Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:17]=2)[N:10]=1.[CH:27]1([CH2:30][CH2:31][OH:32])[CH2:29][CH2:28]1>>[CH:27]1([CH2:30][CH2:31][O:32][C:2]2[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=2[C:9]2[N:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:17]=3)[N:10]=2)[CH2:29][CH2:28]1
Reactant: OCCC1CC1
Reactant: CS(=O)(=O)Cc1cccc(Nc2ncnc(-c3ccc(F)cc3F)n2)c1
Product: CS(=O)(=O)Cc1cccc(Nc2ncnc(-c3ccc(F)cc3OCCC3CC3)n2)c1

Procedure:
Starting with 4-(2,4-difluorophenyl)-N-{3-[(methylsulfonyl)methyl]phenyl}-1,3,5-triazin-2-amine (75 mg; 0.19 mmol), intermediate 42.1, and 2-cyclopropylethanol (46.2 mg; 0.773 mmol), example 48 was prepared analogously to the procedure for the preparation of example 42.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[NH:15][C:16]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)=[C:17]([C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)[N:18]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1.C(OCC)(=O)C>[F:31][C:28]1[CH:29]=[CH:30][C:25]([C:16]2[NH:15][C:14]([CH:11]3[CH2:12][CH2:13][N:8]([CH3:6])[CH2:9][CH2:10]3)=[N:18][C:17]=2[C:19]2[CH:20]=[CH:21][N:22]=[CH:23][CH:24]=2)=[CH:26][CH:27]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(-c3ccncc3)c(-c3ccc(F)cc3)[nH]2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CN1CCC(c2nc(-c3ccncc3)c(-c3ccc(F)cc3)[nH]2)CC1

Procedure:
To a stirring solution of 4-[5-(4-fluorophenyl)-4-pyridin-4-yl-1H-imidazol-2-yl]piperidine-1-carboxylic acid tert-butyl ester (0.90 mmol,0.38 g) in THF (10 mL) was added lithium aluminum hydride (2.7 mmol,2.7 mL of a IM solution in tetrahydrofuran). The reaction was heated to reflux overnight. The reaction was diluted with ethyl acetate (20 mL) and quenched with water (2.0 mL). The suspension was filtered and the filtrates dried over anhydrous sodium sulfate. The filtrates were then evaporated under reduced pressure. The resulting solid was triturated with diethyl ether, filtered and recrystallized from ethanol:diethyl ether to give 160 mg. of the title compound as a white powder.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][N:9]=2)=[CH:4][CH:3]=1.ClC1C=CN=CN=1.ClC1C=CC(B(O)O)=CC=1.[CH:31]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:34]=[CH:33][C:32]=1B(O)O>>[CH:39]1[C:40]2[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:36]=[CH:37][C:38]=1[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: Clc1ccc(-c2ccncn2)cc1
Reactant: OB(O)c1ccc2ccccc2c1
Agent: Clc1ccncn1
Agent: OB(O)c1ccc(Cl)cc1
Product: c1ccc2cc(-c3ccc(-c4ccncn4)cc3)ccc2c1

Procedure:
It is easy to synthesize the following compounds in the same manner as in Example 11 except that 4-(4-chlorophenyl)pyrimidine is synthesized from 4-chloropyrimidine prepared in Example 13 and 4-chlorophenylboronic acid (made by Aldrich Co.) and was reacted with 2-naphthaleneboronic acid (made by Lancaster Co.) to obtain 4-[4-(2-naphthyl)phenyl]-pyrimidine, which is used instead of 2-(benzo[b]thienyl)-5-phenylpyridine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH2:10][C:11]([OH:13])=[O:12].CO.[Si](C=[N+]=[N-])(C)(C)[CH3:17]>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH2:10][C:11]([O:13][CH3:17])=[O:12]
Reactant: COc1ccc(CC(=O)O)c(F)c1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: Cc1ccccc1
Solvent: CO
Product: COC(=O)Cc1ccc(OC)cc1F
Reaction time: 0.25 h

