Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:28]=[CH:27][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]3[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][N:24]([CH3:26])[CH3:25])[CH2:18][CH2:17]3)=[O:15])[CH:8]=2)=[CH:4][CH:3]=1.[C:29]1([CH2:35][C:36]([N:38]=[C:39]=[O:40])=[O:37])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>O1CCCC1.CCCCCC>[CH3:26][N:24]([CH3:25])[CH2:23][CH2:22][N:19]1[CH2:18][CH2:17][N:16]([C:14]([NH:13][C:9]2[CH:8]=[C:7]([O:6][C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:39]([NH:38][C:36](=[O:37])[CH2:35][C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)=[O:40])=[CH:28][CH:27]=3)[CH:12]=[CH:11][N:10]=2)=[O:15])[CH2:21][CH2:20]1
Reactant: O=C=NC(=O)Cc1ccccc1
Reactant: CN(C)CCN1CCN(C(=O)Nc2cc(Oc3ccc(N)cc3)ccn2)CC1
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CN(C)CCN1CCN(C(=O)Nc2cc(Oc3ccc(NC(=O)NC(=O)Cc4ccccc4)cc3)ccn2)CC1
Reaction time: 8 h
Yield: 72 %

Procedure:
To a solution of 4-(4-aminophenoxy)-2-{[4-(2-dimethylaminoethyl)piperazin-1-yl]carbonylamino}pyridine (97.2 mg) in tetrahydrofuran (5 ml) was added a solution of 2-phenylacetyl isocyanate in hexane (0.25 M, 2.6 ml) at room temperature, followed by stirring overnight. The reaction mixture was partitioned between ethyl acetate and a saturated aqueous solution of sodium hydrogencarbonate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was evaporated to give a residue, which was then purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate, then ethyl acetate:methanol=95:5) to provide the titled compound (100 mg, 72%) as white powder.
Reaction SMILES: N(S([O-])(=O)=O)(S([O-])(=O)=O)[O].[K+].[K+].C([O-])(=[O:15])C.[Na+].[OH:18][C:19]1[C:24]([O:25][CH3:26])=[C:23]([O:27][CH3:28])[CH:22]=[C:21]([CH3:29])[C:20]=1[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][C:39]([CH3:42])([OH:41])[CH3:40]>CO.O.O>[OH:41][C:39]([CH3:42])([CH3:40])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][C:20]1[C:19](=[O:18])[C:24]([O:25][CH3:26])=[C:23]([O:27][CH3:28])[C:22](=[O:15])[C:21]=1[CH3:29]
Reactant: CC(=O)[O-]
Reactant: COc1cc(C)c(CCCCCCCCCC(C)(C)O)c(O)c1OC
Agent: [K+]
Agent: [Na+]
Agent: [O]N(S(=O)(=O)[O-])S(=O)(=O)[O-]
Solvent: O
Solvent: CO
Product: COC1=C(OC)C(=O)C(CCCCCCCCCC(C)(C)O)=C(C)C1=O
Temperature: 50 °C
Reaction time: 14 h
Yield: 68.1 %

