Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([Mg]Br)[CH2:2][CH3:3].[CH2:6]([O:13][C:14]([NH:16][CH:17]([CH2:26][CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1)[CH:18]([OH:25])[C:19]([F:24])([F:23])[C:20](O)=[O:21])=[O:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Cl>C(OCC)C>[CH2:6]([O:13][C:14]([NH:16][CH:17]([CH2:26][CH:27]1[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]1)[CH:18]([OH:25])[C:19]([F:24])([F:23])[C:20](=[O:21])[CH2:1][CH2:2][CH3:3])=[O:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CCC[Mg]Br
Reactant: O=C(NC(CC1CCCCC1)C(O)C(F)(F)C(=O)O)OCc1ccccc1
Agent: Cl
Solvent: CCOCC
Product: CCCC(=O)C(F)(F)C(O)C(CC1CCCCC1)NC(=O)OCc1ccccc1

Procedure:
To a rapidly stirred solution of n-propylmagnesium bromide (9 mmol) in anhydrous diethyl ether (20 mL) was added dropwise a solution of 0.641 g (2,25 mmol) of 4-benzyloxycarbonylamino-5-cyclohexyl-2,2-difluoro-3-hydroxy pentanoic acid in anhydrous diethyl ether (10 mL). The mixture was refluxed under nitrogen for two hours after the addition of the acid was completed. The crude mixture was then poured onto a mixture of ice and 0.2N HCl (50 mL). The layers were separated and the aqueous phase was extracted with diethyl ether (3×20 mL). The combined organic layers were washed with a saturated sodium bicarbonate solution and brine. The organic layer was dried over anhydrous magnesium sulphate. Filtration and removal of the solvent in vacuo left an oil. The residue was purified by chromatography (silica gel, ethyl acetate/cyclohexane 1:1) to yield the expected ketone.
Reaction SMILES: Cl[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][C:14]([O:16][CH3:17])=[O:15])=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].C(=O)([O-])[O-].[K+].[K+].[CH2:31]([SH:34])[CH2:32][CH3:33].C(OCC)(=O)C>C(#N)CCC>[CH3:17][O:16][C:14]([CH2:13][C:10]1[CH:11]=[CH:12][C:7]([N:6]2[C:2]([S:34][CH2:31][CH2:32][CH3:33])=[C:3]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:4]=[N:5]2)=[CH:8][CH:9]=1)=[O:15]
Reactant: CCCS
Reactant: COC(=O)Cc1ccc(-n2ncc(C(=O)OC(C)(C)C)c2Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCC#N
Solvent: CCOC(C)=O
Product: CCCSc1c(C(=O)OC(C)(C)C)cnn1-c1ccc(CC(=O)OC)cc1
Temperature: 90 °C

Procedure:
tert-butyl 5-chloro-1-[4-(methoxycarbonylmethyl)phenyl]pyrazole-4-carboxylate (Intermediate#37) (767 mg, 2.19 mmol) was dissolved in butyronitrile (10 mL). Potassium carbonate (906 mg, 6.57 mmol) and propanethiol (284 μL, 2.74 mmol) were added and the mixture heated at 90° C. for 18 h. The reaction mixture was cooled to ambient and ethyl acetate (50 mL) was added. The mixture was washed with water (4×25 mL), dried (MgSO4) and evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel (elution gradient 0-25% EtOAc in isohexane) to afford tert-butyl 1-[4-(methoxycarbonylmethyl)phenyl]-5-propylsulfanyl-pyrazole-4-carboxylate as a yellow oil. (527 mg, 62%).
