Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[C:14](=[O:15])[CH:13]=[CH:12][C:11]([C:16]([OH:18])=O)=[CH:10]1.[NH2:19][C:20]1[CH:21]=[C:22]([CH:29]=[CH:30][C:31]=1[CH3:32])[C:23]([NH:25][CH:26]1[CH2:28][CH2:27]1)=[O:24].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.CCOC(C)=O.CCN(CC)CC>[CH:26]1([NH:25][C:23]([C:22]2[CH:29]=[CH:30][C:31]([CH3:32])=[C:20]([NH:19][C:16]([C:11]3[CH:12]=[CH:13][C:14](=[O:15])[N:9]([C:3]4[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=4[Cl:1])[CH:10]=3)=[O:18])[CH:21]=2)=[O:24])[CH2:28][CH2:27]1
Reactant: O=C(O)c1ccc(=O)n(-c2c(Cl)cccc2Cl)c1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1ccc(=O)n(-c2c(Cl)cccc2Cl)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 66.7 %

Procedure:
To a solution of 1-(2,6-dichlorophenyl)-6-oxo-1,6-dihydro-3-pyridinecarboxylic acid (56 mg) in DMF (0.76 mL) were added 3-amino-N-cyclopropyl-4-methylbenzamide (45 mg), WSC—HCl (57 mg), HOBt (35 mg) and Et3N (27 mg), and the mixture was stirred under a nitrogen atmosphere at room temperature for 16 hr. The reaction mixture was diluted with EtOAc (2 mL), washed with water (4 mL×2) and brine successively, dried over MgSO4, filtered and evaporated in vacuo. The residue was purified by preparative thin layer chromatography eluting with 10% MeOH in CH2Cl2 to give N-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-1-(2,6-dichlorophenyl)-6-oxo-1,6-dihydro-3-pyridinecarboxamide (60 mg).
Reaction SMILES: [Li]CCCC.[CH3:6][Si:7]([CH3:14])([CH3:13])[C:8]1[S:9][CH:10]=[CH:11][CH:12]=1.[Cl:15][C:16]1[N:21]=[C:20](Cl)[CH:19]=[CH:18][N:17]=1>C1COCC1.CCOCC.[Cl-].[Cl-].[Zn+2].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>[Cl:15][C:16]1[N:21]=[C:20]([C:10]2[S:9][C:8]([Si:7]([CH3:14])([CH3:13])[CH3:6])=[CH:12][CH:11]=2)[CH:19]=[CH:18][N:17]=1
Reactant: C[Si](C)(C)c1cccs1
Reactant: Clc1ccnc(Cl)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: C[Si](C)(C)c1ccc(-c2ccnc(Cl)n2)s1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
nBuLi (1.9 mL, 1.6 M solution in hexane, 3.0 mmol) was added to a stirred solution of 0.50 mL (3.0 mmol) of 2-(trimethylsilyl)thiophene in 7 mL of THF at −78° C. The solution was stirred for 30 min at −78° C., then warmed to 0° C. and stirred 30 min, before 6.1 mL (3.0 mmol) of a 0.5 M solution of ZnCl2 in THF was added. The reaction solution was stirred for 30 min at 0° C., then transferred via syringe to a microwave vessel containing 315 mg (2.8 mmol) of 2,4-dichloropyrimidine and 158 mg (0.14 mmol) of tetrakis(triphenylphosphine)palladium(0) in 2 mL of THF. The vessel was sealed and heated in a microwave for 10 min at 160° C., then cooled to rt, diluted with 100 mL of Et2O, dried over MgSO4, filtered, concentrated in vacuo, and purified by flash chromatography eluting with a linear gradient of 20% EtOAc in hexane to 50% EtOAc to deliver the title compound. MS (M+H)+ 269.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH3:12])[C:6]2[O:10][CH:9]=[CH:8][C:7]=2[CH:11]=1.C([O-])([O-])=O.[K+].[K+].[Si](I)(C)(C)C>C(#N)C.CCOC(C)=O>[CH3:12][C:5]1[C:6]2[O:10][CH:9]=[CH:8][C:7]=2[CH:11]=[C:3]([OH:2])[CH:4]=1
Reactant: COc1cc(C)c2occc2c1
Agent: C[Si](C)(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: Cc1cc(O)cc2ccoc12
Temperature: 25 °C
Yield: 26 %

