Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21]([OH:23])=O)=[CH:19][N:18]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.[CH3:32][C:33]([CH3:38])([CH3:37])[C@@H:34]([NH2:36])[CH3:35].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.O>CN(C=O)C>[CH3:35][C@H:34]([NH:36][C:21]([C:20]1[C:14]2[C:15](=[N:16][CH:17]=[C:12]([C:6]3[C:5]4[C:9](=[CH:10][C:2]([F:1])=[CH:3][CH:4]=4)[N:8]([CH3:11])[N:7]=3)[N:13]=2)[N:18]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:30])([CH3:31])[CH3:29])[CH:19]=1)=[O:23])[C:33]([CH3:38])([CH3:37])[CH3:32]
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)O)cn3COCC[Si](C)(C)C)c2ccc(F)cc21
Reactant: C[C@H](N)C(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Product: C[C@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(F)ccc34)nc12)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.4 %

Procedure:
In a round-bottomed flask 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (120 mg, 0.27 mmol) was dissolved in DMF (1.2 ml). (S)-3,3-Dimethylbutan-2-amine (0.25 ml, 1.84 mmol) was added followed by HATU (114 mg, 0.30 mmol) and the yellow solution was stirred at room temperature overnight. Water was added and the resulting suspension was filtered. The filter cake was washed with water and petroleum ether then dried under high vacuum to afford 104 mg (73%) of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((S)-1,2,2-trimethyl-propyl)-amide as a light yellow powder.
Reaction SMILES: [NH2:1][C:2]1[C:11]([CH3:12])=[CH:10][CH:9]=[CH:8][C:3]=1[O:4][CH2:5][C:6]#[N:7].[Cl:13][C:14]1[N:19]=[C:18](Cl)[C:17]([Cl:21])=[CH:16][N:15]=1>>[Cl:13][C:14]1[N:19]=[C:18]([NH:1][C:2]2[C:11]([CH3:12])=[CH:10][CH:9]=[CH:8][C:3]=2[O:4][CH2:5][C:6]#[N:7])[C:17]([Cl:21])=[CH:16][N:15]=1
Reactant: Cc1cccc(OCC#N)c1N
Reactant: Clc1ncc(Cl)c(Cl)n1
Product: Cc1cccc(OCC#N)c1Nc1nc(Cl)ncc1Cl

Procedure:
[2-(2,5-Dichloro-pyrimidin-4-ylamino)-3-methyl-phenoxy]-acetonitrile was prepared from (2-Amino-3-methyl-phenoxy)-acetonitrile and 2,4,5-Trichloropyrimidine in an analogous manner to Example 1230a. Title product obtained as an off-white solid, 365 mg, 29%. MP: 134-136, LCMS 309.07 (M+H), HPLC purity 75%, 1H-NMR (CDCl3, 400 MHz) δ 8.20 (s, 1H), 7.31-7.27 (m, 1H), 7.07 (d, J=7.7 Hz, 1H), 6.95 (d, J=8.2 Hz, 1H), 6.82 (s, 1H), 4.79 (s, 2H), 2.27 (s, 3H).
Reaction SMILES: CCN=C=NCCCN(C)C.CS(C)=O.[CH3:16][O:17][C:18](=[O:34])[CH2:19][CH2:20][CH2:21][C:22]#[C:23][CH2:24][N:25]1[C:30](=[O:31])[CH2:29][CH2:28][CH2:27][C@@H:26]1[CH2:32][OH:33].FC(F)(F)C([O-])=O.[NH+]1C=CC=CC=1>C1C=CC=CC=1>[CH3:16][O:17][C:18](=[O:34])[CH2:19][CH2:20][CH2:21][C:22]#[C:23][CH2:24][N:25]1[C:30](=[O:31])[CH2:29][CH2:28][CH2:27][C@@H:26]1[CH:32]=[O:33]
Reactant: COC(=O)CCCC#CCN1C(=O)CCC[C@@H]1CO
Agent: CCN=C=NCCCN(C)C
Agent: O=C([O-])C(F)(F)F
Agent: c1cc[nH+]cc1
Solvent: CS(C)=O
Solvent: c1ccccc1
Product: COC(=O)CCCC#CCN1C(=O)CCC[C@@H]1C=O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
EDCI (127 mg, 0.66 mmol) and DMSO (62 μL, 0.87 mmol) were added sequentially to a solution of 7-((R)-2-hydroxymethyl-6-oxo-piperidin-1-yl)-hept-5-ynoic acid methyl ester (prepared in accordance with Example 29, step 3, 59 mg, 0.22 mmol) in benzene (2.0 mL) at rt. The mixture was cooled to 0° C. and pyridinium trifluoroacetate (47 mg, 0.24 mmol) was added. The reaction was allowed to warm to rt and then was stirred at rt for 2 h. The solution was decanted from the oily residue and the residue was washed with benzene (3×2 mL). The combined benzene phases were concentrated in vacuo to afford crude 7-((R)-2-formyl-6-oxo-piperidin-1-yl)-hept-5-ynoic acid methyl ester that was used without further purification.
Reaction SMILES: CON(C)[C:4](=[O:28])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]2[CH:12]=[CH:13][C:14]3[O:18][C:17]([CH2:19][CH2:20][N:21]4[CH2:25][CH2:24][CH2:23][C@H:22]4[CH3:26])=[CH:16][C:15]=3[CH:27]=2)[CH:6]=1.[CH2:30]([Mg]Cl)[CH:31]([CH3:33])[CH3:32]>>[CH3:30][CH:31]([CH3:33])[CH2:32][C:4]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]2[CH:27]=[CH:15][C:14]3[O:18][C:17]([CH2:19][CH2:20][N:21]4[CH2:25][CH2:24][CH2:23][C@H:22]4[CH3:26])=[CH:16][C:13]=3[CH:12]=2)[CH:6]=1)=[O:28]
Reactant: CON(C)C(=O)c1cccc(-c2ccc3oc(CCN4CCC[C@H]4C)cc3c2)c1
Reactant: CC(C)C[Mg]Cl
Product: CC(C)CC(=O)c1cccc(-c2ccc3oc(CCN4CCC[C@H]4C)cc3c2)c1
Reaction time: 8 h
Yield: 19 %

