Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:12]=[C:13](I)[C:14]=1[O:15][CH3:16])[C:8]([O:10][CH3:11])=[O:9])([CH3:4])([CH3:3])[CH3:2].[Cu](C#N)[C:19]#[N:20].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:1]([C:5]1[CH:6]=[C:7]([CH:12]=[C:13]([C:19]#[N:20])[C:14]=1[O:15][CH3:16])[C:8]([O:10][CH3:11])=[O:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1cc(I)c(OC)c(C(C)(C)C)c1
Reactant: N#C[Cu]C#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(C#N)c(OC)c(C(C)(C)C)c1
Temperature: 150 °C
Reaction time: 2.5 h
Yield: 75.2 %

Procedure:
Methyl 3-t-butyl-5-iodo-4-methoxybenzoate (2.77 g) was dissolved in N,N-dimethylformamide (30 mL), and copper cyanide (965 mg) was added to the solution, and then the mixture was stirred at 150° C. for 2.5 hours. To the reaction solution, 10% potassium carbonate was added, and then the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=3:1) to obtain the title compound (1.48 g) as a yellow oily substance.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]1[N:15]=[CH:14][C:13]([C:16]([O:18][CH3:19])=[O:17])=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=1.[I:24]I>S([O-])([O-])(=O)=O.[Ag+2].[O-]S([O-])(=O)=O.[Ag+].[Ag+].CO>[F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([I:24])=[CH:4][C:3]=1[C:10]1[N:15]=[CH:14][C:13]([C:16]([O:18][CH3:19])=[O:17])=[C:12]([C:20]([F:23])([F:21])[F:22])[CH:11]=1
Reactant: II
Reactant: COC(=O)c1cnc(-c2ccc(OC)cc2F)cc1C(F)(F)F
Agent: [Ag+2]
Agent: [Ag+]
Agent: O=S(=O)([O-])[O-]
Solvent: CO
Product: COC(=O)c1cnc(-c2cc(I)c(OC)cc2F)cc1C(F)(F)F

Procedure:
Methyl 6-(2-fluoro-4-methoxyphenyl)-4-(trifluoromethyl)pyridine-3-carboxylate (750 mg, 2.278 mmol), iodine (578 mg, 2.278 mmol), silver sulfate (710 mg, 2.278 mmol) and MeOH (20 mL) were stirred in a 70° C. oil bath and monitored by LCMS. The dark color disappeared and LCMS indicated >50% conversion when reaction time=1 hr. Additional I2 (280 mg, 0.788 mmol) and Ag2SO4 (355 mg, 1.074 mmol) were added and resumed stirring/heating for 30 min. The reaction was cooled and quenched by adding Na2S2O3 (sat.). Volatiles were removed under reduced pressure. The pot residue was worked up with brine, extracted with ethyl acetate, dried over Na2SO4, filtered and evaporated in vacuo. The resulting mixture was purified by flash chromatography (SiO2, Biotage SNAP Cartridge, silica gel, KP-Sil, 100 g cartridge). The column was eluted by an EtOAc/hexanes mixture (0% to 40%). Pure fractions were pooled and evaporated to afford a white solid as the titled compound. LCMS calc.=454.96. found=456.03 (M+H)+. 1H NMR (CDCl3, 600 MHz) δ 9.15 (s, 1H), 8.61 (d, J=9.0 Hz, 1H), 8.11 (s, 1H), 6.68 (d, J=11.0, 1H), 4.00 (s, 3H), 3.96 (s, 3H).
