Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([O:14][CH2:15][CH2:16][CH:17]([C:23](OCC)=[O:24])[C:18](OCC)=[O:19])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>CCOCC>[CH2:7]([O:14][CH2:15][CH2:16][CH:17]([CH2:18][OH:19])[CH2:23][OH:24])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCOC(=O)C(CCOCc1ccccc1)C(=O)OCC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: OCC(CO)CCOCc1ccccc1
Temperature: 25 °C
Yield: 87.4 %

Procedure:
To a cooled, stirred suspension of lithium aluminium hydride (103 g, 2.7 mol) in dry ether (2.51) under nitrogen was added ethyl 4-benzyloxy-2-ethoxycarbonyl-butanoate (362 g, 1.23 mol) over a period of 3 hours. On completion of the addition, the reaction mixture was allowed to warm to room temperature, and then heated under reflux for 1 hour. It was then re-cooled and the excess lithium aluminium hydride destroyed by dropwise addition of water (100 ml), 2M sodium hydroxide (100 ml) and water (300 ml). The reaction mixture was filtered, and the filter cake washed well with chloroform. The filtrate was dried (MgSO4), filtered, and evaporated to give 4-benzyloxy-2-hydroxymethylbutan-1-ol as a clear oil (226 g, 87%). δH (CDCl3) 1.35-2.05 (3H, m, CHCH2CH2), 3.30-3.80 (8H, m, 3×CH2O, 2×OH), 4.42 (2H, s, OCH2Ph) 7.26 (5H, s, Ar).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:9])=[C:6]([CH3:8])[CH:7]=1.[Li]CCCC.[B:15](OC(C)C)([O:20]C(C)C)[O:16]C(C)C>C1COCC1>[F:9][C:5]1[CH:4]=[CH:3][C:2]([B:15]([OH:20])[OH:16])=[CH:7][C:6]=1[CH3:8]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Cc1cc(Br)ccc1F
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1cc(B(O)O)ccc1F
Temperature: -78 °C
Reaction time: 0.67 h
Yield: 84 %

Procedure:
5-Bromo-2-fluorotoluene (6 g, 31.7 mmol) was dissolved in dry THF (50 mL) and cooled to −78 C. under N2. n-BuLi (14 mL, 2.5M solution in THF) was added slowly using a dry syringe. Cloudiness appeared. The reaction was stirred for 40 minutes at −78° C. Triisopropyl borate (22 mL, 95 mmol) was slowly added while stirring. The reaction was allowed to warm to room temperature. Stirring continued for an additional 2 hours. A pale yellow, cloudy solution formed. (TLC (1:2 ethyl acetate/hexanes)) indicated disappearance of the starting material. The reaction was quenched by adding 10% aqueous NaOH (200 mL). After stirring for 45 minutes, 10% citric acid solution (300 mL) was added until, pH ˜5.0. The product was extracted with ethyl acetate (500 mL). The organic phase was washed with brine and dried over MgSO4, and filtered. The filtrate was concentrated under reduced pressure to provide an off white solid (yield: 4.1 g, 84%).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH:12]([CH3:14])[CH3:13])=[CH:5][C:6]=1[C:7]([O:9]CC)=O.Cl[C:16]1[N:21]=[CH:20][C:19]([C:22]([O:24]C)=[O:23])=[CH:18][CH:17]=1>>[CH3:14][CH:12]([C:4]1[S:3][C:2]2[N:1]=[C:16]3[CH:17]=[CH:18][C:19]([C:22]([OH:24])=[O:23])=[CH:20][N:21]3[C:7](=[O:9])[C:6]=2[CH:5]=1)[CH3:13]
Reactant: CCOC(=O)c1cc(C(C)C)sc1N
Reactant: COC(=O)c1ccc(Cl)nc1
Product: CC(C)c1cc2c(=O)n3cc(C(=O)O)ccc3nc2s1
Temperature: 142 °C
Yield: 20.8 %

