Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].O1CCOCC1.C(OC([N:15]1[CH2:20][CH2:19][N:18]([C:21]2[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][N:22]=2)[CH2:17][CH2:16]1)=O)(C)(C)C>C(Cl)Cl>[ClH:1].[N+:27]([C:24]1[CH:25]=[CH:26][C:21]([N:18]2[CH2:17][CH2:16][NH:15][CH2:20][CH2:19]2)=[N:22][CH:23]=1)([O-:29])=[O:28].[ClH:1]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc([N+](=O)[O-])cn2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(N2CCNCC2)nc1
Reaction time: 3 h

Procedure:
Added 4M HCl/dioxane (15 ml) to a solution of 4-(5-Nitro-pyridin-2-yl)-piperazine-1-carboxylic acid tert-butyl ester (2.3 g, 7.46 mmol) in MeCl2 (20 ml) at room temperature. Reaction was stirred for 3 hours and solvent was evaporated yielding the product as hydrochloride salt 1-(5-Nitro-pyridin-2-yl)-piperazine hydrochloride 8 (2.2 g)
Reaction SMILES: [I-].[Li+].COC([C:7]1([CH2:31][CH:32]=[CH2:33])[CH:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][CH3:21])[CH2:12][C:11]2[CH:22]=[C:23]([C:26]([F:29])([F:28])[F:27])[CH:24]=[CH:25][C:10]=2[NH:9][C:8]1=[O:30])=O.C(OCC)(=O)C>N1C=CC=CC=1.O>[CH3:21][O:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[CH:13]1[CH2:12][C:11]2[CH:22]=[C:23]([C:26]([F:27])([F:28])[F:29])[CH:24]=[CH:25][C:10]=2[NH:9][C:8](=[O:30])[CH:7]1[CH2:31][CH:32]=[CH2:33]
Reactant: C=CCC1(C(=O)OC)C(=O)Nc2ccc(C(F)(F)F)cc2CC1c1ccccc1OC
Agent: [I-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: O
Product: C=CCC1C(=O)Nc2ccc(C(F)(F)F)cc2CC1c1ccccc1OC
Reaction time: 6.5 h
Yield: 104.7 %

