Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1C=CC=CC=1.[CH2:7]([O:10][C:11]1[C:12]([NH2:21])=[CH:13][C:14]2[C:19]([CH:20]=1)=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:8][CH3:9].[C:22]([CH:25]([C:31]1[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=1)[C:26](OCC)=[O:27])(=O)[CH3:23].C(OCC)(=O)C>CCCCCC>[CH3:38][O:37][C:34]1[CH:35]=[CH:36][C:31]([C:25]2[C:26](=[O:27])[C:13]3[C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=4[CH:20]=[C:11]([O:10][CH2:7][CH2:8][CH3:9])[C:12]=3[NH:21][C:22]=2[CH3:23])=[CH:32][CH:33]=1
Reactant: CCCOc1cc2ccccc2cc1N
Reactant: CCOC(=O)C(C(C)=O)c1ccc(OC)cc1
Solvent: c1ccccc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCCOc1cc2ccccc2c2c(=O)c(-c3ccc(OC)cc3)c(C)[nH]c12
Temperature: 25 °C
Reaction time: 1.17 h
Yield: 26.1 %

Procedure:
To a benzene solution (38 ml) containing 3-propoxynaphthalen-2-ylamine (600 mg, 2.98 mmol) and ethyl α-acetyl-4-methoxyphenylacetate (1.41 g, 5.96 mmol) was added 85 mg of Amberlyst 15 (Sigma-Aldrich). The resulting mixture was heated under reflux for 20 hours using a Dean-Stark trap. The reaction mixture was cooled to room temperature, filtered to remove resin, and then the filtrate was concentrated under reduced pressure. Diphenyl ether (2.8 ml) was added to the residue, and the mixture was then heated with a mantle heater and stirred for 70 minutes under reflux. The resulting reaction mixture was cooled to room temperature, and then directly purified using silica gel column chromatography (dichloromethane:methanol=80:1→70:1). The purified product was concentrated under reduced pressure, giving an oily substance (800 mg, yield: 72%). Ethyl acetate and n-hexane were added to the thus-obtained oily substance to crystallize and then recrystallized from ethyl acetate, giving a pale yellow powder of 2-(4-methoxyphenyl)-3-methyl-5-propoxy-4H-benzo[f]quinolin-1-one (290 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9](=[O:16])[N:10]2[CH2:13][CH:14]=O)=[CH:5][CH:4]=1.[O:17]1[C:26]2[CH:25]=[C:24]([CH2:27][N:28]([CH:36]3[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]3)[C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[N:23]=[CH:22][C:21]=2[O:20][CH2:19][CH2:18]1.CO.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)(Cl)Cl>[O:17]1[C:26]2[CH:25]=[C:24]([CH2:27][N:28]([CH:36]3[CH2:41][CH2:40][N:39]([CH2:14][CH2:13][N:10]4[C:11]5[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=5)[CH:7]=[CH:8][C:9]4=[O:16])[CH2:38][CH2:37]3)[C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[N:23]=[CH:22][C:21]=2[O:20][CH2:19][CH2:18]1
Reactant: CC(C)(C)OC(=O)N(Cc1cc2c(cn1)OCCO2)C1CCNCC1
Reactant: COc1ccc2ccc(=O)n(CC=O)c2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COc1ccc2ccc(=O)n(CCN3CCC(N(Cc4cc5c(cn4)OCCO5)C(=O)OC(C)(C)C)CC3)c2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56 %

