Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:4]([CH2:21][CH:22]([CH3:24])[CH3:23])[C:5](=[O:20])[C:6]2[C:11]([C:12]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[CH:10][C:9](Br)=[CH:8][CH:7]=2.[CH3:25][N:26]1CCCC1=O.[Cl-].[NH4+]>[C-]#N.[Zn+2].[C-]#N.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>[NH2:1][CH2:2][C:3]1[N:4]([CH2:21][CH:22]([CH3:24])[CH3:23])[C:5](=[O:20])[C:6]2[C:11]([C:12]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[CH:10][C:9]([C:25]#[N:26])=[CH:8][CH:7]=2
Reactant: CN1CCCC1=O
Reactant: CC(C)Cn1c(CN)c(-c2ccccc2)c2cc(Br)ccc2c1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Cl-]
Solvent: O
Product: CC(C)Cn1c(CN)c(-c2ccccc2)c2cc(C#N)ccc2c1=O
Temperature: 25 °C
Yield: 74.5 %

Procedure:
A mixture of 3-(aminomethyl)-6-bromo-2-isobutyl-4-phenylisoquinolin-1(2H)-one (15.0 g), zinc cyanide (2.74 g), tetrakis(triphenylphosphine)palladium (1.35 g), N-methylpyrrolidone (75 ml) and water (0.75 ml), was stirred under a nitrogen atmosphere at an inner temperature of 54–56° C. To the reaction mixture was added dropwise saturated aqueous ammonium chloride-25% ammonium hydroxide-water (4:1:4, 37.5 ml) over 30 min at the same temperature, and the mixture was stirred for 1 h and below 5° C. for 1 h. The obtained crystals were collected by filtration and suspended in acetonitrile (105 ml). The suspension was dissolved at 80° C. To the obtained solution was added activated carbon (0.75 g) and the mixture was stirred for 10 min. The activated carbon was filtered off and washed with acetonitrile (15 ml). The filtrate was combined and cooled to 25° C. to give crystals. Water (120 ml) was added dropwise and the obtained mixture was cooled to 5° C. and stirred for 1 h. The obtained crystals were collected by filtration to give the title compound (9.6 g, yield 74.5%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH:13]([CH3:37])[C:14]([O:16][C@H:17]([C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[C:29]([O:35][CH3:36])[CH:28]=1)[CH2:18][C:19]1[C:24]([Cl:25])=[CH:23][N:22]=[CH:21][C:20]=1[Cl:26])=[O:15])[CH:7]=[CH:6]2.CO>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C@@H:13]([CH3:37])[C:14]([O:16][C@H:17]([C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[C:29]([O:35][CH3:36])[CH:28]=1)[CH2:18][C:19]1[C:24]([Cl:25])=[CH:23][N:22]=[CH:21][C:20]=1[Cl:26])=[O:15])[CH:7]=[CH:6]2
Reactant: COc1ccc2cc(C(C)C(=O)O[C@@H](Cc3c(Cl)cncc3Cl)c3ccc(OC)c(OC)c3)ccc2c1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COc1ccc2cc([C@@H](C)C(=O)O[C@@H](Cc3c(Cl)cncc3Cl)c3ccc(OC)c(OC)c3)ccc2c1
Reaction time: 2 h
Yield: 44.4 %

Procedure:
((S)-2-(3,5-dichloropyridin-4-yl)-1-(3,4-dimethoxyphenyl)ethyl) 2-(6-methoxynaphthalen-2-yl)propanoate (diastereoisomeric mixture prepared as described in Ex 1, Step 1, 79 g, 146 mmol) was dissolved in CHCl3 (100 ml), and MeOH (30 ml) was slowly added up to persistent opalescence and the mixture left at RT for 2 hours. The solid formed was collected by filtration and re-crystallized by CHCl3/MeOH (70 ml/20 ml) solvent system to obtain 35 g of the desired compound (yield 88%, ee 98%). Chiral HPLC analysis Rt=42.33 min; eluent:hexane:isopropanol 97:3; 1H NMR (600 MHz, CHLOROFORM-d) δ ppm 8.04 (s, 2H), 7.67 (d, J=8.79 Hz, 1H), 7.58 (d, J=8.52 Hz, 1H), 7.53 (m, 1H), 7.12-7.20 (m, 3H), 6.95 (dd, J=8.24, 1.92 Hz, 1H), 6.78-6.88 (m, 2H), 6.14 (dd, J=10.44, 4.12 Hz, 1H), 3.95 (s, 3H), 3.88 (s, 3H), 3.78-3.81 (m, 4H), 3.55 (dd, J=13.73, 10.44 Hz, 1H), 3.14 (dd, J=13.60, 4.26 Hz, 1H), 1.44 (d, J=7.14 Hz, 3H).