Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([N:13]3[CH2:17][CH2:16][CH2:15][CH:14]3[CH3:18])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH2:19].[CH3:20][C:21]1[NH:25][C:24]2[CH:26]=[CH:27][C:28]([C:30](O)=[O:31])=[CH:29][C:23]=2[N:22]=1>>[CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([N:13]3[CH2:17][CH2:16][CH2:15][CH:14]3[CH3:18])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH:19][C:30]([C:28]1[CH:27]=[CH:26][C:24]2[NH:25][C:21]([CH3:20])=[N:22][C:23]=2[CH:29]=1)=[O:31]
Reactant: Cc1nc2cc(C(=O)O)ccc2[nH]1
Reactant: Cc1cc(N2CCC(N3CCCC3C)C2)ccc1N
Product: Cc1nc2cc(C(=O)Nc3ccc(N4CCC(N5CCCC5C)C4)cc3C)ccc2[nH]1

Procedure:
The title compound was prepared in a manner substantially the same as example 1 by coupling 2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine with 2-methyl-1H-benzoimidazole-5-carboxylic acid. MS: 418.3 (M+H).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[O:7]1[CH:11]=[N:10][N:9]=[C:8]1[C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1.[N:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][CH2:26][C@@H:27]2[CH:32]=COC(=O)[O:28]2)[CH:20]=1.O>CN(C)C=O>[O:7]1[CH:11]=[N:10][N:9]=[C:8]1[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:32][C@H:27]([OH:28])[CH2:26][CH2:25][C:21]2[CH:20]=[N:19][CH:24]=[CH:23][CH:22]=2)=[CH:14][CH:13]=1
Reactant: Oc1ccc(-c2nnco2)cc1
Reactant: O=C1OC=C[C@@H](CCc2cccnc2)O1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: O[C@H](CCc1cccnc1)COc1ccc(-c2nnco2)cc1
Temperature: 90 °C
Yield: 18.3 %

Procedure:
Cesium carbonate (0.72 g) and 4-(1,3,4)-oxadiazol-2-yl-phenol (0.54 g) were added to a solution of (4R)-4-[2-(pyridin-3-yl)ethyl]-1,3-dioxin-2-one (1.20 g, Example 14a)) in dry dimethylformamide (75 ml) and heated at 90° C. for 14 hours. After cooling, the reaction mixture was poured into water (50 ml) and extracted three times with ethyl acetate. The combined organic phases were extracted twice with 2M hydrochloric acid. The combined aqueous extracts were basified by dropwise addition of 2M aqueous sodium hydroxide and the aqueous solution was then extracted three times with ethyl acetate. The organic extracts were combined and dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by normal phase HPLC eluting with 0 to 25% ethanol in dichloromethane to give the title compound as a solid (0.19 g).
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]3[CH2:11][CH2:12][N:13](C(OC(C)(C)C)=O)[CH2:14][C:9]=3[S:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:22][C:23]1[CH:24]=[C:25]([OH:29])[CH:26]=[CH:27][CH:28]=1.Cl.O1CCOCC1>CC(O)C.O1CCOCC1>[N:5]1[C:4]2[S:8][C:9]3[CH2:14][NH:13][CH2:12][CH2:11][C:10]=3[C:3]=2[C:2]([NH:22][C:23]2[CH:24]=[C:25]([OH:29])[CH:26]=[CH:27][CH:28]=2)=[N:7][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCc2c(sc3ncnc(Cl)c23)C1
Reactant: Nc1cccc(O)c1
Agent: Cl
Solvent: CC(C)O
Solvent: C1COCCO1
Product: Oc1cccc(Nc2ncnc3sc4c(c23)CCNC4)c1
Temperature: 80 °C
Yield: 132.1 %

