Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[Cl:8][C:9]1[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[C:13]([Cl:21])[C:10]=1[CH:11]=[O:12].COB(OC)OC.Cl>O1CCCC1.[Zn].C(O)(=O)C>[Cl:8][C:9]1[CH:16]=[C:15]([C:17]([F:19])([F:20])[F:18])[CH:14]=[C:13]([Cl:21])[C:10]=1[CH:11]([OH:12])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)CBr
Reactant: O=Cc1c(Cl)cc(C(F)(F)F)cc1Cl
Agent: COB(OC)OC
Agent: Cl
Agent: [Zn]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCOC(=O)CC(O)c1c(Cl)cc(C(F)(F)F)cc1Cl
Temperature: 25 °C

Procedure:
Ethyl bromoacetate (13.7 ml) was added to a suspension of 30.0 g of 2,6-dichloro-4-trifluoromethylbenzaldehyde (7), 50 ml of trimethoxyborane and 8.5 g of zinc powder in 50 ml of anhydrous tetrahydrofuran with vigorous stirring at room temperature, and the mixture was stirred overnight. The reaction mixture was poured into a mixture of 100 ml of 10% hydrochloric acid and 10 ml of acetic acid, and the resulting mixture was filtered through Celite. The aqueous filtrate was neutralized with a 5% aqueous solution of sodium hydrogencarbonate, followed by extraction with ethyl acetate, drying over anhydrous magnesium sulfate and concentration under reduced pressure, affording 40.7 g of the desired compound in the form of a pale green oil (quantitative crude yield).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH:7][C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([OH:18])[CH:16]=3)[N:11]=[CH:10][N:9]=2)=[N:3]1.F[C:20]1[C:27]([CH3:28])=[CH:26][CH:25]=[CH:24][C:21]=1[C:22]#[N:23].C(O[K])(C)(C)C.O>CN(C)C(=O)C>[CH3:28][C:27]1[C:20]([O:18][C:15]2[CH:16]=[C:17]3[C:12](=[CH:13][CH:14]=2)[N:11]=[CH:10][N:9]=[C:8]3[NH:7][C:4]2[CH:5]=[CH:6][N:2]([CH3:1])[N:3]=2)=[C:21]([CH:24]=[CH:25][CH:26]=1)[C:22]#[N:23]
Reactant: Cn1ccc(Nc2ncnc3ccc(O)cc23)n1
Reactant: Cc1cccc(C#N)c1F
Agent: CC(C)(C)O[K]
Solvent: O
Solvent: CC(=O)N(C)C
Product: Cc1cccc(C#N)c1Oc1ccc2ncnc(Nc3ccn(C)n3)c2c1
Temperature: 110 °C
Reaction time: 4 h
Yield: 23.3 %

Procedure:
4-[(1-Methyl-1H-pyrazol-3-yl)amino]quinazolin-6-ol (90 mg; 0.373 mmol) and 100 mg (0.741 mmol) of 2-fluoro-3-methylbenzonitrile were added to a solution of 105 mg (0.937 mmol) of tert-butoxy potassium in 5 ml of N,N-dimethylacetamide and the mixture was stirred at 110° C. for 4 hours. Water was added to the reaction solution and the mixture was extracted with chloroform. The organic layer was dried and concentrated and the resulting residue was purified by a silica gel chromatography (chloroform:methanol=12:1) to give 31 mg (yield: 23%) of the title compound as a colorless solid.
Reaction SMILES: C([Li])CCC.[CH3:6][Si:7]([C:10]#[CH:11])([CH3:9])[CH3:8].[CH:12](=[O:21])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].Cl>O1CCCC1.C(OCC)C>[CH3:6][Si:7]([CH3:9])([CH3:8])[C:10]#[C:11][CH:12]([OH:21])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: C#C[Si](C)(C)C
Reactant: CCCCCCCCC=O
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCCCCCCC(O)C#C[Si](C)(C)C
Temperature: -70 °C

