Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=1)[CH:13]=[C:12]2[CH:26]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:28]1[CH2:32][C:31](=[O:33])[NH:30][C:29]1=[O:34].N1CCCCC1>CCO>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=1)[CH:13]=[C:12]2[CH:26]=[C:32]1[S:28][C:29](=[O:34])[NH:30][C:31]1=[O:33])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1cn(-c2ccc(Cl)c(Cl)c2)c2ccc(OCc3ccccc3)cc12
Reactant: O=C1CSC(=O)N1
Solvent: C1CCNCC1
Solvent: CCO
Product: O=C1NC(=O)C(=Cc2cn(-c3ccc(Cl)c(Cl)c3)c3ccc(OCc4ccccc4)cc23)S1

Procedure:
A solution of 5-benzyloxy-N-(3,4-dichlorophenyl)-indole-3-carbaldehyde (1 eq.), 2,4-thiazolidinedione (1.5 eq.) and piperidine (1.5 eq.) in EtOH was heated to 70° C. for 18 hrs. Volatiles were removed under reduced pressure and the residue was taken up in EtOAc. Addition of ether precipitated the product, which showed the appropriate mass ion and was greater than 60% pure by HPLC (uv readout at 254 nm): isocratic 35:65 H2O/CH3CN. Pure material was obtained by column chromatography on silica gel; (5:3) EtOAc/hexanes. Purity by HPLC was 85%; m\e 510 (M+1); 44% yield.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=O.[C:11]([O:15][C:16](=[O:19])[NH:17][NH2:18])([CH3:14])([CH3:13])[CH3:12].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[C:11]([O:15][C:16]([NH:17][NH:18][CH2:7][C:6]1[CH:9]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=1[OH:10])=[O:19])([CH3:14])([CH3:13])[CH3:12]
Reactant: O=Cc1cc(Br)ccc1O
Reactant: CC(C)(C)OC(=O)NN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NNCc1cc(Br)ccc1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 5-bromo-2-hydroxybenzaldehyde (10 g g 50 mmol), tert-butylcarbazate (6.7 g, 52 mmol) and acetic acid (3 mL, 52 mmol) in CH2Cl2 (200 mL) was stirred under N2 atmosphere for 60 min at RT. Then sodium triacetoxyborohydride (34 g, 159 mmol) was added portion wise and the resulting mixture was stirred at RT overnight. The reaction was quenched with 2 M HCl (100 mL) and stirred at RT for 1 h. The reaction mixture was partitioned between water (100 mL) and CH2Cl2 (250 mL). The organic layer was washed with sat. NaHCO3 and brine (100 mL each), dried (MgSO4) and evaporated to dryness to give hydrazine 1 as a white solid, 13 g (82%).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[C:11]([OH:13])=O)[CH:4]=[CH:3][N:2]=1.Cl.[CH3:15][NH:16][O:17][CH3:18].C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.C1COCC1>[CH3:18][O:17][N:16]([CH3:15])[C:11]([C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[CH:1]=[N:2][CH:3]=[CH:4]2)=[O:13]
Reactant: CNOC
Reactant: O=C(O)c1cccc2ccncc12
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: C1CCOC1
Product: CON(C)C(=O)c1cccc2ccncc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Commercially available isoquinoline-8-carboxylic acid (0.4 g, 2.31 mmol), N,O-dimethylhydroxylamine hydrochloride (0.45 g, 4.62 mmol), DMAP (0.28 g, 2.31 mmol), and polymer-supported DCC (0.71 g, 3.46 mmol) were charged in a 50 mL round bottom flask. Then anhydrous THF (23 mL) was added. The reaction was stirred overnight at RT. The reaction mixture was filtered and filtrate was concentrated. Purification by normal phase chromatography (0-50% EtOAc in hexane) yielded N-methoxy-N-methylisoquinoline-8-carboxamide (14-2).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@@:13]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)([CH2:16][CH2:17][CH2:18][OH:19])[O:12][C:11]2=[O:27])[CH3:9])=[CH:4][CH:3]=1.[F:28][C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[N:33][CH:34]=1>>[F:26][C:23]1[CH:24]=[CH:25][C:20]([C@:13]2([CH2:16][CH2:17][CH2:18][OH:19])[O:12][C:11](=[O:27])[N:10]([C@H:8]([C:5]3[CH:6]=[CH:7][C:2]([C:31]4[CH:32]=[N:33][CH:34]=[C:29]([F:28])[CH:30]=4)=[CH:3][CH:4]=3)[CH3:9])[CH2:15][CH2:14]2)=[CH:21][CH:22]=1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CCCO)(c2ccc(F)cc2)OC1=O
Reactant: OB(O)c1cncc(F)c1
Product: C[C@@H](c1ccc(-c2cncc(F)c2)cc1)N1CC[C@](CCCO)(c2ccc(F)cc2)OC1=O