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][CH2:15][CH:14]([OH:18])[CH2:13]2)=[CH:8][CH:7]=1.[S:19](Cl)([CH3:22])(=[O:21])=[O:20].CCN(CC)CC>C(Cl)Cl>[CH3:22][S:19]([O:18][CH:14]1[CH2:15][CH2:16][CH2:17][N:12]([C:9]2[CH:8]=[CH:7][C:6]([C:2]3[O:1][CH:5]=[CH:4][N:3]=3)=[CH:11][CH:10]=2)[CH2:13]1)(=[O:21])=[O:20]
Reactant: CS(=O)(=O)Cl
Reactant: OC1CCCN(c2ccc(-c3ncco3)cc2)C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OC1CCCN(c2ccc(-c3ncco3)cc2)C1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a solution of 1-(4-(oxazol-2-yl)phenyl)piperidin-3-ol (85 mg, 0.348 mmol) in CH2Cl2 (2 mL) at 0° C. was added dropwise mesyl chloride (0.033 mL, 0.418 mmol), followed by Et3N (0.058 mL, 0.418 mmol). The reaction was stirred at 0° C. for 5 min, and then at rt for 30 min. After this time, HPLC and LC/MS showed that the desired product formed and there was no starting material remaining. The reaction mixture was concentrated. The residue was dissolved in EtOAc, washed with water, saturated aqueous NaHCO3, and saturated aqueous NaCl. The organic layer was dried over Na2SO4, filtered and concentrated to give the desired product 1-(4-(oxazol-2-yl)phenyl)piperidin-3-yl methanesulfonate (110 mg, 0.341 mmol, 98% yield) as an off-white foam. Anal. Calcd. for C15H18N2O4S m/z 322.3, found: 323.1 (M+H)+.
Reaction SMILES: Cl.Cl.[F:3][C:4]1[C:12]([C:13]2[C:21]3[C:20]([NH2:22])=[N:19][CH:18]=[N:17][C:16]=3[N:15]([CH3:23])[CH:14]=2)=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][CH2:7][NH:8]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.OC(C(F)(F)F)=O.[CH3:64][C:65]1[N:70]=[C:69]([CH2:71][C:72](O)=[O:73])[CH:68]=[CH:67][CH:66]=1>CN(C=O)C.CO.C(Cl)Cl>[F:3][C:4]1[C:12]([C:13]2[C:21]3[C:20]([NH2:22])=[N:19][CH:18]=[N:17][C:16]=3[N:15]([CH3:23])[CH:14]=2)=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][CH2:7][N:8]2[C:72](=[O:73])[CH2:71][C:69]1[CH:68]=[CH:67][CH:66]=[C:65]([CH3:64])[N:70]=1
Reactant: Cn1cc(-c2ccc3c(c2F)CCN3)c2c(N)ncnc21
Reactant: Cc1cccc(CC(=O)O)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1cccc(CC(=O)N2CCc3c2ccc(-c2cn(C)c4ncnc(N)c24)c3F)n1
Temperature: 0 °C
Yield: 52.9 %

Procedure:
To a suspension of 5-(4-fluoro-2,3-dihydro-1H-indol-5-yl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine dihydrochloride (200 mg, 0.56 mmol, 1 equiv) and HATU (235 mg, 0.62 mmol, 1.1 equiv) in DMF (2 mL) at room temperature was added DIEA (412 uL, 2.36 mmol, 4.2 equiv) in one portion. To this mixture was added (6-methyl-2-pyridinyl)acetic acid TFA salt (148 mg) portionwise over a 1 h period. After a total of 2 h, LCMS showed conversion complete. The mixture was poured into 20 mL of ice cold water to give a suspension, which was filtered. The cake was washed with water and dried under house vacuum to afford crude product, which was dissolved in 10% MeOH in DCM and absorbed onto a dryload