Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[C:8]([C:11]([F:14])([F:13])[F:12])[C:7]([C:15]#[N:16])=[CH:6][CH:5]=2.Br[CH2:18][C:19]([O:21][CH3:22])=[O:20].C([O-])([O-])=O.[Cs+].[Cs+]>>[C:15]([C:7]1[C:8]([C:11]([F:12])([F:14])[F:13])=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]([CH2:18][C:19]([O:21][CH3:22])=[O:20])[C:2]([CH3:1])=[CH:10]2)#[N:16]
Reactant: COC(=O)CBr
Reactant: Cc1cc2c(C(F)(F)F)c(C#N)ccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COC(=O)Cn1c(C)cc2c(C(F)(F)F)c(C#N)ccc21

Procedure:
Synthesized as described in Example 4 using 2-methyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile, methyl bromoacetate (1.5 eq), and Cs2CO3 (1.5 eq): MS (ES) m/z 295 (M−1).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH2:4][NH2:5].[CH2:11]([C:13]1[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=1)[CH3:12].Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH2:4][NH:5][C:17](=[O:18])[C:16]1[CH:20]=[CH:21][C:13]([CH2:11][CH3:12])=[CH:14][CH:15]=1
Reactant: NCc1ccc(F)cc1F
Reactant: CCc1ccc(C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CCc1ccc(C(=O)NCc2ccc(F)cc2F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.3 %

Procedure:
To a solution of 2,4-difluorobenzylamine (3.58 g, 25.0 mmol) in methylene chloride (250 mL) were added 4-ethylbenzoic acid (3.94 g, 26.3 mmol) and DMAP (3.36 g, 27.5 mmol) followed by 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (5.27 g, 27.5 mmol) and the reaction mixture was stirred at room temperature overnight. The resulting solution was washed with 5% HCl (3×100 mL), saturated aqueous NaHCO3 (100 mL), and brine (100 mL) and dried over Na2SO4. Concentration in vacuo afforded 6.49 g (94%) of white solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[NH:8][N:9]=[C:10]([OH:11])[C:5]2=[C:4]([CH3:12])[CH:3]=1.[N:13]([CH:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19][CH2:18][CH2:17]1)=[C:14]=[O:15]>C1COCC1.CN(C=O)C>[CH:16]1([NH:13][C:14]([N:9]2[C:10](=[O:11])[C:5]3[C:6](=[N:7][C:2]([Cl:1])=[CH:3][C:4]=3[CH3:12])[NH:8]2)=[O:15])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19][CH2:18][CH2:17]1
Reactant: O=C=NC1CCCc2ccccc21
Reactant: Cc1cc(Cl)nc2[nH]nc(O)c12
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cc1cc(Cl)nc2[nH]n(C(=O)NC3CCCc4ccccc43)c(=O)c12

Procedure:
In analogy to example 1c, 200 mg (1.089 mmol) of 6-chloro-4-methyl-1H-pyrazolo-[3,4-b]pyridin-3-ol were reacted with 226.4 mg (1.2 mmol) of 1-isocyanato-1,2,3,4-tetrahydronaphthalene in THF/DMF at RT. Yield: 142 mg (37%), M+H+: 357.35.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][O:9][CH2:10][C:11](=O)[CH2:12][C:13]([O:15][CH2:16][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:14])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:26][C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][C:34]=1[Cl:35])[CH:30]=O.Cl.[Cl:37][C:38]1[CH:46]=[CH:45][C:41]([C:42]([NH2:44])=[NH:43])=[CH:40][CH:39]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:37][C:38]1[CH:46]=[CH:45][C:41]([C:42]2[NH:44][C:11]([CH2:10][O:9][CH2:8][CH2:7][N:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)=[C:12]([C:13]([O:15][CH2:16][CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:14])[CH:30]([C:29]3[CH:32]=[CH:33][C:34]([Cl:35])=[C:27]([Cl:26])[CH:28]=3)[N:43]=2)=[CH:40][CH:39]=1
Reactant: O=C(COCCN1CCCCC1)CC(=O)OCCCc1ccccc1
Reactant: N=C(N)c1ccc(Cl)cc1
Reactant: O=Cc1ccc(Cl)c(Cl)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(OCCCc1ccccc1)C1=C(COCCN2CCCCC2)NC(c2ccc(Cl)cc2)=NC1c1ccc(Cl)c(Cl)c1
Temperature: 60 °C
Yield: 3 %

