Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:17][CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[C:9]([NH:11][C:12]2[S:13][CH:14]=[CH:15][N:16]=2)=[O:10])=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.Cl.[C:33](Cl)(=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[N:36][CH:35]=1>O1CCCC1>[CH:18]1([CH2:17][CH:8]([C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:33](=[O:40])[C:34]3[CH:39]=[CH:38][CH:37]=[N:36][CH:35]=3)=[CH:7][CH:6]=2)[C:9](=[O:10])[NH:11][C:12]2[S:13][CH:14]=[CH:15][N:16]=2)[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: O=C(Cl)c1cccnc1
Reactant: Nc1ccc(C(CC2CCCC2)C(=O)Nc2nccs2)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(Nc1ccc(C(CC2CCCC2)C(=O)Nc2nccs2)cc1)c1cccnc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 70 %

Procedure:
A solution of 2-(4-amino-phenyl)-3-cyclopentyl-N-thiazol-2-yl-propionamide (prepared in Example 3, 63.0 mg, 0.20 mmol) in tetrahydrofuran (10 mL) was treated with N,N-diisopropylethylamine (0.082 mL, 0.48 mmol) and nicotinoyl chloride hydrochloride (35.6 mg, 0.20 mmol). The reaction mixture was stirred at 25° C. for 24 h. At this time, the reaction was concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 90/10 ethyl acetate/methanol) afforded N-{4-[2-cyclopentyl-1-(thiazol-2-ylcarbamoyl)-ethyl]-phenyl}-nicotinamide (58.9 mg, 70%) as a white solid: mp 240-242° C.; EI-HRMS m/e calcd for C23H24N4O2S (M+) 420.1619, found 420.1625.
Reaction SMILES: N1C2C(=CC=CC=2)C(C(O)=O)=C1.N1C2C=CC=C(C(O)=O)C=2C=C1.C[N:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[C:27]1[C:35]([OH:37])=[O:36].C1(C(O)=O)C2C(=CC=CC=2)C=CC=1.N1C2C(=CC=CC=2)C(C(O)=O)=CC=1.C1(C(O)=O)C2CC3C(=CC=CC=3)C=2C=CC=1.C1C=C2C3C(C(O)=O)=CC=CC=3C(=O)C2=CC=1>>[NH:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[C:27]1[C:35]([OH:37])=[O:36]
Reactant: Cn1c(C(=O)O)cc2ccccc21
Agent: O=C(O)c1c[nH]c2ccccc12
Agent: O=C(O)c1cccc2[nH]ccc12
Agent: O=C(O)c1cccc2c1-c1ccccc1C2=O
Product: O=C(O)c1cc2ccccc2[nH]1

Procedure:
indole-3-carboxylic acid; indole-4-carboxylic acid; (N-methyl)indole-2-carboxylic acid; 2- or 1-naphthalenecarboxylic acid; 2- or 3- or 4-quinolinecarboxylic acid; xanthene-α-carboxylic acid; 1-fluorenecarboxylic acid; 9-fluorenone-4-carboxylic acid;
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10]([NH:13][C:14]3[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=3)[C:17]([OH:19])=[O:18])(=[O:12])=[O:11])=[C:7]([CH3:23])[C:6]=2[CH:24]=1.[CH3:25][N:26]([CH3:31])[CH2:27][CH2:28][CH2:29]O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10]([NH:13][C:14]3[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=3)[C:17]([O:19][CH2:29][CH2:28][CH2:27][N:26]([CH3:31])[CH3:25])=[O:18])(=[O:12])=[O:11])=[C:7]([CH3:23])[C:6]=2[CH:24]=1
Reactant: CN(C)CCCO
Reactant: Cc1c(S(=O)(=O)Nc2cccc(C(=O)O)c2)sc2ccc(Cl)cc12
Product: Cc1c(S(=O)(=O)Nc2cccc(C(=O)OCCCN(C)C)c2)sc2ccc(Cl)cc12
Yield: 99 %

