Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:17]2[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=2[F:24])[C:9](=[O:16])[C:10]#[C:11][Si](C)(C)C)=[N:6][CH:7]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-].[NH4+].[Cl-]>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:17]2[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=2[F:24])[C:9](=[O:16])[C:10]#[CH:11])=[N:6][CH:7]=1
Reactant: C[Si](C)(C)C#CC(=O)C(c1ccc(Br)cn1)c1c(F)cccc1F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: C1CCOC1
Product: C#CC(=O)C(c1ccc(Br)cn1)c1c(F)cccc1F
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of 1-(5-bromopyridin-2-yl)-1-(2,6-difluorophenyl)-4-(trimethylsilyl)but-3-yn-2-one (4.1 g) in THF was added TBAF (12 mL, 1N in THF) at 0° C. After stirring at 0° C. for 15 min, the reaction was poured into aqueous NH4Cl, and extracted with EtOAc. The combined organic layers were washed with water, brine, dried over MgSO4, and concentrated to an oil. The crude product was purified by silica gel chromatography (CH2Cl2) to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH2:4][CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][C:10]([OH:15])=[CH:11][CH:12]=2)[N:7]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:6]1=[O:23].[C:25]([O:29][C:30](=[O:37])[NH:31][CH2:32][CH2:33][CH2:34][CH2:35]Br)([CH3:28])([CH3:27])[CH3:26]>>[CH3:1][O:2][C:3](=[O:24])[CH2:4][CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][C:10]([O:15][CH2:35][CH2:34][CH2:33][CH2:32][NH:31][C:30]([O:29][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:37])=[CH:11][CH:12]=2)[N:7]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:6]1=[O:23]
Reactant: CC(C)(C)OC(=O)NCCCCBr
Reactant: COC(=O)CC1Cc2ccc(O)cc2N(Cc2ccccc2)C1=O
Product: COC(=O)CC1Cc2ccc(OCCCCNC(=O)OC(C)(C)C)cc2N(Cc2ccccc2)C1=O

Procedure:
The title compound is prepared using the conditions of Example 75 and (1-benzyl-7-hydroxy-2-oxo-1,2,3,4-tetrahydro-quinolin-3-yl)-acetic acid methyl ester in place of [7-(3-tert-butoxycarbonylaminopropoxy)-1-benzyl-2-oxo-1,2-dihydro-quinolin-3-yl]acetic acid methyl ester and (4-bromobutyl)carbamic acid tert-butyl ester in place of (2-bromoethyl)carbamic acid tert-butyl ester.
Reaction SMILES: [CH2:1]([C:3]1([OH:26])[C:23]2[CH:22]=[C:21]3[N:9]([CH2:10][C:11]4[C:12]3=[N:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=3[CH:20]=4)[C:8](=[O:24])[C:7]=2[CH2:6]OC1=O)[CH3:2].C(#N)C.Cl([O-])(=O)(=O)=O>CN(C)C=O.O>[CH3:6][C:7]1[C:8](=[O:24])[N:9]2[C:21](=[CH:22][C:23]=1[C:3](=[O:26])[CH2:1][CH3:2])[C:12]1=[N:13][C:14]3[C:19]([CH:20]=[C:11]1[CH2:10]2)=[CH:18][CH:17]=[CH:16][CH:15]=3
Reactant: CCC1(O)C(=O)OCc2c1cc1n(c2=O)Cc2cc3ccccc3nc2-1
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CN(C)C=O
Solvent: O
Solvent: CC#N
Product: CCC(=O)c1cc2n(c(=O)c1C)Cc1cc3ccccc3nc1-2

