Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C:14]([C:15]#[N:16])=[C:13]([CH3:17])[N:12]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=3)[C:11](=[O:28])[NH:10]2)=[C:5]([S:29]([CH3:32])(=[O:31])=[O:30])[CH:4]=1)#[N:2].[H-].[Na+].[Cl:35][CH2:36][S:37](Cl)(=[O:39])=[O:38]>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C:14]([C:15]#[N:16])=[C:13]([CH3:17])[N:12]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=3)[C:11](=[O:28])[N:10]2[S:37]([CH2:36][Cl:35])(=[O:39])=[O:38])=[C:5]([S:29]([CH3:32])(=[O:31])=[O:30])[CH:4]=1)#[N:2]
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(C)(=O)=O)NC(=O)N1c1cccc(C(F)(F)F)c1
Reactant: O=S(=O)(Cl)CCl
Agent: [H-]
Agent: [Na+]
Product: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(C)(=O)=O)N(S(=O)(=O)CCl)C(=O)N1c1cccc(C(F)(F)F)c1
Yield: 69.2 %

Procedure:
Analogously to the preparation of Example 27, (4S)-4-[4-cyano-2-(methylsulfonyl)phenyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carbonitrile (100 mg, 217 μmol; Example 6), sodium hydride (60%, 11.3 mg, 282 μmol) and chloromethanesulfonyl chloride (42 mg, 282 μmol) were reacted with one another for 3 h. This gave the title compound as a colorless solid (86 mg, 69% of theory).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[N:11][CH:12]=[C:13]([CH:19]=2)[C:14]([O:16][CH2:17][CH3:18])=[O:15])O1.Br[C:22]1[O:26][C:25]([CH:27]=[O:28])=[CH:24][CH:23]=1.C([O-])([O-])=O.[Cs+].[Cs+]>O.O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH:27]([C:25]1[O:26][C:22]([C:9]2[CH:10]=[N:11][CH:12]=[C:13]([CH:19]=2)[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:23][CH:24]=1)=[O:28]
Reactant: CCOC(=O)c1cncc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: O=Cc1ccc(Br)o1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)c1cncc(-c2ccc(C=O)o2)c1
Temperature: 25 °C
Yield: 100.2 %

Procedure:
A solution of ethyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinate (570 mg, 2.06 mmol), 5-bromofuran-2-carbaldehyde (300 mg, 1.71 mmol), Cs2CO3 (1.125 g, 3.46 mmol) and PdCl2(dppf) (65 mg, 0.09 mmol) in H2O/dioxane (5%, 10 mL) was heated at reflux for 15 min. The reaction mixture was cooled to rt and diluted with H2O (100 mL). The resulting precipitate was collected by filtration to yield the desired ethyl 5-(5-formylfuran-2-yl)nicotinate (420 mg). LCMS (ES): m/z 246 [M+1]+.
Reaction SMILES: C[N:2]1[C:10]2[C:5](=[CH:6][C:7]([B:11]3[O:15][C:14]([CH3:17])([CH3:16])[C:13]([CH3:19])([CH3:18])[O:12]3)=[CH:8][CH:9]=2)C(C2C=CC=CC=2)=[N:3]1.BrC1C=CC2N=N[N:32](C)[C:31]=2C=1>>[CH3:31][N:32]1[C:5]2[CH:6]=[C:7]([B:11]3[O:15][C:14]([CH3:17])([CH3:16])[C:13]([CH3:18])([CH3:19])[O:12]3)[CH:8]=[CH:9][C:10]=2[N:2]=[N:3]1
Reactant: Cn1nnc2ccc(Br)cc21
Reactant: Cn1nc(-c2ccccc2)c2cc(B3OC(C)(C)C(C)(C)O3)ccc21
Product: Cn1nnc2ccc(B3OC(C)(C)C(C)(C)O3)cc21

Procedure:
Prepared in a manner similar to 1-methyl-3-phenyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole, but using 6-bromo-1-methyl-1H-benzo[d][1,2,3]triazole instead of 5-bromo-1-methyl-3-phenyl-1H-indazole. 1H NMR (400 MHz, CDCl3) δ 8.04 (dd, J=6.8, 1.6 Hz, 2H), 7.79 (d, J=8.6 Hz, 1H), 4.33 (s, 3H), 1.39 (s, 12H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5](Cl)=[CH:4][CH:3]=1.[C:9]1(B(O)O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.N(P(Cl)Cl)(C1CCCCC1)C1CCCCC1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:9]1([C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: OB(O)c1ccccc1
Reactant: Cc1ccc(Cl)cc1
Agent: [Pd]
Agent: ClP(Cl)N(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Cc1ccc(-c2ccccc2)cc1
Reaction time: 24 h
Yield: 62.9 %

