Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[CH:3]([O:27]C)[CH2:4][NH:5][C:6]([C:8]1[C:9]([C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=2)=[C:10]2[N:15]([CH:16]=1)[N:14]=[CH:13][N:12]=[C:11]2[NH2:17])=O.Cl.FC(F)(F)CN.CS(O)(=O)=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.C(=O)([O-])[O-].[Na+].[Na+]>>[N+:24]([C:21]1[CH:22]=[CH:23][C:18]([C:9]2[C:8]([C:6]3[O:27][CH:3]=[CH:4][N:5]=3)=[CH:16][N:15]3[C:10]=2[C:11]([NH2:17])=[N:12][CH:13]=[N:14]3)=[CH:19][CH:20]=1)([O-:26])=[O:25]
Reactant: COC(CNC(=O)c1cn2ncnc(N)c2c1-c1ccc([N+](=O)[O-])cc1)OC
Agent: CS(=O)(=O)O
Agent: Cl
Agent: NCC(F)(F)F
Product: Nc1ncnn2cc(-c3ncco3)c(-c3ccc([N+](=O)[O-])cc3)c12
Temperature: 100 °C
Reaction time: 18 h

Procedure:
The procedure used for the preparation of the first step of intermediate M was used to prepare 4-Amino-5-(4-nitro-phenyl)-pyrrolo[2,1-f][1,2,4]triazine-6-carboxylic acid (2,2-dimethoxy-ethyl)-amide by substituting 2,2-Dimethoxy-ethylamine for 2,2,2-trifluoro-ethylamine hydrochloride salt. To a solution of methanesulfonic acid (1.5 ml) was added P2O5 (225.0 mg, 1.58 mmol) followed by the addition of 4-amino-5-(4-nitro-phenyl)-pyrrolo[2,1-f][1,2,4]triazine-6-carboxylic acid (2,2-dimethoxy-ethyl)-amide (150 mg, 0.388 mmol). The dark brown mixture was heated to 100° C. and allowed to stir for 18 hrs. The mixture was then poured over ice (15 g), stirred for fifteen minutes and enough saturated sodium carbonate solution was added to neutralize the reaction. A white precipitate was filtered and collected (35 mg, 27%). 1H-NMR (DMSO-d6) δ 8.33 (s, 1H), 8.31 (m, 2H), 8.03 (d, J=10 Hz, 2H), 7.73 (d, J=10 Hz, 2H), 7.28 (s, 1H). MS [M+H]+=323.2; LCMS RT=2.51 min.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH2:8][C:9]#[N:10])[CH:5]=[CH:4][CH:3]=1.[N-:11]=[N+:12]=[N-:13].[Na+]>O.[Zn+2].[Br-].[Br-]>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([CH2:8][C:9]2[N:11]=[N:12][NH:13][N:10]=2)[N:7]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#CCc1cccc(Br)n1
Agent: [Br-]
Agent: [Na+]
Agent: [Zn+2]
Solvent: O
Product: Brc1cccc(Cc2nn[nH]n2)n1
Temperature: 110 °C
Reaction time: 18 h

Procedure:
(6-Bromopyridin-2-yl)acetonitrile (Example 235, Step 1) (1.00 g, 5.08 mmol), NaN3 (396 mg, 6.09 mmol), and ZnBr2 (1.14 g, 5.08 mmol) were combined in water (10 mL) in a screw-cap vial, sealed, and vigorously stirred at 110° C. for 18 h. The suspension was filtered, and the isolated solid was washed with water to provide the title compound as a colorless solid.
Reaction SMILES: C([O:8][N:9]([CH2:12][CH:13]([CH2:17][CH2:18][CH2:19][CH3:20])[C:14]([OH:16])=O)[CH:10]=[O:11])C1C=CC=CC=1.[NH:21]1[CH2:25][CH2:24][CH2:23][C@H:22]1[C:26]1[O:27][CH:28]=[CH:29][N:30]=1>>[OH:8][N:9]([CH2:12][CH:13]([C:14]([N:21]1[CH2:25][CH2:24][CH2:23][CH:22]1[C:26]1[O:27][CH:28]=[CH:29][N:30]=1)=[O:16])[CH2:17][CH2:18][CH2:19][CH3:20])[CH:10]=[O:11]
Reactant: CCCCC(CN(C=O)OCc1ccccc1)C(=O)O
Reactant: c1coc([C@@H]2CCCN2)n1
Product: CCCCC(CN(O)C=O)C(=O)N1CCCC1c1ncco1

