Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[S:11][C:12]1[CH:13]=[C:14]([CH2:18][C:19]([OH:21])=[O:20])[CH:15]=[CH:16][CH:17]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:22]([N:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:10]([S:11][C:12]2[CH:13]=[C:14]([CH2:18][C:19]([OH:21])=[O:20])[CH:15]=[CH:16][CH:17]=2)=[C:2]1[CH3:1])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: BrCc1ccccc1
Reactant: Cc1[nH]c2ccccc2c1Sc1cccc(CC(=O)O)c1
Product: Cc1c(Sc2cccc(CC(=O)O)c2)c2ccccc2n1Cc1ccccc1

Procedure:
Prepared according to the procedure described in Example 4, Step 1, using the following starting materials: [3-(2-methyl-1H-indol-3-ylsulfanyl)-phenyl]-acetic acid and benzyl bromide.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[CH:9][S:10][C:3]=12.[CH3:11][NH:12][C:13]([C:15]1[C:19]2[CH:20]=[CH:21][C:22]([OH:24])=[CH:23][C:18]=2[O:17][C:16]=1[CH3:25])=[O:14].C([O-])([O-])=O.[Cs+].[Cs+]>>[CH3:11][NH:12][C:13]([C:15]1[C:19]2[CH:20]=[CH:21][C:22]([O:24][C:2]3[CH:7]=[CH:6][N:5]=[C:4]4[CH:8]=[CH:9][S:10][C:3]=34)=[CH:23][C:18]=2[O:17][C:16]=1[CH3:25])=[O:14]
Reactant: CNC(=O)c1c(C)oc2cc(O)ccc12
Reactant: Clc1ccnc2ccsc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CNC(=O)c1c(C)oc2cc(Oc3ccnc4ccsc34)ccc12

Procedure:
This material was prepared by the reaction of 7-chloro-thieno[3,2-b]pyridine with 6-hydroxy-2-methylbenzofuran-3-carboxylic acid methyl amide 12c and Cs2CO3 in a manner as previously described for example 1. 1H NMR (CD3CN) δ 8.48 (1H,d, J=5.3 Hz), 7.91 (1H, d, J=5.6 Hz), 7.84 (1H, d, J=8.6 Hz), 7.53 (1H, d, J=5.6 Hz), 7.41 (1H, d, J=2.0 Hz), 7.20 (1H, dd, J=8.6, 2.0 Hz), 6.62 (1H, d, J=5.3 Hz), 6.60 (1H, bm), 2.91 (3H, d, J=4.6 Hz) 2.66 (3H, s).
Reaction SMILES: COC=C.C[O:6][C:7]([CH2:13][C:14]([F:17])([F:16])[F:15])=[CH:8][C:9]([F:12])([F:11])[F:10].OS(O)(=O)=O>O>[F:10][C:9]([F:11])([F:12])[CH2:8][C:7](=[O:6])[CH2:13][C:14]([F:16])([F:17])[F:15]
Reactant: COC(=CC(F)(F)F)CC(F)(F)F
Agent: C=COC
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C(CC(F)(F)F)CC(F)(F)F
Reaction time: 0.17 h
Yield: 77.3 %

Procedure:
The vinyl methyl ether, 3-methoxy-1,1,1,5,5,5-hexafluoropent-2-ene, (21.3 g, 102 mmol) was added to 20 mL (36 g) concentrated H2SO4 at 15-20° C. over 15 min Stirring was continued for 10 min. and the reaction mixture poured into 100 mL cold water. The product was extracted with 2×40 mL ether. The combined extracts were washed with brine, dried (Na2SO4) and distilled to give 15.3 g (77% yield) of 1,1,1,5,5,5-hexafluoropentan-3-one, bp 122-123° C.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][C@H:9]([O:13][C:14]1[NH:15][C:16]([NH2:25])=[C:17]2[C:21]([N:22]=1)=[N:20][C:19]([O:23][CH3:24])=[N:18]2)[CH2:10][CH2:11][CH3:12].Br[CH2:27][CH2:28][CH2:29][CH:30]1[CH2:34][CH2:33][O:32][CH2:31]1>>[CH3:8][C@H:9]([O:13][C:14]1[N:22]=[C:21]2[C:17]([N:18]=[C:19]([O:23][CH3:24])[N:20]2[CH2:27][CH2:28][CH2:29][CH:30]2[CH2:34][CH2:33][O:32][CH2:31]2)=[C:16]([NH2:25])[N:15]=1)[CH2:10][CH2:11][CH3:12]
Reactant: CCC[C@H](C)Oc1nc2nc(OC)nc-2c(N)[nH]1
Reactant: BrCCCC1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: CCC[C@H](C)Oc1nc(N)c2nc(OC)n(CCCC3CCOC3)c2n1

