Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[OH-].[K+].[CH2:13]([N:15]1[C:19]([CH:20]=[O:21])=[CH:18][C:17]([NH:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)=[N:16]1)[CH3:14]>CO>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:20]([C:19]3[N:15]([CH2:13][CH3:14])[N:16]=[C:17]([NH:22][CH2:23][C:24]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=4)[CH:18]=3)=[O:21])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Clc1cnc2[nH]ccc2c1
Reactant: CCn1nc(NCc2ccc(F)cc2)cc1C=O
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CCn1nc(NCc2ccc(F)cc2)cc1C(=O)c1c[nH]c2ncc(Cl)cc12
Reaction time: 0.83 h
Yield: 2.1 %

Procedure:
5-Chloro-1H-pyrrolo[2,3-b]pyridine (532, 0.068 g, 0.44 mmol) was combined with methanol (10 mL) and potassium hydroxide (0.16 g, 2.8 mmol). The mixture was stirred for 50 minutes, then 2-ethyl-5-(4-fluoro-benzylamino)-2H-pyrazole-3-carbaldehyde (530, 0.100 g, 0.40 mmol, prepared as described in Example 47, Scheme 162, Step 5) was added and the reaction was stirred overnight at room temperature and then concentrated. Ethyl acetate was added and the mixture was washed with sodium bicarbonate saturated solution and brine. After drying over anhydrous sodium sulfate the solvent was removed under reduced pressure. Purification with silica gel column chromatography eluting with a gradient of ethyl acetate (10-100%) in hexanes provided the desired compound (0.0033 g, 2%). MS (ESI) [M+H+]+=398.1.
Reaction SMILES: [Br:1][CH:2]([CH2:6][CH2:7][Br:8])[C:3](Cl)=[O:4].[CH3:9][NH2:10]>C(Cl)Cl.O>[Br:1][CH:2]([CH2:6][CH2:7][Br:8])[C:3]([NH:10][CH3:9])=[O:4]
Reactant: CN
Reactant: O=C(Cl)C(Br)CCBr
Solvent: ClCCl
Solvent: O
Product: CNC(=O)C(Br)CCBr
Temperature: 30 °C
Reaction time: 0.5 h
Yield: 98 %

Procedure:
2,4-Dibromobutanoyl chloride (CAS no. 82820-87-9) (16.9 g, 64 mmol) in DCM (20 mL) was added dropwise to a solution of methylamine (20 mL) in water (30 mL) and DCM (30 mL) at 10-15° C., then warmed to 30° C. and stirred for 30 minutes. The organic layer was separated and the aqueous layer re-extracted with DCM (2×10 mL), the combined organic layers were washed with brine (20 mL), dried (MgSO4) and evaporated to afford the product (16.3 g, 98%). 1H NMR δ (400 MHz, CDCl3) 2.35-2.45 (m, 1H), 2.57-2.67 (m, 1H), 2.81 (d, 3H), 3.44-3.54 (m, 2H), 4.46 (q, 1H), 6.34 (s, 1H).
Reaction SMILES: I[C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]2=[N:4][C:3]=1[CH2:11][N:12]1[C:20](=[O:21])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]1=[O:22].[F:23][C:24]([F:34])([F:33])[C:25]1[CH:26]=[C:27]([C:31]#[CH:32])[CH:28]=[CH:29][CH:30]=1.C(N(CC)CC)C>CN(C)C=O.[Cu](I)I.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:23][C:24]([F:33])([F:34])[C:25]1[CH:26]=[C:27]([C:31]#[C:32][C:2]2[N:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:5]3=[N:4][C:3]=2[CH2:11][N:12]2[C:20](=[O:21])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]2=[O:22])[CH:28]=[CH:29][CH:30]=1
Reactant: C#Cc1cccc(C(F)(F)F)c1
Reactant: O=C1c2ccccc2C(=O)N1Cc1nc2ccccn2c1I
Agent: I[Cu]I
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C1c2ccccc2C(=O)N1Cc1nc2ccccn2c1C#Cc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 60.8 %

