Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[CH:21][C:4]=1[CH2:5][N:6]1[C:12](=[O:13])[C:11]2[CH:14]=[C:15]([S:18][CH3:19])[CH:16]=[CH:17][C:10]=2[NH:9][C:8](=O)[CH2:7]1.CN(C)C1C=CC(C)=CC=1.P(Cl)(Cl)([Cl:39])=O>C1(C)C=CC=CC=1>[Cl:39][C:8]1[CH2:7][N:6]([CH2:5][C:4]2[CH:21]=[CH:22][C:23]([O:25][CH3:26])=[CH:24][C:3]=2[O:2][CH3:1])[C:12](=[O:13])[C:11]2[CH:14]=[C:15]([S:18][CH3:19])[CH:16]=[CH:17][C:10]=2[N:9]=1
Reactant: COc1ccc(CN2CC(=O)Nc3ccc(SC)cc3C2=O)c(OC)c1
Reactant: O=P(Cl)(Cl)Cl
Solvent: Cc1ccc(N(C)C)cc1
Solvent: Cc1ccccc1
Product: COc1ccc(CN2CC(Cl)=Nc3ccc(SC)cc3C2=O)c(OC)c1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
4-(2,4-Dimethoxy-benzyl)-7-methylsulfanyl-3,4-dihydro-1H-benzo[e][1,4]diazepine-2,5-dione (630 mg, 1.7 mmol) and N,N-dimethyl-p-toluidine (489 μL, 3.4 mmol) were mixed in toluene (5 mL) and heated to 100° C. Then phosphorus oxychloride (170 μL, 1.9 mmol) was added dropwise and heating at 100° C. was continued for 1 h. The resulting dark red solution was used directly in the subsequent step.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:20]=[C:19]2[C:10]([O:11][C:12]3[CH:13]=[CH:14][C:15]([C:36]4[C:37]([F:42])=[N:38][CH:39]=[CH:40][CH:41]=4)=[CH:16][C:17]=3[C:18]32[C:24]2=[N:25][CH:26]=[CH:27][N:23]2[C:22]([NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[N:21]3)=[C:9]([F:43])[CH:8]=1)(=O)=O.C1(C2C=CC=CC=2)C=CC=CC=1P(C(C)(C)C)C(C)(C)C.[NH:67]1[CH2:72][CH2:71][O:70][CH2:69][CH2:68]1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O>[F:43][C:9]1[C:10]2[O:11][C:12]3[C:17](=[CH:16][C:15]([C:36]4[C:37]([F:42])=[N:38][CH:39]=[CH:40][CH:41]=4)=[CH:14][CH:13]=3)[C:18]3([C:24]4=[N:25][CH:26]=[CH:27][N:23]4[C:22]([NH:28][C:29](=[O:30])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[N:21]3)[C:19]=2[CH:20]=[C:7]([N:67]2[CH2:72][CH2:71][O:70][CH2:69][CH2:68]2)[CH:8]=1
Reactant: CC(C)(C)OC(=O)NC1=NC2(c3cc(-c4cccnc4F)ccc3Oc3c(F)cc(OS(=O)(=O)C(F)(F)F)cc32)c2nccn21
Reactant: C1COCCN1
Agent: [Pd]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Solvent: O
Product: CC(C)(C)OC(=O)NC1=NC2(c3cc(-c4cccnc4F)ccc3Oc3c(F)cc(N4CCOCC4)cc32)c2nccn21
Yield: 40.7 %

