Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][OH:12])[CH:5]=[CH:6][CH:7]=1.[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1.C(N(CC)CC)C.[NH4+].[Cl-]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][O:12][S:19]([C:16]2[CH:17]=[CH:18][C:13]([CH3:23])=[CH:14][CH:15]=2)(=[O:21])=[O:20])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCCCc1cccc(Br)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCCCCc2cccc(Br)c2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 133.2 %

Procedure:
A cold (0° C.) solution of 4-(3-bromophenyl)butan-1-ol (1.08 g, 4.7 mmol) and p-toluenesulfonyl chloride (1.2 g, 6.3 mmol) in THF was treated slowly with triethyl amine (1.8 mL, 12.3 mmol), stirred at room temperature for 4 hours, poured into cold saturated aqueous NH4Cl and extracted with ether. The organic extracts were combined, washed with brine, dried over MgSO4 and concentrated in vacuo. Purification of the resultant residue on silica gel (ISCO) using (hexanes/EtOAC 9.5/0.5) as the eluting solvent afforded toluene-4-sulfonic acid 4-(3-bromophenyl)-butyl ester as a colorless oil (2.4 g, 76% yield). m/e (M+NH4)+ 400.1 1H NMR (400 MHz, DMSO-d6) δ ppm, 1.4-1.6 (m, 4H), 2.4 (s, 3H), 2.4-2.5 (m, 2H), 4.0 (t, J=6.0 Hz, 2H), 7.2 (t, J=7.8 Hz, 1H), 7.3-7.3 (m, 1H), 7.3-7.3 (m, J=8.0, 1.0 Hz, 1H), 7.4-7.5 (m, J=8.6 Hz, 2H), 7.7-7.8 (m, 2H).
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([NH:11][C:12]2[N:17]=[C:16]([C:18]3[C:19]([C:27]4[CH:28]=[C:29]([NH:33]C(=O)C(F)(F)F)[CH:30]=[CH:31][CH:32]=4)=[N:20][N:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=34)[CH:15]=[CH:14][N:13]=2)[CH:8]=[CH:9][CH:10]=1.[NH:40]1[CH2:44][CH2:43][CH2:42][CH2:41]1>>[NH2:33][C:29]1[CH:28]=[C:27]([C:19]2[C:18]([C:16]3[CH:15]=[CH:14][N:13]=[C:12]([NH:11][C:7]4[CH:8]=[CH:9][CH:10]=[C:5]([O:4][CH2:3][CH2:2][N:40]5[CH2:44][CH2:43][CH2:42][CH2:41]5)[CH:6]=4)[N:17]=3)=[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][N:21]3[N:20]=2)[CH:32]=[CH:31][CH:30]=1
Reactant: C1CCNC1
Reactant: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3cccc(OCCCl)c3)n2)c1)C(F)(F)F
Product: Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3cccc(OCCN4CCCC4)c3)n2)c1
Temperature: 50 °C
Yield: 74 %

Procedure:
N-(3-{3-[2-({3-[(2-Chloroethyl)oxy]phenyl}amino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-2-yl}phenyl)-2,2,2-trifluoroacetamide (0.5 g, 0.85 mmol) was dissolved in pyrrolidine and heated to 50° C. for 18 h. Upon completion the reaction was then cooled and absorbed directly onto silica gel. Purification via column chromatography using a 0-20% gradient of EtOAc/MeOH w/NH4OH afforded the desired product as a yellow solid, 310 mg, 74% yield. ES-LC/MS m/z 492 [M+H]+.
