Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]([CH3:36])([CH3:35])[C@H:9]2[C@:22]([CH3:25])([CH2:23][CH:24]=1)[C@@H:21]1[C@:12]([CH3:34])([C@@:13]3([CH3:33])[C@H:18]([CH2:19][CH2:20]1)[C@H:17]1[C@H:26]([C:29]([CH3:31])=[CH2:30])[CH2:27][CH2:28][C@:16]1([NH2:32])[CH2:15][CH2:14]3)[CH2:11][CH2:10]2)(=O)=O.[CH3:39][C:40]1[CH:45]=[C:44](B2OC(C)(C)C(C)(C)O2)[CH2:43][CH2:42][C:41]=1[C:55]([O:57][CH2:58][CH3:59])=[O:56]>>[NH2:32][C@:16]12[CH2:28][CH2:27][C@@H:26]([C:29]([CH3:31])=[CH2:30])[C@@H:17]1[C@@H:18]1[C@@:13]([CH3:33])([CH2:14][CH2:15]2)[C@@:12]2([CH3:34])[C@@H:21]([C@:22]3([CH3:25])[C@@H:9]([CH2:10][CH2:11]2)[C:8]([CH3:35])([CH3:36])[C:7]([C:44]2[CH2:43][CH2:42][C:41]([C:55]([O:57][CH2:58][CH3:59])=[O:56])=[C:40]([CH3:39])[CH:45]=2)=[CH:24][CH2:23]3)[CH2:20][CH2:19]1
Reactant: CCOC(=O)C1=C(C)C=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: C=C(C)[C@@H]1CC[C@]2(N)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(OS(=O)(=O)C(F)(F)F)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Product: C=C(C)[C@@H]1CC[C@]2(N)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(C6=CC(C)=C(C(=O)OCC)CC6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12

Procedure:
The title compound was prepared following the method for the preparation of Example 1, Step 1 described above, using (1R,3aS,5aR,5bR,7aR,11aR,11bR,13aR,13bR)-3a-amino-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 trifluoromethanesulfonate and ethyl 2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohexa-1,3-dienecarboxylate as reactants. MS: m/e 557.4 (M−16)+, 2.47 min (method 2). 1H NMR (400 MHz, CHLOROFORM-d) δ 5.65 (s, 1H), 5.28 (d, J=5.8 Hz, 1H), 4.72 (s, 1H), 4.59 (s, 1H), 4.25-4.16 (m, 2H), 2.62-2.48 (m, 1H), 2.48-2.34 (m, 2H), 2.31-2.17 (m, 2H), 2.15 (s, 3H), 2.09-1.97 (m, 2H), 1.80-1.35 (m, 17H), 1.35-1.18 (m, 9H), 1.18-1.04 (m, 6H), 1.02-1.00 (s, 3H), 0.96 (s, 3H), 0.89 (s, 3H).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:15][CH:14]2[CH:10]([CH2:11][N:12]([CH2:16][C:17]3[S:25][C:24]4[C:23]([N:26]5[CH2:31][CH2:30][O:29][CH2:28][CH2:27]5)=[N:22][C:21]([Cl:32])=[N:20][C:19]=4[CH:18]=3)[CH2:13]2)[CH2:9]1)=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O.C[Si]([N:44]=C=O)(C)C>C(Cl)Cl>[Cl:32][C:21]1[N:22]=[C:23]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[C:24]2[S:25][C:17]([CH2:16][N:12]3[CH2:13][CH:14]4[CH2:15][N:8]([C:6]([NH2:44])=[O:7])[CH2:9][CH:10]4[CH2:11]3)=[CH:18][C:19]=2[N:20]=1
Reactant: C[Si](C)(C)N=C=O
Reactant: CC(C)(C)OC(=O)N1CC2CN(Cc3cc4nc(Cl)nc(N5CCOCC5)c4s3)CC2C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)N1CC2CN(Cc3cc4nc(Cl)nc(N5CCOCC5)c4s3)CC2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.1 %