Procedure:
To a solution of (2-fluoro-4-methoxyphenyl)acetic acid (500 mg, 2.72 mmol) in toluene (20 mL) was added MeOH (3 mL) and TMS diazomethane (2.04 mL of a 2M solution in hexanes, 4.08 mmol). After 15 min, the reaction was quenched by the addition of HOAc (250 μL). The reaction was diluted with EtOAc (100 mL) and washed with saturated NaHCO3 (2×25 mL) and brine (25 mL). The organic layer was dried (Na2SO4), filtered and concentrated. Purification of the residue by flash chromatography (0 to 25% EtOAc/hexanes) afforded methyl (2-fluoro-4-methoxyphenyl)acetate. 1H NMR (500 MHz, CDCl3): δ 7.15 (t, J=8.6 Hz, 1H), 6.62-6.68 (m, 2H), 3.78 (s, 3H), 3.70 (s, 3H), 3.60 (s, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][C:9]2=[O:12])=[CH:4][CH:3]=1.[C:13]([O:17]C)(=O)[CH:14]=[CH2:15].[CH3:19][C:20](C)([O-])C.[K+].[OH-].[K+]>C1COCC1.O>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8]3([CH2:15][CH2:14][C:13](=[O:17])[CH2:20][CH2:19]3)[C:9]2=[O:12])=[CH:4][CH:3]=1
Reactant: CC(C)(C)[O-]
Reactant: C=CC(=O)OC
Reactant: O=C1CCCc2ccc(Br)cc21
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C1CCC2(CC1)CCc1ccc(Br)cc1C2=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 81.7 %

Procedure:
7-Bromo-3,4-dihydronaphthalen-1-(2H)-one (10.3 g, 45.8 mmol) and methyl acrylate (9.08 mL, 101 mmol) was dissolved in THF (55 mL) and cooled in an ice bath. Potassium tert-butoxide (6.16 g, 54.9 mmol) was added in portions. The mixture was stirred for 1.5 h at r.t. Water (80 mL) and potassium hydroxide (2.57 g, 45.8 mmol) were added and the mixture was heated to 75° C. overnight in an open system. The mixture was cooled to r.t. and filtered. The obtained solid was dried in vacuo yielding the title compound (11.5 g, 82% yield): 1H NMR (CDCl3) δ ppm 1.74-1.87 (m, 2 H), 2.15 (t, 2 H), 2.24-2.43 (m, 4 H), 2.62-2.72 (m, 2 H), 3.00 (t, 2 H), 7.16 (d, 1 H), 7.61 (dd, 1 H), 8.16 (d, 1 H); MS (ES+) m/z 307, 309 [M+H]+.
Reaction SMILES: [S:1]([NH2:5])([NH2:4])(=[O:3])=[O:2].O.[C:7]1([CH3:17])[CH:12]=[CH:11][C:10]([S:13]([OH:16])(=[O:15])=[O:14])=[CH:9][CH:8]=1.[Cl:18][CH2:19][CH2:20][C:21]#[N:22]>C(Cl)Cl.CC(C)=O>[C:7]1([CH3:17])[CH:8]=[CH:9][C:10]([S:13]([OH:16])(=[O:14])=[O:15])=[CH:11][CH:12]=1.[S:1]([NH:5][C:21](=[NH:22])[CH2:20][CH2:19][Cl:18])(=[O:3])(=[O:2])[NH2:4]
Reactant: N#CCCCl
Reactant: NS(N)(=O)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: ClCCl
Solvent: CC(C)=O
Product: N=C(CCCl)NS(N)(=O)=O
Temperature: 57.5 °C

Procedure:
Sulfamide (9.6 g, 0.1 mole) was added to a suspension of p-toluenesulfonic acid monohydrate (38.0 g, 0.2 mole) in 3-chloropropionitrile (51.3 g, 0.6 mole). The suspension was heated at 55-60° C., for 18 hours. At the end of the heating period, the mixture was cooled to room temperature, diluted with methylene chloride (150 ml), and filtered. The solid, thus obtained, was suspended in acetone (50 ml) and the suspension filtered and the product dried.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:9])[NH:4][C:5](=[O:8])[NH:6][CH:7]=1.[CH3:10]/C(/O[Si](C)(C)C)=N\[Si](C)(C)C.[F:22][C:23]1[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[C:24]=1[CH2:25]Br>ClC(Cl)C>[Br:1][C:2]1[C:3](=[O:9])[NH:4][C:5](=[O:8])[N:6]([CH2:25][C:24]2[C:23]([F:22])=[CH:30][CH:29]=[CH:28][C:27]=2[F:31])[C:7]=1[CH3:10]
Reactant: C/C(=N\[Si](C)(C)C)O[Si](C)(C)C
Reactant: Fc1cccc(F)c1CBr
Reactant: O=c1[nH]cc(Br)c(=O)[nH]1
Solvent: CC(Cl)Cl
Product: Cc1c(Br)c(=O)[nH]c(=O)n1Cc1c(F)cccc1F
Temperature: 80 °C
Yield: 47.5 %

