Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(Cl)(Cl)=O.[F:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:13](=[O:21])[C:14]([C:18]([OH:20])=[O:19])=[CH:15][NH:16][CH:17]=2)=[CH:8][CH:7]=1.[CH3:22]O>>[F:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[C:13](=[O:21])[C:14]([C:18]([O:20][CH3:22])=[O:19])=[CH:15][NH:16][CH:17]=2)=[CH:10][CH:11]=1
Reactant: CO
Reactant: O=C(O)c1c[nH]cc(-c2ccc(F)cc2)c1=O
Solvent: O=S(Cl)Cl
Product: COC(=O)c1c[nH]cc(-c2ccc(F)cc2)c1=O
Temperature: 70 °C
Reaction time: 8 h

Procedure:
Thionyl chloride (0.8 ml) was added to a suspension of 5-(4-fluorophenyl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid (400 mg) in methanol (9 ml) at 0° C. The reaction mixture was stirred at 70° C. overnight. The reaction mixture was returned to room temperature and concentrated under reduced pressure. The resulting residue was washed with saturated aqueous sodium bicarbonate and water, and then further washed with diethyl ether to give 304 mg of the title compound as a solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:32][CH2:31][CH2:30][C@@:10]3([C:14](=[O:15])[N:13]([C@H:16]4[CH2:21][CH2:20][C@@H:19]([O:22][Si](C(C)(C)C)(C)C)[CH2:18][CH2:17]4)[CH2:12][CH2:11]3)[CH2:9]2)=[C:4]([Cl:33])[CH:3]=1.ClCCl.C(=O)([O-])[O-].[K+].[K+].[CH2:43]([NH:45][C:46]([C:48]1[CH:53]=[CH:52][C:51](B2OC(C)(C)C(C)(C)O2)=[CH:50][N:49]=1)=[O:47])[CH3:44]>CN(C)C=O.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>[Cl:33][C:4]1[CH:3]=[C:2]([C:51]2[CH:52]=[CH:53][C:48]([C:46]([NH:45][CH2:43][CH3:44])=[O:47])=[N:49][CH:50]=2)[CH:7]=[CH:6][C:5]=1[N:8]1[CH2:32][CH2:31][CH2:30][C@@:10]2([C:14](=[O:15])[N:13]([C@H:16]3[CH2:21][CH2:20][C@@H:19]([OH:22])[CH2:18][CH2:17]3)[CH2:12][CH2:11]2)[CH2:9]1
Reactant: CCNC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@@H](N2CC[C@]3(CCCN(c4ccc(Br)cc4Cl)C3)C2=O)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCNC(=O)c1ccc(-c2ccc(N3CCC[C@]4(CCN([C@H]5CC[C@@H](O)CC5)C4=O)C3)c(Cl)c2)cn1
Temperature: 150 °C
Reaction time: 8 h

Procedure:
To a stirred mixture of (5S)-7-(4-bromo-2-chlorophenyl)-2-(cis-4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)-2,7-diazaspiro[4.5]decan-1-one (20 mg, 0.00004 mol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (1:1) (2.0 mg), tetrakis(triphenylphosphine)palladium (1.0 mg) and potassium carbonate (14.9 mg, 0.000108 mol) in anhydrous N,N-dimethylformamide (1 mL) was added N-ethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-carboxamide (14.5 mg, 0.054 mmol). The resulting reaction mixture was heated at 150° C. and stirred overnight, followed by the removal of TBS protecting group by the addition of 1.7 M of fluorosilicic acid in water (0.10 mL) and the mixture was stirred at r.t. overnight. The reaction mixture was then directly purified by RP-HPLC to afford the desired product. LC/MS m/e 511.2 (M+H)+. 1H-NMR (400 MHz, DMSO-d6): 8.92 (1H, d, J=2.3 Hz), 8.84 (1H, t, J=5.9 Hz), 8.26 (1H, dd, J=8.2, 2.3 Hz), 8.06 (1H, d, J=8.2 Hz), 7.89 (1H, d, J=2.2 Hz), 7.74 (1H, dd, J=8.5, 2.2 Hz), 7.30 (1H, t, J=8.5 Hz), 4.39 (1H, d, J=3.1 Hz), 3.80 (1H, m), 3.72 (1H, m), 3.24-3.44 (5H, m), 3.01 (1H, d, J=11.4 Hz), 2.63-2.74 (2H, m), 2.40-2.53 (1H, m), 1.64-1.91 (8H, m), 1.41-1.53 (3H, m), 1.20-1.32 (2H, m), 1.13 (3H, t, J=7.2 Hz).
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4].[F:13][C:14]1[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=1[NH2:16].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[F:13][C:14]1[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=1[NH:16][CH2:2][C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4]
Reactant: Nc1ccccc1F
Reactant: O=C(CBr)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(CNc1ccccc1F)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.7 %

