Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:8])[CH2:3][C:4]([CH3:7])([OH:6])[CH3:5].[Br:9][C:10]1[N:11]=[N:12][C:13](Br)=[CH:14][CH:15]=1.[H-].[Na+]>C1COCC1>[Br:9][C:10]1[N:11]=[N:12][C:13]([O:6][C:4]([CH3:7])([CH3:5])[CH2:3][N:2]([CH3:8])[CH3:1])=[CH:14][CH:15]=1
Reactant: Brc1ccc(Br)nn1
Reactant: CN(C)CC(C)(C)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(C)CC(C)(C)Oc1ccc(Br)nn1
Temperature: 0 °C
Reaction time: 8 h
Yield: 65.1 %

Procedure:
In a 100 mL round bottom flask was added 1-(dimethylamino)-2-methylpropan-2-ol (1.48 g, 12.6 mmol, Eq: 1.5), THF and 3,6-dibromopyridazine (2 g, 8.41 mmol, Eq: 1.00). The flask was cooled to 0° C. followed by addition of NaH (572 mg, 14.3 mmol, Eq: 1.7) in one portion. The turbid reaction mixture was allowed to warm to room temperature and was stirred at room temperature overnight. The resultant black reaction mixture was absorbed onto silica gel and purified by LC chromatography eluting with 0-5% MeOH in 1/1 EtOAc/Hex to afford 1.5 g (65%) of the title compound.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:9][C:10]1[N:11]=[C:12](Cl)[C:13]2[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[S:16][C:14]=2[N:15]=1>>[Cl:9][C:10]1[N:11]=[C:12]([NH:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:13]2[CH:18]=[C:17]([C:19]([F:21])([F:22])[F:20])[S:16][C:14]=2[N:15]=1
Reactant: NCc1ccccc1
Reactant: FC(F)(F)c1cc2c(Cl)nc(Cl)nc2s1
Product: FC(F)(F)c1cc2c(NCc3ccccc3)nc(Cl)nc2s1

Procedure:
Following the procedure of Example 1, the reaction of benzylamine with 2,4-dichloro-6-trifluoromethyl-thieno-[2,3-d]-pyrimidine yields 2-chloro-6-trifluoromethyl-4-benzylamino-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: CON(C)[C:4]([C:6]1[C:7]([NH2:15])=[N:8][C:9]([S:12][CH2:13]C)=[N:10][CH:11]=1)=[O:5].Br[C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1[CH2:25][CH3:26]>>[NH2:15][C:7]1[C:6]([C:4]([C:18]2[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=2[CH2:25][CH3:26])=[O:5])=[CH:11][N:10]=[C:9]([S:12][CH3:13])[N:8]=1
Reactant: CCc1ccc(F)cc1Br
Reactant: CCSc1ncc(C(=O)N(C)OC)c(N)n1
Product: CCc1ccc(F)cc1C(=O)c1cnc(SC)nc1N

Procedure:
The compound was prepared from 4-amino-2-ethylsulfanyl-pyrimidine-5-carboxylic acid methoxy-methyl-amide, Example 1, and 2-bromo-1-ethyl-4-fluoro-benzene (prepared from 2-bromo-4-fluoroacetophenone, WO0015634) in an analogous manner as described in Example 169.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][O:8][C:7]([CH2:18][CH3:19])([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)[C:6]=2[CH:20]=1.Br[C:22]1[S:26][C:25]([C:27]#[N:28])=[CH:24][C:23]=1[CH3:29]>>[CH2:18]([C:7]1([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)[C:6]2[CH:20]=[C:2]([C:22]3[S:26][C:25]([C:27]#[N:28])=[CH:24][C:23]=3[CH3:29])[CH:3]=[CH:4][C:5]=2[NH:11][C:10](=[O:12])[CH2:9][O:8]1)[CH3:19]
Reactant: Cc1cc(C#N)sc1Br
Reactant: CCC1(c2cccs2)OCC(=O)Nc2ccc(Br)cc21
Product: CCC1(c2cccs2)OCC(=O)Nc2ccc(-c3sc(C#N)cc3C)cc21

