Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [P:1]([O:8][CH2:9][CH3:10])([O:5][CH2:6][CH3:7])[O:2]CC.[Cl:11][C:12]1[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:13]=1[O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]Br.C(Br)C.[Br-]>>[Cl:11][C:12]1[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:13]=1[O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][P:1](=[O:2])([O:5][CH2:6][CH3:7])[O:8][CH2:9][CH3:10]
Reactant: COc1ccc(OCCCCCCBr)c(Cl)c1
Reactant: CCOP(OCC)OCC
Agent: [Br-]
Solvent: CCBr
Product: CCOP(=O)(CCCCCCOc1ccc(OC)cc1Cl)OCC
Temperature: 158 °C
Yield: 79.2 %

Procedure:
Triethyl phosphite (185 g, 230 ml, 1.1 mole) was placed in a flask equipped with a thermometer, dropping funnel, stirrer and 8 inch Vigreux column with condenser set for downward distillation. The phosphite was heated to 158° C. thereby inducing mild reflux. 6-(2-Chloro-4-methoxyphenoxy)hexyl bromide (320 g, 1 mole) was then added dropwise over a period of 50 minutes. The reaction mixture was heated for an additional 90 minutes at which time distillation of ethyl bromide ceased. The remaining reaction mixture was distilled in vacuo and the fraction (250 g) boiling at 183°-197° C. (0.2-0.3 mm) was collected. The latter was combined with 79 g of product obtained from another run starting from 100 g of bromide and redistilled to give 300 g of diethyl [6-(2-chloro-4-methoxyphenoxy)-hexyl]phosphonate, b.p. 202°-204° C. (0.02 mm).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:14]([CH2:15][CH2:16][CH2:17][CH2:18]Br)=[N:13][NH:12][C:11]=1[NH2:20].[NH2:21][C:22]1NN=C(CCCCO)C=1C1SC2C=CC=CC=2N=1.CN.C1COCC1>>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:14]([CH2:15][CH2:16][CH2:17][CH2:18][NH:21][CH3:22])=[N:13][NH:12][C:11]=1[NH2:20]
Reactant: Nc1[nH]nc(CCCCBr)c1-c1nc2ccccc2s1
Reactant: Nc1[nH]nc(CCCCO)c1-c1nc2ccccc2s1
Agent: CN
Solvent: C1CCOC1
Product: CNCCCCc1n[nH]c(N)c1-c1nc2ccccc2s1

Procedure:
The title compound (30 mg) was prepared using 185 mg (0.39 mmol) of 4-benzothiazol-2-yl-5-(4-bromobutyl)-2H-pyrazol-3-ylamine, which was derived from 4-(5-amino-4-benzothiazol-2-yl-1H-pyrazol-3-yl)butan-1-ol, and 5 mL of a 2 M solution of methylamine in THF (10 mmol). MS (m/z, ES+): 302.4 (M+1, 100%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]([CH3:14])=[CH2:13])[NH:6][C:5]2=[O:15].[Si]([CH:20]=[N+:21]=[N-:22])(C)(C)C>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1([CH3:14])[CH2:13][CH:20]=[N:21][NH:22]1)[NH:6][C:5]2=[O:15]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: C=C(C)c1nc2ccc(Br)cc2c(=O)[nH]1
Product: CC1(c2nc3ccc(Br)cc3c(=O)[nH]2)CC=NN1