Procedure:
The title compound was prepared from (R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-1,3-oxazinan-2-one and 5-fluoropyridin-3-ylboronic acid following a procedure analogous to that described in Example 75 Step 1. LC-MS Method 1 tR=1.5 min, m/z=453 (M+1).
Reaction SMILES: [Mg].Br[C:3]1[S:4][CH:5]=[CH:6][CH:7]=1.Br[C:9]1[CH:10]=[CH:11][C:12]([N:15]([CH3:17])[CH3:16])=[N:13][CH:14]=1.O>C1COCC1>[S:4]1[CH:5]=[CH:6][CH:7]=[C:3]1[C:9]1[CH:10]=[CH:11][C:12]([N:15]([CH3:17])[CH3:16])=[N:13][CH:14]=1
Reactant: CN(C)c1ccc(Br)cn1
Reactant: Brc1cccs1
Agent: [Mg]
Solvent: C1CCOC1
Solvent: O
Product: CN(C)c1ccc(-c2cccs2)cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 29.5 %

Procedure:
To a suspension of magnesium (0.119 g, 4.97 mmol) in THF (3 mL) was added 2-bromothiophene (0.811 g, 4.97 mmol) and the reaction mixture was stirred for 3 h. Another equivalent of 2-bromothiophene (0.811 g, 4.97 mmol) was added and the reaction mixture was heated at the reflux temperature for 2 h, then allowed to cool to room temperature. The resulting mixture was added to a solution of 5-bromo-2-dimethylaminopyridine (1.0 g, 4.97 mmol) in THF (12 mL) and the reaction was heated at the reflux temperature for 11 h, then was allowed to cool to room temperature. The resulting mixture was treated with water (10 mL), extracted with EtOAc (3×30 mL), dried (MgSO4) and concentrated under reduced pressure. The crude product was purified by flash chromatography (10% EtOAc/hex) to give 5-(2-thienyl)-2-dimethylaminopyridine (0.3 g, 29%): TLC (10% EtOAc/hex) Rf 0.24; HPLC ES-MS m/z (relative abundance) 205 (MH+, 100%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:12][CH2:11][CH2:10][NH:9]2)=[CH:4][CH:3]=1.[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[S:19]([C:16]2[CH:17]=[CH:18][C:13]([CH3:23])=[CH:14][CH:15]=2)(=[O:21])=[O:20])=[CH:6][CH:7]=1
Reactant: Fc1ccc([C@H]2CCCN2)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClC(Cl)Cl
Product: Cc1ccc(S(=O)(=O)N2CCC[C@@H]2c2ccc(F)cc2)cc1

Procedure:
The title compound, white solid, m.p. 136° C., [a]D20=174° (c=0.1 in CHCl3) and MS: m/e=319 (M+) was prepared in accordance with the general method of example 1e from (R)-2-(4-fluoro-phenyl)-pyrrolidine and toluene-4-sulfonyl chloride.
Reaction SMILES: [F:1][CH:2]([F:23])[C:3]1[C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([CH2:13][CH:14]([CH3:16])[CH3:15])[C:6]([CH2:17]Cl)=[C:5]([C:19]([F:22])([F:21])[F:20])[N:4]=1.[I-:24].[Na+]>CC(C)=O>[F:1][CH:2]([F:23])[C:3]1[C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([CH2:13][CH:14]([CH3:16])[CH3:15])[C:6]([CH2:17][I:24])=[C:5]([C:19]([F:22])([F:21])[F:20])[N:4]=1
Reactant: [I-]
Reactant: COC(=O)c1c(C(F)F)nc(C(F)(F)F)c(CCl)c1CC(C)C
Agent: [Na+]
Solvent: CC(C)=O
Product: COC(=O)c1c(C(F)F)nc(C(F)(F)F)c(CI)c1CC(C)C