Procedure:
A suspension of 5-bromouracil (18.45 g, 96.6 mmol) in 300 mL of dichloroethane was treated with N,O-bis(trimethylsilyl)acetamide (48 mL, 39.5 g, 194 mmol). The reaction mixture was heated at 80° C. for 3 hr under the nitrogen. The solution was cooled down to ambient temperature, 2,6-difluorobenzyl bromide (25 g, 120 mmol) was added and the reaction mixture was heated at 80° C. overnight under the protection of nitrogen. The reaction was cooled down, quenched with MeOH (15 mL), and partitioned between dichloromethane (500 mL) and water (250 mL). The organic layer was washed with brine, dried (sodium sulfate), and evaporated to give a solid. The crude product was triturated with ether, filtered, and washed with ether three times to give compound 1 (15.2 g,50%) as a white solid; MS (CI) m/z 316.90, 318.90 (MH+).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]2[CH:11]=[CH:12][S:13][C:3]=12.[NH2:14][CH:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH:16]1[OH:28].C(N(CC)C(C)C)(C)C>C(O)(C)C.O>[OH:28][CH:16]1[CH:15]([NH:14][C:2]2[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]3[CH:11]=[CH:12][S:13][C:3]=23)[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17]1
Reactant: O=[N+]([O-])c1cnc2ccsc2c1Cl
Reactant: CC(C)(C)OC(=O)N1CCC(N)C(O)C1
Solvent: O
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(Nc2c([N+](=O)[O-])cnc3ccsc23)C(O)C1
Temperature: 90 °C
Yield: 90.5 %

Procedure:
A mixture of 7-chloro-6-nitrothieno[3,2-b]pyridine (0.61 g, 2.8 mmol) (Example 1, Step 2), tert-butyl 4-amino-3-hydroxypiperidine-1-carboxylate (from Aurora, 0.95 g, 4.4 mmol) and N,N-diisopropylethylamine (0.99 mL, 5.7 mmol) in isopropyl alcohol (7.4 mL) was heated at 90° C. for 2 h. The resulting mixture was diluted with water. The precipitate was collected by filtration, washed with water and air-dried to give the desired product (1 g, 89%). LCMS calculated for C17H23N4O5S (M+H)+: m/z=395.1. Found: 395.0.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][C@H:2]1[C:6](Cl)=[O:7].[BrH:9].[CH3:10]COCC.C(Cl)Cl>>[Br:9][CH2:10][C:6]([C@@H:2]1[CH2:3][CH2:4][CH2:5][O:1]1)=[O:7]
Reactant: CCOCC
Reactant: O=C(Cl)[C@@H]1CCCO1
Reactant: Br
Solvent: ClCCl
Product: O=C(CBr)[C@@H]1CCCO1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 35 %

