Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C(C2C=CC=CC=2)[N:8]2[CH2:11][CH:10]([N:12]3[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]3)[CH2:9]2)C=CC=CC=1>[OH-].[Pd+2].[OH-].[C].CO>[NH:8]1[CH2:11][CH:10]([N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)[CH2:9]1
Reactant: CN1CCN(C2CN(C(c3ccccc3)c3ccccc3)C2)CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CN1CCN(C2CNC2)CC1

Procedure:
To a mixed solution of 1-(1-(diphenylmethyl)azetidin-3-yl)-4-methylpiperazine (1.21 g, 3.75 mmol) described in Production Example 3-1 and methanol (20 mL) was added palladium hydroxide-carbon (500 mg) at room temperature. The resultant mixture was stirred under a hydrogen atmosphere at room temperature and at 0.35 MPa to 0.40 MPa for 4 hours and 45 minutes. The reaction mixture was purged with a nitrogen atmosphere, and then filtrated using Celite. A filtrate was concentrated under a reduced pressure to give the title compound in the form of a mixture (1.00 g) with benzylbenzene. The product was used in the subsequent reaction without further purification.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5](Cl)=[O:6].[N+:14]([C:17]1[CH:18]=[CH:19][C:20]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[N:21][CH:22]=1)([O-:16])=[O:15].C(N(C(C)C)CC)(C)C>ClCCl>[N+:14]([C:17]1[CH:18]=[CH:19][C:20]([N:23]2[CH2:24][CH2:25][N:26]([C:5]([C:4]3[CH:8]=[CH:9][CH:10]=[CH:11][C:3]=3[C:2]([F:13])([F:12])[F:1])=[O:6])[CH2:27][CH2:28]2)=[N:21][CH:22]=1)([O-:16])=[O:15]
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)nc1
Reactant: O=C(Cl)c1ccccc1C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(c1ccccc1C(F)(F)F)N1CCN(c2ccc([N+](=O)[O-])cn2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 40.8 %

Procedure:
2-(Trifluoromethyl)benzoyl chloride (2.0 mL, 11.0 mmol) was added slowly to a solution of 1-(5-nitropyridin-2-yl)piperazine (2.0 g, 10 mmol) and diisopropylethylamine (3.5 mL, 20 mmol) in dichloromethane (15 mL) at 0° C. under argon. The mixture was then stirred at 25° C. for 2 h. The reaction was quenched with H2O. The aqueous phase was extracted with ethyl acetate. The organic phase was washed with saturated NaCl and dried over anhydrous MgSO4. The organic phase was concentrated and then purified by column chromatography to yield [4-(5-nitropyridin-2-yl)piperazin-1-yl]-(2-trifluoromethylphenyl)methanone as a yellow solid (1.55 g, 41% yield). MS (ES+) m/z 381.1 (M+1).
Reaction SMILES: CS(O[CH:6]1[CH2:14][CH2:13][C:12]2[N:8]([C:9]3[N:28]=[CH:27][N:26]=[C:25]([NH2:29])[C:10]=3[C:11]=2[C:15]2[CH:16]=[N:17][C:18]3[C:23]([CH:24]=2)=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:7]1)(=O)=O.[CH3:30][NH2:31]>CO>[CH3:30][NH:31][CH:6]1[CH2:14][CH2:13][C:12]2[N:8]([C:9]3[N:28]=[CH:27][N:26]=[C:25]([NH2:29])[C:10]=3[C:11]=2[C:15]2[CH:16]=[N:17][C:18]3[C:23]([CH:24]=2)=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:7]1
Reactant: CN
Reactant: CS(=O)(=O)OC1CCc2c(-c3cnc4ccccc4c3)c3c(N)ncnc3n2C1
Solvent: CO
Product: CNC1CCc2c(-c3cnc4ccccc4c3)c3c(N)ncnc3n2C1
Temperature: 80 °C
Reaction time: 22 h

