Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN1[C:10]2[C:5](=[CH:6][C:7](S(N3CCC[C@H]3COC3C=CC=CC=3)(=O)=O)=[CH:8][CH:9]=2)[C:4](=O)C1=O.[N:29]1[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH2:36][CH:37]2[CH2:41][CH2:40][CH2:39][N:38]2[S:42]([C:45]2[CH:46]=[C:47]3[C:51](=[CH:52][CH:53]=2)[NH:50][C:49](=[O:54])[C:48]3=[O:55])(=[O:44])=[O:43])[CH:30]=1.C(Br)C1C=CC=CC=1>>[CH2:4]([N:50]1[C:51]2[C:47](=[CH:46][C:45]([S:42]([N:38]3[CH2:39][CH2:40][CH2:41][CH:37]3[CH2:36][O:35][C:31]3[CH:30]=[N:29][CH:34]=[CH:33][CH:32]=3)(=[O:44])=[O:43])=[CH:53][CH:52]=2)[C:48](=[O:55])[C:49]1=[O:54])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CN1C(=O)C(=O)c2cc(S(=O)(=O)N3CCC[C@H]3COc3ccccc3)ccc21
Reactant: O=C1Nc2ccc(S(=O)(=O)N3CCCC3COc3cccnc3)cc2C1=O
Agent: BrCc1ccccc1
Product: O=C1C(=O)N(Cc2ccccc2)c2ccc(S(=O)(=O)N3CCCC3COc3cccnc3)cc21
Yield: 51 %

Procedure:
1-Benzyl-5-(2-(pyridin-3-yl-oxymethyl)-pyrrolidine-1-sulfonyl)-1H-indole-2,3-dione (21b) was prepared according to the same procedure for compound 11a, except using compound 20 and benzyl bromide, and the crude product was purified with ether to afford 61 mg (51%) of 21b as a yellow solid, mp 79.6-80.7° C. 1H NMR (300 MHz, CDCl3) δ 8.25 (s, 1H), 8.22 (t, J=2.7 Hz, 1H), 8.04 (d, J=2.1 Hz, 1H), 7.98 (dd, J=8.4 Hz, J=2.1 Hz, 1H), 7.36 (m, 5H), 7.22 (m, 2H), 6.91 (d, J=8.8 Hz, 1H), 4.97 (s, 2H), 4.25 (m, 1H), 3.99-3.94 (m, 2H), 3.55-3.48 (m, 1H), 3.21-3.15 (m, 1H), 2.10-1.97 (m, 2H), 1.84-1.75 (m, 2H). LRMS (FAB) m/e: 484.1 (M+Li, 100); HRMS (FAB) m/e calcd for C25H23N3O5SLi (M+Li) 484.1518, found 484.1539.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[OH:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][OH:21].C(=O)([O-])[O-].[Na+].[Na+]>C(C(C)=O)C.C(Cl)Cl>[C:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[O:13][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][OH:21])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Oc1ccccc1-c1ccccc1
Reactant: OCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCC(C)=O
Product: OCCCCCCOc1ccccc1-c1ccccc1
Yield: 165.7 %

Procedure:
40.0 g (235 mmol) of 2-phenylphenol from Tokyo Chemical Industry Co., Ltd. and 51.06 g (282 mmol) of 6-bromo-1-hexanol from Tokyo Chemical Industry Co., Ltd. were dissolved in 600 mL of methyl ethyl ketone from Kanto Chemical Co., Inc. to prepare a solution. 97.4 g of sodium carbonate were added to the solution, and refluxed for 8 hrs. After the solution was cooled to have room temperature, it was filtered and condensed. The resultant light brown liquid was dissolved in methylene chloride and washed with water. The isolated organic layer was dried with magnesium sulfide and a solvent was removed therefrom. The residue was refined by silica gel column chromatography using methylene chloride as an eluent to obtain 105.3 g of 6-(2-phenyl-phenoxy)hexane-1-ol.
Reaction SMILES: C([O:3][C:4]([CH:6]1[N:13]2[CH:9]([CH2:10][CH2:11][C:12]2=[O:14])[CH2:8][CH2:7]1)=[O:5])C.[OH-].[Na+].CC(C)=O>C(O)C>[O:14]=[C:12]1[CH2:11][CH2:10][CH:9]2[N:13]1[CH:6]([C:4]([OH:5])=[O:3])[CH2:7][CH2:8]2
Reactant: CCOC(=O)C1CCC2CCC(=O)N21
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: CCO
Product: O=C(O)C1CCC2CCC(=O)N21
Reaction time: 72 h

