Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:4][CH2:3]1.C(N(CC)CC)C.Cl[C:26]([O:28][CH:29]([CH3:31])[CH3:30])=[O:27]>ClCCl>[CH:29]([O:28][C:26]([NH:1][CH:2]1[CH2:3][CH2:4][N:5]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:6][CH2:7]1)=[O:27])([CH3:31])[CH3:30]
Reactant: NC1CCN(C(=O)OCc2ccccc2)CC1
Reactant: CC(C)OC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)OC(=O)NC1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Benzyl 4-aminopiperidine-1-carboxylate (100 mg) and triethylamine (190 μL) are dissolved in dichloromethane (2 mL), treated with isopropyl chloroformate (920 μL, 1 M solution in toluene) and stirred for 2 hours at room temperature. The mixture is partitioned between dichloromethane and saturated aqueous NH4Cl solution. The organic phase is dried (MgSO4) and concentrated. The residue is purified by HPLC on reversed phase to give the title compound. LC (method 1): tR=1.02 min; Mass spectrum (ESI+): m/z=321 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH2:12])[CH:7]=1)[CH3:2].[F:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[O:25][C:24]([C:26](O)=[O:27])=[CH:23][CH:22]=2)=[CH:17][CH:16]=1>>[CH2:1]([O:3][C:4](=[O:13])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH:12][C:26]([C:24]2[O:25][C:21]([C:18]3[CH:19]=[CH:20][C:15]([F:14])=[CH:16][CH:17]=3)=[CH:22][CH:23]=2)=[O:27])[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1cccc(N)c1
Reactant: O=C(O)c1ccc(-c2ccc(F)cc2)o1
Product: CCOC(=O)Cc1cccc(NC(=O)c2ccc(-c3ccc(F)cc3)o2)c1

Procedure:
(3-Amino-phenyl)-acetic acid ethyl ester (44 mg, 0.24 mmol) was coupled to 5-(4-fluoro-phenyl)-furan-2-carboxylic acid (76) (50 mg, 0.24 mmol) using Method C. The crude compound was purified by column chromatography, eluting in 20% EtOAc in heptane to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(=O)(=O)(O)O.[CH2:18](O)[CH3:19]>>[F:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4]([O:6][CH2:18][CH3:19])=[O:5]
Reactant: CCO
Reactant: Cc1cc(F)c(C(=O)O)cc1F
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1cc(F)c(C)cc1F
Yield: 95 %

Procedure:
To a solution of 2,5-difluoro-4-methylbenzoic acid (5 g, 2.904 mmol) in ethanol (100 mL) was added concentrated sulfuric acid (1 mL). The reaction mixture was stirred at reflux for 18 hours. LCMS showed complete consumption of starting material, so the solvents were removed in vacuo and the resulting residue redissolved in EtOAc (50 mL), and washed with saturated aqueous sodium bicarbonate. The organic layer was separated, and the aqueous layer extracted with EtOAc (2×50 mL). The combined organics were dried over sodium sulfate and evaporated to yield the title compound as a pale yellow oil (5.502 g, 95%).
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)[CH2:13][CH2:12]2)=[CH:7][CH:6]=1)C=C.[C:23]1(OC2C=CC=CC=2)[CH:28]=CC=C[CH:24]=1>CCOCC>[CH2:28]([C:10]1[CH:9]=[C:8]([N:11]2[CH2:12][CH2:13][N:14]([C:17]3[CH:18]=[CH:19][N:20]=[CH:21][CH:22]=3)[CH2:15][CH2:16]2)[CH:7]=[CH:6][C:5]=1[OH:4])[CH:23]=[CH2:24]
Reactant: C=CCOc1ccc(N2CCN(c3ccncc3)CC2)cc1
Reactant: c1ccc(Oc2ccccc2)cc1
Solvent: CCOCC
Product: C=CCc1cc(N2CCN(c3ccncc3)CC2)ccc1O
Temperature: 25 °C
Yield: 17.6 %