Procedure:
173 mol of n-butyllithium solution (1.6 mol in hexane) is instilled in a solution of 25 g of trimethylsilylacetylene in 500 ml of tetrahydrofuran with stirring and argon atmosphere at -40° C., is stirred for 30 minutes at -40° C., cooled to -70° C. and 48.1 ml of nonanal is instilled at this temperature. After an hour at -70° C., the mixture is allowed to come to -30° C., 300 ml of 2 n hydrochloric acid is added and shaken with diethyl ether. The organic phases are dried (Na2SO4), concentrated by evaporation and the residue is distilled in a bulb tube at 120°-130° C./0.2 mbar. Thus 48.5 of (3RS)-1-(trimethylsilyl)-1-undecin-3-ol is obtained as a colorless oil.
Reaction SMILES: [CH2:1]([CH2:5][C:6](=O)[CH3:7])[C:2]([CH3:4])=O.[CH2:9]([O:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[C:14]([N+:19]([O-:21])=[O:20])[CH:13]=1)[CH3:10].O>C(O)(=O)C>[CH3:7][C:6]1[N:16]([C:15]2[CH:17]=[CH:18][C:12]([O:11][CH2:9][CH3:10])=[CH:13][C:14]=2[N+:19]([O-:21])=[O:20])[C:2]([CH3:4])=[CH:1][CH:5]=1
Reactant: CC(=O)CCC(C)=O
Reactant: CCOc1ccc(N)c([N+](=O)[O-])c1
Solvent: CC(=O)O
Solvent: O
Product: CCOc1ccc(-n2c(C)ccc2C)c([N+](=O)[O-])c1
Temperature: 25 °C

Procedure:
To a solution of acetonyl acetone (1.95 mL, 16.5 mmol) in acetic acid (100 mL) was added 4-ethoxy-2-nitroaniline (3.0 g, 16.5 mmol) and the red mixture heated at reflux overnight. After cooling to rt, the now black solution was poured into water and extracted with EtOAc (2×200mL). The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo to an oil. Purification by flash chromatography (10% EtOAc/hexanes) gave 2,5-dimethyl-1-(4-ethoxy-2-nitrophenyl)pyrrole as a red oil: 1H NMR (CDCl3, 500 MHz) δ 7.46 (d, 1H), 7.27 (t, 1H), 7.19 (dd, 1H), 5.91 (s, 2H), 4.15 (q, 1H), 1.96 (s, 6H), 1.50 (t, 3H); MS (ESI) 261 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.[CH2:11]([C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]>>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH:23][C:22]2[CH:24]=[CH:25][C:19]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[CH:20][CH:21]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C=O)cc1
Reactant: CCCCCCCCc1ccc(N)cc1
Product: CCCCCCCCc1ccc(NCc2ccc(OC)cc2)cc1
Yield: 99.1 %

Procedure:
By the reaction and treatment in the same manner as in Preparation Example 1 using 4-methoxybenzaldehyde (1.0 g) and 4-octylaniline (1.4 g) as starting materials, [(4-methoxyphenyl)methyl](4-octylphenyl)amine (2.2 g) was obtained.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].C(N(CC)CC)C.[Cl:19][CH2:20][S:21](Cl)(=[O:23])=[O:22].Cl>ClCCl>[Cl:19][CH2:20][S:21]([NH:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5])(=[O:23])=[O:22]
Reactant: NCC(=O)c1ccccc1
Reactant: O=S(=O)(Cl)CCl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CNS(=O)(=O)CCl)c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 75.9 %

