Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6]1[N:11]=[C:10]([CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][C:17]([CH2:21][O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[F:29])([OH:20])[CH2:16][CH2:15]2)[CH:9]=[N:8][CH:7]=1)(C)(C)C.C(=O)(O)[O-].[Na+].ClCCl>C(OCC)(=O)C.Cl.C(OCC)(=O)C>[OH:20][C:17]1([CH2:21][O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[F:29])[CH2:18][CH2:19][N:14]([CH2:13][CH2:12][C:10]2[NH:11][C:6](=[O:5])[CH:7]=[N:8][CH:9]=2)[CH2:15][CH2:16]1
Reactant: CC(C)(C)Oc1cncc(CCN2CCC(O)(COc3ccccc3F)CC2)n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=c1cncc(CCN2CCC(O)(COc3ccccc3F)CC2)[nH]1
Reaction time: 2 h
Yield: 78.8 %

Procedure:
After dissolving 274 mg of 1-[2-(6-tert-butoxypyrazin-2-yl)ethyl]-4-(2-fluorophenoxymethyl)piperidin-4-ol in 3 ml of ethyl acetate, 3 ml of 4N hydrogen chloride/ethyl acetate was added and the mixture was all owed to stand at room temperature for 2 hours. Aqueous sodium bicarbonate solution was added to the reaction solution and extraction was performed with dichloromethane. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. Diethyl ether was added to the residue and the mixture was filtered to obtain the title compound (186 mg, 79% yield).
Reaction SMILES: [Na].[C:2]([O:8][CH3:9])(=[O:7])[CH2:3][C:4]([CH3:6])=[O:5].[CH:10]([S:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:14])=[O:13])=[CH2:11].[CH3:21]O>>[C:15]1([S:12]([CH2:10][CH2:11][CH:3]([C:4](=[O:5])[CH3:6])[C:2]([O:8][CH2:9][CH3:21])=[O:7])(=[O:13])=[O:14])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: C=CS(=O)(=O)c1ccccc1
Reactant: CO
Reactant: COC(=O)CC(C)=O
Agent: [Na]
Product: CCOC(=O)C(CCS(=O)(=O)c1ccccc1)C(C)=O
Reaction time: 0.25 h

Procedure:
Sodium metal (23 mg, 1 mmol) was added to 25 mL of methanol. After the sodium metal was consumed, methyl acetoacetate (1.16 g, 10 mmol) was added to the mixture and stirred for 15 minutes. A solution of phenyl vinyl sulfone (1.68 g, 10 mmol) was added dropwise to the solution and maintained for several hours. The slightly yellow solution was concentrated under reduced pressure, and the residue was diluted with ethyl acetate and washed with saturated aqueous ammonium chloride. The aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with brine, dried over magnesium sulfate, filtered and concentrated to afford a clear oil. The material was purified via flash column chromatography on silica gel (eluting with hexane:ethyl acetate in a gradient from 3:2 to 2:3) to afford 1.40 g of ethyl 2-(2-benzenesulfonylethyl)-3-oxo-butyrate.
Reaction SMILES: C(O)=O.[NH2:4][CH2:5][CH2:6][C:7]1[CH:38]=[CH:37][C:10]([NH:11][CH:12]2[CH2:17][CH2:16][N:15]([S:18]([C:21]3[CH:26]=[CH:25][C:24]([N:27](CCCCCC)[C:28]([NH2:30])=[O:29])=[CH:23][CH:22]=3)(=[O:20])=[O:19])[CH2:14][CH2:13]2)=[CH:9][CH:8]=1.[F:39][C:40]1[CH:50]=[CH:49][C:43]([O:44][CH2:45][C@@H:46]2[CH2:48][O:47]2)=[CH:42][CH:41]=1>>[F:39][C:40]1[CH:50]=[CH:49][C:43]([O:44][CH2:45][C@@H:46]([OH:47])[CH2:48][NH:4][CH2:5][CH2:6][C:7]2[CH:38]=[CH:37][C:10]([NH:11][CH:12]3[CH2:17][CH2:16][N:15]([S:18]([C:21]4[CH:22]=[CH:23][C:24]([NH:27][C:28]([NH:30][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])=[O:29])=[CH:25][CH:26]=4)(=[O:19])=[O:20])[CH2:14][CH2:13]3)=[CH:9][CH:8]=2)=[CH:42][CH:41]=1
Reactant: CCCCCCN(C(N)=O)c1ccc(S(=O)(=O)N2CCC(Nc3ccc(CCN)cc3)CC2)cc1
Reactant: Fc1ccc(OC[C@@H]2CO2)cc1
Solvent: O=CO
Product: CCCCCCNC(=O)Nc1ccc(S(=O)(=O)N2CCC(Nc3ccc(CCNC[C@H](O)COc4ccc(F)cc4)cc3)CC2)cc1
Yield: 63.6 %

