Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH2:27])=[N:5][C:6]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)[N:10]=2)=[N:7][CH:8]=1.[F:28][C:29]1[CH:34]=[C:33](B(O)O)[CH:32]=[CH:31][N:30]=1.C(N(CC)CC)C>ClC(Cl)Cl.CN(C)C1C=CN=CC=1.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[F:28][C:29]1[CH:34]=[C:33]([NH:27][C:4]2[C:3]([O:2][CH3:1])=[CH:8][N:7]=[C:6]([C:9]3[C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[N:11]([CH2:18][C:19]4[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=4)[N:10]=3)[N:5]=2)[CH:32]=[CH:31][N:30]=1
Reactant: COc1ccc(Cn2nc(-c3ncc(OC)c(N)n3)c3ccccc32)cc1
Reactant: OB(O)c1ccnc(F)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: CN(C)c1ccncc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1ccc(Cn2nc(-c3ncc(OC)c(Nc4ccnc(F)c4)n3)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
100 mg of 5-methoxy-2-[1-(4-methoxybenzyl)-1H-indazol-3-yl]pyrimidin-4-amine (1-4-1, 0.277 mmol, 1. eq.), 78.0 mg of (2-fluoropyridin-4-yl)boronic acid (0.553 mmol, 2 eq.) and 205 mg of copper (II) acetate were suspended in 4 ml of trichloromethane. 154 μl of triethylamine (1.11 mmol, 4 eq.) and 16.9 mg of N,N-dimethylpyridin-4-amine (138 mmol, 0.5 eq.) were added. The reaction mixture was stirred at room temperature for 24 hours. The reaction mixture was filtered off over Celite 545 and washed with dichloromethane. The filtrate was concentrated in vacuo. The residue was purified by flash chromatography and preparative HPLC to yield 13 mg (0.03 mmol, 10.9%) of the analytically pure target compound.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:9])=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].N1C=CC=CC=1.[F:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=1[S:24](Cl)(=[O:26])=[O:25]>C(Cl)Cl>[Br:1][C:2]1[C:3]([F:9])=[C:4]([NH:5][S:24]([C:18]2[CH:19]=[C:20]([F:23])[CH:21]=[CH:22][C:17]=2[F:16])(=[O:26])=[O:25])[CH:6]=[CH:7][CH:8]=1
Reactant: Nc1cccc(Br)c1F
Reactant: O=S(=O)(Cl)c1cc(F)ccc1F
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=S(=O)(Nc1cccc(Br)c1F)c1cc(F)ccc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.4 %

Procedure:
3-Bromo-2-fluoroaniline (10 g, 52.63 mmol) was dissolved in DCM (100 mL) under nitrogen atmosphere. Dry pyridine was added (6 mL, 73.68 mmol), followed by 2,5-difluorobenzenesulfonyl chloride (7.08 mL, 52.63 mmol) and the mixture was stirred at r.t. for 2 h. It was then diluted with DCM and washed with aqueous 0.5 N HCl (3×80 mL) and brine. The organic layer was dried over Na2SO4 and evaporated to dryness. The solid was taken up with diethyl ether and stirred for 30 min. It was then filtered and dried at 40° C. under reduced pressure to give 17.8 g of N-(3-bromo-2-fluoro-phenyl)-2,5-difluoro-benzenesulfonamide as a pale yellow solid (92%).
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([C:37]1[C:38]2[CH:45]=[CH:44][CH:43]=[CH:42][C:39]=2[S:40][CH:41]=1)=[O:36]>>[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([C:37]3[C:38]4[CH:45]=[CH:44][CH:43]=[CH:42][C:39]=4[S:40][CH:41]=3)=[O:36])[CH2:16][CH2:17]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Reactant: O=C(CCCCCBr)c1csc2ccccc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCC(=O)c2csc3ccccc23)CC1
Yield: 44.9 %