Procedure:
The product from Example 145 and isobutylmagnesium chloride were processed as described in Example 146, except that after reacting overnight additional isobutylmagnesium chloride (400 mol %) was added and the reaction mixture was stirred for four more hours, to provide the title compound (19% yield). MS (ESI APCI) m/z 390 (M+H)+; 1HNMR (300 MHz, CD3OD) δ 1.01 (d, 6 H), 1.17 (d, 3 H), 1.37-1.53 (m, 1 H), 1.73-1.86 (m, 2 H), 1.94-2.07 (m, 1 H), 2.20-2.35 (m, 2 H), 2.41-2.59 (m, 2 H), 2.95 (d, 2 H), 2.95-3.14 (m, 2 H), 3.19-3.34 (m, 2 H), 6.62 (s, 1 H), 7.49-7.52 (m, 2 H), 7.57 (dd, 1 H), 7.77 (dd, 1 H), 7.86 (ddd, 1 H), 7.93 (ddd, 1 H), 8.19 (dd, 1 H).
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][NH2:7])(=[O:3])[CH3:2].[Cl:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=O)[CH:14]([CH2:20][CH:21]=O)[CH2:13][CH2:12]2>C(Cl)Cl>[Cl:8][C:9]1[CH:18]=[CH:17][C:16]2[C:15]3[N:7]([CH2:6][CH2:5][NH:4][C:1](=[O:3])[CH3:2])[CH:21]=[CH:20][C:14]=3[CH2:13][CH2:12][C:11]=2[CH:10]=1
Reactant: O=CCC1CCc2cc(Cl)ccc2C1=O
Reactant: CC(=O)NCCN
Solvent: ClCCl
Product: CC(=O)NCCn1ccc2c1-c1ccc(Cl)cc1CC2
Yield: 67.5 %