Procedure:
To a mixture of the product from Step D (850 mg, 5.2 mmol) and K2CO3 in acetonitrile (10 mL) was added TMSI (1.1 mL). The mixture was refluxed for 2 hrs. The reaction was cooled to room temperature. The mixture was diluted with EtOAc (100 mL) and washed with brine (30 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with PE:EtOAc=5:1) to afford the title compound (200 mg, 25%) as an oil.
Reaction SMILES: [CH3:1][N:2]([CH3:15])[C:3]1[N:8]=[C:7]([CH2:9][C:10]#N)[C:6]([N+:12]([O-])=O)=[CH:5][CH:4]=1>[Ni].C(OCC)(=O)C>[CH3:1][N:2]([CH3:15])[C:3]1[N:8]=[C:7]2[CH:9]=[CH:10][NH:12][C:6]2=[CH:5][CH:4]=1
Reactant: CN(C)c1ccc([N+](=O)[O-])c(CC#N)n1
Agent: [Ni]
Solvent: CCOC(C)=O
Product: CN(C)c1ccc2[nH]ccc2n1
Reaction time: 3 h
Yield: 27.3 %

Procedure:
A mixture of (6-dimethylamino-3-nitro-2-pyridyl)-acetonitrile (Compound 5c,2.06 g, 10.0 mmol), Raney nickel (0.70 g, washed thoroughly with absolute ethanol), and absolute ethanol/acetic acid (4:1, 50 mL) was shaken under ahydrogen atmosphere (3 atm) for 3 hours. The resulting mixture was filteredthrough diatomaceous earth (Celite (trademark)), and the filtrate was evaporated under reduced pressure. The residual oil was dissolved in water(25 mL), the pH was adjusted to 10 with sodium carbonate, and the mixture was extracted with methylene chloride (3×25 mL). These extracts werecombined, dried (MgSO4), and evaporated under reduced pressure to yield an oil. This oil was dissolved in ethyl acetate (10 mL), and this solution was passed through an alumina (basic) filter (approximately 100 g) followed by ethyl acetate (1500 mL). The resulting filtrate was evaporated under reduced pressure to yield Compound 7j (0.44 g, 2.73 mmol,27%) as a white solid: mp, 149.0°-151.0° C.; IR
Reaction SMILES: [C:1]1([C:7]2[C:8]([C:18](O)=O)=[N:9][O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:21]/[N:22]=[C:23](/[C:25]1[CH:42]=[CH:41][C:28]([CH2:29][N:30]2[CH2:33][CH:32]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:31]2)=[CH:27][CH:26]=1)\[NH2:24].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C>[C:1]1([C:7]2[C:8]([C:18]3[O:21][N:22]=[C:23]([C:25]4[CH:26]=[CH:27][C:28]([CH2:29][N:30]5[CH2:31][CH:32]([C:34]([O:36][C:37]([CH3:39])([CH3:38])[CH3:40])=[O:35])[CH2:33]5)=[CH:41][CH:42]=4)[N:24]=3)=[N:9][O:10][C:11]=2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)c1noc(-c2ccccc2)c1-c1ccccc1
Reactant: CC(C)(C)OC(=O)C1CN(Cc2ccc(/C(N)=N/O)cc2)C1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)C1CN(Cc2ccc(-c3noc(-c4noc(-c5ccccc5)c4-c4ccccc4)n3)cc2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 69.2 %