Procedure:
Prepared similarly to Intermediate 220 from 2-{[(1S)-1-methylbutyl]oxy}-8-(methyloxy)-1H-purin-6-amine trifluoroacetate and 3-(3-bromopropyl)tetrahydrofuran.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[CH:7]=[C:8]1[CH2:11][CH:10]([C:12]([OH:14])=[O:13])[CH2:9]1)([CH3:4])([CH3:3])[CH3:2]>CO.[C].[Pd]>[C:1]([O:5][C:6](=[O:15])[CH2:7][CH:8]1[CH2:9][CH:10]([C:12]([OH:14])=[O:13])[CH2:11]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)C=C1CC(C(=O)O)C1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)CC1CC(C(=O)O)C1
Temperature: 25 °C
Reaction time: 5 h
Yield: 99.1 %

Procedure:
A mixture of 3-(2-(tert-butoxy)-2-oxoethylidene)cyclobutanecarboxylic acid (3.4 g, 16.02 mmol) and 10% palladium-carbon (100 mg, 0.94 mmol, 50%, wet) in MeOH (30 mL) was stirred at room temperature for 5 hr under hydrogen atmosphere (1 atm). The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 30→100% ethyl acetate/hexane) to give 3-(2-(tert-butoxy)-2-oxoethyl)cyclobutanecarboxylic acid (3.40 g, 15.87 mmol, 99%) as a colorless oil.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[C:11]([CH:13]3[CH2:18][CH2:17][N:16]([O:19][CH3:20])[CH2:15][CH2:14]3)[CH:10]=[CH:9][C:8]=2[NH:21][C:22]([C:24]2[N:25](COCC[Si](C)(C)C)[CH:26]=[C:27]([C:29]#[N:30])[N:28]=2)=[O:23])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[C:39]([OH:45])([C:41]([F:44])([F:43])[F:42])=[O:40]>C(Cl)Cl.CCO>[F:42][C:41]([F:44])([F:43])[C:39]([OH:45])=[O:40].[C:1]1([C:7]2[CH:12]=[C:11]([CH:13]3[CH2:18][CH2:17][N:16]([O:19][CH3:20])[CH2:15][CH2:14]3)[CH:10]=[CH:9][C:8]=2[NH:21][C:22]([C:24]2[NH:28][C:27]([C:29]#[N:30])=[CH:26][N:25]=2)=[O:23])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: CON1CCC(c2ccc(NC(=O)c3nc(C#N)cn3COCC[Si](C)(C)C)c(C3=CCCCC3)c2)CC1
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CON1CCC(c2ccc(NC(=O)c3ncc(C#N)[nH]3)c(C3=CCCCC3)c2)CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 58 %

Procedure:
To a solution of 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylic acid [2-cyclohex-1-enyl-4-(1-methoxy-piperidin-4-yl)-phenyl]-amide (as prepared in previous step, 31 mg, 0.020 mmol) in DCM (0.5 mL) and EtOH (11 μL) was added TFA (0.1 mL). The resulting solution was stirred at RT for 6 h. The reaction mixture was concentrated in vacuo and the resulting residue was dried for 1 h, suspended in ether (10 mL) and sonicated for 5 min. The solid formed was collected by suction filtration to obtain the title compound (17.3 mg, 58%). 1H-NMR (DMSO; 400 MHz): δ 9.70 (s, 1H), 8.30 (s, 1H), 7.83 (d, 1H, J=8.4 Hz), 7.14 (d, 1H, J=8.4 Hz), 7.05 (s, 1H), 5.71 (br s, 1H), 3.30-3.55 (m, 5H), 2.41-2.62 (m, 2H), 2.12-2.19 (m, 4H), 1.60-1.85 (m, 8H). Mass spectrum (ESI, m/z): Calcd. for C23H27N5O2, 406.2 (M+H). found 406.1.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH:25]=[O:26])[CH2:23][CH2:22][C:21]([C:27]([NH:29][C:30]4[CH:35]=[CH:34][C:33]([C@@H:36]([OH:43])[C:37]5[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=5)=[CH:32][CH:31]=4)=[O:28])=[CH:20][C:19]=3[CH:44]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:53])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH:25]=[O:26])[CH2:23][CH2:22][C:21]([C:27]([NH:29][C:30]4[CH:31]=[CH:32][C:33]([C@@H:36]([OH:43])[C:37]5[CH:42]=[CH:41][CH:40]=[CH:39][N+:38]=5[O-:53])=[CH:34][CH:35]=4)=[O:28])=[CH:20][C:19]=3[CH:44]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc([C@@H](O)c4ccccn4)cc2)CCN3C=O)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc([C@@H](O)c4cccc[n+]4[O-])cc2)CCN3C=O)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 51.1 %

