Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si](OCCN1[CH2:15][C@H:14]([CH:16]([CH3:18])[CH3:17])[N:13]([C:19]2[CH:24]=[CH:23][N:22]3[N:25]=[CH:26][C:27]([C:28]4[CH:33]=[CH:32][C:31]([C:34]5[N:35](COCC[Si](C)(C)C)[CH:36]=[CH:37][N:38]=5)=[CH:30][CH:29]=4)=[C:21]3[N:20]=2)[C:12]1=[O:47])(C(C)(C)C)(C)C.FC(F)(F)C(O)=[O:51]>ClCCl>[NH:35]1[CH:36]=[CH:37][N:38]=[C:34]1[C:31]1[CH:32]=[CH:33][C:28]([C:27]2[CH:26]=[N:25][N:22]3[CH:23]=[CH:24][C:19]([N:13]4[C@@H:14]([CH:16]([CH3:18])[CH3:17])[CH2:15][O:47][C:12]4=[O:51])=[N:20][C:21]=23)=[CH:29][CH:30]=1
Reactant: CC(C)[C@H]1CN(CCO[Si](C)(C)C(C)(C)C)C(=O)N1c1ccn2ncc(-c3ccc(-c4nccn4COCC[Si](C)(C)C)cc3)c2n1
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)[C@H]1COC(=O)N1c1ccn2ncc(-c3ccc(-c4ncc[nH]4)cc3)c2n1
Reaction time: 0.17 h
Yield: 52 %

Procedure:
A solution of (S)-1-(2-(tert-butyldimethylsilyloxy)ethyl)-4-isopropyl-3-(3-(4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)phenyl)pyrazolo[1,5-a]pyrimidin-5-yl)imidazolidin-2-one (15 mg, 0.022 mmol) in dichloromethane (0.3 mL) and trifluoroacetic acid (0.3 mL) was stirred at ambient temperature for 24 hours. The solvents were evaporated, and the residue was taken up in MeOH. A few drops of 1N LiOH solution was added. The mixture was stirred for 10 minutes. The reaction mixture was diluted with water and extracted with dichloromethane. The combined organic layers were washed with brine, dried and concentrated. The residue was purified by column chromatography (12% MeOH in dichloromethane) to give (S)-3-(3-(4-(1H-imidazol-2-yl)phenyl)pyrazolo[1,5-a]pyrimidin-5-yl)-4-isopropyloxazolidin-2-one (5 mg, 52%) as a pale yellow solid. 1H NMR (400 MHz, CD3OD) δ 8.66 (d, J=7.6 Hz, 1H), 8.47 (s, 1H), 8.18 (d, J=8.4 Hz, 2H), 8.13 (d, J=8.0 Hz, 1H), 7.90 (d, J=8.4 Hz, 2H), 7.16 (s, 2H), 3.2-3.8 (m, 7H), 2.91 (m, 1H), 1.12 (d, 3H), 0.89 (d, 3H). LCMS (APCI+) m/z 432.3 [M+H]
Reaction SMILES: C1(S([N:10]2[CH:14]=[C:13]([C:15]([C:17]3[CH:22]=[C:21]([O:23][CH3:24])[C:20]([O:25][CH3:26])=[C:19]([O:27][CH3:28])[CH:18]=3)=[O:16])[N:12]=[C:11]2[C:29]2[CH:30]=[C:31]3[C:35](=[CH:36][CH:37]=2)[N:34](S(C2C=CC=CC=2)(=O)=O)[C:33]([C:47](=[O:60])[C:48]2[CH:53]=[C:52]([O:54][CH3:55])[C:51]([O:56][CH3:57])=[C:50]([O:58][CH3:59])[CH:49]=2)=[CH:32]3)(=O)=O)C=CC=CC=1.[OH-].[Na+].O>C(O)C>[CH3:24][O:23][C:21]1[CH:22]=[C:17]([CH:18]=[C:19]([O:27][CH3:28])[C:20]=1[O:25][CH3:26])[C:15]([C:13]1[N:12]=[C:11]([C:29]2[CH:30]=[C:31]3[C:35](=[CH:36][CH:37]=2)[NH:34][C:33]([C:47]([C:48]2[CH:49]=[C:50]([O:58][CH3:59])[C:51]([O:56][CH3:57])=[C:52]([O:54][CH3:55])[CH:53]=2)=[O:60])=[CH:32]3)[NH:10][CH:14]=1)=[O:16]
Reactant: COc1cc(C(=O)c2cn(S(=O)(=O)c3ccccc3)c(-c3ccc4c(c3)cc(C(=O)c3cc(OC)c(OC)c(OC)c3)n4S(=O)(=O)c3ccccc3)n2)cc(OC)c1OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1cc(C(=O)c2c[nH]c(-c3ccc4[nH]c(C(=O)c5cc(OC)c(OC)c(OC)c5)cc4c3)n2)cc(OC)c1OC
Reaction time: 8 h
Yield: 30 %