Procedure:
N-Acetylethylenediamine (2.4 g) was dissolved in 40 ml of methylene chloride under argon, treated in succession with 40 g of molecular sieve 4 Å and a solution of 4.8 g of 6-chloro-1,2,3,4-tetrahydro-1-oxo-2-naphthaleneacetaldehyde in 20 ml of methylene chloride and refluxed for 40 hours while stirring. The reaction mixture was cooled, filtered over a Celite® pad and the filtrate was freed from solvent. The crude product, 5.6 g of brown solid, was dissolved in a 6-fold amount of hot ethyl acetate and, after the addition of an 8-fold amount of hexane, boiled briefly. There were obtained 4.2 g (67%) of N-[2-(7-chloro-4,5-dihydro-1H-benz[g]indol-1-yl)ethyl]acetamide; m.pt.: 144°-145° C.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@@H:14]([CH3:15])[CH2:13][N:12]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][C:17]=2[N+:22]([O-])=O)[CH2:11][C@H:10]1[NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H][H]>CO.[Pd]>[NH2:22][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][C:16]=1[N:12]1[CH2:13][C@H:14]([CH3:15])[C@@H:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[C@H:10]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:11]1
Reactant: [H][H]
Reactant: C[C@H]1CN(c2ccncc2[N+](=O)[O-])C[C@@H](NC(=O)OC(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Agent: [Pd]
Solvent: CO
Product: C[C@H]1CN(c2ccncc2N)C[C@@H](NC(=O)OC(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Yield: 99.7 %

Procedure:
A mixture of tert-butyl [(3R,4R,5S)-4-{[tert-butyl(dimethyl)silyl]oxy}-5-methyl-1-(3-nitropyridin-4-yl)piperidin-3-yl]carbamate (13.4 g, 28.7 mmol) in MeOH (80 mL) was hydrogenated in the presence of 10% palladium on carbon (4.6 g) under 60 psi of hydrogen for 16 h. The reaction mixture was filtered through diatomaceous earth and the filtrate was concentrated under reduced pressure to give the sub-title compound (12.5 g, 99%). LCMS calc. for C22H41N4O3Si (M+H)+: m/z=437.3. Found: 437.4.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[Cl:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=1.[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>C1COCC1>[CH2:20]([N:27]1[CH2:32][CH2:31][C:30]([C:19]2[C:10]([Cl:9])=[N:11][C:12]3[C:17]([CH:18]=2)=[CH:16][CH:15]=[CH:14][CH:13]=3)([OH:33])[CH2:29][CH2:28]1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: Clc1ccc2ccccc2n1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: OC1(c2cc3ccccc3nc2Cl)CCN(Cc2ccccc2)CC1
Temperature: -20 °C
Reaction time: 2 h

Procedure:
To a solution of LDA (3.4 ml of 2 M in Hept/THF) at −78° C. in THF (5 ml) was added a solution of 2-chloroquinoline (1.0 g. 6.11 mmol) in THF (10 ml) dropwise, and the reaction mixture stirred at −78° C. for 1 hour before a solution of 1-benzylpiperidin-4-one (1.22 g, 6.22 mmol) in THF (2 ml) was added dropwise. The reaction mixture was stirred from −78° C. to RT over two hours, cooled to −20° C., quenched with water and extracted with EtOAc. The organics combined, dried (Na2SO4) and evaporated to dryness. Purification by column chromatography (1 to 15% MeOH in DCM) gave the desired product. LC/MS (10% to 99%): M/Z (M+H)+ (obs)=353; tR=24.
Reaction SMILES: [Br:1][CH2:2][CH2:3][O:4][C:5]1[C:6]([Cl:16])=[C:7]([CH:11]=[CH:12][C:13]=1[O:14][CH3:15])[C:8](O)=[O:9].S(Cl)([Cl:19])=O>>[Cl:16][C:6]1[C:5]([O:4][CH2:3][CH2:2][Br:1])=[C:13]([O:14][CH3:15])[CH:12]=[CH:11][C:7]=1[C:8]([Cl:19])=[O:9]
Reactant: COc1ccc(C(=O)O)c(Cl)c1OCCBr
Reactant: O=S(Cl)Cl
Product: COc1ccc(C(=O)Cl)c(Cl)c1OCCBr
Temperature: 60 °C
Yield: 100 %

