Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2([C:22]([O:24][CH3:25])=[O:23])[CH2:14][CH2:13][N:12](CC3C=CC=CC=3)[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[H][H]>[Pd].CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2([C:22]([O:24][CH3:25])=[O:23])[CH2:10][CH2:11][NH:12][CH2:13][CH2:14]2)=[CH:4][CH:3]=1
Reactant: [H][H]
Reactant: COC(=O)C1(Nc2ccc(F)cc2)CCN(Cc2ccccc2)CC1
Agent: [Pd]
Solvent: CO
Product: COC(=O)C1(Nc2ccc(F)cc2)CCNCC1

Procedure:
A mixture of 53 parts of methyl 4-[(4-fluorophenyl)amino]-1-(phenylmethyl)-4-piperidinecarboxylate and 400 parts of methanol is hydrogenated at normal pressure and at room temperature with 10 parts of palladium-charcoal catalyst 10%. After the calculated amount of hydrogen is taken up, the catalyst is filtered off and the filtrate is evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and 15% of methanol, previously saturated with gaseous ammonia, as eluent. The pure fractions are collected and the eluent is evaporated. The oily residue solidifies on scratching in hexane. The product is filtered off and dried, yielding methyl 4-[(4-fluorophenyl)amino]-4-piperidinecarboxylate; mp. 83.7° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[OH:10].C(OC([N:18]1[CH2:23][CH2:22][N:21]([C:24]2[C:25]([O:30][CH2:31][CH2:32]O)=[N:26][CH:27]=[CH:28][N:29]=2)[CH2:20][CH2:19]1)=O)(C)(C)C.N(C(OCC)=O)=NC(OCC)=O>>[N:21]1([C:24]2[C:25]([O:30][CH2:31][CH2:32][O:10][C:3]3[CH:4]=[CH:5][C:6]([O:8][CH3:9])=[CH:7][C:2]=3[Cl:1])=[N:26][CH:27]=[CH:28][N:29]=2)[CH2:22][CH2:23][NH:18][CH2:19][CH2:20]1
Reactant: COc1ccc(O)c(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nccnc2OCCO)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Product: COc1ccc(OCCOc2nccnc2N2CCNCC2)c(Cl)c1

Procedure:
The title compound was prepared starting from 2-chloro-4-methoxyphenol (103 mg, 0.65 mmol) and 2-[3-(4-tert-butoxycarbonyl-1-piperazinyl)-2-pyrazinyloxy]ethanol (0.61 mmol; prepared in Example 52, Step 2) according to the procedure described in Example 52, Step 3, but utilizing diethyl azodicarboxylate (DEAD) instead of TMAD. Yield 50 mg (21%) HRMS m/z calcd for C17H21CIN4O3(M)+364.1302, found 364.1307.
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:50])[N:13]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][N:29]([CH:43]3[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]3)[C:30]([NH:32][C:33]3[CH:38]=[CH:37][C:36]([O:39]C(=O)C)=[CH:35][CH:34]=3)=[O:31])[CH:23]=2)[CH:14]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:7][CH:6]=1)(=O)C.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[CH:14]1([N:13]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][N:29]([CH:43]3[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49]3)[C:30]([NH:32][C:33]3[CH:34]=[CH:35][C:36]([OH:39])=[CH:37][CH:38]=3)=[O:31])[CH:23]=2)[C:12]([NH:11][C:8]2[CH:9]=[CH:10][C:5]([OH:4])=[CH:6][CH:7]=2)=[O:50])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]1
Reactant: CC(=O)Oc1ccc(NC(=O)N(Cc2cccc(CN(C(=O)Nc3ccc(OC(C)=O)cc3)C3CCCCCC3)c2)C2CCCCCC2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: O=C(Nc1ccc(O)cc1)N(Cc1cccc(CN(C(=O)Nc2ccc(O)cc2)C2CCCCCC2)c1)C1CCCCCC1
Yield: 57 %