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride (0.50 g) as starting compound, potassium carbonate (0.75 g) and 6-bromo-1-(3-benzo[b]thienyl)-1-hexanone (0.42 g) were reacted and treated in the same manner as in Example 172 to give 0.32 g of 4-amino-5-chloro-N-((1-(6-(3-benzo[b]thienyl)-6-oxohexyl)piperidin-4-yl)-methyl)-2-methoxybenzamide.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[CH:7]=[C:6]2[C:13]1[N:25]([S:26]([C:29]2[CH:35]=[CH:34][C:32]([CH3:33])=[CH:31][CH:30]=2)(=[O:28])=[O:27])[C:16]2=[N:17][CH:18]=[C:19]3[CH:23]=[N:22][N:21]([CH3:24])[C:20]3=[C:15]2[CH:14]=1.B(Br)(Br)Br.CO.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:12][N:8]1[C:9]2[C:5](=[CH:4][C:3]([OH:2])=[CH:11][CH:10]=2)[C:6]([C:13]2[N:25]([S:26]([C:29]3[CH:35]=[CH:34][C:32]([CH3:33])=[CH:31][CH:30]=3)(=[O:28])=[O:27])[C:16]3=[N:17][CH:18]=[C:19]4[CH:23]=[N:22][N:21]([CH3:24])[C:20]4=[C:15]3[CH:14]=2)=[CH:7]1
Reactant: COc1ccc2c(c1)c(-c1cc3c4c(cnc3n1S(=O)(=O)c1ccc(C)cc1)cnn4C)cn2C
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2c(-c3cn(C)c4ccc(O)cc34)cc3c4c(cnc32)cnn4C)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 96.8 %

Procedure:
A solution of 7-(5-methoxy-1-methyl-1H-indol-3-yl)-1-methyl-6-tosyl-1,6-dihydropyrazolo[3,4-d]pyrrolo[2,3-b]pyridine (0.22 g, 0.46 mmol, [WO2009/152133, Example #42]) in DCM (10 mL) was cooled to about 0° C. BBr3 (1.0 M in DCM, 1.39 mL, 1.39 mmol) was added dropwise. The mixture was stirred at rt for about 16 h. The mixture was cooled to about 0° C. and MeOH (0.5 mL) was added dropwise followed by a solution of saturated aqueous NaHCO3 (6 mL). The mixture was concentrated in vacuo and the residue was partitioned between EtOAc (2×75 mL) and saturated aqueous NaHCO3 (50 mL). The organic layer was isolated and washed with saturated aqueous NaHCO3 (50 mL), brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (12 g silica gel column, EtOAc/MeOH/Et3N 100:10:0 to 100:10:1) to give 1-methyl-3-(1-methyl-6-tosyl-1,6-dihydropyrazolo[3,4-d]pyrrolo[2,3-b]pyridin-7-yl)-1H-indol-5-ol (0.21 g, 99%): LC/MS (Table 2, Method a) Rt=2.10 min; MS m/z 472 (M+H)+.
Reaction SMILES: [CH2:1]([OH:5])[CH:2]([OH:4])[CH3:3].[CH3:6][Si:7](Cl)([CH3:9])[CH3:8]>C[Si](N[Si](C)(C)C)(C)C>[Si:7]([O:4][CH:2]([CH2:1][O:5][Si:7]([CH3:9])([CH3:8])[CH3:6])[CH3:3])([CH3:9])([CH3:8])[CH3:6]
Reactant: C[Si](C)(C)Cl
Reactant: CC(O)CO
Agent: C[Si](C)(C)N[Si](C)(C)C
Product: CC(CO[Si](C)(C)C)O[Si](C)(C)C
Temperature: 60 °C

Procedure:
1,2-Propanediol (58.8 g, 0.77 mol) was placed in a 500 mL 3-necked RB flask and treated with 0.2 mL trimethylsilyl chloride. A small volume of HMDS (ca. 10 mL) was added, and an exothermic reaction took place as the mixture became homogeneous. The remainder of the HMDS (170 mL) was added at a controlled rate (ca. 3-5 mL/min), maintaining the reaction temperature at ca. 50-70° C. Heating was continued at 100° C. (1.5 h), 120° C. (1.0 h), and 140° C. (2.5 h). GC analysis (method 1) revealed excess HMDS and one product. Distillation provided 147 g of colorless oil, bp 70-72° C./10 mm. 1H NMR (CDCl3): 3.83 (m, 1 H), 3.50 and 3.38 (AB pattern with additional coupling, 2 H), 1.15 (d, J=7 Hz, 3 H), 0.15 (partially resolved singlets, 18 H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[C:8]([OH:13])=[CH:7][C:6]([CH3:14])=[CH:5]2.[C:15]([O:19][CH2:20][CH3:21])(=[O:18])[CH:16]=[O:17]>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[C:8]([OH:13])=[C:7]([CH:16]([OH:17])[C:15]([O:19][CH2:20][CH3:21])=[O:18])[C:6]([CH3:14])=[CH:5]2
Reactant: Cc1cc(O)c2cc(F)c(Cl)cc2c1
Reactant: CCOC(=O)C=O
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: CCOC(=O)C(O)c1c(C)cc2cc(Cl)c(F)cc2c1O
Reaction time: 0.75 h
Yield: 58.7 %

