Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[NH:13][NH2:14].[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][S:24][C:25](=[C:36]([C:39]#[N:40])[C:37]#[N:38])SCC2C=CC(OC)=CC=2)=[CH:19][CH:18]=1>C(O)(C)C>[NH2:40][C:39]1[N:13]([C:3]2[C:2]([Cl:1])=[CH:7][C:6]([C:8]([F:9])([F:11])[F:10])=[CH:5][C:4]=2[Cl:12])[N:14]=[C:25]([S:24][CH2:23][C:20]2[CH:19]=[CH:18][C:17]([O:16][CH3:15])=[CH:22][CH:21]=2)[C:36]=1[C:37]#[N:38]
Reactant: NNc1c(Cl)cc(C(F)(F)F)cc1Cl
Reactant: COc1ccc(CSC(SCc2ccc(OC)cc2)=C(C#N)C#N)cc1
Solvent: CC(C)O
Product: COc1ccc(CSc2nn(-c3c(Cl)cc(C(F)(F)F)cc3Cl)c(N)c2C#N)cc1

Procedure:
A solution of 2,6-dichloro-4-trifluoromethyl phenyl hydrazine (245 mg, 1.0 mmol) and {bis[(4-methoxyphenyl)methylthio]methylene}methane-1,1-dicarbonitrile (101, 382 mg, 1.0 mmol) in isopropyl alcohol (15 mL) was heated at reflux for 16 h. The solvent was removed under reduced pressure and the desired product 102 obtained after chromatographic separation (silica gel) using ethyl acetate-hexanes (331 mg, 70%). NMR (δ, CDCl3): 7.7 (2H, s); 7.2 (2H, d, J=8.7 Hz); 6.8 (2H, d, J=8.7 Hz); 4.41 (2H, broad); 4.23 (2H, s). MS: M+1=473 (calc.: 473).
Reaction SMILES: [CH3:1][C:2]([CH3:4])=O.C(O)(=O)C.[NH2:9][C:10]1[N:15]=[CH:14][CH:13]=[CH:12][N:11]=1>C(O)C>[CH:2]([NH:9][C:10]1[N:15]=[CH:14][CH:13]=[CH:12][N:11]=1)([CH3:4])[CH3:1]
Reactant: Nc1ncccn1
Reactant: CC(C)=O
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)Nc1ncccn1
Reaction time: 8 h

Procedure:
Ethanol (200 mL), acetone (21 mL, 1.5 eq.), and glacial acetic acid (3.0 mL, 0.28 eq.) were added to the aminopyrimidine solution in the hydrogenation flask. After evacuating and purging, the flask was pressurized with H2 (60 psi). The reductive amination was allowed to proceed overnight. TLC on silica using EtOAc as the eluant gave an Rf=0.41 (streaky) for the isopropylamino-pyrimidine and an Rf=0.11 for the starting aminopyrimidine carbamate. Both TLC and LC/MS confirmed complete reaction with virtually no bis-isopropylaminopyrimidine produced. If necessary, HPLC can be used as an alternative means to monitor progress of the reaction. The crude reaction solution was diluted with EtOAc (1 L) and filtered through a pad of basic alumina (400 mL). The alumina was rinsed with EtOAc (200 mL) and EtOH (200 mL) and the combined organic solutions were concentrated in vacuo. The flask was vented under N2. The viscous oil was redissolved in anhydrous toluene (700 mL) and concentrated. After venting the flask under nitrogen, the product was dried again by azeotropic removal of another 400 mL of toluene. A viscous reddish-brown oil was obtained.
Reaction SMILES: C([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:20]([F:23])([F:22])[F:21])[CH2:10][CH2:9]1)C1C=CC=CC=1.[C:24]([C:28]1[CH:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=1)([CH3:27])([CH3:26])[CH3:25]>>[C:24]([C:28]1[CH:33]=[CH:32][C:31]([S:34]([N:8]2[CH2:9][CH2:10][CH:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[C:20]([F:21])([F:22])[F:23])[CH2:12][CH2:13]2)(=[O:36])=[O:35])=[CH:30][CH:29]=1)([CH3:27])([CH3:25])[CH3:26]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Reactant: FC(F)(F)c1ccccc1C1=CCN(Cc2ccccc2)CC1
Product: CC(C)(C)c1ccc(S(=O)(=O)N2CCC(c3ccccc3C(F)(F)F)CC2)cc1
Yield: 48.8 %

