Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=[O:7])=[CH:4][N:3]=1.[CH3:12][S:13](Cl)(=[O:15])=[O:14].[OH-].[Na+].Cl>C(Cl)Cl>[CH3:12][S:13]([NH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1)(=[O:15])=[O:14]
Reactant: COC(=O)c1ccc(N)nc1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CS(=O)(=O)Nc1ccc(C(=O)O)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 29.6 %

Procedure:
To a solution of methyl 6-aminonicotinate (1.0 g, 6.57 mmol) in CH2Cl2 (50 mL) with TEA (0.96 mL, 6.90 mmol) cooled in an ice bath is added MsCl (0.54 mL, 6.90 mmol) slowly. The crude is allowed to stir at room temperature for 2 hrs. The crude is then concentrated. The crude is dissolved in MeOH (20 mL) and to the crude is added 1 N NaOH (30 mL, 30 mmol). The crude is stirred at room temperature for 18 hrs. The crude is quenched with 1N HCl (32 mL, 32 mmol). The crude is concentrated to remove MeOH and some water is removed as well. The crude is diluted in CH2Cl2 and basified with 1 N NaOH (30 mL). The aq. layer is extracted with CH2Cl2. The aq. layer is acidified with concentrated HCl to bring the PH to 1 via PH paper indicator. The crude is diluted in EtOAc and the aq. layer is extracted with EtOAc. The combined organic layer is washed with brine, dried over MgSO4, filtered, and concentrated to give 6-(methylsulfonamido)nicotinic acid (421 mg) as a yellow solid. HPLC retention time=0.40 minutes (condition D); MS (m+1)=217.2.
Reaction SMILES: [CH3:1][C:2]1[NH:12][C:5]2=[N:6][CH:7]=[C:8]([S:10][CH3:11])[CH:9]=[C:4]2[C:3]=1[CH3:13].CC1NC2=NC(SC)=CC=C2C=1C.[CH2:27](Cl)[C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:29].Cl>>[CH3:1][C:2]1[N:12]=[C:5]2[N:6]([CH2:27][C:28]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[O:29])[CH:7]=[C:8]([S:10][CH3:11])[CH:9]=[C:4]2[C:3]=1[CH3:13]
Reactant: O=C(CCl)c1ccccc1
Reactant: CSc1cnc2[nH]c(C)c(C)c2c1
Agent: CSc1ccc2c(C)c(C)[nH]c2n1
Agent: Cl
Product: CSc1cc2c(C)c(C)nc-2n(CC(=O)c2ccccc2)c1
Yield: 63 %

Procedure:
The title compound was prepared on a 0.6 mmol scale from 2,3-dimethyl-5-methylthiopyrrolo[2,3-b]pyridine (prepared according to the procedure described for 2,3-dimethyl-6-methylthio-pyrrolo[2,3-b]pyridine) and phenacyl chloride as described in Example 43 yielding 140 mg (63%) pure title compound as the hydrochloride.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].Br[C:10]1[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=[O:13].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4][C:10]1[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=[O:13]
Reactant: Nc1ccccc1Cl
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: O=C(O)c1cccc([N+](=O)[O-])c1Nc1ccccc1Cl

Procedure:
A mixture of the known compounds 2-chloroaniline (6.3 g., 0.05 mole) and 2-bromo-3-nitrobenzoic acid (12.3 g., 0.05 mole) was refluxed overnight with 11 g. of potassium carbonate and 0.5 g. of copper-bronze in 125 ml. of ethanol. The ethanol was then removed by evaporation and the residue suspended in water. After filtration, the filtrate was acidified. A solid slowly crystallized, providing the compound 2-(2-chloroanilino)-3-nitrobenzoic acid, m.p. 213°-215° C.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].C1(O)C=CC=CC=1.[CH3:20][O:21][C:22](=[O:27])[CH:23](Br)[CH2:24][CH3:25]>>[CH:6]([C:5]1[CH:8]=[CH:9][C:2]([O:1][CH:23]([CH2:24][CH3:25])[C:22]([O:21][CH3:20])=[O:27])=[C:3]([N+:10]([O-:12])=[O:11])[CH:4]=1)=[O:7]
Reactant: O=Cc1ccc(O)c([N+](=O)[O-])c1
Reactant: CCC(Br)C(=O)OC
Solvent: Oc1ccccc1
Product: CCC(Oc1ccc(C=O)cc1[N+](=O)[O-])C(=O)OC

