Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1O)=[CH:9][C:8]([O:13][CH3:14])=[CH:7][CH:6]=2.P(Br)(Br)[Br:16].C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C>[Br:16][C:11]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:13][CH3:14])[CH:9]=2)[N:4]=[CH:3][C:2]=1[Cl:1]
Reactant: COc1ccc2ncc(Cl)c(O)c2c1
Reactant: BrP(Br)Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2ncc(Cl)c(Br)c2c1
Temperature: 25 °C

Procedure:
3-Chloro-6-methoxy-quinolin-4-ol from above in dry DMF (80 mL) was cooled in ice and phosphorus tribromide (15.6 mL) added drop-wise, and the mixture was stirred, with ice-cooling for 30 minutes then allowed to warm to room temperature and stirred for a further 3.5 hours. It was cooled in ice and sodium carbonate solution was added and the solid was collected, washed well with water, and dried in vacuo, to afford a pale yellow solid (13.2 g). MS (ES) m/z 272/274/276 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH2:8][C:9]2[C:13]([CH3:14])=[N:12][O:11][N:10]=2)[C:6](=[S:15])[NH:5][C:4](=[O:16])[CH:3]=1.[N:17]([O-])=O.[Na+].S(S([O-])=O)([O-])=O.[Na+].[Na+]>>[NH2:17][C:3]1[C:4](=[O:16])[NH:5][C:6](=[S:15])[N:7]([CH2:8][C:9]2[C:13]([CH3:14])=[N:12][O:11][N:10]=2)[C:2]=1[NH2:1]
Reactant: Cc1nonc1Cn1c(N)cc(=O)[nH]c1=S
Reactant: O=N[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Product: Cc1nonc1Cn1c(N)c(N)c(=O)[nH]c1=S
Yield: 89.6 %

Procedure:
The title compound was prepared in accordance with the general method described in Example 12(c) by using 6-amino-1-[(4-methyl-1,2,5-oxadiazol-3-yl)methyl]-2-thioxo-2,3-dihydropyrimidin-4(1H)-one (0.44 g, 1.8 mmol, obtained from Example 16(b)), sodium nitrite (0.14 g, 2.0 mmol) and sodium dithionite (0.64 g, 3.7 mmol) which gave the title compound (0.41 g, 88% yield).
Reaction SMILES: [S:1]1[C:5]2[S:6][CH:7]=[CH:8][C:4]=2[CH:3]=[C:2]1[CH:9]=O.[CH2:11]([O:13][C:14](=[O:19])[CH2:15][N:16]=[N+]=[N-])[CH3:12].[O-]CC.[NH4+].[Cl-].C([O-])(=O)C=C>O.CCOCC.C(O)C>[CH2:11]([O:13][C:14]([C:15]1[NH:16][C:3]2[C:4]3[CH:8]=[CH:7][S:6][C:5]=3[S:1][C:2]=2[CH:9]=1)=[O:19])[CH3:12]
Reactant: CCOC(=O)CN=[N+]=[N-]
Reactant: O=Cc1cc2ccsc2s1
Agent: C=CC(=O)[O-]
Agent: CC[O-]
Agent: [Cl-]
Solvent: CCO
Solvent: CCOCC
Solvent: O
Product: CCOC(=O)c1cc2sc3sccc3c2[nH]1