Procedure:
4-Amino-5-(quinolin-3-yl)-6,7,8,9-tetrahydropyrimido[5,4-b]indolizin-8-yl methanesulfonate (30 mg) obtained in Step 9 of Example 1 was dissolved in a solution of methylamine in 40% methanol (1 ml). The solution was stirred at 60° C. for 1 hour and at 80° C. for 22 hours. After cooling, the reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (developing solvent: ethyl acetate/methanol) to obtain the title compound as a light-yellow, oily substance (8.1 mg).
Reaction SMILES: [CH2:1]([N:3]([CH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)[C:4]1[C:5]([CH3:13])=[C:6]([C:10]([OH:12])=O)[CH:7]=[N:8][CH:9]=1)[CH3:2].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:53][CH2:54][C:55]1[C:56](=[O:63])[NH:57][C:58]([CH3:62])=[CH:59][C:60]=1[CH3:61]>CN(C=O)C.O>[CH3:61][C:60]1[CH:59]=[C:58]([CH3:62])[NH:57][C:56](=[O:63])[C:55]=1[CH2:54][NH:53][C:10]([C:6]1[CH:7]=[N:8][CH:9]=[C:4]([N:3]([CH2:1][CH3:2])[CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]=1[CH3:13])=[O:12]
Reactant: CCN(c1cncc(C(=O)O)c1C)C1CCOCC1
Reactant: Cc1cc(C)c(CN)c(=O)[nH]1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCN(c1cncc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCOCC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 5-[ethyl(oxan-4-yl)amino]-4-methylpyridine-3-carboxylic acid (300 mg, 1.13 mmol) in DMF (10 ml) was added DIPEA (395 μl, 2.27 mmol) and HATU (518 mg, 1.36 mmol). The reaction was stirred at room temperature for 5 min after which time 3-(aminomethyl)-4,6-dimethyl-1,2-dihydropyridin-2-one (89%, 214 mg, 1.25 mmol) was added and the reaction was stirred at room temperature for 18 h. The reaction mixture was then poured onto 500 ml of water and the product was extracted into EtOAc (3×200 ml), the combined organic phase was washed with brine (2×100 ml), dried (Na2SO4) and evaporated. The crude product was then purified using preparative-HPLC and the resulting solid was triturated with diethyl ether and isolated by filtration to afford the title compound as an off white solid (115 mg, 25%). LC-MS 100%, m/z=399.2, 1H NMR (500 MHz, Acetone) δ 10.97 (s, 1H), 8.32 (s, 1H), 8.22 (s, 1H), 7.73 (s, 1H), 5.92 (s, 1H), 4.41 (d, J=5.3 Hz, 2H), 3.85 (dd, J=11.3, 3.0 Hz, 2H), 3.28 (td, J=11.7, 1.9 Hz, 2H), 3.15 (q, J=7.1 Hz, 2H), 3.09 (ddd, J=11.1, 7.2, 3.9 Hz, 1H), 2.32 (d, J=1.5 Hz, 6H), 2.23 (s, 3H), 1.69 (dd, J=12.6, 1.7 Hz, 2H), 1.55 (ddd, J=24.3, 12.2, 4.4 Hz, 2H), 0.85 (t, J=7.1 Hz, 3H).
Reaction SMILES: C([O:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:23]3[C:22](=[O:24])[NH:21][C:20]([CH3:25])=[N:19][C:18]=3[N:17]=[C:16]([S:26][CH2:27][C:28]3[N:29]=[C:30]([C:33]4[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=4)[O:31][CH:32]=3)[C:15]=2[C:40]#[N:41])=[CH:10][CH:9]=1)(=O)C.[OH-].[Li+].Cl>O1CCOCC1.O.O>[Cl:39][C:36]1[CH:37]=[CH:38][C:33]([C:30]2[O:31][CH:32]=[C:28]([CH2:27][S:26][C:16]3[C:15]([C:40]#[N:41])=[C:14]([C:11]4[CH:12]=[CH:13][C:8]([O:7][CH2:6][CH2:5][OH:4])=[CH:9][CH:10]=4)[C:23]4[C:22](=[O:24])[NH:21][C:20]([CH3:25])=[N:19][C:18]=4[N:17]=3)[N:29]=2)=[CH:34][CH:35]=1
Reactant: CC(=O)OCCOc1ccc(-c2c(C#N)c(SCc3coc(-c4ccc(Cl)cc4)n3)nc3nc(C)[nH]c(=O)c23)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: Cc1nc2nc(SCc3coc(-c4ccc(Cl)cc4)n3)c(C#N)c(-c3ccc(OCCO)cc3)c2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
95 mg (0.162 mmol) of 2-{4-[7-({[2-(4-chlorophenyl)-1,3-oxazol-4-yl]methyl}sulfanyl)-6-cyano-2-methyl-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-5-yl]phenoxy}ethyl acetate were initially charged in 10 ml of a dioxane/water mixture 2:1, 7.7 mg (0.323 mmol) of lithium hydroxide were added and the mixture was stirred at RT for 5 h. The reaction mixture was then diluted with water, acidified with 1N hydrochloric acid and extracted with ethyl acetate. The organic phase was dried over sodium sulfate, the drying agent was filtered off and the filtrate was concentrated. The residue was purified by preparative HPLC (mobile phase gradient: acetonitrile/water 10:90→95:5, with 0.1% TFA added). This gave 88 mg (99% of theory) of the target compound.
Reaction SMILES: [N+](C1C=CC([O:10][C:11]([N:13]2[CH:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[C:21]([F:26])[CH:20]=3)[C:17]([C:27]([O:29][CH3:30])=[O:28])=[C:16]([CH2:31][O:32][CH3:33])[NH:15][C:14]2=[O:34])=O)=CC=1)([O-])=O.[C:35]1([C:41]2([C:51]3[N:52]([CH3:56])[CH:53]=[CH:54][CH:55]=3)[CH2:46][CH2:45][N:44]([CH2:47][CH2:48][CH2:49][NH2:50])[CH2:43][CH2:42]2)[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>C(Cl)Cl>[CH3:30][O:29][C:27]([C:17]1[CH:18]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[C:21]([F:26])[CH:20]=2)[N:13]([C:11](=[O:10])[NH:50][CH2:49][CH2:48][CH2:47][N:44]2[CH2:43][CH2:42][C:41]([C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)([C:51]3[N:52]([CH3:56])[CH:53]=[CH:54][CH:55]=3)[CH2:46][CH2:45]2)[C:14](=[O:34])[NH:15][C:16]=1[CH2:31][O:32][CH3:33])=[O:28]
Reactant: Cn1cccc1C1(c2ccccc2)CCN(CCCN)CC1
Reactant: COCC1=C(C(=O)OC)C(c2ccc(F)c(F)c2)N(C(=O)Oc2ccc([N+](=O)[O-])cc2)C(=O)N1
Solvent: ClCCl
Product: COCC1=C(C(=O)OC)C(c2ccc(F)c(F)c2)N(C(=O)NCCCN2CCC(c3ccccc3)(c3cccn3C)CC2)C(=O)N1
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.2 %