Procedure:
tert-Butyl 4-chloro-5,8-dihydropyrido[4′,3′:4,5]thieno[2,3-d]pyrimidine-7(6H)-carboxylate from Example 11A (1.00 g, 3.07 mmol) was dissolved in 2-propanol (10 mL). 3-Aminophenol (352 mg, 3.22 mmol) and a 4 M solution of gaseous hydrogen chloride in dioxane (38 μL, 0.15 mmol) were added, and the mixture was heated to 80° C. for 20 h. Subsequently, further 4 M hydrogen chloride in dioxane (1.54 mL, 6.14 mmol) was added, and the mixture was heated for additional 3 h. The precipitate was collected by suction filtration to yield 1.21 g of the title compound as hydrochloride salt. An analytical amount was dissolved in 1 M aqueous sodium hydroxide solution which was then concentrated in vacuo. The precipitate was collected by suction filtration and dried to yield the product as free base.
Reaction SMILES: [CH:1](=[C:8]1/[N:9]=[C:10]([C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=2[F:21])[NH:11][C:12]/1=[O:13])/[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][C:23]=1/[CH:32]=[CH:33]/[CH:34]=[O:35]>>[F:21][C:15]1[CH:16]=[CH:17][C:18]([F:20])=[CH:19][C:14]=1[C:10]1[NH:11][C:12]2[O:13][C:34](=[O:35])[CH:33]([CH2:32][C:23]3[CH:24]=[CH:25][C:26]4[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH:22]=3)[CH:1]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:8]=2[N:9]=1
Reactant: O=C/C=C/c1ccc2ccccc2c1
Reactant: O=C1NC(c2cc(F)ccc2F)=N/C1=C\c1ccccc1
Product: O=C1Oc2[nH]c(-c3cc(F)ccc3F)nc2C(c2ccccc2)C1Cc1ccc2ccccc2c1
Yield: 71 %

Procedure:
Prepared according to the general procedure using (Z)-4-benzylidene-2-(2,5-difluorophenyl)-1H-imidazol-5(4H)-one and (E)-3-(naphthalen-2-yl)acrylaldehyde. The unpurified residue was purified by flash chromatography using 15% EtOAc/hexanes to afford 15 as an off-white solid (99 mg, 71%). Analytical data for 15: 1H NMR (500 MHz, CDCl3) δ 9.35 (d, J=8.3 Hz, 1H), 7.89 (ddd, J=9.2, 6.1, 3.3 Hz, 1H), 7.86-7.80 (m, 2H), 7.78-7.74 (m, 1H), 7.53-7.45 (m, 3H), 7.38-7.32 (m, 3H), 7.24 (dd, J=8.5, 1.8 Hz, 1H), 7.07-6.92 (m, 4H), 4.08 (d, J=6.8 Hz, 1H), 3.74 (ddd, J=10.4, 6.8, 4.5 Hz, 1H), 3.54 (dd, J=14.8, 4.5 Hz, 1H), 2.60 (dd, J=14.9, 10.3 Hz, 1H); 13C NMR (CDCl3, 126 MHz) δ 168.9, 159.1 (d, JCF=243.3 Hz), 155.3 (d, JCF=241.8 Hz), 148.9, 137.1, 136.4, 135.2, 133.4, 132.3, 129.2, 128.4, 128.4, 128.1, 127.8, 127.7, 127.4, 127.0, 126.3, 125.7, 118.4 (dd, JCF=12.5, 8.9 Hz), 117.1 (dd, JCF=25.6, 8.7 Hz), 116.6 (dd, JCF=24.9, 9.9 Hz), 114.5 (dd, JCF=26.8, 3.9 Hz), 111.0 (d, JCF=3.7 Hz), 47.1, 38.4, 32.9; IR (film) cm−1 3057, 3030, 1770, 1635, 1619, 1530, 1481, 1411, 1172, 1116, 1104, 1032, 814, 766, 738, 701; LRMS (ESI): Mass calcd for [M+H]+ C29H21F2N2O2: 467.2. found 467.4; Enantiomeric ratio was measured by chiral phase HPLC (Chiralcel AD-H; 7% IPA/hexanes 1.0 mL/min, 230 nm), Rt1 (major)=37.8, Rt2 (minor)=48.3 min; er=96:4.
Reaction SMILES: [NH2:1][C:2]1[C:7]([I:8])=[CH:6][N:5]=[C:4]([Cl:9])[CH:3]=1.C(N(CC)CC)C.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>ClCCl>[Cl:9][C:4]1[CH:3]=[C:2]([N:1]([S:18]([CH3:17])(=[O:20])=[O:19])[S:18]([CH3:17])(=[O:20])=[O:19])[C:7]([I:8])=[CH:6][N:5]=1
Reactant: Nc1cc(Cl)ncc1I
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N(c1cc(Cl)ncc1I)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 1.67 h
Yield: 72.9 %

