Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:8][CH2:9][CH3:10])(=[O:7])[CH2:2][CH2:3][C:4]([CH3:6])=[O:5].[CH2:11](O)[CH2:12][OH:13]>C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.C1(C)C=CC=CC=1>[CH3:6][C:4]1([CH2:3][CH2:2][C:1]([O:8][CH2:9][CH3:10])=[O:7])[O:13][CH2:12][CH2:11][O:5]1
Reactant: OCCO
Reactant: CCOC(=O)CCC(C)=O
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)CCC1(C)OCCO1
Yield: 91.5 %

Procedure:
A mixture of ethyl levulinate (58.35 g, 400.0 mmol), ethylene glycol (75.36 g, 1.21 mol), pyridinium p-toluenesulfonate (100 mg) and toluene (200 mL) was heated at reflux under a Dean Stark trap. The trap was emptied every 15 minutes during the reaction until approximately 200 mL of reaction volatiles had been removed. The remaining toluene was removed under reduced pressure, and the resulting oil was partitioned between ethyl acetate (200 mL) and water (50 mL). The organic layer was separated and washed sequentially with water (2×50 mL), saturated aqueous sodium bicarbonate (50 mL), and brine (50 mL); dried over sodium sulfate, filtered, and concentrated under reduced pressure to provide 68.9 g of ethyl 3-(2-methyl-1,3-dioxolan-2-yl)propanoate as a light yellow oil.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:10]([C:11]2[CH:12]=[C:13]([C:17]3[CH2:22][CH2:21][N:20](C(OCC4C=CC=CC=4)=O)[CH2:19][CH:18]=3)[CH:14]=[CH:15][CH:16]=2)[N:9]=[C:8]([C:33]([F:36])([F:35])[F:34])[CH:7]=1.[H][H]>CO.[Pd]>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:10]([C:11]2[CH:12]=[C:13]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[CH:14]=[CH:15][CH:16]=2)[N:9]=[C:8]([C:33]([F:34])([F:35])[F:36])[CH:7]=1
Reactant: O=C(OCc1ccccc1)N1CC=C(c2cccc(-n3nc(C(F)(F)F)cc3-c3ccco3)c2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: FC(F)(F)c1cc(-c2ccco2)n(-c2cccc(C3CCNCC3)c2)n1
Reaction time: 2 h
Yield: 100.1 %

Procedure:
To a stirred solution of 64 (430 mg, 0.871 mmol) in MeOH (4.4 mL) was added palladium on carbon (9.27 mg, 0.087 mmol). Under a balloon of hydrogen the suspension was allowed to stir for 2 h. It was then filtered and filtrate evaporated. The crude was used without any further purification. The title product 65 (315 mg, 100% yield) was isolated as a colorless oil. LRMS (ESI): calc. 361.4; found 362.5 (MH)+.
Reaction SMILES: [C:1]([C:6]1[N:10]2[C:11]([NH2:15])=[CH:12][CH:13]=[CH:14][C:9]2=[N:8][CH:7]=1)(OCC)=[O:2].C[O-].[Na+].CO.Cl>C(#N)C>[NH:15]1[C:11]2[N:10]3[C:9](=[N:8][CH:7]=[C:6]3[C:1]1=[O:2])[CH:14]=[CH:13][CH:12]=2
Reactant: CCOC(=O)c1cnc2cccc(N)n12
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CC#N
Product: O=c1[nH]c2cccc3ncc1n32
Yield: 180 %

