Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]([S:9]([OH:12])(=[O:11])=[O:10])[C:5]([O:7][CH3:8])=[O:6].[C:13]([OH:16])(=[S:15])[CH3:14].CCN(C(C)C)C(C)C>C1COCC1>[C:13]([S:15][CH2:2][CH2:3][CH:4]([S:9]([OH:12])(=[O:11])=[O:10])[C:5]([O:7][CH3:8])=[O:6])(=[O:16])[CH3:14]
Reactant: CC(O)=S
Reactant: COC(=O)C(CCBr)S(=O)(=O)O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C(CCSC(C)=O)S(=O)(=O)O
Temperature: 70 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
5.0 g (19.2 mmol) of 4-bromo-1-methoxy-1-oxobutane-2-sulfonic acid in 100 ml of THF was added 3.0 ml of thioacetic acid and 9.0 ml of DIPEA in 100 ml of THF. The mixture was stirred overnight then refluxed at 70° C. for 1 hr, evaporated and co-evaporated with 3×100 ml of water after being neutralized to pH 7 with NaHCO3. The mixture was redissolved in methanol, filtered through celite, concentrated and purified with SiO2 chromatography eluted with CH3OH/CH2Cl2/HCOOH 37.5:250:1 to 50:250:1) to afford 4.4 g (90% yield) of the title compound. 1H NMR (D2O) 3.95 (dd, 1H, J=4.1, 10.3 Hz), 3.83 (s, 3H), 3.74 (m, 2H), 3.22 (dd, 2H, J=7.4, 14.9 Hz), 2.39 (s, 3H); 13C NMR 203.88, 172.91, 67.32, 56.17, 29.04, 20.61; MS m/z−254.8 (M−H)
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([N:8]=[C:9]([NH2:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[F:12][C:13]([F:24])([F:23])[C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1>>[F:12][C:13]([F:24])([F:23])[C:14]1[CH:19]=[CH:18][C:17]([C:2]2[C:3]3[N:4]([N:8]=[C:9]([NH2:11])[N:10]=3)[CH:5]=[CH:6][CH:7]=2)=[CH:16][CH:15]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: Nc1nc2c(Br)cccn2n1
Product: Nc1nc2c(-c3ccc(C(F)(F)F)cc3)cccn2n1

Procedure:
8-(4-Trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine was prepared from 8-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (504.7 mg, 2.369 mmol) and (4-trifluoromethylphenyl)boronic acid (500.0 mg, 2.632 mmol) in a manner analogous to Step 2c. The reaction product was isolated as a yellow solid (0.64 g, 97%). MP=186-187° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 8.62 (d, J=6.3 Hz, 1H), 8.34 (d, J=8.0 Hz, 2H), 7.88-7.80 (m, 3H), 7.02 (t, J=6.8 Hz, 1H), 6.18 (s, 2H). MS=279 (MH)+. 64b) [4-(4-Methyl-piperazin-1-yl)-phenyl]-[8-(4-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-amine was prepared from 8-(4-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (75.0 mg, 0.270 mmol) and 1-(4-bromo-phenyl)-4-methyl-piperazine (80.0 mg, 0.314 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (30.0 mg, 0.0549 mmol) as the ligand in a manner analogous to Step 2d. The title compound was isolated as a yellow solid (0.033 g, 27%). MP=214-216° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 8.44 (d, J=6.5 Hz, 1H), 8.12 (dm J=8.7 Hz, 2H), 7.77 (d, J=7.4 Hz, 2H), 7.59 (d, J=7.4 Hz, 1H), 7.49 (d, J=7.6 Hz, 2H), 7.00-6.93 (m, 3H), 6.66 (s, 1H), 3.20-3.15 (m, 4H), 2.62-2.57 (m, 4H), 2.36 (s, 3H). MS=453 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([Cl:11])[C:3]=1[CH2:4]O.S(Cl)([Cl:14])=O.CN(C=O)C>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([Cl:11])[C:3]=1[CH2:4][Cl:14]
Reactant: OCc1c(Cl)cc(Cl)cc1Cl
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: ClCc1c(Cl)cc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 100.2 %

