Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][O:3]1)=[O:2].[C-:11]#[N:12].[K+]>>[C:11]([CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=1[C:1]([OH:3])=[O:2])#[N:12]
Reactant: [C-]#N
Reactant: O=C1OCc2ccccc21
Agent: [K+]
Product: N#CCc1ccccc1C(=O)O
Yield: 88.7 %

Procedure:
5.0 g (37.3 mmol) of phthalide and 5.0 g (76.8 mmol) of potassium cyanide, finely ground with a mortar and under vigorous stirring, were heated to 180° C. for 3.5 h in an open round-bottom flask. In the course of this, the melt darkened in color and had solidified after the reaction time. The solid was dissolved in 50 ml of dist. H2O and the solution was extracted twice with 100 ml each time of ethyl acetate. The combined organic phases contain unconverted phthalide and were discarded. The aqueous phase was admixed with 5.0 g of FeSO4.7H2O in order to bind excess cyanide and acidified with concentrated HCl down to a pH of 2. The precipitated solid was filtered off with suction through a frit filled with kieselguhr and washed with ethyl acetate, and the filtrate was transferred to a separating funnel. After phase separation, the aqueous phase was extracted twice more with 100 ml each time of ethyl acetate, the combined organic phases were dried over MgSO4 and the solvent was removed under reduced pressure. 5.34 g (33.1 mmol, 88.7%) of o-cyanomethylbenzoic acid were obtained and were used for the following reaction without further purification.
Reaction SMILES: N12CCCNC1=NCCC2.[CH3:11]/[C:12](/[N+]([O-])=O)=[CH:13]\[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[CH2:23]([O:25][C:26](=[O:30])[CH2:27][N+:28]#[C-:29])[CH3:24]>C(O)(C)C.C1COCC1>[CH2:23]([O:25][C:26]([C:27]1[NH:28][CH:29]=[C:12]([CH3:11])[C:13]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:30])[CH3:24]
Reactant: [C-]#[N+]CC(=O)OCC
Reactant: C/C(=C\c1ccccc1)[N+](=O)[O-]
Agent: C1CN=C2NCCCN2C1
Solvent: CC(C)O
Solvent: C1CCOC1
Product: CCOC(=O)c1[nH]cc(C)c1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.2 %

Procedure:
1,5,7-Triazabicyclo[4.4.0]dec-5-ene on polystyrene (4.7 g, 2.6 mmol/g, 12.2 mmol) was added to a reaction mixture of trans-β-methyl-β-nitrostyrene (997 mg, 6.11 mmol) and isocyanoacetic acid ethyl ester (691 mg, 6.11 mmol) in isopropanol (5 mL) and THF (5 mL) and the reaction mixture was stirred overnight at RT under nitrogen as protective gas. The reaction mixture was filtered out and the residue washed with isopropanol and THF. The desired product 4-methyl-3-phenyl-1H-pyrrole-2-carboxylic acid ethyl ester (1.25 g, 89% of theoretical) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][CH2:6][CH:7]([CH3:11])[C:8]([OH:10])=O)=[O:4].[C:12]([O:16][C:17](=[O:23])[C@@H:18]1[CH2:22][CH2:21][CH2:20][NH:19]1)([CH3:15])([CH3:14])[CH3:13].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[C:12]([O:16][C:17](=[O:23])[C@@H:18]1[CH2:22][CH2:21][CH2:20][N:19]1[C:8](=[O:10])[CH:7]([CH3:11])[CH2:6][CH2:5][C:3]([O:2][CH3:1])=[O:4])([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1
