Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH:2]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)=[CH:9][CH:8]=1)[C:3]([O:5][CH3:6])=[O:4].[CH:24]1([C:30]2[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>>[CH3:6][O:5][C:3](=[O:4])[CH:2]([O:36][C:33]1[CH:34]=[CH:35][C:30]([CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)=[CH:31][CH:32]=1)[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)=[CH:9][CH:8]=1
Reactant: Oc1ccc(C2CCCCC2)cc1
Reactant: COC(=O)C(Br)c1ccc(OCCOc2ccc(Cl)cc2)cc1
Product: COC(=O)C(Oc1ccc(C2CCCCC2)cc1)c1ccc(OCCOc2ccc(Cl)cc2)cc1
Yield: 86.8 %

Procedure:
As described in Example 44, 8.0 g of methyl bromo{p-[2-(p-chlorophenoxy)ethoxy]phenyl}acetate is reacted with 4.05 g of p-cyclohexylphenol to give 8.6 g of product as tan crystals. Recrystallization from methanol gives off-white crystals, mp 108°-110° C.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH3:8])=[C:5]([CH3:7])[N:6]=1.C(O[CH:12]=[C:13]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:14]([O:16][CH2:17][CH3:18])=[O:15])C>C(O)C>[C:19]([C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:12][NH:1][C:2]1[S:3][C:4]([CH3:8])=[C:5]([CH3:7])[N:6]=1)([O:21][CH2:22][CH3:23])=[O:20]
Reactant: Cc1nc(N)sc1C
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Solvent: CCO
Product: CCOC(=O)C(=CNc1nc(C)c(C)s1)C(=O)OCC
Yield: 70.6 %

Procedure:
2-Amino-4,5-dimethylthiazole (2.56 g., 20 mmoles), diethyl ethoxymethylenemalonate (4.8 g., 22 mmoles) and ethanol (5 ml.) were refluxed for 1 hour. The reaction mixture was cooled and the crude product precipitated with hexane. Purified 2-(2,2-dicarbethoxyethenylamino)-4,5-dimethylthiazole (4.21 g., m.p. 82°-83.5° C.) was obtained by recrystallization from hexane.
Reaction SMILES: CS(O[CH:6]([C:24]1[CH:29]=[CH:28][C:27]([Br:30])=[CH:26][CH:25]=1)[CH2:7][CH2:8][CH:9](OS(C)(=O)=O)[C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=1)(=O)=O.[F:31][C:32]1[CH:38]=[CH:37][C:35]([NH2:36])=[CH:34][CH:33]=1.Cl>CN(C=O)C>[Br:30][C:27]1[CH:28]=[CH:29][C:24]([CH:6]2[CH2:7][CH2:8][CH:9]([C:10]3[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=3)[N:36]2[C:35]2[CH:37]=[CH:38][C:32]([F:31])=[CH:33][CH:34]=2)=[CH:25][CH:26]=1
Reactant: Nc1ccc(F)cc1
Reactant: CS(=O)(=O)OC(CCC(OS(C)(=O)=O)c1ccc([N+](=O)[O-])cc1)c1ccc(Br)cc1
Agent: Cl
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(C2CCC(c3ccc(Br)cc3)N2c2ccc(F)cc2)cc1
Temperature: 25 °C

Procedure:
Dissolved the product from Example 39C (5.25 g, 10.05 mmol) in DMF (31 mL) and then added 4-fluoroaniline (9.65 mL, 101 mmol) and heated solution at 50° C. for 18 h. Solution was cooled to room temperature and 1N aq. HCl added (100 mL) then extracted with ethyl acetate (2×200 mL), then combined organic extracts washed with brine, dried and concentrated to an amber oil to which methanol (10 mL) was added and after 3 h a yellow solid (1.05 g, 24%) resulted as the title compound as a 1/1 mixture of trans pyrrolidine isomers.
Reaction SMILES: I.[Cl:2][C:3]1[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[C:4]=1[CH:5]=[N:6][NH:7][C:8](=[NH:11])SC.[CH2:17]([NH2:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(O)C>[CH2:17]([NH:24][C:8]([NH:7][N:6]=[CH:5][C:4]1[C:12]([Cl:16])=[CH:13][CH:14]=[CH:15][C:3]=1[Cl:2])=[NH:11])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: NCc1ccccc1
Reactant: CSC(=N)NN=Cc1c(Cl)cccc1Cl
Agent: I
Solvent: CCO
Product: N=C(NCc1ccccc1)NN=Cc1c(Cl)cccc1Cl