Procedure:
To a solution of (1-(phenylsulfonyl)-2-(1-(phenylsulfonyl)-2-(3,4,5-trimethoxybenzoyl)-1H-indol-5-yl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone (16xaa) (1 mmol) in ethanol (20 mL) was added sodium hydroxide (10 equiv) and stirred overnight in darkness. The reaction mixture was diluted by 50 mL of water and extracted by ethyl acetate (250 mL). The organic layer was dried over magnesium sulfate and concentrated. The residue was purified by flash column chromatography (hexane:ethyl acetate 3:1) or recrystallized from water and methanol to give a white solid. Yield: 30-95%.
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]=[C:13]([C:15]3[O:19][N:18]=[C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:16]=3[C:26]([F:29])([F:28])[F:27])[O:12][N:11]=2)=[C:6]([C:30]([F:33])([F:32])[F:31])[CH:5]=1.[NH:34]1[CH2:39][CH2:38][CH2:37][C@H:36]([C:40]([O:42]CC)=[O:41])[CH2:35]1>CCO>[OH:1][CH:2]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]=[C:13]([C:15]3[O:19][N:18]=[C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:16]=3[C:26]([F:28])([F:27])[F:29])[O:12][N:11]=2)=[C:6]([C:30]([F:32])([F:31])[F:33])[CH:5]=1)[CH2:3][N:34]1[CH2:39][CH2:38][CH2:37][C@H:36]([C:40]([OH:42])=[O:41])[CH2:35]1
Reactant: CCOC(=O)[C@H]1CCCNC1
Reactant: FC(F)(F)c1cc(C2CO2)ccc1-c1noc(-c2onc(-c3ccccc3)c2C(F)(F)F)n1
Solvent: CCO
Product: O=C(O)[C@H]1CCCN(CC(O)c2ccc(-c3noc(-c4onc(-c5ccccc5)c4C(F)(F)F)n3)c(C(F)(F)F)c2)C1
Temperature: 80 °C
Yield: 37.6 %

Procedure:
To a mixture of 3-(4-(oxiran-2-yl)-2-(trifluoromethyl)phenyl)-5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazole (50 mg, 0.107 mmol) in EtOH (5 mL) was added (S)-ethyl piperidine-3-carboxylate (50.5 mg, 0.321 mmol). The reaction mixture was heated at 80° C. overnight and solvents were removed in vacuo. The mixture was treated with 6N HCl in MeCN at 50° C. for 24 h. The reaction mixture was filtered and purified by HPLC. HPLC conditions: PHENOMENEX® Luna C18 5 micron column (250×30 mm); 25-100% CH3CN/water (0.1% TFA); 25 minute gradient; 30 mL/min. Isolated fractions with correct mass were freeze-dried overnight to yield 24 mg of (3S)-1-(2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)-3-(trifluoromethyl)phenyl)ethyl)piperidine-3-carboxylic acid as a TFA salt. 1H NMR (400 MHz, MeOH-d3) δ ppm 7.99-8.06 (1H, m), 7.91-7.96 (1H, m), 7.81-7.90 (1H, m), 7.59 (2H, d, J=6.59 Hz), 7.44-7.56 (3H, m), 3.69-4.04 (1H, m), 3.34-3.64 (3H, m), 3.26-3.35 (2H, m), 2.72-3.14 (2H, m), 2.00-2.22 (1H, m), 1.75-2.00 (2H, m), 1.56 (1H, t, J=12.81 Hz). MS (m+1)=597. HPLC Peak RT=3.4 minutes (Analytical Method A). Purity=92%.
Reaction SMILES: [Si:1]([O:18][CH2:19][C@@H:20]1[N:24]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:23](=O)[CH:22]([CH2:33][Sn](C)(C)C)[CH2:21]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O.C([O-])([O-])=O.[K+].[K+]>C1COCC1.C(Cl)Cl>[Si:1]([O:18][CH2:19][CH:20]1[CH2:21][CH:22]2[CH:23]([CH2:33]2)[N:24]1[C:25]([O:27][C:28]([CH3:30])([CH3:29])[CH3:31])=[O:26])([C:14]([CH3:15])([CH3:17])[CH3:16])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(C)(C)OC(=O)N1C(=O)C(C[Sn](C)(C)C)C[C@@H]1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CC2CC21
Temperature: 0 °C
Reaction time: 2 h
Yield: 67.8 %

