Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[C:7]([OH:24])=[C:8]([C:14]3[CH:22]=[CH:21][CH:20]=[C:19]4[C:15]=3[CH2:16][CH2:17][C:18]4=[O:23])[CH:9]=[CH:10][C:11]=2[O:12][CH3:13])[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:32][C:33]1([CH2:37][OH:38])[CH2:36][O:35][CH2:34]1>C(#N)C>[CH:1]1([CH2:4][O:5][C:6]2[C:7]([O:24][CH2:32][C:33]3([CH2:37][OH:38])[CH2:36][O:35][CH2:34]3)=[C:8]([C:14]3[CH:22]=[CH:21][CH:20]=[C:19]4[C:15]=3[CH2:16][CH2:17][C:18]4=[O:23])[CH:9]=[CH:10][C:11]=2[O:12][CH3:13])[CH2:3][CH2:2]1
Reactant: OCC1(CBr)COC1
Reactant: COc1ccc(-c2cccc3c2CCC3=O)c(O)c1OCC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(-c2cccc3c2CCC3=O)c(OCC2(CO)COC2)c1OCC1CC1
Temperature: 70 °C
Yield: 19.2 %

Procedure:
To a stirring solution of 4-(3-(cyclopropylmethoxy)-2-hydroxy-4-methoxyphenyl)-2,3-dihydro-1H-inden-1-one (80 mg, 0.246 mmol) in acetonitrile (10 mL) was added potassium carbonate (102 mg, 0.740 mmol) and (3-bromomethyl-oxetan-3-yl)-methanol (134 mg, 0.740 mmol) and the resultant reaction mixture was heated to 70° C. for 16 h. The reaction mixture was cooled to RT, filtered through celite and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 0-50% ethyl acetate in pet ether) to afford the title compound as a solid (20 mg, 19.2%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[CH3:12][C:13]1[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:14]=1[NH2:15]>>[CH3:12][C:13]1[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:14]=1[NH:15][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10]
Reactant: O=C(O)Cc1ccccc1Br
Reactant: Cc1ccc(N)c(C)c1
Product: Cc1ccc(Nc2ccccc2CC(=O)O)c(C)c1

Procedure:
In the manner described in example 3, 2-bromophenylacetic acid is condensed with 2,4-dimethylaniline to yield 2-[(2,4-dimethylphenyl)amino]phenylacetic acid.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([Br:7])[N:6]=1.[C:8]1([OH:14])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[Br:7][C:5]1[N:6]=[C:2]([O:14][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[S:3][CH:4]=1
Reactant: Oc1ccccc1
Reactant: Brc1csc(Br)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Brc1csc(Oc2ccccc2)n1
Temperature: 140 °C
Reaction time: 6 h

Procedure:
3.00 g of 2,4-dibromothiazole, 1.74 g of phenol, and 3.44 g of potassium carbonate were added to 75 ml of N,N-dimethylformamide, and the obtained mixture was then stirred at 140° C. for 6 hours. Thereafter, the reaction solution was cooled to a room temperature, and 100 ml of water was then added thereto, followed by extraction with 100 ml of ethyl acetate twice. The organic layer was washed with 100 ml of water twice and then with 50 ml of a saturated brine once. The resultant was dried over magnesium sulfate. The magnesium sulfate was filtrated, and the organic layer was then concentrated. The residue was then purified by column chromatography (Wako Gel C-200; hexane:ethyl acetate=9:1), so as to obtain 2.86 g of an ether compound.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][C:8]=2[C:9]([OH:11])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[F:20][C:21]([F:34])([F:33])[C:22]1[N:23]=[C:24]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[S:25][CH:26]=1>>[CH:1]1([O:6][C:7]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][C:8]=2[C:9]([N:30]2[CH2:31][CH2:32][N:27]([C:24]3[S:25][CH:26]=[C:22]([C:21]([F:34])([F:20])[F:33])[N:23]=3)[CH2:28][CH2:29]2)=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: FC(F)(F)c1csc(N2CCNCC2)n1
Reactant: CS(=O)(=O)c1ccc(OC2CCCC2)c(C(=O)O)c1
Product: CS(=O)(=O)c1ccc(OC2CCCC2)c(C(=O)N2CCN(c3nc(C(F)(F)F)cs3)CC2)c1
Yield: 71 %

