Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][NH2:5]>[Pd].CC#N>[CH3:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][NH:5][CH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH3:4]
Reactant: Cc1ccccc1CN
Agent: [Pd]
Solvent: CC#N
Product: Cc1ccccc1CNCc1ccccc1C
Temperature: 90 °C
Reaction time: 6 h
Yield: 87 %

Procedure:
2-Methylbenzylamine (0.5 mmol) was heated with catalyst Pd@ba-GO (10 mg) and solvent CH3CN (0.2 mL) at 90° C. in a flask open to air for 6 hours, and then stirred also at 90° C. under H2 gas (1 atm) for 6 hours to obtain di-(2-methylbenzyl)amine. Again, an unexpectedly high yield of 87% was observed.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH:9]([C:13]([O:15][CH3:16])=[O:14])[CH:8]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[CH2:7][C:6]=2[CH:25]=1.C[Si](C)(C)[N-][Si](C)(C)C.[K+].P(OCC)(OCC)[O:37]CC>O1CCCC1.CCCCCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[C:9]([OH:37])([C:13]([O:15][CH3:16])=[O:14])[CH:8]([C:17]3[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=3)[CH2:7][C:6]=2[CH:25]=1
Reactant: CCOP(OCC)OCC
Reactant: COC(=O)C1C(=O)Nc2ccc(Cl)cc2CC1c1ccc(OC)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COC(=O)C1(O)C(=O)Nc2ccc(Cl)cc2CC1c1ccc(OC)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 94.4 %

Procedure:
A solution of 7-chloro-1,3,4,5-tetrahydro-3-(methoxycarbonyl)-4-(4-methoxyphenyl)-2H-1-benzazepin-2-one (15 g, 41.7 mmole) in 780 ml of tetrahydrofuran was cooled to -78° C. and 147 ml (167 mmole in tetrahydrofuran) of potassium hexamethyldisilazide solution was added. After stirring for 1 hour, 28.7 ml of triethyl phosphite (166.7 mmole) was added and anhydrous oxygen gas was rapidly bubbled through the resulting solution. The reaction temperature was then raised to 0° C. and allowed to stir for an additional hour. Oxygenation was then discontinued and the reaction was quenched by the addition of 50 ml of acetic acid. The reaction mixture was then concentrated and the residue dissolved in ethyl acetate. The organic solution was washed successively with 1N hydrochloric acid, saturated sodium bicarbonate, and brine and then dried over anhydrous sodium sulfate. Concentration of the dried organic solution afforded a solid which, upon trituration in hexane, gave 14.8 g of the title compound.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([Cl:17])[CH:3]=1.[Cl:18][C:19]1[CH:24]=[C:23](B(O)O)[CH:22]=[CH:21][N:20]=1>>[Cl:17][C:4]1[CH:3]=[C:2]([C:23]2[CH:22]=[CH:21][N:20]=[C:19]([Cl:18])[CH:24]=2)[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=1
Reactant: OB(O)c1ccnc(Cl)c1
Reactant: Cc1c2n(c3c(Br)cc(Cl)cc13)CCNC2=O
Product: Cc1c2n(c3c(-c4ccnc(Cl)c4)cc(Cl)cc13)CCNC2=O

