Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[O:4][C:5]2[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:6]=2[N:7]=1.CCN(C(C)C)C(C)C.[C:24]([N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1)([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25]>C(#N)C.CCOC(C)=O>[N+:12]([C:8]1[C:6]2[N:7]=[C:3]([CH2:2][N:34]3[CH2:33][CH2:32][N:31]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:36][CH2:35]3)[O:4][C:5]=2[CH:11]=[CH:10][CH:9]=1)([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1cccc2oc(CCl)nc12
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCN(Cc2nc3c([N+](=O)[O-])cccc3o2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68 %

Procedure:
To room temperature solution of 2-(Chloromethyl)-4-nitrobenzo[d]oxazole (5.15 g, 24.2 mmol, 1.0 equiv) and DIPEA (4.2 mL, 24.2 mmol, 1.0 equiv) in dry acetonitrile (119 mL) was added N-Boc piperazine as a solid in one portion. The reaction was stirred at room temperature overnight. The mixture was diluted with EtOAc (120 mL), washed with water and brine, dried over sodium sulfate, filtered and concentrated in vacuo. Purification on silica gel (20% EtOAc/80% hexanes—100% EtOAc) provided the title compound as a yellow solid (7.0 g, 68%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[CH:7]=1)[CH3:2].C(N(CC)CC)C.[CH3:30][S:31](Cl)(=[O:33])=[O:32].Cl>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][N:13]([S:31]([CH3:30])(=[O:33])=[O:32])[CH2:14][C:15]2[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=2)[CH:7]=1)[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)Cc1cccc(CNCc2ccc(C)cc2)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)Cc1cccc(CN(Cc2ccc(C)cc2)S(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 67.3 %

Procedure:
To a solution of (3-{[(4-methyl-benzyl)-amino]-methyl}-phenyl)-acetic acid ethyl ester (1 19 mg, 0.401 mmol) and triethylamine (0.61 mL, 0.726 mmol) in CH2Cl2 (2 mL) at 0° C. was added methanesulfonyl chloride (0.031 mL, 0.405 mmol). The reaction was stirred at room temperature for 2.5 h and 1N HCl was added. The product was extracted into CH2Cl2 (3×). The organic solution was dried over MgSO4, filtered, and concentrated in vacuo. The product was purified by medium pressure chromatography (3:1 hexanes:EtOAc) to provide the title compound (101.4 mg). 1H NMR (400 MHz, CDCl3) δ 7.13-7.36 (m, 8H), 4.274.30 (m, 4H), 4.14 (q, 2H), 3.60 (s, 2H), 2.74 (s, 3H), 2.33 (s, 3H); MS 376 (M+1).
Reaction SMILES: CC1(C)[O:9][C:8](=[O:10])[C:5]2([CH2:7][CH2:6]2)[C:4](=[O:11])O1.[F:13][C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][CH:20]=1)[NH2:17]>C(O)C>[F:13][C:14]1[CH:15]=[C:16]([N:17]2[CH2:6][CH2:7][CH:5]([C:8]([OH:9])=[O:10])[C:4]2=[O:11])[CH:18]=[CH:19][CH:20]=1
Reactant: Nc1cccc(F)c1
Reactant: CC1(C)OC(=O)C2(CC2)C(=O)O1
Solvent: CCO
Product: O=C(O)C1CCN(c2cccc(F)c2)C1=O
Yield: 85.3 %

