Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][N:9]=[C:10]2[CH2:15][CH2:14][CH2:13][CH2:12][C:11]2=[N:16][OH:17])=[CH:4][CH:3]=1.N1C=CC=CC=1.O1CCCC1>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[N+:16]([O-:17])=[C:11]3[CH2:12][CH2:13][CH2:14][CH2:15][C:10]3=[N:9]2)=[CH:6][CH:7]=1
Reactant: ON=C1CCCCC1=NNc1ccc(Cl)cc1
Solvent: O
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: [O-][n+]1c2c(nn1-c1ccc(Cl)cc1)CCCC2
Yield: 12.6 %

Procedure:
To a solution of 2-(4-chlorophenylhydrazono)cyclohexanone oxime (1.6 g) in a mixture of 15% aqueous solution of pyridine (25 ml) and tetrahydrofuran (20 ml), a solution of cupric sulfate (CuSO4.5H2O) (2.5 g) in water (10 ml) was added at room temperature, and the resultant mixture was heated under reflux for 2 hours. After cooling, water was added to the mixture, which was then extracted with ethyl acetate. The extract was washed with a saturated aqueous cupric sulfate solution and water in order, dried and concentrated. The residue was purified by silica gel column chromatography using a mixture of n-hexane and ethyl acetate as an eluent to give 0.2 g of 2-(4-chlorophenyl)-4,5,6,7-tetrahydro-1,2,3-benzotriazol-1-oxide (Compound No. 1). M.P., 100°-101° C.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C(Cl)=O.[CH3:23][NH2:24]>C(Cl)Cl.CCOCC>[CH3:23][NH:24][C:14](=[O:16])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)CCCCCCCc1ccccc1
Reactant: CN
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCOCC
Product: CNC(=O)CCCCCCCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83 %

Procedure:
To a solution of 8-phenyl octanoic acid (28.6 g, 129.8 mmol, 1 eq) in CH2Cl2 (100 mL) cooled to 0° C. was added oxalyl chloride (17 mL, 195 mmol, 1.5 eq) dropwise via an addition funnel over 30 minutes. Upon the completion of the addition, the ice bath was removed and the reaction was stirred at rt for 2 h. It was then heated at reflux for 30 minutes. The reaction was cooled to rt and concentrated in vacuo to afford a yellow oil. It was added as a solution in Et2O (100 mL) to a solution of condensed methyl amine (˜20 mL) in Et2O (200 mL) at −78° C. Immediately, a white precipitate formed. The cold bath was removed and the reaction was allowed to stir overnight warming to rt under a stream of N2. The residue was washed with Et2O and concentrated to afford N-methyl-8-phenyloctanamide (25.2 g, 83%) as a yellow-white solid. 1H NMR.(CDCl3) δ 7.68-7.10 (m, 5H); 5.42 (bs, 1H); 3.80 (m, 3H); 2.60 (m, 2H); 2.18 (m, 2H); 1.60 (m, 4H); 1.30 (m, 8H).
Reaction SMILES: [N:1]([CH2:4][C:5]([C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][N:9]=1)([F:7])[F:6])=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH-].[NH4+].[OH-].[Na+]>C1COCC1>[F:7][C:5]([F:6])([C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][N:9]=1)[CH2:4][NH2:1]
Reactant: [N-]=[N+]=NCC(F)(F)c1ccc(Cl)cn1
Agent: [NH4+]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: NCC(F)(F)c1ccc(Cl)cn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 93.7 %

