Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:4][C:5]1[C:10]([NH2:11])=[CH:9][C:8]([C:12]([F:15])([F:14])[F:13])=[CH:7][N:6]=1)[CH2:2][CH3:3].[CH2:16]([S:18][C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21](O)=[O:22])[CH3:17].CCN=C=NCCCN(C)C.C(=O)([O-])[O-].[Na+].[Na+]>N1C=CC=CC=1>[CH2:16]([S:18][C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21]([NH:11][C:10]1[C:5]([NH:4][CH2:1][CH2:2][CH3:3])=[N:6][CH:7]=[C:8]([C:12]([F:15])([F:13])[F:14])[CH:9]=1)=[O:22])[CH3:17]
Reactant: CCSc1ccccc1C(=O)O
Reactant: CCCNc1ncc(C(F)(F)F)cc1N
Agent: CCN=C=NCCCN(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccncc1
Product: CCCNc1ncc(C(F)(F)F)cc1NC(=O)c1ccccc1SCC
Temperature: 95 °C
Yield: 31.3 %

Procedure:
A mixture of N-propyl-5-trifluoromethylpyridin-2,3-diamine (770 mg), 2-ethylsulfanyl-benzoic acid (700 mg), WSC (740 mg), and pyridine (20 ml) was stirred with heating at 95° C. for 7 hours. Into the reaction mixture cooled to room temperature, saturated aqueous sodium carbonate solution was poured, and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography to give 422 mg of 2-ethylsulfanyl-N-(2-propylamino-5-trifluoromethylpyridin-3-yl)-benzamide (Compound (1B)-513).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:18])[C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[C:21]([NH2:29])[CH:20]=1>C(#N)C>[C:1]([O:5][C:6](=[O:7])[N:8]([CH3:18])[C:9]1[CH:10]=[CH:11][C:12]([C:13](=[O:15])[NH:29][C:21]2[CH:20]=[N:19][C:28]3[C:23]([CH:22]=2)=[CH:24][CH:25]=[CH:26][CH:27]=3)=[CH:16][CH:17]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Nc1cnc2ccccc2c1
Reactant: CN(C(=O)OC(C)(C)C)c1ccc(C(=O)O)cc1
Solvent: CC#N
Product: CN(C(=O)OC(C)(C)C)c1ccc(C(=O)Nc2cnc3ccccc3c2)cc1

Procedure:
A solution of 4-(tert-butoxycarbonyl-methyl-amino)-benzoic acid (3.36 g, 13.4 mmol), O-benzotriazol-1-yl-N,N,N,N′N′-tetramethyluronium hexafluorophospate (HBTU) (5.22 g, 13.8 mmol) and N,N-diisopropylethyl (4.8 mL, 27.5 mmol) in acetonitrile (200 mL) was stirred at ambient temperature for ten minutes. Quinolin-3-ylamine (1.93 g, 13.4 mmol) was added, and the solution was heated at reflux for 20 hours. The solvent was evaporated in vacuo, and the residue was partitioned between 1 N aqueous sodium hydroxide and dichloromethane. The product was purified by flash silica gel chromatography, using 67% ethyl acetate in hexane as the eluant to give the product as a colorless solid, 4 g (80%). MS: m/z 378 (MH+). 1H NMR (CDCl3): 1.51 (s, 9 H), 3.29 (s, 3 H), 7.33 (d, 2 H), 7.53 (d of d, 1 H), 7.65 (d of d, 1 H), 7.85 (d, 2 H), 8.04 (d, 1 H), 8.70 (br s, 1 H) and 8.86-8.91 (m, 2 H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[S:8][CH:9]=[C:10]([C:12]3[C:13](=[O:24])[NH:14][C:15]4[C:20]([CH:21]=3)=[CH:19][CH:18]=[C:17]([CH:22]=O)[CH:16]=4)[N:11]=2)=[CH:3][CH:2]=1.[CH:25]1([NH2:30])[CH2:29][CH2:28][CH2:27][CH2:26]1>>[CH:25]1([NH:30][CH2:22][C:17]2[CH:16]=[C:15]3[C:20]([CH:21]=[C:12]([C:10]4[N:11]=[C:7]([C:4]5[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=5)[S:8][CH:9]=4)[C:13](=[O:24])[NH:14]3)=[CH:19][CH:18]=2)[CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: O=Cc1ccc2cc(-c3csc(-c4ccncc4)n3)c(=O)[nH]c2c1
Reactant: NC1CCCC1
Product: O=c1[nH]c2cc(CNC3CCCC3)ccc2cc1-c1csc(-c2ccncc2)n1

