Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)=[CH:4][CH:3]=1.[CH3:18][C:19]1[C:23]([C:24]([N:26]2[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]2)=[O:25])=[C:22]([CH3:33])[NH:21][C:20]=1[CH:34]=O>C(O)C.N1CCCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[C:10](=[CH:34][C:20]2[NH:21][C:22]([CH3:33])=[C:23]([C:24]([N:26]4[CH2:27][CH2:28][N:29]([CH3:32])[CH2:30][CH2:31]4)=[O:25])[C:19]=2[CH3:18])[C:11](=[O:17])[NH:12]3)=[CH:6][CH:7]=1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)N1CCN(C)CC1
Reactant: O=C1Cc2c(cccc2-c2ccc(Cl)cc2)N1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1[nH]c(C=C2C(=O)Nc3cccc(-c4ccc(Cl)cc4)c32)c(C)c1C(=O)N1CCN(C)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 45.5 %

Procedure:
To a solution of 4-(4-chloro-phenyl)-1,3-dihydro-indol-2-one (60.9 mg, 0.25 mmol) and 3,5-dimethyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrole-2-carbaldehyde (64.8 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide 4-(4-Chloro-phenyl)-3-[3,5-dimethyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrol-2-ylmethylene]-1,3-dihydro-indol-2-one as a yellow solid (54 mg, 45%)
Reaction SMILES: [CH2:1]([O:4][N:5]([C@H:18]1[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@H:21]([CH2:31][O:32][Si](C(C)(C)C)(C)C)[C:20]([CH2:40][CH3:41])=[CH:19]1)[S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16])(=[O:8])=[O:7])[CH:2]=[CH2:3].C(ON([C@H]1CN(C(OC(C)(C)C)=O)[C@H](CO)C=C1C)S(C1C=CC=CC=1[N+]([O-])=O)(=O)=O)C=C>>[CH2:1]([O:4][N:5]([C@H:18]1[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:28])([CH3:29])[CH3:30])=[O:25])[C@H:21]([CH2:31][OH:32])[C:20]([CH2:40][CH3:41])=[CH:19]1)[S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16])(=[O:8])=[O:7])[CH:2]=[CH2:3]
Reactant: C=CCON([C@@H]1C=C(CC)[C@@H](CO[Si](C)(C)C(C)(C)C)N(C(=O)OC(C)(C)C)C1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: C=CCON([C@H]1CN(C(=O)OC(C)(C)C)[C@H](CO)C=C1C)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Product: C=CCON([C@@H]1C=C(CC)[C@@H](CO)N(C(=O)OC(C)(C)C)C1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Yield: 86.6 %

Procedure:
The title compound was prepared from (2S,5R)-tert-butyl 5-(N-(allyloxy)-2-nitrophenylsulfonamido)-2-((tert-butyldimethylsilyloxy)methyl)-3-ethyl-5,6-dihydropyridine-1(2H)-carboxylate (Intermediate 209, 7 g, 11.44 mmol) following the procedure described for Intermediate 18. Silica gel chromatography (30%-90% ethyl acetate/hexanes) afforded the title compound (4.93 g, 87%) as an tan foam.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH:11]=[C:10]([OH:15])[CH:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].[OH-].[K+].S(OC)(O[CH3:22])(=O)=O>O>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH:11]=[C:10]([O:15][CH3:22])[CH:9]=[CH:8]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: COS(=O)(=O)OC
Reactant: CC(C)(C)c1ccc2cc(O)ccc2c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: COc1ccc2cc(C(C)(C)C)ccc2c1
Yield: 88 %

Procedure:
To a 2 L round bottomed flask was added 6-t-butyl-2-naphthol (30.67 g; 0.153 mmol) and 550 ml of 15% KOH in water. The solution was stirred while adding dimethyl sulfate (6.0 equiv.) dropwise over 30 min. After the addition was complete, the mixture was allowed to stir for 2 hrs. The solids were collected on a filter and washed with water to afford 28.97 g (88% yield) of the subtitle compound.
