Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@H:5]1[CH2:10][N:9]([C:11]2[N:12]=[C:13]([C:16]3[C:24]4[C:19](=[N:20][CH:21]=[CH:22][CH:23]=4)[N:18](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:17]=3)[S:14][CH:15]=2)[CH2:8][CH2:7][N:6]1C(OC(C)(C)C)=O)[CH:2]([CH3:4])[CH3:3].C([SiH](CC)CC)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([C@@H:5]1[NH:6][CH2:7][CH2:8][N:9]([C:11]2[N:12]=[C:13]([C:16]3[C:24]4[C:19](=[N:20][CH:21]=[CH:22][CH:23]=4)[NH:18][N:17]=3)[S:14][CH:15]=2)[CH2:10]1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)C[C@H]1CN(c2csc(-c3nn(C(c4ccccc4)(c4ccccc4)c4ccccc4)c4ncccc34)n2)CCN1C(=O)OC(C)(C)C
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)C[C@H]1CN(c2csc(-c3n[nH]c4ncccc34)n2)CCN1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl (2S)-2-isobutyl-4-[2-(1-tritylpyrazolo[5,4-b]pyridin-3-yl)thiazol-4-yl]piperazine-1-carboxylate (149 mg, 0.2176 mmol) and triethylsilane (101.2 mg, 139.0 μL, 0.8704 mmol) in DCM (2 mL) at 0° C. was added TFA (0.3 mL,). Then ice-bath removed and mixture stirred at room temperature for 1 h. Added more TFA (0.3 mL) and stirred for a further 1 h. Basified with minimal sat. NaHCO3 and extracted with EtOAc. Organics combined, washed with small amount of water, brine, dried (MgSO4), filtered and concentrated in vacuo. Crude product purified by flash chromatography (12 g SiO2, 0 to 6% MeOH (containing 10% ammonium hydroxide)/DCM) to leave product as a pale green solid after freeze-drying (MeCN/H2O) (18.18 mg, 24%); 1H NMR DMSO-d6 δ 0.87-0.86 (br m, 1H), 0.92 (dd, 6H), 1.31-1.20 (m, 2H), 1.85-1.76 (m, 1H), 2.36 (t, 1H), 2.71 (td, 1H), 2.87-2.78 (m, 2H), 3.00 (d, 1H), 3.80 (dd, 2H), 6.30 (s, 1H), 7.37 (dd, 1H), 8.64 (m, 2H); ES+ 343.08.
Reaction SMILES: Cl.[CH3:2][S:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][NH2:11])=[CH:6][CH:5]=1.[CH3:12][C:13]([CH3:20])([CH3:19])[C:14](=O)[CH2:15][C:16]#[N:17]>C(O)C.C(OCC)(=O)C>[C:13]([C:14]1[CH:15]=[C:16]([NH2:17])[N:10]([C:7]2[CH:8]=[CH:9][C:4]([S:3][CH3:2])=[CH:5][CH:6]=2)[N:11]=1)([CH3:20])([CH3:19])[CH3:12]
Reactant: CC(C)(C)C(=O)CC#N
Reactant: CSc1ccc(NN)cc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: CSc1ccc(-n2nc(C(C)(C)C)cc2N)cc1
Yield: 95 %

Procedure:
Concentrated hydrochloric acid (1 mL) was added dropwise to a mixture of 4-methylthiophenyl hydrazine (2 g, 10.5 mmol) and 4,4-dimethyl-3-oxopentane nitrile (1.44 g, 11.5 mmol) in ethanol (30 mL) and the mixture was heated under reflux for 18 hours. The cooled mixture was then diluted with ethyl acetate, washed with saturated sodium hydrogen carbonate solution, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel, eluting with dichloromethane:methanol, 100:0 to 97:3 to afford the title compound as a yellow oil that crystallised on standing (2.59 g, 95% yield).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([CH3:9])[CH:3]=1.[Li]C(CC)C.C1CCCCC1.[F:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][C:29]=1[C@@H:30]1[N:34]2[CH:35]=[N:36][CH:37]=[C:33]2[C:32](=[O:38])[CH2:31]1)[C:25]#[N:26]>C1COCC1>[CH3:9][C:4]1[CH:3]=[C:2]([C@:32]2([OH:38])[C:33]3[N:34]([CH:35]=[N:36][CH:37]=3)[C@@H:30]([C:29]3[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][C:22]=3[F:21])[CH2:31]2)[CH:7]=[CH:6][C:5]=1[CH3:8]
Reactant: N#Cc1ccc([C@H]2CC(=O)c3cncn32)c(F)c1
Reactant: Cc1ccc(Br)cc1C
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Solvent: C1CCCCC1
Product: Cc1ccc([C@@]2(O)C[C@H](c3ccc(C#N)cc3F)n3cncc32)cc1C
Temperature: -40 °C
Reaction time: 1 h
Yield: 10.7 %

