Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Cl.F[C:15]1[CH:24]=[C:23]([F:25])[CH:22]=[C:21]2[C:16]=1[CH:17]=[CH:18][C:19]([CH3:26])=[N:20]2.CS(C)=O>O>[CH3:26][C:19]1[CH:18]=[CH:17][C:16]2[C:21](=[CH:22][C:23]([F:25])=[CH:24][C:15]=2[N:1]2[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)[N:20]=1
Reactant: Cc1ccc2c(F)cc(F)cc2n1
Reactant: C1CNCCN1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1ccc2c(N3CCNCC3)cc(F)cc2n1
Temperature: 120 °C
Yield: 20.7 %

Procedure:
A stirred mixture of piperazine (20 g), potassium carbonate (32 g), 5,7-difluoro-2-methylquinoline hydrochloride (WO2002034754, 20 g) and dimethylsulfoxide (390 mL) was heated to 120° C. for 15 hours. The mixture was cooled to room temperature, diluted with water (600 mL) and extracted with 6×500 mL portions of a mixture of DCM-ether (15:85). The combined organic extracts were washed with water (200 mL) and brine (200 mL), dried (sodium sulfate) and the solvent was partially evaporated under vacuum. The precipitate formed during the evaporation was filtered-off, washed with ether (50 mL) and dried under vacuum to give the title compound (4.7 g, 21%).
Reaction SMILES: [N:1]1[C:6]2[S:7][C:8]3[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=3[C:5]=2[C:4](C(N)CCN)=[N:3][CH:2]=1.[F:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH:23]=O>>[F:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH2:23][NH:1][CH2:6][CH2:5][CH2:4][NH:3][C:2]1[N:3]=[CH:4][C:5]2[C:9]3[CH2:10][CH2:11][CH2:12][CH2:13][C:8]=3[S:7][C:6]=2[N:1]=1
Reactant: O=Cc1cccc(F)c1
Reactant: NCCC(N)c1ncnc2sc3c(c12)CCCC3
Product: Fc1cccc(CNCCCNc2ncc3c4c(sc3n2)CCCC4)c1

Procedure:
The title compound was prepared (145 mg, 69%) from 3N-(5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-d]pyrimidine-4-yl)-1,3-diaminopropane(150 mg, 0.57 m. mol) and 3-fluorobenzaldehyde (70 mg, 0.57 mmol) by following the general procedure described for Preparation 3. 1H NMR (400 MHz, CDCl3):δ 8.40 (s, 1H), 7.30 (m, 1H), 7.05 (m, 2H), 6.95 (m, 1H), 6.20 (bs, 1H), 3.80 (s, 2H), 3.70 (m, 2H), 2.80 (m, 6H), 1.80 (m, 6H), 1.70 (bs, 1H). MS (ESI) m/z: Calculated: 370.49; Observed: 371.1 (M++1).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([CH2:5][C:6]2[N:7]([C:12]3[CH:17]=[CH:16][C:15]([C:18]4[CH:27]=[C:26]5[C:21]([CH:22]=[CH:23][CH:24]=[N:25]5)=[CH:20][CH:19]=4)=[CH:14][C:13]=3[F:28])[C:8](=[O:11])[NH:9][N:10]=2)[CH2:2]1.C(N(CC)C(C)C)(C)C.[CH3:38][N:39]1[CH2:43]CC[C:40]1=[O:44].CN(C)C(Cl)=O>ClCCl>[F:28][C:13]1[CH:14]=[C:15]([C:18]2[CH:27]=[C:26]3[C:21]([CH:22]=[CH:23][CH:24]=[N:25]3)=[CH:20][CH:19]=2)[CH:16]=[CH:17][C:12]=1[N:7]1[C:8](=[O:11])[NH:9][N:10]=[C:6]1[CH2:5][CH:3]1[CH2:4][N:1]([C:40]([N:39]([CH3:43])[CH3:38])=[O:44])[CH2:2]1
Reactant: O=c1[nH]nc(CC2CNC2)n1-c1ccc(-c2ccc3cccnc3c2)cc1F
Reactant: CN1CCCC1=O
Agent: CN(C)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN(C)C(=O)N1CC(Cc2n[nH]c(=O)n2-c2ccc(-c3ccc4cccnc4c3)cc2F)C1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 18 %