Procedure:
The general procedure from Example 8 was followed using 4-methylchlorobenzene (152 mg, 1.2 mmol) and PhB(OH)2 (1.2 mmol) with Pd2(dba)3 (20 mg, 0.0218 mmol) and (Me3C)2PH(O) from Experiment 2 (14.5 mg, 0.0878 mmol) and CsCO3 (651 mg, 2.0 mmol) in 4.0 mL of 1,4-dioxane. After 24 h, the reaction mixture was chromatographed with 5% ethyl acetate/hexane to give 127 mg (63% yield) of 4-phenyltoluene. It was >95% pure by 1H NMR and GC/MS. 1H NMR (500 MHz, CDCl3): δ7.74 (d, J=7.50 Hz, 2H), 7.65 (d, J=8.05 Hz, 2H), 7.57 (m, 2H), 7.47 (m, 1H), 7.40 (m, 2H), 2.54 (s, 3H) ppm. 13C NMR (125 MHz, CDCl3): δ141.1, 138.3, 136.9, 129.4, 128.6, 126.9, 126.8, 21.0 ppm.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([CH:12]=O)[S:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(O)=O.[Cl:21][C:22]1[CH:37]=[CH:36][C:25]([C:26]([NH:28][CH2:29][CH:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[O:27])=[CH:24][C:23]=1[O:38][CH3:39].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.C[N+](C)(C)C>C(#N)C>[Cl:21][C:22]1[CH:37]=[CH:36][C:25]([C:26]([NH:28][CH2:29][CH:30]2[CH2:31][CH2:32][N:33]([CH2:12][C:9]3[S:10][CH:11]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH:8]=3)[CH2:34][CH2:35]2)=[O:27])=[CH:24][C:23]=1[O:38][CH3:39]
Reactant: COc1cc(C(=O)NCC2CCNCC2)ccc1Cl
Reactant: O=Cc1cc(-c2ccccc2)cs1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C[N+](C)(C)C
Solvent: CC(=O)O
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(C(=O)NCC2CCN(Cc3cc(-c4ccccc4)cs3)CC2)ccc1Cl
Reaction time: 18 h
Yield: 76.7 %

Procedure:
A mixture of 4-phenylthiophene-2-carbaldehyde (0.074 g) and the compound prepared in Example 11 (0.075 g) and acetic acid (0.023 mL) in acetonitrile (1 mL) was stirred at room temperature for 30 minutes. Tetramethylammonium triacetoxyborohydride (0.156 g) was added and the reaction was stirred for 18 hours. The mixture was partitioned between a saturated aqueous sodium bicarbonate solution and ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate:hexane=9:1) to obtain the title compound (0.066 g) having the following physical data.
Reaction SMILES: [CH:1]([C:4]1[C:9]([CH2:10][OH:11])=[C:8]([C:12]2[CH:16]=[CH:15][O:14][CH:13]=2)[C:7]([CH:17]=[CH:18][CH2:19][CH2:20][CH3:21])=[C:6]([CH:22]([CH3:24])[CH3:23])[N:5]=1)([CH3:3])[CH3:2]>CCOC(C)=O>[CH:1]([C:4]1[C:9]([CH2:10][OH:11])=[C:8]([C:12]2[CH:16]=[CH:15][O:14][CH:13]=2)[C:7]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[C:6]([CH:22]([CH3:23])[CH3:24])[N:5]=1)([CH3:3])[CH3:2]
Reactant: CCCC=Cc1c(C(C)C)nc(C(C)C)c(CO)c1-c1ccoc1
Solvent: CCOC(C)=O
Product: CCCCCc1c(C(C)C)nc(C(C)C)c(CO)c1-c1ccoc1
Yield: 6 %