Reactant: COC(=O)CCC(C)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: COC(=O)CCC(C)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Temperature: 0 °C

Procedure:
4-Methoxycarbonyl-2-methylbutanoic acid (3.1 g.) and L-proline tert.-butyl ester (3.78 g.) are dissolved in dichloromethane (40 ml.). The solution is chilled with stirring in an ice bath and dicyclohexylcarbodiimide (4.12 g.) is added. After stirring 15 minutes in the ice bath and 18 hours at room temperature, the precipitate is filtered off and the filtrate is concentrated to dryness in vacuo. The residue is chromatographed on a column of silica gel with chloroform to obtain 1-(4-methoxycarbonyl-2-methylbutanoyl)-L-proline tert.-butyl ester, yield 3.5 g.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13]2[CH:17]=[CH:16][NH:15][N:14]=2)[N:3]=1.CC1(C)C(C)(C)OB([C:26]2[CH:27]=[N:28][NH:29][CH:30]=2)O1>>[NH:15]1[CH:16]=[CH:17][C:13]([NH:12][C:4]2[N:3]=[C:2]([C:26]3[CH:27]=[N:28][NH:29][CH:30]=3)[C:11]3[C:6]([CH:5]=2)=[CH:7][CH:8]=[CH:9][CH:10]=3)=[N:14]1
Reactant: Clc1nc(Nc2cc[nH]n2)cc2ccccc12
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Product: c1ccc2c(-c3cn[nH]c3)nc(Nc3cc[nH]n3)cc2c1

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine and 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole to give (1H-pyrazol-3-yl)-[1-(1H-pyrazol-4-yl)-isoquinolin-3-yl]-amine. LC-MS m/e 277(MH+).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=C([CH:9]=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=1)C=C)([O-:3])=[O:2].C[N+]1([O-])CC[O:19]CC1.[CH3:23][C:24]([CH3:26])=[O:25]>O.O=[Os](=O)(=O)=O>[OH:25][CH:24]([C:26]1[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=1)[CH2:23][OH:19]
Reactant: CC(C)=O
Reactant: C[N+]1([O-])CCOCC1
Reactant: C=Cc1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Agent: O=[Os](=O)(=O)=O
Solvent: O
Product: O=[N+]([O-])c1cc(C(O)CO)cc([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
3,5-Dinitrostyrene (0.50 g, 2.58 mmol) was dissolved in a mixture of acetone and water (8:1, 70 ml) and the solution was cooled to 0° C. OsO4 (0.046 g, 0.18 mmol) and NMO (0.60 g, 5.15 mmol) were added and the solution was stirred at room temperature for 16 h. A solution of Na2S2O5 (1.5 g) in water (120 ml) was added and the organic solvent removed by evaporation. The aqueous phase was extracted with ethyl acetate (2×70 ml) and the combined organic phases were dried (Na2SO4) and evaporated. The product was purified by preparative HPLC. Yield: 0.44 g (75%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][CH2:8][C:9]#[C:10][C:11]([C:13]1[N:14]([CH2:24][CH3:25])[N:15]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:17]=1)=O)([CH3:4])([CH3:3])[CH3:2].O.[NH2:28][NH2:29]>CCO>[C:1]([O:5][C:6](=[O:26])[NH:7][CH2:8][C:9]1[NH:29][N:28]=[C:11]([C:13]2[N:14]([CH2:24][CH3:25])[N:15]=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:17]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCn1nc(-c2ccccc2)cc1C(=O)C#CCNC(=O)OC(C)(C)C