Procedure:
A solution of [7-(methyloxy)-2-oxo-1(2H)-quinolinyl]acetaldehyde (65 mg, 0.3 mmol) and 1,1-dimethylethyl (2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)-4-piperidinylcarbamate (for a synthesis see WO2004/058144 Example 99(h)) (105 mg, 0.3 mmol) in chloroform (3 ml) and MeOH (3 ml) was stirred at rt for 1 h. The mixture was then treated with NaBH(OAc)3 (190.8 mg, 0.9 mmol), stirred at rt for 0.5 h. 1,1-dimethylethyl (2,3-dihydro[1,4]dioxino[2,3-c]pyridin-7-ylmethyl)-4-piperidinylcarbamate (52 mg, 0.15 mmol) and NaBH(OAc)3 (127 mg, 0.6 mmol) were added and the reaction stirred at rt for 1 hour. The solvents were then removed and the residue was subjected to column chromatography on silica gel eluting with 0-10% methanol-DCM to afford the desired compound (92 mg, 56%).
Reaction SMILES: O[C:2]1[CH:3]=[CH:4][C:5]([CH:8]=[C:9]2[NH:14][C:13](=[O:15])[C:12](=[CH:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[NH:11][C:10]2=[O:24])=[N:6][CH:7]=1.[C:25]1(C)[C:26]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:28]=[CH:29][CH:30]=1.[C:36]1(C)C=CC=CC=1>C(Cl)Cl>[C:29]1([CH3:36])[CH:30]=[CH:25][C:26]([S:31]([C:2]2[CH:3]=[CH:4][C:5]([CH:8]=[C:9]3[NH:14][C:13](=[O:15])[C:12](=[CH:16][CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[NH:11][C:10]3=[O:24])=[N:6][CH:7]=2)(=[O:32])=[O:33])=[CH:27][CH:28]=1
Reactant: Cc1ccccc1S(=O)(=O)Cl
Reactant: O=c1[nH]c(=Cc2ccc(O)cn2)c(=O)[nH]c1=CCc1ccccc1
Reactant: Cc1ccccc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)c2ccc(C=c3[nH]c(=O)c(=CCc4ccccc4)[nH]c3=O)nc2)cc1
Temperature: 150 °C
Yield: 10 %

Procedure:
A reaction mixture of compound B (0.05 g, 0.16 mmole; obtained from Example 14), toluenesulfonyl chloride (0.03 g, 0.16 mmole), and 50 mL of toluene was heated to 150° C. for 2 hr. Toluene was removed in vacuo to produce a residue. The residue was chromatographied using silica gel column with a developing solvent (CH2Cl2) to give 0.007 g (10%) of Compound 16.
Reaction SMILES: [CH:1]([N:14]1[CH2:17][CH:16]([N:18]([CH3:26])[C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:15]1)(C1C=CC=CC=1)[C:2]1C=CC=CC=1.C(N(CC)CC)C.C(Cl)(=[O:36])C>[OH-].[Pd+2].[OH-].[C].CO>[C:1]([N:14]1[CH2:17][CH:16]([N:18]([CH3:26])[C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:15]1)(=[O:36])[CH3:2]
Reactant: CC(=O)Cl
Reactant: CN(C(=O)OC(C)(C)C)C1CN(C(c2ccccc2)c2ccccc2)C1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: CCN(CC)CC
Product: CC(=O)N1CC(N(C)C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
tert-Butyl N-(1-benzhydrylazetidin-3-yl)-N-methylcarbamate (I-149) (0.40 g, 1.13 mmol) was dissolved methanol (20 ml), then 20% palladium hydroxide-carbon (containing about 50% water, 20 g) was added, followed by stirring at room temperature under hydrogen atmosphere for 15 hours, and the catalyst was removed by filtration. The solvent was evaporated away under reduced pressure, the resulting residue was dissolved in dichloromethane (10 ml), and triethylamine (0.20 ml, 3.44 mmol) and acetyl chloride (90.0 μl, 26 mmol) were added.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[C:6](=[O:18])[NH:7][C:8]3[CH:17]=[CH:16][CH:15]=[N:14][C:9]=3[N:10]([C:11](Cl)=[O:12])[C:4]=2[CH:3]=1.[CH3:21][CH:22]([N:24]([CH:37]([CH3:39])[CH3:38])[CH2:25][CH2:26][CH2:27][CH:28]1[CH2:33][CH2:32][N:31]([CH2:34][CH2:35][NH2:36])[CH2:30][CH2:29]1)[CH3:23]>C(#N)C>[CH3:39][CH:37]([N:24]([CH:22]([CH3:23])[CH3:21])[CH2:25][CH2:26][CH2:27][CH:28]1[CH2:29][CH2:30][N:31]([CH2:34][CH2:35][NH:36][C:11]([N:10]2[C:4]3[CH:3]=[C:2]([Cl:1])[CH:20]=[CH:19][C:5]=3[C:6](=[O:18])[NH:7][C:8]3[CH:17]=[CH:16][CH:15]=[N:14][C:9]2=3)=[O:12])[CH2:32][CH2:33]1)[CH3:38]
Reactant: CC(C)N(CCCC1CCN(CCN)CC1)C(C)C
Reactant: O=C1Nc2cccnc2N(C(=O)Cl)c2cc(Cl)ccc21
Solvent: CC#N
Product: CC(C)N(CCCC1CCN(CCNC(=O)N2c3cc(Cl)ccc3C(=O)Nc3cccnc32)CC1)C(C)C
Yield: 44 %