cartridge. Purification was done on an Analogix SF25-40 g silica gel cartridge using gradient elution of 1% A in CHCl3 to 60% A in CHCl3 (A was a mixture of 3200/800/80 CHCl3/MeOH/NH4OH, gradient: 0-5 min: 1% A, 5-35 min 5-60% A). The desired product eluted from 27-34% A. The combined fractions were concentrated in vacuo. The residue was dissolved in 10% MeOH in DCM and absorbed onto a dryload cartridge. Purification was done on an Analogix SF25-60 g silica gel cartridge using gradient elution of 1% A in EtOAc 100% A (A was a mixture of 20% MeOH in EtOAc). The desired product eluted from 83-100% A. The combined fractions were concentrated in vacuo. The residue was dissolved in 12 mL of 10% MeOH in DCM and conc in vacuo to a suspension (about 2 mL). This mixture was diluted with 12 mL of MTBE. The resulting suspension was conc in vacuo to reduce to half volume. The mixture was diluted with another 10 mL of MTBE. The suspension was filtered. The cake was washed with MTBE (2×4 mL) and hexane (3×4 mL), and dried under vacuum at 65° C. for 18 h to afford 5-{4-fluoro-1-[(6-methyl-2-pyridinyl)acetyl]-2,3-dihydro-1H-indol-5-yl}-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (123 mg) as white solids. LC-MS (ES) m/z=417 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.45 (s, 3H), 3.25 (t, J=8.5 Hz, 2H), 3.74 (s, 3H), 4.00 (s, 2H), 4.35 (t, J=8.5 Hz, 2H), 5.90-6.17 (br. s., 1.6H), 7.12-7.23 (m, 3H), 7.27 (s, 1H), 7.66 (t, J=7.7 Hz, 1H), 7.92 (d, J=8.1 Hz, 1H), 8.14 (s, 1H). (ES) m/z=417 [M+H]+.
Reaction SMILES: [Li]CCCC.[F:6][C:7]1[CH:8]=[N:9][C:10]2[C:15]([CH:16]=1)=[CH:14][C:13]([O:17][CH3:18])=[CH:12][CH:11]=2.CN([CH:22]=[O:23])C>C1COCC1>[F:6][C:7]1[CH:8]=[N:9][C:10]2[C:15]([C:16]=1[CH:22]=[O:23])=[CH:14][C:13]([O:17][CH3:18])=[CH:12][CH:11]=2
Reactant: CN(C)C=O
Reactant: COc1ccc2ncc(F)cc2c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc2ncc(F)c(C=O)c2c1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 52 %

Procedure:
To a solution of DIPA (15.5 mL) in THF (300 mL), cooled to −78° C., was added n-BuLi (2.35N in hexanes, 44 mL). The reaction mixture was stirred 5 min at this temperature before warming to 0° C. The reaction mixture was stirred 15 min before cooling to −78° C. 3-fluoro-6-methoxy-quinoline (15 g, 84.7 mmol; see WO 2006/058700) in THF (50 mL+10 mL rinse) was added and the mixture was stirred 3 h at −78° C. DMF (3 mL, 1.2 eq.) was added quickly (within one min). After 45 min, the reaction mixture was quenched by adding 1-propanol (8 mL). The mixture was warmed to rt and extracted twice with EA. The combined org. layers were washed with brine, dried over Na2SO4, filtered and concentrated to dryness. The residue triturated in Hept to give the title intermediate as an orange solid (9.0 g, 52% yield).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:22][C:23]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])([CH3:25])[CH3:24])([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:12][C:11]2=[O:31])[CH3:9])=[CH:4][CH:3]=1.[O:32]=[C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][NH:34]1>>[CH3:24][C:23]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])([CH3:25])[CH2:22][C@@:13]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:12][C:11](=[O:31])[N:10]([C@H:8]([C:5]2[CH:6]=[CH:7][C:2]([C:36]3[CH:37]=[CH:38][C:33](=[O:32])[NH:34][CH:35]=3)=[CH:3][CH:4]=2)[CH3:9])[CH2:15][CH2:14]1