Procedure:
The product from step (i) (5 g) was heated under argon in gently refluxing diphenyl ether (15 g) for 2 1/2 hours. The mixture was cooled to room temperature and ether (70 ml) was added. The solid material was filtered and purified by flash chromatography on silica gel, eluting with methanol/dichloromethane (1/4 v/v) to give 2-allyl-4-[4-(4-pyridyl)piperazin-1-yl]phenol (0.88 g) as a solid, m.p. 180°-182° C.; NMR (d6 -DMSO) δ 8.88(1H,s), 8.19(2H,dd), 6.87(2H,dd), 6.7(3H,m), 5.88-6.03(1H,m), 5.0(2H,m), 3.44(4H,t), 3.28(2H,d), 3.05(4H, t); m/e 296 (M+H)+.
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:29]([NH2:31])=[O:30])[CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]=O)[CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2].[BH4-].[Na+]>>[CH2:16]([CH:15]([NH:14][CH2:27][C:23]1[CH:22]=[C:21]([C:18]2[CH:19]=[C:20]3[C:15](=[C:16]([C:29]([NH2:31])=[O:30])[CH:17]=2)[NH:14][CH:13]=[C:12]3[CH:9]2[CH2:8][CH2:7][N:6]([S:3]([CH2:1][CH3:2])(=[O:4])=[O:5])[CH2:11][CH2:10]2)[CH:26]=[CH:25][CH:24]=1)[CH2:20][CH3:19])[CH3:17]
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(C=O)c4)cc23)CC1
Agent: [BH4-]
Agent: [Na+]
Product: CCC(CC)NCc1cccc(-c2cc(C(N)=O)c3[nH]cc(C4CCN(S(=O)(=O)CC)CC4)c3c2)c1
Yield: 161 %

Procedure:
Following the general procedure of example 1, 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-formylphenyl)-1H-indole-7-carboxamide (20 mg, 0.045 mmol), 3-pentanamide (32 uL, 0.27 mmol) and NaBH4 (10 mg, 0.27 mmol) were reacted to give the title compound (18.5 mg, 80%).
Reaction SMILES: Cl.O1CCOCC1.[Br:8][C:9]1[CH:10]=[C:11]2[C:33](=[CH:34][CH:35]=1)[C:15]1[NH:16][C:17]([C@@H:19]3[C@H:24]4[CH2:25][C@H:21]([CH2:22][CH2:23]4)[N:20]3C(OC(C)(C)C)=O)=[N:18][C:14]=1[CH:13]=[CH:12]2.[CH3:36][O:37][C:38]([NH:40][C@@H:41]([CH:45]([CH3:47])[CH3:46])[C:42](O)=[O:43])=[O:39].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl.CO>[Br:8][C:9]1[CH:10]=[C:11]2[C:33](=[CH:34][CH:35]=1)[C:15]1[NH:16][C:17]([C@@H:19]3[C@H:24]4[CH2:25][C@H:21]([CH2:22][CH2:23]4)[N:20]3[C:42](=[O:43])[C@@H:41]([NH:40][C:38](=[O:39])[O:37][CH3:36])[CH:45]([CH3:47])[CH3:46])=[N:18][C:14]=1[CH:13]=[CH:12]2
Reactant: COC(=O)N[C@H](C(=O)O)C(C)C
Reactant: CC(C)(C)OC(=O)N1[C@H]2CC[C@H](C2)[C@H]1c1nc2ccc3cc(Br)ccc3c2[nH]1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: ClCCl
Product: COC(=O)N[C@H](C(=O)N1[C@H]2CC[C@H](C2)[C@H]1c1nc2ccc3cc(Br)ccc3c2[nH]1)C(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
Hydrogen chloride in dioxane solution (4N, 6.78 mL, 27.18 mmol) was added to (1S,3S,4R)-tert-butyl 3-(7-bromo-1H-naphtho[1,2-d]imidazol-2-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate (0.80 g, 1.81 mmol) in methylene chloride:methanol (18.1 mL: 3.6 mL). The suspension was allowed to stir at room temperature for one hour. Upon completion by LCMS, the reaction was concentrated to dryness and the crude product (assumed 1.81 mmol) was suspended in methylene chloride (18 mL). (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (0.38 g, 2.17 mmol) and DIPEA (1.58 mL, 9.04 mmol) were added to the slurry. HATU (1.03 g, 2.71 mmol) was added and the reaction was stirred at room temperature for 3 hours. Upon completion, the crude reaction was diluted in methylene chloride and washed with 1N HCl, and aqueous sodium bicarbonate. The organic layer was concentrated and purified by normal phase chromatography (40-80% ethyl acetate (5% methanol) in hexanes) to give methyl (S)-1-((1S,3S,4R)-3-(7-bromo-1H-naphtho[1,2-d]imidazol-2-yl)-2-azabicyclo[2.2.1]heptan-2-yl)-3-methyl-1-oxobutan-2-ylcarbamate (0.949, >99%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](S(C)(=O)=O)[C:5]([C:12]#[N:13])=[C:4]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=2)[N:3]=1.[CH3:26][O:27][CH2:28][CH2:29][OH:30].C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([O:30][CH2:29][CH2:28][O:27][CH3:26])[C:5]([C:12]#[N:13])=[C:4]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=2)[N:3]=1
Reactant: COCCO
Reactant: COc1cc(-c2nc(N)nc(S(C)(=O)=O)c2C#N)cc(OC)c1OC
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: COCCOc1nc(N)nc(-c2cc(OC)c(OC)c(OC)c2)c1C#N

