Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([CH:12]2[CH2:14][CH2:13]2)=[CH:9][O:10]C)[C:3]=1[O:15][CH:16]([F:18])[F:17].S(=O)(=O)(O)O>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH:8]([CH:12]2[CH2:13][CH2:14]2)[CH:9]=[O:10])[C:3]=1[O:15][CH:16]([F:18])[F:17]
Reactant: COC=C(c1nccc(Cl)c1OC(F)F)C1CC1
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Product: O=CC(c1nccc(Cl)c1OC(F)F)C1CC1
Yield: 56.7 %

Procedure:
130 mg of 2-(4-chloro-3-difluoromethyl-2-pyridyl)-2-cyclopropyl-1-methoxyethene (XI) was dissolved in 10 ml of THF, which was added 3 ml of dilute sulfuric acid and concentrated at 50° C. under reduced pressure. The resulting mixture was poured into water and neutralized with saturated sodium bicarbonate solution, and thereafter, extracted with chloroform. The resulting organic layer was washed with saturated salt water, and thereafter, dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent; hexane:ethyl acetate=4:1) to obtain 70 mg of 2-(4-chloro-3-difluoromethyl-2-pyridyl)-2-cyclopropylethanal (XII).
Reaction SMILES: [NH2:1][CH:2]1[CH:6]([CH2:7][NH2:8])[C:5]([CH3:10])([CH3:9])[CH2:4][CH:3]1[CH3:11].[C:12]([O:18][CH2:19][CH3:20])(=[O:17])[CH2:13][C:14]([CH3:16])=O>CO>[CH2:19]([O:18][C:12]([CH:13]=[C:14]([NH:1][CH:2]1[CH:3]([CH3:11])[CH2:4][C:5]([CH3:10])([CH3:9])[CH:6]1[CH:7]([NH:8][C:14]([CH3:16])=[CH2:13])[C:12]([O:18][CH2:19][CH3:20])=[O:17])[CH3:16])=[O:17])[CH3:20]
Reactant: CC1CC(C)(C)C(CN)C1N
Reactant: CCOC(=O)CC(C)=O
Solvent: CO
Product: C=C(C)NC(C(=O)OCC)C1C(NC(C)=CC(=O)OCC)C(C)CC1(C)C
Reaction time: 8 h
Yield: 95.2 %

Procedure:
To 5-amino-2,2,4-trimethylcyclopentylmethylamine (127.76 g, 0.819 mol) in methanol (700 ml) was slowly added with stirring ethyl acetoacetate (215.85 g, 1.660 mol) in methanol (700 ml) over 35 minutes, during which the temperature increased from 22° C. to 31° C. The reaction mixture was allowed to stand at 21° C. overnight (17 h). Further methanol was added, and removal of solvent and drying (91°/100 Pa) gave 1-(1-ethoxycarbonyl-2-prop-1-enylamino)-2-(1-ethoxycarbonyl-2-prop-1-enylaminomethyl)-3,3,5-trimethylcyclopentane (EEMTCP, formula shown below) as a clear light yellow pourable viscous oil (296.54 g, 95%) identified by 1H-NMR, 13C-NMR, FT-IR and Raman spectra.
Reaction SMILES: [C-:1]#[N:2].[Na+].Br[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([S:12][C:13]([F:16])([F:15])[F:14])=[CH:8][CH:7]=1>CS(C)=O>[F:14][C:13]([F:16])([F:15])[S:12][C:9]1[CH:10]=[CH:11][C:6]([CH2:5][C:1]#[N:2])=[CH:7][CH:8]=1
Reactant: FC(F)(F)Sc1ccc(CBr)cc1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Product: N#CCc1ccc(SC(F)(F)F)cc1
Temperature: 25 °C
Yield: 84.3 %

Procedure:
Sodium cyanide (3.9 g, 0.08 mol) is added to 40 ml of dimethylsulfoxide at 65° C. under N2. The heat is removed and α-bromo-4-trifluoromethylthiotoluene (14.3 g real, 0.053 mol) is added dropwise at such a rate that the exotherm never raises the temperature above 75° C. The red-colored reaction is heated to 90°-95° C. for about 45 minutes, then cooled to room temperature and treated with 50-100 ml of ice water. The aqueous suspension is extracted with several portions of ether which are combined, washed with water, and dried over sodium sulfate. Evaporation in vacuo gives 9.7 g of a dark red oil 95% pure by glc.
Reaction SMILES: [CH:1]1([C:7]2[S:11][CH:10]=[C:9]([C:12]([OH:14])=O)[CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH:46]1[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48][CH2:47]1>C(#N)C>[N:46]1([C:12]([C:9]2[CH:8]=[C:7]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)[S:11][CH:10]=2)=[O:14])[CH2:52][CH2:51][CH2:50][CH2:49][CH2:48][CH2:47]1
Reactant: C1CCCNCC1
Reactant: O=C(O)c1csc(C2CCCCC2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C(c1csc(C2CCCCC2)c1)N1CCCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.9 %

