Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:8]([CH2:18][NH:19]C(=O)OC(C)(C)C)=[C:7]2[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[F:33])=[O:3].FC(F)(F)C(O)=O>>[NH2:19][CH2:18][C:8]1[C:9]([CH2:14][CH:15]([CH3:17])[CH3:16])=[N:10][C:11]2[C:6]([C:7]=1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[F:33])=[CH:5][C:4]([C:2]([NH2:1])=[O:3])=[CH:13][CH:12]=2
Reactant: CC(C)Cc1nc2ccc(C(N)=O)cc2c(-c2ccccc2F)c1CNC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: CC(C)Cc1nc2ccc(C(N)=O)cc2c(-c2ccccc2F)c1CN
Temperature: 25 °C
Reaction time: 1 h
Yield: 61 %

Procedure:
A mixture of tert-butyl [6-(aminocarbonyl)-4-(2-fluorophenyl)-2-isobutylquinolin-3-yl]methylcarbamate (0.32 g, 0.70 mmol) and trifluoroacetic acid (4 ml) was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure and the residue was partitioned between ethyl acetate-tetrahydrofuran (1:1, 50 ml) and 10% aqueous potassium carbonate solution (50 ml). The organic layer was washed with saturated brine (15 ml) and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography. The obtained crude crystals were recrystallized from n-hexane-ethyl acetate to give the title compound (0.15 g, yield 61%) as colorless crystals.
Reaction SMILES: [OH:1][CH:2]([CH2:39][N:40]1[C:49]([CH3:51])([CH3:50])[CH2:48][C:43]2([O:47][CH2:46][CH2:45][O:44]2)[CH2:42][C:41]1([CH3:53])[CH3:52])[CH2:3][O:4][CH:5]1[CH2:10][CH2:9][CH:8]([C:11]([CH:14]2[CH2:19][CH2:18][CH:17]([O:20][CH2:21][CH:22]([OH:38])[CH2:23][N:24]3[C:33]([CH3:35])([CH3:34])[CH2:32][C:27]4([O:31][CH2:30][CH2:29][O:28]4)[CH2:26][C:25]3([CH3:37])[CH3:36])[CH2:16][CH2:15]2)([CH3:13])[CH3:12])[CH2:7][CH2:6]1.[C:54](SC1SC2C=CC=CC=2N=1)(=[O:61])[C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1>C1C=CC=CC=1>[C:54]([O:1][CH:2]([CH2:39][N:40]1[C:41]([CH3:53])([CH3:52])[CH2:42][C:43]2([O:47][CH2:46][CH2:45][O:44]2)[CH2:48][C:49]1([CH3:51])[CH3:50])[CH2:3][O:4][CH:5]1[CH2:10][CH2:9][CH:8]([C:11]([CH:14]2[CH2:19][CH2:18][CH:17]([O:20][CH2:21][CH:22]([O:38][C:54](=[O:61])[C:55]3[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=3)[CH2:23][N:24]3[C:33]([CH3:35])([CH3:34])[CH2:32][C:27]4([O:28][CH2:29][CH2:30][O:31]4)[CH2:26][C:25]3([CH3:37])[CH3:36])[CH2:16][CH2:15]2)([CH3:12])[CH3:13])[CH2:7][CH2:6]1)(=[O:61])[C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1
Reactant: CC(C)(C1CCC(OCC(O)CN2C(C)(C)CC3(CC2(C)C)OCCO3)CC1)C1CCC(OCC(O)CN2C(C)(C)CC3(CC2(C)C)OCCO3)CC1
Reactant: O=C(Sc1nc2ccccc2s1)c1ccccc1
Solvent: c1ccccc1
Product: CC(C)(C1CCC(OCC(CN2C(C)(C)CC3(CC2(C)C)OCCO3)OC(=O)c2ccccc2)CC1)C1CCC(OCC(CN2C(C)(C)CC3(CC2(C)C)OCCO3)OC(=O)c2ccccc2)CC1

