Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:14][CH2:13]2)=[C:4]([N+:9]([O-])=O)[C:5]([NH2:8])=[N:6][CH:7]=1.[CH3:27][N:28]([CH3:37])[C:29]1[CH:36]=[CH:35][C:32]([CH:33]=O)=[CH:31][CH:30]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>C(O)C>[Cl:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:14][CH2:13]2)=[C:4]2[N:9]=[C:33]([C:32]3[CH:35]=[CH:36][C:29]([N:28]([CH3:37])[CH3:27])=[CH:30][CH:31]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CN(C)c1ccc(C=O)cc1
Reactant: Nc1ncc(Cl)c(N2CCN(CCOc3ccccc3)CC2)c1[N+](=O)[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: CN(C)c1ccc(-c2nc3c(N4CCN(CCOc5ccccc5)CC4)c(Cl)cnc3[nH]2)cc1
Temperature: 70 °C

Procedure:
To a mixture of 5-chloro-3-nitro-4-[4-(2-phenoxy-ethyl)-piperazin-1-yl]-pyridin-2-ylamine (0.037 g, 0.10 mmol), ethanol (3 ml), and 4-dimethylamino-benzaldehyde (0.021 g, 0.14 mmol) was added a freshly prepared aqueous solution of Na2S2O4 (1M; 0.4 ml, 0.4 mmol). The reaction mixture was heated at 70° C. for 5.5 h, then allowed to cool to room temperature and the solvents were removed in vacuo. The residue was absorbed on silica gel and the free running powder was placed on a 10 g isolute silica column, which was eluted with 1 to 2.5% gradient of methanol in ethyl acetate/dichloromethane (v/v; 1:1). The title compound was isolated as a pale yellow solid after trituration with diethyl ether (0.011 g, 23%); %); 1H-NMR (500 Mz, DMSO-d6) 2.72 (br s, 4H, piperazine N(CH2)2), 2.79 (t, J=5.46 Hz, 2H, NCH2CH2O), 3.68 (br s, 4H, piperazine N(CH2)2), 4.15 (t, J=5.70 Hz, 2H, NCH2CH2O), 6.82 (d, J=10.17 Hz, 2H) and 8.00 (d, J=8.93 Hz, 2H) (3,5-C6H4—NMe2 and 3,5-C6H4—NMe2) 6.93 (t, J=6.7 Hz, 1H, p-ArH), 6.99 (d, J=8.92 Hz, 2H, o-ArH), 7.30 (t, J=8.16 Hz, 2H, m-ArH), 8.03 (s, 1H, imidazo[4,5-b]pyridine 5-H), 13.10 (s, 1H, imidazo[4,5-b]pyridine N—H); LC-MS (ESI, m/z) 5.57 min—477, 479 [(M+H)+, Cl isotopic pattern]; ESI-HRMS: Found: 477.2162, calculated for C26H30N6OCl (M+H)+: 477.2170.
Reaction SMILES: [C:1]([NH:9][C@@H:10]1[C:16](=[O:17])[N:15]2[C@H:18](C(O)=O)[CH2:19][CH2:20][CH2:21][N:14]2[C:13](=[O:25])[CH2:12][CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O[C:30]([NH:32][C@H:33]([CH:42]([OH:54])[C:43]1[O:44][C:45]2[C:51]([Cl:52])=[CH:50][C:49]([Cl:53])=[CH:48][C:46]=2[N:47]=1)[CH2:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])=[O:31])C=C.C(NC1C(=O)N2C(C(NC(C(O)COCC3C(Cl)=CC=CC=3Cl)CC(OC(C)(C)C)=O)=O)CCCN2C(=O)CC1)(=O)C1C=CC=CC=1>>[C:1]([NH:9][CH:10]1[C:16](=[O:17])[N:15]2[CH:18]([C:30]([NH:32][CH:33]([CH:42]([C:43]3[O:44][C:48]4[C:49]([Cl:53])=[CH:50][C:51]([Cl:52])=[CH:45][C:46]=4[N:47]=3)[OH:54])[CH2:34][C:35]([O:37][C:38]([CH3:40])([CH3:39])[CH3:41])=[O:36])=[O:31])[CH2:19][CH2:20][CH2:21][N:14]2[C:13](=[O:25])[CH2:12][CH2:11]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=CCOC(=O)N[C@@H](CC(=O)OC(C)(C)C)C(O)c1nc2cc(Cl)cc(Cl)c2o1
Reactant: O=C(N[C@H]1CCC(=O)N2CCC[C@@H](C(=O)O)N2C1=O)c1ccccc1
Agent: CC(C)(C)OC(=O)CC(NC(=O)C1CCCN2C(=O)CCC(NC(=O)c3ccccc3)C(=O)N12)C(O)COCc1c(Cl)cccc1Cl
Product: CC(C)(C)OC(=O)CC(NC(=O)C1CCCN2C(=O)CCC(NC(=O)c3ccccc3)C(=O)N12)C(O)c1nc2cc(Cl)cc(Cl)c2o1