Procedure:
Using 4-hydroxy-3-nitrobenzaldehyde as the phenol and methyl-2-bromobutanoate as the alkylating agent in the general procedure of alkylation of substituted 2-nitrophenols gives a clear yellow oil: 1H NMR (DMSO-d6, 400 MHz): δ=9.94 (s, 1H), 8.44 (d, J=2.3 Hz, 1H), 8.13 (dd, J=8.8, 2.0 Hz, 1H), 7.42 (d, J=8.8 Hz, 1H), 5.36 (dd, J=6.6, 4.5 Hz, 1H), 3.70 (s, 3H), 1.88-2.05 (m, 2H), 0.98 ppm (t, J=7.5 Hz, 3H). ESI-MS: m/z 268.2 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([O:11][CH3:12])=[O:10])=[C:6]([CH3:16])[N:5]=[C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:3]=1.C(N(CC)C(C)C)(C)C.[CH3:32][N:33]1[C:41]2[C:36](=[CH:37][C:38](B3OC(C)(C)C(C)(C)O3)=[CH:39][CH:40]=2)[CH2:35][CH2:34]1>COCCOC.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:16][C:6]1[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([O:11][CH3:12])=[O:10])=[C:2]([C:38]2[CH:37]=[C:36]3[C:41](=[CH:40][CH:39]=2)[N:33]([CH3:32])[CH2:34][CH2:35]3)[N:3]=[C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:5]=1
Reactant: CCCC(C(=O)OC)c1c(C)nc(-c2ccccc2)nc1Cl
Reactant: CN1CCc2cc(B3OC(C)(C)C(C)(C)O3)ccc21
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCCC(C(=O)OC)c1c(C)nc(-c2ccccc2)nc1-c1ccc2c(c1)CCN2C
Yield: 61.6 %

Procedure:
This compound was prepared according to general method E from methyl 2-(4-chloro-6-methyl-2-phenylpyrimidin-5-yl)pentanoate (0.08 g; 0.25 mmol), tetrakis(triphenylphosphine) palladium(0) (0.029 mg; 0.025 mmol), N,N-diisopropylethylamine (0.173 mL; 1 mmol) and 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indoline (0.130 g; 0.5 mmol) in DME-water (2 mL) for 30 min. Purification by flash-chromatography on silica gel using a gradient of ethyl acetate (2-40%) in heptane furnished 0.064 g (58%) of the title compound.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:30]=[CH:31][CH:32]=1)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]2[C:20]([C:21]3[CH:26]=[CH:25][N:24]=[C:23]([NH:27][CH3:28])[N:22]=3)=[CH:19][CH:18]=[CH:17][N:16]=2)=[C:10]([CH3:29])[CH:9]=1)=[O:6].[O:33]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34]1.C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1>O.C(OCC)(=O)C>[O:33]1[CH:37]=[CH:36][C:35]([C:2]2[CH:3]=[C:4]([CH:30]=[CH:31][CH:32]=2)[C:5]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]3[C:20]([C:21]4[CH:26]=[CH:25][N:24]=[C:23]([NH:27][CH3:28])[N:22]=4)=[CH:19][CH:18]=[CH:17][N:16]=3)=[C:10]([CH3:29])[CH:9]=2)=[O:6])=[CH:34]1
Reactant: CNc1nccc(-c2cccnc2Oc2ccc(NC(=O)c3cccc(I)c3)cc2C)n1
Reactant: OB(O)c1ccoc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CNc1nccc(-c2cccnc2Oc2ccc(NC(=O)c3cccc(-c4ccoc4)c3)cc2C)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 3-iodo-N-(3-methyl-4-(3-(2-(methylamino)pyrimidin-4-yl)pyridin-2-yloxy)phenyl)benzamide (0.100 g, 0.186 mmol), furan-3-ylboronic acid (0.025 g, 0.22 mmol), [1,1′bis(diphenylphosphino)ferrocene] palladium(II) methylene chloride complex (0.0073 g, 0.01 mmol), sodium carbonate (2M solution in water, 0.20 mL, 0.41 mmol) and dioxane was heated to 80 deg. C. for 3 h. The reaction was cooled to ambient temperature and was allowed to stand overnight. Additional [1,1′bis(diphenylphosphino)ferrocene]palladium(II) methylene chloride complex (0.0073 g, 0.01 mmol) was added and the reaction was heated to 85 deg. C. for 3 hr. The reaction was cooled to ambient temperature and was diluted with water and ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The material was further purified by reverse-phase HPLC using acetonitrile/water/TFA as eluent to give 3-(furan-3-yl)-N-(3-methyl-4-(3-(2-(methylamino)pyrimidin-4-yl)pyridin-2-yloxy)phenyl)benzamide. MS m/z=478 [M+1]+. Calc'd for C28H23N5O3: 477.52.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([O:12][CH:13]([CH3:15])[CH3:14])[CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[N:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][CH2:23][CH2:24]O)[CH:17]=1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC>C1COCC1.CCCCCC>[CH:13]([O:12][C:4]1[CH:5]=[C:6]([CH:11]=[C:2]([O:1][CH2:24][CH2:23][CH2:22][C:18]2[CH:17]=[N:16][CH:21]=[CH:20][CH:19]=2)[CH:3]=1)[C:7]([O:9][CH3:10])=[O:8])([CH3:15])[CH3:14]
Reactant: COC(=O)c1cc(O)cc(OC(C)C)c1
Reactant: OCCCc1cccnc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COC(=O)c1cc(OCCCc2cccnc2)cc(OC(C)C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.2 %

