Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:12]2[CH:13]=[CH:14][C:15]([NH2:17])=[CH:16][C:11]=2[O:10][CH2:9][CH2:8][CH2:7]1)=[O:5])[CH3:2].Cl[C:19]1[N:24]=[C:23]([NH:25][C:26]2[C:35]([F:36])=[CH:34][CH:33]=[CH:32][C:27]=2[C:28]([NH:30][CH3:31])=[O:29])[C:22]([Cl:37])=[CH:21][N:20]=1>>[CH2:1]([O:3][C:4]([N:6]1[C:12]2[CH:13]=[CH:14][C:15]([NH:17][C:19]3[N:24]=[C:23]([NH:25][C:26]4[C:27]([C:28](=[O:29])[NH:30][CH3:31])=[CH:32][CH:33]=[CH:34][C:35]=4[F:36])[C:22]([Cl:37])=[CH:21][N:20]=3)=[CH:16][C:11]=2[O:10][CH2:9][CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CNC(=O)c1cccc(F)c1Nc1nc(Cl)ncc1Cl
Reactant: CCOC(=O)N1CCCOc2cc(N)ccc21
Product: CCOC(=O)N1CCCOc2cc(Nc3ncc(Cl)c(Nc4c(F)cccc4C(=O)NC)n3)ccc21

Procedure:
3-[5-Chloro-4-(2-fluoro-6-methylcarbamoyl-phenylamino)-pyrimidin-2-ylamino]-7,8-dihydro-6H-5-oxa-9-aza-benzocycloheptene-9-carboxylic acid ethyl ester was prepared from 3-amino-7,8-dihydro-6H-5-oxa-9-aza-benzocycloheptene-9-carboxylic acid ethyl ester and 2-(2,5-dichloro-pyrimidin-4-ylamino)-3-fluoro-N-methyl-benzamide in an analogous manner to Example 1410. Product isolated as a yellow foam (135 mg, 66%). LCMS (m/e) 515 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 8.95-8.72 (m, 1H), 8.09 (s, 1H), 7.44-7.17 (m, 4H), 7.15-6.84 (m, 3H), 6.30-6.10 (m, 1H), 4.32-3.95 (m, 4H), 3.87-3.60 (m, 2H), 3.00-2.85 (m, 3H), 2.13-1.98 (m, 2H), 1.41-1.11 (m, 3H); 19F-NMR (CDCl3, 400 MHz) δ −111.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH:6]=[C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[N:14][CH:15]=3)[NH:10][CH:9]=2)[CH2:4][CH2:3]1.[C:17]1([S:23](Cl)(=[O:25])=[O:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1>[CH3:1][N:2]1[CH2:3][CH:4]=[C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[N:14][CH:15]=3)[N:10]([S:23]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)(=[O:25])=[O:24])[CH:9]=2)[CH2:6][CH2:7]1
Reactant: CN1CC=C(c2c[nH]c3ccncc23)CC1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CC=C(c2cn(S(=O)(=O)c3ccccc3)c3ccncc23)CC1

