Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:10]2[N:9]=[N:8][N:7]([CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=2[CH:5]=[CH:4][C:3]=1[O:16][C:17]1[C:22]([C:23](=[O:25])[CH3:24])=[CH:21][CH:20]=[CH:19][N:18]=1.[BH4-].[Na+]>CO>[Br:1][C:2]1[C:10]2[N:9]=[N:8][N:7]([CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=2[CH:5]=[CH:4][C:3]=1[O:16][C:17]1[C:22]([CH:23]([OH:25])[CH3:24])=[CH:21][CH:20]=[CH:19][N:18]=1
Reactant: CC(=O)c1cccnc1Oc1ccc2c(nnn2CC(C)(C)C)c1Br
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(O)c1cccnc1Oc1ccc2c(nnn2CC(C)(C)C)c1Br
Temperature: 25 °C

Procedure:
To a suspension of 1-(2-{[4-bromo-1-(2,2-dimethylpropyl)-1H-1,2,3-benzotriazol-5-yl]oxy}pyridin-3-yl)ethanone (2) (790 mg, 1.959 mmol, 1.0 equiv.) in MeOH (19.6 mL) was slowly added NaBH4 (148 mg, 3.92 mmol, 2.0 equiv.). The mixture was stirred at room temperature until LCMS showed only the desired product. The solvent was evaporated in vacuo and the mixture was partitioned between EtOAc and saturated aqueous NaHCO3. The combined organic extracts were dried with Na2SO4, filtered and concentrated in vacuo. The residue was purified silica gel chromatography (EtOAc/Hexane gradient from 0 to 100%) to obtain product 3 1H NMR (CDCl3) δ 7.96 (1H, d, J=4.9 Hz), 7.89 (1H, d, J=7.4 Hz), 7.48 (1H, d, J=8.8 Hz), 7.38-7.33 (1H, m), 7.05 (1H, dd, J=7.3, 5.0 Hz), 5.40-5.33 (1H, m), 4.41 (2H, s), 1.70 (3H, d, J=6.48 Hz), 1.08 (9H, s) ppm. LRMS m/z (M+H) 405.0 and 407.0 (intensity ratio ˜1:1) found, 405.1 and 407.1 required. The racemic mixture was further separated via chiral HPLC (ChiralPak IC, EtOH/Heptane with 0.1% DEA=1:9, v/v) to obtain enantiomers 3a and 3b.
Reaction SMILES: [CH2:1]([C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[CH:6]=[C:5]([OH:17])[N:4]=1)[CH3:2].[OH-].[K+].Cl[CH2:21][C:22]1[CH:34]=[CH:33][C:25]2[O:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:24]=2[CH:23]=1>C1(C)C=CC=CC=1.C(Cl)Cl>[CH:23]1[C:24]2[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[O:26][C:25]=2[CH:33]=[CH:34][C:22]=1[CH2:21][C:6]1[C:7]2[C:12](=[CH:11][C:10]([O:13][CH3:14])=[C:9]([O:15][CH3:16])[CH:8]=2)[C:3]([CH2:1][CH3:2])=[N:4][C:5]=1[OH:17]
Reactant: ClCc1ccc2oc3ccccc3c2c1
Reactant: CCc1nc(O)cc2cc(OC)c(OC)cc12
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CCc1nc(O)c(Cc2ccc3oc4ccccc4c3c2)c2cc(OC)c(OC)cc12
Temperature: 150 °C
Reaction time: 1.5 h
Yield: 11 %