Procedure:
To a solution (60 ml) of methyl 5-hydroxy-3-isopropoxybenzoate (2.0 g) and 3-(pyridin-3-yl)propanol (1.6 g) in THF were added successively 1,1′-(azodicarbonyl)dipiperidine (2.9 g) and tributylphosphine (2.8 ml) under ice-cooling, and the mixture was stirred overnight at room temperature. n-Hexane (100 ml) was added to the reaction mixture, and the precipitated crystals were removed by filtration. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (LL, Biotage cartridge, ethyl acetate:n-hexane=15:85→1:4) to give methyl 3-isopropoxy-5-(3-pyridin-3-ylpropoxy)benzoate (2.70 g, 86%) as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:11]CC3C=CC=CC=3)[CH:9]=2)[N:4]([NH:19][C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)[CH:3]=1>C(O)C.[Pd]>[CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([OH:11])[CH:9]=2)[N:4]([NH:19][C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)[CH:3]=1
Reactant: Cc1cn(Nc2ccncc2)c2ccc(OCc3ccccc3)cc12
Agent: [Pd]
Solvent: CCO
Product: Cc1cn(Nc2ccncc2)c2ccc(O)cc12
Yield: 31.3 %

Procedure:
3-Methyl-5-phenylmethoxy-1-(4-pyridinylamino)-1H-indole (2.2 g) dissolved in absolute ethanol (80 ml) was hydrogenated at 344.74 Kpa (Parr shaker, 50 psi) over ten percent palladium on carbon (0.26 g) at 50° C. for two hours. The catalyst was removed by filtration and the solids were washed with methanol. Concentration and recrystallization from methanol afforded the title compound as a solid (0.5 g), m.p. 239°-241° C. (dec.).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH2:5][C:6]([NH:8][C:9]([CH3:17])([CH3:16])[CH2:10][C:11]([O:13]CC)=O)=[O:7])[CH3:2]>C1(C)C=CC=CC=1>[CH3:17][C:9]1([CH3:16])[NH:8][C:6](=[O:7])[CH:5]([C:4]([O:3][CH2:1][CH3:2])=[O:18])[C:11](=[O:13])[CH2:10]1
Reactant: CCOC(=O)CC(=O)NC(C)(C)CC(=O)OCC
Solvent: Cc1ccccc1
Product: CCOC(=O)C1C(=O)CC(C)(C)NC1=O
Temperature: 80 °C