Procedure:
Lithium iodide (1.08 g; 8.04 mmole) was added to 1,3,4,5-tetrahydro-3-(methoxycarbonyl)-4-(methoxyphenyl)-3-(2-propenyl)-7-(trifluoromethyl)-2H-1-benzazepin-2-one (870 mg; 2.01 mmole) in pyridine (14 ml), three drops of water were added, and the mixture was refluxed with stirring for 6.5 hours. The solution was dissolved into ethyl acetate and washed with 1N hydrochloric acid (three times). The organic layer was dried (magnesium sulfate) and concentrated giving 0.79 g of solid. The crude material was used "as is" in the next step.
Reaction SMILES: [OH:1][C@H:2]1[C:11](=[O:12])[C:10]2[CH:9]=[CH:8][N:7]3[CH:13]=[C:14]([CH3:16])[N:15]=[C:6]3[C:5]=2[NH:4][C@@H:3]1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[BH4-].[Na+].O>CC(O)C.C[O-].[Na+]>[OH:12][C@@H:11]1[C:10]2[CH:9]=[CH:8][N:7]3[CH:13]=[C:14]([CH3:16])[N:15]=[C:6]3[C:5]=2[NH:4][C@H:3]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:2]1[OH:1]
Reactant: Cc1cn2ccc3c(c2n1)N[C@H](c1ccccc1)[C@@H](O)C3=O
Agent: C[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: Cc1cn2ccc3c(c2n1)N[C@H](c1ccccc1)[C@@H](O)[C@@H]3O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
6 g (20.5 mmol) of (8R,9R)-8-hydroxy-2-methyl-9-phenyl-7,8,9,10-tetrahydroimidazo[1,2-h][1,7]naphthyridin-7-one are suspended in 30 ml of 2-propanol and 2 ml of 0.3% strength methanolic sodium methoxide solution. 0.4 g (10.2 mmol) of sodium borohydride, dissolved in 5 ml of 0.3% methanolic sodium methoxide solution, is added dropwise at 10° C. in the course of 10 minutes. The reaction mixture (suspension) is stirred overnight at room temperature (a solution forms in the course of this). The reaction solution is added to 90 ml of water and extracted three times with 30 ml of ethyl acetate each time. The combined ethyl acetate phases are washed once with water and concentrated. The residue is chromatographed on silica gel (ethyl acetate/2-propanol 95:5). The product fractions are concentrated and crystallized using diethyl ether. The crystals are filtered off with suction and dried at 50° C. in a high vacuum. 4.3 g (71% of theory) of the title compound of m.p. 119° C. (decomposition) are obtained.
Reaction SMILES: Cl.[NH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][C:12]([OH:14])=O)=[CH:3]1.[CH2:15]([C@H:22]1[CH2:26][NH:25][C@H:24]([C:27]([NH:29][C:30]2[CH:35]=[CH:34][C:33]([O:36][C:37]3[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=3)=[CH:32][CH:31]=2)=[O:28])[CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[NH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][C:12]([N:25]2[CH2:26][C@H:22]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:23][C@H:24]2[C:27]([NH:29][C:30]2[CH:35]=[CH:34][C:33]([O:36][C:37]3[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=3)=[CH:32][CH:31]=2)=[O:28])=[O:14])=[CH:3]1
Reactant: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccccc2)CN1
Reactant: O=C(O)Cc1c[nH]c2ccccc12
Agent: Cl
Product: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccccc2)CN1C(=O)Cc1c[nH]c2ccccc12
Yield: 39.3 %

Procedure:
Proceeding as in Example 1, but substituting 2-(1H-indol-3-yl)acetic acid hydrochloride and (2S,4R)-4-benzyl-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide, gave Compound 98, (2S,4R)-1-(2-(1H-indol-3-yl)acetyl)-4-benzyl-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide (12.9 mg, 39.3%). Major isomer: 1H-NMR (400 MHz, DMSO-D6): σ 10.91 (s, 1H), 9.99 (s, 1H), 7.56 (m, 3H), 7.35-7.07 (m, 10H), 7.01-6.94 (m, 5H), 4.50 (m, 1H), 3.75 (m, 2H), 3.69 (s, 2H), 2.61 (m, 3H), 1.90 (m, 2H). MS (EI) for C34H30FN3O3. found 548.6 (MH+).
Reaction SMILES: [CH2:1]([C:6]1[CH:12]=[C:11]([OH:13])[CH:10]=[CH:9][C:7]=1[OH:8])[CH2:2][CH2:3][CH2:4][CH3:5].CCCCCC.CC(=O)OCC>CO>[CH2:1]([C:6]1[C:7](=[O:8])[CH:9]=[CH:10][C:11](=[O:13])[CH:12]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCc1cc(O)ccc1O
Solvent: CO
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCCCCC1=CC(=O)C=CC1=O
Reaction time: 1 h
Yield: 58.9 %

Procedure:
To the solution of 360 mg (2 mmol) of 21 in methanol, 650 mg (2 eq) of FeCl3 was added. The reaction mixture was stirred for 1 hr, and the solvent was removed. Silicagel chromatography (hexane: EA=20:1) gave 210 mg (59% yield) 22 as a brown solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][CH:3]=1.[F:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](Cl)=[O:31])=[C:28]([O:35][CH3:36])[CH:27]=1.IC1C=CC=CC=1C(NCCN1C(=O)CC(=O)NC2C3C(C=CC1=2)=CC=CC=3)=O>>[F:25][C:26]1[CH:34]=[CH:33][C:29]([C:30]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([N:8]3[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]4[C:17]5[C:22]([CH:23]=[CH:24][C:9]3=4)=[CH:21][CH:20]=[CH:19][CH:18]=5)=[CH:4][CH:3]=2)=[O:31])=[C:28]([O:35][CH3:36])[CH:27]=1
Reactant: Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Reactant: COc1cc(F)ccc1C(=O)Cl
Agent: O=C1CC(=O)N(CCNC(=O)c2ccccc2I)c2ccc3ccccc3c2N1
Product: COc1cc(F)ccc1C(=O)Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Yield: 62 %

