Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.[F:23][C:24]([F:28])([F:27])[CH2:25][NH2:26].CCN(C(C)C)C(C)C>CS(C)=O.O>[F:22][C:19]1[CH:20]=[CH:21][C:16]([C:3]2[C:2]([NH:26][CH2:25][C:24]([F:28])([F:27])[F:23])=[N:11][C:10]3[C:5](=[CH:6][CH:7]=[C:8]([C:12]([O:14][CH3:15])=[O:13])[CH:9]=3)[N:4]=2)=[CH:17][CH:18]=1
Reactant: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(Cl)nc2c1
Reactant: NCC(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(NCC(F)(F)F)nc2c1
Yield: 66.7 %

Procedure:
To a solution of methyl 3-chloro-2-(4-fluorophenyl)quinoxaline-6-carboxylate (500 mg, 1.58 mmol) in DMSO (23 ml) was added 2,2,2-trifluoroethan-1-amine (188 mg, 1.90 mmol) and DIEA (407 mg, 3.15 mmol,) with stirring, and the resulting mixture was allowed to react for 4 days at 110° C. in an oil bath. The reaction mixture was diluted with water (80 ml), extracted with dichloromethane (4×15 ml), dried over anhydrous sodium sulfate, and concentrated in vacuo to give the residue, which was purified via silica gel column chromatography (2% ethyl acetate in petroleum ether) to afford methyl 2-(4-fluorophenyl)-3-[(2,2,2-trifluoroethyl)amino]quinoxaline-6-carboxylate as a yellow solid (400 mg, 67%).
Reaction SMILES: [C:1]12(OCC[O:18]1)[C:10]1[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=1)[CH2:4][C@@H:3]([CH2:11][CH2:12][C:13]([O:15]CC)=[O:14])[CH2:2]2.[Li+].[OH-]>C1COCC1.O>[O:18]=[C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@@H:3]([CH2:11][CH2:12][C:13]([OH:15])=[O:14])[CH2:2]1
Reactant: CCOC(=O)CC[C@@H]1Cc2ccccc2C2(C1)OCCO2
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CC[C@H]1CC(=O)c2ccccc2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.6 %

Procedure:
To a stirred solution of (R)-ethyl 3-(3′,4′-dihydro-2′H-spiro[[1,3]dioxolane-2,1′-naphthalen]-3′-yl)propanoate (2.3 g, 7.92 mmol) in THF (10 mL) and water (1 mL) in round bottom flask. LiOH (1.328 g, 55.4 mmol) was added and reaction mixture was stirred at 25° C. for 2 h. Reaction mixture was concentrated and acidified with dilute HCl, stirred for 1 h at RT. Extracted with ethyl acetate (2×30 mL), dried over sodium sulphate, concentrated to get crude title compound (1.6 g, 93%); m/z 262.7
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:18])[CH:8]=2)[N:3]=1.[C:19](OC(=O)C)(=[O:21])[CH3:20]>>[C:19]([NH:1][C:2]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:18])[CH:8]=2)[N:3]=1)(=[O:21])[CH3:20]
Reactant: Nc1cc(-c2ccccc2)c2cc(Cl)ccc2n1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Nc1cc(-c2ccccc2)c2cc(Cl)ccc2n1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
A mixture of 0.1 g of 2-amino-6-chloro-4-phenylquinoline and 8 ml of acetic anhydride was stirred at 70° C. for 1 hour, the solvent was removed by distillation, the solid residue was stirred with water, and the crystalline substance was filtered off.
Reaction SMILES: CS(C)=O.Cl[C:6]1[CH:11]=[C:10]([O:12][CH2:13][C:14]#[C:15][CH3:16])[N:9]=[CH:8][N:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:23]([NH2:25])[CH3:24]>COC(C)(C)C>[CH2:13]([O:12][C:10]1[CH:11]=[C:6]([NH:25][CH2:23][CH3:24])[N:7]=[CH:8][N:9]=1)[C:14]#[C:15][CH3:16]
Reactant: CC#CCOc1cc(Cl)ncn1
Reactant: CCN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COC(C)(C)C
Solvent: CS(C)=O
Product: CC#CCOc1cc(NCC)ncn1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To 20 ml of dimethylsulfoxide were added 1.83 g of 4-chloro-6-(2-butynyloxy)pyrimidine, 2.20 g of potassium carbonate, and 20 ml of ethylamine (2.0 M tetrahydrofuran solution), followed by stirring at 50° C. for 8 hours. The reaction mixture was then left for cooling to room temperature, diluted with tert-butyl methyl ether, and washed twice with an aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and concentrated. The residue was recrystallized from tert-butyl methyl ether to give 1.14 g of 4-(2-butynyloxy)-6-(ethylamino)pyrimidine (the present compound (108)).
Reaction SMILES: C([O:3][C:4](=[O:21])[C:5]1[CH:17]=[C:16]([CH:18]([F:20])[F:19])[CH:15]=[C:7]([C:8]([N:10]([CH3:14])[CH2:11][CH2:12][CH3:13])=[O:9])[CH:6]=1)C.[OH-].[Li+]>C1COCC1>[F:19][CH:18]([F:20])[C:16]1[CH:15]=[C:7]([C:8]([N:10]([CH3:14])[CH2:11][CH2:12][CH3:13])=[O:9])[CH:6]=[C:5]([CH:17]=1)[C:4]([OH:21])=[O:3]
Reactant: CCCN(C)C(=O)c1cc(C(=O)OCC)cc(C(F)F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCN(C)C(=O)c1cc(C(=O)O)cc(C(F)F)c1
Yield: 97.8 %