Procedure:
To a solution prepared by dissolving 1.44 g (7.0 mM) of 3-carbethoxy-5-aminoimidazo[1,2-a]pyridine in 10 ml of acetonitrile followed by addition of 3.2 ml (14.0 mM) of 25% sodium methoxide-methanol and the mixture was refluxed for 1 hour. After completion of the reaction, 1.15 ml (14.0 mM) of 12N-hydrochloric acid was added to the reaction mixture under ice-cooling and the solvent was thoroughly distilled off under reduced pressure to provide 2.01 g (yield 100%) of a crude product as tan-colored solid.
Reaction SMILES: [CH3:1][N:2]([CH3:13])[C:3]1[CH:12]=[CH:11][C:6]([C:7](OC)=[O:8])=[CH:5][N:4]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>CCOCC>[CH3:1][N:2]([CH3:13])[C:3]1[CH:12]=[CH:11][C:6]([CH2:7][OH:8])=[CH:5][N:4]=1
Reactant: COC(=O)c1ccc(N(C)C)nc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CN(C)c1ccc(CO)cn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of methyl 6-dimethylamino-nicotinate (4.14 g, 23.0 mmol) in anhydrous ether (80 mL) at 0° C. was treated with lithium aluminum hydride (1 M in ether, 20 mL, 20 mmol). The mixture was stirred at rt for 0.5 h, cooled again to 0° C. and quenched slowly with sat. aq. NaHCO3 (10 mL). The resulting mixture was stirred at rt for 0.5 h, filtered, and washed with ether. The combined filtrates were dried over Na2SO4 and concentrated to give the title compound as a beige waxy solid (3.5 g, 100%). MS (EST), (M+H)+ 153.4; 1H NMR (CDCl3) δ 8.06 (d, 1H, J=2.4), 7.47 (dd, 1H, J=2.4, 8.8), 6.45 (d, 1H, J=8.8), 4.50 (s, 2H), 3.06 (s, 6H), 1.98 (br s, 1H).
Reaction SMILES: [CH3:1][C:2]1([CH3:30])[CH:29]2[C:24]([CH2:25][NH:26][CH2:27][CH2:28]2)=[C:5]2[C:6]([OH:23])([OH:22])[CH:7]=[C:8]([CH:10]([CH3:21])[CH2:11][CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[CH:9]=[C:4]2[O:3]1.Cl[CH2:32][CH:33]=[CH:34][C:35]1[CH:40]=[C:39]([O:41][CH3:42])[C:38]([O:43][CH3:44])=[C:37]([O:45][CH3:46])[CH:36]=1>CN(C)C=O>[CH3:30][C:2]1([CH3:1])[CH:29]2[C:24]([CH2:25][N:26]([CH2:32][CH:33]=[CH:34][C:35]3[CH:36]=[C:37]([O:45][CH3:46])[C:38]([O:43][CH3:44])=[C:39]([O:41][CH3:42])[CH:40]=3)[CH2:27][CH2:28]2)=[C:5]2[C:6]([OH:22])([OH:23])[CH:7]=[C:8]([CH:10]([CH3:21])[CH2:11][CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[CH:9]=[C:4]2[O:3]1
Reactant: COc1cc(C=CCCl)cc(OC)c1OC
Reactant: CC(CCCc1ccc(F)cc1)C1=CC(O)(O)C2=C3CNCCC3C(C)(C)OC2=C1
Solvent: CN(C)C=O
Product: COc1cc(C=CCN2CCC3C(=C4C(=CC(C(C)CCCc5ccc(F)cc5)=CC4(O)O)OC3(C)C)C2)cc(OC)c1OC

Procedure:
5,5-Dimethyl-8-(4-p-fluorophenyl-1-methylbutyl)-10-hydroxy-1,2,3,4-tetrahydro-5H[1]benzopyrano[4,3-c]pyridin-10-ol (1 mole) and 1-(3-chloropropenyl)3,4,5-trimethoxybenzene (0.5 mole) were reacted in dimethylformamide as described in Example 7 to give the desired product.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23]([NH:25][CH2:26][C:27]([C:30]#[N:31])([CH3:29])[CH3:28])=[O:24])=[C:18]([F:32])[CH:17]=2)=[O:15])[CH2:10][CH2:9]1)C1C=CC=CC=1>[Pd].C(O)C.Cl>[C:30]([C:27]([CH3:29])([CH3:28])[CH2:26][NH:25][C:23]([NH:22][C:19]1[CH:20]=[CH:21][C:16]([C:14]([N:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[O:15])=[CH:17][C:18]=1[F:32])=[O:24])#[N:31]
Reactant: CC(C)(C#N)CNC(=O)Nc1ccc(C(=O)N2CCN(Cc3ccccc3)CC2)cc1F
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CC(C)(C#N)CNC(=O)Nc1ccc(C(=O)N2CCNCC2)cc1F
Yield: 72.2 %