Procedure:
N-[4-({4-[4-(2-Aminoethyl)anilino]-1-piperidinyl}sulfonyl)phenyl]-N-hexylurea formate (0.20 g 0.365 mmol) was reacted with (2S)-2-[(4-fluorophenoxy)methyl]oxirane (0.061 mL, 0.365 mmol) according to Procedure G to give the title compound (0.078 g, 0.116 mmol).
Reaction SMILES: S(=O)(=O)(O)O.[S:6]([C:10]1[CH:11]=[C:12]([C:20]([OH:22])=[O:21])[C:13]2[O:18][CH2:17][CH2:16][O:15][C:14]=2[CH:19]=1)(=[O:9])(=[O:8])[NH2:7].[CH3:23]O>>[CH3:23][O:21][C:20]([C:12]1[C:13]2[O:18][CH2:17][CH2:16][O:15][C:14]=2[CH:19]=[C:10]([S:6](=[O:8])(=[O:9])[NH2:7])[CH:11]=1)=[O:22]
Reactant: NS(=O)(=O)c1cc2c(c(C(=O)O)c1)OCCO2
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(S(N)(=O)=O)cc2c1OCCO2
Yield: 81.2 %

Procedure:
429 g of methanol were introduced into a balloon flask provided with a condenser and then, under cooling, 54 g of 93% sulfuric acid and 111 g of 7-sulfamoyl-1,4-benzodioxane-5-carboxylic acid were added. The mixture was heated under reflux and then cooled. The crystals were dried off, washed with methanol and then treated with 500 cm3 of water and 5 g of sodium carbonate. The precipitate was dried off, washed with water and dried. 95 g of methyl-7-sulfamoyl-1,4-benzodioxane-5-carboxylate were obtained (M.P.: 225°-226° C.; yield: 81%).
Reaction SMILES: [OH:1][CH:2]1[CH2:11][C:10]2[C:9]([NH:12][C:13](=[O:15])[CH3:14])=[CH:8][CH:7]=[CH:6][C:5]=2[CH2:4][CH2:3]1.[CH3:16][S:17](Cl)(=[O:19])=[O:18].N1C=CC=CC=1>C(Cl)Cl>[C:13]([NH:12][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[CH2:11][CH:2]([O:1][S:17]([CH3:16])(=[O:19])=[O:18])[CH2:3][CH2:4]2)(=[O:15])[CH3:14]
Reactant: CS(=O)(=O)Cl
Reactant: CC(=O)Nc1cccc2c1CC(O)CC2
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)Nc1cccc2c1CC(OS(C)(=O)=O)CC2
Yield: 51 %