Procedure:
Prepared from 7-bromo-5-ethyl-5-thien-2-yl-1,5-dihydro-4,1-benzoxazepin-2(3H)-one and 5-bromo-4-methyl-thiophene-2-carbonitrile generally according to the procedures described in examples 82 and 1. An off-white solid: mp 182-184° C.; 1H NMR (DMSO-d6): δ 10.19 (s, 1H), 7.83 (s, 1H), 7.57 (dd, J=4.88, 0.98 Hz, 1H), 7.46 (dd, J=8.3, 1.95 Hz, 1H), 7.33 (d, J=1.95 Hz, 1H), 7.29 (d, J=8.3 Hz, 1H), 7.07 (dd, J=4.88, 3.42 Hz, 1H), 6.98 (dd, J=3.42, 0.98 Hz, 1H), 4.14 (d, J=15.6 Hz, 1H), 3.98 (d, J=15.13 Hz, 1H), 2.47 (m, 1H), 2.35 (m, 1H), 2.21 (s, 3H), 0.77 (t, J=6.84 Hz, 3H); MS (ESI) m/z 395 ([M+H]+); MS (ESI) m/z 393 ([M−H]−); Anal. calcd for C21H18N2O2S2: C: 63.93; H: 4.60; N: 7.10. Found: C: 60.33; H: 4.13; N: 6.65.
Reaction SMILES: [C:1]([C:5]1[N:6]([CH3:24])[C:7](=[O:23])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([O:21]C)=[CH:10][CH:9]=2)([CH3:4])([CH3:3])[CH3:2]>Br>[C:1]([C:5]1[N:6]([CH3:24])[C:7](=[O:23])[C:8]2[C:13]([C:14]=1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[CH:12][C:11]([OH:21])=[CH:10][CH:9]=2)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc2c(=O)n(C)c(C(C)(C)C)c(-c3ccccc3)c2c1
Agent: Br
Product: Cn1c(C(C)(C)C)c(-c2ccccc2)c2cc(O)ccc2c1=O

Procedure:
A mixture of 3-tert-butyl-6-methoxy-2-methyl-4-phenylisoquinolin-1(2H)-one (0.333 g) and 48% HBr (30 mL) was heated at reflux for 8 h. The reaction was concentrated to give 3-tert-butyl-6-hydroxy-2-methyl-4-phenylisoquinolin-1(2H)-one as a brown solid, which was used without further purification.
Reaction SMILES: Cl.[CH2:2]([NH:9][C@H:10]([CH2:14][OH:15])[C:11]([OH:13])=[O:12])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[OH-].[Na+].[Cl:18][CH2:19][C:20](Cl)=[O:21]>O>[CH2:2]([N:9]([C@H:10]([CH2:14][OH:15])[C:11]([OH:13])=[O:12])[C:20](=[O:21])[CH2:19][Cl:18])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=C(O)[C@@H](CO)NCc1ccccc1
Reactant: O=C(Cl)CCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)[C@@H](CO)N(Cc1ccccc1)C(=O)CCl
Temperature: 25 °C
Reaction time: 2 h
Yield: 20 %

Procedure:
To a solution of (R)-2-(benzylamino)-3-hydroxypropanoic acid hydrochloride (9.4 g, 48.2 mmol) and sodium hydroxide (2.57 g, 82.9 mmol) in H2O (30 mL) at 0° C. was added drop wise chloroacetyl chloride (4.9 mL, 62.1 mL) while maintaining the temperature below 10° C. The reaction mixture was then warmed to room temperature and stirred for 2 hours. The reaction mixture was extracted with CH2Cl2 (2×250 mL) and the organic layer dried (MgSO4), filtered and concentrated. The residue was purified by flash chromatography (silica gel, 10 to 30% CH3OH in CH2Cl2 with 1% acetic acid) to provide (R)-2-(N-benzyl-2-chloroacetamido)-3-hydroxypropanoic acid (2.6 g, 20%) as a yellow foam. 1H NMR consistent.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21](O)=[O:22])=[CH:17][C:9]1=2.[F:32][C:33]([F:47])([F:46])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[N:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:29])([F:31])[F:30])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([C:21]([N:43]4[CH2:44][CH2:45][N:40]([C:35]5[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=5[C:33]([F:46])([F:32])[F:47])[CH2:41][CH2:42]4)=[O:22])[CH:24]=[CH:25][CH:26]=3)=[CH:17][C:9]1=2
Reactant: FC(F)(F)c1ccccc1N1CCNCC1
Reactant: O=C(O)c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1
Product: O=C(c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1)N1CCN(c2ccccc2C(F)(F)F)CC1