Procedure:
In a flask placed under an argon flow, 2.1 g (5.21 mmol) of 2-((3-iodoimidazo[1,2-a]pyridin-2-yl)methyl)isoindoline-1,3-dione were solubilised in 11 ml of dimethylformamide with magnetic stirring. To this solution, were added: 0.008 g (0.04 mmol) of copper iodide, 0.921 ml (6.25 mmol) of 3-trifluoromethylphenyl acetylene and 10.89 ml (78 mmol) of triethylamine. The reaction medium was degassed with argon for 10 min before adding 0.477 g (0.521 mmol) of Pd2(dba)3. The mixture was stirred at r.t. for 16 h before being filtered on a silica gel cartridge which was then rinsed with 300 ml of ethyl acetate. The organic phase was washed with 3×150 ml of a saturated NaCl aqueous solution, and then dried on Na2SO4 which was then removed by filtration. The obtained filtrate was concentrated in vacuo. The crude residue was purified by flash chromatography on a silica gel cartridge (eluent: heptane/ethyl acetate gradient, from 50% to 40% of heptane, v/v). 1.41 g (yield=59%) of 2-((3-((3-(trifluoromethyl)phenyl)ethynyl)imidazo[1,2-a]pyridin-2-yl)methyl) isoindoline-1,3-dione were obtained as a brown solid. LC-MS: m/z=446 (MH+); UV purity at 254 nm=97%. 1H NMR (300 MHz, DMSO) δ 8.67 (d, J=6.7 Hz, 1H), 7.91 (dd, J=5.6, 3.0 Hz, 2H), 7.82 (dd, J=5.5, 3.1 Hz, 2H), 7.69 (dd, J=12.5, 8.5 Hz, 2H), 7.63-7.52 (m, 2H), 7.52-7.42 (m, 2H), 7.13 (td, J=6.8, 1.1 Hz, 1H), 5.09 (s, 2H).
Reaction SMILES: [C:1]([C:4]1[C:5]([CH3:22])=[CH:6][C:7]([O:20][CH3:21])=[C:8]([NH:10][C:11](=[S:19])OC2C=CC=CC=2)[CH:9]=1)(=[O:3])[CH3:2].[CH3:23][O:24][C:25]1[CH:26]=[C:27]([N:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH:28]=[C:29]([O:31][CH3:32])[CH:30]=1>>[C:1]([C:4]1[C:5]([CH3:22])=[CH:6][C:7]([O:20][CH3:21])=[C:8]([NH:10][C:11]([N:36]2[CH2:35][CH2:34][N:33]([C:27]3[CH:26]=[C:25]([O:24][CH3:23])[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=3)[CH2:38][CH2:37]2)=[S:19])[CH:9]=1)(=[O:3])[CH3:2]
Reactant: COc1cc(C)c(C(C)=O)cc1NC(=S)Oc1ccccc1
Reactant: COc1cc(OC)cc(N2CCNCC2)c1
Product: COc1cc(OC)cc(N2CCN(C(=S)Nc3cc(C(C)=O)c(C)cc3OC)CC2)c1
Yield: 82 %

Procedure:
Phenyl N-(5-acetyl-2-methoxy-4-methylphenyl)thiocarbamate and 1-(3,5-dimethoxyphenyl)piperazine were reacted by the same way with the example 197 to obtain the titled compound.
Reaction SMILES: [NH3:1].[CH:2]([CH2:15][C:16](Cl)=[S:17])([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>O.C(Cl)Cl>[CH:2]([CH2:15][C:16]([NH2:1])=[S:17])([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: N
Reactant: S=C(Cl)CC(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: O
Product: NC(=S)CC(c1ccccc1)c1ccccc1
Yield: 86 %

Procedure:
35 ml of ammonia in 40 ml of water are introduced into a three-necked flask provided with a condenser and a dropping funnel and the benzhydrylthioacetyl chloride dissolved in about 100 ml of methylene chloride is added drop by drop. Once the addition is complete, the organic phase is washed with a dilute solution of soda and dried over Na2SO4, the solvent is evaporated and the residue is taken up in diisopropyl ether; in this way, the benzhydrylthioacetamide is crystallised. 16.8 g of product (yield=86%) are obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([CH:13]3[CH2:16][N:15]([C:17]([O-:19])=[O:18])[CH2:14]3)[O:10][N:9]=2)=[CH:4][C:3]=1[N+:20]([O-])=O.[CH3:23]CO>>[NH2:20][C:3]1[CH:4]=[C:5]([C:8]2[N:12]=[C:11]([CH:13]3[CH2:16][N:15]([C:17]([O:19][CH3:23])=[O:18])[CH2:14]3)[O:10][N:9]=2)[CH:6]=[CH:7][C:2]=1[CH3:1]
Reactant: Cc1ccc(-c2noc(C3CN(C(=O)[O-])C3)n2)cc1[N+](=O)[O-]
Reactant: CCO
Product: COC(=O)N1CC(c2nc(-c3ccc(C)c(N)c3)no2)C1
Temperature: 78 °C

