Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH:10]([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][CH:13]=2)[CH3:11])=[O:8])=[C:4]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=2)[CH:3]=1.[N:28]([Sn](CCCC)(CCCC)CCCC)=[N+:29]=[N-:30]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH:10]([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[NH:30][N:29]=[N:28][N:19]=3)=[CH:16][CH:17]=2)[CH3:11])=[O:8])=[C:4]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=2)[CH:3]=1
Reactant: CC(NC(=O)c1sc(Cl)cc1Cc1cccc(Cl)c1)c1ccc(C#N)cc1
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Solvent: Cc1ccccc1
Product: CC(NC(=O)c1sc(Cl)cc1Cc1cccc(Cl)c1)c1ccc(-c2nnn[nH]2)cc1
Temperature: 25 °C

Procedure:
A mixture of 5-chloro-3-(3-chlorobenzyl)-N-[1-(4-cyanophenyl)ethyl]thiophene-2-carboxamide from Example 2, Step 1 (192 mg, 0.462 mmol) and azidotributyltin (0.380 mL, 1.39 mmol) in toluene (1 mL) was heated to reflux under N2 for 3 h and cooled to r.t. The crude was purified directly by flash chromatography (2-10% iPrOH/hexanes) to give the desired product as a white solid. MS (−ESI): m/z 456 (M−1)−.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([C:11]2[C:22](=[O:23])[N:21]([CH3:24])[C:14]3[N:15]=[C:16](SC)[N:17]=[CH:18][C:13]=3[CH:12]=2)[CH:5]=1.OOS([O-])=O.[K+].[NH2:32][CH:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1>>[CH3:1][O:2][C:3](=[O:25])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([C:11]2[C:22](=[O:23])[N:21]([CH3:24])[C:14]3[N:15]=[C:16]([NH:32][CH:33]4[CH2:38][CH2:37][O:36][CH2:35][CH2:34]4)[N:17]=[CH:18][C:13]=3[CH:12]=2)[CH:5]=1
Reactant: COC(=O)c1ccc(C)c(-c2cc3cnc(SC)nc3n(C)c2=O)c1
Reactant: NC1CCOCC1
Agent: O=S([O-])OO
Agent: [K+]
Product: COC(=O)c1ccc(C)c(-c2cc3cnc(NC4CCOCC4)nc3n(C)c2=O)c1

Procedure:
4-Methyl-3-(8-methyl-2-methylsulfanyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-6-yl)-benzoic acid methyl ester was treated with OXONE™ following the procedure of step 3 of Example 1, and the resulting sulfonyl compound was treated with 4-amino-tetrahydropyran using the procedure of step 4 of Example 1, to give 4-methyl-3-[8-methyl-7-oxo-2-(tetrahydro-pyran-4-ylamino)-7,8-dihydro-pyrido[2,3-d]pyrimidin-6-yl]-benzoic acid methyl ester: MS (M+H)=409; MP=122.5-126.5° C.
Reaction SMILES: [C:1]([C:4]1[C:13]([NH:14][CH3:15])=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[N+:16]([O-])=O)[N:5]=1)(=[O:3])[CH3:2].[H][H]>C(OCC)(=O)C.[Pd]>[C:1]([C:4]1[C:13]([NH:14][CH3:15])=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH2:16])[N:5]=1)(=[O:3])[CH3:2]
Reactant: CNc1cc2c([N+](=O)[O-])cccc2nc1C(C)=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CNc1cc2c(N)cccc2nc1C(C)=O

Procedure:
650 mg (2.7 mmol) of 2-acetyl(methyl)amino-5-nitroquinoline and 161 mg of 10% Pd—C are stirred in 25 ml of ethyl acetate for 2 hours in a hydrogen atmosphere at room temperature. The batch is filtered and concentrated by evaporation: 490 mg of product.
Reaction SMILES: Br[C:2]1[CH:21]=[CH:20][C:5]([C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=2)=[O:7])=[CH:4][N:3]=1.[C:22]1(B(O)O)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.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][O:18][C:12]1[CH:11]=[C:10]([CH:15]=[CH:14][C:13]=1[O:16][CH3:17])[CH2:9][NH:8][C:6](=[O:7])[C:5]1[CH:20]=[CH:21][C:2]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[N:3][CH:4]=1
Reactant: OB(O)c1ccccc1
Reactant: COc1ccc(CNC(=O)c2ccc(Br)nc2)cc1OC
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: [Cs+]
Solvent: CN(C)C=O
Product: COc1ccc(CNC(=O)c2ccc(-c3ccccc3)nc2)cc1OC
Temperature: 90 °C
Yield: 40.6 %