Procedure:
To a solution of (5R)-tert-butyl 5-(((tert-butyldiphenylsilyl)oxy)methyl)-2-oxo-3-((trimethylstannyl)methyl)pyrrolidine-1-carboxylate (D30) (3.1 g, 6.86 mmol) in THF (200 ml) cooled at −78° C., LiEt3BH 1M sol in THF (17.2 ml) was added dropwise. The reaction was left at −78° C. for 2 hrs then water (50 ml) and the reaction extracted with Et2O (3×100 ml). The organic phases were combined, dried over Na2SO4 and evaporated in vacuo to afford a residue which was dissolved in DCM (120 ml) and cooled at 0° C. TFA (1.31 ml, 17.2 mmol) was added and the reaction was stirred 10 min at this temperature. K2CO3 sat sol (100 ml) was added and the mixture extracted with DCM (3×100 ml). The organic phases were collected, dried over Na2SO4 and evaporated in vacuo to afford a residue which was purified by BiotageSNAP-Si column (50 g) eluting with a mixture cHex/EtOAc 95/5. Collected fractions after solvent evaporation afforded the title compound (D31) (2.1 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:79])[CH2:7][N:8]([CH2:71][C:72](=[O:78])[O:73][C:74]([CH3:77])([CH3:76])[CH3:75])[C:9](=[O:70])[CH2:10][N:11]1[CH:15]=[CH:14][N:13]=[C:12]1[CH2:16][N:17]([CH2:59][C:60]1[CH:65]=[CH:64][C:63]([O:66][CH2:67][C:68]#[CH:69])=[CH:62][CH:61]=1)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23](=[O:58])[NH:24][CH2:25][CH2:26][CH2:27][CH2:28][C@@H:29]([C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[NH:30][C:31](=[O:50])[NH:32][C@H:33]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:34][CH2:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])([CH3:4])([CH3:3])[CH3:2].[N:80]([CH2:83][CH2:84][CH2:85][NH2:86])=[N+:81]=[N-:82]>C1COCC1.O.C(Cl)Cl.[Cu].[O-]S([O-])(=O)=O.[Cu+2]>[NH2:86][CH2:85][CH2:84][CH2:83][N:80]1[CH:69]=[C:68]([CH2:67][O:66][C:63]2[CH:62]=[CH:61][C:60]([CH2:59][N:17]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23](=[O:58])[NH:24][CH2:25][CH2:26][CH2:27][CH2:28][C@@H:29]([C:51]([O:53][C:54]([CH3:55])([CH3:56])[CH3:57])=[O:52])[NH:30][C:31](=[O:50])[NH:32][C@H:33]([C:43]([O:45][C:46]([CH3:47])([CH3:48])[CH3:49])=[O:44])[CH2:34][CH2:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:16][C:12]3[N:11]([CH2:10][C:9]([N:8]([CH2:7][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:79])[CH2:71][C:72](=[O:78])[O:73][C:74]([CH3:77])([CH3:76])[CH3:75])=[O:70])[CH:15]=[CH:14][N:13]=3)=[CH:65][CH:64]=2)[N:82]=[N:81]1
Reactant: C#CCOc1ccc(CN(CCCCCC(=O)NCCCC[C@H](NC(=O)N[C@@H](CCC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)Cc2nccn2CC(=O)N(CC(=O)OC(C)(C)C)CC(=O)OC(C)(C)C)cc1
Reactant: [N-]=[N+]=NCCCN
Agent: [Cu+2]
Agent: [Cu]
Agent: O=S(=O)([O-])[O-]
Solvent: C1CCOC1
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CC[C@H](NC(=O)N[C@@H](CCCCNC(=O)CCCCCN(Cc1ccc(OCc2cn(CCCN)nn2)cc1)Cc1nccn1CC(=O)N(CC(=O)OC(C)(C)C)CC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 24.7 %