Procedure:
To a mixture of 6-chloro-7-fluoro-3-methylnaphthalen-1-ol (2.24 g, 13.78 mmol) in anhydrous dichloromethane (100 mL) at −40° C. was added a 1 M titanium(IV) chloride solution in dichloromethane (13.78 mL, 13.78 mmol) and stirred for 45 min. Ethyl glyoxylate (1.69 g, 16.54 mmol) dissolved in dichloromethane (5 mL) was added over 15 minutes and stirred for 1 hour at −40° C. The reaction was quenched by the addition of Rochelle's salt solution and stirred at room temperature for 2.5 hours. The resulting mixture was washed with water and aqueous layer back-extracted with dichloromethane (2×). The combined organic layer was dried (MgSO4), filtered, concentrated and purified by flash column chromatography (silica gel, 5 to 30% ethyl acetate/hexanes) to give an off-white solid (2.53 g). 1H-NMR: 400 MHz, (CDCl3) δ: 8.48 (s, 1H), 7.89 (d, J=10.5 Hz, 1H), 7.70 (d, J=7.2 Hz, 1H), 7.11 (s, 1H), 5.67 (s, 1H), 4.30 (dq, J=10.8, 7.1 Hz, 1H), 4.15 (dq, J=10.8, 7.1 Hz, 1H), 3.61 (s, 1H), 2.52 (s, 3H), 1.20 (t, J=7.1 Hz, 3H). LCMS-ESI+ (m/z): [M+H]+ calcd for C15H13ClFO4: 311.7; found: 311.0.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[F:9].[N+:10]([O-])([OH:12])=[O:11].CCOCC>OS(O)(=O)=O>[Br:1][C:2]1[CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[C:5]([F:8])=[CH:4][C:3]=1[F:9]
Reactant: O=[N+]([O-])O
Reactant: Fc1ccc(Br)c(F)c1
Agent: O=S(=O)(O)O
Solvent: CCOCC
Product: O=[N+]([O-])c1cc(Br)c(F)cc1F
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 93.3 %