Procedure:
A mixture of 21.33 g (0.1 mol) of 2-amino-5-(1-methylethyl)-3-thiophenecarboxylic acid, ethyl ester (Tetrahedron, Vol. 33, pages 2089-2092, 1977) and 17.16 g (0.1 mol) of 6-chloro-3-pyridinecarboxylic acid, methyl ester (Alfred Bader Chemical Company) is heated in a wax bath at 178°-182° C. for one hundred eighty-seven minutes and then at 182°-205° C. for ninety minutes under nitrogen. The distillate is collected in a Dean-Stark Trap attached to the reaction flask. The mixture is cooled, dissolved in methanol, cooled and 16.2 g of a mixture of 2-(1-methylethyl)-4-oxo-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidine-7-carboxylic acid, methyl ester and the ring-opened diester, 6-[[3-(ethoxycarbonyl)-5-(1-methylethyl)-2-thienyl]amino]-3-pyridinecarboxylic acid, methyl ester, is collected; mp 112°-114° C. A suspension of 11 g of the previous mixture in 250 ml of concentrated hydrochloric acid and 250 ml of water is refluxed in a wax bath at 142° C. for twenty-two hours under nitrogen. The suspension is cooled to room temperature, filtered and the precipitate washed with 300 ml of water and dried to give 6.0 g of 2-(1-methylethyl)-4-oxo-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidine-7-carboxylic acid; mp 264°-266° C. after recrystallization from ethanol.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[Br:9][C:10]1[CH:15]=[C:14]([Si:16]([CH2:21][CH3:22])([CH2:19][CH3:20])[CH2:17][CH3:18])[C:13]([F:23])=[CH:12][N:11]=1.[F:24][CH:25]([F:31])[C:26](OCC)=[O:27]>C1COCC1>[Br:9][C:10]1[N:11]=[C:12]([C:26](=[O:27])[CH:25]([F:31])[F:24])[C:13]([F:23])=[C:14]([Si:16]([CH2:21][CH3:22])([CH2:19][CH3:20])[CH2:17][CH3:18])[CH:15]=1
Reactant: CCOC(=O)C(F)F
Reactant: CC[Si](CC)(CC)c1cc(Br)ncc1F
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC[Si](CC)(CC)c1cc(Br)nc(C(=O)C(F)F)c1F
Reaction time: 3 h
Yield: 75 %

Procedure:
To a freshly prepared solution of LDA (6.25 mmol) in THF (5 ml) was added dropwise a solution of 2-bromo-5-fluoro-4-triethylsilanylpyridine (1.6 g, 5.51 mmol) in THF (12 ml) at −78° C. Stirring was continued at −78° C. for 3 hours. Ethyl 2,2-difluoroacetate (0.58 ml, 5.51 mmol) was added dropwise and the solution was stirred at −78° C. for 3 hours. The reaction mixture was quenched with sat. ammonium chloride solution (20 ml) and ethyl acetate was added. The organic phase was washed with brine, dried over sodium sulfate, filtered and evaporated. The crude brown oil (2.11 g) was chromatographed over silica gel (cyclohexane/ethyl acetate) to give the title compound. 1.53 g (75% yield, mixture of ketone and hydrate form).
Reaction SMILES: [C:1]([C:3]1[C:4]([C:17]([F:20])([F:19])[F:18])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13](=[NH:16])[NH:14][OH:15])[CH:7]=[CH:6]2)#[N:2].[Cl:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][C:30]=1[Cl:31])[C:25](O)=O>>[Cl:21][C:22]1[CH:23]=[C:24]([C:25]2[O:15][N:14]=[C:13]([CH2:12][N:8]3[C:9]4[C:5](=[C:4]([C:17]([F:19])([F:20])[F:18])[C:3]([C:1]#[N:2])=[CH:11][CH:10]=4)[CH:6]=[CH:7]3)[N:16]=2)[CH:28]=[CH:29][C:30]=1[Cl:31]
Reactant: O=C(O)c1ccc(Cl)c(Cl)c1
Reactant: N#Cc1ccc2c(ccn2CC(=N)NO)c1C(F)(F)F
Product: N#Cc1ccc2c(ccn2Cc2noc(-c3ccc(Cl)c(Cl)c3)n2)c1C(F)(F)F