Procedure:
A sample of 4.6 g of 4-ethyl-4-hydroxy-1H-pyrano[3',4':6,7]-indolizino[1,2-b]quinolin-3,14(4H,12H)-dione [(20 S) camptothecin] was stirred with 46 ml of N,N-dimethylformamide. The suspension was heated at reflux, and the disappearance of starting material was monitored by HPLC (C18 reverse phase column, 20-25% acetonitrile:water mobile phase, perchlorate buffer at pH approximately 3.0). The reaction was monitored by UV detection at a wavelength of 228 nm. The only responses detected under these conditions were a peak for N,N-dimethylformamide near the solvent front, a peak for the starting material and a peak for the desired product with a retention time of approximately 3.2 relative to the starting material. The reaction was heated until consumption of the starting material was complete (approximately 8 days). After cooling to ambient temperature the solid product was collected by filtration, and washed with methanol. After drying under vacuum to a constant weight 3.48 g (87%) of product, m.p. 233°-234° C. was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:30])[N:19]([CH2:23][C@H:24]5[O:29][CH2:28][CH2:27][NH:26][CH2:25]5)[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:33]([F:36])([F:35])[F:34])[CH:3]=1.[CH2:37]=O>>[Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:30])[N:19]([CH2:23][C@H:24]5[O:29][CH2:28][CH2:27][N:26]([CH3:37])[CH2:25]5)[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:33]([F:36])([F:35])[F:34])[CH:3]=1
Reactant: C=O
Reactant: O=C1S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C(=O)N1C[C@@H]1CNCCO1
Product: CN1CCO[C@H](CN2C(=O)S/C(=C\c3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)C2=O)C1

Procedure:
(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-{[(2S)-4-methylmorpholin-2-yl]methyl}-1,3-thiazolidine-2,4-dione was prepared from (5Z)-5-({1-[4-chloro-2-(trifluoromethyl)-benzyl]-1H-indazol-5-yl}methylidene)-3-[(2S)-morpholin-2-ylmethyl]-1,3-thiazolidine-2,4-dione (Example 183) and formaldehyde following General Procedure R.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[C@H:7]([CH2:16][CH2:17][CH2:18][NH2:19])[NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])([CH3:4])([CH3:3])[CH3:2].[N:21]#[C:22]Br.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.[Pd].CCOCC>[C:1]([O:5][C:6](=[O:20])[C@H:7]([CH2:16][CH2:17][CH2:18][NH:19][C:22]#[N:21])[NH:8][C:9]([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:10])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCN)C(=O)OC(C)(C)C
Reactant: N#CBr
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@@H](CCCNC#N)C(=O)OC(C)(C)C
Temperature: 22 °C
Reaction time: 0.75 h
Yield: 67 %

Procedure:
To a solution of 6.1 g (14.44 mmol) N5-((Benzyloxy)carbonyl-N2-(tert-butoxycarbonyl-L-ornithine tert-butyl ester in 100 mL ethyl acetate was added 1.0 g 10% palladium on carbon. The suspension was shaken at 22° C. under 50 psi H2 for 45 minutes in a 500 mL Parr bottle. The catalyst was removed by filtration through celite. The resulting solution was concentrated to yield a crude oil. The oil was disolved into 50 mL of diethyl ether and added dropwise to a 0° C. stirred solution of 1.52 g (14.3 mmol) of cyanogen bromide in 30 mL ether. The solution was stirred for 2 h, poured into aqueous sodium bicarbonate, and extraced with ether. The ether solution was dried (magnesium sulfate), concentrated, and purified by silica gel chromatography (100 g, 230-400 mesh silica gel). Elution with a gradient of ethyl acetate in hexanes (30%-60%) gave 3.0 g (67% yield) N2-(tert-butoxycarbonyl)-N5-cyano-L-ornithine tert-butyl ester as an oil.
Reaction SMILES: [F:1][C:2]1([F:16])[CH2:5][CH:4]([C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])[CH2:3]1.CI.[CH3:19][Si]([N-][Si](C)(C)C)(C)C.[K+]>C1COCC1>[F:1][C:2]1([F:16])[CH2:3][C:4]([CH3:19])([C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])[CH2:5]1
Reactant: O=C(OCc1ccccc1)C1CC(F)(F)C1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: CI
Solvent: C1CCOC1
Product: CC1(C(=O)OCc2ccccc2)CC(F)(F)C1
Temperature: -78 °C
Reaction time: 6 h
Yield: 56.5 %

