Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2=[CH:15][N:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=3)[N:17]=[C:11]2[CH2:10][CH2:9]1)=[O:7])([CH3:4])[CH3:3].O=C(N1C=CN=C1)[N:29]1C=CN=C1.N>ClCCl.O>[NH2:29][C:22]([C:21]1[CH:20]=[CH:19][C:18]([N:16]2[CH:15]=[C:12]3[C:11]([CH2:10][CH2:9][N:8]([C:6]([O:5][C:2]([CH3:3])([CH3:1])[CH3:4])=[O:7])[CH2:14][CH2:13]3)=[N:17]2)=[CH:26][CH:25]=1)=[O:23]
Reactant: CC(C)(C)OC(=O)N1CCc2cn(-c3ccc(C(=O)O)cc3)nc2CC1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: N
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N1CCc2cn(-c3ccc(C(N)=O)cc3)nc2CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 4-[6-{[(1,1-dimethylethyl)oxy]carbonyl}-5,6,7,8-tetrahydropyrazolo[3,4-d]azepin-2(4H)-yl]benzoic acid (may be prepared as described in Description 23) (185 mg, 0.52 mmol) in dichloromethane (10 ml) was added 1,1′-(oxomethanediyl)bis-1H-imidazole (168 mg, 1.04 mmol) and the reaction stirred at room temperature, under argon, overnight. Ammonia (0.88M, 35 mg, 2.07 mmol) was added and stirring continued, under argon, at room temperature for 4 hours. The resulting crude mixture was diluted with water, and extracted with dichloromethane (×2). The combined organic fractions were washed with water (×1), dried over magnesium sulphate and solvent evaporated in vacuo to afford the title compound (D36). MS (ES+) m/e 301 [M-tBu]+.
Reaction SMILES: [C:1]1([S:7][C:8]2[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:16]([O:18][C:19](=[O:35])/[CH:20]=C/C1C=CC(CC2C=CC=CC=2)=CC=1)[CH3:17]>>[C:1]1([S:7][C:8]2[CH:15]=[CH:14][C:11](/[CH:12]=[CH:20]/[C:19]([O:18][CH2:16][CH3:17])=[O:35])=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)/C=C/c1ccc(Cc2ccccc2)cc1
Reactant: O=Cc1ccc(Sc2ccccc2)cc1
Product: CCOC(=O)/C=C/c1ccc(Sc2ccccc2)cc1

Procedure:
The title compound was prepared from 4-(phenylthio)benzaldehyde (S41) and triethylphosphonoacetate using the procedure described for ethyl-(E)-3-(4-benzylphenyl)acrylate (S38). Column chromatography (SiO2, 4×8 cm, 10% EtOAc-hexanes) afforded S42 (1.55 g, 5.5 mmol, 84%) as a yellow oil: 1H NMR (CDCl3, 400 MHz) 9.91 (s, 1H), 7.62 (d, 1H, J=15.8 Hz), 7.46-7.21 (m, 9H), 6.38 (d, 1H, J=15.8 Hz); 13C NMR (CDCl3, 100 MHz) 166.8, 143.6, 140.0, 133.4, 132.7, 132.3, 129.4, 129.1, 128.5, 128.0, 117.8, 60.4, 14.2.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:45])[NH:4][C@H:5]([C:10]([NH:12][N:13]([CH2:37][C:38]1[CH:43]=[CH:42][C:41](Br)=[CH:40][CH:39]=1)[CH2:14][C@:15]([OH:36])([C:23](=[O:35])[NH:24][C@H:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:27][C@H:26]1[OH:34])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:11])[C:6]([CH3:9])([CH3:8])[CH3:7].[N:46]1[CH:51]=[CH:50][C:49](B(O)O)=[CH:48][CH:47]=1.C([O-])([O-])=O.[Na+].[Na+].CCO>COCCOC>[CH3:1][O:2][C:3](=[O:45])[NH:4][C@H:5]([C:10]([NH:12][N:13]([CH2:14][C@:15]([OH:36])([C:23](=[O:35])[NH:24][C@H:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:27][C@H:26]1[OH:34])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:37][C:38]1[CH:43]=[CH:42][C:41]([C:49]2[CH:50]=[CH:51][N:46]=[CH:47][CH:48]=2)=[CH:40][CH:39]=1)=[O:11])[C:6]([CH3:9])([CH3:8])[CH3:7]
Reactant: COC(=O)N[C@H](C(=O)NN(Cc1ccc(Br)cc1)C[C@@](O)(Cc1ccccc1)C(=O)N[C@H]1c2ccccc2C[C@H]1O)C(C)(C)C
Reactant: OB(O)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCO
Product: COC(=O)N[C@H](C(=O)NN(Cc1ccc(-c2ccncc2)cc1)C[C@@](O)(Cc1ccccc1)C(=O)N[C@H]1c2ccccc2C[C@H]1O)C(C)(C)C

