Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH3:11].[F:12][C:13]1[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=1[C:15](Cl)=[O:16].[Al+3].[Cl-].[Cl-].[Cl-].Cl>ClC(Cl)C>[F:12][C:13]1[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=1[C:15](=[O:16])[C:8]1[CH:7]=[CH:6][C:5]([O:9][CH3:10])=[C:4]([CH3:11])[C:3]=1[OH:2]
Reactant: O=C(Cl)c1ccccc1F
Reactant: COc1cccc(OC)c1C
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Product: COc1ccc(C(=O)c2ccccc2F)c(O)c1C
Temperature: 5 °C
Reaction time: 18 h

Procedure:
2,6-dimethoxytoluene (20.0 g) and o-fluorobenzoyl chloride (19.8 g) are dissolved in 250 ml of dichloroethane and chilled to 5° C. AlCl3 is added portionwise and when the addition is complete the reaction mixture is allowed to warm to room temperature over 30 minutes, then refluxed 30 minutes. It is then poured into 5% HCl and allowed to stand undisturbed 18 hours. Extraction with ether, followed by drying and concentration, gives crystalline material that is washed with hexane to give 2'-fluoro-2-hydroxy-4-methoxy-3-methylbenzophenone, mp 118°-120° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]#N)[CH:5]=[C:6]([CH3:8])[CH:7]=1.Br[CH:13]([CH:19]([CH3:21])[CH3:20])[C:14]([O:16][CH2:17][CH3:18])=[O:15].C(=O)([O-])[O-:23].[K+].[K+]>O1CCCC1.BrC(C(C)C)C(OCC)=O.[Zn]>[CH3:20][CH:19]([CH3:21])[CH:13]([C:10](=[O:23])[CH2:9][C:4]1[CH:3]=[C:2]([CH3:1])[CH:7]=[C:6]([CH3:8])[CH:5]=1)[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: Cc1cc(C)cc(CC#N)c1
Reactant: CCOC(=O)C(Br)C(C)C
Reactant: O=C([O-])[O-]
Agent: [K+]
Agent: [Zn]
Solvent: C1CCOC1
Product: CCOC(=O)C(C(=O)Cc1cc(C)cc(C)c1)C(C)C
Yield: 52 %