Procedure:
Stir a solution of 5-difluoromethyl-N-methyl-N-propyl-isophthalarnic acid ethyl ester (68 mg, 0.23 mmol), 1 N lithium hydroxide (1.15 mL) and THF (1.15 mL) at room temperature over the weekend. Add water and extract with dichloromethane. Acidify the aqueous with 5 N HCl (240 μL), extract with dichloromethane, dry (magnesium sulfate) and concentrate to give the title compound (61 mg, 100%).
Reaction SMILES: IC1C=CC=CC=1C(Cl)=O.[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][C:22]=1[O:23][CH3:24])[N:19]=[CH:18][CH:17]=[C:16]2[O:25][C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[C:28]([F:33])[CH:27]=1.[I:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[C:41]([N:43]=[C:44]=[S:45])=[O:42]>C1(C)C=CC=CC=1.C(O)C>[I:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[C:41]([N:43]=[C:44]=[S:45])=[O:42].[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][C:22]=1[O:23][CH3:24])[N:19]=[CH:18][CH:17]=[C:16]2[O:25][C:26]1[CH:32]=[CH:31][C:29]([NH:30][C:44]([NH:43][C:41](=[O:42])[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=2[I:34])=[S:45])=[C:28]([F:33])[CH:27]=1
Reactant: COc1cc2nccc(Oc3ccc(N)c(F)c3)c2cc1OC
Agent: O=C(Cl)c1ccccc1I
Agent: O=C(N=C=S)c1ccccc1I
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccccc4I)c(F)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
2-Iodo-1-benzenecarbonyl isothiocyanate was prepared using commercially available 2-iodo-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-fluoroaniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 2-iodo-1-benzenecarbonyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (86 mg, yield 90%).
Reaction SMILES: [Br:1][C:2]1[CH:17]=[C:5]2[NH:6][C:7]([CH3:16])=[C:8]([CH2:11][C:12]([O:14][CH3:15])=[O:13])[C:9](=O)[N:4]2[N:3]=1.O=P(Cl)(Cl)[Cl:20]>>[Br:1][C:2]1[CH:17]=[C:5]2[N:6]=[C:7]([CH3:16])[C:8]([CH2:11][C:12]([O:14][CH3:15])=[O:13])=[C:9]([Cl:20])[N:4]2[N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COC(=O)Cc1c(C)[nH]c2cc(Br)nn2c1=O
Product: COC(=O)Cc1c(C)nc2cc(Br)nn2c1Cl
Temperature: 0 °C
Yield: 82.7 %