Procedure:
To a stirred solution of 2,4,6-trichlorobenzylalcohol (10.0 g; 47.3 mmoles) in chloroform (100 ml) kept under nitrogen atmosphere, thionyl chloride (6.07 mL, 85.1 mmole) was added slowly at 0° C. over a period of 15 minutes followed by catalytic amount of DMF. The reaction mix was allowed to stir at ambient temp for 3 hours. The reaction mixture was quenched with 50 mL of water; the aqueous layer was extracted with DCM (3×100 ml). The combined organic layer was washed with 5% sodium bicarbonate solution (2×50 ml) followed by brine (50 ml) and dried over anhydrous sodium sulphate. The solvent was evaporated under reduced pressure. 10.9 g (100.0% of theory) of 1,3,5-trichloro-2-chloromethyl-benzene was obtained in form of a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[O:38]1[CH2:42][CH2:41][O:40][CH:39]1[CH2:43][NH:44][CH3:45]>>[O:38]1[CH2:42][CH2:41][O:40][CH:39]1[CH2:43][N:44]([CH3:45])[C:21]1[N:20]=[C:19]([O:18][C:11]2[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:8]([NH:7][C:5](=[O:6])[C:4]3[CH:29]=[C:30]([N:32]4[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]4)[CH:31]=[C:2]([F:1])[CH:3]=3)=[CH:9][CH:10]=2)[CH:24]=[CH:23][N:22]=1
Reactant: CNCC1OCCO1
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCCCC4)c3)c3ccccc23)n1
Product: CN(CC1OCCO1)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCCCC4)c3)c3ccccc23)n1

Procedure:
Compound is prepared from 3-fluoro-N-[4-(2-methanesulfonyl-pyrimidin-4-yloxy)-naphthalen-1-yl]-5-piperidin-1-yl-benzamide and [1,3]dioxolan-2-ylmethylmethylamine according to conditions described in general procedure C. Mp: 125-127° C.; 1H NMR (400 MHz, DMSO-d6) δ 1.57-1.61 (m, 6 H), 2.76 (bs, 1 H), 3.04 (bs, 1 H), 3.22-3.32 (m, 7 H), 3.55-3.86 (m, 4 H), 4.74-4.90 (m, 1 H), 6.26 (d, J=5.1 Hz, 1 H), 6.94-6.97 (m, 1 H), 7.15 (d, J=8.8 Hz, 1 H), 7.41 (d, J=8.0 Hz, 1 H), 7.46 (s, 1 H), 7.55-7.60 (m, 3 H), 7.82 (d, J=7.7 Hz, 1 H), 7.96-7.99 (m, 1 H), 8.24 (d, J=5.5 Hz, 1 H), 10.44 (s, 1 H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.CC(CC)=O.[CH2:14]([CH:32]1[CH2:37][C:36](=[O:38])[O:35][C:33]1=[O:34])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31].N#N>COCCOCCOC>[OH:8][C:5]1[CH:6]=[CH:7][C:2]([N:1]=[C:33]([OH:34])[CH:32]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH2:37][C:36]([OH:38])=[O:35])=[CH:3][CH:4]=1
Reactant: CCCCCCCCCCCCCCCCCCC1CC(=O)OC1=O
Reactant: Nc1ccc(O)cc1
Agent: N#N
Solvent: COCCOCCOC
Solvent: CCC(C)=O
Product: CCCCCCCCCCCCCCCCCCC(CC(=O)O)C(O)=Nc1ccc(O)cc1
Temperature: 25 °C