Procedure:
The product was prepared from 3-{[(5-chloro-3-methyl-1-benzothien-2-yl)sulfonyl]amino}benzoic acid (21 mg, 0.055 mmol) (Intermediate 19) and 3-dimethylamino-1-propanol (10.3 mg, 0.100 mmol) according to the General Procedure 7, described in Example 107. The title compound was obtained in 99% yield (25.5 mg). 1H NMR (500 MHz, CDCl3) δ ppm 2.19-2.27 (m, 2 H) 2.53 (s, 3 H) 2.86 (s, 6 H) 3.19-3.25 (m, 2 H) 4.30-4.36 (m, 2 H) 7.35 (dd, J=8.12, 7.78 Hz, 1 H) 7.42 (dd, J=8.67, 2.05 Hz, 1 H) 7.56 (ddd, J=8.12, 2.34, 1.05 Hz, 1 H) 7.70 (dd, J=8.67, 0.57 Hz, 1 H) 7.71 (dd, J=2.05, 0.57 Hz, 1H) 7.75 (ddd, J=7.78, 1.60, 1.05 Hz, 1 H) 7.89 (dd, J=2.34, 1.60 Hz, 1 H) 8.38 (br. s., 1 H). MS (ESI+) m/z 467 [M+H]+.
Reaction SMILES: [CH2:1]([N:5]1[C:14](=[O:15])[C:13]2[NH:12][C:11]([N+:16]([O-])=O)=[N:10][C:9]=2[N:8]([CH2:19][CH2:20][CH2:21][CH3:22])[C:6]1=[O:7])[CH2:2][CH2:3][CH3:4].[Sn].[ClH:24]>>[ClH:24].[CH2:1]([N:5]1[C:14](=[O:15])[C:13]2[NH:12][C:11]([NH2:16])=[N:10][C:9]=2[N:8]([CH2:19][CH2:20][CH2:21][CH3:22])[C:6]1=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1c(=O)c2[nH]c([N+](=O)[O-])nc2n(CCCC)c1=O
Agent: Cl
Agent: [Sn]
Product: CCCCn1c(=O)c2[nH]c(N)nc2n(CCCC)c1=O
Reaction time: 0.17 h

Procedure:
1,3-Di-n-butyl-8-nitro xanthine from Example 1 (8.5 g) was suspended in concentrated hydrochloric acid (85 ml) and then treated at room temperature with tin powder (14.5 g) in small portions. After stirring for 10 minutes the yellow colour of the suspension disappeared. Thereafter the precipitate was filtered off and recrystallised twice from ethanol. The product formed colourless crystals, yield 5.5 g (63%) m.pt >250° C.
Reaction SMILES: [NH2:1][C:2]1[CH:32]=[CH:31][C:5]2[N:6]=[C:7]([O:9][C:10]3[CH:15]=[CH:14][C:13]([NH:16][S:17]([C:20]4[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][C:21]=4[Cl:30])(=[O:19])=[O:18])=[CH:12][CH:11]=3)[S:8][C:4]=2[CH:3]=1.[CH3:33][S:34](Cl)(=[O:36])=[O:35]>>[Cl:30][C:21]1[CH:22]=[C:23]([C:26]([F:27])([F:28])[F:29])[CH:24]=[CH:25][C:20]=1[S:17]([NH:16][C:13]1[CH:14]=[CH:15][C:10]([O:9][C:7]2[S:8][C:4]3[CH:3]=[C:2]([NH:1][S:34]([CH3:33])(=[O:36])=[O:35])[CH:32]=[CH:31][C:5]=3[N:6]=2)=[CH:11][CH:12]=1)(=[O:18])=[O:19]
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ccc2nc(Oc3ccc(NS(=O)(=O)c4ccc(C(F)(F)F)cc4Cl)cc3)sc2c1
Product: CS(=O)(=O)Nc1ccc2nc(Oc3ccc(NS(=O)(=O)c4ccc(C(F)(F)F)cc4Cl)cc3)sc2c1

