Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[N:5][N:6]([CH2:8]Cl)[CH:7]=1.[F:10][C:11]([F:20])([F:19])[CH2:12][CH2:13][CH:14]([C:17]#[N:18])[C:15]#[N:16].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Br:2][C:3]1[CH:4]=[N:5][N:6]([CH2:8][C:14]([CH2:13][CH2:12][C:11]([F:10])([F:19])[F:20])([C:15]#[N:16])[C:17]#[N:18])[CH:7]=1
Reactant: ClCn1cc(Br)cn1
Reactant: N#CC(C#N)CCC(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CC(C#N)(CCC(F)(F)F)Cn1cc(Br)cn1
Yield: 72.4 %

Procedure:
3.27 g of 4-bromo-1-(chloromethyl)-1H-pyrazole hydrochloride and 2.29 g of (3,3,3-trifluoropropyl) malononitrile were dissolved in 28 ml of N,N-dimethylformamide. 3.89 g of potassium carbonate was added to the solution under ice cooling with stirring, followed by stirring at room temperature for overnight. Water was added to the reaction mixture, and then extracted with MTBE. The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 3.28 g of [(4-bromo-1H-pyrazole-1-yl)methyl](3,3,3-trifluoropropyl) malononitrile (referred as the compound of the present invention (21), hereinafter) shown by below formula.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:8])=[CH:4][CH:5]=[CH:6][CH:7]=1.Cl.[S-:10][C:11]#[N:12].[NH4+]>ClC1C=CC=CC=1C>[C:3]1([CH3:8])[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][C:11]([NH2:12])=[S:10]
Reactant: Cc1ccccc1N
Reactant: N#C[S-]
Agent: Cl
Agent: [NH4+]
Solvent: Cc1ccccc1Cl
Product: Cc1ccccc1NC(N)=S
Temperature: 75 °C
Reaction time: 20 h
Yield: 98.3 %

Procedure:
In a reactor, 107.2 g of o-toluidine and 250 ml of o-chlorotoluene were charged and 106 g of 36% hydrochloric acid was charged with stirring. The mixture was heated to 75° C. and 87.5 g of ammonium thiocyanate was admixed with the mixture and the reaction was performed at 75° to 85° C. for 20 hours. The resulting crystal was separated by a filtration and washed with water and dried to obtain 163.5 g of o-tolylthiourea having a melting point of 154° C. The product was analyzed by high speed liquid chromatography to find a purity of 98.0% and an yield of 96.4% as a pure product.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[C:14](=[O:15])[CH:13]=[C:12]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[S:11]1)([O-])=O.C(O)(=O)C.C(O)C>[Fe].O>[NH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[C:14](=[O:15])[CH:13]=[C:12]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[S:11]1
Reactant: O=c1cc(-c2ccccc2)sn1-c1ccccc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CCO
Solvent: O
Solvent: CC(=O)O
Product: Nc1ccccc1-n1sc(-c2ccccc2)cc1=O
Temperature: 25 °C
Yield: 49.5 %

Procedure:
A mixture of 0.560 g (1.880 mmol) N-(2-nitrophenyl)-5-phenyl-4-isothiazolin-3-one, 0.450 g (excess) iron powder, 1 mL glacial acetic acid and 15 mL absolute ethanol was stirred at reflux for one hour. The mixture was allowed to cool to room temperature, poured into 150 mL water and extracted with three 100 mL portions of ethyl acetate. The organic layers were combined, dried, filtered and solvent was evaporated. The resulting solid was recrystallized from ethanol/water to provide 0.250 g (0.930 mmol, 49%) N-(2-aminophenyl) -5-phenyl-4-isothiazolin-3-one, mp=145°-146° C.- NMR (CDCl13 /TMS): 4.15 (bs, 2H), 6.6 (s, 1H), 6.8-7.6 (m, 9H). IR (Nujol): 3358, 3216, 1658. High resolution mass spectrum: Calculated; 269. 074860. Measured; 269.074265. Anal. calcd. for C15H12N2OS: C 67.14, H 4.51, N 10.44, S 11.95; Found C 66.76, H 4.43, N 10.19, S 12.09.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:3]=1[C:4]#[N:5].[NH:11]1[CH2:15][CH2:14][CH2:13][C:12]1=[O:16].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:10][C:7]1[CH:8]=[CH:9][C:2]([N:11]2[CH2:15][CH2:14][CH2:13][C:12]2=[O:16])=[C:3]([CH:6]=1)[C:4]#[N:5]
Reactant: N#Cc1cc(Cl)ccc1Br
Reactant: O=C1CCCN1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: N#Cc1cc(Cl)ccc1N1CCCC1=O
Temperature: 25 °C