Procedure:
3.7 Grams of 4-aminophenol and 80 ml of ethyl methyl ketone were charged in a 300 ml flask equipped with a stirrer and a condenser and stirred in an atmosphere of room temperature. Thereto was added 12.0 g of powdery n-octadecylsuccinic anhydride little by little in several parts, followed by stirring at 70°-75° C. for 1 hour. Then, 120 ml of diglyme was added thereto, followed by heating with gently passing N2 gas to first distill off ethyl methyl ketone and then slowly distill off diglyme. After distilling off most of diglyme (the time required: about 3 hours), 120 ml of toluene was added to the residue, followed by leaving to cool. The precipitated crystal was filtered off and washed. The crystal was recrystallized from n-propanol to obtain 10.6 g of the desired product. m.p. 133°-134° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C@H:19]([CH2:23][CH:24]([CH3:26])[CH3:25])[C:20]([NH2:22])=[O:21])[CH2:12][CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.CCN(CC)CC.[N:34]([CH2:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[C:35]=[O:36].C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH2:37]([NH:34][C:35]([N:16]1[CH2:15][CH2:14][CH:13]([CH2:12][N:11]([C@@H:19]([C:20](=[O:21])[NH2:22])[CH2:23][CH:24]([CH3:26])[CH3:25])[S:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)(=[O:9])=[O:10])[CH2:18][CH2:17]1)=[O:36])[CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: O=C=NCCc1ccccc1
Reactant: CC(C)C[C@H](C(N)=O)N(CC1CCNCC1)S(=O)(=O)c1ccc(Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)C[C@H](C(N)=O)N(CC1CCN(C(=O)NCCc2ccccc2)CC1)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 55.5 %

Procedure:
To a solution of (2R)-2-[N-(4-chlorobenzenesulfonyl)-N-(piperidin-4-ylmethyl)amino]-4-methyl-pentanoic acid amide (Example 126, 0.10 g, 0.22 mmol) and Et3N (32 μL, 0.25 mmol) in CH2Cl2 (3.0 mL) was added (2-isocyanato-ethyl)-benzene (0.040 mL, 0.30 mmol). The reaction was stirred at rt for 18 h and then was poured into sat. aq. NaHCO3 and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, and concentrated to an oily residue. The residue was further purified on a BIOTAGE® system (eluted with 75% EtOAc/hexanes) to afford the desired product as a white solid (67 mg, 52%). MS (ESI), (M+H)+549.00; 1H NMR (CDCl3, 500 MHz) δ 7.71 (d, 2H, J=8.6), 7.71 (d, 2H, J=8.9), 7.15-7.35 (m, 5H), 6.64 (s, 1H), 5.86 (s, 1H), 4.15 (dd, 1H, J=5.2, 9.5), 3.88 (d, 1H, J=13), 3.76 (d, 1H, J=13), 3.46 (t, 2H, J=6.7), 3.21-3.29 (m, 1H), 2.97 (dd, 1H, J=4.6, 14), 2.65-2.85 (m, 4H), 1.75-1.95 (m, 3H), 1.00-1.30 (m, 5H), 0.75-0.80 (m, 1H), 0.72 (d, 3H, J=6.7), 0.67 (d, 3H, J=6.7).
Reaction SMILES: [CH3:1][CH:2]1[CH2:8][CH:7]2[CH:9]([NH2:10])[CH:4]([CH2:5][CH2:6]2)[CH2:3]1.[Cl:11][C:12]1[S:16][C:15]([S:17](Cl)(=[O:19])=[O:18])=[CH:14][CH:13]=1.N1C=CC=CC=1>C(Cl)Cl>[CH3:1][CH:2]1[CH2:3][CH:4]2[CH:9]([NH:10][S:17]([C:15]3[S:16][C:12]([Cl:11])=[CH:13][CH:14]=3)(=[O:19])=[O:18])[CH:7]([CH2:6][CH2:5]2)[CH2:8]1
Reactant: O=S(=O)(Cl)c1ccc(Cl)s1
Reactant: CC1CC2CCC(C1)C2N
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC1CC2CCC(C1)C2NS(=O)(=O)c1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 66 h
Yield: 10 %

Procedure:
3-Methyl-bicyclo[3.2.1]oct-8-ylamine (prepared in Step 2, 0.165 mmol) was dissolved in DCM (1.5 mL) and treated with 5-chlorothiophenesulphonyl chloride (53.7 mg, 0.248 mmol) followed by pyridine (100 μL). The reaction was stirred at room temperature for 66 h, followed by heating at 60° C. for 18 h. The reaction mixture was evaporated and purified by mass-directed preparative HPLC to give the desired product (5.3 mg, 10%) as a mixture of four isomers. m/z 320 (M+H+).
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[O:9]=[C:10]1[C:15]([NH:16][C:17](=[O:26])[O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:14][CH:13]=[CH:12][NH:11]1>ClCCl>[I:1][C:13]1[CH:14]=[C:15]([NH:16][C:17](=[O:26])[O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:10](=[O:9])[NH:11][CH:12]=1
Reactant: O=C1CCC(=O)N1I
Reactant: O=C(Nc1ccc[nH]c1=O)OCc1ccccc1
Solvent: ClCCl
Product: O=C(Nc1cc(I)c[nH]c1=O)OCc1ccccc1
Reaction time: 8 h
Yield: 50.9 %