Procedure:
To a solution of 4-bromo-1,2-dimethylbenzene (77 mg, 0.42 mmol) in THF (1 mL) at −78° C. was added a solution of 1.4 M s-BuLi in cyclohexane (0.33 ml, 0.46 mmol). The crude was warmed to −40° C. and stirred between −40° C. and −30° C. for 1 hr. The crude was cooled to −60° C. A solution of 3-fluoro-4-((R)-7-oxo-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl)-benzonitrile (50 mg, 0.21 mmol) in THF (1 mL) was added. The crude was stirred at −60° C. for 1 hr. The crude was warmed to room temperature in 4 hrs. The crude was quenched with NH4Cl and diluted with EtOAc. The organic layer was washed with brine, dried over MgSO4, filtered, and concentrated. The crude was purified via preparation plate using 7% (2M NH3 in MeOH)/CH2Cl2 to give 7.8 mg of the entitled product as the major diastereomer. MS 348.1 (M+H); LCMS condition A, retention time 1.31 min. 1H NMR (400 MHz, CDCl3) δ ppm 2.20 (s, 3H), 2.20 (s, 3H), 2.91 (dd, 1H), 3.29 (dd, 1H), 5.71 (d, 1H), 6.87 (s, 1H), 7.07 (d, 1H), 7.10-7.20 (m, 2H), 7.21 (s, 1H), 7.34 (d, 1H), 7.36 (s, 1H), 7.39-7.43 (m, 1H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[OH:11][C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][C:13]=1[C:20]([F:23])([F:22])[F:21].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([O:11][C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][C:13]=2[C:20]([F:21])([F:22])[F:23])=[N:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: N#Cc1ccc(O)c(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc(Oc2ccc([N+](=O)[O-])cn2)c(C(F)(F)F)c1
Temperature: 50 °C
Reaction time: 8 h
Yield: 62.5 %

Procedure:
A mixture of 2-chloro-5-nitropyridine (70 mg, 0.44 mmol), 4-hydroxy-3-(trifluoromethyl)benzonitrile (91 mg, 0.49 mmol), K2CO3 (92 mg, 0.66 mmol) in DMF (2 mL) was stirred at 50° C. overnight. Water (4 mL) was added and a precipitate was formed. The solid was filtered-off and it was triturated with MeOH to give the title compound (85 mg) as a brownish solid.
Reaction SMILES: [CH2:1]([N:3]1[C:7]([CH3:8])=[C:6]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)[C:5]([CH2:15][CH3:16])=[N:4]1)[CH3:2].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[BH4-].[Na+]>CO>[CH2:17]([N:12]1[CH2:13][CH:14]=[C:9]([C:6]2[C:5]([CH2:15][CH3:16])=[N:4][N:3]([CH2:1][CH3:2])[C:7]=2[CH3:8])[CH2:10][CH2:11]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCc1nn(CC)c(C)c1-c1ccncc1
Reactant: BrCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCc1nn(CC)c(C)c1C1=CCN(Cc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 7.55 g (35.0 mmol) of 1,3-diethyl-4-(4-pyridyl)-5-methylpyrazole (from Step E) and 4.20 mL (35.0 mmol) of benzyl bromide in 50 mL of MeOH was heated at reflux for 30 min. The mixture was cooled to 0° C. and treated with 2.65 g (70.0 mmol) of sodium borohydride in portions so as to maintain the internal at ˜0° C. The resulting mixture was stirred cold for 30 min, then concentrated. The residue was partitioned between 300 mL of CH2Cl2 and 150 mL of 1.0 N NaOH and the layers were separated. The organic layer was dried over MgSO4. The organic layer was extracted with 300 mL of ether; the extract was dried over MgSO4. The organic layers were combined and concentrated. Chromatography on a Biotage 75L using 9:1 v/v heptane/acetone as the eluant afforded the title compound. 1H-NMR (400 MHz) δ 1.19 (t, J=7.6, 3H), 1.37 (t, J=7.6, 3H), 2.17 (s, 3H), 2.31-2.35 (m, 2H), 2.58 (q, J=7.6, 2H), 2.66 (t, J=5.6, 2H), 3.13 (app q, J=2.8, 2H), 3.65 (s, 2H), 4.01 (q, J=7.6, 2H), 5.46-5.48 (m, 1H), 7.26-7.39 (5H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[Cl:8]([O-:12])(=[O:11])(=[O:10])=[O:9].CS[C:15]1[S:19][CH:18]=[CH:17][S+:16]=1>>[Cl:8]([O-:12])(=[O:11])(=[O:10])=[O:9].[S:16]1[CH:17]=[CH:18][S:19][C:15]1=[N+:5]1[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]1
Reactant: CSc1scc[s+]1
Reactant: CN1CCNCC1
Agent: [O-][Cl+3]([O-])([O-])[O-]
Product: CN1CC[N+](=c2sccs2)CC1