Procedure:
Potassium nitrosodisulfonate (12 g) and sodium acetate (12 g) are suspended in methanol-water (5:2, 210 ml), and 11-(2-hydroxy-3,4-dimethoxy-6-methylpheyl)-2-methylundecan-2-ol (2.4 g) is added thereto. The mixture is stirred at 50° C. for 14 hours and then diluted with water (100 ml). The methanol is distilled off. The aqueous soliution is extracted with ethyl acetate (200 ml), and the extract is washed with water, dried and concentrated under reduced pressure. The residue is subjected to silica gel column chromatography to give 1.7 g of 6-(10-hydroxy-10-methylundecyl)-2,3-dimethoxy-5-methyl-1,4-benzoquinone as an orange oil.
Reaction SMILES: C(O[CH2:5][CH:6]1[CH2:35][CH2:34][N:9]2[C:10]3[C:15]([C:16]([C:17]4[C:18](=O)[O:19][C:20](=[O:32])[C:21]=4[C:22]4[C:30]5[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=5)[N:24]([CH3:31])[CH:23]=4)=[C:8]2[CH2:7]1)=[CH:14][CH:13]=[CH:12][CH:11]=3)(=O)C.[N:36]1C(C)=CC(C)=CC=1C.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[CH:60]([NH:63][CH:64]([CH3:66])[CH3:65])([CH3:62])[CH3:61].[ClH:67]>ClCCl.C(OCC)(=O)C>[ClH:67].[CH:60]([N:63]([CH2:5][CH:6]1[CH2:35][CH2:34][N:9]2[C:10]3[C:15]([C:16]([C:17]4[C:18](=[O:19])[NH:36][C:20](=[O:32])[C:21]=4[C:22]4[C:30]5[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=5)[N:24]([CH3:31])[CH:23]=4)=[C:8]2[CH2:7]1)=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:64]([CH3:66])[CH3:65])([CH3:62])[CH3:61]
Reactant: CC(=O)OCC1CCn2c(c(C3=C(c4cn(C)c5ccccc45)C(=O)OC3=O)c3ccccc32)C1
Reactant: CC(C)NC(C)C
Reactant: Cc1cc(C)nc(C)c1
Agent: Cl
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)N(CC1CCn2c(c(C3=C(c4cn(C)c5ccccc45)C(=O)NC3=O)c3ccccc32)C1)C(C)C
Reaction time: 1.5 h

Procedure:
A solution of 0.8 g of the product of Example 1 and 0.44 g of 2,4,6-collidine in 30 ml of dichloromethane was added to a solution of 0.9 g of trifluoromethanesulfonic anhydride in 10 ml of dichloromethane at 0° C. After 1.5 hour, the mixture was treated with 3.64 g of diisopropylamine and stirred for 16 hours. The mixture was washed with water and then with saturated aqueous sodium bicarbonate solution, dried and concentrated. The solid obtained was dissolved in ethyl acetate and treated wish a saturated solution of hydrogen chloride in ethyl acetate. Removal of the solvent in vacuo gave 260 mg of 3-[6,7,8,9-tetrahydro-8-[(diisopropylamino)methyl]pyrido[1,2-a]indol-10-yl]-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione hydrochloride of melting point 187° C. (decomposition).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[C:18]4[CH2:19][CH2:20][C:21]5([CH2:26][C:17]=4[S:16][C:12]=3[N:13]=[CH:14][N:15]=2)OCC[O:22]5)[CH:5]=[CH:6][C:7]=1[F:8]>C(O)(=O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[C:18]4[CH2:19][CH2:20][C:21](=[O:22])[CH2:26][C:17]=4[S:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Fc1ccc(Nc2ncnc3sc4c(c23)CCC2(C4)OCCO2)cc1Cl
Solvent: CC(=O)O
Solvent: O
Product: O=C1CCc2c(sc3ncnc(Nc4ccc(F)c(Cl)c4)c23)C1
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 98.6 %