Procedure:
A solution of hexahydro-5-oxo-1H-pyrrolizine 3-carboxylic acid ethyl ester (12.6 g, 0.064 mol) in ethanol (35 ml) is treated with a 2N sodium hydroxide solution (35 ml, 0.07 mol) with stirring for 72 hours. The solution is concentrated at reduced pressure and treated with concentrated hydrochloric acid (6 ml) dropwise. The solution is extracted with dichloromethane. The extracts are dried (MgSO4), filtered, and concentrated to yield an oil. Trituration of the oil with acetone yields hexahydro-5-oxo-1H-pyrrolizine 3-carboxylic acid as a white solid with mp 145°-148° C.
Reaction SMILES: CO[C:3](=[O:25])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=3)=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1.[NH:26]1[CH2:31][CH2:30][S:29](=[O:33])(=[O:32])[CH2:28][CH2:27]1>>[O:32]=[S:29]1(=[O:33])[CH2:30][CH2:31][N:26]([C:3]([C:4]2[CH:5]=[N:6][C:7]([O:10][CH2:11][C:12]3[C:13]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=4)=[N:14][O:15][C:16]=3[CH3:17])=[CH:8][CH:9]=2)=[O:25])[CH2:27][CH2:28]1
Reactant: O=S1(=O)CCNCC1
Reactant: COC(=O)c1ccc(OCc2c(-c3cccc(F)c3)noc2C)nc1
Product: Cc1onc(-c2cccc(F)c2)c1COc1ccc(C(=O)N2CCS(=O)(=O)CC2)cn1
Yield: 100 %

Procedure:
As described for example 95, 6-[3-(3-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (103 mg, 0.3 mmol) was converted, using thiomorpholine-S,S-dioxide instead of thiomorpholine, to the title compound (133 mg, 100%) which was obtained as a white foam. MS: m/e=446.0 [M+H]+.
Reaction SMILES: CO[C:3]1[CH:8]=[CH:7][C:6]([O:9]C)=[CH:5][C:4]=1[NH:11][C:12]([C:14]1[C:23]2[C:18](=[CH:19][C:20]([OH:24])=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1)=[O:13].Cl.N1C=CC=CC=1.Cl>>[OH:24][C:20]1[CH:19]=[C:18]2[C:23](=[CH:22][CH:21]=1)[C:14]([C:12]1[O:13][C:3]3[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][C:4]=3[N:11]=1)=[CH:15][CH:16]=[CH:17]2
Reactant: COc1ccc(OC)c(NC(=O)c2cccc3cc(O)ccc23)c1
Agent: Cl
Solvent: c1ccncc1
Product: Oc1ccc2c(-c3nc4cc(O)ccc4o3)cccc2c1
Temperature: 200 °C
Yield: 84.3 %

