Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][CH2:8][CH2:9][CH2:10][C:11](=O)[CH3:12])([CH3:4])([CH3:3])[CH3:2].[NH2:15][C:16]1[C:21]([CH:22]=O)=[CH:20][CH:19]=[CH:18][N:17]=1.[OH-].[K+]>C(O)C>[N:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][N:17]=2)[CH:22]=[CH:12][C:11]=1[CH2:10][CH2:9][CH2:8][NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:14]
Reactant: Nc1ncccc1C=O
Reactant: CC(=O)CCCNC(=O)OC(C)(C)C
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)OC(=O)NCCCc1ccc2cccnc2n1

Procedure:
A mixture of 1-4 (5.0 g, 24.8 mmol), 2-amino-3-formylpyridine 1-5 [3.6 g, 29.8 mmol; for preparation see J. Org. Chem., 48: 3401 (1983)] and 20% KOH (1 ml) in absolute ethanol (100 mL) was heated at reflux for 8 h. Following evaporative removal of the solvent, the residue was chromatographed (silica gel, 70:28:2 chloroform/ethyl acetate/methanol) to give 1-6 as a yellow oil.
Reaction SMILES: [OH-].[K+].[CH2:3]([N:9]1[CH2:14][CH:13]2[CH:11]([C:12]2([C:16]2[CH:17]=[CH:18][C:19]([N+:26]([O-:28])=[O:27])=[C:20]([NH:22]C(=O)C)[CH:21]=2)[CH3:15])[CH2:10]1)[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]>CO.O>[CH2:3]([N:9]1[CH2:14][CH:13]2[CH:11]([C:12]2([C:16]2[CH:17]=[CH:18][C:19]([N+:26]([O-:28])=[O:27])=[C:20]([NH2:22])[CH:21]=2)[CH3:15])[CH2:10]1)[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCN1CC2C(C1)C2(C)c1ccc([N+](=O)[O-])c(NC(C)=O)c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCCCCN1CC2C(C1)C2(C)c1ccc([N+](=O)[O-])c(N)c1
Yield: 76.1 %

Procedure:
To a solution of potassium hydroxide (100 mg, 1.79 mmol) in methanol (5.0 ml) and water 2.0 ml) was added N-[5-(3-hexyl-6-methyl-3-azabicyclo[3.1.0]hex-6-yl)-2-nitrophenyl]acetamide (Preparation 46, 534 mg, 1.49 mmol) in methanol (5 ml). The mixture was heated under reflux for 30 minutes and then was allowed to cool. The solvent was removed in vacuo, water (5 ml) was added and the aqueous solution was extracted with ethyl acetate (3×5 ml). The combined extracts were dried (MgSO4), filtered and concentrated in vacuo to afford the title compound (360 mg, 76%) as a crude oil which was used without further purification.
Reaction SMILES: [CH3:1][N:2]([CH3:8])[C:3](=[O:7])[C@H:4]([CH3:6])[NH2:5].C(N(CC)CC)C.S=[C:17]1[CH2:21][S:20][C:19](=[O:22])[NH:18]1>C(O)C>[CH3:1][N:2]([CH3:8])[C:3](=[O:7])[C@H:4]([CH3:6])[NH:5][C:17]1[CH2:21][S:20][C:19](=[O:22])[N:18]=1
Reactant: O=C1NC(=S)CS1
Reactant: C[C@H](N)C(=O)N(C)C
Solvent: CCO
Solvent: CCN(CC)CC
Product: C[C@H](NC1=NC(=O)SC1)C(=O)N(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the crude product containing N,N-dimethylalaninamide obtained in C) and triethylamine (2 mL) in ethanol (20 mL) was added 4-thioxothiazolidin-2-one (1998 mg) at room temperature. The reaction mixture was stirred at room temperature overnight, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (960 mg).
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=2)[N:8]=1)=O.[C:26]1([NH:32]N)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[C:26]1([N:32]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:15]=[CH:16][C:17]([O:20][C:21]([F:23])([F:24])[F:22])=[CH:18][CH:19]=4)[N:8]=3)=[CH:4][CH:3]=[N:2]2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: NNc1ccccc1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2ccc(OC(F)(F)F)cc2)ccc1=O
Product: O=c1ccn(-c2ccc(OC(F)(F)F)cc2)nc1-c1ccnn1-c1ccccc1
Yield: 64 %