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4]1[CH:9]=[C:8]([CH3:10])[C:7]([S:11]([NH:14][C@H:15]([C:20]([NH:22][C@@H:23]([C:34]([N:36]2[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]2)=[O:35])[CH2:24][C:25]2[CH:30]=[CH:29][C:28]([C:31](=[NH:33])[NH2:32])=[CH:27][CH:26]=2)=[O:21])[CH2:16][C:17](=[O:19])[NH2:18])(=[O:13])=[O:12])=[C:6]([CH3:42])[C:5]=1[CH3:43].C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1.[C@@H:69]1(N)[O:77][C@H:76]([CH2:78][OH:79])[C@H:74]([OH:75])[C@H:72]([OH:73])[C@H:70]1[OH:71]>CN(C=O)C.ClCCl>[ClH:1].[CH3:2][O:3][C:4]1[CH:9]=[C:8]([CH3:10])[C:7]([S:11]([NH:14][C@H:15]([C:20]([NH:22][C@@H:23]([C:34]([N:36]2[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]2)=[O:35])[CH2:24][C:25]2[CH:26]=[CH:27][C:28]([C:31](=[NH:32])[NH2:33])=[CH:29][CH:30]=2)=[O:21])[CH2:16][C:17](=[O:19])[NH:18][C@@H:69]2[O:77][C@H:76]([CH2:78][OH:79])[C@H:74]([OH:75])[C@H:72]([OH:73])[C@H:70]2[OH:71])(=[O:13])=[O:12])=[C:6]([CH3:42])[C:5]=1[CH3:43]
Reactant: COc1cc(C)c(S(=O)(=O)N[C@@H](CC(N)=O)C(=O)N[C@H](Cc2ccc(C(=N)N)cc2)C(=O)N2CCCCC2)c(C)c1C
Reactant: N[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1cc(C)c(S(=O)(=O)N[C@@H](CC(=O)N[C@@H]2O[C@H](CO)[C@H](O)[C@H](O)[C@H]2O)C(=O)N[C@H](Cc2ccc(C(=N)N)cc2)C(=O)N2CCCCC2)c(C)c1C
Temperature: 25 °C
Reaction time: 48 h

Procedure:
2-N-(4-Methoxy-2,3,6-trimethyl-benzenesulfonyl)-L-asparaginyl-4-amidino-D-phenylalanine-piperidide hydrochloride (1.0 g), HOBt (0.23 g) and DCCI (0.37 g) were dissolved in DMF and dichloromethane 1:1 (50 mL) and, after 0.5 h of stirring, β-D-galactopyranosyl-amine (1.0 g) was added. The reaction mixture was stirred for 48 h at room temperature and then filtered and concentrated by evaporation in vacuo. The residue was dissolved in ethyl acetate and washed with water. The crude product was purified by column chromatography on silica gel with chloroform/methanol 5:1. Yield: 1.2 g. TLC analysis: Rf=0.73 (chloroform/methanol 3:1). Barium oxide (0.25 g) was added to a solution of the intermediate compound (1.2 g) in chloroform/methanol 2:1 (100 mL), and the mixture was stirred for 2 h and then filtered. The flitrate was neutralized with methanolic HCl and concentrated by evaporation in vacuo. The residue was purified by column chromatography (Sephadex LH 20). Yield: 1.0 g. TLC analysis: Rf=0.042 (chloroform/methanol 3:1). [α]D +19.3° (c=1 in methanol). M.p. 186°-190° C.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12](Br)[CH:13]=1)(=[O:3])[CH3:2].[Cl:27][C:28]1[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=1B(O)O>>[C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12]([C:29]2[CH:30]=[CH:31][C:32]([F:34])=[CH:33][C:28]=2[Cl:27])[CH:13]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cncc(Br)c1
Reactant: OB(O)c1ccc(F)cc1Cl
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cncc(-c2ccc(F)cc2Cl)c1

Procedure:
By following a procedure analogous to Example 27 starting from 5-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside and 2-chloro-4-fluoro-phenylboronic acid, 5-(2-chloro-4-fluorophenyl)-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside is obtained in the form of an off-white foam (yield 81%).
