Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([N:10]=[C:11]=[O:12])[CH3:9].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]2[CH:25]=[C:24]([CH3:26])[NH:23][N:22]=2)=[CH:16][C:15]=1[C:27]([F:30])([F:29])[F:28].Cl>C(OCC)(=O)C>[CH2:8]([NH:10][C:11]([N:23]1[C:24]([CH3:26])=[CH:25][C:21]([O:20][C:17]2[CH:18]=[CH:19][C:14]([Cl:13])=[C:15]([C:27]([F:30])([F:28])[F:29])[CH:16]=2)=[N:22]1)=[O:12])[CH3:9]
Reactant: Cc1cc(Oc2ccc(Cl)c(C(F)(F)F)c2)n[nH]1
Reactant: CCN=C=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCNC(=O)n1nc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1C
Reaction time: 5 h
Yield: 80.5 %

Procedure:
Triethylamine (0.17 g, 1.7 mmol) and ethyl isocyanate (0.12 g, 1.7 mmol) were added to a solution of 3-(4-chloro-3-trifluoromethylphenyloxy)-5-methylpyrazole (0.42 g, 1.5 mmol) in ethyl acetate (5 ml) at 0° C., and the mixture was allowed to have room temperature gradually and stirred for 5 hours. After completion of the reaction, the reaction mixture was poured into 1N hydrochloric acid (10 ml) and extracted with ethyl acetate (10 ml×2). An organic layer was washed with water (10 ml×2), dried over anhydrous magnesium sulfate and filtered to remove a desiccant, and the solvent was distilled off from the filtrate under reduced pressure. The resultant crude product was purified with a silica gel column (ethyl acetate/hexane=1/15), to give a yellow viscous substance of N-ethyl-3-(4-chloro-3-trifluoromethylphenyloxy)-5-methylpyrazole-1-carboxamide (0.42 g, yield: 80.1%). 1H-NMR (CDCl3, TMS, ppm): δ 1.22 (t, J=7.2 Hz, 3H), 2.59 (d, J=0.8 Hz, 3H), 3.38 (dq, J=5.9 and 7.2 Hz, 2H), 5.73 (q, J=0.8 Hz, 1H), 6.91 (br s, 1H), 7.22 (d, J=8.8 Hz, 1H), 7.49 (dd, J=2.4 and 8.8 Hz, 1H), 7.65 (d, J=2.4 Hz, 1H).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[C:8]([OH:15])[CH:9]=[CH:10][CH:11]=2)[N:6]=1)(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.Cl[CH2:28][C:29](=[O:31])[CH3:30]>C1COCC1>[C:1]([O:4][C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[C:8]([O:15][CH2:28][C:29](=[O:31])[CH3:30])[CH:9]=[CH:10][CH:11]=2)[N:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccc2cccc(O)c2n1
Reactant: CC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(=O)COc1cccc2ccc(OC(C)=O)nc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.6 %

Procedure:
A mixture of 5b (1.02 g, 5 mmol), potassium carbonate (0.69 g, 5 mmol) and dry N,N-dimethylformamide (DMF) (40 ml) was stirred at room temperature for 30 min and then chloroacetone (0.46 g, 5 mmol) in dry THF (10 ml) was added in one portion. The resulting mixture was continued to stir at room temperature for 24 h (monitored by TLC). After this period, it was poured into ice water (100 ml) and the pale yellow solid thus obtained was crystallized from dichloromethane and ether to afford 2-Acetoxy-8-(2-oxopropoxy)quinoline (5c) (0.85 g, 66%). mp: 79°-80° C.; 1H-NMR (CDCl3): δ2.16 (s, 3H, OAc), 2.42 (s, 3H, 3'-CH3), 4.85 (s, 2H, OCH2), 7.06 (d, 3-H), 7.26-7.67 (m, 3H, Ar--H), 8.08 (d, 4-H).
Reaction SMILES: [CH3:1][S:2]([C:4]1[S:8][C:7]([N:9]=[C:10]=[O:11])=[N:6][N:5]=1)=[O:3].[CH2:12]([NH:15][CH2:16][CH2:17][CH:18]=[O:19])[C:13]#[CH:14]>C1C=CC=CC=1>[CH2:12]([N:15]([CH2:16][CH2:17][CH:18]=[O:19])[C:10]([NH:9][C:7]1[S:8][C:4]([S:2]([CH3:1])=[O:3])=[N:5][N:6]=1)=[O:11])[C:13]#[CH:14]
Reactant: CS(=O)c1nnc(N=C=O)s1
Reactant: C#CCNCCC=O
Solvent: c1ccccc1
Product: C#CCN(CCC=O)C(=O)Nc1nnc(S(C)=O)s1