Procedure:
Using the procedure from Example 14A, Step 14D, 1-benzyl-4-[2-(trifluoromethyl)phenyl]-1,2,3,6-tetrahydropyridine (Example 14A, Step 14C, 150 mg, 0.65 mmol) was reacted with 4-tert-butylbenzenesulfonyl chloride (182 mg, 0.78 mmol) to afford the title compound (135 mg), a white solid, in 49% yield.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][C:5]([B:8]([OH:10])[OH:9])=[CH:4][CH:3]=1.Br[CH2:12][C:13]([NH2:15])=[O:14].C([O-])([O-])=O.[K+].[K+]>CC#N>[NH2:15][C:13](=[O:14])[CH2:12][S:1][C:2]1[CH:7]=[CH:6][C:5]([B:8]([OH:10])[OH:9])=[CH:4][CH:3]=1
Reactant: OB(O)c1ccc(S)cc1
Reactant: NC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: NC(=O)CSc1ccc(B(O)O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.7 %

Procedure:
A mixture of 4-mercaptophenylboronic acid (1.0 g, 90%, 5.84 mmol), 2-bromoacetamide (1.8 g, 13 mmol) and K2CO3 (2.70 g, 19.5 mmol) in CH3CN (20 mL) was stirred at ambient temperature overnight. After CH3CN was removed, water was added to the residue, and the solid was collected via filtration and washed with water to give 0.6 g (49%) of {4-[(2-amino-2-oxoethyl)thio]phenyl}boronic acid as a white solid. The boronic acid was used without further purification. 1H NMR (400 MHz, DMSO-d6): δ 8.00 (s, 2H), 7.68 (d, 2H, J=8.2 Hz), 7.55 (bs, 1H), 7.24 (d, 2H, J=8.2 Hz), 7.15 (bs, 1H), 3.61 (s, 2H); LRMS (APCI), m/z 210 (M−H).
Reaction SMILES: C(#N)C.[O:4]=[S:5]1(=[O:16])[CH2:9][CH2:8][CH2:7][N:6]1[CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([N:28]2[C:32]3[CH:33]=[CH:34][C:35]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)=[CH:36][C:31]=3[N:30]=[C:29]2Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1.C(N(C(C)C)CC)(C)C>C(OCC)(=O)C.O>[O:16]=[S:5]1(=[O:4])[CH2:9][CH2:8][CH2:7][N:6]1[CH:10]1[CH2:15][CH2:14][N:13]([C:29]2[N:28]([S:25]([C:22]3[CH:21]=[CH:20][C:19]([O:18][CH3:17])=[CH:24][CH:23]=3)(=[O:27])=[O:26])[C:32]3[CH:33]=[CH:34][C:35]([C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=4)=[CH:36][C:31]=3[N:30]=2)[CH2:12][CH2:11]1
Reactant: O=S1(=O)CCCN1C1CCNCC1
Reactant: COc1ccc(S(=O)(=O)n2c(Cl)nc3cc(-c4ccccc4)ccc32)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COc1ccc(S(=O)(=O)n2c(N3CCC(N4CCCS4(=O)=O)CC3)nc3cc(-c4ccccc4)ccc32)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 41.6 %

Procedure:
To the acetonitrile solution (3 mL) containing 4-(1,1-dioxo-1λ6-isothiazolidin-2-yl)piperidine (136 mg) were added 1-(4-methoxyphenylsulfonyl)-2-chloro-5-phenylbenzimidazole (340 mg) and diisopropylethylamine (0.41 mL), followed by stirring at room temperature for 16 hrs. The reaction mixture was diluted with ethyl acetate and water, and the organic layer was washed with an aqueous saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was separated and purified on a collective thin-layer chromatograph (ethyl acetate) to give the title compound (157 mg).
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4]CC1.[Br:8][C:9]1[CH:10]=[C:11]([S:16]([NH2:19])(=[O:18])=[O:17])[CH:12]=[CH:13][C:14]=1F>>[Br:8][C:9]1[CH:10]=[C:11]([S:16]([NH2:19])(=[O:18])=[O:17])[CH:12]=[CH:13][C:14]=1[NH:7][CH2:1][CH:6]1[CH2:4][CH2:5]1
Reactant: NC1CCCCC1
Reactant: NS(=O)(=O)c1ccc(F)c(Br)c1
Product: NS(=O)(=O)c1ccc(NCC2CC2)c(Br)c1

