Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(N1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16][N:17]2[C:25]3[N:20]4[C:21](=[N:26][CH:27]=[C:19]4[C:18]2=[O:28])[CH:22]=[CH:23][CH:24]=3)CC1)=O)(C)(C)C.[ClH:29]>C(O)C>[ClH:29].[ClH:29].[NH:17]1[CH2:18][CH2:13][CH:12]([CH2:11][CH2:14][CH2:15][CH2:16][N:17]2[C:25]3[N:20]4[C:21](=[N:26][CH:27]=[C:19]4[C:18]2=[O:28])[CH:22]=[CH:23][CH:24]=3)[CH2:15][CH2:16]1
Reactant: CC(C)(C)OC(=O)N1CCC(CCCn2c(=O)c3cnc4cccc2n43)CC1
Agent: Cl
Solvent: CCO
Product: O=c1c2cnc3cccc(n1CCCCC1CCNCC1)n32
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.5 %

Procedure:
To a solution prepared by dissolving 3.82 g (9.94 mM) of 1,2-dihydro-1-[3-(1-tert-butoxycarbonylpiperidin-4-yl)propan-1-yl]-1,4,7b-triazacyclopent[cd]inden-2-one in 50 ml of ethanol was added 10 ml (122 mM) of 12N-hydrochloric acid and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, the reaction mixture was concentrated under reduced pressure and the resulting precipitate was recovered by filtration. The precipitate was rinsed with small amounts of ethanol and ether to provide 2.99 g (yield 84.5%) of the title compound as brown solid.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[CH:8][C:9]2[N:10]([C:12]([CH:15]([C:17]3[CH:18]=[C:19]4[C:23](=[CH:24][C:25]=3[F:26])[N:22]([CH3:27])[N:21]=[CH:20]4)[CH3:16])=[CH:13][N:14]=2)[N:11]=1)=[CH2:5])C.Cl>C(O)(=O)C>[F:26][C:25]1[CH:24]=[C:23]2[C:19]([CH:20]=[N:21][N:22]2[CH3:27])=[CH:18][C:17]=1[CH:15]([C:12]1[N:10]2[N:11]=[C:6]([C:4](=[O:3])[CH3:5])[CH:7]=[CH:8][C:9]2=[N:14][CH:13]=1)[CH3:16]
Reactant: C=C(OCC)c1ccc2ncc(C(C)c3cc4cnn(C)c4cc3F)n2n1
Agent: Cl
Solvent: CC(=O)O
Product: CC(=O)c1ccc2ncc(C(C)c3cc4cnn(C)c4cc3F)n2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.3 %

Procedure:
To a solution of the 6-(1-ethoxyvinyl)-3-(1-(6-fluoro-1-methyl-1H-indazol-5-yl)ethyl)-imidazo[1,2-b]pyridazine (450 mg, 0.985 mmol) in acetic acid (8 mL) was added 3N HCl (0.5 mL). The solution was stirred at rt for 2 h and the solvent was removed under reduced pressure. The residue was diluted with water and its pH was adjusted to basic with aqueous NaHCO3 solution and extracted with DCM. The organic layer was washed with NaHCO3 (aq) and brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by column chromatography to give 300 mg (81%) of the title compound as a yellow solid. LCMS (method B): [MH]+=338, tR=2.49 min.
Reaction SMILES: [C:1]1([C:7]2[C:8]3[CH:22]=[CH:21][CH:20]=[CH:19][C:9]=3[O:10][CH2:11][C:12]=2[CH:13]=[CH:14][CH2:15][C:16](O)=[O:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:23][S:24][C:25]1[C:30]([NH2:31])=[C:29]([S:32][CH3:33])[CH:28]=[C:27]([CH3:34])[N:26]=1>>[CH3:23][S:24][C:25]1[C:30]([NH:31][C:16](=[O:17])[CH2:15][CH:14]=[CH:13][C:12]2[CH2:11][O:10][C:9]3[CH:19]=[CH:20][CH:21]=[CH:22][C:8]=3[C:7]=2[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[C:29]([S:32][CH3:33])[CH:28]=[C:27]([CH3:34])[N:26]=1
Reactant: CSc1cc(C)nc(SC)c1N
Reactant: O=C(O)CC=CC1=C(c2ccccc2)c2ccccc2OC1
Product: CSc1cc(C)nc(SC)c1NC(=O)CC=CC1=C(c2ccccc2)c2ccccc2OC1