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-1-formyl-N-[4-[(R)-hydroxy(2-pyridyl)methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (130 mg) in dichloromethane (20 ml) was added 3-chloroperbenzoic acid (70%, 65 mg) at 0° C., and the mixture was stirred at room temperature for 18 hours. To the-reaction solution was added sodium thiosulfate solution, and the mixture was stirred for several minutes, and extracted with ethyl acetate. The organic layer was washed with sodium bicarbonate solution and saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by column chromatography (ethanol:ethyl acetate 1:4) and recrystallized from ethyl acetate-diisopropylether to give 7-[4-(2-butoxyethoxy)phenyl]-1-formyl-N-[4-[(R)-hydroxy(1-oxidopyridin-2-yl)methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 78) (68.2 mg) as pale yellow crystals.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([CH2:14]Cl)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16]1(=[O:26])[NH:20][C:19](=[O:21])[C:18]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:17]12.[K]>CN(C)C=O>[CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([CH2:14][N:20]2[C:19](=[O:21])[C:18]3=[CH:22][CH:23]=[CH:24][CH:25]=[C:17]3[C:16]2=[O:26])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCC1CN(Cc2ccccc2)CCO1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CC1CN(Cc2ccccc2)CCO1
Temperature: 100 °C
Reaction time: 16 h
Yield: 109.5 %

Procedure:
To a solution of 4-benzyl-2-chloromethyl-morpholine (43 g, 0.19 mol) in 500 ml of dimethylformamide was added potassium phthalimide (37 g, 0.20 mol) and the mixture was stirred at 100° C. for 16 hours. After insolubles were filtered off, the solvent was distilled off from the filtrate under reduced pressure to give crude 4-benzyl-2-phthalimidomethylmorpholine (70 g). This compound was used for the subsequent reaction without purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](Cl)=[N:6][CH:7]=1.[Cl:9][C:10]1[CH:11]=[C:12]([C:17]2[CH:22]=[C:21]([N:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)[N:20]=[C:19]([N:29]3[CH2:33][CH2:32][CH2:31][CH:30]3[CH3:34])[N:18]=2)[CH:13]=[CH:14][C:15]=1[F:16].CCN(C(C)C)C(C)C.CC(N(C)C)=O>CCOC(C)=O>[Cl:9][C:10]1[CH:11]=[C:12]([C:17]2[N:18]=[C:19]([N:29]3[CH2:33][CH2:32][CH2:31][CH:30]3[CH3:34])[N:20]=[C:21]([N:23]3[CH2:24][CH2:25][N:26]([C:5]4[N:4]=[CH:3][C:2]([Br:1])=[CH:7][N:6]=4)[CH2:27][CH2:28]3)[CH:22]=2)[CH:13]=[CH:14][C:15]=1[F:16]
Reactant: Clc1ncc(Br)cn1
Reactant: CC1CCCN1c1nc(-c2ccc(F)c(Cl)c2)cc(N2CCNCC2)n1
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: CC1CCCN1c1nc(-c2ccc(F)c(Cl)c2)cc(N2CCN(c3ncc(Br)cn3)CC2)n1