Procedure:
A mixture of 5 -methylsulfinyl-1,3,4-thiadiazol-2-yl isocyanate dimer (0.05 mole), the dimethyl acetal of 3-propargylaminopropionaldehyde (0.1 mole) and benzene (60 ml) are charged into a glass rection vessel equipped with a mechanical stirrer and reflux condenser. The reaction mixture is heated at reflux for a period of about 15 minutes. After this time the mixture is stripped of benzene under reduced pressure to yield a solid product as the residue. The residue is then recrystallized to yield the desired product the dimethyl acetal of 3-[1-propargyl-3-(5-methylsulfinyl-1,3,4-thiadiazol-2-yl) ureido]propionaldehyde.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C@H:17]([O:24][C:25]3[CH:26]=[CH:27][C:28]4[N:29]([C:31]([N:34]5[C@H:39]([CH3:40])[CH2:38][CH2:37][CH2:36][C@@H:35]5[CH3:41])=[N:32][N:33]=4)[CH:30]=3)[CH2:16][CH2:15]2)=[O:12])[N:7]([C:42]2[CH:43]=[N:44][N:45]([CH2:47][CH2:48][OH:49])[CH:46]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[CH3:59][S:60](Cl)(=[O:62])=[O:61]>C(Cl)Cl>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C@H:17]([O:24][C:25]3[CH:26]=[CH:27][C:28]4[N:29]([C:31]([N:34]5[C@H:35]([CH3:41])[CH2:36][CH2:37][CH2:38][C@@H:39]5[CH3:40])=[N:32][N:33]=4)[CH:30]=3)[CH2:16][CH2:15]2)=[O:12])[N:7]([C:42]2[CH:43]=[N:44][N:45]([CH2:47][CH2:48][O:49][S:60]([CH3:59])(=[O:62])=[O:61])[CH:46]=2)[N:6]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: C[C@@H]1CCC[C@H](C)N1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4cnn(CCO)c4)c4ccccc43)cn12
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[C@@H]1CCC[C@H](C)N1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4cnn(CCOS(C)(=O)=O)c4)c4ccccc43)cn12
Reaction time: 1 h

Procedure:
To an ice-bath cooled solution of Intermediate 124b (174 mg, 0.26 mmol) in DCM (3 mL) was added DIPEA (182 μL, 1.0 mmol) followed by methanesulfonyl chloride (41 μL, 0.52 mmol). The reaction mixture was stirred for 1 h and then quenched with water. The aqueous phase was extracted with DCM (×3) and the combined organic layers were washed with brine, dried (MgSO4) and concentrated in vacuo to afford the title compound (Quantitative). Product used in the following step without further purification. LCMS (Method 4): Rt 3.47 min, m/z 746 [MH+].
Reaction SMILES: [Cl:1][C:2]1[C:14]([CH:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[OH:16])=[C:13]([Cl:23])[CH:12]=[CH:11][C:3]=1[C:4]([O:6]C(C)(C)C)=[O:5].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.O>[Cl:1][C:2]1[C:14]([CH:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[OH:16])=[C:13]([Cl:23])[CH:12]=[CH:11][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: CC(C)(C)OC(=O)c1ccc(Cl)c(C(O)c2ccccn2)c1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(O)c1ccc(Cl)c(C(O)c2ccccn2)c1Cl