Procedure:
To a mixture consisting of 6-bromo-N-(3,4-dimethoxybenzyl)nicotinamide (1.11 g), phenylboronic acid (0.77 g), and tetrakis(triphenylphosphine)palladium(0) (0.365 g) in N,N-dimethylformamide (20 mL) under a nitrogen atmosphere was added a 2 M aqueous cesium carbonate (6 mL). The stirring mixture was heated to 90° C. for two hours and was subsequently partitioned between ethyl acetate (200 mL) and water (200 mL). The phases were separated and the organic phase was washed twice with fresh portions of water (2×200 mL) and brine solution (150 mL), was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to provide an orange solid. The solid was triturated with 1:1 v/v hexanes-ethyl acetate and collected by filtration to afford the title compound as a solid (0.447 g, 40.6% yield); 1H-NMR (300 MHz; CDCl3) δ 9.06 (d, 1H, J=2.1 Hz), 8.20 (dd, 1H, J=8.4, 2.4 Hz), 8.05-8.01 (m, 2H), 7.81 (dd, 1H, J=8.4, 0.6 Hz), 7.51-7.47 (m, 3H), 6.92-6.84 (m, 3H), 6.51 (broad t, 1H), 4.62 (d, 2H, J=5.7 Hz), 3.891 (s, 3H), 3.888 (s, 3H); Rf 0.17 with 7:3 v/v hexanes-ethyl acetate; MS (APCl+) m/z 349 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.[CH3:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[N:30]=[C:31]=[O:32]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:17]=[CH:18][C:19]([NH:22][C:31]([NH:30][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[CH3:23])=[O:32])=[CH:20][CH:21]=1
Reactant: Cc1ccccc1N=C=O
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=O)Nc4ccccc4C)cc3)c2cc1OC
Yield: 82 %

Procedure:
6,7-Dimethoxy-4-(4-aminophenoxy)quinoline (51 mg) was dissolved in toluene (5 ml) with heat, 2-methylphenyl isocyanate (0.2 ml) was added, and the admixture was refluxed with heat for 15 minutes. The resulting residue was purified by column chromatography on silica gel eluting with chloroform/acetone (10/1) to obtain 61 mg of the title compound (yield: 82%).
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([C:14]1[CH:15]=[N:16][N:17]([CH3:20])[C:18]=1Cl)=[O:13])[CH2:8]2.C(N(CC)CC)C.[NH2:28][C:29](C)([CH3:33])[C:30](O)=O>>[CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([C:14]1[CH:15]=[N:16][N:17]([CH3:20])[C:18]=1[NH:28][CH:29]([CH3:33])[CH3:30])=[O:13])[CH2:8]2
Reactant: CC(C)(N)C(=O)O
Reactant: Cn1ncc(C(=O)NC2C3CC4CC(C3)CC2C4)c1Cl
Solvent: CCN(CC)CC
Product: CC(C)Nc1c(C(=O)NC2C3CC4CC(C3)CC2C4)cnn1C

Procedure:
Heating a mixture of 5-chloro-1-methyl-1H-pyrazole-4-carboxylic acid adamantan-2-ylamide (Example 5, 88 mg; 0.30 mmol), triethylamine (0.43 mL; 3.1 mmol) and 2-aminoisobutyric acid (320 mg; 3.1 mmol) under microwave irradiation for 6 hr according to the procedure described for Example 14 provided after purification by reverse phase HPLC, 5-isopropylamino-1-methyl-1H-pyrazole-4-carboxylic acid adamantan-2-ylamide (28 mg, 29%) as an off-white powder. ES-HRMS m/e calcd for C18H29N4O (M+H+) 317.2336, found 317.2334.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[C:4]([CH:9](C(OCC)=O)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[N:5][CH:6]=[CH:7][CH:8]=1.CS(C)=O.[Cl-].[Na+]>O>[F:21][C:2]([F:1])([F:20])[C:3]1[C:4]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[N:5][CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(=O)C(C(=O)OCC)c1ncccc1C(F)(F)F
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)Cc1ncccc1C(F)(F)F
Temperature: 138.5 °C
Reaction time: 0.33 h
Yield: 99.6 %

