Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([OH:15])=O)=[CH:4][CH:3]=1.[NH:16]1[CH2:20][CH2:19][CH:18]([OH:21])[CH2:17]1>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([N:16]2[CH2:20][CH2:19][CH:18]([OH:21])[CH2:17]2)=[O:15])=[CH:6][CH:7]=1
Reactant: OC1CCNC1
Reactant: Cc1ccc(-c2oncc2C(=O)O)cc1
Product: Cc1ccc(-c2oncc2C(=O)N2CCC(O)C2)cc1

Procedure:
The title compound was prepared from 5-(4-methylphenyl)isoxazole-4-carboxylic acid (10.2 mg, 0.050 mmol) and 3-pyrrolidinol (5.2 mg, 0.060 mmol) as described in synthetic method B and thereafter purified by preparative HPLC method B to give a solid (4.9 mg). HRMS calcd for C15H16N2O3: 272.1161, found 272.1157.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:4](=[O:18])[CH:3]=1.[H-].[Na+].[F:21][C:22]([F:29])([F:28])[CH2:23][CH2:24][C:25](Cl)=[O:26].C(=O)([O-])O.[Na+]>CN(C=O)C.O>[C:12]1([N:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][N:7]=3)[C:2]([O:1][C:25](=[O:26])[CH2:24][CH2:23][C:22]([F:29])([F:28])[F:21])=[CH:3][C:4]2=[O:18])[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=c1cc(O)c2cccnc2n1-c1ccccc1
Reactant: O=C(Cl)CCC(F)(F)F
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(CCC(F)(F)F)Oc1cc(=O)n(-c2ccccc2)c2ncccc12
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
In accordance with a process described in JP-61-246183A, 4-hydroxy-1-phenyl-1,8-naphthyridin-2(1H)-one was synthesized. To a suspension of the synthesized compound (953 mg, 4.0 mmol) in DMF (32 mL) was added sodium hydride (purity of about 60%, 176 mg, 4.4 mmol, 1.1 eq.), and the mixture was stirred at a room temperature for 40 minutes. Then, 4,4,4-trifluorobutyryl chloride (4.4 mmol, 1.1 eq.) was added thereto with cooling in an ice bath, and the mixture was stirred at a room temperature for 2 hours. Thereafter, a sodium hydrogencarbonate aqueous solution and water were added to the reaction solution, and the precipitate was separated by filtration and dried to give 1-phenyl-4-(4,4,4-trifluorobutyryloxy)-1,8-naphthyridin-2(1H)-one as a form of crystal (955 mg, yield 66%).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][CH:5]=1)=[O:3].[CH2:11](O)[CH2:12][CH2:13][OH:14].CO>C(Cl)Cl.C1C(=O)N(Br)C(=O)C1>[Cl:10][C:7]1[CH:8]=[CH:9][C:4]([C:2]2([CH3:1])[O:14][CH2:13][CH2:12][CH2:11][O:3]2)=[CH:5][CH:6]=1
Reactant: OCCCO
Reactant: CC(=O)c1ccc(Cl)cc1
Agent: O=C1CCC(=O)N1Br
Solvent: ClCCl
Solvent: CO
Product: CC1(c2ccc(Cl)cc2)OCCCO1
Temperature: 25 °C
Reaction time: 70 h
Yield: 51.7 %

Procedure:
To a stirred mixture of 4-chloroacetophenone (1.3 mL, 10 mmol), triethylformate (2.0 mL, 12 mmol), 1,3-propanediol (2.2 mL, 30 mmol) and dry methanol (1.2 mL) in dry CH2Cl2 (50 mL) was added NBS (53 mg, 0.30 mmol). The mixture was protected from light and stirred at room temperature under an inert atmosphere of nitrogen for 70 h. After the mixture was washed with saturated aqueous sodium bicarbonate solution (20 mL), the aqueous phase was extracted with dichloromethane (3×30 mL). The combined organic solution was washed with water (2×20 mL), brine (1×20 mL), then dried (Na2SO4) and concentrated under reduced pressure. Flash column chromatography of the residue, eluting with 37% aqueous ammonia:ether:hexane (0.02:1:6) afforded 2-(4-chlorophenyl)-2-methyl-1,3-dioxane (20) as a colourless oil (1.1 g, 52%). 1H nmr (200 MHz, CDCl3) 1.49 (s, 3H, CH3), 1.98-2.25 (m, 2H, OCH2CH2CH2O), 3.65-4.10 (m, 4H, OCH2CH2CH2O), 7.30-7.50 (m, 4H, 4×ArH).
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[C:9]([O:11][CH2:12][O:13][CH3:14])[CH:8]=[CH:7][C:6]=1[C:15]1[CH2:20][CH2:19][CH2:18][C:17](=[O:21])[CH:16]=1.[H][H]>[Pd].C(O)C>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[C:9]([O:11][CH2:12][O:13][CH3:14])[CH:8]=[CH:7][C:6]=1[CH:15]1[CH2:20][CH2:19][CH2:18][C:17](=[O:21])[CH2:16]1
Reactant: COCOc1ccc(C2=CC(=O)CCC2)c(OCOC)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: COCOc1ccc(C2CCCC(=O)C2)c(OCOC)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 70 %