Procedure:
The title compound was prepared from 2,6-diisopropyl-3-hydroxymethyl-4-(3-furyl)-5-(pent-1-enyl)pyridine (Example 187) in 6% yield by the methods described in Example 125. FAB-MS: calculated for C21H31NO2 329; found 330 (M+1). 1H NMR (300 MHz, CD3OD): δ 0.83 (t, J=6.8 Hz, 3 H), 1.19-1.36 (m, 19 H), 2.42-2.48 (m, 2 H), 3.25 (septet, J=6.6 Hz, 1 H, 3.45 (septet, J=6.6 Hz, 1 H), 4.38 (s, 2 H), 6.42 (m, 1 H), 7.45-7.46 (m, 1 H), 7.61-7.62 (t, J=1.7 Hz, 1 H). Anal. calc for C21H31NO2: C, 76.55; H, 9.48; N, 4.25. Found: C, 76.41; H, 9.76; N, 4.24. Rf=0.59 (20% EtOAc/hex). mp 98-100 ° C.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([C:11]2[C:15]3[CH:16]=[C:17]([C:20]4[O:21][C:22]([CH3:25])=[N:23][N:24]=4)[CH:18]=[CH:19][C:14]=3[O:13][CH:12]=2)[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:26][NH2:27].O1CCCC1>>[F:1][C:2]1[CH:10]=[C:9]([C:11]2[C:15]3[CH:16]=[C:17]([C:20]4[O:21][C:22]([CH3:25])=[N:23][N:24]=4)[CH:18]=[CH:19][C:14]=3[O:13][CH:12]=2)[CH:8]=[CH:7][C:3]=1[C:4]([NH:27][CH3:26])=[O:6]
Reactant: CN
Reactant: Cc1nnc(-c2ccc3occ(-c4ccc(C(=O)O)c(F)c4)c3c2)o1
Solvent: C1CCOC1
Product: CNC(=O)c1ccc(-c2coc3ccc(-c4nnc(C)o4)cc23)cc1F
Yield: 54 %

Procedure:
In the same manner as in Example 117 and using 2-fluoro-4-[5-(5-methyl-1,3,4-oxadiazol-2-yl)-1-benzofuran-3-yl]benzoic acid instead of 3-[5-(2,3-dihydro-1-benzofuran-5-yl)-1,3,4-oxadiazol-2-yl]propionic acid and 2M methylamine-tetrahydrofuran solution instead of N,O-dimethylhydroxyamine hydrochloride, the title compound (yield 54%) was obtained as pale-yellow crystals.
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:19][C:20]([C:22]2[C:31]3[CH2:30][CH2:29][CH2:28][CH2:27][C:26]=3[CH:25]=[CH:24][CH:23]=2)=[O:21])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:12]=2)[CH2:7]1)=[O:5])C.[OH-].[K+].O>CCO>[C:22]1([C:20]([NH:19][C:6]2([C:4]([OH:5])=[O:3])[CH2:14][C:13]3[C:8](=[CH:9][CH:10]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:12]=3)[CH2:7]2)=[O:21])[C:31]2[CH2:30][CH2:29][CH2:28][CH2:27][C:26]=2[CH:25]=[CH:24][CH:23]=1
Reactant: CCOC(=O)C1(NC(=O)c2cccc3c2CCCC3)Cc2ccc(C(F)(F)F)cc2C1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(NC1(C(=O)O)Cc2ccc(C(F)(F)F)cc2C1)c1cccc2c1CCCC2
Temperature: 25 °C
Reaction time: 3 h
Yield: 101.1 %

Procedure:
The mixture of 2-[(5,6,7,8-tetrahydro-naphthalene-1-carbonyl)-amino]-5-trifluoromethyl-indan-2-carboxylic acid ethyl ester (84) (437 mg, 1.0 mmol) and KOH (1 g, 18 mmol) is dissolved in EtOH (8 mL) and water (1 mL) under a water bath. The water bath is removed when KOH is completely dissolved and the resulting reaction solution is stirred at RT for 3 h. After concentration in vacuo, the residue is dissolved in water (50 mL) and acidified with conc. HCl until no more white precipitate formed. The precipitate is filtered to give a pure product (85) as white solid (408 mg, 100%).
Reaction SMILES: O1CCC(=O)CC1.[C:8]([O:12][C:13]([N:15]1CCC(=O)CC1)=[O:14])([CH3:11])([CH3:10])[CH3:9].[NH2:22][C:23]1([CH2:29][C:30]([O:32][CH3:33])=[O:31])[CH2:28][CH2:27]O[CH2:25][CH2:24]1>>[NH2:22][C:23]1([CH2:29][C:30]([O:32][CH3:33])=[O:31])[CH2:28][CH2:27][N:15]([C:13]([O:12][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:14])[CH2:25][CH2:24]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: COC(=O)CC1(N)CCOCC1
Agent: O=C1CCOCC1
Product: COC(=O)CC1(N)CCN(C(=O)OC(C)(C)C)CC1

