Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6]([C:8]1[CH:46]=[CH:45][C:11]([CH2:12][CH:13](/[CH:26]=[CH:27]/[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[O:34][CH2:35][CH2:36][CH2:37][N:38]2[CH2:43][CH2:42][O:41][CH2:40][C:39]2=[O:44])[CH2:14][CH2:15][C:16]2[CH:25]=[CH:24][C:19]([C:20]([O:22]C)=[O:21])=[CH:18][CH:17]=2)=[CH:10][CH:9]=1)=[O:7].Cl>C1COCC1.O>[C:6]([C:8]1[CH:9]=[CH:10][C:11]([CH2:12][CH:13](/[CH:26]=[CH:27]/[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[O:34][CH2:35][CH2:36][CH2:37][N:38]2[CH2:43][CH2:42][O:41][CH2:40][C:39]2=[O:44])[CH2:14][CH2:15][C:16]2[CH:17]=[CH:18][C:19]([C:20]([OH:22])=[O:21])=[CH:24][CH:25]=2)=[CH:45][CH:46]=1)([OH:7])=[O:5]
Reactant: COC(=O)c1ccc(CCC(/C=C/c2ccccc2OCCCN2CCOCC2=O)Cc2ccc(C(=O)OC)cc2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(CCC(/C=C/c2ccccc2OCCCN2CCOCC2=O)Cc2ccc(C(=O)O)cc2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
66.6 mg (1.59 mmol) of lithium hydroxide monohydrate are added to a solution of 0.31 g (0.53 mmol) of methyl 4-[(4E)-3-[4-(methoxycarbonyl)benzyl]-5-{2-[3-(3-oxomorpholin-4-yl)propoxy]phenyl}-pent-4-en-1-yl]benzoate (Example 23A) in 2 ml of THF and 2 ml of water, and the mixture is stirred at room temperature for 18 h. The mixture is then adjusted to pH 2 using 1 M hydrochloric acid and extracted twice with ethyl acetate. The combined organic phases are dried over sodium sulfate. After filtration, the solvent is removed to dryness and the crude product is purified by preparative HPLC. This gives 89.5 mg (0.16 mmol, 30.3% of theory) of the title compound as a colorless solid.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5](=[O:19])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]2CN[C:15](=O)[NH:14][CH2:13]2)=[CH:8][CH:7]=1.CI.[CH3:22][N:23]([CH:25]=[O:26])[CH3:24]>C1COCC1>[CH3:3][O:4][C:5](=[O:19])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]2[CH2:13][N:14]([CH3:15])[C:25](=[O:26])[N:23]([CH3:24])[CH2:22]2)=[CH:8][CH:7]=1
Reactant: COC(=O)c1ccc(C2CNC(=O)NC2)cc1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: COC(=O)c1ccc(C2CN(C)C(=O)N(C)C2)cc1
Reaction time: 16 h

Procedure:
To a cooled (0° C.) suspension of sodium hydride dispersion (60% in mineral oil (88 mg, 2.2 mmol) in THF (3 mL) is added a solution comprising of 4-(2-oxo-hexahydro-pyrimidin-5-yl)-benzoic acid methyl ester (236 mg, 1 mmol, reference example 95) and methyl iodide (300 μL, 5 mmol) in DMF (4 mL). The resulting mixture is stirred for 16 h. then quenched with water, diluted with ethyl acetate, washed with water and brine, dried over MgSO4 and concentrated to give the title compound (255 mg) as a tan solid. 1H NMR (CDCl3) δ 2.98 (s, 6H), 3.37-3.53 (m, 5H), 3.93 (s, 3H), 7.32 (d, J=8 Hz, 2H), 8.01 (d, J=8 Hz, 2H). MS (ion spray) m/z 263 (M+H)+.
Reaction SMILES: C(OC([CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([N:20]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[C@H:23]([N:30]([C:38](=[O:40])[CH3:39])[C:31]4[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=4)[CH2:22][C@@H:21]3[CH3:41])=[O:19])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)=O)C.[CH2:42]([O:44][C:45](C1CCNCC1)=[O:46])[CH3:43]>>[CH2:42]([O:44][C:45]([CH:7]1[CH2:6][CH2:11][CH2:10][N:9]([C:12]2[CH:13]=[CH:14][C:15]([C:18]([N:20]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[C@H:23]([N:30]([C:38](=[O:40])[CH3:39])[C:31]4[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=4)[CH2:22][C@@H:21]3[CH3:41])=[O:19])=[CH:16][CH:17]=2)[CH2:8]1)=[O:46])[CH3:43]
Reactant: CCOC(=O)C1CCN(c2ccc(C(=O)N3c4ccccc4[C@H](N(C(C)=O)c4ccc(Cl)cc4)C[C@@H]3C)cc2)CC1
Reactant: CCOC(=O)C1CCNCC1
Product: CCOC(=O)C1CCCN(c2ccc(C(=O)N3c4ccccc4[C@H](N(C(C)=O)c4ccc(Cl)cc4)C[C@@H]3C)cc2)C1