Procedure:
N-Iodosuccinimide (0.292 g, 1.30 mmol) was added to a solution of benzyl 2-oxo-1,2-dihydropyridin-3-ylcarbamate (0.317 g, 1.3 mmol) in anhydrous dichloromethane (10 mL) and stirred overnight. The mixture was concentrated and purified by chromatography [silica gel, 0% to 50% ethyl acetate in hexanes gradient elution] to give the title compound (0.245 g). MS 371 (M+1)
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][CH2:12][C:13]#[N:14])[N:6]=1)(=[O:3])[CH3:2].[C:15](OC(=O)C)(=[O:17])[CH3:16].CO>O.N>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:17])[CH3:16])[N:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)Nc1cccc(CCC#N)n1
Agent: N
Solvent: CO
Solvent: O
Product: CC(=O)NCCCc1cccc(NC(C)=O)n1
Temperature: 25 °C
Reaction time: 28 h

Procedure:
2-Acetylamino-6-(2-cyanoethyl)pyridine (11.5 mg, 78 μmol) was dissolved in 25% ammonia water (3.0 ml) and, after purging with nitrogen, palladium black (30 mg) was added thereto. After repurging with nitrogen, the mixture was stirred at room temperature under a hydrogen stream at 9 atmospheres for 28 hours. After nitrogen purging, the palladium black was filtered off and the filtrate was concentrated under reduced pressure. Chloroform (500 μl) was added to the residue and, the mixture was cooled with ice and, after addition of acetic anhydride (100 μl, 1.1 mmol), stirred for 10 minutes. After allowing the temperature to rise to room temperature, stirring was continued for 5 hours. After cooling with ice, methanol (1.0 ml) was added and the mixture was stirred for 1 hour and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography [silica gel 10 g, chloroform-methanol (19:1)→(15:1)] to give 2-acetylamino-6-(3 -acetylaminopropyl)pyridine as a colorless solid (Yield 6 mg (51%)).
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@@:37]2([CH3:38])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:36]2[CH2:35][CH2:34][C@@:33]2([CH3:39])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@@H:21]([S:23][C:24](OC2C=CC=CC=2)=O)[CH3:22])[CH2:12][C@@H:11]([OH:40])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Br[CH2:42][CH2:43][C:44]([CH2:48]C)([OH:47])[CH2:45][CH3:46].O1CCCC1.[OH-].[K+]>CO>[Si:1]([O:8][C@@H:9]1[C@@:37]2([CH3:38])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:36]2[CH2:35][CH2:34][C@@:33]2([CH3:39])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@@H:21]([S:23][CH2:24][CH2:48][C:44]([CH2:45][CH3:46])([OH:47])[CH2:43][CH3:42])[CH3:22])[CH2:12][C@@H:11]([OH:40])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CCC(O)(CC)CCBr
Reactant: C[C@H](SC(=O)Oc1ccccc1)C1=CC[C@H]2C3=CC=C4C[C@@H](O)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCC(O)(CC)CCS[C@@H](C)C1=CC[C@H]2C3=CC=C4C[C@@H](O)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Yield: 121.1 %

Procedure:
Under the same conditions as in Example 3, 1α-(tert-butyldimethylsilyloxy)-3β-hydroxy-20(S)-phenoxycarbonylthiopregna-5,7,16-triene (82.8 mg, 0.143 mmol), 5-bromo-3-ethyl-3-pentanol (139 mg, 0.715 mmol), tetrahydrofuran. (1 ml) and 1M KOH solution in methanol (1 ml) were reacted and worked up, and then the residue was purified by preparative thin layer chromatography (0.5 mm×2, dichloromethane : ethyl acetate=8:1, developed once) to give 99.6 mg of a product, which was directly used in the subsequent reaction because it was difficult to separate from 5-bromo-3-ethyl-3-pentanol.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[O:5][C:6]=1[CH2:7][C:8](OCC)=[O:9].[Li+].[BH4-].Cl>C1COCC1>[CH3:1][C:2]1[N:3]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[O:5][C:6]=1[CH2:7][CH2:8][OH:9]
Reactant: CCOC(=O)Cc1oc(-c2ccccc2)nc1C
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1nc(-c2ccccc2)oc1CCO
Temperature: 25 °C
Reaction time: 8 h
Yield: 25.3 %