Procedure:
To a stirring suspension of methyl 3-(3-(4-methyl-3-nitrophenyl)-1,2,4-oxadiazol-5-yl)azetidine-1-carboxylate (30) (795 mg, 2.50 mmol) in EtOH (20 mL) was added stannous chloride dihydrate (2.3 g, 9.99 mmol). The reaction mixture was heated at 78° C. for 3 hours. Then, the reaction was cooled to room temperature and the solvent was partially concentrated. The pH was adjusted to slightly basic pH with a saturated solution of sodium bicarbonate. The resulting white suspension was filtered and washed with water and ethyl acetate. The aqueous was extracted with ethyl acetate and washed with water, brine and dried over anhydrous sodium sulfate. The solvent was concentrated to give methyl 3-(3-(3-amino-4-methylphenyl)-1,2,4-oxadiazol-5-yl)azetidine-1-carboxylate (31). 1H NMR (400 MHz, d6-DMSO) δ 7.32 (d, J=1.6 Hz, 1H), 7.12 (dd, J=1.6, 7.6 Hz, 1H), 7.30 (d, J=7.6 Hz, 1H), 5.19 (s, 2H), 4.38-4.31 (m, 2H), 4.27-4.20 (m, 1H), 4.19-4.16 (m, 2H), 3.60 (s, 3H), 2.10 (s, 3H). MS m/z 289.12 (M+1)+.
Reaction SMILES: C1(C)C=CC(S([O:10][CH2:11][CH2:12][CH2:13][N:14]([CH3:21])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=O)=O)=CC=1.[N+:23]1([O-])[C:24]([CH3:29])=[CH:25][CH:26]=[CH:27][CH:28]=1.[Cl:31]([O-:35])(=[O:34])(=[O:33])=[O:32].[Na+]>CO.O>[Cl:31]([O-:35])(=[O:34])(=[O:33])=[O:32].[CH3:21][N:14]([CH2:13][CH2:12][CH2:11][O:10][N+:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH3:29])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: Cc1cccc[n+]1[O-]
Reactant: Cc1ccc(S(=O)(=O)OCCCN(C)c2ccccc2)cc1
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CO
Solvent: O
Product: Cc1cccc[n+]1OCCCN(C)c1ccccc1

Procedure:
3-(N-Methylanilino)propyl p-toluenesulfonate (21.2 g, 0.0665 mole) and 2-picoline-N-oxide (7.3 g, 0.0665 mole) were heated together on a steam bath for 1/2 hour. The mixture was allowed to cool, then dissolved in methanol (50 ml). A solution of sodium perchlorate (9.3 g, 0.076 mole) in water (12 ml) was added and the mixture chilled. The solid which separated was collected and washed with a little 90% methanol, then with ether. The yield was 14.3 g (60%), m.p. 111°-113° C.
Reaction SMILES: [C@@H:1]1([N:9]2[C:18]3[N:17]=[CH:16][N:15]=[C:13](O)[C:12]=3[N:11]=[CH:10]2)[O:8][C@H:5]([CH2:6][OH:7])[C@@H:3]([OH:4])[CH2:2]1.C(N(CC)C(C)C)(C)C.[I:28][C:29]1[CH:34]=[CH:33][C:32]([CH:35]([NH2:37])[CH3:36])=[C:31]([N+:38]([O-:40])=[O:39])[CH:30]=1>CN(C=O)C>[I:28][C:29]1[CH:34]=[CH:33][C:32]([CH:35]([NH:37][C:13]2[C:12]3[N:11]=[CH:10][N:9]([C:18]=3[N:17]=[CH:16][N:15]=2)[C@@H:1]2[O:8][C@H:5]([CH2:6][OH:7])[C@@H:3]([OH:4])[CH2:2]2)[CH3:36])=[C:31]([N+:38]([O-:40])=[O:39])[CH:30]=1
Reactant: CC(N)c1ccc(I)cc1[N+](=O)[O-]
Reactant: OC[C@H]1O[C@@H](n2cnc3c(O)ncnc32)C[C@@H]1O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(Nc1ncnc2c1ncn2[C@H]1C[C@H](O)[C@@H](CO)O1)c1ccc(I)cc1[N+](=O)[O-]
Reaction time: 48 h