Procedure:
(2S,4R)-1-(4-{4-[Acetyl-(4-chloro-phenyl)-amino]-2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl}-phenyl)-piperidine-3-carboxylic acid ethyl ester was prepared following the procedure for (2S,4R)-1-(4-{4-[Acetyl-(4-chloro-phenyl)-amino]-2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl}-phenyl)-piperidine-4-carboxylic acid ethyl ester, substituting piperidine-3-carboxylic acid ethyl ester for piperidine-4-carboxylic acid ethyl ester to yield the product.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6]P(=O)(OCC)OCC)=[O:5])[CH3:2].[H-].[Na+].[C:17]1([CH3:30])[CH:22]=[CH:21][C:20]([C:23](=O)[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:19][CH:18]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1>[C:17]1([CH3:30])[CH:18]=[CH:19][C:20](/[C:23](=[CH:6]/[C:4]([O:3][CH2:1][CH3:2])=[O:5])/[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:21][CH:22]=1
Reactant: CCOC(=O)C(=O)c1ccc(C)cc1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)/C=C(\C(=O)OCC)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.5 %

Procedure:
A solution of diethyl ethoxycarbonylmethylphosphonate (3.3 g) in anhydrous tetrahydrofuran (20 ml) is added dropwise to a suspension of sodium hydride (60%, oily) (676 mg) in anhydrous tetrahydrofuran (30 ml) under a nitrogen atmosphere and ice cooling, and further a solution of ethyl 4-tolylglyoxylate (2.96 g) in anhydrous tetrahydrofuran (22 ml) is added dropwise thereto. The mixture is stirred at room temperature for 30 minutes, a 10% aqueous citric acid solution is added to the reaction mixture, and the whole is extracted with ether. The organic layer is washed with water and saturated brine successively, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography to give 3.57 g (88%) of diethyl 2-(4-tolyl)maleate.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:8]2[NH:9][C:10](=[S:13])[NH:11][N:12]=2)[O:5][C:6]=1[CH3:7].Br.Br[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1>>[CH3:1][C:2]1[CH:3]=[C:4]([C:8]2[NH:12][N:11]=[C:10]([S:13][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[N:9]=2)[O:5][C:6]=1[CH3:7]
Reactant: BrCc1ccccn1
Reactant: Cc1cc(-c2n[nH]c(=S)[nH]2)oc1C
Agent: Br
Product: Cc1cc(-c2nc(SCc3ccccn3)n[nH]2)oc1C
Yield: 27 %

Procedure:
Prepared in a similar manner to example 1 using 5-(4,5-dimethylfuran-2-yl)-2H-1,2,4-triazole-3(4H)-thione (example 5a) and 2-(bromomethyl)pyridine hydrobromide. Yield 27%. 1H NMR (500 MHz, dMSO): δ 1.98 (s, 3H), 2.28 (s, 3H), 4.37 (s, 2H), 6.76 (s, 1H), 7.3 (m, 1H), 7.45 (d, 1H), 7.75 (t, 1H), 8.6 (s, 1H). MS (M+H, 287).
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]#[CH:5].[C:6]([C:9]1[CH:10]=[C:11](/[CH:14]=[C:15]2\[C:16](=[O:26])[NH:17][C:18]3[C:23]\2=[C:22](I)[C:21]([F:25])=[CH:20][CH:19]=3)[NH:12][CH:13]=1)(=[O:8])[CH3:7]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CN(C=O)C.CCN(CC)CC>[C:6]([C:9]1[CH:10]=[C:11](/[CH:14]=[C:15]2\[C:16](=[O:26])[NH:17][C:18]3[C:23]\2=[C:22]([C:5]#[C:4][CH2:3][NH:2][CH3:1])[C:21]([F:25])=[CH:20][CH:19]=3)[NH:12][CH:13]=1)(=[O:8])[CH3:7]
Reactant: C#CCNC
Reactant: CC(=O)c1c[nH]c(/C=C2\C(=O)Nc3ccc(F)c(I)c32)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CNCC#Cc1c(F)ccc2c1/C(=C/c1cc(C(C)=O)c[nH]1)C(=O)N2