Procedure:
1.5 g of 2,2-bis{4-[2-hydroxy-3-(7,7,9,9-tetramethyl-1,4-dioxa-8-azaspiro[4.5]dec-8-yl)propoxy]cyclohexyl}propane and 1.2 g of 2-benzoylthiobenzthiazole were refluxed in 30 ml of anhydrous benzene for 4.5 hours. After completion of the reaction, the reaction mixture was treated with an aqueous alkali and then extracted with benzene, giving crystals. The crystals were purified by column chromatography through silica gel eluted with a 4:1 by volume mixture of diethyl ether and ethyl acetate. The desired Compound No. 222 was obtained in the form of a white powder melting at 77°-79° C.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:31]=[CH:30][C:8]([CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH2:18][CH2:19][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:21][CH:22]=3)=[CH:13][N:12]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3]>CO.[Pt].[C]>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([CH:17]3[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:27])([CH3:29])[CH3:28])=[O:24])[CH2:19][CH2:18]3)=[CH:13][N:12]=2)=[CH:30][CH:31]=1)(=[O:3])=[O:4]
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccc(OCc3ccc(S(C)(=O)=O)cc3)nc2)CC1
Agent: [Pt]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(OCc3ccc(S(C)(=O)=O)cc3)nc2)CC1
Reaction time: 17 h
Yield: 51.1 %

Procedure:
To a solution of tert-butyl 4-[2-(4-methanesulfonylbenzyloxy)pyridin-5-yl]-3,6-dihydro-2H-pyridine-1-carboxylate (Example 6) (39 mg, 87.7 μmol) in methanol (2 mL) was added 10% platinum-carbon (15 mg). The mixture was hydrogenated at room temperature for 17 hours and filtered through Celite pad. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/1) to give the title compound as a white crystal (20 mg, yield 51%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N:8]([CH:10]([CH3:13])[CH2:11][OH:12])[CH3:9])[NH:5][C:4](=[O:14])[N:3]=1.C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>O1CCCC1>[CH3:22][S:23]([O:12][CH2:11][CH:10]([N:8]([C:6]1[NH:5][C:4](=[O:14])[N:3]=[C:2]([Cl:1])[CH:7]=1)[CH3:9])[CH3:13])(=[O:25])=[O:24]
Reactant: CS(=O)(=O)Cl
Reactant: CC(CO)N(C)c1cc(Cl)nc(=O)[nH]1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(COS(C)(=O)=O)N(C)c1cc(Cl)nc(=O)[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 4-chloro-6-((1-hydroxypropan-2-yl)(methyl)amino)pyrimidin-2(1H)-one (1.0 g, 4.6 mmol) and triethylamine (1.9 mL, 14 mmol) in tetrahydrofuran (THF) (15 mL) was added MsCl (0.72 mL, 9.2 mmol) at 0˜5° C. The reaction mixture was stirred at room temperature overnight, and then quenched with 1 M NaHCO3 solution, diluted with water and extracted with ethyl acetate. Combined organic parts were dried over anhydrous Na2SO4, filtered and concentrated to give the residue as yellow oil. The crude was used into next step without further purification.
Reaction SMILES: [OH-].[Na+].[CH2:3]([O:5][C@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([F:19])[CH:13]=2)[CH2:8][CH2:7]1)[CH3:4].Cl[CH:21]([F:23])[F:22].C(=O)=O>C1COCC1>[CH2:3]([O:5][C@H:6]1[CH2:7][CH2:8][C@H:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH:21]([F:23])[F:22])=[C:14]([F:19])[CH:13]=2)[CH2:10][CH2:11]1)[CH3:4]
Reactant: CCO[C@H]1CC[C@H](c2ccc(O)c(F)c2)CC1
Reactant: FC(F)Cl
Agent: O=C=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCO[C@H]1CC[C@H](c2ccc(OC(F)F)c(F)c2)CC1
Reaction time: 1 h

Procedure:
11 g of NaOH (32%) are added to a solution of 8.2 of the resultant p-(trans-4-ethoxycyclohexyl)-o-flurophenol in 80 ml of THF and 13.8 g of chlorodifluoromethane are introduced (dry ice reflux condenser). After subsequently stirring for one hour, the solution is decanted off from the precipitate and concentrated to give a residue. Bulb tube distillation gives p-(trans-4-ethoxycyclohexyl)-o-fluorodifluoromethoxybenzene, b.p.1 ~220° C., Tg -62°.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=2)[N:3]=1.[CH:21]1([OH:25])[CH2:24][CH2:23][CH2:22]1>>[CH:21]1([O:25][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=3)[CH:5]=[C:4]([NH:14][C:15]3[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=3)[N:3]=2)[CH2:24][CH2:23][CH2:22]1
Reactant: COc1ccc2c(Cl)nc(Nc3cc(C)[nH]n3)cc2c1
Reactant: OC1CCC1
Product: COc1ccc2c(OC3CCC3)nc(Nc3cc(C)[nH]n3)cc2c1

