Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.[CH2:2]([O:9][C:10]1[C:11](=[O:23])[CH:12]=[C:13]([CH:17]([OH:22])[C:18]([F:21])([F:20])[F:19])[N:14]([CH3:16])[CH:15]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>ClCCl>[CH2:2]([O:9][C:10]1[C:11](=[O:23])[CH:12]=[C:13]([CH:17]([O:22][S:32]([CH3:31])(=[O:34])=[O:33])[C:18]([F:21])([F:19])[F:20])[N:14]([CH3:16])[CH:15]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Cn1cc(OCc2ccccc2)c(=O)cc1C(O)C(F)(F)F
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cn1cc(OCc2ccccc2)c(=O)cc1C(OS(C)(=O)=O)C(F)(F)F
Reaction time: 0.17 h
Yield: 80 %

Procedure:
To a tap-water cooled suspension of 5-benzyloxy-1-methyl-2-(2,2,2-trifluoro-1-hydroxy-ethyl)-1H-pyridin-4-one (1.81 g, 5.8 mmol) in dichloromethane (95 mL) was added triethylamine (0.80 mL, 5.8 mmol) dropwise, followed by methanesulfonyl chloride (0.45 mL, 5.8 mmol). The suspension cleared and a slightly cloudy solution was obtained. The progress of the reaction was monitored by HPLC Method 1 (Example 24), which indicated about 75% conversion at this time. Another portion of triethylamine (0.30 mL, 2.1 mmol) and methanesulfonyl chloride (0.160 mL, 2.1 mmol) was added to the reaction mixture, and a bright yellow clear solution resulted. The reaction was completed within 10 min after the addition. The resulting solution was washed with a brine solution (2×50 mL). The organic layer was dried over Na2SO4, and then filtered. To the filtrate was added morpholine polymer-bound beads (1% cross-linked w/DVB, 200-400 mesh, 2.5-4.0 mmol N/g, 4.3 g), and the mixture was vortexed for 1 h. The solid morpholine beads were removed by filtration. The filtrate was evaporated to dryness, and the residual oil was taken up in dichloromethane and ethyl ether, and a solid product was obtained upon stirring. A first crop of the title compound was collected by filtration (1.80 g, 80% yield, HPLC Method 1 (Example 24); RT=15.0 min, HPLC purity (peak percent area): 99.3% at λ=280 nm). 1H NMR (DMSO-d6) δ ppm: 7.77 (s, 1H), 7.40 (m, 5H), 6.61 (q, J=6 Hz, 1H), 6.43 (s, 1H), 5.01 (s, 2H), 3.77 (s, 3H), 3.50 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH2:4][N:5]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])C(=O)CC.CN1C(=O)N(C)CCC1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH2:37]1C[O:40][CH2:39][CH2:38]1>>[CH3:1][O:2][C:3](=[O:17])[CH:4]([NH:5][C:10]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:11])[C:39](=[O:40])[CH2:38][CH3:37]
Reactant: CCC(=O)N(CC(=O)OC)C(=O)OC(C)(C)C
Reactant: C1CCOC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN1CCCN(C)C1=O
Product: CCC(=O)C(NC(=O)OC(C)(C)C)C(=O)OC
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 81 %

