Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[N:7]([CH2:33][C:34]1[CH:43]=[CH:42][C:37]2[O:38][CH2:39][CH2:40][O:41][C:36]=2[CH:35]=1)[CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]([C:26]3[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=3)=[CH:18][C:17]2=[O:32])[CH2:10][CH2:9]1)(C)(C)C.FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+].[ClH:57].C(OCC)(=O)C>C(Cl)(Cl)Cl>[ClH:57].[O:38]1[C:37]2[CH:42]=[CH:43][C:34]([CH2:33][NH:7][CH:8]3[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]4[C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[C:19]([C:26]5[CH:27]=[CH:28][N:29]=[CH:30][CH:31]=5)=[CH:18][C:17]4=[O:32])[CH2:10][CH2:9]3)=[CH:35][C:36]=2[O:41][CH2:40][CH2:39]1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCN(CCn2c(=O)cc(-c3ccncc3)c3ccccc32)CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: O=c1cc(-c2ccncc2)c2ccccc2n1CCN1CCC(NCc2ccc3c(c2)OCCO3)CC1
Reaction time: 3.5 h

Procedure:
To 1 mL of a chloroform solution containing 42 mg of tert-butyl(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(2-oxo-4-(pyridin-4-yl)quinolin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate, 1 mL of trifluoroacetic acid was added at room temperature and stirred for 3.5 hours, thereafter the solvent was removed under reduced pressure. To the residue thus obtained, chloroform and aqueous saturated sodium hydrogen carbonate solution were added, the organic layer was separated and the aqueous layer was extracted with chloroform. The organic layer and extracts were combined, washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. To the residue thus obtained, 1 mL of 4 mol/L hydrogen chloride/ethyl acetate was added, the resulting solid was filtered to give 21 mg of (1-(2-(4-((2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidin-1-yl)ethyl)-4-(pyridin-4-yl)quinolin-2(1H)-one hydrochloride as a pale yellow solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([S:10]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[CH:16][CH:15]=2)(=[O:12])=[O:11])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[C:26]([C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1)([OH:28])=[O:27]>C(=O)(O)[O-].[Na+].COCCOC>[CH3:9][O:8][C:7]1[CH:6]=[CH:5][C:4]([S:10](=[O:12])(=[O:11])[NH:13][C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[CH:16][CH:15]=2)=[CH:3][C:2]=1[C:32]1[CH:33]=[CH:34][C:29]([C:26]([OH:28])=[O:27])=[CH:30][CH:31]=1
Reactant: COc1ccc(S(=O)(=O)Nc2ccc(N3CCOCC3)cc2)cc1Br
Reactant: O=C(O)c1ccc(B(O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Product: COc1ccc(S(=O)(=O)Nc2ccc(N3CCOCC3)cc2)cc1-c1ccc(C(=O)O)cc1

Procedure:
A mixture of 3-bromo-4-methoxy-N-(4-morpholin-4-yl-phenyl)-benzenesulfonamide (460 mg) and 4-carboxy-phenyl boronic acid (196 mg) in saturated sodium bicarbonate solution (4 ml) and DME (8 ml) was heated to reflux in the presence of tetrakis(triphenylphosphine)palladium0 for 16 h. The mixture was allowed to cool and was evaporated. The residue was then suspended in water and 2M HCl added until the effervescence ceased. The resulting light grey solid was collected and dried (490 mg)
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH2:11]([NH:13][CH2:14][CH2:15][OH:16])[CH3:12]>CS(C)=O>[CH2:11]([N:13]([C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1)[CH2:14][CH2:15][OH:16])[CH3:12]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CCNCCO
Solvent: CS(C)=O
Product: CCN(CCO)c1ccc([N+](=O)[O-])cc1
Temperature: 140 °C
Yield: 84.7 %

Procedure:
In 30 ml of DMSO, 5.0 g (35.4 mmol) of 4-fluoronitrobenzene and 6 g (67.3 mmol) of 2-(ethylamino)ethanol were dissolved. The resultant solution was stirred under heat at 140° C. for 4 hours, followed by extraction with ethyl acetate. The solvent was distilled out under reduced pressure, followed by washing with ethyl acetate, whereby 6.3 g of yellow powder were obtained (yield: 85%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]#[N:8].Cl[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.C1(C)C=CC=CC=1.[NH2-].[Na+]>O>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1)[C:7]#[N:8]
Reactant: Clc1ccccn1
Reactant: N#CCc1cccs1
Agent: [NH2-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: N#CC(c1ccccn1)c1cccs1
Temperature: 60 °C

