Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:5][C:6]1[S:7][C:8]2[N:9]=[CH:10][N:11]=[C:12](Cl)[C:13]=2[N:14]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:16]([N:19]1[CH:23]=[CH:22][N:21]=[C:20]1[C:24]1[S:25][C:26]([Sn](CCCC)(CCCC)CCCC)=[CH:27][C:28]=1[C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][C:30]=1[Cl:36])[CH:17]=[CH2:18]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CN(C=O)C>[CH2:16]([N:19]1[CH:23]=[CH:22][N:21]=[C:20]1[C:24]1[S:25][C:26]([C:12]2[C:13]3[N:14]=[C:6]([NH:5][C:1]([CH3:4])([CH3:3])[CH3:2])[S:7][C:8]=3[N:9]=[CH:10][N:11]=2)=[CH:27][C:28]=1[C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][C:30]=1[Cl:36])[CH:17]=[CH2:18]
Reactant: C=CCn1ccnc1-c1sc([Sn](CCCC)(CCCC)CCCC)cc1-c1ccc(Cl)cc1Cl
Reactant: CC(C)(C)Nc1nc2c(Cl)ncnc2s1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: C=CCn1ccnc1-c1sc(-c2ncnc3sc(NC(C)(C)C)nc23)cc1-c1ccc(Cl)cc1Cl
Temperature: 100 °C
Yield: 75.2 %

Procedure:
A mixture of tert-Butyl-(7-chlorothiazolo[5,4-d]pyrimidin-2-yl)-amine (1.00 g, 4.12 mmol), 1-allyl-2-[3-(2,4-dichlorophenyl)-5-(tributylstannyl)-2-thienyl]-1H-imidazole (1.71 g, 2.75 mmol) and DMF (23 mL) was stirred and degassed with vacuum. The atmosphere was replaced with nitrogen and then bis(triphenylphosphine)palladium(II) chloride (96.4 mg, 0.137 mmol) was added to the mixture. The orange solution was heated at 100° C. for 3 hours and the mixture was allowed to cool to rt. Column chromatography was performed to yield the title compound (1.12 g, 75%) as a pale yellow solid. LCMS: (FA) ES+ 541, 543. 1H NMR (400 MHz, d6-DMSO) δ; 8.73 (bs, 1H), 8.65 (bs, 1H), 8.56 (bs, 1H), 7.75 (d, J=2.5 Hz, 1H), 7.38 (dd, J=8.5, 2.5 Hz, 1H), 7.21 (d, J=1.3 Hz, 1H), 7.12 (d, J=8.5 Hz, 1H), 7.05 (d, J=1.3 Hz, 1H), 5.64-5.55 (m, 1H), 5.06-5.03 (m, 1H), 4.84-4.79 (m, 1H), 4.31-4.27 (m, 2H), 1.49 (s, 9H).
Reaction SMILES: [H-].[Na+].[C:3]1([CH2:9][C:10](=[O:15])[CH2:11][CH2:12][CH2:13][CH3:14])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[CH2:17][C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=1.O>O1CCCC1>[O:15]=[C:10]([CH2:11][CH2:12][CH2:13][CH3:14])[CH:9]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[CH2:17][C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=1
Reactant: CCCCC(=O)Cc1ccccc1
Reactant: N#Cc1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCCCC(=O)C(Cc1ccc(C#N)cc1)c1ccccc1
Temperature: 40 °C
Reaction time: 1.5 h
Yield: 82.2 %

Procedure:
240 mg of sodium hydride as a suspension at 50% in oil were added to a solution of 0.81 g of 1-phenyl-2-hexanone of Step A of Example 7 in 20 ml of tetrahydrofuran and the mixture was stirred for 90 minutes at 40° C. Then, a solution of 900 mg of 4-(bromomethyl)-benzonitrile in 10 ml of tetrahydrofuran was added and after stirring for 2 hours at ambient temperature, the reaction mixture was poured into water. Extraction was carried out with ethyl acetate and the extracts were washed with water, dried, and evaporated to dryness. The residue was chromatographed on silica (eluant: methylene chloride--hexane (1-1)) to obtain 1.1 g of the desired product melting at 70° C.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]1[CH:12]([CH3:13])[CH2:11][CH:10]([C:14]([OH:16])=O)[CH2:9]1)=[O:7])([CH3:4])[CH3:3].CCN(C(C)C)C(C)C.[CH2:26]([NH2:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[CH3:13][CH:12]1[CH2:11][CH:10]([C:14]([NH:33][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:16])[CH2:9][N:8]1[C:6]([O:5][C:2]([CH3:1])([CH3:3])[CH3:4])=[O:7]
Reactant: CC1CC(C(=O)O)CN1C(=O)OC(C)(C)C
Reactant: NCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC1CC(C(=O)NCc2ccccc2)CN1C(=O)OC(C)(C)C
Temperature: 0 °C
Yield: 135.9 %