Procedure:
Under argon atmosphere, at −78° C., to a stirred solution of methyl-2-[tert-butoxycarbonyl-(propanoyl)-amino]-acetate (0.856 g, 3.5 mmol) in dry THF (4 mL) was initially added DMPU (0.89 g, 7.0 mmol) followed by LHMDS (1M solution in THF, 8.75 mL, 8.75 mmol) over a period of 10 min. After stirring at −78° C. for 1.5 h, the reaction mixture was quenched with saturated NH4Cl solution and extracted with AcOEt (3×15 mL). The organic layer was washed with H2O and brine, dried over Na2SO4, filtered, and concentrated in vacuo affording a crude product, which was purified by typical silica gel column chromatography, eluting with petroleum ether/AcOEt (90:10) to give pure product (0.694 g, 81%) as colorless crystals. MS (ESI) m/z: 268 [M−Na]+. 1H NMR (CDCl3): δ 1.13 (t, J=7.2 Hz, 3H), 1.47 (s, 9H), 2.57-2.87 (m, 2H), 3.82 (s, 3H), 5.07 (d, J=7.1 Hz, 1H), 5.73 (d, J=4.5 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]23[CH2:13][CH:12]2[CH2:11][NH:10][CH2:9]3)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[C:20]12([C:30](Cl)=[O:31])[CH2:29][CH:24]3[CH2:25][CH:26]([CH2:28][CH:22]([CH2:23]3)[CH2:21]1)[CH2:27]2>>[C:20]12([C:30]([N:10]3[CH2:11][CH:12]4[C:8]([C:5]5[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=5)([CH2:13]4)[CH2:9]3)=[O:31])[CH2:27][CH:26]3[CH2:25][CH:24]([CH2:23][CH:22]([CH2:28]3)[CH2:21]1)[CH2:29]2
Reactant: Clc1ccc(C23CNCC2C3)cc1
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: O=C(N1CC2CC2(c2ccc(Cl)cc2)C1)C12CC3CC(CC(C3)C1)C2

Procedure:
A sample of 19.35 g of 1-p-chlorophenyl-3-azabicyclo[3.1.0]hexane, 10.59 g of sodium carbonate and 19.87 g of 1-adamantanecarboxylic acid chloride are reacted in accordance with Example 36, yielding the product 3-(1-adamantylcarbonyl)-1-(p-chlorophenyl)-3-azabicyclo[3.1.0]hexane as a white solid, mp 163°-165° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([F:13])[CH2:10][C@H:9]1[CH2:14]OS(C)(=O)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N-:20]=[N+:21]=[N-:22].[Na+]>CN(C=O)C.O>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([F:13])[CH2:10][C@H:9]1[CH2:14][N:20]=[N+:21]=[N-:22])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1C[C@H](F)C[C@H]1COS(C)(=O)=O
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1C[C@H](F)C[C@H]1CN=[N+]=[N-]
Temperature: 75 °C
Reaction time: 8 h

Procedure:
A mixture of (2S,4R)-4-fluoro-2-methanesulfonyloxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (3.3 g, 11.1 mmol) and NaN3 (721 mg, 11.1 mmol) in DMF (50 mL) was stirred at 75° C. under nitrogen overnight. The mixture was diluted with water and extracted with EtOAc (×3). The combined organic extracts were washed with water (×3), dried over Na2SO4, and concentrated. The crude residue was purified by flash column chromatography on silica gel (c-hexane/EtOAc 100/0 to 0/100) to give the desired material. 1H-NMR (400 MHz, DMSO): δ (ppm) 5.25 (d, 1H), 4.03 (m, 1H), 3.92-3.70 (m, 2H), 3.5-3.25 (m, 2H), 2.27 (m, 1H), 2.2-1.8 (m, 1H), 1.43 (s, 9H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[NH:12][C:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:32][CH2:33][CH3:34])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:42](Cl)(=[O:44])[CH3:43]>C(Cl)Cl>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]([C:42](=[O:44])[CH3:43])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[N:12]=2)=[C:7]([O:32][CH2:33][CH3:34])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(=O)Cl
Reactant: CCOc1cc(C(C)(C)C)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOc1cc(C(C)(C)C)ccc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(C)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
To a solution of rac-(4S*,5R*)-2-(4-tert-butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-1H-imidazole (70 mg, 0.13 mmol, example 2) and triethylamine (92 uL, 0.65 mmol) in methylene chloride (3 mL) was added acetyl chloride (59 uL, Aldrich). The reaction mixture was stirred at room temperature overnight then concentrated. Purification of the crude residue by flash chromatography (12 g of silica gel, eluting with 5-30% ethyl acetate in hexane) gave the title compound (56.1 mg, 80%). HR-MS (ES, m/z) calculated for C31H34N2O2Cl2 [(M+H)+] 537.2070, observed 537.2068.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[CH:19][C:20]([O:34][CH3:35])=[C:21]([CH:33]=2)[C:22]([NH:24][C:25]2[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=2[F:32])=[O:23])[CH:5]=[CH:4][N:3]=1.[CH3:36][CH:37]([N:39]1[CH2:44][CH2:43][N:42]([C:45]2[CH:51]=[CH:50][C:48]([NH2:49])=[C:47]([O:52][CH3:53])[CH:46]=2)[CH2:41][CH2:40]1)[CH3:38].Cl.O1CCOCC1.C[O-].[Na+]>FC(F)(F)CO.CO.C(Cl)Cl.CCCCCC>[F:32][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]([F:31])[C:25]=1[NH:24][C:22](=[O:23])[C:21]1[CH:33]=[C:17]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:49][C:48]3[CH:50]=[CH:51][C:45]([N:42]4[CH2:43][CH2:44][N:39]([CH:37]([CH3:36])[CH3:38])[CH2:40][CH2:41]4)=[CH:46][C:47]=3[O:52][CH3:53])[N:7]=2)[CH:18]=[CH:19][C:20]=1[O:34][CH3:35]
Reactant: COc1cc(N2CCN(C(C)C)CC2)ccc1N
Reactant: COc1ccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)cc1C(=O)Nc1c(F)cccc1F
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1COCCO1
Solvent: ClCCl
Product: COc1cc(N2CCN(C(C)C)CC2)ccc1Nc1nccc(-c2c(-c3ccc(OC)c(C(=O)Nc4c(F)cccc4F)c3)nc3ccccn23)n1
Temperature: 175 °C
Yield: 65 %

