Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[C:8](=[N:13][OH:14])[CH2:9][CH2:10][CH2:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br.[CH2:16]([O:18][C:19]([C@@H:21]1[CH2:26][CH2:25][CH2:24][N:23]([CH2:27][CH2:28]Br)[CH2:22]1)=[O:20])[CH3:17].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:16]([O:18][C:19]([C@@H:21]1[CH2:26][CH2:25][CH2:24][N:23]([CH2:27][CH2:28][O:14][N:13]=[C:8]2[CH2:9][CH2:10][CH2:11][CH:12]=[C:7]2[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:22]1)=[O:20])[CH3:17]
Reactant: ON=C1CCCC=C1c1ccccc1
Reactant: CCOC(=O)[C@@H]1CCCN(CCBr)C1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)[C@@H]1CCCN(CCON=C2CCCC=C2c2ccccc2)C1
Temperature: 25 °C
Reaction time: 336 h
Yield: 37.2 %

Procedure:
A mixture of the above oxime (0.55 g, 2.9 mmol), (R)-1-(2-bromoethyl)-3-piperidinecarboxylic acid ethyl ester hydrobromide (1.0 g, 2.9 mmol, EP 374801A), potassium carbonate (1.0 g, 7.3 mmol) and acetone (25 ml) was stirred at ambient temperature for 14 days. The mixture was filtered and the solvent evaporated in vacuo. The residue was purified by column chromatography on silica gel (125 g, heptane/ethyl acetate=1/1) to give 0.4 g of (R)-1-(2-(((2-phenylcyclohex-2-enylidene)amino)oxy)ethyl)-3-piperidinecarboxylic acid ethyl ester as an oil.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[N+:12]([CH:15](O)[CH3:16])([O-:14])=[O:13].C(O)(=[O:20])C.Cl>CO.C(N(CC)CC)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH:8]([OH:9])[CH:15]([N+:12]([O-:14])=[O:13])[CH2:16][OH:20])=[CH:10][CH:11]=1)([O-:3])=[O:2]
Reactant: CC(=O)O
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: CC(O)[N+](=O)[O-]
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: O=[N+]([O-])c1ccc(C(O)C(CO)[N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 70.24 %

Procedure:
7.55 g (0.05 moles) of 4-nitrobenzaldehyde and 4.55 g (0.05 moles) of nitroethanol are suspended in a mixture of 30 ml of methanol and 0.2 ml of triethylamine. The mixture is stirred at 0° C. until dissolution (about 30 minutes) and then allowed to stand at 0° C. for 20 hours. The mixture is acidified (pH 2) with 0.2 ml of acetic acid and 0.2 ml of concentrated hydrochloric acid, and 20 ml of ice-cold water are added. The separated crystals are filtered off, washed with chloroform and dried. 8.5 g (70.24%) of 1-(4-nitrophenyl)-2-nitro-1,3-propanediol are obtained; m.p. 105°-107° C.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[CH:12]/[C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=3)/[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[Cl:20][C:21]1[CH:22]=[CH:23][C:24]([CH3:36])=[C:25]([CH:27]=[N:28][C:29]([O:31][Si](C)(C)C)=[CH2:30])[CH:26]=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:10]=[C:9]2[NH:8][C:7](=[O:11])[C:6]3([CH:12]([C:13]4[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=4)[CH2:31][C:29](=[O:30])[NH:28][CH:27]3[C:25]3[CH:26]=[C:21]([Cl:20])[CH:22]=[CH:23][C:24]=3[CH3:36])[C:5]2=[CH:4][CH:3]=1
Reactant: O=C1Nc2cc(Br)ccc2/C1=C/c1cccc(Cl)c1
Reactant: C=C(N=Cc1cc(Cl)ccc1C)O[Si](C)(C)C
Solvent: Cc1ccccc1
Product: Cc1ccc(Cl)cc1C1NC(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Br)ccc12

Procedure:
