Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[CH2:4][CH:5]([C:9]#[N:10])C(O)=O>CN(C)C=O>[Cl:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[CH2:4][CH2:5][C:9]#[N:10]
Reactant: N#CC(Cc1ccccc1Cl)C(=O)O
Solvent: CN(C)C=O
Product: N#CCCc1ccccc1Cl
Temperature: 25 °C
Reaction time: 6 h
Yield: 94.7 %

Procedure:
Into a 1-liter, three-necked flask equipped with a mechanical stirrer, reflux condenser and nitrogen inlet is placed 138.5 g (0.66 mole) of 2-(o-chlorobenzyl)cyanoacetic acid and 220 ml of dry N,N-dimethylformamide. The mixture is stirred and slowly heated under nitrogen to reflux and held there for 6 hours. The resulting yellow mixture is allowed to cool under nitrogen overnight at room temperature. A precipitate (approximately 0.5 g) that forms is filtered off and the filtrate is poured into 1 liter of water. The organic layer is taken up in three 330-ml portions of ethyl ether/hexane (1:1 v/v), and the solutions are combined and washed once with 150 ml of water. The ethyl ether/hexane solution is dried over anhydrous magnesium sulfate, filtered and evaporated on a rotary evaporator. The residual liquid is distilled under reduced pressure through an insulated 12-inch Vigreux column with the product being collected at 82° C.-85° C./0.3 mm Hg as a colorless liquid identified by infrared, 'H and 13C nuclear magnetic resonance. The yield is 94.7 percent.
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:11]([N:12]2[CH2:24][CH2:23][N:15]3[C:16]4[CH2:17][CH2:18][CH2:19][CH2:20][C:21]=4[CH:22]=[C:14]3[C:13]2=[O:25])=[CH:10][CH:9]=[CH:8][C:7]=1[C:26]1[CH:31]=[C:30]([NH:32][C:33]2[CH:37]=[C:36]([CH2:38][CH3:39])[NH:35][N:34]=2)[C:29](=[O:40])[N:28]([CH3:41])[CH:27]=1)(=O)C.O[Li].O.C1COCC1.C(O)(C)C>O>[CH2:38]([C:36]1[NH:35][N:34]=[C:33]([NH:32][C:30]2[C:29](=[O:40])[N:28]([CH3:41])[CH:27]=[C:26]([C:7]3[C:6]([CH2:5][OH:4])=[C:11]([N:12]4[CH2:24][CH2:23][N:15]5[C:16]6[CH2:17][CH2:18][CH2:19][CH2:20][C:21]=6[CH:22]=[C:14]5[C:13]4=[O:25])[CH:10]=[CH:9][CH:8]=3)[CH:31]=2)[CH:37]=1)[CH3:39]
Reactant: CCc1cc(Nc2cc(-c3cccc(N4CCn5c(cc6c5CCCC6)C4=O)c3COC(C)=O)cn(C)c2=O)n[nH]1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Solvent: CC(C)O
Product: CCc1cc(Nc2cc(-c3cccc(N4CCn5c(cc6c5CCCC6)C4=O)c3CO)cn(C)c2=O)n[nH]1
Temperature: 25 °C
Reaction time: 3 h
Yield: 49.9 %

Procedure:
A 25-mL, single-necked, round-bottomed flask equipped with a magnetic stirring bar was charged with 125b (50 mg, 0.090 mmol), LiOH.H2O (20 mg, 0.83 mmol), THF (2 mL), isopropanol (2 mL), and water (2 mL). After the reaction mixture was stirred at room temperature for 3 h, it was partitioned between dichloromethane (5 mL) and water (5 mL), and the organic phase was extracted with dichloromethane (5 mL×3). The combined organic phases were washed with water (5 mL×2) and brine (5 mL×1), dried (Na2SO4), and concentrated. The crude product was re-dissolved in dichloromethane (3 mL). To this solution was added hexane (10 mL) and the resulting precipitates were filtered to give 50% yield (23 mg) of 2-(3-(5-(5-ethyl-1H-pyrazol-3-ylamino)-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2-(hydroxymethyl)phenyl)-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-1(2H)-one 125 MS (ESI+) m/z 513.3 (M+H).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([NH2:5])=[NH:4].[CH2:8]([O:10][C:11](=[O:18])[C:12](=O)[CH2:13][C:14](=O)[CH3:15])[CH3:9].Cl.C([O-])(O)=O.[Na+]>C(O)C>[CH2:8]([O:10][C:11]([C:12]1[CH:13]=[C:14]([CH3:15])[N:5]=[C:3]([C:2]([F:7])([F:6])[F:1])[N:4]=1)=[O:18])[CH3:9]
Reactant: N=C(N)C(F)(F)F
Reactant: CCOC(=O)C(=O)CC(C)=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1cc(C)nc(C(F)(F)F)n1
Temperature: 2.5 °C
Reaction time: 3 h
Yield: 66.2 %