Procedure:
A mixture of 3-phenylpropyl 4-(2-(1-piperidinyl)ethoxy)acetoacetate (5.46 g, 15.70 mmol), 3,4-dichlorobenzaldehyde (2.75 g, 15.70 mmol), 4-chlorobenzamidine hydrochloride (3.0 g, 15.70 mmol) and potassium carbonate (2.17 g, 15.70 mmol) was stirred in N,N-dimethylformamide (15 ml) for 5 days at room temperature and then heated to 60° C. for 3 days. The DMF was removed in vacuo and ethyl acetate was added to the residue. The precipitate was removed by filtration and the filtrate was washed with water, sodium hydrogen carbonate solution and brine, dried and evaporated to yield an oil. The oil was further purified by flash chromatography and RP-HPLC to give the title compound (300 mg) as an oil. Electrospray MS m/z 640/642 [M+H]+.
Reaction SMILES: [CH3:1][CH2:2][NH:3][C:4]([CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][C@@H:12]1[C@@H:16](/[CH:17]=[CH:18]/[C@@H:19]([OH:28])[CH2:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C@H:15]([OH:29])[CH2:14][C@@H:13]1[OH:30])=[O:5].C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N.C(Cl)Cl>O1CCOCC1>[CH3:1][CH2:2][NH:3][C:4]([CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][C@@H:12]1[C@@H:16](/[CH:17]=[CH:18]/[C:19]([CH2:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[O:28])[C@H:15]([OH:29])[CH2:14][C@@H:13]1[OH:30])=[O:5]
Reactant: CCNC(=O)CCC/C=C\C[C@@H]1[C@@H](/C=C/[C@@H](O)CCc2ccccc2)[C@H](O)C[C@@H]1O
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCNC(=O)CCC/C=C\C[C@@H]1[C@@H](/C=C/C(=O)CCc2ccccc2)[C@H](O)C[C@@H]1O
Temperature: 40 °C
Reaction time: 24 h
Yield: 63.5 %

Procedure:
A mixture of bimatoprost 1 (0.33 g, 0.8 mmol), DDQ (0.68 g, 3.0 mmol), CH2Cl2 (5 mL) and 1,4-dioxane (5 mL) was stirred for 24 h at 40° C. and evaporated in vacuo. The residue was purified by chromatography on a silica gel (20 g, eluent EtOAc then EtOAc/MeOH 20:1) to give 0.21 g (63%) of 15-keto bimatoprost 1c as yellow oil.
Reaction SMILES: Br[CH2:2][C:3]1[S:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1.C([O-])([O-])=O.[K+].[K+].[C:18]([O:22][C:23](=[O:48])[CH2:24][N:25]1[C:29]2[CH:30]=[CH:31][C:32]([NH:34][S:35]([C:38]3[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=3)(=[O:37])=[O:36])=[CH:33][C:28]=2[N:27]=[C:26]1[CH2:45][CH2:46][CH3:47])([CH3:21])([CH3:20])[CH3:19]>CC#N.CCOC(C)=O.O>[C:18]([O:22][C:23](=[O:48])[CH2:24][N:25]1[C:29]2[CH:30]=[CH:31][C:32]([N:34]([CH2:2][C:3]3[S:4][C:5]4[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=4[N:7]=3)[S:35]([C:38]3[CH:39]=[CH:40][C:41]([F:44])=[CH:42][CH:43]=3)(=[O:36])=[O:37])=[CH:33][C:28]=2[N:27]=[C:26]1[CH2:45][CH2:46][CH3:47])([CH3:21])([CH3:20])[CH3:19]
Reactant: CCCc1nc2cc(NS(=O)(=O)c3ccc(F)cc3)ccc2n1CC(=O)OC(C)(C)C
Reactant: BrCc1nc2ccccc2s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC#N
Product: CCCc1nc2cc(N(Cc3nc4ccccc4s3)S(=O)(=O)c3ccc(F)cc3)ccc2n1CC(=O)OC(C)(C)C
Temperature: 80 °C
Reaction time: 8 h