Reactant: O=c1ccc(B(O)O)c[nH]1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CC(C)(C)NS(C)(=O)=O)(c2ccccc2)OC1=O
Product: C[C@@H](c1ccc(-c2ccc(=O)[nH]c2)cc1)N1CC[C@](CC(C)(C)NS(C)(=O)=O)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared from N-(1-((S)-3-((S)-1-(4-bromophenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)-2-methylpropan-2-yl)methanesulfonamide and 2-oxo-1,2-dihydropyridin-5-ylboronic acid following a procedure analogous to that described in Example 4. LC-MS Method 1 tR=1.3 min, m/z=524 (M+1); 1H NMR (CDCl3) 7.81 (d, 1H, J=9 Hz), 7.63 (br s, 1H), 7.39-7.31 (m, 5H), 7.18 (d, 2H, J=8 Hz), 7.03 (d, 2H, J=7 Hz), 6.79 (d, 1H, J=9 Hz), 5.67 (q, 1H, J=6 Hz), 2.93 (s, 3H), 2.90 (m, 1H), 2.49 (d, 1H, J=15 Hz), 2.32 (d, 1H, J=15 Hz), 2.28-2.18 (m, 3H), 1.54 (d, 3H, J=7 Hz), 1.36 (s, 3H), 1.25 (s, 3H).
Reaction SMILES: ClC(=O)C(OC)=O.[C:8]([O:12][C:13]([N:15]1[CH2:20][CH2:19][C:18](C2C=CC=CC=2SC2C=CC(C)=CC=2)(O)[CH2:17][CH2:16]1)=[O:14])([CH3:11])([CH3:10])[CH3:9].CCCC[SnH](CCCC)CCCC.CC(N=NC(C#N)(C)C)(C#N)C>CN(C)C1C=CN=CC=1.C(OCC)(=O)C.C(Cl)(Cl)Cl.CC#N>[C:8]([O:12][C:13]([N:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)=[O:14])([CH3:11])([CH3:9])[CH3:10]
Reactant: Cc1ccc(Sc2ccccc2C2(O)CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CCCC[SnH](CCCC)CCCC
Agent: CN(C)c1ccncc1
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCCCC1
Reaction time: 2 h
Yield: 139.6 %

Procedure:
Methyl Chloro-oxo-acetate (1.37 g, 11.25 mmol) was added to a stirred solution of 1-tert-butoxycarbonyl-4-[2-(4-methylphenylsulfanyl)phenyl]piperidin-4-ol (3.00 g, 7.5 mmol) and 4-(dimethylamino)pyridine (1.65 g, 13.5 mmol) in a mixture of dry CH3CN (24 ml) and CHCl3 (12 mL) at 0° C. under argon. The reaction mixture was allowed to reach room temperature and then stirred 2 h. Ethyl acetate (140 mL) was added and some salts were removed by filtration through celite. The organic phase was washed with sat. NaHCO3 (140 ml), brine (140 mL) and dried (MgSO4). The solvents were evaporated in vacuo and the crude material was dried in vacuo. This material was dissolved in dry toluen (48 mL) under argon. Bu3SnH (3.27 g, 11.25 mmol) and AIBN (0.31 g, 1.88 mmol) were added. The solution was stirred under argon at 90° C. for 2.5 h. The solvent was evaporated in vacuo, and the crude material was purified by flash chromatography on silicagel (eluent: a stepwise gradient of ethylacetat in heptane from 10:90 to 20:80) to produce 44244-methylphenylsulfanyl)phenyl)-piperidine-1-carboxylic acid tert-butyl ester as a clear oil (1.94 g, 67%). This oil was dissolved in MeOH (9.2 mL) and HCl in diethylether (2.0 M) was added at 0° C. The reaction mixture was allowed to warm to room temperature and stirred overnight. The target compound was collected as its hydrochloride. M.p 229-231° C. Calculated for C18H21NS.HCl: C, 67.58; H, 6.63; N, 4.38. Found: C, 67.33; H, 6.97; N, 4.31. LC/MS (m/z) 284 (MH+); RT=2.12; purity (UV, ELSD): 96%, 100%; yield: 0.26 g (46%).