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(4-trifluoromethoxy-phenyl)-1H-pyridazin-4-one (A-8) and phenylhydrazine according to the method described for Example 1 in 64% yield. MS: M=399.1 (M+H)+
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([SH:8])[N:5]=[C:4]([OH:9])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:17][C:18]1[C:19]([CH3:25])=[N:20][N:21]([CH3:24])[C:22]=1[Cl:23]>CN(C=O)C>[Cl:23][C:22]1[N:21]([CH3:24])[N:20]=[C:19]([CH3:25])[C:18]=1[CH2:17][S:8][C:6]1[N:5]=[C:4]([OH:9])[CH:3]=[C:2]([CH3:1])[N:7]=1
Reactant: Cc1cc(O)nc(S)n1
Reactant: Cc1nn(C)c(Cl)c1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(O)nc(SCc2c(C)nn(C)c2Cl)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 22.2 %

Procedure:
6-methyl-2-sulfanylpyrimidin-4-ol (437 mg, 3.0 mmol) was dissolved in anhydrous DMF (25 mL), then potassium carbonate (1.27 g, 9.2 mmol) and crude 4-(bromomethyl)-5-chloro-1,3-dimethyl-1H-pyrazole (1.03 g, 4.6 mmol) were added. The mixture was stirred for 3 hours at room temperature. The solid was removed by filtration and washed with methanol, and the filtrate was evaporated. The residue was dissolved in DCM/MeOH and purified on silica gel using 10% DCM/MeOH to afford 2-{[(5-chloro-1,3-dimethyl-1H-pyrazol-4-yl)methyl]sulfanyl}-6-methylpyrimidin-4-ol (190 mg, 22% yield for 2 steps); 1H NMR (400 MHz, DMSO-d6): δ 2.17 (s, 314), 2.20 (s, 3H), 3.70 (s, 3H), 4.20 (s, 2H), 5.76 (bs, 1H); LRMS (ES+) m/z 285 (80%, M+1), 287 (30%, M+3).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]2[CH:12]=[C:11]([CH2:14]Br)[O:10][C:9]=2[C:8]([O:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[CH:7][CH:6]=1)=[O:4].C(=O)([O-])[O-:23].[Na+].[Na+]>CS(C)=O.O>[CH3:1][O:2][C:3]([C:5]1[C:13]2[CH:12]=[C:11]([CH:14]=[O:23])[O:10][C:9]=2[C:8]([O:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[CH:7][CH:6]=1)=[O:4]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1ccc(OC2CCCC2)c2oc(CBr)cc12
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)c1ccc(OC2CCCC2)c2oc(C=O)cc12
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 34686.7 %

Procedure:
To a well stirred solution of Methyl-7-cyclopentyloxy-2-bromomethylbenzo[b]furan-4-carboxylate (50.0 g, 0.140 moles) in dimethyl sulfoxide (250.0 mL) was added powdered sodium carbonate (22.0 g, 0.21 mmoles) at 105-110° C. and stirred for 2-3 hours. Reaction mixture was cooled to room temperature and diluted with water (2.0 L) and extracted with ethyl acetate (3×500 mL). The combined organic layers were washed with water (2×500 mL) and dried over anhydrous sodium sulfate. Removal of solvent gave crude product (51 g) as brown viscous oil. Purification by silica gel column using chloroform: ethyl acetate (95:5) as an eluent afforded 21 g of pure product.
Reaction SMILES: [CH3:1][CH:2]([OH:22])[C@@H:3]1[C@:20]2([CH3:21])[C@H:6]([C@H:7]3[C@H:17]([CH2:18][CH2:19]2)[C@:15]2([CH3:16])[C@H:10]([CH2:11][CH:12]=[CH:13][CH2:14]2)[CH2:9][CH2:8]3)[CH2:5][CH2:4]1.C1C=C(Cl)C=C(C(OO)=[O:31])C=1>ClCCl>[O:31]1[C@H:12]2[CH2:11][C@H:10]3[C@:15]([CH3:16])([CH2:14][C@@H:13]12)[C@@H:17]1[C@H:7]([C@H:6]2[C@:20]([CH3:21])([CH2:19][CH2:18]1)[C@@H:3]([CH:2]([OH:22])[CH3:1])[CH2:4][CH2:5]2)[CH2:8][CH2:9]3
Reactant: CC(O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4CC=CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC(O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@@H]5O[C@@H]5C[C@]4(C)[C@H]3CC[C@]12C
Temperature: 0 °C
Reaction time: 1 h
Yield: 73.6 %

