Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: OC1C(=O)NN=C(CCC2C=CC=CC=2)C=1.C([O:24][C:25]1[N:26]=[N:27][C:28]([C:39]#[C:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=2[C:47]([F:50])([F:49])[F:48])=[CH:29][C:30]=1[O:31]CC1C=CC=CC=1)C1C=CC=CC=1>>[OH:31][C:30]1[C:25](=[O:24])[NH:26][N:27]=[C:28]([CH2:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=2[C:47]([F:49])([F:48])[F:50])[CH:29]=1
Reactant: FC(F)(F)c1ccccc1C#Cc1cc(OCc2ccccc2)c(OCc2ccccc2)nn1
Agent: O=c1[nH]nc(CCc2ccccc2)cc1O
Product: O=c1[nH]nc(CCc2ccccc2C(F)(F)F)cc1O

Procedure:
Prepared by the same method as for 4-hydroxy-6-(2-phenylethyl)pyridazin-3(2H)-one (Example 1) from 3,4-bis(benzyloxy)-6-((2-trifluoromethylphenyl)ethynyl)pyridazine (Intermediate 40) except that the final product was recrystallised from a mixture of ethyl acetate and heptane.
Reaction SMILES: [C:1]1([O:7][C:8]([N:10]2[CH:23]([C:24]#[CH:25])[C:22]34[O:26][C:17]3([CH:18]([O:27][Si](CC)(CC)CC)[CH2:19][CH2:20][CH2:21]4)[C:16]3[CH:15]=[C:14]([O:35][CH2:36][C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=4[N+:43]([O-:45])=[O:44])[CH:13]=[CH:12][C:11]2=3)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(S)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>C1COCC1.C(OCC)C>[C:1]1([O:7][C:8]([N:10]2[CH:23]([C:24]#[CH:25])[C:22]34[O:26][C:17]3([CH:18]([OH:27])[CH2:19][CH2:20][CH2:21]4)[C:16]3[CH:15]=[C:14]([O:35][CH2:36][C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=4[N+:43]([O-:45])=[O:44])[CH:13]=[CH:12][C:11]2=3)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C#CC1N(C(=O)Oc2ccccc2)c2ccc(OCc3ccccc3[N+](=O)[O-])cc2C23OC12CCCC3O[Si](CC)(CC)CC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: C#CC1N(C(=O)Oc2ccccc2)c2ccc(OCc3ccccc3[N+](=O)[O-])cc2C23OC12CCCC3O
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 88.2 %