Reaction SMILES: Cl.Cl.[O:3]1[CH2:8][CH2:7][N:6]([C@H:9]2[CH2:14][CH2:13][C@H:12]([NH2:15])[CH2:11][CH2:10]2)[CH2:5][CH2:4]1.F[C:17]1[CH:22]=[CH:21][C:20]([S:23]([NH2:26])(=[O:25])=[O:24])=[CH:19][C:18]=1[N+:27]([O-:29])=[O:28].C(N(C(C)C)CC)(C)C>O1CCCC1>[O:3]1[CH2:4][CH2:5][N:6]([C@H:9]2[CH2:10][CH2:11][C@H:12]([NH:15][C:17]3[CH:22]=[CH:21][C:20]([S:23]([NH2:26])(=[O:25])=[O:24])=[CH:19][C:18]=3[N+:27]([O-:29])=[O:28])[CH2:13][CH2:14]2)[CH2:7][CH2:8]1
Reactant: N[C@H]1CC[C@H](N2CCOCC2)CC1
Reactant: NS(=O)(=O)c1ccc(F)c([N+](=O)[O-])c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: NS(=O)(=O)c1ccc(N[C@H]2CC[C@H](N3CCOCC3)CC2)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of EXAMPLE 324J (1.00 g) and 4-fluoro-3-nitrobenzenesulfonamide (0.90 g) in tetrahydrofuran (15 mL) was added diisopropylethylamine (4.75 mL) and the reaction was stirred at room temperature overnight. The reaction was filtered and the solid washed with dichloromethane. The reaction mixture was combined with the washings were concentrated. The resulting solid was triturated with dichloromethane and filtered to give the title compound.
Reaction SMILES: O1CCCCC1[O:7][NH:8][C:9]([C@H:11]([C@@H:21]([CH2:30][CH:31]([CH3:33])[CH3:32])[C:22]([NH:24][NH:25][S:26]([CH3:29])(=[O:28])=[O:27])=[O:23])[CH2:12]/[CH:13]=[CH:14]/[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:10].CS(O[CH2:39][CH:40]1[CH2:44][CH2:43][CH2:42][CH2:41]1)(=O)=O>>[CH:40]1([CH2:39][N:25]([S:26]([CH3:29])(=[O:27])=[O:28])[NH:24][C:22](=[O:23])[C@@H:21]([C@@H:11]([C:9](=[O:10])[NH:8][OH:7])[CH2:12]/[CH:13]=[CH:14]/[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:30][CH:31]([CH3:32])[CH3:33])[CH2:44][CH2:43][CH2:42][CH2:41]1
Reactant: CS(=O)(=O)OCC1CCCC1
Reactant: CC(C)C[C@@H](C(=O)NNS(C)(=O)=O)[C@H](C/C=C/c1ccccc1)C(=O)NOC1CCCCO1
Product: CC(C)C[C@@H](C(=O)NN(CC1CCCC1)S(C)(=O)=O)[C@H](C/C=C/c1ccccc1)C(=O)NO

Procedure:
The starting material was prepared in an analogous manner to that described in Example 15, part (iii), starting from (E)-2(R)-[1(S)-[(tetrahydro-2(RS)-pyranyloxy)carbamoyl]-4-phenyl-3-butenyl]-2′-(methanesulphonyl)-4-methylvalerohydrazide and cyclopentylmethyl methanesulphonate.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH2:16]Cl.[C:21]([C:23]1[C:24](=[O:34])[NH:25][C:26]2[C:31]([CH:32]=1)=[CH:30][C:29]([OH:33])=[CH:28][CH:27]=2)#[N:22].C([O-])([O-])=O.[K+].[K+].CO>CN(C=O)C.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:21]([C:23]1[C:24](=[O:34])[NH:25][C:26]2[C:31]([CH:32]=1)=[CH:30][C:29]([O:33][CH2:16][C:15]1[CH:18]=[CH:19][CH:20]=[C:13]([O:12][CH2:11][C:2]3[CH:3]=[CH:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[N:1]=3)[CH:14]=1)=[CH:28][CH:27]=2)#[N:22]
