Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH:2]([F:29])[O:3][C:4]1[C:5]([O:23][CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[C:6](/[CH:10]=[CH:11]/[C:12]2[N:13]=[C:14]3[N:18]([C:19]=2[C:20]([OH:22])=O)[CH:17]=[CH:16][S:15]3)[CH:7]=[CH:8][CH:9]=1.[F:30][C:31]([F:39])([F:38])[C:32]1[N:33]=[C:34]([NH2:37])[S:35][CH:36]=1.CCN=C=NCCCN(C)C.Cl>CN(C1C=CN=CC=1)C.C1COCC1.CN(C=O)C>[F:29][CH:2]([F:1])[O:3][C:4]1[C:5]([O:23][CH2:24][C:25]([CH3:26])([CH3:28])[CH3:27])=[C:6](/[CH:10]=[CH:11]/[C:12]2[N:13]=[C:14]3[N:18]([C:19]=2[C:20]([NH:37][C:34]2[S:35][CH:36]=[C:32]([C:31]([F:39])([F:38])[F:30])[N:33]=2)=[O:22])[CH:17]=[CH:16][S:15]3)[CH:7]=[CH:8][CH:9]=1
Reactant: Nc1nc(C(F)(F)F)cs1
Reactant: CC(C)(C)COc1c(/C=C/c2nc3sccn3c2C(=O)O)cccc1OC(F)F
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)(C)COc1c(/C=C/c2nc3sccn3c2C(=O)Nc2nc(C(F)(F)F)cs2)cccc1OC(F)F

Procedure:
The title compound was prepared according to the general procedure (Method B) by coupling Intermediate 7A (270 mg, 0.639 mmol) with 4-(trifluoromethyl)-1,3-thiazol-2-amine (116 mg, 0.703 mmol) in the presence of EDCI hydrochloride (245 mg, 1.278 mmol) and DMAP (72 mg, 0.639 mmol) in a mixture of THF and DMF (1:1, 6 mL) to give 127 mg of the product as an off-white solid; 1H NMR (300 MHz, DMSO-d6) δ 1.02 (s, 9H), 3.56 (s, 2H), 7.17 (t, J=74.1 Hz, 1H), 7.20-7.31 (m, 2H), 7.42-7.45 (m, 1H), 7.52 (d, J=15.9 Hz, 1H), 7.67-7.69 (m, 1H), 7.81 (d, J=16.2 Hz, 1H), 8.06-8.10 (m, 2H), 13.01 (br s, 1H); APCI-MS (m/z) 573.26 (MH)+.
Reaction SMILES: Br[CH:2]([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[Cl:9][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([Cl:20])[CH:18]=2)[CH:13]=[C:12]([N:21]([C:23]2[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=2)[CH3:22])[N:11]=1.C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[Cl:9][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([Cl:20])[CH:18]=2)[CH:13]=[C:12]([N:21]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH:2]([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4])=[CH:25][CH:24]=2)[CH3:22])[N:11]=1
Reactant: CN(c1ccc(O)cc1)c1cc2ccc(Cl)cc2c(Cl)n1
Reactant: CCOC(=O)C(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)C(C)Oc1ccc(N(C)c2cc3ccc(Cl)cc3c(Cl)n2)cc1
Yield: 85.5 %

