Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[NH:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[C:16]([C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1)=[O:17].F[C:26]1[C:31]([CH:32]2[CH2:38][CH2:37][N:36]([CH3:39])[C:35](=[O:40])[CH2:34][CH2:33]2)=[CH:30][CH:29]=[CH:28][N:27]=1>CN1CCCC1=O>[NH:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[C:16]([C:18]1[CH:23]=[CH:22][C:21]([O:24][C:26]2[C:31]([CH:32]3[CH2:38][CH2:37][N:36]([CH3:39])[C:35](=[O:40])[CH2:34][CH2:33]3)=[CH:30][CH:29]=[CH:28][N:27]=2)=[CH:20][CH:19]=1)=[O:17]
Reactant: CN1CCC(c2cccnc2F)CCC1=O
Reactant: O=C(c1ccc(O)cc1)c1nc2ccccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: CN1CCC(c2cccnc2Oc2ccc(C(=O)c3nc4ccccc4[nH]3)cc2)CCC1=O
Temperature: 140 °C

Procedure:
A mixture of cesium carbonate (0.29 g, 0.88 mmol), (1H-benzo[d]imidazol-2-yl)(4-hydroxyphenyl)methanone (0.21 g, 0.878 mmol), and 5-(2-fluoropyridin-3-yl)-1-methylazepan-2-one (0.07 g, 0.29 mmol) in 1-methyl-2-pyrrolidinone (0.5 mL) under argon was heated to 140° C. for 48 h, then cooled to room temperature. The resulting mixture was partitioned between ethyl acetate and water, the layers were separated, and the organic layer was washed with 1N aqueous sodium hydroxide (2×), saturated aqueous sodium chloride (1×), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The oil was purified by silica gel chromatography 5-(2-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)pyridin-3-yl)-1-methylazepan-2-one. MS (ESI, pos. ion) m/z: 441.1 (M+1). IC50 (uM) +++++.
Reaction SMILES: [CH:1]([C@:4]1([C:17]([N:19]2[CH2:24][CH2:23][N:22]([C:25]3[N:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][N:26]=3)[CH2:21][CH2:20]2)=[O:18])[CH2:8][CH2:7][C@@H:6]([NH:9]C(=O)OC(C)(C)C)[CH2:5]1)([CH3:3])[CH3:2]>Cl.O1CCOCC1>[CH:1]([C@:4]1([C:17]([N:19]2[CH2:24][CH2:23][N:22]([C:25]3[N:30]=[C:29]([C:31]([F:32])([F:33])[F:34])[CH:28]=[CH:27][N:26]=3)[CH2:21][CH2:20]2)=[O:18])[CH2:8][CH2:7][C@@H:6]([NH2:9])[CH2:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)[C@]1(C(=O)N2CCN(c3nccc(C(F)(F)F)n3)CC2)CC[C@@H](NC(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)[C@]1(C(=O)N2CCN(c3nccc(C(F)(F)F)n3)CC2)CC[C@@H](N)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 116.8 %

Procedure:
tert-Butyl [(1R,3S)-3-isopropyl-3-({4-[4-(trifluoromethyl)pyrimidin-2-yl]piperazin- 1-yl}carbonyl)cyclopentyl]carbamate (290 mg, 0.60 mmol) was dissolved in a 4.0 M solution of HCl in 1,4-dioxane (10 mL). After being stirred at room temperature for 1 h, the mixture was concentrated to give 270 mg of desired product. MS calculated for C18H26F3N5O:(M+H) 386; found 386.1.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]([C:24](O)=[O:25])[CH:13]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:14]([OH:16])=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:28][O:29][C:30](=[O:40])[C@H:31]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[NH2:32]>CN(C)C=O>[CH3:28][O:29][C:30](=[O:40])[C@H:31]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[NH:32][C:24](=[O:25])[C@H:12]([CH:13]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:14](=[O:15])[OH:16])[NH:11][C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:10]
Reactant: O=C(NC(C(=O)O)C(Cc1ccccc1)C(=O)O)OCc1ccccc1
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Agent: Cl
Solvent: CN(C)C=O
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](NC(=O)OCc1ccccc1)C(Cc1ccccc1)C(=O)O
Yield: 21.2 %

