Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:9][N:10]([CH2:16][C:17]2[C:22]([CH:23]([CH3:25])[CH3:24])=[CH:21][CH:20]=[CH:19][N:18]=2)[CH2:11][CH2:12][CH2:13][CH2:14][NH2:15])=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.Cl[CH2:27][CH2:28][N:29]=[C:30]=[O:31].[H-].[Na+]>C(Cl)Cl.C1COCC1>[CH3:1][C:2]1[C:3]([CH2:9][N:10]([CH2:16][C:17]2[C:22]([CH:23]([CH3:25])[CH3:24])=[CH:21][CH:20]=[CH:19][N:18]=2)[CH2:11][CH2:12][CH2:13][CH2:14][N:15]2[CH2:27][CH2:28][NH:29][C:30]2=[O:31])=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cnc(CN(CCCCN)Cc2ncccc2C(C)C)c(C)c1
Reactant: O=C=NCCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cc1cnc(CN(CCCCN2CCNC2=O)Cc2ncccc2C(C)C)c(C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.7 %

Procedure:
To a cold (0° C.) solution of N1-(3,5-Dimethyl-pyridin-2-ylmethyl)-N1-{3-isopropyl-pyridin-2-ylmethyl}-butane-1,4-diamine (163 mg, 0.48 mmol) in CH2Cl2 (5 mL) was added 2-chloroethylisocyanate (50 μL, 0.59 mmol) and the resultant mixture was stirred for 80 minutes then concentrated to provide a yellow oil. To a cold (0° C.) solution of the yellow oil in THF (5 mL) was added NaH (95% dry, 39 mg, 0.98 mmol). The cooling bath was removed and the resultant mixture was stirred at room temperature overnight. The mixture was treated with brine (10 mL) and extracted with CH2Cl2 (5×20 mL). The combined organic extracts were dried (Na2SO4) and concentrated. Purification of the crude material by column chromatography on silica gel (10:1:1 CH2Cl2-MeOH—NH4OH) followed by radial chromatography on silica gel (1 mm plate, 50:1:1 CH2Cl2-MeOH—NH4OH) provided 82 mg (41%) of COMPOUND 151 as a colorless oil. 1H NMR (CDCl3) δ 0.98 (d, 6H, J=6.9 Hz), 1.26-1.36 (m, 2H), 1.42-1.52 (m, 2H), 2.19 (s, 3H), 2.28 (s, 3H), 2.53 (dd, 2H, J=7.2, 7.2 Hz), 2.90-3.06 (m, 3H), 3.27-3.39 (m, 4H), 3.72 (s, 4H), 4.21 (br s, 1H), 7.—(dd, 1H, J=7.2, 4.8 Hz), 7.25 (s, 1H), 7.51 (dd, 1H, J=7.8, 1.5 Hz), 8.19 (s, 1H), 8.33 (dd, 1H, J=4.8, 1.5 Hz); 13C NMR (CDCl3) δ 18.27, 18.30, 23.51 (2 carbons), 24.36, 25.98, 27.46, 38.56, 43.75, 45.40, 54.47, 58.99, 59.59, 123.06, 132.12, 133.16, 133.61, 138.92, 144.24, 145.99, 146.57, 154.48, 156.29, 163.37; ES-MS m/z 410 (M+H). Anal. Calcd. For C24H35N5O.0.7H2O: C, 68.28; H, 8.69; N, 16.59. Found: C, 68.24; H, 8.52; N, 16.36.
Reaction SMILES: [C:1]1(/[CH:7]=[CH:8]/[C:9]2[C:17]3[CH:16]=[CH:15][S:14][C:13]=3[CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.Cl.O>O1CCCC1>[C:1]1([CH2:7][CH2:8][C:9]2[C:17]3[CH:16]=[CH:15][S:14][C:13]=3[CH:12]=[CH:11][CH:10]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C(=C/c1cccc2sccc12)\c1ccccc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: c1ccc(CCc2cccc3sccc23)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 76.1 %