Procedure:
To a stirring acetic acid/water solution (4:1, 300 mL) was added N-(3-chloro-4-fluorophenyl)-5,8-dihydro-6H-spiro[1-benzothieno[2,3-d]pyrimidine-7,2′-[1,3]dioxolan]-4-amine (5.5 g, 14 mmol), and the contents heated at 80° C. for 12 h. The dark colored mixture was cooled to rt, and the solvent removed under reduced pressure. The crude residue was suspended in 1N NaHCO3 (100 mL), stirred for 10 min., and filtered. The filtered solid was triturated with diethyl ether (100 mL) to afford the desired product (4.8 g, 98%) as a dark yellow solid. 1H-NMR (DMSO-d6) δ 8.53 (s, 1H), 8.46 (s, 1H), 7.87 (dd, 1H), 7.60 (m, 1H), 7.40 (t, 1H), 3.73 (s, 2H), 3.43 (t, 2H), 2.64 (s, 2H); LCMS RT=3.01 min; [M+H]+=348.2.
Reaction SMILES: [OH-].[K+].N([CH2:5]NC(N)=O)=O.[CH2:10]([O:12][C:13]([N:15]1[C:23]2[C:18](=[C:19]([Br:24])[CH:20]=[CH:21][CH:22]=2)[C:17]([OH:25])=[N:16]1)=[O:14])[CH3:11]>CCOCC.C1COCC1>[CH2:10]([O:12][C:13]([N:15]1[C:23]2[C:18](=[C:19]([Br:24])[CH:20]=[CH:21][CH:22]=2)[C:17]([O:25][CH3:5])=[N:16]1)=[O:14])[CH3:11]
Reactant: NC(=O)NCN=O
Reactant: CCOC(=O)n1nc(O)c2c(Br)cccc21
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCOC(=O)n1nc(OC)c2c(Br)cccc21
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
To a 0° C. mixture of KOH (50% in H2O, 50 ml) and Et2O (150 ml), N-nitrosomethylurea (10.7 g, 103 mmol) was added portionwise over 40 minute period. After stirring for additional 20 minutes, the mixture was cooled to −78° C. and the upper bright yellow layer was poured into a 0° C. suspension of 4-Bromo-3-hydroxy-indazole-1-carboxylic acid ethyl ester CLXXXIV (2.96 g, 10.4 mmol) in a mixture of Et2O (100 ml) and THF (30 ml). After 2 hours, the yellow solution was warmed to room temperature and was left to stand at room temperature for 24 hours. The mixture was then washed with H2O and brine. The organic layer was dried over MgSO4, filtered, concentrated, and purified via flash chromatography (hexane/EtOAc) affording 4-Bromo-3-methoxy-indazole-1-carboxylic acid ethyl ester CLXXXV as an off-white solid (40% yield).
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N+:12]([O-])=O)[CH3:2].S(=O)(=O)(O)[OH:16].[Al].C(O)(=O)C(C(C(O)=O)O)O>O.C(OCC)(=O)C>[CH2:1]([O:3][CH2:4][CH2:5][C:6]1[CH:11]=[C:10]([OH:16])[CH:9]=[CH:8][C:7]=1[NH2:12])[CH3:2]
Reactant: O=S(=O)(O)O
Reactant: CCOCCc1ccccc1[N+](=O)[O-]
Agent: O=C(O)C(O)C(O)C(=O)O
Agent: [Al]
Solvent: CCOC(C)=O
Solvent: O
Product: CCOCCc1cc(O)ccc1N
Temperature: 90 °C
Reaction time: 0.25 h

Procedure:
58.5 g (0.3 mole) of 1-(β-ethoxyethyl)2-nitrobenzene was added at a temperature of 90° C. to a solution of 100 ml of concentrated sulphuric acid diluted in 1 liter of distilled water. 17 g of aluminium powder was added using a spatula and with vigourous stirring. Stirring was maintained for 40 minutes and then 70 g of tartaric acid was added. Stirring was continued for a further 15 minutes with the temperature maintained at 90° C. and then the reaction medium was cooled and the suspension filtered through sintered glass. The filtrate was neutralised with 20% ammonium hydroxide at a temperature below 20° C. A pinkish beige precipitate was obtained. The precipitate was taken up in 0.5 l of refluxing ethyl acetate, hot filtered and dry concentrated. It was recrystallised again from ethyl acetate to obtain beige crystals of the expected product which had a melting point of 102° C.
Reaction SMILES: [Sn](Cl)(Cl)(Cl)Cl.[C:6]([CH:10]1[CH2:15][CH2:14][C:13](=[O:16])[CH2:12][CH2:11]1)([CH3:9])([CH3:8])[CH3:7].[CH2:17]([CH:19]1[O:21][CH2:20]1)[Br:18].[OH-].[K+]>ClCCl.O>[C:6]([CH:10]1[CH2:11][CH2:12][C:13]2([O:21][CH:19]([CH2:17][Br:18])[CH2:20][O:16]2)[CH2:14][CH2:15]1)([CH3:9])([CH3:7])[CH3:8]
Reactant: BrCC1CO1
Reactant: CC(C)(C)C1CCC(=O)CC1
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)C1CCC2(CC1)OCC(CBr)O2
Temperature: 20 °C
Reaction time: 8 h
Yield: 77.4 %