Procedure:
To a solution of 6-(3,4-difluorophenyl)-4-methoxymethyl-2-oxo-3,6-dihydro-2H-pyrimidine-1,5-dicarboxylic acid 5-methyl ester 1-(4-nitrophenyl)ester (24 mg, 0.05 mmol) in 2 ml of CH2Cl2 was added 3-[4-phenyl-4-(1-methylpyrrol-2-yl)-piperidin-1-yl]-propylamine (15 mg, 0.05 mmol) and resulting solution was stirred for 2 h at 25° C. Reaction mixture was concentrated in vacuo to provide an oil which was subjected to column chromatography over silica gel (5% MeOH/CHCl3) to yield 22 mg (69%) of the desired product, which was converted to HCl salt and recrystallized from EtOAC-Et2O to afford 16 mg of the product as a white solid: mp 139-142° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](O)=[O:8])=[CH:5][C:4]=1/[CH:12]=[CH:13]/[C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=1.[NH2:25][CH:26]([CH2:30][CH3:31])[CH2:27][O:28][CH3:29]>>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH:25][CH:26]([CH2:27][O:28][CH3:29])[CH2:30][CH3:31])=[O:8])=[CH:5][C:4]=1/[CH:12]=[CH:13]/[C:14]1[CH:15]=[CH:16][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:18][CH:19]=1
Reactant: COc1ccc(C(=O)O)cc1/C=C/c1ccc(OC(F)(F)F)cc1
Reactant: CCC(N)COC
Product: CCC(COC)NC(=O)c1ccc(OC)c(/C=C/c2ccc(OC(F)(F)F)cc2)c1