Reaction SMILES: [Cl:1]N1C(=O)N(Cl)C(=O)N(Cl)C1=O.[CH3:13][C:14]1[N:15]=[C:16]([CH3:21])[C:17]([CH3:20])=[N:18][CH:19]=1>ClC(Cl)C>[Cl:1][CH2:13][C:14]1[N:15]=[C:16]([CH3:21])[C:17]([CH3:20])=[N:18][CH:19]=1
Reactant: Cc1cnc(C)c(C)n1
Reactant: O=c1n(Cl)c(=O)n(Cl)c(=O)n1Cl
Solvent: CC(Cl)Cl
Product: Cc1ncc(CCl)nc1C
Temperature: 20 °C
Reaction time: 12 h

Procedure:
7.6 g (32.74 mmol) of trichloroisocyanuric acid are added, over 1 hour, to a solution, maintained at reflux, of 10 g of trimethylpyrazine (81.85 mmol) in 820 ml of dichloroethane. The reaction mixture is refluxed for 6 hours and then cooled to 20° C., stirred for a further 12 hours and filtered. The filtrate is concentrated under reduced pressure, taken up in 200 ml of ethyl ether, filtered again and then concentrated under reduced pressure. 9.6 g of methyldimethylpyrazine chloride are recovered in the form of a mixture, which is used without further purification in the following step.
Reaction SMILES: [Na].[C:2]([C:5]1[CH:6]=[CH:7][C:8]([C:11]#[N:12])=[N:9][CH:10]=1)([OH:4])=[O:3].N[CH2:14][CH2:15][SH:16].Cl>O.C(O)C>[C:2]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[S:16][CH2:15][CH2:14][N:12]=2)=[N:9][CH:10]=1)([OH:4])=[O:3]
Reactant: N#Cc1ccc(C(=O)O)cn1
Reactant: NCCS
Agent: Cl
Agent: [Na]
Solvent: O
Solvent: CCO
Product: O=C(O)c1ccc(C2=NCCS2)nc1

Procedure:
Sodium (11 mmol) is added to a flask containing 75 ml of ethanol. As soon as the sodium has dissolved, 10 mmol of 5-carboxy-2-cyanopyridine and 11 mmol of 2-amino-ethanethiol are added and the solution is refluxed for 24 h. The solution is then diluted with 25 ml of water, made acidic (pH=5) with 2N HCl and evaporated. The residue is dissolved in 100 ml of hot chloroform, the salts are filtered off and the filtrate on cooling gives crystals of the title compound, m.p. 234°-235° C.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][CH:9]=[C:10]([C:26]3[CH2:30][C:29]4([CH2:34][CH2:33][CH2:32][CH2:31]4)[O:28][N:27]=3)[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].FC(F)(F)C(O)=O>ClCCl.C(=O)(O)[O-].[Na+]>[CH2:1]([N:3]1[C:7]2[N:8]=[CH:9][C:10]([C:26]3[CH2:30][C:29]4([CH2:34][CH2:33][CH2:32][CH2:31]4)[O:28][N:27]=3)=[C:11]([NH:12][CH:13]3[CH2:14][CH2:15][NH:16][CH2:17][CH2:18]3)[C:6]=2[CH:5]=[N:4]1)[CH3:2]
Reactant: CCn1ncc2c(NC3CCN(C(=O)OC(C)(C)C)CC3)c(C3=NOC4(CCCC4)C3)cnc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCn1ncc2c(NC3CCNCC3)c(C3=NOC4(CCCC4)C3)cnc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Tert-butyl 4-{[1-ethyl-5-(1-oxa-2-azaspiro[4.4]non-2-en-3-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl]amino}piperidine-1-carboxylate (950 mg, 0.00196 mole) (example 9) was taken in dichloromethane. At 0° C., trifluoroacetic acid (10 ml) was added and the reaction mixture was stirred at room temperature for about 2 hours. It was diluted with dichloromethane and basified with saturated sodium bicarbonate solution. The organic layer was separated, washed with brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure to get the title compound.
