Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[N:7][C:8]([N:11]2[CH2:30][CH2:29][C:14]3[NH:15][C:16]4[CH:17]=[CH:18][C:19]([C:22]5[O:23][C:24]([CH:27]=O)=[CH:25][CH:26]=5)=[CH:20][C:21]=4[C:13]=3[CH2:12]2)=[N:9][CH:10]=1)=[O:4].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[CH3:45][N:46]1[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]1>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[N:9][C:8]([N:11]2[CH2:30][CH2:29][C:14]3[NH:15][C:16]4[CH:17]=[CH:18][C:19]([C:22]5[O:23][C:24]([CH2:27][N:49]6[CH2:50][CH2:51][N:46]([CH3:45])[CH2:47][CH2:48]6)=[CH:25][CH:26]=5)=[CH:20][C:21]=4[C:13]=3[CH2:12]2)=[N:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1cnc(N2CCc3[nH]c4ccc(-c5ccc(C=O)o5)cc4c3C2)nc1
Reactant: CN1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)c1cnc(N2CCc3[nH]c4ccc(-c5ccc(CN6CCN(C)CC6)o5)cc4c3C2)nc1
Reaction time: 0.17 h
Yield: 70.9 %

Procedure:
To a 0° C. solution of methyl-2-{8-[5-(formyl)-2-furyl]-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl}pyrimidine-5-carboxylate (0.12 g, 0.29 mmol) in DCM (20 mL) was added Na(OAc)3BH (0.126 g, 0.59 mmol) and stirred for 10 min. To the reaction mixture was added N-methylpiperzine (0.149 g, 1.49 mmol) under nitrogen atmosphere and the reaction mixture was continued stirring at room temperature for 4 hr. The progress of the reaction was monitored by TLC and upon completion of the reaction the mixture was partitioned between DCM (50 mL) and water (25 mL) and the organic layer was separated, washed with water (2×25 mL), dried over sodium sulfate filtered and the solvent was removed under reduced pressure to give crude residue, which was purified by column chromatography using silica gel to provide methyl-2-{8-[5-((4-methylpiperazin-1-yl)methyl)-2-furyl]-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl}pyrimidine-5-carboxylate (0.1 g, 69.4%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]([NH:11][C:12]2[C:13]([Cl:19])=[N:14][C:15]([CH3:18])=[CH:16][CH:17]=2)=[O:10])[C:5](Cl)=[N:6][CH:7]=1.[CH2:20]([NH2:22])[CH3:21].O>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([C:9]([NH:11][C:12]2[C:13]([Cl:19])=[N:14][C:15]([CH3:18])=[CH:16][CH:17]=2)=[O:10])[C:5]([NH:22][CH2:20][CH3:21])=[N:6][CH:7]=1
Reactant: CCN
Reactant: Cc1ccc(NC(=O)c2cc(Br)cnc2Cl)c(Cl)n1
Solvent: C1CCOC1
Solvent: O
Product: CCNc1ncc(Br)cc1C(=O)Nc1ccc(C)nc1Cl
Reaction time: 0.25 h
Yield: 89 %

