Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: NC1N=CN=C2N(CC(OCC)=O)N=C(C3C=CC(NS(C4C=CC=C(Cl)C=4Cl)(=O)=O)=C(F)C=3)C=12.[O:36]1[C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=2[N:38]=[C:37]1[NH:45][C:46]1[CH:51]=[CH:50][C:49](B2OC(C)(C)C(C)(C)O2)=[CH:48][CH:47]=1.[NH2:61][C:62]1[N:67]=[CH:66][N:65]=[C:64]2[N:68]([C:72]3[C:77]([C:78]#[N:79])=[CH:76][CH:75]=[CH:74][N:73]=3)[N:69]=[C:70](I)[C:63]=12>>[NH2:61][C:62]1[N:67]=[CH:66][N:65]=[C:64]2[N:68]([C:72]3[C:77]([C:78]#[N:79])=[CH:76][CH:75]=[CH:74][N:73]=3)[N:69]=[C:70]([C:49]3[CH:48]=[CH:47][C:46]([NH:45][C:37]4[O:36][C:40]5[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=5[N:38]=4)=[CH:51][CH:50]=3)[C:63]=12
Reactant: CC1(C)OB(c2ccc(Nc3nc4ccccc4o3)cc2)OC1(C)C
Reactant: N#Cc1cccnc1-n1nc(I)c2c(N)ncnc21
Agent: CCOC(=O)Cn1nc(-c2ccc(NS(=O)(=O)c3cccc(Cl)c3Cl)c(F)c2)c2c(N)ncnc21
Product: N#Cc1cccnc1-n1nc(-c2ccc(Nc3nc4ccccc4o3)cc2)c2c(N)ncnc21
Yield: 7.3 %

Procedure:
The procedure for Suzuki coupling, used in the preparation of ethyl 2-[4-amino-3-(4-{[(2,3-dichlorophenyl)sulfonyl]amino}-3-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]acetate, was used to couple N-(1,3-benzoxazol-2-yl)-N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]amine (0.052 g, 0.155 mmol) with 2-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3-pyridyl cyanide (0.045 g, 0.124 mmol). Purification by preparative HPLC (25 to 100% acetonitrile in 0.1 M aqueous ammonium acetate over 20 min at 21 mL/min using an 8μ Hypersil HS C18, 250×21 mm column, Rt 10.1-11.2 min) afforded 2-{4-amino-3-[4-(1,3-benzoxazol-2-ylamino)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl}-3-pyridyl cyanide as a yellow powder (0.004 g, 0.009 mmol): RP-HPLC (25 to 100% acetonitrile in 0.1 M aqueous ammonium acetate over 10 min at 1 mL/min using a 5μ Hypersil HS C18, 250×4.6 mm column) Rt 8.55 min; MS (MH)+ 446.
Reaction SMILES: [ClH:1].C(OC([NH:9][C@@H:10]([C:21]([NH:23][C@H:24]([C:29]([NH:31][C@H:32]([C:40]([N:42]1[CH2:53][CH2:52][CH2:51][C@H:43]1[C:44]([NH:46][CH2:47][C:48]([NH2:50])=[O:49])=[O:45])=[O:41])[CH2:33][CH2:34][CH2:35][NH:36][C:37](=[NH:39])[NH2:38])=[O:30])[CH2:25][CH:26]([CH3:28])[CH3:27])=[O:22])[CH2:11][C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[NH:14][CH:13]=1)=O)(C)(C)C.CO.Cl>O1CCCC1>[ClH:1].[ClH:1].[NH2:9][C@@H:10]([C:21]([NH:23][C@H:24]([C:29]([NH:31][C@H:32]([C:40]([N:42]1[CH2:53][CH2:52][CH2:51][C@H:43]1[C:44]([NH:46][CH2:47][C:48]([NH2:50])=[O:49])=[O:45])=[O:41])[CH2:33][CH2:34][CH2:35][NH:36][C:37](=[NH:38])[NH2:39])=[O:30])[CH2:25][CH:26]([CH3:27])[CH3:28])=[O:22])[CH2:11][C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[NH:14][CH:13]=1
Reactant: CC(C)C[C@H](NC(=O)[C@@H](Cc1c[nH]c2ccccc12)NC(=O)OC(C)(C)C)C(=O)N[C@@H](CCCNC(=N)N)C(=O)N1CCC[C@H]1C(=O)NCC(N)=O
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)C[C@H](NC(=O)[C@H](N)Cc1c[nH]c2ccccc12)C(=O)N[C@@H](CCCNC(=N)N)C(=O)N1CCC[C@H]1C(=O)NCC(N)=O
Reaction time: 1 h

Procedure:
A solution of 1.69 g. of Nα -t-butoxycarbonyl-D-tryptophyl-L-leucyl-L-arginyl-L-prolyl-glycinamide hydrochloride in 20 ml. of methanol and 10 ml. of 3N hydrogen chloride in 10 ml. of tetrahydrofuran is allowed to stand for 1 hour and then evaporated to dryness at 30° C. under reduced pressure. The residue is twice dissolved in 20 ml. of methanol and the solvent evaporated. It is then dried at 45° C. under reduced pressure. The product is used without further purification.
