Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7](Cl)=[O:8].[F:10][C:11]([F:24])([F:23])[O:12][C:13]1[CH:22]=[CH:21][C:16]([C:17](=[N:19]O)[NH2:18])=[CH:15][CH:14]=1.N1C=CC=CC=1.O>O1CCOCC1>[Cl:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]1[O:8][N:19]=[C:17]([C:16]2[CH:15]=[CH:14][C:13]([O:12][C:11]([F:10])([F:23])[F:24])=[CH:22][CH:21]=2)[N:18]=1
Reactant: NC(=NO)c1ccc(OC(F)(F)F)cc1
Reactant: O=C(Cl)c1sccc1Cl
Solvent: O
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: FC(F)(F)Oc1ccc(-c2noc(-c3sccc3Cl)n2)cc1
Temperature: 25 °C
Yield: 74.3 %

Procedure:
A solution of 3-chloro-thiophene-2-carbonyl chloride (72.4 mg, 0.4 mmol) and 4-trifluoromethoxybenzamidoxime (88 mg, 0.4 mmol) in dioxane:pyridine (11 mL, 10:1) was refluxed for 10 h and cooled to room temperature. To the stirred solution was added 20 mL of water to produce precipitates. The solid was collected by filtration and washed with dioxane:water (1:3), and dried to yield 103 mg (75%) of the title compound. 1H NMR (CDCl3): 8.20 (d, J=9.0 Hz, 2H), 7.62 (d, J=5.4 Hz, 1H), 7.35 (bd, J=9.3 Hz, 2H), 7.14 (d, J=5.1 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH:10][C:11]([NH2:13])=[O:12])=[CH:5][CH:4]=1.N1C=CC=CC=1.[CH3:20][O:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1.C(OCC)(=O)C.O1CCCC1>C1(C)C=CC=CC=1.O>[CH3:20][O:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([N:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[NH:10][C:11]([NH2:13])=[O:12])=[O:27])=[CH:24][CH:23]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: COc1ccc(NNC(N)=O)cc1
Solvent: Cc1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(C(=O)N(NC(N)=O)c2ccc(OC)cc2)cc1
Reaction time: 1 h
Yield: 61.9 %

Procedure:
To a suspension of 2-(4-methoxyphenyl)hydrazinecarboxamide (1.81 g, 9.99 mmol) in 20 mL of toluene, pyridine (1.01 mL, 12.5 mmol) and then a solution of 4-methoxybenzoyl chloride (2.13 g, 12.5 mmol) in 10 mL of toluene were added. The mixture was refluxed with stirring for 1 hour. After cooling, 500 mL of ethyl acetate-tetrahydrofuran (9:1) and 100 mL of water were added to the mixture. After vigorous shaking, an insoluble material was isolated by filtration and dired in vacuo to give 2-(4-methoxybenzoyl)-2-(4-methoxyphenyl)hydrazinecarboxamide (1.95 g, 61.9% yield).
Reaction SMILES: [I:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([N+:9]([O-])=O)=[CH:4][N:3]=1.[OH-].[Na+]>Cl.C(OCC)C.ClCCl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[I:1][C:2]1[N:3]=[CH:4][C:5]([NH2:9])=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cc(I)ncc1[N+](=O)[O-]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: Cc1cc(I)ncc1N
Temperature: 100 °C
Reaction time: 4 h
Yield: 57.5 %

Procedure:
To a solution of 1.76 g of 2-iodo-4-methyl-5-nitropyridine in 7.0 mL of concentrated hydrochloric acid and 7.0 mL of diethyl ether was added 6.32 g of tin chloride (II) at room temperature, and stirred at 100° C. for 4 hours. After cooling the solution to room temperature, 5N sodium hydroxide aqueous solution was added to make the solution alkaline. Then the solution was diluted with dichloromethane and the insoluble substances were filtered off through Celite. The organic layer of the filtrate was dried over anhydrous magnesium sulfate, and the solvent was evaporated, to afford 897 mg of the title compound as orange-brown crystals.
Reaction SMILES: [Al].[Li].[H-].[Cl:4][C:5]1[CH:6]=[CH:7][C:8]2[N:14]3[C:15]([CH3:22])=[C:16]([C:18](OC)=[O:19])[N:17]=[C:13]3[CH2:12][N:11]=[C:10]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[F:29])[C:9]=2[CH:30]=1.[OH-].[Na+]>O1CCCC1.O>[Cl:4][C:5]1[CH:6]=[CH:7][C:8]2[N:14]3[C:15]([CH3:22])=[C:16]([CH2:18][OH:19])[N:17]=[C:13]3[CH2:12][N:11]=[C:10]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[F:29])[C:9]=2[CH:30]=1
Reactant: COC(=O)c1nc2n(c1C)-c1ccc(Cl)cc1C(c1ccccc1F)=NC2
Agent: [Al]
Agent: [H-]
Agent: [Li]
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(CO)nc2n1-c1ccc(Cl)cc1C(c1ccccc1F)=NC2
Reaction time: 1 h
Yield: 20 %

