Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([S:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[F:16])=[CH:7][CH:6]=[CH:5][C:4]=1[CH:17](O)[CH3:18].S(Cl)([Cl:22])=O>N1C=CC=CC=1.C1C=CC=CC=1>[CH3:1][O:2][C:3]1[C:4]([CH:17]([Cl:22])[CH3:18])=[CH:5][CH:6]=[CH:7][C:8]=1[S:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[F:16]
Reactant: COc1c(Sc2ccccc2F)cccc1C(C)O
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: COc1c(Sc2ccccc2F)cccc1C(C)Cl
Yield: 79.7 %

Procedure:
A mixture of 1-[2-methoxy-3-(2-fluorophenylthio)phenyl]ethanol (1 g), thionyl chloride (500 mg) and pyridine (2 drops) in benzene (30 ml) was refluxed under heating for 30 minutes. The reaction mixture was evaporated under reduced pressure. To the residue was added water, and the mixture was extracted with diethyl ether. The extract was washed with dil. hydrochloric acid, saturated aqueous sodium bicarbonate and water in turn, dried and then evaporated under reduced pressure to give oily 2-fluorophenyl 2-methoxy-3-(1-chloroethyl)phenyl thioether (850 mg).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([O:8]C)[C:3]=1[C:10]1[NH:11][C:12]([CH2:16][N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[C:13]([CH3:15])[N:14]=1.Cl.C(N(CC)CC)C.[NH2:31][CH2:32][C@H:33]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([Cl:41])[CH:36]=1)[OH:34]>C(O)(=O)C>[Cl:41][C:37]1[CH:36]=[C:35]([C@H:33]([OH:34])[CH2:32][NH:31][C:2]2[CH:7]=[CH:6][NH:5][C:4](=[O:8])[C:3]=2[C:10]2[NH:11][C:12]([CH2:16][N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[C:13]([CH3:15])[N:14]=2)[CH:40]=[CH:39][CH:38]=1
Reactant: COc1nccc(I)c1-c1nc(C)c(CN2CCOCC2)[nH]1
Reactant: NC[C@@H](O)c1cccc(Cl)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Product: Cc1nc(-c2c(NC[C@@H](O)c3cccc(Cl)c3)cc[nH]c2=O)[nH]c1CN1CCOCC1
Temperature: 90 °C
Yield: 11.9 %

Procedure:
4-((2-(4-Iodo-2-methoxypyridin-3-yl)-4-methyl-1H-imidazol-5-yl)methyl)morpholine (0.008 g, 0.019 mmol) was dissolved in acetic acid (2 mL) and concentrated hydrochloric acid (2 mL) and this mixture was stirred at 90° C. for 2 hours. The mixture was then evaporated and the residue was dissolved in 1-methyl-2-pyrrolidone (4 mL) and treated with triethylamine (100 μL, 0.72 mmol) and the hydrochloric acid salt of (S)-2-amino-1-[3-chlorophenyl]ethanol (0.010 g, 0.048 mmol). The mixture was heated at 90° C. for 4 hours, then the solvent was evaporated and the residue was purified by Prep HPLC (ammonium acetate/acetonitrile/water) to give the title compound (0.001 g, 11%) as a white solid. HPLC<95% (220 nm), LCMS (+ESI, M+H+) m/z 444; 1H NMR (400 MHz, methanol-d4) δ (ppm): 2.21 (3H, br s), 2.56 (˜4H, br s), 3.46 (2H, br s), 3.49 (1H, dd, J=6.8 and 13.6 Hz), 3.55 (1H, dd, J=5.3 and 13.6 Hz), 3.61 (4H, br s), 4.79-4.84 (1H, m overlapped by D2O), 6.08 (1H, d, J=7.3 Hz), 7.06 (1H, d, J=7.6 Hz), 7.16 (1H, dt, J=8.4 and 1.8 Hz), 7.20 (1J, t, J=7.7 Hz), 7.27 (1H, br d, J=8.3 Hz), 7.39 (1H, br s).
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[N:11]1[C:14](=[O:15])[C:13]([CH3:17])([CH3:16])[NH:12]1)[CH2:8]2.Br[CH2:19][C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1>>[CH3:16][C:13]1([CH3:17])[N:12]([CH2:19][C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=[CH:22][CH:21]=2)[N:11]([CH:2]2[CH:3]3[CH2:4][CH:5]4[CH2:6][CH:7]([CH2:8][CH:1]2[CH2:10]4)[CH2:9]3)[C:14]1=[O:15]
Reactant: CC1(C)NN(C2C3CC4CC(C3)CC2C4)C1=O
Reactant: BrCc1cccc2ccccc12
Product: CC1(C)C(=O)N(C2C3CC4CC(C3)CC2C4)N1Cc1cccc2ccccc12

