Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8](=[O:11])[C:7]2=O.NN.O.Cl>C(O)CO>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8](=[O:11])[CH2:7]2
Reactant: O=C1Nc2c(F)cccc2C1=O
Agent: Cl
Agent: NN
Solvent: OCCO
Solvent: O
Product: O=C1Cc2cccc(F)c2N1
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 83 %

Procedure:
To a mixture of 7-fluoro-1H-indole-2,3-dione (100 g, 0.606 mol) in ethylene glycol (500 mL) was added an aqueous hydrazine solution (54% wt, 73 g, 1.21 mol) dropwise over 30 minutes. The mixture was heated to 120° C. and stirred for 6 hours. The mixture was cooled to room temperature and water (500 mL) was added. Concentrated hydrochloric acid (HCl; 60 mL) was added, the mixture was warmed to about 35 to about 40° C., and the mixture was stirred for 1 hour. The mixture was then cooled to about 0 to about 5° C. The solid compound was filtered, washed with cold water and dried at 55° C. under vacuum to give an off-white solid (76 g) in 83% yield with 96% HPLC purity.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:20])[N:9]([CH3:19])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([OH:18])=O)[C:6]=2[CH:5]=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.C(=O)=O.Cl.[CH3:37][O:38][C:39](=[O:44])[C@H:40]([CH2:42][OH:43])[NH2:41].C(N(CC)CC)C>CN(C)C=O>[Cl:1][C:2]1[C:7]2[C:8](=[O:20])[N:9]([CH3:19])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([NH:41][C@@H:40]([CH2:42][OH:43])[C:39]([O:38][CH3:37])=[O:44])=[O:18])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)[C@@H](N)CO
Reactant: CN1Cc2c(C(=O)O)ncn2-c2cccc(Cl)c2C1=O
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Agent: O=C=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)[C@H](CO)NC(=O)c1ncn2c1CN(C)C(=O)c1c(Cl)cccc1-2
Temperature: 25 °C
Reaction time: 21 h
Yield: 73.6 %

Procedure:
A suspension of 14.1 g (0.0484 mol) of 7-chloro-5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylic acid in 150 ml of dimethylformamide was treated portionwise with 8.24 g (0.0508 mol). of carbonyidiimidazole while gassing with argon. After completion of the CO2 evolution the mixture was stirred at 65° for 3 hrs. After cooling to 0-5° the white suspension obtained was treated with 8.28 g (0.0532 mol) of L-serine methyl ester hydrochloride and with 7.452 ml (0.0532 mol) of triethylamine and stirred at room temperature for 21 hrs. The white suspension was suction filtered and the filtrate was completely freed from the solvents. The orange oily residue was partitioned between ethyl acetate and water, extracted, chromatographed over silica gel with ethyl acetate/ethanol 9:1 as the eluent and recrystallized from hot ethyl acetate; the mother liquor was then digested with diethyl ether. There were obtained a total of 14.0 g (74%) of methyl (S)-2-(7-chloro-5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-3-ylcarbonylamino)-3-hydroxy-propionate as white crystals; m.p. 178-180°. [α]D20 =+1.2° (CH2Cl2, c=1%).
Reaction SMILES: C[N+]1([O-])CCOCC1.[C:9]([O:13][C:14]([N:16]1[C@@H:20]([CH2:21][C@@H:22]([CH:38]([CH3:40])[CH3:39])[CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([O:32][CH2:33][CH2:34][CH2:35][O:36][CH3:37])[CH:25]=2)[C@H:19]([CH2:41][C@@H:42]([CH:45]([CH3:47])[CH3:46])[CH2:43][OH:44])[O:18][C:17]1([CH3:49])[CH3:48])=[O:15])([CH3:12])([CH3:11])[CH3:10].C([N+](CCC)(CCC)CCC)CC>ClCCl>[C:9]([O:13][C:14]([N:16]1[C@@H:20]([CH2:21][C@@H:22]([CH:38]([CH3:40])[CH3:39])[CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([O:32][CH2:33][CH2:34][CH2:35][O:36][CH3:37])[CH:25]=2)[C@H:19]([CH2:41][C@H:42]([CH:43]=[O:44])[CH:45]([CH3:46])[CH3:47])[O:18][C:17]1([CH3:48])[CH3:49])=[O:15])([CH3:12])([CH3:11])[CH3:10]
Reactant: COCCCOc1cc(C[C@@H](C[C@H]2[C@H](C[C@H](CO)C(C)C)OC(C)(C)N2C(=O)OC(C)(C)C)C(C)C)ccc1OC
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Product: COCCCOc1cc(C[C@@H](C[C@H]2[C@H](C[C@H](C=O)C(C)C)OC(C)(C)N2C(=O)OC(C)(C)C)C(C)C)ccc1OC
Reaction time: 0.17 h