Procedure:
N-[2,4-Dimethylthio-6-methyl-3-pyridyl]-4-(4-phenyl-2H-3-benzo[b]pyranyl)but-3-enamide is prepared under the conditions of Example 1 from 4-(4-phenyl-2H-3-benzo[b]pyranyl)but-3-en-1-oic acid and 2,4-dimethylthio-6-methyl-3-pyridylamine.
Reaction SMILES: [Br:1][CH:2]1[CH2:6][CH:5]([O:7][CH3:8])[CH2:4][CH:3]1[OH:9].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl.O>[Br:1][CH:2]1[CH2:6][CH:5]([O:7][CH3:8])[CH2:4][C:3]1=[O:9]
Reactant: COC1CC(O)C(Br)C1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: O
Product: COC1CC(=O)C(Br)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 134.6 %

Procedure:
Into a round-bottom flask, was placed a solution of 2-Bromo-4-methoxycyclopentanol (compound 461.3, 1.00 g, 3.08 mmol, 1.00 equiv, 60%) in dichloromethane (100 mL). Dess-Martin periodinane (2.00 g, 4.72 mmol, 1.10 equiv) was added in portions and the mixture was stirred overnight at room temperature. The mixture was then diluted with water (20 mL) and quenched with Na2S2O4 (4 g). The aqueous was extracted with dichloromethane (100 mL) and the combined organics was washed with brine (30 mL), dried (Na2SO4), filtered and concentrated in vacuo to obtain the title compound as a brown oil (800 mg, 81%).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:17]=[C:18]4[C:22](=[CH:23][C:24]=3[Cl:25])[NH:21][CH:20]=[C:19]4[C:26]([O:28]C)=[O:27])=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[OH-].[Na+]>CO>[C:1]([N:4]1[CH2:5][CH2:6][CH:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:17]=[C:18]4[C:22](=[CH:23][C:24]=3[Cl:25])[NH:21][CH:20]=[C:19]4[C:26]([OH:28])=[O:27])=[CH:12][CH:11]=2)[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: COC(=O)c1c[nH]c2cc(Cl)c(-c3ccc(C4CCN(C(C)=O)CC4)cc3)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(=O)N1CCC(c2ccc(-c3cc4c(C(=O)O)c[nH]c4cc3Cl)cc2)CC1
Temperature: 70 °C
Yield: 29.4 %

Procedure:
To a solution of methyl 5-[4-(1-acetylpiperidin-4-yl)phenyl]-6-chloro-1H-indole-3-carboxylate (120 mg, 0.30 mmol) in MeOH (4 mL) was added sodium hydroxide (1 mL, 1M). The mixture was heated to 70° C. for 24 h. Solvent was removed under reduced pressure. The residue was acidified to pH=5 and dried in vacuum to give an oil, which was purified by preparative HPLC to give the title compound (35 mg, 30% yield) as an off-white solid.
Reaction SMILES: CC(OC(=O)[NH:7][CH:8]([C:13]([NH:15][CH2:16][C:17]1[NH:21][C:20]2[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=2[N:18]=1)=[O:14])[CH:9]([CH3:12])[CH2:10][CH3:11])(C)C.[F:27][C:28]([F:33])([F:32])[C:29]([OH:31])=[O:30]>C(Cl)Cl>[F:27][C:28]([F:33])([F:32])[C:29]([OH:31])=[O:30].[F:27][C:28]([F:33])([F:32])[C:29]([OH:31])=[O:30].[F:27][C:28]([F:33])([F:32])[C:29]([OH:31])=[O:30].[NH2:7][CH:8]([CH:9]([CH3:12])[CH2:10][CH3:11])[C:13]([NH:15][CH2:16][C:17]1[NH:18][C:19]2[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=2[N:21]=1)=[O:14]
Reactant: CCC(C)C(NC(=O)OC(C)(C)C)C(=O)NCc1nc2ccccc2[nH]1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCC(C)C(N)C(=O)NCc1nc2ccccc2[nH]1