Procedure:
A solution of N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)-acetamide (5 g, 24 mmol), methylsulfonylchloride (6.9 g, 60 mmol) and pyridine (4.7 g, 60 mmol) in methylene chloride (100 mL) was heated at reflux for 8 h. The mixture was then cooled and washed with water. The organic layer was dried over magnesium sulfate, filtered and evaporated. The resulting solid was washed with diethyl ether and dried (3.8 g, 51% yield) without further purification.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[OH:11])[C:5]([OH:7])=[O:6].S(=O)(=O)(O)O.Cl[CH2:18]Cl.C(=O)(O)[O-].[Na+]>CO.C(OCC)(=O)C>[OH:11][C:10]1[CH:9]=[CH:8][C:4]([C:5]([O:7][CH3:18])=[O:6])=[CH:3][C:2]=1[I:1]
Reactant: ClCCl
Reactant: O=C(O)c1ccc(O)c(I)c1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)c1ccc(O)c(I)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 59 %

Procedure:
A solution of 3-iodo-4-Hydroxybenzoic acid (7.25 g, 27.4 mmol) and sulfuric acid (1.9 ml, 36 mmol) in methanol is stirred at 55° C. for 6 hours. TLC (dichloromethane): 30% of starting material. The solution is stirred 12 h at room temperature. TLC (dichloromethane): 10% of starting material and stirred at 55° C. for 2 h. After cooling, ethyl acetate (200 mL) was added and the mixture was adjusted to pH 3 using sodium bicarbonate. The organic layer was washed two times with water and then dried over MgSO4. Filtration and rotary evaporation at 40° C. afforded a white solid. The solid was triturated with hexane, filtered off and dried under reduced pressure. M=4.47 g. Yield: 59%.
Reaction SMILES: C([S:4][CH2:5][C:6]1([CH2:9][C:10]#N)[CH2:8][CH2:7]1)(=O)C.[OH2:12].OS(O)(=O)=O.[CH3:18][OH:19]>>[SH:4][CH2:5][C:6]1([CH2:9][C:10]([O:19][CH3:18])=[O:12])[CH2:7][CH2:8]1
Reactant: O
Reactant: CC(=O)SCC1(CC#N)CC1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)CC1(CS)CC1
Temperature: 25 °C
Yield: 93 %

Procedure:
To a solution of the nitrile of Step 8 (45 g, 266 mmol) in MeOH (1.36 L) was added H2O(84 mL) and conc. H2SO4 (168 mL). The mixture was heated to reflux for 20 hr, cooled to 25° C., H2O(1 L) was added and the product was extracted with CH2Cl2 (2×1.5 L). The organic extract was washed with H2O and dried over Na2SO4. Concentration of the organic solution gave 36 g (93%) of the title compound.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11](O)=[O:12])=[CH:10][C:5]=2[N:4]=[C:3]1[NH:14][C:15]1[S:16][C:17]2[CH:23]=[C:22]([O:24][C:25]([F:28])([F:27])[F:26])[CH:21]=[CH:20][C:18]=2[N:19]=1.[NH2:29][CH2:30][C:31]([N:33]([CH3:35])[CH3:34])=[O:32].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH3:34][N:33]([CH3:35])[C:31]([CH2:30][NH:29][C:11]([C:9]1[CH:8]=[CH:7][C:6]2[N:2]([CH3:1])[C:3]([NH:14][C:15]3[S:16][C:17]4[CH:23]=[C:22]([O:24][C:25]([F:27])([F:26])[F:28])[CH:21]=[CH:20][C:18]=4[N:19]=3)=[N:4][C:5]=2[CH:10]=1)=[O:12])=[O:32]
Reactant: CN(C)C(=O)CN
Reactant: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)O)ccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C(=O)CNC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(OC(F)(F)F)cc3s1)n2C

