Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[N:3]2[C:8]3[N:9]4[CH2:38][CH2:37][C:12]([CH3:39])([O:13][CH2:14][CH2:15][CH2:16][CH2:17][C@H:18]([CH3:36])[O:19][C:20]5[CH:21]=[C:22]([CH3:35])[C:23]([F:34])=[CH:24][C:25]=5[C:26]5[CH:33]=[C:30]([C:31]=1[N:32]=[C:4]2[CH:5]=[C:6]([CH3:50])[C:7]=3[C@H:40]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])[C:41]([O:43]C)=[O:42])[CH:29]=[CH:28][CH:27]=5)[CH2:11][CH2:10]4.C(O[C@@H](C1C(C)=CC2=NC3=CN2C=1N1CCC(C)(OCC=CC[C@H](C)OC2C=C(F)C=CC=2C2C=C3C=CC=2)CC1)C(O)=O)(C)(C)C>>[Br:1][C:2]1[N:3]2[C:8]3[N:9]4[CH2:10][CH2:11][C:12]([CH3:39])([O:13][CH2:14][CH2:15][CH2:16][CH2:17][C@H:18]([CH3:36])[O:19][C:20]5[CH:21]=[C:22]([CH3:35])[C:23]([F:34])=[CH:24][C:25]=5[C:26]5[CH:33]=[C:30]([C:31]=1[N:32]=[C:4]2[CH:5]=[C:6]([CH3:50])[C:7]=3[C@H:40]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])[C:41]([OH:43])=[O:42])[CH:29]=[CH:28][CH:27]=5)[CH2:37][CH2:38]4
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc3c(Br)n2c1N1CCC(C)(CC1)OCCCC[C@H](C)Oc1cc(C)c(F)cc1-c1cccc-3c1
Agent: Cc1cc2nc3cn2c(c1[C@H](OC(C)(C)C)C(=O)O)N1CCC(C)(CC1)OCC=CC[C@H](C)Oc1cc(F)ccc1-c1cccc-3c1
Product: Cc1cc2c(cc1F)-c1cccc(c1)-c1nc3cc(C)c([C@H](OC(C)(C)C)C(=O)O)c(n3c1Br)N1CCC(C)(CC1)OCCCC[C@H](C)O2

Procedure:
Prepared in 24% from methyl(2S)-2-[(22S)-8-bromo-17-fluoro-4,18,22,28-tetramethyl-21,27-dioxa-1,7,34-triazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18-decaen-3-yl]-2-(tert-butoxy)acetate following the procedure for (2S)-2-(tert-butoxy)-2-[(22S)-18-fluoro-4,22,28-trimethyl-21,27-dioxa-1,7,34-triazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18,24-undecaen-3-yl]acetic acid. 1H NMR (600 MHz, DMSO-d6) δ 8.09 (s, 1H), 7.73 (d, J=7.3 Hz, 1H), 7.56 (t, J=7.7 Hz, 1H), 7.43 (d, J=7.3 Hz, 1H), 7.33-7.29 (m, 1H), 7.14 (d, J=6.2 Hz, 1H), 7.04 (d, J=9.9 Hz, 1H), 5.75-5.61 (m, 1H), 4.69-4.59 (m, 1H), 4.31-2.61 (m, 6H), 2.43 (br. s., 3H), 2.27 (s, 3H), 1.94-1.39 (m, 10H), 1.20 (br. s., 3H), 1.15 (br. s., 9H), 1.08 (d, J=5.5 Hz, 3H); LCMS (ESI, M): 735.3.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[C:11]1[N:15]([C:16]2[CH:21]=[CH:20][C:19]([C:22](=[O:31])[N:23]([CH3:30])[CH2:24][CH2:25][CH2:26][N:27]([CH3:29])[CH3:28])=[CH:18][C:17]=2[CH:32]([CH3:34])[CH3:33])[N:14]=[C:13]([C:35]([NH:37][C:38]2([C:48]([OH:50])=[O:49])[CH:45]3[CH2:46][CH:41]4[CH2:42][CH:43]([CH2:47][CH:39]2[CH2:40]4)[CH2:44]3)=[O:36])[CH:12]=1.C[O-].[Na+:53].CCOCC>CO.C(Cl)Cl>[Na+:53].[CH3:10][O:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[C:4]=1[C:11]1[N:15]([C:16]2[CH:21]=[CH:20][C:19]([C:22](=[O:31])[N:23]([CH3:30])[CH2:24][CH2:25][CH2:26][N:27]([CH3:28])[CH3:29])=[CH:18][C:17]=2[CH:32]([CH3:34])[CH3:33])[N:14]=[C:13]([C:35]([NH:37][C:38]2([C:48]([O-:50])=[O:49])[CH:39]3[CH2:40][CH:41]4[CH2:42][CH:43]([CH2:44][CH:45]2[CH2:46]4)[CH2:47]3)=[O:36])[CH:12]=1
Reactant: COc1cccc(OC)c1-c1cc(C(=O)NC2(C(=O)O)C3CC4CC(C3)CC2C4)nn1-c1ccc(C(=O)N(C)CCCN(C)C)cc1C(C)C
Agent: C[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOCC
Solvent: CO
Product: COc1cccc(OC)c1-c1cc(C(=O)NC2(C(=O)[O-])C3CC4CC(C3)CC2C4)nn1-c1ccc(C(=O)N(C)CCCN(C)C)cc1C(C)C
Temperature: 5 °C
Yield: 70.6 %