Procedure:
The title compound is prepared from 2-[(benzyloxy-formyl-amino)-methyl]-hexanoic acid D-7 (R=n-butyl) and 2-(S)-pyrrolidine-2-yl-oxazole E-5 (prepared as described in Procedure E) according to General Procedure D.
Reaction SMILES: [Cl:1][C:2]1[C:20]([O:21][CH:22]([CH3:24])[CH3:23])=[CH:19][C:5]([C:6]([NH:8][C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15]C)=[O:14])=[CH:11][CH:10]=2)=[O:7])=[CH:4][C:3]=1[O:25][CH:26]([CH3:28])[CH3:27]>CO>[Cl:1][C:2]1[C:3]([O:25][CH:26]([CH3:27])[CH3:28])=[CH:4][C:5]([C:6]([NH:8][C:9]2[CH:10]=[CH:11][C:12]([C:13]([OH:15])=[O:14])=[CH:17][CH:18]=2)=[O:7])=[CH:19][C:20]=1[O:21][CH:22]([CH3:24])[CH3:23]
Reactant: COC(=O)c1ccc(NC(=O)c2cc(OC(C)C)c(Cl)c(OC(C)C)c2)cc1
Solvent: CO
Product: CC(C)Oc1cc(C(=O)Nc2ccc(C(=O)O)cc2)cc(OC(C)C)c1Cl
Temperature: 50 °C
Reaction time: 15 h
Yield: 48.6 %

Procedure:
4-(4-Chloro-3,5-diisopropoxybenzamido)benzoic acid (AAA-112) (40 mg, 46%) was prepared from methyl 4-(4-chloro-3,5-diisopropoxybenzamido)benzoate (8) (86 mg, 0.21 mmol) using a procedure essentially the same as in step (ii) for AAA-001 except that MeOH was added dropwise to obtain a solution and the mixture was heated at 50° C. for 2 h then at RT for 15 h: m/z 390 [M−H]− (ES−), 1H NMR (400 MHz, DMSO-d6) δ: 12.74 (1H, br s), 10.44 (1H, s), 8.01-7.84 (4H, m), 7.29 (2H, s), 4.78 (2H, sep), 1.33 (12H, d).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4](Cl)=[O:5].[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]([CH3:21])[NH:16][C:17](=[O:20])[NH:18][N:19]=2)=[CH:10][CH:9]=1.C(N(CC)CC)C>CN(C)C=O>[Cl:1][CH2:2][CH2:3][C:4]([NH:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[CH:15]([CH3:21])[NH:16][C:17](=[O:20])[NH:18][N:19]=2)=[CH:12][CH:13]=1)=[O:5]
Reactant: CC1NC(=O)NN=C1c1ccc(N)cc1
Reactant: O=C(Cl)CCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC1NC(=O)NN=C1c1ccc(NC(=O)CCCl)cc1
Reaction time: 0.5 h