Procedure:
Prepared analogously to Example 1 from 9-chloro-11-(chlorocarbonyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and 2-[4-[3-[bis(methylethyl)amino]propyl]-piperidin-l-yl]ethanamine in a yield of 44% of theory. Colourless crystals, m.p. 175°-176° C. (acetonitrile).
Reaction SMILES: N([O-])=O.[Na+].[Cl:5][C:6]1[S:10][N:9]=[C:8]([Cl:11])[C:7]=1[C:12](N)=[O:13].S(=O)(=O)(O)[OH:16]>O>[Cl:5][C:6]1[S:10][N:9]=[C:8]([Cl:11])[C:7]=1[C:12]([OH:13])=[O:16]
Reactant: O=S(=O)(O)O
Reactant: NC(=O)c1c(Cl)nsc1Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: O=C(O)c1c(Cl)nsc1Cl
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
NaNO2 (1 g, 14.49 mmol, 1.13 equiv), water (30 ml), dichloro-1,2-thiazole-4-carboxamide (2 g, 10.15 mmol, 1.00 equiv) was added to the sulfuric acid solution of the 3,5-dichloroisothiazole-4-carboxamide. The resulting solution was stirred for 30 min at 50° C. The resulting solution was extracted with 3×30 mL of dichloromethane and the organic layers combined and dried over anhydrous sodium sulfate and concentrated. This resulted in 400 mg (crude) of dichloro-1,2-thiazole-4-carboxylic acid as a brown solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[C:4]([S:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Br:18])[CH:3]=1>C(O)(=O)C.CO.[Zn]>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([S:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Br:18])[CH:3]=1
Reactant: O=[N+]([O-])c1ccc(Br)cc1Sc1ccccc1Br
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CO
Product: Nc1ccc(Br)cc1Sc1ccccc1Br
Temperature: 40 °C
Yield: 99 %

Procedure:
To a mixture of 4-bromo-2-(2-bromophenylsulfanyl)-nitrobenzene, 1e (15.56 g; 40 mmol) in acetic acid (200 mL) and methanol (400 mL) was added zinc (15.7 g; 240 mmol) over a 30 min period. The mixture was heated to 40° C. for 1 h overnight, filtered, evaporated, and dried under vacuum overnight. The residue was suspended in 1N NaOH solution and extracted with methylene chloride. The organic phase was dried over MgSO4, filtered, and evaporated. The residue was purified via flash column chromatography (eluent gradient: 0 to 10% EtOAc in heptane) to yield 14.2 g (99%) of title compound 4-bromo-2-(2-bromophenylsulfanyl)-aniline, 2e.
Reaction SMILES: [F:1][C:2]([C:5]1[O:9][C:8]([CH2:10][N:11]2[CH:15]=[C:14]([NH2:16])[CH:13]=[N:12]2)=[CH:7][CH:6]=1)([F:4])[CH3:3].[CH3:17][O:18][C:19]1[C:24]([O:25][CH3:26])=[CH:23][CH:22]=[CH:21][C:20]=1/[CH:27]=[CH:28]/[C:29](O)=[O:30]>>[F:4][C:2]([C:5]1[O:9][C:8]([CH2:10][N:11]2[CH:15]=[C:14]([NH:16][C:29](=[O:30])/[CH:28]=[CH:27]/[C:20]3[CH:21]=[CH:22][CH:23]=[C:24]([O:25][CH3:26])[C:19]=3[O:18][CH3:17])[CH:13]=[N:12]2)=[CH:7][CH:6]=1)([F:1])[CH3:3]
Reactant: CC(F)(F)c1ccc(Cn2cc(N)cn2)o1
Reactant: COc1cccc(/C=C/C(=O)O)c1OC
Product: COc1cccc(/C=C/C(=O)Nc2cnn(Cc3ccc(C(C)(F)F)o3)c2)c1OC

