Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH2:23][CH3:24])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([CH3:25])[CH:3]=1.[O:26]=[C:27]1[NH:31][C@H:30]([CH2:32][O:33]C(=O)C2C=CC=CC=2)[CH2:29][O:28]1>>[CH2:23]([C:19]1[CH:20]=[C:21]([CH3:22])[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([N:31]4[C@H:30]([CH2:32][OH:33])[CH2:29][O:28][C:27]4=[O:26])=[CH:3][C:4]=3[CH3:25])=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=1)[CH3:24]
Reactant: O=C1N[C@H](COC(=O)c2ccccc2)CO1
Reactant: CCc1cnc(N2CCN(C(=O)c3ccc(Br)cc3C)CC2)c(C)c1
Product: CCc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)OC[C@H]4CO)cc3C)CC2)c(C)c1
Yield: 73.4 %

Procedure:
By reaction and treatment in the same manner as in Example 19 and using (4-bromo-2-methylphenyl)[4-(5-ethyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (350 mg) described in Preparation Example 129 and benzoic acid (R)-2-oxooxazolidin-4-ylmethyl ester (289 mg), the title compound (280 mg) was obtained.
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH2:8][C:7](=[O:9])[O:6][C:4]1=[O:5].[Cl:10][C:11]1[CH:12]=[C:13]([CH:15]=[C:16]([Cl:18])[CH:17]=1)[NH2:14]>C1(C)C(C)=CC=CC=1>[Cl:10][C:11]1[CH:12]=[C:13]([N:14]=[C:4]([OH:5])[CH:3]([O:2][CH3:1])[CH2:8][C:7]([OH:6])=[O:9])[CH:15]=[C:16]([Cl:18])[CH:17]=1
Reactant: Nc1cc(Cl)cc(Cl)c1
Reactant: COC1CC(=O)OC1=O
Solvent: Cc1ccccc1C
Product: COC(CC(=O)O)C(O)=Nc1cc(Cl)cc(Cl)c1
Yield: 75 %

Procedure:
130 g (1 mole) of 2-methoxysuccinic acid anhydride and 162 g (1 mole) of 3,5-dichloroaniline are heated under reflux for three hours, in 1500 ml of xylene. The resulting water is azeotropically separated off by means of a water separator. The xylene is then distilled off and the crude product is recrystallized from methanol/water. Melting point: 125° to 126° C.; yield: 75% of the theoretical yield.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[S:6][CH:7]=[C:8]([C:10](OCC)=[O:11])[N:9]=1)[CH3:3].[BH4-].[Na+].C(O)(C)C.[ClH:21]>O>[ClH:21].[CH3:3][N:2]([CH2:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10][OH:11])[N:9]=1)[CH3:1]
Reactant: CCOC(=O)c1csc(CN(C)C)n1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: CN(C)Cc1nc(CO)cs1

Procedure:
Alternatively, a mixture of 2.14 g of ethyl 2-dimethylaminomethyl-4-thiazolecarboxylate and 0.38 g of sodium borohydride in 20 ml. of isopropanol was heated with stirring at reflux temperature for about 14 hours. The reaction mixture was cooled, and 2 ml. of water were added carefully followed by 4 ml. of 5N aqueous hydrochloric acid. The volatile constituents were removed by evaporation. Methanol (10 ml.) was added and the mixture heated to refluxing temperature for about one hour. Methanol was removed by evaporation and the residual solids digested in 10 ml. of isopropanol on the steam bath. The isopropanol solution was separated by decantation and the solids reextracted with 10 ml. of isopropanol. The isopropanol solutions and extracts were combined and the combined solution filtered while hot to remove insoluble material. The filtrate was chilled and a crystalline solid appeared which separated and was recovered by filtration. Recrystallization of the filter cake from isopropanol gave 1.73 g of 2-dimethylaminomethyl-4-thiazolemethanol hydrochloride melting at 153°-154° C.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([CH:10]([OH:17])[C:11]2[N:12]([CH3:16])[CH:13]=[N:14][CH:15]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].CC#N>C(Cl)Cl.O=[Mn]=O>[F:1][C:2]1[CH:9]=[C:8]([C:10]([C:11]2[N:12]([CH3:16])[CH:13]=[N:14][CH:15]=2)=[O:17])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: Cn1cncc1C(O)c1ccc(C#N)c(F)c1
Agent: O=[Mn]=O
Solvent: CC#N
Solvent: ClCCl
Product: Cn1cncc1C(=O)c1ccc(C#N)c(F)c1

