Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:42])([F:41])[C:3]1[CH:8]=[CH:7][C:6]([C:9](=O)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:17]([C:19]2[N:20]=[C:21]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[Cl:39])[N:22]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)[C:23]=2[CH2:24][CH3:25])=[O:18])=[CH:5][CH:4]=1.Cl.Cl.[NH2:45][CH2:46][CH2:47][O:48][NH2:49].N1C=CC=CC=1>C(O)C>[NH2:45][CH2:46][CH2:47][O:48][N:49]=[C:9]([C:6]1[CH:7]=[CH:8][C:3]([C:2]([F:41])([F:1])[F:42])=[CH:4][CH:5]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:17]([C:19]1[N:20]=[C:21]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[Cl:39])[N:22]([C:26]2[CH:27]=[CH:28][C:29]([Cl:32])=[CH:30][CH:31]=2)[C:23]=1[CH2:24][CH3:25])=[O:18]
Reactant: CCc1c(C(=O)NCCCCCCC(=O)c2ccc(C(F)(F)F)cc2)nc(-c2ccccc2Cl)n1-c1ccc(Cl)cc1
Reactant: NCCON
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: CCc1c(C(=O)NCCCCCCC(=NOCCN)c2ccc(C(F)(F)F)cc2)nc(-c2ccccc2Cl)n1-c1ccc(Cl)cc1
Yield: 106.8 %

Procedure:
Part C: 2-(2-chlorophenyl)-1-(4-chlorophenyl)-5-ethyl-1H-imidazole-4-carboxylic acid {7-[4-(trifluoromethyl)phenyl]-7-oxo-heptyl}amide (1.15 g, 1.86 mmol) was dissolved in absolute ethanol (10 ml), and O-(2-aminoethyl)hydroxylamine dihydrochloride (0.276 mg, 1.865 mol) and pyridine (0.18 ml) were successively added. The resulting mixture was stirred at reflux temperature for 20 hours. The mixture was allowed to attain room temperature. After removal of the solvent in vacuo, the residue was dissolved in dichloromethane and washed successively with an aqueous KHSO4 solution and brine. The organic layer was subsequently dried over Na2SO4, filtered and concentrated in vacuo to give 2-(2-chlorophenyl)-1-(4-chlorophenyl)-5-ethyl-1 H-imidazole-4-carboxylic acid [7-(2-amino-ethoxyimino)-7-[4-(trifluoromethyl)phenyl] heptyl]-amide (Compound 2) (1.34 g) as a mixture of E/Z stereoisomers. Melting point: 90-95° C. 1H-NMR (400 MHz, CDCl3) δ 1.05 (t, J=7, 3H), 1.34-1.62 (m, 8H), 2.81 (br t, J=7, 2H), 2.93 (q, J=7, 2H), 3.32-3.42 (m, 4H), 4.44-4.50 (m, 2H), 7.11 (d, J=8, 2H), 7.21-7.34 (m, 5H), 7.37 (d, J=8, 1H), 7.49 (br s, 1H), 7.59 (d, J=8, 2H), 7.71 (d, J=8, 2H), 8.65 (br s, 2H).
Reaction SMILES: [NH2:1][C@@H:2]([C:10]([NH:12][C@@H:13]([C:18]([NH:20][C@@H:21]([C:26]([NH:28][C@H:29]([C:37]([NH:39][C@H:40]([C:45]([OH:47])=[O:46])[C@H:41]([CH2:43][CH3:44])[CH3:42])=[O:38])[CH2:30][CH2:31][CH2:32][NH:33][C:34](=[NH:36])[NH2:35])=[O:27])[CH2:22][CH:23]([CH3:25])[CH3:24])=[O:19])[C@H:14]([CH2:16][CH3:17])[CH3:15])=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:9])[NH2:8].N[C@@H:49]([C:54]([OH:56])=[O:55])[C@H](CC)C.N[C@H:58]([C:63]([OH:65])=[O:64])[C@H](CC)C.N[C@H](C(O)=O)CC(C)C.N[C@H](C(O)=O)CCCNC(=N)N>>[NH2:1][C@@H:2]([C:10]([NH:12][C@@H:13]([C:18]([NH:20][C@@H:21]([C:26]([NH:28][C@H:29]([C:37]([NH:39][C@H:40]([C:45]([OH:47])=[O:46])[C@H:41]([CH2:43][CH3:44])[CH3:42])=[O:38])[CH2:30][CH2:31][CH2:32][NH:33][C:34](=[NH:35])[NH2:36])=[O:27])[CH2:22][CH:23]([CH3:24])[CH3:25])=[O:19])[C@H:14]([CH2:16][CH3:17])[CH3:15])=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:8])[NH2:9].[CH3:49][C:54]([OH:56])=[O:55].[CH3:58][C:63]([OH:65])=[O:64]
Reactant: CC[C@H](C)[C@@H](N)C(=O)O
Reactant: CC[C@H](C)[C@H](N)C(=O)O
Agent: CC(C)C[C@H](N)C(=O)O
Agent: CC[C@H](C)[C@H](NC(=O)[C@H](CCCNC(=N)N)NC(=O)[C@@H](CC(C)C)NC(=O)[C@H](NC(=O)[C@H](N)CCCNC(=N)N)[C@@H](C)CC)C(=O)O
Agent: N=C(N)NCCC[C@H](N)C(=O)O
Product: CC(=O)O

