Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:29])[N:19]([CH2:23][C:24]5[NH:25][CH:26]=[CH:27][N:28]=5)[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:32]([F:35])([F:34])[F:33])[CH:3]=1.[N:36]1([S:41](Cl)(=[O:43])=[O:42])[CH2:40][CH2:39][CH2:38][CH2:37]1>>[Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:29])[N:19]([CH2:23][C:24]5[N:25]([S:41]([N:36]6[CH2:40][CH2:39][CH2:38][CH2:37]6)(=[O:43])=[O:42])[CH:26]=[CH:27][N:28]=5)[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:32]([F:35])([F:34])[F:33])[CH:3]=1
Reactant: O=C1S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C(=O)N1Cc1ncc[nH]1
Reactant: O=S(=O)(Cl)N1CCCC1
Product: O=C1S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C(=O)N1Cc1nccn1S(=O)(=O)N1CCCC1

Procedure:
(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-{[1-(pyrrolidin-1-ylsulfonyl)-1H-imidazol-2-yl]methyl}-1,3-thiazolidine-2,4-dione was prepared from (5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-(1H-imidazol-2-ylmethyl)-1,3-thiazolidine-2,4-dione (from Example 403) and 1-pyrrolidinesulfonyl chloride following General Procedure U.
Reaction SMILES: [CH3:1][O:2][CH:3]1[O:8][CH2:7][CH:6]([CH2:9][OH:10])[CH2:5][O:4]1.[H-].[Na+].Cl[C:14]1[CH:19]=[CH:18][N+:17]([O-:20])=[C:16]([CH3:21])[C:15]=1[CH3:22]>CS(C)=O>[CH3:1][O:2][CH:3]1[O:8][CH2:7][CH:6]([CH2:9][O:10][C:14]2[CH:19]=[CH:18][N+:17]([O-:20])=[C:16]([CH3:21])[C:15]=2[CH3:22])[CH2:5][O:4]1
Reactant: COC1OCC(CO)CO1
Reactant: Cc1c(Cl)cc[n+]([O-])c1C
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COC1OCC(COc2cc[n+]([O-])c(C)c2C)CO1
Temperature: 60 °C
Reaction time: 2.5 h
Yield: 49.5 %

Procedure:
To a dimethylsulfoxide (10 ml) solution of the (2-methoxy-1,3-dioxan-5-yl)methanol (2.0 g, 13.5 mmol) obtained in the same manner of step (6a), sodium hydride, in oil (770 mg, 14.9 mmol as the content was regarded as 55%) was added at room temperature. To the mixture, 4-chloro-2,3-dimethylpyridine 1-oxide (2.13 g, 13.5 mmol) was added and the mixture was stirred at 60° C. for 2.5 hours. After the reaction mixture was cooled to room temperature, it was concentrated. The residue was purified by silica gel column chromatography (NH silica gel, elution solvent: ethyl acetate/methanol) to obtain the title compound (1.8 g, 49.5% yield), which was a cis and trans (1:1) mixture, as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH2:11][C:12]([OH:14])=O)[CH:10]=1)[N:7]([CH2:15][CH:16]([CH3:18])[CH3:17])[N:6]=[CH:5]2.Cl.Cl.[NH2:21][CH2:22][C:23]1[CH:28]=[C:27]([C:29]([O:31][CH3:32])=[O:30])[CH:26]=[CH:25][N:24]=1.Cl.CN(C)CCCN=C=NCC.CN1CCOCC1>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH2:11][C:12]([NH:21][CH2:22][C:23]3[CH:28]=[C:27]([C:29]([O:31][CH3:32])=[O:30])[CH:26]=[CH:25][N:24]=3)=[O:14])[CH:10]=1)[N:7]([CH2:15][CH:16]([CH3:18])[CH3:17])[N:6]=[CH:5]2
Reactant: COC(=O)c1ccnc(CN)c1
Reactant: CC(C)Cn1ncc2cc(Cl)cc(CC(=O)O)c21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COC(=O)c1ccnc(CNC(=O)Cc2cc(Cl)cc3cnn(CC(C)C)c23)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 76.5 %