Procedure:
A solution of 5-bromo-2-chloro-N-(2-chloro-6-methyl-3-pyridinyl)-3-pyridinecarboxamide (1.7 g, 4.8 mmol) and ethylamine (2M in THF, 10.5 mmol, 5.2 mL) in THF (5 mL) was stirred at 90 to 95° C. in a steel autoclave for 16 h. The resulting mixture was poured into water (100 mL), stirred for 15 min and filtered. The solid was washed with water followed by hexane to give the title compound as a yellow solid (1.58 g, 89% yield).
Reaction SMILES: C1C=C[NH+]=CC=1.Br[Br-]Br.[CH3:10][C:11]1[NH:12][C:13](C)=[C:14]([C:29]([O:31][CH2:32]CO)=[O:30])[CH:15]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:16]=1[C:17]([O:19][CH2:20][CH2:21][OH:22])=[O:18]>C(Cl)CCl.N1C=CC=CC=1>[CH3:10][C:11]1[NH:12][C:13]2[CH2:32][O:31][C:29](=[O:30])[C:14]=2[CH:15]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:16]=1[C:17]([O:19][CH2:20][CH2:21][OH:22])=[O:18]
Reactant: CC1=C(C(=O)OCCO)C(c2ccccc2)C(C(=O)OCCO)=C(C)N1
Agent: c1cc[nH+]cc1
Solvent: ClCCCl
Solvent: c1ccncc1
Product: CC1=C(C(=O)OCCO)C(c2ccccc2)C2=C(COC2=O)N1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
2.33 grams of 80 percent pyridinium bromide perbromide (1.46 millimoles) was added to a solution of 500 milligrams (1.51 millimoles) of bis(2-hydroxyethyl) 2,6-dimethyl-4-phenyl-1,4-dihydropyridine-3,5-dicarboxylate in 400 milliliters of ethylene dichloride and 1.6 milliliters of pyridine. The resulting mixture was stirred at 0° C. for 1 hour and then heated at reflux temperature for 2 hours. Thereafter, the mixture was cooled to room temperature, the resulting solution washed with 2N hydrochloric acid, sodium bicarbonate solution and brine, dried over magnesium sulfate, filtered, and the filtrate subjected to reduced pressure to vaporize the solvent and to recover as residue a semi-crystalline solid. The solid was not crystallizable from acetonitrile. The acetonitrile was vaporized to obtain an orange oil which on trituration with ethyl acetate produced crystals. The crystals, after recrystallization twice from ethyl acetate, had a melting point of 185°-186° C. 1H NMR and elemental analyses showed the product to have ethyl acetate solvate of crystallization. Elemental analyses were as follows:
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[C:5]([CH3:10])[CH:4]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]>C(#N)C.O>[OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:5]([CH3:10])[CH:4]=1
Reactant: Cc1cc(CO)ccc1O
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC#N
Product: CCOC(=O)COc1ccc(CO)cc1C
Yield: 96.2 %

Procedure:
To a solution of 4-(hydroxymethyl)-2-methylphenol (7.95 g, 57 mmol) in dry acetonitrile (300 mL) at 5° C., was added cesium carbonate (20.42 g, 62 mmol) and ethyl bromoacetate (6.38 mL, 57 mmol). The resultant mixture was stirred for 3 h at 5° C. under nitrogen. The reaction mixture was diluted with water (500 mL), extracted with EtOAc (2×750 mL), dried (Na2SO4) and the solvents removed in vacuo to afford the title compound as a yellow oil (12.3 g).
Reaction SMILES: [CH2:1]([C@@H:8]([CH2:12][CH2:13][C@H:14]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:15]([NH:17][C@H:18]1[CH2:24][CH2:23][S:22][C@H:21]2[CH2:25][CH2:26][CH2:27][C@@H:28]([C:29]([O:31][CH3:32])=[O:30])[N:20]2[C:19]1=[O:33])=[O:16])[C:9](O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:42][C@H:43]1[C:48]([CH3:50])([CH3:49])[S:47][C@H:46]2[CH2:51][CH2:52][CH2:53][N:45]2[C:44]1=[O:54]>>[CH2:34]([C@@H:14]([CH2:13][CH2:12][C@H:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:9]([NH:42][C@H:43]1[C:48]([CH3:49])([CH3:50])[S:47][C@H:46]2[CH2:51][CH2:52][CH2:53][N:45]2[C:44]1=[O:54])=[O:10])[C:15]([NH:17][C@H:18]1[CH2:24][CH2:23][S:22][C@H:21]2[CH2:25][CH2:26][CH2:27][C@@H:28]([C:29]([O:31][CH3:32])=[O:30])[N:20]2[C:19]1=[O:33])=[O:16])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: COC(=O)[C@@H]1CCC[C@@H]2SCC[C@H](NC(=O)[C@H](CC[C@H](Cc3ccccc3)C(=O)O)Cc3ccccc3)C(=O)N21
Reactant: CC1(C)S[C@H]2CCCN2C(=O)[C@H]1N
Agent: Cl
Product: COC(=O)[C@@H]1CCC[C@@H]2SCC[C@H](NC(=O)[C@H](CC[C@H](Cc3ccccc3)C(=O)N[C@@H]3C(=O)N4CCC[C@@H]4SC3(C)C)Cc3ccccc3)C(=O)N21