Procedure:
3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 1-[2-(trifluoromethyl)phenyl]piperazine as in General Procedure 10 to give the title compound. LCMS: m/z=659.99 (M+H+); retention time=1.1 minutes.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11](=[O:18])OCC(Cl)(Cl)Cl)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[C:19]1([C:25]2[N:29]=[C:28]([N:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)[S:27][N:26]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11]([N:33]3[CH2:34][CH2:35][N:30]([C:28]4[S:27][N:26]=[C:25]([C:19]5[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=5)[N:29]=4)[CH2:31][CH2:32]3)=[O:18])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Reactant: O=C(Nc1ccc2[nH]ccc2c1)OCC(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: O
Product: O=C(Nc1ccc2[nH]ccc2c1)N1CCN(c2nc(-c3ccccc3)ns2)CC1
Temperature: 70 °C
Reaction time: 18 h
Yield: 23.9 %

Procedure:
A mixed solution of 2,2,2-trichloroethyl 1H-indol-5-ylcarbamate (227 mg, 0.738 mmol), 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (200 mg, 0.812 mmol) and diisopropylethylamine (0.129 ml, 0.738 mmol) in dimethyl sulfoxide (2.5 ml) was stirred at 70° C. for 3 hours, and then stirred at 70° C. for 18 hours. Water was poured to the reaction mixture, and the resulting solution was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate=1:1) and recrystallized from a mixed solvent of hexane and tetrahydrofuran to give 71.3 mg (23.9%) of the desired product as a solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:18]3[CH:17]=[CH:16][N:15]=[C:14]([C:19]#[N:20])[C:13]=3[N:12]=[CH:11]2)=[CH:6][CH:5]=1)([O-])=O.[H][H]>CO.[C].[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[C:18]3[CH:17]=[CH:16][N:15]=[C:14]([C:19]#[N:20])[C:13]=3[N:12]=[CH:11]2)=[CH:8][CH:9]=1
Reactant: [H][H]
Reactant: N#Cc1nccc2c1ncn2-c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CO
Product: N#Cc1nccc2c1ncn2-c1ccc(N)cc1
Yield: 30.7 %

Procedure:
In 100 mL of methanol, 240 mg (0.9 mmol) of 1-(4-nitrophenyl)-1H-imidazo[4,5-c]pyridine-4-carbonitrile was dissolved, and 170 mg of 10% palladium carbon was added thereto and the mixture solution was refluxed with stirring in a hydrogen atmosphere for one hour. The palladium carbon was removed by Celite filtration and the reaction solution was concentrated under reduced pressure, and the obtained crude product was purified by a silica gel column (dichloromethane:methanol=40:1) to obtain 65 mg (30%) of a target product as a pale yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][CH:7]=1.[F-].[Cs+].[CH3:13][C:14]([C:16]1[CH:21]=[CH:20][C:19](Cl)=[CH:18][CH:17]=1)=[O:15]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CN(C1C=CC=CC=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1)C.O1CCOCC1>[CH3:1][C:2]1[CH:3]=[C:4]([C:19]2[CH:20]=[CH:21][C:16]([C:14](=[O:15])[CH3:13])=[CH:17][CH:18]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)c1ccc(Cl)cc1
Reactant: Cc1cccc(B(O)O)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: C1COCCO1
Product: CC(=O)c1ccc(-c2cccc(C)c2)cc1
Temperature: 25 °C
Yield: 92.7 %

Procedure:
An oven dried resealable Schlenk tube was purged with argon and charged with palladium acetate (4.4 mg, 0.02 mmol, 2 mol %), ligand 2 [Example 1] (11.9 mg, 0.03 mmol, 3 mol %), 3-methylphenylboronic acid (204 mg, 1.5 mmol), and cesium fluoride (456 mg, 3.0 mmol). The tube was purged with argon, and dioxane (3 mL), and 4-chloroacetophenone (0.13 mL, 1.0 mmol) were added through a rubber septum. The septum was removed, the tube was sealed with a teflon screw cap and the mixture was stirred at room temperature until the starting aryl chloride had been completely consumed as judged by GC analysis. The reaction mixture was then diluted with ether (20 mL) and poured into a separatory funnel. The mixture was washed with 1M NaOH (20 mL), and the layers were separated. The aqueous layer was extracted with ether (20 mL), and the combined organic extracts were dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The crude material was then purified by flash chromatography on silica gel to give 195 mg (93%) of a white solid.
Reaction SMILES: BrBr.[C:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(=[O:5])[CH3:4].C[OH:13].Br>O>[OH:13][CH2:4][C:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5]
Reactant: CO
Reactant: CC(=O)c1ccccc1
Agent: Br
Agent: BrBr
Solvent: O
Product: O=C(CO)c1ccccc1
Temperature: 60 °C