Reaction SMILES: [CH2:1]([O:3][CH2:4][O:5][C:6]1[CH:11]=[C:10]([O:12][CH2:13][O:14][CH2:15][CH3:16])[CH:9]=[CH:8][C:7]=1[O:17][CH3:18])[CH3:2].[Li][CH2:20]CCC.CI>C1COCC1>[CH2:15]([O:14][CH2:13][O:12][C:10]1[CH:9]=[CH:8][C:7]([O:17][CH3:18])=[C:6]([O:5][CH2:4][O:3][CH2:1][CH3:2])[C:11]=1[CH3:20])[CH3:16]
Reactant: [Li]CCCC
Reactant: CCOCOc1ccc(OC)c(OCOCC)c1
Solvent: C1CCOC1
Solvent: CI
Product: CCOCOc1ccc(OC)c(OCOCC)c1C
Temperature: -78 °C
Reaction time: 1 h
Yield: 57.5 %

Procedure:
A solution of 4a (632 mg, 2.27 mmol) in anhydrous THF (1.94 mL) was added dropwise to a solution of nBuLi (2.5 M in hexanes, 1.48 mL, 3.70 mmol) in anhydrous THF (1.62 mL) at room temperature. After one hour, the solution was cooled to −78° C. and methyl iodide (620 μL, 9.87 mmol) was added. The resulting solution was warmed to room temperature over 12 hours, and the reaction was quenched by the addition of saturated aqueous NH4Cl. Water (5 mL) was added and the solution was extracted with CH2Cl2 (3×10 mL). Combined organic fractions were dried (Na2SO4), filtered, and concentrated. The residue was purified via column chromatography (SiO2, 8:1→5:1 Hexane:EtOAc) to afford 5a as a yellow oil (353 mg, 53%): 1H NMR (CDCl3, 500 MHz) 6.74 (d, J=9.0 Hz, 1H), 6.60 (d, J=9.0 Hz, 1H) 5.10 (s, 2H), 5.05 (s, 2H), 3.78 (q, J=7.1 Hz, 2H), 3.72 (s, 3H), 3.67 (q, J=7.1 Hz, 2H), 2.14 (s, 3H), 1.18-1.15 (m, 6H); 13C NMR (CDCl3, 125 MHz) δ 149.1, 146.5, 121.7, 109.0, 108.4, 96.2, 93.0, 64.3, 63.1, 55.1, 28.7, 14.2, 14.1, 8.8; IR (film) νmax 2918, 2359, 1487, 1260, 1248, 1082, 1055, 945, 798 cm−1; HRMS (ESI+) m/z: [M+Na]+ calcd for Cl4H22O5, 293.1365; found, 293.1357.
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].Cl[C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([N+:16]([O-:18])=[O:17])[CH:12]=2)[N:7]=1>C(O)C>[CH:1]([NH:4][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([N+:16]([O-:18])=[O:17])[CH:12]=2)[N:7]=1)([CH3:3])[CH3:2]
Reactant: CC(C)N
Reactant: O=[N+]([O-])c1ccc2nc(Cl)ccc2c1
Solvent: CCO
Product: CC(C)Nc1ccc2cc([N+](=O)[O-])ccc2n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
2.55 mL (29.96 mmol) of isopropylamine is added to a solution of 1.25 g (5.99 mmol) of 2-chloro-6-nitroquinoline in 50 mL of ethanol and the mixture is stirred for 18 hours at ambient temperature. Then the reaction mixture is heated to 65° C. in the microwave for 2 hours. The reaction mixture is then evaporated down, the residue is taken up in 20 mL of DMF, combined with 2.55 mL (29.96 mmol) of isopropylamine, and stirred for 18 hours at ambient temperature. The reaction mixture is evaporated down and the residue is combined with ethyl acetate and water. The organic phase is extracted twice with water. The aqueous phases are extracted twice with ethyl acetate. The combined organic phases are dried over sodium sulfate and the solvent is then removed. Yield: 0.75 g (54.1% of theory); C12H13N3O2 (M=221.25); calc.: molecular ion peak (M+H)+: 232; found: molecular ion peak (M+H)+: 232; Rf value: 0.48 (silica gel, petroleum ether/ethyl acetate (2:1)).