Procedure:
Following the procedure described in the Example 7, using 6-bromo-2-isopropenyl-3H-quinazolin-4-one and TMSCHN2 as starting materials to yield the title compound as a white solid.
Reaction SMILES: C1NCCN(CC(O)=O)CCN(CC(O)=O)CCN(CC(O)=O)C1.[OH-].[Na+].C(#N)C=C.C(C[N:35]1[CH2:46][CH2:45][N:44]([CH2:47][CH2:48][C:49]#[N:50])[CH2:43][CH2:42][N:41](CC(O)=O)[CH2:40][CH2:39][N:38](CC(O)=O)[CH2:37][CH2:36]1)(O)=O>O.CO>[C:49]([CH2:48][CH2:47][N:44]1[CH2:45][CH2:46][NH:35][CH2:36][CH2:37][NH:38][CH2:39][CH2:40][NH:41][CH2:42][CH2:43]1)#[N:50]
Reactant: N#CCCN1CCN(CC(=O)O)CCN(CC(=O)O)CCN(CC(=O)O)CC1
Agent: O=C(O)CN1CCNCCN(CC(=O)O)CCN(CC(=O)O)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C=CC#N
Solvent: CO
Solvent: O
Product: N#CCCN1CCNCCNCCNCC1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
Into a 100 ml round bottom flask containing 5.2 g of DO3A dissolved in 22 ml of H2O (pH adjusted to 8.25 with dilute NaOH) was added 1.35 ml of acrylonitrile. The reaction was allowed to stir at room temperature for 14 hours. After 14 hours, HPLC analysis indicated complete conversion to 1,4,7-tris(carboxymethyl)-10-(2'-cyanoethyl)-1,4,7,10-tetraazacyclododecane. The reaction mixture was taken to dryness on a rotary evaporator to yield a glassy solid. The solid was dissolved in methanol and then taken to dryness on a rotary evaporator to yield 5.9 g of crude 1,4,7-tricarboxymethyl)-10-(2'cyanoethyl)-1,4,7,10-tetraazacyclododecane as a white solid. 3.0 g of the crude 1,4,7-tris(carboxymethyl)-10-(2'-cyanoethyl)-1,4,7,10-tetraazacyclododecane was dissolved in 150 ml of H2O, and the solution acidified with 6 ml of concentrated HCl. The solution was then added to a 500 ml hydrogenation vessel containing 1.5 g of 10% Pd/C and the reaction mixture hydrogenated at 50 psi H2 at room temperature for 14 hours. After 14 hours the catalyst removed over a Celite bed and the filtrate taken to dryness on a rotary evaporator. The sample was dissolved in 200 ml of H2O and applied to a 2.5×20 cm column of Dowex 50X-2 (H+ form). The column was eluted with 4 L of 0.5 H2O and the material eluted off the column with 1.0 L of 0.5M NH4OH. The eluant was concentrated to dryness on a rotary evaporator, the residue dissolved in methanol and taken to dryness on a rotary evaporator to yield 3.8 g of the ammonium salt of 1,4,7-tris(carboxymethyl)-10-(3'-aminopropyl)-1,4,7,10-tetraazacyclododecane.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH:10]=[C:9]([OH:14])[C:8]([F:15])=[C:7]2[F:16])[CH3:2].[CH2:17]([CH:20]1[CH2:25][CH2:24][CH:23]([CH:26](O)[C:27]#[CH:28])[CH2:22][CH2:21]1)[CH2:18][CH3:19].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>C1COCC1.O>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]2[C:11]([CH:10]=[C:9]([O:14][CH:17]([CH:20]3[CH2:21][CH2:22][CH:23]([CH2:26][CH2:27][CH3:28])[CH2:24][CH2:25]3)[C:18]#[CH:19])[C:8]([F:15])=[C:7]2[F:16])=[CH:12][CH:13]=1)[CH3:2]
Reactant: C#CC(O)C1CCC(CCC)CC1
Reactant: CCOc1ccc2cc(O)c(F)c(F)c2c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: C#CC(Oc1cc2ccc(OCC)cc2c(F)c1F)C1CCC(CCC)CC1
Reaction time: 18 h