In a manner similar to the method described in example 157b, E/Z-6-bromo-3-(3-chloro-benzylidene)-2-oxo-2,3-dihydro-indole (0.4 g, 1.10 mmol) prepared in example 157a was reacted with 1-(5-chloro-2-methylphenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene prepared in example 160a, in toluene to give racemic (2′R,3R,4′S)-6-bromo-4′-(3-chlorophenyl)-2,3-dihydro-2′-(5-chloro-2-methylphenyl)-2,6′-dioxospiro[indole-3,3′-piperidine] as a white solid. (Yield 0.3 g, 51%).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:7]=[CH:8][C:9]2[O:13][CH:12]=[CH:11][C:10]=2[CH:14]=1.C([Li])CCC.C1C(=O)N([Cl:27])C(=O)C1.O>C1COCC1.C(OCC)(=O)C>[Cl:27][C:12]1[O:13][C:9]2[CH:8]=[CH:7][C:6]([CH:2]3[O:3][CH2:4][CH2:5][O:1]3)=[CH:14][C:10]=2[CH:11]=1
Reactant: c1cc2cc(C3OCCO3)ccc2o1
Reactant: O=C1CCC(=O)N1Cl
Agent: [Li]CCCC
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Clc1cc2cc(C3OCCO3)ccc2o1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 82.4 %

Procedure:
5-[1,3]Dioxolan-2-yl-benzofuran (50 mg, 0.26 mmol) was dissolved in TIE (2 mL) and the solution was cooled down to −78° C. Butyl lithium (180 uL, 1.1 eq.) was added dropwise. This mixture was stirred 30 min at 25° C. Then the reaction mixture was cooled down to −78° C. and NCS (39 mg, 1.1 eq.) dissolved in 1 mL THF was added dropwise to the reaction mixture. After 1 h30 at −78° C. only small amount of starting material could be detected. The temperature was increased slowly to room temperature overnight. Water and ethyl acetate were added to the mixture and the aqueous layer was extracted 3 times. Combined organic phases was dried over MgSO4, filtrated and evaporated to give 2-Chloro-5-[1,3]dioxolan-2-yl-benzofuran (48.1 mg, 81%) sufficiently pure to be used in the next step.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[N:7][CH:6]=[CH:5][N:4]=1.ClCC1C(C(F)(F)F)=NC=CC=1.[NH:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C@@:23]2([C:41]3[C:32](=[CH:33][C:34]4[O:39][CH2:38][CH2:37][O:36][C:35]=4[CH:40]=3)[O:31][CH2:30]2)[C:22]1=[O:42].N1C2C(=CC=CC=2)C2(C3C(=CC4OCCOC=4C=3)OC2)C1=O>>[N:4]1[CH:5]=[CH:6][N:7]=[CH:8][C:3]=1[CH2:2][N:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C@@:23]2([C:41]3[C:32](=[CH:33][C:34]4[O:39][CH2:38][CH2:37][O:36][C:35]=4[CH:40]=3)[O:31][CH2:30]2)[C:22]1=[O:42]
Reactant: O=C1Nc2ccccc2[C@]12COc1cc3c(cc12)OCCO3
Reactant: ClCc1cnccn1
Agent: FC(F)(F)c1ncccc1CCl
Agent: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCCO3
Product: O=C1N(Cc2cnccn2)c2ccccc2[C@]12COc1cc3c(cc12)OCCO3

Procedure:
Following the procedure as described in Example 5.9, making non-critical variations using 2-(chloromethyl)pyrazine to replace 3-(chloromethyl)-2-(trifluoromethyl)pyridine, and (8S)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one to replace 2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one, (8S)-1′-(pyrazin-2-ylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one was obtained (62%) as a colorless solid: mp 216-218° C.; 1H NMR (300 MHz, CDCl3) δ8.65-8.62 (m, 1H), 8.58-8.50 (m, 2H), 7.27-7.15 (m, 2H), 7.09-7.01 (m, 1H), 6.91-6.85 (m, 1H), 6.51 (s, 1H), 6.31 (s, 1H), 5.13 (ABq, J=55.5, 16.1 Hz, 2H), 4.81 (ABq, J=81.0, 9.0 Hz, 2H), 4.24-4.09 (m, 4H); 13C NMR (300 MHz, CDCl3) δ177.5, 155.2, 151.2, 144.6, 144.2, 143.9, 143.8, 141.7, 138.3, 132.2, 128.8, 124.0, 123.7, 120.8, 111.7, 109.1, 99.4, 80.0, 64.5, 63.8, 58.0, 43.7; MS (ES+) m/z 387.8 (M+1); Anal. Calcd for C22H17N3O4: C, 68.21; H, 4.42; N, 10.85. Found: C, 67.81; H, 4.39; N, 10.84.