Procedure:
A mixture of 6,6-dimethyl-5,7-dioxaspiro[2.5]octane-4,8-dione (0.500 g; 2.94 mmol) and 3-fluoroaniline (0.847 mL; 8.82 mmol) in ethanol (3 mL) was irradiated in a microwave oven for 3 minutes at 100° C. The mixture was concentrated under reduced pressure and the residue was dissolved in a solution of sodium hydroxide 6N, washed with dichloromethane, acidified with a solution of hydrochloric acid 6N to pH=2, extracted with ethyl acetate dried and concentrated under reduced pressure to yield 0.560 g (85%) of a dark orange solid, which was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]2[NH:6][C:7](=[CH:18][N+:19]([O-])=O)[CH2:8][C:9](=[O:17])[N:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:4]=2[CH:3]=1.[CH2:24](O)[CH3:25]>CN(C)C=O.[Ni]>[Cl:1][C:2]1[CH:23]=[CH:22][C:5]2[N:6]3[C:24]([CH3:25])=[N:19][CH2:18][CH:7]3[CH2:8][C:9](=[O:17])[N:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:4]=2[CH:3]=1
Reactant: O=C1CC(=C[N+](=O)[O-])Nc2ccc(Cl)cc2N1c1ccccc1
Reactant: CCO
Agent: [Ni]
Solvent: CN(C)C=O
Product: CC1=NCC2CC(=O)N(c3ccccc3)c3cc(Cl)ccc3N12
Temperature: 25 °C
Reaction time: 21 h

Procedure:
7-Chloro-5-phenyl-1,2,3,4-tetrahydro-2-nitromethylene-5H-1,5-benzodiazepin-4-one 18.3 g (0.055 mole) was dissolved in 300 ml of dimethylformamide by gentle heating on a steam bath. The solution was cooled to room temperature and 400 ml of ethanol and 55 g of Raney nickel were added. The mixture was hydrogenated at atmospheric pressure for 21 hours. The catalyst was filtered off and washed well with tetrahydrofuran and methylene chloride. The filtrate was evaporated and the residue was dissolved in 325 ml of xylene, and 40 ml of triethyl orthoacetate was added to the solution which was then refluxed for 1 hour. The mixture was evaporated and the residue was crystallized from ethyl acetate to yield end product with mp 248°-251°. The analytical sample was recrystallized from methylene chloride/ethyl acetate to give colorless crystals with mp 250°-252°.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:18]COC)=[C:4]([CH:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH3:17])O)[CH:5]=[CH:6][CH:7]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Cl:1][C:2]1[C:3]([OH:18])=[C:4]([CH2:8][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH3:17])[CH:5]=[CH:6][CH:7]=1
Reactant: COCOc1c(Cl)cccc1C(O)c1ccccc1OC
Agent: CC[SiH](CC)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccccc1Cc1cccc(Cl)c1O

Procedure:
(3-Chloro-2-methoxymethoxyphenyl)(2-methoxyphenyl)methanol (15.27 g, 49 mmol) was combined with 15.97 g (100 mmol) of triethylsilane in 150 ml of methylene chloride and to this was added at ambient temperature with stirring under nitrogen 14.8 g (130 mmol) of trifluoroacetic acid. The mixture was stirred for 4 hours and was then poured into saturated aqueous sodium bicarbonate. Additional methylene chloride was added and the organic phase was recovered, dried over magnesium sulfate, and concentrated by evaporation under reduced pressure. The residue was purified by preparative liquid chromatography eluting with a 1:99 mixture of acetone and hexane to obtain 3.98 g (33 percent of theory) of the title compound. The proton nmr spectrum was consistent with the assigned structure.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][OH:18])=[CH:11][CH:10]=2)[N:5]=[CH:4][N:3]=1.ClC1C=C(Cl)N=CN=1.OCCOC1C=CC(N)=CC=1.[F:38][C:39]1[CH:45]=[CH:44][CH:43]=[CH:42][C:40]=1[NH2:41]>>[F:38][C:39]1[CH:45]=[CH:44][CH:43]=[CH:42][C:40]=1[NH:41][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][OH:18])=[CH:11][CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: OCCOc1ccc(Nc2cc(Cl)ncn2)cc1
Reactant: Nc1ccccc1F
Agent: Clc1cc(Cl)ncn1
Agent: Nc1ccc(OCCO)cc1
Product: OCCOc1ccc(Nc2cc(Nc3ccccc3F)ncn2)cc1
Yield: 24 %