Procedure:
A suspension of 3-[2,4-bis(methoxymethoxy)phenyl]-2-cyclohexen-1-one (300 m g) and palladium catalyst (50 mg, 10% palladium on carbon) in ethanol was stirred at ambient temperature under 1 atmosphere of hydrogen. After 16 hr, the mixture was filtered through celite and the filtrate was evaporated in vacuo. The product was dissolved in dichloromethane (15 ml). Celite and pyridinium chlorochromate (430 mg) were added and the mixture was stirred at room temperature. After 3 hr, the mixture was filtered through a pad of silica and eluted with petroleum ether/ethyl acetate (10:3, v/v), then purified by flash column chromatography (SiO2, petroleum ether/ethyl acetate 4:1 v/v) to furnish the title compound as an oil (200 mg, 70%). δH(CDCl3) 1.7-1.9 (2H, overlapping m), 2.05 (1H, m), 2.15 (1H, m), 2.35-2.60 (4H, overlapping m), 3.37 (1H, m), 3.490 (3H, s), 3.492 (3H, s), 5.15 (2H, s), 5.20 (2H, s), 6.70 (1H, dd), 6.82 (1H, d), 7.09 (1H, d).
Reaction SMILES: CO[C:3](=[O:18])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][CH:13]2[O:17][CH2:16][CH2:15][O:14]2)=[CH:6][CH:5]=1.[H-].[CH2:20]([Al+]CC(C)C)C(C)C>C1COCC1>[O:17]1[CH2:16][CH2:15][CH2:20][O:14][CH:13]1[CH2:12][CH2:11][CH2:10][C:7]1[CH:6]=[CH:5][C:4]([CH2:3][OH:18])=[CH:9][CH:8]=1
Reactant: CC(C)C[Al+]CC(C)C
Reactant: COC(=O)c1ccc(CCCC2OCCO2)cc1
Agent: [H-]
Solvent: C1CCOC1
Product: OCc1ccc(CCCC2OCCCO2)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 95.8 %

Procedure:
To a solution of 2.85 g (11.4 mmol) of ester 169 in 25 mL of THF at 0° C. was added 4.4 mL (24.7 mmol) of diisobutylaluminum hydride and the resulting mixture was allowed to stir at 0° C. for 15 min. The reaction was quenched with saturated potassium sodium tartrate and extracted three times with ethyl acetate. The combined organic extracts were dried over MgSO4, filtered and concentrated to yield 2.58 g of the crude alcohol 170 as an oil. 1H NMR consistent with the product.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:11]1[C:40]([CH3:41])=[C:39]([CH:42]=O)[C:38]2=[N:44][C:35]3=[CH:36][N:37]2[C:12]=1[N:13]1[CH2:49][CH2:48][C:16]([CH3:50])([O:17][CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]([CH3:47])[O:23][C:24]2[CH:25]=[CH:26][C:27]([F:46])=[CH:28][C:29]=2[C:30]2[CH:45]=[C:34]3[CH:33]=[CH:32][CH:31]=2)[CH2:15][CH2:14]1)[C:7]([O:9][CH3:10])=[O:8])([CH3:4])([CH3:3])[CH3:2].[CH3:51][CH:52]([NH2:54])[CH3:53].C([BH3-])#N.[Na+]>O1CCCC1.CO>[C:1]([O:5][C@@H:6]([C:11]1[C:40]([CH3:41])=[C:39]([CH2:42][NH:54][CH:52]([CH3:53])[CH3:51])[C:38]2=[N:44][C:35]3=[CH:36][N:37]2[C:12]=1[N:13]1[CH2:49][CH2:48][C:16]([CH3:50])([O:17][CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]([CH3:47])[O:23][C:24]2[CH:25]=[CH:26][C:27]([F:46])=[CH:28][C:29]=2[C:30]2[CH:45]=[C:34]3[CH:33]=[CH:32][CH:31]=2)[CH2:15][CH2:14]1)[C:7]([O:9][CH3:10])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)c(C=O)c2nc3cn2c1N1CCC(C)(CC1)OCCCC[C@H](C)Oc1ccc(F)cc1-c1cccc-3c1
Reactant: CC(C)N
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)[C@@H](OC(C)(C)C)c1c(C)c(CNC(C)C)c2nc3cn2c1N1CCC(C)(CC1)OCCCC[C@H](C)Oc1ccc(F)cc1-c1cccc-3c1
Reaction time: 2 h