Procedure:
The title compound was prepared according to Method B, using compound 19 (90.0 mg, 0.132 mmol), pyridine-4-boronic acid (81.0 mg, 0.659 mmol), Pd(PPh)3Cl2 (4.60 mg, 0.0065 mmol), 2 M Na2CO3 (aq., 0.198 mL, 0.396 mmol), EtOH (0.4 mL) and DME (1.6 mL). Purification by RP-LC-MS (40 min gradient of 0-80% CH3CN in 0.05% aqueous formic acid) yielded the product (15.6 mg, 17%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[C:12]([Br:17])[CH:11]=2)[CH:6]([CH2:7][OH:8])[CH2:5][CH:4]([OH:9])[CH2:3]1.[C:18]([N:26]=[C:27]=[S:28])(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1COCC1>[Br:17][C:12]1[CH:11]=[C:10]([C:2]2([NH:1][C:27]([NH:26][C:18](=[O:25])[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[S:28])[CH2:3][CH:4]([OH:9])[CH2:5][CH:6]2[CH2:7][OH:8])[CH:15]=[CH:14][C:13]=1[F:16]
Reactant: NC1(c2ccc(F)c(Br)c2)CC(O)CC1CO
Reactant: O=C(N=C=S)c1ccccc1
Solvent: C1CCOC1
Product: O=C(NC(=S)NC1(c2ccc(F)c(Br)c2)CC(O)CC1CO)c1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of racemic (1RS,3SR,4RS)-3-amino-3-(3-bromo-4-fluorophenyl)-4-(hydroxymethyl)cyclopentanol (0.48 g, 1.58 mmol) in THF (6.31 mL) is added benzoyl isothiocyanate (0.263 g, 1.58 mmol) and the mixture is stirred at room temperature for 1.5 h. The solvent is removed under reduced pressure and the crude product is purified by silica gel chromatography, eluting with a linear gradient of 0% to 10% methanol in dichloromethane over 20 minutes to give the title compound as racemic mixture (0.602 g, 76%). ES/MS m/e (79Br/81Br) 467, 469 (M+1).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([NH:15][CH:16]2[CH2:27][CH2:26][C:19]3([N:23]=[C:22]([CH3:24])[NH:21][C:20]3=[O:25])[CH2:18][CH2:17]2)(=[O:14])=[O:13])=[CH:8][C:7]=1[CH3:28])[CH3:4].Br[CH:30]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH3:31]>CN(C=O)C.C(=O)(O)[O-].[Na+]>[CH2:3]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([NH:15][CH:16]2[CH2:17][CH2:18][C:19]3([N:23]=[C:22]([CH3:24])[N:21]([CH:30]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[CH3:31])[C:20]3=[O:25])[CH2:26][CH2:27]2)(=[O:13])=[O:14])=[CH:8][C:7]=1[CH3:28])[CH3:4]
Reactant: CCOc1ccc(S(=O)(=O)NC2CCC3(CC2)N=C(C)NC3=O)cc1C
Reactant: CC(Br)c1ccccc1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOc1ccc(S(=O)(=O)NC2CCC3(CC2)N=C(C)N(C(C)c2ccccc2)C3=O)cc1C
Reaction time: 0.08 h
Yield: 55 %

