Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH2:5])[CH2:2][CH2:3][CH3:4].C(N(C(C)C)CC)(C)C.Cl[C:16]1[N:21]2[N:22]=[C:23]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[Cl:38])[C:24]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)=[C:20]2[N:19]=[C:18]([CH3:39])[N:17]=1.O>CN(C=O)C>[CH2:1]([NH:5][C:16]1[N:21]2[N:22]=[C:23]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[Cl:38])[C:24]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)=[C:20]2[N:19]=[C:18]([CH3:39])[N:17]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN
Reactant: Cc1nc(Cl)n2nc(-c3ccccc3Cl)c(-c3ccc(Cl)cc3)c2n1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCCCNc1nc(C)nc2c(-c3ccc(Cl)cc3)c(-c3ccccc3Cl)nn12
Reaction time: 40 h

Procedure:
To a mixture of butylamine (0.17 ml, 0.15 mmol) and diisopropylethylamine (0.037 ml, 0.21 mmol) in DMF (0.75 ml) was added a solution of 4-chloro-7-(2-chlorophenyl)-8-(4-chlorophenyl)-2-methylpyrazolo[1,5-a][1,3,5]triazine (I-2A-1b; 54 mg, 0.14 mmol) in DMF (1.3 ml). After stirring for 40 hours, the reaction was treated with water, dropwise, until a precipitate formed. After several more hours of stirring, the resultant solid was collected by vacuum filtration, and then washed with water and a small amount of isopropyl alcohol to afford 7A-1 (46 mg, 77%) as a solid: +APcI MS (M+1) 426.2; 1H NMR (400 MHz, CD3OD) δ 7.51-7.30 (m, 6H), 7.22-7.18 (m, 2H), 3.63 (t, J=7.1 Hz, 2H), 2.50 (s, 3H), 1.70 (quintet, J=7.3 Hz, 2H), 1.44 (hextuplet, J=7.5 Hz, 2H), 0.98 (t, J=7.5 Hz, 2H).
Reaction SMILES: P([O-])([O-])([O-])=O.[K+].[K+].[K+].[C:9]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.BrC1C=CC=CC=1.C([NH2:35])CCCCC.CCCCCCCCCCCC>[Cu]I.O.C(OCC)C.C1(C)C=CC=CC=1>[C:9]1([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH2:35])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Oc1ccccc1-c1ccccc1
Reactant: CCCCCCN
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: Brc1ccccc1
Solvent: CCCCCCCCCCCC
Solvent: Cc1ccccc1
Product: NCCCCCCc1ccccc1
Temperature: 100 °C

Procedure:
Copper (I) iodide (10 mg, 0.05 mmol, 5 mol %), anhydrous fine powder potassium phosphate (425 mg, 2.0 mmol) and 2-phenylphenol (34 mg, 0.2 mmol, 20 mol %) were put into a screw-capped test tube with a Teflon septum. Anhydrous toluene (1.0 mL), bromobenzene (105 μL, 1.0 mmol) and n-hexylamine (158 μL, 1.2 mmol) were added by micro-syringe at room temperature under air atmosphere. The reaction mixture was heated at 100° C. for 22 hours. The reaction mixture was then allowed to reach room temperature. Diethyl ether (2 mL), water (2 mL) and dodecane (internal standard, 227 μL) were added. The organic layer was analyzed by GC to give 33% GC yield of N-phenylhexylamine.
Reaction SMILES: [C:1]1([C:7]2[C:8]([C:23]([O:25][CH3:26])=[O:24])=[N:9][C:10]([C:13]3[CH:22]=[C:21]4[C:16]([CH2:17][CH2:18][CH2:19][NH:20]4)=[CH:15][CH:14]=3)=[CH:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S:27]1[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[N:29]=[C:28]1[NH:36][C:37](=O)[O:38]C1C=CC([N+]([O-])=O)=CC=1>CC#N>[S:27]1[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[N:29]=[C:28]1[NH:36][C:37]([N:20]1[C:21]2[C:16](=[CH:15][CH:14]=[C:13]([C:10]3[N:9]=[C:8]([C:23]([O:25][CH3:26])=[O:24])[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)=[CH:12][CH:11]=3)[CH:22]=2)[CH2:17][CH2:18][CH2:19]1)=[O:38]
Reactant: O=C(Nc1nc2ccccc2s1)Oc1ccc([N+](=O)[O-])cc1
Reactant: COC(=O)c1nc(-c2ccc3c(c2)NCCC3)ccc1-c1ccccc1
Solvent: CC#N
Product: COC(=O)c1nc(-c2ccc3c(c2)N(C(=O)Nc2nc4ccccc4s2)CCC3)ccc1-c1ccccc1
Temperature: 25 °C