Procedure:
2.241 g (20 mmol) of 2,2,2-trifluoro-acetamidine were dissolved in 80 ml ethanol and treated with 3.163 g (20 mmol) of 2,4-dioxo-pentanoic acid ethyl ester. The resulting solution was cooled to 0-5° C. and treated with 120 ml of HCl-saturated ethanol. The reaction mixture was allowed to warm-up to RT and stirred for additional 3 hours. The mixture was then added dropwise under cooling to 800 ml saturated NaHCO3 solution. The resulting mixture was then extracted twice with 300 ml DCM and the combined organic phases were dried over magnesium sulfate, filtered and concentrated in vacuo to yield 3.1 g of a yellow oil. This residue was then purified by silicagel chromatography (eluent:heptane/ethyl acetate 100:0 to 30:70) leading to a colorless oil which crystallized spontaneously, leading to 1.3 g of 6-methyl-2-trifluoromethyl-pyrimidine-4-carboxylic acid ethyl ester.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([O:21][CH3:22])=[C:11]([C:13]([C:16]2[NH:17][CH2:18][CH2:19][N:20]=2)=[CH:14][CH:15]=1)[NH2:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:23]([N:25](CC)CC)C.N#CBr>C(Cl)Cl.C(=O)(O)[O-].[Na+]>[CH2:1]([O:8][C:9]1[CH:15]=[CH:14][C:13]2[C:16]3[N:20]([CH2:19][CH2:18][N:17]=3)[C:23]([NH2:25])=[N:12][C:11]=2[C:10]=1[O:21][CH3:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1c(OCc2ccccc2)ccc(C2=NCCN2)c1N
Reactant: CCN(CC)CC
Agent: N#CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COc1c(OCc2ccccc2)ccc2c1N=C(N)N1CCN=C21
Temperature: 0 °C

Procedure:
A mixture of 3-(benzyloxy)-6-(4,5-dihydro-1H-imidazol-2-yl)-2-methoxyaniline (100 g, 336 mmol) and triethylamine (188 mL) in DCM (3 L) was cooled to 0° C. and treated with cyanogen bromide (78.4 g, 740 mmol). The reaction mixture was stirred and allowed to warm to room temperature gradually. After 16 h the reaction mixture was diluted with a solution of saturated sodium bicarbonate and extracted with CH2Cl2. The organic layer was washed 3 times with saturated bicarbonate solution followed by multiple washes with brine. The organic layer was dried (sodium sulfate) and concentrated under reduced pressure to give a semi solid (130 g with triethylamine salt contamination): 1H NMR (DMSO-d6) δ: 7.30-7.48 (7H, m), 5.31 (2H, s), 4.32 (2H, m), 4.13 (2H, m), 3.81 (3H, s).
Reaction SMILES: [Br-:1].[NH2:2][CH2:3][CH2:4][CH2:5][N+:6]([CH2:9][CH2:10][NH:11][C:12]([C:14]1[C:19]([NH2:20])=[N:18][C:17]([NH2:21])=[C:16]([Cl:22])[N:15]=1)=[O:13])([CH3:8])[CH3:7].[CH2:23]([O:30][C:31]1[CH:36]=[CH:35][C:34]([CH2:37][C:38](O)=[O:39])=[CH:33][CH:32]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.CN1CCOCC1.C1(N=C=NC2CCCCC2)CCCCC1.ON1C2C=CC=CC=2N=N1>CN(C=O)C>[Br-:1].[CH2:23]([O:30][C:31]1[CH:32]=[CH:33][C:34]([CH2:37][C:38]([NH:2][CH2:3][CH2:4][CH2:5][N+:6]([CH2:9][CH2:10][NH:11][C:12]([C:14]2[C:19]([NH2:20])=[N:18][C:17]([NH2:21])=[C:16]([Cl:22])[N:15]=2)=[O:13])([CH3:7])[CH3:8])=[O:39])=[CH:35][CH:36]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: C[N+](C)(CCCN)CCNC(=O)c1nc(Cl)c(N)nc1N
Reactant: O=C(O)Cc1ccc(OCc2ccccc2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Agent: [Br-]
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: C[N+](C)(CCCNC(=O)Cc1ccc(OCc2ccccc2)cc1)CCNC(=O)c1nc(Cl)c(N)nc1N
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of (3-amino-propyl)-{2-[(3,5-diamino-6-chloro-pyrazine-2-carbonyl)-amino]-ethyl}-dimethyl-ammonium bromide (Intermediate M) (1.0 g, 2.52 mmol), 4-benzyloxyphenylacetic acid (0.61 g, 2.52 mmol), N-methylmorpholine (1.0 mL, 9.10 mmol), N,N′-dicyclohexylcarbodiimide (0.52 g, 2.52 mmol) and 1-hydroxybenzotriazole (0.34 g, 2.52 mmol) in anhydrous DMF (20 mL) is stirred under a nitrogen atmosphere at RT for 16 h. The reaction mixture is concentrated under vacuum and is purified by column chromatography (basic alumina, 0-3% MeOH in DCM) to afford the title compound as a white solid. M+ 540. 1H NMR (400 MHz, DMSO-d6) δ 8.23 (1H, t), 8.07 (1H, t), 7.52 (2H, br), 7.41-7.28 (5H, m), 7.16 (2H, d), 7.09 (2H, br), 6.91 (2H, d), 5.05 (2H, s), 3.58-3.3.51 (2H, m), 3.40-3.25 (6H, m), 3.11-3.03 (2H, m), 3.02 (6H, s), 1.87-1.75 (2H, m).
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Li]CCCC.[CH2:19]1[O:21][CH2:20]1>C1COCC1.CCOCC>[CH:1]1[C:13]2[CH:12]([CH2:19][CH2:20][OH:21])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: C1CO1
Reactant: c1ccc2c(c1)Cc1ccccc1-2
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: OCCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 66.5 %

