Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[CH3:10][C:11]([C:13]1[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH3:22])=[C:15]([O:23][CH3:24])[CH:14]=1)=[O:12].[OH-].[Na+].Cl>CO>[OH:1][C:2]1[CH:9]=[CH:8][C:5](/[CH:6]=[CH:10]/[C:11]([C:13]2[CH:14]=[C:15]([O:23][CH3:24])[C:16]([O:21][CH3:22])=[C:17]([O:19][CH3:20])[CH:18]=2)=[O:12])=[CH:4][CH:3]=1
Reactant: COc1cc(C(C)=O)cc(OC)c1OC
Reactant: O=Cc1ccc(O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cc(C(=O)/C=C/c2ccc(O)cc2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 24 h
Yield: 4.9 %

Procedure:
To a stirred solution of 4-hydroxybenzaldehyde (1.0 g, 8.19 mmol) and 3,4,5-trimethoxyacetophenone (1.72 g, 8.19 mmol) in methanol (30 ml) was added a 50% w/v solution of aqueous NaOH (1 ml). The mixture was stirred for 24 hours at room temperature, acidified with 2N HCl and extracted with ethyl acetate (3×30 ml). The combined organic phase was dried over anhydrous MgSO4, filtered, and the solvent evaporated in vacuo. The product was purified by column chromatography using hexane/ethyl acetate (7:3) as eluent to afford the title compound as a pale yellow solid (0.125 g, 5%). 1H-NMR (CDCl3) δ 7.8 (1H, d), 7.6 (2H, m), 7.4 (1H, s), 7.25 (2H, m), 6.9 (2H, d), 5.6 (1H, bs) 3.95 (9H, s). Mass Spectrum (FAB) m/e 315 (M+1).
Reaction SMILES: Br[CH2:2][C:3]1[N:8]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[C:7](=[O:19])[NH:6][C@H:5]([C:20]2[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][CH:21]=2)[C:4]=1[C:28](OCC)=[O:29].C(O)(=O)C(O)=O.[CH2:39]([NH:41][NH2:42])[CH3:40]>O1CCOCC1>[CH2:39]([N:41]1[CH2:2][C:3]2[N:8]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:16])[F:17])[CH:10]=3)[C:7](=[O:19])[NH:6][C@H:5]([C:20]3[CH:21]=[CH:22][C:23]([C:26]#[N:27])=[CH:24][CH:25]=3)[C:4]=2[C:28](=[O:29])[NH:42]1)[CH3:40]
Reactant: CCOC(=O)C1=C(CBr)N(c2cccc(C(F)(F)F)c2)C(=O)N[C@@H]1c1ccc(C#N)cc1
Reactant: CCNN
Agent: O=C(O)C(=O)O
Solvent: C1COCCO1
Product: CCN1CC2=C(C(=O)N1)[C@@H](c1ccc(C#N)cc1)NC(=O)N2c1cccc(C(F)(F)F)c1
Temperature: 120 °C
Reaction time: 3 h

Procedure:
200 mg (0.393 mmol) of ethyl (4R)-6-(bromomethyl)-4-(4-cyanophenyl)-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxylate (Example 6A) were dissolved in 1 ml of dioxane, 71 mg (0.472 mmol) of ethylhydrazine oxalate were added and the mixture was stirred at 120° C. for 3 hours. The reaction mixture was then concentrated, and the residue that remained was purified by preparative HPLC (Method 10). The product fractions were combined and concentrated, and the solid that remained was dried under reduced pressure (Yield: 26.0 mg, 15% of theory).
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[N:7][C:8]2[C:13]([C:14]=1O)=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:2][CH2:3][CH3:4].P(Cl)(Cl)([Cl:18])=O>>[CH2:1]([C:5]1[N:6]=[N:7][C:8]2[C:13]([C:14]=1[Cl:18])=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nnc2ccccc2c1O
Reactant: O=P(Cl)(Cl)Cl
Product: CCCCc1nnc2ccccc2c1Cl