Procedure:
To methyl 2-(2-bromo-5-methyl-7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimidin-6-yl)acetate (180 mg, 0.600 mmol) was added POCl3 (1 mL, 10.73 mmol). The reaction mixture was heated at reflux for 1 h. After cooling, the reaction mixture was added drop-wise to ice-water. A brown solid precipitated. The solid was filtered and washed with water to give the title compound (158 mg, 83%). 1H NMR (500 MHz, DMSO-d6) δ ppm 2.56 (3H, s), 3.69 (3H, s), 4.01 (2H, s), 6.99 (1H, s).
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH:6]2[S:7][CH2:8][C:9]3[CH:13](O)[O:12][C:11](=[O:15])[C:10]=3[N:5]2[C:4]1=[O:16].[NH2:17][OH:18]>ClCCl>[NH2:2][CH:3]1[C:4](=[O:16])[N:5]2[C:10]([C:11]([OH:12])=[O:15])=[C:9]([CH:13]=[N:17][OH:18])[CH2:8][S:7][C@H:6]12
Reactant: NC1C(=O)N2C3=C(CSC12)C(O)OC3=O
Reactant: NO
Agent: Cl
Solvent: ClCCl
Product: NC1C(=O)N2C(C(=O)O)=C(C=NO)CS[C@H]12
Reaction time: 2 h

Procedure:
A suspension of 0.79 g of the hydrochloride of 6-amino-1,4,5a,6-tetrahydro-3-hydroxy-1,7-dioxo-3H,7H-azeto[2,1-b]furo[3,4-d][1,3]thiazin in 10 ml of dichloromethane is treated under stirring at 4° with 2.67 g of N,O-bis-(trimethylsilyl)acetamide. A clear solution is obtained within 10 minutes. 0.21 g of the hydrochloride of hydroxylamine are added. The reaction mixture is stirred for ca. 2 hours under nitrogen at 4° and the solvent is evaporated off. The residue is treated with 10 ml of isopropylalkohol, precooled to 1°. 7-Amino-3-[(hydroxyimino)methyl]-3-cephem-4-carboxylic acid precipitates in form of almost colourless crystals which are filtered off, washed with 5 ml of acetone and dried.
Reaction SMILES: C([Li])(CC)C.C1C[C@H]2N(C[C@H]3[C@@H]4CCCCN4C[C@@H]2C3)CC1.[C:23]([O:27][C:28]([N:30]1[CH2:34][CH2:33][CH2:32][C:31]1([CH3:36])[CH3:35])=[O:29])([CH3:26])([CH3:25])[CH3:24].[CH2:37]([N:44]([CH2:55][C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1)[C@@H:45]([CH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)[CH:46]=[O:47])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.[Cl-].[NH4+]>C(OCC)C.C(OCC)(=O)C>[C:23]([O:27][C:28]([N:30]1[C:31]([CH3:36])([CH3:35])[CH2:32][CH2:33][C@@H:34]1[C@@H:46]([OH:47])[C@@H:45]([N:44]([CH2:37][C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)[CH2:55][C:56]1[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=1)[CH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)=[O:29])([CH3:26])([CH3:24])[CH3:25]
Reactant: O=C[C@H](Cc1ccccc1)N(Cc1ccccc1)Cc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCCC1(C)C
Agent: C1CCN2C[C@@H]3C[C@@H](CN4CCCC[C@@H]34)[C@H]2C1
Agent: [Cl-]
Agent: [Li]C(C)CC
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1[C@@H]([C@@H](O)[C@H](Cc2ccccc2)N(Cc2ccccc2)Cc2ccccc2)CCC1(C)C
Reaction time: 2 h
Yield: 11.9 %