Procedure:
To a well-stirred solution containing 61.5 g. of 2-thienylacetonitrile and 56.5 g. of 2-chloropyridine in 400 ml. of toluene, slowly add a stirred suspension of 40 g. of sodamide in 300 ml. of toluene keeping the reaction temperature at 60°-65° C by cooling with an ice bath. After completing the addition maintain the temperature at 60° C for 2 hrs., add 200 ml. of water to the cooled reaction mixture, decant the tarry by-products and separate the aqueous layer. Evaporate in vacuo the resulting solution and dilute the thick black residue with 300 ml. of ether. Filter the separated solid and evaporate the filtrate. The desired product is distilled off at 145°-150° C/1 ml. and is recrystallized from alcohol to yield α-(2-thienyl)-2-pyridylacetonitrile, m.p. 48°-50° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[CH:9]=[CH:10]/[C:11]([N:13]2[CH2:19][CH2:18][C:17](=[O:20])[NH:16][CH2:15][CH2:14]2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8].[Cl:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]I>>[Cl:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][N:16]1[C:17](=[O:20])[CH2:18][CH2:19][N:13]([C:11](=[O:12])/[CH:10]=[CH:9]/[C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[CH2:14][CH2:15]1
Reactant: O=C1CCN(C(=O)/C=C/c2ccc(Cl)c(Cl)c2)CCN1
Reactant: ClCCCCCI
Product: O=C(/C=C/c1ccc(Cl)c(Cl)c1)N1CCC(=O)N(CCCCCCl)CC1

Procedure:
In analogy to the procedure described in example 5A, 1-[(E)-3-(3,4-dichloro-phenyl)-acryloyl]-[1,4]diazepan-5-one (intermediate 1A]) and 1-chloro-5-iodopentane gave the title compound as yellow oil. MS: 416.9 (MH+, 3Cl).
Reaction SMILES: [C:1]([O:4][CH2:5][C@H:6]1[O:10][C@@H:9]([N:11]2[CH:19]=[C:17]([CH3:18])[C:15](=[O:16])[NH:14][C:12]2=[O:13])[CH2:8][C@@H:7]1[OH:20])(=[O:3])[CH3:2].[CH3:21][S:22](Cl)(=[O:24])=[O:23]>N1C=CC=CC=1>[C:1]([O:4][CH2:5][C@H:6]1[O:10][C@@H:9]([N:11]2[CH:19]=[C:17]([CH3:18])[C:15](=[O:16])[NH:14][C:12]2=[O:13])[CH2:8][C@@H:7]1[O:20][S:22]([CH3:21])(=[O:24])=[O:23])(=[O:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cc(C)c(=O)[nH]c2=O)C[C@@H]1O
Solvent: c1ccncc1
Product: CC(=O)OC[C@H]1O[C@@H](n2cc(C)c(=O)[nH]c2=O)C[C@@H]1OS(C)(=O)=O
Temperature: 0 °C

Procedure:
The 5'-O-acetylthymidine obtained in Example 7 was dissolved in 100 ml of pyridine and cooled to 0° C. Then, 11.57 g (2 equivalents) of methanesulfonyl chloride were added thereto. After these were reacted at 0° C. for 1.5 hours, 5.79 g (one equivalent) of methanesulfonyl chloride were added thereto and reacted at 0° C. for 1.5 hours. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in methylene chloride, and the insoluble substances were removed by filtration. The organic layer was washed with water; aqueous, saturated sodium hydrogencarbonate solution; water; and saturated saline solution in this order, dried with anhydrous sodium sulfate and concentrated under reduced pressure to obtain 10.4 g of 5'-O-acetyl-3'-O-methanesulfonylthymidine. The product was used in the next reaction, without being isolated.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][NH:6]2.[IH:11]>>[I:11][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][NH:6]2
Reactant: I
Reactant: Clc1ncnc2[nH]cnc12
Product: Ic1ncnc2[nH]cnc12
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
A mixture of 6-chloro-9H-purine (684 mg, 4.46 mmol) and 6 mL of 57% hydriodic acid were stirred at 0° C. for 1.5 hours. The reaction yielded 840 mg of the product as a white powder. The solid was filtered off, suspended in 5 mL of water and brought to pH=8 with aqueous ammonia solution. The suspension was cooled down to 0° C. and the solid was filtered off, washed with cold water and dried to give the product.
Reaction SMILES: [OH:1][C:2]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[Br:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:20]=[C:21]=[O:22]>>[OH:1][C:2]1[CH:8]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:6]=[CH:5][C:3]=1[NH:4][C:21]([NH:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[Br:13])=[O:22]
Reactant: Nc1ccc(C(F)(F)F)cc1O
Reactant: O=C=Nc1ccccc1Br
Product: O=C(Nc1ccc(C(F)(F)F)cc1O)Nc1ccccc1Br
Yield: 66.6 %

