Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:20]([CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].[Cl-:46].[Ca+2].[Cl-].Cl>C(Cl)Cl>[CH2:1]([C:20]([Cl:46])([CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: [Cl-]
Reactant: CCCCCCCCCCCCCCCCCCCC(O)(CCCCCCCCCC)CCCCCCCCCCCCCC
Agent: Cl
Agent: [Ca+2]
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCCCCC(Cl)(CCCCCCCCCC)CCCCCCCCCCCCCC

Procedure:
One mole of n-nonadecyl-n-tetradecyl-n-decylcarbinol is added to 0.2 liters of methylene chloride and 0.32 moles calcium chloride. Approximately 1.5 moles of HCl gas is slowly bubbled through the solution. The product mixture is then washed with 1 liter of a 10% sodium carbonate solution. The organic layer is dried with magnesium sulfate and the methylene chloride is evaporated off to give n-nonadecyl-n-tetradecyl-n-decylmethylchloride.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:34])[C:5]([OH:33])([CH3:32])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH:16]2[CH2:20][N:19]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)[C:18](=[O:30])[N:17]2[CH3:31])=[CH:9][CH:8]=1)[CH3:2].[H-].[Na+].I[CH2:38][CH2:39][CH2:40][CH3:41].C1OCCOCCOCCOCCOCCOC1>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:34])[C:5]([O:33][CH2:38][CH2:39][CH2:40][CH3:41])([CH3:32])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14][CH2:15][CH:16]2[CH2:20][N:19]([CH2:21][C:22]3[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=3)[C:18](=[O:30])[N:17]2[CH3:31])=[CH:11][CH:12]=1)[CH3:2]
Reactant: CCCCI
Reactant: CCOC(=O)C(C)(O)Cc1ccc(OCCC2CN(Cc3ccc(OC)cc3)C(=O)N2C)cc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCOC(C)(Cc1ccc(OCCC2CN(Cc3ccc(OC)cc3)C(=O)N2C)cc1)C(=O)OCC
Temperature: 0 °C
Reaction time: 18 h
Yield: 64.4 %

Procedure:
A slurry of 2-hydroxy-3-(4-{2-[1-(4-methoxy-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-ethoxy}-phenyl)-2-methyl-propionic acid ethyl ester (7.35 g, 15.62 mmol) and sodium hydride (2.5 g, 62.5 mmol, 60% dispersion on mineral oil) in DMF (50 mL) i stirred for 45 minutes, then cooled to 0° C. Iodobutane (36 mL, 312 mmol, d=1.617) and 18-crown-6 16.5 g, 62.5 mmol) are added, then the reaction mixture is stirred 18 h at ambient temperature and diluted with ethyl acetate. The organic layer is washed, then dried concentrated in vacuo, and diluted with ethanol (400 mL) and 5N NaOH (40 mL). The reaction mixture is refluxed for 1 h, cooled to ambient temperature, and concentrated in vacuo. The residue is washed, dried, concentrated, and re-dissolved in ethanol (300 mL). Concentrated H2SO4 (30 mL) is added to the reaction solution, then the mixture is refluxed 1 h, cooled to ambient temperature, concentrated, and diluted with ethyl acetate. The organic layer is washed, dried, and concentrated to provide the title compound (5.3 g, 65%). 1H NMR (400 MHz, CDCl3): δ 7.17 (d, 2H, J=8.8 Hz), 7.09 (d, 2H, J=8.8 Hz), 6.84 (d, 2H, J=8.8 Hz), 6.70 (d, 2H, J=8.8 Hz), 4.32, 4.28 (ABq, 2H, J=14.7 Hz), 4.17-4.11 (m, 2H), 3.93 (t, 2H, J=5.9 Hz), 3.78 (s, 3H), 3.61-3.53 (m, 3H), 3.40-3.31 (m, 3H), 2.97-2.89 (m, 3H), 2.97-2.89 (m, 3H), 2.81 (s, 3H), 2.25-2.15 (m, 1H), 1.89-1.81 (m, 1H), 1.59-1.49 (m, 2H), 1.42-1.33 (m, 2H), 1.29 (s, 3H), 1.24 (t, 3H, J=7.2 Hz), 0.91 (t, 3H, J=7.2 Hz). Rf=0.43 in 50% acetone in hexanes.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([N:11]1[C:20]2[C:15](=[CH:16][C:17]([O:23][CH3:24])=[C:18]([CH3:22])[C:19]=2[CH3:21])[CH2:14][C:13]2([CH2:27][CH2:26][CH2:25]2)[CH2:12]1)=[S:10].C([O-])([O-])=O.[Cs+].[Cs+]>[Cu](I)I.O(CCOC)C>[CH3:24][O:23][C:17]1[CH:16]=[C:15]2[C:20](=[C:19]([CH3:21])[C:18]=1[CH3:22])[N:11]([C:9]1[S:10][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[N:8]=1)[CH2:12][C:13]1([CH2:27][CH2:26][CH2:25]1)[CH2:14]2
Reactant: COc1cc2c(c(C)c1C)N(C(=S)Nc1ccccc1Br)CC1(CCC1)C2
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Product: COc1cc2c(c(C)c1C)N(c1nc3ccccc3s1)CC1(CCC1)C2
Temperature: 90 °C
Yield: 91.6 %