Reaction SMILES: [CH2:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:32])[CH2:15][NH:16][C:17]([C:19]2[CH:28]=[C:27]([OH:29])[C:26]3[C:21](=[CH:22][C:23]([CH3:31])=[C:24]([CH3:30])[CH:25]=3)[N:20]=2)=[O:18])[CH2:10][CH2:9]1)=[O:7])[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:39]([O:46][C:47](=[O:50])[CH2:48]Br)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>CN(C=O)C.O>[CH2:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14](=[O:32])[CH2:15][NH:16][C:17]([C:19]2[CH:28]=[C:27]([O:29][CH2:48][C:47]([O:46][CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)=[O:50])[C:26]3[C:21](=[CH:22][C:23]([CH3:31])=[C:24]([CH3:30])[CH:25]=3)[N:20]=2)=[O:18])[CH2:12][CH2:13]1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)N1CCN(C(=O)CNC(=O)c2cc(O)c3cc(C)c(C)cc3n2)CC1
Reactant: O=C(CBr)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCOC(=O)N1CCN(C(=O)CNC(=O)c2cc(OCC(=O)OCc3ccccc3)c3cc(C)c(C)cc3n2)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 250 mg 4-{2-[(4-Hydroxy-6,7-dimethyl-quinoline-2-carbonyl)-amino]-acetyl}-piperazine-1-carboxylic acid butyl ester in 1.5 ml of DMF, 202 mg of cesium carbonate and 142 mg of Bromo-acetic acid benzyl ester were added and the reaction mixture was stirred for 12 h at RT. Then, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was dried over MgSO4 and the solvents were removed under reduced pressure. The isolated crude product was pure enough for the next reaction step. Yield: 290 mg.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:17]1([CH2:23][CH2:24][CH2:25][CH:26]([NH:36][C:37](=[O:47])[C@H:38]([CH2:40][C:41]2[CH:42]=[N:43][CH:44]=[CH:45][CH:46]=2)[NH2:39])[CH2:27][CH2:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(CC)C(C)C)(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[C:30]1([CH2:29][CH2:28][CH2:27][CH:26]([NH:36][C:37](=[O:47])[C@H:38]([CH2:40][C:41]2[CH:42]=[N:43][CH:44]=[CH:45][CH:46]=2)[NH:39][C:14]([CH:11]2[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][CH2:12]2)=[O:16])[CH2:25][CH2:24][CH2:23][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Reactant: N[C@@H](Cc1cccnc1)C(=O)NC(CCCc1ccccc1)CCCc1ccccc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(C(=O)N[C@@H](Cc2cccnc2)C(=O)NC(CCCc2ccccc2)CCCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
1-tert-Butoxycarbonyl-piperidine-4-carboxylic acid (0.66 g; 2.89 mmol) is dissolved in methylene chloride (25 mL) at ambient temperature. 3-(3-Pyridyl)-alanine [4-phenyl-1-(3-phenyl-propyl)-butyl]-amide (85) (1.00 g; 2.41 mmol), N,N-diisopropylethylamine (0.68 g; 5.29 mmol) and PyBOP (1.50 g; 2.89 mmol) are added sequentially. The reaction is stirred for 5 hours at room temperature, then concentrated under reduced pressure. The residue is purified via silica gel chromatography (80%→100% ethyl acetate in hexanes) affording the desired product (86) as a white solid. ESMS: MH+ 627.6
