Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[CH:10]=2)[N:5]=[CH:4][N:3]=1.[CH:19]1([NH2:22])[CH2:21][CH2:20]1>>[CH:19]1([NH:22][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([C:12]4[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=4)[CH:10]=3)[N:5]=[CH:4][N:3]=2)[CH2:21][CH2:20]1
Reactant: NC1CC1
Reactant: Fc1ccc(-c2ccc3ncnc(Cl)c3c2)cc1
Product: Fc1ccc(-c2ccc3ncnc(NC4CC4)c3c2)cc1
Yield: 80 %

Procedure:
This compound was synthesized from 4-chloro-6-(4-fluorophenyl)-quinazoline and cyclopropylamine in 80% yield, using the procedure described example 37 and was characterized by its mass spectrum as follows: MS (m/z): 298 ([M+H]+, 100).
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:18][C:17]([CH3:20])([CH3:19])[CH2:16][C:15]2[N:14]=[C:13]([CH:21]([CH3:23])[CH3:22])[C:12]([CH:24]=[O:25])=[C:11]([C:26]3[CH2:27][CH2:28][O:29][CH2:30][CH:31]=3)[C:10]1=2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Br[C:33]1[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:35][N:34]=1>>[Si:1]([O:8][C@H:9]1[CH2:18][C:17]([CH3:19])([CH3:20])[CH2:16][C:15]2[N:14]=[C:13]([CH:21]([CH3:22])[CH3:23])[C:12]([C@H:24]([C:33]3[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:35][N:34]=3)[OH:25])=[C:11]([C:26]3[CH2:27][CH2:28][O:29][CH2:30][CH:31]=3)[C:10]1=2)([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:2])[CH3:3]
Reactant: FC(F)(F)c1ccc(Br)nc1
Reactant: CC(C)c1nc2c(c(C3=CCOCC3)c1C=O)[C@@H](O[Si](C)(C)C(C)(C)C)CC(C)(C)C2
Product: CC(C)c1nc2c(c(C3=CCOCC3)c1[C@@H](O)c1ccc(C(F)(F)F)cn1)[C@@H](O[Si](C)(C)C(C)(C)C)CC(C)(C)C2

Procedure:
Obtained by starting from (S)-5-(tert-butyldimethylsilyloxy)-4-(3,6-dihydro-2H-pyran-4-yl)-2-isopropyl-7,7-dimethyl-5,6,7,8-tetrahydroquinoline-3-carbaldehyde and 2-bromo-5-(trifluoromethyl)pyridine.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:29][C:30]1[C:37]([C:38]([F:41])([F:40])[F:39])=[CH:36][CH:35]=[CH:34][C:31]=1[CH:32]=O>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:32][C:31]3[CH:34]=[CH:35][CH:36]=[C:37]([C:38]([F:39])([F:41])[F:40])[C:30]=3[Cl:29])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1cccc(C(F)(F)F)c1Cl
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Product: FC(F)(F)c1cccc(CNc2cccc(-c3c(Cc4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)c1Cl

Procedure:
This compound was prepared according to the procedure of example 66, substituting 3-(3-benzyl-8-trifluoromethyl-quinolin-4-yl)-phenylamine and 2-chloro-3 trifluoromethyl-benzaldehyde. MS (ESI) m/z 552.
Reaction SMILES: [N:1]1([C:6]2[CH:39]=[CH:38][C:9]([CH2:10][C:11]3[C:12](Cl)=[N:13][C:14]4[C:19]([C:20]=3[Cl:21])=[CH:18][C:17]([C:22]([C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=3)([C:24]3[N:28]([CH3:29])[CH:27]=[N:26][CH:25]=3)[OH:23])=[CH:16][CH:15]=4)=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.[CH3:40][O:41][CH2:42][CH2:43][OH:44].C1(C)C=CC=CC=1.[H-].[Na+]>CCOC(C)=O>[Cl:21][C:20]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:22]([C:30]3[CH:31]=[CH:32][C:33]([Cl:36])=[CH:34][CH:35]=3)([C:24]3[N:28]([CH3:29])[CH:27]=[N:26][CH:25]=3)[OH:23])[CH:18]=2)[N:13]=[C:12]([O:44][CH2:43][CH2:42][O:41][CH3:40])[C:11]=1[CH2:10][C:9]1[CH:38]=[CH:39][C:6]([N:1]2[CH:5]=[CH:4][CH:3]=[N:2]2)=[CH:7][CH:8]=1
Reactant: Cn1cncc1C(O)(c1ccc(Cl)cc1)c1ccc2nc(Cl)c(Cc3ccc(-n4cccn4)cc3)c(Cl)c2c1
Reactant: COCCO
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COCCOc1nc2ccc(C(O)(c3ccc(Cl)cc3)c3cncn3C)cc2c(Cl)c1Cc1ccc(-n2cccn2)cc1
Temperature: 0 °C