Procedure:
Following general procedure B, starting from 1-[5-(1,1-difluoro-ethyl)-furan-2-ylmethyl]-1H-pyrazol-4-ylamine and (E)-3-(2,3-dimethoxy-phenyl)-acrylic acid. LC-MS-conditions 05b: tR=1.06 min; [M+H]+=418.09.
Reaction SMILES: [Br:1][C:2]1[C:8]([O:9][CH3:10])=[CH:7][C:5]([NH2:6])=[C:4]([N+:11]([O-])=O)[CH:3]=1>CO.CC(O)=O.[Zn]>[Br:1][C:2]1[CH:3]=[C:4]([NH2:11])[C:5]([NH2:6])=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1cc(N)c([N+](=O)[O-])cc1Br
Agent: [Zn]
Solvent: CO
Solvent: CC(=O)O
Product: COc1cc(N)c(N)cc1Br
Temperature: 0 °C
Reaction time: 2 h
Yield: 87.5 %

Procedure:
To a stirred mixture of 4-bromo-5-methoxy-2-nitroaniline (5 g, 20 mmol) in MeOH (50 mL) and HOAc (20 mL) at 0° C. under argon was added zinc powder (5.3 g, 80 mmol) portionwise. The mixture was stirred for 2 h, then filtered, and the filtrate was cooled to 0° C. The pH of the filtrate was adjusted to pH˜9 by addition of solid Na2CO3. The mixture was then partitioned between EtOAc (250 mL) and water (200 mL). The EtOAc layer was separated, dried over Na2SO4, filtered, and concentrated under reduced pressure to afford 4-bromo-5-methoxybenzene-1,2-diamine (3.8 g, 88%) as a dark purple solid. The material was used in the next step without further purification. 1H NMR (300 MHz, DMSO-d6) δ 6.66 (s, 1H), 6.34 (s, 1H), 4.08-4.83 (m, 4H), 3.63 (s, 3H). LCMS (ESI) m/z 217 and 219 (M+H)+.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7](Cl)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[OH:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=1[O:24][CH2:25][CH2:26][O:27][CH3:28])[CH:19]=[O:20].Cl>C(O)C.O.C(OCC)(=O)C>[CH2:7]([O:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=1[O:24][CH2:25][CH2:26][O:27][CH3:28])[CH:19]=[O:20])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: COCCOc1ccc(C=O)cc1O
Reactant: ClCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: COCCOc1ccc(C=O)cc1OCc1ccccc1
Temperature: 90 °C
Yield: 93 %