Procedure:
A mixture of compound 58 (0.155 g, 0.58 mmoles) and methyl 2-(aminomethyl)pyridine-4-carboxylate dihydrochloride (0.139 g, 0.58 mmoles) (see WO2003070732, example 6, step 2 for preparation, which is incorporated by reference in its entirety) in dichloromethane (20 ml) was treated with N,N,N′,N′-tetramethyl-O-(1H-benzotriazol-1-yl)uranium hexafluorophosphate (0.264 g, 0.69 mmoles) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.133 g, 0.69 mmoles) and N-methylmorpholine (0.255 ml, 2.32 mmoles) then stirred at ambient temperature under a nitrogen atmosphere for 18 h. The mixture was washed with water (2×20 ml) and saturated brine (20 ml) then separated and dried over sodium sulphate, filtered and evaporated to dryness. The residue was chromatographed on silica gel eluting with an ethyl acetate/isohexane gradient. This gave the title compound as a colorless oil (0.184 g 76%).
Reaction SMILES: [H-].[Na+].Cl.[NH2:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([OH:11])[CH2:7][CH2:6]1.Cl[C:13]1[N:18]=[CH:17][CH:16]=[CH:15][N:14]=1>O1CCCC1>[N:14]1[CH:15]=[CH:16][CH:17]=[N:18][C:13]=1[O:11][C@H:8]1[CH2:9][CH2:10][C@H:5]([NH2:4])[CH2:6][CH2:7]1
Reactant: N[C@H]1CC[C@H](O)CC1
Reactant: Clc1ncccn1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N[C@H]1CC[C@H](Oc2ncccn2)CC1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
60% sodium hydride was added to 10 ml of a tetrahydrofuran suspension containing 1.00 g of trans-4-aminocyclohexanol hydrochloride and the mixture was refluxed for 1 hour. After cooling to room temperature, 2-chloropyrimidine was slowly added thereto and the mixture was stirred at room temperature for 6 hours. The reaction mixture was poured into ice-cold water and extracted with chloroform. The extract was washed with brine and dried over anhydrous sodium sulfate, and then, the solvent was removed under reduced pressure. The residue was purified by NH-silica gel column chromatography (solvent: ethyl acetate-hexane (1:4) to chloroform alone) to obtain 788 mg of trans-4-(2-pyrimidinyloxy)cyclohexylamine (Reference Example 9-46 in Table 6).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)=[CH:4][CH:3]=1.[O:16]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[CH:18]=[C:17]1[C:25]1[O:26][CH:27]=[C:28]([CH2:30]Cl)[N:29]=1>>[O:16]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[CH:18]=[C:17]1[C:25]1[O:26][CH:27]=[C:28]([CH2:30][O:1][C:2]2[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]3[CH:15]=[CH:14][N:13]=[CH:12]3)=[CH:4][CH:3]=2)[N:29]=1
Reactant: Oc1ccc(CCCn2ccnc2)cc1
Reactant: ClCc1coc(-c2cc3ccccc3o2)n1
Product: c1ccc2oc(-c3nc(COc4ccc(CCCn5ccnc5)cc4)co3)cc2c1
Yield: 85 %