Procedure:
was prepared from the acid (212e) and (3S,4RS) t-butyl N-(allyloxycarbonyl)-3-amino-4-hydroxy-4-(5,7-dichlorobenzoxazol-2-yl)butanoate (204) by an analogous method as that used for compound 215e to afford a mixture of diastereomers (613 mg, 87%) as a glass: IR film) 3328, 1229, 1660, 1534, 1454, 1422, 1399, 1276, 1254, 1155; 1H NMR (CDCl3) δ7.80 (2H, d), 7.60-7.35 (5H, m), 1155; 1H NMR (CDCl3) δ7.80 (2H, d), 7.60-7.35 (5H, m), 7.05 (2H, m), 5.13 (3H, m), 4.74 (1H, m), 4.51 (1H, m), 3.25 (1H, m), 3.1-2.6 (5H, m), 2.33 (1H, m), 2.1-1.5 (5H, m), 1.43 and 1.41 (9H combined, 2×s). MS ES+ Da/e 688 (M+1)+ Cl35 55%, 690 (M+1)+ Cl37 35%, 328 100%.
Reaction SMILES: [CH3:1][C:2](=[O:6])[CH:3]=[CH:4][CH3:5].Cl[Mg][CH2:9][Si:10]([CH3:13])([CH3:12])[CH3:11]>C(OCC)C>[CH3:5][CH:4]([CH2:9][Si:10]([CH3:13])([CH3:12])[CH3:11])[CH2:3][C:2](=[O:6])[CH3:1]
Reactant: CC=CC(C)=O
Reactant: C[Si](C)(C)C[Mg]Cl
Solvent: CCOCC
Product: CC(=O)CC(C)C[Si](C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 43 %

Procedure:
A solution of 8.00 g pent-3-en-2-one in 50 mL dry diethyl ether was dropped to a solution of 73.5 mL of chloro[(trimethylsilyl)methyl]magnesium (1.0M in diethyl ether) and 955 mg of CuBr at −5° C. under Argon. The mixture was stirred for 1 hour at room temperature. An aqueous work-up followed by silica gel chromatography yielded 5.20 g (43%) of a colourless oil.
Reaction SMILES: Br.Br[CH:3]1[C:8](=[O:9])[CH:7](Br)[C:6]([CH3:12])([CH3:11])[NH:5][C:4]1([CH3:14])[CH3:13].[OH-].[K+].[OH-].[NH4+:18]>>[C:8]([CH:7]1[CH2:14][C:4]([CH3:3])([CH3:13])[NH:5][C:6]1([CH3:11])[CH3:12])(=[O:9])[NH2:18]
Reactant: CC1(C)NC(C)(C)C(Br)C(=O)C1Br
Reactant: [NH4+]
Agent: Br
Agent: [K+]
Agent: [OH-]
Product: CC1(C)CC(C(N)=O)C(C)(C)N1

