Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[C:15]([OH:17])[N:14]4[N:18]=[CH:19][CH:20]=[C:13]4[N:12]=3)[CH2:7][CH2:6]2)OCC1.O=C(C1CCCC2([O:35][CH2:34][CH2:33][O:32]2)C1)CC(OCC)=O.O=C(C1CCC2(OCCO2)CC1)CC(OCC)=O>>[O:32]1[C:6]2([CH2:5][CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[C:15]([OH:17])[N:14]4[N:18]=[CH:19][CH:20]=[C:13]4[N:12]=3)[CH2:7]2)[O:35][CH2:34][CH2:33]1
Reactant: CCOC(=O)CC(=O)C1CCCC2(C1)OCCO2
Reactant: Oc1cc(C2CCC3(CC2)OCCO3)nc2ccnn12
Agent: CCOC(=O)CC(=O)C1CCC2(CC1)OCCO2
Product: Oc1cc(C2CCCC3(C2)OCCO3)nc2ccnn12

Procedure:
5-(1,4-dioxaspiro[4.5]decan-7-yl)pyrazolo[1,5-a]pyrimidin-7-ol was synthesized in a manner similar to the synthesis of 5-(1,4-dioxaspiro[4.5]decan-8-yl)pyrazolo[1,5-a]pyrimidin-7-ol, but with ethyl 3-oxo-3-(1,4-dioxaspiro[4.5]decan-7-yl)propanoate substituted for ethyl 3-oxo-3-(1,4-dioxaspiro[4.5]decan-8-yl)propanoate.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([OH:9])=O.C1C=NC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[CH3:29][O:30][C:31](=[O:50])[C:32]1[CH:37]=[CH:36][C:35]([NH:38][CH:39]2[CH2:44][CH2:43][CH2:42][CH2:41][CH:40]2[C:45]([F:48])([F:47])[F:46])=[C:34]([NH2:49])[CH:33]=1>CN(C=O)C.O.C(Cl)CCl>[CH3:29][O:30][C:31](=[O:50])[C:32]1[CH:37]=[CH:36][C:35]([NH:38][CH:39]2[CH2:44][CH2:43][CH2:42][CH2:41][CH:40]2[C:45]([F:48])([F:46])[F:47])=[C:34]([NH:49][C:7](=[O:9])[CH2:6][C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)[CH:33]=1
Reactant: O=C(O)Cc1cccs1
Reactant: COC(=O)c1ccc(NC2CCCCC2C(F)(F)F)c(N)c1
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: COC(=O)c1ccc(NC2CCCCC2C(F)(F)F)c(NC(=O)Cc2cccs2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.7 %

Procedure:
To a solution of 0.71 g of thiophen-2-yl-acetic acid in 10 ml of dry DMF 0.68 g of HOAT, 1.22 g of EDC and 2.25 ml of DIPEA were added at 0° C. After 30 min 1.44 g of 3-Amino-4-(2-trifluoromethyl-cyclohexylamino)-benzoic acid methyl ester were added, and the reaction was stirred at rt for 16 h. The reaction was then poured into water and extracted with ethyl acetate three times. The combined organic phases were washed with saturated aqueous sodium bicarbonate solution and brine, dried over magnesium sulphate and concentrated to obtain 2.00 g (100%) of 3-(2-Thiophen-2-yl-acetylamino)-4-(2-trifluoromethyl-cyclohexylamino)-benzoic acid methyl ester, which was used without further purification.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[Cl:11][C:12]1[C:17]([O:18][CH3:19])=[C:16]([C:20](OC)=[O:21])[CH:15]=[C:14]([CH:24]2[CH2:26][CH2:25]2)[C:13]=1[C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=1[F:34].O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>C1COCC1>[Cl:11][C:12]1[C:17]([O:18][CH3:19])=[C:16]([CH2:20][OH:21])[CH:15]=[C:14]([CH:24]2[CH2:26][CH2:25]2)[C:13]=1[C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=1[F:34]
Reactant: COC(=O)c1cc(C2CC2)c(-c2ccc(F)cc2F)c(Cl)c1OC
Agent: CC(C)C[Al+]CC(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: COc1c(CO)cc(C2CC2)c(-c2ccc(F)cc2F)c1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.3 %