Procedure:
To a solution of 2-(2-Azido-1,1-difluoro-ethyl)-5-chloro-pyridine (1.94 g, 8.87 mmol) (prepared essentially as described for Example 14b) in THF (30 mL) cooled in an ice bath were added triphenylphosphine pellets (2.6 g, 9.76 mmol). The mixture was stirred at room temperature for 16 h. Ammonium hydroxide solution (10 mL) was added to the mixture followed by additional stirring for 4 h. NaOH solution (3 N, 40 mL) was then added and the mixture was heated at 40° C. for 1 h. The organic layer was separated and washed with HCl solution (2 N, 60 mL). The aqueous layer was then basified with 4 N NaOH solution and extracted with EtOAc twice. The solvent was evaporated to leave a pale yellow oil (1.6 g, 93% yield). 1H NMR (300 Hz, CDCl3) δ 8.59 (d, 1H), 7.78 (dd, 1H), 7.62 (d, 1H), 3.40 (t, 2H); LC/MS (m/z) [M+1]+ 193.0 (calculated for C7H7ClF2N2, 192.0).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[S:19][C:20]([C:24](O)=[O:25])=[C:21]([CH3:23])[N:22]=3)[CH2:14][C@H:13]2[O:27][CH3:28])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].Cl.[CH3:30][NH:31][CH3:32].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C>CC(N(C)C)=O.ClCCl>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[S:19][C:20]([C:24]([N:31]([CH3:32])[CH3:30])=[O:25])=[C:21]([CH3:23])[N:22]=3)[CH2:14][C@H:13]2[O:27][CH3:28])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CNC
Reactant: CCc1[nH]c(C(=O)N[C@H]2CCN(c3nc(C)c(C(=O)O)s3)C[C@H]2OC)nc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC(=O)N(C)C
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCc1[nH]c(C(=O)N[C@H]2CCN(c3nc(C)c(C(=O)N(C)C)s3)C[C@H]2OC)nc1Cl
Yield: 65.9 %

Procedure:
The same operation as in Example (1g) was performed using cis(±)-2-(4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl)-4-methyl-1,3-thiazole-5-carboxylic acid obtained in Example (14a) (40 mg, 0.09 mmol), dimethylamine hydrochloride (9 mg, 0.11 mmol), WSC hydrochloride (59 mg, 0.31 mmol), HOBT (21 mg, 0.15 mmol), diisopropylethylamine (0.020 mL, 0.11 mmol), dichloromethane (0.75 mL) and DMA (0.75 mL), to obtain 27 mg of the title compound as a yellow oily substance (62%).
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(O[C:12](=[O:15])[CH2:13][Cl:14])C.Cl>CCOCC>[Cl:14][CH2:13][C:12]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[OH:15]
Reactant: CCOC(=O)CCl
Reactant: Brc1ccccc1
Agent: Cl
Agent: [Mg]
Solvent: CCOCC
Product: OC(CCl)(c1ccccc1)c1ccccc1
Reaction time: 1 h

Procedure:
15 g of magnesium chips are reacted with 94.2 g of bromobenzene in 250 ml of absolute ether at 30° to 35° C., followed by the dropwise addition over a period of 30 minutes at 0° to 10° C. of 24.5 g of chloroacetic acid ethyl ester. After stirring for 1 hour, the reaction mixture is poured onto ice, acidified with dilute hydrochloric acid and extracted by shaking with methylene chloride. The organic phase is washed twice with water, subsequently dried over sodium sulphate and concentrated in vacuo. The oily residue is distilled in a high vacuum at 135°-140° C./0.03 Torr. 2-Chloro-1,1-diphenyl-ethan-1-ol melting at 64° to 66° C. is obtained in a yield of 32.8 g.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[Cl:11][C:12]1[C:17]([O:18][CH:19]([CH3:21])[CH3:20])=[C:16]([C:22](OC)=[O:23])[CH:15]=[C:14]([CH:26]2[CH2:28][CH2:27]2)[C:13]=1[C:29]1[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=1.O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>C1COCC1>[Cl:11][C:12]1[C:17]([O:18][CH:19]([CH3:21])[CH3:20])=[C:16]([CH2:22][OH:23])[CH:15]=[C:14]([CH:26]2[CH2:28][CH2:27]2)[C:13]=1[C:29]1[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=1
Reactant: COC(=O)c1cc(C2CC2)c(-c2ccc(F)cc2)c(Cl)c1OC(C)C
Agent: CC(C)C[Al+]CC(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)Oc1c(CO)cc(C2CC2)c(-c2ccc(F)cc2)c1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.6 %