Procedure:
Using Method C above, N-methylpropargyl amine (43.6 mg, 0.66 mmol) was coupled with (Z)-3-[(4-acetyl-1H-pyrrol-2-yl)methylene]-1,3-dihydro-5-fluoro-4-iodo-2H-indol-2-one (100 mg, 0.25 mmol) (Example 90B) using (Ph3P)4Pd (30.1 mg) and Cul (6.0 mg) as catalyst in DMF (6 mL) and Et3N (6 mL) as solvent at 89° C. for 5 h to yield (Z)-3-[(4-Acetyl-1H-pyrrol-2-yl)methylene]-1,3-dihydro-5-fluoro-4-[3-(N-methylamino)-1-propynyl]-2H-indol-2-one. (Yield 10 mg, 12%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[O:17][CH:16]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:15][CH2:14]3)=[N:8][CH:9]=1)([O-:3])=[O:2].[CH2:27](C1C=CC(C2CCC3C(=CC=C(O)C=3)O2)=CC=1)[CH3:28]>>[CH2:27]([C:24]1[CH:23]=[CH:22][C:21]([CH:16]2[CH2:15][CH2:14][C:13]3[C:18](=[CH:19][CH:20]=[C:11]([O:10][C:7]4[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][N:8]=4)[CH:12]=3)[O:17]2)=[CH:26][CH:25]=1)[CH3:28]
Reactant: CCc1ccc(C2CCc3cc(O)ccc3O2)cc1
Reactant: O=[N+]([O-])c1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)nc1
Product: CCc1ccc(C2CCc3cc(Oc4ccc([N+](=O)[O-])cn4)ccc3O2)cc1

Procedure:
2-[2-(4-Ethylphenyl)chroman-6-yloxy]-5-nitropyridine was prepared as described for 5-nitro-2-(2-phenylchroman-6-yloxy)pyridine in Example 1(b) starting from 205 mg of 2-(4-ethylphenyl)chroman-6-ol. The product was recrystallised from a mixture of 2-propanol and acetone. 1H NMR (400 MHz, CDCl3) δ: 9.04 (d, 1H, J 2.8 Hz), 8.60 (dd, 1H, J 9.1, 2.8 Hz), 7.36 (d, 2H, J 8.1 Hz), 7.24 (d, 2H, J 8.1 Hz), 7.20 (d, 1H, J 9.1 Hz), 7.00 (d, 1H, J 2.7 Hz), 6.96 (dd, 1H, J 8.8, 2.7 Hz), 6.89 (d, 1H, J 2.7 Hz), 5.11 (dd, 1H, J 10.1, 2.2 Hz), 2.98 (m, 1H), 2.75 (m, 1H), 2.62 (q, 2H, J 7.5 Hz), 2.16 (m, 1H), 2.01 (m, 1H), 1.19 (t, 3H, J 7.5 Hz).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][NH:9][CH2:10][CH2:11][OH:12])=[CH:4][CH:3]=1.I[CH2:14][CH2:15][CH3:16].C(N(CC)CC)C>C(#N)C>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]([CH2:14][CH2:15][CH3:16])[CH2:10][CH2:11][OH:12])=[CH:4][CH:3]=1
Reactant: CCCI
Reactant: OCCNCc1ccc(Cl)nc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCCN(CCO)Cc1ccc(Cl)nc1