Procedure:
By using 5-(4-aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione obtained in Example 1, (3), and 4-fluoro-2-methoxybenzoyl chloride, the title compound (yield 62%) was obtained in the same manner as that of Example 1, (4).
Reaction SMILES: [Li][CH2:2]CCC.[CH:6]([C@H:8]1[O:16][C@H:15]2[C@H:11]([N:12]=[C:13]([N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[S:14]2)[C@@H:10]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=2)[C@@H:9]1[O:36][CH2:37][C:38]1[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=1)=O.OC[C@H]1O[C@H]2[C@H](N=C(N(C)C(=O)OC(C)(C)C)S2)[C@@H](OCC2C=CC(OC)=CC=2)[C@@H]1OCC1C=CC(OC)=CC=1.CN(C)C1S[C@H]2O[C@H](CO)[C@@H](OCC3C=CC(OC)=CC=3)[C@H](OCC3C=CC(OC)=CC=3)[C@H]2N=1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[CH3:45][O:44][C:41]1[CH:42]=[CH:43][C:38]([CH2:37][O:36][C@@H:9]2[C@@H:8]([CH:6]=[CH2:2])[O:16][C@H:15]3[C@H:11]([N:12]=[C:13]([N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:22])[CH3:23])[S:14]3)[C@H:10]2[O:26][CH2:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=2)=[CH:39][CH:40]=1
Reactant: COc1ccc(CO[C@@H]2[C@H]3N=C(N(C)C(=O)OC(C)(C)C)S[C@H]3O[C@H](C=O)[C@H]2OCc2ccc(OC)cc2)cc1
Reactant: [Li]CCCC
Agent: COc1ccc(CO[C@@H]2[C@H]3N=C(N(C)C(=O)OC(C)(C)C)S[C@H]3O[C@H](CO)[C@H]2OCc2ccc(OC)cc2)cc1
Agent: COc1ccc(CO[C@@H]2[C@H]3N=C(N(C)C)S[C@H]3O[C@H](CO)[C@H]2OCc2ccc(OC)cc2)cc1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: C=C[C@H]1O[C@@H]2SC(N(C)C(=O)OC(C)(C)C)=N[C@@H]2[C@@H](OCc2ccc(OC)cc2)[C@@H]1OCc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A suspension of methyltriphenylphosphonium bromide (1.85 g, 5.18 mmol) in tetrahydrofuran (35 mL) was treated with n-BuLi (1.9 ml, 2.5M) for 30 min at 0° C., and followed by addition of tert-butyl (3aR,5S,6S,7R,7aR)-5-formyl-6,7-bis(4-methoxybenzyloxy)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-2-yl(methyl)carbamate (44) prepared from compound 28 by a procedure identical to that described for the conversion of 10 to 11) (0.6 g, 1.05 mmol) in THF (5 mL). The resulting solution was stirred overnight at room temperature, quenched by water (25 mL), and extracted with dichloromethane (3×25 ml). The combined organic layers were dried over magnesium sulfate and concentrated under vacuum to give a residue, which was purified by a silica gel column, eluted with 20% ethyl acetate in petroleum ether to give crude compound 45 as a yellow oil (220 mg, purity 50% by LC-MS). (ES, m/z): [M+H]+ 571.0.
Reaction SMILES: C([O:3][C:4](=[O:33])[CH:5]([O:30][CH2:31][CH3:32])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[N:16]=[C:17]([C:21]3[CH:26]=[C:25]([Cl:27])[CH:24]=[C:23]([Cl:28])[CH:22]=3)[O:18][C:19]=2[CH3:20])=[CH:9][C:8]=1[CH3:29])C.[Li+].[OH-]>>[Cl:28][C:23]1[CH:22]=[C:21]([C:17]2[O:18][C:19]([CH3:20])=[C:15]([CH2:14][O:13][C:10]3[CH:11]=[CH:12][C:7]([CH2:6][CH:5]([O:30][CH2:31][CH3:32])[C:4]([OH:33])=[O:3])=[C:8]([CH3:29])[CH:9]=3)[N:16]=2)[CH:26]=[C:25]([Cl:27])[CH:24]=1
Reactant: CCOC(=O)C(Cc1ccc(OCc2nc(-c3cc(Cl)cc(Cl)c3)oc2C)cc1C)OCC
Agent: [Li+]
Agent: [OH-]
Product: CCOC(Cc1ccc(OCc2nc(-c3cc(Cl)cc(Cl)c3)oc2C)cc1C)C(=O)O