Procedure:
Diisobutyl aluminum hydride (1.5 M toluene solution, 19.0 mL) was added at 0° C. to a mixture of methyl 2-chloro-6-cyclopropyl-4′-fluoro-3-isopropoxybiphenyl-4-carboxylate (3.45 g) and THF (40 mL), and the resultant mixture was stirred at the same temperature as above for 20 minutes in a nitrogen atmosphere. Sodium sulfate decahydrate was added to the reaction mixture, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was filtered, and then, the solvent in the filtrate was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (2.82 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]2[CH2:16][O:15]2)=[CH:4][CH:3]=1.[F:17][C:18]([F:28])([F:27])[C:19]1[CH:20]=[C:21]([CH2:25][SH:26])[CH:22]=[CH:23][CH:24]=1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([OH:15])[CH2:16][S:26][CH2:25][C:21]2[CH:22]=[CH:23][CH:24]=[C:19]([C:18]([F:17])([F:27])[F:28])[CH:20]=2)=[CH:4][CH:3]=1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C1CO1
Reactant: FC(F)(F)c1cccc(CS)c1
Product: Cc1noc(-c2ccc(Br)cc2)c1C(O)CSCc1cccc(C(F)(F)F)c1

Procedure:
Prepared according to the procedure described in Example 58, Step 1, using 5-(4-bromo-phenyl)-3-methyl-4-oxiranyl-isoxazole and (3-trifluoromethyl-phenyl)-methanethiol.
Reaction SMILES: I[C:2]1[C:10]2[CH:9]=[N:8][CH:7]=[N:6][C:5]=2[N:4]([C:11]2([CH2:14][O:15][CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][O:17]3)[CH2:13][CH2:12]2)[CH:3]=1.C([Li])CCC.[Br:27][C:28]1[CH:29]=[N:30][CH:31]=[C:32]([CH:39]=1)[C:33](N(OC)C)=[O:34]>C(OCC)C>[Br:27][C:28]1[CH:39]=[C:32]([C:33]([C:2]2[C:10]3[CH:9]=[N:8][CH:7]=[N:6][C:5]=3[N:4]([C:11]3([CH2:14][O:15][CH:16]4[CH2:21][CH2:20][CH2:19][CH2:18][O:17]4)[CH2:13][CH2:12]3)[CH:3]=2)=[O:34])[CH:31]=[N:30][CH:29]=1
Reactant: CON(C)C(=O)c1cncc(Br)c1
Reactant: Ic1cn(C2(COC3CCCCO3)CC2)c2ncncc12
Agent: [Li]CCCC
Solvent: CCOCC
Product: O=C(c1cncc(Br)c1)c1cn(C2(COC3CCCCO3)CC2)c2ncncc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 35 %

Procedure:
To a stirred solution of 5-Iodo-7-[1-(tetrahydro-pyran-2-yloxymethyl)-cyclopropyl]-7H-pyrrolo[2,3-d]pyrimidine (Preparation 249, 450 mg, 1.13 mmol) in diethyl ether (6 mL) was added n-butyl lithium (2M in hexane, 0.62 mL, 1.24 mmol) drop wise at −70° C. Then a solution of 5-Bromo-N-methoxy-N-methyl-nicotinamide (304 mg, 1.24 mmol) in diethyl ether (2.5 mL) was added drop wise at −70° C. and stirred at same temperature for another 30 minutes. The reaction was allowed to warm to room temperature slowly. The reaction was quenched with saturated aqueous ammonium chloride solution (10 mL) and extracted with ethyl acetate (3×20 mL). The combined organic layer was washed with water (20 mL), brine (20 mL), dried over sodium sulphate and evaporated in vacuo. The crude material was purified by column chromatography on silica gel (gradient of dichloromethane:methanol 100:0 to 98:2) to afford the title compound as a light brown sticky solid in 35% yield, 250 mg.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[C:6]2[CH:16]=[CH:15][C:14]([O:17]C)=[CH:13][C:7]=2[O:8][C:9]=1[CH:10]([CH3:12])[CH3:11])=[O:4].B(Br)(Br)Br>>[CH3:1][NH:2][C:3]([C:5]1[C:6]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][C:7]=2[O:8][C:9]=1[CH:10]([CH3:12])[CH3:11])=[O:4]
Reactant: CNC(=O)c1c(C(C)C)oc2cc(OC)ccc12
Agent: BrB(Br)Br
Product: CNC(=O)c1c(C(C)C)oc2cc(O)ccc12

