Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1([CH:13]2[CH2:18][N:17]([S:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[N+:28]([O-:30])=[O:29])(=[O:21])=[O:20])[CH2:16][CH2:15][NH:14]2)[CH2:5][N:4](C(OC(C)(C)C)=O)[CH2:3]1.Cl.O1CCOCC1>CO>[N+:28]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[S:19]([N:17]1[CH2:16][CH2:15][NH:14][CH:13]([C:2]2([OH:1])[CH2:5][NH:4][CH2:3]2)[CH2:18]1)(=[O:21])=[O:20])([O-:30])=[O:29]
Reactant: CC(C)(C)OC(=O)N1CC(O)(C2CN(S(=O)(=O)c3ccccc3[N+](=O)[O-])CCN2)C1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: O=[N+]([O-])c1ccccc1S(=O)(=O)N1CCNC(C2(O)CNC2)C1
Temperature: 60 °C

Procedure:
To a solution of 1,1-dimethylethyl 3-hydroxy-3-{4-[(2-nitrophenyl)sulfonyl]piperazin-2-yl}azetidine-1-carboxylate (308 mg, 0.70 mmol) in methanol (10 mL) was added HCl in dioxane (4 N, 1.75 mL, 7.0 mmol), and the mixture was heated to 60° C. for 30 minutes. The solution was concentrated to provide 3-{4-[(2-nitrophenyl)sulfonyl]piperazin-2-yl}azetidin-3-ol as a sticky white solid. This material was dissolved in dichloromethane (7 mL). To the solution was added N,N-diisopropylethylamine (1.16 mL, 7.0 mmol) followed by 3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]benzoyl fluoride (277 mg, 0.7 mmol), prepared using procedures similar to those described in Reference 1, and the resulting mixture was stirred at room temperature for 16 hours. The solution was concentrated and the residue was purified by column chromatography (95% dichloromethane:5% methanol) to provide 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-{4-[(2-nitrophenyl)sulfonyl]piperazin-2-yl}azetidin-3-ol as a pale yellow foam (453 mg, 0.63 mmol, 90% yield). 1H NMR. (400 MHz, CDCl3): 8.49 (s, 1H), 7.96 (dd, 1H), 7.71 (m, 2H), 7.53 (dd, 1H), 7.39 (dd, 1H), 7.33 (d, 1H), 7.15 (m, 1H), 6.84 (br s, 1H), 6.62 (m, 1H), 4.29-3.97 (br m, 4H), 3.79-3.62 (m, 3H), 3.26-2.99 (br m, 3H), 2.92-2.62 (br m, 3H); MS (EI) for C26H23F3IN5O6S: 718 (MH+).
Reaction SMILES: [Li]CCCC.[NH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][N:8]=1.[Si:14]([O:21][CH:22]([CH2:28][CH2:29][CH2:30][CH3:31])[C:23](OCC)=[O:24])([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15].O>C1COCC1.CCOC(C)=O>[Si:14]([O:21][CH:22]([CH2:28][CH2:29][CH2:30][CH3:31])[C:23]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][N:8]=1)=[O:24])([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:15])[CH3:16]
Reactant: Cc1ccc(N)nc1
Reactant: CCCCC(O[Si](C)(C)C(C)(C)C)C(=O)OCC
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CCCCC(O[Si](C)(C)C(C)(C)C)C(=O)Nc1ccc(C)cn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 22.1 %

Procedure:
n-BuLi (2.25 mL, 1.6 M in hexanes, 3.60 mmol) was added slowly to a stirred solution of 2-amino-5-picoline (390 mg, 3.60 mmol) in anhydrous THF (6 mL). The reaction mixture was kept at ambient temperature for 10 minutes before it was added to a solution of ethyl 2-{[tert-butyl(dimethyl)silyl]oxy}hexanoate (Step 1) (820 mg, 3.00 mmol) in anhydrous THF (4 mL). The reaction mixture was stirred at ambient temperature for 1 h. Water and EtOAc were added and the two phases were separated. The organic phase was washed with water, dried over MgSO4 and concentrated in vacuo. The residue was purified with column chromatography (silica gel, eluting with a gradient consisting of 0-100% EtOAc in heptane) to give the title compound as a colourless oil (223 mg), 1H NMR (300 MHz, CDCl3) δ 8.87 (br s, 1H), 8.13 (m, 2H), 7.51 (dd, 1H), 4.25 (t, 1H), 2.29 (s, 3H), 1.79 (m, 2H), 1.35 (m, 4H), 0.98 (s, 8H), 0.89 (t, 3H), 0.14 (d, 6H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[CH:10]=2)[N:5]=[CH:4][N:3]=1.[CH2:19]([NH2:22])[CH2:20][CH3:21]>>[CH2:19]([NH:22][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[CH:10]=2)[N:5]=[CH:4][N:3]=1)[CH2:20][CH3:21]
Reactant: CCCN
Reactant: Fc1ccc(-c2ccc3ncnc(Cl)c3c2)cc1
Product: CCCNc1ncnc2ccc(-c3ccc(F)cc3)cc12
Yield: 83 %