Procedure:
3.5 g (9.9 mmol) of tert-butyl 2,4-dichloro-3-((2-pyridyl)(hydroxymethyl))benzoate in 120 ml of toluene and 60 ml of water together with 1.9 g of p-toluenesulfonic acid are heated under reflux for 9 h. After cooling, the organic phase is separated off and the aqueous phase is admixed with a solution of 23.8 g of sodium dihydrogen phosphate in 280 ml of water and extracted with ethyl acetate. The combined organic phases are dried over sodium sulfate, filtered and freed from the solvent under reduced pressure. Yield: 1.9 g; 1H NMR, δ [ppm], (DMSO-d6): 6.5 (m), 7.2 (m), 7.5 (d), 7.6 (d), 7.95 (m), 8.4 (d), 13.5 (broad s)
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[N:7]([C:9]1[CH:14]=[CH:13][C:12](I)=[CH:11][CH:10]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[CH2:17]([OH:22])[CH2:18][CH2:19][C:20]#[CH:21]>N1CCCCC1.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>[C:1]([O:5][C:6](=[O:16])[N:7]([C:9]1[CH:14]=[CH:13][C:12]([C:21]#[C:20][CH2:19][CH2:18][CH2:17][OH:22])=[CH:11][CH:10]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C(=O)OC(C)(C)C)c1ccc(I)cc1
Reactant: C#CCCCO
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCNCC1
Product: CN(C(=O)OC(C)(C)C)c1ccc(C#CCCCO)cc1
Temperature: 45 °C
Reaction time: 0.17 h
Yield: 115.8 %

