Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [BH4-].[Na+].[OH-].[Na+].[C:5]1([C:11]2([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:19]3[CH:15]([CH2:16][NH:17][CH:18]3[C:20](=[O:28])[CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:14](=[O:29])[CH2:13][CH2:12]2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.Cl>CO.ClCCl.O>[C:30]1([C:11]2([C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:19]3[CH:15]([CH2:16][NH:17][CH:18]3[C:20](=[O:28])[CH2:21][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:14]([OH:29])[CH2:13][CH2:12]2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=C1CCC(c2ccccc2)(c2ccccc2)C2C1CNC2C(=O)Cc1ccccc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: O=C(Cc1ccccc1)C1NCC2C(O)CCC(c3ccccc3)(c3ccccc3)C12
Reaction time: 2 h
Yield: 11.9 %

Procedure:
A solution of 0.12 g of sodium borohydride and 0.05 cm3 of 10N sodium hydroxide in 20 cm3 of methanol is added over 10 minutes to a suspension, cooled to +5° C., of 2.0 g of (3aRS,7aRS)-7,7-diphenyl-2-phenylacetyl-4-perhydro-isoindolone in 100 cm3 of methanol. The reaction mixture is stirred for 2 hours at low temperature, followed by the addition of 0.5 cm3 of 1N hydrochloric acid and concentration to a reduced volume, at 40° C. under reduced pressure (2.7 kPa). The residue is taken up in 50 cma of water and 150 cm3 of dichloromethane. After stirring, the organic phase is dried over magnesium sulphate and concentrated to dryness. The solid is crystallized from acetonitrile, the crystals are washed with acetonitrile and diisopropyl oxide, drained and then dried. 0.24 g of (3aRS,4RS,7aRS)-7,7-diphenyl-2-phenyl-acetyl-4-perhydroisoindolol is obtained in the form of white crystals; melting point 220° C.
Reaction SMILES: Cl[C:2]1[N:10]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]=1[CH:17]=[O:18].[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20]>O1CCOCC1>[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][N:29]([C:2]2[N:10]([C:11]3[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=3)[C:5]3=[N:6][CH:7]=[CH:8][CH:9]=[C:4]3[C:3]=2[CH:17]=[O:18])[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=Cc1c(Cl)n(-c2cccnc2)c2ncccc12
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCN(c2c(C=O)c3cccnc3n2-c2cccnc2)CC1
Temperature: 95 °C
Yield: 85 %

Procedure:
A solution of 2-chloro-1-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde (46 mg, 0.179 mmol) in 1,4-dioxane (4 mL) is treated with piperazine-1-carboxylic acid tert-butyl ester (157 mg, 0.843 mmol) and the resulting yellow solution is heated-to 95° C. under a reflux condenser for 29 hours. The reaction mixture is evaporated to give a red oil. The residue is purified by flash chromatography on a 5-gram silica gel cartridge by elution with dichloromethane:ethyl acetate (3:1, increasing to 2:1 to 1:1). Fractions containing the product are combined and the solvent evaporated to give 62 mg of 4-(3-formyl-1-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridin-2-yl)-piperazine-1-carboxylic acid tert-butyl ester as a orange waxy solid (85% yield). MS: m/e 408 (M+H), 430 (M+Na). 1H NMR (300 MHz, CDCl3): 10.29 (1H, s), 8.78 (1H, d), 8.74 (1H, dd), 8.50 (1H, d), 8.20 (1H, dd), 7.94 (1H, dm), 7.59 (1H, dd), 7.22 (1H, dd), 3.39-3.28 (8H, m), 1.46 (9H, s).
Reaction SMILES: Br[C:2]1[C:10]2[O:9][CH2:8][CH:7]([C:11]3[CH:16]=[CH:15][C:14]([CH:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=3)[C:6]=2[C:5]([CH3:20])=[C:4]([NH:21][C:22](=[O:28])[CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:3]=1[CH3:29].[N:30]1[CH:35]=[CH:34][CH:33]=[C:32](B(O)O)[CH:31]=1>>[CH:17]([C:14]1[CH:13]=[CH:12][C:11]([CH:7]2[C:6]3[C:5]([CH3:20])=[C:4]([NH:21][C:22](=[O:28])[CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:3]([CH3:29])=[C:2]([C:32]4[CH:31]=[N:30][CH:35]=[CH:34][CH:33]=4)[C:10]=3[O:9][CH2:8]2)=[CH:16][CH:15]=1)([CH3:19])[CH3:18]
Reactant: Cc1c(Br)c2c(c(C)c1NC(=O)CC(C)(C)C)C(c1ccc(C(C)C)cc1)CO2
Reactant: OB(O)c1cccnc1
Product: Cc1c(NC(=O)CC(C)(C)C)c(C)c2c(c1-c1cccnc1)OCC2c1ccc(C(C)C)cc1
Yield: 32 %