Procedure:
A mixture of N-(2,5-dimethoxyphenyl)-6-hydroxy-1-naphthamide (2.0 g, 6.2 mmol), and pyridine hydrochloride (4.0 g, 34.6 mmol) was heated at 200° C. for 1 h. The reaction mixture was cooled to room temperature, acidified with HCl (2N) and extracted with EtOAc. The organic extracts were dried over MgSO4. Evaporation and purification by flash chromatography (hexanes/EtOAc 1/1) gave a tan solid (1.45 g, 85% yield, m.p. 232-234° C.); MS m/e 278 (M+H)+.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]([CH3:36])[O:5][C:6]1[CH:7]=[C:8]([C:23]2[NH:27][C:26]([C:28]3[S:29][C:30]([C:33]([OH:35])=O)=[CH:31][N:32]=3)=[CH:25][CH:24]=2)[CH:9]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=2)[CH:11]=1.Cl.[CH2:38]([NH2:40])[CH3:39].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C)C=O.C(OCC)(=O)C.O>[CH2:38]([NH:40][C:33]([C:30]1[S:29][C:28]([C:26]2[NH:27][C:23]([C:8]3[CH:9]=[C:10]([O:12][C:13]4[CH:14]=[CH:15][C:16]([S:19]([CH3:22])(=[O:20])=[O:21])=[CH:17][CH:18]=4)[CH:11]=[C:6]([O:5][C@@H:4]([CH3:36])[CH2:3][O:2][CH3:1])[CH:7]=3)=[CH:24][CH:25]=2)=[N:32][CH:31]=1)=[O:35])[CH3:39]
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(-c2ccc(-c3ncc(C(=O)O)s3)[nH]2)c1
Reactant: CCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCNC(=O)c1cnc(-c2ccc(-c3cc(Oc4ccc(S(C)(=O)=O)cc4)cc(O[C@@H](C)COC)c3)[nH]2)s1
Temperature: 25 °C
Reaction time: 20 h
Yield: 87.3 %

Procedure:
2-(5-{3-[(1S)-2-Methoxy-1-methylethoxy]-5-[4-(methylsulfonyl)phenoxy]phenyl}-1H-pyrrol-2-yl)-1,3-thiazole-5-carboxylic acid (62.8 mg, 0.119 mmol) synthesized in Example (5d) was dissolved in N,N-dimethylformamide (5 mL), and ethylamine hydrochloride (23.3 mg, 0.286 mmol), HATU (63.8 mg, 0.168 mmol) and N,N-diisopropylethylamine (80 μL, 0.46 mmol) were added, followed by stirring at room temperature for 20 hours under nitrogen atmosphere. Water (20 mL) was added to the reaction solution, and extraction was carried out with ethyl acetate (20 mL). The organic layer was washed with saturated brine, and subsequently dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=50%-80%) to afford the desired compound (57.7 mg, yield 87%) as a yellow solid.
Reaction SMILES: BrC1C=CC(O)=C(C2C=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:18]4[N:22]([CH:23]5[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]5)[C:21]5[CH:29]=[CH:30][C:31]([C:33]([OH:35])=[O:34])=[CH:32][C:20]=5[N:19]=4)[CH:14]=3)[N:9]=2)C=1.[OH:37][C:38]1[C:43]([N+:44]([O-:46])=[O:45])=[CH:42][C:41]([CH3:47])=[CH:40][C:39]=1[C:48](=O)[CH3:49].[OH-].[K+]>C(O)C>[CH:23]1([N:22]2[C:21]3[CH:29]=[CH:30][C:31]([C:33]([OH:35])=[O:34])=[CH:32][C:20]=3[N:19]=[C:18]2[C:13]2[CH:14]=[C:15]3[C:10](=[CH:11][CH:12]=2)[N:9]=[C:48]([C:39]2[CH:40]=[C:41]([CH3:47])[CH:42]=[C:43]([N+:44]([O-:46])=[O:45])[C:38]=2[OH:37])[CH:49]=[CH:16]3)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]1
Reactant: CC(=O)c1cc(C)cc([N+](=O)[O-])c1O
Reactant: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(-c4cc(Br)ccc4O)ccc3c1)n2C1CCCCC1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(-c2ccc3cc(-c4nc5cc(C(=O)O)ccc5n4C4CCCCC4)ccc3n2)c(O)c([N+](=O)[O-])c1
Yield: 31 %