Procedure:
Instead of tetrahydro-4H-pyran-4-one, 1-(tert-butoxycarbonyl)-4-piperidone (5.00 g) was used and treated by the same techniques as in Reference Example 1-1(1) and (2) to give the titled compound as a colorless solid (4.65 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[F:13])[CH:5]=[CH:6][C:7]([OH:9])=O.P(Cl)(OCC)(OCC)=O.C(N(CC)CC)C.[CH3:30][N:31]([CH3:42])[CH2:32][CH2:33][NH:34][C@H:35]1[CH2:40][CH2:39][C@H:38]([CH3:41])[CH2:37][CH2:36]1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:30][N:31]([CH3:42])[CH2:32][CH2:33][N:34]([C@H:35]1[CH2:36][CH2:37][C@H:38]([CH3:41])[CH2:39][CH2:40]1)[C:7](=[O:9])[CH:6]=[CH:5][C:4]1[CH:10]=[CH:11][C:12]([F:13])=[C:2]([F:1])[CH:3]=1
Reactant: CN(C)CCN[C@H]1CC[C@H](C)CC1
Reactant: O=C(O)C=Cc1ccc(F)c(F)c1
Agent: CCOP(=O)(Cl)OCC
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)CCN(C(=O)C=Cc1ccc(F)c(F)c1)[C@H]1CC[C@H](C)CC1

Procedure:
Using 1.1 g of 3,4-difluorocinnamic acid, 1.4 ml of diethyl chlorophosphate, 1.4 ml of triethylamine, 60 ml of methylene chloride, 1.4 ml of N-(2-dimethylaminoethyl)-trans-4-methylcyclohexylamine (Example 78), and 0.25 g of 4-dimethylaminopyridine, a reaction similar to that conducted in Example 81 was carried out. As a result, 1.74 g of N-(2-dimethylaminoethyl)-N-(trans-4-methylcyclohexyl)-3,4-difluorocinnamamide (a compound of the present invention) was obtained as white crystal, which had the following physiochemical properties:
Reaction SMILES: [Li+].[Cl-].[CH3:3][C:4]1[CH:9]=[CH:8][C:7]([P:10]([C:15](=[O:22])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)(=[O:14])[O:11]CC)=[C:6]([CH3:23])[C:5]=1[CH3:24].OS(O)(=O)=O>CN(C)C=O>[CH3:3][C:4]1[CH:9]=[CH:8][C:7]([P:10]([C:15](=[O:22])[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)(=[O:11])[OH:14])=[C:6]([CH3:23])[C:5]=1[CH3:24]
Reactant: CCOP(=O)(C(=O)c1ccccc1)c1ccc(C)c(C)c1C
Agent: O=S(=O)(O)O
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: Cc1ccc(P(=O)(O)C(=O)c2ccccc2)c(C)c1C
Temperature: 35 °C
Reaction time: 8 h
Yield: 91.5 %

Procedure:
17 g of LiCl were dissolved in 250 ml of dimethylformamide in a 2 l stirred flask fitted with internal thermometer and condenser. A solution of 86 g of ethyl trimethylbenzoylphenylphosphinate in 50 ml of DMF was subsequently added dropwise over the course of one hour. The reaction mixture was subsequently stirred overnight at 65° C. 850 ml of ice-water were added dropwise to the mixture, giving a slightly cloudy solution. After warming to 35° C., 450 ml of 0.5 M H2SO4 were added until a pH of 1.5-2 had been reached, whereupon colorless crystals were precipitated. Stirring was continued at 5° C. for one hour. The crystals were filtered off and washed twice with 200 ml of water each time. Drying gave 71.7 g of 98% pure trimethylbenzoylphenylphosphinic acid (HPLC).
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[C:4]([CH3:6])([CH3:5])[CH:3]1[C:7]([OH:9])=O.[NH2:11][C:12]1[N:17]=[N:16][C:15]([N:18]2[CH2:23][CH2:22][N:21]([C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:32]([F:35])([F:34])[F:33])=[O:25])[CH2:20][CH2:19]2)=[CH:14][CH:13]=1>>[F:35][C:32]([F:33])([F:34])[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[C:24]([N:21]1[CH2:20][CH2:19][N:18]([C:15]2[N:16]=[N:17][C:12]([NH:11][C:7]([CH:3]3[C:4]([CH3:5])([CH3:6])[C:2]3([CH3:1])[CH3:10])=[O:9])=[CH:13][CH:14]=2)[CH2:23][CH2:22]1)=[O:25]
Reactant: CC1(C)C(C(=O)O)C1(C)C
Reactant: Nc1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1
Product: CC1(C)C(C(=O)Nc2ccc(N3CCN(C(=O)c4ccccc4C(F)(F)F)CC3)nn2)C1(C)C