Procedure:
This material was prepared from 6-methoxy-2-(1-methylethyl)benzo[b]furan-3-carboxylic acid methylamide 15b (173 mg, 0.84 mmole) by treatment with BBr3 in a manner as previously described for example 1d to give 157 mg (80%) of a crisp foam. 1H NMR (DMSO-d6) δ9.54 (1H, s), 7.76 (1H, d, J=4.6 Hz), 7.45 (1H, d, J=8.6 Hz), 6.88 (1H, d, J=2.0 Hz), 6.74 (1H, dd, J=2.0, 8.6 Hz), 3.68-3.61 (1H, m), 2.75 (3H, d, J=4.6 Hz), 1.24 (6H, d, J=7.1 Hz).
Reaction SMILES: [C:1]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])(=[O:6])[CH2:2][C:3]([O-:5])=O.[Cl-].[Mg+2].[Cl-].[CH3:15][C:16]1([CH3:26])[O:20][C:19](=[O:21])[CH:18]([CH2:22]C(O)=O)[O:17]1.C(N1C=CN=C1)(N1C=CN=C1)=O>O1CCCC1.CN(C)C=O.C(N(CC)CC)C>[CH3:15][C:16]1([CH3:26])[O:20][C:19](=[O:21])[CH:18]([CH2:22][C:3](=[O:5])[CH2:2][C:1]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6])[O:17]1
Reactant: CC1(C)OC(=O)C(CC(=O)O)O1
Reactant: CC(C)(C)OC(=O)CC(=O)[O-]
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Cl-]
Agent: [Mg+2]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)CC(=O)CC1OC(C)(C)OC1=O
Yield: 77.2 %

Procedure:
132 g of mono-tert-butyl malonate was dissolved in 1.5 l of tetrahydrofuran, and 49.2 g of magnesium chloride and 134 ml of triethylamine were added thereto with stirring under cooling with ice. The mixture was stirred at room temperature for 3 hours. Added to this solution was a liquid separately prepared by stirring 60.0 g of 2,2-dimehtyl-1,3-dioxolan-4-on-5-ylacetic acid (Tetrahedron Letter, vol. 28, p. 1685 (1987)) in a liquid mixture of 500 ml of tetrahydrofuran and 100 ml of dimethylformamide together with 64.2 g of 1,1'-carbonyldiimidazole at room temperature for 2 hours. The mixture was stirred at room temperature overnight. Insoluble matters were separated by filtration. Then, the filtrate was evaporated to dryness under reduced pressure. The residue was dissolved in a liquid mixture of ethyl ether and water and then adjusted to pH 3 to 4 by an addition of 1N hydrochloric acid. The organic layer was collected by separation, then washed with a saturated sodium chloride aqueous solution and dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure. The residue was dissolved in ethyl acetate and then passed through a column of 300 g of activated aluminum oxide. The solution passed through the column was evaporated to dryness under reduced pressure to obtain 72.4 g (yield: 77%) of tert-butyl 4-(2,2-dimethyl-1,3-dioxolan-4-on-5-yl)-3-oxobutyrate.
Reaction SMILES: [CH3:1][S:2][C:3]1[C:11]2[C:6](=[CH:7][C:8]([NH2:12])=[CH:9][CH:10]=2)[N:5]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:4]=1.[C:19]([O:23][C:24]([N:26]1[CH2:29][CH:28]([C:30](O)=[O:31])[CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O.C(N(CC)CC)C>[CH3:1][S:2][C:3]1[C:11]2[C:6](=[CH:7][C:8]([NH:12][C:30]([CH:28]3[CH2:29][N:26]([C:24]([O:23][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:25])[CH2:27]3)=[O:31])=[CH:9][CH:10]=2)[N:5]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:4]=1
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)O)C1
Reactant: CSc1nn(-c2ccccc2)c2cc(N)ccc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CSc1nn(-c2ccccc2)c2cc(NC(=O)C3CN(C(=O)OC(C)(C)C)C3)ccc12
Temperature: 15 °C
Reaction time: 2 h

Procedure:
Into a 50-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 3-(methylthio)-1-phenyl-1H-indazol-6-amine (500 mg, 1.96 mmol, 1.00 equiv) in N,N-dimethylformamide (5 mL), triethylamine (0.5 mL), 1-(tert-butoxycarbonyl)azetidine-3-carboxylic acid (470 mg, 2.34 mmol, 1.19 equiv), HATU (2.235 g, 5.88 mmol, 3.00 equiv). The resulting solution was stirred for 2 h at 15° C. The solids were filtered out. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:5˜1:3) to yield tert-butyl 3-((3-(methylthio)-1-phenyl-1H-indazol-6-yl)carbamoyl)azetidine-1-carboxylate as a white solid. MS: 439 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[Cl:9])[NH2:5].Cl[CH2:11][C:12]([OH:14])=[O:13]>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][CH2:11][C:12]([OH:14])=[O:13])[CH:6]=[CH:7][C:8]=1[Cl:9]
Reactant: Nc1ccc(Cl)c(Cl)c1
Reactant: O=C(O)CCl
Product: O=C(O)CNc1ccc(Cl)c(Cl)c1