Procedure:
A mixture of methyl 3-phenyl-6-(1,2,3,4-tetrahydroquinolin-7-yl)picolinate (29H) (17 mg, 0.049 mmol) and 4-nitrophenyl benzo[d]thiazol-2-ylcarbamate (19) (15.5 mg, 0.049 mmol) in anhydrous CH3CN (0.8 mL) was heated to reflux for 6 hours, cooled to rt, concentrated under reduced pressure, and the crude material was purified by column chromatography on silica gel eluting with a gradient of PE:EtOAc 72:28-55:45, to provide the desired product methyl 641-(benzo[d]thiazol-2-ylcarbamoyl)-1,2,3,4-tetrahydroquinolin-7-yl)-3-phenylpicolinate (29I): 1H NMR (300 MHz, CDCl3) δ 8.23 (1H, d), 8.13 (1H, d), 7.85-7.76 (3H, m), 7.66 (1H, d), 7.48-7.35 (4H, m), 7.34-7.28 (2H, m), 6.89 (1H, d), 3.98 (2H, t), 3.71 (3H, s), 2.85 (2H, t), 2.09 (2H, m).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[C:8]2[C:3]=1[CH2:4][N:5]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=1)[C:6](=[O:23])[N:7]2[C:15]1[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][C:16]=1[Cl:22].C([O-])([O-])=O.[Na+].[Na+].[Cl:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1B(O)O.C(O)C.O>C1(C)C=CC=CC=1.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[C:2]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[C:8]2[C:3]=1[CH2:4][N:5]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=1)[C:6](=[O:23])[N:7]2[C:15]1[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][C:16]=1[Cl:22]
Reactant: OB(O)c1ccccc1Cl
Reactant: COc1ccc(CN2Cc3c(Br)cc([N+](=O)[O-])cc3N(c3c(Cl)cccc3Cl)C2=O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1ccc(CN2Cc3c(-c4ccccc4Cl)cc([N+](=O)[O-])cc3N(c3c(Cl)cccc3Cl)C2=O)cc1
Temperature: 100 °C

Procedure:
1.07 g of 5-bromo-1-(2,6-dichlorophenyl)-3-(4-methoxybenzyl)-7-nitro-3,4-dihydroquinazolin-2(1H)-one (1.99 mmol) were dissolved in 26 mL of toluene. Na2CO3 (1.26 g, 11.9 mmol), 2-chlorophenylboronic acid (934 mg, 5.97 mmol), and ethanol/water (6.4 mL:6.4 mL) were added under argon followed by Pd(Ph3P)4 (115 mg, 0.0995 mmol). The resulting reaction mixture was stirred at 100° C. for ca.4 h, cooled to rt, diluted with 150 mL of ethyl acetate, washed with 2×100 mL of saturated aqueous NaHCO3 and 100 mL of brine, dried over Na2SO4, and concentrated under reduced pressure. The product was purified by flash chromatography on Biotage 40M column, eluting with 80:20 hexanes-acetone to yield 5-(2-chlorophenyl)-1-(2,6-dichlorophenyl)-3-(4-methoxybenzyl)-7-nitro-3,4-dihydroquinazolin-2(1H)-one. Mass spectrum (ESI) 568.1 (M+1).
Reaction SMILES: O1CCOCC1.[CH:7]([C:9]1[CH:14]=[CH:13][C:12](B(O)O)=[CH:11][CH:10]=1)=[O:8].Br[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-:27])=[O:26])[C:20]=1[O:28][CH3:29].C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[N+:25]([C:21]1[C:20]([O:28][CH3:29])=[C:19]([C:12]2[CH:13]=[CH:14][C:9]([CH:7]=[O:8])=[CH:10][CH:11]=2)[CH:24]=[CH:23][CH:22]=1)([O-:27])=[O:26]
Reactant: O=Cc1ccc(B(O)O)cc1
Reactant: COc1c(Br)cccc1[N+](=O)[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COc1c(-c2ccc(C=O)cc2)cccc1[N+](=O)[O-]
Yield: 79.7 %