Procedure:
To a stirred, cooled (-78° C.) solution of 6.00 g (36.1 mmol) of fluorene in 75 mL of THF was added 15.4 mL (36.2 mmol) of 2.35 M n-BuLi in hexanes dropwise. The resulting dark orange mixture was stirred for 1.5 h and 26.0 mL (36.4 mmol) of 1.4 M ethylene oxide in Et2O was added. The resulting bright orange mixture was warmed slowly to room temperature over 3.5 h, quenched with saturated aqueous NH4Cl and concentrated at reduced pressure. The residue was poured into water and extracted twice with Et2O. The combined organic layers were washed with brine and dried over magnesium sulfate. Solvent was removed at reduced pressure and the crude product was chromatographed on 150 g of flash silica gel eluting with 25% EtOAc in hexane to afford 5.05 g (67%) of the desired alcohol as a white solid, mp 98°-99° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:55])[C@@H:4]([NH:20][C:21]([C@@H:23]1[CH2:36][C:35]2[CH:34]=[C:33]3[C:28]([O:29][C@H:30]([C:39]4[CH:44]=[CH:43][C:42]([OH:45])=[CH:41][CH:40]=4)[C:31](=[O:38])[N:32]3[CH3:37])=[CH:27][C:26]=2[CH2:25][N:24]1[C@H:46]([C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)[CH2:47][CH3:48])=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.[Cl:56][C:57]1[CH:58]=[C:59]([CH:62]=[CH:63][C:64]=1[Cl:65])[CH2:60]Br.C(=O)([O-])[O-].[K+].[K+].C(=O)(O)[O-].[Na+]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:55])[C@@H:4]([NH:20][C:21]([C@@H:23]1[CH2:36][C:35]2[CH:34]=[C:33]3[C:28]([O:29][C@H:30]([C:39]4[CH:40]=[CH:41][C:42]([O:45][CH2:60][C:59]5[CH:62]=[CH:63][C:64]([Cl:65])=[C:57]([Cl:56])[CH:58]=5)=[CH:43][CH:44]=4)[C:31](=[O:38])[N:32]3[CH3:37])=[CH:27][C:26]=2[CH2:25][N:24]1[C@H:46]([C:49]1[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=1)[CH2:47][CH3:48])=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:13]=[CH:14][C:15]([C:18]#[N:19])=[CH:16][CH:17]=2)=[CH:8][CH:7]=1
Reactant: CC[C@@H](c1ccccc1)N1Cc2cc3c(cc2C[C@H]1C(=O)N[C@@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)C(=O)OC)N(C)C(=O)[C@@H](c1ccc(O)cc1)O3
Reactant: Clc1ccc(CBr)cc1Cl
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC[C@@H](c1ccccc1)N1Cc2cc3c(cc2C[C@H]1C(=O)N[C@@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)C(=O)OC)N(C)C(=O)[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)O3
Temperature: 25 °C
Reaction time: 6 h
Yield: 98.7 %

