Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:18]=[CH:17][C:16]([S:19]([N:22]([CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[C:23]3[CH:24]=[CH:25][C:26]([F:33])=[C:27]([CH:32]=3)[C:28]([O:30]C)=[O:29])(=[O:21])=[O:20])=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].O.[OH-].[Li+].O.Cl>C1COCC1>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]#[C:12][C:13]2[CH:18]=[CH:17][C:16]([S:19]([N:22]([CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[C:23]3[CH:24]=[CH:25][C:26]([F:33])=[C:27]([CH:32]=3)[C:28]([OH:30])=[O:29])(=[O:21])=[O:20])=[CH:15][CH:14]=2)=[CH:9][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCCCN(c1ccc(F)c(C(=O)OC)c1)S(=O)(=O)c1ccc(C#Cc2ccc(CCCC)cc2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCN(c1ccc(F)c(C(=O)O)c1)S(=O)(=O)c1ccc(C#Cc2ccc(CCCC)cc2)cc1
Temperature: 100 °C
Reaction time: 0.69 h
Yield: 90.9 %

Procedure:
To a solution of methyl 5-[({4-[(4-butylphenyl)ethynyl]phenyl}sulfonyl)(hexyl)amino]-2-fluorobenzoate (207 mg; 0.38 mmol) in anhydrous THF (7 mL) were added lithium hydroxide monohydrate (158 mg; 3.77 mmol) and water (3 mL). The reaction mixture was stirred under MW at 100° C. for 2500 s. Then an aqueous solution of HCl (1N) was added and the mixture extracted with EtOAc (2×50 mL). The combined organic layers were washed with brine, dried over magnesium sulfate and the solvent was removed under reduced pressure to give 185 mg (91.7%) of the title compound as a brown cream. HPLC, Rt: 5.71 min (purity=98.5%). LC/MS, M−(ESI): 534.3. 1H NMR (MeOD) δ: 7.66 (d, J=8.66 Hz, 2H), 7.58 (d, J=8.66 Hz, 3H), 7.46 (d, J=7.91 Hz, 2H), 7.31. (m, 1H), 7.23 (m, 3H), 3.61 (m, 3H), 2.66 (t, J=7.53 Hz, 2H), 1.63 (qt, J=7.34 Hz, 2H), 1.35 (m, 12H), 0.96 (t, J=7.91 Hz, 3H), 0.87 (t, J=6.97 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:6]([CH2:7][O:8][C:9]2[CH:19]=[CH:18][C:12]([C:13](OCC)=[O:14])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.O.[NH2:23][NH2:24]>C(O)C>[CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:6]([CH2:7][O:8][C:9]2[CH:19]=[CH:18][C:12]([C:13]([NH:23][NH2:24])=[O:14])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1
Reactant: CCOC(=O)c1ccc(OCc2ccc(OC)cc2)cc1
Reactant: NN
Solvent: CCO
Solvent: O
Product: COc1ccc(COc2ccc(C(=O)NN)cc2)cc1

Procedure:
A 250 mL round bottomed flask was charged with ethyl 4-(4-methoxybenzyloxy)benzoate (11.45 g, 60.18 mmol) and ethanol (110 mL). Hydrazine monohydrate was then added and the mixture was placed under reflux for 48 h. The reaction mixture was concentrated to dryness and chloroform (150 mL) was added. The mixture was decanted and the insoluble white residue was washed once more with chloroform to remove traces of starting material. The white solid (5.3 g, 32%) was dried in vacuo and 1H NMR analysis was consistent with the title compound. 1H NMR (DMSO d6, 400 MHz) δ 9.6 (br s, 1 H), 7.77 (d, J=9 Hz, 2 H), 7.36 (d, J=9 Hz, 2 H), 7.03 (d, J=9 Hz, 1 H), 6.94 (d, J=9 Hz, 1 H), 5.05 (s, 2 H), 3.74.
Reaction SMILES: FC(F)(F)C(OC(=O)C(F)(F)F)=O.[OH:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([NH2:21])=O)=[C:17]([O:24][CH3:25])[CH:16]=1.N1C=CC=CC=1>O1CCCC1>[OH:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]#[N:21])=[C:17]([O:24][CH3:25])[CH:16]=1
Reactant: COc1cc(O)ccc1C(N)=O
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: COc1cc(O)ccc1C#N
Temperature: 25 °C
Reaction time: 18 h
Yield: 60 %