Procedure:
To a solution of 5-α-pregn-2-en-20-ol (12) (660 mg, 2.18 mmol) in anhydrous dichloromethane (20 mL) at 0° C. under an atmosphere of argon was added in six portions m-CPBA (733 mg, 3.27 mmol). The solution was stirred over a period of 1 h at 0° C. and then allowed to return to room temperature overnight. The resulting solution was diluted with dichloromethane (30 mL) and successively washed with a Na2S2O3 aqueous solution (10%) and a Na2CO3 aqueous solution (10%), dried with MgSO4, filtered and evaporated to dryness. Purification by FCC (EtOAc/hexanes, 5:95) yielded 511 mg (73%) of title compound 13 as a white solid. 1H NMR (acetone-d6) δ: 0.74 (s, 18-CH3), 0.79 (s, 19-CH3), 1.07 (d, J=6.1 Hz, 21-CH3), 0.60-2.30 (residual CH and CH2), 3.06 (m, 2×CH of epoxide), 3.62 (m, 20-CH); 13C NMR (CDCl3) δ: 12.4, 12.9, 20.7, 23.6, 24.4, 25.6, 28.4, 29.0, 31.7, 33.6, 35.4, 36.2, 38.2, 39.9, 42.3, 51.1, 52.4, 53.7, 55.7, 58.5, 70.6, LRMS for C21H34O2 [M+H]+: 319.1 m/z.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[N:8]=[C:7]2[N:9]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=3)[C:10]([C:12]([OH:14])=O)=[CH:11][C:6]2=[CH:5][CH:4]=1.[NH2:25][C:26]1[CH:27]=[N:28][C:29]([Cl:32])=[CH:30][CH:31]=1>>[Cl:32][C:29]1[N:28]=[CH:27][C:26]([NH:25][C:12]([C:10]2[N:9]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=3)[C:7]3=[N:8][C:3]([C:2]([F:24])([F:23])[F:1])=[CH:4][CH:5]=[C:6]3[CH:11]=2)=[O:14])=[CH:31][CH:30]=1
Reactant: Nc1ccc(Cl)nc1
Reactant: O=C(O)c1cc2ccc(C(F)(F)F)nc2n1Cc1cccc(F)c1
Product: O=C(Nc1ccc(Cl)nc1)c1cc2ccc(C(F)(F)F)nc2n1Cc1cccc(F)c1

Procedure:
According to a method similar to that described in Stage 6.1, by reacting 0.5 g (1.48 mmol) of 6-trifluoromethyl-1-[(3-fluorophenyl)methyl]-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid, described in Stage 15.2 with 0.288 (2.22 mmol) of 3-amino-6-chloropyridine, we obtain 0.33 g of the expected compound in the form of a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11](=O)[CH2:12][CH2:13][N:14](C)C)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].Cl.O.[NH2:20]N>CCO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH2:12][CH2:13][NH:14][N:20]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: NN
Reactant: COc1ccc(C(=O)CCN(C)C)cc1OC
Agent: Cl
Solvent: O
Solvent: CCO
Product: COc1ccc(C2=NNCC2)cc1OC
Temperature: 80 °C
Yield: 100 %

Procedure:
A 100 mL round bottom flask equipped with a stir bar, Vigreux column and nitrogen inlet was charged with 1-(3,4-dimethoxy-phenyl)-3-dimethylamino-propan-1-one.HCl, (1.4 g, 5 mmol) EtOH, (20 mL) and hydrazine monohydrate, (0.3 mL, 6 mmol). The mixture was heated at 80° C. for 2 h. LC-MS and TLC analysis showed consumption of SM. The solvent was evaporated under reduced pressure and trace hydrazine and EtOH was removed under high vacuum for 30 min. The material was used as in the next step. Amount obtained 1030 mg, 5 mmol, 100% yield. LC-MS (ESI) m/e 207 (M+H). Step 3
Reaction SMILES: C([O-])(=O)C.[NH4+:5].[F:6][C:7]1[C:8]([I:22])=[C:9]([CH3:21])[C:10]2[C:15](=O)[O:14]C(=O)[NH:12][C:11]=2[C:18]=1[O:19][CH3:20]>CN(C)C=O>[NH2:12][C:11]1[C:18]([O:19][CH3:20])=[C:7]([F:6])[C:8]([I:22])=[C:9]([CH3:21])[C:10]=1[C:15]([NH2:5])=[O:14]
Reactant: COc1c(F)c(I)c(C)c2c(=O)oc(=O)[nH]c12
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Product: COc1c(N)c(C(N)=O)c(C)c(I)c1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 96.2 %