Procedure:
β-Chloropropionyl chloride (1.25 ml) was added dropwise to a stirred solution of 6-(4-aminophenyl)-5-methyl-4,5-dihydro-1,2,4-triazin-3(2H)-one (2.04 g) and triethylamine (1.53 ml) in N,N-dimethylformamide (DMF) (10.5 ml) under ice cooling and the stirring was continued for 30 minutes. The solution was evaporated in vacuo and the residue as triturated with water under ice-cooling. The precipitates were collected by filtration, washed with water and dried to give 6-[4-(β-chloropropionylamino)phenyl]-5-methyl-4,5-dihydro-1,2,4-triazin-3(2H)-one (1.55 g).
Reaction SMILES: ClC(Cl)(OC(=O)[O:6][C:7]([Cl:10])(Cl)Cl)Cl.Cl.[CH3:14][O:15][CH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.N1C=CC=CC=1>ClCCl>[CH3:14][O:15][CH:16]1[CH2:21][CH2:20][N:19]([C:7]([Cl:10])=[O:6])[CH2:18][CH2:17]1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COC1CCNCC1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC1CCN(C(=O)Cl)CC1

Procedure:
To a stirred solution of triphosgene (7.4 g, 0.025 mmol) in dichloromethane (200 ml) at ice bath was added dropwise a solution of 4-methoxy-piperidine hydrochloride salt (10 g, 0.066 mmol) and pyridine (10.9 g, 0.139 mmol) in dichloromethane (100 ml). The mixture was stirred over night and filtered through a silica pad, eluting with dichloromethane and evaporated. After trituration with diisopropyl ether, the mixture was used without purification.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[C:17]([F:18])=[CH:16][C:12]([C:13]([NH2:15])=[O:14])=[C:11]([NH:19][C:20]2[CH:21]=[C:22]3[C:27](=[C:28]([O:30]CC4C=CC=CC=4)[CH:29]=2)[N:26]=[CH:25][CH:24]=[CH:23]3)[N:10]=1>[OH-].[OH-].[Pd+2].CO>[NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[C:17]([F:18])=[CH:16][C:12]([C:13]([NH2:15])=[O:14])=[C:11]([NH:19][C:20]2[CH:21]=[C:22]3[C:27](=[C:28]([OH:30])[CH:29]=2)[N:26]=[CH:25][CH:24]=[CH:23]3)[N:10]=1
Reactant: NC(=O)c1cc(F)c(N[C@@H]2CCCC[C@@H]2N)nc1Nc1cc(OCc2ccccc2)c2ncccc2c1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: NC(=O)c1cc(F)c(N[C@@H]2CCCC[C@@H]2N)nc1Nc1cc(O)c2ncccc2c1
Yield: 73.2 %

Procedure:
A methanol (5 ml) solution containing 6-(((cis)-2-aminocyclohexyl)amino)-2-((8-(benzyloxy)quinolin-6-yl)amino)-5-fluoronicotinamide (20 mg) was prepared and was subjected to a hydrogenation reaction (room temperature; 1 bar; flow rate: 1 ml/min; 20% Pd(OH)2/C) using H-cube™. Then, the solvent was distilled away under reduced pressure. The residue was dissolved in ethyl acetate, 4M hydrogen chloride/1,4-dioxane (50 μl) was added, the resulting precipitate was collected by filtration, and a yellow solid of 6-(((cis)-2-aminocyclohexyl)amino)-5-fluoro-2-((8-hydroxyquinolin-6-yl)amino)nicotinamide (12 mg) was thus obtained.
Reaction SMILES: [CH:1]1([CH:6]=[C:7]([C:17]2[CH:22]=[CH:21][C:20]([C:23](=[O:25])[CH3:24])=[CH:19][CH:18]=2)[C:8]2[NH:16][C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1>[Pd].CO>[CH:1]1([CH2:6][CH:7]([C:17]2[CH:18]=[CH:19][C:20]([CH:23]([OH:25])[CH3:24])=[CH:21][CH:22]=2)[C:8]2[NH:16][C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(=O)c1ccc(C(=CC2CCCC2)c2cc3cccnc3[nH]2)cc1
Agent: [Pd]
Solvent: CO
Product: CC(O)c1ccc(C(CC2CCCC2)c2cc3cccnc3[nH]2)cc1
Temperature: 50 °C
Yield: 14.5 %