Procedure:
To a solution of benzyl 3,3-difluorocyclobutanecarboxylate (2 g, 8.84 mmol) and MeI (2.202 mL, 35.4 mmol), in THF (15 mL) at −78° C. under a N2 atmosphere was added a solution of KHMDS (35.4 mL, 17.68 mmol, 0.5 M in toluene). The reaction mixture was then stirred at −78° C. for 6 h after which it was allowed to warm to RT and stir overnight. The reaction mass was then quenched with a saturated aq. solution of NH4Cl and extracted with diethyl ether (3×25 mL). The combined organic fractions were washed with water, dried over Na2SO4, filtered and concentrated under vacuum. The crude product was purified by silica gel chromatography (40 g REDISEP® column, eluting with 20% EtOAc in hexanes). Fractions containing the product were combined and evaporated to afford the Intermediate 296A as a pale yellow liquid (1.2 g, 56.5%). 1H NMR (400 MHz, chloroform-d) δ ppm 7.50-7.23 (m, 5H), 5.17 (s, 2H), 3.22-2.97 (m, 2H), 2.60-2.28 (m, 2H), 1.51 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8]/[C:9](/[C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[N:10]/O)[CH:3]=1.C(N(CC)CC)C.FC(F)(F)C(OC(=O)C(F)(F)F)=O.[Cl-].[NH4+]>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH:8]2[C:9]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)=[N:10]2)[CH:3]=1
Reactant: COc1ccc(/C(Cc2cc(Br)ccn2)=N\O)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(C2=NC2c2cc(Br)ccn2)cc1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a stirred solution of (Z)-2-(4-bromopyridin-2-yl)-1-(4-methoxyphenyl)ethanone oxime (2.7 g, 8.4 mmol) and triethylamine (4.7 mL, 33.6 mmol) in dichloromethane at 0° C., was added trifluoroacetic anhydride (1.3 mL, 9.2 mmol). The mixture was stirred at 0° C. for 20 minutes then at room temperature for 5 hours. A saturated solution of ammonium chloride (20 mL) was added and the mixture was diluted with dichloromethane (20 mL). The separated aqueous layer was extracted with dichloromethane (3×25 mL). The combined organic layers were washed with brine, dried over anhydrous MgSO4, filtered and concentrated under reduced pressure to afford a residue which was purified by automated flash-chromatography (ethyl acetate/hexanes; 5/95). The title compound was obtained as a colorless solid (2.1 g, 83%); LCMS m/z 303.0, 305.0 (M+H)+, ret. time 2.57 min.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([CH:17]=[O:18])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[Si]([C:23]([F:26])([F:25])[F:24])(C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-].Cl>C1COCC1>[F:24][C:23]([F:26])([F:25])[CH:17]([C:8]1[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:10][C:9]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[OH:18]
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: CS(=O)(=O)c1ccc(C=O)c(-c2ccccc2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc(C(O)C(F)(F)F)c(-c2ccccc2)c1
Reaction time: 2 h

Procedure:
To a solution of 5-(methylsulfonyl)-[1,1′-biphenyl]-2-carbaldehyde (1 g, 3.8 mmol) was added TMS-CF3 (1.0 g, 7.7 mmol) in THF (10 mL). The reaction was cooled to 0° C. to and TBAF (0.57 mL, 0.57 mmol) was added dropwise. The reaction mixture was stirred for 2 h, then 3 N HCl (2 mL) was added to the mixture and the reaction mixture was stirred for an additional 30 min. The mixture was extracted with ethyl acetate, washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. Purification on normal phase silica gel provided 2,2,2-trifluoro-1-(5-(methylsulfonyl)-[1,1′-biphenyl]-2-yl)ethanol as a white solid.
Reaction SMILES: [C:1]([Si:5]([CH3:14])([CH3:13])[O:6][C@@H:7]1[CH2:11][CH2:10][C@H:9](O)[CH2:8]1)([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.C1(P([N:60]=[N+:61]=[N-:62])(C2C=CC=CC=2)=O)C=CC=CC=1>O1CCCC1>[N:60]([C@@H:9]1[CH2:10][CH2:11][C@@H:7]([O:6][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:14])[CH3:13])[CH2:8]1)=[N+:61]=[N-:62]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CC[C@H](O)C1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)O[C@@H]1CC[C@@H](N=[N+]=[N-])C1
Temperature: 0 °C
Reaction time: 0.04 h