Procedure:
On purification of H-D-Arg-Ile-D-Leu-Arg-Ile-OH by column chromatography there was isolated a fraction which, according to amino acid analysis, was H-D-Arg-D-allo-Ile-D-Leu-Arg-Ile-OH. Amorphous substance, amino acid analysis: D-allo-Ile (0.9), Ile (1.06), Leu (1.03), Arg (1.87).
Reaction SMILES: [C:1](OCC1C=CC(N(C)C)=CC=1)(=[O:5])[C:2]([CH3:4])=[CH2:3].C(Cl)(=O)C(C)=C.[CH3:23][N:24]([CH3:34])[C:25]1[CH:33]=[CH:32][C:28]([CH2:29][CH2:30][OH:31])=[CH:27][CH:26]=1.C(N(CC)CC)C.C1(=O)C=CC(=O)C=C1>C1C=CC=CC=1>[C:1]([O:31][CH2:30][CH2:29][C:28]1[CH:32]=[CH:33][C:25]([N:24]([CH3:23])[CH3:34])=[CH:26][CH:27]=1)(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C=C(C)C(=O)OCc1ccc(N(C)C)cc1
Reactant: CN(C)c1ccc(CCO)cc1
Agent: C=C(C)C(=O)Cl
Agent: O=C1C=CC(=O)C=C1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: C=C(C)C(=O)OCCc1ccc(N(C)C)cc1

Procedure:
This monomer was synthesized in a manner analogous to the published method used for the synthesis of 4-(dimethylamino)benzyl methacrylate. Thus, 4.55 g (0.0435 mol) methacryloyl chloride in 4.55 g benzene was added dropwise to a solution of 5.0 g (0.03 mol) 4-dimethylaminophenethyl alcohol, 3.64 g (0.036 mol) triethylamine, and 8.7 g benzene in the presence of p-benzoquinone and CuCl(I) with stirring and cooling, keeping the temperature below 15° C. The reaction mixture was left to stir for one hour in a room temperature water bath (about 25° C.). The solution was filtered to remove triethylamine hydrochloride. The benzene filtrate was washed with water and then with saturated sodium carbonate solution, dried over sodium sulfate anhydrous, filtered, and the benzene removed with the rotary evaporator (water bath 20-25° C.). The monomer was distilled in vacuo in the presence of CuCl(I) and 2,2-diphenyl-1-picrylhydrazyl (DPPH), bp=115-122° C./95-100, μHg. The monomer was recrystallized from petroleum ether, mp=42-43° C. The analysis for nitrogen showed 5.86% N (calc. 6.00). NMR δ(ppm): 1.9 (s, 3, CH2═C(CH3)—); 2.8 (m, 2, —CH2—CH2—C6H4—); 2.9 (s, 6, CH3)2); 4.2-4.3 (m, 2, —(O)C—O—CCH2—CH2—); 5.5, 6.1 (d, s, 2, CH2═C); 6.7, 7.1 (d, d, 4, aromitic H).
Reaction SMILES: Br[CH:2]([CH2:4][CH2:5][CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:3].[CH3:10][O:11][C:12]1[CH:13]=[C:14]([OH:20])[CH:15]=[C:16]([O:18][CH3:19])[CH:17]=1>>[CH3:3][CH:2]([O:20][C:14]1[CH:15]=[C:16]([O:18][CH3:19])[CH:17]=[C:12]([O:11][CH3:10])[CH:13]=1)[CH2:4][CH2:5][CH2:6][CH:7]([CH3:9])[CH3:8]
Reactant: COc1cc(O)cc(OC)c1
Reactant: CC(C)CCCC(C)Br
Product: COc1cc(OC)cc(OC(C)CCCC(C)C)c1