Procedure:
5-(Cyclohexyl)-thiophene-3-carboxylic acid (0.03 g, 0.14 mmol) was dissolved in acetonitrile (2 mL). Triethylamine (0.42 mmol), HATU (0.15 mmol) and azepane (0.14 mmol) were added and the reaction stirred at room temperature overnight. The resulting solution was purified directly by HPLC, eluting with 10%-98% acetonitrile in water (0.1% formic acid) over 30 minutes. The fractions containing the desired product were concentrated under vacuum to give the title compound (0.022 g). LCMS m/z 292.22 [M+H]+ RT=13.57 min (Analytical Method 1). 1H NMR δ (ppm) (CHCl3-d): 7.2 (s, 1H), 6.95 (s, 1H), 3.7-3.4 (m, 4H), 2.8 (m, 1H), 2.1 (m, 2H), 1.9-1.2 (m, 16H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][N:12]([C:14]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[O:15])[CH2:11][CH:10]([C:22]([OH:24])=O)[CH2:9]2)=[CH:4][C:3]=1[C:25]([F:28])([F:27])[F:26].O[N:30]=[C:31]([NH2:37])[CH2:32][S:33]([CH3:36])(=[O:35])=[O:34]>>[CH3:36][S:33]([CH2:32][C:31]1[N:37]=[C:22]([CH:10]2[CH2:9][CH:8]([C:5]3[CH:6]=[CH:7][C:2]([CH3:1])=[C:3]([C:25]([F:28])([F:27])[F:26])[CH:4]=3)[CH2:13][N:12]([C:14]([N:16]3[CH2:17][CH2:18][O:19][CH2:20][CH2:21]3)=[O:15])[CH2:11]2)[O:24][N:30]=1)(=[O:35])=[O:34]
Reactant: CS(=O)(=O)CC(N)=NO
Reactant: Cc1ccc(C2CC(C(=O)O)CN(C(=O)N3CCOCC3)C2)cc1C(F)(F)F
Product: Cc1ccc(C2CC(c3nc(CS(C)(=O)=O)no3)CN(C(=O)N3CCOCC3)C2)cc1C(F)(F)F