Procedure:
Add sec-butyllithium (2.9 mL, 2.1 mmol) dropwise to a solution of freshly distilled (−)-sparteine (1 mL, 4.3 mmol) in diethyl ether (25 mL) over 3 min at −78° C. Add 2,2-dimethylpyrrolidine-1-carboxylic acid tert-butyl ester (645 mg, 3.2 mmol) in diethyl ether (2 mL) dropwise over 10 min. Stir 2 h, add 2-(S)-dibenzylamino-3-phenylpropionaldehyde (967 mg, 2.9 mmol) in diethyl ether (2 mL) over 5 min and stir 20 min. Add saturated aqueous ammonium chloride solution and ethyl acetate and let warm to room temperature, separate the layers, extract the aqueous layer with ethyl acetate, wash the organic layer with saturated aqueous sodium chloride solution, dry (magnesium sulfate), concentrate and purify (silica gel chromatography, eluting with 4:1 hexanes:ethyl acetate) to give the title compound as a colorless oil (182 mg, 12%).
Reaction SMILES: C1([Si](OC)(OC)OC)C=CC=CC=1.C(O[Si](OCC)(OCC)OCC)C.C[Si](OCC)(OCC)OCC.[CH3:38][S:39]([O-:42])(=[O:41])=[O:40].C(O[Si](CCC[N+:56]1[CH2:60][CH2:59][N:58](C)[CH:57]=1)(OCC)OCC)C.Cl.C(OCC(O)C)C>O.CC(C)=O.CO.C(O)C>[CH3:38][S:39]([O-:42])(=[O:41])=[O:40].[NH+:56]1[CH:60]=[CH:59][NH:58][CH:57]=1
Reactant: CCO[Si](CCC[N+]1=CN(C)CC1)(OCC)OCC
Agent: CCOCC(C)O
Agent: CCO[Si](C)(OCC)OCC
Agent: CCO[Si](OCC)(OCC)OCC
Solvent: O
Solvent: CO
Solvent: CC(C)=O
Product: c1c[nH+]c[nH]1
Temperature: 25 °C

Procedure:
4.92 g of phenyltrimethoxysilane, 72.40 g of tetraethoxysilane, 22.04 g of methyltriethoxysilane, 0.64 g of the 30% ethanol solution of triethoxysilylpropyl-3-methyl-4,5-dihydroimidazolium methanesulfonate, and 150 g of acetone were charged into a 500 mL flask to be dissolved and the resultant mixed solution was warmed while stirring the mixed solution with a magnetic stirrer to reflux. Next, 33.10 g of 0.01 M hydrochloric acid was added to the mixed solution. The mixed solution was subjected to the reaction for 240 minutes and then the resultant reaction solution was cooled down to room temperature. Then, 200 g of propylene glycol monoethyl ether was added to the reaction solution, and ethanol and methanol as reaction by-products, acetone, water, and hydrochloric acid were distilled off under reduced pressure to obtain a hydrolysis-condensation product. The polymer thus obtained corresponded to Formula (VII-13):
Reaction SMILES: [CH2:1]([O:3][P:4]([O-:8])[O:5][CH2:6][CH3:7])[CH3:2].[C:9]1(=[O:15])[CH2:14][CH2:13][CH2:12][CH:11]=[CH:10]1>>[O:15]=[C:9]1[CH2:14][CH:13]([P:4]([O:5][CH2:6][CH3:7])(=[O:8])[O:3][CH2:1][CH3:2])[CH2:12][CH2:11][CH2:10]1
Reactant: CCOP([O-])OCC
Reactant: O=C1C=CCCC1
Product: CCOP(=O)(OCC)C1CCCC(=O)C1