Procedure:
1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid dimethylcarbamoylmethyl-amide (41 mg) was prepared by following General Procedure F using 1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzimidazole-5-carboxylic acid (41 mg), 2-amino-N,N-dimethyl-acetamide (0.33 ml), HBTU (38 mg), and DIEA (0.1 ml). LC/MS: m/z 494. 1H NMR (DMSO-d6, 400 MHz): δ 8.42 (t, 1H), 8.09 (s, 1H), 7.90 (m, 1H), 7.78 (br, 1H), 7.72 (br, 1H), 7.48 (d, 1H), 7.44 (d, 1H), 7.34 (m, 1H), 4.11 (d, 2H), 3.63 (s, 3H), and 3.00 (d, 6H).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].C(O)CCO.C(O)(=O)C.[CH:21](N)=[NH:22]>>[F:11][C:9]1[CH:10]=[C:2]2[C:3]([C:4](=[O:5])[NH:22][CH:21]=[N:1]2)=[CH:7][CH:8]=1
Reactant: Nc1cc(F)ccc1C(=O)O
Reactant: N=CN
Solvent: CC(=O)O
Solvent: OCCCO
Product: O=c1[nH]cnc2cc(F)ccc12
Temperature: 120 °C
Reaction time: 3.5 h

Procedure:
2-Amino-4-fluorobenzoic acid and 1,3-propanediol were stirred together and heated to 120° C. Formamidine acetate was added and the mixture stirred for 3.5 hour to yield 7-fluoroquinazoline-4-one. A solution of potassium hydroxide in 1,3-propanediol was then added to the mixture over a period of 2 hours and 50 minutes, which was then cooled 15° C. Following this, the mixture was heated to 125° C. for 5 hour before cooling to 75° C. Dilute hydrochloric acid (about 6% w/w) was gradually added to the reaction mixture until pH 4.5 was achieved. The mixture was cooled to 0° C. over 6 hour and maintained at that temperature for a further hour prior to isolation of the crude product by centrifugation. The crude material was washed with water and dried in vacuo before dissolving in methanol at gentle reflux and partially concentrating under reduced pressure at a temperature of 42° C. This solution was then cooled to 0° C. over a period of 3 hour and the resultant product was isolated by filtration, prior to drying in vacuo. 7-(3-Hydroxypropoxy)quinazolin-4(3H)-one was recovered in a 73% yield.
Reaction SMILES: [O:1]=[C:2]1[C@@H:8]2[CH2:9][CH2:10][CH2:11][C@@:7]2([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=2)[CH2:6][CH2:5][CH2:4][NH:3]1.[C:20]1(C)C=CC=CC=1.[NH2-].[Na+].CI>O>[O:1]=[C:2]1[C@H:8]2[CH2:9][CH2:10][CH2:11][C@@:7]2([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=2)[CH2:6][CH2:5][CH2:4][N:3]1[CH3:20]
Reactant: COc1cccc([C@]23CCCNC(=O)[C@@H]2CCC3)c1
Reactant: Cc1ccccc1
Agent: [NH2-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: COc1cccc([C@@]23CCC[C@@H]2C(=O)N(C)CCC3)c1
Temperature: 25 °C

Procedure:
A solution of 5.0 g. of dl-trans-1-oxo-5a-(3-methoxyphenyl)-decahydrocyclopent[c]azepine in 40 ml. of anhydrous toluene was added dropwise over thirty minutes to a stirred solution of 1.2 g. of sodium amide in 40 ml. of anhydrous toluene. The reaction mixture was heated at reflux for four hours, and then cooled to 25° C. and stirred while a solution of 4 g. of methyl iodide in 40 ml. of toluene was added in one portion. The reaction mixture was next heated to reflux and stirred for thirteen hours. After cooling the reaction mixture again to 25° C., 100 ml. of water was added dropwise over fifteen minutes. The aqueous layer was then separated, and the organic layer was washed with water, dried, and the solvent was removed by evaporation under reduced pressure to provide 5.3 g. of predominantly dl-cis-1-oxo-2-methyl-5a-(3-methoxyphenyl)-decahydrocyclopent[a]azepine. The product so formed was recrystallized three times from diisopropyl alcohol to afford pure dl-cis-1-oxo-2-methyl-5a-(3-methoxyphenyl)-decahydrocyclopent[ c]azepine. M.P. 103°-104° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[CH2:5][NH:6][C:7]1[C:12]([Cl:13])=[CH:11][N:10]=[C:9]([Cl:14])[N:8]=1.Cl.C(N(CC)CC)C.[N+:26]([C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=1)[C:32](Cl)=[O:33])([O-:28])=[O:27]>C1COCC1>[Cl:14][C:9]1[N:8]=[C:7]([NH:6][CH2:5][C:4]2[CH:3]=[C:2]([NH:1][C:32](=[O:33])[C:31]3[CH:35]=[CH:36][CH:37]=[C:29]([N+:26]([O-:28])=[O:27])[CH:30]=3)[CH:17]=[CH:16][CH:15]=2)[C:12]([Cl:13])=[CH:11][N:10]=1
Reactant: Nc1cccc(CNc2nc(Cl)ncc2Cl)c1
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1cccc(CNc2nc(Cl)ncc2Cl)c1)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70 %

