Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[C:4]([F:9])[C:3]=1[C:10]1[S:11][CH:12]=[C:13]([C:15]([O:17]C)=[O:16])[N:14]=1.O[C@@H:20]1[CH2:24][CH2:23][O:22][CH2:21]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[F:9][C:4]1[CH:5]=[C:6]([O:8][C@@H:20]2[CH2:24][CH2:23][O:22][CH2:21]2)[CH:7]=[C:2]([F:1])[C:3]=1[C:10]1[S:11][CH:12]=[C:13]([C:15]([OH:17])=[O:16])[N:14]=1
Reactant: COC(=O)c1csc(-c2c(F)cc(O)cc2F)n1
Reactant: O[C@@H]1CCOC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C(O)c1csc(-c2c(F)cc(O[C@@H]3CCOC3)cc2F)n1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of methyl 2-(2,6-difluoro-4-hydroxy-phenyl)thiazole-4-carboxylate (207 mg, 0.763 mmol) and (R)-3-hydroxytetrahydrofuran (3 equiv., 206 mg) in tetrahydrofuran (5 mL) was added triphenylphosphine (3 equiv., 600 mg) and diisopropyl azodicarboxylate (3 equiv., 0.45 mL) The mixture was stirred at RT for 2 days. The mixture was concentrated and partitioned between EtOAc and water. The organic layer was washed with sat. NaHCO3, brine, dried over Na2SO4 and concentrated. This residue was diluted with THF (3 mL) and water (1 mL) and LiOH (36 mg) was added. After stirring at rt for 2.5 hours, the reaction was neutralized with 1 N HCl(aq), diluted with EtOAc and washed with brine. The organic extracts were dried (Na2SO4) and concentrated in vacuo to provide the title compound, contaminated with triphenylphosphine oxide, and other by-products, which was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-])=O)[C:3]=1[O:11][CH3:12]>CO.[Pd]>[F:1][C:2]1[C:3]([O:11][CH3:12])=[C:4]([CH:5]=[CH:6][CH:7]=1)[NH2:8]
Reactant: COc1c(F)cccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: COc1c(N)cccc1F
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 1-fluoro-2-methoxy-3-nitrobenzene (25.0 g, 146 mmol) and Pd/C (10%, 7.5 g) in 500 mL of MeOH was stirred at room temperature under 55 psi of H2 for 4 hours before filtration. The filtrate was concentrated to give the title compound.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][C:16]([OH:18])=O)[CH2:11][CH2:10]1.[NH2:19][C@@H:20]([CH2:38][O:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:21]([NH:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)=[CH:26][CH:25]=1)=[O:22]>>[CH2:40]([O:39][CH2:38][C@H:20]([NH:19][C:16](=[O:18])[CH2:15][N:12]1[CH2:11][CH2:10][N:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[F:2])[CH2:14][CH2:13]1)[C:21]([NH:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)=[CH:26][CH:25]=1)=[O:22])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: O=C(O)CN1CCN(c2ccccc2F)CC1
Reactant: N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Agent: Cl
Product: O=C(CN1CCN(c2ccccc2F)CC1)N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Yield: 27.3 %

Procedure:
Proceeding as in Example 1, but substituting 2-(4-(2-fluorophenyl)piperazin-1-yl)acetic acid hydrochloride and (S)-2-amino-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)propanamide, gave Compound 127, (S)-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)-2-(2-(4-(2-fluorophenyl)piperazin-1-yl)acetamido)propanamide (13.1 mg, 27.3%); Major isomer: 1H-NMR (400 MHz, DMSO-D6): 10.23 (s, 1H), 8.02 (d, 1H), 7.60 (d, 2H), 7.25-7.30 (m, 5H), 7.19-7.23 (m, 2H), 7.10-7.19 (m, 2H), 6.98-7.04 (m, 6H), 4.71 (m, 1H), 4.53 (s, 2H), 3.72-3.80 (m, 2H), 3.07 (d, 2H), 3.00 (m, 4H), 2.63 (m, 4H). MS (EI) for C34H34F2N4O4. found 601.6 (MH+).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([CH2:9][CH:10]([OH:12])[CH3:11])=[N:6][C:7]=1Br.[CH2:13]([NH:20][C:21]([C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][C:24]=1[F:32])=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC>[NH2:1][C:2]1[C:7]([C:26]2[CH:27]=[CH:28][C:23]([C:21]([NH:20][CH2:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=[O:22])=[C:24]([F:32])[CH:25]=2)=[N:6][C:5]([CH2:9][CH:10]([OH:12])[CH3:11])=[CH:4][N:3]=1
Reactant: O=C(NCc1ccccc1)c1ccc(B(O)O)cc1F
Reactant: CC(O)Cc1cnc(N)c(Br)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(O)Cc1cnc(N)c(-c2ccc(C(=O)NCc3ccccc3)c(F)c2)n1
Temperature: 120 °C
Reaction time: 0.17 h