Procedure:
Using an analogous reaction procedure to that described in Example 6, 4-chloro-6-[4'-(2-hydroxyethoxy)anilino]pyrimidine (0.52 g) (prepared from the reaction of 4,6-dichloropyrimidine and 4-(2-hydroxyethoxy)aniline) was reacted with 2-fluoroaniline (1 ml). The reaction product was chromatographed on silica and recrystallised from a mixture of methylene chloride, methanol and hexane to give 4-(2'-fluoroanilino)- 6-[4'-(2-hydroxyethoxy)anilino]pyrimidine in 24% yield, m.p. 163°-166° C.;
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([CH2:35][N:36]([CH:45]=[O:46])[O:37]CC2C=CC=CC=2)[C:8]([N:10]2[C@H:14]([C:15]([NH:17][C:18]3[C:23]([CH3:24])=[CH:22][CH:21]=[CH:20][N:19]=3)=[O:16])[CH2:13][CH2:12][N:11]2C(OCC2C=CC=CC=2)=O)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1>CO.[OH-].[OH-].[Pd+2]>[CH:1]1([CH2:6][C@H:7]([CH2:35][N:36]([CH:45]=[O:46])[OH:37])[C:8]([N:10]2[C@H:14]([C:15]([NH:17][C:18]3[C:23]([CH3:24])=[CH:22][CH:21]=[CH:20][N:19]=3)=[O:16])[CH2:13][CH2:12][NH:11]2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Cc1cccnc1NC(=O)[C@@H]1CCN(C(=O)OCc2ccccc2)N1C(=O)[C@H](CC1CCCC1)CN(C=O)OCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: Cc1cccnc1NC(=O)[C@@H]1CCNN1C(=O)[C@H](CC1CCCC1)CN(O)C=O
Reaction time: 0.25 h
Yield: 36.8 %

Procedure:
To a solution of phenylmethyl (3S)-2-[(2R)-3-cyclopentyl-2-({formyl[(phenylmethyl)oxy]amino}methyl)propanoyl]-3-{[(3-methyl-2-pyridinyl)amino]carbonyl}-1-pyrazolidinecarboxylate (179 mg, 0.285 mmol) in methanol (6 ml) was added 20% palladium hydroxide on carbon (72 mg, 0.285 mmol). The mixture was hydrogenated under balloon pressure for 1 h 15 min and then filtered. The mixture was purified by reverse-phase HPLC to yield (3S)-2-((2R)-3-cyclopentyl-2-{[formyl(hydroxy)amino]methyl}propanoyl)-N-(3-methyl-2-pyridinyl)-3-pyrazolidinecarboxamide (44 mg, 0.105 mmol, 37% yield). LC/MS: (M+H)+: 404.
Reaction SMILES: C([O:8][CH2:9][CH:10]([C:21]1[N:30]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:29](=[O:37])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][C:27]=2[CH3:38])[N:22]=1)[NH:11][C:12]1[N:20]=[CH:19][N:18]=[C:17]2[C:13]=1[N:14]=[CH:15][NH:16]2)C1C=CC=CC=1.C([O-])([O-])=O.[Na+].[Na+]>C(O)C.[OH-].[OH-].[Pd+2]>[OH:8][CH2:9][CH:10]([C:21]1[N:30]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:29](=[O:37])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][C:27]=2[CH3:38])[N:22]=1)[NH:11][C:12]1[N:20]=[CH:19][N:18]=[C:17]2[C:13]=1[N:14]=[CH:15][NH:16]2
Reactant: Cc1cccc2nc(C(COCc3ccccc3)Nc3ncnc4[nH]cnc34)n(-c3ccccc3)c(=O)c12
Agent: [Pd+2]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: Cc1cccc2nc(C(CO)Nc3ncnc4[nH]cnc34)n(-c3ccccc3)c(=O)c12
Reaction time: 336 h

Procedure:
A suspension of compound 28 (60 mg, (0.097 mmol), Pd(OH)2 (cat.), and aqueous Na2CO3 (0.5 mL) in ethanol (2.5 mL) was hydrogenated at 45 psi for 14 days. The mixture was filtered to removed solvents, and the resulting filtrate was purified by HPLC to provide the product 41 as a white solid. MS (ES): m/z 414 (M+H), 396, 261. Compound 41 is shown below.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[C:8]([CH3:10])[C:7]([CH:11]=[CH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[C:6]([CH3:20])[CH:5]=1>C(O)C.C1COCC1.[Pd]>[CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[C:8]([CH3:10])[C:7]([CH2:11][CH2:12][C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])=[C:6]([CH3:20])[CH:5]=1
Reactant: COC(=O)c1cc(C)c(C=CC(=O)OC(C)(C)C)c(C)c1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: COC(=O)c1cc(C)c(CCC(=O)OC(C)(C)C)c(C)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 95.7 %