Procedure:
To a mixture of (−)-(1S,3R)-3-(tert-butyl-dimethyl-silanyloxy)-cyclopentanol (670 mg, 3.09 mmol) (from Example 27b supra) and triphenyl phosphine (1.06 g, 4.02 mmol) (Aldrich) in anhydrous tetrahydrofuran (60 mL) cooled at 0° C. was added dropwise diethyl azodicarboxylate (640 μL, 0.70 g, 4.02 mmol) (Aldrich). After 2 to 3 minutes, followed a dropwise addition of diphenylphosphoryl azide (860 μL, 1.1 g, 4.02 mmol) (Aldrich). The mixture was allowed to slowly warm up to room temperature and after overnight stirring was partitioned between ethyl acetate and water. The organic layer was collected, dried over sodium sulfate filtered and concentrated to a residue that was purified by chromatography with a silica gel column using a 0–20% diethyl ether in hexanes gradient to give (−)-(1R,3R)-(3-azido-cyclopentyloxy)-tert-butyl-dimethyl-silane as a colorless liquid. (Yield 540 mg, 72%).
Reaction SMILES: [ClH:1].[N:2]1([C:9]2[CH:10]=[C:11]([NH:16][S:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH:27]([F:29])[F:28])(=[O:19])=[O:18])[CH:12]=[CH:13][C:14]=2[CH3:15])[CH2:8][CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[CH2:30]=O>[BH4-].[Na+].C(#N)C>[ClH:1].[F:28][CH:27]([F:29])[O:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[S:17]([NH:16][C:11]1[CH:12]=[CH:13][C:14]([CH3:15])=[C:9]([N:2]2[CH2:8][CH2:7][CH2:6][N:5]([CH3:30])[CH2:4][CH2:3]2)[CH:10]=1)(=[O:19])=[O:18]
Reactant: Cc1ccc(NS(=O)(=O)c2ccccc2OC(F)F)cc1N1CCCNCC1
Reactant: C=O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CC#N
Product: Cc1ccc(NS(=O)(=O)c2ccccc2OC(F)F)cc1N1CCCN(C)CC1

Procedure:
The title compound was prepared from the title compound of Example 2 under reductive amination conditions employing an aqueous solution of formaldehyde and sodium borohydride in acetonitrile as solvent.
Reaction SMILES: [O:1]=[C:2]1[C:7]2[NH:8][C:9]3[C:14]([C:6]=2[CH2:5][CH2:4][NH:3]1)=[CH:13][C:12]([O:15][CH3:16])=[C:11]([Cl:17])[C:10]=3[Cl:18].[OH-:19].[K+].Cl>C(O)C.O>[NH2:3][CH2:4][CH2:5][C:6]1[C:14]2[C:9](=[C:10]([Cl:18])[C:11]([Cl:17])=[C:12]([O:15][CH3:16])[CH:13]=2)[NH:8][C:7]=1[C:2]([OH:19])=[O:1]
Reactant: COc1cc2c3c([nH]c2c(Cl)c1Cl)C(=O)NCC3
Reactant: [OH-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CCO
Product: COc1cc2c(CCN)c(C(=O)O)[nH]c2c(Cl)c1Cl
Yield: 96.9 %