Procedure:
A solution of 11.7 g. of methyl 3-(2,6-dichlorobenzylidene)thiocarbazimidate hydroiodide (U.S. Pat. No. 3,657,337) and 3.37 g. of benzylamine in 25 ml. of ethanol is heated at reflux for 18 hours and then evaporated to dryness under reduced pressure. The residue is partitioned between 80 ml. of diethyl ether and 100 ml. of water and the aqueous extract is made alkaline with ammonia. A pale yellow solid is recovered by filtration and recrystallized from aqueous ethanol, giving the desired product as colorless crystals, m.p. 133°-135° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([O:12][C@H:13]3[CH2:18][CH2:17][C@H:16]([NH2:19])[CH2:15][CH2:14]3)[S:11][C:7]=2[CH:6]=[CH:5][CH:4]=1.[O:20]=[C:21]1[NH:26][C:25]2[CH:27]=[C:28]([CH:31]=O)[CH:29]=[CH:30][C:24]=2[O:23][CH2:22]1.[BH4-].[Na+]>ClCCCl.CO>[CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([O:12][C@H:13]3[CH2:18][CH2:17][C@H:16]([NH:19][CH2:31][C:28]4[CH:29]=[CH:30][C:24]5[O:23][CH2:22][C:21](=[O:20])[NH:26][C:25]=5[CH:27]=4)[CH2:15][CH2:14]3)[S:11][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: O=Cc1ccc2c(c1)NC(=O)CO2
Reactant: COc1cccc2sc(O[C@H]3CC[C@H](N)CC3)nc12
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCCl
Product: COc1cccc2sc(O[C@H]3CC[C@H](NCc4ccc5c(c4)NC(=O)CO5)CC3)nc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
trans-4-(4-methoxy-benzothiazol-2-yloxy)-cyclohexylamine (0.5 mmol, intermediate 25.b) and 3-oxo-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbaldehyde (0.5 mmol) were dissolved in DCE (4 ml) and MeOH (4 ml). The mixture was stirred at RT overnight, NaBH4 (1 eq) was added and stirring continued for 1 h. The reaction mixture was partitioned between DCM and NH4OH. The organic layer was dried over MgSO4 and concentrated under reduced pressure. Purification by chromatography (EtOAc/MeOH 9:1 +1% NH4OH) and crystallisation from ether gave 36 mg (16%) of the title compound as a colourless solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:5]=1[CH2:14][CH:15]([CH:24]([C:29]([O:31][CH3:32])=[O:30])[C:25]([O:27][CH3:28])=[O:26])[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)([O-:3])=[O:2].[H-].[Na+].I[CH3:36]>CN(C)C=O>[CH3:36][C:24]([CH:15]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)[CH2:14][C:5]1[CH:6]=[C:7]([C:10]([F:11])([F:12])[F:13])[CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])([C:29]([O:31][CH3:32])=[O:30])[C:25]([O:27][CH3:28])=[O:26]
Reactant: CI
Reactant: COC(=O)C(C(=O)OC)C(Cc1cc(C(F)(F)F)ccc1[N+](=O)[O-])c1ccc(OC)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(C)(C(=O)OC)C(Cc1cc(C(F)(F)F)ccc1[N+](=O)[O-])c1ccc(OC)cc1
Yield: 95.5 %

Procedure:
[2-(2-Nitro-5-trifluoromethylphenyl)-1-(4-methoxyphenyl)ethyl]propanedioic acid, dimethyl ester (7.00 g; 15.4 mmole) was dissolved in dry dimethylformamide (35 ml) under argon. Prewashed (hexane) 50% sodium hydride (0.89 g; 18.4 mmole) was added with stirring. Stirring was continued for 20 minutes before iodomethane (filtered through alumina) (11.6 g; 5.1 ml; 81.5 mmole; sp. gr.=2.24-2.27; 5 eq.) was added dropwise. The mixture was allowed to stir a total of 4.5 hours. The solution was partitioned between ethyl acetate and 1N hydrochloric acid, and the organic layer was collected and washed again with 1N hydrochloric acid, saturated potassium carbonate, saturated sodium chloride, and dried (magnesium sulfate). The concentrated residue was flashed (silica gel/9:1-hexane:ethyl acetate, followed by 8:2-hexane:ethyl acetate). The product was collected from the appropriate fractions and concentrated giving 6.90 g of the title compound as a viscous oil.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]2[CH:14]=[CH:13][O:12][C:9]2=[N:10][CH:11]=1)=O)C.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[O:12]1[C:9]2=[N:10][CH:11]=[C:6]([CH2:4][OH:3])[CH:7]=[C:8]2[CH:14]=[CH:13]1
Reactant: CCOC(=O)c1cnc2occc2c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1cnc2occc2c1
Temperature: -20 °C
Reaction time: 3 h
Yield: 33.7 %