Procedure:
Using N-(7-bromo-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide obtained in Example 35 and pyridin-3-ylboronic acid, the title compound was obtained in the same manner as in Example 107. Yield: 32%. Melting point: 142-144° C. (ethyl acetate-hexane).
Reaction SMILES: [OH:1][C:2]1[C:3]([CH2:20][O:21][CH3:22])([CH3:19])[O:4][C:5]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:6]=2[C:7]=1[C:8](=[S:11])[NH:9][CH3:10].O1CCCC1.[BH4-].[Na+]>CO>[CH3:10][NH:9][C:8]([CH:7]1[C:6]2[CH:12]=[C:13]([N+:16]([O-:18])=[O:17])[CH:14]=[CH:15][C:5]=2[O:4][C:3]([CH2:20][O:21][CH3:22])([CH3:19])[CH:2]1[OH:1])=[S:11]
Reactant: CNC(=S)C1=C(O)C(C)(COC)Oc2ccc([N+](=O)[O-])cc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CNC(=S)C1c2cc([N+](=O)[O-])ccc2OC(C)(COC)C1O
Yield: 39 %

Procedure:
To a mixture of 5.1 g of 3-hydroxy-2-methoxymethyl-N,2-dimethyl-6-nitro-2H-1-benzopyran-4-carbothioamide, 75 ml of tetrahydrofuran and 125 ml of methanol was added 3.0 g of sodium borohydride (NaBH4). The mixture was stirred under ice-cooling for 2 hours and subsequently stirred at room temperature for 24 hours. The reaction solution was vacuum-distilled and water was added to it and the resultant solution was extracted with methylene chloride. After an organic layer was washed with water and dried, the solvent was distilled to obtain 2 g of N-methyl-3,4-dihydro-3-hydroxy-2-methoxymethyl-2-methyl-6-nitro-2H-1-benzopyran-4-carbothioamide. Subsequently, to 1 g of the obtained benzopyran derivative were added 1.17 g of p-toluenesulfonyl chloride and 25 ml of pyridine. The resultant mixture was refluxed with heating for 1 hour and the solvent was distilled. Ice water was added to the residue and it was acidified to be hydrochloric acid and extracted with methylene chloride. An organic layer was washed with water and dried, and the solvent was distilled. The resultant residue was purified according to silica gel column chromatography (developing solution, hexane:AcOEt=1:1) to obtain 680 mg of 2-methoxymethyl-N,2-dimethyl-6-nitro-2H-1-benzopyran-4-carboxamide with a melting point of 128°-130° C.
Reaction SMILES: C(N1CCC(C(O)=O)C1)C1C=CC=CC=1.[NH:16]1[CH2:20][CH2:19][CH:18]([C:21]([OH:23])=[O:22])[CH2:17]1.C(N(CC)CC)C.[C:31]([O:35][C:36](N=[N+]=[N-])=[O:37])([CH3:34])([CH3:33])[CH3:32].[N-]=[N+]=[N-]>C(O)(=O)C.[Pd].CN(C=O)C.O>[C:31]([O:35][C:36]([N:16]1[CH2:20][CH2:19][CH:18]([C:21]([OH:23])=[O:22])[CH2:17]1)=[O:37])([CH3:34])([CH3:33])[CH3:32]
Reactant: O=C(O)C1CCNC1
Reactant: CC(C)(C)OC(=O)N=[N+]=[N-]
Agent: [Pd]
Agent: O=C(O)C1CCN(Cc2ccccc2)C1
Agent: [N-]=[N+]=[N-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(C(=O)O)C1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of 205 g. (1 mol.) of N-benzylpyrrolidine-3-carboxylic acid (CA, 64 14173d) is dissolved in glacial acetic acid (1 l.) and hydrogenated in the presence of 40 g. of 10% palladium on charcoal until no more starting material is detected by TLC. The catalyst is filtered off and the filtrate is concentrated to dryness in vacuo. The residual 3-pyrrolidine carboxylic acid is dissolved in a mixture of DMF-H2O (2:1) (2 liters), triethylamine (1 mol.), t-butoxycarbonyl azide (1.5 mol.) is added and the mixture is stirred at room temperature for two days. Periodically the pH is tested with pH paper, and after twenty-four hours more azide (0.5 mol.) is added. The solvent is concentrated in vacuo to remove the DMF, the aqueous phase is acidified with citric acid (to pH 2-3) and extracted with ethyl acetate. The organic phase is concentrated to dryness in vacuo to yield the product 1-(t-butyloxycarbonyl)-3-pyrrolidinecarboxylic acid.
Reaction SMILES: OC1C=CC=CC=1C(=O)C.C(=O)C1C(=CC=CC=1)O.BrCC(C1C=CC(OC)=CC=1)=O.BrCC(C1C=CC(Cl)=CC=1)=O.[CH3:43][C:44]1[C:48]2[CH:49]=[CH:50][CH:51]=[CH:52][C:47]=2[O:46][C:45]=1[C:53](=[O:62])[C:54]1[CH:59]=[CH:58][C:57]([O:60]C)=[CH:56][CH:55]=1>>[CH3:43][C:44]1[C:48]2[CH:49]=[CH:50][CH:51]=[CH:52][C:47]=2[O:46][C:45]=1[C:53](=[O:62])[C:54]1[CH:59]=[CH:58][C:57]([OH:60])=[CH:56][CH:55]=1
Reactant: COc1ccc(C(=O)c2oc3ccccc3c2C)cc1
Agent: CC(=O)c1ccccc1O
Agent: COc1ccc(C(=O)CBr)cc1
Agent: O=C(CBr)c1ccc(Cl)cc1
Solvent: O=Cc1ccccc1O
Product: Cc1c(C(=O)c2ccc(O)cc2)oc2ccccc12