Procedure:
The synthesis was performed following a procedure of Stara, Irena G.; Stary, Ivo; Kollarovic, Adrian; Teply, Filip; Saman, David; Fiedler, Pavel. Coupling reactions of halobenzenes with alkynes. The synthesis of phenylacetylenes and symmetrical or unsymmetrical 1,2-diphenylacetylenes. Collect. Czech. Chem. Commun. (1999), 64(4), 649-672. A solution of 4.45 g (12.5 mmol) of (4-Iodo-phenyl)-methyl-carbamic acid tert-butyl ester in 25 ml piperidine was degassed (argon) and treated with 722 mg (0.625 mmol) Pd(PPh3)4 and 119 mg (0.625 mmol) Cul. The reaction mixture was stirred at 45° C. for 10 min and then slowly (45 min) heated to 80° C. while adding 0.9 ml (9.4 mmol) of 4-pentin-1-ol. At 80° C. a second portion of 0.9 ml (9.4 mmol) 4-pentin-1-ol was added during 45 min. The reaction mixture was stirred at this temperature for 2 h and then extracted with chilled water acidified with KHSO4/Et2O (3×). The organic phases were washed with aqueous 10% NaCl, dried (Na2SO4) and evaporated. Purification by flash-chromatography on silica gel (CH2Cl2/EtOAc 95:5) yielded 3.15 g (87%) of [4-(5-Hydroxy-pent-1-ynyl)-phenyl]-methyl-carbamic acid tert-butyl ester, mp: 103-105° C.; MS: 289 (M).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]([NH2:15])([CH:12]([F:14])[F:13])[CH2:5][CH2:6][CH2:7][NH:8][C:9](=[O:11])[CH3:10].[C:17](Cl)(=[O:20])[CH2:18][CH3:19].C(N(CC)CC)C>CCOCC>[CH3:1][O:2][C:3](=[O:16])[C:4]([CH:12]([F:14])[F:13])([NH:15][C:17](=[O:20])[CH2:18][CH3:19])[CH2:5][CH2:6][CH2:7][NH:8][C:9](=[O:11])[CH3:10]
Reactant: CCC(=O)Cl
Reactant: COC(=O)C(N)(CCCNC(C)=O)C(F)F
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CCC(=O)NC(CCCNC(C)=O)(C(=O)OC)C(F)F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 0.47 g of 5-acetylamino-2-amino-2-difluoromethylpentanoic acid methylester in 10 ml of ether is added simultaneously at 0° C. 0.18 g of propionylchloride and 0.2 g of triethylamine. The reaction mixture is stirred at room temperature for 2 hours then extracted with ethylacetate. The organic phase is washed with a solution of sodium bicarbonate, water, then brine and dried over magnesium sulfate. Evaporation of the solvent gives 5-acetylamino-2-difluoromethyl-2-propionylaminopentanoic acid methylester.
Reaction SMILES: [CH3:1][C:2]1([CH3:33])[CH:7]2[CH2:8][CH:3]1[CH2:4][CH2:5][CH:6]2[CH2:9][CH2:10][N:11]1[CH2:32][CH2:31][C:14]2([N:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:17][N:16]([CH2:25][CH2:26][CH2:27][NH:28][CH3:29])[C:15]2=[O:30])[CH2:13][CH2:12]1.[C:34]([O:38][C:39]([N:41]1[CH2:48][CH2:47][C:44]2([O:46][CH2:45]2)[CH2:43][CH2:42]1)=[O:40])([CH3:37])([CH3:36])[CH3:35]>C(O)C>[C:34]([O:38][C:39]([N:41]1[CH2:48][CH2:47][C:44]([CH2:45][N:28]([CH2:27][CH2:26][CH2:25][N:16]2[C:15](=[O:30])[C:14]3([CH2:13][CH2:12][N:11]([CH2:10][CH2:9][CH:6]4[CH2:5][CH2:4][CH:3]5[CH2:8][CH:7]4[C:2]5([CH3:1])[CH3:33])[CH2:32][CH2:31]3)[N:18]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:17]2)[CH3:29])([OH:46])[CH2:43][CH2:42]1)=[O:40])([CH3:37])([CH3:36])[CH3:35]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CO2
Reactant: CNCCCN1CN(c2ccccc2)C2(CCN(CCC3CCC4CC3C4(C)C)CC2)C1=O
Solvent: CCO
Product: CN(CCCN1CN(c2ccccc2)C2(CCN(CCC3CCC4CC3C4(C)C)CC2)C1=O)CC1(O)CCN(C(=O)OC(C)(C)C)CC1
Yield: 89.7 %

Procedure:
2.6 g (5.74 mmol) of compound (24) was placed in a flask and diluted with 20 ml ethanol. To this solution was added 1.88 g (8.81 mmol) of the epoxide (32) and the mixture was heated to reflux until TLC showed complete conversion. For work-up the solvent was evaporated and the residue was taken up with ethyl acetate. After washing with aqueous potassium carbonate solution drying over sodium sulphate and concentration in vacuo the raw material was purified via flash column chromatography yielding a light yellow viscous oil (3.51 g, 5.15 mmol, 89.8% yield).
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][CH2:5][N:4]([C:7]([N:9]2[C@@:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)([CH3:14])[C@@:12]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)([CH3:22])[N:11]=[C:10]2[C:30]2[CH:31]=[N:32][C:33]([C:39]([CH3:42])([CH3:41])[CH3:40])=[CH:34][C:35]=2[O:36][CH2:37][CH3:38])=[O:8])[CH2:3]1.[C:43](O)(=[O:47])[C:44]([NH2:46])=[O:45]>>[C:39]([C:33]1[N:32]=[CH:31][C:30]([C:10]2[N:9]([C:7]([N:4]3[CH2:5][CH2:6][CH:2]([NH:1][C:43](=[O:47])[C:44]([NH2:46])=[O:45])[CH2:3]3)=[O:8])[C@@:13]([C:15]3[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=3)([CH3:14])[C@@:12]([C:23]3[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=3)([CH3:22])[N:11]=2)=[C:35]([O:36][CH2:37][CH3:38])[CH:34]=1)([CH3:41])([CH3:40])[CH3:42]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(N)C1
Reactant: NC(=O)C(=O)O
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(NC(=O)C(N)=O)C1