Procedure:
Using the procedure of Step F of Example 1, 1.2 g of the product of Step B and 10 ml of phosphorous oxychloride were reacted to obtain after chromatography on silica (eluant: hexane--ethyl acetate (6-4)), 1.16 g of the desired product melting at 50° C.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:33][O:34][CH2:35][C:36](=[O:39])[NH:37][NH2:38])[C:10]([NH:12][CH:13]2[C:31](=[O:32])[N:15]3[C:16]([C:28]([OH:30])=[O:29])=[C:17]([CH2:20][S:21][C:22]4[S:23][C:24]([CH3:27])=[N:25][N:26]=4)[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1.C/C(/O[Si](C)(C)C)=N\[Si](C)(C)C.[C:52]([O:55][C:56]1[CH:57]=[C:58]([CH:62]=[CH:63][C:64]=1[O:65][C:66](=[O:68])[CH3:67])[C:59]([Cl:61])=[O:60])(=[O:54])[CH3:53].CCOCC>C(Cl)Cl.CO>[ClH:61].[NH2:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:33][O:34][CH2:35][C:36](=[O:39])[NH:37][NH:38][C:59](=[O:60])[C:58]2[CH:62]=[CH:63][C:64]([O:65][C:66](=[O:68])[CH3:67])=[C:56]([O:55][C:52](=[O:54])[CH3:53])[CH:57]=2)[C:10]([NH:12][CH:13]2[C:31](=[O:32])[N:15]3[C:16]([C:28]([OH:30])=[O:29])=[C:17]([CH2:20][S:21][C:22]4[S:23][C:24]([CH3:27])=[N:25][N:26]=4)[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1
Reactant: CC(=O)Oc1ccc(C(=O)Cl)cc1OC(C)=O
Reactant: Cc1nnc(SCC2=C(C(=O)O)N3C(=O)C(NC(=O)C(=NOCC(=O)NN)c4csc(N)n4)[C@H]3SC2)s1
Agent: C/C(=N\[Si](C)(C)C)O[Si](C)(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CO
Solvent: CCOCC
Product: CC(=O)Oc1ccc(C(=O)NNC(=O)CON=C(C(=O)NC2C(=O)N3C(C(=O)O)=C(CSc4nnc(C)s4)CS[C@H]23)c2csc(N)n2)cc1OC(C)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.1 %

Procedure:
In 3 ml of methylene chloride was suspended 0.35 g (0.53 mmole) of 7-[2-(2-amino-1,3-thiazol-4-yl)-2-carbazoylmethoxyiminoacetamido]-3-[(5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl]-3-cephem-4-carboxylic acid.dihydrochloride obtained in Reference example 9 and the suspension was dissolved by adding 1.35 g (6.66 mmole) of N,O-bis(trimethylsilyl)acetamide. To the mixture was added 0.136 g (0.53 mmole) of 3,4-diacetoxybenzoic acid chloride and the mixture was stirred at room temperature for one hour. The mixture was poured into 200 ml of ether and added thereto a small amount of methanol while stirring. The resulting precipitates were collected by filtration, washed with water and then dried to obtain 0.42 g of the title compound. (Yield: 94.1%)
Reaction SMILES: [C:1]([C:3]1[N:4]=[C:5]([O:14][C@H:15]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16]2)[C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][C:7]=2[F:13])#[N:2].[NH2:27][NH2:28].O>CO>[F:13][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[C:5]([O:14][C@H:15]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16]1)=[N:4][C:3]([C:1]([NH:27][NH2:28])=[NH:2])=[CH:12]2
Reactant: NN
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Oc2nc(C#N)cc3cccc(F)c23)C1
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC[C@H](Oc2nc(C(=N)NN)cc3cccc(F)c23)C1