Procedure:
To a 250-mL three neck round-bottom flask, which was purged and maintained with an inert atmosphere of nitrogen, was added a solution of (diazomethyl)trimethylsilane (20 mL, 2 M in hexane) in ether (150 mL). A solution of (S)-tetrahydrofuran-2-carbonyl chloride (compound 257.1, 5.00 g, 37.2 mmol, 1.00 equiv) in ether/DCM (25/10 mL) was added dropwise at 0° C. and stirred for 20 min at 0° C. Hydrogen bromide (48%) (8 mL, 1.50 equiv) was added dropwise. The resulting solution was stiffed for 30 min at 10° C., then washed with 2×100 mL of water and 1×50 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified using silica gel column chromatography with ethyl acetate/petroleum ether (1:50) as eluent to furnish 2.50 g (35%) of (S)-2-bromo-1-(tetrahydrofuran-2-yl)ethanone as a yellow oil.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][NH:6][CH2:5][CH2:4][NH:3]1.Cl[C:9]1[N:10]([CH2:31][C:32]([F:35])([F:34])[F:33])[C:11]2[C:16]([N:17]=1)=[C:15]([N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)[N:14]=[C:13]([C:24]1[CH:25]=[N:26][C:27]([NH2:30])=[N:28][CH:29]=1)[N:12]=2.CN1CC[CH2:39][C:38]1=[O:42]>>[C:38]([N:3]1[CH2:4][CH2:5][N:6]([C:9]2[N:10]([CH2:31][C:32]([F:35])([F:34])[F:33])[C:11]3[C:16]([N:17]=2)=[C:15]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[N:14]=[C:13]([C:24]2[CH:25]=[N:26][C:27]([NH2:30])=[N:28][CH:29]=2)[N:12]=3)[CH2:7][C@H:2]1[CH3:1])(=[O:42])[CH3:39]
Reactant: Nc1ncc(-c2nc(N3CCOCC3)c3nc(Cl)n(CC(F)(F)F)c3n2)cn1
Reactant: C[C@@H]1CNCCN1
Reactant: CN1CCCC1=O
Product: CC(=O)N1CCN(c2nc3c(N4CCOCC4)nc(-c4cnc(N)nc4)nc3n2CC(F)(F)F)C[C@H]1C
Temperature: 100 °C
Reaction time: 2 h
Yield: 52 %

Procedure:
(2R)-2-Methylpiperazine (241 mg, 2.41 mmol) and N-methyl-2-pyrrolidone (2 ml) were added to 5-[8-chloro-6-morpholin-4-yl-9-(2,2,2-trifluoroethyl)-9H-purin-2-yl]pyrimidin-2-amine (200 mg, 0.48 mmol) and the resulting mixture was stirred at 100° C. for 2 hours. The reaction mixture was partitioned with chloroform and water, the organic layer was dried over magnesium sulfate, and the solvent was concentrated under reduced pressure. Acetic anhydride (68 μl) and triethylamine (200 μl) were added to the residue with ice cooling and the resulting mixture was stirred for 1 hour and partitioned with ethyl acetate and saturated aqueous sodium bicarbonate solution. The organic layer was dried over magnesium sulfate, then the solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (chloroform:methanol=20:1) to give the title compound (127 mg, 52%) as a colorless solid.
Reaction SMILES: F[B-](F)(F)F.[CH3:6][O+](C)C.F[B-](F)(F)F.[F:15][C:16]1[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[CH:18][C:17]=1[CH:26]([NH:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]2[N:41]=[C:40]([CH3:42])[O:39][N:38]=2)=[CH:33][CH:32]=1)[C:27]([NH2:29])=[S:28].C(=O)([O-])O.[Na+]>ClCCl>[CH3:6][S:28][C:27](=[NH:29])[CH:26]([C:17]1[CH:18]=[C:19]([O:24][CH3:25])[C:20]([O:22][CH3:23])=[CH:21][C:16]=1[F:15])[NH:30][C:31]1[CH:32]=[CH:33][C:34]([C:37]2[N:41]=[C:40]([CH3:42])[O:39][N:38]=2)=[CH:35][CH:36]=1
Reactant: C[O+](C)C
Reactant: COc1cc(F)c(C(Nc2ccc(-c3noc(C)n3)cc2)C(N)=S)cc1OC
Agent: F[B-](F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COc1cc(F)c(C(Nc2ccc(-c3noc(C)n3)cc2)C(=N)SC)cc1OC
Temperature: 25 °C
Reaction time: 15 h
Yield: 100 %

Procedure:
After adding 3.62 g of trimethyloxonium tetrafluoroborate (hereinafter, “Me3O+BF4−”) to a solution of 8.59 g of 2-(2-fluoro-4,5-dimethoxyphenyl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylamino]thioacetamide in 400 ml of dichloromethane under a nitrogen atmosphere, the mixture was stirred at room temperature for 15 hours. Saturated aqueous sodium hydrogencarbonate was added to the reaction mixture and extraction was performed with dichloromethane. After washing the organic layer with saturated brine, it was dried over anhydrous sodium sulfate. The desiccating agent was filtered, and the filtrate was concentrated under reduced pressure to give the title compound (8.89 g, crude product) as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[CH:9]=[N:8][CH2:7][CH2:6]2.[CH2:15]([Cl:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O1CCOCC1>[Cl-:22].[CH2:15]([N+:8]1[CH2:7][CH2:6][C:5]2[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=2)[CH:9]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: ClCc1ccccc1
Reactant: COc1cc2c(cc1OC)CCN=C2
Solvent: C1COCCO1
Product: COc1cc2c(cc1OC)CC[N+](Cc1ccccc1)=C2
Product: [Cl-]

