Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][S:10](=[O:13])(=[O:12])[OH:11])=[C:5]([O:14][CH3:15])[CH:4]=1)#[N:2].C(=O)([O-])[O-].[Na+:20].[Na+]>O>[Na+:20].[C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][S:10](=[O:11])(=[O:12])[O-:13])=[C:5]([O:14][CH3:15])[CH:4]=1)#[N:2]
Reactant: COc1cc(C#N)ccc1NS(=O)(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: COc1cc(C#N)ccc1NS(=O)(=O)[O-]

Procedure:
To a soultion of N-(4-cyano-2-methoxyphenyl)-sulfamic acid (1 mmol) in water (1 mL) at 0° will be added sodium carbonate (1.5 mmol). The reaction is concentrated and the crude material may be purified by recrystalization to give N-(4-cyano-2-methoxyphenyl)-sulfamic acid sodium salt.
Reaction SMILES: [C:1]1([C:11]2([OH:17])[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.[C:18](OC(=O)C)(=O)[CH3:19].[H-].[H-].[H-].[H-].[Li+].[Al+3].[OH-].[Na+]>C(Cl)(Cl)Cl.C1COCC1.C1C=CC=CC=1.N1C=CC=CC=1>[CH2:18]([N:14]1[CH2:13][CH2:12][C:11]([C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][N:2]=2)([OH:17])[CH2:16][CH2:15]1)[CH3:19]
Reactant: OC1(c2nccc3ccccc23)CCNCC1
Reactant: CC(=O)OC(C)=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: c1ccccc1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCN1CCC(O)(c2nccc3ccccc23)CC1

Procedure:
A mixture of 2.28 g. of 4-(1-isoquinolyl)-piperidin-4-ol, 1 ml. of pyridine, 1 ml. of acetic anhydride and 20 ml. of benzene is stirred for 3 hours at 25°. The crude 1-acetyl-4-(1-isoquinolyl)-piperidin-4-ol obtained after the customary work up is heated under reflux with 0.7 g. of LiAlH4 in 40 ml. of THF for 24 hours, under nitrogen. The mixture is worked up with sodium hydroxide solution and chloroform in the customary manner to give 1-ethyl-4-(1-isoquinolyl)-piperidin-4-ol, m.p. 275°-276°.
Reaction SMILES: [C:1]([N:4]([C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH3:23])=[CH:18][C:17]=2[O:24]CC2C=CC=CC=2)=[C:11]([F:32])[CH:10]=1)[CH2:5][CH2:6][CH2:7][NH2:8])(=[O:3])[CH3:2].O1CCCC1>CO>[C:1]([N:4]([C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH3:23])=[CH:18][C:17]=2[OH:24])=[C:11]([F:32])[CH:10]=1)[CH2:5][CH2:6][CH2:7][NH2:8])(=[O:3])[CH3:2]
Reactant: CCc1ccc(Oc2ccc(N(CCCN)C(C)=O)cc2F)c(OCc2ccccc2)c1
Solvent: C1CCOC1
Solvent: CO
Product: CCc1ccc(Oc2ccc(N(CCCN)C(C)=O)cc2F)c(O)c1
Yield: 90.2 %