Procedure:
To a solution of 5-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-butyl ester (250 mg, 0.52 mmol) in DCM (4.5 mL) was added TFA (0.5 mL). The reaction mixture stirred at RT for 1 h, then loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH then eluted with 2 M NH3 in MeOH, and concentrated in vacuo. The resultant residue was dissolved in DCM (5 mL) and trimethylsilyl isocyanate (139 μL, 1.0 mmol) was added. The reaction mixture was stirred at RT for 1 h, then partitioned between DCM and a saturated aqueous solution of NaHCO3. The organic layer was separated and washed with brine, then dried (Na2SO4) and concentrated in vacuo to give the title compound as a colourless oil (185 mg, 84%).
Reaction SMILES: [CH3:1][Si:2]([CH3:29])([CH3:28])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[C:11]2[N:12]=[CH:13][N:14]=[C:15]([C:16]3[CH:17]=[N:18][N:19]([C@H:21]4[CH2:26][CH2:25][C@H:24]([OH:27])[CH2:23][CH2:22]4)[CH:20]=3)[C:10]=2[CH:9]=[CH:8]1.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>C(Cl)Cl>[CH3:30][S:31]([O:27][C@H:24]1[CH2:23][CH2:22][C@H:21]([N:19]2[CH:20]=[C:16]([C:15]3[C:10]4[CH:9]=[CH:8][N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:29])([CH3:28])[CH3:1])[C:11]=4[N:12]=[CH:13][N:14]=3)[CH:17]=[N:18]2)[CH2:26][CH2:25]1)(=[O:33])=[O:32]
Reactant: CS(=O)(=O)Cl
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn([C@H]4CC[C@H](O)CC4)c3)ncnc21
Solvent: ClCCl
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn([C@H]4CC[C@H](OS(C)(=O)=O)CC4)c3)ncnc21
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To trans-4-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclohexanol (154 mg, 0.372 mmol) was added DCM (1.0 mL) and TEA (73 μL, 0.52 mmol). The resulting solution was then cooled to 0° C. and methanesulfonyl chloride (34 μL, 0.45 mmol) was added. The reaction was held for 2 hours, at which point tlc and LCMS indicated complete reaction. The reaction was partitioned between water and DCM, the phases were separated and the aqueous phase was extracted with additional solvent. The combined organic phase was washed with water, then saturated NaCl, then was dried over MgSO4 and reduced in vacuo to give the crude product which was used without further purification (173 mg, 95%). 1H NMR (400 MHz, CDCl3): δ 8.83 (s, 1H), 8.24 (s, 2H), 8.24 (s, 1H), 7.39 (d, 1H), 6.80 (d, 1H), 5.67 (s, 2H), 4.77 (m, 1H), 4.27 (m, 1H), 3.54 (m, 2H), 3.06 (s, 3H), 2.36 (m, 4H), 2.03 (m, 2H), 1.82 (m, 2H), 1.53 (m, 2H), 0.92 (m, 2H), −0.06 (s, 9H). MS (EI) m/z=492.1 (M+H).
Reaction SMILES: [Cl:1][CH2:2]C(=O)CC1SC=CC=1.[S:11]1[CH:15]=[C:14]([CH2:16][C:17]([OH:19])=O)[C:13]2[CH:20]=[CH:21][CH:22]=[CH:23][C:12]1=2.S(Cl)(Cl)=O>>[S:11]1[CH:15]=[C:14]([CH2:16][C:17](=[O:19])[CH2:2][Cl:1])[C:13]2[CH:20]=[CH:21][CH:22]=[CH:23][C:12]1=2
Reactant: O=C(O)Cc1csc2ccccc12
Reactant: O=C(CCl)Cc1cccs1
Solvent: O=S(Cl)Cl
Product: O=C(CCl)Cc1csc2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 56 %