Procedure:
The title compound is prepared by the procedure of Example 2 using 0.588 g of product from Example 11 in 6 ml of methylene chloride and 1.3 g of trifluoroacetic acid (TFA). The resulting desired intermediate is used as is in the next reaction. The 1HNMR indicates the correct product with associated TFA molecules.
Reaction SMILES: [I:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([N+:9]([O-])=O)[CH:3]=1.O.O.[Sn](Cl)Cl>C(O)C>[I:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([NH2:9])[CH:3]=1
Reactant: Nc1ccc(I)cc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Product: Nc1ccc(I)cc1N
Yield: 92 %

Procedure:
Commercial 4-iodo-2-nitroaniline was reduced with 5 eq tin dichloride dihydrate in ethanol solution (75° C., 2 h) to give 92% 4-iodo-1,2-phenylenediamine as light red solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](F)[C:3]=1[N+:9]([O-:11])=[O:10].O.[NH2:13][NH2:14]>C1COCC1>[F:1][C:2]1[C:3]([N+:9]([O-:11])=[O:10])=[C:4]([NH:13][NH2:14])[CH:5]=[CH:6][CH:7]=1
Reactant: NN
Reactant: O=[N+]([O-])c1c(F)cccc1F
Solvent: O
Solvent: C1CCOC1
Product: NNc1cccc(F)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 0.01 M 2,6-difluoronitrobenzene and 0.01 M hydrazine hydrate (99% strength) in 30 ml of THF was stirred overnight at RT (exothermic reaction) and the residue was brought to crystallization after distilling off the solvent by treating with diisopropyl ether. Crystalline substance, m.p.: 93-95° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:32]=[CH:33][C:34]=1[O:35][CH3:36])[CH2:6][CH:7]1[C:13]2[CH:14]=[C:15]([O:20][CH3:21])[C:16]([O:18][CH3:19])=[CH:17][C:12]=2[CH2:11][CH2:10][CH2:9][N:8]1[CH:22]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:23]([OH:25])=O.[NH2:37][CH2:38][CH2:39][C:40]([N:42]([CH2:44][CH3:45])[CH3:43])=[O:41]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:32]=[CH:33][C:34]=1[O:35][CH3:36])[CH2:6][CH:7]1[C:13]2[CH:14]=[C:15]([O:20][CH3:21])[C:16]([O:18][CH3:19])=[CH:17][C:12]=2[CH2:11][CH2:10][CH2:9][N:8]1[CH:22]([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:23]([NH:37][CH2:38][CH2:39][C:40]([N:42]([CH2:44][CH3:45])[CH3:43])=[O:41])=[O:25]
Reactant: CCN(C)C(=O)CCN
Reactant: COc1ccc(CC2c3cc(OC)c(OC)cc3CCCN2C(C(=O)O)c2ccccc2)cc1OC
Product: CCN(C)C(=O)CCNC(=O)C(c1ccccc1)N1CCCc2cc(OC)c(OC)cc2C1Cc1ccc(OC)c(OC)c1

Procedure:
prepared by reaction of [1-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-phenyl-acetic acid with 3-amino-N-ethyl-N-methyl-propionamide.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:9])=[C:4]([SH:8])[CH:5]=[CH:6][CH:7]=1.Cl.Cl[CH2:12][C:13]1[NH:14][CH2:15][CH2:16][N:17]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[ClH:1].[Cl:1][C:2]1[C:3]([CH3:9])=[C:4]([S:8][CH2:12][C:13]2[NH:17][CH2:16][CH2:15][N:14]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: ClCC1=NCCN1
Reactant: Cc1c(S)cccc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: Cc1c(Cl)cccc1SCC1=NCCN1
Reaction time: 25 h