Procedure:
The captioned compound was synthesized from 4-methoxy-3-[(E)-2-(4-trifluoromethoxyphenyl)vinyl]benzoic acid obtained in step B of Example 2-2-1 and 2-amino-1-methoxybutane in accordance with the same procedure as in the methods described in step C of Example 1-2-3.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([OH:25])[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.F[C:28]1[CH:35]=[CH:34][CH:33]=[CH:32][C:29]=1[C:30]#[N:31]>>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([O:25][C:28]5[CH:35]=[CH:34][CH:33]=[CH:32][C:29]=5[C:30]#[N:31])[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: N#Cc1ccccc1F
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(O)ccc(F)c43)ccc21
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Oc5ccccc5C#N)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-7-fluoro-4-hydroxy-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 2-fluoro-benzonitrile following a procedure analogous to that described for Intermediate 12. LC (method 2): tR=1.11 min; Mass spectrum (ESI+): m/z=460 [M+H]+.
Reaction SMILES: [CH:1](=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[NH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][NH2:17]>C(O)(C)C.[Ni]>[OH:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[CH2:1][NH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][NH:17][CH2:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[OH:4]
Reactant: NCCCCCCN
Reactant: O=Cc1ccccc1O
Agent: [Ni]
Solvent: CC(C)O
Product: Oc1ccccc1CNCCCCCCNCc1ccccc1O

Procedure:
122.1 g of a bisazomethine prepared from 2 mols of salicylaldehyde and 1 mol of hexamethylenediamine and having a melting point of 72°-73° C. are hydrogenated in 550 ml of isopropanol in an autoclave in the presence of 8 g of Raney nickel at 75° C. and under a pressure of 90 atmospheres. The product crystallises out at room temperature and is dissolved by boiling with the addition of a further 650 ml of isopropanol. The catalyst is filtered off, and N,N'-bis-(2-hydroxybenzyl)hexamethylenediamine crystallises out on cooling.
Reaction SMILES: [CH:1]([NH:4][C:5]1[C:10]([C:11](O)=[O:12])=[CH:9][N:8]=[C:7]([S:14][CH3:15])[N:6]=1)([CH3:3])[CH3:2].S(Cl)([Cl:18])=O>>[CH:1]([NH:4][C:5]1[C:10]([C:11]([Cl:18])=[O:12])=[CH:9][N:8]=[C:7]([S:14][CH3:15])[N:6]=1)([CH3:3])[CH3:2]
Reactant: CSc1ncc(C(=O)O)c(NC(C)C)n1
Reactant: O=S(Cl)Cl
Product: CSc1ncc(C(=O)Cl)c(NC(C)C)n1
Temperature: 50 °C

Procedure:
To 3.5 (15.4 mmol) of 4-(isopropylamino)-2-(methylthio)pyrimidine-5-carboxylic acid is added 9.0 mL (123.2 mmol) of thionyl chloride, and the reaction mixture is heated at 50° C. for 1 hour, cooled to room temperature, and concentrated. The residue is twice suspended in anhydrous toluene and concentrated to give a colorless solid, 4-(isopropylamino)-2-(methylthio) pyrimidine-5-carboxylic acid chloride.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][NH:9][CH2:10][C:11]1[CH:12]=[C:13]([C:17]2[CH:22]=[CH:21][C:20]([CH2:23][CH:24]3[S:28][C:27](=[O:29])[NH:26][C:25]3=[O:30])=[CH:19][CH:18]=2)[CH:14]=[CH:15][CH:16]=1.[O:31]1[C:35]([C:36](Cl)=[O:37])=[CH:34][CH:33]=[N:32]1>>[O:29]=[C:27]1[NH:26][C:25](=[O:30])[CH:24]([CH2:23][C:20]2[CH:19]=[CH:18][C:17]([C:13]3[CH:14]=[CH:15][CH:16]=[C:11]([CH2:10][N:9]([CH3:8])[C:36]([C:35]4[O:31][N:32]=[CH:33][CH:34]=4)=[O:37])[CH:12]=3)=[CH:22][CH:21]=2)[S:28]1
Reactant: O=C(Cl)c1ccno1
Reactant: CNCc1cccc(-c2ccc(CC3SC(=O)NC3=O)cc2)c1
Solvent: O=C(O)C(F)(F)F
Product: CN(Cc1cccc(-c2ccc(CC3SC(=O)NC3=O)cc2)c1)C(=O)c1ccno1