Procedure:
(Step 1) To a solution (139 ml) of 2-bromo-5-chlorobenzonitrile (15.0 g), pyrrolidin-2-one (7.90 ml) and cesium carbonate (45.2 g) in 1,4-dioxane were added tris(dibenzylideneacetone)dipalladium (1.59 g) and 4,5-bis(biphenylphosphino)-9,9-dimethylxanthine (2.0 g) at room temperature under a nitrogen atmosphere, and the mixture was heated under reflux for 3 hr. The mixture was allowed to cool to room temperature, and extracted with ethyl acetate and water. The organic layer was filtered through celite, and washed with ethyl acetate. The filtrate was dried over sodium sulfate, and filtered. The solvent was evaporated under reduced pressure. The obtained residue was purified by column chromatography (ethyl acetate:hexane=1:10→1:1) to give 5-chloro-2-(2-oxopyrrolidin-1-yl)benzonitrile (12.5 g) as yellow crystals.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:28]=[CH:27][C:16]([CH2:17][CH2:18][NH:19]C(=O)OC(C)(C)C)=[CH:15][CH:14]=1)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].Cl.O1CCOCC1>C(Cl)Cl>[NH2:19][CH2:18][CH2:17][C:16]1[CH:15]=[CH:14][C:13]([O:12][CH2:11][CH2:10][CH2:9][P:4](=[O:5])([O:3][CH2:1][CH3:2])[O:6][CH2:7][CH3:8])=[CH:28][CH:27]=1
Reactant: CCOP(=O)(CCCOc1ccc(CCNC(=O)OC(C)(C)C)cc1)OCC
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCOP(=O)(CCCOc1ccc(CCN)cc1)OCC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl 4-(3-(diethoxyphosphoryl)propoxy)phenethylcarbamate (1 eq) in DCM (0.14 M) was added 4M HCl in dioxane (50 eq). The resulting mixture was stirred at room temperature for 2 hours. The mixture was concentrated en vaccuo. The crude material was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-15% MeOH/DCM to give the product as a yellowish oil.
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([OH:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:21][O:22][CH2:23][CH2:24][NH:25][C:26]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:27].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl>[CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:21][O:22][CH2:23][CH2:24][NH:25][C:26]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:33])([CH3:32])[CH3:34])=[O:27])=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Reactant: CC(C)(C)OC(=O)NC(=O)NCCON
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC(=O)NCCONC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.4 %

Procedure:
To a mixture of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid 1 (0.210 g, 0.760 mmol, US 2005/20572 A1) in DCM (6.0 mL) were added tert-butyl {[2-(aminooxy)ethyl]carbamoyl}carbamate 84 (0.250 g, 1.140 mmol), 1-hydroxybenzotriazole (0.154 g, 1.140 mmol) and 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.218 g, 1.140 mmol) sequentially at room temperature. The mixture was stirred at room temperature overnight, diluted with DCM and concentrated to provide a residue which was subjected to chromatography to give 85 (0.31 g, 85%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:9]([CH3:13])=[C:10]([CH3:12])[N:11]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1.[CH2:14]([C:16]1[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[C:17]=1[CH:18]=O)[CH3:15].C([BH3-])#N.[Na+]>CO.[Cl-].[Zn+2].[Cl-]>[CH2:14]([C:16]1[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[C:17]=1[CH2:18][NH:1][C:2]1[C:3]2[N:4]([C:9]([CH3:13])=[C:10]([CH3:12])[N:11]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1)[CH3:15]
Reactant: CCc1cccc(C)c1C=O
Reactant: Cc1cc(N)c2nc(C)c(C)n2c1
Agent: [BH3-]C#N
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: CCc1cccc(C)c1CNc1cc(C)cn2c(C)c(C)nc12
Yield: 32.5 %