Procedure:
From 2-amino-4-methanesulfonyl-6-(3,4,5-trimethoxy-phenyl)-pyrimidine-5-carbonitrile, 2-methoxyethanol and DBU in DME. EI-MS m/e (%): 360 (M+, 100), 302 (36), 287 (28), 259 (32), 43 (42).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]3[N:9]([C:13]([C:28]4[CH:29]=[CH:30][C:31]([C:34]#[N:35])=[N:32][CH:33]=4)=[C:14]([C:16]#[C:17][C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)[N:15]=3)[N:10]=[CH:11][CH:12]=2)[CH2:3][CH2:2]1.[N-:36]=[N+:37]=[N-:38].[Na+].Cl.C(N(CC)CC)C>CN(C=O)C>[NH:36]1[C:34]([C:31]2[N:32]=[CH:33][C:28]([C:13]3[N:9]4[N:10]=[CH:11][CH:12]=[C:7]([N:4]5[CH2:3][CH2:2][O:1][CH2:6][CH2:5]5)[C:8]4=[N:15][C:14]=3[C:16]#[C:17][C:18]3[CH:27]=[CH:26][C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[N:19]=3)=[CH:29][CH:30]=2)=[N:35][N:38]=[N:37]1
Reactant: N#Cc1ccc(-c2c(C#Cc3ccc4ccccc4n3)nc3c(N4CCOCC4)ccnn23)cn1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C(#Cc1nc2c(N3CCOCC3)ccnn2c1-c1ccc(-c2nnn[nH]2)nc1)c1ccc2ccccc2n1
Temperature: 25 °C

Procedure:
A solution of compound 39a (0.20 g, 0.44 mmol), sodium azide (50 mg, 0.77 mmol), and triethylamine hydrochloride (0.10 g, 0.73 mmol) in DMF (5 mL) was stirred at 100° C. for 1 h. After cooling to rt, the reaction was quenched with water (20 mL). The resulting mixture was extracted with DCM (2×30 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue obtained was purified by flash column chromatography on silica gel (MeOH:CH2Cl2 (1:50, v/v)) to obtain a residue, which was further purified by reverse phase Prep-HPLC. This resulted in the title compound 21 as a yellow solid. 1H-NMR (300 MHz, DMSO-d6) δ (ppm): 8.85-8.91 (m, 1H), 8.34 (d, J=8.7 Hz, 1H), 8.30-8.23 (m, 2H), 7.98-7.60 (m, 6H), 6.51 (d, J=6.0 Hz, 1H), 3.90-3.81 (m, 4H), 3.64-3.53 (m, 4H). Mass Spectrum (LCMS, ESI pos.): Calcd. for C22H20N10O: 501.2 (M+H). Found: 501.2.
Reaction SMILES: [CH3:1][CH:2]([S:4]([NH2:7])(=[O:6])=[O:5])[CH3:3].[H-].[Na+].[CH3:10][C:11]1([CH3:36])[CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:21](O)=[O:22])[CH:18]=2)[NH:13][CH:12]1[C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)[CH:25]=1.C(N1C=CN=C1)(N1C=CN=C1)=O>CN(C)C=O>[CH3:10][C:11]1([CH3:36])[CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:21]([NH:7][S:4]([CH:2]([CH3:3])[CH3:1])(=[O:6])=[O:5])=[O:22])[CH:18]=2)[NH:13][CH:12]1[C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)[CH:25]=1
Reactant: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1cccc(N2CCOCC2)c1
Reactant: CC(C)S(N)(=O)=O
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)S(=O)(=O)NC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(N3CCOCC3)c1)N2
Temperature: 25 °C
Reaction time: 1 h
Yield: 18.1 %