Procedure:
To a solution of 4-[(E)-2-phenylvinyl]benzo[b]thiophene (0.56 g) and triethyl amine (2.63 mL) in tetrahydrofuran (25 mL) was added 2,4,6-triisopropylbenzenesulfonylhydrazide (5 g), and the mixture was refluxed overnight under an argon atmosphere. After the reaction mixture was cooled to room temperature, 2 mol/L hydrochloric acid was added to the mixture, and the mixture was stirred for 10 minutes. The mixture was poured into water, and the mixture was extracted with diethyl ether. The extract was washed with water and brine and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane) to give a mixture of the starting material and the title compound (0.43 g). This mixture was dissolved in triethylamine (2.04 g) and tetrahydrofuran (18 mL), and 2,4,6-triisopropylbenzenesulfonylhydrazide (3.28 g) was added to the solution, and the mixture was refluxed overnight under an argon atmosphere. The reaction mixture was cooled to room temperature and 2 mol/L hydrochloric acid was added to the mixture, and the mixture was stirred for 10 minutes. The mixture was poured into water, and the mixture was extracted with diethyl ether. The extract washed with water and brine and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane) to give the title compound (0.4 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][N:9]2C(=O)C3C(=CC=CC=3)C2=O)[CH:5]=[N:6][CH:7]=1.O.NN>CCO>[Br:1][C:2]1[CH:3]=[C:4]([CH2:8][NH2:9])[CH:5]=[N:6][CH:7]=1
Reactant: O=C1c2ccccc2C(=O)N1Cc1cncc(Br)c1
Agent: NN
Solvent: O
Solvent: CCO
Product: NCc1cncc(Br)c1
Yield: 115.8 %

Procedure:
A solution of 2-((5-bromopyridin-3-yl)methyl)isoindoline-1,3-dione (LIII) (1.9 g, 6.0 mmol, 1 eq) and hydrazine hydrate (2.0 g, 40 mmol, 6 eq) in EtOH (20 mL) was heated at 70° C. for 3 h. The mixture was filtered through a Celite® pad and the filtrate was concentrated in vacuo, the crude product was dissolved in 1N HCl solution (15 mL) and concentrated to dryness, then it was washed with acetone (10 mL×3), the precipitate was collected by filtration, dried in vacuo to give (5-bromopyridin-3-yl)methanamine (LIV) (1.3 g, 6.95 mmol, 97.7% yield) as a white solid. 1H NMR (D2O, 500 MHz) δ ppm 4.34 (s, 2H), 8.56 (s, 1H), 8.75 (d, J=1.2 Hz, 1H), 8.91 (d, J=1.6 Hz, 1H). ESIMS found for C6H7BrN2 m/z 187 (M+H).
Reaction SMILES: [Br:1][C:2]1[C:3]([O:17]C)=[CH:4][C:5]2[S:9][C:8]([NH:10][C:11]([NH:13][CH2:14][CH3:15])=[O:12])=[N:7][C:6]=2[CH:16]=1.Br.[OH-].[Na+]>>[Br:1][C:2]1[C:3]([OH:17])=[CH:4][C:5]2[S:9][C:8]([NH:10][C:11]([NH:13][CH2:14][CH3:15])=[O:12])=[N:7][C:6]=2[CH:16]=1
Reactant: CCNC(=O)Nc1nc2cc(Br)c(OC)cc2s1
Agent: Br
Agent: [Na+]
Agent: [OH-]
Product: CCNC(=O)Nc1nc2cc(Br)c(O)cc2s1
Temperature: 110 °C
Reaction time: 47 h