Procedure:
10.5 g (46.8 mmol) of 6-ethoxy-3,4-difluoronaphthalen-2-ol are initially introduced in 100 ml of THF together with 10.0 g (55.5 mmol) of 1-(4-propylcyclohexyl)prop-2-yn-1-ol and 15.0 g (57.2 mmol) of triphenylphosphine, and 11.5 ml (59.1 mmol) of DIAD are added over the course of 20 min with ice-cooling. After 18 h at RT, water is added, and the mixture is extracted a number of times with MTBE. The combined organic phases are washed with water and saturated sodium chloride soln., and the solution is dried using sodium sulfate. The residue remaining after removal of the solvents is purified by column chromatography (SiO2, n-heptane:MTBE=2:1). The further purification is carried out by recrystallisation from n-heptane, giving 7-ethoxy-1,2-difluoro-3-[1-(4-propylcyclohexyl)prop-2-ynyloxy]naphthalene as a yellowish solid.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[CH:16]=[CH:15][C:8]([O:9][CH:10]([CH3:14])[C:11](Cl)=[O:12])=[CH:7][CH:6]=1.[N:22]1([CH2:27][CH2:28][OH:29])[CH2:26][CH2:25][CH2:24][CH2:23]1>C1(C)C=CC=CC=1>[ClH:1].[N:22]1([CH2:27][CH2:28][O:29][C:11](=[O:12])[CH:10]([O:9][C:8]2[CH:15]=[CH:16][C:5]([O:4][C:3]3[CH:17]=[CH:18][C:19]([Cl:21])=[CH:20][C:2]=3[Cl:1])=[CH:6][CH:7]=2)[CH3:14])[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: CC(Oc1ccc(Oc2ccc(Cl)cc2Cl)cc1)C(=O)Cl
Reactant: OCCN1CCCC1
Solvent: Cc1ccccc1
Product: CC(Oc1ccc(Oc2ccc(Cl)cc2Cl)cc1)C(=O)OCCN1CCCC1
Product: Cl
Temperature: 60 °C

Procedure:
0.06 mol=20.73 g of 2-[4'-(2",4"-dichlorophenoxy)phenoxy]-propionic acid chloride dissolved in 30 ml absolute toluene were added dropwise at room temperature to a solution of 0.06 mol=6.9 g of 2-pyrrolidino-ethanol in 50 ml absolute toluene and the mixture was stirred for a further hour at 60° C. After cooling to 0° C., the formed precipitate was filtered off and recrystallized from acetone. 21.0 g=76% of the theory of 2-[4'-(2",4"-dichloro-phenoxy)phenoxy]-propionic acid 2-pyrrolidino-eth-1-yl ester hydrochloride were obtained melting at 160°-162° C. ##STR17##
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.[CH:9]([S:12]([C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1)(=[O:14])=[O:13])([CH3:11])[CH3:10].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CC#N.CCOC(C)=O.O.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH:9]([S:12]([C:15]1[CH:20]=[CH:19][C:18]([C:2]2[N:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=2)=[CH:17][CH:16]=1)(=[O:13])=[O:14])([CH3:11])[CH3:10]
Reactant: CC(C)S(=O)(=O)c1ccc(B(O)O)cc1
Reactant: Nc1cnc(Br)cn1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)S(=O)(=O)c1ccc(-c2cnc(N)cn2)cc1
Temperature: 60 °C
Yield: 80.7 %

Procedure:
5-Bromopyrazin-2-amine (5 g, 28.74 mmol), (4-isopropylsulfonylphenyl)boronic acid (7.866 g, 34.49 mmol) and K3PO4 (12.20 g, 57.48 mmol) were combined in MeCN (100 mL)/Water (25 mL) and Pd[P(tBu)3]2 (734.4 mg, 1.437 mmol) was added. The reaction was heated at 60° C. for 1 hour. The reaction mixture was cooled to ambient temperature and diluted with EtOAc and water. The layers were separated and the aqueous layer extracted with EtOAc (×3). The combined organic layers were dried (MgSO4), filtered and concentrated in vacuo. The residue was triturated from DCM and isolated by filtration to give the sub-title compound as an orange solid (6.43 g, 76% Yield). 1H NMR (400.0 MHz, DMSO) δ 1.17 (d, 6H), 3.43 (sept, 1H), 6.86 (s, 2H), 7.87 (d, 2H), 8.00 (s, 1H), 8.20 (d, 2H) and 8.67 (s, 1H) ppm; MS (ES+) 278.2.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([O:7][CH2:8][C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=2)[CH2:3][CH2:2]1.Cl.[NH2:18][OH:19].C(N(CC)CC)C>C(O)C>[OH:19][N:18]=[C:13]([C:12]1[CH:11]=[CH:10][C:9]([CH2:8][O:7][CH:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)=[CH:16][CH:15]=1)[NH2:14]
Reactant: N#Cc1ccc(COC2CCOCC2)cc1
Reactant: NO
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: NC(=NO)c1ccc(COC2CCOCC2)cc1
Temperature: 25 °C