Procedure:
The urea was prepared from 2-hydroxy 4-trifluoromethyl aniline(example 7a, 0.171g, 1 mmol) and 2-bromo phenyl isocyanate(1 mmol) by general Method B. It was purified by dilution with methylene chloride and precipitation with hexane. Filtering afforded the desired compound(0.25 g, 54%). EI-MS m/z 375(M+H)+
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]([NH2:12])=[N:10][N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:13][C:14]1[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1.CCOC(C)=O>N1C=CC=CC=1.CCCCCC>[CH3:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([NH:12][C:9]2[NH:10][N:11]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:8]=2)(=[O:22])=[O:21])=[CH:16][CH:15]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1nnc(-c2ccccc2)[nH]1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1ccc(S(=O)(=O)Nc2nc(-c3ccccc3)n[nH]2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 48.4 %

Procedure:
To a solution of 5-phenyl-4H-1,2,4-triazol-3-amine (354 mg, 2 mmol) in dry pyridine (10 mL) was added 4-methylbenzenesulfonyl chloride (427 mg, 2.24 mmol). The solution was stirred at room temperature under Argon. After 48 h, the pyridine was removed in vacuo and flashed off with toluene. The residue was partitioned between CH2Cl2 and 1M NaOH. The organic phase was washed with 1M NaOH until no turbidity was observed on rectification of a small sample. The alkaline phase was made acidic (˜pH 3) with 1M HCl and extracted with CH2Cl2. After drying over Na2SO4, the solvent was removed in vacuo to give 0.41 g crude product. The crude product was dissolved hot EtOAc (16 mL), diluted with hexane (16 mL), and seeded to give fine white needles (304 mg) with mp 220-221° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7](I)[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=1)[CH:9]=2)=[O:4].[C:25]([Cu])#[N:26].C(Cl)Cl>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([C:25]#[N:26])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=1)[CH:9]=2)=[O:4]
Reactant: COC(=O)c1nc(I)c2cc(Oc3cccc(Cl)c3)ccc2c1O
Reactant: N#C[Cu]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)c1nc(C#N)c2cc(Oc3cccc(Cl)c3)ccc2c1O
Temperature: 120 °C
Reaction time: 0.17 h

Procedure:
7-(3-Chloro-phenoxy)-4-hydroxy-1-iodo-isoquinoline-3-carboxylic acid methyl ester (120 mg, 0.26 mmol) and CuCN (47 mg, 0.53 mmol) were suspended in DMF (1.1 mL). The resulting mixture was heated at 120° C. for 7 minutes and then cooled to room temperature. The reaction crude was poured into CH2Cl2 (30 mL) and stirred vigorously for 10 minutes at room temperature. The resulting suspension was filtered through a pad of celite and the filtrate was washed with H2O and brine sequentially. The organic layer was dried over MgSO4, concentrated, and purified by flash chromatography (0-50% EtOAc/hexanes) to give the title compound in 62 mg. MS: (−) m/z 353.25 (M−1).
Reaction SMILES: [F:1][C:2]1([F:24])[C:6]([F:8])([F:7])[C:5]2[CH:9]=[CH:10][CH:11]=[C:12]([CH2:13][CH:14]3[CH2:23][CH2:22][C:17]4([O:21][CH2:20][CH2:19][O:18]4)[CH2:16][CH2:15]3)[C:4]=2[O:3]1>[Pd].C(O)C>[F:24][C:2]1([F:1])[C:6]([F:7])([F:8])[C:5]2[CH:9]=[CH:10][CH:11]=[C:12]([CH:13]=[C:14]3[CH2:23][CH2:22][C:17]4([O:21][CH2:20][CH2:19][O:18]4)[CH2:16][CH2:15]3)[C:4]=2[O:3]1
Reactant: FC1(F)Oc2c(CC3CCC4(CC3)OCCO4)cccc2C1(F)F
Agent: [Pd]
Solvent: CCO
Product: FC1(F)Oc2c(C=C3CCC4(CC3)OCCO4)cccc2C1(F)F