Procedure:
Synthesized as described in Example 72 from 2-[5-cyano-4-(trifluoromethyl)-1H-indol-1-yl]-N-hydroxyethanimidamide and 3,4-dichlorobenzoic acid: MS (ESI): m/z 437 (M+1).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([OH:6])=O.[NH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:12]=1[C:13]([NH:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=3)=[C:24]([Cl:36])[CH:23]=1)=[N:14][CH:15]=[N:16]2>>[Cl:36][C:24]1[CH:23]=[C:22]([NH:21][C:13]2[C:12]3[C:17](=[CH:18][CH:19]=[CH:20][C:11]=3[O:10][CH2:9][CH2:8][NH:7][C:4](=[O:6])[CH2:3][O:2][CH3:1])[N:16]=[CH:15][N:14]=2)[CH:27]=[CH:26][C:25]=1[O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=1
Reactant: NCCOc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Reactant: COCC(=O)O
Product: COCC(=O)NCCOc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Yield: 50 %

Procedure:
The procedure described in Example 1 was repeated using methoxyacetic acid and 5-(2-aminoethoxy)-N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]quinazolin-4-amine (obtained as described in Example 2.6, preparation of starting materials) to give the title compound in 50% yield; NMR spectrum (DMSO-d6) 3.20 (s, 3H), 3.68 (m, 2H), 3.73 (s, 2H), 4.38 (t, 2H), 5.29 (s, 2H), 7.14 (d, 1H), 7.21 (d, 1H), 7.34 (m, 2H), 7.55 (t, 1H), 7.71 (t, 1H), 7.86 (t, 1H), 7.97 (d, 1H), 8.17 (m, 1H), 8.44 (s, 1H), 8.58 (d, 1H), 9.81 (s, 1H); Mass Spectrum MH+ 494.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=O.[Br-].[C:9]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:11])=[O:10]>C1COCC1>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=[CH:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][C:9]([OH:11])=[O:10]
Reactant: O=Cc1ccco1
Reactant: O=C(O)CCCCCCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: O=C(O)CCCCCCCCC=Cc1ccco1
Yield: 58.9 %

Procedure:
This compound was synthesized from 2-furaldehyde (1.92 g, 20 mmol) and 9-carboxynonyltriphenylphosphonium bromide (10.27 g, 20 mmol) in THF (100 mL) by a Wittig reaction. Crystallization (petroleum ether) afforded the product (2.95 g, 59%) as white crystals (mp 45-46° C.); IR: 3450-2500 cm-1 ; 1H-NMR: 1.33 (m, 8H), 1.46 (m, 2H), 1.65 (m, 2H), 2.34 (t, 2H), 2.45 (m, 2H), 5.55 (m, 1H), 6.18 (d, 1H), 6.25 (d, 1H), 6.38 (d, 1H), 7.38 (s, 1H), 9.80 (bs, 1H). Anal. Calcd. for C15H22O3 :C, 71.97, H, 8.86%; Found: C, 71.93, H, 8.87%. Z:E=43:57.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.CO[C:11](=[O:29])[C:12]1[CH:20]=[CH:19][C:15]([C:16]([NH2:18])=O)=[C:14]([C:21]2[C:22]([CH3:28])=[N:23][N:24]([CH3:27])[C:25]=2[CH3:26])[CH:13]=1.CN(C[N:34]1[C:38]2=[N:39][C:40]([N:43]3[CH2:48][CH2:47][CH:46]([N:49]([CH3:51])[CH3:50])[CH2:45][CH2:44]3)=[CH:41][CH:42]=[C:37]2[N:36]=[CH:35]1)C>>[CH3:50][N:49]([CH3:51])[CH:46]1[CH2:47][CH2:48][N:43]([C:40]2[N:39]=[C:38]3[NH:34][C:35]([C:11]([C:12]4[CH:20]=[CH:19][C:15]([C:16]#[N:18])=[C:14]([C:21]5[C:22]([CH3:28])=[N:23][N:24]([CH3:27])[C:25]=5[CH3:26])[CH:13]=4)=[O:29])=[N:36][C:37]3=[CH:42][CH:41]=2)[CH2:44][CH2:45]1
Reactant: CN(C)Cn1cnc2ccc(N3CCC(N(C)C)CC3)nc21
Reactant: COC(=O)c1ccc(C(N)=O)c(-c2c(C)nn(C)c2C)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Product: Cc1nn(C)c(C)c1-c1cc(C(=O)c2nc3ccc(N4CCC(N(C)C)CC4)nc3[nH]2)ccc1C#N