Procedure:
2-Bromomethyl benzothiazole (0.27 mmol) and K2CO3 (63 mg, 0.45 mmol) were added to a solution of [5-(4-fluoro-benzenesulfonylamino)-2-propyl-benzoimidazol-1-yl]-acetic acid tert-butyl ester (40 mg, 0.09 mmol) in CH3CN (1 mL), and stirred overnight at 80° C. The reaction mixture was diluted with EtOAc and H2O, and then filtered through an Extrelut column. The column was washed with EtOAc, and the filtrate was concentrated. The crude product was carried onto the next reaction without any further purification or characterization.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[Cl:14])[C:4](=[O:15])[C:3]=1[CH:16]=O.Cl.[NH2:19][OH:20].C([O-])(=O)C.[Na+]>CO.O>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[Cl:14])[C:4](=[O:15])[C:3]=1[CH:16]=[N:19][OH:20]
Reactant: O=Cc1c(Cl)ccn(-c2ccccc2Cl)c1=O
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: O=c1c(C=NO)c(Cl)ccn1-c1ccccc1Cl
Temperature: 75 °C
Yield: 92.1 %

Procedure:
A mixture of 4-chloro-1-(2-chlorophenyl)-2-oxo-1,2-dihydropyridine-3-carbaldehyde obtained in Step B (995 mg), hydroxylamine hydrochloride (516 mg) and sodium acetate (609 mg) in methanol/water (4:1, 12.4 mL) was heated at 75° C. for 2 hr, cooled to room temperature, and poured into ice water. The resulting solid was collected by filtration, washed with water, and dried under reduced pressure to give the title compound (968 mg).
Reaction SMILES: C(O)(=O)C.[CH2:5]([NH:12][C:13]1[CH:18]=[CH:17][C:16](/[CH:19]=[CH:20]/[N+:21]([O-:23])=[O:22])=[CH:15][CH:14]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[BH4-].[Na+]>CS(C)=O>[CH2:5]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][N+:21]([O-:23])=[O:22])=[CH:15][CH:14]=1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: O=[N+]([O-])/C=C/c1ccc(NCc2ccccc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CS(C)=O
Product: O=[N+]([O-])CCc1ccc(NCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.5 %

Procedure:
To an acetic acid (5.8 mL) and dimethyl sulfoxide (100 mL) solution of benzyl-(4-((E)-2-nitro-vinyl)-phenyl)-amine (5.82 g, 22.9 mmol) described in Manufacturing Example 68-1-2 was added sodium borohydride (1.39 g, 36.6 mmol) at room temperature while cooling appropriately. This mixture was stirred for 1 hour at room temperature. The mixture was partitioned into ethyl acetate and water. The organic layer was separated, washed with water, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by silica gel column chromatography (heptane:ethyl acetate=4:1-2:1) to obtain the title compound (2.79 g, 48%).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.Br[C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[C:18]#[N:19].C(C1C=C(NC2CCN(C(OC(C)(C)C)=O)CC2)C=CC=1)#N>>[C:18]([C:17]1[CH:20]=[CH:21][CH:22]=[CH:23][C:16]=1[NH:1][CH:2]1[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]1)#[N:19]
Reactant: N#Cc1ccccc1Br
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: CC(C)(C)OC(=O)N1CCC(Nc2cccc(C#N)c2)CC1
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccccc2C#N)CC1

Procedure:
The title compound was prepared from 1,1-dimethylethyl 4-amino-1-piperidinecarboxylate and 2-bromobenzonitrile using a method similar to that described for D5 in Description 5.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]([CH2:18][C@H:19]([OH:28])[CH2:20][O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:4][CH:3]=1.[CH:29](=O)[CH2:30][CH3:31]>>[OH:28][C@H:19]([CH2:20][O:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[CH2:18][N:10]([CH2:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][CH2:29][CH2:30][CH3:31])=[CH:3][CH:4]=1)[C:11](=[O:17])[O:12][C:13]([CH3:14])([CH3:16])[CH3:15]
Reactant: CCC=O
Reactant: CC(C)(C)OC(=O)N(CCc1ccc(N)cc1)C[C@H](O)COc1ccccc1
Product: CCCNc1ccc(CCN(C[C@H](O)COc2ccccc2)C(=O)OC(C)(C)C)cc1
Yield: 100.3 %