Procedure:
(3-(4-(1H-Pyrazol-1-yl)benzyl)-2,4-dichloroquinolin-6-yl)(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methanol (100 mg, 0.174 mmol, Intermediate 64), 2-methoxyethanol (13.7 μL, 0.174 mmol), toluene (2 mL) and sodium hydride (60% dispersion in mineral oil, 17.4 mg, 0.435 mmol) were combined in a round bottom flask under an N2 atmosphere. The contents were heated to reflux and refluxed overnight. The reaction solution turned from a heterogeneous white mixture to slightly yellowish with a moderate amount of precipitate. The contents were cooled to 0° C. in an ice water bath then transferred to a separatory funnel with EtOAc dilution and extracted with saturated, aqueous NH4Cl and saturated, aqueous NaHCO3 solutions. The organic phase was separated then dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography (silica gel, 0-10% DCM/(10% of a 2 M NH3 MeOH in DCM)) then further purified via reverse phase chromatography using acetonitrile with ammonium hydroxide in water as eluent to afford the title compound. MS (ESI): mass calcd. for C33H29Cl2N5O3, 613.2. m/z found, 614.3 [M+H]+. 1H NMR (400 MHz, CD3OD) δ ppm 8.14 (d, J=2.5 Hz, 1H), 8.11 (d, J=2.1 Hz, 1H), 7.88 (s, 1H), 7.80 (d, J=8.8 Hz, 1H), 7.68 (d, J=1.7 Hz, 1H), 7.64 (dd, J=8.8, 2.1 Hz, 1H), 7.60 (d, J=8.6 Hz, 2H), 7.45 (d, J=8.6 Hz, 2H), 7.41-7.32 (m, 4H), 6.50-6.46 (m, 1H), 6.36 (s, 1H), 4.66-4.59 (m, 2H), 4.35 (s, 2H), 3.81-3.74 (m, 2H), 3.49 (s, 3H), 3.40 (s, 3H).
Reaction SMILES: F[C:2]1[C:7]([F:8])=[C:6]([C:9]2[CH:10]=[N:11][C:12]([NH2:30])=[C:13]([O:15][C@@H:16]([C:18]3[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=3[N:25]3[N:29]=[CH:28][CH:27]=[N:26]3)[CH3:17])[CH:14]=2)[CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl.[OH:38][CH:39]1[CH2:42][NH:41][CH2:40]1>CS(C)=O>[NH2:30][C:12]1[N:11]=[CH:10][C:9]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([N:41]3[CH2:42][CH:39]([OH:38])[CH2:40]3)[C:7]=2[F:8])=[CH:14][C:13]=1[O:15][C@@H:16]([C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1[N:25]1[N:26]=[CH:27][CH:28]=[N:29]1)[CH3:17]
Reactant: OC1CNC1
Reactant: C[C@@H](Oc1cc(-c2ccnc(F)c2F)cnc1N)c1cc(F)ccc1-n1nccn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: C[C@@H](Oc1cc(-c2ccnc(N3CC(O)C3)c2F)cnc1N)c1cc(F)ccc1-n1nccn1
Yield: 29.8 %

Procedure:
2′,3′-Difluoro-5-[(R)-1-(5-fluoro-2-[1,2,3]triazol-2-yl-phenyl)-ethoxy-[3,4′]bipyridinyl-6-ylamine (example 129) (35 mg, 0.085 mmol, 1.0 eq) and potassium carbonate (115 mg, 0.833 mmol, 9.8 eq) and 3-hydroxyazetidine hydrochloride (91.3 mg, 0.833 mmol, 9.8 eq) in anhydrous DMSO (2 mL) were microwaved for 10 min. at 150° C. The mixture was filtered, concentrated, and purified with a reverse phase pre-HPLC under acidic condition to give the title compound (11.8 mg, 30% yield) as a amorphous solid after lyophilization.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([Cl:10])(=[O:9])=[O:8])=[CH:3][CH:2]=1.[Br:12]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:12][CH2:11][C:1]1[CH:2]=[CH:3][C:4]([S:7]([Cl:10])(=[O:9])=[O:8])=[CH:5][CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: O=S(=O)(Cl)c1ccc(CBr)cc1
Yield: 28.6 %