Procedure:
Thieno[2,3-b]thiophene-2-carbaldehyde (Dopper, J. H. et al., J. Am. Chem. Soc., 95: 3692-8 (1973)) was annulated according to Procedure H (aldehyde and azido-acetic acid ethyl ester added as ethanol solution (1 M of ester) to −20° C. ethoxide solution; −20° C. 30 min, −20° C. to room temperature over 2.5 h; reaction poured into cold saturated aqueous NH4Cl; after ether extraction, acrylate organic phase washed with water until aqueous phase was neutral; 0.35 M solution of crude acrylate heated).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][N:3]=[C:2]1[C:6]1[CH:30]=[CH:29][C:9]([CH:10]=[C:11]2[CH2:16][CH2:15][N:14]([C:17](=[O:28])[C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=3)[CH2:13][CH2:12]2)=[CH:8][CH:7]=1.[H][H].C(OCC)(=O)C>C(O)C.[C].[Pd]>[O:1]1[CH2:5][CH2:4][N:3]=[C:2]1[C:6]1[CH:30]=[CH:29][C:9]([CH2:10][CH:11]2[CH2:12][CH2:13][N:14]([C:17](=[O:28])[C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:25])([F:26])[F:27])=[CH:20][CH:19]=3)[CH2:15][CH2:16]2)=[CH:8][CH:7]=1
Reactant: O=C(c1ccc(C(F)(F)F)cc1)N1CCC(=Cc2ccc(C3=NCCO3)cc2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=C(c1ccc(C(F)(F)F)cc1)N1CCC(Cc2ccc(C3=NCCO3)cc2)CC1

Procedure:
441 mg (1 mmol) of 4-[4-(2-oxazolin-2-yl)benzylidene]-1-(4-trifluoromethylbenzoyl)piperidine are hydrogenated (ambient temperature, 30 minutes, hydrogen pressure 50 psi) in 10 ml of anhydrous ethanol and 2.5 ml of ethyl acetate in the presence of 0.5 g of palladium-carbon (10%). The catalyst is then suction-filtered, the filtrate is evaporated under reduced pressure at a bath temperature of 50° C. and the residue is purified by column chromatography (Silica gel; ethyl acetate). 200 mg (48% of theory) of the title compound of melting point 115° C. are obtained.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]([NH:5][CH2:6][C:7]([OH:9])=[O:8])=[O:4].[C:12]1(/[C:18](=[CH:21]\[CH3:22])/[CH2:19]O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl.CN(C)C1C=CN=CC=1>[F:1][C:2]([F:10])([F:11])[C:3]([NH:5][CH2:6][C:7]([O:9][CH2:19]/[C:18](/[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[CH:21]/[CH3:22])=[O:8])=[O:4]
Reactant: C/C=C(/CO)c1ccccc1
Reactant: O=C(O)CNC(=O)C(F)(F)F
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: C/C=C(/COC(=O)CNC(=O)C(F)(F)F)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 86.9 %

Procedure:
To a suspension of N-trifluoroacetylglycine (11, 3.68 g, 21.50 mmol) and (E)-2-phenyl-2-buten-1-ol (12, 2.68 g, 19.32 mmol) in DCM (60 mL) at −40° C. under N2 was added via cannula a solution of dicyclohexylcarbodiimide (4.43 g, 21.50 mmol) and 4-dimethylaminopyridine (0.269 g, 2.15 mmol) in DCM (60 mL). The solution was stirred at ambient temperature for 18 h and filtered, and the precipitate was washed with DCM (2×40 mL). The combined filtrate and washing was washed with 10% citric acid (2×25 mL), H2O (10 mL), 6% NaHCO3 (2×25 mL), and 5 M NaCl (20 mL), and dried, and the solvent was evaporated. The residue was chromatographed (silica gel, 150 g; 4:1 hexane-EtOAc) to afford 5.06 g (87%) of 13 as a pale yellow oil that solidified on standing: mp 49-50° C.; Rf0.66 (4:1 hexane-EtOAc); 1H NMR δ 7.37 (2H, t, J=7.5 Hz), 7.30 (1H, t, J=7.2 Hz), 7.18 (2H, d, J=7.6 Hz), 6.75 (1H, br s), 5.95 (1H, q, J=6.9 Hz), 4.91 (2H, s), 4.06 (2H, d, J=4.9 Hz), 1.66 (3H, d, J=6.9 Hz); 13C NMR δ 167.9, 156.7 (m), 137.3, 135.4, 135.4, 128.5, 128.4, 127.4, 116.9, 70.8, 41.4, 14.6; MS APCI+ m/z 302.1026 [M+H]+ (calcd for C14H15F3NO3, 302.1004); anal. C, 55.73, H, 4.93, N, 4.67%, calcd for C14H14F3NO3, C, 55.82, H, 4.68, N, 4.65%.
Reaction SMILES: [Cl:1][C:2]1[S:6][N:5]=[C:4]([Cl:7])[C:3]=1[Cl:8].[F:9][P-:10]([F:15])([F:14])([F:13])([F:12])[F:11].[CH3:16]COCC>>[F:9][P-:10]([F:15])([F:14])([F:13])([F:12])[F:11].[CH3:16][N+:5]1[S:6][C:2]([Cl:1])=[C:3]([Cl:8])[C:4]=1[Cl:7]
Reactant: CCOCC
Reactant: Clc1nsc(Cl)c1Cl
Agent: F[P-](F)(F)(F)(F)F
Product: C[n+]1sc(Cl)c(Cl)c1Cl
Yield: 61 %