Procedure:
3,5-Dibromo-4-oxo-2,2,6,6-tetramethylpiperidine (II, 30 gm) was added slowly, with stirring, to ammonium hydroxide (500 mL). When the solid is dissolved, potassium hydroxide is added, which results in the precipitation of (III). After filtering the solid, additional potassium hydroxide is added to the remaining solution until the precipitation of more material no longer is observed. The precipitates are combined, dried and recrystallized from benzene, giving a white solid (III, 10 gm, 68%) mp 176°-178° C. (lit ref. [1, except pg. 204] mp 180°-181° C). Both I.R. and NMR confirm the structure of (III).
Reaction SMILES: FC(F)(F)C(O)=O.[NH:8]1[CH2:12][CH2:11][C@@H:10]([S:13][C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)[CH2:9]1.[CH2:21]([CH:29]1[CH2:31][O:30]1)[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[OH:30][C@@H:29]([CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:31][N:8]1[CH2:12][CH2:11][C@@H:10]([S:13][C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)[CH2:9]1
Reactant: Oc1ccc(S[C@@H]2CCNC2)cc1
Reactant: c1ccc(CCC2CO2)cc1
Solvent: O=C(O)C(F)(F)F
Product: Oc1ccc(S[C@@H]2CCN(C[C@@H](O)CCc3ccccc3)C2)cc1

Procedure:
The title compound, MS: m/e=344.4 (M+H+) was prepared from (R)-4-(pyrrolidin-3-yl-sulfanyl)-phenol trifluoro-acetic acid and (RS)-2-phenethyl-oxirane.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:17])[C:10]1[CH:15]=[CH:14][C:13](Cl)=[N:12][CH:11]=1.[NH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][NH2:25]>>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:17])[C:10]1[CH:15]=[CH:14][C:13]([NH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][NH2:25])=[N:12][CH:11]=1
Reactant: Nc1ccccc1NC(=O)c1ccc(Cl)nc1
Reactant: NCCCCCCN
Product: NCCCCCCNc1ccc(C(=O)Nc2ccccc2N)cn1
Yield: 66.9 %

Procedure:
N-(2-Aminophenyl)-6-chloronicotinamide (248 mg, 1 mmol) and 1,6-diaminohexane (5.80 g, 50 mmol) were heated to 80° C. for 3 hours. The excess 1,6-diaminohexane was removed under vacuum. To the residue was added 5 ml of 0.20 M NaOH. The mixture was extracted with 100 ml of ethyl acetate. The ethyl acetate was removed under vacuum to give the title compound (219 mg, 67% yield) as a brown solid. LC-MS (m/z) 328 (M+1).
Reaction SMILES: N([C:6]([CH2:11][OH:12])([CH2:9]O)CO)[CH2:2][C:3]([OH:5])=[O:4].[OH-:13].[Na+].[Mg+2].[Cl-].[Cl-].CC1[N+](CC2C(N)=NC(C)=NC=2)=CS[C:20]=1[CH2:33][CH2:34][O:35]P(OP(O)(O)=O)(O)=O.[Cl-]>>[CH3:20][CH:33]([O:5][C:3]([CH3:2])=[O:4])[C:34]([OH:35])=[O:13].[O:12]=[C:11]([CH2:6][CH3:9])[C:34]([O-:35])=[O:13]
Reactant: [OH-]
Reactant: Cc1ncc(C[n+]2csc(CCOP(=O)(O)OP(=O)(O)O)c2C)c(N)n1
Reactant: O=C(O)CNC(CO)(CO)CO
Agent: [Cl-]
Agent: [Mg+2]
Agent: [Na+]
Product: CC(=O)OC(C)C(=O)O
Product: CCC(=O)C(=O)[O-]