Procedure:
4-Amino-2-chloro-5-iodopyridine (11) (1.01 g, 3.97 mmol) was dissolved in dichloromethane (8.5 mL) and triethylamine (2.48 mL, 1.78 g 17.6 mmol) was added. The suspension was cooled in an ice/water bath. A solution of methanesulfonyl chloride (1.56 mL, 2.31 g, 20.1 mmol) in dichloromethane (4.2 mL) was added dropwise. The reaction was stirred at room temperature for 100 min. More triethylamine (1.25 mL) was added to the reaction, which was then cooled in ice. To the cooled reaction was added dropwise a solution of methanesulfonyl chloride (0.78 mL, 1.15 g, 10 mmol) in dichloromethane (2.1 mL) and stirring at room temperature was continued for 16 h. The reaction was diluted with dichloromethane and washed twice with water. The residue was purified by flash chromatography eluting with dichloromethane, then 5% ethyl acetate in dichloromethane to give the title compound (13) (1.188 g 72%). 1H-NMR (500 MHz, DMSO-d6): 3.69 (s, 6H), 8.03 (s, 1H), 8.99 (s, 1H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([O:10][C:11]3[C:20]4[C:15](=[CH:16][C:17]([O:23][CH2:24][C@H:25]5[CH2:27][O:26]5)=[C:18]([O:21][CH3:22])[CH:19]=4)[N:14]=[CH:13][N:12]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[CH:28]([NH2:31])([CH3:30])[CH3:29]>C1COCC1>[OH:26][C@H:25]([CH2:27][NH:31][CH:28]([CH3:30])[CH3:29])[CH2:24][O:23][C:17]1[CH:16]=[C:15]2[C:20]([C:11]([O:10][C:6]3[CH:5]=[C:4]4[C:9](=[CH:8][CH:7]=3)[NH:1][CH:2]=[CH:3]4)=[N:12][CH:13]=[N:14]2)=[CH:19][C:18]=1[O:21][CH3:22]
Reactant: COc1cc2c(Oc3ccc4[nH]ccc4c3)ncnc2cc1OC[C@H]1CO1
Reactant: CC(C)N
Solvent: C1CCOC1
Product: COc1cc2c(Oc3ccc4[nH]ccc4c3)ncnc2cc1OC[C@H](O)CNC(C)C
Temperature: 75 °C
Reaction time: 18 h
Yield: 68 %