Procedure:
Diisobutylaluminum hydride (1.5 M toluene solution, 6 mL) was added at 0° C. to a THF (40 mL) solution of methyl 2-chloro-6-cyclopropyl-2′,4′-difluoro-3-methoxybiphenyl-4-carboxylate (1.17 g), and the mixture was stirred at room temperature for 1 hour in a nitrogen atmosphere. Diisobutylaluminum hydride (1.5 M toluene solution, 2 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 30 minutes in a nitrogen atmosphere. Then, diisobutylaluminum hydride (1.5 M toluene solution, 2 mL) was further added thereto, and the mixture was stirred at room temperature for 30 minutes in a nitrogen atmosphere. Sodium sulfate decahydrate was added to the reaction mixture at 0° C., and the mixture was filtered through celite. Then, the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (1.07 g).
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=1.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1>>[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]4=[C:7]([CH3:16])[C:6]=3[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=2)=[CH:23][CH:22]=1
Reactant: Cc1c2n(c3c(Br)cc(C#N)cc13)CCNC2=O
Reactant: COc1ccc(B(O)O)cc1
Product: COc1ccc(-c2cc(C#N)cc3c(C)c4n(c23)CCNC4=O)cc1

Procedure:
The title compound, light grey solid (34 mg, 41%), MS (ISP) m/z=332.6 [(M+H)+], mp 285° C., was prepared in accordance with the general method of example 1 from 6-bromo-10-methyl-1-oxo-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole-8-carbonitrile (intermediate 16) (76 mg, 0.25 mmol) and commercially available 4-methoxy-phenylboronic acid (49.4 mg, 0.325 mmol).
Reaction SMILES: [ClH:1].C(OC([N:9]1[CH2:14][CH2:13][N:12]([C:15]2[C:20]([CH3:21])=[CH:19][C:18]([N+:22]([O-:24])=[O:23])=[CH:17][N:16]=2)[CH2:11][CH2:10]1)=O)(C)(C)C>C(Cl)Cl.O1CCOCC1>[ClH:1].[CH3:21][C:20]1[C:15]([N:12]2[CH2:11][CH2:10][NH:9][CH2:14][CH2:13]2)=[N:16][CH:17]=[C:18]([N+:22]([O-:24])=[O:23])[CH:19]=1
Reactant: Cc1cc([N+](=O)[O-])cnc1N1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: Cc1cc([N+](=O)[O-])cnc1N1CCNCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97 %

Procedure:
Add a solution of HCl 4M in dioxane (4 equiv) to a solution of 4-(3-Methyl-5-nitro-pyridin-2-yl)-piperazine-1-carboxylic acid tert-butyl ester (7.77 g, 24.13 mmol) in DCM (73 mL). Stir mixture at room temperature overnight. Add 2 more equiv of the HCl in dioxane solution. After no starting material is detected by LCMS, filter solid and dry under reduced pressure to obtain 6.91 g of 1-(3-methyl-5-nitro-pyridin-2-yl)-piperazine hydrochloride as a yellowish solid (97% yield). ES+(m/z): 259 [M+1].
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[C:11]2[C:6](=[C:7]([CH3:23])[CH:8]=[C:9]([C:13]([C:15]3[C:16]([CH3:22])=[N:17][N:18]([CH3:21])[C:19]=3[OH:20])=[O:14])[C:10]=2[CH3:12])[S:5](=[O:25])(=[O:24])[CH2:4][CH2:3]1.N1C=CC=CC=1.Cl.[C:34](Cl)(=[O:41])[C:35]1[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=1>ClCCCl.[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1>[CH3:1][C:2]1([CH3:26])[C:11]2[C:6](=[C:7]([CH3:23])[CH:8]=[C:9]([C:13]([C:15]3[C:16]([CH3:22])=[N:17][N:18]([CH3:21])[C:19]=3[O:20][C:34]([C:35]3[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=3)=[O:41])=[O:14])[C:10]=2[CH3:12])[S:5](=[O:25])(=[O:24])[CH2:4][CH2:3]1
Reactant: O=C(Cl)c1ccncc1
Reactant: Cc1cc(C(=O)c2c(C)nn(C)c2O)c(C)c2c1S(=O)(=O)CCC2(C)C
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: Cl
Agent: [Cl-]
Solvent: c1ccncc1
Solvent: ClCCCl
Product: Cc1cc(C(=O)c2c(C)nn(C)c2OC(=O)c2ccncc2)c(C)c2c1S(=O)(=O)CCC2(C)C
Yield: 76.9 %