Procedure:
Under nitrogen atmosphere, ammonium acetate (4.62 g, 60.0 mmol) was added to an N,N-dimethylformamide (120 ml) solution of 7-fluoro-6-iodo-8-methoxy-5-methyl-1H-benzo[d][1,3]oxazine-2,4-dione (I-31) (4.2 g, 12.0 mmol), followed by stirring at room temperature for 16 hours. The reaction liquid was concentrated under reduced pressure, the residue was dissolved in ethyl acetate, washed three times with saturated brine, then dried over anhydrous magnesium sulfate. After filtration and concentration under reduced pressure, the resulting residue was suspended in diisopropyl ether, followed by filtration and drying to obtain the entitled compound (3.74 g, 96%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH2:11][C@H:10]([CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:9]2)=[C:4]([F:22])[CH:3]=1.[C:23]1(=O)[CH2:26][CH2:25][CH2:24]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C>>[F:22][C:4]1[CH:3]=[C:2]([NH:1][CH:23]2[CH2:26][CH2:25][CH2:24]2)[CH:7]=[CH:6][C:5]=1[N:8]1[CH2:12][CH2:11][C@H:10]([CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:18])([CH3:19])[CH3:20])[CH2:9]1
Reactant: O=C1CCC1
Reactant: CC(C)(C)OC(=O)NC[C@H]1CCN(c2ccc(N)cc2F)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Product: CC(C)(C)OC(=O)NC[C@H]1CCN(c2ccc(NC3CCC3)cc2F)C1

Procedure:
tert-Butyl (R)-[1-(4-amino-2-fluorophenyl)pyrrolidin-3-yl]methylcarbamate was alkylated with cyclobutanone using triacetoxyborohydride as reducing agent by method N. This resulted in the product with the molecular weight of 363.48 (C20H30FN3O2); MS (ESI): 364 (M+H+).
Reaction SMILES: [CH:1]1([N:5]2[CH2:10][CH2:9][N:8]([C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[NH:18][C:17]([C:22]([N:24]3[CH2:29][CH2:28][C:27]([F:31])([F:30])[CH2:26][CH2:25]3)=[O:23])=[CH:16]4)=[O:12])[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[CH3:32][S:33]([C:36]1[CH:41]=[CH:40][C:39](B(O)O)=[CH:38][CH:37]=1)(=[O:35])=[O:34].N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH:1]1([N:5]2[CH2:6][CH2:7][N:8]([C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[N:18]([C:39]3[CH:40]=[CH:41][C:36]([S:33]([CH3:32])(=[O:35])=[O:34])=[CH:37][CH:38]=3)[C:17]([C:22]([N:24]3[CH2:25][CH2:26][C:27]([F:30])([F:31])[CH2:28][CH2:29]3)=[O:23])=[CH:16]4)=[O:12])[CH2:9][CH2:10]2)[CH2:2][CH2:3][CH2:4]1
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCC(F)(F)CC3)cc2c1)N1CCN(C2CCC2)CC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CS(=O)(=O)c1ccc(-n2c(C(=O)N3CCC(F)(F)CC3)cc3cc(C(=O)N4CCN(C5CCC5)CC4)ccc32)cc1
Yield: 12 %

Procedure:
The title compound was synthesized in analogy to example 66, from [5-(4-cyclobutyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone (example 41), 4-(methanesulphonyl)benzeneboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a light brown solid (12%).
Reaction SMILES: Cl/[CH:2]=[CH:3]/[C:4](=[O:14])[C:5]([CH3:13])([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:6].C(COC)OC.[Br-:21].[Li+]>CCOCC>[Br:21]/[CH:2]=[CH:3]/[C:4](=[O:14])[C:5]([CH3:13])([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:6]
Reactant: CC(C)(C(=O)/C=C/Cl)c1ccccc1
Reactant: [Br-]
Agent: [Li+]
Solvent: CCOCC
Solvent: COCCOC
Product: CC(C)(C(=O)/C=C/Br)c1ccccc1