Procedure:
(28.5 mg, 86%); from 3-(1-methyl-1,2,3,6-tetrahydro-4-pyridinyl)-5-azaindole (20 mg, 0.094 mmol), benzenesulfonyl chloride (24 μL, 0.188 mmol) and 1M NaN(TMS)2 (250 μL, 0.25 mmol) in THF (1 mL) at RT.
Reaction SMILES: [C:1](Cl)(=[O:6])[C:2]([O:4][CH3:5])=[O:3].[C:8]([C:11]1[CH:29]=[CH:28][C:14]([O:15][CH2:16][CH2:17][CH2:18][O:19][C:20]2[CH:21]=[C:22]([C:24]([CH3:27])=[CH:25][CH:26]=2)[NH2:23])=[C:13]([CH2:30][CH2:31][C:32]([F:35])([F:34])[F:33])[C:12]=1[OH:36])(=[O:10])[CH3:9].C(N(CC)CC)C>C(Cl)Cl>[C:8]([C:11]1[CH:29]=[CH:28][C:14]([O:15][CH2:16][CH2:17][CH2:18][O:19][C:20]2[CH:21]=[C:22]([NH:23][C:1](=[O:6])[C:2]([O:4][CH3:5])=[O:3])[C:24]([CH3:27])=[CH:25][CH:26]=2)=[C:13]([CH2:30][CH2:31][C:32]([F:34])([F:33])[F:35])[C:12]=1[OH:36])(=[O:10])[CH3:9]
Reactant: CC(=O)c1ccc(OCCCOc2ccc(C)c(N)c2)c(CCC(F)(F)F)c1O
Reactant: COC(=O)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C(=O)Nc1cc(OCCCOc2ccc(C(C)=O)c(O)c2CCC(F)(F)F)ccc1C
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of 1.9 ml (21 mmol) of methyl chlorooxalate in 8 ml of methylene chloride is added dropwise to a solution, cooled to 0°, of 7.5 g of 3-{3-[4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-propoxy}-6-methylaniline and 3.0 g of triethylamine in 60 ml of methylene chloride in the course of about 5 minutes. The reaction mixture is subsequently stirred at room temperature for 90 minutes and poured onto ice-water and the organic phase is separated off. The methylene chloride phase is washed with water, dried over sodium sulfate and concentrated under reduced pressure. Crystallisation of the residue from methylene chloride/ether gives methyl N-{{3-{3-[4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-propoxy}-6-methylphenyl}}-oxamate.
Reaction SMILES: [F:1][C:2]1[N:10]=[C:9](F)[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[NH3:12].O>C(N)=O>[NH2:12][C:9]1[CH:8]=[CH:7][C:3]([C:4]([NH2:6])=[O:5])=[C:2]([F:1])[N:10]=1
Reactant: N
Reactant: NC(=O)c1ccc(F)nc1F
Solvent: NC=O
Solvent: O
Product: NC(=O)c1ccc(N)nc1F
Reaction time: 24 h
Yield: 31 %

Procedure:
A solution of 2,6-difluoronicotinamide (4.68 g, 0.029 mmol) in dry formamide (30 mL) is saturated with ammonia and allowed to stand at room temperature for 24 h. Water (50 mL) is added and the resultant precipitate is filtered off and washed well with water, to give 6-amino-2-fluoronicotinamide (1.41 g, 31%) mp 236-237° C. 1H NMR (DMSO) δ 7.89 (1H, dd, J=10.4, 8.4 Hz), 7.31, 7.16 (1H, 1H, 2 brs,), 6.93 (2H, brs), 6.36 (1H, dd, J=8.4, 2.4 Hz).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[NH:21][C:19]3[C:20]4[C:11](=[N:12][NH:13][C:14](=[O:22])[C:15]=4[CH:16]=[CH:17][CH:18]=3)[CH:10]2[C:23]2[CH:33]=[CH:32][C:26]([C:27]([N:29]([CH3:31])[CH3:30])=[O:28])=[CH:25][CH:24]=2)=[CH:5][CH:4]=1)=O.C(O)(=O)C.[CH3:38][NH:39][CH3:40].[BH4-].[Na+]>C(Cl)Cl>[CH3:38][N:39]([CH2:1][C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[NH:21][C:19]3[C:20]4[C:11](=[N:12][NH:13][C:14](=[O:22])[C:15]=4[CH:16]=[CH:17][CH:18]=3)[CH:10]2[C:23]2[CH:24]=[CH:25][C:26]([C:27]([N:29]([CH3:30])[CH3:31])=[O:28])=[CH:32][CH:33]=2)=[CH:7][CH:8]=1)[CH3:40]
Reactant: CN(C)C(=O)c1ccc(C2c3n[nH]c(=O)c4cccc(c34)NC2c2ccc(C=O)cc2)cc1
Reactant: CNC
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CN(C)Cc1ccc(C2Nc3cccc4c(=O)[nH]nc(c34)C2c2ccc(C(=O)N(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 10 %