Procedure:
Following General procedure P (LDA metallation, ketone formation and in situ deprotection) using 3-(1,3,5-Trimethyl-1H-pyrazol-4-yl)-terephthalamic acid methyl ester and [1-(3-dimethylaminomethyl-3H-imidazo[4,5-b]pyridin-5-yl)-piperidin-4-yl]-dimethyl-amine to give 4-[5-(4-dimethylamino-piperidin-1-yl)-3H-imidazo[4,5-b]pyridine-2-carbonyl]-2-(1,3,5-trimethyl-1H-pyrazol-4-yl)-benzonitrile. (84%). HRMS m/z 501.2721 (M+H)+.
Reaction SMILES: [CH2:1]([N:4]=[C:5]=[O:6])[CH2:2][CH3:3].[CH:7]1([CH2:13][NH2:14])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1>C1C=CC=CC=1>[CH:7]1([CH2:13][NH:14][C:5]([NH:4][CH2:1][CH2:2][CH3:3])=[O:6])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: NCC1CCCCC1
Reactant: CCCN=C=O
Solvent: c1ccccc1
Product: CCCNC(=O)NCC1CCCCC1
Reaction time: 0.25 h
Yield: 95.7 %

Procedure:
Propyl isocyanate (Aldrich, 42 mL, 0.442 mol) was added dropwise to a solution of cyclohexanemethylamine (Aldrich, 50.1 g, 0.442 mol) in anhydrous benzene (800 mL) at 0° C. under nitrogen. The solution was then stirred for 15 min before being concentrated in vacuo to a volume of 250 mL. The colorless crystals which formed upon standing at 0° C. were filtered off, washed with hexanes (2×70 mL), and dried (0.5 Torr) to give 1-(cyclohexylmethyl)-3-propylurea (83.90 g, 96%), m.p. 60°-61° C.; 1H-NMR (DMSO-d6) consistent with structure.
Reaction SMILES: [N:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([C@H:4]3[CH2:11][NH2:12])[CH2:2]1)[CH2:8]2.[NH:13]1[C:21]2[C:16](=[CH:17][C:18]([C:22](O)=[O:23])=[CH:19][CH:20]=2)[CH:15]=[CH:14]1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>N1C=CC=CC=1>[N:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([C@H:4]3[CH2:11][NH:12][C:22]([C:18]3[CH:17]=[C:16]4[C:21](=[CH:20][CH:19]=3)[NH:13][CH:14]=[CH:15]4)=[O:23])[CH2:2]1)[CH2:8]2
Reactant: O=C(O)c1ccc2[nH]ccc2c1
Reactant: NCC1C2CC3CC1CN(C3)C2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: c1ccncc1
Product: O=C(NCC1C2CC3CC1CN(C3)C2)c1ccc2[nH]ccc2c1

