Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:14])[N:4]([CH3:13])[C:5]2[C:10]([C:11]=1[NH2:12])=[CH:9][CH:8]=[CH:7][CH:6]=2.CCN(CC)CC.[CH2:22]([O:29][C:30]([N:32]1[CH2:37][CH2:36][CH:35]([C:38](Cl)=O)[CH2:34][CH2:33]1)=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(Cl)Cl>[CH2:22]([O:29][C:30]([N:32]1[CH2:37][CH2:36][CH:35]([C:38]2[NH:1][C:2]3[C:3](=[O:14])[N:4]([CH3:13])[C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=4[C:11]=3[N:12]=2)[CH2:34][CH2:33]1)=[O:31])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: O=C(Cl)C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: Cn1c(=O)c(N)c(N)c2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cn1c(=O)c2[nH]c(C3CCN(C(=O)OCc4ccccc4)CC3)nc2c2ccccc21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 18.1 %

Procedure:
To a suspension of 3,4-diamino-1-methyl-1H-quinolin-2-one (0.60 g, 1.59 mmol) in CH2Cl2 (10 mL) were added Et3N (0.177 g, 1.74 mmol) and 4-chlorocarbonyl-piperidine-1-carboxylic acid benzyl ester (0.45 g, 1.60 mmol) at 0° C. The reaction mixture was stirred at room temperature for 1.5 h, and then excess acid chloride was quenched by addition of MeOH. The mixture was concentrated in vacuo, and the amide intermediate was taken up in 5 mL of HOAc and heated at reflux for 7 h. After cooling to room temperature, the solvent was evaporated under reduced pressure. The cyclized product was purified by flash chromatography, to give 4-(5-methyl-4-oxo-4,5-dihydro-3H-imidazo[4,5-c]quinolin-2-yl)-piperidine-1-carboxylic acid benzyl ester (0.12 g, 18% yield). 1H-NMR (DMSO): δ 8.08 (m, 1H), 7.60 (m, 1H), 7.43 (m, 1H), 7.32 (m, 6H), 5.02 (s, 2H), 3.91 (m, 2H), 3.34 (s, 3H), 2.81 (m, 3H), 1.78 (m, 2H), 1.39 (m, 2H). MS: calculated for C24H24N4O3+H 417.2; found: 417.4.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:23]3[C:22]([O:24][C@@H:25]4[CH2:30][CH2:29][CH2:28][NH:27][CH2:26]4)=[N:21][CH:20]=[N:19][C:18]=3[O:17][C:16]=2[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[F:37])=[CH:11][CH:10]=1)[CH3:8].[CH3:38][O:39][C:40](=[O:45])[CH2:41][CH2:42][CH2:43]Br>C1COCC1.C(#N)C.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:38][O:39][C:40](=[O:45])[CH2:41][CH2:42][CH2:43][N:27]1[CH2:28][CH2:29][CH2:30][C@@H:25]([O:24][C:22]2[C:23]3[C:15]([C:12]4[CH:13]=[CH:14][C:9]([CH2:7][CH3:8])=[CH:10][CH:11]=4)=[C:16]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=4[F:37])[O:17][C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:26]1
Reactant: COC(=O)CCCBr
Reactant: CCc1ccc(-c2c(-c3ccccc3F)oc3ncnc(O[C@@H]4CCCNC4)c23)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CC#N
Solvent: C1CCOC1
Product: CCc1ccc(-c2c(-c3ccccc3F)oc3ncnc(O[C@@H]4CCCN(CCCC(=O)OC)C4)c23)cc1
Temperature: 80 °C
Reaction time: 13 h