Procedure:
To a solution of (14S,18S)-tri-tert-butyl 1-(1-(2-(bis(2-(tert-butoxy)-2-oxoethyl)amino)-2-oxoethyl)-1H-imidazol-2-yl)-8,16-dioxo-2-(4-(prop-2-yn-1-yloxy)benzyl)-2,9,15,17-tetraazaicosane-14,18,20-tricarboxylate (65 mg, 0.0586 mmol) and 3-azidopropan-1-amine (200 mg, 2.0 mmol) in THF (2.0 mL) and water (0.5 mL) was added copper powder (10 mg) and 1 N CuSO4 (0.05 mL). The mixture was stirred at room temperature for 2 h under nitrogen, diluted with DCM and washed with an aqueous saturated solution of EDTA. The solvent was evaporated under reduce pressure to afford a residue, which was purified by Biotage SP4 to afford (14S,18S)-tri-tert-butyl 2-(4-((1-(3-aminopropyl)-1H-1,2,3-triazol-4-yl)methoxy)benzyl)-1-(1-(2-(bis(2-(tert-butoxy)-2-oxoethyl)amino)-2-oxoethyl)-1H-imidazol-2-yl)-8,16-dioxo-2,9,15,17-tetraazaicosane-14,18,20-tricarboxylate (17.5 mg, 25%). MS (ESI), 605.8 (M/2+H)′.
Reaction SMILES: [H-].[Na+].[CH3:3][S:4]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[NH:14][CH:15]=[CH:16][C:17]=2[C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)=[CH:9][CH:8]=1)(=[O:6])=[O:5].[C:25](Cl)(=[O:27])[CH3:26]>CN(C=O)C>[C:25]([N:14]1[CH:15]=[CH:16][C:17]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)=[C:13]1[C:10]1[CH:9]=[CH:8][C:7]([S:4]([CH3:3])(=[O:5])=[O:6])=[CH:12][CH:11]=1)(=[O:27])[CH3:26]
Reactant: CC(=O)Cl
Reactant: CS(=O)(=O)c1ccc(-c2[nH]ccc2-c2ccc(F)cc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)n1ccc(-c2ccc(F)cc2)c1-c1ccc(S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 25 %

Procedure:
A suspension of sodium hydride (2.64 g, 0.11 mole) in 100 ml dry N,N'-dimethylformamide was heated dropwise with a solution of 2-(4-methylsulfonylphenyl)-3-(4-fluorophenyl)-1H-pyrrole (31.56 g, 0.1 mole) in 200 ml dry N,N'-dimethylformamide and stirred for one hour at room temperature. The mixture was then treated dropwise with acetyl chloride (7.9 g, 0.1 mole). The mixture was stirred for three hours and concentrated in vacuo. The residue was triturated with water, collected by filtration, dried, and column chromatographed on silica gel with toluene-ethyl acetate (3:2) as the mobile phase. The product was collected in 25% yield; m.p. 211°-214°.
Reaction SMILES: [C:1]1([CH2:7][CH:8]=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:10]1([CH2:16][CH2:17][NH2:18])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1>[CH2:8]([NH:18][CH2:17][CH2:16][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NCCc1ccccc1
Reactant: O=CCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Product: c1ccc(CCNCCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 11 %