Procedure:
30.15 g (120 mmol) of tin(IV) chloride were added dropwise to 115.5 g (750 mmol) of 4-tert-butylcyclohexanone in 700 ml of absolute dichloromethane at 5° C., followed by the dropwise addition of 205.5 g (1.5 mol) of epibromohydrin ##STR9## in 370 ml of absolute dichloromethane in the course of 5 hours. The mixture was stirred overnight at room temperature (20° C.), hydrolyzed with a solution of 42 g of KOH in 180 ml of water while cooling, and worked up in a conventional manner. Distillation of the crude product (279 g) under reduced pressure gave 169 g (77.5%) of 8-tert-butyl-2-bromomethyl-1,4-dioxaspiro[4,5]decane of boiling point 110° C./0.2 mbar.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:5]([CH3:7])[N:6]=1.C(N(CC)CC)C.Cl.[C:21](Cl)(=[O:28])[C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1>O1CCCC1>[C:21]([NH:1][C:2]1[S:3][C:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:5]([CH3:7])[N:6]=1)(=[O:28])[C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1
Reactant: CCOC(=O)c1sc(N)nc1C
Reactant: O=C(Cl)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)c1sc(NC(=O)c2ccncc2)nc1C
Temperature: 25 °C
Reaction time: 48 h
Yield: 90 %

Procedure:
To a mixture of ethyl 2-amino-4-methylthiazole-5-carboxylate (5.70 g, 30.60 mmol) and triethylamine (10.0 mL, 71.80 mmol) in tetrahydrofuran (100 mL) was added isonicotinoyl chloride hydrochloride (6.00 g, 32.00 mmol). The reaction mixture was stirred at ambient temperature for 2 days. The solvent was removed by evaporation and the resulting white solid was washed sequentially with water, 10% sodium bicarbonate solution, and water, then dried to afford the title compound in 90% yield (8.10 g); 1H NMR (DMSO-d6, 300 MHz) δ 8.77 (d, J=6.0 Hz, 2H), 8.77 (d, J=6.0 Hz, 2H), 4.23 (q, J=7.2 Hz, 2H), 2.34 (s, 3H). 1.27 (t, J=7.2 Hz, 3H); MS (ES+) m/z 292.0 (M+1).
Reaction SMILES: C(OC(=O)C1C=CC(NC2CCCCC2)=C(NC(C2C=C3C(=CC=2)N=[C:26]([C:31]2[C:36]([C:37]4[CH:42]=[CH:41][C:40](Cl)=[CH:39][CH:38]=4)=[CH:35][CH:34]=[C:33](C(N4CCCC4)=O)[CH:32]=2)C=C3)=O)C=1)C.ClC1C=CC(C2C([C:63]3[CH:72]=[CH:71][C:70]4[C:65](=[CH:66][CH:67]=[C:68]([C:73]5[N:77]([CH:78]6[CH2:83][CH2:82][CH2:81][CH2:80][CH2:79]6)[C:76]6[CH:84]=[CH:85][C:86]([C:88]([OH:90])=[O:89])=[CH:87][C:75]=6[N:74]=5)[CH:69]=4)[N:64]=3)=CC(C(N3CCCC3)=O)=CC=2)=CC=1.C1(C(C2C=CC=CC=2)C(C)=O)C=CC=CC=1.C(C1C=CC=CC=1)(=O)C>>[CH:36]([C:63]1[CH:72]=[CH:71][C:70]2[C:65](=[CH:66][CH:67]=[C:68]([C:73]3[N:77]([CH:78]4[CH2:83][CH2:82][CH2:81][CH2:80][CH2:79]4)[C:76]4[CH:84]=[CH:85][C:86]([C:88]([OH:90])=[O:89])=[CH:87][C:75]=4[N:74]=3)[CH:69]=2)[N:64]=1)([C:31]1[CH:26]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(-c4cc(C(=O)N5CCCC5)ccc4-c4ccc(Cl)cc4)ccc3c1)n2C1CCCCC1
Reactant: CCOC(=O)c1ccc(NC2CCCCC2)c(NC(=O)c2ccc3nc(-c4cc(C(=O)N5CCCC5)ccc4-c4ccc(Cl)cc4)ccc3c2)c1
Agent: CC(=O)C(c1ccccc1)c1ccccc1
Solvent: CC(=O)c1ccccc1
Product: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(C(c4ccccc4)c4ccccc4)ccc3c1)n2C1CCCCC1