Procedure:
To a solution of (+/−)-1-(5-amino-6-bromopyrazin-2-yl)propan-2-ol (30 mg, 0.129 mmol) in DME (970 μL) was added 4-(benzylcarbamoyl)-3-fluorophenylboronic acid (31.8 mg, 0.116 mmol), PdCl2(dppf)CH2Cl2 adduct (10.56 mg, 0.013 mmol), 2M Na2CO3 (323 μL). The reaction mixture was stirred at 120° C. for 10 min in microwave. The reaction mixture was partitioned between EtOAc and water. the organic was dried and concentrated. the crude product was purified by Prep HPLC. The pure fraction was combined and desalt to yield (+/−)-4-(3-amino-6-(2-hydroxypropyl)pyrazin-2-yl)-N-benzyl-2-fluorobenzamide. LCMS (m/z): 381.2 (MH+), 0.67 min; 1H NMR (400 MHz, CD3OD) δ ppm 7.95-7.81 (m, 2H), 7.66 (dd, J=1.6, 8.2 Hz, 1H), 7.58 (dd, J=1.6, 11.7 Hz, 1H), 7.43-7.31 (m, 4H), 7.31-7.19 (m, 1H), 4.62 (s, 2H), 4.16-4.04 (m, 1H), 2.79 (d, J=6.3 Hz, 2H), 1.23 (d, J=6.3 Hz, 3H).
Reaction SMILES: [C:1]([C:4]1[CH:18]=[CH:17][C:7]2[O:8][C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][O:11][C:6]=2[CH:5]=1)(=O)[CH3:2]>C(O)(=O)C.[Pd]>[CH2:1]([C:4]1[CH:18]=[CH:17][C:7]2[O:8][CH:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:10][O:11][C:6]=2[CH:5]=1)[CH3:2]
Reactant: CCOC(=O)C1=COc2cc(C(C)=O)ccc2O1
Agent: [Pd]
Solvent: CC(=O)O
Product: CCOC(=O)C1COc2cc(CC)ccc2O1
Yield: 70 %

Procedure:
Hydrogenate a solution of 3 g of ethyl 6-acetyl-1,4-benzodioxin-2-carboxylate in 15 cm3 of acetic acid under hydrogen pressure (50 psi) in the presence of 0.750 g of 5% palladium on carbon. The crude product obtained by concentrating to dryness is purified by chromatography on a silica column (eluant: petroleum ether/diethyl ether, 70:30). Ethyl 6-ethyl-2,3-dihydro-1,4-benzodioxin-2-carboxylate is thereby obtained in a yield of 70%. ##STR29##
Reaction SMILES: [N:1]1([CH2:4][C@:5]23[CH2:39][CH2:38][C@@H:37]([C:40]([CH3:42])=[CH2:41])[C@@H:6]2[C@@H:7]2[C@@:20]([CH3:23])([CH2:21][CH2:22]3)[C@@:19]3([CH3:24])[C@@H:10]([C@:11]4([CH3:36])[C@@H:16]([CH2:17][CH2:18]3)[C:15]([CH3:26])([CH3:25])[C:14]([C:27]3[CH:35]=[CH:34][C:30]([C:31]([OH:33])=[O:32])=[CH:29][CH:28]=3)=[CH:13][CH2:12]4)[CH2:9][CH2:8]2)CC1.Br[CH2:44][CH2:45][OH:46]>>[OH:46][CH2:45][CH2:44][NH:1][CH2:4][C@:5]12[CH2:39][CH2:38][C@@H:37]([C:40]([CH3:42])=[CH2:41])[C@@H:6]1[C@@H:7]1[C@@:20]([CH3:23])([CH2:21][CH2:22]2)[C@@:19]2([CH3:24])[C@@H:10]([C@:11]3([CH3:36])[C@@H:16]([CH2:17][CH2:18]2)[C:15]([CH3:26])([CH3:25])[C:14]([C:27]2[CH:35]=[CH:34][C:30]([C:31]([OH:33])=[O:32])=[CH:29][CH:28]=2)=[CH:13][CH2:12]3)[CH2:9][CH2:8]1
Reactant: C=C(C)[C@@H]1CC[C@]2(CN3CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: OCCBr
Product: C=C(C)[C@@H]1CC[C@]2(CNCCO)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12