Procedure:
The process of Example 50 was repeated except that 715 mg (2.00 mmol) of N-benzyloxycarbonyl-(β-benzyl)-D,L-aspartic acid and 215 mg of L-phenylalanine methyl ester hydrochloride, 200 mg of Prolisin and 200 mg of the inhibitor were reacted. As a result, an 110 mg amount (yield of 21.2%) of N-benzyloxycarbonyl-(β-benzyl)-L-aspartyl-L-phenylalanine methyl ester having an [α]D22 = -12.8 (C=1.0 dimethylformamide) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH2:4][C:5]1([CH3:22])[CH2:10][CH2:9][C:8]2[C:11]([CH3:21])=[C:12]([O:17][CH2:18][CH:19]=[CH2:20])[C:13]([CH3:16])=[C:14]([CH3:15])[C:7]=2[O:6]1.C([O-])(=O)C.[Na+].[I:29]I.S([O-])([O-])(=O)=S.[Na+].[Na+]>O1CCCC1.CCOCC.O>[CH3:1][O:2][C:3](=[O:23])[CH2:4][C:5]1([CH3:22])[CH2:10][CH2:9][C:8]2[C:11]([CH3:21])=[C:12]([O:17][CH2:18][CH2:19][CH2:20][I:29])[C:13]([CH3:16])=[C:14]([CH3:15])[C:7]=2[O:6]1
Reactant: II
Reactant: C=CCOc1c(C)c(C)c2c(c1C)CCC(C)(CC(=O)OC)O2
Agent: CC(=O)[O-]
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)CC1(C)CCc2c(C)c(OCCCI)c(C)c(C)c2O1
Temperature: 25 °C
Reaction time: 18 h
Yield: 76.7 %

Procedure:
To a stirred, ice-cold solution of 1M borane in tetrahydrofuran (10 ml) was added, dropwise, a solution of 2 ml (1.64 g) of cyclohexene in 6 ml of dry tetrahydrofuran. The mixture was allowed to stir at 0°-5° C. for 1.5 hours. Tothe resulting slurry of dicyclohexylborane was added, dropwise a solution of 1.59 g of the allyl ether from Example 18 in 4 ml of tetrahydrofuran. The mixture was stirred at 0°-5° C. for 1 hour and at room temperature for 18 hours at which point 20 ml of 1M methanolic sodium acetate was added dropwise followed by 23.8 ml of 0.4M methanolic iodine. The resulting mixture was stirred at room temperature for 4 hours whereupon 3.1 ml of aqueous sodium thiosulfate was added. The reaction mixture was poured into water worked-up with ether in the usual manner. Chromatography of the crude product (4.4 g) on 100 g of silica gel afforded 1.71 g (76.7%) of racemic-3,4-dihydro-6-(3-iodopropoxy)2,5,7,8-tetramethyl-2H-1-benzopyran-2-acetic acid methyl ester as an oil, eluted with 19:1 and 9:1 hexane-ethyl acetate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:10]([Cl:22])=[N:11][C:12]([C:16]2[N:21]=[CH:20][CH:19]=[CH:18][N:17]=2)=[CH:13][C:14]=1[Cl:15].[CH3:23][CH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>>[Cl:15][C:14]1[CH:13]=[C:12]([C:16]2[N:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[N:11]=[C:10]([N:27]2[CH2:28][CH2:29][CH:24]([CH3:23])[CH2:25][CH2:26]2)[C:9]=1[C:3]1[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1].[Cl:22][C:10]1[C:9]([C:3]2[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])=[C:14]([N:27]2[CH2:28][CH2:29][CH:24]([CH3:23])[CH2:25][CH2:26]2)[CH:13]=[C:12]([C:16]2[N:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[N:11]=1
Reactant: CC1CCNCC1
Reactant: Fc1cccc(Cl)c1-c1c(Cl)cc(-c2ncccn2)nc1Cl
Product: CC1CCN(c2cc(-c3ncccn3)nc(Cl)c2-c2c(F)cccc2Cl)CC1
Product: CC1CCN(c2nc(-c3ncccn3)cc(Cl)c2-c2c(F)cccc2Cl)CC1