Procedure:
In a manner analogous to the method described in examples 99, (3-amino-pyrrolidin-1-yl )-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazol-1-yl]-methanone was coupled with oxalamic acid (Aldrich) to give the title product. HR-MS (ES, m/z) calculated for C35H41Cl2N6O4 [(M+H)+] 679.2561, observed 679.2561.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](OS(C(F)(F)F)(=O)=O)=[CH:4][C:3]=1[CH:16]([CH3:35])[C:17]([OH:34])([C:22]1[CH:23]=[CH:24][C:25]2[O:30][CH2:29][C:28](=[O:31])[N:27]([CH3:32])[C:26]=2[CH:33]=1)[C:18]([F:21])([F:20])[F:19].[C:36]([C:39]1[CH:44]=[CH:43][C:42](B(O)O)=[CH:41][CH:40]=1)([OH:38])=[O:37].O.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:42]2[CH:43]=[CH:44][C:39]([C:36]([OH:38])=[O:37])=[CH:40][CH:41]=2)=[CH:4][C:3]=1[CH:16]([CH3:35])[C:17]([OH:34])([C:22]1[CH:23]=[CH:24][C:25]2[O:30][CH2:29][C:28](=[O:31])[N:27]([CH3:32])[C:26]=2[CH:33]=1)[C:18]([F:19])([F:20])[F:21]
Reactant: CC(c1cc(OS(=O)(=O)C(F)(F)F)ccc1Cl)C(O)(c1ccc2c(c1)N(C)C(=O)CO2)C(F)(F)F
Reactant: O=C(O)c1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(c1cc(-c2ccc(C(=O)O)cc2)ccc1Cl)C(O)(c1ccc2c(c1)N(C)C(=O)CO2)C(F)(F)F
Temperature: 80 °C
Reaction time: 5 h
Yield: 40 %

Procedure:
To a suspension of trifluoromethanesulfonic acid 4-chloro-3-[3,3,3-trifluoro-2-hydroxy-1-methyl-2-(4-methyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl)-propyl]-phenyl ester (100 mg), 4-carboxyphenylboronic acid (48 mg) and dichloro[1,1′-bis(diphenylphosphino)ferrocene]dichloromethane adduct (7.5 mg) in dioxan (0.54 ml) under argon were added water (0.4 ml) and a 2 M aqueous sodium carbonate solution (0.27 ml). The mixture was stirred at 80° C. for 7 h, at 50° C. for 2 days and again at 80° C. for 5 h. The mixture was filtered and to the filtrate was added an aqueous KHSO4 solution. The mixture was extracted with EtOAc. The organic phase was dried (MgSO4), filtered and concentrated. The product was purified by chromatography (SiO2, CH2Cl2/MeOH 1:0=>85:15) to give the title compound (38 mg) as a light brown solid. MS (m/e, ISP neg. ion)=518.2 [M−H+].
Reaction SMILES: [H-].[Na+].[NH2:3][CH:4]1[N:9]=[C:8]([Cl:10])[N:7]=[C:6](F)[N:5]1[O:12][CH:13]([F:15])[F:14].[CH2:16]([OH:18])[CH3:17]>>[NH2:3][CH:4]1[N:9]=[C:8]([Cl:10])[N:7]=[C:6]([O:18][CH2:16][CH3:17])[N:5]1[O:12][CH:13]([F:15])[F:14]
Reactant: CCO
Reactant: NC1N=C(Cl)N=C(F)N1OC(F)F
Agent: [H-]
Agent: [Na+]
Product: CCOC1=NC(Cl)=NC(N)N1OC(F)F
Reaction time: 0.25 h