Procedure:
The title compound was prepared following the general procedures described above for the synthesis of 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(aziridin-1-ylmethyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoic acid using 2-bromoethanol as the alkylating reagent in step 1. The product was isolated as a white solid (21.9 mg, 79.9%). LCMS: m/e 588.9 (MH+), 2.373 min (method 9). 1H NMR (500 MHz, DMSO-d6) δ 7.88 (d, J=8.2 Hz, 2H), 7.23 (d, J=8.2 Hz, 2H), 5.25 (d, J=4.9 Hz, 1H), 4.72 (s, 1H), 4.61 (s, 1H), 3.74 (m, 2H), 3.14 (br. s., 1H), 3.08 (m, 2H), 2.80-2.68 (m, 1H), 2.45 (m, 1H), 2.12-1.94 (m, 2H), 1.93-1.79 (m, 2H), 1.74-1.58 (m, 8H), 1.57-1.29 (m, 8H), 1.28-1.13 (m, 4H), 1.08 (s, 4H) 1.00 (3H, s), 0.96 (3H, s), 0.91 (6H, s).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[NH:7][CH2:8][CH3:9].[O:12]1[CH:16]=[CH:15][C:14](B2OC(C)(C)C(C)(C)O2)=[CH:13]1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1COCC1>[CH2:8]([NH:7][C:6]1[CH:10]=[C:2]([C:14]2[CH:15]=[CH:16][O:12][CH:13]=2)[CH:3]=[CH:4][C:5]=1[CH3:11])[CH3:9]
Reactant: CC1(C)OB(c2ccoc2)OC1(C)C
Reactant: CCNc1cc(Br)ccc1C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: CCNc1cc(-c2ccoc2)ccc1C
Yield: 98 %

Procedure:
0.69 g (3.20 mmol) of 5-bromo-N-ethyl-2-methylaniline and 0.93 g (4.80 mmol) of 3-furan boronic acid pinacol ester were dissolved in 7 mL of THF. 1.56 g (4.80 mmol) of cesium carbonate and 370 mg (0.32 mmol) of tetrakis(triphenyl phosphine)palladium(0) were added thereto and heated under reflux for 22 hours. After completion of the reaction, filtration was conducted, and the filtrate was condensed. The resulting crude product was separated and purified using silica gel column chromatography to give N-ethyl-5-(furan-3-yl)-2-methylaniline (yield: 98%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18](Br)=[CH:17][C:16]=2[CH2:22][N:23]2[CH2:27][CH2:26][O:25][C:24]2=[O:28])[CH:7]=1)[CH3:2].[C:30]1(B(O)O)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[CH2:1]([O:3][C:4](=[O:29])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:17][C:16]=2[CH2:22][N:23]2[CH2:27][CH2:26][O:25][C:24]2=[O:28])[CH:7]=1)[CH3:2]
Reactant: OB(O)c1ccccc1
Reactant: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(Br)cc2CN2CCOC2=O)c1
Product: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(-c3ccccc3)cc2CN2CCOC2=O)c1