Procedure:
To a solution of phenylacetaldehyde (6.0 g, 50 mmol) and 2-phenylethylamine in THF (200 mL) is added sodium triacetoxy-borohydride drop wise. The solution is stirred under nitrogen overnight at room temperature. The solution is quenched with aq. saturated sodium bicarbonate (200 mL), and extracted with EtOAc (4×100 mL). The organic extracts are combined, dried and concentrated under vacuum. The residue is purified by flash chromatography (silica gel; EtOAc/MeOH 9:1) to provide 1.25 g (11%) of the compound D as a clear oil. M+H+=226.10.
Reaction SMILES: I[C:2]1[CH:10]2[CH:5]([N:6]=[CH:7][N:8]=[C:9]2[NH:11][CH3:12])[N:4]([CH2:13][CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH:3]=1.COC(O)C(O)OC.[OH:30][C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][CH:36]=1.C(=O)([O-])[O-].[Na+].[Na+]>>[OH:30][C:31]1[CH:36]=[C:35]([C:2]2[CH:10]3[CH:5]([N:6]=[CH:7][N:8]=[C:9]3[NH:11][CH3:12])[N:4]([CH2:13][CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH:3]=2)[CH:34]=[CH:33][CH:32]=1
Reactant: OB(O)c1cccc(O)c1
Reactant: CNC1=NC=NC2C1C(I)=CN2CCC(=O)OC(C)(C)C
Agent: COC(O)C(O)OC
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CNC1=NC=NC2C1C(c1cccc(O)c1)=CN2CCC(=O)OC(C)(C)C
Reaction time: 8 h

Procedure:
t-butyl 3-(5-iodo-4-(methylamino)-4aH-pyrrolo[2,3-d]pyrimidin-7(7aH)-yl)propanoate (123 mmol) from above was placed in a 25 ml round bottom flask, whereupon 3.1 ml dimethoxy ethyleneglycol was added. 3-Hydroxyphenylboronic acid (492 mmol pre-dissolved in 0.66 ml ethanol) was added at once, and was followed by 0.5 ml saturated aqueous sodium carbonate. Pd0(PPh3)4 (14 mg, 12 umol) was added to the reaction, the vessel was purged with argon, and set to stir at 80 C overnight. The reaction was subsequently cooled, and filtered through a bed of celite. The filtrate was evaporated in vacuo, and the residual material was adhered to silica gel using ethyl acetate as solvent. Silica gel chromatography (ethyl acetate:hexanes) and evaporation in vacuo of the requisite fractions yielded the desired product. MS m/z=369.22.
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9](Cl)[C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[N:17]1[CH:22]=[CH:21][CH:20]=[C:19](B(O)O)[CH:18]=1>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]([C:5]1[N:10]=[C:9]([C:19]2[CH:18]=[N:17][CH:22]=[CH:21][CH:20]=2)[C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1cnc(C(C)(C)C)nc1Cl
Reactant: OB(O)c1cccnc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: CCOC(=O)c1cnc(C(C)(C)C)nc1-c1cccnc1
Yield: 28.3 %

Procedure:
Using a procedure analogous to Example B41, ethyl 2-tert-butyl-4-chloropyrimidine-5-carboxylate from Example B40 (0.30 g, 1.24 mmol) and pyridin-3-ylboronic acid (1.8 g, 1.48 mmol) in presence of tetrakis(triphenylphosphine)palladium(0) (71 mg, 0.062 mmol) were combined to afford ethyl 2-tert-butyl-4-(pyridin-3-yl)pyrimidine-5-carboxylate (0.10 g, 28% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[C:13]([F:15])[C:12]([N:16]2[C:21](=[O:22])[CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[N:18]([CH3:27])[C:17]2=[O:28])=[CH:11][C:3]=1[O:4][C:5]1([C:8]([OH:10])=O)[CH2:7][CH2:6]1.S(Cl)([Cl:31])=O>>[Cl:1][C:2]1[CH:14]=[C:13]([F:15])[C:12]([N:16]2[C:21](=[O:22])[CH:20]=[C:19]([C:23]([F:26])([F:24])[F:25])[N:18]([CH3:27])[C:17]2=[O:28])=[CH:11][C:3]=1[O:4][C:5]1([C:8]([Cl:31])=[O:10])[CH2:6][CH2:7]1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(OC3(C(=O)O)CC3)c(Cl)cc2F)c1=O
Reactant: O=S(Cl)Cl
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(OC3(C(=O)Cl)CC3)c(Cl)cc2F)c1=O

