Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@@:4]1([CH3:25])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[NH:6][C:5]1=[O:24])[CH:2]=[CH2:3].[H-].[Na+].[Cl:28][C:29]1[N:34]=[C:33](Cl)[CH:32]=[CH:31][N:30]=1>CS(C)=O>[CH2:1]([C@@:4]1([CH3:25])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C:31]2[CH:32]=[CH:33][N:34]=[C:29]([Cl:28])[N:30]=2)[C:5]1=[O:24])[CH:2]=[CH2:3]
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)NC1=O
Reactant: Clc1ccnc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N(c2ccnc(Cl)n2)C1=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of (3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methylpiperidin-2-one (Example 71, Step D) (100 mg, 0.27 mmol) in 1.1 mL of DMSO was added sodium hydride (60% suspension in mineral oil, 32 mg, 0.80 mmol) at room temperature. The reaction mixture was stirred for 15 minutes, and was treated with 2,4-dichloropyrimidine (200 mg, 1.3 mmol). The reaction mixture was stirred at 60° C. for 5 hours. The reaction mixture was cooled to room temperature and quenched with water and extracted (2×EtOAc). The combined organic layers were washed with sat. aq. NaCl solution, dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure. Purification of the residue by silica gel prep plate (50% EtOAc/hexanes) provided the title compound as a colorless solid.
Reaction SMILES: [CH:1]1([CH:7](O)[CH:8]=[CH2:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C=CCCC=C.S(Br)([Br:19])=O>ClCCCl>[Br:19][CH2:9]/[CH:8]=[CH:7]/[CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C=CC(O)C1CCCCC1
Reactant: O=S(Br)Br
Agent: C=CCCC=C
Solvent: ClCCCl
Product: BrC/C=C/C1CCCCC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 42.5 %

Procedure:
To a solution of Example 36A (5.62 g, 40.1 mmol) and 1,5-hexadiene (3.56 mL, 30.1 mmol) in 1,2-dichloroethane (70 mL), stirring at 0° C., was added thionyl bromide (4.66 mL, 60.12 mmol). The reaction was stirred for 2 hours at 0° C. and then quenched with water. The mixture was extracted with diethyl ether and the diethyl ether layer was washed with saturated sodium bicarbonate solution, dried with sodium sulfate, filtered, and concentrated in vacuo to give the title compound (3.46 g, 43%). 1H NMR (300 MHz, CDCl3): δ ppm 1.16 m, 6 H) 1.69 m, 4 H) 1.98 m, 1 H) 3.94 m, 2 H) 5.65 m, 2 H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11](=O)[NH:12][CH:13]=2)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:17])=O>>[Cl:17][C:11]1[CH:10]=[CH:9][C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[CH:13][N:12]=1
Reactant: O=c1ccc(-c2ccc(Cl)cc2)c[nH]1
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1ccc(-c2ccc(Cl)nc2)cc1

Procedure:
A mixture of 22.27 g. of 5-(4-chlorophenyl)-2(1H)-pyridinone and 100 ml. of phosphorus oxychloride is refluxed for 16 hours, chilled and poured onto cracked ice. The solid formed is collected by filtration and then is dissolved in chloroform. The chloroform solution is washed with water and with saturated sodium bicarbonate and then is dried over magnesium sulfate. The solvent is evaporated at reduced pressure to yield 21.1 g. of the product of the Example as a gray solid, m.p. 113°-115° C.
Reaction SMILES: [C:1]1([C:7]2[NH:8][CH:9]=[C:10]([C:12]3[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=3)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C(=O)N([I:27])C(=O)C1>CC#N.CCOC(C)=O>[I:27][C:9]1[NH:8][C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[N:11][C:10]=1[C:12]1[CH:13]=[CH:14][C:15]([C:16]#[N:17])=[CH:18][CH:19]=1
Reactant: N#Cc1ccc(-c2c[nH]c(-c3ccccc3)n2)cc1
Reactant: O=C1CCC(=O)N1I
Solvent: CC#N
Solvent: CCOC(C)=O
Product: N#Cc1ccc(-c2nc(-c3ccccc3)[nH]c2I)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.8 %