Reaction SMILES: I.[CH3:2][N:3]1[C:8](=[O:9])[N:7]2[CH:10]=[N:11][C:12]([C:13](=[NH:23])[NH:14][CH2:15][C:16](=O)[C:17]3[S:18][CH:19]=[CH:20][CH:21]=3)=[C:6]2[N:5]=[N:4]1.I>Cl>[CH3:2][N:3]1[C:8](=[O:9])[N:7]2[CH:10]=[N:11][C:12]([C:13]3[NH:14][CH:15]=[C:16]([C:17]4[S:18][CH:19]=[CH:20][CH:21]=4)[N:23]=3)=[C:6]2[N:5]=[N:4]1
Reactant: Cn1nnc2c(C(=N)NCC(=O)c3cccs3)ncn2c1=O
Agent: Cl
Agent: I
Product: Cn1nnc2c(-c3nc(-c4cccs4)c[nH]3)ncn2c1=O
Temperature: 80 °C
Reaction time: 2 h
Yield: 89.3 %

Procedure:
A mixture of crude 3-methyl-4-oxo-N-(2-oxo-2-(thiophen-2-yl)ethyl)-3,4-dihydroimidazo[5,1-d][1,2,3,5]tetrazine-8-carboximidamide hydroiodide (40 mg) in 3N HCl (3 mL) was heated at 80° C. overnight. After being cooled to room temperature, the mixture was left at 4° C. for 2 hours and the precipitate was filtered and washed successively with cold water, ethyl acetate and diethyl ether to give the a mixture of the hydrochloride and hydroiodide salts of the title compound (24 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([SH:8])[CH:5]=[CH:6][CH:7]=1.CN(C=O)C.C([O-])([O-])=O.[K+].[K+].Br[C:21]1[CH:29]=[CH:28][C:27]([Br:30])=[CH:26][C:22]=1[C:23]([OH:25])=[O:24]>O>[Cl:1][C:2]1[CH:3]=[C:4]([S:8][C:21]2[CH:29]=[CH:28][C:27]([Br:30])=[CH:26][C:22]=2[C:23]([OH:25])=[O:24])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1cc(Br)ccc1Br
Reactant: Sc1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)c1cc(Br)ccc1Sc1cccc(Cl)c1
Temperature: 150 °C
Yield: 60.9 %

Procedure:
To a mixture of 3-chlorothiophenol (20 g, 0.138 mol), cupric acetate (1.75 g) and DMF (199 mL) under N2 was added in portions K2CO3 (23 g). The mixture was heated to 150° C. and then 2,5-dibromobenzoic acid (43.5 g) was added. The mixture was heated overnight, poured into water (600 mL), filtered, the filtrate was treated with charcoal and filtered again. The filtrate was acidified with conc. HCl, extracted with CHCl3, the organic layer was washed with brine and dried over Na2SO4. The solvent was removed in vacuo to afford 28.9 g of 2-[(3-chlorophenyl)thio]-5-bromobenzoic acid.