Procedure:
2-Chloro-N-[4-(6-methanesulfonylamino-benzothiazol-2-yloxy)-phenyl]-4-trifluoromethyl-benzenesulfonamide was synthesized from N-[4-(6-amino-benzothiazol-2-yloxy)-phenyl]-2-chloro-4-trifluoromethyl-benzenesulfonamide (448) and methanesulfonyl chloride (Aldrich) in a similar manner as described in Examples 70-91. 1H NMR (400 MHz, DMSO-d6) δ 11.07 (s, 1H), 9.82 (s, 1H), 8.26 (d, J=8.2 Hz, 1H), 8.16 (d, J=1.1 Hz, 1H), 7.95 (dd, J=8.3, 1.2 Hz, 1H), 7.75 (d, J=2.2 Hz, 1H), 7.62 (d, J=8.7 Hz, 1H), 7.37-7.34 (m, 2H), 7.24 (dd, J=8.7, 2.2 Hz, 1H), 7.23-7.19 (m, 2H). MS (EI): m/z 576 (M−H).
Reaction SMILES: C(OC([N:11]1[CH2:25][CH2:24][C:14]2([O:18][C:17](=[O:19])[N:16]([CH2:20][CH2:21][CH3:22])[C:15]2=[CH2:23])[CH2:13][CH2:12]1)=O)C1C=CC=CC=1.NN>O.CO.[Pd]>[CH2:23]=[C:15]1[C:14]2([CH2:24][CH2:25][NH:11][CH2:12][CH2:13]2)[O:18][C:17](=[O:19])[N:16]1[CH2:20][CH2:21][CH3:22]
Reactant: C=C1N(CCC)C(=O)OC12CCN(C(=O)OCc1ccccc1)CC2
Agent: [Pd]
Agent: NN
Solvent: CO
Solvent: O
Product: C=C1N(CCC)C(=O)OC12CCNCC2
Temperature: 25 °C
Yield: 95 %

Procedure:
A suspension containing 0.5 g of 10% by weight palladium-on-carcoal catalyst in 5 ml of water is added to the solution of 5.0 g of 8-benzyloxycarbonyl-4-methylene-2-oxo-3-n-propyl-1-oxa-3,8-diazaspiro[4,5]decane in 45 ml of methanol at 0° C. under argon while stirring. To this mixture 1 ml of 45.8% aqueous hydrazine solution is introduced and the reaction mixture is refluxed for 10 to 15 minutes. After cooling down to room temperature and filtering off the catalyst the solvent is evaporated under reduced pressure and the crude evaporation residue is recrystallized from benzene to give the title compound in 95% yield, m.p.: 96°-97° C.
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].[CH:7]([C:9]1[CH:10]=[C:11](B(O)O)[CH:12]=[CH:13][CH:14]=1)=[O:8].Br[C:19]1[N:24]=[CH:23][CH:22]=[CH:21][N:20]=1>O.COCCOC.ClCCl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N:20]1[CH:21]=[CH:22][CH:23]=[N:24][C:19]=1[C:11]1[CH:10]=[C:9]([CH:14]=[CH:13][CH:12]=1)[CH:7]=[O:8]
Reactant: O=Cc1cccc(B(O)O)c1
Reactant: Brc1ncccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: ClCCl
Solvent: O
Product: O=Cc1cccc(-c2ncccn2)c1
Yield: 63.3 %

Procedure:
A mixture of Na2CO3 (4.74 g, 44.72 mmol) and 3-formylphenylboronic acid (3.40 g, 22.67 mmol) in water (15 mL) were added to a solution of 2-bromopyrimidine (3.00 g, 18.87 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.72 g, 0.62 mmol) in DME (30 mL) and the mixture was heated to reflux for 24 h. The cooled reaction mixture was diluted with dichloromethane, washed with sat. aq. NaHCO3 and brine, dried (MgSO4), and concentrated. Purification by chromatography (SiO2, 1:1 hexane/ethyl acetate) yielded 2.20 g (63%) of the title compound. MS 185 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][CH2:6][C:7]2([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[C:13]1([CH:7]2[C:8]3[C:4](=[C:3]([O:2][CH3:1])[CH:11]=[CH:10][CH:9]=3)[CH:5]=[CH:6]2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: COc1cccc2c1CCC2(O)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: COc1cccc2c1C=CC2c1ccccc1
Yield: 66.7 %