Reaction SMILES: [CH:1]([NH:4][C:5]([C:7]1[C:15]2[C:11](=[CH:12][NH:13][N:14]=2)[CH:10]=[C:9]([CH3:16])[C:8]=1[NH:17][C:18]([C:20]1[N:21]([C:27]2[C:32]([Cl:33])=[CH:31][CH:30]=[CH:29][N:28]=2)[N:22]=[C:23]([O:25][CH3:26])[CH:24]=1)=[O:19])=[O:6])([CH3:3])[CH3:2].[CH2:34]([O:36][C:37](=[O:43])[CH2:38][S:39][C:40](Cl)=[O:41])[CH3:35].C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH2:34]([O:36][C:37](=[O:43])[CH2:38][S:39][C:40]([N:13]1[CH:12]=[C:11]2[C:15]([C:7]([C:5](=[O:6])[NH:4][CH:1]([CH3:3])[CH3:2])=[C:8]([NH:17][C:18]([C:20]3[N:21]([C:27]4[C:32]([Cl:33])=[CH:31][CH:30]=[CH:29][N:28]=4)[N:22]=[C:23]([O:25][CH3:26])[CH:24]=3)=[O:19])[C:9]([CH3:16])=[CH:10]2)=[N:14]1)=[O:41])[CH3:35]
Reactant: CCOC(=O)CSC(=O)Cl
Reactant: COc1cc(C(=O)Nc2c(C)cc3c[nH]nc3c2C(=O)NC(C)C)n(-c2ncccc2Cl)n1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCOC(=O)CSC(=O)n1cc2cc(C)c(NC(=O)c3cc(OC)nn3-c3ncccc3Cl)c(C(=O)NC(C)C)c2n1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
In a vial, 6-{[2-(3-chloro-pyridin-2-yl)-5-methoxy-2H-pyrazole-3-carbonyl]-amino}-5-methyl-2H-indazole-7-carboxylic acid isopropyl amide (0.200 g, 0.427 mmol) was suspended in chloroform (1 ml), then a solution of (chlorocarbonylthio)-acetic acid ethyl ester (0.086 g, 0.471 mmol) in chloroform (1 ml) was added, followed by triethylamine (0.065 ml). The reaction mixture became a clear solution that was stirred for 1 hour at a temperature of 20° C. The reaction mixture was concentrated and the residue was purified by flash chromatography over silica gel using a 50% ethyl acetate-50% cyclohexane mixture. The desired compound was isolated as a yellow solid showing the physical properties reported in the corresponding table (P.41.).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH2:11]O)=[CH:8][C:6]=2[N:7]=1.P(Br)(Br)[Br:20]>C1(C)C=CC=CC=1.C(Cl)(Cl)Cl>[Br:20][CH2:11][C:9]1[S:10][C:5]2[C:4]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:3][C:2]([Cl:1])=[N:7][C:6]=2[CH:8]=1
Reactant: OCc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Reactant: BrP(Br)Br
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: Clc1nc(N2CCOCC2)c2sc(CBr)cc2n1
Temperature: 100 °C

Procedure:
To (2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-yl)-methanol (1.42 g) in toluene (14 ml) warmed to 40° C. was added phosphorous tribromide (0.16 ml) and the mixture was then heated to 100° C. After heating for 6 hours the reaction mixture was cooled, diluted with chloroform, washed with brine, dried (MgSO4) and the solvent removed in vacuo to yield 6-bromomethyl-2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (1.40 g).
