Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]21[CH2:14][CH2:13][C:12](=O)[CH2:11][CH2:10]2.C1C2C(=CC=CC=2)CCC21CCC(=O)CC2.[NH2:32][OH:33].[OH-].[Na+]>>[CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]21[CH2:14][CH2:13][C:12](=[N:32][OH:33])[CH2:11][CH2:10]2
Reactant: O=C1CCC2(CC1)Cc1ccccc1C2
Reactant: NO
Agent: O=C1CCC2(CC1)CCc1ccccc1C2
Agent: [Na+]
Agent: [OH-]
Product: ON=C1CCC2(CC1)Cc1ccccc1C2

Procedure:
The first step of the process comprises reacting a spiro (cyclohexane-1,2'-indan)-4-one (II) or a 3',4'-dihydrospiro[cyclohexane-1,2'(1'H)-naphthalen]-4-one (II) with an acid addition salt of hydroxylamine and an alkali metal hydroxide such as sodium hydroxide at reflux temperature for from about 4 to about 8 hours to obtain the corresponding spiro(cyclohexane-1,2'-indan)-4-one oxime (III) or the corresponding 3',4'-dihydrospiro[cyclohexane-1,2'-(1'H)naphthalen]-4-one oxime (III), respectively.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:3]=1[C:4]#[N:5].I[CH2:12][C:13]([F:16])([F:15])[F:14].C(=O)([O-])[O-].[K+].[K+].CCOC(C)=O>CN(C=O)C>[F:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH2:12][C:13]([F:16])([F:15])[F:14])=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1cc(O)ccc1F
Reactant: FC(F)(F)CI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#Cc1cc(OCC(F)(F)F)ccc1F
Temperature: 25 °C
Reaction time: 24 h
Yield: 47.9 %

Procedure:
To a solution of 2-fluoro-5-hydroxy-benzonitrile (Alfa Aesar, 137 mg, 1.0 mmol) was added 2-iodo-1,1,1,-trifluoroethane (117 L, 1.2 mmol) and potassium carbonate (165 mg, 1.2 mmol) in DMF (20 mL) and stirred at RT for 24 hours. The reaction was dissolved into EtOAc and washed with water three times and the combined organic layers were dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica gel column chromatography using hexanes:ethyl acetate 5:1 to give the tile compound as white solid (105 mg, 48%).
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([NH:15][C@H:16]1[CH2:20][CH2:19][N:18]([C:21]2[CH:33]=[CH:32][C:24]([C:25]([O:27]C(C)(C)C)=[O:26])=[C:23]([NH:34][CH:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)[CH:22]=2)[CH2:17]1)=O)(C)(C)C>ClCCl>[NH2:15][C@H:16]1[CH2:20][CH2:19][N:18]([C:21]2[CH:33]=[CH:32][C:24]([C:25]([OH:27])=[O:26])=[C:23]([NH:34][CH:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)[CH:22]=2)[CH2:17]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(c2ccc(C(=O)OC(C)(C)C)c(NC3CCOCC3)c2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@H]1CCN(c2ccc(C(=O)O)c(NC3CCOCC3)c2)C1
Temperature: 25 °C
Reaction time: 30 h
Yield: 137.6 %

Procedure:
19.7 ml (25 eq) of trifluoroacetic acid is added to a solution of 4.72 g (10.23 mmol) of tert-butyl (S)-4-(3-(tert-butoxycarbonylamino)pyrrolidin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)benzoate in 100 ml of dichloromethane. The reaction medium is stirred at room temperature for 30 hours. The solvents are evaporated and the residue is redissolved in diethyl ether and triturated until a solid is obtained. The solid formed is filtered and dried under vacuum to yield 4.3 g (100%) of a yellow powder of (S)-4-(3-aminopyrrolidin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)benzoic acid in the form of a trifluoroacetic acid salt.
Reaction SMILES: O.[NH2:2][NH2:3].C[O:5][C:6]([C:8]1[N:13]=[C:12]([N:14]2[CH2:18][CH2:17][CH2:16][CH:15]2[C:19]2[O:23][N:22]=[C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)[CH:20]=2)[N:11]=[C:10]([NH:30][C:31]2[CH:35]=[C:34]([CH3:36])[NH:33][N:32]=2)[CH:9]=1)=O>CO>[NH2:2][NH:3][C:6]([C:8]1[N:13]=[C:12]([N:14]2[CH2:18][CH2:17][CH2:16][CH:15]2[C:19]2[O:23][N:22]=[C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)[CH:20]=2)[N:11]=[C:10]([NH:30][C:31]2[CH:35]=[C:34]([CH3:36])[NH:33][N:32]=2)[CH:9]=1)=[O:5]
Reactant: NN
Reactant: COC(=O)c1cc(Nc2cc(C)[nH]n2)nc(N2CCCC2c2cc(-c3ccccn3)no2)n1
Solvent: O
Solvent: CO
Product: Cc1cc(Nc2cc(C(=O)NN)nc(N3CCCC3c3cc(-c4ccccn4)no3)n2)n[nH]1
Yield: 68.2 %