Reaction SMILES: [C:1]([C:3]1[C:4]([N:23]2[CH2:27][CH2:26][C@@H:25]([OH:28])[CH2:24]2)=[N:5][CH:6]=[C:7]([CH:22]=1)[C:8]([NH:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][C:18]([F:21])([F:20])[F:19])=[CH:13][CH:12]=1)=[O:9])#[N:2].OS([O-])=O.[Na+].[CH2:34](N)[CH2:35][NH2:36].[NH4+]>CCOC(C)=O>[NH:2]1[CH2:34][CH2:35][N:36]=[C:1]1[C:3]1[C:4]([N:23]2[CH2:27][CH2:26][C@@H:25]([OH:28])[CH2:24]2)=[N:5][CH:6]=[C:7]([CH:22]=1)[C:8]([NH:10][C:11]1[CH:12]=[CH:13][C:14]([O:17][C:18]([F:19])([F:20])[F:21])=[CH:15][CH:16]=1)=[O:9]
Reactant: NCCN
Reactant: N#Cc1cc(C(=O)Nc2ccc(OC(F)(F)F)cc2)cnc1N1CC[C@@H](O)C1
Agent: O=S([O-])O
Agent: [NH4+]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(C2=NCCN2)c1
Temperature: 100 °C

Procedure:
A stirred mixture of (R)-5-cyano-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 70.2, 1 g, 2.55 mmol), NaHSO3 (0.953 g, 15.3 mmol) and ethylenediamine (7.66 g, 1.27 mmol) was treated dropwise with 40% aq. ammonium silfide (4.34 mL, 25.5 mmol) and heated at 100° C. for 18 h. The cooled mixture was treated with EtOAc, washed with sat. aq. NaHCO3 and brine, was dried over anhydrous Na2SO4 and the solvent was evaporated off under reduced pressure. The crude product was purified by flash chromatography (RediSep® Silica gel column, DCM/(5% aq. NH3 in MeOH) from 0 to 40% (5% aq. NH3 in MeOH)) to afford the product as a pale-yellow solid. HPLC (Condition 4) tR=3.89 min, UPLC-MS (Condition 8) tR=0.72 min, m/z=436.2 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.67-1.98 (m, 3H) 3.40-3.75 (m, 8H) 4.30 (br. s, 1H) 4.91 (br. s, 1H) 7.31 (d, J=8.60 Hz, 2H) 7.78-7.91 (m, 2H) 8.06 (d, J=2.35 Hz, 1H) 8.71 (d, J=2.35 Hz, 1H) 10.17 (s, 1H).