Procedure:
A stirred mixture of 8-amino-2,3,6-trimethylimidazo[1,2-a]pyridine (0.5 g, 2.8 mmol), 2-ethyl-6-methylbenzaldehyde (0.45 g, 3 mmol) and zinc(II)chloride (0.4 g, 3 mmol) in 50 ml methanol was treated with sodium cyanoborohydride (0.19 g, 3 mmol) and refluxed for 20 h. The methanol was evaporated under reduced pressure and the residue was dissolved in dichloromethylene and water. The organic layer was separated, dried over sodium sulfate and evaporated under reduced pressure. The residue was chromatographed on silicagel with dichloromethylene:methanol (10:1) which yielded 0.28 g (33%) of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10](OS(C)(=O)=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C-:18]#[N:19].[Na+].C(OCC)(=O)C.O>CS(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([C:18]#[N:19])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [C-]#N
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](OS(C)(=O)=O)C1
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CC[C@H](C#N)C1
Temperature: 100 °C
Reaction time: 1 h
Yield: 60.8 %

Procedure:
To a solution of (R)-1-t-butoxycarbonyl-3-methanesulfonyloxypyrrolidine (20 g) in dimethyl sulfoxide (200 ml) was added sodium cyanide (11 g) at ambient temperature under nitrogen. After stirring at 100° C. under nitrogen for 1 hour, the solution was taken up into a mixture of ethyl acetate and water. The organic layer was separated, and washed with water and brine successively. The dried solvent was evaporated, and the residue was chromatographed on silica gel eluting with a mixture of n-hexane and ethyl acetate (2:1, V/V) to give (S)-1-t-butoxycarbonyl-3-cyanopyrrolidine (9.0 g).
Reaction SMILES: C1([O:7][C:8](=[O:34])NC2C=CC(OC3C=CC(NC(=O)C4C=CC(Cl)=C(Cl)C=4)=CN=3)=CC=2)C=CC=CC=1.[CH2:35]([N:45]1[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1)[C:36]1[CH:44]=[CH:43][C:42]2[O:41][CH2:40][O:39][C:38]=2[CH:37]=1>CN(C=O)C>[CH2:35]([N:45]1[CH2:50][CH2:49][N:48]([C:8]([OH:34])=[O:7])[CH2:47][CH2:46]1)[C:36]1[CH:44]=[CH:43][C:42]2[O:41][CH2:40][O:39][C:38]=2[CH:37]=1
Reactant: O=C(Nc1ccc(Oc2ccc(NC(=O)c3ccc(Cl)c(Cl)c3)cn2)cc1)Oc1ccccc1
Reactant: c1cc2c(cc1CN1CCNCC1)OCO2
Solvent: CN(C)C=O
Product: O=C(O)N1CCN(Cc2ccc3c(c2)OCO3)CC1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a solution of {4-[5-(3,4-dichlorobenzoyl-amino)pyridin-2-yloxy]phenyl}-carbamic acid phenyl ester (320 mg, 0.65 mmol) in DMF (4 mL) was added 1-piperonylpiperazine (285 mg, 1.29 mmol), and the resulting solution was stirred for 17 hours at room temperature. This reaction solution was concentrated under reduced pressure. Water was added to the residue, and extracted with ethyl acetate. The ethyl acetate layer was washed with brine, dried over anhydrous magnesium sulfate, and evaporated. The residue was then purified by silica gel column chromatography (dichloromethane:methanol=25:1). The obtained residue was dissolved in a mixed solvent of ethanol-ethyl acetate. To the resulting solution was added a solution of 4 N hydrogen chloride in ethyl acetate to bring the pH to 3. The precipitated white powder was then filtered off and washed with ethanol, to thereby yield 330 mg of the title compound.
Reaction SMILES: [C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:21]=[C:20]3[C:15]([CH:16]=[C:17]([C:28](O)=[O:29])[N:18]=[C:19]3[CH2:22][CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)=[CH:14][CH:13]=2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].Cl.C[O:33][C:34](=[O:41])[C@@H:35]([NH2:40])[C:36]([CH3:39])([CH3:38])[CH3:37]>>[C:1]([C@H:5]1[CH2:6][CH2:7][C@H:8]([O:11][C:12]2[CH:21]=[C:20]3[C:15]([CH:16]=[C:17]([C:28]([NH:40][C@H:35]([C:36]([CH3:39])([CH3:38])[CH3:37])[C:34]([OH:33])=[O:41])=[O:29])[N:18]=[C:19]3[CH2:22][CH:23]3[CH2:24][CH2:25][CH2:26][CH2:27]3)=[CH:14][CH:13]=2)[CH2:9][CH2:10]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc(C(=O)O)nc(CC4CCCC4)c3c2)CC1
Reactant: COC(=O)[C@@H](N)C(C)(C)C
Agent: Cl
Product: CC(C)(C)[C@@H](NC(=O)c1cc2ccc(O[C@H]3CC[C@H](C(C)(C)C)CC3)cc2c(CC2CCCC2)n1)C(=O)O

