Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[CH2:5][N:6]1[CH:10]=[C:9](I)[CH:8]=[N:7]1)[CH3:2].[CH3:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][SH:20])=[CH:17][CH:16]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.CCN(C(C)C)C(C)C>O1CCOCC1.CCOC(C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:1]([O:3][C:4](=[O:12])[CH2:5][N:6]1[CH:10]=[C:9]([S:20][CH2:19][C:18]2[CH:21]=[CH:22][C:15]([O:14][CH3:13])=[CH:16][CH:17]=2)[CH:8]=[N:7]1)[CH3:2]
Reactant: CCOC(=O)Cn1cc(I)cn1
Reactant: COc1ccc(CS)cc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCOC(=O)Cn1cc(SCc2ccc(OC)cc2)cn1
Temperature: 90 °C

Procedure:
(4-Iodo-pyrazol-1-yl)-acetic acid ethyl ester (1.8 g, 10.3 mmol), 4-methoxybenzyl mercaptan (1.43 mL, 10.3 mmol), Xantphos (0.298 g, 0.515 mmol) and then Hünig's base (3.7 mL, 21.2 mmol) were dissolved in dioxane (100 mL). The reaction was purged with N2 (g) for 10 minutes and then tris(dibenzylideneacetone)dipalladium(0) (0.235 g, 0.258 mmol) was added. The reaction was heated to 90° C. for 2 hours then cooled and diluted with EtOAc. The organic portion was washed with H2O and brine, with back-extraction, then dried and concentrated. The crude material was purified on silica gel (0-20% EtOAc in hexanes) to afford the title compound.
Reaction SMILES: [O:1]1[C:5]([C:6]2[CH:11]=[CH:10][C:9]([S:12](Cl)(=[O:14])=[O:13])=[CH:8][CH:7]=2)=[CH:4][N:3]=[CH:2]1.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([NH2:23])=[C:19]([C:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=[CH:26][N:25]=2)[CH:18]=1>>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][S:12]([C:9]2[CH:10]=[CH:11][C:6]([C:5]3[O:1][CH:2]=[N:3][CH:4]=3)=[CH:7][CH:8]=2)(=[O:14])=[O:13])=[C:19]([C:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=[CH:26][N:25]=2)[CH:18]=1
Reactant: O=S(=O)(Cl)c1ccc(-c2cnco2)cc1
Reactant: Nc1ccc(Cl)cc1-c1nccc2ccccc12
Product: O=S(=O)(Nc1ccc(Cl)cc1-c1nccc2ccccc12)c1ccc(-c2cnco2)cc1

Procedure:
The title compound was prepared according to the general procedure using 4-oxazol-5-yl-benzenesulfonyl chloride and 4-chloro-2-isoquinolin-1-yl-phenylamine and purified by preparative HPLC. MS: (M+H)/z=462.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15](=[NH:17])[NH2:16])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.Cl([O-])(=O)(=O)=O.[CH3:23][NH2+:24][CH3:25].C[O-].[Na+]>C(O)CC.CO>[CH3:23][N:24]([CH:10]=[N:9][C:6]1[CH:5]=[N:17][C:15]([N:12]2[CH2:11][CH2:10][N:9]([C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)[CH2:14][CH2:13]2)=[N:16][CH:7]=1)[CH3:25]
Reactant: COc1ccc(N2CCN(C(=N)N)CC2)cc1
Reactant: C[NH2+]C
Agent: C[O-]
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CO
Solvent: CCCO
Product: COc1ccc(N2CCN(c3ncc(N=CN(C)C)cn3)CC2)cc1
Reaction time: 2 h
Yield: 62.5 %