Procedure:
A solution of 4-[(tetrahydro-2H-pyran-4-yloxy)methyl]benzonitrile (Step 1, 1.50 g, 6.90 mmol), hydroxylamine hydrochloride (1.06 g, 15.2 mmol) and triethylamine (2.11 mL, 15.2 mmol) in ethanol (35 mL) was stirred and heated at reflux for 1 h. After being cooled to rt, the reaction mixture was evaporated to dryness. The resulting material was treated with ethyl acetate, and the solid was filtered off. The ethyl acetate solution was washed with water and saturated sodium chloride solution, dried with anhydrous magnesium sulfate and filtered. After evaporation of the solvent, the title compound was obtained (556 mg, 32%): 1H NMR (400 MHz, CDCl3) δ 7.62 (d, 2H), 7.38 (d, 2H), 4.85 (broad s, 2H), 4.60 (s, 2H), 4.00-3.92 (m, 2H), 3.62-3.55 (m, 1H), 3.49-3.40 (m, 2H), 1.96-1.90 (m, 2H), 1.72-1.60 (m, 2H); ES-MS m/z 251, HPLC RT (Method K) 0.34 min.
Reaction SMILES: [C:1](Cl)(Cl)=[S:2].[NH2:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][C:7]=1[Cl:14]>O>[Cl:14][C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][C:6]=1[N:5]=[C:1]=[S:2])[C:10]#[N:11]
Reactant: N#Cc1ccc(N)c(Cl)c1
Reactant: S=C(Cl)Cl
Solvent: O
Product: N#Cc1ccc(N=C=S)c(Cl)c1

Procedure:
To a suspension of thiophosgene (2 mL) in water (5 mL) was added 4-amino-3-chloro-benzonitrile (1 g, 7 mmol) in small portions over a period of 1 h at 25° C. The mixture was extracted with ethyl acetate (3×25 mL). Combined organic phase was washed with brine (1×50 mL), dried (MgSO4) and concentrated to dryness in vacuo. The title compound 3d was obtained as a tan solid (1.3 g, 96% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[C:13](=[O:17])[N:12]([C@@H:18]([CH:23]([CH3:25])[CH3:24])[C:19]([O:21][CH3:22])=[O:20])[CH2:11]3)=[CH:4][CH:3]=1.[F:26][C:27]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:28]=1[C:29](Br)=[O:30]>>[F:26][C:27]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:28]=1[C:29]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[C:13](=[O:17])[N:12]([C@@H:18]([CH:23]([CH3:25])[CH3:24])[C:19]([O:21][CH3:22])=[O:20])[CH2:11]3)=[CH:4][CH:3]=1)=[O:30]
Reactant: O=C(Br)c1ccc(F)cc1F
Reactant: COC(=O)[C@H](C(C)C)N1Cc2cc(-c3ccc(N)cc3)ccc2C1=O
Product: COC(=O)[C@H](C(C)C)N1Cc2cc(-c3ccc(NC(=O)c4ccc(F)cc4F)cc3)ccc2C1=O