Reactant: ClCc1cccc(OCc2ccc3ccccc3n2)c1
Reactant: N#Cc1cc2cc(O)ccc2[nH]c1=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: CO
Solvent: CN(C)C=O
Product: N#Cc1cc2cc(OCc3cccc(OCc4ccc5ccccc5n4)c3)ccc2[nH]c1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 4.7 %

Procedure:
3-(2-quinolinylmethoxy)benzyl chloride (3.49 g, 12.3 mmol) was added to a solution of 2.45 g (12.3 mmol) of 3-cyano-6-hydroxy-1,2-dihydroquinolin-2-one in 100 ml of DMF, followed by the further addition of 2.04 g (14.8 mmol) of K2CO3 and 396 mg (1.23 mmol) of tetra-n-butylammonium bromide. The resulting mixture was stirred under an argon gas stream at room temperature for 24 hours. The reaction mixture was concentrated under reduced pressure, followed by the addition of CHCl3 --MeOH and water to extract the reaction product into the organic layer. The organic layer was dried over Na2SO4 and then concentrated under reduced pressure. The residue was subjected to chromatography on a silica gel column. Subsequent to elution with CHCl3, recrystallization was conducted from a CHCl3 --MeOH mixed solvent, whereby 250 mg of the title compound were obtained as yellow powder (yield: 4.7%).
Reaction SMILES: C([O:8][C:9](=[O:25])[CH2:10][CH2:11][C:12]#[C:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]([F:24])([F:23])[F:22])[CH:15]=1)C1C=CC=CC=1.[Li+].[OH-]>C1COCC1.CO>[F:22][C:21]([F:23])([F:24])[O:20][C:16]1[CH:15]=[C:14]([C:13]#[C:12][CH2:11][CH2:10][C:9]([OH:25])=[O:8])[CH:19]=[CH:18][CH:17]=1
Reactant: O=C(CCC#Cc1cccc(OC(F)(F)F)c1)OCc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)CCC#Cc1cccc(OC(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a solution of 5-(3-trifluoromethoxy-phenyl)-pent-4-ynoic acid benzyl ester (500 mg, 1.4 mmol) in THF/methanol 2/1 (13.5 ml) was added 1 N aqueous LiOH solution (8.6 ml). The reaction mixture was stirred for 2 h at ambient temperature and concentrated under reduced pressure. The residue was dissolved in 1 N NaOH/ice water 1/1 and ethyl acetate and the layers were separated. The aqueous layer was brought to pH 1 with 1 N HCl and extracted two times with ethyl acetate. The combined extracts were washed with ice water/brine 1/1, dried over sodium sulfate and the solvent was evaporated in vacuo to give the title compound (370 mg, 1.4 mmol, quant.) as colorless crystals.