Procedure:
Methyl(2S)-2-(tert-butoxy)-2-[(22S)-17-fluoro-5-formyl-4,22,28-trimethyl-21,27-dioxa-1,7,34-triazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18-decaen-3-yl]acetate (40 mg, 0.058 mmol, 1.0 equiv) was mixed with propan-2-amine (6.90 mg, 0.117 mmol, 2.0 equiv) in Tetrahydrofuran (583 μl) and Methanol (146 μl). The solution was stirred for 2 hours. LCMS show about 50% conversion to imine. Then to this solution was added sodium cyanoborohydride (21.99 mg, 0.350 mmol, 6.0 equiv) and stirred for 2 hours. The mixture was used for next reaction directly. LCMS (ESI, M+1): 729.4.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.C(=O)([O-])[O-].[K+].[K+].[Cl:12][C:13]1[CH:30]=[C:29]([Cl:31])[CH:28]=[CH:27][C:14]=1[CH2:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]([CH2:25]Br)=[CH2:24]>CN(C)C=O>[Cl:12][C:13]1[CH:30]=[C:29]([Cl:31])[CH:28]=[CH:27][C:14]=1[CH2:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]([CH2:25][N:1]1[CH:5]=[N:4][CH:3]=[N:2]1)=[CH2:24]
Reactant: c1nc[nH]n1
Reactant: C=C(CBr)c1ccccc1OCc1ccc(Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=C(Cn1cncn1)c1ccccc1OCc1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.3 %

Procedure:
1,2,4-Triazole (59 mg, 0.854 mmole) and potassium carbonate (129 mg, 0.933 mmole) were suspended in dimethylformamide (1 ml) and a solution of 2-[2-(2,4-dichlorobenzyloxy)phenyl]-3-bromo-1-propene (290 mg, 0.779 mmole) in dimethylformamide (2 ml) was added dropwise to the suspension. Then, after stirring overnight at room temperature, the reaction mixture was worked up according to the same manner as in Example 25 to obtain the title compound (0.20 g, 71.2%). By comparing 1H-NMR and Rf value of TLC of the resulting compound with those of the product of the alternative process described in Example 34, it was confirmed that both chemical structures were identical with each other.
Reaction SMILES: S(Cl)(Cl)=O.C1C2C(C(O)=O)C3C(=CC=CC=3)C=2C=CC=1.[CH:21]1[C:33]2[CH:32]([C:34]([NH2:36])=O)[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:25]=2[CH:24]=[CH:23][CH:22]=1.P(Cl)(Cl)(Cl)=O>>[C:34]([CH:32]1[C:33]2[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=2[C:26]2[C:31]1=[CH:30][CH:29]=[CH:28][CH:27]=2)#[N:36]
Reactant: NC(=O)C1c2ccccc2-c2ccccc21
Agent: O=C(O)C1c2ccccc2-c2ccccc21
Solvent: O=P(Cl)(Cl)Cl
Solvent: O=S(Cl)Cl
Product: N#CC1c2ccccc2-c2ccccc21
Yield: 65 %