Procedure:
The above lactam was hydrolyzed with base according to the following procedure: 5 g of 1-oxo-6-methoxy-7,8-dichloro-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole were dissolved in a mixture of 77 ml of ethanol and 51 ml of water. 13.9 g of potassium hydroxide were added, and the solution was heated to refluxing temperature overnight under a nitrogen atmosphere. The reaction mixture was cooled, and the pH adjusted to about 4 by the addition of 12N aqueous hydrochloric acid. A precipitate formed in the acidic solution, which precipitate was isolated by filtration, and the filter cake washed with water. 5.15 g of 3-(2-aminoethyl)-5-methoxy-6,7-dichloroindol-2-carboxylic acid were obtained. The compound melted at 248°-249° C.
Reaction SMILES: [C:1]12([C:11]3[CH:12]=[C:13](B(O)O)[CH:14]=[CH:15][C:16]=3[O:17][CH3:18])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.FC(F)(F)S(O[C:28]1[CH:37]=[CH:36][C:35]2[C:30](=[CH:31][CH:32]=[C:33]([Br:38])[CH:34]=2)[CH:29]=1)(=O)=O.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[K+].[Br-]>C(Cl)(Cl)Cl.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.C1COCC1>[C:1]12([C:11]3[CH:12]=[C:13]([C:28]4[CH:29]=[C:30]5[C:35](=[CH:36][CH:37]=4)[CH:34]=[C:33]([Br:38])[CH:32]=[CH:31]5)[CH:14]=[CH:15][C:16]=3[O:17][CH3:18])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: COc1ccc(B(O)O)cc1C12CC3CC(CC(C3)C1)C2
Reactant: O=S(=O)(Oc1ccc2cc(Br)ccc2c1)C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [Br-]
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: COc1ccc(-c2ccc3cc(Br)ccc3c2)cc1C12CC3CC(CC(C3)C1)C2

Procedure:
3-(1-adamantyl)-4-methoxyphenylboronic acid (150 mg, 0.32 mmol), 6-bromo-2-naphtalenyl trifluoromethanesulphonate (93 mg, 0.26 mmol), K3PO4 (222 mg, 1.05 mmol), KBr (34 mg, 0.29 mmol) and THF (2 ml) were introduced into a Schlenk tube. Next, the reaction mixture was deoxygenated (3 froze/thaw cycles). Next, Pd(PPh3)4 (15 mg, 0.013 mmol) was added and the mixture was again deoxygenated (2 froze/thaw cycles). After heating at reflux for 18 h, the mixture was brought at room temperature and was diluted with CHCl3 (5 ml). The solution was filtered through celite and washings with CHCl3 (2×5 ml) were carried out. The evaporation of the joined organic phases gave a residue which was redissolved in CHCl3 (5 ml) and washed with H2O (2×5 ml). The organic phase was dried with Na2SO4 and after evaporation to dryness, a crude was obtained (97 mg) which was recrystallized with the minimum volume of toluene at reflux. The title compound was obtained (68 mg, 58%) as a pale yellow powder. IR (KBr) 2900, 2847, 1600, 1489, 1456, 1442, 1262, 1237, 1178, 1142, 1103, 1061, 1026, 877, 809 y 470. M/Z (El) 448 [M+ (81Br), 76%] y 446 [M+ (79Br), 100].
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[C:16]1([C:22]2[CH:29]=[CH:28][C:25]([CH2:26]Cl)=[CH:24][CH:23]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O>CN(C=O)C>[C:22]1([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:23]=[CH:24][C:25]([CH2:26][N:12]2[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[C:5]3[C:13]2=[CH:1][CH:2]=[CH:3][CH:4]=3)=[CH:28][CH:29]=1
Reactant: ClCc1ccc(-c2ccccc2)cc1
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: c1ccc(-c2ccc(Cn3c4ccccc4c4ccccc43)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.3 %

Procedure:
Carbazole (8.25 g, 49 mmol) was dissolved in N,N'-dimethylformamide (100 ml). Under a atmosphere of nitrogen was added sodium hydride (2.56 g, 64 mmol of a 60% suspension in mineral oil) in portion during 15 minutes. The mixture was then stirred at room temperature for 0.5 h. To the resulting mixture was added 4-phenylbenzylchloride (10 g, 49 mmol) in portions during 10 minutes. Then additional N,N'-dimethylformamide (100 ml) was added and the mixture was stirred at room temperature for 3.5 h. Water (125 ml) was added and the mixture was stirred vigorously at room temperature for 0.5 h, the solid formed was filtered off, washed with water (2×100 ml) and with hexane (2×100 ml). Drying in vacuo at 50° C. for 16 h afforded 15.9 g (97%) of 9-(biphenyl-4-ylmethyl)-9H-carbazole as a solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:6][CH:5]=1.[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1>>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([S:30]([NH:1][CH2:2][CH2:3][C:4]2[CH:5]=[CH:6][C:7]([CH:10]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:8][CH:9]=2)(=[O:32])=[O:31])=[CH:26][CH:25]=1
Reactant: NCCc1ccc(C(CCCC(=O)O)c2cccnc2)cc1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Product: O=C(O)CCCC(c1ccc(CCNS(=O)(=O)c2ccc(Cl)cc2)cc1)c1cccnc1