Procedure:
A microwave vial was charged with 5-(tert-butoxycarbonylamino)-5′-fluoro-2′-(2-fluoropyridin-3-yl)spiro[imidazo[1,5-a]imidazole-7,9′-xanthene]-7′-yl trifluoromethanesulfonate (300 mg, 0.462 mmol), Pd2dba3 (21.15 mg, 0.023 mmol), biphenyl-2-yldi-tert-butylphosphine (16.54 mg, 0.055 mmol) and morpholine (141 mg, 1.617 mmol) and capped under argon gas. LiHMDS (1 M in THF) (1.155 mL, 1.155 mmol) was added and the mixture was microwaved at 90° C. for 10 min. Twenty five ml of water was added, and the aqueous layer was extracted with EtOAc and the combined organic layers were dried, filtered and concentrated. The crude material (product) was purified via silica gel column chromatography (RediSep 40 g column) using 0-100% 90/10/1 (DCM/MeOH/ammonia) in DCM to afford tert-butyl 4′-fluoro-7′-(2-fluoropyridin-3-yl)-2′-morpholinospiro[imidazo[1,5-a]imidazole-7,9′-xanthene]-5-ylcarbamate (110 mg, 0.188 mmol, 40.6% yield) as an off white solid. This material was treated with TFA (0.323 ml, 4.19 mmol) in DCM (2 ml) and stirred at RT for one hour. The solution was concentrated, neutralized with sodium barcabonate solution and extracted with DCM. The organic extracts were combined, dried, filtered and concentrated. The crude product (racemic concentrate) was purified via silica gel column chromatography using 0-100% 90/10/1 (DCM/MeOH/ammonia) in DCM, then the racemates were separated using chiral SFC to afford (S)-4′-fluoro-7′-(2-fluoropyridin-3-yl)-2′-morpholinospiro[imidazo[1,5-a]imidazole-7,9′-xanthen]-5-amine (Example no. 9A) and (R)-4′-fluoro-7′-(2-fluoropyridin-3-yl)-2′-morpholinospiro[imidazo[1,5-a]imidazole-7,9′-xanthen]-5-amine (Example no. 9B).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[N:3]1.[Li]CCCC.[Cl:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([C:23]([C:25]3[C:26]([CH3:31])=[N:27][O:28][C:29]=3[CH3:30])=[O:24])[CH:21]=2)[N:16]=[C:15]([O:32][CH3:33])[C:14]=1[CH2:34][C:35]1[CH:40]=[CH:39][C:38]([C:41]([F:44])([F:43])[F:42])=[CH:37][CH:36]=1>C1COCC1>[Cl:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([C:23]([C:25]3[C:26]([CH3:31])=[N:27][O:28][C:29]=3[CH3:30])([C:6]3[N:2]([CH3:1])[N:3]=[N:4][CH:5]=3)[OH:24])[CH:21]=2)[N:16]=[C:15]([O:32][CH3:33])[C:14]=1[CH2:34][C:35]1[CH:36]=[CH:37][C:38]([C:41]([F:43])([F:42])[F:44])=[CH:39][CH:40]=1
Reactant: Cn1ccnn1
Reactant: COc1nc2ccc(C(=O)c3c(C)noc3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1nc2ccc(C(O)(c3c(C)noc3C)c3cnnn3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Temperature: -43 °C
Reaction time: 0.33 h

Procedure:
To a flask containing 1-methyl-1H-1,2,3-triazole (200 mg, 2.41 mmol) was added THF (17 mL) and the solution was cooled to −43° C. using a CH3CN—CO2 bath. n-BuLi, (2.5 M in hexanes, 0.88 mL, 2.19 mmol) was then added dropwise to provide a white suspension. The suspension was stirred at −40° C. for 20 minutes, then a homogeneous solution of (4-chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinolin-6-yl)(3,5-dimethylisoxazol-4-yl)methanone (500 mg, 1.05 mmol, Intermediate 63: step b) in 2 mL THF was introduced. A dark brownish solution immediately resulted. The reaction mixture was allowed to warm gradually to 0° C. over 25 minutes, then was quenched with aqueous NH4Cl solution. The aqueous portion was extracted with EtOAc (3×35 mL) and the combined organics were washed with brine, dried over MgSO4, filtered and concentrated to dryness. The residue was purified by FCC (20% EtOAc-hexanes increasing to 50% EtOAc) to provide the title compound as a white solid. 1H NMR (500 MHz, CDCl3) δ 8.08 (d, J=2.1 Hz, 1H), 7.85 (d, J=8.7 Hz, 1H), 7.61-7.46 (m, 3H), 7.39 (d, J=8.1 Hz, 2H), 6.94 (s, 1H), 4.81 (s, 1H), 4.32 (s, 2H), 4.09 (s, 3H), 3.98 (s, 3H), 1.95 (s, 3H), 1.82 (s, 3H); MS (ESI): mass calc. for Chemical Formula: C27H23ClF3N5O3; Exact Mass: 557.1. m/z found, 557.9 (M+H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:14]=[C:13]2[NH:15][CH:16]=[N:17][C:12]2=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21](F)[C:20]=1[C:26]([F:29])([F:28])[F:27].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.CCOCC>[CH2:1]([O:8][C:9]1[N:14]=[C:13]2[N:15]([C:21]3[CH:22]=[CH:23][CH:24]=[C:19]([F:18])[C:20]=3[C:26]([F:27])([F:29])[F:28])[CH:16]=[N:17][C:12]2=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(COc2ccc3nc[nH]c3n2)cc1
Reactant: Fc1cccc(F)c1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: Fc1cccc(-n2cnc3ccc(OCc4ccccc4)nc32)c1C(F)(F)F
Temperature: 80 °C