Procedure:
Add 1677 mg (12.1 mmol) of potassium carbonate to a solution of 2250 mg (4.9 mmol) of 5-(4-ethylphenyl)-6-(2-fluorophenyl)-4-[(3R)-piperidin-3-yloxy]furo[2,3-d]pyrimidine in 100 ml of THF and 10 ml of acetonitrile. Then add 0.74 ml (1054 mg, 5.8 mmol) of 4-brombutyric acid methyl ester and 72 mg (0.19 mmol) of tetra-n-butylammonium iodide. Stir the reaction mixture at 80° C. for 13 hours. After cooling to room temperature, filter off the residue, wash with THF, concentrate the filtrate under reduced pressure and purify the residue by column chromatography on silica gel (eluent: cyclohexane/ethyl acetate 1:2). 2005 mg (75% of theory) of the target compound are obtained.
Reaction SMILES: FC(F)(F)C([N:5]1[CH2:11][CH:10]([CH3:12])[C:9]2[CH:13]=[C:14]([Br:21])[C:15]([O:17][CH2:18][CH:19]=[CH2:20])=[CH:16][C:8]=2[CH2:7][CH:6]1[CH3:22])=O.[OH-].[Na+]>CO.O>[CH2:18]([O:17][C:15]1[C:14]([Br:21])=[CH:13][C:9]2[CH:10]([CH3:12])[CH2:11][NH:5][CH:6]([CH3:22])[CH2:7][C:8]=2[CH:16]=1)[CH:19]=[CH2:20]
Reactant: C=CCOc1cc2c(cc1Br)C(C)CN(C(=O)C(F)(F)F)C(C)C2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: C=CCOc1cc2c(cc1Br)C(C)CNC(C)C2
Reaction time: 3 h
Yield: 93.4 %

Procedure:
A solution of N-trifluoroacetyl-7-allyloxy-8-bromo-1,4-dimethyl-2,3,4,5-tetrahydro-1H-3-benzazepine (0.028 g, 0.069 mmol) in methanol (2 mL) was treated with 15% aqueous NaOH (2 mL), and stirred for 3 hours at 20 C. The product mixture was diluted with water (10 mL), extracted twice with EtOAc (10 mL), the combined organic phases were washed with brine (10 mL), dried with Na2SO4 and concentrated to give 0.020 g of a clear oil. 1H NMR (400 MHz, CDCl3) d 7.30 (s, 1H), 6.64 (s, 1H), 6.06 (m, 1H), 5.47 (d, J=17 Hz, 1H), 5.30 (d, J=11 Hz, 1H), 4.56 (s, 2H), 3.03 (m, 2H), 2.90 (dd, J=9, 14 Hz, 1H), 2.80 (m, 1H), 2.65 (d, J=14 Hz, 1H), 2.55 (dd, J=10, 14 Hz, 1H), 1.77 (bs, 1H), 1.30 (d, J=7 Hz, 3H), 1.20 (d, J=6 Hz, 3H).
Reaction SMILES: Cl[C:2]1[C:7]([F:8])=[C:6]([S:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[CH:4][N:3]=1.[CH3:16][C:17]1[N:18]=[C:19]([NH2:22])[S:20][CH:21]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(OCC)(=O)C>[F:8][C:7]1[C:2]([NH:22][C:19]2[S:20][CH:21]=[C:17]([CH3:16])[N:18]=2)=[N:3][CH:4]=[CH:5][C:6]=1[S:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Fc1c(Sc2ccccc2)ccnc1Cl
Reactant: Cc1csc(N)n1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=P([O-])([O-])[O-]
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1csc(Nc2nccc(Sc3ccccc3)c2F)n1
Temperature: 90 °C
Reaction time: 8 h
Yield: 54.9 %