Procedure:
This compound was synthesized from 4-chloro-6-(4-fluorophenyl)-quinazoline and n-propylamine in 83% yield, using the procedure described for example 37, and was characterized by its mass spectrum as follows: MS (m/z): 282 ([M+H]+, 100).
Reaction SMILES: Br[C:2]1[C:10]2[N:9]=[C:8]([N:11]3[CH2:16][CH2:15][N:14]([C:17]4[C:22]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:20]=[CH:19][N:18]=4)[CH2:13][CH2:12]3)[N:7](COCC[Si](C)(C)C)[C:6]=2[CH:5]=[C:4]([C:35]([F:38])([F:37])[F:36])[CH:3]=1.[C:39]([O:43][C:44]([N:46]1[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]1)=[O:45])([CH3:42])([CH3:41])[CH3:40]>>[C:39]([O:43][C:44]([N:46]1[CH2:51][CH2:50][N:49]([C:2]2[C:10]3[N:9]=[C:8]([N:11]4[CH2:12][CH2:13][N:14]([C:17]5[C:22]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:20]=[CH:19][N:18]=5)[CH2:15][CH2:16]4)[NH:7][C:6]=3[CH:5]=[C:4]([C:35]([F:37])([F:38])[F:36])[CH:3]=2)[CH2:48][CH2:47]1)=[O:45])([CH3:42])([CH3:40])[CH3:41]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: C[Si](C)(C)CCOCn1c(N2CCN(c3ncccc3C(F)(F)F)CC2)nc2c(Br)cc(C(F)(F)F)cc21
Product: CC(C)(C)OC(=O)N1CCN(c2cc(C(F)(F)F)cc3[nH]c(N4CCN(c5ncccc5C(F)(F)F)CC4)nc23)CC1

Procedure:
4-Bromo-6-trifluoromethyl-2-[4-(3-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazole from Example 146a reacted with piperazine-1-carboxylic acid tert-butyl ester under the conditions of Example 127b to give the title compound.
Reaction SMILES: [C:1](#[N:5])[CH2:2][C:3]#[N:4].N[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[SH:13]>C(O)C>[S:13]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:4]=[C:3]1[CH2:2][C:1]1[S:13][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:5]=1
Reactant: N#CCC#N
Reactant: Nc1ccccc1S
Solvent: CCO
Product: c1ccc2sc(Cc3nc4ccccc4s3)nc2c1
Reaction time: 8 h
Yield: 82 %

Procedure:
To produce the above compound, in a two-neck 100 ml round bottom flask with a condenser and a stir bar, malononitrile (2.64 g, 40 mmol) was dissolved in absolute ethanol (40 ml). 2-amino thiophenol (10 g, 80 mmol) was slowly added to this solution under stirring. Under a nitrogen blanket, the reaction mixture was heated and refluxed for six hours. After cooling, the flask was refrigerated overnight. Pale green crystals of bis(2-benzothiazolyl) methane that formed were recovered following vacuum filtration, washing with hexane and drying (yield: 82%). 2.82 g (10 mmol) of the bis(2-benzothiazolyl) methane was dissolved in chloroform (50 ml) in an erlenmeyer flask. Hydrobromic acid (10 mmol) in glacial acetic acid was added dropwise with gentle stirring. A canary yellow precipitate formed within minutes, causing thickening of the reaction mixture. Stirring was continued for one hour at room temperature. A fine yellow powder was recovered, following filtration and washing with ether. The yield was quantitative and the bis(2-benzothiazolyl) methane monohydrobromide product was sufficiently pure to be used in the next step.
Reaction SMILES: [CH2:1]([NH2:5])[CH2:2][CH2:3][CH3:4].[CH3:6][CH2:7][O:8][C:9]([CH3:11])=[O:10].[CH3:12][CH2:13][CH2:14]CCCC>C(Cl)Cl.[Pd]>[CH2:1]([NH:5][CH:13]([CH3:14])/[CH:12]=[CH:11]/[C:9]([O:8][CH2:7][CH3:6])=[O:10])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCCCC
Reactant: CCCCN
Reactant: CCOC(C)=O
Agent: [Pd]
Solvent: ClCCl
Product: CCCCNC(C)/C=C/C(=O)OCC
Yield: 65 %