Procedure:
The compound of example 316 was prepared analogous to compound of example 304 by reaction of compound of example 223 with 2,4-difluoro benzoyl bromide. The compound of example 316 was used directly without isolation, for the preparation of compound of example 317.
Reaction SMILES: [OH:1][C:2]1([C:15]2[CH:24]=[CH:23][C:18]([O:19][CH2:20][C:21]#[N:22])=[CH:17][CH:16]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[NH:8][S:9]([CH:12]([CH3:14])[CH3:13])(=[O:11])=[O:10].COCCO[AlH2-]OCCOC.[Na+].O>C1COCC1.C1(C)C=CC=CC=1.C1(C)C=CC=CC=1>[NH2:22][CH2:21][CH2:20][O:19][C:18]1[CH:23]=[CH:24][C:15]([C:2]2([OH:1])[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]2[NH:8][S:9]([CH:12]([CH3:13])[CH3:14])(=[O:11])=[O:10])=[CH:16][CH:17]=1
Reactant: CC(C)S(=O)(=O)NC1CCCCC1(O)c1ccc(OCC#N)cc1
Agent: COCCO[AlH2-]OCCOC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)S(=O)(=O)NC1CCCCC1(O)c1ccc(OCCN)cc1
Temperature: 25 °C
Yield: 118.1 %

Procedure:
Into a 100 mL, 3 neck flask with stirrer, 2-[4-(1-hydroxy-2-{[(methylethyl)sulfonyl]amino}cyclohexyl)phenoxy]ethanenitrile (400 mg) in THF-toluene 1:1 (30 mL) was added dropwise to Red-Al® (3 mL, 65% solution in toluene) while stirring at room temperature under a nitrogen atmosphere. The reaction mixture was then stirred for two hours at this temperature. The mixture was poured into water and the desired material was extracted with ethyl acetate. The organic layer was washed once with water, dried over potassium carbonate, filtered, and concentrated under reduced vacuum to yield the intermediate title compound (478 mg, 89%) as a white foam. This material was used without further purification. Ion spray M.S. 355.2 (M*−1). Calculated for C17H28N2O4S-H2O: Theory: C 54.51, H 8.07. Found: C 54.20, H 8.29.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:12]([CH2:15][N:16]2[C:24]3[C:19](=[CH:20][C:21]([C:25](=[O:38])[NH:26][C@H:27]([C:29]4[CH:34]=[CH:33][CH:32]=[C:31]([CH:35]([CH3:37])[CH3:36])[CH:30]=4)[CH3:28])=[CH:22][CH:23]=3)[C:18]([CH3:39])=[C:17]2[CH3:40])=[CH:11][C:3]=1[O:4][C@@H:5]([CH3:10])[C:6]([O:8]C)=[O:7].CS(C)=O.O.[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:14]=[CH:13][C:12]([CH2:15][N:16]2[C:24]3[C:19](=[CH:20][C:21]([C:25](=[O:38])[NH:26][C@H:27]([C:29]4[CH:34]=[CH:33][CH:32]=[C:31]([CH:35]([CH3:36])[CH3:37])[CH:30]=4)[CH3:28])=[CH:22][CH:23]=3)[C:18]([CH3:39])=[C:17]2[CH3:40])=[CH:11][C:3]=1[O:4][C@@H:5]([CH3:10])[C:6]([OH:8])=[O:7]
Reactant: COC(=O)[C@H](C)Oc1cc(Cn2c(C)c(C)c3cc(C(=O)N[C@@H](C)c4cccc(C(C)C)c4)ccc32)ccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Solvent: CO
Product: Cc1c(C)n(Cc2ccc(Cl)c(O[C@@H](C)C(=O)O)c2)c2ccc(C(=O)N[C@@H](C)c3cccc(C(C)C)c3)cc12