Procedure:
To 5-[3-(2-chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-2-(methyloxy)benzamide (Intermediate Example 2) (100 mg, 0.20 mmol) and 4-[4-(1-methylethyl)-1-piperazinyl]-2-(methyloxy)aniline (Example 175, step B) (51 mg, 0.20 mmol) in 2,2,2-trifluoroethanol (1.0 mL) was added 4 M HCl in dioxane (102 μL, 0.41 mmol). The mixture was stirred and heated on a Biotage microwave at 175° C. for 35 min, then cooled to rt. The mixture was neutralized with 0.5M sodium methoxide in MeOH. The mixture was concentrated under vacuum and the residue purified by silica gel chromatography to give a yellow oil. The oil was dissolved in minimal DCM, then hexane was added until a precipitate was formed. The slurry was cooled at −10° C. for 30 min, then poured through a Teflon filter, washing the solids with cold hexanes. The solids were dried under vacuum to give the title compound (95 mg, 0.13 mmol, 66%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 9.79 (s, 1H), 9.37 (br s, 1H), 8.45 (s, 1H), 8.20 (d, 1H, J=5.32 Hz), 8.10 (d, 1H, J=1.83 Hz), 7.76-7.80 (m, 1H), 7.69 (d, 1H, J=8.98 Hz), 7.35-7.47 (m, 3H), 7.29 (d, 1H, J=8.61 Hz), 7.19 (t, 2H, J=8.06 Hz), 6.95 (t, 1H, J=6.87 Hz), 6.67 (d, 1H, J=2.38 Hz), 6.53 (d, 1H, J=5.13 Hz), 6.48 (dd, 1H, J=2.47 and 8.71 Hz), 3.99 (s, 3H), 3.80 (s, 2H), 3.11-3.16 (m, 4H), 2.64-2.72 (m, 1H), 2.56-2.61 (m, 4H), 1.01 (d, 6H, J=6.42 Hz). MS (ESI): 705 [M+H]+.
Reaction SMILES: F[C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][N:13]=[C:14]([C:17]4[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=4)[CH:15]=3)[N:10]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[N:9]=2)[CH:5]=[CH:4][CH:3]=1.[NH:31]1[CH2:36][CH2:35][CH2:34][C@@H:33]([OH:37])[CH2:32]1.CCN(C(C)C)C(C)C>CCO>[N:19]1[CH:20]=[CH:21][CH:22]=[C:17]([C:14]2[CH:15]=[C:16]3[C:8]([C:6]4[N:7]=[C:2]([N:31]5[CH2:36][CH2:35][CH2:34][C@@H:33]([OH:37])[CH2:32]5)[CH:3]=[CH:4][CH:5]=4)=[N:9][N:10]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:11]3=[CH:12][N:13]=2)[CH:18]=1
Reactant: O[C@@H]1CCCNC1
Reactant: C[Si](C)(C)CCOCn1nc(-c2cccc(F)n2)c2cc(-c3cccnc3)ncc21
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: C[Si](C)(C)CCOCn1nc(-c2cccc(N3CCC[C@@H](O)C3)n2)c2cc(-c3cccnc3)ncc21
Temperature: 120 °C