Procedure:
50 mg (0.12) of 7-(4-tert-Butyl-cyclohexyloxy)-1-cyclopentylmethyl-isoquinoline-3-carboxylic acid (Example 430) was reacted with (2S)-amino-3,3-dimethyl-butyric acid methyl ester HCL (24.7 mg, 0.14 mmol) as described in general procedure A. The resulting ester was hydrolyzed by sonication at rt for 3 h and then usual work up as described in general procedure C afforded 54.3 mg of the title compound as a white solid.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:22]=[CH:21][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[O:12][C:13]=2[CH3:14])=[CH:5][CH:4]=1.[CH2:23]([O:25][C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][C:27]=1[CH2:33][C:34]([O:36][CH3:37])=[O:35])[CH3:24].CN(C)C=O.[H-].[Na+]>O>[CH3:37][O:36][C:34](=[O:35])[CH2:33][C:27]1[CH:28]=[C:29]([O:32][CH2:2][C:3]2[CH:22]=[CH:21][C:6]([O:7][CH2:8][C:9]3[N:10]=[C:11]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[O:12][C:13]=3[CH3:14])=[CH:5][CH:4]=2)[CH:30]=[CH:31][C:26]=1[O:25][CH2:23][CH3:24]
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CCl)cc1
Reactant: CCOc1ccc(O)cc1CC(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1ccc(OCc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)cc1CC(=O)OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 50.3 %

Procedure:
To a mixture of 4-(4-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole (1.00 g), methyl 2-(2-ethoxy-5-hydroxyphenyl)acetate (0.60 g) and N, N-dimethylformamide (30 mL) was added sodium hydride (60%, oil, 0.14 g) under ice-cooling, and the mixture was stirred at room temperature for 2 hrs. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. After concentration of the organic layer, the residue was subjected to silica gel column chromatography to give crystals (0.70 g, 70%) of methyl-2-[2-ethoxy-5-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]acetate from a fraction eluted with ethyl acetate-hexane (1:4, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 82-83° C.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][C:2]1=[O:11].[H-].[Na+].[Cl:14][CH2:15][CH2:16][CH2:17]I>CN(C=O)C>[Cl:14][CH2:15][CH2:16][CH2:17][N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][C:2]1=[O:11]
Reactant: ClCCCI
Reactant: O=C1CCc2ccccc2N1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1CCc2ccccc2N1CCCCl
Temperature: 0 °C
Reaction time: 1 h
Yield: 74 %