Reaction SMILES: [CH2:1]([N:3]1[C:8]([C:9]2[O:13][C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[N:11][N:10]=2)=[C:7]([OH:20])[C:6]2[CH:21]=[CH:22][CH:23]=[CH:24][C:5]=2[S:4]1(=[O:26])=[O:25])[CH3:2].[CH:27]1([C:32](O)=[O:33])[CH2:31][CH2:30][CH2:29][CH2:28]1.C1(N=C=NC2CCCCC2)CCCCC1.O>N1C=CC=CC=1>[CH:27]1([C:32]([O:20][C:7]2[C:6]3[CH:21]=[CH:22][CH:23]=[CH:24][C:5]=3[S:4](=[O:26])(=[O:25])[N:3]([CH2:1][CH3:2])[C:8]=2[C:9]2[O:13][C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[N:11][N:10]=2)=[O:33])[CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: CCN1C(c2nnc(-c3ccccc3)o2)=C(O)c2ccccc2S1(=O)=O
Reactant: O=C(O)C1CCCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: c1ccncc1
Solvent: O
Product: CCN1C(c2nnc(-c3ccccc3)o2)=C(OC(=O)C2CCCC2)c2ccccc2S1(=O)=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 83.3 %

Procedure:
A mixture of 2-ethyl-4-hydroxy-3-(2-phenyl-1,3,4-oxadiazol-5-yl)-1,2-benzothiazine 1,1-dioxide (0.739 g), cyclopentanecarboxylic acid (0.34 g) and N,N'-dicyclohexylcarbodiimide (1.55 g) in pyridine (2.5 ml) was stirred at room temperature for 16 hours. Water (7 ml) was added to the reaction mixture and the solid thus formed was filtered and washed with water. The solid was then dissolved in chloroform and filtered. The filtrate was concentrated. The residue was recrystallized from toluene to give the title compound (0.776 g). M.P.: 194°-196° C.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][Si:5]([CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:7])[CH3:6].[NH3:16]>>[NH2:16][CH2:2][CH2:3][O:4][Si:5]([CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:7])[CH3:6]
Reactant: N
Reactant: C[Si](C)(CCc1ccccc1)OCCCl
Product: C[Si](C)(CCc1ccccc1)OCCN

Procedure:
reacting said (chloromethyl) phenylethyldimethylmethoxysilane with ammonia under heat and pressure, and distilling the reaction mixture to yield (aminomethyl) phenylethyldimethylmethoxysilane.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][CH2:15][C:14](=O)[CH2:13][C:9]21[CH2:12][CH2:11][CH2:10]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])(=O)C.[NH4+].C([BH3-])#[N:24].[Na+].Cl>CO>[C:1]([O:5][C:6]([N:8]1[CH2:16][CH2:15][CH:14]([NH2:24])[CH2:13][C:9]21[CH2:12][CH2:11][CH2:10]2)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [BH3-]C#N
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC12CCC2
Agent: CC(=O)[O-]
Agent: Cl
Agent: [NH4+]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(N)CC12CCC2
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A of solution 8-Oxo-5-aza-spiro[3.5]nonane-5-carboxylic acid tert-butyl ester (Tetrahedron Letters 42, 4815 (2001)) (488 mg, 2.04 mmol) in 11 ml of MeOH was treated with ammonium acetate (1.5 g, 20.4 mmol) and sodium cyanoborohydride (100 mg, 1.6 mmol). This mixture was stirred at room temperature for 72 hours. Afterwards 0.8 ml 1N-HCl were added and stirring continued for 10 minutes. For extraction with EtOAc the solution was basified with 1N-NaOH. The crude was purified by chromatography on silicagel (DCM/MeOH/ammonia:9/1/0.1). Yield: 0.27 g (55%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([OH:16])[CH2:13][CH2:12][NH:11][CH2:10][C:9]2([CH3:15])[CH3:14])=[CH:4][CH:3]=1.[C:17]([O:21][C:22]([NH:24][C@H:25]([CH2:29][CH3:30])[C:26](O)=[O:27])=[O:23])([CH3:20])([CH3:19])[CH3:18].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.CCN(C(C)C)C(C)C>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([OH:16])[CH2:13][CH2:12][N:11]([C:26](=[O:27])[C@H:25]([NH:24][C:22](=[O:23])[O:21][C:17]([CH3:19])([CH3:18])[CH3:20])[CH2:29][CH3:30])[CH2:10][C:9]2([CH3:14])[CH3:15])=[CH:4][CH:3]=1
Reactant: CC1(C)CNCC[C@]1(O)c1ccc(Cl)cc1
Reactant: CC[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@@H](NC(=O)OC(C)(C)C)C(=O)N1CC[C@](O)(c2ccc(Cl)cc2)C(C)(C)C1

Procedure:
(S)-4-(4-chlorophenyl)-3,3-dimethylpiperidin-4-ol (100 mg, 0.42 mmol), (R)-2-(tert-butoxycarbonylamino)butanoic acid (102 mg, 0.50 mmol), HOBT (68 mg, 0.5 mmol), EDC (155 mg, 1 mmol), DIPEA (129 mg, 1 mmol), and chloroform (2 mL) was stirred overnight at rt. The reaction mixture was then partitioned between methylene chloride and saturated sodium bicarbonate solution, the layers were separated and the organic extracts were dried over magnesium sulfate, filtered, and concentrated to yield the product, which was used in next step without further purification.