Procedure:
A suspension of Zn powder (31.5 g, 0.48 mol) in tetrahydrofuran (300 ml) was boiled under reflux, and then it was added thereto a few drops of ethyl 2-bromo-3-methylbutanoate to initiate the reaction. After 45 mn under reflux and under magnetic stirring, it was added thereto 3,5-dimethylphenylethanenitrile (13.2 g, 91 mmol), and then, dropwise, the remainder of ethyl 2-bromo-3-methylbutanoate (in total 19.1 g, 91 mmol). The ebullition was maintained for 15 mn, the mixture was then cooled, and then it was added thereto tetrahydrofuran (500 ml) and a 50% aqueous potassium carbonate solution (100 ml). After 45 mn under vigorous stirring, the organic phase was separated by decantation and the aqueous phase was washed with tetrahydrofuran (2×100 ml). The collected organic phases were treated with 10% aqueous hydrochloric acid solution (300 ml) for 45 mn. After elimination of tetrahydrofuran by distillation under reduced pressure, the residue was taken again with dichloromethane (300 ml), and the organic phase was washed with a saturated sodium monohydrogenocarbonate solution (100 ml), dried over magnesium sulfate and concentrated. The distillation of the residue (134° C., 10−1 mmHg) gave ethyl 3-methyl-2-(3,5-dimethylphenylacetyl)butanoate (13.2 g, 52%).
Reaction SMILES: [Cl:1][C:2]1[C:27]([C:28]([F:31])([F:30])[F:29])=[CH:26][CH:25]=[CH:24][C:3]=1[CH2:4][N:5]([CH2:10][CH:11]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:6][CH2:7][CH2:8][OH:9].[N:32]1([C:38]2[CH:39]=[C:40](O)[CH:41]=[CH:42][CH:43]=2)[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1(C)C=CC=CC=1>[ClH:1].[Cl:1][C:2]1[C:27]([C:28]([F:29])([F:30])[F:31])=[CH:26][CH:25]=[CH:24][C:3]=1[CH2:4][N:5]([CH2:10][CH:11]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[CH2:6][CH2:7][CH2:8][O:9][C:42]1[CH:41]=[CH:40][CH:39]=[C:38]([N:32]2[CH2:33][CH2:34][O:35][CH2:36][CH2:37]2)[CH:43]=1
Reactant: OCCCN(Cc1cccc(C(F)(F)F)c1Cl)CC(c1ccccc1)c1ccccc1
Reactant: Oc1cccc(N2CCOCC2)c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Cl
Product: FC(F)(F)c1cccc(CN(CCCOc2cccc(N3CCOCC3)c2)CC(c2ccccc2)c2ccccc2)c1Cl
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A stirring solution of 3-[(2-chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-amino]-propan-1-ol (282 mg, 0.38 mmol) in toluene (25 mL) was treated with 3-morpholin-4-yl-phenol (75 mg, 0.42 mmol). Polymer bound triphenylphosphine (224 mg, 0.67 mmol, 3 mmol/g, Fluka Chemie) was then added, and the mixture was stirred for 15 minutes. The reaction mixture was then cooled to 0° C. and diisopropylazodicarboxylate (127 mg, 0.63 mmol) was added in a dropwise fashion. After stirring at room temperature overnight, the crude reaction mixture was filtered and the solid washed with toluene (25 mL). The filtrate was concentrated in vacuo. Purification by preparative HPLC (YMC 75×30 mm, 25 ml/min, 85-100% CH3CN over) led to the isolation of the morpholine product. The free base was treated with 1 M HCl in Et2O (0.1 ml) and the mixture was concentrated in vacuo to afford the title compound as a solid, 104 mg (41%). MS(ES) m/e 609.4 (M+).
Reaction SMILES: O[C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[CH:4][C:3]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12].[Cl:16][C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][C:23]=1[Cl:24])[NH2:20]>>[Cl:16][C:17]1[CH:18]=[C:19]([NH:20][C:2]2[N:7]3[N:8]=[CH:9][CH:10]=[C:6]3[N:5]=[CH:4][C:3]=2[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:21]=[CH:22][C:23]=1[Cl:24]
Reactant: CCOC(=O)c1cnc2ccnn2c1O
Reactant: Nc1ccc(Cl)c(Cl)c1
Product: CCOC(=O)c1cnc2ccnn2c1Nc1ccc(Cl)c(Cl)c1
Yield: 71.2 %

Procedure:
Using ethyl 7-hydroxypyrazolo[1,5-a]pyrimidine-6-carboxylate (3.0 g, 14.5 mmol) and 3,4-dichloroaniline (1.88 g, 11.6 mmol) instead of 4-fluoro-2-methylaniline, and in the same manner as in Example 1 step 1, the title compound (2.90 g, 57%) was obtained.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[N:11]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[C:14]([Br:19])[CH:13]=3)[C:10](=[O:20])[O:9][N:8]=2)=[N:4][O:5][N:6]=1.CO[CH:23](OC)[CH2:24][NH:25][S:26]([NH:29]C(=O)OCC)(=[O:28])=[O:27].ClCCCl.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>>[Br:19][C:14]1[CH:13]=[C:12]([N:11]2[C:10](=[O:20])[O:9][N:8]=[C:7]2[C:3]2[C:2]([NH:1][CH2:23][CH2:24][NH:25][S:26]([NH2:29])(=[O:28])=[O:27])=[N:6][O:5][N:4]=2)[CH:17]=[CH:16][C:15]=1[F:18]
Reactant: Nc1nonc1-c1noc(=O)n1-c1ccc(F)c(Br)c1
Reactant: CCOC(=O)NS(=O)(=O)NCC(OC)OC
Agent: CC[SiH](CC)CC
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Product: NS(=O)(=O)NCCNc1nonc1-c1noc(=O)n1-c1ccc(F)c(Br)c1
Temperature: 0 °C