Procedure:
1.52 g of t-butyl (S)-N-[2-(4-aminophenyl)ethyl]-N-(2-hydroxy-3-phenoxypropyl)carbamate and 0.23 g of propionaldehyde were subjected to a reductive amination reaction to obtain 1.69 g of t-butyl (S)-N-(2-hydroxy-3-phenoxypropyl)-N-[2-(4-propylaminophenyl)ethyl]carbamate.
Reaction SMILES: [CH:1]([C:4]1[CH:17]=[CH:16][C:7]([O:8][CH:9]([CH3:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[CH2:18]([O:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30]Cl)=[CH:28][CH:27]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C1(NC2CCCCC2)CCCCC1>>[CH2:18]([O:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30][C:9]([O:8][C:7]2[CH:16]=[CH:17][C:4]([CH:1]([CH3:2])[CH3:3])=[CH:5][CH:6]=2)([CH3:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:28][CH:27]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCOC(=O)C(C)Oc1ccc(C(C)C)cc1
Reactant: ClCc1ccc(OCc2ccccc2)cc1
Agent: C1CCC(NC2CCCCC2)CC1
Product: CCOC(=O)C(C)(Cc1ccc(OCc2ccccc2)cc1)Oc1ccc(C(C)C)cc1
Yield: 71.3 %

Procedure:
In a similar manner to that described in Reference example 7(c), a reaction was carried out using ethyl 2-(4-isopropylphenoxy)propionate (4.72 g) and 4-benzyloxybenzyl chloride (6.00 g) and dicyclohexylamine (3.62 g) instead of diisopropylamine and the reaction mixture was treated to afford the desired compound (6.16 g) as a syrup.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[O:13][N:12]=[C:11]([C:14]3[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=3)[CH2:10]2)=[CH:5][C:4]=1[OH:26].C(=O)([O-])[O-].[K+].[K+].Br[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][O:39][C:40]1[CH:45]=[CH:44][C:43]([CH:46]2[NH:55][C:54](=[O:56])[C:53]3[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=3)[NH:47]2)=[CH:42][C:41]=1[O:57][CH3:58]>CN(C=O)C.C(OCC)(=O)C.CCCCCC>[CH3:58][O:57][C:41]1[CH:42]=[C:43]([CH:46]2[NH:55][C:54](=[O:56])[C:53]3[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=3)[NH:47]2)[CH:44]=[CH:45][C:40]=1[O:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][O:26][C:4]1[CH:5]=[C:6]([CH:9]2[O:13][N:12]=[C:11]([C:14]3[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=3)[CH2:10]2)[CH:7]=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: COc1ccc(C2CC(c3cc(OC)c(OC)c(OC)c3)=NO2)cc1O
Reactant: COc1cc(C2NC(=O)c3ccccc3N2)ccc1OCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc(C2NC(=O)c3ccccc3N2)ccc1OCCCCCOc1cc(C2CC(c3cc(OC)c(OC)c(OC)c3)=NO2)ccc1OC
Temperature: 30 °C
Reaction time: 30 h
Yield: 78.2 %