Procedure:
To a 1 ml solution containing 0.1 M tricine-NaOH, pH 8, 10 mM MgCl2, 0.1 mM thiamine pyrophosphate, and 0.1 mM flavin adenine dinucleotide were added various concentrations of pyruvate (10 μM to 10 mM), α-keto-butyrate (10 μM to 80 mM), or acetolactate (0.15 to 5.5 mM). After allowing the solution to equilibrate with air (21 % O2), the level of dissolved oxygen was monitored by use of a commercially available oxygen-sensitive electrode (Hansatech) and polarographic electronics as described by Sweet et al. (Analytical Biochemistry 107:337 (1980)). In the absence of further additions, negligible oxygen was consumed over a 30 minute period. To initiate the consumption of oxygen, 20 μl of a 2 mg/ml stock solution of acetolactate synthase was added if pyruvate or α-acetolactate were used as substrate, or 5 μl of a 49 mg/ml stock solution of acetolactate synthase was added if α-ketobutyrate was used as substrate. The limiting rate of oxygen consumption at saturating concentrations of pyruvate, α-ketobutyrate, or α-acetolactate are illustrated in Table 1. The concentrations of α-acetolactate or α-ketobutyrate that gave half of the maximum rate (the Michaelis constant) were 1.4 mM and 32 μM, respectively. The rate of oxygen consumption was constant over the range of concentrations of pyruvate examined, indicating that the Michaelis constant for this substrate was substantially lower than 10 μM.
Reaction SMILES: [CH:1]([O:4][C:5]1[C:6]([N+:18]([O-:20])=[O:19])=[CH:7][C:8]([CH3:17])=[C:9]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)[CH:10]=1)([CH3:3])[CH3:2].[I:21][CH3:22]>C1COCC1>[I-:21].[CH:1]([O:4][C:5]1[C:6]([N+:18]([O-:20])=[O:19])=[CH:7][C:8]([CH3:17])=[C:9]([C:11]2[CH:16]=[CH:15][N+:14]([CH3:22])=[CH:13][CH:12]=2)[CH:10]=1)([CH3:3])[CH3:2]
Reactant: CI
Reactant: Cc1cc([N+](=O)[O-])c(OC(C)C)cc1-c1ccncc1
Solvent: C1CCOC1
Product: Cc1cc([N+](=O)[O-])c(OC(C)C)cc1-c1cc[n+](C)cc1
Product: [I-]
Temperature: 40 °C
Reaction time: 48 h

Procedure:
4-(5-Isopropoxy-2-methyl-4-nitro-phenyl)-pyridine (Example 7, Step 1, 217 mg, 0.797 mmol) is dissolved in anhydrous THF (9 mL). Iodomethane (0.10 mL, 1.61 mmol, 2 equiv.) is added and the reaction is stirred at 40° C. in a sealed tube for 2 days. The volatiles are removed under vacuum generating 4-(5-Isopropoxy-2-methyl-4-nitro-phenyl)-1-methyl-pyridinium iodide as a brown solid: ESMS m/z 287.1 (M+).
Reaction SMILES: C(OC([N:8]1[CH2:27][CH2:26][N:11]2[C:12](=[O:25])[C:13]3[C:18]([C@@H:10]2[CH2:9]1)=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:14]=3[C:21]([F:24])([F:23])[F:22])=O)(C)(C)C.[ClH:28]>CCOCC.O>[ClH:28].[CH3:20][O:19][C:16]1[CH:17]=[C:18]2[C:13]([C:12](=[O:25])[N:11]3[CH2:26][CH2:27][NH:8][CH2:9][C@H:10]32)=[C:14]([C:21]([F:24])([F:22])[F:23])[CH:15]=1
Reactant: COc1cc2c(c(C(F)(F)F)c1)C(=O)N1CCN(C(=O)OC(C)(C)C)C[C@@H]21
Agent: Cl
Solvent: CCOCC
Solvent: O
Product: COc1cc2c(c(C(F)(F)F)c1)C(=O)N1CCNC[C@@H]21
Reaction time: 1 h

Procedure:
To a stirring solution of N-(t-butoxycarbonyl)-(R)-1,3,4,10b-tetrahydro-9-methoxy-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-one (40 mg, 0.1 mmol) in dry ether (2 mL) was added hydrochloric acid (1 mL). The reaction was stirred for 1 h and then conc. in vacuo to a white solid. The solid was dissolved in water and lyophilized to 10 mg of a white solid. MS (ESI) 287 (M−Cl).
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([C:12]2[C:17]([Br:18])=[CH:16][N:15]=[C:14]([Cl:19])[N:13]=2)[CH2:9]1)=O)(C)(C)C>Cl.CO>[ClH:19].[NH:8]1[CH2:11][CH:10]([C:12]2[C:17]([Br:18])=[CH:16][N:15]=[C:14]([Cl:19])[N:13]=2)[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CC(c2nc(Cl)ncc2Br)C1
Agent: Cl
Solvent: CO
Product: Clc1ncc(Br)c(C2CNC2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 200 %