Procedure:
To a solution of 1.9 g of furo[2,3-b]pyridine-5-carboxylic acid ethyl ester (GB 2289276) in 30 ml of THF was added dropwise 17.3 ml of a LiAlH4 (2.3M THF) solution at −20° C. The reaction mixture was stirred for 3 h at −20° C. and then quenched by addition of 1M NaOH solution. The resulting mixture was filtrated over a pad of celite, washed with THF and the filtrate was concentrated in vacuo. Purification by CC using EtOAc yielded 0.5 g of furo[2,3-b]pyridin-5-yl-methanol as yellow oil.
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]1([C:14]2[CH:18]=[C:17]([CH2:19][N:20]3[CH2:25][CH2:24][CH:23]([CH2:26][NH:27]C(=O)OC(C)(C)C)[CH2:22][CH2:21]3)[O:16][N:15]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>ClCCl>[C:8]1([C:14]2[CH:18]=[C:17]([CH2:19][N:20]3[CH2:21][CH2:22][CH:23]([CH2:26][NH2:27])[CH2:24][CH2:25]3)[O:16][N:15]=2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CC(C)(C)OC(=O)NCC1CCN(Cc2cc(-c3ccccc3)no2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCC1CCN(Cc2cc(-c3ccccc3)no2)CC1
Reaction time: 8 h
Yield: 83 %

Procedure:
Trifluoroacetic acid (2.1 mL) was added to a room temperature solution of the compound prepared in Example 8 (0.99 g) in dichloromethane (10 mL). The reaction was stirred overnight and then concentrated. The crude residue was azeotroped with a solution of hexane and toluene, diluted with ethyl acetate and washed with an aqueous 10% sodium carbonate solution. The organics were dried over anhydrous magnesium sulfate and concentrated to obtain the title compound (0.60 g) having the following physical data.
Reaction SMILES: C(OC([NH:11][C@H:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:19]=[C:20]([CH:25]=[CH:26][C:27]=2[F:28])[C:21]([O:23][CH3:24])=[O:22])[CH2:14][C@H:13]1[O:29][CH3:30])=O)C1C=CC=CC=1>[C].[Pd]>[NH2:11][C@H:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:19]=[C:20]([CH:25]=[CH:26][C:27]=2[F:28])[C:21]([O:23][CH3:24])=[O:22])[CH2:14][C@H:13]1[O:29][CH3:30]
Reactant: COC(=O)c1ccc(F)c(N2CC[C@H](NC(=O)OCc3ccccc3)[C@H](OC)C2)c1
Agent: [Pd]
Product: COC(=O)c1ccc(F)c(N2CC[C@H](N)[C@H](OC)C2)c1
Yield: 26.6 %

Procedure:
The same operation as in Example (160c) was performed using methyl cis(±)-3-(4-{[benzyloxy)carbonyl]amino}-3-methoxypiperidin-1-yl)-4-fluorobenzoate obtained in Example (181a) (101 mg, 0.24 mmol) and a 10% palladium-carbon catalyst (100 mg), to obtain 18 mg of the title compound as a colorless oily substance (26%). The resulting compound was used for the next reaction without purification.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:12][C:13]3[CH:18]=[CH:17][C:16]([S:19]([OH:22])(=[O:21])=O)=[CH:15][CH:14]=3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.Cl.S(Cl)(Cl)(=O)=O.[NH2:29][CH:30]1[CH2:35][CH2:34][CH2:33][N:32]([CH2:36][CH3:37])[CH2:31]1>>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:12][C:13]3[CH:14]=[CH:15][C:16]([S:19]([NH:29][CH:30]4[CH2:35][CH2:34][CH2:33][N:32]([CH2:36][CH3:37])[CH2:31]4)(=[O:22])=[O:21])=[CH:17][CH:18]=3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: CCN1CCCC(N)C1
Reactant: O=S(=O)(O)c1ccc(Nc2ccnc3cc(Br)ccc23)cc1
Agent: Cl
Solvent: O=S(=O)(Cl)Cl
Product: CCN1CCCC(NS(=O)(=O)c2ccc(Nc3ccnc4cc(Br)ccc34)cc2)C1