Procedure:
5.55 g (35 mmol) of 3-chloro-2-methyl-thiophenol, 5.43 g (35 mmol) of 2-chloromethyl-2-imidazoline hydrochloride and 5 g of potassium carbonate are stirred in 40 ml of ethanol at room temperature. After 25 h, the mixture is filtered and the filtrate is concentrated to dryness. The crude product is purified by column chromatography on silica gel. After the eluting agent has been stripped off, ethanolic hydrochloric acid is added to the residue and the product is precipitated by addition of ether. White crystals of melting point 208°-209° C. are obtained.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[NH:8][N:9]=[C:10]([OH:11])[C:5]2=[C:4]([CH3:12])[CH:3]=1.[N:13]([C@@H:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18][CH2:17]1)=[C:14]=[O:15]>C1COCC1.CN(C=O)C>[C@@H:16]1([NH:13][C:14]([N:9]2[C:10](=[O:11])[C:5]3[C:6](=[N:7][C:2]([Cl:1])=[CH:3][C:4]=3[CH3:12])[NH:8]2)=[O:15])[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18][CH2:17]1
Reactant: Cc1cc(Cl)nc2[nH]nc(O)c12
Reactant: O=C=N[C@H]1CCc2ccccc21
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cc1cc(Cl)nc2[nH]n(C(=O)N[C@H]3CCc4ccccc43)c(=O)c12

Procedure:
In analogy to example 1c, 200 mg (1.089 mmol) of 6-chloro-4-methyl-1H-pyrazolo-[3,4-b]pyridin-3-ol were reacted with 208.1 mg (1.2 mmol) of (S)-1-isocyanatoindane in THF/DMF at RT. Yield: 153 mg (41%), M+H+: 343.32.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7](F)=[C:6]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:5]=1.Cl.[CH3:17][NH:18][CH3:19].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([N:18]([CH3:19])[CH3:17])=[C:6]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:5]=1
Reactant: COC(=O)c1ccc(F)c(S(C)(=O)=O)c1
Reactant: CNC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COC(=O)c1ccc(N(C)C)c(S(C)(=O)=O)c1
Temperature: 60 °C
Reaction time: 7 h
Yield: 56 %

Procedure:
To a stirred solution of 5.23 g (22.5 mmol) 4-Fluoro-3-methanesulfonyl-benzoic acid methyl ester (J. Med. Chem.; 40; 13; 1997; 2017-2034) and 60.0 ml dimethylsulphoxid were added 2.23 g (27.0 mmol) dimethylamine hydrochloride and 6.54 g (47.3 mmol) potassium carbonate. The reaction mixture was stirred for 7 h at 60° C. in an autoclave and was concentrated with high vacuum rotation evaporator at 65° C. The residue was diluted with dichloromethane, washed twice with water. The combined water phases were extracted with dichloromethane. The combined dichloromethane phases were washed with diluted sodium hydrogen carbonate solution, dried with sodium sulphate and concentrated. The oily crude was purified by column chromatography and the desired product 10a was obtained in 56% yield (3.24 g, 12.6 mmol).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:13])[C:5]([NH:8][CH2:9][CH:10]2[CH2:12][CH2:11]2)=[CH:6][CH:7]=1.C(N(CC)C(C)C)(C)C.[C:23]([CH2:27][C:28](Cl)=[O:29])([CH3:26])([CH3:25])[CH3:24]>C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][CH:10]2[CH2:12][CH2:11]2)=[C:4]([NH:13][C:28](=[O:29])[CH2:27][C:23]([CH3:26])([CH3:25])[CH3:24])[CH:3]=1
Reactant: Nc1cc(Br)ccc1NCC1CC1
Reactant: CC(C)(C)CC(=O)Cl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)CC(=O)Nc1cc(Br)ccc1NCC1CC1
Temperature: 25 °C
Yield: 70.4 %

Procedure:
To a solution of 4-bromo-N1-(cyclopropylmethyl)benzene-1,2-diamine (Step B, 11.3 g, 46.9 mmol) and N,N-diisopropylethylamine (6.06 g, 46.9 mmol) in ethyl acetate (88 mL) was added tert-butylacetyl chloride (6.31 g, 46.9 mmol) at 0° C. and the mixture was allowed to warm to room temperature for 15 h. The reaction mixture was washed with saturated sodium hydrogen carbonate aqueous solution (100 mL×2), brine (50 mL). The resulting ethyl acetate solution of reaction mixture was dried over magnesium sulfate and concentrated under reduced pressure. The crude product was washed with ethyl acetate to afford the title compound (11.2 g, 70%) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[C:8]3[NH:16][N:15]=[N:14][C:9]=3[N:10]=[C:11]([NH2:13])[N:12]=2)=[CH:4][CH:3]=1.[Br:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25]Br)[N:20]=1>CCCCCC.CCOC(C)=O>[Br:17][CH2:18][C:19]1[N:20]=[C:21]([CH2:25][N:14]2[C:9]3[N:10]=[C:11]([NH2:13])[N:12]=[C:7]([C:5]4[O:6][C:2]([CH3:1])=[CH:3][CH:4]=4)[C:8]=3[N:16]=[N:15]2)[CH:22]=[CH:23][CH:24]=1
Reactant: BrCc1cccc(CBr)n1
Reactant: Cc1ccc(-c2nc(N)nc3nn[nH]c23)o1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1ccc(-c2nc(N)nc3c2nnn3Cc2cccc(CBr)n2)o1