Procedure:
The title compound, off-white solid (47 mg, 54%), MS (ISP) m/z=346.4 [(M+H)+], mp 270° C., was prepared in accordance with the general method of example 1 from 6-bromo-8-chloro-10-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 12) (78.4 mg, 0.25 mmol) and commercially available 2-chloro-pyridin-4-ylboronic acid (51.1 mg, 0.325 mmol).
Reaction SMILES: [C:1]1([C:7]2[C:8](=[O:18])[NH:9][C:10](=[O:17])[N:11]3[CH2:16][CH2:15][CH2:14][S:13][C:12]=23)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:26][CH2:27][CH2:28][CH2:29][Cl:30]>CN(C)C=O>[Cl:30][CH2:29][CH2:28][CH2:27][CH2:26][N:9]1[C:8](=[O:18])[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[C:12]2[S:13][CH2:14][CH2:15][CH2:16][N:11]2[C:10]1=[O:17]
Reactant: ClCCCCBr
Reactant: O=c1[nH]c(=O)n2c(c1-c1ccccc1)SCCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=c1c(-c2ccccc2)c2n(c(=O)n1CCCCCl)CCCS2
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To a suspension of 5.28 g (20.3 mmol) of 9-phenyl-3,4-dihydro-2H,6H-pyrimido-[6,1-b][1,3]thiazine-6,8(7H)-dione and 2.80 g (20.3 mmol) of potassium carbonate in 80 ml of N,N-dimethylformamide, 3.46 ml (30 mmol) of 1-bromo-4-chlorobutane was added at room temperature, followed by stirring at 60° C. for 2 hours and then at 100° C. for 3 hours. After cooling, the reaction mixture was concentrated to dryness. The residue was dissolved in methylene chloride-water; the organic layer was washed with water and dried. The oily substance obtained by distilling off the solvent was purified by column chromatography (eluent, n-hexane/ethyl acetate=5/1→2/1) to yield 4.58 g (64.5%, light white powder) of the desired product.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]([OH:10])([CH3:9])[CH3:8])=[CH:3][CH:2]=1.C([Li])CCC.[C:16]12([C:26](Cl)=[O:27])[CH2:25][CH:20]3[CH2:21][CH:22]([CH2:24][CH:18]([CH2:19]3)[CH2:17]1)[CH2:23]2>C1COCC1.CCCCCC>[C:16]12([C:26]([O:10][C:7]([C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)([CH3:9])[CH3:8])=[O:27])[CH2:23][CH:22]3[CH2:21][CH:20]([CH2:19][CH:18]([CH2:24]3)[CH2:17]1)[CH2:25]2
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Reactant: CC(C)(O)c1ccncc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(OC(=O)C12CC3CC(CC(C3)C1)C2)c1ccncc1
Yield: 70.8 %

Procedure:
The method followed that described in Example 1, but using 2-(4-pyridyl)propan-2-ol (0.69 g, 5.0 mmol) in THF (20 ml), n-butyllithium (2.5 M; 2.0 ml, 5.0 mmol) in hexane, and 1-adamantanecarbonyl chloride (1.09 g, 5.5 mmol) in THF (6 ml). Chromatography, on elution with ether-petrol-triethylamine 50:50:1, gave the title compound (1.06 g, 71%) as an oil. IR νmax 1730 cm-1 ; 1H-NMR (CDCl3) δ1.71 (6H, s, CMe2), 1.71 and 1.90 (12H, 2s, adamantyl CH2), 2.02 (3H, s, adamantyl CH), 7.23 (2H, d, J 6.1 Hz, Py 3 and 5-H), 8.56 (2H, d, J 6.1 Hz, Py 2 and 6-H). Anal. Calcd: C, 76.22; H, 8.42; N, 4.68. Found: C, 76.17; H, 8.47; N, 4.64%.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([S:19][CH3:20])[O:7][C@H:6]1[C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[C:23]([CH2:28][C:29]2[CH:34]=[CH:33][C:32](/[CH:35]=[CH:36]/[CH2:37][C:38]([O:40][CH3:41])=[O:39])=[CH:31][CH:30]=2)[CH:22]=1)(=[O:3])[CH3:2]>C1COCC1.CO.[Pd]>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([S:19][CH3:20])[O:7][C@H:6]1[C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[C:23]([CH2:28][C:29]2[CH:30]=[CH:31][C:32]([CH2:35][CH2:36][CH2:37][C:38]([O:40][CH3:41])=[O:39])=[CH:33][CH:34]=2)[CH:22]=1)(=[O:3])[CH3:2]
Reactant: COC(=O)C/C=C/c1ccc(Cc2cc([C@@H]3O[C@H](SC)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]3OC(C)=O)ccc2C)cc1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)CCCc1ccc(Cc2cc([C@@H]3O[C@H](SC)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]3OC(C)=O)ccc2C)cc1
Yield: 93.7 %