Procedure:
Reaction of methyl 2-(difluoromethyl)-5-(chloromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (U.S. Pat. No. 5,169,432 example 3) with sodium iodide in refluxing acetone according to the procedure known to those in the art yielded the product.
Reaction SMILES: [C:1]([CH:3]1[CH2:6][N:5]([C:7](=[O:31])[C@H:8]([NH:10][C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19](Br)[N:20]=3)[N:15]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[CH:14]=2)=[O:12])[CH3:9])[CH2:4]1)#[N:2].[Cl:32][C:33]1[CH:41]=[C:40]2[C:36]([C:37]([Sn](CCCC)(CCCC)CCCC)=[N:38][N:39]2[CH3:42])=[CH:35][CH:34]=1>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[C:1]([CH:3]1[CH2:6][N:5]([C:7](=[O:31])[C@H:8]([NH:10][C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:37]4[C:36]5[C:40](=[CH:41][C:33]([Cl:32])=[CH:34][CH:35]=5)[N:39]([CH3:42])[N:38]=4)[N:20]=3)[N:15]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[CH:14]=2)=[O:12])[CH3:9])[CH2:4]1)#[N:2]
Reactant: C[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12)C(=O)N1CC(C#N)C1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nn(C)c2cc(Cl)ccc12
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: C[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(Cl)ccc34)nc12)C(=O)N1CC(C#N)C1
Temperature: 90 °C
Reaction time: 3 h
Yield: 98 %

Procedure:
In a round-bottomed flask, 2-bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethyl]-amide (0.135 g, 0.27 mmol) and 6-chloro-1-methyl-3-tributylstannyl-1H-indazole (crude from step 3, 342 mg, 0.38 mmol) were dissolved in DMF (2.4 ml). The flask was evacuated and backfilled with argon then tetrakis(triphenylphosphine)palladium(0) (16 mg, 0.014 mmol) and copper(I) iodide (11 mg, 0.058 mmol) were added. The reaction mixture was stirred at 90° C. in an oil bath for 3 h. The reaction mixture was cooled to room temperature, quenched with water and extracted with diethyl ether (2×). The combined organic layers were washed twice with water and once with brine then dried over sodium sulfate, filtered and concentrated. The residue was absorbed on silica gel and purified by chromatography with MeOH/CH2Cl2/0.5% NH4OH (gradient 0-2.5% MeOH) to afford 157 mg (90%) of 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethyl]-amide as a light yellow solid.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:11]=[C:10]2[N:12]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[C:30]4[NH:34][N:33]=[N:32][N:31]=4)=[CH:20][CH:19]=3)[C:13]([CH2:15][CH3:16])=[N:14][C:9]2=[C:8]([CH3:35])[CH:7]=1)=O)C.[NH:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1.[H-].[Na+].CC(O)=O>C1COCC1>[CH2:15]([C:13]1[N:12]([CH2:17][C:18]2[CH:19]=[CH:20][C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]3[NH:34][N:33]=[N:32][N:31]=3)=[CH:22][CH:23]=2)[C:10]2=[N:11][C:6]([C:4]([N:36]3[CH2:41][CH2:40][O:39][CH2:38][CH2:37]3)=[O:3])=[CH:7][C:8]([CH3:35])=[C:9]2[N:14]=1)[CH3:16]
Reactant: CCOC(=O)c1cc(C)c2nc(CC)n(Cc3ccc(-c4ccccc4-c4nnn[nH]4)cc3)c2n1
Reactant: C1COCCN1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCc1nc2c(C)cc(C(=O)N3CCOCC3)nc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Reaction time: 16 h