Procedure:
To a mixture of (S)-tert-butyl 3-((3-cyano-8-fluoroisoquinolin-1-yl)oxy)pyrrolidine-1-carboxylate (600 mg, 1.61 mmol) in MeOH (15 mL) was added NH2NH2—H2O (10 mL) and the resulting mixture was heated to reflux for 2 hours. The solvent was removed in vacuo to afford the title compound as a white solid, which was used without further purification (500 mg).
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:22]=4[O:31][CH2:32][CH:33]4[CH2:35][CH2:34]4)[C:15]=3[NH:14][C:13]=2[CH3:36])=[O:11])[CH2:5][CH2:4]1.[C:37](Cl)(=[O:40])[CH2:38][CH3:39]>>[CH:33]1([CH2:32][O:31][C:22]2[CH:23]=[CH:24][C:25]([C:27]([F:30])([F:29])[F:28])=[CH:26][C:21]=2[C:20]2[C:15]3[NH:14][C:13]([CH3:36])=[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@H:3]([NH:2][C:37](=[O:40])[CH2:38][CH3:39])[CH2:4][CH2:5]4)=[O:11])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:34][CH2:35]1
Reactant: CCC(=O)Cl
Reactant: Cc1[nH]c2c(-c3cc(C(F)(F)F)ccc3OCC3CC3)ncnc2c1C(=O)N[C@H]1CC[C@H](N)CC1
Agent: Cl
Product: CCC(=O)N[C@H]1CC[C@H](NC(=O)c2c(C)[nH]c3c(-c4cc(C(F)(F)F)ccc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from N-(trans-4-aminocyclohexyl)-4-[2-(cyclopropylmethoxy)-5-(trifluoromethyl)phenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f32) and commercially available propionyl chloride the title compound is obtained as colorless solid. Alternative the above obtained solid is re-crystalised from ethylene glycol/water mixture (5/1).
Reaction SMILES: [CH:1]1([C:4]2(O)[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[S:11][C:10]3[C:5]2=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH2:3][CH2:2]1.C(O)(=O)C.[BrH:23]>O>[Br:23][CH2:3][CH2:2][CH:1]=[C:4]1[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[S:11][C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2
Reactant: Br
Reactant: OC1(C2CC2)c2ccccc2Sc2ccccc21
Solvent: O
Solvent: CC(=O)O
Product: BrCCC=C1c2ccccc2Sc2ccccc21
Reaction time: 0.5 h

Procedure:
To the above crude alcohol (25.2 g) was added glacial acetic acid (120 ml). The mixture was cooled on an ice-bath and a mixture of glacial acetic acid (60 ml) and 47% hydrobromic acid (30 ml) was added. The mixture was stirred for 30 minutes, poured into water (600 ml) and extracted with diethyl ether (3×200 ml). The combined organic phases were washed with water, dried (Na2SO4) and the solvent was evaporated in vacuo to give 19.5 g of crude 9-(3-bromo-1-propylidene)-9H-thioxanthene. Rf =0.35 (SiO2 ; THF/heptane=1:9).
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[C:12]([O:15][C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[C:18]([F:23])[CH:17]=1)[CH:11]=[CH:10][CH:9]=2)=[O:5])C.[Li+].[OH-]>CO.O>[F:23][C:18]1[CH:17]=[C:16]([CH:21]=[C:20]([F:22])[CH:19]=1)[O:15][C:12]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:13]=1[CH:14]=[C:6]([C:4]([OH:5])=[O:3])[NH:7]2
Reactant: CCOC(=O)c1cc2c(Oc3cc(F)cc(F)c3)cccc2[nH]1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1cc2c(Oc3cc(F)cc(F)c3)cccc2[nH]1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
156 (260 mg, 0.82 mmol) is dissolved in 10 ml of methanol and treated with a solution of LiOH (40 mg, 1.6 mmol) in 5 ml of water. The mixture is stirred at room temperature for 18 hours. After evaporation, the crude product is acidified at 0° C. with 2M HCl and extracted with ethyl acetate. The organic layers are dried over sodium sulphate and evaporated.
Reaction SMILES: Br[CH:2]=[CH:3][CH3:4].[Mg].[CH3:6][C:7]1[CH2:12][CH2:11][CH2:10][C:9]([CH3:14])([CH3:13])[C:8]=1[CH:15]=[O:16].[NH4+].[Cl-]>O1CCCC1>[CH3:6][C:7]1[CH2:12][CH2:11][CH2:10][C:9]([CH3:13])([CH3:14])[C:8]=1[CH:15]([OH:16])[CH:2]=[CH:3][CH3:4]
Reactant: CC=CBr
Reactant: CC1=C(C=O)C(C)(C)CCC1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC=CC(O)C1=C(C)CCCC1(C)C
Reaction time: 2 h