Procedure:
This compound is prepared in a manner analogous to that of Step C of Example 2, by the hydrogenation of 8.9 grams (0.026 mole) of 8-(2,2,3,3-tetrafluoro-2,3-dihydrobenzofuran-7-ylmethylene)-1,4-dioxaspiro[4.5]decane in the presence of 0.4 gram (catalyst) of 10% palladium on charcoal in 50 mL of ethanol, yielding 8-(2,2,3,3-tetrafluoro-2,3-dihydrobenzofuran-7-ylmethyl)-1,4-dioxaspiro[4.5]decane.
Reaction SMILES: [CH2:1]1[CH2:8][O:7][S:4](=[O:6])(=[O:5])[CH2:3][CH2:2]1.[H-].[NH2:10][NH2:11]>CO>[S:4]([CH2:3][CH2:2][CH2:1][CH2:8][NH:10][NH2:11])([OH:7])(=[O:6])=[O:5]
Reactant: NN
Reactant: O=S1(=O)CCCCO1
Agent: [H-]
Solvent: CO
Product: NNCCCCS(=O)(=O)O
Temperature: 70 °C
Reaction time: 1 h

Procedure:
103 ml of 1,4-butanesultone was added to 378 g of hydrazine hydride (80%) dropwise slowly, and stirred for 30 minutes at room temperature and for further 1 hour at 70° C. Water and hydrazine hydride were removed to obtain white crystals. These crystals were dispersed in 1.5 liters of methanol, and then refluxed for 1 hour and allowed to stand at room temperature. The crystals were collected, twice washed with 100 ml of methanol, and dried to obtain 115 g of 4-sulfobutylhydrazine. (m.p.: 152°-154° C.)
Reaction SMILES: [CH2:1]([O:8][N:9]=[C:10]1[C:18]2([CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[C:17]2[C:12](=[CH:13][CH:14]=[C:15](Br)[CH:16]=2)[NH:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:25][C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][C:31]=1[F:32]>C1COCC1.O>[CH2:1]([O:8][N:9]=[C:10]1[C:18]2([CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:29]3[CH:28]=[CH:27][C:26]([F:25])=[C:31]([F:32])[CH:30]=3)[CH:16]=2)[NH:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1ccc2c(c1)C1(CCCCC1)C(=NOCc1ccccc1)N2
Reactant: OB(O)c1ccc(F)c(F)c1
Solvent: C1CCOC1
Solvent: O
Product: Fc1ccc(-c2ccc3c(c2)C2(CCCCC2)C(=NOCc2ccccc2)N3)cc1F
Yield: 69 %

Procedure:
Prepared from 5′-bromospiro{cyclohexane-1,3′-[3H]indol}-2′ (1′H)-one 2′(O-benzyloxime) (1.0 g, 2.6 mmol) and 3,4-difluorophenyl boronic acid (1.6 g, 5.2 mmol of a 50% solution of acid in THF/water) according to Example 45 procedure A. The product was purified by flash silica gel chromatography (eluant: 10:0.5 hexane:ethyl acetate) to give the desired product (0.75 g, 1.7 mmol, 69%) as a viscous oil. 1H NMR (500 MHz, DMSO-d6) δ 1.41-1.78 (8H, m) 1.95-1.99 (2H, q) 5.00 (2H, s) 6.82 (1H, d) 7.28-7.46 (8H, m) 7.58 (1H, q) 7.67-7.71 (1H, m) 9.61 (1H, s); MS (ESI(−ve)) m/z 417 (M−H)−.
Reaction SMILES: [CH3:1][C:2]1[C:3]([NH2:9])=[N:4][C:5]([CH3:8])=[CH:6][N:7]=1.[CH2:10]([O:12][C:13]([N:15]=[C:16]=[S:17])=[O:14])[CH3:11]>O1CCOCC1>[CH2:10]([O:12][C:13](=[O:14])[NH:15][C:16](=[S:17])[NH:9][C:3]1[C:2]([CH3:1])=[N:7][CH:6]=[C:5]([CH3:8])[N:4]=1)[CH3:11]
Reactant: CCOC(=O)N=C=S
Reactant: Cc1cnc(C)c(N)n1
Solvent: C1COCCO1
Product: CCOC(=O)NC(=S)Nc1nc(C)cnc1C
Temperature: 25 °C
Reaction time: 18 h
Yield: 96.7 %