Reactant: NN
Solvent: CCO
Solvent: O
Product: CCn1nc(-c2ccccc2)cc1-c1cc(CNC(=O)OC(C)(C)C)[nH]n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
To the above-prepared [4-(2-ethyl-5-phenyl-2H-pyrazol-3-yl)-4-oxo-but-2-ynyl]-carbamic acid tert-butyl ester in EtOH (5 mL), hydrazine monohydrate was added (excess, 5 drops), and the mixture was stirred at room temperature for 2 hours. The resulting mixture was concentrated in vacuo to a thick oil, diluted with ethyl acetate, washed sequentially with water and brine, dried over Na2SO4, filtered, and concentrated in vacuo. Flash chromatography (silica gel, hexanes/ethyl acetate gradient) provided the title compound (175 mg, 98% yeild) as a white foam. 1H NMR (CDCl3, 400 MHz): 7.86 (d, 2H); 7.39 (dd, 2H); 7.28 (dd, 1H); 6.72 (s, 1H); 6.36 (s, 1H); 5.12 (broad dd, 1H); 4.58 (q, 2H); 4.31 (d, 2H); 1.49 (s, 9H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[N:7]([C@H:12]1[CH2:16][C@@H:15]([N:17]2[CH:25]=[N:24][C:23]3[C:18]2=[N:19][C:20]([Cl:27])=[N:21][C:22]=3Cl)[CH:14]=[CH:13]1)[C:8](=[O:11])[CH2:9][CH3:10])([CH3:4])([CH3:3])[CH3:2].[CH3:29][CH2:30][CH:31]([NH2:34])[CH2:32][CH3:33]>C1COCC1>[C:1]([O:5][C:6](=[O:28])[N:7]([C@H:12]1[CH2:16][C@@H:15]([N:17]2[CH:25]=[N:24][C:23]3[C:18]2=[N:19][C:20]([Cl:27])=[N:21][C:22]=3[NH:34][CH:31]([CH2:32][CH3:33])[CH2:30][CH3:29])[CH:14]=[CH:13]1)[C:8](=[O:11])[CH2:9][CH3:10])([CH3:3])([CH3:4])[CH3:2]
Reactant: CCC(N)CC
Reactant: CCC(=O)N(C(=O)OC(C)(C)C)[C@@H]1C=C[C@H](n2cnc3c(Cl)nc(Cl)nc32)C1
Solvent: C1CCOC1
Product: CCC(=O)N(C(=O)OC(C)(C)C)[C@@H]1C=C[C@H](n2cnc3c(NC(CC)CC)nc(Cl)nc32)C1
Temperature: 50 °C
Reaction time: 18 h

Procedure:
[(1S,4R)-4-(2,6-Dichloro-purin-9-yl)-cyclopent-2-enyl]-propionyl-carbamic acid tert-butyl ester (700 mg, 1.64 mmol) is dissolved in THF (15 ml) under an atmosphere of argon. 3-Pentyl-amine (315 mg, 3.61 mmol) is added and the reaction mixture is stirred at 50° C. The reaction is shown to be complete by LCMS after 18 hours. The reaction mixture is partitioned between dichloromethane (50 ml) and 0.1M HCl (50 ml). The organic layer is washed with water (20 ml) and brine (20 ml), dried over MgSO4, filtered and the solvent is removed in vacuo to give the title compound. 1H nmr (CDCl3, 400 MHz); 8.10(s, 1H), 6.00(m, 1H), 5.70(m, 1H), 5.60(m, 2H), 5.45(m, 1H), 4.20(m, 1H), 3.65(m, 1H), 3.00(m, 1H), 2.65(m, 3H), 1.95(m, 1H), 1.60(m, 3H), 1.45(s, 9H), 1.10(m, 4H), 0.85(t, 6H), MS (ES+) m/e 477 (MH+).