Procedure:
Prepared analogously to Example 10e from 5-(4-(2-aminoethyl)phenyl)-5-(3-pyridyl)pentanoic acid and 4-chlorobenzenesulphonic acid chloride.
Reaction SMILES: S([O:6][CH3:7])(OC)(=O)=O.Cl.O[C:10]1[C:15]2=[N:16][C:17]([CH3:24])=[C:18]([CH2:21][CH2:22][OH:23])[C:19](=[O:20])[N:14]2[CH:13]=[CH:12][CH:11]=1.[OH-].[Na+]>O>[OH:23][CH2:22][CH2:21][C:18]1[C:19](=[O:20])[N:14]2[CH:13]=[CH:12][CH:11]=[C:10]([O:6][CH3:7])[C:15]2=[N:16][C:17]=1[CH3:24]
Reactant: COS(=O)(=O)OC
Reactant: Cc1nc2c(O)cccn2c(=O)c1CCO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1cccn2c(=O)c(CCO)c(C)nc12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 49.8 %

Procedure:
Dimethyl sulfate (2.52 g) was added dropwise to a mixture of intermediate 9 (4.4 g) and sodium hydroxide (0.8 g) in water (10 ml), while cooling in ice water. The reaction mixture was stirred for 15 minutes at RT, then it was heated for 1 hour using a warm water bath. The reaction mixture was cooled and extracted with CH2Cl2. The precipitate in the separated aqueous layer was filtered off and purified by column chromatography over silica gel (eluent: CH2Cl2 /CH3OH 97/3). The pure fractions were collected and the solvent was evaporated. The residue was crystallized from CH3CN. The crystals were filtered off and dried, yielding 2 g (42%) of 3-(2-hydroxyethyl)-9-methoxy-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (intermediate 10).
Reaction SMILES: [O:1]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][C:9]=2[C:11](=[CH2:27])[CH2:12][NH:13][C:14]2[CH:19]=[C:18]([C:20]3[CH:21]=[N:22][C:23]([CH3:26])=[CH:24][CH:25]=3)[N:17]=[CH:16][N:15]=2)[O:4][CH2:3][CH2:2]1>CO>[O:1]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][C:9]=2[CH:11]([CH3:27])[CH2:12][NH:13][C:14]2[CH:19]=[C:18]([C:20]3[CH:21]=[N:22][C:23]([CH3:26])=[CH:24][CH:25]=3)[N:17]=[CH:16][N:15]=2)[O:4][CH2:3][CH2:2]1
Reactant: C=C(CNc1cc(-c2ccc(C)nc2)ncn1)c1ccnc2c1OCCO2
Solvent: CO
Product: Cc1ccc(-c2cc(NCC(C)c3ccnc4c3OCCO4)ncn2)cn1
Reaction time: 2 h