Procedure:
6.10 g of diethyl (3-trifluoromethyl-2-pyridyl)malonate and 20 ml of dimethyl sulfoxide were mixed. To the mixture was added 1.40 g of sodium chloride and 0.72 g of water. The mixture was stirred for about 20 minutes at an inner temperature of 132 to 145° C. The reaction mixture was allowed to cool to room temperature, then, to the reaction mixture was added water, and extracted with ethyl acetate. The organic layer was washed with saturated brine twice, and dried over anhydrous magnesium sulfate, then, concentrated under reduced pressure, to obtain 4.64 g of ethyl (3-trifluoromethyl-2-pyridyl)acetate.
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].[NH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>CCOCC>[CH3:1][NH:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:4]
Reactant: Nc1ccccc1
Reactant: CN=C=O
Solvent: CCOCC
Product: CNC(=O)Nc1ccccc1

Procedure:
1-Methyl-3-phenylurea was prepared by the dropwise addition of methylisocyanate (6 ml, 0.1 mole) over three hours to an ether solution (100 ml) containing aniline (9 ml, 0.1 mole) at 4° C. with stirring. 1-Methyl-3-phenylurea precipitated as purple crystals which were recrystallized from ethanol, m.p. 150° C.
Reaction SMILES: [C:1]([N:4]1[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[C:13](Cl)[CH:12]=[CH:11][C:10]=2[C:16]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[C:29]([CH3:30])=[CH:28][C:27]([CH3:31])=[CH:26][N:25]=3)[CH2:20][CH2:19]2)=[O:17])[C:5]1=[O:32])(=[O:3])[CH3:2].[O:33]1[CH2:37][CH2:36][NH:35][C:34]1=[O:38]>>[C:1]([N:4]1[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[C:13]([N:35]3[CH2:36][CH2:37][O:33][C:34]3=[O:38])[CH:12]=[CH:11][C:10]=2[C:16]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[C:29]([CH3:30])=[CH:28][C:27]([CH3:31])=[CH:26][N:25]=3)[CH2:20][CH2:19]2)=[O:17])[C:5]1=[O:32])(=[O:3])[CH3:2]
Reactant: O=C1NCCO1
Reactant: CC(=O)N1CCN(c2cc(Cl)ccc2C(=O)N2CCN(c3ncc(C)cc3C)CC2)C1=O
Product: CC(=O)N1CCN(c2cc(N3CCOC3=O)ccc2C(=O)N2CCN(c3ncc(C)cc3C)CC2)C1=O
Yield: 10.2 %

Procedure:
By reaction and treatment in the same manner as in Example 201 and using 1-acetyl-3-{5-chloro-2-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]phenyl}imidazolidin-2-one (221.5 mg) described in Preparation Example 126 and oxazolidin-2-one (42.3 mg), the title compound (25.2 mg) was obtained.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][N:14]=[C:13]([C:17]#[N:18])[CH:12]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O.C(OCC)(=O)C>[C:17]([C:13]1[CH:12]=[C:11]([CH2:10][CH2:9][OH:8])[CH:16]=[CH:15][N:14]=1)#[N:18]
Reactant: CC(C)(C)[Si](C)(C)OCCc1ccnc(C#N)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: CCOC(C)=O
Product: N#Cc1cc(CCO)ccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.9 %