Procedure:
Sodium hydride (4.74 mg, 0.119 mmol) was added at room temperature to 4-ethoxy-3-methyl-N-(2-methyl-4-oxo-1,3-diazaspiro[4.5]dec-1-en-8-yl)benzenesulfonamide (Example 471, 30 mg, 0.079 mmol) in DMF (988 μl). The reaction was stirred five minutes then a solution of (1-bromoethyl)benzene (16.18 μl, 0.119 mmol) in 200 ul DMF was added and the reaction stirred overnight at room temperature. After 16 hours, LCMS and HPLC indicated approximately 4:1 product:smarting material. The reaction was diluted with saturated sodium bicarbonate and extracted with multiple volumes ethyl acetate. The combined organics were rinsed 1× brine and dried over sodium sulfate. TLC (ethyl acetate) gave a product Rf 0.38 and starting material on the baseline. The crude was chromatographed on Biotage 12S by manual step gradient 7-100% EtOAc/heptane to yield the product as an off-white solid (21 mg). LCMS [M+H]=484.2.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[CH:9][C:10]([C:14]3[N:18]4[CH:19]=[C:20]([C@@H:23]([N:28]5[CH2:32][CH2:31][C@H:30]([NH:33]C(=O)OC(C)(C)C)[CH2:29]5)[C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:22][C:17]4=[N:16][N:15]=3)=[N:11]2)=[CH:6][C:5]=1[F:41])[CH3:2]>C(O)(C(F)(F)F)=O>[CH2:1]([O:3][C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[CH:9][C:10]([C:14]3[N:18]4[CH:19]=[C:20]([C@@H:23]([N:28]5[CH2:32][CH2:31][C@H:30]([NH2:33])[CH2:29]5)[C:24]([F:26])([F:25])[F:27])[CH:21]=[CH:22][C:17]4=[N:16][N:15]=3)=[N:11]2)=[CH:6][C:5]=1[F:41])[CH3:2]
Reactant: CCOc1cc2nc(-c3nnc4ccc([C@@H](N5CC[C@H](NC(=O)OC(C)(C)C)C5)C(F)(F)F)cn34)ccc2cc1F
Solvent: O=C(O)C(F)(F)F
Product: CCOc1cc2nc(-c3nnc4ccc([C@@H](N5CC[C@H](N)C5)C(F)(F)F)cn34)ccc2cc1F
Yield: 85 %

Procedure:
tert-butyl (S)-1-((R)-1-(3-(7-ethoxy-6-fluoro quinolin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-2,2,2-trifluoroethyl)pyrrolidin-3-ylcarbamate (265 mg, 0.461 mmol) was stirred in TFA (3 mL) for 1 hour and then concentrated. The residue was dissolved in minimum methanol and added dropwise to a 4N HCl in ether solution. The resulting solid was filtered and dried to yield (S)-1-((R)-1-(3-(7-ethoxy-6-fluoro quinolin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-2,2,2-trifluoroethyl)pyrrolidin-3-amine (186 mg, 85.0% yield) hydrochloride as an off-white solid. LCMS APCI (+) m/z 475 (M+H). Specific rotation: [α]24D=1.84° (c=1.03, MeOH).
Reaction SMILES: C(OC([N:8]1[CH2:14][C@@H:13]([CH2:15][NH:16][C:17]([C:19]2[CH:27]=[C:26]([F:28])[C:25]([F:29])=[CH:24][C:20]=2[C:21]([OH:23])=[O:22])=[O:18])[C@H:12]([C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[C:32]([Cl:37])[CH:31]=2)[O:11][CH2:10][CH2:9]1)=O)(C)(C)C.C(OCC)(=O)C.Cl>>[ClH:36].[Cl:37][C:32]1[CH:31]=[C:30]([C@@H:12]2[O:11][CH2:10][CH2:9][NH:8][CH2:14][C@H:13]2[CH2:15][NH:16][C:17]([C:19]2[CH:27]=[C:26]([F:28])[C:25]([F:29])=[CH:24][C:20]=2[C:21]([OH:23])=[O:22])=[O:18])[CH:35]=[CH:34][C:33]=1[Cl:36]
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(Cl)c2)[C@H](CNC(=O)c2cc(F)c(F)cc2C(=O)O)C1
Agent: Cl
Solvent: CCOC(C)=O
Product: O=C(O)c1cc(F)c(F)cc1C(=O)NC[C@@H]1CNCCO[C@H]1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 37.6 %