Procedure:
To a solution of 1-{[(1,1-dimethylethyl)oxy]carbonyl}-5-methyl-3-pyrrolidinecarboxylic acid (0.9 g, 3.93 mmol) in CH2Cl2 (15 mL) at room temperature was added Hunig's base (0.89 mL, 5.10 mmol, 1.3 equiv) and benzylamine (0.56 mL, 5.10 mmol, 1.3 equiv) in one portion. The resulting mixture was chilled in an ice bath, followed by addition of HATU (1.64 g, 4.32 mmol, 1.1 equiv) in one portion, and the reaction mixture was stirred in the ice bath for 30 minutes. The mixture was filtered through celite, and rinsed with CH2Cl2. The filtrate was washed with water and dried over Na2SO4, followed by filtration and concentration in vacuo. The resulting residue was purified by silica gel column chromatography resulting in 1.70 g of the title compound as an oil. The ratio of cis/trans isomers could not be determined. LC-MS (ES) m/z=319 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([N:11]3[C:23](=[O:24])[C:22]4[C:13](=[N:14][C:15]5[C:20]([C:21]=4[O:25][Si:26]([CH:33]([CH3:35])[CH3:34])([CH:30]([CH3:32])[CH3:31])[CH:27]([CH3:29])[CH3:28])=[N:19][CH:18]=[CH:17][C:16]=5[CH3:36])[C:12]3=[O:37])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[Br:38]N1C(=O)CCC1=O>C(OCC)(=O)C>[Br:38][CH2:36][C:16]1[CH:17]=[CH:18][N:19]=[C:20]2[C:15]=1[N:14]=[C:13]1[C:12](=[O:37])[N:11]([C:8]3([C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)[CH2:10][CH2:9]3)[C:23](=[O:24])[C:22]1=[C:21]2[O:25][Si:26]([CH:30]([CH3:31])[CH3:32])([CH:33]([CH3:35])[CH3:34])[CH:27]([CH3:28])[CH3:29]
Reactant: Cc1ccnc2c(O[Si](C(C)C)(C(C)C)C(C)C)c3c(nc12)C(=O)N(C1(c2ccc(F)cc2)CC1)C3=O
Reactant: O=C1CCC(=O)N1Br
Solvent: CCOC(C)=O
Product: CC(C)[Si](Oc1c2c(nc3c(CBr)ccnc13)C(=O)N(C1(c3ccc(F)cc3)CC1)C2=O)(C(C)C)C(C)C

Procedure:
As a further example, 7-[1-(4-fluoro-phenyl)-cyclopropyl]-4-methyl-9-triisopropylsilanyloxy-pyrrolo[3,4-b][1,5]naphthyridine-6,8-dione A20.17, prepared according to the procedures described above, is reacted with N-bromosuccinimide in refluxing ethyl acetate to give 4-bromomethyl-7-[1-(4-fluoro-phenyl)-cyclopropyl]-9-triisopropylsilanyloxy-pyrrolo[3,4-b][1,5]naphthyridine-6,8-dione A20.18. The product is then heated at 120° C. with excess of a trialkyl phosphite to give after deprotection the phosphonate A20.19.
Reaction SMILES: [O-2].[La+3:2].[O-2].[O-2].[La+3].[N+:6]([O-:9])([OH:8])=[O:7]>>[N+:6]([O-:9])([O-:8])=[O:7].[La+3:2].[N+:6]([O-:9])([O-:8])=[O:7].[N+:6]([O-:9])([O-:8])=[O:7]
Reactant: O=[N+]([O-])O
Agent: [La+3]
Agent: [O-2]
Product: O=[N+]([O-])[O-]