Reaction SMILES: [CH2:1]([C:5]1[C:6]([CH3:29])=[C:7]([C:10]2[O:14][C:13]([C:15]3[CH:26]=[C:25]([CH3:27])[C:18]([O:19][CH2:20][CH:21]([OH:24])[CH2:22]O)=[C:17]([CH3:28])[CH:16]=3)=[N:12][N:11]=2)[S:8][CH:9]=1)[CH:2]([CH3:4])[CH3:3].CC[N:32](CC)CC.CS(Cl)(=O)=O.N>C1COCC1.CO>[NH2:32][CH2:22][CH:21]([OH:24])[CH2:20][O:19][C:18]1[C:25]([CH3:27])=[CH:26][C:15]([C:13]2[O:14][C:10]([C:7]3[S:8][CH:9]=[C:5]([CH2:1][CH:2]([CH3:4])[CH3:3])[C:6]=3[CH3:29])=[N:11][N:12]=2)=[CH:16][C:17]=1[CH3:28]
Reactant: Cc1cc(-c2nnc(-c3scc(CC(C)C)c3C)o2)cc(C)c1OCC(O)CO
Reactant: CCN(CC)CC
Agent: CS(=O)(=O)Cl
Agent: N
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(-c2nnc(-c3scc(CC(C)C)c3C)o2)cc(C)c1OCC(O)CN
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 3-{4-[5-(4-isobutyl-3-methyl-thiophen-2-yl)-[1,3,4]oxadiazol-2-yl]-2,6-dimethyl-phenoxy}-propane-1,2-diol (90 mg, 0.22 mmol) in THF (4 mL) are added NEt3 (0.14 mL) and, subsequently, methanesulfonlychloride (0.02 mL, 0.26 mmol). The mixture is stirred at rt for 3 h. A solution of NH3 in MeOH (7M, 4 mL) is added and the mixture is heated at 60° C. for 15 h. The mixture is evaporated, 1M aq. NaOH (3 mL) is added and the mixture is extracted with EA (2×20 mL). The organic extracts are dried (Na2SO4), filtered and evaporated to give crude 1-amino-3-{4-[5-(4-isobutyl-3-methyl-thiophen-2-yl)-[1,3,4]oxadiazol-2-yl]-2,6-dimethylphenoxy}-propan-2-ol; LC-MS: tR=0.86 min, [M+1]+=416.32.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]([C:16]3[CH:17]=[C:18]([OH:22])[CH:19]=[CH:20][CH:21]=3)=[C:14]3[C:9]([C:10]([C:23]([F:26])([F:25])[F:24])=[CH:11][CH:12]=[CH:13]3)=[N:8]2)=[C:4]([F:29])[CH:3]=1.C[O:31][C:32](=[O:41])[CH:33](Br)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[Li+].[OH-]>ClCCl.C1COCC1.O>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]([C:16]3[CH:17]=[C:18]([CH:19]=[CH:20][CH:21]=3)[O:22][CH:33]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:32]([OH:41])=[O:31])=[C:14]3[C:9]([C:10]([C:23]([F:25])([F:26])[F:24])=[CH:11][CH:12]=[CH:13]3)=[N:8]2)=[C:4]([F:29])[CH:3]=1
Reactant: Oc1cccc(-c2c3cccc(C(F)(F)F)c3nn2Cc2ccc(Cl)cc2F)c1
Reactant: COC(=O)C(Br)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [Li+]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C(Oc1cccc(-c2c3cccc(C(F)(F)F)c3nn2Cc2ccc(Cl)cc2F)c1)c1ccccc1

Procedure:
3-[2-(4-Chloro-2-fluoro-benzyl)-7-trifluoromethyl-2H-indazol-3-yl]-phenol (25 mg, 1 eq) was treated with bromo-phenyl-acetic acid methyl ester (41 mg, 3 eq) and cesium carbonate (95 mg, 5 eq) in dichloromethane (2 mL) until the reaction mixture was completed as judged by TLC. Water was added followed by extraction with dichloromethane. Subsequently, the ester was hydrolyzed in aq. LiOH (1M, 15 eq)/THF 1:1. Purification by flash chromatography, eluent: 2-5% methanol in dichloromethane, afforded the title compound in 55% yleld.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:12]2[C:11](=O)[N:10]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:16][CH:15]=3)[C:9](=[O:26])[C:8]=2[C:7]([O:27][CH2:28][CH3:29])=[C:6]2[CH:30]=[CH:31][CH:32]=[CH:33][C:5]=12)[CH3:2].CCOCC>C(O)(=O)C.[Zn]>[CH2:1]([O:3][C:4]1[C:12]2[CH2:11][N:10]([C:14]3[CH:15]=[CH:16][C:17]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:18][CH:19]=3)[C:9](=[O:26])[C:8]=2[C:7]([O:27][CH2:28][CH3:29])=[C:6]2[CH:30]=[CH:31][CH:32]=[CH:33][C:5]=12)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(N2C(=O)c3c(c(OCC)c4ccccc4c3OCC)C2=O)cc1