Procedure:
1-(4-(4-Benzylpiperazine-1-carbonyl)-2-fluorophenyl)-3-(2-cyano-2-methylpropyl)urea (4.12 mmol, 1.802 g) and 10% palladium on carbon (0.824 mmol, 0.877 g) were stirred in ethanol (40 mL) under a hydrogen atmosphere at 5 bar at room temperature overnight with a few drops of 5M hydrochloric acid. The catalyst was filtered off and the filtrate concentrated under reduced pressure to afford the title compound (1.033 g). MS (ESI) m/z 348.3 [M+H]+
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][O:6][CH2:5][CH2:4][NH:3]1.[Br:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][C:10]=1[F:17].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl>ClC(Cl)C>[Br:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13][N:3]2[CH2:4][CH2:5][O:6][CH2:7][C@@H:2]2[CH3:1])=[CH:11][C:10]=1[F:17]
Reactant: C[C@H]1COCCN1
Reactant: O=Cc1ccc(Br)c(F)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: C[C@H]1COCCN1Cc1ccc(Br)c(F)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 88.8 %

Procedure:
(S)-3-Methylmorpholine (119 mg, 0.86 mmol), 4-bromo-3-fluorobenzaldehyde (175 mg, 0.86 mmol) triethylamine (132 μl, 0.95 mmol) and sodium triacetoxyborohydride (274 mg, 1.29 mmol) were dissolved in dichloroethane (2.5 ml). The mixture was stirred at ambient temperature under argon atmosphere for 24 h. Hydrochloric acid (1M) was added until pH 1-2. The mixture was washed with dichloromethane. The aqueous phase was made alkaline with KOH (1M, aq) and extracted with dichloromethane. The combined organic phases were dried over Na2SO4 and concentrated in vacuo to give (S)-4-(4-bromo-3-fluorobenzyl)-3-methylmorpholine (220 mg, 89%).
Reaction SMILES: C([O:4][CH2:5][CH2:6][N:7]1[C:13]2[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:12]=2[C:11]2([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[F:28])[O:19][CH2:20][CH2:21][N:10]2[CH2:9][C:8]1=[O:29])(=O)C.[OH-].[Na+].O>CO>[Cl:18][C:16]1[CH:15]=[CH:14][C:13]2[N:7]([CH2:6][CH2:5][OH:4])[C:8](=[O:29])[CH2:9][N:10]3[CH2:21][CH2:20][O:19][C:11]3([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[F:28])[C:12]=2[CH:17]=1
Reactant: CC(=O)OCCN1C(=O)CN2CCOC2(c2ccccc2F)c2cc(Cl)ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C1CN2CCOC2(c2ccccc2F)c2cc(Cl)ccc2N1CCO
Reaction time: 3 h

Procedure:
A solution of 0.5g (0.0012 M) of 7-(2-acetoxyethyl)-10-chloro-11b-(2-fluorophenyl)-2,3,5,11b-tetrahydrooxazolo[3,2-d][1,4]benzodiazepin-6(7H)-one in 5 ml of methanol was treated with 2 ml of 3N sodium hydroxide. After 3 hours, 50 ml of water was added and the solution was extracted with 40 ml of dichloromethane, which was then dried over anhydrous sodium sulfate and evaporated to dryness. The residue was crystallized from a mixture of methanol and water to give 10-chloro-11b-(2-fluorophenyl)-7-(2-hydroxyethyl)-2,3,5,11b-tetrahydrooxazolo(3,2-d)[1,4]benzodiazepin-6(7H)-one as white prisms, m.p. and m.m.p. 141°-146°.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:36])[NH:4][C@H:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16]1[NH:17][C:18]([C:21]2[CH:26]=[CH:25][C:24]([C:27]3[S:31][C:30]4[CH:32]=[C:33](Br)[S:34][C:29]=4[CH:28]=3)=[CH:23][CH:22]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7].C(OC([N:44]1[C:48]([Sn](CCCC)(CCCC)CCCC)=[CH:47][N:46]=[C:45]1[C@@H:62]1[CH2:66][CH2:65][CH2:64][N:63]1[C:67]([O:69][C:70]([CH3:73])([CH3:72])[CH3:71])=[O:68])=O)(C)(C)C>C1(C)C=CC=CC=1.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>[C:70]([O:69][C:67]([N:63]1[CH2:64][CH2:65][CH2:66][C@H:62]1[C:45]1[NH:46][C:47]([C:33]2[S:34][C:29]3[CH:28]=[C:27]([C:24]4[CH:25]=[CH:26][C:21]([C:18]5[NH:17][C:16]([C@@H:12]6[CH2:13][CH2:14][CH2:15][N:11]6[C:9](=[O:10])[C@@H:5]([NH:4][C:3]([O:2][CH3:1])=[O:36])[CH:6]([CH3:8])[CH3:7])=[N:20][CH:19]=5)=[CH:22][CH:23]=4)[S:31][C:30]=3[CH:32]=2)=[CH:48][N:44]=1)=[O:68])([CH3:73])([CH3:71])[CH3:72]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc([C@@H]2CCCN2C(=O)OC(C)(C)C)n1C(=O)OC(C)(C)C
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ncc(-c2ccc(-c3cc4sc(Br)cc4s3)cc2)[nH]1)C(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ncc(-c2ccc(-c3cc4sc(-c5cnc([C@@H]6CCCN6C(=O)OC(C)(C)C)[nH]5)cc4s3)cc2)[nH]1)C(C)C
Yield: 43 %