Procedure:
1.0 Gram (2.7 mmol) of the 4,4,5,8-tetramethyl-6-(1,3-dimethyl-5-hydroxypyrazol-4-yl)carbonylthiochroman-1,1-dioxide obtained in Preparation Example 6 was dissolved in 10 ml of 1,2-dichloroethane, and further, 0.26 g (3.2 mmol) of pyridine, 0.57 g (3.2 mmol) of isonicotinic acid chloride hydrochloride and 10 mg of benzyltriethylammonium chloride were added. The mixture was allowed to react at room temperature for 3 hours. The extraction of the reaction mixture was carried out by adding ethyl acetate, and the extract was consecutively washed with 10% hydrochloric acid, with a saturated sodium bicarbonate aqueous solution and with a saturated sodium chloride aqueous solution. The solvent was removed by filtration under reduced pressure, and the resultant oily substance was washed with an ethyl acetate/n-hexane mixed solvent (1:1 (V/V)) to form a solid. The mixture was filtered to give 1.0 g (yield 80%) of 4,4,5,8-tetramethyl-6-(1,3-dimethyl-5-(pyridin-4-yl)carbonyloxypyrazol-4-yl) carbonylthiochroman-1,1-dioxide (Compound No. 42).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:17]2[CH:22]=[CH:21][C:20]([CH:23]=[O:24])=[CH:19][CH:18]=2)=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:17]2[CH:18]=[CH:19][C:20]([CH2:23][OH:24])=[CH:21][CH:22]=2)=[CH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1ccc(-c2cn(Cc3ccccc3)c3ccccc23)cc1
Agent: [BH4-]
Agent: [Na+]
Product: OCc1ccc(-c2cn(Cc3ccccc3)c3ccccc23)cc1
Yield: 51 %

Procedure:
N-Benzyl-3-(4-formylphenyl)indole (9) and NaBH4 are allowed to react in the same manner as described above in the preparation of compound 7 to afford compound 10 in 51% yield. mp 122° C.; IR (cm−1): 3462, 1742; 1H NMR (CDCl3): δ 7.94–7.97 (m, 1H), 7.64–7.68 (d, 3H), 7.41–7.45 (d, 10H), 5.34 (s, 2H), 4.72 (s, 2H). HRMS: m/z 313.1466 (calculated for C22H19NO, 313.1467).
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:16])[O:4][C:5]1[C:13]2[O:12][C:11]([CH3:15])([CH3:14])[CH2:10][C:9]=2[CH:8]=[CH:7][CH:6]=1.[Cl:17]Cl>C(Cl)(Cl)Cl.C(Cl)(Cl)(Cl)Cl>[CH3:1][NH:2][C:3](=[O:16])[O:4][C:5]1[C:13]2[O:12][C:11]([CH3:14])([CH3:15])[CH2:10][C:9]=2[CH:8]=[C:7]([Cl:17])[CH:6]=1
Reactant: CNC(=O)Oc1cccc2c1OC(C)(C)C2
Reactant: ClCl
Solvent: ClC(Cl)Cl
Solvent: ClC(Cl)(Cl)Cl
Product: CNC(=O)Oc1cc(Cl)cc2c1OC(C)(C)C2
Yield: 88.9 %