Procedure:
A 50 mL flask was charged with 3,4-dihydro-1H-quinolin-2-one (2.00 g, 13.6 mmol) and sodium hydride (60% in oil, 0.712 g, 16.3 mmol) in DMF (50 mL, dry) and stirred at 0° C. for 1 h, followed by addition of 1-chloro-3-iodo-propane (2.77 g, 13.6 mmol) and stirring at rt for 20 h. The reaction mixture was quenched with water (10 mL), and the product was extracted into EtOEt (3×25 mL). The combined organic layers were dried (Na2SO4), evaporated and purified by flash CC (SiO2; EtOAc/heptane 1:4) to give the crude title compound (85LM31) (2.25 g). 1H NMR (CDCl3) δ 7.29-7.22 (m, 1H), 7.17 (d, J=7.4 Hz, 1H), 7.08-6.98 (m, 2H), 4.10 (t, J=7.3 Hz, CH2), 3.62 (t, J=5.9 Hz, CH2), 2.88 (t, J=7.3 Hz, CH2), 2.63 (t, J=7.3 Hz, CH2), 2.19-2.10 (m, 2H); 13C NMR (CDCl3) δ 170.5, 140.0, 128.2, 127.8, 126.3, 123.2, 115.0, 43.3, 40.2, 32.2, 30.5, 26.0.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([OH:10])[C:5]=1[N:11]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[S:12]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)(=[O:14])=[O:13].[Si:31]([O:38][CH2:39][CH2:40][CH2:41]Br)([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32]>>[CH3:1][O:2][C:3](=[O:30])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:41][CH2:40][CH2:39][O:38][Si:31]([C:34]([CH3:35])([CH3:37])[CH3:36])([CH3:32])[CH3:33])[C:5]=1[N:11]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[S:12]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)(=[O:13])=[O:14]
Reactant: COC(=O)c1cccc(O)c1N(Cc1ccccc1)S(=O)(=O)c1ccc(OC)cc1
Reactant: CC(C)(C)[Si](C)(C)OCCCBr
Product: COC(=O)c1cccc(OCCCO[Si](C)(C)C(C)(C)C)c1N(Cc1ccccc1)S(=O)(=O)c1ccc(OC)cc1
Yield: 72.2 %

Procedure:
In the same manner as described in Example 38, 0.35 g (0.820 mmol) of the product of Example 37 and 0.290 g (1.147 mmol) of 1-t-butyldimethylsilyloxy-3-bromopropane provided 0.355 g (72%) of the desired product as a colorless oil. Electrospray Mass Spec: 600 (M+H).
Reaction SMILES: Br[C:2]1[C:3]([CH3:18])=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[O:6][CH:5]2[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[CH3:19][C:20]1[C:24](B(O)O)=[C:23]([CH3:28])[O:22][N:21]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:19][C:20]1[C:24]([C:2]2[C:3]([CH3:18])=[C:4]3[C:8](=[CH:9][CH:10]=2)[C:7](=[O:11])[O:6][CH:5]3[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:23]([CH3:28])[O:22][N:21]=1
Reactant: Cc1c(Br)ccc2c1C(c1ccccc1)OC2=O
Reactant: Cc1noc(C)c1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Cc1noc(C)c1-c1ccc2c(c1C)C(c1ccccc1)OC2=O
Temperature: 90 °C
Reaction time: 16 h