Agent: [Zn]
Solvent: CCOCC
Solvent: CC(=O)O
Product: CCOC(=O)Cc1ccc(N2Cc3c(c(OCC)c4ccccc4c3OCC)C2=O)cc1
Reaction time: 18 h
Yield: 32.2 %

Procedure:
Ethyl [4-(4,9-diethoxy-1,3-dioxo-1,3-dihydro-2H-benzo[f]isoindol-2-yl)phenyl]acetate (339, 73 mmol) and zinc (909, 1.38 mol) were refluxed in acetic acid for 66 h. An additional quantity of zinc (25 g, 0.38 mol) was added and reflux continued for 18 h. The mixture was filtered hot and the filtrate was evaporated to a yellow solid. The solid was purified by 800 g Biotage column eluting with 20% ethyl acetate/hexane to give a white solid, which was triturated in ether to give a white solid. A further fraction was obtained by crystallisation from the ether residues. A total of 10.2 g, 32% of ethyl [4-(4,9-diethoxy-1-oxo-1,3-dihydro-2H-benzo[f]isoindol-2-yl)phenyl]acetate was obtained.
Reaction SMILES: Br[C:2]1[CH:6]=[N:5][N:4]([CH2:7][CH3:8])[C:3]=1[CH:9]([OH:19])[CH2:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[CH2:20]([O:22][C:23]([C:25]1([C:28]2[CH:33]=[CH:32][C:31]([C:34]3[CH:39]=[CH:38][C:37](B4OC(C)(C)C(C)(C)O4)=[CH:36][CH:35]=3)=[CH:30][CH:29]=2)[CH2:27][CH2:26]1)=[O:24])[CH3:21]>>[CH2:20]([O:22][C:23]([C:25]1([C:28]2[CH:29]=[CH:30][C:31]([C:34]3[CH:35]=[CH:36][C:37]([C:2]4[CH:6]=[N:5][N:4]([CH2:7][CH3:8])[C:3]=4[CH:9]([OH:19])[CH2:10][CH2:11][CH2:12][C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)=[CH:38][CH:39]=3)=[CH:32][CH:33]=2)[CH2:27][CH2:26]1)=[O:24])[CH3:21]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(B4OC(C)(C)C(C)(C)O4)cc3)cc2)CC1
Reactant: CCn1ncc(Br)c1C(O)CCCc1ccccc1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4cnn(CC)c4C(O)CCCc4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 5, Step 2, using the following starting materials: 1-(4-bromo-2-ethyl-2H-pyrazol-3-yl)-4-phenyl-butan-1-ol and 1-[4′-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [N:1]1[NH:2][C:3](=[O:10])[N:4]2[CH:9]=[CH:8][CH:7]=[N:6][C:5]=12.[Br:11][CH2:12][CH2:13][CH2:14]Br.[H-].[Na+].CN(C)C=O>C(OCC)(=O)C.O>[Br:11][CH2:12][CH2:13][CH2:14][N:2]1[C:3](=[O:10])[N:4]2[CH:9]=[CH:8][CH:7]=[N:6][C:5]2=[N:1]1
Reactant: O=c1[nH]nc2ncccn12
Reactant: BrCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: O=c1n(CCCBr)nc2ncccn12
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 2H-[1,2,4]triazolo[4,3-a]pyrimidin-3-one (CAS 63206-77-9) (1.0 g), 1,3-dibromopropane (1.55 ml), sodium hydride (60% in oil) (353 mg) and N,N-dimethylformamide (20 ml) was stirred at room temperature for one day. After further addition of 1,3-dibromopropane (3.88 ml) and sodium hydride (60% in oil) (353 mg), stirring was continued at 80° C. for 2 hours. Water was added to the reaction mixture, and extraction was performed with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (190 mg).