Procedure:
When an equivalent amount of o-hydroxyacetophenone is substituted in the procedure of Example 11 for salicylaldehyde and α-bromo-p-methoxyacetophenone is substituted for α-bromo-p-chloroacetophenone, there is ultimately obtained 3-methyl-2-(4-methoxybenzoyl)benzofuran. Demethylation of 3-methyl-2-(4-methoxybenzoyl)-benzofuran as described above gives 3-methyl-2-(4-hydroxybenzoyl)benzofuran.
Reaction SMILES: [N:1]1([CH2:6][C@@H:7]([O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:21](=[O:25])[CH2:20][CH2:19][CH2:18][C:17]=3[C:16]=2[CH2:26][S:27]([C:30]2[CH:31]=[C:32]([CH:36]=[CH:37][CH:38]=2)[C:33](O)=[O:34])(=[O:29])=[O:28])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[CH:39]1([NH2:44])[CH2:43][CH2:42][CH2:41][CH2:40]1>>[CH:39]1([NH:44][C:33](=[O:34])[C:32]2[CH:36]=[CH:37][CH:38]=[C:30]([S:27]([CH2:26][C:16]3[C:17]4[CH2:18][CH2:19][CH2:20][C:21](=[O:25])[C:22]=4[CH:23]=[CH:24][C:15]=3[O:14][C@@H:7]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH2:6][N:1]3[CH:5]=[CH:4][N:3]=[CH:2]3)(=[O:28])=[O:29])[CH:31]=2)[CH2:43][CH2:42][CH2:41][CH2:40]1
Reactant: NC1CCCC1
Reactant: O=C(O)c1cccc(S(=O)(=O)Cc2c(O[C@H](Cn3ccnc3)c3ccccc3)ccc3c2CCCC3=O)c1
Product: O=C(NC1CCCC1)c1cccc(S(=O)(=O)Cc2c(O[C@H](Cn3ccnc3)c3ccccc3)ccc3c2CCCC3=O)c1
Yield: 98.7 %