Procedure:
A mixture of ethyl 2-bromopropionate (1.6 g), 4-[N-(1,7-dichloroisoquinolin-3-yl)-N-methylamino]phenol (2.76 g), anhydrous potassium carbonate (1.19 g) and methyl ethyl ketone was heated under reflux for a period of 3 hours. The mixture was cooled, washed with water and was dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure to give an oil which was purified by column chromatography over silica gel (eluant dichloromethane) to give ethyl 2-{4-[N-(1,7-dichloroisoquinolin-3-yl)-N-methylamino]phenoxy}propionate (3.10 g) as a yellow oil which crystallised from ethanol, mp 86° C. The assigned structure was confirmed by proton magnetic resonance spectroscopy and mass spectrometry. Proton magnetic resonance spectrum (CDCl3 ; δ in ppm): 1.3 (3H, t); 1.65 (3H, d); 3.45 (3H, s); 4.25 (2H, q); 4.75 (1H, q); 6.40 (1H, s); 6.85-7.35 (6H, m); 8.00 (1H, s).
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.Cl[CH2:6][C:7]1[O:8][C:9]([CH3:12])=[N:10][N:11]=1>>[CH:1]1([NH:4][CH2:6][C:7]2[O:8][C:9]([CH3:12])=[N:10][N:11]=2)[CH2:3][CH2:2]1
Reactant: NC1CC1
Reactant: Cc1nnc(CCl)o1
Product: Cc1nnc(CNC2CC2)o1
Temperature: 25 °C
Reaction time: 16 h
Yield: 34.6 %

Procedure:
A mixture of cyclopropanamine (765-30-0, 194 mg, 236 μL, 3.39 mmol) and 2-(chloromethyl)-5-methyl-1,3,4-oxadiazole (3914-42-9, 90 mg, 679 μmol) was stirred for 16 h at ambient temperature. The mixture was concentrated under reduced pressure and the residue taken up in ice-water/saturated aqueous Na2CO3 solution 1/1 (20 mL) and EtOAc (30 mL). The layers were separated and the aqueous layer was extracted one more time with EtOAc (30 mL). The combined extracts were washed with ice-water/brine 1/1 (15 mL), dried over Na2SO4 and brought to dryness to give the title compound (36 mg, 35%) as yellow oil which was sufficiently pure to be used in the next reaction step; MS (EI): m/e=154.2 [MH+].
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH:11]([CH2:14][CH3:15])[CH2:12][CH3:13])=[C:6]([NH:16][C:17](=O)[CH2:18][C:19]2[O:20][CH:21]=[CH:22][CH:23]=2)[CH:5]=1.Cl>O1CCOCC1>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[CH:8][C:7]2[N:10]([CH:11]([CH2:14][CH3:15])[CH2:12][CH3:13])[C:17]([CH2:18][C:19]3[O:20][CH:21]=[CH:22][CH:23]=3)=[N:16][C:6]=2[CH:5]=1)=[O:25]
Reactant: CCC(CC)Nc1ccc(C(=O)OC)cc1NC(=O)Cc1ccco1
Agent: Cl
Solvent: C1COCCO1
Product: CCC(CC)n1c(Cc2ccco2)nc2cc(C(=O)OC)ccc21
Yield: 105.5 %

Procedure:
4.70 g of 4-(1-Ethyl-propylamino)-3-(2-furan-2-yl-acetylamino)-benzoic acid methyl ester were dissolved in 25 ml of dry dioxane and 50 ml of 4M hydrochloric acid in dioxane were added. The reaction was heated to reflux for 10 h and concentrated to yield 4.70 g (100%) of 1-(1-Ethyl-propyl)-2-furan-2-ylmethyl-1H-benzoimidazole-5-carboxylic acid methyl ester which was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:8](Cl)=[CH:7][C:5]([NH2:6])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.[CH2:13]1[C:15]2([CH2:19][CH2:18][NH:17][CH2:16]2)[CH2:14]1.C(=O)([O-])[O-].[K+].[K+].C(Cl)Cl.CCO>CS(C)=O>[CH2:14]1[C:15]2([CH2:19][CH2:18][N:17]([C:8]3[C:2]([Cl:1])=[CH:3][C:4]([N+:10]([O-:12])=[O:11])=[C:5]([NH2:6])[CH:7]=3)[CH2:16]2)[CH2:13]1
Reactant: Nc1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Reactant: C1CC2(CC2)CN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCO
Product: Nc1cc(N2CCC3(CC3)C2)c(Cl)cc1[N+](=O)[O-]