Procedure:
Trichloroisothiazole (15 ml) and 6.2 g (0.03 mol) of trimethyloxomium hexafluorophosphate were heated at 90° for 1 hr under nitrogen. After cooling, ether (100 ml) was added and the solid collected to yield 6.3 g (61%) of product, mp >240. Spectral data (NMR and IR) were consistent with the assigned structure.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH2:9])=[CH:5][CH:6]=[CH:7][CH:8]=1.[CH2:10]([O:12][CH2:13][CH2:14]Cl)[CH3:11].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:10]([O:12][CH2:13][CH2:14][NH:9][C:4]1[C:3](=[CH:8][CH:7]=[CH:6][CH:5]=1)[O:2][CH3:1])[CH3:11]
Reactant: CCOCCCl
Reactant: COc1ccccc1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOCCNc1ccccc1OC
Yield: 40.2 %

Procedure:
A suspension of 12.3 g (100 mmol) o-anisidine M10, 11.9 g (110 mmol) chloroethyl ethyl ether M14, 15.2 g (110 mmol) K2CO3 and 9.1 g (55 mmol) KI in 55 ml DMF was heated at 95° C. for 18 hours. DMF was evaporated and the residue was dissolved in 100 ml CHCl3 and 100 ml saturated NaCl. The organic layer was dried over Na2SO4. The solvent was evaporated to give 19.4 g crude oil. The crude oil was purified with a plug packed with 84 g silica gel 100 with CHCl3/cyclohexane (1:1, v/v) as eluant to afford 7.85 g pure product (yield: 40%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH:8]=O)=[CH:6][C:5]([CH3:10])=[C:4]([CH3:11])[N:3]=1.C(O)(=O)[CH2:13][C:14]([OH:16])=[O:15]>N1C=CC=CC=1>[Cl:1][C:2]1[C:7]([CH:8]=[CH:13][C:14]([OH:16])=[O:15])=[CH:6][C:5]([CH3:10])=[C:4]([CH3:11])[N:3]=1
Reactant: O=C(O)CC(=O)O
Reactant: Cc1cc(C=O)c(Cl)nc1C
Solvent: c1ccncc1
Product: Cc1cc(C=CC(=O)O)c(Cl)nc1C
Yield: 87 %

Procedure:
A mixture of 2-chloro-5,6-dimethyl-3-pyridinecarboxaldehyde (16.85 g), malonic acid (11.45 g) piperidine (10 ml) and pyridine (100 ml) was heated under reflux for 1 hour and evaporated to an oil. This oil was dissolved in sodium hydroxide solution and was extracted with chloroform (discarded). The aqueous phase was acidified with hydrochloric acid and was extracted with chloroform. The chloroform extracts were washed with water and evaporated to give 3-(2-chloro-5,6-dimethyl-3-pyridyl)acrylic acid (18.3 g, 87%) m.p. 150°-158°. This acid was esterified using ethanol and sulphuric acid to give the ethyl ester m.p. 85°-88°.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:14]([OH:16])=O)[C:5]2[CH:6]=[N:7][N:8]([CH:11]3[CH2:13][CH2:12]3)[C:9]=2[CH:10]=1.[NH2:17][CH2:18][C:19]1[C:20](=[O:27])[NH:21][C:22]([CH3:26])=[CH:23][C:24]=1[CH3:25]>>[Br:1][C:2]1[CH:3]=[C:4]([C:14]([NH:17][CH2:18][C:19]2[C:20](=[O:27])[NH:21][C:22]([CH3:26])=[CH:23][C:24]=2[CH3:25])=[O:16])[C:5]2[CH:6]=[N:7][N:8]([CH:11]3[CH2:12][CH2:13]3)[C:9]=2[CH:10]=1
Reactant: O=C(O)c1cc(Br)cc2c1cnn2C1CC1
Reactant: Cc1cc(C)c(CN)c(=O)[nH]1
Product: Cc1cc(C)c(CNC(=O)c2cc(Br)cc3c2cnn3C2CC2)c(=O)[nH]1
Reaction time: 12 h