Procedure:
(4S,7S,10aS)-Methyl 4-((2R,5R)-2,5-dibenzyl-6-((3R,8aS)-2,2-dimethyl-4-oxohexahydro-2H-pyrrolo[2,1-b][1,3]thiazin-3-ylamino)-6-oxohexanamido)-5-oxooctahydro-2H-pyrido[2,1-b][1,3]thiazepine-7-carboxylate was synthesized as described in General Procedure H using Intermediate 23 (15 mg, 0.026 mmol) and Intermediate 29 (8.0 mg, 0.040 mmol) to give a white solid (15 mg, 72% yield). Anal. Calcd. for C40H52N4O6S2 m/z 748.4. found: 749.3 (M+H)+; 1H NMR (500 MHz, CD3OD) δ ppm 8.14 (d, J=7.70 Hz, 1H), 7.95 (d, J=9.35 Hz, 1H), 7.28-7.08 (m, 10H), 5.56 (dd, J=6.05, 2.75 Hz, 1H), 5.21-5.12 (m, 1H), 5.07-4.99 (m, 2H), 4.79 (d, J=9.35 Hz, 1H), 3.69-3.57 (m, 4H), 3.43-3.35 (m, 1H), 3.12-3.04 (m, 1H), 2.94 (br. s., 1H), 2.88-2.77 (m, 3H), 2.75-2.66 (m, 3H), 2.43 (dd, J=13.20, 6.60 Hz, 1H), 2.36 (d, J=13.75 Hz, 1H), 2.16-1.88 (m, 4H), 1.88-1.68 (m, 5H), 1.68-1.57 (m, 5H), 0.87 (s, 3H), 0.84 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[NH:6][C:5](=[O:7])[NH:4][C:3]1=[O:8].[Cl-].[Li+].[CH2:12]1[O:15][CH:13]1[CH3:14]>CN(C)C=O>[OH:15][CH:13]([CH3:12])[CH2:14][N:6]1[C:2]([CH3:9])([CH3:1])[C:3](=[O:8])[N:4]([CH2:12][CH:13]([OH:15])[CH3:14])[C:5]1=[O:7]
Reactant: CC1(C)NC(=O)NC1=O
Reactant: CC1CO1
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: CC(O)CN1C(=O)N(CC(C)O)C(C)(C)C1=O
Temperature: 50 °C