Procedure:
The procedure of Zahler et al. was followed with minor modification (Zahler, R.; Koster, W. H.; Slusarchyk, W. A. EP 0138407). To a solution of benzyl bromoacetate (18.0 g, 12.5 mL, 79.6 mmol) and o-fluoroaniline (8.8 g, 7.7 mL, 100 mol %), in anhydrous DMF (60 mL) was added anhydrous K2CO3 (11 g, 100 mol %), and the mixture was stirred at rt overnight. The reaction mixture was diluted with water (120 mL) and extracted with EtOAc (3×200 mL). The combined organic layer was washed with water, dried, and then concentrated. Purification by LPLC (5% EtOAc- hexane) provided 18.0 g (88%) of the title compound as a colorless oil: 1H NMR (CDCl3) δ7.39-7.35 (m, 5H), 7.03-6.97 (m, 2H), 6.72-6.67 (m, 1H), 6.59 (dt, J=8.4, J=1.2, 1H), 5.23 (s, 2H), 4.01 (s, 2H); 13C (CDCl3) δ170.59, 151.66 (d, J=240), 135.24, 128.64 (2 carbons), 128.52, 128.39 (2 carbons), 124.55 (d, J=3.5), 117.79 (d, J=7.1), 114.71 (d, J=17.7), 112.28 (d, J=3.5), 67.11, 45.54; MS (EI, m/z)259 (M+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=O)[CH2:6][CH2:5]2.Cl.[O:13]([NH2:15])[CH3:14].N1C=CC=CC=1>C(O)C>[CH3:14][O:13]/[N:15]=[C:7]1\[CH2:6][CH2:5][C:4]2[C:8]\1=[CH:9][CH:10]=[C:2]([Br:1])[CH:3]=2
Reactant: CON
Reactant: O=C1CCc2cc(Br)ccc21
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: CO/N=C1\CCc2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.3 %

Procedure:
To 5-bromoindanone (6.03 g) in 40 mL ethanol was added 3.58 g methoxylamine hydrochloride and 3.5 mL pyridine. The mixture was stirred at ambient temperature for 1 hour and heated at 80° C. for 3 hours. The volatiles were removed under vacuum and the solid residue partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The ethyl acetate was washed with brine, dried over magnesium sulfate, filtered, and evaporated under vacuum to yield 6.74 g (98% yield) of a tan solid. 1H NMR (CDCl3) was consistent with an isomeric mixture of the desired structure, with the E oxime isomer as the major component. LC/MS indicated 2 close peaks, both with a M+1 molecular ion of m/z 242.0 by positive ESI.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][CH:11]([C:23]2[CH:27]=[CH:26][S:25][CH:24]=2)[CH2:12][CH2:13][CH2:14][O:15][Si](C(C)(C)C)(C)C)[CH:3]=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C(O)C>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][CH:11]([C:23]2[CH:27]=[CH:26][S:25][CH:24]=2)[CH2:12][CH2:13][CH2:14][OH:15])[CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)OCCCC(Oc1cc(Cl)ccc1C#N)c1ccsc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCO
Product: N#Cc1ccc(Cl)cc1OC(CCCO)c1ccsc1
Temperature: 55 °C
Reaction time: 18 h
Yield: 88.3 %