Procedure:
In substantially the same manner as in Working Example 72, 1-[3-(4-hydroxyphenyl)propyl]imidazole was allowed to react with 2-(2-benzofuranyl)-4-chloromethyl oxazole to give 2-(2-benzofuranyl)-4-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]oxazole. The yield was 85%. Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 122-123° C.
Reaction SMILES: [CH3:1][C:2]([O:4][C@H:5]1[C:14]2[C@@:15]3([CH3:30])[C@@H:26]([CH2:27][O:28][CH3:29])[O:25][C:23](=[O:24])[C:17]4=[CH:18][O:19][C:20]([C:21](=[O:22])[C:13]=2[C@@H:8]2[CH2:9][CH2:10][C@H:11]([OH:12])[C@@:7]2([CH3:31])[CH2:6]1)=[C:16]34)=[O:3].C(N(CC)CC)C.[CH2:39]1[C@@H:42]([C:43]([OH:45])=[O:44])[NH:41][CH2:40]1>C(Cl)Cl>[C:2]([O:4][CH:5]1[C:14]2[C:15]3([CH3:30])[C:16]([C:17](=[CH:18][N:41]4[CH2:40][CH2:39][CH:42]4[C:43]([OH:45])=[O:44])[C:23](=[O:24])[O:25][CH:26]3[CH2:27][O:28][CH3:29])=[C:20]([OH:19])[C:21](=[O:22])[C:13]=2[CH:8]2[C:7]([CH3:31])([CH:11]([OH:12])[CH2:10][CH2:9]2)[CH2:6]1)(=[O:3])[CH3:1]
Reactant: COC[C@H]1OC(=O)c2coc3c2[C@@]1(C)C1=C(C3=O)[C@@H]2CC[C@H](O)[C@@]2(C)C[C@H]1OC(C)=O
Reactant: O=C(O)[C@@H]1CCN1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCC1OC(=O)C(=CN2CCC2C(=O)O)C2=C(O)C(=O)C3=C(C(OC(C)=O)CC4(C)C(O)CCC34)C21C
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 100 mg (0.23 mmol) 17-hydroxywortmannin and triethylamine (65 μL, 0.46 mmol) in 2 mL CH2Cl2 is added L-azetidine-2-carboxylic acid (47 mg, 0.46 mmol). The reaction mixture is stirred at room temperature for 12 hours and then concentrated in vacuo. The residue is dissolved in EtOAc and precipitated with hexane. The precipitate is washed two times with hexane to give the product as a yellow solid. MS (ESI) m/z 533 (M+H).
Reaction SMILES: [N+:1]([C:4]1[CH:16]=[CH:15][C:7]([O:8][CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N(CC)CC)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>C(Cl)Cl>[CH3:24][S:25]([N:12]1[CH2:11][CH2:10][CH:9]([O:8][C:7]2[CH:15]=[CH:16][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[CH2:14][CH2:13]1)(=[O:27])=[O:26]
Reactant: O=[N+]([O-])c1ccc(OC2CCNCC2)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)N1CCC(Oc2ccc([N+](=O)[O-])cc2)CC1
Reaction time: 1 h
Yield: 86.3 %

Procedure:
A solution of 4-(4-nitro-phenoxy)-piperidine (7.80 g, 35.1 mmol) and triethylamine (7.77 mL, 56.2 mmol) in DCM (100 mL) at 0° C. was treated dropwise with methanesulfonyl chloride (3.26 mL, 42.1 mmol) and stirred cold for 1 hour. The mixture was diluted with DCM, washed with 1M HCl, a saturated NaHCO3 solution, water and brine, dried over Na2SO4 and concentrated under vacuum to leave the title compound (9.10 g, 86% yield) as a yellow/orange solid. 1H NMR (300 MHz, CDCl3) δ 8.21 (d, J=9.2 Hz, 2H), 6.97 (d, J=9.2 Hz, 2H), 4.68 (m, 1H), 3.39 (m, 4H), 2.84 (s, 3H), 2.05 (m, 4H). LCMS (m/z, Method A) ES+ 301.0 [M+1]+.
Reaction SMILES: [OH-].[K+].[OH:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[NH:12][C:11](=[O:14])[CH2:10][CH2:9]2.[CH2:15]([OH:20])[CH:16]([OH:19])[CH2:17]Cl>CO>[OH:19][CH:16]([CH2:15][OH:20])[CH2:17][O:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[NH:12][C:11](=[O:14])[CH2:10][CH2:9]2
Reactant: O=C1CCc2cccc(O)c2N1
Reactant: OCC(O)CCl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C1CCc2cccc(OCC(O)CO)c2N1
Yield: 33.8 %

Procedure:
0.8 g of potassium hydroxide was dissolved in 50 ml of methanol, and 1.63 g of 8-hydroxy-3,4-dihydrocarbostyril and 1.4 g of glycerol α-monochlorohydrin were added to the resulting solution followed by refluxing the mixture for 3 hours. The raction mixture was then concentrated to dryness, and the resulting residue was extracted with 50 ml of chloroform. The extract was washed with a 2% aqueous sodium hydroxide solution and then water, and then dried over anhydrous sodium sulfate. The chloroform was then removed by distillation and the resulting residue was recrystallized from ethanol to give 0.8 g of 8-(2,3-dihydroxy)propoxy-3,4-dihydrocarbostyril as a light yellow amorphous solid having a melting point of 182° - 184° C.
Reaction SMILES: [NH:1]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:2][C:3]([NH:5][C@H:6]([C:14]([NH:16][C@H:17]([C:22](O)=[O:23])[CH2:18][CH:19]([CH3:21])[CH3:20])=[O:15])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4].ON1C(=O)CCC1=O.C1(N=C=NC2CCCCC2)CCCCC1.[NH2:55][CH2:56][C:57]([O:59][CH2:60][C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1)=[O:58]>CN(C)C=O.S(C1C=CC(C)=CC=1)([O-])(=O)=O.C(N(CC)CC)C>[NH:1]([C:25]([O:27][C:28]([CH3:30])([CH3:31])[CH3:29])=[O:26])[CH2:2][C:3]([NH:5][C@H:6]([C:14]([NH:16][C@H:17]([C:22]([NH:55][CH2:56][C:57]([O:59][CH2:60][C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1)=[O:58])=[O:23])[CH2:18][CH:19]([CH3:21])[CH3:20])=[O:15])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4]
Reactant: NCC(=O)OCc1ccccc1
Reactant: CC(C)C[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)CNC(=O)OC(C)(C)C)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: O=C1CCC(=O)N1O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)C[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)CNC(=O)OC(C)(C)C)C(=O)NCC(=O)OCc1ccccc1
Temperature: 4 °C
Reaction time: 2 h
Yield: 62.3 %