Procedure:
According to the procedure of example 20 (b) except substituting 4-ethyl-2-methoxy-1-[4-nitro-2-(trifluoromethyl) phenoxy]benzene for N-acetyl-N1-[4-(2-Benzyloxy-4-ethylphenoxy)-3-fluorophenyl]propan-1,3-diamine (70 mg, 0.16 mmol) and tetrahydrofurane for methanol (15 mL), the title compound (50 mg, 91%) was obtained as a brown liquid, after purification on silica gel (dichloromethane/ethyl acetate: 5/5)
Reaction SMILES: Cl.[NH2:2][C:3]1[C:4]2[C:14]([O:15][CH2:16][C@H:17]3[CH2:22][CH2:21][CH2:20][NH:19][CH2:18]3)=[CH:13][CH:12]=[CH:11][C:5]=2[NH:6][S:7](=[O:10])(=[O:9])[N:8]=1.[N:23]1[CH:28]=[CH:27][CH:26]=[N:25][C:24]=1[CH2:29][C:30](O)=[O:31]>>[NH2:2][C:3]1[C:4]2[C:14]([O:15][CH2:16][C@H:17]3[CH2:22][CH2:21][CH2:20][N:19]([C:30](=[O:31])[CH2:29][C:24]4[N:25]=[CH:26][CH:27]=[CH:28][N:23]=4)[CH2:18]3)=[CH:13][CH:12]=[CH:11][C:5]=2[NH:6][S:7](=[O:9])(=[O:10])[N:8]=1
Reactant: O=C(O)Cc1ncccn1
Reactant: NC1=NS(=O)(=O)Nc2cccc(OC[C@H]3CCCNC3)c21
Agent: Cl
Product: NC1=NS(=O)(=O)Nc2cccc(OC[C@H]3CCCN(C(=O)Cc4ncccn4)C3)c21

Procedure:
Prepared as in Example 2 from (S)-5-(piperidin-3-ylmethoxy)-1H-benzo[c][1,2,6]thiadiazin-4-amine-2,2-dioxide hydrochloride (Example 2a) and 2-(pyrimidin-2-yl)acetic acid (Example 31a) (10% yield). 1H NMR (400 MHz, DMSO-d6) δ 1.31-1.47 (m, 2H), 1.57-1.76 (m, 1H), 1.85 (m, 1H), 2.00 (d, 1H, J=7.9 Hz), 2.03-2.25 (m, 1H), 3.00 (m, 1H), 3.69-4.22 (m, 6H), 6.56 (m, 1H), 6.65 (m, 1H), 7.32 (t, 1H, J=4.9 Hz), 7.39 (t, 1H, J=4.9 Hz), 7.53-7.84 (m, 2H), 8.70 (d, 1H, J=4.9 Hz), 8.76 (d, 1H, J=4.9 Hz), 10.98 (br s, 1H). MS 431 (MH+).
Reaction SMILES: C(=O)([O-])[O-:2].[Cs+].[Cs+].[CH3:7][O:8][C:9]1[C@@:10]2([CH2:30][CH:31]=[C:32]([CH3:34])[CH3:33])[CH2:16][CH:14]3[O:15][C@@:11]2([O:28][CH3:29])[C@H:12]([CH2:26][CH:27]=1)[C@@:13]3([CH2:18][CH2:19][CH2:20][C:21]([O:24][CH3:25])([CH3:23])[CH3:22])[CH3:17].CCCCCCCCC.C(OO)(C)(C)C.O=O.FC(F)(F)C(OC1C(OC(=O)C(F)(F)F)=C(I)C=CC=1)=O>CCOC(C)=O.CCCCCC>[CH3:7][O:8][C:9]1[C@@:10]2([CH2:30][CH:31]=[C:32]([CH3:34])[CH3:33])[CH2:16][CH:14]3[O:15][C@@:11]2([O:28][CH3:29])[C@H:12]([C:26](=[O:2])[CH:27]=1)[C@@:13]3([CH2:18][CH2:19][CH2:20][C:21]([O:24][CH3:25])([CH3:22])[CH3:23])[CH3:17]
Reactant: O=C([O-])[O-]
Reactant: COC1=CC[C@H]2[C@]3(OC)OC(C[C@]13CC=C(C)C)[C@@]2(C)CCCC(C)(C)OC
Agent: CC(C)(C)OO
Agent: O=C(Oc1cccc(I)c1OC(=O)C(F)(F)F)C(F)(F)F
Agent: O=O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CCCCCCCCC
Product: COC1=CC(=O)[C@H]2[C@]3(OC)OC(C[C@]13CC=C(C)C)[C@@]2(C)CCCC(C)(C)OC
Temperature: -78 °C
Reaction time: 2 h
Yield: 29.1 %