Procedure:
This compound was prepared according to the method described in example 8768 employing 3-(2-pyridin-4-yl-thiazol-4-yl)-1H-quinolin-2-one-7-carbaldehyde and cyclopentylamine to give a yellow solid. MS m/z: 403.2 (M+1).
Reaction SMILES: [CH:1]([C@@H:3]1[C@@H:7]([C:8]2[CH:12]=[CH:11][S:10][CH:9]=2)[CH2:6][N:5]([C@H:13]([CH2:26][CH:27]2[CH2:30][CH2:29][CH2:28]2)[C:14]([O:16]CC2C=CC(OC)=CC=2)=[O:15])[CH2:4]1)=O.[F:31][C:32]1[CH:37]=[CH:36][C:35]([CH2:38][CH2:39][CH2:40][CH:41]2[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]2)=[CH:34][CH:33]=1.Cl>>[F:31][C:32]1[CH:33]=[CH:34][C:35]([CH2:38][CH2:39][CH2:40][CH:41]2[CH2:42][CH2:43][N:44]([CH2:1][C@@H:3]3[C@@H:7]([C:8]4[CH:12]=[CH:11][S:10][CH:9]=4)[CH2:6][N:5]([C@H:13]([CH2:26][CH:27]4[CH2:28][CH2:29][CH2:30]4)[C:14]([OH:16])=[O:15])[CH2:4]3)[CH2:45][CH2:46]2)=[CH:36][CH:37]=1
Reactant: Fc1ccc(CCCC2CCNCC2)cc1
Reactant: COc1ccc(COC(=O)[C@@H](CC2CCC2)N2C[C@H](c3ccsc3)[C@@H](C=O)C2)cc1
Agent: Cl
Product: O=C(O)[C@@H](CC1CCC1)N1C[C@H](CN2CCC(CCCc3ccc(F)cc3)CC2)[C@@H](c2ccsc2)C1
Yield: 74.6 %

Procedure:
The title compound was prepared from 21 mg (0.046 mmol) of 2-(R)-(3-(R)-formyl-4-(S)-(3-thienyl)pyrrolidin-1-yl)-3-(cyclobutyl) propanoic acid, (4-methoxy)benzyl ester (from EXAMPLE 87, Step F), 11.7 mg (0.046 mmol) of 4-(3-(4-fluorophenyl)propyl)piperidine.HCl (from EXAMPLE 96, Step B) using procedures analogous to those described in EXAMPLE 1, Step J and EXAMPLE 10, Step F to provide 17.6 mg (72%) of the title compound: RF: 0.28 (90:10:1 v/v/v CH2Cl2/MeOH/NH4OH); 1H NMR (300 MHz, CD3OD) δ 1.01-3.48 (m, 33H), 6.80-6.86 (m, 2H), 6.99-7.05 (m, 3H), 7.18 (m, 1H), 7.33 (m, 1H); ESI-MS 513 (M+H); HPLC A: 2.72min.
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:24]C)[N:12]2[CH2:15][CH2:16][CH2:17][CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)=[C:8]([NH2:26])[N:7]=1)[CH2:2][CH2:3][CH3:4].I[CH2:28][CH2:29][CH2:30][CH3:31]>>[NH2:26][C:8]1[N:7]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:24])[N:12]2[CH2:15][CH2:16][CH2:17][CH:18]1[CH2:23][CH2:22][N:21]([CH2:28][CH2:29][CH2:30][CH3:31])[CH2:20][CH2:19]1
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCC3CCNCC3)c2n1
Reactant: CCCCI
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCCC3CCN(CCCC)CC3)c2n1