Procedure:
Trifluoroacetic anhydride (1.3 ml, 9.36 mmol) was added to a solution of 4-hydroxy-2-methoxybenzamide {Liebigs Ann Chem (1982)1836-1869} (600 mg, 3.6 mmol) and pyridine (0.72 ml, 9.36 mmol), in tetrahydrofuran (10 ml), and the mixture was stirred at room temperature for 18 hours. The reaction mixture was then concentrated under reduced pressure and treated with 2M hydrochloric acid (100-ml). It was then extracted with ethyl acetate (2×100 ml). The organic layers were combined and washed with brine (100 ml), dried over magnesium sulphate, filtered and then evaporated under reduced pressure to give an orange solid. The crude product was purified by flash chromatography on silica gel eluting with pentane:ethyl acetate (70:30 to 50:50, by volume) to provide the title compound (320 mg, 60%) as a pale yellow solid.
Reaction SMILES: ClCC(=O)CCCC[N:8]1[C:12](=O)[C:11]2=[CH:14][CH:15]=[CH:16][CH:17]=C2C1=O.[F:20][C:21]([F:31])([F:30])[CH2:22][NH:23][C:24]([NH:26][C:27]([NH2:29])=[S:28])=[NH:25]>C(O)C>[F:31][C:21]([F:20])([F:30])[CH2:22][N:23]=[C:24]([NH2:25])[NH:26][C:27]1[S:28][CH:17]=[C:16]([CH2:15][CH2:14][CH2:11][CH2:12][NH2:8])[N:29]=1
Reactant: O=C(CCl)CCCCN1C(=O)c2ccccc2C1=O
Reactant: N=C(NCC(F)(F)F)NC(N)=S
Solvent: CCO
Product: NCCCCc1csc(NC(N)=NCC(F)(F)F)n1
Reaction time: 0.5 h

Procedure:
To a solution of N-(6-chloro-5-oxohexyl)phthalimide (3.4 g.) in ethanol was added N-(2,2,2-trifluoroethylamidino)-thiourea (2.75 g.) in ethanol (30 ml.). The mixture was heated under reflux for 2 hours and the reaction mixture concentrated to small volume by evaporation. Following treatment of the resulting solution with ether until the solution was just turbid, crystalline 2-[2-(2,2,2-trifluoroethyl)guanidino]-4-(4-phthalimidobutyl)thiazole hydrochloride (3.6 g.) was precipitated. This material (2.1 g.) in ethanol (20 ml.) and water (5 ml.) was heated to boiling and the solution pH was adjusted to 12 by addition of 2 N sodium hydroxide. After heating on a steam bath for 10 minutes, the solution pH was adjusted to 3 with conc. hydrochloric acid and heating continued for a further 0.5 hour. The solution was cooled, adjusted to pH 12 with 2 N sodium hydroxide and extracted with ethyl acetate (2×30 ml.). Evaporation of the washed (H2O), dried (magnesium sulphate) extract gave 2-[2-(2,2,2-trifluoroethyl)guanidino]-4-(4-aminobutyl)-thiazole as a pale yellow gum which was used without further purification.
Reaction SMILES: C(OC([N:8]1[C:13](=[O:14])[CH:12]2[CH:10]([CH:11]2[C:15]([O-:17])=[O:16])[CH:9]1[C:18]([O-:20])=[O:19])=O)(C)(C)C.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH:30]=[CH:31][CH:32]=1)[C:26]([NH:28][NH2:29])=[O:27]>C1COCC1.[C-]#N.[K+]>[C:15]([CH:11]1[CH:12]([C:13]([NH:29][NH:28][C:26](=[O:27])[C:25]2[CH:30]=[CH:31][CH:32]=[C:23]([O:22][CH3:21])[CH:24]=2)=[O:14])[CH:10]1[CH:9]([C:18]([OH:20])=[O:19])[NH2:8])([OH:17])=[O:16]
Reactant: COc1cccc(C(=O)NN)c1
Reactant: CC(C)(C)OC(=O)N1C(=O)C2C(C(=O)[O-])C2C1C(=O)[O-]
Agent: [C-]#N
Agent: [K+]
Solvent: C1CCOC1
Product: COc1cccc(C(=O)NNC(=O)C2C(C(=O)O)C2C(N)C(=O)O)c1
Reaction time: 8 h
Yield: 133.3 %