Procedure:
100 mg (0.23 mmol) of the compound from Example 160A and 53 mg (0.35 mmol) of N′-hydroxy-2-(methylsulphonyl)ethanimidamide were reacted according to the General Method 2. Yield: 65 mg (54% of theory)
Reaction SMILES: [O:1]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26]O)=[C:22]([CH2:28]O)[CH:21]=1)[Si:2]([C:15]([CH3:18])([CH3:17])[CH3:16])([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(CC)C(C)C)(C)C.CS(Cl)(=O)=O.[C:44]1([CH2:50][CH2:51][CH2:52][NH2:53])[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>C(#N)C>[O:1]([CH2:19][C:20]1[CH:21]=[C:22]2[C:23](=[CH:24][CH:25]=1)[CH2:26][N:53]([CH2:52][CH2:51][CH2:50][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[CH2:28]2)[Si:2]([C:15]([CH3:18])([CH3:16])[CH3:17])([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: NCCCc1ccccc1
Reactant: CC(C)(C)[Si](OCc1ccc(CO)c(CO)c1)(c1ccccc1)c1ccccc1
Agent: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)(C)[Si](OCc1ccc2c(c1)CN(CCCc1ccccc1)C2)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5.867 g (14.429 mM) of [4-(tert-butyldiphenylsiloxymethyl)-2-hydroxymethylphenyl]methanol and 12.6 ml (72.1 mM) of N,N-diisopropylethylamine in 100 ml of acetonitrile was added a solution of 3.47 g (30.3 mM) of methanesulfonyl chloride in 10 ml of acetonitrile dropwise with ice-cooling and the mixture was stirred at 0° C. for 0.5 hour. To this reaction mixture was added 2.15 g (15.9 mM) of 3-phenylpropylamine and the mixture was stirred at 80° C. overnight. The solvent was then distilled off under reduced pressure and the residue was diluted with aqueous solution of sodium hydrogen carbonate and extracted with 3 portions of ethyl acetate. The pooled organic layer was dried over MgSO4 and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=6/1 to 3/1) to provide the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([NH:11][C@@H:12]([CH:36]([CH3:39])[CH2:37][CH3:38])[C:13]([NH:15][C:16]1([C:33]([OH:35])=O)[CH2:28][C:27]2[C:26]3[C:21](=[C:22]([C:29]([F:32])([F:31])[F:30])[CH:23]=[CH:24][CH:25]=3)[NH:20][C:19]=2[CH2:18][CH2:17]1)=[O:14])=[O:10].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:73][O:74][NH:75][C:76](=[O:83])[C@@H:77]([NH2:82])[CH:78]([CH3:81])[CH2:79][CH3:80]>CN(C=O)C>[CH3:73][O:74][NH:75][C:76]([C@@H:77]([NH:82][C:33]([C@:16]1([NH:15][C:13](=[O:14])[C@@H:12]([NH:11][C:9](=[O:10])[CH2:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[CH:36]([CH3:39])[CH2:37][CH3:38])[CH2:28][C:27]2[C:26]3[C:21](=[C:22]([C:29]([F:32])([F:30])[F:31])[CH:23]=[CH:24][CH:25]=3)[NH:20][C:19]=2[CH2:18][CH2:17]1)=[O:35])[CH:78]([CH3:81])[CH2:79][CH3:80])=[O:83]
Reactant: CCC(C)[C@H](N)C(=O)NOC
Reactant: CCC(C)[C@H](NC(=O)Cc1ccccc1F)C(=O)NC1(C(=O)O)CCc2[nH]c3c(C(F)(F)F)cccc3c2C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCC(C)[C@H](NC(=O)Cc1ccccc1F)C(=O)N[C@]1(C(=O)N[C@H](C(=O)NOC)C(C)CC)CCc2[nH]c3c(C(F)(F)F)cccc3c2C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
0.500 g (0.91 mmol) of (R/S)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl-pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1H-carbazole-3-carboxylic acid (synthesized in according to WO 2006/005484), 0.521 g (1.37 mmol) of HATU and 2.0 mL (11.76 mmol) of DIPEA were dissolved in DMF and stirred for 30 min at room temperature. 0.220 g (1.37 mmol) of (S)-2-Amino-3-methyl-pentanoic acid methoxy-amide were added and the reaction mixture and heated at 110° C. for 3 h. The solvent was removed under vacuum and the residue was purified by high performance liquid chromatography.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:21][CH2:20][C@@:19]2([CH3:22])[C@@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:18]2[CH2:17][CH2:16][C@@:15]2([CH3:23])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:12](=[O:14])[CH3:13])[CH2:3]1.[C:24]1([CH3:34])[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1.Cl>N1C=CC=CC=1>[C:24]1([CH3:34])[CH:29]=[CH:28][C:27]([S:30]([O:1][C@@H:2]2[CH2:21][CH2:20][C@@:19]3([CH3:22])[C@@H:4]([CH2:5][CH2:6][C@@H:7]4[C@@H:18]3[CH2:17][CH2:16][C@@:15]3([CH3:23])[C@H:8]4[CH2:9][CH2:10][C@@H:11]3[C:12](=[O:14])[CH3:13])[CH2:3]2)(=[O:32])=[O:31])=[CH:26][CH:25]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: Cl
Solvent: c1ccncc1
Product: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](OS(=O)(=O)c5ccc(C)cc5)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
3α-Hydroxy-5α-pregnan-20-one (5.12 g) in pyridine (40 mL) was treated with toluene-p-sulphonyl chloride (5.6 g) , and the reaction mixture was stirred at room temperature for 18.0 h. This solution was poured into dilute (5%) hydrochloric acid (200 mL) and washed three times with chloroform (150 mL portions). The combined organic phase was extracted with more 5% hydrochloric acid and water, dried over magnesium sulfate and evaporated to an oil which on standing crystallized and gave 3α-toluene-p-sulphonyloxy-5α-pregnan-20-one as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH:4]([NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH:6]=[CH2:7].[CH3:17][C:18]1[CH:27]=[C:26]([CH2:28][O:29][C:30]2[CH:38]=[CH:37][C:33]([CH:34]=[N:35][OH:36])=[CH:32][CH:31]=2)[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]=1>>[CH3:1][O:2][C:3](=[O:16])[CH:4]([NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH:6]1[O:36][N:35]=[C:34]([C:33]2[CH:32]=[CH:31][C:30]([O:29][CH2:28][C:26]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[N:19]=[C:18]([CH3:17])[CH:27]=3)=[CH:38][CH:37]=2)[CH2:7]1
Reactant: C=CCC(NC(=O)OC(C)(C)C)C(=O)OC
Reactant: Cc1cc(COc2ccc(C=NO)cc2)c2ccccc2n1
Product: COC(=O)C(CC1CC(c2ccc(OCc3cc(C)nc4ccccc34)cc2)=NO1)NC(=O)OC(C)(C)C
Yield: 65 %