Procedure:
A mixture of compound 62 (0.131 mmol), compound 61 (0.141 mmol), and Pd(PPh3)4 (0.017 mmol) was refluxed in dry toluene under nitrogen overnight. Solvent was removed under reduced pressure. The residue was purified by silica gel chromatography (eluent: DCM to DCM/MeOH 5%) to give compound 63 as an orange solid in 43% yield. MS (ESI, EI+) m/z=744.6 (MH+).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH:26]=[CH:27][N:28]=1)[C:6]([NH:8][C:9]1[S:10][C:11]2[C:17]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[CH:16][CH:15]=[C:14]([O:24][CH3:25])[C:12]=2[N:13]=1)=[O:7].[I-].[Na+].Br[CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34]>CN(C=O)C>[CH2:36]([O:35][C:33](=[O:34])[CH2:32][N:28]1[CH:27]=[CH:26][C:5]([C:6](=[O:7])[NH:8][C:9]2[S:10][C:11]3[C:17]([N:18]4[CH2:19][CH2:20][O:21][CH2:22][CH2:23]4)=[CH:16][CH:15]=[C:14]([O:24][CH3:25])[C:12]=3[N:13]=2)=[CH:4][C:3]1=[O:2])[CH3:37]
Reactant: COc1cc(C(=O)Nc2nc3c(OC)ccc(N4CCOCC4)c3s2)ccn1
Reactant: CCOC(=O)CBr
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1ccc(C(=O)Nc2nc3c(OC)ccc(N4CCOCC4)c3s2)cc1=O

Procedure:
From 2-methoxy-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide with sodium iodide and ethyl bromoacetate in DMF. ES-MS m/e (%): 495 (M+Na+, 25), 473 (M+H+, 100).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1.Cl[C:14]1[N:19]=[C:18]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([N:27]3[CH:31]=[C:30]([CH3:32])[N:29]=[CH:28]3)=[C:23]([O:33][CH3:34])[CH:22]=2)[CH:17]=[C:16]([C:35]([F:38])([F:37])[F:36])[CH:15]=1>>[CH3:34][O:33][C:23]1[CH:22]=[C:21]([NH:20][C:18]2[CH:17]=[C:16]([C:35]([F:37])([F:38])[F:36])[CH:15]=[C:14]([NH:8][C:7]3[CH:9]=[CH:10][C:4]([O:3][C:2]([F:11])([F:12])[F:1])=[CH:5][CH:6]=3)[N:19]=2)[CH:26]=[CH:25][C:24]=1[N:27]1[CH:31]=[C:30]([CH3:32])[N:29]=[CH:28]1
Reactant: COc1cc(Nc2cc(C(F)(F)F)cc(Cl)n2)ccc1-n1cnc(C)c1
Reactant: Nc1ccc(OC(F)(F)F)cc1
Product: COc1cc(Nc2cc(C(F)(F)F)cc(Nc3ccc(OC(F)(F)F)cc3)n2)ccc1-n1cnc(C)c1