Procedure:
A suspension of 3-bromoethoxy-2-chloro-4-methoxybenzoic acid (1.4 g, 4.5 mmol) in thionyl chloride (20 ml) is heated at 60 ° C. until dissolved (˜20 min) plus an additional 30 minutes. The reaction mixture is cooled to room temperature and excess thionyl chloride is evaporated under reduced pressure. The resulting residue is evaporated at reduced pressure with toluene (50 ml) two times to obtain 1.5 g (100%) of 2-chloro-3-bromoethoxy-4-methoxybenzoic acid chloride.
Reaction SMILES: FC(F)(F)C(OC(=O)C(F)(F)F)=[O:4].[CH3:14][C:15]1[C:20]([F:21])=[C:19]([Cl:22])[CH:18]=[CH:17][N+:16]=1[O-].CO>ClCCl>[OH:4][CH2:14][C:15]1[C:20]([F:21])=[C:19]([Cl:22])[CH:18]=[CH:17][N:16]=1
Reactant: Cc1c(F)c(Cl)cc[n+]1[O-]
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: CO
Product: OCc1nccc(Cl)c1F
Reaction time: 72 h

Procedure:
Trifluoroacetic anhydride (16.18 ml) was added dropwise at 10°-15° to a solution of 2-methyl-3-fluoro-4-chloropyridine-N-oxide (6.17 g) in dichloromethane (50 ml). After three days at room temperature, methanol (30 ml) was added to the cooled solution. The excess solvent was removed and the residue dissolved in water. After basifying (NaOH), the solution was extracted with dichoromethane. The extracts were dried (K2CO3) and evaporated to dryness to give a solid which was purified by column chromatography (silica gel; 1% MeOH/CHCl3) to give 2-hydroxymethyl-3-fluoro-4-chloropyridine (3.8 g) m.p. indeterminate)
Reaction SMILES: O=[C:2]([CH3:15])[CH2:3][C:4]1[O:9][C:8](=[O:10])[C:7]2[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=2[N:5]=1.Cl.[NH:17]([C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1)[NH2:18].C([O-])(=O)C.[Na+]>C(O)C>[CH3:15][C:2]1[CH:3]=[C:4]([NH:5][C:6]2[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=2[C:8]([OH:9])=[O:10])[N:17]([C:19]2[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=2)[N:18]=1
Reactant: CC(=O)Cc1nc2ccccc2c(=O)o1
Reactant: NNc1ccncc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: Cc1cc(Nc2ccccc2C(=O)O)n(-c2ccncc2)n1
Temperature: 25 °C
Yield: 49.1 %

Procedure:
A solution of 2-(2-oxopropyl)-4H-3,1-benzoxazin-4-one (16.7 g, 82.4 mmol), 4-hydrazinopyridine hydrochloride (12.0 g, 82.4 mmol) and sodium acetate (8.10 g, 98.9 mmol) in ethanol (300 mL) was heated under reflux for 30 minutes. The solution was cooled to room temperature and concentrated under reduced pressure. The residue was poured into water and the resulting crude crystals were collected by filtration. The crystals were washed with ethanol and air dried to give the title compound (11.9 g, 49% yield).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH:13]([CH3:15])[CH3:14])[C:6]([OH:8])=O)#[N:2].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.O[NH:31][C:32](=[NH:50])[C:33]1[CH:41]=[CH:40][CH:39]=[C:38]2[C:34]=1[CH:35]=[CH:36][N:37]2[CH2:42][CH2:43][CH2:44][C:45]([O:47][CH2:48][CH3:49])=[O:46]>CN(C=O)C>[C:1]([C:3]1[CH:4]=[C:5]([C:6]2[O:8][N:50]=[C:32]([C:33]3[CH:41]=[CH:40][CH:39]=[C:38]4[C:34]=3[CH:35]=[CH:36][N:37]4[CH2:42][CH2:43][CH2:44][C:45]([O:47][CH2:48][CH3:49])=[O:46])[N:31]=2)[CH:9]=[CH:10][C:11]=1[O:12][CH:13]([CH3:15])[CH3:14])#[N:2]
Reactant: CC(C)Oc1ccc(C(=O)O)cc1C#N
Reactant: CCOC(=O)CCCn1ccc2c(C(=N)NO)cccc21
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CCOC(=O)CCCn1ccc2c(-c3noc(-c4ccc(OC(C)C)c(C#N)c4)n3)cccc21
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 52.7 %