Procedure:
Degassed toluene (10 mL) was added to a mixture of 2-chloro-3-fluoro-4-(phenylthio)pyridine (0.500 g, 2.09 mmol), 4-methylthiazol-2-amine (0.238 g, 2.09 mmol), tris(dibenzylideneacetone)dipalladium (0) (0.0955 g, 0.104 mmol) and potassium phosphate (0.487 g, 2.29 mmol), and then degassed water (3 mL) was added. The reaction was stirred overnight at 90° C., then partitioned between ethyl acetate and water, washed with brine, dried, and concentrated. The crude material was purified by MPLC (Biotage), eluting with 3:1 hexane:ethyl acetate to afford the desired product (0.364 g, 55.0% yield) as white crystals. 1H NMR (d6-DMSO) δ 2.24 (s, 3H), 6.21 (t, 1H), 6.56 (s, 1H), 7.52-7.61 (m, 5H), 7.93 (d, 1H), 11.35 (bs, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][C:31]=1[Cl:32])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([O:15][CH2:16][CH:17]2[CH2:21][O:20]C(C)(C)[O:18]2)=[C:7]1[C:24]([O:26][CH2:27][CH3:28])=[O:25]>O1CCCC1.Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][C:31]=1[Cl:32])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([O:15][CH2:16][CH:17]([OH:18])[CH2:21][OH:20])=[C:7]1[C:24]([O:26][CH2:27][CH3:28])=[O:25]
Reactant: CCOC(=O)c1c(OCC2COC(C)(C)O2)c2ccccc2n1Cc1ccc(Cl)c(Cl)c1
Agent: Cl
Solvent: C1CCOC1
Product: CCOC(=O)c1c(OCC(O)CO)c2ccccc2n1Cc1ccc(Cl)c(Cl)c1

Procedure:
Ethyl N-(3,4-dichlorobenzyl)-3-(2,2-dimethyl-1,3-dioxolane-4-ylmethoxy)-indole-2-carboxylate [Compound 70] (15.92 g) was dissolved in tetrahydrofuran (70 ml) and hydrochloric acid (4M, 33 ml), and stirred at ambient temperature for 4 hours. The reaction was concentrated in vacuo, added to water (200 ml) and extracted with ethyl acetate (3×200 ml). The combined organic extracts were dried (MgSO4), and concentrated in vacuo, and the residue purified by column chromatography using 70% ethyl acetate:iso-hexane as eluent, to afford the product as a dark yellow oil that crystallised upon standing to off white crystals (9.37 g, 65%); NMR d (CD3SOCD3)1.27 (t, 3H), 3.50 (m, 2H), 3.83 (m, 1H), 4.08 (m, 1H), 4.20 (m, 1H), 4.27 (q, 2H), 4.58 (t, 1H), 4.88 (d, 1H), 5.73 (s, 2H), 6.88 (d, 1H), 7.15 (t, 1H), 7.33 (m, 2H), 7.54 (m, 2H), 7.82 (d, 1H), M/z (+) 438.3 (MH+).
Reaction SMILES: S(O)(O)(=O)=O.[CH3:6][O:7][C:8](=[NH:10])[NH2:9].O.[OH-].[Na+].[CH:14]([N:17]=[C:18]=[O:19])([CH3:16])[CH3:15]>CC(C)=O>[CH:14]([NH:17][C:18](=[O:19])[NH:10][C:8](=[NH:9])[O:7][CH3:6])([CH3:16])[CH3:15]
Reactant: CC(C)N=C=O
Reactant: COC(=N)N
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: COC(=N)NC(=O)NC(C)C
Reaction time: 3 h

Procedure:
To 114 parts of 2-methylpseudourea sulfate in 400 parts of water at 0°C is added 106 parts of 50% sodium hydroxide, followed by 400 parts of acetone, and 51 parts of isopropyl isocyanate. The reaction mixture is allowed to come to room temperature in 3 hrs. The organic solvent is then evaporated under vacuum, the aqueous residue saturated with sodium chloride, and the mixture extracted with methylene chloride. The organic extract is dried and the methylene chloride evaporated to yield 78 parts of methyl 4-isopropylallophanimidate, m.p. 64°-67°C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1/[CH:8]=[CH:9]/[C:10]([OH:12])=[O:11].[CH3:13][C:14]([Si:17](Cl)([CH3:19])[CH3:18])([CH3:16])[CH3:15].N1C=CN=C1.[Li+].[OH-]>CN(C=O)C.C1COCC1.O>[C:14]([Si:17]([CH3:19])([CH3:18])[O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1/[CH:8]=[CH:9]/[C:10]([OH:12])=[O:11])([CH3:16])([CH3:15])[CH3:13]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C(O)/C=C/c1ccccc1O
Agent: [Li+]
Agent: [OH-]
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1ccccc1/C=C/C(=O)O
Temperature: 25 °C
Reaction time: 24 h
Yield: 53.9 %