Procedure:
To a stirred solution of 4-(8-(4-formylphenyl)-3-oxo-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-9-yl)-N,N-dimethylbenzamide (140 mg, 0.32 mmol) in dried DCM (20 mL) was added acetic acid followed by dimethylamine (57 mg, 1.3 mmol). After the addition, the mixture was stirred at room temperature overnight. Then the mixture was cooled to 0° C. Sodium borohydride (102 mg, 0.48 mmol) was added. After the addition, the mixture was stirred at this temperature for 12 hr. DCM was removed under reduced pressure. The residue was washed with ethyl acetate/methanol (10/1) and filtered. The filtrate was concentrated to give the crude product, which was purified by prep-HPLC to give the title compound as a white solid (15 mg, yield 10%). 1H-NMR (400 MHz, CD3OD) δ (ppm): 2.19 (dd, 6H), 2.93 (s, 3H), 3.06 (s, 3H), 3.40 (dd, 2H), 4.34 (d, 1H), 4.16-7.19 (m, 5H), 7.23-7.26 (m, 4H), 7.54 (d, 1H), 7.61 (t, 1H). LC-MS (ESI) m/z: 468(M+1)+.
Reaction SMILES: Cl.[NH2:2][C:3]([CH3:10])([CH3:9])[C:4]([O:6][CH2:7][CH3:8])=[O:5].C(=O)([O-])[O-].[K+].[K+].[Cl:17][CH2:18][CH2:19][CH2:20]I.O>CN(C=O)C>[Cl:17][CH2:18][CH2:19][CH2:20][NH:2][C:3]([CH3:10])([CH3:9])[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: ClCCCI
Reactant: CCOC(=O)C(C)(C)N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(C)(C)NCCCCl
Reaction time: 8 h
Yield: 102.5 %

Procedure:
A solution of ethyl aminoisobutyrate hydrochloride (10 g) in DMF (50 mL) was cooled to 0° C. To the solution were added potassium carbonate (18 g) and 1-chloro-3-iodopropane (12 g), and the mixture was stirred overnight at 0° C. to room temperature. Water was added to the reaction solution and the mixture was extracted with ethyl acetate toluene organic layer was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to give 12.5 g of crude ethyl 2-(3-chloropropylamino)isobutyrate.
Reaction SMILES: [SH:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1.C[O-].[Na+].CO.[NH2:16][S:17]([CH2:20][CH2:21][CH2:22]I)(=[O:19])=[O:18]>CO>[S:17]([CH2:20][CH2:21][CH2:22][S:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1)(=[O:19])(=[O:18])[NH2:16]
Reactant: Sc1ccc2nccn2n1
Reactant: NS(=O)(=O)CCCI
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: NS(=O)(=O)CCCSc1ccc2nccn2n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 59.2 %

Procedure:
6-Mercaptoimidazo[1,2-b]pyridazine (1.5 g) and 28 W/W % sodium methoxide-methanol solution (2.1 g) were stirred in 30 ml of methanol at 50° C. for 3 hours. The mixture was cooled to room temperature, 3.0 g of 3-aminosulfonyl-1-iodopropane were added and stirred at room temperature for 1.5 hours. The mixture was distilled to remove the solvent and the residue was subjected to a silica gel chromatography, which was eluted with successive 2 V/V % methanol-chloroform, 2.5 V/V % methanol-chloroform and 3.2 V/V % methanol-chloroform. The fractions containing the object compound were collected and concentrated. The precipitate was collected by filtration, thereby yielding 1.6 g of 6-(3-sulfamoyl-propylthio)imidazo [1,2-b]pyridazine.
Reaction SMILES: O.[Cl:2][C:3]1[N:8]=[CH:7][C:6]([CH2:9][NH2:10])=[CH:5][CH:4]=1.[CH2:11]1[C:16](=[O:17])[O:15][CH2:14][C:12]1=O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Cl:2][C:3]1[N:8]=[CH:7][C:6]([CH2:9][NH:10][C:12]2[CH2:14][O:15][C:16](=[O:17])[CH:11]=2)=[CH:5][CH:4]=1
Reactant: O=C1COC(=O)C1
Reactant: NCc1ccc(Cl)nc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: O=C1C=C(NCc2ccc(Cl)nc2)CO1