Procedure:
A mixture of 4,5-diphenylisoxazole-3-carboxylic acid (26.5 mg, 0.1 mmol), (Z)-tert-butyl 1-(4-(N′-hydroxycarbamimidoyl)benzyl)azetidine-3-carboxylate, Int.1, (30.5 mg, 0.100 mmol), HOBT (16.85 mg, 0.110 mmol) and EDC (21.09 mg, 0.110 mmol) in DMF (1 mL) was stirred at rt for 18 hr. The reaction mixture was warmed to 60° C. for 2 hr and 70° C. for 2 hr. After cooling to rt overnight, the reaction mixture was partitioned between EtOAc (30 ml) and saturated sodium bicarbonate solution (30 ml). The organic layer was washed with water (2×30 ml) and brine (20 ml). After drying (MgSO4) and filtration, the organic layer was concentrated to a yellow solid that was chromatographed on a 4 gm Isco silica gel cartridge, eluting with a 0-60% EtOAc/Hex gradient. The pure fractions were concentrated to afford tert-butyl 1-(4-(5-(4,5-diphenylisoxazol-3-yl)-1,2,4-oxadiazol-3-yl)benzyl)azetidine-3-carboxylate (37 mg, 0.069 mmol, 69.2% yield) as a white solid. HPLC retention time=1.90 minutes (YMC Combi 4.6×30 mm S-5 ODS column) eluting with 10-90% aqueous methanol+0.1 TFA a 2 minute gradient.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([Cl:9])=[CH:4][C:3]=1[CH2:10][C:11](O)=[S:12].S(Cl)([Cl:16])=O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([Cl:9])=[CH:4][C:3]=1[CH2:10][C:11]([Cl:16])=[S:12]
Reactant: OC(=S)Cc1cc(Cl)c(Cl)cc1Cl
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: S=C(Cl)Cc1cc(Cl)c(Cl)cc1Cl
Temperature: 25 °C
Yield: 110.6 %

Procedure:
A solution of 2,4,5-trichlorophenylthioacetic acid (6.0 g, 22.1 mmol) in methylene chloride (30 mL) and thionyl chloride (10 mL, 137 mmol) was heated at reflux for 3 h. The reaction mixture was allowed to cool to room temperature and was concentrated in vacuo. The residue was evaporated two times from toluene (50 mL) to give 6.7 g of 2,4,5-trichlorophenylthioacetyl chloride as a pale yellow oil (100% yield). 1H NMR (300 MHz, CDCl3) a 4.12 (s, 2 H), 7.54 (s, 1 H), 7.56 (s, 1 H). A solution of (6R)-trans-3-chloromethyl-7-amino-8-oxo-5-thia-1-azabicyclo-[4.2.0]oct-2-ene-2-carboxylate, diphenylmethyl ester (4.15 g, 10 mmol) in THF (50 mL) was cooled to 0° C. and treated with N-methylmorpholine (1.2 g, 11.9 mmol) and 2,4,5-trichlorophenylthioacetyl chloride (3.3 g, 10.8 mmol). The reaction mixture was stirred for 1 h at 0° C., diluted with ethyl acetate (500 mL) and washed with water (500 mL). The organic solution was then dried (MgSO4) and the solvents were evaporated in vacuo. The remaining residue was stirred with ether. The product solidified and was collected by filtration to give 4.5 g (60% yield) of title product as a white solid, m.p. 173° C. 1H NMR (300 MHz, CDCl3)δ 3.45 (d, J=18.3 Hz, 1 H), 3.61 (d, J=18.3 Hz, 1 H), 3.68 (d, J=16.8 Hz, 1 H), 3.76 (d, J=16.8 Hz, 1 H), 4.37 (d, J=11.9 Hz, 1 H), 4.42 (d, J=11.9 Hz, 1 H), 4.98 (d, J=5.0 Hz, 1 H), 5.80 (dd, J=5.0, 8.9 Hz, 1 H), 6.99 (s, 1 H), 7.22 (d, J=8.9 Hz, 1 H), 7.30-7.45 (m, 10 H), 7.38 (s, 1 H), 7.51 (s, 1 H). Anal. Calcd. for C29H22N2O4S2Cl4 : C, 52.11; H, 3.32; N, 4.19. Found: C, 52.06; H, 3.42; N, 4.19.
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]=1[B:13]1[O:17][C:16]([CH3:19])([CH3:18])[C:15]([CH3:21])([CH3:20])[O:14]1.[C:22]([NH2:26])([CH3:25])([CH3:24])[CH3:23].ClCCl.ClCCl.CO>C1COCC1>[C:22]([NH:26][CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]=1[B:13]1[O:17][C:16]([CH3:19])([CH3:18])[C:15]([CH3:21])([CH3:20])[O:14]1)([CH3:25])([CH3:24])[CH3:23]
Reactant: CC1(C)OB(c2c(CBr)ccc3ccccc23)OC1(C)C
Reactant: CC(C)(C)N
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)NCc1ccc2ccccc2c1B1OC(C)(C)C(C)(C)O1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 30.0 g (86.5 mmol) of 2-[2-(bromomethyl)-1-naphthyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane and 91.0 ml (63.3 g, 865 mmol) of tert-butylamine in 200 ml of THF was stirred at room temperature for 48 h. The resulting mixture was filtered through glass frit (G3) and then evaporated to dryness. The product was isolated by flash chromatography on silica gel 60 (40-63 urn; eluent: dichloromethane and then dichloromethane-methanol=1:1, vol.). Yield 27.4 g (94%). Anal. Calc. for C21H30BNO2: C, 74.34; H, 8.91; N, 4.13. Found: C, 74.49; H, 9.09; N, 3.98. 1H NMR (CDCl3): 8.80 (br. s, 1H, NH), 8.53 (m, 1H, 8-H in naphthyl), 7.88 (d, J=8.3 Hz, 1H, 4-H in naphthyl), 7.83 (d, J=8.3 Hz, 1H, 3-H in naphthyl), 7.71 (m, 1H, 5-H in naphthyl), 7.47 (m, 1H, 7-H in naphthyl), 7.41 (m, 1H, 6-H in naphthyl), 4.44 (s, 2H, CH2N), 1.49 (s, 12H, CMe2CMe2), 1.41 (s, 9H, tBu).
Reaction SMILES: [N:1]1([S:7]([C:10]2[CH:19]=[C:18]3[C:13]([CH2:14][CH2:15][NH:16][CH2:17]3)=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH:20]([O:23][C:24]1[CH:32]=[CH:31][C:30]([S:33]([CH3:36])(=[O:35])=[O:34])=[CH:29][C:25]=1[C:26](O)=[O:27])([CH3:22])[CH3:21]>>[CH:20]([O:23][C:24]1[CH:32]=[CH:31][C:30]([S:33]([CH3:36])(=[O:35])=[O:34])=[CH:29][C:25]=1[C:26]([N:16]1[CH2:15][CH2:14][C:13]2[C:18](=[CH:19][C:10]([S:7]([N:1]3[CH2:2][CH2:3][O:4][CH2:5][CH2:6]3)(=[O:9])=[O:8])=[CH:11][CH:12]=2)[CH2:17]1)=[O:27])([CH3:22])[CH3:21]
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)O
Reactant: O=S(=O)(c1ccc2c(c1)CNCC2)N1CCOCC1
Product: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCc2ccc(S(=O)(=O)N3CCOCC3)cc2C1