Procedure:
Intermediate 6 (1.30 g, 3.94 mmol) was suspended in hydrogen bromide solution (6.82 mL, 47% aq., 59.1 mmol) and the resulting suspension warmed to 110° C. Hydrogen bromide solution (14 mL, 47% aq., 121.3 mmol) was added portion-wise over the course of the reaction. After 47 h, the reaction mixture was cooled to RT then in ice and the pH adjusted with sodium hydroxide solution (1 M, aq.) to pH 8. The mixture was filtered and the resulting solid washed with H2O and ACN. The solid was sucked dry to give i (1.01 g, 81%). MS 315.87 & 317.84 [M+H]+.
Reaction SMILES: CN1CCOCC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl:32][C:33]1[CH:34]=[C:35]2[C:39](=[C:40]([C:42]([OH:44])=O)[CH:41]=1)[NH:38][CH:37]=[CH:36]2.[C:45]([C:49]1[CH:65]=[CH:64][C:52]([CH2:53][NH:54][CH2:55][CH2:56][C:57]2[CH:62]=[CH:61][C:60]([F:63])=[CH:59][CH:58]=2)=[C:51]([Cl:66])[CH:50]=1)([CH3:48])([CH3:47])[CH3:46]>CN(C=O)C.O>[C:45]([C:49]1[CH:65]=[CH:64][C:52]([CH2:53][N:54]([CH2:55][CH2:56][C:57]2[CH:58]=[CH:59][C:60]([F:63])=[CH:61][CH:62]=2)[C:42]([C:40]2[CH:41]=[C:33]([Cl:32])[CH:34]=[C:35]3[C:39]=2[NH:38][CH:37]=[CH:36]3)=[O:44])=[C:51]([Cl:66])[CH:50]=1)([CH3:48])([CH3:46])[CH3:47]
Reactant: CC(C)(C)c1ccc(CNCCc2ccc(F)cc2)c(Cl)c1
Reactant: O=C(O)c1cc(Cl)cc2cc[nH]c12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: O
Product: CC(C)(C)c1ccc(CN(CCc2ccc(F)cc2)C(=O)c2cc(Cl)cc3cc[nH]c23)c(Cl)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 82.5 %

Procedure:
106 mg (1.05 mmol) of N-methyl morpholine and then 199 mg (0.53 mmol) of HBTU were added to 68 mg (0.35 mol) of 5-chloro-1H-indol-7-carboxylic acid and 136 mg (0.39 mmol) of (4-tert-butyl-2-chloro-benzyl)-[2-(4-fluoro-phenyl)-ethyl]-amine dissolved in 3.5 ml DMF at rt under nitrogen. The reaction mixture was stirred at rt for 3 h. Water was added and the reaction mixture was extracted twice with EtOAc. The combined organic layers were washed once with 1N aqueous HCl solution, once with saturated aqueous NaHCO3 solution and once with saturated aqueous NaCl solution, dried over sodium sulfate, filtered and the solvent was evaporated. The residue was purified by column chromatography (20 g silica gel, heptane/EtOAc 7:3) to yield 160 mg (92%) product as a light yellow foam. MS (EI) 496.1 (M)+.
Reaction SMILES: C([O:5][C:6](=[O:42])[C@@H:7]([NH:28][S:29]([C:32]1[CH:37]=[CH:36][C:35]([C:38]([F:41])([F:40])[F:39])=[CH:34][CH:33]=1)(=[O:31])=[O:30])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][C:19](=[O:27])[NH:20][C:21]2[NH:22][CH2:23][CH2:24][CH2:25][N:26]=2)=[CH:11][CH:10]=1)(C)(C)C>FC(F)(F)C(O)=O.O>[NH:26]1[CH2:25][CH2:24][CH2:23][N:22]=[C:21]1[NH:20][C:19]([CH2:18][CH2:17][CH2:16][O:15][C:12]1[CH:13]=[CH:14][C:9]([CH2:8][C@H:7]([NH:28][S:29]([C:32]2[CH:37]=[CH:36][C:35]([C:38]([F:41])([F:39])[F:40])=[CH:34][CH:33]=2)(=[O:31])=[O:30])[C:6]([OH:42])=[O:5])=[CH:10][CH:11]=1)=[O:27]
Reactant: CC(C)(C)OC(=O)[C@H](Cc1ccc(OCCCC(=O)NC2=NCCCN2)cc1)NS(=O)(=O)c1ccc(C(F)(F)F)cc1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: O=C(CCCOc1ccc(C[C@H](NS(=O)(=O)c2ccc(C(F)(F)F)cc2)C(=O)O)cc1)NC1=NCCCN1
Reaction time: 2 h