Procedure:
2-bromo-6-methyl-heptane was reacted with 3,5-dimethoxy-phenol to obtain 1-[(1,5-dimethyl-hexyl)-oxy]-3,5-dimethoxy-benzene (boiling point = 135°C/0.4 mmHg);
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)[CH:3]=1.Cl.Cl[C:21]1C=CC(C(O)=O)=C(NC2C=CC(OC)=CC=2)C=1.S(OC)(OC)(=O)=O.ClC1C=CC(C(OC)=O)=C(NC2C=CC(OC)=CC=2)C=1.B(Br)(Br)Br>CO>[CH3:21][C:3]1[C:4]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)=[C:5]([CH:9]=[CH:10][C:2]=1[Cl:1])[C:6]([OH:8])=[O:7]
Reactant: O=C(O)c1ccc(Cl)cc1Nc1ccc(O)cc1
Reactant: COc1ccc(Nc2cc(Cl)ccc2C(=O)O)cc1
Agent: BrB(Br)Br
Agent: COC(=O)c1ccc(Cl)cc1Nc1ccc(OC)cc1
Agent: Cl
Solvent: CO
Solvent: COS(=O)(=O)OC
Product: Cc1c(Cl)ccc(C(=O)O)c1Nc1ccc(O)cc1

Procedure:
[I; R=4-Cl, R' and R"=H, Alk=CH3, OH at 4-position] is obtainable by esterification of 4-chloro-2-(4-hydroxyphenylamino)benzoic acid with methanol and hydrochloric acid; or by esterification of 4-chloro-2-(4-methoxyphenylamino)benzoic acid with dimethyl sulfate, followed by de-etherification of the resulting methyl 4-chloro-2-(4-methoxyphenylamino)benzoate with boron tribromide.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([N:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)(=[O:17])=[O:16])[C:5]([Cl:23])=[CH:4][N:3]=1.[CH3:24][N:25]1[CH2:30][CH2:29][N:28]([CH2:31][C:32]2[CH:38]=[CH:37][C:35]([NH2:36])=[CH:34][CH:33]=2)[CH2:27][CH2:26]1>C(Cl)Cl.CO>[Cl:23][C:5]1[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([N:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)(=[O:17])=[O:16])=[N:7][C:2]([NH:36][C:35]2[CH:34]=[CH:33][C:32]([CH2:31][N:28]3[CH2:27][CH2:26][N:25]([CH3:24])[CH2:30][CH2:29]3)=[CH:38][CH:37]=2)=[N:3][CH:4]=1
Reactant: O=S(=O)(c1ccccc1Nc1nc(Cl)ncc1Cl)N1CCCC1
Reactant: CN1CCN(Cc2ccc(N)cc2)CC1
Solvent: ClCCl
Solvent: CO
Product: CN1CCN(Cc2ccc(Nc3ncc(Cl)c(Nc4ccccc4S(=O)(=O)N4CCCC4)n3)cc2)CC1
Yield: 50 %