Procedure:
Hydrazine mono-hydrate (1.6 ml, 20.6 mmol) was added to a mixture of 6-methoxycarbonyl-2-{2-[3-(pyrid-2-yl)isoxazol-5-yl]pyrrolidin-1-yl}-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidine (Example 56) (1.54 g, 3.45 mmol) in methanol (20.0 ml) at ambient temperature. The resulting reaction mixture was heated at reflux for 1 hour then allowed to cool. The resulting solid was collected by filtration and washed with methanol to give the title compound (1.05 g, 68.3%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[CH2:7][NH:8][CH2:9][CH2:10][NH2:11].[CH3:12][N:13]([CH3:19])[CH2:14][CH2:15][N:16]=[C:17]=[S:18]>>[CH3:12][N:13]([CH3:19])[CH2:14][CH2:15][NH:16][C:17]([NH:11][CH2:10][CH2:9][NH:8][CH2:7][C:2]1[N:3]=[CH:4][CH:5]=[CH:6][N:1]=1)=[S:18]
Reactant: CN(C)CCN=C=S
Reactant: NCCNCc1ncccn1
Product: CN(C)CCNC(=S)NCCNCc1ncccn1

Procedure:
Treating N-(2-pyrimidylmethyl)ethylenediamine with 2-dimethylaminoethyl isothiocyanate, then concentrating and separating by column chromatography by the procedure of Example 40 (a)(ii) gives the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([OH:12])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].I[CH2:16][C:17]([O:19][Na])=[O:18]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([O:12][CH2:16][C:17]([OH:19])=[O:18])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(CI)O[Na]
Reactant: CC(C)(C)OC(=O)N1CC(O)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC(OCC(=O)O)C1
Reaction time: 0.25 h