Procedure:
An EtOAc (30 mL, sparged for 30 min with O2 directly prior to the reaction) slurry of cesium carbonate (12.76 g, 36.2 mmol, 4 equiv.), 31 (3.55 g, 9.04 mmol, 1 equiv.), and a nonane solution of tert-butyl hydroperoxide (5.5 M, 6.6 mL, 36 mmol, 4 equiv.) was cooled to −78° C. in a 3-neck 300-mL round-bottom flask with O2 bubbling through the slurry via glass pipette. An EtOAc (25 mL) solution of bis(trifluoroacetoxy)iodobenzene (11.67 g, 27.1 mmol, 3 equiv.) was added dropwise over 30 min, following by an EtOAc (5 mL) rinse of the flask that contained the bis(trifluoroacetoxy)iodobenzene. The slurry was stirred at −78° C. for 2 h and subsequently slowly warmed to 0° C. over 2.25 h. The resulting pink slurry was subsequently quenched at 0° C. with saturated aqueous Na2S2O3, O2 bubbling was suspended, and the resulting yellow mixture was stirred vigorously at room temperature for 45 min. The mixture was then extracted thrice with EtOAc. The organic extracts were combined, washed with H2O and brine, dried over Na2SO4, filtered, and concentrated in vacuo to a yellow oil. Flash column chromatography (300 mL SiO2, 7:3 hexane:EtOAc) afforded 1.07 g (2.63 mmol, 29% yield) of 32 as a viscous yellow syrup. TLC Rf 0.18 (1:1 hexane:EtOAc). 1H NMR (600 MHz; CDCl3): δ 5.33 (s, 1H), 5.29 (t, J=7.2 Hz, 1H), 3.90 (d, J=5.7 Hz, 1H), 3.70 (s, 3H), 3.46 (s, 3H), 3.12 (s, 3H), 2.67 (s, 1H), 2.41 (dd, J=15.0, 6.1 Hz, 1H), 2.34 (dd, J=14.9, 8.0 Hz, 1H), 2.00 (d, J=13.0 Hz, 1H), 1.93 (dd, J=13.1, 5.7 Hz, 1H), 1.69 (s, 3H), 1.62 (s, 3H), 1.39-1.29 (m, 4H), 1.26 (s, 3H), 1.23-1.11 (m, 2H), 1.09 (s, 6H). 13C NMR (126 MHz; CDCl3): δ 198.0, 181.3, 133.0, 122.1, 115.4, 100.8, 80.7, 74.5, 56.7, 56.4, 52.2, 49.3, 48.6, 48.1, 40.9, 38.8, 34.6, 32.1, 28.0, 26.3, 25.3, 25.0, 18.2, 17.9.
Reaction SMILES: C([Li])CCC.CCCCCC.Br[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19].[CH2:20]([N:27]1[CH2:32][CH2:31][C:30](=[O:33])[CH2:29][CH2:28]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[Cl-].[NH4+].C(=O)([O-])O.[Na+]>O1CCCC1>[CH2:20]([N:27]1[CH2:32][CH2:31][C:30]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:19])([OH:33])[CH2:29][CH2:28]1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: Cc1ccccc1Br
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1ccccc1C1(O)CCN(Cc2ccccc2)CC1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
In a nitrogen atmosphere, 75 mL of 1.50 M n-butyllithium/hexane solution was dropwise added to tetrahydrofuran (100 mL) solution of 12 mL of 2-bromotoluene at −78° C., and stirred at −78° C. for 30 minutes. Tetrahydrofuran (50 mL) solution of 18.5 mL of 1-benzyl-4-piperidone was dropwise added to the reaction liquid, and stirred at room temperature for 4 hours. Aqueous saturated ammonium chloride solution and aqueous saturated sodium hydrogencarbonate solution were added in that order to the reaction liquid, extracted with ether, and the ether layer was washed with saturated saline water and dried with anhydrous sodium sulfate. The solvent was evaporated off under reduced pressure to obtain crude 1-benzyl-4-o-tolylpiperidin-4-ol as a yellow oily substance.
Reaction SMILES: [ClH:1].[CH2:2]([C:4]1[CH:13]=[C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]3[N:29]=[N:30][N:31](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:32]=3)=[CH:18][CH:17]=2)[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:52][CH2:53][CH2:54][OH:55])[N:10]=2)[N:5]=1)[CH3:3]>C(O)C>[ClH:1].[CH2:2]([C:4]1[CH:13]=[C:12]([O:14][CH2:15][C:16]2[CH:17]=[CH:18][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]3[NH:32][N:31]=[N:30][N:29]=3)=[CH:20][CH:21]=2)[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:52][CH2:53][CH2:54][OH:55])[N:10]=2)[N:5]=1)[CH3:3]
Reactant: CCc1cc(OCc2ccc(-c3ccccc3-c3nnn(C(c4ccccc4)(c4ccccc4)c4ccccc4)n3)cc2)c2nc(OCCO)ccc2n1
Agent: Cl
Solvent: CCO
Product: CCc1cc(OCc2ccc(-c3ccccc3-c3nnn[nH]3)cc2)c2nc(OCCO)ccc2n1
Reaction time: 1 h