Procedure:
Similar procedure as described in example 10 was used, starting from (1-Chloro-6-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and cyclobutanol to give (1-Cyclobutoxy-6-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS: m/e 325 (MH+).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][C@H:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:5][C@H:4]([OH:14])[CH2:3]1.[H-].[Na+].S(C1C=CC(C)=CC=1)(O[CH3:21])(=O)=O.O>C1COCC1>[CH3:21][O:14][C@H:4]1[CH2:5][C@@H:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:7][N:2]([CH3:1])[CH2:3]1
Reactant: COS(=O)(=O)c1ccc(C)cc1
Reactant: CN1C[C@@H](O)C[C@@H](c2ccccc2)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CO[C@H]1C[C@@H](c2ccccc2)CN(C)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of cis-1-methyl-5-phenyl-3-piperidinol (2.03 g) in THF (20 ml) was treated with 60% sodium hydride dispersion in oil (480 mg) and heated 15 min. at reflux. The mixture was cooled to room temperature and treated with methyl tosylate (1.86 g) in THF (5 ml). The reaction mixture was stirred for 1 hour at ambient temperature, treated with water (5 ml) and the solvents removed under reduced pressure. The residue was partitioned between water (100 ml) and ether (100 ml). The organic phase was dried over magnesium sulphate and the solvent removed under reduced pressure. The resulting oil was triturated with cyclohexane (10 ml) and the resulting crystals (300 mg; unchanged starting material) removed by filtration. The mother liquors were evaporated under reduced pressure and the resulting gum converted to the fumarate which was recrystallised from methanol/ethyl acetate to give the title compound as the sesquifumarate (500 mg) Mpt. 152°-4°
Reaction SMILES: [CH:1]1([O:7][CH:8]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=2)[C:9]([NH2:11])=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:20][N:21]=[C:22]=[O:23]>C1(C)C=CC=CC=1>[CH:1]1([O:7][CH:8]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=2)[C:9]([NH:11][C:22]([NH:21][CH3:20])=[O:23])=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC(=O)C(OC1CCCCC1)c1ccc(Cl)c(Cl)c1
Reactant: CN=C=O
Solvent: Cc1ccccc1
Product: CNC(=O)NC(=O)C(OC1CCCCC1)c1ccc(Cl)c(Cl)c1
Yield: 87.3 %

Procedure:
A solution of rac-2-cyclohexyloxy-2-(3,4-dichloro-phenyl)-acetamide (291 mg, 0.96 mmol) in toluene (10 mL) was treated with methyl isocyanate (0.09 mL, 1.44 mmol). The resulting solution was heated at reflux for 24 h and then the cooled reaction was concentrated in vacuo. The reaction product was purified by flash chromatography (Merck Silica gel 60, 230-400 mesh, 90/10 hexanes/ethyl acetate) to give 1-[cyclohexyloxy-(3,4-dichloro-phenyl)-acetyl]-3-methyl-urea (301 mg, 87% yield) as a colorless oil: EI-HRMS m/e calcd for C16H20N2Cl2O3 (M+H)+359.0929, found 359.0922.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](OS(C(F)(F)F)(=O)=O)=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[NH:8][N:7]=[CH:6]2.[CH3:22][Si:23]([C:26]#[CH:27])([CH3:25])[CH3:24].C(N(CC)CC)C>CN(C=O)C>[CH3:1][O:2][C:3]1[C:4]([C:27]#[C:26][Si:23]([CH3:25])([CH3:24])[CH3:22])=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[NH:8][N:7]=[CH:6]2
Reactant: COc1ccc2c(=O)[nH]ncc2c1OS(=O)(=O)C(F)(F)F
Reactant: C#C[Si](C)(C)C
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc2c(=O)[nH]ncc2c1C#C[Si](C)(C)C
Temperature: 60 °C
Yield: 75.6 %