Reaction SMILES: [NH:1]([C:57]([O:59][CH2:60][CH:61]1[C:73]2[C:68](=[CH:69][CH:70]=[CH:71][CH:72]=2)[C:67]2[C:62]1=[CH:63][CH:64]=[CH:65][CH:66]=2)=[O:58])[C@@H:2]([C:15]([NH:17][C@@H:18]([C:31]([NH:33][C@H:34]([C:39]([NH:41][C@H:42]([C:47]([O:49]CC1C=CC=CC=1)=[O:48])[CH2:43][CH:44]([CH3:46])[CH3:45])=[O:40])[CH2:35][CH:36]([CH3:38])[CH3:37])=[O:32])[CH2:19][CH2:20][CH2:21][CH2:22][NH:23]C(OC(C)(C)C)=O)=[O:16])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7]C(OC(C)(C)C)=O.FC(F)(F)C(O)=O.C([SiH](C(C)C)C(C)C)(C)C>O>[NH:1]([C:57]([O:59][CH2:60][CH:61]1[C:62]2[C:67](=[CH:66][CH:65]=[CH:64][CH:63]=2)[C:68]2[C:73]1=[CH:72][CH:71]=[CH:70][CH:69]=2)=[O:58])[C@@H:2]([C:15]([NH:17][C@@H:18]([C:31]([NH:33][C@H:34]([C:39]([NH:41][C@H:42]([C:47]([OH:49])=[O:48])[CH2:43][CH:44]([CH3:46])[CH3:45])=[O:40])[CH2:35][CH:36]([CH3:38])[CH3:37])=[O:32])[CH2:19][CH2:20][CH2:21][CH2:22][NH2:23])=[O:16])[CH2:3][CH2:4][CH2:5][CH2:6][NH2:7]
Reactant: CC(C)C[C@H](NC(=O)[C@@H](CCCCNC(=O)OC(C)(C)C)NC(=O)[C@@H](CCCCNC(=O)OC(C)(C)C)NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)N[C@@H](CC(C)C)C(=O)OCc1ccccc1
Agent: CC(C)[SiH](C(C)C)C(C)C
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)C[C@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](CCCCN)NC(=O)[C@@H](CCCCN)NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The crude crystals (100 mg) of Fmoc-D-Lys(Boc)-D-Lys(Boc)-Leu-Leu-OBzl (2-MeO-4-OC12OC22) were added to a solution (2 ml) of trifluoroacetic acid:triisopropylsilane:water=95:2.5:2.5 under ice-cooling, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure, and methyl tert-butyl ether (MTBE)/cyclohexane was added to the residue. The precipitate was washed at 40° C. and collected by filtration to give Fmoc-D-Lys-D-Lys-Leu-Leu-OH (29 mg).