Procedure:
This compound was made in a manner analogous to that set forth in Step B of Example 2, using 11.3 grams (about 0.055 mole) of 2-{[(6-chloro-3-pyridyl)methyl]amino}ethan-1-ol, 25.4 grams (0.150 mole) of 1-iodopropane, and 14.5 grams (0.143 mole) of triethylamine in 50 mL of acetonitrile. The yield of the subject compound was about 2.2 grams.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:17])[C@@H:3]([C:5]1[CH:6]=[CH:7][C:8]([OH:16])=[C:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=1)[OH:4].[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:25]=[C:26]([O:30][CH3:31])[C:27]=1[O:28][CH3:29])[CH:23]=O>CO>[OH:16][C:8]1[CH:7]=[CH:6][C:5]([C@@H:3]([OH:4])[C@@H:2]([NH:1][CH2:23][C:22]2[CH:25]=[C:26]([O:30][CH3:31])[C:27]([O:28][CH3:29])=[C:20]([O:19][CH3:18])[CH:21]=2)[CH3:17])=[CH:10][C:9]=1[NH:11][S:12]([CH3:15])(=[O:14])=[O:13]
Reactant: COc1cc(C=O)cc(OC)c1OC
Reactant: C[C@H](N)[C@H](O)c1ccc(O)c(NS(C)(=O)=O)c1
Solvent: CO
Product: COc1cc(CN[C@@H](C)[C@H](O)c2ccc(O)c(NS(C)(=O)=O)c2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 35.4 %

Procedure:
Borane-pyridine complex (135 μL, 1.28 mmol) was added to a methanol solution (4 mL) of an amine (3) (111 mg, 0.43 mmol) and 3,4,5-trimethoxybenzaldehyde (111 mg, 0.55 mmol) at 40° C. and the mixture was stirred for 1.5 hours. The reaction mixture was allowed to cool to room temperature and extracted after addition of water with a mixed solvent (ethyl acetate: methanol=10:1), and the organic layer was washed with saturated aqueous sodium chloride solution. The organic layer was dried and concentrated, and the crude product obtained was purified by amine silica gel column chromatography (eluant:chloroform:methanol=7:1), to give a desired amine (7) as a white solid (67 mg, yield 36%).
Reaction SMILES: [C:1](Cl)(=O)C.[OH:5][C@@H:6]1[C@H:10]([OH:11])[CH:9]([OH:12])[O:8][C@@H:7]1[CH2:13][OH:14].C[O-].[Na+].CO>CO.C1(C)C=CC=CC=1>[OH:5][C@@H:6]1[C@H:10]([OH:11])[CH:9]([O:12][CH3:1])[O:8][C@@H:7]1[CH2:13][OH:14]
Reactant: OC[C@H]1OC(O)[C@@H](O)[C@H]1O
Reactant: CC(=O)Cl
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Product: COC1O[C@H](CO)[C@H](O)[C@@H]1O
Reaction time: 1 h

Procedure:
720 mL of acetyl chloride was added dropwise to 1200 mL of a methanol solution of 12.0 kg of (2R,3R,4S)-3,4,5-trihydroxy-2-hydroxymethyloxolane at a temperature of 15° C. or lower over 30 minutes, and the obtained mixture was then stirred at a temperature of 20° C. to 30° C. for 1 hour. Thereafter, 2100 mL of a 28% sodium methoxide/methanol solution and 1000 mL of toluene were added to the reaction mixture, and methanol was then distilled away under reduced pressure, to obtain 4500 mL of a toluene solution of (2R,3R,4S)-3,4-dihydroxy-2-hydroxymethyl-5-methoxyoxolane.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[N:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]2[CH:26]=[C:27]3[C:31](=[CH:32][C:33]=2[C:34]2[CH:39]=[CH:38][C:37]([O:40][CH2:41][C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)=[CH:36][CH:35]=2)[N:30](COCC[Si](C)(C)C)[N:29]=[C:28]3[NH:56][C:57](=[O:61])[CH2:58][CH2:59][CH3:60])[CH:20]=1.C(OCC)(=O)C>O1CCCC1>[N:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]2[CH:26]=[C:27]3[C:31](=[CH:32][C:33]=2[C:34]2[CH:35]=[CH:36][C:37]([O:40][CH2:41][C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)=[CH:38][CH:39]=2)[NH:30][N:29]=[C:28]3[NH:56][C:57](=[O:61])[CH2:58][CH2:59][CH3:60])[CH:20]=1
Reactant: CCCC(=O)Nc1nn(COCC[Si](C)(C)C)c2cc(-c3ccc(OCc4ccccc4)cc3)c(-c3cccnc3)cc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCC(=O)Nc1n[nH]c2cc(-c3ccc(OCc4ccccc4)cc3)c(-c3cccnc3)cc12
Yield: 84.2 %