Procedure:
Following the procedure of Example 2, making variations only as required to use 2,2,3,3-tetramethylcyclopropanecarboxylic acid in place of benzyloxyacetic acid to react with [4-(6-aminopyridazin-3-yl)piperazin-1-yl](2-trifluoromethylphenyl)-methanone, the title compound was obtained as a white powder (48% yield). 1H NMR (300 MHz, CDCl3) δ 8.77, 8.28, 7.72, 7.60, 7.53, 7.34, 6.99, 4.01-3.85, 3.63-3.60, 3.52-3.45, 3.31-3.27, 1.78-1.74, 1.28, 1.20. MS (ES+) m/z 476.3 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:33]=[C:32]([OH:34])[CH:31]=[CH:30][C:11]=3[C:12]=2[C:13]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][N:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)=[CH:17][CH:16]=2)=[O:14])=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:33]=[C:32]([OH:34])[CH:31]=[CH:30][C:11]=3[C:12]=2[CH:13]([C:15]2[CH:16]=[CH:17][C:18]([O:21][CH2:22][CH2:23][N:24]3[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]3)=[CH:19][CH:20]=2)[OH:14])=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(OCCN2CCCCC2)cc1)c1c(-c2ccc(O)cc2)oc2cc(O)ccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Oc1ccc(-c2oc3cc(O)ccc3c2C(O)c2ccc(OCCN3CCCCC3)cc2)cc1
Yield: 57.9 %

Procedure:
4.57 g (0.01 mol) of [2-(4-hydroxyphenyl)-6-hydroxybenzofuran-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methanone was dissolved in 250 mL of THF and 2 g (0.053 mol) of LiAlH4 was slowly added over a period of twenty minutes to the stirring solution. The reaction mixture was stirred and kept under a nitrogen atmosphere and the reaction was allowed to proceed for eighteen hours at room temperature and then it was concentrated to dryness in vacuo. 500 mL of EtOAc was slowly added along with 2 mL of water. After stirring for 10 minutes, 500 mL of water was added and the EtOAc layer was removed. The EtOAc layer was washed with an additional 500 mL of water and the layers were separated. The EtOAc layer was dried with anhydrous Na2SO4 and concentrated to dryness to yield 2.66 g of the title compound as tan amorphous powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:14]=[CH2:15])[CH:6]=[C:7]([O:12][CH3:13])[C:8]=1[CH2:9][CH2:10][CH3:11].Br[C:17]1[C:22]([F:23])=[CH:21][C:20]([F:24])=[CH:19][C:18]=1[F:25]>>[CH3:13][O:12][C:7]1[CH:6]=[C:5]([CH:14]=[CH:15][C:21]2[C:22]([F:23])=[CH:17][C:18]([F:25])=[CH:19][C:20]=2[F:24])[CH:4]=[C:3]([O:2][CH3:1])[C:8]=1[CH2:9][CH2:10][CH3:11]
Reactant: C=Cc1cc(OC)c(CCC)c(OC)c1
Reactant: Fc1cc(F)c(Br)c(F)c1
Product: CCCc1c(OC)cc(C=Cc2c(F)cc(F)cc2F)cc1OC
Yield: 58 %

Procedure:
This compound was synthesized from (3,5-dimethoxy-4-1-propylphenyl)ethene and 1-bromo-2,4,6-trifluorobenzene in 58% yield in the same procedure as described in preparation of 31B. 1HNMR (CDCl3, ppm): δ 1.32 (d, J=7.0 Hz, 6H), 3.62 (qint, J=7.1 Hz, 1H), 3.89 (s, 6H), 6.73 (s, 2H), 6.79-7.55 (m, 4H).
Reaction SMILES: [N+]([C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=C[NH:10]2)=[CH:6][CH:5]=1)([O-])=O.[N:13]([O-])=O.[Na+].Cl>O>[NH:10]1[C:11]2[C:7](=[CH:6][CH:5]=[CH:4][CH:12]=2)[CH:8]=[N:13]1
Reactant: O=[N+]([O-])c1ccc2cc[nH]c2c1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: c1ccc2[nH]ncc2c1
Reaction time: 2.5 h
Yield: 154.3 %