Procedure:
To 1 L of toluene was added 14 g (0.058 mol) of 4-methoxy-1-phenyl-indan-1-ol and 100 mg of p-toluenesulfonic acid monohydrate and the solvent was distilled in vacuo (40 mm) until an oily residue was obtained. The oil was chromatographed (silica, 1:1 hexane/methylene chloride followed by ether) to afford 8.6 g (60.2 %) of 1-phenyl-4-methoxy-indene as a pale red oil.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[F:29][C:30]([F:71])([F:70])[C:31]1[CH:32]=[C:33]([CH:67]=[CH:68][CH:69]=1)[CH2:34][NH:35][C:36](=[O:66])[C:37]1[CH:42]=[CH:41][N:40]=[C:39]([C:43]2[CH:48]=[C:47]([N:49]3[CH2:54][CH2:53][CH2:52][CH2:51][CH2:50]3)[CH:46]=[CH:45][C:44]=2[NH:55][C:56](=[O:65])[C:57]2[CH:62]=[CH:61][CH:60]=[C:59]([CH2:63]Br)[CH:58]=2)[CH:38]=1>CN(C)C=O>[F:29][C:30]([F:71])([F:70])[C:31]1[CH:32]=[C:33]([CH:67]=[CH:68][CH:69]=1)[CH2:34][NH:35][C:36]([C:37]1[CH:42]=[CH:41][N:40]=[C:39]([C:43]2[CH:48]=[C:47]([N:49]3[CH2:54][CH2:53][CH2:52][CH2:51][CH2:50]3)[CH:46]=[CH:45][C:44]=2[NH:55][C:56]([C:57]2[CH:58]=[C:59]([CH:60]=[CH:61][CH:62]=2)[CH2:63][N:2]([CH3:1])[CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][C:14]([O:16][C:17]([CH3:19])([CH3:18])[CH3:20])=[O:15])=[O:65])[CH:38]=1)=[O:66]
Reactant: CNCCOCCOCCOCCC(=O)OC(C)(C)C
Reactant: O=C(NCc1cccc(C(F)(F)F)c1)c1ccnc(-c2cc(N3CCCCC3)ccc2NC(=O)c2cccc(CBr)c2)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(CCOCCOCCOCCC(=O)OC(C)(C)C)Cc1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
Into a 8-mL round-bottom flask, was placed a solution of tert-butyl 3-(2-(2-(2-(methylamino)ethoxy)ethoxy)ethoxy)propanoate (89.3 mg, 0.31 mmol, 1.00 equiv) in N,N-dimethylformamide (6 mL), potassium carbonate (84.7 mg, 0.61 mmol, 1.99 equiv), potassium iodide (10.2 mg, 0.06 mmol, 0.20 equiv), and N-(3-(trifluoromethyl)benzyl)-2-(2-(3-(bromomethyl)benzamido)-5-(piperidin-1-yl)phenyl)isonicotinamide (200 mg, 0.31 mmol, 1.00 equiv). The resulting solution was stirred overnight at 70° C. The solids were filtered out. The resulting mixture was concentrated under vacuum. The residue was dissolved in 20 mL of dichloromethane. The resulting mixture was washed with 2×20 mL of water. The resulting mixture was washed with 1×20 mL of brine, dried over sodium sulfate, and concentrated under vacuum. This resulted in 264 mg (crude) of product as yellow oil.
Reaction SMILES: [Br:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([OH:14])=O)=[CH:7][CH:6]=1.S(Cl)([Cl:17])=O>>[Br:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([Cl:17])=[O:14])=[CH:7][CH:6]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)Cc1ccc(OCCBr)cc1
Product: O=C(Cl)Cc1ccc(OCCBr)cc1
Yield: 86 %