Procedure:
Ethyl (4-methyl-2-phenyl-1,3-oxazol-5-yl)acetate (0.922 g, 3.76 mmol) in THF (6 mL) at rt, was added LiBH4 2M/THF (9.41 mL, 4.70 mmol). The reaction was stirred overnight at rt, then treated with 2 N HCl until pH 7. The solvent THF was removed under reduced pressure, EtOAc was added, and phases separated. The combined organic extracts were dried over MgSO4 and solvent concentrated in vacuo. The crude material was purified by Biotage using a gradient of 10 to 100% EtOAc/Hexane as solvent mixture. This gave 2-(4-methyl-2-phenyl-1,3-oxazol-5-yl)ethanol (0.193 g, 25% yield) as colorless oil. ES-MS m/z 204.2 (MH)+); HPLC RT (min.) 2.02; 1H NMR (Acetone-d6) δ 7.98–7.95 (m, 2H), 7.52–7.42 (m, 3H), 3.95 (s br, 1H), 3.82 (t, 2H)m, 2.90 (t, 2H), 2.13 (s, 3H).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[C:10](=O)[O:9][CH:8]2OCC)([CH3:4])([CH3:3])[CH3:2].O.[NH2:19][NH2:20].C(O)(=O)C>O>[C:1]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[C:10](=[O:9])[NH:20][N:19]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC1OC(=O)c2ccc(C(C)(C)C)cc21
Reactant: NN
Solvent: CC(=O)O
Solvent: O
Product: CC(C)(C)c1ccc2c(=O)[nH]ncc2c1
Reaction time: 8 h
Yield: 92.3 %

Procedure:
2.9 g (12 mmol) of 5-tert-butyl-3-ethoxy-3H-isobenzofuran-1-one was weighed into a 50 mL round bottom flask fitted with a stir bar and cap. Added 10 mL (130 mmol) of hydrazine monohydrate. Added 15 mL of glacial acetic acid. Stirred at 100° overnight. Poured the reaction mixture into 200 mL of stirred water. Collected the solids by filtration and washed with water. Dried under high vacuum to obtain 2.24 g of the title compound as an off-white solid. MS (ESI) 203 (M+H)+.
Reaction SMILES: [Br-:1].[OH:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:36])[CH2:10][N+:11]23[CH2:18][CH2:17][CH:14]([CH2:15][CH2:16]2)[C@@H:13]([O:19][C:20](=[O:35])[C@@H:21]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:12]3)=[CH:5][CH:4]=1.[CH3:37][S:38](Cl)(=[O:40])=[O:39].CC#N.O>C(Cl)Cl>[Br-:1].[CH3:37][S:38]([O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:36])[CH2:10][N+:11]23[CH2:16][CH2:15][CH:14]([CH2:17][CH2:18]2)[C@@H:13]([O:19][C:20](=[O:35])[C@@H:21]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[NH:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:12]3)=[CH:5][CH:4]=1)(=[O:40])=[O:39]
Reactant: CS(=O)(=O)Cl
Reactant: O=C(C[N+]12CCC(CC1)[C@@H](OC(=O)[C@H](Nc1ccccc1)c1ccccc1)C2)c1ccc(O)cc1
Agent: [Br-]
Solvent: O
Solvent: ClCCl
Solvent: CC#N
Product: CS(=O)(=O)Oc1ccc(C(=O)C[N+]23CCC(CC2)[C@@H](OC(=O)[C@H](Nc2ccccc2)c2ccccc2)C3)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 31.2 %