Procedure:
Reaction of 31 (rac-Ethyl (2E)-4-(diethoxyphosphinyloxy)pent-2-enoate) (280 mg, 1.0 mmol) with nBuNH2 (198 μL, 2.0 mmol) and 8 mol % [Pd] in CH2Cl2 (10 ml) at room temperature according to Example 2. Flash chromatography (AcOEt:heptane fraction 50:50 to 55:45) yields 10 (rac-Ethyl (2E)-N-butyl-4-aminopent-2-enoate) (130 mg, 65%) as a yellow oil.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]#[N:7].C1[CH2:12][O:11]CC1.[Li].CCCCCCC.C1C[O:24]CC1.C(C1C=CC=CC=1)C>>[C:6]([C:2]1[S:1][C:5]([C:12]([OH:11])=[O:24])=[CH:4][CH:3]=1)#[N:7]
Reactant: C1CCOC1
Reactant: N#Cc1cccs1
Agent: [Li]
Solvent: CCCCCCC
Solvent: CCc1ccccc1
Product: N#Cc1ccc(C(=O)O)s1
Reaction time: 0.17 h
Yield: 22 %

Procedure:
In a 500 mL receiving flask are placed thiophene-2-carbonitrile (5.0 mL, 53.8 mmol) and THF (270 mL) and cooled in an acetone/solid CO2 bath. Lithium disopropylaoide (40.3 mL, 80.7 mmol, 2.0M solution in heptane/THF/ethylbenzene) is added in a slow stream via syringe. The solution is stirred for 10 min then quenched with an excess of dry ice. The reaction mixture is warned in a water bath and the THF removed in vacuo. The slurry is taken up in 1N NaOH and extracted with ether (3×). The aqueous layer is then acidified to pH<6 with conc. HCl, whereupon a brown precipitate forms. This precipitate is filtered off and to the resulting eluent is added 1N HCl which results in precipitation of the product. The product is collected by filtration then triturated with CH2Cl2Purification over silica gel (1:2.5:100 formic acid:MeOH:CH2Cl2) provides the product as a solid (1.79 g, 22%). 1H NMR (400 MHz, CDCl3) δ 14.10, 8.00, 7.80.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]3[C:13]([C:19]([F:22])([F:21])[F:20])=[CH:14][C:15]([C:17]#[N:18])=[CH:16][C:11]=3[NH:10][C:9]2=[O:23])[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].[CH3:26][CH2:27][N:28]([CH2:31][CH2:32]Cl)[CH2:29][CH3:30].Cl.[C:35](=[O:38])(O)[O-:36].[Na+]>CN(C)C=O.C(N(CC)CC)C>[F:20][C:19]([F:22])([F:21])[C:35]([OH:36])=[O:38].[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]3[C:13]([C:19]([F:21])([F:22])[F:20])=[CH:14][C:15]([C:17]([NH2:18])=[O:36])=[CH:16][C:11]=3[N:10]([CH2:26][CH2:27][N:28]([CH2:31][CH3:32])[CH2:29][CH3:30])[C:9]2=[O:23])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C([O-])O
Reactant: CCN(CC)CCCl
Reactant: N#Cc1cc(C(F)(F)F)c2c(c1)[nH]c(=O)n2-c1cccc(Cl)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCN(CC)CCn1c(=O)n(-c2cccc(Cl)c2)c2c(C(F)(F)F)cc(C(N)=O)cc21
Product: O=C(O)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 38 %