Procedure:
In an atmosphere of nitrogen, a solution of 280 g. of 1-bromopropene in 430 ml. of tetrahydrofuran was added dropwise at 63°-65° into a suspension of 53.3 g. of magnesium turnings in 660 ml. of tetrahydrofuran. During the addition the reflux condenser fitting the reaction vessel was cooled to -40° to -50° in order to prevent escaping of the vapours of unreacted 1 -bromopropene. The mixture was stirred for an additional 21/2 hours at 60°-62° after which it was cooled to 0°. A solution of 278 g. of β-cyclocitral in 350 ml. of tetrahydrofuran was then added dropwise between 0° and 7°. The mixture was allowed to stand overnight then it was poured onto a mixture of ice and saturated aqueous NH4Cl solution. The organic layer was removed and the aqueous phase extracted with petroleum-ether (b.p. 30°-50°). The combined extracts were washed as usual, dried and then evaporated under vacuum. The residue gave 350 g. of crude 2,6,6-trimethyl-1-[1-hydroxy-2-butenyl]-1-cyclohexene which was used without further purification.
Reaction SMILES: C([O:8][C:9]1[CH:36]=[CH:35][C:34]([O:37][CH:38]2[CH2:43][CH2:42][N:41]([CH3:44])[CH2:40][CH2:39]2)=[CH:33][C:10]=1[C:11]([NH:13][C:14]1[CH:26]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:24]=[CH:23][C:15]=1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:12])C1C=CC=CC=1>[C].[Pd].CO>[OH:8][C:9]1[CH:36]=[CH:35][C:34]([O:37][CH:38]2[CH2:39][CH2:40][N:41]([CH3:44])[CH2:42][CH2:43]2)=[CH:33][C:10]=1[C:11]([NH:13][C:14]1[CH:26]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:24]=[CH:23][C:15]=1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:12]
Reactant: CN1CCC(Oc2ccc(OCc3ccccc3)c(C(=O)Nc3cc(-c4ccccc4)ccc3C(=O)OC(C)(C)C)c2)CC1
Agent: [Pd]
Solvent: CO
Product: CN1CCC(Oc2ccc(O)c(C(=O)Nc3cc(-c4ccccc4)ccc3C(=O)OC(C)(C)C)c2)CC1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a methanol (5.0 mL) solution of the obtained tert-butyl 2-(2-(benzyloxy)-5-((1-methylpiperidin-4-yl)oxy)benzamido)-4-phenylbenzoate, 10% palladium-carbon (0.11 g) was added, followed by stirring under a hydrogen atmosphere at room temperature for 2 hours and 40 minutes. The insoluble substance was removed by filtration, and the obtained residue was purified by silica gel column chromatography [eluent: 100-90% chloroform/methanol] to obtain 0.13 g of tert-butyl 2-(2-hydroxy-5-((1-methylpiperidin-4-yl)oxy)benzamido)-4-phenylbenzoate as a light yellow solid.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:50][CH2:51][CH3:52])[C@@H:5]([N:7]([CH2:39][C:40]1[CH:41]=[CH:42][CH:43]=[C:44]2[C:49]=1[N:48]=[CH:47][CH:46]=[CH:45]2)[C:8](=[O:38])[C@@H:9]([NH:20]C(=O)OCC1C2C=CC=CC=2C2C1=CC=CC=2)[CH2:10][C:11]1[C:16]([CH3:17])=[CH:15][C:14]([OH:18])=[CH:13][C:12]=1[CH3:19])[CH3:6])[CH3:2].N1CCCCC1>>[NH2:20][C@@H:9]([CH2:10][C:11]1[C:16]([CH3:17])=[CH:15][C:14]([OH:18])=[CH:13][C:12]=1[CH3:19])[C:8]([N:7]([C@@H:5]([CH3:6])[CH:4]([O:50][CH2:51][CH3:52])[O:3][CH2:1][CH3:2])[CH2:39][C:40]1[CH:41]=[CH:42][CH:43]=[C:44]2[C:49]=1[N:48]=[CH:47][CH:46]=[CH:45]2)=[O:38]
Reactant: CCOC(OCC)[C@H](C)N(Cc1cccc2cccnc12)C(=O)[C@H](Cc1c(C)cc(O)cc1C)NC(=O)OCC1c2ccccc2-c2ccccc21
Solvent: C1CCNCC1
Product: CCOC(OCC)[C@H](C)N(Cc1cccc2cccnc12)C(=O)[C@@H](N)Cc1c(C)cc(O)cc1C
Yield: 115.4 %