Procedure:
100 g of molecular sieve (0.3 nm) and 16.6 g of N-methylmorpholine-N-oxide are added to 53 g of 3-tert-butoxycarbonyl-5(S)-(3-hydroxy-2(S)-isopropyl-propyl)-4(S)-{2(S)-isopropyl-3-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-propyl}-2,2-dimethyl-1,3-oxazolidine in 1.8 liters of dichloromethane at room temperature. The reaction mixture is stirred for 10 minutes and then 1.60 g of tetrapropylammonium perrutherate are added. The reaction mixture is stirred for a further 30 minutes and then filtered. The filtrate is diluted with dichloromethane and then washed in succession with 2M sodium sulfite solution, saturated sodium chloride solution and 1M copper(II) sulfate. The organic phase is concentrated by evaporation and the crude title compound is obtained: Rf (ethyl acetate/hexane=1:2)=0.43.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13](B2OC(C)(C)C(C)(C)O2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:25])[CH:11]=2)[CH:6]=1.Br[C:28]1[CH:33]=[CH:32][C:31]([S:34][C:35]2[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=2)=[CH:30][CH:29]=1.C(=O)(O)[O-].[Na+].O>C(COC)OC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([C:28]2[CH:33]=[CH:32][C:31]([S:34][C:35]3[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=3)=[CH:30][CH:29]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:25])[CH:11]=2)[CH:6]=1
Reactant: COC(=O)Cc1cc2ccc(Cl)cc2c(B2OC(C)(C)C(C)(C)O2)c1C
Reactant: Clc1ccc(Sc2ccc(Br)cc2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COC(=O)Cc1cc2ccc(Cl)cc2c(-c2ccc(Sc3ccc(Cl)cc3)cc2)c1C
Yield: 35.9 %

Procedure:
A stirred solution of [6-chloro-3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]-dioxaborolan-2-yl)-naphthalen-2-yl]-acetic acid methyl ester (0.2 g, 0.53 mmol) in dimethoxyethane (5 mL) was purged with argon for 5 minutes at room temperature. Tetrakis(triphenylphosphine)palladium(0) (0.031 g, 0.027 mmol), crude 1-bromo-4-(4-chlorophenylsulfanyl)-benzene (0.24 g) and 1.0 M aqueous sodium bicarbonate (5 mL, 5 mmol) were added simultaneously to the reaction mixture under argon. The reaction mixture was refluxed for 2 hours and then brought to room temperature. Water was added and the resulting mixture was extracted twice with ethyl acetate. The combined organic extracts were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product, which was finally purified using flash chromatography (0-3% ethyl acetate in hexanes) to give {6-chloro-4-[4-(4-chloro-phenylsulfanyl)-phenyl]-3-methyl-naphthalen-2-yl}-acetic acid methyl ester (0.089 g, 34%) as a solid.
Reaction SMILES: S(Cl)([Cl:3])=O.[O:5]1[CH:9]=[CH:8][CH:7]=[C:6]1[C:10]1[O:11][C:12]([CH3:27])=[C:13]([CH2:15][O:16][C:17]2[CH:24]=[CH:23][C:20]([CH2:21]O)=[CH:19][C:18]=2[O:25][CH3:26])[N:14]=1>O1CCCC1>[Cl:3][CH2:21][C:20]1[CH:23]=[CH:24][C:17]([O:16][CH2:15][C:13]2[N:14]=[C:10]([C:6]3[O:5][CH:9]=[CH:8][CH:7]=3)[O:11][C:12]=2[CH3:27])=[C:18]([O:25][CH3:26])[CH:19]=1
Reactant: COc1cc(CO)ccc1OCc1nc(-c2ccco2)oc1C
Reactant: O=S(Cl)Cl
Solvent: C1CCOC1
Product: COc1cc(CCl)ccc1OCc1nc(-c2ccco2)oc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 85 %