Procedure:
Prepared in analogy to example 62 from 4-(trifluoromethoxy)aniline and (6-chloro-4-trifluoromethyl-pyridin-2-yl)-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine. The title compound was obtained as a yellowish solid (Yield=33%). MS ISP (m/e): 524.2 (100) [(M+H)+]. 1H NMR (CDCl3, 300 MHz): δ (ppm)=7.65 (d, 1H), 7.42 (d, 2H), 7.19 (d, 2H), 7.13 (d, 1H), 6.97 (dxd, 1H), 6.89 (s, 1H), 6.65 (s, 1H), 6.58 (s, 1H), 6.48 (s, 1H), 6.42 (s, 1H), 3.74 (s, 3H), 2.31 (s, 3H).
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([C:17]2[CH:18]=[N:19][C:20]3[C:25]([CH:26]=2)=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:9]=1)=[O:7]>O1CCCC1.O>[C:6]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([C:17]2[CH:18]=[N:19][C:20]3[C:25]([CH:26]=2)=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:9]=1)([OH:7])=[O:5]
Reactant: COC(=O)c1cn(-c2cnc3ccccc3c2)c2ccccc12
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cn(-c2cnc3ccccc3c2)c2ccccc12
Reaction time: 18 h
Yield: 150.2 %

Procedure:
0.291 g (6.93 mmol) of lithium hydroxide monohydrate and 30 cm3 of water are added at a temperature in the region of 22° C. to 0.7 g (2.31 mmol) of 3-methoxycarbonyl-1-(quinol-3-yl)-1H-indole dissolved in 30 cm3 of tetrahydrofuran. After stirring at the reflux point of the solvent for 18 hours, the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa) to give a residue which is taken up in 15 cm3 of water and then triturated with 7 cm3 of N hydrochloric acid. After filtering off and drying the solid residue under reduced pressure (2.7 kPa) at 40° C., 1 g of 3-carboxy-1-(quinol-3-yl)-1H-indole is obtained in the form of a pale yellow solid. Mass spectrum (EI): m/e 288 (M+·).
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][C:5]([C:6]([NH:8][CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([N:17]3[C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=4[NH:19][C:18]3=[O:26])[CH2:13][CH2:12]2)=[O:7])=[C:4]([N+:29]([O-])=O)[CH:3]=1.[H][H]>[Ni].CO>[NH2:29][C:4]1[CH:3]=[C:2]([F:1])[CH:28]=[CH:27][C:5]=1[C:6]([NH:8][CH2:9][CH2:10][N:11]1[CH2:12][CH2:13][CH:14]([N:17]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[NH:19][C:18]2=[O:26])[CH2:15][CH2:16]1)=[O:7]
Reactant: O=C(NCCN1CCC(n2c(=O)[nH]c3ccccc32)CC1)c1ccc(F)cc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Ni]
Solvent: CO
Product: Nc1cc(F)ccc1C(=O)NCCN1CCC(n2c(=O)[nH]c3ccccc32)CC1

Procedure:
A mixture of 8.7 parts of 4-fluoro-N-{2-[4-(2,3-dihydro-2-oxo- 1H-benzimidazol-1-yl)-1-piperidinyl] ethyl}-2-nitrobenzamide and 120 parts of methanol is hydrogenated at normal pressure and at room temperature with 2 parts of Raney-nickel catalyst. After the calculated amount of hydrogen is taken up, the catalyst is filtered off and the filtrate is evaporated. The residue is crystallized from a mixture of methanol and 2-propanol. The product is filtered off and dried, yielding 4.5 parts of 2-amino-N-{2-[4-(2,3-dihydro-2-oxo- 1H-benzimidazol-1-yl)-1-piperidinyl] ethyl}-4-fluorobenzamide; mp. 229.3° C.
Reaction SMILES: [CH2:1]([C:15]1[CH:26]=[CH:25][C:18]([O:19][CH2:20][CH:21]([OH:24])[CH2:22][OH:23])=[CH:17][CH:16]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[C:27](Cl)([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.CCOCC>N1C=CC=CC=1>[CH2:1]([C:15]1[CH:26]=[CH:25][C:18]([O:19][CH2:20][CH:21]([OH:24])[CH2:22][O:23][C:27]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)=[CH:17][CH:16]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCCCCCCCCCCCCCc1ccc(OCC(O)CO)cc1
Solvent: CCOCC
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCc1ccc(OCC(O)COC(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reaction time: 72 h