Procedure:
Following the procedure and workup for Compound 354, Compound 354e (100 mg, 0.256 mmol) was reacted with 1-(2-hydroxy-5-methyl-3-nitro-phenyl)-ethanone (0.256 mmol) in ethanol (2 mL) using 10% w/v KOH in ethanol (506 μL, 0.64 mmol) to produce the title compound (40 mg, 31% yield).
Reaction SMILES: [C:1]([CH:3]([C:34]1[C:39]([Cl:40])=[CH:38][CH:37]=[CH:36][C:35]=1[Cl:41])[C:4]1[N:9]=[N:8][C:7]([S:10][C:11]2[CH:33]=[CH:32][CH:31]=[CH:30][C:12]=2[CH2:13][NH:14][C:15](=[O:29])[C:16]2[CH:21]=[C:20]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[CH:19]=[C:18]([F:28])[CH:17]=2)=[CH:6][CH:5]=1)#[N:2].S(=O)(=O)(O)[OH:43]>>[NH2:2][C:1](=[O:43])[CH:3]([C:4]1[N:9]=[N:8][C:7]([S:10][C:11]2[CH:33]=[CH:32][CH:31]=[CH:30][C:12]=2[CH2:13][NH:14][C:15](=[O:29])[C:16]2[CH:21]=[C:20]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[CH:19]=[C:18]([F:28])[CH:17]=2)=[CH:6][CH:5]=1)[C:34]1[C:35]([Cl:41])=[CH:36][CH:37]=[CH:38][C:39]=1[Cl:40]
Reactant: N#CC(c1ccc(Sc2ccccc2CNC(=O)c2cc(F)cc(N3CCOCC3)c2)nn1)c1c(Cl)cccc1Cl
Reactant: O=S(=O)(O)O
Product: NC(=O)C(c1ccc(Sc2ccccc2CNC(=O)c2cc(F)cc(N3CCOCC3)c2)nn1)c1c(Cl)cccc1Cl
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 67 %

Procedure:
N-[2-({6-[Cyano(2,6-dichlorophenyl)methyl]pyridazin-3-yl}sulfanyl)benzyl]-3-fluoro-5-(morpholin-4-yl)benzamide (92 mg, 0.15 mmol) was treated with concentrated sulfuric acid (2 mL) and the mixture was stirred at 70° C. for 30 min. The solution was cooled to RT, quenched with ice-water and extracted into DCM. The organic layer was washed with aqueous saturated NaHCO3, dried over MgSO4, filtered, and the filtrate was concentrated in vacuo. Purification by flash column chromatography (DCM:MeOH from 97.3:2.7 to 95:5) afforded the title compound (63 mg, 67%) which co-exists in solution as a mixture of the amide and the enol-amine. LCMS (Method 3): Rt 10.15 & 11.27 min, m/z 626 [MH−]. 1H NMR (400 MHz, CD3OD) (ratio amide/enol-amine 1:0.8): 7.65 (1H, dd, J 7.6, 1.2), 7.57-7.43 (5.4H, m), 7.42-7.37 (3.6H, m), 7.36-7.29 (3.6H, m), 7.21 (0.8H, t, J 1.8), 7.17-7.13 (2H, m), 6.99 (0.8H, ddd, J 9, 2.3, 1.4), 6.95-6.93 (1H, m), 6.85-6.80 (1.8H, m), 6.58 (0.8H, d, J 9.9), 6.15 (0.8H, d, J 9.9), 5.98 (1H, s), 4.73 (1.6H, s), 4.71 (2H, d, J 1.8), 3.82 (7.2H, t, J 4.8), 3.22-3.17 (7.2H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([C:19]2[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=2[F:26])[CH2:12][CH2:13][CH2:14][CH2:15][O:16]C=C)(=[O:10])=[O:9])=[CH:4][CH:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([CH:11]([C:19]2[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=2[F:26])[CH2:12][CH2:13][CH2:14][CH2:15][OH:16])(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: C=COCCCCC(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: O=S(=O)(c1ccc(Cl)cc1)C(CCCCO)c1cc(F)ccc1F
Temperature: 25 °C
Reaction time: 14 h