Procedure:
Prepared from 7-(5-methyl-2-furyl)-1H-[1,2,3]triazolo[4,5-d]pyrimidin-5-ylamine and 2,6-bis(bromomethyl)pyridine by the alkylation method described in Example 36; NMR δH (400 MHz, DMSO) 2.46 (3H, s), 4.64 (2H, s), 5.75 (2H, s), 6.50 (1H, d, J 3.5 Hz), 7.04 (1H, d, J 8.0 Hz), 7.31 (2H, s), 7.49 (1H, d, J 7.5 Hz), 7.80 (1H, t, J 7.5 Hz), 7.88 (1H, d, J 3.5 Hz). TLC (Hexane:EtOAc (1:1)) Rf=0.28**
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.[CH3:11][NH:12][CH3:13]>>[CH3:11][N:12]([CH3:13])[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1
Reactant: CNC
Reactant: CC(=O)c1ccc(F)cc1
Product: CC(=O)c1ccc(N(C)C)cc1
Reaction time: 2 h

Procedure:
A mixture containing 50 g of p-fluoroacetophenone and 150 ml of 40% aqueous dimethylamine is warmed in a pressure bottle at 90°-100° C. After two hours, a pale yellow oil is formed. The mixture is cooled, and the oil solidifies. The solid is collected and washed well with H2O to give 54.93 of p-dimethylaminoacetophenone, mp 101°-103° C., after heptane recrystallization. A 72 g sample of this acetophenone is heated with 129 g of N-chlorosuccinimide in 700 ml of toluene to reflux temperature and maintained at this temperature for 35 minutes. The mixture is cooled and filtered. The filter cake is washed with 200 ml of toluene, and the filtrate and wash solution are evaporated to dryness in vacuo to afford 66 g of oil. This oil is chromatographed on SiO2 with 40% hexane/CH2Cl2 to give 38.9 g of 3.5-dichloro-4-dimethylaminoacetophenone as a yellow oil. A 5.22 g sample of this oil is added portionwise to 2.75 g of SeO2 in 20 ml of dioxane and 0.7 ml of H2O at 55°-60° C. This mixture is heated at reflux temperature for 4.5 hours, cooled and filtered through siliceous earth. The filter cake is washed with 20 ml of dioxane. The dioxane solutions are cooled to 15° C. and 2.77 g of t-butylamine is added dropwise to afford a tan precipitate. After stirring 15 minutes at room temperature, the mixture is diluted with 200 ml of ethanol, cooled to 5° C. and 7 g of NaBH4 is added portionwise. After 15 hours, the mixture is treated with 300-400 g of ice and 200 ml of H2O at below 10° C. The mixture is stirred to dissolve all solids and extracted with 300 ml of CH2Cl2. The CH2Cl2 layer is washed with 100 ml of H2O, dried (MgSO4) and evaporated to dryness in vacuo to give 5.6 g of orange oil. This oil is dissolved in ethyl ether, decolorized with activated carbon and concentrated to 15 ml. On cooling, crystals are obtained. The title product is collected as white crystals, mp 96°-99° C.
Reaction SMILES: [Na].[Cl:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[OH:11].[C:12]([O:16][CH2:17][CH3:18])(=[O:15])[CH:13]=[CH2:14]>C(O)C>[Cl:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[O:11][CH2:14][CH2:13][C:12]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: C=CC(=O)OCC
Reactant: COc1ccc(O)c(Cl)c1
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)CCOc1ccc(OC)cc1Cl
Temperature: 105 °C