Procedure:
Example 238a was prepared according to the procedure used for the preparation of Example 96a, substituting cyclopropylmethanamine for cyclohexanamine, and 3-bromo-4-fluorobenzenesulfonamide for Example 86a, respectively, to provide the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[CH2:9]O.[CH3:11][C:12]1[CH:17]=[C:16]([C:18]([CH3:20])=O)[CH:15]=[C:14]([CH3:21])[CH:13]=1.[OH-].[K+]>C1(C)C=CC=CC=1>[Br:8][C:5]1[CH:4]=[C:3]2[C:2](=[CH:7][CH:6]=1)[N:1]=[C:18]([C:16]1[CH:17]=[C:12]([CH3:11])[CH:13]=[C:14]([CH3:21])[CH:15]=1)[CH:20]=[CH:9]2
Reactant: CC(=O)c1cc(C)cc(C)c1
Reactant: Nc1ccc(Br)cc1CO
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: Cc1cc(C)cc(-c2ccc3cc(Br)ccc3n2)c1
Temperature: 25 °C

Procedure:
(2-Amino-5-bromophenyl)methanol (22 g, 109 mmol), 3,5-dimethylacetophenone (24.2 g, 163 mmol), RuCl2(PPh3)3 (1.05 g, 1.09 mmol), KOH (11.0 g, 196 mmol) were refluxed in 270 mL of toluene for 18 h. Water was collected from the reaction using a Dean-stark trap. The reaction mixture was allowed to cool to room temperature and filtered through a silica gel plug and eluted with 5% ethyl acetate in hexanes. The product was further purified by Kugelrohr distillation and crystallization from methanol.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([C:14](Cl)=[O:15])[CH2:11][C:10]2([CH3:13])[CH3:12])=[CH:5][CH:4]=1.Cl.[NH2:18][C:19]1[N:24]=[C:23]([C:25]2[CH:30]=[CH:29][C:28]([S:31]([NH:34][CH3:35])(=[O:33])=[O:32])=[CH:27][CH:26]=2)[CH:22]=[CH:21][CH:20]=1>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([C:14]([NH:18][C:19]3[CH:20]=[CH:21][CH:22]=[C:23]([C:25]4[CH:26]=[CH:27][C:28]([S:31](=[O:33])(=[O:32])[NH:34][CH3:35])=[CH:29][CH:30]=4)[N:24]=3)=[O:15])[CH2:11][C:10]2([CH3:13])[CH3:12])=[CH:5][CH:4]=1
Reactant: COc1ccc(C2(C(=O)Cl)CC2(C)C)cc1
Reactant: CNS(=O)(=O)c1ccc(-c2cccc(N)n2)cc1
Agent: Cl
Solvent: c1ccncc1
Product: CNS(=O)(=O)c1ccc(-c2cccc(NC(=O)C3(c4ccc(OC)cc4)CC3(C)C)n2)cc1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
1-(4-Methoxyphenyl)-2,2-dimethylcyclopropanecarbonyl chloride (0.20 mmol) was added to a solution of 4-(6-aminopyridin-2-yl)-N-methylbenzenesulfonamide HCl salt (60 mg, 0.20 mmol) in pyridine (1 mL) at room temperature. The reaction was stirred at 60° C. overnight and then was concentrated, dissolved in DMSO and purified by LC-MS to yield 1-(4-methoxyphenyl)-2,2-dimethyl-N-(6-(4-(N-methylsulfamoyl)-phenyl)pyridin-2-yl)cyclo-propanecarboxamide. ESI-MS m/z calc. 465.2. found 466.5 (M+1)+. Retention time 1.98 minutes.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][NH:15][C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH:22]1([C:25](Cl)=[O:26])[CH2:24][CH2:23]1>C(Cl)Cl>[C:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][N:15]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[C:25]([CH:22]2[CH2:24][CH2:23]2)=[O:26])[CH2:9]1)([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: O=C(Cl)C1CC1
Reactant: CC(C)(C)OC(=O)N1CCCC(CNc2cccnc2)C1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCCC(CN(C(=O)C2CC2)c2cccnc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73 %