Procedure:
In methanol (30 ml) was dissolved 2-[1-[(4-chlorophenyl)sulfonyl]-5-vinyloxypentyl]-1,4-difluorobenzene (0.90 g, 2.3 mmol). After addition of p-toluenesulfonic acid monohydrate (20 mg, 0.11 mmol), the resulting mixture was stirred at room temperature for 14 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane:ethyl acetate=3:2) to yield a white solid. The resulting white solid was washed with diisopropyl ether, whereby the title compound (0.73 g, 85%) was obtained as a white powder.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][C@:11]([CH3:18])([CH:13]([O:16][CH3:17])[O:14][CH3:15])[C@@H:10]3[O:19][C@@H:9]3[C:8]=2[CH:20]=1)([O-:3])=[O:2].[F:21][C:22]([F:39])([F:38])[O:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][CH2:31][C:32]2[N:33]=[N:34][N:35]([CH3:37])[N:36]=2)=[CH:26][CH:25]=1>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][C@:11]([CH3:18])([CH:13]([O:16][CH3:17])[O:14][CH3:15])[C@H:10]([OH:19])[C@@H:9]([N:30]([C:27]3[CH:26]=[CH:25][C:24]([O:23][C:22]([F:39])([F:38])[F:21])=[CH:29][CH:28]=3)[CH2:31][C:32]3[N:33]=[N:34][N:35]([CH3:37])[N:36]=3)[C:8]=2[CH:20]=1)([O-:3])=[O:2]
Reactant: COC(OC)[C@@]1(C)Oc2ccc([N+](=O)[O-])cc2[C@H]2O[C@H]21
Reactant: Cn1nnc(CNc2ccc(OC(F)(F)F)cc2)n1
Product: COC(OC)[C@@]1(C)Oc2ccc([N+](=O)[O-])cc2[C@H](N(Cc2nnn(C)n2)c2ccc(OC(F)(F)F)cc2)[C@H]1O
Yield: 42 %

Procedure:
The same procedure as step 3 of example 1 was accomplished, except for using the epoxide compound (300 mg, 1.07 mmol) obtained in step 1 of example 2 and N-(4-trifluoromethoxyphenyl)-N-(2-methyl-2H-tetrazol-5-ylmethyl)amine. The crude product was purified by silica gel column chromatography (developing solvent-n-hexane:ethyl acetate=2:1), to give desired compound (248 mg, yield: 42%).
Reaction SMILES: S(OOS([O-])(=O)=O)([O-])(=O)=[O:2].[K+].[K+].[CH3:13][S:14][C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[NH:17][CH:16]=1.[Cl-].[Na+]>O.CO>[CH3:13][S:14]([C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[NH:17][CH:16]=1)=[O:2]
Reactant: CSc1c[nH]c2ccccc12
Reactant: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CS(=O)c1c[nH]c2ccccc12

Procedure:
Potassium persulfate (KHSO5, 55 g, 179 mmol) in water (300 ml) was slowly added to a solution of 3-methylthioindole (29.3 g, 179 mmol) in methanol (300 ml) cooled in a ice bath. One half hour after the addition was completed, water was added, the solution was saturated with sodium chloride and the product was extracted into chloroform. The extract was dried, evaporated in vacuo and the residue was crystallized from chloroform-ethyl acetate to give the title product.
Reaction SMILES: C([O:4][C@H:5]([CH2:10]Br)[CH2:6][C:7]([OH:9])=[O:8])(=O)C.[CH2:12]([N:14]([CH2:17][CH3:18])[CH2:15][CH3:16])[CH3:13]>O>[CH2:12]([N:14]([CH2:17][CH3:18])[CH2:15][CH3:16])[CH3:13].[O:4]1[CH2:10][C@@H:5]1[CH2:6][C:7]([OH:9])=[O:8]
Reactant: CC(=O)O[C@H](CBr)CC(=O)O
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(O)C[C@H]1CO1
Reaction time: 2 h