Procedure:
To a solution of 1-ethyl-6,7-dimethoxyisoquinolin-3-ol SLA 28136 (50 mg, 214 μmol) in toluene (10 mL) in a 20 mL microwave vial equipped with a magnetic stirrer was added a 2 N aq. KOH solution (0.11 mL, 0.22 mmol) at RT followed by 2-(chloromethyl)dibenzo[b,d]furan CCH 34116-2 (47 mg, 217 μmol) and the mixture was stirred at 150° C. for 1.5 h under microwave irradiation. After cooling to RT, the mixture was diluted with a mixture CH2Cl2:MeOH=9:1 (50 mL), washed with brine (10 mL), dried over Na2SO4, filtered and concentrated at 40° C. under vacuum. Purification by column chromatography (SiO2, eluent CH2Cl2:MeOH=100:0 to 96:4) gave 4-(dibenzo[b,d]furan-2-ylmethyl)-1-ethyl-6,7-dimethoxyisoquinolin-3-ol (10 mg, 11%). This free base was dissolved in MeOH (2 mL) in a 10 mL round-bottomed flask equipped with a magnetic stirrer before addition of a 0.2 M HCl solution in MeOH (0.25 mL). The reaction mixture was stirred for 5 min at RT and concentrated at 40° C. under vacuum to afford 4-(dibenzo[b,d]furan-2-ylmethyl)-1-ethyl-6,7-dimethoxyisoquinolin-3-ol hydrochloride 6 as a pale brown solid (11 mg, 11% yield).
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[NH2:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[N:18]=[CH:17][CH:16]=[CH:15]2>>[N:18]1[C:19]2[C:14](=[CH:13][C:12]([NH:11][C:2]3[C:3]([C:4]([OH:6])=[O:5])=[CH:7][CH:8]=[CH:9][N:10]=3)=[CH:21][CH:20]=2)[CH:15]=[CH:16][CH:17]=1
Reactant: Nc1ccc2ncccc2c1
Reactant: O=C(O)c1cccnc1Cl
Product: O=C(O)c1cccnc1Nc1ccc2ncccc2c1
Temperature: 140 °C

Procedure:
A mixture of 2-chloronicotinic acid (1.5 g) and 6-aminoquinoline (1.4 g) was heated at 140° C. neat for 2 h. The reaction was cooled to give a brown solid used in the next step without further purification. MS (ES+): 266 (M+H)+; (ES−): 264 (M−H)−.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]2[O:9][C:10]([CH2:20][CH3:21])=[C:11]([C:13]([O:15][CH2:16][CH2:17][CH2:18][CH3:19])=[O:14])[N:12]=2)[CH2:4][C@H:3]1[O:22][CH2:23][CH2:24][CH3:25].[Cl:26][C:27]1[N:28]=[C:29]([C:34](O)=[O:35])[NH:30][C:31]=1[CH2:32][CH3:33].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CC(N(C)C)=O.ClCCl>[Cl:26][C:27]1[N:28]=[C:29]([C:34]([NH:1][C@H:2]2[CH2:7][CH2:6][N:5]([C:8]3[O:9][C:10]([CH2:20][CH3:21])=[C:11]([C:13]([O:15][CH2:16][CH2:17][CH2:18][CH3:19])=[O:14])[N:12]=3)[CH2:4][C@H:3]2[O:22][CH2:23][CH2:24][CH3:25])=[O:35])[NH:30][C:31]=1[CH2:32][CH3:33]
Reactant: CCc1[nH]c(C(=O)O)nc1Cl
Reactant: CCCCOC(=O)c1nc(N2CC[C@H](N)[C@H](OCCC)C2)oc1CC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CC(=O)N(C)C
Product: CCCCOC(=O)c1nc(N2CC[C@H](NC(=O)c3nc(Cl)c(CC)[nH]3)[C@H](OCCC)C2)oc1CC
Yield: 41.2 %

Procedure:
The same operation as in Example (106d) was performed using butyl cis(±)-2-(4-amino-3-propoxypiperidin-1-yl)-5-ethyl-1,3-oxazole-4-carboxylate obtained in Example (113h) (0.70 g, 2.0 mmol), 4-chloro-5-ethyl-1H-imidazole-2-carboxylic acid (85% content, 0.2 g, 1 mmol), WSC hydrochloride (0.5 g, 2.5 mmol), HOBt (0.2 g, 1.5 mmol), dichloromethane (5 mL) and DMA (3 mL), to obtain 0.21 g of the title compound as a colorless amorphous solid (41%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH2:23][CH3:24])=[C:8]2[N:13]([CH:14]=1)[N:12]=[CH:11][N:10]=[C:9]2[NH:15][C:16]1[CH:21]=[CH:20][C:19](Br)=[CH:18][CH:17]=1)=[O:5])[CH3:2].NC1C=C2C(=CC=1)[N:31]([CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[N:30]=[CH:29]2>>[CH2:1]([O:3][C:4]([C:6]1[C:7]([CH2:23][CH3:24])=[C:8]2[N:13]([CH:14]=1)[N:12]=[CH:11][N:10]=[C:9]2[NH:15][C:16]1[CH:21]=[C:20]2[C:19](=[CH:18][CH:17]=1)[N:31]([CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[N:30]=[CH:29]2)=[O:5])[CH3:2]
Reactant: Nc1ccc2c(cnn2Cc2ccccc2)c1
Reactant: CCOC(=O)c1cn2ncnc(Nc3ccc(Br)cc3)c2c1CC
Product: CCOC(=O)c1cn2ncnc(Nc3ccc4c(cnn4Cc4ccccc4)c3)c2c1CC