Reaction SMILES: [NH2:1][C@H:2]([CH2:24][CH3:25])[C:3]([NH:5][C:6]1[CH:7]=[N:8][C:9]([O:12][C:13]2[C:18]3[C:19]4([CH2:22][O:23][C:17]=3[CH:16]=[CH:15][CH:14]=2)[CH2:21][CH2:20]4)=[CH:10][CH:11]=1)=[O:4].Cl[C:27](Cl)([O:29]C(=O)OC(Cl)(Cl)Cl)Cl>ClCCl>[CH2:24]([C@H:2]1[NH:1][C:27](=[O:29])[N:5]([C:6]2[CH:7]=[N:8][C:9]([O:12][C:13]3[C:18]4[C:19]5([CH2:22][O:23][C:17]=4[CH:16]=[CH:15][CH:14]=3)[CH2:21][CH2:20]5)=[CH:10][CH:11]=2)[C:3]1=[O:4])[CH3:25]
Reactant: CC[C@@H](N)C(=O)Nc1ccc(Oc2cccc3c2C2(CC2)CO3)nc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Product: CC[C@H]1NC(=O)N(c2ccc(Oc3cccc4c3C3(CC3)CO4)nc2)C1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 149.6 %

Procedure:
To a solution of (2R)-2-amino-N-[6-(spiro[1-benzofuran-3,1′-cyclopropan]-4-yloxy)-3-pyridinyl]butanamide (Intermediate 89, 90 mg) in dry dichloromethane (15 ml) TEA (0.185 ml, 1.326 mmol) was added and the reaction mixture was cooled to 0° C. A solution of triphosgene (35.4 mg, 0.119 mmol) in dry dichloromethane (5 mL) was slowly added and the reaction mixture was stirred for 30 minutes at the same temperature. The reaction was quenched with water (10 ml) and two phases were separated. The organic layer was dried over sodium sulphate, filtered and evaporated. The residue was purified by flash chromatography (Biotage system) on silica gel using a 10 g SNAP column and cyclohexane/ethyl acetate 8:2 to cyclohexane/ethyl acetate 1:1 as eluents affording the title compound (65 mg, 0.178 mmol) as a white solid.
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]1[CH:14]=[C:13]([N:15]2[CH:19]=[N:18][N:17]=[N:16]2)[CH:12]=[CH:11][C:10]=1[C:20]1[CH:21]=[CH:22][C:23]2[O:27][C:26]([CH:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)=[N:25][C:24]=2[CH:34]=1.[CH3:35][S:36](Cl)(=[O:38])=[O:37].C(Cl)Cl.O>C(Cl)Cl>[F:8][C:9]1[CH:14]=[C:13]([N:15]2[CH:19]=[N:18][N:17]=[N:16]2)[CH:12]=[CH:11][C:10]=1[C:20]1[CH:21]=[CH:22][C:23]2[O:27][C:26]([CH:28]3[CH2:29][CH2:30][N:31]([S:36]([CH3:35])(=[O:38])=[O:37])[CH2:32][CH2:33]3)=[N:25][C:24]=2[CH:34]=1
Reactant: CS(=O)(=O)Cl
Reactant: Fc1cc(-n2cnnn2)ccc1-c1ccc2oc(C3CCNCC3)nc2c1
Solvent: O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)N1CCC(c2nc3cc(-c4ccc(-n5cnnn5)cc4F)ccc3o2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64 %

Procedure:
5-[2-fluoro-4-(1H-tetrazol-1-yl)-phenyl]-2-(piperidin-4-yl)benzo[d]oxazole 2,2,2-trifluoroacetate (30 mg, 0.06 mmol) was dissolved in DCM (5 ml) and added TEA (60 mg, 0.6 mmol) and stirred the mixture at rt for 30 mins. To this mixture added methanesulphonyl chloride (14 mg, 0.12 mmol) and stirred at rt for 2 h. Work up (DCM/H2O) followed by purification on combiflash using a gradient mixture of EtOAc and Petether (7:3) as eluent afforded the titled compound (17 mg) as a brown solid. M. P.: 209-212° C. MS (m/z): 443.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.S(Cl)([Cl:12])(=O)=O>C(Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][Cl:12])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)Cl
Reactant: Sc1ccc(Cl)cc1
Solvent: ClC(Cl)(Cl)Cl
Product: ClSc1ccc(Cl)cc1
Temperature: 10 °C

Procedure:
A solution of 4-chlorothiophenol, 1 (20.15 g, 0.139 mol) in 170 mL of anhydrous carbon tetrachloride was placed in a 0.5 L 3-neck round bottom flask equipped with a magnetic stirrer, thermocouple, addition funnel, nitrogen line, heating mantle, condenser and caustic scrubber to absorb acidic gases (SO2 and HCl). A catalytic amount of pyridine (3 mL) was added to the solution, and the flask's content was chilled to ˜10° C. Sulfuryl chloride (55.2 g, 0.409 mol) was slowly added to the solution of 1, and the reaction mixture was gently refluxed for 3 hours. The resulting red solution was cooled to room temperature, quickly filtered through glass wool, and concentrated by rotary evaporation to yield 23 g of 4-chlorobenzene sulfenyl chloride, 2 as a viscous red oil. This crude material was used immediately for preparation of 4.