Procedure:
A mixture of 217 g of 5,5-dimethylhydantoin (1.695 mols) 3.61 g of lithium chloride (5 mol percent) and 560 ml of dimethylformamide is stirred at 50° C. 230 g of propene oxide (propylene oxide) (3.955 mols) are added dropwise to the clear solution over the course of 4 hours, 50°-55° C. The reaction is slightly exothermic. After the dropwise addition, the temperature is slowly raised to 90° C. After 5 hours at 90° C. the dimethylformamide is distilled off in a waterpump vacuum and thereafter the product is dried to constant weight at 100° C. and 0.1 mm Hg. 415 g of a pale yellow highly viscous oil (100% of theory) are obtained. The crude product is distilled at 0.1 to 0.2 mm Hg and 170°-172° C.: 386.0 g yield of pure material (93.5% of theory). On cooling the 1,3-di(β-hydroxy-n-propyl)- 5,5-dimethylhydantoin solidifies to give white crystals of melting point 65°-67° C. The elementary analysis shows 11.81% N (calculated, 11.47% N), and the molecular weight was determined by vapour pressure osmometry to be 247 (theory 244). The infrared spectrum shows the absence of N-H-amide frequencies at 3.1 to 3.2μ and the presence of C--OH frequencies at 2.90μ.
Reaction SMILES: [OH:1][C:2]1([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.Cl[CH2:16][CH2:17][CH2:18][NH:19][C:20]([NH:22][C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[N:26]=[C:25]([CH3:33])[CH:24]=1)=[O:21].OC1(C2C=CC(C)=CC=2)CCN(CCNC(NC2C3C(=CC=CC=3)N=C(C)C=2)=O)CC1>>[CH2:8]([C:2]1([OH:1])[CH2:7][CH2:6][N:5]([CH2:16][CH2:17][CH2:18][NH:19][C:20]([NH:22][C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[N:26]=[C:25]([CH3:33])[CH:24]=2)=[O:21])[CH2:4][CH2:3]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Cc1cc(NC(=O)NCCCCl)c2ccccc2n1
Reactant: OC1(Cc2ccccc2)CCNCC1
Agent: Cc1ccc(C2(O)CCN(CCNC(=O)Nc3cc(C)nc4ccccc34)CC2)cc1
Product: Cc1cc(NC(=O)NCCCN2CCC(O)(Cc3ccccc3)CC2)c2ccccc2n1

Procedure:
Prepared from 4-hydroxy-4-benzyl-piperidine and 1-(3-chloro-propyl)-3-(2-methyl-quinolin-4-yl)-urea using the method exemplified with Example 341, 1-[2-(4-hydroxy-4-p-tolyl-piperidin-1-yl)-ethyl]-3-(2-methyl-quinolin-4-yl)-urea.
Reaction SMILES: [CH3:1][O:2][P:3]([CH2:7][NH:8][CH:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:16][CH:15]=1)[C:10]([OH:12])=O)([O:5][CH3:6])=[O:4].Cl.[C:27]([O:31][C:32](=[O:36])[CH2:33][CH2:34][NH2:35])([CH3:30])([CH3:29])[CH3:28].OC1C2N=NNC=2C=CC=1.C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC>CN(C)C=O.C(OCC)(=O)C>[CH3:1][O:2][P:3]([CH2:7][NH:8][CH:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[CH:16][CH:15]=1)[C:10]([NH:35][CH2:34][CH2:33][C:32]([O:31][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:36])=[O:12])([O:5][CH3:6])=[O:4]
Reactant: CC(C)(C)OC(=O)CCN
Reactant: COP(=O)(CNC(Cc1ccc(-c2ccccc2)cc1)C(=O)O)OC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COP(=O)(CNC(Cc1ccc(-c2ccccc2)cc1)C(=O)NCCC(=O)OC(C)(C)C)OC

Procedure:
A solution of 2-(dimethylphosphonomethylamino)-3-(4-biphenylyl)-propionic acid (2.27 g, 6.25 mmol), β-alanine t-butyl ester hydrochloride (1.36 g, 7.5 mmol), hydroxybenzotriazole (1.05 g, 6.85 mmol), triethylamine (2.41 mL, 17.3 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC, 1.6 g, 8.22 mmol) in dimethylformamide (60 mL) is stirred for 3 hours at room temperature, then diluted with ethyl acetate, washed with ice water, dried (Na2SO4) and chromatographed on silica gel [CH2Cl2 :MeOH:hexanes/76:4:20] to obtain t-butyl N-[2-(dimethylphosphonomethylamino)-3-(4-biphenylyl)-propionyl]-3-aminopropionate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]3[CH:14]=[C:15]([C:18]4[O:22][C:21]([SH:23])=[N:20][N:19]=4)[CH:16]=[CH:17][C:12]=3[N:11]=[CH:10]2)=[CH:5][CH:4]=1.Cl[CH2:25][C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=1)[C:29]([OH:31])=[O:30]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]3[CH:14]=[C:15]([C:18]4[O:22][C:21]([S:23][CH2:25][C:26]5[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=5)[C:29]([OH:31])=[O:30])=[N:20][N:19]=4)[CH:16]=[CH:17][C:12]=3[N:11]=[CH:10]2)=[CH:5][CH:4]=1
Reactant: O=C(O)c1cccc(CCl)c1
Reactant: COc1ccc(-n2cnc3ccc(-c4nnc(S)o4)cc32)cc1
Product: COc1ccc(-n2cnc3ccc(-c4nnc(SCc5cccc(C(=O)O)c5)o4)cc32)cc1
Yield: 31 %