Procedure:
(2S,3S,4R,5S,6R)-2-(3-(4-((E)-4-methoxy-4-oxobut-1-en-1-yl)benzyl)-4-methylphenyl)-6-(methylthio)tetrahydro-2H-pyran-3,4,5-triyl triacetate (8, 1.74 g, 3.0 mmol) was dissolved in a 1:1 (v:v) THF/MeOH solution. Pd/C (10% wet, 174 mg) was added and the reaction hydrogenated at 40 psi for 3 hours. The reaction was monitored by 1H NMR. Upon completion, the reaction was filtered over Celite with excess MeOH. Removal of solvents in vacuo provided the product as a light yellow solid (1.65 g, 94% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.11-7.20 (m, 2 H), 7.07 (t, J=7.8 Hz, 3 H), 6.99 (d, J=8.1 Hz, 2 H), 5.33 (dd, J=9.6 Hz, 1 H), 5.21 (dd, J=9.6 Hz, 1 H), 5.12 (dd, J=9.6 Hz, 1 H), 4.52 (d, J=9.9 Hz, 1 H), 4.39 (d, J=9.9 Hz, 1 H), 3.85-4.00 (m, 2 H), 3.67 (s, 3 H), 2.61 (t, J=7.6 Hz, 2H), 2.33 (t, J=7.5 Hz, 2 H), 2.21 (s, 3 H), 2.18 (s, 3 H), 2.10 (s, 3 H), 2.01 (s, 3 H), 1.93 (quin, J=7.6 Hz, 2 H), 1.75 (s, 3 H). MS (ES+) [M+NH4]+=604.
Reaction SMILES: [Cl-].[Na+].[Cl-].[Ca+2].[Cl-].[OH2:6].C1O[C@H]2[C@H](O)[C@H]([O:15][C@@H:16]3[C@@H:21]([OH:22])[C@H:20]([O:23][C@H:24]4[C@@H:28]5[C@H:29]([OH:44])[C@H:30]([O:32][C@@H]6[C@@H](O)[C@H](O)O[C@H](CO)[C@@H]6O)[O:31][C@H:25]4[CH2:26][O:27]5)[O:19][C@H:18]([CH2:45][OH:46])[C@@H:17]3[OH:47])O[C@@H]1[C@H]2O>C(O)C(N)(CO)CO.Cl>[CH2:26]1[O:6][C@H:28]2[C@H:29]([OH:44])[C@H:30]([OH:32])[O:31][C@@H:25]1[C@H:24]2[O:23][C@@H:20]1[O:19][C@H:18]([CH2:45][OH:46])[C@H:17]([OH:47])[C@H:16]([O:32][C@@H:30]2[O:31][C@H:25]3[CH2:26][O:27][C@H:28]([C@@H:24]3[O:23][C@@H:20]3[O:19][C@H:18]([CH2:45][OH:46])[C@H:17]([OH:47])[C@H:16]([OH:15])[C@H:21]3[OH:22])[C@@H:29]2[OH:44])[C@H:21]1[OH:22]
Reactant: OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O[C@@H]2O[C@H]3CO[C@@H]([C@@H]2O)[C@@H]3O[C@@H]2O[C@H](CO)[C@H](O)[C@H](O[C@@H]3O[C@H]4CO[C@@H]([C@@H]3O)[C@@H]4O)[C@H]2O)[C@H]1O
Reactant: O
Agent: Cl
Agent: NC(CO)(CO)CO
Agent: [Ca+2]
Product: OC[C@H]1O[C@@H](O[C@H]2[C@H]3OC[C@@H]2O[C@@H](O[C@H]2[C@@H](O)[C@@H](CO)O[C@@H](O[C@H]4[C@H]5OC[C@@H]4O[C@@H](O)[C@H]5O)[C@@H]2O)[C@H]3O)[C@H](O)[C@@H](O)[C@H]1O
Reaction time: 0.02 h