Procedure:
4-[2-(tert-Butyldimethylsilyloxy)ethyl]-2-cyanopyridine (12.8 g, 48.8 mmol) and a solution of tetrabutylammonium fluoride (1 M in THF, 73 mL, 73 mmol) were charged to a round bottom flask and stirred at room temperature overnight. The mixture was diluted with water and ethyl acetate. The layers were separated and the water layer extracted with ethyl acetate. The organic layers were combined, washed with water and brine, dried (Na2SO4), filtered and concentrated. The residue was purified by chromatography (SiO2, 50:1 CH2Cl2: methanol) to provide 2-cyano-4-(2-hydroxyethyl)pyridine (4.4 g, 61%) as an off white solid.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH2:5]([N:7]1[C:11]2=[N:12][C:13]([CH2:25][CH3:26])=[C:14]([CH2:23]O)[C:15]([NH:16][CH:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[C:10]2[CH:9]=[N:8]1)[CH3:6]>>[Cl:3][CH2:23][C:14]1[C:13]([CH2:25][CH3:26])=[N:12][C:11]2[N:7]([CH2:5][CH3:6])[N:8]=[CH:9][C:10]=2[C:15]=1[NH:16][CH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CO
Reactant: O=S(Cl)Cl
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CCl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59.8 %

Procedure:
To a solution of thionyl chloride (1.46 mL, 20.0 mmol) was added [1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methanol (0.609 g, 2.0 mmol) slowly. The mixture was stirred at room temperature for 30 min and then was concentrated on rotavap under vacuum. The residue was twice taken up in DCM (5 mL) and concentrated on rotavap to afford the title compound 0.386 g (60%). LC-MS m/z 319 (M+H)+ [molecular ion of the compound with methoxy from LC-MS solvent methanol where OMe substituted chloro group of the original product].
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1/[CH:10]=[CH:11]/[C:12]([O:14][CH2:15][CH3:16])=[O:13].Br[CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.CC(C)=O>[C:22]([O:21][C:19](=[O:20])[CH2:18][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1/[CH:10]=[CH:11]/[C:12]([O:14][CH2:15][CH3:16])=[O:13])([CH3:25])([CH3:24])[CH3:23]
Reactant: CCOC(=O)/C=C/c1cc2ccccc2[nH]1
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C/c1cc2ccccc2n1CC(=O)OC(C)(C)C
Temperature: 60 °C
Reaction time: 24 h
Yield: 98 %

Procedure:
To a solution of the product of Step 2 (20 g) in 300 mL of DMF was added 30 g of BrCH2CO2-t-Bu and 65 g of Cs2CO3. The reaction mixture was stirred at 60° C. for 24 h, and was then diluted with 300 ml of acetone and filtered. The filtrate was concentrated and the residue was purified by silica gel chromatography eluted with 1:2 EtOAc/hexane to give 30 g of the title compound as a syrup.
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:9][C@H:8]2[C:10]([OH:12])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:13][Li]>C(OCC)C>[C:1]1([C@@H:7]2[CH2:9][C@H:8]2[C:10](=[O:12])[CH3:13])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)[C@@H]1C[C@H]1c1ccccc1
Reactant: [Li]C
Solvent: CCOCC
Product: CC(=O)[C@@H]1C[C@H]1c1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
trans-2-Phenyl-1-cyclopropanecarboxylic acid (2.0 g, 12.3 mmol) was dissolved in diethyl ether (40 mL) and cooled to 0° C. Methyllithium (1.6 M in hexanes, 16.8 mL, 27 mmol) was added dropwise and then the reaction stirred for 1 hour. The reaction was quenched with MeOH then submitted to standard aqueous workup and silica gel chromatography (0-40% EtOAc in hexanes) to afford the title compound.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([C:22]2[O:26][N:25]=[C:24]([Br:27])[N:23]=2)[CH:8]=[C:9]([C:18]([CH3:21])([CH3:20])[CH3:19])[C:10]=1[O:11]COCCOC)([CH3:4])[CH3:3]>[Br-].[Zn+2].[Br-]>[Br:27][C:24]1[N:23]=[C:22]([C:7]2[CH:6]=[C:5]([C:2]([CH3:1])([CH3:3])[CH3:4])[C:10]([OH:11])=[C:9]([C:18]([CH3:21])([CH3:20])[CH3:19])[CH:8]=2)[O:26][N:25]=1
Reactant: COCCOCOc1c(C(C)(C)C)cc(-c2nc(Br)no2)cc1C(C)(C)C
Agent: [Br-]
Agent: [Zn+2]
Product: CC(C)(C)c1cc(-c2nc(Br)no2)cc(C(C)(C)C)c1O
Yield: 56.6 %