Procedure:
Anhydrous DMF (5 mL) was added slowly to a stirred mixture of 3-hydroxyazetidine-1-carboxylic acid tert-butyl ester (350 mg, 2.0 mmol) and NaH (121 mg of a 60% dispersion in mineral oil, 3.0 mmol) at 0° C. After 15 min, ICH2CO2Na (630 mg, 3.0 mmol) was added, then stirring was continued at 20° C. for 65 h. The solvent was removed in vacuo, then the residue was partitioned between H2O (15 mL) and EtOAc (10 mL). The organic phase was extracted with saturated aqueous Na2CO3 (2×10 mL), then the combined aqueous extracts were acidified to pH 2 with 2 M HCl, before being extracted with EtOAc (2×50 mL). The EtOAc extracts were washed with brine, before being dried (MgSO4). Filtration, solvent evaporation, and column chromatography (IH-EtOAc, 1:1) furnished the title compound. δH (CDCl3): 1.45 (s, 9H), 3.90-4.00 (m, 2H), 4.10-4.19 (m, 4H), 4.36-4.42 (m, 1H), 10.10-10.30 (br s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:23][CH3:24])=[C:6]([S:8]([N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:20](O)=[O:21])[CH:18]=3)[CH2:13][CH2:12]2)(=[O:10])=[O:9])[CH:7]=1.CN1CCOCC1.N1C(Cl)=NC(Cl)=NC=1Cl.[Cl:41][C:42]1[CH:47]=[CH:46][C:45]([NH2:48])=[CH:44][CH:43]=1>CC(C)=O>[Cl:41][C:42]1[CH:47]=[CH:46][C:45]([NH:48][C:20]([C:17]2[CH:18]=[C:19]3[C:14]([CH2:13][CH2:12][N:11]3[S:8]([C:6]3[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=3[O:23][CH3:24])(=[O:10])=[O:9])=[CH:15][CH:16]=2)=[O:21])=[CH:44][CH:43]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: COc1ccc(Cl)cc1S(=O)(=O)N1CCc2ccc(C(=O)O)cc21
Agent: Clc1nc(Cl)nc(Cl)n1
Solvent: CC(C)=O
Solvent: CN1CCOCC1
Product: COc1ccc(Cl)cc1S(=O)(=O)N1CCc2ccc(C(=O)Nc3ccc(Cl)cc3)cc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 1-(5-chloro-2-methoxy-benzenesulfonyl)-2,3-dihydro-1H-indole-6-carboxylic acid (30 mg, 0.082 mmol) in acetone (0.9 ml) was treated with N-methylmorpholine (0.025 ml, 2.4 equiv.) and cyanuric chloride (18 mg, 0.098 mmol, 1.2 equiv.) and stirred at room temperature for 2 hours. 4-Chloro-phenyl-amine (12 mg, 0.098 mol, 1.2 equiv.) was then added, and the mixture was stirred for 12 hours at room temperature. The solvent was evaporated, and the residue dissolved in methanol (2.5 ml) and purified by preparative HPLC (ZORBAX Eclipse XDB-C18, 21.2×50 mm, 5 μm, gradient acetonitrile/water+0.1% formic acid). 1-(5-Chloro-2-methoxy-benzenesulfonyl)-2,3-dihydro-1H-indole-6-carboxylic acid (4-chloro-phenyl)-amide was obtained as a white solid, 10.6 mg (27%). MS (ISP): m/e=474.9, 477.8 (M−H), δH (300 MHz; d6-DMSO) 10.33 (1H, s), 7.86 (1H, d), 7.79 (2H, d), 7.71 (1H, s), 7.69 (1H, d), 7.60 (1H, d), 7.40 (2H, d), 7.35 (1H, d), 7.21 (1H, d), 4.10 (2H, t), 3.66 (3H, s), 3.12 (2H, t).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C@H:11]([N:13]=[CH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH3:12].C([BH3-])#N.[Na+].Cl>C(O)C.CCCCCCC>[CH2:14]([NH:13][C@@H:11]([C:2]1[C:1]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:5]=[CH:4][CH:3]=1)[CH3:12])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: C[C@@H](N=Cc1ccccc1)c1ccc2ccccc2c1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCCCCCC
Solvent: CCO
Product: C[C@@H](NCc1ccccc1)c1cccc2ccccc12
Temperature: 47.5 °C
Reaction time: 5.5 h

Procedure:
To a stirred solution of (1R)-1-(2-naphthyl)-N-(phenylmethylene) ethanamine (4, 10 g, 0.038 mol) in ethanol (200 mL) was added sodium cyanoborohydride (3.63 g, 0.057 mol) at 25-30° C. The reaction mass was further stirred at 45-50° C. for 5-6 h. Upon completion of the reaction (by TLC), the reaction mass was cooled, quenched with water (100 mL), and extracted with n-heptane (100 mL). The organic layer was separated, washed with water (100 mL), and concentrated under reduced pressure to provide a thick oil. The oil was dissolved in n-heptane (90 mL) and stirred, and the pH of the solution was adjusted to 1-2 using concentrated hydrochloric acid. The precipitated solid was filtered, washed with n-heptane (10 mL), and dried under vacuum to yield the title compound as a white crystalline solid. Yield: 8.2 g, (81.42%); HPLC purity: 99.10%; IR (KBr) cm−1: 3445, 2965, 2759, 2728, 2682, 1596, 1457, 1378, 801, 781, 779; MS: m/z=262.07 [M+H]+; 1H NMR (400 MHz, CDCl3): δ=1.73-1.75 (d, J=8.8 Hz, 3H), 3.95-3.99 (br dd, 1H), 4.16-4.19 (br dd, 1H), 5.24-5.26 (q, J=8.8 Hz, 1H), 7.38-7.39 (m, 3H), 7.48-7.50 (t, 2H), 7.57-7.59 (m, 2H), 7.64-7.66 (d, 1H), 7.98-8.03 (m, 3H), 8.08-8.11 (d, J=9.2 Hz, 1H), 9.72 (bs, 1H), 10.48 (bs, 1H). 13C NMR (100 MHz, CDCl3): δ=21.15 (CH3), 48.34 (CH2), 51.48 (CH), 121.35, 125.04, 125.9, 126.69, 128.52, 129.0, 129.11, 129.61, 130.21, 130.76, 132.11, 133.60.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.OS(O)(=O)=O.OO.[CH3:15][NH:16][CH:17]=[O:18]>>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:17]([NH:16][CH3:15])=[O:18])[CH:3]=1
Reactant: CNC=O
Reactant: Clc1ccncc1
Agent: O=S(=O)(O)O
Agent: OO
Product: CNC(=O)c1cc(Cl)ccn1
Temperature: 60 °C
Reaction time: 1 h
Yield: 5.3 %