Procedure:
The procedure described above for the synthesis of 1-chloro-3-(thiophen-2-yl)propan-2-one was followed. To prepare the acid chloride, 2-(benzo[b]thiophen-3-yl)acetic acid (1.00 g, 5.20 mmol) was added to 6 mL thionyl chloride in a 25 mL round-bottomed flask. The mixture was stirred overnight at room temperature, and the thionyl chloride then removed in vacuo and the residue azeotroped twice with toluene. The acid chloride was then reacted with diazomethane and HCl. The crude product was purified by flash chromatography over silica gel (2-30% ethyl acetate in hexanes) to give pure material (0.661 g, 56% yield): 1H NMR (400 MHz, CDCl3) δ 4.12 (s, 2H) 4.14 (d, J=1.0 Hz, 2H) 7.36-7.44 (m, 3H) 7.67-7.71 (m, 1H) 7.87-7.90 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][N:11]=2)[CH:7]=[C:6](I)[CH:5]=1.[CH:19]([C:22]1[NH:23][CH:24]=[CH:25][N:26]=1)([CH3:21])[CH3:20].C([O-])([O-])=O.[K+].[K+]>CS(C)=O.O.[Cu]I>[CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][N:11]=2)[CH:7]=[C:6]([N:23]2[CH:24]=[CH:25][N:26]=[C:22]2[CH:19]([CH3:21])[CH3:20])[CH:5]=1
Reactant: COC(=O)c1cc(I)cc(-c2ccc(C)cn2)c1
Reactant: CC(C)c1ncc[nH]1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)c1cc(-c2ccc(C)cn2)cc(-n2ccnc2C(C)C)c1
Temperature: 100 °C
Yield: 56.7 %

Procedure:
To a solution of 3-iodo-5-(5-methyl-pyridin-2-yl)-benzoic acid methyl ester (500 mg, 1.42 mmol) in DMSO (10 ml) was added 2-Isopropylimidazole (312 mg, 2.83 mmol), CuI (54 mg, 0.283 mmol), N,N′-dimethylglycine HCl salt (79 mg, 0.567 mmol) and K2CO3 (391 mg, 2.83 mmol) under N2 atmosphere. The mixture was heated to 100° C. overnight. After cooling to room temperature, the mixture was diluted with H2O (15 ml). The mixture was extracted with EtOAc. The combined organic layers were washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure. The residue was purified by flash chromatography (30%-75% EtOAc in hexanes) to afford 3-(2-isopropyl-imidazol-1-yl)-5-(5-methyl-pyridin-2-yl)-benzoic acid methyl ester as an off-white solid (270 mg, 57%).
Reaction SMILES: C(OC([NH:8][C@@H:9]1[CH2:16][N:15]2[C:17]3[CH:18]=[C:19]([C:30]([O:32][CH3:33])=[O:31])[CH:20]=[CH:21][C:22]=3[C:23]([CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)=[C:14]2[C:13]2[CH:34]=[CH:35][CH:36]=[CH:37][C:12]=2[O:11][CH2:10]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[NH2:8][C@@H:9]1[CH2:16][N:15]2[C:17]3[CH:18]=[C:19]([C:30]([O:32][CH3:33])=[O:31])[CH:20]=[CH:21][C:22]=3[C:23]([CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)=[C:14]2[C:13]2[CH:34]=[CH:35][CH:36]=[CH:37][C:12]=2[O:11][CH2:10]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)C[C@@H](NC(=O)OC(C)(C)C)COc1ccccc1-3
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)C[C@@H](N)COc1ccccc1-3
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
Methyl (7R)-7-[(tert-butoxycarbonyl)amino]-14-cyclohexyl-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxylate (0.14 M) in DCM was treated with TFA (10 eq) and stirred at RT for 1 h. The reaction was diluted with DCM and cautiously basified with aq. NaHCO3, before separating the phases and extracting the aqueous with DCM. The combined organics were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to afford the product as an off-white foam (100%) that was used without further purification. (ES+) m/z 405 (M+H)+; [α]D, +42.3, c=1, MeOH
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:10]=[C:11]2[C:15](=[O:16])[C:14]3[CH:17]=[CH:18][C:19]([OH:21])=[CH:20][C:13]=3[O:12]2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[C:22](Cl)(=[O:25])[CH2:23][CH3:24].C(OCC)(=O)C>N1C=CC=CC=1>[CH3:1][C:2]1[CH:3]=[C:4]([CH:10]=[C:11]2[C:15](=[O:16])[C:14]3[CH:17]=[CH:18][C:19]([O:21][C:22](=[O:25])[CH2:23][CH3:24])=[CH:20][C:13]=3[O:12]2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(C=C2Oc3cc(O)ccc3C2=O)cc1C
Reactant: CCC(=O)Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CCC(=O)Oc1ccc2c(c1)OC(=Cc1ccc(OC)c(C)c1)C2=O
Temperature: 25 °C