Procedure:
The product of Example 1B was reacted with indole-5-carboxylic acid, N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride, 1-hydroxybenzotriazole and 4-di(methylamino)pyridine in pyridine as described in Example 3 to afford the title compound: 1H NMR (methanol-d4, 500 MHz) δ 1.82-1.89 (m, 2 H), 1.96 (br s, 3 H), 2.22-2.28 (m, 2 H), 2.31 (t, 1 H), 3.31-3.36 (m, 2 H), 3.41-3.47 (m, 2 H), 3.60-3.66 (m, 2 H), 6.54 (dd, J=3.20, 0.76 Hz, 1 H), 7.22-7.28 (m, 1H), 7.32 (d, J=3.05 Hz, 1 H), 7.42 (d, J=8.54 Hz, 1 H), 7.60-7.62 (m, 1 H), 7.64-7.70 (m, 1 H), 8.11 ppm (d, J=1.22 Hz, 1 H); MS (ESI) m/z 310 (M+H)+.
Reaction SMILES: [S:1]1[C:5]2[C:6]([C:10]([O:12][CH3:13])=[O:11])=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=N1>O1CCOCC1.[Pd]>[NH2:3][C:4]1[C:5]([SH:1])=[C:6]([CH:7]=[CH:8][CH:9]=1)[C:10]([O:12][CH3:13])=[O:11]
Reactant: COC(=O)c1cccc2nnsc12
Agent: [Pd]
Solvent: C1COCCO1
Product: COC(=O)c1cccc(N)c1S

Procedure:
A solution of 1 g of methyl benzo-1,2,3-thiadiazole-7-carboxylate in 40 ml of dioxane is hydrogenated over 0.5 g of palladium-on-charcoal (5%) at 160° C under an initial pressure of 150 bar. After the starting substance has reacted completely, the catalyst is filtered off and rinsed with dioxane, the filtrate is evaporated, avoiding contact with air, and the residue is purified over silica gel (hexanelethyl acetate (6:4)). The title compound of melting point 174-175° C. is obtained by this procedure.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C@@H:5]([CH3:7])[C@H:4]([C:8]([OH:10])=O)[O:3]1.[N+]([O-])(O)=O.[N+:15]([O:18][CH2:19][CH2:20][NH2:21])([O-:17])=[O:16].C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1>>[N+:15]([O:18][CH2:19][CH2:20][NH:21][C:8]([C@@H:4]1[O:3][C:2](=[O:1])[NH:6][C@H:5]1[CH3:7])=[O:10])([O-:17])=[O:16]
Reactant: C[C@@H]1NC(=O)O[C@H]1C(=O)O
Reactant: NCCO[N+](=O)[O-]
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: O=[N+]([O-])O
Product: C[C@@H]1NC(=O)O[C@H]1C(=O)NCCO[N+](=O)[O-]
Yield: 16.6 %

Procedure:
Following a procedure similar to that described in Example 1, but using 312 mg of (4S,5R)-2-oxo-4-methyloxazolidine-5-carboxylic acid, 372 mg of N-(2-nitrooxyethyl)amine nitrate and 0.47 ml of diphenylphosphoryl azide, 83 mg of the title compound were obtained as a colorless oil.
Reaction SMILES: [C:1]([NH:5][C:6](=[O:43])[NH:7][C:8]1[C:9]([C:22]2[C:23]([Cl:42])=[C:24]([NH:29][C:30](=[O:41])[C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:40])([F:39])[F:38])[CH:32]=3)[CH:25]=[CH:26][C:27]=2[Cl:28])=[CH:10][C:11]2[CH:16]=[N:15][C:14](S(C)(=O)=O)=[N:13][C:12]=2[N:21]=1)([CH3:4])([CH3:3])[CH3:2].[NH4+].CC[N:47](C(C)C)C(C)C>CO>[NH2:47][C:14]1[N:15]=[CH:16][C:11]2[CH:10]=[C:9]([C:22]3[C:23]([Cl:42])=[C:24]([NH:29][C:30](=[O:41])[C:31]4[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:38])([F:39])[F:40])[CH:32]=4)[CH:25]=[CH:26][C:27]=3[Cl:28])[C:8]([NH:7][C:6]([NH:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:43])=[N:21][C:12]=2[N:13]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(C)(C)NC(=O)Nc1nc2nc(S(C)(=O)=O)ncc2cc1-c1c(Cl)ccc(NC(=O)c2cccc(C(F)(F)F)c2)c1Cl
Agent: [NH4+]
Solvent: CO
Product: CC(C)(C)NC(=O)Nc1nc2nc(N)ncc2cc1-c1c(Cl)ccc(NC(=O)c2cccc(C(F)(F)F)c2)c1Cl
Temperature: 80 °C
Reaction time: 4 h