Procedure:
Caution: this is a highly hazardous, potentially explosive reaction. To a stirring solution of 4-chloropyridine (10.0 g) in N-methylformamide (250 mL) at room temp. was added conc. H2SO4 (3.55 mL) to generate an exotherm. To this mixture was added H2O2 (30% wt in H2O, 17 mL) followed by FeSO4.7H2O (0.56 g) to generate another exotherm. The resulting mixture was stirred in the dark at room temp. for 1 h, then warmed slowly over 4 h to 45° C. When bubbling had subsided, the reaction was heated at 60° C. for 16 h. The resulting opaque brown solution was diluted with H2O (700 mL) followed by a 10% NaOH solution (250 mL). The resulting mixture was extracted with EtOAc (3×500 mL). The organic phases were washed separately with a saturated NaCl solution (3×150 mL), then they were combined, dried (MgSO4) and filtered through a pad of silica gel with the aid of EtOAc. The resulting brown oil was purified by column chromatography (gradient from 50% EtOAc/50% hexane to 80% EtOAc/20% hexane). The resulting yellow oil crystallized at 0° C. over 72 h to give 4-chloro-N-methyl-2-pyridinecarboxamide (0.61 g, 5.3%): TLC (50% EtOAc/50% hexane) Rf0.50; 1H NMR (CDCl3) δ 3.04 (d, J=5.1 Hz, 3H), 7.43 (dd, J=5.4, 2.4 Hz, 1H), 7.96 (brs, 1H), 8.21 (s, 1H), 8.44 (d, J=5.1 Hz, 1 H); CI-MS m/z 171 ((M+H)+).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][C@@H:2]1[CH2:6]O.[NH:8]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[NH:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(/C(OC(C)(C)C)=O)=N\C(OC(C)(C)C)=O>C1COCC1>[O:1]1[CH2:5][CH2:4][CH2:3][C@@H:2]1[CH2:6][N:8]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[NH:9][C:10]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:11]
Reactant: CC(C)(C)OC(=O)NNC(=O)OC(C)(C)C
Reactant: OC[C@H]1CCCO1
Agent: CC(C)(C)OC(=O)/N=N/C(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NN(C[C@H]1CCCO1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 95.2 %

Procedure:
To a mixture of (R)-(tetrahydrofuran-2-yl)methanol (Fluka, 4.0 g, 39.2 mmol) and di-tert-butyl hydrazine-1,2-dicarboxylate (9.1 g, 39.2 mmol) in THF (50 mL) was added triphenylphosphine (14.4 g, 54.8 mmol) followed by (E)-di-tert-butyl diazene-1,2-dicarboxylate (12.6 g, 54.8 mmol), portionwise. This mixture was stirred at ambient temperature for 16 h then was concentrated under reduced pressure and purified by column chromatography (SiO2, 99% hex/EtOAc to 25% hex/EtOAc) to give the title compound (11.8 g, 37.3 mmol, 95% yield). MS (DCI/NH3) m/z 317 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=2[N:16]([CH3:21])[CH2:17][CH2:18][C:19]#[N:20])[C:5]([Cl:22])=[CH:4][N:3]=1.[NH2:23][C:24]1[CH:25]=[CH:26][C:27]2[C:33]([CH3:35])([CH3:34])[CH2:32][CH2:31][C:30](=[O:36])[NH:29][C:28]=2[CH:37]=1>>[Cl:22][C:5]1[C:6]([NH:8][C:9]2[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=2[N:16]([CH3:21])[CH2:17][CH2:18][C:19]#[N:20])=[N:7][C:2]([NH:23][C:24]2[CH:25]=[CH:26][C:27]3[C:33]([CH3:34])([CH3:35])[CH2:32][CH2:31][C:30](=[O:36])[NH:29][C:28]=3[CH:37]=2)=[N:3][CH:4]=1
Reactant: CC1(C)CCC(=O)Nc2cc(N)ccc21
Reactant: CN(CCC#N)c1cccc(F)c1Nc1nc(Cl)ncc1Cl
Product: CN(CCC#N)c1cccc(F)c1Nc1nc(Nc2ccc3c(c2)NC(=O)CCC3(C)C)ncc1Cl