Procedure:
In a round bottom flask under nitrogen at room temperature, a mixture of 5-(3-azetidinylmethyl)-4-[2-fluoro-4-(7-quinolinyl)phenyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (0.38 mmol) in dichloromethane (2 mL) was treated with N,N-diisopropylethylamine (0.77 mmol) by syringe and stirred for 2 min. The starting material did not dissolve. N-methyl-2-pyrrolidone (2 mL) was added to the mixture and some material dissolved. The mixture was heated with a heat gun to accelerate dissolution and was then left to cool to room temperature. Dimethylcarbamoyl chloride (0.38 mmol) was then added dropwise by syringe to the reaction, which was stirred for 1 h. The reaction mixture was concentrated to remove the dichloromethane. The resultant solution was directly purified by reverse phase HPLC (10-70% acetonitrile/water with 0.1% NH4OH) and subsequently purified by silica gel chromatography (0-3% methanol/ethyl acetate) to provide the title compound as a white solid (31 mg, 18%). MS(ES)+ m/e 447.2 [M+H]+.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[F:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([N:23]2[CH2:28][CH2:27][CH2:26][CH2:25][C@H:24]2[C:29]([OH:31])=O)(=[O:22])=[O:21])=[CH:16][CH:15]=1.[NH2:32][NH:33][C:34]([NH2:36])=[S:35]>O1CCCC1.O1CCOCC1>[F:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([N:23]2[CH2:28][CH2:27][CH2:26][CH2:25][C@H:24]2[C:29]([NH:32][NH:33][C:34](=[S:35])[NH2:36])=[O:31])(=[O:22])=[O:21])=[CH:16][CH:15]=1
Reactant: NNC(N)=S
Reactant: O=C(O)[C@@H]1CCCCN1S(=O)(=O)c1ccc(F)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: NC(=S)NNC(=O)[C@@H]1CCCCN1S(=O)(=O)c1ccc(F)cc1
Yield: 49.4 %

Procedure:
1,1′-Carbonyidimidazole (195 mg) was added to a solution of (2S)-1-[(4-fluorophenyl)sulfonyl]-2-piperidinecarboxylic acid (287 mg) [see Preparation 38] in tetrahydrofuran (5 ml). The reaction mixture was stirred and heated under reflux for 1 hour and then evaporated under reduced pressure to afford a yellow gum. The gum was dissolved in 1,4-dioxane (5 ml) and thiosemicarbazide (182 mg) was added. The reaction mixture was heated under reflux for 1.25 hour. After this time the cooled mixture was purified by column chromatography on MCI (trade mark) reverse phase gel eluting with a solvent gradient of 30:70 changing to 70:30, by volume, methanol:water to afford 2-((2S)-1-[(4-fluorophenyl)sulfonyl]-2-piperidylcarbonyl)-1-hydrazinecarbothioamide (178 mg) as a white foam.
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=1.[CH3:16][N:17]1[C:25]2[C:20](=[CH:21][C:22](B3OC(C)(C)C(C)(C)O3)=[CH:23][CH:24]=2)[CH:19]=[CH:18]1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[Cl:13][C:10]1[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=[C:2]([C:22]2[CH:21]=[C:20]3[C:25](=[CH:24][CH:23]=2)[N:17]([CH3:16])[CH:18]=[CH:19]3)[C:11]=1[CH3:12]
Reactant: Cn1ccc2cc(B3OC(C)(C)C(C)(C)O3)ccc21
Reactant: Cc1c(Cl)nc2cc(F)cc(F)c2c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: Cc1c(-c2ccc3c(ccn3C)c2)nc2cc(F)cc(F)c2c1Cl
Temperature: 100 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 2,4-dichloro-5,7-difluoro-3-methylquinoline (1.0 g, 4.03 mmol) in toluene (8.1 mL) was added 1-methylindole-5-boronic acid pinacol ester (1.037 g, 4.03 mmol), potassium carbonate (1.67 g, 12.09 mmol) and palladium tetrakistriphenylphosphine (0.466 g, 0.403 mmol). The reaction was stirred at 100° C. and stirring continued for 16 h. The reaction mixture was cooled to rt and concentrated in vacuo. The crude material was purified by column chromatography on silica gel, eluting with 0-50% EtOAc in hexanes to provide 4-chloro-5,7-difluoro-3-methyl-2-(1-methyl-1H-indol-5-yl)quinoline as a clear solid. Mass Spectrum (ESI) m/e=343.1 (M+1).
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[C:11]2[C:6](=[CH:7][C:8]([C:12]#[C:13][Si](C)(C)C)=[CH:9][CH:10]=2)[NH:5][C:4](=[O:18])[CH2:3]1.C([O-])([O-])=O.[K+].[K+].CC1(C)C2C(=CC=C(C#C)C=2)NC(=O)C1>CO>[CH3:1][C:2]1([CH3:19])[C:11]2[C:6](=[CH:7][C:8]([C:12]#[CH:13])=[CH:9][CH:10]=2)[NH:5][C:4](=[O:18])[CH2:3]1
Reactant: CC1(C)CC(=O)Nc2cc(C#C[Si](C)(C)C)ccc21
Agent: C#Cc1ccc2c(c1)C(C)(C)CC(=O)N2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1ccc2c(c1)NC(=O)CC2(C)C