Procedure:
1-(3-Chlorophenyl)-2-oxo-7-(trifluoromethyl)-2,3-dihydro-1H-benzimidazole-5-carbonitrile (31.4 mg) was dissolved in N,N-dimethylformamide (3 ml), and to the solution was added sodium hydride (4.8 mg). The mixture was stirred at room temperature for 5 minutes. 2-Chlorotriethylamine hydrochloride (20.8 mg) and triethylamine (0.019 ml) were added, and the mixture was stirred at 60-70° C. for 1 hour. After allowing to cool, to the reaction mixture was added saturated aqueous sodium bicarbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The resultant residue was dissolved in 2-methyl-2-propanol (4 ml) and heated at 50° C. To the solution was added powdered potassium hydroxide (130.4 mg), and the mixture was stirred for 1 hour. After allowing to cool, to the reaction mixture was added saturated aqueous sodium bicarbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The resultant residue was purified by HPLC using condition 1 to give the title compound (20.0 mg, 38%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14](Cl)=[O:15])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[NH2:21][CH2:22][CH2:23][C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1>>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:21][CH2:22][CH2:23][C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)=[O:15])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: O=C(Cl)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Reactant: NCCc1cccnc1
Product: O=C(NCCc1cccnc1)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1

Procedure:
Prepared according to the procedure described for example 50 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carbonyl chloride (100 mg, 0.27 mmol) and 3-(2-aminoethyl)pyridine (39 mg, 0.32 mmol). The title compound was obtained as a solid (75 mg, 49% yield). 1H NMR (400 MHz, d6-DMSO) δ: 8.98 (2H, s), 8.91 (1H, m), 8.40 (2H, m), 8.38 (1H, s), 7.62 (1H, m), 7.30 (1H, m), 3.48 (2H, m), 2.81 (2H, m). MS m/z: 455.01, 457.00 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1Cl)([O-:3])=[O:2].C([O-])(=O)C.[NH4+:15].N>>[N+:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1[NH2:15])([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cnccc1Cl
Reactant: [NH4+]
Agent: CC(=O)[O-]
Agent: N
Product: Nc1ccncc1[N+](=O)[O-]
Yield: 59.3 %

Procedure:
Five grams (31.5 mmol) of 3-nitro-4-chloropyridine was mixed with 26 g of ammonium acetate, and the mixture was heated at 130°-140° C. for 3 hours. The mixture was allowed to cool, and then adjusted to pH 10 with concentrated aqueous ammonia. The precipitated powder was collected by filtration to obtain 2.6 g of the intended product (yield: 59%).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH2:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][CH:21]([OH:24])[CH2:20][CH2:19]1)=[O:17])[CH2:12][C:13]#[CH:14].C(N(CC)CC)C>ClCCl>[CH2:11]([O:15][C:16]([N:18]1[CH2:19][CH2:20][C:21](=[O:24])[CH2:22][CH2:23]1)=[O:17])[CH2:12][C:13]#[CH:14]
Reactant: C#CCCOC(=O)N1CCC(O)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: C#CCCOC(=O)N1CCC(=O)CC1
Temperature: 25 °C
Yield: 87.3 %

Procedure:
25 ml of oxalyl chloride was added to 500 ml of dichloromethane, into which 41 ml of dimethyl sulfoxide was gradually dropped in a stream of nitrogen at a temperature of from -50° C. to -70° C. Subsequently, 10.3 g of N-(3-butynyloxycarbonyl)-4-hydroxypiperidine was dissolved in 50 ml of dichloromethane, followed by gradually dropping into the reaction mixture. Finally, 120 ml of triethylamine was dropped, followed by gradually increasing the temperature up to room temperature. The reaction solution was charged into a saturated saline solution, extracted three times with dichloromethane and dried with anhydrous magnesium sulfate, after which the solvent was distilled off under reduced pressure. The resultant residue was purified by the use of silica gel column chromatography (elution solvent: hexane:ethyl acetate=3.1), thereby obtaining 8.9 g of the intended compound.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[O:6][C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[CH:9]=1)=O.[CH2:14](O)C.[NH2:17][C:18](=[S:25])[CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22]>O>[O:6]1[C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[CH:9]=[C:5]1[C:3]1[N:17]=[C:18]([CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:14])=[O:22])[S:25][CH:2]=1
Reactant: COC(=O)CCC(N)=S
Reactant: O=C(CBr)c1cc2ccccc2o1
Reactant: CCO
Solvent: O
Product: CCOC(=O)CCc1nc(-c2cc3ccccc3o2)cs1