Procedure:
3.3 ml of a 1M lithium aluminium, hydride solution in tetrahydrofuran was cooled to −75° C. and a solution of 1.26 g of methyl 8-chloro -6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,2-a][1,4]benzodiazepine-2-carboxylate in 15 ml of tetrahydrofuran was added dropwise. After 1 h. in a dry ice/acetone bath the mixture was brought to 0° C. and left for a further h. For the working up, 0.1 ml of water was added dropwise at 0° C. while stirring intensively, 0.1 ml of 15% sodium hydroxide solution was added after 5 min., finally 0.3 ml of water was added after a further 10 min. After 12 h. the mixture was filtered, the residue was suspended in 100 ml of methanol, stirred well for 1 h. and filtered. The combined filtrates were concentrated in a vacuum and purified by chromatography on 80 g of silica gel with dichloromethane containing 5% methanol. There were obtained 234 mg (20%) of 8-chloro-6-(2-fluoro-phenyl)-1-methyl-4H-imidazo[1,2-a][1,4]benzodiazepine-2-methanol. For the preparation of the methanesulphonic acid salt, 230 mg of this product were dissolved in 10 ml of dichloromethane and 6.0 ml of a 0.1M methanesulphonic acid solution in diethyl ether were slowly added dropwise. After removal of the solvent in a vacuum the residue was taken up in 10 ml of water, filtered and lyophilized. There were isolated 183 mg of hygroscopic 8-chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo-[1,2-a][1,4]benzodiazepine-2-methanol methanesulphonate (1:2) of m.p. 116° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:17])=[C:6]([C@:8]2([CH3:16])[C@@H:13]([F:14])[CH2:12][O:11][C:10]([NH2:15])=[N:9]2)[CH:7]=1.[Cl:18][C:19]1[C:20]([C:26](O)=[O:27])=[N:21][CH:22]=[C:23]([Cl:25])[CH:24]=1>>[NH2:15][C:10]1[O:11][CH2:12][C@H:13]([F:14])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:26]([C:20]3[C:19]([Cl:18])=[CH:24][C:23]([Cl:25])=[CH:22][N:21]=3)=[O:27])[CH:3]=[CH:4][C:5]=2[F:17])([CH3:16])[N:9]=1
Reactant: O=C(O)c1ncc(Cl)cc1Cl
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)OC[C@@H]1F
Product: C[C@]1(c2cc(NC(=O)c3ncc(Cl)cc3Cl)ccc2F)N=C(N)OC[C@@H]1F

