Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C)C(N(C)C)=N.[CH3:9][O:10][C:11](=[O:40])[CH:12](P(OC)(OC)=O)[NH:13][C:14](=[O:33])[C:15]1[CH:20]=[CH:19][C:18]([C:21]([NH:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([OH:31])[CH:26]=2)=[O:22])=[CH:17][C:16]=1[Cl:32].[CH2:41]([C:43]1[S:44][C:45]([CH:49]=O)=[C:46]([CH3:48])[N:47]=1)[CH3:42]>ClCCl>[CH3:9][O:10][C:11](=[O:40])/[C:12](/[NH:13][C:14](=[O:33])[C:15]1[CH:20]=[CH:19][C:18]([C:21]([NH:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([OH:31])[CH:26]=2)=[O:22])=[CH:17][C:16]=1[Cl:32])=[CH:49]/[C:45]1[S:44][C:43]([CH2:41][CH3:42])=[N:47][C:46]=1[CH3:48]
Reactant: COC(=O)C(NC(=O)c1ccc(C(=O)NCc2cccc(O)c2)cc1Cl)P(=O)(OC)OC
Reactant: CCc1nc(C)c(C=O)s1
Agent: CN(C)C(=N)N(C)C
Solvent: ClCCl
Product: CCc1nc(C)c(/C=C(\NC(=O)c2ccc(C(=O)NCc3cccc(O)c3)cc2Cl)C(=O)OC)s1
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 35.7 %

Procedure:
1,1,3,3-Tetramethylguanidine (107 mg, 0.9 mmol) was added to a solution of rac.-N-[2-chloro-4-[[(3-hydroxybenzyl)amino]carbonyl]benzoyl]-2-(dimethoxyphosphinyl)glycine methyl ester (Example 141; 300 mg, 0.6 mmol) in dichloromethane (10 mL) at ˜5° C. The solution was stirred at ˜5° C. for 30 min and then 2-ethyl-4-methylthiazole-5-carboxaldehyde (Example 60; 192 mg, 1.2 mmol) was added. The solution was stirred overnight at room temperature, then silica gel was added and the solvent was evaporated. The residue was applied to a column of silica gel and unreacted 2-ethyl-4-methylthiazole-5-carboxaldehyde was eluted with 50% ethyl acetate/hexanes. Evaporation of the appropriate fractions eluted with 5% methanol/dichloromethane gave (Z)-2-[[2-chloro-4-[[(3-hydroxybenzyl)amino]carbonyl]benzoyl]amino]-3-(2-ethyl-4-methylthiazole-5-yl)propenoic acid methyl ester (110 mg, 35% yield) as a colorless solid, mp>200° C.
Reaction SMILES: I[C:2]1[N:3]=[CH:4][N:5]2[CH:9]=[CH:8][S:7][C:6]=12.[N+:10]([C:13]1[CH:29]=[CH:28][C:16]([CH2:17][O:18][C:19]([N:21]2[CH2:25][CH2:24][CH2:23][C@H:22]2[CH:26]=[O:27])=[O:20])=[CH:15][CH:14]=1)([O-:12])=[O:11]>>[N+:10]([C:13]1[CH:29]=[CH:28][C:16]([CH2:17][O:18][C:19]([N:21]2[CH2:25][CH2:24][CH2:23][C@H:22]2[CH:26]([OH:27])[C:2]2[N:3]=[CH:4][N:5]3[CH:9]=[CH:8][S:7][C:6]=23)=[O:20])=[CH:15][CH:14]=1)([O-:12])=[O:11]
Reactant: Ic1ncn2ccsc12
Reactant: O=C[C@@H]1CCCN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Product: O=C(OCc1ccc([N+](=O)[O-])cc1)N1CCC[C@H]1C(O)c1ncn2ccsc12
Yield: 65.9 %