Procedure:
To a mixture of 3-(6-fluoropyridin-2-yl)-5-(pyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridine (200 mg, 0.5 mmol) and (R)-piperidin-3-ol (100 mg, 1.0 mmol) in EtOH 5 mL, was added DIPEA 5 mL. The reaction mixture was heated at 120° C. for 15 h, and the reaction was monitored by LCMS. Upon completion of the reaction, the solvent was distilled off and the crude material was purified via flash chromatography, eluting with 5% to 30% heptane/ethyl acetate to afford (R)-1-(6-(5-(pyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-c]pyridin-3-yl)pyridin-2-yl)piperidin-3-ol as a yellow oil, (163 mg, 65%). ESI MS m/z=502.2 (M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[N:12]1[CH2:17][CH2:16][CH:15]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[S:25]([CH3:28])(=[O:27])=[O:26])[CH2:14][CH2:13]1.[F:29][C:30]([F:59])([F:58])[C:31]1[C:35](B(O)O)=[CH:34][N:33]([C:39]([C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[N:32]=1>>[CH3:28][S:25]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[O:18][CH:15]1[CH2:16][CH2:17][N:12]([C:5]2[C:4]3[C:9](=[CH:10][CH:11]=[C:2]([C:35]4[C:31]([C:30]([F:58])([F:59])[F:29])=[N:32][N:33]([C:39]([C:46]5[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=5)([C:52]5[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=5)[C:40]5[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=5)[CH:34]=4)[CH:3]=3)[N:8]=[CH:7][CH:6]=2)[CH2:13][CH2:14]1)(=[O:27])=[O:26]
Reactant: CS(=O)(=O)c1ccccc1OC1CCN(c2ccnc3ccc(Br)cc23)CC1
Reactant: OB(O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)nc1C(F)(F)F
Product: CS(=O)(=O)c1ccccc1OC1CCN(c2ccnc3ccc(-c4cn(C(c5ccccc5)(c5ccccc5)c5ccccc5)nc4C(F)(F)F)cc23)CC1
Yield: 94.2 %

Procedure:
80 mg 6-bromo-4-[4-(2-methylsulfonylphenoxy)-piperidin-1-yl] quinoline (compound in Production Example 222) and 95 mg 3-trifluoromethyl-1-trityl-1H-4-pyrazolylboronic acid (compound in Production Example 31) were reacted in the same manner as in Example 9, to give 124 mg 4-[4-(2-methylsulfonylphenoxy)piperidin-1-yl]-6-(3-trifluoromethyl-1-trityl-1H-pyrazol-4-yl) quinoline. This product was reacted in the same manner as in Example 67, to give 70 mg of the title compound as colorless crystals.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[F:14])[N:10]([C:15]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[N:9]=[C:8]2[CH:34]=[CH2:35])=[O:4].Br[C:37]1[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=1>>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[F:14])[N:10]([C:15]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[N:9]=[C:8]2/[CH:34]=[CH:35]/[C:37]1[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=1)=[O:4]
Reactant: Brc1cccnc1
Reactant: C=Cc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(F)c(C(=O)OC)cc12
Product: COC(=O)c1cc2c(/C=C/c3cccnc3)nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c2cc1F