Procedure:
1.2 ml of N-methylpiperazine and 1.0 g of 2-methylthio-1,3-dithiolium perchlorate were treated in the same manner as in Example 26, and the product was recrystallized from acetone-ethyl ether, whereby 0.9 g (yield: 74.8%) of 1-(1,3-dithiol-2-ylidene)-4-methylpiperazinium perchlorate (Compound No. 31) was obtained as crystals having a melting point of 192° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)=[CH:4][CH:3]=1.Cl[CH2:17][C:18]1[CH:19]=[CH:20][C:21]2[O:25][C:24]([C:26]3[S:27][CH:28]=[CH:29][CH:30]=3)=[N:23][C:22]=2[CH:31]=1>>[N:11]1([CH2:10][CH2:9][CH2:8][C:5]2[CH:6]=[CH:7][C:2]([O:1][CH2:17][C:18]3[CH:19]=[CH:20][C:21]4[O:25][C:24]([C:26]5[S:27][CH:28]=[CH:29][CH:30]=5)=[N:23][C:22]=4[CH:31]=3)=[CH:3][CH:4]=2)[CH:15]=[CH:14][N:13]=[CH:12]1
Reactant: Oc1ccc(CCCn2ccnc2)cc1
Reactant: ClCc1ccc2oc(-c3cccs3)nc2c1
Product: c1csc(-c2nc3cc(COc4ccc(CCCn5ccnc5)cc4)ccc3o2)c1
Yield: 53 %

Procedure:
In substantially the same manner as in Working Example 109, 1-[3-(4-hydroxyphenyl)propyl]imidazole was allowed to react with 5-chloromethyl-2-(2-thienyl)benzoxazole to give 5-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]-2-(2-thienyl)benzoxazole. The yield was 53%. Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 130-131° C.
Reaction SMILES: [C:1]([S:4][CH:5]([CH2:9][CH2:10][CH2:11][NH:12]C(OCC1C=CC=CC=1)=O)[C:6]([OH:8])=[O:7])(=[O:3])[CH3:2].CCOCC>Br.C(O)(=O)C>[C:1]([S:4][CH:5]([CH2:9][CH2:10][CH2:11][NH2:12])[C:6]([OH:8])=[O:7])(=[O:3])[CH3:2]
Reactant: CC(=O)SC(CCCNC(=O)OCc1ccccc1)C(=O)O
Agent: Br
Solvent: CC(=O)O
Solvent: CCOCC
Product: CC(=O)SC(CCCN)C(=O)O

Procedure:
A solution of 2-acetylthio-5-benzyloxycarbonylaminopentanoic acid (1.6 g.) in 2N hydrobromic acid in acetic acid (10 ml.) is kept at room temperature for thirty minutes. Ether is added to maximum precipitation and the supernatant is decanted. The residue is dissolved in water and applied to a column of Dowex 50 in the hydrogen cycle. The column is washed with water, and 2-acetylthio-5-aminopentanoic acid is eluted with M pyridine-acetic acid buffer pH 6.5.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:14]=3[C:21](=[O:23])[CH3:22])=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:24][CH3:25].[N:26]1([C:32](Cl)=[O:33])[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[N:26]1([C:32]([O:1][C:2]2[CH:11]=[C:10]3[C:5]([C:6]([O:12][C:13]4[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:14]=4[C:21](=[O:23])[CH3:22])=[CH:7][CH:8]=[N:9]3)=[CH:4][C:3]=2[O:24][CH3:25])=[O:33])[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1
Reactant: COc1ccc(Oc2ccnc3cc(O)c(OC)cc23)c(C(C)=O)c1
Reactant: O=C(Cl)N1CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(Oc2ccnc3cc(OC(=O)N4CCOCC4)c(OC)cc23)c(C(C)=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 14.8 %