Procedure:
Prepared according to the procedure described in Example 84, Step 1, using the following starting materials: {3-[4-bromo-2-(2-oxo-oxazolidin-3-ylmethyl)-phenoxy]-4-methoxy-phenyl}-acetic acid ethyl ester and phenylboronic acid.
Reaction SMILES: C(OC([N:8]1[CH:15]2[CH:11]([N:12]([C:26]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[O:27])[CH2:13][CH:14]2[CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([F:24])=[C:20]([F:25])[CH:19]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:29]([O:28][C:26]([N:12]1[CH2:13][CH:14]([CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([F:24])=[C:20]([F:25])[CH:19]=2)[CH:15]2[NH:8][CH2:9][CH2:10][CH:11]12)=[O:27])[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: CC(C)(C)OC(=O)N1CCC2C1C(COc1ccc(F)c(F)c1)CN2C(=O)OCc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(OCc1ccccc1)N1CC(COc2ccc(F)c(F)c2)C2NCCC21
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A solution of phenol-ether 78 (0.86 g, 1.8 mmol) in DCM (10 mL) was treated with TFA (3 mL) at 0° C. After 20 min, the reaction was warmed to ambient temperature. After 1 h, the solution was concentrated, diluted with EtOAc, washed successively with saturated aqueous NaHCO3, and brine, dried over anhydrous Na2SO4, filtered and concentrated. The aqueous phase was back-extracted with DCM and the combined organic extracts were concentrated to give amine 80 as an orange-colored oil that was used without further purification. Mass spectrum, m/z [389.5] (M+H)+.
Reaction SMILES: [CH3:1][N:2]([CH3:19])[CH2:3][C:4]1[CH:5]=[N:6][CH:7]=[C:8](B2OC(C)(C)C(C)(C)O2)[CH:9]=1.Br[C:21]1[CH:22]=[C:23]2[C:27](=[C:28]([C:30]([NH2:32])=[O:31])[CH:29]=1)[NH:26][CH:25]=[C:24]2[CH:33]1[CH2:38][CH2:37][N:36]([S:39]([CH2:42][CH3:43])(=[O:41])=[O:40])[CH2:35][CH2:34]1.C(=O)([O-])[O-].[K+].[K+]>>[CH3:19][N:2]([CH2:3][C:4]1[CH:9]=[C:8]([C:21]2[CH:22]=[C:23]3[C:27](=[C:28]([C:30]([NH2:32])=[O:31])[CH:29]=2)[NH:26][CH:25]=[C:24]3[CH:33]2[CH2:34][CH2:35][N:36]([S:39]([CH2:42][CH3:43])(=[O:40])=[O:41])[CH2:37][CH2:38]2)[CH:7]=[N:6][CH:5]=1)[CH3:1]
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(Br)cc23)CC1
Reactant: CN(C)Cc1cncc(B2OC(C)(C)C(C)(C)O2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cncc(CN(C)C)c4)cc23)CC1
Yield: 16 %

Procedure:
Following the general procedure of 5-(5-{[(cyclopropylmethyl)amino]methyl}-3-pyridinyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide, 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinecarbaldehyde (30 mg, 0.129 mmol), a 2 M solution of dimethylamine in THF (0.065 mL, 0.129 mmol), and NaCNBH3 (16 mg, 0.258 mmol) were reacted to give 23 mg of crude dimethyl{[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinyl]methyl}amine. The crude dimethyl{[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinyl]methyl}amine was then reacted with 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (30 mg, 0.0723 mmol), potassium carbonate (60 mg, 0.434 mmol), and chloro-2-(dimethylaminormethyl)-ferrocen-1-yl-(dinorbornylphosphine)palladium(II) (4.4 mg, 0.00723 mmol) to give 5.4 mg of the title compound (16%).
Reaction SMILES: [OH:1][CH2:2][C:3]([CH2:8][OH:9])([CH3:7])[C:4]([OH:6])=[O:5].[C:10]1([B:16](O)O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C1(C)C=CC=CC=1>O1CCCC1>[CH3:7][C:3]1([C:4]([OH:6])=[O:5])[CH2:8][O:9][B:16]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[O:1][CH2:2]1
Reactant: CC(CO)(CO)C(=O)O
Reactant: OB(O)c1ccccc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC1(C(=O)O)COB(c2ccccc2)OC1
Reaction time: 3 h
Yield: 94 %