Procedure:
A mixture of 3-cyano-4-[(1-methylethyl)oxy]benzoic acid (can be prepared as described in WO2005/58848) (1.21 g, 5.88 mmol), EDC (1.35 g, 7.05 mmol) and HOBt (1.08 g, 7.05 mmol) in dry DMF (85 ml) was stirred for 20 minutes at RT. Added ethyl 4-{4-[(hydroxyamino)(imino)methyl]-1H-indol-1-yl}butanoate (D59) (1.70 g, 5.88 mmol) and stirred at RT for 1 hour. Heated mixture at 80° C. for 5 hours and left overnight at RT. Heated at 80° C. for 6 hours then evaporated off the DMF. Added EtOAc (200 ml) and washed with sat. NaHCO3 (200 ml) and water (200 ml). Dried over MgSO4 and evaporated off the solvent. Subjected the residue to chromatography using the biotage (EtOAc/hexane 1:2) and evaporated the cleanest fractions to yield 1.42 g the title compound as a white solid. δH (400 MHz, d6-DMSO) 1.15 (3H, t), 1.39 (6H, d), 2.04 (2H, apparent quintet), 2.24 (2H, t), 4.00 (2H, q), 4.31 (2H, t), 4.94-5.04 (1H, m), 7.10 (1H, dd), 7.31 (1H, t), 7.56-7.60 (2H, m), 7.77 (1H, d), 7.95 (1H, d), 8.45 (1H, dd), 8.56 (1H, d). MS (ES) C26H26N4O4 requires 458; found 459 (MH+).
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]1[CH:30]=[CH:29][CH:28]=[CH:27][C:10]=1[CH:11]=[C:12]1[C:17](=[O:18])[C:16](=[CH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[F:26])[CH2:15][NH:14][CH2:13]1.[C:31](Cl)(=[O:49])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48].C(=O)([O-])[O-].[K+].[K+]>ClCCCl>[C:31]([N:14]1[CH2:13][C:12](=[CH:11][C:10]2[CH:27]=[CH:28][CH:29]=[CH:30][C:9]=2[F:8])[C:17](=[O:18])[C:16](=[CH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[F:26])[CH2:15]1)(=[O:49])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48]
Reactant: CCCCCCCCCCCCCCCCCC(=O)Cl
Reactant: O=C1C(=Cc2ccccc2F)CNCC1=Cc1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCCC(=O)N1CC(=Cc2ccccc2F)C(=O)C(=Cc2ccccc2F)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 67.2 %

Procedure:
Triethylamine (0.4 ml, 2.85 mmol) was added to a solution of compound 1 (300 mg, 0.96 mmol) in ice-cold 1,2 dichloroethane. A solution of stearoyl chloride (450 mg, 1.49 mmol) in 1,2-dichloroethane was added drop-wise to the ice-cold solution of compound 1. The reaction mixture was stirred at room temperature for 16 h. After completion of the reaction, 10% potassium carbonate solution (10 ml) was added, and stirred for 30 min. The organic phase was separated, dried with anhydrous sodium sulfate, and concentrated to obtain a shiny solid of 25 (373 mg, 67% yield). 1H NMR (300 MHz, CDCl3): δ 7.92, 7.89 (2s, 2H, C═CH), 7.50-7.35 (m, 4H, Ar—H), 7.30-7.14 (m, 4H, Ar—H), 4.79, 4.55 (2s, 4H), 2.44 (td, 2H, J=7.3, 2.3), 2.09 (t, 2H, J=7.6), 1.65 (t, 2H, J=7.0), 1.41 (t, 2H, J=7.3), 1.40-1.05 (m, 24H), 0.87 (t, 3H, J=6.7, CH3). 13C NMR (75 MHz, CDCl3): δ 172.05, 133.77, 133.40, 133.48, 130.76, 130.23, 124.29, 116.39, 116.09, 115.81, 46.45, 43.48, 35.26, 33.08, 31.92, 29.69, 29.37, 28.86, 25.06, 24.21, 22.69, 14.12. ESI Mass calculated for C37H50F2NO2(M+H)+578.38. found 578.40.
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:35])=[C:7]2[C:12](=[C:13]([C:15]3[N:16]=[N:17][CH:18]=[CH:19][CH:20]=3)[N:14]=1)[N:11]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:10](=[O:28])[C:9]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[CH:8]2)=[O:4].[NH2:36][CH2:37][CH2:38][C:39]([OH:41])=[O:40].C[O-].[Na+]>C([O-])(O)=O.[Na+]>[CH2:21]([N:11]1[C:12]2[C:7](=[C:6]([OH:35])[C:5]([C:3]([NH:36][CH2:37][CH2:38][C:39]([OH:41])=[O:40])=[O:4])=[N:14][C:13]=2[C:15]2[N:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[CH:8]=[C:9]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:10]1=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: NCCC(=O)O
Reactant: COC(=O)c1nc(-c2cccnn2)c2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Agent: C[O-]
Agent: O=C([O-])O
Agent: [Na+]
Product: O=C(O)CCNC(=O)c1nc(-c2cccnn2)c2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Temperature: 25 °C
Yield: 27.7 %