Procedure:
0.206 g of the compound obtained in EXAMPLE 1' and 0.026 g of sodium methylate are dissolved in 1 ml of MeOH and a few drops of DCM, and this solution is then poured into 50 ml of ether cooled to 5° C. The gelatinous precipitate formed is drained and dried over P2O5 and under vacuum. 0.15 g of the expected product is obtained, m.p.=191° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([NH:10][C:11](=[N:14][C:15]2[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[C:17]([O:25][CH3:26])[CH:16]=2)SC)=O)[CH:5]=[C:4]([CH3:27])[N:3]=1.[NH:28]([CH2:30][C@@H:31]([OH:34])[CH2:32][CH3:33])[NH2:29]>C(O)C>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[N:28]([CH2:30][C@@H:31]([OH:34])[CH2:32][CH3:33])[N:29]=[C:11]([NH:14][C:15]3[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[C:17]([O:25][CH3:26])[CH:16]=3)[N:10]=2)[CH:5]=[C:4]([CH3:27])[N:3]=1
Reactant: CC[C@H](O)CNN
Reactant: COc1cc(N=C(NC(=O)c2cc(C)nc(Cl)c2)SC)cc(C(F)(F)F)c1
Solvent: CCO
Product: CC[C@H](O)Cn1nc(Nc2cc(OC)cc(C(F)(F)F)c2)nc1-c1cc(C)nc(Cl)c1
Reaction time: 8 h

Procedure:
A mixture of intermediate D6 (8.356 g, 0.020 mol) and intermediate D3 (2.083 g, 0.020 mol) in ethanol (200 ml) was stirred overnight at reflux. Subsequently, the solvent was evaporated to yield intermediate D7 (S-enantiomer) as a yellow oil that was used as such in the next reaction step.
Reaction SMILES: C([Li])CCC.[CH:6]1([C:9]#[CH:10])[CH2:8][CH2:7]1.[CH3:11][C@:12]12[C:18]([CH3:20])([CH3:19])[C@:15]([C:21]([N:23](C([C@@]34C(C)(C)[C@@](C)(CC3)C(=O)O4)=O)[C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=3[C:31](=[O:36])[C:32]([F:35])([F:34])[F:33])=[O:22])([CH2:16][CH2:17]1)[O:14][C:13]2=[O:50]>O1CCCC1>[Cl:30][C:27]1[CH:28]=[CH:29][C:24]([NH:23][C:21]([C@@:15]23[C:18]([CH3:19])([CH3:20])[C@@:12]([CH3:11])([CH2:17][CH2:16]2)[C:13](=[O:50])[O:14]3)=[O:22])=[C:25]([C@@:31]([OH:36])([C:10]#[C:9][CH:6]2[CH2:8][CH2:7]2)[C:32]([F:33])([F:34])[F:35])[CH:26]=1
Reactant: C#CC1CC1
Reactant: CC1(C)[C@@]2(C)CC[C@]1(C(=O)N(C(=O)[C@@]13CC[C@@](C)(C(=O)O1)C3(C)C)c1ccc(Cl)cc1C(=O)C(F)(F)F)OC2=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC1(C)[C@@]2(C)CC[C@]1(C(=O)Nc1ccc(Cl)cc1[C@@](O)(C#CC1CC1)C(F)(F)F)OC2=O
Reaction time: 1 h