Procedure:
To 2-({[(6R,7R)-4-(tert-butoxycarbonyl)-7-(3,4-dichlorophenyl)-1,4-oxazepan-6-yl]methyl}carbamoyl)-4,5-difluorobenzoic acid (102 mg) was added 4.0 M hydrogen chloride-ethyl acetate solution (4 mL), and the mixture was stirred at room temperature for 1 hr. The residue obtained by concentration under reduced pressure was separated by HPLC (C18, mobile phase: water/acetonitrile (containing 5 mM AcONH4)), and the obtained fraction was concentrated under reduced pressure to give the title compound (17 mg).
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:30]/[O:31][C:32]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)/[C:27](O)=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:52][CH:53]1[C:79](=[O:80])[N:55]2[C:56]([C:63]([O:65][CH:66]([C:73]3[CH:78]=[CH:77][CH:76]=[CH:75][CH:74]=3)[C:67]3[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=3)=[O:64])=[C:57]([CH:60]=[CH:61][CH3:62])[CH2:58][S:59][C@H:54]12.C/C(/O[Si](C)(C)C)=N\[Si](C)(C)C>ClCCl>[C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:30]/[O:31][C:32]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)([C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)/[C:27]([NH:52][CH:53]2[C:79](=[O:80])[N:55]3[C:56]([C:63]([O:65][CH:66]([C:67]4[CH:68]=[CH:69][CH:70]=[CH:71][CH:72]=4)[C:73]4[CH:74]=[CH:75][CH:76]=[CH:77][CH:78]=4)=[O:64])=[C:57](/[CH:60]=[CH:61]\[CH3:62])[CH2:58][S:59][C@H:54]23)=[O:28])[N:25]=1)([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C(O)/C(=N\OC(c1ccccc1)(c1ccccc1)c1ccccc1)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: CC=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(N)[C@H]2SC1
Agent: C/C(=N\[Si](C)(C)C)O[Si](C)(C)C
Agent: Cl
Solvent: ClCCl
Product: C/C=C\C1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)/C(=N\OC(c3ccccc3)(c3ccccc3)c3ccccc3)c3csc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)n3)[C@H]2SC1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a mixture of 2-(2-tritylaminothiazol-4-yl)-2-(Z)-trityloxyiminoacetic acid (873 mg, 1.30 m moles) and dichloromethane (5 ml) was added phsophorous pentachloride (297 ng, 1.43 m moles) at -5° C. The mixture was allowed to stand for 20 min at the same temperature and added dropwise to a solution of diphenylmethyl 7-amino-3-(1-propenyl)-3-cephem-4-carboxylate hydrochloride (443 mg, 1 m mole) and N,O-bis(trimethylsilyl)acetamide (0.74 ml, 4.4 m moles) in dichloromethane (5 ml) at -5° C. The reaction mixture was allowed to stand for 20 min. at the same temperature and poured into ice-water. Extraction of the mixture with ethyl acetate and evaporation of the extracts under reduced pressure gave the crude product as an oil, which was chromatographed on a column of silica gel (eluted with chloroform) to give the title compound as an amorphous powder. Yield 510 mg (48%).
Reaction SMILES: [CH3:1][N:2]([CH3:35])[CH2:3][CH2:4][NH:5][C:6]1[C:7]([F:34])=[CH:8][C:9]2[N:13]=[C:12]([C:14]3[C:18]([NH:19][C:20](=[O:26])[N:21]([CH2:24][CH3:25])[CH2:22][CH3:23])=[CH:17][N:16](C4CCCCO4)[N:15]=3)[NH:11][C:10]=2[CH:33]=1>ClCCl.FC(F)(F)C(O)=O>[CH3:35][N:2]([CH3:1])[CH2:3][CH2:4][NH:5][C:6]1[C:7]([F:34])=[CH:8][C:9]2[N:13]=[C:12]([C:14]3[C:18]([NH:19][C:20](=[O:26])[N:21]([CH2:22][CH3:23])[CH2:24][CH3:25])=[CH:17][NH:16][N:15]=3)[NH:11][C:10]=2[CH:33]=1
Reactant: CCN(CC)C(=O)Nc1cn(C2CCCCO2)nc1-c1nc2cc(F)c(NCCN(C)C)cc2[nH]1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCN(CC)C(=O)Nc1c[nH]nc1-c1nc2cc(F)c(NCCN(C)C)cc2[nH]1
Yield: 67.2 %

