Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])(=[O:4])[NH:2][NH2:3].C(N(CC)CC)C.[CH2:17]([O:24][C:25]1[CH:34]=[C:33]2[C:28]([C:29](Cl)=[C:30]([N+:35]([O-:37])=[O:36])[CH:31]=[N:32]2)=[CH:27][CH:26]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>ClCCl.O.C(Cl)(Cl)Cl>[CH2:17]([O:24][C:25]1[CH:34]=[C:33]2[C:28]([C:29]([NH:3][NH:2][C:1]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])=[C:30]([N+:35]([O-:37])=[O:36])[CH:31]=[N:32]2)=[CH:27][CH:26]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=[N+]([O-])c1cnc2cc(OCc3ccccc3)ccc2c1Cl
Reactant: CC(C)(C)OC(=O)NN
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)NNc1c([N+](=O)[O-])cnc2cc(OCc3ccccc3)ccc12
Temperature: 25 °C
Reaction time: 15 h
Yield: 57.2 %

Procedure:
A solution of tert-butyl carbazate (33.1 g, 251 mmol) in 150 mL of dichloromethane was treated with triethylamine (66.5 mL, 502 mmol). The solution was placed under an atmosphere of nitrogen and cooled in a cold-water bath. The solution was treated with a solution of 7-benzyloxy-4-chloro-3-nitroquinoline (71.7 g, 228 mmol) in 350 mL of dichloromethane over 1 h. The reaction was stirred and allowed to warm to ambient temperature. After 15 h, the reaction was diluted with 200 mL of water and 250 mL of CHCl3 and the phases were separated. The organic portion was washed with water (200 mL), brine (200 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to yield an orange solid. The solid was recrystallized from dichloromethane to yield 53.5 g of tert-butyl N′-(7-benzyloxy-3-nitroquinolin-4-yl)hydrazinecarboxylate as yellow crystals.
Reaction SMILES: CCN(CC)CC.[CH3:8][S:9]([C:12]1[CH:17]=[CH:16][C:15]([CH:18]([CH2:22][CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:19]([OH:21])=[O:20])=[CH:14][CH:13]=1)(=[O:11])=[O:10].C(Cl)(=O)C(C)(C)C.[Li]CCCC.C([C@@H]1COC(=O)N1)C1C=CC=CC=1.C([C@@H]1COC(=O)N1C(=O)[C@@H](C1C=CC(S(C)(=O)=O)=CC=1)CC1CCOCC1)C1C=CC=CC=1.C([C@@H]1COC(=O)N1C(=O)[C@H](C1C=CC(S(C)(=O)=O)=CC=1)CC1CCOCC1)C1C=CC=CC=1.[Li+].[OH-].OO>C1COCC1.O.C1COCC1.O.CCOCC.C1COCC1>[CH3:8][S:9]([C:12]1[CH:13]=[CH:14][C:15]([C@@H:18]([CH2:22][CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:19]([OH:21])=[O:20])=[CH:16][CH:17]=1)(=[O:11])=[O:10]
Reactant: CS(=O)(=O)c1ccc(C(CC2CCOCC2)C(=O)O)cc1
Agent: CC(C)(C)C(=O)Cl
Agent: CS(=O)(=O)c1ccc([C@@H](CC2CCOCC2)C(=O)N2C(=O)OC[C@H]2Cc2ccccc2)cc1
Agent: CS(=O)(=O)c1ccc([C@H](CC2CCOCC2)C(=O)N2C(=O)OC[C@H]2Cc2ccccc2)cc1
Solvent: O
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CS(=O)(=O)c1ccc([C@@H](CC2CCOCC2)C(=O)O)cc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