Procedure:
The title compound was prepared in the same manner as described for example 3 (step c) from 6-bromo-1-cyclopropyl-1H-indazole-4-carboxylic acid (0.22 g, 0.783 mmol) and 3-(aminomethyl)-4,6-dimethyl-2(1H)-pyridinone (0.221 g, 1.174 mmol), wherein the reaction stir time was 12 h. The title compound was collected as a white solid (0.27 g, 81%); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.06-1.17 (m, 4H), 2.12 (s, 3H), 2.20 (s, 3H), 3.76-3.85 (m, 1H), 4.33 (d, J=5.05 Hz, 2H), 5.88 (s, 1H), 7.76 (d, J=1.52 Hz, 1H), 8.10 (s, 1H), 8.30 (d, J=1.01 Hz, 1H), 8.64 (t, J=4.93 Hz, 1H), 11.54 (s, 1H); LC-MS (ES) m/z=414.8 [M+H].
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]([N:6]1[CH2:11][CH2:10][C:9]([C:12]2[C:17]([F:18])=[CH:16][C:15]([N:19]3[CH2:23][C@H:22]([CH2:24][N:25]([C:33]4[CH:37]=[CH:36][O:35][N:34]=4)C(OC(C)(C)C)=O)[O:21][C:20]3=[O:38])=[CH:14][C:13]=2[F:39])=[CH:8][CH2:7]1)=[O:5].FC(F)(F)C(O)=O>ClCCl.O>[OH:1][CH2:2][CH2:3][C:4]([N:6]1[CH2:11][CH2:10][C:9]([C:12]2[C:13]([F:39])=[CH:14][C:15]([N:19]3[CH2:23][C@H:22]([CH2:24][NH:25][C:33]4[CH:37]=[CH:36][O:35][N:34]=4)[O:21][C:20]3=[O:38])=[CH:16][C:17]=2[F:18])=[CH:8][CH2:7]1)=[O:5]
Reactant: CC(C)(C)OC(=O)N(C[C@H]1CN(c2cc(F)c(C3=CCN(C(=O)CCO)CC3)c(F)c2)C(=O)O1)c1ccon1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: O=C(CCO)N1CC=C(c2c(F)cc(N3C[C@H](CNc4ccon4)OC3=O)cc2F)CC1
Reaction time: 0.17 h
Yield: 70.9 %