Procedure:
To a suspension of 2′-deoxyinosine (150 mg, 0.6 mmol) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphonate (BOP, 379 mg, 0.86 mmol) in anhydrous DMF (1.5 mL), N,N-diisopropylethylamine (186 μL, 1.1 mmol) was added followed by the addition of a solution of 1-(4-iodo-2-nitrophenyl)ethylamine (460 mg, 1.57 mmol) in anhydrous DMF (0.5 mL). The mixture was stirred under nitrogen atmosphere for 48 hours. DMF was removed in vacuo, and the crude product was purified by silica gel column chromatography to yield N6-[1-(4-iodo-2-nitrophenyl)ethyl]-2′-deoxyadenosine dA.20 (204 mg, 65%, 1:1 mixture of diastereomers) as a white foam.
Reaction SMILES: [CH2:1]([CH:5]1[C:9]2([CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[O:8][C:7](=[O:15])[NH:6]1)[CH2:2][CH2:3][CH3:4].[CH3:16][C:17]1[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[C:18]=1[C:19]([N:21]1[CH2:26][CH2:25][C:24](=O)[CH2:23][CH2:22]1)=[O:20].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CC(O)=O.N>C(Cl)Cl>[CH2:1]([CH:5]1[C:9]2([CH2:14][CH2:13][N:12]([CH:24]3[CH2:25][CH2:26][N:21]([C:19](=[O:20])[C:18]4[C:28]([CH3:32])=[CH:29][CH:30]=[CH:31][C:17]=4[CH3:16])[CH2:22][CH2:23]3)[CH2:11][CH2:10]2)[O:8][C:7](=[O:15])[NH:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: Cc1cccc(C)c1C(=O)N1CCC(=O)CC1
Reactant: CCCCC1NC(=O)OC12CCNCC2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: N
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCCCC1NC(=O)OC12CCN(C1CCN(C(=O)c3c(C)cccc3C)CC1)CC2
Reaction time: 24 h
Yield: 73 %

Procedure:
To a solution of 4-butyl-1-oxa-3,8-diaza-spiro[4.5]decane-2-one (12: R=H; R′=n-Bu; 1.09 g; 5.1 mmol)) in 30 mL DCM was added 1.24 g (5.4 mmol) of 1-(2,6-dimethyl-benzoyl)-piperidin-4-one followed by 2.1 mL (7.1 mmol) of Ti(IV)(O-i-Pr)4 The reaction mixture stirred under nitrogen for 18 h. of Sodium triacetoxyborohydride (1.6 g: 7.7 mmol) was added to the reaction mixture followed by glacial HOAc (0.365 mL; 6.4 mmol). The reaction mixture stirred for 24 h. Aqueous ammonia (20 mL; 10% aqueous solution) was added and the solution stirred for an additional 10 min. The mixture was filtered by gravity through a cartridge of ChemElute™. The organics were evaporated under reduced pressure and the residue was purified by flash chromatography on silica gel with gradient elution (2% to 10% methanol in ethyl acetate with 0.4% ammonia) to provide 1.6 g (73%) of 4-butyl-8-[1-(2,6-dimethyl-benzoyl)-piperidin-4-yl]-1-oxa-3,8-diaza-spiro[4.5]decane-2-one: ms [M]+=428.
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:6])[CH2:4][CH3:5].[O-]CC.[Na+].Cl.[NH:12]1[CH2:17][CH2:16][CH:15]([CH2:18][CH2:19][O:20][C:21]2[CH:31]=[CH:30][C:24]([C:25](OCC)=O)=[CH:23][CH:22]=2)[CH2:14][CH2:13]1>C(O)C>[CH2:4]([C:3]1[N:6]=[C:25]([C:24]2[CH:23]=[CH:22][C:21]([O:20][CH2:19][CH2:18][CH:15]3[CH2:16][CH2:17][NH:12][CH2:13][CH2:14]3)=[CH:31][CH:30]=2)[O:1][N:2]=1)[CH3:5]
Reactant: CCC(=N)NO
Reactant: CCOC(=O)c1ccc(OCCC2CCNCC2)cc1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCc1noc(-c2ccc(OCCC3CCNCC3)cc2)n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 89.9 %