Procedure:
A solution of 14 g. of 1-chloro-4-methyl-4- phenyl-1-trans-1-penten-3-one in 90 ml. of dimethoxyethane was treated with 24 g. of lithium bromide and refluxed for 24 hours. The mixture was diluted at 0° C. with ether, washed with brine, dried with MgSO4 and evaporated to dryness. The residue was redissolved in dimethoxyethane, treated with lithium bromide and refluxed for an additional 24 hours. After the exact same process was repeated thrice and the crude product was chromatographed on silica gel. Elution with 5% ethyl acetate in hexane afforded 8.9 g. of the title produce as a yellow oil, λmaxfilm 3.4, 5.88, 6.32, 6.66, 6.78, 6.88, 7.70, 9.25, 9.48, 9.98, 10.64, 12.80, 13.10 and 14.25 μ.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([Cl:19])=[CH:5][C:6]=1[CH:7]1[CH2:16][C:15]2[N:14]=[N:13][CH:12]=[C:11]([CH3:17])[C:10]=2[C:9](=O)[CH2:8]1.Cl.[NH2:21][NH:22][C:23]([NH:25][OH:26])=[NH:24].Cl>C(O)C>[ClH:1].[Cl:1][C:2]1[S:3][C:4]([Cl:19])=[CH:5][C:6]=1[CH:7]1[CH2:16][C:15]2[N:14]=[N:13][CH:12]=[C:11]([CH3:17])[C:10]=2[C:9](=[N:21][NH:22][C:23](=[NH:24])[NH:25][OH:26])[CH2:8]1
Reactant: N=C(NN)NO
Reactant: Cc1cnnc2c1C(=O)CC(c1cc(Cl)sc1Cl)C2
Agent: Cl
Solvent: CCO
Product: Cc1cnnc2c1C(=NNC(=N)NO)CC(c1cc(Cl)sc1Cl)C2
Temperature: 90 °C
Reaction time: 1.5 h
Yield: 81.9 %

Procedure:
To a mixture of 7-(2,5-dichlorothiophen-3-yl)-4-methyl-5,6,7,8-tetrahydrocinnolin-5-one (145 mg) and 1-amino-3-hydroxyguanidine hydrochloride (61 mg) were added ethanol (3 ml) and concentrated hydrochloric acid (0.05 ml), and the mixture was stirred at 90° C. for 1.5 hours. The reaction solution was concentrated under reduced pressure, and the residue was recrystallized from ethanol-acetone to give 7-(2,5-dichlorothiophen-3-yl)-5-(1-hydroxyguanidin-3-yl)imino-4-methyl-5,6,7,8-tetrahydrocinnoline hydrochloride (Compound 155) (80 mg) as whitish gray crystals.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2)([OH:3])=[O:2].C(N1C=CN=C1)(N1[CH:19]=[CH:18]N=C1)=O.CCO.[H-].[Na+]>C1COCC1>[CH2:18]([O:2][C:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2)=[O:3])[CH3:19]
Reactant: O=C(O)c1ccc2[nH]ccc2c1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc2[nH]ccc2c1
Reaction time: 2 h
Yield: 127.7 %

Procedure:
Combine 5-carboxyindole (4.8 g, 29.8 mmol) in 150 mL THF and carbonyldiimidazole (9.7 g, 59.6 mmol) and stir overnight at ambient temperature. Treat the reaction mixture with 25 mL EtOH and 1.2 g (29.8 mmol) of a 60% oil dispersion of NaH and stir for 2 hours. Concentration under vacuum gives a residue. Partition the residue between 150 mL EtOAc and 100 mL brine. Separate the layers, dry the organic layer over MgSO4, filter, and concentrated to an oil. Chromatograph on silica gel eluting with 1% MeOH in CHCl3 to give 7.2 g of an oil. Crystallize the oil from toluene gives the title compound: Analysis for C11H11NO2: calcd: C, 69.83; H, 5.86; N, 7.40; found: C, 69.82; H, 5.90; N, 7.38; ISMS 190 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:22])[CH2:9][NH:10][C:11]([CH:13]2[CH2:18][CH2:17][N:16]([CH2:19][C:20]#[N:21])[CH2:15][CH2:14]2)=[O:12])=[CH:4][CH:3]=1.O.[C:24](=O)(O)[O-:25].[Na+].C=O>C(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:22])[CH:9]([NH:10][C:11]([CH:13]2[CH2:14][CH2:15][N:16]([CH2:19][C:20]#[N:21])[CH2:17][CH2:18]2)=[O:12])[CH2:24][OH:25])=[CH:6][CH:7]=1
Reactant: O=C([O-])O
Reactant: N#CCN1CCC(C(=O)NCC(=O)c2ccc(F)cc2)CC1
Agent: C=O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: N#CCN1CCC(C(=O)NC(CO)C(=O)c2ccc(F)cc2)CC1
Temperature: 40 °C
Reaction time: 3 h
Yield: 380.7 %