Procedure:
To a suspension of propane-2-sulfonic acid amide (168 mg, 1.37 mmol) in N,N-dimethylformamide (1.5 mL) was added sodium hydride (52 mg, 1.3 mmol). The resulting mixture was stirred at 25° C. for 1 h. A solution of 3,3-dimethyl-2-(3-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (100 mg, 0.27 mmol) and 1,1′-carbonyldiimidazole (89 mg, 0.55 mmol) in N,N-dimethylformamide (1 mL) was stirred at 70° C. for 1 h. Then the above suspension of propane-2-sulfonic acid amide and sodium hydride in N,N-dimethylformamide was added and the mixture was allowed to stir at 25° C. for 1 h. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded Propane-2-sulfonic acid [3,3-dimethyl-2-(3-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-6-carbonyl]-amide (23 mg, 18%) as a white solid: LC/MS m/e calcd for C25H33N3O4S (M+H)+: 472.62, observed: 472.1.
Reaction SMILES: [CH2:1]([C:8]([OH:15])([CH2:11][CH2:12][CH2:13][CH3:14])[CH2:9][OH:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>ClCCl.C(OCC)(=O)C>[CH3:23][S:24]([CH:9]([OH:10])[C:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([OH:15])[CH2:11][CH2:12][CH2:13][CH3:14])(=[O:26])=[O:25]
Reactant: CCCCC(O)(CO)Cc1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCC(O)(Cc1ccccc1)C(O)S(C)(=O)=O
Yield: 96.4 %

Procedure:
To a stirred solution of the product from Example 19B (416 mg, 2.0 mmol) in 4 mL of dichloromethane at 0° C. was added triethylamine (0.34 mL, 2.4 mmol) followed by the addition of methanesulfonyl chloride (0.17 mL, 2.2 mmol). The mixture was placed in a refrigerator overnight. The resulting cloudy mixture was diluted with ethyl acetate and extracted with water, 3N aqueous HCl, water and brine, dried (Na2SO4), filtered, and concentrated to provide 552 mg (96%) of the title compound as an oil that was used directly.
Reaction SMILES: C(O)(=O)C.Br.C(OC([NH:16][C@H:17]([C:24]([N:26]1[CH2:39][CH2:38][CH2:37][C@H:27]1[C:28]([NH:30][CH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1)=[O:29])=[O:25])[CH2:18][C:19]1[N:23]=[CH:22][NH:21][CH:20]=1)=O)C1C=CC=CC=1>CCOCC>[NH2:16][C@H:17]([C:24]([N:26]1[CH2:39][CH2:38][CH2:37][C@H:27]1[C:28]([NH:30][CH:31]1[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]1)=[O:29])=[O:25])[CH2:18][C:19]1[N:23]=[CH:22][NH:21][CH:20]=1
Reactant: O=C(N[C@@H](Cc1c[nH]cn1)C(=O)N1CCC[C@H]1C(=O)NC1CCCCC1)OCc1ccccc1
Agent: Br
Solvent: CC(=O)O
Solvent: CCOCC
Product: N[C@@H](Cc1c[nH]cn1)C(=O)N1CCC[C@H]1C(=O)NC1CCCCC1
Temperature: 25 °C
Yield: 188.2 %

Procedure:
To 15 ml of ice-cooled acetic acid solution of 25% hydrobromic acid was added 1.14 g of compound (37) and the reaction was maintained for 3 hours at room temperature. The reaction mixture thus obtained was added to 150 ml of desiccated ether, the precipitates thus formed were quickly collected by filtration and dried overnight in the desiccator at reduced pressure to provide 1.53 g of L-histidyl-N-cyclohexyl-L-prolinamide.2-hydrobromide.
Reaction SMILES: C([O:8][C:9]([CH2:11][C@H:12]([N:38]1[C:42](=[O:43])[C:41]2=[CH:44][CH:45]=[CH:46][CH:47]=[C:40]2[C:39]1=[O:48])[C:13]([N:15]1[CH:20]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:19][CH2:18][CH2:17][N:16]1C(OCC1C=CC=CC=1)=O)=[O:14])=[O:10])C1C=CC=CC=1>CO.[Pd]>[C:9]([CH2:11][C@H:12]([N:38]1[C:42](=[O:43])[C:41]2=[CH:44][CH:45]=[CH:46][CH:47]=[C:40]2[C:39]1=[O:48])[C:13]([N:15]1[CH:20]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:19][CH2:18][CH2:17][NH:16]1)=[O:14])([OH:10])=[O:8]
Reactant: CC(C)(C)OC(=O)C1CCCN(C(=O)OCc2ccccc2)N1C(=O)[C@H](CC(=O)OCc1ccccc1)N1C(=O)c2ccccc2C1=O
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)C1CCCNN1C(=O)[C@H](CC(=O)O)N1C(=O)c2ccccc2C1=O
Yield: 94.5 %