Procedure:
Concentrated hydrochloric acid (20 ml) was added to a hot suspension of 2-ethyl-6-(2-hydroxyethoxy)-4-[(2 '-(2-triphenylmethyl2H-tetrazol-5-yl)biphenyl-4-yl)methoxy]-1,5-naphthyridine (A) (6.3 g) in ethanol (60 ml). The resulting solution was allowed to cool and left to stand for 1 hour. Volatile material was removed by evaporation and the residue was triturated with ethanol to give 2-ethyl-6-(2-hydroxyethoxy)-4-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methoxy]-1,5-naphthyridine hydrochloride (3.8 g), as a white powder, m.p. 180°-181° C.; NMR (d6 -DMSO): 1.4(t,3H), 3.2(q,2H), 3.85(t,2H), 4.5(t,2H), 5.65(s,2H), 7.2(d,2H), 7.5-7.8 (complex m,8H), 8.6(d,1H); 13C NMR: (benzylic CH2) 71.5; mass spectrum (+ve FAB, DMSO/m-nitrobenzyl alcohol (NBA)): 469 (M+H)+ ; microanalysis, found: C, 61.2; H,4.9; N,16.2; H2O, 0.6%; C26H24N6O3.HCl.0.25H2O requires: C,61.3; H,5.0; N,16.5; H2O, 0.9%.
Reaction SMILES: Br[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][NH:6]2.[NH2:11][CH:12]([C:14]1[N:15]=[C:16]([C:31]#[N:32])[C:17]2[C:22]([C:23]=1[C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=1)=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH3:13].C(N(CC)C(C)C)(C)C>C(O)C>[F:30][C:26]1[CH:25]=[C:24]([C:23]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]([C:31]#[N:32])=[N:15][C:14]=2[CH:12]([NH:11][C:2]2[N:10]=[CH:9][N:8]=[C:7]3[C:3]=2[N:4]=[CH:5][NH:6]3)[CH3:13])[CH:29]=[CH:28][CH:27]=1
Reactant: CC(N)c1nc(C#N)c2ccccc2c1-c1cccc(F)c1
Reactant: Brc1ncnc2[nH]cnc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CC(Nc1ncnc2[nH]cnc12)c1nc(C#N)c2ccccc2c1-c1cccc(F)c1
Temperature: 90 °C