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][N:5]=[C:6]2[C:11]=1[N:10]=[C:9]([O:12][CH3:13])[CH:8]=[CH:7]2.COC1[N:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[N:22]=[CH:21][CH:20]=[C:19]2O.P(Br)(Br)Br.C[N:32](C=O)C>>[CH3:13][O:12][C:9]1[N:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[CH:4][CH:3]=[C:2]2[N:22]1[CH:21]=[C:20]2[C:25]([CH2:24][CH2:23][CH:18]([NH2:17])[CH2:19]2)=[N:32]1
Reactant: COc1ccc2nccc(O)c2n1
Reactant: COc1ccc2nccc(Br)c2n1
Reactant: CN(C)C=O
Agent: BrP(Br)Br
Product: COc1ccc2nccc(-n3cc4c(n3)CCC(N)C4)c2n1
Temperature: 25 °C
Yield: 75 %

Procedure:
8-Bromo-2-methoxy-[1,5]naphthyridine. To a suspension of 6-methoxy-[1,5]naphthyridin-4-ol (8.8 g, 0.050 mol) in DMF (167 mL) was added PBr3 (4.7 mL, 0.050 mol) at 45° C. The suspension became homogeneous and then a suspension formed over 20 min. The mixture was cooled to RT and the solid was filtered and washed with Et2O (100 mL). Further solids precipitated from the filtrate and were collected. Water (50 mL) was added to the solid and the suspension was basified with 1 N NaOH (200 mL). The aqueous layer was extracted with CH2Cl2 (3×250 mL), washed with brine (150 mL), dried (MgSO4) and concentrated. The resulting residue was purified on SiO2 (0-60% EtOAc/hexanes) to provide 8.9 g (75%) of the title compound as a white solid. MS (ESI): exact mass calculated for C9H7BrN2O, 237.97; m/z found, 239.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6): 8.57 (d, J=4.7, 1H), 8.27 (d, J=9.0, 1H), 8.05 (d, J=4.7, 1H), 7.30 (d, J=9.0, 1H), 4.04 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@@H:6]([C@@H:11]1[CH2:16][CH2:15][CH2:14][O:13][CH2:12]1)[C:7]([O:9]C)=[O:8])=[O:4].[Li+].[OH-].Cl>C1COCC1.O>[CH3:1][O:2][C:3]([NH:5][C@@H:6]([C@@H:11]1[CH2:16][CH2:15][CH2:14][O:13][CH2:12]1)[C:7]([OH:9])=[O:8])=[O:4]
Reactant: COC(=O)N[C@H](C(=O)OC)[C@@H]1CCCOC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)N[C@H](C(=O)O)[C@@H]1CCCOC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 105.6 %

Procedure:
To a solution of (S)-methyl 2-(methoxycarbonylamino)-2-((S)-tetrahydro-2H-pyran-3-yl)acetate (126 mg, 0.545 mmol) in THF (4 mL) stirring at rt was added a solution of 1M LiOH (1.090 mL, 1.090 mmol) in water. The reaction was stirred at rt for 3 h, neutralized with 1M HCl (1.1 mL) and extracted with EtOAc (3×10 mL). The organics were dried, filtered and concentrated to yield (S)-2-(methoxycarbonylamino)-2-((S)-tetrahydro-2H-pyran-3-yl)acetic acid (Cap-177a) (125 mg) as a clear colorless oil. LC-MS retention time 0.44 min; m/z 218.00 (MH+). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a PHENOMENEX® Luna 10 u C18 3.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where Solvent A was 5% MeOH/95% H2O/10 mM ammonium acetate and Solvent B was 5% H2O/95% MeOH/10 mM ammonium acetate. MS data was determined using a MICROMASS® Platform for LC in electrospray mode. 1H NMR (400 MHz, chloroform-d) δ ppm 5.28 (d, J=8.8 Hz, 1H), 4.38 (dd, J=8.7, 5.6 Hz, 1H), 3.96-4.04 (m, 1H), 3.91 (d, J=11.0 Hz, 1H), 3.71 (s, 3H), 3.33-3.41 (m, 1H), 3.24-3.32 (m, 1H), 2.10-2.24 (m, 1H), 1.74-1.83 (m, 1H), 1.63-1.71 (m, 2H), 1.35-1.49 (m, 1H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]=[C:3]([C:7]2[N:12]=[C:11]([F:13])[C:10]3[O:14][C:15]4[C:20]([C@@:21]5([CH2:26][CH2:25][O:24][C:23]([NH2:27])=[N:22]5)[C:9]=3[CH:8]=2)=[CH:19][C:18]([NH2:28])=[CH:17][CH:16]=4)[CH2:2]1.[Cl:29][C:30]1[CH:31]=[CH:32][C:33]([C:36](O)=[O:37])=[N:34][CH:35]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:27][C:23]1[O:24][CH2:25][CH2:26][C@:21]2([C:9]3[CH:8]=[C:7]([C:3]4[CH2:2][O:1][CH2:6][CH2:5][CH:4]=4)[N:12]=[C:11]([F:13])[C:10]=3[O:14][C:15]3[C:20]2=[CH:19][C:18]([NH:28][C:36](=[O:37])[C:33]2[CH:32]=[CH:31][C:30]([Cl:29])=[CH:35][N:34]=2)=[CH:17][CH:16]=3)[N:22]=1
Reactant: NC1=N[C@@]2(CCO1)c1cc(N)ccc1Oc1c2cc(C2=CCCOC2)nc1F
Reactant: O=C(O)c1ccc(Cl)cn1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: NC1=N[C@@]2(CCO1)c1cc(NC(=O)c3ccc(Cl)cn3)ccc1Oc1c2cc(C2=CCCOC2)nc1F
Temperature: 25 °C
Reaction time: 15 h
Yield: 25.8 %

Procedure:
To a solution of (S)-3-(5,6-dihydro-2H-pyran-3-yl)-1-fluoro-5′,6′-dihydrospiro[chromeno[2,3-c]pyridine-5,4′-[1,3]oxazine]-2′,7-diamine (0.095 g, 0.248 mmol) in DMF (1 mL) were added 5-chloro-2-pyridinecarboxylic acid (0.043 g, 0.273 mmol), 0-(−7-azabenzotriazol-1-yl)-n,′n,′n,′n′-tetramethyluronium pf6 (0.099 g, 0.261 mmol) and Hunig's base (0.086 ml, 0.497 mmol) and the resulting mixture was stirred at rt for 15 h. The mixture was quenched with 5 drops of 2 N HCl and stirred for 1 min followed by the addition of water and extracted with EtOAc. The combined organics were dried over Na2SO4, filtered, concentrated and chromatographed on silica gel using 0-3% MeOH/DCM. The product was repurified by HPLC to afford (S)—N-(2′-amino-3-(5,6-dihydro-2H-pyran-3-yl)-1-fluoro-5′,6′-dihydrospiro[chromeno[2,3-c]pyridine-5,4′-[1,3]oxazin]-7-yl)-5-chloropicolinamide as a white solid (0.0334 g, 0.064 mmol, 25.8% yield). MS m/z=522.0 [M+H]+.