Procedure:
A mixture of 4.0 parts of N-hydroxypropanimidamide, 2.9 parts of sodiumethoxide, 94.8 parts of ethanol and 25.3 parts of molecular sieve was stirred for 15 min. at room temperature. There were added 7.5 parts of ethyl 4-[2-(4-piperidinyl)ethoxy]benzoate monohydrochloride and stirring was continued for 12 hours at reflux temperature. The cooled reaction mixture was filtered and the filtrate was evaporated. The residue was partitioned between water and dichloromethane. The organic layer was separated, dried, filtered and evaporated, yielding 6.5 parts (89.9%) of 4-[2-[4-(3-ethyl-1,2,4-oxadiazol-5-yl)phenoxy]ethyl]piperidine (interm. 7).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:46])[CH2:15][CH2:16][CH:17]2[CH2:24][N:23]3[C:25]4[CH:26]=[C:27]([C:38]([O:40][CH3:41])=[O:39])[CH:28]=[CH:29][C:30]=4[C:31]([CH:32]4[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]4)=[C:22]3[C:21]3[CH:42]=[CH:43][CH:44]=[CH:45][C:20]=3[O:19][CH2:18]2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:32]1([C:31]2[C:30]3[CH:29]=[CH:28][C:27]([C:38]([O:40][CH3:41])=[O:39])=[CH:26][C:25]=3[N:23]3[C:22]=2[C:21]2[CH:42]=[CH:43][CH:44]=[CH:45][C:20]=2[O:19][CH2:18][CH:17]([CH2:16][CH2:15][C:14](=[O:46])[N:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[CH2:24]3)[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(CCC(=O)N1CCN(C(=O)OC(C)(C)C)CC1)COc1ccccc1-3
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(CCC(=O)N1CCNCC1)COc1ccccc1-3
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
Methyl 7-{3-[4-(tert-butoxycarbonyl)piperazin-1-yl]-3-oxopropyl}-14-cyclohexyl-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxylate (0.04 M) in DCM was treated with TFA (170 eq) and stirred at RT overnight. The volatiles were then removed in vacuo and the residue partitioned between sat. aq. NaHCO3 and EtOAc. The combined organics were washed with brine, dried (Na2SO4), filtered and concentrated in vacuo to afford the product as an off-white foam (100%) that was used without further purification. (ES+) m/z 530 (M+H)+.
Reaction SMILES: [C:1]1(=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:8]([C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[C:13]([OH:15])=[O:14])N>C(O)(=O)C>[CH2:5]1[C:6]2[NH:8][C:10]3[C:18](=[CH:17][CH:16]=[C:12]([C:13]([OH:15])=[O:14])[CH:11]=3)[C:1]=2[CH2:2][CH2:3][CH2:4]1
Reactant: O=C1CCCCC1
Reactant: NNc1cccc(C(=O)O)c1
Solvent: CC(=O)O
Product: O=C(O)c1ccc2c3c([nH]c2c1)CCCC3

Procedure:
A mixture of 2,3,4,9-tetrahydro-1H-carbazole-7-carboxylic acid and 2,3,4,9-tetrahydro-1H-carbazole-5-carboxylic acid was obtained by allowing cyclohexanone and 3-hydrazinobenzoic acid to undergo the reaction under heating in acetic acid. By separating and purifying this mixture by a silica gel column chromatography, 2,3,4,9-tetrahydro-1H-carbazole-5-carboxylic acid [Reference Example 16a: FAB: 216 (M+H)+] and 2,3,4,9-tetrahydro-1H-carbazole-7-carboxylic acid [Reference Example 16b: FAB: 216 (M+H)+] were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][CH:25]=1)[C:5]([N:8]([CH2:18][CH2:19][C:20](=O)[CH3:21])[C:9](=[O:17])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([CH3:7])[CH3:6].[OH-].[K+]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][CH:25]=1)[C:5]([N:8]1[CH2:18][CH2:19][C:20]([CH3:21])=[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:9]1=[O:17])([CH3:7])[CH3:6]
Reactant: CC(=O)CCN(C(=O)Cc1ccccc1)C(C)(C)c1cccc(Cl)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CC1=C(c2ccccc2)C(=O)N(C(C)(C)c2cccc(Cl)c2)CC1
Yield: 47.6 %