Procedure:
5-(Benzyloxy)-3H-imidazo[4,5-b]pyridine (0.10 g, 0.44 mmol) and 1,3-difluoro-2-(trifluoromethyl)benzene (0.12 g, 0.67 mmol) were dissolved in DMF (1.0 mL) and Cs2CO3 (0.29 g, 0.89 mmol) was added. The reaction mixture was heated to 80° C. overnight. The solution was then diluted with ether and washed with water. The aqueous layer was back extracted with additional ether. The combined organic portions were washed with brine, dried over MgSO4 and concentrated under reduced pressure to give the title compound.
Reaction SMILES: C(N1C=CN=C1)([N:3]1C=CN=C1)=O.[NH2:13][C:14]1[N:18]([C:19]2[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=2)[N:17]=[C:16]([NH:28][C:29]2[CH:34]=[C:33]([O:35][CH3:36])[C:32]([O:37][CH3:38])=[C:31]([O:39][CH3:40])[CH:30]=2)[N:15]=1.N>CN(C=O)C>[NH2:13][C:14]1[N:18]([C:19]2[CH:20]=[CH:21][C:22]([C:23]([NH2:3])=[O:24])=[CH:26][CH:27]=2)[N:17]=[C:16]([NH:28][C:29]2[CH:34]=[C:33]([O:35][CH3:36])[C:32]([O:37][CH3:38])=[C:31]([O:39][CH3:40])[CH:30]=2)[N:15]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COc1cc(Nc2nc(N)n(-c3ccc(C(=O)O)cc3)n2)cc(OC)c1OC
Agent: N
Solvent: CN(C)C=O
Product: COc1cc(Nc2nc(N)n(-c3ccc(C(N)=O)cc3)n2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0° C., 1,1′-carbonyldiimidazole (83 mg, 0.5 mmol) was added to a solution of 4-[5-amino-3-(3,4,5-trimethoxy-phenylamino)-[1,2,4]triazol-1-yl]-benzoic acid (100 mg, 0.25 mmol) in DMF (3 mL). The reaction mixture was stirred at rt. for 1 h, and ammonia (7.0M in MeOH, 1 mL) was added. The reaction mixture was stirred at rt. for 2 days. The mixture was then purified by semi-prep HPLC. FIA-MS: m/e=385.1 (M+H), 383.1 (ES−). Rt=3.60 min (method A). 1H-NMR (500 MHz, DMSO(d6)): 8.87 (s, 1H), 8.02 (br.s, 1H), 7.99 (d, 2H), 7.67 (d, 2H), 7.39 (br.s, 1H), 7.00 (s, 2H), 6.62 (s, 2H), 3.78 (s, 6H), 3.65 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][C:13]=1[Cl:14])[C:5](N(OC)C)=[O:6].[CH3:15][Mg]Br>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([C:5](=[O:6])[CH3:15])[CH:11]=[CH:12][C:13]=1[Cl:14]
Reactant: C[Mg]Br
Reactant: CON(C)C(=O)c1ccc(Cl)c(Br)c1
Solvent: C1CCOC1
Product: CC(=O)c1ccc(Cl)c(Br)c1
Temperature: -5 °C
Reaction time: 2 h
Yield: 90.9 %