Procedure:
1.2 g (0.0466 mol) of 97% sodium hydride were added a little at a time to 150 ml of ethanol at 20°-35° C. and dissolved by stirring for 15 minutes. Then, while stirring at 0° C., 10.0 g (0.046 mol) of 2-amino-4-chlorodifluoromethoxy-6-fluoro-1,3,5-triazine were added, and the mixture was stirred at 0° C. for 1 hour and at 22° C. overnight. The residue from concentration under reduced pressure was taken up in methylene chloride, extracted with water and dried. Concentration yielded 10.6 g (94.6% of theory) of the title compound of melting point 63°-65° C.
Reaction SMILES: [ClH:1].C(OC([N:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH2:21][NH:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH2:11][CH2:10]1)=O)(C)(C)C>CO>[ClH:1].[N:12]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH2:21][NH:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH2:13][CH2:14][NH:9][CH2:10][CH2:11]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccccc2CNS(C)(=O)=O)CC1
Agent: Cl
Solvent: CO
Product: CS(=O)(=O)NCc1ccccc1N1CCNCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 99 %

Procedure:
Methanolic hydrogen chloride (4M, 2.5 mL) was added to a stirred, cooled (0° C.) suspension of N-[2-(4-t-butoxycarbonylpiperazin-1-yl)phenylmethyl]methanesulfonamide (330 mg, 0.89 mmol) in methanol (1 mL) and the mixture was stirred at room temperature for 4 h. The solvent was evaporated under reduced pressure to give the title compound as an off-white solid (269 mg, 99%), δH (360 MHz, d6 -DMSO) 9.15 (2H, br s), 7.44 (1H, d, J 7.6 Hz), 7.42 (1H, br t, J 5.6 Hz), 7.31 (1H, t, J 7.6 Hz), 7.16 (2H, m), 4.22 (2H, d, J 5.6 Hz), 3.23 (4H, m), 3.06 (4H, m), and 2.92 (3H, s). m/e (ES+) 270 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C@H:4]([CH2:6][S:7][C:8]([CH3:11])([CH3:10])[CH3:9])[NH2:5].[C:13]([S:16][CH2:17][CH:18]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:19](O)=[O:20])(=[O:15])[CH3:14]>CO>[CH3:1][O:2][C:3](=[O:12])[C@H:4]([CH2:6][S:7][C:8]([CH3:9])([CH3:11])[CH3:10])[NH:5][C:19](=[O:20])[CH:18]([CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[CH2:17][S:16][C:13](=[O:15])[CH3:14]
Reactant: CC(=O)SCC(Cc1ccccc1)C(=O)O
Reactant: COC(=O)[C@@H](N)CSC(C)(C)C
Solvent: CO
Product: COC(=O)[C@H](CSC(C)(C)C)NC(=O)C(CSC(C)=O)Cc1ccccc1

Procedure:
React S-(t-butyl)-L-cysteine methyl ester (2.32 g) and 3-acetylthio-2-benzylpropionic acid (3.22 g) in the manner described in Example 1, Step 1 to give an orange solid. Chromatograph this solid on a column of silica gel (2 L, 60-200 mesh) and elute with ethyl acetate:hexane 3:17 to give Isomer A, a clear oil (1.09 g), [α]26 =-44.9° (MeOH); overlap Isomer A and Isomer B (0.52 g); and Isomer B, a clear oil (0.75 g), [α]D26 =+8.3° (MeOH).
Reaction SMILES: F[C:2]1[C:7]([CH:8]2[CH2:12][CH2:11][C:10]([CH3:14])([OH:13])[CH2:9]2)=[CH:6][CH:5]=[CH:4][N:3]=1.[NH:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N:17]=[C:16]1[C:24]([C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=1)=[O:25].C(=O)([O-])[O-].[Cs+].[Cs+]>CN1C(=O)CCC1>[NH:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N:17]=[C:16]1[C:24]([C:26]1[CH:31]=[CH:30][C:29]([O:32][C:2]2[C:7]([C@H:8]3[CH2:12][CH2:11][C@:10]([OH:13])([CH3:14])[CH2:9]3)=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:28][CH:27]=1)=[O:25]
Reactant: O=C(c1ccc(O)cc1)c1nc2ccccc2[nH]1
Reactant: CC1(O)CCC(c2cccnc2F)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: C[C@@]1(O)CC[C@H](c2cccnc2Oc2ccc(C(=O)c3nc4ccccc4[nH]3)cc2)C1
Temperature: 180 °C