Procedure:
In a manner analogous to Example 59, 0.8 g (0.002 mole) of 5-[3,5-bis(1,1-dimethylethyl)-4-[(2-methoxyethoxy)methoxy]phenyl]-3-bromo-1,2,4-oxadiazole is reacted with 2.0 g (0.009 mole) of zinc bromide to give 0.4 g (65%) of 4-(3-bromo-1,2,4-oxadiazol-5-yl)-2,6-bis(1,1-dimethylethyl)phenol, mp 113°-115° C.
Reaction SMILES: [CH2:1]([C:3]1[C:7]([C:8]([NH:10][CH3:11])=[O:9])=[C:6]([CH2:12][C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=O)[O:5][N:4]=1)[CH3:2].S(=O)(=O)(O)O>>[CH2:1]([C:3]1[C:7]2[C:8](=[O:9])[N:10]([CH3:11])[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:12][C:6]=2[O:5][N:4]=1)[CH3:2]
Reactant: CCc1noc(CC(=O)c2ccccc2)c1C(=O)NC
Agent: O=S(=O)(O)O
Product: CCc1noc2cc(-c3ccccc3)n(C)c(=O)c12

Procedure:
A mixture of 11.0 g. (0.0405 mole) of 3-ethyl-N-methyl-5-phenacyl-4-isoxazole carboxamide and 120 ml. of 2 M sulfuric acid is refluxed for 18 hours. The mixture is cooled and extracted with methylene chloride. The methylene chloride layer is washed with water and then brine, dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo. The residue is triturated with ether and filtered to give 3-ethyl-5-methyl-6-phenyl-isoxazolo[4,5-c]pyridin-4(5H)-one, m.p. 167° to 169° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH:23]([CH3:25])[CH3:24])/[CH:9]=[C:10](\[C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1)/[C:11]([O:13]CC)=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[OH-].[Na+]>CCO>[C:1]([O:5][C:6]([N:8]([CH:23]([CH3:25])[CH3:24])/[CH:9]=[C:10](\[C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1)/[C:11]([OH:13])=[O:12])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CCOC(=O)/C(=C/N(C(=O)OC(C)(C)C)C(C)C)c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)N(/C=C(/C(=O)O)c1ccc(Cl)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 89.8 %

Procedure:
(E)-ethyl 3-((tert-butoxycarbonyl)(isopropyl)amino)-2-(4-chlorophenyl)acrylate (133.5 kg, 362.9 mol) was added into a mixture of H2O (252 L), NaOH (58.25 kg, 1456 mol) and EtOH (383.5 L) stirred at room temperature. The mixture was warmed to 40-45° C. for 2.5 h until a clear solution was formed. The mixture was concentrated to a minimum working volume maintaining the temperature below 50° C. The mixture was then cooled to 10-25° C. and a solution of HCl was added (842 L of 2N HCl and 11 L of 35% HCl) until a final pH=2˜4 was obtained. The aqueous layer was separated and the organic layer was washed with 25% aqueous NaCl (810 L). n-Heptane was added while distilling to form a suspension. The product was collected and washed with n-heptane and dried at 40-45° C. for ˜10 h to afford 110.7 kg (90.5% yield) of (E)-3-(tert-butoxycarbonyl(isopropyl)amino)-2-(4-chlorophenyl)acrylic acid having 99.9 A % purity by HPLC. E-configuration was confirmed using single crystal x-ray analysis (See FIG. 1).
Reaction SMILES: C([Sn](CCCC)(OCCCC)[O:6][Sn:7]([CH2:17][CH2:18][CH2:19][CH3:20])([CH2:13][CH2:14][CH2:15][CH3:16])[O:8][CH2:9][CH2:10][CH2:11][CH3:12])CCC>C(O)CCC>[CH2:17]([Sn:7]([CH2:13][CH2:14][CH2:15][CH3:16])([O:6][CH2:9][CH2:10][CH2:11][CH3:12])[O:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH2:18][CH2:19][CH3:20]
Reactant: CCCCO[Sn](CCCC)(CCCC)O[Sn](CCCC)(CCCC)OCCCC
Solvent: CCCCO
Product: CCCCO[Sn](CCCC)(CCCC)OCCCC
Temperature: 140 °C
Reaction time: 0.1 h
Yield: 47 %

