Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[CH3:15][NH2:16].O>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:16][CH3:15])(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13]
Reactant: CN
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)Cl)ccc1Cl
Solvent: O
Solvent: C1CCOC1
Product: CNS(=O)(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-chloro-3-nitrobenzenesulfonyl chloride (2.0 g, 7.8 mmol) in THF (10 mL) was added excess methylamine (2M solution in THF). The reaction solution was stirred at room temperature for 1 hr. Water was then added and the product was extracted into chloroform. The combined extracts were washed, dried over sodium sulfate, filtered and evaporation to yield 2.3 g of the crude 4-chloro-N-methyl-3-nitrobenzenesulfonamide as an oil. The crude material was used in the subsequent step without further purification.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([C:15]([N:17]2[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[CH2:21][N:20]3[C:28]([C:31]([NH:33][CH2:34][C:35]4[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=4)=[O:32])=[CH:29][CH:30]=[C:19]3[CH2:18]2)=[O:16])=[CH:11][CH:10]=1)=O.Cl.[NH2:42][OH:43].N1C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>CO>[OH:43]/[N:42]=[CH:1]/[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:10]=[CH:11][C:12]([C:15]([N:17]2[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[CH2:21][N:20]3[C:28]([C:31]([NH:33][CH2:34][C:35]4[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=4)=[O:32])=[CH:29][CH:30]=[C:19]3[CH2:18]2)=[O:16])=[CH:13][CH:14]=1
Reactant: O=Cc1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)NCc4cccnc4)n3Cc3ccccc32)cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CO
Product: O=C(NCc1cccnc1)c1ccc2n1Cc1ccccc1N(C(=O)c1ccc(-c3ccccc3/C=N/O)cc1)C2
Yield: 89 %

Procedure:
To a solution of 10-[(2′-formyl-1,1′-biphenyl-4-yl)carbonyl]-N-(pyridin-3-ylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide of Example 56 (0.500 g, 0.95 mmol) and hydroxylamine hydrochloride (0.132 g, 1.90 mmol) in methanol (15 mL) was added pyridine (0.155 mL, 1.90 mmol) and the reaction mixture heated to reflux under nitrogen for 1 hour. The cooled reaction mixture was then poured into 5% w/v aqueous sodium carbonate solution (100 mL) and extracted with ethyl acetate (100 mL). The organic extract was washed with water (100 mL) and brine (100 mL), dried over anhydrous magnesium sulfate, and concentrated in vacuo to afford a white foam. Crystallization of the crude product from dichloromethane gave the title compound (0.458 g, 89%) as a white crystalline solid, m.p. 165-167° C.
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[H][H].[F:19][C:20]1[CH:21]=[C:22]([CH:25]=[C:26]([F:28])[CH:27]=1)[CH:23]=O>C(COC)OC.O>[CH2:15]([O:14][C:12](=[O:13])[CH2:11][CH2:23][C:22]1[CH:21]=[C:20]([F:19])[CH:27]=[C:26]([F:28])[CH:25]=1)[CH3:16]
Reactant: [H][H]
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: O=Cc1cc(F)cc(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CCOC(=O)CCc1cc(F)cc(F)c1
Temperature: 15 °C
Reaction time: 0.5 h
Yield: 70.2 %