Procedure:
To a solution of ethyl (1SR, 2 SR, 5RS, 6RS) 3-tert-butoxycarbonyl-4-oxo-3-azabicyclo[3.1.0]hexane-2,6-dicarboxylate (150 mg, 0.44 mmol) in dry THF (3 mL) under argon was added 3-methoxybenzoic hydrazide (438 mg, 2.64 mmol) and potassium cyanide (1.43 mg, 0.02 mmol). After stirring overnight in an ultrasonic bath, the solvent was removed under reduced pressure. The residue was directly purified by flash chromatography (hexane/ethyl acetate 1/1) to give 206 mg of the desired compound (92% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[C:3]=1[C:12]1[NH:13][C:14]2[CH:20]=[C:19]([C:21](Cl)=[O:22])[CH:18]=[CH:17][C:15]=2[N:16]=1.[N:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][C:25]=1[NH2:34].CCN(C(C)C)C(C)C>C1COCC1>[N:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][C:25]=1[NH:34][C:21]([C:19]1[CH:18]=[CH:17][C:15]2[N:16]=[C:12]([C:3]3[C:4]([C:8]([F:10])([F:11])[F:9])=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[NH:13][C:14]=2[CH:20]=1)=[O:22]
Reactant: O=C(Cl)c1ccc2nc(-c3c(Cl)cccc3C(F)(F)F)[nH]c2c1
Reactant: Nc1ccc2ccccc2n1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(Nc1ccc2ccccc2n1)c1ccc2nc(-c3c(Cl)cccc3C(F)(F)F)[nH]c2c1
Temperature: 60 °C

Procedure:
To a stirred suspension of 2-(2-chloro-6-trifluoromethylphenyl)-3H-benzoimidazole-5-carbonyl chloride (394 mg, 1.0 mmol) and quinolin-2-ylamine (144 mg, 1.0 mmol) in THF (6 mL) was added DIPEA (0.53 ml, 3.0 mmol). The solution was heated at 60° C. for 2 days and the reaction was quenched with water and aqueous layer was extracted with EtOAc. The organic layer was washed with water, brine, dried with MgSO4, and filtered. The solvent was removed under reduced pressure and the residue was purified by flash chromatography using heptane/EtOAc (1:4) as eluent to give 2-(2-chloro-6-trifluoromethylphenyl)-3H-benzoimidazole-5-carboxylic acid quinolin-2-ylamide as a white solid. 1H NMR (Methanol-d4, 400 MHz): δ 8.45 (d, 1H), 8.37 (d, 1H), 8.08 (d, 1H), 7.94 (m, 4H), 7.83 (m, 1H), 7.74 (m, 1H), 7.54 (m, 1H). MS (m/z) 467.1 (M+1); Retention time: 1.45 min (Method 10).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2)#[N:2].[C:12]1(=[O:17])[CH2:16][CH2:15][CH:14]=[CH:13]1>>[O:17]=[C:12]1[CH2:16][CH2:15][CH:14]([C:6]2[C:5]3[C:9](=[CH:10][CH:11]=[C:3]([C:1]#[N:2])[CH:4]=3)[NH:8][CH:7]=2)[CH2:13]1
Reactant: O=C1C=CCC1
Reactant: N#Cc1ccc2[nH]ccc2c1
Product: N#Cc1ccc2[nH]cc(C3CCC(=O)C3)c2c1
Yield: 81.8 %