Procedure:
The title compound was prepared from compound B of Example 139 using the process described for the preparation of example 139 except 5-amino-1-benzyl-1H-indazole was used to add to the chloroimidate. MS: (M+H)+=441.24
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]1[NH:11][CH:12]=[C:13]([C:15]2[C:16]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[N:17][O:18][C:19]=2[CH3:20])[N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.F[C:28]1[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][CH:29]=1>>[CH2:1]([O:8][CH2:9][C:10]1[N:11]([C:28]2[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][CH:29]=2)[CH:12]=[C:13]([C:15]2[C:16]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[N:17][O:18][C:19]=2[CH3:20])[N:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: Cc1onc(-c2ccccc2)c1-c1c[nH]c(COCc2ccccc2)n1
Product: Cc1onc(-c2ccccc2)c1-c1cn(-c2ccc([N+](=O)[O-])cc2)c(COCc2ccccc2)n1
Yield: 80 %

Procedure:
As described for Example 63, 4-(2-benzyloxymethyl-1H-imidazol-4-yl)-5-methyl-3-phenyl-isoxazole (38 mg, 0.11 mmol) using 1-fluoro-4-nitrobenzene instead of 4-fluoroacetophenone was converted to the title compound (41 mg, 80%) which was obtained as a yellow solid. MS: m/e=467.0 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][C:10](=[O:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:18][C:19]#[N:20]>C1COCC1.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:18][C:19]#[N:20])[C:10](=[O:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: N#CCBr
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Agent: [I-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(CC#N)C(=O)C1
Reaction time: 0.67 h
Yield: 54.3 %

Procedure:
4-(tert-Butyloxycarbonyl)-piperazin-2-one (8.0 g, 40 mmol), EXAMPLE 40, is dissolved in THF (160 mL), cooled in an ice bath and treated with 60% sodium hydride (1.9 g, 48 mmol). The reaction mixture is stirred 40 minutes, then treated with tetra-butylammonium iodide (0.35 g, 0.95 mmol) and bromoacetonitrile (3.4 mL, 48 mmol). After 2 h the reaction is quenched with water, concentrated to a small volume and extracted with methylene chloride (3×). The combined organic extracts are concentrated and the residue is chromatographed (50% ethyl acetate/hexane) to give 4-(tert-butyloxycarbonyl)-1-cyanomethyl-piperazin-2-one (5.2 g, 21.7 mmol). This material is dissolved in ethanol (140 mL) and treated with platinum oxide (0.83 g) at 50 PSI of hydrogen gas for 24 hours. The catalyst is removed by filtration and the solution is concentrated to yield 4-(tert-butyloxycarbonyl)-1-(2-aminoethyl)-piperazin-2-one (5.2 g, 21.6 mmol). 1H NMR (CDCl3, 300 MHz) δ4.08 (s, 2H), 3.62 (m, 2H), 3.44 (t, 2H), 3.38 (t, 2H), 2.89 (t, 2H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH2:9])=[O:8].[Cl:10][CH2:11][C:12]([CH2:14]Cl)=O>>[Cl:10][CH2:11][C:12]1[N:9]=[C:7]([CH2:6][C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)[O:8][CH:14]=1
Reactant: NC(=O)Cc1cccs1
Reactant: O=C(CCl)CCl
Product: ClCc1coc(Cc2cccs2)n1
Yield: 27 %

Procedure:
In substantially the same manner as in Reference Example 47, 2-thiopheneacetamide was reacted with 1,3-dichloroacetone to give 4-chloromethyl-2-(2-thienylmethyl)oxazole. The yield was 27%. Oily substance.
Reaction SMILES: [C-:1]#[N:2].[K+].CS(O[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:22])=[CH:12][C:11]=1[CH3:23])(=O)=O>CN(C=O)C.O>[Cl:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[C:13]1[CH:14]=[CH:15][C:10]([CH2:9][C:1]#[N:2])=[C:11]([CH3:23])[CH:12]=1
Reactant: Cc1cc(-c2ccccc2Cl)ccc1COS(C)(=O)=O
Reactant: [C-]#N
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(-c2ccccc2Cl)ccc1CC#N
Temperature: 80 °C
Reaction time: 12 h