Procedure:
Prepared in analogy to example 1 (b) from 2-cyclopentyloxy-5-methanesulfonyl-benzoic acid (Example A4) and 1-(4-trifluoromethyl-thiazol-2-yl)-piperazine (Example 49(a)). The crude material was purified by chromatography (SiO2, ethyl acetate/heptane) followed by trituration in pentane to yield the title compound as a crystalline white solid (yield 71%). MS (m/e): 504.0 (M+H+, 100%).
Reaction SMILES: [C:1]([C:5]1[O:9][C:8]([NH2:10])=[N:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.Cl[C:19]([O:21][CH2:22][C:23]([Cl:26])([Cl:25])[Cl:24])=[O:20]>CC#N>[Cl:24][C:23]([Cl:26])([Cl:25])[CH2:22][O:21][C:19](=[O:20])[NH:10][C:8]1[O:9][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[N:6][N:7]=1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: CC(C)(C)c1nnc(N)o1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)c1nnc(NC(=O)OCC(Cl)(Cl)Cl)o1
Reaction time: 1 h
Yield: 73.3 %

Procedure:
To a suspension of 5-tert-butyl-[1,3,4]oxadiazol-2-ylamine (Atlantic, 141 mg, 1.00 mmol) and Et3N (279 μL, 2.00 mmol) in MeCN (2 mL), 2,2,2-trichloroethyl chloroformate (207 μL, 1.50 mmol) was added in 4 portions over 1 min at RT (CARE: exotherm to −40° C.). The resulting suspension was stirred for 1 h. The suspension was filtered, washing the solid with MeCN (3 mL), and concentrated to leave a yellow-brown paste. Purification by FCC, using 0-2.5% MeOH in DCM, gave a buff foam (232 mg, 73%). 1H NMR (400 MHz, CDCl3): 1.42 (9H, s), 4.86 (2H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]2[CH2:6][CH:7]3[CH:11]([C:12](=[O:13])[C:4]=2[CH:3]=1)[CH2:10][N:9]([CH3:14])[CH2:8]3.[CH3:17][Li].[Cl-].[NH4+].O>O1CCCC1.CCOCC>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]2[CH2:6][CH:7]3[CH:11]([C:12]([CH3:17])([OH:13])[C:4]=2[CH:3]=1)[CH2:10][N:9]([CH3:14])[CH2:8]3
Reactant: [Li]C
Reactant: CN1CC2Cc3ccc(Cl)cc3C(=O)C2C1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: CN1CC2Cc3ccc(Cl)cc3C(C)(O)C2C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 43 g of 6-chloro-3a,4,9,9a-tetrahydro-2-methylbenz[f]isoindolin-4-one in 430 ml of tetrahydrofuran is added dropwise at room temperature with stirring to 170 ml of a ca. 5% solution of methyl lithium in ether in a nitrogen atmosphere and the mixture is stirred for 51/2 hours at room temperature. Thereafter, saturated ammonium chloride solution and water are added and the mixture extracted with methylene chloride. The organic phase is dried over sodium sulphate and evaporated. The residue is crystallised from ether/petroleum ether to yield 6-chloro-3a,4,9,9a-tetrahydro-2,4-dimethylbenz[f]-isoindolin-4-ol. M.P. 125°-130°.
Reaction SMILES: F[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([N+:11]([O-:13])=[O:12])[C:3]=1[CH3:14].[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:18]=1[OH:25]>>[N+:11]([C:4]1[C:3]([CH3:14])=[C:2]([C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=1)[O:25][C:18]1[CH:19]=[C:20]([O:23][CH3:24])[CH:21]=[CH:22][C:17]=1[O:16][CH3:15])([O-:13])=[O:12]
Reactant: Cc1c([N+](=O)[O-])ccc([N+](=O)[O-])c1F
Reactant: COc1ccc(OC)c(O)c1
Product: COc1ccc(OC)c(Oc2c([N+](=O)[O-])ccc([N+](=O)[O-])c2C)c1