Procedure:
Dimethoxyethane 350 ml was added to 60% sodium hydride 14.4 g (360 mmol), the mixture was stirred at room temperature while a solution of ethyl diethylphosphonoacetate 80.7 g (360 mmol) in dimethoxyethane (50 ml) was added dropwise. After the generation of hydrogen gas was stopped, the solution was cooled to 15° C., and a solution of 3,5-difluorobenzaldehyde 50.0 g (352 mmol) in dimethoxy ethane (50 ml) was added dropwise keeping the liquid temperature below 25° C. After addition, the mixture was stirred for 30 minutes, the reactant was added to water 300 ml, and the product was extracted with diethylether. The extract was washed with a sodium chloride aqueous solution, and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent: heptane/ethyl acetate=3/1). Such obtained purified material was hydrogenated in the presence of 5% palladium carbon as a catalyst in ethanol 300 ml. After hydrogenation, the catalyst was filtered off, the solvent was distilled off under reduced pressure to obtain 3-(3,5-difluorophenyl) propionic acid ethyl ester 53.0 g (247 mmol). The yield was 70.2% from 3,5-difluorobenzaldehyde.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=[C:12]([OH:23])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]([F:22])([F:21])[F:20])[C:10]#[N:11].ClC(Cl)C.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>C(N(CC)CC)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=[C:12]([O:23][S:29]([CH3:28])(=[O:31])=[O:30])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]([F:20])([F:21])[F:22])[C:10]#[N:11]
Reactant: CS(=O)(=O)Cl
Reactant: N#CC(=C(O)c1ccccc1C(F)(F)F)c1ccc(Cl)cc1Cl
Solvent: CC(Cl)Cl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OC(=C(C#N)c1ccc(Cl)cc1Cl)c1ccccc1C(F)(F)F

Procedure:
93 mg of triethylamine was added to a mixture comprising 0.30 g of α-(2,4-dichlorophenyl)-β-hydroxy-β-(2-trifluoromethylphenyl)acrylonitrile and 7 ml of dichloroethane. Then, 96 mg of methanesulfonyl chloride was added thereto, and the mixture was reacted for 17 hours at room temperature.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:31])[C:5]([CH3:30])=[C:6]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=3)=[C:17]([CH:21]=2)[C:18](O)=[O:19])[C:7](=[O:11])[C:8]=1[O:9][CH3:10].[CH3:32][O:33][C:34]1[CH:39]=[CH:38][C:37]([NH2:40])=[CH:36][CH:35]=1.C(N(CC)CC)C.[Cl-].ClC1N(C)CC[NH+]1C>C(Cl)Cl.O>[CH3:1][O:2][C:3]1[C:4](=[O:31])[C:5]([CH3:30])=[C:6]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=3)=[C:17]([CH:21]=2)[C:18]([NH:40][C:37]2[CH:38]=[CH:39][C:34]([O:33][CH3:32])=[CH:35][CH:36]=2)=[O:19])[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(N)cc1
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(-c3cccc(OC)c3)c(C(=O)O)c2)=C(C)C1=O
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC1=C(OC)C(=O)C(Cc2ccc(-c3cccc(OC)c3)c(C(=O)Nc3ccc(OC)cc3)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 54.5 %

Procedure:
5-(5,6-Dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-(3-methoxyphenyl) benzoic acid (100 mg, 0.2369 mmol) was dissolved in methylene chloride (20 ml), then p-anisidine (58 mg, 0.4715 mmol), triethylamine (48 mg, 0.4752 mmol) and 2-chloro-1,3-dimethylimidazolinium chloride (80 mg, 0.4733 mmol) were added thereto at room temperature and the mixture was stirred at room temperature for 16 hours. The reaction solution was poured into water and extracted with ethyl acetate. The extract was washed with water and dried and the solvent was evaporated therefrom. The residue was purified by preparative thin layer silica gel (hexane:ethyl acetate=1:1) to give the title compound (68 mg, 0.1290 mmol, 54%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH2:8][CH3:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:11].Cl[C:19](=[O:25])[CH2:20][C:21]([O:23][CH3:24])=[O:22]>>[CH3:24][O:23][C:21](=[O:22])[CH2:20][C:19]([NH:1][C:2]1[C:7]([CH2:8][CH3:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:10](=[O:11])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:25]
Reactant: COC(=O)CC(=O)Cl
Reactant: CCc1cccc(C(=O)c2ccccc2)c1N
Product: CCc1cccc(C(=O)c2ccccc2)c1NC(=O)CC(=O)OC