Procedure:
37.3 mg of (2S)-3-{4-[3-(1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl)-propoxy]-phenyl}-2-(4-trifluoromethylbenzenesulfonylamino)-propionic acid tert-butyl ester were dissolved in trifluoroacetic acid/water (95/5) and stirred for 2 hours. The solvent was removed in vacuo, and the residue was dissolved in acetic acid/water and lyophilized. Yield 27.6 mg. MS (ES+): m/e=557.1 (M+H)+.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[N:12]=[C:11]([NH:13][CH2:14][CH2:15][O:16][C:17](OC3C=CC=CC=3)=[O:18])[N:10]=[C:9]([CH2:26][CH2:27][CH3:28])[N:8]=2)[CH2:3][CH2:2]1.[NH3:29]>ClCCl>[NH2:29][C:17]([O:16][CH2:15][CH2:14][NH:13][C:11]1[N:12]=[C:7]([N:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)[N:8]=[C:9]([CH2:26][CH2:27][CH3:28])[N:10]=1)=[O:18]
Reactant: CCCc1nc(NCCOC(=O)Oc2ccccc2)nc(N2CCOCC2)n1
Reactant: N
Solvent: ClCCl
Product: CCCc1nc(NCCOC(N)=O)nc(N2CCOCC2)n1
Reaction time: 7 h
Yield: 97.4 %

Procedure:
19.4 g (0.05 mole) of 2-morpholino-4-[[2-[(phenoxycarbonyl)oxy]ethyl]amino]-6-propyl-1,3,5-triazine, dissolved in 100 ml of anhydrous dichloromethane are introduced into one liter of liquid ammonia. Stirring is continued for 7 hours at a temperature of between -35° C. and -45° C. The ammonia is then evaporated and the organic phase is washed successively with an aqueous solution of sodium bicarbonate and with water. It is dried over sodium sulfate and the solvent is evaporated under reduced pressure. The residue obtained crystallizes in a 50:50 mixture (v/v) of ethyl acetate-hexane. 15.1 g of 2-[[2-[(aminocarbonyl)oxy]ethyl]amino]-4-morpholino-6-propyl-1,3,5-triazine are obtained.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BH4-].[Na+].Cl[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11]>O1CCCC1>[CH2:13]([O:12][C:10]([N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH2:2]1)=[O:11])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: c1ccncc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N1C=CC=CC1
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 74.3 %