Procedure:
Heat a solution of 5-bromo-2-chloropyrimidine (Lancaster Chemicals, 565 mg), 4-(3-chloro-4-fluorophenyl)-2-(2-methylpyrrolidin-1-yl)-6-piperazin-1-yl-pyrimidine (1000 mg), DIEA (500 mg) and DMA (5 mL) at 110° C. for 3 h under nitrogen. Dilute with EtOAc (15 mL), wash with water (3×10 mL), dry (Na2SO4), and evaporate. Purify by silica gel chromatography, eluting with 1:1 hexanes:EtOAc to provide the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C:11](=O)[C@@H:10]([NH:14][C:15]([C:17]2[S:18][C:19]([Cl:22])=[CH:20][CH:21]=2)=[O:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl-].[NH4+].CC[N:27](C(C)C)C(C)C.[BH4-].[Na+]>CCO.CCOC(C)=O.CC([O-])C.CC([O-])C.CC([O-])C.CC([O-])C.[Ti+4]>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]([NH:14][C:15]([C:17]2[S:18][C:19]([Cl:22])=[CH:20][CH:21]=2)=[O:16])[C@@H:11]([NH2:27])[CH2:12]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(C)(C)OC(=O)N1CC(=O)[C@@H](NC(=O)c2ccc(Cl)s2)C1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [BH4-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CC(NC(=O)c2ccc(Cl)s2)[C@@H](N)C1
Temperature: 40 °C
Reaction time: 5 h

Procedure:
35.2 A solution of 500 mg (S)-3-[(5-chloro-thiophene-2-carbonyl)-amino]-4-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester in 20 ml EtOH was treated with 155 mg ammonium chloride, 0.49 ml Hünig's base and 0.86 ml tetraisopropyl orthotitanate. The reaction mixture was stirred for 5 hrs at 40° C. Then it was cooled to 0° C., treated with 110 mg NaBH4 and stirred at r.t. overnight. The mixture was diluted with EtOAc and washed with H2O. The organic layer was dried over MgSO4, filtered and concentrated. The crude product was purified by column chromatography (silica gel, gradient: CH2Cl2->CH2Cl2/MeOH 9:1) to give 180 mg (S)-3-amino-4-[(5-chloro-thiophene-2-carbonyl)-amino]-pyrrolidine-1-carboxylic acid tert-butyl ester as yellow solid. MS 344.3 ([M−H]−)
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[OH-].[Ca+2].[OH-].[C:13](Cl)(=O)CC.N>C(Cl)Cl.C(C(C)=O)C>[C:3]([CH2:2][C:1]([O:7][CH2:8][CH3:9])=[O:6])(=[O:4])[CH2:5][CH3:13]
Reactant: CCC(=O)Cl
Reactant: CCOC(=O)CC(C)=O
Agent: N
Agent: [Ca+2]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCC(C)=O
Product: CCOC(=O)CC(=O)CC
Yield: 92.9 %

Procedure:
Under the same conditions as in Example 1, 130 g (1.0 mol) of ethyl acetoacetate in a mixture of 1.2 l of methylene chloride and 300 ml of methyl ethyl ketone were reacted with 77.8 g (1.05 mol) of calcium hydroxide and 106.5 g (1.15 mol) of propionyl chloride. The subsequent reaction time after the ammonia had been metered in was 4 hours at a pH of 9.3. This gave 134 g (GC purity 72.0%) of ethyl propionylacetate (yield 67.0%).
Reaction SMILES: C([O:3][C:4](=[O:26])[C:5]([O:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([CH3:25])([CH3:24])[CH3:23])[CH:17]=1)([CH3:14])[CH2:6][C:7]1[CH:12]=[CH:11][C:10](O)=[CH:9][CH:8]=1)C.[CH3:27][C:28]1[O:32][C:31]([C:33]2[CH:38]=[CH:37][C:36]([C:39]3[S:40][CH:41]=[CH:42][CH:43]=3)=[CH:35][CH:34]=2)=[N:30][C:29]=1[CH2:44][CH2:45][O:46]S(C1C(C)=CC=CC=1)(=O)=O.C([O-])([O-])=O.[K+].[K+].[OH-].[Na+]>C(O)C>[C:22]([C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][CH:19]=1)[O:15][C:5]([CH3:14])([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:46][CH2:45][CH2:44][C:29]2[N:30]=[C:31]([C:33]3[CH:34]=[CH:35][C:36]([C:39]4[S:40][CH:41]=[CH:42][CH:43]=4)=[CH:37][CH:38]=3)[O:32][C:28]=2[CH3:27])=[CH:11][CH:12]=1)[C:4]([OH:26])=[O:3])([CH3:25])([CH3:23])[CH3:24]
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1cccc(C(C)(C)C)c1
Reactant: Cc1ccccc1S(=O)(=O)OCCc1nc(-c2ccc(-c3cccs3)cc2)oc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CCO
Product: Cc1oc(-c2ccc(-c3cccs3)cc2)nc1CCOc1ccc(CC(C)(Oc2cccc(C(C)(C)C)c2)C(=O)O)cc1