Reaction SMILES: B.[Na].C(OC(C)C)(C)C.[OH-].[Na+].[F:12][C:13]([F:25])([F:24])[C:14]([OH:23])([C:19]([F:22])([F:21])[F:20])[C:15](OC)=[O:16].Cl>O>[F:12][C:13]([F:24])([F:25])[C:14]([C:19]([F:20])([F:22])[F:21])([OH:23])[CH2:15][OH:16]
Reactant: COC(=O)C(O)(C(F)(F)F)C(F)(F)F
Agent: B
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC(C)OC(C)C
Product: OCC(O)(C(F)(F)F)C(F)(F)F
Reaction time: 24 h
Yield: 95 %

Procedure:
Synthesis was carried out in accordance with the procedure described in U.S. Pat. No. 7,868,199. In a nitrogen atmosphere, 84 g of sodium boron hydride, 1,450 g of diisopropyl ether (IPE), 2,000 g of water and 1.7 g of 25 wt % NaOH aqueous solution were ice cooled, to which 500 g of methyl 3,3,3-trifluoro-2-hydroxy-2-(trifluoromethyl)propanoate was added dropwise. Stirring was continued for 24 hours at room temperature. Under ice cooling, 444 g of 20 wt % hydrochloric acid aqueous solution was added dropwise to quench the reaction. After the water layer was removed, the organic layer was washed with water and concentrated at 50° C. and a slightly reduced pressure of 6.7 kPa, obtaining 682 g of a 61 wt % IPE solution of 3,3,3-trifluoro-2-trifluoromethyl-1,2-propane diol (yield 95%). The compound was used in the subsequent reaction without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:18]([O-:20])=[O:19])[C:5]([N:8]2[CH2:13][CH2:12][CH:11]([CH2:14][C:15]([OH:17])=O)[CH2:10][CH2:9]2)=[N:6][CH:7]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.N1C=CC=CC=1.[CH3:49][N:50]1[CH2:56][CH2:55][CH2:54][NH:53][CH2:52][CH2:51]1>CN(C)C=O.O>[Br:1][C:2]1[CH:3]=[C:4]([N+:18]([O-:20])=[O:19])[C:5]([N:8]2[CH2:9][CH2:10][CH:11]([CH2:14][C:15]([N:53]3[CH2:54][CH2:55][CH2:56][N:50]([CH3:49])[CH2:51][CH2:52]3)=[O:17])[CH2:12][CH2:13]2)=[N:6][CH:7]=1
Reactant: O=C(O)CC1CCN(c2ncc(Br)cc2[N+](=O)[O-])CC1
Reactant: CN1CCCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: c1ccncc1
Solvent: O
Solvent: CN(C)C=O
Product: CN1CCCN(C(=O)CC2CCN(c3ncc(Br)cc3[N+](=O)[O-])CC2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69 %

Procedure:
To a solution of 0.350 g (1.02 mmol) of (5′-bromo-3′-nitro-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-acetic acid in dimethylformamide (5 mL) is added 0.450 g (1.19 mmol) of O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate followed by 0.380 mL (2.13 mmol) of pyridine. The mixture is stirred at room temperature for 1 hour then 0.225 mg (1.97 mmol) of N-methylhomopiperizine is added and the mixture is stirred at room temperature