Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:4]1([S:7](Cl)(=[O:9])=[O:8])[CH2:6][CH2:5]1)[CH:2]=[CH2:3].[C:11]([O:15][C:16]([N:18]1[C:22]2=[C:23]([NH2:38])[C:24]([NH:29][C:30]3[CH:35]=[CH:34][C:33]([Br:36])=[CH:32][C:31]=3[F:37])=[C:25]([CH3:28])[C:26](=[O:27])[N:21]2[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C(OC(=O)C)C>N1C=CC=CC=1>[C:11]([O:15][C:16]([N:18]1[C:22]2=[C:23]([NH:38][S:7]([C:4]3([CH2:1][CH:2]=[CH2:3])[CH2:6][CH2:5]3)(=[O:9])=[O:8])[C:24]([NH:29][C:30]3[CH:35]=[CH:34][C:33]([Br:36])=[CH:32][C:31]=3[F:37])=[C:25]([CH3:28])[C:26](=[O:27])[N:21]2[CH2:20][CH2:19]1)=[O:17])([CH3:12])([CH3:13])[CH3:14]
Reactant: C=CCC1(S(=O)(=O)Cl)CC1
Reactant: Cc1c(Nc2ccc(Br)cc2F)c(N)c2n(c1=O)CCN2C(=O)OC(C)(C)C
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: C=CCC1(S(=O)(=O)Nc2c(Nc3ccc(Br)cc3F)c(C)c(=O)n3c2N(C(=O)OC(C)(C)C)CC3)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 66.9 %

Procedure:
1-Allyl-cyclopropanesulfonyl chloride (121 mg, 0.001 mol) was added to a stirred solution of 8-amino-7-(4-bromo-2-fluoro-phenylamino)-6-methyl-5-oxo-2,3-dihydro-5H-imidazo[1,2-a]pyridine-1-carboxylic acid tert-butyl ester (150 mg, 0.0003 mol) in pyridine (3 mL). The resulting mixture was stirred at room temperature for 12 hours. The reaction was monitored by TLC (100% ethylacetate). The reaction mixture was concentrated and partitioned between ethylacetate and water. The organic layer concentrated to afford the crude product. Purification by column chromatography on silica gel (60% ethylacetate in hexane) afforded 120 mg of the product (60.6% yield).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][C:24](=[C:27]3[C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=4[CH2:31][CH2:30][N:29]4[C:38]([C:41]([OH:43])=[O:42])=[CH:39][N:40]=[C:28]34)[CH2:23][CH2:22]2)=[CH:15][CH:14]=1.Cl.CN(C)CCCN=C=NCC.[C:56]1([CH2:62]O)[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][N:21]2[CH2:22][CH2:23][C:24](=[C:27]3[C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=4[CH2:31][CH2:30][N:29]4[C:38]([C:41]([O:43][CH2:62][C:56]5[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=5)=[O:42])=[CH:39][N:40]=[C:28]34)[CH2:25][CH2:26]2)=[CH:15][CH:14]=1
Reactant: OCc1ccccc1
Reactant: O=C(O)c1cnc2n1CCc1ccccc1C2=C1CCN(CCc2ccc(OCc3ccc4ccccc4n3)cc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: O=C(OCc1ccccc1)c1cnc2n1CCc1ccccc1C2=C1CCN(CCc2ccc(OCc3ccc4ccccc4n3)cc2)CC1
Yield: 62.4 %

Procedure:
A mixture of compound 7 (3 g) and N,N-dimethyl-4-pyridinamine (1.22 g) in DCM (100 ml) was stirred till complete dissolution. 1-(3-Dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (1.8 g) was added portionwise and the mixture was stirred at room temperature for 15 minutes. A solution of benzenemethanol (0.54 g) in DCM was added. The mixture was stirred at room temperature overnight. The solvent was evaporated. The residue was purified over silica gel on a glass filter (eluent CH2Cl2/CH3OH 97/3 to 95/5). The pure fractions were collected and the solvent was evaporated. The residue was crystallized from ACN. The precipitate was filtered off and dried, yielding 2.06 g (62%) of phenylmethyl 6,11-dihydro-11-[1-[2-[4-(2-quino-linyl-methoxy)phenyl]ethyl]-4-piperidinylidene]-5H-imidazo[2,1-b][3]benzazepine-3-carboxylate (compound 9).