Procedure:
To a suspension of 2,2-bis(hydroxymethyl)propionic acid (131 g, 0.98 mole) in tetrahydrofuran (500 ml) was added a solution of phenylboronic acid (122 g, 1.0 mole) in tetrahydrofuran (500 ml). The mixture was stirred for 3 h and toluene (1.0 L) was added. Water was removed by azeotropic distillation with toluene. Heptanes (500 ml) was added to the precipitated product, heated to reflux and cooled. The mixture was filtered and washed with heptanes (2×300 ml). The solids were dried under vacuum at 70–75° C. until constant weight to give 94% yield. 1H NMR: δ (DMSO-d6) 7.65 (d, 2H, Ar), 7.40 (m, 3H, Ar), 4.35 (d, 2H, CH2), 3.92 (d, 2H, CH2), 1.17 (s, 3H, CH3)
Reaction SMILES: Br[CH2:2][CH2:3][F:4].[N+:5]([C:8]1[CH:9]=[N:10][NH:11][CH:12]=1)([O-:7])=[O:6].C([O-])([O-])=O.[K+].[K+]>CC#N>[F:4][CH2:3][CH2:2][N:10]1[CH:9]=[C:8]([N+:5]([O-:7])=[O:6])[CH:12]=[N:11]1
Reactant: O=[N+]([O-])c1cn[nH]c1
Reactant: FCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=[N+]([O-])c1cnn(CCF)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.7 %

Procedure:
1-Bromo-2-fluoroethane (5 g, 38.5 mmol) was added to a stirred mixture of 4-nitro-1H-pyrazole (4.35 g, 38.5 mmol) and K2CO3 (13.3 g, 96.3 mmol) in MeCN (120 mL). The mixture was stirred at room temperature for 30 min and then heated to 50° C. for 18 hr. The mixture was cooled and the solid filtered and washed with MeCN. The filtrate was concentrated under reduced pressure and the crude residue purified via silica gel chromatography (0-100% EtOAc/isohexane) to give 1-(2-fluoroethyl)-4-nitro-1H-pyrazole as a colourless solid (5.13 g, 84%). 1H NMR (400 MHz, CDCl3) δ 8.24 (s, 1H), 8.11 (s, 1H), 4.89-4.72 (m, 2H), 4.57-4.40 (m, 2H)
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[C:13]1(B(O)O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Na+].[Na+].O>CN(C)C=O>[N+:10]([C:3]1[CH:4]=[C:5]([CH:6]=[O:7])[CH:8]=[CH:9][C:2]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([O-:12])=[O:11]
Reactant: O=Cc1ccc(Br)c([N+](=O)[O-])c1
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1ccc(-c2ccccc2)c([N+](=O)[O-])c1
Temperature: 90 °C
Reaction time: 17 h
Yield: 81 %

Procedure:
4-Bromo-3-nitrobenzaldehyde (2.0 g) was suspended in N,N-dimethylformamide (30 mL), phenylboronic acid (1.3 g), sodium carbonate (1.8 g), water (6 mL) and tetrakis-(triphenylphosphine)palladium(0) (1.0 g) were added, and the resulting mixture was stirred at 90° C. for 17 hours. The reaction mixture was cooled to room temperature and then partitioned between ethyl acetate (100 mL) and water (100 mL). The organic layer was washed successively with water (50 mL) and brine (50 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=2/1) to give the title compound (1.6 g).
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[C:7](=[O:31])[C:8]4[CH:20]=[C:19](Br)[C:18]([O:22][CH2:23][C@H:24]5[CH2:28][O:27]C(C)(C)[O:25]5)=[CH:17][C:9]=4[C:10]([CH3:16])([CH3:15])[C:11]=3[NH:12]2)=[CH:4][CH:3]=1.[C:32]([Cu])#[N:33].C(OCC)(=O)C>CC(N(C)C)=O>[Cl:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[C:7](=[O:31])[C:8]4[CH:20]=[C:19]([C:32]#[N:33])[C:18]([O:22][CH2:23][C@H:24]([OH:25])[CH2:28][OH:27])=[CH:17][C:9]=4[C:10]([CH3:15])([CH3:16])[C:11]=3[NH:12]2)=[CH:4][CH:3]=1
Reactant: CC1(C)OC[C@H](COc2cc3c(cc2Br)C(=O)c2c([nH]c4cc(Cl)ccc24)C3(C)C)O1
Reactant: N#C[Cu]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CC1(C)c2cc(OC[C@H](O)CO)c(C#N)cc2C(=O)c2c1[nH]c1cc(Cl)ccc21
Temperature: 220 °C
Reaction time: 2 h
Yield: 26.3 %