Procedure:
The product from step (c) (1.12 g, 2.65 mmol) was dissolved in ethanol (60 ml) and pyridinium p-toluenesulphonate (0.067 g, 0.27 mmol) added. The reaction was heated to 55° C. and stirred for 18 h. The reaction was cooled and the solvent removed in vacuo. The residue was dissolved in ethyl acetate (180 ml) and the organic layer washed with aqueous saturated sodium bicarbonate solution (2×30 ml), water (2×30 ml) and brine (20 ml). After drying over magnesium sulphate, the solution was evaporated in vacuo to give the title compound as a colourless oil (0.72 g, 88%).
Reaction SMILES: [CH3:1][N:2]([CH3:7])[S:3]([CH3:6])(=[O:5])=[O:4].C([Li])CCC.[NH2:13][C:14]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:15]=1[C:16](OCC)=[O:17]>>[NH2:13][C:14]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:15]=1[C:16](=[O:17])[CH2:6][S:3](=[O:5])(=[O:4])[N:2]([CH3:7])[CH3:1]
Reactant: CN(C)S(C)(=O)=O
Reactant: CCOC(=O)c1cc(OC)ccc1N
Agent: [Li]CCCC
Product: COc1ccc(N)c(C(=O)CS(=O)(=O)N(C)C)c1

Procedure:
In a similar manner to that described in Example 12(a), N,N-dimethylmethanesulphonamide was reacted with n-butyl lithium and the product was reacted with ethyl 2-amino-5-methoxybenzoate to give the novel compound 1-(2-amino-5-methoxyphenyl)-2-(N,N-dimethylsulphamoyl)ethanone, m.p. 198°-200°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]=[C:12]=[O:13])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:14][C:15]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:16]=1[C:17]([OH:19])=O>>[Cl:24][C:21]1[CH:20]=[C:16]2[C:15](=[CH:23][CH:22]=1)[NH:14][C:12](=[O:13])[N:11]([S:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)(=[O:9])=[O:10])[C:17]2=[O:19]
Reactant: Nc1ccc(Cl)cc1C(=O)O
Reactant: O=C=NS(=O)(=O)c1ccc(Cl)cc1
Product: O=c1[nH]c2ccc(Cl)cc2c(=O)n1S(=O)(=O)c1ccc(Cl)cc1
Yield: 48.3 %

Procedure:
630 mg (2.90 mmol) of 4-chlorobenzenesulfonylisocyanate and 500 mg (2.92 mmol) of 2-amino-5-chlorobenzoic acid were treated in the same way as in Example 1 to obtain 520 mg of the above-identified compound (yield 47.9%). Properties; colorless crystal, Melting point: 223°-225° C., PMR (δppm, DMSO-d6): 7.11 (1H,d), 7.69 (1H,q), 7.78 (3H,m), 8.15 (2H,d), 11.67 (1H,s).
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1[N:5]=[CH:6][N:7]([C:9]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:8]=1.[NH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>C(O)C>[C:10]1([C:9]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:7]2[CH:8]=[C:4]([CH2:3][CH2:2][N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)[N:5]=[CH:6]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: ClCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: C1CNCCN1
Solvent: CCO
Product: c1ccc(C(c2ccccc2)(c2ccccc2)n2cnc(CCN3CCNCC3)c2)cc1

Procedure:
A solution of 4-(2-chloroethyl)-1-(triphenylmethyl)imidazole (5.89 g, 15.8 mmol) and piperazine (27.2 g, 316 mmol) in ethanol (80 mL) were heated to reflux for 2 hours. The solvent was removed in vacuo and the residue partitioned between methylene chloride and saturated sodium bicarbonate. The organic layer was separated, washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo to provide the titled product as a yellow oil which was sufficiently pure for use in the next step.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[N:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][C:12]2[S:16][C:15]([NH:17][C:18](=[O:26])[CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:14][N:13]=2)=[CH:4][CH:3]=1.[CH3:27][C:28]1[O:32][C:31]([CH2:33][C:34]2[CH:35]=[C:36]([CH2:40][C:41](O)=[O:42])[CH:37]=[CH:38][CH:39]=2)=[N:30][N:29]=1.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>CN(C=O)C.O>[CH3:27][C:28]1[O:32][C:31]([CH2:33][C:34]2[CH:35]=[C:36]([CH2:40][C:41]([NH:1][C:2]3[N:7]=[N:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][C:12]4[S:16][C:15]([NH:17][C:18](=[O:26])[CH2:19][C:20]5[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=5)=[N:14][N:13]=4)=[CH:4][CH:3]=3)=[O:42])[CH:37]=[CH:38][CH:39]=2)=[N:30][N:29]=1
Reactant: Nc1ccc(CCCCc2nnc(NC(=O)Cc3ccccc3)s2)nn1
Reactant: Cc1nnc(Cc2cccc(CC(=O)O)c2)o1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nnc(Cc2cccc(CC(=O)Nc3ccc(CCCCc4nnc(NC(=O)Cc5ccccc5)s4)nn3)c2)o1
Yield: 7.3 %