Procedure:
100 ml (1.37 mol) of thionyl chloride are added to 21.0 g (0.10 mol) of fluorene-9-carboxylic acid and the mixture is refluxed for about 90 minutes. The excess thionyl chloride is evaporated off on a vacuum rotary evaporator. The residue is taken up three times with about 50 ml of toluene each time and the mixture evaporated on a vacuum rotary evaporator. The oily residue is added in portions to a mixture of about 1 kg of ice and 240 ml of concentrated ammonia solution. The fluorene-9-carboxylic acid amide which has precipitated is filtered off, washed with water and dried under a high vacuum. The dried fluorene-9-carboxylic acid amide is then added to 160 ml (1.75 mol) of phosphorus oxychloride and the mixture is refluxed for about 2 hours. The reaction mixture is cooled and concentrated on a vacuum rotary evaporator. The residue is taken up in toluene and the mixture is washed with water. The organic phases are combined, dried over sodium sulfate and concentrated on a vacuum rotary evaporator. Crystallization of the residue from cyclohexane gives 12.4 g (65%) of 9-cyano-fluorene, melting point 152°-154° C. (compound (101), Table 1).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([C:11]1[NH:12][C:13]([CH2:17][OH:18])=[C:14]([Cl:16])[N:15]=1)[CH2:8][CH2:9][CH3:10].Br[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[C:33]2[N:37]([C:38]3[CH:43]=[CH:42][C:41]([N+:44]([O-:46])=[O:45])=[CH:40][CH:39]=3)[N:36]=[N:35][N:34]=2)=[CH:23][CH:22]=1.O>CN(C=O)C>[CH2:7]([C:11]1[N:12]([CH2:20][C:21]2[CH:22]=[CH:23][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:33]3[N:37]([C:38]4[CH:43]=[CH:42][C:41]([N+:44]([O-:46])=[O:45])=[CH:40][CH:39]=4)[N:36]=[N:35][N:34]=3)=[CH:25][CH:26]=2)[C:13]([CH2:17][OH:18])=[C:14]([Cl:16])[N:15]=1)[CH2:8][CH2:9][CH3:10]
Reactant: O=[N+]([O-])c1ccc(-n2nnnc2-c2ccccc2-c2ccc(CBr)cc2)cc1
Reactant: CCCCc1nc(Cl)c(CO)[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCc1nc(Cl)c(CO)n1Cc1ccc(-c2ccccc2-c2nnnn2-c2ccc([N+](=O)[O-])cc2)cc1
Temperature: 25 °C

Procedure:
Potassium carbonate (0.48 g) was added to a solution of 2-butyl-4-chloro-5-hydroxymethylimidazole (prepared as described in U.S. Pat. No. 4,355,040) (0.56 g) and 5-(4'-bromomethylbiphenyl-2-yl)-1-(4-nitrophenyl)-1H-tetrazole (1.3 g) in DMF (15 ml) and the mixture was stirred under an atmosphere of argon at 60° C. for 5 hours. The mixture was cooled to ambient temperature, water (60 ml) was added and the mixture was extracted with ethyl acetate (3×50 ml). The combined extracts were washed with satured sodium chloride solution, dried (MgSO4) and the solvent removed by evaporation. The residue was purified by flash chromatography, eluting with ethyl acetate/hexane (1:1 v/v), to give 2-butyl-4-chloro-5-hydroxymethyl-1-[(2'-(1-(4-nitrophenyl)-1H-tetrazol-5-yl)biphenyl-4-yl)methyl]imidazole (180 mg) as a pale yellow solid, m.p. 182°-186° C.; NMR (CDCl3) 0.87(t,3H), 1.32(m,2 H), 1.65(m,2H), 2.49(t,2H), 4.57(s,2H), 5.15(s,2H), 6.58(d,2H), 6.75(d,2H), 6.90(dd,2H), 7.36(dd,1H), 7.65(m,2H), 7.85(dd,1H), 8.00(dd,2H); mass spectrum (+ve FAB, DMSO/CH3OH/m-nitrobenzyl alcohol): 544 (M+H)+.
Reaction SMILES: N[CH:2]1C2(CC2)CN[CH2:3]1.[C:9]([O:15][CH2:16][CH3:17])(=[O:14])[CH2:10][C:11]([CH3:13])=[O:12].BrCCBr>>[C:11]([C:10]1([C:9]([O:15][CH2:16][CH3:17])=[O:14])[CH2:3][CH2:2]1)(=[O:12])[CH3:13]
Reactant: CCOC(=O)CC(C)=O
Reactant: NC1CNCC12CC2
Solvent: BrCCBr
Product: CCOC(=O)C1(C(C)=O)CC1