NEt3 (15.4 mL, 110 mmol) was added to a stirred suspension of 2-(4-methanesulfonylphenyl)-3-(tetrahydropyran-4-yl)propanoic acid (Preparation 41, 30.0 g, 96.0 mmol) in anhydrous THF (300 mL) at 0° C. After 10 min, pivaloyl chloride (13.6 mL, 110 mmol) was added dropwise over 20 min and the mixture was stirred at 0° C. for 2 h. Meanwhile, n-BuLi (45.3 mL of a 2.5M solution in hexanes, 115 mmol) was added to a solution of (R)-(+)-4-benzyl-2-oxazolidinone (20.4 g, 115 mmol) in anhydrous THF (300 mL) at −78° C. The mixture was stirred at −78° C. to 20° C. over 2 h. The solution thus obtained was added dropwise to the abovementioned mixed anhydride solution at −78° C. The reaction was stirred at −78° C. for 1 h and then at 20° C. for 4 h, before being treated with H2O (300 mL). The THF was removed in vacuo, then the remainder was extracted with EtOAc (3×300 mL). The combined organic layers were washed with H2O, dried (Na2SO4), filtered, and concentrated in vacuo. Chromatographic separation (EtOAc-n-C6H14, 1:2 to 1:1) afforded two products: (1) (4R)-4-benzyl-3-[(2R)-2-[4-(methylsulfonyl)phenyl]-3-(tetrahydro-2H-pyran-4-yl)propanoyl]-1,3-oxazolidin-2-one: mp 139-141° C. (from Et2O-THF); (2) (4R)-4-benzyl-3-[(2S)-2-[4-(methylsulfonyl)phenyl]-3-(tetrahydro-2H-pyran-4-yl)propanoyl]-1,3-oxazolidin-2-one: m/z (APCI+)=472 [M+H]+. A solution of LiOH (1.5 g, 64 mmol) and 35% aqueous H2O2 (14.5 g, 128 mmol) in H2O (400 mL) was added dropwise over 40 min to a stirred solution of (4R)-4-benzyl-3-[(2R)-2-[4-(methylsulfonyl)phenyl]-3-(tetrahydro-2H-pyran-4-yl)propanoyl]-1,3-oxazolidin-2-one (15.1 g, 10.9 mmol) in THF-H2O (3:1, 1.6 L) at 0° C. The reaction was stirred at 0° C. for 1.5 h, then the remaining oxidant was destroyed with 10% aqueous Na2SO3. The mixture was washed with Et2O (4×300 mL), acidified with 10% aqueous HCl, and extracted with EtOAc (3×200 mL). The combined organic layers were washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. Trituration with Et2O-hexanes gave the title compound: mp 217° C.; the absolute configuration was determined by X-ray crystallographic analysis.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:16]([CH:17]([OH:33])[C:18]4[C:19]([F:32])=[C:20]([NH:25][S:26]([CH2:29][CH2:30][CH3:31])(=[O:28])=[O:27])[CH:21]=[CH:22][C:23]=4[F:24])=[CH:15][NH:14][C:11]3=[N:12][CH:13]=2)=[CH:4][CH:3]=1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl.O>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:16]([C:17]([C:18]4[C:19]([F:32])=[C:20]([NH:25][S:26]([CH2:29][CH2:30][CH3:31])(=[O:27])=[O:28])[CH:21]=[CH:22][C:23]=4[F:24])=[O:33])=[CH:15][NH:14][C:11]3=[N:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(O)c2c[nH]c3ncc(-c4ccc(Cl)cc4)cc23)c1F
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: O
Solvent: C1COCCO1
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2c[nH]c3ncc(-c4ccc(Cl)cc4)cc23)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 50 %