Procedure:
A mixture of 2 g 1,3-bis[[3-(p-acetoxyphenyl)-1-cycloheptylureido]methyl]benzene (compound of Example 42), 30 ml ethanol and 30 ml of 5% aqueous sodium carbonate solution was heated under reflux for ten minutes. After distilling off the ethanol under reduced pressure, water was added to the residue, and the resulting mixture was acidified by addition of concentrated hydrochloric acid under ice cooling. The solid which separated out was collected by filtration and recrystallized from methanol, giving 1 g of 1,3-bis[[1-cycloheptyl-3-(p-hydroxyphenyl)ureido]methyl]benzene.
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([N:10]1[CH2:15][CH2:14][C:13]([C:17]#[CH:18])([OH:16])[CH2:12][CH2:11]1)(=[O:9])[CH3:8].[F:19][C:20]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:21]=1[CH2:22]Cl>CN(C=O)C>[C:7]([N:10]1[CH2:15][CH2:14][C:13]([C:17]#[CH:18])([O:16][CH2:22][C:21]2[CH:24]=[C:25]([F:28])[CH:26]=[CH:27][C:20]=2[F:19])[CH2:12][CH2:11]1)(=[O:9])[CH3:8]
Reactant: C#CC1(O)CCN(C(C)=O)CC1
Reactant: Fc1ccc(F)c(CCl)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C#CC1(OCc2cc(F)ccc2F)CCN(C(C)=O)CC1
Temperature: 10 °C
Reaction time: 0.25 h
Yield: 59.8 %

Procedure:
A solution of 7.04 g of potassium t-butoxide (62.9 mmole) in 20 ml of dry DMF was added dropwise to a chilled solution of 10 g of 1-acetyl-4-ethynyl-4-hydroxypiperidine (59.9 mmole) in 75 ml of dry DMF, at such a rate as to maintain the temperature at 10° C. The mixture was allowed to equilibrate at 10° C. for 15 min. after which time it was cooled to -20° C. To this solution was added 9.73 g of 2,5-difluorobenzylchloride (59.9 mmole) at such a rate as to maintain the temperature around -20° C. After complete addition, the reaction mixture was warmed to 0° C. and allowed to react for 1 hr. The reaction appeared to be complete by GLC and was quenched with ice and water. The products were extracted into ether and dried over K2CO3. After filtration, the solvent was removed under vacuum. The crystalline product was recrystallized from cyclohexane and dried, affording 10.5 g of 1-acetyl-4-ethynyl-4-(2,5-difluorophenylmethoxy)piperidine (35.8 mmole, 59.83%). This material appeared pure by GLC (99% on OV225, temperature program: 200° C. (2 min), rate=25° C./min, 250° C. (15 min), flow=30 ml/min tR =4.00 min) and by TLC on silica gel in hexane:ethylacetate (1:1), Rf =0.2. MS (ci MH+ =294).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[CH:11]([CH3:16])[C:12]([O:14]C)=[O:13].[OH-].[Na+].[CH3:19]O>>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[C:11]([CH3:16])([CH3:19])[C:12]([OH:14])=[O:13]
Reactant: CO
Reactant: COC(=O)C(C)n1ccc2c(F)cccc21
Agent: [Na+]
Agent: [OH-]
Product: CC(C)(C(=O)O)n1ccc2c(F)cccc21
Temperature: 75 °C
Yield: 84 %

Procedure:
A mixture of 1-Methyl 2-(4-fluoro-1H-indol-1-yl)propanoate (21.3 g, 91 mmol), 1 N aq. NaOH (150 mL), and methanol (150 mL) was heated to 75° C. overnight. The volatiles were removed by evaporation under reduced pressure at 50° C. and ethyl acetate (250 mL) and water (200 mL) were added to the residue. The layers were separated and the aqueous layer was acidified with concentrated HCl to pH<1. The acidified layer was extracted with ethyl acetate (1×200 mL, 1×50 mL) and the combined extracts were washed with brine (100 mL), dried over sodium sulfate, filtered, and evaporated to dryness under reduced pressure at 50° C. to obtain the desired acid as a yellow oil (16.8 g, 76 mmol, 84% yield). 1H-NMR (300 MHz, CDCl3): δ 7.12-6.99 (m, 2H), 6.83-6.77 (m, 2H), 6.63-6.62 (m 1H), 1.92 (s, 6H).
Reaction SMILES: [CH:1]1([N:7]([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[C:8](Cl)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:17][C:18]1[CH:19]=[C:20]([CH:26]=[CH:27][CH:28]=1)[CH2:21][NH:22][C:23]([NH2:25])=[O:24]>>[CH:1]1([N:7]([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[C:8]([NH:25][C:23]([NH:22][CH2:21][C:20]2[CH:26]=[CH:27][CH:28]=[C:18]([Cl:17])[CH:19]=2)=[O:24])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC(=O)NCc1cccc(Cl)c1
Reactant: O=C(Cl)N(C1CCCCC1)C1CCCCC1
Product: O=C(NCc1cccc(Cl)c1)NC(=O)N(C1CCCCC1)C1CCCCC1