Procedure:
2-Fluoro-4-[hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-benzonitrile (0.655 g, 2.83 mmol) and MnO2 (1.23 g, 14.2 mmol) were stirred in CH2Cl2 (50 mL) and CH3CN (5 mL) for 3 h. The solution was filtered and concentrated to yield the title compound.
Reaction SMILES: C([O:5][C:6](=[O:30])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([Cl:17])=[CH:14][CH:15]=2)[C:10]([CH:18]2[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[S:20](=[O:28])(=[O:27])[NH:19]2)=[C:9]1[CH3:29])(C)(C)C.[F:31][C:32]1[CH:39]=[CH:38][C:35]([CH2:36]Br)=[CH:34][CH:33]=1>>[Cl:17][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[N:8]([CH2:7][C:6]([OH:5])=[O:30])[C:9]([CH3:29])=[C:10]2[CH:18]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[S:20](=[O:28])(=[O:27])[N:19]1[CH2:36][C:35]1[CH:38]=[CH:39][C:32]([F:31])=[CH:33][CH:34]=1
Reactant: Cc1c(C2NS(=O)(=O)c3ccccc32)c2cc(Cl)ccc2n1CC(=O)OC(C)(C)C
Reactant: Fc1ccc(CBr)cc1
Product: Cc1c(C2c3ccccc3S(=O)(=O)N2Cc2ccc(F)cc2)c2cc(Cl)ccc2n1CC(=O)O

Procedure:
The title compound was prepared by the method described for example 14 using the product from example 6, step c) and 4-fluorobenzyl bromide. 1H NMR (DMSO-d6) 13.2 (bs, 1H), 8.05 (d, J=8.1 Hz, 1H), 7.67 (t, J=7.2 Hz, 1H), 7.62 (dt, J=1.5, 75 Hz, 1H), 7.44 (d, J=8.7 Hz, 1H), 7.19-6.96 (m, 6H), 6.83 (s, 1H), 5.83 (s, 1H), 5.01 (d, J=18.3 Hz, 1H), 5.00 (d, J=18.3 Hz, 1H), 4.50 (d, J=15.6 Hz, 1H), 3.83 (d, J=15.6 Hz, 1H), 2.11 (s, 3H); MS: ESI (negative): 497, 499 (M−H).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([F:12])[C:9]([O:13][CH3:14])=[CH:8][C:7]=2[C:15]2[CH:20]=[CH:19][N:18]=[C:17]3[C:21]([C:33]([OH:35])=O)=[C:22]([CH3:32])[N:23]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:16]=23)[CH2:3][CH2:2]1.[NH2:36][C@H:37]1[CH2:42][CH2:41][C@H:40]([NH:43][C:44](=[O:50])[O:45][C:46]([CH3:49])([CH3:48])[CH3:47])[CH2:39][CH2:38]1>>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([F:12])[C:9]([O:13][CH3:14])=[CH:8][C:7]=2[C:15]2[CH:20]=[CH:19][N:18]=[C:17]3[C:21]([C:33]([NH:36][C@H:37]4[CH2:42][CH2:41][C@H:40]([NH:43][C:44](=[O:50])[O:45][C:46]([CH3:48])([CH3:47])[CH3:49])[CH2:39][CH2:38]4)=[O:35])=[C:22]([CH3:32])[N:23]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:29])[CH3:30])[C:16]=23)[CH2:2][CH2:3]1
Reactant: COc1cc(-c2ccnc3c(C(=O)O)c(C)n(COCC[Si](C)(C)C)c23)c(OCC2CC2)cc1F
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](N)CC1
Product: COc1cc(-c2ccnc3c(C(=O)N[C@H]4CC[C@H](NC(=O)OC(C)(C)C)CC4)c(C)n(COCC[Si](C)(C)C)c23)c(OCC2CC2)cc1F