Procedure:
Using the method in Example 172, 3-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfonyl}benzoic acid (53 mg, 0.10 mmol, 0.20M in DMF) and cyclopentylamine (26 mg, 0.30 mmol, 0.6M in DMF) were combined to give 59 mg of the desired compound: Low resolution mass spectrum (LC-MS, APCI) m/z 598 [M+H]+.
Reaction SMILES: C(O[C:4]([C:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[NH:13][N:12]=2)[NH:8][CH:7]=1)=[O:5])C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[CH2:41]([NH2:49])[CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>CN(C=O)C>[CH2:41]([NH:49][C:4]([C:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[NH:13][N:12]=2)[NH:8][CH:7]=1)=[O:5])[CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: CCOC(=O)c1c[nH]c(-c2n[nH]c3ncccc23)c1
Reactant: NCCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C(NCCc1ccccc1)c1c[nH]c(-c2n[nH]c3ncccc23)c1
Temperature: 40 °C

Procedure:
A mixture of 5-(1H-pyrazolo[3,4-b]pyridin-3-yl)-1H-pyrrole-3-carboxylic acid (50 mg, 0.22 mmol) (from Example 11), HOBt (74 mg, 2.5 eq.), EDAC (105 mg, 2.5 eq.), phenethylamine (106 mg, 4 eq.) and TEA (0.5 mL) in DMF (1 mL) was heated at 40° C. for overnight. The reaction was concentrated and purified on a silica gel column to give the titled compound as a white solid.
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][NH:11][C:12]1[CH:13]=[C:14]([C:18]2[N:19]=[C:20]([S:23][CH2:24][C:25]([NH:27][CH:28]3[CH2:33][CH2:32][N:31]([CH2:34][C:35]4[CH:40]=[CH:39][C:38]([Cl:41])=[C:37]([Cl:42])[CH:36]=4)[CH2:30][CH2:29]3)=[O:26])[S:21][CH:22]=2)[CH:15]=[CH:16][CH:17]=1)=O)(C)(C)C.C(OCC)(=O)C.[ClH:49]>C(OCC)(=O)C>[ClH:41].[ClH:49].[NH2:8][CH2:9][CH2:10][NH:11][C:12]1[CH:13]=[C:14]([C:18]2[N:19]=[C:20]([S:23][CH2:24][C:25]([NH:27][CH:28]3[CH2:33][CH2:32][N:31]([CH2:34][C:35]4[CH:40]=[CH:39][C:38]([Cl:41])=[C:37]([Cl:42])[CH:36]=4)[CH2:30][CH2:29]3)=[O:26])[S:21][CH:22]=2)[CH:15]=[CH:16][CH:17]=1
Reactant: CC(C)(C)OC(=O)NCCNc1cccc(-c2csc(SCC(=O)NC3CCN(Cc4ccc(Cl)c(Cl)c4)CC3)n2)c1
Agent: Cl
Solvent: CCOC(C)=O
Product: NCCNc1cccc(-c2csc(SCC(=O)NC3CCN(Cc4ccc(Cl)c(Cl)c4)CC3)n2)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
The product (238 mg) of Example 154 was dissolved in ethyl acetate (1 mL), and a 4 mol/L hydrogen chloride-ethyl acetate solution (0.55 mL) was added to the solution under ice-cooling. The mixture was stirred at room temperature for 20 hrs, and the resulting solids were collected by filtration to give the title compound (201 mg) as a white powder.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[CH:11]=[C:10]([C:12]2[S:13][C:14]([CH3:17])=[CH:15][CH:16]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7](Br)[CH:8]=2)[O:3]1.[Li]C(C)(C)C.CN([CH:28]=[O:29])C>C1COCC1.CCCCC.C(OCC)(=O)C>[CH3:1][C:2]1([CH3:19])[CH:11]=[C:10]([C:12]2[S:13][C:14]([CH3:17])=[CH:15][CH:16]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH:28]=[O:29])[CH:8]=2)[O:3]1
Reactant: Cc1ccc(C2=CC(C)(C)Oc3ccc(Br)cc32)s1
Reactant: CN(C)C=O
Agent: [Li]C(C)(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCCCC
Product: Cc1ccc(C2=CC(C)(C)Oc3ccc(C=O)cc32)s1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a cold (-78° C.) solution of 2,2-dimethyl-4(5-methyl-thien-2-yl)-6-bromo-chrom-3-ene (Compound R, 1.2 g, 3.6 mmol) in THF (10 mL), was added t-BuLi in pentane (1.7M solution, 2.3 mL). After 30 minutes, DMF (465 mg, 5 mmol) was added and the mixture was allowed to warm to ambient temperature and stirred for 3 hours. The mixture was diluted with ethyl acetate (150 mL), washed with brine (10 mL), dried and the solvent was removed by evaporation. Purification by chromatography on silica gel column gave the title compound as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[C:11]([N+:12]([O-])=O)=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1>C1COCC1.CO.[Pd]>[NH2:12][C:11]1[C:2]([NH2:1])=[N:3][CH:4]=[C:5]([CH:10]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1cnc(N)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1cnc(N)c(N)c1
Reaction time: 15 h
Yield: 99.6 %