Procedure:
To a vial containing 3-(2-fluoropyridin-3-yl)-1-methylcyclopentanol (570 mg, 2.92 mmol), (1H-benzo[d]imidazol-2-yl)(4-hydroxyphenyl)methanone (1043 mg, 4.38 mmol), and cesium carbonate (2378 mg, 7.30 mmol) was added NMP (5.389 mL) before sealing and purging the vessel of air with nitrogen. The reaction mixture was set to heated at 180° C. for 5 h with microwave irradiation. It was diluted with ethyl acetate and washed with 5 N NaOH. The organic layer was dried over magnesium sulfate, filtered, and concentrated under reduced pressure to a brown oil. The crude mixture of diastereomers was purified by SFC to yield four compounds. MS (ESI, pos. ion) m/z: 414.2 (M+1). IC50 (uM) +++++.
Reaction SMILES: [OH:1][C@H:2]1[C:11]2[CH:10]=[CH:9][N:8]3[CH:12]=[C:13]([CH3:15])[N:14]=[C:7]3[C:6]=2[NH:5][C@H:4]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C@H:3]1[OH:22].[C:23]1(C)C=CC(S(O)(=O)=O)=CC=1.CC(C)=O>COC(OC)(C)C>[OH:22][C@H:3]1[C@H:2]([O:1][CH3:23])[C:11]2[CH:10]=[CH:9][N:8]3[CH:12]=[C:13]([CH3:15])[N:14]=[C:7]3[C:6]=2[NH:5][C@@H:4]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: Cc1cn2ccc3c(c2n1)N[C@H](c1ccccc1)[C@@H](O)[C@H]3O
Solvent: CC(C)=O
Solvent: COC(C)(C)OC
Product: CO[C@@H]1c2ccn3cc(C)nc3c2N[C@H](c2ccccc2)[C@H]1O
Temperature: 25 °C
Reaction time: 96 h

Procedure:
To a suspension of 0.62 g (2.10 mmol) (7S,8R,9R)-7,8-dihydroxy-2-methyl-9-phenyl-7.8.9.10-tetrahydroimidazo[1.2-h][1.7]naphthyridine in dimethoxypropane is added 0.51 g (26.2 mmol) p-toluenesulphonic acid and acetone (4.0 ml). The mixture is stirred for 6 h at 60° C. and 96 h at 25° C. The reaction is quenched by adding of saturated aqueous sodium hydrogen carbonate solution. Subsequently the mixture is extracted twice with dichloromethane. The combined organic layers are washed with brine, dried over sodium sulphate and evaporated in vacuo. The crude product is purified by column chromatography (dichloromethane/methanol: 100/3) to give 0.12 g (0.34 mmol/16%) of the title compound as an amorphous solid. 1H-NMR (200 MHz, [D6] DMSO): δ=2.29 (s, 3H), 3.25 (s, 3 H), 4.05 (q, 1H), 4.32 (d, 1H), 4.47 (dd, 1H), 6.61 (d, 1H), 7.19–7.46 (m, 5H), 7.54 (s, 1H), 7.72 (d, 1 H).
Reaction SMILES: [F:1][C:2]1[C:7]([Sn](CCCC)(CCCC)CCCC)=[CH:6][CH:5]=[CH:4][N:3]=1.[Br:21][C:22]1[C:26](Br)=[CH:25][S:24][CH:23]=1.[F-].[K+]>CN1CCCC1=O.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Br:21][C:22]1[C:26]([C:7]2[C:2]([F:1])=[N:3][CH:4]=[CH:5][CH:6]=2)=[CH:25][S:24][CH:23]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccnc1F
Reactant: Brc1cscc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [F-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: Fc1ncccc1-c1cscc1Br
Temperature: 100 °C
Yield: 27.6 %