Procedure:
To a solution of 632 (ca. 386 mM) in 1,4-dioxane was added 2,3-dichloro-5,6-dicyanobenzoquinone (83.8 g, 502 mM) followed by water (final 4.8%). The resulting mixture was stirred 2 hours at room temperature and then quenched with one volume of saturated sodium bicarbonate. The mixture was evaporated in vacuo to remove 1,4-dioxane and extracted 3× with ethyl acetate. The combined organic layers were dried over sodium sulfate and evaporated in vacuo to give a crude solid that was purified on a silica-gel column with 94:5:1 dichloromethane/methanol/ammonium hydroxide as eluent to give P-0956 (approximately 50% yield for 3 steps) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([CH2:7][CH2:8]O)=[CH:4][CH:3]=1.[OH-:10].[Na+].Cl.[Cl-].[Na+]>O>[CH3:8][C:7]1[C:5](=[O:6])[CH2:4][CH:3]([OH:10])[C:2]=1[CH3:1]
Reactant: Cc1ccc(CCO)o1
Reactant: [OH-]
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: CC1=C(C)C(O)CC1=O
Temperature: 50 °C
Reaction time: 22 h

Procedure:
In a reaction vessel, water (100 ml) and 5-methyl-2-furylmethylcarbinol (5 g) were charged, and the pH value was adjusted to 5.5 with an aqueous 1/3N NaOH solution and an aqueous 1/3N HCl solution. The temperature was elevated up to 100° C. to reflux, and the mixture was stirred under reflux for 16 hours while maintaining the pH value of 4.0 to 5.7 by the addition of an aqueous 1/3N NaOH solution and an aqueous 1/3N HCl solution. After cooling to 50° C., concentrated hydrochloric acid (10 g; corresponding to 0.9N) was added, and stirring was continued at 50° C. for 22 hours. After cooling, the reaction mixture was neutralized with an aqueous 20% NaOH solution and an aqueous 1/3N NaOH solution. Then, sodium chloride (30 g) was added thereto, and the mixture was extracted with toluene (50 ml) five times. The extract was concentrated at 60° C. under reduced pressure to remove toluene, whereby an oily substance (4.4 g) was obtained. The crude product was subjected to column chromatography with silica gel (60 g) (developing solvent, ethyl acetate-n-hexane (1:2 by volume)), and the objective fraction was concentrated to obtain 2-methyl-3-methyl-4-hydroxy-2-cyclopentenone (3.2 g). Yield, 64%.
Reaction SMILES: [H-].[Na+].[C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]=[CH:8]2)#[N:4].C[N:15]1C(=O)CCC1>>[C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([NH2:15])[CH:9]=[CH:8]2)#[N:4]
Reactant: CN1CCCC1=O
Reactant: N#Cc1ccc2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Product: N#Cc1ccc2c(ccn2N)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 16 %

Procedure:
NaH (60%, 60 mmol) is portion-wise added to a solution of 5-cyano-1H-indole (20 mmol) in NMP (35 mL), and the reaction mixture is 0° C. for 1 h. A solution of HOSA (60 mmol) in NMP (14 mL) is added drop-wise at 0° C. The reaction mixture is warmed to rt and stirred overnight, then quenched with water and extracted with EtOAc. The organic layer is separated, washed with water three times and with brine, dried (Na2SO4), filtered and concentrated in vacuo. The residue is purified by silica gel chromatography eluting with 20-40% EtOAc in heptane to afford 5-cyano-indole-1-ylamine (531 mg, 16%) as a solid. 1H NMR (300 MHz, CDCl3): δ 4.88 (br, 2N—H), 6.53 (d, H), 7.32 (d, H), 7.54 (q, 2H), 7.98 (d, H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10](=[S:13])SC)=[N:7][CH:8]=1.[NH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10]([NH:14][CH2:15][CH2:16][CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:23])([CH3:22])[CH3:24])=[S:13])=[N:7][CH:8]=1
Reactant: COc1ccc(NC(=S)SC)nc1
Reactant: CC(C)(C)OC(=O)NCCCN
Product: COc1ccc(NC(=S)NCCCNC(=O)OC(C)(C)C)nc1
Yield: 100.1 %