Procedure:
The product of Step 1 (700 mg, 2.85 mmol) was dissolved in 10 mL of MeCN, to which was added NIS (770 mg, 3.42 mmol) and catalytic amount of TPA. After stirring at rt overnight, the reaction was diluted with EtOAc, washed with aq NaHCO3, aq Na2S2O3, water, and brine. The organic layer was dried over MgSO4, filtered, and concentrated to give 770 mg of 4-(5-iodo-2-phenyl-1H-imidazol-4-yl)benzonitrile. LCMS: [M+1]=372.
Reaction SMILES: C(N(CC)CC)C.[C:8]1([CH2:14][C:15](Cl)=[O:16])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl.[Cl:19][C:20]1[CH:21]=[C:22]([C:26]2([C:36]3[CH:41]=[CH:40][CH:39]=[C:38]([Cl:42])[CH:37]=3)[CH:34]3[CH:30]([CH2:31][NH:32][CH2:33]3)[C:29](=[O:35])[CH2:28][CH2:27]2)[CH:23]=[CH:24][CH:25]=1>ClCCl>[Cl:42][C:38]1[CH:37]=[C:36]([C:26]2([C:22]3[CH:23]=[CH:24][CH:25]=[C:20]([Cl:19])[CH:21]=3)[CH:34]3[CH:30]([CH2:31][N:32]([C:15](=[O:16])[CH2:14][C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=4)[CH2:33]3)[C:29](=[O:35])[CH2:28][CH2:27]2)[CH:41]=[CH:40][CH:39]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: O=C1CCC(c2cccc(Cl)c2)(c2cccc(Cl)c2)C2CNCC12
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1CCC(c2cccc(Cl)c2)(c2cccc(Cl)c2)C2CN(C(=O)Cc3ccccc3)CC12
Temperature: 25 °C
Reaction time: 2 h
Yield: 16.4 %

Procedure:
Triethylamine (0.45 cc) and then phenylacetyl chloride (0.49 g) are added to a solution, cooled to +4° C., of 7,7-bis(3-chlorophenyl)perhydro-4-isoindolone hydrochloride (1.06 g) in dichloromethane (20 cc). The reaction mixture is stirred for 2 hours at 25° C. and then washed with water (3×30 cc) and saturated sodium chloride solution (3×30 cc). The organic phase is dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a column of silica gel (particle size 0.04-0.063 mm, diameter 2.2 cm, height 23 cm), eluting under a nitrogen pressure of 0.5 bar with a mixture of cyclohexane and ethyl acetate (55:45) and collecting 15-cc fractions. Fractions 7 to 18 are concentrated to dryness under reduced pressure (2.7 kPa) and the residue is crystallized in acetonitrile. The crystals are drained, washed with isopropyl ether and dried. (3aRS,7aRS)-7,7-Bis(3 -chlorophenyl)-2-(phenylacetyl)perhydro-4-isoindolone (0.21 g) is obtained. M.p. 160° C.
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4]([CH3:7])[N:3]=1.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[Cl:31][C:32]1[C:33]([C:39](O)=[O:40])=[N:34][C:35]([Cl:38])=[CH:36][CH:37]=1>C(Cl)(Cl)Cl>[Cl:31][C:32]1[C:33]([C:39]([NH:1][C:2]2[S:6][N:5]=[C:4]([CH3:7])[N:3]=2)=[O:40])=[N:34][C:35]([Cl:38])=[CH:36][CH:37]=1
Reactant: O=C(O)c1nc(Cl)ccc1Cl
Reactant: Cc1nsc(N)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClC(Cl)Cl
Product: Cc1nsc(NC(=O)c2nc(Cl)ccc2Cl)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.3 %