Reaction SMILES: Cl[CH2:2][C:3]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[N:6]=[N:5][N:4]=1.[CH2:18]([S:20]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)(=[O:22])=[O:21])[CH3:19].C(N(CC)CC)C>C(#N)C>[CH2:18]([S:20]([N:23]1[CH2:24][CH2:25][N:26]([CH2:2][C:3]2[N:7]([C:8]3[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=3)[N:6]=[N:5][N:4]=2)[CH2:27][CH2:28]1)(=[O:22])=[O:21])[CH3:19]
Reactant: FC(F)(F)c1cccc(-n2nnnc2CCl)c1
Reactant: CCS(=O)(=O)N1CCNCC1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCS(=O)(=O)N1CCN(Cc2nnnn2-c2cccc(C(F)(F)F)c2)CC1
Temperature: 120 °C
Reaction time: 0.33 h

Procedure:
5-(Chloromethyl)-1-[3-(trifluoromethyl)phenyl]-1H-tetrazole (79 mg, 0.301 mmol, commercially available from UkrOrgSynthesis, Kiev, Ukraine) and 1-(ethylsulfonyl)piperazine (53.6 mg, 0.301 mmol, Sigma-Aldrich) were dissolved in acetonitrile (1.5 ml). Triethylamine (0.046 ml, 0.331 mmol) was added, and the mixture was heated in a microwave with stirring at 120° C. for 20 min. The reaction mixture was concentrated in vacuo and the residue purified by high pH MDAP to yield the title compound as a colourless solid (70 mg).
Reaction SMILES: [C:1]([N:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[C:7]([N+]([O-])=O)=[CH:6][C:5]2[CH:17]=[CH:18][CH:19]=[CH:20][C:4]1=2)#[N:2].C([O:23]CCO)C>Cl.[Fe]>[C:1]([N:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[C:7](=[O:23])[CH2:6][C:5]2[CH:17]=[CH:18][CH:19]=[CH:20][C:4]1=2)#[N:2]
Reactant: N#CN1c2ccccc2C=C([N+](=O)[O-])c2ccccc21
Reactant: CCOCCO
Agent: [Fe]
Agent: Cl
Product: N#CN1c2ccccc2CC(=O)c2ccccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
26.3 g (0.1 mole) of 5-cyano-10-nitro-5H-dibenz[b,f]azepine are suspended in a mixture of 265 ml of ethylene glycol monoethyl ether and 75 ml of concentrated hydrochloric acid. 40 g of iron powder are added in small portions at 40° in the course of 40 minutes and the temperature is maintained at 40° by external cooling. The mixture is stirred for a further 2 hours at room temperature, is then heated to 80°, the precipitated product dissolving again, and is filtered through a heated suction filter, which is subsequently washed with ethylene glycol monoethyl ether. The crystallisation which commences in the filtrate is completed by adding 200 of ml of water. After cooling for one hour in an ice-bath, filtration is carried out followed by washing with a mixture of ethylene glycol monoethyl ether and water in a ratio of 1:1. 5-cyano-10-oxo-10,11-dihydro-5H-dibenz[b,f]azepine is obtained which is identified, by comparing the IR spectra, with material from Example 27.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:11]=[C:12]([O:16][CH2:17][CH3:18])[C:13]=1[O:14][CH3:15])[C:7]([O:9]C)=[O:8])[CH3:2].O.[OH-].[Na+].Cl>C(O)C>[CH2:17]([O:16][C:12]1[CH:11]=[C:6]([CH:5]=[C:4]([O:3][CH2:1][CH3:2])[C:13]=1[O:14][CH3:15])[C:7]([OH:9])=[O:8])[CH3:18]
Reactant: CCOc1cc(C(=O)OC)cc(OCC)c1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCOc1cc(C(=O)O)cc(OCC)c1OC
Temperature: 70 °C

Procedure:
63 g of methyl 3,5-diethoxy-4-methoxybenzoate prepared in Referential Example 2 was dissovled in 200 ml of ethanol and 80 ml of water and 44 g of caustic soda was added thereto. The mixture was heated at 70° C. for 2 hr while stirring, cooled, weakly acidified with dilute hydrochloric acid and extracted with dichloromethane. The organic phase was washed with water and dried over anhydrous magnesium sulfate, and the solvent was then distilled off to prepare 48 g of the crude product (white solid).