Procedure:
Methyl 5-methoxy-2-pyridyldithiocarbamate (950 mg) and t-butyl 3-aminopropylcarbamate (772 mg) were treated in a similar manner to in Reference Example 58, and crystallized from n-hexane-ethanol to give the title compound (1.51 g).
Reaction SMILES: [CH2:1]([C:3]1[NH:4][C:5](=[S:8])[O:6][CH:7]=1)[CH3:2].C(N1C(=O)C2=CC=CC=[C:13]2[C:12]1=[S:21])C>>[CH2:1]([C:3]1[N:4]=[C:5]([S:8][S:21][CH2:12][CH3:13])[O:6][CH:7]=1)[CH3:2]
Reactant: CCN1C(=O)c2ccccc2C1=S
Reactant: CCc1coc(=S)[nH]1
Product: CCSSc1nc(CC)co1

Procedure:
Starting from 4-ethyl-2-thiono-4-oxazoline and N-ethylthiophthalimide there is obtained (4-ethyl-2-oxazolyl)ethyl-disulphide. nD20 =1.5549. IR (liq.): bands inter alia at 3000, 2970, 1590, 1485, 1250, 1135, 1080, 950, 760 cm-1.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH2:13][CH2:12][CH2:11][C:10]=2[C:14]2[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=2)=[CH:5][CH:4]=1.[H-].[Na+].[CH3:26]I>C1COCC1>[CH3:26][O:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH2:13][CH2:12][CH2:11][C:10]=2[C:14]2[CH:15]=[CH:16][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:18][CH:19]=2)=[CH:5][CH:4]=1
Reactant: CI
Reactant: CS(=O)(=O)c1ccc(C2=C(c3ccc(CO)cc3)CCC2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCc1ccc(C2=C(c3ccc(S(C)(=O)=O)cc3)CCC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 30.4 %

Procedure:
Under nitrogen, a stirred solution of 79 mg (0.24 mmol) of 1-[2-(4-hydroxymethylphenyl)cyclopenten-1-yl]-4-(methylsulfonyl)benzene (Example 9) in 2 mL of dry THF at 0° C. was treated with 15 mg (0.6 mmol) of sodium hydride (95%). After 30 minutes, 0.1 mL (1.6 mmol) of methyl iodide was added and the reaction was allowed to warm to ambient temperature overnight. The solvent was removed in vacuo; the residue was dissolved in ethyl acetate and washed with water, dried (MgSO4), and reconcentrated. Purification by silica gel chromatography (MPLC) with hexane/ethyl acetate (5:1) and subsequent lyophilization from acetonitrile/water (1:1) gave 25 mg (30%) of 1-[2-(4-methoxymethylphenyl)cyclopenten-1-yl]-4-(methylsulfonyl)benzene as a colorless solid: NMR (CDCl3) δ2.09 (m, J=7 Hz, 2H), 2.92 (t, J=7 Hz, 4H), 3.03 (s, 3H), 3.40 (s, 3H), 4.42 (s, 2H), 7.12 (d, J=8 Hz, 2H), 7.20 (d, J=8 Hz, 2H), 7.33 (d, J=8 Hz, 2H), 7.73 (d, J=8 Hz, 2H); MS (EI) m/e (rel intensity) 342 (100), 81 (27), 69 (62). HRMS. Calc'd for C20H22O3S: 342.1290. Found: 342.1301. Anal. Calc'd for C20H22O3S: C, 70.15; H, 6.48; S, 9.36. Found: C, 69.86; H, 6.64; S, 9.38.
Reaction SMILES: [F:1][C:2]1[C:11]([F:12])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:13]3[N:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:15][N:14]=3)[CH:8]=2)[C:3]=1[OH:26].[CH2:27]([CH:30]1[O:32][CH:31]1[CH2:33]O)[CH2:28][CH3:29]>>[F:1][C:2]1[C:3]([O:26][CH2:33][CH:31]2[CH:30]([CH2:27][CH2:28][CH3:29])[O:32]2)=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[CH:8]=[C:7]([C:13]1[N:14]=[CH:15][C:16]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:17][N:18]=1)[CH:6]=[CH:5]2
Reactant: CCCCCCOc1cnc(-c2ccc3c(O)c(F)c(F)cc3c2)nc1
Reactant: CCCC1OC1CO
Product: CCCCCCOc1cnc(-c2ccc3c(OCC4OC4CCC)c(F)c(F)cc3c2)nc1