Procedure:
Prepared in analogy to example 1.1 from 7-(morpholine-4-sulfonyl)-1,2,3,4-tetrahydro-isoquinoline (CA [185059-05-6]) and 2-isopropoxy-5-methanesulfonyl-benzoic acid (Example 2.1). MS (m/e): 523.2 (M+H+).
Reaction SMILES: C[O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][CH2:11][CH2:12]Cl.[NH:15]1[CH2:20][CH2:19][CH:18]([C:21]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[N:23]([CH2:30][CH2:31][C:32]3[CH:36]=[CH:35][S:34][CH:33]=3)[CH:22]=2)[CH2:17][CH2:16]1.C(=O)([O-])[O-].[K+].[K+]>CC(CC(C)C)=O>[S:34]1[CH:35]=[CH:36][C:32]([CH2:31][CH2:30][N:23]2[C:24]3[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:21]([CH:18]3[CH2:19][CH2:20][N:15]([CH2:12][CH2:11][O:10][C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=4[C:3]([OH:2])=[O:14])[CH2:16][CH2:17]3)=[CH:22]2)=[CH:33]1
Reactant: c1ccc2c(c1)c(C1CCNCC1)cn2CCc1ccsc1
Reactant: COC(=O)c1ccccc1OCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)CC(C)C
Product: O=C(O)c1ccccc1OCCN1CCC(c2cn(CCc3ccsc3)c3ccccc23)CC1
Yield: 99.3 %