Procedure:
The (S)-methyl 2-(2-chloro-5-((5-(((S)-1-(3-isopropylphenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)phenoxy)propanoate was dissolved in methanol (1.5 mL), DMSO (˜1.5 mL) and water (0.1 mL) then NaOH (2 N, 0.1 mL) was added dropwise. The reaction was monitored by LC/MS. It was stirred until all the starting material was consumed (˜3 h). It was acidified with trifluoroacetic acid, filtered and purified by preparative HPLC to yield the title compound. ESI-MS (m/z): 547.1 [M+H]+.
Reaction SMILES: N#N.[Br:3][C:4]1[S:5][C:6]([C:9](=[O:11])[CH3:10])=[CH:7][N:8]=1.[CH2:12](O)[CH2:13][OH:14].COC(OC)OC>C([O-])(O)=O.[Na+]>[Br:3][C:4]1[S:5][C:6]([C:9]2([CH3:10])[O:14][CH2:13][CH2:12][O:11]2)=[CH:7][N:8]=1
Reactant: OCCO
Reactant: CC(=O)c1cnc(Br)s1
Agent: N#N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COC(OC)OC
Product: CC1(c2cnc(Br)s2)OCCO1
Temperature: 95 °C

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and a condenser under inert atmosphere (N2), a solution of 1-(2-bromo-thiazol-5-yl)-ethanone (2.20 g, 10.68 mmol) in ethylene glycol (11.46 mL, 205.53 mmol) was treated with trimethylorthoformate (2.39 mL, 21.76 mmol) followed by LiBF4 (204 mg, 2.14 mmol). The reaction mixture was heated at 95° C. for 2 days. Sat. aq. NaHCO3 (50 mL) was added and the mixture was extracted with EA (50 mL). The org. extracts were washed with brine (2×50 mL), dried over MgSO4, filtered, and the solvent was removed under reduced pressure. Purification of the residue by FC (4:1 hept-EA) gave the title compound as a yellow oil. TLC: rf (3:1 hept-EA)=0.80. LC-MS-conditions 01: tR=0.84 min, [M+H]+=251.85.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[S:10][C:9]([CH:11](N2C(=O)C3C(=CC=CC=3)C2=O)[CH2:12][CH2:13][CH3:14])=[CH:8][C:7]=1[CH3:26].O.[NH2:28]N>O1CCCC1>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[S:10][C:9]([CH2:11][CH2:12][CH2:13][CH2:14][NH2:28])=[CH:8][C:7]=1[CH3:26]
Reactant: CCCC(c1cc(C)c(C2OCCO2)s1)N1C(=O)c2ccccc2C1=O
Reactant: NN
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(CCCCN)sc1C1OCCO1

Procedure:
N-[[5-(1,3-Dioxolan-2-yl)-4-methyl-2-thienyl]-4-butyl]-isoindole-1,3(2H)-dione (16.1 g) and hydrazine hydrate (8 ml) were stirred at room temperature in tetrahydrofuran (150 ml) for 24 h. The mixture was filtered and the filtrate was distilled to give the title compound as a red-brown oil (5.34 g), b.p. 230°/0.1 mm.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([Br:11])[C:3]=1[O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]CBr.[C:21]1(=[O:31])[NH:25][C:24](=[O:26])[C:23]2=[CH:27][CH:28]=[CH:29][CH:30]=[C:22]12.[K].[CH3:33]C(C)=O>>[Br:11][C:4]1[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=[C:2]([Br:1])[C:3]=1[O:12][CH:13]([CH3:33])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][N:25]1[C:21](=[O:31])[C:22]2[C:23](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:24]1=[O:26]
Reactant: O=[N+]([O-])c1cc(Br)c(OCCCCCCCBr)c(Br)c1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(C)=O
Agent: [K]
Product: CC(CCCCCN1C(=O)c2ccccc2C1=O)Oc1c(Br)cc([N+](=O)[O-])cc1Br
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 11 (1.33 g, 2.34 mmol) in acetone (30 mL) was added potassium phthalimide (0.56 g, 3.05 mmol). The resulting mixture was stirred for 24 hours under reflux conditions. The reaction mixture was cooled to room temperature and filtered through Celite. The filtrate was concentrated in vacuo. MPLC purification (Hexanes:EtOAc/80:20) of the residue gave 12 as a white amorphous solid (1.18 g, 80%). 1H NMR (CDCl3) δ 8.63 (s, 2H), 7.83-7.85 (m, 2H), 7.70-7.72 (m, 2H), 4.02 (t, J=6.4 Hz, 2H), 3.70 (t, J=7.2 Hz, 2H), 1.91-1.95 (m, 2H), 1.69-1.73 (m, 2H), 1.55-1.58 (m, 2H), and 1.40-1.46 (m, 2H).
Reaction SMILES: Cl[Si:2]([CH2:11][CH2:12][CH2:13][CH3:14])([CH2:7][CH2:8][CH2:9][CH3:10])[CH2:3][CH2:4][CH2:5][CH3:6].C(=O)=O.Br[C:19]([F:22])([F:21])[F:20].C(N(CC)P(N(CC)CC)N(CC)CC)C>CC(C)=O.ClCCl>[CH2:3]([Si:2]([CH2:11][CH2:12][CH2:13][CH3:14])([CH2:7][CH2:8][CH2:9][CH3:10])[C:19]([F:22])([F:21])[F:20])[CH2:4][CH2:5][CH3:6]
Reactant: FC(F)(F)Br
Reactant: CCCC[Si](Cl)(CCCC)CCCC
Agent: CCN(CC)P(N(CC)CC)N(CC)CC
Agent: O=C=O
Solvent: ClCCl
Solvent: CC(C)=O
Product: CCCC[Si](CCCC)(CCCC)C(F)(F)F
Temperature: -78 °C
Yield: 67.1 %