Procedure:
To a solution of 8.2 g of (E)-3-(2-hydroxy-phenyl)-acrylic acid and 15.2 g of TBDMS-Cl in 10 ml of DMF was added 11.9 g of imidazole and the mixture was stirred at room temperature for 24 h. After aqueous work-up, the bis-silylated product was saponified with 2.1 g of LiOH in THF-H2O for 0.5 h at 0° C. The mixture was concentrated in vacuo and TBDMS-OH removed by extraction with hexane. The aqueous layer was acidified to pH 4 with KHSO4 and extracted with EtOAc. The organic phases were washed with brine, dried (Na2SO4) and evaporated to dryness. The semi-solid residue was suspended in hexane, filtered and the filtrate evaporated to dryness to yield 7.5 g of a pale yellow oil, which solidified upon standing.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:18]([CH3:20])[CH3:19])[C:5]2[CH2:10][CH2:9][C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)(O)[C:6]=2[N:7]=1.Cl>CC(O)C.CCOCC>[Cl:1][C:2]1[N:3]=[C:4]([N:18]([CH3:20])[CH3:19])[C:5]2[CH2:10][CH:9]=[C:8]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:6]=2[N:7]=1
Reactant: CN(C)c1nc(Cl)nc2c1CCC2(O)c1ccccc1
Agent: Cl
Solvent: CCOCC
Solvent: CC(C)O
Product: CN(C)c1nc(Cl)nc2c1CC=C2c1ccccc1
Temperature: 80 °C
Yield: 62.7 %

Procedure:
To a solution of 2-chloro-4-(dimethylamino)-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-ol (85 mg) in i-PrOH (5 mL) was added HCl in ether (1M solution), and the reaction mixture was heated at 80° C. from 3 h. The solution was cloudy and turned to clear yellow solution by the end of the reaction. The solvents were removed, and the reaction mixture was worked up with EtOAc and saturated NaHCO3 to give the title compound as a brownish solid (50 mg). LC-MS (M−H2O+H)+=272.07.
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][C:8]=2[OH:17])[CH:5]=[N:4][CH:3]=[N:2]1.F[C:19]1[CH:20]=[CH:21][C:22]([N+:27]([O-:29])=[O:28])=[C:23]([CH:26]=1)[NH:24][CH3:25].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH3:25][NH:24][C:23]1[CH:26]=[C:19]([O:17][C:8]2[CH:9]=[CH:10][C:11]([C:13]([F:16])([F:15])[F:14])=[CH:12][C:7]=2[CH2:6][N:1]2[CH:5]=[N:4][CH:3]=[N:2]2)[CH:20]=[CH:21][C:22]=1[N+:27]([O-:29])=[O:28]
Reactant: CNc1cc(F)ccc1[N+](=O)[O-]
Reactant: Oc1ccc(C(F)(F)F)cc1Cn1cncn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CNc1cc(Oc2ccc(C(F)(F)F)cc2Cn2cncn2)ccc1[N+](=O)[O-]
Yield: 59.4 %