Procedure:
Potassium carbonate (11.8 g, 85.7 mmol) and benzyl chloride (10 mL, 86.9 mmol) were added to a liquid mixture of 3-hydroxy-4-(2-methoxyethoxy)benzaldehyde described in Production Example 20-1 (12.9 g, 65.9 mmol) in ethanol (130 mL) under nitrogen atmosphere at room temperature, and the mixture was heated under reflux at 90° C. for 2 hours. The mixture was cooled to 0° C. and then 2 M hydrochloric acid, ethyl acetate, and water were added for partition. The organic layer was washed with a saturated saline solution, dried over anhydrous magnesium sulfate, and then filtered. The solvent was evaporated and the resultant residue was purified with silica gel column chromatography (n-heptane:ethyl acetate=9:1-1:1). The target fraction was concentrated under vacuum to obtain the title compound (17.6 g, 93%).
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:30])[CH2:6][CH2:7][CH:8]([NH:12][C:13]([O:15][CH2:16][CH:17]1[C:29]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[C:23]2[C:18]1=[CH:19][CH:20]=[CH:21][CH:22]=2)=[O:14])[C:9]([OH:11])=[O:10])[CH:2]=[CH2:3].[CH2:31](O)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.CCN=C=NCCCN(C)C.CN(C1C=CC=CN=1)C>C(Cl)Cl>[CH2:31]([O:10][C:9](=[O:11])[CH:8]([NH:12][C:13]([O:15][CH2:16][CH:17]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:23]=2[C:24]2[C:29]1=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:14])[CH2:7][CH2:6][C:5]([O:4][CH2:1][CH:2]=[CH2:3])=[O:30])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: C=CCOC(=O)CCC(NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reactant: OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Product: C=CCOC(=O)CCC(NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)OCc1ccccc1
Temperature: 22 °C
Reaction time: 6 h
Yield: 10 %

Procedure:
Treatment with Fmoc-Cl followed by coupling to benzyl alcohol using 1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimide [by] hydrochloride (EDCl) provided 2-(9H-Fluoren-9-ylmethoxycarbonylamino)-pentanedioic acid 5-allyl ester 1-benzyl ester 6 in 82% yield. To a solution of 1.5 g (36.6 mmol) of 5 in 5 mL of CH2Cl2 was added 0.42 mL (40.3 mmol) of benzyl alcohol, 0.912 g (47.6 mmol) of EDCI, and 45 mg (3.66 mmol) of dimethylaminopyridine (DMAP). The reaction mixture was stirred at 22° C. for 6 h, diluted with 20 mL of CH2Cl2, and extracted with H2O (1×15 mL), 0.1M HCl (2×15 mL), and brine (2×10 mL). The organic layer was dried (Na2SO4), concentrated in vacuo, and chromatographed on SiO2 (Hexanes/EtOAc, 5:1) to give 1.83 g (82%) of 6 as a white solid: Mp 66.2°-67.1° C. (EtOAc/Hexanes); [α]D +1.4° (C 1.64, CHCl3, 21° C.); IR (neat) 3314, 1726, 1682, 1527, 1443, 1414, 1383, 1254, 1173, 1099, 1082, 980, 754, 735 cm-1 ; 1H NMR δ 7.75 (d, 2 H, J=7.4 Hz), 7.59 (d, 2 H, J=7.1 Hz), 7.41-7.27 (m, 9 H), 5.95-5.85 (m, 1 H), 5.44 (d, 1 H, J=8.2 Hz), 5.34-5.19 (m, 4 H), 4.56(d, 2 H, J=5.6 Hz), 4.5-4.4 (m, 3 H), 4.21 (t, 1 H, J=7.0 Hz), 2.5-2.0 (m, 4 H); 13C NMR δ 172.2, 171.6, 155.8, 143.7, 143.5, 141.1, 135.0, 131.8, 128.5, 128.3, 128.1, 127.6, 126.9, 124.9, 119.8, 118.3, 67.2, 66.9, 66.2, 53.3, 47.0, 28.0, 27.3; MS (FAB, MNBA/MeOH) m/z (relative intensity) 500 ([M+H]+, 40), 465 (8), 448 (14), 433 (12), 413 (8), 386 (38), 371 (24), 349 (9), 324 (16), 309 (26), 293 (11), 265 (10), 247 (24), 231 (56), 215 (39), 202 (26), 191 (24), 179 (67), 165 (48), 154 (67), 143 (31), 133 (71), 117 (100).
Reaction SMILES: C(OC(=O)[N:7]([CH:20]1[CH2:23][N:22]([S:24]([C:27]2[CH:32]=[CH:31][C:30]([O:33][CH2:34][CH2:35][CH2:36][CH3:37])=[CH:29][CH:28]=2)(=[O:26])=[O:25])[CH2:21]1)[CH2:8][C@H:9]([OH:19])[CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH2:34]([O:33][C:30]1[CH:29]=[CH:28][C:27]([S:24]([N:22]2[CH2:21][CH:20]([NH:7][CH2:8][C@H:9]([OH:19])[CH2:10][O:11][C:12]3[CH:13]=[CH:14][C:15]([OH:18])=[CH:16][CH:17]=3)[CH2:23]2)(=[O:25])=[O:26])=[CH:32][CH:31]=1)[CH2:35][CH2:36][CH3:37]
Reactant: CCCCOc1ccc(S(=O)(=O)N2CC(N(C[C@H](O)COc3ccc(O)cc3)C(=O)OC(C)(C)C)C2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCOc1ccc(S(=O)(=O)N2CC(NC[C@H](O)COc3ccc(O)cc3)C2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 111 %