Reaction SMILES: CC(C)([O-])C.[K+].[Cl:7][CH:8]([Cl:18])[CH:9]1[CH:14]2[CH:12]([C:13]2([CH3:16])[CH3:15])[C:11](=[O:17])[O:10]1.Cl>CS(C)=O.O>[Cl:7][C:8]([Cl:18])=[CH:9][C@H:14]1[C:13]([CH3:16])([CH3:15])[C@H:12]1[C:11]([OH:17])=[O:10]
Reactant: CC1(C)C2C(=O)OC(C(Cl)Cl)C21
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CC1(C)[C@H](C=C(Cl)Cl)[C@@H]1C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Potassium tertiary butoxide (0.45 mmol) was added to a solution of 4-dichloromethyl-6,6-dimethyl-3-oxabicyclo[3.1.0]hexan-2-one (0.16 mmol) in dry dimethylsulphoxide (0.4 ml) and stirred at room temperature for 1/2 hour. The solution was then diluted with water, acidified with concentrated hydrochloric acid and extracted with CDCl3. NMR analysis showed a virtually quantitative yield of the desired cis acid.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5]([C:8]1[CH:9]=[CH:10][C:11]([OH:17])=[C:12]([CH:16]=1)[C:13]([OH:15])=[O:14])(=[O:7])=[O:6].C[Si]([N-][Si](C)(C)C)(C)C.[K+]>C1COCC1.C1(C)C=CC=CC=1.C1COCC1.C(OCC)(=O)C>[CH:4]1([S:5]([C:8]2[CH:9]=[CH:10][C:11]([OH:17])=[C:12]([CH:16]=2)[C:13]([OH:15])=[O:14])(=[O:7])=[O:6])[CH2:2][CH2:3]1
Reactant: O=C(O)c1cc(S(=O)(=O)CCCCl)ccc1O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: O=C(O)c1cc(S(=O)(=O)C2CC2)ccc1O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 8.0 mmol 5-(3-chloro-propane-1-sulfonyl)-2-hydroxy-benzoic acid in 30 ml THF at −78° C. was added dropwise over 30 min 23.9 mmol of a 0.9 M solution of potassium bis(trimethylsilyl)amide in toluene. The reaction mixture was then allowed to warm to RT and stirring continued for a further 30 min at RT. The mixture was then diluted with THF/ethyl acetate (1:1) and washed sequentially with 1 M aq HCl and saturated aqueous NaCl solution, dried with Na2SO4, and concentrated in vacuo. The residue was triturated in ether/pentane to afford the title compound. MS (m/e): 241.2 ([M−H]−, 100%)
Reaction SMILES: ClC1C=C(Cl)C=CC=1C1N=C(CC)C(N[C@H]2[C@@H](OCC)CN([C:26]3[S:27][CH:28]=[CH:29][N:30]=3)C2)=NC=1CC.[CH2:33]([O:35][C@H:36]1[CH2:40][NH:39][CH2:38][C@H:37]1[NH:41][C:42]1[C:47]([CH2:48][CH3:49])=[N:46][C:45]([C:50]2[C:51]([C:58]([F:61])([F:60])[F:59])=[N:52][C:53]([O:56][CH3:57])=[CH:54][CH:55]=2)=[C:44]([CH2:62][CH3:63])[N:43]=1)[CH3:34]>>[CH2:33]([O:35][C@H:36]1[CH2:40][N:39]([C:26]2[S:27][CH:28]=[CH:29][N:30]=2)[CH2:38][C@H:37]1[NH:41][C:42]1[C:47]([CH2:48][CH3:49])=[N:46][C:45]([C:50]2[C:51]([C:58]([F:61])([F:60])[F:59])=[N:52][C:53]([O:56][CH3:57])=[CH:54][CH:55]=2)=[C:44]([CH2:62][CH3:63])[N:43]=1)[CH3:34]
Reactant: CCO[C@H]1CNC[C@H]1Nc1nc(CC)c(-c2ccc(OC)nc2C(F)(F)F)nc1CC
Reactant: CCO[C@H]1CN(c2nccs2)C[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC
Product: CCO[C@H]1CN(c2nccs2)C[C@H]1Nc1nc(CC)c(-c2ccc(OC)nc2C(F)(F)F)nc1CC

Procedure:
Following the procedure for the preparation of 5-(2,4-dichlorophenyl)-N-[(3R,4S)-4-ethoxy-1-(1,3-thiazol-2-yl)pyrrolidin-3-yl}-3,6-diethylpyrazin-2-amine but starting with N-[(3R,4S)-4-ethoxypyrrolidin-3-yl]-3,6-diethyl-5-[6-methoxy-2-(trifluoromethyl)pyridin-3-yl]pyrazin-2-amine provided the title compound as an amorphous solid. 1H NMR (CDCl3) δ 1.15, 1.30, 2.45, 2.68, 3.48˜3.58, 3.77, 3.88, 4.04, 4.29, 4.94, 5.29, 6.56, 6.98, 7.56; IR (diffuse reflectance) 2974, 2350 (w), 2337 (w), 1921 (w), 1607, 1568, 1538 (s), 1477 (s), 1397, 1342, 1278 (s), 1239, 1192, 1175, 1137 (s) cm−1 HRMS (ESI) calcd for C24H29N6O2SF3+H1 523.2103. found 523.2108.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[CH2:14][C@H:13]3[C@H:11]([CH2:12]3)[C@H:10]2[CH2:15][NH2:16])=[O:8])[N:6]=1.[O:24]1[C:28]2=[CH:29][CH:30]=[CH:31][C:32]([C:33](O)=[O:34])=[C:27]2[CH2:26][CH2:25]1>>[NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[CH2:14][C@H:13]3[C@H:11]([CH2:12]3)[C@H:10]2[CH2:15][NH:16][C:33]([C:32]2[CH:31]=[CH:30][CH:29]=[C:28]3[O:24][CH2:25][CH2:26][C:27]=23)=[O:34])=[O:8])[N:6]=1
Reactant: O=C(O)c1cccc2c1CCO2
Reactant: NC[C@@H]1[C@H]2C[C@H]2CN1C(=O)c1nc(N)sc1-c1cccc(F)c1
Product: Nc1nc(C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2cccc3c2CCO3)c(-c2cccc(F)c2)s1

Procedure:
prepared by reaction of [2-Amino-5-(3-fluoro-phenyl)-thiazol-4-yl]-((1S,2 S,5R)-2-aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-methanone with 2,3-Dihydro-benzofuran-4-carboxylic acid. LC-MS (basic): tR=0.79 min; [M+H]+=479.4.
Reaction SMILES: C[O-].[Na+].C(O)C.[OH:7][C:8]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:9]=1[CH:10]=O.Br[CH2:18][C:19]1[C:20]([C:25]#[N:26])=[CH:21][CH:22]=[CH:23][CH:24]=1>CN(C)C=O.O>[C:25]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[C:18]1[O:7][C:8]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:9]=2[CH:10]=1)#[N:26]
Reactant: N#Cc1ccccc1CBr
Reactant: Cc1ccc(O)c(C=O)c1
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCO
Product: Cc1ccc2oc(-c3ccccc3C#N)cc2c1
Temperature: 75 °C
Reaction time: 0.33 h
Yield: 63.3 %

Procedure:
A 500 mL 3-neck round bottom flask equipped with a magnetic stirrer, dropping funnel, thermometer and nitrogen bubbler was charged with 10.7 g (108 mmol) of sodium methoxide and 75 mL of absolute ethanol. A solution of 24.9 g (183 mmol) of 2-hydroxy-5-methylbenzaldehyde in 75 mL of dry dimethylformamide was added dropwise over 15 minutes. The mixture was stirred for 20 minutes then treated dropwise over 20 minutes with a solution of 34.8 g (177 mmol) of α-bromo-o-tolunitrile in 75 mL of dry dimethylformamide. The mixture was heated at 75° C. for 30 minutes, then allowed to cool for one hour. A suspension of 10.7 g (188 mmol) of sodium methoxide in 20 mL of dry dimethylformamide was added and the resulting mixture heated at 90° C. for 1.5 hours. The reaction mixture was concentrated under vacuum at 50° C. to give a brown solid that was slurried in 100-200 mL of cold water and filtered. The solids were triturated with 200 mL of methanol, filtered, washed with additional methanol, then air dried. After drying in a dessicator under high vacuum, 26.1 g (112 mmol, 63%) of the product was isolated as a beige solid. 1H NMR (200 MHz,CDCl3): 2.45 (s,3H), 7.17 (d,8 Hz,1H), 7.4 (m,3H), 7.6-7.8 (m,3H), 8.10 (d,8 Hz,1H).