Procedure:
To a solution of 60 mL of 1,4-dioxane and 10 mL of water was added 4-formylphenylboronic acid (3.0 g, 0.02 mol), followed by 1-bromo-2-methoxy-3-nitro-benzene 1c (4.64 g, 0.02 mol), tetrakis(triphenylphosphine)palladium (1.15 g, 1 mmol) and sodium carbonate (4.24 g, 0.04 mol). Upon completion of the addition, the mixture was heated to reflux for 5 hours. The reaction was monitored by TLC until the disappearance of the starting materials. The mixture was filtered and the filter cake was washed with ethyl acetate. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography to obtain the title compound 3′-nitro-2′-methoxy-biphenyl-4-carbaldehyde 32a (4.1 g, 80.4%) as a yellow solid.
Reaction SMILES: C(O)(=O)C.[F:5][C:6]1[C:11]([O:12][CH2:13][CH2:14][OH:15])=[CH:10][C:9]([O:16][CH3:17])=[CH:8][C:7]=1[CH:18]([NH:31][C:32]1[CH:40]=[CH:39][C:35]([C:36]([NH2:38])=[NH:37])=[CH:34][CH:33]=1)[C:19]1[NH:23][C:22](=[O:24])[N:21]([C:25]2[N:30]=[CH:29][CH:28]=[CH:27][N:26]=2)[N:20]=1.CN(C=O)C.[N+](C1C=CC([O:55][C:56](=O)[C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)=CC=1)([O-])=O.C(N(CC)CC)C>C(O)(=O)C>[NH2:37][C:36](=[N:38][C:56](=[O:55])[C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1)[C:35]1[CH:34]=[CH:33][C:32]([NH:31][CH:18]([C:7]2[CH:8]=[C:9]([O:16][CH3:17])[CH:10]=[C:11]([O:12][CH2:13][CH2:14][OH:15])[C:6]=2[F:5])[C:19]2[NH:23][C:22](=[O:24])[N:21]([C:25]3[N:26]=[CH:27][CH:28]=[CH:29][N:30]=3)[N:20]=2)=[CH:40][CH:39]=1
Reactant: COc1cc(OCCO)c(F)c(C(Nc2ccc(C(=N)N)cc2)c2nn(-c3ncccn3)c(=O)[nH]2)c1
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: COc1cc(OCCO)c(F)c(C(Nc2ccc(C(N)=NC(=O)c3ccccc3)cc2)c2nn(-c3ncccn3)c(=O)[nH]2)c1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a mixture of 4-({[2-fluoro-3-(2-hydroxyethoxy)-5-methoxyphenyl]-(5-oxo-1-pyrimidin-2-yl-4,5-dihydro-1H-[1,2,4]triazol-3-yl)methyl}amino)benzamidine acetic acid salt [CAS No. 951803-95-5] (613 mg) and DMF (5 mL), benzoic acid 4-nitrophenyl ester [CAS No. 959-22-8] (280 mg) and triethylamine (0.2 mL) were added and the resulting mixture was stirred at 50° C. overnight. Acetic acid was added to the reaction solution, and the solvent was evaporated under reduced pressure. The residue obtained was purified by NAM silica gel column chromatography (mixed solvent of methanol-ethyl acetate) to obtain the captioned compound (492 mg).
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[C:17]([N:24]1[CH2:29][CH2:28][C:27](=O)[CH2:26][CH2:25]1)([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18]>>[C:20]([O:19][C:17]([N:24]1[CH2:29][CH2:28][CH:27]([NH:15][C:12]2[CH:11]=[CH:10][C:9]([O:8][CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:16])=[CH:14][CH:13]=2)[CH2:26][CH2:25]1)=[O:18])([CH3:23])([CH3:21])[CH3:22]
Reactant: CC(C)(C)OC(=O)COc1ccc(N)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Product: CC(C)(C)OC(=O)COc1ccc(NC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Yield: 94.9 %