Reaction SMILES: [S:1]1[CH:5]=[C:4]([C:6]2[C:10]([CH:11]=O)=[CH:9][N:8]([C:13]3[CH:21]=[CH:20][C:16]([C:17]([OH:19])=[O:18])=[CH:15][CH:14]=3)[N:7]=2)[C:3]2[CH:22]=[CH:23][CH:24]=[CH:25][C:2]1=2.Cl.[NH2:27]O.C([O-])=O.[Na+].O>C(O)=O>[S:1]1[CH:5]=[C:4]([C:6]2[C:10]([C:11]#[N:27])=[CH:9][N:8]([C:13]3[CH:21]=[CH:20][C:16]([C:17]([OH:19])=[O:18])=[CH:15][CH:14]=3)[N:7]=2)[C:3]2[CH:22]=[CH:23][CH:24]=[CH:25][C:2]1=2
Reactant: NO
Reactant: O=Cc1cn(-c2ccc(C(=O)O)cc2)nc1-c1csc2ccccc12
Agent: Cl
Agent: O=C[O-]
Agent: [Na+]
Solvent: O=CO
Solvent: O
Product: N#Cc1cn(-c2ccc(C(=O)O)cc2)nc1-c1csc2ccccc12
Temperature: 25 °C
Reaction time: 5 h
Yield: 50.4 %

Procedure:
A solution of 4-(3-benzo[b]thiophene-3-yl-4-formylpyrazole-1-yl)benzoic acid (0.26 g), hydroxylamine hydrochloride (0.058 g) and sodium formate (0.10 g) in formic acid (5 mL) was heated under reflux for 24 hours. To this reaction mixture was added water at room temperature, and this mixture was extracted with ethyl acetate. This organic layer was washed with brine, dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. This obtained residue was dissolved with pyridine (5 mL), to this mixture was added trifluoroacetic anhydride (0.48 g) in a dropwise manner under ice cooling, and this mixture was stirred at room temperature for 5 hours. To this reaction mixture was added 2 mol/L hydrochloric acid, and this mixture was extracted with ethyl acetate. This organic layer was washed with brine, dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. The obtained residue was washed with n-hexane/diethyl ether=1/1 to give the title compound (0.13 g).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH2:8].[CH3:9][C:10]([CH3:14])(O)[C:11]#N.[OH2:15]>>[CH3:9][C:10]1([CH3:14])[NH:8][C@H:3]2[C@@H:2]([CH2:7][CH2:6][CH2:5][CH2:4]2)[NH:1][C:11]1=[O:15]
Reactant: CC(C)(O)C#N
Reactant: O
Reactant: N[C@@H]1CCCC[C@H]1N
Product: CC1(C)N[C@@H]2CCCC[C@H]2NC1=O

Procedure:
The disclosure deals with novel synthesis involving (a) hydrogenation of a cis-3,3-dialkyl-3,4-dihydroquinoxaline-2-one in the presence of a suitable hydrogenation catalyst, at elevated temperature and pressure, to yield a cis-3,3-dialkyl decahydroquinoxaline-2-one; (b) reaction of trans-1,2-diaminocyclohexane with acetone cyanohydrin in the presence of water to yield trans-3,3-dimethyl-decahydroquinoxaline-2-one; and (c) a reaction of 1,2-diamine with a saturated acyclic or cyclic monoketone or aldehyde and a holoform, in the presence of (i) a phase transfer catalyst (ii) an organic solvent, and (iii) solid or aqueous alkali to yield 2-keto-1,4-diazacycloalkanes. Such compounds exhibit exceptional UV light stabilizing property.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([OH:16])=[C:11]([Cl:17])[CH:10]=2)[C:5]([F:18])=[CH:4][N:3]=1.[OH:19][C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=1)[NH2:23]>>[Cl:17][C:11]1[CH:10]=[C:9]([NH:8][C:6]2[C:5]([F:18])=[CH:4][N:3]=[C:2]([NH:23][C:22]3[CH:24]=[CH:25][CH:26]=[C:20]([OH:19])[CH:21]=3)[N:7]=2)[CH:14]=[C:13]([CH3:15])[C:12]=1[OH:16]
Reactant: Nc1cccc(O)c1
Reactant: Cc1cc(Nc2nc(Cl)ncc2F)cc(Cl)c1O
Product: Cc1cc(Nc2nc(Nc3cccc(O)c3)ncc2F)cc(Cl)c1O

Procedure:
In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, the reaction of 2-chloro-5-fluoro-N4-(3-chloro-4-hydroxy-5-methylphenyl)-4-pyrimidineamine with 3-hydroxyaniline gave N4-(3-chloro-4-hydroxy-5-methylphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine. LCMS: retn, time: 18.20 min.; purity: 94%; MS (m/e): 360 (M+); 1 (DMSO-d6): δ 9.26 (1H, s), 9.23 (1H, s), 9.16 (1H, s), 8.89 (1H, s), 8.14 (1H, d, J=4.5 Hz), 7.66 (1H, d, J=2.1 Hz), 7.60 (1H, d, J=2.1 Hz), 7.29 (1H, d, J=8.4 Hz), 7.11 (1H, s), 7.06 (1H, t, J=8.4 Hz), 6.41 (1H, d, J=8.4 Hz), 2.30 (3H, s).