Procedure:
The title compound was synthesized in four steps as described for Compound 13, Compound 25, Compound 27, Q=ethyl and Compound 204, respectively, except 1,1-diphenylacetone was used in the first step, instead of acetophenone.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].CC(C1C=CC(OCC2OC2)=CC=1)(C1C=C[C:15]([O:18][CH2:19][CH:20]2OC2)=[CH:14]C=1)C.C1(C=CC=C(O)C=1)O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(C1C=CC(OCC2OC2)=CC=1)(C1C=CC(OCC2OC2)=CC=1)C>C1(C)C=CC=CC=1>[C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].[CH3:14][CH2:15][O:18][CH2:19][CH3:20]
Reactant: CC(C)(c1ccc(OCC2CO2)cc1)c1ccc(OCC2CO2)cc1
Agent: Oc1cccc(O)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CCOCC
Temperature: 112 °C

Procedure:
A resorcinol/diglycidyl ether of bisphenol A addition product was prepared in a 3-liter reactor equipped with an agitator, thermometer and reflux condenser. The reactor was charged with about 330.3 g. resorcinol, 1500 ml. toluene and 3.0 g. triphenylphosphine. The stirred charge was heated to reflux at about 112° C. and about 654.0 g. diglycidyl ether of bisphenol A (Ciba-Geigy Araldite GY 6004) was added dropwise in about 2.5 hours. The charge was refluxed for about one hour, devolatilized at reduced pressure and about 36.0 g. amorphous silica was added to obtain a light tan resorcinol ether compound (RE4) having a 77° C. softening point, and having a 0.45 wt. % residual oxirane oxygen.
Reaction SMILES: [C:1]12([C:7]3[CH:12]=[CH:11][C:10]([N:13]4[CH2:17][C@H:16]([CH2:18][NH:19][C:20](=[O:22])[CH3:21])[O:15][C:14]4=[O:23])=[CH:9][CH:8]=3)[CH2:6][CH:5]1[CH2:4][NH:3][CH2:2]2.[O:24]1[C:28]([C:29](O)=[O:30])=[CH:27][CH:26]=[N:25]1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>CN(C=O)C>[O:24]1[C:28]([C:29]([N:3]2[CH2:4][CH:5]3[C:1]([C:7]4[CH:8]=[CH:9][C:10]([N:13]5[CH2:17][C@H:16]([CH2:18][NH:19][C:20](=[O:22])[CH3:21])[O:15][C:14]5=[O:23])=[CH:11][CH:12]=4)([CH2:6]3)[CH2:2]2)=[O:30])=[CH:27][CH:26]=[N:25]1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(C34CNCC3C4)cc2)C(=O)O1
Reactant: O=C(O)c1ccno1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(=O)NC[C@H]1CN(c2ccc(C34CC3CN(C(=O)c3ccno3)C4)cc2)C(=O)O1
Temperature: 25 °C
Yield: 66.7 %