Procedure:
The mixture of 3-(5-bromo-2-chloro-pyrimidin-4-yl)-azetidine-1-carboxylic acid tert-butyl ester (0.7 g, 2.0 mmol) in HCl/MeOH (10 mL) was stirred at RT for 1 h. Then it was concentrated to give 4-azetidin-3-yl-5-bromo-2-chloro-pyrimidine hydrochloride (0.57 g, 2.0 mmol, yield 100%) which was used in the next step without further purification. ESI-MS (M+1): 248 calc. for C7H7BrClN3 247.
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1)=[O:4].[NH:12]1[CH:16]=[N:15][CH:14]=[N:13]1.C(N(CC)CC)C.O>C(#N)C>[N:12]1([CH2:2][C:3]([C:5]2[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=2)=[O:4])[CH:16]=[N:15][CH:14]=[N:13]1
Reactant: c1nc[nH]n1
Reactant: O=C(CCl)c1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: O
Product: O=C(Cn1cncn1)c1ccc(Cl)cc1

Procedure:
2,4'-Dichloroacetophenone (0.03 mol) and 1,2,4-triazole (0.03 mol) were suspended in acetonitrile (50 ml) and cooled to -20°. Triethylamine (0.03 mol) was added dropwise with stirring. After stirring at -20° for 2 hours, the mixture was poured into water, and the product filtered off, washed with water, dried and crystallised from toluene to give pale yellow needles of 2-(1,2,4-triazol-1-yl)-4'-chloroacetophenone, m.p. 151°-3°.
Reaction SMILES: [CH2:1]([N:4]1[C:8]([CH2:9][CH2:10][CH3:11])=[CH:7][CH:6]=[C:5]1[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([NH2:19])[CH:14]=1)[CH2:2][CH3:3].[O-:20][C:21]#[N:22].[Na+].FC(F)(F)C(O)=O.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC=CC=1>[CH2:1]([N:4]1[C:8]([CH2:9][CH2:10][CH3:11])=[CH:7][CH:6]=[C:5]1[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([NH:19][C:21]([NH2:22])=[O:20])[CH:14]=1)[CH2:2][CH3:3]
Reactant: CCCc1ccc(Cc2cccc(N)c2)n1CCC
Reactant: N#C[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CCCc1ccc(Cc2cccc(NC(N)=O)c2)n1CCC
Temperature: 25 °C
Yield: 80.2 %