Procedure:
2-Aminoacetophenone hydrochloride (4.56 g, 26.6 mmol) was dissolved in dichloromethane (250 mL). To the solution was added triethylamine (9.30 mL, 66.7 mmol), and the mixture was stirred at room temperature for 10 minutes. After the reaction mixture was cooled to 0° C., chloromethanesulfonyl chloride (purity 90%, 3.60 mL, 36.3 mmol) was added, and the mixture was stirred at the same temperature for 1 hour. To the reaction mixture was added 2 mol/L hydrochloric acid, and the mixture was extracted with chloroform. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. To the residue was added diethyl ether, and the deposited crystals were collected by filtration and dried to give 2-(chloromethylsulfonylamino)acetophenone (5.00 g, 76%).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10][C:11]([OH:13])=O.[NH:16]1[CH2:21][CH2:20][C:19]2([C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH2:24][N:23]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:22]2)[CH2:18][CH2:17]1>>[F:14][C:2]([F:1])([F:15])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10][C:11]([N:16]1[CH2:17][CH2:18][C:19]2([C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH2:24][N:23]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:22]2)[CH2:20][CH2:21]1)=[O:13]
Reactant: O=C(O)CCc1ccccc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1Cc2ccccc2C2(CCNCC2)C1
Product: CC(C)(C)OC(=O)N1Cc2ccccc2C2(CCN(C(=O)CCc3ccccc3C(F)(F)F)CC2)C1

Procedure:
The title compound was prepared following a procedure analogous to that described in Example 1 using 3-(2-(trifluoromethyl)phenyl)propanoic acid and tert-butyl 1H-spiro[isoquinoline-4,4′-piperidine]-2(3H)-carboxylate. LC-MS Method 1 tR=2.18, min, m/z=503
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][N:9]([S:12](Cl)(=[O:14])=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4][N:3]1[C:16]1[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=1.[CH3:27][NH:28][CH2:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=1>>[CH3:27][N:28]([CH2:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=1)[S:12]([N:9]1[CH2:10][CH2:11][C:6]2([C:2](=[O:1])[N:3]([C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=3)[CH2:4][CH2:5]2)[CH2:7][CH2:8]1)(=[O:14])=[O:13]
Reactant: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCN(S(=O)(=O)Cl)CC2
Reactant: CNCCc1ccccn1
Product: CN(CCc1ccccn1)S(=O)(=O)N1CCC2(CCN(c3ccc(OC(F)(F)F)cc3)C2=O)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
This material was prepared in analogy to example 285 step B) from 1-Oxo-2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decane-8-sulfonyl chloride and methyl-(2-pyridin-2-yl-ethyl)-amine. The reaction was subjected to work-up and purification after stirring for 2 h at room temperature. MS (ESI): 513.5 (MH+).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH:6]=[CH:7][CH:8]=1.C(N(CC)CC)C.[N+:24]([C:27]1[CH:28]=[C:29]([S:33](Cl)(=[O:35])=[O:34])[CH:30]=[CH:31][CH:32]=1)([O-:26])=[O:25].C([O-])([O-])=O.[Na+].[Na+]>O1CCCC1>[N+:24]([C:27]1[CH:28]=[C:29]([S:33]([NH:1][CH2:2][C:3]2[CH:4]=[C:5]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:13])([CH3:15])[CH3:14])[CH:6]=[CH:7][CH:8]=2)(=[O:35])=[O:34])[CH:30]=[CH:31][CH:32]=1)([O-:26])=[O:25]
Reactant: CC(C)(C)OC(=O)Nc1cccc(CN)c1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)Nc1cccc(CNS(=O)(=O)c2cccc([N+](=O)[O-])c2)c1
Temperature: 25 °C
Yield: 109.1 %

Procedure:
To a stirring solution of tert-butyl [3-(aminomethyl)phenyl]carbamate (2.00 g, 9.0 mmol) and triethylamine (1.32 mL, 9.45 mmol) in dry tetrahydrofuran (25.5 mL) at 0° C. was slowly added a solution of m-nitrobenzenesulfonyl chloride (2.09 g, 9.45 mmol) in tetrahydrofuran (7.3 mL). The resulting mixture was slowly warmed up to rt and stirred for one additional hour at rt. The reaction mixture was treated with Na2CO3 (aq) and layers separated. The aqueous layer was extracted with EtOAc three times. The combined organic layers were dried, filtered and concentrated to give the desired product as an off-white powder (4.0 g, 100%). LCMS for C18H21N3O6S (M-Boc+H)+: m/z=308.0. 1H NMR (400 MHz, CD3OD): δ 8.43 (t, J=2.0 Hz, 1H), 8.31 (ddd, J=8.0, 2.0, 1.2 Hz, 1H), 8.04 (dt, J=8.0, 2.8 Hz, 1H), 7.64 (t, J=8.0 Hz, 1H), 7.19 (br, 1H), 7.04 (m, 2H), 6.77 (dt, J=7.2, 1.2 Hz, 1H), 4.13 (s, 2H).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH:10]=2)O1.Br[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.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>[N:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[C:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])[CH2:11][CH:10]=1
Reactant: Brc1ccccn1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
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: O
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CC=C(c2ccccn2)CC1
Temperature: 85 °C
Yield: 74.6 %