Procedure:
From 2,3-difluoro-6-(5-hexyloxypyrimidin-2-yl)naphthalen-1-ol and (3-propyloxiranyl)methanol by means of the Mitsunobu reaction.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([CH2:22][C:23](O)=[O:24])[C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:26]([N:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([CH2:36][NH:37][CH2:38][CH3:39])[N:31]=1)[CH3:29])[CH3:27]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([C:15]2[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=2)[CH2:22][C:23]([N:37]([CH2:38][CH3:39])[CH2:36][C:32]2[CH:33]=[CH:34][CH:35]=[C:30]([N:28]([CH2:26][CH3:27])[CH3:29])[N:31]=2)=[O:24])(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCNCc1cccc(N(C)CC)n1
Reactant: Cc1ccc(N(CC(=O)O)S(=O)(=O)c2ccc(C(C)(C)C)cc2)cc1
Product: CCN(Cc1cccc(N(C)CC)n1)C(=O)CN(c1ccc(C)cc1)S(=O)(=O)c1ccc(C(C)(C)C)cc1

Procedure:
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-p-tolyl-amino]-acetic acid with ethyl-(6-ethylaminomethyl-pyridin-2-yl)-methyl-amine
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[S:16][C:15]([C:17]3[C:18]([CH2:25][CH3:26])=[C:19]([CH:22]=[CH:23][CH:24]=3)[CH:20]=O)=[N:14][N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[NH:27]1[CH2:31][CH2:30][CH:29]([C:32]([OH:34])=[O:33])[CH2:28]1.CC(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[S:16][C:15]([C:17]3[C:18]([CH2:25][CH3:26])=[C:19]([CH2:20][N:27]4[CH2:31][CH2:30][CH:29]([C:32]([OH:34])=[O:33])[CH2:28]4)[CH:22]=[CH:23][CH:24]=3)=[N:14][N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10]
Reactant: O=C(O)C1CCNC1
Reactant: CCc1c(C=O)cccc1-c1nnc(-c2ccc(OC(C)C)c(Cl)c2)s1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CCc1c(CN2CCC(C(=O)O)C2)cccc1-c1nnc(-c2ccc(OC(C)C)c(Cl)c2)s1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 46.3 %

Procedure:
To a solution of 3-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,3,4-thiadiazol-2-yl)-2-ethylbenzaldehyde (100 mg, 0.258 mmol) (D11) in Ethanol (10 mL) stirred at room temperature was added 3-pyrrolidinecarboxylic acid (119 mg, 1.034 mmol) and AcOH (0.15 mL, 2.62 mmol). The reaction mixture was stirred at room temperature for 10 min, and sodium triacetoxyborohydride (110 mg, 0.522 mmol) was added. The reaction mixture was continuously stirred overnight. The reaction was quenched with water, and EtOH was evaporated in vacuo. The mixture was extracted by EA/THF for 3 times. The combined organic solution was washed by brine, dried over anhydrous Na2SO4. The dried solution was filtered and concentrated, and dissolved in THF. The residue was purified by Mass Directed AutoPrep to afford 1-{[3-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,3,4-thiadiazol-2-yl)-2-ethylphenyl]methyl}-3-pyrrolidinecarboxylic acid (E44) (58 mg) as a TFA salt (off-white solid).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17]([C:18](O)=[O:19])=[C:16]([CH:21]([CH3:23])[CH3:22])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]2=[O:24])=[CH:4][CH:3]=1.S(Cl)([Cl:27])=O>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17]([C:18]([Cl:27])=[O:19])=[C:16]([CH:21]([CH3:23])[CH3:22])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]2=[O:24])=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: CC(C)c1c(C(=O)O)n(-c2ccc(F)cc2)c(=O)c2ccccc12
Product: CC(C)c1c(C(=O)Cl)n(-c2ccc(F)cc2)c(=O)c2ccccc12