Procedure:
The title compound is prepared analogously to Example A from 6,7-dimethoxy-3,4-dihydroisoquinoline and benzyl chloride in dioxan. The melting point: 181°-183° C. (Decomp.)
Reaction SMILES: CO[CH:3](OC)[CH2:4][CH:5](OC)OC.S(=O)(=O)(O)O.[NH:17]([C:19]1[N:23]([C:24]2[C:29]([Cl:30])=[CH:28][C:27]([C:31]([F:34])([F:33])[F:32])=[CH:26][C:25]=2[Cl:35])[N:22]=[CH:21][C:20]=1[S:36]([C:39]([F:42])([F:41])[F:40])(=[O:38])=[O:37])[NH2:18].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[Cl:30][C:29]1[CH:28]=[C:27]([C:31]([F:32])([F:33])[F:34])[CH:26]=[C:25]([Cl:35])[C:24]=1[N:23]1[C:19]([N:17]2[CH:5]=[CH:4][CH:3]=[N:18]2)=[C:20]([S:36]([C:39]([F:42])([F:41])[F:40])(=[O:37])=[O:38])[CH:21]=[N:22]1
Reactant: NNc1c(S(=O)(=O)C(F)(F)F)cnn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Reactant: COC(CC(OC)OC)OC
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCO
Product: O=S(=O)(c1cnn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1-n1cccn1)C(F)(F)F
Yield: 76.7 %

Procedure:
1.2 ml (0.0078 mole) of 1,1,3,3-tetramethoxypropane and 0.2 ml (0.0034 mole) of 96 percent strength sulphuric acid are added in sequence to 3 g (0.0068 mole) of 5-hydrazino-4-(trifluoromethylsulphonyl)-1-(2,6-dichloro-4-trifluoromethyl-phenyl)-pyrazole in 7 ml of ethanol at 20° C. to 25° C. The reaction mixture is heated at the reflux temperature for 2 hours, cooled, and neutralized with 0.36 g (0.0034 mole) of sodium carbonate, and the solvent is removed in vacuo. The residue is suspended in water, filtered, washed again with water and dried. 2.5 g (77% of theory) of 1-(2,6-dichloro-4-trifluoromethyl-phenyl)-5-(pyrazol-1-yl)-4-trifluoromethylsulphonyl-pyrazole of melting point 127° C. to 133° C. are obtained.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]=[CH:11][CH:12]=O)=[CH:2]1.[NH2:14][C:15]1[S:16][C:17]2[CH2:18][CH2:19][NH:20][CH2:21][CH2:22][C:23]=2[N:24]=1.C([BH3-])#N.[Na+]>>[NH2:14][C:15]1[S:16][C:17]2[CH2:18][CH2:19][N:20]([CH2:12][CH:11]=[CH:10][C:3]3[C:4]4[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=4)[NH:1][CH:2]=3)[CH2:21][CH2:22][C:23]=2[N:24]=1
Reactant: O=CC=Cc1c[nH]c2ccccc12
Reactant: Nc1nc2c(s1)CCNCC2
Agent: [BH3-]C#N
Agent: [Na+]
Product: Nc1nc2c(s1)CCN(CC=Cc1c[nH]c3ccccc13)CC2
Yield: 11 %

Procedure:
Prepared from 3-(3-indolyl)acrolein and 1 equivalent of 2-amino-4,5,7,8-tetrahydro-6H- thiazolo[5,4-d]azepine by reductive amination with 0.9 equivalents of sodium cyanoborohydride. Purification of the crude product by column chromatography is carried out using neutral aluminium oxide of activity stage I (toluene/ethyl acetate/ethanol=4:1:0.5). Yield: 11% of theory, Melting point: 155°-160° C.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]3[NH:18][C:17](=[O:19])[NH:16][C:12]3=[N:13][C:14]=2[CH3:15])=[CH:5][CH:4]=1.[C:20](Cl)(=[O:25])[CH2:21][CH2:22][CH2:23][CH3:24]>>[CH2:21]([C:20]([NH:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]3[NH:18][C:17](=[O:19])[NH:16][C:12]3=[N:13][C:14]=2[CH3:15])=[CH:5][CH:4]=1)=[O:25])[CH2:22][CH2:23][CH3:24]
Reactant: Cc1nc2[nH]c(=O)[nH]c2cc1-c1ccc(N)cc1
Reactant: CCCCC(=O)Cl
Agent: Cl
Product: CCCCC(=O)Nc1ccc(-c2cc3[nH]c(=O)[nH]c3nc2C)cc1