Procedure:
p-Toluenesulfonyl chloride (0.52 mol, 100 g), N-bromosuccinimide (0.62 mol, 110.3 g), and benzoyl peroxide (5 g) were heated to reflux in carbon tetrachloride (500 ml) for 1 hour. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was triturated with isopropyl ether to afford 40.1 g of title product as a white solid; m.p. 70°-73° C.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([C:14]1[N:19]=[CH:18][C:17]([CH2:20][O:21][CH:22]3[CH2:27][CH2:26][N:25]([C:28]#[N:29])[CH2:24][CH2:23]3)=[CH:16][CH:15]=1)[CH:9]=[CH:8]2)(=[O:4])=[O:3].[OH:30][NH:31][C:32](=N)[CH:33]([CH3:35])[CH3:34]>>[CH:33]([C:32]1[N:29]=[C:28]([N:25]2[CH2:24][CH2:23][CH:22]([O:21][CH2:20][C:17]3[CH:18]=[N:19][C:14]([N:10]4[C:11]5[C:7](=[CH:6][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:13][CH:12]=5)[CH:8]=[CH:9]4)=[CH:15][CH:16]=3)[CH2:27][CH2:26]2)[O:30][N:31]=1)([CH3:35])[CH3:34]
Reactant: CC(C)C(=N)NO
Reactant: CS(=O)(=O)c1ccc2c(ccn2-c2ccc(COC3CCN(C#N)CC3)cn2)c1
Product: CC(C)c1noc(N2CCC(OCc3ccc(-n4ccc5cc(S(C)(=O)=O)ccc54)nc3)CC2)n1

Procedure:
The title compound was prepared by following the similar procedure as described in Example-4 using 4-((6-(5-(methylsulfonyl)-1H-indol-1-yl)pyridin-3-yl)methoxy) piperidine-1-carbonitrile (intermediate 38) and N-hydroxy-isobutyramidine (0.010 g, 5.8%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:20])=[C:15](F)[C:16]=3[Cl:18])[C:11](=[O:21])[C:10]([C:22]([OH:24])=[O:23])=[CH:9]2)[CH:5]=[CH:4][C:3]=1[F:25].[CH3:26][NH2:27]>N1C=CC=CC=1>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:20])=[C:15]([NH:27][CH3:26])[C:16]=3[Cl:18])[C:11](=[O:21])[C:10]([C:22]([OH:24])=[O:23])=[CH:9]2)[CH:5]=[CH:4][C:3]=1[F:25]
Reactant: Nc1nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Cl)c32)ccc1F
Reactant: CN
Solvent: c1ccncc1
Product: CNc1c(F)cc2c(=O)c(C(=O)O)cn(-c3ccc(F)c(N)n3)c2c1Cl
Temperature: 25 °C
Reaction time: 17 h
Yield: 103.2 %

Procedure:
1-(6-Amino-5-fluoropyridin-2-yl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (158 mg) and an aqueous solution (about 40%; 165 mg) of methylamine were added to pyridine (480 mg), and the mixture was stirred at room temperature for 17 hours. The reaction mixture was concentrated under reduced pressure, and ethanol (1 ml) was added to the residue. Deposits were collected by filtration and washed with ethanol and diisopropyl ether in that order to obtain the title compound (168 mg) as a pale yellow powder.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([O:15][CH2:16][C:17]2[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][N:18]=2)[N:3]=1.[Cl:24]N1C(=O)CCC1=O>CN(C=O)C>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][C:10]([Cl:24])=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([O:15][CH2:16][C:17]2[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][N:18]=2)[N:3]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cc1cccnc1COc1nc(N)nc(-c2ccco2)c1C#N
Solvent: CN(C)C=O
Product: Cc1cccnc1COc1nc(N)nc(-c2ccc(Cl)o2)c1C#N