Procedure:
A solution of 3-bromo-4-chloro-N-methoxy-N-methylbenzamide 105 (2.04 g, 7.3 mmol), was dissolved in 30 mL of dry THF. The solution was chilled to −5° C. in a salt bath under N2. Via syringe, methylmagnesium bromide (2.7 mL, 8.1 mmol) was added slowly to the solution. The solution was stirred for 2 h at −5° C., and then it was warmed to room temperature where it was stirred for another 1 h. The reaction was quenched with saturated NH4Cl, and it was diluted with ether and water. The organic solution was extracted with water and brine. The organic phase was dried over MgSO4, filtered, and concentrated in vacuo. The crude material was then filtered through a bed of silica and the filtrate was concentrated to give 1-(3-bromo-4-chlorophenyl)ethanone 106 (1.55 g, 91% yield) as a white solid.
Reaction SMILES: Cl[C:2]1[CH:24]=[CH:23][C:5]2[C:6](=[O:22])[C:7]3[CH:14]=[C:13]([O:15][CH2:16][CH2:17][O:18]C(=O)C)[CH:12]=[CH:11][C:8]=3[CH2:9][CH2:10][C:4]=2[CH:3]=1.[F:25][C:26]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:27]=1[NH2:28].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.CC([O-])(C)C.[K+]>CC([O-])=O.CC([O-])=O.[Pd+2].CC(O)(C)C.C1(C)C=CC=CC=1>[F:25][C:26]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:27]=1[NH:28][C:2]1[CH:24]=[CH:23][C:5]2[C:6](=[O:22])[C:7]3[CH:14]=[C:13]([O:15][CH2:16][CH2:17][OH:18])[CH:12]=[CH:11][C:8]=3[CH2:9][CH2:10][C:4]=2[CH:3]=1
Reactant: CC(=O)OCCOc1ccc2c(c1)C(=O)c1ccc(Cl)cc1CC2
Reactant: Nc1ccc(F)cc1F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: CC(C)(C)O
Solvent: Cc1ccccc1
Product: O=C1c2ccc(Nc3ccc(F)cc3F)cc2CCc2ccc(OCCO)cc21
Yield: 34 %

Procedure:
For the preparation of the compound by method C, 0.62 g (1.8 mmol) of 2-chloro-7-(2-acetoxyethoxy)-10,11-dihydrodibenzo[a,d]-cyclohepten-5-one, 0.25 g (1.9 mmol) of 2,4-difluoroaniline, 0.05 g (0.22 mmol) of Pd(OAc)2, 0.10 g (0.21 mmol) of 2-(dicyclohexylphosphino)-2′-,4′-,-6′-triisopropyl-biphenyl, 0.70 g (6.2 mmol) of KOt-Bu, 5 ml of toluene and 1 ml of t-BuOH are used. Yield: 34%; C23H19F2NO3 (Mr=395.41)
Reaction SMILES: [CH3:1][C:2]1[C:8](=[O:9])[NH:7][C:5](=[O:6])[N:4]([C@@H:10]2[O:14][C@H:13]([CH2:15][OH:16])[C@@H:12]([N:17]=[N+:18]=[N-:19])[CH2:11]2)[CH:3]=1.Br[CH2:21][CH2:22][CH2:23][N:24]1[C:28](=[O:29])[C:27]2=[CH:30][CH:31]=[CH:32][CH:33]=[C:26]2[C:25]1=[O:34].C[O-].[Na+].O>CN1C(=O)N(C)CCC1.CC(O)=O>[C:25]1(=[O:34])[N:24]([CH2:23][CH2:22][CH2:21][N:7]2[C:8](=[O:9])[C:2]([CH3:1])=[CH:3][N:4]([C@@H:10]3[O:14][C@H:13]([CH2:15][OH:16])[C@@H:12]([N:17]=[N+:18]=[N-:19])[CH2:11]3)[C:5]2=[O:6])[C:28](=[O:29])[C:27]2=[CH:30][CH:31]=[CH:32][CH:33]=[C:26]12
Reactant: Cc1cn([C@H]2C[C@H](N=[N+]=[N-])[C@@H](CO)O2)c(=O)[nH]c1=O
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Agent: C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CN1CCCN(C)C1=O
Product: Cc1cn([C@H]2C[C@H](N=[N+]=[N-])[C@@H](CO)O2)c(=O)n(CCCN2C(=O)c3ccccc3C2=O)c1=O
Temperature: 70 °C