Procedure:
A mixture of 6-bromo-9H-purine (5.48 mg, 0.0275 mmol), 3-(1-aminoethyl)-4-(3-fluorophenyl)isoquinoline-1-carbonitrile (4 mg, 0.01 mmol), and N,N-diisopropylethylamine (0.00480 mL, 0.0276 mmol) in ethanol (0.05 mL) was heated at 90° C. under nitrogen overnight. The mixture was evaporated and the resulting mixture was purified on a RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile in water with 0.2% ammonium hydroxide, at a flow rate of 30 mL/min) to give the desired product. LCMS calculated for C23H17FN7 (M+H)+: m/z=410.2; Found: 410.1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:35]2[CH:39]=[N:38][N:37]=[N:36]2)=[C:6](/[CH:8]=[CH:9]/[C:10]([NH:12][C@@H:13]([CH2:30][C:31]([O:33][CH3:34])=[O:32])[C:14]([NH:16][C:17]2[CH:29]=[CH:28][C:20]([C:21]([O:23]C(C)(C)C)=[O:22])=[CH:19][CH:18]=2)=[O:15])=[O:11])[CH:7]=1.ClC1C=CC(N2C=NN=N2)=C(/C=C/C(O)=O)C=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CO.CCOC(C)=O.[Pd]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:35]2[CH:39]=[N:38][N:37]=[N:36]2)=[C:6](/[CH:8]=[CH:9]/[C:10]([NH:12][C@@H:13]([CH2:30][C:31]([O:33][CH3:34])=[O:32])[C:14]([NH:16][C:17]2[CH:29]=[CH:28][C:20]([C:21]([OH:23])=[O:22])=[CH:19][CH:18]=2)=[O:15])=[O:11])[CH:7]=1
Reactant: COC(=O)C[C@H](NC(=O)/C=C/c1cc(Cl)ccc1-n1cnnn1)C(=O)Nc1ccc(C(=O)OC(C)(C)C)cc1
Agent: [Pd]
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)C[C@H](NC(=O)/C=C/c1cc(Cl)ccc1-n1cnnn1)C(=O)Nc1ccc(C(=O)O)cc1
Reaction time: 12 h

Procedure:
(S,E)-tert-butyl 4-(2-(3-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)acrylamido)-4-methoxy-4-oxobutanamido)benzoate: 44BA was dissolved in MeOH (50 mL), treated with 5% Pd/C, and placed under hydrogen atmosphere (50 psi). After 12 h, the mixture was filtered through a plug of Celite® and the filter-cake was rinsed several times with MeOH. The combined filtrate was concentrated. The resulting oil was dissolved in THF (50 mL) and then (E)-3-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)acrylic acid (0.89 g, 3.56 mmol), BOP (1.57 g, 3.56 mmol), and TEA (1.48 mL, 10.67 mmol) were added at 25° C. with stirring. After 2 h, the reaction mixture was diluted with EtOAc, washed with water and then brine, dried over sodium sulfate, filtered, and concentrated. Purification by flash chromatography (40 g column; (100% hexane/0% EtOAC to 0% hexane over 30 min) afforded 44BB (1.8 g, 55%) as a white solid. LCMS m/z 555 [M+H]+.
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([CH:18]([O:21][Si](C)(C)C)[C:19]#N)=[CH:14][CH:13]=1.[Cl:26][C:27]1[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:28]=1CCl.Cl.[OH-].[K+]>C1COCC1>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([C:18](=[O:21])[CH2:19][C:30]2[CH:29]=[CH:28][C:27]([Cl:26])=[CH:32][C:31]=2[Cl:33])=[CH:14][CH:13]=1
Reactant: C[Si](C)(C)OC(C#N)c1ccc(Cl)cc1
Reactant: ClCc1ccc(Cl)cc1Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Product: O=C(Cc1ccc(Cl)cc1Cl)c1ccc(Cl)cc1
Reaction time: 1 h