Reaction SMILES: O[C:2]1([CH3:16])[CH2:11][CH2:10][C:9]2[C:4](=[C:5]([CH3:15])[C:6]([CH3:14])=[C:7]([OH:13])[C:8]=2[CH3:12])[O:3]1.[OH-].[K+].Cl.C(OCC)(=O)C.[C:26](#[N:28])[CH3:27]>>[OH:13][C:7]1[C:6]([CH3:14])=[C:5]([CH3:15])[C:4]2[O:3][C:2]([CH3:16])([CH2:27][C:26]#[N:28])[CH2:11][CH2:10][C:9]=2[C:8]=1[CH3:12]
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(O)O2
Reactant: CC#N
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(CC#N)O2

Procedure:
A mixture of 9.0 g (40.5 mmoles) of 2,6-dihydroxy-2,5,7,8-tetramethylchroman and 4.54 g (69 mmoles) of 85% KOH in 61 ml of acetonitrile was rapidly stirred and refluxed for 4 hr. The dark-colored mixture, which consisted of two phases, was cooled in an ice bath and treated dropwise, with stirring, with 25 ml of 3 N aqueous HCl whereupon the reaction mixture became lighter in color. This mixture was poured into 1 N aqueous HCl and worked-up with ethyl acetate in the usual manner (the organic extracts were additionally washed with saturated aqueous NaHCO3 solution) affording 14.8 g of rac.-3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-acetonitrile as a red solid.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])[CH3:3].ON1C2C=CC=CC=2N=N1.[CH3:25][S:26]([C:29]1[CH:37]=[CH:36][C:32]([C:33](O)=[O:34])=[CH:31][CH:30]=1)(=[O:28])=[O:27].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[C:2]([O:5][C:6](=[O:7])[NH:8][CH:9]1[CH2:10][CH2:11][N:12]([C:33](=[O:34])[C:32]2[CH:31]=[CH:30][C:29]([S:26]([CH3:25])(=[O:28])=[O:27])=[CH:37][CH:36]=2)[CH2:13][CH2:14]1)([CH3:1])([CH3:3])[CH3:4]
Reactant: CS(=O)(=O)c1ccc(C(=O)O)cc1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1CCN(C(=O)c2ccc(S(C)(=O)=O)cc2)CC1
Temperature: 22 °C
Reaction time: 23 h
Yield: 90.6 %

Procedure:
To an ice-cooled slurry of 4-N-BOC-amino-piperidine (400.8 mg, 2.0 mmol), 1-hydroxybenzotriazole (HOBt, 342.3 mg, 2.53 mmol), and p-(methylsulfonyl)-benzoic acid (445.9 mg, 2.23 mmol) in dichloromethane (6 mL) is added 1,3-dicyclohexylcarbodiimide (DCC, 496.7 mg, 2.40 mmol). The reaction mixture is stirred at 22° C. for 23 hours. The crude product is purified on a silica gel chromatography with ethyl acetate-hexanes to provide a white solid (692.9 mg, 90.6% yield, ES+(m/z) 383.1 [M+H]).