Reaction SMILES: [N:1]1([CH2:6][C@H:7]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[O:8][C:9]2[C:10]([CH2:20][S:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)(=[O:23])=[O:22])=[C:11]3[C:16](=[CH:17][CH:18]=2)[C:15](=[O:19])[CH2:14][CH2:13][CH2:12]3)[CH:5]=[CH:4][N:3]=[CH:2]1.[CH2:36]=[O:37].CS(C)=O>C(O)C>[OH:37][CH2:36][C:2]1[N:1]([CH2:6][C@H:7]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[O:8][C:9]2[C:10]([CH2:20][S:21]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)(=[O:23])=[O:22])=[C:11]3[C:16](=[CH:17][CH:18]=2)[C:15](=[O:19])[CH2:14][CH2:13][CH2:12]3)[CH:5]=[CH:4][N:3]=1
Reactant: O=C1CCCc2c1ccc(O[C@H](Cn1ccnc1)c1ccccc1)c2CS(=O)(=O)c1ccccc1
Reactant: C=O
Solvent: CCO
Solvent: CS(C)=O
Product: O=C1CCCc2c1ccc(O[C@H](Cn1ccnc1CO)c1ccccc1)c2CS(=O)(=O)c1ccccc1
Temperature: 130 °C
Reaction time: 24 h
Yield: 61 %

Procedure:
A mixture of (S)-6-[2-(1H-imidazol-1-yl)-1-phenylethoxy]-5-[(phenylsulfonyl)methyl]-3,4-dihydro-1(2H)-naphthalenone (see example 3, 250 mg, 0.51 mmol), paraformaldehyde (1.5 g) and dimethylsulfoxide (6 mL) was stirred at 130° C. for 24 h. The mixture was diluted with ethanol (10 mL), filtered, concentrated, diluted with water (50 mL) and extracted with ethyl acetate (4×10 mL). The combined extracts were washed with water (3×10 mL), dried (brine, Na2SO4), and concentrated. The residue was purified by dry-flash column chromatography (SiO2, 2.5-22.5% 2-propanol-dichloromethane) to give (S)-6-{2-[2-(hydroxymethyl)-1H-imidazol-1-yl]-1-phenylethoxy}-5-[(phenylsulfonyl)methyl]-3,4-dihydro-1(2H)-naphthalenone as a white solid, 161 mg, 61% yield. NMR spectrum was consistent with structure. MS EI: M+* 517.1816 (M+* 517.1797).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:10]([CH3:20])[C:11](=[O:19])[CH:12]=[CH:13][C:14]=2[C:15]([O:17]C)=O)=[C:4]([F:21])[CH:3]=1.[Si:22]([O:29][C@@H:30]([CH3:34])[CH2:31][O:32][NH2:33])([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23].C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:10]([CH3:20])[C:11](=[O:19])[CH:12]=[CH:13][C:14]=2[C:15]([NH:33][O:32][CH2:31][C@@H:30]([O:29][Si:22]([C:25]([CH3:26])([CH3:28])[CH3:27])([CH3:24])[CH3:23])[CH3:34])=[O:17])=[C:4]([F:21])[CH:3]=1
Reactant: COC(=O)c1ccc(=O)n(C)c1Nc1ccc(Br)cc1F
Reactant: C[C@@H](CON)O[Si](C)(C)C(C)(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C[C@@H](CONC(=O)c1ccc(=O)n(C)c1Nc1ccc(Br)cc1F)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of methyl 2-(4-bromo-2-fluorophenylamino)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylate (0.050 g, 0.14 mmol) and (S)—O-(2-(tert-butyldimethylsilyloxy)propyl)hydroxylamine (0.072 g, 0.35 mmol) in THF (1.50 mL) at 0° C. was slowly added lithium bis(trimethylsilyl)amide (0.70 ml, 0.70 mmol). After addition, the reaction mixture was stirred for 1 hour at room temperature and then quenched by with saturated NaHCO3. The reaction mixture was partitioned between EtOAc and sat NaCl. The layers were separated and the aqueous layer was back-extracted with EtOAc (1×). The combined organic layers were dried (Na2SO4), filtered and concentrated under reduced pressure to yield a crude brown solid that was used without further purification in the next step.