Procedure:
32 g of LiHMDS are placed in 245 ml of THF at 0° C., and 40 g of (4-chlorophenyl) ((trimethylsilyl)oxy)acetonitrile are added slowly at −78° C., followed by 32.64 g of 2,4-dichloro-1-(chloromethyl)benzene. The temperature is allowed to return to AT overnight, and the reaction is then hydrolyzed with 170 ml of a 3N HCl solution, with gases being trapped in a solution of KOH (4N). After separation by settling out, the organic phase is evaporated, then taken up in DCM and agitated for 1 hour with 170 ml of NaOH (2N). The DCM is evaporated off and the expected compound is then crystallized from pentane. 38.6 g are obtained, Mp=119° C.
Reaction SMILES: [Br-].[CH2:2]([N+:4]1([CH2:17][CH3:18])[CH2:12][C:11]2[CH:10]=[C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]3=[CH:7][C:6]=2[CH2:5]1)[CH3:3].[NH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>>[CH2:2]([N:4]([CH2:5][C:6]1[C:11]([CH2:12][N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)=[CH:10][C:9]2[C:8](=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:7]=1)[CH2:17][CH3:18])[CH3:3]
Reactant: CC[N+]1(CC)Cc2cc3ccccc3cc2C1
Reactant: C1COCCN1
Agent: [Br-]
Product: CCN(CC)Cc1cc2ccccc2cc1CN1CCOCC1

Procedure:
2,2-Diethylbenz[f]isoindolinium bromide (13 g) was refluxed with morpholine (150 ml) for 30 hr. Morpholine was evaporated and the residue was partitioned between sodium hydroxide solution and ether; the ether layer was evaporated to dryness and the residue purified by chromatography [eluent, diethylamine:cyclohexane = 1:4, silica (250 g)] and distillation to give 2-diethylaminomethyl-3-morpholinomethylnaphthalene, b.p. 160°/0.015 mm.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][CH:3]=1.Br[CH2:12][C:13](=O)[C:14]([O:16][CH2:17][CH3:18])=[O:15].C(=O)([O-])O.[Na+]>O1CCCC1>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]2[O:7][CH:12]=[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[N:8]=2)=[CH:4][CH:3]=1
Reactant: NC(=O)c1ccc(F)cc1
Reactant: CCOC(=O)C(=O)CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1coc(-c2ccc(F)cc2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of p-fluorobenzamide (5 g), ethyl bromopyruvate (9.92 ml), and sodium hydrogen carbonate (15 g) in tetrahydrofuran (150 ml) was refluxed for 20 hours. After cooling the reaction mixture, insoluble material was removed by filtration through Cellite and the filtrate was concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (30 ml) and trifluoroacetic anhydride (30 ml) was added to the mixture in an ice bath. After stirring at room temperature for one hour, a saturated aqueous sodium hydrogen carbonate solution was added to the mixture in an ice bath, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography (solvent: ethyl acetate n-hexane=1:9) to obtain ethyl 2-(4-fluorophenyl)oxazol-4-carboxylate (7.44 g) as colorless solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([OH:16])[CH2:13][CH:12]3[C@H:14]([OH:15])[CH:9]2[CH2:10][CH2:11]3)=[CH:4][CH:3]=1.[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1.C(=O)(O)[O-].[Na+]>N1C=CC=CC=1>[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23]([O:15][C@H:14]2[CH:12]3[CH2:11][CH2:10][CH:9]2[C@@:8]([OH:16])([C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=2)[CH2:13]3)(=[O:25])=[O:24])=[CH:19][CH:18]=1
Reactant: Cc1ccc([C@@]2(O)CC3CCC2[C@H]3O)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: Cc1ccc([C@@]2(O)CC3CCC2[C@H]3OS(=O)(=O)c2ccc(C)cc2)cc1
Reaction time: 36 h