Procedure:
To a solution of 2,3-dihydro-2,2-dimethyl-7-benzofuranyl methylcarbamate (33.2 g, 0.15 mol) in 150 ml of chloroform and 300 ml of carbon tetrachloride, chlorine (10.7 g, 0.15 mol) was gradually fed at a temperature of from 10° to 15° C. under stirring. The precipitated crystals were collected by filtration and washed with hexane, whereby 34.1 g of 5-chloro-2,3-dihydro-2,2-dimethyl-7-benzofuranyl methylcarbamate was obtained. The melting of this product was 167°-169° C. The structure was confirmed by 1H-NMR spectrum. Then, the product was added to 100 ml of a 10% aqueous sodium hydroxide-methanol solution and heated at 80° C. for 3 hours. The reaction solution was neutralized with hydrochloric acid and extracted with ether. The ether layer was washed with water, dried over anhydrous sodium sulfate and concentrated, whereby 23.0 g of 5-chloro-2,3-dihydro-2,2-dimethyl-7-benzofuranol was obtained. The melting point of this product was 65.5°-66.5° C. The phenol thus obtained, was reacted with O-ethyl-S-n-propyldithiophosphoryl chloride in the same manner as in Example 1, whereby the compound (No. 18) identified in Table 1 was obtained.
Reaction SMILES: CO[C:3](=[O:11])[C@@H:4]([CH2:9][OH:10])[NH:5][C:6](=[O:8])[CH3:7].[CH2:12]([NH2:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C>C(OC)(C)(C)C>[C:6]([NH:5][C@H:4]([CH2:9][OH:10])[C:3]([NH:19][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:11])(=[O:8])[CH3:7]
Reactant: COC(=O)[C@@H](CO)NC(C)=O
Reactant: NCc1ccccc1
Solvent: CCN(CC)CC
Solvent: COC(C)(C)C
Product: CC(=O)N[C@H](CO)C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 92.9 %

Procedure:
N-Acetyl-D-serine methyl ester (25 g, 0.155 mole) was dissolved in benzylamine (33.2 g, 0.3101 mole) at 0-5° C. To this triethylamine (3.13 g, 0.031 mole) was added at 0-5° C. The reaction mixture was allowed to cool to room temperature and stirred for 12 hr. To the thick colorless precipitate formed 300 ml methyl tert-butyl ether was added and stirred for 6 hr. The product was filtered and dried under vacuum to obtain (R)-2-acetamido-N-benzyl-3-hydroxy-propionamide (34.03 g, Yield: 93%, HPLC: 98.9, Chiral HPLC: 98.8%)
Reaction SMILES: [F:1][CH2:2][C:3]([C:7]1[CH:11]=[C:10]([NH:12][C:13](=[O:21])OC2C=CC=CC=2)[N:9]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:8]=1)([CH3:6])[CH2:4][F:5].[CH3:28][O:29][C:30]1[CH:31]=[C:32]2[C:37](=[CH:38][C:39]=1[O:40][CH3:41])[N:36]=[CH:35][N:34]=[C:33]2[S:42][C:43]1[CH:44]=[C:45]([CH:47]=[CH:48][CH:49]=1)[NH2:46].C(N(CC)C(C)C)(C)C>C1COCC1>[F:1][CH2:2][C:3]([C:7]1[CH:11]=[C:10]([NH:12][C:13]([NH:46][C:45]2[CH:47]=[CH:48][CH:49]=[C:43]([S:42][C:33]3[C:32]4[C:37](=[CH:38][C:39]([O:40][CH3:41])=[C:30]([O:29][CH3:28])[CH:31]=4)[N:36]=[CH:35][N:34]=3)[CH:44]=2)=[O:21])[N:9]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:8]=1)([CH3:6])[CH2:4][F:5]
Reactant: CC(CF)(CF)c1cc(NC(=O)Oc2ccccc2)n(-c2ccccc2)n1
Reactant: COc1cc2ncnc(Sc3cccc(N)c3)c2cc1OC
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2ncnc(Sc3cccc(NC(=O)Nc4cc(C(C)(CF)CF)nn4-c4ccccc4)c3)c2cc1OC
Yield: 40 %