Procedure:
To 5-(ethoxycarbonyl)-2-ethyl-7-methyl-3-(2'-(tetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine (30 mg) in THF (1 mL) at RT was added 0.25 mL of morpholine and NaH (20 mg of an 80% dispersion). After stirring for 16 hours, 1% aqueous HOAc (2 mL) was added. Extractive workup (EtOAc), and purification (SiO2, 75/25/1 CH2Cl2 /MeOH/NH4OH) gave 10 mg of a solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1[C@H:12]2[CH2:24][C@H:23]3[O:25][C@@:22]3([CH3:26])[C@@H:13]2[C@H:14]([O:17][C:18](=[O:21])[NH:19][CH3:20])[O:15][CH:16]=1)=[O:10])C1C=CC=CC=1>C(OCC)(=O)C.[C].[Pd]>[CH3:1][O:8][C:9]([C:11]1[C@H:12]2[CH2:24][C@H:23]3[O:25][C@@:22]3([CH3:26])[C@@H:13]2[C@H:14]([O:17][C:18](=[O:21])[NH:19][CH3:20])[O:15][CH:16]=1)=[O:10]
Reactant: CNC(=O)O[C@@H]1OC=C(C(=O)OCc2ccccc2)[C@H]2C[C@H]3O[C@@]3(C)[C@H]12
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CNC(=O)O[C@@H]1OC=C(C(=O)OC)[C@H]2C[C@H]3O[C@@]3(C)[C@H]12
Reaction time: 24 h
Yield: 67.7 %

Procedure:
1.35 g of (1S,4aS,6R,7S,7aR)-6,7-epoxy-7-methyl-1-(methylcarbamoyloxy)-1,4a,5,7a-tetrahydrocyclopenta [c] pyrane-4-carboxylic acid benzylester described in Step 5 of Example 1 were dissolved in ethyl acetate followed by suspension of 60 mg of 5% palladium-carbon catalyst and stirring for 24 hours under hydrogen gas atmosphere at 1 atm. After filtering out the insoluble matter, the filtrate was concentrated. The residue was dissolved in methanol-ether followed by dropwise addition of 3.0. ml of trimethylsilyldiazomethane (2.0 M, hexane solution) and stirring for 30 minutes at room temperature. The reaction mixture was then extracted with ethyl acetate. After washing the organic phase with brine, it was dried over magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel chromatography to obtain a colorless powder from the hexane-ether eluate in the form of (1S,4aS,6R,7S,7aR)-6,7-epoxy-7-methyl-1-(methylcarbamoyloxy)-1,4a,5,6,7,7a-hexahydrocyclopenta [c] pyrane-4-carboxylic acid methylester (720 mg, yield: 68%). The physicochemical properties of this compound are described in Table 12, Compound No. 57.
Reaction SMILES: [OH:1][C:2]1([CH2:15][CH:16]=O)[CH2:14][CH2:13][C:5]2([O:10][CH2:9][C:8]([CH3:12])([CH3:11])[CH2:7][O:6]2)[CH2:4][CH2:3]1.[Br:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]([NH2:28])([CH3:27])[CH3:26])=[CH:21][CH:20]=1>>[Br:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]([NH:28][CH2:16][CH2:15][C:2]2([OH:1])[CH2:3][CH2:4][C:5]3([O:6][CH2:7][C:8]([CH3:12])([CH3:11])[CH2:9][O:10]3)[CH2:13][CH2:14]2)([CH3:26])[CH3:27])=[CH:23][CH:24]=1
Reactant: CC(C)(N)c1ccc(Br)cc1
Reactant: CC1(C)COC2(CCC(O)(CC=O)CC2)OC1
Product: CC1(C)COC2(CCC(O)(CCNC(C)(C)c3ccc(Br)cc3)CC2)OC1
Yield: 75 %