Reaction SMILES: [CH3:1]I.[N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[C:5]([CH2:13][C:14]2[C:15](=[O:21])[NH:16][C:17](=[S:20])[NH:18][CH:19]=2)[CH:4]=1.[OH-].[K+]>C(O)C>[CH3:1][S:20][C:17]1[NH:16][C:15](=[O:21])[C:14]([CH2:13][C:5]2[CH:4]=[N:3][C:12]3[C:7]([CH:6]=2)=[CH:8][CH:9]=[CH:10][CH:11]=3)=[CH:19][N:18]=1
Reactant: CI
Reactant: O=c1[nH]c(=S)[nH]cc1Cc1cnc2ccccc2c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CSc1ncc(Cc2cnc3ccccc3c2)c(=O)[nH]1
Reaction time: 0.5 h
Yield: 98.4 %

Procedure:
Methyl iodide (0.56 g) was added to a stirred solution of 1,2-dihydro-5-[(3-quinolinyl)methyl]-2-thioxo-4(3H)-pyrimidinone (1.2 g) and potassium hydroxide (0.23 g) in aqueous ethanol (50%, 20 ml) at 60°. After 30 min., the solution was cooled and the solid which separated was crystallised from aqueous ethanol to give the title compound (1.1 g), m.p. 220°-221°.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14](O)=[O:15])=[CH:11][CH:12]=2)[C@H:7]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)=[CH:20][CH:19]=2)[CH2:6][C@@H:5]1[CH3:30])(=[O:3])[CH3:2].[CH:31]([NH2:34])([CH3:33])[CH3:32]>>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]([NH:34][CH:31]([CH3:33])[CH3:32])=[O:15])=[CH:11][CH:12]=2)[C@H:7]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH2:25][CH2:26][O:27][CH2:28][CH2:29]3)=[CH:20][CH:19]=2)[CH2:6][C@@H:5]1[CH3:30])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccc(C(=O)O)cc2[C@H](Nc2ccc(N3CCOCC3)cc2)C[C@@H]1C
Reactant: CC(C)N
Product: CC(=O)N1c2ccc(C(=O)NC(C)C)cc2[C@H](Nc2ccc(N3CCOCC3)cc2)C[C@@H]1C
Yield: 86.4 %

Procedure:
Reactions and treatments were carried out in the same manner as in Example 110, using 82 mg of (2S,4R)-1-acetyl-2-methyl-4-[(4-morpholinophenyl)amino]-1,2,3,4-tetrahydroquinoline-6-carboxylic acid and 36 mg of isopropylamine. Thus, 78 mg (86%) of the title compound was obtained as a pale yellow amorphous substance.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[C:9]([C:14]#N)=[CH:10][N:11](C)C)=[CH:4][N:3]=1.[N+]([O-])([O-])=O.[F:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29]([NH2:31])=[NH2+:30])=[CH:24][CH:23]=1.[OH-].[Na+]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:10]#[N:11])=[CH:14][N:31]=[C:29]([NH:28][C:25]3[CH:24]=[CH:23][C:22]([F:21])=[CH:27][CH:26]=3)[N:30]=2)=[CH:4][N:3]=1
Reactant: NC(=[NH2+])Nc1ccc(F)cc1
Reactant: CN(C)C=C(C#N)C(=O)c1ccc(Cl)nc1
Agent: O=[N+]([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Product: N#Cc1cnc(Nc2ccc(F)cc2)nc1-c1ccc(Cl)nc1

Procedure:
4-[2-Chloropyridin-5-yl]-5-cyano-N-(4-fluorophenyl)pyrimidine-2-amine was prepared from 1-(2-chloropyridin-5-yl)-2-cyano-3-dimethylamino propen-1-one (8.0 g, 36 mmol), 4-fluorophenylguanidinium nitrate (8.23 g, 37.8 mmol) and sodium hydroxide (1.49 g, 37.8 mmol) as a yellow solid (7.23 g). δH (d6 DMSO) 10.66 (1H, bs), 9.00 (1H, s), 8.95 (1H, d, J 2.3 Hz), 8.38 (1H, dd, J 8.4,2.5 Hz), 7.80 (1H, d, J 8.4 Hz), 7.77-7.74 (2H, m) and 7.24-7.20 (2H, m).