Procedure:
Using the procedure described in Example 159B, phenyl 3-(1,3-difluoro-2-methylpropan-2-yl)-1-phenyl-1H-pyrazol-5-ylcarbamate as described in Example 167B (0.186 g, 0.5 mmol), 3-(6,7-dimethoxyquinazolin-4-ylthio)aniline from Example 115B (0.125 g, 0.4 mmol), and N,N-diisopropylethylamine (0.8 mL) in THF (6 mL) at 50° C. for 6 hours, to afford 1-[3-(1,3-difluoro-2-methylpropan-2-yl)-1-phenyl-1H-pyrazol-5-yl]-3-[3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl]urea as solid (95 mg, 40%). 1H NMR (300 MHz, DMSO-d6) δ 9.27 (s, 1H), 8.69 (s, 1H), 8.56 (s, 1H), 7.80 (s, 1H), 7.23-7.80 (m, 10H), 6.51 (s, 1H), 4.71 (m, 2H), 4.55 (m, 2H), 3.99 (s, 6H), 1.31 (s, 3H); LC-MS (ESI) m/z 591 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1.[CH2:13](O)[CH2:14][OH:15].CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[O:15]1[C:2]2([CH2:7][CH2:6][CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]2)[O:1][CH2:13][CH2:14]1
Reactant: OCCO
Reactant: CCOC(=O)C1CCC(=O)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)C1CCC2(CC1)OCCO2
Temperature: 25 °C

Procedure:
A mixture of ethyl 4-oxocyclohexanecarboxylate (11.7 g, 68.7 mmol), ethylene glycol (5.75 mL, 103 mmol) and p-TsOH (0.620 g, 3.26 mmol) in toluene (60 mL) was stirred at reflux using a Dean-Stark trap to collect water over 4 hrs. The resulting mixture was cooled to room temperature, quenched with a saturated aqueous NaHCO3 solution (30 mL) and diluted with EtOAc (100 mL). The organic layer was washed with brine (30 mL), dried over anhydrous sodium sulfate and filtered. The solvent was removed under reduced pressure to afford a yellow oil. The crude material was adsorbed onto silica and purification by chromatography eluting with 0-100% EtOAc in iso-hexane afforded the title compound;
Reaction SMILES: [NH:1]1[C:5]2=[CH:6][N:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.C([N-]C(C)C)(C)C.[Li+].[C:18]1([S:24](Cl)(=[O:26])=[O:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C([O-])(O)=O.[Na+]>O1CCCC1.C1COCC1.CCCCCCC>[C:18]1([S:24]([N:1]2[C:5]3=[CH:6][N:7]=[CH:8][CH:9]=[C:4]3[CH:3]=[CH:2]2)(=[O:26])=[O:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: c1cc2cc[nH]c2cn1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: O=C([O-])O
Agent: [Li+]
Solvent: CCCCCCC
Solvent: C1CCOC1
Product: O=S(=O)(c1ccccc1)n1ccc2ccncc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.7 %