Procedure:
About 13 parts of bromine was added with stirring to a mixture of 474.6 parts of acetophenone in about 640 parts of methanol, while the mixture was stirred and maintained at a temperature between 5°-10° C. Hydrogen bromide gas was then introduced into the mixture until bromine coloration disappeared, at which point an additional amount of bromine was added over a 2 hour period to make a total of 631.3 parts. There was then added 71 parts of water while the mixture was stirred and externally cooled for a period of about 30 minutes. An excess of about 2700 parts of water was then slowly added to effect the precipitation in the form of crystals of α-bromo acetophenone from the mixture. The crystals were decanted by means of a vacuum siphon, washed, then neutralized with a 20% sodium hydroxide solution and decanted to dryness. There was then added about 940 parts water, 1600 parts of methanol, 333 parts of sodium bicarbonate and a sodium formate solution prepared from 161 parts of a 90% formic acid and sufficient sodium hydroxide to neutralize the acid. The mixture was heated at 60° C. with vigorous stirring for 7 hours after which time it was cooled to ambient temperature and filtered. Based on method of preparation and gas chromatographic analysis of the mixture there was produced α-hydroxy acetophenone in quantitative yields.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:8]([F:17])([F:16])[C:9]([F:15])([F:14])[C:10]([F:13])([F:12])[F:11])=[N:4][NH:5][C:6]=1[CH3:7].C([O-])([O-])=O.[K+].[K+].Cl[CH2:25][C:26]([N:28]1[CH2:33][CH2:32][N:31]([C:34]2[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=2)[CH2:30][CH2:29]1)=[O:27].CN(C=O)C>CCCCCC.C(OCC)(=O)C>[NH2:1][C:2]1[C:3]([C:8]([F:17])([F:16])[C:9]([F:14])([F:15])[C:10]([F:11])([F:12])[F:13])=[N:4][N:5]([CH2:25][C:26]([N:28]2[CH2:29][CH2:30][N:31]([C:34]3[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=3)[CH2:32][CH2:33]2)=[O:27])[C:6]=1[CH3:7]
Reactant: Cc1[nH]nc(C(F)(F)C(F)(F)C(F)(F)F)c1N
Reactant: O=C(CCl)N1CCN(c2ccc(Cl)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1c(N)c(C(F)(F)C(F)(F)C(F)(F)F)nn1CC(=O)N1CCN(c2ccc(Cl)cc2)CC1

Procedure:
Protocol T was followed using 4-Amino-3-heptafluoropropyl-5-methyl-1H-pyrazole, K2CO3, 2-Chloro-1-[4-(4-chloro-phenyl)-piperazin-1-yl]-ethanone and DMF. Column chromatography using a solvent mixture (hexane/ethyl acetate=1/4, Rf=0.42) afforded the title compound as colorless oil. 1H NMR (400 MHz, CDCl3); 6.88–6.94 (d, 2H), 7.22–7.26 (d, 2H), 4.98 (s, 2H), 3.64–3.82 (m, 4H), 3.1–3.22 (m, 4H), 2.98(s, 2H), 2.18 (s, 3H). MS (ES) M+H) expected=501.82, found 502.1.
Reaction SMILES: [OH:1][C:2]1([C:26]2[N:30](COCC[Si](C)(C)C)[C:29]3[CH:39]=[C:40]([C:43]#[N:44])[CH:41]=[CH:42][C:28]=3[N:27]=2)[C:12]2[C:13]3[C:5](=[CH:6][N:7]([S:16]([C:19]4[CH:25]=[CH:24][C:22]([CH3:23])=[CH:21][CH:20]=4)(=[O:18])=[O:17])[C:8]=3[C:9]([CH3:15])=[CH:10][C:11]=2[CH3:14])[CH2:4][CH2:3]1.OC1(C2N(COCC[Si](C)(C)C)C3C=CC(C#N)=CC=3N=2)C2C3C(=CN(S(C4C=CC(C)=CC=4)(=O)=O)C=3C(C)=CC=2C)CC1.F[B-](F)(F)F.[Li+]>O>[OH:1][C:2]1([C:26]2[NH:27][C:28]3[CH:42]=[CH:41][C:40]([C:43]#[N:44])=[CH:39][C:29]=3[N:30]=2)[C:12]2[C:13]3[C:5](=[CH:6][N:7]([S:16]([C:19]4[CH:20]=[CH:21][C:22]([CH3:23])=[CH:24][CH:25]=4)(=[O:18])=[O:17])[C:8]=3[C:9]([CH3:15])=[CH:10][C:11]=2[CH3:14])[CH2:4][CH2:3]1
Reactant: Cc1ccc(S(=O)(=O)n2cc3c4c(c(C)cc(C)c42)C(O)(c2nc4ccc(C#N)cc4n2COCC[Si](C)(C)C)CC3)cc1
Agent: Cc1ccc(S(=O)(=O)n2cc3c4c(c(C)cc(C)c42)C(O)(c2nc4cc(C#N)ccc4n2COCC[Si](C)(C)C)CC3)cc1
Agent: F[B-](F)(F)F
Agent: [Li+]
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2cc3c4c(c(C)cc(C)c42)C(O)(c2nc4cc(C#N)ccc4[nH]2)CC3)cc1
Temperature: 70 °C

