Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]([OH:9])=O)=[CH:3][N:2]=1.C1C=CC2N(O)N=NC=2C=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.C([O:47][C:48](=[O:67])[C@H:49]([CH3:66])[CH2:50][C@H:51]([NH2:65])[CH2:52][C:53]1[CH:58]=[CH:57][C:56]([C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=2)=[CH:55][CH:54]=1)C.CCN(C(C)C)C(C)C>CN(C=O)C.O>[C:56]1([C:59]2[CH:60]=[CH:61][CH:62]=[CH:63][CH:64]=2)[CH:55]=[CH:54][C:53]([CH2:52][C@@H:51]([NH:65][C:7]([C:4]2[CH:5]=[CH:6][N:1]=[N:2][CH:3]=2)=[O:9])[CH2:50][C@@H:49]([CH3:66])[C:48]([OH:67])=[O:47])=[CH:58][CH:57]=1
Reactant: O=C(O)c1ccnnc1
Reactant: CCOC(=O)[C@H](C)C[C@H](N)Cc1ccc(-c2ccccc2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: C[C@H](C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1ccnnc1)C(=O)O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of pyridazine-4-carboxylic acid (21 mg, 0.17 mmol) in DMF (6 mL) is added HOBT (26 mg, 0.17 mmol) and HBTU (65 mg, 0.17 mmol) and the mixture is stirred at room temperature for 10 minutes. (2R,4S)-4-Amino-5-biphenyl-4-yl-2-methyl-pentanoic acid ethyl ester hydrochloride (50 mg, 0.14 mmol) and DIEA (42 mg, 0.56 mmol) are added. After stirring the mixture at room temperature for 18 hours, water is added and the mixture is extracted three times with ethyl acetate. The combined organic layers are washed with water and brine then is dried over magnesium sulfate. The solvent is removed under reduced pressure to give the title compound; HPLC retention time 1.19 minutes (condition C); MS 390.3 (M+H); 1H NMR (400 MHz, DMSO-d6): δ ppm 1.08-1.10 (d, J=7.07Hz, 3H), 1.59-1.66 (m, 1H), 1.88-1.95 (m, 1H), 2.46-2.53 (m, 1H), 2.85-2.87 (d, J=6.82Hz, 2H), 4.22-4.30 (m, 1H), 7.29-7.32 (m, 2H), 7.33-7.36 (m, 1H), 7.42-7.46 (m, 2H), 7.57-7.59 (m, 2H), 7.62-7.65 (m, 2H), 7.91-7.93 (q, J=2.27Hz, 1H), 8.76-8.78 (d, J=8.59Hz, 1H), 9.41-9.43 (m, 1H), 9.45-9.46 (m, 1H), 12.09 (s, 1H).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([O:56][Si:57]([C:60]([CH3:63])([CH3:62])[CH3:61])([CH3:59])[CH3:58])[CH2:16][NH:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][O:25][C:26]2[CH:31]=[CH:30][C:29]([O:32]CC3C=CC=CC=3)=[C:28]([C@@H:40]([C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)[CH2:41][CH2:42][N:43]([CH:47]([CH3:49])[CH3:48])[CH:44]([CH3:46])[CH3:45])[CH:27]=2)=[CH:11][C:10]=1[NH:64][S:65]([CH3:68])(=[O:67])=[O:66])C1C=CC=CC=1.C([O-])=O.[NH4+]>C(O)C.[OH-].[Pd+2].[OH-]>[Si:57]([O:56][C@H:15]([C:12]1[CH:13]=[CH:14][C:9]([OH:8])=[C:10]([NH:64][S:65]([CH3:68])(=[O:66])=[O:67])[CH:11]=1)[CH2:16][NH:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[C:28]([C@@H:40]([C:50]2[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=2)[CH2:41][CH2:42][N:43]([CH:47]([CH3:49])[CH3:48])[CH:44]([CH3:46])[CH3:45])[CH:27]=1)([C:60]([CH3:63])([CH3:61])[CH3:62])([CH3:59])[CH3:58]
Reactant: CC(C)N(CC[C@H](c1ccccc1)c1cc(OCCCCCCCNC[C@H](O[Si](C)(C)C(C)(C)C)c2ccc(OCc3ccccc3)c(NS(C)(=O)=O)c2)ccc1OCc1ccccc1)C(C)C