Procedure:
Following a procedure analogous to that used in Example step 1c, but using the product from step 8b and 4-(2-methyl-quinolin-4-ylmethoxy)-benzaldehyde oxime from step 1b, the crude product was prepared and purified by FCC on silica gel eluting ethyl acetate:hexanes (gradient) to give 2-tert-butoxycarbonylamino-3-{3-[4-(2-methyl-quinolin-4-ylmethoxy)-phenyl]-4,5-dihydro-isoxazol-5-yl}-propionic acid methyl ester (1.15 g, 65%) as an oil. MS found: (M+H)+=520.
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:26][CH3:27])C1C=CC=CC=1>C(O)(C(F)(F)F)=O>[OH:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:26][CH3:27]
Reactant: COc1cc2c(Oc3ccccc3)ncnc2cc1OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2c(Oc3ccccc3)ncnc2cc1O
Yield: 89 %

Procedure:
7-Benzyloxy-6-methoxy-4-phenoxyquinazoline (160 mg, 0.44 mmol) in TFA (3 ml) was heated at reflux for 30 minutes. The solvent was removed by evaporation and the residue treated with aqueous sodium hydrogen carbonate solution. The precipitated product was collected by filtration, washed with water and dried to give 7-hydroxy-6-methoxy-4-phenoxyquinazoline (105 mg, 88%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][C:13]2[O:14][C:15]([CH2:21][OH:22])=[C:16]([OH:20])[C:17](=[O:19])[CH:18]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH2:23](OC1C(=O)C=C(CNS(C2C=CC=CC=2)(=O)=O)OC=1CO)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:23]([O:20][C:16]1[C:17](=[O:19])[CH:18]=[C:13]([CH2:12][NH:11][S:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)(=[O:10])=[O:9])[O:14][C:15]=1[CH2:21][OH:22])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=c1cc(CNS(=O)(=O)c2ccc(Cl)cc2)oc(CO)c1O
Reactant: O=c1cc(CNS(=O)(=O)c2ccccc2)oc(CO)c1OCc1ccccc1
Product: O=c1cc(CNS(=O)(=O)c2ccc(Cl)cc2)oc(CO)c1OCc1ccccc1
Yield: 46.17 %

Procedure:
N-(5-Benzyloxy-6-hydroxymethyl-4-oxo-4H-pyran-2-ylmethyl)-4-chloro-benzenesulfonamide (10-07) (3.5 g, 46.17%) was synthesized as a white solid from 4-chloro-N-(5-hydroxy-6-hydroxymethyl-4-oxo-4H-pyran-2-ylmethyl)-benzenesulfonamide (9-07) (6.0 g, 17.39 mmol) following the procedure described for N-(5-benzyloxy-6-hydroxymethyl-4-oxo-4H-pyran-2-ylmethyl)-benzenesulfonamide (10-01).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:27]([F:30])([F:29])[F:28])=[N:4][N:5]([CH2:8][C:9]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[C:21]([O:23]C)[C:20]([Cl:25])=[CH:19][C:18]=3[Cl:26])[CH2:13][CH2:12]2)=[O:10])[C:6]=1[CH3:7].B(Br)(Br)Br>C(Cl)Cl>[Cl:1][C:2]1[C:3]([C:27]([F:30])([F:29])[F:28])=[N:4][N:5]([CH2:8][C:9]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[C:21]([OH:23])[C:20]([Cl:25])=[CH:19][C:18]=3[Cl:26])[CH2:13][CH2:12]2)=[O:10])[C:6]=1[CH3:7]
Reactant: COc1cc(N2CCC(C(=O)Cn3nc(C(F)(F)F)c(Cl)c3C)CC2)c(Cl)cc1Cl
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)C1CCN(c2cc(O)c(Cl)cc2Cl)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.5 %