Procedure:
12 g of 5-amino-3-methyl-1,2,4-thiadiazole, 21.1 g of N-hydroxybenzotriazole hydrate and 29.8 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride were added to a chloroform (500 ml) solution of 21 g of 3,6-dichloro-2-pyridinecarboxylic acid, and stirred at room temperature for 1 hour and then stirred overnight at 50° C. The reaction liquid was diluted with chloroform, then washed with aqueous 0.2 N hydrochloric acid solution, water and saturated saline water. After this was dried with anhydrous magnesium sulfate, the solvent was evaporated away under reduced pressure, and ethyl acetate was added to the resulting residue for crystallization to obtain 22.7 g of the entitled compound as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[O:11]([CH2:19][C:20]([NH2:23])([CH3:22])[CH3:21])[Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13]>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH2:4][NH:23][C:20]([CH3:22])([CH3:21])[CH2:19][O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:13])[CH3:14]
Reactant: CC(C)(N)CO[Si](C)(C)C(C)(C)C
Reactant: O=Cc1ccc(F)cc1F
Solvent: Cc1ccccc1
Product: CC(C)(CO[Si](C)(C)C(C)(C)C)NCc1ccc(F)cc1F
Temperature: 0 °C
Yield: 88.6 %

Procedure:
To a solution of 2,4-difluorobenzaldehyde (1.42 g, 10.0 mmol) in toluene (30 ml) was added 1-t-butyldimethylsiloxy-2-methyl-2-propylamine (2.03 g, 10.0 mmol) and stirred under reflux using a Dean-Stark trap to remove water for 6 hours. The solvent was evaporated and the residue was dissolved in methanol (10 ml). The solution was cooled to 0° C. in ice-water bath and an excess amount of NaBH4 was added. The mixture was gradually warmed to room temperature and stirring was continued until the Schiff base disappeared. The mixture was added to 1N NaOH aqueous solution, extracted with toluene, washed with sat. NaCl aqueous solution and dried over MgSO4. The solvent was evaporated to give the crude title compound (2.92 g; 92% in 2 steps).
Reaction SMILES: [CH3:1][C:2]([CH3:10])([CH3:9])[CH2:3][C@@H:4]([C:6]([OH:8])=O)[NH2:5].[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]=[C:19]=[O:20])=[CH:14][CH:13]=1.[CH3:21][N:22]1[CH2:26][CH2:25][N:24]=[C:23]1[C:27]1[CH:32]=[CH:31][C:30]([NH2:33])=[CH:29][CH:28]=1.C(Cl)CCl>CN(C=O)C.O>[CH3:21][N:22]1[CH2:26][CH2:25][N:24]=[C:23]1[C:27]1[CH:32]=[CH:31][C:30]([NH:33][C:6](=[O:8])[CH:4]([CH2:3][C:2]([CH3:1])([CH3:10])[CH3:9])[NH:5][C:19]([NH:18][C:15]2[CH:16]=[CH:17][C:12]([Cl:11])=[CH:13][CH:14]=2)=[O:20])=[CH:29][CH:28]=1
Reactant: CN1CCN=C1c1ccc(N)cc1
Reactant: CC(C)(C)C[C@H](N)C(=O)O
Reactant: O=C=Nc1ccc(Cl)cc1
Solvent: ClCCCl
Solvent: O
Solvent: CN(C)C=O
Product: CN1CCN=C1c1ccc(NC(=O)C(CC(C)(C)C)NC(=O)Nc2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.2 %

Procedure:
To a solution of DL-γ-methylleucine (48 mg, 0.33 mmol) in DMF (2 mL), 4-chlorophenyl isocyanate (50 mg, 0.33 mmol) was added. The mixture was then stirred at room temperature overnight. To the reaction mixture, 4-(1-Methyl-4,5-dihydro-1H-imidazol-2-yl)-phenylamine (150 mg, 0.86 mmol) and H2O (0.5 mL, to solubilize the amine) were added. To the solution, EDC (127 mg, 0.66 mmol) was added. After being stirred at room temperature overnight, the solution was concentrated in vacuo. The residue was purified by HPLC to give the titled compound as a powder (77 mg). MS 456.2 and 458.2 (M+H, Cl pattern).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.[CH3:24][S:25]([CH2:28][S:29](Cl)(=[O:31])=[O:30])(=[O:27])=[O:26]>C(Cl)Cl.C(N(CC)CC)C>[Cl:1][C:2]1[N:3]=[C:4]([N:18]2[CH2:19][CH2:20][O:21][CH2:22][CH2:23]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([S:29]([CH2:28][S:25]([CH3:24])(=[O:27])=[O:26])(=[O:31])=[O:30])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1
Reactant: CS(=O)(=O)CS(=O)(=O)Cl
Reactant: Clc1nc(N2CCOCC2)c2sc(CN3CCNCC3)cc2n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)CS(=O)(=O)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Temperature: 25 °C