Procedure:
1.77 g (6.5 mmol) of 4,4-dimethyl-2-oxo-1,2,3,4-tetrahydro-7-[(trimethylsilyl)ethynyl]quinoline (Compound 19), and 175 mg (1.3 mmol) of K2CO3 in 60 ml of methanol were reacted substantially in accordance with the procedure used for the preparation of 4,4-dimethyl-2-oxo-1,2,3,4-tetrahydro-6-ethynylquinoline (Compound 3), to give the title compound as an orange oil. The product was used in the next reaction without further purification.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH:24][C:25](=[O:43])[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[C:36]([CH2:41][CH3:42])=[N:37][CH:38]=[CH:39][CH:40]=2)[CH:30]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:41]([C:36]1[C:35]([C:31]2[CH:30]=[C:29]([C:27]3[CH2:26][C:25](=[O:43])[NH:24][C:9]4[CH:10]=[C:11]([C:20]([F:21])([F:23])[F:22])[C:12]([O:14][CH2:15][C:16]([F:18])([F:19])[F:17])=[CH:13][C:8]=4[N:7]=3)[CH:34]=[CH:33][CH:32]=2)=[CH:40][CH:39]=[CH:38][N:37]=1)[CH3:42]
Reactant: CCc1ncccc1-c1cccc(C(=O)CC(=O)Nc2cc(C(F)(F)F)c(OCC(F)(F)F)cc2NC(=O)OC(C)(C)C)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCc1ncccc1-c1cccc(C2=Nc3cc(OCC(F)(F)F)c(C(F)(F)F)cc3NC(=O)C2)c1

Procedure:
The title compound was prepared from [2-{3-[3-(2-ethyl-pyridin-3-yl)-phenyl]-3-oxo-propionylamino}-5-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example M216) (335 mg, 0.536 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as an off-white solid (159 mg, 58%).
Reaction SMILES: [CH3:1][C:2]1(C)OC(=O)[CH:5]([C:9](=[O:14])[CH2:10][CH:11]([CH3:13])[CH3:12])[C:4](=[O:15])[O:3]1>CCO>[CH2:2]([O:3][C:4](=[O:15])[CH2:5][C:9](=[O:14])[CH2:10][CH:11]([CH3:12])[CH3:13])[CH3:1]
Reactant: CC(C)CC(=O)C1C(=O)OC(C)(C)OC1=O
Solvent: CCO
Product: CCOC(=O)CC(=O)CC(C)C

Procedure:
Compound 9 was dissolved in EtOH (150 mL) and refluxed overnight. The reaction mixture was evaporated to yield product (10.315 g), which was shown by NMR to be pure. 1H NMR (500 MHz, CDCl3): δ 0.93 (d, 6H), 1.28 (t, 3H), 2.16 (m, 1H), 2.42 (d, 2H), 3.41 (2, 2H), 4.20 (q, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([O:10][CH3:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].Cl.CO[NH2:15].CC(C)([O-])C.[K+]>CN(C=O)C.[Cu]Cl>[NH2:15][C:5]1[C:6]([O:10][CH3:11])=[CH:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: COc1cccc([N+](=O)[O-])c1
Reactant: CON
Agent: Cl[Cu]
Agent: CC(C)(C)[O-]
Agent: Cl
Solvent: CN(C)C=O
Product: COc1cccc([N+](=O)[O-])c1N
Temperature: 25 °C
Reaction time: 6 h
Yield: 50.5 %