Procedure:
1.2 g of 1-[2-chloro-4-fluoro-5-{3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl}phenoxy]cyclopropanecarboxylic acid was dissolved in 12 ml of thionyl chloride and the solution was heated under reflux for 2 hours. The reaction mixture was concentrated under reduced pressure to obtain 1-[2-chloro-4-fluoro-5-{3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl}phenoxy]cyclopropanecarboxylic acid chloride.
Reaction SMILES: [C:1]([C:4]1[CH:18]=[CH:17][C:7]([O:8][CH2:9][C:10]([N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[O:11])=[CH:6][CH:5]=1)(=O)[CH3:2].[CH2:19]([NH2:22])[CH2:20][NH2:21]>C(O)(=O)C>[NH2:21][CH2:20][CH2:19][NH:22][CH:1]([C:4]1[CH:18]=[CH:17][C:7]([O:8][CH2:9][C:10]([N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[O:11])=[CH:6][CH:5]=1)[CH3:2]
Reactant: NCCN
Reactant: CC(=O)c1ccc(OCC(=O)N2CCCC2)cc1
Solvent: CC(=O)O
Product: CC(NCCN)c1ccc(OCC(=O)N2CCCC2)cc1

Procedure:
By using 2-(4-acetylphenoxy)-1-(pyrrolidin-1-yl)ethanone (250 mg), ethylenediamine (400 μl) and acetic acid (700 μl) as starting materials, the title compound (163.8 mg) was obtained in the same manner as that of Reference Example 64, (1).
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:5][CH:6]=1.C(=O)([O-])O.[Na+:15].O.O.O.O.O.O.O.S([O-])([O-])=O.[Na+].[Na+].C[O-].[Na+].CO>O>[Br:1][C:2]1[S:3][C:4]([S:7]([O-:9])=[O:8])=[CH:5][CH:6]=1.[Na+:15]
Reactant: O=S(=O)(Cl)c1ccc(Br)s1
Agent: C[O-]
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Solvent: CO
Solvent: O
Product: O=S([O-])c1ccc(Br)s1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 59 %

Procedure:
2-Bromothiophene-5-sulphonyl chloride (prepared as described in Bull. Chem. Soc. Japan, 1985,58,1063-1064)(6.5 g, 25 mmol) was added slowly to a stirred solution of sodium hydrogen carbonate (4.2 g, 50 mmol) and sodium sulphite heptahydrate (12.6 g, 50 mmol) in water (50 ml), at 70° C. The mixture was stirred at this temperature for 1.5 hours, then ice (20 g) was added, and the mixture was washed with ether (2×50 ml). The cold aqueous phase was acidified to pH 1with 2 M hydrochloric acid and extracted quickly with ether (3×50 ml). The combined extracts were dried (MgSO4) and added to a solution of sodium methoxide in methanol (prepared from sodium metal (1.7 g, 75 mmol) and methanol (25 ml)). The mixture was then evaporated to dryness to give sodium 2-bromothiophene-5-sulphinate as a white solid, which was immediately dissolved in dry DMF (25 ml) and cooled to -25 ° C. Bromonitromethane (7.0 g, 50 mmol) was then added, the cooling bath removed, and the stirred mixture irradiated with a lamp (240 watt) for 10 minutes. Ice was then added, the mixture washed with ether (3×100 ml), and the aqueous phase acidified with 2 M hydrochloric acid. The aqueous phase was then extracted with ether (3×100 ml) and the combined extracts evaporated to give an oil which was purified by chromatography on silica gel (Merck Kieselgel Art. 7734) eluting with chloroform, to give 2-bromo-5-(nitromethylsulphonyl)thiophene as a white crystalline solid (4.2 g), m.p. 103°-104° C. (after recrystallisation from ether); in 59% yield; NMR: 5.65(s,2H), 7.25(d,2H), 7.6(d,2H); m/e (electron impact) 287(M+); microanalysis, found: C,21.2; H,1.5; N,4.8%; C5H4BrNO4S2 requires: C,21.0; H,1.4; N,4.9%.
Reaction SMILES: [P:1]([O-:46])([O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][N+:42]([CH3:45])([CH3:44])[CH3:43])([O:3][CH2:4][CH:5]([OH:26])[CH2:6][O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[O:2].[CH3:47][N:48]=[C:49]=[O:50]>C(N(CC)CC)C>[P:1]([O-:46])([O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][N+:42]([CH3:45])([CH3:44])[CH3:43])([O:3][CH2:4][CH:5]([O:26][C:49](=[O:50])[NH:48][CH3:47])[CH2:6][O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[O:2]
Reactant: CCCCCCCCCCCCCCCCCCOCC(O)COP(=O)([O-])OCCCCCCCCCCCCCC[N+](C)(C)C
Reactant: CN=C=O
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCCCOCC(COP(=O)([O-])OCCCCCCCCCCCCCC[N+](C)(C)C)OC(=O)NC
Yield: 68 %