Procedure:
To a solution of 4-(2-tert-butoxycarbonyl-vinyl)-3,5-dimethyl-benzoic acid methyl ester (11.2 g, 38.6 mmol) in ethanol (50 mL) and THF (50 mL), Pd/C (1.0 g, 10% Pd) is added. The mixture is stirred for 16 h at rt under 2.5 bar of H2. The catalyst is filtered off and the filtrate is concentrated and dried under HV to give 4-(2-tert-butoxycarbonyl-ethyl)-3,5-dimethyl-benzoic acid methyl ester (10.8 g) as a colourless oil; LC-MS: tR=1.08 min.
Reaction SMILES: [I-:1].[Na+].[C:3]([O:7][C:8]([NH:10][C@@H:11]1[C:36](=[O:37])[N:13]2[C:14]([C:20]([O:22][CH:23]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:21])=[C:15]([CH2:18]Cl)[CH2:16][S:17][C@H:12]12)=[O:9])([CH3:6])([CH3:5])[CH3:4].[CH3:38][N:39]1[CH:43]=[CH:42][CH:41]=[N:40]1.O1CCCC1>CC(C)=O.O.C(OCC)(=O)C>[I-:1].[C:3]([O:7][C:8]([NH:10][C@@H:11]1[C:36](=[O:37])[N:13]2[C:14]([C:20]([O:22][CH:23]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:21])=[C:15]([CH2:18][N+:40]3[N:39]([CH3:38])[CH:43]=[CH:42][CH:41]=3)[CH2:16][S:17][C@H:12]12)=[O:9])([CH3:6])([CH3:5])[CH3:4]
Reactant: Cn1cccn1
Reactant: CC(C)(C)OC(=O)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CCl)CS[C@H]12
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: Cn1ccc[n+]1CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC(=O)OC(C)(C)C)[C@H]2SC1
Reaction time: 0.17 h

Procedure:
To a solution of sodium iodide (1.46 g) in acetone (5 ml) was added benzhydryl 7β-tert-butoxycarbonylamino-3-chloromethyl-3-cephem-4-carboxylate (5 g) at ambient temperature. The mixture was stirred at the same temperature for 10 minutes and N-methylpyrazole (5 ml) was added thereto. The resultant mixture was stirred at the same temperature for 24 hours and poured into a mixture of tetrahydrofuran (25 ml), ethyl acetate (25 ml) and water (25 ml). The separated organic layer was washed with brine, and dried over magnesium sulfate. The solution was evaporated in vacuo to give benzhydryl 7β-tert-butoxycarbonylamino-3-(2-methyl-1-pyrazolio)methyl-3-cephem-4-carboxylate iodide (6.45 g), the physical data of which were identical to those of the compound prepared in Preparation 3.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]([N:24]4[CH2:29][CH2:28][CH:27]([NH2:30])[CH2:26][CH2:25]4)=[O:23])=[CH:18][CH:17]=3)[N:10]=2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:38](OC(=O)C)(=[O:40])[CH3:39]>C1COCC1>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]3[CH:17]=[CH:18][C:19]([C:22]([N:24]4[CH2:25][CH2:26][CH:27]([NH:30][C:38](=[O:40])[CH3:39])[CH2:28][CH2:29]4)=[O:23])=[CH:20][CH:21]=3)[N:10]=2)=[CH:5][CH:4]=1
Reactant: NC1CCN(C(=O)c2ccc(Nc3nccc(-c4ccc(Cl)cc4)n3)cc2)CC1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)NC1CCN(C(=O)c2ccc(Nc3nccc(-c4ccc(Cl)cc4)n3)cc2)CC1
Reaction time: 0.67 h
Yield: 45.8 %