Procedure:
In analogy to the procedure described in example 1 g], [rac]-3-{4-[2-(3,5-dichloro-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-methyl-phenyl}-2-ethoxy-propionic acid ethyl ester was treated with LiOH to obtain [rac]-3-{4-[2-(3,5-dichloro-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-methyl-phenyl}-2-ethoxy-propionic acid as colorless liquid, which can be separated into its antipodes by methods known in the art, such as separation of the antipodes via diastereomeric salts by crystallization with optically pure amines such as e.g. (R) or (S)-1-phenyl-ethylamine, (R) or (S)-1-naphthalen-1-yl-ethylamine, brucine, quinine and quinidine or by separation of the antipodes by specific chromatographic methods using either a chiral adsorbens or a chiral eluent to give the title compound.
Reaction SMILES: [CH:1]1([N:7]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[C:8](=[O:18])[NH:9][C:10]2[S:11][CH:12]=[C:13]([C:15](O)=[O:16])[N:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>>[CH:1]1([N:7]([CH:19]2[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]2)[C:8]([NH:9][C:10]2[S:11][CH:12]=[C:13]([C:15]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[O:16])[N:14]=2)=[O:18])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)c1csc(NC(=O)N(C2CCCCC2)C2CCCCC2)n1
Reactant: C1COCCN1
Product: O=C(c1csc(NC(=O)N(C2CCCCC2)C2CCCCC2)n1)N1CCOCC1
Yield: 24 %

Procedure:
Prepared in 24% yield (61 mg) as described in general procedure (K) from 2-(3,3-dicyclohexylureido)-thiazole-4-carboxylic acid (210 mg, 0.60 mmol) and morpholine (52 mg, 0.60 mmol).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH:8]=[N:7]2.C([Sn](CCCC)(CCCC)[C:24]([O:26]CC)=[CH2:25])CCC>C1(C)C=CC=CC=1.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl>[O:12]([C:9]1[CH:8]=[N:7][C:6]2[C:11]([N:10]=1)=[C:2]([C:24](=[O:26])[CH3:25])[CH:3]=[CH:4][CH:5]=2)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: Clc1cccc2ncc(Oc3ccccc3)nc12
Agent: Cl[Pd]Cl
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Solvent: Cc1ccccc1
Product: CC(=O)c1cccc2ncc(Oc3ccccc3)nc12