Reaction SMILES: CO[C:3]([C:5]1[CH:6]=[N:7][C:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)=[N:9][CH:10]=1)=[O:4].Cl.[CH3:22][NH:23][O:24][CH3:25].C([Mg]Cl)(C)C>O1CCCC1>[CH3:25][O:24][N:23]([CH3:22])[C:3]([C:5]1[CH:10]=[N:9][C:8]([C:11]2[CH:12]=[CH:13][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:15][CH:16]=2)=[N:7][CH:6]=1)=[O:4]
Reactant: CNOC
Reactant: COC(=O)c1cnc(-c2ccc(C(F)(F)F)cc2)nc1
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: C1CCOC1
Product: CON(C)C(=O)c1cnc(-c2ccc(C(F)(F)F)cc2)nc1
Temperature: -30 °C
Yield: 40 %

Procedure:
2-(4-Trifluoromethyl-phenyl)-pyrimidine-5-carboxylic acid methyl ester (5.6 g, 19.84 mmol) is dissolved into anhydrous tetrahydrofuran (THF) (100 mL) and then cooled to −30° C. while stirring under nitrogen. N,O-dimethylhydroxylamine hydrochloride (3.12 g, 32.0 mmol) is then added to the solution in one portion. Isopropyl magnesium chloride (30 mL, 2M in THF, 60 mmol) is slowly added to the cooled suspension over 1 h. After complete consumption of starting material, then 30% solution of ammonium chloride is added with stirring: The reaction is diluted with diethyl ether and extracted. The organic layer is collected and washed with cold water (2×) and brine. The solution is then dried over anhydrous sodium sulfate, filtered, and concentrated. The 2-(4-trifluoromethyl-phenyl)-pyrimidine-5-carboxylic acid methoxy-methyl-amide (2.46 g, 7.936 mmol) is obtained in pure form after flash column chromatography.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[NH:15][C:16]1[N:21]=[C:20]([CH3:22])[C:19]([C:23]([O:25][CH3:26])=[O:24])=[C:18]([C:27]2[CH:28]=[N:29][N:30]([CH3:32])[CH:31]=2)[N:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Se](=O)=[O:34]>O1CCOCC1>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[NH:15][C:16]1[N:21]=[C:20]([CH:22]=[O:34])[C:19]([C:23]([O:25][CH3:26])=[O:24])=[C:18]([C:27]2[CH:28]=[N:29][N:30]([CH3:32])[CH:31]=2)[N:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=[Se]=O
Reactant: COC(=O)c1c(C)nc(N[C@@H]2CCCC[C@@H]2NC(=O)OC(C)(C)C)nc1-c1cnn(C)c1
Solvent: C1COCCO1
Product: COC(=O)c1c(C=O)nc(N[C@@H]2CCCC[C@@H]2NC(=O)OC(C)(C)C)nc1-c1cnn(C)c1
Temperature: 100 °C

Procedure:
To a 25 mL round bottom flask was added methyl 2-((1R,2S)-2-(tert-butoxycarbonylamino)cyclohexylamino)-4-methyl-6-(1-methyl-1H-pyrazol-4-yl)pyrimidine-5-carboxylate (0.17 g, 0.382 mmol), selenium dioxide (0.085 g, 0.765 mmol) and dioxane. The reaction mixture was heated at 100° C. overnight, cooled to RT, and filtered through a bed of Celite 545, which was rinsed with MeOH. The solvent was removed to give the title compound as yellowish-brown foam, which was used in the next step without further purification (245 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[C:3]=1[C:4]([C:6]1[C:16]([OH:17])=[CH:15][C:9]2[C:10]([C:12](N)=[O:13])=[CH:11][C:8]=2[CH:7]=1)=[O:5].C(O)(=[O:25])C>Cl>[Cl:1][C:2]1[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[C:3]=1[C:4]([C:6]1[C:16]([OH:17])=[CH:15][C:9]2[C:10]([C:12]([OH:25])=[O:13])=[CH:11][C:8]=2[CH:7]=1)=[O:5]
Reactant: NC(=O)C1=Cc2cc(C(=O)c3c(Cl)cccc3Cl)c(O)cc21
Reactant: CC(=O)O
Agent: Cl
Product: O=C(O)C1=Cc2cc(C(=O)c3c(Cl)cccc3Cl)c(O)cc21

Procedure:
2 g of 4-(2,6-dichlorobenzoyl)-5-hydroxybenzocyclobutene-1-carboxamide in 20 ml of acetic acid and 20 ml of concentrated hydrochloric acid are stirred for 4 hours at 95°-100°. The mixture is left to cool, filtered with suction, washed with water and recrystallised from trichloromethane/hexane. 4-(2,6-dichlorobenzoyl)-5-hydroxybenzocyclobutene-1-carboxylic acid is obtained having a melting point of 202°-203°.