Procedure:
Thionyl chloride (2.59 g) was added dropwise to a stirred suspension of 4-[2-(2-furyl)-5-methyl-4oxazolylmethoxy]-3-methoxybenzyl alcohol (6.30 g) in tetrahydrofuran (100 ml) at 0° C. After stirring at room temperature for 1 hours, the reaction mixture was poured onto ice to give 4-(4-chloromethyl-2-methoxyphenoxymethyl)-2-(2-furyl)-5-methyloxazole as crystals (5.67 g, yield 85%).
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([O:14]C)=[O:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl>CO.O1CCCC1>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([OH:14])=[O:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc2nccc(Br)c2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccc2nccc(Br)c2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 81.8 %

Procedure:
Methyl 4-bromo-6-quinolinecarboxylate (6.00 g) was dissolved in methanol (60 ml) and tetrahydrofuran (40 ml). A 1N aqueous sodium hydroxide solution (30 ml) was added to the solution while stiring at room temperature and the mixture was stirred at room temperature for 3 hr. A 1N aqueous sodium hydroxide solution (20 ml) was added and the mixture was heated under reflux for 2 hr. The reaction mixture was adjusted to pH 4 with 1N hydrochloric acid. The resulting solid was collected by filtration and washed with water and ether to give 4-bromo-6-quinolinecarboxylic acid (4.65 g) as a white powder.
Reaction SMILES: [CH2:1]([O:3][C:4](Cl)=[O:5])[CH3:2].[NH2:7][CH2:8][CH2:9][CH2:10][C:11]1[NH:15][C:14]2[CH:16]=[CH:17][C:18]([C:20]3[CH:21]([CH3:27])[CH2:22][C:23](=[O:26])[NH:24][N:25]=3)=[CH:19][C:13]=2[N:12]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.O>[CH2:1]([O:3][C:4]([NH:7][CH2:8][CH2:9][CH2:10][C:11]1[NH:15][C:14]2[CH:16]=[CH:17][C:18]([C:20]3[CH:21]([CH3:27])[CH2:22][C:23](=[O:26])[NH:24][N:25]=3)=[CH:19][C:13]=2[N:12]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)Cl
Reactant: CC1CC(=O)NN=C1c1ccc2[nH]c(CCCN)nc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CCOC(=O)NCCCc1nc2cc(C3=NNC(=O)CC3C)ccc2[nH]1
Temperature: 25 °C
Reaction time: 3 h
Yield: 52 %

Procedure:
0.45 ml (4 7 mmol) of ethylchloroformate are added dropwise over a period of 10 minutes to a solution of 1 00 g (3.5 mmol) of 6-[2-(3-aminopropyl)-1H-benzimidazol-5-yl]-4,5-dihydro -5-methyl-3(2H)-pyridazinone and 1 25 g (9.0 mmol) of potassium carbonate in 10 ml of acetone and 10 ml of water with cooling in an ice bath. After 3 hours' stirring at room temperature, the reaction mixture is filtered and the filtrate is diluted with 20 ml of water and extracted three times with 20 ml portions of dichloromethane. The combined organic phases are dried and concentrated by evaporation under vacuum and the residue is chromatographed on silica gel with dichloromethane/methanol (9:1) as solvent. The polar main fraction (Rf 0 46) yields 0.65 g (52%) of the title compound in the form of a yellowish, amorphous solid after concentration by evaporation under vacuum.
Reaction SMILES: C([O:3][C:4](=[O:34])[CH:5]([C:10]1[CH:11]=[C:12]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[CH:13]=[C:14](OS(C(F)(F)F)(=O)=O)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])C.[C:35]([C:37]1[CH:42]=[CH:41][C:40](B(O)O)=[CH:39][CH:38]=1)#[N:36]>>[C:35]([C:37]1[CH:42]=[CH:41][C:40]([C:14]2[CH:15]=[C:10]([CH:5]([CH2:6][CH:7]([CH3:9])[CH3:8])[C:4]([OH:34])=[O:3])[CH:11]=[C:12]([C:24]3[CH:25]=[CH:26][C:27]([C:30]([F:31])([F:32])[F:33])=[CH:28][CH:29]=3)[CH:13]=2)=[CH:39][CH:38]=1)#[N:36]
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: CCOC(=O)C(CC(C)C)c1cc(OS(=O)(=O)C(F)(F)F)cc(-c2ccc(C(F)(F)F)cc2)c1
Product: CC(C)CC(C(=O)O)c1cc(-c2ccc(C#N)cc2)cc(-c2ccc(C(F)(F)F)cc2)c1