Procedure:
To a solution of hydrochloride salt of N-{3-[4-(3-aza-bicyclo[3.1.0]hex-1-yl)-phenyl]-2-oxo-oxazolidin-5(S)-yl-methyl}-acetamide (Intermediate IV) (200 mg, 0.57 mmol), in DMF (10 mL), were added isoxazole-5-carboxylic acid (71 mg, 0.63 mmol), EDC (130 mg, 0.68 mmol), HOBt (89 mg, 0.68 mmol) and NMM (0.19 mL, 1.71 mmol) at 0° C. The reaction mixture was stirred at r.t. and progress of the reaction was monitored by TLC. On completion, DMF was evaporated in vacuo and residue was dissolved in chloroform (50 mL). The organic layer was washed with water (25 mL), brine (25 mL), dried over anhydrous sodium sulphate and concentrated in vacuo. The residue was purified by column chromatography (silica gel, 0.4:9.6 MeOH:CHCl3) to provide the title compound (156 mg, 67%) as white solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH:9]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)[C:10]([F:13])([F:12])[F:11])[N:5]=[C:4]([NH2:21])[N:3]=1.B([C:25]1[CH:36]=[CH:35][C:28]([CH2:29][C@@H:30]([C:32]([OH:34])=[O:33])[NH2:31])=[CH:27][CH:26]=1)(O)O.C(#N)C.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[NH2:31][CH:30]([CH2:29][C:28]1[CH:35]=[CH:36][C:25]([C:2]2[CH:7]=[C:6]([O:8][CH:9]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)[C:10]([F:13])([F:12])[F:11])[N:5]=[C:4]([NH2:21])[N:3]=2)=[CH:26][CH:27]=1)[C:32]([OH:34])=[O:33]
Reactant: N[C@@H](Cc1ccc(B(O)O)cc1)C(=O)O
Reactant: Cc1ccc(C(Oc2cc(Cl)nc(N)n2)C(F)(F)F)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: Cc1ccc(C(Oc2cc(-c3ccc(CC(N)C(=O)O)cc3)nc(N)n2)C(F)(F)F)cc1
Temperature: 150 °C
Yield: 32.7 %

Procedure:
A microwave vial was charged with 4-chloro-2-amino-6-[1-(4-methylphenyl)-2,2,2-trifluoro-ethoxy]-pyrimidine (33 mg, 0.1 mmol), 4-borono-L-phenylalanine (31 mg, 0.15 mmol) and 1 ml of acetonitrile, 0.7 ml of water. Aqueous sodium carbonate (0.3 ml, 1N) was added to above solution followed by 5 mol percent of dichlorobis(triphenylphosphine)-palladium(II). The reaction vessel was sealed and heated to 150° C. for 5 minutes with microwave. After cooling, the reaction mixture was evaporated to dryness. The residue was dissolved in 2.5 ml of methanol, was then purified by Prep-LC to give 14.6 mg of 2-amino-3-(4-{2-amino-6-[2,2,2-trifluoro-1-(4-methylphenyl)-ethoxy]-pyrimidin-4-yl}-phenyl)-propionic acid. 1H NMR (300 MHz, CD3OD) δ 7.94 (d, J=8.20 Hz, 2H), 7.47 (d, J=7.24 Hz, 4 H), 7.27 (d, J=8.01 Hz, 2H) 6.80 (s, 1H), 6.75 (m, 1H), 4.30 (t, 1 H), 3.21-3.44 (m, 2 H), 2.37 (s, 3H).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[SH:11].Br[CH2:13][CH2:14][CH2:15][O:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][O:18]1>C1COCC1>[F:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[S:11][CH2:13][CH2:14][CH2:15][O:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][O:18]1
Reactant: Fc1ccc(S)c(F)c1
Reactant: BrCCCOC1CCCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Fc1ccc(SCCCOC2CCCCO2)c(F)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 84 %