Procedure:
The process was carried out as indicated in point 5.4. above, using 0.366 g (1.83 mmol) of the 2-fluoro-3,6-dinitrotoluene prepared in point 7.4. above and 0.282 g (1.83 mmol) of 2,5-dimethoxyphenol prepared in point 7.5. above. The title product was isolated in the form of a yellow solid, using a 70:30 mixture of light mineral spirit (60-80° C.):diethyl ether as eluent (0.400 g, 65.5%).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[Cl:32][C:33]1[N:34]=[CH:35][C:36]2[N:41]=[C:40]([C:42]3[CH:47]=[C:46]([CH3:48])[C:45]([OH:49])=[C:44]([CH3:50])[CH:43]=3)[O:39][C:37]=2[N:38]=1.O[CH:52]1[CH2:55][CH:54]([C:56]([O:58][CH2:59][C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=2)=[O:57])[CH2:53]1>O1CCCC1.C(N(CC)CC)C>[Cl:32][C:33]1[N:34]=[CH:35][C:36]2[N:41]=[C:40]([C:42]3[CH:43]=[C:44]([CH3:50])[C:45]([O:49][CH:52]4[CH2:55][CH:54]([C:56]([O:58][CH2:59][C:60]5[CH:61]=[CH:62][CH:63]=[CH:64][CH:65]=5)=[O:57])[CH2:53]4)=[C:46]([CH3:48])[CH:47]=3)[O:39][C:37]=2[N:38]=1
Reactant: O=C(OCc1ccccc1)C1CC(O)C1
Reactant: Cc1cc(-c2nc3cnc(Cl)nc3o2)cc(C)c1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1cc(-c2nc3cnc(Cl)nc3o2)cc(C)c1OC1CC(C(=O)OCc2ccccc2)C1
Reaction time: 0.25 h

Procedure:
At 0° C., 1.14 g of triphenylphosphine and 0.69 ml of diethyl azodicarboxylate were initially charged in 30 ml of tetrahydrofuran, and the mixture was stirred for 15 min. 1.00 g of 4-(5-chlorooxazolo[5,4-d]pyrimidin-2-yl)-2,6-dimethylphenol, 0.61 ml of triethylamine and 0.90 g of benzyl 3-hydroxycyclobutanecarboxylate were then added, and the reaction was stirred under argon, initially at room temperature for 6 h. Another 1.14 g of triphenylphosphine and 0.69 ml of diethyl azodicarboxylate were then added, and the reaction was stirred for 12 h. After another addition of 1.14 g of triphenylphosphine and 0.69 ml of diethyl azodicarboxylate and 2 further hours of reaction time at room temperature, the reaction was concentrated and the resulting residue was purified by flash chromatography (silica gel, heptane/ethyl acetate). This gave 1.45 g (86%) of the title compound.
Reaction SMILES: [O-:1][CH2:2][CH3:3].[Na+].[Na].C(O)C.Br[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([Br:16])[N:11]=1>CCOC(C)=O>[Br:16][C:12]1[CH:13]=[CH:14][CH:15]=[C:10]([O:1][CH2:2][CH3:3])[N:11]=1
Reactant: CC[O-]
Reactant: Brc1cccc(Br)n1
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOc1cccc(Br)n1
Temperature: 90 °C
Reaction time: 2.5 h

Procedure:
To a sodium ethoxide solution, prepared by addition of sodium (36 mg, 1.58 mmol) to ethanol (2 mL), was added 2,6-dibromopyridine (250 mg, 1.06 mmol). The mixture was stirred at 90° C. for 2.5 h, then was diluted with EtOAc. The organic phase was washed with water (2×) and brine, dried (Na2SO4) and concentrated. The crude material was purified by flash chromatography (0 to 10% EtOAc/hexanes gradient) to afford 163 mg of 156.1 as a colorless oil. LCMS (2 min gradient) RT=1.68 min, 202.1 (M+H)+.
Reaction SMILES: [Se](=O)=[O:2].[CH3:4][N:5]([CH3:20])[C:6](=[O:19])[S:7][C:8]1[CH:17]=[C:16]2[C:11]([CH:12]=[CH:13][C:14]([CH3:18])=[N:15]2)=[CH:10][CH:9]=1>>[CH3:20][N:5]([CH3:4])[C:6](=[O:19])[S:7][C:8]1[CH:17]=[C:16]2[C:11]([CH:12]=[CH:13][C:14]([CH:18]=[O:2])=[N:15]2)=[CH:10][CH:9]=1
Reactant: Cc1ccc2ccc(SC(=O)N(C)C)cc2n1
Reactant: O=[Se]=O
Product: CN(C)C(=O)Sc1ccc2ccc(C=O)nc2c1
Temperature: 100 °C
Yield: 57.1 %