Procedure:
A solution of 280 mg AZT, 310 mg N-(3-bromopropyl)-phthalimide (BPP) and 300 ul of sodium methoxide solution (4.4M NaOMe in MeOH) in 1 ml DMPU was heated at 70° C. for one hour, then 145 mg BPP and 300 ul NaOMe solution was added and the mixture heated for another hour at 70° C. Another 175 mg BPP was added and heating was continued for a total of 4hours at 70° C. The reaction mixture was diluted with 10 volumes deionized water, acidified with 200 ul HOAc and extracted into EtOAc. The organic phase was washed with 5% NaHCO3, deionized water, 0.1M HOAc and saturated NaCl, then concentrated and chromatographed by preparative TLC on silica gel-F 2000 um using the solvent system CHCl3 /MeOH/HOAc(96.7+3.3+0.33). The product (Rf =0.35) was eluted with MeOH. It was immunologically active in an AZT assay by FPIA.
Reaction SMILES: C(OC(=O)[CH:5]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=1[Cl:23])[C:6]([C:8]1[CH:13]=[N:12][C:11]([CH3:14])=[CH:10][N:9]=1)=[O:7])C.[Cl-].[Na+].O.CS(C)=O>C(OCC)(=O)C>[Cl:23][C:16]1[CH:17]=[C:18]([O:21][CH3:22])[CH:19]=[CH:20][C:15]=1[CH2:5][C:6]([C:8]1[CH:13]=[N:12][C:11]([CH3:14])=[CH:10][N:9]=1)=[O:7]
Reactant: CCOC(=O)C(C(=O)c1cnc(C)cn1)c1ccc(OC)cc1Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: O
Product: COc1ccc(CC(=O)c2cnc(C)cn2)c(Cl)c1
Yield: 66.9 %

Procedure:
A mixture of 2-(2-chloro-4-methoxy-phenyl)-3-(5-methyl-pyrazin-2-yl)-3-oxo-propionic acid ethyl ester (700 mg, 2 mmol), sodium chloride (130 mg), water (55 mg) and DMSO (10 mL) was heated for 5 h to 140° C. Upon cooling, the reaction mixture was taken up in ethyl acetate and washed (water, brine). The organic layer was dried (Na2SO4), and the solvent was evaporated. Purification of the residue by column chromatography (silica gel, heptane:ethyl acetate=100:0-80:20) gave the title compound (370 mg, 67%). 1H NMR (300 MHz, CDCl3) 9.13 (1H, s), 8.54 (1H, s), 7.18 (1H, d), 6.97 (1H, d), 6.70 (1H, dd), 4.57 (2H, s), 3.80 (3H, s), 2.68 (3H, s); MS (m/e)=277.0 [MH+].
Reaction SMILES: [O:1]1CCO[CH:2]1[C:6]1[CH:7]=[C:8]([N:17]2[CH2:22][CH2:21][N:20]([CH:23]([CH3:25])[CH3:24])[CH2:19][CH2:18]2)[CH:9]=[C:10]([O:12][C:13]([F:16])([F:15])[F:14])[CH:11]=1.C(O)=O>O>[CH:23]([N:20]1[CH2:19][CH2:18][N:17]([C:8]2[CH:7]=[C:6]([CH:11]=[C:10]([O:12][C:13]([F:16])([F:15])[F:14])[CH:9]=2)[CH:2]=[O:1])[CH2:22][CH2:21]1)([CH3:25])[CH3:24]
Reactant: CC(C)N1CCN(c2cc(OC(F)(F)F)cc(C3OCCO3)c2)CC1
Solvent: O
Solvent: O=CO
Product: CC(C)N1CCN(c2cc(C=O)cc(OC(F)(F)F)c2)CC1
Temperature: 60 °C
Yield: 69.6 %