Procedure:
A solution containing agarose at a concentration of 0.2%(w/v) or 0.5%(w/v) in 20 mM Tris-HCl buffer (pH 7.2) containing 10 mM sodium chloride (in case of Agarase I) or 20 mM Tris-HCl buffer (pH 7.2) containing 10 mM calcium chloride and 10 mM sodium chloride (in case of Agarase II) was prepared. 180 μl of this solution as a substrate was mixed with 20 μl of an enzyme solution. The mixture was reacted at 50° C. for 5 to 30 minutes, preferably 10 minutes, and then heated in boiling water or at 75° C. for 1 minute to stop the reaction. 30 μl of the reaction mixture was subjected to a TSKgel α-2500 column (inner diameter: 7.8 mm; length: 300 mm; Tosoh). Elution was carried out using a 70% acetonitrile solution as an eluent at a flow rate of 0.8 ml/minute. Agarotetraose eluted at a retention time of about 25 minutes or neoagarotetraose eluted at a retention time of about 24 minutes, which was generated by the enzymatic reaction, was quantified. One unit (1 U) is defined as the amount of the enzyme that produces 1 μmol of agarotetraose or neoagarotetraose in 10 minutes.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:20]Br.[Cl:22][C:23]1[CH:24]=[C:25]([CH2:30]O)[CH:26]=[C:27]([I:29])[CH:28]=1>C(Cl)Cl>[Br:20][CH2:30][C:25]1[CH:26]=[C:27]([I:29])[CH:28]=[C:23]([Cl:22])[CH:24]=1
Reactant: OCc1cc(Cl)cc(I)c1
Reactant: BrBr
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Clc1cc(I)cc(CBr)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97 %

Procedure:
To a stirred ice-cooled solution of triphenylphosphine in 10 mL of CH2Cl2 was added dropwise a solution of bromine in 5 ml of CH2Cl2. After the reaction mixture was stirred at room temperature for 30 min and cooled at ice bath temperature, a solution of the above (3-chloro-5-iodo-phenyl)-methanol in 15 ml of CH2Cl2 was added dropwise. The reaction mixture was stirred 0° C. for another 1 h and concentrated. The residue was washed with hexane several times and the combined hexane layer was concentrated to give 1-bromomethyl-3-chloro-5-iodo-benzene (1.2 g, 97%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][C:26]=1[Cl:27])[CH2:5][C@@H:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][C@@H:7]1[N:15](C)[C:16](OC(C)(C)C)=O.FC(F)(F)C(O)=O.C([O-])(O)=O.[Na+]>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][C:26]=1[Cl:27])[CH2:5][C@@H:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][C@@H:7]1[NH:15][CH3:16]
Reactant: CN(C(=O)OC(C)(C)C)[C@H]1Cc2ccccc2[C@H]1Cc1ccc(Cl)c(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN[C@H]1Cc2ccccc2[C@H]1Cc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.4 %