Procedure:
The title compound is prepared from (9-hydroxy-3,3-dimethyl-1,5-dioxa-spiro[5.5]undec-9-yl)-acetaldehyde and 1-(4-bromo-phenyl)-1-methyl-ethylamine following a procedure analogous to that described in Step 3 of Intermediate 2. Yield: 75% of theory; LC (method 5): tR=1.12 min; Mass spectrum (ESI+): m/z=440/442 (Br) [M+H]+.
Reaction SMILES: C([O:4][C:5]1[CH:23]=[CH:22][C:8]([CH2:9][C@H:10]2[CH2:15][CH2:14][C:13]3[CH:16]=[C:17]([CH:20]=[O:21])[CH:18]=[CH:19][C:12]=3[O:11]2)=[CH:7][CH:6]=1)(=O)C>CO.O1CCCC1.[OH-].[Na+]>[CH:20]([C:17]1[CH:18]=[CH:19][C:12]2[O:11][C@@H:10]([CH2:9][C:8]3[CH:22]=[CH:23][C:5]([OH:4])=[CH:6][CH:7]=3)[CH2:15][CH2:14][C:13]=2[CH:16]=1)=[O:21]
Reactant: CC(=O)Oc1ccc(C[C@H]2CCc3cc(C=O)ccc3O2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=Cc1ccc2c(c1)CC[C@H](Cc1ccc(O)cc1)O2
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.8 %

Procedure:
(R)-(-)-2-(4-Acetoxybenzyl)-3,4-dihydro-6- formyl-2H-benzopyran (15.7 g, 51 mmol) was dissolved in a mixture of methanol (200 ml), tetrahydrofuran (200 ml) and 2M NaOH (200 ml) and stirred at room temperature for 2 hours. The reaction mixture was concentrated in vacuo, diluted with water (100 ml) and acidified with 10% HCl (250 ml). The aqueous solution was extracted with ethyl acetate (2×500 ml) and the combined organics were washed with water (250 ml), brine (250 ml), and dried (MgSO4). The solvent was removed in vacuo and the residue was crystallized from hexanes/ethyl acetate (3:1) to afford 10.1 g of the title compound, m.p. 134°-135° C.; [α]D -155.2° (c 1.0, MeOH);
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[O:15]([CH2:22][C:23]1[CH:31]=[C:26]2[CH:27]=[N:28][CH2:29][CH2:30][N:25]2[N:24]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[F:32][C:33]1[CH:41]=[CH:40][C:36]([C:37](Cl)=[O:38])=[CH:35][CH:34]=1>C(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+]>[F:32][C:33]1[CH:41]=[CH:40][C:36]([C:37]([N:28]2[CH2:29][CH2:30][N:25]3[N:24]=[C:23]([CH2:22][O:15][C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH:31]=[C:26]3[CH2:27]2)=[O:38])=[CH:35][CH:34]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: C1=NCCn2nc(COc3ccccc3)cc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: O=C(c1ccc(F)cc1)N1CCn2nc(COc3ccccc3)cc2C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 87.2 %

Procedure:
Sodium triacetoxyborohydride (20.8 mg, 0.093 mmol) was added to a stirred solution of 2-phenoxymethyl-6,7-dihydro-pyrazolo[1,5-a]pyrazine (15 mg, 0.062 mmol) in DCM (0.5 mL). The mixture was stirred at room temperature for 16 hours and then, 4-fluorobenzoyl chloride (0.011 mL, 0.093 mmol) was added and the mixture stirred at room temperature for 1 hour. The mixture was diluted with a saturated solution of Na2CO3 and extracted with DCM. The organic layer was separated, dried (Na2SO4), filtered and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica; AcOEt in DCM 0/100 to 50/50). The desired fractions were collected and the solvents evaporated in vacuo to yield rac-(4-fluoro-phenyl)-(2-phenoxymethyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-5-yl)-methanone (19 mg, 84% yield) as a colourless oil that precipitated upon standing. 1H NMR (500 MHz, CDCl3) δ ppm 1.56 (d, J=6.9 Hz, 3H), 3.59 (br. s., 1H), 4.34 (br. s., 1H), 4.05-4.22 (m, 1H), 4.22-4.32 (m, 1H), 5.04 (s, 2H), 5.58 (br. s., 1H), 6.15 (br. s., 1H), 6.96 (t, J=7.4 Hz, 1H), 7.00 (d, J=7.8 Hz, 2H), 7.10-7.20 (m, 2H), 7.27-7.34 (m, 2H), 7.40-7.49 (m, 2H).
Reaction SMILES: [O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][S:10][C:6]=2[CH2:5][CH:4]([C:11]([O:13]CC2C=CC=CC=2)=[O:12])[N:3]1[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(O)(C)C.C(O)C>[O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][S:10][C:6]=2[CH2:5][CH:4]([C:11]([OH:13])=[O:12])[N:3]1[CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: O=C(OCc1ccccc1)C1Cc2sccc2C(=O)N1Cc1ccccc1
Solvent: CC(C)O
Solvent: CCO
Product: O=C(O)C1Cc2sccc2C(=O)N1Cc1ccccc1
Yield: 70 %