Procedure:
A solution of 8-chloro-2-phenoxyquinoxaline (253 mg, 0.986 mmol), tributyl(1-ethoxyvinyl)stannane (499 μl, 1.478 mmol, Aldrich), and PdCl2(Amphos)2 (34.9 mg, 0.049 mmol) in toluene (9.9 ml) was stirred at 110° C. in a sealed tube for 16 h. Purification by silica gel (100% hexanes to 10% EtOAc/hexanes) provided 1-(3-phenoxyquinoxalin-5-yl)ethanone as a white solid. MS (ESI, pos. ion) m/z: 365.2 (M+1).
Reaction SMILES: C([O:8][C:9]([C@@H:11]1[CH2:16][C@@H:15]2[C@@H:13]([CH2:14]2)[N:12]1[C:17](=[O:31])[CH2:18][N:19]1[C:23]2=[CH:24][N:25]=[CH:26][CH:27]=[C:22]2[C:21]([C:28](=[O:30])[CH3:29])=[N:20]1)=[O:10])C1C=CC=CC=1>C1COCC1.[Pd]>[C:28]([C:21]1[C:22]2[C:23](=[CH:24][N:25]=[CH:26][CH:27]=2)[N:19]([CH2:18][C:17]([N:12]2[C@H:11]([C:9]([OH:10])=[O:8])[CH2:16][C@@H:15]3[C@H:13]2[CH2:14]3)=[O:31])[N:20]=1)(=[O:30])[CH3:29]
Reactant: CC(=O)c1nn(CC(=O)N2[C@@H]3C[C@@H]3C[C@H]2C(=O)OCc2ccccc2)c2cnccc12
Agent: [Pd]
Solvent: C1CCOC1
Product: CC(=O)c1nn(CC(=O)N2[C@@H]3C[C@@H]3C[C@H]2C(=O)O)c2cnccc12
Reaction time: 72 h

Procedure:
To a solution of (1R,3S,5R)-2-[2-(3-acetyl-pyrazolo[3,4-c]pyridin-1-yl)-acetyl]-2-aza-bicyclo[3.1.0]hexane-3-carboxylic acid benzyl ester (2.26 g, 5.4 mmol) in THF (20 mL) was added Pd/C 10% (60 mg). The reaction was placed under hydrogen atmosphere and was stirred for 72 h. The catalyst was removed by filtration through a pad of Celite and washed with MeOH. Solvents were concentrated to give the title compound. MS (UPLC-MS): 329 [M+H]+; tR (HPLC conditions d): 2.29 min.
Reaction SMILES: O[CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N:12]3[C:17](=[O:18])[C:16]([CH2:19][C:20]4[CH:25]=[CH:24][C:23]([C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=5[C:32]5[NH:36][C:35](=[O:37])[O:34][N:33]=5)=[CH:22][CH:21]=4)=[C:15]([CH2:38][CH2:39][CH3:40])[N:14]=[C:13]3[CH3:41])[CH:10]=2)[O:5][C:4]([CH3:43])([CH3:42])[CH2:3]1.Cl>C(#N)C.C(OCC)(=O)C>[CH3:42][C:4]1([CH3:43])[CH2:3][CH:2]([NH:12][C:17](=[O:18])[CH3:16])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N:12]3[C:17](=[O:18])[C:16]([CH2:19][C:20]4[CH:25]=[CH:24][C:23]([C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=5[C:32]5[NH:36][C:35](=[O:37])[O:34][N:33]=5)=[CH:22][CH:21]=4)=[C:15]([CH2:38][CH2:39][CH3:40])[N:14]=[C:13]3[CH3:41])[CH:10]=2)[O:5]1
Reactant: CCCc1nc(C)n(-c2ccc3c(c2)C(O)CC(C)(C)O3)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCCc1nc(C)n(-c2ccc3c(c2)C(NC(C)=O)CC(C)(C)O3)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 153.1 %