Reaction SMILES: [CH2:1]([C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[C:5]([OH:21])=[C:6]([O:19][CH3:20])[CH:7]=[C:8]2/[CH:13]=[C:14](\[CH3:18])/[C:15]([OH:17])=[O:16])[CH3:2].[C:22](OC(=O)C)(=[O:24])[CH3:23].O>N1C=CC=CC=1>[C:22]([O:21][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[CH:12][C:3]=2[CH2:1][CH3:2])[C:8](/[CH:13]=[C:14](/[CH3:18])\[C:15]([OH:17])=[O:16])=[CH:7][C:6]=1[O:19][CH3:20])(=[O:24])[CH3:23]
Reactant: CCc1cccc2c(/C=C(\C)C(=O)O)cc(OC)c(O)c12
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: O
Product: CCc1cccc2c(/C=C(/C)C(=O)O)cc(OC)c(OC(C)=O)c12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
440 mg of (E)-3-(5-ethyl-4-hydroxy-3-methoxy-1-naphthyl)-2-methylpropenoic acid was dissolved in 2.4 ml of pyridine and 0.42 ml of acetic anhydride was added, followed by stirring at room temperature for 1 hour. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with dilute hydrochloric acid and water in this order, dried over anhydrous magnesium sulfate and concentrated in vacuo. The resultant crystals were washed with hexane to obtain 390 mg of the titled compound as colorless crystals.
Reaction SMILES: S[C:2]1[O:3][C:4]2[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:5]=2[N:6]=1.P(Cl)(Cl)(Cl)(Cl)Cl.[CH3:20][N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>C1C=CC=CC=1>[CH3:20][N:21]1[CH2:26][CH2:25][N:24]([C:2]2[O:3][C:4]3[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:5]=3[N:6]=2)[CH2:23][CH2:22]1
Reactant: CN1CCNCC1
Reactant: O=[N+]([O-])c1ccc2nc(S)oc2c1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: c1ccccc1
Product: CN1CCN(c2nc3ccc([N+](=O)[O-])cc3o2)CC1
Reaction time: 2 h

Procedure:
A 200 mg portion of 2-mercapto-6-nitrobenzoxazole dissolved in 40 ml of anhydrous benzene was mixed with 680 mg of phosphorus pentachloride, and the mixture was refluxed under heating for 48 hours. Under cooling with ice, 2.04 g of N-methylpiperazine dissolved in 5 ml of anhydrous benzene was added to the resulting solution, and the reaction was carried out for 2 hours at the same temperature. After adding the same amount of N-methylpiperazine, the reaction was continued for additional 72 hours at room temperature. Precipitated materials in the reaction solution were removed by filtration, and the resulting filtrate was concentrated under a reduced pressure. The thus obtained residue was dissolved in 300 ml of ethyl acetate, washed three times with water, dehydrated with sodium sulfate and then concentrated under a reduced pressure. The resulting residue was purified by a silica gel column chromatography (chloroform:methanol=15:1) to obtain 230 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[CH2:10]([O:14][C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1)[CH2:11][CH2:12][CH3:13].Cl.[OH-].[Na+]>CC(C)=O.O>[Cl:1][C:2]1[N:7]=[C:6]([NH:19][C:18]2[CH:17]=[CH:16][C:15]([O:14][CH2:10][CH2:11][CH2:12][CH3:13])=[CH:21][CH:20]=2)[C:5]([F:9])=[CH:4][N:3]=1