Procedure:
An about 364 mg portion of 3-(4-tetradecylphenoxy)-1,2-propanediol was dissolved in about 1.5 ml of dry pyridine and about 501 mg of tritylchloride was added. The mixture was stirred under argon for about 72 hours, ether was added and the mixture was washed with ice-cold dilute (about 1N) hydrochloric acid, sodium bicarbonate solution, brine, then dried and the solvent evaporated. The residue was recrystallized from ethanol, giving about 700 mg of the desired title compound.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6](/[C:8](=[N:10]/[C:11]2[C:16]([CH:17]([CH3:19])[CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=2[CH:20]([CH3:22])[CH3:21])/[CH3:9])[CH:5]=[CH:4][CH:3]=1.[CH3:23][Al](C)C.[OH-].[K+]>C1(C)C=CC=CC=1>[Br:1][C:2]1[N:7]=[C:6]([C:8]([NH:10][C:11]2[C:16]([CH:17]([CH3:18])[CH3:19])=[CH:15][CH:14]=[CH:13][C:12]=2[CH:20]([CH3:22])[CH3:21])([CH3:23])[CH3:9])[CH:5]=[CH:4][CH:3]=1
Reactant: C/C(=N\c1c(C(C)C)cccc1C(C)C)c1cccc(Br)n1
Reactant: C[Al](C)C
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CC(C)c1cccc(C(C)C)c1NC(C)(C)c1cccc(Br)n1
Temperature: 25 °C

Procedure:
In argon atmosphere, to a solution of 3.61 g (10.0 mmol) of N-[(1E)-1-(6-bromopyridin-2-yl)ethylidene]-2,6-diisopropylaniline in 80 ml of dry toluene cooled to 0° C. a solution of 1.44 g (20.0 mmol) of AlMe3 in 20 ml of dry toluene was added dropwise by vigorous stirring for ten minutes. The resulting mixture was slowly warmed to room temperature, stirred for 25 min at 40° C., cooled to 0° C., and then 80 ml of 5% KOH was added dropwise for 1 h at this temperature. The aqueous layer was separated, the organic layer was washed with 80 ml of water, 80 ml of brine, dried over Na2SO4, and then evaporated to dryness. Yield 3.52 g (94%) of yellowish crystalline solid. Anal. calc. for C20H27BrN2: C, 64.00; H, 7.25, N, 7.46. Found: C, 64.11; H, 7.19; N, 7.40. 1H NMR (CDCl3): δ 7.48-7.54 (m, 2H, 4, 5-H in pyridine), 7.34 (dd, J=6.9 Hz, J=1.6 Hz, 1H, 3-H in pyridine), 7.04-7.08 (m, 3H, 3, 4, 5-H in 2, 6-iPr2C6H3), 3.98 (br.s, 1H, NH), 3.15 (sep, J=6.9 Hz, 2H, CHMe2), 1.44 (s, 6H, Me2C), 7.08 (d, J=6.9 Hz, 12H, CHMe2).
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:36])=[C:7]2[C:12](=[C:13]([C:15]3[CH:16]=[N:17][CH:18]=[C:19]([F:21])[CH:20]=3)[N:14]=1)[N:11]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:10](=[O:29])[C:9]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[CH:8]2)=[O:4].[NH2:37][CH2:38][CH2:39][C:40]([OH:42])=[O:41].C[O-].[Na+]>C([O-])(O)=O.[Na+]>[CH2:22]([N:11]1[C:12]2[C:7](=[C:6]([OH:36])[C:5]([C:3]([NH:37][CH2:38][CH2:39][C:40]([OH:42])=[O:41])=[O:4])=[N:14][C:13]=2[C:15]2[CH:16]=[N:17][CH:18]=[C:19]([F:21])[CH:20]=2)[CH:8]=[C:9]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:10]1=[O:29])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: NCCC(=O)O
Reactant: COC(=O)c1nc(-c2cncc(F)c2)c2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Agent: C[O-]
Agent: O=C([O-])O
Agent: [Na+]
Product: O=C(O)CCNC(=O)c1nc(-c2cncc(F)c2)c2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Temperature: 25 °C
Yield: 38.8 %