Procedure:
The title compound was prepared from a Suzuki coupling of 4-Methyl-2-(5-trifluoromethanesulfonyloxy-4′-trifluoromethyl-biphenyl-3-yl)-pentanoic acid ethyl ester (intermediate Example 1g) with 4-cyano-phenylboronic acid under the conditions described in Example 1; 1H NMR (400 MHz, MeOD) δ ppm 0.88 (dd, J=6.60, 3.18 Hz, 6H) 1.47 (dt, J=13.45, 6.72 Hz, 1H) 1.66 (ddd, J=13.63, 7.09, 6.91 Hz, 1H) 1.91-2.00 (m, 1H) 3.77 (t, J=7.83 Hz, 1H) 7.61 (dd, J=4.16, 1.71 Hz, 2H) 7.68 (d, J=8.31 Hz, 2H) 7.73-7.81 (m, 7H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1.[OH-].[K+].[CH:18]([C:21]1[CH:26]=[CH:25][C:24]([CH:27]=[CH2:28])=[CH:23][N:22]=1)([CH3:20])[CH3:19]>CN1CCCC1=O.O>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:28][CH2:27][C:24]3[CH:23]=[N:22][C:21]([CH:18]([CH3:19])[CH3:20])=[CH:26][CH:25]=3)[C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1
Reactant: CN1CCc2[nH]c3ccc(Cl)cc3c2C1
Reactant: C=Cc1ccc(C(C)C)nc1
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: O
Product: CC(C)c1ccc(CCn2c3c(c4cc(Cl)ccc42)CN(C)CC3)cn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 16.3 %

Procedure:
To a solution of 8-Chloro-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.1 g, 0.00045 mol) in N-methyl 2-pyrolidone (1.0 mL) was added powdered potassium hydroxide (0.140 g, 0.0025 mol) and allowed to stir for 10 min at RT. 2-Isopropyl-5-vinyl-pyridine (0.185 g, 0.00125 mol) was added and stirred for further 4 h. at 100 deg C. After completion (TLC), reaction mixture was diluted with water (15 mL) and extracted with ethyl acetate (3×50 mL). The organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure using rotary evaporator. The crude was purified through column chromatography (7% MeOH:DCM in silica 100-200 mesh, Diameter of column—2.5 cm, Height of silica—approx. 5 inch), Then further purified by preparative TLC, to give the desired compound as yellow oil (0.027 g, 15% yield). 8-Chloro-5-[2-(6-isopropyl-pyridin-3-yl)-ethyl]-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.027 g, 0.00007 mol) was dissolved in THF (1.0 mL). A solution of oxalic acid dihydrate (0.009 g, 0.00007 mol) in THF (0.5 mL) was added and stirred for 30 min at RT, Precipitate obtained was filtered and dried to give oxalate salt as off white solid (0.027 g, 81% yield).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]([NH:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[CH:9]=1)=[O:4].C([O-])([O-])=O.[Ca+2].[I:23]Cl>CO>[F:1][C:2]([F:16])([F:17])[C:3]([NH:5][CH2:6][CH2:7][C:8]1[CH:9]=[C:10]([O:14][CH3:15])[CH:11]=[CH:12][C:13]=1[I:23])=[O:4]
Reactant: ClI
Reactant: COc1cccc(CCNC(=O)C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CO
Product: COc1ccc(I)c(CCNC(=O)C(F)(F)F)c1
Reaction time: 8 h
Yield: 99.7 %