Procedure:
(S)-3-(4′-Cyano-biphenyl-4-yl)-2-{[(3R,7S)-3-(4-hydroxy-phenyl)-1-methyl-2-oxo-6-((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionic acid methyl ester (15 mg) was dissolved in 1 mL of DMF and 3,4-dichlorobenzyl bromide (46 mg) and potassium carbonate (26 mg) were added. The mixture was stirred at room temperature for 6 hours and was poured onto ethyl acetate and saturated sodium bicarbonate. The organic layer was dried over sodium sulfate and concentrated. The residue was purified over silica (hexanes-ethyl acetate-MeOH, 6-4-0.1) to provide (S)-3-(4′-cyano-biphenyl-4-yl)-2-{[(3R,7S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-6-((S)-1-phenyl-propyl)-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl]-amino}-propionic acid methyl ester (18 mg, LC/MS: m/z 894). 1H NMR (400 MHz, d6 acetone): 7.92-7.81 (m, 5H), 7.66 (s, 1H), 7.57 (m, 3H), 7.43 (m, 1H), 7.32-7.21 (m, 7H), 7.01-6.94 (m, 5H), 6.66 (s, 1H), 5.60 (s, 1H), 5.1 (s, 2H), 4.78 (m, 1H), 3.74 (s, 3H), 3.66 (m, 1H), 3.56 (d, 1H), 3.46 (m, 1H), 3.35 (s, 3H), 3.34 (d, 1H), 3.02-2.98 (m, 2H), 2.27 (m, 2H), 1.90-1.66 (m, 2H), 0.60 (t, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[N:12]=[CH:13][C:14]([C:17]([NH2:19])=O)=[N:15][CH:16]=2)[CH2:7][CH2:6]1.C(N(CC)CC)C.FC(F)(F)C(OC(=O)C(F)(F)F)=O>>[Br:1][C:2]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:3]=1[O:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[N:12]=[CH:13][C:14]([C:17]#[N:19])=[N:15][CH:16]=2)[CH2:7][CH2:6]1
Reactant: NC(=O)c1cnc(N2CCC(Oc3cc(F)ccc3Br)CC2)cn1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(CC)CC
Product: N#Cc1cnc(N2CCC(Oc3cc(F)ccc3Br)CC2)cn1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a suspension of 5-[4-(2-bromo-5-fluorophenoxy)piperidin-1-yl]pyrazine-2-carboxamide from Step 4 (1.65 g, 4.17 mmol) in TBF (50 mL) at 0° C. was added triethylamine (1.45 mL, 10.5 mmol) followed by trifluoroacetic anhydride (0.885 mL, 6.26 mmol). After a period of 10 min at 0° C., the reaction mixture was raised gradually to room temperature. The mixture was then partitioned between ethyl acetate and aqueous sodium bicarbonate. The organic phase was separated, dried over sodium sulfate and evaporated. The crude mixture was purified by flash chromatography (35% ethyl acetate in hexane) to provide the title compound.
Reaction SMILES: C([Si]([C:8]1[C:13]([F:14])=[C:12]([C:15]2[C:23]3[C:18](=[N:19][CH:20]=[CH:21][CH:22]=3)[NH:17][N:16]=2)[N:11]=[C:10]([N:24]2[CH2:29][CH2:28][NH:27][C@H:26]([C@:30]([CH3:39])([O:34][Si](C)(C)C)[CH:31]([CH3:33])[CH3:32])[CH2:25]2)[C:9]=1[F:40])(C)C)(C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.CCOC(C)=O>[F:40][C:9]1[C:10]([N:24]2[CH2:29][CH2:28][NH:27][C@H:26]([C@:30]([OH:34])([CH:31]([CH3:32])[CH3:33])[CH3:39])[CH2:25]2)=[N:11][C:12]([C:15]2[C:23]3[C:18](=[N:19][CH:20]=[CH:21][CH:22]=3)[NH:17][N:16]=2)=[C:13]([F:14])[CH:8]=1
Reactant: CC(C)[C@@](C)(O[Si](C)(C)C)[C@@H]1CN(c2nc(-c3n[nH]c4ncccc34)c(F)c([Si](C)(C)C(C)(C)C)c2F)CCN1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)[C@@](C)(O)[C@@H]1CN(c2nc(-c3n[nH]c4ncccc34)c(F)cc2F)CCN1
Reaction time: 8 h
Yield: 84.1 %