Procedure:
To a solution of N—{3-[7-(3-tert-butyl-ureido)-2-methanesulfonyl-pyrido[2,3-d]pyrimidin-6-yl]-2,4-dichloro-phenyl}-3-trifluoromethyl-benzamide (80 mg, 0.12 mmol) in methanol (5 ml) is added ammonium (methanol solution, 20 ml, 0.14 mmol) and DIEA (41 μl, 0.24 mmol). The reaction is stirred at 80° C. for 4 hours. The methanol is removed by rotary evaporation and the crude product is purified by RP-HPLC to give the title compound as a white solid: 1H NMR 400 MHz (DMSO) δ 10.46 (s, 1H), 8.93 (s, 1H), 8.27 (s, 1H), 8.23 (d, 2H, J=8.0 Hz), 8.00 (s, 1H), 7.96 (d, 1H, J=8.4 Hz), 7.76 (m, 3H), 7.68 (d, 1H, J=8.8 Hz), 7.48 (s, 2H), 1.32 (s, 9H); MS m/z 592.2 (M+1).
Reaction SMILES: [CH2:1]([O:9][N:10]1[C:15]([CH3:17])([CH3:16])[CH2:14][CH:13]([N:18]([C:76]2[N:81]=[C:80](Cl)[N:79]=[C:78]([NH:83][CH2:84][CH2:85][CH2:86][CH2:87][CH:88]3[CH2:93][C:92]([CH3:95])([CH3:94])[N:91]([O:96][CH2:97][CH2:98][CH2:99][CH2:100][CH2:101][CH2:102][CH2:103][CH3:104])[C:90]([CH3:106])([CH3:105])[CH2:89]3)[N:77]=2)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][N:25]([CH:57]2[CH2:62][C:61]([CH3:64])([CH3:63])[N:60]([O:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH3:73])[C:59]([CH3:75])([CH3:74])[CH2:58]2)[C:26]2[N:31]=[C:30](Cl)[N:29]=[C:28]([NH:33][CH2:34][CH2:35][CH2:36][CH2:37][CH:38]3[CH2:43][C:42]([CH3:45])([CH3:44])[N:41]([O:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54])[C:40]([CH3:56])([CH3:55])[CH2:39]3)[N:27]=2)[CH2:12][C:11]1([CH3:108])[CH3:107])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH2:109]([CH2:111][NH2:112])[OH:110]>>[CH2:1]([O:9][N:10]1[C:15]([CH3:17])([CH3:16])[CH2:14][CH:13]([N:18]([C:76]2[N:81]=[C:80]([NH:112][CH2:111][CH2:109][OH:110])[N:79]=[C:78]([NH:83][CH2:84][CH2:85][CH2:86][CH2:87][CH:88]3[CH2:93][C:92]([CH3:95])([CH3:94])[N:91]([O:96][CH2:97][CH2:98][CH2:99][CH2:100][CH2:101][CH2:102][CH2:103][CH3:104])[C:90]([CH3:106])([CH3:105])[CH2:89]3)[N:77]=2)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][N:25]([CH:57]2[CH2:62][C:61]([CH3:64])([CH3:63])[N:60]([O:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH3:73])[C:59]([CH3:75])([CH3:74])[CH2:58]2)[C:26]2[N:31]=[C:30]([NH:112][CH2:111][CH2:109][OH:110])[N:29]=[C:28]([NH:33][CH2:34][CH2:35][CH2:36][CH2:37][CH:38]3[CH2:43][C:42]([CH3:45])([CH3:44])[N:41]([O:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54])[C:40]([CH3:56])([CH3:55])[CH2:39]3)[N:27]=2)[CH2:12][C:11]1([CH3:108])[CH3:107])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCON1C(C)(C)CC(CCCCNc2nc(Cl)nc(N(CCCCCCN(c3nc(Cl)nc(NCCCCC4CC(C)(C)N(OCCCCCCCC)C(C)(C)C4)n3)C3CC(C)(C)N(OCCCCCCCC)C(C)(C)C3)C3CC(C)(C)N(OCCCCCCCC)C(C)(C)C3)n2)CC1(C)C
Reactant: NCCO
Product: CCCCCCCCON1C(C)(C)CC(CCCCNc2nc(NCCO)nc(N(CCCCCCN(c3nc(NCCO)nc(NCCCCC4CC(C)(C)N(OCCCCCCCC)C(C)(C)C4)n3)C3CC(C)(C)N(OCCCCCCCC)C(C)(C)C3)C3CC(C)(C)N(OCCCCCCCC)C(C)(C)C3)n2)CC1(C)C