Procedure:
A mixture was made of N-(2-bromophenyl)-6′-methoxy-7′,8′-dimethyl-2′,4′-dihydro-1′H-spiro[cyclobutane-1,3′-quinoline]-1′-carbothioamide (200 mg), Cs2CO3 (176 mg), copper iodide (8.5 mg) 1,10-phenanthioline (16.2 mg) and 2 mL 1,2 dimethoxylethane. The mixture was then heated up in a 90° C. oil bath for 1 hour, filtered and evaporated. The residue was passed through a silica gel column (hexane:dichloromethane=10:1), 2-(6′-methoxy-7′,8′-dimethyl-2′,4′-dihydro-1′H-spiro[cyclobutane-1,3′-quinoline]-1′-yl)benzo[d]thiazole (150 mg) was obtained. 1H-NMR (300 MHz, CDCl3) δ=7.86-6.58 (d, J=8.1 Hz, 1H); 6.58-6.44 (m, 1H); 7.41-7.19 (m, 1H); 7.17-6.96 (m, 1H); 6.64 (s, 1H); 3.87 (s, 3H); 2.76 (s, 2H); 2.18 (s, 3H); 2.17 (s, 3H); 1.96-1.52 (m, 6H) ppm.
Reaction SMILES: [O:1]=[C:2]([C@@:17]1([OH:58])[CH2:34][C@H:33]([O:35][C@@H:36]2[O:50][C@@H:49]([CH3:51])[C@H:39]3[O:40][C@H:41]4[N:46]([C@H:38]3[CH2:37]2)[CH2:45][CH2:44][O:43][C@@H:42]4[O:47][CH3:48])[C:32]2[C:19](=[C:20]([OH:57])[C:21]3[C:22](=[O:56])[C:23]4[C:28]([C:29](=[O:53])[C:30]=3[C:31]=2[OH:52])=[C:27]([O:54][CH3:55])[CH:26]=[CH:25][CH:24]=4)[CH2:18]1)[CH2:3][O:4][CH:5]1[O:10][CH:9]([CH2:11][O:12][CH2:13][C:14]([OH:16])=[O:15])[CH2:8][CH2:7][CH2:6]1.O[N:60]1[C:64](=[O:65])[CH2:63][CH2:62][C:61]1=[O:66].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[O:1]=[C:2]([C@@:17]1([OH:58])[CH2:34][C@H:33]([O:35][C@@H:36]2[O:50][C@@H:49]([CH3:51])[C@H:39]3[O:40][C@H:41]4[N:46]([C@H:38]3[CH2:37]2)[CH2:45][CH2:44][O:43][C@@H:42]4[O:47][CH3:48])[C:32]2[C:19](=[C:20]([OH:57])[C:21]3[C:22](=[O:56])[C:23]4[C:28]([C:29](=[O:53])[C:30]=3[C:31]=2[OH:52])=[C:27]([O:54][CH3:55])[CH:26]=[CH:25][CH:24]=4)[CH2:18]1)[CH2:3][O:4][CH:5]1[O:10][CH:9]([CH2:11][O:12][CH2:13][C:14]([O:16][N:60]2[C:64](=[O:65])[CH2:63][CH2:62][C:61]2=[O:66])=[O:15])[CH2:8][CH2:7][CH2:6]1
Reactant: COc1cccc2c1C(=O)c1c(O)c3c(c(O)c1C2=O)C[C@@](O)(C(=O)COC1CCCC(COCC(=O)O)O1)C[C@@H]3O[C@H]1C[C@H]2[C@H](O[C@@H]3[C@@H](OC)OCCN32)[C@H](C)O1
Reactant: O=C1CCC(=O)N1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: COc1cccc2c1C(=O)c1c(O)c3c(c(O)c1C2=O)C[C@@](O)(C(=O)COC1CCCC(COCC(=O)ON2C(=O)CCC2=O)O1)C[C@@H]3O[C@H]1C[C@H]2[C@H](O[C@@H]3[C@@H](OC)OCCN32)[C@H](C)O1
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
To a solution of the acid intermediate 49 obtained from step 3 of the process (2 mg, 0.0024 mmol) in dry dichloromethane (1 ml) cooled at 0° C., N-hydroxysuccinimide (1 mg, 0.00792 mmol) and N,N′-dicyclohexylcarbodiimide (1 mg, 0.004556 mmol) were added. The reaction mixture was stirred at 0° C. for 2.5 h, until disappearance of the starting material (HPLC-MS analysis). The solvent evaporated under vacuum and the residue treated with ethyl ether (2×4 ml). The suspension was stirred for 10 minutes, the solid removed by filtration and the organic solution concentrated in vacuo, affording 2 mg of 50 (red solid) as a mixture of diastereoisomers. MS (ESI): 911 [M+H]+. Retention time=6.12, 6.30, 6.42 min (method 1).
Reaction SMILES: BrC1C(=O)NC(C)=CC=1OCC1C=CC(F)=CC=1F.Br[CH2:21][C:22]1[N:23]=[CH:24][C:25]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[N:26][CH:27]=1.[H-].[Na+].C(O)(=O)C>C1COCC1>[CH3:21][C:22]1[N:23]=[CH:24][C:25]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[N:26][CH:27]=1
Reactant: CCOC(=O)c1cnc(CBr)cn1
Agent: Cc1cc(OCc2ccc(F)cc2F)c(Br)c(=O)[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCOC(=O)c1cnc(C)cn1
Temperature: 55 °C
Yield: 90.3 %