Procedure:
To a solution of N-(1-Boc-piperidin-3-ylmethyl)-N-(pyridin-3-yl) amine 17 (56 mg, 0.19 mmol) and piperidinomethyl polystyrene resin (3.5 mM/g, 60 mg) in 0.6 mL of dry CH2Cl2 was added cyclopropanecarbonyl chloride (98%, 21 μL, 1.2 eq.) at room temperature. After being shaken at room temperature overnight, the reaction mixture was passed through an aminopropyl NH2 cartridge and washed with CH2Cl2. Removal of CH2Cl2 afforded Cyclopropanecarboxylic acid N-(1-Boc-piperidin-3-ylmethyl)-N-(pyridin-3-yl) amide 22 (50 mg, 73%). LRMS 260 (M-100)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]=[C:4]([NH:14][C:15]2[S:16][CH:17]=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:19]=2)[CH:3]=1.CC1(C)C(C)(C)OB([C:34]2[C:35]([C:41]([F:44])([F:43])[F:42])=[CH:36][C:37]([NH2:40])=[N:38][CH:39]=2)O1>O1CCOCC1.C(=O)([O-])[O-].[Na+].[Na+].[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[NH2:40][C:37]1[N:38]=[CH:39][C:34]([C:2]2[N:7]=[C:6]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[N:5]=[C:4]([NH:14][C:15]3[S:16][CH:17]=[C:18]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[N:19]=3)[CH:3]=2)=[C:35]([C:41]([F:44])([F:42])[F:43])[CH:36]=1
Reactant: Clc1cc(Nc2nc(-c3ccccc3)cs2)nc(N2CCOCC2)n1
Reactant: CC1(C)OB(c2cnc(N)cc2C(F)(F)F)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: Nc1cc(C(F)(F)F)c(-c2cc(Nc3nc(-c4ccccc4)cs3)nc(N3CCOCC3)n2)cn1

Procedure:
A solution of N-(6-chloro-2-morpholinopyrimidin-4-yl)-4-phenylthiazol-2-amine (15 mg, 0.040 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)pyridin-2-amine (23 mg, 0.080 mmol) and 1,1′-bis(diphenylphosphino)ferrocene palladium (II) chloride (6.6 mg, 0.0080 mmol) in 0.5 mL of 1,4-dioxane and 0.05 mL of 2 M aq. sodium carbonate was heated in the microwave at 120° C. for 600 seconds. The crude product was purified by reverse phase prep HPLC to give N-(6-(6-amino-4-(trifluoromethyl)pyridin-3-yl)-2-morpholinopyrimidin-4-yl)-4-phenylthiazol-2-amine. LC/MS (m/z): 500 (MH+), Rt 2.46 minutes.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][N:6]=1.[CH3:12][S:13]([C:16]1[CH:21]=[CH:20][C:19](/[C:22](=[CH:26]\[CH:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)/[C:23](O)=[O:24])=[CH:18][CH:17]=1)(=[O:15])=[O:14]>>[CH3:12][S:13]([C:16]1[CH:17]=[CH:18][C:19](/[C:22](=[CH:26]\[CH:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)/[C:23]([NH:1][C:2]2[S:3][C:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][N:6]=2)=[O:24])=[CH:20][CH:21]=1)(=[O:15])=[O:14]
Reactant: CS(=O)(=O)c1ccc(/C(=C\C2CCOCC2)C(=O)O)cc1
Reactant: CCOC(=O)c1cnc(N)s1
Product: CCOC(=O)c1cnc(NC(=O)/C(=C/C2CCOCC2)c2ccc(S(C)(=O)=O)cc2)s1