Procedure:
A solution of Compound 325 (45.27 g, 72.3 mmol) and tert-butylthiol (5.70 mL, 50.6 mmol) in THF (250 mL) was treated at zero degrees C with tetra-n-butylammonium fluoride (TBAF, 75.9 mL, 1.0M solution in THF, 75.9 mmol). The reaction mixture was stirred at 20° C. for 30 minutes, diluted with ethyl ether (750 mL), poured into water (1500 mL), and separated. The organic layer was washed with water (2×2000 mL), dried over anhydrous MgSO4, and evaporated in vacuo. The residue was purified by suspending it in hot acetonitrile (500 mL), cooling to 10° C., and filtering. The white solid was washed with acetonitrile (100 mL) and ethyl ether (200 mL) to give 32.70 g (88 percent) of Compound 326: white crystalline solid (about 3:1 mixture of diastereomers as determined by 1H NMR); mp 207°-209° C. (acetonitrile); Rf =0.46 (silica, 10 percent ethyl acetate in dichloromethane); IR (CHCl3) νmax 3469, 3196, 2950, 2922, 1689, 1521, 1495, 1386 cm-1 ; 1H NMR (500 MHz, DMSO-d6) δ 8.13 (dd, J=7.8, 1.2 Hz, 1 H, aromatic), 7.84 (br dd, J=7.8, 1.2 Hz, 1 H, aromatic), 7.79 (td, J=7.8, 1.2 Hz, 1 H, aromatic), 7.63 (td, J=7.8, 1.2 Hz, 1 H, aromatic), 7.60 (d, J=2.7 Hz, 1 H, H1, major isomer), 7.55 (d, J=2.7 Hz, 1 H, H1, minor isomer), 7.49-7.13 (m, 6 H, aromatic), 7.04 (dd, J=8.8, 2.7 Hz, 1 H, H3, major isomer), 7.01 (dd, J=8.8, 2.7 Hz, 1 H, H3, minor isomer), 5.65-5.44 (m, 2 H, benzylic; 1 H, OH; 1 H, H6, minor isomer), 5.31 (m, 1 H, H6, major isomer), 4.67 (br s, 1 H, H10, minor isomer), 4.48 (dt, J=9.0, 6.5 Hz, 1 H, H10, major isomer), 2.27 (dd, J=14.1, 6.7 Hz, 1 H, CH2, minor isomer), 2.22 (dd, J=14.8, 5.4 Hz, 1 H, CH2, major isomer), 1.80-1.20 (m, 5 H, CH2); 13CNMR (125 MHz, DMSO-d6) δ 155.6, 153.3, 150.8, 147.6, 134.0, 132.2, 129.5, 129.4, 129.3, 128.5, 128.2, 125.8, 124.8, 121.7, 115.8, 115.4, 114.1, 78.5, 76.0, 72.8, 67.0 and 66.7, 66.0, 62.4 and 60.2, 47.5, 29.1 and 27.3, 25.1 and 23.7, 22.4 and 19.8; MS (FAB+) m/e (rel intensity) 513 (M+H, 100), 391 (86); HRMS for C27H25N2O7 (M+H), calcd 513.1662, found 513.1662. Anal. Calcd for C29H24N2O7 : C, 67.96; H, 4.72; N, 5.47. Found: C, 67.71; H, 4.84; N, 5.36.
Reaction SMILES: [C:1]([O:5][C:6](=[O:42])[N:7]([C:30]1[CH:35]=[CH:34][C:33]([N:36]2[CH2:41][CH2:40][O:39][CH2:38][CH2:37]2)=[CH:32][CH:31]=1)[C:8]1[C:9]2[N:10]([N:27]=[CH:28][N:29]=2)[C:11]([Sn](CCCC)(CCCC)CCCC)=[CH:12][N:13]=1)([CH3:4])([CH3:3])[CH3:2].Br[C:44]1[CH:45]=[C:46]2[C:51](=[CH:52][CH:53]=1)[C:50](=[O:54])[NH:49][CH2:48][CH2:47]2>CN(C=O)C.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>[C:1]([O:5][C:6](=[O:42])[N:7]([C:30]1[CH:35]=[CH:34][C:33]([N:36]2[CH2:37][CH2:38][O:39][CH2:40][CH2:41]2)=[CH:32][CH:31]=1)[C:8]1[C:9]2[N:10]([N:27]=[CH:28][N:29]=2)[C:11]([C:44]2[CH:45]=[C:46]3[C:51](=[CH:52][CH:53]=2)[C:50](=[O:54])[NH:49][CH2:48][CH2:47]3)=[CH:12][N:13]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C1NCCc2cc(Br)ccc21
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc(N(C(=O)OC(C)(C)C)c2ccc(N3CCOCC3)cc2)c2ncnn12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(c1ccc(N2CCOCC2)cc1)c1ncc(-c2ccc3c(c2)CCNC3=O)n2ncnc12
Temperature: 90 °C
Reaction time: 8 h
Yield: 37 %

Procedure:
To a degassed solution of (4-morpholin-4-yl-phenyl)-(5-tributylstannanyl-[1,2,4]triazolo[1,5-a]pyrazin-8-yl)-carbamic acid tert-butyl ester (100 mg, 0.15 mmol) and 6-bromo-3,4-dihydro-2H-isoquinolin-1-one in DMF (1 mL) is added tetrakis(triphenylphosphine)palladium(0) (17 mg, 0.015 mmol) and the reaction mixture is stirred at 90° C. overnight. After removing the solvent in vacuo, the residue is purified by silica gel column chromatography. Elution with 1:1 petroleum ether:ethyl acetate and ethyl acetate affords the target compound as a yellow solid (30 mg, 37%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([O:14][CH2:15][C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18](Br)[CH:17]=2)[C@@H:9]1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:33][N:34]1[C:38]([Sn](CCCC)(CCCC)CCCC)=[CH:37][N:36]=[N:35]1>C1(C)C=CC=CC=1.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>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([O:14][CH2:15][C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([C:38]3[N:34]([CH3:33])[N:35]=[N:36][CH:37]=3)[CH:17]=2)[C@@H:9]1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnnn1C
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](OCc2cc(Br)cc(C(F)(F)F)c2)[C@@H]1c1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: Cn1nncc1-c1cc(CO[C@H]2CCCN(C(=O)OC(C)(C)C)[C@H]2c2ccccc2)cc(C(F)(F)F)c1
Temperature: 25 °C
Yield: 99.6 %