Procedure:
To a solution of (±) cis-1-(3,4-dichlorobenzyl)-2-(N-methyl-N-tert-butoxycarbonyl-amino)indane (1.016 g, 2.5 mmol) in dichloromethane (20 ml) at 0° C. was added trifluoroacetic acid (4 ml) dropwise. The solution was then stirred at room temperature for 2 h, poured into saturated aqueous NaHCO3 (150 ml) and extracted with dichloromethane (3×30 ml). The combined organic phases were dried over sodium sulfate, and concentrated in vacuo. The residue was subjected to column chromatography on silica eluting with 5% ethanol in chloroform to afford the title compound as a colourless oil (585 mg) which was converted to the HCl salt and crystallised to afford a white solid. m.p.>245° C. dec. (from ethanol-diethyl ether).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]([CH3:28])[C:10]([C:12]1[S:24][C:23]2[C:22]3[CH:21]=[C:20]([C:25](O)=[O:26])[CH:19]=[CH:18][C:17]=3[O:16][CH2:15][C:14]=2[CH:13]=1)=[O:11].[CH3:29][NH:30][CH3:31]>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]([CH3:28])[C:10]([C:12]1[S:24][C:23]2[C:22]3[CH:21]=[C:20]([C:25]([N:30]([CH3:31])[CH3:29])=[O:26])[CH:19]=[CH:18][C:17]=3[O:16][CH2:15][C:14]=2[CH:13]=1)=[O:11]
Reactant: CNC
Reactant: CN(C(=O)c1cc2c(s1)-c1cc(C(=O)O)ccc1OC2)c1ccc(F)cc1F
Product: CN(C)C(=O)c1ccc2c(c1)-c1sc(C(=O)N(C)c3ccc(F)cc3F)cc1CO2

Procedure:
Following the procedure of Example 15 and General Procedure C, 2-((2,4-difluorophenyl)(methyl)carbamoyl)-4H-thieno[3,2-c]chromene-8-carboxylic acid and dimethylamine were coupled to give 111bp. 1H NMR (400 MHz, CDCl3) δ 7.15-7.31 (m, 3 H), 6.82-7.00 (m, 4 H,), 5.13 (s, 2 H), 3.33 (m, 3 H), 2.94-3.13 (m, 6 H). LCMS (ESI) m/z: 429.1.
Reaction SMILES: [C:1]1([C:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([CH2:12][CH2:13][CH2:14][CH:15]=[CH2:16])[CH:8]([OH:11])[CH2:9][CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cr](O)(O)(=O)=O>CC(C)=O>[C:17]1([C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([CH2:12][CH2:13][CH2:14][CH:15]=[CH2:16])[C:8](=[O:11])[CH2:9][CH3:10])[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: C=CCCCC(c1ccccc1)(c1ccccc1)C(O)CC
Agent: O=[Cr](=O)(O)O
Solvent: CC(C)=O
Product: C=CCCCC(C(=O)CC)(c1ccccc1)c1ccccc1
Reaction time: 0.17 h
Yield: 78.8 %

Procedure:
One hundred seventy milligrams of 4,4-diphenylnon-8-en-3-ol was dissolved in acetone (10 ml), and then treated with 2.7M chromic acid solution (0.04 ml). After 10 min, the excess oxidant was destroyed with isopropanol, and the mixture was diluted with ether (20 ml). Filtration through a pad of celite and concentration yielded 133 mg of 4,4-diphenylnon-8-en-3-one, as an amorphous white solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][C:10]#[N:11].[NH2:12][C:13]1[N:18]=[C:17]([NH2:19])[C:16]([CH:20]=O)=[CH:15][N:14]=1>>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[C:10]([NH2:11])=[N:19][C:17]2[N:18]=[C:13]([NH2:12])[N:14]=[CH:15][C:16]=2[CH:20]=1
Reactant: N#CCc1cccc(Cl)c1Cl
Reactant: Nc1ncc(C=O)c(N)n1
Product: Nc1ncc2cc(-c3cccc(Cl)c3Cl)c(N)nc2n1