Procedure:
KCN (1.1 eq.) was added to a stirred solution of (2′-chloro-3-methylbiphenyl-4-yl)methyl methanesulfonate (1 eq.) from step 2 in DMF (0.13M). The suspension was stirred 12 h. at 80° C. The final mixture was cooled down to room temperature, poured in water and extracted with Et2O. The organic extract was washed with water (2×), brine, dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography on silica gel (Combi-Flash by ISCO), eluting with Hex/EtOAc (0 to 50% in 30 min) to afforded the desired compound as a beige solid.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[C:6]1([N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[C:7]=1[CH3:13].C(=O)([O-])[O-].[Ca+2]>C(C(C)=O)C>[Cl:1][CH2:2][C:3]([N:17]1[CH2:18][CH2:19][N:14]([C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[C:7]=2[CH3:13])[CH2:15][CH2:16]1)=[O:4]
Reactant: O=C(Cl)CCl
Reactant: Cc1cccc(N2CCNCC2)c1C
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CCC(C)=O
Product: Cc1cccc(N2CCN(C(=O)CCl)CC2)c1C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Chloroacetyl chloride (1.47 ml, 18.5 mmol) is added dropwise to a solution of 1-(2,3-xylyl)piperazine (3.2 g, 16.8 mmol) and calcium carbonate (5 g, 50 mmol) in methyl ethyl ketone (40 ml) cooled to 0° C. The reaction mixture is stirred at this temperature for 1 h 30 and it is then filtered through Celite. The Celite is rinsed several times with ethyl acetate and 3M sodium hydroxide solution. The two phases of the filtrate are then separated and the organic phase is dried over magnesium sulfate, filtered and concentrated.
Reaction SMILES: [O:1]([C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]([C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=3)[CH:16]2[C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:11][CH:10]=1)[Si](C(C)(C)C)(C)C.[OH-].[Na+]>CCO>[OH:1][C:9]1[CH:10]=[CH:11][C:12]([CH:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]([C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=3)[CH:16]2[C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:13][CH:14]=1
Reactant: CCOC(=O)C1C(c2ccc(OC)cc2)c2ccccc2C1c1ccc(O[Si](C)(C)C(C)(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)C1C(c2ccc(O)cc2)c2ccccc2C1c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 101.9 %

Procedure:
To a solution of ethyl (1RS,2SR,3SR)-1-(4-t-butyldimethylsiloxyphenyl)-3-(4-methoxyphenyl)indane-2-carboxylate (723 mg, 1.4 mmol) in EtOH (20 ml) was added 1M NaOH (1.6 ml, 1.6 mmol), and the resulting mixture was stirred at room temperature for 30 min. The mixture was then partitioned between 3M HCl and EtOAc. The aqueous phase was extracted with EtOAc, and the combined organic extracts were washed successively with H2O and saturated aqueous NaCl and dried. The solvent was removed in vacuo to afford the title compound (554 mg, 100%).
Reaction SMILES: [C:1]([C:5]1[S:9][C:8]([CH:10]2[CH2:15][CH:14](C(O)=O)[CH2:13][CH2:12][N:11]2[C:19]([O:21][CH3:22])=[O:20])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].N1(C(N2C=CN=C2)=O)C=CN=C1.[CH2:35]([O:37][C:38](=[O:43])[CH2:39][C:40](O)=[O:41])[CH3:36].[K].[Cl-].[Mg+2].[Cl-].Cl>C1COCC1>[C:1]([C:5]1[S:9][C:8]([C@H:10]2[CH2:15][C@@H:14]([C:40](=[O:41])[CH2:39][C:38]([O:37][CH2:35][CH3:36])=[O:43])[CH2:13][CH2:12][N:11]2[C:19]([O:21][CH3:22])=[O:20])=[CH:7][CH:6]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CCOC(=O)CC(=O)O
Reactant: COC(=O)N1CCC(C(=O)O)CC1c1ccc(C(C)(C)C)s1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Cl-]
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)[C@H]1CCN(C(=O)OC)[C@@H](c2ccc(C(C)(C)C)s2)C1
Temperature: 25 °C
Reaction time: 6 h
Yield: 70.4 %