Procedure:
To a solution of sodium ethoxide, obtained from sodium metal (0.122 g, 5.55 mmol) in anhydrous ethanol (7 mL), a solution of ethyl 3-[(3-ethoxy-3-oxopropanoyl)amino]-3-methylbutanoate (1.2 g, 4.62 mmol) in dry toluene (7 mL) was added dropwise at room temperature, under stirring. The reaction mixture was heated at 80° C. for 2 hours then it was concentrated to reduced volume and the residue was dissolved in toluene (15 mL). The organic phase was extracted with water (40 mL), the aqueous phase was acidified to pH 2-3 with 1 N HCl and extracted with ethyl acetate (4×50 mL). The organic phase was washed with brine, dried over anhydrous sodium sulphate and concentrated to give ethyl 6,6-dimethyl-2,4-dioxopiperidine-3-carboxylate as a yellow solid (0.7 g, Y=71%) which was used for the next step without further purification.
Reaction SMILES: [I:1]I.C([Sn](CCCC)(CCCC)[C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[O:14][C:13]([C:18]1[CH:23]=[CH:22][C:21]([NH:24][CH3:25])=[CH:20][CH:19]=1)=[CH:12][C:11]2=[O:26])CCC.S(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[I:1][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[O:14][C:13]([C:18]1[CH:23]=[CH:22][C:21]([NH:24][CH3:25])=[CH:20][CH:19]=1)=[CH:12][C:11]2=[O:26]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc2oc(-c3ccc(NC)cc3)cc(=O)c2c1
Reactant: II
Agent: O=S([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CNc1ccc(-c2cc(=O)c3cc(I)ccc3o2)cc1

Procedure:
A chloroform solution of iodine (1.5 ml, 1 M) was added to a chloroform solution (20 ml) that contained compound 8 (100 mg, 0.185 mmol) at room temperature. The obtained mixture was reacted at room temperature for 10 minutes, and a saturated sodium bisulfite aqueous solution (15 ml) was then added thereto, so as to terminate the reaction. The chloroform layer was separated, and it was then dried over sodium sulfate. Thereafter, the solvent was distilled away under reduced pressure, and the residue was then subjected to silica gel column chromatography using ethyl acetate/hexane (1/2) as an elution solvent, so as to obtain a product of interest, 6-iodo-4′-methylaminoflavone (compound 10). Yield: 20 mg (yield constant: 28.7%) 1H NMR (300 MHz, CDCl3) δ8.53 (s, 1H), 7.90 (d, J=9.0 Hz, 1H), 7.75 (d, J=8.4 Hz, 2H), 7.28 (d, J=10.8 Hz, 1H), 6.64-6.69 (m, 3H), 4.15 (s, 1H), 2.93 (s, 3H). MS m/z 377 (M+).
Reaction SMILES: [NH2:1][C:2]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Cl:11])[CH:9]=2)[NH:4][C:3]1=[O:12].[H-].[Na+].Br[CH2:23][C:24]1[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][C:25]=1[O:34][CH3:35].O>CN(C=O)C>[NH2:1][C:2]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Cl:11])[CH:9]=2)[N:4]([CH2:23][C:24]2[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][C:25]=2[O:34][CH3:35])[C:3]1=[O:12]
Reactant: NC1(c2ccccc2Cl)C(=O)Nc2ccc(Cl)cc21
Reactant: COC(=O)c1ccc(CBr)c(OC)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(CN2C(=O)C(N)(c3ccccc3Cl)c3cc(Cl)ccc32)c(OC)c1
Reaction time: 0.5 h