Procedure:
To 2-chloro-4-morpholino-6-((piperazin-1-yl)methyl)thieno[3,2-d]pyrimidine (54 mg) in DCM (2 ml) and triethylamine (44 ul) was added methylsulfonylmethylsulfonyl chloride (45 ul) at 0° C. The reaction mixture was allowed to warm up to room temperature overnight. Aqueous work-up and purification on silica gave 2-chloro-6-(4-methanesulfonylmethanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (35 mg).
Reaction SMILES: [C:1]([O:9][CH:10]1[CH2:15][C:14]([CH3:17])([CH3:16])[N:13]([O:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH:21]=[CH:20]2)[C:12]([CH3:26])([CH3:25])[CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:27]([O:35][CH:36]1[CH2:41][C:40]([CH3:43])([CH3:42])[N:39]([OH:44])[C:38]([CH3:46])([CH3:45])[CH2:37]1)(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(OOC(C)(C)C)(C)(C)C>ClC1C=CC=CC=1Cl>[C:1]([O:9][CH:10]1[CH2:15][C:14]([CH3:17])([CH3:16])[N:13]([O:18][CH:19]2[CH2:24][CH2:23][CH:22]([O:44][N:39]3[C:40]([CH3:43])([CH3:42])[CH2:41][CH:36]([O:35][C:27](=[O:34])[C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH2:37][C:38]3([CH3:46])[CH3:45])[CH:21]=[CH:20]2)[C:12]([CH3:26])([CH3:25])[CH2:11]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C)CC(OC(=O)c2ccccc2)CC(C)(C)N1OC1C=CCCC1
Reactant: CC1(C)CC(OC(=O)c2ccccc2)CC(C)(C)N1O
Agent: CC(C)(C)OOC(C)(C)C
Solvent: Clc1ccccc1Cl
Product: CC1(C)CC(OC(=O)c2ccccc2)CC(C)(C)N1OC1C=CC(ON2C(C)(C)CC(OC(=O)c3ccccc3)CC2(C)C)CC1
Temperature: 135 °C
Yield: 5.2 %

Procedure:
A mixture of 43.6 grams (122 mmol) of the compound prepared in Example 21A, 40.5 grams (147 mmol) of 4-benzoyloxy-1-oxyl-2,2,6,6-tetramethylpiperidine, 17.8 grams (122 mmol) of di-tert-butyl peroxide and 50 ml of 1,2-dichlorobenzene is heated at 135° C. for 5.5 hours in a Fisher-Porter pressure bottle. Fresh di-tert-butyl peroxide (8.0 grams, 55 mmol) is added and the reaction mixture is heated at 135° C. for an additional three hours. The crude reaction mixture is purified by flash chromatography on silica gel (hexane; then 100:3 heptane:ethyl acetate) to afford 4.0 grams of the title compound as a while solid melting at 140°-142° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.CN(C)[C:17](=O)[CH3:18].C(=O)([O-])[O-].[K+].[K+].C(I)C>C(OCC)C.O>[CH2:17]([N:12]1[CH:13]=[C:9]([B:4]2[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:14])([CH3:1])[O:3]2)[CH:10]=[N:11]1)[CH3:18]
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: CC(=O)N(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCI
Solvent: CCOCC
Solvent: O
Product: CCn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Temperature: 60 °C
Reaction time: 8 h
Yield: 38 %