Procedure:
By following the procedure of Example 8, 661 mg of the alcohol derivative obtained in Example 25 was reacted with 2 ml of methyl isocyanate and 1 ml of triethylamine to give 485 mg (yield: 68%) of the desired product.
Reaction SMILES: [CH2:1]([C:4]1[C:5]([C:15]2[O:19][N:18]=[C:17]([C:20]3[CH:37]=[CH:36][C:23]([CH2:24][N:25]4[CH2:28][CH:27]([C:29]([O:31]C(C)(C)C)=[O:30])[CH2:26]4)=[CH:22][CH:21]=3)[N:16]=2)=[N:6][O:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)[CH2:2][CH3:3].[F:38][C:39]([F:44])([F:43])[C:40]([OH:42])=[O:41]>ClCCl>[F:38][C:39]([F:44])([F:43])[C:40]([OH:42])=[O:41].[CH2:1]([C:4]1[C:5]([C:15]2[O:19][N:18]=[C:17]([C:20]3[CH:37]=[CH:36][C:23]([CH2:24][N:25]4[CH2:28][CH:27]([C:29]([OH:31])=[O:30])[CH2:26]4)=[CH:22][CH:21]=3)[N:16]=2)=[N:6][O:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)[CH2:2][CH3:3]
Reactant: CCCc1c(-c2nc(-c3ccc(CN4CC(C(=O)OC(C)(C)C)C4)cc3)no2)noc1-c1ccccn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCc1c(-c2nc(-c3ccc(CN4CC(C(=O)O)C4)cc3)no2)noc1-c1ccccn1