Procedure:
1-{2-[(7-Hydroxy-6-methoxy-4-quinolyl)oxy]-5-methoxyphenyl}-1-ethanone (intermediate 4) (86 mg), morpholine-4-carbonyl chloride (114 mg), and potassium carbonate (175 mg) were suspended in N,N-dimethylformamide (2 ml), and the suspension was stirred at room temperature overnight. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using methanol-chloroform to give the title compound (17 mg, yield 15%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:17]=[C:16]([N:18]3[C:22]([CH2:23][O:24]C4CCCCO4)=[CH:21][C:20]([CH3:31])=[N:19]3)[N:15]=[C:14]3[C:10]=2[N:11]=[CH:12][N:13]3[CH3:32])=[CH:4][CH:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:17]=[C:16]([N:18]3[C:22]([CH2:23][OH:24])=[CH:21][C:20]([CH3:31])=[N:19]3)[N:15]=[C:14]3[C:10]=2[N:11]=[CH:12][N:13]3[CH3:32])=[CH:4][CH:3]=1
Reactant: Cc1cc(COC2CCCCO2)n(-c2nc(Nc3ccc(Cl)cc3)c3ncn(C)c3n2)n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: Cc1cc(CO)n(-c2nc(Nc3ccc(Cl)cc3)c3ncn(C)c3n2)n1
Yield: 30.6 %

Procedure:
(4-Chloro-phenyl)-{9-methyl-2-[3-methyl-5-(tetrahydro-pyran-2-yloxymethyl)pyrazol-1-yl]-9H-purin-6-yl}-amine (240 mg, 0.53 mmol) was dissolved in methanol (30 mL). p-Toluenesulfonic acid monohydrate (90 mg, 0.48 mmol) was added and the reaction mixture was heated to reflux for 24 hours. Upon cooling a white crystalline compound was formed. The crystals were stirred with potassium carbonate (2 M), collected by filtration, washed with water and dried to give {2-[6-(4-chloro-phenylamino)-9-methyl-9H-purin-2-yl]-5-methyl-2H-pyrazol-3-yl}-methanol (60 mg, 31%)
Reaction SMILES: [OH-].[Na+].[CH2:3]([OH:6])[CH2:4][OH:5].[CH2:7](Br)[CH:8]=[CH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>O>[C:10]1(/[CH:9]=[CH:8]/[CH2:7][O:5][CH2:4][CH2:3][OH:6])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: OCCO
Reactant: BrCC=Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: OCCOC/C=C/c1ccccc1
Yield: 40.5 %

Procedure:
8 Milliliters of 85% sodium hydroxide aqueous solution mixed with 46 g of ethylene glycol was heated at 40°-50° C., and 15 g of cinnamyl bromide was added dropwise thereto. After the addition was finished, the reaction mixture was heated at 100°-110° C. for 2 hours. The reaction mixture was allowed to cool, and poured into 50 ml of water, then extracted with ether. The ether extract was washed with water and a saturated aqueous solution of sodium chloride in this order, and dried with anhydrous sodium sulfate. The solvent was removed by evaporation, the residue thus obtained was purified by means of a silica gel column chromatography (eluent: chloroform) to yield 5.5 g of 2-[3-phenyl- 2(E)-propenyloxy]ethanol.
Reaction SMILES: C1(C[NH:8][C:9]2[CH:10]=[C:11]([CH2:15][CH2:16][CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH:12]=[CH:13][CH:14]=2)CCCCC1.[CH3:26][CH2:27][CH2:28][CH:29]([S:33](Cl)(=[O:35])=[O:34])[CH2:30][CH2:31][CH3:32]>>[CH2:28]([CH:29]([S:33]([NH:8][C:9]1[CH:10]=[C:11]([CH2:15][CH2:16][CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:22])([CH3:23])[CH3:24])[CH:12]=[CH:13][CH:14]=1)(=[O:35])=[O:34])[CH2:30][CH2:31][CH3:32])[CH2:27][CH3:26]
Reactant: CCCC(CCC)S(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)NCCCc1cccc(NCC2CCCCC2)c1
Product: CCCC(CCC)S(=O)(=O)Nc1cccc(CCCNC(=O)OC(C)(C)C)c1