Procedure:
Using general procedure A, (4-amino-phenoxy)-acetic acid tert-butyl ester (Renodon-Corniere, Axelle; et al., J. Med. Chem., 45, 4, 2002, 944-954) (4.84 g, 21.6 mmol) and 1-Boc-4-piperidone (3.4 g, 17.1 mmol) afforded 4-(4-tert-butoxycarbonylmethoxy-phenylamino)-piperidine-1-carboxylic acid tert-butyl ester (6.6 g, 95%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([NH:14][CH2:15][C:16]2[CH:25]=[C:24]3[C:19]([CH2:20][CH2:21][CH2:22][CH:23]3[C:26]([F:29])([F:28])[F:27])=[CH:18][C:17]=2[O:30][CH3:31])[C@@H:9]1[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=O)(C)(C)C.FC(C1C=CC(OC(F)(F)F)=C(C=1)CN[C@H]1CCCN[C@H]1C1C=CC=CC=1)(F)C>>[CH3:31][O:30][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][C:16]=1[CH2:15][NH:14][C@H:10]1[CH2:11][CH2:12][CH2:13][NH:8][C@H:9]1[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH:23]([C:26]([F:29])([F:27])[F:28])[CH2:22][CH2:21][CH2:20]2
Reactant: COc1cc2c(cc1CN[C@H]1CCCN(C(=O)OC(C)(C)C)[C@H]1c1ccccc1)C(C(F)(F)F)CCC2
Agent: CC(F)(F)c1ccc(OC(F)(F)F)c(CN[C@H]2CCCN[C@H]2c2ccccc2)c1
Product: COc1cc2c(cc1CN[C@H]1CCCN[C@H]1c1ccccc1)C(C(F)(F)F)CCC2

Procedure:
This compound was prepared from Compound 92 in the same manner of Compound 27.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([N:7]([CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:8]([C:10]2[CH:29]=[CH:28][C:13]3[N:14]([CH3:27])[C:15]([CH2:17][NH:18][C:19]4[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=4)=[N:16][C:12]=3[CH:11]=2)=[O:9])[CH:2]=1.[ClH:37].C(O)C.C(=O)([O-])[O-].[NH4+:45].[NH4+]>ClCCl.C(O)C>[ClH:37].[ClH:37].[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([N:7]([CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:8]([C:10]2[CH:29]=[CH:28][C:13]3[N:14]([CH3:27])[C:15]([CH2:17][NH:18][C:19]4[CH:20]=[CH:21][C:22]([C:25](=[NH:45])[NH2:26])=[CH:23][CH:24]=4)=[N:16][C:12]=3[CH:11]=2)=[O:9])[CH:2]=1
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C#N)cc1)n2C)c1cccnc1
Reactant: [NH4+]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C)c1cccnc1
Yield: 86 %