Procedure:
The title compound was prepared in analogy to example 21 step A from (2-amino-3-ethyl-phenyl)-phenyl-methanone and methyl 3-chloro-3-oxopropanoate. White solid. MS (ESI): 326.2 (M+H)+.
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[CH:5]=[C:6]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[NH:7][C:8]=1[CH3:9].CCN(CC)CC.OS([O-])=O.[Na+]>C(Cl)Cl>[Br:1][C:5]1[C:4]([Cl:3])=[C:8]([CH3:9])[NH:7][C:6]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)c1cc(Cl)c(C)[nH]1
Reactant: BrBr
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1[nH]c(C)c(Cl)c1Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 106.2 %

Procedure:
Bromine (0.56 ml, 11 mmol) was added to a solution of 1 g (5.3 mmol) of ethyl 4-chloro-5-methyl-1H-pyrrole-2-carboxylate (Intermediate 7) and 0.8 ml (5.7 mmol) Et3N in CH2Cl2. After stirring at room temperature for 2 h, aqueous NaHSO3 was added and the CH2Cl2 was removed and the aqueous residue was partitioned between water and EtOAc. The EtOAc was separated and washed with brine. Drying (MgSO4) and removal of solvent gave 1.5 g of product as a solid. MS (ES) (MH+): 240 for C8H9BrClNO2; NMR (d6-DMSO): 1.3 (t, 3H), 2.2 (s, 3H), 4.2 (q, 2H), 12.3 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[NH:23][C:10]3=[CH:11][C:12]4[C:13]([CH3:22])([CH3:21])[C:14](=[O:20])[N:15]([CH2:18][CH3:19])[C:16]=4[CH:17]=[C:9]3[N:8]=2)=[N:4][NH:5][CH:6]=1.[O:24]([CH2:31][C:32](Cl)=[O:33])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH2:18]([N:15]1[C:16]2[CH:17]=[C:9]3[N:8]=[C:7]([C:3]4[C:2]([NH:1][C:32](=[O:33])[CH2:31][O:24][C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)=[CH:6][NH:5][N:4]=4)[NH:23][C:10]3=[CH:11][C:12]=2[C:13]([CH3:22])([CH3:21])[C:14]1=[O:20])[CH3:19]
Reactant: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4N)nc3cc21
Reactant: O=C(Cl)COc1ccccc1
Product: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4NC(=O)COc4ccccc4)nc3cc21

Procedure:
N-[3-(5-Ethyl-7,7-dimethyl-6-oxo-1,5,6,7-tetrahydro-imidazo[4,5-f]indol-2-yl)-1H-pyrazol-4-yl]-2-phenoxy-acetamide was prepared using 2-(4-amino-1H-pyrazol-3-yl)-5-ethyl-7,7-dimethyl-5,7-dihydro-1H-imidazo[4,5-f]indol-6-one (250 mg, 0.81 mmol) and phenoxy acetyl chloride (122 μl, 0.89 mmol). The title compound was obtained as yellow powder (218 mg, 61%).
Reaction SMILES: [NH2:1][C:2]1([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.CC1C=CC(S(O)(=O)=O)=CC=1.C(N(CC)CC)C.[N:36]1([C:42](Cl)=[O:43])[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1>C(=O)([O-])[O-].[Na+].[Na+].C(Cl)(Cl)Cl>[N:36]1([C:42]([NH:1][C:2]2([C:8]([O:10][CH2:11][C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]2)=[O:43])[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1
Reactant: NC1(C(=O)OCc2ccccc2)CCCCC1
Reactant: O=C(Cl)N1CCOCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=C(NC1(C(=O)OCc2ccccc2)CCCCC1)N1CCOCC1
Temperature: 60 °C
Yield: 87.2 %