Procedure:
Ethyl 2-aminothiazole-5-carboxylate (0.73 g, 4.26 mmol) was condensed with (E)-2-(4-methanesulfonylphenyl)-3-(tetrahydropyran-4-yl)acrylic acid (Preparation 25, 0.33 g, 1.07 mmol), using the procedure described in EXAMPLE 65, to give (E)-ethyl 2-[2-(4-methanesulfonylphenyl)-3-(tetrahydropyran-4-yl)acryloylamino]thiazole-5-carboxylate: m/z (ES+)=465.3 [M+H]+. This ester (0.50 g, 1.07 mmol) was saponified, employing the protocol described in EXAMPLE 127, to furnish (E)-2-[2-(4-methanesulfonylphenyl)-3-(tetrahydropyran-4-yl)acryloylamino]thiazole-5-carboxylic acid: m/z (ES−)=435.2 [M−H]−. Utilising the approach described in EXAMPLE 129, this acid (0.16 g, 0.37 mmol) was transformed into the title compound: RTA=2.87 min; m/z (ES+)=450.2 [M+H]+.
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[O:23][C:22]([CH:24]=O)=[CH:21][CH:20]=2)=[CH:15][CH:14]=1.C(O)(=O)C1C=CC=CC=1.N1CCCCC1>C1C=CC=CC=1.O>[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]2[O:23][C:22]([CH:24]=[C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][CH2:10][CH3:11])=[O:8])=[CH:21][CH:20]=2)=[CH:17][CH:18]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: O=Cc1ccc(-c2ccc(Cl)cc2)o1
Agent: O=C(O)c1ccccc1
Solvent: C1CCNCC1
Solvent: c1ccccc1
Solvent: O
Product: CCOC(=O)C(=Cc1ccc(-c2ccc(Cl)cc2)o1)C(=O)OCC

Procedure:
Diethyl malonate (88 g, 0.55 mole) and 5-(p-chlorophenyl)-2-furaldehyde (104 g, 0.50 mole) were placed in 1.0 liter of benzene containing benzoic acid (10 g) and piperidine (18 ml). The 2.0 liter flask was equipped with a Dean-Stark trap for water removal, and the mixture was refluxed for 4 hours on a steam bath. The mixture was concentrated to an oil under reduced pressure. Washing the residue with benzene (500 ml) yielded a dark solid which was recrystallized from cyclohexane yielding yellow product (111 g, 64% yeild), m.p. 78°-80°.
Reaction SMILES: [I:1][C:2]1[CH:17]=[C:16]([N+:18]([O-])=O)[CH:15]=[CH:14][C:3]=1[CH2:4][CH2:5][NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10].CO.C(O)(=O)C.C(=O)([O-])[O-].[Na+].[Na+]>C(OCC)(=O)C.[Fe]>[NH2:18][C:16]1[CH:15]=[CH:14][C:3]([CH2:4][CH2:5][NH:6][C:7](=[O:13])[O:8][C:9]([CH3:10])([CH3:11])[CH3:12])=[C:2]([I:1])[CH:17]=1
Reactant: CC(C)(C)OC(=O)NCCc1ccc([N+](=O)[O-])cc1I
Agent: [Fe]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)NCCc1ccc(N)cc1I
Temperature: 50 °C
Yield: 90.6 %

Procedure:
Into the reaction was added tert-butyl (2-iodo-4-nitrobenzyl)methylcarbamate (4.90 g, 12.5 mmol), methanol (85 mL), acetic acid (14.2 mL) and iron (4.19 g, 75.0 mmol) powder. The reaction solution was heated at 50° C. for 1.5 h. After cooling to room temperature, the reaction solution was diluted with ethyl acetate and a saturated sodium carbonate solution. The reaction mixture was filtered through a pad of celite and washed with EtOAc. The aqueous layer was extracted with ethyl acetate once. The combined organic solutions were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography to yield the desired product (4.10 g, 91%). LCMS calculated for C13H191N2O2Na (M+H)+: m/z=385.1.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([O:8][CH2:9][CH3:10])=[O:7].[Al+3].[Cl-].[Cl-].[Cl-].[C:15](Cl)(=[O:17])[CH3:16].CO>ClCCCl.ClCCl>[C:15]([C:4]1[CH:3]=[C:2]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[NH:1][CH:5]=1)(=[O:17])[CH3:16]
Reactant: CCOC(=O)c1ccc[nH]1
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Solvent: CO
Solvent: ClCCl
Product: CCOC(=O)c1cc(C(C)=O)c[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.7 %