Procedure:
A solution of 11.1 g of benzyl tert.butyl hexahydro-2-[3-benzyloxycarbonyl-2(S)-phthalimidopropionyl]-1,3-pyridazinedicarboxylate (diastereomer B) in 220 ml of methanol was hydrogenated over 1.1 g of 10% palladium-on-carbon for 18 hours. The catalyst was removed by filtration and the filtrate was evaporated to give 6.9 g (94%) of tert.butyl hexahydro-2-[3-carboxy-2(S)-phthalimidopropionyl]-3-pyridazinecarboxylate (diastereomer B) in the form of a gum.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[O:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:16]=[C:17]([CH:20]=[C:21](B3OC(C)(C)C(C)(C)O3)[CH:22]=2)[C:18]#[N:19])[CH2:11][CH2:10]1.BrC1C=C(C=C(N2CCOCC2)C=1)C#N.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1>>[Cl:1][C:2]1[N:7]=[C:6]([C:21]2[CH:20]=[C:17]([CH:16]=[C:15]([N:12]3[CH2:11][CH2:10][O:9][CH2:14][CH2:13]3)[CH:22]=2)[C:18]#[N:19])[CH:5]=[CH:4][N:3]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: CC1(C)OB(c2cc(C#N)cc(N3CCOCC3)c2)OC1(C)C
Agent: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Agent: N#Cc1cc(Br)cc(N2CCOCC2)c1
Product: N#Cc1cc(-c2ccnc(Cl)n2)cc(N2CCOCC2)c1

Procedure:
3-(2-Chloropyrimidin-4-yl)-5-morpholinobenzonitrile was prepared according procedure B from 2,4-dichloropyrimidine and 3-morpholino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile which was synthesized by following procedure A using 3-bromo-5-morpholinobenzonitrile and bis(pinacolato)diboron.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[C:10](OC)[CH:9]=[C:8](Cl)[C:5]=1[CH:6]=O)([O-])=O.C(O)C.Cl.Cl.[NH2:20][C:21](N)=N>C1C=CC=CC=1.[Fe]>[N:1]1[C:4]2[C:5](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[N:20][CH:21]=1
Reactant: COc1cc(Cl)c(C=O)c([N+](=O)[O-])c1
Reactant: N=C(N)N
Agent: [Fe]
Agent: Cl
Solvent: CCO
Solvent: c1ccccc1
Product: c1ccc2ncncc2c1

Procedure:
The nitro group of 2-nitro-4-methoxy-6-chlorobenzaldehyde (1 equivalent) is reduced to the amine by refluxing in benzene or ethanol with iron powder (the powder having been pretreated with concentrated hydrochloric acid). This amine is then treated with guanidine hydrochloride as described above (step k) to yield the quinazoline (COMPOUND XXIII) which is purified by column chromatography and/or crystallization. Benzoylation of this product is performed as described above (step d), to yield COMPOUND XXII.
Reaction SMILES: [CH:1]([NH:4][CH2:5][CH2:6][OH:7])([CH3:3])[CH3:2].[C:8]([Si:12](Cl)([CH3:14])[CH3:13])([CH3:11])([CH3:10])[CH3:9].[Si](OCCNC)(C(C)(C)C)(C)C>>[Si:12]([O:7][CH2:6][CH2:5][NH:4][CH:1]([CH3:3])[CH3:2])([C:8]([CH3:11])([CH3:10])[CH3:9])([CH3:14])[CH3:13]
Reactant: CC(C)NCCO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CNCCO[Si](C)(C)C(C)(C)C
Product: CC(C)NCCO[Si](C)(C)C(C)(C)C
Yield: 38 %