Procedure:
Lanthanum oxide (La2O3) 21.2 g (0.065 mole) was completely dissolved in an aqueous solution of nitric acid, heated and concentrated to form lanthanum nitrate.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([C:11]([C:13]3[CH:14]=[N:15][CH:16]=[C:17]([NH2:19])[CH:18]=3)=[O:12])=[CH:9][N:8]([C:20]([CH3:30])([CH3:29])[CH2:21][O:22]C3CCCCO3)[C:6]=2[N:7]=1.[CH:31]1([C:34]2[CH:35]=[N:36][N:37]([CH2:39][C:40](O)=[O:41])[CH:38]=2)[CH2:33][CH2:32]1>>[NH2:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([C:11]([C:13]3[CH:18]=[C:17]([NH:19][C:40](=[O:41])[CH2:39][N:37]4[CH:38]=[C:34]([CH:31]5[CH2:32][CH2:33]5)[CH:35]=[N:36]4)[CH:16]=[N:15][CH:14]=3)=[O:12])=[CH:9][N:8]([C:20]([CH3:29])([CH3:30])[CH2:21][OH:22])[C:6]=2[N:7]=1
Reactant: O=C(O)Cn1cc(C2CC2)cn1
Reactant: CC(C)(COC1CCCCO1)n1cc(C(=O)c2cncc(N)c2)c2cnc(N)nc21
Product: CC(C)(CO)n1cc(C(=O)c2cncc(NC(=O)Cn3cc(C4CC4)cn3)c2)c2cnc(N)nc21

Procedure:
The title compound was prepared according to the method described for Example 1 using {2-amino-7-[1,1-dimethyl-2-(tetrahydro-pyran-2-yloxy)-ethyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}-(5-amino-pyridin-3-yl)-methanone (Preparation 49) and (4-Cyclopropyl-pyrazol-1-yl)-acetic acid to afford the title compound as a white solid in 72% yield, 16.5 mg.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:31])[C:6]2[CH:11]=[C:10]([F:12])[C:9]([CH3:13])=[C:8]([C:14]3[CH:15]=[C:16]4[C:21](=[CH:22][CH:23]=3)[C:20](=[O:24])[N:19]([CH2:25][CH:26]3[CH2:28][CH2:27]3)[CH:18]=[C:17]4[CH:29]=O)[CH:7]=2)[CH2:3][CH2:2]1.[OH:32][CH2:33][C@@H:34]1[CH2:39][NH:38][CH2:37][CH2:36][N:35]1C(OC(C)(C)C)=O>>[CH:1]1([NH:4][C:5](=[O:31])[C:6]2[CH:11]=[C:10]([F:12])[C:9]([CH3:13])=[C:8]([C:14]3[CH:15]=[C:16]4[C:21](=[CH:22][CH:23]=3)[C:20](=[O:24])[N:19]([CH2:25][CH:26]3[CH2:27][CH2:28]3)[CH:18]=[C:17]4[CH2:29][N:38]3[CH2:37][CH2:36][NH:35][C@H:34]([CH2:33][OH:32])[CH2:39]3)[CH:7]=2)[CH2:2][CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCNC[C@H]1CO
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC3CC3)cc(C=O)c2c1
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC3CC3)cc(CN3CCN[C@H](CO)C3)c2c1

Procedure:
The title compound was prepared as a solid according to the method of Example 81 using the product of Example 75 step i) and (S)-2-(hydroxymethyl)-piperazine-1-carboxylic acid, tert-butyl ester.
Reaction SMILES: [O-]CC.[Na+:4].[CH3:5][C:6]([CH3:40])([CH3:39])[CH2:7][CH2:8][C@:9]1([CH3:38])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([OH:19])=[C:11]([C:20]2[NH:25][C:24]3[CH:26]=[CH:27][C:28]([NH:30][S:31]([CH3:34])(=[O:33])=[O:32])=[CH:29][C:23]=3[S:22](=[O:36])(=[O:35])[N:21]=2)[C:10]1=[O:37]>C(O)C>[CH3:5][C:6]([CH3:40])([CH3:39])[CH2:7][CH2:8][C@:9]1([CH3:38])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([O-:19])=[C:11]([C:20]2[NH:25][C:24]3[CH:26]=[CH:27][C:28]([NH:30][S:31]([CH3:34])(=[O:33])=[O:32])=[CH:29][C:23]=3[S:22](=[O:36])(=[O:35])[N:21]=2)[C:10]1=[O:37].[Na+:4]
Reactant: CC(C)(C)CC[C@@]1(C)C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C(O)c2ccccc21
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)CC[C@@]1(C)C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C([O-])c2ccccc21
Temperature: 25 °C
Yield: 93.3 %