Reaction SMILES: OC[C:3]1C(=O)N(NC2C=CC=CC=2)C(=O)[NH:7][CH:8]=1.Br.BrC[C:21]1[CH:22]=[C:23]([CH:33]=[CH:34][CH:35]=1)[NH:24][C:25]1[NH:30][C:29](=[O:31])[NH:28][C:27](=[O:32])[CH:26]=1.C([S-:38])#N.[K+]>C(O)(=O)C>[SH:38][C:21]1[CH:22]=[C:23]([CH:33]=[CH:34][CH:35]=1)[N:24]([CH2:3][C:8]#[N:7])[C:25]1[NH:30][C:29](=[O:31])[NH:28][C:27](=[O:32])[CH:26]=1
Reactant: O=c1[nH]cc(CO)c(=O)n1Nc1ccccc1
Reactant: O=c1cc(Nc2cccc(CBr)c2)[nH]c(=O)[nH]1
Reactant: N#C[S-]
Agent: Br
Agent: [K+]
Solvent: CC(=O)O
Product: N#CCN(c1cccc(S)c1)c1cc(=O)[nH]c(=O)[nH]1
Yield: 80 %

Procedure:
6-chlorouracil (1 mmol) and meta-aminobenzyl alcohol (2.0 mmol) were dissolved in 10 ml 2-methoxyethanol to form a reaction mixture. The mixture was then stirred at reflux for 10 hours to form 6-(meta-hydroxymethyl anilino)uracil with a yield of 86%. The hydroxy group was displaced by a bromo group by reacting the hydroxymethyl anilino-uracil (0.5 mmol) with 30% HBr in acetic acid (10 ml), thus forming 6-(meta-bromomethyl anilino)uracil with a yield of 90%. The bromo group was further replaced by a thiocyanate group by reacting 0.4 mmol 6-(meta-bromomethyl anilino)uracil with 2 mmol KSCN to form 6-(meta-mercaptocyanomethyl anilino)uracil (MMCMAU) with a yield of 80%. mMCMAU was then hydrolyzed to 6-(meta-thiomethyl anilino)uracil in 5 mL of 2N NaOH. The final product, 6-(meta-disulfidemethyl anilino)uracil, was formed quantitatively by reacting 6-(meta-thiomethyl anilino)uracil with methyl methane thiosulfonate in 2 molar excess.