Procedure:
Bis(triphenylphosphine)palladium dichloride (5.0 mg) was added to a degassed solution of [2S,3S]-1-tert-butoxycarbonyl-2-phenyl-3-[3-bromo-5-(trifluoromethyl)phenylmethoxy]piperidine (330 mg), and 1-methyl-5-tributylstannanyl-1H-[1,2,3]triazole (713 mg) in dry toluene (15.0 ml) under a dry nitrogen atmosphere. The resulting solution was warmed to reflux for 4 hours. After this time the reaction was cooled to room temperature and the solvent removed under reduced pressure. The residue was partitioned between aqueous NaHCO3 solution (10 ml, satd.) and ethyl acetate. The organic layer was washed with brine (10 ml), dried over MgSO4, filtered and the solvent removed under pressure. Purification by MPLC (1:1 ethyl acetate/n-hexane) afforded [2S,3S]-1-tert-butoxycarbonyl-2-phenyl-3-[3-(1-methyl-1H-[1,2,3]triazol-5-yl)-5-(trifluoromethyl)phenylmethoxy]piperidine as a yellow foam (330 mg). 1H NMR (360 MHz,CDCl3) δ 1.45 (9H, s), 1.74 (2H, m), 2.00 (2H, m), 2.75 (1H, t d, J=7.2, 3.0 Hz), 3.91 (2H,m), 4.03 (3H, s), 4.74 (2H, s), 5.71 (1H, br s), 7.27-7.33 (3H, m), 7.44-7.62 (5H, m), 7.75 (1H, s).
Reaction SMILES: C([NH:4][C:5]1[NH:6][C:7](=[O:33])[C:8]([CH2:18][CH2:19][CH2:20][NH:21][C:22]2[CH:32]=[CH:31][C:25]([C:26]([O:28]CC)=[O:27])=[CH:24][CH:23]=2)=[C:9]([N:11](C(=O)C)C(=O)C)[N:10]=1)(=O)C.[OH-].[Na+]>C(O)C>[NH2:4][C:5]1[NH:6][C:7](=[O:33])[C:8]([CH2:18][CH2:19][CH2:20][NH:21][C:22]2[CH:32]=[CH:31][C:25]([C:26]([OH:28])=[O:27])=[CH:24][CH:23]=2)=[C:9]([NH2:11])[N:10]=1
Reactant: CCOC(=O)c1ccc(NCCCc2c(N(C(C)=O)C(C)=O)nc(NC(C)=O)[nH]c2=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1nc(N)c(CCCNc2ccc(C(=O)O)cc2)c(=O)[nH]1
Temperature: 70 °C
Yield: 77.2 %

Procedure:
To a solution of 0.22 g (0.47 mmol) of ethyl 4-[3-[2-(acetylamino)-4-(diacetylamino)-1,6-dihydro-6-oxo-5-pyrimidinyl]propylamino]benzoate in 7.0 ml of 95% ethyl alcohol was added 15 ml of 1.0N NaOH. The reaction was heated at 70° C. for 20 hours. The mixture was reduced by spin evaporation in vacuo to a 10-ml volume and adjusted to pH 5 with 1.0N HCl. The precipitate was collected by filtration, washed with water, and dried in vacuo to yield 0.11 g (71% of theory) of 4-[3-(2,4-diamino-1,6-dihydro-6-oxo-5-pyrimidinyl)propylamino]benzoic acid one-half sodium salt as a white solid, mp 273° (dec.); HPLC on Versapack C-18 (10 micron; 4.6×250 mm) with aqueous 60% methanol containing 0.2% trifluoroacetic acid gave one major peak, k1 =0.58; NMR (DMSO-d6) δ 1.58 (m, 2H, CCH2C), 2.24 (t, 2H, Het--CH2), 3.02 (m, 2H, CH2N), 5.77 (br s, 2H, NH2), 5.94 (br s, 2H, NH2), 6.46 (t, 1H, NH--Ar), 6.54 (d, 2H, Ar), 7.65 (d, 2H, Ar), 9.80 (br s, 1H, NH), 11.95 (br s, 0.5 H, CO2H). Elemental analysis. Calculated for C14H16N5O3Na0.5.0.75 H2O (MW 327.82); C, 51.29; H, 5.53; N, 21.36; Na, 3.51. Found: C, 51.34; H, 5.39; N, 21.32; Na, 3.33.
Reaction SMILES: [OH-].[Na+].[O:3]1[CH:5]([CH2:6]Cl)[CH2:4]1.[C:8]1([CH:14]([C:27]2[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=2)[CH:15]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)[C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>CO>[O:3]1[CH2:4][CH:5]1[CH2:6][O:33][C:30]1[CH:31]=[CH:32][C:27]([CH:14]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:15]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)[C:16]([F:17])([F:18])[F:19])=[CH:28][CH:29]=1
Reactant: ClCC1CO1
Reactant: Oc1ccc(C(c2ccccc2)C(c2ccc(Cl)cc2)C(F)(F)F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: FC(F)(F)C(c1ccc(Cl)cc1)C(c1ccccc1)c1ccc(OCC2CO2)cc1
Reaction time: 2 h
Yield: 64.1 %