Procedure:
The Boc-Gly-Phe-Leu-OH obtained in Example 18 (2.4 g) and N-hydroxysuccinimide (656 mg) were dissolved in N,N-dimethylformamide (50 ml), cooled to 4° C., and then added with N,N′-dicyclohexylcarbodiimide (1.17 g), and stirred for 2 hours. To this solution, a N,N-dimethylformamide solution (40 ml) in which tosylate of H-Gly-OBzl (1.9 g) and triethylamine (0.79 ml) had been dissolved was added, and the mixture was allowed to react with stirring at room temperature for 16 hours. This reaction mixture was evaporated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: dichloromethane:methanol=50:1 solution) to give the title compound (2.0 g).
Reaction SMILES: [CH3:1][C:2]([CH3:22])=[CH:3][CH2:4][CH2:5]/[C:6](/[CH3:21])=[CH:7]/[CH2:8][CH2:9]/[C:10](/[CH3:20])=[CH:11]/[CH2:12][S:13][CH2:14][C@H:15]([NH2:19])[C:16]([OH:18])=[O:17].[CH2:23]1[C@H:30]([N:31]2[C:40](=[O:41])[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[C:32]2=[O:33])[C:28](=[O:29])[O:27][C:25](=[O:26])[CH2:24]1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[C:16]([C@@H:15]([NH:19][C:25](=[O:26])[CH2:24][CH2:23][C@H:30]([N:31]1[C:40](=[O:41])[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:32]1=[O:33])[C:28]([OH:29])=[O:27])[CH2:14][S:13][CH2:12]/[CH:11]=[C:10](\[CH3:20])/[CH2:9][CH2:8]/[CH:7]=[C:6](\[CH3:21])/[CH2:5][CH2:4][CH:3]=[C:2]([CH3:22])[CH3:1])([OH:18])=[O:17]
Reactant: CC(C)=CCC/C(C)=C/CC/C(C)=C/CSC[C@H](N)C(=O)O
Reactant: O=C1CC[C@H](N2C(=O)c3ccccc3C2=O)C(=O)O1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)=CCC/C(C)=C/CC/C(C)=C/CSC[C@H](NC(=O)CC[C@@H](C(=O)O)N1C(=O)c2ccccc2C1=O)C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of S-trans, trans-farnesyl-L-cysteine (325 mg, 1 mmol) and N-phthaloyl-L-glutamic anhydride (259 mg, 1 mmol) in CH2Cl2 (10 mL) was added N,N-diisopropyl-ethyl-amine (0.87 mL, 5 mmol). The solution was stirred at room temperature for 2 h. The reaction was quenched with 1N HCl (10 mL) and the pH was adjusted to 2.0-3.0. The mixtures were extracted with ethyl acetate (15 mL×3). The organic layer was dried over Na2SO4 and concentrated in vacuo and the residue was purified by preparative HPLC (350 mg, 60%) to yield Compound C-2, which is identical to the S—R stereoisomer of the Compound C racemate in Examples 5 and 5a. 1H-NMR (500 MHz, CDCl3): δ 1.50 (s, 3H), 1.52 (s, 3H), 1.55 (s, 3H), 1.60 (s, 3H), 1.86-1.98 (m, 8H), 2.33-2.43 (m, 2H), 2.54-2.57 (m, 2H), 2.78 (dd, J=5.0, 15.0 Hz, 1H), 2.91 (dd, J=5.0, 15.0 Hz, 1H), 3.06 (dd, J=5.0, 10.0 Hz, 1H), 3.14 (dd, J=5.0, 10.0 Hz, 1H), 4.65 (dd, J=5.0, 10.0 Hz, 1H), 4.96 (t, J=5.0 Hz, 1H), 5.00 (m, 2H), 5.11 (t, J=5.0 Hz, 1H), 6.79 (d, J=10.0 Hz, 1H), 7.63-7.65 (m, 2H), 7.74-7.76 (m, 2H), 8.00 (broad, 2H). 13C-NMR (125 MHz, CDCl3): δ 16.06, 16.18, 17.76, 25.19, 25.78, 26.47, 26.73, 29.77, 32.59, 32.79, 39.65, 39.72, 51.10, 51.85, 119.37, 123.76, 123.80, 124.36, 131.39, 131.62, 134.40, 135.36, 140.24, 167.75, 172.78, 173.05, 174.51; ES-MS: mass calcd for Chemical Formula: C31H40N2O7S 584.72. Found (M+) m/z 585.3, (M+Na) m/z 607.3.
Reaction SMILES: C[O:2][C:3](=[O:25])[C@@H:4]([N:9]([CH2:11][C:12]1[CH:13]([CH:23]=[O:24])[O:14][C:15]2[C:20]([CH:21]=1)=[C:19]([Cl:22])[CH:18]=[CH:17][CH:16]=2)[CH3:10])[CH2:5][CH:6]([CH3:8])[CH3:7].O.[OH-].[Li+]>O1CCCC1.O>[Cl:22][C:19]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:20]=1[CH2:21][C:12]([CH2:11][N:9]([CH3:10])[C@@H:4]([CH2:5][CH:6]([CH3:7])[CH3:8])[C:3]([OH:25])=[O:2])=[C:13]([CH:23]=[O:24])[O:14]2
Reactant: COC(=O)[C@H](CC(C)C)N(C)CC1=Cc2c(Cl)cccc2OC1C=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)C[C@@H](C(=O)O)N(C)CC1=C(C=O)Oc2cccc(Cl)c2C1
Yield: 88.6 %