Procedure:
To a mixture of 3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one (6.0 g, 0.018 mol) and ethyl 5-(bromomethyl)pyrazine-2-carboxylate (4.9 g, 0.02 mol) in THF (50.0 mL) was added NaH (0.5 g) and heated at 55° C. under argon atmosphere for 3 h. The reaction mixture was cooled, added acetic acid (1.2 ml)and concentrated under reduced pressure. The residue was triturated with water and filtered the solid. It was washed with water, followed by ethanol and dried in vacuo to afford the title compound (3.0 g, 78%)as alight brown powder: 1H NMR (CD3OD/400 MHz) δ 9.10 (d. 1H, J=1.2 Hz), 8.77 (d, 1H, J=1.2 Hz), 7.61 (m, 1H), 7.01 (m 2H), 6.54 (s, 1H), 5.54 (s, 2H), 5.30 (s, 2H), 4.43 (q, 2H, J=6.8 Hz), 2.52 (s, 3H), and 1,39 (t, 3H, J=6.8 Hz); 19F NMR (CD3OD/400 MHz) δ−111.64 (m), and −116.04 (m); ES-HRMS m/z 494.0482 (M+H C21H19N3O4BrF2 requires 494.0522).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH:14]2[CH2:19][CH2:18][CH:17]([N:20]3C(=O)C4C(=CC=CC=4)C3=O)[CH2:16][CH2:15]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.NN.O>C(O)C.ClCCl>[CH2:1]([N:8]1[CH2:9][CH2:10][N:11]([CH:14]2[CH2:19][CH2:18][CH:17]([NH2:20])[CH2:16][CH2:15]2)[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1c2ccccc2C(=O)N1C1CCC(N2CCN(Cc3ccccc3)CC2)CC1
Agent: NN
Solvent: O
Solvent: ClCCl
Solvent: CCO
Product: NC1CCC(N2CCN(Cc3ccccc3)CC2)CC1
Reaction time: 24 h