Agent: [Pd+2]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: CC(C)N(CC[C@H](c1ccccc1)c1cc(OCCCCCCCNC[C@H](O[Si](C)(C)C(C)(C)C)c2ccc(O)c(NS(C)(=O)=O)c2)ccc1O)C(C)C
Temperature: 80 °C

Procedure:
N-{2-(Benzyloxy)-5-[(1R)-2-[(7-{4-(benzyloxy)-3-[(1R)-3-(diisopropylamino)-1-phenylpropyl]phenoxy}heptyl)amino]-1-{[tert-butyl(dimethyl)silyl]oxy}ethyl]phenyl}methanesulfonamide (Preparation 19, 96 mg, 0.10 mmol) and palladium hydroxide (20% by weight on carbon, 25 mg, 0.04 mmol) were dissolved in ethanol (3 ml), then ammonium formate (69 mg, 1.1 mmol) was added and heated to 80° C. for 1 hour. The reaction was cooled to room temperature and the mixture was filtered through Arbocel™ and the solvent removed in vacuo. The residue was dissolved in dichloromethane (containing a trace of methanol) and washed with water (brine was added to aid in the separation), the organic layer was dried (magnesium sulphate), filtered, and the solvents removed in vacuo to yield the title compound as a white foam, 68 mg.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:9]([CH2:10][O:11][C:12](=[O:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[O:8][CH:7](Br)[C@H:6]1[F:21])(=[O:3])[CH3:2].[Cl:22][C:23]1[C:24]([N:34]([Si](C)(C)C)[Si](C)(C)C)=[N:25][C:26](=[O:33])[N:27]([Si](C)(C)C)[CH:28]=1.ClC1C(N)=NC(=O)NC=1.S([O-])([O-])(=O)=O.[NH4+].[NH4+]>C(Cl)Cl.C[Si](C)(C)N[Si](C)(C)C>[C:1]([O:4][C@@H:5]1[C@@H:9]([CH2:10][O:11][C:12](=[O:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[O:8][C@@H:7]([N:27]2[CH:28]=[C:23]([Cl:22])[C:24]([NH2:34])=[N:25][C:26]2=[O:33])[C@H:6]1[F:21])(=[O:3])[CH3:2]
Reactant: C[Si](C)(C)N(c1nc(=O)n([Si](C)(C)C)cc1Cl)[Si](C)(C)C
Reactant: CC(=O)O[C@H]1[C@H](F)C(Br)O[C@@H]1COC(=O)c1ccccc1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: Nc1nc(=O)[nH]cc1Cl
Agent: O=S(=O)([O-])[O-]
Solvent: ClCCl
Product: CC(=O)O[C@H]1[C@H](F)[C@H](n2cc(Cl)c(N)nc2=O)O[C@@H]1COC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 120 h

Procedure:
To a solution of 3-O-acetyl-5-O-benzoyl-2-deoxy-2-fluoro-D-arabinofuranosyl bromide (3.6 g, 0.01 mol) in methylene chloride (50 ml) is added a methylene chloride solution of 5-chloro-tris(trimethylsilyl)cytosine [prepared from 4.3 g, 0.03 mol. of 5-chlorocytosine as follows: a mixture of 5-chlorocytosine and 5-15 mg of ammonium sulfate in 43 ml of hexamethyldisilazane is heated to reflux until a clear solution is obtained. The excess hexamethyldisilazane is removed by evaporation in vacuo and the residue is dissolved in 25 ml of methylene chloride]. The mixture is stirred for 5 days at room temperature. Methanol (7 ml) is added to the reaction mixture, and the suspension is filtered through a Celite pad which is thoroughly washed with methylene chloride. The combined filtrate and washings are evaporated to dryness in vacuo and the residue is crystallized from ethanol to give 860 mg of 1-(3-O-acetyl-5-O-benzoyl-2-deoxy-2-fluoro-β-D-arabinofuranosyl)-5-chlorocytosine, m.p. 233°.