Procedure:
7.1 cm3 of tetrabutylammonium fluoride as a 1M solution in tetrahydrofuran are added to 700 mg of N-[5-(3-pyridyl)-6-[4-(phenylmethoxy)phenyl]-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indazol-3-yl]butanamide, described previously, in 50 cm3 of tetrahydrofuran, and the mixture is refluxed for 18 hours; after cooling, 75 cm3 of ethyl acetate are added and the organic phase is washed successively with 2×75 cm3 of saturated sodium hydrogen carbonate solution and then with 50 cm3 of saturated sodium chloride solution. The organic phase is separated out after settling of the phases has taken place, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2 kPa; 50° C.) to give 850 mg of crude product, which is purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-60 μm; diameter 3 cm), eluting with a cyclohexane/ethyl acetate mixture (70/30 by volume). The fractions containing the expected product are combined and evaporated under reduced pressure (2 kPa; 50° C.); the residue is dried (90 Pa; 45° C.) to give 460 mg of N-[5-(3-pyridyl)-6-[4-(phenylmethoxy)phenyl]-1H-indazol-3-yl]butanamide in the form of cream-coloured crystals.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[O:13]1[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][CH2:21][OH:22])[CH2:15][CH2:14]1.O[C:24]1[CH:33]=[C:32]2[C:27]([C:28](=[O:42])[N:29]([CH2:34][O:35][C:36](=[O:41])[C:37]([CH3:40])([CH3:39])[CH3:38])[CH:30]=[N:31]2)=[CH:26][C:25]=1[O:43][CH3:44].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[CH3:44][O:43][C:25]1[CH:26]=[C:27]2[C:32](=[CH:33][C:24]=1[O:22][CH2:21][CH2:20][CH2:19][N:16]1[CH2:17][CH2:18][O:13][CH2:14][CH2:15]1)[N:31]=[CH:30][N:29]([CH2:34][O:35][C:36](=[O:41])[C:37]([CH3:38])([CH3:39])[CH3:40])[C:28]2=[O:42]
Reactant: OCCCN1CCOCC1
Reactant: COc1cc2c(=O)n(COC(=O)C(C)(C)C)cnc2cc1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc2c(=O)n(COC(=O)C(C)(C)C)cnc2cc1OCCCN1CCOCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.7 %

Procedure:
Diethyl azodicarboxylate (2.67 ml, 17 mmol) was added dropwise to a solution of 3-morpholinopropan-1-ol (1.54 g, 10 mmol), 7-hydroxy-3,4-dihydro-6-methoxy-3-((pivaloyloxy)methyl)quinazolin-4-one (2.6 g, 8.5 mmol) and triphenylphosphine (4.45 g, 17 mmol) in methylene chloride (40 ml). After stirring for 2 hours at ambient temperature, the volatiles were removed by evaporation. The residue was purified by column chromatography eluting with methylene chloride/methanol (97/3 followed by 95/5) to give 3,4-dihydro-6-methoxy-3-((pivaloyloxy)metyl)-7-(3-morpholinopropoxy)quinazolin-4-one (3.6 g, 97%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10]O)=[CH:6][C:5]=1[N+:12]([O-:14])=[O:13].[CH2:16]([N:18](CC)[CH2:19][CH3:20])[CH3:17].C1(C)C=CC(S(Cl)(=O)=O)=CC=1.N1CCCC1>ClCCl>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:18]2[CH2:19][CH2:20][CH2:17][CH2:16]2)=[CH:6][C:5]=1[N+:12]([O-:14])=[O:13]
Reactant: COC(=O)c1ccc(CO)cc1[N+](=O)[O-]
Reactant: CCN(CC)CC
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: C1CCNC1
Solvent: ClCCl
Product: COC(=O)c1ccc(CN2CCCC2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 44.8 %

Procedure:
To a solution of 4-hydroxymethyl-2-nitro-benzoic acid methyl ester (2.0 g, 9.47 mmol) in dry dichloromethane (80 mL) under argon, at room temperature, triethylamine (1.6 mL, 10.9 mmol, 1.15 eq.) and then p-toluenesulfonyl chloride (2.08 g, 10.9 mmol, 1.15 eq.) were added. The reaction mixture was stirred at room temperature for 1 h, then pyrrolidine (1.6 mL, 18.94 mmol, 2 eq.) was added and the mixture stirred for additional 24 hours. The solvent was evaporated and the residue purified by flash chromatography on silica gel, using dichloromethane-ethanol 95:5 as eluant, affording the title compound (1.12 g).
Reaction SMILES: C(ON=O)(C)(C)C.[NH2:8][C:9]1[O:10][C:11]2[C:16]([CH:17]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:18]=1[C:19]#[N:20])=[CH:15][CH:14]=[C:13](N)[CH:12]=2>CN(C=O)C>[NH2:8][C:9]1[O:10][C:11]2[C:16]([CH:17]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:18]=1[C:19]#[N:20])=[CH:15][CH:14]=[CH:13][CH:12]=2
Reactant: N#CC1=C(N)Oc2cc(N)ccc2C1c1ccccc1
Agent: CC(C)(C)ON=O
Solvent: CN(C)C=O
Product: N#CC1=C(N)Oc2ccccc2C1c1ccccc1
Temperature: 65 °C
Reaction time: 1.5 h
Yield: 12 %