Procedure:
4,4,5,5-Tetramethyl-2-(1H-pyrazol-4-yl)-1,3,2-dioxaborolane (5.0 g), N,N-dimethylacetamide (50 ml), potassium carbonate (5.3 g) and ethyl iodide (2.1 ml) were mixed, and the mixture was stirred at 60° C. overnight. The reaction mixture was cooled to room temperature, water (100 ml) and ethyl ether (100 ml) were added, and the mixture was partitioned in a separatory funnel. The aqueous layer was further extracted with ethyl ether (100 ml), and the organic layers were combined. The organic layer was washed 3 times with water (100 ml) and once with saturated brine (100 ml), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, hexane (50 ml) was added to the obtained residue and the mixture was partitioned in a separatory funnel. The organic layer was washed 3 times with water (40 ml) and once with saturated brine (40 ml), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give the title compound (2.1691 g, 38%).
Reaction SMILES: [Si:1]([O:8][C@@H:9]([C:25]1[CH:30]=[C:29](Cl)[CH:28]=[CH:27][C:26]=1[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH:10]1[CH2:15][CH2:14][N:13]([C:16]2[CH:24]=[CH:23][C:19]([C:20]([OH:22])=O)=[CH:18][CH:17]=2)[CH2:12][CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH2:38]([N:40]([CH2:43][C@@H:44]1[N:49]([CH2:50][CH2:51][C@@H:52]([NH:61][C:62]2[CH:67]=[CH:66][C:65]([S:68]([NH2:71])(=[O:70])=[O:69])=[CH:64][C:63]=2[S:72]([C:75]([F:78])([F:77])[F:76])(=[O:74])=[O:73])[CH2:53][S:54][C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[CH2:48][CH2:47][O:46][CH2:45]1)[CH2:41][CH3:42])[CH3:39].C(Cl)C[Cl:81]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Si:1]([O:8][C@@H:9]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:32]1[CH:33]=[CH:34][C:35]([Cl:81])=[CH:36][CH:37]=1)[CH:10]1[CH2:11][CH2:12][N:13]([C:16]2[CH:17]=[CH:18][C:19]([C:20]([NH:71][S:68]([C:65]3[CH:66]=[CH:67][C:62]([NH:61][C@H:52]([CH2:51][CH2:50][N:49]4[CH2:48][CH2:47][O:46][CH2:45][C@@H:44]4[CH2:43][N:40]([CH2:41][CH3:42])[CH2:38][CH3:39])[CH2:53][S:54][C:55]4[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=4)=[C:63]([S:72]([C:75]([F:76])([F:78])[F:77])(=[O:74])=[O:73])[CH:64]=3)(=[O:69])=[O:70])=[O:22])=[CH:23][CH:24]=2)[CH2:14][CH2:15]1)([C:4]([CH3:5])([CH3:7])[CH3:6])([CH3:3])[CH3:2]
Reactant: ClCCCl
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](c1cc(Cl)ccc1-c1ccccc1)C1CCN(c2ccc(C(=O)O)cc2)CC1
Reactant: CCN(CC)C[C@H]1COCCN1CC[C@H](CSc1ccccc1)Nc1ccc(S(N)(=O)=O)cc1S(=O)(=O)C(F)(F)F
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCN(CC)C[C@H]1COCCN1CC[C@H](CSc1ccccc1)Nc1ccc(S(=O)(=O)NC(=O)c2ccc(N3CCC([C@@H](O[Si](C)(C)C(C)(C)C)c4ccccc4-c4ccc(Cl)cc4)CC3)cc2)cc1S(=O)(=O)C(F)(F)F
Yield: 43.2 %