for 1 h. The mixture is diluted with water and extracted with ethyl acetate. The combined organic phase is washed with water followed by brine then dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue is purified by flash silica gel chromatography to provide 0.310 g (69.2%) of 2-(5′-bromo-3′-nitro-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-1-(4-methyl-[1,4]diazepan-1-yl)-ethanone as an orange oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([CH3:12])=[C:6]2[CH2:13][C:14]([OH:16])=O.C(Cl)(=O)C(Cl)=O.[NH:23]1[CH:27]=[C:26]([C:28]2[CH:29]=[C:30]3[C:35](=[CH:36][CH:37]=2)[CH:34]=[N:33][C:32]([NH2:38])=[CH:31]3)[CH:25]=[N:24]1.N1C=CC=CC=1.C([O-])([O-])=O.[K+].[K+]>C1COCC1.O.CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([CH3:12])=[C:6]2[CH2:13][C:14]([NH:38][C:32]1[N:33]=[CH:34][C:35]2[C:30]([CH:31]=1)=[CH:29][C:28]([C:26]1[CH:25]=[N:24][NH:23][CH:27]=1)=[CH:37][CH:36]=2)=[O:16]
Reactant: COc1ccc2[nH]c(C)c(CC(=O)O)c2c1
Reactant: Nc1cc2cc(-c3cn[nH]c3)ccc2cn1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: COc1ccc2[nH]c(C)c(CC(=O)Nc3cc4cc(-c5cn[nH]c5)ccc4cn3)c2c1
Temperature: 25 °C
Reaction time: 0.04 h

Procedure:
To a solution of 2-(5-methoxy-2-methyl-1H-indol-3-yl)acetic acid (219.2 mg, 0.5 mmol) in 5 mL of anhydrous THF was added oxalyl chloride (119.6 mg, 0.95 mmol), and 100 μL of DMF also was added. A effervescence occurred. Within 1-4 minutes the effervescence stopped. The mixture was stirred for 30 minute at room temperature, followed by addition of 6-(1H-Pyrazol-4-yl)-isoquinolin-3-ylamine in 5 mL of pyridine (100.0 mg, 0.5 mmol). The reaction was stirred at the ambient temperature over 16 hours as it was monitored by LC/MS. To the reaction mixture was added K2CO3 (196.7 mg, 1.4 mmol) and water (2 mL). The solution was heated to 70° C. for 5 hours. Removal of the solvents provided a crude mixture that was purified by HPLC using H2O/CH3CN/0.1% acetic acid as a mobile phase to give the title compound as a crystalline solid product (9.9 mg, 5.1%). 1H NMR (DMSO-d6, 400 MHz): δ 3.68 (2H, s), 3.73 (3H, s), 6.90 (2H, d, J=8.8 Hz), 7.31 (2H, d, J=8.6 Hz), 7.31 (1H, d, J=8.6 Hz), 7.81 (1H, dd, J=8.6, 1.5 Hz), 8.00 (1H, d, J=8.8 Hz), 8.08 (1H s), 8.10-8.22 (1H, m), 8.40 (2H, s), 9.03 (1H, s), 10.69 (1H, s), 13.09 (1H, s). 13CNMR (DMSO-d6, 100 MHz): δ 40.13, 55.00, 106.29, 113.75, 120.55, 124.10, 124.38, 127.87, 128.04, 130.12, 135.25, 137.87, 147.50, 150.75, 158.04, 170.13. HRMS: m/z 359.14959, calc 359.15025. MS m/z, (APCI); 359.1 [(M+1)+100].