Procedure:
To a mixture of N-(3-aminobenzyl)-2,5-dichloropyrimidin-4-amine.hydrogen chloride (0.10 g, 0.29 mmol) (prepared according to Example 3, step B) and triethylamine (0.16 mL, 1.2 mmol) in THF (3 mL) was added slowly 3-nitrobenzoyl chloride (54 mg, 0.29 mmol). The resulting mixture was stirred at rt for 2 hours and concentrated under vacuum. The residue was partitioned in EtOAc and water. The organic layer was dried over Na2SO4, filtered, and concentrated under vacuum to give the desired product as a yellow solid (90 mg, 70%). LCMS for C18H14Cl2N5O3 (M+H)+: m/z=418.0, 420.0.
Reaction SMILES: [ClH:1].[CH3:2][NH:3][C:4](=O)[O:5]C1C=C2C(=CC=1)C(CN(CCC(N1CCC3C=C(OC)C(OC)=CC=3CC1)=O)C)C2.[CH3:37][O:38][C:39]1[C:65]([O:66][CH3:67])=[CH:64][C:42]2[CH2:43][CH2:44][N:45]([C:48](=[O:63])[CH2:49][CH2:50][N:51]([CH2:53][CH:54]3[C:61]4[C:56](=[CH:57][CH:58]=[C:59]([OH:62])[CH:60]=4)[CH2:55]3)[CH3:52])[CH2:46][CH2:47][C:41]=2[CH:40]=1>>[ClH:1].[CH3:2][NH:3][C:4](=[O:5])[O:62][C:59]1[CH:60]=[C:61]2[C:56](=[CH:57][CH:58]=1)[CH2:55][CH:54]2[CH2:53][N:51]([CH2:50][CH2:49][C:48]([N:45]1[CH2:46][CH2:47][C:41]2[CH:40]=[C:39]([O:38][CH3:37])[C:65]([O:66][CH3:67])=[CH:64][C:42]=2[CH2:43][CH2:44]1)=[O:63])[CH3:52]
Reactant: COc1cc2c(cc1OC)CCN(C(=O)CCN(C)CC1Cc3ccc(O)cc31)CC2
Reactant: CNC(=O)Oc1ccc2c(c1)CC2CN(C)CCC(=O)N1CCc2cc(OC)c(OC)cc2CC1
Agent: Cl
Product: CNC(=O)Oc1ccc2c(c1)C(CN(C)CCC(=O)N1CCc3cc(OC)c(OC)cc3CC1)C2

Procedure:
Obtained in the same manner as the compound of Example 44 but using the compound of Example 45 instead of the compound of Example 43.
Reaction SMILES: Cl.Cl.[CH3:3][C:4]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][CH:12]([NH2:15])[CH2:11][CH2:10]2)[S:6][N:5]=1.Cl[C:17]1[N:22]=[C:21]([C:23]([OH:26])([CH3:25])[CH3:24])[CH:20]=[C:19]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=2)[N:18]=1.C(N(CC)C(C)C)(C)C>O1CCOCC1>[CH3:3][C:4]1[N:8]=[C:7]([N:9]2[CH2:10][CH2:11][CH:12]([NH:15][C:17]3[N:22]=[C:21]([C:23]([OH:26])([CH3:25])[CH3:24])[CH:20]=[C:19]([C:27]4[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:34])[F:35])=[CH:29][CH:28]=4)[N:18]=3)[CH2:13][CH2:14]2)[S:6][N:5]=1
Reactant: Cc1nsc(N2CCC(N)CC2)n1
Reactant: CC(C)(O)c1cc(-c2ccc(C(F)(F)F)cc2)nc(Cl)n1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: Cc1nsc(N2CCC(Nc3nc(-c4ccc(C(F)(F)F)cc4)cc(C(C)(C)O)n3)CC2)n1