Procedure:
[2-(tert-Butyl-dimethylsilanyloxy)-ethyl]-isopropyl-amine (8-b) (20 gm, 37.4%) was synthesized as a yellow liquid from 2-isopropylamino-ethanol (18-b) (25 g, 242.31 mmol) and tert-butyl-chloro-dimethyl-silane (25.5 g, 242.31 mmol) following the procedure as described for [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-methyl-amine (8-a).
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[C:11]([C:13]([N:15]3[CH2:20][CH2:19][CH:18]([N:21]4[CH2:26][CH2:25][CH2:24][C@@H:23]([C:27]([N:29]5[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]5)=[O:28])[CH2:22]4)[CH2:17][CH2:16]3)=[O:14])[CH:10]=[C:9]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O-:41][C:42]#[N:43].[Na+]>O.C(O)CC.O1CCOCC1>[C:1]1([C:7]2[CH:12]=[C:11]([C:13]([N:15]3[CH2:16][CH2:17][CH:18]([N:21]4[CH2:26][CH2:25][CH2:24][C@@H:23]([C:27]([N:29]5[CH2:34][CH2:33][N:32]([C:42]([NH2:43])=[O:41])[CH2:31][CH2:30]5)=[O:28])[CH2:22]4)[CH2:19][CH2:20]3)=[O:14])[CH:10]=[C:9]([C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N#C[O-]
Reactant: O=C(c1cc(-c2ccccc2)nc(-c2ccccc2)c1)N1CCC(N2CCC[C@@H](C(=O)N3CCNCC3)C2)CC1
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCCO
Solvent: O
Product: NC(=O)N1CCN(C(=O)[C@@H]2CCCN(C3CCN(C(=O)c4cc(-c5ccccc5)nc(-c5ccccc5)c4)CC3)C2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 40 %

Procedure:
(3R)-(2,6-Diphenyl-pyridin-4-yl)-[3-(piperazine-1-carbonyl)-[1,4′]bipiperidinyl-1′-yl]-methanone (21.4 mg, 0.040 mmol) and sodium cyanate (0.060 mmol, 3.9 mg) were heated at 100° C. in a water-dioxane-n-propanol solution. After 2 h an additional aliquot of sodium cyanate (4 mg) was added and heating was continued for another 1 hour then the solution was allowed to stir at ambient temperature for an additional 42 h. The solvent was removed under vacuum and the product was purified by silica gel chromatography eluting with a 5% to 10% methanol-dichloromethane gradient to give the title compound (9.3 mg, 40%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[N:16]([CH3:20])[C:15]2[N:21]([CH3:33])[C:22](=[O:32])[C:23]([C:25]4[CH:30]=[CH:29][C:28]([Br:31])=[CH:27][CH:26]=4)=[CH:24][C:14]3=2)[NH:8][N:7]=1)=[O:5])[CH3:2].I[CH3:35]>>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:35])[N:8]=[C:9]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[N:16]([CH3:20])[C:15]2[N:21]([CH3:33])[C:22](=[O:32])[C:23]([C:25]4[CH:26]=[CH:27][C:28]([Br:31])=[CH:29][CH:30]=4)=[CH:24][C:14]3=2)[CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(-c2ccc3c(c2)c2cc(-c4ccc(Br)cc4)c(=O)n(C)c2n3C)[nH]n1
Reactant: CI
Product: CCOC(=O)c1cc(-c2ccc3c(c2)c2cc(-c4ccc(Br)cc4)c(=O)n(C)c2n3C)nn1C

Procedure:
The process is carried out as in Example 36 above, with compound B 5-[3-(4-bromophenyl)-1,9-dimethyl-2-oxo-2,9-dihydro-1H-pyrido[2,3-b]indol-6-yl]-1H-pyrazole-3-carboxylic acid ethyl ester and iodomethane
Reaction SMILES: CO.Cl.[C:4]([O:8][C:9]([CH2:11][O:12][N:13]=[C:14]([C:31]1[N:32]=[C:33]([NH:36]C=O)[S:34][CH:35]=1)[C:15]([NH:17][CH:18]1[C:29](=[O:30])[N:20]2[C:21]([C:26]([OH:28])=[O:27])=[C:22]([Cl:25])[CH2:23][S:24][C@H:19]12)=[O:16])=[O:10])([CH3:7])([CH3:6])[CH3:5].C(=O)(O)[O-].[Na+]>O.C(OCC)(=O)C>[C:4]([O:8][C:9]([CH2:11][O:12][N:13]=[C:14]([C:31]1[N:32]=[C:33]([NH2:36])[S:34][CH:35]=1)[C:15]([NH:17][CH:18]1[C:29](=[O:30])[N:20]2[C:21]([C:26]([OH:28])=[O:27])=[C:22]([Cl:25])[CH2:23][S:24][C@H:19]12)=[O:16])=[O:10])([CH3:7])([CH3:5])[CH3:6]
Reactant: CC(C)(C)OC(=O)CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(Cl)CS[C@H]12)c1csc(NC=O)n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(Cl)CS[C@H]12)c1csc(N)n1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 82.4 %