Procedure:
A mixture of 2-(4-fluorophenyl)-4-isopropyl-1-oxo-1,2-dihydroisoquinoline-3-carboxylic acid (19.9 g) and thionyl chloride (213 ml) was refluxed for 90 minutes. Excess thionyl chloride was removed in vacuo to give crude 2-(4-fluorophenyl)-4-isopropyl-1-oxo-1,2-dihydroisoquinoline-3-carbonyl chloride (21 g) in the form of a grey/green solid, m.p. 113°-115° C. [Elemental analysis: C, 66.2; H, 4.49; N, 4.06; Cl, 10.8%; calculated: C, 66.4; H, 4.40; N, 4.07; Cl, 10.3%].
Reaction SMILES: C([O:3][C:4](=O)[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]#[C:12][CH2:13][N:14]2[CH:18]=[C:17]([C:19]3[N:27]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])[C:26]4[C:25](=[O:36])[N:24]([CH2:37][CH2:38][CH3:39])[C:23](=[O:40])[N:22]([CH2:41][CH2:42][CH3:43])[C:21]=4[N:20]=3)[CH:16]=[N:15]2)[CH:6]=1)C.[BH4-].[Na+].O>C1COCC1>[OH:3][CH2:4][C:5]1[CH:6]=[C:7]([C:11]#[C:12][CH2:13][N:14]2[CH:18]=[C:17]([C:19]3[N:27]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:33])([CH3:35])[CH3:34])[C:26]4[C:25](=[O:36])[N:24]([CH2:37][CH2:38][CH3:39])[C:23](=[O:40])[N:22]([CH2:41][CH2:42][CH3:43])[C:21]=4[N:20]=3)[CH:16]=[N:15]2)[CH:8]=[CH:9][CH:10]=1
Reactant: CCCn1c(=O)c2c(nc(-c3cnn(CC#Cc4cccc(C(=O)OCC)c4)c3)n2COCC[Si](C)(C)C)n(CCC)c1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCCn1c(=O)c2c(nc(-c3cnn(CC#Cc4cccc(CO)c4)c3)n2COCC[Si](C)(C)C)n(CCC)c1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 54.2 %

Procedure:
To a solution of 3-(3-{4-[2,6-dioxo-1,3-dipropyl-7-(2-trimethylsilanyl-ethoxymethyl)-2,3,6,7-tetrahydro-1H-purin-8-yl]-pyrazol-1-yl}-prop-1-ynyl)-benzoic acid ethyl ester (50 mg, 0.08 mmol) in THF (5 ml), NaBH4 (5 mg, 0.16 mmol) was added slowly at 0° C. It was stirred for 3 h at room temperature. Water was added to reaction mixture and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4 and then filtered and concentrated under vacuum. The residue obtained was purified by column chromatography to obtain 8-{1-[3-(3-hydroxymethyl-phenyl)-prop-2-ynyl]-1H-pyrazol-4-yl}-1,3-dipropyl-7-(2-trimethylsilanyl-ethoxymethyl)-3,7-dihydro-purine-2,6-dione (25 mg, 54%) as an yellow oil.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:18][C:17]2([CH2:21][CH2:20][CH2:19]2)[CH2:16][C:15]2[N:14]=[C:13]([CH:22]([CH3:24])[CH3:23])[C:12]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[C:11](I)[C:10]1=2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[O:31]1[CH2:36][CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH2:33][CH2:32]1.C(=O)([O-])[O-].[Cs+].[Cs+].[F-].[Cs+]>O.O1CCCC1.C1(C)C=CC=CC=1>[Si:1]([O:8][CH:9]1[CH2:18][C:17]2([CH2:21][CH2:20][CH2:19]2)[CH2:16][C:15]2[N:14]=[C:13]([CH:22]([CH3:24])[CH3:23])[C:12]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[C:11]([C:34]3[CH2:35][CH2:36][O:31][CH2:32][CH:33]=3)[C:10]1=2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Reactant: CCOC(=O)c1c(C(C)C)nc2c(c1I)[C@@H](O[Si](C)(C)C(C)(C)C)CC1(CCC1)C2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [F-]
Solvent: Cc1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1c(C(C)C)nc2c(c1C1=CCOCC1)C(O[Si](C)(C)C(C)(C)C)CC1(CCC1)C2