Procedure:
Following the procedure of Example 1, 2,3-dichlorophenylacetonitrile was reacted with 2,4-diamino-5-pyrimidinecarboxaldehyde to give the title compound; mp 366°-369° C. (dec).
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([C:12]3[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[C:15](=[O:22])[C:14](=[N:23]O)[CH:13]=3)=[CH:8][CH:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:25][N:26]1[C:34]2[C:29](=[CH:30][C:31]([N+:35]([O-:37])=[O:36])=[CH:32][CH:33]=2)[C:28]([CH3:39])([CH3:38])[C:27]1=[CH2:40]>>[CH3:25][N:26]1[C:27]2([O:22][C:15]3[C:16]4[C:21]([C:12]([C:9]5[CH:8]=[CH:7][C:6]([N:1]6[CH2:2][CH2:3][CH2:4][CH2:5]6)=[CH:11][CH:10]=5)=[CH:13][C:14]=3[N:23]=[CH:40]2)=[CH:20][CH:19]=[CH:18][CH:17]=4)[C:28]([CH3:38])([CH3:39])[C:29]2[C:34]1=[CH:33][CH:32]=[C:31]([N+:35]([O-:37])=[O:36])[CH:30]=2
Reactant: C=C1N(C)c2ccc([N+](=O)[O-])cc2C1(C)C
Reactant: O=C1C(=NO)C=C(c2ccc(N3CCCC3)cc2)c2ccccc21
Product: CN1c2ccc([N+](=O)[O-])cc2C(C)(C)C12C=Nc1cc(-c3ccc(N4CCCC4)cc3)c3ccccc3c1O2

Procedure:
The method according to claim 9, wherein 4-(4-pyrrolidinophenyl)-1,2-naphthoquinone-2-oxime and 1,3,3-trimethyl-2-methylene-5-nitroindoline are reacted to form 1,3-Dihydro-1,3,3-trimethyl-5-nitro-6′-(4-pyrrolidinophenyl)spiro-[2H-indole-2,2′[2H]naphth[1,2-b][1,4]oxazine].
Reaction SMILES: C=O.[CH2:3]([O:10][C:11]1[CH:12]=[C:13]([CH2:19][CH:20]([NH:22][C:23](=[O:25])[CH3:24])[CH3:21])[CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.O.[C:27](OCC)(=O)C>C1(C)C=CC=CC=1.CC1C=CC(S(O)(=O)=O)=CC=1>[CH2:3]([O:10][C:11]1[CH:12]=[C:13]2[C:14](=[CH:15][C:16]=1[O:17][CH3:18])[CH2:27][N:22]([C:23](=[O:25])[CH3:24])[CH:20]([CH3:21])[CH2:19]2)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: COc1ccc(CC(C)NC(C)=O)cc1OCc1ccccc1
Reactant: CCOC(C)=O
Agent: C=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: COc1cc2c(cc1OCc1ccccc1)CC(C)N(C(C)=O)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 94 %

Procedure:
Paraformaldehyde (6.32 g) was added portionwise to a solution of 211 (2.21 g, 7.04 mmol) in toluene (55 ml) with pTSA (60 mg). The reaction mixture was heated under reflux for 2 h. Further paraformaldehyde (632 mg) was added and heating under reflux was continued overnight. Additional pTSA (60 mg) and paraformaldehyde (1.9 g) was added to the reaction mixture portionwise over 2 h. The solution was cooled to rt, water (50 ml) and ethyl acetate (60 ml) were added. The layers were separated and the organic layer was washed with water (2×50 ml) and brine (50 ml), dried (MgSO4) and concentrated in vacuo to afford the title compound (2.15 g, 94%) as a colourless oil. 1H NMR indicated a mixture of conformers, signals for both conformers are listed 1.04, 1.12 (3H, d, J=6.7 Hz, CH3CH), 2.14, 2.17 (3H, s, CH3CO), 2.38-2.51 (1H, m, CHH for both conformers), 2.89-3.06 (1H, m, CHH for both conformers), 3.84, 3.85 (3H, s, OCH3), 4.06-4.6 (2H, m, CH2 for both conformers), 5.01-5.02 (3H, m, CHCH3 and CH2Ph for both conformers), 6.6-6.64 (2H, m, 2×CH for both conformers), 7.28-7.44 (5H, m, 5×CH, phenyl for both conformers). LC/MS (ES+) tr=1.02 min, m/z 348.19 (M++Na).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:19][CH2:18][C:17]3[C:12](=[CH:13][N:14]=[CH:15][CH:16]=3)[CH2:11]2)=[CH:6][CH:5]=1)([O-])=O.[H][H]>[Pd]>[CH2:11]1[C:12]2[C:17](=[CH:16][CH:15]=[N:14][CH:13]=2)[CH2:18][CH2:19][N:10]1[C:7]1[CH:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=1
Reactant: O=[N+]([O-])c1ccc(N2CCc3ccncc3C2)cc1
Reactant: [H][H]
Agent: [Pd]
Product: Nc1ccc(N2CCc3ccncc3C2)cc1
Reaction time: 3.5 h
Yield: 108.5 %