Procedure:
A mixture of 5-Bromo-4-methyl-3-phenyl-3H-isobenzofuran-1-one (100 mg, 0.33 mmol), 3,5-dimethylisoxazole-4-boronic acid (93 mg, 0.66 mmol, 2 eq.), 1N Na2CO3 (0.66 mL, 0.66 mmol) and Pd(PPh3)4 (62 mg, 0.033 mmol, 0.1 eq.) in dioxane (20 mL) is stirred at 90° C. for 16 hours. After cooled to room temperature, the mixture is evaporated in vacuo. The residue is purified by preparative-TLC using a petrol ether ethyl acetate mixture to afford the desired compound as a white solid.
Reaction SMILES: [C:1]1([CH3:15])[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)[CH:2]=1.Cl[C:17]1[C:18]2[S:25][C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:23][C:19]=2[N:20]=[CH:21][N:22]=1>>[C:26]1([C:24]2[S:25][C:18]3[C:17]([NH:14][C:11]4[CH:12]=[CH:13][C:8]([NH:7][C:3]5[CH:2]=[C:1]([CH3:15])[CH:6]=[CH:5][CH:4]=5)=[CH:9][CH:10]=4)=[N:22][CH:21]=[N:20][C:19]=3[CH:23]=2)[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: Clc1ncnc2cc(-c3ccccc3)sc12
Reactant: Cc1cccc(Nc2ccc(N)cc2)c1
Product: Cc1cccc(Nc2ccc(Nc3ncnc4cc(-c5ccccc5)sc34)cc2)c1
Yield: 21 %

Procedure:
Utilizing a procedure analogous to that described in Example 61, the title compound was prepared in 21% yield from N-m-Tolyl-benzene-1,4-diamine (230 mg, 1.16 mmol) and 4-chloro-6-phenyl-thieno[3,2-d]pyrimidine 250 mg, 1.16 mmol). RP18-HPLC RT: 7.432 minutes; APl MS: 409.1 (M+1); MP: 170-171° C.
Reaction SMILES: [C:1]([N:8]1[CH2:12][CH2:11][CH:10]=[CH:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].ClC1C=CC=C(C(OO)=[O:21])C=1>C(Cl)Cl>[C:4]([O:3][C:1]([N:8]1[CH2:12][CH:11]2[CH:10]([O:21]2)[CH2:9]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1C=CCC1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC2OC2C1
Temperature: 25 °C
Reaction time: 17 h
Yield: 55 %