Procedure:
According to the procedure described in the synthesis method of Compound IV-1, (9H-fluoren-9-yl)methyl (S)-1-(((S)-1,1-diethoxypropan-2-yl)(quinolin-8-ylmethyl)amino)-3-(4-hydroxy-2,6-dimethylphenyl)-1-oxopropan-2-ylcarbamate (Compound III-9) 512 mg (0.73 mmol) was treated with piperidine and purified on silica gel column chromatography (n-hexane:ethyl acetate=9:1, chloroform:methanol=100:0 and 8:2) to obtain the title compound 404 mg (115%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1C)=[O:10].ClC1C=CC2N=[C:24](C3C=CC=CC=3)[O:25]C(=O)C=2C=1>>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[O:25][CH3:24])=[O:10]
Reactant: O=c1oc(-c2ccccc2)nc2ccc(Cl)cc12
Reactant: Cc1ccccc1C(=O)c1cc(Cl)ccc1N
Product: COc1ccccc1C(=O)c1cc(Cl)ccc1N
Yield: 84 %

Procedure:
In a manner similar to that described above for compound 1m, 6-chloro-2-phenyl-benzo[d][1,3]oxazin-4-one was converted to in (84% yield) MS m/z=262 (M+H).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][N:5]1[CH2:12][CH:11]2[O:13][CH:7]([CH2:8][N:9]([CH2:14][CH2:15][O:16][C:17]3[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][C:18]=3[F:25])[CH2:10]2)[CH2:6]1.[F:26][C:27]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=1[S:34](Cl)(=[O:36])=[O:35].C(N(CC)CC)C>C(Cl)Cl>[C:21]([C:20]1[CH:23]=[CH:24][C:17]([O:16][CH2:15][CH2:14][N:9]2[CH2:10][CH:11]3[O:13][CH:7]([CH2:6][N:5]([CH2:4][CH2:3][NH:2][S:34]([C:28]4[CH:29]=[CH:30][C:31]([F:33])=[CH:32][C:27]=4[F:26])(=[O:36])=[O:35])[CH2:12]3)[CH2:8]2)=[C:18]([F:25])[CH:19]=1)#[N:22]
Reactant: N#Cc1ccc(OCCN2CC3CN(CCN)CC(C2)O3)c(F)c1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1F
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#Cc1ccc(OCCN2CC3CN(CCNS(=O)(=O)c4ccc(F)cc4F)CC(C2)O3)c(F)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 56.5 %

Procedure:
4-{2-[7-(2-Amino-ethyl)-9-oxa-3,7-diaza-bicyclo[3.3.1]non-3-yl]-ethoxy}-3-fluoro-benzonitrile hydrochloride salt (0.266 g, 0.6 mmol; prep N above) and 2,4-difluorobenzenesulfonyl chloride (0.170 g, 0.80 mmol) were dissolved in DCM (6 mL). Triethylamine (0.416 mL, 3 mmol) was added and the reaction mixture was stirred at room temperature for 20 h under a nitrogen atmosphere. The reaction mixture was concentrated and then redissolved in DCM (3 mL) and transferred to a phase separator. The DCM layer was washed with water (3 mL) and the layers were separated. The retained water was extracted with DCM (3 mL) and the layers were separated. The combined DCM fractions were concentrated under reduced pressure. The crude product was purified by chromatography on silica gel using methanol saturated with ammonia in dichloromethane as eluent, which afforded 173 mg (56%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][CH2:11][CH2:12][C:13]2([OH:26])[CH2:25][CH2:24][C:16]3([O:21]CC(C)(C)CO3)[CH2:15][CH2:14]2)[CH3:9])=[CH:4][CH:3]=1.Cl[C:28](Cl)([O:30]C(=O)OC(Cl)(Cl)Cl)Cl>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]([N:10]2[CH2:11][CH2:12][C:13]3([CH2:14][CH2:15][C:16](=[O:21])[CH2:24][CH2:25]3)[O:26][C:28]2=[O:30])[CH3:9])=[CH:6][CH:7]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: C[C@H](NCCC1(O)CCC2(CC1)OCC(C)(C)CO2)c1ccc(F)cc1
Product: C[C@@H](c1ccc(F)cc1)N1CCC2(CCC(=O)CC2)OC1=O
Yield: 50 %