Procedure:
In the same manner as in Example 1 and using 5-[1-(4-methoxyphenyl)-1H-benzimidazol-6-yl]-1,3,4-oxadiazole-2-thiol instead of 5-(benzothiazol-6-yl)-1,3,4-oxadiazole-2-thiol and 3-(chloromethyl)benzoic acid instead of 3-(trifluoromethyl)benzyl chloride, the title compound (yield 31%) was obtained as colorless crystals.
Reaction SMILES: N#N.O[CH2:4][C:5]1[O:9][N:8]=[C:7]([C:10](=[O:12])[CH3:11])[CH:6]=1.CCN(CC)CC.S([Cl:24])(C)(=O)=O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:24][CH2:4][C:5]1[O:9][N:8]=[C:7]([C:10](=[O:12])[CH3:11])[CH:6]=1
Reactant: CC(=O)c1cc(CO)on1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Agent: N#N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)c1cc(CCl)on1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 1-(5-hydroxymethyl-isoxazol-3-yl)-ethanone (262 mg, 1.86 mmol) in dry CH2Cl2 (2.6 mL) was treated at 0° C. with Et3N (0.34 mL, 2.41 mmol) followed by DMAP (23 mg, 0.19 mmol) and Ms-Cl (0.17 mL, 2.23 mmol). After stirring at rt for 2 h, the reaction mixture was quenched with water (10 mL), extracted with CH2Cl2 (2×10 mL) and the combined org. extracts were dried over NaSO4, filtered, and the solvents were removed under reduced pressure to give crude 1-(5-chloromethyl-isoxazol-3-yl)-ethanone as a pale yellow oil. In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of this crude 1-(5-chloromethyl-isoxazol-3-yl)-ethanone in DMF (3.0 mL) was added to a solution of 4-nitro-2H-[1,2,3]triazole (210 mg, 1.84 mmol) in DMF (3.0 mL) pre-treated for 30 min with DIPEA (0.63 mL, 3.68 mmol) and the reaction mixture was stirred for 16 h at 50° C. Water (10 mL), followed by EA (10 mL) were added. The aq. layer was extracted with EA (10 mL) and the combined org. extracts were dried over NaSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (2:1 hept-EA) gave the title compound as a pale yellow oil: TLC:rf (2:1 hept-EA)=0.26. LC-MS-conditions 02: tR=0.90 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][CH:21]=[CH:20][C:4]=1[CH2:5][NH:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([N+:17]([O-])=O)[CH:13]=2)[N:8]=1>C(OCC)(=O)C.[Pd]>[CH3:1][O:2][C:3]1[CH:23]=[CH:22][CH:21]=[CH:20][C:4]=1[CH2:5][NH:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([NH2:17])[CH:13]=2)[N:8]=1
Reactant: COc1ccccc1CNc1ccc2cc([N+](=O)[O-])ccc2n1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1ccccc1CNc1ccc2cc(N)ccc2n1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
(2-Methoxy-benzyl)-(6-nitro-quinolin-2-yl)-amine (0.5 g, 2.0 mmol) were dissolved in ethyl acetate (25 ml). Upon addition of Pd/C (10%, 0.1 g) the reaction mixture was stirred for 45 min at ambient temperature under an atmosphere of hydrogen. Then the catalyst was filtered off, the filter washed with ethyl acetate and the filtrate evaporated. N2-(2-Methoxy-benzyl)-quinoline-2,6-diamine was obtained as a yellow foam (0.40 g, 87%); MS: m/e=280.5 (M+H+).
Reaction SMILES: [NH2:1][C:2]([C:4]1[CH:29]=[CH:28][C:7]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[C@H:18]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:17][CH2:16]3)=[C:6]([CH2:30][CH2:31][CH3:32])[CH:5]=1)=[S:3].Br[CH:34]1[CH2:39][CH2:38][CH2:37][O:36][C:35]1=O>CCO>[CH2:26]([O:25][C:23](=[O:24])[CH2:22][C@H:18]1[C:19]2[C:15](=[CH:14][C:13]([O:12][CH2:11][CH2:10][CH2:9][O:8][C:7]3[CH:28]=[CH:29][C:4]([C:2]4[S:3][C:34]5[CH2:39][CH2:38][CH2:37][O:36][C:35]=5[N:1]=4)=[CH:5][C:6]=3[CH2:30][CH2:31][CH3:32])=[CH:21][CH:20]=2)[CH2:16][CH2:17]1)[CH3:27]
Reactant: CCCc1cc(C(N)=S)ccc1OCCCOc1ccc2c(c1)CC[C@H]2CC(=O)OCC
Reactant: O=C1OCCCC1Br
Solvent: CCO
Product: CCCc1cc(-c2nc3c(s2)CCCO3)ccc1OCCCOc1ccc2c(c1)CC[C@H]2CC(=O)OCC
Temperature: 25 °C
Yield: 28.8 %