Procedure:
3-({2-[5-Chloro-2-(5,5-dimethyl-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-8-ylamino)-pyrimidin-4-ylamino]-3-fluoro-phenyl}-methyl-amino)-propionitrile was prepared from 3-{[2-(2,5-Dichloro-pyrimidin-4-ylamino)-3-fluoro-phenyl]-methyl-amino}-propionitrile and 8-Amino-5,5-dimethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one in an analogous manner to Example 1221d. Product isolated a white lyophilate (27 mg, 36%). HPLC purity 99%, LCMS 510.15 (M+H), 1H-NMR (CDCl3, 400 MHz) δ 12.03 (s, 1H), 7.94 (s, 1H), 7.70 (s, 1H), 7.53-7.49 (m, 1H), 7.30-7.26 (m, 2H), 7.18-7.13 (m, 2H), 7.07-7.03 (m, 2H), 3.29 (t, J=6.3 Hz, 2H), 2.74 (s, 3H), 2.53 (t, J=6.3 Hz, 2H), 2.37 (t, J=6.2 Hz, 2H), 2.10 (t, J=7.0 Hz, 2H), 1.36 (s, 6H).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH3:19])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[C:20](OC(=O)C)(=[O:22])C>C(O)=O>[CH:20]([NH:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH3:19])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1)=[O:22]
Reactant: CCOCCON=C(C(=O)OCC)c1csc(N)n1
Reactant: CC(=O)OC(C)=O
Solvent: O=CO
Product: CCOCCON=C(C(=O)OCC)c1csc(NC=O)n1
Yield: 68.1 %

Procedure:
Ethyl 2-(2-aminothiazol-4-yl)-2-(2-ethoxyethoxyimino)acetate (syn isomer, 11.5 g.), acetic anhydride (8.2 g.) and formic acid (3.7 g.) were treated in a similar manner to that of Example A-(4) to give ethyl 2-(2-formamidothiazol-4-yl)-2-(2-ethoxyethoxyimino)acetate (syn isomer, 8.6 g.).
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[CH:5][N:4]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)[N:3]=1.[N+:13]([O-])([OH:15])=[O:14].S(=O)(=O)(O)O>>[Cl:1][C:2]1[C:6]([N+:13]([O-:15])=[O:14])=[CH:5][N:4]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)[N:3]=1
Reactant: O=[N+]([O-])O
Reactant: Clc1ccn(-c2cccnc2)n1
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1cn(-c2cccnc2)nc1Cl

Procedure:
In step 2a, 3-(3-chloro-1H-pyrazol-1-yl)pyridine (5b) is nitrated with nitric acid (HNO3), preferably in the presence of sulfuric acid (H2SO4) to yield 3-(3-chloro-4-nitro-1H-pyrazol-1-yl)pyridine (2-6). The nitration may be conducted at temperatures from about −10° C. to about 30° C.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1.[Si:10](Cl)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11].N1C=CN=C1.C1(O)C=CC=CC=1>C(Cl)Cl>[Si:10]([O:7][CH2:6][C:5]1[CH:8]=[CH:9][C:2]([NH2:1])=[CH:3][CH:4]=1)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Nc1ccc(CO)cc1
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: Oc1ccccc1
Product: CC(C)(C)[Si](C)(C)OCc1ccc(N)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.9 %