Procedure:
To a mixture of 20 g of 4-(4-methoxyphenyl)-1-piperazinecarboximidamide and 21 g of N-[3-(dimethylamino)methylene]amino]-2-propenylidene]-N-methylmethanaminium perchlorate in 200 ml of 1-propanol were added dropwise 70 ml of a solution of sodium methoxide in methanol (1M). After stirring for 2 hours there were added dropwise again 70 ml of a solution of sodium methoxide in methanol (1M). Then the mixture was stirred and refluxed for 2 hours. After cooling, the reaction mixture was evaporated and the residue was purified by column chromatography (eluent: CH2Cl2 /CH3OH 97:3). The eluent of the desired fraction was evaporated, yielding 15 g (62.5%) of N-[(dimethylamino)methylene]-2-[4-(4-methoxyphenyl)-1-piperazinyl]-5-pyrimidinamine (interm. 24);
Reaction SMILES: [C:1]([Si:5]([O:8][CH2:9][CH2:10][C:11]1[S:12][C:13]([Cl:16])=[CH:14][CH:15]=1)([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.CC1(C)CCCC(C)(C)N1.Cl.C1C[O:36][CH2:35]C1>CN(C=O)C>[Si:5]([O:8][CH2:9][CH2:10][C:11]1[S:12][C:13]([Cl:16])=[C:14]([CH:35]=[O:36])[CH:15]=1)([C:1]([CH3:4])([CH3:2])[CH3:3])([CH3:6])[CH3:7]
Reactant: CC(C)(C)[Si](C)(C)OCCc1ccc(Cl)s1
Reactant: C1CCOC1
Agent: CC1(C)CCCC(C)(C)N1
Agent: Cl
Agent: [Li]CCCC
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCc1cc(C=O)c(Cl)s1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
tert-butyl(2-(5-chlorothiophen-2-yl)ethoxy)dimethylsilane (0.8 g) (example 278, step a) was added dropwise over 5 min to a stirred solution of butyl lithium (2.5M in hexanes 1.7 mL) and 2,2,6,6-tetramethylpiperidine (0.73 mL) in THF (25 mL) at −78° C. The resulting mixture was stirred for 2 hrs and DMF (0.67 mL) was added. The mixture was stirred for a further 1 hr and allowed to warm to RT. The reaction was cautiously poured into HCl solution (0.5M, 200 mL) and extracted with ethyl acetate (3×100 mL). The combined organic solutions were washed with water (2×100 mL), brine (100 mL), dried over sodium sulphate, filtered and evaporated in vacuo. The resulting oil was purified by silica gel chromatography eluting with iso-hexane to 5% ether in iso-hexane gradient. The fractions containing product were combined and evaporated in vacuo to give the subtitle compound as a clear oil. Yield (0.8 g)
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:26]=[CH:25][C:8]([CH2:9][NH:10][C:11]([C:13]2[C:18](=[O:19])[C:17](Br)=[C:16]([CH3:21])[N:15]([CH:22]([CH3:24])[CH3:23])[CH:14]=2)=[O:12])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[F:27][C:28]([F:39])([F:38])[C:29]1[CH:34]=[C:33](B(O)O)[CH:32]=[CH:31][N:30]=1.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[CH3:1][S:2]([C:5]1[CH:26]=[CH:25][C:8]([CH2:9][NH:10][C:11]([C:13]2[C:18](=[O:19])[C:17]([C:33]3[CH:32]=[CH:31][N:30]=[C:29]([C:28]([F:39])([F:38])[F:27])[CH:34]=3)=[C:16]([CH3:21])[N:15]([CH:22]([CH3:24])[CH3:23])[CH:14]=2)=[O:12])=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: OB(O)c1ccnc(C(F)(F)F)c1
Reactant: Cc1c(Br)c(=O)c(C(=O)NCc2ccc(S(C)(=O)=O)cc2)cn1C(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1c(-c2ccnc(C(F)(F)F)c2)c(=O)c(C(=O)NCc2ccc(S(C)(=O)=O)cc2)cn1C(C)C
Temperature: 75 °C
Reaction time: 18 h