Procedure:
The title compound is prepared from 9-{2-[(S)-1-(4-fluoro-phenyl)-ethylamino]-ethyl}-3,3-dimethyl-1,5-dioxa-spiro[5.5]undecan-9-ol and triphosgene following a procedure analogous to that described in Step 4 of Intermediate 2. Yield: 50% of theory; LC (method 5): tR=1.11 min; Mass spectrum (ESI+): m/z=306 [M+H]+.
Reaction SMILES: Cl[CH2:2][CH2:3][C@H:4]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[O:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13](=[O:15])[CH3:14])=[CH:8][C:7]=1[CH3:16].CC(C)=O.[I-:27].[K+]>C(OCC)C>[I:27][CH2:2][CH2:3][C@H:4]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[O:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13](=[O:15])[CH3:14])=[CH:8][C:7]=1[CH3:16]
Reactant: [I-]
Reactant: CC(=O)Oc1ccc(O[C@H](CCCl)c2ccccc2)c(C)c1
Agent: [K+]
Solvent: CCOCC
Solvent: CC(C)=O
Product: CC(=O)Oc1ccc(O[C@H](CCI)c2ccccc2)c(C)c1
Yield: 70 %

Procedure:
A mixture of (R)-3-chloro-1-phenyl-1-(2-methyl-4-acetoxyphenoxy)propane (0.200 gm, 0.63 mMol) and 15 mL acetone saturated with potassium iodide was stirred at reflux under argon overnight. The reaction mixture was poured into 50 mL diethyl ether and the resulting suspension was filtered. The filtrated was washed with saturated aqueous sodium hydrogen sulfite followed by water. The remaining organic phase was dried over magnesium sulfate and concentrated under reduced pressure to provide 0.18 gm (70%) of the desired compound as a colorless oil.
Reaction SMILES: Cl[CH:2]=[C:3]([Cl:7])[C:4](=[O:6])[CH3:5].[C:8]([SH:12])([CH3:11])([CH3:10])[CH3:9].C(N(CC)CC)C>C(OCC)C>[Cl:7][C:3]([C:4](=[O:6])[CH3:5])=[CH:2][S:12][C:8]([CH3:11])([CH3:10])[CH3:9]
Reactant: CC(=O)C(Cl)=CCl
Reactant: CC(C)(C)S
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CC(=O)C(Cl)=CSC(C)(C)C
Temperature: 5 °C
Reaction time: 18 h
Yield: 60.7 %

Procedure:
To a mixture of 20.85 g (0.15 mole) 1,2-dichloro-1-buten-3-one and 13.53 g (0.15 mole) t-butylmercaptan in 300 ml ethyl ether, cooled to 5° C. is added dropwise 15.18 g (0.15 mole) triethylamine in 50 ml ether. After stirring at room temperature for 18 hours the mixture is heated at reflux for 2 days. The resulting mixture is washed with water, brine and the organic layer dried over magnesium sulfate. Evaporation of ether affords a brown oil which is distilled in vacuo to yield 17.56 g of product as a light yellow liquid, B.P. 75° (0.1 mm) which crystallized upon standing, M.P. 73° C. Mass spectrum (m/e) 192 (molecular ion), 138, 136.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:9]2[CH:14]=[C:13]([Cl:15])[CH:12]=[C:11](Cl)[C:10]=2Cl)=[C:4]([CH2:18][O:19][CH3:20])[N:3]=1.[Cl:21]C1C=C(CC#N)C=CC=1Cl>>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:9]2[CH:10]=[CH:11][C:12]([Cl:21])=[C:13]([Cl:15])[CH:14]=2)=[C:4]([CH2:18][O:19][CH3:20])[N:3]=1
Reactant: N#CCc1ccc(Cl)c(Cl)c1
Reactant: COCc1nc(N)nc(N)c1-c1cc(Cl)cc(Cl)c1Cl
Product: COCc1nc(N)nc(N)c1-c1ccc(Cl)c(Cl)c1

Procedure:
This compound was prepared in an analogous manner to the compound of Example 2 from 3,4-dichlorophenylacetonitrile (Aldrich), mp. 204°-206° C.
Reaction SMILES: C(Cl)(Cl)Cl.[Cl:5][C:6]1[CH:7]=[C:8]([CH:12]2[C:16]([OH:17])=[C:15]([C:18]([CH3:20])=[O:19])[CH2:14][S:13]2)[CH:9]=[CH:10][CH:11]=1.S(Cl)(Cl)(=O)=O>O>[Cl:5][C:6]1[CH:7]=[C:8]([C:12]2[S:13][CH:14]=[C:15]([C:18]([CH3:20])=[O:19])[C:16]=2[OH:17])[CH:9]=[CH:10][CH:11]=1
Reactant: CC(=O)C1=C(O)C(c2cccc(Cl)c2)SC1
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: O=S(=O)(Cl)Cl
Product: CC(=O)c1csc(-c2cccc(Cl)c2)c1O
Temperature: -15 °C
Reaction time: 1 h
Yield: 98.7 %