Procedure:
Sodium (0.055 g; 2.4 mmol) and ethanol (1.5 mL) was added to a melt of 2-chloro-4-methoxyphenol (5.20 g; 32.8 mmol). When all the sodium was dissolved, ethyl acrylate (4.1 g; 41 mmol) was added and the mixture was heated at 105° C. for 7 days. The mixture was then cooled to RT and partitioned between ether and water. The mixture was made acidic with HCl (2M; aq.) and extracted with ether three times. The combined organic layer was washed with NaOH (2M; aq), dried (CaCl2) and evaporated. The crude product (2.7 g) was purified using preparative RPLC (CH3CN:0.1M ammonium acetate (60:40)). Yield 1.90 g (22%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[O:13][C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[N:11][C:10]=2[C:20]2[CH:29]=[CH:28][C:23]([C:24](OC)=[O:25])=[CH:22][CH:21]=2)=[CH:4][CH:3]=1.CCOC(C)=O.[NH2:36][NH2:37]>CCO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[O:13][C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[N:11][C:10]=2[C:20]2[CH:29]=[CH:28][C:23]([C:24]([NH:36][NH2:37])=[O:25])=[CH:22][CH:21]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(-c2nc(-c3ccccc3)oc2Sc2ccc(Cl)cc2)cc1
Reactant: NN
Solvent: CCOC(C)=O
Solvent: CCO
Product: NNC(=O)c1ccc(-c2nc(-c3ccccc3)oc2Sc2ccc(Cl)cc2)cc1

Procedure:
Methyl 4-{5-[(4-chlorophenyl)thio]-2-phenyl-1,3-oxazol-4-yl}benzoate from Step B (33 mg, 0.077 mmol) was suspended in 1 mL of EtOH and 0.5 mL of anhydrous hydrazine, and heated to reflux for 2 h. EtOAc was added and washed with water 3 times. The organics were dried (MgSO4), and concentrated to afford 4-{5-[(4-chlorophenyl)thio]-2-phenyl-1,3-oxazol-4-yl}benzohydrazide which was used with out further purification. LCMS: m/z 421.1 (M+H)+.
Reaction SMILES: C([O:3][C:4](=[O:22])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][C:8]=1[CH2:14][NH:15][CH2:16][C:17]([O:19]CC)=O)C.[CH2:23]([N:31]=[C:32]=[O:33])[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[Br:13][C:10]1[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]([OH:3])=[O:22])=[C:8]([CH2:14][N:15]2[CH2:16][C:17](=[O:19])[N:31]([CH2:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:32]2=[O:33])[CH:9]=1
Reactant: O=C=NCCc1ccccc1
Reactant: CCOC(=O)CNCc1cc(Br)ccc1OCC(=O)OCC
Product: O=C(O)COc1ccc(Br)cc1CN1CC(=O)N(CCc2ccccc2)C1=O

Procedure:
Prepared from 4-bromo-2-[(ethoxycarbonylmethylamino)methyl]phenoxyacetic acid ethyl ester and phenethylisocyanate according to GP12: LC/MS (an10p8): Rt 2.2 min, m/z 445 [M−H]−; 1H NMR (DMSO-d6): δ 2.84 (t, J=7.2 Hz, 2H), 3.59 (t, J=7.2 Hz, 2H), 3.94 (s, 2H), 4.45 (s, 2H), 4.76 (s, 2H), 6.93 (d, J=8.6 Hz, 1H), 7.17-7.46 (m, 7H), 12.45 (br. s, 1H).
Reaction SMILES: [CH3:1][C:2]([CH3:36])([CH3:35])[CH2:3][C:4]([NH:6][C:7]1[C:8]([CH3:34])=[C:9]([CH3:33])[C:10]2[O:14][CH2:13][CH:12]([C:15]3[CH:16]=[CH:17][C:18]([CH:28]([CH3:30])[CH3:29])=[C:19]([CH:27]=3)[O:20][CH2:21][C:22](OCC)=[O:23])[C:11]=2[C:31]=1[CH3:32])=[O:5].[Li].O>C1COCC1>[OH:23][CH2:22][CH2:21][O:20][C:19]1[CH:27]=[C:15]([CH:12]2[C:11]3[C:31]([CH3:32])=[C:7]([NH:6][C:4](=[O:5])[CH2:3][C:2]([CH3:36])([CH3:35])[CH3:1])[C:8]([CH3:34])=[C:9]([CH3:33])[C:10]=3[O:14][CH2:13]2)[CH:16]=[CH:17][C:18]=1[CH:28]([CH3:29])[CH3:30]
Reactant: CCOC(=O)COc1cc(C2COc3c(C)c(C)c(NC(=O)CC(C)(C)C)c(C)c32)ccc1C(C)C
Agent: [Li]
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(C)c2c(c(C)c1NC(=O)CC(C)(C)C)C(c1ccc(C(C)C)c(OCCO)c1)CO2
Temperature: 25 °C
Reaction time: 60 h
Yield: 70.6 %