Procedure:
A mixture of 3-(4-amino-1,2,5-oxadiazol-3-yl)-4-(3-bromo-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one (68 mg, 0.20 mmol; from Step D) and ethyl {[(2,2-dimethoxyethyl)amino]sulfonyl}carbamate (154 mg, 0.600 mmol, 3.0 equiv.) in 1,2-dichloroethane (2.50 mL, 31.7 mmol) was stirred at 0° C. To this mixture was added trifluoroacetic acid (1.00 mL, 13.0 mmol) and triethylsilane (105 μL, 0.66 mmol, 3.3 equiv.)=drop-wise. The reaction mixture was stirred at 0° C. for 3 h. HPLC indicated 97.5% conversion to the desired product. The reaction mixture was cooled to 0° C. and quenched with saturated sodium bicarbonate to pH ˜8. The mixture was extracted in ethyl acetate (3×10 mL). The combined organic extracts were washed with brine, dried over sodium sulfate and concentrated. The residue was stirred in a mixture of heptane and diethyl ether overnight. The solids were collected by filtration, washed with heptane to give the desired product (95 mg, 88%) as a crude off-white solid. 1H NMR (300 MHz, DMSO-d6) δ 11.18 (s, 1H), 8.08 (m, 1H), 7.70 (m, 2H), 7.59 (t, 1H, J=8.7 Hz), 6.56 (s, 1H), 4.04 (d, 2H, J=7.2 Hz), 3.35 (m, 2H), 3.11 (m, 2H), 1.15 (t, 3H, J=7.2 Hz); C15H15BrFN7O7S (MW 536.29), LCMS (EI) m/e 536/538 (M++H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:9])[CH:5]=[C:6]([CH3:8])[CH:7]=1.Cl[Si:11]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[C:24]1([Si:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:2]2[CH:3]=[C:4]([CH3:9])[CH:5]=[C:6]([CH3:8])[CH:7]=2)[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: Cl[Si](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cc1cc(C)cc(Br)c1
Product: Cc1cc(C)cc([Si](c2ccccc2)(c2ccccc2)c2ccccc2)c1

Procedure:
In the same manner as described in preparation 1, 5-bromo-m-xylene was allowed to react with chlorotriphenylsilane, and afforded TPSIX. The yield and properties are summarized in Table 1.
Reaction SMILES: CO.[F:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][CH2:14][Si:13](OC)(OC)[CH2:12][CH2:11]2)=[CH:6][CH:5]=1.C(C1C=CC=CC=1)(=O)C>C(N(CC)CC)C>[F:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:11][CH2:12][SiH2:13][CH2:14][CH2:15]2)=[CH:6][CH:5]=1
Reactant: CO[Si]1(OC)CCC(c2ccc(F)cc2)CC1
Solvent: CC(=O)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CO
Product: Fc1ccc(C2CC[SiH2]CC2)cc1