Procedure:
A mixture of 4-aminobenzyl alcohol (30.0 g, 81.2 mmol), tert-butyldimethylsilyl chloride (12.24 g, 81.2 mmol), imidazole (11.05 g, 162.4 mmol) and anhydrous CH2Cl2 (200 mL) was stirred at room temperature overnight. TLC analysis showed the appearance of a new spot and the disappearance of starting phenol. The solvent was removed in vacuo and then the remaining oily product was loaded onto a silica gel column and purified by chromatography, eluting with 3:1 hexane-ethyl acetate to afford 15.41 g (80%) of the title compound as a pale orange oil: 1H NMR (DMSO-d6) δ6.95 (d, J=8.4, 2H), 6.53 (d, J=8.4, 2H), 4.96 (s, 2H), 4.50 (s, 2H), 0.88 (s, 9H), 0.04 (s, 6H); 13C NMR (DMSO-d6) δ147.65, 128.04, 127.58, 113.57, 64.69, 25.82, 17.97, -5.18; MS (EI, m/z) 237 (M+).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:15]=1[NH:21][S:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)(=[O:24])=[O:23])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:31](=O)([O-])[O-].[K+].[K+].IC>CN(C=O)C>[CH3:31][N:21]([C:15]1[CH:16]=[CH:17][C:18]([CH3:20])=[CH:19][C:14]=1[O:13][CH2:12][CH2:11][CH2:10][CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[S:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)(=[O:23])=[O:24]
Reactant: O=C([O-])[O-]
Reactant: Cc1ccc(NS(=O)(=O)c2ccccc2)c(OCCCCNC(=O)OC(C)(C)C)c1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cc1ccc(N(C)S(=O)(=O)c2ccccc2)c(OCCCCNC(=O)OC(C)(C)C)c1
Reaction time: 18 h
Yield: 99.1 %

Procedure:
To a solution of 176 mg (0.405 mmol) of N- [2- [4-(tert-butoxycarbonylamino)butyloxy]-4-methylphenyl]benzenesulfonamide in 1.5 mL of anhydrous DMF was added 78.4 mg (0.567 mmol) of powdered anhydrous potassium carbonate and 28 mL (0.446 mmol) of iodomethane. After stirring for 18 h, the mixture was partitioned between 20 mL of ethyl acetate and 20 mL of water. The organic layer was washed with water (2×15 mL), brine (15 mL), dried (Na2SO4) and concentrated to give 180 mg (99%) of the title compound as a colorless syrup. 1 H-NMR (300 MHz, CDCl3) δ 7.70 (m, 2H), 7.56 (m, 1H), 7.46 (m, 2H), 7.14 (d, 1H, J=2.2 Hz), 7.05 (dd, 1H, J=8.4, 2.2 Hz), 6.68 (d, 1H, J=8.4), 4.53 (br s, 1H), 3.61 (t, 2H, J=6.0 Hz), 3.19 (s, 3H), 3.06 (q, 2H, J=6.3 Hz), 2.28 (s, 3H), 1.46 (s, 9H), 1.30-1.41 (m, 4H). Mass spectrum (MALDI-TOF, gentisic acid matrix) calcd. for C23H32 N2O5S: 349.2 (M-BOC+2H). Found: 349.8.
Reaction SMILES: [C:1]1([CH:7]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[Br:20]N1C(=O)CCC1=O>O1CCCC1.C(Cl)(Cl)Cl>[Br:20][C:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC(=O)C(C(=O)OCC)c1ccccc1
Reactant: O=C1CCC(=O)N1Br
Agent: [H-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: CCOC(=O)C(Br)(C(=O)OCC)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of diethyl 2-phenylmalonate (15 ml) in 200 ml of tetrahydrofuran, kept at 0° C. and under nitrogen atmosphere, 3.475 g of sodium hydride are added and the mixture is kept 30 minutes under stirring at 0° C., then it is brought to room temperature. After cooling again to 0° C., the reaction mixture is added with 14.3 g of N-bromosuccinimide. After about 15 minutes, the white solid which separated is filtered off and the filtrate is concentrated to dryness to give a residue which is redissolved in chloroform and dried over sodium sulfate. The solvent is evaporated under reduced pressure to give 15.66 g of the product.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:9])=[N:6][CH:7]=1.BrC1C=NC(C2C=CC=CC=2)=NC=1.C([N:36]1[CH:40]=[CH:39][N:38]=[C:37]1[C:41]1[CH:42]=[N:43][CH:44]=[CH:45][CH:46]=1)C1C=CC=CC=1>>[C:10]1([C:8]([C:5]2[N:4]=[CH:3][C:2]([C:40]3[NH:36][C:37]([C:41]4[CH:42]=[N:43][CH:44]=[CH:45][CH:46]=4)=[N:38][CH:39]=3)=[CH:7][N:6]=2)=[O:9])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: c1ccc(Cn2ccnc2-c2cccnc2)cc1
Reactant: O=C(c1ccccc1)c1ncc(Br)cn1
Agent: Brc1cnc(-c2ccccc2)nc1
Product: O=C(c1ccccc1)c1ncc(-c2cnc(-c3cccnc3)[nH]2)cn1