Procedure:
Starting from 7-[2-(cyclopropylmethoxy)-4-fluoro-5-methoxyphenyl]-2-methyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[3,2-b]pyridine-3-carboxylic acid (example D.c7) and commercially available tert-butyl trans-(4-amino-cyclohexyl)-carbamate the title compound is obtained as pale yellow viscous oil.
Reaction SMILES: [CH:1]12[O:6][CH:5]1[CH2:4][N:3]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2]2.[CH2:14]([NH2:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(O)C>[CH2:14]([NH:21][C@@H:5]1[C@@H:1]([OH:6])[CH2:2][N:3]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:4]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC(C)(C)OC(=O)N1CC2OC2C1
Reactant: NCc1ccccc1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1C[C@H](NCc2ccccc2)[C@@H](O)C1
Yield: 85.2 %

Procedure:
A solution of the epoxide (4.6 g, 24.9 mmol) of step A and benzylamine (5.2 g, 48.6 mmol) in ethanol was stirred at 85° C. overnight. The solvent was removed by concentration under reduced pressure to give a solid. The solid was washed with a mixed solvent of 50% EtOAc/hexanes to provide 6.2 g of the desired compound. MS calculated (M+H)+ 293, found 293.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)[CH:5]=[CH:6][CH:7]=1.Cl[CH2:17][C:18]1[N:19]=[C:20]([C:23]2[S:24][CH:25]=[CH:26][CH:27]=2)[O:21][CH:22]=1>>[N:11]1([CH2:10][CH2:9][CH2:8][C:4]2[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=2)[O:1][CH2:17][C:18]2[N:19]=[C:20]([C:23]3[S:24][CH:25]=[CH:26][CH:27]=3)[O:21][CH:22]=2)[CH:15]=[CH:14][N:13]=[CH:12]1
Reactant: Oc1cccc(CCCn2ccnc2)c1
Reactant: ClCc1coc(-c2cccs2)n1
Product: c1cc(CCCn2ccnc2)cc(OCc2coc(-c3cccs3)n2)c1
Yield: 78 %

Procedure:
In substantially the same manner as in Working Example 72, 1-[3-(3-hydroxyphenyl)propyl]imidazole was allowed to react with 4-chloromethyl-2-(2-thienyl)oxazole to give 4-[3-[3-(1-imidazolyl)propyl]phenoxymethyl]-2-(2-thienyl)oxazole, oily substance. The yield was 78%.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[CH:5]=1)[CH3:2].Br[CH2:12][C:13]([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[O:14].C(=O)([O-])[O-].[K+].[K+].O>CC(C)=O>[CH2:1]([N:3]([CH2:12][C:13]([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[O:14])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[CH:5]=1)[CH3:2]
Reactant: O=C(CBr)OCC(F)(F)F
Reactant: CCNc1cccc(C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CCN(CC(=O)OCC(F)(F)F)c1cccc(C)c1
Yield: 94.5 %