Procedure:
From 2-amino-4-furan-2-yl-6-(3-methyl-pyridin-2-ylmethoxy)-pyrimidine-5-carbonitrile and N-chlorosuccinimide in DMF. ES-MS m/e (%): 344 (M{37Cl}+H+, 35), 342 (M{35Cl}+H+, 100).
Reaction SMILES: [CH3:1][N:2]([CH2:18][C@H:19]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:20][CH:21]=C)[C:3](=[O:17])[C:4]1[CH:9]=[C:8]([N:10]2[CH:14]=[N:13][N:12]=[N:11]2)[CH:7]=[CH:6][C:5]=1[O:15][CH3:16].CC(C)=[O:31].C(O)(C)(C)C.O.C[N+]1([O-])CCOCC1.I([O-])(=O)(=O)=O.[Na+]>C(OCC)(=O)C.[Os](=O)(=O)(=O)=O.CO.ClCCl.O1CCCC1.O>[CH3:1][N:2]([CH2:18][C@H:19]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:20][CH:21]=[O:31])[C:3](=[O:17])[C:4]1[CH:9]=[C:8]([N:10]2[CH:14]=[N:13][N:12]=[N:11]2)[CH:7]=[CH:6][C:5]=1[O:15][CH3:16]
Reactant: C=CC[C@H](CN(C)C(=O)c1cc(-n2cnnn2)ccc1OC)c1ccccc1
Reactant: CC(C)=O
Agent: O=[Os](=O)(=O)=O
Agent: C[N+]1([O-])CCOCC1
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: CC(C)(C)O
Product: COc1ccc(-n2cnnn2)cc1C(=O)N(C)C[C@@H](CC=O)c1ccccc1
Reaction time: 18 h

Procedure:
Combine (S)-N-methyl-N-(2-phenylpent-4-enyl)-2-methoxy-5-(1H-tetrazol-1-yl) benzamide (3.13 g, 8.3 mmol), acetone/t-butanol/water (2/1/1, 90 mL), and a solution of N-methylmorpholine N-oxide (2.06 mL, 50% in water, 9.95 mmol). Add a solution of osmium tetraoxide (2.56 mL, 4% in water, 0.5 mmol). After 18 hours, evaporate in vacuo to remove most of the acetone and extract the evaporated reaction mixture with dichloromethane. Extract the organic layer with an aqueous 10% solution of sodium thiosulfate. Dry the organic layer over MgSO4, filter, and evaporate in vacuo to give a residue: Rf =0.22 (silica gel, 7% methanol/dichloromethane/0.1% concentrated ammonium hydroxide). Combine the residue (3.6 g, 8.3 mmol) and tetrahydrofuran/water (90 mL, 4/1). Add sodium meta-periodate (2.13 g, 9.95 mmol). After 1 hour, filter the reaction mixture, rinse the solids with tetrahydrofuran, and evaporate the filtrate to obtain a residue. Dilute the residue with ethyl acetate (150 mL), extract with brine, dry over MgSO4, filter, and evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting with 5% methanol/dichloromethane/0.1% concentrated ammonium hydroxide to give the title compound: Rf =0.33 (silica gel, 7% methanol/dichloromethane/0.1% concentrated ammonium hydroxide). [α]D20 =-13.7° (c=0.59, chloroform).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[NH:24][CH2:23][CH2:22][C:21]([C:25]([O:27][CH3:28])=[O:26])=[CH:20][C:19]=3[CH:29]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].[O:30]1[CH:34]=[CH:33][C:32]([CH:35]=O)=[CH:31]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>ClCCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:35][C:32]4[CH:33]=[CH:34][O:30][CH:31]=4)[CH2:23][CH2:22][C:21]([C:25]([O:27][CH3:28])=[O:26])=[CH:20][C:19]=3[CH:29]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=Cc1ccoc1
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: O
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3Cc2ccoc2)cc1
Temperature: 25 °C
Reaction time: 120 h
Yield: 85.9 %