Procedure:
A solution of 1.13 g of 3-amino-5-chloro-3-(2-chlorophenyl)-1,3-dihydroindol-2-one in 7 ml of DMF is cooled to 0° C. under an argon atmosphere and 0.120 g of sodium hydride as an 80% dispersion in oil is added. After stirring for 30 minutes, 1 g of methyl 4-bromomethyl-3-methoxybenzoate is added and the reaction mixture is stirred for 1 hour at 0° C. It is poured into water and the precipitate formed is filtered off, washed with water, taken up with AcOEt, dried over sodium sulfate and evaporated under vacuum. The residue is chromatographed on silica using a DCM/AcOEt mixture (93/7; v/v) as the eluent to give the expected product after crystallization from a DCM/iso ether mixture. m=1.88 g. M.p.=152° C.
Reaction SMILES: [CH3:1][N:2]([CH:13]1[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]1)[C:3]1[O:4][C:5]2[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][C:6]=2[N:7]=1.[Cl:20][C:21]1[N:22]=[CH:23][C:24]([C:27](O)=[O:28])=[N:25][CH:26]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.N>CN(C1C=CN=CC=1)C.CC#N.CO.C(Cl)Cl>[CH3:1][N:2]([CH:13]1[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]1)[C:3]1[O:4][C:5]2[CH:11]=[CH:10][C:9]([NH:12][C:27]([C:24]3[CH:23]=[N:22][C:21]([Cl:20])=[CH:26][N:25]=3)=[O:28])=[CH:8][C:6]=2[N:7]=1
Reactant: O=C(O)c1cnc(Cl)cn1
Reactant: CN1CCC(N(C)c2nc3cc(N)ccc3o2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: ClCCl
Solvent: CO
Product: CN1CCC(N(C)c2nc3cc(NC(=O)c4cnc(Cl)cn4)ccc3o2)CC1

Procedure:
The title compound was prepared using N2-Methyl-N2-(1-methyl-piperidin-4-yl)-benzooxazole-2,5-diamine (0.368 g, 1.41 mmol), 5-Chloro-pyrazine-2-carboxylic acid (0.247 g, 1.55 mmol), HATU (0.645 g, 1.70 mmol), and DMAP (0.016 g, 0.141 mmol) in CH3CN (20 mL). The compound was subjected to flash column chromatography (120 g column, 2-8% 2N NH3 in MeOH/CH2Cl2) to yield an impure mixture, which was carried on to the next reaction (0.316 g).
Reaction SMILES: [O:1]1[CH2:12][CH:2]1[CH2:3][O:4][C:5]1[CH:6]=[C:7]([OH:11])[CH:8]=[CH:9][CH:10]=1.[CH3:13][CH:14]([NH2:23])[CH2:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CCCCCC>CCOCC>[CH3:13][CH:14]([NH:23][CH2:12][CH:2]([OH:1])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([OH:11])[CH:6]=1)[CH2:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Oc1cccc(OCC2CO2)c1
Reactant: CC(N)COc1ccccc1
Solvent: CCCCCC
Solvent: CCOCC
Product: CC(COc1ccccc1)NCC(O)COc1cccc(O)c1
Yield: 38 %

Procedure:
A mixture of 1.66 g. (10 mmole) of 3-(2,3-epoxy-1-propoxy)-phenol and 4.5 g. (30 mmole) of 1-methyl-2-phenoxyethylamine was heated at 80° C. overnight. The mixture was taken up in ether, and hexane was added to precipitate the product. Recrystallization from ethyl acetate gave 1-(1-methyl-2-phenoxyethylamino)-3-(3-hydroxyphenoxy)-2-propanol (38%); mp 124°-127° C.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]2[CH:7]=[C:8]([OH:11])[CH:9]=[CH:10][C:4]=2[C:3]=1[Br:12].[H-].[Na+].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O>CN(C=O)C.C(OCC)(=O)C>[CH2:15]([O:11][C:8]1[CH:9]=[CH:10][C:4]2[C:3]([Br:12])=[C:2]([Br:1])[S:6][C:5]=2[CH:7]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: BrCc1ccccc1
Reactant: Oc1ccc2c(Br)c(Br)sc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: Brc1sc2cc(OCc3ccccc3)ccc2c1Br
Reaction time: 0.33 h
Yield: 92 %