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[NH:13][C:12]([C:14]2([C:17](OC)=[O:18])[CH2:16][CH2:15]2)=[N:11][C:10]=1[C:21]1[N:26]=[C:25]2[O:27][C:28]([NH:30][C@@H:31]([CH3:36])[CH2:32][O:33][CH2:34][CH3:35])=[N:29][C:24]2=[CH:23][CH:22]=1.C1COCC1.[BH4-].[Li+]>C(OCC)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[NH:13][C:12]([C:14]2([CH2:17][OH:18])[CH2:15][CH2:16]2)=[N:11][C:10]=1[C:21]1[N:26]=[C:25]2[O:27][C:28]([NH:30][C@@H:31]([CH3:36])[CH2:32][O:33][CH2:34][CH3:35])=[N:29][C:24]2=[CH:23][CH:22]=1
Reactant: CCOC[C@H](C)Nc1nc2ccc(-c3nc(C4(C(=O)OC)CC4)[nH]c3-c3ccc(F)cc3F)nc2o1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCOC[C@H](C)Nc1nc2ccc(-c3nc(C4(CO)CC4)[nH]c3-c3ccc(F)cc3F)nc2o1
Temperature: 0 °C
Reaction time: 1 h
Yield: 59.9 %

Procedure:
Methyl 1-[5-(2,4-difluorophenyl)-4-[2-[[(1S)-2-ethoxy-1-methyl-ethyl]amino]oxazolo[5,4-b]pyridin-5-yl]-1H-imidazol-2-yl]cyclopropanecarboxylate (0.9 g, 1.99 mmol) is dissolved in dry diethyl ether (20 mL) and dry THF (7 mL) under a nitrogen atmosphere and cooled to 0° C. Lithium borohydride (87 mg, 3.99 mmol) is added portionwise and the mixture stirred at 0° C. for 1 h. The remaining reactants are quenched by adding 1 N HCl until pH=1 to the mixture at RT dropwise for 30 min. The mixture is washed with ethyl acetate, the aqueous layer basified (until pH=8) with NaOH, and extracted with dichloromethane. The combined organic layers are dried over MgSO4, filtered, and concentrated under reduced pressure. The residue is purified by normal phase chromatography (120 g silica-gel cartridge) using a gradient of hexane-ethanol to afford the title compound (0.56 g, 60%). LC-ES/MS m/z 470.2 (M+1); [α]D22−18.00°, (c=0.50, MeOH); [α]D22−18.0°, (c=0.50, CHCl3).
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([CH:14]([CH3:16])[CH3:15])[C:11]=1[O:12][CH3:13])[CH:7]=O)([CH3:3])[CH3:2].[OH:17][C:18]1[CH:26]=[C:25]2[C:21]([CH2:22][C:23](=[O:27])[NH:24]2)=[CH:20][CH:19]=1>>[CH:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([CH:14]([CH3:16])[CH3:15])[C:11]=1[O:12][CH3:13])[CH:7]=[C:22]1[C:21]2[C:25](=[CH:26][C:18]([OH:17])=[CH:19][CH:20]=2)[NH:24][C:23]1=[O:27])([CH3:3])[CH3:2]
Reactant: COc1c(C(C)C)cc(C=O)cc1C(C)C
Reactant: O=C1Cc2ccc(O)cc2N1
Product: COc1c(C(C)C)cc(C=C2C(=O)Nc3cc(O)ccc32)cc1C(C)C

Procedure:
3,5-Diisopropyl-4-methoxybenzaldehyde was condensed with 6-hydroxy-2-oxindole to give 0.3 g of 3-(3,5-Diisopropyl-4-methoxybenzylidene)-6-hydroxy-1,3-dihydroindol-2-one as a yellow-orange solid.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([NH2:11])[N:3]=1.FC(F)(F)C(=N[Si](C)(C)C)O[Si](C)(C)C.S(O)(C(F)(F)F)(=O)=O.C(O[C@@H:39]1[O:61][C@H:60]([CH2:62][O:63][C:64](=[O:71])[C:65]2[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=2)[C@@H:50]([O:51][C:52](=[O:59])[C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)[C@H:40]1[O:41][C:42](=[O:49])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)(=O)C>CC(OC)(C)C.CC#N>[C:42]([O:41][C@@H:40]1[C@H:50]([O:51][C:52](=[O:59])[C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)[C@@H:60]([CH2:62][O:63][C:64](=[O:71])[C:65]2[CH:66]=[CH:67][CH:68]=[CH:69][CH:70]=2)[O:61][C@H:39]1[N:8]1[C:9]2[N:10]=[C:2]([Cl:1])[N:3]=[C:4]([NH2:11])[C:5]=2[N:6]=[CH:7]1)(=[O:49])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: Nc1nc(Cl)nc2nc[nH]c12