Procedure:
Prepared as described in General Procedure 1 using dicyclohexyl carbamoyl chloride and 3-chlorobenzyl urea.
Reaction SMILES: [C:1]([OH:11])(=O)[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.CN(C=O)C.C(Cl)(C([Cl:21])=O)=O>C(Cl)Cl>[C:4]1([CH2:3][CH2:2][C:1]([Cl:21])=[O:11])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C(O)CCc1ccccc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)CCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 105.1 %

Procedure:
A 200 mL flask fitted with a stir-bar and septum with an Ar inlet was charged with hydrocinnamic acid (5.00 g, 33.3 mmol), DMF (0.1 mL), and CH2Cl2 (30 mL). To the resultant solution was added (COCl)2 (2M in CH2Cl2, 20.0 mL, 40.0 mmol) over 30 min. The mixture stirred overnight at rt, and then was concentrated in vacuo to give 5.9 g of 74 as a yellow oil (100%). HPLC analysis (15:10:75 H2O:A1:MeOH) showed a purity of 99% with a retention time of 5.3 min.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([CH2:11]O)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[I-:24].[Na+]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[I:24][CH2:11][CH:8]1[CH2:9][CH2:10][C:5]2([O:4][CH2:3][CH2:2][O:1]2)[CH2:6][CH2:7]1
Reactant: OCC1CCC2(CC1)OCCO2
Reactant: [I-]
Agent: CN(C)c1ccncc1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Na+]
Solvent: ClCCl
Product: ICC1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.5 %

Procedure:
A solution of (1,4-dioxa-spiro[4.5]dec-8-yl)-methanol (1.60 g, 9.29 mmol) in methylene chloride (50 mL) was treated with 4-(dimethylamino)pyridine (1.26 g, 10.22 mmol) and p-toluenesulfonyl chloride (1.86 g, 9.75 mmol). The reaction mixture was stirred at 25° C. for 2 h, and was then washed with a saturated aqueous sodium bicarbonate solution (1×25 mL). The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting oil was dissolved in acetone (30 mL) and treated with sodium iodide (4.73 g, 31.53 mmol). The reaction was heated under reflux for 2 h, cooled to 25° C., and then concentrated in vacuo. The resulting residue was suspended in ethyl acetate (50 mL), washed with water (2×15 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 19/1 hexanes/ethyl acetate) afforded 8-iodomethyl-1,4-dioxa-spiro[4.5]decane (2.32 g, 88.6%) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9](=[O:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[C:4]([C:17]2[C:25]3[C:20](=[N:21][CH:22]=[CH:23][N:24]=3)[N:19](S(C3C=CC=CC=3)(=O)=O)[CH:18]=2)[CH:3]=1.[OH-].[Na+].CO>O1CCOCC1>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9](=[O:16])[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:5]=[C:4]([C:17]2[C:25]3[C:20](=[N:21][CH:22]=[CH:23][N:24]=3)[NH:19][CH:18]=2)[CH:3]=1
Reactant: O=C(Nc1cc(-c2cn(S(=O)(=O)c3ccccc3)c3nccnc23)cc(Cl)n1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Product: O=C(Nc1cc(-c2c[nH]c3nccnc23)cc(Cl)n1)c1ccccc1
Yield: 48.8 %