Procedure:
A suspension of 3-nitroanisole (1.550 g, 10.12 mmol) and O-methylhydroxylamine hydrochloride (1.078 g, 12.91 mmol) in DMF (15 mL) was added to a cold (0° C.) solution of potassium tert-butoxide (5.870 g, 52.30 mmol) and copper(I) chloride (0.200 g, 2.02 mmol) in DMF (35 mL). The cooling bath was removed and the resultant slurry was stirred at room temperature for 6 hours. The reaction mixture was poured into saturated aqueous NH4Cl (50 mL) and the mixture was extracted with CH2Cl2 (4×50 mL). The combined organic extracts were dried (Na2SO4) and concentrated. Purification of the crude material by column chromatography on silica gel (5:1 hexanes-ethyl acetate) followed by radial chromatography on silica gel (2 mm plate, 5:1 hexanes-ethyl acetate) provided 0.860 g (50%) of 2-amino-3-methoxy-nitrobenzene as a red solid. 1H NMR (CDCl3) □ 3.92 (s, 3H), 6.44 (br s, 2H), 6.61 (dd, 1H, J=9.0, 9.0 Hz), 6.88 (d, 1H, J=9.0 Hz), 7.74 (d, 1H, J=9.0 Hz).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]([C:18]2[C:23]([CH3:24])=[CH:22][CH:21]=[CH:20][C:19]=2[CH3:25])[C:9]2[NH:13][C:12]3[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=3[N:10]=2)[CH:5]=[CH:4][N:3]=1.[CH3:26][N:27]1[CH2:32][CH2:31][N:30]([C:33]2[CH:38]=[CH:37][C:36]([NH2:39])=[CH:35][CH:34]=2)[CH2:29][CH2:28]1.[OH-].[Na+]>CC(O)=O>[NH:10]1[C:11]2[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=2[N:13]=[C:9]1[N:8]([C:18]1[C:23]([CH3:24])=[CH:22][CH:21]=[CH:20][C:19]=1[CH3:25])[C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:39][C:36]2[CH:35]=[CH:34][C:33]([N:30]3[CH2:29][CH2:28][N:27]([CH3:26])[CH2:32][CH2:31]3)=[CH:38][CH:37]=2)[N:7]=1
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Reactant: Cc1cccc(C)c1N(c1ccnc(Cl)n1)c1nc2ccccc2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: Cc1cccc(C)c1N(c1ccnc(Nc2ccc(N3CCN(C)CC3)cc2)n1)c1nc2ccccc2[nH]1
Temperature: 100 °C

Procedure:
A pressure tube was charged with a solution of 2-(N-(2-chloropyrimid-4-yl)-2,6-dimethylphenylamino)-1H-benzimidazole (50 mg, 0.14 mmol), from Example 155 Step F, 4-(4-methylpiperazin-1-yl)-phenylamine (27 mg, 0.14 mmol) in glacial AcOH (2 mL). The reaction, a dark brown solution, was heated to 100° C. for 18 h. The reaction was cooled to RT then basified by careful addition of 5M NaOH (15 mL). The aqueous solution was extracted with CH2Cl2. The combined organic extracts were dried (Na2SO4) and the solvent was removed in vacuo. The residue was purified by column chromatography (silica; CH2Cl2:MeOH; 9:1; containing TEA (0.2%)) to afford a light brown solid. MS m/z=505 (M+H). Calc'd for C30H32N8=504.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7](B(O)O)[C:6]([O:12][CH3:13])=[CH:5][N:4]=1.Br[C:15]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=1[N+:22]([O-:24])=[O:23]>CC(C1C=C(C(C)C)C(C2C(P(C3CCCCC3)C3CCCCC3)=CC=CC=2)=C(C(C)C)C=1)C.C1C=[C-]C(CCN)=CC=1.Cl[Pd+]>[Cl:21][C:19]1[CH:18]=[CH:17][C:16]([N+:22]([O-:24])=[O:23])=[C:15]([C:7]2[C:6]([O:12][CH3:13])=[CH:5][N:4]=[C:3]([O:2][CH3:1])[CH:8]=2)[CH:20]=1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1Br
Reactant: COc1cc(B(O)O)c(OC)cn1
Agent: Cl[Pd+]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: NCCc1[c-]cccc1
Product: COc1cc(-c2cc(Cl)ccc2[N+](=O)[O-])c(OC)cn1