Procedure:
A flask equipped with a dry ice condenser was flame dried under a nitrogen sream, and charged with 5.0g (20 mmol) of chlorotri-n-butylsilane and 10 mL of dichloromethane. After cooling the resulting solution to -78° C. and charging the condenser with dry ice and acetone, 6.2 mL (66 mmol) of bromotrifluoromethane (Freon 13Bl) that had been condensed into a graduated tube was warmed to room temperature and allowed to distill into the flask. The cooling bath was removed and the mixture was allowed to warm to the temperature of the refluxing Freon (-59° C.). To this cold solution was added, dropwise, 8.0 mL (29 mmol) of hexaethylphosphorous triamide. The resulting solution was stirred at reflux for 1 hour. Removal of the condenser and continued stirring for 1 hour resulted in evaporation of excess Freon and warming of the solution to room temperature. Dilution with 30 mL of dichloromethane, water (three 30 mL portions) and 1N HCl (two 30 mL portions) washing, drying (MgSO4), and concentration afforded a residue which was short path distilled to give 3.6 g (64% yield) of tri-n-butyltrifluoromethylsilane: bp 53°-58° C. at 0.5 torr; 1H NMR (CDCl3)δ0.60-1.10 (m, 5H), 1.10-1.56 (m, 4H); 19F NMR (CDCl3, relative to CFCl3)-61.6 ppm (s); IR (neat) 2956, 2925, 2872, 1214, 1058 cm-1 ; mass spectrum (70 eV) m/z (relative intensity) 199 (30, M-CF3), 143 (80), 105 (30), 101 (27), 87 (30), 77 (66), 63 (43), 59 (41), 55 (54), 47 (25), 43 (20), 41 (100). Anal. Calcd. for C13H27F3Si: C, 58.16; H, 10.14. Found: C, 58.26; H, 10.09.
Reaction SMILES: Cl[C:2]1[C:7]2[NH:8][C:9]3[C:14]([C:6]=2[C:5]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([S:22]([CH2:25][CH3:26])(=[O:24])=[O:23])[CH:17]=2)=[CH:4][N:3]=1)=[CH:13][C:12]([CH3:15])=[CH:11][N:10]=3.[CH3:27][N:28]([CH3:33])[CH2:29][CH2:30][CH2:31][NH2:32]>>[CH2:25]([S:22]([C:18]1[CH:17]=[C:16]([C:5]2[C:6]3[C:14]4[CH:13]=[C:12]([CH3:15])[CH:11]=[N:10][C:9]=4[NH:8][C:7]=3[C:2]([NH:32][CH2:31][CH2:30][CH2:29][N:28]([CH3:33])[CH3:27])=[N:3][CH:4]=2)[CH:21]=[CH:20][CH:19]=1)(=[O:24])=[O:23])[CH3:26]
Reactant: CCS(=O)(=O)c1cccc(-c2cnc(Cl)c3[nH]c4ncc(C)cc4c23)c1
Reactant: CN(C)CCCN
Product: CCS(=O)(=O)c1cccc(-c2cnc(NCCCN(C)C)c3[nH]c4ncc(C)cc4c23)c1