Procedure:
Prepared similarly to Example 14 from 2-(butyloxy)-8-(methyloxy)-9-[3-(4-piperidinyl)propyl]-9H-purin-6-amine and 1-iodobutane.
Reaction SMILES: Cl.[CH:2]1([N:6]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[NH:19][C:18]([C:23]([OH:25])=O)=[CH:17]4)=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3]1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[F:48][C:49]1([F:55])[CH2:54][CH2:53][NH:52][CH2:51][CH2:50]1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH:2]1([N:6]2[CH2:7][CH2:8][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[NH:19][C:18]([C:23]([N:52]3[CH2:53][CH2:54][C:49]([F:55])([F:48])[CH2:50][CH2:51]3)=[O:25])=[CH:17]4)=[O:13])[CH2:10][CH2:11]2)[CH2:3][CH2:4][CH2:5]1
Reactant: FC1(F)CCNCC1
Reactant: O=C(O)c1cc2cc(C(=O)N3CCN(C4CCC4)CC3)ccc2[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1ccc2[nH]c(C(=O)N3CCC(F)(F)CC3)cc2c1)N1CCN(C2CCC2)CC1
Yield: 83 %

Procedure:
The title compound was synthesized in analogy to example 1, from 5-(4-cyclobutyl-piperazine-1-carbonyl)-1H-indole-2-carboxylic acid hydrochloride, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (commercially available), 4,4-difluoropiperidine (commercially available) and N,N-diisopropylethylamine in N,N-dimethylformamide, to give the desired product as a light brown solid (83%).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5](=[O:17])[CH2:6][C:7]1[C:15]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[NH:9][C:8]=1[CH3:16].C1COCC1.CN(C=O)C.[Cl:28][C:29]1[CH:30]=[C:31]([S:36](Cl)(=[O:38])=[O:37])[CH:32]=[CH:33][C:34]=1[Cl:35]>C1COCC1>[CH3:3][O:4][C:5](=[O:17])[CH2:6][C:7]1[C:15]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[N:9]([S:36]([C:31]2[CH:32]=[CH:33][C:34]([Cl:35])=[C:29]([Cl:28])[CH:30]=2)(=[O:38])=[O:37])[C:8]=1[CH3:16]
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(Cl)c1
Reactant: COC(=O)Cc1c(C)[nH]c2ncccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COC(=O)Cc1c(C)n(S(=O)(=O)c2ccc(Cl)c(Cl)c2)c2ncccc12
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
To an ice-cooled stirring suspension of NaH (60% dispersion in mineral oil; 63 mg, 1.6 mmol) in THF (3 mL) is added a solution of (2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-acetic acid methyl ester (200 mg, 1 mmol) in 3:1 THF/DMF (4 mL). After 45 minutes, a solution of 3,4-dichloro-benzenesulfonyl chloride (214 μL, 1.4 mmol) in THF (3 mL) is added. After 10 minutes, the reaction mixture is added to ice/water and extracted with EtOAc. The organic layer is washed with brine and evaporated. The crude product is purified by flash chromatography (3:1 iso-hexane/EtOAc elution), to afford [1-(3,4-dichloro-benzenesulfonyl)-2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl]-acetic acid methyl ester; MH+=413.
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4]2[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:5]=2[N:6]=1.[H-].[Na+].[N+]([C:17]1[O:21][C:20]([CH:22]=[O:23])=[CH:19][CH:18]=1)([O-])=O>O1CCCC1.O.C(OCC)(=O)C>[CH3:11][C:9]1[CH:8]=[CH:7][C:5]2[NH:6][C:2]([S:1][C:17]3[O:21][C:20]([CH:22]=[O:23])=[CH:19][CH:18]=3)=[N:3][C:4]=2[CH:10]=1
Reactant: Cc1ccc2nc(S)[nH]c2c1
Reactant: O=Cc1ccc([N+](=O)[O-])o1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc2[nH]c(Sc3ccc(C=O)o3)nc2c1
Temperature: 20 °C