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=O)[C:3]2[CH2:7][CH2:8][CH2:9][CH2:10][C:2]1=2.C(O)(=O)C.[F:16][C:17]1[CH:23]=[C:22]([F:24])[CH:21]=[C:20]([F:25])[C:18]=1[NH2:19]>C(Cl)Cl>[F:16][C:17]1[CH:23]=[C:22]([F:24])[CH:21]=[C:20]([F:25])[C:18]=1[N:19]1[C:1](=[O:11])[C:2]2[CH2:10][CH2:9][CH2:8][CH2:7][C:3]=2[C:4]1=[O:6]
Reactant: O=C1OC(=O)C2=C1CCCC2
Reactant: Nc1c(F)cc(F)cc1F
Solvent: CC(=O)O
Solvent: ClCCl
Product: O=C1C2=C(CCCC2)C(=O)N1c1c(F)cc(F)cc1F

Procedure:
A solution of 5.3 parts of 3,4,5,6-tetrahydrophthalic anhydride in 100 parts of glacial acetic acid was treated with 5 parts of 2,4,6-trifluoroaniline at once. After refluxing for 24 hours, the acetic acid was stripped from the reaction mixture under 300 mm hg pressure. The residue was dissolved in 100 parts of methylene chloride and washed with 100 parts of 10% aqueous sodium carbonate. After drying over anhydrous sodium sulfate, the solution was stripped under 300 mm hg pressure. The resulting pink oil was crystallized from 70 parts of methanol at -40°C to yield 4.7 parts white crystals of 2-(2,4,6-trifluorophenyl)-4,5,6,7-tetrahydro-2H-isoindole-1,3-dione melting at 91°-92°C.
Reaction SMILES: C[Si](C)(C)[C:3]#[C:4][C:5]1[S:9][C:8]([C:10]([O:12]CC)=[O:11])=[CH:7][CH:6]=1.[Li+].[OH-].O.Cl>C1COCC1>[C:4]([C:5]1[S:9][C:8]([C:10]([OH:12])=[O:11])=[CH:7][CH:6]=1)#[CH:3]
Reactant: CCOC(=O)c1ccc(C#C[Si](C)(C)C)s1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: C#Cc1ccc(C(=O)O)s1
Temperature: 40 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl 5-(2-trimethylsilyl-ethyn-1-yl)-thiophene-2-carboxylate prepared above (529 mg, 2.10 mmol) in THF (20 mL), 1N aq. LiOH (7.0 mL, 7.0 mmol) was added. After the mixture was stirred at 40° C. overnight, it was poured into water. The aqueous solution was acidified with 1N HCl to pH 1. The product was extracted with EtOAc. The EtOAc solution was washed with brine, dried over MgSO4, concentared in vacuo to give 5-ethynyl-thiophene-2-carboxylic acid (316 mg). MS 153 (M+H).