Procedure:
A solution of N-trifluoroacetyl-3-methoxyphenethylamine (15.8 g, 64 mmol) in methanol (325 mL) was cooled to −78 C, and treated with CaCO3 (14.7 g, 145 mmol), followed by a solution of ICl (29 g, 181 mmol) in methanol (40 mL). The reaction was allowed to warm to 20 C while stirring overnight and then filtered, concentrated, dissolved in EtOAc (200 mL), washed twice with 5% aqueous sodium bisulfite (100 mL), once with brine (100 mL), dried with Na2SO4 and concentrated to give 23.8 g of a white solid powder. 1H NMR (400 MHz, CDCl3) d 7.68 (d, J=9 Hz, 1 H), 6.76 (s, 1 H), 6.57 (d, J=9 Hz, 1 H), 6.42 (bs, 1 H), 3.77 (s, 3 H), 3.61 (dd, J=7, 7 Hz, 2 H), 2.99 (dd, J=7, 7 Hz, 2 H). MS calculated for C11H11F3INO2+H: 374, observed: 374.
Reaction SMILES: Cl[C:2]1[C:3]2[N:11]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:10]([CH3:20])=[C:9]([C:21]([O:23][CH3:24])=[O:22])[C:4]=2[N:5]=[C:6]([CH3:8])[N:7]=1.[CH:25]1([CH2:28][O:29][C:30]2[CH:35]=[C:34]([O:36][CH3:37])[C:33]([F:38])=[CH:32][C:31]=2B2OC(C)(C)C(C)(C)O2)[CH2:27][CH2:26]1>>[CH:25]1([CH2:28][O:29][C:30]2[CH:35]=[C:34]([O:36][CH3:37])[C:33]([F:38])=[CH:32][C:31]=2[C:2]2[C:3]3[N:11]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:10]([CH3:20])=[C:9]([C:21]([O:23][CH3:24])=[O:22])[C:4]=3[N:5]=[C:6]([CH3:8])[N:7]=2)[CH2:26][CH2:27]1
Reactant: COc1cc(OCC2CC2)c(B2OC(C)(C)C(C)(C)O2)cc1F
Reactant: COC(=O)c1c(C)n(COCC[Si](C)(C)C)c2c(Cl)nc(C)nc12
Product: COC(=O)c1c(C)n(COCC[Si](C)(C)C)c2c(-c3cc(F)c(OC)cc3OCC3CC3)nc(C)nc12

Procedure:
Starting from methyl 4-chloro-2,6-dimethyl-5-{[2-(trimethylsilyl)ethoxy]methyl}-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylate (example A.11) and 2-(2-cyclopropylmethoxy-5-fluoro-4-methoxy-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (example B.c15) the title compound is obtained as off white solid.
Reaction SMILES: CN(C)[CH:3]=[C:4]1[CH2:9][O:8][CH2:7][CH:6]([C:10]([O:12][CH3:13])=[O:11])[C:5]1=O.[N+]([O-])(O)=O.[N+]([O-])(O)=O.[CH3:24][O:25][C:26]1[CH:27]=[C:28]([NH:38][C:39]([NH2:41])=[NH:40])[CH:29]=[CH:30][C:31]=1[N:32]1[CH:36]=[C:35]([CH3:37])[N:34]=[CH:33]1>>[CH3:24][O:25][C:26]1[CH:27]=[C:28]([NH:38][C:39]2[N:41]=[CH:3][C:4]3[CH2:9][O:8][CH2:7][CH:6]([C:10]([O:12][CH3:13])=[O:11])[C:5]=3[N:40]=2)[CH:29]=[CH:30][C:31]=1[N:32]1[CH:36]=[C:35]([CH3:37])[N:34]=[CH:33]1
Reactant: COC(=O)C1COCC(=CN(C)C)C1=O
Reactant: COc1cc(NC(=N)N)ccc1-n1cnc(C)c1
Solvent: O=[N+]([O-])O
Product: COC(=O)C1COCc2cnc(Nc3ccc(-n4cnc(C)c4)c(OC)c3)nc21

Procedure:
The title compound was prepared from crude methyl 5-[1-dimethylamino-methylidene]-4-oxo-tetrahydro-pyran-3-carboxylate (97 mg, 0.45 mmol) and N-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-guanidine dinitrate (114 mg, 0.31 mmol) using in analogous manner the procedure described in example 45b). Obtained as a pale-yellow oil (8 mg, 7%). MS ISP (m/e): 396.4 [(M+H)+].
Reaction SMILES: [CH3:1]C(C)C(=O)C(P(=O)([O-])[O-])=[N+]=[N-].[CH:13]([CH2:15][CH2:16][C:17]1[O:18][C:19]2[CH:25]=[CH:24][C:23]([C:26]([O:28][CH3:29])=[O:27])=[CH:22][C:20]=2[CH:21]=1)=O.C([O-])([O-])=O.[K+].[K+]>CO>[CH2:16]([C:17]1[O:18][C:19]2[CH:25]=[CH:24][C:23]([C:26]([O:28][CH3:29])=[O:27])=[CH:22][C:20]=2[CH:21]=1)[CH2:15][C:13]#[CH:1]
Reactant: CC(C)C(=O)C(=[N+]=[N-])P(=O)([O-])[O-]
Reactant: COC(=O)c1ccc2oc(CCC=O)cc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#CCCc1cc2cc(C(=O)OC)ccc2o1
Temperature: 25 °C
Yield: 91.7 %