Procedure:
2-(Bromoacetyl)benzofuran (650 ml) was added to an ethanol (12 ml) solution of methyl 4-amino-4-thioxobutyrate (400 mg), which was heated under reflux overnight. After cooling, water was added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was dried, concentrated, and then purified by silica gel column chromatography (eluent: hexane/ethyl acetate=4/1). The obtained crystals were washed with hexane to obtain ethyl 3-[4-(2-benzofuranyl)thiazol-2-yl]propionate (460 mg).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.[Br:35][C:36]1[CH:37]=[C:38]([C:43]([F:46])([F:45])[F:44])[C:39](O)=[N:40][CH:41]=1.C(P(CCCC)CCCC)CCC.C(OC(C)C)(C)C>C1(C)C=CC=CC=1>[Br:35][C:36]1[CH:37]=[C:38]([C:43]([F:46])([F:44])[F:45])[C:39]([O:1][CH2:2][CH2:3][CH:4]2[CH2:5][CH2:6][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:8][CH2:9]2)=[N:40][CH:41]=1
Reactant: Oc1ncc(Br)cc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCC(CCO)CC1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Solvent: CC(C)OC(C)C
Product: CC(C)(C)OC(=O)N1CCC(CCOc2ncc(Br)cc2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.1 %

Procedure:
tert-Butyl 4-(2-hydroxyethyl)piperidine-1-carboxylate (7.7 g) and 1,1′-(azodicarbonyl)dipiperidine (11.6 g) were added to a mixture of 5-bromo-3-(trifluoromethyl)pyridine-2-ol (7 g) and toluene (124 mL) at room temperature. Tributylphosphine (11.6 mL) was added thereto under ice-cooling, and the mixture was stirred at room temperature overnight. After diisopropylether was added to the reaction mixture, the mixture was stirred, and the insoluble material was separated by filtration. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (Hex:EtOAc=100:0 to 70:30), whereby tert-butyl 4-(2-{[5-bromo-3-(trifluoromethyl)pyridin-2-yl]oxy}ethyl)piperidine-1-carboxylate (8.93 g) was obtained as a colorless oil.
Reaction SMILES: O([C@:9]([C@@H:21]([CH:23]([O:25][Si](C(C)(C)C)(C)C)O)[OH:22])([OH:20])[C:10]([F:19])([F:18])[C:11]([O:13]S(C)(=O)=O)=O)[Si](C(C)(C)C)(C)C.[CH3:33][C:34]1[C:35]([O:45][Si](C)(C)C)=[N:36][C:37]([O:40][Si](C)(C)C)=[N:38][CH:39]=1.ClCCCl.FC(F)(F)S(O[Si](C)(C)C)(=O)=O>CO>[CH3:33][C:34]1[C:35](=[O:45])[NH:36][C:37](=[O:40])[N:38]([C:11]([C:10]([F:18])([F:19])[C@@H:9]([C@@H:21]([CH2:23][OH:25])[OH:22])[OH:20])=[O:13])[CH:39]=1
Reactant: Cc1cnc(O[Si](C)(C)C)nc1O[Si](C)(C)C
Reactant: CC(C)(C)[Si](C)(C)OC(O)[C@@H](O)[C@](O)(O[Si](C)(C)C(C)(C)C)C(F)(F)C(=O)OS(C)(=O)=O
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCCl
Solvent: CO
Product: Cc1cn(C(=O)C(F)(F)[C@H](O)[C@H](O)CO)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 2.59 g. of 3,5-bis(t-butyldimethylsiloxy)-1-methanesulfonyloxy-2-desoxy-2,2-difluororibose was added 1.60 g. of 5-methyl-2,4-bis(trimethylsilyloxy)pyrimidine and 45 ml. of dry 1,2-dichloroethane. To this mixture was added 1.45 g. of trifluoromethane-sulfonyloxytrimethylsilane, and the clear solution was stirred under nitrogen at reflux for about 2-3 hours. The reaction was then cooled to ambient temperature and 1.35 ml. of methanol were added and the suspension was stirred for 30 minutes. The precipitate was filtered and the filtrate was reduced to one-half its volume under vacuum and then diluted with an equal volume of dichloromethane. The solution was washed with saturated aqueous sodium bicarbonate and then with saturated aqueous sodium chloride, and dried over anhydrous sodium sulfate. The solution was filtered and the filtrate was saturated with anhydrous hydrogen bromide. The reaction mixture was stirred for 30 minutes and was then concentrated under vacuum. The residue was dissolved in methanol and the solution was evaporated to dryness under vacuum. The residue was dissolved in water and the solution was extracted twice with diethyl ether. The water layer was then evaporated to dryness. The residue was taken up in ethanol and evaporated repeatedly to azeotrope off all water. One g. of crude product was obtained, and was chromatographed on 30 g. of Woelm silica gel (70-150 mesh), eluting with ethyl acetate to yield 0.76 g. of desired product. It was further purified by recrystallization from ethyl acetate to obtain 0.37 g. of white crystalline product. nmr (CD3OD, 90 MHz) δ 1.93 (s, 3H); 3.5-4.67 (series of m, 4H); 4.83 (bs, 3H); 6.3 (t, J=9 Hz, 1H); 7.47 (m, 1H); mass spec. m/e=278 =Parent.
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:9])=[N:4][CH:5]=[N:6][C:7]=1[NH2:8].Cl.Br[C:12]([CH3:35])([CH3:34])[C:13]([C:15]1[CH:20]=[CH:19][C:18]([C:21]23[CH2:28][CH2:27][C:24]([CH2:29][C:30]([O:32][CH3:33])=[O:31])([CH2:25][CH2:26]2)[CH2:23][CH2:22]3)=[CH:17][CH:16]=1)=O>O.C(O)C>[NH2:8][C:7]1[C:2]2[N:1]=[C:13]([C:15]3[CH:16]=[CH:17][C:18]([C:21]45[CH2:28][CH2:27][C:24]([CH2:29][C:30]([O:32][CH3:33])=[O:31])([CH2:25][CH2:26]4)[CH2:23][CH2:22]5)=[CH:19][CH:20]=3)[C:12]([CH3:35])([CH3:34])[O:9][C:3]=2[N:4]=[CH:5][N:6]=1
Reactant: Nc1ncnc(O)c1N
Reactant: COC(=O)CC12CCC(c3ccc(C(=O)C(C)(C)Br)cc3)(CC1)CC2
Agent: Cl
Solvent: O
Solvent: CCO
Product: COC(=O)CC12CCC(c3ccc(C4=Nc5c(N)ncnc5OC4(C)C)cc3)(CC1)CC2
Temperature: 100 °C
Yield: 64.2 %