Procedure:
The condensation of (4R,5R)-4-(5-amino-2-fluoro-phenyl)-5-fluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate A8.2) and 3,5-dichloro-pyridine-2-carboxylic acid (CAS 81719-53-1) following procedure I yielded the title compound as a crystalline white solid. MS (ISP): m/z=415.1 [M+H]+and 417.1 [M+2+H]+.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Br:7][C:8]1[CH:16]=[C:15]([CH3:17])[CH:14]=[CH:13][C:9]=1[C:10]([OH:12])=O.[Si]([CH:22]=[N+:23]=[N-:24])(C)(C)C.C([O-])(O)=O.[Na+]>C1COCC1.CCOC(C)=O.CN(C=O)C>[Br:7][C:8]1[CH:16]=[C:15]([CH3:17])[CH:14]=[CH:13][C:9]=1[C:10](=[O:12])[CH:22]=[N+:23]=[N-:24]
Reactant: Cc1ccc(C(=O)O)c(Br)c1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)C=[N+]=[N-])c(Br)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Oxalyl chloride (0.891 mL, 10.2 mmol) was slowly added to a solution of 2-bromo-4-methylbenzoic acid (813 mg, 3.78 mmol) and DMF (0.16 mL) in THF (35 mL) under nitrogen. The resulting mixture was stirred at room temperature for 30 minutes, then the volatiles were removed in vacuo and the residue azeotroped with toluene (2×20 mL). The resulting residue was taken up in anhydrous acetonitrile (40 mL) and chilled to 0° C. under a nitrogen atmosphere. A solution of TMS-diazomethane (2.0 M in Et2O; 4.35 mL, 8.70 mmol) was rapidly added and the resulting mixture was stirred at room temperature for 1 hour. EtOAc (30 mL) and saturated aqueous NaHCO3 (20 mL) were added and the layers separated. The aqueous layer was extracted with EtOAc (2×30 mL), then the combined organic extracts were washed with water (×2), brine, dried (MgSO4), filtered and evaporated in vacuo. The residue was adsorbed onto silica gel and purified by column chromatography (Biotage Isolera, 25 g SiO2 cartridge, 10-20% EtOAc in petroleum benzine 40-60° C.) to give the title compound A83 as a yellow oil (667 mg, 74%); 1H NMR (400 MHz, CDCl3) δ 7.43 (d, J=0.6 Hz, 1H), 7.36 (d, J=7.5 Hz, 1H), 7.15 (dd, J=7.8, 0.7 Hz, 1H), 5.73 (s, 1H), 2.35 (s, 3H).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][O:8][C:9]1[CH:10]=[C:11]([N:18]2[CH2:23][CH2:22][CH:21]([OH:24])[CH2:20][CH2:19]2)[CH:12]=[CH:13][C:14]=1[N+:15]([O-:17])=[O:16]>C(Cl)Cl.CS(C)=O>[CH3:7][O:8][C:9]1[CH:10]=[C:11]([N:18]2[CH2:23][CH2:22][C:21](=[O:24])[CH2:20][CH2:19]2)[CH:12]=[CH:13][C:14]=1[N+:15]([O-:17])=[O:16]
Reactant: COc1cc(N2CCC(O)CC2)ccc1[N+](=O)[O-]
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Product: COc1cc(N2CCC(=O)CC2)ccc1[N+](=O)[O-]
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 98.3 %

Procedure:
Oxalyl chloride (11.9 mL, 23.78 mmol) was dissolved in DCM (200 mL) and cooled to −78° C. DMSO (3.4 mL, 47.58 mmol) in DCM (15 mL) was added to the solution dropwise via an addition funnel. Upon completion of addition, the reaction was allowed to stir 10 min. 1-[3-(methyloxy)-4-nitrophenyl]-4-piperidinol (4.04 g, 15.86 mmol) in DMSO (6 mL) and DCM (15 mL) was added dropwise via addition funnel. Upon completion of addition, the reaction was allowed to stir 15 minutes. TEA (11.0 mL, 79.3 mmol) was then added dropwise via addition funnel. Upon completion of addition, the bath was removed and the reaction was allowed to warm to rt. The reaction was stirred until alcohol was consumed as indicated by TLC. The solvent was removed in vacuo and the residue was taken up in EtOAc. The suspension was washed twice with H2O, followed by brine. The organic layer was dried with MgSO4, filtered and concentrated to provide the title compound of step B (3.91 g, 15.59 mmol, 97%) as a bright yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.47-2.51 (m, 4H), 3.82 (t, J=6.2 Hz, 4H), 3.91 (s, 3H), 6.52 (d, J=2.6 Hz, 1H), 6.61 (dd, J=9.5, 2.6 Hz, 1H), 7.91 (d, J=9.5 Hz, 1H).
Reaction SMILES: [Li][CH2:2][CH2:3]CC.[C:6]([N:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]1[CH:19]=O)([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].CCOC(C)=O.CCCCCC>[Br-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C.C1COCC1.O>[C:6]([N:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]1/[CH:19]=[CH:2]\[CH3:3])([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7]
Reactant: CC(C)(C)OC(=O)N1CCCCC1C=O
Reactant: [Li]CCCC
Agent: CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: C/C=C\C1CCCCN1C(=O)OC(C)(C)C
Temperature: -30 °C
Reaction time: 0.5 h
Yield: 39.7 %