Procedure:
A solution of (R)-4-(4-((tert-butyldimethylsilyloxy)(4′-chlorobiphenyl-2-yl)methyl)piperidin-1-yl)benzoic acid, (INTERMEDIATE 13, 109 mg, 0.20 mmol), 4-((R)-4-((S)-3-((diethylamino)methyl)morpholino)-1-(phenylthio)butan-2-ylamino)-3-(trifluoromethylsulfonyl)benzenesulfonamide (INTERMEDIATE 88, 130 mg, 0.20 mmol), EDC (78 mg, 0.41 mmol), DMAP (49.7 mg, 0.41 mmol), TEA (0.028 ml, 0.20 mmol) and DCM (5 ml) was stirred overnight at room temperature. The reaction mixture was diluted with DCM (50 ml) and washed successively with water (2×50 ml) and brine (50 ml). The organic phase was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography (ISCO, eluting with 0-20 MeOH/DCM over 19 minutes) to give the title product (100 mg, yield: 42.5%).
Reaction SMILES: [CH3:1][N:2]([CH3:21])[C:3]1[CH:4]=[C:5]([CH:12]=[C:13]([S:15]([F:20])([F:19])([F:18])([F:17])[F:16])[CH:14]=1)[C:6](N(OC)C)=[O:7].[CH2:22]1COCC1.C[Mg]Br.Cl>C(OCC)(=O)C.O>[CH3:1][N:2]([CH3:21])[C:3]1[CH:4]=[C:5]([C:6](=[O:7])[CH3:22])[CH:12]=[C:13]([S:15]([F:19])([F:18])([F:20])([F:17])[F:16])[CH:14]=1
Reactant: CON(C)C(=O)c1cc(N(C)C)cc(S(F)(F)(F)(F)F)c1
Reactant: C1CCOC1
Agent: C[Mg]Br
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Product: CC(=O)c1cc(N(C)C)cc(S(F)(F)(F)(F)F)c1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
3-Dimethylamino-N-methoxy-N-methyl-5-pentafluorosulfanylbenzamide (980 mg) was dissolved in abs. THF (50 ml), and methylmagnesium bromide solution (2.1 ml; 3M solution in diethyl ether) was added dropwise while stirring at 0° C. After the addition had ended, the ice bath was removed and the mixture was stirred at RT for 1 h. To complete the reaction, more methylmagnesium bromide solution (0.3 ml) was added and the mixture was stirred for a further 2 h. After storing overnight in a refrigerator, the reaction mixture was admixed with 1 N hydrochloric acid while cooling. Addition of water and ethyl acetate was followed by extraction twice more with ethyl acetate, and the combined organic phases were dried with magnesium sulfate, filtered and concentrated. The residue was purified by means of chromatography on silica gel (100/0 to 50/50 n-heptane/ethyl acetate within 30 min). The product-containing fractions were combined, the solvent was removed and the residue was dried under high vacuum. 650 mg of the title compound were obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][N:17]2[C:22](=[O:23])[C:21]3=[CH:24][S:25][CH:26]=[C:20]3[NH:19][C:18]2=[O:27])[CH2:11][CH2:10]1.C(N(CC)CC)C.[C:35](Cl)(=[O:37])[CH3:36]>C(Cl)Cl>[C:35]([N:19]1[C:20]2=[CH:26][S:25][CH:24]=[C:21]2[C:22](=[O:23])[N:17]([CH2:16][CH2:15][N:12]2[CH2:11][CH2:10][N:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[O:2][CH3:1])[CH2:14][CH2:13]2)[C:18]1=[O:27])(=[O:37])[CH3:36]
Reactant: CC(=O)Cl
Reactant: COc1ccccc1N1CCN(CCn2c(=O)[nH]c3cscc3c2=O)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccccc1N1CCN(CCn2c(=O)c3cscc3n(C(C)=O)c2=O)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.5 %