Procedure:
Using the procedure set forth in U.S. Pat. No. 3,598,859, N-(3,4-dichlorophenyl)glycine was prepared using 3,4-dichloroaniline (Aldrich) and 2-chloroacetic acid (Aldrich).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:18])([CH2:16][NH2:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:18])([CH2:16][NH:17][S:27]([C:24]1[CH:23]=[CH:22][C:21]([O:20][CH3:19])=[CH:26][CH:25]=1)(=[O:29])=[O:28])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1
Reactant: NCC(O)(Cn1cncn1)c1ccc(Cl)cc1Cl
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Product: COc1ccc(S(=O)(=O)NCC(O)(Cn2cncn2)c2ccc(Cl)cc2Cl)cc1

Procedure:
Following the procedure described in the preceeding examples but using 2-(2,4-dichlorophenyl)-3-amino-1-(1H-1,2,4-triazol-1-yl)propan-2-ol and p-methoxybenzenesulfonylchloride, the title compound was obtained in a similar yield: mp 56°-66° C.; 1H NMR (80 MHz, CDCl3)δ(TMS) 8.0-7.5 (m, 4H, arom), 7.3-6.9 (m, 3H, arom.), 5.24 (br s, 1H, NH), 4.96 (AB system, Δv=0.52, J=14.5 Hz, 2H, CH2 -Tr), 3.85 (s, 3H, OMe), 3.55 (dq, Jd =5.2 Hz, Jq =J=14 Hz, 2H, CH2NH), 2.16 (s, 1H, N=CH), 2.03 (s, 1H, N=CH). Anal calcd. for C18H18Cl2N4O4S: C 47.27%; H 3.97%; N 12.25 %. Found: C 47.56%; H 4.08%; N 12.09%.
Reaction SMILES: [Br:1][C:2]1[C:10]2[NH:9][N:8]=[CH:7][C:6]=2[C:5]2[CH2:11][O:12][C:13](=[O:21])[C@H:14]([CH2:16][C:17]([O:19]C)=[O:18])[CH2:15][C:4]=2[CH:3]=1.[OH2:22].O.[OH-].[Li+]>O1CCCC1.CO>[Br:1][C:2]1[CH:3]=[C:4]([CH2:15][C@@H:14]([CH2:16][C:17]([OH:19])=[O:18])[C:13]([OH:12])=[O:21])[C:5]([CH2:11][OH:22])=[C:6]2[C:10]=1[NH:9][N:8]=[CH:7]2
Reactant: O
Reactant: COC(=O)C[C@@H]1Cc2cc(Br)c3[nH]ncc3c2COC1=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)C[C@H](Cc1cc(Br)c2[nH]ncc2c1CO)C(=O)O
Temperature: 25 °C
Reaction time: 5 h
Yield: 73 %