Procedure:
Sulfonation of aniline 17 by heptane-4-sulfonyl chloride following the method used in Example 6 gives tert-butyl 3-(3-(1-propylbutylsulfonamido)phenyl)propylcarbamate.
Reaction SMILES: [Na].[CH:2]1([OH:7])[CH2:6][CH2:5][CH2:4][CH2:3]1.[Br:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]Br>>[Br:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:7][CH:2]1[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: OC1CCCC1
Reactant: BrCCCCCBr
Agent: [Na]
Product: BrCCCCCOC1CCCC1

Procedure:
1.15 g(0.05 moles) of sodium in small pieces are added under a nitrogen atmosphere to 43 g (0.50 moles) of absolute cyclopentanol, and the mixture is stirred at 60° until all the sodium is dissolved after a period of 16 hours. After the solution has been cooled to 20°, 11.5 g (0.05 moles) of 1,5-dibromopentane are added and the mixture is stirred under reflux for 18 hours. The precipitated sodium bromide is then removed by filtration and the filtrate is freed of excess cyclopentanol by distillation. The fraction boiling in the temperature range 115°-118°/1.0 mm is collected, and consists of the desired product.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]([NH2:8])=[O:7])=[CH:2]1.[Cl:9][CH2:10][C:11]([CH2:13]Cl)=O>>[Cl:9][CH2:10][C:11]1[N:8]=[C:6]([C:3]2[CH:4]=[CH:5][S:1][CH:2]=2)[O:7][CH:13]=1
Reactant: NC(=O)c1ccsc1
Reactant: O=C(CCl)CCl
Product: ClCc1coc(-c2ccsc2)n1
Yield: 50 %

Procedure:
In substantially the same manner as in Reference Example 47, 3-thiophenecarboxamide was allowed to react with 1,3-dichloroacetone to give 4-chloromethyl-2-(3-thienyl)oxazole. The yield was 50%. Recrystallization from ethyl acetate-hexane gave colorless needles, mp 91-92° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C@@H:4]1[CH2:8][CH:7]([OH:9])[CH2:6][N:5]1[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].C(N(CC)CC)C.[CH3:25][S:26](Cl)(=[O:28])=[O:27].Cl>ClCCl>[CH3:1][O:2][C:3](=[O:17])[C@@H:4]1[CH2:8][CH:7]([O:9][S:26]([CH3:25])(=[O:28])=[O:27])[CH2:6][N:5]1[C:10]([O:12][C:13]([CH3:14])([CH3:16])[CH3:15])=[O:11]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)[C@@H]1CC(O)CN1C(=O)OC(C)(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H]1CC(OS(C)(=O)=O)CN1C(=O)OC(C)(C)C
Reaction time: 2 h

Procedure:
A solution of 4-hydroxy-N-tert-butoxycarbonyl-proline methyl ester (5.89 g, 24 mmol) and triethylamine (4 mL, 28.8 mmol) in dichloromethane (80 mL) was cooled to 0° C. and treated with methylsulfonyl chloride (2.1 mL). After stirring an additional 2 h, the reaction mixture was acidified with 2% HCl (20 mL) and extracted with dichloromethane (3×20 mL). The combined organic layers were washed successively with sat. aq NaHCO3, and sat. aq NaCl, dried over MgSO4 and concentrated. Purification by flash column chromatography (5% ethyl acetate in heptane) gave 4-methylsulfonyloxy-N-tert-butoxycarbonyl-proline methyl ester. 1H NMR (CDCl3), 5.25 (m, 1H), 4.41 (m, 1H), 3.78 (m, 5H), 3.06 (s, 3H), 2.61 (m, 1H), 2.22 (m, 1H), 1.46 (s, 9H).
Reaction SMILES: Br[C:2]1[S:6][C:5]([NH:7][C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:12]=2[C:18]([CH:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)=[O:19])=[O:9])=[N:4][CH:3]=1.[SH:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][C:33]([OH:35])=[O:34])=[CH:28][CH:27]=1>>[CH:20]1([C:18]([C:12]2[CH:13]=[C:14]([CH3:17])[CH:15]=[CH:16][C:11]=2[NH:10][C:8](=[O:9])[NH:7][C:5]2[S:6][C:2]([S:25][C:26]3[CH:27]=[CH:28][C:29]([CH2:32][C:33]([OH:35])=[O:34])=[CH:30][CH:31]=3)=[CH:3][N:4]=2)=[O:19])[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: O=C(O)Cc1ccc(S)cc1
Reactant: Cc1ccc(NC(=O)Nc2ncc(Br)s2)c(C(=O)C2CCCC2)c1
Product: Cc1ccc(NC(=O)Nc2ncc(Sc3ccc(CC(=O)O)cc3)s2)c(C(=O)C2CCCC2)c1
Yield: 28.2 %