Procedure:
Compound 32 (16 mg, 0.041 mmol) was heated with 3-dimethylamino-1-propylamine (1 mL) at 206° C. in the microwave for 30 min. Purification by prep-HPLC gave 10.2 (55%) of the title compound as a pale yellow solid. 1H NMR (400 MHz, MeOD-d4): δ 8.65 (br s, 1H), 8.17 (s, 1H), 8.12 (d, 1H, J=7.6 Hz), 7.98 (d, 1H, J=7.6 Hz), 7.91 (t, 1H, J=7.6 Hz), 7.67 (s, 1H), 7.66 (s, 1H), 3.80 (t, 2H, J=6.8 Hz), 3.28-3.43 (m, 4H), 2.96 (s, 6H), 2.29-2.38 (m, 5H), 1.28 (t, 3H, J=7.2 Hz). MS (ES) [m+H] calc'd for C24H29N5O2S, 452; found 452.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:21][C:22]([C:24]2[C:25](=[O:40])[N:26]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[N:27]([CH2:30][CH:31]([OH:33])[CH3:32])[C:28]=2[CH3:29])=[O:23])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:19][CH3:20])=[CH:16][CH:17]=2)[N:12]=[CH:11][CH:10]=1.[CH3:41][N:42]([CH3:47])[CH2:43][C:44](O)=[O:45].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C1C=CN=CC=1)C.CN(C=O)C.C(Cl)Cl>[CH3:41][N:42]([CH3:47])[CH2:43][C:44]([O:33][C@H:31]([CH3:32])[CH2:30][N:27]1[C:28]([CH3:29])=[C:24]([C:22](=[O:23])[NH:21][C:4]2[CH:5]=[CH:6][C:7]([O:8][C:9]3[C:18]4[C:13](=[CH:14][C:15]([O:19][CH3:20])=[CH:16][CH:17]=4)[N:12]=[CH:11][CH:10]=3)=[C:2]([F:1])[CH:3]=2)[C:25](=[O:40])[N:26]1[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)=[O:45]
Reactant: COc1ccc2c(Oc3ccc(NC(=O)c4c(C)n(CC(C)O)n(-c5ccccc5)c4=O)cc3F)ccnc2c1
Reactant: CN(C)CC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc2c(Oc3ccc(NC(=O)c4c(C)n(C[C@@H](C)OC(=O)CN(C)C)n(-c5ccccc5)c4=O)cc3F)ccnc2c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 90.6 %

Procedure:
To a mixture of (R)—N-(3-fluoro-4-(7-methoxyquinolin-4-yloxy)-phenyl-1-(2-hydrox-ylpropyl)-5-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (1.08 g, 2.0 mmol), N,N-dimethylglycine (0.516 g, 5 mmol Alfa Aesar), HATU (1.902 g. 5 mmol) and DMAP (62.5 mg, 0.5 mmol, Aladdin) was added TEA (1.012 g, 10 mmol) in DMF (12.5 mL) under nitrogen atmosphere at 0° C. The reaction was stirred at 0° C. for 2 hrs, and then warmed up to room temperature and continued to stir overnight. The reaction was diluted with 100 mL of CH2Cl2. The resulted solution was washed with 0.1 N HCl (10 mL×2), saturated NaHCO3 (20 mL×2) and followed by water (20 mL). The organic phase was dried over Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (EtOAc/MeOH=2/1) to give the title compound as a yellow solid (1.1367 g, 84%).