Procedure:
A mixture of 13.5 g (0.1 mole) N-ethyl-m-toluidine, 22.1 g (0.1 mole) trifluoroethyl bromoacetate and 7.0 g (0.051 mole) potassium carbonate in 100 ml of acetone was heated at reflux for two hours. Water (10 ml) was added and the mixture heated at reflux overnight. Solvent was removed on a rotary evaporator, ether added and the layers separated. The aqueous layer was extracted with ether. The combined ether solution was washed once with 50 ml of water and dried over sodium sulfate. Removal of ether gave 26.0 g brown oil which gave one spot by thin layer chromatography and was used as isolated (94%).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[C:4]([NH:20][C:21]1[CH:22]=[N:23][CH:24]=[C:25]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[CH:26]=1)=[C:5]([CH3:19])[C:6]([N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)=[N:7]2.[O:33]1[CH2:38][CH2:37][C:36](=O)[CH2:35][CH2:34]1>>[F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[C:4]([NH:20][C:21]1[CH:22]=[N:23][CH:24]=[C:25]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[CH:26]=1)=[C:5]([CH3:19])[C:6]([N:13]1[CH2:14][CH2:15][N:16]([CH:36]3[CH2:37][CH2:38][O:33][CH2:34][CH2:35]3)[CH2:17][CH2:18]1)=[N:7]2
Reactant: Cc1c(N2CCNCC2)nc2cc(F)cc(F)c2c1Nc1cncc(N2CCOCC2)c1
Reactant: O=C1CCOCC1
Product: Cc1c(N2CCN(C3CCOCC3)CC2)nc2cc(F)cc(F)c2c1Nc1cncc(N2CCOCC2)c1

Procedure:
Essentially prepared according to Procedure L using 5,7-difluoro-3-methyl-N-(5-morpholinopyridin-3-yl)-2-(piperazin-1-yl)quinolin-4-amine (67.0 mg, 0.15 mmol) and dihydro-2H-pyran-4(3H)-one to give 5,7-difluoro-3-methyl-N-(5-morpholinopyridin-3-yl)-2-(4-(tetrahydro-2H-pyran-4-yl)piperazin-1-yl)quinolin-4-amine. 1H NMR (CDCl3) δ ppm 1H NMR 7.93 (1H, d, J=2.5 Hz), 7.69 (1H, d, J=2.2 Hz), 7.30 (1H, ddd, J=10.0, 2.6, 1.3 Hz), 6.87 (1H, d, J=12.7 Hz), 6.79 (1H, ddd, J=13.9, 8.7, 2.4 Hz), 6.58 (1H, t, J=2.3 Hz), 4.07 (2H, dd, J=11.2, 3.9 Hz), 3.80-3.92 (4H, m), 3.46-3.53 (4H, m), 3.41 (2H, td, J=11.7, 1.6 Hz), 3.16 (4H, dd, J=5.7, 3.9 Hz), 2.75-2.93 (4H, m), 2.06 (3H, s), 1.87 (2H, d, J=12.3 Hz), 1.61-1.78 (2H, m). Mass Spectrum (ESI) m/e=525.4 (M+1).
Reaction SMILES: [OH:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][CH:5]([OH:10])[CH2:4][C:3]1([CH3:12])[CH3:11].[CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]=1>>[CH:18]1([O:1][N:2]2[C:7]([CH3:8])([CH3:9])[CH2:6][CH:5]([OH:10])[CH2:4][C:3]2([CH3:12])[CH3:11])[CH2:17][CH2:16][CH2:15][CH:14]=[CH:13]1
Reactant: C1=CCCCC1
Reactant: CC1(C)CC(O)CC(C)(C)N1O
Product: CC1(C)CC(O)CC(C)(C)N1OC1C=CCCC1
Temperature: 70 °C
Yield: 17.5 %