Procedure:
A mixture of 1-{4-[2-cyclopentyl-1-(1H-pyrrolo[2,3-b]pyridin-2-yl)-vinyl]-phenyl}-ethanone (240 mg, 0.72 mmol) and 10% palladium on activated carbon (100 mg) in methanol (200 mL) was heated at 50° C. under hydrogen (50 psi) for 16 h. The mixture was cooled to room temperature, the catalyst was removed by filtration and washed with ethyl acetate. The filtrate was concentrated in vacuo. Purification using a 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 1-{4-[2-cyclopentyl-1-(1H-pyrrolo[2,3-b]pyridin-2-yl)-ethyl]-phenyl}-ethanol (35 mg, 14%): LC/MS m/e calcd for C22H26N2O [M+H]+ 335.47, observed 335.2; 1H NMR (400 MHz, CD3OD) δ ppm 1.17 (m, 2H), 1.39 (d, J=6.5 Hz, 3H), 1.43 (m, 2H), 1.52-1.85 (m, 5H, H), 2.05 (m, 1H), 2.16 (m, 1H), 4.13 (t, J=7.8 Hz, 1H), 4.77 (q, J=6.5 Hz, 1H), 6.30 (s, 1H), 7.01 (br, 1H), 7.27 (m, 4H), 7.86 (d, J=7.1 Hz, 1H), 8.05 (br, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[C:12]([N:17]=[C:18]=[O:19])(=[O:16])[CH:13]([CH3:15])[CH3:14]>C1(C)C=CC=CC=1>[C:12]([NH:17][C:18]([N:7]1[C:8]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:10][CH:9]=2)[CH2:5][C:6]1=[O:11])=[O:19])(=[O:16])[CH:13]([CH3:15])[CH3:14]
Reactant: CC(C)C(=O)N=C=O
Reactant: O=C1Cc2cc(Cl)ccc2N1
Solvent: Cc1ccccc1
Product: CC(C)C(=O)NC(=O)N1C(=O)Cc2cc(Cl)ccc21
Temperature: 25 °C
Yield: 23 %

Procedure:
To a stirred slurry of 8.38 g (0.05 mole) of 5-chloro-2-oxindole in 250 ml of toluene was added 6.79 g (0.06 mole) of isobutyryl isocyanate, and the reaction mixture was heated under reflux for 5.5 hours. The reaction mixture was cooled to room temperature, a small amount of insoluble material was removed by filtration, and then the solvent was removed by evaporation in vacuo. The residue was recrystallized from acetonitrile (with the aid of decolorizing carbon), followed by recrystallization from ethanol, to give 3.23 g of the title compound as pink crystals, m.p. 139°-141° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]2[N:11]=[C:12]([NH:15][C:16](=[O:18])[CH3:17])[S:13][CH:14]=2)=[CH:4][CH:3]=1>C(OCC)(=O)C.[C].[Pd]>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[N:11]=[C:12]([NH:15][C:16](=[O:18])[CH3:17])[S:13][CH:14]=2)=[CH:4][CH:3]=1
Reactant: CC(=O)Nc1nc(C=Cc2ccc(O)cc2)cs1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(=O)Nc1nc(CCc2ccc(O)cc2)cs1
Yield: 82.1 %