Procedure:
(S)-Methyl 2-(4-bromo-8-oxo-6,7,8,10-tetrahydro-3H-oxepino[3,4-e]indazol-7-yl)acetate (135 mg, 0.368 mmol) was dissolved in a mixture of tetrahydrofuran (4.0 mL) and methanol (4.0 mL). Water (4.0 mL) was added to the mixture followed by lithium hydroxide hydrate (31.5 mg, 0.751 mmol). Reaction stirred at room temperature for 5 hours. Another 30 mg of lithium hydroxide hydrate was added to the mixture. Reaction stirred at room temperature for 18 hours. Reaction was quenched with 1.6 mL 1N hydrochloric acid. Organic solvents were removed from the mixture by roto-vap. Material was extracted from the remaining aqueous twice with ethyl acetate and the aqueous phase was discarded. Organics were dried MgSO4, filtered and then concentrated to dryness. Title compound was obtained as white solid in 73% yield. MS (M−H)−=355.2, 357.1.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:7](Br)[C:8]#[CH:9]>C(OCC)C>[CH2:9]([N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[C:8]#[CH:7]
Reactant: C#CCBr
Reactant: C1CCNCC1
Solvent: CCOCC
Product: C#CCN1CCCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of piperidine (8.5 ml) in diethyl ether (100 ml) was added propargyl bromide (3 ml) on an ice bath, the solution was stirred overnight at room temperature, then diethyl ether was added thereto followed by filtering, and the solvent was evaporated in vacuo to provide the title compound (6.0 g).
Reaction SMILES: [C:1]([CH2:3][N:4]1[CH2:9][CH2:8][CH:7]([C:10](=[O:18])[C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[CH2:6][CH2:5]1)#[N:2].[ClH:19].[H][H]>C(O)(=O)C.[Pt]=O>[ClH:19].[NH2:2][CH2:1][CH2:3][N:4]1[CH2:5][CH2:6][CH:7]([C:10](=[O:18])[C:11]2[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=2)[CH2:8][CH2:9]1
Reactant: [H][H]
Reactant: N#CCN1CCC(C(=O)c2ccc(F)cc2)CC1
Agent: O=[Pt]
Agent: Cl
Solvent: CC(=O)O
Product: NCCN1CCC(C(=O)c2ccc(F)cc2)CC1
Reaction time: 6 h

Procedure:
14.1 g (0.05 mol) of N-(cyanomethyl)-4-(p-fluorobenzoyl)-piperidine are dissolved in 1.5 liters of glacial acetic acid and 30 ml of concentrated hydrochloric acid and hydrogenated together with 2 g of platinum oxide in a hydrogen atmosphere. After 6 hours, the theoretical amount of 2.25 liters of hydrogen is absorbed. The catalyst is then filtered off with suction and the filtrate is concentrated to approximately 30 ml in a water-jet vacuum. There is added to the resulting crystal mass 5 ml of isopropanol and 15 ml of ether and filtration with suction is carried out. After filtration with suction and drying, N-(2-aminoethyl)-4-(p-fluorobenzoyl)-piperidine hydrochloride is obtained which, after recrystallisation from methanol, melts at 265° with decomposition.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C@@H:3]([OH:8])[C:4](C#N)=[O:5].[OH-:11].[Na+].OO.Cl>>[F:1][C:2]([F:10])([F:9])[C@@H:3]([OH:8])[C:4]([OH:11])=[O:5]
Reactant: N#CC(=O)[C@H](O)C(F)(F)F
Reactant: [OH-]
Agent: Cl
Agent: OO
Agent: [Na+]
Product: O=C(O)[C@H](O)C(F)(F)F
Temperature: 65 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
To a flask charged with (S)-3,3,3-trifluoro-2-hydroxypropanoyl cyanide (139 mg, 1 mmol) was added 3 N NaOH (6 mL) and 30% H2O2 (2.25 mL). The reaction mixture was heated at 65° C. for 1 h, then at 100° C. for a further 1 h. The reaction mixture was allowed to cooled to room temperature over 1 hr, then cool to 0° C. and the solution acidified with 6 N HCl (3 mL). The aqueous portion was extracted with ether (4×10 mL). The combined organic portions were dried over MgSO4, filtered and concentrated to give (S)-3,3,3-trifluoro-2-hydroxypropanoic acid as a clear oil (129 mg, 90% yield). NMR: 400 MHz 1H (CDCl3) 4.45 ppm, 1 H, m; 2.77 ppm, 2 H, m.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]2[NH:6][CH2:7][CH2:8][O:9][C:4]=2[CH:3]=1.[C:12](N1C=CN=C1)([N:14]1C=CN=C1)=[S:13].N>C1COCC1>[Br:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]([C:12](=[S:13])[NH2:14])[CH2:7][CH2:8][O:9][C:4]=2[CH:3]=1
Reactant: Brc1ccc2c(c1)OCCN2
Reactant: S=C(n1ccnc1)n1ccnc1
Agent: N
Solvent: C1CCOC1
Product: NC(=S)N1CCOc2cc(Br)ccc21
Temperature: 120 °C
Reaction time: 16 h
Yield: 58.9 %