Procedure:
A suspension of ethyltriphenylphosphonium bromide (7.31 g, 19.68 mmol) in 40 mL of THF was cooled to −30° C. and treated with n-BuLi (10.9 mL, 19.68 mmol) dropwise. The deep red solution was slowly warmed to 0° C., stirred for 30 min, and then cooled to −78° C. The ylide was treated with a solution of N-Boc-piperidine-2-carboxaldehyde (3.53 g, 17.89 mmol) in 10 mL of THF, and the mixture was slowly warmed to room temperature. The mixture was diluted with water, and the organic layer was separated. The aqueous layer was extracted with ether and the combined extracts were dried over K2CO3 and then concentrated to give a crude product as an oil. Chromatography on silica with 5% EtOAc/hexane afforded 1.6 g (41%) of the product which was homogenous by TLC analysis. 1H NMR (250 MHz) δ 5.73-5.51 (m, 2H), 5.05-5.01 (m, 1H), 3.98-3.93 (br d, 1H), 2.90-2.81 (m, 1H), 1.7-1.39 (m, 18H); 13C NMR (62.7 MHz) 154.8 (s), 128.0 (s), 125.8 (s), 79.0 (s), 47.7 (s), 39.6 (s), 30.3 (s), 28.5 (s), 25.6 (s), 19.5 (s), 13.2 (s) ppm.
Reaction SMILES: [CH3:1][C:2](O)([C:4]#[CH:5])[CH3:3].CCN(CC)CC.C(OC(=O)C)(=O)C.[NH4+].[Cl-].[NH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(Cl)Cl.CN(C1C=CN=CC=1)C.Cl[Cu]>[CH3:1][C:2]([NH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:4]#[CH:5])[CH3:3]
Reactant: C#CC(C)(C)O
Reactant: Nc1ccccc1
Agent: Cl[Cu]
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Solvent: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C#CC(C)(C)Nc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.6 %

Procedure:
In a 500 mL r.b., a solution of 2-methyl-3-butyn-2-ol (10.0 mL, 0.10 mol, 1.3 equiv) in CH2Cl2 (100 mL) was treated sequentially with Et3N (15.0 mL, 0.107 mol, 1.4 equiv), acetic anhydride (11.6 mL, 0.12 mol, 1.5 equiv), and DMAP (0.61 g, 5.0 mmol, 5.0 mol %). The reaction mixture was stirred at rt for 2 h and poured into sat'd NH4Cl (60 mL). The layers were separated. The aqueous layer was extracted with CH2Cl2 (2×100 mL). The organic layers were washed with 1 N HCl (2×100 mL), combined, dried (MgSO4), filtered through a pad of Celite, and the volatiles were removed by distillation (<45° C. distillate). The residue was dissolved in THF (100 mL) and aniline (7.00 mL, 77 mmol) was added slowly via syringe, followed by CuCl (0.76 g, 10 mol%). The reaction mixture was heated to reflux for 3 h. The resulting red solution was allowed to cool to rt, the bulk of the volatiles were removed in vacuo, and the residue was diluted with EtOAc (120 mL). The solution was washed with sat'd NH4Cl (2×100 mL) and brine (1×100 mL). The aqueous layers were extracted with EtOAc (2×100 mL). The combined organic layers were dried (MgSO4), filtered, and concentrated. Purification by silica gel chromatography (hexane:EtOAc, 16:1) afforded 10.5 g (87%) of 2-methyl-3-butyn-2-yl(phenyl)amine as a pale yellow liquid. Data for 2-methyl-3-butyn-2-yl(phenyl)amine: 1H NMR (400 MHz, CDCl3) 7.20 (t, J=7.7, 2H), 6.95 (d, J=7.7, 2H), 6.80 (t, J=7.7, 1H), 3.65 (br s, 1H), 2.36 (s, 1H), 1.61 (s, 6H).
Reaction SMILES: [NH2:1][C:2]1[N:3]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[C:4]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)=[CH:5][C:6]=1[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1O)=[O:8].CC1C=CC(S([O:39][CH2:40][C@H:41]2[O:45][C:44]([CH3:47])([CH3:46])[O:43][CH2:42]2)(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.[Cl-].[Na+].O>[NH2:1][C:2]1[N:3]([C:22]2[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=2)[C:4]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)=[CH:5][C:6]=1[C:7]([C:9]1[CH:10]=[CH:11][CH:12]=[C:13]([O:39][CH2:40][C@H:41]2[CH2:42][O:43][C:44]([CH3:46])([CH3:47])[O:45]2)[CH:14]=1)=[O:8]
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2COC(C)(C)O2)cc1
Reactant: Nc1c(C(=O)c2ccccc2O)cc(-c2cccnc2)n1-c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)OC[C@H](COc2cccc(C(=O)c3cc(-c4cccnc4)n(-c4ccc(F)cc4)c3N)c2)O1
Temperature: 25 °C
Reaction time: 16 h
Yield: 89.7 %