Procedure:
In a stainless steel autoclave, 500 mg (1.4 mmol) of 3-(2-chloro-6-fluorophenyl)-2,4-dichloro-6-(pyrimidin-2-yl)pyridine (Example C) and 15 g of 4-methylpiperidin were heated at 140° C. for 12 h. The volatile components were removed under reduced pressure and the residue was chromatographed on silica gel using cyclohexane/ethyl acetate. It was possible to isolate 220 mg of 4-chloro-3-(2-chloro-6-fluorophenyl)-2-(4-methylpiperidinyl)-6-(pyrimidin-2-yl)pyridine (m.p. 129° C.) and 60 mg of 2-chloro-3-(2-chloro-6-fluorophenyl)-4-(4-methylpiperidinyl)-6-(pyrimidin-2-yl)pyridine (m.p. 129° C.).
Reaction SMILES: [CH3:1][C:2]1[C:8](=[O:9])[C:7]2[N:10]3[C@@:14]([O:21][CH3:22])([C@H:15]([CH2:16][O:17][C:18]([NH2:20])=[O:19])[C:6]=2[C:4](=[O:5])[C:3]=1OC)[C@H:13]1[N:23]([CH3:24])[C@H:12]1[CH2:11]3.Cl.[Cl:28][CH2:29][CH2:30][NH2:31].C([O-])(=O)C.[Na+]>CO>[C:18](=[O:17])([OH:19])[NH2:20].[OH:17][CH2:16][CH:15]1[C:6]2[C:4](=[O:5])[C:3]([NH:31][CH2:30][CH2:29][Cl:28])=[C:2]([CH3:1])[C:8](=[O:9])[C:7]=2[N:10]2[CH2:11][CH:12]3[N:23]([CH3:24])[CH:13]3[C:14]12[O:21][CH3:22]
Reactant: NCCCl
Reactant: COC1=C(C)C(=O)C2=C(C1=O)[C@@H](COC(N)=O)[C@@]1(OC)[C@@H]3[C@H](CN21)N3C
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC12C(CO)C3=C(C(=O)C(C)=C(NCCCl)C3=O)N1CC1C2N1C
Product: NC(=O)O
Reaction time: 0.17 h
Yield: 82.9 %

Procedure:
To a solution of 33 mg (0.09 mmol) of N-methylmitomycin A in 5 ml of anhydrous methanol, a solution of 56 mg of 2-chloroethylamine hydrochloride (0.5 mmol) in 2.5 ml of methanol and a solution of 41 mg sodium acetate (0.5 mmol) in 2.5 ml of methanol were added alternatively with constant stirring over a period of 10 minutes. The stirred reaction mixture was checked frequently by TLC and the reaction appeared to be complete in 24 hours. The solvent was evaporated and the residue was chromatographed using silica-gel as adsorbent. The fraction obtained by eluting the column with ethyl acetate was evaporated under reduced pressure. Recrystallization from a mixture of chloroform and hexane gave 16 mg (38% yield) of the desired product as purple-colored crystals having a melting point of 73°-74° C. (decomposing) and providing the following analysis:
Reaction SMILES: [F:1][C:2]1C=CC(C=O)=CC=1.N1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.[CH3:16][C:17]([OH:19])=O.O>C1C=CC=CC=1.CCOCC>[F:1][CH2:2][C:17]([C:16]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:19]
Reactant: CC(=O)O
Reactant: C1CCNCC1
Reactant: O=Cc1ccc(F)cc1
Solvent: c1ccccc1
Solvent: O
Solvent: CCOCC
Product: O=C(CF)c1ccccc1
Yield: 82 %