Procedure:
A mixture of 17.05 g (0.10 mol) of 1-oxyl-4-hydroxy-2,2,6,6-tetramethylpiperidine and 100 mL (0.99 mol) of cyclohexene under a nitrogen atmosphere is heated at 70° C. for 72 hours. The reaction mixture is filtered to remove 1,4-dihydroxy-2,2,6,6-tetramethylpiperidine and the filtrate is washed with 5 w/v % ascorbic acid (2×50 mL) and distilled water (2×50 mL). The organic phase is dried over anhydrous sodium sulfate and the volatiles are removed in vacuo. The residue is recrystallized from acetonitrile to give 4.44 g (36% yield) of a white solid melting at 65-66.5° C.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH2:21][C:22]([OH:24])=O.Cl.[C:26]1([C@:32]2([OH:53])[CH2:40][CH2:39][C:38]([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[C@@H:37]3[C@H:33]2[CH2:34][NH:35][CH2:36]3)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(N(CC)CC)C>C(Cl)Cl>[C:26]1([C@:32]2([OH:53])[CH2:40][CH2:39][C:38]([C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=3)([C:47]3[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=3)[C@@H:37]3[C@H:33]2[CH2:34][N:35]([C:22](=[O:24])[CH2:21][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[O:14][CH3:13])[CH2:36]3)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O[C@@]1(c2ccccc2)CCC(c2ccccc2)(c2ccccc2)[C@H]2CNC[C@H]21
Reactant: COc1ccccc1CC(=O)O
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccccc1CC(=O)N1C[C@@H]2[C@H](C1)C(c1ccccc1)(c1ccccc1)CC[C@@]2(O)c1ccccc1
Temperature: 25 °C
Yield: 34.4 %

Procedure:
0.28 g of carbonyldiimidazole is added to a solution of 0.28 g of (2-methoxyphenyl)-acetic acid in 20 cm3 of dry methylene chloride. The mixture is stirred at room temperature for I hour and a suspension of 0.7 g of (3aS,4S,7aS)-4,7,7-triphenyl-perhydroisoindol-4-ol hydrochloride in 20 cm3 of dry methylene chloride and then 0.48 cm3 of triethylamine are subsequently added in succession. The reaction mixture is stirred at room temperature for 24 hours, diluted with 100 cm3 of methylene chloride, washed with 100 cm3 of water (twice) and then with 100 cm3 of an aqueous saturated solution of sodium chloride, dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed over a Merck silica gel column (particle size 0.04-0.06 mm, diameter 2 cm, height 16 cm) by eluting under a pressure of 0.5 bar of nitrogen with a mixture of cyclohexane and ethyl acetate (55/45 by volume) and collecting fractions of 20 cm3. Fractions 7 to 8 are combined and then concentrated to dryness under reduced pressure (2.7 kPa). The residue is crystallised in 16 cm3 of acetonitrile. The crystals are filtered off and dried. 0.3 g of (3aS,4S,7aS)-4,7,7-triphenyl-2-[(2-methoxyphenyl)-acetyl]-perhydroisoindol-4-ol is obtained in the form of white crystals which melt at 236° C.
Reaction SMILES: [CH2:1]([C:4]1[C:13]2[O:12][C:11]([C:14]3[N:18]([CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[N:17]=[N:16][N:15]=3)=[CH:10][C:9](=[O:26])[C:8]=2[C:7]([O:27][CH2:28][CH2:29][CH:30]([CH3:32])[CH3:31])=[CH:6][CH:5]=1)[CH:2]=[CH2:3]>[Pd].C(O)C>[CH3:31][CH:30]([CH3:32])[CH2:29][CH2:28][O:27][C:7]1[C:8]2[C:9](=[O:26])[CH:10]=[C:11]([C:14]3[N:18]([CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[N:17]=[N:16][N:15]=3)[O:12][C:13]=2[C:4]([CH2:1][CH2:2][CH3:3])=[CH:5][CH:6]=1
Reactant: C=CCc1ccc(OCCC(C)C)c2c(=O)cc(-c3nnnn3Cc3ccccc3)oc12
Agent: [Pd]
Solvent: CCO
Product: CCCc1ccc(OCCC(C)C)c2c(=O)cc(-c3nnnn3Cc3ccccc3)oc12
Reaction time: 20 h