Procedure:
A mixture of 0.6 g (1.6 mmol) of [2-amino-1-(4-fluorophenyl)-5-pyridin-3-yl-1H-pyrrol-3-yl](hydroxyphenyl)methanone, 1.06 g (3.7 mmol) of L-α,β-isopropylideneglycerol-γ-tosylate and 1.2 g (8.7 mmol) of potassium carbonate in 10 mL of DMF was heated at 80°. After 16 h, the reaction mixture was cooled to room temperature, poured into brine and extracted with ethyl acetate. The extracts were dried over sodium sulfate, concentrated under reduced pressure and purified by flash chromatography (gradient elution: 15-50% ethyl acetate/hexane) to give 0.7 g (90%) of [2-amino-1-(4-fluorophenyl)-5-pyridin-3-yl-1H-pyrrol-3-yl]-[3-(2,2-dimethyl-[1,3 ]dioxolan-4(S)-ylmethoxy)-phenyl]-methanone.
Reaction SMILES: [NH2:1][C:2]1[C:11]([CH3:12])=[CH:10][C:9]([Cl:13])=[CH:8][C:3]=1[C:4](OC)=[O:5].[CH3:14][NH2:15].O>C(#N)C.C(O)CO>[NH2:1][C:2]1[C:11]([CH3:12])=[CH:10][C:9]([Cl:13])=[CH:8][C:3]=1[C:4]([NH:15][CH3:14])=[O:5]
Reactant: CN
Reactant: COC(=O)c1cc(Cl)cc(C)c1N
Solvent: OCCO
Solvent: O
Solvent: CC#N
Product: CNC(=O)c1cc(Cl)cc(C)c1N
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 85.5 %

Procedure:
To a suspension of methyl 2-amino-5-chloro-3-methylbenzoate (i.e. the product of Example 2) (4.03 g, 20.2 mmol) in acetonitrile (12.4 g) was added a solution of methylamine (3.1 g, 0.10 mol) in ethylene glycol (12.4 g). The mixture was heated at 60° C. for 23 h, and then cooled to room temperature. Water (25 mL) was added dropwise, and the resulting slurry was cooled to 5° C. and stirred for 10 minutes at this temperature. The mixture was filtered, and the solids were washed with water (3×10 mL), and dried under nitrogen to afford the title compound as white needles, 3.43 g (85.5% yield).
Reaction SMILES: C([S:4][CH:5]([CH3:12])[C:6](=[O:11])[C:7]([F:10])([F:9])[F:8])(=O)C.CN(C)C=O.[C:18]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])#[N:19]>CC(=O)OCC>[NH2:19][C:18]1[S:4][CH:5]([CH3:12])[C:6]([OH:11])([C:7]([F:10])([F:9])[F:8])[C:20]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: CC(=O)SC(C)C(=O)C(F)(F)F
Reactant: CCOC(=O)CC#N
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C1=C(N)SC(C)C1(O)C(F)(F)F
Temperature: 0 °C