Procedure:
A mixture of 2-(3-tert-butyl-phenoxy)-3-(4-hydroxyphenyl)-2-methylpropionic acid ethyl ester (0.030 mmol) (see Ex. 23, Part B), toluenesulfonic acid 2-(5-methyl-2-(4-thiophen-2-yl-phenyl)-oxazol-4-yl)ethyl ester (0.030 mmol) (see Ex. 3, Part B) and 325 mesh K2CO3 (0.084 g, 0.60 mmol) in ethanol (2 mL) was heated to reflux for 24 h under N2. Aqueous 5N NaOH (0.5 mL) and additional ethanol (1 mL) was added to the reaction mixture and it was heated at reflux for an additional 2 h. The reaction was cooled and the solvent removed in vacuo. The residue was acidified with aqueous 1 N HCl (5 mL), extracted with water and CH2Cl2 and the organic layer dried by passing it through a Varian Chem Elut 1003 cartridge. The solvent was removed in vacuo to give 2-(3-tert-butyl-phenoxy)-2-methyl-3-(4-{2-[5-methyl-2-(4-thiophen-2-yl-phenyl)-oxazol-4-yl]-ethoxy)-phenyl)-propionic acid. 1H NMR (400 MHz, CDCl3) δ 7.97 (d, 2H, J=8.60 Hz), 7.67 (d, 2H, J=8.60 Hz), 7.36 (dd, 1H, J=3.91 Hz, 1.17 Hz), 7.33 (dd, 1H, J=3.91 Hz, 1.17 Hz), 7.20–7.16 (m, 3H), 7.12–7.07 (m, 2H), 6.89 (t, 1H, J=1.96 Hz), 6.84 (d, 2H, J=8.60 Hz), 6.72 (dd, 1H, J=8.60 Hz, 2.74 Hz), 4.22 (t, 2H, J=6.65 Hz), 3.25 (d, 1H, J=14.08 Hz), 3.15 (d, 1H, J=14.08 Hz), 3.01 (t, 2H, J=6.65 Hz), 2.40 (s, 3H), 1.43 (s, 3H), 1.26 (s, 9H). HRMS (ES+) m/z exact mass calcd for C36H38NO5S 596.2471, found 596.2454.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH:5]=O.[CH2:11]([NH2:15])[CH2:12][CH2:13][CH3:14]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][NH:15][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCN
Reactant: O=Cc1ccc(Cl)c(Cl)c1
Product: CCCCNCc1ccc(Cl)c(Cl)c1
Yield: 53.5 %

Procedure:
Following a procedure analogous to that for the synthesis of Example 106, 3,4-dichlorobenzaldehyde (10.0 g, 57.1 mmol) and butan-1-amine (4.18 g, 57.1 mmol) were converted to the title compound (7.09 g, 53%). 1H NMR (CDCl3) δ 7.45 (d, J=2.0 Hz, 1H), 7.40 (d, J=8.1 Hz, 1H), 7.19 (dd, J=2.0, 8.1 Hz, 1H), 3.79 (s, 2H), 2.68-2.59 (m, 2H), 1.59-1.45 (m, 2H), 1.36 (qd, J=7.3, 15.0 Hz, 2H), 0.92 (t, J=7.4 Hz, 3H); MS (ESI+) m/z 232.1 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH3:7].C([Li])CCC.[Cl:13][C:14]1[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[CH:30][C:15]=1[O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]SC1SCC(=O)N=1>O1CCCC1>[Cl:13][C:14]1[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[CH:30][C:15]=1[O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1
Reactant: Cc1ccccn1
Reactant: COc1ccc(OCCCCCCSC2=NC(=O)CS2)c(Cl)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(OCCCCCCCc2ccccn2)c(Cl)c1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
Under a nitrogen atmosphere, add 152 mg. 2-picoline and 1.5 ml. tetrahydrofuran (THF) and cool to -28° C. Add 104 mg. n-butyl lithium and stir about 30 minutes at -78° C. Add 20 mg. of the iodide prepared in Examples 2 and 3 in 1 ml. THF. Stir 1 hour at -78° C., let warm to room temperature and stir about 15 hours. Work up with water and methylene chloride then wash with water and brine then dry over sodium sulfate. Elute on a coarse silica column with methylene chloride then 50% ethylacetate/methylene chloride to obtain the title compound. Prepare the hydrochloride salt by reaction of the title compound with 0.1N HCl.
Reaction SMILES: [N:1]1[CH:5]=[N:4][N:3]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[OH:12])[N:2]=1.[OH-].[Na+].I[CH3:16]>CN(C)C=O.O.C(OCC)(=O)C>[CH3:16][N:1]1[CH:5]=[N:4][N:3]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[OH:12])[NH:2]1
Reactant: Oc1ccccc1-n1ncnn1
Reactant: CI
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CN1C=NN(c2ccccc2O)N1
Temperature: 25 °C
Reaction time: 15 h
Yield: 65.2 %