Procedure:
(4-{2-[3-(2-Cyclopentanecarbonyl-4-methyl-phenyl)-ureido]-thiazol-5-ylsulfanyl}-phenyl)-acetic acid (140 mg, 30%) was prepared from 1-(5-bromo-thiazol-2-yl)-3-(2-cyclopentanecarbonyl-4-methyl-phenyl)-urea (408 mg, 1 mmol) and (4-mercapto-phenyl)-acetic acid (336 mg, 2 mmol) following the general procedure Y.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([C:14]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[C:27]([CH3:28])=[CH:26][C:25]([CH3:29])=[CH:24][N:23]=3)[CH2:18][CH2:17]2)=[O:15])=[C:6]([N:8]2[CH2:12][CH2:11][O:10][C:9]2=[O:13])[CH:7]=1.[CH3:30][CH:31]1[NH:35][C:34](=[O:36])[CH2:33][CH2:32]1>>[CH3:28][C:27]1[C:22]([N:19]2[CH2:20][CH2:21][N:16]([C:14]([C:5]3[CH:4]=[CH:3][C:2]([N:35]4[C:34](=[O:36])[CH2:33][CH2:32][CH:31]4[CH3:30])=[CH:7][C:6]=3[N:8]3[CH2:12][CH2:11][O:10][C:9]3=[O:13])=[O:15])[CH2:17][CH2:18]2)=[N:23][CH:24]=[C:25]([CH3:29])[CH:26]=1
Reactant: CC1CCC(=O)N1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Cl)cc3N3CCOC3=O)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)CCC4C)cc3N3CCOC3=O)CC2)c(C)c1
Yield: 21 %

Procedure:
Using 3-{5-chloro-2-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]phenyl}oxazolidin-2-one (207 mg) described in Preparation Example 168 and 5-methylpyrrolidin-2-one (50 mg) and by the reaction and treatment in the same manner as in Example 352, the title compound (50 mg) was obtained.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][CH:9]2[C:28]([OH:30])=O)[CH:5]=[CH:6][CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:65][C:66]1[CH:74]=[CH:73][C:69]([C:70]([NH2:72])=[O:71])=[CH:68][CH:67]=1>C(Cl)Cl>[C:70]([C:69]1[CH:73]=[CH:74][C:66]([NH:65][C:28]([CH:9]2[CH:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:31])[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:26])([CH3:25])[CH3:27])[NH:10]2)=[O:30])=[CH:67][CH:68]=1)(=[O:71])[NH2:72]
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Reactant: NC(=O)c1ccc(N)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)CC1NC(C(=O)Nc2ccc(C(N)=O)cc2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (100 mg, 0.17 mmol) in methylene chloride (10 mL), HATU (Aldrich, 98 mg, 0.26 mmol) was added followed by the addition of DIPEA (90 uL, 0.52 mmol) and 4-amino benzamide (Aldrich, 35 mg, 0.26 mmol). The mixture was stirred at rt overnight. The reaction was quenched with addition of water. The mixture was extracted with methylene chloride (2×10 mL) and the extracts were dried with magnesium sulfate. The solvent was removed and the residue was purified on an ISCO machine (40 g column, eluent, 20% EtOAc/hexanes) to give a white solid. 30 mg.
Reaction SMILES: [C:1]1([N:7]2[C:16]3[N:15]=[CH:14][CH:13]=[CH:12][C:11]=3[C:10]3O[CH2:18][CH2:19][C:9]=3[C:8]2=[O:20])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.OCCN.[CH2:25]([NH2:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[C:1]1([N:7]2[C:16]3[N:15]=[CH:14][CH:13]=[CH:12][C:11]=3[C:10]3[N:32]([CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH2:18][CH2:19][C:9]=3[C:8]2=[O:20])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=c1c2c(c3cccnc3n1-c1ccccc1)OCC2
Reactant: NCc1ccccc1
Solvent: NCCO
Product: O=c1c2c(c3cccnc3n1-c1ccccc1)N(Cc1ccccc1)CC2