Procedure:
A solution of trifluoro-methanesulfonic acid 6-methoxy-1-oxo-1,2-dihydro-phthalazin-5-yl ester (4.52 g, 13.94 mmoles), prepared as described in example 59, trimethylsilylethyne (3.94 ml, 27.88 mmoles), bis(triphenylphosphine)PdCl2 (245 mg, 0.384 mmole) and triethylamine (6.56 ml) in DMF (30 ml) was heated at 60° C. for 4 hours. Further trimethylsilylethyne (2 ml) was added and the mixture was heated at 90° C. for 3 hours. After evaporation of the solvent, the residue was taken up in ethyl acetate and the solid was filtered off. After evaporation, the residue was taken up in diethylcarbonate, washed with water, dried, evaporated again, taken up in ethyl ether and filtered giving 2.87 g of the title compound (yield: 75.6%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](O)=[N:8][C:9]2[C:14]([C:15]=1[CH3:16])=[CH:13][CH:12]=[C:11]([C:17]([F:20])([F:19])[F:18])[CH:10]=2)=[O:5])[CH3:2].O=P(Cl)(Cl)[Cl:24]>>[CH2:1]([O:3][C:4]([C:6]1[C:7]([Cl:24])=[N:8][C:9]2[C:14]([C:15]=1[CH3:16])=[CH:13][CH:12]=[C:11]([C:17]([F:20])([F:19])[F:18])[CH:10]=2)=[O:5])[CH3:2]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1c(O)nc2cc(C(F)(F)F)ccc2c1C
Product: CCOC(=O)c1c(Cl)nc2cc(C(F)(F)F)ccc2c1C
Temperature: 25 °C
Yield: 98.6 %

Procedure:
4.3 g (14.4 mmol) 2-hydroxy-4-methyl-7-(trifluoromethyl)quinoline-3-carboxylic acid ethyl ester (precursor VVV05) were heated together with 13.3 ml (144.1 mmol) POCl3 for 2 h at 100° C. After cooling to RT the mixture was concentrated to small volume under vacuum. 4.5 g (14.2 mmol, 98%) 2-chloro-4-methyl-7-(trifluoromethyl)quinoline-3-carboxylic acid ethyl ester were obtained as residue.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1OS(C(F)(F)F)(=O)=O.[NH2:27][CH2:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][CH:36]2[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]2)=[CH:31][N:30]=1>>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1[NH:27][CH2:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][CH:36]2[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41]2)=[CH:31][N:30]=1
Reactant: NCc1ccc(OC2CCCCC2)cn1
Reactant: O=C(N1CCc2ccc(Cl)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Product: O=C(N1CCc2ccc(Cl)c(NCc3ccc(OC4CCCCC4)cn3)c2CC1)C(F)(F)F
Yield: 65 %

Procedure:
Use a method similar to the General Procedure 1-2 to couple 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (705 mg, 1.66 mmol) and 2-aminomethyl-5-cyclohexyloxy-pyridine (410 mg, 1.99 mmol). Purify the crude mixture by chromatography on silica gel (150 g, pre-packed cartridge) eluting with hexane/EtOAc (1:0 to 9:1 gradient) to obtain 7-chloro-6-[(5-cyclohexyloxy-pyridin-2-ylmethyl)-amino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (520 mg, 65%). MS (APCI+) m/z: 482 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:16][C:9]2=[N:10][C:11]([Cl:15])=[C:12]([CH3:14])[CH:13]=[C:8]2[CH:7]=1)=[O:5])[CH3:2].CC(C)([O-])C.[K+].[C:23]([O:27][C:28]([N:30]1[CH2:34][C@H:33]([CH3:35])OS1(=O)=O)=[O:29])([CH3:26])([CH3:25])[CH3:24]>CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1[N:16]([C@H:33]([CH3:35])[CH2:34][NH:30][C:28]([O:27][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:29])[C:9]2=[N:10][C:11]([Cl:15])=[C:12]([CH3:14])[CH:13]=[C:8]2[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2cc(C)c(Cl)nc2[nH]1
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)S(=O)(=O)O1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2cc(C)c(Cl)nc2n1[C@H](C)CNC(=O)OC(C)(C)C
Yield: 87.8 %