Procedure:
On a water separator, 5.00 g (35.1 mmol) of 1-(6-chloropyridin-3-yl)methylamine, 3.51 g (35.1 mmol) of tetronic acid and 20 mg (0.12 mmol) of 4-toluenesulphonic acid in 200 ml of toluene are heated under reflux for 24 hours. The reaction mixture is concentrated, and the residue that remains is then purified by column chromatography on silica gel (silica gel 60—Merck, particle size: 0.04 to 0.063 mm) using the mobile phase ethyl acetate. This gives 4.96 g (63% of theory) of 4-[[(6-chloropyridin-3-yl)methyl]amino]furan-2(5H)-one, which can be used for subsequent reactions.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:10])[CH:9]=1)[CH:5]=O.[CH2:11]([NH2:14])[CH2:12][NH2:13].[BH4-].[Na+].C(NCCN)C1C=CC=CC=1>CO>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:10])[CH:9]=1)[CH2:5][NH:13][CH2:12][CH2:11][NH2:14]
Reactant: O=Cc1cc(F)cc(F)c1
Reactant: NCCN
Agent: NCCNCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: NCCNCc1cc(F)cc(F)c1
Yield: 55 %

Procedure:
At 16.77 g (0.118 mol) quantity of 3,5-difluorobenzaldehyde was treated with 50 ml ethylenediamine and 4.47 g (0.118 mol) sodium borohydride in 500 ml methanol by the method prescribed for N-benzylethylenediamine (Example 1) to give 12.0 g (55% yield) of desired product, b.p. 90°-92° C. at 199.98-226.65 Nm-2.
Reaction SMILES: [C:1]([SiH2:5][O:6][C:7]([CH3:17])([CH3:16])[C:8]1[CH:9]=[C:10]([CH2:14]O)[CH:11]=[CH:12][CH:13]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:18]([N:20](CC)CC)C.CS(Cl)(=O)=O.[C-]#N.[Na+]>ClCCl.CN(C=O)C>[C:1]([SiH2:5][O:6][C:7]([CH3:17])([CH3:16])[C:8]1[CH:9]=[C:10]([CH2:14][C:18]#[N:20])[CH:11]=[CH:12][CH:13]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCN(CC)CC
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1cccc(CO)c1
Agent: CS(=O)(=O)Cl
Agent: [C-]#N
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)[SiH2]OC(C)(C)c1cccc(CC#N)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.3 %

Procedure:
To a stirred solution of [3-(tert-butyl-dimethyl-silanyloxymethyl)-phenyl]-methanol (10.52 g, 41.67 mmol) in dichloromethane (80 ml) at 0° C. (ice bath), was added triethylamine (8.78 ml, 62.5 mmol) followed by methanesulfonyl chloride (3.87 ml, 50 mmol). After stirring for 2 hr, the reaction mixture was washed with aqueous saturated sodium bicarbonate solution, dried with anhydrous magnesium sulfate, filtered, and evaporated in vacuo to give a pale yellow oil. The crude product was then dissolved in anhydrous DMF (80 ml) and sodium cyanide (6.28 g, 128 mmol) was added into the mixture. The mixture was stirred in an oil bath (60° C.) for 2 hr. After cooling to room temperature, the mixture was partitioned between ether and water. The ether layer was taken, washed with water twice, dried with anhydrous magnesium sulfate, filtered, and evaporated in vacuo. The residue was purified by silica gel column chromatography (eluent, EA: hexanes (from 1:20 to 1:10)) to afford 8.2 g (75%) of a pale yellow oil. 1H NMR (200 MHz, CDCl3) δ 0.11 (6H, s), 0.95 (9H, s), 3.75 (2H, s), 4.75 (2H, s), 7.27-7.35 (4H, m).
Reaction SMILES: OS(O)(=O)=O.[C:6]([O:9][CH:10]=[CH2:11])(=O)[CH3:7].OCC[N:15]1[C:19](=[O:20])[C:18]([CH3:22])([CH3:21])[NH:17][C:16]1=[O:23]>C([O-])(=O)C.[Hg+]>[CH:10]([O:9][CH2:6][CH2:7][N:15]1[C:19](=[O:20])[C:18]([CH3:22])([CH3:21])[NH:17][C:16]1=[O:23])=[CH2:11]
Reactant: CC1(C)NC(=O)N(CCO)C1=O
Reactant: C=COC(C)=O
Agent: CC(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Hg+]
Product: C=COCCN1C(=O)NC(C)(C)C1=O
Yield: 57.5 %