Procedure:
To a solution of methyl 7-(4-butoxyethoxyphenyl)-2,3-dihydro-1-benzazepine-4-carboxylate (300 mg) and 3-furaldehyde (365 mg) in 1,2-dichloroethane (10 ml) was added sodium triacetoxyborohydride (402 mg), and the mixture was stirred under nitrogen atmosphere at room temperature for 5 days. Then, water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried with magnesium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified with silica gel column chromatography (hexane:ethyl acetate=1:1) to give methyl 7-(4-butoxyethoxyphenyl)-1-(3-furylmethyl)-2,3-dihydro-1-benzazepine-4-carboxylate (310 mg) as yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][C:21]([N:23]3[CH2:30][CH2:29][C:26]4([CH2:28][CH2:27]4)[C@H:25]([OH:31])[CH2:24]3)=[O:22])[C:14](=[O:32])[C@@H:13]2[CH3:33])[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].CCO>CCCCCCC>[Cl:1][C:2]1[CH:3]=[C:4]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][C:21]([N:23]3[CH2:30][CH2:29][C:26]4([CH2:27][CH2:28]4)[C@H:25]([OH:31])[CH2:24]3)=[O:22])[C:14](=[O:32])[C@H:13]2[CH3:33])[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:9])[F:10]
Reactant: C[C@H]1C(=O)N(CCCC(=O)N2CCC3(CC3)[C@H](O)C2)CCN1c1ccc(C(F)(F)F)c(Cl)c1
Solvent: CCCCCCC
Solvent: CCO
Product: C[C@@H]1C(=O)N(CCCC(=O)N2CCC3(CC3)[C@H](O)C2)CCN1c1ccc(C(F)(F)F)c(Cl)c1
Yield: 27 %

Procedure:
The title compounds were prepared by chiral separation of (S)-4-(3-chloro-4-trifluoromethyl-phenyl)-1-[4-((S)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-4-oxo-butyl]-3-methyl-piperazin-2-one (63% ds) on a Reprosil Chiral NR, (40% EtOH in n-heptane) to give 27% of (R)-4-(3-chloro-4-trifluoromethyl-phenyl)-1-[4-((S)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-4-oxo-butyl]-3-methyl-piperazin-2-one (example 61) as off-white foam, MS: 488.19 (MH+, Cl) and 42% of (S)-4-(3-chloro-4-trifluoromethyl-phenyl)-1-[4-((S)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-4-oxo-butyl]-3-methyl-piperazin-2-one (example 60) as off-white foam, MS: 488.19 (MH+, Cl).
Reaction SMILES: Br[C:2]1[C:10]([Cl:11])=[CH:9][C:5]2[N:6]=[CH:7][O:8][C:4]=2[CH:3]=1.[NH2:12][C:13]1[CH:18]=[CH:17][C:16](B2OC(C)(C)C(C)(C)O2)=[CH:15][N:14]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].CC(=O)OCC>C(#N)C.O1CCOCC1.O>[Cl:11][C:10]1[C:2]([C:16]2[CH:17]=[CH:18][C:13]([NH2:12])=[N:14][CH:15]=2)=[CH:3][C:4]2[O:8][CH:7]=[N:6][C:5]=2[CH:9]=1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Reactant: Clc1cc2ncoc2cc1Br
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: Nc1ccc(-c2cc3ocnc3cc2Cl)cn1
Temperature: 85 °C
Yield: 67.4 %

Procedure:
A mixture of 6-bromo-5-chlorobenzoxazole (30) (232 mg, 1 mmol), 2-aminopyridine-5-boronic acid pinacol ester (11) (220 mg, 1 mmol), Bis(di-tret-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium (II) (A-Phos) (70 mg, 0.1 mmol) and K3PO4 (212 mg, 1 mmol) in 2 ml ACN, 2 ml dioxane, 0.5 ml H2O was bubbled with argon before heated at 85° C. for 2 h. After cooling down to r.t., the reaction mixture was taken up in ethyl acetate, washed with aq. NaHCO3 and brine, dried over Na2SO4, concentrated to dryness. The resulting red solid was dissolved in DCM and subjected to silica gel column purification using 0-100% B (A: hexane; B: EA) to furnish 165.6 mg 31 as an orange solid (yield: 67.4%)
Reaction SMILES: [F:1][C:2]1[C:3]([NH:22][CH3:23])=[CH:4][C:5]2[O:10][CH2:9][N:8]([C:11]3[CH:19]=[CH:18][C:14]([C:15](O)=[O:16])=[CH:13][CH:12]=3)[C:7](=[O:20])[C:6]=2[CH:21]=1.Cl.CN(C)CCCN=C=NCC.[Cl:36][C:37]1[S:41][C:40]([S:42]([NH2:45])(=[O:44])=[O:43])=[CH:39][CH:38]=1>C(Cl)Cl.CN(C)C1C=CN=CC=1>[Cl:36][C:37]1[S:41][C:40]([S:42]([NH:45][C:15](=[O:16])[C:14]2[CH:18]=[CH:19][C:11]([N:8]3[C:7](=[O:20])[C:6]4[CH:21]=[C:2]([F:1])[C:3]([NH:22][CH3:23])=[CH:4][C:5]=4[O:10][CH2:9]3)=[CH:12][CH:13]=2)(=[O:44])=[O:43])=[CH:39][CH:38]=1
Reactant: NS(=O)(=O)c1ccc(Cl)s1
Reactant: CNc1cc2c(cc1F)C(=O)N(c1ccc(C(=O)O)cc1)CO2
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CNc1cc2c(cc1F)C(=O)N(c1ccc(C(=O)NS(=O)(=O)c3ccc(Cl)s3)cc1)CO2
Temperature: 25 °C
Reaction time: 8 h
Yield: 160 %