Procedure:
A mixture of (2R)-4-(indol-5-yloxy)-6-methoxy-7-(oxiran-2-ylmethoxy)quinazoline (100 mg, 0.28 mmol), (prepared as described for the starting material in Example 292), and isopropylamine (1.0 ml) in THF (10 ml) was stirred at 75° C. for 18 hours under an atmosphere of nitrogen and then allowed to cool to ambient temperature. The mixture was filtered and the filtrate evaporated in vacuo. The residue was purified by silica gel chromatography, gradient elution with dichloromethane/methanolic ammonia (7M) (100/0 to 90/10) to give (2R)-7-(2-hydroxy-3-(isopropylamino)propoxy)4-(indol-5-yloxy)-6-methoxyquinazoline (82 mg, 68%).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([CH2:6][CH2:7][NH:8][C:9](=[O:27])[C:10]1[CH:15]=[CH:14][C:13]([NH:16][CH2:17]CCN2CCSCC2)=[C:12]([NH2:26])[CH:11]=1)=[O:5]>C(OCC)(=O)C.C(O)C>[CH3:2][O:3][C:4]([CH2:6][CH2:7][NH:8][C:9](=[O:27])[C:10]1[CH:15]=[CH:14][C:13]([NH:16][CH3:17])=[C:12]([NH2:26])[CH:11]=1)=[O:5]
Reactant: COC(=O)CCNC(=O)c1ccc(NCCCN2CCSCC2)c(N)c1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: CNc1ccc(C(=O)NCCC(=O)OC)cc1N

Procedure:
The same procedure is used as in (2). Rf value: 0.28 (silica gel; ethyl acetate/ethanol=50:2)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][N:16]2C(=O)C3=CC=CC=C3C2=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.NN>C(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][NH2:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(CCN2C(=O)c3ccccc3C2=O)CC1
Agent: NN
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(CCN)CC1
Temperature: 25 °C
Yield: 62.8 %

Procedure:
A mixture of N-[2-[1-tert-butoxycarbonylpiperidin-4-yl]ethyl]phthalimide (1.0 g) and hydrazine hydrate (0.16 ml) in ethanol (10 ml) was refluxed for 1 hour. After cooling to room temperature, the mixture was evaporated. The residue was chromatographed on alumina eluting with chloroform and the fractions containing the object product were collected and evaporated to give 2-[1-tert-butoxycarbonylpiperidin-4-yl]ethylamine (0.4 g) as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:10][C@:9]2([NH:15][C:16]([C@@H:18]2[CH2:23][CH2:22][CH2:21][CH2:20][N:19]2[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[O:17])[C:11]([O:13]C)=[O:12])=[CH:4][CH:3]=1.O.[OH-].[Li+]>C1COCC1.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]2[CH2:10][C@:9]2([NH:15][C:16]([C@@H:18]2[CH2:23][CH2:22][CH2:21][CH2:20][N:19]2[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[O:17])[C:11]([OH:13])=[O:12])=[CH:6][CH:7]=1
Reactant: COC(=O)[C@@]1(NC(=O)[C@@H]2CCCCN2C(=O)OC(C)(C)C)C[C@@H]1c1ccc(Br)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCCC[C@H]1C(=O)N[C@]1(C(=O)O)C[C@@H]1c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.6 %

Procedure:
To a stirred solution of (S)-tert-butyl 2-((1R,2R)-2-(4-bromophenyl)-1-(methoxycarbonyl)-cyclopropylcarbamoyl)piperidine-1-carboxylate (3 g) in THF (45 mL) and water (30 mL) was added lithium hydroxide monohydrate (0.298 g). The mixture was stirred at RT for 2 h. The mixture was partitioned between 0.1 N HCl(aq) and ethyl acetate, and the aqueous phase was extracted twice more with ethyl acetate. The combined organic phases were dried over sodium sulphate, filtered and concentrated in vacuo to leave the title compound (2.90 g) as a white solid.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1.[H-].[Na+].Cl[C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[C:19]([C:27]#[N:28])[N:18]=1>CN1C(=O)CCC1>[C:27]([C:19]1[N:18]=[C:17]([NH:1][C@H:2]2[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]2)[C:26]2[C:21]([CH:20]=1)=[CH:22][CH:23]=[CH:24][CH:25]=2)#[N:28]
Reactant: N#Cc1cc2ccccc2c(Cl)n1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)N1CC[C@H](Nc2nc(C#N)cc3ccccc23)C1
Temperature: 140 °C
Reaction time: 1 h