Procedure:
A solution of 1.5 g (0.007 mol) of 2-(2-chloro-ethoxy)-benzoic acid methyl ester (prepared in Example 1, part C) in 5 mL of methyl-iso-butylketone was added to a suspension of 2 g (0.065 mol) of 3-piperidin-4-yl-1-(2-thiophen-3-yl-ethyl)-1H-indole and 1.8 g (0.013 mol) of potassium carbonate in 45 mL of methyl-iso-butylketone. The reaction mixture was refluxed for 18 h. The crude mixture was filtered to remove inorganic salts and the solvent was removed under reduced pressure affording 3.3 g of a crude oil. The crude mixture was purified by flash chromatography over silica gel affording 1.5 g (48% of yield) of 2-(2-{4-[1-(2-thiophen-3-yl-ethyl)-1H-indol-3-yl]-piperidin-1-yl}-ethoxy)-benzoic acid methyl ester. This ester was dissolved in a mixture of 25 mL of methanol/THF 3:2 and hydrolysed with 2N NaOH at room temperature for 16 hours. The crude mixture was neutralised with 2N HCl aqueous solution and the solvent was removed under reduced pressure. The crude residue was precipitated with dichloromethane and then recrystallised with methanol affording 1.3 g of the expected acid.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([C:10]3[N:11]=[C:12]([SH:24])[NH:13][C:14]=3[C:15]3[CH:20]=[CH:19][C:18]4[O:21][CH2:22][O:23][C:17]=4[CH:16]=3)=[CH:4][C:3]=2[O:2]1.Br[CH2:26][CH2:27]Br.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:22]1[O:21][C:18]2[CH:19]=[CH:20][C:15]([C:14]3[N:13]4[C:12]([S:24][CH2:26][CH2:27]4)=[N:11][C:10]=3[C:5]3[CH:6]=[CH:7][C:8]4[O:9][CH2:1][O:2][C:3]=4[CH:4]=3)=[CH:16][C:17]=2[O:23]1
Reactant: Sc1nc(-c2ccc3c(c2)OCO3)c(-c2ccc3c(c2)OCO3)[nH]1
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: c1cc2c(cc1-c1nc3n(c1-c1ccc4c(c1)OCO4)CCS3)OCO2
Temperature: 0 °C

Procedure:
A slurry of 3.5 g. (0.01 mole) of 4,5-bis(3,4-methylenedioxyphenyl)-2-mercaptoimidazole, 2.0 g. (0.01 mole) of 1,2-dibromoethane and 2 g. (0.014 mole) of potassium carbonate in dimethylformamide (45 ml.) was refluxed for 2.5 hours and then poured into 500 ml. of ice water. The precipitate was collected, washed with water and dried. Chromatography (alumina/chloroform) gave 5,6-bis(3,4-methylenedioxyphenyl)-2,3-dihyroimidazo[2,1-b]thiazole. This was dissolved in methanol and treated with aqueous hydrobromic acid. The solvent was removed and the residue recrystallized from methanol to give 5,6-bis(3,4-methylenedioxyphenyl)-2,3-dihydroimidazo[2,1-b]thiazole hydrobromide, m.p. 278°-280° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([NH:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[N:8][CH:9]=[N:10]2)=[CH:5][C:4]=1[N+:26]([O-])=O.CN>>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([NH:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[N:20]3[CH2:21][CH2:22][O:23][CH2:24][CH2:25]3)=[N:8][CH:9]=[N:10]2)=[CH:5][C:4]=1[NH2:26]
Reactant: COc1cc2ncnc(Nc3ccccc3N3CCOCC3)c2cc1[N+](=O)[O-]
Agent: CN
Product: COc1cc2ncnc(Nc3ccccc3N3CCOCC3)c2cc1N
Yield: 35 %

Procedure:
The procedure of Example 23 was repeated except for using 7-methoxy-N-(2-morpholinophenyl)-6-nitroquinazolin-4-amine instead of 7-methoxy-6-nitroquinazolin-4-yl)methylamine in <Step 7> to obtain the title compound (65 mg, 35%).
Reaction SMILES: [C:1]([C:5]1[S:9][C:8]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:20]#[C:21][C:22]4[CH:32]=[CH:31][C:25]([C:26]([O:28]CC)=[O:27])=[CH:24][CH:23]=4)[CH:18]=3)[S:13][C:12]([CH3:34])([CH3:33])[CH:11]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl>C1COCC1.CCO>[C:1]([C:5]1[S:9][C:8]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([CH2:20][CH2:21][C:22]4[CH:32]=[CH:31][C:25]([C:26]([OH:28])=[O:27])=[CH:24][CH:23]=4)[CH:18]=3)[S:13][C:12]([CH3:34])([CH3:33])[CH:11]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2ccc(C(C)(C)C)s2)=CC(C)(C)S3)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CC1(C)C=C(c2ccc(C(C)(C)C)s2)c2cc(CCc3ccc(C(=O)O)cc3)ccc2S1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.2 %