Procedure:
Prepared analogously to Example 25d from 1-methyl-2-[N-(4-cyanophenyl)aminomethyl]benzimidazol-5-yl-carboxylic acid-N-(3-pyridyl)-N-(2-ethoxycarbonylethyl)amide and ethanolic hydrochloric acid, ethanol, and ammonium carbonate. Yield: 86% of theory, C27H29N7O3 (499.6); Rf value: 0.09 (silica gel; dichloromethane/ethanol=4:1); EKA mass spectrum: (M+H)+=500.
Reaction SMILES: FC(F)(F)[C:3]([NH:5][C:6]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][N:8]([CH3:14])[N:7]=1)=O.CI.[OH-].[K+]>CC(C)=O>[CH3:14][N:8]1[CH:9]=[C:10]([N+:11]([O-:13])=[O:12])[C:6]([NH:5][CH3:3])=[N:7]1
Reactant: Cn1cc([N+](=O)[O-])c(NC(=O)C(F)(F)F)n1
Agent: [K+]
Agent: [OH-]
Solvent: CI
Solvent: CC(C)=O
Product: CNc1nn(C)cc1[N+](=O)[O-]
Reaction time: 0.08 h

Procedure:
100 g (4.20 mmoles) of 3-trifluoroacetylamino-1-methyl-4-nitropyrazol are heated with 2.12 g (16.8 mmoles) methyl iodide in 10 ml absolute acetone to 50° C. 940 mg (16.8 mmoles) powdered potassium hydroxide are then added and the reaction mixture is heated to boiling for 5 minutes. The solvent is distilled off in the rotary evaporator in vacuum and the residue is separated by means of column chromatography using silica gel with ether/toluene (5:1).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][O:4][C:3]2[CH:7]=[C:8]([CH:11]([O:16][CH3:17])[C:12]([NH:14][NH2:15])=[O:13])[CH:9]=[CH:10][C:2]1=2.[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:25]=[C:26]([O:30][CH3:31])[C:27]=1[O:28][CH3:29])[CH:23]=O>C(O)C.C(O)(=O)C.CCOCC>[O:1]1[CH2:6][CH2:5][O:4][C:3]2[CH:7]=[C:8]([CH:11]([O:16][CH3:17])[C:12]([NH:14]/[N:15]=[CH:23]/[C:22]3[CH:25]=[C:26]([O:30][CH3:31])[C:27]([O:28][CH3:29])=[C:20]([O:19][CH3:18])[CH:21]=3)=[O:13])[CH:9]=[CH:10][C:2]1=2
Reactant: COc1cc(C=O)cc(OC)c1OC
Reactant: COC(C(=O)NN)c1ccc2c(c1)OCCO2
Solvent: CCOCC
Solvent: CC(=O)O
Solvent: CCO
Product: COc1cc(/C=N/NC(=O)C(OC)c2ccc3c(c2)OCCO3)cc(OC)c1OC

Procedure:
In a round-bottom glass flask equipped with a magnetic stir bar 2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-methoxyacetohydrazide (1 eq., 1.1 mmol; 260 mg) was dissolved in ethanol (10 mL) at room temperature. To this well stirred solution, acetic acid (˜3 drops) and 3,4,5-trimethoxy-benzaldehyde (1.2 eq, 1.3 mmol; 260 mg) were added, and the reaction mixture was heated for 12 hours. The mixture was then cooled and the crude product was diluted with Et2O and filtered and the solid was washed thoroughly with Et2O to yield: 300 mg (65%) of (2-1).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C@H:2]1[CH:6]=[CH:7][C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1.[O:14]=[C:15]([OH:27])[C@@H:16]([C@H:18]([C@H:20]([C@@H:22]([C:24]([OH:26])=[O:25])[OH:23])[OH:21])[OH:19])[OH:17]>C(O)C.O>[O:14]=[C:15]([OH:27])[C@@H:16]([C@H:18]([C@H:20]([C@@H:22]([C:24]([OH:26])=[O:25])[OH:23])[OH:21])[OH:19])[OH:17].[NH:1]1[CH2:5][CH2:4][CH2:3][C@H:2]1/[CH:6]=[CH:7]/[C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1.[NH:1]1[CH2:5][CH2:4][CH2:3][C@H:2]1/[CH:6]=[CH:7]/[C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1
Reactant: C(=C[C@@H]1CCCN1)c1cccnc1
Agent: O=C(O)[C@@H](O)[C@H](O)[C@H](O)[C@@H](O)C(=O)O
Solvent: O
Solvent: CCO
Product: C(=C/[C@@H]1CCCN1)\c1cccnc1
Temperature: 70 °C