Procedure:
2.5M n-Butyllithium (2.05 mL, 5.14 mmol) was added slowly to a solution of cyclopropyl acetylene (0.34 g, 5.14 mmol) in tetrahydrofuran (4 mL) in an ice-salt-bath under argon, and then N,N-bis((1S,4R)-4,7,7-trimethyl-3-oxo-2-oxabicyclo[2.2.1]heptane-1-carbonyl)-4-chloro-2-(2,2,2-trifluoroacetyl)aniline (11, 1 g, 1.71 mmol) in THF (2 mL) was added. The reaction mixture was stirred for 1 hour. The reaction was quenched with 10% citric acid aqueous, the mixture was extracted with ethyl acetate and the two layers were separated. The organic layer was evaporated to dryness to give a crude oil and further crystallized with ethyl acetate and petroleum ether to give pure (1S,4R)-N-(4-chloro-2-((S)-4-cyclopropyl-1,1,1-trifluoro-2-hydroxybut-3-yn-2-yl)phenyl)-4,7,7-trimethyl-3-oxo-2-oxabicyclo[2.2.1]heptane-1-carboxamide (10).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:7]=[C:6]([CH2:8][N:9]([CH2:13][CH2:14][CH3:15])[CH2:10][CH2:11][CH3:12])[O:5][N:4]=1.[CH:16](OC)=[O:17]>>[CH2:10]([N:9]([CH2:8][C:6]1[O:5][N:4]=[C:3]([CH2:2][NH:1][CH:16]=[O:17])[N:7]=1)[CH2:13][CH2:14][CH3:15])[CH2:11][CH3:12]
Reactant: COC=O
Reactant: CCCN(CCC)Cc1nc(CN)no1
Product: CCCN(CCC)Cc1nc(CNC=O)no1
Yield: 79 %

Procedure:
A solution of 15.6 g (73.5 mmol) of (3-aminomethyl-1,2,4-oxadiazol-5-ylmethyl)-dipropylamine in 100 ml of methyl formate was heated at reflux for seven hours. Subsequently, the solution was evaporated and the residue was chromatographed (silica gel, methylene chloride/methanol 19:1). There were obtained 14 g (79%) of N-(5-dipropylaminomethyl-1,2,4-oxadiazol-3-ylmethyl)-formamide, Rf=0.28 (silica gel, methylene chloride/methanol 19:1).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:19])[CH:10]=1)[C:5]([OH:7])=[O:6].[C:20](OC(=O)C)(=[O:22])[CH3:21]>C(O)(=O)C>[C:20]([O:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:19])[CH:10]=1)[C:5]([OH:7])=[O:6])(=[O:22])[CH3:21]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ccccc1COc1cc(O)cc(C(=O)O)c1
Solvent: CC(=O)O
Product: CC(=O)Oc1cc(OCc2ccccc2C)cc(C(=O)O)c1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
3-Hydroxy-5-(2-methylbenzyloxy) benzoic acid (20.30 g, 78.6 mM) and acetic anhydride (125 ml, 1.32M) in acetic acid (125 ml) were refluxed for 16 hours. The reaction was cooled and the solvent evaporated ‘in vacuo’. Acetic acid (125 nml) and water (125 ml) were added to the resulting residue and the mixture was stirred for 1 hour at 50° C. Toluene (100 ml) was added and the solvent distilled off ‘in vacuo’ to give 3-acetoxy-5-(2-methylbenzyloxy) benzoic acid as a colourless solid (23.6 g); H1 NMR δ (d6-DMSO) 2.25 (3H s) 2.32 (3H s) 5.12 (2H s) 7.09–7.25 (7H, m).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[C:6]([F:11])[C:3]=1[C:4]#[N:5].[H-].[Na+].CS(O[CH2:19][CH2:20][O:21][C:22]1[CH:31]=[CH:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=1)(=O)=O>CN(C)C=O>[F:1][C:2]1[CH:9]=[C:8]([O:10][CH2:19][CH2:20][O:21][C:22]2[CH:31]=[CH:30][C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=2)[CH:7]=[C:6]([F:11])[C:3]=1[C:4]#[N:5]
Reactant: CS(=O)(=O)OCCOc1ccc2ccccc2c1
Reactant: N#Cc1c(F)cc(O)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1c(F)cc(OCCOc2ccc3ccccc3c2)cc1F
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 69 %