Procedure:
A stirred solution of 2 g (7.7 mmol) of 1,5-dipropyl-2-(3'-aminobenzyl)pyrrole in 200 ml of benzene was treated with 1 g (15.3 mmol) of sodium cyanate followed by the dropwise addition, over a 11/2 hour period, of a solution of 1.5 ml (19 mmol) of trifluoroacetic acid in 100 ml of benzene. The reaction mixture was stirred at room temperature for 1 more hour, poured into 300 ml of saturated aqueous sodium carbonate solution and extracted with ethyl acetate (3×300 ml). The combined extracts were washed with water (2×300 ml), dried and evaporated in vacuo. The residue was purified by column chromatography on 100 g of silica gel, using hexane-ethyl acetate (55:45) as eluant, thus obtaining 1.85 g (83%) of the title compound, 1,5-dipropyl-2-(3'-ureidobenzyl)pyrrole, which was recrystallized from acetone-hexane. M.P. 123°-126° C.
Reaction SMILES: [F:1][C:2]1[CH:53]=[CH:52][CH:51]=[CH:50][C:3]=1[CH2:4][C:5]1([OH:49])[CH2:10][CH2:9][CH2:8][CH:7]([NH:11][C:12]([C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[N:19](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[N:18]=[C:17]3[C:42]2[CH:47]=[CH:46][N:45]=[C:44]([CH3:48])[CH:43]=2)=[O:13])[CH2:6]1.[SiH](CC)(CC)CC>C(O)(C(F)(F)F)=O>[F:1][C:2]1[CH:53]=[CH:52][CH:51]=[CH:50][C:3]=1[CH2:4][C:5]1([OH:49])[CH2:10][CH2:9][CH2:8][CH:7]([NH:11][C:12]([C:14]2[CH2:15][C:16]3[C:20](=[CH:21][CH:22]=2)[N:19]=[N:18][C:17]=3[C:42]2[CH:47]=[CH:46][N:45]=[C:44]([CH3:48])[CH:43]=2)=[O:13])[CH2:6]1
Reactant: Cc1cc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3ccc(C(=O)NC4CCCC(O)(Cc5ccccc5F)C4)cc23)ccn1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C2=C3CC(C(=O)NC4CCCC(O)(Cc5ccccc5F)C4)=CC=C3N=N2)ccn1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
N-(3-(2-fluorobenzyl)-3-hydroxycyclohexyl)-3-(2-methylpyridin-4-yl)-1-trityl-1H-indazole-5-carboxamide was stirred in neat TFA at room temperature for 10 minutes, and then Et3SiH (5 equiv.) was added. The reaction mixture was stirred at room temperature for 5 minutes, and then concentrated. The titled compound was obtained and purified by reverse phase HPLC.
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]([CH3:19])[C:3]1=[O:20].[N+:21]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[N:30]=[C:31]=[O:32])([O-:23])=[O:22]>O1CCCC1>[CH3:19][N:4]1[C:5]2[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=2[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:8][CH:2]([NH:1][C:31]([NH:30][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[N+:21]([O-:23])=[O:22])=[O:32])[C:3]1=[O:20]
Reactant: CN1C(=O)C(N)N=C(c2ccccc2)c2ccccc21
Reactant: O=C=Nc1ccccc1[N+](=O)[O-]
Solvent: C1CCOC1
Product: CN1C(=O)C(NC(=O)Nc2ccccc2[N+](=O)[O-])N=C(c2ccccc2)c2ccccc21
Reaction time: 8 h

Procedure:
Equimolar amounts of 3(R,S)-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one and 2-nitrophenylisocyanate were mixed in 8 ml of dry tetrahydrofuran at room temperature. The reaction mixture was allowed to stand for 8 hours and was then filtered. The collected solids were washed with tetrahydrofuran and dried in vacuo over P2O5 to give the analytical product: m.p 260°-261° C.
Reaction SMILES: [CH3:1][O:2][C:3]12[CH2:11][CH2:10][CH:7]([CH:8]=[CH:9]1)[C:6](=[O:12])[CH2:5][C:4]2=[O:13].[C:14]1(C)C=CC=CC=1.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Cl:33][C:34]1[CH:47]=[CH:46][C:37]([C:38]2[CH:39]=[CH:40][C:41]([CH3:45])=[C:42]([Pb+3])[CH:43]=2)=[CH:36][CH:35]=1.Cl>C(Cl)(Cl)Cl.CN(C)C1C=CN=CC=1>[Cl:33][C:34]1[CH:47]=[CH:46][C:37]([C:38]2[CH:39]=[CH:40][C:41]([CH2:45][CH3:14])=[C:42]([CH:5]3[C:6](=[O:12])[CH:7]4[CH2:10][CH2:11][C:3]([O:2][CH3:1])([CH:9]=[CH:8]4)[C:4]3=[O:13])[CH:43]=2)=[CH:36][CH:35]=1
Reactant: Cc1ccc(-c2ccc(Cl)cc2)cc1[Pb+3]
Reactant: COC12C=CC(CC1)C(=O)CC2=O
Reactant: Cc1ccccc1
Agent: CC(=O)[O-]
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClC(Cl)Cl
Product: CCc1ccc(-c2ccc(Cl)cc2)cc1C1C(=O)C2C=CC(OC)(CC2)C1=O
Temperature: 80 °C
Reaction time: 0.17 h