Procedure:
A solution of N-(5-(4-(6-aminopyridazin-3-yl)butyl)-1,3,4-thiadiazol-2-yl)-2-phenylacetamide 348 (0.035 g, 0.094 mmol), 2-(3-((5-methyl-1,3,4-oxadiazol-2-yl)methyl)phenyl)acetic acid 1107 (0.023 g, 0.094 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (0.045 g, 0.235 mmol), 1-hydroxybenzotriazole (0.032 g, 0.235 mmol) in DMF (1.75 mL) was stirred for 16 hours and diluted with water (20 mL). The mixture was extracted with EtOAc (3×20 mL) the organic layers combined, washed with water (3×20 mL), brine (2×20 mL) and dried over Na2SO4. The Na2SO4 was removed by filtration and the volatiles removed under reduced pressure. The crude material was purified by reverse phase chromatography giving 0.004 g of 2-(3-((5-methyl-1,3,4-oxadiazol-2-yl)methyl)phenyl)-N-(6-(4-(5-(2-phenylacetamido)-1,3,4-thiadiazol-2-yl)butyl)pyridazin-3-yl)acetamide 652. 1H NMR 300 MHz DMSO-d6: δ 12.62 (s, 1H), 11.24 (s, 1H), 8.16 (d, 1H, J=12.2 Hz), 7.54 (d, 1H, J=12.2 Hz), 7.3-7.1 (m, 9H), 4.20 (s, 2H), 3.78 (s, 2H), 3.74 (s, 2H), 2.99 (m, 2H), 2.87 (m, 2H), 2.41 (s, 3H), 1.72 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[C:12]1[CH:17]=[CH:16][N:15]=[C:14](OS(C(F)(F)F)(=O)=O)[C:13]=1[N+:26]([O-:28])=[O:27].Cl.[CH:30]1([CH:33]([NH2:36])[CH2:34][CH3:35])[CH2:32][CH2:31]1>>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[C:12]1[CH:17]=[CH:16][N:15]=[C:14]([NH:36][CH:33]([CH:30]2[CH2:32][CH2:31]2)[CH2:34][CH3:35])[C:13]=1[N+:26]([O-:28])=[O:27]
Reactant: CCC(N)C1CC1
Reactant: O=[N+]([O-])c1c(-c2ccc(C(F)(F)F)cc2Cl)ccnc1OS(=O)(=O)C(F)(F)F
Agent: Cl
Product: CCC(Nc1nccc(-c2ccc(C(F)(F)F)cc2Cl)c1[N+](=O)[O-])C1CC1
Yield: 99.7 %

Procedure:
Trifluoro-methanesulfonic acid 4-(2-chloro-4-trifluoromethyl-phenyl)-3-nitro-pyridin-2-yl-ester (0.62 g, 1.38 mmol), prepared substantially as described in Part C of Example 19a, and 1-cyclopropyl-propylamine HCl (0.37 g, 2.75 mmol) were treated substantially as described in Part C of Example 19a to produce 0.55 g (100%) of [4-(2-chloro-4-trifluoromethyl-phenyl)-3-nitro-pyridin-2-yl]-(1-cyclopropyl-propyl)-amine: MS (AP) m/z 399.8 [(M+H)+, 25].
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[N:5][C:6](=[O:9])[NH:7][CH:8]=1.C(N(CC)CC)C.[CH2:17]([O:24][CH2:25]Cl)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>ClCCl>[CH2:17]([O:24][CH2:25][N:5]1[CH:4]=[C:3]([Cl:2])[CH:8]=[N:7][C:6]1=[O:9])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: ClCOCc1ccccc1
Reactant: O=c1ncc(Cl)c[nH]1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=c1ncc(Cl)cn1COCc1ccccc1