Reaction SMILES: [C:1](Cl)(=[O:13])[CH2:2][C:3]1[CH:12]=[CH:11][C:8]([O:9][CH3:10])=[C:5]([O:6][CH3:7])[CH:4]=1.S(O)(O)(=O)=O.COC1C(OC)=CC2C(=C[C:26](=[O:35])[N:27](C)[CH:28]=2)C=1>>[CH:26]([N:27]([CH3:28])[C:1](=[O:13])[CH2:2][C:3]1[CH:12]=[CH:11][C:8]([O:9][CH3:10])=[C:5]([O:6][CH3:7])[CH:4]=1)=[O:35]
Reactant: COc1cc2cc(=O)n(C)cc2cc1OC
Reactant: COc1ccc(CC(=O)Cl)cc1OC
Agent: O=S(=O)(O)O
Product: COc1ccc(CC(=O)N(C)C=O)cc1OC

Procedure:
Taking into account that the homoveratric acid chloride is obtained with a yield of 83%, the overall yield of 6,7-dimethoxy-N-methyl-2H-3-isoquinolone sulfate, in 3 steps, is 32%, which constitutes a considerable improvement as compared to the process of N. J. Mc Corkindale and A. W. Mc Culloch (4 steps and an overall yield of 13.3%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[Li]CCCC.CCCCCC.[CH3:17][C:18]([CH3:28])([CH3:27])/[CH:19]=[N:20]/[S:21]([C:23]([CH3:26])([CH3:25])[CH3:24])=[O:22]>C1COCC1>[CH3:17][C:18]([CH3:28])([CH3:27])[CH:19]([NH:20][S:21]([C:23]([CH3:26])([CH3:25])[CH3:24])=[O:22])[C:2]1[S:1][CH:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)/C=N/S(=O)C(C)(C)C
Reactant: c1cscn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(C)C(NS(=O)C(C)(C)C)c1nccs1
Temperature: -75 °C
Reaction time: 0.5 h
Yield: 91.9 %

Procedure:
To a solution of thiazole (247 mg, 206 μl, 2.91 mmol) in 10 mL dry THF under argon at −73° C. was slowly added a 1.6M solution of BuLi in hexane (1.82 ml, 2.91 mmol). The resulting reaction mixture was stirred at −75° C. for 30 min and a solution of (E)-N-(2,2-dimethylpropylidene)-2-methylpropane-2-sulfinamide (Example 306a) (500 mg, 2.64 mmol) in 5 mL dry THF was added. The reaction mixture was stirred at −75° C. for 30 min, then cooling bath was removed and reaction stirred at r.t for 1 h. The reaction was quenched by the addition of few drops of water, the reaction mixture poured into ethyl acetate, and the solution was then extracted with aqueous NaHCO3 1M. The organic phase was collected, dried over Na2SO4 and evaporated down to dryness to give the title compound (666 mg, 92%) as crude dark orange oil. The crude was used without any further purification, MS (EI): m/e=275.2 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:46])([F:45])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:21]([C:26]4[CH:27]=[C:28]([C:33]5[CH:38]=[CH:37][C:36]([C:39]([O:41]C)=[O:40])=[CH:35][C:34]=5[CH3:43])[CH:29]=[CH:30][C:31]=4[F:32])=[N:22][CH:23]=[CH:24][N:25]=3)[C@H:14]2[CH3:44])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.O.[OH-].[Li+].O.Cl>O1CCOCC1>[F:11][C:9]([F:10])([F:12])[C:7]1[CH:6]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:21]([C:26]4[CH:27]=[C:28]([C:33]5[CH:38]=[CH:37][C:36]([C:39]([OH:41])=[O:40])=[CH:35][C:34]=5[CH3:43])[CH:29]=[CH:30][C:31]=4[F:32])=[N:22][CH:23]=[CH:24][N:25]=3)[C@H:14]2[CH3:44])[CH:4]=[C:3]([C:2]([F:1])([F:46])[F:45])[CH:8]=1