Procedure:
Into a 100-mL round-bottom flask, was placed 3-(acetylsulfanyl)-1,1,1-trifluorobutan-2-one (5.8 g, 28.97 mmol, 1.00 equiv), N,N-dimethylformamide (10 mL). This was followed by the addition of TEA (3 g, 29.65 mmol, 1.02 equiv) and ethyl 2-cyanoacetate (3.27 g, 28.91 mmol, 1.00 equiv) dropwise with stirring at 0° C. The resulting solution was stirred overnight at 25° C. Then it was diluted with 20 mL of EA. The organic phase was separated and washed with 3×20 mL of H2O. The mixture was dried over anhydrous sodium sulfate. The solids were filtered out. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (30/70). The collected fractions were combined and concentrated under vacuum. This resulted in 6.5 g (79%) of ethyl 2-amino-4-hydroxy-5-methyl-4-(trifluoromethyl)-4,5-dihydrothiophene-3-carboxylate as a dark red liquid.
Reaction SMILES: [C:1]([NH:5][C:6]1[C:7](Cl)=[N:8][C:9]2[C:14]([N:15]=1)=[C:13]([C:16]1[NH:24][C:23]3[CH2:22][CH2:21][NH:20][C:19](=[O:25])[C:18]=3[CH:17]=1)[CH:12]=[CH:11][CH:10]=2)([CH3:4])([CH3:3])[CH3:2].Cl.[NH:28]1[CH2:31][CH:30]([OH:32])[CH2:29]1.C(N(C(C)C)C(C)C)C>CS(C)=O.C(Cl)Cl>[C:1]([NH:5][C:6]1[C:7]([N:28]2[CH2:31][CH:30]([OH:32])[CH2:29]2)=[N:8][C:9]2[C:14]([N:15]=1)=[C:13]([C:16]1[NH:24][C:23]3[CH2:22][CH2:21][NH:20][C:19](=[O:25])[C:18]=3[CH:17]=1)[CH:12]=[CH:11][CH:10]=2)([CH3:4])([CH3:3])[CH3:2]
Reactant: OC1CNC1
Reactant: CC(C)(C)Nc1nc2c(-c3cc4c([nH]3)CCNC4=O)cccc2nc1Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: ClCCl
Product: CC(C)(C)Nc1nc2c(-c3cc4c([nH]3)CCNC4=O)cccc2nc1N1CC(O)C1
Yield: 66.8 %

Procedure:
A solution of 2-(3-(tert-butylamino)-2-chloroquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (345) (28 mg, 0.07 mmol), azetidin-3-ol hydrochloride (41 mg, 0.37 mmol, Matrix Scientific, Columbia, S.C.), and N-ethyl-N-isopropylpropan-2-amine (81 pt, 0.45 mmol) in DMSO (0.75 mL) was stirred at 50° C. for 1 h. The reaction mixture was diluted with DCM (100 mL), added to a separatory funnel, and washed with saturated aq. NaHCO3 (2×75 mL) before the organic layer was separated, dried over Na2SO4, and concentrated. The crude product was adsorbed onto silica and was purified via automated flash chromatography (silica gel) with 1-5% of 2 M NH3 in MeOH/DCM to give 2-(3-(tert-butylamino)-2-(3-hydroxyazetidin-1-yl)quinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (346) (19 mg, 61% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.53 (s, 9H) 2.85 (t, J=6.94 Hz, 2H) 3.43 (td, J=6.75, 2.35 Hz, 2H) 3.94 (dd, J=9.00, 5.09 Hz, 2H) 4.41 (dd, J=8.80, 6.85 Hz, 2H) 4.57 (sxt, J=5.91 Hz, 1H) 5.64-5.71 (m, 2H) 6.95 (s, 1H) 6.96 (s, 1H) 7.24 (t, J=7.82 Hz, 1H) 7.36 (dd, J=7.92, 1.27 Hz, 1H) 7.61 (dd, J=7.43, 1.37 Hz, 1H) 12.00 (s, 1H). MS (ESI, pos. ion) m/z: 407.1 (M+1).
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[ClH:14].[O:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N:17]=[C:16]1[C:24]1[CH:34]=[CH:33][C:27]([CH2:28][O:29][CH2:30][CH2:31][NH2:32])=[CH:26][CH:25]=1.[H-].[Na+]>C1COCC1>[ClH:14].[O:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N:17]=[C:16]1[C:24]1[CH:34]=[CH:33][C:27]([CH2:28][O:29][CH2:30][CH2:31][NH:32][CH2:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:26][CH:25]=1
Reactant: ICCCOCCc1ccccc1
Reactant: NCCOCc1ccc(-c2nc3ccccc3o2)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: c1ccc(CCOCCCNCCOCc2ccc(-c3nc4ccccc4o3)cc2)cc1