Procedure:
A solution of 5.34 parts of 5-[8-allyl-5-(3-methyl-n-butoxy)-4-oxo-4H-1-benzopyran-2-yl]-N-benzyltetrazole in 1000 parts of ethanol was hydrogenated at room temperature and pressure for 20 hours using 0.14 parts of 5% palladium on charcoal as catalyst. The reaction mixture was filtered and the solvent removed by evaporation. Crystallisation of the residue from chloroform/light petroleum (40:60) gave 1.89 parts of 5-[5-(3-methyl-n-butoxy)-8-n-propyl-4-oxo-4H-1-benzopyran-2-yl]-N-benzyltetrazole, m.p. 87°-87.5° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:13][OH:14])[CH:7]=[C:8]([CH:12]=1)[C:9]([OH:11])=[O:10])([O-])=O.[H][H]>O1CCOCC1.O.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([CH2:13][OH:14])[CH:7]=[C:8]([CH:12]=1)[C:9]([OH:11])=[O:10]
Reactant: O=C(O)c1cc(CO)cc([N+](=O)[O-])c1
Reactant: [H][H]
Agent: [Pd]
Solvent: O
Solvent: C1COCCO1
Product: Nc1cc(CO)cc(C(=O)O)c1
Yield: 121.4 %

Procedure:
5-Nitro-3-hydroxymethyl benzoic acid (39.6 g, 0.20 mol) was suspended in a mixture of dioxane (25 ml) and water (50 ml). Palladium on carbon (5%) was added and the mixture was hydrogenated in a Parr apparatus until the stoichiometric amount of hydrogen had been consumed. The catalyst was filtered off and the filtrate passed into concentrated hydrochloric acid (12M, 17 ml). The filtrate was evaporated to dryness to give 40.6 g of a crystalline product. Yield is almost quantitative. The product was used without further purification.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:22]=[CH:21][C:9]3[C:10]4[N:11]=[C:12]([C:18](O)=[O:19])[S:13][C:14]=4[CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:3]=[N:2]1.[NH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][C@H:24]1[CH2:29][OH:30]>>[OH:30][CH2:29][C@H:24]1[CH2:25][CH2:26][CH2:27][CH2:28][N:23]1[C:18]([C:12]1[S:13][C:14]2[CH2:15][CH2:16][O:17][C:8]3[CH:7]=[C:6]([C:4]4[CH:3]=[N:2][NH:1][CH:5]=4)[CH:22]=[CH:21][C:9]=3[C:10]=2[N:11]=1)=[O:19]
Reactant: OC[C@@H]1CCCCN1
Reactant: O=C(O)c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2
Product: O=C(c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2)N1CCCC[C@@H]1CO

Procedure:
Following the procedure for 103, 8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid (50.0 mg, 0.2 mmol) was reacted with (S)-piperidin-2-ylmethanol (1.2 equiv) to give 162 (12.1 mg, M+1 411.1)
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:14][CH2:13][CH2:12][C@H:11]2[CH2:15][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:9])=[C:4]([F:21])[CH:3]=1.[N:22]1[CH:27]=[C:26](B(O)O)[CH:25]=[N:24][CH:23]=1>>[F:21][C:4]1[CH:3]=[C:2]([C:26]2[CH:27]=[N:22][CH:23]=[N:24][CH:25]=2)[CH:7]=[CH:6][C:5]=1[C:8]([N:10]1[CH2:14][CH2:13][CH2:12][C@H:11]1[CH2:15][N:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1)=[O:9]
Reactant: OB(O)c1cncnc1
Reactant: O=C(c1ccc(Br)cc1F)N1CCC[C@H]1CN1CCCC1
Product: O=C(c1ccc(-c2cncnc2)cc1F)N1CCC[C@H]1CN1CCCC1