Procedure:
Taking 7-amino-5-azaspiro[2.4]heptane as an example, ethyl acetoacetate is first reacted with 1,2-dibromoethane in the presence of a base to give ethyl 1-acetyl-1-cyclopropanecarboxylate. Then, using bromine, the acetyl group of this compound is brominated to give ethyl 1-bromoacetyl-1-cyclopropanecarboxylate. This bromoacetyl compound is then cyclized with benzylamine to give 5-benzyl-4,7-dioxo-5-azaspiro[2.4]heptane. When this compound is reacted with hydroxylamine hydrochloride, the ketone in the 7-position is converted to an oxime to give 5-benzyl-7-(hydroxyimino)-4-oxo-5-azaspiro[2.4]heptane. This oxime is reduced with lithium aluminum hydride to give a spiro ring-containing aminopyrrolidine compound, viz., 7-amino-5-benzyl-5-azaspiro[2.4]heptane. When the benzyl group of this compound is eliminated by an ordinary procedure, such as catalytic hydrogenolysis, 7-amino-5-azaspiro[2.4]heptane, which is a racemic compound, is obtained. When this cleavage of the benzyl group after the amino group is protected by the reaction of 2-(tert-butoxycarbonylamino)-2-phenylacetonitrile (hereinafter referred to briefly as BOC-ON), 7-tert-butoxycarbonylamino-5-azaspiro[2.4]heptane is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:26][CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH2:21][CH2:22][C:23]([OH:25])=O)[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(Cl)(=O)C(Cl)=O.N1C(C)=CC=CC=1C.[NH2:46][CH2:47][CH2:48][N:49]1[CH2:54][CH2:53][O:52][CH2:51][CH2:50]1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:26][CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH2:21][CH2:22][C:23](=[O:25])[NH:46][CH2:47][CH2:48][N:49]3[CH2:54][CH2:53][O:52][CH2:51][CH2:50]3)[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9]
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2ccn(CCC(=O)O)n2)cc1Cl
Reactant: NCCN1CCOCC1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2ccn(CCC(=O)NCCN3CCOCC3)n2)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 26.6 %

Procedure:
To a solution containing 3-{3-[2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionylamino]-pyrazol-1-yl}-propionic acid (prepared in example 9, 50 mg, 0.11 mmol) in methylene chloride (2 mL) was then added a 2.0 M solution of oxalylchloride in methylene chloride (59 μL, 0.12 mmol) at 0° C. and allowed to stir at 25° C. for 1 h, after which time 2,6-lutidine (17 μL, 0.14 mmol) was added to the solution at 0° C. After 1 h, 4-(2-aminoethyl) morpholine (15 μL, 0.11 mmol) was added and the reaction was allowed to proceed for 16 h. The reaction solution was washed with 1.0 M aqueous hydrochloric acid solution, dried over sodium sulfate, concentrated in vacuo and purified by ISCO flash column chromatography (Teledyne Isco RediSep Flash Column 10 g; 0% methanol/methylene chloride to 10% methanol/methylene chloride) to afford 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-{1-[2-(2-morpholin-4-yl-ethylcarbamoyl)-ethyl]-1H-pyrazol-3-yl}-propionamide (17 mg, 27%) as a white solid: ESI-LRMS m/e calcd for C27H38ClN5O5S [M+] 579.2, found 580.3 [M+H+]; 1H NMR (400 MHz, CDCl3) δ ppm 0.99-1.11 (m, 2H, CH2), 1.37-1.85 (m, 8H, 4×CH2), 2.05-2.18 (m, 1H, CH), 2.25-2.37 (m, 6H, 3×NCH2), 2.57 (t, J=6.4 Hz, 2H, COCH2), 3.18 (s, 3H, SO2CH3), 3.21 (q, J=5.4 Hz, 2H, CONCH2), 3.47 (t, J=7.5 Hz, 1H, CH), 3.50-3.58 (m, 4H, 2×OCH2), 4.23 (t, J=6.4 Hz, 2H, NCH2), 5.94 (brm, 1, NH), 6.50 (d, J=2.3 Hz, 1H, Ar), 7.22 (d, J=2.3 Hz, 1H, Ar), 7.38 (dd, Jo=8.2, Jm=1.7 Hz. 1H, Ar), 7.51 (d, Jm=1.7 Hz, 1H, Ar), 7.84 (s, 1H, NH), 8.00 (d, Jo=8.2 Hz, 1H, Ar).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:12]([C:13]3[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:14]=3[F:20])[N:11]=[C:10]([C:21]3[CH:22]=[C:23]([OH:27])[CH:24]=[CH:25][CH:26]=3)[C:4]=2[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:35][CH2:36][OH:37].O>CN(C=O)C>[Cl:1][C:2]1[C:3]2[N:12]([C:13]3[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:14]=3[F:20])[N:11]=[C:10]([C:21]3[CH:22]=[C:23]([CH:24]=[CH:25][CH:26]=3)[O:27][CH2:35][CH2:36][OH:37])[C:4]=2[C:5]([O:8][CH3:9])=[N:6][CH:7]=1
Reactant: COc1ncc(Cl)c2c1c(-c1cccc(O)c1)nn2-c1c(F)cccc1F
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ncc(Cl)c2c1c(-c1cccc(OCCO)c1)nn2-c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 3-(7-chloro-1-(2,6-difluorophenyl)-4-methoxy-1H-pyrazolo[4,3-c]pyridin-3-yl)phenol (30 mg), potassium carbonate (7 mg) and 2-bromoethanol (21 μL) in DMF (3 mL) was stirred at 70° C. for 5 hr. The mixture was allowed to be cooled to room temperature, potassium carbonate (107 mg) and 2-bromoethanol (55 μL) were added thereto, and the mixture was stirred overnight at 7° C. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (15 mg).
Reaction SMILES: [C:1](=O)(O)[O-].[Na+].CI.[CH3:8][N:9]([CH3:27])[C:10]([C@@H:12]1[CH2:16][C@H:15]([S:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[CH2:14][NH:13]1)=[O:11]>CN(C)C=O>[CH3:8][N:9]([CH3:27])[C:10]([C@@H:12]1[CH2:16][C@H:15]([S:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=2)[CH2:14][N:13]1[CH3:1])=[O:11]
Reactant: COc1ccc(CS[C@@H]2CN[C@H](C(=O)N(C)C)C2)cc1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1ccc(CS[C@H]2C[C@@H](C(=O)N(C)C)N(C)C2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 26.4 %