Procedure:
In a two-neck round bottom flask with an argon inlet, 4.0 g of ethyl pyrrole 2-carboxylate (28.8 mmol) is dissolved in 100 ml of 1,2-dichloroethane. Subsequently, 8.0 g of AlCl3 is added slowly. A solution of 4.4 ml of acetyl chloride (62 mmol) in 50 ml of 1,2-dichloroethane was then added dropwise over a period of 15 min. After stirring the reaction mixture at room temperature for one hour, it is carefully poured onto 200 g of crushed ice. After hydrolysis, the mixture is transferred into a separatory funnel and the organic phase is separated off. The aqueous phase is extracted with dichloromethane (2×200 ml), and the combined organic phases are washed with a saturated solution of aqueous sodium bicarbonate (1×100 ml) and with water (1×100 ml) before being dried over magnesium sulfate. The solvent is then removed under vacuum. Chromatographic workup (silica gel; 1% methanol in dichloromethane as eluent) yielded the product as a pale brown powder (4.0 g, 76% yield). 1H NMR (δ ppm, CDCl3): 10.41 (s, br, 1H, NH); 7.51 (dd, J=3.34, 1.62 Hz, 1H, α-pyrrolic); 7.28 (dd, J=1.62, 2.31 Hz, 1H, β-pyrrolic); 4.29 (q, J=7.12 Hz, 2H, CO2Et); 2.39 (s, 3H, Me); 1.31 (t, J=7.12 H, 3H, CO2Et). 13C NMR (δ ppm, CDCl3): 193.55; 161.07; 127.00; 126.54; 124.04; 114.86; 60.83; 27.13; 14.15. Exact mass calculated for C9H12NO3 (M+H)=182.081718, found=182.081495.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:3]=1[CH:4](O)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[F:11].[SH:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22]>Cl>[ClH:17].[NH2:1][C:2]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:3]=1[CH:4]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[F:11])[S:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22]
Reactant: O=C(O)CCS
Reactant: Nc1ccc(Cl)cc1C(O)c1ccccc1F
Agent: Cl
Product: Nc1ccc(Cl)cc1C(SCCC(=O)O)c1ccccc1F

Procedure:
100 g of 2-amino-5-chloro-2'-fluorobenzhydrol, 45.6 g of 3-mercaptopropionic acid and 200 ml of 6N hydrochloric acid are stirred together at 100° for 1.5 hours. After cooling the mixture, the precipitated crystals are filtered off and washed with 6N hydrochloric acid. There is obtained 3-[(2-amino-5-chlorophenyl)(2-fluorophenyl)methylthio]propionic acid hydrochloride of melting point 139°-141°.
Reaction SMILES: C([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]/[CH:14]=[CH:15]/[CH:16]=[CH:17]/[CH3:18])(=O)C.O1CCCCC1OCCCCCCCCCC=CC=CC>CO.O>[CH2:5]([OH:4])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH:14]=[CH:15][CH:16]=[CH:17][CH3:18]
Reactant: C/C=C/C=C/CCCCCCCCCOC(C)=O
Agent: CC=CC=CCCCCCCCCCOC1CCCCO1
Solvent: CO
Solvent: O
Product: CC=CC=CCCCCCCCCCO
Yield: 66 %