Procedure:
2-(Adamantan-2-yl)-4,4-dimethyl-1,2-diazetidin-3-one and 1-(bromomethyl)naphthalene were used for a similar reaction and treatment as Process 6 of Example 1, and the title compound was obtained as a colorless oil.
Reaction SMILES: Cl.Cl.[NH:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[C:20]4[C:15](=[N:16][CH:17]=[N:18][C:19]=4[NH2:21])[N:14]([CH3:22])[N:13]=3)=[CH:9][CH:10]=2)[CH2:5][CH2:4]1.[F:23][C:24]1[C:25]([CH3:34])=[C:26]([CH2:30][C:31](O)=[O:32])[CH:27]=[CH:28][CH:29]=1.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>CN(C=O)C.O>[F:23][C:24]1[C:25]([CH3:34])=[C:26]([CH2:30][C:31]([N:3]2[C:11]3[C:6](=[CH:7][C:8]([C:12]4[C:20]5[C:15](=[N:16][CH:17]=[N:18][C:19]=5[NH2:21])[N:14]([CH3:22])[N:13]=4)=[CH:9][CH:10]=3)[CH2:5][CH2:4]2)=[O:32])[CH:27]=[CH:28][CH:29]=1
Reactant: Cn1nc(-c2ccc3c(c2)CCN3)c2c(N)ncnc21
Reactant: Cc1c(F)cccc1CC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cc1c(F)cccc1CC(=O)N1CCc2cc(-c3nn(C)c4ncnc(N)c34)ccc21
Reaction time: 8 h
Yield: 85.1 %

Procedure:
In a 20 mL vial with cap, to the solution of 3-(2,3-dihydro-1H-indol-5-yl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine 2HCl (70 mg, 0.206 mmol), (3-fluoro-2-methylphenyl)acetic acid (34.7 mg, 0.206 mmol), HATU (78 mg, 0.206 mmol) in DMF (2 mL) was added Hunig's base (0.144 mL, 0.825 mmol). The mixture was stirred overnight. The reaction was poured into water, and an off-white solid formed. The solid was filtered to give the title compound (73 mg) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.15 (d, J=1.52 Hz, 3H), 3.24-3.31 (m, 2H), 3.94 (s, 3H), 3.97 (s, 2H), 4.27-4.34 (m, 2H), 7.04-7.11 (m, 2H), 7.19 (d, J=6.32 Hz, 1H), 7.44 (d, J=8.08 Hz, 1H), 7.53 (s, 1H), 8.16 (d, J=8.08 Hz, 1H), 8.25 (s, 1H).
Reaction SMILES: C([O:5][C:6](=[O:16])[C@H:7]([CH3:15])[NH:8][CH:9]1[CH2:13][CH2:12][O:11][C:10]1=[O:14])(C)(C)C.[ClH:17]>C(OCC)(=O)C>[ClH:17].[O:14]=[C:10]1[CH:9]([NH:8][C@H:7]([C:6]([OH:16])=[O:5])[CH3:15])[CH2:13][CH2:12][O:11]1
Reactant: C[C@H](NC1CCOC1=O)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: C[C@H](NC1CCOC1=O)C(=O)O