Procedure:
A mixture of 1-benzyl-5-hydroxy-2-oxo-3-phenyl-8-pyridazin-3-yl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (45 mg, 0.097 mmol), β-alanine (864 mg, 9.7 mmol) and NaOMe solution (15.5 mL, 7.8 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was partitioned between EtOAc and water. 1 M HCl was added with vigorous stirring until pH was about 3-4. The aqueous layer was extracted with additional EtOAc, and the organic layers were combined, dried over MgSO4 and concentrated. The crude product was purified by silica gel chromatography (20-100% EtOAc/hexanes+1% AcOH). The product isolated was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH about 3-4, and the resulting precipitate was isolated by filtration to give 14 mg of the title compound as a yellow solid. MS: (+) m/z 522.35 (M+1).
Reaction SMILES: [NH2:1][C:2]1[N:11]=[CH:10][C:9]2[CH2:8][CH2:7][C:6]3[C:12]([C:16]([NH:18][C:19]4[C:24]([CH2:25][CH3:26])=[CH:23][CH:22]=[CH:21][C:20]=4[CH2:27][CH3:28])=[O:17])=[N:13][N:14]([CH3:15])[C:5]=3[C:4]=2[N:3]=1.[C:29]([N:36]1[CH2:41][CH2:40][C:39](=O)[CH2:38][CH2:37]1)([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30].C(O)(C(F)(F)F)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[OH-].[Na+]>CN(C)C=O>[CH2:27]([C:20]1[CH:21]=[CH:22][CH:23]=[C:24]([CH2:25][CH3:26])[C:19]=1[NH:18][C:16]([C:12]1[C:6]2[CH2:7][CH2:8][C:9]3[CH:10]=[N:11][C:2]([NH:1][CH:39]4[CH2:40][CH2:41][N:36]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:37][CH2:38]4)=[N:3][C:4]=3[C:5]=2[N:14]([CH3:15])[N:13]=1)=[O:17])[CH3:28]
Reactant: CCc1cccc(CC)c1NC(=O)c1nn(C)c2c1CCc1cnc(N)nc1-2
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: CCc1cccc(CC)c1NC(=O)c1nn(C)c2c1CCc1cnc(NC3CCN(C(=O)OC(C)(C)C)CC3)nc1-2
Reaction time: 20 h
Yield: 80 %

Procedure:
To a solution of 8-amino-N-(2,6-diethylphenyl)-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide (1.0 g, 2.66 mmol) in dry dimethylformamide (20 mL), were added 1-Boc-4-piperidone (1.06 g mL, 5.32 mmol), CF3COOH (1.7 mL, 22.7 mmol) and NaBH(OAc)3 (1.12 g, 5.32 mmol). After 20 hours, NaOH 2N (12 mL, 24 mmol) was added dropwise to the mixture. The precipitate was filtered, washed with water and dried. The crude material was purified by flash chromatography on silica gel eluted with dichloromethane/methanol 97:3 to give the 1.2 g of to the pure title compound (80% yield).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([CH:12]=[CH:13][C:14](=[CH2:16])[CH3:15])[C:4](=[O:17])[C:3]=1[C:18]([O:20]CC)=O.[C:23]([NH:36][NH2:37])(=[O:35])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]>>[C:23]([NH:36][NH:37][C:18]([C:3]1[C:4](=[O:17])[N:5]([CH:12]=[CH:13][C:14](=[CH2:16])[CH3:15])[C:6]2[C:11]([C:2]=1[OH:1])=[CH:10][CH:9]=[CH:8][CH:7]=2)=[O:20])(=[O:35])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]
Reactant: CCCCCCCCCCCC(=O)NN
Reactant: C=C(C)C=Cn1c(=O)c(C(=O)OCC)c(O)c2ccccc21
Product: C=C(C)C=Cn1c(=O)c(C(=O)NNC(=O)CCCCCCCCCCC)c(O)c2ccccc21