Procedure:
A solution of 2-(4-nitrophenyl)-1,2,3,4-tetrahydro-2,7-naphthyridine (11.5 g; 0.045 mol) in IMS (230 mL) was hydrogenated under a hydrogen balloon in the presence of 10% Pd/C (1.2 g). After 3.5 hours tlc analysis indicated the reaction was complete. The hydrogen atmosphere was replaced by argon and degassed DCM (100 mL) was added to re-dissolve the precipitated product. The mixture was filtered through Celite and washed through with degassed DCM:IMS (1:1; 200 mL). To the yellow filtrate was quickly added concentrated hydrochloric acid (40 mL) with stirring and a precipitate crashed out after a few seconds. After 10 minutes, the mixture was filtered, washed with 1:1 DCM:IMS then twice with ether. The off-yellow product was dried in vacuo at 50° C. to afford the title compound as a beige solid (11 g) m.p.>220° C. 1H NMR (DMSO-d6) δ: 8.82 (s, 1H), 8.68 (d, J=6.2 Hz, 1H), 7.86 (d, J=5.9 Hz, 1H), 7.26-7.32 (m, 2H), 7.10-7.16 (m, 2H), 4.61 (s, 2H), 3.67 (t, J=5.9 Hz, 2H), 3.17 (t, J=5.7 Hz, 2H)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].[Br:9][C:10]1[CH:17]=[C:14]([CH:15]=O)[C:13]([OH:18])=[CH:12][CH:11]=1>N1C=CC=CC=1>[OH:18][C:13]1[CH:12]=[CH:11][C:10]([Br:9])=[CH:17][C:14]=1[C:15]1[S:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[N:1]=1
Reactant: O=Cc1cc(Br)ccc1O
Reactant: Nc1ccccc1S
Solvent: c1ccncc1
Product: Oc1ccc(Br)cc1-c1nc2ccccc2s1

Procedure:
2-Aminothiophenol (12.5 g, 0.1 mole) was dissolved in 30 ml. of pyridine and 20.1 g (0.1 mole) of 5-bromosalicylaldehyde was added dropwise during 15 minutes. The solution was warmed on a steam bath for 2 hours and then a stream of air was bubbled through the mixture while heating for another hour. The mixture was poured into 300 ml. of 2 N HCl which was then stirred until crystals formed. The product was removed by filtration, washed with water and recrystallized from ethanol, mp. 164°-165°. Yield, 8.0 g. (26%).
Reaction SMILES: [CH:1]([NH:3][C:4]1[C:5]([CH3:12])=[N:6][NH:7][C:8]=1[C:9]([NH2:11])=[O:10])=O.C[O-].[Na+]>CN(C)C=O>[CH3:12][C:5]1[C:4]2[N:3]=[CH:1][N:11]=[C:9]([OH:10])[C:8]=2[NH:7][N:6]=1
Reactant: Cc1n[nH]c(C(N)=O)c1NC=O
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1n[nH]c2c(O)ncnc12