Procedure:
15.0 g (0.042 mol) of N-(3-chloro-α,α-dimethylbenzyl)-N-(3-oxobutyl)phenylacetamide prepared in accordance with the method of Reference Example 10, was dissolved in 100 ml of ethanol, and 1.3 g (0.02 mol) of potassium hydroxide powder was added thereto. The mixture was refluxed under heating for three hours. After completion of the reaction, ethanol as distilled off under reduced pressure, and then ice water was added to the residue and extracted with ethyl acetate. The ethyl acetate layer was washed with water and then drived over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue thereby obtained was purified by chromatography by using a column packed with silica gel (n-hexane/ethyl acetate) to obtain 6.8 g (yield: 48.1%) of the desired compound.
Reaction SMILES: [C:1]1([C:7]2[CH2:11][CH2:10][NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[C:13](Cl)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[N:16][CH:15]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[C:13]([N:9]1[CH2:10][CH2:11][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[N:8]1)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[N:16][CH:15]=1
Reactant: O=C(Cl)c1cccnc1
Reactant: c1ccc(C2=NNCC2)cc1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C(c1cccnc1)N1CCC(c2ccccc2)=N1
Reaction time: 0.5 h
Yield: 74.2 %

Procedure:
3-Phenyl-2-pyrazoline (2.9 g) synthesized in Reference Example 2 was dissolved in chloroform (20 ml). Thereto were added nicotinic acid chloride hydrochloride (4 g) and triethylamine (6 ml) with ice-cooling. Stirring was conducted for 30 minutes at room temperature. The reaction mixture was washed with water and concentrated under vacuum. The residue was purified by silica gel column chromatography (methanol:chloroform=1/100) to obtain 3.7 g of a title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[CH2:16][C:6]2[N:7]=[C:8]([N:10]3[CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)[S:9][C:5]=2[C:4](=[O:17])[CH2:3]1.[NH2:19]OS(O)(=O)=O>C(O)=O>[CH3:1][C:2]1([CH3:18])[CH2:3][C:4](=[O:17])[NH:19][C:5]2[S:9][C:8]([N:10]3[CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)=[N:7][C:6]=2[CH2:16]1
Reactant: CC1(C)CC(=O)c2sc(N3CCOCC3)nc2C1
Reactant: NOS(=O)(=O)O
Solvent: O=CO
Product: CC1(C)CC(=O)Nc2sc(N3CCOCC3)nc2C1
Yield: 22.6 %

Procedure:
To a stirred solution of Example 48 (1.00 g, 3.77 mmol) in formic acid (40 mL) was added, dropwise, hydroxylamine-O-sulfonic acid (0.64 g, 5.66 mmol). After refluxing overnight the reaction mixture was quenched with ice/water and neutralised with aqueous 5% NaOH and then extracted with DCM (2×40 μL). The organics were combined, dried (MgSO4), filtered and concentrated in vacuo. Purification by column chromatography (SiO2, 3:1 DCM/EtOAc) gave the title compound (0.24 g, 22%) as an off-white solid. δH (DMSO-d6) 10.77 (1H, s), 3.69 (4H, m), 3.42 (4H, m), 2.52 (2H, s), 2.25 (2H, s), 0.98 (6H, s). LCMS (ES+) 282.0 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:5])=[O:4].[CH:6](=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>O>[CH:6](=[N:1][C@H:2]([C:3]([OH:5])=[O:4])[CH:6]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[OH:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: NCC(=O)O
Reactant: O=Cc1ccccc1
Solvent: O
Product: O=C(O)[C@@H](N=Cc1ccccc1)C(O)c1ccccc1
Reaction time: 16.5 h