Procedure:
600 mg of 6-fluoro-1-trityl-3-vinyl-1H-indazole-5-carboxylic acid methyl ester and 190 μl of 3-bromopyridine were treated in the same manner as described in Example 124, to afford 75 mg of the title compound as a colorless powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:31](O)(=[O:33])=[O:32])[C:6](=[CH:27][C:28]=1[O:29][CH3:30])/[CH:7]=[CH:8]/[C:9]1[N:17]([CH3:18])[C:16]2[C:15](=[O:19])[N:14]([CH2:20][CH2:21][CH3:22])[C:13](=[O:23])[N:12]([CH2:24][CH2:25][CH3:26])[C:11]=2[N:10]=1.[CH2:35]([CH2:37][NH2:38])[OH:36]>>[OH:36][CH2:35][CH2:37][NH:38][S:31]([C:5]1[C:6](=[CH:27][C:28]([O:29][CH3:30])=[C:3]([O:2][CH3:1])[CH:4]=1)/[CH:7]=[CH:8]/[C:9]1[N:17]([CH3:18])[C:16]2[C:15](=[O:19])[N:14]([CH2:20][CH2:21][CH3:22])[C:13](=[O:23])[N:12]([CH2:24][CH2:25][CH3:26])[C:11]=2[N:10]=1)(=[O:33])=[O:32]
Reactant: CCCn1c(=O)c2c(nc(/C=C/c3cc(OC)c(OC)cc3S(=O)(=O)O)n2C)n(CCC)c1=O
Reactant: NCCO
Product: CCCn1c(=O)c2c(nc(/C=C/c3cc(OC)c(OC)cc3S(=O)(=O)NCCO)n2C)n(CCC)c1=O
Yield: 57.2 %

Procedure:
Substantially the same procedure as in Example 2 was repeated using 1.00 g (1.96 mmol) of Compound 1 obtained in Example 1 and 1.2 ml (20.3 mmol) of ethanolamine. The resulting crude crystals were recrystallized from toluene to give 600 mg (yield 55%) of Compound 14 as yellow plates.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[NH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:30]1[CH:42]=[CH:41][C:33]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])=[C:32]([NH:43][C:44]([C:46]2[CH:47]=[N:48][CH:49]=[C:50]([C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)[CH:51]=2)=[O:45])[CH:31]=1>O.C(Cl)(Cl)Cl.C(Cl)Cl.C(O)(=O)C>[CH2:1]([NH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:30]1[CH:42]=[CH:41][C:33]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])=[C:32]([NH:43][C:44]([C:46]2[CH:47]=[N:48][CH:49]=[C:50]([C:52]3[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=3)[CH:51]=2)=[O:45])[CH:31]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccccc2N)cc1NC(=O)c1cncc(-c2ccccc2)c1
Reactant: O=Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1ccc(-c2ccccc2NCc2ccccc2)cc1NC(=O)c1cncc(-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Benzaldehyde (0.027 mL) and sodium triacetoxyborohydride (70 mg) were added to a methylene chloride (1 mL) suspension of tert-butyl 4-(2-aminophenyl)-2-(5-phenylpyridine-3-carboxamido)benzoate (0.10 g) at room temperature, followed by stirring at the same temperature for 3 hours and 30 minutes. Methylene chloride (2 mL) was added to the reaction mixture at room temperature, followed by stirring at the same temperature for 1 hour and 50 minutes. Acetic acid (0.013 mL) and sodium triacetoxyborohydride (47 mg) were added to the reaction mixture at room temperature, followed by stirring at the same temperature for 2 hours and 50 minutes. Sodium triacetoxyborohydride (47 mg), methylene chloride (3 mL), and benzaldehyde (0.027 mL) were added to the reaction mixture at room temperature, followed by heating to reflux for 1 hour and 30 minutes. The reaction mixture was cooled to room temperature, and then sodium triacetoxyborohydride (47 mg) was added thereto, followed by heating to reflux for 4 hours and 40 minutes. The reaction mixture was cooled to room temperature, and then chloroform and water were added thereto. The organic layer was separated and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent:85-60% hexane/ethyl acetate] to obtain 78 mg of tert-butyl 4-(2-(benzylamino)phenyl)-2-(5-phenylpyridine-3-carboxamido)benzoate as a light yellow solid.
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:9][N:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])(=[O:12])=[O:11])[C:7](=[O:20])[N:6]1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[Cl:27])=[O:4].[OH-].[Na+]>>[Cl:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[S:10]([N:8]1[CH2:9][C@@H:5]([C:3]([OH:4])=[O:2])[N:6]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[Cl:27])[C:7]1=[O:20])(=[O:11])=[O:12]
Reactant: COC(=O)[C@@H]1CN(S(=O)(=O)c2ccccc2Cl)C(=O)N1c1ccccc1Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)[C@@H]1CN(S(=O)(=O)c2ccccc2Cl)C(=O)N1c1ccccc1Cl