Procedure:
To a suspension of 1H-pyrrolo[2,3-c]pyridine (700 mg, 5.9 mmol) in tetrahydrofuran (14.0 mL) was added lithium diisopropylamide (2.9 mL of a 2 M solution in THF/heptane, 5.9 mmol) at −78° C. After 0.5 h, benzenesulfonyl chloride (0.79 mL, 6.2 mmol) was added dropwise. The mixture was allowed to slowly warm to ambient temperature overnight. The reaction mixture was poured into 2% aq NaHCO3 (30 mL) and extracted with EtOAc (2×25 mL). The combined extracts were washed with H2O (20 mL) and saturated NaCl (20 mL), dried (Na2SO4) and concentrated under reduced pressure. Purification by column chromatography (silica gel, 1:1 hexanes/EtOAc) gave 1-(phenylsulfonyl)-1H-pyrrolo[2,3-c]pyridine (1.2 g, 80%): 1H NMR (500 MHz, DMSO-d6) δ 6.94 (1H, d, J=6.0 Hz), 7.59-7.66 (3H, m), 7.70-7.75 (1H, m), 8.07-8.10 (3H, m), 8.38 (1H, d, J=8.8 Hz), 9.23 (1H, s); ESI MS m/z 259 [C13H10N2O2S+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5](/[CH:9]=[CH:10]/[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:4]=1[N+:17]([O-])=O.[H][H]>CO.[Pd]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:4]=1[NH2:17]
Reactant: COc1cccc(/C=C/c2ccccc2)c1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COc1cccc(CCc2ccccc2)c1N
Reaction time: 18 h
Yield: 105.6 %

Procedure:
2.25 g of 1-methoxy-2-nitro-3-[(E)-2-phenylvinyl]benzene are added to 0.18 g of palladium-on-charcoal (10%) suspended in 90 ml of methanol, and placed under 4 bar of hydrogen. After 18 hours, the reaction medium is filtered through talc and the filtrate is concentrated to give 2.115 g of the expected product.
Reaction SMILES: [C:1]([C:8]1[S:9][CH:10]=[CH:11][CH:12]=1)(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].O.NN.C(O)CO[CH2:19][CH2:20]O.[OH-].[K+]>O>[CH2:1]([C:8]1[S:9][CH:10]=[CH:11][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:8][CH2:1][CH2:2][CH2:3][CH2:19][CH3:20]
Reactant: OCCOCCO
Reactant: CCCCCC(=O)c1cccs1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CCCCCCCCCCCCc1cccs1
Temperature: 50 °C

Procedure:
In a 5 liter-five-necked flask, 266 g (1.0 mol) of 2-hexanoylthiophene, 392.4 ml of 60% hydrazine hydrate and 3 liter of diethyleneglycol were placed and reacted for 6 hours at 195° C. with distilling-off of excessive water and hydrazine hydrate. The mixture was cooled to 50° C. and 210.6 g of KOH was added thereto, followed by heating again to react for 2.5 hours at 155° C. After the reaction, the reaction mixture was poured into 10 liter of water, extracted two times with 2 liter of isopropyl ether, followed by drying with CaCl2 and distilling-off of the solvent to obtain 229 g of a crude product. The crude product was subjected to reduced-pressure distillation in an atmosphere of nitrogen to obtain 168 g of a pure product (yield: 66.7 b.p.: 121.5° C./0.7 mmHg
Reaction SMILES: [C:1]1([C:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8](O)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:23][CH2:24][CH2:25][CH2:26][N:27]1[CH2:32][CH2:31][CH:30]([C:33]2[CH:34]=[C:35]([NH:40][C:41](=[O:45])[CH:42]([CH3:44])[CH3:43])[CH:36]=[CH:37][C:38]=2[CH3:39])[CH2:29][CH2:28]1>>[CH3:44][CH:42]([CH3:43])[C:41]([NH:40][C:35]1[CH:36]=[CH:37][C:38]([CH3:39])=[C:33]([CH:30]2[CH2:31][CH2:32][N:27]([CH2:26][CH2:25][CH2:24][NH:23][C:8](=[O:9])[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:28][CH2:29]2)[CH:34]=1)=[O:45]
Reactant: Cc1ccc(NC(=O)C(C)C)cc1C1CCN(CCCN)CC1
Reactant: O=C(O)C(c1ccccc1)(c1ccccc1)c1ccccc1
Product: Cc1ccc(NC(=O)C(C)C)cc1C1CCN(CCCNC(=O)C(c2ccccc2)(c2ccccc2)c2ccccc2)CC1