Procedure:
In the same manner as in Example 9, 21.0 g of 4-(p-fluorophenyl)-1,1-dichloro-1-silacyclohexane was obtained from 4-(p-fluorophenyl)-1,1-diphenyl-1-silacyclohexane obtained in Preparatory Example 5. A mixture of 50.0 g of methanol and 30 g of triethylamine was added to the solution obtained above, followed by agitation under reflux for 1 hour. The resultant solution was concentrated, to which 200 ml of hexane was added thereby permitting secondarily produced hydrochloride to be precipitated. The precipitate was removed by filtration and the resulting filtrate was concentrated to obtain a mixture of 4-(p-fluorophenyl)-1,1-dimethoxy-1-silacyclohexane and acetophenone. The mixture was subjected to distillation under reduced pressure to remove the acetophenone therefrom. The resultant residue was dissolved in 100 ml of THF and added to a solution of 10.0 g of lithium aluminium hydride in 100 ml of THF. The reaction mixture was agitated under reflux for 1 hour, which was poured into 200 ml of 5% hydrochloric acid and extracted with ethyl acetate. The ethyl acetate solution was washed with brine, dried and concentrated by a usual manner, followed by purification through silica gel chromatography to obtain 14.7 g of 4-(p-fluorophenyl)-1-silacyclohexane. Subsequently, 14.0 g of 4-(p-fluorophenyl)-1-silacyclohexane was added to 100 ml of toluene, into which chlorine gas was blown to obtain 4-(p-fluorophenyl)-1-chloro-1-silacyclohexane. This solution was dropped in 100 ml of a THF solution of 1 mole/liter of trans-2-(4-n-propylcyclohexyl)ethylmagnesium bromide at room temperature. The reaction mixture was charged into 200 ml of 5% hydrochloric acid and extracted with ethyl acetate. The ethyl acetate solution was washed with brine, dried and concentrated, followed by purification through silica gel chromatography to obtain 20.8 g of the intended product. The thus obtained product exhibited nematic liquid crystal properties at a temperature between 49.1° C. and 62.9° C. and was found to be very useful as a liquid crystal substance.
Reaction SMILES: CC([Si](C)(C)[O:6][C@H:7]([C:51]1[CH:52]=[N:53][CH:54]=[CH:55][CH:56]=1)[CH2:8][N:9]([CH2:17][C@H:18]1[CH2:27][CH2:26][C:25]2[C:20](=[CH:21][CH:22]=[C:23]([C:28]3[CH:43]=[CH:42][C:31]([C:32]([O:34]CC4C=CC=CC=4)=[O:33])=[C:30]([O:44][C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)[CH:29]=3)[CH:24]=2)[O:19]1)C(OC(C)(C)C)=O)(C)C.Cl>C(O)C.O1CCOCC1.[Pd]>[OH:6][C@H:7]([C:51]1[CH:52]=[N:53][CH:54]=[CH:55][CH:56]=1)[CH2:8][NH:9][CH2:17][C@H:18]1[CH2:27][CH2:26][C:25]2[C:20](=[CH:21][CH:22]=[C:23]([C:28]3[CH:43]=[CH:42][C:31]([C:32]([OH:34])=[O:33])=[C:30]([O:44][C:45]4[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=4)[CH:29]=3)[CH:24]=2)[O:19]1
Reactant: CC(C)(C)OC(=O)N(C[C@H]1CCc2cc(-c3ccc(C(=O)OCc4ccccc4)c(Oc4ccccc4)c3)ccc2O1)C[C@H](O[Si](C)(C)C(C)(C)C)c1cccnc1
Agent: [Pd]
Agent: Cl
Solvent: C1COCCO1
Solvent: CCO
Product: O=C(O)c1ccc(-c2ccc3c(c2)CC[C@H](CNC[C@H](O)c2cccnc2)O3)cc1Oc1ccccc1