Procedure:
See Callant, P. D. H. L.; Vandewalle, M. An efficient preparation and the intramoleucalur cyclopropanation of a-diazo-b-ketophosphonates and a-diazophoshonoacetates. Snyth. Commun. 1984, 14, 155-161. A solution of dimethyl-1-diazo-2-oxopropylphosphonate (8.9 g, 46.4 mmol) in dry methanol (50 mL) was added to a stirring mixture of 97 (8.5 g, 36.6 mmol) and K2CO3 (10.2 g, 74 mmol) in 500 mL of dry methanol. The mixture was stirred at room temperature until complete conversion was attained according to HPLC (2 hours) and concentrated. The residue was diluted with diethyl ether (500 mL), washed with water (2×100 mL) and dried over CaCl2. The solvent was removed following by recrystallization (EtOAc/hexanes, 9/1) to give white crystals (7.66 g, 92%): mp 57-58° C. 1H NMR (DMSO-d6) δ8.23 (d, J=1.6 Hz, 1H), 7.88 (dd, J=8.8, 1.6 Hz, 1H), 7.63 (d, J=8.8 Hz, 1H), 6.82 (s, 1H), 3.86 (s, 3H), 3.00 (t, J=7.1 Hz, 2H), 2.84 (t, J=2.8 Hz, 1H), 2.63 (td, J=7.1, 2.8 Hz, 2H). HPLC (method B) tR 6.73 min (100.00 area %). Anal. (C14H12O3.0.2H2O) C, H.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[C:6]12([NH2:16])[CH2:15][CH:10]3[CH2:11][CH:12]([CH2:14][CH:8]([CH2:9]3)[CH2:7]1)[CH2:13]2.C(N(CC)CC)C>C(OCC)C>[C:6]12([NH:16][C:1](=[O:4])[CH:2]=[CH2:3])[CH2:13][CH:12]3[CH2:11][CH:10]([CH2:9][CH:8]([CH2:14]3)[CH2:7]1)[CH2:15]2
Reactant: C=CC(=O)Cl
Reactant: NC12CC3CC(CC(C3)C1)C2
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: C=CC(=O)NC12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of acryloyl chloride (4.05 ml, 0.05 mole) in ethyl ether (25 ml) was added to a cold (+5° C.) solution of 1-adamantaneamine (7.65 g, 0.05 mole) and triethylamine (15.3 ml, 0.11 mole) in ethyl ether (300 ml) and the solution stirred for 72 hours at room temperature. The solvent was removed on a rotary evaporator. The residue was dissolved in ethyl acetate (100 ml), washed with 10 percent hydrochloric acid (100 ml) and water (50 ml), dried over sodium sulfate, filtered and the solvent removed in vacuo leaving an oily solid which was crystallized from methanol-ethyl acetate-hexane. The structure was confirmed by NMR.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][CH2:11][CH3:12])=[CH:4][C:3]=1[N+:13]([O-])=O.C.[H][H]>CO>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][CH2:11][CH3:12])=[CH:4][C:3]=1[NH2:13]
Reactant: [H][H]
Reactant: CCCCOc1ccc(N)c([N+](=O)[O-])c1
Solvent: CO
Product: CCCCOc1ccc(N)c(N)c1

Procedure:
2.1 G. of 1-amino-4-n-butoxy-2-nitrobenzene, prepared according to Example XXXV, and 1 g. of 5% palladized charcoal in 100 ml. methanol are treated with hydrogen at atmospheric pressure until the theoretical uptake of hydrogen has occurred. The mixture is filtered and the filtrate evaporated to give 1,2-diamino-4-n-butoxybenzene. This is treated, in 60 ml. acetone, with 7.0 g. methoxycarbonyl isothiocyanate. The mixture is kept at room temperature overnight and then concentrated under vacuum. The residue is stirred with water, filtered and recrystallized from dichloromethane/benzene yielding 1,2-bis-(3-methoxycarbonyl-2-thioureido)-4-n-butoxybenzene.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[Br:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1.[CH3:21][CH2:22][O:23]C(C(F)F)=O>C1COCC1>[Br:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[C:16]([C:22](=[O:23])[CH3:21])[CH:15]=1
Reactant: Fc1ccc(Br)cc1
Reactant: CCOC(=O)C(F)F
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC(=O)c1cc(Br)ccc1F
Temperature: -70 °C
Reaction time: 2.5 h