Procedure:
A solution of pyridine (4.0 g., 0.050 mol) and NaBH4 (1.0 g, 0.026 mol) in 20 ml of tetrahydrofuran is treated with benzyl chloroformate (8.5 g, 0.05 mol) over about 1 hour followed by stirring for 1.5 hour at -78° C. The mixture is added to ice-water and extracted with ether, and the extract is washed with 3% HCl solution and 3% NaOH solution. After the extract is dried and evaporated, 8.0 g of N-benzyloxycarbonyl-1,2-dihydropyridine is obtained in 74% yield. A 5% solution of N-benzyloxycarbonyl-1,2-dihydropyridine is then irradiated using a Rayonet photochemical reactor (RP-300 lamps) until the NMR spectrum shows consumption of the starting materials. The solvent is evaporated to give the crude product, N-(benzyloxycarbonyl)-2-azabicyclo[2.2.0]hex-5-ene (VIII). Pure (VIII) is obtained by passing the crude product through basic alumina with ether. (VIII) is then reacted with ozone in methanol at -78° C. followed by reaction with peroxyacetic acid to form cis-N-(benzyloxycarbonyl)-azetidine-2,3-dicarboxylic acid.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([C@H:10]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[CH3:28])[CH2:11][C:12]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([CH3:20])[CH:15]=2)=[O:13])=[CH:6][CH:5]=1.I[CH3:30]>O1CCCC1>[Br:3][C:4]1[CH:9]=[CH:8][C:7]([C@H:10]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[CH3:28])[CH:11]([CH3:30])[C:12]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([CH3:20])[CH:15]=2)=[O:13])=[CH:6][CH:5]=1
Reactant: CI
Reactant: Cc1cc(C(=O)C[C@H](c2ccc(Br)cc2)c2ccc(Cl)cc2C)ccn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(C(=O)C(C)[C@H](c2ccc(Br)cc2)c2ccc(Cl)cc2C)ccn1
Temperature: 0 °C
Yield: 68.7 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 23 mg, 0.54 mmol) was added to a solution of (R)-3-(4-bromophenyl)-3-(4-chloro-2-methylphenyl)-1-(2-methylpyridin-4-yl)propan-1-one (example 282, step 1; 208 mg, 0.49 mmol) in tetrahydrofuran (7 mL), then after 90 min the reaction mixture was cooled to 0° C. and treated with iodomethane (73 mg, 0.54 mmol). The ice bath was removed, then after 2 h the reaction mixture was partitioned between sat. aq. ammonium chloride solution and ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered, and evaporated. Chromatography (SiO2; heptane-ethyl acetate 1:1) produced the title compound (149 mg, 70%). Light yellow oil, MS (ESI+): m/z=442.3 ([M+H]+).
Reaction SMILES: [Br:1][C:2]1[C:3]([N:20]2[CH2:25][CH2:24][N:23](C(NC3C=CC=CC=3)=O)[CH2:22][CH2:21]2)=[C:4]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([N:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1.BrC1C(N2CCN([CH:52]([C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][N:55]=3)[CH3:53])CC2)=C([N+]([O-])=O)C(N)=NC=1.[O-]S(S([O-])=O)=O.[Na+].[Na+].CN(C1C=CC(C=O)=CC=1)C>CN(C=O)C>[Br:1][C:2]1[C:3]([N:20]2[CH2:21][CH2:22][N:23]([CH:52]([C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][N:55]=3)[CH3:53])[CH2:24][CH2:25]2)=[C:4]2[N:10]=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([N:17]([CH3:18])[CH3:19])=[CH:15][CH:16]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CN(C)c1ccc(-c2nc3c(N4CCN(C(=O)Nc5ccccc5)CC4)c(Br)cnc3[nH]2)cc1
Reactant: CC(c1ccccn1)N1CCN(c2c(Br)cnc(N)c2[N+](=O)[O-])CC1
Agent: CN(C)c1ccc(C=O)cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(c1ccccn1)N1CCN(c2c(Br)cnc3[nH]c(-c4ccc(N(C)C)cc4)nc23)CC1
Reaction time: 16 h
Yield: 49 %

Procedure:
This was prepared using the same procedure as for 4-(6-bromo-2-(4-(dimethylamino)phenyl)-3H-imidazo[4,5-b]pyridin-7-yl)-N-phenylpiperazine-1-carboxamide, but here using 5-bromo-3-nitro-4-(4-(1-(pyridin-2-yl)ethyl)piperazin-1-yl)pyridin-2-amine (100 mg, 0.24 mmol), DMF (1.5 mL), 1M Na2S2O4 (3 eq, 0.74 mmol, 0.74 mL) and 4-(N,N-dimethylamino)benzaldehyde (1.05 eq, 0.26 mmol, 38 mg). After 16 h, filtration of the precipitate, washing with cold water (1 mL) and trituration with Et2O gave the product (61 mg, 49%) as a pale yellow solid; 1H-NMR (500 MHz, DMSO-d6) 1.58 (br s, 3H, CHCH3), 2.44-2.58 (2 m, 4H, piperazine N(CH2)2), 3.01 (s, 6H, N(CH3)2), 3.72-3.90 (br s, 5H, piperazine N(CH2)2 & CHCH3), 6.83 (d, J=9.0 Hz, 2H, N,N-dimethylaminophenyl), 7.43 (br, 1H, pyridine H-5 or H-3), 7.52 (s, br, 1H, pyridine H-3 or H-5), 7.91-7.98 (m, 1H, pyridine H-4), 8.00 (d, J=8.9 Hz, 2H, N,N-dimethylaminophenyl), 8.17 (s, 1H, imidazo[4,5-b]pyridine H-5), 8.70 (br, 1H, pyridine H-6), 13.20 (br s, 1H, imidazo[4,5-b]pyridine NH);
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:15]=[C:16]([NH:20][C:21]([C:23]4[N:24]([CH3:29])[N:25]=[C:26]([CH3:28])[CH:27]=4)=[O:22])[CH:17]=[CH:18][CH:19]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:30].C1COCC1.[NH2:36][C:37]1[CH:45]=[CH:44][C:40]([C:41]([OH:43])=[O:42])=[CH:39][CH:38]=1.[O-]S([O-])(=O)=O.[Na+].[Na+]>CCOC(C)=O>[CH3:29][N:24]1[C:23]([C:21]([NH:20][C:16]2[CH:15]=[C:14]([CH:19]=[CH:18][CH:17]=2)[C:12]([C:8]2[CH:7]=[C:6]3[C:11]([C:3](=[CH:2][NH:36][C:37]4[CH:45]=[CH:44][C:40]([C:41]([OH:43])=[O:42])=[CH:39][CH:38]=4)[C:4](=[O:30])[NH:5]3)=[CH:10][CH:9]=2)=[O:13])=[O:22])=[CH:27][C:26]([CH3:28])=[N:25]1
Reactant: Nc1ccc(C(=O)O)cc1
Reactant: Cc1cc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CO)c2)n(C)n1
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CNc3ccc(C(=O)O)cc3)c2)n(C)n1
Temperature: 65 °C
Reaction time: 24 h