Procedure:
The title compound is prepared in a manner substantially analogous to Procedure SS starting from (4-bromo-2-fluoro-phenyl)-(2-(S)-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone and 5-Pyrimidine boronic acid. MS (M+H) 355.2
Reaction SMILES: [N:1]([CH2:4][C@H:5]1[C@@H:8]([NH:9][C:10](=[O:19])[CH2:11][O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:7](=[O:20])[NH:6]1)=[N+]=[N-].S([O-])([O-])(=O)=O.[Mg+2].[C:27]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)(=[O:30])[CH:28]=O>[Pd].C(O)C.C(Cl)Cl>[CH2:32]([O:31][C:27](=[O:30])[CH:28]=[N:1][CH2:4][C@H:5]1[C@@H:8]([NH:9][C:10](=[O:19])[CH2:11][O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:7](=[O:20])[NH:6]1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: O=CC(=O)OCc1ccccc1
Reactant: [N-]=[N+]=NC[C@@H]1NC(=O)[C@@H]1NC(=O)COc1ccccc1
Agent: [Pd]
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCl
Solvent: CCO
Product: O=C(COc1ccccc1)N[C@H]1C(=O)N[C@H]1CN=CC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A suspension of 0.499 g (1.81 mmole) of cis-2-azidomethyl-4-oxo-3-phenoxyacetylaminoazetidine and 0.189 g of 10% palladium on carbon in 25 ml of absolute ethanol was hydrogenated at atmospheric pressure and at 40° for 1 hour. The solution was filtered through celite and the solvent was removed in vacuo to afford a colorless gum which was dissolved in 15 ml of methylene dichloride. Anhydrous magnesium sulfate was added followed by addition of a solution of 0.314 g (1.91 mmole) of benzyl glyoxalate in 10 ml of methylene dichloride. The reaction mixture was stirred at room temperature under argon for 2.5 hours then was allowed to stand at 0° overnight. After filtering the reaction mixture, the solvents were removed in vacuo to give a semi-crystalline residue which was recrystallized from ethyl acetate-hexane to give N-(cis-4-oxo-3-phenoxyacetylamino-2-azetidinylmethyl)iminoacetic acid benzyl ester as a colorless solid.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[C:5]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][N:10]=2)[N:4]=[C:3]1[O:15][CH:16]1[CH2:21][CH2:20][N:19]([C:22]2[CH:41]=[CH:40][C:25]([CH2:26][N:27]3[CH2:32][CH2:31][N:30](C(OC(C)(C)C)=O)[CH2:29][CH2:28]3)=[CH:24][CH:23]=2)[CH2:18][CH2:17]1.FC(F)(F)C(O)=O>ClCCl>[CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[C:5]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][N:10]=2)[N:4]=[C:3]1[O:15][CH:16]1[CH2:21][CH2:20][N:19]([C:22]2[CH:23]=[CH:24][C:25]([CH2:26][N:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)=[CH:40][CH:41]=2)[CH2:18][CH2:17]1
Reactant: Cn1c(OC2CCN(c3ccc(CN4CCN(C(=O)OC(C)(C)C)CC4)cc3)CC2)nc(-c2ccncn2)cc1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1c(OC2CCN(c3ccc(CN4CCNCC4)cc3)CC2)nc(-c2ccncn2)cc1=O
Reaction time: 8 h
Yield: 67.5 %

Procedure:
To a solution of tert-butyl 4-{4-[4-(1-methyl-6-oxo-1,6-dihydro-[4,4′]bipyrimidinyl-2-yloxy)piperidin-1-yl]benzyl}piperazine-1-carboxylate (470 mg, 0.83 mmol) in dichloromethane (4.2 ml) was added trifluoroacetic acid (3.9 g, 34 mmol) at room temperature. The mixture was stirred overnight. After concentration under reduced pressure, the residue was dissolved into water. The aqueous solution was washed with ethyl acetate and basified with potassium carbonate. Extraction with chloroform was performed three times and the organic layer was dried over sodium sulfate, concentrated in vacuo to afford 1-methyl-2-[1-(4-piperazin-1-ylmethyl-phenyl)piperidin-4-yloxy]-1H-[4,4′]bipyrimidinyl-6-one as a pale yellow solid (260 mg, 0.56 mmol, 67%).
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][C:9]([F:12])([F:11])[F:10])=[CH:6][CH:5]=[CH:4][C:3]=1[C:13]1[CH2:14][CH2:15][N:16]([CH2:19][CH2:20][CH3:21])[CH2:17][CH:18]=1.Cl>[Pd]>[F:1][C:2]1[C:7]([O:8][C:9]([F:10])([F:11])[F:12])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:13]1[CH2:14][CH2:15][N:16]([CH2:19][CH2:20][CH3:21])[CH2:17][CH2:18]1
Reactant: CCCN1CC=C(c2cccc(OC(F)(F)F)c2F)CC1
Agent: [Pd]
Agent: Cl
Product: CCCN1CCC(c2cccc(OC(F)(F)F)c2F)CC1