Procedure:
7-[[(2S)-1-(4-Nitrobenzyloxycarbonyl)pyrrolidin-2-yl]hydroxymethyl]imidazo[5,1-b]thiazole (2.21 g) was prepared in the same manner as in step a) of Synthesis Example 1, except that 2.50 g of 7-iodoimidazo[5,1-b]thiazole and 2.32 g of (2S)-1-(4-nitrobenzyloxycarbonyl)pyrrolidine-2-aldehyde were used as the starting compounds.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]2[CH2:16][NH:15][CH2:14][C:13]3[S:17][CH:18]=[CH:19][C:12]2=3)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].CN(C)C=O.Cl.[CH3:26][N:27]([CH3:40])[CH2:28][CH2:29][O:30][C:31]1[CH:39]=[CH:38][C:34]([C:35](O)=[O:36])=[CH:33][CH:32]=1.Cl.CN(C)CCCN=C=NCC>C(N(CC)CC)C.ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]2[CH2:16][N:15]([C:35]([C:34]3[CH:33]=[CH:32][C:31]([O:30][CH2:29][CH2:28][N:27]([CH3:40])[CH3:26])=[CH:39][CH:38]=3)=[O:36])[CH2:14][C:13]3[S:17][CH:18]=[CH:19][C:12]2=3)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CN(C)CCOc1ccc(C(=O)O)cc1
Reactant: COc1ccc(C2CNCc3sccc32)cc1OC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc(C2CN(C(=O)c3ccc(OCCN(C)C)cc3)Cc3sccc32)cc1OC

Procedure:
Similarly as described in example 22 using a solution of 4-(3,4-Dimethoxyphenyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine in N,N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol), a suspension of 4-(2-dimethylaminoethoxy)benzoic acid hydrochloride in N,N-dimethylformamide (0.375 M, 0.4 ml, 0.15 mmol), triethylamine (42 pi), and 0.25 ml of a suspension of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride in dichloromethane (1.73 9 in 8.3 ml) affords the title compound.
Reaction SMILES: [C:1]1([N:7]2[CH2:11][CH2:10][NH:9][C:8]2=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:14](Cl)([O:16]C(=O)OC(Cl)(Cl)Cl)Cl.[CH2:25]([N:27]1[CH:31]=[C:30]([C:32]2[S:40][C:39]3[C:34](=[N:35][CH:36]=[CH:37][C:38]=3[O:41][C:42]3[CH:47]=[CH:46][C:45]([NH2:48])=[CH:44][C:43]=3[F:49])[CH:33]=2)[N:29]=[CH:28]1)[CH3:26].CCN(C(C)C)C(C)C>C1COCC1>[CH2:25]([N:27]1[CH:31]=[C:30]([C:32]2[S:40][C:39]3[C:34](=[N:35][CH:36]=[CH:37][C:38]=3[O:41][C:42]3[CH:47]=[CH:46][C:45]([NH:48][C:14]([N:9]4[CH2:10][CH2:11][N:7]([C:1]5[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=5)[C:8]4=[O:12])=[O:16])=[CH:44][C:43]=3[F:49])[CH:33]=2)[N:29]=[CH:28]1)[CH3:26]
Reactant: O=C1NCCN1c1ccccc1
Reactant: CCn1cnc(-c2cc3nccc(Oc4ccc(N)cc4F)c3s2)c1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCn1cnc(-c2cc3nccc(Oc4ccc(NC(=O)N5CCN(c6ccccc6)C5=O)cc4F)c3s2)c1
Temperature: 60 °C
Reaction time: 3 h
Yield: 44.6 %