Procedure:
4-(7-Bromo-4-quinolylamino)benzenesulphonic acid is converted to the corresponding sulphonyl chloride hydrochloride and reacted with 3-amino--ethylpiperidine in a similar manner to that described in Example 1(b) to give the title compound.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]([NH:11][C:12]2[CH:13]=[C:14]([C:18]3[N:27]=[C:26]([NH:28][C:29]4[CH:30]=[C:31]5[C:35](=[CH:36][CH:37]=4)[N:34](C(OC(C)(C)C)=O)[N:33]=[CH:32]5)[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[N:19]=3)[CH:15]=[CH:16][CH:17]=2)=[O:10])[CH2:4][CH2:3]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:34]1[C:35]2[C:31](=[CH:30][C:29]([NH:28][C:26]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[N:19]=[C:18]([C:14]4[CH:13]=[C:12]([NH:11][C:9](=[O:10])[CH2:8][N:5]5[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]5)[CH:17]=[CH:16][CH:15]=4)[N:27]=3)=[CH:37][CH:36]=2)[CH:32]=[N:33]1
Reactant: CN1CCN(CC(=O)Nc2cccc(-c3nc(Nc4ccc5c(cnn5C(=O)OC(C)(C)C)c4)c4ccccc4n3)c2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN1CCN(CC(=O)Nc2cccc(-c3nc(Nc4ccc5[nH]ncc5c4)c4ccccc4n3)c2)CC1

Procedure:
To tert-butyl 5-(2-(3-(2-(4-methylpiperazin-1-yl)acetamido)phenyl)-quinazolin-4-ylamino)-1H-indazole-1-carboxylate (22 mmol) was added a solution of 1:1 TFA:CH2Cl2 (2 mL) and stirred at RT for 2 h. The reaction mixture was concentrated in vacuo and the crude product was purified by prep HPLC (method 10-35—90 mins) to afford N-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenyl)-2-(4-methylpiperazin-1-yl)acetamide. (33 mg, 33%)
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1[N:5]=[C:6]2[CH:11]=[N:10][CH:9]=[CH:8][N:7]2[C:12]=1[C:13]([O:15]CC)=[O:14].Cl>O>[CH3:3][C:4]1[N:5]=[C:6]2[CH:11]=[N:10][CH:9]=[CH:8][N:7]2[C:12]=1[C:13]([OH:15])=[O:14]
Reactant: CCOC(=O)c1c(C)nc2cnccn12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1nc2cnccn2c1C(=O)O
Yield: 6.4 %

Procedure:
A solution of sodium hydroxide (1.754 g, 43.9 mmol) in water (25 ml) was added to crude ethyl 2-methylimidazo[1,2-a]pyrazine-3-carboxylate (4.5 g, 21.93 mmol). The reaction is exothermic and goes to completion in minutes without additional heating. The mixture was acidified with concentrated HCl to pH 5. The solution was injected onto a preparative C18 column and washed with water and then eluted with 20% CH3CN/water. The product fractions were combined and concentrate to yield 2-Methyl-imidazo[1,2-a]pyrazine-3-carboxylic acid (250 mg, 6%) as a tan solid. LCMS (Table 1, Method a) Rt=0.84 min, m/z 176.18 (M−H)−; 1H NMR (400 MHz, DMSO-d6) δ 9.12 (m, 2H), 8.12 (m, 1H), 2.66 (s, 3H).
Reaction SMILES: [OH:1][CH:2]1[CH2:9][CH2:8][C:5]2([O:7][CH2:6]2)[CH:4]([C:10]2([CH3:18])[CH:12]([CH2:13][CH:14]=[C:15]([CH3:17])[CH3:16])[O:11]2)[CH:3]1[O:19][CH3:20].O1CCC[CH2:22]1.[H-].[Na+].IC>C(OCC)C>[CH3:20][O:19][CH:3]1[CH:2]([O:1][CH3:22])[CH2:9][CH2:8][C:5]2([O:7][CH2:6]2)[CH:4]1[C:10]1([CH3:18])[CH:12]([CH2:13][CH:14]=[C:15]([CH3:17])[CH3:16])[O:11]1
Reactant: C1CCOC1
Reactant: COC1C(O)CCC2(CO2)C1C1(C)OC1CC=C(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CCOCC
Product: COC1CCC2(CO2)C(C2(C)OC2CC=C(C)C)C1OC