Procedure:
A stirred mixture of 2,6-difluoro-4-hydroxybenzonitrile (3 g) in dimethylformamide (30 mL) under argon was treated with 55% sodium hydride (0.842 g), stirred for 30 minutes and treated with 2-(2-naphthalenyloxy)ethyl methanesulfonate (5.1 g). The mixture was heated at 60° C. overnight and evaporated to dryness. The residue was mixed with water and excess sodium hydroxide solution, the product was extracted twice with dichloromethane, and the organic layers were washed with water. The combined organic layers were dried (Na2SO4), filtered, and evaporated. The crude material was purified by HPLC (dichloromethane-hexane 2:1) and crystallized from dichloromethane-hexane to provide 4.3 g of 2,6-difluoro-4-[2-(2-naphthalenyloxy) ethoxy]benzonitrile as a colorless solid, mp 148°-149° C.
Reaction SMILES: N#N.[CH3:3][C:4]1([C:9]2[S:13][C:12]([CH2:14]O)=[CH:11][CH:10]=2)[O:8][CH2:7][CH2:6][O:5]1.CCN(CC)CC.S([Cl:27])(C)(=O)=O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:27][CH2:14][C:12]1[S:13][C:9]([C:4]2([CH3:3])[O:8][CH2:7][CH2:6][O:5]2)=[CH:10][CH:11]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC1(c2ccc(CO)s2)OCCO1
Agent: CN(C)c1ccncc1
Agent: N#N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(c2ccc(CCl)s2)OCCO1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of [5-(2-methyl-[1,3]dioxolan-2-yl)-thiophen-2-yl]-methanol (400 mg, 2.00 mmol) in dry CH2Cl2 (3.7 mL) was treated at 0° C. with Et3N (0.36 mL, 2.60 mmol) followed by DMAP (24 mg, 0.20 mmol) and Ms-Cl (0.19 mL, 2.40 mmol). The reaction mixture was stirred at rt for 2 h before being quenched with water (5 mL), extracted with CH2Cl2 (10 mL) and the combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure to give crude 2-(5-chloromethyl-thiophen-2-yl)-2-methyl-[1,3]dioxolane as an orange oil. A solution of the crude material in acetone (5.0 mL) was treated, under inert atmosphere (N2) with K2CO3 (829 mg, 6.00 mmol) followed by 5-nitro-1H-pyrazole (226 mg, 2.00 mmol) and TBA bromide (129 mg, 0.40 mmol). The resulting mixture was stirred at rt overnight. Water (15 mL) and EA (20 mL) were added. The aq. layer was extracted with EA (20 mL) and the combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (60:40 hept-EA) gave the title compound as a yellow oil. TLC: rf (60:40 hept-EA)=0.24. LC-MS-conditions 02: tR=0.96 min; [M+H]+=296.20.
Reaction SMILES: [CH2:1]([NH:5][C:6](=[O:10])[C@H:7]([CH3:9])[NH2:8])[CH:2]([CH3:4])[CH3:3].[F:11][C:12]1[CH:13]=[C:14]([CH2:19][C@H:20]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[C@H:21]2[CH2:23][O:22]2)[CH:15]=[C:16]([F:18])[CH:17]=1>C(O)(C)C>[C:27]([O:26][C:25](=[O:31])[NH:24][CH:20]([CH2:19][C:14]1[CH:13]=[C:12]([F:11])[CH:17]=[C:16]([F:18])[CH:15]=1)[CH:21]([OH:22])[CH2:23][NH:8][CH:7]([C:6](=[O:10])[NH:5][CH2:1][CH:2]([CH3:4])[CH3:3])[CH3:9])([CH3:28])([CH3:29])[CH3:30]
Reactant: CC(C)CNC(=O)[C@H](C)N
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cc(F)cc(F)c1)[C@H]1CO1
Solvent: CC(C)O
Product: CC(C)CNC(=O)C(C)NCC(O)C(Cc1cc(F)cc(F)c1)NC(=O)OC(C)(C)C