Procedure:
A mixture of tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (0.500 g, 1.04 mmol), 2-bromopyridine (0.164 g, 1.04 mmol), sodium carbonate (0.439 g, 4.14 mmol), tetrakis(triphenylphosphine)palladium(0) (0.120 g, 0.103 mmol) in ethylene glycol dimethyl ether (20 mL) and water (10 mL) was heated at about 85° C. for about 12 hours. The reaction mixture was allowed to cool to ambient temperature and the solvent was removed under reduced pressure. The residue was partitioned between water (25 mL) and dichloromethane (50 mL). The organic layer was separated and the aqueous layer was further extracted with dichloromethane (2×50 mL). The combined organic extracts were dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by using preparative RP-HPLC (Rainin C18, 8 mm, 300 Å, 35 cm; 5-100% acetonitrile—0.1M ammonium acetate over 20 min, 100% acetonitrile hold 10 minutes, 21 mL/min) to give tert-butyl 4-(pyridin-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (0.202 g, 0.776 mmol) as a white solid; RP-HPLC (Table 1, Method b) Rt 2.78 min; m/z: (M+H)+ 261.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][C:20]([CH3:22])=[CH2:21]>CN(C=O)C.O>[CH3:21][C:20](=[CH2:19])[CH2:22][O:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cccc(O)c1
Reactant: C=C(C)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C=C(C)COc1cccc(C(=O)OC)c1
Temperature: 90 °C
Reaction time: 1 h
Yield: 0.1 %

Procedure:
Methyl 3-hydroxybenzoate (1 g, 6.57 mmol) was dissolved in DMF (10 ml) to give a colorless solution. To the solution potassium carbonate (1.089 g, 7.88 mmol) and 3-Bromo-2-methylpropene (0.729 ml, 7.23 mmol) were added. The reaction mixture was heated to 90° C. and stirred for 1 h. After cooling the reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed with water, dried over Na2SO4 and evaporated under vacuum to afford the title compound (1.180 mg)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][OH:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>C1COCC1>[CH3:24][S:25]([O:16][CH2:15][CH2:14][N:11]1[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:13][CH2:12]1)(=[O:27])=[O:26]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCN(CCO)CC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(CCOS(C)(=O)=O)CC1

Procedure:
A solution of tert-butyl-4-(2-hydroxyethyl)-piperazine-1-carboxylate (Maybridge, 0.29 g, 1.2 mmol), triethylamine (0.56 mL, 4.1 mmol), and methanesulfonyl chloride (0.15 mL, 1.9 mmol) in 10 mL THF were processed as described in Example 1C to give the title compound that was used directly in the next reaction.
Reaction SMILES: [NH2:1][C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][C:5](=[O:7])[NH2:6].[OH-].[Na+].[CH2:13]([CH:15]([CH2:20][CH2:21][CH2:22][CH3:23])[CH2:16][N:17]=[C:18]=[O:19])[CH3:14]>O.O1CCOCC1>[CH2:13]([CH:15]([CH2:20][CH2:21][CH2:22][CH3:23])[CH2:16][NH:17][C:18]([NH:1][C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][C:5](=[O:7])[NH2:6])=[O:19])[CH3:14]
Reactant: NC(=O)CC[C@H](N)C(=O)O
Reactant: CCCCC(CC)CN=C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CCCCC(CC)CNC(=O)N[C@@H](CCC(N)=O)C(=O)O
Reaction time: 24 h
Yield: 88.2 %