Procedure:
To a stirred mixture of methyl 6-amino-5-nitronicotinate (2 g, 10.15 mmol) in a mixture of THF (30 mL) and MeOH (10 mL) at rt was added palladium (10 wt % on activated carbon, 100 mg), and the mixture stirred under hydrogen gas (1 atmosphere) for 15 h. The mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to afford methyl 5,6-diaminonicotinate (1.69 g, 100%) as a yellow solid which did not require further purification. 1H NMR (300 MHz, DMSO-d6) δ 7.94 (d, J=2.1 Hz, 1H), 7.16 (d, J=2.1 Hz, 1H), 6.27 (br s, 2H), 4.92 (br s, 2H), 3.74 (s, 3H). LCMS (ESI) m/z 168 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([S:8][C:9]2[CH:16]=[CH:15][C:12]([CH2:13][OH:14])=[CH:11][C:10]=2[N+:17]([O-])=O)=[N:4][CH:5]=[CH:6][N:7]=1.[Cl-].[NH4+]>O1CCCC1.CC(O)C.O.[Fe]>[NH2:17][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][C:9]=1[S:8][C:3]1[C:2]([Cl:1])=[N:7][CH:6]=[CH:5][N:4]=1)[CH2:13][OH:14]
Reactant: O=[N+]([O-])c1cc(CO)ccc1Sc1nccnc1Cl
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CC(C)O
Solvent: C1CCOC1
Product: Nc1cc(CO)ccc1Sc1nccnc1Cl
Yield: 102.2 %

Procedure:
1.60 g of 4-[(3-chloropyrazin-2-yl)thio]-3-nitrobenzyl alcohol was dissolved in a solvent mixture of tetrahydrofuran (20 ml)/2-propanol (20 ml)/water (7 ml). After adding 0.16 g of ammonium chloride and 1.50 g of iron powder, the resulting mixture was heated under reflux for 30 minutes. Then the reaction mixture was filtered through celite and concentrated under reduced pressure. After adding ethanol, the reaction mixture was concentrated under reduced pressure. Then tetrahydrofuran was added to the residue and the insoluble matters were separated by filtration. After distilling off the solvent under reduced pressure, 1.47 g of the title compound was obtained as yellow crystals.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][C@:8]([CH2:19][OH:20])([CH3:18])[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)([CH3:4])([CH3:3])[CH3:2]>C(Cl)Cl.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[C:1]([O:5][C:6](=[O:21])[NH:7][C@:8]([CH:19]=[O:20])([CH3:18])[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])=[CH:13][CH:12]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@](C)(CO)CCc1ccc(O)cc1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Solvent: ClCCl
Product: CCCCCCCOc1ccc(CC[C@](C)(C=O)NC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of [(R)-1-hydroxymethyl-3-(4-hydroxy-phenyl)-1-methyl-propyl]-carbamic acid tert-butyl ester (1.98 g, 5.03 mMol) in CH2Cl2 (20 ml) is added N-morpholine-N-oxide (884 mg, 7.54 mMol) and tetra-n-propylammonium perruthenate (177 mg, 0.50 mMol). The mixture is stirred at RT for 1 hour. The mixture is then filtered over a short pad of SiO2 eluting with diethyl ether. The filtrate is concentrated under reduced pressure to give the title compound. The crude product is sufficiently pure to be used in the next stage without further purification.
Reaction SMILES: CS(O[CH2:6][C:7]1[N:12]=[CH:11][C:10]2[N:13]=[CH:14][N:15]([C:16]3[S:17][C:18]([C:34](=[O:36])[NH2:35])=[C:19]([O:21][C@@H:22]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[C:30]([F:33])([F:32])[F:31])[CH3:23])[CH:20]=3)[C:9]=2[CH:8]=1)(=O)=O.[C:37]([N:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1)(=[O:39])[CH3:38]>ClCCl>[C:37]([N:40]1[CH2:45][CH2:44][N:43]([CH2:6][C:7]2[N:12]=[CH:11][C:10]3[N:13]=[CH:14][N:15]([C:16]4[S:17][C:18]([C:34]([NH2:35])=[O:36])=[C:19]([O:21][C@@H:22]([C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=5[C:30]([F:32])([F:33])[F:31])[CH3:23])[CH:20]=4)[C:9]=3[CH:8]=2)[CH2:42][CH2:41]1)(=[O:39])[CH3:38]
Reactant: C[C@@H](Oc1cc(-n2cnc3cnc(COS(C)(=O)=O)cc32)sc1C(N)=O)c1ccccc1C(F)(F)F
Reactant: CC(=O)N1CCNCC1
Solvent: ClCCl
Product: CC(=O)N1CCN(Cc2cc3c(cn2)ncn3-c2cc(O[C@H](C)c3ccccc3C(F)(F)F)c(C(N)=O)s2)CC1