Procedure:
To a solution of 6-hydroxy-5-methoxy-4-[2-methyl-3-(3-methyl-2-butenyl)oxiranyl]-1-oxaspiro[2,5]octane (14.1 mg) in freshly distilled tetrahydrofuran (0.5 ml) was added sodium hydride (60% oil dispersion, 2.0 mg) in one portion in an ice bath. The suspension was stirred for half an hour at the same temperature and thereto iodomethane (71 mg) was added. After stirring for 2 hours at ambient temperature, the mixture was diluted with diethyl ether and washed with water. The organic layer was dried and evaporated to give a crude oil which was purified by column chromatography on silica gel eluted by a mixture of diethyl ether and n-hexane (1:2) to yield 5,6-dimethoxy-4-[2-methyl-3-(3-methyl-2-butenyl)oxiranyl]-1-oxaspiro[2,5]octane (14.2 mg) as an oil.
Reaction SMILES: Cl.[CH3:2][S:3]([C:6]1[CH:24]=[CH:23][C:9]([O:10][CH2:11][C:12]2[N:13]=[C:14]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[S:15][CH:16]=2)=[CH:8][CH:7]=1)(=[O:5])=[O:4].C1COCC1.Cl[C:31]([O:33][CH:34]([CH3:36])[CH3:35])=[O:32]>CCN(CC)CC>[CH:34]([O:33][C:31]([N:20]1[CH2:21][CH2:22][CH:17]([C:14]2[S:15][CH:16]=[C:12]([CH2:11][O:10][C:9]3[CH:8]=[CH:7][C:6]([S:3]([CH3:2])(=[O:4])=[O:5])=[CH:24][CH:23]=3)[N:13]=2)[CH2:18][CH2:19]1)=[O:32])([CH3:36])[CH3:35]
Reactant: CS(=O)(=O)c1ccc(OCc2csc(C3CCNCC3)n2)cc1
Reactant: CC(C)OC(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)OC(=O)N1CCC(c2nc(COc3ccc(S(C)(=O)=O)cc3)cs2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To the HCl salt (Intermediate 3, 43 mg, ˜0.12 mmol) of 4-[4-(4-Methanesulfonyl-phenoxymethyl)-thiazol-2-yl]-piperidine was added 3 mL of THF, followed by isopropyl chloroformate (1.0 M solution in toluene, 0.15 mL, 0.15 mmol) and Et3N (0.05 mL). The resulting mixture was stirred at room temperature for 2 hours, and then partitioned between EtOAc and H2O. After concentration of the organic layer in vacuo, the residue was purified by silica gel column chromatography with EtOAc/hexanes (40-70%) to give the desired product. 1H NMR (CDCl3): δ 7.86 (2H, d, J=9.0 Hz), 7.23 (1H, s), 7.11 (2H, d, J=9.0 Hz), 5.22 (2H, s), 4.92 (1H, m), 4.24 (2H, m), 3.17 (1H, m), 3.03 (3H, s), 2.90 (2H, m), 2.10 (2H, m), 1.72 (2H, m), 1.23 (6H, d, J=6.4 Hz).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]([CH3:12])[C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.F[C:14]1[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][C:15]=1[CH:16]=[O:17].C(=O)([O-])[O-].[K+].[K+]>C1COCC1>[CH:16]([C:15]1[CH:18]=[C:19]([C:22]([F:23])([F:24])[F:25])[CH:20]=[CH:21][C:14]=1[O:1][C:2]1[CH:3]=[C:4]([CH:8]([CH3:12])[C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1)=[O:17]
Reactant: CC(C(=O)O)c1cccc(O)c1
Reactant: O=Cc1cc(C(F)(F)F)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C(=O)O)c1cccc(Oc2ccc(C(F)(F)F)cc2C=O)c1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
2-(3-Hydroxy-phenyl)-propionic acid (0.1 g, 0.60 mmol), 2-fluoro-5-(trifluoromethyl)benzaldehyde (0.115 g, 0.60 mmol), and potassium carbonate (0.165 g, 1.19 mmol) were combined in THF and stirred at 70° C. overnight. The mixture was partitioned between H2O and EtOAc and acidified with 1N aqueous HCl to pH 1, and then extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated, and residue was purified by silica gel chromatography to give the desired product.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3](B(O)O)[CH:2]=1.C(=O)([O-])[O-].[K+].[K+].[Br:16][C:17]1[CH:18]=[C:19]2[C@:30]3([CH2:34][O:33][C:32]([NH2:35])=[N:31]3)[C:29]3[C:24](=[CH:25][CH:26]=[C:27](I)[CH:28]=3)[O:23][C:20]2=[N:21][CH:22]=1.O1CCOCC1>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.O>[Br:16][C:17]1[CH:18]=[C:19]2[C@:30]3([CH2:34][O:33][C:32]([NH2:35])=[N:31]3)[C:29]3[C:24](=[CH:25][CH:26]=[C:27]([C:3]4[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=4)[CH:28]=3)[O:23][C:20]2=[N:21][CH:22]=1
Reactant: OB(O)c1cccnc1
Reactant: NC1=N[C@@]2(CO1)c1cc(I)ccc1Oc1ncc(Br)cc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: NC1=N[C@@]2(CO1)c1cc(-c3cccnc3)ccc1Oc1ncc(Br)cc12
Temperature: 80 °C