Procedure:
To a solution of 1-phenylimidazolidin-2-one (211) (100 mg, 0.62 mmol) [P. Mayer, P. Brunel, C. Chaplain, C. Piedecoq, F. Calmel, P. Schambel, P. Chopin, T. Wurch, P. J. Pauwels, M. Marien, J.-L. Vidaluc, T. Imbert J. Med. Chem. 2000, 43, 3653-3664; W. Su, Y. Zhang J. Chem. Res. Synop. 2000, 9, 440-441] in THF (6 mL) was added triphosgene (189 mg, 0.62 mmol) and the solution was stirred for 3 hrs at 60° C. The reaction mixture was cooled to RT before the addition of aniline 15 (229 mg, 0.65 mmol) and DIPEA (648 μL, 3.72 mmol) and stirring was continued for an hour. The reaction mixture was concentrated and partitioned between EtOAc and water. A precipitate was formed which was collected by filtration. The organic layer was separated, dried and concentrated. The residue was combined with the collected precipitate, dry loaded to a column and eluted with EtOAc/MeOH (9:1), to produce title compound 210 (150 mg, 43% yield) as an off-white solid. 1H NMR (DMSO-d6) δ (ppm): 10.57 (s, 1H), 8.42 (d, J=5.5 Hz, 1H), 7.95 (d, J=1.1 Hz, 1H), 7.83 (dd, J=2.5 and 13.3 Hz, 2H), 7.77 (d, J=1.2 Hz, 1H), 7.66 (s, 1H), 7.61 (dd, J=1.0 and 8.8 Hz, 1H), 7.49-7.41 (m, 4H), 7.16 (t, J=7.2 Hz, 1H), 6.57 (d, J=5.5 Hz, 1H), 4.03 (q, 2H), 4.04-3.92 (m, 4H), 1.38 (t, 3H). MS (m/z): 543.0 (M+H).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([O:10][C:11]3[CH:12]=[C:13]([NH:17][C:18](=[O:30])[C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([C:25]5([C:28]#[N:29])[CH2:27][CH2:26]5)[CH:20]=4)[CH:14]=[CH:15][CH:16]=3)=[N:6][N:5]2[CH:31]=1.[CH3:32][C:33]1[CH:41]=[CH:40][C:36]([C:37](Cl)=[O:38])=[CH:35][N:34]=1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[C:28]([C:25]1([C:21]2[CH:20]=[C:19]([CH:24]=[CH:23][CH:22]=2)[C:18]([NH:17][C:13]2[CH:12]=[C:11]([CH:16]=[CH:15][CH:14]=2)[O:10][C:7]2[CH:8]=[CH:9][C:4]3[N:5]([CH:31]=[C:2]([NH:1][C:37](=[O:38])[C:36]4[CH:40]=[CH:41][C:33]([CH3:32])=[N:34][CH:35]=4)[N:3]=3)[N:6]=2)=[O:30])[CH2:27][CH2:26]1)#[N:29]
Reactant: Cc1ccc(C(=O)Cl)cn1
Reactant: N#CC1(c2cccc(C(=O)Nc3cccc(Oc4ccc5nc(N)cn5n4)c3)c2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)Nc2cn3nc(Oc4cccc(NC(=O)c5cccc(C6(C#N)CC6)c5)c4)ccc3n2)cn1
Yield: 22.8 %

Procedure:
Using N-{3-[(2-aminoimidazo[1,2-b]pyridazin-6-yl)oxy]phenyl}-3-(1-cyanocyclopropyl)benzamide (150 mg, 0.365 mmol), 6-methylnicotinoyl chloride (75 mg, 0.548 mmol), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (105 mg, 0.548 mmol), 1-hydroxybenzotriazole (74 mg, 0.548 mmol) and N,N-dimethylformamide (5 mL) as starting materials and in the same manner as in Example 380, the title compound (44 mg, 23%) was obtained as a pale-green powder.
Reaction SMILES: [NH:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[N+:19]([C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1)([O-:21])=[O:20]>ClCCl>[N+:19]([C:22]1[CH:23]=[CH:24][C:25]([C:26]([N:1]2[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=3[CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:27])=[CH:29][CH:30]=1)([O-:21])=[O:20]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: c1ccc2c(c1)CCCCN2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1ccc([N+](=O)[O-])cc1)N1CCCCc2ccccc21
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 77 %

Procedure:
To a solution of 5.0 g of 1,2,3,4-tetrahydro-5H-1-benzazepine and 5.91 ml of triethylamine in 50 ml of dichloromethane, chilled in an ice bath, is added, dropwise, 6.32 g of 4-nitrobenzoyl chloride in 75 ml of dichloromethane. The mixture is stirred at 0° C. for 1.5 hr and then at room temperature for 18 hours. The mixture is washed with H2O, 2M HCl, 1M NaOH and dried (Na2SO4). The solvent is removed and the residue recrystallized from ethanol with the aid of activated carbon to give 7.75 g of light yellow crystals, m.p. 148.5°-150.5° C.
Reaction SMILES: [CH:1]([NH:4][C:5]([NH:7][C@H:8]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:9][C:10](O)=[O:11])=[O:6])([CH3:3])[CH3:2].S(Cl)(Cl)=O>C1(C)C=CC=CC=1.O>[CH:1]([N:4]1[C:10](=[O:11])[CH2:9][C@@H:8]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[NH:7][C:5]1=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)NC(=O)N[C@@H](CC(=O)O)c1ccccc1
Solvent: O
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: CC(C)N1C(=O)C[C@@H](c2ccccc2)NC1=O