Procedure:
To a solution of (R)-1-(2-(4-hydroxyphenyl)-2-oxoethyl)-3-((R)-2-phenyl-2-(phenylamino)acetoxy)-1-azoniabicyclo[2.2.2]octane bromide (diastereomer 1 of I71) (70 mg, 0.13 mmol) in DCM, were sequentially added methanesulfonyl chloride (9.9 μl, 0.13 mmol) and then TEA (17.7 μl, 0.13 mmol). The reaction mixture was stirred at room temperature for two days. The solvent was evaporated, and the crude product was purified first by trituration with Et2O and then by preparative HPLC (eluents: CH3CN/H2O) to obtain (R)-1-(2-(4-(methylsulfonyloxy)phenyl)-2-oxoethyl)-3-((R)-2-phenyl-2-(phenylamino)acetoxy)-1-azoniabicyclo[2.2.2]octane bromide (25.5 mg, 31.9% yield).
Reaction SMILES: FC(F)(F)C(O)=O.N[C@@H]1CCN(C2N=C3C(N=CN3[C@@H]3C[C@H](NC(=O)COCC4C=CC=CC=4)[C@@H](O)[C@H]3O)=C(NCC(C3C=CC=CC=3)C3C=CC=CC=3)N=2)C1.[Cl:57][C:58]1[N:66]=[C:65]2[C:61]([N:62]=[CH:63][N:64]2[C@@H:67]2[CH2:71][C@H:70]([NH:72][C:73](=[O:76])[CH2:74][CH3:75])[C@@H:69]([OH:77])[C@H:68]2[OH:78])=[C:60]([NH:79][CH2:80][CH:81]([C:88]2[CH:93]=[CH:92][CH:91]=[CH:90][CH:89]=2)[C:82]2[CH:87]=[CH:86][CH:85]=[CH:84][CH:83]=2)[N:59]=1.[N:94]1([C@@H:99]2[CH2:103][CH2:102][NH:101][CH2:100]2)[CH2:98][CH2:97][CH2:96][CH2:95]1>>[ClH:57].[N:94]1([C@@H:99]2[CH2:103][CH2:102][N:101]([C:58]3[N:66]=[C:65]4[C:61]([N:62]=[CH:63][N:64]4[C@@H:67]4[CH2:71][C@H:70]([NH:72][C:73](=[O:76])[CH2:74][CH3:75])[C@@H:69]([OH:77])[C@H:68]4[OH:78])=[C:60]([NH:79][CH2:80][CH:81]([C:82]4[CH:87]=[CH:86][CH:85]=[CH:84][CH:83]=4)[C:88]4[CH:89]=[CH:90][CH:91]=[CH:92][CH:93]=4)[N:59]=3)[CH2:100]2)[CH2:98][CH2:97][CH2:96][CH2:95]1
Reactant: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(Cl)nc32)[C@H](O)[C@@H]1O
Reactant: C1CCN([C@@H]2CCNC2)C1
Agent: N[C@@H]1CCN(c2nc(NCC(c3ccccc3)c3ccccc3)c3ncn([C@@H]4C[C@H](NC(=O)COCc5ccccc5)[C@@H](O)[C@H]4O)c3n2)C1
Solvent: O=C(O)C(F)(F)F
Product: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(N4CC[C@@H](N5CCCC5)C4)nc32)[C@H](O)[C@@H]1O
Product: Cl

Procedure:
The title compound is prepared analogously to N-{(1S,2R,3S,4R)-4-[2-((R)-3-amino-pyrrolidin-1-yl)-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentyl}-2-benzyloxy-acetamide trifluoroacetate (Example 1 step 2) by replacing 2-benzyloxy-N-{(1S,2R,3S,4R)-4-[2-chloro-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentyl}-acetamide with N-{(1S,2R,3S,4R)-4-[2-chloro-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentyl}-propionamide (Intermediate J) and by replacing (3R)-3-aminopyrrolidine with (R)-[1,3′]bipyrrolidinyl (Intermediate N). (MH+ 625.4)
Reaction SMILES: [Br:1][C:2]1[C:3]([N:16]2[CH2:20][CH2:19][C@@H:18]([NH:21]C(=O)OC(C)(C)C)[CH2:17]2)=[C:4]2[C:10]([NH:11][C:12](=[O:15])[CH2:13][OH:14])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.C(O)(C(F)(F)F)=O.C(Cl)[Cl:37]>>[ClH:37].[NH2:21][C@@H:18]1[CH2:19][CH2:20][N:16]([C:3]2[C:2]([Br:1])=[CH:7][N:6]=[C:5]3[NH:8][CH:9]=[C:10]([NH:11][C:12](=[O:15])[CH2:13][OH:14])[C:4]=23)[CH2:17]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCN(c2c(Br)cnc3[nH]cc(NC(=O)CO)c23)C1
Reactant: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cl
Product: N[C@@H]1CCN(c2c(Br)cnc3[nH]cc(NC(=O)CO)c23)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85 %