Procedure:
A mixture of 2-fluoro-3-tributylstannylpyridine (1.9 g), 3, 4-dibromothiophene (1.5 g) and Pd(Ph3P)2Cl2 (0.175 g) in N-methylpyrrolidinone (7.5 mL), in a sealed tube, was heated at 100° C. for 16 hours. The mixture was cooled and stirred with aqueous potassium fluoride for 6 hours. The mixture was diluted with ethyl acetate, washed with water, dried filtered and evaporated. The residue was fractionated by chromatography to give 3-bromo-4-(2-fluoropyridin-3-yl)thiophene (0.35 g), mp 48-50° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH:2]1[C:7]([OH:9])=[O:8].[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1.C(N(CC)CC)C>ClCCl>[CH3:10][O:11][C:12]1[CH:13]=[CH:14][C:15]([S:18]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH:2]2[C:7]([OH:9])=[O:8])(=[O:20])=[O:19])=[CH:16][CH:17]=1
Reactant: O=C(O)C1COCCN1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)N2CCOCC2C(=O)O)cc1

Procedure:
3-Morpholinecarboxylic acid is reacted with 4-methoxybenzenesulfonyl chloride in dichloromethane in the presence of triethylamine, to give 4-[(4-methoxyphenyl) sulfonyl]-3-morpholinecarboxylic acid.
Reaction SMILES: C(OC(=O)[NH:10][CH2:11][C@H:12]1[CH2:17][CH2:16][C@H:15]([C:18]2[N:26]3[C:21]([C:22]([NH2:27])=[N:23][CH:24]=[N:25]3)=[C:20]([C:28]3[CH:33]=[CH:32][C:31]([O:34][C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)=[CH:30][CH:29]=3)[N:19]=2)[CH2:14][CH2:13]1)C1C=CC=CC=1.Cl>O1CCOCC1>[NH2:10][CH2:11][C@H:12]1[CH2:13][CH2:14][C@H:15]([C:18]2[N:26]3[C:21]([C:22]([NH2:27])=[N:23][CH:24]=[N:25]3)=[C:20]([C:28]3[CH:29]=[CH:30][C:31]([O:34][C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=4)=[CH:32][CH:33]=3)[N:19]=2)[CH2:16][CH2:17]1
Reactant: Nc1ncnn2c1c(-c1ccc(Oc3ccccc3)cc1)nc2[C@H]1CC[C@H](CNC(=O)OCc2ccccc2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: NC[C@H]1CC[C@H](c2nc(-c3ccc(Oc4ccccc4)cc3)c3c(N)ncnn32)CC1

Procedure:
A solution of trans-{4-[4-amino-5-(4-phenoxy-phenyl)-imidazo[5,1-f][1,2,4]triazin-7-yl]-cyclohexylmethyl}-carbamic acid benzyl ester (20.0 mg, 0.0364 mmol) and 4 M of HCl in 1,4-dioxane (2 mL) was heated to reflux overnight. The solution was concentrated in vacuo and left to dry in the vacuum oven overnight to afford the title compound as a yellow solid. 1H NMR (400 MHz, CDCl3): δ=1.23-1.37 (m, 2H), 1.83-1.99 (m, 3H), 2.03-2.09 (m, 2H), 2.15-2.24 (m, 2H), 2.86 (d, J=4.0 Hz, 2H), 3.44-3.56 (m, 1H), 7.12 (d, J=8.1 Hz, 2H), 7.17-7.26 (m, 3H), 7.44 (t, J=7.8 Hz, 3H), 7.66 (d, J=3.5 Hz, 2H), 8.00-8.10 (m, 1H). MS (ES+): m/z 415.02 (100) [MH+]. HPLC: tR=2.26 min (OpenLynx, polar—5 min).