Reactant: CC(=O)O[C@@H]1O[C@H](COC(=O)c2ccccc2)[C@@H](OC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Agent: C[Si](C)(C)N=C(O[Si](C)(C)C)C(F)(F)F
Agent: O=S(=O)(O)C(F)(F)F
Solvent: COC(C)(C)C
Solvent: CC#N
Product: Nc1nc(Cl)nc2c1ncn2[C@@H]1O[C@H](COC(=O)c2ccccc2)[C@@H](OC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Temperature: 27.5 °C

Procedure:
Under an atmosphere of N2(g), 2-chloroadenine (A (9), 50 g, 294.9 mmol), MeCN (600 mL), and BSTFA (227.5 g, 883.8 mmol) were stirred and heated under reflux until the mixture turned mostly clear (about 1 h). TfOH (8.77 g, 58.5 mmol) and 1-O-acetyl-2,3,5-tri-O-benzoyl-β-D-ribofuranose (C, 142.5 g, 282.5 mmol) were sequentially added into the mixture and were stirred at reflux for about 1 h. The mixture was cooled to 20-35° C. and diluted with MTBE (500 mL), and washed over a 0.5 to 1 h period with saturated NaHCO3 (750 mL). The organic phase was evaporated in vacuo at 40 to 50° C. to give 2′,3′,5′-tri-O-benzoyl-2-chloroadenosine (D): 1H NMR (300 MHz, CDCl3) δ 7.9-8.1 (m, 6H), 7.94 (s, 1H), 7.3-7.6 (m, 9H), 6.45 (d, J=2.7 Hz 1H), 6.15 (m, 2H), 5.30 (s, 2H), 4.90 (dd, J4′,5a=3.2 Hz, J5′a,5′b=12.0 Hz, 1H), 4.82 (m, 1H), 4.72 (dd, J4′,5a=4.1 Hz, J5′a,5′b=12.0 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 166.3, 165.5, 165.4, 156.4, 154.7, 151.1, 139.1, 134.1, 134.1, 133.8, 130.2, 130.1, 129.9, 129.4, 129.0, 128.8, 128.5, 119.1, 86.5, 81.3, 74.6, 71.7, 64.0.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@H:13]2[CH2:26][O:25][C:16]3[CH:17]=[CH:18][C:19]4[CH2:20][CH2:21][CH2:22][O:23][C:24]=4[C:15]=3[O:14]2)(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+].[F:33][C:34]1[CH:35]=[C:36]2[C:40](=[CH:41][CH:42]=1)[NH:39][CH:38]=[C:37]2[C:43]1[CH2:44][CH2:45][NH:46][CH2:47][CH:48]=1>O1CCCC1.CN(C)C=O>[F:33][C:34]1[CH:35]=[C:36]2[C:40](=[CH:41][CH:42]=1)[NH:39][CH:38]=[C:37]2[C:43]1[CH2:44][CH2:45][N:46]([CH2:12][CH:13]2[CH2:26][O:25][C:16]3[CH:17]=[CH:18][C:19]4[CH2:20][CH2:21][CH2:22][O:23][C:24]=4[C:15]=3[O:14]2)[CH2:47][CH:48]=1
Reactant: Fc1ccc2[nH]cc(C3=CCNCC3)c2c1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc4c(c3O2)OCCC4)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Fc1ccc2[nH]cc(C3=CCN(CC4COc5ccc6c(c5O4)OCCC6)CC3)c2c1

Procedure:
To a mixture of (2R)-2,3,8,9-tetrahydro-7H-[1,4]dioxino[2,3-h]chromen-2-ylmethyl 4-methylbenzenesulfonate (0.25 g, 0.66 mmole) and potassium carbonate (0.22 g, 1.55 mmole) in 1:1 tetrahydrofuran/dimethylformamide (20 mL) was added 0.45 g (2.08 mmole) of 5-fluoro-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole. The reaction mixture was refluxed under nitrogen for six hours. After completion, the mixture was evaporated to dryness under reduced pressure and the residue was column chromatographed on silica gel with methylene chloride to remove impurities and 4% methanol/methylene chloride to elute the desired product as an oil, which was crystallized from isopropanol with the addition of a solution of oxalic acid in hot isopropanol to give 0.040 g (6%) of the (S)-enantiomer of the title compound as a dark yellow solid, m.p. 146-148° C.