Procedure:
A solution of sodium ethoxide (31.4 g, 0.462 mol) in ethanol (450 mL) was added over 50 minutes to a solution of the product of Example 49-7 (223.16 g, 0.420 mol) in ethanol (1700 mL) at 73° C. The product precipitated and the slurry was cooled slowly to room temperature and the product was isolated by filtration and dried to give the title compound (216.9 g, 93%).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.[CH3:14][S-:15].[Na+]>CN(C)C=O.C(OCC)(=O)C>[CH3:14][S:15][C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1
Reactant: C[S-]
Reactant: CCOC(=O)Cc1ccc(Cl)nc1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1ccc(SC)nc1
Temperature: 25 °C
Reaction time: 23 h
Yield: 40.2 %

Procedure:
To a solution of ethyl (6-chloropyridin-3-yl)acetate (10.7 g) in N,N-dimethylformamide (100 mL) was added sodium methanethiolate (11.3 g), and the mixture was stirred at room temperature for 23 hr. The reaction mixture was diluted with ethyl acetate, washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=5:95-50:50, volume ratio) to give the title compound (4.55 g, yield 40%) as a colorless oil. MS: 212 (MH+).
Reaction SMILES: [H][H].[CH2:3]([OH:11])[CH2:4][C:5]#[C:6][CH2:7][CH2:8][CH2:9][CH3:10].N1C=CC=CC=1>CCCCCC.[Pd].CC([O-])=O.CC([O-])=O.[Pb+2]>[CH2:3]([OH:11])[CH2:4]/[CH:5]=[CH:6]\[CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCC#CCCO
Reactant: [H][H]
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: c1ccncc1
Solvent: CCCCCC
Product: CCCC/C=C\CCO

Procedure:
Hydrogen gas was blown into a solution prepared by dissolving 126 g of 3-octyn-1-ol in 100 ml of n-hexane with admixture of 10 g of a Lindlar catalyst and 10 g of pyridine and the introduction of hydrogen was continued for about 4 hours when absorption of hydrogen had ceased. Removal of solid matter from the reaction mixture by filtration and stripping of n-hexane gave cis-3-octen-1-ol, which was dissolved in a mixture of 250 g of methylene chloride and 111 g of triethylamine.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH:4]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)[CH2:5][C:6]1[C:7]([Cl:13])=[N:8][C:9](Cl)=[N:10][CH:11]=1.[NH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(N(CC)C(C)C)(C)C>C(O)CCC.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:22])[CH:4]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)[CH2:5][C:6]1[C:7]([Cl:13])=[N:8][C:9]([NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[N:10][CH:11]=1
Reactant: COC(=O)C(Cc1cnc(Cl)nc1Cl)c1ccc(OC)cc1
Reactant: Nc1ccccc1
Solvent: CCCCO
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C(Cc1cnc(Nc2ccccc2)nc1Cl)c1ccc(OC)cc1
Temperature: 100 °C