Procedure:
To a solution of [1-(4-butoxy-benzenesulfonyl)-azetidin-3-yl]-[(2S)-2-hydroxy-3-(4-hydroxy-phenoxy)-propyl]-carbamic acid tert-butyl ester (0.11 g, 0.2 mmol) in dichloromethane (2 ml) was added trifluoroacetic acid (0.15 ml, 2 mmol). The mixture was stirred at room temperature for 2 h, and then quenched with saturated sodium carbonate solution and extracted with dichloromethane. The organic solution was washed with brine, dried over sodium sufate, and evaporated to give 0.10 g of a white solid; m.p. 55-58° C.; MS (ES) m/z 451 (MH+); HRMS (CI) Calcd. for C22H31N2O6S (MH+): 451.1903, Found: 451.1882.
Reaction SMILES: [C:1]1([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH:6]=[CH:5][C:4]([C@@:7]2([S:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH2:11][N:10]([C:12](=[O:29])[C@@H:13]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH:19]=[CH2:20])[C@H:9]([C:30]([O:32]C)=[O:31])[CH2:8]2)=[CH:3][CH:2]=1.O.[OH-].[Li+]>C1COCC1.CO.O>[C:1]1([C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH:2]=[CH:3][C:4]([C@@:7]2([S:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH2:11][N:10]([C:12](=[O:29])[C@@H:13]([NH:21][C:22]([O:24][C:25]([CH3:27])([CH3:28])[CH3:26])=[O:23])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH:19]=[CH2:20])[C@H:9]([C:30]([OH:32])=[O:31])[CH2:8]2)=[CH:5][CH:6]=1
Reactant: C=CCCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@](SCCCC)(c2ccc(-c3ccccc3)cc2)C[C@H]1C(=O)OC
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: C=CCCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@](SCCCC)(c2ccc(-c3ccccc3)cc2)C[C@H]1C(=O)O
Reaction time: 3 h
Yield: 88 %

Procedure:
To a solution of (2S,4R)-methyl 4-(biphenyl-4-yl)-1-((S)-2-(tert-butoxycarbonylamino)non-8-enoyl)-4-(butylthio)pyrrolidine-2-carboxylate (135 mg, 0.217 mmol) in THF (1.5 mL) and methanol (1.500 mL) was added pre-made solution of lithium hydroxide monohydrate (18.19 mg, 0.433 mmol) in water (1.5 mL). The resulting cloudy solution was stirred at room for 3 hours. Quenched with 5% citric acid, extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4, filtered, concentrated to afford the desired product (2S,4R)-4-(biphenyl-4-yl)-1-((S)-2-(tert-butoxycarbonylamino)non-8-enoyl)-4-(butylthio)pyrrolidine-2-carboxylic acid (129 mg, 0.191 mmol, 88% yield) as a white foam. LC-MS (retention time: 3.67 min, method C), MS m/z 609 (M+H).
Reaction SMILES: N1C=CC=C(C[O:8][CH2:9][CH2:10][NH2:11])C=1.[Na].[N:13]1[CH:18]=[CH:17][CH:16]=[C:15](CO)[CH:14]=1.ClCC#N>CN(C)C=O>[N:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:8][CH2:9][C:10]#[N:11])[CH:14]=1
Reactant: OCc1cccnc1
Reactant: NCCOCc1cccnc1
Agent: N#CCCl
Agent: [Na]
Solvent: CN(C)C=O
Product: N#CCOc1cccnc1