Procedure:
2-(Tetrazol-3-yl)phenol (32.8 g, 202.3 mmol) is dissolved in dimethylformamide (100 mL) and water (25 mL) and cooled in ice. Sodium hydroxide (8.49 g, 212.3 mmol) in water (20 mL) is added and the solution is warmed to ambient temperature. After thirty minutes, iodomethane (31.58 g, 222.5 mmol) is added neat. The solution is stirred for 15 hours then diluted with ethyl acetate (300 mL) and water (500 mL). The aqueous layer is washed three times with ethyl acetate (300 mL) and the organic layers are combined, washed three times with water (1 L), once with brine (1.2 L), dried over magnesium sulfate, filtered and concentrated in vacuo. The solid is purified by flash column chromatography (80% hexane:20% ethyl acetate gradient to 50% hexane:50% ethyl acetate as an eluent) to give 23.5 g of 2-(1-methyltetrazol-3-yl)phenol (66%).
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([CH2:21][N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:17]=3)[N:12]([CH2:28][S:29][CH3:30])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1.O.C1(C)C=CC(S(O)(=O)=[O:41])=CC=1.ClC1C=C(C=CC=1)C(OO)=O>ClCCl>[Cl:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([CH2:21][N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:17]=3)[N:12]([CH2:28][S:29]([CH3:30])=[O:41])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: CSCn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CN3CCOCC3)ccc21
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: O
Product: CS(=O)Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CN3CCOCC3)ccc21
Reaction time: 1 h
Yield: 76 %

Procedure:
A solution of N-(4-chlorobenzyl)-1-[(methylsulfanyl)methyl]-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-quinolinecarboxamide (0.14 gm) from Example No. 73 in dichloromethane (4 mL) at 0° C. is added p-toluenesulfonic acid hydrate (0.06 gm) followed by m-chloroperoxybenzoic acid (˜85%) (0.06 gm). The mixture is stirred for 1 hr. The reaction mixture is diluted with dichloromethane, washed with saturated aqueous sodium sulfite, saturated aqueous sodium bicarbonate, brine, dried (Na2SO4) and concentrated under reduced pressure. The crude product is purified by recrystallization from methanol-acetonitrile to afford 0.11 gm of the title compound as a white solid.
Reaction SMILES: C([Li])CCC.[CH2:6]([O:8][C:9]#[CH:10])[CH3:7].[CH2:11]([Sn:15](Cl)([CH2:20][CH2:21][CH2:22][CH3:23])[CH2:16][CH2:17][CH2:18][CH3:19])[CH2:12][CH2:13][CH3:14]>C(OCC)C>[CH2:20]([Sn:15]([CH2:11][CH2:12][CH2:13][CH3:14])([CH2:16][CH2:17][CH2:18][CH3:19])[C:10]#[C:9][O:8][CH2:6][CH3:7])[CH2:21][CH2:22][CH3:23]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: C#COCC
Agent: [Li]CCCC
Solvent: CCOCC
Product: CCCC[Sn](C#COCC)(CCCC)CCCC
Temperature: -35 °C
Reaction time: 2 h