Procedure:
To a solution of ethyl 4-[[4-(5-tert-butylthiophen-2-yl)-2,2-dimethyl(2H)-thiochromen-6-yl]-ethynyl]-benzoate (Compound 232, 88.0 mg, 0.181 mmol) in 2.0 mL THF and 2.0 mL EtOH was added NaOH (160.0 mg, 4.0 mmol, 4.0 mL of a 1M aqueous solution). The resulting solution was stirred overnight at room temperature. The reaction mixture was acidified with 10% aqueous HCl and extracted with EtOAc. The combined organic layers were washed with H2O, saturated aqueous NaCl, and dried (Na2SO4) before removing the solvent under reduced pressure. The residual solid was recrystallized from CH3CN to give 68.0 mg (82%) of the title compound as a pale-yellow solid. 1H NMR (300 MHz, d6 -acetone) δ: 8.03 (2H, d, J=8.3 Hz), 7.63 (2H, d, J=8.3 Hz), 7.62 (1H, s), 7.44 (2H, d, J=1.2 Hz), 6.87 (2H, s), 6.11 (1H, s), 1.45 (6H, s), 1.39 (9H, s).
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][N:6]=1.C([Mg]Cl)(C)C.[C:12]([C:15]1[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=1)(=[O:14])[CH3:13]>C1COCC1>[OH:14][C:12]([C:15]1[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=1)([C:4]1[S:3][CH:2]=[N:6][CH:5]=1)[CH3:13]
Reactant: COC(=O)c1ccc(C(C)=O)cc1
Reactant: Brc1nccs1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C(C)(O)c2cncs2)cc1
Temperature: -20 °C
Reaction time: 1 h
Yield: 62.1 %

Procedure:
A flask was charged with 2-bromothiazole (1.386 ml, 15.55 mmol) and THF (30.6 ml) and then sealed and purged with Argon. The solution was cooled to −20° C. and isopropylmagnesium chloride (2 M, 8.16 ml, 16.32 mmol) was added drop wise. The reaction was stirred for 1 hour and then warmed to 0° C. After stirring for 60 minutes, the solution was cooled to −78° C. and methyl 4-acetylbenzoate (3.05 g, 17.10 mmol) in THF (5.11 ml) was added drop wise. The reaction stirred for an additional 30 minutes at −78° C. then warmed to room temperature. After stirring for 1 hour, the reaction was quenched with aqueous saturated NH4Cl and extracted with ethyl acetate (2×). The combined organics were dried over Na2SO4, filtered and concentrated. The crude mixture was purified by flash chromatography on silica (10-75% ethyl acetate/hexanes). The mixed fractions were combined, concentrated and re-purified by column chromatography on silica (10-75% ethyl acetate/hexanes). The desired fractions were combined and concentrated to afford methyl 4-[1-hydroxy-1-(1,3-thiazol-5-yl)ethyl]benzoate (2.54 g, 9.65 mmol, 62.0% yield). MS ESI: [M+H]+ m/z 264.0.
Reaction SMILES: [CH2:1]([C:3]([C:22]1[CH:35]=[CH:34][C:25]([O:26][CH2:27][C:28](=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30])=[C:24]([CH3:36])[CH:23]=1)([C:6]1[CH:11]=[CH:10][C:9]([B:12]2[O:16][C:15]([CH3:18])([CH3:17])[C:14]([CH3:20])([CH3:19])[O:13]2)=[C:8]([CH3:21])[CH:7]=1)[CH2:4][CH3:5])[CH3:2].CCC(C)[BH-](C(C)CC)C(C)CC.[Li+].[Cl-].[NH4+]>O1CCCC1>[CH2:1]([C:3]([C:22]1[CH:35]=[CH:34][C:25]([O:26][CH2:27][CH:28]([OH:33])[C:29]([CH3:32])([CH3:31])[CH3:30])=[C:24]([CH3:36])[CH:23]=1)([C:6]1[CH:11]=[CH:10][C:9]([B:12]2[O:13][C:14]([CH3:19])([CH3:20])[C:15]([CH3:17])([CH3:18])[O:16]2)=[C:8]([CH3:21])[CH:7]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1ccc(B2OC(C)(C)C(C)(C)O2)c(C)c1
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCC(CC)(c1ccc(OCC(O)C(C)(C)C)c(C)c1)c1ccc(B2OC(C)(C)C(C)(C)O2)c(C)c1
Reaction time: 0.33 h
Yield: 83.3 %