Procedure:
To a solution of 3,6-dimethyl-pyrazin-2-ylamine (5 g, 40.65 mmol) in dioxane (150 ml) was added ethoxycarbonyl isothiocyanate (4.75 ml, 40.65 mmol) at 25° C., and the reaction mixture was stirred for 18 hours at 25° C. Volatiles were removed in vacuo. The resultant residue was dissolved in ethyl acetate, washed with water twice, and brine, dried over anhydrous sodium sulfate, filtered, and evaporated affording ethyl-N-[(3,6-dimethylpyrazin-2-yl)carbamothioyl]carbamate (10 g, 96.73%) as a light yellow solid. MS: m/z=255 (M+H+)
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1[O:8][C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:6][C:5]=1[CH2:15][O:16][C:17]1[CH:37]=[CH:36][C:20]([CH2:21][O:22]/[N:23]=[C:24](\[C:30]2[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=2)/[C:25]([O:27]CC)=[O:26])=[CH:19][CH:18]=1.Cl>O1CCCC1>[CH3:3][C:4]1[O:8][C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:6][C:5]=1[CH2:15][O:16][C:17]1[CH:37]=[CH:36][C:20]([CH2:21][O:22]/[N:23]=[C:24](\[C:30]2[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=2)/[C:25]([OH:27])=[O:26])=[CH:19][CH:18]=1
Reactant: CCOC(=O)/C(=N/OCc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1)c1cccnc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(CO/N=C(/C(=O)O)c2cccnc2)cc1
Temperature: 40 °C
Reaction time: 1 h
Yield: 87.3 %

Procedure:
A 1N aqueous saturated solution of sodium hydroxide (5 ml) was added to a solution of ethyl E-2-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-2-(3-pyridyl)acetate (520 mg) in tetrahydrofuran (10 ml)-metbanol (5 ml) and stirred at 40° C. for 1 hour. 1N hydrochloric acid (5.5 ml) was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The residue was recrystallized from acetone-diisopropyl ether to obtain E-2-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-2-(3-pyridyl)acetic acid (427 mg, yield 88%) as colorless crystals. m.p. 130-131° C. (decomposition)
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][C@@H:10]([C:13]([C:26]#[N:27])([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:9]1)C1C=CC=CC=1.Cl.[H][H]>[C].[Pd].C(O)C>[C:26]([C:13]([C@@H:10]1[CH2:11][CH2:12][NH:8][CH2:9]1)([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)#[N:27]
Reactant: N#CC(c1ccccc1)(c1ccccc1)[C@@H]1CCN(Cc2ccccc2)C1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: N#CC(c1ccccc1)(c1ccccc1)[C@@H]1CCNC1
Temperature: 60 °C
Reaction time: 3 h
Yield: 80.6 %