Procedure:
4-Hydroxyphenylacetic acid (100 g, 0.6 mol) and cesium carbonate (250 g) were suspended in 300 mL of anhydrous acetonitrile followed by addition of 1,2-dibromoethane (300 mL). The suspension was brought to reflux for 24 hours in a 2 L 3 neck round bottom flask fitted with a mechanical stirrer and reflux condenser then cooled to room temperature. The mixture was diluted to a volume of 2 L by addition of ethyl ether and the suspension was filtered. Concentration of the filtrate in vacuo afforded a colorless oil which was purified by vacuum distillation (0.2 mm Hg, 140-145° C.) to give methyl 4-(2-bromoethoxy)-phenylacetate (93.14 g, 60% yield) as a colorless oil. The methyl 4-(2-bromoethoxy)-phenylacetate was taken into methanol (250 mL) and the resulting solution was cooled to 0° C. Sodium hydroxide (29 g) in a minimum of water was added to the methanol solution in portions and the mixture was stirred at 0° C. for an additional 30 minutes. The solution was warmed to room temperature then concentrated to a white solid. The residue was taken into water and the solution washed once with ethyl ether. The aqueous solution was then acidified to pH 1 by addition of concentrated aqueous hydrochloric acid to give a thick suspension. Filtration and drying afforded 4-(2-bromoethoxy)-phenylacetic acid (86 g, 97% yield) as a colorless solid. The 4-(2-bromoethoxy)-phenylacetic acid (50 g) was taken into thionyl chloride (70 mL) and brought to reflux under an atmosphere of nitrogen for 2 hours. Fractional vacuum distillation (0.2 mm Hg, 139-140° C.) afforded 4-(2-bromoethoxy)phenylacetyl chloride (46.0 g, 86% yield) as a colorless oil that quickly crystallized on cooling. 1H NMR (CDCl3) 6.95, 6.76, 6.60 (m, 11H, Ar—H), 4.68 (m, 1H), 4.24 (m, 2H), 3.80 (m, 1H), 3.41-3.63 (m, 3H), 3.07 (m, 1H), 2.87 (m, 2H), 2.61 (m, 1H); ES-MS (m/z) 458 [M+H]+.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[C:7]([O:9]C)[CH:6]=[CH:5][C:4]=1[C:11]1[C:12](=[O:33])[O:13][C:14]2[C:19]([C:20]=1[CH2:21][CH2:22][O:23]C)=[CH:18][CH:17]=[C:16]([O:25][S:26]([C:29]([F:32])([F:31])[F:30])(=[O:28])=[O:27])[CH:15]=2.B(Br)(Br)Br.O.C(OCC)(=O)C>C(Cl)Cl>[OH:2][C:3]1[CH:8]=[C:7]([OH:9])[CH:6]=[CH:5][C:4]=1[C:11]1[C:12](=[O:33])[O:13][C:14]2[C:19]([C:20]=1[CH2:21][CH2:22][OH:23])=[CH:18][CH:17]=[C:16]([O:25][S:26]([C:29]([F:31])([F:32])[F:30])(=[O:28])=[O:27])[CH:15]=2
Reactant: COCCc1c(-c2ccc(OC)cc2OC)c(=O)oc2cc(OS(=O)(=O)C(F)(F)F)ccc12
Agent: BrB(Br)Br
Solvent: O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=c1oc2cc(OS(=O)(=O)C(F)(F)F)ccc2c(CCO)c1-c1ccc(O)cc1O
Temperature: -30 °C
Reaction time: 4 h