Procedure:
2-Methoxy-5-[3-(3,4,5-trimethoxy-phenyl)-4,5-dihydro-isoxazol-5-yl]phenol (11a) (359.37 mg, 1.0 mmol) in DMF (20 mL) was added anhydrous potassium carbonate (690 mg, 5.0 mmol) and 2-[4-(5-Bromo-pentyloxy)-3-methoxy-phenyl]-2,3-dihydro-1H-quinazolin-4-one (2d) (419.31 mg, 1.0 mmol). The reaction mixture was stirred at a temperature of 30° C. for 30 h and the reaction was monitored by TLC using ethyl acetate-hexane (6:4) as a solvent system. Then to this ice is added and extracted with ethyl acetate. The solvent was evaporated under vacuum to afford the crude product. This was further purified by column chromatography using ethyl acetate:hexane (6:4) as a solvent system to obtain the pure product (12d) (546 mg, 80% yield).
Reaction SMILES: [F:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[NH:10][C:11]1[C:16]([C:17]2[N:25]=[CH:24][N:23]=[C:22]3[C:18]=2[N:19]=[CH:20][N:21]3[CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][O:27]2)=[CH:15][CH:14]=[CH:13][N:12]=1.[CH2:32]([S:35](Cl)(=[O:37])=[O:36])[CH2:33][CH3:34].N1C=CC=CC=1>ClCCl>[F:1][C:2]1[C:3]([NH:10][C:11]2[C:16]([C:17]3[N:25]=[CH:24][N:23]=[C:22]4[C:18]=3[N:19]=[CH:20][N:21]4[CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][O:27]3)=[CH:15][CH:14]=[CH:13][N:12]=2)=[C:4]([F:9])[CH:5]=[CH:6][C:7]=1[NH:8][S:35]([CH2:32][CH2:33][CH3:34])(=[O:37])=[O:36]
Reactant: Nc1ccc(F)c(Nc2ncccc2-c2ncnc3c2ncn3C2CCCCO2)c1F
Reactant: CCCS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCS(=O)(=O)Nc1ccc(F)c(Nc2ncccc2-c2ncnc3c2ncn3C2CCCCO2)c1F
Temperature: 50 °C
Reaction time: 2 h
Yield: 94 %

Procedure:
The 2,6-difluoro-N1-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-yl)benzene-1,3-diamine (20 mg, 0.047 mmol) prepared at Step 9 was added and dissolved into dichloromethane solvent. 1-propansulfonyl chloride (6 uL, 0.052 mmol) and pyridine (8 uL, 0.094 mmol) were added into the reaction solution and stirred at 50° C. for 2 hours. After the reaction, the reactant was washed with 1N aqueous hydrochloric acid solution and salt water. After extraction with dichloromethane, the organic layer was dried with sulfuric anhydride magnesium and vacuum concentrated, and then refined by means of column chromatography, so that 23 mg of the target compound, N-(2,4-difluoro-3-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-ylamino)phenyl)propan-1-sulfonamide (percentage yield: 94%), was obtained.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]1[CH:17]2[N:12]([S:13](=[O:23])(=[O:22])[C:14]3[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=3[CH2:16]2)[CH2:11][CH2:10][N:9]1C(OC(C)(C)C)=O>>[CH2:8]1[CH:17]2[N:12]([S:13](=[O:22])(=[O:23])[C:14]3[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=3[CH2:16]2)[CH2:11][CH2:10][NH:9]1
Reactant: CC(C)(C)OC(=O)N1CCN2C(Cc3ccccc3S2(=O)=O)C1
Solvent: O=C(O)C(F)(F)F
Product: O=S1(=O)c2ccccc2CC2CNCCN21
Reaction time: 1 h

Procedure:
Cold trifluoroacetic acid (2 mL) was added to cold 1,1-dimethylethyl 1,2,3,4,11,11a-hexahydropyrazino[1,2-b][1,2]benzothiazine-2-carboxylate 6,6-dioxide (151 mg, 0.446 mmol). After 1 h, the reaction was concentrated in vacuo. The residue was partitioned between dichloromethane (10 mL) and 0.5 N sodium carbonate (2 mL). The organic layer was dried (sodium sulfate) and concentrated in vacuo. The residue was chromatographed (Diacel Chiracel OJ, 5×50 cm, 35% 1:1 methanol/ethanol:hexanes containing 0.3% triethylamine, 50 mL/min). Fractions containing the more rapidly eluting enantiomer concentrated in vacuo. The residue was taken up in 50% aqueous methanol (1 mL) and was loaded onto a 1-g methanol-activated water-equilibrated SCX-type cation exchange column. The column was washed with water (5 mL) and 25% aqueous methanol (5 mL). The column was eluted with 2 N methanolic ammonia. Concentration of this fraction in vacuo provided (−) 1,2,3,4,11,11a-hexahydropyrazino[1,2-b][1,2]benzothiazine 6,6-dioxide: LCMS (pos. ion spectrum) m/z 239.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2)([O-:3])=[O:2].[H-].[Na+].[CH3:15][O:16][C:17](=[O:23])[CH2:18][CH2:19][CH2:20][CH2:21]Br>C(#N)C>[CH3:15][O:16][C:17]([CH2:18][CH2:19][CH2:20][CH2:21][N:9]1[C:10]2[C:6](=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=2)[CH:7]=[CH:8]1)=[O:23]
Reactant: O=[N+]([O-])c1ccc2[nH]ccc2c1
Reactant: COC(=O)CCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Product: COC(=O)CCCCn1ccc2cc([N+](=O)[O-])ccc21
Reaction time: 21 h
Yield: 90.5 %