Procedure:
A mixed solution obtained by mixing 3.5 g of 79% pure (S)-1-benzyl-3-(1-cyano-1,1-diphenylmethyl)-pyrrolidine with 2.8 ml of ethanol and adding dropwise 0.72 ml of 35% aqueous hydrochloric acid thereto with cooling on an ice-water bath was charged, together with 139 mg of moist 5% palladium-carbon (water content 52% by weight), into an autoclave, hydrogen was introduced thereinto and the autoclave was heated to raise the temperature to 60° C. and the pressure to 203 kPa, and the reaction was allowed to proceed for 3 hours. Hydrogen absorption came to an end in 2.6 hours after the start of hydrogen introduction. After completion of the reaction, the reaction mixture was cooled to room temperature and depressurized. The reaction mixture was taken out, the catalyst was filtered off, the filtrate obtained was concentrated under reduced pressure, toluene and water were added to the thus-obtained oily concentrate, and the pH was adjusted to 13 by adding dropwise 30% aqueous sodium hydroxide with stirring on an ice-water bath. The toluene layer was recovered, the aqueous layer was further extracted with toluene, and the toluene layers were combined, washed with a saturated aqueous solution of sodium chloride, dried with anhydrous sodium sulfate and, after filtration, concentrated under reduced pressure and further dried under vacuum to give 2.1 g of (S)-3-(1-cyano-1,1-diphenylmethyl)-pyrrolidine as an oil (yield: 91 mole percent).
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:19]=[CH:18][C:9]([C:10]([CH2:12][C:13]([O:15]CC)=[O:14])=O)=[CH:8][CH:7]=1)(=[O:4])=[O:3].Cl.[NH2:21]O.CO.C([O-])(=O)C>O>[CH3:1][S:2]([NH:5][C:6]1[CH:19]=[CH:18][C:9]([C:10]2[CH2:12][C:13](=[O:14])[O:15][N:21]=2)=[CH:8][CH:7]=1)(=[O:4])=[O:3]
Reactant: NO
Reactant: CCOC(=O)CC(=O)c1ccc(NS(C)(=O)=O)cc1
Agent: CC(=O)[O-]
Agent: Cl
Solvent: O
Solvent: CO
Product: CS(=O)(=O)Nc1ccc(C2=NOC(=O)C2)cc1

Procedure:
To a mixture 23.0 g of ethyl 4-methanesulfonamidobenzoylacetate, 5.8 g of hydroxylamine hydrochloride, and 35 ml of methanol, 8.2 g of pottasium acetate was added, and the mixture was refluxed for 30 minutes while being heated. The reaction mixture was poured into 210 ml of water, and the precipitated crystals were collected by filtering and dried, thereby obtaining 1.39 of 3-(4-methanesulfonamidophenyl)isoxazolin-5-one.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([CH:7]2[NH:12][CH2:11][CH2:10][N:9]([C:13]3[CH:22]=[C:21]4[C:16]([C:17](=[O:28])[C:18]([C:25]([OH:27])=[O:26])=[CH:19][N:20]4[CH2:23][CH3:24])=[CH:15][C:14]=3[F:29])[CH2:8]2)=[CH:4][CH:3]=1.[CH2:30]=O>C(O)(=O)C>[Br:1][C:2]1[S:6][C:5]([CH:7]2[N:12]([CH3:30])[CH2:11][CH2:10][N:9]([C:13]3[CH:22]=[C:21]4[C:16]([C:17](=[O:28])[C:18]([C:25]([OH:27])=[O:26])=[CH:19][N:20]4[CH2:23][CH3:24])=[CH:15][C:14]=3[F:29])[CH2:8]2)=[CH:4][CH:3]=1
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCNC(c4ccc(Br)s4)C3)cc21
Reactant: C=O
Solvent: CC(=O)O
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCN(C)C(c4ccc(Br)s4)C3)cc21

Procedure:
A 150 mg portion of 7-[3-(5-bromo-2-thienyl)-1piperazinyl]-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid was dissolved in a mixture of 0.6 ml of 37% formaldehyde and 0.75 ml of glacial acetic acid, heated on a steam bath for 2 hours and then evaporated. The residue was diluted with 3 ml of water, adjusted to pH 7 with 1N sodium hydroxide and the solid collected, giving 120 mg of the desired product, mp 243°-245° C. (dec.).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH3:11])=[CH:5]2.[Br:12][CH2:13][CH2:14][CH2:15][CH2:16]Br>>[Br:12][CH2:13][CH2:14][CH2:15][CH2:16][O:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH3:11])=[CH:5]2
Reactant: BrCCCCBr
Reactant: Cc1cc2cc(O)ccc2[nH]1
Product: Cc1cc2cc(OCCCCBr)ccc2[nH]1