Procedure:
0.8 g (20 mmoles) of sodium hydroxide and 14.8 g (160 mmoles) of 1,2-epoxy-3-chloropropane are added to a solution of 6.03 g (16 mmoles) of 1-phenyl-3,3,3-trifluoro-1-(4-hydroxyphenyl)-2-(4-chlorophenyl)-propane in 60 ml of methanol. The mixture is boiled for 2 hours and then processed as described in Example 25. The product is crystallized from methanol. 4.44 g (64%) of the aimed compound are obtained; m.p.: 141°-144° C.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[N:14]=[N:13][C:12]([NH:15][NH2:16])=[CH:11][C:10]=1[CH:17]([CH3:19])[CH3:18].[N:20]#[C:21]Br.C(=O)([O-])[O-].[K+].[K+]>C(O)C.O.CCO.O>[Cl:8][C:9]1[C:10]([CH:17]([CH3:19])[CH3:18])=[CH:11][C:12]2[N:13]([C:21]([NH2:20])=[N:16][N:15]=2)[N:14]=1
Reactant: CC(C)c1cc(NN)nnc1Cl
Reactant: N#CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Product: CC(C)c1cc2nnc(N)n2nc1Cl
Reaction time: 8 h

Procedure:
(6-Chloro-5-isopropylpyridazin-3-yl)hydrazine trifluoroacetic acid salt (W3.013; 400 mg) was initially charged in ethanol/water (6/1 ml) at RT while stirring. Thereafter, cyanogen bromide (353 mg, dissolved in a mixture of 1 ml of EtOH and 0.5 ml of water) was cautiously added dropwise. After stirring for 5 hours, the mixture was left to stand overnight and stirred for a further day. After standing overnight, the solvent was drawn off and the residue was admixed with water. Once the residue had been alkalized with saturated potassium carbonate solution, it was extracted three times with dichloromethane. The combined organic phases were dried over sodium sulfate and, after filtering off the desiccant, dried under reduced pressure. 400 mg of the title compound were obtained in sufficient purity.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[N+:10]([O-])=O.[H][H]>CO.[Pd]>[NH2:10][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:2]=1[OH:1])[C:6]#[N:7]
Reactant: N#Cc1ccc(O)c([N+](=O)[O-])c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: N#Cc1ccc(O)c(N)c1
Yield: 100.2 %