Procedure:
To a 2 l of three-necked flask equipped with thermometer, pH meter and mechanical stirrer were charged distilled water (1 l), (S)-3-acetoxy-4-bromobutyric acid (90 g, 0.4 mol) and triethylamine (12 g, 1.2 mol). The reaction mixture was stirred at 0˜5° C. for 2 hours to afford (S)-3,4-epoxybutyric acid triethylamine salt. Over 99% of conversion was detected by NMR.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]#[N:9])=[N:6][CH:7]=1.C(N(CC)CC)C.[Cl:17][CH2:18][CH2:19][C:20](Cl)=[O:21]>ClCCl>[Cl:17][CH2:18][CH2:19][C:20]([NH:1][C:2]1[CH:7]=[N:6][C:5]([C:8]#[N:9])=[CH:4][CH:3]=1)=[O:21]
Reactant: N#Cc1ccc(N)cn1
Reactant: O=C(Cl)CCCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#Cc1ccc(NC(=O)CCCl)cn1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To a suspension of 5-amino-2-cyanopyridine (1.00 g, 8.4 mmol) in dry dichloromethane (10 mL) was added triethylamine (1.27 g, 12.6 mmol) and the reaction mixture was stirred at 0° C. To the reaction mixture 3-chloropropionyl chloride (1.42 g, 12.6 mmol) was added drop wise over a period of 15 minutes, and the reaction mixture was stirred at 0° C. for 1 hour and then at room temperature for 4 hours. The reaction mixture was diluted with dichloromethane (50 mL) and washed with saturated sodium bicarbonate solution (50 mL) and water (50 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated to obtain the crude product, which was purified over silica gel using methanol/chloroform as eluent. The pure fraction was concentrated to obtain 3-chloro-N-(6-cyanopyridin-3-yl)propionamide. To a solution of potassium hydroxide (0.1 g, 1.5 mmol) in dry methanol (20 mL) was added hydroxylamine hydrochloride (0.105 g, 1.5 mmol) and the mixture was stirred for 30 minutes. White precipitate of potassium chloride obtained was filtered and to the filtrate was added 3-chloro-N-(6-cyanopyridin-3-yl)propionamide (0.209 g, 1.0 mmol) as obtained herein above, and the reaction mixture was stirred at reflux temperature for 4 hours. The reaction mixture was then concentrated and the crude product obtained was triturated with diethyl ether to obtain a solid which was crystallized from ethyl acetate/petroleum ether to obtain the title compound.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[OH-].[Na+].[C:16](Cl)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>O1CCOCC1.O.[Cl-].[Na+].O>[C:16]([N:11]1[CH2:10][CH2:9][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:13][CH2:12]1)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccccc2)CC1
Yield: 89.8 %