Procedure:
Phenylmethyl 4-{(2R)-2-[([(2R)-2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-2-(3-pyridinyl)ethyl]{[(1,1-dimethylethyl)oxy]carbonyl}amino)methyl]-3,4-dihydro-2H-chromen-6-yl}-2-(phenyloxy)benzoate (Example 191, 69 mg, 0.086 mmol) was stirred over a suspension of 10% Pd/C (7 mg) in ethanol (5 mL) under a hydrogen atmosphere for 15 hours. Solids were removed by filtration through Celite®, and the filtrate was concentrated in vacuo. The carboxylic acid intermediate was collected as a colorless oil (25 mg, 41%): 1H NMR (300 MHz, CD3OD) δ 8.66-8.58 (m, 2H), 7.99 (d, 1H), 7.92 (d, 1H), 7.58-7.54 (m, 2H), 7.51-7.41 (m, 2H), 7.37-7.34 (m, 2H), 7.21-7.16 (m, 2H), 7.10 (d, 2H), 6.86 (d, 1H), 5.27-5.15 (m, 1H), 4.38-4.31 (m, 1H), 3.86-3.54 (m, 4H), 2.96-2.90 (m, 2H), 2.13-2.00 (m, 1H), 1.87-1.75 (m, 1H), 1.56 (d, 9H), 1.00 (s, 9H), 0.18 (d, 3H), 0.00 (s, 3H). The carboxylic acid intermediate (25 mg, 0.04 mmol) was stirred in an excess of 4M HCl in dioxane at room temperature for 18 hours. The volatile components were removed by rotary evaporation, and the residue was washed with dichloromethane. After drying under vacuum, the title compound was collected as the di-hydrochloride salt (16 mg, 80%): 1H NMR (300 MHz, CD3OD) δ 9.04 (broad s, 1H), 8.89 (broad s, 1H), 8.77 (d, 1H), 8.15 (t, 1H), 8.00 (d, 1H), 7.46 (d, 1H), 7.38-7.33 (m, 4H), 7.14-7.08 (m, 2H), 6.98 (d, 3H), 5.45 (d, 1H), 4.50 (t, 1H), 3.76-3.55 (m, 5H), 3.52-3.35 (m, 2H), 2.99-2.85 (m, 2H), 2.18-2.11 (m, 1H), 1.85-1.75 (m, 1H); MS m/z 497.2 (MH+ of the free base).
Reaction SMILES: [CH3:1][CH:2]([NH2:5])[CH2:3][OH:4].[OH:6][CH2:7][C:8](=O)[CH3:9]>CO.[Pt](=O)=O>[NH:5]([CH:8]([CH3:9])[CH2:7][OH:6])[CH:2]([CH3:1])[CH2:3][OH:4]
Reactant: CC(N)CO
Reactant: CC(=O)CO
Agent: O=[Pt]=O
Solvent: CO
Product: CC(CO)NC(C)CO
Reaction time: 20 h

Procedure:
Platinum dioxide (800 mg) was added to a solution of dl-2-amino-1-propanol (100 g) and hydroxyacetone (115 g) in methanol (1100 mL). The reaction mixture was hydrogenated at 60 psi for 20 hours, after which time, the catalyst was filtered off and the solvent was removed under reduced pressure to afford crude 2,2′-iminodipropan-1-ol.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:10](=[O:12])OC(=O)[N:7]([CH3:14])[C:6]=2[CH:5]=[CH:4][C:3]=1[F:15].[C:16]([C:20]1[CH:37]=[CH:36][C:23]([CH2:24][NH:25][CH2:26][CH2:27][C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[C:30]([Cl:35])[CH:29]=2)=[CH:22][CH:21]=1)([CH3:19])([CH3:18])[CH3:17]>CN(C=O)C.C(OCC)(=O)C>[C:16]([C:20]1[CH:37]=[CH:36][C:23]([CH2:24][N:25]([CH2:26][CH2:27][C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[C:30]([Cl:35])[CH:29]=2)[C:10](=[O:12])[C:11]2[C:6]([NH:7][CH3:14])=[CH:5][CH:4]=[C:3]([F:15])[C:2]=2[Cl:1])=[CH:22][CH:21]=1)([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)c1ccc(CNCCc2ccc(Cl)c(Cl)c2)cc1
Reactant: Cn1c(=O)oc(=O)c2c(Cl)c(F)ccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CNc1ccc(F)c(Cl)c1C(=O)N(CCc1ccc(Cl)c(Cl)c1)Cc1ccc(C(C)(C)C)cc1
Temperature: 140 °C
Yield: 27.1 %