Procedure:
To a solution of N-{4-[2-(4-hydroxyphenyl)vinyl]-1,3-thiazol-2-yl}acetamide (932.3 mg, 3.58 mmol) in ethyl acetate (50 ml) was added 10% palladium carbon, and the mixture was hydrogenated at room temperature and atmospheric pressure. After the completion of the reaction, the reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (FUJI SILYSIA CHEMICAL LTD. BW-300SP 30 g, dichloromethane:methanol=40:1→20:1) to give N-{4-[2-(4-hydroxyphenyl)ethyl]-1,3-thiazol-2-yl}acetamide (771.3 mg, 2.94 mmol, yield 82.1%) as a white solid.
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)(C)=O.[Br:9][C:10]1[CH:18]=[CH:17][C:16]2[C:12](=[CH:13][N:14]([CH3:19])[N:15]=2)[C:11]=1/[CH:20]=[CH:21]/[C:22]#[N:23]>CS(C)=O.C(OCC)(=O)C>[Br:9][C:10]1[CH:18]=[CH:17][C:16]2[C:12](=[CH:13][N:14]([CH3:19])[N:15]=2)[C:11]=1[CH:20]1[CH2:4][CH:21]1[C:22]#[N:23]
Reactant: C[S+](C)(C)=O
Reactant: Cn1cc2c(/C=C/C#N)c(Br)ccc2n1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: Cn1cc2c(C3CC3C#N)c(Br)ccc2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 44.4 %

Procedure:
To a suspension of sodium hydride (19.6 mg, 0.490 mmol) in dimethyl sulfoxide (2 mL) was added trimethylsulfoxonium iodide (117 mg, 0.531 mmol) at room temperature, and the mixture was stirred at room temperature for 1 hr. Thereto was added a solution of (2E)-3-(5-bromo-2-methyl-2H-indazol-4-yl)acrylonitrile (107 mg, 0.408 mmol) in dimethyl sulfoxide (2 mL), and the mixture was stirred for 48 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=30/70→100/0) to give the title compound (50.0 mg, yield 44%).
Reaction SMILES: [C:1]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1)(=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[NH2:23][C:24]1[S:25][C:26]([CH2:29][OH:30])=[N:27][N:28]=1.Cl>N1C=CC=CC=1>[OH:30][CH2:29][C:26]1[S:25][C:24]([NH:23][S:19]([C:16]2[CH:17]=[CH:18][C:13]([NH:12][C:1](=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])=[CH:14][CH:15]=2)(=[O:21])=[O:20])=[N:28][N:27]=1
Reactant: CCCCCCCCCC(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1nnc(CO)s1
Agent: Cl
Solvent: c1ccncc1
Product: CCCCCCCCCC(=O)Nc1ccc(S(=O)(=O)Nc2nnc(CO)s2)cc1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 73 %

Procedure:
To a solution of 4-decanamidobenzenesulfonyl chloride (435 mg, 1.26 mmol) in pyridine (5 mL) was added 2-amino-5-hydroxymethyl-1,3,4-thiadiazole (150 mg, 1.15 mmol). The reaction mixture was stirred at room temperature for 4.5 h, then 2 M HCl (15 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (3×30 mL). The organic extracts were washed with water (20 mL), brine (20 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by chromatography on silica gel (70-230 mesh) eluted with CH2Cl2:methanol 9:1 to give the product as a solid, mp 69-70° C., in 73% yield (370 mg, 0.84 mmol); 1H NMR (300 MHz, DMSO-d6) δ 0.84 (t, 3H, J=7.2 Hz), 1.23 (m, 12H), 1.54-1.57 (m, 2H), 2.29 (t, 2H, J=7.5 Hz), 4.57 (d, 2H, J=4.8 Hz), 6.08 (t, 1H, J=5.0 Hz), 7.73 (m, 4H), 10.22 (s, 1H), 14.01 (s, 1H); 13C NMR (75 MHz, DMSO-d6) δ 14.6, 22.8, 25.6, 30.0, 29.4, 29.5, 29.6, 31.9, 37.1, 59.1, 119.3, 127.6, 136.1, 143.5, 161.7, 168.1, 172.6; MS (LCQ, ESI+) Calcd for C19H29N4O4S2 441.2, found 441.1 (M+H)+; HRMS (ESI+, m/z) Calcd for C19H29N4O4S2 441.1630, found 441.1624 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:12])[N:3]=1.[CH:13]([O:16][C:17]1[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=1)([CH3:15])[CH3:14]>>[CH:13]([O:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=[C:4]([CH3:12])[N:3]=2)=[CH:19][CH:18]=1)([CH3:15])[CH3:14]
Reactant: CC(C)Oc1ccc(N)cc1
Reactant: Cc1nc(Cl)c2ccccc2n1
Product: Cc1nc(Nc2ccc(OC(C)C)cc2)c2ccccc2n1