Procedure:
The solution of 2-(1H-1,2,4-triazol-1-ylmethyl)-4-(trifluoromethyl)phenol (1.0 g) from Example 62, 5-fluoro-N-methyl-2-nitroaniline (700 mg) and K2CO3 (0.57 g) in DMF (10 ml) was heated at 100° C. for 90 minutes. After the solution was left to stand at room temperature, water was added to the solution, the aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by chromatography on a silica gel column (methylene chloride:methanol=99:1), to give the title compound (960 mg; 59%).
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][C@H:6]([C:16]([O:18]CC)=O)[CH2:7][C:8]1[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH3:15])[CH:9]=1)=[O:4].C(N(CC)C(C)C)(C)C>CO>[CH3:15][O:14][C:10]1[CH:9]=[C:8]([CH2:7][CH:6]2[NH:5][C:3](=[O:4])[CH2:2][NH:1][C:16]2=[O:18])[CH:13]=[CH:12][N:11]=1
Reactant: CCOC(=O)[C@H](Cc1ccnc(OC)c1)NC(=O)CN
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: COc1cc(CC2NC(=O)CNC2=O)ccn1
Temperature: 70 °C
Reaction time: 18 h
Yield: 93.1 %

Procedure:
To a 100-mL round-bottomed flask was added ethyl glycyl-3-(2-methoxy-4-pyridinyl)alaninate (1.70 g, 6.03 mmol) and N,N-diisopropylethylamine (1.05 mL, 6.03 mmol) in MeOH (20 mL). The reaction mixture was stirred at 70° C. for 18 h and allowed to cool to room temperature. The solid formed was filtered and washed with MeOH to give 3-((2-methoxy-4-pyridinyl)methyl)-2,5-piperazinedione (1.32 g) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[N:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH2:11](O)[CH3:12].CCN(C(C)C)C(C)C>S(Cl)(Cl)=O>[CH2:11]([O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][N:9]=[CH:10][C:2]=1[Cl:1])[CH3:12]
Reactant: O=C(O)c1ccncc1Cl
Reactant: CCO
Solvent: CCN(C(C)C)C(C)C
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1ccncc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 94 %

Procedure:
A suspension of 3-chloro-isonicotinic acid (1.0 g, 6.35 mmol) in thionyl chloride (10 ml) was heated under reflux for 2.5 hours. After cooling to ambient temperature, the solution was concentrated to dryness and then azeotroped with toluene (10 ml) to afford an oil. The resultant oil was added dropwise over 10 minutes to a cooled (0° C.) solution of ethanol (15 ml) and DIPEA (5 ml). The reaction was stirred at room temperature for 18 hours then concentrated in vacuo before water (20 ml) was added. The solution was extracted with ethyl acetate (30 ml) and the organic phase was dried over sodium sulfate then concentrated to give the title compound as an orange oil (1.1 g, 94%). 1H NMR (CDCl3, 400 MHz) 8.72 (s, 1H), 8.59 (d, J=4.9 Hz, 1H), 7.63 (dd, J=4.9 Hz, 0.5 Hz, 1H), 4.44 (q, J=7.3 Hz, 2H), 1.42 (t, J=7.3 Hz, 3H).
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[CH3:6][C:7]1([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:16][CH2:15][C:14]2[C:9](=[C:10]([CH3:19])[C:11]([CH3:18])=[CH:12][C:13]=2[CH3:17])[O:8]1.C(=O)([O-])O.[Na+]>ClCCl>[CH2:24]([O:23][C:21]([CH2:20][C:7]1([CH3:6])[CH2:16][CH2:15][C:14]2[C:9](=[C:10]([CH3:19])[C:11]([CH3:18])=[C:12]([S:2]([Cl:1])(=[O:5])=[O:3])[C:13]=2[CH3:17])[O:8]1)=[O:22])[CH3:25]
Reactant: O=S(=O)(O)Cl
Reactant: CCOC(=O)CC1(C)CCc2c(C)cc(C)c(C)c2O1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)CC1(C)CCc2c(C)c(S(=O)(=O)Cl)c(C)c(C)c2O1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of chlorosulfonic acid (2.79 ml) in dichloromethane (CH2Cl2) (15 ml) was added dropwise to a solution of ethyl (2,5,7,8-tetramethylchroman-2-yl)acetate (2.90 g) in CH2Cl2 (100 ml) at 0-10° C. over an hour. After stirring at room temperature for 5 hours, the reaction mixture was poured into chilled saturated aqueous sodium hydrogen carbonate (sat. aq. NaHCO3). The separated organic phase was washed with sat. aq. NaHCO3, water, and brine, and dried over MgSO4. After filtration, the filtrate was concentrated under reduced pressure to give 2-ethoxycarbonylmethyl-2,5,7,8-tetramethylchroman-6-sulfonyl chloride as a syrup (3.29 g).
Reaction SMILES: [NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=2)[CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:33][CH:34]1[CH:39]2[CH2:40][CH2:41][N:36]([CH2:37][CH2:38]2)[CH2:35]1>O1CCCC1>[NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([NH:33][CH:34]2[CH:39]3[CH2:40][CH2:41][N:36]([CH2:37][CH2:38]3)[CH2:35]2)=[O:8])=[C:4]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=2)[CH:3]=1
Reactant: NC1CN2CCC1CC2
Reactant: Nc1cc(OCc2cccc(Cl)c2)c(C(=O)O)cc1Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: Nc1cc(OCc2cccc(Cl)c2)c(C(=O)NC2CN3CCC2CC3)cc1Cl
Reaction time: 0.75 h
Yield: 73.3 %