Procedure:
A vial charged with pyridin-3-ylboronic acid (0.295 g, 2.401 mmol), palladiumtetrakis (0.126 g, 0.109 mmol), potassium carbonate (1.509 g, 10.92 mmol), and (S)-3-bromo-7-iodo-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-2′-amine (1.000 g, 2.183 mmol) was treated with 11 mL dioxane followed by 4.5 mL water. The vial was flushed with argon and was heated to 80° C. for 4 hours. The reaction mixture was diluted with EtOAc and dried over MgSO4. The organics were then concentrated, and the crude residue was purified by column chromatography yielding (S)-3-bromo-7-(pyridin-3-yl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-2′-amine
Reaction SMILES: [NH2:1][C:2]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]([CH2:15][CH3:16])[CH3:14])=[CH:9][CH:8]=1)=[O:5].[OH:23][CH2:24][CH2:25][O:26][C:27]1[C:34]([CH3:35])=[CH:33][C:30]([CH:31]=O)=[CH:29][C:28]=1[CH3:36]>C(O)C.[Cu](Cl)Cl>[CH:13]([C:10]1[CH:9]=[CH:8][C:7]([N:6]2[C:4](=[O:5])[C:3]3[C:2](=[CH:20][CH:19]=[C:18]([O:21][CH3:22])[CH:17]=3)[N:1]=[C:31]2[C:30]2[CH:33]=[C:34]([CH3:35])[C:27]([O:26][CH2:25][CH2:24][OH:23])=[C:28]([CH3:36])[CH:29]=2)=[CH:12][CH:11]=1)([CH2:15][CH3:16])[CH3:14]
Reactant: CCC(C)c1ccc(NC(=O)c2cc(OC)ccc2N)cc1
Reactant: Cc1cc(C=O)cc(C)c1OCCO
Agent: Cl[Cu]Cl
Solvent: CCO
Product: CCC(C)c1ccc(-n2c(-c3cc(C)c(OCCO)c(C)c3)nc3ccc(OC)cc3c2=O)cc1