Procedure:
In 5 ml of an ethyl acetate solution saturated with hydrochloric acid, 1.66 g of N-(2-oxo-3-tetrahydrofuranyl)-L-alanine t-butyl ester was dissolved. The resultant solution was stirred for 3 hours at room temperature. Crystals which had precipitated were collected by filtration. After washing the crystals with ethyl acetate and then with ether, they were dried to obtain 1.31 g of N-(2-oxo-3-tetrahydrofuranyl)-L-alanine hydrochloride as colorless crystals.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH:5][C:6]([N:8]1[CH2:13][CH:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH2:11][CH:10]([C:24]([OH:26])=O)[CH2:9]1)=[O:7].O[N:28]=[C:29]([CH:31]1[CH2:33][CH2:32]1)[NH2:30]>>[CH:31]1([C:29]2[N:30]=[C:24]([CH:10]3[CH2:11][CH:12]([C:14]4[CH:15]=[CH:16][C:17]([C:20]([F:21])([F:22])[F:23])=[CH:18][CH:19]=4)[CH2:13][N:8]([C:6]([NH:5][CH2:4][CH2:3][O:2][CH3:1])=[O:7])[CH2:9]3)[O:26][N:28]=2)[CH2:33][CH2:32]1
Reactant: NC(=NO)C1CC1
Reactant: COCCNC(=O)N1CC(C(=O)O)CC(c2ccc(C(F)(F)F)cc2)C1
Product: COCCNC(=O)N1CC(c2ccc(C(F)(F)F)cc2)CC(c2nc(C3CC3)no2)C1
Yield: 38.8 %

Procedure:
100 mg (0.267 mmol) of the compound from Example 105A and 54 mg (0.534 mmol) of N′-hydroxycyclopropanecarboximidamide were reacted according to the General Method 2. Diastereomer separation of 64 mg of the cis/trans isomer mixture according to Method 14C gave 45.4 mg of the title compound and 5.5 mg of the trans isomer.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]2[C@H:13]([NH:14][CH:15]3[CH2:17][CH2:16]3)[CH2:12][N:11]([C:18]([CH:20]3[CH2:25][CH2:24][N:23]([C:26]([C:28]4([CH3:31])[CH2:30][CH2:29]4)=[O:27])[CH2:22][CH2:21]3)=[O:19])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl[C:33]([O:35][C:36]1[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=1)=[O:34]>>[F:42][C:39]1[CH:40]=[CH:41][C:36]([O:35][C:33](=[O:34])[N:14]([C@H:13]2[C@H:9]([C:4]3[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=3)[CH2:10][N:11]([C:18]([CH:20]3[CH2:25][CH2:24][N:23]([C:26]([C:28]4([CH3:31])[CH2:30][CH2:29]4)=[O:27])[CH2:22][CH2:21]3)=[O:19])[CH2:12]2)[CH:15]2[CH2:16][CH2:17]2)=[CH:37][CH:38]=1
Reactant: CC1(C(=O)N2CCC(C(=O)N3C[C@@H](NC4CC4)[C@H](c4ccc(Cl)c(Cl)c4)C3)CC2)CC1
Reactant: O=C(Cl)Oc1ccc(F)cc1
Product: CC1(C(=O)N2CCC(C(=O)N3C[C@@H](N(C(=O)Oc4ccc(F)cc4)C4CC4)[C@H](c4ccc(Cl)c(Cl)c4)C3)CC2)CC1

Procedure:
In analogy to the procedure described for the synthesis of example 1 (step h), the title compound rac-{(3S,4R)-4-(3,4-dichloro-phenyl)-1-[1-(1-methyl cyclopropanecarbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-cyclopropyl-carbamic acid 4-fluoro-phenyl ester was prepared from rac-[(3R,4S)-3-(3,4-Dichloro-phenyl)-4-cyclopropylamino-pyrrolidin-1-yl]-[1-(1-methyl-cyclopropanecarbonyl)-piperidin-4-yl]-methanone instead of rac-{4-[(3S,4R)-3-(3,4-dichloro-phenyl)-4-methylamino-pyrrolidine-1-carbonyl]-piperidin-1-yl}-(1-methyl-cyclopropyl)-methanone using 4-fluorophenyl chloroformate and was obtained as a colorless foam. MS m/e: 602.3 [M]+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([CH:11]=[CH:12][C:13]([O:15][CH3:16])=[O:14])[CH:3]=1.ClC1C=CC(C(O)=O)=C(C=CC(O)=O)C=1>>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])[CH:3]=1
Reactant: COC(=O)C=Cc1cc(Cl)ccc1C(=O)O
Agent: O=C(O)C=Cc1cc(Cl)ccc1C(=O)O
Product: COC(=O)CCc1cc(Cl)ccc1C(=O)O