Procedure:
Example 94 was prepared from triphenylacetic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]-4-methylphenyl}-2-methylpropanamide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCl3) δ 7.39 (dd, 1H, J=1.6, 8.0 Hz), 7.35–7.27 (m, 15H), 7.22–7.20 (m, 2H), 7.09 (d, 1H, J=8.0 Hz), 6.25 (br s, 1H), 3.45 (dd, 2H, J=6.8, 12.4 Hz), 2.90 (d, 2H, J=10.8 Hz), 2.63 (m, 1H), 2.52 (m, 1H), 2.33–2.29 (m, 2H), 2.28 (s, 3H), 1.97 (t, 2H, J=10.0 Hz), 1.72–1.57 (m, 6H), 1.27 (d, 6H, J=6.8 Hz); ESMS m/e: 588.3 (M+H)+.
Reaction SMILES: ClCCl.[OH:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH:6]1[NH:11][C:12](=[O:27])[C:13]1[C:18]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:17][CH:16]=[CH:15][N:14]=1.[OH-].[Na+]>C(OCC)C>[O:4]=[C:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH:6]1[NH:11][C:12](=[O:27])[C:13]1[C:18]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:17][CH:16]=[CH:15][N:14]=1
Reactant: O=C(NC1CCCCC1O)c1ncccc1OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: ClCCl
Product: O=C(NC1CCCCC1=O)c1ncccc1OCc1ccccc1
Reaction time: 2 h

Procedure:
To 20 ml dichloromethane solution of 3.4 g 1,1,1-tris(acetoxy)-1,1-dihydro-1,2-benziodoxole-3(1H)-one, was added 20 ml dichloromethane solution of 1.3 g N-(2-hydroxycyclohexyl)-3-benzyloxypicolinic amide at room temperature. After stirring the solution for 2 hours, the solution reacted was poured into 80 ml diehtyl ether, and 2N-aqueous solution of sodium hydroxide and ice were added to the resulting solution. The organic layer obtained was washed with aqueous solution of sodium hydrogencarbonate, water and saturated saline solution in turn and was then dried by using anhydrous magnesium sulfate. The solvent used was removed by distillation under reduced pressure, affording oily substance, N-(2-oxocyclohexyl)-3-benzyloxypicolinic amide in an amount of 1.18 g.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[N:9][C:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[C:7]2[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1.[F:25][C:26]([F:39])([F:38])[C:27]1[C:35]2[CH:34]=[C:33]([CH:36]=O)[S:32][C:31]=2[CH:30]=[CH:29][CH:28]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[N:9][C:8]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[C:7]2[C:18]1[CH:19]=[C:20]([NH:24][CH2:36][C:33]2[S:32][C:31]3[CH:30]=[CH:29][CH:28]=[C:27]([C:26]([F:38])([F:25])[F:39])[C:35]=3[CH:34]=2)[CH:21]=[CH:22][CH:23]=1
Reactant: Nc1cccc(-c2c(-c3ccccc3)nnc3c(Cl)cccc23)c1
Reactant: O=Cc1cc2c(C(F)(F)F)cccc2s1
Product: FC(F)(F)c1cccc2sc(CNc3cccc(-c4c(-c5ccccc5)nnc5c(Cl)cccc45)c3)cc12