Reaction SMILES: COCCOCC[N:8](CCOCCOC)CCOCCOC.[C:23]([NH:27][C:28]([CH3:35])([CH3:34])[CH2:29][S:30]([OH:33])(=[O:32])=[O:31])(=[O:26])[CH:24]=[CH2:25]>>[NH4+:8].[C:23]([NH:27][C:28]([CH3:35])([CH3:34])[CH2:29][S:30]([O-:33])(=[O:31])=[O:32])(=[O:26])[CH:24]=[CH2:25]
Reactant: COCCOCCN(CCOCCOC)CCOCCOC
Reactant: C=CC(=O)NC(C)(C)CS(=O)(=O)O
Product: C=CC(=O)NC(C)(C)CS(=O)(=O)[O-]
Product: [NH4+]
Temperature: 25 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
A nitrogen purged 50 ml schlenk flask was charged with freshly distilled tris[2-(2-methoxyethoxy)-ethyl]amine (1.69 g, 5.24 mmol) and 2-acrylamido-2-methyl-1-propanesulfonic acid (AMPS) (1.09 g, 5.24 mmol) and stirred at ambient temperature for 8 hr or until completely dissolved. Total dissolution completes formation of the AMPS-ammonium salt monomer as a transparent light amber oil in a 99% yield which was used immediately without further purification.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH:5]1[CH:10]=[C:9]([OH:11])[CH:8]=[C:7]([C:12]([F:15])([F:14])[F:13])[CH:6]=1>>[N+:1]([C:10]1[CH:5]=[CH:6][C:7]([C:12]([F:15])([F:14])[F:13])=[CH:8][C:9]=1[OH:11])([O-:4])=[O:2]
Reactant: O=[N+]([O-])O
Reactant: Oc1cccc(C(F)(F)F)c1
Product: O=[N+]([O-])c1ccc(C(F)(F)F)cc1O
Yield: 27 %

Procedure:
2-Nitro-5-trifluoromethylphenol was prepared by adding concentrated HNO3 (6 mL) drop-wise to a,a,a-trifluoro-m-cresol (5 g, 30.8 mmol) at room temperature. Meter the addition was complete the reaction was quenched with saturated at sodium acetate and extracted with EtOAc. The organic was separated, dried over sodium sulfate and filtered. Concentration of the solution in vacuo afforded an oil which was purified by column chromatography (gradient 100% hexane to 50% EtOAc/hexanes) to afford the titled compound as an oil(1.7 g, 27%). 1H NMR (CDCl3): 10.6 (s, 1H, OH), 8.26(d, 1H, J=7.8 Hz), 7.45(s, 1H, arom), 7.26(d, 1H, J=7.8 Hz)
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[C:13](Cl)[CH:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:19][C:20]1[CH:25]=[C:24]([O:26][CH3:27])[C:23]([F:28])=[CH:22][C:21]=1B(O)O>>[CH2:1]([O:8][C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[C:13]([C:21]2[CH:22]=[C:23]([F:28])[C:24]([O:26][CH3:27])=[CH:25][C:20]=2[Cl:19])[CH:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(Cl)c(B(O)O)cc1F
Reactant: O=[N+]([O-])c1c(Cl)ccnc1OCc1ccccc1
Product: COc1cc(Cl)c(-c2ccnc(OCc3ccccc3)c2[N+](=O)[O-])cc1F
Yield: 63 %

Procedure:
2-Benzyloxy-4-chloro-3-nitro-pyridine (Wilde, et. al. WO 99/01454) (3.8 g, 14.3 mmol) and 2-chloro-5-fluoro-4-methoxyphenylboronic acid (Preparation 1) (3.8 g, 18.6 mmol) were treated substantially as described in Part A of Example 19a to give 3.5 g (63%) of 2-benzyloxy-4-(2-chloro-5-fluoro-4-methoxy-phenyl)-3-nitro-pyridine: 1H NMR (400 MHz, CDCl3) δ ppm 8.30 (d, J=5.4 Hz, 1 H), 7.45–7.42 (m, 2H), 7.40–7.29 (m, 3H), 7.04 (d, J=7.6 Hz, 1 H), 7.00 (d, J=10.8 Hz, 1 H), 6.91 (d, J=5.4 Hz, 1 H), 5.54 (s, 2 H), 3.91 (s, 3 H).