Procedure:
Diethyl 5-oxocyclohexanephosphonate (B.Pt. 142°-3° C./0.2 mm) was prepared by the base catalysed addition of diethylphosphite to 2-cyclohexen-1-one.
Reaction SMILES: O[CH:2]1[C:7]([CH3:9])([CH3:8])[O:6][C:5]2[CH:10]=[CH:11][S:12][C:4]=2[CH:3]1[N:13]1[CH2:17][CH2:16][CH2:15][C:14]1=[O:18].[C:19]([O:22]C(=O)C)(=[O:21])[CH3:20]>Cl(O)(=O)(=O)=O>[C:19]([O:22][C:11]1[S:12][C:4]2[CH:3]([N:13]3[CH2:17][CH2:16][CH2:15][C:14]3=[O:18])[CH2:2][C:7]([CH3:9])([CH3:8])[O:6][C:5]=2[CH:10]=1)(=[O:21])[CH3:20]
Reactant: CC(=O)OC(C)=O
Reactant: CC1(C)Oc2ccsc2C(N2CCCC2=O)C1O
Agent: [O-][Cl+3]([O-])([O-])O
Product: CC(=O)Oc1cc2c(s1)C(N1CCCC1=O)CC(C)(C)O2
Temperature: 0 °C

Procedure:
A solution of 5,6-dihydro-6-hydroxy-5,5-dimethyl-7-(2-oxopyrrolidin-1-yl)-7H-thieno[3,2-b]pyran (2.0 g, 7.48 mmol) and perchloric acid (70%, 10 drops) in acetic anhydride (20 mL) were stirred for 1 h at 0°-5° C. The solution was poured into ice water (100 mL). The product was extracted into dichloromethane, washed with water (4x), and evaporated in vacuo. The resultant oil was purified by flash chromatography, using 1% methanol in dichloromethane as the eluant, then crystallized from hexanes to give the product, 2.12 g (92%), as a colorless solid: mp 92°-93° C.; IR(KBr): 1745 and 1684 cm-1 ; MS: 310 (MH+); 1H NMR (CDCl3): δ 1.37 (s, 3H), 1.38 (s, 3H), 1.98 (m, 2H), 2.10 (s, 3H), 2.37 (m, 2H), 3.24 (m, 1H), 3.40 (m, 1H), 5.15 (d, J=9.1 Hz, 1H), 5.44 (d, J=9.1 Hz, 1H), 6.58 (d, J=5.4 Hz, 1H) and 7.13 (d, J=5.4 Hz, 1H).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([CH3:8])[N:3]1[C:9]1[N:13]2[CH:14]=[C:15]([O:18][C@H:19]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[C@@H:22]([NH2:29])[CH2:21][CH2:20]3)[CH:16]=[CH:17][C:12]2=[N:11][N:10]=1.ClC(Cl)(Cl)C[O:33][C:34](=O)[NH:35][C:36]1[N:37]([C:45]2[CH:50]=[CH:49][CH:48]=[C:47]([CH2:51][OH:52])[CH:46]=2)[N:38]=[C:39]([C:41]([CH3:44])([CH3:43])[CH3:42])[CH:40]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[C:41]([C:39]1[CH:40]=[C:36]([NH:35][C:34]([NH:29][C@@H:22]2[C:23]3[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=3)[C@H:19]([O:18][C:15]3[CH:16]=[CH:17][C:12]4[N:13]([C:9]([N:3]5[C@H:2]([CH3:1])[CH2:7][CH2:6][CH2:5][C@@H:4]5[CH3:8])=[N:10][N:11]=4)[CH:14]=3)[CH2:20][CH2:21]2)=[O:33])[N:37]([C:45]2[CH:50]=[CH:49][CH:48]=[C:47]([CH2:51][OH:52])[CH:46]=2)[N:38]=1)([CH3:44])([CH3:42])[CH3:43]
Reactant: CC(C)(C)c1cc(NC(=O)OCC(Cl)(Cl)Cl)n(-c2cccc(CO)c2)n1
Reactant: C[C@@H]1CCC[C@H](C)N1c1nnc2ccc(O[C@@H]3CC[C@H](N)c4ccccc43)cn12
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1CCC[C@H](C)N1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4cccc(CO)c4)c4ccccc43)cn12
Temperature: 80 °C
Reaction time: 7 h
Yield: 144.5 %