Procedure:
To a solution of 5-bromo-1-isopropyl-6-methyl-4-oxo-1,4-dihydro-pyridine-3-carboxylic acid 4-methanesulfonyl-benzylamide (preparation 5, 24 mg, 0.054 mmol), 2-(trifluoromethyl)pyridine-4-boronic acid (13 mg, 0.068 mmol), 1,1′-[bis(diphenylphosphino)ferrocene]dichloropalladium(II) (5 mg, 0.007 mmol) in acetonitrile (0.15 mL) is added 2 M aqueous K2CO3 solution (0.055 mL, 0.11 mmol). After stirring for 18 h at 75° C., the reaction mixture is filtered and purified by preparative reversed-phase HPLC (XBridge, gradient of methanol in water, 0.3% NH4OH, 60° C.). Yield: 4 mg (15% of theory); ESI mass spectrum: [M+H]+=508; Retention time HPLC: 0.88 min (Z003_001).
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[C:2]1=[C:11]1[C:15]([CH3:17])([CH3:16])[O:14][C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([O:24]C)[CH:19]=3)=[N:12]1)[CH2:8]2.B(I)(I)I.O>C(Cl)Cl>[CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[C:2]1=[C:11]1[C:15]([CH3:17])([CH3:16])[O:14][C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([OH:24])[CH:19]=3)=[N:12]1)[CH2:8]2
Reactant: COc1cccc(C2=NC(=C3C4CC5CC(C4)CC3C5)C(C)(C)O2)c1
Agent: IB(I)I
Solvent: ClCCl
Solvent: O
Product: CC1(C)OC(c2cccc(O)c2)=NC1=C1C2CC3CC(C2)CC1C3
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 7 mmol 4-adamantylidene-2-(3'-methoxyphenyl)-5,5-dimethyl-oxazoline in 20 ml absolute methylene chloride is added dropwise to a solution of 14 mmol boron triiodide while stirring at -25° C. with the exclusion of air and water. The mixture is heated to room temperature within one hour and stirred for a further 4 h. After admixing with 50 ml water the organic phase is separated and dried over sodium sulfate. The solvent is removed by distillation. The oily residue is separated by column chromatography (silica gel: ethyl acetate/petroleum ether 1:3).
Reaction SMILES: C([C:8]1[CH:33]=[CH:32][C:11]([C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:27])([F:26])[C:22]([F:25])([F:24])[F:23])=[C:17]([O:28][CH2:29][CH2:30][NH2:31])[CH:16]=2)=[O:13])=[C:10]([Cl:34])[N:9]=1)(OC(C)(C)C)=O.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:31][CH2:30][CH2:29][O:28][C:17]1[CH:16]=[C:15]([NH:14][C:12](=[O:13])[C:11]2[CH:32]=[CH:33][CH:8]=[N:9][C:10]=2[Cl:34])[CH:20]=[CH:19][C:18]=1[C:21]([F:26])([F:27])[C:22]([F:25])([F:24])[F:23]
Reactant: CC(C)(C)OC(=O)c1ccc(C(=O)Nc2ccc(C(F)(F)C(F)(F)F)c(OCCN)c2)c(Cl)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCCOc1cc(NC(=O)c2cccnc2Cl)ccc1C(F)(F)C(F)(F)F
Reaction time: 2 h

Procedure:
To a solution of 500 mg (0.98 mmol) Boc-N-[3-(2-Amino-ethoxy)-4-pentafluoroethyl-phenyl]-2-chloro-nicotinamide in 10 ml CH2Cl2 was added 10 ml TFA and stirred for 2 h. The reaction was concentrated down, treated with 6N aqueous NaOH, and extracted 3 times with CH2Cl2. The combined organic extracts were dried over Na2SO4, filtered, concentrated down, and dried under vacuum, yielding the titled compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20](O)=[O:21])=[CH:16][CH:15]=1.[F:23][C:24]([F:34])([F:33])[C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH2:28][NH2:29]>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]([NH:29][CH2:28][C:27]2[CH:30]=[CH:31][CH:32]=[C:25]([C:24]([F:23])([F:33])[F:34])[CH:26]=2)=[O:21])=[CH:16][CH:15]=1
Reactant: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)O)cc3)c2)o1
Reactant: NCc1cccc(C(F)(F)F)c1
Product: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)NCc4cccc(C(F)(F)F)c4)cc3)c2)o1