Procedure:
1.16 g of 2-mercapto-5-methylbenzimidazole in 14 mL of tetrahydrofurane (THF) are dropped into a 100 mL three-neck flask, and then 309 mg of sodium hydride is added. The mixture is stirred at reflux temperature for 30 minutes followed by addition of 1 g of 5-nitro furaldehyde in 7 mL of THF. The reaction medium is allowed to cool down to room temperature (ca. 20° C.) and then poured in a mixture of 200 mL of water and 100 mL of ethyl acetate (EtOAc). The organic layer is isolated and the aqueous layer is extracted twice with EtOAc (2×100 mL). The organic layers are combined, dried on magnesium sulfate, and concentrated under reduced pressure. 1.8 g of 5-(5-Methyl-1H-benzimidazol-2-ylsulfanyl)-furan-2-carbaldehyde is collected. Analytical LC/MS method B: RT: 2.98 min; [M+H]+: 259; 80% UV purity
Reaction SMILES: [H-].[Na+].[NH2:3][C@@H:4]([C:9]([OH:11])=[O:10])[C:5]([SH:8])([CH3:7])[CH3:6].[CH:12](I)([CH3:14])[CH3:13].Cl>C(O)C>[NH2:3][C@@H:4]([C:5]([S:8][CH:12]([CH3:14])[CH3:13])([CH3:7])[CH3:6])[C:9]([OH:11])=[O:10]
Reactant: CC(C)(S)[C@@H](N)C(=O)O
Reactant: CC(C)I
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)SC(C)(C)[C@H](N)C(=O)O
Temperature: 5 °C
Reaction time: 0.08 h

Procedure:
NaH (1.3 g) was added in portions to 70 mL ethanol while cooling. Subsequently D-penicillamine (4.0 g) was added. The mixture kept stirring for 5 minutes at 5° C., after which isopropyl iodide (2.8 mL) was added. The mixture was allowed to stir 16 h at ambient temperature. 2 N HCl was added followed by evaporation of the volatiles to give 11.9 g crude 2-(R)-amino-3-isopropylsulfanyl-3-methyl-butyric acid, which was used in the next step without further purification.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[NH2:11][C@@H:12]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].C(N(CC)CC)C>ClCCl>[N+:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:11][C@@H:12]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:18])[CH3:19])=[O:15])([O-:10])=[O:9]
Reactant: CC(C)(C)OC(=O)C[C@@H](N)c1ccccc1
Reactant: O=[N+]([O-])c1ccccc1F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)C[C@@H](Nc1ccccc1[N+](=O)[O-])c1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 2-fluoronitrobenzene (150 mg, 1.06 mmol) in dichloromethane (4 mL) was added tert-butyl (3R)-3-amino-3-phenylpropanoate (235 mg, 1.06 mmol) and triethylamine (300 μL, 2.12 mmol). The solution was stirred at room temperature for 4 hours, and was then evaporated in vacuo. The residue was purified by flash column chromatography on silica gel, eluting with dichloromethane, to afford the title compound, 1H NMR: (CD3OD), 8.76 (br m, 1H), 8.18 (d, J=7.69, 1H), 7.44 (d, J=7.69, 2H), 7.40-7.37 (m, 2H), 7.32-7.28 (m, 1H), 6.84 (d, J=8.79 1H), 6.73-6.69 (m, 1H), 5.12 (dd, J=13.18, 6.59 1H), 2.91 (d, J=6.59 2H), 1.41 (s, 9H).
Reaction SMILES: [Cr](O)(O)(=O)=O.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[Na+].[Na+].S(=O)(=O)(O)O.[CH3:22][C:23]1[O:28][CH2:27][N:26]([C:29]([CH3:36])([CH:31]([OH:35])[CH2:32][CH:33]=[CH2:34])[CH3:30])[C:25](=[O:37])[C:24]=1[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>O.CCOCC>[CH3:22][C:23]1[O:28][CH2:27][N:26]([C:29]([CH3:30])([C:31](=[O:35])[CH2:32][CH:33]=[CH2:34])[CH3:36])[C:25](=[O:37])[C:24]=1[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: C=CCC(O)C(C)(C)N1COC(C)=C(c2ccccc2)C1=O
Agent: O=[Cr](=O)(O)O
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CCOCC
Product: C=CCC(=O)C(C)(C)N1COC(C)=C(c2ccccc2)C1=O
Yield: 12.1 %