Procedure:
A stirred solution of 0.34 g (1.42 mmol) 6-chloro-5-methyl-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid ethyl ester in 7 mL N,N-dimethylformamide was cooled to 0° C. Potassium tert-butoxide (0.17 g, 1.50 mmol) was added and after 30 min. 0.37 g (1.57 mmol) (S)-5-methyl-2,2-dioxo-[1,2,3]oxathiazolidine-3-carboxylic acid tert-butyl ester was added and the cooling bath was removed. After 3 h the reaction mixture was poured into 10% aqueous citric acid solution and extracted three times with ethyl acetate. The combined organic layers were washed with water and brine, dried over magnesium sulfate, filtered and evaporated. The residue was purified by column chromatography over silica gel (0.030–0.063 mm) with ethyl acetate:n-hexane (1:5) as eluant to give the product as a colourless solid (87.8%).
Reaction SMILES: [CH:1]1([NH:7][C:8]2[CH:13]=[CH:12][C:11]([C@@H:14]3[O:19][CH2:18][CH2:17][N:16]([C@@H:20]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH3:21])[CH2:15]3)=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C=O.[C:30](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[CH:1]1([N:7]([C:8]2[CH:9]=[CH:10][C:11]([C@@H:14]3[O:19][CH2:18][CH2:17][N:16]([C@@H:20]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH3:21])[CH2:15]3)=[CH:12][CH:13]=2)[CH3:30])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: C[C@H](c1ccccc1)N1CCO[C@@H](c2ccc(NC3CCCCC3)cc2)C1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Product: C[C@H](c1ccccc1)N1CCO[C@@H](c2ccc(N(C)C3CCCCC3)cc2)C1
Reaction time: 0.5 h
Yield: 100.5 %

Procedure:
To a solution of (S)-2-(4-(cyclohexylamino)phenyl)-4-((R)-1-phenylethyl)morpholine (6.95 g, 19.1 mmol) and formalin (35%, 8.18 ml, 95.4 mmol) was added sodium triacetoxyborohydride (12.1 g, 57.2 mmol) at room temperature. After stirring for 30 minutes, the resulting suspension was partitioned between ethyl acetate and 1 N sodium hydroxide. The aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by silica gel chromatography eluting 5-20% ethyl acetate in hexane to furnish (2S)-2-(4-(N-cyclohexyl-N-methylamino)phenyl)-4-((1R)-1-phenylethyl)morpholine (7.27 g, quant.) as a pale yellow oil.
Reaction SMILES: Cl.[NH2:2][C:3]1([C:9]2[O:13][N:12]=[C:11]([C:14]3[CH:15]=[CH:16][C:17]([CH3:32])=[C:18]([NH:20][C:21]([C:23]4[N:27]5[CH:28]=[CH:29][CH:30]=[CH:31][C:26]5=[N:25][CH:24]=4)=[O:22])[CH:19]=3)[N:10]=2)[CH2:6][C:5]([F:8])([F:7])[CH2:4]1.Cl[C:34]([O:36][CH3:37])=[O:35]>N1C=CC=CC=1>[F:7][C:5]1([F:8])[CH2:6][C:3]([NH:2][C:34](=[O:35])[O:36][CH3:37])([C:9]2[O:13][N:12]=[C:11]([C:14]3[CH:15]=[CH:16][C:17]([CH3:32])=[C:18]([NH:20][C:21]([C:23]4[N:27]5[CH:28]=[CH:29][CH:30]=[CH:31][C:26]5=[N:25][CH:24]=4)=[O:22])[CH:19]=3)[N:10]=2)[CH2:4]1
Reactant: COC(=O)Cl
Reactant: Cc1ccc(-c2noc(C3(N)CC(F)(F)C3)n2)cc1NC(=O)c1cnc2ccccn12
Agent: Cl
Solvent: c1ccncc1
Product: COC(=O)NC1(c2nc(-c3ccc(C)c(NC(=O)c4cnc5ccccn45)c3)no2)CC(F)(F)C1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a stirring solution of N-(5-(5-(1-amino-3,3-difluorocyclobutyl)-1,2,4-oxadiazol-3-yl)-2-methylphenyl)imidazo[1,2-a]pyridine-3-carboxamide hydrochloride (166) in anhydrous pyridine (1 mL) at 0° C. was added drop-wise methyl chloroformate (19 uL, 0.26 mmol). The reaction was stirred to room temperature for 20 minutes. The crude was concentrated and purified by preparative HPLC to yield methyl (3,3-difluoro-1-(3-(3-(imidazo[1,2-a]pyridine-3-carboxamido)-4-methylphenyl)-1,2,4-oxadiazol-5-yl)cyclobutyl)carbamate (F174). MS m/z 483.1 (M+1)+.
Reaction SMILES: [CH2:1]1[CH:9]2[N:4]([CH2:5][CH:6]=[C:7]([C:10]3[C:18]4[C:13](=[N:14][CH:15]=[CH:16][CH:17]=4)[NH:12][CH:11]=3)[CH2:8]2)[CH2:3][CH2:2]1.[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1>[C:19]([N:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][N:14]=2)[C:10]([C:7]2[CH2:8][CH:9]3[N:4]([CH2:3][CH2:2][CH2:1]3)[CH2:5][CH:6]=2)=[CH:11]1)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: C1=C(c2c[nH]c3ncccc23)CC2CCCN2C1
Reactant: O=C(Cl)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(c1ccccc1)n1cc(C2=CCN3CCCC3C2)c2cccnc21