Procedure:
2′-Methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-N-(3-trifluoromethylbenzyl)-1,1′-biphenyl-4-carboxamide was prepared from 2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxylic acid and 3-trifluoromethylbenzylamine using method N. NMR; δH [2H6]—DMSO 9.24,(1H, t), 8.00,(2H, d), 7.90,(1H, dd), 7.77,(1H, d), 7.69-7.52,(7H, m), 4.59,(2H, d), 2.56,(3H, s), 2.31,(3H, s). LCMS; retention time 3.59 min, MH+ 452.
Reaction SMILES: [F:1]/[C:2](/[C@H:9]1[CH2:14][CH2:13][C@H:12]([CH2:15][CH2:16][CH3:17])[CH2:11][CH2:10]1)=[C:3](/[F:8])\[Si](C)(C)C.[F-].[K+].O>C(#N)C>[F:1]/[C:2](/[C@H:9]1[CH2:14][CH2:13][C@H:12]([CH2:15][CH2:16][CH3:17])[CH2:11][CH2:10]1)=[CH:3]/[F:8]
Reactant: CCC[C@H]1CC[C@H](/C(F)=C(\F)[Si](C)(C)C)CC1
Agent: [F-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CCC[C@H]1CC[C@H](/C(F)=C\F)CC1

Procedure:
Then, 18.2 g (0.07 mol) of the obtained (Z)-1,2-difluoro-1-(trans-4-n-propylcyclohexyl)-2-trimethylsilylethylene was dissolved in 50 ml of acetonitrile, and then 8.12 g (0.14 mol) of potassium fluoride and 3.78 g (0.21 mol) of water were added thereto. The mixture was reacted for one hour at 50° C. The reaction mixture was cooled, and then 200 ml of water was added thereto. The mixture was extracted with methylene chloride. The organic layer was washed with a saturated sodium chloride aqueous solution and dried over CaCl2. After filtration, the solvent and low boiling substances were distilled off, and the residue was further distilled under reduced pressure to obtain 10.5 g (yield: 80%) of (E)-1,2-difluoro-1-(trans-4-n-propylcyclohexyl)ethylene.
Reaction SMILES: [BH4-].[Na+].B(F)(F)F.CCOCC.[O:12]=[C:13]1[N:17]([CH2:18][C@@H:19]2[CH2:23][C@@H:22]([OH:24])[CH2:21][N:20]2[C:25]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][C:32]([N+:35]([O-:37])=[O:36])=[CH:31][CH:30]=2)=[O:26])[C:16](=O)[CH2:15][NH:14]1>O1CCCC1>[OH:24][C@H:22]1[CH2:21][N:20]([C:25]([O:27][CH2:28][C:29]2[CH:30]=[CH:31][C:32]([N+:35]([O-:37])=[O:36])=[CH:33][CH:34]=2)=[O:26])[C@H:19]([CH2:18][N:17]2[CH:16]=[CH:15][NH:14][C:13]2=[O:12])[CH2:23]1
Reactant: O=C1CNC(=O)N1C[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: FB(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C(OCc1ccc([N+](=O)[O-])cc1)N1C[C@H](O)C[C@H]1Cn1cc[nH]c1=O
Reaction time: 12 h
Yield: 4.2 %

Procedure:
To a suspension of sodium borohydride (6.03 g) in tetrahydrofuran (270 ml) was added boron trifluoride etherate (72 ml) at 0° C. under stirring. After stirring for 10 minutes, to the suspension was added a solution of (2S,4R)-2-(2,4-dioxoimidazolidin-3-yl)methyl-4-hydroxy-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (27.3 g) obtained in Preparation 10 in tetrahydrofuran (140 ml) and the mixture was stirred for 14 hours at ambient temperature This reaction mixture was evaporated in vacuo and to the residue was added a solution of conc. hydrochloric acid (31 ml) in methanol (400 ml). After standing for 12 hours at ambient temperature, the solution was evaporated in vacuo and the resulting residue was poured into saturated aqueous sodium hydrogen carbonate (450 ml). The aqueous layer was extracted three times with a mixture of ethyl acetate (200 ml) and tetrahydrofuran (200 ml) and evaporated in vacuo. The resulting residue was chromatographed on silica gel (600 ml) eluting with a mixture of methanol and dichloromethane (5:95, V/V) to give (2 S,4R)-4-hydroxy-1-(4-nitrobenzyloxycarbonyl)-2-(2-oxo-4-imidazolin-1-yl)methylpyrrolidine (1.11 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][CH2:8][CH:9]([S:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:10](OC)[O:11]C)([CH3:4])([CH3:3])[CH3:2].C(O)(=O)C>O1CCCC1.O>[C:1]([O:5][C:6](=[O:23])[NH:7][CH2:8][CH:9]([S:15][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[CH:10]=[O:11])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(OC)C(CNC(=O)OC(C)(C)C)SCc1ccccc1
Solvent: O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCC(C=O)SCc1ccccc1
Temperature: 50 °C
Reaction time: 8 h
Yield: 65.8 %