Procedure:
Steps 4 and 5: In analogy to example 1, (S)-1-(2-chloro-benzenesulfonyl)-3-(2-chloro-phenyl)-2-oxo-imidazolidine-4-carboxylic acid methyl ester was hydrolyzed using sodium hydroxide solution to give (S)-1-(2-chloro-benzenesulfonyl)-3-(2-chloro-phenyl)-2-oxo-imidazolidine-4-carboxylic acid. Finally, (S)-1-(2-chloro-benzenesulfonyl)-3-(2-chloro-phenyl)-2-oxo-imidazolidine-4-carboxylic acid was coupled with 1-(2,5-dimethylphenyl)piperazine to give the title compound as a colorless solid. MS: 587.2 ([M+H]+)
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:14]=[CH:13][C:7]([O:8][CH:9]2[CH2:12][NH:11][CH2:10]2)=[CH:6][CH:5]=1)[CH3:2].C(OC(=O)[NH:21][C@H:22]([C:24]1[CH:29]=[CH:28][C:27](Br)=[CH:26][CH:25]=1)[CH3:23])(C)(C)C.CC([O-])(C)C.[K+].C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C>O1CCOCC1.O.CO>[CH2:1]([O:3][C:4]1[CH:14]=[CH:13][C:7]([O:8][CH:9]2[CH2:12][N:11]([C:27]3[CH:28]=[CH:29][C:24]([C@@H:22]([NH2:21])[CH3:23])=[CH:25][CH:26]=3)[CH2:10]2)=[CH:6][CH:5]=1)[CH3:2]
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1ccc(Br)cc1
Reactant: CCOc1ccc(OC2CNC2)cc1
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Solvent: C1COCCO1
Product: CCOc1ccc(OC2CN(c3ccc([C@H](C)N)cc3)C2)cc1
Temperature: 120 °C
Reaction time: 2 h

Procedure:
To 5.0 g (21.8 mmol) 3-(4-ethoxy-phenoxy)-azetidine and 6.5 g (21.8 mmol) (S)-[1-(4-bromo-phenyl)-ethyl]-carbamic acid tert-butyl ester (1.3) in 80 mL 1,4-dioxane under an argon atmosphere are added 8.6 g (87.1 mmol) KOtBu, 0.65 g (2.18 mmol) 2-(di-tert-butylphosphino)biphenyl and 1.0 g (1.09 mmol) tris-(dibenzylideneacetone)-dipalladium(0). The mixture is stirred for 2 h at 120° C. Subsequently 200 mL MeOH and 5 mL water are added and the mixture is filtered and concentrated in vacuo. The residue is taken up in ethyl acetate and is washed with water. The organic layer is concentrated and the residue is purified by HPLC (eluent A: water+0.1% NH4OH, eluent B: MeOH) to yield the desired product.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([O:13][CH3:14])[CH:6]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH:22]([CH3:27])[CH2:23][CH2:24][C:25]#[N:26].O>CN(C)C=O>[CH3:1][N:2]([CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([O:13][CH3:14])[CH:6]=1)[CH2:27][CH2:22][CH2:23][CH2:24][CH2:25][NH2:26]
Reactant: CC(Br)CCC#N
Reactant: CNCCc1ccc(OC)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(CCN(C)CCCCCN)cc1OC
Yield: 55 %