Procedure:
The title compound is prepared from the reaction of N,N'-bis(1-octyloxy-2,2,6,6-tetramethylpiperidin-4-yl)-N,N'-bis{2-chloro-4-[N-(1-octyloxy-2,2,6,6-tetramethylpiperidin-4-yl)butylamino]-1,3,5-triazin-6-yl}-1,6-hexanediamine and ethanolamine.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([C:17]([CH3:20])([CH3:19])[CH3:18])[C:12]=1[O:13][CH2:14][O:15][CH3:16])[CH2:8][NH2:9])([CH3:4])[CH3:3].[C:21]1([NH:27][C:28](N)=[S:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(O)(=O)C>C1(C)C=CC=CC=1>[CH3:4][C:2]([C:5]1[CH:6]=[C:7]([CH2:8][NH:9][C:28]([NH:27][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[S:29])[CH:10]=[C:11]([C:17]([CH3:20])([CH3:19])[CH3:18])[C:12]=1[O:13][CH2:14][O:15][CH3:16])([CH3:1])[CH3:3]
Reactant: NC(=S)Nc1ccccc1
Reactant: COCOc1c(C(C)(C)C)cc(CN)cc1C(C)(C)C
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: COCOc1c(C(C)(C)C)cc(CNC(=S)Nc2ccccc2)cc1C(C)(C)C
Yield: 59.3 %

Procedure:
The above-titled compound was prepared substantially in accordance with the procedure described in Example 6A using 5.2 g (18.5 mmol) of 3,5-bis(1,1-dimethylethyl)-4-(methoxymethoxy) benzylamine (prepared substantially in accordance with the procedures described in Example 1), 3.86 g (25.4 mmol) of N-phenylthiourea, 1.11 g (18.5 mol) of acetic acid and 180 ml of toluene. Such reaction provided 4.55 g of N[[3,5-bis(1,1-dimethylethyl)-4-(methoxymethoxy]phenyl]methyl]-N'-phenylthiourea. The methoxymethyl hydroxy protecting group was then removed, substantially in accordance with the procedure described in Example 6B, to provide 790 mg of title compound. m.p. 176°-179° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:22])[CH2:13][CH2:12][C:11]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)([C:14]#[N:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Br[CH2:24][CH2:25][CH:26]1[CH2:28][CH2:27]1.[H-].[Na+].O>CN(C=O)C>[CH:26]1([CH2:25][CH2:24][O:22][C:8]2([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[CH2:13][CH2:12][C:11]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)([C:14]#[N:15])[CH2:10][CH2:9]2)[CH2:28][CH2:27]1
Reactant: N#CC1(c2ccccc2)CCC(O)(c2ccc(F)cc2)CC1
Reactant: BrCCC1CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CC1(c2ccccc2)CCC(OCCC2CC2)(c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 96 h
Yield: 47.1 %