Reaction SMILES: Cl.Cl.[NH2:3][CH:4]1[CH2:12][CH2:11][C:7]2[NH:8][CH:9]=[N:10][C:6]=2[CH2:5]1.C[O-].[Na+].CO.C(N(CC)CC)C.[CH:25]1([CH2:31][CH2:32][CH2:33][CH2:34][C:35]([Cl:37])=[O:36])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>CC(N(C)C)=O>[ClH:37].[NH:8]1[C:7]2[CH2:11][CH2:12][CH:4]([NH:3][C:35](=[O:36])[CH2:34][CH2:33][CH2:32][CH2:31][CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[CH2:5][C:6]=2[N:10]=[CH:9]1
Reactant: NC1CCc2[nH]cnc2C1
Reactant: O=C(Cl)CCCCC1CCCCC1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Solvent: CO
Product: O=C(CCCCC1CCCCC1)NC1CCc2[nH]cnc2C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 38.2 %

Procedure:
To a mixture of 5-amino-4,5,6,7-tetrahydro-1H-benzimidazole, dihydrochloride (420 mg, 2.0 mmol) and DMA (10 ml), 5.4 M NaOMe in MeOH (0.74 ml, 4.0 mmol) was added. triethylamine (0.276 ml, 2 mmol) was added followed by dropwise addition of 5-cyclohexylpentanoic acid chloride (609 mg, 3.0 mmol). When addition was complete the mixture was stirred at ambient temperature for 30 min and then heated at 80° C. for 1 hour and finally allowed to cool to ambient temperature within 1 hour. The volatiles were evaporated and the residue was stirred vigorously with a mixture of H2O (100 ml), 1 N hydrochloric acid (10 ml) and diethyl ether (50 ml). The phases were separated and the aqueous phase was washed with diethyl ether (2×50 ml) and then made alkaline to pH 10-11 with 4 N sodium hydroxide. The alkaline mixture was extracted with ethyl acetate (2×50 ml) and the organic extracts were evaporated in vacuo. The residue was dissolved in 1 N hydrochloric acid and evaporated to dryness. The residue was re-evaporated with acetone to give 260 mg (38%) of the title compound.