Procedure:
2.5 g of N-methyl-(2-(3,4-dimethoxyphenyl)ethyl)amine was dissolved in 25 ml of N,N-dimethylformamide, followed by the addition of 1.95 g of anhydrous potassium carbonate and 1.65 ml of 4-bromovaleronitrile. The obtained mixture was reacted at a room temperature for 16 hours, followed by the addition of water. The obtained mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water and a saturated aqueous solution of common salt, dried over anhydrous potassium carbonate and distilled to remove the solvent. 40 ml of ethanol, 3.2 ml of concentrated hydrochloric acid and 0.3 g of platinum oxide were added to the obtained residue to carry out hydrogenation at a room temperature under 3 kg/cm2 for 6 hours. The catalyst was filtered out and the filtrate was concentrated under a reduced pressure, followed by the addition of concentrated aqueous ammonia. The obtained mixture was extracted with chloroform. The chloroform phase was dried over anhydrous potassium carbonate and distilled to remove the solvent. The residue was purified by silica gel column chromatography [solvent: dichloromethane/methanol/concentrated aqueous ammonia (100:10:1)] to obtain 1.95 g of the title compound as a yellow oil (yield: 55%).
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[N:6]2[CH2:9][CH2:10][CH2:11][NH:12][C:5]2=[N:4][C:3]=1[C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1.[CH2:19]([CH:27]1[CH2:29][O:28]1)[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[NH4+].[Cl-]>CN(C=O)C>[Br:1][C:2]1[C:7](=[O:8])[N:6]2[CH2:9][CH2:10][CH2:11][N:12]([CH2:29][CH:27]([OH:28])[CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:5]2=[N:4][C:3]=1[C:13]1[CH:14]=[CH:15][N:16]=[CH:17][CH:18]=1
Reactant: O=c1c(Br)c(-c2ccncc2)nc2n1CCCN2
Reactant: c1ccc(CCC2CO2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: O=c1c(Br)c(-c2ccncc2)nc2n1CCCN2CC(O)CCc1ccccc1
Temperature: 25 °C

Procedure:
A mixture of 3-Bromo-2-pyridin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one (0.45 g, 1.46 mmol) and 2-Phenethyl-oxirane (0.65 g, 4.4 mmol) in DMF (20 mL) was treated LiHMDS (5 mL, 5 mml). The mixture was heated at 90 C for 1 h and was cooled to room temperature. Saturated NH4Cl (50 mL) was added and the mixture was extracted with CH2Cl2 (3×20 mL). The organic phase was washed with H2O (3×), dried (Na2SO4), and concentrated. The resulting brown oil was chromatographed on silica with 1-5% (2N NH3-MeOH)/CH2Cl2 to afford the product as a white solid. M+1 457.
Reaction SMILES: [O:1]([CH2:8][C:9]#[C:10]/[CH:11]=[CH:12]\[C:13]#[C:14][Si](C)(C)C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.O[Li].O>C1COCC1.CCOCC>[O:1]([CH2:8][C:9]#[C:10][CH:11]=[CH:12][C:13]#[CH:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)C#C/C=C\C#CCOc1ccccc1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: C#CC=CC#CCOc1ccccc1
Reaction time: 4 h
Yield: 93.9 %

Procedure:
To a solution of the product of step (b) (5.0 g, 19.7 mmol) in 20 mL THF was added 5 mL of water and LiOH-H2O (5.6 g, 133 mmol). The solution was stirred for 4 h, diluted with ether and washed with water. The aqueous layer extracted with ether and then ethyl acetate. The organic fractions were combined, dried (MgSO4) and concentrated. The residue was chromatographed over silica (30:1 hexane/ethyl acetate) to give 3.37 g of (94%) of 7-phenoxy-3-heptene-1,5-diyne.