Reactant: COC(=O)c1ccc(-c2ccc(F)c(-c3nccnc3CN3C(=O)O[C@H](c4cc(C(F)(F)F)cc(C(F)(F)F)c4)[C@@H]3C)c2)c(C)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(C(=O)O)ccc1-c1ccc(F)c(-c2nccnc2CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)c1

Procedure:
Methyl 3′-[3-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)pyrazin-2-yl]-4′-fluoro-2-methylbiphenyl-4-carboxylate (Step F, 16 mg, 0.025 mmol) and lithium hydroxide monohydrate (5.18 mg, 0.124 mmol) were stirred in 1,4-dioxane (0.914 mL)/water (0.571 mL) at room temperature for 2 days. Crude mixture was acidified with HCl (1N) and purified by preparative HPLC (Kromasil 100-5C18, 100×21.1 mm) eluting with MeCN/water+0.1% TFA (10% to 100% organic in 10 min, hold 100% in 2 min, 20 mL/min). Related fractions were pooled and evaporated in vacuo to afford an aqueous mixture. The resulting aqueous mixture was extracted with EtOAc, washed with water and then with brine, dried (Na2SO4), filtered and concentrated to afford a colorless glass as the titled compound. LCMS calc. 633.15=; found=634.25 (M+H)+. 1H NMR (500 MHz, CDCl3, 1:1 mixture of atropisomers): δ 8.70 (d, J=2.5 Hz, 1H), 8.68 (d, J=2.5 Hz, 1H), 8.01 (s, 1H), 7.95 (dd, J=8, 1.5 Hz, 1H), 7.89 (s, 1H), 7.78 (s, 1H), 7.51-7.46 (m, 2H), 7.37 (d, J=8 Hz, 1H), 7.31 (t, J=8 Hz, 1H), 5.74 (d, J=8.5 Hz, 1H), 4.95 (d, J=17 Hz, 1H), 4.44-4.36 (m, 2H), 2.37 (s, 3H), 0.77 (d, J=6 Hz, 3H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].C([O:27][C:28](=O)[CH2:29][C:30](=[O:50])[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]2[O:41][N:40]=[C:39]([CH2:42][O:43][CH:44]3[CH2:49][CH2:48][CH2:47][CH2:46][O:45]3)[CH:38]=2)[CH:32]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:28](=[O:27])[CH2:29][C:30](=[O:50])[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]2[O:41][N:40]=[C:39]([CH2:42][O:43][CH:44]3[CH2:49][CH2:48][CH2:47][CH2:46][O:45]3)[CH:38]=2)[CH:32]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2cc(COC3CCCCO3)no2)c1
Reactant: CN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Product: CN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3cc(COC4CCCCO4)no3)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared from (2-amino-5-dimethylamino-4-trifluoromethyl-phenyl)-carbamic acid tert.-butyl ester (Example J6) (565 mg, 1.77 mmol) and (RS)-3-oxo-3-{3-[3-(tetrahydro-pyran-2-yloxymethyl)-isoxazol-5-yl]-phenyl}-propionic acid tert.-butyl ester (Example K12) (710 mg, 1.77 mmol) according to the general procedure M. Obtained as a yellow amorphous substance (721 mg).