Procedure:
A mixture of EXAMPLE 17A (40.0 mg, 0.082 mmol) and 20% sodium hydroxide (0.1 mL) in dioxane (1.5 mL) was heated at 50° C. for 2 h. The mixture was concentrated and the residue treated with water, sonicated, filtered, and washed with water. The solids were dissolved in 6 mL hot 1:1 dimethylsulfoxide/methanol. After cooling, a precipitate formed and additional methanol was added. The solids were filtered, washed with methanol, and dried to give 14.0 mg (32%) of the title compound. 1H NMR (300 MHz, DMSO-D6) 7.41-7.67 (m, 3H), 7.95-8.16 (m, 3H), 8.39 (d, J=2.4 Hz, 1H), 8.60 (d, J=2.8 Hz, 1H), 8.77 (s, 1H), 9.08 (d, J=1.2 Hz, 1H), 10.98 (s, 1H), 12.74 (s, 1H). MS (ESI) m/z 350.5 (M+H)+.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([C@H:7]([NH2:11])[C:8]([OH:10])=[O:9])=[CH:3][CH:2]=1.[N+:12]([O-])([OH:14])=[O:13].[OH-].[Na+]>S(=O)(=O)(O)O.O>[NH2:11][C@@H:7]([C:4]1[CH:3]=[CH:2][CH:1]=[C:6]([N+:12]([O-:14])=[O:13])[CH:5]=1)[C:8]([OH:10])=[O:9]
Reactant: O=[N+]([O-])O
Reactant: N[C@H](C(=O)O)c1ccccc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: N[C@H](C(=O)O)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of L-phenylglycine (10 g) in 40 mL of conc. sulfuric acid was cooled in an ice water/acetone bath. 90% Nitric acid (3.72 mL) was added dropwise over a 30 minute period at such a rate as to keep the internal temperature below 10° C. After addition was complete, stirring was continued for 1 hour at 0° C. and then the reaction mixture was allowed to warm to room temperature over 1.5 hours. The reaction mixture was poured onto 200 g of crushed ice and the resulting mixture was neutralized with sodium hydroxide to pH 7. The reaction mixture was diluted with 600 mL of water, Celite was added and the resulting suspension was filtered and concentrated to give the crude product D contaminated with sodium sulfate. This material was taken to the next step without further purification.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:23][CH:24]1[C:51](=[O:52])[N:26]2[CH:27]([C:41]([O:43][CH2:44][C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)=[O:42])[C:28]3([S:40][C@H:25]12)[CH2:33][CH2:32][N:31]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:30][CH2:29]3.C(N(CC)CC)C.[C:60]1([CH2:66][C:67](Cl)=[O:68])[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1>ClCCl>[C:34]1([N:31]2[CH2:32][CH2:33][C:28]3([CH:27]([C:41]([O:43][CH2:44][C:45]4[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=4)=[O:42])[N:26]4[C:51](=[O:52])[CH:24]([NH:23][C:67](=[O:68])[CH2:66][C:60]5[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=5)[C@H:25]4[S:40]3)[CH2:29][CH2:30]2)[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: NC1C(=O)N2C(C(=O)OCc3ccccc3)C3(CCN(c4ccccc4)CC3)S[C@H]12
Reactant: O=C(Cl)Cc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Cc1ccccc1)NC1C(=O)N2C(C(=O)OCc3ccccc3)C3(CCN(c4ccccc4)CC3)S[C@H]12
Temperature: 15 °C
Reaction time: 3 h
Yield: 87.7 %