Procedure:
As shown in step 8-ii of Scheme 8, N-[2-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-8-yl)allyl]-6-(6-methyl-3-pyridyl)pyrimidin-4-amine (150 mg, 0.4151 mmol) was dissolved in MeOH and the reaction mixture was placed under an atmosphere of H2. After stirring for 2 hours, the mixture was filtered, concentrated under reduced pressure, and purified by medium pressure silica gel chromatography (0-5% MeOH/DCM) to produce N-(2-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-8-yl)propyl)-6-(6-methylpyridin-3-yl)pyrimidin-4-amine (Compound 2029): LCMS=364.39 (M+H); 1H NMR (300 MHz, CDCl3) δ 9.00 (d, J=2.0 Hz, 1H), 8.63 (s, 1H), 8.20 (dd, J=8.1, 2.3 Hz, 1H), 7.81 (d, J=5.0 Hz, 1H), 7.27 (d, J=4.2 Hz, 1H), 6.82 (d, J=5.1 Hz, 1H), 6.71 (s, 1H), 4.43 (dd, J=5.1, 3.0 Hz, 2H), 4.27 (dd, J=5.1, 3.0 Hz, 2H), 3.56 (m, 3H), 2.62 (s, 3H), 1.32 (d, 3H).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][O:10][CH2:11][CH2:12][CH2:13][O:14][C:15]1[C:23]2[O:22][CH:21]=[CH:20][C:19]=2[CH:18]=[C:17]([CH2:24][OH:25])[CH:16]=1>ClCCl>[Br:1][C:18]1[C:19]2[CH:20]=[CH:21][O:22][C:23]=2[C:15]([O:14][CH2:13][CH2:12][CH2:11][O:10][CH3:9])=[CH:16][C:17]=1[CH2:24][OH:25]
Reactant: O=C1CCC(=O)N1Br
Reactant: COCCCOc1cc(CO)cc2ccoc12
Solvent: ClCCl
Product: COCCCOc1cc(CO)c(Br)c2ccoc12
Reaction time: 0.17 h
Yield: 92.8 %

Procedure:
N-Bromosuccinimide (978 mg) was added to a solution of [7-(3-methoxypropoxy)-1-benzofuran-5-yl]methanol (1.18 g) in dichloromethane (30 ml) under ice-cooling and the mixture was stirred at the same temperature for 10 minutes. The reaction mixture was concentrated in vacuo and the resulted residue was purified with a silica gel column chromatography (eluting solvent: n-hexane/ethyl acetate=1/1) to give [4-bromo-7-(3-methoxypropoxy)-1-benzofuran-5-yl]methanol (1.46 g) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)=[CH:11][C:10]([C:20]([F:23])([F:22])[F:21])=[N:9]1.[CH3:24][S:25]([C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][CH:33]=1)(=[O:27])=[O:26].CCN(CC)CC>C(Cl)Cl.CC([O-])=O.CC([O-])=O.[Cu+2]>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:14]=[CH:15][C:16]([O:19][C:32]3[CH:31]=[CH:30][CH:29]=[C:28]([S:25]([CH3:24])(=[O:27])=[O:26])[CH:33]=3)=[CH:17][CH:18]=2)=[CH:11][C:10]([C:20]([F:23])([F:21])[F:22])=[N:9]1
Reactant: CS(=O)(=O)c1cccc(B(O)O)c1
Reactant: Oc1ccc(-c2cc(C(F)(F)F)nn2-c2ccccc2Cl)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)c1cccc(Oc2ccc(-c3cc(C(F)(F)F)nn3-c3ccccc3Cl)cc2)c1
Temperature: 20 °C
Reaction time: 8 h
Yield: 35.7 %

Procedure:
A mixture of 4-(1-(2-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)phenol (169 mg, 0.5 mmol), 3-methylsulfonylphenylboronic acid (200 mg, 1 mmol), Cu(OAc)2 (181 mg, 1 mmol), and NEt3 (35 μL, 2.5 mmol) and molecule sieves (4A) in DCM was shaken overnight at 20° C. Solid was removed by filtration and filtrate was evaporated to give a crude, which was purified by column chromatography on silica gel eluting with EtOAc-hexane (1:4 to 1:2) to afford 1-(2-chlorophenyl)-5-(4-{[3-(methylsulfonyl)phenyl]oxy}phenyl)-3-(trifluoromethyl)-1H-pyrazole (88 mg). 1H-NMR: CDCl3: 7.68 (m, 1H), 7.55 (m, 2H), 7.48 (m, 1H), 7.62-7.40 (m, 2H), 7.27 (m, 2H), 7.21 (m, 1H), 6.93 (m, 1H), 6.80 (s, 1H), 3.04 (s, 3H), MS(ES): 493 [M+H]+.