Procedure:
Without addition of an additional hydrogenation catalyst, 43 g of 4-chloro-2-(3-hydroxy-3-oxo-1-propenyl)-benzoic acid in the form of the isolated solid from Example 5 in 400 ml of methanol are hydrogenated at 40° C. and a hydrogen pressure of from 20 to 40 bar. Filtration through Celite® and removal of the solvents under reduced pressure gives 35.3 g of product which, according to gas chromatography, contains 81 % of 4-chloro-2-(3-methoxy-3-oxo-1-propenyl)-benzoic acid. The same product is obtained using, instead of 4-chloro-2-(3-hydroxy-3-oxo-1-propenyl)-benzoic acid, 4-chloro-2-(3-methoxy-3-oxo-1-propenyl)-benzoic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:20](=[O:21])[C:19]3[C:14](=[CH:15][C:16]([O:22][CH2:23][CH:24]4[CH2:26][O:25]4)=[CH:17][CH:18]=3)[O:13][CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:20](=[O:21])[C:19]3[C:14](=[CH:15][C:16]([O:22][CH2:23][CH:24]([OH:25])[CH2:26][N:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)=[CH:17][CH:18]=3)[O:13][CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: C1COCCN1
Reactant: COc1ccc(-c2coc3cc(OCC4CO4)ccc3c2=O)cc1OC
Solvent: CCO
Product: COc1ccc(-c2coc3cc(OCC(O)CN4CCOCC4)ccc3c2=O)cc1OC
Yield: 52.1 %

Procedure:
A mixture of compound 4 (obtained from example 2) (0.35 g, 1 mmol), morpholine (0.43 g, 5 mmol), and ethanol (30 mL) was refluxed for 6 hrs (TLC monitoring). After removal of solvent in vacuo, the residue was treated with H2O (50 mL). The resulting precipitate was collected and purified by column chromatography (MeOH/CH2Cl2=1:25) to give the title compound 6a (0.23 g, 51% yield). M.p.: 135-136° C.
Reaction SMILES: Br[C:2]1[C:10]2[C:6](=[CH:7][N:8]([CH3:11])[N:9]=2)[CH:5]=[CH:4][C:3]=1[CH3:12].[C:13]([Cu])#[N:14].O>CN1C(=O)CCC1>[CH3:11][N:8]1[CH:7]=[C:6]2[C:10]([C:2]([C:13]#[N:14])=[C:3]([CH3:12])[CH:4]=[CH:5]2)=[N:9]1
Reactant: Cc1ccc2cn(C)nc2c1Br
Reactant: N#C[Cu]
Solvent: O
Solvent: CN1CCCC1=O
Product: Cc1ccc2cn(C)nc2c1C#N
Temperature: 130 °C
Yield: 40 %

Procedure:
To a solution of 7-bromo-2,6-dimethyl-2H-indazole (1 equiv.) in NMP, was added CuCN (2 equiv.) and heated at 130° C. for 16 h. On completion, water was added to quench the reaction, solid precipitated was filtered and purified by column chromatography to afford the title compound (40-60% yield)
Reaction SMILES: CCN[C:4]1[N:9]=[C:8]([Cl:10])[N:7]=[C:6]([NH:11][CH:12]([CH3:14])[CH3:13])[N:5]=1.N1C(Cl)=NC(Cl)=NC=1[Cl:17].C(N)(C)C.[OH-].[Na+]>>[Cl:10][C:8]1[N:9]=[C:4]([Cl:17])[N:5]=[C:6]([NH:11][CH:12]([CH3:14])[CH3:13])[N:7]=1
Reactant: CCNc1nc(Cl)nc(NC(C)C)n1
Reactant: Clc1nc(Cl)nc(Cl)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)N
Product: CC(C)Nc1nc(Cl)nc(Cl)n1