Procedure:
A mixture of 4-fluorobenzaldehyde (4.768 g, 38.4 mmol), the compound from Example 95, part A (6.000 g, 38.4 mmol), piperidine (380 μl), and HOAc (75 μl) was refluxed in benzene (40 ml) with removal of water (Dean-Stark trap) for 16 hours. The cooled mixture was diluted with Et2O and washed successively with 5% HCl, saturated NaHCO3, H2O, and brine, then dried (Na2SO4), filtered, and stripped to yield an oil. Distillation of the oil (bp 127°-135° C. at 0.2 mm Hg) afforded compound A (9.299 g, 82%) as a pale yellow liquid.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[C:7]([O:10][C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13]([OH:15])=O)(=[O:9])[CH3:8].[NH2:20][C:21]1[CH:33]=[C:32]([CH2:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:31]=[CH:30][C:22]=1[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24].C(=O)([O-])O.[Na+]>C(N(CC)CC)C.C(Cl)Cl.CN(C)C=O>[C:7]([O:10][C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13]([NH:20][C:21]1[CH:33]=[C:32]([CH2:34][CH2:35][C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:31]=[CH:30][C:22]=1[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[O:15])(=[O:9])[CH3:8]
Reactant: CC(=O)Oc1ccccc1C(=O)O
Reactant: CC(C)(C)OC(=O)c1ccc(CCc2ccccc2)cc1N
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Oc1ccccc1C(=O)Nc1cc(CCc2ccccc2)ccc1C(=O)OC(C)(C)C
Reaction time: 1 h

Procedure:
2.0 mL of methylene chloride, 2.7 μL of N,N-dimethylformamide and 0.061 mL of oxalyl chloride were added to 0.13 g of 2-acetoxybenzoic acid at room temperature sequentially and stirred at the same temperature for 1 hour. The reaction mixture was added to a mixed solution of 3.0 mL of methylene chloride and 0.45 mL of triethylamine containing 60 mg of tert-butyl 2-amino-4-phenethylbenzoate at room temperature and stirred at the same temperature for 1 hour. A saturated sodium hydrogen carbonate aqueous solution was added to the reaction mixture, and the organic layer was separated, and the solvent was evaporated under reduced, pressure. The obtained residue was purified with silica gel column chromatography [Flash Tube 2008 manufactured by Trikonex Company, eluent; hexane; ethyl acetate=4:1] to obtain tert-butyl 2-(2-acetoxybenzamido)-4-phenethylbenzoate.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH:4]1[CH2:8][C:7]2[CH:9]=[CH:10][CH:11]=[C:12]([C:13]3[C:18]([Cl:19])=[CH:17][C:16]([Cl:20])=[CH:15][C:14]=3[Cl:21])[C:6]=2[O:5]1.C(N(C(C)C)CC)(C)C.Cl[C:32]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:33]>>[CH3:1][N:2]([CH2:3][CH:4]1[CH2:8][C:7]2[CH:9]=[CH:10][CH:11]=[C:12]([C:13]3[C:14]([Cl:21])=[CH:15][C:16]([Cl:20])=[CH:17][C:18]=3[Cl:19])[C:6]=2[O:5]1)[C:32](=[O:33])[O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CNCC1Cc2cccc(-c3c(Cl)cc(Cl)cc3Cl)c2O1
Solvent: CCN(C(C)C)C(C)C
Product: CN(CC1Cc2cccc(-c3c(Cl)cc(Cl)cc3Cl)c2O1)C(=O)OCc1ccccc1
Yield: 94 %