Procedure:
The same compound may also be obtained as follows: 0.3 g of H2SO4 is added dropwise, with vigorous stirring, to 400 ml of freshly distilled vinyl acetate, 0.002 g of Cu resinate and 0.96 g of mercury acetate, at -25° C., in a 1 litre round-bottomed flask. 41.4 g of 3-hydroxyethyl-5,5-dimethyl-hydantoin are then added, with brief stirring, under conditions such that the temperature in the flask does not rise above -20°. The resulting dispersion is kept at a temperature between -20° C. and -30° C., with slow stirring, and after 16 hours the undissolved alcohol (5.2 g) is filtered off, the solution is poured into ice water which contains sufficient sodium carbonate that the pH value resulting after addition of the solution is 8 or above, and finally the organic phase is separated from the aqueous phase, washed twice with water, dried over sodium sulphate and concentrated on a rotary evaporator. 27.4 g (= 57.5% of theory) of 3-vinyloxyethyl-5,5-dimethyl-hydantoin are obtained.
Reaction SMILES: Br[C:2]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:3]=1[O:4][CH2:5][C:6]([N:8]([CH:18]([CH3:20])[CH3:19])[NH:9][C:10](=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7].C([O-])([O-])=O.[Na+].[Na+].[C:32]1([CH3:41])[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1B(O)O>COCCOC>[F:25][C:23]1[CH:22]=[CH:21][C:3]([O:4][CH2:5][C:6]([N:8]([CH:18]([CH3:20])[CH3:19])[NH:9][C:10](=[O:17])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:7])=[C:2]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=2[CH3:41])[CH:24]=1
Reactant: CC(C)N(NC(=O)c1ccccc1)C(=O)COc1ccc(F)cc1Br
Reactant: Cc1ccccc1B(O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Cc1ccccc1-c1cc(F)ccc1OCC(=O)N(NC(=O)c1ccccc1)C(C)C
Yield: 44.8 %

Procedure:
A solution of benzoic acid N′-[2-(2-bromo-4-fluoro-phenoxy)-acetyl]-N′-isopropyl-hydrazide (50 mg, 0.122 mmol) in DME (3 ml)/2M Na2CO3 (0.215 ml, 0.427 mmol) was treated with 2-tolylboronic acid (25 mg, 0.183 mmol) and Pd[PPh3]4 (28 mg, 0.024 mmol) for 12 hours at 90° C. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude was absorbed on silica and purified on a silica gel column with a 30-50% ethyl acetate/hexanes gradient to afford the product as a beige solid (23 mg, 44%). LC-MS m/e 421.31 (M+H+)
Reaction SMILES: [CH:1]1[C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][C:11](=[O:12])[C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:13](=O)([O:16]C)[O:14][CH3:15].[H-].[Na+].Cl>O1CCCC1.O>[O:12]=[C:11]1[CH:10]([C:13]([O:14][CH3:15])=[O:16])[CH2:9][CH2:8][CH2:7][C:6]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]1=2
Reactant: O=C1CCCCc2ccccc21
Reactant: COC(=O)OC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)C1CCCc2ccccc2C1=O

Procedure:
To a solution of 6,7,8,9-tetrahydro-5H-benzo[a]cyclohepten-5-one (24.99 g, 156.0 mmol) and dimethyl carbonate (42.2 g, 468 mmol) in tetrahydrofuran (150 ml) was added a suspension (12.5 g, 312 mmol) of 60% sodium hydride in liquid paraffin at room temperature and the mixture was heated under reflux for 1 hr. The reaction solution was poured into water, acidified with 1N hydrochloric acid and extracted twice with ethyl acetate. The collected organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=15/1) to give methyl 5-oxo-6,7,8,9-tetrahydro-5H-benzo[a]cycloheptene-6-carboxylate as a yellow liquid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][NH:9][CH2:10][CH2:11][OH:12])=[CH:4][CH:3]=1.[CH3:13][O:14][CH2:15][CH2:16]Br.C(N(C(C)C)CC)(C)C>O1CCOCC1>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]([CH2:16][CH2:15][O:14][CH3:13])[CH2:10][CH2:11][OH:12])=[CH:4][CH:3]=1
Reactant: OCCNCc1ccc(Cl)nc1
Reactant: COCCBr
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: COCCN(CCO)Cc1ccc(Cl)nc1
Temperature: 95 °C
Yield: 58.6 %