Procedure:
In particular the preparation of atrazine is generally carried out by a discontinuous method, by reacting, in a first reaction stage, cyanuric chloride with isopropylamine in the presence of sodium hydroxide to give 2,4-dichloro-6-isopropylamino-s-triazine. This latter is reacted, in a second stage, with ethylamine and with a further quantity of sodium hydroxide with the subsequent formation of the desired product: 2-chloro-4-ethylamino-6-isopropylamino-s-triazine.
Reaction SMILES: [BrH:1].C(OC([N:7]1[CH2:12][CH2:11][C:10]2[N:13]3[CH:18]=[C:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[N:16]=[C:14]3[S:15][C:9]=2[CH2:8]1)=O)C.Br>C(O)(=O)C>[BrH:1].[BrH:1].[C:19]1([C:17]2[N:16]=[C:14]3[N:13]([CH:18]=2)[C:10]2[CH2:11][CH2:12][NH:7][CH2:8][C:9]=2[S:15]3)[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CCOC(=O)N1CCc2c(sc3nc(-c4ccccc4)cn23)C1
Agent: Br
Solvent: CC(=O)O
Product: c1ccc(-c2cn3c4c(sc3n2)CNCC4)cc1
Yield: 186.2 %

Procedure:
A mixture of 4.1 g of 7-ethoxycarbonyl-2-phenyl-5,6,7,8-tetrahydroimidazo[2',1':2,3]thiazolo[5,4-c]pyridine hydrobromide and 50 ml of a solution of hydrobromic acid in acetic acid (20% (w/w) hydrobromic acid) was heated on a boiled water bath for 2 hours. The precipitated crystals were filtered off and washed with a mixture of ethanol and n-hexane to give 3.9 g of 2-phenyl-5,6,7,8-tetrahydroimidazo[2',1':2,3]thiazolo[5,4-c]pyridine dihydrobromide, melting at 315°-316° C. with decomposition.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=2)[CH:6]=[C:7]([CH3:22])[C:8]=1[C:9]([N:11]1[CH2:16][CH2:15][CH:14]([N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[CH2:13][CH2:12]1)=[O:10].B(Br)(Br)Br.C(=O)([O-])O.[Na+]>C(Cl)Cl>[OH:2][C:3]1[CH:4]=[C:5]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=2)[CH:6]=[C:7]([CH3:22])[C:8]=1[C:9]([N:11]1[CH2:12][CH2:13][CH:14]([N:17]2[CH2:18][CH2:19][CH2:20][CH2:21]2)[CH2:15][CH2:16]1)=[O:10]
Reactant: COc1cc(-c2cccc(C(F)(F)F)c2)cc(C)c1C(=O)N1CCC(N2CCCC2)CC1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cc(-c2cccc(C(F)(F)F)c2)cc(O)c1C(=O)N1CCC(N2CCCC2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 37.8 %