Procedure:
The sub-title compound was prepared from 4,5-dichloro-2-nitroaniline (470 mg, 2.3 mmol), 5-aza-spiro[2.4]heptane (320 mg, 3.3 mmol) and potassium carbonate (470 mg, 3.4 mmol) in DMSO (5 mL) in analogy to example 3, step (a). Yield: 550 mg (91%). Rf(TLC): 0.85 (silica gel, DCM:EtOH 99:1). HPLC-method F: Rf=1.01 min. MS m/z: 533 [2M+H]+.
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5](B(O)O)[C:4]=2[CH:3]=[CH:2]1.[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19]([OH:22])(=[O:21])=[O:20])=[CH:15][CH:14]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.N1C=C([C:40]2[S:44][C:43]([O:45][C@@H:46]3[CH:53]4[CH2:54][N:49]5[CH2:50][CH:51]([CH2:55][CH:47]3[CH2:48]5)[CH2:52]4)=[N:42]C=2)C=N1.[NH3:56]>>[C:13]1([CH3:23])[CH:14]=[CH:15][C:16]([S:19]([OH:22])(=[O:20])=[O:21])=[CH:17][CH:18]=1.[NH:1]1[C:9]2[C:4](=[C:5]([C:40]3[S:44][C:43]([O:45][C@@H:46]4[CH:53]5[CH2:54][N:49]6[CH2:50][CH:51]([CH2:55][CH:47]4[CH2:48]6)[CH2:52]5)=[N:42][N:56]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: c1n[nH]cc1-c1cnc(OC2C3CC4CC2CN(C4)C3)s1
Reactant: N
Reactant: OB(O)c1cccc2[nH]ccc12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: c1cc(-c2nnc(OC3C4CC5CC3CN(C5)C4)s2)c2cc[nH]c2c1

Procedure:
The free base of the title compound was prepared from the product of Example 41B (190 mg, 0.60 mmol) and indole-4-boronic acid (192 mg, 1.19 mmol; Frontier) according to Method F, and converted to the p-toluenesulfonate salt using the procedure of Method H: 1H NMR (300 MHz, methanol-D4) δ ppm 1.96 (d, J=12.5 Hz, 2H), 2.19 (s, 1H), 2.33 (d, J=13.5 Hz, 2H), 2.36 (s, 3H), 2.64 (s, 2H), 3.52-3.77 (m, 6H), 5.36 (s, 1H), 7.04 (d, J=3.0 Hz, 1H), 7.17-7.27 (m, 3H), 7.43 (d, J=3.4 Hz, 1H), 7.49 (d, J=6.7 Hz, 1H), 7.58 (d, J=8.1 Hz, 1H), 7.70 (d, J=8.1 Hz, 2H). MS (DCI/NH3) m/z=354 (M+H)+. Anal. Calcd. for C19H20N4OS.C7H8O3S: C, 59.92; H, 5.38; N, 10.68. Found: C, 56.90; H, 5.11; N, 10.13.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]3[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=3[S:14][CH:15]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].C(Cl)Cl.[Br:23]Br.[O-]S([O-])(=S)=O.[Na+].[Na+]>C(Cl)(Cl)(Cl)Cl>[Br:23][C:15]1[S:14][C:13]2[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=2[C:11]=1[C:8]1[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:6][CH:7]=1
Reactant: BrBr
Reactant: CS(=O)(=O)c1ccc(-c2csc3ccccc23)cc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: CS(=O)(=O)c1ccc(-c2c(Br)sc3ccccc23)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-(4-(methanesulfonyl)phenyl)benzo[b]thiophene (1 g) from Step 2 in CH2Cl2 (70 mL) one equivalent of a 1M Br2 solution in CCl4 was added. The mixture was stirred at 25° C. for 2 hrs, then a 10% Na2S2O3 solution was added. After extraction with EtOAc, the organic layers were washed with a saturated solution of NaHCO3 (3×), brine, and dried over MgSO4, filtered and the solvent evaporated under vacuum. Purification by column chromatography using 5% EtOAc in toluene afforded the title compound.
Reaction SMILES: C1([C:4]2([N:7]([CH2:40][C:41]3[CH:46]=[C:45]([CH2:47][CH2:48][CH2:49][O:50][CH3:51])[CH:44]=[C:43]([OH:52])[CH:42]=3)[C:8](=[O:39])[CH:9]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][O:29][C:30]4[C:35]([Cl:36])=[CH:34][C:33]([CH3:37])=[CH:32][C:31]=4[Cl:38])=[CH:22][CH:21]=3)[CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:6][CH2:5]2)CC1.[N:53]1[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=1[CH2:59][CH2:60]O.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC>C1(C)C=CC=CC=1.CCOCC>[CH:4]1([N:7]([CH2:40][C:41]2[CH:42]=[C:43]([O:52][CH2:60][CH2:59][C:54]3[CH:55]=[CH:56][CH:57]=[CH:58][N:53]=3)[CH:44]=[C:45]([CH2:47][CH2:48][CH2:49][O:50][CH3:51])[CH:46]=2)[C:8](=[O:39])[CH:9]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][O:29][C:30]3[C:35]([Cl:36])=[CH:34][C:33]([CH3:37])=[CH:32][C:31]=3[Cl:38])=[CH:22][CH:21]=2)[CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:16])([CH3:17])[CH3:15])[CH2:5][CH2:6]1
Reactant: COCCCc1cc(O)cc(CN(C(=O)C(CNC(=O)OC(C)(C)C)Cc2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)C2(C3CC3)CC2)c1
Reactant: OCCc1ccccn1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: COCCCc1cc(CN(C(=O)C(CNC(=O)OC(C)(C)C)Cc2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)C2CC2)cc(OCCc2ccccn2)c1
Temperature: 100 °C