Procedure:
A solution of (S)-3-{[(isopropylamino)carbonyl]amino}-3-phenylpropanoic acid from Step A (465 mg, 1.86 mmol) and thionyl chloride (0.270 mL, 3.72 mmol) in toluene (19 mL) was heated at reflux for 1 h. The reaction mixture was cooled, diluted with water (25 mL), and extracted with CH2Cl2 (3×25 mL). The combined CH2Cl2 extracts were dried over Na2SO4, filtered, and concentrated in vacuo to provide the title compound. MS: m/z=233 (M+1).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[NH2:7][CH2:8][CH:9]([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[C:15]([F:20])[CH:14]=1)[CH2:10][CH2:11][OH:12].C(N(CC)CC)C>C(Cl)Cl>[F:20][C:15]1[CH:14]=[C:13]([CH:9]([CH2:8][NH:7][C:2]([O:4][CH2:5][CH3:6])=[O:3])[CH2:10][CH2:11][OH:12])[CH:18]=[CH:17][C:16]=1[F:19]
Reactant: NCC(CCO)c1ccc(F)c(F)c1
Reactant: CCOC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)NCC(CCO)c1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.5 %

Procedure:
Ethyl chloroformate (3.9 mL, 40.8 mmol) was added dropwise to a stirred cooled (−40° C.) solution of 4-amino-3-(3,4-difluorophenyl)-1-butanol (7.45 g, 37 mmol) and triethylamine (5.94 mL, 42.6 mmol) in DCM (180 mL). The solution was stirred at room temperature for 30 min and at room temperature overnight. The material was washed twice with 1N HCl, twice with saturated sodium bicarbonate; dried (Na2SO4), filtered and the solvent removed to provide the title compound (8.85 g, 88%) as a yellow oil. 1H-NMR (CDCl3) δ 1.18-1.23 (t, 3H, CH) 1.72-1.98 (m, 3H) 2.96-3.00 (m, 1H, CH) 3.24-3.29 (m, 1H, CH) 3.45-4.04 (m, 3H, CH), 4.06-4.14 (m, 2H, CH) 4.66 (br. s, 1H, OH or NH) 6.91-7.37 (m, 3H, ArH). MS m/z 274 (M+H).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][C@@H:6]([C:8]([O:10][CH3:11])=[O:9])[C@@H:5]([N:12]2[CH2:16][CH2:15][C@H:14]([NH:17][C:18]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:19])[C:13]2=[O:28])[CH2:4][CH2:3]1.[CH3:29][C:30]([CH3:32])=O.[BH-](OC(C)=O)(OC(C)=O)O[C:35](C)=O.[Na+].C=O>C(Cl)Cl>[CH2:21]([O:20][C:18]([NH:17][C@H:14]1[CH2:15][CH2:16][N:12]([C@H:5]2[CH2:4][CH2:3][C@@H:2]([N:1]([CH:30]([CH3:32])[CH3:29])[CH3:35])[CH2:7][C@H:6]2[C:8]([O:10][CH3:11])=[O:9])[C:13]1=[O:28])=[O:19])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: COC(=O)[C@@H]1C[C@H](N)CC[C@@H]1N1CC[C@H](NC(=O)OCc2ccccc2)C1=O
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1N1CC[C@H](NC(=O)OCc2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 6 h
Yield: 50 %