Procedure:
The title compound was prepared according to synthesis procedure B described above from 2,5-dichloro-N-(2-(pyrrolidin-1-ylsulfonyl)phenyl)pyrimidin-4-amine and 4-((4-methylpiperazin-1-yl)methyl)aniline in 50% yield (yellow solid) after flash chromatography eluent (CH2Cl2/CH3OH 99:1 gradually increasing to 95:5). 1H NMR (400 MHz, CDCl3): δ 9.58 (s, 1H), 8.61 (d, 1H, J=8.2 Hz), 8.18 (s, 1H), 7.96 (d, 1H, J=7.9 Hz), 7.58 (t, 1H, J=7.7 Hz), 7.51 (d, 2H, J=8.2 Hz), 7.30 (d, 2H, J=8.2 Hz), 7.26 (m, 1H), 3.53 (s, 2H), 3.30 (m, 4H), 2.53 (bs, 8H), 2.34 (s, 3H), 1.84 (m, 4H); MS (ESI): 542.20 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:7]([O:8][CH3:9])=[C:6]([CH2:10][O:11][CH3:12])[N:5]=[CH:4][N:3]=1.[NH2:13][CH:14]1[CH2:18][S:17][CH:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:15]1.C1(C2CC(=O)CS2)C=CC=CC=1.C(N(CC)CC)C>O>[CH3:9][O:8][C:7]1[C:2]([NH:13][CH:14]2[CH2:18][S:17][CH:16]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:15]2)=[N:3][CH:4]=[N:5][C:6]=1[CH2:10][O:11][CH3:12]
Reactant: NC1CSC(c2ccccc2)C1
Reactant: COCc1ncnc(Cl)c1OC
Agent: O=C1CSC(c2ccccc2)C1
Solvent: O
Solvent: CCN(CC)CC
Product: COCc1ncnc(NC2CSC(c3ccccc3)C2)c1OC
Temperature: 85 °C

Procedure:
1.6 g (8.5 mmol) of 4-chloro-5-methoxy-6-methoxymethylpyrimidine, 1.5 g (8.5 mmol) of 4-amino-2-phenyltetrahydrothiophene (prepared from 2-phenyl-4-oxo-tetrahydrothiophene (cf. D. N. Reinhard, W. P. Trompenaars, I. Geevers, Synthesis 1978, 368) analogously to the route given in Example B) and 2 ml (14 mmol) of triethylamine were heated for 24 hours at 85° C. After cooling, the mixture was diluted with water and extracted with ether, and the organic phase was washed with saturated NaCl solution. After drying and concentrating, the residue was purified by column chromatography using petroleum ether/ethyl acetate (9:1). This gave 1.18 g (42% of theory) of a pale yellow syrup.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[C:10]([S:18][CH3:19])=[N:11][C:12]([CH3:17])=[CH:13][C:14]=1[S:15][CH3:16].[CH2:20]1C[O:23][CH2:22][CH2:21]1>O>[CH3:19][S:18][C:10]1[C:9]([NH:8][C:22](=[O:23])[CH:21]=[CH2:20])=[C:14]([S:15][CH3:16])[CH:13]=[C:12]([CH3:17])[N:11]=1
Reactant: CSc1cc(C)nc(SC)c1N
Reactant: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: C=CC(=O)Nc1c(SC)cc(C)nc1SC
Reaction time: 14 h
Yield: 44 %

Procedure:
Triethylamine (277 mg, 2.75 mmol) was added to a solution of 3-amino-2,4-bis(methylthio)-6-methylpyridine (500 mg, 2.50 mmol) in THF (10 ml), then a solution of acryloyl acid chloride (225 mg, 2.50 mmol) in THF (3 ml) was gradually dropped thereinto and the mixture was stirred for 14 hours. The reaction solution was diluted with water and extracted with ethyl acetate. The organic layer was washed with a sodium chloride solution and dried over anhydrous sodium sulfate, the solvent was evaporated therefrom and the resulting crystals were recrystallized from chloroform-ethyl acetate-hexane to provide 276 mg (yield 44%) of N-[2,4-bis(methylthio)-6-methyl-3-pyridyl]acrylamide as colorless powdery crystals.
Reaction SMILES: Br[C:2]1[CH:8]2[CH2:9][CH:5]([CH2:6][CH2:7]2)[C:4](=[O:10])[CH:3]=1.[CH3:11][O:12][CH2:13][CH2:14][O:15][CH2:16][C:17]1[N:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:18]=1[C:19]([OH:21])=[O:20].CCN(C(C)C)C(C)C>ClC1C=CC=CC=1.[Cl-].[Cl-].[Zn+2]>[CH3:11][O:12][CH2:13][CH2:14][O:15][CH2:16][C:17]1[C:18]([C:19]([O:21][C:2]2[CH:8]3[CH2:9][CH:5]([CH2:6][CH2:7]3)[C:4](=[O:10])[CH:3]=2)=[O:20])=[CH:22][CH:23]=[C:24]([C:26]([F:29])([F:27])[F:28])[N:25]=1
Reactant: O=C1C=C(Br)C2CCC1C2
Reactant: COCCOCc1nc(C(F)(F)F)ccc1C(=O)O
Agent: [Cl-]
Agent: [Zn+2]
Solvent: Clc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: COCCOCc1nc(C(F)(F)F)ccc1C(=O)OC1=CC(=O)C2CCC1C2
Temperature: 25 °C