Procedure:
This procedure will also produce 1,2,3,5-tetrahydro-1-(n-butyl)-5-phenyl-4H-Pyrrolo[3,2-c][1,8]naphthyridin-4-one when 1-phenyl-3-(2-hydroxyethyl)-4-hydroxy-[1,8]naphthyridin-2-one is substituted for 3,5-dihydro-5-phenyl-furo[3,2-c][1,8]naphthyridin-4(2H)-one and n-butylamine is substituted for benzylamine. Furthermore, 1,2,3,5-tetrahydro-5-(3-chlorophenyl)-1-(2-hydroxyethyl)-2-methyl-4H-pyrrolo[3,2-c][1,8]naphthyridin-4-one may be produced by this procedure when 1-(3-chlorophenyl)-4-hydroxy-3-(2-hydroxypropyl)-[1,8]naphthyridin-2-one is substituted for 3,5-dihydro-5-phenyl-furo[3,2-c][1,8]naphthyridin-4(2H)-one and 2-hydroxyethylamine is substituted for benzylamine.
Reaction SMILES: C1CO[C:8]23OCCO[C:3]2([C@:4]2([CH2:27][CH2:26][C@H:25]4[C@@H:15]([CH2:16][C@H:17]([C:28]#[CH:29])[CH:18]5[C@:23]4([CH3:24])[CH2:22][CH2:21][CH2:20][CH2:19]5)[C@@H:6]2[CH2:7]3)[CH3:5])[O:2]1.C([C@@H]1C2[C@](C)(CCC(=[O:50])C2)[C@@H]2[C@H]([C@H]3[C@@](CC2)(C)C(=O)CC3)C1)#N>>[C:28]([C@@H:17]1[CH:18]2[C@:23]([CH3:24])([CH2:22][CH2:21][C:20](=[O:50])[CH2:19]2)[C@@H:25]2[C@H:15]([C@H:6]3[C@@:4]([CH2:27][CH2:26]2)([CH3:5])[C:3](=[O:2])[CH2:8][CH2:7]3)[CH2:16]1)#[CH:29]
Reactant: C#C[C@H]1C[C@@H]2[C@H](CC[C@@]3(C)[C@H]2CC24OCCOC23OCCO4)[C@@]2(C)CCCCC12
Reactant: C[C@]12CCC(=O)CC1[C@@H](C#N)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Product: C#C[C@H]1C[C@@H]2[C@H](CC[C@]3(C)C(=O)CC[C@@H]23)[C@@]2(C)CCC(=O)CC12
Yield: 46 %

Procedure:
The title compound II-bb was prepared in 46% yield from 3,3:17,17-bis(ethylendioxy)-6α-ethynylandrostane by the procedure described above for the preparation of 6α-cyanoandrostane-3,17-dione (II-ac, Prepn. 3). The combined organic extracts were washed with H2O, dried over Na2SO4 and evaporated to dryness. The residue was purified by flash chromatography (SiO2, cyclohexane/CH2Cl2/acetone 80/10/10). 1H-NMR (300 MHz, acetone-d6, ppm from TMS): δ 2.69-0.78 (m, 22H), 1.12 (s, 3H), 0.87 (s, 3H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[OH-:12].[Na+].Cl>>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]([N+:9]([O-:11])=[O:10])=[C:2]([OH:12])[CH:7]=1
Reactant: [OH-]
Reactant: O=[N+]([O-])c1ccc(Cl)cc1Cl
Agent: Cl
Agent: [Na+]
Product: O=[N+]([O-])c1ccc(Cl)cc1O
Temperature: 100 °C
Reaction time: 21 h

Procedure:
57.6 g (0.3 mol) of 2,4-dichloronitrobenzene were admixed with 10 g (0.014 mol) of dimethyldi(ethoxypolyoxypropyl)ammonium chloride and 150 ml of 20% by weight strength NaOH at 60° C. The two-phase reaction mixture was stirred for 21 hours at 100° C. and subsequently brought to pH 1 using HCl. Amount of 5-chloro-2-nitrophenol formed: after 21 hours: 40 GC area-%.