Procedure:
Referring now to FIG. 22, under a nitrogen atmosphere, selenium dioxide (67.3 mg, 0.606 mmol) was added to a solution of 17 (99.1 mg, 0.4027 mmol) in xylenes (3 mL). The mixture was heated to 100° C. for 3 h, then filtered hot through cotton, rinsing with chloroform. The product was adsorbed onto silica gel and purified by column chromatography (4:6 EtOAc/hexane) to afford 18 (60 mg, 0.230 mmol, 57%) as a white solid: 1H NMR (CDCl3) δ 10.21 (1H, s), 8.41 (1H, d, J=8.8 Hz), 8.33 (1H, d, J=8.4 Hz), 8.06 (1H, d, J=8.8 Hz), 7.91 (1H, d, J=8.8 Hz), 7.80 (1H, dd, J=1.6, 8.4 Hz) 3.17 (3H, s), 3.07 (3H, s); 13C NMR (CDCl3) δ 193.6, 165.8, 152.9, 147.7, 137.2, 136.8, 135.6, 132.21, 129.9, 127.9, 118.1, 37.0; FTIR (neat) 2922, 2876, 1705, 1661, 1366, 853, 758 cm−1; MS (ESI) m/z calculated for (C13H12N2O2S+H)+ 261, found 261; HRMS (ESI) m/z calculated for (C13H12N2O2S+H)+ 261.0692, found 261.0661.
Reaction SMILES: [N:1]1([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([C:21]4[CH:22]=[C:23]5[CH:29]=[CH:28][NH:27][C:24]5=[N:25][CH:26]=4)[CH:19]=3)[N:14]=[CH:13][N:12]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.CC1(C)C(C)(C)OB(C2C=C3C=CN([Si:47]([CH:54]([CH3:56])[CH3:55])([CH:51]([CH3:53])[CH3:52])[CH:48]([CH3:50])[CH3:49])C3=NC=2)O1.C(=O)([O-])O.[Na+]>O1CCOCC1.O.CC(=O)OCC.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>[N:1]1([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([C:21]4[CH:22]=[C:23]5[CH:29]=[CH:28][N:27]([Si:47]([CH:54]([CH3:56])[CH3:55])([CH:51]([CH3:53])[CH3:52])[CH:48]([CH3:50])[CH3:49])[C:24]5=[N:25][CH:26]=4)[CH:19]=3)[N:14]=[CH:13][N:12]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: c1ccc2c(c1)CCCN2c1ncnc2ccc(-c3cnc4[nH]ccc4c3)cc12
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2cc(B3OC(C)(C)C(C)(C)O3)cnc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc2cc(-c3ccc4ncnc(N5CCCc6ccccc65)c4c3)cnc21
Yield: 56.6 %

Procedure:
0.25 g of 4-(3,4-dihydro-2H-quinolin-1-yl)-6-(1H-pyrrolo[2,3-b]pyridin-5-yl)-quinazoline, 0.31 g of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine, 0.16 g of sodium hydrogencarbonate and 90 mg of PdCl2(PPh3)2 in 5.00 ml of dioxane and 0.50 ml of water are heated at 90° C. under nitrogen in a flask until the reaction is complete (HPLC check, about 18 hours). The cooled reaction solution is diluted with EA and washed 3 times with water. The organic phase is dried over sodium sulfate and purified by means of column chromatography (gradient heptane: EA 5-100% in 16 min), giving 0.20 g of 4-(3,4-dihydro-2H-quinolin-1-yl)-6-(1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-quinazoline as yellow oil (yield 50%, content 83%).
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[C:10]([CH3:15])[CH:9]=2)[N:5]=[C:4]1[CH2:16][C:17]([OH:19])=O)[CH3:2].CCN(C(C)C)C(C)C.[N:29]1([C:35]2[N:40]=[CH:39][CH:38]=[CH:37][N:36]=2)[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.ClCCl>[CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[C:10]([CH3:15])[CH:9]=2)[N:5]=[C:4]1[CH2:16][C:17]([N:32]1[CH2:33][CH2:34][N:29]([C:35]2[N:36]=[CH:37][CH:38]=[CH:39][N:40]=2)[CH2:30][CH2:31]1)=[O:19])[CH3:2]
Reactant: c1cnc(N2CCNCC2)nc1
Reactant: CCn1cc(-c2ccc(F)c(C)c2)nc1CC(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCn1cc(-c2ccc(F)c(C)c2)nc1CC(=O)N1CCN(c2ncccn2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 70.6 %