Procedure:
6-Nitroindole (AA1, 1.0 g, 6.2 mmol) was suspended in a solution of sodium nitrite (4.3 g, 62 mmol) in H2O (123 mL). To the suspension 6N HCl was added slowly until the pH was about pH 1. The resulting mixture was stirred at about rt, with protection from light, for about 2.5 h and extracted with EtOAc (120 mL×3). The combined extracts were washed with H2O (50 mL), brine (50 mL), dried (Na2SO4) and evaporated to give 1.13 g of indazole AA2 as a yellow-pink solid. A solution of AA2 (450 mg, 2.4 mmol) and pyrrolidine (836 mg, 11.8 mmol) in ClCH2CH2Cl:DMF:HOAc (90:9:1) were stirred at about rt for about 20 min, to which was then added NaB(OAc)3H (1.25 g, 5.9 mmol) in one portion. The mixture was stirred at about rt for about 1 h, and then diluted with EtOAc (200 mL), washed with saturated NaHCO3 (30 mL), brine (30 mL), dried (Na2SO4) and evaporated to afford 570 mg of AA3 as a viscous brown solid. 6-Nitroindazole AA3 (4.4 g, 17.8 mmol) was dissolved in dry THF (200 mL) under argon and 2,6-dichlorobenzyl bromide (4.3 g, 17.8 mmol) was added, followed by portionwise addition of pulverized KOH (1.17 g, 17.8 mmol) over about the next 20 min. The reaction was stirred at about rt for about 1 h and then evaporated in vacuo to an oil, which was partitioned between ethyl acetate (500 mL) and water (100 mL). The organic layer was separated and washed twice with water, three times with brine, dried (Na2SO4) and evaporated in vacuo to a brown solid. This was purified by flash column chromatography using DCM:MeOH (19:1) to afford 2.4 g of a tan solid which was combined with ferric chloride hexahydrate (0.30 g, 1.1 mmol) and activated charcoal (3.0 g, 0.25 mmol) in MeOH (200 mL). Dimethyl hydrazine (32 g, 0.53 mmol) was added and the reaction was refluxed for about 2 h, cooled to about rt and filtered through dicalite, which was washed several times with DCM:MeOH (4:1). The combined filtrates were evaporated in vacuo to a brown solid, which was purified by flash chromatography with DCM:MeOH:NH4OH (90:8:1) to give 1.75 g of amine AA4.
Reaction SMILES: [OH-].[NH4+].C[Si](C)(C)[O:5][CH:6]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]([NH2:14])=[O:13])[C:7]1=[O:15]>>[OH:5][CH:6]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]([NH2:14])=[O:13])[C:7]1=[O:15]
Reactant: C[Si](C)(C)OC1CCN(CC(N)=O)C1=O
Agent: [NH4+]
Agent: [OH-]
Product: NC(=O)CN1CCC(O)C1=O

Procedure:
Ethyl (R/S)-2-(3-trimethylsilyloxy-2-oxo-1-pyrrolidinyl)acetate is obtained analogously to the process in accordance with paragraph (a) of Example 1. After treatment with 25% ammonium hydroxide solution and acidic hydrolysis of the (R/S)-2-(3-trimethylsilyloxy-2-oxo-1-pyrrolidinyl)acetamide, there is obtained crude (R/S)-2-(3-hydroxy-2-oxo-1-pyrrolidinyl)acetamide. After chromatography on silica gel (granular size 0.2-0.5 mm) and elution with acetonitrile/methanol (1:1), (R/S)-2-(3-hydroxy-2-oxo-1-pyrrolidinyl)acetamide in about 80-90% purity can be detected.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[H-].[Na+].Br[C:12]1[S:13][C:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][N:16]=1>CS(C)=O.[Cl-].[Na+].O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:12]2[S:13][C:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][N:16]=2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: CCOC(=O)c1cnc(Br)s1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)c1cnc(Oc2ccc(Cl)cc2)s1
Temperature: 150 °C
Reaction time: 0.33 h