Procedure:
A solution of 17.78 ml (126 mmol) diisopropyl amine in 375 ml THF was cooled to −78° C. A 1.6 M solution of BuLi in hexanes (79 ml, 126 mmol) was added drop wise. After 15 minutes 20 g of 4-bromo-1-fluoro benzene (114 mmol) was added dropwise while keeping the temperature below −60° C. After stirring for 2.5 h at −70° C. 13.22 ml ethyl difluoro acetate were added. The mixture was warmed to −40° C. and then quenched by pouring the mixture onto 1M HCl. The mixture was extracted with ligroine, dried with MgSO4.H2O, concentrated and purified by column chromatography (silica gel; hexane/5-15% TBME) to give the desired product as a yellow liquid. 1H-NMR (CDCl3, 360 MHz): 8.09 (dd, 1H), 7.82-7.77 (m, 1H), 7.17 (t, 1H), 6.45 (t, 1H, CHF2)
Reaction SMILES: [N+:1]([O-:4])([O-])=[O:2].[K+].O.[C:7]([C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([O:20][CH2:21][CH3:22])=[N:12][CH:11]=1)([OH:9])=[O:8]>S(=O)(=O)(O)O>[C:7]([C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][C:18]=2[N+:1]([O-:4])=[O:2])[C:13]([O:20][CH2:21][CH3:22])=[N:12][CH:11]=1)([OH:9])=[O:8]
Reactant: CCOc1ncc(C(=O)O)c2ccccc12
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Product: CCOc1ncc(C(=O)O)c2c([N+](=O)[O-])cccc12
Temperature: 0 °C
Reaction time: 16 h
Yield: 100.7 %

Procedure:
A solution of potassium nitrate (34.9 g) in sulphuric acid (density 1.83; 280 cc) is added dropwise to a solution, stirred and cooled by iced water, of 4-carboxy-1-ethoxyisoquinoline (69.5 g) in sulphuric acid (density 1.83; 420 cc), whilst keeping the temperature below 20° C. The reactants are kept in contact for 16 hours at a temperature of about 20° C. and the reaction solution is then poured onto crushed ice (7 kg). The fine yellow crystals which precipitate are filtered off and then washed with water until a neutral filtrate is obtained. After drying, crude 4-carboxy-1-ethoxy-5-nitroisoquinoline (84.5 g) is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[Cl:10][C:11]1[CH:12]=[C:13]([CH:15]=[CH:16][C:17]=1[CH3:18])[NH2:14]>>[NH2:14][C:13]1[CH:12]=[C:11]([Cl:10])[C:17]([CH3:18])=[CH:16][C:15]=1[C:4]([C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[Cl:1])=[O:5]
Reactant: Cc1ccc(N)cc1Cl
Reactant: O=Cc1ccccc1Cl
Product: Cc1cc(C(=O)c2ccccc2Cl)c(N)cc1Cl

Procedure:
(2-amino-4-chloro-5-methylphenyl)-(2-chlorophenyl)-methanone (Xhh) was prepared by reacting 2-chlorobenzaldehyde with 0.0318 moles of 3-chloro-4-methyl aniline in a manner analogous to Example 1. MH+/Z=280.
Reaction SMILES: [CH2:1]([C:3]1([C:13]2[C:21]3[C:16](=[C:17]([NH2:22])[CH:18]=[CH:19][CH:20]=3)[NH:15][CH:14]=2)[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[CH2:5][CH2:4]1)[CH3:2].[C:23](OC(=O)C)(=[O:25])[CH3:24]>>[CH2:1]([C:3]1([C:13]2[C:21]3[C:16](=[C:17]([NH:22][C:23](=[O:25])[CH3:24])[CH:18]=[CH:19][CH:20]=3)[NH:15][CH:14]=2)[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[CH2:5][CH2:4]1)[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CCC1(c2c[nH]c3c(N)cccc23)CCc2cc(F)ccc21
Product: CCC1(c2c[nH]c3c(NC(C)=O)cccc23)CCc2cc(F)ccc21

Procedure:
Utilizing 3-(1-ethyl-5-fluoro-indan-1-yl)-1H-indol-7-ylamine and acetic anhydride, the title compound is prepared as in example 15. 0.16 g (46%). LC-MS m/z 337.1 (M++1).