Procedure:
50 mg (1-ethyl-4-(4-fluoro-3-methyl-phenyl)-1H-imidazol-2-yl)-acetic acid was dissolved in 2 mL DMF. 100 mg PFTU and 60 μL DIPEA were added to this solution and the mixture was stirred for 10 min at RT. 160 mg 2-piperazin-1-yl-pyrimidine was added and the reaction was stirred over night. Then, potassium carbonate solution (5%) and dichlormethane were added, the organic layer was separated and the solvent was removed. The residue was purified by HPLC and crystallized with diisopropylether to give 55 mg of the desired compound.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[CH2:15]([SH:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C([O-])([O-])=O.[Na+].[Na+]>CCO.O>[CH3:9][O:8][C:6](=[O:7])[C:5]1[CH:10]=[CH:11][C:2]([S:22][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:3]([N+:12]([O-:14])=[O:13])[CH:4]=1
Reactant: COC(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: SCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COC(=O)c1ccc(SCc2ccccc2)c([N+](=O)[O-])c1
Yield: 177.2 %

Procedure:
A solution of methyl 4-chloro-3-nitrobenzoate (1 g, 4.65 mmol) in EtOH (13 ml) was added to a solution of benzylmercaptan (0.65 ml, 5.53 mmol), Na2CO3 (0.64 g, 6.1 mmol) and water (3 ml) and the reaction was heated under reflux for 4 h. After cooling, the mixture was diluted with water. The resulting precipitate was collected by filtration, washed with n-hexane and dried to give the title compound (2.5 g, 88%). The structure was confirmed by 1H NMR.
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][N:8]([C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH2:21][C@H:20]([CH2:22][O:23][C:24]5[CH:28]=[CH:27][O:26][N:25]=5)[O:19][C:18]4=[O:29])=[CH:13][C:12]=3[F:30])[CH2:7][CH2:6]2)[O:4]CC1>C(O)(=O)C.O>[O:4]=[C:5]1[CH2:6][CH2:7][N:8]([C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:21][C@H:20]([CH2:22][O:23][C:24]4[CH:28]=[CH:27][O:26][N:25]=4)[O:19][C:18]3=[O:29])=[CH:13][C:12]=2[F:30])[CH2:9][CH2:10]1
Reactant: O=C1O[C@@H](COc2ccon2)CN1c1ccc(N2CCC3(CC2)OCCO3)c(F)c1
Solvent: CC(=O)O
Solvent: O
Product: O=C1CCN(c2ccc(N3C[C@H](COc4ccon4)OC3=O)cc2F)CC1
Yield: 88.8 %