Procedure:
A solution of ethyl ((1S)-5-{3-[4-(aminocarbonothioyl)-2-propylphenoxy]propoxy}-2,3-dihydro-1H-inden-1-yl)acetate (0.5 g, 1.1 mmol) (Example 144) and 3-bromotetrahydro-2H-pyran-2-one (1.2 g, 6.6 mmol) (Example 151) in EtOH (anhydrous, 15 mL) was heated at 70° C. for 18 h. The reaction mixture was cooled to rt, and concentrated under reduced pressure. Purification by silica gel flash chromatography (EtOAc/hexane (v/v)=1:2) gave 0.17 g (29%) of the title compound as a light yellow oil. LC-MS: RT=4.52 min, (M+H)+:536.4.
Reaction SMILES: Br[C:2]1[C:14](=[O:15])[N:13]([CH:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[C:5]2[N:6]=[C:7]([NH:11][CH3:12])[N:8]=[C:9]([CH3:10])[C:4]=2[CH:3]=1.[C:21]([O:25][CH2:26][CH3:27])(=[O:24])[CH:22]=[CH2:23].C1(N(C)C2CCCCC2)CCCCC1.F[B-](F)(F)F.C([PH+](C(C)(C)C)C(C)(C)C)(C)(C)C.[Cl-].[Li+]>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].O1CCOCC1>[CH:16]1([N:13]2[C:5]3[N:6]=[C:7]([NH:11][CH3:12])[N:8]=[C:9]([CH3:10])[C:4]=3[CH:3]=[C:2](/[CH:23]=[CH:22]/[C:21]([O:25][CH2:26][CH3:27])=[O:24])[C:14]2=[O:15])[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: C=CC(=O)OCC
Reactant: CNc1nc(C)c2cc(Br)c(=O)n(C3CCCC3)c2n1
Agent: [Pd]
Agent: CC(C)(C)[PH+](C(C)(C)C)C(C)(C)C
Agent: CN(C1CCCCC1)C1CCCCC1
Solvent: C1COCCO1
Product: CCOC(=O)/C=C/c1cc2c(C)nc(NC)nc2n(C2CCCC2)c1=O
Temperature: 75 °C
Yield: 90 %