Procedure:
A mixture of 5-chloro-6-fluoro-1-methyl-1H-benzo[d][1,3]oxazine-2,4-dione (83 mg, 0.36 mmol) and (4-tert-butylbenzyl)-[2-(3,4-dichloro-phenyl)-ethyl]-amine (122 mg, 0.36 mmol) in DMF (2 ml) was heated to 140° C. for 2 h and then at 110° C. overnight. The reaction mixture was then cooled to RT and the mixture was diluted with ethyl acetate and washed with water and brine. The organic layer was dried (MgSO4), filtered and concentrated in vacuo to give a residue which was purified by flash column chromatography to give the desired product (51 mg, 27%) as a white solid. MS (ISP) 521.9 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]3[CH2:14][CH2:15][CH2:16][C:11]3=[C:10]([CH:17]([OH:30])[C:18]3[CH:23]=[CH:22][C:21]([CH2:24][C:25](OCC)=[O:26])=[CH:20][CH:19]=3)[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[NH3:31]>CO>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]3[CH2:14][CH2:15][CH2:16][C:11]3=[C:10]([CH:17]([OH:30])[C:18]3[CH:19]=[CH:20][C:21]([CH2:24][C:25]([NH2:31])=[O:26])=[CH:22][CH:23]=3)[CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)Cc1ccc(C(O)c2cc(-c3cccc(Cl)c3)nc3c2CCC3)cc1
Reactant: N
Solvent: CO
Product: Cl
Product: NC(=O)Cc1ccc(C(O)c2cc(-c3cccc(Cl)c3)nc3c2CCC3)cc1
Yield: 55 %

Procedure:
Following general procedure C, ethyl 2-(4-((2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)(hydroxy)methyl)phenyl)acetate (0.018 g, 0.043 mmol) was reacted with ammonia in methanol (7.0 M, 4 mL), followed by formation of the hydrochloride salt to afford the title compound (0.010 g, 55%) as a white solid. MW=429.34. 1H NMR (DMSO-d6, 500 MHz) δ 8.11-8.09 (m, 1H), 8.06 (s, 1H), 8.01-7.97 (m, 1H), 7.60-7.54 (m, 2H), 7.43 (s, 1H), 7.34 (d, J=8.0 Hz, 2H), 7.21 (d, J=8.0 Hz, 2H), 6.82 (s, 1H), 5.80 (s, 1H), 3.33 (s, 2H), 3.06-2.93 (m, 3H), 2.71-2.61 (m, 2H), 2.11-2.01 (m, 2H); APCI MS m/z 393 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:3]([CH3:16])[C:4]2[C:9]([C:10]=1[CH:11]=O)=[CH:8][C:7]([N+:13]([O-:15])=[O:14])=[CH:6][CH:5]=2.C([O-])([O-])=O.[K+].[K+].[SH:23][CH2:24][C:25]([O:27][CH3:28])=[O:26].O>CO>[CH3:16][N:3]1[C:4]2[C:9](=[CH:8][C:7]([N+:13]([O-:15])=[O:14])=[CH:6][CH:5]=2)[C:10]2[CH:11]=[C:24]([C:25]([O:27][CH3:28])=[O:26])[S:23][C:2]1=2
Reactant: Cn1c(Cl)c(C=O)c2cc([N+](=O)[O-])ccc21
Reactant: COC(=O)CS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: COC(=O)c1cc2c3cc([N+](=O)[O-])ccc3n(C)c2s1
Reaction time: 8 h