Procedure:
In a 22-l round bottomed flask, suspend 1-cyanomethyl-piperidine-4-carboxylic acid-[2-(4-fluorophenyl)-2-oxoethyl] amide (1.004 kg, 3.31 moles) in absolute ethanol (5.0 l) and process water (2.5 l). To the suspension is added sodium bicarbonate (55.62 g, 0.662 moles) and 37% formaldehyde (400 ml, 4.93 moles), then the suspension is warmed to 40° C. and the reaction followed by HPLC. Upon completion, the reaction is quenched by added ice water (5.0 l) and brine (5.0 l). The reaction is stirred for three hours, then the crystals are collected by vacuum filtration, washed with process water (1.0 l) and dried at ambient temperature and 25 in Hg to give 1-cyanomethyl-piperidine-4-carboxylic acid-[2-(4-fluorophenyl)-1-hydroxymethyl-2-oxoethyl] amide (839 g, 2.52 moles). 1H NMR (400 MHz, d6 DMSO) d 1.52 (m, 2H), 1.67 (t, 2H), 2.12 (t, 2H), 2.23 (m, 1H), 2.77 (m, 2H), 3.38 (s, 1H), 3.65 (m, 1H), 3.68 (s, 2H), 3.75 (m, 1H), 5.15 (m, 1H), 5.25 (m, 1H), 7.16 (t, 2H), 8.06 (q, 2H), 8.40 (d, 1H).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[Li+].[CH3:17]C([N-]C(C)C)C.CI.[NH4+].[Cl-]>C1COCC1>[CH3:17][C:8]1([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:9][CH2:10][C:5]2([O:4][CH2:3][CH2:2][O:1]2)[CH2:6][CH2:7]1
Reactant: CC(C)[N-]C(C)C
Reactant: CCOC(=O)C1CCC2(CC1)OCCO2
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CI
Product: CCOC(=O)C1(C)CCC2(CC1)OCCO2
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
Ethyl 1,4-dioxaspiro[4.5]decane-8-carboxylate (Int-18a, 2.14 g, 10 mmol) was dissolved in dry THF (20 mL) and the solution was cooled to −78° C. LDA (1.8 M in THF, 6.6 mL) was added to the mixture dropwise and the mixture was stirred for 15 min. Then CH3I (1.87 mL, 30 mmol) was added to the mixture at −78° C. and the reaction was allowed to warm up to room temperature. The reaction was stirred overnight. NH4Cl (aq.) was added to quench the reaction which was extracted with ethyl acetate (50 mL×3). The combined organics was washed with water and brine and dried over Na2SO4. After concentration, the residue was purified by column chromatography (0-50% ethyl acetate in hexane) which gave ethyl 8-methyl-1,4-dioxaspiro[4.5]decane-8-carboxylate (Int-18b) (2.09 g) as an oil. HPLC-MS tR=1.68 min (UV254 nm); mass calculated for formula C12H20O4 228.1, observed LCMS m/z 229.1 (M+H).
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([OH:8])[C:3]=1[C:9]1[CH:17]=[CH:16][C:12]2[O:13][CH2:14][O:15][C:11]=2[CH:10]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:25][CH2:26][O:27][C:28](=[O:30])[CH3:29].O>CN(C)C=O>[C:28]([O:27][CH2:26][CH2:25][O:8][C:4]1[C:3]([C:9]2[CH:17]=[CH:16][C:12]3[O:13][CH2:14][O:15][C:11]=3[CH:10]=2)=[C:2]([NH2:1])[N:6]([CH3:7])[N:5]=1)(=[O:30])[CH3:29]
Reactant: CC(=O)OCCBr
Reactant: Cn1nc(O)c(-c2ccc3c(c2)OCO3)c1N
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)OCCOc1nn(C)c(N)c1-c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 16 h
Yield: 35.7 %