Procedure:
To a stirred solution of (2S)-3-(2-pyrrolidin-2-ylvinyl)pyridine (120 mg, 0.689 mmol) in ethanol (2 mL), galactaric acid (72.4 mg, 0.344 mmol) was added. The mixture was heated at 70° C., sonicated and then water (1–2 drops) was added; this process was repeated until most of the solid dissolved. The remaining insoluble material was removed by filtration. To the filtrate anhydrous diethyl ether was added dropwise until it became cloudy. After 16 h at 4° C. a precipitate was formed; this was filtered and vacuum dried to give 120 mg (61.9% yield) of product as a light brown solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:14][CH2:15][CH2:16][CH3:17])[NH:5][C:4](=[O:18])[C:3]=1[C:19]([OH:21])=[O:20].S(=O)(=O)(O)O.[CH3:27]O>>[CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:14][CH2:15][CH2:16][CH3:17])[NH:5][C:4](=[O:18])[C:3]=1[C:19]([O:21][CH3:27])=[O:20]
Reactant: CO
Reactant: CCCOc1ccccc1-c1cc(C)c(C(=O)O)c(=O)[nH]1
Agent: O=S(=O)(O)O
Product: CCCOc1ccccc1-c1cc(C)c(C(=O)OC)c(=O)[nH]1

Procedure:
A mixture of 1,2-dihydro-4-methyl-2-oxo-6-(2-propoxyphenyl)pyridine-3-carboxylic acid (0.75 g), methanol (50 ml) and concentrated sulfuric acid (0.5 ml) was heated under reflux for 6 hours. The residue left after evaporation was treated with water (30 ml) and potassium carbonate was added to pH 10. The resultant solid was washed with water and with ether to afford the title compound, 0.6 g, m.p. 167°-169° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[N:10][C:11]=1[CH:12]([O:15][CH3:16])[O:13][CH3:14])[N:8]([C:17]([NH:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][N:21]=1)=[O:18])[CH2:7][CH2:6][CH2:5]2.[CH:28]1(B(O)O)[CH2:30][CH2:29]1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C(Cl)Cl.CC([O-])=O.CC([O-])=O.[Pd+2].O.C1(C)C=CC=CC=1>[C:26]([C:23]1[CH:24]=[CH:25][C:20]([NH:19][C:17]([N:8]2[C:9]3[C:4](=[CH:3][C:2]([CH:28]4[CH2:30][CH2:29]4)=[C:11]([CH:12]([O:15][CH3:16])[O:13][CH3:14])[N:10]=3)[CH2:5][CH2:6][CH2:7]2)=[O:18])=[N:21][CH:22]=1)#[N:27]
Reactant: OB(O)C1CC1
Reactant: COC(OC)c1nc2c(cc1Br)CCCN2C(=O)Nc1ccc(C#N)cn1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COC(OC)c1nc2c(cc1C1CC1)CCCN2C(=O)Nc1ccc(C#N)cn1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
A tube was charged with 6-bromo-N-(5-cyanopyridin-2-yl)-7-(dimethoxymethyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide (intermediate 2H, 30 mg, 0.069 mmol), cyclopropylboronic acid (7.75 mg, 0.090 mmol), tricyclohexylphosphine (0.195 mg, 0.694 μmol), K3PO4 (51.6 mg, 0.243 mmol), toluene (0.5 ml) and H2O (0.05 ml) and flushed with argon. Then, Pd(OAc)2 (0.779 mg, 3.47 μmol) was added, the tube was sealed and the reaction mixture was stirred at 100° C. for 1 h. The reaction mixture was cooled to room temperature, diluted with DCM and washed with water. The organic phase was then dried over Na2SO4, filtered and evaporated. The crude material was purified by supercritical fluid chromatography (SFC 1, DEAP column) to give the title compound as a colorless solid. (UPLC-MS 3) tR 1.25 min; ESI-MS 394.2 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:16]([OH:18])=[O:17])[CH:13]([CH3:15])[CH3:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.CS(O[N:31]=[C:32]([C:38]#[N:39])[C:33]([O:35][CH2:36][CH3:37])=[O:34])(=O)=O>C(OCC)(=O)C>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:16]([O:18][N:31]=[C:32]([C:38]#[N:39])[C:33]([O:35][CH2:36][CH3:37])=[O:34])=[O:17])[CH:13]([CH3:15])[CH3:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CCOC(=O)C(C#N)=NOS(C)(=O)=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C#N)=NOC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C
Temperature: 25 °C
Reaction time: 20 h
Yield: 96 %