Procedure:
To a solution of ethyl (5-(5-((3,3-dimethylbutanoyl)amino)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-3-yl)-2-isopropylphenoxy)acetate (200 mg, 0.49 mmol) obtained in Example 188 in THF (5 mL) was added with ice-cooling lithium borotetrahydride (43 mg, 2.00 mmol). The reaction solution was warmed to room temperature and stirred for 60 hours. The reaction solution was added to ice and water was added to the reaction solution, and the product was extracted with ethyl acetate. The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 157 mg (yield: 71%) of the title compound. Melting point: 155-156° C. (ethyl acetate-hexane).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([O:9][CH2:10][C@H:11]2[CH2:16][CH2:15][C@H:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:13][CH2:12]2)[CH:5]=[CH:4][C:3]=1[OH:22].[CH2:23](Br)[CH2:24][CH2:25][CH3:26].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:23]([O:22][C:3]1[CH:4]=[CH:5][C:6]([O:9][CH2:10][C@H:11]2[CH2:16][CH2:15][C@H:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:13][CH2:12]2)=[C:7]([F:8])[C:2]=1[F:1])[CH2:24][CH2:25][CH3:26]
Reactant: CCCCC[C@H]1CC[C@H](COc2ccc(O)c(F)c2F)CC1
Reactant: CCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCC[C@H]1CC[C@H](COc2ccc(OCCCC)c(F)c2F)CC1

Procedure:
0.1 mol of 2,3-difluoro-4-(trans-4-pentylcyclohexyl)methoxyphenol, 0.11 mol of butyl bromide and 0.11 mol of potassium carbonate are heated for 16 hours at 100° in 100 ml of dimethylformamide (DMF). After cooling, the inorganic salts are filtered off with suction, the filtrate is concentrated, and water is added. 1-butyloxy-2,3-difluoro-4-(trans-4-pentylcyclohexyl)methoxybenzene is obtained by extraction with dichloromethane.
Reaction SMILES: [SH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.CS(O[CH:17]1[CH2:20][N:19]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:18]1)(=O)=O.C([O-])([O-])=O.[Cs+].[Cs+].CCOC(C)=O>CN(C=O)C>[CH3:9][O:8][C:6]([C:5]1[CH:4]=[CH:3][C:2]([S:1][CH:17]2[CH2:18][N:19]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:20]2)=[CH:11][CH:10]=1)=[O:7]
Reactant: COC(=O)c1ccc(S)cc1
Reactant: CC(C)(C)OC(=O)N1CC(OS(C)(=O)=O)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(SC2CN(C(=O)OC(C)(C)C)C2)cc1
Temperature: 90 °C
Reaction time: 3 h
Yield: 53.9 %

Procedure:
Methyl 4-mercaptobenzoate (3.00 g, 17.8 mmol) and tert-butyl 3-(methylsulfonyloxy)azetidine-1-carboxylate (4.48 g, 17.8 mmol) were dissolved in DMF (30 mL). Cs2CO3 (6.97 g, 21.4 mmol) was added and the mixture was stirred at 90° C. for 3 hours, then cooled to room temperature. EtOAc (50 ml) was added and the solids were filtered off. The filtrate was washed with a saturated aqueous K2CO3 solution (20 mL), dried (MgSO4) and then evaporated. The residue was purified by column chromatography eluting with heptane, EtOAc/heptane (5:95, then 10:90). There was obtained 3.10 g (53%) of 59A as a solid. 1H NMR (500 MHz, CDCl3): δ 1.45 (s, 9H), 3.89 (m, 2H), 3.90 (s, 3H), 4.11 (m, 1H), 4.42 (t, 2H), 7.16 (d, 2H), 7.95 (d, 2H).