Procedure:
3-(4-(1,4-Dioxa-8-azaspiro[4,5]decan-8-yl)-3-fluorophenyl)-5(R)-(isoxazol-3-yloxymethyl)oxazolidin-2-one (3.58 g, 8.52 mmol) was dissolved in a mixture of glacial acetic acid (50 ml) and water (50 ml), and heated at 50° for 12 hours. Solvent was evaporated, the residue azeotroped with toluene (50 ml), then partitioned between EtOAc (150 ml) and water (100 ml). The organic layer was washed with saturated aqueous sodium bicarbonate solution (2×100 ml), water (100 ml), dried (magnesium sulfate) and evaporated. The residue was purified by chromatography on a 90 g silica Biotage column eluting with a gradient from 5:1 EtOAc to isohexane to EtOAc. Relevant fractions were combined to give the desired product (2.84 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=3)[CH:13]=[CH:12]2)=[CH:7][CH:6]=1)[CH3:2].P(Cl)(Cl)(Cl)=O.[OH-].[Na+].Cl.CN(C)[CH:34]=[O:35]>>[CH2:1]([O:3][C:4](=[O:23])[C:5]1[CH:6]=[CH:7][C:8]([N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=3)[C:13]([CH:34]=[O:35])=[CH:12]2)=[CH:9][CH:10]=1)[CH3:2]
Reactant: CN(C)C=O
Reactant: CCOC(=O)c1ccc(-n2ccc3ccc([N+](=O)[O-])cc32)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1ccc(-n2cc(C=O)c3ccc([N+](=O)[O-])cc32)cc1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
To a solution of 4-(6-nitroindol-1-yl)benzoic acid ethyl ester (0.53 g) in N,N-dimethylformamide (6 mL) was added phosphoryl chloride (0.31 g) under ice cooling and this mixture was stirred at 70° C. overnight. After cooling to ambient temperature, to this reaction mixture was added 2 mol/L aqueous sodium hydroxide solution and this mixture was stirred at 30 minutes. This reaction mixture was poured into 1 mol/L hydrochloric acid, and the precipitated solid was collected by filtration, and washed with water and n-hexane, and dried under reduced pressure at 40° C. to give 4-(3-formyl-6-nitroindol-1-yl)benzoic acid ethyl ester (0.46 g). To a solution of this aldehyde (0.46 g) in tetrahydrofuran (10 mL) were added hydroxylamine hydrochloride (0.19 g) and pyridine (0.43 g) at room temperature, and this mixture was stirred at 80° C. for 8 hours. To this reaction mixture was added acetic anhydride (0.42 g) at 80° C., this mixture was stirred at same temperature overnight. After cooling to ambient temperature, to this reaction mixture was added 1 mol/L hydrochloric acid, and the precipitated solid was collected by filtration. This solid was washed with water, n-hexane and diethyl ether to give the title compound (0.13 g).
Reaction SMILES: [C:1]1([S:7]([CH2:10][C:11]2[C:16]([C:17]([OH:19])=[O:18])=[C:15]([NH:20]CCNC(OC(C)(C)C)=O)[C:14]([C:31]3[CH:35]=[CH:34][O:33][CH:32]=3)=[CH:13][CH:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.NC1C(C2C=COC=2)=CC=C(CS(C2C=CC=CC=2)(=O)=O)C=1C(OC)=O>>[NH2:20][C:15]1[C:14]([C:31]2[CH:35]=[CH:34][O:33][CH:32]=2)=[CH:13][CH:12]=[C:11]([CH2:10][S:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)(=[O:9])=[O:8])[C:16]=1[C:17]([OH:19])=[O:18]
Reactant: CC(C)(C)OC(=O)NCCNc1c(-c2ccoc2)ccc(CS(=O)(=O)c2ccccc2)c1C(=O)O
Agent: COC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(-c2ccoc2)c1N
Product: Nc1c(-c2ccoc2)ccc(CS(=O)(=O)c2ccccc2)c1C(=O)O

Procedure:
Prepared as a yellow foam by proceeding in a similar manner to Intermediate 121, starting from methyl 2-amino-6-(benzenesulphonylmethyl)-3-(furan-3-yl)benzoate (Intermediate 212).
Reaction SMILES: [F:1][C:2]([F:25])([C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][N:19]=1)[C:3]1[N:12]=[C:11](SC)[C:10]2[C:5](=[C:6]([C:15]([NH2:17])=[O:16])[CH:7]=[CH:8][CH:9]=2)[N:4]=1.ClC1C=CC=C(C(OO)=O)C=1.S([O-])([O-])(=O)=S.[Na+].[Na+].C(=O)(O)[O-].[Na+].[CH3:49][C:50]1[NH:54][N:53]=[C:52]([NH2:55])[CH:51]=1>C(Cl)Cl.C1COCC1>[F:1][C:2]([F:25])([C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][N:19]=1)[C:3]1[N:12]=[C:11]([NH:55][C:52]2[CH:51]=[C:50]([CH3:49])[NH:54][N:53]=2)[C:10]2[C:5](=[C:6]([C:15]([NH2:17])=[O:16])[CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: Cc1cc(N)n[nH]1
Reactant: CSc1nc(C(F)(F)c2ccc(F)cn2)nc2c(C(N)=O)cccc12
Agent: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cc1cc(Nc2nc(C(F)(F)c3ccc(F)cn3)nc3c(C(N)=O)cccc23)n[nH]1
Reaction time: 1.5 h
Yield: 50.2 %