Procedure:
To a suspension of 1.53 g (0.002 mole) of benzyl 6-amino-1'-phenyl-spiro[penam-2,4'-piperidine]-3-carboxylate di-p-toluenesulfonate (prepared according to the method described in Example 1.8.3. of our Application Ser. No. 06/162,616, filed June 24, 1980) in 100 ml of anhydrous dichloromethane is added all at once 404 mg (0.004 mole) of triethylamine in 10 ml of dichloromethane. The solution is cooled to a temperature of from 0° to -5° C. and then there are simultaneously added dropwise a solution of 340 mg (0.022 mole) of phenylacetyl chloride in 30 ml of dichloroemethane and a solution of 220 mg (0.022 mole) of triethylamine in 30 ml of dichloromethane, the addition taking place over the course of about 1 hour. Thereafter, the reaction mixture is stirred for 3 hours at 15° C., then successively washed with water, with a saturated aqueous solution of sodium hydrogen carbonate and again with water. After evaporating the solution to dryness and recrystallizing the residue from ethyl acetate/hexane (1:3 v/v), there are obtained 950 mg of benzyl 1'-phenyl-6-(2-phenylacetamido)-spiro[penam-2,4'-piperidine]-3-carboxylate. Yield: 88%; M.P. 120°-121° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]([OH:16])=O)[CH:11]=[CH:10][C:9]=2[CH:17]2[CH2:19][CH2:18]2)[CH:5]=[CH:6][CH:7]=1.[NH2:20][C:21]([CH2:28][CH3:29])([CH2:26][CH3:27])[C:22]([NH:24][CH3:25])=[O:23]>>[CH2:26]([C:21]([NH:20][C:14]([C:12]1[CH:11]=[CH:10][C:9]([CH:17]2[CH2:19][CH2:18]2)=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[N:13]=1)=[O:16])([C:22](=[O:23])[NH:24][CH3:25])[CH2:28][CH3:29])[CH3:27]
Reactant: CCC(N)(CC)C(=O)NC
Reactant: O=C(O)c1ccc(C2CC2)c(-c2cccc(Cl)c2)n1
Product: CCC(CC)(NC(=O)c1ccc(C2CC2)c(-c2cccc(Cl)c2)n1)C(=O)NC

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-(3-chloro-phenyl)-5-cyclopropyl-pyridine-2-carboxylic acid (Example 48 e) and 2-amino-2-ethyl-N-methyl-butyramide (Example 70 b) as starting materials, MS (EI): m/e=400.2 [M+H]+.
Reaction SMILES: I/[CH:2]=[CH:3]/[CH:4]([O:10][C:11]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].C1(C)C=CC=CC=1.C([Li:44])CCC>CCCCCC>[CH2:24]([C:11]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[O:10][CH:4]([CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])/[CH:3]=[CH:2]/[Li:44])[C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=1
Reactant: [Li]CCCC
Reactant: CCCCCC(/C=C/I)OC(Cc1ccc(OC)cc1)(c1ccccc1)c1ccccc1
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: [Li]/C=C/C(CCCCC)OC(Cc1ccc(OC)cc1)(c1ccccc1)c1ccccc1
Temperature: -40 °C

Procedure:
To a solution of 5.26 g. of 1-iodo-3-(p-anisyldiphenylmethoxy)-trans-1-octene (Example 956) in 10 ml. of toluene, cooled to -78° C., is added under an inert atmosphere 1 molar equivalent of n-butyllithium dissolved in hexane. The reaction mixture is allowed to warm to -40° C. and is maintained at that temperature for 1 hour to yield a hydrocarbon solution of 3-(p-anisyldiphenylmethoxy)-trans-1-octenyllithium.
Reaction SMILES: CO.Cl.[CH3:4][O:5][N:6]=[C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH2:18][O:19]C1CCCCO1)[C:8]([NH:10][CH3:11])=[O:9]>[Cl-].[Na+].O>[OH:19][CH2:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C:7](=[N:6][O:5][CH3:4])[C:8]([NH:10][CH3:11])=[O:9]
Reactant: CNC(=O)C(=NOC)c1ccccc1COC1CCCCO1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CNC(=O)C(=NOC)c1ccccc1CO
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.5 %