Procedure:
N1-Isobutyl-L-alaninamide (3.8 g, 26 mmol) and tert-butyl (1S)-2-(3,5-difluorophenyl)-1-[(2S)-oxiran-2-yl]ethylcarbamate prepared by the method in Example S-3 (3.1 g, 10.4 mmol) in isopropanol (50 mL) are refluxed 4 h. The reaction is cooled and concentrated under reduced pressure. Purification by flash column chromatography (silica, 8% methanol/chloroform) gives the title compound. ESI MS m/z 444.1 [M+H]+.
Reaction SMILES: [CH:1]1([C:4]2[S:8][C:7]([N:9]=[C:10]=[O:11])=[N:6][N:5]=2)[CH2:3][CH2:2]1.[CH2:12]([NH:17][CH:18]([CH2:21][O:22][CH3:23])[CH:19]=[O:20])[CH2:13][CH2:14][CH2:15][CH3:16]>C1C=CC=CC=1>[CH2:12]([N:17]([CH:18]([CH2:21][O:22][CH3:23])[CH:19]=[O:20])[C:10]([NH:9][C:7]1[S:8][C:4]([CH:1]2[CH2:3][CH2:2]2)=[N:5][N:6]=1)=[O:11])[CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: O=C=Nc1nnc(C2CC2)s1
Reactant: CCCCCNC(C=O)COC
Solvent: c1ccccc1
Product: CCCCCN(C(=O)Nc1nnc(C2CC2)s1)C(C=O)COC

Procedure:
5-Cyclopropyl-1,3,4-thiadiazol-2-yl isocyanate dimer (0.05 mole), the dimethyl acetal of 2-pentylamino-3-methoxypropionaldehyde (0.1 mole) and benzene (60 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture is heated at reflux for a period of about 30 minutes. After this time the mixture is stripped of benzene under reduced pressure to yield a solid product as the residue. This residue is then recrystallized to yield the desired product the dimethyl acetal of 2-[1-pentyl-3-(5-cyclopropyl-1,3,4-thiadiazol-2-yl)-ureido]-3-methoxypropionaldehyde.
Reaction SMILES: CO[C:3](=[O:25])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=3)=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1.[NH2:26][CH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>>[F:24][C:20]1[CH:19]=[C:18]([C:13]2[C:12]([CH2:11][O:10][C:7]3[CH:8]=[CH:9][C:4]([C:3]([NH:26][CH:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)=[O:25])=[CH:5][N:6]=3)=[C:16]([CH3:17])[O:15][N:14]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: COC(=O)c1ccc(OCc2c(-c3cccc(F)c3)noc2C)nc1
Reactant: NC1CCOCC1
Product: Cc1onc(-c2cccc(F)c2)c1COc1ccc(C(=O)NC2CCOCC2)cn1
Yield: 85 %