Procedure:
Chromic acid [1.7 ml of a solution prepared by the addition of a solution of sodium dichromate (0.4 g) in water (1.2 ml) to concentrated sulphuric acid (0.54 ml) and diluted to 2 ml with water] was added dropwise at 25° C. to a stirred solution of 2-(2,3-dihydro-6-methyl-4-oxo-5-phenyl-4H-1,3-oxazin-3-yl)-2-methylhex-5-ene-3-ol (1.0 g) in ether. After 18 hours the ether layer was separated, washed with sodium bicarbonate solution (2N) and with brine, dried (magnesium sulphate) and evaporated. The residue was purified by dry column chromatography on silica gel eluting with dichloromethane, to give 2-(2,3-dihydro-6-methyl-4-oxo-5-phenyl-4H-1,3-oxazin-3-yl)-2-methylhex-5-en-3-one (Compound 7, 0.12 g) as a yellow oil, NMR 1H δ1.4(s,6H), 1.88(s,3H), 3.22(d,2H), 5.05(m,2H), 5.22(s,2H), 5.9(m.1H), 7.2-7.35(m,5H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:37]=[C:38]([O:42][CH3:43])[C:39]=1[O:40][CH3:41])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:19][CH2:20][N:21]2[CH2:27][CH2:26][CH2:25][N:24]([C:28]3[NH:32][C:31]4[CH:33]=[CH:34][CH:35]=[CH:36][C:30]=4[N:29]=3)[CH2:23][CH2:22]2)([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:9]1)=[O:7].Cl[CH2:45][C:46]1[CH:50]=[CH:49][O:48][CH:47]=1>>[CH3:43][O:42][C:38]1[CH:37]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:39]=1[O:40][CH3:41])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:19][CH2:20][N:21]2[CH2:27][CH2:26][CH2:25][N:24]([C:28]3[N:29]([CH2:45][C:46]4[CH:50]=[CH:49][O:48][CH:47]=4)[C:30]4[CH:36]=[CH:35][CH:34]=[CH:33][C:31]=4[N:32]=3)[CH2:23][CH2:22]2)([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:9]1)=[O:7]
Reactant: ClCc1ccoc1
Reactant: COc1cc(C(=O)N2CCC(CCN3CCCN(c4nc5ccccc5[nH]4)CC3)(c3ccccc3)C2)cc(OC)c1OC
Product: COc1cc(C(=O)N2CCC(CCN3CCCN(c4nc5ccccc5n4Cc4ccoc4)CC3)(c3ccccc3)C2)cc(OC)c1OC

Procedure:
Prepare by the method of Example 35.1 using 1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine (prepared from (−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine (R,R)-di-p-anisoyltartaric acid salt) and 3-(chloromethyl)furan (J. Am. Chem. Soc. 72, 2195-2199 (1950)) to give the title compound.
Reaction SMILES: C(ON=O)(C)(C)C.Br[CH:9]1[CH2:14][CH2:13][CH2:12][CH:11]=[CH:10]1.[N+:15]([C:18]1[CH:19]=[C:20]([CH:22]=[C:23]([N+:25]([O-:27])=[O:26])[CH:24]=1)N)([O-:17])=[O:16]>CC#N>[N+:15]([C:18]1[CH:19]=[C:20]([CH:14]2[CH2:13][CH2:12][CH2:11][CH:10]=[CH:9]2)[CH:22]=[C:23]([N+:25]([O-:27])=[O:26])[CH:24]=1)([O-:17])=[O:16]
Reactant: BrC1C=CCCC1
Reactant: Nc1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Agent: CC(C)(C)ON=O
Solvent: CC#N
Product: O=[N+]([O-])c1cc(C2C=CCCC2)cc([N+](=O)[O-])c1
Temperature: 26.5 °C
Reaction time: 1 h
Yield: 12.1 %