Procedure:
Methanol (2 ml) and a 36% aqueous hydrochloric acid solution (0.01 g, 0.0001 mol) were added to an E/Z mixture of 2-methoxyimino-N-methyl-2-[2-(2-tetrahydropyranyloxymethyl)phenyl]acetamide (0.31 g, 0.001 mol), and the mixture was stirred at room temperature for 30 minutes. After completion of the reaction, half-saturated brine (80 ml) was added, and the mixture was extracted with dichloromethane (50 ml) twice. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (ethyl acetate/n-hexane) to obtain 2-(2-hydroxymethylphenyl)-2-methoxyimino-N-methylacetamide (0.21 g, Yield: 94.6%, E/Z=97/3) as colorless crystals.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C:13]([CH2:16][OH:17])([CH2:14][OH:15])[O:12][C@@H:11]([N:18]2[CH:26]=[C:24]([CH3:25])[C:22](=[O:23])[NH:21][C:19]2=[O:20])[C@@H:10]1[OH:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH3:34][O:35][C:36]1[CH:57]=[CH:56][C:39]([C:40](Cl)([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[C:41]2[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=2)=[CH:38][CH:37]=1>O1CCCC1.[N+]([O-])([O-])=O.[Ag+]>[CH2:1]([O:8][C@H:9]1[C@@:13]([CH2:14][O:15][C:40]([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)([C:41]2[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=2)[C:39]2[CH:38]=[CH:37][C:36]([O:35][CH3:34])=[CH:57][CH:56]=2)([CH2:16][OH:17])[O:12][C@@H:11]([N:18]2[CH:26]=[C:24]([CH3:25])[C:22](=[O:23])[NH:21][C:19]2=[O:20])[C@@H:10]1[OH:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: Cc1cn([C@@H]2OC(CO)(CO)[C@H](OCc3ccccc3)[C@H]2O)c(=O)[nH]c1=O
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: COc1ccc(C(OC[C@]2(CO)O[C@@H](n3cc(C)c(=O)[nH]c3=O)[C@H](O)[C@H]2OCc2ccccc2)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 32.4 %

Procedure:
To a solution of nucleoside 1-(3-O-Benzyl-4-C-hydroxymethyl-β-D-xylofuranosyl)thymine 5 (5.38 g, 14.2 mmol) in anhydrous tetrahydrofuran (400 cm3) was added AgNO3 (2.66 g, 15.7 mmol) followed by anhydrous pyridine (5.7 cm3) and 4,4′-dimethoxytrityl chloride (5.30 g, 15.6 mmol). The mixture was stirred in the dark under nitrogen for 18 h at room temperature. The reaction was quenched by addition of a saturated aqueous solution of sodium hydrogen carbonate (10 cm3) and the resulting mixture was extracted with dichloromethane. The combined organic phase was evaporated to dryness under reduced pressure and the residue was co-evaporated with toluene and was purified by silica gel column chromatography using dichloromethane/methanol/pyridine (0.5% methanol; 0.5% pyridine, v/v) as eluent to afford nucleoside 6 (3.13 g, 31%) as a white foam after evaporation of the solvents. δC ((CD3)2SO) 164.1 (C-4), 158.4, 145.1, 138.5, 137.0, 135.9, 135.7, 130.1, 130.1, 129.2, 128.5, 128.5, 128.2, 128.1, 127.7, 127.6, 127.0, 125.7, 113.5 (DMT, benzyl, C-6), 151.4 (C-2), 110.1 (C-5), 85.8, 85.2, 84.6, 83.5 (C-1′, C-3′, C-4′, DMT), 76.8 (C-2′), 72.3 (CH2Ph), 65.2 (C-5″), 62.1 (C-5′), 55.4 (2× CH3O), 12.6 (5-CH3).
Reaction SMILES: [N:1]([C:4]1[N:9]=[CH:8][N:7]=[C:6]([O:10][C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[N:17]=[CH:16][CH:15]=[CH:14]3)[CH:5]=1)=[N+]=[N-]>C1COCC1.C(O)(=O)C.[Pd]>[NH2:1][C:4]1[N:9]=[CH:8][N:7]=[C:6]([O:10][C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[NH:17][CH2:16][CH2:15][CH2:14]3)[CH:5]=1
Reactant: [N-]=[N+]=Nc1cc(Oc2ccc3ncccc3c2)ncn1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: Nc1cc(Oc2ccc3c(c2)CCCN3)ncn1