Procedure:
A small screw cap test tube was charged with 2,5-Dimethyl-2H-pyrazole-3-carboxylic acid [3-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (as prepared in Example 60, 100 mg, 0.249 mmol) and THF (2 mL). To the resulting solution was added 4-Amino-benzoic acid (37.5 mg, 0.274 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature. The yellow solid was dissolved into a solution of 98% EtOAc/2% i-prOH (3 mL) and washed with water (3×2 mL). The organic layers were combined and dried over anhydrous Na2SO4 affording 47.8% (0.062 g, 0.119 mmol) of the title compound.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11](=O)[CH2:12][CH3:13])=[CH:10][C:5]=2[N:4]=[CH:3]1.[Cl:15][CH2:16][CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]([C:27]2[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=2)=O)=[CH:21][CH:20]=1>>[Cl:15][CH2:16][CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22](/[C:25](/[C:27]2[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=2)=[C:11](\[C:9]2[CH:8]=[CH:7][C:6]3[N:2]([CH3:1])[CH:3]=[N:4][C:5]=3[CH:10]=2)/[CH2:12][CH3:13])=[CH:21][CH:20]=1
Reactant: CCC(=O)c1ccc2c(c1)ncn2C
Reactant: O=C(c1ccc(O)cc1)c1ccc(OCCCl)cc1
Product: CC/C(=C(\c1ccc(O)cc1)c1ccc(OCCCl)cc1)c1ccc2c(c1)ncn2C