Procedure:
Stirred 4-aminopiperidyl 4-{[4-(4-chlorophenyl)pyrimidin-2-yl]amino}phenyl ketone hydrochloride (300 mg, 0.582 mmol) in 10 mL THF with triethylamine (0.293 mg, 2.91 mmol). Acetic anhydride (89 mg, 0.873 mmol) was added and the reaction was stirred for 40 minutes. The solution was concentrated down and purified by preperative HPLC to give N-{1-[(4-{[4-(4-chlorophenyl)pyrimidin-2-yl]amino}phenyl)carbonyl]-4-piperidyl}acetamide (0.120 g, 46% yield): HPLC Retention time; 6.92 min. (Method B) M+1; 450.4
Reaction SMILES: C[O:2][C:3](=O)[C@H:4]([CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[S:18][C:17]3[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=3[C:15]=2[CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH2:32][N:33]3[CH2:37][CH2:36][CH2:35][CH2:34]3)=[CH:26][CH:25]=2)=[CH:10][CH:9]=1)[NH2:5].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[NH2:5][C@H:4]([CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[S:18][C:17]3[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=3[C:15]=2[CH2:23][C:24]2[CH:25]=[CH:26][C:27]([O:30][CH2:31][CH2:32][N:33]3[CH2:34][CH2:35][CH2:36][CH2:37]3)=[CH:28][CH:29]=2)=[CH:12][CH:13]=1)[CH2:3][OH:2]
Reactant: COC(=O)[C@@H](N)COc1ccc(-c2sc3ccccc3c2Cc2ccc(OCCN3CCCC3)cc2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: N[C@@H](CO)COc1ccc(-c2sc3ccccc3c2Cc2ccc(OCCN3CCCC3)cc2)cc1

Procedure:
O-[4-[3-[4-[2-(1-Pyrrolidinyl)ethoxy]benzyl]benzo[b]-thiophen-2-yl]phenyl]-L-serine methyl ester in THF (4 mL) was treated with lithium aluminum hydride (22 mg) at ambient temperature under argon for 5 h. The reaction was quenched with water (0.5 mL) and sodium hydroxide solution (1.0 M, 1 mL) and stirred for 10 more min. before it was concentrated under reduced pressure. The residue was extracted with dichloromethane (20 mL×3) from brine (30 mL). The combined organic layers were dried with sodium sulfate and concentrated under reduced pressure. Chromatography with Et3N:MeOH:EtOAc (5:10:85) followed by NH4OH:MeOH:EtOAc (5:10:85) afforded the product (27 mg).
Reaction SMILES: FC(F)(F)C(O)=O.C([O:12][C:13]([CH:15]1[CH2:19][CH2:18][C:17](=[O:20])[N:16]1[C:21](=[O:30])[C:22](=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:14])(C)(C)C>ClCCl>[O:20]=[C:17]1[N:16]([C:21](=[O:30])[C:22](=[O:29])[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C@H:15]([C:13]([OH:14])=[O:12])[CH2:19][CH2:18]1
Reactant: CC(C)(C)OC(=O)C1CCC(=O)N1C(=O)C(=O)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(C(=O)N1C(=O)CC[C@H]1C(=O)O)c1ccccc1
Reaction time: 2 h
Yield: 99.4 %

Procedure:
Trifluoroacetic acid (40 ml) was added to a solution of 5-oxo-1-(2-oxo-2-phenylacetyl)pyrrolidine-2-carboxylic acid tert-butyl ester (5.00 g) in dichloromethane (40 ml) and the solution was stirred for 2 hours. All volatiles were removed under reduced pressure and the residue triturated with ether:hexane (1:1). The white solid was collected by filtration and washed with hexane to give the sub-title compound (4.09 g).
Reaction SMILES: C[O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[CH:5][CH:4]=1.CNC>>[OH:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[CH:5][CH:4]=1
Reactant: COc1ccc(C=O)cc1
Agent: CNC
Product: O=Cc1ccc(O)cc1
Temperature: 140 °C
Reaction time: 15 h
Yield: 0.8 %