Procedure:
To a solution of t-butylnitrite (0.027 g, 0.26 mmol) in anhydrous DMF was added 2,7-diamino-3-cyano-4-phenyl-4H-chromene (53 mg, 0.201 mmol) in one portion. The reaction was immediately immersed into a 65° C. oil bath. Gas evolution occurred slowly. After stirring at 65° C. for 1.5 h, the reaction was quenched with addition of water (5 mL), and extracted with EtOAc (3×10 mL). The EtOAc extracts were washed with brine (2×5 mL), dried over MgSO4, and evaporated. The red residue was purified by chromatography on silica gel with EtOAc and hexane (1:2) as eluant to yield 6 mg (12%) of the title compound as a light yellow solid. 1H NMR (CD3Cl, 300 MHz): 7.35–7.17 (m, 6H), 7.06–6.96 (m, 3H), 4.75 (s, 1H), 4.61 (brs, 2H).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:4][CH2:3]1.[H-].[Na+].[CH3:20][N:21]([CH3:27])[S:22]([CH:25]=[CH2:26])(=[O:24])=[O:23].O>O1CCCC1>[CH3:20][N:21]([CH3:27])[S:22]([CH2:25][CH2:26][O:1][CH:2]1[CH2:3][CH2:4][N:5]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:6][CH2:7]1)(=[O:24])=[O:23]
Reactant: C=CS(=O)(=O)N(C)C
Reactant: O=C(OCc1ccccc1)N1CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CN(C)S(=O)(=O)CCOC1CCN(C(=O)OCc2ccccc2)CC1
Reaction time: 0.5 h
Yield: 62 %

Procedure:
Benzyl 4-hydroxypiperidine-1-carboxylate (5.0 g, 21.2 mmol) was dissolved in tetrahydrofuran (100 ml), and while cooling with ice, sodium hydride (content 55%) (1.0 g, 22.9 mmol) was added. The resulting mixture was stirred for 30 minutes while cooling with ice, to which 20 mL of a solution of N,N-dimethylethenesulfonamide in tetrahydrofuran (3.0 g, 22.2 mmol) was added dropwise over five minutes. The resulting mixture was stirred for 30 minutes while cooling with ice, and then for three hours at room temperature. The resulting reaction liquid was poured into water and then extracted with ethyl acetate. The resulting organic layer was sequentially washed with water and saturated brine, and then dried over sodium sulfate. The solvent was distilled off under reduced pressure. The residue thus obtained was purified by silica gel column chromatography (hexane:ethyl acetate, 50:50-0:100, V/V) to give the desired title compound (4.9 g, yield 62%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11]([NH:13][CH:14]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=3)[C:15]([F:18])([F:17])[F:16])=[O:12])=[CH:8][C:7]=2[CH:29]=1)#[N:2].Cl>CO.[Pd]>[NH2:2][CH2:1][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11]([NH:13][CH:14]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:26])[F:27])[CH:20]=3)[C:15]([F:16])([F:17])[F:18])=[O:12])=[CH:8][C:7]=2[CH:29]=1
Reactant: N#Cc1ccc2oc(C(=O)NC(c3cccc(C(F)(F)F)c3)C(F)(F)F)cc2c1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: NCc1ccc2oc(C(=O)NC(c3cccc(C(F)(F)F)c3)C(F)(F)F)cc2c1
Reaction time: 2 h