Procedure:
[I; Ar 4-CH3 (CH2)3CONHC6H4, R1 and R3H, R5 =CH3 ]was prepared from 3 g 6-(4-aminophenyl)-1,3-dihydro-5-methyl-2H-imidazo[4,5-b]pyridin-2-one hydrochloride and 1.86 ml valeryl chloride according to the procedure of Example 7, and was obtained (1.16 g) as a colorless solid, m.p. above 300° C. when recrystallized from ethanol.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][OH:6].[C:10]1([P:16]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[CH3:29][O:30][C:31]([C@H:33]1[CH2:37][C:36](=[O:38])[N:35]([C:39]2[CH:44]=[CH:43][C:42](O)=[CH:41][CH:40]=2)[CH2:34]1)=[O:32].[N:46]([C:54]([O:56][CH:57]([CH3:59])[CH3:58])=[O:55])=[N:47][C:48]([O:50][CH:51]([CH3:53])[CH3:52])=[O:49].C1(P(=O)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[CH3:29][O:30][C:31]([C@H:33]1[CH2:37][C:36](=[O:38])[N:35]([C:39]2[CH:44]=[CH:43][C:42]([O:6][CH2:5][C:4]3[CH:7]=[CH:8][CH:9]=[C:2]([F:1])[CH:3]=3)=[CH:41][CH:40]=2)[CH2:34]1)=[O:32].[C:23]1([P:16]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1.[NH:46]([C:54]([O:56][CH:57]([CH3:59])[CH3:58])=[O:55])[NH:47][C:48]([O:50][CH:51]([CH3:52])[CH3:53])=[O:49]
Reactant: OCc1cccc(F)c1
Reactant: CC(C)OC(=O)N=NC(=O)OC(C)C
Reactant: COC(=O)[C@H]1CC(=O)N(c2ccc(O)cc2)C1
Agent: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)OC(=O)NNC(=O)OC(C)C
Product: COC(=O)[C@H]1CC(=O)N(c2ccc(OCc3cccc(F)c3)cc2)C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 110.6 mmol of 3-fluoro-benzylalcohol and 108.8 mmol of triphenylphosphine in 150 ml of tetrahydrofuran was added dropwise, within 50 min under a nitrogen atmosphere at 0° C., to a solution of 100.5 mmol of (S)-1-(4-hydroxy-phenyl)-5-oxo-pyrrolidine-3-carboxylic acid methyl ester and 100.5 mmol of diisopropyl azodicarboxylate in 200 ml of tetrahydrofuran. The mixture was left to warm to RT and stirring was continued for 18 hours. The mixture was evaporated under reduced pressure. The solid residue was triturated in 400 ml of ether to leave a white solid mainly consisting of the product and triphenylphosphinoxide. After filtration, the solid material was triturated in 100 ml of cold methanol to yield (S)-1-[4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylic acid methyl ester as a white solid [MS: m/e=344 (M+H)+] together with traces of triphenylphosphine and diisopropyl hydrazodicarboxylate.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[CH2:3][O:4][CH2:5][C:6]#[N:7].[Na].[CH3:11][OH:12]>>[F:1][C:2]([F:9])([F:8])[CH2:3][O:4][CH2:5][C:6](=[NH:7])[O:12][CH3:11]
Reactant: N#CCOCC(F)(F)F
Reactant: CO
Agent: [Na]
Product: COC(=N)COCC(F)(F)F

Procedure:
Obtained using the procedure described in section a of Example 2, starting with 19.6 g (0.141 mole) of (2,2,2-trifluoroethoxy)acetonitrile and 0.3 g (0.013 gram-atom) of sodium in 95 ml of methanol. Reaction time: 24 hours. Yld: 15.6 g (65%), b.p.15 44°-47° C.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].O=S(Cl)[Cl:16]>ClC(Cl)C>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:16])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc(F)c([N+](=O)[O-])c1
Solvent: CC(Cl)Cl
Product: O=C(Cl)c1ccc(F)c([N+](=O)[O-])c1
Temperature: 80 °C