Procedure:
A solution of (S)-2-[(5-chloro-2-formyl-2H-chromen-3-ylmethyl)-methyl-amino]-4-methyl-pentanoic acid methyl ester (2.0 g, 5.71 mmol) and lithium hydroxide monohydrate (0.312 g, 7.40 mmol) was stirred at 25° C. for 2 hours in tetrahydrofuran-water (3:1) mixture (90 mL). The reaction mixture was concentrated in vacuo to remove tetrahydrofuran, and the residue was acidified with 2N hydrochloric acid, and diluted with water. The resulting solution was extracted with ethyl acetate (3×). The combined organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was removed in vacuo to afford (S)-2-[(5-chloro-2-formyl-4H-chromen-3-ylmethyl)-methyl-amino]-4-methyl-pentanoic acid (1.78 g, 93.6%).
Reaction SMILES: [CH3:1][CH:2]([CH3:6])[C:3](Cl)=[O:4].[I:7][C:8]1[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=1[NH2:10]>>[I:7][C:8]1[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=1[NH:10][C:3](=[O:4])[CH:2]([CH3:6])[CH3:1]
Reactant: Nc1ccccc1I
Reactant: CC(C)C(=O)Cl
Product: CC(C)C(=O)Nc1ccccc1I

Procedure:
Prepared by Procedure Q1 using 2-methylpropanoyl chloride and 2-iodoaniline: ESMS m/e: 289.9 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[CH:3]([C:17]1[CH:22]=[C:21]([Cl:23])[C:20]([Cl:24])=[C:19]([Cl:25])[CH:18]=1)/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[C:12](=O)[CH2:11][CH2:10][CH2:9]2.Cl.[NH2:29][OH:30].C([O-])(=O)C.[Na+]>CCO>[F:1][C:2]([F:27])([F:26])[CH:3]([C:17]1[CH:22]=[C:21]([Cl:23])[C:20]([Cl:24])=[C:19]([Cl:25])[CH:18]=1)/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[C:12](=[N:29][OH:30])[CH2:11][CH2:10][CH2:9]2
Reactant: NO
Reactant: O=C1CCCc2cc(/C=C/C(c3cc(Cl)c(Cl)c(Cl)c3)C(F)(F)F)ccc21
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: ON=C1CCCc2cc(/C=C/C(c3cc(Cl)c(Cl)c(Cl)c3)C(F)(F)F)ccc21