Procedure:
Preparation according to preparation 18: 4-[2-fluoro-3-(trifluoromethoxy)phenyl]-1-propyl-1,2,3,6-tetrahydro-pyridine (0.55 g, 1.8 mmol), palladium on carbon (0.09 g) and hydrochloric acid (0.5 ml, cone). Yield: 0.22 g (40%). The amine was converted to the hydrochloric acid salt and recrystallized from ethanol/diethyl ether: M.p. 221-222° C. MS m/z (relative intensity, 70 eV) 305 (M+, 3), 277 (14), 276 (bp), 233 (6) 193 (8).
Reaction SMILES: Cl.[OH:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[N:8][C:9]([C:12]2[N:13]([CH3:20])[C:14]([N+:17]([O-:19])=[O:18])=[CH:15][N:16]=2)=[N:10][CH:11]=1.[C:21](OC(=O)C)(=[O:23])[CH3:22]>O>[C:21]([O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[N:10][C:9]([C:12]2[N:13]([CH3:20])[C:14]([N+:17]([O-:19])=[O:18])=[CH:15][N:16]=2)=[N:8][CH:7]=1)(=[O:23])[CH3:22]
Reactant: CC(=O)OC(C)=O
Reactant: Cn1c([N+](=O)[O-])cnc1-c1ncc(OCCO)cn1
Agent: Cl
Solvent: O
Product: CC(=O)OCCOc1cnc(-c2ncc([N+](=O)[O-])n2C)nc1

Procedure:
0.29 g. (1 millimole) of 5-(2-hydroxyethoxy)-2-(5-nitro-1-methyl-2-imidazolyl)-pyrimidine hydrochloride is heated in 3 ml. of acetic anhydride to 100° C. for 1 hour. After cooling, the reaction mixture is introduced into water and the product is filtered off; m.p. 148°-150° C.
Reaction SMILES: [C:1]([C:3]1[NH:7][C:6]([CH2:8][CH2:9][CH3:10])=[N:5][C:4]=1[N:11]1[C:15]([Cl:16])=[CH:14][CH:13]=[C:12]1[Cl:17])#[N:2].C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:25]2[C:29]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[C:36]3[CH:41]=[CH:40][C:39]([CH2:42]Br)=[CH:38][CH:37]=3)=[N:28][N:27]=[N:26]2)C=CC=CC=1>>[C:1]([C:3]1[N:7]([CH2:42][C:39]2[CH:40]=[CH:41][C:36]([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=3[C:29]3[NH:25][N:26]=[N:27][N:28]=3)=[CH:37][CH:38]=2)[C:6]([CH2:8][CH2:9][CH3:10])=[N:5][C:4]=1[N:11]1[C:15]([Cl:16])=[CH:14][CH:13]=[C:12]1[Cl:17])#[N:2]
Reactant: BrCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CCCc1nc(-n2c(Cl)ccc2Cl)c(C#N)[nH]1
Product: CCCc1nc(-n2c(Cl)ccc2Cl)c(C#N)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1

Procedure:
Using the procedure from Example 13, 5-cyano-4-(2,5-dichloro-1H-pyrrol-1-yl)-2-propylimidazole (Example 30) and N-triphenylmethyl-5-[4'-(bromomethyl)biphenyl-2-yl]tetrazole (Example 12) are reacted and deprotected to give the title compound.