Procedure:
Water (1.3 mL) was added to a suspension of 1-(3-(1,3-dioxolan-2-yl)-5-(trifluoromethoxy)phenyl)-4-isopropylpiperazine (22, 996 mg, 2.76 mmol) and formic acid (6.71 g, 145 mmol). The mixture was heated to 60° C. for 20 h. The reaction mixture was concentrated to a brown oil in vacuo. The oil was dissolved in EtOAc (100 mL) and the solution was washed with saturated aq. NaHCO3 solution (100 mL) and brine (100 mL). After drying over Na2SO4, the suspension was filtered and the filtrate concentrated to an orange oil. The residue was purified by silica gel chromatography eluting with 0-80% EtOAc in hexanes to afford the title compound (608 mg, 70%) as an orange oil: 1H NMR (500 MHz, CDCl3) δ 9.92 (s, 1H), 6.93 (s, 1H), 7.31 (s, 1H), 7.13 (s, 1H), 6.92 (s, 1H), 3.30-3.28 (m, 4H), 2.73 (sept, 1H), 2.70-2.64 (m, 4H), 1.10 (d, J=6.5 Hz, 6H).
Reaction SMILES: [O:1]([CH2:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15]O)=[N:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:37]>>[Cl:37][CH2:15][C:12]1[CH:11]=[CH:10][C:9]([CH2:8][O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:14][N:13]=1
Reactant: ClC(Cl)(Cl)Cl
Reactant: OCc1ccc(COc2ccccc2)cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: ClCc1ccc(COc2ccccc2)cn1
Temperature: 25 °C

Procedure:
To a solution of carbon tetrachloride (20 mL) of a known compound (5-phenoxymethyl-pyridin-2-yl)-methanol (1.4 g) was added triphenylphosphine (2.1 g) at room temperature, which was heated to reflux for 6 hours and 15 minutes under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, after which the solvent was evaporated under a reduced pressure. The residue was purified by silica gel column chromatography (heptane:ethyl acetate=2:1) to obtain the titled compound (1.3 g).
Reaction SMILES: [C:1]([C:5]1[C:16]([O:17][CH3:18])=[CH:15][C:8]([CH2:9][NH:10][S:11]([CH3:14])(=[O:13])=[O:12])=[C:7](B2OC(C)(C)C(C)(C)O2)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:28]([O:35][C:36]1[C:41](Br)=[CH:40][CH:39]=[C:38]([CH3:43])[N:37]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C([O-])([O-])=O.[Na+].[Na+]>CO.C(Cl)Cl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:28]([O:35][C:36]1[C:41]([C:7]2[CH:6]=[C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])[C:16]([O:17][CH3:18])=[CH:15][C:8]=2[CH2:9][NH:10][S:11]([CH3:14])(=[O:12])=[O:13])=[CH:40][CH:39]=[C:38]([CH3:43])[N:37]=1)[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: COc1cc(CNS(C)(=O)=O)c(B2OC(C)(C)C(C)(C)O2)cc1C(C)(C)C
Reactant: Cc1ccc(Br)c(OCc2ccccc2)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COc1cc(CNS(C)(=O)=O)c(-c2ccc(C)nc2OCc2ccccc2)cc1C(C)(C)C
Yield: 27.9 %

Procedure:
step 2—A sealed tube containing 72 (51 mg, 0.13 mmol), 2-benzyloxy-3-bromo-6-methyl-pyridine (51 mg, 0.19 mmol), Na2CO3 (40 mg, 0.38 mmol) and Pd(PPh3)4 (15 mg, 0.013 mmol) in a mixture of MeOH (3 mL) and DCM (1 mL) was irradiated in a microwave synthesizer at 125° C. for 30 min. The reaction mixture was diluted with DCM, filtered through a pad of CELITE, and the filtrate was concentrated. The crude residue was purified on a preparative SiO2 TLC plate developed with 5% MeOH/DCM to afford 17 mg (28%) of N-[2-(2-benzyloxy-6-methyl-pyridin-3-yl)-4-tert-butyl-5-methoxy-benzyl]-methanesulfonamide (74).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([N+:13]([O-])=O)=[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH3:11])[N:5]2[N:4]=1.[ClH:16]>>[ClH:16].[CH3:1][O:2][C:3]1[C:12]([NH2:13])=[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH3:11])[N:5]2[N:4]=1
Reactant: COc1nn2c(C)cccc2c1[N+](=O)[O-]
Agent: Cl
Product: COc1nn2c(C)cccc2c1N