Procedure:
The starting amine, (3-pyridinyl)methyloxyethylamine, was prepared by the following procedure: reaction of the sodium salt of 3-pyridinylmethanol and chloracetonitrile in dimethylformamide gave 2-(3-pyridinyloxy)acetonitrile, which, upon reduction with borane in tetrahydroduran solution, gave the desired amine.
Reaction SMILES: I[CH2:2][I:3].N(OCCC(C)C)=O.NC1[C:14]2[C:37]([CH3:39])([CH3:38])[C:36](=[O:40])[NH:35][C:15]=2[N:16]=[C:17]([C:19]2[C:27]3[C:22](=[N:23][CH:24]=[C:25]([F:28])[CH:26]=3)[N:21]([CH2:29][CH:30]3[CH2:34][CH2:33][CH2:32][CH2:31]3)[N:20]=2)[N:18]=1>>[CH:30]1([CH2:29][N:21]2[C:22]3=[N:23][CH:24]=[C:25]([F:28])[CH:26]=[C:27]3[C:19]([C:17]3[N:18]=[C:2]([I:3])[C:14]4[C:37]([CH3:38])([CH3:39])[C:36](=[O:40])[NH:35][C:15]=4[N:16]=3)=[N:20]2)[CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: ICI
Reactant: CC1(C)C(=O)Nc2nc(-c3nn(CC4CCCC4)c4ncc(F)cc34)nc(N)c21
Agent: CC(C)CCON=O
Product: CC1(C)C(=O)Nc2nc(-c3nn(CC4CCCC4)c4ncc(F)cc34)nc(I)c21
Temperature: 85 °C
Reaction time: 8 h

Procedure:
40.549 g (151.398 mmol) of diiodomethane and 4.420 g (37.738 mmol) of isopentyl nitrite were added to 711 mg (1.799 mmol) of 4-amino-2-[1-(cyclopentylmethyl)-5-fluoro-1H-pyrazolo[3,4-b]pyridin-3-yl]-5,5-dimethyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one. The mixture was stirred at 85° C. for 8 h. After cooling, the mixture was filtered, and the filtrate was diluted with cyclohexane and sucked through silica gel. The silica gel was washed with cyclohexane and the product was eluted with dichloromethane/methanol (v/v=50:2). The collected fractions were concentrated on a rotary evaporator, taken up in 20 ml of ethyl acetate and 5 ml of isopropanol, filtered and concentrated again. The residue was triturated with 5 ml of isopropanol. The solid was filtered off with suction and dried under high vacuum. This gave 230 mg (purity 92%, 23% of theory) of the target compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.[Cl:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=1.CCO>O.CCOC(C)=O>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[O:11][CH:17]([C:16]1[CH:19]=[CH:20][C:13]([Cl:12])=[CH:14][CH:15]=1)[CH2:9][C:8]2=[O:10]
Reactant: O=Cc1ccc(Cl)cc1
Reactant: CC(=O)c1cc(Br)ccc1O
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: O
Product: O=C1CC(c2ccc(Cl)cc2)Oc2ccc(Br)cc21
Yield: 89.2 %