Reaction SMILES: [Br:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([NH:8][CH:9](O)[C:10]([Cl:13])([Cl:12])[Cl:11])=[O:7])=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)(Cl)Cl.BrC1C=CC(C(NC(Cl)C(Cl)(Cl)Cl)=O)=CC=1.[Cl:39][C:40]1[CH:46]=[CH:45][C:43]([NH2:44])=[CH:42][CH:41]=1>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([NH:8][CH:9]([NH:44][C:43]2[CH:45]=[CH:46][C:40]([Cl:39])=[CH:41][CH:42]=2)[C:10]([Cl:13])([Cl:12])[Cl:11])=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(NC(O)C(Cl)(Cl)Cl)c1ccc(Br)cc1
Reactant: Nc1ccc(Cl)cc1
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: O=C(NC(Cl)C(Cl)(Cl)Cl)c1ccc(Br)cc1
Solvent: ClC(Cl)Cl
Product: O=C(NC(Nc1ccc(Cl)cc1)C(Cl)(Cl)Cl)c1ccc(Br)cc1
Temperature: 50 °C
Reaction time: 18 h

Procedure:
A solution of 4-bromo-N-(2,2,2-trichloro-1-hydroxyethyl)benzamide (0.67 g, 1.93 mmol) in chloroform (15 mL) was treated with PCl5 (0.42 g, 1.91 mmol). The mixture was heated to 50° C. for 30 minutes before cooling to room temperature and pouring into crushed ice. The organic layer was dried over MgSO4 and filtered. The solution of 4-bromo-N-(1,2,2,2-tetrachloroethyl)benzamide was cooled to room temperature before addition of 4-chloroaniline (0.52 mL, 4.0 mmol), and the mixture was allowed to stir for 18 hours. The mixture was quenched with 2 M HCl and extracted with ether. The organic solution was dried over MgSO4, filtered, and concentrated onto silica gel. The material was purified on an MPLC with 7:3 CH2Cl2:hexanes to give 4-bromo-N-(2,2,2-trichloro-1-(4-chlorophenylamino)ethyl)benzamide (Compound 6) as a solid. The product may be further purified by an appropriate recrystallization such as in ether.
Reaction SMILES: CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[OH:32][C:33]1[N:38]=[C:37]([C:39]([OH:41])=O)[CH:36]=[CH:35][CH:34]=1.FC(F)(F)C(O)=O.[CH3:49][O:50][C:51]1[CH:71]=[CH:70][C:54]([O:55][C:56]2[CH:69]=[CH:68][C:59]([CH2:60][NH:61][C:62]([C:64]3([NH2:67])[CH2:66][CH2:65]3)=[O:63])=[CH:58][CH:57]=2)=[C:53]([C:72]([F:75])([F:74])[F:73])[CH:52]=1>CN(C=O)C>[CH3:49][O:50][C:51]1[CH:71]=[CH:70][C:54]([O:55][C:56]2[CH:69]=[CH:68][C:59]([CH2:60][NH:61][C:62]([C:64]3([NH:67][C:39]([C:37]4[CH:36]=[CH:35][CH:34]=[C:33]([OH:32])[N:38]=4)=[O:41])[CH2:65][CH2:66]3)=[O:63])=[CH:58][CH:57]=2)=[C:53]([C:72]([F:73])([F:74])[F:75])[CH:52]=1
Reactant: O=C(O)c1cccc(O)n1
Reactant: COc1ccc(Oc2ccc(CNC(=O)C3(N)CC3)cc2)c(C(F)(F)F)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(Oc2ccc(CNC(=O)C3(NC(=O)c4cccc(O)n4)CC3)cc2)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
74 μL (0.43 mmol) of DIPEA and 57.7 mg (0.18 mmol) of TBTU were added to a solution of 20 mg (0.14 mmol) of 6-hydroxypicolinic acid in 100 μL DMF and the mixture was stirred for 5 min at RT. Then 71 mg (0.14 mmol) of 1-amino-cyclopropanecarboxylic acid 4-(4-methoxy-2-trifluoromethyl-phenoxy)-benzylamide-trifluoroacetic acid salt (from 84a) was added and the mixture was stirred for 3 days at ambient temperature. The reaction mixture was purified by chromatography (reversed phase).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:7][CH3:8])[CH2:4][NH:5][CH3:6].[Cl:9][C:10]1[CH:26]=[CH:25][CH:24]=[CH:23][C:11]=1[O:12][CH:13]([C:15]1[S:19][C:18]([N:20]=[C:21]=[O:22])=[N:17][N:16]=1)[CH3:14]>C1C=CC=CC=1>[Cl:9][C:10]1[CH:26]=[CH:25][CH:24]=[CH:23][C:11]=1[O:12][CH:13]([C:15]1[S:19][C:18]([NH:20][C:21](=[O:22])[N:5]([CH3:6])[CH2:4][CH:3]([O:7][CH3:8])[O:2][CH3:1])=[N:17][N:16]=1)[CH3:14]