Procedure:
A 50 mL round-bottomed flask, equipped with a drying tube, was charged with dry pyridine (5 mL), [2R*,7S*]-2-(4-methylphenyl)bicyclo[2.2.1]-heptane-2,7-diol (0.8 g, 3.7 mmole, prepared as in Part C above) and p-toluenesulfonyl chloride (0.74 g, 3.88 mmole), and the resultant reaction mixture allowed to stand for 36 hours at ambient temperature. Saturated sodium bicarbonate solution (25 mL) was then added, and the resultant mixture extracted twice with 25 mL aliquots of diethyl ether. The ether extracts were combined, washed with distilled water and dried over anhydrous sodium sulfate, then the ether was removed on a rotary evaporator. The pale yellow solid residue thus produced was purified by flash column chromatography on silica gel using a 1:1 v/v diethyl ether/hexane mixture as eluant, then recrystallized from diethyl ether/pentane to give the desired product as a white crystalline solid, yield 1.0 g, 74% based upon the diol starting material. This product decomposed at 68° C. before melting. The product was characterized as follows:
Reaction SMILES: [CH:1]([O-])=[O:2].[Na+].C(Cl)(=O)C(C)(C)C.[S:12]1[CH:16]=[CH:15][C:14]2[CH:17]=[C:18]([CH2:21][CH2:22][O:23][CH2:24][CH2:25][NH:26][CH:27]([CH3:30])[CH2:28][OH:29])[CH:19]=[CH:20][C:13]1=2.[OH-].[Na+]>CC(C)=O.C(OCC)(=O)C.O>[S:12]1[CH:16]=[CH:15][C:14]2[CH:17]=[C:18]([CH2:21][CH2:22][O:23][CH2:24][CH2:25][N:26]([CH:27]([CH3:30])[CH2:28][OH:29])[CH:1]=[O:2])[CH:19]=[CH:20][C:13]1=2
Reactant: O=C[O-]
Reactant: CC(CO)NCCOCCc1ccc2sccc2c1
Agent: CC(C)(C)C(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: CC(CO)N(C=O)CCOCCc1ccc2sccc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.6 %

Procedure:
In 2.4 mL of acetone is suspended 0.38 g of sodium formate, to which is added 0.37 mL of pivaloyl chloride. The mixture is stirred at ambient temperature for 2 hours. Then, at an ice-cooled temperature, 4 mL of a solution of 0.50 g of 2-{[2-(2-benzo[b]thiophen-5-ylethoxy)ethyl]-amino}-1-propanol in acetone is added, and the resulting mixture is stirred at ambient temperature for 2 hours. Water and ethyl acetate are added to the reaction mixture, pH is adjusted to 8.5 with 2 mol/L aqueous solution of sodium hydroxide, and the organic layer is separated. The organic layer is washed with saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, the solvent is distilled off under reduced pressure, and the residue is purified by column chromatography (eluent: chloroform). Thus, 0.46 g of N-[2-(2-benzo[b]thiophen-5-ylethoxy)ethyl]-N-(2-hydroxy-1-methylethyl)-formamide (is obtained as an oily product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:25])([CH2:19][N:20]1[CH:24]=[N:23][CH:22]=[N:21]1)[CH:10]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)[OH:11].C(N(CC)CC)C.C(Cl)(=O)[C:34](Cl)=[O:35].C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1([CH2:19][N:20]2[CH:24]=[N:23][CH:22]=[N:21]2)[CH:10]([C:12]2[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=2)[O:11][C:34](=[O:35])[O:25]1
Reactant: O=C(Cl)C(=O)Cl
Reactant: OC(c1ccc(F)cc1)C(O)(Cn1cncn1)c1ccc(Cl)cc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=C1OC(c2ccc(F)cc2)C(Cn2cncn2)(c2ccc(Cl)cc2Cl)O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 51.3 %