Procedure:
A solution of 4-amino-5-chloro-2-[(3-chlorophenyl)methoxy]benzoic acid (3.13 g, 10 mmol) in anhydrous tetrahydrofuran (10 mL) under nitrogen was treated with 1,1'-carbonyldiimidazole (1.87 g, 11.5 mmol), stirred for 45 minutes, and degassed over 15 minutes under a stream of nitrogen. A solution of 3-aminoquinuclidine (1.85 g, 14.7 mmol) in anhydrous tetrahydrofuran (5 mL) was added, and the mixture was stirred at room temperature for 18 hours, then concentrated in vacuo and partitioned between 3N sodium hydroxide (50 mL) and toluene (100 mL) containing some 2-propanol. The organic layer was separated and the aqueous solution was extracted with toluene (50 mL) containing some 2-propanol. The combined organic solution was dried (Na2SO4), concentrated in vacuo, and rinsed with water in order to remove the remaining imidazole by-product. The residue was dried azeotropically with toluene, then taken up in tetrahydrofuran and filtered through a short column of alumina (eluted with 10% methanol/tetrahydrofuran). The filtrate was concentrated in vacuo, triturated from cold ether/petroleum ethers (30°-60° C.), and recrystallized from acetonitrile (2 crops) to afford 3.08 g (73%) of pale yellow solid; mp 168°-169° C.
Reaction SMILES: [H-].[Na+].[CH3:3][C@@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:27])[CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)=[CH:15][CH:14]=1.Br[CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31]>CS(C)=O.C1(C)C=CC=CC=1>[CH2:33]([O:32][C:30](=[O:31])[CH2:29][CH:20]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1)[C:19]([C:16]1[CH:17]=[CH:18][C:13]([O:12][CH2:11][CH2:10][CH2:9][N:5]2[CH2:6][CH2:7][CH2:8][C@H:4]2[CH3:3])=[CH:14][CH:15]=1)=[O:27])[CH3:34]
Reactant: C[C@@H]1CCCN1CCCOc1ccc(C(=O)Cc2ccccn2)cc1
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CS(C)=O
Product: CCOC(=O)CC(C(=O)c1ccc(OCCCN2CCC[C@H]2C)cc1)c1ccccn1
Reaction time: 0.5 h
Yield: 40.3 %