Procedure:
3-(4-(1-(3-Hydroxypropanoyl)-1,2,5,6-tetrahydropyrid-4-yl)-3,5-difluorophenyl)-5(R)-(N-(t-butoxycarbonyl)isoxazol-3-ylaminomethyl)oxazolidin-2-one (176 mg, 0.32 mM), was dissolved in dichloromethane (1 ml) and treated with trifluoroacetic acid (1 ml) at ambient temperature. After stirring for 10 minutes, the mixture was diluted with water (15 ml) and dichloromethane (15 ml), the organic layer separated, washed with water (2×15 ml), and dried (magnesium sulfate). Solvent was removed, and the residue triturated with diethyl ether to give the desired product (102 mg). NMR (DMSO-d6) δ: 2.20 (m, 1H); 2.28 (m, 1H); 2.48 (m overlapped by DMSO, 2H); 3.42 (br m overlapped by H2O, ˜4H); 3.55 (br m, ˜3H); 3.83 (t, 1H); 4.01 (m, 1H); 4.06 (m, 2H); 4.81 (m, 1H); 5.78 (s, 1H); 5.92 (s, 1H); 6.47 (br s, 1H); 7.26 (d, 2H); 8.31 (s, 1H). MS (ESP): 449 (MH+) for C21H22F2N4O5
Reaction SMILES: [H-].[Na+].[C:3]([NH:6][C:7]1[C:16]([C@H:17]2[CH2:21][CH2:20][O:19][C@H:18]2[CH2:22]OS(C)(=O)=O)=[CH:15][CH:14]=[C:13]([NH:28][C:29](=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31])[C:8]=1[C:9]([O:11][CH3:12])=[O:10])(=[O:5])[CH3:4].[Cl-].[NH4+]>C1COCC1>[C:3]([N:6]1[C:7]2[C:16](=[CH:15][CH:14]=[C:13]([NH:28][C:29](=[O:34])[C:30]([CH3:33])([CH3:31])[CH3:32])[C:8]=2[C:9]([O:11][CH3:12])=[O:10])[C@H:17]2[CH2:21][CH2:20][O:19][C@H:18]2[CH2:22]1)(=[O:5])[CH3:4]
Reactant: COC(=O)c1c(NC(=O)C(C)(C)C)ccc([C@H]2CCO[C@H]2COS(C)(=O)=O)c1NC(C)=O
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COC(=O)c1c(NC(=O)C(C)(C)C)ccc2c1N(C(C)=O)C[C@@H]1OCC[C@H]21
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 113.6 %

Procedure:
Sodium hydride (60% oil dispersion, 0.02 g) was added to a solution of methyl 2-acetylamino-6-(2,2-dimethylpropionylamino)-3-[cis-(2RS,3RS)-2-(methanesulfonyl-oxymethyl)tetrahydrofuran-3-yl]benzoate (Intermediate 31, 0.166 g) in THF (3 mL) and the mixture was stirred at room temperature for 20 minutes. A saturated aqueous solution of ammonium chloride was added and the mixture was extracted with DCM, dried (MgSO4) and filtered. The filtrate was evaporated to dryness to give methyl cis-(3aRS,9bRS)-5-acetyl-7-(2,2-dimethylpropionylamino)-1,2,3a,4,5,9b-hexahydrofuro[2,3-c]quinoline-6-carboxylate (0.15 g) as a tan coloured solid.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([CH3:13])=[CH:5][C:6]([CH2:11][OH:12])=[N:7][C:8]=1[O:9][CH3:10].[Br:14][C:15]1[CH:16]=[C:17]([C:28](O)=[O:29])[C:18]2[C:19]([CH3:27])=[CH:20][N:21]([CH:24]([CH3:26])[CH3:25])[C:22]=2[CH:23]=1.C1C=NC2N(O)N=NC=2C=1.C(Cl)CCl>ClCCl.CN(C=O)C>[Br:14][C:15]1[CH:16]=[C:17]([C:28]([NH:1][CH2:2][C:3]2[C:8]([O:9][CH3:10])=[N:7][C:6]([CH2:11][OH:12])=[CH:5][C:4]=2[CH3:13])=[O:29])[C:18]2[C:19]([CH3:27])=[CH:20][N:21]([CH:24]([CH3:25])[CH3:26])[C:22]=2[CH:23]=1
Reactant: COc1nc(CO)cc(C)c1CN
Reactant: Cc1cn(C(C)C)c2cc(Br)cc(C(=O)O)c12
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1nc(CO)cc(C)c1CNC(=O)c1cc(Br)cc2c1c(C)cn2C(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.7 %