Procedure:
The title compound was prepared from 4-chloro-2-methyl-quinazoline (100 mg, 0.56 mmol), 4-isopropoxy-phenylamine (84.66 mg, 0.56 mmol) by a procedure similar to Example 78. 1H NMR (CDCl3): 7.84-7.72 (m, 3H), 7.70-7.66 (m, 2H)), 7.50-7.45 (m, 1H), 7.30 (brs, 1H), 6.96-6.93 (m, 2H), 4.59-4.51 (m, 1H), 2.68 (s, 3H), 1.36 (d, J=6.3 Hz, 6H).
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[O:11]1[CH2:16][CH2:15][CH:14]([CH2:17][NH2:18])[CH2:13][CH2:12]1>>[CH3:7][N:6]1[C:2]([NH:18][CH2:17][CH:14]2[CH2:15][CH2:16][O:11][CH2:12][CH2:13]2)=[C:3]([N+:8]([O-:10])=[O:9])[CH:4]=[N:5]1
Reactant: Cn1ncc([N+](=O)[O-])c1Cl
Reactant: NCC1CCOCC1
Product: Cn1ncc([N+](=O)[O-])c1NCC1CCOCC1
Yield: 93 %

Procedure:
Reaction of 5-chloro-1-methyl-4-nitro-1H-pyrazole and (tetrahydro-2H-pyran-4-yl)methanamine gave 1-methyl-4-nitro-N-((tetrahydro-2H-pyran-4-yl)methyl)-1H-pyrazol-5-amine as an off-white solid (277 mg, 93%). 1H NMR (400 MHz, CDCl3) δ 7.88 (d, J=1.6 Hz, 1H), 6.75 (s, 1H), 4.01 (dd, J=11.6, 4.3 Hz, 2H), 3.85 (d, J=1.0 Hz, 3H), 3.44-3.32 (m, 4H), 1.90-1.76 (m, 1H), 1.75-1.68 (m, 2H), 1.38 (qd, J=12.4, 4.4 Hz, 2H)
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[CH2:15][CH2:14][C:13]([CH3:17])([CH3:16])[C:12]2[CH:11]=[C:10]3[C:5]([CH:6]=[CH:7][C:8]([C:18]4[S:19][CH:20]=[C:21]([C:23]([O:25]CC)=[O:24])[CH:22]=4)=[CH:9]3)=[CH:4][C:3]1=2.[OH-].[Na+]>>[CH3:1][C:2]1([CH3:28])[CH2:15][CH2:14][C:13]([CH3:16])([CH3:17])[C:12]2[CH:11]=[C:10]3[C:5]([CH:6]=[CH:7][C:8]([C:18]4[S:19][CH:20]=[C:21]([C:23]([OH:25])=[O:24])[CH:22]=4)=[CH:9]3)=[CH:4][C:3]1=2
Reactant: CCOC(=O)c1csc(-c2ccc3cc4c(cc3c2)C(C)(C)CCC4(C)C)c1
Agent: [Na+]
Agent: [OH-]
Product: CC1(C)CCC(C)(C)c2cc3cc(-c4cc(C(=O)O)cs4)ccc3cc21