Reaction SMILES: [C:1]1([C:7]2[S:11][C:10]([NH2:12])=[N:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:13](N1C=CN=C1)([N:15]1[CH:19]=[CH:18][N:17]=[CH:16]1)=[S:14]>C(#N)C>[C:1]1([C:7]2[S:11][C:10]([NH:12][C:13]([N:15]3[CH:19]=[CH:18][N:17]=[CH:16]3)=[S:14])=[N:9][CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1ncc(-c2ccccc2)s1
Reactant: S=C(n1ccnc1)n1ccnc1
Solvent: CC#N
Product: S=C(Nc1ncc(-c2ccccc2)s1)n1ccnc1
Temperature: 65 °C
Reaction time: 2 h

Procedure:
To 5-phenylthiazol-2-amine (0.52 g, 2.9 mmol) in acetonitrile (6 mL) was added 1,1′-thiocarbonyldiimidazole (0.68 g, 3.8 mmol). The reaction mixture was stirred at 65° C. for 2 hours. The precipitate was filtered and washed with acetonitrile (2×20 mL) to yield intermediate N-(5-phenylthiazol-2-yl)-1H-imidazole-1-carbothioamide. The intermediate was taken up in N,N-dimethylformamide (30 mL) and treated with (3-(aminomethyl)-3-hydroxy-1-ammoniobicyclo[2.2.2]octan-1-yl)trihydroborate (0.5 g, 2.9 mmol). The reaction mixture was stirred for 5 hours at 65° C. The reaction was concentrated in vacuo and purified via silica gel chromatography (30-100% ethyl acetate/hexane). The product fractions were combined and concentrated in vacuo to yield (3-hydroxy-3-((3-(5-phenylthiazol-2-yl)thioureido)methyl)-1-ammoniobicyclo[2.2.2]octan-1-yl)trihydroborate (0.85 g, 2.19 mmol, 74.4% yield) as a white powder. LC/MS confirmed product with loss of BH3 in the LC/MS conditions: retention time 3.26 (M+1−BH3=375.33).
Reaction SMILES: N(C(OC(C)C)=O)=NC(OC(C)C)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:34][C:35]1[CH:40]=[CH:39][C:38]([CH:41](O)[C:42]2[C:46]([CH2:47][NH:48][S:49]([C:52]3[CH:57]=[CH:56][C:55]([C:58]([F:61])([F:60])[F:59])=[CH:54][CH:53]=3)(=[O:51])=[O:50])=[CH:45][N:44]([CH2:62][O:63][CH3:64])[N:43]=2)=[CH:37][CH:36]=1>C1COCC1>[F:34][C:35]1[CH:40]=[CH:39][C:38]([CH:41]2[C:42]3=[N:43][N:44]([CH2:62][O:63][CH3:64])[CH:45]=[C:46]3[CH2:47][N:48]2[S:49]([C:52]2[CH:57]=[CH:56][C:55]([C:58]([F:61])([F:60])[F:59])=[CH:54][CH:53]=2)(=[O:51])=[O:50])=[CH:37][CH:36]=1
Reactant: COCn1cc(CNS(=O)(=O)c2ccc(C(F)(F)F)cc2)c(C(O)c2ccc(F)cc2)n1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COCn1cc2c(n1)C(c1ccc(F)cc1)N(S(=O)(=O)c1ccc(C(F)(F)F)cc1)C2
Temperature: 25 °C
Reaction time: 16 h
Yield: 74 %

Procedure:
Diisopropyl azodicarboxylate (45 μL, 0.228 mmol) was added dropwise to a stirred solution of triphenylphosphine (60 mg, 0.228 mmol) and N-((3-((4-fluorophenyl)(hydroxy)methyl)-1-(methoxymethyl)-1H-pyrazol-4-yl)methyl)-4-(trifluoromethyl)benzenesulfonamide (45) (90 mg, 0.190 mmol) in THF (5 mL) under nitrogen at 0° C. Reaction was warmed to rt and stirred 16 hr. The reaction was concentrated in vacuo. The resulting crude product was purified via column chromatography using EtOAc/hexane gradients to yield 6-(4-fluorophenyl)-2-(methoxymethyl)-5-(4-(trifluoromethyl)phenylsulfonyl)-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole (46) (64 mg, 71%) as a white solid.