Procedure:
84 mg of sodium bicarbonate and 41 μl of methyl iodide were added, whilst ice-cooling, to a solution of 163 mg of (2S, 4S)-2-(N,N-dimethylcarbamoyl)-4-(4-methoxybenzylthio)pyrrolidine [prepared as described in step (4) above] dissolved in 1.5 ml of dry dimethylformamide, and the mixture was stirred at room temperature for 4 hours. At the end of this time, the reaction mixture was poured into a saturated aqueous solution of sodium bicarbonate and extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under reduced pressure, and the residue was purified by chromatography using a Lobar column (Merck, LiChroprep Si60, size A). 45 mg of the title compound were obtained, as an oil, from the fractions eluted with a 3:1 by volume mixture of ethyl acetate and methanol.
Reaction SMILES: Cl.[CH3:2][N:3]1[CH2:8][CH2:7][CH2:6][CH:5]([CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)[CH2:4]1.[Cl:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][C:23](=[O:28])[C:22]2=[CH:29]O.CCN(CC)CC>>[Cl:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][C:23](=[O:28])[C:22]2=[CH:29][NH:17][C:14]1[CH:13]=[CH:12][C:11]([O:10][CH2:9][CH:5]2[CH2:6][CH2:7][CH2:8][N:3]([CH3:2])[CH2:4]2)=[CH:16][CH:15]=1
Reactant: CN1CCCC(COc2ccc(N)cc2)C1
Reactant: O=C1Nc2ccc(Cl)cc2C1=CO
Agent: Cl
Solvent: CCN(CC)CC
Product: CN1CCCC(COc2ccc(NC=C3C(=O)Nc4ccc(Cl)cc43)cc2)C1
Yield: 49.3 %