Procedure:
A solution of 2-(4-chloro-5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)-1-(1-(2,4-dichloro-5-methoxyphenyl)piperidin-4-yl)ethanone (100 mg, 0.206 mmol) in anhydrous DCM (1.5 mL) was cooled to −78° C. and then treated with boron tribromide (0.619 mL of a 1.0 M solution in heptanes, 0.619 mmol). The mixture was stirred for 30 min and the cooling bath was removed so that the reaction could warm to RT. After 3 h at RT, the reaction was poured unto crushed ice and extracted with DCM. The extract was dried (MgSO4) and concentrated on a rotary evaporator to give 2-(4-chloro-5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)-1-(1-(2,4-dichloro-5-hydroxyphenyl)piperidin-4-yl)ethanone (80 mg, 0.170 mmol, 82% yield) as a pale yellow solid. LC-MS: 470.13, [M+H]; tR=2.10 min (method a).
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[O:4][CH2:5][C@H:6]1[CH2:10][CH2:9][CH2:8][NH:7]1.[C:15](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O>[Br:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[O:4][CH2:5][C@H:6]1[CH2:10][CH2:9][CH2:8][N:7]1[CH3:15]
Reactant: Brc1ccccc1OC[C@H]1CCCN1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CN1CCC[C@@H]1COc1ccccc1Br
Yield: 38.6 %

Procedure:
(2R)-2-[(2-Bromophenoxy)methyl]pyrrolidine (1.84 g), potassium carbonate (1.09 g) and methyl iodide (0.49 ml) were stirred in dimethylformamide (10 ml) for 2 h at room temperature. The mixture was concentrated in vacuo and water added (50 ml). The mixture was extracted with diethyl ether (3×30 ml). The organic portions were combined and washed with water (2×20 ml), brine (2×20 ml) and dried (MgSO4) and concentrated in vacuo yielding the title compound as a pale orange oil (0.75 g).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7](Br)[CH:8]([CH3:10])[CH3:9].[CH2:12]([O:14][C:15]([C:17]1[S:21][C:20]([C:22]2[CH:27]=[CH:26][C:25]([OH:28])=[C:24]([C:29]#[N:30])[CH:23]=2)=[N:19][C:18]=1[CH3:31])=[O:16])[CH3:13].O>CN(C)C=O>[CH2:12]([O:14][C:15]([C:17]1[S:21][C:20]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:7][CH:8]([CH3:10])[CH3:9])=[C:24]([C:29]#[N:30])[CH:23]=2)=[N:19][C:18]=1[CH3:31])=[O:16])[CH3:13]
Reactant: CCOC(=O)c1sc(-c2ccc(O)c(C#N)c2)nc1C
Reactant: CC(C)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1sc(-c2ccc(OCC(C)C)c(C#N)c2)nc1C
Temperature: 75 °C
Reaction time: 1 h

Procedure:
Potassium carbonate (300 g, 2.17 mol) and isobutyl bromide (142.7 g, 1.041 mol) were added to a solution of ethyl-2-(3-cyano-4-hydroxyphenyl)-4-methyl-5-thiazole carboxylate (100 g, 0.347 mol) in dimethylformamide (300 mL), and the reaction mixture was heated at a temperature of about 75° C. for about 8 hours. After completion of reaction, the reaction mixture was cooled to about 40° C. and water was added. The reaction mixture was further cooled to about 0° C. and stirred for about 1 hour. The solid thus obtained was filtered, washed with water and dried to give title compound. (Yield: 111g, 92.9%)
Reaction SMILES: C(OC([N:8]1[CH:13]([CH3:14])[CH2:12][N:11]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]3[CH:27]=[CH:26][N:25]=[C:24](Cl)[N:23]=3)[CH:17]=2)[CH2:10][CH:9]1[CH3:29])=O)(C)(C)C.[NH2:30][CH2:31][CH2:32][C:33]1[CH:38]=[CH:37][C:36]([OH:39])=[CH:35][CH:34]=1>>[CH3:29][CH:9]1[NH:8][CH:13]([CH3:14])[CH2:12][N:11]([CH2:15][C:16]2[CH:17]=[C:18]([C:22]3[CH:27]=[CH:26][N:25]=[C:24]([NH:30][CH2:31][CH2:32][C:33]4[CH:38]=[CH:37][C:36]([OH:39])=[CH:35][CH:34]=4)[N:23]=3)[CH:19]=[CH:20][CH:21]=2)[CH2:10]1
Reactant: CC1CN(Cc2cccc(-c3ccnc(Cl)n3)c2)CC(C)N1C(=O)OC(C)(C)C
Reactant: NCCc1ccc(O)cc1
Product: CC1CN(Cc2cccc(-c3ccnc(NCCc4ccc(O)cc4)n3)c2)CC(C)N1