Procedure:
Added dropwise were 10 ml of 35% hydrochloric acid and then, in portions, 1.8 g of 2-methoxy-7-methyl-3-nitropyrazolo[1,5-a]pyridine.
Reaction SMILES: Br[C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:11]3([CH2:15][CH2:14][N:13]([CH:16]4[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]4)[C:12]3=[O:22])[CH2:10][C@@H:9]([OH:23])[CH2:8]2)=[CH:4][CH:3]=1.O1CCOCC1.CN[C@H]1CCCC[C@@H]1NC.[F:42][C:43]([F:50])([F:49])[C:44]1[CH:48]=[CH:47][NH:46][N:45]=1>[Cu]I>[CH:16]1([N:13]2[CH2:14][CH2:15][C:11]3([N:7]([CH2:6][C:5]4[CH:24]=[CH:25][C:2]([N:46]5[CH:47]=[CH:48][C:44]([C:43]([F:50])([F:49])[F:42])=[N:45]5)=[CH:3][CH:4]=4)[CH2:8][C@H:9]([OH:23])[CH2:10]3)[C:12]2=[O:22])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: O=C1N(C2CCCCC2)CCC12C[C@@H](O)CN2Cc1ccc(Br)cc1
Reactant: FC(F)(F)c1cc[nH]n1
Agent: [Cu]I
Agent: CN[C@H]1CCCC[C@@H]1NC
Solvent: C1COCCO1
Product: O=C1N(C2CCCCC2)CCC12C[C@@H](O)CN2Cc1ccc(-n2ccc(C(F)(F)F)n2)cc1
Temperature: 100 °C
Reaction time: 16 h

Procedure:
To a solution of (3R)-1-(4-bromobenzyl)-7-cyclohexyl-3-hydroxy-1,7-diazaspiro[4.4]nonan-6-one (25.0 mg, 0.0000614 mol; prepared as in Example 37) in 1,4-dioxane (0.8 mL, 0.01 mol) was added (1S,2S)—N,N′-dimethylcyclohexane-1,2-diamine (1.7 mg, 0.000012 mol), copper(I) iodide (1.2 mg, 0.0000061 mol), and 3-(trifluoromethyl)-1H-pyrazole (17 mg, 0.00012 mol). After stirring the resulting mixture at 100° C. for 16 h, the crude reaction mixture was purified by prep.-HPLC under pH=10 conditions to afford the desired product. LC-MS: 463.2 (M+1H)+.
Reaction SMILES: [C:1]([O:5][CH:6]([C:11]1[C:12]([C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[O:27][CH2:26][CH2:25][CH2:24]3)=[C:13]2[CH:20]=[CH:19][NH:18][C:14]2=[N:15][C:16]=1[CH3:17])[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].[F:31][C:32]1[CH:39]=[CH:38][CH:37]=[C:36]([O:40][CH3:41])[C:33]=1[CH2:34]Br>>[C:1]([O:5][CH:6]([C:11]1[C:12]([C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[O:27][CH2:26][CH2:25][CH2:24]3)=[C:13]2[CH:20]=[CH:19][N:18]([CH2:34][C:33]3[C:36]([O:40][CH3:41])=[CH:37][CH:38]=[CH:39][C:32]=3[F:31])[C:14]2=[N:15][C:16]=1[CH3:17])[C:7]([OH:9])=[O:8])([CH3:2])([CH3:4])[CH3:3]
Reactant: COc1cccc(F)c1CBr
Reactant: COC(=O)C(OC(C)(C)C)c1c(C)nc2[nH]ccc2c1-c1ccc2c(c1)CCCO2
Product: COc1cccc(F)c1Cn1ccc2c(-c3ccc4c(c3)CCCO4)c(C(OC(C)(C)C)C(=O)O)c(C)nc21