Procedure:
Treatment of (±)-N-methyl-1-[7-(2,4,6-trichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine (1.1 g, 3.57 mmol) with diisopropylethylamine (0.69 g, 5.35 mmol) and benzyl chloroformate (0.0.82 g, 4.28 mmol) generally according to the procedure described for Intermediate 12 provided 1.6 g (99%) of (±)-benzyl methyl{[7-(2,4,6-trichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}carbamate as a colorless oil.
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:3]=1[C:4]1[C:5]([O:20][CH3:21])=[CH:6][C:7]([O:16][CH2:17][CH2:18][CH3:19])=[CH:8][C:9]=1[C:10]2=[O:15].Cl.Cl[CH2:24][CH2:25][N:26]([CH2:29][CH3:30])[CH2:27][CH3:28].C[O-].[Na+]>CO.ClC1C=CC=CC=1>[CH2:25]([N:26]([CH2:29][CH3:30])[CH2:27][CH2:28][O:1][C:2]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:3]=1[C:4]1[C:5]([O:20][CH3:21])=[CH:6][C:7]([O:16][CH2:17][CH2:18][CH3:19])=[CH:8][C:9]=1[C:10]2=[O:15])[CH3:24]
Reactant: CCCOc1cc(OC)c2c(c1)C(=O)c1cccc(O)c1-2
Reactant: CCN(CC)CCCl
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: Clc1ccccc1
Solvent: CO
Product: CCCOc1cc(OC)c2c(c1)C(=O)c1cccc(OCCN(CC)CC)c1-2
Yield: 47.1 %

Procedure:
In a manner analagous to Example 9B, react 5-hydroxy-2-propoxy-4-methoxy-fluoren-9-one (1.75 g, 6.1) in 5 mL methanol and 100 mL chlorobenzene with 2-chloroethyldiethyl amine hydrochloride (4.4 g, 25 mmole) and sodium methoxide (0.51 g, 9.5 mmole) and reflux for 2 hours then continue as in Example 9B to give 1.1 g. of the title compound (2.9 mmole, 47%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([CH3:13])([CH3:12])[CH2:7][CH2:6][C:5]2([CH3:15])[CH3:14].[NH2:16][C:17]1[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][C:18]=1[N+:25]([O-:27])=[O:26].CC([O-])(C)C.[Na+].C(PC1C=CC=CC=1C1C=CC=CC=1)(C)(C)C>C1COCC1>[N+:25]([C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][C:17]=1[NH:16][C:2]1[CH:11]=[CH:10][C:9]2[C:8]([CH3:13])([CH3:12])[CH2:7][CH2:6][C:5]([CH3:15])([CH3:14])[C:4]=2[CH:3]=1)[C:21]#[N:22])([O-:27])=[O:26]
Reactant: N#Cc1ccc(N)c([N+](=O)[O-])c1
Reactant: CC1(C)CCC(C)(C)c2cc(Br)ccc21
Agent: CC(C)(C)Pc1ccccc1-c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC1(C)CCC(C)(C)c2cc(Nc3ccc(C#N)cc3[N+](=O)[O-])ccc21
Temperature: 80 °C