Procedure:
To a solution of 4-chlorophenol (4.24 g, 33 mmol) in DMSO (100 mL) was added sodium hydride (857 mg of a 97% dry sample, 34.65 mmol) and the mixture was stirred for 20 mins. Ethyl 2-bromo-5-thiazolecarboxylate (7.79 g, 33 mmol) was then added as a solution in DMSO (10 mL) and the reaction was heated at 150° C. for 18 hrs. It was then cooled to r.t., diluted with brine (150 mL) and extracted with ethylacetate (3×150 mL). The organics were combined, dried with MgSO4 and concentrated to afford ethyl 2-(4-chlorophenoxy)-5-thiazolecarboxylate which was used as is.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH:3]([CH2:6][N:7]2[CH2:11][CH2:10][NH:9][C:8]2=[N:12][N+:13]([O-:15])=[O:14])[CH2:2]1.[H-].[Na+].[C:18](Cl)(=[O:22])[CH2:19][CH2:20][CH3:21]>C(#N)C>[CH2:19]([C:18]([N:9]1[CH2:10][CH2:11][N:7]([CH2:6][CH:3]2[CH2:4][CH2:5][O:1][CH2:2]2)[C:8]1=[N:12][N+:13]([O-:15])=[O:14])=[O:22])[CH2:20][CH3:21]
Reactant: O=[N+]([O-])N=C1NCCN1CC1CCOC1
Reactant: CCCC(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Product: CCCC(=O)N1CCN(CC2CCOC2)C1=N[N+](=O)[O-]
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 67.8 %

Procedure:
A mixture of 0.30 g of 1-[(tetrahydro-3-furanyl)methyl]-2-(nitroimino)imidazolidine, 0.084 g of sodium hydride (60%) and 10 ml of acetonitrile was stirred at 50° C. for 30 minutes. After this mixture was cooled on ice, 0.22 g of n-butanoyl chloride was added dropwise thereto over 30 minutes, and the solution was then stirred at room temperature for 2 hours. After the completion of reaction, insolubles were removed by filtration, and the filtrate was then concentrated under a reduced pressure. The resultant residue was purified by silica gel column chromatography (2:1 ethyl acetate/acetone) to obtain 0.27 g of 1-(propylcarbonyl)-2-(nitroimino)-3-[(tetrahydro-3-furanyl) methyl]imidazolidine.
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([O:24]C(C)(C)C)=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:29]=[C:30]([C:34]([NH:36][CH:37]([C:41](=O)[CH3:42])[CH:38]([CH3:40])[CH3:39])=[O:35])[CH:31]=[C:32]([CH3:33])[C:6]=2[N:5]=1)[CH2:2][CH3:3]>P(Cl)(Cl)(Cl)=O>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3[C:17]([C:22]([OH:24])=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:14][CH:15]=2)[C:7]2[CH:29]=[C:30]([C:34]3[O:35][C:41]([CH3:42])=[C:37]([CH:38]([CH3:40])[CH3:39])[N:36]=3)[CH:31]=[C:32]([CH3:33])[C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc2c(C)cc(C(=O)NC(C(C)=O)C(C)C)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: O=P(Cl)(Cl)Cl
Product: CCCc1nc2c(C)cc(-c3nc(C(C)C)c(C)o3)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1
Temperature: 105 °C
Reaction time: 2.5 h

Procedure:
3.9 g (6.7 mMol) of tert.butyl 4'-[[2-n-propyl-4-methyl-6-[N-(1-acetyl-2-methyl-n-propyl)-aminocarbonyl]-1H-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylate are dissolved in 50 ml of phosphorusoxychloride and stirred for 2.5 hours at 105° C. Then the phosphorusoxychloride is removed, the residue is decomposed with water at 80° C. and, after cooling, mixed with conc. ammonia. The pH is adjusted to 5 by the addition of glacial acetic acid, the precipitate thus formed is suction filtered, washed with water, taken up in methylene chloride/methanol (9:1) and dried over magnesium sulphate. The crude product is chromatographed on silica gel (particle size: 0.032-0.063 mm) using as eluant petroleum ether/ethyl acetate/glacial acetic acid (1:1:0.002) and methylene chloride/ethanol/glacial acetic acid (20:1:0.002). The uniform fractions are combined, evaporated down, triturated with ether and suction filtered.