Procedure:
A solution of 4-hydroxy-3-nitrobenzonitrile (10 g, 61 mmol) in MeOH (200 mL) was treated with hydrogen gas through a balloon in the presence of 5% Pd on active carbon (0.5 g) at room temperature for 24 hours. The mixture was filtered, and the filtrate was concentrated to give the product (8.2 g, 100%).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][O:9]2)=[CH:4][C:3]=1B1OC(C)(C)C(C)(C)O1.[C:21]([O:25][C@@H:26]([C:31]1[C:32](I)=[C:33]2[CH:40]=[CH:39][N:38]([CH2:41][C:42]3[CH:47]=[CH:46][C:45]([F:48])=[C:44]([F:49])[CH:43]=3)[C:34]2=[N:35][C:36]=1[CH3:37])[C:27]([O:29]C)=[O:28])([CH3:24])([CH3:23])[CH3:22]>>[C:21]([O:25][C@@H:26]([C:31]1[C:32]([C:3]2[CH:4]=[C:5]3[C:10](=[CH:11][C:2]=2[F:1])[O:9][CH2:8][CH2:7][CH2:6]3)=[C:33]2[CH:40]=[CH:39][N:38]([CH2:41][C:42]3[CH:47]=[CH:46][C:45]([F:48])=[C:44]([F:49])[CH:43]=3)[C:34]2=[N:35][C:36]=1[CH3:37])[C:27]([OH:29])=[O:28])([CH3:24])([CH3:22])[CH3:23]
Reactant: CC1(C)OB(c2cc3c(cc2F)OCCC3)OC1(C)C
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2c(ccn2Cc2ccc(F)c(F)c2)c1I
Product: Cc1nc2c(ccn2Cc2ccc(F)c(F)c2)c(-c2cc3c(cc2F)OCCC3)c1[C@H](OC(C)(C)C)C(=O)O

Procedure:
The title compound was prepared from 2-(7-fluorochroman-6-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane and (S)-methyl 2-(tert-butoxy)-2-(1-(3,4-difluorobenzyl)-4-iodo-6-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)acetate in a manner similar to that described in Example 87. The crude acid was recrystallized from an isopropanol/water mixture to give the title compound as a single isomer. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm=7.36 (d, J=8.2 Hz, 1 H), 7.16-6.96 (m, 4 H), 6.68 (d, J=11.1 Hz, 1 H), 6.16 (s., 1 H), 5.57-5.45 (m, 2 H), 5.30 (d, J=15.2 Hz, 1 H), 4.26 (t, J=5.1 Hz, 2 H), 2.87-2.75 (m, 2 H), 2.71 (s, 3 H), 2.05 (d, J=4.9 Hz, 2 H), 1.02 (s, 9 H); LCMS (m/z) ES+=539 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1.[OH-].[K+].Br[CH2:19][C:20]1([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)[O:24][CH2:23][CH2:22][O:21]1.O>CN1C(=O)CCC1>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:19][C:20]3([C:25]4[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=4)[O:21][CH2:22][CH2:23][O:24]3)[C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1
Reactant: CN1CCc2[nH]c3ccc(Cl)cc3c2C1
Reactant: Clc1ccc(C2(CBr)OCCO2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN1CCCC1=O
Product: CN1CCc2c(c3cc(Cl)ccc3n2CC2(c3ccc(Cl)cc3)OCCO2)C1
Temperature: 100 °C
Reaction time: 0.08 h

Procedure:
8-Chloro-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (1 g, 4.4 mmol) was dissolved in 10 mL of NMP. KOH (1.77 g, 31.78 mmol) was added at RT under nitrogen atmosphere and the reaction mixture was stirred for 5 min. 2-Bromomethyl-2-(4-chlorophenyl)-1,3-dioxolane (1.68 mg, 6.81 mmol) was added and the reaction mixture was heated at 100° C. for 3 h. Water was added and the product was extracted with EtOAc. The organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 0-2% MeOH:DCM.
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][C:6]([C:11]([C:13]3[CH:14]=[C:15]([NH:19][C:20]([C:22]4[CH:23]=[N:24][N:25]([CH3:28])[C:26]=4[CH3:27])=[O:21])[CH:16]=[CH:17][CH:18]=3)=[O:12])=[CH:7][CH:8]=2)[NH:3]1.[CH:29](OCC)=[O:30].[O-]CC.[Na+]>C(O)C>[OH:30][CH:29]=[C:10]1[C:9]2[C:4](=[CH:5][C:6]([C:11]([C:13]3[CH:14]=[C:15]([NH:19][C:20]([C:22]4[CH:23]=[N:24][N:25]([CH3:28])[C:26]=4[CH3:27])=[O:21])[CH:16]=[CH:17][CH:18]=3)=[O:12])=[CH:7][CH:8]=2)[NH:3][C:2]1=[O:1]
Reactant: CCOC=O
Reactant: Cc1c(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4)c2)cnn1C
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: Cc1c(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CO)c2)cnn1C
Temperature: 78 °C
Yield: 74 %