Procedure:
A solution of 4-formylamino-3-methylpyrazole-5-carboxamide (21.0 g, 125 mmol) and sodium methoxide (about 30 mg) in dimethylformamide (42 ml) was heated at reflux for 6 hrs. in an oil bath maintained at 160°. Some product crystallized in the hot reaction mixture. Cooling, filtering and washing with ethanol afforded (after drying in a vacuum oven at 120°) 15.03 g (80.2%) of a white solid, m.p. 340°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][C:14]2[N:19]=[C:18]([O:20][CH3:21])[N:17]=[C:16]([C:22]3[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=3)[C:25]([OH:27])=O)[CH:15]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].OC1C2N=NNC=2C=CC=1.Cl.CN(C)CCCN=C=NCC.[NH2:53][CH2:54][CH2:55][N:56]1[CH2:60][CH2:59][CH2:58][CH2:57]1.C(N(CC)C(C)C)(C)C>C(Cl)Cl.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][C:14]2[N:19]=[C:18]([O:20][CH3:21])[N:17]=[C:16]([C:22]3[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=3)[C:25]([NH:53][CH2:54][CH2:55][N:56]3[CH2:60][CH2:59][CH2:58][CH2:57]3)=[O:27])[CH:15]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: NCCN1CCCC1
Reactant: COc1nc(NCCc2ccc(OC)c(OC)c2)cc(-c2cccc(C(=O)O)c2)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COc1nc(NCCc2ccc(OC)c(OC)c2)cc(-c2cccc(C(=O)NCCN3CCCC3)c2)n1
Yield: 23.7 %

Procedure:
A solution of 3-{6-[2-(3,4-dimethoxy-phenyl)-ethylamino]-2-methoxy-pyrimidin-4-yl}-benzoic acid [0.15 mmol, Example 35(k)], hydroxybenzotriazole (41 mg, 0.3 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (58 mg, 0.3 mmol), N-(2-aminoethyl)pyrrolidine (38 μL, 0.3 mmol) and N,N-diisopropylethylamine (105 μL, 0.6 mmol) in DCM (3 mL) is stirred at ambient temperature under a nitrogen atmosphere for 18 hours. The reaction is poured into water (20 mL) and extracted twice with EtOAc (25 mL). The organic extracts are combined and dried over magnesium sulfate, filtered and concentrated by rotary evaporator. The resulting solid is subjected to flash column chromatography on silica gel eluting with 10 to 60% EtOAc in heptane gradient to afford 3-{6-[2-(3,4-dimethoxy-phenyl)-ethylamino]-2-methoxy-pyrimidin-4-yl}-N-(2-pyrrolidin-1-yl-ethyl)-benzamide [18 mg, 24%, Example 25(b)]. LCMS: RT=2.1 minutes, MS: 506 (M+H). IC50=30 nM
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:21])([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[CH2:9][C:10](OCC)=[O:11])=[CH:4][CH:3]=1.[CH3:22][NH2:23]>O.C(O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:21])([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[CH2:9][C:10]([NH:23][CH3:22])=[O:11])=[CH:4][CH:3]=1
Reactant: CN
Reactant: CCOC(=O)CC(O)(c1ccc(Br)cc1)c1cccnc1
Solvent: O
Solvent: CCO
Product: CNC(=O)CC(O)(c1ccc(Br)cc1)c1cccnc1
Yield: 79 %

Procedure:
19.4 g (0.05 mole) of ethyl 3-(4-bromophenyl)-3-hydroxy-3-(3-pyridyl)-propanoate, 200 ml of 40% solution of methylamine in water and 30 ml of absolute ethanol was stirred for 24 hours at room temperature. The precipitate was filtered off and recrystallized from isopropyl alcohol, which gave 13.2 g (79%) of the amide. M.p. 188°-191° C. The formula C15H15BrN2O2 was verified through elemental analysis. (The elemental analyses throughout this application were carried out for all elements of the compounds prepared, and are within ± 0.4 percent of the theoretical values if not otherwise stated.) ##STR28##