Procedure:
To a solution of t-butylnitrite (119 μl, 1.0 mmol) and 3-bromocyclohexene (860 μl, 7.5 mmol) in CH3CN (0.5 ml), 3,5-dinitroaniline (92 mg, 0.5 mmol) was added during 10 minutes, while maintaining the temperature of the reaction mixture at 23-30° C. After stirring for one hour at room temperature the volatile material in the reaction mixture was removed at reduced pressure. Column chromatography (heptane-ethyl acetate 23:2) followed by preparative HPLC gave 15 mg (12%) of 3-(3,5-dinitrophenyl)cyclohexene as bright yellow crystals. 1H NMR (CDCl3, 300 MHz) δ 8.90, (t, 1H, J=2.1 Hz), 8.42, (d, 2H, J=2.1 Hz), 6.19-6.06, (m, 1H), 5.74-5.66, (m, 1H), 3.67, (m, 1H), 2.25-2.07, (m, 3H), 1.80-1.51, (m, 3H).
Reaction SMILES: C([O:5][C:6](=[O:26])[C:7]1[CH:12]=[CH:11][C:10]([N:13]2[S:17](=[O:19])(=[O:18])[C:16]3[CH:20]=[CH:21][CH:22]=[CH:23][C:15]=3[S:14]2(=[O:25])=[O:24])=[CH:9][CH:8]=1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[O:18]=[S:17]1(=[O:19])[C:16]2[CH:20]=[CH:21][CH:22]=[CH:23][C:15]=2[S:14](=[O:25])(=[O:24])[N:13]1[C:10]1[CH:11]=[CH:12][C:7]([C:6]([OH:26])=[O:5])=[CH:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)c1ccc(N2S(=O)(=O)c3ccccc3S2(=O)=O)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1ccc(N2S(=O)(=O)c3ccccc3S2(=O)=O)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of tert-butyl-4-(1,1,3,3-tetraoxidobenzo[d][1,3,2]dithiazol-2-yl)benzoate, 5, (0.77 g; 1.8 mmol) in dichloromethane (10 mL) was treated with trifluoroacetic acid (5 mL) and allowed to stir at ambient temperature for a period of 2 hours. The solvent was removed under reduced pressure to afford 4-(1,1,3,3-tetraoxidobenzo[d][1,3,2]dithiazol-2-yl)benzoic acid, 6, (0.67 g; 84%). The compound was used without further purification.
Reaction SMILES: [CH:1]1([CH2:4][N:5]([CH2:24][CH2:25][CH3:26])[C:6]2[N:11]=[CH:10][N:9]=[C:8]([C:12]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([CH:21]=O)=[CH:17][C:16]=3[CH3:23])=[O:13])[CH:7]=2)[CH2:3][CH2:2]1.Cl.[NH2:28][CH2:29][CH2:30][CH2:31][C:32]([O:34]C(C)(C)C)=O.C(=O)([O-])[O-].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C>C(Cl)Cl>[CH:1]1([CH2:4][N:5]([CH2:24][CH2:25][CH3:26])[C:6]2[N:11]=[CH:10][N:9]=[C:8]([C:12]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([CH2:21][N:28]4[CH2:29][CH2:30][CH2:31][C:32]4=[O:34])=[CH:17][C:16]=3[CH3:23])=[O:13])[CH:7]=2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)CCCN
Reactant: CCCN(CC1CC1)c1cc(C(=O)Nc2ccc(C=O)cc2C)ncn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: ClCCl
Product: CCCN(CC1CC1)c1cc(C(=O)Nc2ccc(CN3CCCC3=O)cc2C)ncn1
Reaction time: 18 h
Yield: 72 %