Reaction SMILES: Cl[C:2]1[N:20]=[C:5]2[C:6]([C:10]3[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=3)=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[N:21]1([CH:27]2[CH2:33][CH2:32][C:31]3[CH:34]=[C:35]([NH2:38])[CH:36]=[CH:37][C:30]=3[CH2:29][CH2:28]2)[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[CH3:19][S:16]([C:13]1[CH:14]=[CH:15][C:10]([C:6]2[C:5]3[N:4]([N:3]=[C:2]([NH:38][C:35]4[CH:36]=[CH:37][C:30]5[CH2:29][CH2:28][CH:27]([N:21]6[CH2:26][CH2:25][O:24][CH2:23][CH2:22]6)[CH2:33][CH2:32][C:31]=5[CH:34]=4)[N:20]=3)[CH:9]=[CH:8][CH:7]=2)=[CH:11][CH:12]=1)(=[O:18])=[O:17]
Reactant: Nc1ccc2c(c1)CCC(N1CCOCC1)CC2
Reactant: CS(=O)(=O)c1ccc(-c2cccn3nc(Cl)nc23)cc1
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CS(=O)(=O)c1ccc(-c2cccn3nc(Nc4ccc5c(c4)CCC(N4CCOCC4)CC5)nc23)cc1

Procedure:
[8-(4-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-(7-morpholin-4-yl-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yl)-amine was prepared from 2-chloro-8-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridine (100.0 mg, 0.3249 mmol) and 7-morpholin-4-yl-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamine (88.0 mg, 0.357 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (36.0 mg, 0.0658 mmol) as the ligand in a manner analogous to Example 2d. Product isolated as a yellow foam (0.107 g, 63%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.50 (d, J=6.6 Hz, 1H), 8.23 (d, J=8.5 Hz, 2H), 8.08 (d, J=8.4 Hz, 2H), 7.65 (d, J=7.4 Hz, 1H), 7.36 (dd, J=8.1, 2.2 Hz, 1H), 7.31 (d, J=2.0 Hz, 1H), 7.10 (d, J=8.1 Hz, 1H), 7.01 (t, J=7.1 Hz, 1H), 6.81 (s, 1H), 3.73-3.67 (m, 4H), 3.10 (s, 3H), 2.85 (ddd, J=13.7, 13.7, 7.5 Hz, 2H), 2.76-2.51 (m, 7H), 2.10 (ddd, J=11.2, 11.2, 11.2 Hz, 2H), 1.44 (dddd, J=23.3, 11.5, 11.5, 11.5 Hz, 2H). MS=518 (MH)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:9][CH2:10][C:11]([NH:13][C:14]2[C:15]([CH3:23])=[C:16]([CH:20]=[CH:21][CH:22]=2)[C:17]([OH:19])=O)=[O:12])[CH:5]=[CH:6][C:7]=1[F:8].[CH3:24][N:25]([CH3:29])[CH2:26][CH2:27][NH2:28].F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1.CN(C1C=CC=CN=1)C.C(N(CC)C(C)C)(C)C>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]([NH:9][CH2:10][C:11]([NH:13][C:14]2[C:15]([CH3:23])=[C:16]([CH:20]=[CH:21][CH:22]=2)[C:17]([NH:28][CH2:27][CH2:26][N:25]([CH3:29])[CH3:24])=[O:19])=[O:12])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CN(C)CCN
Reactant: Cc1c(NC(=O)CNc2ccc(F)c(F)c2)cccc1C(=O)O
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: CN(C)c1ccccn1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1c(NC(=O)CNc2ccc(F)c(F)c2)cccc1C(=O)NCCN(C)C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 3-[2-(3,4-difluorophenylamino)acetylamino]-2-methylbenzoic acid (0.2 g), N,N-dimethylethylenediamine (0.08 ml), bromotripyrrolidinophosphonium hexafluorophosphate (PyBroP®) (0.34 g), dimethylaminopyridine (0.07 g) and N,N-diisopropylethylamine (0.31 ml) in dimethylformamide (5 ml) was stirred at room temperature under N2 for 18 hours. The reaction mixture was partitioned between ethyl acetate and water and the organic phase was washed with water and brine, dried (MgSO4) and evaporated. The crude product was triturated with diethyl ether. The resultant solid was triturated with ethyl acetate and filtered. Yield 70 mg.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10](O)=[O:11].B.C1COCC1>O1CCCC1.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:13])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][OH:11]