Procedure:
N-Benzyloxycarbonyl-L-valine (1.26 g) and triethylamine (0.70 ml) are dissolved in ethyl acetate (10 ml). To the solution is added ethyl 2-methanesulfonyloxyimino-2-cyanoacetate (1.1 g) and the mixture is stirred at room temperature for 20 hours. The reaction mixture is washed with water, dried and then concentrated to give ethyl 2-(N-benzyloxycarbonyl-L-valyloxyimino)-2-cyanoacetate (1.8 g) as an oily substance.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12]CC2C=CC=CC=2)=[C:8]([CH2:20][NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH:7]=1>C1COCC1>[CH3:1][O:2][C:3](=[O:29])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]([CH2:20][NH:21][C:22]([O:24][C:25]([CH3:27])([CH3:26])[CH3:28])=[O:23])[CH:7]=1
Reactant: COC(=O)CCc1ccc(OCc2ccccc2)c(CNC(=O)OC(C)(C)C)c1
Solvent: C1CCOC1
Product: COC(=O)CCc1ccc(O)c(CNC(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A solution of 3-[4-benzyloxy-3-(tert-butoxycarbonylamino-methyl)-phenyl]-propionic acid methyl ester (8.50 g, 21.3 mmol) in THF (100 mL) was treated with 5% Pd-on-carbon (1.1 g) and shaken under a hydrogen atmosphere (60 psi) at ambient temperature for 6 h. The mixture was filtered through Celite and concentrated to a pale yellow solid (5.63 g, 85%).
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]2=[C:7]([CH2:10][OH:11])[N:8]=[CH:9][N:4]2[CH:3]=1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>ClCCl.C(OCC)C.S([O-])([O-])(=O)=O.[Mg+2]>[Br:1][C:2]1[S:6][C:5]2=[C:7]([CH:10]=[O:11])[N:8]=[CH:9][N:4]2[CH:3]=1
Reactant: OCc1ncn2cc(Br)sc12
Agent: O=[Cr](=O)([O-])Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CCOCC
Solvent: ClCCl
Product: O=Cc1ncn2cc(Br)sc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 18.2 %