Reaction SMILES: [F-].C([NH3+])(C)(C)C.[Si]([O:14][CH2:15][C:16]1[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][C:17]=1[C:26]1[CH:31]=[C:30]([CH:32]([CH3:34])[CH3:33])[C:29]([F:35])=[C:28]([OH:36])[C:27]=1[O:37][CH3:38])(C(C)(C)C)(C)C.[NH4+].[Cl-]>C1COCC1>[F:35][C:29]1[C:30]([CH:32]([CH3:33])[CH3:34])=[CH:31][C:26]([C:17]2[CH:18]=[CH:19][C:20]([C:22]([F:24])([F:25])[F:23])=[CH:21][C:16]=2[CH2:15][OH:14])=[C:27]([O:37][CH3:38])[C:28]=1[OH:36]
Reactant: COc1c(-c2ccc(C(F)(F)F)cc2CO[Si](C)(C)C(C)(C)C)cc(C(C)C)c(F)c1O
Agent: CC(C)(C)[NH3+]
Agent: [Cl-]
Agent: [F-]
Solvent: C1CCOC1
Product: COc1c(-c2ccc(C(F)(F)F)cc2CO)cc(C(C)C)c(F)c1O
Temperature: 25 °C

Procedure:
tert-Butylammonium fluoride (1M in THF, 179 μL, 0.179 mmol) was added dropwise to a stirred solution of 2′-({[tert-butyl(dimethyl)silyl]oxy}methyl)-4-fluoro-5-isopropyl-2-methoxy-4′-(trifluoromethyl)biphenyl-3-ol (76.8 mg, 0.163 mmol) in THF (2 mL) at 0° C. and the reaction was allowed to warm to room temperature overnight. Saturated NH4Cl (10 ml) was added and the mixture was extracted with EtOAc (3×20 mL). The combined extracts were dried (Na2SO4) and concentrated in vacuo to give the crude product. This was purified by flash chromatography (Si, 12×160 mm, 0-40% EtOAc in hexanes gradient) to afford 4-fluoro-2′-(hydroxymethyl)-5-isopropyl-2-methoxy-4′-(trifluoromethyl)biphenyl-3-ol. Rf=0.26 (20% EtOAc in hexanes). 1H NMR (600 MHz, CDCl3) δ 7.85 (s, 1H), 7.63 (d, J=7.9 Hz, 1H), 7.41 (d, J=8.0 Hz, 1H), 6.53 (d, J=7.7 Hz, 1H), 4.50 (br s, 1H), 4.47 (s, 1H), 3.42 (s, 3H), 3.25-3.19 (m, 1H), 1.24 (br s, 6H).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[C:12]([N+:19]([O-])=O)[CH:11]=2)=[N:7][CH:8]=1.[CH3:24][P:25](=[O:29])([CH2:27]N)[CH3:26]>C1(C)C=CC=CC=1>[N+:16]([C:13]1[CH:14]=[CH:15][C:10]([O:9][C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:23])([F:22])[F:1])=[CH:8][N:7]=2)=[CH:11][C:12]=1[NH:19][CH2:24][P:25](=[O:29])([CH3:27])[CH3:26])([O-:18])=[O:17]
Reactant: CP(C)(=O)CN
Reactant: O=[N+]([O-])c1ccc(Oc2ccc(C(F)(F)F)cn2)cc1[N+](=O)[O-]
Solvent: Cc1ccccc1
Product: CP(C)(=O)CNc1cc(Oc2ccc(C(F)(F)F)cn2)ccc1[N+](=O)[O-]

Procedure:
A solution of 4.97 g of (5-trifluoromethyl-2-pyridyloxy)-3,4-dinitrobenzene in 15 ml of toluene is refluxed, and 3.21 g of melted P,P-dimethyl-aminomethylphosphine oxide are added dropwise. The mixture is refluxed for a further 2 hours, nitrous gases being evolved at the start. The brown solution is subsequently concentrated by evaporation, and the residue is recrystallised from 50 ml of ethyl acetate to thus obtain 4.10 g (70% of theory) of N-[2-nitro-5-(5-trifluoromethyl-2-pyridyloxy)-phenyl]-P,P-dimethyl-aminomethylphosphine oxide in the form of yellow crystals, m.p. 158°-160° C.
Reaction SMILES: [CH3:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[N:12]1([CH:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)[CH2:19][NH2:20])[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1>>[CH3:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:20][CH2:19][CH:18]([N:12]1[CH2:13][CH2:14][O:15][CH2:16][CH2:17]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1)=[O:6]
Reactant: Cc1cccc(C(=O)O)c1C
Reactant: NCC(c1ccccn1)N1CCOCC1
Product: Cc1cccc(C(=O)NCC(c2ccccn2)N2CCOCC2)c1C

Procedure:
From 2,3-dimethylbenzoic acid and (2-morpholin-4-yl-2-pyridin-2-ylethyl)amine.