Procedure:
In analogy to example 3.1, 5-hydroxy-2-methylindole and 1,4-dibrombutane were converted to yield 5-(4-Bromo-butoxy)-2-methyl-1H-indole as colorless solid, mp 85° C., MS: 281 (M, 1Br).
Reaction SMILES: [CH3:1][C:2]1[C:6]2[N:7]=[CH:8][N:9]([CH2:12][C:13]([NH:15][CH:16]3[CH2:20][C:19](=[O:21])[O:18][CH:17]3[O:22]CC3C=CC=CC=3)=[O:14])[C:10](=[O:11])[C:5]=2[NH:4][CH:3]=1>CO.[Pd]>[CH3:1][C:2]1[C:6]2[N:7]=[CH:8][N:9]([CH2:12][C:13]([NH:15][C@H:16]([CH:17]=[O:22])[CH2:20][C:19]([OH:21])=[O:18])=[O:14])[C:10](=[O:11])[C:5]=2[NH:4][CH:3]=1
Reactant: Cc1c[nH]c2c(=O)n(CC(=O)NC3CC(=O)OC3OCc3ccccc3)cnc12
Agent: [Pd]
Solvent: CO
Product: Cc1c[nH]c2c(=O)n(CC(=O)N[C@H](C=O)CC(=O)O)cnc12
Reaction time: 2 h
Yield: 78.2 %

Procedure:
A mixture of 42 (131 mg, 0.33 mmol), in methanol (50 ml) and 10% palladium on carbon (100 mg) was stirred vigorously under an atmosphere of hydrogen for 2 h. An additional quantity of catalyst (100 mg) was added and the mixture hydrogenated for a further 2 h. The mixture was filtered through a 0.2 μM nylon membrane, and concentrated. The residue was recrystallized from methanol/diethyl ether to afford 79 mg (78%) of 43 as a hygroscopic white solid: mp. 222-226° C.; (decomp.); [α]D32 +0.5 (c 0.02, MeOH); IR (KBr) 3282, 1680, 1558, 1425 1275; 1H NMR (CD3OD) δ 8.03 (1H, s), 7.18 (1H, d, J=0.7), 4.79-4.74 (2H, m), 4.63-4.59 (1H, 2×d, J=3.6), 4.36-4.25 (1H, m), 2.78-2.39 (2H, m), 2.24 (3H, d, J=0.7). Anal. Calcd for C13H14N4O5. 1.4H2O: C, 47.10; H, 5.12; N, 16.90. Found: C, 47.00; H, 4.79; N, 16.59. FABMS m/e 307, 306 (M+), 244, 207, 190, 152, 115 (100%) ##STR130## (1S,9S) t-Butyl 6,10-dioxo-octahydro-9-(3-phenylpropionylamino)-6H-pyridazino [1,2-a] [1,2]diazepine-1-carboxylate (44a). To a solution of (1S,9S)t-butyl 9-amino-6,10-dioxo-octahydro-6H-pyridazino [1,2-a][1,2]diazepine-1-carboxylate (690 mg; 2.32 mmol; GB 2128984) in dioxane (16 ml) and water (4 ml) at 0° C. was added solid sodium bicarbonate (292 mg; 3.48 mmol) followed by dropwise addition of 3-phenylpropionyl chloride (470 mg; 2.78 mmol). The mixture was stirred at room temperature for 2 h then more sodium bicarbonate (200 mg; 2.38 mmol) and 3-phenylpropionyl chloride (100 mg; 0.6 mmol) was added. The mixture was stirred for a further 2 h at room temperature, diluted with ethyl acetate (50 ml), washed with saturated sodium bicarbonate (2×25 ml) then dried (MgSO4) and concentrated. The residue was purified by flash chromatography (0-50% ethyl acetate/chloroform) and finally crystallized by trituration with ether to afford 860 mg (86%) of a white solid: mp. 137-138° C.; [α]D23 -95.1° (c 0.549, CH2Cl2); IR (KBr) 3327, 1736, 1677, 1664, 1536, 1422, 1156; 1H NMR (CDCl3) δ 7.24 (5H, m), 6.50 (1H, d, J=7.5), 5.24 (1H, m), 4.90 (1H, m), 4.60 (1H, m), 3.44 (IR, m), 2.93 (2H, m), 2.84 (1H, m), 2.64 (1H, m), 2.54 (2H, m), 2.26 (2H, m), 1.70 (4H, m), 1.70 (9H, s). MS(FAB, m/z): 430 (M+ +1), 374, 242, 105, 91.