Procedure:
215 mg (purity 85%, 1.0 mmol) of 2,5-dimethoxypyridin-4-ylboronic acid and 236 mg (1.0 mmol) of 2-bromo-4-chloro-1-nitrobenzene in the presence of XPhos precatalyst were reacted according to General Method 2B. Yield: 124 mg (purity 93%, 39% of theory)
Reaction SMILES: [CH:1]([N:4]([C:11]([C:13]1[S:14][C:15]2[CH2:16][CH2:17][O:18][C:19]3[CH:26]=[C:25]([Br:27])[CH:24]=[CH:23][C:20]=3[C:21]=2[N:22]=1)=O)[NH:5][C:6](=O)[CH2:7][O:8][CH3:9])([CH3:3])[CH3:2].C(O)(=O)C.C([O-])(=O)C.[NH4+:36]>O(Cl)Cl.[P+5]>[Br:27][C:25]1[CH:24]=[CH:23][C:20]2[C:21]3[N:22]=[C:13]([C:11]4[N:4]([CH:1]([CH3:3])[CH3:2])[N:5]=[C:6]([CH2:7][O:8][CH3:9])[N:36]=4)[S:14][C:15]=3[CH2:16][CH2:17][O:18][C:19]=2[CH:26]=1
Reactant: [NH4+]
Reactant: COCC(=O)NN(C(=O)c1nc2c(s1)CCOc1cc(Br)ccc1-2)C(C)C
Agent: CC(=O)[O-]
Agent: ClOCl
Agent: [P+5]
Solvent: CC(=O)O
Product: COCc1nc(-c2nc3c(s2)CCOc2cc(Br)ccc2-3)n(C(C)C)n1
Temperature: 100 °C
Reaction time: 18 h
Yield: 45.9 %

Procedure:
A suspension of 8-bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid N-isopropyl-N′-(2-methoxy-acetyl)-hydrazide (2.66 g, 5.86 mmol) in phosphorus (V) oxychloride (26 mL) was stirred at 100° C. for 18 h. The reaction mixture was concentrated in vacuo and the resultant residue azeotroped with toluene (×4) affording a brown solid. The solid was treated with acetic acid (26 mL) and ammonium acetate (4.51 g, 58.6 mmol) before the mixture was stirred at 125° C. for 1 h. A further addition of ammonium acetate (2.31 g, 30.0 mmol) was made and the reaction stirred at 125° C. for 2 h before being concentrated in vacuo. The resultant residue was diluted with water and extracted with DCM (×2) before the combined organic extracts were washed with saturated sodium bicarbonate solution followed by brine, then dried (Na2SO4) and concentrated in vacuo to give a pale brown solid. The solid was treated with phosphorus (V) oxychloride (26 mL) and stirred at 100° C. for 24 h before being concentrated in vacuo then treated with acetic acid (23 mL) and ammonium acetate (4.23 g, 55.0 mmol). The mixture was stirred at 125° C. for 1.5 h then concentrated in vacuo and azeotroped with toluene (×4). The resultant residue was diluted with water and extracted with DCM (×2) and the combined organic extracts were washed with saturated sodium bicarbonate solution followed by brine, then dried (Na2SO4) and concentrated in vacuo to give a brown solid. The solid was recrystallised from methanol/chloroform to give the title compound as a dark brown solid (1.17 g, 2.69 mmol, 46%). LCMS RT=4.97 min, [M+H]+=435/437. 1H NMR 400 MHz (DMSO-d6) δ: 8.23 (1H, d, J=8.58 Hz), 7.36 (1H, dd, J=8.58, 2.10 Hz), 7.26 (1H, d, J=2.07 Hz), 5.72-5.71 (1H, m), 4.39 (2H, s), 4.35 (2H, t, J=5.02 Hz), 3.39 (2H, t, J=5.02 Hz), 3.29 (3H, s), 1.49 (6H, d, J=6.59 Hz).
Reaction SMILES: [CH3:1][C:2]1([CH3:30])[C:11]2[CH:10]=[CH:9][C:8]([C:12]#[C:13][C:14]3[CH:24]=[CH:23][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:16][CH:15]=3)=[CH:7][C:6]=2[C:5]([S:25]([CH2:28][CH3:29])(=[O:27])=[O:26])=[CH:4][CH2:3]1.[CH3:31][C:32]1(C)C2C=CC(C#CC3C=CC(C(OCC)=O)=CC=3)=CC=2C(SC2C=CC=CC=2)=[CH:34][CH2:33]1>>[CH3:30][C:2]1([CH3:1])[C:11]2[CH:10]=[CH:9][C:8]([C:12]#[C:13][C:14]3[CH:15]=[CH:16][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:23][CH:24]=3)=[CH:7][C:6]=2[C:5]([S:25]([C:28]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:29]=2)(=[O:26])=[O:27])=[CH:4][CH2:3]1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(S(=O)(=O)CC)=CCC3(C)C)cc1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(Sc2ccccc2)=CCC3(C)C)cc1
Product: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(S(=O)(=O)c2ccccc2)=CCC3(C)C)cc1