Procedure:
A solution of 1-(4-{1-ethyl-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-propyl}-2-methyl-phenoxy)-3,3-dimethyl-butan-2-one (Example 30-(2); 0.50 g, 1.02 mmol) in tetrahydrofuran (10 mL) was cooled to −78° C. A 1 M solution of L-selectride (R) in tetrahydrofuran (1.0 mL) was added dropwise, and the mixture was stirred for 20 minutes. A saturated aqueous ammonium chloride solution was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (5% ethyl acetate/hexane) to give the title compound (0.42 g, 83%).
Reaction SMILES: [CH3:1][NH:2][CH:3]([CH3:5])[CH3:4].Cl.[NH2:7][C:8]1[S:9][CH:10]=[C:11]([CH2:13]Cl)[N:12]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH:3]([N:2]([CH2:13][C:11]1[N:12]=[C:8]([NH2:7])[S:9][CH:10]=1)[CH3:1])([CH3:5])[CH3:4]
Reactant: CNC(C)C
Reactant: Nc1nc(CCl)cs1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CC(C)N(C)Cc1csc(N)n1
Reaction time: 96 h

Procedure:
N-methyl-N-isopropylamine (3.02 g, 41 mmol) is added to a suspension of 2-amino-4-chloromethylthiazole hydrochloride (0.185 g, 1.0 mmol) in 15 mL ethanol. The reaction mixture is allowed to stand at room temperature for 4 days. The mixture was poured into aqueous potassium carbonate. The resulting aqueous suspension is extracted with dichloromethane. The organic layer is dried over MgSO4 and condensed to brown oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:9][CH3:10])=[C:6]([OH:8])[CH:7]=1.C(N(CC)CC)C.[Si:18](Cl)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:9][CH3:10])=[C:6]([CH:7]=1)[O:8][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COc1ccc(Br)cc1O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(Br)cc1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 100 %

Procedure:
To a solution of 5-bromo-2-methoxy-phenol (3.5 g, 17.2 mmol) dissolved in methylene chloride (50 mL) are added triethylamine (2.08 g, 20.6 mmol) and 4-dimethylaminopyridine (0.15 g, 0.86 mmol). Then tert-butyldimethylsilyl chloride is added slowly and the reaction mixture is stirred at room temperature for 16 h. The reaction is quenched with 10% of citric acid, and then the organic layer is washed with saturated sodium bicarbonate solution, a saturated sodium chloride solution, dried with magnesium sulfate, and concentrated in vacuo. Purification by silica gel chromatography (15% ethyl acetate-hexane) provides 5.6 g (100%) of the title compound as a colorless oil. 1H NMR (CDCl3): δ 6.82 (m, 2H), 6.58 (d, J=9 Hz, 1H), 3.74 (s, 3H), 0.95 (s, 9H), 0.05 (s, 6H).
Reaction SMILES: [CH:1]1([NH:7][C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([OH:16])=O)[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1>>[CH:1]1([NH:7][C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=3)=[O:16])[CH:9]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)c1cc(NC2CCCCC2)ncn1
Reactant: Nc1ccc(O)cc1
Product: O=C(Nc1ccc(O)cc1)c1cc(NC2CCCCC2)ncn1

Procedure:
Following the general method as outlined in Example 1, starting from 6-(cyclohexylamino)pyrimidine-4-carboxylic acid (Intermediate 4) and 4-aminophenol (Aldrich), the title compound was obtained as a slightly yellow solid.