Procedure:
A mixture of (S)-tert-butyl 3-aminopyrrolidine-1-carboxylate (434 mg, 2.333 mmol) in NMP (2.5 mL) at 0° C. was treated with NaH (93 mg, 2.333 mmol) and stirred for 1 hour. Next, 1-chloroisoquinoline-3-carbonitrile (400 mg, 2.121 mmol) was added and the reaction mixture was stirred at RT for 15 minutes and then heated at 140° C. for 15 minutes in a microwave reactor. The crude reaction mixture, which contained the title compound, was used without further purification. ESI-MS m/z [M+H]+ 339.4.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:6]=1[S:14](Cl)(=[O:16])=[O:15])([CH3:4])([CH3:3])[CH3:2].[NH4+:18].[OH-]>CCOCC.O>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:6]=1[S:14]([NH2:18])(=[O:16])=[O:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: [NH4+]
Reactant: CC(C)(C)c1ccc([N+](=O)[O-])cc1S(=O)(=O)Cl
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Product: CC(C)(C)c1ccc([N+](=O)[O-])cc1S(N)(=O)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 34 %

Procedure:
To a solution of 2-tert-butyl-5-nitrobenzene-1-sulfonyl chloride (100 mg, 0.36 mmol) in ether (2 mL) was added aqueous NH4OH (128 μL, 3.6 mmol) at 0° C. The mixture was stirred at room temperature overnight, diluted with water and extracted with ether. The combined ether extracts were washed with brine and dried over Na2SO4. After removal of solvent, the residue was purified by column chromatography (0-50% EtOAc-Hexane) to give 2-tert-butyl-5-nitrobenzene-1-sulfonamide (31.6 mg, 34%).
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH2:13][CH2:14][CH3:15])[NH:6]2.Br[CH2:17][CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=1[F:27]>>[Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH2:13][CH2:14][CH3:15])[N:6]2[CH2:17][CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=1[F:27]
Reactant: Fc1ccc(OCCBr)c(F)c1
Reactant: CCCc1cc2c(Cl)c(C#N)ccc2[nH]1
Product: CCCc1cc2c(Cl)c(C#N)ccc2n1CCOc1ccc(F)cc1F

Procedure:
Synthesized as described in Example 4 from 4-chloro-2-propyl-1H-indole-5-carbonitrile and 1-[(2-bromoethyl)oxy]-2,4-difluorobenzene: 1H NMR (400 MHz, DMSO-d6) δ 7.89 (s, 1H), 7.79 (d, J=8.7 Hz, 1H), 7.51 (d, J=8.7 Hz, 1H), 7.25-7.14 (m, 1H), 7.08-6.99 (m, 1H), 6.96-6.85 (m, 1H), 4.67 (t, J=4.9 Hz, 2H), 4.28 (t, J=4.9 Hz, 2H), 2.89 (t, J=7.3 Hz, 2H), 1.73-1.57 (m, 2H), 0.93 (t, J=7.3 Hz, 3H); MS (ES) m/z 375 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])=[CH:5][C:4]=1[NH:19][S:20]([CH3:23])(=[O:22])=[O:21].Cl[CH2:25][CH2:26][N:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])=[CH:5][C:4]=1[N:19]([CH2:25][CH2:26][N:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1)[S:20]([CH3:23])(=[O:22])=[O:21]
Reactant: ClCCN1CCOCC1
Reactant: COc1ccc(C(=O)OCc2ccccc2)cc1NS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)OCc2ccccc2)cc1N(CCN1CCOCC1)S(C)(=O)=O
Temperature: 80 °C
Reaction time: 3 h