Reactant: CNCC(OC)OC
Reactant: CC(Oc1ccccc1Cl)c1nnc(N=C=O)s1
Solvent: c1ccccc1
Product: COC(CN(C)C(=O)Nc1nnc(C(C)Oc2ccccc2Cl)s1)OC
Yield: 72.7 %

Procedure:
Methylaminoacetaldehyde dimethylacetal (4.2 grams, 0.035 mole) was slowly added at ambient temperature to a 30 milliliter benzene solution containing 9.9 grams (0.035 mole) of the 5-[1-(2-chlorophenoxy)ethyl]-1,3,4-thiadiazol-2-yl isocyanate dimer (prepared above). The resulting solution was refluxed for 20 minutes, cooled and topped on a roto-vac at 70° C. to 13.4 grams of an orange oil which partially crystallized upon standing. The entire sample was recrystallized from a minimum amount of ethylacetate/hexane solution. The crystals were filtered off and dried in a vacuum oven at 80° C. to give 10.2 grams of white crystals of 3-[5-(2-chlorophenoxy)ethyl]-1,3,4-thiadiazol-2-yl]-1-methyl-1-1(2,2-dimethoxyethyl)urea. (Melting point 101°-104° C.).
Reaction SMILES: [C:1]([CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[F:16])[CH2:6][CH2:5]1)#[N:2].[H-].[H-].[H-].[H-].[Li+].[Al+3].[OH-].[Na+]>C(OCC)C.O>[NH2:2][CH2:1][CH2:3][N:4]1[CH2:5][CH2:6][N:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[F:16])[CH2:8][CH2:9]1
Reactant: N#CCN1CCN(c2ccccc2F)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: NCCN1CCN(c2ccccc2F)CC1
Yield: 183.1 %

Procedure:
1-(Cyanomethyl)-4-(2-fluorophenyl)piperazine (9.0 g, 41.0 mmol) was added in portions to a suspension of LiAlH4 (2.34 g, 61.6 mmol) in diethyl ether (200 ml) over 1/2 hour. The mixture was heated to reflux for 5 hours. Water (3 ml) was slowly added to the mixture, followed by a 15% solution of sodium hydroxide in water (3 ml) and water (9 ml). The inorganic solids were removed by filtration, and the filtrate was dried over MgSO4. The solvent was removed in vacuo to give the product (16.76 g, 70% yield) as an amber oil which slowly crystallized to a colorless solid, mp 108°-112° C. IR (KBr) 1502 cm-1 ; mass spectrum m/z 224 (MH+); 1H NMR (CDCl3) δ1.38 (s, 2H, NH2), 2.33-3.23 (m, 12H, NCH2), 6.80-7.06 (m, 4 H, Ph-H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5](I)=[CH:4][N:3]=1.C(N(CC)CC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:36][Si:37]([C:40]#[CH:41])([CH3:39])[CH3:38]>C1COCC1.[Pd](Cl)Cl.[Cu](I)I>[Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([C:41]#[C:40][Si:37]([CH3:39])([CH3:38])[CH3:36])=[CH:4][N:3]=1
Reactant: Clc1ncc(I)c(Cl)n1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd]Cl
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1cnc(Cl)nc1Cl

Procedure:
66.55 g of 2,4-dichloro-5-iodo-pyrimidine is stirred for three hours in 1.2 litres of absolute THF with 70 ml of triethylamine, 4.9 g of palladium chloride, 13.3 g of triphenylphosphine, 4 g of copper iodide and 39.3 ml of trimethylsilylacetylene at 40° C. After the reaction has ended the solvent is eliminated in vacuo and the dark red oil remaining is subjected to fractional distillation. The product is distilled over at 0.01 Torr and 100° C.