Procedure:
1-methoxybicyclo[3.2.2]non-6-en-2,4-dione (0.080 g, 0.044 mmol) stirred in dry chloroform (4 ml) under a nitrogen atmosphere. 4-Dimethylaminopyridine (0.268 g, 2.2 mmol) is added, followed by dry toluene (1 ml) and the mixture is heated to 80° C. To this reaction mixture is then added 4′-chloro-4-methylbiphen-3-yl-lead triacetate (0.400 g, 0.67 mmol) portionwise, over 4 minutes, and the mixture is held at 80° C. for 3¼ hour. The reaction mixture is cooled to room temperature, acidified with dilute aqueous hydrochloric acid (10 ml), stirred vigorously for 10 minutes, then filtered through diatomaceous earth and the filter cake is washed with dichloromethane (10 ml). The filtrate is poured into a separating funnel, the organic layer collected and the aqueous phase is extracted with dichloromethane (2×10 ml). The organic fractions are combined, dried over anhydrous magnesium sulfate, filtered and the filtrate is concentrated under vacuum. The residue is taken up in N,N-dimethylformamide (approximately 2 ml) and purified by preparative reverse-phase HPLC to give 3-(4′-chloro-4-ethylbiphen-3-yl)-1-methoxybicyclo[3.2.2]non-6-ene-2,4-dione.
Reaction SMILES: Cl.[F:2][C:3]1[C:8]([F:9])=[CH:7][CH:6]=[C:5]([F:10])[C:4]=1[C@@H:11]([NH2:13])[CH3:12].C([O:18][C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]1[CH:32]=[CH:31][C:30]([CH2:33][N:34]2[C:42]3[C:37](=[CH:38][C:39]([C:43](O)=[O:44])=[CH:40][CH:41]=3)[C:36]([CH3:46])=[C:35]2[CH3:47])=[CH:29][CH:28]=1)=[O:20])(C)(C)C>>[CH3:47][C:35]1[N:34]([CH2:33][C:30]2[CH:31]=[CH:32][C:27]([C:22]3[C:21]([C:19]([OH:20])=[O:18])=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:28][CH:29]=2)[C:42]2[C:37]([C:36]=1[CH3:46])=[CH:38][C:39]([C:43](=[O:44])[NH:13][C@H:11]([C:4]1[C:5]([F:10])=[CH:6][CH:7]=[C:8]([F:9])[C:3]=1[F:2])[CH3:12])=[CH:40][CH:41]=2
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Reactant: C[C@H](N)c1c(F)ccc(F)c1F
Agent: Cl
Product: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)O)cc2)c2ccc(C(=O)N[C@@H](C)c3c(F)ccc(F)c3F)cc12

Procedure:
The title compound was prepared following the same general protocol as described in Step 8-9, Example 1, using the (S)-1-(2,3,6-trifluorophenyl)ethanamine hydrochloride and the 1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid. ESI-MS (m/z): 557 [M+H]+.
Reaction SMILES: [Br:1]Br.[CH2:3]([O:10][C:11](=[O:22])[NH:12][C@H:13]1[CH2:18][CH2:17][C@H:16]([C:19](=[O:21])[CH3:20])[CH2:15][CH2:14]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>CO>[CH2:3]([O:10][C:11](=[O:22])[NH:12][C@H:13]1[CH2:18][CH2:17][C@H:16]([C:19](=[O:21])[CH2:20][Br:1])[CH2:15][CH2:14]1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: BrBr
Reactant: CC(=O)[C@H]1CC[C@H](NC(=O)OCc2ccccc2)CC1
Solvent: CO
Product: O=C(N[C@H]1CC[C@H](C(=O)CBr)CC1)OCc1ccccc1
Temperature: 10 °C
Reaction time: 4 h