Procedure:
After 2-[(3-methyl-4-methoxyphenyl)methylene]-6-hydroxy-3(2H)-benzofuranone 0.525 g was dissolved in pyridine 5 ml, propionyl chloride 0.218 ml was added, and the mixture was refluxed for 1.5 hours. The reaction mixture was cooled to room temperature, ethyl acetate 50 ml was added, and the mixture was washed with 2N-hydrochloric acid 50 ml, saturated salt solution 50 ml, saturated sodium bicarbonate solution 50 ml, and saturated sodium chloride solution 50 ml. The ethyl acetate solution was dehydrated with anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was fractionated by silica gel column chromatography (silica gel: 50 g, eluted with solvent 350 ml of hexane:ethyl acetate=1:1) and concentrated to dryness at a temperature of 40° C. under reduced pressure to obtain crystals. The crystals were recrystallized with ethyl acetate 2 ml/hexane 5 ml and filtered. The crystals were dried over phosphorous pentoxide at a temperature of 60° C. for five hours under reduced pressure to obtain the desired compound 322.9 mg.
Reaction SMILES: [NH2:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4].[F:7][C:8]1[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:9]=1[C:10](Cl)=[O:11]>C(Cl)Cl.O>[F:7][C:8]1[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:9]=1[C:10]([NH:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4])=[O:11]
Reactant: O=C(Cl)c1c(F)cccc1F
Reactant: CC(C)(N)CO
Solvent: O
Solvent: ClCCl
Product: CC(C)(CO)NC(=O)c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.9 %

Procedure:
To a 0° C. solution of 2-amino-2-methylpropanol (10.1 g, 113.3 mmol) in CH2Cl2 (75 mL) under nitrogen was added dropwise a solution of 2,6-difluorobenzoyl chloride (10.0 g, 56.6 mmol) in CH2Cl2 (50 mL). The reaction mixture was then warmed to room temperature and stirred overnight. The reaction mixture was diluted with H2O, and the aqueous phase was extracted with CH2Cl2, dried (MgSO4) and concentrated. Purification via trituration with hexanes afforded 12.05 g (93%) of the amide, a white solid. 1H NMR (400 MHz, CDCl3) δ 1.41 (s, 6 H), 3.66-3.75 (m, 2 H), 3.77-3.87 (m, 1 H), 5.94 (s, 1 H), 6.90-6.99 (m, 2 H), 7.31-7.41 (m, 1 H).
Reaction SMILES: [C:1]1([C@H:7]([CH3:11])[C:8]([OH:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)(O)[O-].[Na+].[CH2:17](O)[CH3:18]>S(=O)(=O)(O)O>[C:1]1([C@H:7]([CH3:11])[C:8]([O:10][CH2:17][CH3:18])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCO
Reactant: C[C@H](C(=O)O)c1ccccc1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCOC(=O)[C@@H](C)c1ccccc1
Yield: 84 %