Procedure:
This compound was prepared in the same manner as for Intermediate 2, using 5-cyanoindole (4.26 g, 30 mmol) and 2-cyclopenten-1-one (2.95 g, 36 mmol) to give 5.5 g (82%) of the desired product: mp 136–138° C.; MS (ESI) m/z 224 [M]+.
Reaction SMILES: [Cl:1][CH2:2][CH:3]([OH:6])[CH2:4][OH:5].[CH3:7][N:8]([CH3:13])[CH2:9][CH2:10][CH2:11][CH3:12].[OH-].[Na+].CN(C)C>O>[Cl-:1].[OH:6][CH:3]([CH2:4][OH:5])[CH2:2][N+:8]([CH2:9][CH2:10][CH2:11][CH3:12])([CH3:13])[CH3:7]
Reactant: CCCCN(C)C
Reactant: OCC(O)CCl
Agent: CN(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCC[N+](C)(C)CC(O)CO
Product: [Cl-]
Temperature: 40 °C
Reaction time: 1 h

Procedure:
In a 2 L reactor system 543.27 g of 3-chloro-1,2-dihydroxypropane (99.6%, 4.90 moles) is added to 721.03 g of distilled water. The solution is brought to 25° C. Over 45 minutes 479.54 g dimethylbutylamine (99.5%, 4.72 moles) is added to the reactor. After one hour of mixing the temperature is increased to 40° C. and held for one hour. The temperature is then increased to 50° C. and held for 2.5 hours. The temperature is then increased to 60° C. and held for one hour. External heating is turned off and the reaction solution is allowed to stir overnight (16 hours). The pH is then increased to 10.6 by adding 3.52 g sodium hydroxide (50%) and the temperature is increased to 40° C. After 30 minutes, 2.89 g sodium hydroxide (50%) is added to increase the pH from 9.9 to 10.7. After 30 additional minutes, 2.96 g of sodium hydroxide (50%) is added to increase the pH from 9.4 to 10.7. 6.84 g of 3-chloro-1,2-dihydroxypropane is then added and the solution is allowed to stir at room temperature for 60 hours. 11.39 g of trimethylamine (43.6%) and 1.80 g sodium hydroxide (50%) is then added. The solution is allowed to stir overnight (16 hours) at room temperature. The solution was then heated to 40° C. and purged with nitrogen to remove the excess trimethylamine. The solution is cooled to room temperature, the pH was adjusted to 6.9 and it is filtered through Whatman 42 filter paper. The isolated product has the following structure:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[CH2:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.[F:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[SH:22].[O-]CC.[Na+]>C(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH2:14][S:22][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[F:15])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:6][CH:7]=1
Reactant: C=C(C(=O)OCC)c1ccc(F)cc1
Reactant: Fc1ccccc1S
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(CSc1ccccc1F)c1ccc(F)cc1
Temperature: 25 °C
Yield: 82.2 %

Procedure:
The crude product from Step A (3.9 g, 20 mole) was taken up in 20 ml of ethanol. To this solution, being stirred at room temperature, was added 2-fluorothiophenol (2.5 g, 20 mmole) and 50 mg of solid sodium ethoxide. After stirring for eight hours the ethanol was concentrated and the residue taken up in ether. The ether mixture was washed twice with 15% NaOH solution, dried (MgSO4) and concentrated to a colorless oil (5.3 g, 82% yield). 1H NMR (CDCl3) δ: 7.28 (4H, m), 7.06 (4H, m), 4.13 (2H, m), 3.72 (1H, m), 3.55 (1H, m), 3.20 (1H, dd, J=6, 12 Hz), 1.21 (3H, t, J=6 Hz).
Reaction SMILES: C1COCC1.[C:6]1([Mg]Br)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.Cl[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH:21]1[O:25][CH2:24][CH2:23][O:22]1.C(OCC)C>CCCCCC>[C:19]1([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:18]=[CH:17][C:16]([CH:21]2[O:25][CH2:24][CH2:23][O:22]2)=[CH:15][CH:20]=1
Reactant: Clc1ccccc1C1OCCO1
Reactant: Br[Mg]c1ccccc1
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: c1ccc(-c2ccc(C3OCCO3)cc2)cc1
Reaction time: 48 h
Yield: 88 %