Procedure:
22.1 A solution of 19.6 g N-Boc-pyrroline in 200 ml CH2Cl2 was cooled to −10° C. and was treated in two portions with 30 g meta-chloroperbenzoic acid. The mixture was stirred for 17 h, slowly warming up to room temperature. Then, the white precipitate was filtered off and washed with dichloromethane. The filtrate was washed with 5% aq. NaHSO3, sat. aq. NaHCO3 and brine, dried (MgSO4), filtered and concentrated. The crude product was purified by chromatography (silica gel; gradient: cyclohexane->cyclohexane/EtOAc 65:35) to give 11.8 g 6-oxa-3-aza-bicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester as a light yellow oil. MS 186.1 ([M+H]+)
Reaction SMILES: [C:1]1([CH:7]2[O:14][CH2:13][C@H:12]3[C@:10]([CH2:15]O)([CH2:11]3)[CH2:9][O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:17][C:18]1[N:26]=[C:25]([NH2:27])[N:24]=[C:23]2[C:19]=1[N:20]=[CH:21][NH:22]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>CC1CCCO1>[Cl:17][C:18]1[N:26]=[C:25]([NH2:27])[N:24]=[C:23]2[C:19]=1[N:20]=[CH:21][N:22]2[CH2:15][C@:10]12[CH2:11][C@H:12]1[CH2:13][O:14][CH:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[O:8][CH2:9]2
Reactant: OC[C@@]12COC(c3ccccc3)OC[C@@H]1C2
Reactant: Nc1nc(Cl)c2nc[nH]c2n1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC1CCCO1
Product: Nc1nc(Cl)c2ncn(C[C@@]34COC(c5ccccc5)OC[C@@H]3C4)c2n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In a reactor, a mixture of [(1S,7R)-4-phenyl-3,5-dioxabicyclo[5.1.0]octan-1-yl]methanol (750 g, 3.4 mol) (5c), 6-chloro-9H-purin-2-amine (7c) (479 g, 2.8 mol) and triphenylphosphine (930 g, 3.5 mol) in 2-methyltetrahydrofuran (7.4 L) was stirred at room temperature for 30 minutes, and then heated to 65° C. (+/−5° C.). To this mixture was dosed a solution of DIAD (711 g, 3.5 mol) in 2-methyltetrahydrofuran (740 mL) over a period of 1 hour. The mixture was stirred during 1 hour at reflux and then allowed to cool to room temperature overnight. Solids were removed by filtration. The reactor was rinsed with 2-methyltetrahydrofuran (740 mL) and this liquid was used to wash the solids on the filter. The filtrate was submitted as such in the next step (6′).
Reaction SMILES: [N+:1]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([O:14][C:15]2[N:20]=[CH:19][N:18]=[C:17]([NH:21][C:22]([NH2:24])=[O:23])[CH:16]=2)=[CH:6][CH:5]=1)([O-])=O.C(Cl)Cl.C1COCC1.[H][H]>CO.CC(O)=O.[Pt]>[NH2:1][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([O:14][C:15]2[N:20]=[CH:19][N:18]=[C:17]([NH:21][C:22]([NH2:24])=[O:23])[CH:16]=2)=[CH:6][CH:5]=1
Reactant: NC(=O)Nc1cc(Oc2ccc([N+](=O)[O-])c3ccccc23)ncn1
Reactant: [H][H]
Agent: [Pt]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CO
Product: NC(=O)Nc1cc(Oc2ccc(N)c3ccccc23)ncn1

Procedure:
A solution of 1-(6-(4-nitronaphthalen-1-yloxy)pyrimidin-4-yl)urea (60 mg, 0.184 mmol) in a mixture of MeOH, DCM and THF (1:1:1 v/v/v, 30 mL) containing AcOH (2 drops) was subjected to hydrogenation by passage through a Thales H-cube (1.0 mL min−1, RT, 70 mm CatCart, 10% Pt/C, full hydrogen mode). The resulting solution was evaporated in vacuo to afford the title compound, Intermediate R1, as a brown glassy solid (58 mg, 76% purity, 81%); Rt 1.23 min (Method 1 basic); m/z 296 (M+H)+ (ES+). This material was used directly in the next step (below) without further purification.
Reaction SMILES: C([O:3][C:4](=[O:33])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([CH2:15][C:16](=[O:32])[NH:17][CH2:18][C:19]#[C:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][C:28]([F:31])([F:30])[F:29])=[CH:23][CH:22]=3)[CH:13]=2)[CH:8]=[CH:7]1)C.[Li+].[OH-]>>[F:30][C:28]([F:29])([F:31])[O:27][C:24]1[CH:23]=[CH:22][C:21]([C:20]#[C:19][CH2:18][NH:17][C:16]([CH2:15][C:12]2[CH:13]=[C:14]3[C:9]([CH:8]=[CH:7][N:6]3[CH2:5][C:4]([OH:33])=[O:3])=[CH:10][CH:11]=2)=[O:32])=[CH:26][CH:25]=1
Reactant: CCOC(=O)Cn1ccc2ccc(CC(=O)NCC#Cc3ccc(OC(F)(F)F)cc3)cc21
Agent: [Li+]
Agent: [OH-]
Product: O=C(O)Cn1ccc2ccc(CC(=O)NCC#Cc3ccc(OC(F)(F)F)cc3)cc21

Procedure:
In analogy to the procedure described for example 1 e], (6-{[3-(4-trifluoromethoxy-phenyl)-prop-2-ynylcarbamoyl]-methyl}-indol-1-yl)-acetic acid ethyl ester was treated with LiOH to obtain the title compound as off-white solid.