Procedure:
A mixture of 5-chloropyrimidin-2-one hydrochloride (10 mmol) and triethylamine (20 mmol) in dichloromethane (50 ml) were stirred together until all the solid material had dissolved, before a solution of chloromethyl benzyl ether (see Preparation 1a and 1b) (10 mmol) in dichloromethane (10 ml) was added with stirring at room temperature. The mixture was stirred for 3 hours at room temperature before the solvent was distilled off. The residue was triturated with water (40 ml), extracted into chloroform (3×40 ml) and the dried (MgSO4) solution evaporated; yield 2.40 g (96%). The product was purified by trituration with ether and had m.p. 125° C. (acetone). 1H NMR (CDCl3): δ4.68 (CH2Ph), 5.32 (CH2O), 7.30 (Ph), 7.72 and 8.48 (H-4, H-6, J 3 Hz).
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([CH:22]2[CH2:24][CH2:23]2)[N:5]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[C:6]=1[C:7]1[CH:12]=[CH:11][N:10]=[C:9](Cl)[N:8]=1.[NH2:25][CH2:26][C@@H:27]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH3:28].C(N(C(C)C)CC)(C)C.C(=O)([O-])[O-].[Na+].[Na+]>CN1C(=O)CCC1>[C:32]([O:31][C:30](=[O:36])[NH:29][C@@H:27]([CH3:28])[CH2:26][NH:25][C:9]1[N:8]=[C:7]([C:6]2[N:5]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[C:4]([CH:22]3[CH2:24][CH2:23]3)=[N:3][C:2]=2[Br:1])[CH:12]=[CH:11][N:10]=1)([CH3:35])([CH3:33])[CH3:34]
Reactant: C[C@@H](CN)NC(=O)OC(C)(C)C
Reactant: C[Si](C)(C)CCOCn1c(C2CC2)nc(Br)c1-c1ccnc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](CNc1nccc(-c2c(Br)nc(C3CC3)n2COCC[Si](C)(C)C)n1)NC(=O)OC(C)(C)C
Temperature: 110 °C

Procedure:
A mixture of 4-(4-bromo-2-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)-2-chloropyrimidine (5.50 g, 12.8 mmol), (S)-tert-butyl 1-aminopropan-2-ylcarbamate (SM-1, 2.68 g, 15.4 mmol), diisopropylethylamine (2.68 mL, 15.4 mmol) and sodium carbonate (2.71 g, 25.6 mmol) in NMP (8 mL) was heated with 110° C. oil bath for 3.5 hours and LCMS analysis of an aliquot indicated reaction completion with desired product. The reaction was allowed to cool to ambient temperature, then partitioned between EtOAc (20 mL) and water (60 mL). The EtOAc layer was washed with water (60 mL), dried (Na2SO4), and concentrated to a light yellow foam (6.89 g, 12.1 mmol). A small portion of material was further purified by flash chromatography (SiO2, EtOAc in heptane): LCMS(m/z) 567.3 (MH+), tR=1.03 minutes; 1H NMR (CDCl3, 300 MHz) δ-0.09 (s, 9H), 0.80 (t, J=8.2 Hz, 2H), 0.98-1.07 (m, 2H), 1.10-1.18 (m, 2H), 1.21 (t, J=6.5 Hz, 3H), 1.40 (s, 9H), 1.91-2.08 (m, 1H), 3.41 (t, J=8.2 Hz, 2H), 3.44-3.59 (m, 2H), 3.82-4.01 (m, 1H), 4.65-4.87 (m, 1H), 5.41-5.61 (m, 1H), 5.78-5.99 (m, 2H), 7.10 (d, J=5.0 Hz, 1H), 8.33 (d, J=5.2 Hz, 1H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][CH2:12][C@H:11]([NH:15][C@@H:16]3[CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]3[NH:22][C:23](=[O:35])CC3C4C(=CC=CC=4)N(C)C=3)[CH2:10]2)=[CH:5][CH:4]=1)#[N:2].[Cl:36][C:37]1[CH:42]=[CH:41][CH:40]=[C:39]([N:43]=C=O)[CH:38]=1>>[Cl:36][C:37]1[CH:38]=[C:39]([NH:43][C:23]([NH:22][C@@H:17]2[CH2:18][CH2:19][CH2:20][CH2:21][C@H:16]2[NH:15][C@H:11]2[CH2:12][CH2:13][CH2:14][N:9]([C:6]3[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=3)[CH2:10]2)=[O:35])[CH:40]=[CH:41][CH:42]=1
Reactant: Cn1cc(CC(=O)N[C@@H]2CCCC[C@H]2N[C@H]2CCCN(c3ccc(C#N)cc3)C2)c2ccccc21
Reactant: O=C=Nc1cccc(Cl)c1
Product: N#Cc1ccc(N2CCC[C@H](N[C@@H]3CCCC[C@H]3NC(=O)Nc3cccc(Cl)c3)C2)cc1