Procedure:
To a solution of tert-butyl (3-{cyclopropyl[3-hydroxy-5-(3-methoxypropyl)benzyl] (cyclopropyl)amino}-2-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]benzyl}-3-oxopropyl)carbamate from Example 70, Step 2 (1 eq.) in toluene (0.1 M) was added 2-pyridin-2-ylethanol (1.2 eq.) and 1,1′-(azodicarbonyl)-dipiperidine (1.2 eq.). The resulting orange solution was deoxygenated before tributylphosphine (1.2 eq.) was added. The now yellow-orange solution was heated at 100° C. for 14 h. The reaction mixture was cooled to RT, diluted with ether, and washed with 1 N aq. NaOH. The aqueous wash was back extracted with ether and the combined organic extracts were dried over MgSO4. Filtration and concentration of the filtrate in vacuo afforded a red oil. Purification of the crude product thus obtained by way of flash chromatography (SiO2, 4:1 (v/v) Hex:EtOAc→EtOAc) afforded the title compound as a pale yellow oil.
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:6]=[C:7]([C:11]([O:13][CH3:14])=[S:12])[S:8][C:9]=1[CH3:10])=O.[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[NH:22][C:23]([NH2:25])=[S:24]>>[BrH:1].[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[NH:22][C:23]1[S:24][CH:2]=[C:3]([C:5]2[CH:6]=[C:7]([C:11]([O:13][CH3:14])=[S:12])[S:8][C:9]=2[CH3:10])[N:25]=1
Reactant: NC(=S)Nc1ccccc1Cl
Reactant: COC(=S)c1cc(C(=O)CBr)c(C)s1
Product: Br
Product: COC(=S)c1cc(-c2csc(Nc3ccccc3Cl)n2)c(C)s1
Yield: 87.8 %