Procedure:
Using a THF solution of phenylmagnesium bromide (1.34 mL, 1.01 M, 1.35 mmol) and 2-chlorophenyl-[1,3]-dioxolan (184.6 mg, 1.0 mmol) as starting material, the reaction was performed at a scale of 1.0 mmol at 70° C. for 48 hours in the same manner as in Example 2. After performing silica gel column chromatography (diethylether=5, 10 and 20% in hexane), the above compound was obtained as a white solid (0.199 g, yield=88%, purity=>99% (GC analysis)).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[CH:13]=[C:14]([NH:18][C:19](=[O:23])[CH:20]([CH3:22])[CH3:21])[CH:15]=[CH:16][CH:17]=2)[CH2:8][CH2:7]1.[F:24][C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][C:33]=1[F:34])[C:28](Cl)=[O:29]>C1COCC1.C(Cl)Cl>[F:24][C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][C:33]=1[F:34])[C:28]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[CH2:7][CH2:8][CH:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([NH:18][C:19](=[O:23])[CH:20]([CH3:21])[CH3:22])[CH:13]=2)[CH2:10][CH2:11]1)=[O:29]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCN)CC2)c1
Reactant: O=C(Cl)c1ccc(F)c(F)c1
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCNC(=O)c3ccc(F)c(F)c3)CC2)c1

Procedure:
Prepared by Procedure Q2 (THF/DCM, 1:3) and Scheme AT using N-(3-[1-(4-aminobutyl)-4-piperidinyl]phenyl}-2-methylpropanamide and 3,4-difluorobenzoyl chloride: ESMS m/e: 458.0 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[CH:4]=[CH:5][CH2:6]Cl.[NH2:12][C:13]1[S:14][C:15]2[CH2:16][CH2:17][NH:18][CH2:19][CH2:20][C:21]=2[N:22]=1.CCOCC>C(Cl)(Cl)Cl>[NH2:12][C:13]1[S:14][C:15]2[CH2:16][CH2:17][N:18]([CH2:6][CH:5]=[CH:4][C:3]3[CH:8]=[CH:9][CH:10]=[CH:11][C:2]=3[F:1])[CH2:19][CH2:20][C:21]=2[N:22]=1
Reactant: Nc1nc2c(s1)CCNCC2
Reactant: Fc1ccccc1C=CCCl
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Product: Nc1nc2c(s1)CCN(CC=Cc1ccccc1F)CC2
Yield: 36 %

Procedure:
Prepared from 2-fluoro-cinnamyl chloride and 2 equivalents of 2-amino-4,5,7,8-tetrahydro-6H-thiazolo-[5,4-d]azepine in chloroform. Yield: 36% of theory, Melting point: 96°-102° C. (ether).
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([C:9]2[O:10][C:11]([C:14]3[S:15][CH:16]=[CH:17][C:18]=3[CH3:19])=[N:12][N:13]=2)[C:5]([NH2:8])=[N:6][CH:7]=1.C1COCC1.C(=O)(OC(C)(C)C)[O:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=O>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Br:1][C:2]1[N:3]=[C:4]([C:9]2[O:10][C:11]([C:14]3[S:15][CH:16]=[CH:17][C:18]=3[CH3:19])=[N:12][N:13]=2)[C:5]([NH:8][C:27](=[O:26])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: Cc1ccsc1-c1nnc(-c2nc(Br)cnc2N)o1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cc1ccsc1-c1nnc(-c2nc(Br)cnc2NC(=O)OC(C)(C)C)o1
Temperature: 25 °C
Reaction time: 2 h
Yield: 110.1 %

Procedure:
5-bromo-3-[5-(3-methyl-2-thienyl)-1,3,4-oxadiazol-2-yl]pyrazin-2-amine (11.49 g, 33.98 mmol) and DMAP (415.1 mg, 3.398 mmol) were suspended in DCM (172.4 mL) and THF (172.4 mL) and cooled in an icebath. tert-butoxycarbonyl tert-butyl carbonate (22.24 g, 101.9 mmol) was added portionwise. The reaction mixture was allowed to warm to ambient temperature and stirred for 2 hours. The reaction mixture was filtered through plug of silica gel and concentrated in vacuo. The residue was dissolved in ethylacetate, washed with aq NaHCO3 (×1), brine (×1), dried over MgSO4 and passed through short silica gel column. The mixture was concentrated in vacuo to low bulk, diluted with petrol and stirred at 50° C. for 5 min. The mixture was filtered to give tert-butyl (5-bromo-3-(5-(3-methylthiophen-2-yl)-1,3,4-oxadiazol-2-yl)pyrazin-2-yl)carbamate as a colourless solid (16.4 g, 89%). H NMR (400.0 MHz, DMSO-d6) δ 1.4 (9H, s), 2.7 (3H, s), 7.0 (1H, d), 7.5 (1H, d), 8.7 (1H, s); LC/MS m/z 440.1 [M−100+1]+.
Reaction SMILES: I[C:2]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[CH3:13][OH:14].C(N(CC)CC)C.CN(C)[CH:24]=[O:25]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:4][C:3]1[CH:5]=[CH:6][C:7]([C:9]([F:12])([F:11])[F:10])=[CH:8][C:2]=1[C:13]([O:25][CH3:24])=[O:14]
Reactant: Nc1ccc(C(F)(F)F)cc1I
Reactant: CO
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(C(F)(F)F)ccc1N
Temperature: 50 °C
Reaction time: 120 h