Procedure:
In a similar manner as described for example 58, 108 mg of [1-(5-carbamoyl-4-{(1R)-1-[2-(trifluoromethyl)phenyl]ethoxy}-2-thienyl)-1H-imidazo[4,5-c]pyridin-6-yl]methyl methanesulfonate and 128.2 mg of 1-acetylpiperazine in 2.5 ml dichloromethane give the title compound.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[NH:8][C:9](=[O:12])[NH:10][CH:11]=1)=[O:5])C.[OH-].[Na+].Cl>CO.O>[F:19][C:16]1[CH:17]=[CH:18][C:13]([CH:7]2[C:6]([C:4]([OH:5])=[O:3])=[CH:11][NH:10][C:9](=[O:12])[NH:8]2)=[CH:14][CH:15]=1
Reactant: CCOC(=O)C1=CNC(=O)NC1c1ccc(F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C1NC=C(C(=O)O)C(c2ccc(F)cc2)N1
Yield: 71.5 %

Procedure:
4-(4-Fluoro-phenyl)-2-oxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid ethyl ester (3.6 g) was suspended in 67 mL MeOH and 2.5 M NaOH (23 mL) was added. The mixture was heated at 65° for 6 hours, then cooled, diluted with water and acidified with conc. HCl. The resulting precipitate was recovered by filtration and air dried to yield 4-(4-fluoro-phenyl)-2-oxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid(2.3 g).
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([C:14]1[CH:15]=[N:16][N:17]([C:20]([CH3:23])([CH3:22])[CH3:21])[C:18]=1Cl)=[O:13])[CH2:8]2.[NH:24]1[CH2:29][CH2:28][CH:27]([OH:30])[CH2:26][CH2:25]1>>[CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([C:14]1[CH:15]=[N:16][N:17]([C:20]([CH3:23])([CH3:22])[CH3:21])[C:18]=1[N:24]1[CH2:29][CH2:28][CH:27]([OH:30])[CH2:26][CH2:25]1)=[O:13])[CH2:8]2
Reactant: CC(C)(C)n1ncc(C(=O)NC2C3CC4CC(C3)CC2C4)c1Cl
Reactant: OC1CCNCC1
Product: CC(C)(C)n1ncc(C(=O)NC2C3CC4CC(C3)CC2C4)c1N1CCC(O)CC1

Procedure:
Heating a mixture of 1-tert-butyl-5-chloro-1H-pyrazole-4-carboxylic acid adamantan-2-ylamide (Example 36, 101 mg; 0.30 mmol) and piperidin-4-ol (303 mg; 3.0 mmol) under microwave irradiation according to the procedure described in Example 37, Step 5 provided after purification by reverse phase HPLC, 1-tert-butyl-5-(4-hydroxy-piperidin-1-yl)-1H-pyrazole-4-carboxylic acid adamantan-2-ylamide (14 mg, 12%) as an off-white powder. ES-HRMS m/e calcd for C23H37N4O2 (M+H+) 357.2649, found 357.2650.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][CH2:9][CH2:10][N:11]([CH2:14][CH3:15])[CH2:12][CH3:13])[C:5]([N+:16]([O-:18])=[O:17])=[C:4]([NH:19][CH2:20][CH2:21][N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])[CH:3]=1.C(O)(=O)C.C(O)=O.[ClH:34]>C(N(CC)CC)C.O.C(O)C.[Pd]>[ClH:1].[ClH:34].[CH2:14]([N:11]([CH2:12][CH3:13])[CH2:10][CH2:9][NH:8][C:6]1[CH:7]=[CH:2][CH:3]=[C:4]([NH:19][CH2:20][CH2:21][N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])[C:5]=1[N+:16]([O-:18])=[O:17])[CH3:15]
Reactant: CCN(CC)CCNc1cc(Cl)cc(NCCN(CC)CC)c1[N+](=O)[O-]
Agent: [Pd]
Agent: Cl
Solvent: O=CO
Solvent: CC(=O)O
Solvent: O
Product: CCN(CC)CCNc1cccc(NCCN(CC)CC)c1[N+](=O)[O-]