Procedure:
To a solution of N-Boc-piperazine (14) (1.00 g, 5.37 mmol) in dioxane (5 mL), a solution of NaOH (0.50 g, 12.9 mmol) in water (5 mL) followed by a solution of benzoyl chloride (0.75 mL, 6.44 mmol) in dioxane (2 mL) under vigorous stirring were added. The reaction mixture was stirred at ambient temperature for 4 hours, diluted with brine (20 mL), and extracted with ethyl acetate (2×25 mL). The organic extract was washed successively with brine (20 mL), saturated NaHCO3 (20 mL), saturated KH2PO4 (20 mL), and dried (Na2SO4). The solvents were evaporated to give the title compound (1.400 g, 90%) which was used in the next step of the synthesis without further purification. 1H NMR (CDCl3, HMDS), δ: 1.41 (s, 9H), 2.86 (t, J=5.0 Hz, 4H); 3.62 (t, J=5.0 Hz, 4H); 7.34 (s, 5H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7](F)=[N:6][CH:5]=1.Cl.[C:13]([O:17][C:18]([N:20]1[CH2:25][C@@H:24]([CH3:26])[NH:23][CH2:22][C@@H:21]1[CH3:27])=[O:19])([CH3:16])([CH3:15])[CH3:14].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.C(OCC)(=O)C>[C:13]([O:17][C:18]([N:20]1[CH2:25][C@@H:24]([CH3:26])[N:23]([C:7]2[CH:8]=[CH:9][C:4]([C:3]([O:2][CH3:1])=[O:11])=[CH:5][N:6]=2)[CH2:22][C@@H:21]1[CH3:27])=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)[C@@H](C)CN1
Reactant: COC(=O)c1ccc(F)nc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(N2C[C@H](C)N(C(=O)OC(C)(C)C)C[C@H]2C)nc1

Procedure:
A mixture of 6-fluoronicotinic acid methyl ester (1.0 g, 6.4 mmol), (2S,5R)-2,5-dimethyl-piperazine-1-carboxylic acid tert-butyl ester HCl (1.6 g, 6.4 mmol), and potassium carbonate (1.78 g, 12.9 mmol) were stirred in DMSO (10 mL) at 120° C. for 2 h, cooled, diluted with ethyl acetate (50 mL), washed with water (2×10 mL), dried over magnesium sulfate, filtered and concentrated.
Reaction SMILES: [H-].[Na+].CS(C)=O.[NH2:7][C:8]1[C:13]([CH3:14])=[CH:12][C:11]([OH:15])=[C:10]([CH3:16])[CH:9]=1.[CH2:17]([O:24][C:25]1[CH:34]=[C:33]2[C:28]([C:29](Cl)=[CH:30][CH:31]=[N:32]2)=[CH:27][C:26]=1[O:36][CH3:37])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O>[CH2:17]([O:24][C:25]1[CH:34]=[C:33]2[C:28]([C:29]([O:15][C:11]3[C:10]([CH3:16])=[CH:9][C:8]([NH2:7])=[C:13]([CH3:14])[CH:12]=3)=[CH:30][CH:31]=[N:32]2)=[CH:27][C:26]=1[O:36][CH3:37])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: COc1cc2c(Cl)ccnc2cc1OCc1ccccc1
Reactant: Cc1cc(O)c(C)cc1N
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COc1cc2c(Oc3cc(C)c(N)cc3C)ccnc2cc1OCc1ccccc1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 52.2 %

Procedure:
Sodium hydride (60 wt %, 1.17 g) was added to dimethyl sulfoxide (25 ml), and the mixture was stirred at 60° C. for 30 min and was then cooled to room temperature. Next, 4-amino-2,5-dimethylphenol (4.00 g) was added thereto, and the mixture was stirred at room temperature for 10 min. 7-(Benzyloxy)-4-chloro-6-methoxyquinoline (4.36 g) was then added thereto. The mixture was stirred for 22 hr before water was added to the reaction solution, followed by extraction with chloroform. The chloroform layer was then washed with a saturated aqueous sodium hydrogencarbonate solution and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and methanol was added to the residue to prepare a suspension. The precipitated crystal was collected by suction filtration to give 3.04 g (yield 52%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]3[C:17]([CH3:18])=[C:16]([C:19]([O:21][CH3:22])=[O:20])[S:15][C:11]=3[N:12]=[CH:13][N:14]=2)=[C:4]([OH:23])[CH:3]=1.CS(O[CH:29]1[CH2:33][CH2:32][N:31]([S:34]([CH3:37])(=[O:36])=[O:35])[CH2:30]1)(=O)=O.C(=O)([O-])[O-].[K+].[K+].CCOC(C)=O>CN(C=O)C.O>[CH3:22][O:21][C:19]([C:16]1[S:15][C:11]2[N:12]=[CH:13][N:14]=[C:9]([NH:8][C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=3[O:23][CH:29]3[CH2:33][CH2:32][N:31]([S:34]([CH3:37])(=[O:36])=[O:35])[CH2:30]3)[C:10]=2[C:17]=1[CH3:18])=[O:20]
Reactant: COC(=O)c1sc2ncnc(Nc3ccc(F)cc3O)c2c1C
Reactant: CS(=O)(=O)OC1CCN(S(C)(=O)=O)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1sc2ncnc(Nc3ccc(F)cc3OC3CCN(S(C)(=O)=O)C3)c2c1C
Temperature: 60 °C