Procedure:
After neutralizing 203 g (500 mmol) of phenylmethyl 1-aminocyclohexanecarboxylate•p-toluenesulfonate with a 10% sodium carbonate solution, the mixture was extracted with chloroform and dried over anhydrous magnesium sulfate. The solid material was filtered off, and after adding 56 g (550 mmol) of triethylamine to the chloroform layer, 75 g (500 mmol) of 4-morpholinecarbonyl chloride was added dropwise, and the mixture was heated in an oil bath (60° C.) for 3 days. After completion of the reaction, the reaction mixture was washed successively in the order of water, a 10% aqueous potassium hydrogen sulfate solution, a saturated aqueous sodium hydrogen carbonate solution and a saturated NaCl solution, and dried over anhydrous sodium sulfate. After removing the solvent under reduced pressure, the resulting crystals were washed with ether to obtain 151 g (Yield: 87%) of the title compound.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1([C:22]([F:25])([F:24])[F:23])[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[C:6]2[CH:15]=[C:16]([N+:19]([O-:21])=[O:20])[CH:17]=[CH:18][C:5]=2[O:4]1.ClC1C=CC=C(C(OO)=[O:36])C=1.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl>[F:27][C:2]([F:1])([F:26])[C:3]1([C:22]([F:24])([F:25])[F:23])[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N+:10]=2[O-:36])[C:6]2[CH:15]=[C:16]([N+:19]([O-:21])=[O:20])[CH:17]=[CH:18][C:5]=2[O:4]1
Reactant: O=[N+]([O-])c1ccc2c(c1)C(c1ccccn1)=CC(C(F)(F)F)(C(F)(F)F)O2
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc2c(c1)C(c1cccc[n+]1[O-])=CC(C(F)(F)F)(C(F)(F)F)O2
Yield: 67.2 %

Procedure:
In 4 ml of methylene chloride was dissolved 200 mg of 2,2-bistrifluoromethyl-6-nitro-4-(2-pyridyl)-2H-1-benzopyran and 210 mg of m-chloroperbenzoic acid (67%) was added thereto with stirring under ice-cooling. The mixture was stirred at room temperature for 14 hours. Potassium carbonate solution was added thereto and the mixture was extracted with methylene chloride. The organic layer was washed with water and dried. The solvent was distilled off and the resultant residue was purified using silica gel column chromatography (developing solution, MeOH:CH2Cl2 =1:99) to obtain 140 mg of 2-(2,2-bistrifluoromethyl-6-nitro-2H-1-benzopyran-4-yl)pyridine N-oxide represented by the following formula having a melting point of 208-210° C.
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([Cl:17])=[C:5]([CH:10]=[CH:11][C:12]=1[S:13]([CH3:16])(=[O:15])=[O:14])[C:6]([O:8][CH3:9])=[O:7].[CH3:18][O-:19].[Na+]>CO>[CH3:9][O:8][C:6](=[O:7])[C:5]1[CH:10]=[CH:11][C:12]([S:13]([CH3:16])(=[O:15])=[O:14])=[C:3]([CH2:2][O:19][CH3:18])[C:4]=1[Cl:17]
Reactant: C[O-]
Reactant: COC(=O)c1ccc(S(C)(=O)=O)c(CBr)c1Cl
Agent: [Na+]
Solvent: CO
Product: COCc1c(S(C)(=O)=O)ccc(C(=O)OC)c1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 103.1 %