Procedure:
In a manner similar to that of Example 37(e), by reacting 500 mg (1.1 mmol) of 5-(3′-methylaminomethylbiphenyl-4-ylmethyl)thiazolidine-2,4-dione trifluoroacetate with 170 mg (1.3 mmol) of 5-isoxazolecarboxylic acid chloride, and after purification, 120 mg (26%) of N-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]-N-methylisoxazole-5-carboxamide are obtained in the form of a white solid with a melting point of 160° C.
Reaction SMILES: Cl[C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[CH:12]/C3C=CC=C(Cl)C=3)/[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[CH2:20]([O:22][CH:23]=[CH:24][C:25](=[CH2:31])[O:26][Si](C)(C)C)[CH3:21]>C1(C)C=CC=CC=1>[CH2:20]([O:22][CH:23]1[C:6]2([C:5]3[C:9](=[CH:10][CH:2]=[CH:3][CH:4]=3)[NH:8][C:7]2=[O:11])[CH2:12][CH2:26][C:25](=[O:31])[CH2:24]1)[CH3:21]
Reactant: C=C(C=COCC)O[Si](C)(C)C
Reactant: O=C1Nc2cc(Cl)ccc2/C1=C/c1cccc(Cl)c1
Solvent: Cc1ccccc1
Product: CCOC1CC(=O)CCC12C(=O)Nc1ccccc12
Temperature: 140 °C
Reaction time: 16 h
Yield: 23.7 %

Procedure:
To a suspension of E/Z-6-chloro-3-(3-chloro-benzylidene)-1,3-dihydro-indol-2-one (1.45 g, 15.0 mmol) in toluene (20 mL) in a sealed tube was added (3-ethoxy-1-methylene-allyloxy)-trimethyl-silane (1.24 g, 7.5 mmol). The reaction mixture was allowed to stir at 140° C. for 16 hrs. The solvent was removed by concentration. The residue was dissolved in MeOH (50 mL) and treated with 4 N NaOH (5 mL) at rt for 0.5 h. The reaction mixture was then diluted with AcOEt and washed with water and brine. After concentration the residue was purified by flash column (5%-30% AcOEt in Hex) to give a mixture (1.2 g) of rac-(1R,2R)-6′-chloro-2-(3-chlorophenyl)spiro[5-cyclohexene-1,3′-[3H]indole]-2′,4(1′H)-dione and rac-(1R,2S,6R)-6′-chloro-2-3-chlorophenyl)-6-ethoxy-spiro[cyclohexane-1,3′-[3H]indole]-2′,4(1′H)-dione (0.46 g, 18.6%) as white amorphous which was used for next steps without further purification. A small amount mixture was separated by normal phase HPLC gave rac-(1R,2S,6R)-6′-chloro-2-(3-chlorophenyl)-6-ethoxy-spiro[cyclohexane-1,3′-[3H]indole]-2′,4(1′H)-dione. MS+:358 (M+1).
Reaction SMILES: [Br:1][C:2]1[C:3]([C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)=[N:4][C:5]([NH2:11])=[N:6][C:7]=1[S:8]([CH3:10])=O.SC[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1.C1CCN2C(=NCCC2)CC1>O1CCOCC1>[Br:1][C:2]1[C:3]([C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)=[N:4][C:5]([NH2:11])=[N:6][C:7]=1[S:8][CH2:10][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1Br
Reactant: SCCc1ccccn1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1COCCO1
Product: Nc1nc(SCCc2ccccn2)c(Br)c(-c2ccco2)n1

Procedure:
From 5-bromo-4-furan-2-yl-6-methanesulfinyl-pyrimidin-2-yl-amine, 2-mercaptoethylpyridine and DBU in dioxane. ES-MS m/e (%): 379 (M{81Br}+H+, 100), 377 (M{79Br}+H+, 95).
Reaction SMILES: [C:1](O)(=O)[CH2:2][C:3]([OH:5])=[O:4].[CH:8]1(C=O)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.N1CCCCC1.Cl>N1C=CC=CC=1.O>[CH:8]1([CH:1]=[CH:2][C:3]([OH:5])=[O:4])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: O=CC1CCCCC1
Reactant: O=C(O)CC(=O)O
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCNCC1
Solvent: O
Product: O=C(O)C=CC1CCCCC1
Temperature: 25 °C