Reaction SMILES: C([O:3][P:4]([C:9]1[C:13]([P:14]([O:19]CC)([O:16]CC)=[O:15])=[CH:12][S:11][CH:10]=1)([O:6]CC)=[O:5])C.I[Si](C)(C)C>C(#N)C>[P:14]([C:13]1[C:9]([P:4]([OH:5])([OH:6])=[O:3])=[CH:10][S:11][CH:12]=1)([OH:19])([OH:16])=[O:15]
Reactant: CCOP(=O)(OCC)c1cscc1P(=O)(OCC)OCC
Agent: C[Si](C)(C)I
Solvent: CC#N
Product: O=P(O)(O)c1cscc1P(=O)(O)O
Temperature: 25 °C
Reaction time: 12 h
Yield: 97 %

Procedure:
In acetonitrile, 0.200 g (0.561 mmols) of 3,4-bis(diethoxyphosphoryl)thiophene was dissolved, to which 0.5613 g (2.805 mmols) of commercially available iodotrimethylsilane was added at room temperature. Thereafter, the mixture was stirred at room temperature for 12 hours. After the reaction, the solvent was removed by distilling off under reduced pressure, followed by addition of methanol and stirring at room temperature for further 12 hours. The methanol was removed by distilling off under reduced pressure, followed by addition of distilled water under stirring and separation of an aqueous phase. The thus separated aqueous phase was washed several times with chloroform and the aqueous phase was concentrated and evaporated to dryness to obtain the specific substance of white crystals at a yield of 0.1333 g (yield: 97%).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([NH:34][CH2:35][CH3:36])=[C:8]([N:10]=[C:11]2[N:15]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:14](=[O:23])[C:13](=[C:24]3[N:28]([CH3:29])[C:27]4[CH:30]=[CH:31][CH:32]=[CH:33][C:26]=4[S:25]3)[S:12]2)[CH:9]=1)(=O)[CH3:2].Cl.[NH2:38][OH:39]>N1C=CC=CC=1>[CH2:16]([N:15]1[C:14](=[O:23])[C:13](=[C:24]2[N:28]([CH3:29])[C:27]3[CH:30]=[CH:31][CH:32]=[CH:33][C:26]=3[S:25]2)[S:12][C:11]1=[N:10][C:8]1[CH:9]=[C:4]([C:1](=[N:38][OH:39])[CH3:2])[CH:5]=[CH:6][C:7]=1[NH:34][CH2:35][CH3:36])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CCNc1ccc(C(C)=O)cc1N=C1SC(=C2Sc3ccccc3N2C)C(=O)N1Cc1ccccc1
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: CCNc1ccc(C(C)=NO)cc1N=C1SC(=C2Sc3ccccc3N2C)C(=O)N1Cc1ccccc1
Temperature: 80 °C

Procedure:
To the product of Example 38 was added hydroxylamine hydrochloride (2 equiv) and pyridine. The resulting mixture was heated at 80° C. for 24 h, cooled, concentrated and chromatographed (TEA-washed silica gel, 0–50% EtOAc/Hex) to give the title compound. 1H-NMR (DMSO-d6): δ 11.07 (1H, s), 7.88 (1H, s), 7.67 (2H, m), 7.53 (1H, d), 7.39 (2H, m), 7.21–7.33 (5H, m), 7.09–7.14 (1H, m), 5.05 (2H, s). 3.92 (2H, q), 3.27 (3H, s), 2.23 (3H, s), 1.03 (3H, t); MS(ESI): 530 (MH+).
Reaction SMILES: C([NH:4][CH2:5][C:6]([C:9]1[CH:24]=[CH:23][C:12]2[N:13]=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=3)[NH:15][C:11]=2[CH:10]=1)([CH3:8])[CH3:7])(=O)C.Cl>C(O)C>[NH2:4][CH2:5][C:6]([C:9]1[CH:24]=[CH:23][C:12]2[N:13]=[C:14]([C:16]3[CH:17]=[CH:18][C:19]([CH3:22])=[CH:20][CH:21]=3)[NH:15][C:11]=2[CH:10]=1)([CH3:8])[CH3:7]
Reactant: CC(=O)NCC(C)(C)c1ccc2nc(-c3ccc(C)cc3)[nH]c2c1
Agent: Cl
Solvent: CCO
Product: Cc1ccc(-c2nc3ccc(C(C)(C)CN)cc3[nH]2)cc1

Procedure:
1.45 g. of the compound prepared in Example 26 is boiled under reflux for 48 hours in 35 ml. ethanol and 35 ml. concentrated hydrochloric acid. The solvent is removed in a vacuum and the residue is dissolved in water and neutralised with 2N aqueous ammonia solution. The substance which precipitates out is filtered off with suction. There is obtained 1.1 g. of the title compound; m.p. 45°-48° C.