Procedure:
3-Chloro-9-bromo-8-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl methoxy)-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one (Compound S7-2, 17 mg, 37 μmol) was dissolved in DMA, added with CuCN (17 mg, 5 eq.), and stirred at 220° C. for 2 hr under irradiation with microwave. After cooling, the reaction solution was added with ethyl acetate, and the precipitated solid was filtered to remove the solvent. The resulting residues were purified by HPLC to obtain the title compound (4 mg).
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:16][CH2:17][Cl:18].C(=O)([O-])[O-].[Cs+].[Cs+].O>C(#N)C>[Cl:18][CH2:17][CH2:16][O:14][C:11]1[CH:10]=[CH:9][C:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:13][CH:12]=1
Reactant: Oc1ccc(Cc2ccccc2)cc1
Reactant: ClCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC#N
Product: ClCCOc1ccc(Cc2ccccc2)cc1
Yield: 86 %

Procedure:
A solution of 4-(benzyl)phenol (638 mg, 3.46 mmol), 1-bromo-2-chloroethane (2.3 mL, 27.7 mmol) and cesium carbonate (4.5 g, 27.7 mmol) in 35 mL of acetonitrile was heated at reflux for 12 hours. After cooling, water was added. The mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. Flash chromatography gave 734 mg of 1-(2-chloroethoxy)-4-(benzyl)benzene, 1H NMR (300 MHz, CDCl3) δ 7.29 (dd, 2H), 7.19 (dd, 1H), 7.18 (d, 2H), 7.12 (d, 2H), 6.85 (d, 2H), 4.21 (t, 2H), 3.93 (s, 2H), 3.80 (t, 2H) ppm.
Reaction SMILES: O=C(Cl)[O:3][C:4](Cl)(Cl)Cl.[F:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][CH2:17][C:18]2[C:19]([NH:26][CH3:27])=[N:20][C:21]([S:24][CH3:25])=[N:22][CH:23]=2)=[CH:12][C:11]=1[N+:28]([O-:30])=[O:29].CCN(CC)CC>O1CCOCC1>[F:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH2:17][C:18]3[C:19](=[N:20][C:21]([S:24][CH3:25])=[N:22][CH:23]=3)[N:26]([CH3:27])[C:4]2=[O:3])=[CH:12][C:11]=1[N+:28]([O-:30])=[O:29]
Reactant: CNc1nc(SC)ncc1CNc1ccc(F)c([N+](=O)[O-])c1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CSc1ncc2c(n1)N(C)C(=O)N(c1ccc(F)c([N+](=O)[O-])c1)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.9 %

Procedure:
To a solution of diphosgene (3.5 g, 17.7 mmol) in dioxane (350 mL) at 0° C. was slowly added a solution comprised of 5-((4-fluoro-3-nitrophenylamino)methyl)-N-methyl-2-(methylthio)pyrimidin-4-amine (5.2 g, 16.1 mmol) and Et3N (4.5 mL, 32.1 mmol) in dioxane (250 mL). The resultant reaction mixture was stirred at RT overnight. The solvent was removed in vacuo and the residue was partitioned between EtOAc and H2O. The combined organics were dried (Na2SO4) and concentrated to give crude product, which was washed with cold MeOH (5 mL) to give 3-(4-fluoro-3-nitrophenyl)-1-methyl-7-(methylthio)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (5.0 g, 89% yield) as a brown solid. 1H NMR (300 MHz, DMSO-d6): δ 8.26 (s, 1 H), 8.20 (m, 1 H), 7.82 (m, 1 H), 7.64 (dd, J=6.9, 8.4 Hz, 1 H), 4.82 (s, 2 H), 3.29 (s, 3 H), 2.50 (s, 3 H); MS (ESI) m/z: 350.3 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[SH:12].[H-].[Na+].F[C:16]1[C:23]([C:24]([F:27])([F:26])[F:25])=[CH:22][CH:21]=[CH:20][C:17]=1[C:18]#[N:19]>CN(C=O)C>[NH2:1][C:2]1[CH:7]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:5]=[CH:4][C:3]=1[S:12][C:16]1[C:23]([C:24]([F:25])([F:27])[F:26])=[CH:22][CH:21]=[CH:20][C:17]=1[C:18]#[N:19]
Reactant: N#Cc1cccc(C(F)(F)F)c1F
Reactant: Nc1cc(C(F)(F)F)ccc1S
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1cccc(C(F)(F)F)c1Sc1ccc(C(F)(F)F)cc1N
Reaction time: 0.5 h
Yield: 71.1 %