Procedure:
To a solution consisting of (S)-2-phenylpropanoic acid (1.0 g, 6.7 mmol, from Chem-Impex) in ethanol (30 mL) was added concentrated sulfuric acid (4 drops). The reaction mixture was stirred at reflux overnight in a vessel equipped with a Dean-Stark condenser. To the mixture was added solid sodium bicarbonate and the resulting mixture was filtered and concentrated under vacuum to afford the title compound (1.0 g, 84%) as a colorless oil; TLC Rf 0.5 (solvent system: 15:85:1 v/v/v ethyl acetate-heptane-acetic acid). The product was carried directly onto the next step without further purification.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:23][CH:24]2[CH2:26][CH2:25]2)[C:5]2[C:10]([C:11]#[N:12])=[CH:9][N:8](S(C3C=CC(C)=CC=3)(=O)=O)[C:6]=2[N:7]=1.[NH2:27][C:28]1[CH:33]=[CH:32][C:31]([N:34]2[CH2:39][CH2:38][N:37]([C:40](=[O:42])[CH3:41])[CH2:36][CH2:35]2)=[CH:30][CH:29]=1.C[Si](Cl)(C)C>C(O)CCC>[C:40]([N:37]1[CH2:36][CH2:35][N:34]([C:31]2[CH:32]=[CH:33][C:28]([NH:27][C:2]3[N:3]=[C:4]([NH:23][CH:24]4[CH2:25][CH2:26]4)[C:5]4[C:10]([C:11]#[N:12])=[CH:9][NH:8][C:6]=4[N:7]=3)=[CH:29][CH:30]=2)[CH2:39][CH2:38]1)(=[O:42])[CH3:41]
Reactant: Cc1ccc(S(=O)(=O)n2cc(C#N)c3c(NC4CC4)nc(Cl)nc32)cc1
Reactant: CC(=O)N1CCN(c2ccc(N)cc2)CC1
Agent: C[Si](C)(C)Cl
Solvent: CCCCO
Product: CC(=O)N1CCN(c2ccc(Nc3nc(NC4CC4)c4c(C#N)c[nH]c4n3)cc2)CC1
Temperature: 135 °C
Reaction time: 20 h
Yield: 15.5 %

Procedure:
A mixture of 2-chloro-4-(cyclopropylamino)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile (150 mg, 0.387 mmol), 1-(4-(4-aminophenyl)piperazin-1-yl)ethanone (132 mg, 0.602 mmol) and trimethylsilyl chloride (0.200 mL, 1.58 mmol) in nBuOH (4 mL) was stirred at 135° C. for 20 h. It was concentrated in vacuo. The residue was purified by HPLC to give the titled compound (25 mg). MS 417.4 (M+H); UV 203.4, 254.0, 291.5 nm.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5](O)=[O:6].B.C1COCC1.C1COCC1.O.[Cl-].[NH4+]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH2:5][OH:6])[CH:8]=[CH:9][C:10]=1[CH3:11]
Reactant: Cc1ccc(C(=O)O)cc1Br
Agent: B
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(CO)cc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 102.3 %

Procedure:
15 g (70 mmol) of 3-bromo-4-methylbenzoic acid are placed in 150 ml of anhydrous THF in a round-bottomed flask and under a stream of nitrogen. 84 ml of 1M borane/THF are added dropwise and the reaction medium is stirred overnight at room temperature. A THF/water (50/50) solution is added slowly at 0° C. and the mixture is then poured into saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic phase is dried over magnesium sulfate, filtered and then evaporated. 14.4 g (100%) of the expected product are obtained in the form of a yellow oil.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH:10]([NH:12][C:13](=[O:15])[CH3:14])[CH3:11])=[CH:5][CH:4]=1)#[CH:2].[Cl:16][C:17]1[N:22]=[CH:21][C:20](I)=[CH:19][N:18]=1.CCN(C(C)C)C(C)C>C1COCC1.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.[Cu]I>[Cl:16][C:17]1[N:22]=[CH:21][C:20]([C:2]#[C:1][C:3]2[CH:8]=[CH:7][C:6]([CH2:9][CH:10]([NH:12][C:13](=[O:15])[CH3:14])[CH3:11])=[CH:5][CH:4]=2)=[CH:19][N:18]=1
Reactant: Clc1ncc(I)cn1
Reactant: C#Cc1ccc(CC(C)NC(C)=O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)NC(C)Cc1ccc(C#Cc2cnc(Cl)nc2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To 1.20 g (5.96 mmol) N-(1-(4-ethynylphenyl)propan-2-yl)acetamide (I58.3) in 10 mL THF are added 1.43 g (5.96 mmol) 2-chloro-5-iodopyrimidine, 418 mg (0.60 mmol) bis(triphenylphosphine)dichloropalladium, 56.8 mg (0.30 mmol) CuI and 2.03 mL (11.9 mmol) DIPEA. The reaction mixture is stirred at r.t. for 4 h. The solvent is removed in vacuo and the residue is purified by column chromatography (silica gel, DCM/MeOH 98/2).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]([C:12]1[C:13]([Cl:19])=[N:14][C:15]([Br:18])=[CH:16][CH:17]=1)O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(S(F)(F)[F:26])CC)C>C(Cl)Cl>[CH2:1]([O:8][CH2:9][CH:10]([C:12]1[C:13]([Cl:19])=[N:14][C:15]([Br:18])=[CH:16][CH:17]=1)[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: OC(COCc1ccccc1)c1ccc(Br)nc1Cl
Solvent: ClCCl
Product: FC(COCc1ccccc1)c1ccc(Br)nc1Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 31.7 %