Procedure:
1.4 g of (66) was added to a slurry of excess K2CO3 in 100 ml of MeOH. 2 ml of methyl 2-mercaptoacetate was added and the mixture left with stirring overnight. Addition of water precipitated the product, which was washed with MeOH and water to give 640 mg of (67). M.p. 269°-71° C.
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].CS(O[CH2:19][CH:20]([CH2:26][CH:27]=[CH2:28])[CH2:21][CH2:22][CH2:23][C:24]#[N:25])(=O)=O.C(O)(=O)C>O1CCCC1>[C:24]([CH2:23][CH2:22][CH2:21][CH:20]([CH2:26][CH:27]=[CH2:28])[CH2:19][CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][CH2:10][CH3:11])=[O:8])#[N:25]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: C=CCC(CCCC#N)COS(C)(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: C=CCC(CCCC#N)CC(C(=O)OCC)C(=O)OCC
Reaction time: 0.5 h

Procedure:
A solution of 5410 g of diethyl malonate in 2000 ml of tetrahydrofuran is added to a mixture of 1351 g of 60% sodium hydride in mineral oil in 36 L of tetrahydrofuran over a period of 4 hours, keeping the temperature below 26°, and the mixture is stirred for 1/2 hour. A solution of 3705 g of 6-methanesulfonyloxy-5-(2-propenyl)-hexanenitrile in 200 ml tetrahydrofuran is added rapidly and the mixture is heated under reflux for 24 hours and allowed to cool overnight. The mixture is neutralized to pH 7 with glacial acetic acid (about 1 L) and evaporated to dryness. A solution of the residue in 30 L of ether is washed consecutively with water, saturated sodium bicarbonate solution, water and brine, and evaporated to dryness. The mineral oil is separated in a separatory funnel and the remaining product is washed three times with heptane, concentrated at 80°/0.01 mm Hg, and distilled at 150° to remove diethyl malonate and obtain crude diethyl [5-cyano-2-(2-propenyl)-pentyl]-malonate.
Reaction SMILES: ClC1[CH:35]=[CH:34][CH:33]=[CH:32][C:3]=1[CH2:4][O:5][CH2:6][CH2:7][N:8]([C@H:25]1[CH2:30][CH2:29][C@H:28]([CH3:31])[CH2:27][CH2:26]1)[C:9](=[O:24])[NH:10][C:11]1[S:12][C:13]([S:16]CC(C)(C)C(O)=O)=[CH:14][N:15]=1.Br.BrCC1C=CC=C[N:40]=1.C([O:47][C:48](=[O:57])[CH2:49]SC1SC(N)=NC=1)C>>[CH3:31][C@H:28]1[CH2:29][CH2:30][C@H:25]([N:8]([CH2:7][CH2:6][O:5][CH2:4][C:3]2[CH:32]=[CH:33][CH:34]=[CH:35][N:40]=2)[C:9](=[O:24])[NH:10][C:11]2[S:12][C:13]([S:16][CH2:49][C:48]([OH:57])=[O:47])=[CH:14][N:15]=2)[CH2:26][CH2:27]1
Reactant: BrCc1ccccn1
Reactant: CC(C)(CSc1cnc(NC(=O)N(CCOCc2ccccc2Cl)[C@H]2CC[C@H](C)CC2)s1)C(=O)O
Reactant: CCOC(=O)CSc1cnc(N)s1
Agent: Br
Product: C[C@H]1CC[C@H](N(CCOCc2ccccn2)C(=O)Nc2ncc(SCC(=O)O)s2)CC1

Procedure:
The compound was prepared following an analogous procedure to the one described for the synthesis of 3-{2-[3-[2-(2-chloro-benzyloxy)-ethyl]-3-(trans-4-methyl -cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-2,2-dimethyl-propionic acid using 2-bromomethylpyridine hydrobromide and (2-aminothiazol-5-ylsulfanyl) acetic acid ethyl ester.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[OH:9].C(=O)([O-])[O-].[K+].[K+].I[CH2:17][CH2:18][CH3:19].O>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[O:9][CH2:17][CH2:18][CH3:19]
Reactant: CCCI
Reactant: Oc1cc(F)ccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCOc1cc(F)ccc1Br
Temperature: 25 °C
Reaction time: 10 h