Procedure:
To a solution of 3-(2,4-dichloro-pyrimidin-5-yl)-2-(4-methoxy-phenyl)-propionic acid methyl ester (341 mg, 1.0 mmol) (from Example 1d supra) in n-butanol (10 mL) was added aniline (200 mg, 2.15 mmol) (Aldrich) followed by N,N-diisopropylethylamine (258 mg, 2.0 mmol) (Aldrich) and the reaction mixture was heated at 100° C. for 12 hours. After cooling, the reaction mixture was diluted with ethyl acetate (100 mL) and successively washed with saturated aqueous ammonium chloride solution (30 mL), water (30 mL) and brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography (silica gel) to give 3-(4-chloro-2-phenylamino-pyrimidin-5-yl)-2-(4-methoxy-phenyl)-propionic acid methyl ester. (Yield 45.1 mg, 11.3%).
Reaction SMILES: [OH:1][CH:2](CO)[CH2:3][CH2:4][C:5]1[N:10]=[C:9]([NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH:8]=[CH:7][CH:6]=1.O1CCCC1.O.I([O-])(=O)(=O)=O.[Na+]>C(OCC)(=O)C>[C:15]([O:14][C:12]([NH:11][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:4][CH2:3][CH:2]=[O:1])[N:10]=1)=[O:13])([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)OC(=O)Nc1cccc(CCC(O)CO)n1
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)Nc1cccc(CCC=O)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirring solution of N-[6-(3,4-dihydroxybutyl)(2-pyridyl)](tert-butoxy)carboxamide in tetrahydrofuran/water (1 eq/1 eq, 0.1M) was added sodium metaperiodate (1.3 eq) at 0° C. and stirred for 1 hr. The reaction was warmed to room temperature and diluted with ethyl acetate. The reaction was extracted with saturated sodium bicarbonate, dried with sodium sulfate, filtered and concentrated in vacuo to yield the product. EI-MS m/z 251(M+H)+
Reaction SMILES: [OH:1][CH2:2][CH2:3][C@H:4]([O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]1[CH:18]=[CH:17][C:16]([C:19]([O:21]C)=[O:20])=[C:15]([N+:23]([O-:25])=[O:24])[CH:14]=1)[CH3:5].C[Si](C)(C)[O-].[K+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1>[OH:1][CH2:2][CH2:3][C@H:4]([O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]1[CH:18]=[CH:17][C:16]([C:19]([OH:21])=[O:20])=[C:15]([N+:23]([O-:25])=[O:24])[CH:14]=1)[CH3:5]
Reactant: COC(=O)c1ccc(-c2ccccc2O[C@H](C)CCO)cc1[N+](=O)[O-]
Agent: C[Si](C)(C)[O-]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [K+]
Solvent: C1CCOC1
Product: C[C@H](CCO)Oc1ccccc1-c1ccc(C(=O)O)c([N+](=O)[O-])c1
Reaction time: 7 h
Yield: 100 %

Procedure:
To a tetrahydrofuran solution (20.0 ml) of methyl 2′-{[(1R)-3-hydroxy-1-methylpropyl]oxy}-3-nitrobiphenyl-4-carboxylate (793 mg) was added at room temperature potassium trimethylsilanolate (982 mg), followed by stirring for 7 hours. A 10% aqueous citric acid solution was added to the reaction solution, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to afford 2′-{[(1R)-3-hydroxy-1-methylpropyl]oxy}-3-nitrobiphenyl-4-carboxylic acid (761 mg).
Reaction SMILES: C(O[C:5]1[N:10]=[CH:9][C:8]([C@@H:11]([NH:13][C:14]([C@H:16]2[CH2:18][C@@H:17]2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:15])[CH3:12])=[CH:7][CH:6]=1)(C)C.[Cl:25]C1N=CC([C@@H](N)C)=CC=1>>[Cl:25][C:5]1[N:10]=[CH:9][C:8]([C@@H:11]([NH:13][C:14]([C@H:16]2[CH2:18][C@@H:17]2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:15])[CH3:12])=[CH:7][CH:6]=1
Reactant: C[C@H](N)c1ccc(Cl)nc1
Reactant: CC(C)Oc1ccc([C@H](C)NC(=O)[C@H]2C[C@@H]2c2ccccc2)cn1
Product: C[C@H](NC(=O)[C@H]1C[C@@H]1c1ccccc1)c1ccc(Cl)nc1

Procedure:
Prepared analogously to Compound 1 using IM46 and commercially available (S)-1-(6-Chloro-pyridin-3-yl)-ethylamine (Aurora building blocks catalogue nr A06.81-4.555). Yield=1.40 g (71%), 1H-NMR (500 MHz, DMSO) δ 8.68 (d, 1H), 8.36 (s, 1H), 7.78 (d, 1H), 7.48 (d, 1H), 7.28 (m, 2H), 7.18 (m, 1H), 7.11 (d, 2H), 4.99 (m, 1H), 2.20 (m, 1H), 1.92 (m, 1H), 1.37 (m, 4H), 120 (m, 1H). LC-MS (m/z) 301.2 and 303.1 (MH+), tR=0.87 min (method B).
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:29][O:30][C:31]1[C:38]([O:39][CH3:40])=[CH:37][C:34]([CH:35]=O)=[C:33]([N+:41]([O-:43])=[O:42])[CH:32]=1>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:35][C:34]3[CH:37]=[C:38]([O:39][CH3:40])[C:31]([O:30][CH3:29])=[CH:32][C:33]=3[N+:41]([O-:43])=[O:42])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(C=O)c([N+](=O)[O-])cc1OC
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Product: COc1cc(CNc2cccc(-c3c(Cc4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)c([N+](=O)[O-])cc1OC