Procedure:
To 2-(difluoro(5-fluoropyridin-2-yl)methyl)-4-(methylthio)quinazoline-8-carboxamide (191 mg, 0.52 mmol) in DCM (8 mL) at 0° C. was added 3-chloroperbenzoic acid (70%, 192 mg, 0.78 mmol) and the mixture was stirred for 90 min. The mixture was diluted with DCM and then aq sodium thiosulfate was added, followed by addition of saturated aq sodium bicarbonate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. To the residue were added THF (5 mL) and 5-methyl-1H-pyrazol-3-amine (153 mg, 1.58 mmol) and the mixture was stirred at rt for 15 min. The mixture was concentrated under reduced pressure and purified by preparative HPLC (Varian diphenyl reverse phase column, eluted with gradient of solvent B=0.05% AcOH/ACN and solvent A=5% ACN/0.05% AcOH/H2O) to afford 2-(difluoro(5-fluoropyridin-2-yl)methyl)-4-((5-methyl-1H-pyrazol-3-yl)amino)quinazoline-8-carboxamide (108 mg, 50%). 1H NMR (300 MHz, DMSO-d6) δ ppm 2.20 (s, 3H) 6.08 (s, 1H) 7.76 (t, J=7.82 Hz, 1H) 7.92 (d, J=3.39 Hz, 1H) 7.98-8.11 (m, 2H) 8.58-8.75 (m, 2H) 8.89 (d, J=7.54 Hz, 1H) 9.91 (d, J=3.20 Hz, 1H) 10.80-11.38 (m, 1H) 12.17 (br s, 1H); LC-MS (ESI) m/z 414 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[O:7][C:6]([CH:8]=[O:9])=[CH:5][CH:4]=1.[CH3:12][Mg+].[Br-].[NH4+].[Cl-]>C1COCC1>[F:11][C:2]([F:10])([F:1])[C:3]1[O:7][C:6]([CH:8]([OH:9])[CH3:12])=[CH:5][CH:4]=1
Reactant: O=Cc1ccc(C(F)(F)F)o1
Reactant: C[Mg+]
Agent: [Br-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(O)c1ccc(C(F)(F)F)o1
Reaction time: 1 h
Yield: 97.8 %

Procedure:
To 5-trifluoromethyl-furan-2-carbaldehyde (0.76 g, 4.6 mmol) in THF (20 mL) at 0° C. was added MeMgBr (3M in Et2O, 3 mL, 6 mmol) dropwise over 1 h. After an additional 1 h, ½ saturated NH4Cl (aq.) was added and the mixture extracted with EtOAc (2×). The combined organics were washed with brine and dried to give 0.81 g (97%) of the title compound. 1H NMR (CDCl3): 6.74-6.73 (m, 1H), 6.32-6.31 (m, 1H), 4.91 (q, J=6.5 Hz, 1H), 1.57 (d, J=6.6 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[C:10]2[C:5](=[C:6]([NH:11][C:12]([C:14]3[S:18][C:17]([CH3:19])=[N:16][C:15]=3[C:20]([F:23])([F:22])[F:21])=O)[CH:7]=[CH:8][CH:9]=2)[CH:4]([CH3:24])[CH2:3]1.C[S:27]P1(=S)SP(=S)(SC)S1>O1CCCC1>[CH3:1][C:2]1([CH3:25])[C:10]2[C:5](=[C:6]([NH:11][C:12]([C:14]3[S:18][C:17]([CH3:19])=[N:16][C:15]=3[C:20]([F:23])([F:22])[F:21])=[S:27])[CH:7]=[CH:8][CH:9]=2)[CH:4]([CH3:24])[CH2:3]1
Reactant: Cc1nc(C(F)(F)F)c(C(=O)Nc2cccc3c2C(C)CC3(C)C)s1
Reactant: CSP1(=S)SP(=S)(SC)S1
Solvent: C1CCOC1
Product: Cc1nc(C(F)(F)F)c(C(=S)Nc2cccc3c2C(C)CC3(C)C)s1
Reaction time: 10 h
Yield: 67.1 %

Procedure:
0.20 g of N-(1,1,3-trimethyl-4-indanyl)-2-methyl-4-trifluoromethylthiazole-5-carboxamide and 0.18 g of 2,4-bis(methylthio)-1,3,2,4-dithiadiphosphetan-2,4-disulfide were dissolved in 5 ml of tetrahydrofuran and reaction was effected for 10 hours under reflux. The reaction mixture was concentrated and the residue was chromatographed on silica gel (eluent; n-hexane:chloroform:tetrahydrofuran=6:2:1) to obtain 0.14 g of N-(1,1,3-trimethyl-4-indanyl)-2-methyl-4-trifluoromethylthiazole-5-carbothioamide (yield 65%).