Procedure:
To a mixture of (±)-2-(5-hydroxy-6,8-dimethyl-1-tosyl-1,3,4,5-tetrahydrobenzo[cd]indol-5-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-6-carbonitrile and (±)-2-(5-hydroxy-6,8-dimethyl-1-tosyl-1,3,4,5-tetrahydrobenzo[cd]indol-5-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole-5-carbonitrile (50 mg, 0.08 mmol), lithium tetrafluoroborate (1.5 mL, 1.5 mmol) and H2O (0.15 mL) were added. The reaction was heated to 70° C. overnight. It was quenched with a sat. NaHCO3 solution. The layers were separated and the aqueous layer was extracted with EtOAc. It was purified using FCC eluting with heptane:EtOAc 1:2 to give the title compound. MS (ESI+) m/z 497.4 (M+H).
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[C:3](OC)=[O:4].[CH2:9]([CH2:11][NH2:12])[OH:10].C1C=C2C(C(O)(O)C(=O)C2=CC=1)=O>>[F:1][C:2]([F:8])([F:7])[C:3]([NH2:12])=[O:4].[CH2:9]([CH2:11][NH2:12])[OH:10]
Reactant: COC(=O)C(F)(F)F
Agent: O=C1c2ccccc2C(=O)C1(O)O
Solvent: NCCO
Product: NC(=O)C(F)(F)F
Reaction time: 2 h

Procedure:
In a round-bottom flask, methyl trifluoroacetate (10.5 g, 81.9 mmol) was added to neat ethanolamine (4.0 g, 66 mmol) at room temperature with continuous stirring. Reaction completion was determined by the absence of ninhydrin activity. After 2 h, the reaction was concentrated by rotary evaporation and purified by distillation (11 mm Hg, b.p. 127° C.), yielding a colorless oil, 9.5 g, 93%.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH:7]=O)=[CH:5][NH:4][N:3]=1.[C:9]([O:18]CC)(=[O:17])[CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].CC([O-])(C)C.[K+]>C(O)(C)(C)C>[CH2:15]([O:14][C:12]([C:11](=[CH:7][C:6]1[C:2]([CH3:1])=[N:3][NH:4][CH:5]=1)[CH2:10][C:9]([OH:18])=[O:17])=[O:13])[CH3:16]
Reactant: CCOC(=O)CCC(=O)OCC
Reactant: Cc1n[nH]cc1C=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: CCOC(=O)C(=Cc1c[nH]nc1C)CC(=O)O
Temperature: 80 °C
Yield: 102.4 %