Procedure:
6.3 g (16 mmol) of the ester prepared in Example 1 and 100 ml of a 2N methanolic sodium hydroxide solution were introduced into a round-bottomed flask and the mixture was heated at reflux for one hour. The reaction medium was evaporated to dryness, the residue taken up in water, acidified to pH 1 with concentrated hydrochloric acid and the solids filtered. The product obtained was recrystallized from an ethyl alcohol/water mixture and 4.5 g (77%) of the expected acid of melting point 223°-225° C. were recovered.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH2:8].[Cl:9][C:10]1[C:11]([N:15]=[C:16]=[S:17])=[CH:12][S:13][CH:14]=1>C1COCC1>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:16]([NH:15][C:11]1[C:10]([Cl:9])=[CH:14][S:13][CH:12]=1)=[S:17]
Reactant: S=C=Nc1cscc1Cl
Reactant: Nc1ccccc1N
Solvent: C1CCOC1
Product: Nc1ccccc1NC(=S)Nc1cscc1Cl
Temperature: 25 °C
Reaction time: 20 h

Procedure:
0.86 g of 1,2-diaminobenzene (o-phenylenediamine) is added to a solution of 1.4 g of 4-chloro-3-thienyl isothiocyanate in 40 ml of anhydrous THF, the mixture is stirred at room temperature for about 20 hours and the solvent is distilled off under reduced pressure. The residue is treated with water and extracted with ethyl acetate, the solvent is distilled off again and the residue is purified using medium-pressure silica gel column chromatography using a 1:1 mixture of ethyl acetate and toluene. Brown-yellow solid.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:45]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH2:44].[C:46]([O:50][C:51]([N:53]1[CH2:58][CH2:57][CH:56]([CH2:59][C:60](O)=[O:61])[CH2:55][CH2:54]1)=[O:52])([CH3:49])([CH3:48])[CH3:47]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:45]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:60](=[O:61])[CH2:59][CH:56]1[CH2:57][CH2:58][N:53]([C:51]([O:50][C:46]([CH3:48])([CH3:47])[CH3:49])=[O:52])[CH2:54][CH2:55]1
Reactant: CC(C)(C)OC(=O)N1CCC(CC(=O)O)CC1
Reactant: Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)OC(=O)N1CCC(CC(=O)Nc2ccc3cc2CCc2cncc(c2)Nc2ncc(Cl)c(n2)N3)CC1
Yield: 59 %

Procedure:
The desired compound was prepared according to the procedure of Example A27 using 6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-amine tris(trifluoroacetate) and [1-(tert-butoxycarbonyl)piperidin-4-yl]acetic acid as the starting materials in 59% yield. LCMS for C29H35ClN7O3 (M+H)+: m/z=564.2.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][C:16]=2[CH2:25][NH:26][CH2:27][CH3:28])[CH:7]=1)[CH3:2].[C:30](Cl)(=[O:32])[CH3:31]>>[CH2:1]([O:3][C:4](=[O:29])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:22])[F:23])=[CH:17][C:16]=2[CH2:25][N:26]([C:30](=[O:32])[CH3:31])[CH2:27][CH3:28])[CH:7]=1)[CH3:2]
Reactant: CC(=O)Cl
Reactant: CCNCc1cc(C(F)(F)F)ccc1Oc1cc(CC(=O)OCC)ccc1OC
Product: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(C(F)(F)F)cc2CN(CC)C(C)=O)c1