Procedure:
To a solution of 2-(benzyloxy)-1-(6-bromo-2-chloropyridin-3-yl)ethanol (1.54 g, 4.49 mmol) in DCM (10 mL) at 0° C. was added diethylaminosulfur trifluoride (0.594 ml, 4.49 mmol). The resulting mixture was stirred at 0° C. for 30 min, then warmed to RT and stirred for 1 h. The mixture was concentrated in vacuo and the resulting residue purified using column chromatography (eluted with 0-20% ethyl acetate/hexane) to provide 3-(2-(benzyloxy)-1-fluoroethyl)-6-bromo-2-chloropyridine (490 mg, yield: 32%)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:9][C:10]2[C:15]([C:16](=[O:18])[CH:17]=1)=[C:14]([O:19]C)[CH:13]=[C:12]([O:21]C)[C:11]=2[C@@H:23]1[CH2:27][CH2:26][N:25]([CH3:28])[C@H:24]1[C:29]([OH:31])=[O:30].Cl.N1C=CC=CC=1>O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:9][C:10]2[C:15]([C:16](=[O:18])[CH:17]=1)=[C:14]([OH:19])[CH:13]=[C:12]([OH:21])[C:11]=2[C@@H:23]1[CH2:27][CH2:26][N:25]([CH3:28])[C@H:24]1[C:29]([OH:31])=[O:30]
Reactant: COc1cc(OC)c2c(=O)cc(-c3ccccc3Cl)oc2c1[C@@H]1CCN(C)[C@H]1C(=O)O
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: CN1CC[C@@H](c2c(O)cc(O)c3c(=O)cc(-c4ccccc4Cl)oc23)[C@@H]1C(=O)O
Temperature: 180 °C

Procedure:
Compound of example 143 (0.25 g, 0.563 mmol) was treated with pyridine hydrochloride (2.5 g, 21 mmol) and the reaction mixture was further heated at 180° C. for 2 h. Water (1 mL) was added after completion of the reaction and reaction mixture was purified on HP-20 column using water as eluant, followed by methanol and water in the ratio 70:30 to obtain the title compound.
Reaction SMILES: [OH:1][C:2]1[C:7]([O:8][CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][O:10]2)=[CH:6][CH:5]=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16].C(=O)([O-])[O-].[K+].[K+].Br[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27]>C(C(C)=O)C>[CH2:29]([O:28][C:26]([CH2:25][O:1][C:2]1[C:7]([O:8][CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][O:10]2)=[CH:6][CH:5]=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16])=[O:27])[CH3:30]
Reactant: CCOC(=O)CBr
Reactant: O=[N+]([O-])c1cccc(OC2CCCCO2)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)COc1c(OC2CCCCO2)cccc1[N+](=O)[O-]