Procedure:
Benzyl 4-methoxy-3-(methylsulfonamido)benzoate (1.5 g, 4.47 mmol, Compound 144 may be prepared in analogous manner as described in Scheme 19, Step 1 and 2) was dissolved in DMF (10 ml), then 4-(2-chloroethyl)morpholine (6.69 g, 44.7 mmol) and K2CO3 (1.23 g, 8.94 mmol) were added, and the mixture was stirred at 80° C. for 3 hours. The reaction was quenched with water, and the product was extracted with EtOAc. The organic phase was washed with water (3×), then dried over Na2SO4 and evaporated under vacuum to yield 1.5 g of crude.
Reaction SMILES: [CH2:1]([S:5]([C:7]1[N:11]=[CH:10][NH:9][N:8]=1)=[O:6])[CH2:2][CH2:3][CH3:4].[CH2:12]([N:15]([CH2:19][CH2:20][CH3:21])[C:16](Cl)=[O:17])[CH2:13][CH3:14].O1CCCC1>C(N(CC)CC)C>[CH2:12]([N:15]([CH2:19][CH2:20][CH3:21])[C:16]([N:9]1[CH:10]=[N:11][C:7]([S:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[O:6])=[N:8]1)=[O:17])[CH2:13][CH3:14]
Reactant: CCCCS(=O)c1nc[nH]n1
Reactant: CCCN(CCC)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCS(=O)c1ncn(C(=O)N(CCC)CCC)n1

Procedure:
A mixture of 6.9 g. 3-n-butylsulphinyl-1,2,4-triazole, 8.0 ml. dipropylcarbamoyl chloride, 25 ml. dry tetrahydrofuran and 10 ml. dry triethylamine was refluxed under anhydrous conditions for 2 hours. The cooled reaction mixture was filtered and the filtrate distilled under reduced pressure to give an oily residue which subsequently solidified. This solid product was recrystallized from petroleum ether to give 1-dipropylcarbamoyl-3-n-butylsulphinyl-1,2,4-triazole, m.p. 39° - 40° C. Elemental analysis satisfactory.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5]1)(=O)C.[Br:13]Br>C(O)(=O)C>[Br:13][C:9]1[CH:8]=[C:7]2[C:12](=[CH:11][CH:10]=1)[NH:4][CH2:5][CH2:6]2
Reactant: BrBr
Reactant: CC(=O)N1CCc2ccccc21
Solvent: CC(=O)O
Product: Brc1ccc2c(c1)CCN2
Yield: 85 %

Procedure:
Gall et al. [J. Org. Chem., Vol. 20 (1955), p. 1538] describes the direct bromination of 1-acetyl-indoline in glacial acetic acid with bromine followed by saponification to obtain 5-bromo-indoline in 85% yield but attempts to repeat the process with chlorine results in only about a 45% yield of 5-chloro-1-acetyl-indoline. The latter result is not surprising in view of references such as Thesing et al. [Chem. Ber., Vol. 95 (1962), p. 2205], German Pat. No. 1,123,668, British Pat. No. 919,864 and the Chemistry of Heterocyclic Compounds, Vol. 25, Indoles, part II, Wiley Interscience, New York, London, Sidney, Toronto, 1972 p. 129 which teach that the reaction of N-acetylated-indoline-2-sulfonates in glacical acetic acid with chlorine, hypochlorous acid or alkali metal hypochlorites results in a variety of chlorinated products including 5- and 7-chloro compounds. Japanese Patent Application Ser. No. P 69-27967 (1969) teaches that these difficulties may be avoided by reacting 1-acetyl-indoline with N-chlorosuccinimide in carbon tetrachloride.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH2:6][OH:7])=[CH:2]1.[H-].[Na+].[Cl:10][C:11]1[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[C:13](Cl)[N:12]=1>O1CCCC1>[Cl:10][C:11]1[CH:16]=[C:15]([C:17]([F:18])([F:19])[F:20])[CH:14]=[C:13]([O:7][CH2:6][C:3]2[CH:4]=[CH:5][S:1][CH:2]=2)[N:12]=1
Reactant: OCc1ccsc1
Reactant: FC(F)(F)c1cc(Cl)nc(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: FC(F)(F)c1cc(Cl)nc(OCc2ccsc2)c1