Procedure:
Methyl 4-(2-bromoacetyl)-5-methylthiothiophene-2-carboxylate (50 mg) was allowed to react with 2-chlorophenyl thiourea (26.7 mg) as described in Example 154, step (a), to give 58 mg (75%) of methyl 4-{2-[(2-chlorophenyl)amino]-(1,3-thiazol-4-yl)}-5-methylthiothiophene-2-carboxylate hydrobromide. 1H NMR (DMSO-d6, 300 MHz) δ2.66 (s, 3H), 3.82 (s, 3H), 7.04 (m, 1H), 7.32-7.38 (m, 2H), 7.47 (dd, 1H, J=1.4, 8.7 Hz), 8.12 (s, 1H), 8.56 (dd, 1H, J=1.4, 8.3 Hz), 9.75 (s, 1H); Mass Spectrum (ESI) m/z calcd. for C16H13ClN2O2S3, 396.94 (M+H), found 397.1.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][CH:12]([CH3:14])[CH3:13])(=[O:10])=[O:9].[H-].[Na+].[Cl:17][C:18]1[N:23]=[C:22](Cl)[C:21]([Cl:25])=[CH:20][N:19]=1.O>CN1C(=O)N(C)CC1>[Cl:17][C:18]1[N:23]=[C:22]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[S:8]([NH:11][CH:12]([CH3:14])[CH3:13])(=[O:10])=[O:9])[C:21]([Cl:25])=[CH:20][N:19]=1
Reactant: Clc1ncc(Cl)c(Cl)n1
Reactant: CC(C)NS(=O)(=O)c1ccccc1N
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCN(C)C1=O
Solvent: O
Product: CC(C)NS(=O)(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 37.6 %

Procedure:
To a solution of 2-amino-N-isopropyl-benzenesulfonamide (16.1 g, 75.1 mmol) in DMI (150 mL) is added sodium hydride (6.6 g, 165.3 mmol) portionwise at 0° C. After the mixture is stirred at room temperature for one hour, 2,4,5-trichloropyrimidine (20.7 g, 112.7 mmol) is added at 0° C. After further stirring at room temperature for 5 hrs, water is added and the mixture is extracted with AcOEt three times. Organic layer is washed with brine, dried over sodium sulfate and evaporated under reduced pressure. The residue is purified by silica gel column chromatography (Hexane to Hexane:AcOEt=4:1) to afford the title compound as pale brown solid (10.2 g, 38%).
Reaction SMILES: [Br:1][C:2]([F:10])([F:9])[C:3]([F:8])([F:7])[CH2:4][CH2:5]Br.[C:11]([O-:19])(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[Na+].C1(C)C=CC=CC=1.O>CS(C)=O>[C:11]([O:19][CH2:5][CH2:4][C:3]([F:8])([F:7])[C:2]([Br:1])([F:10])[F:9])(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C([O-])c1ccccc1
Reactant: FC(F)(Br)C(F)(F)CCBr
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Solvent: Cc1ccccc1
Product: O=C(OCCC(F)(F)C(F)(F)Br)c1ccccc1
Temperature: 60 °C
Reaction time: 3.5 h

Procedure:
In 42 g of dimethyl sulfoxide were dissolved 10.0 g (0.035 mole) of 1,4-dibromo-1,1,2,2,-tetrafluorobutane and 5.0 g (0.035 mole) of sodium benzoate, which was stirred at 60° C. for 3.5 hours. The reaction solution was cooled to room temperature, after which toluene and water were added. The organic layer was taken out and washed once with 20 g of an aqueous saturated sodium hydrogen carbonate solution and twice with 20 g of an aqueous saturated sodium chloride solution. The organic layer was concentrated under reduced pressure, obtaining a compound, 4-bromo-3,3,4,4-tetrafluorobutyl benzoate. Colorless oily matter, 4.1 g.
Reaction SMILES: [C:1]1([N:7]2[C:11]3=[N:12][C:13]([Cl:17])=[N:14][C:15](Cl)=[C:10]3[CH:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:18][C@@H:19]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:20][OH:21]>C(O)C>[C:1]1([N:7]2[C:11]3=[N:12][C:13]([Cl:17])=[N:14][C:15]([NH:18][C@@H:19]([CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH2:20][OH:21])=[C:10]3[CH:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Clc1nc(Cl)c2cnn(-c3ccccc3)c2n1
Reactant: N[C@H](CO)Cc1ccccc1
Solvent: CCO
Product: OC[C@H](Cc1ccccc1)Nc1nc(Cl)nc2c1cnn2-c1ccccc1
Reaction time: 24 h
Yield: 97 %