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.CN(C=O)C.C1(C)C=CC=CC=1.S(Cl)([Cl:38])=O>>[Cl:38][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: O=S(Cl)Cl
Reactant: COc1cc2c(O)ncnc2cc1OCCCN1CCOCC1
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: COc1cc2c(Cl)ncnc2cc1OCCCN1CCOCC1
Yield: 66 %

Procedure:
A solution of 4-hydroxy-6-methoxy-7-(3-morpholinopropoxy)quinazoline (2.87 g, 9 mmol) and DMF (1 ml) in thionyl chloride (35 ml) was refluxed for 45 minutes. After addition of toluene, the volatiles were removed by evaporation. The residue was partitioned between ethyl acetate and water and the aqueous layer was adjusted to pH8 with 2M aqueous sodium hydroxide. The organic layer was washed with water and brine, dried (MgSO4) and the volatiles were removed by evaporation. The solid residue was purified by column chromatography eluting with a mixture of methylene chloride, acetonitrile and methanol (50/47.5/2.5) to give 4-chloro-6-methoxy-7-(3-morpholinopropoxy)quinazoline (2 g, 66%).
Reaction SMILES: C[N:2]1[C:6]([C:7]([F:10])([F:9])[F:8])=[CH:5][C:4]([NH:11][C:12](=[O:20])OC2C=CC=CC=2)=[N:3]1.[CH3:21][O:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][C:32]=1[O:33][CH2:34][CH2:35][O:36][CH3:37])[N:29]=[CH:28][N:27]=[C:26]2[S:38][C:39]1[CH:40]=[C:41]([CH:43]=[CH:44][CH:45]=1)[NH2:42].[CH:46](N(CC)C(C)C)(C)C>C1COCC1>[CH3:21][O:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][C:32]=1[O:33][CH2:34][CH2:35][O:36][CH3:37])[N:29]=[CH:28][N:27]=[C:26]2[S:38][C:39]1[CH:40]=[C:41]([NH:42][C:12]([NH:11][C:4]2[N:3]([CH3:46])[N:2]=[C:6]([C:7]([F:8])([F:9])[F:10])[CH:5]=2)=[O:20])[CH:43]=[CH:44][CH:45]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: COCCOc1cc2ncnc(Sc3cccc(N)c3)c2cc1OC
Reactant: Cn1nc(NC(=O)Oc2ccccc2)cc1C(F)(F)F
Solvent: C1CCOC1
Product: COCCOc1cc2ncnc(Sc3cccc(NC(=O)Nc4cc(C(F)(F)F)nn4C)c3)c2cc1OC
Yield: 7 %

Procedure:
Using the procedure described in Example 159B, phenyl 1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-ylcarbamate described in Example 165A (0.114 g, 0.4 mmol), 3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-ylthio)aniline described in Example 231A (0.143 g, 0.4 mmol), and N,N-diisopropylethylamine (0.5 mL) in THF (6 mL) at 50° C. for 3 hours, to afford 1-{3-[6-methoxy-7-(2-methoxyethoxy)quinazolin-4-ylthio]phenyl}-3-[1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl]urea as solid (0.015 g, 7%). 1H NMR (300 MHz, CDCl3) δ 9.45 (br, 1H), 8.76 (s, 1H), 7.78 (m, 1H), 7.63 (d, 1H), 7.43 (t, 1H), 7.26-7.38 (m, 4H), 6.32 (s, 1H), 4.34 (t, 2H), 4.04 (s, 3H), 3.89 (s and t, 5H), 3.49 (s, 3H); LC-MS (ESI) m/z 549 (M+H)+.