Procedure:
A solution of malonic acid (30 g, 0.29 mol), cyclohexanecarbaldehyde (17.3 mL, 0.14 mol), and piperidine (2.9 mL, 0.029 mol) in pyridine (90 mL) was stirred at 70° C. for 18 h. The resulting mixture was cooled to room temperature and then treated with water (200 mL). The resulting solution was acidified to pH 2 with 1N HCl and extracted thrice with ethyl acetate (100 mL). The ethyl acetate extracts were pooled, washed successively with water and brine, then dried over sodium sulfate, filtered and concentrated to yield 3-cyclohexyl-acrylic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:26]([O:28]C)=[O:27])[C:5]([CH3:25])=[C:6]([CH:24]=1)[O:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[CH2:10][CH2:9]1.[OH-].[Na+].Cl>O1CCCC1.CO.O>[CH2:17]([O:16][C:14]([N:11]1[CH2:10][CH2:9][CH:8]([O:7][C:6]2[C:5]([CH3:25])=[C:4]([CH:3]=[C:2]([Cl:1])[CH:24]=2)[C:26]([OH:28])=[O:27])[CH2:13][CH2:12]1)=[O:15])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: COC(=O)c1cc(Cl)cc(OC2CCN(C(=O)OCc3ccccc3)CC2)c1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cc1c(OC2CCN(C(=O)OCc3ccccc3)CC2)cc(Cl)cc1C(=O)O
Temperature: 45 °C
Reaction time: 1 h
Yield: 75.2 %

Procedure:
To a solution of benzyl 4-(5-chloro-3-(methoxycarbonyl)-2-methylphenoxy)piperidine-1-carboxylate (0.68 g, 1.627 mmol) in tetrahydrofuran (5 mL) and methanol (15 mL) was added 3 N NaOH (2.71 mL, 8.14 mmol). The reaction mixture was stirred for 1 h, then heated at 45° C. for 3 h. The volatiles were removed in vacuo to give an aqueous residue, which was diluted with water (25 mL) and cooled (ice bath). The mixture was acidified to pH˜3-4 with 1 M HCl and stirred for 15 min. The solids were filtered, washed with water, and dried under high vacuum overnight to give 3-((1-((benzyloxy)carbonyl)piperidin-4-yl)oxy)-5-chloro-2-methylbenzoic acid (0.52 g, 1.223 mmol, 75% yield). 1H NMR δ 1.54-1.72 (m, 2H), 1.83-1.98 (m, 2H), 2.29 (s, 3H), 3.38 (br. s., 2H), 3.58-3.70 (m, 2H), 4.72 (tt, 1H), 5.09 (s, 2H), 7.24-7.46 (m, 7H), 13.28 (br. s., 1H). MS(ES) [M+H]+ 404.1.
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][C@H:7]2[CH2:12][C@H:11]([C:13]3[O:17][NH:16][C:15](=[O:18])[CH:14]=3)[CH2:10][CH2:9][N:8]2[C:19]([O:21][CH3:22])=[O:20])=[CH:4][CH:3]=1.CCO.C(#N)C>C(=O)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C@@H:7]2[CH2:12][C@@H:11]([C:13]3[O:17][NH:16][C:15](=[O:18])[CH:14]=3)[CH2:10][CH2:9][N:8]2[C:19]([O:21][CH3:22])=[O:20])=[CH:23][CH:24]=1
Reactant: COC(=O)N1CC[C@@H](c2cc(=O)[nH]o2)C[C@@H]1Cc1ccc(F)cc1
Agent: O=C=O
Solvent: CCO
Solvent: CC#N
Product: COC(=O)N1CC[C@H](c2cc(=O)[nH]o2)C[C@H]1Cc1ccc(F)cc1
Yield: 30.3 %