Procedure:
To a stirred solution of 5-nitroindole (0.324 g, 2.0 mmol) in anhydrous acetonitrile (10 ml) was added sodium hydride (0.057 g, 2.38 mmol). The resulting red-brown solution was stirred for 45 minutes, before the addition of a solution of methyl-5-bromovalerate (0.429 g, 2.2 mmol) in anhydrous acetonitrile (1 ml). The solution was stirred for 21 hours, during which time a solid precipitated. Analysis by TLC in chloroform:ethanol (99:1) after 2 hours showed 2 components (starting material: Rf=0.5, 1-(4-methoxycarbonyl butyl)5-nitroindole: Rf=0.8). Further analysis after 21 hours indicated the reaction was essentially complete. The reaction mixture was poured into ethyl acetate (20 ml) and molar HCl (20 ml) and the phases separated. The aqueous phase was extracted with ethyl acetate (20 ml) and the combined organic layer washed with molar sodium bicarbonate solution. The ethyl acetate solution was dried over anhydrous sodium sulphate, filtered and rotary evaporated to give a yellow oil (0.5 g, 1.81 mmol, 91%).
Reaction SMILES: [BH4-].[Na+].C([O:5][C:6](=O)[CH2:7][CH:8]1[N:13]2[CH:14]=[C:15]([I:17])[CH:16]=[C:12]2[C:11](=[O:18])[NH:10][CH2:9]1)C>CCO>[OH:5][CH2:6][CH2:7][CH:8]1[N:13]2[CH:14]=[C:15]([I:17])[CH:16]=[C:12]2[C:11](=[O:18])[NH:10][CH2:9]1
Reactant: CCOC(=O)CC1CNC(=O)c2cc(I)cn21
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: O=C1NCC(CCO)n2cc(I)cc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 100 %

Procedure:
Sodium borohydride (0.870 g, 23.0 mmol) was added to an ice-cooled stirred solution of ethyl(7-iodo-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-4-yl)acetate (1.00 g, 2.87 mmol) in EtOH (30 mL), under N2. The reaction mixture was stirred at room temperature for 18 h, and then it was quenched by water addition (10 ml). The solvent was evaporated to dryness and the residue dissolved in THF (30 ml)/brine (30 ml) and extracted with THF (3×30 mL). The organic phase was dried over Na2SO4 and concentrated to dryness to give the title compound (0.878 g, 2.87 mmol, 100%) as a solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.[C:10]([C:12](=[CH:21]OCC)[C:13]([NH:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[O:14])#[N:11]>>[C:10]([C:12](=[CH:21][NH:7][C:6]1[CH:8]=[CH:9][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[C:13]([NH:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[O:14])#[N:11]
Reactant: CCOC=C(C#N)C(=O)NC(=O)OCC
Reactant: COc1ccc(N)cc1
Product: CCOC(=O)NC(=O)C(C#N)=CNc1ccc(OC)cc1