Procedure:
Sodium hydride (60%) (1.72 g, 44.8 mmol) was added to a solution of 2,4-difluorobenzenethiol (CAS no. 1996-44-7) (4.6 mL, 40 mmol) in THF (150 mL) at 0° C., under argon. The mixture was allowed to warm to room temperature and 2-(3-bromopropoxy)oxane (CAS no. 33821-94-2) (7.6 mL, 45 mmol) was added. The reaction was stirred at ambient temperature for 16 hours. The mixture was poured into ice/water (250 mL) and extracted with ethyl acetate (250 mL). The organic extract was washed with brine, dried (MgSO4) and the solvent removed under reduced pressure. The residue was purified by flash chromatography, eluting with 0-10% ethyl acetate in isohexane afford the product (10.8 g, 84%). 1H NMR δ(400 MHZ, CDCl3): 1.49-1.61 (m, 4H), 1.65-1.73 (m, 1H), 1.75-1.90 (m, 3H), 2.96 (t, 2H), 3.46-3.52 (m, 2H), 3.79-3.87 (m, 2H), 4.55-4.56 (m, 1H), 6.80-6.86 (m, 2H), 7.38-7.44 (m, 1H).
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[C:13]([O:17][C:18]([CH2:20][O:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][C:30]=1[O:31][CH2:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C:25](O)=[O:26])=[O:19])([CH3:16])([CH3:15])[CH3:14].C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C.[C:59]([O:63][CH2:64][C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1)(=[O:62])[NH:60][NH2:61]>CN(C=O)C>[C:13]([O:17][C:18]([CH2:20][O:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][C:30]=1[O:31][CH2:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C:25]([NH:61][NH:60][C:59]([O:63][CH2:64][C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1)=[O:62])=[O:26])=[O:19])([CH3:15])([CH3:16])[CH3:14]
Reactant: NNC(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)COc1ccc(C(=O)O)cc1OCC(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)COc1ccc(C(=O)NNC(=O)OCc2ccccc2)cc1OCC(=O)OC(C)(C)C
Reaction time: 0.5 h

Procedure:
1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.92 g) was added to a mixture of the product of step (c) (3.82 g), HOBT (1.71 g), diisopropylethylamine (1.75 ml) and DMF (30 ml) at ambient temperature and stirred for 30 minutes. Benzyl carbazate (1.66 g) in DMF (10 ml) was added and the mixture was stirred for 20 hours at ambient temperature. The solvent was removed by evaporation. The residue was dissolved in ethyl acetate (160 ml) and the solution was washed with 1M citric acid solution (25 ml), water (2×25 ml), 1M sodium hydroxide solution (20 ml), water (25 ml) and with saturated sodium chloride solution (25 ml) and dried (MgSO4). The solvent was removed by evaporation to give benzyl 3-(3,4-di-t-butoxycarbonylmethoxybenzoyl)carbazate as a gum; NMR Spectrum (d6 -DMSO) 1.43 (s, 18H), 4.70 (s, 2H), 4.75 (s, 2H), 5.11 (s, 2H), 6.96 (d, 1H), 7.34 (br s, 5H), 7.4 (d, 1H), 7.49 (dd, 1H), 9.28 (br s, 1H), 10.17 (br s, 1H); Mass Spectrum (+ve FAB, DMSO/GLYCEROL) 530 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:17](=[O:18])[C:16]3[C:15]4[C:10](=[CH:11][C:12]([C:19]#[N:20])=[CH:13][CH:14]=4)[NH:9][C:8]=3[C:7]([CH3:22])([CH3:21])[C:6]=2[CH:23]=1.Cl[CH2:25][CH2:26][N:27]([CH2:30][CH3:31])[CH2:28][CH3:29].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C(=O)C>[CH2:26]([N:27]([CH2:30][CH3:31])[CH2:28][CH2:29][O:1][C:2]1[CH:3]=[CH:4][C:5]2[C:17](=[O:18])[C:16]3[C:15]4[C:10](=[CH:11][C:12]([C:19]#[N:20])=[CH:13][CH:14]=4)[NH:9][C:8]=3[C:7]([CH3:21])([CH3:22])[C:6]=2[CH:23]=1)[CH3:25]
Reactant: CCN(CC)CCCl
Reactant: CC1(C)c2cc(O)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CCN(CC)CCOc1ccc2c(c1)C(C)(C)c1[nH]c3cc(C#N)ccc3c1C2=O
Temperature: 100 °C
Reaction time: 4 h
Yield: 33 %