Procedure:
A mixture of sodium hydride (0.092 g, 3.8 mmoL) in 10 mL of DMSO was stirred under N2 as the product from step 3 (1.0 g, 3.8 mmol) in 5.0 mL of DMSO was added dropwise. After the reaction was stirred for 30 min, a solution of ethyl bromoacetate (0.64 g, 8.83 mmol) in 6.0 mL of toluene was added dropwise, and the reaction was stirred at rt for 1 h. The reaction was then quenched with NH4Cl solution and the solvent was evaporated. The residue was extracted with CH2Cl2 (3×20 mL), combined, washed with saturated NaHCO3, saturated NaCl then dried over Na2SO4. The crude product was purified by flash chromatography using 10% MeOH in CH2Cl2 to give the product (0.65 g, 52%).
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.Cl[C:8]1[N:9]=[C:10]([NH:19][CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]3[O:28][CH2:29][O:30][C:24]=3[CH:23]=2)[C:11]2[C:16]([CH3:17])=[C:15]([CH3:18])[S:14][C:12]=2[N:13]=1>>[CH3:1][C:2]1[N:3]([C:8]2[N:9]=[C:10]([NH:19][CH2:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]4[O:28][CH2:29][O:30][C:24]=4[CH:23]=3)[C:11]3[C:16]([CH3:17])=[C:15]([CH3:18])[S:14][C:12]=3[N:13]=2)[CH:4]=[CH:5][N:6]=1
Reactant: Cc1ncc[nH]1
Reactant: Cc1sc2nc(Cl)nc(NCCc3ccc4c(c3)OCO4)c2c1C
Product: Cc1sc2nc(-n3ccnc3C)nc(NCCc3ccc4c(c3)OCO4)c2c1C

Procedure:
Following the procedure of Example 97, the reaction of 2-methylimidazole with 2-chloro-5,6-dimethyl-4-(3,4-methylenedioxyphenethylamino)-thieno-[2,3-d]-pyrimidine gives 2-(2-methylimidazol-1-yl)-5,6-dimethyl-4-(3,4-methylenedioxyphenethylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH:1]1([CH2:6][NH:7][C:8](=[O:21])[CH2:9][C:10]2[CH:18]=[C:17]3[C:13]([C:14]([CH:19]=[O:20])=[CH:15][NH:16]3)=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH2:23][C:24]1[CH:36]=[CH:35][C:27]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[CH:26][C:25]=1[O:37][CH3:38].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH:1]1([CH2:6][NH:7][C:8]([CH2:9][C:10]2[CH:18]=[C:17]3[C:13]([C:14]([CH:19]=[O:20])=[CH:15][N:16]3[CH2:23][C:24]3[CH:36]=[CH:35][C:27]([C:28]([O:30][C:31]([CH3:34])([CH3:32])[CH3:33])=[O:29])=[CH:26][C:25]=3[O:37][CH3:38])=[CH:12][CH:11]=2)=[O:21])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=Cc1c[nH]c2cc(CC(=O)NCC3CCCC3)ccc12
Reactant: COc1cc(C(=O)OC(C)(C)C)ccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C(=O)OC(C)(C)C)ccc1Cn1cc(C=O)c2ccc(CC(=O)NCC3CCCC3)cc21
Reaction time: 48 h
Yield: 97.5 %