Procedure:
A mixture of 1-(5-bromo-2-hydroxy-phenyl)-ethanone (6 g, 28 mmol), 4-chloro-benzaldehyde (3.92 g, 28 mmol), and borax (10H2O, 10.67 g, 28 mmol) in H2O (60 mL) and EtOH (36 mL) was stirred at 110° C. overnight. The mixture was filtered to give a solid cake. The cake was dissolved in EtOAc and filtered. The filtrate was dried, filtered, and concentrated to give 6-bromo-2-(4-chloro-phenyl)-chroman-4-one (8.43 g, 89%). 1H-NMR (CDCl3): 2.88 (m, 1H), 3.04 (m, 1H), 5.44 (m, 1H), 6.94 (m, 1H), 7.39 (m, 4H), 7.57 (m, 1H), 8.02 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[N:7][N:8]([CH2:10][C:11]([OH:13])=O)[CH:9]=1)=[O:4].S(Cl)(Cl)=O.[NH2:18][C:19]1[CH:24]=[C:23]([Cl:25])[C:22]([C:26]2[CH:31]=[CH:30][C:29]([N:32]3[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]3)=[CH:28][CH:27]=2)=[CH:21][C:20]=1[C:38]([O:40][CH3:41])=[O:39]>C1(C)C=CC=CC=1.ClCCl>[Cl:25][C:23]1[CH:24]=[C:19]([NH:18][C:11](=[O:13])[CH2:10][N:8]2[CH:9]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[CH:6]=[N:7]2)[C:20]([C:38]([O:40][CH3:41])=[O:39])=[CH:21][C:22]=1[C:26]1[CH:27]=[CH:28][C:29]([N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)=[CH:30][CH:31]=1
Reactant: COC(=O)c1cnn(CC(=O)O)c1
Reactant: COC(=O)c1cc(-c2ccc(N3CCCCC3)cc2)c(Cl)cc1N
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: COC(=O)c1cnn(CC(=O)Nc2cc(Cl)c(-c3ccc(N4CCCCC4)cc3)cc2C(=O)OC)c1
Temperature: 90 °C
Reaction time: 2 h
Yield: 97.2 %

Procedure:
To a solution of 2-(4-(methoxycarbonyl)-1H-pyrazol-1-yl)acetic acid (ChemCollect GmbH, 401 mg, 2.175 mmol) in toluene (10 mL) was added thionyl chloride (0.317 mL, 4.35 mmol) and the reaction mixture was stirred at 90° C. for 2 h. The solvent was removed under reduced pressure and the residue was added to a solution of methyl 4-amino-6-chloro-4′-(piperidin-1-yl)-[1,1′-biphenyl]-3-carboxylate (Intermediate 48) (500 mg, 1.45 mmol) in dichloromethane (10 mL). The reaction mixture was stirred at room temperature overnight. Solvent was removed under reduced pressure and water was added. Precipitate was observed, solid was filtered and dried to give the title compound methyl 1-(2-((2-chloro-5-(methoxycarbonyl)-4′-(piperidin-1-yl)-[1,1′-biphenyl]-4-yl)amino)-2-oxoethyl)-1H-pyrazole-4-carboxylate (720 mg, 1.409 mmol, 97% yield) as a cream solid. LCMS: (M+H)+=511; Rt=4.04 min.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][N:5]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:13][CH:12]=2)[C:6]=1[C:7]([NH2:9])=[O:8].[F:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1>>[C:17]([C:14]1[CH:15]=[CH:16][C:11]([CH2:10][N:5]2[C:6]([C:7]([NH2:9])=[O:8])=[C:2]([NH:1][C:26](=[O:27])[C:25]3[CH:29]=[CH:30][C:22]([F:21])=[CH:23][CH:24]=3)[N:3]=[CH:4]2)=[CH:12][CH:13]=1)([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)c1ccc(Cn2cnc(N)c2C(N)=O)cc1
Reactant: O=C(Cl)c1ccc(F)cc1
Product: CC(C)(C)c1ccc(Cn2cnc(NC(=O)c3ccc(F)cc3)c2C(N)=O)cc1
Yield: 56 %

Procedure:
An amidation reaction and post-treatment were carried out under the same conditions as in Example 1, using 2.63 g (9.66 mmol) of 4-amino-1-(4-t-butylbenzyl)-5-imidazolecarboxamide which was prepared in the same manner as in Example 57 and 4-fluorobenzoyl Chloride instead of benzoyl chloride to obtain 2.13 g of 1-(4-t-butylbenzyl)-4-(4-fluorobenzoylamino)-5-imidazolecarboxamide (yield 56%).