Procedure:
3-(4-Hydroxy-2,2-dimethyl-3,4-dihydro-2H-chromen-6-yl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one (1.0 g) was dissolved in acetonitrile (10 mL), and concentrated hydrochloric acid (1.0 mL) was added dropwise at 0° C. The reaction mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound (0.82 g, 76%) as a colorless solid.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]([O:15][CH2:16][CH3:17])(=[O:14])[CH2:10][C:11]([CH3:13])=[O:12].C(N(CC)CC)C>O1CCCC1.C(Cl)(Cl)(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[O:12]=[C:11]([CH:13]=[CH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:10][C:9]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC(=O)CC(C)=O
Reactant: O=Cc1ccccc1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)CC(=O)C=Cc1ccccc1
Reaction time: 0.08 h

Procedure:
To a cold (5°) solution of 0.015 moles of benzaldehyde and 0.015 moles of ethyl acetoacetate in 60 ml of tetrahydrofuran was added 0.060 mole of triethylamine. After the mixture was stirred for 5 minutes, a solution of 0.020 moles of titanium tetrachloride in 15 ml of carbon tetrachloride was added dropwise over 10 minutes. The reaction mixture was then stirred for 20 hours, after which the title product was isolated by the extraction and chromatography methods described in Example 1. The material prepared by this procedure was identical to that prepared by the method of Example 1, as indicated by the reverse phase chromatographic method described in Example 2.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([NH2:12])[C:9]2[C:4](=[N:5][CH:6]=[C:7]([CH2:13][N:14]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)N=2)[N:3]=1.[CH:27]1C2NC3C(=CC=CC=3)C=2C=CC=1.[H-].[Na+].Br.NC1N=C(N)C2C=C(CBr)C=NC=2N=1>>[NH2:1][C:2]1[N:11]=[C:10]([NH2:12])[C:9]2[CH:27]=[C:7]([CH2:13][N:14]3[C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:26]=4[C:20]4[C:15]3=[CH:16][CH:17]=[CH:18][CH:19]=4)[CH:6]=[N:5][C:4]=2[N:3]=1
Reactant: Nc1nc(N)c2nc(CN(c3ccccc3)c3ccccc3)cnc2n1
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Agent: Br
Agent: Nc1nc(N)c2cc(CBr)cnc2n1
Agent: [H-]
Product: Nc1nc(N)c2cc(Cn3c4ccccc4c4ccccc43)cnc2n1

Procedure:
N-[(2,4-Diaminopyrido[2,3-d]pyrimdin-6-yl)methyl]carbazole (Formula I: Ar=2,4-diaminopyrido[2,3-[pyrindin-6-yl; W=CH2; X=N; Z=chemical bond; m=n=0) is prepared similarly to N-[(2,4-diaminopteridin-6-yl)methyl]N,N-diphenylamine as disclosed above by using carbazole (129 mg, 0.77 mmol), NaH (50 mg, 2.1 mmol), and 2,4-diamino-6-bromomethylpyrido[2,3-d]pyrimidine hydrobromide (100 mg, 0.3 mmol). The product can be purified by chromatography.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=O)[CH2:9]2)=[CH:4][CH:3]=1.[CH2:13]([NH2:16])[CH2:14][CH3:15].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH:8]([NH:16][CH2:13][CH2:14][CH3:15])[CH2:9]2)=[CH:4][CH:3]=1
Reactant: CCCN
Reactant: O=C1CCc2ccc(Br)cc2C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CCCNC1CCc2ccc(Br)cc2C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 7-bromo-3,4-dihydro-1H-naphthalen-2-one, prepared as described in J. Med. Chem, 1993, 36, 2279-2291, (5.2 g, 23 mmol) in 1,2 dichloroethane (30 mL), propyl amine (1.63 g, 28 mmol) was added, followed by addition of sodium triacetoxyborohydride (7.3 g, 34.5 mmol). The reaction was stirred at ambient temperature under nitrogen for 24 h, at which time it was concentrated in vacuo. The remaining solid was partitioned between 1 M sodium hydroxide and ethyl acetate. The ethyl acetate was washed with brine, dried over magnesium sulfate, and filtered to yield (7-bromo-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amine (2.75 g).
Reaction SMILES: [CH2:1]([C:3]1[O:4][CH2:5][CH2:6][N:7]=1)[CH3:2].[C:8]1([OH:14])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[O:14]([CH2:5][CH2:6][NH:7][C:3](=[O:4])[CH2:1][CH3:2])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Oc1ccccc1
Reactant: CCC1=NCCO1
Product: CCC(=O)NCCOc1ccccc1
Yield: 90 %