Procedure:
from 3-(1,2,3,5,8,8a-hexahydro-7-indolizinyl)-1H-7-Azaindole (10 mg, 0.0418 mmol), benzoyl chloride (13 μL, 0.12 mmol) and 1M NaN(TMS)2 (100 μL, 0.10 mmol) in THF (1 mL) at RT.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:9])[C:5](C)=[CH:6][CH:7]=1.[Mg]>O1CCCC1.[Cu](Cl)Cl>[C:9]1([C:4]2[CH:3]=[CH:2][CH:7]=[CH:6][CH:5]=2)[CH:4]=[CH:3][CH:2]=[CH:7][CH:6]=1
Reactant: Cc1ccc(Br)cc1C
Agent: Cl[Cu]Cl
Agent: [Mg]
Solvent: C1CCOC1
Product: c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Yield: 50.8 %

Procedure:
A solution of 13.7 g of 4-bromo-o-xylene in 50 ml of dry tetrahydrofuran is added dropwise to a suspension of magnesium filings (1.95 g) in 50 ml of dry tetrahydrofuran in the course of 1 hour. After refluxing in an argon atmosphere for 2 hours, the mixture is cooled to room temperature and 9.4 g of anhydrous copper(II) chloride are added in portions. The mixture is poured onto ice-water and extracted twice with 100 ml of diethyl ether each time. The organic phase is washed with 2 N hydrochloric acid and saturated sodium chloride solution. Drying with magnesium sulfate, evaporation and crystallisation of the residue from ethanol gives 2.9 g of biphenyl.
Reaction SMILES: [SH:1][C:2]1[N:6]([CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C:5]2[CH:15]=[CH:16][CH:17]=[CH:18][C:4]=2[N:3]=1.[CH2:19]([O:21][C:22]([N:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26](=[O:33])[N:25]1[CH2:34][CH2:35][CH2:36]Cl)=[O:23])[CH3:20].[I-].[K+].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH2:19]([O:21][C:22]([N:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26](=[O:33])[N:25]1[CH2:34][CH2:35][CH2:36][S:1][C:2]1[N:6]([CH2:7][C:8]([O:10][C:11]([CH3:13])([CH3:14])[CH3:12])=[O:9])[C:5]2[CH:15]=[CH:16][CH:17]=[CH:18][C:4]=2[N:3]=1)=[O:23])[CH3:20]
Reactant: CC(C)(C)OC(=O)Cn1c(S)nc2ccccc21
Reactant: CCOC(=O)n1c2ccccc2c(=O)n1CCCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)n1c2ccccc2c(=O)n1CCCSc1nc2ccccc2n1CC(=O)OC(C)(C)C