Procedure:
In a manner similar to that described in Example 231, 4-(1-methyl-piperidin-3-ylmethoxy)-phenylamine hydrochloride (158 mg, 1.2 equiv.) and 5-chloro-3-hydroxymethylene-1,3-dihydro-indol-2-one (100 mg, 0.51 mmol, 1 equiv.) with the addition of anhydrous Et3N (2.11 equiv.) are reacted to give the named compound as a yellow solid (100 mg, 49%).
Reaction SMILES: COC(=O)N[C@@H](C(C)C)C(N1[C@H](C2NC(C3C=CC4C(=CC=C([C:30]5[CH:35]=[CH:34][C:33]([C:36]6[NH:40][C:39]([C@@H:41]7[CH2:49][C:44]8([O:48][CH2:47][CH2:46][O:45]8)[CH2:43][N:42]7[C:50](=[O:60])[C@@H:51]([NH:55][C:56]([O:58][CH3:59])=[O:57])[CH:52]([CH3:54])[CH3:53])=[N:38][CH:37]=6)=[CH:32][CH:31]=5)C=4)C=3)=CN=2)CC2(CC2)C1)=O.BrC1C=C2C(=CC=1)C=C(C1NC([C@@H]3CC4(CC4)CN3C(=O)[C@@H](NC(=O)OC)C(C)C)=NC=1)C=C2.BrC1C=CC(C2NC([C@@H]3CC4(OCCO4)CN3C(=O)[C@@H](NC(=O)OC)C(C)C)=NC=2)=CC=1.Br[C:132]1[CH:137]=[CH:136][C:135]([C:138]2[NH:142][C:141]([C@@H:143]3[CH2:147][CH2:146][CH2:145][N:144]3[C:148]([O:150][C:151]([CH3:154])([CH3:153])[CH3:152])=[O:149])=[N:140][CH:139]=2)=[CH:134][CH:133]=1>>[CH3:59][O:58][C:56]([NH:55][C@@H:51]([CH:52]([CH3:53])[CH3:54])[C:50]([N:42]1[C@H:41]([C:39]2[NH:40][C:36]([C:33]3[CH:32]=[CH:31][C:30]([C:132]4[CH:133]=[CH:134][C:135]([C:138]5[NH:142][C:141]([C@@H:143]6[CH2:147][CH2:146][CH2:145][N:144]6[C:148]([O:150][C:151]([CH3:154])([CH3:153])[CH3:152])=[O:149])=[N:140][CH:139]=5)=[CH:136][CH:137]=4)=[CH:35][CH:34]=3)=[CH:37][N:38]=2)[CH2:49][C:44]2([O:48][CH2:47][CH2:46][O:45]2)[CH2:43]1)=[O:60])=[O:57]
Reactant: COC(=O)N[C@H](C(=O)N1CC2(CC2)C[C@H]1c1ncc(-c2ccc3cc(-c4ccc(-c5cnc([C@@H]6CC7(CN6C(=O)[C@@H](NC(=O)OC)C(C)C)OCCO7)[nH]5)cc4)ccc3c2)[nH]1)C(C)C
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1ncc(-c2ccc(Br)cc2)[nH]1
Agent: COC(=O)N[C@H](C(=O)N1CC2(CC2)C[C@H]1c1ncc(-c2ccc3cc(Br)ccc3c2)[nH]1)C(C)C
Agent: COC(=O)N[C@H](C(=O)N1CC2(C[C@H]1c1ncc(-c3ccc(Br)cc3)[nH]1)OCCO2)C(C)C
Product: COC(=O)N[C@H](C(=O)N1CC2(C[C@H]1c1ncc(-c3ccc(-c4ccc(-c5cnc([C@@H]6CCCN6C(=O)OC(C)(C)C)[nH]5)cc4)cc3)[nH]1)OCCO2)C(C)C

Procedure:
Title compound was prepared according to the method employed to prepare (S)-1-((S)-6-(5-(6-(4-(2-((S)-7-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-1,4-dioxa-7-azaspiro[4.4]nonan-8-yl)-1H-imidazol-5-yl)phenyl)naphthalen-2-yl)-1H-imidazol-2-yl)-5-azaspiro[2.4]heptan-5-yl)-3-methyl-1-oxobutan-2-yl-carbamic acid methyl ester, except instead of methyl (S)-1-((S)-6-(5-(6-bromonaphthalen-2-yl)-1H-imidazol-2-yl)-5-azaspiro[2.4]heptan-5-yl)-3-methyl-1-oxobutan-2-ylcarbamate and methyl (S)-1-((S)-8-(5-(4-bromophenyl)-1H-imidazol-2-yl)-1,4-dioxa-7-azaspiro[4.4]nonan-7-yl)-3-methyl-1-oxobutan-2-ylcarbamate, methyl (S)-1-((S)-8-(5-(4-bromophenyl)-1H-imidazol-2-yl)-1,4-dioxa-7-azaspiro[4.4]nonan-7-yl)-3-methyl-1-oxobutan-2-ylcarbamate (600 mg, 1.182 mmol) and (S)-tert-butyl 2-(5-(4-bromophenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (510 mg, 1.3 mmol). The amount for all the other reagents were adjusted accordingly. 489 mg (56%).