Procedure:
In the process of this invention, there is no particular limitation on the sequence of charging the starting materials, the solvent, and the other materials. For example, an organic solvent having dissolved therein glycine, water and the aldehyde and optionally the phase transfer catalyst are charged, and with stirring, the alkali as a solid or an aqueous solution is charged or added dropwise to perform the reaction. Alternatively, it is possible to dissolve glycine in water and the alkali, and then add dropwise a solution of the benzaldehyde and the surface-active agent in an organic solvent to perform the reaction. Another method comprises charging or dropwise adding the alkali as a solid or aqueous solution into or to a mixture of glycine, water, the benzaldehyde, the organic solvent and the surface active agent, thereby performing the reaction. The reaction may be carried out at a temperature of 0° to 80° C. for 1 to 50 hours, preferably 10° to 60° C. for 3 to 30 hours. In this manner, the alkali metal or alkaline earth metal salt of the N-benzylidene-β-phenylserine is formed.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:5]2[N:6]([CH3:12])[C:7](=[O:11])[CH2:8][CH2:9][CH2:10][C:4]=2[CH:3]=1.Cl[C:16]1[N:21]=[C:20]([NH:22][C:23]2[CH:32]=[CH:31][CH:30]=[CH:29][C:24]=2[C:25]([NH:27][CH3:28])=[O:26])[C:19]([Cl:33])=[CH:18][N:17]=1>COCCO>[Cl:33][C:19]1[C:20]([NH:22][C:23]2[CH:32]=[CH:31][CH:30]=[CH:29][C:24]=2[C:25]([NH:27][CH3:28])=[O:26])=[N:21][C:16]([NH:1][C:2]2[CH:14]=[CH:13][C:5]3[N:6]([CH3:12])[C:7](=[O:11])[CH2:8][CH2:9][CH2:10][C:4]=3[CH:3]=2)=[N:17][CH:18]=1
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: CN1C(=O)CCCc2cc(N)ccc21
Solvent: COCCO
Product: CNC(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)CCCC(=O)N3C)ncc1Cl
Temperature: 120 °C
Yield: 11 %

Procedure:
7-Amino-1-methyl-1,3,4,5-tetrahydrobenzo[b]azepin-2-one (166 mg, 0.87 mmol) and 2-(2,5-dichloro-pyrimidin-4-ylamino)-N-methyl-benzamide (259 mg, 0.87 mmol) were suspended in 2-methoxyethanol (9 ml), and heated to 120° C. for 18 hours. Concentration afforded a brown residue. Purification by preparative TLC (5% MeOH/CH2Cl2) gave a slightly impure yellow oil which was then triturated with acetone to give the title compound as a white solid, 45 mg. (11% yield) 1H NMR (400 MHz, DMSO-d6) δ 11.58 (s, 1H), 9.52 (s, 1H), 8.64-8.81 (m, 2H), 8.22 (s, 1H), 7.69-7.75 (m, 1H), 7.42-7.59 (m, 3H), 7.12-7.26 (m, 2H), 3.19 (s, 3H), 2.74-2.80 (m, 2H), 2.49-2.60 (m, 2H), 1.95-2.20 (m, 5H); MS (m/e) 451 (M+1); mp 244-246° C.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]#[C:11][C:12]2[CH:13]=[C:14]([Cl:20])[C:15]([C:18]#[N:19])=[N:16][CH:17]=2)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[H][H]>C(O)C.[Pt]=O>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12]2[CH:13]=[C:14]([Cl:20])[C:15]([C:18]#[N:19])=[N:16][CH:17]=2)=[CH:6][CH:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc(C#Cc2cnc(C#N)c(Cl)c2)cc1
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CCO
Product: CC(=O)c1ccc(CCc2cnc(C#N)c(Cl)c2)cc1
Reaction time: 0.5 h

Procedure:
To a solution of 5-((4-acetylphenyl)ethynyl)-3-chloropicolinonitrile (from the previous step) (1 eq) in ethanol (0.1 M) was added Platinum Oxide (30 mol %). Hydrogen gas was introduced via a balloon, and the reaction was stirred for 0.5 hour. The mixture was filtered through a pad of celite, washing with dichloromethane. The filtrate was concentrated en vaccuo and purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-100% ethyl acetate in hexane to give 5-(4-acetylphenethyl)-3-chloropicolinonitrile as an off-white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][OH:9])[CH:5]=[CH:4][N:3]=1.[C:10]([Si:14]([CH3:17])([CH3:16])Cl)([CH3:13])([CH3:12])[CH3:11].N1C=CN=C1>CN(C=O)C.O>[Si:14]([O:9][CH2:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[CH:7]=1)([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:17])[CH3:16]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCc1ccnc(Cl)c1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCc1ccnc(Cl)c1
Reaction time: 1 h

Procedure:
To a solution of (2-chloropyridin-4-yl)methanol (0.307 g, 2.14 mmol) in 20 mL of DMF at 0° C. under an atmosphere of nitrogen was added tert-butyldimethylchlorosilane (0.355 g, 2.35 mol) and imidazole (0.160 g, 2.35 mmol). After 1 h, the mixture was diluted with water, washed 3× with water, dried over sodium sulfate, filtered, and concentrated in vacuo. The resultant residue was subjected to silica gel chromatography eluting with 0-15% EtOAc in hexanes to provide 4-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-chloropyridine that gave a mass ion (ES+) of 258.1 for [M+H]+.