Procedure:
The title compound was prepared in a manner similar to that described in Example 27, Step H from methyl 2-(tert-butoxy)-2-(4-(chroman-6-yl)-6-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)acetate and 2-fluoro-6-methoxybenzyl bromide. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.48-7.40 (m, 1 H), 7.32-7.28 (m, 1 H), 7.26-7.17 (m, 1 H), 7.04-6.99 (m, 1 H), 6.90 (dd, J=6.3, 8.3 Hz, 1 H), 6.78-6.69 (m, 2 H), 6.16-6.09 (m, 1 H), 5.62-5.55 (m, 2 H), 5.50-5.42 (m, 1 H), 4.30-4.24 (m, 2 H), 3.83 (d, J=1.8 Hz, 3 H), 2.94-2.78 (m, 2 H), 2.78-2.71 (m, 3 H), 2.07-2.03 (m, 2 H), 1.01-0.93 (s, 9 H); LC/MS (m/z) ES+=533.37 (M+1).
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5](/[CH:7]=[CH:8]/[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[N:4][CH:3]=1>CO.[Pd]>[CH3:1][C:2]1[S:6][C:5]([CH2:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[N:4][CH:3]=1
Reactant: CCOC(=O)/C=C/c1ncc(C)s1
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)CCc1ncc(C)s1
Yield: 99.4 %

Procedure:
To a solution of (E)-ethyl 3-(5-methylthiazol-2-yl)acrylate (200 mg, 1.01 mmol,) in methanol (5 mL) was added 5% Pd/C (20 mg). The reaction was purged with nitrogen and then hydrogen and then was stirred under a hydrogen atmosphere (balloon). The reaction was filtered. The filtrate was concentrated to give ethyl 3-(5-methylthiazol-2-yl)propanoate (200 mg, 99% yield) as a light yellow oil. LCMS retention time 1.33 min; LCMS MH+ 200.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]#[C:6][C:7]1[CH:8]=[N:9][CH:10]=[C:11]([S:13]([CH3:16])(=[O:15])=[O:14])[CH:12]=1)[CH3:2].[C:18]([O:22][C:23]([N:25]1[C:34]2[C:29](=[CH:30][CH:31]=[C:32]([CH2:35][CH2:36][O:37][C:38]3[CH:39]=[C:40]4[C:44](=[CH:45][CH:46]=3)[NH:43][CH:42]=[CH:41]4)[N:33]=2)[CH2:28][CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19]>>[C:18]([O:22][C:23]([N:25]1[C:34]2[C:29](=[CH:30][CH:31]=[C:32]([CH2:35][CH2:36][O:37][C:38]3[CH:39]=[C:40]4[C:44](=[CH:45][CH:46]=3)[N:43]([C:6]([C:7]3[CH:8]=[N:9][CH:10]=[C:11]([S:13]([CH3:16])(=[O:14])=[O:15])[CH:12]=3)=[CH:5][C:4]([O:3][CH2:1][CH3:2])=[O:17])[CH:42]=[CH:41]4)[N:33]=2)[CH2:28][CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: CCOC(=O)C#Cc1cncc(S(C)(=O)=O)c1
Reactant: CC(C)(C)OC(=O)N1CCCc2ccc(CCOc3ccc4[nH]ccc4c3)nc21
Product: CCOC(=O)C=C(c1cncc(S(C)(=O)=O)c1)n1ccc2cc(OCCc3ccc4c(n3)N(C(=O)OC(C)(C)C)CCC4)ccc21
Yield: 80 %

Procedure:
The title compound was synthesized from (5-methanesulfonyl-pyridin-3-yl)-propynoic acid ethyl ester and 7-[2-(1H-indol-5-yloxy)-ethyl]-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid tert-butyl ester using the procedure described in Example 16, step (d1), in 80% yield. Mass Spectrum (LCMS, ESI) calculated for C29H31N4O5S: 547.2 (M-Boc+H); found 547.3 (−Boc).