Procedure:
Intermediate 142 was coupled with tyramine following procedure F. The resulting product was deprotected following procedure G2. LC-MS showed the product had the expected M+H+ of 418. 1H NMR (Varian 300 MHz, CD3OD, shifts relative to the solvent peak at 3.3 ppm) δ 8.67 (s, 1H) 8.56 (d, 1H)) 8.52 (d, 1H) 8.00 (d, 1H) 7.75 (t, 1H) 7.65 (d, 1H) 7.15 (d, 2H) 6.67 (d, 2H) 4.70 (s, 2H) 3.75 (d, 2H) 3.70 (d, 2H) 3.60-3.66 (m, 2H) 3.40 (t, 2H) 2.96 (t, 2H) 1.44 (d, 6H).
Reaction SMILES: Cl.Cl.[OH:3][CH:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH:5]1[N:10]1[CH2:15][CH2:14][C:13]2([C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:18][CH2:17][CH2:16]2)[CH2:12][CH2:11]1.[I:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH2:29]Br.C(N(CC)CC)C>CCO>[I:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH2:29][N:7]1[CH2:8][CH2:9][CH:4]([OH:3])[CH:5]([N:10]2[CH2:15][CH2:14][C:13]3([C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH2:18][CH2:17][CH2:16]3)[CH2:12][CH2:11]2)[CH2:6]1
Reactant: OC1CCNCC1N1CCC2(CCCc3ccccc32)CC1
Reactant: BrCc1cccc(I)c1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: OC1CCN(Cc2cccc(I)c2)CC1N1CCC2(CCCc3ccccc32)CC1

Procedure:
A mixture of 21c and 22c derived from a mixture of 19c and 20c as described above (676 mg, 1.81 mmol), 3-iodobenzylbromide (2.17 mmol, 645 mg), and triethylamine (10 mL) in absolute EtOH (20 mL) was refluxed for 18 h. Volatiles were removed under reduced pressure and the red residue was treated with water. After extraction in dichloromethane (3×30 mL), the combined organic layers were washed with brine, dried over Na2SO4 and concentrated to give a dark red semi-solid residue. Chromatographic purification (silica gel, 50% ethyl acetate-hexanes) afforded 276 mg (30%) of the crude product as a yellow oil. The two regioisomers were separated by HPLC (Silica gel, Hexane/Isopropanol/Triethylamine: 98/2/0.02) and 13d was obtained as a white crystalline solid (166 mg, 18%). Only a trace of the other isomer was recovered. The hydrochloride of 13d was prepared in said methanolic saturated HCl and subsequently recrystallized from 50% i-PrOH-hexanes to provide a white powder; mp 245° C. 1H NMR ((CDCl3) δ1.59-2.06 (m, 8, 2 N--C H2 --C H2), 2.41-2.48 (m, 2, Ar--C H2 --CH2), 2.52-2.62 (m, 2, C H2 --CHOH), 2.75-2.78 (m, 4, Ar--CH2 --C H2 --C H2), 2.83-2.92 (m, 2, C H2 --CH2 --CHOH), 3.01-3.06 (d, 2, N--C H2 --CHN, J=10.0 Hz), 3.38-3.56 (m, 3, Ar--CH2 --N+CH--N), 3.85 (s, 1, C H--OH), 7.02-7.31 (m, 5, arom.), 7.44-7.48 (d, 1, arom., J=7.8 Hz), 7.58-7.62 (d, 1, arom., J=7.9 Hz), 7.68 (s, 1, arom.).
Reaction SMILES: [C:1]([CH2:4][NH:5][C@@H:6]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]([N:20]3[CH2:25][CH2:24][CH:23]([C:26]4[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=4)[CH2:22][CH2:21]3)=[O:19])=[CH:13][CH:12]=2)[CH2:7]1)(=[O:3])[CH3:2].[H-].[Na+].I[CH3:36].O>CN(C=O)C>[C:1]([CH2:4][NH:5][C@@H:6]1[CH2:10][CH2:9][N:8]([C:11]2[CH:12]=[CH:13][C:14]([N:17]([CH3:36])[C:18]([N:20]3[CH2:21][CH2:22][CH:23]([C:26]4[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=4)[CH2:24][CH2:25]3)=[O:19])=[CH:15][CH:16]=2)[CH2:7]1)(=[O:3])[CH3:2]
Reactant: CI
Reactant: CC(=O)CN[C@@H]1CCN(c2ccc(NC(=O)N3CCC(c4ccc(F)cc4)CC3)cc2)C1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)CN[C@@H]1CCN(c2ccc(N(C)C(=O)N3CCC(c4ccc(F)cc4)CC3)cc2)C1
Reaction time: 2 h