Procedure:
Trifluoro-methanesulfonic acid 3-(2,4-dimethoxy-phenyl)-4-(2-methoxy-ethyl)-2-oxo-2H-chromen-7-yl ester (450 mg, 0.92 mol) was dissolved in CH2Cl2 (10 mL) at room temperature in a 200 ml round bottom flask. The reaction mixture was then cooled to −30° C., and BBr3 (1.8 ml) was added and the reaction mixture stirred at room temperature for 4 h. The reaction mixture was cooled to 0° C. and water (40 mL) was added, followed by ethyl acetate (50 mL). The reaction mixture was then poured into a separation funnel. The organic layer was separated and washed with water (1×40 ml) and brine (1×30 ml). The organic layer was dried over sodium sulfate and concentrated. The product was purified on silica gel eluted with 50%-100% ethyl acetate in hexanes to yield trifluoro-methanesulfonic acid 3-(2,4-dihydroxy-phenyl)-4-(2-hydroxy-ethyl)-2-oxo-2H-chromen-7-yl ester as a light yellow foam
Reaction SMILES: C(O[C:6]([N:8]([C:10]1[CH:37]=[CH:36][C:13]([CH2:14][N:15]2[C:19]3=[N:20][C:21]([C:24](=[O:34])[NH:25][S:26]([CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])(=[O:28])=[O:27])=[CH:22][CH:23]=[C:18]3[N:17]=[C:16]2[CH3:35])=[C:12]([Cl:38])[CH:11]=1)C)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[Cl:38][C:12]1[CH:11]=[C:10]([NH:8][CH3:6])[CH:37]=[CH:36][C:13]=1[CH2:14][N:15]1[C:19]2=[N:20][C:21]([C:24](=[O:34])[NH:25][S:26]([CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])(=[O:28])=[O:27])=[CH:22][CH:23]=[C:18]2[N:17]=[C:16]1[CH3:35]
Reactant: CCCCCS(=O)(=O)NC(=O)c1ccc2nc(C)n(Cc3ccc(N(C)C(=O)OC(C)(C)C)cc3Cl)c2n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCCS(=O)(=O)NC(=O)c1ccc2nc(C)n(Cc3ccc(NC)cc3Cl)c2n1
Reaction time: 1 h
Yield: 97.4 %

Procedure:
To a solution of 3-(4-(N-(tert-butoxycarbonyl)-N-methylamino)-2-chlorobenzyl)-2-methyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine (1.91 g) in dichloromethane (19 ml) was added trifluoroacetic acid (14.5 ml) under ice-cooling, and the mixture was stirred for 1 hr. The solvent was evaporated and methanol (19 ml) was added to the residue for re-dissolution. Water (9.5 ml) was added and 1N aqueous sodium hydroxide solution was added dropwise under ice-cooling to adjust to about pH 4. The resulting precipitate was collected by filtration and dried under reduced pressure to give 3-(2-chloro-4-(methylamino)benzyl)-2-methyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine (1.53 g) as a white powder.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:34])=[C:4]([CH:31]=[CH:32][CH:33]=1)[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:29][CH3:30])=[C:13]([O:16][C@@H:17]3[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18]3)[CH:14]=2)[N:9]=[CH:8][N:7]=1.Cl>C(#N)C>[ClH:1].[Cl:1][C:2]1[C:3]([F:34])=[C:4]([CH:31]=[CH:32][CH:33]=1)[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:29][CH3:30])=[C:13]([O:16][C@@H:17]3[CH2:21][CH2:20][NH:19][CH2:18]3)[CH:14]=2)[N:9]=[CH:8][N:7]=1
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1O[C@@H]1CCN(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: CC#N
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1O[C@@H]1CCNC1
Temperature: 25 °C
Yield: 190.1 %