Procedure:
Employing the same general procedure as for the preparation of ethyl 4-[(7,8-dihydro-8,8-dimethyl-5-ethylsulfonylnaphth-3-yl)ethynyl]benzoate (Compound 153), 50 mg (0.11 mmol) of ethyl 4-[(7,8-dihydro-8,8-dimethyl-5-phenylthionaphth-3-yl)ethynyl]benzoate (Compound 155) was converted into the title compound (white solid, recrystallized from ethyl alcohol) using 157 mg (0.46 mmol) of 50% 3-chloroperoxybenzoic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:17][C:16]3[C:11](=[CH:12][C:13]([C:25]([O:27]C)=[O:26])=[CH:14][CH:15]=3)[N:10]=2)=[CH:5][CH:4]=1.[Li+].[OH-].CO>O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:17][C:16]3[C:11](=[CH:12][C:13]([C:25]([OH:27])=[O:26])=[CH:14][CH:15]=3)[N:10]=2)=[CH:7][CH:8]=1
Reactant: COC(=O)c1ccc2cc(-c3ccccc3)c(-c3ccc(OC)cc3)nc2c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccc(-c2nc3cc(C(=O)O)ccc3cc2-c2ccccc2)cc1
Temperature: 50 °C
Reaction time: 5 h
Yield: 58.8 %

Procedure:
Methyl 2-(4-methoxyphenyl)-3-phenylquinoline-7-carboxylate (40 mg, 0.11 mmol, 1.00 equiv), LiOH (13 mg, 0.54 mmol, 5.00 equiv), methanol (5 mL), and water (0.5 mL) were placed in a 50-mL round-bottom flask and stirred for 5 hr at 50° C. in an oil bath. The resulting mixture was concentrated under vacuum, diluted with 10 mL of H2O, and the pH adjusted to 4-5 with 1N HCl. The resulting solids were collected by filtration and dried in an oven under reduced pressure, yielding 23 mg (59%) of 2-(4-methoxyphenyl)-3-phenylquinoline-7-carboxylic acid as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][C@H:9]2[CH3:14])=[CH:4][C:3]=1[O:15][CH3:16].[NH:17]1[CH:21]=[CH:20][N:19]=[C:18]1[C:22]1[C:30]2[C:25](=[N:26][CH:27]=[CH:28][CH:29]=2)[N:24]([CH2:31][C:32](O)=[O:33])[N:23]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:32](=[O:33])[CH2:31][N:24]3[C:25]4=[N:26][CH:27]=[CH:28][CH:29]=[C:30]4[C:22]([C:18]4[NH:17][CH:21]=[CH:20][N:19]=4)=[N:23]3)[CH2:10][C@H:9]2[CH3:14])=[CH:4][C:3]=1[O:15][CH3:16]
Reactant: O=C(O)Cn1nc(-c2ncc[nH]2)c2cccnc21
Reactant: COc1cc(N2CCNC[C@H]2C)ccc1Cl
Product: COc1cc(N2CCN(C(=O)Cn3nc(-c4ncc[nH]4)c4cccnc43)C[C@H]2C)ccc1Cl

Procedure:
The title compound was prepared following Protocol A. (R)-1-(4-Chloro-3-methoxyphenyl)-2-methylpiperazine and [3-(1H-imidazol-2-yl)pyrazolo[3,4-b]pyridin-1-yl]acetic acid were used as the coupling components. The crude product was purified by silica gel chromatography (1% to 7.5% MeOH in CH2Cl2) to provide 1-[(R)-4-(4-chloro-3-methoxyphenyl)-3-methylpiperazin-1-yl]-2-[3-(1H-imidazol-2-yl)-pyrazolo[3,4-b]pyridin-1-yl]ethanone as a tan solid: 1H NMR (CDCl3, 400 MHz) δ 8.76 (d, 0.6H), 8.66 (dd, 0.3H), 8.57-8.54 (m, 1H), 7.29-7.19 (m, 4H), 6.48-6.40 (m, 2H), 5.53-5.40 (m, 2H), 4.26 (br. d, 0.6H), 4.00 (br. d, 0.6H), 3.88 (s, 1.3H), 3.86 (s, 1.7H), 3.80-3.49 (m, 3.2H), 3.33 (br. s, 0.6H), 3.17-3.14 (m, 2H), 1.51-1.42 (m, 3H); LC/MS m/z (M+H)+ 466.4.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[C:11]([C:12](OCC)=[O:13])=[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][N:5]2[N:4]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+]>O1CCCC1>[F:18][C:2]([F:1])([F:17])[C:3]1[C:11]([CH2:12][OH:13])=[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][N:5]2[N:4]=1
Reactant: CCOC(=O)c1c(C(F)(F)F)nn2ccccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1c(C(F)(F)F)nn2ccccc12
Temperature: -70 °C
Reaction time: 3 h
Yield: 98.5 %