Procedure:
A solution of 1-(3-methyl-[1,2,4]thiadiazol-5-yl)-piperidin-4-ylamine dihydrochloride (54.2 mg, 0.2 mmol), 2-[2-chloro-6-(4-trifluoromethyl-phenyl)-pyrimidin-4-yl]-propan-2-ol (69.7 mg, 0.22 mmol) and N,N-diisopropylethyl amine (120 L, 0.7 mmol) in dioxane (2 mL) was heated at 200° C. in a microwave oven for 2 hours. The reaction was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel with CH2Cl2/MeOH 19:1 (v/v) as eluent. The title compound was obtained as a brown viscous oil (26 mg, 27%). MS ISP (m/e): 479.1 (100) [(M+H)+].
Reaction SMILES: S1C=[CH:4][CH:3]=[CH:2]1.C(O)C.[NH:9]1[CH2:14][CH2:13][CH:12]([NH:15][C:16]2[N:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[CH2:11][CH2:10]1.[H][H]>[Pd].CO.CC(=O)C>[CH3:2][CH:3]([N:9]1[CH2:10][CH2:11][CH:12]([NH:15][C:16]2[N:17]=[CH:18][CH:19]=[CH:20][N:21]=2)[CH2:13][CH2:14]1)[CH3:4]
Reactant: c1cnc(NC2CCNCC2)nc1
Reactant: c1ccsc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: CCO
Solvent: CC(C)=O
Product: CC(C)N1CCC(Nc2ncccn2)CC1

Procedure:
To 0.5 parts of a solution of 2 parts of thiophene in 40 parts of ethanol, are added 4 parts of 2-propanone, 4.5 parts of N-(4-piperidinyl)-2-pyrimidinamine and 120 parts of methanol. The whole is hydrogenated at normal pressure and at room temperature with 2 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen is taken up, the catalyst is filtered off and the filtrate is evaporated. The residue is dissolved in trichloromethane. The solution is washed successively with a diluted sodium hydroxide solution and with water, dried, filtered and evaporated, yielding 3 parts of N-[1-(1-methylethyl)-4-piperidinyl]-2-pyrimidinamine as a residue.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:14]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:12]=[CH:11][C:4]=2[N:5]([CH3:10])[C:6](=[O:9])[CH2:7][N:8]=1.C(C1C=C(B(O)O)C=CC=1)=O.[Cl:32][C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[C:37]([Cl:39])[CH:38]=1>>[Cl:32][C:33]1[CH:34]=[C:35]([C:2]2[C:3]3[CH:14]=[C:13]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[CH:12]=[CH:11][C:4]=3[N:5]([CH3:10])[C:6](=[O:9])[CH2:7][N:8]=2)[CH:36]=[C:37]([Cl:39])[CH:38]=1
Reactant: CN1C(=O)CN=C(Cl)c2cc(-c3ccccc3)ccc21
Reactant: OB(O)c1cc(Cl)cc(Cl)c1
Agent: O=Cc1cccc(B(O)O)c1
Product: CN1C(=O)CN=C(c2cc(Cl)cc(Cl)c2)c2cc(-c3ccccc3)ccc21
Yield: 22 %