Procedure:
Obtained by starting from (S)-ethyl 5′-(tert-butyldimethylsilyloxy)-4′-iodo-2′-isopropyl-6′,8′-dihydro-5′H-spiro[cyclobutane-1,7′-quinoline]-3′-carboxylate and 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane. A 2 M solution of caesium carbonate in water is used instead caesium fluoride. The reaction is run in tetrahydrofurane/toluene 4:1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12](=O)[CH2:13]Cl)[CH2:7][CH2:6][CH2:5]2.C(=O)([O-])[O-].[K+].[K+].[CH3:22][NH:23][CH2:24][CH2:25][OH:26]>C(#N)C.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][CH2:13][N:23]([CH3:22])[CH2:24][CH2:25][OH:26])[CH2:7][CH2:6][CH2:5]2
Reactant: CNCCO
Reactant: O=C(CCl)N1CCCc2cc(Br)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CN(CCO)CCN1CCCc2cc(Br)ccc21
Temperature: 80 °C
Reaction time: 8 h
Yield: 83.9 %

Procedure:
A solution of 6-bromo-1-(2-iodoethyl)-1,2,3,4-tetrahydroquinoline (compound 1, 0.475 g, 1.298 mmol) in acetonitrile (19 mL) and water (1 mL) in a 50 mL pressure vessel fitted with a stir-bar was treated with potassium carbonate (1.793 g, 12.98 mmol) and 2-(methylamino)ethanol (0.975 g, 12.98 mmol) and the sealed vessel stirred at 80° C. overnight. After 18 hours the mixture was partitioned between CH2Cl2 (100 mL) and water (20 mL) and transferred to a separatory funnel. The organic layer was separated and the aqueous layer (pH=12); extracted further with CH2Cl2. The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated to a brown residue. Purification on silica gel eluting with 5% 2M NH3 in methanol/95% dichloromethane yielded a pale yellow oil, 2 (341 mg, 84%). 1H-NMR (DMSO-d6) δ 7.06 (dd, 1H, J=8.8, 2.5 Hz), 6.99 (d, 1H, J=2.4 Hz), 6.48 (d, 1H, J=8.8), 4.34 (t, 1H, J=5.3 Hz), 3.44 (q, 2H, J=6.2 Hz), 3.32-3.25 (m, 4H), 2.64 (t, 2H, J=6.2 Hz), 2.47-2.41 (m, 4H), 2.23 (s, 3H), 1.83-1.76 (m, 2H). MS (ESI+): 313/315 (MH+, 100).
Reaction SMILES: [NH2:1][C:2]1[C:18]([N:19]([CH2:22][CH3:23])[CH2:20][CH3:21])=[CH:17][C:5]2[NH:6][C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[O:15][CH3:16])=[N:8][C:4]=2[CH:3]=1.[Cl:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][CH:26]=1>>[CH2:22]([N:19]([CH2:20][CH3:21])[C:18]1[C:2]([NH:1][C:29](=[O:30])[C:28]2[CH:32]=[CH:33][C:25]([Cl:24])=[CH:26][CH:27]=2)=[CH:3][C:4]2[N:8]=[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[O:15][CH3:16])[NH:6][C:5]=2[CH:17]=1)[CH3:23]
Reactant: CCN(CC)c1cc2[nH]c(-c3ccccc3OC)nc2cc1N
Reactant: O=C(Cl)c1ccc(Cl)cc1
Product: CCN(CC)c1cc2[nH]c(-c3ccccc3OC)nc2cc1NC(=O)c1ccc(Cl)cc1
Yield: 80.2 %