Procedure:
To a stirred solution of (5-(aminomethyl)-6-methoxy-4-methylpyridin-2-yl)methanol (0.29 g, 1.591 mmol), 6-bromo-1-isopropyl-3-methyl-1H-indole-4-carboxylic acid (0.48 g, 1.621 mmol), and HOAt (0.22 g, 1.616 mmol) in Dichloromethane (15 mL) and DMF (5 mL) was added EDC free base (0.30 g, 1.932 mmol). The reaction was stirred at RT for 3 h then evaporated to dryness under vacuum. The remaining was purified by silica gel chromatography (Analogix, SF25-60g, 0 to 20% EtOAc in CH2Cl2) to give the product 6-bromo-N-((6-(hydroxymethyl)-2-methoxy-4-methylpyridin-3-yl)methyl)-1-isopropyl-3-methyl-1H-indole-4-carboxamide (0.73 g, 1.586 mmol, 100% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ=8.46 (t, J=4.9 Hz, 1H), 7.77 (d, J=1.8 Hz, 1H), 7.33 (d, J=1.0 Hz, 1H), 6.99 (d, J=1.5 Hz, 1H), 6.90 (s, 1H), 5.31 (t, J=5.9 Hz, 1H), 4.74 (quin, J=6.6 Hz, 1H), 4.45 (d, J=5.1 Hz, 1H), 4.43 (d, J=5.8 Hz, 2H), 3.83 (s, 3H), 2.40 (s, 3H), 2.10 (s, 3H), 1.38 (d, J=6.8 Hz, 6H). MS(ES)+ m/e 460.2 [M+H]+.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([OH:17])=[C:8]2[CH:14]=[N:13][N:12]([CH2:15][CH3:16])[C:9]2=[N:10][CH:11]=1)=[O:5])C.[OH-].[Na+]>CCO.O>[CH2:15]([N:12]1[C:9]2=[N:10][CH:11]=[C:6]([C:4]([OH:5])=[O:3])[C:7]([OH:17])=[C:8]2[CH:14]=[N:13]1)[CH3:16]
Reactant: CCOC(=O)c1cnc2c(cnn2CC)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCn1ncc2c(O)c(C(=O)O)cnc21

Procedure:
1-Ethyl-4-hydroxy-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid ethyl ester (10.0 g, 42.6 mmol) was suspended in 50 mL EtOH. To this suspension was added 6 N NaOH (21.3 mL, 3 eq). The resulting light brown solution was heated at reflux for 3 hr before being diluted with 100 mL water. The aqueous solution was extracted with diethyl ether (50 mL×3) and the organic layer was discarded. The aqueous layer was acidified with 1 N HCl and a white precipitate formed. The title compound was collected by filtration and rinsed with water and diethyl ether affording a white solid (7.9 g, 90%): mp 218° C. (decomposed); LRMS (m/z) 208 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH2:4][CH2:5][CH2:6][CH:7]1[CH2:12][CH2:11][N:10]([CH2:13][CH2:14]OCC2C=CC=CC=2)[CH2:9][CH2:8]1.[CH3:24][O:25][C:26](=O)[CH2:27][CH2:28][CH2:29][CH:30]1[CH2:35][CH2:34]NCC1>>[CH3:1][O:2][C:3](=[O:23])[CH2:4][CH2:5][CH2:6][CH:7]1[CH2:8][CH2:9][N:10]([CH2:13][CH2:14][CH2:24][O:25][CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:35][CH:34]=2)[CH2:11][CH2:12]1
Reactant: COC(=O)CCCC1CCNCC1
Reactant: COC(=O)CCCC1CCN(CCOCc2ccccc2)CC1
Product: COC(=O)CCCC1CCN(CCCOCc2ccccc2)CC1
Yield: 40 %