Procedure:
2.5 g of the starting material 1-phenyl-4,6-dichloropyrazolo[3,4-d]pyrimidine was suspended in 60 ml of ethanol. Next, 4.28 g of (S)-(-)-2-amino-3-phenyl-1-propanol was added and the reaction was allowed to stir for 24 hours. The solvent was then removed under vacuum and the crude oil was purified by flash chromatography (10-15-20% isopropyl alcohol/hexane) to yield 3.5 g of (S)-β-[(1-phenyl-6-chloro-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino]benzenepropanol (97%).
Reaction SMILES: N([O-])=[O:2].[Na+].N[C:6]1[N:7]=[N+:8]([O-:17])[C:9]2[CH:15]=[C:14]([OH:16])[CH:13]=[CH:12][C:10]=2[N:11]=1>C(O)(C(F)(F)F)=O>[OH:2][C:6]1[N:7]=[N+:8]([O-:17])[C:9]2[CH:15]=[C:14]([OH:16])[CH:13]=[CH:12][C:10]=2[N:11]=1
Reactant: O=N[O-]
Reactant: Nc1nc2ccc(O)cc2[n+]([O-])n1
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: [O-][n+]1nc(O)nc2ccc(O)cc21
Temperature: 20 °C
Reaction time: 3 h

Procedure:
Sodium nitrite (22 mmol) was added in small portions to a stirred solution of 3-amino-7-hydroxybenzo[e][1,2,4]triazine 1-oxide (20 mmol) in TFA (40 mL) at 5° C., and the solution stirred at 20° C. for 3 h. The solution was poured into ice/water (400 mL), stirred 30 min, filtered, washed with water (3×10 mL) and dried.
Reaction SMILES: [O:1]=[C:2]1[C:11](=[O:12])[C:10]2[N:9]=[C:8]([C:13]([O:15][CH3:16])=[O:14])[CH:7]=[C:6]([C:17]([O:19][CH3:20])=[O:18])[C:5]=2[C:4]2[NH:21][C:22]([C:24]([O:26][CH3:27])=[O:25])=[CH:23][C:3]1=2.[CH2:28](O)[CH2:29][OH:30].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[O:12]=[C:11]1[C:10]2[N:9]=[C:8]([C:13]([O:15][CH3:16])=[O:14])[CH:7]=[C:6]([C:17]([O:19][CH3:20])=[O:18])[C:5]=2[C:4]2[NH:21][C:22]([C:24]([O:26][CH3:27])=[O:25])=[CH:23][C:3]=2[C:2]21[O:30][CH2:29][CH2:28][O:1]2
Reactant: OCCO
Reactant: COC(=O)c1cc(C(=O)OC)c2c(n1)C(=O)C(=O)c1cc(C(=O)OC)[nH]c1-2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: COC(=O)c1cc(C(=O)OC)c2c(n1)C(=O)C1(OCCO1)c1cc(C(=O)OC)[nH]c1-2
Temperature: 25 °C