Procedure:
1,5-Dimethyl-1H-pyrazole-4-carboxylic acid [3-(2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (0.172 g, 0.4594 mmol) and ethyl formate (0.111 mL, 1.37 mmol) were dissolved in anhydrous ethanol (5 mL). The resulting solution was treated in dropwise fashion with a 21 wt % solution of sodium ethoxide in ethanol (0.86 mL, 2.3 mmol). This reaction mixture was heated at 78° C. for 0.5 h, producing a black oil. Subsequently, the reaction mixture was cooled to room temperature, and then the reaction pH was adjusted to pH 1 with dropwise addition of 1M HCH(aq) causing the formation of a brown precipitate. The suspension was filtered and the solids were washed with 0° C. EtOH to afford the pure 1,5-Dimethyl-1H-pyrazole-4-carboxylic acid [3-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (0.136 g, 0.34 mmol, 74%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]1[NH:16][C:15]([C@@H:17]3[CH2:22][C@@H:21]4[C@@H:19]([CH2:20]4)[N:18]3[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[N:14][CH:13]=1)[CH:6]=[CH:5]2.[C:30]([C:32]1[NH:36][C:35]([C@@H:37]2[CH2:42][C@@H:41]3[C@@H:39]([CH2:40]3)[N:38]2[C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])=[N:34][CH:33]=1)#[CH:31].C(N(CC)CC)C>CN(C=O)C.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>[C:46]([O:45][C:43]([N:38]1[C@H:37]([C:35]2[NH:34][CH:33]=[C:32]([C:30]#[C:31][C:2]3[CH:3]=[C:4]4[C:9](=[CH:10][CH:11]=3)[CH:8]=[C:7]([C:12]3[N:16]=[C:15]([C@@H:17]5[CH2:22][C@@H:21]6[C@@H:19]([CH2:20]6)[N:18]5[C:23]([O:25][C:26]([CH3:28])([CH3:27])[CH3:29])=[O:24])[NH:14][CH:13]=3)[CH:6]=[CH:5]4)[N:36]=2)[CH2:42][C@@H:41]2[C@H:39]1[CH2:40]2)=[O:44])([CH3:49])([CH3:48])[CH3:47]
Reactant: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H]2C[C@H]1c1ncc(-c2ccc3cc(Br)ccc3c2)[nH]1
Reactant: C#Cc1cnc([C@@H]2C[C@H]3C[C@H]3N2C(=O)OC(C)(C)C)[nH]1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H]2C[C@H]1c1nc(C#Cc2ccc3cc(-c4c[nH]c([C@@H]5C[C@H]6C[C@H]6N5C(=O)OC(C)(C)C)n4)ccc3c2)c[nH]1
Temperature: 50 °C
Yield: 104.5 %

Procedure:
Nitrogen was bubbled through a solution of (1R,3S,5R)-tert-butyl 3-(5-(6-bromonaphthalen-2-yl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate (400 mg, 0.880 mmol), (1R,3S,5R)-tert-butyl 3-(5-ethynyl-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate (313 mg, 1.14 mmol) and Cu(I)I (8.4 mg, 0.044 mmol) in triethylamine (0.37 mL, 2.6 mmol) and DMF (8 mL) for 10 min. Then Pd(PPh3)4 (50.9 mg, 0.044 mmol) was added, nitrogen was bubbled through the reaction mixture for 1 min, and then the flask was sealed and heated at 50° C. for 16 h. The reaction was concentrated to under high vacuum) and the residual solids were triturated with EtOAc (˜5 mL) and collected by filtration (rinsing with EtOAc and hexanes) to yield tert-butyl(1R,3S,5R)-3-(4-(6-((2-((1R,3S,5R)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-imidazol-4-yl)ethynyl)-2-naphthyl)-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate (595 mg) as a light yellow solid. The material was used without further purification. LC-MS retention time 3.140 min; m/z 647.35 (MH+). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a PHENOMENEX® Luna 3u C18 2.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 0.8 mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 4 min, a hold time of 1 min, and an analysis time of 5 min where Solvent A was 10% MeOH/90% H2O/0.1% trifluoroacetic acid and Solvent B was 10% H2O/90% MeOH/0.1% trifluoroacetic acid. MS data was determined using a MICROMASS® Platform for LC in electrospray mode.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([C:13]3[CH:18]=[CH:17][C:16]([C@@H:19]4[O:24][CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20]4)=[CH:15][CH:14]=3)=[N:10][N:9]=2)=[CH:4][CH:3]=1.[ClH:32].CCOCC>O1CCOCC1>[ClH:32].[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([C:13]3[CH:14]=[CH:15][C:16]([C@@H:19]4[O:24][CH2:23][CH2:22][NH:21][CH2:20]4)=[CH:17][CH:18]=3)=[N:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(-c3nnc(-c4ccc(F)cc4)o3)cc2)C1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: Fc1ccc(-c2nnc(-c3ccc([C@H]4CNCCO4)cc3)o2)cc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 84 %