Procedure:
To a solution comprising 12.0 g of methyl 3-bromomethyl-2-chloro-4-methanesulfonylbenzoate prepared in Reference Example 3(1) and 100 ml of methanol, 50 ml of a methanol solution containing 1.7 g of sodium methoxide was added, and the mixture was stirred at room temperature overnight. The solvent was distilled off under reduced pressure. Then, dilute hydrochloric acid was added to the residue, and the mixture was extracted with chloroform. The extract was washed with water and dried over anhydrous sodium sulfate. Then, the solvent was distilled off to obtain 9.5 g of the desired product as a crude product. The crude product was purified by silica gel column chromatography (eluted with benzene) to obtain 7.5 g of a purified product as an oily substance.
Reaction SMILES: [OH:1][CH:2]([C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=1)[CH:3]([NH:18][C:19]([C:21]1[CH:22]=[CH:23][CH:24]=[C:25]2[CH2:31][CH2:30][CH2:29][CH:28]=[CH:27][C:26]=12)=[O:20])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]([F:17])([F:16])[CH:13]([F:15])[F:14])[CH:6]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:46][C:47]1[CH:56]=[CH:55][C:50]([C:51]([O:53][CH3:54])=[O:52])=[CH:49][CH:48]=1>CN(C)C=O.O>[C:21]1([C:19]([NH:18][CH:3]([CH2:4][C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]([F:16])([F:17])[CH:13]([F:15])[F:14])[CH:6]=2)[CH:2]([C:32]2[CH:37]=[CH:36][C:35]([O:38][CH2:46][C:47]3[CH:56]=[CH:55][C:50]([C:51]([O:53][CH3:54])=[O:52])=[CH:49][CH:48]=3)=[CH:34][CH:33]=2)[OH:1])=[O:20])[C:26]2[CH:27]=[CH:28][CH2:29][CH2:30][CH2:31][C:25]=2[CH:24]=[CH:23][CH:22]=1
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: O=C(NC(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1ccc(O)cc1)c1cccc2c1C=CCCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(COc2ccc(C(O)C(Cc3cccc(OC(F)(F)C(F)F)c3)NC(=O)c3cccc4c3C=CCCC4)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of N-{(1RS,2SR)-2-hydroxy-2-(4-hydroxyphenyl)-1-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]ethyl}-6,7-dihydro-5H-benzo[a][7]annulene-1-carboxamide (600 mg, 1.13 mmol) in N,N-dimethylformamide (20 ml) were added potassium carbonate (470 mg, 3.40 mmol) and methyl 4-(bromomethyl)-benzoate (780 mg, 3.40 mmol), and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed successively with water and saturated brine, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1-2:1). Recrystallization from ethyl acetate-hexane gave the objective substance (361 mg, 47%).
Reaction SMILES: [CH:1]1([C:4]2[N:16]3[C:7]([C:8]4[CH:9]=[C:10]([C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=5)[C:11]([C:17]5[CH:22]=[CH:21][C:20]([C:23]6([NH:27]C(=O)OC(C)(C)C)[CH2:26][CH2:25][CH2:24]6)=[CH:19][CH:18]=5)=[N:12][C:13]=4[CH:14]=[CH:15]3)=[N:6][N:5]=2)[CH2:3][CH2:2]1.[ClH:41].CCOC(C)=O>CO.C(Cl)Cl>[ClH:41].[CH:1]1([C:4]2[N:16]3[C:7]([C:8]4[CH:9]=[C:10]([C:35]5[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=5)[C:11]([C:17]5[CH:22]=[CH:21][C:20]([C:23]6([NH2:27])[CH2:24][CH2:25][CH2:26]6)=[CH:19][CH:18]=5)=[N:12][C:13]=4[CH:14]=[CH:15]3)=[N:6][N:5]=2)[CH2:2][CH2:3]1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4ccn5c(C6CC6)nnc5c4cc3-c3ccccc3)cc2)CCC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CO
Product: NC1(c2ccc(-c3nc4ccn5c(C6CC6)nnc5c4cc3-c3ccccc3)cc2)CCC1
Temperature: 25 °C

Procedure:
To a solution of tert-butyl {1-[4-(3-cyclopropyl-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl)phenyl]cyclobutyl}carbamate (MJK-9) (899.4 mg, 18.26 mmol) in MeOH (5 mL) and DCM (15 mL) was added a 4N solution of HCl in EtOAc (4.23 mL, 16.92 mmol). The sealed reaction mixture was permitted to stir at room temperature. After 18 hours the reaction mixture was filtered to give 1-[4-(3-methyl-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl)phenyl]cyclobutanamine hydrochloride (1-23) as a yellow solid. HRMS (M+H)+: observed=432.2186, calculated=432.2183.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[CH:21]=[N:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=2)[CH:7]=1)=[O:4].[NH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1.C([O-])([O-])=O.[K+].[K+].[N-]=C=O>CC#N.C(OCC)(=O)C>[N:22]1([CH2:2][C:3]([NH:5][C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([C:12]3[CH:21]=[N:20][C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[N:13]=3)[CH:7]=2)=[O:4])[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: O=C(CCl)Nc1cccc(-c2cnc3ccccc3n2)c1
Reactant: C1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [N-]=C=O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: O=C(CN1CCCC1)Nc1cccc(-c2cnc3ccccc3n2)c1
Temperature: 100 °C
Reaction time: 1 h
Yield: 40.3 %