Procedure:
Prepared from 5-chloro-1-methyl-7-phenyl-1,3-dihydro-benzo[e][1,4]diazepin-2-one using the same method described for Example 9 and instead of using 3-formylbenzene boronic acid, we used 3,5-dichlorophenyl boronic acid. The title compound (34 mg) was obtained as a beige solid, (yield=22%).
Reaction SMILES: CCN(C(C)C)C(C)C.[Br:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[O:17][C:16](=[O:21])[C:15]([C:22]([OH:24])=O)=[CH:14]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[N:49]1[C:50]([C:58]2[CH:59]=[C:60]([NH2:64])[CH:61]=[CH:62][CH:63]=2)=[CH:51][N:52]2[CH:57]=[CH:56][CH:55]=[CH:54][C:53]=12>CN(C=O)C>[N:49]1[C:50]([C:58]2[CH:59]=[C:60]([NH:64][C:22]([C:15]3[C:16](=[O:21])[O:17][C:18]4[C:13]([CH:14]=3)=[CH:12][C:11]([Br:10])=[CH:20][CH:19]=4)=[O:24])[CH:61]=[CH:62][CH:63]=2)=[CH:51][N:52]2[CH:57]=[CH:56][CH:55]=[CH:54][C:53]=12
Reactant: Nc1cccc(-c2cn3ccccc3n2)c1
Reactant: O=C(O)c1cc2cc(Br)ccc2oc1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1cccc(-c2cn3ccccc3n2)c1)c1cc2cc(Br)ccc2oc1=O
Temperature: 25 °C
Yield: 70.2 %

Procedure:
DIEA (35.6 μL, 0.2 mmol) was added to 6-bromo-3-carboxy-coumarin (50.0 mg, 0.19 mmol) and HATU (77.7 mg, 0.2 mmol) in 2 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-Imidazo[1,2-a]pyridin-2-yl-phenylamine (38.9 mg, 0.19 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 61.4 mg of product in 68% yield: LCMS (ESI) m/z 461 (MH+).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH2:9])[CH:3]=1.[NH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1>>[CH3:8][C:6]1[N:5]=[C:4]([NH2:9])[CH:3]=[C:2]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH:7]=1
Reactant: Cc1cc(Cl)cc(N)n1
Reactant: C1COCCN1
Product: Cc1cc(N2CCOCC2)cc(N)n1
Temperature: 150 °C

Procedure:
To 4-chloro-6-methylpyridin-2-amine (150 mg, 1.05 mmol) in a nitrogen purged vial was added morpholine (0.917 mL, 10.5 mmol). The reaction mixture was sealed and heated at 150° C. for 1.5 hours. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in DCM (10 mL) and washed with aqueous saturated sodium bicarbonate solution. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-10% methanol/DCM with 1% ammonium hydroxide, linear gradient) to give 6-methyl-4-morpholinopyridin-2-amine. MS ESI calc'd. for C10H16N3O [M+H]+ 194. found 194. 1H NMR (500 MHz, DMSO-d6) δ 6.00 (s, 1H), 5.62 (s, 1H), 5.42 (s, 2H), 3.63 (m, 4H), 3.08 (m, 4H), 2.08 (s, 3H).
Reaction SMILES: [O:1]([CH:8]([CH3:11])[CH2:9][NH2:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:12]1([CH2:18][C:19](Cl)=[O:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[Na+].[Na+].O>C1C=CC=CC=1>[O:1]([CH:8]([CH3:11])[CH2:9][NH:10][C:19](=[O:20])[CH2:18][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: CC(CN)Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Product: CC(CNC(=O)Cc1ccccc1)Oc1ccccc1