Procedure:
tert-butyl-[2-[(3S)-3-[(1R)-1,2-dimethyl-1-trimethylsilyloxy-propyl]piperazin-1-yl]-3,5-difluoro-6-(1H-pyrazolo[3,4-b]pyridin-3-yl)-4-pyridyl]-dimethyl-silane (60 g, 101.9 mmol) was dissolved in THF (216.0 mL) at room temperature. TBAF in THF (214.0 mL of 1 M, 214.0 mmol) was added dropwise via cannula to the brown solution over 45 minutes. The reaction was stirred overnight, after which time the deprotection was complete by Lc/Ms. The mixture was diluted with EtOAc (600 ml) and washed with saturated aqueous NaHCO3 (100 ml then 2×200 ml). The organic phase was further washed with a 2:3 mixture of saturated brine:water (100 ml) until no remaining Bu4N+ salts were observed Lc/Ms analysis. The organic phase was dried over MgSO4, filtered and concentrated in vacuo to give a brown solid. The solid was triturated with diethyl ether, filtered and dried to give a orange brown solid (34.5 g, 84%). The solid was recrystallised from isopropanol. This afforded the title compound as a beige solid (23 g); 1H NMR (d6-DMSO) 0.84 (3H, d), 0.90 (3H, d), 1.06 (3H, s), 1.83 (2H, m), 2.74 (2H, d), 2.85 (2H, d), 3.09 (1H, d), 3.78 (1H, d), 4.04 (1H, d), 4.13 (1H, s), 7.30 (1H, dd), 7.92 (1H, dd), 8.60 (1H, dd), 8.77 (1H, dd), 13.99 (1H, brs); 19F NMR (decoupled) −128.5, −124.1; MS ES(+) 403.0 (M+1).
Reaction SMILES: [PH2](=O)O.C(N(CC)CC)C.C[Si](Cl)(C)C.[CH2:16]([O:23][C:24]([CH:26]([CH2:40][CH2:41][C:42]([O:44][CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)=[O:43])[CH2:27][P:28](CCCC1C=CC=CC=1)(=[O:30])[OH:29])=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(Cl)(Cl)Cl>[CH2:16]([O:23][C:24]([CH:26]([CH2:40][CH2:41][C:42]([O:44][CH2:45][C:46]1[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=1)=[O:43])[CH2:27][PH:28](=[O:29])[OH:30])=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(CCC(CP(=O)(O)CCCc1ccccc1)C(=O)OCc1ccccc1)OCc1ccccc1
Agent: C[Si](C)(C)Cl
Agent: O=[PH2]O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=C(CCC(C[PH](=O)O)C(=O)OCc1ccccc1)OCc1ccccc1
Temperature: 0 °C

Procedure:
Dry phosphinic acid (100 g, 1.52 mol) was dissolved in 100 ml of chloroform and treated with triethylamine (155 g, 1.52 mol). The mixture was evaporated and transferred to a three liter flask, containing 750 mL of chloroform. The solution was stirred by means of a mechanical stirrer and the flask cooled to 0° C. The clear solution was treated with triethylamine (277 g, 2.72 mol) followed by trimethylsilyl chloride (281 g, 2.58 mol). Once addition of trimethylsilyl chloride was complete dibenzyl 2-methylenepentanedioate (2) in 150 mL of chloroform was added dropwise over 20 minutes. The low temperature bath was removed and the mixture warmed to room temperature. After 6 hours the thick slurry was filtered and the filtrate cooled to 0° C. The filtrate was then quenched with 5% hydrochloric acid and the organic layer removed. The aqueous layer was extracted with chloroform, the organics combined, dried (MgSO4) and evaporated under reduced pressure to give 55 g of 2,4-di(benzyloxycarbonyl)butylphosphinic acid (6) as a light yellow liquid. The liquid was purified by flash chromatography and eluted using 3:1 hexanes/ethyl acetate containing 5-trifluoroacetic acid to give 40 g (7%) of the desired product. Rf 0.28 (3:1 Hex./EtOAc 5% TFA); 1H NMR (CDCl3): 7.3 ppm (m, 10H), 7.2 ppm (d, 1H), 5.12 ppm (s, 2H), 2.9 ppm (m, 1H), 2.4 ppm (t, 2H), 2.2 ppm (m, 1H), 2.0 ppm (m, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].OS(O)(=O)=O.CO.[CH3:18][CH2:19]O>C(Cl)(Cl)Cl>[OH:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([O:9][CH2:18][CH3:19])=[O:8]
Reactant: O=C(O)c1cncc(O)c1
Reactant: CCO
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cncc(O)c1
Temperature: 110 °C
Reaction time: 12 h