Procedure:
2-(5-tert-Butylthiophen-2-yl)-1-(methoxycarbonyl)piperidine-4-carboxylic acid (1.125 g, 3.46 mmol) (reference compound 18) was dissolved in THF (30 mL) and di(1H-imidazol-1-yl)methanone (0.911 g, 5.62 mmol) added. The suspension was stirred at room temperature under nitrogen for 6 h (flask 1). In a separate flask 3-ethoxy-3-oxopropanoic acid, potassium salt (1.509 g, 8.82 mmol) and magnesium chloride (0.84 g, 8.82 mmol) were suspended in THF (30 mL) and stirred with an oversized stirring bar at 50° C. under nitrogen for 20 h (flask 2). The white suspension in flask 2 was then added to flask 1. The thick white suspension was stirred at room temperature for 18 h. The reaction mixture was acidified by addition of 3 M HCl to pH 1. The solvent was evaporated in vacuo. MTBE (250 mL) and water were added, shaken and the phases separated. The organic phase was washed with water (200 mL), satd NaHCO3 (200 mL), brine (200 mL), dried with a phase separator and evaporated in vacuo. The residue was purified by automated flash chromatography on a Biotage® KP-SIL 100 g column. A gradient from 10% EtOAc in heptane over 2 CV followed by 10% to 40% of EtOAc in heptane over 9 CV was used as mobile phase. Cis-methyl 2-(5-tert-butylthiophen-2-yl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (0.963 g, 70.4%) was isolated. Cis-isomer: MS m/z 396 (M+H)+
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[NH2:24][C:25]1[CH:30]=[CH:29][C:28](B2OC(C)(C)C(C)(C)O2)=[CH:27][N:26]=1>>[NH2:24][C:25]1[N:26]=[CH:27][C:28]([C:2]2[CH:11]=[CH:10][C:9]3[N:8]=[CH:7][C:6]4[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]5[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=5)[C:5]=4[C:4]=3[CH:3]=2)=[CH:29][CH:30]=1
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Product: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(-c4ccc(N)nc4)cc3c21

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A, 40 mg, 0.105 mmol) and 2-aminopyridine-5-boronic acid pinacol ester (Aldrich, Buchs, Switzerland, 26 mg, 0.125 mmol) to give the title compound as a white solid. (HPLC: tR 2.02 min (Method A); M+H=386 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.90 (s, 1H), 8.16-8.10 (m, 1H), 8.07-7.98 (m, 2H), 7.86-7.78 (m, 1H), 7.54-7.46 (m, 1H), 7.42-7.36 (m, 1H), 6.54-6.46 (m, 1H), 6.20 (s, br, 2H), 3.91 (s, 3H), 3.56 (s, 3H), 1.95 (s, 3H))
Reaction SMILES: [H-].[Na+].F[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N+:10]([O-:12])=[O:11].[NH2:13][C:14]1[C:18]([CH3:19])=[CH:17][N:16]([CH3:20])[C:15]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22]>>[CH3:20][N:16]1[CH:17]=[C:18]([CH3:19])[C:14]([NH:13][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N+:10]([O-:12])=[O:11])=[C:15]1[C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: CCOC(=O)c1c(N)c(C)cn1C
Reactant: O=[N+]([O-])c1ccccc1F
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)c1c(Nc2ccccc2[N+](=O)[O-])c(C)cn1C
Temperature: 0 °C
Reaction time: 3 h
Yield: 87 %