Procedure:
To a solution of 6-bromo-1,1,4,4-tetramethyl-1,2,3,4-tetrahydronaphthalene (61.3 mmol) and 4-amino-3-nitrobenzonitrile (61.3 mmol) in THF (150 mL) are added NaOtBu (67.4 mmol), 2-(t-butylphosphino)biphenyl (6.13 mmol), and Pd2(bda)3 (3.06 mmol) at room temperature. The reaction mixture is heated at 80° C. for 2 h. After cooling, the mixture is filtered through Celite. The filtrate is diluted with H2O and extracted with EtOAc. The organic layer is dried over MgSO4 and evaporated in vacuo. The resulting solid is washed with a mixture of hexane and EtOAc (8:1) to give (30).
Reaction SMILES: F[C:2]1[C:12]([F:13])=[CH:11][C:10]([C:14]2[CH:15]=[C:16]3[C:22]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[O:29][CH3:30])=[N:21][N:20](COCC[Si](C)(C)C)[C:17]3=[N:18][CH:19]=2)=[CH:9][C:3]=1[C:4]([N:6]([CH3:8])[CH3:7])=[O:5].[CH2:39]([N:41]([CH2:49][CH3:50])[CH:42]1[CH2:47][CH2:46][CH:45]([NH2:48])[CH2:44][CH2:43]1)[CH3:40]>S([O-])(O)(=O)=O.[K+].FC(F)(F)C(O)=O>[CH2:49]([N:41]([CH2:39][CH3:40])[CH:42]1[CH2:47][CH2:46][CH:45]([NH:48][C:2]2[C:12]([F:13])=[CH:11][C:10]([C:14]3[CH:15]=[C:16]4[C:22]([C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=5[O:29][CH3:30])=[N:21][NH:20][C:17]4=[N:18][CH:19]=3)=[CH:9][C:3]=2[C:4]([N:6]([CH3:8])[CH3:7])=[O:5])[CH2:44][CH2:43]1)[CH3:50]
Reactant: COc1ccccc1-c1nn(COCC[Si](C)(C)C)c2ncc(-c3cc(F)c(F)c(C(=O)N(C)C)c3)cc12
Reactant: CCN(CC)C1CCC(N)CC1
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Product: CCN(CC)C1CCC(Nc2c(F)cc(-c3cnc4[nH]nc(-c5ccccc5OC)c4c3)cc2C(=O)N(C)C)CC1
Reaction time: 48 h

Procedure:
Into a 5 mL screw-cap vial were added 2,3-difluoro-5-[3-(2-methoxy-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-N,N-dimethyl-benzamide (266 mg, 0.46 mmol) and 4-diethylamino-cyclohexylamine (468 mg, 2.74 mmol, mixture of cis/trans isomers). The vial was sealed and placed in heated block at 120° C. for 48 h. The reaction solution was suspended in 1 N aqueous potassium hydrogensulfate solution and loaded onto a 5 g C18 functionalized silica gel cartridge. The plug was washed with 1 N aqueous potassium hydrogensulfate and water. Elution with acetonitrile and evaporation of the solvent afforded a brown oil which was dissolved in 5 mL trifluoroacetic acid. The resulting mixture was stirred for 1 h and then the reaction mixture was concentrated. The residue was dissolved in 2 mL of methanol and 200 μL ethylenediamine were added. The mixture was diluted with 2 mL of DMSO and purified by reverse-phase HPLC to afford 43.4 mg (0.63 mmol, 14%) of both diastereomers of 2-(4-diethylamino-cyclohexylamino)-3-fluoro-5-[3-(2-methoxy-phenyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-N,N-dimethyl-benzamide separately as colorless powders. More polar diastereomer (21.3 mg) 1H NMR (500 MHz, DMSO-d6) δ 13.75 (s, 1H), 8.81 (d, J=1.5 Hz, 1H), 8.27 (d, J=2 Hz, 1H), 7.62 (dd, J=8 Hz, J2=2 Hz, 1H), 7.58 (dd, J=14 Hz, J2=2 Hz, 1H), 7.45 (m, 1H), 7.30 (d, J=2 Hz, 1H), 7.19 (d, J=8 Hz, 1H), 7.08 (td, J=7.5 Hz, J2=1 Hz, 1H), 4.53 (dd, J=8 Hz, J2=1.5 Hz, 1H), 3.82 (s, 3H), 3.12 (m, 1H), 2.75-3.05 (m, 7H), 2.44 (q, J=7 Hz, 4H), 1.89 (m, 2H), 1.69 (m, 2H), 1.19 (m, 4H), 0.93 (t, J=7 Hz, 6H). MS: m/z 559.3 (M+H+). Less polar diastereomer (22.1 mg) 1H NMR (500 MHz, DMSO-d6) δ 13.76 (s, 1H), 8.83 (d, J=2.5 Hz, 1H), 8.30 (d, J=2.5 Hz, 1H), 7.64 (dd, J=4.5 Hz, J2=1.5 Hz, 1H), 7.61 (t, J=2 Hz, 1H), 7.45 (m, 1H), 7.42 (d, J=2 Hz, 1H), 7.20 (d, J=8 Hz, 1H), 7.08 (t, J=7.5 Hz, 1H), 4.99 (dd, J=10 Hz, J2=1 Hz, 1H), 3.82 (s, 3H), 3.68 (m, 1H), 3.32 (m, 1H), 2.97 (bs, 6H), 2.46 (q, J=7 Hz, 4H), 1.70 (m, 2H), 1.50 (m, 2H), 1.43 (m, 2H), 1.35 (m, 2H), 0.94 (t, J=7 Hz, 6H). MS: m/z 559.3 (M+H+).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.C([CH:15]([C:19]([OH:21])=[O:20])[C:16]([OH:18])=O)(C)(C)C>>[C:3]([O:21][C:19]([C:15]1[C:16](=[O:18])[O:1][C:2]2[C:3]([CH:4]=1)=[CH:6][CH:7]=[C:8]([OH:10])[CH:9]=2)=[O:20])([CH3:6])([CH3:4])[CH3:2]
Reactant: CC(C)(C)C(C(=O)O)C(=O)O
Reactant: O=Cc1ccc(O)cc1O
Product: CC(C)(C)OC(=O)c1cc2ccc(O)cc2oc1=O