Procedure:
300 mg of palladium at a concentration of 10% on calcium carbonate are added to 0.015 mole (5.8 g) of 4-chloro-2-(β-diethylaminoethyl)amino-6-(β-diethylaminoethyl)aminonitrobenzene in 11.1 ml of triethylamine, after which 2.86 ml of acetic acid and 2.1 ml of formic acid are added dropwise. After the end of the additions, the materials are heated under reflux for 3 hours 30 minutes. The reaction mixture is diluted with 10 ml of water. The catalyst is removed by hot filtration. The filtrate is evaporated to dryness under vacuum. The inorganic salts are precipitated by adding acetone and are removed by filtration. After evaporation of the acetone, an oil is obtained and this, after treatment with a solution of hydrochloric acid in absolute ethanol, leads to the expected product which is isolated by evaporating off the alcohol and precipitating with ethyl ether.
Reaction SMILES: C[O:2][C:3]1[C:11]([O:12][CH3:13])=[C:10]([O:14][CH3:15])[C:9]([O:16]C)=[C:8]2[C:4]=1[CH2:5][C:6]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][OH:32])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:7]2.N1C(C(O)=O)=CC=CC=1C(O)=O.C1COCC1.O=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+]>O>[OH:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][C:6]1([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:5][C:4]2[C:3](=[O:2])[C:11]([O:12][CH3:13])=[C:10]([O:14][CH3:15])[C:9](=[O:16])[C:8]=2[CH2:7]1
Reactant: COc1c2c(c(OC)c(OC)c1OC)CC(CCCCCCCCO)(c1ccccc1)C2
Agent: O=C(O)c1cccc(C(=O)O)n1
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Solvent: C1CCOC1
Solvent: O
Product: COC1=C(OC)C(=O)C2=C(CC(CCCCCCCCO)(c3ccccc3)C2)C1=O
Reaction time: 0.25 h
Yield: 58.2 %

Procedure:
To a solution of 8-(4,5,6,7-tetramethoxy-2-phenylindan-2-yl)octanol (1.00 g), 2,6-pyridinedicarboxylic acid (1.13 g), THF (20 ml), and water (10 ml) was dropwise added a solution of CAN (4.92 g) in water (10 ml) with cooling with ice. After the reaction mixture was stirred for 15 min, water was added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was washed with water, and saturated aqueous sodium chloride and dried. The solvent was removed in vacuo. The residue was purified by silica gel column chromatography (hexane to hexane:ethyl acetate=4:1) to yield the entitled compound (542 mg) as an oil.
Reaction SMILES: [CH2:1]([CH:3]([NH:6][C:7](=[O:11])[O:8][CH2:9][CH3:10])[CH2:4][OH:5])[CH3:2].[Br:12][CH:13]([CH3:17])[C:14](Br)=[O:15]>>[CH2:1]([CH:3]([NH:6][C:7](=[O:11])[O:8][CH2:9][CH3:10])[CH2:4][O:5][C:14](=[O:15])[CH:13]([Br:12])[CH3:17])[CH3:2]
Reactant: CC(Br)C(=O)Br
Reactant: CCOC(=O)NC(CC)CO
Product: CCOC(=O)NC(CC)COC(=O)C(C)Br

Procedure:
by using ethyl 1-ethyl-2-hydroxy-ethylcarbamate and 2-bromopropionyl bromide there is obtained ethyl 1-ethyl-2-(2-bromopropionyloxy)-ethylcarbamate, nD20 1.4736;