Reactant: COC(=O)CCCCCCC(=O)O
Agent: B
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)CCCCCCCO
Reaction time: 8 h

Procedure:
A solution of suberic acid monomethyl ester (1.5 g, 7.97 mmol, 1.0 equiv.) in tetrahydrofuran (THF) (32.0 mL, .25M) at −20° C. was treated dropwise with BH3.THF (IM solution in THF, 7.97 mL, 7.97 mmol, 1.0 equiv.). The reaction mixture was stirred overnight and was subsequently allowed to reach room temperature. The reaction mixture was then diluted with ethyl acetate (100 mL) and quenched with methanol (10 mL) and 10% HCl (10 mL). Extraction with NaHCO3 (1×20 mL), water (2×10 mL), and brine (1×10 mL), afforded methyl-8-hydroxy-octanoate
Reaction SMILES: [CH3:1][O:2][C:3](=[O:35])[NH:4][CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]([C:15](=[O:34])[CH2:16][C:17]([CH3:33])([CH3:32])[CH2:18][C@H:19]([NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C@@H:20]([OH:23])[CH2:21][NH2:22])[CH2:6]1.C(=O)([O-])[O-].[Na+].[Na+].[C:42](Cl)(=[O:47])[C:43]([CH3:46])([CH3:45])[CH3:44]>C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:35])[NH:4][CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]([C:15](=[O:34])[CH2:16][C:17]([CH3:33])([CH3:32])[CH2:18][C@H:19]([NH:24][C:25]([O:27][C:28]([CH3:30])([CH3:29])[CH3:31])=[O:26])[C@@H:20]([OH:23])[CH2:21][NH:22][C:42](=[O:47])[C:43]([CH3:46])([CH3:45])[CH3:44])[CH2:6]1
Reactant: COC(=O)NC1Cc2ccccc2N(C(=O)CC(C)(C)C[C@H](NC(=O)OC(C)(C)C)[C@@H](O)CN)C1
Reactant: CC(C)(C)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COC(=O)NC1Cc2ccccc2N(C(=O)CC(C)(C)C[C@H](NC(=O)OC(C)(C)C)[C@@H](O)CNC(=O)C(C)(C)C)C1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 0.030 g of [1-(7-amino-5(S)-tert-butoxycarbonylamino-6(S)-hydroxy-3,3-dimethyl-heptanoyl)-1,2,3,4-tetrahydro-quinolin-3(R,S)-yl]-carbamic acid methyl ester in 0.6 ml of ethyl acetate at room temperature under argon is added 0.6 ml of saturated aqueous sodium carbonate solution. The mixture is stirred for 15 minutes at room temperature and and 0.011 ml of pivaloyl chloride are added. The mixture is stirred at room temperature for 1.5 hours. The layers are separated and the aqueous layer is extracted with ethyl acetate (2×). The combined organic layers are dried over sodium sulphate, filtered and concentrated. The title compound is obtained as a beige oil from the residue by means of flash chromatography (SiO2 60 F). Rt=4.46 (gradient I).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:14][C:13](=[O:15])[CH:12]=[CH:11][N:10]2C(OCC2C=CC=CC=2)=O)[CH:5]=[CH:6][C:7]=1[F:8]>CO.[Pd]>[F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[CH2:14][C@@H:13]([OH:15])[CH2:12][CH2:11][NH:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C1C=CN(C(=O)OCc2ccccc2)C(c2ccc(F)c(F)c2)C1
Agent: [Pd]
Solvent: CO
Product: O[C@H]1CCN[C@@H](c2ccc(F)c(F)c2)C1
Yield: 101 %

Procedure:
A solution of benzyl 2-(3,4-difluorophenyl)-4-oxo-3,4-dihydropyridine-1(2H)-carboxylate (6.70 g, 19.50 mmol) (reagent preparation 20) in methanol (100 mL) was hydrogenated with catalytic 10% palladium on carbon in a Parr shaker at 35 psi. The catalyst was filtered off and the filtrate was concentrated then dried to give (±)-(2R,4S)-2-(3,4-difluorophenyl)piperidin-4-ol (4.2 g, quantitative). 1H NMR (400 MHz, d6-DMSO): 7.33 (m, 1H), 7.28 (m, 1H), 7.02 (m, 1H), 5.00 (t, 1H), 4.49 (d, 1H), 3.91 (m, 1H), 3.77 (m, 1H), 3.21 (m, 1H), 2.11 (2t, 1H), 1.95 (2q, 1H), 1.70 (m, 1H), 1.50 (m, 1H). MS (EI) for C11H13F2NO: 214 (MH+).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[CH2:9][CH:8]([CH2:13][C:14]([OH:16])=[O:15])[CH2:7]2)([O-])=O.C(=O)(O)[O-].[Na+].S(=O)(=O)(O)O.[CH2:27](O)[CH3:28]>S(=O)(=O)(O)O>[NH2:1][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[CH2:9][CH:8]([CH2:13][C:14]([O:16][CH2:27][CH3:28])=[O:15])[CH2:7]2
Reactant: CCO
Reactant: O=C(O)CC1Cc2ccc([N+](=O)[O-])cc2C1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCOC(=O)CC1Cc2ccc(N)cc2C1

Procedure:
A solution of (5-nitro-indan-2-yl)-acetic acid [2.22 g, Reference Example 9(a)] in ethanol (100 ml) containing sulfuric acid (5 drops) was refluxed for 4 hours, after which HPLC showed only a trace of free acid remaining. The mixture was treated with solid sodium bicarbonate to neutralise the sulfuric acid and then filtered. The filtrate was placed under a nitrogen atmosphere then 10% palladium on carbon (0.14 g) was added. The mixture was stirred rapidly and hydrogen was bubbled through the solution from a balloon. The reaction was monitored by HPLC until reduction was completed (4 hours) when the reaction mixture was filtered through a pad of celite. The filtrate was evaporated to give the title compound (2.16 g) as a dark red oil which was used without further purification.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([B:6]2[O:14][C:11]([CH3:13])([CH3:12])[C:8]([CH3:10])([CH3:9])[O:7]2)[CH:3]=[N:2]1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Br[CH2:26][CH:27]1[CH2:29][CH2:28]1>C1COCC1>[CH:27]1([CH2:26][N:2]2[CH:3]=[C:4]([B:6]3[O:7][C:8]([CH3:9])([CH3:10])[C:11]([CH3:13])([CH3:12])[O:14]3)[CH:5]=[N:1]2)[CH2:29][CH2:28]1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: BrCC1CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CC1(C)OB(c2cnn(CC3CC3)c2)OC1(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 84.4 %

Procedure:
To a stirred solution of pyrazole-4-boronic acid pinacol ester (0.25 g, 1.29 mmol) in THF (5 mL) was added a solution of sodium bis(trimethylsilyl)amide (0.71 mL, 2M in THF, 1.42 mmol), followed by (bromomethyl)cyclopropane (0.19 mL, 1.93 mmol). The reaction mixture was stirred at r.t. in a sealed tube for 16 h, then at 80° C. for 4 h. Additional (bromomethyl)cyclopropane (0.06 mL, 0.65 mmol) was added. The reaction mixture was stirred at 80° C. for 16 h, then concentrated in vacuo. EtOAc (30 mL) and aqueous sat. NH4Cl (15 mL) were added. The organic fraction was separated, washed with H2O (15 mL), then brine (15 mL), dried (MgSO4), filtered and concentrated in vacuo to give the title compound (0.27 g, 84%) as a clear yellow oil that was used without further purification. δH (CDCl3) 7.82 (1H, s), 7.80 (1H, s), 3.99 (2H, d, J 7.2 Hz), 1.32 (12H, s), 1.32-1.19 (1H, m), 0.70-0.59 (2H, m), 0.42-0.33 (2H, m). LCMS (ES+) 249.0 (M+H)+, RT 3.42 minutes (Method 1).