Procedure:
Add a solution of 2,3-dibromo-benzo[b]thiophen-6-ol (43.9 g, 143 mmol) in DMF (1000 mL), dropwise, to a suspension of sodium hydride in DMF (1.5 L) at 0° C. Stir for 20 minutes, add benzyl bromide (17 mL, 143 mmol). Remove ice bath, and stir at room temperature for 2 hours. Pour reaction mixture into water (8 L) and ethyl acetate (4 L) and stir overnight. Separate layers and wash organic layer with water (3×800 mL) and brine (800 mL). Dry with sodium sulfate, filter, and concentrate in vacuo to give 52.4 g of 6-benzyloxy-2,3-dibromo-benzo[b]thiophene (92%).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[N:9]([CH3:10])[CH:8]=[C:7]([C:11]#[N:12])[CH:6]=1)=O.C(C1N(C)C=C(C#N)C=1)(=O)C.[OH:24][CH2:25][C:26]([NH:29][C:30]([NH2:32])=[S:31])([CH3:28])[CH3:27]>C(O)C>[OH:24][CH2:25][C:26]([NH:29][C:30]1[S:31][CH:2]=[C:3]([C:5]2[N:9]([CH3:10])[CH:8]=[C:7]([C:11]#[N:12])[CH:6]=2)[N:32]=1)([CH3:28])[CH3:27]
Reactant: Cn1cc(C#N)cc1C(=O)CBr
Reactant: CC(C)(CO)NC(N)=S
Agent: CC(=O)c1cc(C#N)cn1C
Solvent: CCO
Product: Cn1cc(C#N)cc1-c1csc(NC(C)(C)CO)n1

Procedure:
The above prepared 2:1 mixture of 5-(2-bromo-acetyl)-1-methyl-1H-pyrrole-3-carbonitrile and 5-acetyl-1-methyl-1H-pyrrole-3-carbonitrile in ethanol (50 mL) was treated with N-(2-Hydroxy-1,1-dimethylethyl)thiourea, prepared in step 2 of Example 52, and heated under reflux. The mixture was filtered while still hot, and the precipitate washed with ethanol, and then partitioned between 1 N sodium carbonate and ethyl acetate. The organic layer was washed with water, dried (anhydrous MgSO4) and evaporated to afford 5-{2-[(2-hydroxy-1,1-dimethylethyl)amino]-1,3-thiazol-4-yl}-1-methyl-1H-pyrrole-3-carbonitrile (1.10 g, 3.98 mmol), as a yellow oil. ANLC 100% at 210-370 nm, 7.8 min; 100% at 248 nm, 7.8 min, the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. pH=3.5/ACN+MeOH) for 10 min, hold 4 min. HRMS: calcd for C13H16N4OS [M+H]+, 277.11176; found (ESI, [M+H]+), 277.1126.
Reaction SMILES: [CH2:1]([NH:4][C:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)[S:7][C:6]=1[C:16]([O:18]C)=[O:17])[CH2:2][CH3:3].C[O-].[Na+].CO.Cl>O>[CH2:1]([NH:4][C:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)[S:7][C:6]=1[C:16]([OH:18])=[O:17])[CH2:2][CH3:3]
Reactant: CCCNc1cc(-c2ccncc2)sc1C(=O)OC
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCCNc1cc(-c2ccncc2)sc1C(=O)O
Yield: 87.8 %

Procedure:
A mixture of methyl 3-(propylamino)-5-(pyridin-4-yl)thiophene-2-carboxylate (0.573 g, 2.07 mmol), sodium methoxide (0.335 g, 6.21 mmol), methanol (8.0 mL) and water (2.0 mL) was refluxed overnight. The mixture was cooled in an ice-bath and conc. HCl (0.510 mL, 6.21 mmol) was added. The resultant yellow precipitate was collected by filtration and washed with water and methanol to afford the title compound (0.477 g, 88%) as a yellow solid:
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]2[S:10][C:9]([CH:11]=O)=[C:8]([CH3:13])[C:6]=2[N:7]=1.[C:20]([N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21]>>[Cl:1][C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]2[S:10][C:9]([CH2:11][N:30]3[CH2:29][CH2:28][N:27]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:32][CH2:31]3)=[C:8]([CH3:13])[C:6]=2[N:7]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Cc1c(C=O)sc2c(N3CCOCC3)nc(Cl)nc12
Product: Cc1c(CN2CCN(C(=O)OC(C)(C)C)CC2)sc2c(N3CCOCC3)nc(Cl)nc12