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC([N:15]1[CH2:20][CH2:19][CH:18]([CH:21]([CH3:33])[CH:22]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:23][S:24][C:25](=[O:27])[CH3:26])[CH2:17][CH2:16]1)=O)(C)(C)C>C(Cl)Cl>[CH2:31]([O:30][C:28](=[O:29])[CH:22]([CH2:23][S:24][C:25](=[O:27])[CH3:26])[CH:21]([CH:18]1[CH2:17][CH2:16][NH:15][CH2:20][CH2:19]1)[CH3:33])[CH3:32]
Reactant: CCOC(=O)C(CSC(C)=O)C(C)C1CCN(C(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C(CSC(C)=O)C(C)C1CCNCC1
Reaction time: 1.5 h
Yield: 80 %

Procedure:
TFA (2 mL) was added to a solution of 4-(3-acetylsulfanyl-2-ethoxycarbonyl-1-methyl-propyl)-piperidine-1-carboxylic acid tert-butyl ester (0.17 g, 0.439 mmol) in methylene chloride (10 mL). The reaction was stirred for 90 min and concentrated under reduced pressure. The crude product was purified using HPLC (10→50% acetonitrile in water, 0.1% TFA) to give 2-acetylsulfanylmethyl-3-piperidin4-yl-butyric acid ethyl ester (101 mg, 54%) as the TFA salt.
Reaction SMILES: [ClH:1].O1CCOCC1.[N:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][CH2:15][CH:16]2[CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18][N:17]2[C:29]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[O:30])[CH:9]=1>CO>[ClH:1].[ClH:1].[N:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][CH2:15][CH:16]2[CH2:21][NH:20][CH2:19][CH2:18][N:17]2[C:29]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[O:30])[CH:9]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OCc2ccccc2)C(CCc2cccnc2)C1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: O=C(OCc1ccccc1)N1CCNCC1CCc1cccnc1
Reaction time: 1 h
Yield: 58 %

Procedure:
4 M HCl in 1,4-dioxane (6 mL, 24 mmol) was added to a solution of 1-benzyl 4-tert-butyl 2-(2-(pyridin-3-yl)ethyl)piperazine-1,4-dicarboxylate (130.2 mg, 0.306 mmol) in MeOH (1 mL). After 1 h, the reaction mixture was concentrated under reduced pressure and purified by HPLC (5 to 50% MeCN/0.1% TFA in H2O/0.1% TFA gradient). The fractions containing the desired product were concentrated under reduced pressure. The material was dissolved in MeOH (1 mL) and 4 M HCl in 1,4-dioxane (0.015 mL) was added. The mixture was concentrated under reduced pressure to give 71.0 mg (58%) of the desired product. LC-MS: RT=3.50 min, [M+H]+=326.2.