Procedure:
The compound is prepared by saponification of 4-oxo-5-benzyloxycarbonyl-5-benzyl-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine (Example 13), to give pink crystals, M.p.=258° C. (isopropanol-ethanol), Yield: 70%.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[N:18]=[CH:17][C:16]([CH2:19][NH:20][C:21]3[CH:33]=[CH:32][C:24]4[O:25][C:26]([CH3:31])([CH3:30])[O:27][C:28](=[O:29])[C:23]=4[CH:22]=3)=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[CH:34]1([CH2:39][CH2:40][C:41](Cl)=[O:42])[CH2:38][CH2:37][CH2:36][CH2:35]1>>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]#[C:12][C:13]2[N:18]=[CH:17][C:16]([CH2:19][N:20]([C:21]3[CH:33]=[CH:32][C:24]4[O:25][C:26]([CH3:31])([CH3:30])[O:27][C:28](=[O:29])[C:23]=4[CH:22]=3)[C:41](=[O:42])[CH2:40][CH2:39][CH:34]3[CH2:38][CH2:37][CH2:36][CH2:35]3)=[CH:15][CH:14]=2)=[CH:9][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(C#Cc2ccc(CNc3ccc4c(c3)C(=O)OC(C)(C)O4)cn2)cc1
Reactant: O=C(Cl)CCC1CCCC1
Product: CCCCc1ccc(C#Cc2ccc(CN(C(=O)CCC3CCCC3)c3ccc4c(c3)C(=O)OC(C)(C)O4)cn2)cc1

Procedure:
The titled compound was prepared following the procedure B using 6-[({6-[(4-butylphenyl)ethynyl]-3-pyridinyl}methyl)amino]-2,2-dimethyl-4H-1,3-benzodioxin-4-one and 3-cyclopentylpropionyl chloride as a yellow oil (73%). 1H NMR (CDCl3, 300 MHz) δ 8.28 (s, 1H), 7.77 (m, 2H), 7.48 (m, 3H), 7.16 (d, J=8.3 Hz. 2H), 7.05 (m, 1H), 6.93 (d, J=8.7 Hz, 1H), 4.87 (s, 2H), 2.61 (t, J=7.5 Hz, 2H), 2.05 (m, 2H), 1.74 (s, 6H), 1.68-1.29 (m, 13H), 0.92 (m, 5H). M+ (ESI): 565.3. HPLC, Rt: 5.43 min (Purity: 97.6%).
Reaction SMILES: [N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:26]([OH:28])=O)[CH2:10]2)=[O:8])[CH2:6][CH2:5][S:4][CH2:3][CH2:2]1.O[NH:30][C:31]([C:33]1([O:36][CH3:37])[CH2:35][CH2:34]1)=[NH:32]>>[CH3:37][O:36][C:33]1([C:31]2[N:32]=[C:26]([CH:11]3[CH2:12][CH:13]([C:15]4[CH:20]=[CH:19][C:18]([CH2:21][C:22]([F:23])([F:25])[F:24])=[CH:17][CH:16]=4)[CH2:14][N:9]([C:7]([N:1]4[CH2:2][CH2:3][S:4][CH2:5][CH2:6]4)=[O:8])[CH2:10]3)[O:28][N:30]=2)[CH2:35][CH2:34]1
Reactant: O=C(O)C1CC(c2ccc(CC(F)(F)F)cc2)CN(C(=O)N2CCSCC2)C1
Reactant: COC1(C(=N)NO)CC1
Product: COC1(c2noc(C3CC(c4ccc(CC(F)(F)F)cc4)CN(C(=O)N4CCSCC4)C3)n2)CC1