Procedure:
5-Amino-6-diethylamino-2-(2-methoxyphenyl)-1H-benzo[d]-imidazole (187 mg, 0.6 mmol) was reacted with 4-chlorobenzoyl chloride (105 mg, 0.6 mmol) in the same manner as that described above to give the desired product (216 mg, 80% yield) as pale yellow powder: 1H-NMR (300 MHz, CDCl3) δ 0.99 (t, 6H, J=7.2 Hz), 3.05 (q, 4H, J=7.2 Hz), 4.07 (s, 3H), 7.05 (d, 1H, J=8.4 Hz), 7.11 (t, 1H, J=7.8 Hz), 7.41 (t, 1H, J=7.8 Hz), 7.47 (d, 2H, J=8.4 Hz), 7.67 (s, 1H), 7.88 (d, 2H, J=8.4 Hz), 8.55 (d, 1H, J=6.9 Hz), 8.86 (s, 1H); 13C NMR (75 MHz, CDCl3) δ13.1, 50.6, 55.9, 111.5, 117.7, 121.7, 128.3, 129.0, 129.8, 131.1, 132.5, 133.9, 136.0, 137.7, 150.2, 156.7, 163.4; ESI MS m/z 449.2 [M+H]+.
Reaction SMILES: Cl.[N:2]1[N:3]([CH2:7][C:8]([OH:10])=O)[N:4]=[CH:5][CH:6]=1.[F:11][C:12]1[CH:40]=[CH:39][C:15]([O:16][C:17]2[CH:22]=[CH:21][C:20]([NH:23][C:24]([C@@H:26]3[CH2:30][C@@H:29]([CH2:31][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=4[CH3:38])[CH2:28][NH:27]3)=[O:25])=[CH:19][CH:18]=2)=[CH:14][CH:13]=1>>[N:4]1[N:3]([CH2:7][C:8]([N:27]2[CH2:28][C@H:29]([CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[CH3:38])[CH2:30][C@H:26]2[C:24]([NH:23][C:20]2[CH:21]=[CH:22][C:17]([O:16][C:15]3[CH:39]=[CH:40][C:12]([F:11])=[CH:13][CH:14]=3)=[CH:18][CH:19]=2)=[O:25])=[O:10])[N:2]=[CH:6][CH:5]=1
Reactant: Cc1ccccc1C[C@H]1CN[C@H](C(=O)Nc2ccc(Oc3ccc(F)cc3)cc2)C1
Reactant: O=C(O)Cn1nccn1
Agent: Cl
Product: Cc1ccccc1C[C@@H]1C[C@@H](C(=O)Nc2ccc(Oc3ccc(F)cc3)cc2)N(C(=O)Cn2nccn2)C1

Procedure:
Proceeding as in Example 1, but substituting 2-(2H-1,2,3-triazol-2-yl)acetic acid hydrochloride and (2S,4R)—N-(4-(4-fluorophenoxy)phenyl)-4-(2-methylbenzyl)pyrrolidine-2-carboxamide, gave Compound 48, (2S,4R)-1-(2-(2H-1,2,3-triazol-2-yl)acetyl)-N-(4-(4-fluorophenoxy)phenyl)-4-(2-methylbenzyl)pyrrolidine-2-carboxamide. Major isomer: 1H-NMR (400 MHz, DMSO-D6): δ 9.98 (s, 1H), 7.80 (s, 1H), 7.54 (d, 2H), 7.24-7.08 (m, 6H), 7.04-6.92 (m, 4H), 5.49 (q, 2H), 4.53-4.48 (m, 1H), 3.90-3.83 (m, 1H), 2.80-2.62 (m, 3H), 2.29 (s, 3H), 2.05-1.88 (m, 2H). MS (EI) for C29H28FN5O3. found 514.2 (MH+).