Procedure:
A solution of 2-bromo-7-hydroxymethylimidazo [5,1-b]thiazole (44 mg, 0.19 mmol) in dichloromethane (4 ml) was added to a suspension of pyridinium chlorochromate (121 mg, 0.56 mmol) in dichloromethane (2 ml), and the mixture was stirred at room temperature for 30 min. After the completion of the reaction, the reaction solution was diluted with diethyl ether, anhydrous magnesium sulfate was added thereto, and the mixture was stirred at room temperature for additional 10 min. The reaction mixture was filtered through Celite. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography on silica gel (ethyl acetate:methanol=60:1) to give 2-bromoimidazo[5,1-b]thiazole-7-carbaldehyde (8 mg, 18%) as a white solid.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][C:8]([N:10]1[CH2:23][CH2:22][CH2:21][C@H:11]1[C:12]([N:14]1[CH2:20][CH2:19][CH2:18][C@H:15]1[CH2:16][OH:17])=[O:13])=[O:9].C(N(CC)CC)C>CS(C)=O>[O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][C:8]([N:10]1[CH2:23][CH2:22][CH2:21][C@H:11]1[C:12]([N:14]1[CH2:20][CH2:19][CH2:18][C@H:15]1[CH:16]=[O:17])=[O:13])=[O:9]
Reactant: O=C1CCCN1CC(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1CO
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: O=C[C@@H]1CCCN1C(=O)[C@@H]1CCCN1C(=O)CN1CCCC1=O
Reaction time: 1 h
Yield: 69.1 %

Procedure:
To a solution of N-[(2-oxo-1-pyrrolidinyl)acetyl]-L-prolyl-L-prolinol (965 mg) in DMSO (5 ml) were added triethylamine (2.5 ml) and sulfur trioxide pyridine complex (1.89 g) under ice-cooling, and the mixture was stirred at a temperature of 10°-15° C. for 1 hour. The reaction mixture was concentrated at room temperature, and the residue was purified by silica gel column chromatography (chloroform-methanol) to give 663 mg of N-[(2-oxo-1-pyrrolidinyl)acetyl]-L-prolyl-L-prolinal.
Reaction SMILES: [CH3:1][N:2]([CH3:16])[CH2:3][CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH:14]=O)[CH:12]=2)[NH:7][CH:6]=1.[CH2:17]([O:24][C:25]([NH:27][NH2:28])=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CO>[CH2:17]([O:24][C:25]([NH:27][N:28]=[CH:14][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:4][CH2:3][N:2]([CH3:16])[CH3:1])=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CN(C)CCc1c[nH]c2ccc(C=O)cc12
Reactant: NNC(=O)OCc1ccccc1
Solvent: CO
Product: CN(C)CCc1c[nH]c2ccc(C=NNC(=O)OCc3ccccc3)cc12

Procedure:
A 50 ml flask is charged with 3-(2-dimethylamino-ethyl)-1H-indole-5-carbaldehyde (Reference Example 9; 2.16 g, 10 mmol), hydrazinecarboxylic acid benzyl ester (1.66 g, 10 mmol), and methanol (30 ml). This mixture is heated at reflux over night, and then the solvent is removed on the rotavapor to leave the hydrazone as a foam. 1H-NMR (CDCl3, 300 MHz) δ 2.24 (s, 6H, N(CH3)2); 2.55, 2.81 (2 m, 2H each, CH2CH2NHMe2); 5.22 (s, 2H, OCH2); 6.86 (d, 1H, J=2 Hz, H-2); 7.09 (d, 1H, J=8.5 Hz, H-7); 7.23-7.36 (m, Ph-H); 7.43 (dd, 1H, J=1.5 Hz, H-6); 7.62 (d, 1H, H-4); 7.79 (br s, 1H, N═CH); 9.35 (br s, NH); 9.50 (s, 1H, H-1). 13C-NMR (CDCl3, 75 MHz) δ 23.57 (CH2); 45.36 (N(CH3)2); 60.26 (CH2NMe2); 67.47 (OCH2); 112.17 (C-7); 114.3 (C-3); 119.51 (C-4); 120.69 (C-6); 123.32 (C-2); 125.15 (C-5); 127.48 (C-9); 128.33, 128.50 (2C), 128.73 (2C), 136.40 (q) (Ph C); 137.76 (C-8) 147.50 (N═CH); 154.10 (NC═O).