Procedure:
A solution of (1R,2S,5R)-methyl 5-amino-2-((S)-3-(benzyloxycarbonylamino)-2-oxopyrrolidin-1-yl)cyclohexanecarboxylate from step 4 (0.75 g, 1.9 mmol) in CH2Cl2 (10 ml) was treated with acetone (1 ml) and NaBH(OAc)3 (0.85 g, 4 mmol) and stired at room temperature for 6 h. A solution of 37% aq formaldehyde (2 ml) was added and stirred at room temperature overnight. The solution was diluted with CH2Cl2 (50 ml) and washed with 1 N NaOH, water, brine, concentrated in vacuo and the residue chromatographed (1:9:90 NH4OH:MeOH:CH2Cl2) to give 0.4 g (50%) of (1R,2S,5R)-methyl 2-((S)-3-(benzyloxycarbonylamino)-2-oxopyrrolidin-1-yl)-5-(isopropyl(methyl)amino)-cyclohexanecarboxylate as a white foam. MS found: (M+H)+=446.3.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[C:8]([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)[N:7]=[C:6]2[C:22](O)=[O:23].Cl.[OH:26][C:27]1[C:36]([O:37][CH3:38])=[CH:35][CH:34]=[C:33]2[C:28]=1[CH2:29][CH2:30][NH:31][CH2:32]2>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[C:8]([C:15]1[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=1)[N:7]=[C:6]2[C:22]([N:31]1[CH2:30][CH2:29][C:28]2[C:33](=[CH:34][CH:35]=[C:36]([O:37][CH3:38])[C:27]=2[OH:26])[CH2:32]1)=[O:23]
Reactant: COc1ccc2c(c1O)CCNC2
Reactant: COc1cc2nc(-c3ccc(F)cc3)nc(C(=O)O)c2cc1OC
Agent: Cl
Product: COc1cc2nc(-c3ccc(F)cc3)nc(C(=O)N3CCc4c(ccc(OC)c4O)C3)c2cc1OC
Yield: 18 %

Procedure:
Reaction of 6,7-dimethoxy-2-(4-fluorophenyl)quinazoline-4-carboxylic acid with 5-hydroxy-6-methoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride gave compound 109 (18.0% yield). 1H NMR (300 MHz, DMSO-d6) δ 2.67 and 2.92 (2t, 2H), 3.45-4.06 (m, 11H), 4.37 and 4.90 (2s, 2H), 6.27-7.11 (m, 3H), 7.36-7.42 (m, 1H), 7.50-7.65 (m, 2H), 8.12-8.20 (m, 1H), 8.29-8.35 (m, 1H), 8.68 and 8.73 (2s, 1H); MS (ESI) m/z 490 ([M+H]+).
Reaction SMILES: Cl[CH:2]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[CH:10][CH:9]=1)[C:3](OC)=[O:4].[NH2:23][C:24]([NH2:26])=[S:25].C(=O)([O-])O.[Na+]>S1(CCCC1)(=O)=O>[NH:23]=[C:24]1[NH:26][C:3](=[O:4])[CH:2]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:10][CH:9]=2)[S:25]1
Reactant: NC(N)=S
Reactant: COC(=O)C(Cl)Cc1ccc(OCCN2CCOCC2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=S1(=O)CCCC1
Product: N=C1NC(=O)C(Cc2ccc(OCCN3CCOCC3)cc2)S1
Yield: 40.1 %

Procedure:
A mixture of 10.0 g methyl 2-chloro-3-[4-(2-morpholinoethyloxy)phenyl]propionate and 4.64 g thiourea is heated in the presence of 100 ml of sulfolane at 120° C. for 4 hours. After cooling, a saturated aqueous solution of sodium hydrogen carbonate is added and the mixture is extracted with ethyl acetate. The extract is washed with water, dried over sodium sulfate and distilled to remove the ethyl acetate, whereupon 4.1 g (40.2%) of 2-imino-5-[4-(2-morpholinoethyloxy)benzyl]thiazolidin-4-one is obtained as crystals. These crystals are recrystallized from ethyl acetate-methanol. Colorless needles, m.p. 189°-190° C.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[NH:17]1[CH:21]=[CH:20][N:19]=[C:18]1[C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1.CCOC(C)=O>CN(C=O)C.O>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:17]2[CH:21]=[CH:20][N:19]=[C:18]2[C:22]2[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: c1cc(-c2ncc[nH]2)ccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(-n2ccnc2-c2ccncc2)cc1
Temperature: 100 °C