Procedure:
tert-Butyl[2-(benzylthio)-3,3-dimethoxypropyl]carbamate (9.4 g) was dissolved in tetrahydrofuran (50 mL) and water (50 mL), and acetic acid (100 mL) was added. The reaction mixture was stirred overnight at 50° C., and concentrated, and the residue was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with saturated brine, dried over sodium sulfate, and filtrated, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel chromatography to give the title compound (5.35 g, yield 66%) as a pale-yellow oil from a fraction eluted with ethyl acetate-hexane (1:19).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:12]=[CH:11][N:10]([Si](C(C)C)(C(C)C)C(C)C)[CH:9]=2)[CH:5]=[CH:4][C:3]=1[N:23]1[S:27](=[O:29])(=[O:28])[NH:26][C:25](=[O:30])[CH2:24]1.C1C=CN=CC=1.F.[Si](OC)(C)(C)C>CC#N>[OH:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:12]=[CH:11][NH:10][CH:9]=2)[CH:5]=[CH:4][C:3]=1[N:23]1[S:27](=[O:29])(=[O:28])[NH:26][C:25](=[O:30])[CH2:24]1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc(-c2ccc(N3CC(=O)NS3(=O)=O)c(O)c2)c1
Agent: CO[Si](C)(C)C
Agent: F
Solvent: CC#N
Solvent: c1ccncc1
Product: O=C1CN(c2ccc(-c3cc[nH]c3)cc2O)S(=O)(=O)N1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 5-[2-hydroxy-4-(1-triisopropylsilanyl-1H-pyrrol-3-yl)-phenyl]-1,1-dioxo-1,2,5-thiadiazolidin-3-one in MeCN (10 mL) is added HF-Pyridine (0.2 mL, 2.23 mmol) and the reaction mixture is stirred at RT for 2 h. TMSOMe (5 mL) is added to consume unreacted HF, and the crude reaction mixture is concentrated in vacuo. The residue is purified by reverse phase MPLC using 1-40% MeCN/H2O as eluent to give the title compound: (M−1)−=292.
Reaction SMILES: C(#N)C.O([C:11]([NH:13][C:14]1[CH:15]=[C:16]([C:20]2[N:21]([CH3:26])[N:22]=[N:23][C:24]=2[SH:25])[CH:17]=[CH:18][CH:19]=1)=[O:12])C1C=CC=CC=1.C(O)(=O)C(O)=O.[NH2:33][CH2:34][CH2:35][CH2:36][P:37](=[O:44])([O:41][CH2:42][CH3:43])[O:38][CH2:39][CH3:40]>C(N(CC)CC)C>[CH2:42]([O:41][P:37]([CH2:36][CH2:35][CH2:34][NH:33][C:11](=[O:12])[NH:13][C:14]1[CH:15]=[C:16]([C:20]2[N:21]([CH3:26])[N:22]=[N:23][C:24]=2[SH:25])[CH:17]=[CH:18][CH:19]=1)([O:38][CH2:39][CH3:40])=[O:44])[CH3:43]
Reactant: CCOP(=O)(CCCN)OCC
Reactant: Cn1nnc(S)c1-c1cccc(NC(=O)Oc2ccccc2)c1
Agent: O=C(O)C(=O)O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOP(=O)(CCCNC(=O)Nc1cccc(-c2c(S)nnn2C)c1)OCC
Yield: 94 %