Procedure:
The solution of ethyl 3-amino-1,4-dimethyl-1H-pyrrole-2-carboxylate in dimethyl formamide obtained in Example 19 is cooled to 0° C.; 3.0 g of 80% sodium hydride and 14.1 g of 2-fluoronitrobenzene are added thereto with stirring. After removing the ice-bath, the temperature rises to 40° C. and, simultaneously, an evolution of gas can be observed; this evolution subsides after 3 hours. The mixture is stirred overnight, cooled to 0° C.; 100 g of ice and 100 ml of water are then added. The precipitate formed is filtered off and is washed thoroughly with cold (0° C.) methanol. 13.5 g (87%) of the title compound of m.p. 114° C. (from ethanol) are obtained.
Reaction SMILES: C[O:2][C:3](=[O:29])[CH2:4][CH2:5][C:6]1[C:7](=[O:28])[N:8]([NH:13][C:14]([C:16]2[CH:17]=[N:18][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[N:20][CH:21]=2)=[O:15])[C:9](=[O:12])[NH:10][CH:11]=1.[Li+].[OH-]>CO.O.C1COCC1>[O:12]=[C:9]1[N:8]([NH:13][C:14]([C:16]2[CH:21]=[N:20][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[N:18][CH:17]=2)=[O:15])[C:7](=[O:28])[C:6]([CH2:5][CH2:4][C:3]([OH:29])=[O:2])=[CH:11][NH:10]1
Reactant: COC(=O)CCc1c[nH]c(=O)n(NC(=O)c2cnc(-c3ccccc3)nc2)c1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)CCc1c[nH]c(=O)n(NC(=O)c2cnc(-c3ccccc3)nc2)c1=O
Yield: 0 %

Procedure:
3-{2,4-Dioxo-3-[(2-pheyl-pyrimidine-5-carbonyl)-amino]-1,2,3,4-tetrahydro-pyrimidin-5-yl}-propionic acid methyl ester (0.22 mol) is hydrolyzed by LiOH (0.88 mol) in MeOH/water/THF (1:1:1) at rt overnight. MeOH and THF are evaporated in vacuo. The residue is acidified by 5% aqueous HCl. The resulting precipitate is collected and dried to afford 3-{2,4-dioxo-3-[(2-pheyl-pyrimidine-5-carbonyl)-amino]-1,2,3,4-tetrahydro-pyrimidin-5-yl}-propionic acid (40 mg, 48%). MS: 383 (M+H); 1H NMR (300 MHz, CD3OD): δ 2.68-2.77 (m, 2H), 2.98-2.90 (m, 2H), 5.49 (s. N—H), 7.48-7.60 (m, 3H), 8.41-8.56 (m, 2H), 9.32 (s, 2H).
Reaction SMILES: [NH:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[C:5](=O)[CH2:4][CH2:3][CH2:2]1.Cl.[CH3:14][O:15][NH2:16].C([O-])(=O)C.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[CH3:14][O:15]/[N:16]=[C:9]1/[CH2:8][CH2:7][NH:1][CH2:2][C:3]2[CH:4]=[CH:5][CH:6]=[CH:11][C:10]/1=2
Reactant: CON
Reactant: O=C1CCCNc2ccccc21
Agent: CC(=O)[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Product: CO/N=C1/CCNCc2ccccc21
Yield: 67.7 %

Procedure:
A mixture of 1,2,3,4-tetrahydro-1-benzazepin-5-one (500 mg, 2.530 mmol), O-methyl hydroxylamine hydrochloride (211 mg, 2.530 mmol), sodium acetate (208 mg, 2.530 mmol) and sodium carbonate (536 mg, 5.060 mmol) in ethanol was refluxed for 3 hours. The resulting mixture was concentrated in vacuo to remove ethanol and to the residue was added water (15 mL). The residue in water was extracted with dichloromethane (15 mL×3). The organic layers were combined, dried over sodium sulfate, and concentrated in vacuo to afford 326 mg of the desired product (yield was 67%).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:11]=[C:10]([C:12]([NH2:14])=[O:13])[CH:9]=[CH:8][N:7]=2)[N:3]=[CH:2]1.Br[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[Cl:23].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[CH2:16][N:1]1[CH:5]=[C:4]([C:6]2[CH:11]=[C:10]([C:12]([NH2:14])=[O:13])[CH:9]=[CH:8][N:7]=2)[N:3]=[CH:2]1
Reactant: NC(=O)c1ccnc(-c2c[nH]cn2)c1
Reactant: Clc1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: NC(=O)c1ccnc(-c2cn(Cc3ccccc3Cl)cn2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42 %