Procedure:
1-Fluoro-4-nitro-benzene (80.2 g, 0.57 mmol) is dissolved in DMF (550 mL) and to that solution is added K2CO3 (157.0 g, 1.14 mmol). To that solution is added 4-(1H-imidazol-2-yl)-pyridine (55.0 g, 0.38 mmol) and the reaction is heated at 100° C. for 18 h. The solution is then cooled to RT and EtOAc (1.5 L) and water (2.0 L) are then added and the suspension is vacuum filtered. The resulting solid was then purified by column chromatography (EtOAc) to afford 4-[1-(4-nitro-phenyl)-1H-imidazol-2-yl]-pyridine as a brown solid.
Reaction SMILES: [NH2:1][CH:2]1[CH:11]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:10]2[CH:9]=[C:8]([CH2:19][NH:20][S:21]([CH2:24][CH:25]3[CH2:27][CH2:26]3)(=[O:23])=[O:22])[CH:7]=[CH:6][C:5]=2[CH2:4][CH2:3]1.[O:28]1[CH2:31][C:30](=O)[CH2:29]1.C[Si]([C:37]#[N:38])(C)C>C(OCC)(=O)C>[CH2:12]([CH:11]1[C:10]2[CH:9]=[C:8]([CH2:19][NH:20][S:21]([CH2:24][CH:25]3[CH2:27][CH2:26]3)(=[O:23])=[O:22])[CH:7]=[CH:6][C:5]=2[CH2:4][CH2:3][CH:2]1[NH:1][C:30]1([C:37]#[N:38])[CH2:31][O:28][CH2:29]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: NC1CCc2ccc(CNS(=O)(=O)CC3CC3)cc2C1Cc1ccccc1
Reactant: C[Si](C)(C)C#N
Reactant: O=C1COC1
Solvent: CCOC(C)=O
Product: N#CC1(NC2CCc3ccc(CNS(=O)(=O)CC4CC4)cc3C2Cc2ccccc2)COC1
Temperature: 200 °C

Procedure:
N-((7-Amino-8-benzyl-5,6,7,8-tetrahydronaphthalen-2-yl)methyl)-1-cyclopropylmethanesulfonamide (0.083 g, 0.216 mmol) and 3-oxetanone (0.031 g, 0.432 mmol) were sealed in a vial and heated at 200° C. for 2 minutes. Trimethylsilyl cyanide (0.58 mL, 0.432 mmol) was added, the vial was resealed and the mixture was heated again at 200° C. for 2 minutes. The mixture was diluted with ethyl acetate (40 mL) and washed with 1N NaOH (1×20 mL) and brine (1×20 mL). The organic extract was collected, dried on MgSO4 and evaporated under reduced pressure to give a brown oil. The residue was purified by flash-chromatography on silica gel (100% heptane then up to 60% ethyl acetate in n-heptane). (24.9 mg, 0.048 mmol, 22.3%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([Cl:9])[CH:8]=1)[NH2:5].[I:10]N1C(=O)CCC1=O.C(=O)([O-])O.[Na+]>C(O)(=O)C.C(Cl)Cl>[I:10][C:3]1[C:2]([Cl:1])=[CH:8][C:7]([Cl:9])=[CH:6][C:4]=1[NH2:5]
Reactant: O=C1CCC(=O)N1I
Reactant: Nc1cc(Cl)cc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: Nc1cc(Cl)cc(Cl)c1I
Yield: 45.7 %

Procedure:
Dissolve 3,5-dichloroaniline (10g, 61.5mmol) in 1:1 acetic acid/methylene chloride (200mL). Add N-iodosuccinimide (16.9g, 61.5mmol) as a solid and stir at room temperature in the absence of light for 8 hours. Pour the solution into saturated sodium hydrogen carbonate (200mL) and extract into methylene chloride (100mL). Wash with saturated sodium hydrogen carbonate (200mL), dry (MgSO4) and evaporate the solvent in vacuo. Purify by silica gel chromatography to give the title compound (8.1g, 45%); mp 61°-63° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=1.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH:31]=[C:32]([O:36][CH3:37])[C:33]=1[O:34][CH3:35])[C:28](Cl)=[O:29].C(N(CC)CC)C>CCOCC>[CH3:1][O:2][C:3](=[O:22])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:19])([F:21])[F:20])[CH:13]=1)[C:28](=[O:29])[C:27]1[CH:26]=[C:25]([O:24][CH3:23])[C:33]([O:34][CH3:35])=[C:32]([O:36][CH3:37])[CH:31]=1
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Reactant: COC(=O)CCCCCCCNc1cccc(C(F)(F)F)c1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: COC(=O)CCCCCCCN(C(=O)c1cc(OC)c(OC)c(OC)c1)c1cccc(C(F)(F)F)c1