Procedure:
8-Hydroxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile (Compound A6, 25 mg, 0.083 mmol) was dissolved in N,N-dimethylacetamide (1 mL), added with 2-chloroethyldiethylamine (16 mg, 1.1 eq.) and cesium carbonate (54 mg, 2 eq.) in order and stirred at 100° C. for 4 hr. The reaction solution was poured over water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. The drying agent was removed by filtration and the residues obtained after concentration under reduced pressure were purified by amino silica gel column chromatography (ethyl acetate/hexane) to obtain the title compound (11 mg, 32%).
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][C:8]2[C:17]3[C:12](=[C:13]([C:21](O)=[O:22])[CH:14]=[C:15]([N+:18]([O-:20])=[O:19])[CH:16]=3)[N:11]=[CH:10][N:9]=2)=[CH:4][C:3]=1[C:26]([F:29])([F:28])[F:27].C1N=C[N:32](C(N2C=NC=C2)=O)C=1.[NH4+].[Cl-].O>CS(C)=O>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][C:8]2[C:17]3[C:12](=[C:13]([C:21]([NH2:32])=[O:22])[CH:14]=[C:15]([N+:18]([O-:20])=[O:19])[CH:16]=3)[N:11]=[CH:10][N:9]=2)=[CH:4][C:3]=1[C:26]([F:27])([F:28])[F:29]
Reactant: O=C(O)c1cc([N+](=O)[O-])cc2c(NCc3ccc(Cl)c(C(F)(F)F)c3)ncnc12
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CS(C)=O
Solvent: O
Product: NC(=O)c1cc([N+](=O)[O-])cc2c(NCc3ccc(Cl)c(C(F)(F)F)c3)ncnc12
Temperature: 50 °C
Reaction time: 3 h
Yield: 96 %

Procedure:
To a solution of 4-{[4-chloro-3-(trifluoromethyl)benzyl]amino}-6-nitroquinazoline-8-carboxylic acid (40 mg, 0.09 mmol) in 1 mL of anhydrous DMSO, CDI (22 mg, 0.14 mmol, 1.5 equiv.) was added. The resulting mixture was stirred at 50° C. for 3 h. After cooling down to rt, NH4Cl (11 mg, 0.14 mmol, 1.5 equiv.) was added. The reaction mixture was stirred at rt overnight. The reaction mixture was poured into water. The yellow precipitate was collected as the desired product by filtration, followed by washed with water in 96% yield. 1HNMR (in DMSO): 4.90 (d, J=5.5 Hz, 2H), 7.66-7.72 (m, 2H), 7.93 (s, 1H), 8.19 (d, J=3.3 Hz, 1H), 8.72 (s, 1H), 9.17 (d, J=2.6 Hz, 1H), 9.53 (d, J=2.6 Hz, 1H), 9.87 (t, J=5.8 Hz, 1H), 10.22 (d, J=3.3 Hz, 1H). Mass: M+H+: 426.
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:5]2[CH2:6][C@H:7](OC)[B:8]([OH:10])[O:9][C:4]=2[C:3]=1[C:15]([OH:17])=[O:16].[CH3:18][N:19]1[CH:23]=[N:22][N:21]=[C:20]1[SH:24]>>[F:1][C:2]1[CH:14]=[CH:13][C:5]2[CH2:6][C@H:7]([S:24][C:20]3[N:19]([CH3:18])[CH:23]=[N:22][N:21]=3)[B:8]([OH:10])[O:9][C:4]=2[C:3]=1[C:15]([OH:17])=[O:16]
Reactant: CO[C@H]1Cc2ccc(F)c(C(=O)O)c2OB1O
Reactant: Cn1cnnc1S
Product: Cn1cnnc1S[C@H]1Cc2ccc(F)c(C(=O)O)c2OB1O

Procedure:
Compound 24 was prepared from Compound 19G (example 19) following methods described in steps 5 and 6 of Example 1 utilizing 4-methyl-3-mercapto-1,2,4-triazole.