Procedure:
The crude 6-azido-4-(quinolin-6-yloxy)-pyrimidine (36.4 mMol) in 324 ml of THF/acetic acid 4:1 is hydrogenated in the presence of 6 g Pd/C (10% Engelhard 4505). Then the catalyst is filtered off and the filtrate concentrated in vacuuo. The residue is put to pH 10 by addition of sat. Na2CO3 solution and extracted 3× with EtOAC. The organic phases are washed with water and brine, dried (Na2SO4) and after addition of 40 g of SiO2 concentrate in vacuo. The resulting powder is put on top of a SiO2 chromatography column and the title compound eluated with EtOAc: MS: [M+1]+=243.
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:6][CH:5]=1)=[C:2]=[O:3].[NH2:17][CH2:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][CH:24]([C:27]2[CH:28]=[C:29]([NH:33][C:34](=[O:38])[CH:35]([CH3:37])[CH3:36])[CH:30]=[CH:31][CH:32]=2)[CH2:23][CH2:22]1>>[CH3:36][CH:35]([CH3:37])[C:34]([NH:33][C:29]1[CH:30]=[CH:31][CH:32]=[C:27]([CH:24]2[CH2:23][CH2:22][N:21]([CH2:20][CH2:19][CH2:18][NH:17][C:2]([NH:1][C:4]3[CH:9]=[CH:8][C:7]([O:10][C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=4)=[CH:6][CH:5]=3)=[O:3])[CH2:26][CH2:25]2)[CH:28]=1)=[O:38]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Reactant: O=C=Nc1ccc(Oc2ccccc2)cc1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCNC(=O)Nc3ccc(Oc4ccccc4)cc3)CC2)c1

Procedure:
Prepared by Procedure P and Scheme AM using 1-isocyanato-4-phenoxybenzene and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}-2-methylpropanamide: ESMS m/e: 515.5 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:7]2[N:8]=[CH:9][C:10]([O:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=3)=[CH:11][C:6]=2[C:5](=[O:23])[N:4]([CH2:24][CH2:25][CH2:26][O:27][CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][O:29]2)[C:3]1=[O:34].[Li+].CC([N-]C(C)C)C.[F:43][C:44]([F:54])([F:53])[C:45]1[CH:52]=[CH:51][C:48]([CH:49]=[O:50])=[CH:47][CH:46]=1>C1COCC1>[OH:50][CH:49]([C:48]1[CH:47]=[CH:46][C:45]([C:44]([F:43])([F:53])[F:54])=[CH:52][CH:51]=1)[C:11]1[C:6]2[C:5](=[O:23])[N:4]([CH2:24][CH2:25][CH2:26][O:27][CH:28]3[CH2:33][CH2:32][CH2:31][CH2:30][O:29]3)[C:3](=[O:34])[N:2]([CH3:1])[C:7]=2[N:8]=[CH:9][C:10]=1[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:20])([F:21])[F:22])[CH:14]=1
Reactant: Cn1c(=O)n(CCCOC2CCCCO2)c(=O)c2cc(Oc3cccc(C(F)(F)F)c3)cnc21
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cn1c(=O)n(CCCOC2CCCCO2)c(=O)c2c(C(O)c3ccc(C(F)(F)F)cc3)c(Oc3cccc(C(F)(F)F)c3)cnc21
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 69.9 %

Procedure:
To a solution of 1-methyl-3-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-6-(3-(trifluoromethyl) phenoxy)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (210 mg, 0.438 mmol) in THF (5 mL) at −78° C. was added LDA (1.8 M in THF, 1.2 mL, 2.16 mmol). The reaction was stirred at −78° C. for 30 min then 4-(trifluoromethyl)benzaldehyde (153 mg, 0.879 mmol) was added. The reaction was stirred for 1 h, quenched with aq. NaHCO3 (5 mL) then diluted with EA (10 mL) and water (10 mL). The organic layer was dried over Na2SO4 and concentrated to a residue which was purified by Prep TLC eluted with PE/EA (4:1) to give 5-(hydroxy(4-(trifluoromethyl)phenyl)methyl)-1-methyl-3-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-6-(3-(trifluoromethyl)phenoxy)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (200 mg, 69.9% yield) as a clear oil. LCMS: [MH+-THP] 570 and TR=1.933 min.