Procedure:
A stirred mixture of 6.0 grams (0.03 mole) of 2-{[(6-chloro(3-pyridyl))methyl]amino}ethan-1-ol (known compound), 4.6 grams (0.033 mole) of 2-bromoethyl methyl ether and 5.8 grams (0.045 mole) if diisopropylethylamine in 120 mL of 1,4-dioxane was heated at 95° C. for 36 hours. After this time the reaction mixture was cooled to ambient temperature and was concentrated under reduced pressure to a residue. The residue was purified by column chromatography on silica gel, eluting with a mixture of methanol and methylene chloride. The appropriate fractions were combined and concentrated under reduced pressure, yielding 4.3 grams of 2-{[(6-chloro(3-pyridyl))methyl](2-methoxyethyl)amino}ethan-1-ol as an oil. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:11]=[C:12]([N:17]2[CH2:22][CH2:21][C:20](=O)[CH2:19][CH2:18]2)[CH:13]=[CH:14][C:15]=1[Cl:16].[NH:24]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[N:24]1([CH:20]2[CH2:21][CH2:22][N:17]([C:12]3[CH:13]=[CH:14][C:15]([Cl:16])=[C:10]([C:2]4[NH:3][C:4]5[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=5[N:1]=4)[CH:11]=3)[CH2:18][CH2:19]2)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: C1CCCNCC1
Reactant: O=C1CCN(c2ccc(Cl)c(-c3nc4ccccc4[nH]3)c2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: Clc1ccc(N2CCC(N3CCCCCC3)CC2)cc1-c1nc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.2 %

Procedure:
To a suspension of 1-[3-(1H-benzoimidazol-2-yl)-4-chloro-phenyl]-piperidin-4-one (0.10 g, 0.31 mmol) in dichloromethane (2 mL) was added azepane (0.05 mL, 0.46 mmol). After 30 min stirring at room temperature a drop of acetic acid was added, and after 1 h a further aliquot of azepane (0.05 mL, 0.46 mmol) was added, followed by sodium triacetoxyborohydride (NaB(OAc)3H) (0.10 g, 0.46 mmol). The reaction mixture was stirred at room temperature overnight, then the solvent was removed under reduced pressure, and the crude product dissolved in dichloromethane (10 mL). To the solution PS-isocyanate resin (PS-NCO) (Argonaut, loading 0.93 mmol/g) was added, then the mixture was shaken at room temperature overnight and filtered. The solvent was removed under reduced pressure to obtain a solid residue that was washed with EtOAc and Et2O then dried to give the desired product (0.07 g, 58%).
Reaction SMILES: [H-].[Na+].CN(C)C=O.[OH:8][C:9]1[C:10]([I:17])=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH:12]=[O:13].Br[CH2:19][C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[CH2:21]>CCOCC>[I:17][C:10]1[C:9]([O:8][CH2:21][C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH2:19])=[CH:16][CH:15]=[CH:14][C:11]=1[CH:12]=[O:13]
Reactant: O=Cc1cccc(O)c1I
Reactant: C=C(CBr)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: C=C(COc1cccc(C=O)c1I)c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
6.72 g (0.28 mmol) of sodium hydride are dissolved in 660 ml of ether and 120 ml of dimethylformamide under argon, and 64.1 g (0.26 mol) of 3-hydroxy-2-iodobenzaldehyde in 65 ml of ether are slowly added. After the mixture has been stirred at room temperature for 15 minutes, 61 g (0.28 mol) of 3-bromo-2-phenyl-1-propene, dissolved in 60 ml of ether, are added dropwise and the mixture is stirred overnight.
Reaction SMILES: [CH:1]12[CH:7]([C:8]([OH:10])=O)[CH:4]([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[NH2:11][C@H:12]1[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[CH2:13]1>>[F:25][C:22]1[CH:23]=[CH:24][C:19]([CH2:18][CH2:17][N:14]2[CH2:15][CH2:16][C@H:12]([NH:11][C:8]([CH:7]3[CH:4]4[CH2:3][CH2:2][CH:1]3[CH2:6][CH2:5]4)=[O:10])[CH2:13]2)=[CH:20][CH:21]=1
Reactant: O=C(O)C1C2CCC1CC2
Reactant: N[C@H]1CCN(CCc2ccc(F)cc2)C1
Product: O=C(N[C@H]1CCN(CCc2ccc(F)cc2)C1)C1C2CCC1CC2