Procedure:
A mixture of 27 g of a 6.2% solution of 4-bromobicyclo[3.2.1]oct-3-en-2-one (Preparation Example P1) in chlorobenzene, 110 mg of ZnCl2, 2.34 g of 2-methoxyethoxymethyl-6-trifluoromethylnicotinic acid and 1.2 g of Hünig's base is stirred at room temperature under a nitrogen atmosphere until a dark-brown solution is formed. The reaction mixture is then maintained under moderate reflux for 19 hours in an oil bath, with stirring. The mixture is then divided into 2 portions. To one portion there are added a further 1.12 g of 2-methoxyethoxymethyl-6-trifluoromethylnicotinic acid, 0.06 g of ZnCl2 and 0.6 g of Hünig's base. The reaction mixture is then maintained under moderate reflux for 12 hours in an oil bath, with stirring. The solution is then washed twice with 0.1M hydrochloric acid (20 ml each time) and twice with water (20 ml each time). After drying the organic solution using magnesium sulfate and concentrating in vacuo, 3.9 g of 4-(2-methoxyethoxymethyl-6-trifluoromethyl-pyridin-3-ylcarbonyloxy)-bicyclo[3.2.1]oct-3-en-2-one are obtained in the form of a brown oil.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([Cl:9])=[C:4]([Cl:10])[N:3]=1.[CH:11]1([C:14]2[NH:18][N:17]=[C:16]([NH2:19])[CH:15]=2)[CH2:13][CH2:12]1.C(N(CC)CC)C>CN1C(=O)CCC1>[Cl:8][C:7]1[C:2]([NH:19][C:16]2[CH:15]=[C:14]([CH:11]3[CH2:13][CH2:12]3)[NH:18][N:17]=2)=[N:3][C:4]([Cl:10])=[C:5]([Cl:9])[CH:6]=1
Reactant: Nc1cc(C2CC2)[nH]n1
Reactant: Clc1cc(Cl)c(Cl)nc1Cl
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: Clc1cc(Cl)c(Nc2cc(C3CC3)[nH]n2)nc1Cl
Temperature: 25 °C
Yield: 12.8 %

Procedure:
A solution of 2,3,5,6-tetrachloropyridine (0.20 g, 0.9 mmol), 5-cyclopropyl-1H-pyrazol-3-amine (0.20 g, 1.8 mmol), and triethylamine (0.10 g, 1.4 mmol) in NMP (2 ml) was heated in a microwave at 200° C. for 30 min. The reaction was cooled to 25° C., quenched with water (10 ml), and extracted with MTBE (4×30 ml). The combined organic fractions were then dried, filtered, and concentrated. The resulting solid was purified by column chromatography (DCM-MeOH=50:1) to give the title compound (0.035 g, 12%). MS: Calcd.: 303. Found: [M+H]+ 303.
Reaction SMILES: Cl.[CH3:2][N:3]1[C:8]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][O:18][C:19]3[CH:24]=[C:23]([N+:25]([O-:27])=[O:26])[CH:22]=[CH:21][C:20]=3[OH:28])[CH2:11][CH2:10]2)=[CH:7][C:6](=[O:29])[N:5]([CH3:30])[C:4]1=[O:31].[CH2:32](Br)[CH:33]=[CH2:34].C(=O)([O-])[O-].[K+].[K+].O>CC(C)=O>[CH3:2][N:3]1[C:8]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][O:18][C:19]3[CH:24]=[C:23]([N+:25]([O-:27])=[O:26])[CH:22]=[CH:21][C:20]=3[O:28][CH2:34][CH:33]=[CH2:32])[CH2:11][CH2:10]2)=[CH:7][C:6](=[O:29])[N:5]([CH3:30])[C:4]1=[O:31]
Reactant: C=CCBr
Reactant: Cn1c(N2CCN(CCCOc3cc([N+](=O)[O-])ccc3O)CC2)cc(=O)n(C)c1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: C=CCOc1ccc([N+](=O)[O-])cc1OCCCN1CCN(c2cc(=O)n(C)c(=O)n2C)CC1
Yield: 77.4 %