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:7][CH2:8][N:9]([S:27]([C:30]2[CH:39]=[CH:38][C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:31]=2)(=[O:29])=[O:28])[CH:10]2[CH:15]3[CH:11]2[CH2:12][N:13]([C:16]2[N:21]=[CH:20][C:19]([C:22]([O:24]CC)=O)=[CH:18][N:17]=2)[CH2:14]3)[CH:4]=[CH:5][N:6]=1.Cl.[NH2:41][OH:42].[O-]CC.[Na+].O>CCO>[OH:42][NH:41][C:22]([C:19]1[CH:20]=[N:21][C:16]([N:13]2[CH2:14][CH:15]3[CH:11]([CH:10]3[N:9]([CH2:8][CH2:7][N:3]3[CH:4]=[CH:5][N:6]=[C:2]3[CH3:1])[S:27]([C:30]3[CH:39]=[CH:38][C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[CH:31]=3)(=[O:28])=[O:29])[CH2:12]2)=[N:17][CH:18]=1)=[O:24]
Reactant: CCOC(=O)c1cnc(N2CC3C(C2)C3N(CCn2ccnc2C)S(=O)(=O)c2ccc3ccccc3c2)nc1
Reactant: NO
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1nccn1CCN(C1C2CN(c3ncc(C(=O)NO)cn3)CC21)S(=O)(=O)c1ccc2ccccc2c1
Temperature: 50 °C
Yield: 19.7 %

Procedure:
To a solution of ethyl 2-{6-[[2-(2-methylimidazol-1-yl)ethyl](naphthalene-2-sulfonyl)amino]-3-azabicyclo[3.1.0]hex-3-yl}pyrimidine-5-carboxylate (0.211 g, 0.38 mmol) in EtOH (6 ml) in a sealed tube, was added hydroxylamine hydrochloride (0.460 g, 6.6 mmol) and sodium ethoxide (0.358 g, 5.3 mmol). The mixture was heated at 50° C. for 18 h, then water (20 ml) was added, and the product extracted with DCM (3×100 ml) and EtOAc (2×100 ml). The combined organic extracts were dried (MgSO4) and concentrated and the product purified by recrystallisation (MeOH) to give the title compound as a white solid (40 mg, 20%). LCMS Purity >98%, m/z 534 [M+H]+, 1H NMR (300 MHz, d6-DMSO) δ: 1.71 (1H, m), 1.82 (2H, m), 2.34 (3H, s), 3.43-3.55 (4H, m), 3.71 (2H, d, J=11.9 Hz), 4.14 (2H, t, J=6.5 Hz), 6.76 (1H, d, J=1.2 Hz), 7.08 (1H, d, J=1.2 Hz), 7.66-7.76 (2H, m), 7.88 (1H, dd, J=1.8, 10.5 Hz), 8.06 (1H, dd, J=2.0, 7.1 Hz), 8.18 (1H, d, J=8.7 Hz), 8.25 (1H, dd, J=2.0, 8.9 Hz), 8.57-8.62 (3H, m), 8.98 (1H, br s), 11.02 (1H, br s).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2([C:16]([OH:18])=[O:17])[CH2:12][CH:11]2[C:13]([OH:15])=[O:14])=[CH:6][CH:5]=1)([O-])=O.Cl.[OH-].[Na+]>C(O)C.[Pd].CO>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([C:10]2([C:16]([OH:18])=[O:17])[CH2:12][CH:11]2[C:13]([OH:15])=[O:14])=[CH:6][CH:5]=1
Reactant: O=C(O)C1CC1(C(=O)O)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CCO
Product: Nc1ccc(C2(C(=O)O)CC2C(=O)O)cc1

Procedure:
20 g of 1-(4-nitrophenyl)-1,2-cyclopropanedicarboxylic acid are dissolved in 200 ml of ethanol and the solution is hydrogenated in the presence of 5% palladium on carbon. The suspension so obtained is diluted with methanol and the precipitated product is dissolved by addition of 1 equivalent of methanolic hydrochloric acid. A part of the solvent is stripped off in vacuo, then 1 equivalent of 2N sodium hydroxide solution is added and the mixture is evaporated to dryness. The residue is crystallised from water and dried in vacuo over KOH pellets at 60° C. The title compound (b) is obtained in the form of light brown crystals with a melting point above 230° C. and Rf=0.55 on thin-layer silica gel plates in the system methylene chloride/glacial acetic acid (20:10:2).