Procedure:
A solution of tert-butyl 1-(4-(5-(4-propyl-5-(pyridin-2-yl)isoxazol-3-yl)-1,2,4-oxadiazol-3-yl)benzyl)azetidine-3-carboxylate in dichloromethane (0.5 mL) and trifluoroacetic acid (0.5 mL) was stirred at room temperature for 30 minutes. The reaction mixture was concentrated to yield 1-(4-(5-(4-propyl-5-(pyridin-2-yl)isoxazol-3-yl)-1,2,4-oxadiazol-3-yl)benzyl)azetidine-3-carboxylic acid trifluoroacetic acid salt (17.4 mg). The compound had an HPLC retention time=7.75 min.—Column: Xbridge Ph 3.5 u 4.6×150 mm; Gradient time: 12 min, hold for 3 minutes; Flow rate=2 ml/min; Solvent A=5% MeCN—95% Water—0.05% TFA; Solvent B=95% MeCN—5% water—0.05% TFA; Start % B=10; Final % B=100. LC-MS: M+1=446+. 1H NMR (500 MHz, MeOD) δ ppm 1.04 (t, 3H), 1.73-1.83 (m, 2H), 3.34-3.40 (m, 2H), 3.73 (t, J=8.25 Hz, 1H), 4.39 (d, J=7.42 Hz, 4H), 4.54 (s, 2H), 7.51 (ddd, J=6.74, 4.67, 2.06 Hz, 1H), 7.70 (d, J=8.25 Hz, 2H), 7.98-8.06 (m, 2H), 8.30 (d, J=8.25 Hz, 2H), and 8.78 (d, J=4.40 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4](C2CCC(F)(F)C3C=CC=CC=3N2)[CH:3]=1.ClC1C=C(Cl)C2C(=CC=C(C)C=2)N=1.[CH3:39][O:40][N:41]=[C:42]1[C:48]2[CH:49]=[CH:50][CH:51]=[CH:52][C:47]=2[CH2:46][NH:45][CH2:44][CH2:43]1.NC1(CNC2C3C(=CC=C(C)C=3)N=C(N3CC/C(=N\OC)/C4C=CC=CC=4C3)C=2)COC1>>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:45]2[CH2:44][CH2:43]/[C:42](=[N:41]\[O:40][CH3:39])/[C:48]3[CH:49]=[CH:50][CH:51]=[CH:52][C:47]=3[CH2:46]2)[CH:3]=1
Reactant: Cc1ccc2nc(C3CCC(F)(F)c4ccccc4N3)cc(Cl)c2c1
Reactant: CON=C1CCNCc2ccccc21
Agent: CO/N=C1\CCN(c2cc(NCC3(N)COC3)c3cc(C)ccc3n2)Cc2ccccc21
Agent: Cc1ccc2nc(Cl)cc(Cl)c2c1
Product: CO/N=C1\CCN(c2cc(Cl)c3cc(C)ccc3n2)Cc2ccccc21

Procedure:
The title compound was prepared in analogy to 2-(4-chloro-6-methylquinolin-2-yl)-5,5-difluoro-2,3,4,5-tetrahydro-1H-benzazepine in Example 110-1 in Scheme 56 by using 2,4-dichoro-6-methylquinoline and N-methoxy-1,2,3,4-tetrahydro-5H-2-benzazepin-5-imine. N-[(3-Aminooxetan-3-yl)methyl]-2-[(5E)-5-(methoxyimino)-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl]-6-methylquinolin-4-amine
Reaction SMILES: CON(C)[C:4](=[O:20])[CH:5]([O:18][CH3:19])[C:6]1[CH:7]=[N:8][C:9]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:10][CH:11]=1.[Br:22][C:23]1[C:28]([O:29][CH3:30])=[CH:27][C:26]([C:31]2[O:32][CH:33]=[CH:34][CH:35]=2)=[CH:25][C:24]=1[O:36][CH3:37]>>[Br:22][C:23]1[C:24]([O:36][CH3:37])=[CH:25][C:26]([C:31]2[O:32][C:33]([C:4](=[O:20])[CH:5]([O:18][CH3:19])[C:6]3[CH:7]=[N:8][C:9]([N:12]4[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]4)=[CH:10][CH:11]=3)=[CH:34][CH:35]=2)=[CH:27][C:28]=1[O:29][CH3:30]
Reactant: COC(C(=O)N(C)OC)c1ccc(N2CCCCC2)nc1
Reactant: COc1cc(-c2ccco2)cc(OC)c1Br
Product: COc1cc(-c2ccc(C(=O)C(OC)c3ccc(N4CCCCC4)nc3)o2)cc(OC)c1Br
Yield: 65 %

Procedure:
N,2-Dimethoxy-N-methyl-2-(6-(piperidin-1-yl)pyridin-3-yl)acetamide was reacted with 2-(4-bromo-3,5-dimethoxyphenyl)furan according to the procedure used for Example 12. Purification by chromatography (20-75% EtOAc-hexanes) gave 1-(5-(4-bromo-3,5-dimethoxyphenyl)furan-2-yl)-2-methoxy-2-(6-(piperidin-1-yl)pyridin-3-yl)ethanone as a light yellow solid (0.328 g, 65% yield). MS: m/z 515.4 [M+H]+.