Procedure:
(R)-4-(4-Fluorophenyl)piperidine-1-carboxylic acid {4-[3-(acetylmethylamino)pyrrolidin-1-yl]phenyl}amide (22 mg) was added to a suspension of sodium hydride (95% in oil; 0.005 g) in DMF (1 ml). After evolution of gas ceased, iodomethane (0.02 ml) was added. After two hours, the reaction mixture was cautiously hydrolyzed with water and extracted with dichloromethane. The organic phase was dried over magnesium sulfate and concentrated, and the residue was crystallized from pentane. This resulted in the product with the molecular weight of 452.58 (C26H33FN4O2); MS (ESI): 453 (M+H+).
Reaction SMILES: [C:1]([N:4]([C:20](=[O:22])[CH3:21])[C:5]1[C:10]([CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[CH:9][CH:8]=[CH:7][C:6]=1[S:16](O)(=[O:18])=[O:17])(=[O:3])[CH3:2].P(Cl)(Cl)(Cl)(Cl)[Cl:24]>ClCCl>[C:1]([N:4]([C:20](=[O:22])[CH3:21])[C:5]1[C:10]([CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[CH:9][CH:8]=[CH:7][C:6]=1[S:16]([Cl:24])(=[O:18])=[O:17])(=[O:3])[CH3:2]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: CC(=O)N(C(C)=O)c1c(C2CCCC2)cccc1S(=O)(=O)O
Solvent: ClCCl
Product: CC(=O)N(C(C)=O)c1c(C2CCCC2)cccc1S(=O)(=O)Cl

Procedure:
A solution of 1.55 g (3.6 mmol) of 2-(diacetylamino)-3-cyclopentylbenzenesulphonic acid and 1.12 g (5.4 mmol) of phosphorus pentachloride in 10 ml of dichloromethane is heated at the reflux temperature for 2.5 hours, and the reaction medium is then concentrated under reduced pressure. The residue thus obtained is purified by chromatography on a column of florisil™, eluting with dichloromethane.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1)#[N:2].[CH2:12]([NH:19][C:20]([C:22]1[S:26][C:25]([NH2:27])=[N:24][C:23]=1[CH3:28])=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH2:12]([NH:19][C:20]([C:22]1[S:26][C:25]([NH:27][C:7](=[O:8])[C:6]2[CH:10]=[CH:11][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)=[N:24][C:23]=1[CH3:28])=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Cc1nc(N)sc1C(=O)NCc1ccccc1
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Product: Cc1nc(NC(=O)c2ccc(C#N)cc2)sc1C(=O)NCc1ccccc1
Yield: 23 %

Procedure:
Following the procedure as described in Example 2, making variations only as required to use 4-cyanobenzoyl chloride in place of benzoyl chloride to react with 2-amino-4-methylthiazole-5-carboxylic acid benzylamide, the title compound was obtained as a white solid in 23% yield; m.p. 256-258° C.; 1H NMR (DMSO-d6, 300 MHz) δ 8.64 (t, J=5.7 Hz, 1H), 8.19 (d, J=8.2 Hz, 2H), 7.99 (d, J=8.2 Hz, 2H), 7.49-7.18 (m, 5H), 4.37 (d, J=5.7 Hz, 2H), 2.51 (s, 3H); MS (ES+) m/z 377.2 (M+1).