Procedure:
2,4-dihydroxyl benzaldehyde and tert-butyl malonic acid are reacted to obtain 7-hydroxyl-3-coumarin formic acid tert-butyl ester, which in turn is Mitsunobu condensed with 2-(5-methyl-2-phenyl-4-oxazole)ethanol to obtain the compound 17. The solvents used in Mitsunobu reaction are the anhydrous inert solvents, such as anhydrous tetrahydrofuran, anhydrous dioxane, anhydrous benzene, anhydrous ether, chloroform, dichloromethane or the like, and the anhydrous tetrahydrofuran is preferable. The reaction temperature is between −10-100° C., and the room temperature is preferable. The reaction time is between 0.1-72 hours, and 24 hours are preferable.
Reaction SMILES: [C:1]([CH:3]=[C:4]1[CH2:7][N:6](C(OC(C)(C)C)=O)[CH2:5]1)#[N:2].CCN(C(C)C)C(C)C.[CH2:24]([S:26](Cl)(=[O:28])=[O:27])[CH3:25]>Cl.O1CCOCC1.O>[CH2:24]([S:26]([N:6]1[CH2:5][C:4](=[CH:3][C:1]#[N:2])[CH2:7]1)(=[O:28])=[O:27])[CH3:25]
Reactant: CCS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CC(=CC#N)C1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CCS(=O)(=O)N1CC(=CC#N)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
tert-Butyl 3-(cyanomethylidene)azetidine-1-carboxylate (5.0 g, 26 mmol) was dissolved in 4M HCl in dioxane (25.7 mL) and allowed to stir at ambient temperature for 16 hours. The mixture was concentrated to dryness in vacuo, then dissolved in DCM (30.0 mL) and cooled to −10° C. DIPEA (11.6 g, 90.0 mmol) was added followed by ethanesulfonyl chloride (5.0 g, 39 mmol). The resulting mixture was allowed to stir for 7 hours before the mixture was diluted with water and extracted with DCM. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by MPLC on silica gel (using a gradient elution of 5-70% EtOAc/heptane). Desired fractions were identified, combined, and concentrated in vacuo to afford the title compound.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[C:11]([O:15][C:16](=[O:27])[NH:17][C@H:18]([C:20](=[O:26])[NH:21][CH2:22][CH:23]([OH:25])[CH3:24])[CH3:19])([CH3:14])([CH3:13])[CH3:12].C(N(CC)CC)C>C(Cl)Cl>[C:11]([O:15][C:16](=[O:27])[NH:17][C@H:18]([C:20](=[O:26])[NH:21][CH2:22][C:23](=[O:25])[CH3:24])[CH3:19])([CH3:12])([CH3:13])[CH3:14]
Reactant: CC(O)CNC(=O)[C@H](C)NC(=O)OC(C)(C)C
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CC(=O)CNC(=O)[C@H](C)NC(=O)OC(C)(C)C
Yield: 60.2 %