Procedure:
A mixture of Intermediate 96c (150 mg, 0.38 mmol), Intermediate 29c (161 mg, 0.38 mmol) and DIPEA (133 μL, 0.77 mmol) in dioxane (4 mL) was stirred at 80° C. for 7 hours. After cooling, the reaction mixture was partitioned between water and DCM. The aqueous phase was extracted with EtOAc (×3) and the combined organic layers were washed with brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was purified by FCC on silica, using a gradient of 1-10% MeOH in DCM to afford the title compound (364 mg, 95%) as a glassy white solid %). LCMS (Method 4): Rt 3.50 min, m/z 663 [MH+].
Reaction SMILES: [Cl:1][C:2]1[C:11]([C:12]2([C:15]#[N:16])[CH2:14][CH2:13]2)=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].O1CCCC1.CO>O>[Cl:1][C:2]1[C:11]([C:12]2([C:15]#[N:16])[CH2:14][CH2:13]2)=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1cccc(C2(C#N)CC2)c1Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: N#CC1(c2cccc(C(=O)O)c2Cl)CC1
Yield: 71.1 %

Procedure:
Using methyl 2-chloro-3-(1-cyanocyclopropyl)benzoate (684 mg, 2.90 mmol), lithium hydroxide•monohydrate (207 mg, 4.93 mmol), tetrahydrofuran (10 mL), methanol (3 mL) and water (3 mL) as starting materials, and in the same manner as in Example A1(iii), the title compound (457 mg, 71%) was obtained as a white powder.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:19]3=[N:20][CH:21]=[C:22](Cl)[CH:23]=[C:18]3[N:17]([CH2:25][CH3:26])[C:16]2=[O:27])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(P(C(C)(C)C)C1C(C)=C(C)C(C)=C(C)C=1C1C(C(C)C)=CC(C(C)C)=CC=1C(C)C)(C)(C)C.[OH-:62].[K+].Cl>O1CCOCC1.O.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]>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:19]3=[N:20][CH:21]=[C:22]([OH:62])[CH:23]=[C:18]3[N:17]([CH2:25][CH3:26])[C:16]2=[O:27])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [OH-]
Reactant: CCn1c(=O)n(-c2ccc(OCc3ccccc3)cc2)c2ncc(Cl)cc21
Agent: [Pd]
Agent: Cc1c(C)c(C)c(P(C(C)(C)C)C(C)(C)C)c(-c2c(C(C)C)cc(C(C)C)cc2C(C)C)c1C
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: CCn1c(=O)n(-c2ccc(OCc3ccccc3)cc2)c2ncc(O)cc21
Temperature: 100 °C
Reaction time: 3 h
Yield: 80.1 %

Procedure:
A mixture of 3-[4-(benzyloxy)phenyl]-6-chloro-1-ethyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (1.72 g), Pd2 dba3 (0.21 g), 2-di-tert-butylphosphino-3,4,5,6-tetramethyl-2′,4′,6′-triisopropyl-1,1′-biphenyl (0.44 g) and KOH (1.10 g) in dioxane (15 ml,) and water (15 mL) was stirred at 100° C. under Ar atmosphere for 3 h. After stirring at room temperature overnight, the mixture was acidified with 1 N HCl aq (11 mL) and diluted with water. The mixture was extracted with AcOEt. The organic layer was dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 10%-70% AcOEt in hexane) to give 3-[4-(benzyloxy)phenyl]-1-ethyl-6-hydroxy-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (1.31 g) as a pale yellow solid.
Reaction SMILES: CS(O[CH2:6][C@H:7]1[N:17]2[C:18]3[N:9]([C:10](=[O:30])[CH2:11][N:12]([C:20]([O:22][CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[O:21])[C:13]=3[CH:14]=[CH:15][C:16]2=[O:19])[CH2:8]1)(=O)=O.N1C=CC=CC=1.[NH:37]1[CH2:42][CH2:41][CH:40]([NH:43][C:44](=[O:50])[O:45][C:46]([CH3:49])([CH3:48])[CH3:47])[CH2:39][CH2:38]1>C(#N)C>[CH3:48][C:46]([O:45][C:44]([NH:43][CH:40]1[CH2:39][CH2:38][N:37]([CH2:6][C@H:7]2[N:17]3[C:18]4[N:9]([C:10](=[O:30])[CH2:11][N:12]([C:20]([O:22][CH2:23][C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)=[O:21])[C:13]=4[CH:14]=[CH:15][C:16]3=[O:19])[CH2:8]2)[CH2:42][CH2:41]1)=[O:50])([CH3:47])[CH3:49]
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: CS(=O)(=O)OC[C@@H]1CN2C(=O)CN(C(=O)OCc3ccccc3)c3ccc(=O)n1c32
Solvent: c1ccncc1
Solvent: CC#N
Product: CC(C)(C)OC(=O)NC1CCN(C[C@@H]2CN3C(=O)CN(C(=O)OCc4ccccc4)c4ccc(=O)n2c43)CC1
Temperature: 70 °C
Reaction time: 8 h
Yield: 47.6 %