Reaction SMILES: [H-].[Na+].CC[O:5][C:6]([CH:8](P(OCC)(OCC)=O)[F:9])=[O:7].[N:18]12[CH2:25][CH2:24][CH:21]([CH2:22][CH2:23]1)[C:20](=O)[CH2:19]2.[BH3:27].[CH2:28]1COC[CH2:29]1>C(O)(=O)C.O.C1COCC1>[CH2:28]([CH:19]1[C:20](=[C:8]([F:9])[C:6]([OH:5])=[O:7])[CH:21]2[CH2:24][CH2:25][N:18]1[CH2:23][CH2:22]2)[CH3:29].[BH3:27]
Reactant: CCOC(=O)C(F)P(=O)(OCC)OCC
Reactant: C1CCOC1
Reactant: O=C1CN2CCC1CC2
Agent: B
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCC1C(=C(F)C(=O)O)C2CCN1CC2
Temperature: 50 °C
Reaction time: 2 h
Yield: 70.5 %

Procedure:
Sodium hydride (60 wt. %, 83.6 g, 2.09 mol) was added to a mixture of triethyl 2-fluoro-2-phosphonoacetate (506 g, 2.09 mol) and THF (3.0 l) with ice-cooling, and the mixture was stirred for 2 hours. A THF (600 ml) solution of 3-quinuclidinone (238 g, 1.90 mol) was added and the mixture was stirred at room temperature for 5 days. Water (500 ml) was added to the reaction mixture and the mixture was concentrated under a reduced pressure. Water (2.5 l) was added to the residue, and then the reaction product was extracted with chloroform (1.5 l×2). The extract was washed with saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate and then concentrated under a reduced pressure. THF (1.0 l) was added to the resulting yellow oily material, and then a borane-THF complex (1.0M THF solution, 2.1 l, 2.1 mol) was added dropwise with ice-cooling spending 2.5 hours. After additional 0.5 hour of stirring, water (400 ml) was added to the reaction mixture and the mixture was concentrated under a reduced pressure. Ethyl acetate was added to the resulting residue, the mixture was washed with water and saturated sodium chloride aqueous solution in that order, dried over anhydrous magnesium sulfate, and then concentrated under a reduced pressure. The resulting residue was washed with hexane (400 ml) and dried under a reduced pressure. Ethanol (2.8 l) was added to the resulting brown solid (402 g) and then, while heating at 50° C., sodium hydride (60 wt. %, 4.24 g, 106 mmol) was added, and the mixture was stirred for 7 hours. After spontaneous cooling, acetic acid (5.4 ml) was added to the reaction mixture, and the mixture was concentrated under a reduced pressure. Ethyl acetate was added to the residue, and the mixture was washed with water and saturated sodium chloride aqueous solution in that order, dried over anhydrous magnesium sulfate, and then concentrated under a reduced pressure. Ethanol (1.2 l) was added to the resulting brown solid, and the mixture was stirred for 20 minutes. The insoluble matter was removed by filtration and then the resulting filtrate was concentrated under a reduced pressure to give the title compound (304 g, E/Z mixture) as a brown oil.