Procedure:
Dimethylsulfoxide (7.16 ml, 100.8 mmol) is added to a solution of oxalyl chloride (4.41 ml, 50.4 mmol) in 126 mL of methylene chloride at −78° C. The mixture is left to stir for fifteen minutes, and a solution of (2RS, 1S)-[1-(2-hydroxy-propylcarbamyl)-ethyl]-carbamic acid tert-butyl ester (9.92 g, 40.32 mmol) in 100 mL of CH2Cl2 is added dropwise. After stirring for 15 minutes at −78° C., the reaction is quenched with triethylamine (28 mL, 381 mmol), and the temperature is allowed to rise to room temperature. The volatile solvents are removed, and the residue is purified by flash column (SiO2, 60% EtOAc/Hexane). The product (1S)-[1-(2-oxo-propylcarbamoyl)-ethyl]-carbamic acid tertbutyl ester (5.93 g, 60%) is isolated as a white solid. MS C11H20N2O4 MS m/z: 245.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:10]=[CH:9][N:8]([CH:11]3[CH2:15][CH2:14][CH2:13][CH2:12]3)[C:4]=2[N:5]=[CH:6][N:7]=1.[I:16]Cl>>[I:16][C:10]1[C:3]2[C:2]([Cl:1])=[N:7][CH:6]=[N:5][C:4]=2[N:8]([CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)[CH:9]=1
Reactant: ClI
Reactant: Clc1ncnc2c1ccn2C1CCCC1
Product: Clc1ncnc2c1c(I)cn2C1CCCC1
Temperature: 25 °C

Procedure:
To a stirred solution of 4-Chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine (1A, 116 g, 0.52 mole) in 1200 mL CH2CL2 was slowly added a dark brown solution of iodine monochloride (1.0 M, 785 mL) at room temperature over 30 minutes. The reaction mixture was refluxed for 22 h, cooled to room temperature and concentrated. The residue was redissolved in EtOAc, washed with saturated Na2SO3, H2O and brine. The organic layer was dried over Na2SO4 and concentrated. The residue was then recrystalized from i-PrOH to furnish 95 g white crystalline product.
Reaction SMILES: CN1C([CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:21][CH2:20][N:19]([C:22]4[CH2:23][CH2:24][C:25]5[N:26]([C:28]([C:31]([F:34])([F:33])[F:32])=[N:29][N:30]=5)[N:27]=4)[CH2:18][CH2:17]3)=[CH:12][CH:11]=2)=CC=N1.OCC[N:38]1[CH2:43][CH2:42][N:41]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:40][CH2:39]1>>[F:34][C:31]([F:32])([F:33])[C:28]1[N:26]2[N:27]=[C:22]([N:19]3[CH2:18][CH2:17][N:16]([C:13]4[CH:14]=[CH:15][C:10]([O:9][CH2:8][CH2:7][N:38]5[CH2:39][CH2:40][N:41]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:42][CH2:43]5)=[CH:11][CH:12]=4)[CH2:21][CH2:20]3)[CH:23]=[CH:24][C:25]2=[N:30][N:29]=1
Reactant: Cn1nccc1CCOc1ccc(N2CCN(C3=Nn4c(nnc4C(F)(F)F)CC3)CC2)cc1
Reactant: CC(C)(C)OC(=O)N1CCN(CCO)CC1
Product: CC(C)(C)OC(=O)N1CCN(CCOc2ccc(N3CCN(c4ccc5nnc(C(F)(F)F)n5n4)CC3)cc2)CC1
Yield: 60 %

Procedure:
Obtained in 60% yield by an analogous method to Example 29, preparation of starting materials, starting from 4-{4-[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperazin-1-yl}phenol (obtained as described in Example 16, preparation of starting materials) and tert-butyl 4-(2-hydroxyethyl)piperazine-1-carboxylate (CAS 77279-24-4).