Procedure:
A feed pump was used to start feeding the starting material 1,1,3,3-tetrabutyl-1,3-di(butyloxy)-distannoxane prepared in the same manner as in Example 12 from supply line 77 at 280 g/Hr and the reactant 1-butanol (manufactured by Wako Pure Chemical Industries Ltd., Japan, industrial product) from supply line 78 at 1,330 g/Hr. The holding time in the reactor was 6 minutes. Reaction solution which accumulated in the reactor lower portion was circulated at 6,000 g/Hr by the circulation line 80 and the reboiler 81 while heating at a temperature of about 140° C. The liquid temperature inside the reactor was 140° C., and the pressure of the back pressure valve 89 was adjusted to 0.096 MPa-G. Continuous supply was continued in this state for 10 hours, after which the system reached a steady state. Low boiling point components flowed from the reactor upper portion 84 and through the low boiling point component recovery line 86 for liquefaction at the condenser 87, and were thereby recovered from the liquid-phase recovery line 91 at 1,031 g/Hr. Furthermore, from the reactor lower portion 85, a dibutyltin alkoxide-containing component was recovered at 602 g/Hr from the extraction line 92. Analysis of the recovered liquid showed that, using dibutyltin oxide as a reference, the liquid contained a dibutyltin alkoxide consisting of a yield of about 47.0% dibutyl-di(butyloxy)tin and 52.9% of 1,1,3,3-tetrabutyl-1,3-di(butyloxy)-distannoxane. Tributyltin butoxide had a yield of 0.012%. Meanwhile, the liquid recovered from the liquid-phase recovery line 91 was transparent and contained 2,200 ppm of moisture. The dehydration rate in the column reactor was 0.21 mol/Hr, which was greater than the value 0.00037 mol/Hr calculated from expression (16).
Reaction SMILES: FC(F)(F)C(O)=O.COC[O:11][C:12]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:13]=1[C:22]1[N:27]=[CH:26][N:25]=[C:24]([O:28][C:29]2[C:34]3[N:35]=[C:36]([NH:38][C:39](=[O:41])[CH3:40])[S:37][C:33]=3[CH:32]=[CH:31][CH:30]=2)[CH:23]=1>ClCCl>[OH:11][C:12]1[CH:17]=[C:16]([C:18]([F:21])([F:19])[F:20])[CH:15]=[CH:14][C:13]=1[C:22]1[N:27]=[CH:26][N:25]=[C:24]([O:28][C:29]2[C:34]3[N:35]=[C:36]([NH:38][C:39](=[O:41])[CH3:40])[S:37][C:33]=3[CH:32]=[CH:31][CH:30]=2)[CH:23]=1
Reactant: COCOc1cc(C(F)(F)F)ccc1-c1cc(Oc2cccc3sc(NC(C)=O)nc23)ncn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4O)ncn3)cccc2s1