Procedure:
To a solution of 2-amino-N-(4-sec-butyl-phenyl)-5-methoxy-benzamide (0.450 g, 1.51 mmol) and 4-(2-hydroxy-ethoxy)-3,5-dimethyl-benzaldehyde (0.290 g, 1.51 mmol) in anhydrous ethanol (20 mL) was added anhydrous copper (II) chloride (0.610 g, 4.53 mmol). The reaction mixture was stirred at reflux for 4 hours under nitrogen. The solvent was removed and the residue was diluted with dichloromethane (100 mL) and water (100 mL). After separation, the organic phase was further washed with water (100 mL), then brine (100 mL), and dried over sodium sulfate. The crude product was purified by column chromatography on silica gel (230-400 mesh) using hexane/ethyl acetate=1:1 to give the title compound as white solid. Yield: 260 mg (36%). MP 152-154° C. 1H-NMR (400 Hz, CDCl3): δ 7.78 (d, 1H), 7.74 (s. 1H), 7.40 (m, 1H), 7.14 (m, 2H), 7.08 (m, 2H), 6.94 (s, 2H), 3.96 (s, 3H), 3.90 (m, 2H), 3.78 (t, 2H), 2.56 (m, 1H), 2.12 (s, 6H), 2.08 (t, 1H), 1.60 (m, 1H), 1.50 (m, 2H), 1.20 (d, 3H), 0.72 (t, 3H). MS (ES+) m/z: 473.29 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:16][C:15](=[O:17])[O:14][C:8]3([CH2:13][CH2:12][NH:11][CH2:10][CH2:9]3)[C:6]=2[CH:7]=1.Br[CH2:19][CH2:20][CH:21]=[C:22]1[C:28]2[CH:29]=[CH:30][CH:31]=[N:32][C:27]=2[CH2:26][O:25][C:24]2[CH:33]=[CH:34][C:35]([C:37]([OH:40])([CH3:39])[CH3:38])=[CH:36][C:23]1=2.[I-].[K+]>C(O)(C)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:16]([CH2:19][CH2:20][CH:21]=[C:22]3[C:28]4[CH:29]=[CH:30][CH:31]=[N:32][C:27]=4[CH2:26][O:25][C:24]4[CH:33]=[CH:34][C:35]([C:37]([OH:40])([CH3:39])[CH3:38])=[CH:36][C:23]3=4)[C:15](=[O:17])[O:14][C:8]3([CH2:13][CH2:12][NH:11][CH2:10][CH2:9]3)[C:6]=2[CH:7]=1
Reactant: O=C1Nc2ccc(Cl)cc2C2(CCNCC2)O1
Reactant: CC(C)(O)c1ccc2c(c1)C(=CCCBr)c1cccnc1CO2
Agent: [I-]
Agent: [K+]
Solvent: CC(C)O
Product: CC(C)(O)c1ccc2c(c1)C(=CCCN1C(=O)OC3(CCNCC3)c3cc(Cl)ccc31)c1cccnc1CO2
Temperature: 80 °C
Reaction time: 5 h
Yield: 10 %

Procedure:
A solution of 6-chloro-1,2-dihydro-2-oxo-spiro[4H-3,1-benzoxazin-4,4′-piperidine] (Made by the procedure of Bock, et al. GB2,355,465, 0.25g, 0.7 mmol) in isopropanol (5 mL) was treated with 2-[5-(3-Bromo-propylidene)-5,11-dihydro-10-oxa-1-aza-dibenzo[a,d]cyclohepten-7-yl]-propan-2-ol (0.19 g, 0.50 mmol) and catalytic potassium iodide. The solution was stirred at 80° C. for 5 hr, and evaporated in vacuo. The residue was purified by reverse-phase preparative HPLC to yield 0.029 g (10%) of the title compound, 1H-NMR (CD3OD) δ: 1.50 (3H, s), 2.18 (2H, brs), 2.95-3.2 (6H, m), 5.30 (2H, brs), 6.18 (1H, t), 6.79 (1H, m), 6.92 (1H, m), 7.12 (1H, m), 7.38 (2H, m), 7.48 (2H, m), 7.81 (2H, m), 8.31 (1H, m), 8.55 (1H, d). ESI-MS m/z: 546 [M+1].
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.Cl.[N:56]1[N:57]=[CH:58][N:59]2[CH2:64][CH2:63][NH:62][CH2:61][C:60]=12>CN(C=O)C>[N:56]1[N:57]=[CH:58][N:59]2[CH2:64][CH2:63][N:62]([C:19]([C:18]3[CH:17]=[N:16][C:15]([O:14][CH2:13][C:3]4[C:4]([C:7]5[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=5)=[N:5][O:6][C:2]=4[CH3:1])=[CH:23][CH:22]=3)=[O:21])[CH2:61][C:60]=12
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Reactant: c1nnc2n1CCNC2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)N2CCn3cnnc3C2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.8 %

Procedure:
To a solution of 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (500 mg, 1.6 mmol) in DMF (10 mL) were added 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (569 mg, 1.8 mmol), N,N-diisopropyl ethyl amine (1.38 mL, 8.1 mmol) and 5,6,7,8-tetrahydro-(1,2,4)triazolo(4,3-a)-pyrazine hydrochloride (1.8 mmol). The resulting reaction mixture was stirred overnight at room temperature. Concentration and purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 1:1 and then dichloromethane:methanol=9:1) afforded the title compound (605 mg, 86%) which was obtained as a white foam. MS: m/e=417.4 [M+H]+.