Procedure:
1-(3-Chlorophenyl)-3-((1R,2R)-2-((S)-1-(4-cyanophenyl)piperidin-3-ylamino)cyclohexyl)urea was synthesized using 4-((S)-3-((1R,2R)-2-aminocyclohexylamino)piperidin-1-yl)benzonitrile (from intermediate D, Example 10) (60 mg, 0.20 mmol) and 1-chloro-3-isocyanatobenzene (30.9 mg, 0.20 mmol) according to General Procedure G to give 20 mg (22%) of a white solid. Anal. Calcd. for C25H30ClN5O m/z 451.2, found: 452.2 (M+H)+; 1H NMR (400 MHz, DMSO-d6) δ ppm 9.00 (s, 1H), 7.66 (s, 1H), 7.43 (d, J=8.9 Hz, 2H), 7.24 (t, J=8.0 Hz, 1H), 7.17 (d, J=8 Hz, 1H), 6.95 (m, 3H), 6.45 (bs, 1H), 3.88 (d, J=11.3 Hz, 1H), 3.72 (d, J=12.6 Hz, 1H), 2.84 (m, 4H), 1.97 (m, 4H), 1.68 (m, 3H), 1.50 (m, 4H), 1.25 (m, 2H).
Reaction SMILES: [Na].[N+:2]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:6]=1[CH3:12])([O-:4])=[O:3].[C:13](OCC)(=[O:19])[C:14]([O:16]CC)=[O:15].O>C(O)C>[CH3:11][C:7]1[CH:8]=[CH:9][CH:10]=[C:5]([N+:2]([O-:4])=[O:3])[C:6]=1[CH2:12][C:13](=[O:19])[C:14]([OH:16])=[O:15]
Reactant: CCOC(=O)C(=O)OCC
Reactant: Cc1cccc([N+](=O)[O-])c1C
Agent: [Na]
Solvent: CCO
Solvent: O
Product: Cc1cccc([N+](=O)[O-])c1CC(=O)C(=O)O
Temperature: 25 °C
Reaction time: 18 h
Yield: 94.2 %

Procedure:
Sodium metal (3.80 g, 165 mmol) was dissolved in absolute ethanol (66 mL) at 0° C. The 3-nitro-o-xylene (10 g, 66.2 mmol) and diethyl oxalate (18 mL, 132 mmol) were then added and the reaction was warmed to room temperature and stirred for 18 hours. The reaction was refluxed for 30 minutes, then cooled and water (22 mL) was added and the reaction was stirred at room temperature for one hour. The reaction was concentrated to remove the ethanol, then extracted with ethyl acetate, washed with brine, dried over sodium sulfate, filtered and concentrated to provide the desired product (13.92 g, 94%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:23]([F:26])([F:25])[F:24])[O:13][N:12]=[C:11]([C:14]3[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.S(Cl)([Cl:29])=O>C1C=CC=CC=1.CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:23]([F:25])([F:24])[F:26])[O:13][N:12]=[C:11]([C:14]3[CH:15]=[CH:16][C:17]([C:18]([Cl:29])=[O:19])=[CH:21][CH:22]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1
Yield: 173.1 %

Procedure:
In a suspension of 1.00 g of 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]benzoic acid in 10 ml of benzene, 0.44 g of thionyl chloride and a catalytic amount (2 to 3 drops) of N,N-dimethylformamide were added, and stirred under reflux with heat for 2.5 hours. After the completion of the reaction, the solvent was distilled off under reduced pressure to obtain 1.81 g of crude 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]benzoic acid chloride as pale yellow oily substance.
Reaction SMILES: [C:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.ClC(OCC)=O.[NH2:27][CH2:28][CH2:29][O:30][C:31]1[CH:40]=[CH:39][C:34]([C:35]([O:37][CH3:38])=[O:36])=[CH:33][CH:32]=1>C(Cl)(Cl)Cl>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([C:9]([NH:27][CH2:28][CH2:29][O:30][C:31]2[CH:40]=[CH:39][C:34]([C:35]([O:37][CH3:38])=[O:36])=[CH:33][CH:32]=2)=[O:11])=[CH:12][CH:13]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)c1ccc(OCCN)cc1
Reactant: CC(C)(C)c1ccc(C(=O)O)cc1
Agent: CCOC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(OCCNC(=O)c2ccc(C(C)(C)C)cc2)cc1
Yield: 91.9 %