Procedure:
2-Chloro-7-methyl-4-morpholinothieno[3,2-d]pyrimidine-6-carbaldehyde 36 (495 mg) was reacted with Boc-piperazine via General Procedure B-3 to give tert-butyl 4-((2-chloro-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazine-1-carboxylate.
Reaction SMILES: [CH3:1][C:2]1([CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=2)[CH2:11][C:10](=[O:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:13]([OH:15])=[O:14])[CH:8]=2)[O:3]1.[CH3:27]O.Cl>O1CCOCC1>[CH3:1][C:2]1([CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=2)[CH2:11][C:10](=[O:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:13]([O:15][CH3:27])=[O:14])[CH:8]=2)[O:3]1
Reactant: CC1(COc2ccc([N+](=O)[O-])cc2)CC(=O)c2cc(C(=O)O)ccc2O1
Reactant: CO
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)c1ccc2c(c1)C(=O)CC(C)(COc1ccc([N+](=O)[O-])cc1)O2
Reaction time: 8 h

Procedure:
A mixture of 22 g of 2-methyl-2-(4-nitrophenoxymethyl)-4-oxochroman-6-carboxylic acid (prepared as described in Preparation 42), 100 ml of methanol and 200 ml of a 4N solution of hydrogen chloride in dioxane was allowed to stand overnight at room temperature. At the end of this time, the solvent was stripped from the reaction mixture by evaporation under reduced pressure. The residue was then dissolved in benzene, and the resulting solution was washed with water and dried over anhydrous sodium sulfate. The solvent was then removed by evaporation under reduced pressure. The residue was purified by column chromatography through silica gel, eluted with a 20:1 by volume mixture of benzene and ethyl acetate, to afford 16.1 g of the title compound, melting at 144°-145° C.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[O:5][C:6]2[CH:13]=[CH:12][CH:11]=[CH:10][C:7]=2[C:8]=1[CH3:9].[O:14]=[C:15]1[CH2:20][O:19][C:18]2[CH:21]=[C:22]([CH:25]=[CH:26][C:27](O)=[O:28])[CH:23]=[N:24][C:17]=2[NH:16]1.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.CN(C)CCCN=C=NCC>CN(C=O)C.O>[CH3:1][N:2]([CH2:3][C:4]1[O:5][C:6]2[CH:13]=[CH:12][CH:11]=[CH:10][C:7]=2[C:8]=1[CH3:9])[C:27](=[O:28])/[CH:26]=[CH:25]/[C:22]1[CH:23]=[N:24][C:17]2[NH:16][C:15](=[O:14])[CH2:20][O:19][C:18]=2[CH:21]=1
Reactant: CNCc1oc2ccccc2c1C
Reactant: O=C(O)C=Cc1cnc2c(c1)OCC(=O)N2
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(CN(C)C(=O)/C=C/c2cnc3c(c2)OCC(=O)N3)oc2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.3 %

Procedure:
To a solution of methyl-(3-methyl-benzofuran-2-ylmethyl)-amine (152 mg, 0.87 mmol) in DMF (5 mL) were added in sequential order 3-(3-Oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-acrylic acid (175 mg, 0.79 mmol), 1-hydroxybenzotriazole (121 mg, 0.87 mmol), diisopropylethylamine (412 uL, 2.37 mmol), and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (174 mg, 0.87 mmol). The mixture was stirred at room temperature overnight, cooled in an ice bath and treated with water under rapid stirring. The precipitated product was filtered and dried, triturated with diethyl ether to yield the title compound (150 mg, 50%) as a light brown solid and as a mixtures of amide rotamers. 1H NMR (400 MHz, DMSO-d6) δ 11.46 (s, 1H), 8.19 (s, 1H), 7.89 (s, 1H), 7.5-7.59 (m, 3H), 7.24-7.32 (m, 3H), 4.8-5.02 (m, 2H), 4.70 (s, 2H), 2.95-3.19 (m, 3H), 2.28 (s, 3H); MS (ESI) m/e 378 (C21H19N3O4+H)+.