Procedure:
(R)-tert-Butyl 1-(5-bromo-3-(2-hydroxyacetamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)pyrrolidin-3-ylcarbamate (0.150 g, 0.330 mmol) was placed in DCM (3 mL) at room temperature. TFA (1 mL) was then added, and the reaction was stirred at room temperature for 1 hour and concentrated to dryness. The resulting residue was then purified by reverse phase chromatography (Biotage SP4, C-18 25M+, 0-50% CH3CN/water). The resulting product was next dissolved in minimal DCM (with MeOH to aid solubility) and added to a stirred solution of 1M HCl in ether. The resulting solid was filtered, washed with ether and dried to give (R)—N-(4-(3-aminopyrrolidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-hydroxyacetamide hydrochloride (0.120 g, 85% yield) as a solid. 1H NMR (400 MHz, D2O) δ 8.17 (s, 1H), 7.46 (s, 1H), 4.13 (s, 2H), 4.01-3.93 (m, 11-10, 3.91-3.88 (m, 1H), 3.68-3.61 (m, 1H), 3.60-3.53 (m, 2H), 2.41-2.38 (m, 1H), 2.05-2.02 (m, 1H). LCMS (APCI+) m/z 354, 356 (M+H)+.
Reaction SMILES: O1CCCC1.[O:6]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21](Cl)=[N:22][OH:23])=[CH:16][CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:25]([C:27]1[C:28]([NH2:33])=[N:29][CH:30]=[CH:31][CH:32]=1)#[CH:26].C(N(CC)CC)C>O>[O:6]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21]2[CH:26]=[C:25]([C:27]3[C:28]([NH2:33])=[N:29][CH:30]=[CH:31][CH:32]=3)[O:23][N:22]=2)=[CH:16][CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: ON=C(Cl)Cc1ccc(COc2ccccc2)cc1
Reactant: C#Cc1cccnc1N
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Nc1ncccc1-c1cc(Cc2ccc(COc3ccccc3)cc2)no1
Temperature: 50 °C
Reaction time: 2 h
Yield: 31.4 %

Procedure:
To a tetrahydrofuran (3 mL) solution of (4-phenoxymethyl-phenyl)-acetohydroximoyl chloride (150 mg, 0.545 mmol) described in Manufacturing Example 86-1-5 and 3-ethynyl-pyridin-2-ylamine (41 mg, 0.348 mmol) described in Manufacturing Example 1-2-3 was added triethylamine (104 μL, 0.747 mmol), which was stirred for 2 hours at 50° C. Water was added to the reaction solution at room temperature, which was then extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was evaporated under a reduced pressure. The residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=4:1-2:1) to obtain the title compound (39 mg, 20%).
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1.[OH:13][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]2[C:23]=1[N:22]=[CH:21][CH:20]=[CH:19]2.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:11]=[CH:12][C:3]=1[CH2:2][O:13][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]2[C:23]=1[N:22]=[CH:21][CH:20]=[CH:19]2
Reactant: Oc1cccc2cccnc12
Reactant: BrCc1ccc2ccccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: c1ccc2cc(COc3cccc4cccnc34)ccc2c1
Temperature: 25 °C
Yield: 75.9 %

Procedure:
2-(bromomethyl) naphthalene (663 mg, 3 mmol) was added to a stirred mixture of 8-hydroxy quinoline (435 mg, 3 mmol), K2CO3 (621 mg, 4.5 mmol) in acetone (20 ml) at room temperature. The reaction mixture was stirred at rt over weekend and then partitioned between EtOAc and water. Water layer was extracted with EtOAc (2×100 ml). The combined organic phase was washed with water (2×100 ml), brine and dried over sodium sulfate. After removal of solvent, the residue was washed with ether to give 650 mg of compound I-81. 1H-NMR (500 MHz, CDCl3).