Reaction SMILES: [NH3:1].[CH2:2]([O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13](Cl)(=[O:15])=[O:14])=[CH:9][CH:8]=1)[CH2:3][CH2:4][CH3:5]>O>[CH2:2]([O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13]([NH2:1])(=[O:15])=[O:14])=[CH:9][CH:8]=1)[CH2:3][CH2:4][CH3:5]
Reactant: CCCCOc1ccc(S(=O)(=O)Cl)cc1
Reactant: N
Solvent: O
Product: CCCCOc1ccc(S(N)(=O)=O)cc1
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
100 ml of methanolic ammonia solution were added dropwise to 10 g of 4-n-butoxybenzenesulfonyl chloride, while cooling with ice. After the mixture had been stirred at 20° C. for 1/2 hour, water was added, the mixture was acidified to pH 1 to 2 and the product was filtered off with suction, melting point 99° to 101° C.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[C:16]([CH3:20])([CH3:19])[N:15]([CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][OH:29])[CH:23]=4)[C:14]3=[O:30])[CH:10]=[N:9]2)=[C:5]([CH3:31])[O:4][N:3]=1.[H-].[Na+].I[CH3:35]>CN(C)C=O.C(OCC)(=O)C>[CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[C:16]([CH3:20])([CH3:19])[N:15]([CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][O:29][CH3:35])[CH:23]=4)[C:14]3=[O:30])[CH:10]=[N:9]2)=[C:5]([CH3:31])[O:4][N:3]=1
Reactant: CI
Reactant: Cc1noc(C)c1Cn1cc(N2C(=O)N(Cc3cccc(CO)c3)C(C)(C)C2=O)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COCc1cccc(CN2C(=O)N(c3cnn(Cc4c(C)noc4C)c3)C(=O)C2(C)C)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 36 %

Procedure:
To a solution of 3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)-1-(3-(hydroxymethyl)benzyl)-5,5-dimethylimidazolidine-2,4-dione (Example 12-34) (559 mg, 1.32 mmol) in anhydrous dimethylformamide (10 mL) at 0° C., was added sodium hydride (53 mg, 1.32 mmol), followed by iodomethane (99 ul, 1.58 mmol). The reaction was allowed to warm to room temperature and stirred for about 4 hours. The resulting mixture was diluted with ethyl acetate (40 mL) and ice water (10 mL), The organic phase was collected, dried over anhydrous MgSO4, filtered and then concentrated on the rotovap. The residue was purified by reverse phase HPLC (gradient 10% to 100% methanol/water) and further purified by column chromatography (60% EtOAc in hexane). Yield 36%, colorless gel. 1H NMR (DMSO-d6, 400 MHz): δ1.29 (s, 6H), 2.14 (s, 3H), 2.40 (s, 3H), 3.25 (s, 3H), 4.37 (s, 2H), 4.55 (s, 2H), 5.18 (s, 2H), 7.19 (t, 1H) 7.30 (d, 2H), 7.32 (s, 1H), 7.82 (s, 1H) 8.20 (s, 1H). MS 438 (MH+). The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.13 μM.
Reaction SMILES: [C:1]([N:3]1[C:11]2[CH:10]=[CH:9][C:8]([CH3:12])=[CH:7][C:6]=2[C:5]2[CH2:13][N:14]([CH3:17])[CH2:15][CH2:16][C:4]1=2)#[CH:2].Br[C:19]1[CH:20]=[CH:21][C:22]([CH3:25])=[N:23][CH:24]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>O>[CH3:17][N:14]1[CH2:15][CH2:16][C:4]2[N:3]([C:1]#[C:2][C:19]3[CH:24]=[N:23][C:22]([CH3:25])=[CH:21][CH:20]=3)[C:11]3[CH:10]=[CH:9][C:8]([CH3:12])=[CH:7][C:6]=3[C:5]=2[CH2:13]1
Reactant: Cc1ccc(Br)cn1
Reactant: C#Cn1c2c(c3cc(C)ccc31)CN(C)CC2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Product: Cc1ccc2c(c1)c1c(n2C#Cc2ccc(C)nc2)CCN(C)C1
Temperature: 80 °C
Yield: 14.8 %

Procedure:
A mixture of 5-Ethynyl-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (156 mg, 0.69 mmol), 5-bromo-2-methyl-pyridine (100 mg, 0.58 mmol), dichlorobistriphenylphosphine palladium (II) (12 mg, 0.017 mmol) and TBAF.3H2O (548 mg, 1.74 mmol) were added to a reaction vessel and the contents heated at 80° C. for 5 min in microwave. After completion of starting material (as monitored by TLC & LCMS), the reaction mixture was poured into water (25 mL) and the desired compound extracted with EtOAc (3×50 mL). The organic layer was dried over sodium sulfate, concentrated under vacuum and purified by reverse phase chromatography to obtain 27 mg of 2,8-dimethyl-5-(6-methyl-pyridin-3-ylethynyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole and mg of 5-[1-fluoro-2,2-bis-(6-methyl-pyridin-3-yl)-vinyl]-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole. 1H NMR (CDCl3, free base) δ (ppm): 8.58 (s, 1H), 7.98 (s, 1H), 7.58 (d, 1H), 7.20 (d, 1H), 7.10 (d, 2H), 7.0 (d, 1H), 6.96 (d, 1H), 6.82 (d, 1H), 3.62 (m, 2H), 2.90-2.70 (m, 4H), 2.60 (s, 3H), 2.50 (s, 3H), 2.40 (s, 6H).