Procedure:
A mixture of N-cyclopentylmethyl-3-formylindole-6-acetamide (0.52 g), t-butyl 4-bromomethyl-3-methoxybenzoate (0.66 g), and potassium carbonate (0.37 g) in N,N-dimethylformamide (10 ml) was stirred for 48 hr under a nitrogen atmosphere. Water was added to give a precipitate which was collected by filtration and purified by flash chromatography, eluting with 1:49 methanol:chloroform, to give t-butyl 4-[6-(cyclopentylmethylcarbamoyl)methyl-3-formylindol-1-ylmethyl]-3-methoxybenzoate (0.90 g, 97%) as a white solid; partial NMR (80 MHz, CDCl3): 1.56 (s, 9H, C(CH3)3), 3.09(t, 2H, NHCH2), 3.65(s, 2H, COCH2), 3.93(s, 3H, OCH3), 9.98(s, 1H, CHO).
Reaction SMILES: [CH3:1][NH:2][C:3]([CH2:5][NH:6][C:7]([C:9]1[CH:14]=[C:13]([O:15][C:16]2[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=2)[CH:12]=[CH:11][N:10]=1)=[O:8])=[O:4].Cl.N[CH2:25]C(NC)=O>>[CH3:1][N:2]([CH3:25])[C:3]([CH2:5][NH:6][C:7]([C:9]1[CH:14]=[C:13]([O:15][C:16]2[CH:17]=[CH:18][C:19]([NH2:22])=[CH:20][CH:21]=2)[CH:12]=[CH:11][N:10]=1)=[O:8])=[O:4]
Reactant: CNC(=O)CNC(=O)c1cc(Oc2ccc(N)cc2)ccn1
Reactant: CNC(=O)CN
Agent: Cl
Product: CN(C)C(=O)CNC(=O)c1cc(Oc2ccc(N)cc2)ccn1

Procedure:
The title compound was prepared in the same manner described for 4-(4-aminophenoxy)pyridine-2-carboxylic acid methylcarbamoylmethylamide, substituting 2-amino-N,N′-dimethylacetamide hydrochloride for 2-amino-N-methylacetamide hydrochloride. 1H-NMR (DMSO-d6) δ 8.75 (t, J=4.8 Hz, 1H), 8.49 (d, J=5.4 Hz, 1H), 7.33 (d, J=2.7 Hz, 1H), 7.32 (d, J=2.7 Hz, 1H), 6.86 (d, J=8.7 Hz, 2H), 6.63 (d, J=9.0 Hz, 2H), 5.18 (s, 2H), 4.11 (d, J=5.4 Hz, 2H), 2.96 (s, 3H), 2.85 (s, 3H); MS LC-MS [M+H]+=315.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[N:11][O:12][C:13]=1[C:14]1[C:22]2[C:17](=[N:18][CH:19]=[C:20]([C:23]3[CH2:28][CH2:27][CH:26]([NH2:29])[CH2:25][CH:24]=3)[CH:21]=2)[NH:16][CH:15]=1.N1([O:39][S:40]([CH3:43])(=O)=[O:41])C2C=CC=CC=2N=N1.C(O)(C(F)(F)F)=O>CN(C=O)C.CCN(C(C)C)C(C)C>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[N:11][O:12][C:13]=1[C:14]1[C:22]2[C:17](=[N:18][CH:19]=[C:20]([C:23]3[CH2:28][CH2:27][CH:26]([NH:29][S:40]([CH3:43])(=[O:41])=[O:39])[CH2:25][CH:24]=3)[CH:21]=2)[NH:16][CH:15]=1
Reactant: NC1CC=C(c2cnc3[nH]cc(-c4oncc4-c4cccc(F)c4F)c3c2)CC1
Reactant: CS(=O)(=O)On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)NC1CC=C(c2cnc3[nH]cc(-c4oncc4-c4cccc(F)c4F)c3c2)CC1
Reaction time: 1 h
Yield: 45.9 %

Procedure:
To a solution of 4-{3-[4-(2,3-Difluoro-phenyl)-isoxazol-5-yl]-1H-pyrrolo [2,3-b]pyridin-5-yl}-cyclohex-3-enylamine (47 mg, 0.12 mmol) in DMF (2 ml) was added methanesulfonic acid benzotriazol-1-yl ester (27 mg, 0.13 mmol) and Hunig base (10 drops) and stirred for 1 h. TFA was added, and the reaction mixture was purified by HPLC to give the methanesulfonamide (25.9 mg) in 46% yield.