Procedure:
1 g of 1,3-dimethyl-6-{4-[3-(2-hydroxy-5-nitrophenyloxy)propyl]piperazin-1-yl}-2,4(1H,3H)-pyrimidinedione (Compound 145--free form), 0.31 g of allyl bromide and 0.36 g of potassium carbonate were suspended in 10 ml of dry acetone and heated under reflux for 5 hours. The reaction mixture was poured into 60 ml of water and then extracted three times with 30 ml portions of chloroform. The extract was washed first with a 0.5 N aqueous solution of sodium hydroxide and then with water. The chloroform solution was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by chromatography on a silica gel column (eluent: chloroform/methanol=20/1, by volume). The resulting oily substance was crystallized from ethanol, thereby obtaining 0.78 g of 1,3-dimethyl-6-{4-[3-(2-allyloxy-5-nitrophenyloxy)propyl]piperazin-1-yl}-2,4(1H,3H)-pyrimidinedione as crystals.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1.[CH3:12][N:13]=[C:14]=[S:15]>C(O)C>[CH3:12][NH:13][C:14]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1)=[S:15]
Reactant: CN=C=S
Reactant: NCCCCc1ccccn1
Solvent: CCO
Product: CNC(=S)NCCCCc1ccccn1
Yield: 67.3 %

Procedure:
The reaction of 2-(4-aminobutyl)pyridine (3.0 g) and methyl isothiocyanate (1.6 g) in ethanol (25 ml) for 0.5 hours followed by chromatography of the product on silica and elution with ethyl acetate affords N-methyl-N'-(4-(2-pyridyl)butyl)thiourea (3.0 g) as a colourless oil.
Reaction SMILES: [CH:1]([Si:4]([CH:20]([CH3:22])[CH3:21])([CH:17]([CH3:19])[CH3:18])[O:5][CH2:6][CH:7]1[CH2:12][CH2:11][CH:10]([CH2:13][C:14](O)=[O:15])[CH2:9][CH2:8]1)([CH3:3])[CH3:2].C(Cl)(=O)C(C)(C)C.C(N(CC)CC)C.[Cl-].[Li+].[C:39]1([CH2:45][CH:46]2[CH2:50][O:49][C:48](=[O:51])[NH:47]2)[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>>[C:39]1([CH2:45][CH:46]2[CH2:50][O:49][C:48](=[O:51])[N:47]2[C:14](=[O:15])[CH2:13][CH:10]2[CH2:11][CH2:12][CH:7]([CH2:6][O:5][Si:4]([CH:1]([CH3:3])[CH3:2])([CH:17]([CH3:19])[CH3:18])[CH:20]([CH3:21])[CH3:22])[CH2:8][CH2:9]2)[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1
Reactant: CC(C)[Si](OCC1CCC(CC(=O)O)CC1)(C(C)C)C(C)C
Reactant: O=C1NC(Cc2ccccc2)CO1
Agent: CC(C)(C)C(=O)Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: CCN(CC)CC
Product: CC(C)[Si](OCC1CCC(CC(=O)N2C(=O)OCC2Cc2ccccc2)CC1)(C(C)C)C(C)C