Procedure:
A solution of 5-cyano-N-{2,2,2-trifluoro-1-[3-(trifluoromethyl)phenyl]ethyl}-1-benzofuran-2-carboxamide (273 mg, 0.66 mmol) in methanol (10 ml) was admixed with concentrated hydrochloric acid (0.42 ml) and palladium on carbon (10%; 50 mg) and stirred under a hydrogen atmosphere for 2 h. The reaction mixture was then filtered through Celite® and a silica gel pad.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C@@H:11]([NH:13][C:14]([C@H:16]2[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:18][N:17]2C(OC(C)(C)C)=O)=[O:15])[CH3:12])=[CH:7][CH:6]=1)=[O:4].O1CCOCC1.[ClH:39]>>[ClH:39].[CH2:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:25][C@H:16]([C:14]([NH:13][C@H:11]([C:8]2[CH:7]=[CH:6][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:10][CH:9]=2)[CH3:12])=[O:15])[NH:17]1
Reactant: COC(=O)c1ccc([C@H](C)NC(=O)[C@H]2Cc3ccccc3CN2C(=O)OC(C)(C)C)cc1
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)c1ccc([C@H](C)NC(=O)[C@H]2Cc3ccccc3CN2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
Dissolve tert-butyl (3R)-3-[[(1S)-1-(4-methoxycarbonylphenyl)ethyl]carbamoyl]-3,4-dihydro-1H-isoquinoline-2-carboxylate (5.5 g, 12.5 mmol) in a 4 M solution of hydrogen chloride in 1,4-dioxane (30 mL, 120 mmol). Stir the mixture overnight at room temperature, and then concentrate the mixture under reduced pressure to furnish the title compound as a white solid (4.70 g, 100% yield). Mass spectrum (m/z): 339 ([M+H]+), 677 ([2M+H]+), 699 ([2M+Na]+).
Reaction SMILES: [CH3:1][C:2]([CH3:6])=[CH:3][CH:4]=O.[C:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:9])[CH3:8]>[O-2].[Zn+2]>[CH3:1][C:2](=[CH:3][CH:4]=[CH:8][C:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:9])[CH3:6]
Reactant: CC(C)=CC=O
Reactant: CC(=O)c1ccccc1
Agent: [O-2]
Agent: [Zn+2]
Product: CC(C)=CC=CC(=O)c1ccccc1
Yield: 87 %

Procedure:
50 Parts of 3,3-dimethylacrolein and 100 parts of acetophenone together with 10 parts of zinc oxide are kept for 3 hours at a temperature of 180° C under a pressure of 50 atmospheres. The reaction mixture is subjected to fractional distillation. 75.3 parts of 2-methyl-6-phenyl-2,4-hexadien-6-one (87% of theory based on 3,3-dimethylacrolein) is obtained at a conversion of 78% of theory. Boiling point: 107° to 110° C at 10116 4 mm.
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]2)[N:6]=[C:5]([N:16]2[CH2:21][CH2:20][CH:19]([C:22]([OH:24])=O)[CH2:18][CH2:17]2)[N:4]=1.[Cl:25][C:26]1[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:27]=1[CH2:33][NH2:34].C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[Cl:25][C:26]1[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:27]=1[CH2:33][NH:34][C:22]([CH:19]1[CH2:20][CH2:21][N:16]([C:5]2[N:4]=[C:3]([NH:2][CH3:1])[N:8]=[C:7]([N:9]3[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]3)[N:6]=2)[CH2:17][CH2:18]1)=[O:24]
Reactant: CNc1nc(N2CCC(C(=O)O)CC2)nc(N2CCN(C)CC2)n1
Reactant: NCc1ccc(Cl)cc1Cl
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CNc1nc(N2CCC(C(=O)NCc3ccc(Cl)cc3Cl)CC2)nc(N2CCN(C)CC2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 22.7 %

Procedure:
To a solution of 1-[4-(methylamino)-6-(4-methyl-1-piperazinyl)-1,3,5-triazin-2-yl]-4-piperidinecarboxylic acid (84 mg, 0.25 mmol, 1.0 equiv), [(2,4-dichlorophenyl)methyl]amine (44 μL, 0.31 mmol, 1.3 equiv), and diisopropylethylamine (DIEA, 70 μL, 0.38 mmol, 1.5 equiv) in DMF (1.6 mL) was added BOP (166 mg, 0.38 mmol, 1.5 equiv). The reaction mixture was stirred overnight at room temperature. The resulting solution was filtered and purified using reverse-phase HPLC (Sunfire, 10-45% CH3CN/H2O, 0.1% TFA, 12 min) to afford 28 mg (23%) of the title compound. MS (ES+): m/e 493.1 [M]+.