Procedure:
A suspension of trimethyl 4,5-dioxo-4,5-dihydro-1H-pyrrolo[2,3-f]quinoline-2,7,9-tricarboxylate, 1 (1.2 g, 3.22 mMol) in benzene (200 mL) was treated with ethylene glycol (10 mL) and p-toluensulfonic acid (60 mg, 0.32 mMol). The resulting mixture was heated at reflux under a Dean-Stark trap and reflux condenser for 14 hours. The orange suspension became a yellow solution. The heat was turned off, the trap was removed, and the condenser was replaced. To the hot solution, a mixture of benzene (75 mL) and DCM (75 mL) was cautiously added. The resulting solution was allowed to cool to room temperature, and then washed with 5% aqueous NaHCO3 (100 mL). The organic layer was separated and washed with water (100 mL). The organic layer was separated, dried over Na2SO4, and filtered. Evaporation of solvent at reduced pressure gave a yellow solid. Flash chromatography on silica gel (40 g), eluting with EtOAc-DCM-Hexane (50:25:25) gave purified 2 (1/02 g, 74.4%) as a yellow solid upon evaporation of solvent. 1H-NMR (CDCl3, δ) 12.31 (s, 1H, NH), 8.77 (s, 1H, H-8), 7.15 (d, 1H, H-3), 4.35 (m, 2H, OCH2), 4.30 (m, 2H, OCH2), 4.11 (s, 1H, CO2CH3), 4.07 (s, 1H, CO2CH3), 3.93 (s, 1H, CO2CH3).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[N:8]=[C:7]([CH3:13])[C:6]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:5]2O.P(Cl)(Cl)([Cl:22])=O.N>>[Cl:22][C:5]1[C:4]2[C:9](=[CH:10][C:11]([F:12])=[C:2]([F:1])[CH:3]=2)[N:8]=[C:7]([CH3:13])[C:6]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CCOC(=O)c1c(C)nc2cc(F)c(F)cc2c1O
Reactant: O=P(Cl)(Cl)Cl
Agent: N
Product: CCOC(=O)c1c(C)nc2cc(F)c(F)cc2c1Cl

Procedure:
A suspension of 4-hydroxy quinoline 60 was refluxed with phosphorus oxychloride for 30 minutes. To the cooled reaction mixture was added aqueous ammonia and the product was obtained by extracting with methylene chloride, dried over sodium sulfate and concentrated in vacuo. 1H NMR (CDCl3) δ (ppm): 1.44 (3H, t, J=7.14 Hz), 2.70 (3H, s), 4.50 (2H, q, J=7.14 Hz), 7.62 (1H, t, J=7.69 Hz), 7.78 (1H, dd, J=10.71, 7.69 Hz), 7.95 (2H, d, J=10.72, 8.24 Hz). m/z 286.7 (MH+).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=2)[N:6]=[C:5]2[CH2:16][CH2:17][CH2:18][C:4]=12.[CH3:19][O:20][CH2:21][CH2:22][C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][CH:24]=1>C(O)(C)C>[ClH:2].[Cl:15][C:11]1[CH:10]=[C:9]([C:7]2[N:6]=[C:5]3[CH2:16][CH2:17][CH2:18][C:4]3=[C:3]([NH:27][C:26]3[CH:25]=[CH:24][C:23]([CH2:22][CH2:21][O:20][CH3:19])=[CH:29][CH:28]=3)[CH:8]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: Clc1cccc(-c2cc(Cl)c3c(n2)CCC3)c1
Reactant: COCCc1ccc(N)cc1
Agent: Cl
Solvent: CC(C)O
Product: COCCc1ccc(Nc2cc(-c3cccc(Cl)c3)nc3c2CCC3)cc1
Yield: 64.7 %

Procedure:
Following general procedure A2 except using iso-propanol as a solvent, 4-chloro-2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridine hydrochloride (0.107 g, 0.35 mmol) was reacted with 4-(2-methoxyethyl)aniline (0.108 g, 0.71 mmol), followed by formation of the hydrochloride salt to afford the title compound (0.094 g, 64%) as a white solid. MW=415.36. 1H NMR (DMSO-d6, 500 MHz) δ 14.03 (s, 1H), 9.75 (s, 1H), 7.89 (t, J=1.9 Hz, 1H), 7.71-7.67 (m, 2H), 7.59 (t, J=7.9 Hz, 1H), 7.36-7.32 (m, 4H), 6.99 (s, 1H), 3.57 (t, J=6.8 Hz, 2H), 3.25 (s, 3H), 3.15 (t, J=7.5 Hz, 2H), 2.91 (t, J=7.2 Hz, 2H), 2.85 (t, J=6.8 Hz, 2H), 2.24 (quin, J=7.5 Hz, 2H); APCI MS m/z 379 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[NH:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([S:17][CH3:18])[N:12]=3)[C:5]2=[CH:4][N:3]=1.[NH2:19][CH:20]1[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]1.C(N(CC)CC)C>CC(O)C>[C:29]([O:28][C:26]([N:23]1[CH2:24][CH2:25][CH:20]([NH:19][C:2]2[N:7]=[C:6]3[NH:8][N:9]=[C:10]([C:11]4[CH:16]=[CH:15][N:14]=[C:13]([S:17][CH3:18])[N:12]=4)[C:5]3=[CH:4][N:3]=2)[CH2:21][CH2:22]1)=[O:27])([CH3:32])([CH3:30])[CH3:31]
Reactant: CSc1nccc(-c2n[nH]c3nc(Cl)ncc23)n1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: CSc1nccc(-c2n[nH]c3nc(NC4CCN(C(=O)OC(C)(C)C)CC4)ncc23)n1