Procedure:
2-Iodo-4-(trifluoromethyl)aniline (8.0 g, 27.9 mmol), methanol (5 mL) and triethylamine (10 mL) were dissolved in dimethylformamide (50 ml) and, under a carbon monoxide atmosphere, tetrakis(triphenylphosphine)palladium (1.6 g, 1.4 mmol) was added and the mixture was stirred at 50° C. for 5 days. The solvent was evaporated and work-up according to a conventional method gave a crude product of methyl 2-amino-5-(trifluoromethyl)benzoate. The obtained crude product was dissolved in tetrahydrofuran (20 ml), lithium aluminum hydride (1.0 g, 26.3 mmol) was added under cooling, and the mixture was stirred for 2 hrs. Water (1 ml), 30% aqueous sodium hydroxide solution (1 ml) and water (3 mL) were sequentially added, the precipitate was filtered off, and the filtrate was concentrated to give a crude product of [2-amino-5-(trifluoromethyl)phenyl]methanol. Sodium nitrite (59 mg, 0.86 mmol) was dissolved in conc. sulfuric acid (0.77 mL) and, after cooling, a solution of a crude product (0.15 g, 0.78 mmol) of [2-amino-5-(trifluoromethyl)phenyl]methanol in acetic acid (1.72 ml). After stiring for 30 min. 10% aqueous potassium iodide solution (4.64 mL) was added. After stirring with heating at 70° C. for 30 min, the mixture was worked-up according to a conventional method, and the obtained crude product was purified by silica gel column chromatography (5% to 7.5% ethyl acetate/hexane) to give the title compound (96 mg, 0.32 mmol, 40%).
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[N:9]1([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14][CH2:13][CH:12]([C:15]([O:17][CH3:18])=[O:16])[CH2:11][CH2:10]1.CN(CCN(C)C)C.[O:34]=[CH:35][C@@H:36]([NH:38][C:39](=[O:45])[O:40][C:41]([CH3:44])([CH3:43])[CH3:42])[CH3:37]>C1COCC1>[C:41]([O:40][C:39]([NH:38][CH:36]([CH3:37])[CH:35]([C:12]1([C:15]([O:17][CH3:18])=[O:16])[CH2:11][CH2:10][N:9]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14][CH2:13]1)[OH:34])=[O:45])([CH3:44])([CH3:43])[CH3:42]
Reactant: COC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: C[C@@H](C=O)NC(=O)OC(C)(C)C
Agent: CC(C)[N-]C(C)C
Agent: CN(C)CCN(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C1(C(O)C(C)NC(=O)OC(C)(C)C)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of LDA (prepared by adding n-BuLi (27.7 mL, 55.5 mmol) to diisopropylamine (8.04 mL, 57.3 mmol) in THF (40 mL) at 0° C., stir for 30 min) was added 1-tert-butyl 4-methyl piperidine-1,4-dicarboxylate (4500 mg, 18.5 mmol) in TMEDA (16.6 mL, 111 mmol) dropwise via syringe pump at −78° C. for 20 min. The mixture was stirred at the same temperature for 30 min, and (S)-tert-butyl (1-oxopropan-2-yl)carbamate (9931 mg, 57.3 mmol) in THF (20 mL) was added slowly by syringe pump for 20 min. The mixture was stirred at −78° C. for 30 min, and quenched with saturated NH4Cl at −78° C., warmed up to rt and diluted with EtOAc (200 mL). The organic layer was separated, and the aqueous layer was extracted with EtOAc (100 mL). The combined organic layers were washed with brine, dried (MgSO4), and concentrated. The residue was purified by column chromatography (MeOH/DCM, gradient 0-10%) to afford the title compound. LC/MS: [(M+1)]+=417
Reaction SMILES: [CH3:1][C:2]1([N+:13]([O-])=O)[CH2:5][N:4]([CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:3]1.C(O)(=O)C.ClCCl>C(OCC)(=O)C.[Fe]>[NH2:13][C:2]1([CH3:1])[CH2:5][N:4]([CH2:6][C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:3]1
Reactant: CC1([N+](=O)[O-])CN(Cc2ccccc2)C1
Agent: [Fe]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC1(N)CN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of 3-methyl-3-nitro-N-benzylazetidine [the product of step 2] (3.9 g, 18.9 mmol) in ethyl acetate (370 ml) and 5% acetic acid (370 ml) is heated to reflux. Iron powder (5.25 g, 94.1 mmol) is added portion-wise every 5 minutes. After the addition is complete the reaction mixture is heated at reflux for 6 hours. The cooled reaction mixture is filtered through Hyflo, and the residue washed with ethyl acetate. The filtrate is transferred to a separating funnel and the organic layer separated and discarded. The aqueous layer is treated with 30% NaOH solution with ice cooling to give a pH of ca. 11. Dichloromethane is then added and the mixture vigorously stirred at ambient temperature for 10 minutes. This mixture is filtered through Hyfol, the filtrate transferred to a separating funnel and the organic layer is separated, dried (Na2SO4), filtered, and concentrated. The crude oily product (2.30 g, 69%) is used in the next step without further purification. 1H-NMR (CDCl3): 7.2 (m, 5H), 3.62 (s, 2H), 3.27 (d, 2H), 2.88 (d, 2H), 1.68 (bs, 2H), 1.4 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][NH2:6].[Cl:11][C:12]1[N:13]=[C:14](Cl)[C:15]2[C:20]3[CH2:21][CH2:22][CH2:23][CH2:24][C:19]=3[S:18][C:16]=2[N:17]=1>>[Cl:11][C:12]1[N:13]=[C:14]([NH:6][CH2:5][C:4]2[CH:7]=[CH:8][C:9]([Cl:10])=[C:2]([Cl:1])[CH:3]=2)[C:15]2[C:20]3[CH2:21][CH2:22][CH2:23][CH2:24][C:19]=3[S:18][C:16]=2[N:17]=1
Reactant: Clc1nc(Cl)c2c3c(sc2n1)CCCC3
Reactant: NCc1ccc(Cl)c(Cl)c1
Product: Clc1nc(NCc2ccc(Cl)c(Cl)c2)c2c3c(sc2n1)CCCC3