Procedure:
A 100 ml glass autoclave is charged with 8.84 g (65.0 mmol) of 4-methoxybenzaldehyde and 51.2 g (455 mmol) of dimethylamine (40% solution in water). The autoclave is closed and the biphasic reaction mixture is stirred at 140° C. (autogenous pressure 7.5 bar) for 15 h. Excess dimethylamine and water are removed under reduced pressure, methyl tert-butyl ether is added and the mixture is acidified with 30% hydrochloric acid in water. After phase separation and removal of all volatile constituents of the organic phase, 6.5 g (0.53 mmol, 81% yield) of 4-hydroxybenzaldehyde are obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:10][C:11]([C:20]2[CH:25]=[CH:24][C:23]([NH2:26])=[C:22]([NH:27][CH2:28][CH:29]3[CH2:31][CH2:30]3)[CH:21]=2)=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:13]=1.[CH3:32]OC(OC)OC>C(O)(=O)C>[CH:29]1([CH2:28][N:27]2[C:22]3[CH:21]=[C:20]([C:11]4[NH:10][C:9]([C:3]5[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=5[F:1])=[N:13][C:12]=4[C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[CH:25]=[CH:24][C:23]=3[N:26]=[CH:32]2)[CH2:30][CH2:31]1
Reactant: COC(OC)OC
Reactant: Nc1ccc(-c2[nH]c(-c3c(F)cccc3F)nc2-c2ccccc2)cc1NCC1CC1
Solvent: CC(=O)O
Product: Fc1cccc(F)c1-c1nc(-c2ccccc2)c(-c2ccc3ncn(CC4CC4)c3c2)[nH]1
Temperature: 25 °C

Procedure:
Heat a mixture of 2-(2,6-difluorophenyl)-4-phenyl-5-(3-(cyclopropylmethyl)amino-4-aminophenyl)imidazole (0.100 g, 0.24 mmol) and trimethylorthoformate (2 mL) in acetic acid (4 mL) at 120° C. for 1 hour. Cool the reaction mixture to room temperature and concentrate under reduced pressure. Dilute the residue with methanol and pour over an SCX column, eluting sequentially with methanol followed by 2N ammonia in methanol. Combine the basic fractions and concentrate under reduced pressure. Subject the residue to silica gel chromatography, eluting with 95:5 dichloromethane:methanol to provide the title compound as a white solid.
Reaction SMILES: [Br-].[F:2][C:3]([Zn+])([F:5])[F:4].I[C:8]1[N:9]=[C:10]([NH2:26])[C:11]2[N:12]=[CH:13][N:14]([C:24]=2[N:25]=1)[C@@H:15]1[O:23][C@H:20]([CH2:21][OH:22])[C@@H:18]([OH:19])[C@H:16]1[OH:17]>CN(C=O)C.CN(P(N(C)C)(N(C)C)=O)C.[Cu](Br)Br>[F:2][C:3]([F:5])([F:4])[C:8]1[N:9]=[C:10]([NH2:26])[C:11]2[N:12]=[CH:13][N:14]([C:24]=2[N:25]=1)[C@@H:15]1[O:23][C@H:20]([CH2:21][OH:22])[C@@H:18]([OH:19])[C@H:16]1[OH:17]
Reactant: Nc1nc(I)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Reactant: FC(F)(F)[Zn+]
Agent: Br[Cu]Br
Agent: [Br-]
Solvent: CN(C)C=O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: Nc1nc(C(F)(F)F)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 63 %