Procedure:
Phenylmethyl (1S)-1-{[(methylsulfonyl)oxy]methyl}-3,8-dioxo-1,2,3,4-tetrahydro-5H,8H-2a,5,8a-triazaacenaphthylene-5-carboxylate (232 mg, 0.508 mmol) was dissolved in dry acetonitrile (10 ml) at room temperature under argon and treated with pyridine (0.049 ml, 0.610 mmol). 1,1-Dimethylethyl 4-piperidinylcarbamate (127 mg, 0.610 mmol) was then added and the reaction was heated at 70° C. overnight. Then 0.049 ml of pyridine and 127 mg of 1,1-dimethylethyl 4-piperidinylcarbamate were added to the reaction and the temperature was increased to 80° C. for 8 h and then the reaction was stirred at room temperature overnight. The solvent was evaporated and the residue partitioned between sat NaHCO3 and DCM (50/50 ml). The layers were separated and the aqueous layer was extracted with DCM again (2×50 ml). The combined organic extracts were dried (MgSO4) filtered and evaporated to afford 280 mg of crude product which was purified by silica chromatography using a 0-5% methanol/dichloromethane gradient to afford the product as a yellow gum (130 mg, 47.6%).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3]1.C([Li])(C)(C)C.CCCCC.[CH3:21][N:22]([CH3:36])[C:23]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:28][CH2:27][C:26](=[O:29])[CH2:25][CH2:24]1>C1COCC1>[CH3:21][N:22]([CH3:36])[C:23]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:28][CH2:27][C:26]([C:3]2[N:2]([CH3:1])[C:10]3[C:5]([CH:4]=2)=[CH:6][CH:7]=[CH:8][CH:9]=3)([OH:29])[CH2:25][CH2:24]1
Reactant: Cn1ccc2ccccc21
Reactant: CN(C)C1(c2ccccc2)CCC(=O)CC1
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: C1CCOC1
Product: CN(C)C1(c2ccccc2)CCC(O)(c2cc3ccccc3n2C)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 29.9 %

Procedure:
A solution of N-methylindol (400 mg, 3.05 mmol) in dry THF (20 ml) was cooled to −5° C. under a stream of argon. Tert-butyllithium (3.65 mmol, 2.15 ml of a 1.7 molar pentane solution) was added dropwise in such a way that a reaction temperature of 0° C. was not exceeded. Once all the substance had been added, the reaction mixture was stirred for 2 hours at 0° C. A solution of 4-dimethylamino-4-phenylcyclohexanone (662 mg, 3.05 mmol) in dry THF (5 ml) was added dropwise at 0° C. The mixture was stirred for 15 minutes at 0° C. and then 4 hours at ambient temperature. The reaction mixture was quenched with saturated ammonium chloride solution (20 ml), the organic phase was separated and the aqueous phase extracted four times with dichloromethane (20 ml). The combined organic phases were dried over sodium sulfate, filtered and the solvent removed under vacuum. Purification was carried out by flash chromatography with cyclohexane/ethylacetate (V:V=7:3) over silica gel. 318 mg 4-dimethylamino-1-(1-methyl-1H-indol-2-yl)-4-phenylcyclohexanol with a melting point of 163–165° C. were obtained.