Procedure:
Reagents: Comp 29 (0.66 mmols, 0.2 g); dodecanoyl hydrazine (0.73 mmols, 0.16 g). Yield: 0.125 g (40%), white solid, m.p.=107° C.-108° C.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([C:6]1[S:7][C:8]([C:12]#[C:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:9][C:10]=1[NH2:11])=[O:5].[CH2:18]([O:25][CH:26]1[CH2:29][C:28](=O)[CH2:27]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.C(OCC)(=O)C>[CH3:2][O:3][C:4]([C:6]1[S:7][C:8]([C:12]#[C:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:9][C:10]=1[NH:11][CH:28]1[CH2:29][CH:26]([O:25][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:27]1)=[O:5]
Reactant: O=C1CC(OCc2ccccc2)C1
Reactant: COC(=O)c1sc(C#CC(C)(C)C)cc1N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)c1sc(C#CC(C)(C)C)cc1NC1CC(OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 115.7 %

Procedure:
A mixture of 3-amino-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic acid methyl ester, hydrochloride salt (750 mg, 2.74 mmol) and 3-benzyloxy-cyclobutanone (2.5 g, 14.3 mmol) in DCM (40 mL) was treated with sodium triacetoxyborohydride (3.34 g, 15.8 mmol) portionwise. The mixture was stirred at room temperature for 3 hours. The solution was diluted with ethyl acetate, washed sequentially with saturated aqueous sodium bicarbonate, water, and brine. The organic phase was dried over magnesium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (0-10% ethyl acetate:hexanes). This resulted in 1.26 g (quant. yield) of 3-(3-benzyloxy-cyclobutylamino)-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic acid methyl ester as a mixture of cis- and trans-isomers.
Reaction SMILES: [N:1]1[N:2]([C:10]2[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH2:17]Cl)[C:11]=2[OH:19])[N:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.C(=O)(O)[O-:21].[Na+]>O1CCCC1.O>[N:1]1[N:2]([C:10]2[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH2:17][OH:21])[C:11]=2[OH:19])[N:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: O=C([O-])O
Reactant: Cc1cc(CCl)c(O)c(-n2nc3ccccc3n2)c1
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(CO)c(O)c(-n2nc3ccccc3n2)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 51.5 %

Procedure:
To a suspension of 2-(2H-Benzotriazol-2-yl)-6-chloromethyl-4-methyl-phenol (20.0 g, 73 mmol) in a mixture of tetrahydrofuran and water (180 g, 5:1) sodium bicarbonate (9.2 g, 110 mmol) is added. The reaction mixture is stirred at room temperature for 5 hours and evaporated to dryness. The crude product is purified by column chromatography (ethyl acetate/heptane 1:4) to yield 9.6 g of 2-(2H-Benzotriazol-2-yl)-6-hydroxymethyl-4-methyl-phenol.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1.[Cl:15][C:16]1[CH:17]=[C:18](N(C2CC2)CC2C=CC(OC)=CC=2)[C:19]2[N:20]([C:22]([C:25]#[N:26])=[CH:23][N:24]=2)[N:21]=1>>[Cl:15][C:16]1[CH:17]=[C:18]([N:5]([CH2:6][C:7]2[CH:8]=[CH:9][C:10]([O:13][CH3:14])=[CH:11][CH:12]=2)[CH2:4][CH2:3][O:2][CH3:1])[C:19]2[N:20]([C:22]([C:25]#[N:26])=[CH:23][N:24]=2)[N:21]=1
Reactant: COCCNCc1ccc(OC)cc1
Reactant: COc1ccc(CN(c2cc(Cl)nn3c(C#N)cnc23)C2CC2)cc1
Product: COCCN(Cc1ccc(OC)cc1)c1cc(Cl)nn2c(C#N)cnc12

Procedure:
15A was prepared from 2-methoxy-N-(4-methoxybenzyl)ethanamine and 1F following the procedure employed in the preparation of 1G. HPLC: Rt=3.20 min. (CHROMOLITH® column 4.6×50 mm eluting with 10-90% aqueous methanol over 4 min. containing 0.1% TFA, 4 mL/min., monitoring at 220 nm). MS (ES): m/z=372.1 [M+H]+.