Procedure:
To a suspension of 1-bromo-2,4-difluorobenzene (11.7 mL, 104 mmol) in 96 mL concentrated H2SO4 at 0° C. was added concentrated HNO3 (85 mL) dropwise maintaining the temperature below 20° C. The resulting mixture was stirred for 10 minutes at 0° C., then poured into a mixture of ether and ice water with vigorous stirring. The aqueous phase was separated and extracted with ether. The combined organic phases were washed with aqueous NaHCO3 and brine, dried and concentrated. The residue was purified using silica gel column chromatography with 15% acetone in hexanes to provide 1-bromo-2,4-difluoro-5-nitrobenzene (23 g, 96.6 mmol, 93.3% yield) as yellow oil.
Reaction SMILES: [CH2:1]([C:3]1[O:8][C:7](=[O:9])[C:6]([C:10](=[O:13])[CH2:11][CH3:12])=[C:5]([OH:14])[CH:4]=1)[CH3:2].[Li+].CC([N-]C(C)C)C.Br[CH2:24][CH2:25][CH2:26][O:27][Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29].CN(P(N(C)C)(N(C)C)=O)C>C1COCC1>[Si:28]([O:27][CH2:26][CH2:25][CH2:24][CH:1]([C:3]1[O:8][C:7](=[O:9])[C:6]([C:10](=[O:13])[CH2:11][CH3:12])=[C:5]([OH:14])[CH:4]=1)[CH3:2])([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29]
Reactant: CCC(=O)c1c(O)cc(CC)oc1=O
Reactant: CC(C)(C)[Si](C)(C)OCCCBr
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCC(=O)c1c(O)cc(C(C)CCCO[Si](C)(C)C(C)(C)C)oc1=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
6-Ethyl-4-hydroxy-3-propionyl-2-H-pyran-2-one (III; 0.5 g; 2.56 mmol) was dissolved in 20 ml anhydrous THF and cooled to 0° C. under argon. To the cooled solution, was added LDA (5.12 ml of 1.5 M in cyclohexane; 7.68 mmol; Aldrich) and the reaction mixture was stirred for 30 min. To the cooled reaction mixture, was added 3-bromopropoxy-t-butyldimethylsilane (0.77 g; 3.07 mmol; Aldrich) and 1 ml HMPA (Aldrich). The reaction mixture was stirred for 30 min at 0° C., quenched with saturated NH4Cl, extracted with 3×20 ml EtOAc, dried with anhydrous Na2SO4, and evaporated to an oil. The product was purified via silica chromatography (10% EtOAc in hexanes).
Reaction SMILES: CC1C=CC(S([O-])(=O)=O)=CC=1.[CH3:12][O:13][C:14]1[CH:15]=[N+:16]([CH3:27])[C:17]2[C:22]([CH:23]=1)=[C:21]([N+:24]([O-:26])=[O:25])[CH:20]=[CH:19][CH:18]=2.[BH4-].[Na+].O>CO>[CH3:12][O:13][C:14]1[CH2:15][N:16]([CH3:27])[C:17]2[C:22]([CH:23]=1)=[C:21]([N+:24]([O-:26])=[O:25])[CH:20]=[CH:19][CH:18]=2
Reactant: COc1cc2c([N+](=O)[O-])cccc2[n+](C)c1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC1=Cc2c(cccc2[N+](=O)[O-])N(C)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-methoxy-1-methyl-5-nitroquinolinium 4-methylbenzenesulfonate in methanol is added sodium borohydride at room temperature. The mixture is stirred at room temperature for 2 h and water is added. Water is added and the mixture is extracted with ethyl acetate. The organic layer is dried, filtered and concentrated under reduced pressure to give 3-methoxy-1-methyl-5-nitro-1,2-dihydroquinoline.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH3:11][CH2:12][Mg+].[Br-].B(F)(F)F.CCOCC>CCOCC>[Br:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[C:4]1([NH2:5])[CH2:12][CH2:11]1
Reactant: CC[Mg+]
Reactant: N#Cc1ccc(F)cc1Br
Agent: FB(F)F
Agent: [Br-]
Solvent: CCOCC
Product: NC1(c2ccc(F)cc2Br)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.2 %

Procedure:
To a stirred solution of 2-bromo-4-fluorobenzonitrile (5 g, 25 mmol) and Ti(Oi-Pr)4 (9.05 mL, 27.5 mmol) in ether (100 mL) at −78° C. was added EtMgBr (18.3 mL, 55 mmol) dropwise. The solution was allowed to warm to room temperature and stirred for 1 hour before BF3-Et2O (6.25 mL) was added and stirring continued at room temperature for another 1 hour. The reaction solution was quenched with 1 N HCl solution, and washed with EtOAc. The aqueous layer was adjusted to pH˜10 with aq. NaOH (2 N) solution and then exacted with EtOAc (3×). The combined organic layers were dried over anhy. Na2SO4, filtered, and concentrated in vacuo. The residue was then purified by column chromatography to give title compound (3.0 g, yield 52.2%) as yellowish oil.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:9]1([CH2:14][C:15]([N:17]2[CH2:21][C@H:20]([NH2:22])[CH2:19][C@H:18]2[C:23]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][C:33]3[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=3)=[CH:28][CH:27]=2)=[O:24])=[O:16])[CH:13]=[N:12][CH:11]=[N:10]1.CN(C=O)C.C(=O)([O-])[O-].[K+].[K+]>CO>[N:9]1([CH2:14][C:15]([N:17]2[CH2:21][C@H:20]([NH:22][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:19][C@H:18]2[C:23]([NH:25][C:26]2[CH:27]=[CH:28][C:29]([O:32][C:33]3[CH:34]=[CH:35][C:36]([F:39])=[CH:37][CH:38]=3)=[CH:30][CH:31]=2)=[O:24])=[O:16])[CH:13]=[N:12][CH:11]=[N:10]1
Reactant: BrCc1ccccc1
Reactant: N[C@@H]1C[C@@H](C(=O)Nc2ccc(Oc3ccc(F)cc3)cc2)N(C(=O)Cn2cncn2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](NCc2ccccc2)CN1C(=O)Cn1cncn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 24.4 %