Procedure:
40 ml of acetonitrile was added to 5.0 g of 4-(3-phenoxycarbonylaminophenyl)-3-methyl-5-mercaptotriazole (6) prepared in Step 1-5. 8.2 g of triethylamine was added to the system. 4.1 g of oxalic acid salt of diethyl 3-aminopropylphosphonate (8) prepared in Step 1-7 was added to the system. The system was then allowed to undergo reaction at a temperature of 50° C. over 4 hours. After the completion of the reaction, the solvent was distilled off under reduced pressure. 100 ml of water was added to the residue to deposit 62 g of a crystal of 4-[3-{3-(3-diethylphosphonopropyl)ureido}phenyl]-3-methyl-5-mercaptotriazole (9). (Yield: 94%; m.p. 128° C.)
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[CH:13]=[C:12]([NH:14][CH2:15][CH:16]([CH3:18])[CH3:17])[C:11]([Cl:19])=[CH:10][C:9]=1[NH2:20])([CH3:4])([CH3:3])[CH3:2].C([O:26][C:27](=O)[CH2:28][C:29]([C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]2[O:41][N:40]=[C:39]([CH3:42])[CH:38]=2)[CH:32]=1)=[O:30])(C)(C)C>>[C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[CH:13]=[C:12]([NH:14][CH2:15][CH:16]([CH3:17])[CH3:18])[C:11]([Cl:19])=[CH:10][C:9]=1[NH:20][C:27](=[O:26])[CH2:28][C:29]([C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]2[O:41][N:40]=[C:39]([CH3:42])[CH:38]=2)[CH:32]=1)=[O:30])([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)CNc1cc(NC(=O)OC(C)(C)C)c(N)cc1Cl
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)on1
Product: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(Cl)c(NCC(C)C)cc3NC(=O)OC(C)(C)C)c2)on1

Procedure:
The title compound was prepared from (2-amino-4-chloro-5-isobutylamino-phenyl)-carbamic acid tert-butyl ester (Example J34) (314 mg, 1.0 mmol) and 3-[3-(3-methyl-isoxazol-5-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K4) (301 mg, 1.0 mmol) according to the general procedure M. Obtained as an off-white foam (340 mg, 63%).
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH:5]1[CH2:8][CH:7]([C:9]2[N:13]3[CH:14]=[CH:15][N:16]=[C:17]([NH2:18])[C:12]3=[C:11]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH:20]=3)[N:10]=2)[CH2:6]1)[CH3:3].N1CC[CH2:34]1>>[N:2]1([CH2:4][C@@H:5]2[CH2:6][C@H:7]([C:9]3[N:13]4[CH:14]=[CH:15][N:16]=[C:17]([NH2:18])[C:12]4=[C:11]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH2:26][C:27]5[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=5)[CH:20]=4)[N:10]=3)[CH2:8]2)[CH2:1][CH2:34][CH2:3]1
Reactant: CN(C)CC1CC(c2nc(-c3cccc(OCc4ccccc4)c3)c3c(N)nccn23)C1
Reactant: C1CNC1
Product: Nc1nccn2c1c(-c1cccc(OCc3ccccc3)c1)nc2[C@H]1C[C@@H](CN2CCC2)C1

Procedure:
Procedures for 3-(3-Dimethylaminomethyl-cyclobutyl)-1-(3-benzyloxyphenyl)-imidazo[1,5-a]pyrazin-8-ylamine were followed, replacing dimethylamine with azetidine, LC-MS (ES, Pos.): m/z 440 [MH+].
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[F:6][C:7]1[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[C:8]=1[NH2:9].[C:15]([O:19][C:20]([NH:22][C@@H:23]([CH:38]([CH3:40])[CH3:39])[C:24]([N:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28][C@H:27]1[C:35](O)=[O:36])=[O:25])=[O:21])([CH3:18])([CH3:17])[CH3:16]>N1C=CC=CC=1>[F:6][C:7]1[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[C:8]=1[NH:9][C:35]([C@@H:27]1[CH2:28][C:29]2[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:26]1[C:24](=[O:25])[C@@H:23]([NH:22][C:20](=[O:21])[O:19][C:15]([CH3:18])([CH3:17])[CH3:16])[CH:38]([CH3:40])[CH3:39])=[O:36]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1c2ccccc2C[C@H]1C(=O)O
Reactant: Nc1c(F)cccc1F
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1c2ccccc2C[C@H]1C(=O)Nc1c(F)cccc1F
Temperature: 25 °C
Yield: 89.2 %