Procedure:
p-tert-Butylbenzoic acid (5.35 g) and 3.34 g of triethylamine were dissolved in 70 ml of chloroform and 3.26 g of ethyl chloroformate was dropped into the above mixture with stirring and cooling at 0° to 5° C. After the dropping, the mixture was stirred at the same temperature for 30 minutes and, after addition of 5.86 g of methyl 4-(2-aminoethoxy)benzoate thereto, the mixture was stirred for 6 hours more. The reaction solution was washed with 10% hydrochloric acid, saturated potassium carbonate solution, and water, dried with anhydrous magnesium sulpahte, concentrated in vacuo, and the residue was crystallised with n-hexane to give 9.8 g of crystals which were further recrystallised from ethyl acetate to give 7.64 g (yield: 71.65%) of the product, m.p. 112°-114° C.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10](=[N:17][C:18]1[CH:22]=[CH:21][NH:20][N:19]=1)[CH:11]1[CH2:15][CH2:14][O:13][C:12]1=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl>O>[CH2:1]([O:8][CH2:9][C:10]1[NH:17][C:18]2[N:19]([N:20]=[CH:21][CH:22]=2)[C:12](=[O:16])[C:11]=1[CH2:15][CH2:14][OH:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1OCCC1C(COCc1ccccc1)=Nc1cc[nH]n1
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Product: O=c1c(CCO)c(COCc2ccccc2)[nH]c2ccnn12
Reaction time: 0.67 h
Yield: 100 %

Procedure:
To 1.18 g of 3-{[2-(benzyloxy)-1-(tetrahydro-2-oxo-3-furyl)ethylidene]amino}pyrazole were added 600 μl of triethylamine and 2.0 ml of water, and the mixture was stirred for 40 minutes while heating under reflux. After the reaction system was allowed to coom to room temperature, 1N hydrochloric acid was added to adjust the pH of the reaction mixture to 4. After the reaction mixture was extracted with chloroform, and the organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off to obtain 1.18 g (yield: quantitative) of the intended product.
Reaction SMILES: C([N:8]1[C@@H:13]2[C@@H:14]([O:16][CH3:17])[CH2:15][C@@:9]1([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C@H:10]([O:18][CH2:19][C:20]1[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[C:22]([C:30]([F:33])([F:32])[F:31])[CH:21]=1)[CH2:11][CH2:12]2)C1C=CC=CC=1>[Pd]>[F:29][C:26]([F:27])([F:28])[C:24]1[CH:25]=[C:20]([CH2:19][O:18][C@@H:10]2[CH2:11][CH2:12][C@@H:13]3[NH:8][C@@:9]2([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:15][C@@H:14]3[O:16][CH3:17])[CH:21]=[C:22]([C:30]([F:31])([F:32])[F:33])[CH:23]=1
Reactant: CO[C@H]1C[C@@]2(c3ccccc3)[C@H](OCc3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC[C@@H]1N2Cc1ccccc1
Agent: [Pd]
Product: CO[C@H]1C[C@]2(c3ccccc3)N[C@H]1CC[C@H]2OCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of (1R*,2R*,5S*,6S*)-8-benzyl-2-{[8,5-bis(trifluoromethyl)phenyl]methoxy}-6-methoxy-1-phenyl-8-azabicyclo[3.2.1]octane (Example 45; 17 mg, 0.031 mmol), 5% palladium on charcoal (106 mg, 0.05 mmol) ethanol (10 ml) was stirred under hydrogen atmosphere (1 atm) at +65° C. for 1 hour. The reaction mixture was cooled to room temperature, flushed with nitrogen gas and filtered through a pad of Celite™. The filtrate was concentrated to give the title compound.