Procedure:
To a mixture prepared by adding to 3-thiophenemethanol (1.27 g, 0.0093×1.2 mol) successively tetrahydrofuran and sodium hydride (0.39 g, (ca.60% in mineral oil), 0.0093×1.05 mol), 2,6-dichloro-4-trifluoromethylpyridine (2.0 g, 0.0093 mol) was added, and the resultant solution was refluxed for about 1 hour.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[C:15]([N+:17]([O-])=O)[CH:14]=[CH:13][C:3]=1[O:4][CH:5]([CH3:12])[CH2:6][N:7]([CH2:10][CH3:11])[CH2:8][CH3:9].ClCCl.CO.N>CO>[Cl:1][C:2]1[CH:16]=[C:15]([NH2:17])[CH:14]=[CH:13][C:3]=1[O:4][CH:5]([CH3:12])[CH2:6][N:7]([CH2:8][CH3:9])[CH2:10][CH3:11]
Reactant: CCN(CC)CC(C)Oc1ccc([N+](=O)[O-])cc1Cl
Agent: N
Solvent: ClCCl
Solvent: CO
Product: CCN(CC)CC(C)Oc1ccc(N)cc1Cl

Procedure:
Prepared analogously to Example 3.1.b. from [2-(2-chloro-4-nitrophenoxy)propyl]diethylamine in methanol in a reaction time of 8 hours. Yield: 6.7 g (93.5% of theory); C13H21ClN2O (M=256.77); calc.: molecular ion peak (M+H)+: 257/259; found: molecular ion peak (M+H)+: 257/259; Rf value: 0.4 (silica gel, dichloromethane/methanol/ammonia (50:10:0.1)).
Reaction SMILES: [CH3:1][CH:2]([OH:5])[CH2:3][CH3:4].[H-].[Na+].Cl[C:9]1[C:14]([CH:15]=[CH:16][C:17]([OH:19])=[O:18])=[CH:13][CH:12]=[C:11]([C:20]([F:23])([F:22])[F:21])[N:10]=1>CN(C=O)C.CCOC(C)=O>[CH:2]([O:5][C:9]1[C:14]([CH:15]=[CH:16][C:17]([OH:19])=[O:18])=[CH:13][CH:12]=[C:11]([C:20]([F:21])([F:23])[F:22])[N:10]=1)([CH2:3][CH3:4])[CH3:1]
Reactant: CCC(C)O
Reactant: O=C(O)C=Cc1ccc(C(F)(F)F)nc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCC(C)Oc1nc(C(F)(F)F)ccc1C=CC(=O)O
Reaction time: 0.17 h
Yield: 67.6 %

Procedure:
2-Butanol (70.1 mg, 0.945 mmol) and sodium hydride (70 mg, 1.8 mmol) were added in DMF. The reaction mixture was stirred for 10 mins and then 3-(2-chloro-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (67 mg, 0.266 mmol) was added into the reaction mixture. The reaction mixture was diluted with EtOAc, and washed with water and brine. The organic layer was dried over anhydrous MgSO4 and concentrated under reduced pressure. The resulting residue was purified by column chromatography (Hex/EtOAc=1/1) to give the title product (52 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([OH:8])[N:5]=[C:4]2[NH:9][N:10]=[C:11]([OH:12])[C:3]=12.[F:13][C:14]([F:25])([F:24])[CH:15]1[CH2:20][CH2:19][N:18]([C:21](Cl)=[O:22])[CH2:17][CH2:16]1.C(N(CC)CC)C>N1C=CC=CC=1>[OH:8][C:6]1[N:5]=[C:4]2[NH:9][N:10]=[C:11]([O:12][C:21]([N:18]3[CH2:17][CH2:16][CH:15]([C:14]([F:24])([F:13])[F:25])[CH2:20][CH2:19]3)=[O:22])[C:3]2=[C:2]([CH3:1])[CH:7]=1
Reactant: Cc1cc(O)nc2[nH]nc(O)c12
Reactant: O=C(Cl)N1CCC(C(F)(F)F)CC1
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: Cc1cc(O)nc2[nH]nc(OC(=O)N3CCC(C(F)(F)F)CC3)c12
Reaction time: 2 h