Procedure:
A solution of 18 mg of 3-[3-[6-(2-dimethylaminoethylamino)-5-fluoro-1H-benzimidazol-2-yl]-1-(tetrahydro-pyran-2-yl)-1H-pyrazol-4-yl]-1,1-diethylurea in 1 mL of dichloromethane and 500 μL of trifluoroacetic acid are stirred for 72 hours at ambient temperature. After evaporation of the solvent under vacuum in a rotary evaporator, the reaction crude is purified by flash chromatography on an Analogix RS-4 cartridge with an eluent of 100% dichloromethane to 90/10 dichloromethane/ammoniacal methanol. 10 mg of 3-{3-[6-(2-dimethylaminoethylamino)-5-fluoro-1H-benzimidazol-2-yl]-1H-pyrazol-4-yl}-1,1-diethylurea in the form of trifluoroacetate are isolated. 1H NMR (300 MHz, DMSO-d6, δ in ppm), after addition of a drop of TFA-d1 (CF3COOD-d1) and of a drop of acetic acid-d4-(CD3OD-d4): 1.16 (t, J=7.0 Hz, 6H); 2.87 (s, 6H); 3.38 (m, 6H); 3.51 (t, J=6.0 Hz, 2H); 6.89 (d, J=7.5 Hz, 1H); 7.44 (d, J=11.0 Hz, 1H); 7.98 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5](/[CH:6]=[CH:7]/[C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1.[CH2:13](O)[CH3:14]>S(=O)(=O)(O)O>[CH2:13]([O:9][C:8](=[O:10])/[CH:7]=[CH:6]/[C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:12][CH:11]=1)[CH3:14]
Reactant: CCO
Reactant: O=C(O)/C=C/c1ccc(Cl)cc1
Agent: O=S(=O)(O)O
Product: CCOC(=O)/C=C/c1ccc(Cl)cc1
Temperature: 70 °C

Procedure:
To a solution of trans-4-chlorocinnamic acid (10 g, 55 mmol) in ethanol (60 mL) was added a catalytic amount of concentrated sulfuric acid (2-3 drops), and the mixture was heated (70° C.) until a majority of the starting material was consumed as evidenced by LCMS. The reaction mixture was concentrated and the contents were redissolved in ethyl acetate. The organic phase was extracted with an aqueous solution of sodium bicarbonate (5%, 3×) followed by a brine wash. The organic phase was dried (MgSO4), filtered and concentrated to afford trans-4-chlorocinnamic acid ethyl ester as a colorless oil. MS (ESI) m/z 211.1 ([M+H]+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([OH:13])[CH:6]=1.[Br:15][C:16]1[CH:17]=[CH:18][C:19](F)=[C:20]([CH:23]=1)[CH:21]=[O:22]>>[CH3:1][O:2][C:3](=[O:14])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([O:13][C:19]2[CH:18]=[CH:17][C:16]([Br:15])=[CH:23][C:20]=2[CH:21]=[O:22])[CH:6]=1
Reactant: COC(=O)Cc1ccc(OC)c(O)c1
Reactant: O=Cc1cc(Br)ccc1F
Product: COC(=O)Cc1ccc(OC)c(Oc2ccc(Br)cc2C=O)c1

Procedure:
Prepared according to the procedure described in Example 7, Step 2, using the following starting materials: (3-hydroxy-4-methoxy-phenyl)-acetic acid methyl ester and 5-bromo-2-fluorobenzaldehyde.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:16])[C:11](OCC)=[O:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].[BH4-].[Na+]>C(O)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH:10]([OH:16])[CH2:11][OH:12])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CCOC(=O)C(=O)c1ccc([N+](=O)[O-])cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: O=[N+]([O-])c1ccc(C(O)CO)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 91.4 %

Procedure:
To a stirred solution of ethyl 2-(4-nitrophenyl)-2-oxoacetate (10.0 g, 47.8 mmol) in ethanol (100 mL) was slowly added sodium borohydride (4.54 g, 119.5 mmol) at 0° C. After the addition was completed, the reaction mixture was allowed to warm to RT and stirred for 12 h. The reaction was quenched by acetone (10 mL) and concentrated. The residue was purified by silica gel column chromatography (dichloromethane/methanol=5/1) to afford the title compound (8.0 g, 87%) as a brown solid. MS (ES+) C8H9NO4 requires: 183, found: 184 [M+H]+.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Br[C:6]1[CH:11]=[CH:10][N:9]=[C:8]([C:12]#[N:13])[C:7]=1[O:14][CH3:15]>CN(C)C=O>[N:1]([C:6]1[CH:11]=[CH:10][N:9]=[C:8]([C:12]#[N:13])[C:7]=1[O:14][CH3:15])=[N+:2]=[N-:3]
Reactant: COc1c(Br)ccnc1C#N
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1c(N=[N+]=[N-])ccnc1C#N