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:13][CH2:12][C@@H:11]([O:14][C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[C:21](=[O:25])[NH:20][CH:19]=[CH:18]3)[CH2:10][CH2:9]1)(C)(C)C>ClCCl.FC(F)(F)C(O)=O>[NH2:7][C@@H:8]1[CH2:9][CH2:10][C@H:11]([O:14][C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[C:21](=[O:25])[NH:20][CH:19]=[CH:18]3)[CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](Oc2ccc3c(=O)[nH]ccc3c2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@H]1CC[C@@H](Oc2ccc3c(=O)[nH]ccc3c2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A suspension of 6-Hydroxy-2H-isoquinolin-1-one (0.1 g, 0.62 mmol) and potassium carbonate (0.13 g, 0.93 mmol) in DMF (2.5 ml) was heated to 110° C. and a solution of methanesulfonic acid trans-4-tert-butoxycarbonylaminocyclohexyl ester (0.27 g, 0.93 mmol) in DMF (1.5 ml) was added dropwise. Heating was continued at 110° C. for 16 hours and the solvent removed in vacuo. The residue was taken up in chloroform/isopropanol (3:1) and washed with 1M NaOH. The organics were collected through a hydrophobic frit and concentrated to afford crude product. The residue was purified by prep-H PLC to give cis-[4-(1 -oxo-1,2-dihydroisoquinolin-6-yloxy)cyclohexyl]carbamic acid tert-butyl, EI-MS: m/z=359.1 [M+H]+. A mixture of the above cis-[4-(1-Oxo-1,2-dihydroisoquinolin-6-yloxy)cyclohexyl]carbamic acid tert-butyl ester in dichloromethane (0.9 ml) and trifluoroacetic acid (0.1 ml) was stirred at ambient temperature for 1 hour. The mixture was concentrated in vacuo then purified by ion exchange chromatography to give cis-6-(4-aminocyclohexyloxy)-2H-isoquinolin-1-one ( 3.1 mg), El-MS: m/z=259.1 [M+H]+.
Reaction SMILES: [CH3:1][C:2]([C:6]1[C:11]([C:12]#[C:13][Si](C)(C)C)=[CH:10][CH:9]=[CH:8][N:7]=1)([CH3:5])[C:3]#[N:4].C1COCC1.[OH-].[Na+].Cl>CCOC(C)=O.CCCCCC>[C:12]([C:11]1[C:6]([C:2]([CH3:5])([CH3:1])[C:3]#[N:4])=[N:7][CH:8]=[CH:9][CH:10]=1)#[CH:13]
Reactant: CC(C)(C#N)c1ncccc1C#C[Si](C)(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C#Cc1cccnc1C(C)(C)C#N
Reaction time: 1.5 h
Yield: 82.8 %

Procedure:
To a solution of 2-methyl-2-(3-(2-(trimethylsilyl)ethynyl)pyridin-2-yl)propanenitrile (1.6 g, 6.6 mmol) and THF (20 mL, 244 mmol), was added NaOH (13 mL, 66 mmol). After 1.5 hours, TLC (30% EtOAc/hexane) showed complete reaction to provide a product with a lower spot. The reaction was acidified with 5N HCl (pH=2) and then was extracted with EtOAc. The organic layer was washed with water and brine (3× each) and then dried over MgSO4 and concentrated in vacuo to give a yellow oil. The crude product was purified by silica flash chromatography (0-75% EtOAc/hexane) to give the desired product as a light-orange crystalline solid (0.93 g, 83%). MS (m/z)=171 (M+H)+. Calculated for C11H10N2 170.2.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[N:7]([CH:15]1[CH2:18][NH:17][CH2:16]1)[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[F:27][C:28]1[CH:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=1>ClCCl>[C:1]([O:5][C:6](=[O:19])[N:7]([CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[CH:15]1[CH2:18][N:17]([S:34]([C:31]2[CH:32]=[CH:33][C:28]([F:27])=[CH:29][CH:30]=2)(=[O:36])=[O:35])[CH2:16]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N(Cc1ccccc1)C1CNC1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N(Cc1ccccc1)C1CN(S(=O)(=O)c2ccc(F)cc2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 90.7 %

Procedure:
To a solution of azetidin-3-yl-benzyl-carbamic acid tert-butyl ester (0.20 g, 0.76 mmol) in dichloromethane (2 ml) was added triethylamine (0.15 g, 1.5 mmol) followed by 4-fluorobenzenesulfonyl chloride (0.17 g, 0.84 mmol). The mixture was stirred at room temperature for 18 h. It was then quenched with 50% sodium carbonate solution and the volatiles were evaporated. The residue was diluted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate, and evaporated. The crude material was washed with hexanes to give 0.29 g of a colorless gum; MS (ES) m/z 420.9 (MH+); HRMS (FAB) Calcd. for C21H26FN2O4S (MH+): 421.1597, Found: 421.1633.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([C:13]([O:15]C)=O)=[C:10](/[N:17]=[CH:18]/[N:19]([CH3:21])C)[CH:9]=2)=[CH:4][CH:3]=1.[CH3:22][N:23]1[CH2:28][CH2:27][CH:26]([O:29][C:30]2[CH:35]=[C:34](CN)[CH:33]=[CH:32][N:31]=2)[CH2:25][CH2:24]1.C1(O)C=CC=CC=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:12][C:11]3[C:13](=[O:15])[N:19]([CH2:21][C:34]4[CH:33]=[CH:32][N:31]=[C:30]([O:29][CH:26]5[CH2:27][CH2:28][N:23]([CH3:22])[CH2:24][CH2:25]5)[CH:35]=4)[CH:18]=[N:17][C:10]=3[CH:9]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)c1sc(-c2ccc(Cl)cc2)cc1/N=C/N(C)C
Reactant: CN1CCC(Oc2cc(CN)ccn2)CC1
Solvent: Oc1ccccc1
Product: CN1CCC(Oc2cc(Cn3cnc4cc(-c5ccc(Cl)cc5)sc4c3=O)ccn2)CC1
Temperature: 120 °C

Procedure:
Methyl 5-(4-chlorophenyl)-3-{[(1E)-(dimethylamino)methylene]amino}thiophene-2-carboxylate (0.388 g, 1.20 mmol) and 1-{2-[(1-methylpiperidin-4-yl)oxy]pyridin-4-yl}methanamine (0.242 g, 1.09 mmol, from step b above) were mixed with 1.0 g of phenol and heated to 120° C. for 2 h. The mixture was purified by preparative HPLC (Kromasil C8-50×250 mm, CH3CN/0, 1 M NH4OAc 5/95-50/50 and CH3CN/0, 2% HOAc 5/95-50/50). The product was freeze dried from water. Yield: 0.154 g (27%). 1H NMR (400 MHz, DMSO-d6) δ 8.63 (s, 1H), 8.09 (d, 1H), 7.94 (s, 1H), 7.90 (m, 2H), 7.58 (m, 2H), 6.88 (m, 1H), 6.60 (bs, 1H), 5.20 (s, 2H), 4.95 (m, 1H), 2.60 (m, 2H), 2.15 (s, 3H), 2.12 (m, 2H), 1.92 (m, 2H), 1.62 (m, 2H). 13C NMR (100 MHz, DMSO-d6) δ 163.7, 158.6, 156.8, 150.6, 149.4, 147.9, 135.1, 131.9, 130.0, 128.7, 122.5, 122.4, 116.1, 109.7, 53.4, 48.5, 46.5, 31.3. MS (ESI+) 467/469 (M+1H+).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:12][C:9]3([CH2:11][CH2:10]3)[CH2:8][C:7]([CH3:14])([CH3:13])[C:6]=2[CH:15]=1.C(N(CC)CC)C.[CH3:23][Si:24]([C:27]#[CH:28])([CH3:26])[CH3:25]>[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[CH3:13][C:7]1([CH3:14])[C:6]2[CH:15]=[C:2]([C:28]#[C:27][Si:24]([CH3:26])([CH3:25])[CH3:23])[CH:3]=[CH:4][C:5]=2[O:12][C:9]2([CH2:11][CH2:10]2)[CH2:8]1
Reactant: C#C[Si](C)(C)C
Reactant: CC1(C)CC2(CC2)Oc2ccc(Br)cc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC1(C)CC2(CC2)Oc2ccc(C#C[Si](C)(C)C)cc21

Procedure:
Following general procedure D and using 6-bromo-3,4-dihydro-4,4-dimethylspiro[2H-1-benzopyran-2,1′-cyclopropane] (Intermediate 36, 0.44 g, 1.65 mmol), triethyl amine (4 mL), anhydrous tetrahydrofuran (5 mL), copper(I)iodide (0.95 g, 0.5 mmol), trimethylsilyl acetylene (1.62 g, 16.5 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.4 g, 0.56 mmol), the title compound was obtained as a brown oil (0.4 g, 86%).