Reactant: CCCCOc1ccc(N)cc1
Reactant: Fc1cnc(Cl)nc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: CCCCOc1ccc(Nc2nc(Cl)ncc2F)cc1
Temperature: 25 °C
Yield: 80 %

Procedure:
To a solution of 2,4-dichloro-5-fluoropyrimidine (0.5 g, 3.0 mmol) and 4-n-butoxyaniline (0.49 g, 3 mmol) in acetone/H2O (1:9 mL) at room temperature was added concentrated HCl (0.1 mL). The mixture was heated at reflux for 1 h, cooled to room temperature, and made basic with 2 N NaOH (2 mL). The aqueous layer was extracted with EtOAc (2×50 mL) and the combined organic extracts were dried (Na2SO4), filtered, and concentrated in vacuo. The crude black solid was purified by chromatography (4:1 hexanes/EtOAc) to afford 2-chloro-N4-(4-n-butyloxyphenyl)-5-fluoro-4-pyrimidineamine (0.71 g, 80%) as a brown oil: 1H NMR (300 MHz, CDCl3) δ 8.01 (d, J=2.7 Hz, 1H), 7.51-7.46 (m, 2H), 6.95-6.89 (m, 2H), 6.83 (bs, 1H), 3.99-3.95 (t, J=6.5 Hz, 2H), 1.82-1.57 (m, 2H), 1.53-1.43 (m, 2H), 0.98 (t, J=7.2 Hz, 3H).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[N:33]=[C:19]4[CH:20]=[CH:21][CH:22]=[C:23]([C:24]5[CH:25]=[N:26][N:27]([CH2:29][C:30]([OH:32])=O)[CH:28]=5)[N:18]4[N:17]=3)=[CH:11][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.CCN=C=NCCCN(C)C.C(N(C(C)C)CC)(C)C.C1C=CC2N(O)N=NC=2C=1.[CH2:64]([NH2:69])[C:65]([CH3:68])([CH3:67])[CH3:66]>CN(C)C=O>[CH3:66][C:65]([CH3:68])([CH3:67])[CH2:64][NH:69][C:30](=[O:32])[CH2:29][N:27]1[CH:28]=[C:24]([C:23]2[N:18]3[N:17]=[C:16]([NH:15][C:12]4[CH:13]=[CH:14][C:9]([O:8][CH2:7][CH2:6][N:1]5[CH2:2][CH2:3][CH2:4][CH2:5]5)=[CH:10][CH:11]=4)[N:33]=[C:19]3[CH:20]=[CH:21][CH:22]=2)[CH:25]=[N:26]1
Reactant: O=C(O)Cn1cc(-c2cccc3nc(Nc4ccc(OCCN5CCCC5)cc4)nn23)cn1
Reactant: CC(C)(C)CN
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)CNC(=O)Cn1cc(-c2cccc3nc(Nc4ccc(OCCN5CCCC5)cc4)nn23)cn1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of (4-{2-[4-(2-pyrrolidin-1-yl-ethoxy)-phenylamino]-[1,2,4]triazolo[1,5-a]pyridin-5-yl}-pyrazol-1-yl)-acetic acid (0.60 g, 0.128 mmol) in dimethylformamide (1 ml) was added EDCI (50 mg, 0.256 mmol), diisopropylethylamine (112 μl, 0.640 mmol), HOBT (35 mg, 0.256 mmol) and finally neopentylamine (30 μl, 0.256 mmol). The mixture was stirred for 18 hours at room temperature, then filtered and concentrated in vacuo. The title compound was purified by preparatory HPLC to yield the desired product. LCMS method: 2, RT: 2.51 min, MI: 517 [M+1]; 1H NMR (300 MHz, DMSO) 9.40 (s, 1H), 8.85 (s, 1H), 8.42 (s, 1H), 8.16 (s, 2H), 7.61 (d, 2H), 7.54 (d, 1H), 7.40 (dd, 2H), 6.92 (d, 2H), 4.98 (s, 2H), 4.02 (t, 2H), 2.93 (d, 2H), 2.87 (t, 2H), 2.63 (s, 4H), 1.69 (s, 4H), 0.83 (m, 9H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH3:9])[C:3]=1[NH:10][CH2:11][C:12]1[CH:17]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=2)[CH:15]=[C:14]([CH3:25])[C:13]=1[O:26][CH3:27].