Reaction SMILES: [Br:1][C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[CH2:4][C:5]1[N:10]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[C:8]([OH:15])=[C:7]([OH:16])[N:6]=1.[C:21](Cl)(=[O:23])[CH3:22].[NH4+].[Cl-]>C(Cl)Cl>[CH3:14][O:13][C:11]([C:9]1[N:10]=[C:5]([CH2:4][C:3]2[CH:17]=[CH:18][CH:19]=[CH:20][C:2]=2[Br:1])[NH:6][C:7](=[O:16])[C:8]=1[O:15][C:21](=[O:23])[CH3:22])=[O:12]
Reactant: CC(=O)Cl
Reactant: COC(=O)c1nc(Cc2ccccc2Br)nc(O)c1O
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Product: COC(=O)c1nc(Cc2ccccc2Br)[nH]c(=O)c1OC(C)=O
Reaction time: 1 h
Yield: 97.8 %

Procedure:
In a round-bottomed flask, methyl 2-(2-bromobenzyl)-5,6-dihydroxypyrimidine-4-carboxylate (300 mg, 885 μmol) was combined with DCM (10 ml) to give a brown suspension. Acetyl chloride (1M in DCM) (2.21 ml, 2.21 mmol) was added slowly at room temperature. The mixture was stirred for one hour and then poured onto aqueous saturated NH4Cl solution and extracted with DCM. The organic phase was washed with brine solution, dried (Na2SO4), and evaporated to dryness under reduced pressure. Chromatography (SiO2; DCM) provided the title product as a white solid (0.33 g; 97%). LCMS: m/z=381/383 (MH+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1.[CH:23]1[C:35]2[NH:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:27]=2[CH:26]=[C:25]([C:36]2[C:41]3[O:42][C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=4[C:40]=3[CH:39]=[CH:38][CH:37]=2)[CH:24]=1.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.CC(C)([O-])C.[Na+]>CCCCCC.C1(C)C=CC=CC=1>[CH:39]1[C:40]2[C:44]3[CH:45]=[CH:46][CH:47]=[CH:48][C:43]=3[O:42][C:41]=2[C:36]([C:25]2[CH:24]=[CH:23][C:35]3[N:34]([C:2]4[CH:7]=[CH:6][C:5]([C:8]5[N:9]([C:17]6[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=6)[C:10]6[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=6[N:12]=5)=[CH:4][CH:3]=4)[C:33]4[C:28]([C:27]=3[CH:26]=2)=[CH:29][CH:30]=[CH:31][CH:32]=4)=[CH:37][CH:38]=1
Reactant: c1ccc2c(c1)[nH]c1ccc(-c3cccc4c3oc3ccccc34)cc12
Reactant: Brc1ccc(-c2nc3ccccc3n2-c2ccccc2)cc1
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: c1ccc(-n2c(-c3ccc(-n4c5ccccc5c5cc(-c6cccc7c6oc6ccccc67)ccc54)cc3)nc3ccccc32)cc1
Yield: 71 %

Procedure:
To a 100-mL three-neck flask were added 0.70 g (1.0 mmol) of 2-(4-bromophenyl)-3-phenylbenzimidazole and 0.67 g (1.0 mmol) of 4-(9H-carbazol-3-yl)dibenzofuran, and the air in the flask was replaced with nitrogen. To this mixture were added 15 mL of toluene, 0.10 mL of tri(tert-butyl)phosphine (a 10 wt % hexane solution), 0.48 g (4.3 mmol) of sodium tert-butoxide. This mixture was degassed while being stirred under reduced pressure. This mixture was stirred at 110° C. for 20 hours. After the stirring, the mixture was washed twice with about 30 mL of water, and the mixture was separated into an organic layer and an aqueous layer. Then, the aqueous layer was subjected