Procedure:
A solution of 2.8 g (10.8 mmol) of ethyl 2-trifluoromethylpyrazolo[1,5-a]pyridine-3-carboxylate in 50 ml of tetrahydrofuran is added dropwise to a mixture of 0.5 g (11.9 mmol) of lithium aluminium hydride in suspension in 45 ml of tetrahydrofuran at −70° C. After stirring for 3 h at −70° C., the mixture is brought to ambient temperature, then 1.8 ml of a 2N aqueous sodium hydroxide solution is added. The mixture is filtered, dried over magnesium sulphate, filtered and concentrated. 2.3 g (100%) of (2-trifluoromethylpyrazolo[1,5-a]pyridin-3-yl)methanol are obtained in the form of a yellow solid.
Reaction SMILES: [NH2:1][NH:2][C:3]([NH2:5])=[S:4].[CH3:6][O:7][CH2:8][C:9](O)=O.P(Cl)(Cl)(Cl)=O.[Na]>O1CCOCC1.O>[CH3:6][O:7][CH2:8][C:9]1[S:4][C:3]([NH2:5])=[N:2][N:1]=1
Reactant: NNC(N)=S
Reactant: COCC(=O)O
Agent: [Na]
Solvent: O=P(Cl)(Cl)Cl
Solvent: C1COCCO1
Solvent: O
Product: COCc1nnc(N)s1
Temperature: 80 °C
Yield: 81 %

Procedure:
To a suspension of thiosemicarbazide a24 (40 g, 0.44 mol, 1 eq) in dioxane (400 ml) at room temperature is added methoxyacetic acid (39.56 g, 0.44 mol, 1 eq) in one portion, and the reaction mixture is heated at 80° C. then phosphorous oxychloride (67.54 g, 0.44 mol, 1 eq) is carefully added over 1.5 hours. After reaction completion (4 hours), water is added and the solution is neutralised to pH=6-7 with sodium hydroxyde pellets. After extraction EtOAc/iPrOH (9/1) and evaporation under vacuum, the residue is recrystallized from MeTHF/iPrOH to afford 51 g of pure 5-(methoxymethyl)-1,3,4-thiadiazol-2-amine a25.
Reaction SMILES: [BrH:1].Cl[C:3]1[C:12]2[N:13]=[C:14]([NH2:21])[N:15]([CH2:16][C:17]([CH3:20])([OH:19])[CH3:18])[C:11]=2[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:4]=1.[NH3:22]>CO>[BrH:1].[NH2:21][C:14]1[N:15]([CH2:16][C:17]([CH3:20])([OH:19])[CH3:18])[C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[C:3]([NH2:22])[C:12]=2[N:13]=1
Reactant: CC(C)(O)Cn1c(N)nc2c(Cl)nc3ccccc3c21
Reactant: N
Agent: Br
Solvent: CO
Product: CC(C)(O)Cn1c(N)nc2c(N)nc3ccccc3c21
Temperature: 150 °C

Procedure:
1-(4-Chloro-2-amino-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol hydrobromide (2.00 g, 5.38 mmol) and ammonia (50 mL of a 7 N solution in methanol) were added to a high-pressure vessel, which was sealed and heated overnight in an oven at 150° C. The solvent was removed under reduced pressure, and the residue was suspended in acetonitrile, isolated by filtration, washed with warm acetonitrile (2×100 mL), washed with diethyl ether (100 mL), washed with methanol, and dried under high vacuum to provide 1.02 g of 1-(2,4-diamino-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-ol hydrobromide as a white powder, mp >230° C.