Procedure:
Trifluoroacetic acid (0.10 mL, 1.3 mmol, Aldrich) was added dropwise to a solution of N-{4-[6-(2-methoxymethoxy-4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-benzothiazol-2-yl}-acetamide, (Example 136(b)), (0.50 g, 1.0 mmol) in dichloromethane (10 mL) with stirring and cooling in an ice bath. The reaction mixture was stirred for 16 h at room temperature, diluted with dichloromethane (5 mL) and quenched with satd sodium bicarbonate solution. The reaction mixture was diluted with water (100 mL), extracted with dichloro-methane (2×100 mL), and the combined organic extracts were concentrated in vacuum. The resulting white solid was suspended in MeOH (50 mL), collected by filtration, and dried under vacuum to obtain the title compound as a white solid. Mp: 302–304° C. MS (ESI, pos. ion.) m/z: 445 (M+1).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[N:10][C:9]=2[C:17]2[CH:18]=[CH:19][C:20]([F:24])=[C:21]([CH:23]=2)[NH2:22])[CH:5]=[CH:4][N:3]=1.N1C=CC=CC=1.[F:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[C:33]=1[S:39](Cl)(=[O:41])=[O:40]>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[N:10][C:9]=2[C:17]2[CH:18]=[CH:19][C:20]([F:24])=[C:21]([NH:22][S:39]([C:33]3[C:34]([F:38])=[CH:35][CH:36]=[CH:37][C:32]=3[F:31])(=[O:41])=[O:40])[CH:23]=2)[CH:5]=[CH:4][N:3]=1
Reactant: O=S(=O)(Cl)c1c(F)cccc1F
Reactant: CC(C)(C)c1nc(-c2ccc(F)c(N)c2)c(-c2ccnc(Cl)n2)s1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)c1nc(-c2ccc(F)c(NS(=O)(=O)c3c(F)cccc3F)c2)c(-c2ccnc(Cl)n2)s1
Temperature: 0 °C
Yield: 61.8 %

Procedure:
To a solution of 5-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluoroaniline (13 g, 36 mmol) in DCM (100 mL) was added pyridine (8.5 g, 107 mmol). The mixture was cooled to 0° C. 2,6-Difluorobenzene-1-sulfonyl chloride (9.1 g, 43 mmol) in DCM (20 mL) was added dropwise to the mixture. The reaction was stirred at rt over night. Then the reaction was washed with water (100 mL), and extracted with DCM (2×200 mL). The organic layer was washed with brine, dried over anhydrous NaSO4, filtrated and concentrated under reduced pressure to give the crude product, which was purified by column chromatography on silica gel (petroleum ether:DCM 1:2) to afford the title compound (12 g, 62.2% yield, two batches combined). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.95-11.05 (br, 1H), 8.54 (d, J=5.2 Hz, 1H), 7.67-7.79 (m, 1H), 7.45-7.50 (m, 2H), 7.22-7.37 (m, 3H), 7.10 (d, J=5.2 Hz, 1H), 1.42 (s, 9H). MS (ES+): 539 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[OH-].[Na+].[C:17](Cl)(=O)[CH2:18][CH2:19][CH2:20][CH3:21].Cl>C1COCC1>[CH2:18]([C:17]1[N:6]=[C:4]([OH:5])[C:3]2[C:2](=[CH:10][CH:9]=[C:8]([C:11]([F:12])([F:13])[F:14])[CH:7]=2)[N:1]=1)[CH2:19][CH2:20][CH3:21]
Reactant: NC(=O)c1cc(C(F)(F)F)ccc1N
Reactant: CCCCC(=O)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCCc1nc(O)c2cc(C(F)(F)F)ccc2n1
Reaction time: 4 h
Yield: 83.1 %

Procedure:
Preparation D11, Step 1: 2-amino-5-(trifluoromethyl)-benzamide (100 mg, 0.49 mmol, 1 eq) was suspended in THF (5 mL) at 0° C. then 1.000N NaOH (0.73 mL, 0.735 mmol, 1.5 eq) was added. Valeryl chloride (87 μL, 0.735 mmol, 1.5 eq) was slowly dripped into the mixture. After 4 hours, little reaction. Added more 1.000N NaOH (5.84 mL, 5.88 mmol, 12 eq) followed by more valeryl chloride (0.70 mL, 5.88 mmol, 12 eq). After the reaction was complete, added conc. HCl until pH=3. Stripped off the THF. Extracted the aqueous 3 times with ethyl acetate. The organic layers were combined, dried (sodium sulfate) and stripped to give an oil. Purified over silica gel in 9:1 to 1:1 hexanes/ethyl acetate to give 2-butyl-6-(trifluoromethyl)quinazolin-4-ol (110 mg) as a white solid. Yield=78%. LCMS detects (M+H)+=271.21.