Procedure:
As described in example 3(b), the reaction is carried out with 6.3 g (20 mmol) of 8-[3-(trifluoromethyl)-phenylamino]-caprylic acid methyl ester, 6.9 g (30 mmol) of 3.4.5-trimethoxybenzoic acid chloride, 2.5 g (25 mmol) of triethylamine and 150 cc. of ether. Reaction time: 24 hours, reaction temperature: 25° C. The crude product is used in the next reaction step without further purification.
Reaction SMILES: N1C(C[OH:8])=CC=CC=1CO.[C:11]([C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1)([CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:13])[CH3:12]>>[C:11]([C:19]1[CH:24]=[C:23]([OH:8])[C:22](=[CH:21][CH:20]=1)[OH:25])([CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:12])[CH3:13]
Reactant: CC(C)(C)CC(C)(C)c1ccc(O)cc1
Reactant: OCc1cccc(CO)n1
Product: CC(C)(C)CC(C)(C)c1ccc(O)c(O)c1
Yield: 54 %

Procedure:
The procedure of Example 9 was repeated, except 0.2% by weight of pyridine-2,6-dimethanol was used as a catalyst and the reaction was carried out at 50°C. Consequently, the conversion of para-tert.-octyl phenol was 6.2%, 4-tert.-octyl pyrocatechol was formed in a yield of 54% based on the converted octyl phenol and the conversion of perpropionic acid was 97.2%.
Reaction SMILES: CI.[NH2:3][C:4]1[C:8]([NH:9][C:10]([NH:12][C:13]2[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:20])=S)=[C:7]([CH3:21])[S:6][C:5]=1[CH3:22]>C(O)C>[ClH:19].[Cl:20][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]([Cl:19])[C:13]=1[NH:12][C:10]1[NH:9][C:8]2=[C:7]([CH3:21])[S:6][C:5]([CH3:22])=[C:4]2[N:3]=1
Reactant: Cc1sc(C)c(NC(=S)Nc2c(Cl)cccc2Cl)c1N
Solvent: CI
Solvent: CCO
Product: Cc1sc(C)c2[nH]c(Nc3c(Cl)cccc3Cl)nc12
Product: Cl
Reaction time: 10 h

Procedure:
0.664 g of methyl iodide was added to a solution of 0.27 g of N-(3-amino-2,5-dimethyl-4-thienyl)-N′-(2,6-dichlorophenyl)thiourea in 30 ml of anhydrous ethanol and the mixture was boiled under reflux conditions for approx. 10 hours. After the solvent had been distilled off on a Rotavapor, the residue was admixed with water and extracted repeatedly with ethyl acetate. The combined organic phases were dried over sodium sulfate and the solvent was distilled off on a Rotavapor. The residue was then purified by column chromatography on silica gel using a mixture of 20 parts by volume of ethyl acetate, 10 parts by volume of n-heptane, 3 parts by volume of glacial acetic acid. After the solvent had been distilled off, the residue was dissolved in a little ethyl acetate, made strongly acidic using a hydrogen chloride gas-saturated diethyl ether solution, and the amorphous precipitate was fully crystallized by heating. M.p. 270–273° C.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.ClC(OCC)=O.[O:17]([C:24]1[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C1COCC1>[Cl:1][C:2]1[C:3]([C:4]([NH:28][C:27]2[CH:26]=[CH:25][C:24]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:30][CH:29]=2)=[O:6])=[CH:7][CH:8]=[CH:9][N:10]=1
Reactant: O=C(O)c1cccnc1Cl
Reactant: Nc1ccc(Oc2ccccc2)cc1
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Product: O=C(Nc1ccc(Oc2ccccc2)cc1)c1cccnc1Cl
Reaction time: 0.08 h

Procedure:
2-Chloronicotinic acid (0.78 g, 5.0 mmol) and TEA (1.6 ml, 10.0 mmol) were added to anhydrous THF (50 ml) under a N2 atmosphere at 0° C. After stirring for 5 min, ethyl chloroformate (0.54 g, 5.0 mmol) was added dropwise and the mixture gradually came to RT over a period of 1 h. 4-Phenoxyaniline (0.83 g, 5.0 mmol) was added and the mixture was stirred for 14 h. The mixture was partitioned between H2O and EtOAc. The aqueous layer was extracted two additional times with EtOAc (50 ml). The combined organic layers were then washed with brine, dried over Na2SO4, and evaporated. The resulting brown oil was used directly in the subsequent reaction without further purification. MS m/z: 325 (M+1). Calc'd for C18H13ClN2O2: 324.07.