Procedure:
To a stirred mixture of 5-hydroxynicotinic acid (25 g, 0.1797 mol, Combi Blocks) in EtOH (500 mL) was added a catalytic amount of conc. H2SO4. The resulting reaction mixture was stirred for 12 h at 110° C. After completion of the reaction (monitored by TLC, 10% MeOH in CHCl3), EtOH was removed under reduced pressure and the reaction mixture was quenched with sat'd NaHCO3 solution (50 mL) and extracted with EtOAc (50 mL×3). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford the title compound as a solid. 1H NMR (400 MHz, CDCl3) δ: 11.00 (br.s., 1H), 8.74 (s, 1H), 8.42 (d, J=2.1 Hz, 1H), 7.90 (t, J=3.9 Hz, 1H), 4.43 (q, J=7.2 Hz, 2H), 1.43 (t, J=6.9 Hz, 3H). MS (ESI, positive ion) m/z: 168 (M+H).
Reaction SMILES: [CH3:1][C:2]([CH3:13])([C:4](=[O:12])[CH2:5][C:6](=[O:11])[C:7]([CH3:10])([CH3:9])[CH3:8])[CH3:3].C(=O)([O-])[O-].[K+].[K+].[CH:20]1([CH2:23]Br)[CH2:22][CH2:21]1.[I-].[K+]>C(O)C>[CH3:8][C:7]([CH3:10])([C:6](=[O:11])[CH:5]([CH2:23][CH:20]1[CH2:22][CH2:21]1)[C:4](=[O:12])[C:2]([CH3:13])([CH3:1])[CH3:3])[CH3:9]
Reactant: BrCC1CC1
Reactant: CC(C)(C)C(=O)CC(=O)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCO
Product: CC(C)(C)C(=O)C(CC1CC1)C(=O)C(C)(C)C
Reaction time: 8 h

Procedure:
To a solution of 2,2,6,6-tetramethyl-3,5-heptanedione (18.4 g) in ethanol (100 ml) was added potassium carbonate (20.7 g) followed by cyclopropylmethyl bromide (13.5 g). The mixture was heated at reflux for 16 hours. Potassium iodide (2 g) and further cyclopropylmethyl bromide (2 g) was added to the reaction mixture and reflux continued for a further 8 hours. The reaction mixture was cooled and concentrated in vacuo. To the residue was added water and the resultant mixture was extracted with ether. The ether extracts were washed with water and dried. Concentration in vacuo gave the product as an oil which was used without further purification.
Reaction SMILES: C[C:2]1=[CH:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8](=[O:17])[O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]1.[CH3:18]O>[Pd]>[CH3:18][CH:15]1[CH2:16][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8](=[O:17])[O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]1
Reactant: CC1=CCCCCC(=O)OCCCCCCC1
Reactant: CO
Agent: [Pd]
Agent: C/C1=C/CCCCC(=O)OCCCCCCC1
Product: CC1CCCCCCCC(=O)OCCCCC1
Yield: 83 %