Procedure:
Methanol (15 ml) and conc. hydrochloric acid (0.8 g) were added to 7-[2-(tert-butoxycarbonylmethoxyimino)-2-(2-formamidothiazol-4-yl)acetamido]-3-chloro-3-cephem-4-carboxylic acid (syn isomer, 2.2 g), and stirred at room temperature for 2.5 hours. To the resultant solution were added ethyl acetate (50 ml) and water (50 ml), and then the solution was adjusted to pH 7.5 with a saturated solution of sodium bicarbonate. After separating the aqueous layer, the aqueous solution was saturated with sodium chloride, and adjusted to pH 3.0 with 10% hydrochloric acid. After adding water, the solution was extracted with ethyl acetate. The extract was washed with a saturated solution of sodium chloride, dried over magnesium sulfate and concentrated in vacuo. The residue was triturated with diisopropyl ether and the precipitates were collected by filtration and dried to give 7-[2-(tert-butoxycarbonylmethoxyimino)-2-(2-aminothiazol-4-yl)acetamido]-3-chloro-3-cephem-4-carboxylic acid (syn isomer, 1.72 g).
Reaction SMILES: C[O:2][C:3](=[O:41])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([C:16]2[CH:21]=[CH:20][C:19]([NH:22][S:23]([C:26]3[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[C:28]([C:36]([F:39])([F:38])[F:37])[CH:27]=3)(=[O:25])=[O:24])=[CH:18][CH:17]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:40])[CH:11]=2)[CH:6]=1.[OH-].[Na+]>C(O)C>[F:35][C:32]([F:33])([F:34])[C:30]1[CH:31]=[C:26]([S:23]([NH:22][C:19]2[CH:18]=[CH:17][C:16]([C:13]3[C:12]4[C:7](=[CH:8][CH:9]=[C:10]([F:40])[CH:11]=4)[CH:6]=[C:5]([CH2:4][C:3]([OH:41])=[O:2])[C:14]=3[CH3:15])=[CH:21][CH:20]=2)(=[O:25])=[O:24])[CH:27]=[C:28]([C:36]([F:38])([F:39])[F:37])[CH:29]=1
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(-c2ccc(NS(=O)(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)cc2)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1c(CC(=O)O)cc2ccc(F)cc2c1-c1ccc(NS(=O)(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1
Reaction time: 4 h
Yield: 83 %

Procedure:
To a solution of {4-[4-(3,5-bis-trifluoromethyl-benzenesulfonylamino)-phenyl]-6-fluoro-3-methyl-naphthalen-2-yl}-acetic acid methyl ester (21 mg, 0.035 mmol) in ethanol (2 mL) was added sodium hydroxide solution (105 uL, 1.0 N,) at room temperature. The resulting clear solution was stirred for 4 h. Then, the solvents were removed under vacuum and the residue was diluted with water (10 mL), acidified with 1.0 N hydrochloric acid, extracted with ethyl acetate (2×20 mL). The combined organic extracts were washed with brine solution (20 mL) and dried over anhydrous magnesium sulfate. Filtration of the drying agent and concentration of the solvent under vacuum provided the desired {4-[4-(3,5-bis-trifluoromethyl-benzenesulfonylamino)-phenyl]-6-fluoro-3-methyl-naphthalen-2-yl}-acetic acid (17 mg, 83%) as a light brown foam. 1H NMR (300 MHz, DMSO-d6) δ ppm 12.45 (br. s, 1 H), 10.59 (br. s, 1 H), 8.53 (br. s, 1 H), 8.21 (s, 2 H), 7.89-8.03 (m, 1 H), 7.83 (s, 1 H), 7.34 (t, J=8.2 Hz, 1 H), 7.25 (d, J=7.5 Hz, 2 H), 7.16 (d, J=7.8 Hz, 2 H), 6.59 (d, J=11.2 Hz, 1 H), 3.81 (br. s, 2 H), 1.98 (s, 3 H). HRMS calcd. for C27H17F7NO4S [(M−H)−] 584.0772, obsd. 584.0771.