Procedure:
To a solution of 3-methyl-1H-pyrazole-4-carbaldehyde (9 g, 82 mmol) and diethyl succinate (57 g, 327 mmol) in t-butanol (50 mL), a solution of t-BuOK (37.3 g, 245 mmol) in t-butanol (40 mL) was added and the mixture was heated to 80° C. for 4 hours. The mixture was concentrated; the obtained residue was dissolved in water (50 mL), acidified (pH˜2) using 6 N HCl and extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with aqueous NaHCO3 (2×50 mL). The combined aqueous layers were acidified (pH˜2) and extracted with ethyl acetate (2×100 mL). The combined ethyl acetate layers were washed with saturated aqueous NaCl (25 mL), dried over anhydrous Na2SO4 and concentrated to afford 3-(ethoxycarbonyl)-4-(3-methyl-1H-pyrazol-4-yl)but-3-enoic acid (20 g, 100%) as gum. 1H NMR (CDCl3) δ 7.85 (s, 1H), 7.65 (s, 1H), 4.3 (t, 2H), 3.65 (s, 2H), 4.4 (s, 3H), 1.3 (t, 3H).
Reaction SMILES: [P:1](Cl)([Cl:4])([Cl:3])=[O:2].[OH:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[CH:13]=[C:12]([C@H:17]([CH3:22])[C:18]([O:20][CH3:21])=[O:19])[CH:11]=[CH:10]2.C(N(CC)CC)C>C(OCC)C>[Cl:3][P:1]([O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[CH:13]=[C:12]([C@H:17]([CH3:22])[C:18]([O:20][CH3:21])=[O:19])[CH:11]=[CH:10]2)([Cl:4])=[O:2]
Reactant: O=P(Cl)(Cl)Cl
Reactant: COC(=O)[C@@H](C)c1ccc2cc(O)ccc2c1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: COC(=O)[C@@H](C)c1ccc2cc(OP(=O)(Cl)Cl)ccc2c1
Temperature: 25 °C
Yield: 95 %

Procedure:
Phosphorus oxychloride (0.202 mL, 1 equiv) and (S)-methyl 2-(6-hydroxynaphthalen-2-yl)propanoate (Aldrich, 500 mg, 1 equiv) were stirred in anhydrous diethyl ether (25 mL). Anhydrous triethylamine was added (0.302 mL, 1 equiv) at −78° C. and the solution was allowed to warm to room temperature after 25 min, the triethylamine hydrochloride salt was filtered off and the solvent was removed under reduced pressure to give a clear pale yellow thick syrup (750 mg, 95%).
Reaction SMILES: Cl[O:2][N:3]=[CH:4][C:5]1[C:6]([CH3:11])=[CH:7][CH:8]=[CH:9][CH:10]=1.[CH2:12]=[C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:15](=[O:16])[O:14]1.C(N(CC)CC)C>CCOCC>[CH3:11][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[C:4]1[CH2:12][C:13]2([C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:15](=[O:16])[O:14]2)[O:2][N:3]=1
Reactant: C=C1OC(=O)c2ccccc21
Reactant: Cc1ccccc1C=NOCl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: Cc1ccccc1C1=NOC2(C1)OC(=O)c1ccccc12
Temperature: 25 °C
Reaction time: 40 h
Yield: 58.7 %