Procedure:
To a solution of 400 mg of 2-(2,4-dichlorophenyl)-1-(4-fluorophenyl)-3-(1H-1,2,4-triazol-1-yl)-1,2-propanediol and 430 mg of triethylamine in 20 ml of dry chloroform is added a solution of 532 mg of oxalyl chloride and 2 ml of dry chloroform in small portions with ice-cooling, and the mixture is stirred at room temperature for 1 hour. The reaction mixture is mixed with ice-water and aqueous sodium bicarbonate solution and extracted with methylene chloride. The organic layer is washed with water, dried over anhydrous sodium sulfate, and concentrated. The residue is chromatographed on a column of silica-gel and eluted with benzene-ethyl acetate (1:1 v/v). The eluate is concentrated, and the resulting residue is crystallized from ethyl acetate-isopropyl ether to give 219 mg of 4-(2,4-dichlorophenyl)-5-(4-fluorophenyl)-2-oxo-4-(1H-1,2,4-triazol-1-yl)methyl-1,3-dioxolane as crystals. m.p. 190°-191° C. Yield: 51.3%
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]2[C:6]=1[CH:7]=[CH:8][C:9](=[O:16])[NH:10]2)=[O:4].[C:17]([NH2:21])([CH3:20])([CH3:19])[CH3:18]>C(O)C>[C:17]([NH:21][CH2:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]2[C:6]=1[CH:7]=[CH:8][C:9](=[O:16])[NH:10]2)=[O:4])([CH3:20])([CH3:19])[CH3:18]
Reactant: O=C(CCl)c1ccc(O)c2[nH]c(=O)ccc12
Reactant: CC(C)(C)N
Solvent: CCO
Product: CC(C)(C)NCC(=O)c1ccc(O)c2[nH]c(=O)ccc12
Yield: 44.4 %

Procedure:
8.0 g of the 5-chloroacetyl-8-hydroxycarbostyril (IV) (IV) obtained Example 4 or 8 was suspended in 100 ml of ethanol, and 10 g of tert-butylamine was added dropwise to the resulting suspension while stirring followed by stirring at 55° to 60° C. for 5 hours. After the mixture was concentrated to half the volume, concentrated hydrochloric acid was added thereto to adjust the mixture to a pH of 2 to 3. The precipitated crystals were filtered, washed with acetone and recrystallized from ethanol to obtain 4.1 g of 5-tert-butylaminoacetyl-8-hydroxycarbostyril (II) having a melting point of 291° - 293° C. (with decomposition) as pale yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([CH2:30][C:31](O)=[O:32])[C:25]=1[CH3:34])(=[O:12])=[O:11].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[CH:56]1([NH:59][CH2:60][C@@H:61]2[CH2:66][CH2:65][CH2:64][NH:63][CH2:62]2)[CH2:58][CH2:57]1>CN(C=O)C>[CH:56]1([NH:59][CH2:60][C@@H:61]2[CH2:66][CH2:65][CH2:64][N:63]([C:31](=[O:32])[CH2:30][C:26]3[C:25]([CH3:34])=[C:24](/[CH:23]=[C:16]4\[C:17](=[O:22])[NH:18][C:19]5[C:15]\4=[CH:14][C:13]([S:10]([CH2:9][C:3]4[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=4[Cl:1])(=[O:11])=[O:12])=[CH:21][CH:20]=5)[NH:28][C:27]=3[CH3:29])[CH2:62]2)[CH2:58][CH2:57]1
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1CC(=O)O
Reactant: C1CNC[C@H](CNC2CC2)C1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1CC(=O)N1CCC[C@@H](CNC2CC2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.7 %

Procedure:
A mixture of {5-[5-(2,6-dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrol-3-yl}-acetic acid (200 mg, 0.38 mmol), HOBt (52 mg), EDAC (130 mg), cyclopropyl-(R)-1-piperidin-3-ylmethyl-amine (103 mg) and TEA (7 drops) in DMF (2 mL) was stirred at rt for overnight. The reaction was concentrated and purified on a silica gel column to give 89 mg of the titled compound.