Procedure:
2-Amino-4-trifluoromethylthiophenol (5.74 g, 25 mmol) was added to a mixture of sodium hydride (2.0 g of 60% oil dispersion, 50 mmol) in DMF (100 ml) at 0° under nitrogen. After stirring for 30 minutes at 0°, 2-fluoro-3-trifluoromethylbenzonitrile (4.73 g, 25 mmol) in DMF (20 ml) was added and the mixture kept at room temperature overnight. The reaction mixture was evaporated and azeotroped with toluene, then the residue was partitioned between chloroform and water and the layers separated. Drying (magnesium sulphate) and evaporation of the organic layer gave a residue which was purified by chromatography on silica gel, eluting with dichloromethane. Recrystallisation from cyclohexane afforded the product as colourless needles (6.44 g).
Reaction SMILES: [CH3:1][N:2]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[O:16])[C:8]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]1=2.[Cl:17][S:18]([OH:21])(=O)=[O:19]>>[CH3:1][N:2]1[C:15]2[C:10](=[CH:11][C:12]([S:18]([Cl:17])(=[O:21])=[O:19])=[CH:13][CH:14]=2)[C:9](=[O:16])[C:8]2[CH:7]=[C:6]([S:18]([Cl:17])(=[O:21])=[O:19])[CH:5]=[CH:4][C:3]1=2
Reactant: O=S(=O)(O)Cl
Reactant: Cn1c2ccccc2c(=O)c2ccccc21
Product: Cn1c2ccc(S(=O)(=O)Cl)cc2c(=O)c2cc(S(=O)(=O)Cl)ccc21
Temperature: 25 °C
Yield: 99.7 %

Procedure:
A mixture of 10-methylacridin-9(10H)-one (4.2 g, 20 mmole) and chlorosulfonic acid (100 mL, 1.5 mole) was heated at reflux for 5 hours. Reaction mixture was then condensed, cooled down to room temperature and poured carefully on 500 g of ice. The yellow precipitate of product was collected by filtration, washed with water and dried to provide 8.1 g of the title compound. This material was used for next step without purification.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:24]=[CH:23][CH:22]=[CH:21][C:6]=1[CH2:7][NH:8][C:9]([C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[N:14][CH:15]=[CH:16][CH:17]=2)[N:12]=1)=[O:10].CI.[C:27](OCC)(=O)C>CN(C=O)C>[CH3:3][O:4][C:5]1[CH:24]=[CH:23][CH:22]=[CH:21][C:6]=1[CH2:7][N:8]([CH3:27])[C:9]([C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[N:14][CH:15]=[CH:16][CH:17]=2)[N:12]=1)=[O:10]
Reactant: CCOC(C)=O
Reactant: COc1ccccc1CNC(=O)c1ccc2cccnc2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1ccccc1CN(C)C(=O)c1ccc2cccnc2n1
Reaction time: 0.5 h

Procedure:
To a suspension of sodium hydride (10 mg) in DMF (1 mL) at 0° C. was added a solution of the compound of Example 1 (68 mg, 0.23 mmol) in DMF (1mL). The reaction mixture was stirred at the same temperature for 30 minutes then methyl iodide (20 μL, 0.32 mmol) was added. Reaction mixture was stirred at room temperature overnight. It was then poured into ethyl acetate, washed with water, brine, dried over magnesium sulfate and concentrated to give a white solid. Purification was done using a silica gel column and ethyl acetate as the eluent. 1H NMR (300 MHz; CDCl3): Mixture of rotamers 9.13 (m, 1H); 8.29−8.18 (m, 2H); 7.86 (dd, 1H, J=8.2 and 12 Hz); 7.58−7.11 (complex mixture; 3H); 6.98−6.71 (complex mixture, 2H); 4.91 and 4.85 (2s, 2H) and 3.84 and 3.58 (2 s, 3H); 3.18 and 3.04 (2 s, 3H) ppm.