Procedure:
500 mg of the compound of Example 1, 760 mg of (2-bromoethyl)cyclopropane (Chorvat et al., J. Med. Chem. 28, 194-200 (1985)) and 122 mg of sodium hydride in 20 ml of anhydrous DMF were stirred at room temperature for 19 h. 760 mg of (2-bromoethyl)cyclopropane and 122 mg of sodium hydride were then added and the mixture was stirred at room temperature for 4 days. The reaction mixture was then treated with 100 ml of water and extracted three times with 50 ml each of EA. The combined organic phases were dried over magnesium sulfate and the solvent was removed in vacuo. 290 mg of the title compound were obtained as a pale yellow oil.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.S(Cl)(Cl)=O.[CH2:10]([S:17][CH2:18][C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[OH:27])=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(Cl)Cl>[OH:27][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[C:19]([C:2]1[NH:1][CH:5]=[CH:4][N:3]=1)=[CH:18][S:17][CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=C(CSCc1ccccc1)c1ccccc1O
Reactant: c1c[nH]cn1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: Oc1ccccc1C(=CSCc1ccccc1)c1ncc[nH]1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 4.08 g of imidazole and 30 ml of dry methylene chloride, 1.78 g of thionyl chloride was added with ice-cooling. After stirring the reaction mixture for 30 minutes, 2.58 g of 2-benzylthio-2'-hydroxyacetophenone was added, followed by further stirring at room temperature for 2 hours. Ice water was added to the reaction mixture, followed by extraction with methylene chloride. The organic, i.e., methylene chloride layer was washed with water, dried over magnesium sulfate and then concentrated. The residue was dissolved in chloroform and was then subjected to chromatography on a silica gel column. Upon concentration of the resultant eluate, there were obtained 180 mg of Isomer A (m.p. 196°-198° C.; Compound 1) and 1.0 g of Isomer B (m.p. 136.5°-138° C.; Compound 2) of 1-(2-hydroxyphenyl)-1-imidazolyl-2-benzylthioethylene (in formula (I), R1, R2, R3 =H, R4 =--SCH2C6H5), both, as colorless crystals.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:23]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:22])([F:21])[C:17]([Cl:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[NH:25]1[CH2:29][CH2:28][C@@H:27]([OH:30])[CH2:26]1>>[Br:1][C:2]1[C:3]([N:25]2[CH2:29][CH2:28][C@@H:27]([OH:30])[CH2:26]2)=[N:4][CH:5]=[C:6]([CH:23]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:22])([F:21])[C:17]([Cl:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8]
Reactant: O[C@@H]1CCNC1
Reactant: O=C(Nc1ccc(C(F)(F)C(F)(F)Cl)cc1)c1cnc(Cl)c(Br)c1
Product: O=C(Nc1ccc(C(F)(F)C(F)(F)Cl)cc1)c1cnc(N2CC[C@@H](O)C2)c(Br)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Stage 8.1 using 5-bromo-6-chloro-N-(4-(2-chloro-1,1,2,2-tetrafluoroethyl)phenyl)nicotinamide (Stage 31.2) and (R)-pyrrolidin-3-ol to afford a white powder. HPLC (Condition 4) tR=6.05 min, UPLC-MS (Condition 3) tR=1.18 min, m/z=498 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([CH2:13][C:14](O)=[S:15])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[NH2:19][CH2:20][CH2:21][OH:22]>>[OH:22][CH2:21][CH2:20][NH:19][C:14](=[S:15])[CH2:13][C:10]1[CH:11]=[CH:12][C:7]([O:6][C:5]2[CH:17]=[CH:18][C:2]([Cl:1])=[CH:3][CH:4]=2)=[CH:8][CH:9]=1
Reactant: NCCO
Reactant: OC(=S)Cc1ccc(Oc2ccc(Cl)cc2)cc1
Product: OCCNC(=S)Cc1ccc(Oc2ccc(Cl)cc2)cc1

Procedure:
On subjecting the acid of Example 10 to an amidification reaction with 2-amino-ethanol in accordance with the working method described in Example 7, CRL 40,272 is obtained.