Procedure:
4-Methyl-1H-pyrazolo[3,4-b]pyridine-3,6-diol (1 g, 6.05 mmol), 4-trifluoromethyl-piperidine-1-carbonyl chloride (1.436 g, 6.6 mmol) and triethylamine (1.68 ml, 12.11 mmol) were stirred in 25 ml of pyridine at room temp for 1 h. Addition of 0.5 ml of triethylamine was followed by stirring for 2 h, concentration and addition of ethyl acetate and water. The resulting precipitate was filtered off with suction and dried. Yield: 765 mg (37%) of 4-trifluoromethylpiperidine-1-carboxylic acid 6-hydroxy-4-methyl-1H-pyrazolo[3,4-b]pyridin-3-yl ester. The organic phase was separated off, concentrated and purified by preparative HPLC (PR18, acetonitrile/water 0.1% TFA). Yield: 96 mg (5%) of 4-trifluoromethylpiperidine-1-carboxylic acid 6-hydroxy-4-methyl-1H-pyrazolo[3,4-b]pyridin-3-yl ester. M+H+: 345.13; 102 mg (3%) of 4-trifluoromethylpiperidine-1-carboxylic acid 4-methyl-3-(4-trifluoromethylpiperidine-1-carbonyloxy)-1H-pyrazolo[3,4-b]pyridin-6-yl ester, M+H+: 524.20; 106 mg (3%) of 4-trifluoromethylpiperidine-1-carboxylic acid 6-hydroxy-4-methyl-1-(4-trifluoromethylpiperidine-1-carbonyl)-1H-pyrazolo[3,4-b]pyridin-3-yl ester, M+H+: 524.52; 54 mg (1.3%) of 4-trifluoromethylpiperidine-1-carboxylic acid 4-methyl-3-(4-trifluoromethylpiperidine-1-carbonyloxy)-1-(4-trifluoromethylpiperidine-1-carbonyl)-1H-pyrazolo[3,4-b]pyridin-6-yl ester, M+H+: 703.36.
Reaction SMILES: C([O:7][C:8]1[C:13](=[O:14])[N:12]2[CH:15]=[CH:16][CH:17]=[CH:18][C:11]2=[N:10][C:9]=1[C:19]([O:21]C)=O)(=O)C(C)(C)C.[F:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][NH2:29])=[CH:26][CH:25]=1.C(N(CC)CC)C>CO>[F:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][NH:29][C:19]([C:9]2[N:10]=[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][N:12]3[C:13](=[O:14])[C:8]=2[OH:7])=[O:21])=[CH:26][CH:25]=1
Reactant: COC(=O)c1nc2ccccn2c(=O)c1OC(=O)C(C)(C)C
Reactant: NCc1ccc(F)cc1
Solvent: CCN(CC)CC
Solvent: CO
Product: O=C(NCc1ccc(F)cc1)c1nc2ccccn2c(=O)c1O
Temperature: 60 °C

Procedure:
Methyl 3-[(pivaloyl)oxy]-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxylate was dissolved in methanol. p-Fluorobenzylamine (2 eqs.) was added and the reaction was stirred and heated to 60° C. for 2 hours. A precipitate had formed and further methanol and 1 eq. of triethylamine were added. After 2 more hours at 60° C. the reaction mixture was partitioned between EtOAc and 1 M HCl. The organic phase was extracted with 0.1 M aqueous NaOH. The aqueous phase was separated and acidified with 1 M HCl. The aqueous phase was extracted with EtOAc and the organic phase was dried over Na2SO4, filtered and concentrated to dryness. The title compound was obtained as a yellow solid.