Procedure:
To a solution of o-tolualdehyde chlorooxime (26.8 g, 0.158 mole), 3-methylenephthalide (14.6 g, 0.1 mole) and ether (400 ml.) was added dropwise a solution of triethylamine (16 g, 0.158 mole) in 30 ml. of ether at 5°-10° C. in 45 minutes. The mixture was stirred at room temperature for 40 hours and filtered. The solid material collected was dissolved in 1 liter of chloroform and 200 ml. of water. The chloroform solution was then washed two times with water, dried over CaSO4 and concentrated under vacuum to give 16.4 g of white solid, m.p. 146°-149° C. The original ether solution was washed two times with water, dried over CaSO4 and concentrated to 100 ml. Another 1.64 g of the spiro compound precipitated out. The ether solution was then further concentrated to 10.8 g of yellow-brown oil which did not contain a significant amount of the desired product. Recrystallization of 12 g of the crude spiro compound from tetrahydrofuran-ether gave 9.87 g of a pure white solid, m.p. 159°-164° C. with decomposition.
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.Br[C:37]1[S:38][CH:39]=[C:40]([C:42]([NH:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[N:41]=1>>[C:45]([NH:44][C:42]([C:40]1[N:41]=[C:37]([C:16]2[CH:15]=[CH:14][C:13]([C@@H:11]([N:7]3[CH2:6][CH2:5][C@:4]([CH2:3][C:2]([OH:1])([CH3:34])[CH3:35])([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)[O:9][C:8]3=[O:10])[CH3:12])=[CH:18][CH:17]=2)[S:38][CH:39]=1)=[O:43])([CH3:48])([CH3:46])[CH3:47]
Reactant: CC(C)(C)NC(=O)c1csc(Br)n1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Product: C[C@@H](c1ccc(-c2nc(C(=O)NC(C)(C)C)cs2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared from (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one and 2-bromo-N-tert-butylthiazole-4-carboxamide following a procedure analogous to that described in Example 1 Step 2. LC-MS Method 2 tR=1.315 min, m/z=478.3; 1H NMR (CDCl3) 1.18 (s, 3H), 1.36 (s, 3H), 1.49 (s, 9H), 2.11 (d, 3H), 2.14 (s, 4H), 2.33 (m, 1H), 2.80 (m, 1H), 5.64 (m, 1H), 7.19 (m, 2H), 7.28-7.39 (m, 5H), 7.60 (m, 2H), 7.94 (s, 1H)
Reaction SMILES: [C:1]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]3[C:27]4[C:22](=[CH:23][CH:24]=[C:25]([C:28]5[CH:29]=[N:30][C:31]6[C:36]([CH:37]=5)=[CH:35][CH:34]=[CH:33][CH:32]=6)[CH:26]=4)[N:21]=[CH:20][C:19]=3[C:38]([O:40]CC)=[O:39])=[CH:13][C:12]=2[C:43]([F:46])([F:45])[F:44])[CH2:7][CH2:6]1)(=[O:4])[CH2:2][CH3:3].[OH-].[Na+].Cl>C1COCC1.CO.O>[C:1]([N:5]1[CH2:6][CH2:7][N:8]([C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]3[C:27]4[C:22](=[CH:23][CH:24]=[C:25]([C:28]5[CH:29]=[N:30][C:31]6[C:36]([CH:37]=5)=[CH:35][CH:34]=[CH:33][CH:32]=6)[CH:26]=4)[N:21]=[CH:20][C:19]=3[C:38]([OH:40])=[O:39])=[CH:13][C:12]=2[C:43]([F:44])([F:45])[F:46])[CH2:9][CH2:10]1)(=[O:4])[CH2:2][CH3:3]
Reactant: CCOC(=O)c1cnc2ccc(-c3cnc4ccccc4c3)cc2c1Nc1ccc(N2CCN(C(=O)CC)CC2)c(C(F)(F)F)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CCC(=O)N1CCN(c2ccc(Nc3c(C(=O)O)cnc4ccc(-c5cnc6ccccc6c5)cc34)cc2C(F)(F)F)CC1
Reaction time: 8 h

Procedure:
To a solution of compound 5.4 ethyl 4′-(4-(4-propionylpiperazin-1-yl)-3-(trifluoromethyl)phenylamino)-3,6′-biquinoline-3′-carboxylate in THF/MeOH/H2O (1:1:1, 6 mL) at room temperature was added NaOH (76 mg, 1.9 mmol, 5 equiv.). The resulting solution was stirred overnight. To the mixture was added HCl (1N) to adjust the pH to 4, and EtOAC (20 mL) to extract the product. The organic layer was concentrated to afford the desired product 5.5 4′-(4-(4-propionylpiperazin-1-yl)-3-(trifluoromethyl)phenylamino)-3,6′-biquinoline-3′-carboxylic acid. LC-MS (M+H): 622.21
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[S:7]([CH2:9][N:10]1[C:20](=[O:21])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[S:11]1(=[O:13])=[O:12])=[O:8].ClC1C=CC=C(C(OO)=[O:30])C=1>>[N:3]1[CH:4]=[CH:5][CH:6]=[N:1][C:2]=1[S:7]([CH2:9][N:10]1[C:20](=[O:21])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[S:11]1(=[O:13])=[O:12])(=[O:30])=[O:8]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=C1c2ccccc2S(=O)(=O)N1CS(=O)c1ncccn1
Product: O=C1c2ccccc2S(=O)(=O)N1CS(=O)(=O)c1ncccn1

Procedure:
Following a procedure similar to that described in Example 32A, 0.75 g (0.0023 mol) of 2-(2-pyrimidinylsulfinylmethyl)saccharin was oxidized with 0.4 g (0.0023 mol) of 3-chloroperbenzoic acid in 50 ml of MDC and the product recrystallized from 75:25 acetonitrile:ethanol to give 2-(2-pyrimidinylsulfonylmethyl)saccharin, mp 225°-227° C.