Procedure:
6-bromo-8-cyclopentyl-4-methyl-2-(methylamino)pyrido[2,3-d]pyrimidin-7(8H)-one (375 mg, 1.1 mmole), ethyl acrylate (442 mg, 4.42 mmole), N-cyclohexyl-N-methylcyclohexanamine (280 mg, 1.43 mmole), tri-tert-butylphosphonium tetrafluoroborate (9.61 mg, 0.03 mmole), lithium chloride (42.4 mg, 3.3 mmole), tris(dibenzylideneacetone)dipalladium(0)) (30.3 mg, 0.03 mmole) and 1,4-dioxane (10 ml) were added to a reaction vial equipped with a stir bar. The reaction vial was flushed with nitrogen, capped, and heated at 75° C. for 75 min. The reaction mixture was cooled to ambient temperature, filtered through Celite™, and washed with ethyl acetate. The filtrate and washing were combined, and the volatiles were removed under reduced pressure to a yellow solid residue. This solid residue was crystallized from boiling heptane:ethyl acetate (50 ml: 50 ml). Upon cooling to ambient temperature, needle-liked yellow crystals formed and collected by filtration to give the title compound as a beta-trans isomer (356 mg, 90% yield).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14](Br)[CH:15]=2)[CH:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:18]1(B(O)O)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>O.C(O)C.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>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:15]=2)[CH:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1ccc2ccn(Cc3ccccc3)c2c1
Reactant: OB(O)c1ccccc1
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: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: c1ccc(Cn2ccc3ccc(-c4ccccc4)cc32)cc1
Yield: 58.4 %

Procedure:
1-Benzyl-6-phenyl-1H-indole was prepared by coupling 1-benzyl-6-bromo-1H-indole (3.48 g , 12.2 mmol), and phenylboronic acid (1.63 g, 13.4 mmol), using tetrakis(triphenylphosphine)palladium (0.976 g, 0.846 mmol), and sodium carbonate (5.2 g, 49 mmol) in water (25 mL), ethanol (5 mL), and toluene (55 mL), according to the procedure described in Step 2 of Example 2. Purification by flash chromatography using 0-2.5% ethyl acetate in hexane as an eluant afforded the title compound as a light green solid (2.02 g, 58%), mp: 109-110° C. Mass spectrum (+ES, [M+H]+) m/z 284; 1HNMR (500 MHz, DMSO-d6): δ 7.75 (s, 1H), 7.6-7.65 (m, 3H), 7.55 (d, 1H, J=3.1 Hz), 7.45 (t, 2H, J=7.5 Hz), 7.3-7.35 (m, 4H), 7.2-7.25 (m, 3H), 6.5 (d, 1H, J=3.0 Hz), and 5.5 ppm (s, 2H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:17][CH3:18])=[C:9]([O:12][CH2:13][CH2:14][CH2:15][Cl:16])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[NH2:19][C:20]1[C:25]([Cl:26])=[CH:24][N:23]=[C:22]2[O:27][CH2:28][O:29][C:21]=12>>[Cl:16][CH2:15][CH2:14][CH2:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:17][CH3:18])[N:5]=[CH:4][N:3]=[C:2]2[NH:19][C:20]1[C:25]([Cl:26])=[CH:24][N:23]=[C:22]2[O:27][CH2:28][O:29][C:21]=12
Reactant: Nc1c(Cl)cnc2c1OCO2
Reactant: COc1cc2ncnc(Cl)c2cc1OCCCCl
Product: COc1cc2ncnc(Nc3c(Cl)cnc4c3OCO4)c2cc1OCCCCl
Yield: 58 %