Procedure:
A solution of n-butyllithium (18.7 mL-1.6 M in hexanes, 30.0 mmole) was added to anhydrous ethyl ether (20 mL) and the resulting mixture was then cooled to −30 to −40 ° C. A solution of ethoxy acetylene (5.00 g-40% in hexanes, 28.5 mmole) in ethyl ether (10 mL) was then added dropwise over 10 minutes. The resulting suspension was allowed to warm to room temperature, tributyltin chloride (9.29 g, 28.5 mmole) was added dropwise over 10 minutes and the mixture was stirred for 2 hrs. The mixture was filtered through a celite pad, washed with ethyl ether and concentrated in vacuo to give an assumed quantitative yield of the crude product as a red oil: 1H NMR (dmso-d6/300 MHz) 4.04 (q, 2H, J=7.05 Hz), 1.54-1.44 (m, 6H), 1.34-1.21 (m, 12H), 0.96-0.78 (m, 15H).
Reaction SMILES: [C:1]([N:4]1[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[C:13](Cl)[CH:12]=[CH:11][C:10]=2[C:16]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[C:29]([CH3:30])=[CH:28][C:27]([CH3:31])=[CH:26][N:25]=3)[CH2:20][CH2:19]2)=[O:17])[C:5]1=[O:32])(=[O:3])[CH3:2].[CH3:33][C@@H:34]1[CH2:38][O:37][C:36](=[O:39])[NH:35]1>>[C:1]([N:4]1[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[C:13]([N:35]3[C@H:34]([CH3:33])[CH2:38][O:37][C:36]3=[O:39])[CH:12]=[CH:11][C:10]=2[C:16]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[C:29]([CH3:30])=[CH:28][C:27]([CH3:31])=[CH:26][N:25]=3)[CH2:20][CH2:19]2)=[O:17])[C:5]1=[O:32])(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCN(c2cc(Cl)ccc2C(=O)N2CCN(c3ncc(C)cc3C)CC2)C1=O
Reactant: C[C@@H]1COC(=O)N1
Product: CC(=O)N1CCN(c2cc(N3C(=O)OC[C@H]3C)ccc2C(=O)N2CCN(c3ncc(C)cc3C)CC2)C1=O
Yield: 11.8 %

Procedure:
By reaction and treatment in the same manner as in Example 201 and using 1-acetyl-3-{5-chloro-2-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]phenyl}imidazolidin-2-one (519 mg) described in Preparation Example 126 and (R)-4-methyloxazolidin-2-one (115 mg) described in Preparation Example 25, the title compound (69.9 mg) was obtained.
Reaction SMILES: [OH:1][CH2:2]/[CH:3]=[C:4](/[CH3:17])\[CH2:5][CH2:6]/[CH:7]=[C:8](\[CH3:16])/[CH2:9][CH2:10][C:11](=[O:15])[C:12]([CH3:14])=[CH2:13].C([S:21][CH2:22][CH2:23][NH:24][C:25](=[O:27])[CH3:26])(=O)C.C(N(CC)CC)C>CO>[C:25]([NH:24][CH2:23][CH2:22][S:21][CH2:13][CH:12]([CH3:14])[C:11](=[O:15])[CH2:10][CH2:9]/[C:8](/[CH3:16])=[CH:7]/[CH2:6][CH2:5]/[C:4](/[CH3:17])=[CH:3]\[CH2:2][OH:1])(=[O:27])[CH3:26]
Reactant: CC(=O)NCCSC(C)=O
Reactant: C=C(C)C(=O)CC/C(C)=C/CC/C(C)=C\CO
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(=O)NCCSCC(C)C(=O)CC/C(C)=C/CC/C(C)=C\CO
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of 3.5 g (0.0148 mol) of (6E,10Z)-12-hydroxy-2,6,10-trimethyl-1,6,10-dodecatrien-3-one in 110 ml of methanol is treated with 7.15 g of N-(2-acetylthioethyl)acetamide and 6.2 ml of triethylamine. The solution is stirred under argon at room temperature for 24 hours. The solvents are removed on a rotary evaporator. The residue is taken up three times with toluene and freed from solvent on a rotary evaporator. The crude product can be used directly for the acetylation described in Example 12 or can be chromatographed on silica gel with ether-methanol 15:1. After chromatographic purification there is obtained (2Z,6E)-12-[(2-acetamidoethyl)thio]-3,7,11-trimethyl-10-oxo-2,6-dodecadien-1-ol which exhibits the following bands in the IR spectrum: 1737 cm-1, 1715 cm-1, 1437 cm-1, 1366 cm-1, 1277 cm-1,1235 cm-1, 1157 cm-1, 1136 cm-1, 1022 cm-1.