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:35][C:36]([O:38][CH:39]([CH3:41])[CH3:40])=[O:37].O>CC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:35][C:36]([O:38][CH:39]([CH3:41])[CH3:40])=[O:37])=[C:4]([CH3:9])[C:3]=1[NH:10][CH2:11][C:12]1[CH:17]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=2)[CH:15]=[C:14]([CH3:25])[C:13]=1[O:26][CH3:27]
Reactant: CC(C)OC(=O)CBr
Reactant: COc1c(C)cc(-c2cccc(F)c2)cc1CNc1c(F)ccc(O)c1C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC(C)=O
Product: COc1c(C)cc(-c2cccc(F)c2)cc1CNc1c(F)ccc(OCC(=O)OC(C)C)c1C
Reaction time: 0.5 h
Yield: 55.4 %

Procedure:
To a solution of 4-fluoro-3-[[5-(3-fluorophenyl)-2-methoxy-3-methyl-phenyl]methylamino]-2-methyl-phenol (94 mg, 0.25 mmol, 1.0 eq) in acetone (4 mL) at room temperature was added Cs2CO3 (124.4 mg, 0.38 mmol, 1.5 eq). The reaction mixture was stirred for 30 min, then isopropyl bromoacetate (55.3 mg, 1.2 mmol, 1.2 eq) was added and stirring continued for a further 2 h. Water was added and the aqueous layer extracted with EtOAc. The organic extract was washed with water and brinc, dried (Na2SO4), filtered and evaporated in vacuo. The residue was purified by column chromatography (petroleum ether:EtOAc, 20:1) to give the title compound as a colorless oil (65 mg, 54%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:26]=[CH:25][C:6]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][C:13](/[CH:17]=[C:18]4/[C:19](=[O:24])[NH:20][C:21](=[O:23])[S:22]/4)=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[C:5]([C:27]([F:30])([F:29])[F:28])[CH:4]=1.Cl.[CH2:32]([N:34]([CH2:37][CH2:38]Cl)[CH2:35][CH3:36])[CH3:33]>>[CH2:32]([N:34]([CH2:37][CH3:38])[CH2:35][CH2:36][N:20]1[C:19](=[O:24])/[C:18](=[CH:17]/[C:13]2[CH:12]=[C:11]3[C:16](=[CH:15][CH:14]=2)[N:8]([CH2:7][C:6]2[CH:25]=[CH:26][C:3]([O:2][CH3:1])=[CH:4][C:5]=2[C:27]([F:30])([F:29])[F:28])[N:9]=[CH:10]3)/[S:22][C:21]1=[O:23])[CH3:33]
Reactant: CCN(CC)CCCl
Reactant: COc1ccc(Cn2ncc3cc(/C=C4\SC(=O)NC4=O)ccc32)c(C(F)(F)F)c1
Agent: Cl
Product: CCN(CC)CCN1C(=O)S/C(=C\c2ccc3c(cnn3Cc3ccc(OC)cc3C(F)(F)F)c2)C1=O

Procedure:
(5Z)-3-[2-(Diethylamino)ethyl]-5-({1-[4-methoxy-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-1,3-thiazolidine-2,4-dione was prepared from [(5Z)-5-({1-[4-methoxy-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidine (from Example 8) and N,N-diethylaminoethyl chloride hydrochloride following General Procedure H.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][N:12]2[C:20]3[N:19]=[C:18]([CH2:21][C:22]4[S:23][CH:24]=[CH:25][CH:26]=4)[NH:17][C:16]=3[C:15](=[O:27])[N:14]([CH2:28][CH2:29][CH3:30])[C:13]2=[O:31])=[CH:6][CH:5]=1)([O-])=O.O.NN.[H][H]>[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][N:12]2[C:20]3[N:19]=[C:18]([CH2:21][C:22]4[S:23][CH:24]=[CH:25][CH:26]=4)[NH:17][C:16]=3[C:15](=[O:27])[N:14]([CH2:28][CH2:29][CH3:30])[C:13]2=[O:31])=[CH:8][CH:9]=1
Reactant: [H][H]
Reactant: CCCn1c(=O)c2[nH]c(Cc3cccs3)nc2n(CCc2ccc([N+](=O)[O-])cc2)c1=O
Agent: [Pd]
Agent: NN
Solvent: O
Product: CCCn1c(=O)c2[nH]c(Cc3cccs3)nc2n(CCc2ccc(N)cc2)c1=O

Procedure:
By the method of Example 2, 2-thiopheneacetic acid is reacted with 5,6-diamino -1-[2-(4-nitrophenyl)ethyl]-3-propyluracil (6) to yield 3-[2-(4-nitrophenyl)ethyl]-1-propyl-8-[(thiophen-2-yl)methyl]xanthine. By methods well known in the art, 3-[2-(4-nitrophenyl)ethyl]-1-propyl-8-[(thiophen-2-yl)methyl]xanthine is reduced with hydrazine hydrate or hydrogen gas in the presence of a palladium catalyst to yield 3-[2-(4-aminophenyl)ethyl]-1-propyl-8-[(thiophen-2-yl)methyl]xanthine.
Reaction SMILES: [CH2:1]([C@H:8]([NH:17][C:18](=[O:37])[C@@H:19]([N:24]1[CH2:28][CH2:27][N:26]([CH2:29][C:30]2[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=2)[C:25]1=[O:36])[C@@H:20]([CH3:23])[CH2:21][CH3:22])[C@H:9]([OH:16])[CH2:10][NH:11][CH2:12][CH:13]([CH3:15])[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:38]([C:40]1[CH:45]=[CH:44][C:43]([S:46](Cl)(=[O:48])=[O:47])=[CH:42][CH:41]=1)#[N:39].C(N(CC)CC)C>ClCCl>[CH2:1]([C@H:8]([NH:17][C:18](=[O:37])[C@@H:19]([N:24]1[CH2:28][CH2:27][N:26]([CH2:29][C:30]2[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=2)[C:25]1=[O:36])[C@@H:20]([CH3:23])[CH2:21][CH3:22])[C@H:9]([OH:16])[CH2:10][N:11]([S:46]([C:43]1[CH:42]=[CH:41][C:40]([C:38]#[N:39])=[CH:45][CH:44]=1)(=[O:48])=[O:47])[CH2:12][CH:13]([CH3:14])[CH3:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC[C@H](C)[C@@H](C(=O)N[C@@H](Cc1ccccc1)[C@H](O)CNCC(C)C)N1CCN(Cc2cccnc2)C1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC[C@H](C)[C@@H](C(=O)N[C@@H](Cc1ccccc1)[C@H](O)CN(CC(C)C)S(=O)(=O)c1ccc(C#N)cc1)N1CCN(Cc2cccnc2)C1=O
Yield: 74.1 %

Procedure:
Example 785A (50 mg, 0.098 mmol) was dissolved in dichloromethane (1 mL) and combined with p-cyanobenzenesulfonyl chloride (24 mg, 1.2 equivalents) and triethylamine (41 μL, 3 equivalents) at 25° C. for 16 h. The mixture was quenched with 1N NaHCO3 and extracted with ethyl acetate. The organic layer was evaporated, and the residue was purified using ethyl acetate to give 49 mg (74%) of the title compound.