Procedure:
Using an analogous procedure to that described in Example 1, 4-chloro-6-(3-chloropropoxy)-7-methoxyquinazoline was reacted with 4-amino-5-chloro-2,3-methylenedioxypyridine to give the title compound in 58% yield; NMR Spectrum: (CDCl3) 2.4 (m, 2H), 3.8 (t, 2H), 4.05 (s, 3H), 4.35 (t, 2H), 6.15 (s, 2H), 7.05 (s, 1H), 7.2 (s, 1H), 7.3 (s, 1H), 7.75 (s, 1H), 8.7 (s, 1H); Mass Spectrum: M+H+ 423 and 425.
Reaction SMILES: [N:1]([CH:4]([C:8]1[CH:12]=[CH:11][S:10][CH:9]=1)[C:5]([OH:7])=[O:6])=[N+]=[N-].Cl>[Pd].C(O)C>[NH2:1][CH:4]([C:8]1[CH:12]=[CH:11][S:10][CH:9]=1)[C:5]([OH:7])=[O:6]
Reactant: [N-]=[N+]=NC(C(=O)O)c1ccsc1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: NC(C(=O)O)c1ccsc1
Reaction time: 2 h

Procedure:
0.3 g. of palladium/barium sulfate catalyst are added to a solution of 6 g. of DL-α-azido-3-thiopheneacetic acid in 40 ml. of ethanol and 40 ml. of 0.5N hydrochloric acid. Hydrogenation takes place at about 60 psig. after 2 hours. After filtration, the volume is concentrated to about 30 ml. When the pH is brought to 6.5 with ammonia, the amino acid separates as a white powder. After washing with ethanol/water and drying, 3.5 g. of the product, DL-α-amino-3-thiopheneacetic acid, are obtained; m.p. 283°-285°.
Reaction SMILES: [CH2:1]([CH:5]1[CH2:13][C:12]2[C:7](=[C:8](Cl)[CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:15])[CH2:2][CH2:3][CH3:4].[C:16]1(B(O)O)[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[Na+].[Na+].O>C(O)CO.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:1]([CH:5]1[CH2:13][C:12]2[C:7](=[C:8]([C:24]3[C:25]4[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=4)[CH:21]=[CH:22][CH:23]=3)[CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:15])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC1Cc2cccc(Cl)c2C1=O
Reactant: OB(O)c1cccc2ccccc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: OCCO
Product: CCCCC1Cc2cccc(-c3cccc4ccccc34)c2C1=O
Temperature: 125 °C
Reaction time: 5 h
Yield: 86.2 %

Procedure:
Using a method similar to Example 16 d), 10.02 g (0.045 mol) of 2-butyl-7-chloro-1-indanone, 10.06 g (0.0585 mol) of 1-naphthylboronic acid and 11.9 g (0.122 mol) of sodium carbonate were placed in 135 ml of ethylene glycol/27 ml of water in the reaction vessel, the mixture was degassed a number of times and saturated with argon. After addition of 5 mg (0.022 mmol) of palladium acetate and 0.051 g (0.09 mmol) of TMSPP, the reaction mixture was stirred for 5 hours at 125° C. After addition of 120 ml of water, the aqueous phase was extracted 4 times with 100 ml each time of ether, the combined ether phases were washed with 50 ml of water and 50 ml of saturated sodium chloride solution and dried over magnesium sulfate. Removal of the solvent gave 12.2 g of (34) as an oil.
Reaction SMILES: [C:1]([N:3]=[C:4]([C:7]1[CH:11]=[CH:10][S:9][CH:8]=1)OC)#[N:2].[C:12]1([CH2:18][CH2:19][NH2:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CO>[C:1]([NH:3][C:4]([C:7]1[CH:11]=[CH:10][S:9][CH:8]=1)=[N:20][CH2:19][CH2:18][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)#[N:2]
Reactant: COC(=NC#N)c1ccsc1
Reactant: NCCc1ccccc1
Solvent: CO
Product: N#CNC(=NCCc1ccccc1)c1ccsc1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 94.5 %

Procedure:
Methyl N-cyano-3-thiophenecarboximidate (0.33 g, 2.0 mmol) was dissolved in methanol (2 ml), and 2-phenylethylamine (0.27 g, 2.2 mmol) was added. The mixture was stirred at room temperature for 40 minutes. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue thus obtained was crystallized from diethyl ether to give the title compound (0.48 g, 1.89 mmol, yield: 95%) as colorless crystals.