Procedure:
A chloroform (25 mL) solution of 2-(3-chlorophenyl)-3-hydroxy-4-methylcarbonyl-2,5-dihydrothiophene (2.49 g, 8.02 mmol, purity: 82%) was cooled to −43° C., and to this solution, a chloroform (50 mL) solution of sulfuryl chloride (0.77 mL, 1.1 equivalent amounts) was dropwise added over a period of 32 minutes, followed by stirring at −15° C. for 1 hour. The temperature of the solution was raised to 0° C., and water (5 mL) was dropwise added, followed by liquid separation. The obtained chloroform solution was sequentially washed with water, a saturated salt solution, a sodium hydroxide aqueous solution, a saturated sodium thiosulfate aqueous solution and a saturated salt solution, and dried over anhydrous magnesium sulfate. The drying agent was removed by filtration, and the solvent was distilled off to give the desired product as a yellow solid (2.0 g, yield: 99%).
Reaction SMILES: Br[C:2]1[CH2:6][CH2:5][C:4](=[O:7])[C:3]=1[CH3:8].CC1(C)C(C)(C)OB([C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[NH:22][CH:21]=[CH:20]3)O1>>[NH:22]1[C:23]2[C:19](=[CH:18][C:17]([C:2]3[CH2:6][CH2:5][C:4](=[O:7])[C:3]=3[CH3:8])=[CH:25][CH:24]=2)[CH:20]=[CH:21]1
Reactant: CC1=C(Br)CCC1=O
Reactant: CC1(C)OB(c2ccc3[nH]ccc3c2)OC1(C)C
Product: CC1=C(c2ccc3[nH]ccc3c2)CCC1=O
Yield: 92 %

Procedure:
Synthesized from 3-bromo-2-methylcyclopent-2-enone and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole according to the general procedure described for the Suzuki coupling. Purification by automated flash chromatography using gradient elution (0 to 100% ethyl acetate/hexanes) and further recrystallization yielded the product (138 mg, 92%) as pale yellow solid. 1H NMR (CDCl3, 300 MHz): δ 7.86 (s, 1H), 7.47-7.39 (m, 2H), 7.27 (t, J=3.0 Hz, 1H), 6.62 (t, J=2.1 Hz, 1H), 3.02-2.97 (m, 2H), 2.57-2.54 (m, 2H), 2.05 (t, 3H, J=1.8). 13C NMR (CDCl3, 75 MHz): δ 210.0, 168.3, 136.2, 134.5, 128.2, 127.8, 125.3, 121.9, 120.6, 111.1, 103.4, 34.2, 29.7, 10.5. LCMS (ESI): mass calcd for (C14H13NO) m/z 211.10; measured [M+H]+: m/z 212.03.
Reaction SMILES: [NH:1]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C@H:2]([C:6]([OH:8])=O)[CH:3]([CH3:5])[CH3:4].[NH2:16][C@H:17]([C:22]([OH:24])=[O:23])[CH2:18][CH:19]([CH3:21])[CH3:20].C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)Cl>[NH:1]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C@H:2]([C:6]([NH:16][C@H:17]([C:22]([OH:24])=[O:23])[CH2:18][CH:19]([CH3:21])[CH3:20])=[O:8])[CH:3]([CH3:4])[CH3:5]
Reactant: CC(C)C[C@H](N)C(=O)O
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CC(C)C[C@H](NC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C)C(=O)O

Procedure:
To 25 ml of a solution of 0.35 g of Boc-Val-OH in methylene chloride the H-Leu-resin described above was added and 5 ml of a solution of 0.33 g of DCC in methylene chloride was then added to the resulting mixture. The mixture was reacted at room temperature for 2 hours. After washing the resin 6 times with 30 ml of methylene chloride, the resin was added to 25 ml of a methylene chloride solution of 0.35 g of Boc-Val-OH and 0.55 g of 1-hydroxybenzotriazole. Then, 5 ml of a methylene chloride solution of 0.33 g of DCC was added thereto and the resulting mixture was again reacted in a similar manner (double coupling). The resin was thoroughly washed with methylene chloride to obtain Boc-Val-Leu-resin.