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:8]2=[C:9]([C:13]3[CH:14]=[N:15][N:16]([CH3:28])[C:17]=3[C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=3)[N:10]=[C:11]([CH3:12])[N:7]2[N:6]=[CH:5][N:4]=1.C1N=C(N)C2N=CN([C@@H]3[O:42][C@H](COP(OP(OC[C@H]4O[C@@H](N5C=C(C(N)=O)CC=C5)[C@H](O)[C@@H]4O)(O)=O)(O)=O)[C@@H](O)[C@H]3OP(O)(O)=O)C=2N=1>>[CH3:1][NH:2][C:3]1[C:8]2=[C:9]([C:13]3[CH:14]=[N:15][N:16]([CH3:28])[C:17]=3[C:18]3[CH:19]=[CH:20][C:21]([C:24]([F:26])([F:27])[F:25])=[CH:22][CH:23]=3)[N:10]=[C:11]([CH2:12][OH:42])[N:7]2[N:6]=[CH:5][N:4]=1
Reactant: CNc1ncnn2c(C)nc(-c3cnn(C)c3-c3ccc(C(F)(F)F)cc3)c12
Reactant: NC(=O)C1=CN([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](OP(=O)(O)O)[C@@H]3O)[C@@H](O)[C@H]2O)C=CC1
Product: CNc1ncnn2c(CO)nc(-c3cnn(C)c3-c3ccc(C(F)(F)F)cc3)c12

Procedure:
N,7-Dimethyl-5-{1-methyl-5-[4-(trifluoromethyl)phenyl]-1H-pyrazol-4-yl}imidazo[5,1-f][1,2,4]triazin-4-amine, at a substrate concentration of 50 μM, was incubated for 1 hour with rat liver microsomes and NADPH (1 mM) (21.1 mg/mL protein concentration; 25 mL incubation volume). Incubations were extracted with 4 volumes of acetonitrile. Following centrifugation at 3400 rpm, the supernatant was evaporated at 25° C. in a Turbovap. The residue was reconstituted with 5% aqueous acetonitrile and subjected to preparative reverse-phase HPLC purification (Column: Zorbax Rx-C8 [Agilent], 250×9.6 mm, 5 μm; Mobile phase A: aqueous 5 mM ammonium formate, pH 3; Mobile phase B: acetonitrile; Gradient: 10% to 90% B; UV detection at 254 mm). The fractions containing the M+16 metabolite were dried down to provide the product as a solid. MS m/z 404 (M+H). 1H NMR (600 MHz, DMSO-d6) δ 2.71 (d, J=4.8 Hz, 3H), 3.86 (s, 3H), 4.69 (s, 2H), 6.68 (br q, J=4.7 Hz, 1H), 7.55 (d, J=8.0 Hz, 2H), 7.70 (s, 1H), 7.76 (d, J=8.0 Hz, 2H), 7.85 (s, 1H).
Reaction SMILES: [Br-].[CH3:2][O:3][C:4]([C:6]1[CH:7]=[C:8]([CH:29]=[CH:30][CH:31]=1)[CH2:9][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:5].[O-][CH2:33][CH3:34].[Na+].[CH:36](=O)C>>[CH:9]([C:8]1[CH:7]=[C:6]([CH:31]=[CH:30][CH:29]=1)[C:4]([O:3][CH2:2][CH3:36])=[O:5])=[CH:33][CH3:34]
Reactant: CC[O-]
Reactant: COC(=O)c1cccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c1
Reactant: CC=O
Agent: [Br-]
Agent: [Na+]
Product: CC=Cc1cccc(C(=O)OCC)c1

Procedure:
The preparation of begins with the known methyl 3-(bromomethyl)benzoate. This halide is heated in xylene solution with triphenylphosphine to yield (3-methoxycarbonylbenzyl)triphenylphosphonium bromide. The phosphonium salt is converted to the ylide with sodium ethoxide and the ylide caused to react with acetaldehyde to yield ethyl 3-(1-propenyl)benzoate. (Note that the ethyl ester has been obtained as a result of transesterification with solvent ethanol.) The ester is heated with N-bromosuccinimide in carbon tetrachloride for an extended period to yield ethyl 3-(3-bromo-1-propenyl)benzoate. This compound is treated with the anion derived from methyl methylthiomethyl sulfoxide as described in section (b) above. The resulting dimethylmercaptal S-oxide is hydrolyzed with acid catalysis to ethyl 3-(4-oxo-1-butenyl)benzoate. Hydrogenation of this olefinic aldehyde over a palladium catalyst affords the aldehyde intermediate XXIII.