Procedure:
The title compound was prepared from 4-Fluoro-3-nitro-benzoic acid (1.00 g, 5.40 mmol) dissolved in dichloroethane (25 mL) to which was added SOCl2 (6.427 g, 54.02 mmol). This mixture was heated to 80° C. for 12 h at which point all the solvent was removed on under vacuum and the crude oil was taken forward without purification (1.10 g, 100%).
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH:6](/[CH:9]=[C:10]2/[C:11]([NH:16][CH2:17][C:18]#[CH:19])=[N:12][C:13](=[O:15])[S:14]/2)[CH2:5][CH2:4]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:27][C:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31]([C:38]#[N:39])=[CH:30][CH:29]=1.O>CN(C=O)C>[O:15]=[C:13]1[N:12]=[C:11]([NH:16][CH2:17][C:18]#[CH:19])/[C:10](=[CH:9]/[CH:6]2[CH2:7][CH2:8][N:3]([CH2:27][C:28]3[C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[C:31]([C:38]#[N:39])=[CH:30][CH:29]=3)[CH2:4][CH2:5]2)/[S:14]1
Reactant: C#CCNC1=NC(=O)S/C1=C\C1CCNCC1
Reactant: N#Cc1ccc(CBr)c2ccccc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C#CCNC1=NC(=O)S/C1=C\C1CCN(Cc2ccc(C#N)c3ccccc23)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.1 %

Procedure:
To a solution of (5Z)-5-(piperidin-4-ylmethylidene)-4-(prop-2-yn-1-ylamino)-1,3-thiazol-2(5H)-one dihydrochloride (200 mg) in DMF (3 mL) were added potassium carbonate (345 mg) and 4-(bromomethyl)naphthalene-1-carbonitrile (153 mg). The reaction mixture was stirred at room temperature overnight, water was added, and the mixture was extracted with ethyl is acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) and recrystallized from ethyl acetate/heptane to give the title compound (134 mg).
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:8]([N:10]1[CH2:14][CH2:13][CH2:12][C@H:11]1[C:15]#[N:16])=[O:9])[C@H:4]([CH2:6][CH3:7])[CH3:5].[C:17](=O)([O:25]C1C=CC([N+]([O-])=O)=CC=1)[O:18][CH:19]([O:21][C:22](=[O:24])[CH3:23])[CH3:20].C(N(CC)CC)C>ClCCl>[C:22]([O:21][CH:19]([O:18][C:17]([NH:2][C@H:3]([C:8]([N:10]1[CH2:14][CH2:13][CH2:12][C@H:11]1[C:15]#[N:16])=[O:9])[C@H:4]([CH2:6][CH3:7])[CH3:5])=[O:25])[CH3:20])(=[O:24])[CH3:23]
Reactant: CC(=O)OC(C)OC(=O)Oc1ccc([N+](=O)[O-])cc1
Reactant: CC[C@H](C)[C@H](N)C(=O)N1CCC[C@H]1C#N
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC[C@H](C)[C@H](NC(=O)OC(C)OC(C)=O)C(=O)N1CCC[C@H]1C#N
Yield: 69.6 %

Procedure:
A solution of (2S)-1-(isoleucyl)pyrrolidine-2-carbonitrile hydrochloride (500 mg, 2.04 mmol; prepared according to Jenkins et al., WO95/15309), α-acetoxyethyl p-nitrophenyl carbonate (610 mg, 2.27 mmol; prepared according to Alexander et al., J. Med. Chem. 31, 318, 1988) and triethylamine (250 mg, 2.50 mmol) in dichloromethane (40 ml) was stirred at room temperature for 18 hours. After this time the solvent was removed in vacuo and the residue was taken up in ethyl acetate (70 ml). This solution was washed with 0.3M KHSO4, sat. NaHCO3, water and brine, dried (Na2SO4) and evaporated. The residue was purified by flash chromatography (eluant EtOAc:Pet. Ether 60-80° C.; 3:7) yielding a colourless oil identified as the title compound (480 mg, 1.42 mmol, 70%).