Procedure:
A solution of 3-[2-[4-(2-methoxyphenyl)piperazin-1-yl]ethyl]thieno[3,4-d]pyrimidine-2,4-dione (1.0 g, 2.6 mmol) in methylene chloride (50 ml) was cooled by an external ice bath and triethylamine (0.393 g, 3.88 mmol) and acetyl chloride (0.305 g, 3.88 mmol) were added. After stirring for 1 hour, the mixture was warmed to room temperature and quenched with water (10 ml). The separated organic layer was washed with water and saturated brine and dried over magnesium sulfate. The solution was concentrated in vacuo, treated with toluene (10 ml) and reconcentrated to give the product (0.93 g, 83.5% yield) which was recrystallized from methylene chloride-hexanes to give the analytical sample as light brown crystals, mp 128°-129° C.
Reaction SMILES: C([CH:3](Br)[C:4](=O)[C:5]([O-:7])=[O:6])C.[C:10](=[S:13])([S-:12])[NH2:11].[NH4+].O.[CH3:16][CH2:17]O>>[C:5]([C:4]1[N:11]=[C:10]([SH:12])[S:13][CH:3]=1)([O:7][CH2:16][CH3:17])=[O:6]
Reactant: CCO
Reactant: NC(=S)[S-]
Reactant: CCC(Br)C(=O)C(=O)[O-]
Agent: [NH4+]
Solvent: O
Product: CCOC(=O)c1csc(S)n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Ethylbromopyruvate (7.1 mL, 56.8 mmol) was added to a slurry of ammonium dithiocarbamate (6.25 g, 56.8 mmol) in EtOH (35 mL). The solution was stirred at rt 18 h, then heated at 70°-80° C. for 2 h. The solution was cooled to 10° C. and water (70 mL) was added. The resulting precipitate was recrystallized from EtOH to give 0.7 g of 4-carboethoxy-2-mercapto thiazole. NCS (0.42 g, 3.17 mmol) was added to a solution of 4-carboethoxy-2-mercapto thiazole (0.15 g, 0.79 mmol) in CH2Cl2 (3.2 mL) and the solution layered with water (1.6 mL) and stirred for 2 h. The layers were separated and the water layer extracted with CH2Cl2. The combined extracts were concentrated and the residue dissolved in acetone (1 mL) and NH4OH (1.6 mL) added. After 5 min the acetone was removed in vacuo and the residue taken up in water and extracted with EtOAc (6×5 mL). The combined extracts were dried (MgSO4), filtered, concentrated and purified by chromatography using 35% EtOAc/hexane to give 0.1 g (54%) 4-carboethoxy-2-thiazole sulfonamide as a pale yellow solid.
Reaction SMILES: [CH2:1]([CH:3]1[C:8](=[O:9])[CH2:7][CH2:6][CH2:5][C:4]1=[O:10])[CH3:2].[CH3:11][CH:12]1C(=O)CCCC1=O>>[OH:9][CH:8]([CH2:3][CH2:1][CH3:2])[CH2:7][CH2:6][CH2:5][C:4](=[O:10])[CH:11]=[CH2:12]
Reactant: CCC1C(=O)CCCC1=O
Reactant: CC1C(=O)CCCC1=O
Product: C=CC(=O)CCCC(O)CCC

Procedure:
Employing procedures similar to those described in Example 1, except that 2-ethylcyclohexane-1,3-dione is substituted for 2-methylcyclohexane-1,3-dione, 7-hydroxydec-1-en-3-one is produced.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([O:9][CH3:10])=[C:4]([Cl:11])[N:3]=1.[NH3:12].O>CS(C)=O>[Cl:1][C:2]1[N:7]=[C:6]([NH2:12])[C:5]([O:9][CH3:10])=[C:4]([Cl:11])[N:3]=1
Reactant: COc1c(Cl)nc(Cl)nc1Cl
Reactant: N
Solvent: O
Solvent: CS(C)=O
Product: COc1c(N)nc(Cl)nc1Cl
Yield: 88 %

Procedure:
2,4,6-Trichloro-5-methoxypyrimidine (1.0 g, 4.7 mmol, see U.S. Pat. No. 3,984,411 for preparation) was dissolved in 15 mL dry dimethyl sulfoxide (DMSO) and treated with a stream of ammonia gas for 30 min. The mixture was poured into 30 mL water and the precipitated product was collected by filtration and washed with water. This solid was dissolved in 40 mL ethyl acetate, washed twice with water, washed once with brine, dried and evaporated to give the title compound (800 mg, 88% yield): mp 155-156° C.: 1HNMR (DMSO-d6+D2O) δ 3.71 (s, 3H).
Reaction SMILES: [CH2:1]([O:17][CH2:18][C:19](=[CH2:22])[CH2:20][OH:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[H-].[Na+].[CH3:25][S:26]([O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]OS(C)(=O)=O)(=[O:28])=[O:27]>CN(C)C=O>[CH2:1]([O:17][CH2:18][C:19](=[CH2:22])[CH2:20][O:21][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][O:29][S:26]([CH3:25])(=[O:28])=[O:27])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: C=C(CO)COCCCCCCCCCCCCCCCC
Reactant: CS(=O)(=O)OCCCCCOS(C)(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=C(COCCCCCCCCCCCCCCCC)COCCCCCOS(C)(=O)=O
Temperature: 54 °C
Reaction time: 20 h

Procedure:
3-Hexadecyloxy-2-methylenepropan-1-ol (from Preparation 1) (4.45 g), sodium hydride dispersion (55-60% in oil, 1.4 g), and 1,5-dimethanesulfonyloxypentane (10.9 g) were mixed in dry dimethylformamide (33 ml) and stirred at 54° C. for 20 hours. Following the work-up procedure described in Preparation 7, the desired product was obtained.