Procedure:
The title compound is prepared by the method described in Example 1, except that (5-bromopyrimidin-2-yl)(phenyl)methanone (prepared according to the procedure described in WO 2008/121670 p. 94) is used instead of 5-bromo-2-phenylpyrimidine and 3-(1-benzyl-1H-imidazol-2yl)pyridine is used instead of 1-benzyl-2-phenyl-1H-imidazole in Step C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([OH:7])=O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[NH2:35][C:36]1[CH:37]=[N:38][C:39]2[CH2:40][CH2:41][N:42]([CH2:46][C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)[CH2:43][C:44]=2[CH:45]=1>CN(C)C=O.ClCCl>[CH2:46]([N:42]1[CH2:41][CH2:40][C:39]2[N:38]=[CH:37][C:36]([NH:35][C:5](=[O:7])[C:4]3[CH:8]=[CH:9][C:10]([O:11][CH3:12])=[C:2]([Br:1])[CH:3]=3)=[CH:45][C:44]=2[CH2:43]1)[C:47]1[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=1
Reactant: Nc1cnc2c(c1)CN(Cc1ccccc1)CC2
Reactant: COc1ccc(C(=O)O)cc1Br
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc(C(=O)Nc2cnc3c(c2)CN(Cc2ccccc2)CC3)cc1Br
Temperature: 2.5 °C
Reaction time: 72 h
Yield: 49.2 %

Procedure:
3-Bromo-4-methoxybenzoic acid (270 mg; 1.17 mmol) was dissolved in N,N-dimethylformamide (5 ml), the solution was cooled to 0-5° C. and treated with 1-hydroxybenzotriazole(158 mg; 1.17 mmol) then 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (224 mg; 1.17 mmol) and the mixture stirred at 0-5° C. for 0.5 h and treated with a solution of 3-amino-6-benzyl-5,6,7,8-tetrahydro[1,6]naphthyridine (255 mg; 1.06 mmol) in DMF (5 ml). The reaction mixture was stirred at ambient temperature for 72 h then diluted with dichloromethane (100 ml). The resulting mixture was washed with water (5×25 ml), saturated brine, dried (anhydrous magnesium sulfate) and evaporated to dryness in vacuo to yield a mobile, brown oil, which on trituration under 60-80° C. petroleum ether gave a biege powder, which was collected by filtration, washed with 60-80° C. petroleum ether and dried in air. Recrystallisation from ethyl acetate 60-80° C. petroleum ether gave the title compound as a beige powder (236 mg; 49%), m.p. 214-215° C.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:8][C:3]=1[CH2:4][N:5]=[C:6]=[O:7].[C:18]([NH:21][NH2:22])(=[O:20])[CH3:19]>O1CCCC1>[C:18]([NH:21][NH:22][C:6]([NH:5][CH2:4][C:3]1[CH:8]=[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:10]=[CH:11][C:2]=1[CH3:1])=[O:7])(=[O:20])[CH3:19]
Reactant: CC(=O)NN
Reactant: Cc1ccc(-c2ccccc2)cc1CN=C=O
Solvent: C1CCOC1
Product: CC(=O)NNC(=O)NCc1cc(-c2ccccc2)ccc1C
Temperature: 25 °C
Yield: 28.3 %

Procedure:
To a solution of 2.47 g (11.1 mmol) of crude 2-methyl-5-phenylbenzylisocyanate in 50 ml of tetrahydrofuran was added 0.82 g of acetohydrazide and the mixture was heated under reflux for 1 hour. After allowing to cool to room temperature, the reaction mixture was concentrated, and the residue was recrystallized from ethanol to obtain 0.93 g (3.13 mmol) of 1-acetyl-4-(2-methyl-5-phenylbenzyl)semicarbazide.