Procedure:
To a solution of 0.51 g (1.1 mmol) of (3-methoxy-5-methyl-3′-trifluoromethyl-biphenyl-4-yl)-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone (example 44) in 15 ml of CH2Cl2 was added at 0° C. 0.39 ml=0.57 g (2.3 mmol) of a boron tribromide solution (1.0 molar in CH2Cl2) drop by drop and the reaction mixture was the warmed up to RT. After 4 hours, it was poured into crashed ice, neutralized with sodium hydrogen carbonate solution and extracted twice with CH2Cl2; the organic phases were washed with water, dried over magnesium sulfate, filtered and evaporated. The residue was purified by flash column chromatography (CH2Cl2/MeOH 1:0 to 4:1) to give 0.18 g (36%) of the title compound as colorless amorphous solid. MS: 433.2 (MH+).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[F:7][CH2:8][CH2:9][NH2:10].[C:11]([C:13]1[N:18]=[CH:17][C:16]([C:19]2[C:31]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[N:24]([C:32]4[CH:44]=[CH:43][C:35]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])=[C:34](F)[CH:33]=4)[C:23]=3[CH:22]=[CH:21][CH:20]=2)=[CH:15][CH:14]=1)#[N:12]>CS(C)=O.O>[C:11]([C:13]1[N:18]=[CH:17][C:16]([C:19]2[C:31]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[N:24]([C:32]4[CH:33]=[CH:34][C:35]([C:36]([O:38][C:39]([CH3:40])([CH3:41])[CH3:42])=[O:37])=[C:43]([NH:10][CH2:9][CH2:8][F:7])[CH:44]=4)[C:23]=3[CH:22]=[CH:21][CH:20]=2)=[CH:15][CH:14]=1)#[N:12]
Reactant: NCCF
Reactant: CC(C)(C)OC(=O)c1ccc(-n2c3ccccc3c3c(-c4ccc(C#N)nc4)cccc32)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)c1ccc(-n2c3ccccc3c3c(-c4ccc(C#N)nc4)cccc32)cc1NCCF
Temperature: 90 °C
Yield: 19.6 %

Procedure:
4.83 g of potassium carbonate and 3 g (40 mmol) of 2-fluoroethylamine are successively added to a solution of 0.7 g of 2-methylpropan-2-yl 4-[4-(6-cyanopyridin-3-yl)-9H-carbazol-9-yl]-2-fluorobenzoate, obtained in stage 1 of Example 49, in 5 ml of dimethyl sulphoxide. The reaction mixture is heated at 90° C. for 2 hours and 50 minutes in a microwave, and then diluted with distilled water. The aqueous phase is washed twice with ethyl acetate and the combined organic phases are washed with water and a saturated solution of sodium chloride, dried over magnesium sulphate and concentrated to dryness under reduced pressure. The residue is purified by silica gel chromatography, elution being carried out with dichloromethane, so as to give 0.15 g of 2-methylpropan-2-yl 4-[4-(6-cyanopyridin-3-yl)-9H-carbazol-9-yl]-2-[(2-fluoroethyl)amino]benzoate in the form of a white powder, the characteristics of which are the following:
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[CH2:7][S:8][CH2:9][CH2:10][NH2:11].[CH2:12]([N:14]=[C:15]=[S:16])[CH3:13]>C(O)C>[CH2:12]([NH:14][C:15]([NH:11][CH2:10][CH2:9][S:8][CH2:7][C:6]1[NH:5][CH:4]=[N:3][C:2]=1[CH3:1])=[S:16])[CH3:13]
Reactant: Cc1nc[nH]c1CSCCN
Reactant: CCN=C=S
Solvent: CCO
Product: CCNC(=S)NCCSCc1[nH]cnc1C
Yield: 86.4 %