Procedure:
To prepare (E,E)-10,12-tetradecadien-1-ol acetate (I), the tetradecadiene (D) (5.6 g) in 200 ml methanol containing eight drops concentrated HCl was refluxed for 15 minutes. After the solution was cooled, 400 ml of water was added, and the mixture was extracted three times with hexane. The hexane extract was dried over sodium sulfate, and the hexane was removed with a rotary evaporator leaving 3 g crude 10,12-tetradecadienol, which was purified by silica gel liquid chromatography. Unwanted side products were eluted with 10% ether/hexane, and the alcohol was eluted with 50% ether/hexane, giving 2.4 g (66% yield based on the dodecenenitrile (B)).
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([O:10][C:11](=[O:35])[C:12]([CH:14]([C:21]1[CH:22]=[N:23][C:24]([NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[CH:25][CH:26]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH2:13])[CH3:9].C(OCC)(=O)C.[C:42]([OH:45])(=[S:44])[CH3:43]>>[CH2:8]([O:10][C:11](=[O:35])[CH:12]([CH2:13][S:44][C:42](=[O:45])[CH3:43])[CH:14]([C:21]1[CH:22]=[N:23][C:24]([NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[CH:25][CH:26]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[CH3:9]
Reactant: CC(O)=S
Reactant: C=C(C(=O)OCC)C(c1ccccc1)c1ccc(NC(=O)OC(C)(C)C)nc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)C(CSC(C)=O)C(c1ccccc1)c1ccc(NC(=O)OC(C)(C)C)nc1
Temperature: 45 °C
Yield: 73 %

Procedure:
Triethylamine (0.105 g, 1.04 mmol) was added to a solution of 2-[(6tert-butoxycarbonylamino-pyridin-3-yl)-phenyl-methyl]-acrylic acid ethyl ester (0.36 g, 0.94 mmol) in thioacetic acid (4 mL) at 0° C. under argon. The mixture was heated at 45° C. for 24 h. Ethyl acetate was added and the organic phase was washed with aqueous saturated sodium bicarbonate and brine and dried. After filtration and evaporation in vacuo the crude product was purified by flash chromatography (toluene/ethyl acetate, 1:0→5:1) to give 2-acetylsulfanylmethyl-3-(6-tert-butoxycarbonylamino-pyridin-3-yl)-3-phenyl-propionic acid ethyl ester (0.314 g, 73%).
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][C:7]2([OH:20])[CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[ClH:23].C(O)C>C(O)C>[ClH:23].[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2([OH:20])[CH2:8][CH2:9][NH:10][CH2:11][CH2:12]2)=[CH:21][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)(Cc2ccc(F)cc2)CC1
Agent: Cl
Solvent: CCO
Product: OC1(Cc2ccc(F)cc2)CCNCC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of tert-butyl 4-(4-fluorobenzyl)-4-hydroxypiperidine-1-carboxylate (2.0 g) in ethanol (10 mL) was added 2.0 M HCl/ethanol solution (20 mL), and the mixture was stirred at room temperature for 3 hr. The solvent was evaporated under reduced pressure, and the obtained solid was recrystallized from ethanol/hexane to give the title compound (1.4 g).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[NH2:10].[CH2:11]=O.C[O-].[Na+].[BH4-].[Na+]>CO.C(OCC)(=O)C>[CH3:11][NH:10][C:3]1[CH:4]=[CH:5][C:6]([O:8][CH3:9])=[CH:7][C:2]=1[CH3:1]
Reactant: COc1ccc(N)c(C)c1
Reactant: C=O
Agent: C[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: CNc1ccc(OC)cc1C
Temperature: 50 °C
Yield: 91.1 %

Procedure:
A suspension of [2-methyl-4-(methyloxy)phenyl]amine (5 ml, 39.2 mmol), paraformaldehyde (5.88 g, 196 mmol), and sodium methoxide (10.58 g, 196 mmol) in methanol (100 ml) was maintained at 50° C. for 5 hours, cooled, and sodium borohydride (7.41 g, 196 mmol) was added portionwise. The resulting suspension was re-heated to 50° C. and maintained for 16 hours. The reaction was cooled, poured into ethyl acetate/saturated sodium bicarbonate, and the organic layer was dried over sodium sulfate, filtered, taken to a residue under reduced pressure, and purified by column chromatography to afford N,2-dimethyl-4-(methyloxy)aniline (5.40 g, 35.7 mmol, 91% yield) as a pale orange oil. 1H NMR (400 MHz, DMSO-d6) δ ppm 6.55-6.68 (m, 2 H), 6.34-6.40 (m, 1 H), 4.47-4.66 (m, 1 H), 3.62 (s, 3 H), 2.66 (d, J=5.0 Hz, 3 H), 2.04 (s, 3 H).