Procedure:
A solution of trifluoromethylzinc bromide (1.308 g, 6.10 mmol) in DMF (25 mL) and HMPA (10 mL) was added to copper bromide (0.438 g, 3.05 mmol) and the resulting mixture was stirred for 30 min. 2-Iodoadenosine (0.800 g, 2.03 mmol) was added and the solution was warmed at 70° C. for 4 h. The solvents were evaporated and the residue was purified on silica gel with 10% methanol/chloroform to give 2-trifluoromethyladenosine in 63% yield. 2-Trifluoromethyladenosine was converted to IV by using in sequence the following procedures: Procedure A (58% yield), Procedure B (84% yield), Procedure C (51% yield), Procedure D (73% yield), Procedure E (75% yield), and Procedure F (53% yield): mp 173°-175° C.; 13NMR (Me2SO-d6) δ25.7, 31.8, 62.8, 82.1, 84.5, 119.8, 141.1, 148.3, 156.2; 1H NMR (Me2SO-d6) δ2.10 (m, 2 H), 2.40 (m, 2H), 3.51 (m, 2H), 4.13 (m, 1H), 4.88 (m, 1H), 6.25 (m, 1H), 7.85 (br.s, 2H), 8.54 (s, 1H); UV (H2O) λmax 259.5 nm (λ11300); FAB HRMS obsd (M+ +H) 304.0996, calcd for C11H12F3N5O2 304.1021.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][C:8]1([C:18](OCC)=[O:19])[CH2:17][CH2:16][C:11]2([O:15][CH2:14][CH2:13][O:12]2)[CH2:10][CH2:9]1>C(OCC)C>[CH3:7][C:8]1([CH2:18][OH:19])[CH2:17][CH2:16][C:11]2([O:12][CH2:13][CH2:14][O:15]2)[CH2:10][CH2:9]1
Reactant: CCOC(=O)C1(C)CCC2(CC1)OCCO2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CC1(CO)CCC2(CC1)OCCO2
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 99.3 %

Procedure:
Under a nitrogen atmosphere, lithium aluminum hydride (31.2 mmol, 1.25 g, 2.43 eq.) was added to a stirred solution of 3(12.84 mmol, 2.93 g) in anhydrous ethyl ether (275 mL) cooled to 0° C. in an ice bath. The resulting mixture was stirred at room temperature for 1.5 hours. In order to quench remaining lithium aluminum hydride, water (2.48 mL) followed by 40% aqueous sodium hydroxide solution (1.68 mL) and additional water (3.47 mL) were successively added with stirring to the reaction mixture. The insoluble precipitate was then removed by decanting and filtration. The filtrate was dried over magnesium sulfate, filtered, and concentrated in vacuo to give 4 (12.75 mmol, 2.28 g, 99%) as a yellow oil that was used in the next reaction without further purification: 1H NMR (CDCl3) δ 3.94 (4H, s), 3.39 (2H, s), 1.68-1.35 (8H, m), 0.96 (3H, s); 13C NMR (CDCl3) δ 109.3, 71.8, 64.4, 34.5, 31.5, 30.7, 21.3.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[N:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:15]1[CH:16]=[CH:17][CH:18]=[N:19][C:14]=1[CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ncccn2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: c1cnc(C2CCNCC2)nc1

Procedure:
1.5 g of the compound of step 1 of Example 26 was dissolved in 30 ml of methylene chloride, 10 ml of TFA was added, then the resultant mixture was agitated at room temperature for 30 minutes.
Reaction SMILES: N1C=CC=CC=1.[NH2:7][C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[C:10]([Cl:18])[CH:9]=1.[CH3:19][N:20]([CH3:25])[S:21](Cl)(=[O:23])=[O:22]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:19][N:20]([CH3:25])[S:21]([NH:7][C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[C:10]([Cl:18])[CH:9]=1)(=[O:23])=[O:22]
Reactant: CN(C)S(=O)(=O)Cl
Reactant: COC(=O)c1ccc(N)cc1Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1ccc(NS(=O)(=O)N(C)C)cc1Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Pyridine (0.4 mL) was added to a solution of methyl 4-amino-2-chlorobenzoate (0.3 g) in CH2Cl2 (10 mL) at 0° C. under N2. N,N-Dimethylsulfamoyl chloride (0.21 mL) was added and the mixture was stirred at room temperature for 16 hours and refluxed for 5 hours. DMAP (0.4 g) was added and the mixture was stirred for 3 hours. The mixture was diluted with CH2Cl2 (100 mL), washed successively with 1N HCl, brine, satd. NaHCO3 and brine, dried and evaporated. The residue was purified by flash column chromatography (silica gel; eluent: EtOAc/hexane 1:3) to give 0.31 g of methyl 4-(N,N-dimethylsulfamoyl)amino-2-chlorobenzoate. ESMS: m/z 293 (MH+)