Procedure:
Following the above procedure, p-methoxyaniline (0.05 mol) is reacted with α-cyano-β-ethoxy-N-ethoxycarbonyl-acrylamide (0.05 mol) to yield α-cyano-β-(4-methoxyanilino)-N-ethoxycarbonylacrylamide, which is cyclized by heating in tetralin to yield 5-cyano-1-(4-methoxyphenyl)uracil, m.p. 304.5°-306.5°.
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][OH:4].[H-].[Na+].F[C:10]1[CH:17]=[CH:16][C:15]([CH:18]=[O:19])=[CH:14][C:11]=1[C:12]#[N:13]>CN(C=O)C>[CH:18]([C:15]1[CH:16]=[CH:17][C:10]([O:4][CH2:3][C:2]([F:6])([F:5])[F:1])=[C:11]([CH:14]=1)[C:12]#[N:13])=[O:19]
Reactant: OCC(F)(F)F
Reactant: N#Cc1cc(C=O)ccc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1cc(C=O)ccc1OCC(F)(F)F
Reaction time: 0.17 h
Yield: 50.4 %

Procedure:
A solution of 2,2,2-trifluoroethanol (0.098 ml, 1.341 mmol) in DMF (9 ml) was cooled in an ice bath. Sodium hydride (60%; 38.6 mg, 0.965 mmol) was added and the resulting mixture was stirred for 10 mins before adding 2-fluoro-5-formylbenzonitrile (Aldrich; 200 mg, 1.341 mmol). The ice bath was removed and the reaction mixture was stirred at room temperature overnight. The mixture was partitioned between ethyl acetate (15 ml) and brine (7 ml). The organic layer was washed with water (2×8 ml) and brine (7 ml), passed through a phase separation cartridge and concentrated under vacuum. The residue was purified by column chromatography on silica, eluting with 0-40% ethyl acetate in cyclohexane gave the title compound as a white solid (155 mg).
Reaction SMILES: [CH2:1]([N:7]1[C:16]2[C:11](=[CH:12][C:13]([C:17](=[O:19])[CH3:18])=[CH:14][CH:15]=2)[C:10]([CH3:21])([CH3:20])[CH2:9][C:8]1=[O:22])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].I[CH2:24][CH2:25]C1C=CC=CC=1>>[C:3]1([CH2:2][CH2:1][N:7]2[C:16]3[C:11](=[CH:12][C:13]([C:17](=[O:19])[CH3:18])=[CH:14][CH:15]=3)[C:10]([CH3:21])([CH3:20])[CH2:9][C:8]2=[O:22])[CH:25]=[CH:24][CH:6]=[CH:5][CH:4]=1
Reactant: ICCc1ccccc1
Reactant: CCCCCCN1C(=O)CC(C)(C)c2cc(C(C)=O)ccc21
Product: CC(=O)c1ccc2c(c1)C(C)(C)CC(=O)N2CCc1ccccc1
Yield: 34 %

Procedure:
Following a procedure similar to that used for the preparation of Intermediate 6a but using (2-iodo-ethyl)benzene as the alkylating reagent the title compounds was obtained as a colorless oil (34% yield).
Reaction SMILES: [CH2:1]([C:3]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][NH:5][N:4]=1)[CH3:2].[CH2:12]([O:14][C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[CH:19][CH:20]=1)[CH3:13].N1C=CC=CC=1>CN(C)C(=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH2:12]([O:14][C:15]1[CH:20]=[C:19]([N:5]2[CH:6]=[C:7]([C:8]([O:10][CH3:11])=[O:9])[C:3]([CH2:1][CH3:2])=[N:4]2)[CH:18]=[CH:17][CH:16]=1)[CH3:13]
Reactant: CCOc1cccc(B(O)O)c1
Reactant: CCc1n[nH]cc1C(=O)OC
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CC(=O)N(C)C
Solvent: c1ccncc1
Product: CCOc1cccc(-n2cc(C(=O)OC)c(CC)n2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.8 %

Procedure:
Methyl 3-ethyl-1H-pyrazole-4-carboxylate (6.9 g) synthesized in Example 39(1) was dissolved in N,N-dimethylacetamide (150 mL), 3-ethoxyphenylboronic acid (15.0 g), copper acetate (16.4 g) and pyridine (14.5 mL) were added, and the mixture was stirred at room temperature overnight. The reaction mixture was filtered through celite, 1N hydrochloric acid (70 mL) was added to the filtrate, and the mixture was extracted with diethyl ether. The extract was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:2, volume ratio) to give the title object compound (4.4 g, 36%) as a pale-yellow oil.