Procedure:
A mixture of tert-butyl (2-mercapto-benzoimidazol-1-yl)-acetate (Intermediate 3-I, 66 mg, 0.25 mmol), 2-(3-chloro-propyl)-3-oxo-2,3-dihydro-indazole-1-carboxylic acid ethyl ester (alkylating agent G-01d, 70 mg, 0.25 mmol), a few crystals of potassium iodide and K2CO3 (69 mg, 0.5 mmol) in acetone (1 ml) is refluxed overnight. Evaporation of the solvent under a stream of air affords a residue that is purified by flash-chromatography on silica-gel (AcOEt/heptane, 3:2), yielding the title compound as a colourless oil: tR=2.75 min (LC-2), ESI-MS (pos.): m/z 511.15 [M+H]+; 1H-NMR (CDCl3): δ (ppm) 1.37 (s, 9H, tBu), 1.37 (t, 3H, CH3), 2.14 (quint., 2H, CH2CH2N), 3.28 (m, 2H, SCH2), 4.30-4.40 (m, 4H), 4.69 (s, 2H, CH2CO2), 7.10 (m, 3Harom), 7.26 (t, 1Harom), 7.55 (m, 2Harom), 7.81 (t, 2Harom).
Reaction SMILES: O[CH2:2][CH:3]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N:12]3[CH2:16][C@H:15]([CH2:17][NH:18][C:19](=[O:21])[CH3:20])[O:14][C:13]3=[O:22])[CH:9]=2)[N:4]1[CH:23]=[O:24].C(N(S(F)(F)[F:31])CC)C.C([O-])(O)=O.[Na+]>C(Cl)Cl>[F:31][CH2:2][CH:3]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N:12]3[CH2:16][C@H:15]([CH2:17][NH:18][C:19](=[O:21])[CH3:20])[O:14][C:13]3=[O:22])[CH:9]=2)[N:4]1[CH:23]=[O:24]
Reactant: CC(=O)NC[C@H]1CN(c2ccc3c(c2)CC(CO)N3C=O)C(=O)O1
Reactant: CCN(CC)S(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)NC[C@H]1CN(c2ccc3c(c2)CC(CF)N3C=O)C(=O)O1
Temperature: -70 °C
Reaction time: 20 h
Yield: 42.1 %

Procedure:
A stirred mixture of the product from Step 11 (0.085 g, 0.255 mmol)) and CH2Cl2 (10 ml), under nitrogen is cooled to −70° C. and treated, dropwise stirring 2 min, with a solution of (diethylamino)sulfur trifluoride (0.07 ml, 0.53 mmol) in CH2Cl2 (1 ml). The mixture is allowed to warm to ambient temperature slowly during 3 h. Additional CH2Cl2 (10 ml) is added and the mixture is kept at ambient temperature for 20 h, cooled to −70° C. and treated with 0.07 ml of additional DAST. It is kept at −70° C. for 1 h and at ambient temperature for 4 h, mixed with ice cold, saturated NaHCO3 and extracted with EtOAc. The extracts are washed with water and brine, dried (MgSO4) and concentrated. Chromatography of the residue on silica gel with 3.5% MeOH—CH2Cl2 gave 0.036 g of the titled product: HRMS (FAB) calcd for C16H18FN3O4+H 336.1359, found 336.1351; 1H NMR [300 MHz, (CD3)2SO] δ1.81 (s, 3H), 2.85, 3.00 (m, m, 1H), 3.38 (m, 3H), 3.71 (m, 1H), 4.06 (m, 1H), 4.30-4.88 (m, 4H), 7.30 (m, 1H), 7.43, 7.87 (d, d, 1H), 7.50 (m, 1H), 8.23 (t, 1H), 8.45, 9.00 (s, s, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([O:9][C:10]2[C:15]([CH:16]([CH3:18])[CH3:17])=[CH:14][C:13]([OH:19])=[C:12]([I:20])[CH:11]=2)=[CH:4][N:3]=1.[CH2:21](Br)[CH3:22]>CN(C=O)C>[CH2:21]([O:19][C:13]1[C:12]([I:20])=[CH:11][C:10]([O:9][C:5]2[C:6]([NH2:8])=[N:7][C:2]([NH2:1])=[N:3][CH:4]=2)=[C:15]([CH:16]([CH3:18])[CH3:17])[CH:14]=1)[CH3:22]
Reactant: CC(C)c1cc(O)c(I)cc1Oc1cnc(N)nc1N
Reactant: CCBr
Solvent: CN(C)C=O
Product: CCOc1cc(C(C)C)c(Oc2cnc(N)nc2N)cc1I
Yield: 78.9 %

Procedure:
To a solution of 4-(2,4-Diamino-pyrimidin-5-yloxy)-2-iodo-5-isopropyl-phenol (0.2 g, 0.52 mmol) in anhydrous DMF (2 ml) was added EtBr (57 mg, 0.52 mmol) in portions. The reaction mixture was partitioned between EtOAc and H2O. The organic extract was dried over Na2SO4, filtered and concentrated. Flash chromatography on silica (3% MeOH in methylene chloride with 1% NH4OH) gave 5-(4-Ethoxy-5-iodo-2-isopropyl-phenoxy)-pyrimidine-2,4-diamine (0.17 g, 28%) as a yellow solid. (M+H)=415.