Procedure:
(i) A solution of 4-methyl-5-[(2-aminoethyl)thiomethyl]imidazole (6.9 g.) and ethyl isothiocyanate (3.84 g.) in ethanol was heated under reflux for 2 hours. Concentration followed by recrystallisation of the residue from aqueous ethanol gave N-ethyl-N'-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]thiourea (9.0 g.), m.p. 140°-141°. (Found: C, 46.5; H, 7.1; N, 21.7; S, 25.1. C10H18N4S2 requires: C, 46.5; H, 7.0; N, 21.7; S, 24.8).
Reaction SMILES: CO.[F:3][C:4]1[CH:29]=[CH:28][C:7]([NH:8][C:9]2[CH:18]=[C:17]([CH:19]=[CH:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:16]=[CH:15][C:10]=2[C:11]([O:13][CH3:14])=[O:12])=[CH:6][CH:5]=1>[C].[Pd].C(OCC)(=O)C>[F:3][C:4]1[CH:5]=[CH:6][C:7]([NH:8][C:9]2[CH:18]=[C:17]([CH2:19][CH2:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:16]=[CH:15][C:10]=2[C:11]([O:13][CH3:14])=[O:12])=[CH:28][CH:29]=1
Reactant: COC(=O)c1ccc(C=CCc2ccccc2)cc1Nc1ccc(F)cc1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(CCCc2ccccc2)cc1Nc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixed solution of methanol 8 mL and ethyl acetate 2 mL of the obtained methyl 2-(4-fluoroanilino)-4-(3-phenyl-1-propenyl)benzoate, 5% palladium-carbon 0.060 g was added, and it was stirred under hydrogen atmosphere at room temperature for 1 hour. Insoluble matter of the reaction mixture was filtrated, and the solvent was removed under reduced pressure. The obtained residue was refined by silica gel column chromatography [Trikonex company, Flash Tube 2008, eluent; hexane:ethyl acetate=10:1] to give methyl 2-(4-fluoroanilino)-4-(3-phenylpropyl)benzoate 0.10 g of colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4](/[CH:8]=[CH:9]/[CH2:10][NH:11][C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])[CH:5]=[CH:6][CH:7]=1.[O:18]1[C:20]2([CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[CH2:19]1>CCO.O>[F:16][C:13]([F:14])([F:15])[C:12]([NH:11][CH2:10]/[CH:9]=[CH:8]/[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][CH2:19][C:20]2([OH:18])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[CH:3]=1)=[O:17]
Reactant: Nc1cccc(/C=C/CNC(=O)C(F)(F)F)c1
Reactant: C1CCC2(CC1)CO2
Solvent: CCO
Solvent: O
Product: O=C(NC/C=C/c1cccc(NCC2(O)CCCCC2)c1)C(F)(F)F

Procedure:
A mixture of (E)-N-(3-(3-aminophenyl)allyl)-2,2,2-trifluoroacetamide (0.8 g, 3.28 mmol) and 1-oxaspiro[2.5]octane (0.55 g, 4.91 mmol) in EtOH:H2O(9:1) was stirred under reflux for 36 hrs and concentrated under reduced pressure. Purification by column chromatography (20% to 30% EtOAc—hexanes gradient) gave (E)-2,2,2-trifluoro-N-(3-(3-((1-hydroxycyclohexyl)methylamino)phenyl)allyl)acetamide as an off-white solid. Yield (0.5 g, 43%); 1H NMR (400 MHz, DMSO-d6) δ 9.71 (s, 1H), 7.00 (t, J=8.0 Hz, 1H), 6.67 (s, 1H), 6.55 (t, J=8.8 Hz, 2H), 6.41 (d, J=16.0 Hz, 1H), 6.61-6.09 (m, 1H), 5.22 (t, J=5.2 Hz, 1H), 4.20 (s, 1H), 3.95 (t, J=5.2 Hz, 2H), 2.94 (d, J=5.6, 2H), 1.61-1.49 (m, 5H), 1.41-1.36 (m, 4H), 1.25-1.19 (m, 1H).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10](Cl)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:13][O:14][C:15](=[O:26])[CH:16]([O:18][C:19]1[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][CH:20]=1)[CH3:17].C(N(CC)CC)C>CC(C)=O>[CH3:13][O:14][C:15](=[O:26])[CH:16]([O:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:10](=[O:11])[CH2:9][O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:21][CH:20]=1)[CH3:17]
Reactant: O=C(Cl)COCc1ccccc1
Reactant: COC(=O)C(C)Oc1ccc(N)cc1
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)C(C)Oc1ccc(NC(=O)COCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 59.7 %