Procedure:
The acid (8.5 g, 25.9 mmol) from step F was treated with 3.14 g (3.2 mL, 26 mmol) of pivaloyl chloride and 10.5 g (14.5 mL, 26 mmol) of triethylamine followed by 1.32 g (28 mmol) of lithium chloride and 4.60 g (26 mmol) of 4-phenylmethyl-2-oxazolidinone according to the procedure of G.-J. Ho and D. J. Mathre, J. Org. Chem. 1995, 60, 2271–2273 to provide, after purification by flash chromatography on silica gel (10% ethyl acetate/hexane), 11.5 g (91%) of the title compound. 1H NMR (500 MHz, CDCl3) δ 7.32 (m, 2H), 7.27 (m, 1H), 7.23 (d, 2H, J=6.9 Hz), 5.31 (m, 1H),
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:6]2[C:7]([CH2:10][C:11]([OH:13])=[O:12])=[CH:8][O:9][C:5]=2[CH:4]=1.OS(O)(=O)=O.[CH3:21]O>>[CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:6]2[C:7]([CH2:10][C:11]([O:13][CH3:21])=[O:12])=[CH:8][O:9][C:5]=2[CH:4]=1
Reactant: COc1ccc2c(CC(=O)O)coc2c1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1coc2cc(OC)ccc12
Yield: 98 %

Procedure:
A mixture of (6-methoxy-benzofuran-3-yl)-acetic acid (2 g, 9.7 mmol) and H2SO4 (0.3 mL) in methanol (40 mL) was refluxed for 8 h and then concentrated. An aqueous NaHCO3 solution was added, followed by extraction with CH2Cl2. The combined organic layers were dried over anhydrous MgSO4 and evaporated to give a brown oil, which was purified on a silica gel column eluting with EtOAc/hexane (1:10) to give methyl 2-(6-methoxybenzofuran-3-yl)acetate (2.1 g, 98%)
Reaction SMILES: [CH2:1]([O:8][C@@H:9]([C@H:12]1[CH2:16][O:15][C:14]2([CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[O:13]1)[CH:10]=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22]1([Mg]Cl)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[Cl-].[NH4+]>C(OCC)C.O1CCCC1>[CH2:1]([O:8][C@@H:9]([C@H:12]1[CH2:16][O:15][C:14]2([CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[O:13]1)[CH:10]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[OH:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cl[Mg]c1ccccc1
Reactant: O=C[C@@H](OCc1ccccc1)[C@H]1COC2(CCCCC2)O1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: OC(c1ccccc1)[C@@H](OCc1ccccc1)[C@H]1COC2(CCCCC2)O1
Temperature: -5 °C
Reaction time: 2 h

Procedure:
A solution of 4.30 g (0.015 mmol) of α(S)-benzyloxy-1,4-dioxaspiro[4,5]decane-2(R)-acetaldehyde in 50 ml of anhydrous diethyl ether was cooled to -8° C. and 15 ml of a 2M solution of phenylmagnesium chloride in tetrahydrofuran were added dropwise over a period of 1 hour. The mixture was stirred at -5° C. for 2 hours, then allowed to warm to room temperature and poured into 50 ml of 10% ammonium chloride solution. The mixture was extracted twice with 100 ml of ethyl acetate each time. The ethyl acetate extracts were dried over anhydrous magnesium sulphate and evaporated. The residue was subjected to flash chromatography on silica gel using 5% methanol in dichloromethane for the elution. There were obtained 2.47 g of β(R)-benzyloxy-α(RS)-phenyl-1,4-dioxaspiro[4,5]decane-2(R)-ethanol in the form of a colourless gum; MS (C.I.): m/e 369 [M+H]+.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([O:33][CH:34]([CH2:36][CH2:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH3:35])[CH:12]=[C:13]2[C:18]=1[CH:17]([C:19](OC1C=CC([N+]([O-])=O)=CC=1)=[O:20])[CH2:16][C:15]([CH3:32])([CH3:31])[CH2:14]2)C1C=CC=CC=1.[NH2:45][C:46]([NH2:48])=[O:47].[H-].[Na+]>CS(C)=O>[OH:8][C:9]1[CH:10]=[C:11]([O:33][CH:34]([CH2:36][CH2:37][CH2:38][C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH3:35])[CH:12]=[C:13]2[C:18]=1[CH:17]([C:19]([NH:45][C:46]([NH2:48])=[O:47])=[O:20])[CH2:16][C:15]([CH3:32])([CH3:31])[CH2:14]2
Reactant: NC(N)=O
Reactant: CC(CCCc1ccccc1)Oc1cc2c(c(OCc3ccccc3)c1)C(C(=O)Oc1ccc([N+](=O)[O-])cc1)CC(C)(C)C2
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(CCCc1ccccc1)Oc1cc(O)c2c(c1)CC(C)(C)CC2C(=O)NC(N)=O