Procedure:
To a solution of 6-chloro-3-(2-methylsulfanyl-pyrimidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidine (from Example 7 supra) (500 mg, 1.8 mmol) in 2-propanol (40 mL) was added tert-butyl 4-aminopiperidine-1-carboxylate (395 mg, 2.0 mmol) followed by triethylamine (198 mg, 2.0 mmol). The reaction mixture was stirred with heating at reflux for 15 hours. The solvent was then removed under reduced pressure. The residue was extracted with dichloromethane (3×30 mL), washed with water (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to afford 4-[3-(2-methylsulfanyl-pyrimidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino]-piperidine-1-carboxylic acid tert-butyl ester. (Yield 700 mg, 88.2%).
Reaction SMILES: [CH3:1][C:2]1[O:12][C:5]2[CH2:6][N:7]([CH3:11])[CH2:8][CH:9]([OH:10])[C:4]=2[CH:3]=1.[C:13]([C:16]1[CH:21]=[CH:20][C:19](F)=[CH:18][C:17]=1[Cl:23])(=[O:15])[NH2:14]>>[ClH:23].[C:13]([C:16]1[CH:21]=[CH:20][C:19]([O:10][CH:9]2[CH2:8][N:7]([CH3:11])[CH2:6][C:5]3[O:12][C:2]([CH3:1])=[CH:3][C:4]2=3)=[CH:18][C:17]=1[Cl:23])(=[O:15])[NH2:14]
Reactant: NC(=O)c1ccc(F)cc1Cl
Reactant: Cc1cc2c(o1)CN(C)CC2O
Product: Cc1cc2c(o1)CN(C)CC2Oc1ccc(C(N)=O)c(Cl)c1
Product: Cl

Procedure:
The same method as in Example 3 was conducted using 2,6-dimethyl-4,5,6,7-tetrahydrofuro[2,3-c]pyridin-4-ol (Reference Example 2) instead of 6-methyl-4,5,6,7-tetrahydrofuro[2,3-c]pyridin-4-ol (Reference Example 1) and was conducted using 4-carbamoyl-3-chloro-1-fluorobenzene instead of 1,3-difluorobenzene to give the objective compound.
Reaction SMILES: [C:1]([CH2:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7](O)=[O:8])(O)=[O:2].[NH4+:14].[OH-]>>[C:7]1(=[O:8])[C:6]2[C:5](=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:4][C:1](=[O:2])[NH:14]1
Reactant: [NH4+]
Reactant: O=C(O)Cc1ccccc1C(=O)O
Agent: [OH-]
Product: O=C1Cc2ccccc2C(=O)N1
Temperature: 200 °C
Reaction time: 8 h
Yield: 74 %

Procedure:
2-(Carboxymethyl)benzoic acid (10 g, 55.6 mmol) was dissolved in concentrated NH4OH (15 mL) and then was evaporated to dryness under reduced pressure. The process was repeated with additional NH4OH (5 mL). The resulting residue was treated with 1,2-dichlorobenzene (20 mL) and heated with stirring at 200° C. without a condenser allowing the solvent to evaporate. The concentrated mixture was allowed to cool to room temperature, diluted with methanol (20 mL), and allowed to stand overnight. The precipitate was collected by filtration, washed with methanol, and dried under reduced pressure to provide the title compound as tan needles (6.6 g, 74%).