Procedure:
A mixture of 7-bromo-3,4-dihydro-2H-benzo[1,4]oxazine (7.07 g, 33.00 mmol) and 1,1′-thiocarbonyldiimidazole (8.86 g, 49.70 mmol) in THF (83 mL) was heated to 120° C. under microwave irradiation, in a sealed tube, for 20 minutes, and then cooled to r.t. NH3 (110 mL, 7N solution in MeOH, 770 mmol) was added. The reaction mixture was stirred at r.t. for 16 h, and then concentrated in vacuo. The residue was triturated with 1M aqueous HCl, then Et2O, water and again Et2O, and then dried in vacuo to give the title compound (5.31 g, 59%) as a cream solid. δH (DMSO-d6) 8.66-7.53 (2H, m), 7.39 (1H, d, J 8.7 Hz), 7.15 (1H, d, J 2.3 Hz), 7.07 (1H, dd, J 8.9 and 2.3 Hz), 4.30-4.20 (4H, m). LCMS (ES+) 272.9 and 274.9 (M+H)+, RT 3.12 minutes (Method 7).
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][C:4]([CH2:7][PH:8](=[O:13])[O:9][CH:10]([CH3:12])[CH3:11])=[CH:3]1.[Si:14](Cl)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15].C(N(CC)CC)C>CN(C=O)C.CN(C1C=CN=CC=1)C>[Si:14]([O:1][CH:2]1[CH2:6][CH2:5][C:4]([CH2:7][PH:8](=[O:13])[O:9][CH:10]([CH3:11])[CH3:12])=[CH:3]1)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]
Reactant: CC(C)O[PH](=O)CC1=CC(O)CC1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)O[PH](=O)CC1=CC(O[Si](C)(C)C(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 84.3 %

Procedure:
A solution of isopropyl (3-hydroxycyclopentenyl)methylphosphinate (3) (3.5 g, 17.2 mmol) in anhydrous DMF (60 cm3) was treated with t-butyldimethylsilyl chloride (2.85 g, 18.9 mmol), triethylamine (3.6 g, 34.3 mmol) and DMAP (250 mg). The reaction mixture was stirred at room temperature for 16 h, after which time the solvent was removed in vacuo. The residue was partitioned between DCM (50 cm3) and water (30 cm3) and the aqueous layer was further extracted with DCM (3×20 cm3). The combined organic layers were washed with water (2×30 cm3) and brine (40 cm3), dried over anhydrous Na2SO4, filtered and the solvent removed under reduced pressure. The crude product was purified by short column vacuum chromatography on silica gel (5% ethanol/ethyl acetate) to yield the title compound (4) as a colourless oil (4.62 g, 85%): 1H NMR (300 MHz, CDCl3) δ 0.065 and 0.067 (6H, 2×s), 0.870 and 0.874 (9H, 2×s), 1.22 and 1.24 (3H, 2×d, J=6.3 and 6.3 Hz, OCHCH3), 1.31 and 1.33 (3H, 2×d, J=6.0 and 6.0 Hz, OCHCH3), 1.45 and 1.49 (3H, 2×d, J=14.4 and 14.4 Hz, PCH3), 1.69-1.83 (1H, m, C(5)—H), 2.24-2.46 (2H, m, C(5)—H′ and C(4)—H), 2.54-2.68 (1H, m, C(4)—H′), 4.55 (1H, m, OCHCH3), 4.95 (1H, m, C(3)—H), 6.46 (1H, m, C(2)—H), 13 C NMR (75.46 MHz, CDCl3) δ −4.81 and −4.75 (Si(CH3)2, 2×s), 14.0 and 14.19 (PCH3, d, JPC=101.3 and 101.8 Hz), 18.07 and 18.10 (SiC(CH3)3, 2×s), 23.90 and 23.96 (POCCH3, 2×d, 3JPOCC=4.8 Hz), 24.43 (POCCH3, overlapping d, 3JPOCC=3.3 Hz), 25.76 (SiC(CH3)3, br. s), 31.34 (C(4), d, 3JPC=11.5 Hz), 34.42 and 34.55 (C(5), 2×d, 2JPC=9.5 Hz), 68.95 and 68.99 (POCHCH3, d, 2JPOC=6.5 and 5.9 Hz), 77.98 and 78.24 (C(3), d, 3JPC=6.9 and 6.7 Hz), 137.78 and 138.08 (C(2), d, JPC=125.0 and 125.6 Hz), 147.2 (C(1), d, J=10.7 Hz), 31P NMR (121 MHz, CDCl3) δ 38.1, 38.5, (ESI) 319.1869 (MH+-C15H32O3PSi requires 319.1858).