Procedure:
As described for example 92, 6-[3-(3-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (103 mg, 0.3 mmol) was converted, using 4-aminotetrahydropyran instead of cyclopropylamine, to the title compound (105 mg, 85%) which was obtained as a white solid. MS: m/e=412.5 [M+H]+.
Reaction SMILES: Br.[NH2:2][C:3]1[S:4][CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][NH:16]C(=O)C(F)(F)F)=[CH:10][CH:9]=2)[N:7]=1.[OH-].[Na+]>CO.O>[NH2:16][CH2:15][CH2:14][C:11]1[CH:10]=[CH:9][C:8]([C:6]2[N:7]=[C:3]([NH2:2])[S:4][CH:5]=2)=[CH:13][CH:12]=1
Reactant: Nc1nc(-c2ccc(CCNC(=O)C(F)(F)F)cc2)cs1
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: NCCc1ccc(-c2csc(N)n2)cc1
Yield: 92 %

Procedure:
4-{4-(2-Aminoethyl)phenyl}-2-thiazolamine: A solution of N-{2-{4-(2-bromoacetyl)phenyl}ethyl}-2,2,2-trifluoroacetamide (5.55 g, 16.4 mmol), prepared in Example 1(b), and thiourea (1.25 g, 16.4 mmol) in isopropanol (60 mL) was heated at reflux for 1 h. The reaction mixture was concentrated under reduced pressure to give crude N-{2-{4-(2-amino-4-thiazolyl)phenyl}ethyl}-2,2,2-trifluoroacetamide hydrobromide (6.51 g, ~100% yield). A solution of the crude hydrobromide and aqueous 4N NaOH (14.3 mL, 57.4 mmol) in MeOH (70 mL) and H2O (10 mL) was heated at reflux for 20 min. The solution was cooled, H2O (30 mL) was added and the MeOH was carefully evaporated under reduced pressure while keeping the solution cool. The resulting suspension was cooled to 0°. The crystals obtained by filtration were washed with cold H2O then air-dried to give 4-{4-(2-aminoethyl)phenyl}-2-thiazolamine (3.3 g, 92% yield): 1H NMR (DMSO-d6) δ 7.69 (d, J=8.2 Hz, 2H), 7.18 (d, J=8.2 Hz, 2H), 7.03 (broad s, 2H), 6.92 (s, 1H), 2.76 (t, J=7.1 Hz, 2H), 2.62 (t, J=7.1 Hz, 2H).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[C:14]([C:15]([NH2:17])=[O:16])=[CH:13][N:12]=[C:11](S(C)(=O)=O)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=1.[F-].[K+].C(=O)(O)[O-].[Na+]>O.CN1C(=O)CCC1>[CH2:1]([NH:8][C:9]1[C:14]([C:15]([NH2:17])=[O:16])=[CH:13][N:12]=[C:11]([NH:30][C:27]2[CH:28]=[CH:29][C:24]([O:23][CH3:22])=[CH:25][CH:26]=2)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)c1ncc(C(N)=O)c(NCc2ccccc2)n1
Reactant: COc1ccc(N)cc1
Agent: O=C([O-])O
Agent: [F-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: COc1ccc(Nc2ncc(C(N)=O)c(NCc3ccccc3)n2)cc1
Temperature: 95 °C
Reaction time: 21 h
Yield: 24 %