Procedure:
Benzyl bromide (0.111 mL, 0.934 mmol) was added to a flask charged with (2S,4R)-1-(2-(1H-1,2,4-triazol-1-yl)acetyl)-4-amino-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide (0.330 g, 0.778 mmol), DMF (3 mL) and potassium carbonate (0.429 g, 3.11 mmol). The reaction mixture was stirred at ambient temperature for 1 hour and then diluted with methanol (2 mL). Product was purified by reverse phase HPLC to give Compound 179, (2S,4R)-1-(2-(1H-1,2,4-triazol-1-yl)acetyl)-4-(benzylamino)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide (97 mg, 0.19 mmol, 24%) as an off-white solid. 1H-NMR (400 MHz, DMSO-d6): 10.08 (s, 1H), 8.44 (s, 1H), 7.95 (s, 1H), 7.57 (d, J=9.6 Hz, 2H), 7.38-7.30 (m, 4H), 7.26-7.16 (m, 3H), 7.03-6.93 (m, 4H), 5.24-5.21 (m, 2H), 4.53-4.48 (m, 1H), 3.85-3.79 (m, 1H), 3.75 (s, 2H), 3.51-3.45 (m, 2H), 3.17 (d, J=6.0 Hz, 1H), 2.15-2.00 (m, 2H). MS (EI) for C28H27FN6O3. found 515.2 (MH+).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:16]([S:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[N+:36]([O-:38])=[O:37])(=[O:29])=[O:28])[CH:17]2[CH2:26][C:25]3[N:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH2:19][CH2:18]2)=[CH:11][CH:10]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][N:16]([CH:17]2[CH2:26][C:25]3[N:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH2:19][CH2:18]2)[S:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[N+:36]([O-:38])=[O:37])(=[O:28])=[O:29])=[CH:13][CH:14]=1
Reactant: CC(C)(C)OC(=O)NCc1ccc(CN(C2CCc3cccnc3C2)S(=O)(=O)c2ccccc2[N+](=O)[O-])cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCc1ccc(CN(C2CCc3cccnc3C2)S(=O)(=O)c2ccccc2[N+](=O)[O-])cc1
Reaction time: 0.33 h
Yield: 57.2 %

Procedure:
To a stirred solution of (4-{[(2-Nitro-benzenesulfonyl)-(5,6,7,8-tetrahydro-quinolin-7-yl)-amino]-methyl}-benzyl)-carbamic acid tert-butyl ester (160 mg, 0.29 mmol) in anhydrous CH2Cl2 (2 mL) was added TFA (2 mL). The resultant solution was stirred at room temperature overnight. The mixture was concentrated in vacuo, dissolved with MeOH, and added NaHCO3. The mixture was stirred for 20 min, diluted with CH2Cl2, filtered through celite. The crude product was purified by flash chromatography on silica gel (1:1:98 CH3OH—NH3 H2O—CH2Cl2) afforded the title compound (75 mg, 57%) as a white foam.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]=[C:15]([F:17])[CH:16]=1)[CH2:5][NH:6][C:7](=[O:13])[CH:8]([CH3:12])[C:9]([OH:11])=O.O1CCCC1.[NH2:23][CH:24]1[N:30]=[C:29]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:28]2[CH:37]=[CH:38][CH:39]=[CH:40][C:27]=2[N:26]([CH3:41])[C:25]1=[O:42].Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C>>[F:17][C:15]1[CH:14]=[C:4]([CH:3]=[C:2]([F:1])[CH:16]=1)[CH2:5][NH:6][C:7](=[O:13])[CH:8]([CH3:12])[C:9]([NH:23][CH:24]1[C:25](=[O:42])[N:26]([CH3:41])[C:27]2[CH:40]=[CH:39][CH:38]=[CH:37][C:28]=2[C:29]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[N:30]1)=[O:11]
Reactant: CN1C(=O)C(N)N=C(c2ccccc2)c2ccccc21
Reactant: CC(C(=O)O)C(=O)NCc1cc(F)cc(F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C(=O)NCc1cc(F)cc(F)c1)C(=O)NC1N=C(c2ccccc2)c2ccccc2N(C)C1=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 67 %