Procedure:
Adding 2-ethyl-2-oxazoline to hot (150°) phenol and maintaining heating at about 175° for 16 additional hours. The oil is then quenched in water to give N-(2-phenoxyethyl)propionamide (IV) in approximately 90% yield.
Reaction SMILES: O[CH2:2][CH:3]([CH2:5]O)O.[CH2:7]([O:9][C:10]([C:12]1[CH:18]=[CH:17][C:15](O)=[CH:14][CH:13]=1)=[O:11])[CH3:8]>O>[CH2:8]([CH:7]1[C:18]2[C:12](=[CH:13][CH:14]=[CH:15][CH:17]=2)[C:10](=[O:11])[O:9]1)[CH2:2][CH2:3][CH3:5]
Reactant: CCOC(=O)c1ccc(O)cc1
Reactant: OCC(O)CO
Solvent: O
Product: CCCCC1OC(=O)c2ccccc21

Procedure:
100 g of gelatin, 40 g of glycerin, 120 g of water and 200 mg of ethylparaben are used. The gelatin solution is prepared by the same protocol as in Example 1.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH3:23])[C:10](=[O:22])[N:11]([CH3:21])[C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Cl.Cl[CH2:32][C:33]1[CH:42]=[CH:41][C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[N:34]=1>>[CH3:20][O:19][C:16]1[CH:15]=[CH:14][C:13]([C:12]2[N:11]([CH3:21])[C:10](=[O:22])[N:9]([CH3:23])[C:8]=2[C:5]2[CH:6]=[CH:7][C:2]([O:1][CH2:32][C:33]3[CH:42]=[CH:41][C:40]4[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=4)[N:34]=3)=[CH:3][CH:4]=2)=[CH:18][CH:17]=1
Reactant: COc1ccc(-c2c(-c3ccc(O)cc3)n(C)c(=O)n2C)cc1
Reactant: ClCc1ccc2ccccc2n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1ccc(-c2c(-c3ccc(OCc4ccc5ccccc5n4)cc3)n(C)c(=O)n2C)cc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 39.5 %

Procedure:
To a stirred solution of 4-(4-hydroxyphenyl)-5-(4-methoxyphenyl)-1,3-dimethyl-1H-imidazol-2(3H)-one (0.35 g, 1.12 mmol) in AcN (20 mL) was added K2CO3 (0.46 g, 3.3 mmol) at RT. The reaction mixture was heated to 80° C. for 30 min, and then 2-(chloromethyl)quinoline hydrochloride (0.29 g, 1.35 mmol) was added and the mixture stirred for an additional 3 h at 80° C. Then the mixture was concentrated in vacuo and the residue was dissolved in EtOAc (30 mL). The organic layer was washed with water, dried over Na2SO4, filtered, and then concentrated in vacuo to obtain the crude product. The crude material was purified via silica gel column chromatography eluting with 80% EtOAc/20% hexanes to afford 4-(4-methoxyphenyl)-1,3-dimethyl-5-(4-(quinolin-2-ylmethoxy)phenyl)-1H-imidazol-2(3H)-one (0.2 g, 39%) as a solid. 1H NMR (500 MHz, CDCl3): δ 8.21 (d, J=7.2 Hz, 1H), 8.05 (d, J=8.4 Hz, 1H), 7.84 (d, J=7.2 Hz, 1H), 7.74-7.72 (m, 1H), 7.64 (d, J=7.6 Hz, 1H), 7.59-7.56 (m, 1H), 7.11-7.05 (m, 4H), 6.93 (d, J=7.2 Hz, 2H), 6.82 (d, J=7.6 Hz, 2H), 5.39 (s, 2H), 3.81 (s, 3H), 3.19 (s, 6H). MS: M+H: m/z=452.2 and HPLC: 97%, (Condition-H).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH2:12])[C:8]([CH3:11])=[N:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C[O:14][C:15](=O)[C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[C:18]([N:23]2[CH:27]=[C:26]([C:28]3[CH:29]=[N:30][N:31]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[C:32]=3[CH2:33][CH3:34])[N:25]=[CH:24]2)[CH:17]=1>>[C:1]([C:5]1[CH:6]=[C:7]([NH:12][C:15](=[O:14])[C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[C:18]([N:23]3[CH:27]=[C:26]([C:28]4[CH:29]=[N:30][N:31]([C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=5)[C:32]=4[CH2:33][CH3:34])[N:25]=[CH:24]3)[CH:17]=2)[C:8]([CH3:11])=[N:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ncc(C(C)(C)C)cc1N
Reactant: CCc1c(-c2cn(-c3cc(C(=O)OC)ccc3C)cn2)cnn1-c1ccccc1
Product: CCc1c(-c2cn(-c3cc(C(=O)Nc4cc(C(C)(C)C)cnc4C)ccc3C)cn2)cnn1-c1ccccc1