Procedure:
A 5 ml portion of NMP solution containing 300 mg of 4-benzylamino-2-(methylsulfonyl)pyrimidine-5-carboxamide was mixed with 122 mg of p-anisidine and 58 mg of potassium fluoride, followed by stirring at 90 to 100° C. for 21 hours. During this period, 58 mg of potassium fluoride was added three times. The reaction mixture was cooled down to room temperature, diluted with water, mixed with saturated sodium bicarbonate aqueous solution and then extracted with ethyl acetate. The organic layer was washed with saturated brine, and then the solvent was evaporated. The resulting residue was purified by a silica gel column chromatography (chloroform:methanol) and then recrystallized (methanol-THF) to obtain 82 mg of 4-benzylamino-2-[(4-methoxyphenyl)amino]pyrimidine-5-carboxamide as colorless crystals.
Reaction SMILES: Br[C:2]1[CH:19]=[CH:18][C:5]2[CH2:6][N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1.[NH:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.CC(C)([O-])C.[Na+]>O1CCOCC1.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].O>[N:20]1([C:2]2[CH:19]=[CH:18][C:5]3[CH2:6][N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:8][CH2:9][O:10][C:4]=3[CH:3]=2)[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: CC(C)(C)OC(=O)N1CCOc2cc(Br)ccc2C1
Reactant: C1CCNC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCOc2cc(N3CCCC3)ccc2C1
Yield: 37.8 %

Procedure:
A solution of tert-butyl 8-bromo-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (300 mg, 0.915 mmol), pyrrolidine (0.250 ml, 3.00 mmol), X-phos (26.1 mg, 0.0546 mmol), tris(dibenzylideneacetone)dipalladium(0) (16.6 mg, 0.00187 mmol) and sodium tert-butoxide (131 mg, 1.37 mmol) in dioxane (6 ml) was stirred under an argon atmosphere for 1 hr at 80° C. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by NH silica gel column chromatography (hexane:ethyl acetate=1:1) to give the desired product (110 mg, 37.8%) as an oil.
Reaction SMILES: [OH:1][CH:2]([C:18]1[N:19](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:20]=[CH:21][N:22]=1)[CH:3]1[C:16](=[O:17])[N:7]2[C:8]3[C:13]([C:14]([CH3:15])=[C:6]2[CH2:5][CH2:4]1)=[CH:12][CH:11]=[CH:10][CH:9]=3>C(O)(=O)C.O>[OH:1][CH:2]([C:18]1[NH:22][CH:21]=[CH:20][N:19]=1)[CH:3]1[C:16](=[O:17])[N:7]2[C:8]3[C:13]([C:14]([CH3:15])=[C:6]2[CH2:5][CH2:4]1)=[CH:12][CH:11]=[CH:10][CH:9]=3
Reactant: Cc1c2n(c3ccccc13)C(=O)C(C(O)c1nccn1C(c1ccccc1)(c1ccccc1)c1ccccc1)CC2
Solvent: CC(=O)O
Solvent: O
Product: Cc1c2n(c3ccccc13)C(=O)C(C(O)c1ncc[nH]1)CC2
Yield: 71.7 %

Procedure:
A solution of 8,9-dihydro-7-[(hydroxy)(1-trityl-1H-imidazol-2-yl)methyl]-10-methylpyrido[1,2-a]indol-6(7H)-one (376 mg) in acetic acid (15 ml) and water (5 ml) was stirred at 60° C. for 2.5 hours. After evaporation of the solvent, the residue was diluted with water, neutralized with an aqueous solution of sodium hydrogencarbonate, and extracted three times with chloroform. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and evaporated in vacuo. Purification of the residue with silica gel column chromatography (15% methanol-chloroform), followed by recrystallization from methanol, gave 8,9-dihydro-7-[(hydroxy)(1H-imidazol-2-yl)-methyl]-10-methylpyrido[1,2-a]indol-6(7H)-one (148 mg).
Reaction SMILES: Br[CH2:2][C:3]1[N:4]([CH3:28])[C:5]2[C:10]([N:11]=1)=[C:9]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[N:8]=[C:7]([N:18]1[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[N:20]=[C:19]1[CH3:27])[N:6]=2.[O:29]1[CH2:34][CH2:33][CH:32]([NH2:35])[CH2:31][CH2:30]1>>[CH3:28][N:4]1[C:3]([CH2:2][NH:35][CH:32]2[CH2:33][CH2:34][O:29][CH2:30][CH2:31]2)=[N:11][C:10]2[C:5]1=[N:6][C:7]([N:18]1[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[N:20]=[C:19]1[CH3:27])=[N:8][C:9]=2[N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: NC1CCOCC1
Reactant: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CBr)n(C)c2n1
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CNC3CCOCC3)n(C)c2n1