Procedure:
A solution of 2-chloro-N-(3-quinoxalin-2-ylphenyl)acetamide (100 mg, 0.336 mmol), pyrrolidine (34 μL, 0.403 mmol) and K2CO3 (112 mg, 0.806 mmol) in MeCN (5 mL) was stirred at 50° C. for 18 hrs. HPLC analysis still showed starting material and therefore, the reaction mixture was further stirred at 100° C. for 1 h to afford completion. The mixture was cooled to room temperature and ethyl acetate (20 mL) was added, the organic phase was washed with water (20 mL) and then brine (20 mL), and dried over MgSO4, and solvent evaporated. The resulting oily solid was dissolved in DCM (5 mL) and stirred overnight with polystyrene methylisocyanate (“PS-isocyanate” 276 mg, 0.4 mmol, 1.46 mmol/g) to remove any excess pyrrolidine. The polymer was filtered and the organic phase was remove in vacuo, to afford 2-pyrrolidin-1-yl-N-(3-quinoxalin-2-ylphenyl)acetamide (45 mg, 40% yield). LCMS calculated for C20H20N4O (M+H): 333.41. found 333.21. 1H-NMR (DMSO-d6, 400 Mhz) δH: 9.95 (s, 1H), 9.51 (s, 1H), 8.55 (s, 1H), 8.20-8.14 (m, 2H), 8.08-8.02 (m, 1H), 7.95-7.82 (m, 3H), 7.58-7.50 (m, 1H), 3.40 (s, 2H), 2.65-2.55 (m, 4H), 1.85-1.75 (m, 4H).
Reaction SMILES: [C:1]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]([O:10][CH:11]1[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C:19]([OH:21])=O)[CH2:13][CH2:12]1)=[O:9].CCN(C(C)C)C(C)C.[NH2:37][CH2:38][C:39]1[CH:40]=[C:41]([CH:44]=[CH:45][CH:46]=1)[CH2:42][OH:43].CCN=C=NCCCN(C)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[OH:43][CH2:42][C:41]1[CH:40]=[C:39]([CH:46]=[CH:45][CH:44]=1)[CH2:38][NH:37][C:19]([CH2:18][CH2:17][N:14]1[CH2:13][CH2:12][CH:11]([O:10][C:8](=[O:9])[NH:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:16][CH2:15]1)=[O:21]
Reactant: O=C(O)CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1
Reactant: NCc1cccc(CO)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1)NCc1cccc(CO)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 57.3 %

Procedure:
To a stirred solution of 3-[4-(Biphenyl-2-ylcarbamoyloxy)piperidin-1-yl]propionic acid (0.5 g, 1.36 mmol; prepared as described in Preparation 11) in DCM (200 mL) was added DIPEA (10.7 mL, 6.12 mmol), 3-aminomethylbenzyl alcohol (0.33 g, 1.9 mmol), DMAP (0.14 g, 0.14 mmol) and EDCI (0.364 g, 1.9 mmol). The reaction mixture was stirred at room temperature for 2 hours. The mixture was concentrated, taken up in EtOAc (20 mL) and then washed with K2CO3 (3×10 mL), H2O (1×10 mL), brine (1×10 mL), dried over magnesium sulfate, filtered and concentrated. The mixture was purified on silica gel (7% MeOH/CHCl3) to afford 0.38 g of the title intermediate (57% yield).
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1([C:12]#[N:13])[CH2:11][NH:10][CH2:9]1.CCN(C(C)C)C(C)C.[CH2:23]([S:26](Cl)(=[O:28])=[O:27])[CH2:24][CH3:25]>C(Cl)Cl>[CH2:23]([S:26]([N:10]1[CH2:9][C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][N:2]=2)([C:12]#[N:13])[CH2:11]1)(=[O:28])=[O:27])[CH2:24][CH3:25]
Reactant: N#CC1(c2ccccn2)CNC1
Reactant: CCCS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCS(=O)(=O)N1CC(C#N)(c2ccccn2)C1
Reaction time: 4 h