Reaction SMILES: C(=O)[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C(O)C.C(O[CH:17]([O:21][CH2:22][CH3:23])[O:18][CH2:19][CH3:20])C>[Cl-].[NH4+]>[CH2:22]([O:21][CH:17]([O:18][CH2:19][CH3:20])[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)[CH3:23]
Reactant: O=Cc1ccc(C=O)cc1
Reactant: CCOC(OCC)OCC
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: CCOC(OCC)c1ccc(C=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.1 %

Procedure:
A mixture of terephthalaldehyde (10 g, 74.55 mmol), ammonium chloride (160 mg, 3.0 mmol) in ethanol (10.3 g, 223.6 mmol) was added dropwise triethoxymethane (12.15 g, 82 mmol) at 0° C. After the addition, the mixture was stirred at room temperature overnight. The mixture was concentrated, the residue was purified by silica gel chromatography to give the title compound (7.0 g, yield 50%) as a white solid. LC-MS (ESI) m/z: 209 (M+1)+.
Reaction SMILES: C1C[C@H](C(O)=O)CC[C@H]1CN.[CH3:12][CH:13]([CH3:34])[CH2:14][C:15]([O:17][CH:18]([O:20][C:21]([NH:23][CH2:24][C@H:25]1[CH2:30][CH2:29][C@H:28]([C:31]([OH:33])=[O:32])[CH2:27][CH2:26]1)=[O:22])[CH3:19])=[O:16].C(=O)(O)[O-].[Na+:39].C(#N)C>O>[CH3:12][CH:13]([CH3:34])[CH2:14][C:15]([O:17][CH:18]([O:20][C:21]([NH:23][CH2:24][C@H:25]1[CH2:26][CH2:27][C@H:28]([C:31]([O-:33])=[O:32])[CH2:29][CH2:30]1)=[O:22])[CH3:19])=[O:16].[Na+:39]
Reactant: CC(C)CC(=O)OC(C)OC(=O)NC[C@H]1CC[C@H](C(=O)O)CC1
Agent: NC[C@H]1CC[C@H](C(=O)O)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CC(C)CC(=O)OC(C)OC(=O)NC[C@H]1CC[C@H](C(=O)[O-])CC1

Procedure:
Following the general procedure for the formation of the corresponding sodium carboxylates of acyloxyalkyl carbamates of tranexamic acid, 1.976 g (6.0 mmol) of trans-4-{[1-(3-methylbutanoyloxy)ethoxycarbonyl]aminomethyl}-cyclohexanecarboxylic acid 19 was reacted with 504.1 mg (6.0 mmol) of sodium bicarbonate (NaHCO3) in 20 mL of a mixture of acetonitrile and water (1:1) to yield 2.11 g (quant.) of the title compound 20 as a colorless powder. 1H NMR (400 MHz, DMSO-d6): δ=0.72-0.84 (m, 2H), 0.89 (d, J=6.4 Hz, 6H), 1.07-1.21 (m, 2H), 1.22-1.32 (m, 1H), 1.38 (d, J=5.2 Hz, 3H), 1.58-1.74 (br. m, 3H), 1.76-1.84 (br. m, 2H), 1.88-2.01 (m, 1H), 2.08-2.20 (m, 2H), 2.74-2.85 (m, 2H), 6.66 (q, J=5.6 Hz, 1H), 7.42 (t, J=6.4 Hz, 1H). MS (ESI) m/z 352.18 (M+Na)+; 328.14 (M−H)−.