Procedure:
2-Phenoxypropylamine (4.6 g.) was added to a mixture of phenylacetyl chloride (4.6 g.) and anhydrous sodium carbonate (3.3 g.) in dry benzene (20 ml.); there was an exothermic reaction and effervescence. The mixture was heated to reflux for 1 hour, cooled, treated with water, and then shaken. The benzene layer was separated, dried over anhydrous sodium sulphate, filtered, and diluted with light petroleum (b.p. 60°-80°) to give pure N-(2-phenoxypropyl) phenylacetamide, m.p. 94°-96°.
Reaction SMILES: [Li+].[OH-:2].OO.[Cl:5][C:6]1[CH:41]=[CH:40][C:9]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([C@@H:18]([C:35]3[CH:39]=[CH:38][O:37][N:36]=3)[CH2:19]C(N3[C@@H](CC4C=CC=CC=4)COC3=O)=O)=[CH:14][CH:13]=2)=[CH:8][C:7]=1[O:42][C:43]([F:46])([F:45])[F:44].C1[CH2:51][O:50]CC1>O>[Cl:5][C:6]1[CH:41]=[CH:40][C:9]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([C@@H:18]([C:35]3[CH:39]=[CH:38][O:37][N:36]=3)[CH2:19][C:51]([OH:50])=[O:2])=[CH:14][CH:13]=2)=[CH:8][C:7]=1[O:42][C:43]([F:45])([F:44])[F:46]
Reactant: [OH-]
Reactant: C1CCOC1
Reactant: O=C(C[C@@H](c1ccc(OCc2ccc(Cl)c(OC(F)(F)F)c2)cc1)c1ccon1)N1C(=O)OC[C@@H]1Cc1ccccc1
Agent: OO
Agent: [Li+]
Solvent: O
Product: O=C(O)C[C@@H](c1ccc(OCc2ccc(Cl)c(OC(F)(F)F)c2)cc1)c1ccon1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
A fresh aqueous solution of LiO2H, prepared from mixing a solution of LiOH (2.1 mL, 3.33 M in water) with H2O2 (1.54 mL, 33% in water) at 0° C., was slowly added to a cooled mixture of 35.3 (2.02 g, 3.39 mmol) in THF (20.0 mL) and water (10 mL) at 0° C. The resulting reaction mixture was stirred at 0° C. for 1.5 hours. The reaction was then quenched by adding a 1.5 N aqueous solution of Na2SO3 at 0° C. Water (150 mL) was added, and the aqueous solution was extracted with diethyl ether (30×3 mL) and acidified with concentrated HCl to a pH of 2. The mixture was then extracted with EtOAc (60×2 mL, 40×2 mL). The organic layer was dried with Na2SO4, and the solvent was removed to give the crude intermediate, (S)-3-(4-(4-chloro-3-(trifluoromethoxy)benzyloxy)phenyl)-3-(isoxazol-3-yl)propanoic acid. This intermediate was treated with EtOH (20 mL) and HCl (0.5 mL, 1.0 M in ether) at room temperature overnight. The solvent was evaporated to provide the crude product 35.4 which was used without further purification. MS ESI (pos.) m/e: 470 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH3:10].N1C=CC=CC=1.[CH3:17][C:18](=[CH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:19](Cl)=[O:20]>CC(C)=O>[CH3:9][O:8][C:6]1[CH:5]=[CH:4][C:3]([CH3:10])=[C:2]([NH:1][C:19](=[O:20])[C:18]([CH3:17])=[CH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:7]=1
Reactant: CC(=Cc1ccccc1)C(=O)Cl
Reactant: COc1ccc(C)c(N)c1
Solvent: CC(C)=O
Solvent: c1ccncc1
Product: COc1ccc(C)c(NC(=O)C(C)=Cc2ccccc2)c1
Yield: 84.3 %

Procedure:
2-Amino-4-methoxytoluene (13.2 g, 89.7 mmol) and pyridine (10 ml) were dissolved in acetone (112 ml), to which α-methylcinnamoylchloride (19.4 g, 107.6 mmol) was added while cooling and stirring. The mixture was stirred overnight at room temperature. The solvent was evaporated, and the residue was dissolved in chloroform, washed with water, dried, and condensed. The residue was purified by alumina chromatography (chloroform), and subjected to recrystallization with chloroform--n-hexane to obtain 21.27 g of the title compound as colorless crystals (84.4%).