Procedure:
Following the same procedure described for the preparation of compound 3a, the compound 3b was synthesized in 40% yield from compound 2 as a yellow oil. 1H NMR (300 MHz, CD3OD) δ 1.21 (m, 4H), 1.42 (m, 1H), 1.49 (m, 2H), 1.83 (d, 2H), 1.93 (m, 2H), 2.31 (m, 2H), 2.69 (m, 2H), 2.99 (m, 2H), 3.35 (m, 2H), 3.60 (m, 5H), 4.50 (m, 2H), 7.28 (m, 5H). m/z (ESI): 334 [C20H31NO3+H]+.
Reaction SMILES: [C:1]1([C:7]([NH:9][CH:10]2[CH2:15][CH:14]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)[CH2:13][N:12]([C:26](OC3C=CC([N+]([O-])=O)=CC=3)=[O:27])[CH2:11]2)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[NH2:39][C@@H:40]1[CH2:45][CH2:44][C@H:43]([OH:46])[CH2:42][CH2:41]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[OH:46][CH:43]1[CH2:44][CH2:45][CH:40]([NH:39][C:26]([N:12]2[CH2:13][CH:14]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:23])[F:24])=[CH:18][CH:17]=3)[CH2:15][CH:10]([NH:9][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[O:8])[CH2:11]2)=[O:27])[CH2:41][CH2:42]1
Reactant: N[C@H]1CC[C@@H](O)CC1
Reactant: O=C(NC1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)Oc2ccc([N+](=O)[O-])cc2)C1)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(NC1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)NC2CCC(O)CC2)C1)c1ccccc1

Procedure:
80 mg (0.16 mmol) of 4-nitrophenyl 3-[(phenylcarbonyl)amino]-5-[4-(trifluoromethyl)phenyl]piperidine-1-carboxylate were initially charged in 1.7 ml of DMF, and 71 mg (0.47 mmol) of cis-4-aminocyclohexanol hydrochloride and 129 mg (0.94 mmol) of potassium carbonate were added. The mixture was reacted in a microwave (Emrys Optimizer) at 150° C. for 15 min. The crude product was then purified by preparative HPLC (Reprosil C18, water/acetonitrile gradient). Yield: 3 mg (4% of theory)
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([OH:13])=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].S(Cl)([Cl:16])=O>C1C=CC=CC=1>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([Cl:16])=[O:13])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)Cc1ccc([N+](=O)[O-])cc1
Solvent: c1ccccc1
Product: O=C(Cl)Cc1ccc([N+](=O)[O-])cc1
Yield: 91 %

Procedure:
To mixture of p-nitrophenylacetic acid (1 g, 5.5 mmol) in benzene (10 ml) was added thionyl chloride (0.8 ml) at room temperature. The reaction mixture was heated to reflux for 12 hr and then cooled. The excess thionyl chloride and benzene were removed in vacuo to obtain (4-nitro-phenyl)-acetyl chloride (1 g, 91%).
Reaction SMILES: CN(C)C=O.[N:6]1([CH2:12][CH2:13][CH2:14][N:15]2[C:23]3[C:18](=[CH:19][C:20]([Cl:24])=[CH:21][CH:22]=3)[C:17]([NH2:25])=[N:16]2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.Br.Br[CH2:28][CH2:29][CH2:30][N:31]([CH2:34][CH3:35])[CH2:32][CH3:33].C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)Cl.O>[N:6]1([CH2:12][CH2:13][CH2:14][N:15]2[C:23]3[C:18](=[CH:19][C:20]([Cl:24])=[CH:21][CH:22]=3)[C:17]([NH:25][CH2:28][CH2:29][CH2:30][N:31]([CH2:34][CH3:35])[CH2:32][CH3:33])=[N:16]2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: Nc1nn(CCCN2CCCCC2)c2ccc(Cl)cc12
Reactant: CCN(CC)CCCBr
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCN(CC)CCCNc1nn(CCCN2CCCCC2)c2ccc(Cl)cc12
Temperature: 80 °C
Reaction time: 12 h
Yield: 54.2 %