Procedure:
(S)-tert-Butyl 2-(4-(5-(4-fluorophenyl)-1,3,4-oxadiazol-2-yl)phenyl)morpholine-4-carboxylate (45 mg, 0.105 mmol) was dissolved in dioxane (1 ml) and a solution of HCl in dioxane (4M, 0.317 ml, 1.27 mmol) was added. The reaction mixture was stirred for 2 h at 60° C. After cooling ether (2 ml) was added and the solid was filtered off. It was washed with ether and dried in vacuo to afford (S)-2-(4-(5-(4-fluorophenyl)-1,3,4-oxadiazol-2-yl)phenyl)morpholine hydrochloride (32 mg, 84%) as a white solid. MS (ISP): 326.1 ([M+H]+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][C:16]=2[NH2:22])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:23]([O:25][C:26]([O:40][CH2:41][CH3:42])([CH3:39])[C:27](OC1C=CC([N+]([O-])=O)=CC=1)=[O:28])[CH3:24]>CN(C1C=CN=CC=1)C.C(#N)C.C(OCC)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][C:16]=2[NH:22][C:27](=[O:28])[C:26]([O:40][CH2:41][CH3:42])([O:25][CH2:23][CH3:24])[CH3:39])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(C)(OCC)C(=O)Oc1ccc([N+](=O)[O-])cc1
Reactant: Cc1ccc(NC2CCN(C(=O)OC(C)(C)C)CC2)c(N)c1
Agent: CN(C)c1ccncc1
Solvent: CCOCC
Solvent: CC#N
Product: CCOC(C)(OCC)C(=O)Nc1cc(C)ccc1NC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 80 °C
Yield: 61.8 %

Procedure:
4-(2-Amino-4-methyl-phenylamino)-piperidine-1-carboxylic acid tert-butyl ester (400 mg, 1.31 mmol), p-nitrophenyl 2,2-diethoxyproprionate (1.00 g, 3.50 mmol), and DMAP (1.00 g, 8.2 mmol) were combined in acetonitrile (3 mL) and heated in an oil bath at 80° C. for 2 h. The mixture was cooled, diluted with diethyl ether (100 mL), washed once each with saturated aqueous NH4Cl and water, three times with 5% aqueous sodium hydroxide solution, once with brine and dried over anhydrous MgSO4 and concentrated under reduced pressure. The residue was adsorbed on a silica gel pad, and the pad was eluted with 25% ethyl acetate in hexanes to give 4-[2-(2,2-diethoxy-propionylamino)-4-methyl-phenylamino]-piperidine-1-carboxylic acid tert-butyl ester (550 mg, 0.81 mmol, 62%) of a pale yellow oil.
Reaction SMILES: P(Br)(Br)[Br:2].[F:5][C:6]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:15]O>C(OCC)C>[Br:2][CH2:15][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]([N+:12]([O-:14])=[O:13])[C:6]=1[F:5]
Reactant: BrP(Br)Br
Reactant: O=[N+]([O-])c1cccc(CO)c1F
Solvent: CCOCC
Product: O=[N+]([O-])c1cccc(CBr)c1F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 70 %

Procedure:
A solution of phosphorus tribromide (4.8 mL) in anhydrous diethylether (100 mL) was added at 0° C. to a solution of (2-fluoro-3-nitrophenyl)methanol (compound 2c-1) (7.52 g, 46.3 mmol) in anhydrous diethylether (130 mL), and the mixture was stirred at 30 minutes at 0° C. The reaction mixture was then poured into ice water and extracted with ethyl acetate. The organic extract was washed in series with saturated sodium hydrogen carbonate solution, water and saturated saline, and dried over magnesium sulfate. The title compound (7.10 g, 70%) was then obtained as a brown oil.