Procedure:
According to general procedure of McMurry reaction as example 1, step D described, 1-(1-methyl-1H-benzo[d]imidazol-5-yl)propan-1-one (730 mg, 2.2 eq) was reacted with (4-(2-chloroethoxy)phenyl)(4-hydroxyphenyl)methanone (500 mg, 1.0 eq) to give the separated (Z)-isomer and (E)-isomer of the product. (Z)-isomer: 1H NMR (400 MHz, CDCl3) δ 7.81 (s, 1H), 7.62 (s, 1H), 7.11-7.15 (m, 3H), 7.01 (dd, J=8.4 Hz, 1.2 Hz, 1H), 6.83 (dd, J=6.8 Hz, 2.0 Hz, 2H), 6.79 (dd, J=6.8 Hz, 2.0 Hz, 2H), 6.49 (dd, J=6.8 Hz, 2.0 Hz, 2H), 4.05 (t, J=5.6 Hz, 2H), 3.79 (s, 3H), 3.69 (t, J=6.0 Hz, 2H), 2.53 (q, J=7.2 Hz, 2H), 0.91 (t, J=7.2 Hz, 3H).
Reaction SMILES: [CH2:1]([C@@H:4]1[CH2:9][CH2:8][CH2:7][C@H:6]([O:10][CH2:11][C:12]2[N:13]=[C:14]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[CH:19]=3)[O:15][C:16]=2[CH3:17])[CH2:5]1)[CH:2]=C.I([O-])(=O)(=O)=[O:27].[Na+].C(OC)(C)(C)C>C(OCC)C.O.[Os](=O)(=O)(=O)=O>[CH3:25][O:24][C:20]1[CH:19]=[C:18]([C:14]2[O:15][C:16]([CH3:17])=[C:12]([CH2:11][O:10][C@@H:6]3[CH2:7][CH2:8][CH2:9][C@H:4]([CH2:1][CH:2]=[O:27])[CH2:5]3)[N:13]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: C=CC[C@@H]1CCC[C@H](OCc2nc(-c3cccc(OC)c3)oc2C)C1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: COC(C)(C)C
Product: COc1cccc(-c2nc(CO[C@@H]3CCC[C@H](CC=O)C3)c(C)o2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
750 mg of 4-(cis-3-allylcyclohexyloxymethyl)-2-(3-methoxyphenyl)-5-methyloxazole are dissolved in 20 ml of diethyl ether, and 1.4 g of sodium periodate, dissolved in 20 ml of water, are added. At 0° C., 1 ml of an osmium tetroxide solution (2.5% by weight in tert-butanol) is added, and the mixture is stirred vigorously at room temperature. After 8 hours, 100 ml of methyl tert-butyl ether are added and the mixture is washed with a saturated sodium thiosulfate solution. The organic phase is dried over MgSO4 and the solvent is then removed under reduced pressure. This gives 740 mg of {cis-3-[2-(3-methoxyphenyl)-5-methyloxazol-4-ylmethoxy]-cyclohexyl}acetaldehyde as a yellow-brown oil. C20H25NO4 (343.43), MS(ESI): 344 (M+H+), Rf(n-heptane:ethyl acetate=2:1)=0.10.
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6](=[O:15])[NH:5][C:4](=[O:16])[C:3]=1Br.[CH3:18][NH2:19]>>[NH2:1][C:2]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6](=[O:15])[NH:5][C:4](=[O:16])[C:3]=1[NH:19][CH3:18]
Reactant: CN
Reactant: Nc1c(Br)c(=O)[nH]c(=O)n1Cc1ccccc1
Product: CNc1c(N)n(Cc2ccccc2)c(=O)[nH]c1=O
Temperature: 5 °C

Procedure:
6-Amino-1-benzyl-5-bromouracil (134 g) was stirred with 40% aqueous methylamine solution (750 ml) for 24 hours. After cooling to 5° C., the precipitate was filtered and dried under suction to provide 6-amino-1-benzyl-5-methylaminouracil (55 g).
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[CH:8]=[CH:9][C:10]([CH3:31])=[C:11]([N:13]3[CH:21]=[N:20][C:19]4[C:14]3=[N:15][CH:16]=[N:17][C:18]=4[C:22]3[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][CH:23]=3)[CH:12]=2)=[O:6])[CH2:3][CH2:2]1.CN.O[N:35]1[C:39]2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C=O)C.O>[CH:1]1([NH:4][C:5](=[O:6])[C:7]2[CH:8]=[CH:9][C:10]([CH3:31])=[C:11]([N:13]3[CH:21]=[N:20][C:19]4[C:14]3=[N:15][CH:16]=[N:17][C:18]=4[C:22]3[CH:30]=[CH:29][C:25]([C:26](=[O:28])[NH:35][CH3:39])=[CH:24][CH:23]=3)[CH:12]=2)[CH2:3][CH2:2]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1cnc2c(-c3ccc(C(=O)O)cc3)ncnc21
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: CNC(=O)c1ccc(-c2ncnc3c2ncn3-c2cc(C(=O)NC3CC3)ccc2C)cc1
Temperature: 20 °C
Reaction time: 4 h
Yield: 80.1 %