Reaction SMILES: I([O-])(=O)(=O)=O.[CH2:6]([O:13][C:14]1[C:15]([CH2:24][CH:25]=[O:26])=[CH:16][CH:17]=[C:18]2[C:23]=1[N:22]=[CH:21][CH:20]=[CH:19]2)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:27]1([Mg]Br)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>O1CCCC1>[CH2:6]([O:13][C:14]1[C:15]([CH2:24][CH:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[OH:26])=[CH:16][CH:17]=[C:18]2[C:23]=1[N:22]=[CH:21][CH:20]=[CH:19]2)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: Br[Mg]c1ccccc1
Reactant: O=CCc1ccc2cccnc2c1OCc1ccccc1
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: C1CCOC1
Product: OC(Cc1ccc2cccnc2c1OCc1ccccc1)c1ccccc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 34 %

Procedure:
To a stirring solution of 3-[8-(benzyloxy)quinolin-7-yl]propane-1,2-diol (8.08 mmol) in tetrahydrofuran (60 mL) and water (20 mL) in a round bottom flask was added sodium (meta)periodate (8.08 mmol, 1.0 eq.) all at once and the resulting solution was stirred for 30 min. The tetrahydrofuran was then removed by rotary evaporation at room temperature (elevated temperatures will result in decomposition of the product) and the resulting heterogeneous mixture was diluted with water (40 mL) and washed with diethyl ether (2×50 mL). The organic layers were combined, dried (MgSO4), filtered and concentrated (at room temperature) to give the product as a pale yellow oil that was analytically pure and used directly in the ensuing step. (Caution: Compound decomposes rapidly at temperatures greater than 25° C., in the presence of silica gel, and potentially if brought to dryness in presence of periodate salts present in crude reaction mixture.) To a stirring solution of the (8-benzyloxy-quinolin-7-yl)-acetaldehyde (8.08 mmol, 1.0 eq.) from the initial step in tetrahydrofuran (10 mL) at −78° C. was dropwise added a 1M solution of phenylmagnesium bromide in THF (8.08 mmol, 1.0 eq.). On completion of addition, the reaction mixture was allowed to stir at −78° C. for 1 h and was then warmed to room temperature and stirred 30 min. The reaction was then quenched by addition of saturated aqueous sodium bicarbonate solution (5 mL) and allowed to stir for 5 min. The resulting solution was diluted with water (50 mL) and extracted with ethyl acetate (3×50 mL). The organic layers were combined, dried (MgSO4), filtered and concentrated to give a thick yellow syrup that was purified by column chromatography using 20% ethyl acetate/hexanes to give the final product as a pale yellow solid (2.72, 34% for 2 steps). MS (ESI) m/z 356.3; HRMS: calcd for C24H21NO2+H+, 356.16451; found (ESI-FTMS, [M+H]1+), 356.16552.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[NH:8][C:9](=[O:11])[O:10][C:5]2=[CH:4][CH:3]=1.[I:12][C:13]1[CH:14]=[C:15]([CH2:19]O)[CH:16]=[CH:17][CH:18]=1>>[I:12][C:13]1[CH:14]=[C:15]([CH:16]=[CH:17][CH:18]=1)[CH2:19][N:8]1[C:6]2=[N:7][C:2]([CH3:1])=[CH:3][CH:4]=[C:5]2[O:10][C:9]1=[O:11]
Reactant: Cc1ccc2oc(=O)[nH]c2n1
Reactant: OCc1cccc(I)c1
Product: Cc1ccc2oc(=O)n(Cc3cccc(I)c3)c2n1

Procedure:
Reaction of 5-methyl-3H-oxazolo[4,5-b]pyridin-2-one with (3-iodophenyl)methanol under Mitsunobu conditions gives 3-(3-iodobenzyl)-5-methyl-3H-oxazolo[4,5-b]pyridin-2-one; ESI: 367 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[F:14][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:24]=1[CH:23]([CH3:25])[NH:22][CH2:21][CH2:20]2>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:22]3[CH2:21][CH2:20][C:19]4[C:24](=[C:15]([F:14])[CH:16]=[CH:17][CH:18]=4)[CH:23]3[CH3:25])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Reactant: CC1NCCc2cccc(F)c21
Product: CC1c2c(F)cccc2CCN1C(=O)c1cc2ncc(Br)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 8-fluoro-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.