Reaction SMILES: [CH:1]1([CH2:4][C:5]([OH:7])=O)[CH2:3][CH2:2]1.C(N(C(C)C)C(C)C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[CH:44]([C:47]1[CH:52]=[CH:51][C:50]([NH:53][C:54]([CH:56]2[CH2:61][CH2:60][NH:59][CH2:58][CH2:57]2)=[O:55])=[CH:49][CH:48]=1)([CH3:46])[CH3:45]>C(#N)C>[CH:44]([C:47]1[CH:48]=[CH:49][C:50]([NH:53][C:54]([CH:56]2[CH2:61][CH2:60][N:59]([C:5](=[O:7])[CH2:4][CH:1]3[CH2:2][CH2:3]3)[CH2:58][CH2:57]2)=[O:55])=[CH:51][CH:52]=1)([CH3:46])[CH3:45]
Reactant: O=C(O)CC1CC1
Reactant: CC(C)c1ccc(NC(=O)C2CCNCC2)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)c1ccc(NC(=O)C2CCN(C(=O)CC3CC3)CC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.3 %

Procedure:
Cyclopropylacetic acid (0.055 g) was dissolved in acetonitrile (6 ml), ethyl-diisopropyl-amine (0.129 g), BOP (0.221 g) was added at RT under an argon atmosphere and the mixture was stirred for 30 minutes at RT. Then piperidine-4-carboxylic acid (4-isopropyl-phenyl)-amide (0.123 g) in acetonitrile (2 ml) was added dropwise at RT and the reaction mixture was stirred for 12 h until completion of the reaction. It was then partitioned between ethyl acetate and aqueous 1M HCl, the layers were separated and the aqueous layer washed with 2M aqueous KHCO3 then dried over Na2SO4. The solvent was evaporated off, the residue purified by flash chromatography (AcOEt/heptane, gradient from 0 to 60%) to give 1-(2-cyclopropyl-acetyl)-piperidine-4-carboxylic acid (4-isopropyl-phenyl)-amide (0.158 g) as an off-white solid. MS (ESI): 329.17 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([CH2:20][CH2:21][N:22]([CH:26]([CH3:28])[CH3:27])[CH:23]([CH3:25])[CH3:24])([CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]1[CH3:19])[C:9]#[N:10].[OH-:29].[Na+]>S(=O)(=O)(O)O.O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([CH2:20][CH2:21][N:22]([CH:23]([CH3:25])[CH3:24])[CH:26]([CH3:28])[CH3:27])([CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]1[CH3:19])[C:9]([NH2:10])=[O:29]
Reactant: [OH-]
Reactant: CC1CCCCN1CCC(C#N)(CCN(C(C)C)C(C)C)c1ccccc1F
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: CC1CCCCN1CCC(CCN(C(C)C)C(C)C)(C(N)=O)c1ccccc1F
Temperature: 0 °C

Procedure:
7 Parts of the preceding acetonitrile is dissolved in a solution of 67 parts by volume of concentrated sulfuric acid and 3 parts by volume of water. The resulting solution is heated on a steam bath for about 2 hours and then cooled to about 0° C. and made alkaline by the addition of diluted sodium hydroxide. The alkaline solution is extracted with ether, the ether extract dried over calcium sulfate, stripped of solvent and the residue crystallized from pentane to afford α-(o-fluorophenyl)-α-[2-(diisopropylamino)ethyl]-α-[2-(2-methyl-1-piperidinyl)ethyl]acetamide, melting at about 90°-91° C. This compound has the following structural formula ##STR30##