Procedure:
Trans-methyl 2-(4-fluorobenzyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (0.268 g, 0.8 mmol) was subjected to chiral preparative HPLC (Column: Chiralcel OJ (250×30), 5 μm particle size, mobile phase: 10% EtOH in CO2 (175 bar), flow rate 150 mL/min) to yield (2S,4S)-methyl 2-(4-fluorobenzyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)-piperidine-1-carboxylate (81 mg, 30%), Chiral purity 99.8% ee, Optical rotation [α]D20=+29.3 (acetonitrile, c=1)
Reaction SMILES: CO[C:3]([C:5]1[C:10]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:9][CH:8]=[CH:7][N:6]=1)=[O:4].[Cl:18][C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][CH:25]=1)[NH2:22]>>[Cl:18][C:19]1[CH:20]=[C:21]([NH:22][C:3]([C:5]2[C:10]([NH:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:9][CH:8]=[CH:7][N:6]=2)=[O:4])[CH:23]=[CH:24][CH:25]=1
Reactant: Nc1cccc(Cl)c1
Reactant: COC(=O)c1nccnc1Nc1ccccc1
Product: O=C(Nc1cccc(Cl)c1)c1nccnc1Nc1ccccc1

Procedure:
The title compound, MS: m/e=325.1 (M+H+), was prepared in accordance with the general method of example 1, step 2 from 3-phenylamino-pyrazine-2-carboxylic acid methyl ester and 3-chloroaniline.
Reaction SMILES: Cl[CH2:2][CH:3]([OH:12])[CH2:4][CH2:5][C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1.[C:13]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[OH:25])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[OH-].[Na+]>C(O)C>[C:19]1([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[O:25][CH2:2][CH:3]([OH:12])[CH2:4][CH2:5][C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1
Reactant: Oc1ccccc1-c1ccccc1
Reactant: OC(CCl)CCc1cccnc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: OC(CCc1cccnc1)COc1ccccc1-c1ccccc1
Yield: 34.9 %

Procedure:
Prepared according to the method described in Example 24b) from (±)-α-(chloromethyl)-3-pyridinepropanol (1.0 g, Example 24a), 2-phenylphenol (0.92 g), ethanol (45 ml) and aqueous sodium hydroxide (1.0 M, 5 ml) with heating at reflux for 1 hour. After work up the residue was purified by column chromatography over silica eluting with hexane:acetone (2:1) to give the title compound as a colourless oil (0.60 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5](O)=[O:6].C1C=CC2N(O)N=NC=2C=1.Cl.[CH3:22][O:23][NH:24][CH3:25].C(Cl)CCl>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([N:24]([O:23][CH3:22])[CH3:25])=[O:6]
Reactant: CNOC
Reactant: O=C(O)c1ccnc(Br)c1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CON(C)C(=O)c1ccnc(Br)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.7 %

Procedure:
To 2-bromoisonicotinic acid, (25.2 g, 124 mmol), HOBt (20.2 g, 149 mmol) and O,N-dimethyl-hydroxylamine hydrochloride (14.6 g, 149 mmol) in DMF (150 mL) at 0° C., was added diisopropylethyalamine (26.0 mL, 149 mmol). EDC (28.6 g, 149 mmol) was then added and the mixture stirred at room temperature for 1 hour. The mixture was then poured into ice cold water (500 mL) and the resulting solution extracted with EtOAc (3×150 mL). The combined organic fraction was were washed with water (2×200 mL), 0.5 M HCl (200 mL), sat. NaHCO3 solution, brine (200 mL) and then dried (MgSO4). The solvent was evaporated in vacuo to give 2-bromo-N-methoxy-N-methyl-isonicotinamide (23 g, 75%)
Reaction SMILES: [NH2:1][C:2]1[O:3][CH:4]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:5](=[O:7])[N:6]=1.N[CH2:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>>[CH2:8]([CH:4]1[O:3][C:2]([NH:1][CH2:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=[N:6][C:5]1=[O:7])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: NC1=NC(=O)C(Cc2ccccc2)O1
Reactant: NCC1CCCCC1
Product: O=C1N=C(NCC2CCCCC2)OC1Cc1ccccc1

Procedure:
Synthesis was performed from 2-amino-5-benzyl-1,3-oxazol-4(5H)-one and aminomethylcyclohexane according to Method G+H.