Procedure:
Prepared according to the procedure described in Example 3, Step 3, using the following starting materials: [3-(2-ethylaminomethyl-4-trifluoromethyl-phenoxy)-4-methoxy-phenyl]-acetic acid ethyl ester and acetyl chloride.
Reaction SMILES: [C:1]([N:4]1[CH2:8][C@H:7]([OH:9])[CH2:6][C@H:5]1[C:10]([OH:12])=O)(=[O:3])[CH3:2].C1(N=C=NC2CCCCC2)CCCCC1.ON1C2C=CC=CC=2N=N1.Cl.Cl.[N:40]1([C:46]2[CH:51]=[CH:50][C:49]([N:52]3[CH2:56][C@H:55]([CH2:57][O:58][C:59]4[CH:63]=[CH:62][O:61][N:60]=4)[O:54][C:53]3=[O:64])=[CH:48][C:47]=2[F:65])[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1.C(N(CC)C(C)C)(C)C>ClCCl.CN(C=O)C>[C:1]([N:4]1[CH2:8][C@H:7]([OH:9])[CH2:6][C@H:5]1[C:10]([N:43]1[CH2:42][CH2:41][N:40]([C:46]2[CH:51]=[CH:50][C:49]([N:52]3[CH2:56][C@H:55]([CH2:57][O:58][C:59]4[CH:63]=[CH:62][O:61][N:60]=4)[O:54][C:53]3=[O:64])=[CH:48][C:47]=2[F:65])[CH2:45][CH2:44]1)=[O:12])(=[O:3])[CH3:2]
Reactant: O=C1O[C@@H](COc2ccon2)CN1c1ccc(N2CCNCC2)c(F)c1
Reactant: CC(=O)N1C[C@H](O)C[C@H]1C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(=O)N1C[C@H](O)C[C@H]1C(=O)N1CCN(c2ccc(N3C[C@H](COc4ccon4)OC3=O)cc2F)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A suspension of (2S,4R)-1-acetyl-4-hydroxy-2-pyrrolidinecarboxylic acid (173 mg, 1 mmol) in dichloromethane (10 ml) and DMF (2 ml) under nitrogen was treated successively with dicyclohexylcarbodiimide (227 mg, 1.1 mmol) and 1-hydroxybenzotriazole (149 mg, 1.1 mmol), then stirred at ambient temperature for 1 hour. A solution of 3-(4-(piperazin-1-yl)-3-fluorophenyl)-5(R)-(isoxazol-3-yloxymethyl)oxazolidin-2-one dihydrochloride (435 mg, 1 mmol) and N,N-diisopropylethylamine (258 mg, 2 mmol) in dichloromethane (5 ml) was added, and the mixture stirred for 18 hours. Solid was filtered off, the organic solution evaporated to dryness, and the residue purified by chromatography on a 10 g silica Mega Bond Elut® column, eluting with a gradient increasing in polarity from 0 to 15% MeOH in dichloromethane. Relevant fractions were combined and evaporated to give the desired product after trituration with diethyl ether (210 mg).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([N:20]([CH2:28][C@H:29]([OH:38])[CH2:30][O:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)C(=O)OC(C)(C)C)[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([C:14]2[N:15]([CH3:19])[CH:16]=[CH:17][CH:18]=2)=[O:13])=[CH:7][CH:6]=1.[ClH:39]>C(O)C>[ClH:39].[OH:1][CH2:2][C@@H:3]([NH:20][CH2:28][C@H:29]([OH:38])[CH2:30][O:31][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([C:14]2[N:15]([CH3:19])[CH:16]=[CH:17][CH:18]=2)=[O:13])=[CH:7][CH:6]=1
Reactant: Cn1cccc1C(=O)Nc1ccc(C[C@@H](CO)N(C[C@H](O)COc2ccccc2)C(=O)OC(C)(C)C)cc1
Agent: Cl
Solvent: CCO
Product: Cn1cccc1C(=O)Nc1ccc(C[C@@H](CO)NC[C@H](O)COc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
tert-Butyl N-[(1S)-2-hydroxy-1-[4-[[(1-methyl-1H-pyrrol-2-yl)carbonyl]amino]benzyl]ethyl]-N-[(2S)-2-hydroxy-3-phenoxypropyl]carbamate (158 mg) was dissolved in 4N hydrogen chloride in ethanol (2.0 ml) and the solution was stirred at room temperature for 2 hours. The solvent was removed by evaporation and the residual solid was dried under reduced pressure to give N-[4-[(2S)-3-hydroxy-2-[[(2S)-2-hydroxy-3-phenoxypropyl]amino]propyl]phenyl]-1-methyl-1H-pyrrole-2-carboxamide hydrochloride (125 mg) as a pale orange crystalline solid.