Procedure:
A solution of 6-((cyclopropylmethyl)(propyl)amino)-N-(4-formyl-2-methylphenyl)pyrimidine-4-carboxamide (Intermediate 29, 100 mg; 0.28 mmol) in DCM (5 ml) was treated with tert-butyl 4-aminobutanoate hydrochloride (Bachem, 244.6 mg; 1.25 mmol) and polymer supported carbonate (150 mg) followed by polymer supported triacetoxy borohydride (150 mg). After stirring for 18 hours the mixture was filtered and the solvent removed in vacuo. The residue was purified by column chromatography (silica) eluting with petroleum ether containing increasing amounts of EtOAc to give the title compound as a white solid (85 mg, 70%).
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[C:3]([CH3:8])[CH:2]=1.[C:9]1(=[O:15])[O:14][C:12](=[O:13])[CH2:11][CH2:10]1.[Cl-].[Al+3].[Cl-].[Cl-]>>[CH3:8][C:3]1[CH:2]=[CH:1][C:6]([OH:7])=[C:5]([CH:4]=1)[C:9]([CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[O:15]
Reactant: Cc1ccc(O)cc1
Reactant: O=C1CCC(=O)O1
Agent: [Al+3]
Agent: [Cl-]
Product: Cc1ccc(O)c(C(=O)CCC(=O)O)c1

Procedure:
p-Cresol was reacted with succinic anhydride and aluminium chloride in a similar manner to the procedure described in Example 8 (i) to give 3-(5-methyl-2-hydroxybenzoyl)-propionic acid.
Reaction SMILES: C1[CH:5]2[C@@H:6]3[CH:10]=[CH:9][C@H:8]([CH:4]2C=C1)[CH2:7]3.[CH2:11]([O:15][C:16](=[O:19])C=C)[CH2:12][CH2:13][CH3:14].C1(C=CC(O)=CC=1)O>>[CH2:11]([O:15][C:16]([C:6]12[CH2:7][CH:8]([CH2:4][CH2:5]1)[CH:9]=[CH:10]2)=[O:19])[CH2:12][CH2:13][CH3:14]
Reactant: C1=CC2C(C1)[C@@H]1C=C[C@H]2C1
Reactant: C=CC(=O)OCCCC
Agent: Oc1ccc(O)cc1
Product: CCCCOC(=O)C12C=CC(CC1)C2
Temperature: 190 °C
Reaction time: 5 h
Yield: 78 %

Procedure:
DCPD (dicyclopentadiene, Aldrich, 180 ml, 1.34 mol), butylacrylate (JUNSEI, 500 ml, 3.49 mol), and hydroquinone (2.7 g, 0.025 mol) were put in a 2 L autoclave. After heating to 190° C., reaction was carried out for 5 hours while stirring at 300 rpm. After the reaction was completed, the reaction mixture was cooled down and transferred to a distillation unit. The reaction mixture was distilled at 1 torr using a vacuum pump at 80° C. to obtain the product (yield: 78%). The mole ratio of exo-isomers to endo-isomers of the product was 56.2:43.8.
Reaction SMILES: [NH2:1][C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][C:5](=[O:7])[NH2:6].[F:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH:18]=[CH:19][C:20](ON1C(=O)CCC1=O)=[O:21].C(=O)([O-])O.[Na+].O>O1CCOCC1>[F:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH:18]=[CH:19][C:20]([NH:1][C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][C:5](=[O:7])[NH2:6])=[O:21]
Reactant: O=C(C=Cc1ccccc1F)ON1C(=O)CCC1=O
Reactant: NC(=O)CC[C@H](N)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: NC(=O)CC[C@H](NC(=O)C=Cc1ccccc1F)C(=O)O
Yield: 57.1 %