Procedure:
The title compound was prepared from 3-(8-chloro-3-phenyl-cinnolin-4-yl)-phenylamine and 4-trifluoromethyl-benzo[b]thiophene-2-carbaldehyde according the procedure of Example 5 Step 5. MS (ESI) m/z 546.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([O:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][CH2:21][CH2:22][CH2:23][C:24]([OH:26])=[O:25])=[C:4]([CH2:27][CH3:28])[N:3]=1.OS(O)(=O)=O.C(OCC)(OCC)O[CH2:36][CH3:37].C([O-])([O-])=O.[K+].[K+]>CCO>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([O:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][CH2:21][CH2:22][CH2:23][C:24]([O:26][CH2:36][CH3:37])=[O:25])=[C:4]([CH2:27][CH3:28])[N:3]=1
Reactant: CCOC(OCC)OCC
Reactant: CCc1nc(N)nc(N)c1OCCCOc1ccccc1OCCCC(=O)O
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)CCCOc1ccccc1OCCCOc1c(N)nc(N)nc1CC
Temperature: 25 °C
Reaction time: 8 h
Yield: 65 %

Procedure:
To a solution of 2,4-diamino-6-ethyl-5-(3-(2-(3-carboxypropoxy)phenoxy)propoxy)pyrimidine (0.3904 g, 1 mmol) and a catalytic amount of con. H2SO4 in EtOH (4 mL) was added triethyl orthoformate (2 mL) and the solution was left stirring at 25° C. for 8 hours. The reaction mixture was neutralized with K2CO3 and evaporated to dryness. The crude product was diluted with water and extracted with CH2Cl2. Evaporation to dryness gave the desired ester as white semi-solid (0.2720 g, 65%). 1H NMR (500 MHz, DMSO-d6): 0.99 (3H, t, J=7.5 Hz), 1.15 (3H, t, J=7.1 Hz), 1.93 (2H, m), 2.13 (2H, m), 2.33 (2H, q, J=7.5 Hz), 2.45 (2H, t, J=7.3 Hz), 3.78 (2H, t, J=6.0 Hz), 3.95 (2H, t, J=6.3 Hz), 4.03 (2H, q, J=7.1 Hz), 4.13 (2H, t, J=6.0 Hz), 5.54 (2H, s), 6.07 (2H, s), 6.87-6.90 (2H, m), 6.95-7.01 (2H, m).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([N:14]2[CH:18]=[CH:17][CH:16]=[CH:15]2)[CH:13]=1)[C:8]([OH:10])=O)=[O:4].[OH:19][CH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.ON1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C>ClCCl>[OH:19][CH:20]1[CH2:25][CH2:24][N:23]([C:8]([C:7]2[CH:6]=[C:5]([CH:13]=[C:12]([N:14]3[CH:18]=[CH:17][CH:16]=[CH:15]3)[CH:11]=2)[C:3]([O:2][CH3:1])=[O:4])=[O:10])[CH2:22][CH2:21]1
Reactant: OC1CCNCC1
Reactant: COC(=O)c1cc(C(=O)O)cc(-n2cccc2)c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: COC(=O)c1cc(C(=O)N2CCC(O)CC2)cc(-n2cccc2)c1
Temperature: 25 °C
Reaction time: 30 h
Yield: 89.2 %

Procedure:
To a mixture of 3-methoxycarbonyl-5-(pyrrol-1-yl)-benzoic acid (3.0 g), 4-hydroxypiperidine (1.23 g) and 1-hydroxybenzotriazole (1.81 g) in dichloromethane (100 ml) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (2.57 g) under ice cooling, and the solution was stirred for 30 hours at room temperature. After evaporating the solvent, the residue was dissolved in a mixture of ethyl acetate and a saturated aqueous sodium hydrogencarbonate solution under stirring. The organic layer was successively washed with water and brine, and dried over magnesium sulfate. The solvent was evaporated in vacuo and the residue was purified by column chromatography on silica gel eluting with a mixture of chloroform and methanol (50:1). The fractions containing the desired product were collected and evaporated in vacuo to afford methyl 3-[(4-hydroxypiperidin-1-yl)carbonyl]-5-(pyrrol-1-yl)benzoate (3.56 g).