Procedure:
To a solution of 5,6-diaminopyrimidin-4-ol (280 mg, 2.2 mmol) in water (8 mL), absolute ethanol (25 mL) and 1M HCl (2.2 mL, 2.2 mmol) was added a solution of methyl {4-[4-(2-bromo-2-methylpropanoyl)phenyl]bicyclo[2.2.2]oct-1-yl}acetate (Intermediate 9; 877 mg, 2.15 mmol) in absolute EtOH (80 mL). The solution was heated to 100° C. overnight then allowed to cool to ambient temperature, evaporated to dryness, and the residue treated with 2M NaOH to adjust the pH to 10. The resulting suspension was filtered to provide a yellow solid which was purified on a 12 g presearch silica cartridge dry loading on silica (2 g) and eluting with 0-2.5-5% MeOH-DCM to provide the title compound as a white solid (601 mg, 1.38 mmol, 64%)1H NMR δ 1.59-1.63 (12H, m), 1.79-1.83 (6H, m), 2.16 (2H, s), 3.59 (3H, s), 6.91 (2H, s), 7.39 (2H, d), 7.64 (2H, d), 7.95 (1H, s); MS m/e MH+ 435.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[C:13](Cl)[C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)[C:5]1=[O:22])(=O)C.[CH3:23][N:24]([CH2:26][C:27]1[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][CH:28]=1)[CH3:25].[OH-].[Na+]>CN(C=O)C.CO>[CH3:25][N:24]([CH2:26][C:27]1[CH:33]=[CH:32][C:30]([NH:31]/[C:13](=[C:6]2\[C:5](=[O:22])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[CH:10][CH:11]=3)/[C:14]2[CH:15]=[CH:16][C:17]([CH3:20])=[CH:18][CH:19]=2)=[CH:29][CH:28]=1)[CH3:23]
Reactant: CC(=O)N1C(=O)C(=C(Cl)c2ccc(C)cc2)c2ccccc21
Reactant: CN(C)Cc1ccc(N)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CN(C)C=O
Product: Cc1ccc(/C(Nc2ccc(CN(C)C)cc2)=C2/C(=O)Nc3ccccc32)cc1