Procedure:
A total of 5 g of 2-bromo-5-fluoro-phenol was dissolved in 66 ml of N,N-dimethylformamide. Under ice-cooling, 5.42 g of potassium carbonate and 3.07 ml of iodopropane were added, and the mixture was stirred at room temperature for 10 hours. Water was added to the reaction mixture, followed by extracting with diethyl ether. The resulting organic layer was washed with brine, dried over magnesium sulfate and the solvent was evaporated, to give 8.29 g of the title compound as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10]C)[CH:9]=1)[CH:5]=[O:6].B(Br)(Br)Br.O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([OH:10])[CH:9]=1)[CH:5]=[O:6]
Reactant: COc1cc(Cl)cc(C=O)c1
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: O=Cc1cc(O)cc(Cl)c1
Reaction time: 2 h
Yield: 24.8 %

Procedure:
A solution of 3-chloro-5-methoxybenzaldehyde (22.8 g, 134 mmol; see step (i) above) in CH2Cl2 (250 mL) was cooled to 0° C. Boron tribromide (15.8 mL, 167 mmol) was added dropwise over 15 min. After stirring, the reaction-mixture for 2 h, H2O (50 mL) was added slowly. The solution was then extracted with Et2O (2×100 mL). The organic layers were combined, dried (Na2SO4), filtered and concentrated in vacuo. Flash chromatography on silica gel eluting with Hex:EtOAc (4:1) afforded the sub-title compound (5.2 g, 25%).
Reaction SMILES: Cl[C:2]1[C:7]([I:8])=[CH:6][N:5]=[CH:4][N:3]=1.[CH3:9][NH2:10]>>[I:8][C:7]1[C:2]([NH:10][CH3:9])=[N:3][CH:4]=[N:5][CH:6]=1
Reactant: Clc1ncncc1I
Reactant: CN
Product: CNc1ncncc1I
Yield: 78 %

Procedure:
A solution of 4-chloro-5-iodopyrimidine 67A (2.03 g, 8.44 mmol) in 40% aqueous MeNH2 solution was stirred at RT for 17 h. The mixture was then extracted with DCM (2×150 ml). The combined organic phase were dried concentrated to give 5-iodo-4-methylaminopyrimidine 67B (1.55 g, 78%) as an orange solid which was used for the next step without further purification.
Reaction SMILES: [OH-].[K+].[C:3]([CH2:5][C:6]([NH2:8])=[O:7])#[N:4].[O:9]([C:16]1[CH:17]=[C:18]([N:22]=[C:23]=[S:24])[CH:19]=[CH:20][CH:21]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.Cl>CN(C=O)C.O>[C:3]([CH:5]([C:23](=[S:24])[NH:22][C:18]1[CH:19]=[CH:20][CH:21]=[C:16]([O:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:17]=1)[C:6]([NH2:8])=[O:7])#[N:4]
Reactant: N#CCC(N)=O
Reactant: S=C=Nc1cccc(Oc2ccccc2)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: N#CC(C(N)=O)C(=S)Nc1cccc(Oc2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 72.4 %

Procedure:
To a suspension of 85% powdered KOH in 20 ml DMF was added 1.74 g of cyanoacetamide at room temperature. The solution was stirred at room temperature for 15 minutes and then cooled in a water bath at room temperature. To this solution 4.7 g of 3-phenoxy-phenyl isothiocyanate was added dropwise. The solution exothermed slightly with the internal temperature rising to 28° C. during the addition. The solution was stirred at room temperature for 16 h, then diluted with 150 ml water and extracted with ethyl acetate to remove small amounts of starting material and by-products. The aqueous layer was isolated and acidified with 1N HCl to pH 1 with vigorous stirring. The resulting tan precipitate was filtered, washed with water, and dried for 16 hours in a vacuum oven to afford 4.66 g of 2-cyano-2-(3-phenoxy-phenylthiocarbamoyl)-acetamide.