Procedure:
Following the procedure of Example 1, the reaction of 3,4-dichlorobenzylamine with 2,4-dichloro-5,6,7,8-tetrahydro-[1]-benzothieno-[2,3-d]-pyrimidine yields 2-chloro-5,6,7,8-tetrahydro-4-(3,4-dichlorobenzylamino)-[1]-benzothieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH:1]1([S:7][C:8]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12]C=2C#N)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-:20].[Na+].[CH2:22]([OH:24])[CH3:23]>O>[CH:1]1([S:7][C:8]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:23]=2[C:22]([OH:20])=[O:24])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCO
Reactant: [OH-]
Reactant: N#Cc1ccc(C(F)(F)F)cc1SC1CCCCC1
Agent: [Na+]
Solvent: O
Product: O=C(O)c1ccc(C(F)(F)F)cc1SC1CCCCC1

Procedure:
2-Cyclohexylsulphenyl-4-trifluoromethylbenzonitrile (10.55 g) was added to a mixture of sodium hydroxide (52.75 g) in aqueous ethanol and the resultant mixture was stirred and heated at reflux for 23 hours. It was cooled, diluted with water and filtered. The filtrate was acidified and extracted with dichloromethane, washed with water, dried (MgSO4) and filtered to give 2-cyclohexylsulphenyl-4-trifluoromethylbenzoic acid (10.7 g) as an off-white solid m.p. 115.4°-116.4° C.