Procedure:
Prepared analogously to Example 2 from 1-acetyl-3-[1-chloro-1-(p-tolyl)-methylidene)-2-indolinone and 4-dimethylaminomethyl-aniline in DMF and subsequent treatment with sodium hydroxide solution in methanol.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C@H:17]([O:24][C:25]3[CH:26]=[CH:27][C:28]4[N:29]([C:31]([N:34]5[CH2:39][CH2:38][CH2:37][CH2:36][C@@H:35]5[CH3:40])=[N:32][N:33]=4)[CH:30]=3)[CH2:16][CH2:15]2)=[O:12])[N:7]([C:41]2[CH:42]=[C:43]([CH:50]=[CH:51][CH:52]=2)[CH2:44][O:45]S(C)(=O)=O)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:53]1[CH2:58][CH2:57][CH2:56][CH2:55][CH2:54]1.C1C[O:62]CC1>>[CH:44]([OH:45])=[O:62].[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C@H:17]([O:24][C:25]3[CH:26]=[CH:27][C:28]4[N:29]([C:31]([N:34]5[CH2:39][CH2:38][CH2:37][CH2:36][C@@H:35]5[CH3:40])=[N:32][N:33]=4)[CH:30]=3)[CH2:16][CH2:15]2)=[O:12])[N:7]([C:41]2[CH:52]=[CH:51][CH:50]=[C:43]([CH2:44][N:53]3[CH2:58][CH2:57][CH2:56][CH2:55][CH2:54]3)[CH:42]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@H]1CCCCN1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4cccc(COS(C)(=O)=O)c4)c4ccccc43)cn12
Reactant: C1CCOC1
Reactant: C1CCNCC1
Product: C[C@H]1CCCCN1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4cccc(CN5CCCCC5)c4)c4ccccc43)cn12
Product: O=CO
Temperature: 50 °C
Reaction time: 24 h
Yield: 25 %

Procedure:
To a solution of Intermediate 167b (0.22 mmol) in THF (2.5 mL) was added piperidine (424 μL, 4.3 mmol) and the reaction stirred at 50° C. for 24 h. The crude reaction mixture was cooled and partitioned between EtOAc and water. The aqueous phase was extracted with EtOAc (×3) and the combined organic layers were washed with brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was purified by FCC on silica, using a gradient of 0-10% (2M NH3 in MeOH) in DCM, followed by MDAP (Method 7) purification, to give the title compound (44 mg, 25%). LCMS (Method 5): Rt 3.69 min, m/z 716 [MH+]. 1H NMR (400 MHz, d6-DMSO): 0.86 (3H, d, J=6.2 Hz), 1.23 (9H, s), 1.28-1.33 (2H, m), 1.38-1.48 (6H, m), 1.58-1.66 (2H, m), 1.70-1.92 (4H, m), 1.95-2.12 (2H, m), 2.26-2.34 (4H, m), 2.86 (1H, ddd, J=12.7, 9.0, 3.9 Hz), 3.11 (1H, dt, J=11.9, 4.1 Hz), 3.23-3.29 (1H, m), 3.44 (2H, s), 4.77 (1H, td, J=8.4, 5.7 Hz), 5.46 (1H, t, J=4.2 Hz), 6.28 (1H, s), 6.99 (1H, d, J=8.6 Hz), 7.15 (1H, dd, J=9.8, 2.1 Hz), 7.20-7.25 (2H, m), 7.25-7.29 (2H, m), 7.29-7.36 (3H, m), 7.39 (1H, t, J=7.8 Hz), 7.59 (1H, d, J=10.0 Hz), 7.64 (1H, d, J=1.8 Hz), 8.06 (1H, s), 8.12 (1.8H, s).