Procedure:
According to General Method 6A, 93.1 mg (0.224 mmol) of the compound from Example 45A and 32.0 mg (0.246 mmol) of N-hydroxy-1-methoxycyclopropanecarboximidamide from Example 64A were reacted. Yield: 31.1 mg (27% of theory)
Reaction SMILES: [H-].[Na+].[C:3]([O:9][CH3:10])(=[O:8])[CH2:4][C:5]([CH3:7])=[O:6].[C:11](Cl)(=O)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]CC>O1CCCC1>[O:6]=[C:5]([CH2:7][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH3:11])[CH2:4][C:3]([O:9][CH3:10])=[O:8]
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Reactant: COC(=O)CC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCC(=O)CC(=O)OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 55 %

Procedure:
Four liters of a suspension of 440 g (11 mol) of 60% sodium hydride in dried tetrahydrofuran was cooled to 0° C. Thereto was added dropwise 1.8 L of a tetrahydrofuran solution of 1.161 kg (10 mol) of methyl acetoacetate. After this mixture was stirred at room temperature for 1 hour, 3.023 kg (11 mol) of hexadecanoyl chloride was added dropwise at 0 to 5° C. and the resultant mixture was stirred at room temperature overnight. Thereafter, the tetrahydrofuran was distilled off, and the residue was poured into ice water and extracted with 8 L of ethyl acetate. The ethyl acetate was distilled off, and the residue was poured into a mixture of 400 g of a 28% methanol solution of sodium methoxide and 1.2 L of methanol. The resultant mixture was stirred with heating at 60 to 65° C. for 6 hours. The reaction mixture was cooled with ice, and the pH thereof was then adjusted to 5 with 10% sulfuric acid. This reaction mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with 5% aqueous sodium carbonate solution and saturated aqueous common salt solution. Thereafter, the ethyl acetate was distilled off and the concentrate was recrystallized from methanol to obtain 1.72 kg (5.5 mol) of methyl 3-oxooctadecanoate. Yield, 55%.
Reaction SMILES: Cl.[CH2:2]([S:9][C:10](=[NH:12])[NH2:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[F:13][C:14]1[CH:19]=[CH:18][C:17]([C:20](=O)[CH:21]([C:23]2[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:25][CH:24]=2)Br)=[CH:16][CH:15]=1.C([O-])(O)=O.[Na+]>CCO>[CH2:2]([S:9][C:10]1[NH:11][C:20]([C:17]2[CH:18]=[CH:19][C:14]([F:13])=[CH:15][CH:16]=2)=[C:21]([C:23]2[CH:24]=[CH:25][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:27][CH:28]=2)[N:12]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: N=C(N)SCc1ccccc1
Reactant: CS(=O)(=O)c1ccc(C(Br)C(=O)c2ccc(F)cc2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CS(=O)(=O)c1ccc(-c2nc(SCc3ccccc3)[nH]c2-c2ccc(F)cc2)cc1
Yield: 17.5 %

Procedure:
A mixture of S-benzylisothiourea hydrochloride (300 mg, 1.5 mmol), 1-(4-fluorophenyl)-2-(4-methylsulfonylphenyl)-2-bromoethan-1-one (Example 1, Method B, step 1) (500 mg, 1.3 mmol) and NaHCO3 (500 mg, 6 mmol) in EtOH (10 ml) was heated to reflux for 3 hours. After evaporation of the solvent, the residue was treated with water (25 ml) and extracted with methylene chloride (25 ml). After drying (MgSO4), the organic phase was evaporated. The residue was purified by chromatography on silica gel, eluting with ethyl acetate/toluene (25/75). The crude material was recrystallized from toluene and hexane to give 100 mg (17%) of titled product: m.p. 155-156° C. Anal. Calc'd. for C23H19FN2O2S2: C, 62.99; H, 4.37; N, 6.39; S, 14.62. Found: C, 62.93; H, 4.41; N, 5.98; S, 14.33.