Procedure:
Methyl 4-(4-fluoro-2-hydroxyphenylamino)-5-methylthieno[2,3-d]pyrimidine-6-carboxylate (described in V.1) (1.0 g), 1-(methylsulfonyl)pyrrolidin-3-yl methansulfonate and potassium carbonate (664.0 mg) were combined in DMF (15.0 ml) and heated at 60° C. overnight. The temperature was increased at 80° C. and heated for 6 h again. The reaction mixture was allowed to cool overnight. The mixture was portioned between EtOAc and water. The suspension was fitlered, solid washed with EtOAc and air-dried under vacuum.
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:8]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)=[N:9][N:10]2[C:15]=1[CH:14]=[CH:13][N:12]=[C:11]2[S:16][CH3:17])=O.Cl.[CH:27]1([NH:32][C:33]([NH2:35])=[NH:34])[CH2:31][CH2:30][CH2:29][CH2:28]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[CH:27]1([NH:32][C:33]2[N:35]=[C:5]([C:7]3[C:8]([C:18]4[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=4)=[N:9][N:10]4[C:15]=3[CH:14]=[CH:13][N:12]=[C:11]4[S:16][CH3:17])[CH:4]=[CH:3][N:34]=2)[CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: CSc1nccc2c(C(=O)/C=C/N(C)C)c(-c3ccc(F)cc3)nn12
Reactant: N=C(N)NC1CCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CSc1nccc2c(-c3ccnc(NC4CCCC4)n3)c(-c3ccc(F)cc3)nn12
Temperature: 100 °C
Reaction time: 4 h
Yield: 27 %

Procedure:
To a solution of (2E)-3-(dimethylamino)-1-[2-(4-fluorophenyl)-7-(methylsulfanyl)pyrazolo[1,5-c]pyrimidin-3-yl]prop-2-en-1-one (660 mg, 1.85 mmol) and N-cyclopentylguanidine hydrochloride (600 mg, 3.71 mmol) in N,N-dimethylformamide (10 mL) was added potassium carbonate (760 mg, 5.55 mmol). The reaction mixture was heated to 100° C. for 1 hour and then to 115° C. for 4 hours. The reaction was allowed to cool to room temperature and diluted with water. The mixture was extracted with ethyl acetate, washed with brine, dried over magnesium sulfate, filtered and concentrated. The residue was purified using silica gel chromatography eluting with 50% acetone in dichloromethane to yield N-cyclopentyl-4-[2-(4-fluorophenyl)-7-(methylsulfanyl)pyrazolo[1,5-c]pyrimidin-3-yl]pyrimidin-2-amine (210 mg, 32%). 1H NMR (CDCl3): δ 8.05(d,1H), 7.94 (m, 2H), 7.64 (dd, 2H), 7.13 (t, 2H), 6.29 (d, 1H), 5.21 (bs, 1H), 4.31 (m, 1H), 2.72 (s, 3H), 2.06 (m, 2H), 1.49–1.82 (m, 6H). MS m/z 421 (M+1).