Procedure:
25 g (0.10 mol) of Z-8-methyloxacyclopentadec-7-en-2-one were dissolved in 150 ml of methanol and hydrogenated (1.5 hours) with 2 g of 5% palladium-on-carbon with 100 mbar over-pressure. Then, the mixture was filtered over Celite, and the solution was concentrated, distilled in a bulb-tube and chromatographed. There were obtained 20 g (83%) of 8-methyloxacyclopentadecan-1-one were obtained having the following characteristics:
Reaction SMILES: Cl.C1COCC1.[Si]([O:14][C:15]1[C:19]2[C:20]([CH3:40])=[C:21]([N:26]3[CH2:31][CH2:30][N:29]([C:32]4[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=4)[CH2:28][CH2:27]3)[C:22]([CH3:25])=[C:23]([CH3:24])[C:18]=2[O:17][CH:16]=1)(C(C)(C)C)(C)C>O.C(=O)(O)[O-].[Na+]>[CH3:39][O:38][C:35]1[CH:34]=[CH:33][C:32]([N:29]2[CH2:28][CH2:27][N:26]([C:21]3[C:22]([CH3:25])=[C:23]([CH3:24])[C:18]4[O:17][CH2:16][C:15](=[O:14])[C:19]=4[C:20]=3[CH3:40])[CH2:31][CH2:30]2)=[CH:37][CH:36]=1
Reactant: COc1ccc(N2CCN(c3c(C)c(C)c4occ(O[Si](C)(C)C(C)(C)C)c4c3C)CC2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(N2CCN(c3c(C)c(C)c4c(c3C)C(=O)CO4)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.9 %

Procedure:
1N hydrochloric acid (5 mL) was added to a solution of THF (25 mL) containing 1-(3-{[tert-butyl(dimethyl)silyl]oxy}-4,6,7-trimethyl-1-benzofuran-5-yl)-4-(4-methoxyphenyl)piperazine (560 mg, 1.16 mmol) synthesized in Reference Example 108, and the mixture was stirred at room temperature for 1 hour. The resulting mixture was diluted with saturated sodium bicarbonate water. THF in the reaction mixture was removed under reduced pressure, and the residue was extracted using ethyl acetate. The extract was washed with saturated saline, and dried using anhydrous magnesium sulfate, followed by concentration under reduced pressure. The residue was purified by silica gel chromatography (hexane-ethyl acetate 95:5 to 85/15) to give 310 mg of the title compound (yield: 73%).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[F:26][C:27]1[C:28]([C:34](O)=[O:35])=[N:29][CH:30]=[C:31]([F:33])[CH:32]=1>>[F:26][C:27]1[C:28]([C:34]([N:20]2[CH2:21][CH2:22][CH:17]([N:15]3[C:14](=[O:23])[C:13]([CH3:25])([CH3:24])[C:12]([C:6]4[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:4]([O:3][CH3:2])[CH:5]=4)=[N:16]3)[CH2:18][CH2:19]2)=[O:35])=[N:29][CH:30]=[C:31]([F:33])[CH:32]=1
Reactant: O=C(O)c1ncc(F)cc1F
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(C(=O)c4ncc(F)cc4F)CC3)C(=O)C2(C)C)cc1OC

Procedure:
The title compound is prepared analogously as described for GP2-WU2 using 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one (compound B1) and 3,5-difluoropyridine-2-carboxylic acid as starting compounds. The crude product is purified by chromatography (amino phase silica gel and DCM) to yield the title compound.
Reaction SMILES: FC(F)(F)C([NH:5][C:6]1[N:7]=[C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:21])[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:10][N:9]2[C:22]=1[S:23][CH3:24])=O>CO.C(Cl)Cl>[NH2:5][C:6]1[N:7]=[C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:21])[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:10][N:9]2[C:22]=1[S:23][CH3:24]
Reactant: CSc1c(NC(=O)C(F)(F)F)nc2ccc(C(=O)c3ccccc3)cn12
Solvent: CO
Solvent: ClCCl
Product: CSc1c(N)nc2ccc(C(=O)c3ccccc3)cn12
Temperature: 25 °C
Reaction time: 48 h
Yield: 0.1 %

Procedure:
The 2-trifluoroacetamido-3-methylthio-6-benzoyl-imidazo[1,2-a]pyridine (100 mg, 263 mmol) was dissolved in 20 mL of a mixture of MeOH/CH2Cl2 1:1, and 5 g of silica gel was added. The mixture was stirred at RT for 2 days. The residue was filtered and washed with CH2Cl2 and the solution was concentrated in vacuo to give 63 mg (850%) of a yellow solid. 1H-NMR (200 MHz, CDCl3) d 2.12 (s, 3H, SMe), 4.40 (bs, 2H, NH2), 7.46-7.80 (m, 7H, ArH+H7+H8), 8.68 (d, J57=1.7, H5). 13C-NMR (50 MHz, CDCl3) d 18.0 (SMe), 95.0, 122.7, 125.8, 127.7, 128.5, 129.6, 132.6, 137.4, 145.3, 156.1, 193.5.