Procedure:
4-(3-chloro-2-fluoroanilino)-6-[(3R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yloxy]-7-methoxyquinazoline (2.3 g, 4.7 mmole) was dissolved in acetonitrile (35 ml) and hydrogen chloride (4.0M in 1,4-dioxane) (4.7 ml, 18.8 mmole) was added. The mixture was heated to reflux for one hour. After cooling to room temperature, the solid was filtered, washed with acetonitrile and diethylether, and dried under vacuum to give 4-(3-chloro-2-fluoroanilino)-6-[(3R)-pyrrolidin-3-yloxy]-7-methoxyquinazoline hydrochloride as a white solid (1.9 g, 95%); 1H NMR Spectrum (DMSO d6) 2.17-2.29 (m, 1H); 2.34-2.44 (m, 1H); (m, 3H); 3.72-3.84 (m, 1H); 4.00 (s, 3H); 5.44 (m, 1H); 7.31-7.38 (m, 1H); 7.45 (s, 1H); 7.49-7.55 (m, 1H); 7.59-7.65 (m, 1H); 8.67 (s, 1H); 8.80 (s, 1H); 9.43 (br.s 1H); 9.62 (br.s, 1H); 12.25 (br.s, 1H); Mass Spectrum: (M−H)− 387.
Reaction SMILES: [I:1][C:2]1[N:6]([CH3:7])[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)=[N:4][C:3]=1[C:14]1[CH:23]=[CH:22][C:17]([C:18]([NH:20][NH2:21])=[O:19])=[CH:16][CH:15]=1.[C:24](O)(C(F)(F)F)=O>C(OCC)(OCC)OCC>[I:1][C:2]1[N:6]([CH3:7])[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)=[N:4][C:3]=1[C:14]1[CH:23]=[CH:22][C:17]([C:18]2[O:19][CH:24]=[N:21][N:20]=2)=[CH:16][CH:15]=1
Reactant: Cn1c(-c2ccccn2)nc(-c2ccc(C(=O)NN)cc2)c1I
Reactant: O=C(O)C(F)(F)F
Solvent: CCOC(OCC)OCC
Product: Cn1c(-c2ccccn2)nc(-c2ccc(-c3nnco3)cc2)c1I
Temperature: 130 °C

Procedure:
4-(5-Iodo-1-methyl-2-pyridin-2-yl-1H-imidazol-4-yl)benzohydrazide (4.9 g, 12 mmol) was suspended in 60 mL of triethyl orthoformate, to which was added 1 mL of TFA. The suspension was heated at 130° C. The reaction was cooled to rt, and the precipitate was collected, washed with hexanes and dried to give 4.8 g of the title compound. 1H NMR (500 MHz, (CDCl3): 8.62 (m, 1H), 8.57 (s, 1H), 8.11 (m, 1H), 8.09 (s, 4H), 7.82 (m, 1H), 7.32 (m, 1H), 4.13 (s, 3H). LCMS: [M+1]=430.
Reaction SMILES: [CH:1]([N:4]1[C:12](=[O:13])[NH:11][C:10]2[C:5]1=[N:6][C:7]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([OH:23])[CH:18]=1)=[N:8][C:9]=2[C:14]([O-:16])=O)([CH3:3])[CH3:2].[NH2:24]C1C(C([O-])=O)=NC(C2C=CC=C(O)C=2)=NC=1NC(C)C.C(N1C=CN=C1)(N1C=CN=C1)=O>>[CH:1]([N:4]1[C:12](=[O:13])[NH:11][C:10]2[C:5]1=[N:6][C:7]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([OH:23])[CH:18]=1)=[N:8][C:9]=2[C:14]([NH2:24])=[O:16])([CH3:2])[CH3:3]
Reactant: CC(C)Nc1nc(-c2cccc(O)c2)nc(C(=O)[O-])c1N
Reactant: CC(C)n1c(=O)[nH]c2c(C(=O)[O-])nc(-c3cccc(O)c3)nc21
Agent: O=C(n1ccnc1)n1ccnc1
Product: CC(C)n1c(=O)[nH]c2c(C(N)=O)nc(-c3cccc(O)c3)nc21
Yield: 63 %