Procedure:
4-(8-(Bromomethyl)-9-methyl-2-(2-methyl-1H-benzo[d]imidazol-1-yl)-9H-purin-6-yl)morpholine (50 mg) was reacted with tetrahydro-2H-pyran-4-amine via General Procedure E to give 8.6 mg of 288 following reverse phase purification. MS (Q1) 463.2 (M)+
Reaction SMILES: FC(F)(F)C(O)=O.C([SiH](CC)CC)C.[F:15][C:16]1[CH:21]=[C:20]([C@H:22]2[CH2:27][CH2:26][C@H:25]([C@H:28]3[CH2:33][CH2:32][C@H:31]([CH2:34][CH2:35][CH3:36])[CH2:30][CH2:29]3)[CH2:24][CH2:23]2)[CH:19]=[C:18]([F:37])[C:17]=1[C:38](=O)[C@@H:39]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[CH3:40].[OH-].[Na+]>ClCCCl>[F:15][C:16]1[CH:21]=[C:20]([C@H:22]2[CH2:27][CH2:26][C@H:25]([C@H:28]3[CH2:29][CH2:30][C@H:31]([CH2:34][CH2:35][CH3:36])[CH2:32][CH2:33]3)[CH2:24][CH2:23]2)[CH:19]=[C:18]([F:37])[C:17]=1[CH2:38][C@@H:39]([C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1)[CH3:40]
Reactant: CCC[C@H]1CC[C@H]([C@H]2CC[C@H](c3cc(F)c(C(=O)[C@H](C)c4ccccc4)c(F)c3)CC2)CC1
Agent: CC[SiH](CC)CC
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Product: CCC[C@H]1CC[C@H]([C@H]2CC[C@H](c3cc(F)c(C[C@H](C)c4ccccc4)c(F)c3)CC2)CC1
Temperature: 60 °C
Reaction time: 10 h

Procedure:
Then, 5 ml of trifluoroacetic acid and 2.6 g (23 mmol) of triethylsilane were added to a 1,2-dichloroethane 8 ml solution of 4.1 g (9.1 mmol) of (R)-1-[2,6-difluoro-4-[trans-4-(trans-4-propylcyclohexyl)cyclohexyl]phenyl]-2-phenyl-1-propanone at room temperature, followed by stirring at 60° C. for 10 hours. This reaction liquid was poured into 200 ml of a 5% sodium hydroxide solution, and after extraction with toluene, washing with water, drying, distillation of the solvent, recrystallization and purification by silica gel column chromatography were carried out to obtain 2.5 g of aimed (S)-1-[2,6-difluoro-4-[trans-4-(trans-4-propylcyclohexyl)cyclohexyl]phenyl]-2-phenylpropane.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[C:4]([S:11]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)(=[O:13])=[O:12])[N:3]=1.[CH3:23]N>O1CCOCC1.C(O)C>[Br:1][C:2]1[CH:7]=[C:6]([NH:8][CH3:23])[CH:5]=[C:4]([S:11]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)(=[O:13])=[O:12])[N:3]=1
Reactant: CN
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)c2cc([N+](=O)[O-])cc(Br)n2)cc1
Solvent: CCO
Solvent: C1COCCO1
Product: CNc1cc(Br)nc(S(=O)(=O)c2ccc([N+](=O)[O-])cc2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 68 %

Procedure:
0.10 g (0.00026 mol) of 2-bromo-4-nitro-6-(4-nitrobenzenesulphonyl)-pyridine was dissolved in 3.2 ml of dioxane and treated with 3.2 ml of 8M methylamine in ethanol. The mixture was stirred at room temperature for 3 hrs., the solvents were removed and the residue was chromatographed on silica gel with ethyl acetate/hexane 1:4. There was obtained 0.065 g (68%) of [2-bromo-6-(4-nitrobenzenesulphonyl)-pyridin-4-yl]-methylamine as pale yellow crystals; m.p.: 191-192° C.