Procedure:
Benzyloxyacetyl chloride (28 g, 152 mmol) was added dropwise to a mixture of 2-(4-aminophenoxy)propionic acid methyl ester 18 (20 g, 102.5 mmol) and triethylamine (23 ml, 165 mmol) in acetone (120 ml) at 0° C. and stirred at room temperature for 12 hrs. Solids were filtered off, acetone distilled off and water (100 ml) added. Crude 68 was extracted into chloroform, washed with 5% sodium bicarbonate (2×100 ml), water (200 ml), dried over sodium sulphate and distilled. Crude 68 was purified by column chromatography on silica gel using benzene as eluant to get pure 68 (21 g, 59.8%) as a light brown powder. M.p: 67-70° C.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([CH2:31][C:32]1[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=1)[C:9](=[O:30])[N:10]1[CH2:15][CH2:14][N:13]([C:16]2[C:17]3[S:24][C:23]([C:25]4[CH:29]=[CH:28][S:27][CH:26]=4)=[CH:22][C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:12][CH2:11]1)(C)(C)C.[ClH:40]>C(Cl)Cl.O1CCOCC1>[ClH:38].[ClH:40].[NH2:7][CH:8]([CH2:31][C:32]1[CH:33]=[CH:34][C:35]([Cl:38])=[CH:36][CH:37]=1)[C:9]([N:10]1[CH2:11][CH2:12][N:13]([C:16]2[C:17]3[S:24][C:23]([C:25]4[CH:29]=[CH:28][S:27][CH:26]=4)=[CH:22][C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:14][CH2:15]1)=[O:30]
Reactant: CC(C)(C)OC(=O)NC(Cc1ccc(Cl)cc1)C(=O)N1CCN(c2ncnc3cc(-c4ccsc4)sc23)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: NC(Cc1ccc(Cl)cc1)C(=O)N1CCN(c2ncnc3cc(-c4ccsc4)sc23)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of product {1-(4-chlorobenzyl)-2-oxo-2-[4-(6-thiophen-3-yl-thieno[3,2-d]pyrimidin-4-yl)-piperazin-1-yl]-ethyl}-carbamic acid tert-butyl ester in DCM (4 mL) was added HCl in Dioxane (4M, 1 mL). The mixture was stirred at room temperature for 4 hours. The solvent was removed to afford the product 2-Amino-3-(4-chlorophenyl)-1-[4-(6-thiophen-3-yl-thieno[3,2-d]pyrimidin-4-yl)-piperazin-1-yl]-propan-1-one dihydrochloride quantitatively. MS (ESI+) [M+H]+ 484.
Reaction SMILES: [OH-:1].[Li+].[CH2:3]([N:10]1[C@@H:15]2[C@H:16]([C:18]3[N:22](CC(OC)=O)[N:21]=[N:20][N:19]=3)[CH2:17][C@@:11]1([C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[C@H:12]([O:28][CH2:29][C:30]1[CH:35]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:33]=[C:32]([C:40]([F:43])([F:42])[F:41])[CH:31]=1)[CH2:13][CH2:14]2)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:50]1[CH2:54][O:53]CC1>O>[CH2:3]([N:10]1[C@@H:15]2[C@H:16]([C:18]3[N:22]=[N:21][N:20]([CH2:50][C:54]([OH:1])=[O:53])[N:19]=3)[CH2:17][C@@:11]1([C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[C@H:12]([O:28][CH2:29][C:30]1[CH:35]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:33]=[C:32]([C:40]([F:41])([F:43])[F:42])[CH:31]=1)[CH2:13][CH2:14]2)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: C1CCOC1
Reactant: COC(=O)Cn1nnnc1[C@@H]1C[C@@]2(c3ccccc3)[C@H](OCc3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC[C@@H]1N2Cc1ccccc1
Reactant: [OH-]
Agent: [Li+]
Solvent: O
Product: O=C(O)Cn1nnc([C@@H]2C[C@@]3(c4ccccc4)[C@H](OCc4cc(C(F)(F)F)cc(C(F)(F)F)c4)CC[C@@H]2N3Cc2ccccc2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94 %

Procedure:
Lithium hydroxide (40 mg, 0.9 mmol) was added to a solution of (1R*,2 R*,5S*,6R*)-8-benzyl-2-{[3,5-bis(trifluoromethyl)phenyl]methoxy}-6-(2-methoxycarbonylmethyl-2H-tetrazol-5-yl)-1-phenyl-8-azabicyclo[3.2.1]octane (Example 144a; 0.6 g, 0.91 mmol) in water (5 ml) and THF (5 ml). The reaction mixture was stirred at room temperature for 30 minutes then partitioned between 5% citric acid solution and ethyl acetate. The organic layer was separated, dried (MgSO4), filtered and concentrated to yield the title compound (0.55 g, 94%).