Procedure:
7-Norbornanecarboxylic acid and (S)-3-amino-1-(2-(4-fluorophenyl)ethyl)pyrrolidine were reacted under the same conditions as in Example 23 to give (S)-N-(1-(2-(4-fluorophenyl)ethyl)pyrrolidin-3-yl)-7-norbornanecarboxamide.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[CH:8]=2)[N:6]=1.[N:15]1([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:14][O:13][C:9]1[CH:8]=[C:7]([C:5]2[N:6]=[C:2]([N:18]3[CH2:17][CH2:16][N:15]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:20][CH2:19]3)[S:3][CH:4]=2)[CH:12]=[CH:11][CH:10]=1
Reactant: COc1cccc(-c2csc(Br)n2)c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cccc(-c2csc(N3CCN(C(=O)OC(C)(C)C)CC3)n2)c1
Yield: 51.1 %

Procedure:
A solution of 2-bromo-4-(3-methoxyphenyl)-1,3-thiazole (3.70 g, 13.7 mmol), tert-butyl piperazine-1-carboxylate (3.83 g, 20.5 mmol) and potassium carbonate (1.89 g, 13.7 mmol) in dimethylformamide (50 ml) was stirred at 120° C. for 7 hours. Water was poured to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to give 2.63 g (51.2%) of the desired product as a solid.
Reaction SMILES: C([NH:4][C:5]1[N:9]([C:10]2[CH:15]=[C:14]([S:16][CH2:17][C:18]([F:21])([F:20])[F:19])[C:13]([CH3:22])=[CH:12][C:11]=2[F:23])[N:8]=[C:7]([O:24][C:25]([F:33])([F:32])[CH:26]([F:31])[C:27]([F:30])([F:29])[F:28])[CH:6]=1)(=O)C.S(=O)(=O)(O)O>C(O)C.O>[NH2:4][C:5]1[N:9]([C:10]2[CH:15]=[C:14]([S:16][CH2:17][C:18]([F:20])([F:21])[F:19])[C:13]([CH3:22])=[CH:12][C:11]=2[F:23])[N:8]=[C:7]([O:24][C:25]([F:32])([F:33])[CH:26]([F:31])[C:27]([F:28])([F:29])[F:30])[CH:6]=1
Reactant: CC(=O)Nc1cc(OC(F)(F)C(F)C(F)(F)F)nn1-c1cc(SCC(F)(F)F)c(C)cc1F
Agent: O=S(=O)(O)O
Solvent: CCO
Solvent: O
Product: Cc1cc(F)c(-n2nc(OC(F)(F)C(F)C(F)(F)F)cc2N)cc1SCC(F)(F)F
Temperature: 25 °C
Yield: 81.7 %

Procedure:
1.2 g of 5-acetylamino-1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl}-3-(1,1,2,3,3,3-hexafluoropropoxy)pyrazole was dissolved in 50 mL of ethanol, and an aqueous solution comprising 0.5 g of concentrated sulfuric acid in 2.0 mL of water was added, followed by reflux with heating for 6 hours. After cooling to room temperature, the solvent was distilled off under reduced pressure, and extraction with ethyl acetate was carried out. The organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (developing solvent ethyl acetate:hexane=1:4) to obtain 0.9 g of 5-amino-1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl}-3-(1,1,2,3,3,3-hexafluoropropoxy)pyrazole.