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:17])=[C:6]([CH:8]=[N:9][C:10]([O:12][Si](C)(C)C)=[CH2:11])[CH:7]=1.C(OC([N:25]1[C:33]2[C:28](=[CH:29][CH:30]=[C:31]([Cl:34])[CH:32]=2)/[C:27](=[CH:35]/[C:36]2[CH:41]=[C:40]([Cl:42])[CH:39]=[CH:38][C:37]=2[O:43][CH:44]2[CH2:49][CH2:48][N:47]([C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[CH2:46][CH2:45]2)/[C:26]1=[O:57])=O)(C)(C)C>C1(C)C=CC=CC=1>[C:53]([O:52][C:50]([N:47]1[CH2:48][CH2:49][CH:44]([O:43][C:37]2[CH:38]=[CH:39][C:40]([Cl:42])=[CH:41][C:36]=2[CH:35]2[CH2:12][C:10](=[O:11])[NH:9][CH:8]([C:6]3[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=3[CH3:17])[C:27]32[C:28]2[C:33](=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=2)[NH:25][C:26]3=[O:57])[CH2:45][CH2:46]1)=[O:51])([CH3:56])([CH3:54])[CH3:55]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(Cl)cc2/C=C2\C(=O)N(C(=O)OC(C)(C)C)c3cc(Cl)ccc32)CC1
Reactant: C=C(N=Cc1cc(F)ccc1C)O[Si](C)(C)C
Solvent: Cc1ccccc1
Product: Cc1ccc(F)cc1C1NC(=O)CC(c2cc(Cl)ccc2OC2CCN(C(=O)OC(C)(C)C)CC2)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 65 °C
Reaction time: 3 h
Yield: 24.9 %

Procedure:
To a solution of 1-(5-fluoro-2-methyl-phenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene (15 mL, 30 mmol) in toluene (50 mL) was added E/Z-3-[2-(1-tert-Butoxycarbonyl-piperidin-4-yloxy)-5-chloro-benzylidene]-6-chloro-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester (3.6 g, 6 mmol). The reaction mixture was stirred under argon at 65° C. for 3 h and then heated at 130° C. for 4 h. After cooled to room temperature, the mixture was concentrated. The residue was purified by chromatography to give the title compound as a white solid (Yield: 1 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:16](NCC2C=CC(C(OC)=O)=CC=2)=[O:17])[C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)=[N:6][CH:7]=1.[NH2:30][C:31]([C:34]1[CH:43]=[CH:42][C:37]([C:38]([O:40][CH3:41])=[O:39])=[CH:36][CH:35]=1)([CH3:33])[CH3:32]>>[F:1][C:2]1[CH:3]=[C:4]([C:16]([NH:30][C:31]([C:34]2[CH:43]=[CH:42][C:37]([C:38]([O:40][CH3:41])=[O:39])=[CH:36][CH:35]=2)([CH3:32])[CH3:33])=[O:17])[C:5]([O:8][C:9]2[CH:10]=[CH:11][C:12]([F:15])=[CH:13][CH:14]=2)=[N:6][CH:7]=1
Reactant: COC(=O)c1ccc(C(C)(C)N)cc1
Reactant: COC(=O)c1ccc(CNC(=O)c2cc(F)cnc2Oc2ccc(F)cc2)cc1
Product: COC(=O)c1ccc(C(C)(C)NC(=O)c2cc(F)cnc2Oc2ccc(F)cc2)cc1

Procedure:
The title compound was prepared according to the procedure described in step 3 of Example 1 from 5-fluoro-2-(4-fluorophenoxy)nicotinic acid (step 3 of Example 1) and methyl 4-(1-amino-1-methylethyl)benzoate: 1H-NMR (CDCl3) δ 8.33 (1H, br.s), 8.24 (1H, dd, J=8.2, 3.1 Hz), 8.04–7.99 (3H, m), 7.51 (2H, dd, J=6.7, 1.9 Hz), 7.18–7.16 (4H, m), 3.90 (3H, s), 1.80 (6H, s); MS (ESI) m/z 427 (M+H)+, 425 (M−H)−.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10][C:11]2[CH:12]=[C:13]([C:18]3([O:28][CH3:29])[CH2:22][CH2:21][N:20]([CH2:23][C:24]([F:27])([F:26])[F:25])[CH2:19]3)[CH:14]=[C:15]([F:17])[CH:16]=2)=[CH:6][CH:5]=1)(=O)[CH3:2].Cl.[NH2:31][OH:32]>>[F:17][C:15]1[CH:16]=[C:11]([S:10][C:7]2[CH:6]=[CH:5][C:4]([C:1](=[N:31][OH:32])[CH3:2])=[CH:9][CH:8]=2)[CH:12]=[C:13]([C:18]2([O:28][CH3:29])[CH2:22][CH2:21][N:20]([CH2:23][C:24]([F:25])([F:27])[F:26])[CH2:19]2)[CH:14]=1
Reactant: COC1(c2cc(F)cc(Sc3ccc(C(C)=O)cc3)c2)CCN(CC(F)(F)F)C1
Reactant: NO
Agent: Cl
Product: COC1(c2cc(F)cc(Sc3ccc(C(C)=NO)cc3)c2)CCN(CC(F)(F)F)C1
Yield: 81 %

Procedure:
Using an analogous procedure to that described in Example 27, 3-[3-(4-acetylphenylthio)-5-fluorophenyl]-3-methoxy-1-(2,2,2-trifluoroethyl)pyrrolidine was reacted with hydroxylamine hydrochloride to give 3-{5-fluoro-3-[4-(1-hydroxyiminoethyl)phenylthio]phenyl}-3-methoxy-1-(2,2,2-trifluoroethyl)pyrrolidine as a gum in 81% yield.
Reaction SMILES: [S:1]1[CH2:5][C:4](=[O:6])[NH:3][C:2]1=[O:7].C([Li])CCC.[CH3:13][O:14][C:15](=[O:43])[C:16]([C:28]1[CH:33]=[CH:32][C:31]([O:34][C:35]2[CH:40]=[CH:39][C:38]([CH2:41]Br)=[CH:37][CH:36]=2)=[CH:30][CH:29]=1)=[CH:17][C:18]1[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[C:20]([O:26][CH3:27])[CH:19]=1>C1COCC1>[CH3:13][O:14][C:15](=[O:43])[C:16]([C:28]1[CH:33]=[CH:32][C:31]([O:34][C:35]2[CH:40]=[CH:39][C:38]([CH2:41][CH:5]3[S:1][C:2](=[O:7])[NH:3][C:4]3=[O:6])=[CH:37][CH:36]=2)=[CH:30][CH:29]=1)=[CH:17][C:18]1[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[C:20]([O:26][CH3:27])[CH:19]=1
Reactant: O=C1CSC(=O)N1
Reactant: COC(=O)C(=Cc1cc(OC)cc(OC)c1)c1ccc(Oc2ccc(CBr)cc2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COC(=O)C(=Cc1cc(OC)cc(OC)c1)c1ccc(Oc2ccc(CC3SC(=O)NC3=O)cc2)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
2,4-Thiazolidinedione (2.83 g, 24.2 mmol) was dissolved in dry THF (170 mL) and cooled to 0° C. under argon. Butyllithium (1.6 M in hexanes, 30 mL, 48.0 mmol) was added dropwise. Stirring continued for 0.5 h at 0° C. Under argon, 13 (5.7 g, 11.8 mmol) was dissolved in dry THF (30 mL) and was added rapidly via syringe to the above suspension with rapid stirring. The temperature was maintained at 0° C. for 45 min before quenching with aqueous HCl (5%, 40 mL). Additional H2O (40 mL) was added and extracted with ethyl acetate (3×30 mL). Organic layers were combined, washed with brine, dried over anhydrous magnesium sulfate, filtered and the solvent was evaporated. Flash chromatography over silica gel using hexanes-ethyl acetate (3:2) as eluting solvent yielded the title compound, 11, (0.93 g, 15%). The melting point and 1H NMR of compound 11 made by this method were identical to those for compound 11 produced by the synthetic route starting from compound 10 described above.