Procedure:
The title compound was prepared from {3-[3-benzyl-8-(trifluoromethyl)quinolin-4-yl]phenyl}amine and 4,5-dimethoxy-2-nitro-benzaldehyde according to the procedure of Example 66. MS (ES) m/z 574.1.
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:3]=1[C:14]([O:16]CC)=[O:15].[OH-].[K+].C(O)C.S([O:34][CH2:35][C:36]1([CH2:40][CH3:41])[CH2:39][O:38][CH2:37]1)(C1C=CC(C)=CC=1)(=O)=O>C1(C)C=CC=CC=1.O>[CH2:40]([C:36]1([CH2:35][O:34][C:7]2[CH:2]=[C:3]([C:14]([OH:16])=[O:15])[C:4]([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)=[CH:5][CH:6]=2)[CH2:39][O:38][CH2:37]1)[CH3:41]
Reactant: CCC1(COS(=O)(=O)c2ccc(C)cc2)COC1
Reactant: CCOC(=O)c1c(O)cccc1-c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: CCC1(COc2ccc(-c3ccccc3)c(C(=O)O)c2)COC1
Temperature: 60 °C
Reaction time: 1 h
Yield: 51.7 %

Procedure:
12 g of ethyl hydroxybiphenylcarboxylate and 15 g of potassium hydroxide were added to 100 mL of ethanol, and stirred at 60° C. for 1 hour. After decreasing the temperature to 45° C., 15 g of 3-((tosyloxy)methyl)-3-ethyloxetane was added dropwise thereto, and then refluxed for 2 hours. Water and toluene were added thereto, and the toluene layer was separated. The toluene layer was washed with 3% hydrochloric acid, a saturated sodium carbonate solution and water, and then toluene was distilled off. 20 g of sodium hydroxide, 500 mL of ethanol and 100 mL of water were added to the resulting residue, and refluxed for 2 hours. A residue obtained by distilling ethanol off was put in 300 mL of 5% hydrochloric acid to obtain crystals. The crystals thus obtained by filtering were recrystallized from ethanol to obtain 8 g of 4-(3-ethyloxetane-3-ylmethoxy)biphenylcarboxylic acid (OX2), which had a melting point of 222 to 225° C.
Reaction SMILES: C([O:3][C:4]([CH2:6][C:7](=[O:39])[CH2:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([O:15][C:16]([N:18]2[CH2:27][CH2:26][C:25]3[C:20](=[CH:21][CH:22]=[C:23]([NH:28][C:29]([NH:31][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=4[F:38])=[O:30])[CH:24]=3)[CH2:19]2)=[O:17])[CH2:11][CH2:10]1)=O)C.Cl.[NH2:41]O>C(O)C>[OH:3][C:4]1[CH:6]=[C:7]([CH2:8][C@H:9]2[CH2:10][CH2:11][C@H:12]([O:15][C:16]([N:18]3[CH2:27][CH2:26][C:25]4[C:20](=[CH:21][CH:22]=[C:23]([NH:28][C:29]([NH:31][C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=5[F:38])=[O:30])[CH:24]=4)[CH2:19]3)=[O:17])[CH2:13][CH2:14]2)[O:39][N:41]=1
Reactant: CCOC(=O)CC(=O)C[C@H]1CC[C@H](OC(=O)N2CCc3cc(NC(=O)Nc4ccccc4F)ccc3C2)CC1
Reactant: NO
Agent: Cl
Solvent: CCO
Product: O=C(Nc1ccc2c(c1)CCN(C(=O)O[C@H]1CC[C@H](Cc3cc(O)no3)CC1)C2)Nc1ccccc1F
Temperature: 80 °C