Procedure:
At 5° C., a suspension of L-(+)-glutamine (23.1 g, 158 mmol) in 1:1 water/dioxane (300 ml) was treated successively with a solution of 2N aq. NaOH (79 ml) and with 2-ethylhexyl isocyanate (25 g, 158 mmol). The resulting mixture was stirred for 24 h while its temperature rose to 20° C. (final pH value: 6) and filtered. The filtrate was washed twice with ethyl acetate (200 ml) and the combined organic phases were acidify with a 2N aq. HCl solution to pH 1. Filtration of the resulting precipitate and drying under vacuum gave N2-[(2-ethylhexylamino)carbonyl]-L-glutamine (42 g, 88%, white solid).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][O:5][C@@H:4]2[C@H:7]([O:10][C:11]3[NH:12][C:13]4[C:14]([N:28]=3)=[N:15][C:16]([C:20]3[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=3)=[C:17]([Cl:19])[CH:18]=4)[CH2:8][O:9][C@H:3]12.[CH2:29](N)[CH2:30][NH2:31].C(=S)=S>>[Cl:19][C:17]1[CH:18]=[C:13]2[NH:12][C:11]([O:10][C@H:7]3[C@H:4]4[O:5][CH2:6][C@@H:2]([OH:1])[C@H:3]4[O:9][CH2:8]3)=[N:28][C:14]2=[N:15][C:16]=1[C:20]1[CH:27]=[CH:26][C:23]([C:24]2[NH:31][CH2:30][CH2:29][N:25]=2)=[CH:22][CH:21]=1
Reactant: N#Cc1ccc(-c2nc3nc(O[C@@H]4CO[C@H]5[C@@H]4OC[C@H]5O)[nH]c3cc2Cl)cc1
Reactant: NCCN
Solvent: S=C=S
Product: O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2Oc1nc2nc(-c3ccc(C4=NCCN4)cc3)c(Cl)cc2[nH]1
Temperature: 50 °C

Procedure:
A vial was charged with 4-[2-[[(3R,3aR,6R,6aR)-3-hydroxy-2,3,3a,5,6,6a-hexahydro-furo[3,2-b]furan-6-yl]oxy]-6-chloro-1H-imidazo[4,5-b]pyridin-5-yl]benzonitrile (24.8 mg, 0.062 mmol), ethylenediamine (0.5 ml, 7.46 mmol), and carbon disulfide (5 μl, 0.083 mmol). The reaction mixture was heated to 50° C. for 19 h. The reaction mixture was cooled to room temperature before being concentrated under reduced pressure to 0.1 mL. The concentrated reaction mixture was purified by preparative HPLC reverse phase (C-18), using a 30×150 mm Sunfire™ column and eluting with a 0%-30% acetonitrile/water+0.05% TFA gradient, followed by a 30% acetonitrile/water+0.05% TFA flush. The product fractions were combined, evaporated under reduced pressure, and lyophilized from ethanol and benzene to give the title compound as a white solid. LC-MS: calculated for C21H20ClN5O4 441.12 observed m/e: 442.19 (M+H)+ (Rt 0.25/2 min); 1H NMR δ (ppm) (CD3OD): 7.95 (s, 4H), 7.85 (s, 1H), 5.54 (qt, J=5.3 Hz, 1H), 4.96 (t, J=5.2 Hz, 1H), 4.46 (t, J=5.0 Hz, 1H), 4.26-4.30 (m, 1H), 4.16 (dd, J=5.7 Hz, J=10.3 Hz, 1H), 4.14 (s, 4H), 4.11 (dd, J=4.7 Hz, J=10.2 Hz, 1H), 3.89 (dd, J=6.8 Hz, J=8.1 Hz, 1H), 3.59 (t, J=8.6 Hz, 1H).
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5]2[S:7][C:8]([C:10]#[N:11])=[CH:9][C:4]=2[CH2:3]1.[NH:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[CH:17]=O>N1CCCCC1.CC(O)C>[O:1]=[C:2]1[NH:6][C:5]2[S:7][C:8]([C:10]#[N:11])=[CH:9][C:4]=2/[C:3]/1=[CH:17]/[C:13]1[NH:12][CH:16]=[CH:15][CH:14]=1
Reactant: N#Cc1cc2c(s1)NC(=O)C2
Reactant: O=Cc1ccc[nH]1
Solvent: C1CCNCC1
Solvent: CC(C)O
Product: N#Cc1cc2c(s1)NC(=O)/C2=C\c1ccc[nH]1
Temperature: 75 °C
Yield: 20.7 %