Procedure:
The same procedures as in Example 129 were carried out from L-glutamine (2.0 g), 2,5-dioxopyrrolidin-1-yl 3-(2-fluorophenyl)acrylate (3.6 g), sodium hydrogencarbonate (1.2 g), water (60 mL), and dioxane (160 mL), to give the captioned compound (2.3 g, 58%) as crystals.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([I:10])=[CH:6][CH:5]=1)=[O:3].[CH3:11][O:12][C:13]1[CH:14]=[C:15]([Mg]Br)[CH:16]=[CH:17][CH:18]=1>C1COCC1>[I:10][C:7]1[CH:8]=[CH:9][C:4]([C:2]([C:17]2[CH:16]=[CH:15][CH:14]=[C:13]([O:12][CH3:11])[CH:18]=2)([OH:3])[CH3:1])=[CH:5][CH:6]=1
Reactant: CC(=O)c1ccc(I)cc1
Reactant: COc1cccc([Mg]Br)c1
Solvent: C1CCOC1
Product: COc1cccc(C(C)(O)c2ccc(I)cc2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 4-iodoacetophenone (2 g, 7.97 mmol) in THF (20 ml) was immersed in an ice-bath and (3-methoxyphenyl)magnesium bromide 1M in THF (23.90 ml, 23.90 mmol) was added slowly by syringe. The reaction mixture was stirred at r.t. for 3 hrs. The reaction mixture was quenched with 20 ml aqueous saturated NH4Cl solution and diluted with ethyl acetate. The organic phase was separated and washed with brine. The organic phase was dried over Na2SO4, filtered and concentrated in vacuo to obtain the crude product which was purified by automated column chromatography (n-heptane (isom. mixture)/ethyl acetate). Organic solvents were removed to obtain title compound as yellowish oil.
Reaction SMILES: [C:1]([NH:5][C:6]1[C:7]([CH3:24])=[N:8][C:9]2[C:14]([N:15]=1)=[C:13]([C:16]1[NH:20][N:19]=[C:18]([C:21](O)=[O:22])[CH:17]=1)[CH:12]=[CH:11][CH:10]=2)([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.Cl.[Cl:35][CH2:36][CH2:37][NH2:38].F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1>CN(C=O)C.C(Cl)Cl>[C:1]([NH:5][C:6]1[C:7]([CH3:24])=[N:8][C:9]2[C:14]([N:15]=1)=[C:13]([C:16]1[NH:20][N:19]=[C:18]([C:21]([NH:38][CH2:37][CH2:36][Cl:35])=[O:22])[CH:17]=1)[CH:12]=[CH:11][CH:10]=2)([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1nc2cccc(-c3cc(C(=O)O)n[nH]3)c2nc1NC(C)(C)C
Reactant: NCCCl
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1nc2cccc(-c3cc(C(=O)NCCCl)n[nH]3)c2nc1NC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a 50-mL round-bottomed flask was added 5-(3-(tert-butylamino)-2-methylquinoxalin-5-yl)-1H-pyrazole-3-carboxylic acid (467b) (69 mg, 0.21 mmol), DCM (4 mL), DMF (1 mL), DIPEA (0.15 mL, 0.85 mmol), 2-chloroethanamine hydrochloride (49 mg, 0.42 mmol) (Sigma-Aldrich), and (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (110 mg, 0.21 mmol) (Sigma-Aldrich). The reaction mixture was stirred at RT for 16 h and the solvent was completely remover under vacuum. 5-(3-(tert-Butylamino)-2-methylquinoxalin-5-yl)-N-(2-chloroethyl)-1H-pyrazole-3-carboxamide (471a) was taken to next step without purification. m/z (ESI, +ve) 387.0 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][C-:3]1[CH:7]=[CH:6][CH:5]=[CH:4]1.[CH-:8]1[CH:12]=[CH:11][CH:10]=[CH:9]1.[Fe+2:13].CS(O)(=O)=O.[CH2:19]1[O:22][CH:20]1[CH3:21]>ClCCl>[OH:22][CH2:19][CH2:20][CH2:21][O:1][CH2:2][C-:3]1[CH:7]=[CH:6][CH:5]=[CH:4]1.[CH-:8]1[CH:12]=[CH:11][CH:10]=[CH:9]1.[Fe+2:13]
Reactant: OC[c-]1cccc1
Reactant: CC1CO1
Agent: [Fe+2]
Agent: CS(=O)(=O)O
Agent: c1cc[cH-]c1
Solvent: ClCCl
Product: OCCCOC[c-]1cccc1

Procedure:
21.6 g hydroxymethylferrocene was dissolved in 250 ml dichloromethane and 2.16 g methanesulfonic acid was added. Then 5.8 g of propylene oxide was added dropwise at room temperature while stirring. After this addition was complete, the mixture was stirred for another 24 hours at room temperature. Then the mixture was washed several times with saturated sodium bicarbonate solution and with distilled water. After the solution was dried, the solvent was drawn off by vacuum and 22.5 g of the desired product obtained.