Procedure:
To 4-(6-fluoro-7-(methylamino)-4-oxo-2H-benzo[e][1,3]oxazin-3(4H)-yl)benzoic acid (0.02 g, 0.063 mmol) in methylene chloride (2 ml) was added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.013 g, 0.068 mmol), N,N-dimethylpyridin-4-amine (0.008 g, 0.068 mmol) followed by 5-chlorothiophene-2-sulfonamide (0.014 g, 0.07 mmol) and the mixture stirred at room temperature for 8 hr. The solvent was removed and the product purified on HPLC (C18) to give N-(5-chlorothiophen-2-ylsulfonyl)-4-(6-fluoro-7-(methylamino)-4-oxo-2H-benzo[e] [1,3] oxazin-3(4H)-yl) benzamide (0.05 g, 15%). RP-HPLC: 2.58 min; ES-MS (M+H)+=496.0; 1H-NMR (MeOH-d4) δ (ppm): 2.8 (s, 3), 5.6 (s, 2), 6.2 (d, 1), 7.1 (d, 1), 7.3 (d, 1), 7.4 (d, 2), 7.7 (d, 1), 7.9 (d, 2).
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[C:8]([C:10]2[CH:15]=[C:14]([S:16][CH2:17][CH2:18][NH:19][C:20](=[O:25])[CH2:21][CH2:22][CH2:23][NH2:24])[N:13]=[C:12]([NH2:26])[N:11]=2)[C:7]([CH3:27])=[CH:6][C:5]=1[CH3:28].O.[OH-].[Li+].Cl.C(OCC)(=O)C.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>O.CO.O1CCCC1>[NH2:26][C:12]1[N:13]=[C:14]2[CH:15]=[C:10]([C:8]3[CH:9]=[C:4]([C:3](=[O:2])[NH:24][CH2:23][CH2:22][CH2:21][C:20](=[O:25])[NH:19][CH2:18][CH2:17][S:16]2)[C:5]([CH3:28])=[CH:6][C:7]=3[CH3:27])[N:11]=1
Reactant: COC(=O)c1cc(-c2cc(SCCNC(=O)CCCN)nc(N)n2)c(C)cc1C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cc(C)c2cc1C(=O)NCCCC(=O)NCCSc1cc-2nc(N)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.6 %