Procedure:
To a solution of the 4-[9-(5-Cyclopropylcarbamoyl-2-methyl-phenyl)-9H-purin-6-yl]-benzoic acid (10 mg, 0.024 mmol) and the methyl amine (3.0 mg, 0.097 mmol) in 0.5 mL of dry DMF was added 1-hydroxybenzotriazole (7.4 mg, 0.048 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (9.2 mg, 0.048 mmol) at 20° C. The reaction mixture was stirred at 20° C. for 4 hours. And then 2 mL of water was added. The product was collected by filtration to give a colorless solid (8.2 mg, 80%). HPLC tR=1.99 min; MS m/z 427 [M+H]+.
Reaction SMILES: ClC1C=C(C=CC=1OC)CN.Cl[C:13]1[N:14]=[C:15](Cl)[C:16]2[CH:21]=[C:20]([N+]([O-])=O)[S:19][C:17]=2[N:18]=1>>[N:18]1[C:17]2[S:19][CH:20]=[CH:21][C:16]=2[CH:15]=[N:14][CH:13]=1
Reactant: O=[N+]([O-])c1cc2c(Cl)nc(Cl)nc2s1
Agent: COc1ccc(CN)cc1Cl
Product: c1ncc2ccsc2n1

Procedure:
Following the procedure of Example 1, the reaction of 3-chloro-4-methoxybenzylamine with 2,4-dichloro-6-nitro-thieno-[2,3-d]-pyrimidine yields 2-chloro-6-nitro-4-93-chloro-4-methoxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2([CH2:17][CH2:16][N:15]([C:18](=[O:33])[C:19]3[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[C:21]([C:29]([F:32])([F:31])[F:30])[CH:20]=3)[CH2:14][CH2:13]2)[C:11](=[O:34])[N:10]([CH3:35])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:36]C1C=C(C=CC=1)C=O>>[F:28][C:25]([F:26])([F:27])[C:23]1[CH:24]=[C:19]([CH:20]=[C:21]([C:29]([F:32])([F:31])[F:30])[CH:22]=1)[C:18]([N:15]1[CH2:16][CH2:17][C:12]2([N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[C:6]([Cl:36])[CH:7]=3)[CH2:9][N:10]([CH3:35])[C:11]2=[O:34])[CH2:13][CH2:14]1)=[O:33]
Reactant: O=Cc1cccc(Cl)c1
Reactant: CN1CN(Cc2ccccc2)C2(CCN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC2)C1=O
Product: CN1CN(Cc2cccc(Cl)c2)C2(CCN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC2)C1=O

Procedure:
The title compound, MS: m/e=534.2 (M+H+), was prepared in accordance with the general method of example 88 from 1-benzyl-8-(3,5-bis-trifluoromethyl-benzoyl)-3-methyl-1,3,8-triaza-spiro[4.5]decan-4-one and 3-chlorobenzaldehyde.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:4]([C:8](OCC)=[O:9])[CH:5]=[N:6][CH:7]=1.[H-].C([Al+]CC(C)C)C(C)C.C(O)(=O)C.CC(=O)OCC>C1(C)C=CC=CC=1.CCCCCC>[Cl:1][C:2]1[CH:7]=[N:6][CH:5]=[C:4]([CH:8]=[O:9])[C:3]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC(=O)c1cncc(Cl)c1C(=O)OCC
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(Cl)cncc1C=O
Reaction time: 2 h
Yield: 100.3 %

Procedure:
To a solution of diethyl 5-chloropyridine-3,4-dicarboxylate (2.43 g, 9.43 mmol) in 100 mL of toluene was added diisobutylaluminiumhydride (2.68 g, 18.86 mL, 1 molar) in hexane at −70° C. The reaction mixture was stirred for 2 h at this temperature. The reaction mixture was poured into an 5% aqueous acetic acid solution followed by the addition of EA. The phases were separated and the organic phase was washed with aq. NaHCO3 solution. The organic phase was dried and concentrated to give 2.02 g (100%) of the title compound as brown oil.