Procedure:
To 1 g (0.0155 moles) of sodium azide in 25 mL of dimethylformamide at 0° C., there is added gently 3 g (0.0141 moles) of 4-bromo-2-cyano-3-methoxypyridine from Example b), dissolved in 40 mL of dimethylformamide.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[CH2:12][CH2:11][CH2:10][C:9]2[S:13][CH:14]=[CH:15][C:8]=2[C:7]1=[O:16].[Br:17]Br.O>C(O)(=O)C>[Br:17][C:14]1[S:13][C:9]2[CH2:10][CH2:11][CH2:12][N:6]([CH2:5][CH2:4][CH2:3][CH2:2][Cl:1])[C:7](=[O:16])[C:8]=2[CH:15]=1
Reactant: O=C1c2ccsc2CCCN1CCCCCl
Reactant: BrBr
Solvent: CC(=O)O
Solvent: O
Product: O=C1c2cc(Br)sc2CCCN1CCCCCl
Temperature: 25 °C
Reaction time: 3 h
Yield: 102.1 %

Procedure:
To a solution of 3.0 g of 5-(4-chlorobutyl)-5,6,7,8-tetrahydro-4H-thieno[3,2-c]azepin-4-one in 20 ml of acetic acid was added dropwise a solution of 2.1 g of bromine in 5 ml of acetic acid for 10 minutes. After the mixture was stirred at room temperature for 3 hours, the mixture was poured into chilled water and extracted with chloroform. The extract was washed with water, dried over magnesium sulfate and then concentrated under reduced pressure to give 4.0 g of 2-bromo-5-(4-chlorobutyl)-5,6,7,8-tetrahydro-4H-thieno[3,2-c]azepin-4-one as a pale brown oil. The obtained compound was employed in the subsequent reaction without purification.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[S:18][CH3:19])[C:10]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:9]([CH3:25])[NH:8][C:7]=1[CH3:26])=[O:5])[CH3:2].ClC1C=CC=C(C(OO)=[O:35])C=1>C(Cl)Cl>[CH3:26][C:7]1[NH:8][C:9]([CH3:25])=[C:10]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[S:18]([CH3:19])=[O:35])[C:6]=1[C:4]([O:3][CH2:1][CH3:2])=[O:5]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCC)C1c1ccccc1SC
Solvent: ClCCl
Product: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCC)C1c1ccccc1S(C)=O
Yield: 96.6 %

Procedure:
A solution of 1.092 g (2.91 mm) of diethyl-2,6-dimethyl-4-(2-methylthiophenyl)-1,4-dihydropyridine-3,5-dicarboxylate 33 in 35 mL of dry CH2Cl2 was stirred at -78° C. under Ar and treated with 650 mg (3.20 mm) of m-chloroperbenzoic acid. After 1 hour the reaction was diluted with CH2Cl2 (150 mL) and washed with 10% aqueous sodium thiosulfate, H2O, and brine, dried (anhydrous MgSO4), filtered and concentrated to give 1.10 g of crude sulfoxide 34 (100%) used without purification for the following step.
Reaction SMILES: [C:1]([O:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[O:11])=[CH:8][C:7]=1[O:14][CH3:15])([CH3:4])([CH3:3])[CH3:2].[OH-].[K+].[O-:18][Mn](=O)(=O)=O.[K+]>O1CCOCC1>[C:1]([O:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]([OH:18])=[O:11])=[CH:8][C:7]=1[O:14][CH3:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: COc1cc(C=O)ccc1OC(C)(C)C
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COc1cc(C(=O)O)ccc1OC(C)(C)C
Reaction time: 16 h
Yield: 48.9 %

