:23])[NH:31][CH2:30][CH2:29][C:26]2([CH2:27][CH2:28]2)[CH2:25]1
Reactant: COC(=O)c1ccc([C@H](C)NC(=O)C2(C)CC3(CCN2C(=O)OC(C)(C)C)CC3)cc1
Agent: CC(C)(C)OC(N)=O
Product: COC(=O)c1ccc([C@H](C)NC(=O)C2(C)CC3(CCN2)CC3)cc1
Yield: 99 %

Procedure:
The title compound (D92) (19 mg) was prepared according to the general procedure for t-Butyl carbamate (Boc) cleavage starting from tert-butyl 5-(((S)-1-(4-(methoxycarbonyl)phenyl)ethyl)carbamoyl)-5-methyl-6-azaspiro[2.5]octane-6-carboxylate (D57) (25 mg)
Reaction SMILES: O[CH2:2][C:3]1[O:4][C:5]([C:14]2[CH:19]=[CH:18][C:17]([S:20]([NH2:23])(=[O:22])=[O:21])=[CH:16][CH:15]=2)=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1.C(N(CC)CC)C.[Cl-].[Li+].CS([Cl:37])(=O)=O>O1CCCC1.C(OCC)(=O)C>[Cl:37][CH2:2][C:3]1[O:4][C:5]([C:14]2[CH:19]=[CH:18][C:17]([S:20]([NH2:23])(=[O:22])=[O:21])=[CH:16][CH:15]=2)=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1
Reactant: NS(=O)(=O)c1ccc(-c2oc(CO)nc2-c2ccccc2)cc1
Reactant: CS(=O)(=O)Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: NS(=O)(=O)c1ccc(-c2oc(CCl)nc2-c2ccccc2)cc1
Reaction time: 3 h

Procedure:
A solution of 4-[2-hydroxymethyl-4-phenyloxazol-5-yl]benzenesulfonamide (Step 2) (1.0 g, 3 mmol) and triethylamine (0.61 g, 6 mmol) was stirred in tetrahydrofuran (100 mL) at 0° C. Lithium chloride (0.25 g, 6 mmol) was added, followed by the dropwise addition of methanesulfonyl chloride (0.38 g, 3.3 mmol). After stirring for 3 h from 0° C. to 25° C., ethyl acetate (100 mL) was added, and the mixture was washed with 1N hydrochloric acid, brine and water, dried over magnesium sulfate, filtered, and concentrated. The crude product was purified by flash column chromatography on silica gel eluting with a 1:1 mixture of ethyl acetate:hexanes. The appropriate fractions were concentrated to a clear oil which solidified upon standing to give 4-[2-chloromethyl-4-phenyloxazol-5-yl]benzenesulfonamide as a white solid which was used in the next step without further purification or characterization.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:11]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)=[CH:10][C:9]([C:19]([O:21]C)=[O:20])=[N:8]1.[OH-].[Li+]>CO.C1COCC1.O.O>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:11]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)=[CH:10][C:9]([C:19]([OH:21])=[O:20])=[N:8]1
Reactant: COC(=O)c1cc(-c2ccc(C)cc2)n(C2CCCCO2)n1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cc1ccc(-c2cc(C(=O)O)nn2C2CCCCO2)cc1
Reaction time: 16 h
Yield: 102.3 %

Procedure:
Methyl 1-(tetrahydro-2H-pyran-2-yl)-5-p-tolyl-1H-pyrazole-3-carboxylate (363 mg, 0.70 mmol) was dissolved in a mixture of MeOH/THF/H2O (1:2:1, 4 mL). Lithium hydroxide was added and the reaction mixture was stirred for 16 hrs. The reaction mixture was diluted with water and washed with DCM. The aqueous phase was evaporated. 1-(Tetrahydro-2H-pyran-2-yl)-5-p-tolyl-1H-pyrazole-3-carboxylic acid (205 mg, quantitative) was obtained as a white solid which was used without further purification in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:13]([CH3:14])[N:12]=[C:11]([CH3:15])[C:10]=1[N+:16]([O-])=O.[Cl-].[NH4+]>C(O)C.C(OCC)(=O)C.[Fe]>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:13]([CH3:14])[N:12]=[C:11]([CH3:15])[C:10]=1[NH2:16]
Reactant: Cc1nn(C)c(-c2ccc(F)cc2Cl)c1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1nn(C)c(-c2ccc(F)cc2Cl)c1N
Temperature: 80 °C

Procedure:
A mixture of 5-(2-chloro-4-fluorophenyl)-1,3-dimethyl-4-nitro-1H-pyrazole (i.e. the product of Step A) (0.2 g, 0.74 mmol), iron powder (0.2 g, 3.6 mmol) and saturated aqueous ammonium chloride solution (1 mL) in ethanol (5 mL) was heated at 80° C. for 4 h. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and filtered through a pad of Celite® (diatomaceous earth) on a sintered glass frit funnel. The filtrate was concentrated under reduced pressure and the resulting material was purified by silica gel column chromatography (ethyl acetate as eluant) to provide the title compound (0.14 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[N:12]=[C:13]([C:15]([O:17]C)=O)[CH:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:6]=2[CH:25]=1.[NH3:26]>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[N:12]=[C:13]([C:15]([NH2:26])=[O:17])[CH:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:6]=2[CH:25]=1
Reactant: COC(=O)c1cc2n(n1)-c1ccc(Cl)cc1C(c1ccccc1)=NC2
Reactant: N
Solvent: CO
Product: NC(=O)c1cc2n(n1)-c1ccc(Cl)cc1C(c1ccccc1)=NC2
Reaction time: 16 h

Procedure:
A solution of 750 mg. (2.13 mmol) of the end product of Example 9 in 50 ml. methanol in a glass bomb was cooled to 3° and saturated with ammonia. The glass bomb was then sealed and the reaction heated to 70° with stirring, for 16 hours. After cooling to 5°, the bomb was opened, the contents transferred to a r.b. flask and concentrated in vacuo. Recrystallization from acetone/hexane yielded end product, mp 216°-218°. An analytical sample was prepared by an additional recrystallization from acetone/hexane and obtained as pale yellow needles: mp 217°-219°.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:27]I>C1COCC1>[C:1]([O:5][C:6](=[O:24])[N:7]([CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)=[CH:12][CH:11]=1)[CH3:27])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCc1ccc(Oc2ccc(F)cc2)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(CCc1ccc(Oc2ccc(F)cc2)cc1)C(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 52.8 %

Procedure:
{2-[4-(4-fluoro-phenoxy)-phenyl]-ethyl}-carbamic acid tert-butyl ester (3.018 mmol, 1 eq) was dissolved in dry THF (30 ml) and NaH (3.621 mmol, 1.2 eq) was added. After 30 min, the reaction mixture was treated with methyl iodide (30.176 mmol, 10 eq) and was stirred overnight. After overnight the excess NaH was quenched by a slow addition of water, diluted with brine (30 ml) and extracted with Et2O (3×20 ml). Combined organic layers were dried over anhydrous Na2SO4, filtered and evaporated to give a product without further purification {2-[4-(4-fluoro-phenoxy)-phenyl]-ethyl}-methyl-carbamic acid tert-butyl ester (1.592 mmol, yield=53%, purity=97%). [M+H]+=272.28 1H NMR (300 MHz, CDCl3) δ/ppm 1.55 (s, 9H), 7.24 (m, 5H), 3.39 (br. s., 2H), 6.83-7.03 (m, 5H), 7.06-7.17 (m, 2H), 7.24 (s, 2H)