Procedure:
Phosphorus oxychloride (164 mg, 0.1 mL, 1.07 mmol, Eq: 2.16) was added dropwise to a cooled (ice-bath) solution of 2,6-difluoroaniline (264 mg, 0.22 mL, 2.04 mmol, Eq: 4.12) and (S)-1-((S)-2-(tert-butoxycarbonylamino)-3-methylbutanoyl)indoline-2-carboxylic acid (0.18 g, 497 μmol, Eq: 1.00) in pyridine (4 mL). The cooling bath was removed and the reaction was stirred at rt. After 1 h the reaction mixture was diluted with toluene (10 mL) and concentrated in vacuo. The residue was treated with water (10 mL) and extracted with EtOAc (2×10 mL). The combined organic layers were washed with 0.1 M aqueous HCl (10 mL) and brine (10 mL) and then concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 12 g, 0% to 30% EtOAc in hexanes) to give tert-butyl (S)-1-((S)-2-(2,6-difluorophenylcarbamoyl)indolin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate (0.21 g), m/z=474 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:14]([OH:16])=O)[C:10]([CH3:13])([CH3:12])[CH3:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:17][C@H:18]([CH2:23][OH:24])[CH2:19][CH:20]([CH3:22])[CH3:21].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CN1CCOCC1>C(#N)C>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:14]([NH:17][C@H:18]([CH2:23][OH:24])[CH2:19][CH:20]([CH3:22])[CH3:21])=[O:16])[C:10]([CH3:11])([CH3:12])[CH3:13])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)O)C(C)(C)C
Reactant: CC(C)C[C@H](N)CO
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CC#N
Solvent: CN1CCOCC1
Product: CC(C)C[C@@H](CO)NC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)C
Temperature: 25 °C
Reaction time: 19 h
Yield: 80.4 %

Procedure:
To a suspension of N-tert-butyloxycarbonyl-L-tert-butylglycine 8 (2.43 g, 10.5 mmol), L-leucinol 9 (1.23 g, 10.5 mmol) and TBTU (3.44 g, 11.5 mmol) in acetonitrile (30 mL) at 0° (ice bath) was added N-methyl morpholine (1.3 mL, 11.5 mmol). The resulting mixture was stirred 19 h (allowing the ice bath to warm to room temperature) and the white solid was collected on a filter (486 mg, 14% yield). The mother liquors were purified by flash chromatography (SiO2, 25-35% EtOAc-hexane) affording N-tert-butyloxycarbonyl-L-tert-butylglycyl-L-leucinol 10 (2.79 g, 80% yield) as a white solid (including the filtered solid).
Reaction SMILES: C([Li])CCC.Br[C:7]1[N:8]=[C:9]([N:17]2[CH2:23][CH2:22][CH2:21][N:20]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:19][CH2:18]2)[C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2.[F:31][C:32]1[N:43]=[CH:42][CH:41]=[CH:40][C:33]=1[C:34](N(OC)C)=[O:35]>O1CCCC1>[F:31][C:32]1[N:43]=[CH:42][CH:41]=[CH:40][C:33]=1[C:34]([C:7]1[N:8]=[C:9]([N:17]2[CH2:23][CH2:22][CH2:21][N:20]([C:24]([O:26][C:27]([CH3:29])([CH3:28])[CH3:30])=[O:25])[CH2:19][CH2:18]2)[C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:35]
Reactant: CON(C)C(=O)c1cccnc1F
Reactant: CC(C)(C)OC(=O)N1CCCN(c2nc(Br)cc3ccccc23)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCN(c2nc(C(=O)c3cccnc3F)cc3ccccc23)CC1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 45.6 %

Procedure:
A 2.5M n-butyl lithium in tetrahydrofuran solution (0.16 ml, 0.40 mmol) was added dropwise to a solution of tert-butyl 4-(3-bromoisoquinolin-1-yl)-1,4-diazepane-1-carboxylate (155 mg, 0.38 mmol) in tetrahydrofuran (8 ml), cooled to −78° C. The reaction mixture was stirred at that temperature for 10 minutes. A solution of 2-fluoro-N-methoxy-N-methylnicotinamide (70 mg, 0.38 mmol) in tetrahydrofuran (3 ml) was added dropwise. The reaction mixture was allowed to warm up to room temperature and was stirred for 2 hours. The reaction was quenched with a saturated aqueous solution of ammonium chloride and extracted into ethyl acetate. The organic phase was dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified on silica gel by flash column chromatography to afford the title compound as a yellow solid (78 mg, 46% yield).