Procedure:
9-Isopropyl-2-(3-hydroxy-phenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxylate. 5-Amino-6-isopropylamino-2-(3-hydroxy-phenyl)-pyrimidine-4-carboxylate (0.43 g, 1.4 mmol) and 1,1′-carbonyldiimidazole (1.1 g, 6.8 mmol) were reacted according to General Procedure F. The crude residue was triturated with methylene chloride and cold hexanes to afford the title compound as a white solid (0.29 g, 0.85 mmol, 63% yield). MS (ESI) m/z 343.4 [M+1]+.
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[O:24])=[CH:19][CH:18]=3)=[CH:13][C:11]=2[CH:12]=1)(=O)=O.[NH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1>>[N:31]1([CH2:6][CH2:7][C:8]2[O:9][C:10]3[CH:16]=[CH:15][C:14]([C:17]4[CH:18]=[CH:19][C:20]([C:23]([N:25]5[CH2:30][CH2:29][O:28][CH2:27][CH2:26]5)=[O:24])=[CH:21][CH:22]=4)=[CH:13][C:11]=3[CH:12]=2)[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: CS(=O)(=O)OCCc1cc2cc(-c3ccc(C(=O)N4CCOCC4)cc3)ccc2o1
Reactant: C1CCNCC1
Product: O=C(c1ccc(-c2ccc3oc(CCN4CCCCC4)cc3c2)cc1)N1CCOCC1

Procedure:
The product from Example 23D and piperidine were processed as described in Example 1D to provide the titled compound. 1H NMR (300 MHz, CD3OD) δ 7.82 (m, 1H), 7.73 (d, J=8.1, 2H), 7.54 (m, 2H), 7.51 (d, J=8.1 Hz, 2H), 6.77(s, 1H), 3.32-3.8 (m, 14H), 3.07 (m, 2H), 1.5-2.1 (m, 6H); MS (DCI) m/z 419 (M+H)+;
Reaction SMILES: [OH:1][C:2]1([CH2:9][N:10]2[CH2:15][CH2:14][C:13]3[NH:16][C:17]([CH:20]=O)=[C:18]([CH3:19])[C:12]=3[C:11]2=[O:22])[CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][CH2:3]1.[F:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[NH:29][C:28](=[O:33])[CH2:27]2>>[F:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[NH:29][C:28](=[O:33])[C:27]2=[CH:20][C:17]1[NH:16][C:13]2[CH2:14][CH2:15][N:10]([CH2:9][C:2]3([OH:1])[CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][CH2:3]3)[C:11](=[O:22])[C:12]=2[C:18]=1[CH3:19]
Reactant: O=C1Cc2cc(F)ccc2N1
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CC1(O)CCN(C)CC1)CC2
Product: Cc1c(C=C2C(=O)Nc3ccc(F)cc32)[nH]c2c1C(=O)N(CC1(O)CCN(C)CC1)CC2
Yield: 37.98 %

Procedure:
The title compound was prepared under the same conditions as described in Example 1 with 5-(4-hydroxy-1-methyl-piperidin-4-ylmethyl)-3-methyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde and 5-fluoro-1,3-dihydro-indol-2-one as starting materials to give 2-(5-fluoro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-5-(4-hydroxy-1-methyl-piperidin-4-ylmethyl)-3-methyl-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one (16 mg, 37.98%) as an orange solid.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].[CH3:22][O:23][CH2:24][CH:25](O)C>>[C:1]([C:5]1[CH:6]=[C:7]([CH2:16][CH2:17][C:18]([O:20][CH2:21][CH:24]([O:23][CH3:22])[CH3:25])=[O:19])[CH:8]=[C:9]([C:12]([CH3:13])([CH3:14])[CH3:15])[C:10]=1[OH:11])([CH3:2])([CH3:3])[CH3:4]
Reactant: COCC(C)O
Reactant: COC(=O)CCc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Product: COC(C)COC(=O)CCc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1

Procedure:
The title compound was prepared from methyl 3-(3,5-di-t-butyl-4-hydroxyphenyl)propionate and propylene glycol monomethyl ether, by a procedure analogous to that of Reference Example 10. White powder with mellting point 73°-74° C.