Procedure:
To a stirred solution of ((E)-6-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)-3,4-dihydronaphthalen-1(2H)-one (0.4 g, 0.92 mmol) in EtOH (50 mL) were added hydroxylamine hydrochloride (0.128 g, 1.85 mmol) and sodium acetate (NaOAc, 0.23 g, 2.77 mmol), and the reaction mixture was heated at reflux for 3 h. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with water and extracted with EtOAc. The combined organic extracts were washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure to give the crude compound, which was purified by flash column chromatography (SiO2, 100-200 mesh; 10-15% EtOAc in petroleum ether). The title compound was isolated as a solid (0.3 g, 73%): mp 155-158° C.; 1H NMR (400 MHz, CDCl3) δ 7.89 (d, J=8.4 Hz, 1H), 7.41 (s, 2H), 7.24 (m, 1H), 7.17 (m, 1H), 6.57 (d, J=16 Hz, 1H), 6.46 (dd, J=16.0, 8.0 Hz, 1H), 4.13 (m, 1H), 2.82 (m, 4H), 2.04 (m, 2H); ESIMS m/z 445.95 ([M−H]−).
Reaction SMILES: Cl[C:2]1[N:12]=[CH:11][C:10]([F:13])=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH2:14]([S:16][C:17]1[CH:18]=[C:19]([OH:23])[CH:20]=[CH:21][CH:22]=1)[CH3:15].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1>[CH2:7]([O:6][C:4](=[O:5])[C:3]1[CH:9]=[C:10]([F:13])[CH:11]=[N:12][C:2]=1[O:23][C:19]1[CH:20]=[CH:21][CH:22]=[C:17]([S:16][CH2:14][CH3:15])[CH:18]=1)[CH3:8]
Reactant: CCSc1cccc(O)c1
Reactant: CCOC(=O)c1cc(F)cnc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CCOC(=O)c1cc(F)cnc1Oc1cccc(SCC)c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 15 %

Procedure:
Ethyl 2-chloro-5-fluoro-nicotinate (J. Med. Chem. 1993, 36, 2676, M. Winn et. al.) (5.0 g, 24 mmol), 3-ethylsulfanylphenol (3.8 g, 24 mmol) and caesium carbonate (7.98 g, 24 mmol) were suspended in dioxan (50 ml) and the reaction was heated to 100° C. and stirred at this temperature under nitrogen for 8 h. The reaction was cooled to room temperature, filtered and the solid washed with ethyl acetate (50 ml). The filtrate was concentrated under reduced pressure, and the residue was purified by flash column chromatography on silica gel eluting with cyclohexane:ethyl acetate (95:5) to give 5-fluoro-2-(3-ethylsulfanyl-phenoxy)-nicotinic acid ethyl ester (1.16 g).
Reaction SMILES: [F:1][C:2]1[C:3]([NH:17][C:18]2[CH:29]=[CH:28][CH:27]=[CH:26][C:19]=2[C:20]([NH:22][CH:23]([CH3:25])[CH3:24])=[O:21])=[N:4][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([CH:15]=O)=[CH:11][CH:10]=2)=[N:6][CH:7]=1.[CH3:30][S:31]([CH2:34][CH2:35][NH2:36])(=[O:33])=[O:32]>C(Cl)Cl>[F:1][C:2]1[C:3]([NH:17][C:18]2[CH:29]=[CH:28][CH:27]=[CH:26][C:19]=2[C:20]([NH:22][CH:23]([CH3:25])[CH3:24])=[O:21])=[N:4][C:5]([NH:8][C:9]2[CH:10]=[CH:11][C:12]([CH2:15][NH:36][CH2:35][CH2:34][S:31]([CH3:30])(=[O:33])=[O:32])=[CH:13][CH:14]=2)=[N:6][CH:7]=1
Reactant: CS(=O)(=O)CCN
Reactant: CC(C)NC(=O)c1ccccc1Nc1nc(Nc2ccc(C=O)cc2)ncc1F
Solvent: ClCCl
Product: CC(C)NC(=O)c1ccccc1Nc1nc(Nc2ccc(CNCCS(C)(=O)=O)cc2)ncc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 20 %