Procedure:
Example 152 was prepared from 5-tert-butyl-2-methyl-pyridin-3-ylamine (see U.S. provisional application 60/567,693) and 3-[4-(5-ethyl-1-phenyl-1H-pyrazol-4-yl)-imidazol-1-yl]-4-methyl-benzoic acid methyl ester (Example 151) in the same manner as Example 151. ESI MS m/z 519 [C32H34N6O+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:17]=[C:16]([C:18](OC)=[O:19])[CH:15]=[C:14]2[C:9]=1[CH2:10][NH:11][C:12](=[O:30])[N:13]2[C:22]1[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:23]=1[Cl:29].[H-].[Al+3].[Li+].[H-].[H-].[H-].Cl.C(OCC)(=O)C>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:17]=[C:16]([CH2:18][OH:19])[CH:15]=[C:14]2[C:9]=1[CH2:10][NH:11][C:12](=[O:30])[N:13]2[C:22]1[C:23]([Cl:29])=[CH:24][CH:25]=[CH:26][C:27]=1[Cl:28]
Reactant: COC(=O)c1cc(-c2ccccc2Cl)c2c(c1)N(c1c(Cl)cccc1Cl)C(=O)NC2
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C1NCc2c(-c3ccccc3Cl)cc(CO)cc2N1c1c(Cl)cccc1Cl
Reaction time: 1.5 h

Procedure:
To a stirred solution of methyl 5-(2-chlorophenyl)-1-(2,6-dichlorophenyl)-2-oxo-1,2,3,4-tetrahydroquinazoline-7-carboxylate (INTERMEDIATE 32) (8.23 g) in THF (140 mL) was added lithium aluminum hydride (14 mL of a 1.0M solution in THF) and the mixture was let stir 1.5 h. More lithium aluminum hydride (4.5 mL of a 1.0M solution in THF) was added and the mixture was stirred overnight. Another portion of lithium aluminum hydride (4.5 mL of a 1.0M solution in THF) was added and stirred 4 h. The reaction was carefully poured into a flask containing 1N aqueous HCl (500 mL) and stirred. To the mixture was added ethyl acetate (500 mL) and the layers were mixed, then separated. The organic layer was washed with brine (300 mL), dried over anhydrous MgSO4, filtered and concentrated. The resulting solid was triturated with hexanes, then CH2Cl2 to give the 5-(2-chlorophenyl)-1-(2,6-dichlorophenyl)-7-(hydroxymethyl)-3,4-dihydroquinazolin-2(1H)-one compound.