Procedure:
To a mixture of trans-6-[3-(2-fluoro-phenyl)-ureido]-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 4-(3-ethoxycarbonyl-2-oxo-propyl)-cyclohexyl ester (127 mg) obtained in Example (42a) and ethanol (3 mL), hydroxylamine hydrochloride (164 mg) was added at room temperature in the same way as in Example (42b). The reaction mixture was heated at 80° C. for 12 hours and concentrated. The residue was purified by column chromatography (dichloromethane/ethyl acetate). The obtained solid was purified by PTLC (dichloromethane/ethyl acetate=1:1) to obtain the title compound (34 mg, 28%) as an orange solid.
Reaction SMILES: [Br-].[OH:2][C@@H:3]1[CH:8]2[CH2:9][CH2:10][N+:5]([CH2:11][C:12](=[O:19])[NH:13][C:14]3[CH:18]=[CH:17]O[N:15]=3)([CH2:6][CH2:7]2)[CH2:4]1.[Br:20]C[C:22]([NH:24]C1C=CN=CN=1)=O>>[Br-:20].[OH:2][C@@H:3]1[CH:8]2[CH2:9][CH2:10][N+:5]([CH2:11][C:12](=[O:19])[NH:13][C:14]3[CH:18]=[CH:17][N:24]=[CH:22][N:15]=3)([CH2:6][CH2:7]2)[CH2:4]1
Reactant: O=C(CBr)Nc1ccncn1
Reactant: O=C(C[N+]12CCC(CC1)[C@@H](O)C2)Nc1ccon1
Agent: [Br-]
Product: O=C(C[N+]12CCC(CC1)[C@@H](O)C2)Nc1ccncn1

Procedure:
This compound was prepared by an analogous method to (R)-3-Hydroxy-1-(isoxazol-3-ylcarbamoylmethyl)-1-azonia-bicyclo[2.2.2]octane bromide (Intermediate A) by replacing 2-bromo-N-isoxazol-3-yl-acetamide (Ai) with 2-bromo-N-pyrimidin-4-yl-acetamide (Qi).
Reaction SMILES: C1(N[C:8]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:9])C=CC=CC=1.NC(N)=O.N.[CH2:22]([OH:24])[CH3:23]>CCCCCCCC([O-])=O.CCCCCCCC([O-])=O.[Zn+2]>[CH2:22]([O:24][C:8](=[O:9])[NH:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[CH3:23]
Reactant: CCO
Reactant: O=C(Nc1ccccc1)Nc1ccccc1
Agent: CCCCCCCC(=O)[O-]
Agent: N
Agent: NC(N)=O
Product: CCOC(=O)Nc1ccccc1

Procedure:
Following the procedure of Example 1, 573 g of N,N'-diphenyl urea and 2080 g of ethanol (approximately 96%) were reacted for 1.5 hours at 190° C. in the pressure apparatus described in Example 1. After cooling this mixture, 162 g of urea and 5.8 g of zinc octoate were added to the pressure reactor and then reacted for 5.5 hours at 200° C. with removal of the ammonia formed. After cooling and venting of the apparatus, the reaction mixture was removed, filtered and subjected to fractional distillation. Excess alcohol was separated from the reaction mixture at atmospheric pressure. 783 g (87.8% of the theoretical yield) of N-phenyl carbamic acid ethyl ester distilled off at 0.2 mbar. The N-phenyl carbamic acid ethyl ester crystals melted at 49° to 51° C.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[CH2:6]([O:13][C:14]1[CH:23]=[CH:22][C:21]2[N+:20]([O-])=[CH:19][C:18]3[N:25]=[C:26]([CH2:32][O:33][CH3:34])[N:27]([CH2:28][CH:29]([CH3:31])[CH3:30])[C:17]=3[C:16]=2[CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:6]([O:13][C:14]1[CH:23]=[CH:22][C:21]2[N:20]=[C:19]([Cl:3])[C:18]3[N:25]=[C:26]([CH2:32][O:33][CH3:34])[N:27]([CH2:28][CH:29]([CH3:31])[CH3:30])[C:17]=3[C:16]=2[CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: COCc1nc2c[n+]([O-])c3ccc(OCc4ccccc4)cc3c2n1CC(C)C
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCc1nc2c(Cl)nc3ccc(OCc4ccccc4)cc3c2n1CC(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Phosphorous oxychloride (1.78 g, 11.6 mmol) was added dropwise to a solution of 8-benzyloxy-1-(2-methylpropyl)-2-methoxymethyl-5-oxido-1H-imidazo[4,5-c]quinoline in 10 mL of DMF. After 1 hour, the reaction was poured onto 700 mL of ice and stirred overnight. Solid potassium carbonate was then added until the pH of the reached 10. After 30 minutes of stirring, the mixture was filtered. The resulting solid was washed with water and dried under a stream of air to give 3.75 g of 8-benzyloxy-4-chloro-1-(2-methylpropyl)-2-methoxymethyl-1H-imidazo[4,5-c]quinoline as a yellow-tan solid.