Procedure:
5-Amino-4-(1,3-benzodioxol-5-yl)-1-methyl-1H-pyrazol-3-ol (Preparation 34) (11.39 g) was dissolved in dimethylformamide (40 ml), cesium carbonate (15.9 g) was added followed by 2-bromoethylacetate (8.16 g). The mixture was stirred at room temperature for 16 hours. The mixture was treated with water (750 ml) and extracted with ethyl acetate (2×250 ml). The organic fractions were combined washed with water (3×350 ml), brine (250 ml), dried over magnesium sulfate, filtered and evaporated. The crude product was purified on silica (300 g) eluting with ethyl acetate:hexane (3:1) to yield the title compound as a white solid (5.57 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[CH2:7][CH:6]([N:8]2[C:12]([C:13]([OH:15])=[O:14])=[CH:11][N:10]=[CH:9]2)[C:5]2[CH:16]=[CH:17][CH:18]=[CH:19][C:4]=2[O:3]1.C(N1C=CN=C1)(N1[CH:27]=[CH:26]N=C1)=O.C(=O)=O.[O-]CC.[Na+]>CN(C)C=O.C(O)C>[CH3:1][C:2]1([CH3:20])[CH2:7][CH:6]([N:8]2[C:12]([C:13]([O:15][CH2:26][CH3:27])=[O:14])=[CH:11][N:10]=[CH:9]2)[C:5]2[CH:16]=[CH:17][CH:18]=[CH:19][C:4]=2[O:3]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC1(C)CC(n2cncc2C(=O)O)c2ccccc2O1
Agent: CC[O-]
Agent: O=C=O
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Product: CCOC(=O)c1cncn1C1CC(C)(C)Oc2ccccc21
Yield: 63.5 %

Procedure:
A solution of 3.3 parts of 1-(2,3-dihydro-2,2-dimethyl-4H-1-benzopyran-4-yl)-1H-imidazole-5-carboxylic acid in 45 parts in warm N,N-dimethylformamide was cooled to room temperature and then 2 parts of 1,1'-carbonylbis[1H-imidazole] were added. The whole was stirred at room temperature till CO2 evolution had ceased (±30 minutes). The mixture was heated to ±70° C. and 2.4 parts of ethanol and 0.1 parts of sodium ethoxide were added. Stirring was continued over weekend at ±70° C. After evaporation, the residue was taken up in water and trichloromethane. The organic layer was washed with water, dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using trichloromethane as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from hexane. The product was filtered off and dried, yielding 2.36 parts (63.5%) of ethyl 1-(2,3-dihydro-2,2-dimethyl-4H-1-benzopyran-4-yl)-1H-imidazole-5-carboxylate; mp. 80.9° C. (compound 1.138).
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([O:10]CC)=[O:9].[CH3:17][C:18]1[CH:39]=[CH:38][CH:37]=[CH:36][C:19]=1[CH2:20][N:21]1[C:29]2[C:24](=[CH:25][C:26](/[C:30](/[CH3:35])=[CH:31]/[C:32](O)=[O:33])=[CH:27][CH:28]=2)[CH:23]=[CH:22]1>>[CH3:17][C:18]1[CH:39]=[CH:38][CH:37]=[CH:36][C:19]=1[CH2:20][N:21]1[C:29]2[C:24](=[CH:25][C:26](/[C:30](/[CH3:35])=[CH:31]/[C:32]([NH:1][C:2]3[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=3[O:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9])=[O:33])=[CH:27][CH:28]=2)[CH:23]=[CH:22]1
Reactant: C/C(=C\C(=O)O)c1ccc2c(ccn2Cc2ccccc2C)c1
Reactant: CCOC(=O)CCCOc1ccccc1N
Product: C/C(=C\C(=O)Nc1ccccc1OCCCC(=O)O)c1ccc2c(ccn2Cc2ccccc2C)c1

Procedure:
291 mg of compound 31 was obtained in a similar manner to those described in the Examples 1 and 2 using 521 mg of ethyl 4-(2-aminophenoxy)butyrate and 517 mg of 3-[1-(2-methylbenzyl)indol-5-yl]isocrotonic acid obtained according to the procedures described in the Reference Examples 1-4.