Procedure:
A suspension of 3-pyridin-2-ylazetidine-3-carbonitrile hydrochloride (365 mg, 1.9 mmol) in CH2Cl2 (10 mL) at 0° C. was treated with i-Pr2NEt (1.1 mL, 6.3 mmol) and n-PrSO2Cl (0.35 mL, 3.1 mmol) dropwise. After 4 h, the reaction was quenched with the addition of 2 M aqueous NaOH (10 mL) and stirred 72 h before being extracted with CH2Cl2 (3×20 mL). The combined organic extracts were dried (Na2SO4) and concentrated under reduced pressure to afford 1-(propylsulfonyl)-3-pyridin-2-ylazetidine-3-carbonitrile (II-1) as an orange oil. Analytical LCMS: single peak (214 nm), 2.664 min. This material was used in subsequent reactions without further purification.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]([N:5]([CH2:15][CH:16]1[O:21][CH2:20][CH2:19][NH:18][CH2:17]1)[C@@H:6]1[CH2:8][C@H:7]1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:4].O=[CH:25][CH2:26][CH2:27][C:28]1[CH:38]=[CH:37][C:31]([C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:30][CH:29]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[F:23][C:2]([F:22])([F:1])[C:3]([N:5]([CH2:15][CH:16]1[CH2:17][N:18]([CH2:25][CH2:26][CH2:27][C:28]2[CH:38]=[CH:37][C:31]([C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:30][CH:29]=2)[CH2:19][CH2:20][O:21]1)[C@@H:6]1[CH2:8][C@H:7]1[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)=[O:4]
Reactant: O=C(N(CC1CNCCO1)[C@@H]1C[C@H]1c1ccccc1)C(F)(F)F
Reactant: CCOC(=O)c1ccc(CCC=O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CCOC(=O)c1ccc(CCCN2CCOC(CN(C(=O)C(F)(F)F)[C@@H]3C[C@H]3c3ccccc3)C2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 2,2,2-trifluoro-N-(morpholin-2-ylmethyl)-N-((1R,2S)-2-phenylcyclopropyl)acetamide (150 mg, 0.457 mmol) in 1,2-dichloroethane (DCE) (3 mL) were added ethyl 4-(3-oxopropyl)benzoate (113 mg, 0.548 mmol) and sodium triacetoxyborohydride (145 mg, 0.685 mmol), and the mixture was stirred at room temperature for 18 h. The reaction was quenched with water (5 mL) and extracted with DCM (3×). The extract was dried (Na2SO4) and concentrated. The residue was purified using column chromatography (silica gel, 20 to 100% EtOAc/hexanes) to give 200 mg or product as colorless oil. MS: (M+H)+=395.2. 1H NMR (400 MHz, METHANOL-d4) δ ppm 1.34-1.46 (m, 4H), 1.56 (br. s., 1H), 1.71-1.94 (m, 3H), 2.07-2.22 (m, 1H), 2.29-2.46 (m, 2H), 2.57 (br. s., 1H), 2.67-2.78 (m, 3H), 3.12-3.22 (m, 1H), 3.53-3.69 (m, 3H), 3.75-3.94 (m, 2H), 4.29-4.43 (m, 2H), 7.07-7.46 (m, 7H), 7.89-8.04 (m, 2H).