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH2:45][CH2:46][OH:47])[N+:4]([CH2:14][C:15]2[CH2:16][S:17][C@@H:18]3[C@H:25]([NH:26][C:27](=[O:43])/[C:28](/[C:37]4[N:41]=[C:40]([NH2:42])[S:39][N:38]=4)=[N:29]\[O:30][C:31]([C:34]([OH:36])=[O:35])([CH3:33])[CH3:32])[C:24](=[O:44])[N:19]3[C:20]=2[C:21]([O-:23])=[O:22])=[CH:5][C:6]=1[N:7]([CH2:10][CH2:11][CH2:12][NH2:13])C=O.Cl.C(=O)([O-])O.[Na+]>CO>[NH2:1][C:2]1[N:3]([CH2:45][CH2:46][OH:47])[N+:4]([CH2:14][C:15]2[CH2:16][S:17][C@@H:18]3[C@H:25]([NH:26][C:27](=[O:43])/[C:28](/[C:37]4[N:41]=[C:40]([NH2:42])[S:39][N:38]=4)=[N:29]\[O:30][C:31]([C:34]([OH:36])=[O:35])([CH3:33])[CH3:32])[C:24](=[O:44])[N:19]3[C:20]=2[C:21]([O-:23])=[O:22])=[CH:5][C:6]=1[NH:7][CH2:10][CH2:11][CH2:12][NH2:13]
Reactant: CC(C)(O/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(C[n+]3cc(N(C=O)CCCN)c(N)n3CCO)CS[C@H]12)c1nsc(N)n1)C(=O)O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CC(C)(O/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(C[n+]3cc(NCCCN)c(N)n3CCO)CS[C@H]12)c1nsc(N)n1)C(=O)O
Reaction time: 6.5 h
Yield: 18.8 %

Procedure:
To a stirred suspension of 3-({3-amino-4-[N-(3-aminopropyl)-N-formylamino]-2-(2-hydroxyethyl)-1-pyrazolio}methyl)-7β-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(1-carboxy-1-methylethoxyimino)acetamido]-3-cephem-4-carboxylate (100 mg) in methanol (1.4 ml) was added concentrated hydrochloric acid (0.125 ml) at room temperature, and the mixture was stirred for 6.5 hours. To the above solution was added sodium hydrogen carbonate (109 mg), and the mixture was purified by preparative HPLC (ODS column; acetonitrile:phosphate buffer (pH 7)=5:95). The eluate containing a desired product was evaporated to remove acetonitrile, made acidic with diluted hydrochloric acid and chromatographed on Diaion® HP20 (Mitsubishi Chemical Corporation) eluting with 20% aqueous 2-propanol. The eluate was concentrated under reduced pressure and lyophilized to give 3-({3-amino-4-[(3-aminopropyl)amino]-2-(2-hydroxyethyl)-1-pyrazolio}methyl)-7β-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(1-carboxy-1-methylethoxyimino)acetamido]-3-cephem-4-carboxylate (18 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][O:10]C(=O)C)=[N:7][CH:8]=1.C([O-])(O)=O.[Na+].C([O-])([O-])=O.[K+].[K+]>Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][OH:10])=[N:7][CH:8]=1
Reactant: COc1ccc(COC(C)=O)nc1
Agent: Cl
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Product: COc1ccc(CO)nc1
Temperature: 105 °C
Reaction time: 1.33 h

Procedure:
Acetic acid 5-methoxy-pyridin-2-ylmethyl ester (10.5 g, 58 mmol) was dissolved in HCl (25%, 30 ml) and the resultant reaction mixture was stirred at ca. 105° C. for 80 min under an argon atmosphere. Solid NaHCO3 was added in portions followed by aqueous K2CO3 solution to achieve an alkaline pH 10. This resultant mixture was extracted with ethyl acetate (4×) and the combined organic extracts were washed with water, brine, dried (MgSO4) filtered and then concentrated under reduced pressure. The crude oil was purified over silica gel (ethyl acetate/n-heptane 1:1 to 2:1): yellow solid 4.8 g (56%);