Procedure:
5-{2-Amino-6-[2-(4-aminobutyrylamino)ethylsulfanyl]pyrimidin-4-yl}-2,4-dimethylbenzoic acid methyl ester (153 mg, 0.37 mmol) obtained in Step 4 above was dissolved by adding tetrahydrofuran (2 ml), methanol (2 ml), and water (1 ml), and then lithium hydroxide monohydrate (160 mg, 3.82 mmol) was added thereto. The resulting mixture was stirred at room temperature for 8 hours. The reaction solution was cooled to 0° C., and 4N hydrochloric acid-ethyl acetate solution (2 ml) was added thereto. The solvent was distilled off under reduced pressure. The resulting residue was dissolved in dimethylformamide (255 ml). (3-Dimethylaminopropyl)ethylcarbodiimide hydrochloride (736 mg, 3.84 mmol), N-hydroxybenzotriazole (519 mg, 3.84 mmol), and diisopropylethylamine (2.67 ml, 15.32 mmol) were added to the solution, and stirred at room temperature for 14 hours. The reaction solution was distilled off under reduced pressure. Water was added to the resulting residue, and extracted three times with ethyl acetate. The organic layers were combined together and washed with water and a saturated aqueous sodium chloride solution, and then dried over magnesium sulfate. After filtration, anhydrous magnesium sulfate was washed with ethyl acetate. The filtrate and washing solution was combined together, and ethyl acetate was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (developing solvent: dichloromethane:methanol=20:1) to yield 4-amino-18,20-dimethyl-7-thia-3,5,10,15-tetraazatricyclo[15.3.1.12,6]docosa-1(20),2(22),3,5,17(21),18-hexaene-11,16-dione (Compound 11) (65 mg, 46%).
Reaction SMILES: [C:1]([NH:4][C:5]1[N:9]([C:10]2[CH:15]=[C:14]([S:16][CH2:17][C:18]([F:21])([F:20])[F:19])[C:13]([CH3:22])=[CH:12][C:11]=2[F:23])[N:8]=[C:7]([O:24][C:25]([F:40])([F:39])[C:26]([F:38])([F:37])[C:27]([F:36])([F:35])[C:28]([F:34])([F:33])[C:29]([F:32])([F:31])[F:30])[CH:6]=1)(=O)C.[H-].[Na+].CI.O>CN(C)C=O>[F:23][C:11]1[CH:12]=[C:13]([CH3:22])[C:14]([S:16][CH2:17][C:18]([F:21])([F:20])[F:19])=[CH:15][C:10]=1[N:9]1[C:5]([NH:4][CH3:1])=[CH:6][C:7]([O:24][C:25]([F:40])([F:39])[C:26]([F:37])([F:38])[C:27]([F:35])([F:36])[C:28]([F:34])([F:33])[C:29]([F:32])([F:31])[F:30])=[N:8]1
Reactant: CC(=O)Nc1cc(OC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)nn1-c1cc(SCC(F)(F)F)c(C)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: CNc1cc(OC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)nn1-c1cc(SCC(F)(F)F)c(C)cc1F
Reaction time: 0.5 h
Yield: 90.7 %

Procedure:
0.45 g of 5-acetylamino-1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl}-3-(1,1,2,2,3,3,4,4,5,5,5-undecafluoropentyloxy)pyrazole was dissolved in 5 mL of N,N-dimethylformamide, the solution was dropwise added to a suspension having 40 mg of sodium hydride suspended in 10 mL of N,N-dimethylformamide under cooling with ice, and after completion of the dropwise addition, stirring was carried out at room temperature for 30 minutes. The reaction solution was cooled with ice again, and 0.15 g of methyl iodide was added, followed by stirring at room temperature for one hour. Then, water was injected, extraction with ethyl acetate was carried out, followed by washing with water, and the organic layer was dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure, the obtained residue was dissolved in 10 mL of ethanol, and 10 mL of a 35 mass % hydrochloric acid aqueous solution was added, followed by stirring under reflux with heating for one hour. Then, the reaction mixture was poured into water, extraction with ethyl acetate was carried out, followed by washing with water, and the organic layer was dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (developing solvent ethyl acetate:hexane=1:4) to obtain 0.39 g of 1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl}-5-methylamino-3-(1,1,2,2,3,3,4,4,5,5,5-undecafluoropentyloxy)pyrazole.
Reaction SMILES: [CH:1]1[C:6]([NH2:7])=[CH:5][CH:4]=[C:3]([OH:8])[CH:2]=1.C(N(CC)CC)C.[Cl:16][C:17]1[CH:25]=[CH:24][CH:23]=[CH:22][C:18]=1[C:19](Cl)=[O:20]>ClCCl>[Cl:16][C:17]1[CH:25]=[CH:24][CH:23]=[CH:22][C:18]=1[C:19]([NH:7][C:6]1[CH:5]=[CH:4][C:3]([OH:8])=[CH:2][CH:1]=1)=[O:20]
Reactant: O=C(Cl)c1ccccc1Cl
Reactant: Nc1ccc(O)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(O)cc1)c1ccccc1Cl
Reaction time: 1 h

Procedure:
A suspension of p-aminophenol linked to the Wang's resin from Step A (1 eq) in dichloromethane was treated with triethylamine (2 ml/mmol) and 2-chloro-benzoyl chloride (10 eq). The mixture reaction was stirred for 1 hour and then the resin was filtered, washed with MeOH/CH2Cl2 several times and dried. The resin was then treated with TEA 95% H2O 5% and stirred at room temperature for 30 minutes. Filtered and washed with dichloromethane/methanol and concentrated to dryness to afford the title compound.