Procedure:
4-tert-Butoxy-3-methoxybenzaldehyde (130 mg, 0.62 mmol) was suspended in a mixture of dioxane (520 μL) and potassium hydroxide (6.5 mL of 0.20 M, 1.3 mmol). KMnO4 (150 mg, 0.93 mmol) was added and the reaction was stirred vigorously for 16 h. The reaction mixture was filtered and then concentrated to 3 mL. Hydrochloric acid (1M, 4 mL) was added and the resulting precipitate was filtered (after standing for 15 minutes) and washed with 1M HCl and a small amount of water to yield 4-tert-butoxy-3-methoxy-benzoic acid (68 mg, 49%) as a white solid. Rf=0.23 (SiO2, 40% ethyl acetate in hexanes); ESI-MS m/z calc. 224.1, found 225.2 (M+1)+. Retention time: 1.66 minutes (3 min run). 1H NMR (400 MHz, DMSO) δ 12.80 (s, 1H), 7.66-7.41 (m, 2H), 7.09 (d, J=8.8 Hz, 1H), 3.78 (s, 3H), 1.32 (s, 9H).
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[N:31]=[C:20]3[N:21]=[CH:22][CH:23]=[C:24]([C:25]4[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=4)[N:19]3[N:18]=2)[CH2:13][CH2:12]1)=O)C1C=CC=CC=1.Br>CCOCC>[N:14]1([C:17]2[N:31]=[C:20]3[N:21]=[CH:22][CH:23]=[C:24]([C:25]4[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=4)[N:19]3[N:18]=2)[CH2:13][CH2:12][NH:11][CH2:16][CH2:15]1
Reactant: O=C(OCc1ccccc1)N1CCN(c2nc3nccc(-c4ccncc4)n3n2)CC1
Agent: Br
Solvent: CCOCC
Product: c1cc(-c2ccnc3nc(N4CCNCC4)nn23)ccn1

Procedure:
To an 8.0 g amount of 4-[7-(4-pyridyl)[1,2,4]triazolo[1,5-a]pyrimidin-2-yl]-1-piperazine carboxylic acid benzyl ester in 125 ml round bottom flask was added 25.0 ml of hydrobromic acid (31% in glacial acetic acid). The mixture was allowed to react for 20 minutes then was cooled. Ether was added to separate the precipitate. The precipitate was collected by filtration and dissolved in water. The solution was adjusted to a pH greater than pH 7 with 5N sodium hydroxide and extracted with three equal portions of chloroform. The extracts were combined and evaporated in vacuo to a syrup. The syrup was dissolved in hot ethanol and hexane was added to crystallize the crude product which was collected and washed with hexane. The crude product was recrystallized from 25 ml of cold ethanol, filtered, washed with ethanol/hexane then hexane. The material was dried in vacuo at 60° C. and gave 4.2 g of the product of the example as yellow crystals, mp 147°- 149° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:13][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[NH:16][CH:15]=1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:23]12[CH2:30][CH2:29][CH:26]([CH2:27][CH2:28]1)[C@@H:25](O)[CH2:24]2.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C>[C:1]([O:5][C:6]([NH:8][CH:9]([CH2:13][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[NH:16][CH:15]=1)[C:10]([O:12][C@@H:25]1[CH:26]2[CH2:29][CH2:30][N:23]([CH2:28][CH2:27]2)[CH2:24]1)=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC(Cc1c[nH]c2ccccc12)C(=O)O
Reactant: O[C@H]1CN2CCC1CC2
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)NC(Cc1c[nH]c2ccccc12)C(=O)O[C@H]1CN2CCC1CC2
Yield: 69.6 %

Procedure:
A solution of 2-(tert-butoxycarbonylamino)-3-(1H-indol-3-yl)propanoic acid (100 mg, 0.33 mmol), (R)-quinuclidin-3-ol (50.1 mg, 0.39 mmol), HOBT (53.3 mg, 0.39 mmol) and EDC (76 mg, 0.39 mmol) in DMF (2 ml) was heated at 90° C. for 1.5 hours under microwave irradiation. The solvent was evaporated. The residue was taken up with EtOAc and washed with 1N Na2CO3, water and brine. The organic phase was dried over Na2SO4, filtered and evaporated to obtain (R)-quinuclidin-3-yl 2-(tert-butoxycarbonylamino)-3-(1H-indol-3-yl)propanoate (95 mg, 69.9% yield), which was used as such in the next step.