Procedure:
To 60 ml of anhydrous N,N-dimethylformamide were added 9.59 g of 1-(3-piperidinopropyl)-3-amino-5-chloroindazole, 8.98 g of 3-bromopropyldiethylamine hydrobromide and 7.89 g of anhydrous potassium carbonate, and the mixture was stirred for 12 hours at 80° C. After cooling, the mixture was added with 80 ml of water and extracted with diethyl ether. The diethyl ether layer was extracted three times with 2N hydrochloric acid, and the hydrochloric acid layer was washed with diethyl ether. The pH of the layer was adjusted to at least 11 with potassium carbonate, and the alkali layer was extracted three times with chloroform. The chloroform layer was dried over anhydrous sodium sulfate, and chloroform was removed under reduced pressure. The residue thus obtained was subjected to an alumina-column chromatography (alumina: 200 g) using chloroform as the developing solvent to give 7.18 g of 1-(3-piperidinopropyl)-3-(3-diethylaminopropylamino)-5-chloroindazole having the following analytical values in a yield of 54%.
Reaction SMILES: [CH:1]1([CH2:6][C@@H:7]([C:20]([NH:22][NH:23][C:24]2[C:29]([F:30])=[C:28]([NH:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=3)[N:27]=[C:26]([CH3:39])[N:25]=2)=[O:21])[CH2:8][N:9]([O:12]CC2C=CC=CC=2)[CH:10]=[O:11])[CH2:5][CH2:4][CH2:3][CH2:2]1>CO>[CH:1]1([CH2:6][C@@H:7]([C:20]([NH:22][NH:23][C:24]2[C:29]([F:30])=[C:28]([NH:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=3)[N:27]=[C:26]([CH3:39])[N:25]=2)=[O:21])[CH2:8][N:9]([OH:12])[CH:10]=[O:11])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1nc(NCc2ccccn2)c(F)c(NNC(=O)[C@H](CC2CCCC2)CN(C=O)OCc2ccccc2)n1
Solvent: CO
Product: Cc1nc(NCc2ccccn2)c(F)c(NNC(=O)[C@H](CC2CCCC2)CN(O)C=O)n1
Reaction time: 2.75 h
Yield: 27.8 %

Procedure:
[(2R)-2-(Cyclopentylmethyl)-3-(2-{5-fluoro-2-methyl-6-[(2-pyridinylmethyl)amino]-4-pyrimidinyl}hydrazino)-3-oxopropyl][(phenylmethyl)oxy]formamide (0.0999 g, 0.1867 mmol) was dissolved in 10 mL of MeOH, degassed and placed under nitrogen. Then 10% Pd(C) (0.025 g) was added and the contents were degassed and stirred under a hydrogen balloon for 2.75 h. The contents were then degassed and filtered through an Acrodisc (CR PTFE 0.45 μm). The resulting filtrate was concentrated and purified by RP-HPLC to provide [(2R)-2-(cyclopentylmethyl)-3-(2-{5-fluoro-2-methyl-6-[(2-pyridinylmethyl)amino]-4-pyrimidinyl}hydrazino)-3-oxopropyl]hydroxyformamide as a beige solid (0.0231 g, 28%). LCMS: (M+H)+=446.5.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[CH:4][CH:3]=1.[NH:25]1[CH2:30][CH2:29][S:28](=[O:32])(=[O:31])[CH2:27][CH2:26]1>>[O:31]=[S:28]1(=[O:32])[CH2:29][CH2:30][N:25]([C:19]([C:18]2[CH:17]=[N:16][C:15]([O:14][CH2:13][C:12]3[C:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)=[N:9][O:10][C:11]=3[CH3:24])=[CH:23][CH:22]=2)=[O:21])[CH2:26][CH2:27]1
Reactant: O=S1(=O)CCNCC1
Reactant: Cc1onc(-c2ccc(F)cc2)c1COc1ccc(C(=O)O)cn1
Product: Cc1onc(-c2ccc(F)cc2)c1COc1ccc(C(=O)N2CCS(=O)(=O)CC2)cn1
Yield: 55 %

Procedure:
As described for example 105, 6-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid (99 mg, 0.33 mmol) was converted, using thiomorpholine-S,S-dioxide instead of 2,2,2-trifluoroethylamine, to the title compound (73 mg, 55%) which was obtained as a white solid. MS: m/e=446.1 [M+H]+.