Procedure:
By reacting 1.2 g. (2 mmole) p-nitrophenyl 8-benzyloxy-3,3-dimethyl-6-(5-phenyl-2-pentyloxy)tetralin-1-carboxylate, 0.3 g. (5 mmole) urea and 0.248 g. (10 mmole) sodium hydride in 12 ml. dimethylsulfoxide at room temperature for one hour and isolation of product by the method of Example 89, Part B and removal of benzyl group by hydrogenolysis by the procedure of Example 89, Part C affords the pure title compound in 36% overall yield. 1H-NMR (CDCl3) ppm (delta): 0.77 (s, 3H), 1.1 (m, 8H), 1.7 (m, 4H), 2.5 (m, 4H), 3.6 (m, 1H), 4.16 (m, 1H), 5.7 (s, 1H), 6.1 (s, 2H), 7.1 (s, 5H), 8.2 (s, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2([CH3:13])[CH3:12].C(Cl)Cl.Cl.[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1>C(N(CC)CC)C>[CH3:12][C:5]1([CH3:13])[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([NH:1][C:18]([C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)=[O:25])[CH:3]=2)[NH:7][C:6]1=[O:11]
Reactant: O=C(Cl)c1ccncc1
Reactant: CC1(C)C(=O)Nc2ccc(N)cc21
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(C)C(=O)Nc2ccc(NC(=O)c3ccncc3)cc21

Procedure:
A suspension of 5.0 g. (0.028 mol) 5-amino-3,3-dimethylindolin-2-one in 100 ml. methylene chloride containing 14 ml. triethylamine is mixed, while cooling, with 7.0 g. (0.04 mol) isonicotinic acid chloride hydrochloride. Subsequently, the reaction mixture is evaporated and the residue is digested with water, filtered with suction and recrystallised from ethanol. Yield: 5.8 g. (73% of theory); m.p.>300° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10]Br)=[C:6]([F:12])[C:5]=1[F:13].[Br:15][C:16]1[N:20]=[C:19]([CH2:21][CH2:22][CH2:23][CH3:24])[NH:18][C:17]=1[CH:25]=[O:26].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:18]2[C:17]([CH:25]=[O:26])=[C:16]([Br:15])[N:20]=[C:19]2[CH2:21][CH2:22][CH2:23][CH3:24])=[C:6]([F:12])[C:5]=1[F:13]
Reactant: COC(=O)c1ccc(CBr)c(F)c1F
Reactant: CCCCc1nc(Br)c(C=O)[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCc1nc(Br)c(C=O)n1Cc1ccc(C(=O)OC)c(F)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.9 %

Procedure:
4-bromomethyl-2,3-difluorobenzoic acid methyl ester (3.5 g, 13.2 mmol), 5-bromo-2-butyl-3H-imidazole-4-carbaldehyde (3.1 g, 13.2 mmol) and potassium carbonate (1.8 g, 13.2 mmol) were combined and dissolved in DMF (20 mL, 300 mmol). The mixture was stirred at room temperature overnight. The mixture was then diluted with water and extracted with EtOAc. The organic layer was washed with saturated aqueous NaCl, dried over MgSO4, filtered, and concentrated. The crude reaction was purified by silica gel chromatography (0-50% EtOAc:hexanes) to obtain 4.16 g of intermediate (8a) as a yellow solid. MS m/z: [M+H+] calcd for C17H7BrF2N2O3, 416.23; found 417.1. 1H-NMR (CDCl3): 9.68 (1H, s), 7.64 (1H, t), 6.55 (1H, t), 5.64 (2H, s), 3.95 (3H, s), 2.63 (2H, t), 1.69 (2H, m), 1.36 (2H, m) 0.90 (3H, t).