Procedure:
To a solution of 0.073 g (0.3 mmol) N-(3,5-difluoro-benzyl)-2-methyl-malonamic acid in 5 ml of tetrahydrofuran 0.080 g (0.3 mmol) of (3RS)-3-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one, 0.058 g (0.3 mmol) of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride, 0.040 g (0.3 mmol) of 1-hydroxybenzotrizole hydrate and 0.039 g (0.3 mmol) of N,N-diisopropyl-ethylamine were added. The mixture was stirred at room temperature for 18 h. After concentration in vacuo 0.5 N HCl (5 ml) was added and the mixture was extracted with dichloromethane (three times 5 ml). The combined organic layers were extracted with 0.5 N aqueous NaHCO3 solution, dried (MgSO4) and evaporated on the rotary evaporator. The residue was purified by flash chromatography (hexane/ethyl acetate=3:1) to yield 0.099 g (67%) of the diastereomeric mixture of title compound as white solid.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([NH:13][S:14]([C:17]2[S:18][CH:19]=[CH:20][CH:21]=2)(=[O:16])=[O:15])[CH:10]=[C:9]1[C:22]([O:24]CC)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:29]I.O>CN(C)C=O>[CH2:1]([N:8]1[C:9]([CH:22]=[O:24])=[CH:10][C:11]([N:13]([CH3:29])[S:14]([C:17]2[S:18][CH:19]=[CH:20][CH:21]=2)(=[O:16])=[O:15])=[CH:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CI
Reactant: CCOC(=O)c1cc(NS(=O)(=O)c2cccs2)cn1Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(c1cc(C=O)n(Cc2ccccc2)c1)S(=O)(=O)c1cccs1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 57 %

Procedure:
To a solution of ethyl 1-benzyl-4-[(2-thienylsulfonyl)amino]-1H-pyrrole-2-carboxylate (19.5 g) in N,N-dimethylformamide (100 mL) was slowly added sodium hydride (60%, oily, 2.2 g) at 0° C., and the mixture was stirred at room temperature for 30 min. Methyl iodide (3.4 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography to give a yellow oil from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio). To a solution of the yellow oil in tetrahydrofuran (150 mL) was slowly added lithium aluminum hydride (2.2 g) in small portions. The reaction mixture was stirred at room temperature for 1 hr, and water (2.2 mL), 15% aqueous sodium hydroxide solution (2.2 mL) and water (6.6 mL) were successively added to the reaction mixture under ice-cooling. The reaction mixture was stirred for 1 hr, and the insoluble material was filtered off. The filtrate was concentrated, manganese dioxide (30 g) was added to a solution of the residue in tetrahydrofuran (200 mL), and the mixture was stirred at room temperature overnight. The manganese dioxide was filtered off and the filtrate was concentrated. The residue was subjected to silica gel column chromatography to give N-(1-benzyl-5-formyl-1H-pyrrol-3-yl)-N-methylthiophene-2-sulfonamide (10.3 g, yield 57%) as a yellow oil from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio).
Reaction SMILES: [O:1]=[C:2]([C:5]1[C:6]([C:15](O)=[O:16])=[CH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:3][CH3:4].[H-].[Al+3].[Li+].[H-].[H-].[H-].O>C1COCC1>[OH:16][CH2:15][C:6]1[C:5]([CH:2]([OH:1])[CH2:3][CH3:4])=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=1
Reactant: CCC(=O)c1cc2ccccc2cc1C(=O)O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CCC(O)c1cc2ccccc2cc1CO
Reaction time: 2 h