Procedure:
2-({5-Fluoro-2-[(4-formylphenyl)amino]-4-pyrimidinyl}amino)-N-(1-methylethyl)benzamide (80 mg, 0.2 mmol, 1.0 eq), [2-(methylsulfonyl)ethyl]amine (100 mg, 0.6 mmol, 3.0 eq), and CH2Cl2 (2.0 mL) were added to a vessel, which was sealed and stirred at room temperature for 16 h. Solvent was removed by evaporation to leave a residue. NaBCNH4 (37 mg, 0.6 mmol, 3.0 eq) in CH2Cl2 (2.0 mL) was added was added to the residue and the reaction mixture was stirred at room temperature until the reaction was substantially complete, as determined by HPLC. The final product was purified by preparative HPLC using water (0.1% formic acid); acetonitrile (0.1% formic acid) as mobile phase. The desired compound was isolated as an off-white solid. (20 mg, 20% yield) MS: M(C24H29FN6O3S)=500.60, (M+H)+=501.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:14][CH2:15][CH3:16])[CH2:5][NH:6][CH2:7][CH:8]1[O:13][CH2:12][CH2:11][CH2:10][O:9]1)[CH3:2].C1C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+].[Cl:29][CH2:30][C:31](Cl)=[O:32]>O>[CH2:1]([O:3][CH:4]([O:14][CH2:15][CH3:16])[CH2:5][N:6]([CH2:7][CH:8]1[O:13][CH2:12][CH2:11][CH2:10][O:9]1)[C:31](=[O:32])[CH2:30][Cl:29])[CH3:2]
Reactant: CCOC(CNCC1OCCCO1)OCC
Reactant: O=C(Cl)CCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Product: CCOC(CN(CC1OCCCO1)C(=O)CCl)OCC

Procedure:
N-(2,2-Diethoxyethyl)-N-(1,3-dioxan-2-ylmethyl)-amine (4 grams), benzene (100 ml), water (100 ml) and sodium carbonate (2 grams) are charged into a glass reaction vessel equipped with a mechanical stirrer and thermometer. The mixture is cooled to a temperature of 5° to 10° C and chloroacetyl chloride (1.5 ml) is added dropwise with stirring. After the addition is completed stirring is continued until the reaction mixture reaches room temperature. After this time the organic phase is separated from the aqueous phase and is washed with water. The washed solution is then dried over anhydrous magnesium sulfate, filtered and stripped of solvent under reduced pressure to yield the desired product N-(2,2-diethoxyethyl)-N-(1,3-dioxan-2-ylmethyl)-α-chloroacetamide as the residue.
Reaction SMILES: C([N:8]1[C@@H:13]2[C@H:14]([C:16]3[O:17][CH:18]=[C:19]([CH3:21])[N:20]=3)[CH2:15][C@@:9]1([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C@H:10]([O:22][CH2:23][C:24]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[C:26]([C:34]([F:37])([F:36])[F:35])[CH:25]=1)[CH2:11][CH2:12]2)C1C=CC=CC=1>[Pd]>[F:37][C:34]([F:35])([F:36])[C:26]1[CH:25]=[C:24]([CH2:23][O:22][C@@H:10]2[CH2:11][CH2:12][C@@H:13]3[NH:8][C@@:9]2([C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH2:15][C@H:14]3[C:16]2[O:17][CH:18]=[C:19]([CH3:21])[N:20]=2)[CH:29]=[C:28]([C:30]([F:33])([F:31])[F:32])[CH:27]=1
Reactant: Cc1coc([C@@H]2C[C@@]3(c4ccccc4)[C@H](OCc4cc(C(F)(F)F)cc(C(F)(F)F)c4)CC[C@@H]2N3Cc2ccccc2)n1
Agent: [Pd]
Product: Cc1coc([C@@H]2C[C@]3(c4ccccc4)N[C@H]2CC[C@H]3OCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.7 %

Procedure:
A mixture of (1R*,12R*,5S*,6R*)-8-benzyl-2-{[3,5-bis(trifluoromethyl)phenyl]methoxy}-6-[4-methyloxazol-2-yl]-1-phenyl-8-azabicyclo[3.2.1]octane (Example 76; 53 mg, 0.09 mmol), 10% palladium on charcoal (135 mg) ethanol (10 ml) was stirred under hydrogen atmosphere (1 atm) at +65° C. for 30 minutes. The reaction mixture was cooled to room temperature, flushed with nitrogen gas and filtered through a pad of Celite™. The filtrate was concentrated and purified by preparative TLC (dichloromethane:methanol) to give the title compound (38 mg, 84%). The hydrochloride salt of the title compound was prepared by treatment with ethereal HCl.