Procedure:
5,6-Dihydro-5-oxo-4H-thieno[2,3-b]pyrrole-2-carbonitrile (32 mg, 0.2 mmol) was dissolved in a solution of 1% piperidine in 2-propanol (1 ml). Pyrrole-2-carboxaldehyde (37 mg, 0.39 mmol) was added in one portion and the mixture heated at 75° C. for 1 hour. The reaction mixture was poured into an ice/water mixture (6 ml) and the precipitated solid was collected by filtration and washed with water to give 10 mg of (Z)-5,6-dihydro-5-oxo-4-[(1H-pyrrol-2-yl)methylene]-4H-thieno[2,3-b]pyrrole-2-carbonitrile as a yellow solid. MS(ES): m/e 242 [M+H].
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([OH:23])[N:20]=[CH:19][C:16]=43)[CH:10]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].O[C:25]([CH3:32])([CH3:31])[C:26]([O:28][CH2:29][CH3:30])=[O:27].CO>C(Cl)Cl>[CH2:29]([O:28][C:26](=[O:27])[C:25]([O:23][C:21]1[N:20]=[CH:19][C:16]2[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]=2[CH:22]=1)[CH:10]=[C:9]([C:8]1[N:4]([CH:1]([CH3:3])[CH3:2])[N:5]=[CH:6][N:7]=1)[N:18]=3)([CH3:32])[CH3:31])[CH3:30]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1cnc(O)cc1OCC2
Reactant: CCOC(=O)C(C)(C)O
Solvent: ClCCl
Solvent: CO
Product: CCOC(=O)C(C)(C)Oc1cc2c(cn1)-c1nc(-c3ncnn3C(C)C)cn1CCO2
Yield: 40 %

Procedure:
Following the procedures of Example 426, 2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulen-8-ol from Example 93 and ethyl 2-hydroxyisobutyrate were reacted and the crude product was subjected to flash chromatography (SiO2, gradient 0-5% methanol in DCM) to give 2-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulen-8-yloxy]-2-methyl-propionic acid ethyl ester as a yellow oil (103 mg, 40%). LCMS: RT=3.52 min, [M+H]+=427
Reaction SMILES: [OH:1][C:2]1[CH:26]=[CH:25][C:5]([C:6]([C:8]2[N:16]3[C:11]([CH:12]=[CH:13][CH:14]=[CH:15]3)=[C:10]([CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[CH2:27]([C:31]1[CH:36]=[CH:35][C:34]([CH:37]([C:39]2[CH:44]=[CH:43][C:42]([CH2:45][CH:46]([CH3:48])[CH3:47])=[CH:41][CH:40]=2)Cl)=[CH:33][CH:32]=1)[CH:28]([CH3:30])[CH3:29].C(N(C(C)C)CC)(C)C>ClCCl>[CH2:45]([C:42]1[CH:43]=[CH:44][C:39]([CH:37]([C:34]2[CH:35]=[CH:36][C:31]([CH2:27][CH:28]([CH3:30])[CH3:29])=[CH:32][CH:33]=2)[O:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([C:8]3[N:16]4[C:11]([CH:12]=[CH:13][CH:14]=[CH:15]4)=[C:10]([CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:9]=3)=[O:7])=[CH:25][CH:26]=2)=[CH:40][CH:41]=1)[CH:46]([CH3:48])[CH3:47]
Reactant: CCOC(=O)CCCc1cc(C(=O)c2ccc(O)cc2)n2ccccc12
Reactant: CC(C)Cc1ccc(C(Cl)c2ccc(CC(C)C)cc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)CCCc1cc(C(=O)c2ccc(OC(c3ccc(CC(C)C)cc3)c3ccc(CC(C)C)cc3)cc2)n2ccccc12
Yield: 22 %