to extraction twice with about 30 mL of toluene. The organic layer and the solution of the extract were combined and washed once with about 100 mL of saturated brine. The obtained organic layer was dried over magnesium sulfate, and this mixture was subjected to filtration through Celite (produced by Wako Pure Chemical Industries, Ltd., Catalog No. 531-16855), Florisil (produced by Wako Pure Chemical Industries, Ltd., Catalog No. 540-00135), and alumina. The obtained filtrate was concentrated to give a brown solid. The obtained brown solid was purified by silica gel column chromatography (a developing solvent in which the ethyl acetate/toluene ratio was 5:95), and further recrystallized from hexane/toluene, so that 0.86 g of a pale brown solid was obtained in 71% yield. The synthesis scheme of Step 2 is illustrated in (b-2).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16]C)=[CH:12][C:11]=2[CH3:18])=[O:9])=[CH:4][CH:3]=1.[Al+3].[Cl-].[Cl-].[Cl-].O>C1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][C:11]=2[CH3:18])=[O:9])=[CH:4][CH:3]=1
Reactant: COc1ccc(C(=O)c2ccc(Br)cc2)c(C)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: c1ccccc1
Product: Cc1cc(O)ccc1C(=O)c1ccc(Br)cc1
Temperature: 90 °C
Yield: 123.5 %

Procedure:
To a solution of (4-bromophenyl)[2-methyl-4-(methyloxy)phenyl]methanone (27) (1.12 g, 3.67 mmoL) in benzene (25 mL) was added AlCl3 (1.98 g, 14.85 mmol). The mixture was heated at 90° C. for 3 h. Upon cooling, water (25 mL) was added, and the mixture was extracted with Et2O. The organics were dried with MgSO4 and concentrated. The crude material was purified by chromatography on silica gel (EtOAc:hexanes) to yield 1.32 g (86%) of compound 28. 1H NMR (400 MHz, DMSO-d6): δ 2.26 (s, 3H), 6.63 (dd, J=2.4 Hz, 8.4 Hz, 1H), 6.72 (d, J=2.2 Hz, 1H), 7.18 (d, J=8.4 Hz, 1H), 7.55 (d, J=8.4 Hz, 2H), 7.70 (d, J=8.4 Hz, 2H), 10.10 (s, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[C:16]([C:20]#[N:21])=[CH:17][NH:18][CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:22]([O:24][C:25](=[O:37])[C:26]1[CH:31]=[CH:30][C:29](F)=[CH:28][C:27]=1[O:33][CH2:34][O:35][CH3:36])[CH3:23].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O>[CH2:22]([O:24][C:25](=[O:37])[C:26]1[CH:31]=[CH:30][C:29]([N:18]2[CH:19]=[C:15]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:16]([C:20]#[N:21])=[CH:17]2)=[CH:28][C:27]=1[O:33][CH2:34][O:35][CH3:36])[CH3:23]
Reactant: CCOC(=O)c1ccc(F)cc1OCOC
Reactant: N#Cc1c[nH]cc1-c1ccccc1OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1ccc(-n2cc(C#N)c(-c3ccccc3OCc3ccccc3)c2)cc1OCOC
Temperature: 65 °C
Reaction time: 15 h
Yield: 87.2 %

Procedure:
To a solution of 4-(2-benzyloxyphenyl)-1H-pyrrole-3-carbonitrile (1.5 g), 4-fluoro-2-methoxymethoxybenzoic acid ethyl ester (1.4 g) in N,N-dimethylformamide (25 mL) was added cesium carbonate, and this mixture was stirred at 65° C. for 15 hours. This reaction mixture was poured into water, the precipitated solid was collected by filtration, and washed with water and n-hexane, dried under reduced pressure at 50° C. to give the title compound (2.3 g).