Procedure:
A mixture of 2-(1H-imidazol-4-yl)pyridine-4-carboxamide (PREPARATION 7)), 1-bromomethyl-2-chlorobenzene (260 mg, 1.28 mmol) and K2CO3 (176 mg, 1.28 mmol) in DMF (8 mL) was stirred overnight at rt, LC/MS showed the reaction was completed, purified by FCC to give the title compound (83 mg, 42%) as a yellow solid. [M+H] Calc'd for C16H13ClN4O, 313. Found, 313.
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([CH2:11][NH:12][C:13]2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=2[N+:21]([O-])=O)[CH2:7][CH2:6]1)=[O:4].[H][H]>[Pd]>[CH3:1][O:2][C:3]([C@H:5]1[CH2:6][CH2:7][C@H:8]([CH2:11][NH:12][C:13]2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=2[NH2:21])[CH2:9][CH2:10]1)=[O:4]
Reactant: COc1ccc([N+](=O)[O-])c(NC[C@H]2CC[C@H](C(=O)OC)CC2)c1
Reactant: [H][H]
Agent: [Pd]
Product: COc1ccc(N)c(NC[C@H]2CC[C@H](C(=O)OC)CC2)c1

Procedure:
trans-4-[(5-Methoxy-2-nitro-phenylamino)-methyl]cyclohexane carboxylic acid methyl ester (800 mg, 2.48 mmol) was dissolved in 10 ml of EtAc mixed with 80 mg of Pd/C (10%, wet) and transferred in a Eyela reactor. The mixture was left overnight under 5 bar of hydrogen, then the solution was filtered through cellulose and the solvent removed under reduced pressure to give the titled compound as a brown solid. (700 mg, yield=96%)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:10]2[CH:18]([CH:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)[CH:17]3[C:12]([C:13]4[CH:27]=[CH:26][C:25]([C:28]([OH:30])=[O:29])=[CH:24][C:14]=4[CH2:15][CH2:16]3)=[N:11]2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[N:31]([CH2:38][CH2:39]O)([CH2:35][CH2:36][OH:37])[CH2:32][CH2:33][OH:34]>>[Cl:1][C:2]1[CH:3]=[C:4]([N:10]2[CH:18]([CH:19]3[CH2:20][CH2:21][CH2:22][CH2:23]3)[CH:17]3[C:12]([C:13]4[CH:27]=[CH:26][C:25]([C:28]([O:30][CH2:39][CH2:38][N:31]([CH2:35][CH2:36][OH:37])[CH2:32][CH2:33][OH:34])=[O:29])=[CH:24][C:14]=4[CH2:15][CH2:16]3)=[N:11]2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: N#Cc1ccc(N2N=C3c4ccc(C(=O)O)cc4CCC3C2C2CCCC2)cc1Cl
Reactant: OCCN(CCO)CCO
Product: N#Cc1ccc(N2N=C3c4ccc(C(=O)OCCN(CCO)CCO)cc4CCC3C2C2CCCC2)cc1Cl

Procedure:
The title compound was prepared from (±)-(3SR,3aRS)-2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylic acid, Example 15 and triethanolamine according to Method E. 1H NMR (400 MHz, CDCl3) δ ppm 1.17-1.66 (m, 7H), 1.70-1.82 (m, 1H), 1.88-2.02 (m, 1H), 2.06-2.18 (m, 1H), 2.23-2.45 (m, 1H), 2.79-2.85 (m, 4H), 2.86-2.97 (m, 1H), 3.03 (t, J=5.50 Hz, 2H), 3.07-3.17 (m, 1H), 3.48 (ddd, J=13.90, 9.47, 4.83 Hz, 1H), 3.63-3.70 (m, 4H), 4.48 (t, J=5.50 Hz, 2H), 4.63 (dd, J=9.40, 5.37 Hz, 1H), 7.01 (dd, J=8.86, 2.15 Hz, 1H), 7.29 (d, J=2.15 Hz, 1H), 7.45 (d, J=8.86 Hz, 1H), 7.82-7.99 (m, 2H), 8.15 (d, J=8.59 Hz, 1H). ES-MS m/z 551 (M+H)
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19](=[S:21])[NH:18][C:17]3=[O:22])=[CH:12][CH:13]=2)[CH:8]=[N:7]1.I[CH3:34]>>[F:32][C:2]([F:31])([F:1])[C:3]1[CH:26]=[C:25]([C:27]([F:28])([F:29])[F:30])[CH:24]=[CH:23][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19]([S:21][CH3:34])=[N:18][C:17]3=[O:22])=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: O=C1NC(=S)SC1=Cc1ccc2c(cnn2Cc2ccc(C(F)(F)F)cc2C(F)(F)F)c1
Reactant: CI
Product: CSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)S1

Procedure:
5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazol-4-one was prepared from 5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-thioxo-thiazolidin-4-one and iodomethane following General Procedure C.