Procedure:
The above carboxylic acid (11 g) in THF (150 ml) was added to lithium aluminium hydride (6.0 g) in THF (150 ml) over 0.5 hr. The reaction mixture was stirred for 2 hr. and water was carefully added. The resultant slurry was washed with ether (3×100 ml) and the combined ethereal washings were dried (magnesium sulphate) and evaporated to dryness to give 2-hydroxymethyl-3-(1'-hydroxypropyl)naphthalene as an oil; a small portion was recrystallised from light petroleum (b.p. 60°-80°)/chloroform to give a crystalline solid, m.p. 70°.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[CH2:17][O:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:18]12([CH2:28][NH2:29])[CH2:27][CH:22]3[CH2:23][CH:24]([CH2:26][CH:20]([CH2:21]3)[CH2:19]1)[CH2:25]2>C(O)(C)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([OH:16])[CH2:17][NH:29][CH2:28][C:18]23[CH2:27][CH:22]4[CH2:21][CH:20]([CH2:26][CH:24]([CH2:23]4)[CH2:25]2)[CH2:19]3)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(COc2ccc(C3CO3)cc2)cc1
Reactant: NCC12CC3CC(CC(C3)C1)C2
Solvent: CC(C)O
Product: OC(CNCC12CC3CC(CC(C3)C1)C2)c1ccc(OCc2ccccc2)cc1
Yield: 23.2 %

Procedure:
2-(4-(benzyloxy)phenyl)oxirane (2 g, 8.8 mmol) and (1-adamantylmethyl)amine (1.46 g, 8.8 mol) were dissolved in isopropyl alcohol (30 mL) and heated under reflux overnight. The mixture was concentrated to give the crude product, which was purified by column chromatography to afford 1-(4-(benzyloxy)phenyl)-2-((1-adamantylmethyl)amino)ethanol (0.8 g, 23%). 1H NMR: (CDCl3, 400 MHz) δ=1.51 (m, 6H), 1.60-1.72 (m, 6H), 1.97 (m, 3H), 2.32&2.45 (dd, 2H), 2.64 (m, 1H), 2.73 (m, 1H), 2.94 (m, 1H), 3.40 (brs, 3H), 4.79 (m, 1H), 6.93 (m, 2H), 7.26-7.43 (m, 7H).
Reaction SMILES: [CH:1]12[O:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([C:9]1[N:14]=[C:13]([N:15]3[CH2:20][CH2:19][C:18](=O)[CH2:17][CH2:16]3)[N:12]=[C:11]([C:22]3[CH:27]=[CH:26][C:25]([NH:28][C:29]([NH:31][C:32]4[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=4)=[O:30])=[CH:24][CH:23]=3)[N:10]=1)[CH2:2]2.C(O)(C(F)(F)F)=O.Cl.[NH2:46][CH2:47][C:48]([NH2:50])=[O:49]>C(N(CC)CC)C>[CH:5]12[O:8][CH:1]([CH2:7][CH2:6]1)[CH2:2][N:3]([C:9]1[N:10]=[C:11]([C:22]3[CH:27]=[CH:26][C:25]([NH:28][C:29]([NH:31][C:32]4[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=4)=[O:30])=[CH:24][CH:23]=3)[N:12]=[C:13]([N:15]3[CH2:16][CH2:17][CH:18]([NH:46][CH2:47][C:48]([NH2:50])=[O:49])[CH2:19][CH2:20]3)[N:14]=1)[CH2:4]2
Reactant: O=C1CCN(c2nc(-c3ccc(NC(=O)Nc4ccncc4)cc3)nc(N3CC4CCC(C3)O4)n2)CC1
Reactant: NCC(N)=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)CNC1CCN(c2nc(-c3ccc(NC(=O)Nc4ccncc4)cc3)nc(N3CC4CCC(C3)O4)n2)CC1

Procedure:
Starting from 1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-oxopiperidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea.TFA (50 mg) and glycinamide hydrochloride (18 mg) and triethylamine (10 drops) and following the procedure as outlined in example 118 the title compound was isolated as its di-TFA salt after HPLC purification; MS (ES+) 559.8 (M+H)+