Procedure:
A mixture of ethyl 4-[3-(4-hydroxybenzoyl]indolizin-1-yl]butyrate (400 mg), bis(4-isobutylphenyl)chloromethane (430 mg) and diisopropylethylamine (736 mg) in dichloromethane (20 ml) was refluxed for 14 hours and evaporated. The residue was dissolved in ethyl acetate. The solution was washed with water and brine, dried over magnesium sulfate and evaporated. The residue was chromatographed on silica gel eluting with n-hexane and ethyl acetate (4:1) to give ethyl 4-[3-[4-[bis(4-isobutylphenyl)methoxy]benzoyl]indolizin-1-yl]butyrate (158 mg) as an oil.
Reaction SMILES: [NH2:1][C:2]1[S:3]C2C(F)=CC=CC=2N=1.[F:12][C:13]1[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:14]=1[NH2:15].FC1C(F)=CC=C(F)C=1N>>[NH2:1][C:2]1[S:3][C:16]2[CH:17]=[CH:18][C:19]([F:20])=[C:13]([F:12])[C:14]=2[N:15]=1
Reactant: Nc1cccc(F)c1F
Reactant: Nc1nc2cccc(F)c2s1
Agent: Nc1c(F)ccc(F)c1F
Product: Nc1nc2c(F)c(F)ccc2s1

Procedure:
The title compound was prepared following the route for 2-amino-7-fluoro-1,3-benzothiazole from 2,3-difluoroaniline, starting from 2,3,6-trifluoroaniline and conducting the first step at 100° C. for 4 h.
Reaction SMILES: [CH3:1][N:2]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH:3]([CH3:7])[C:4]([OH:6])=O.C1(N=C=NC2CCCCC2)CCCCC1.[NH2:30][C:31]1[N:36]=[C:35]([C:37]#[C:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:34]([NH:45][C:46]([CH:48]2[CH2:53][CH2:52][O:51][CH2:50][CH2:49]2)=[O:47])=[CH:33][CH:32]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:11]([O:10][C:8](=[O:9])[N:2]([CH3:1])[CH:3]([CH3:7])[C:4]([NH:30][C:31]1[CH:32]=[CH:33][C:34]([NH:45][C:46]([CH:48]2[CH2:53][CH2:52][O:51][CH2:50][CH2:49]2)=[O:47])=[C:35]([C:37]#[C:38][C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[N:36]=1)=[O:6])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C(=O)O)N(C)C(=O)OC(C)(C)C
Reactant: Nc1ccc(NC(=O)C2CCOCC2)c(C#Cc2ccccc2)n1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C(=O)Nc1ccc(NC(=O)C2CCOCC2)c(C#Cc2ccccc2)n1)N(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A mixture of 2-[methyl-[(2-methylpropan-2-yl)oxycarbonyl]amino]propanoic acid (34 mg, 0.17 mmol) and N,N′-dicyclohexylcarbodiimide (17 mg, 0.08 mmol) in DCM (1 ml) is stirred at RT for 20 minutes. This mixture is added to N-[6-amino-2-(2-phenylethynyl)pyridin-3-yl]oxane-4-carboxamide D5b (28 mg, 0.09 mmol) and DIPEA (17 μl; 0.10 mmol) in DCM (1 ml). After stirring for 6 days at 40° C. the reaction mixture is diluted with DCM and extracted with water. The combined organic layers are dried over MgSO4 to and concentrated in vacuo. The crude product (70 mg) is used in the next step without further purification.