Procedure:
To a solution of 1-iodo-3-(2-phenylethoxy)propane (0.566 g; 1.95 mmol) in dry THF (9 ml) is added 2-[4-(benzoxazol-2-yl)benzyloxy]ethylamine hydrochloride (0.59 g; 1.9 mmol). NaH (78 mg; 1.9 mmol) is then added at room temperature. The reaction mixture is heated at reflux for 30 minutes, then cooled, concentrated in vacuo, and the residue column chromatographed with 10% MeOH/CH2Cl2The product is dissolved in EtOH acidified with HCl/EtOH concentrated to a solid and recrystallized from CH2Cl2 /petroleum ether to obtain N-[2-(4-(benzoxazol-2-yl)benzyloxy)ethyl]-3-(2-phenylethoxy)propanamine hydrochloride. (m.p. 134°-135° C.).
Reaction SMILES: Cl[C:2]1[S:3][C:4]([Cl:23])=[C:5]([CH2:7][O:8][N:9]=[C:10]([C:17]2[N:21]([CH3:22])[N:20]=[N:19][N:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:6]=1.N#N.[CH:26]1([C:29]#[CH:30])[CH2:28][CH2:27]1.C(N(C(C)C)C(C)C)C>C1COCC1.CCOC(C)=O.[Cu](I)I.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>[Cl:23][C:4]1[S:3][C:2]([C:30]#[C:29][CH:26]2[CH2:28][CH2:27]2)=[N:6][C:5]=1[CH2:7][O:8][N:9]=[C:10]([C:17]1[N:21]([CH3:22])[N:20]=[N:19][N:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: C#CC1CC1
Reactant: Cn1nnnc1C(=NOCc1nc(Cl)sc1Cl)c1ccccc1
Agent: I[Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: Cn1nnnc1C(=NOCc1nc(C#CC2CC2)sc1Cl)c1ccccc1
Reaction time: 0.05 h
Yield: 84.6 %

Procedure:
To a stirred solution of N-[(2,5-dichloro-1,3-thiazol-4-yl)methoxy]-1-(1-methyl-1H-tetrazol-5-yl)-1-phenylmethanimine (0.15 g, 0.406 mmol, 1 eq.) in 3 ml dry THF “degassed” with N2, was added Cyclopropylacetylene (0.029 g, 0.447 mmol, 1.1 eq.) followed by N-ethyldiisopropylamine (0.209 g, 1.62 mmol, 4 eq.), Copper Iodide (0.015 g, 0.081 mmol, 0.2 eq.) and Tetrakis(triphenylphosphine)palladium (0.046 g, 0.041 mmol, 0.1 eq.). The reaction was microwaved 120° C./normal/fixed hold/pre stir 100 s for 180 s. The reaction was diluted with EtOAc and filtered through a “celite” plug. The solvent was evaporated and the residue purified by chromatography on silica gel to give N-{[5-chloro-2-(cyclopropylethynyl)-1,3-thiazol-4-yl]methoxy}-1-(1-methyl-1H-tetrazol-5-yl)-1-phenylmethanimine (0.137 g, 71% yield, 78:5 mixture of stereoisomers) as a yellow viscous oil.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=1[NH:18][C:19](=[O:38])[CH2:20][C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]2[CH:34]=[CH:33][N:32]=[C:31]([CH:35]([CH3:37])[CH3:36])[CH:30]=2)[CH:24]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:35]([C:31]1[CH:30]=[C:29]([C:25]2[CH:24]=[C:23]([C:21]3[CH2:20][C:19](=[O:38])[NH:18][C:9]4[CH:10]=[C:11]([C:14]([F:16])([F:17])[F:15])[CH:12]=[CH:13][C:8]=4[N:7]=3)[CH:28]=[CH:27][CH:26]=2)[CH:34]=[CH:33][N:32]=1)([CH3:37])[CH3:36]
Reactant: CC(C)c1cc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)ccc3NC(=O)OC(C)(C)C)c2)ccn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)c1cc(-c2cccc(C3=Nc4ccc(C(F)(F)F)cc4NC(=O)C3)c2)ccn1

Procedure:
The title compound was prepared from (2-{3-[3-(2-isopropyl-pyridin-4-yl)-phenyl]-3-oxo-propionylamino}-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example M251) (0.23 g, 0.43 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (150 mg, 83%).