Procedure:
Bromine (160 μL, 3.12 mmol, 1.0 eq) is added at 10° C. to a stirred solution of (trans-4-acetyl-cyclohexyl)-carbamic acid benzyl ester (850 mg, 3.12 mmol, 1.0 eq) in methanol (30 mL). After 4 hours stirring at 10° C., the reaction mixture is diluted with petroleum ether (15 mL) and the resulting precipitate is collected by filtration to afford [trans-4-(2-bromo-acetyl)-cyclohexyl]-carbamic acid benzyl ester as a white solid (920 mg, 83% yield).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][NH:11][C:12]3[N:17]=[C:16]([NH:18][C:19]4[CH:23]=[C:22]([C@@H:24]5[CH2:26][C@H:25]5[C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)[NH:21][N:20]=4)[CH:15]=[CH:14][N:13]=3)=[CH:9][C:4]=2[N:3]=[CH:2]1.O1CCCC[CH:34]1N1C2C=CC(CN)=CC=2N=C1>>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C@@H:10]([NH:11][C:12]3[N:17]=[C:16]([NH:18][C:19]4[CH:23]=[C:22]([C@@H:24]5[CH2:26][C@H:25]5[C:27]5[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=5)[NH:21][N:20]=4)[CH:15]=[CH:14][N:13]=3)[CH3:34])=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: NCc1ccc2c(c1)ncn2C1CCCCO1
Reactant: c1ccc([C@@H]2C[C@H]2c2cc(Nc3ccnc(NCc4ccc5[nH]cnc5c4)n3)n[nH]2)cc1
Product: C[C@H](Nc1nccc(Nc2cc([C@@H]3C[C@H]3c3ccccc3)[nH]n2)n1)c1ccc2[nH]cnc2c1

Procedure:
N2-(1H-Benzimidazol-5-ylmethyl)-N4-[5-[(trans)-2-phenylcyclopropyl]-1H-pyrazol-3-yl]pyrimidine-2,4-diamine (I-27) prepared analogously starting from 91 and condensing with (1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[d]imidazol-5-yl)methanamine (28) and subsequently removing the pyran in accord with the procedure in steps 6 and 7 of example 1.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][CH:13]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7].[C-:14]#[N:15].[Na+]>CSC.O>[C:14]([CH2:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][CH:13]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])#[N:15]
Reactant: [C-]#N
Reactant: CCOC(=O)c1cccc(CCl)c1
Agent: [Na+]
Solvent: CSC
Solvent: O
Product: CCOC(=O)c1cccc(CC#N)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 89.1 %

Procedure:
To a solution of ethyl 3-(chloromethyl)benzoate (5.0 g, 25.1 mmol) in dimethylsulfide (50 mL) was added sodium cyanide (1.85 g, 37.8 mmol), and the mixture was stirred at room temperature for 15 hr. The reaction mixture was diluted with water, extracted with ethyl acetate, and the extract was washed successively with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (carrier: silica gel, eluent: hexane-ethyl acetate) to give the title compound (4.23 g, 89%) as a colorless oil.
Reaction SMILES: [CH3:1][CH:2]1[C:7](=[O:8])[NH:6][C:5]2[CH:9]=[CH:10][CH:11]=[CH:12][C:4]=2[O:3]1.[Br:13]Br>C(O)(=O)C>[Br:13][C:11]1[CH:10]=[CH:9][C:5]2[NH:6][C:7](=[O:8])[CH:2]([CH3:1])[O:3][C:4]=2[CH:12]=1
Reactant: CC1Oc2ccccc2NC1=O
Reactant: BrBr
Solvent: CC(=O)O
Product: CC1Oc2cc(Br)ccc2NC1=O
Reaction time: 8 h

Procedure:
In 56 ml of glacial acetic acid, 6 g of 2-methyl-1,4-benzoxazin-3-(4H)-one is precooled at 0° C. and mixed drop by drop with 1.9 ml of bromine in 19 ml of glacial acetic acid. It is allowed to reach room temperature and stirred for another 8 hours. The mixture is poured onto ice water, the crystals are suctioned off and washed with water. 9.3 g of crude product results, which is recrystallized from ethanol/water. 7-Bromo-2-methyl-1,4-benzoxazin-3-(4H)-one is obtained as a by-product. As an alternative, 4-bromo-2-aminophenol can also be reacted according to the described processes.