Reaction SMILES: [NH2:1][C:2]1[O:3][C:4]([C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[N:6]=1.O.[NH4+].[OH-].[C:23](OC(=O)C)(=[O:25])[CH3:24]>>[C:23]([NH:1][C:2]1[O:3][C:4]([C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[N:6]=1)(=[O:25])[CH3:24]
Reactant: Nc1nc(-c2ccc(F)cc2)c(-c2ccncc2)o1
Reactant: CC(=O)OC(C)=O
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: CC(=O)Nc1nc(-c2ccc(F)cc2)c(-c2ccncc2)o1
Temperature: 25 °C

Procedure:
A mixture of 2-amino-4-(4-fluorophenyl)-5-(4-pyridyl)oxazole (0.090 g, 0.353 mmol) in acetic anhydride (4 mL) was stirred at room temperature. After 72 h the mixture was poured into H2O and neutralized with conc. NH4OH. The resulting precipitate was filtered and washed with H2O. Purification by column chromatography (0-5% MeOH/CHCl3), followed by recrystallization from MeOH afforded the title compound as a white solid (30.0 mg):ESMS (m/z): 298.0 (M++H).
Reaction SMILES: [F:1][C:2]1([F:36])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14]([NH:16][C:17]4[N:18]=[C:19]([C:27]5[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=5)[C:30](O)=[O:31])[C:20]5[C:25]([CH:26]=4)=[CH:24][CH:23]=[CH:22][CH:21]=5)=[O:15])[CH2:13][CH2:12]3)=[CH:10][C:4]=2[O:3]1.S(Cl)([Cl:39])=O.CN(C)C=O>ClCCl>[F:1][C:2]1([F:36])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14]([NH:16][C:17]4[N:18]=[C:19]([C:27]5[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=5)[C:30]([Cl:39])=[O:31])[C:20]5[C:25]([CH:26]=4)=[CH:24][CH:23]=[CH:22][CH:21]=5)=[O:15])[CH2:13][CH2:12]3)=[CH:10][C:4]=2[O:3]1
Reactant: O=C(O)c1cccc(-c2nc(NC(=O)C3(c4ccc5c(c4)OC(F)(F)O5)CC3)cc3ccccc23)c1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1cccc(-c2nc(NC(=O)C3(c4ccc5c(c4)OC(F)(F)O5)CC3)cc3ccccc23)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 3-(3-(1-(2,2-di fluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)isoquinolin-1-yl)benzoic acid (1.26 g, 2.58 mmol) in dichloromethane (5 mL) was added thionyl chloride (922 mg, 564 μL, 7.75 mmol) and N,N-dimethyl formamide (20 μL). The reaction mixture was stirred at room temperature for 30 minutes before it was evaporated to dryness to yield 3-(3-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)isoquinolin-1-yl)benzoyl chloride as a yellow solid.