Procedure:
A mixture of 38.4 g of 2-hydroxy-3-(tetrahydropyran-2-yloxy)-nitrobenzene, 22.2 g of potassium carbonate and 27.0 g of ethyl bromoacetate in 400 ml of methyl ethyl ketone is heated to the reflux temperature for 16 hours, whilst stirring, and then filtered; the filter residue is rinsed with 100 ml of methyl ethyl ketone. The combined filtrates are evaporated under reduced pressure. The residual yellowish oil is taken up in 400 ml of diethyl ether, the solution is clarified by filtration, with the addition of 2 g of an active charcoal formulation and the filtrate is evaporated under reduced pressure. The residual oil solidifies after some time to give a mass of crystals and gives 2-ethoxycarbonylmethoxy-3-(tetrahydropyran-2-yloxy)-nitrobenzene; melting point 65°-66°.
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9](=[O:18])[NH:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[C:24]#[N:25].[H-].[Na+]>CN(C)C=O>[C:1]1([C:7]2[NH:8][C:9](=[O:18])[N:10]([CH2:20][C:21]3[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=3)[C:24]#[N:25])[C:11]=2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: N#Cc1cccc(CBr)c1
Reactant: O=c1[nH]c(-c2ccccc2)c(-c2ccccc2)[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1cccc(Cn2c(-c3ccccc3)c(-c3ccccc3)[nH]c2=O)c1

Procedure:
In a manner similar to Preparation 1 above, 2,3-dihydro-4,5-diphenyl-1H-imidazol-2-one (1.2 g, 5 mmol) was reacted with 3-(bromomethyl)benzonitrile (0.39 g, 2 mmol) and sodium hydride (0.18 g, 5 mmol) in dimethylformamide (20 mL) to give 3-[(2,3-dihydro-4,5-diphenyl-2-oxo-1H-imidazol-1-yl)methyl]benzonitrile after chromatography on silica; NMR (DMSO-d6) 11.02 (s,1), 7.4 (m,4), 7.3 (m,2), 7.2 (m,7), 4.75 (s,2) ppm.
Reaction SMILES: [O:1]([NH:8][C:9](=O)[CH:10]=[CH:11][S:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)(Cl)Cl>C1(C)C=CC=CC=1>[O:1]([N:8]=[C:9]([S:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH:10]=[CH:11][S:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(C=CSc1ccccc1)NOc1ccccc1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: C(=CC(=NOc1ccccc1)Sc1ccccc1)Sc1ccccc1
Reaction time: 2.5 h
Yield: 41.8 %

Procedure:
N-phenoxy-3-(phenylthio)acrylamide (0.50 g) was suspended to toluene (5 ml), then phosphorus pentachloride (0.42 g) was added thereto under ice-cooling and stirred at same temperature for 2.5 hours. The reaction mixture was concentrated under reduced pressure. The residue was dissolved to ethanol (15 ml). Sodium salt of thiophenol (0.73 g) was added to the solution under ice-cooling and heat refluxing for 2.5 hours. t-Butyl methyl ether (100 ml) was added to the reaction mixture, washed successively with 1N aqueous sodium hydroxide solution, water and aqueous saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered off inorganic salt and concentrated under reduced pressure. The residue was purified by medium pressure preparative high performance liquid chromatography (hexane:ethyl acetate=30:11) to obtain phenyl N-(phenoxy)-3-(phenylthio)thioacrylimidate (0.14 g) as yellow oil.
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH:12]=O)=[CH:4]1)[CH3:2].[N+:14]([CH3:17])([O-:16])=[O:15].C([O-])(=O)C.[NH4+].C(OC(=O)C)C>CCCCCC>[CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH:12]=[CH:17][N+:14]([O-:16])=[O:15])=[CH:4]1)[CH3:2]
Reactant: CCn1cc(C=O)c2ccccc21
Reactant: C[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCn1cc(C=C[N+](=O)[O-])c2ccccc21
Temperature: 25 °C
Yield: 74.3 %

Procedure:
1-Ethyl-1H-indole-3-carbaldehyde (I-38b: 5.2 g, 29.885 mmol), nitromethane (46.81 mL, 866.66 mmol) and ammonium acetate (1.17 g, 15.241 mmol) were taken in a reaction flask. The flask was refluxed for 16 hours under nitrogen atmosphere. The reaction was monitored by TLC (25% ethylacetate in hexane). The reaction mixture was cooled to room temperature and the reaction mixture was partitioned between water and ethylacetate. The organic layer was washed with water, brine solution, dried over Na2SO4 and concentrated to afford 4.8 g of the product (75% yield).