Procedure:
A mixture of 1-benzyl-8-(5-fluoro-pyridin-3-yl)-5-hydroxy-2-oxo-3-phenyl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (32 mg, 0.067 mmol), β-alanine (593 mg, 6.7 mmol) and NaOMe solution (10 mL, 5.0 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was partitioned between EtOAc and water. 1 M HCl was added with vigorous stirring until pH was about 3-4. The aqueous layer was extracted with additional EtOAc, and the organic layers were combined, dried over MgSO4 and concentrated. The residue was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH about 3-4 with 6 M HCl, and the resulting precipitate was isolated by filtration. The crude solid was purified by silica gel chromatography (5-80% EtOAc/hexanes+1% AcOH). The product isolated was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH about 3-4 with 6 M HCl, and the resulting precipitate was isolated by filtration to give 14 mg of the title compound as a light yellow solid. MS: (+) m/z 539.29 (M+1).
Reaction SMILES: [OH:1][CH2:2][C:3]1[S:4][C:5]2[CH2:6][N:7]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:9][C:10]=2[N:11]=1.C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>ClCCl>[CH3:26][S:27]([O:1][CH2:2][C:3]1[S:4][C:5]2[CH2:6][N:7]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:9][C:10]=2[N:11]=1)(=[O:29])=[O:28]
Reactant: CC(C)(C)OC(=O)N1CCc2nc(CO)sc2C1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCc2nc(COS(C)(=O)=O)sc2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
To a dichloromethane solution (15 ml) of tert-butyl 2-(hydroxymethyl)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate (1 eq.) was added triethylamine (2.5 eq.) and methane sulfonylchloride (1.2 eq.) at 0° C. and the resulting reaction mixture was stirred at ambient temperature for 2 h. The reaction was quenched with ice and diluted with dichloromethane. The organic layer was successively washed with water and brine and finally dried over sodium sulfate. Evaporation of the organic layer under reduced pressure gave the crude product which was used directly in the next step without further purification. Yield: 80%.
Reaction SMILES: Br[C:2]1[O:6][C:5]([C:7]([N:9]([CH2:12][CH3:13])[CH2:10][CH3:11])=[O:8])=[CH:4][CH:3]=1.[Br:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][CH2:22][C:23]#[CH:24]>>[Br:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][CH2:22][C:23]#[C:24][C:2]1[O:6][C:5]([C:7]([N:9]([CH2:12][CH3:13])[CH2:10][CH3:11])=[O:8])=[CH:4][CH:3]=1
Reactant: CCN(CC)C(=O)c1ccc(Br)o1
Reactant: C#CCOCCCCCCBr
Product: CCN(CC)C(=O)c1ccc(C#CCOCCCCCCBr)o1
Yield: 95.4 %

Procedure:
5-Bromo-N,N-diethyl-2-furancarboxamide (2.0 g) was treated with 3-[(6-bromohexyl)oxy]-1-propyne (1.87 g) according to the method of Intermediate 9 except that the reaction mixture was stirred under nitrogen at 60° for 4h, and hexane-ether (5:1 then 2:1 then 1:1) was used as the eluant for FCC. This afforded the title compound as a dark yellow oil (2.98 g), t.l.c. (diethyl ether) Rf 0.35.
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][CH:6]([CH2:9][NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH2:5][CH2:4]1)#[N:2].[CH:18]([N-]C(C)C)(C)C.[Li+].CI>O1CCCC1>[C:1]([C:3]1([CH3:18])[CH2:4][CH2:5][CH:6]([CH2:9][NH:10][C:11](=[O:17])[O:12][C:13]([CH3:14])([CH3:16])[CH3:15])[CH2:7][CH2:8]1)#[N:2]
Reactant: CC(C)(C)OC(=O)NCC1CCC(C#N)CC1
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: CC1(C#N)CCC(CNC(=O)OC(C)(C)C)CC1
Temperature: 25 °C

Procedure:
To a cooled (−78° C.) solution of tert-butyl (4-cyanocyclohexyl)methylcarbamate (500 mg) in tetrahydrofuran (10 mL) was added lithium diisopropylamide (2.0 mL, 2M in heptane). The mixture was stirred at −78° C. for 30 minutes before the addition of CH3I (1 mL). The mixture was then stirred and the temperature was allowed to warm to room temperature. The reaction was quenched with aqueous NH4Cl and the mixture was extracted with ethyl acetate (300 mL) and washed with water, brine and dried over Na2SO4. Filtration and evaporation of the solvent and silica gel chromatography (40% ethyl acetate in hexane) of the crude material gave the title compound.