Procedure:
To a solution of 2-[4-(4-benzyl-1-piperazinyl)cyclohexyl]-1H-isoindole-1,3(2H)-dione (5.00 g, 12.4 mmol) in ethanol-dichloromethane (10:3/65 ml) was added NH2NH2-water (2.4 ml /50.0 mmol) and the mixture was stirred for 1 day. After filtration, the filtrate was concentrated in vacuo. The residue was purified by column chromatography (NH2 gel/dichloromethane) to give a colorless oil (2.82 g/89%).
Reaction SMILES: Cl.[Cl:2]/[CH:3]=[CH:4]/[CH2:5][NH:6][CH2:7][CH3:8].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N)CCC.[C:33]([C:37]#[CH:38])([CH3:36])([CH3:35])[CH3:34]>[Cu]I.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O1CCCC1>[ClH:2].[CH3:34][C:33]([CH3:36])([CH3:35])[C:37]#[C:38]/[CH:3]=[CH:4]/[CH2:5][NH:6][CH2:7][CH3:8]
Reactant: C#CC(C)(C)C
Reactant: CCNC/C=C/Cl
Agent: [Cu]I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: C1CCOC1
Solvent: CCCCN
Product: CCNC/C=C/C#CC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 72 %

Procedure:
To 15 ml of tetrahydrofuran were added 1.56 g (10 mmol) of (E)-N-(3-chloro-2-propenyl)ethylamine hydrochloride, 95.2 mg (0.5 mmol) of copper (I) iodide, 44.9 mg (0.2 mmol) of palladium acetate and 105 mg (0.4 mmol) of triphenylphosphine, and further, 2.97 ml (30 mmol) of n-butylamine and 1.47 ml (12 mmol) of tert-butylacetylene under ice cooling. The mixture was stirred for 18 hours at room temperature, and concentrated under reduced pressure. The residue was subjected to silica gel chromatography (n-hexane→n-hexane/ethyl acetate=9/1→3/7). The desired fractions were put together and concentrated under reduced pressure. The residue was dissolved in 3 ml of 17% hydrogen chloride isopropyl alcohol solution, and the solvent and excess hydrogen chloride were distilled off. The resulting crystals were suspended in 20 ml of a mixture of ethyl acetate and diisopropyl ether (1/3), cooled, filtered, washed with 5 ml of diisopropyl ether and dried to obtain 1.46 g (yield: 72%) of the above identified compound as off-white crystalline powder.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]([NH:11][CH:12]1[CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13]1)(=O)[CH2:8][CH3:9].[Cl-].[NH4+]>O1CCCC1>[CH2:7]([NH:11][CH:12]1[CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13]1)[CH2:8][CH3:9]
Reactant: CCC(=O)NC1Cc2ccccc2C1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Product: CCCNC1Cc2ccccc2C1
Yield: 100 %

Procedure:
In 100 ml of tetrahydrofuran was suspended 5.7 g of lithium aluminum hydride, and 150 ml of a solution containing 18.9 g of 2-(propionylamino) indane dissolved in tetrahydrofuran was added dropwise to the suspension. The mixture was refluxed under heating for 2 hours. After cooling, excess lithium aluminum hydride was treated with a saturated ammonium chloride aqueous solution, and insolubles were removed by filtration. The filtrate was concentrated, and chloroform was added to the residue. The mixture was washed with water and dried, and the solvent was removed to obtain 17.5 g of 2-(propylamino)indane.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:29]=[CH:28][C:7]2[O:8][C:9]3[CH:27]=[CH:26][CH:25]=[CH:24][C:10]=3[C@@H:11]3[C@H:16]([NH:17][C:18](=[O:23])[C:19]([F:22])([F:21])[F:20])[CH2:15][CH2:14][CH2:13][N:12]3[C:6]=2[CH:5]=1.[CH3:30]I>CN(C=O)C>[Cl:3][C:4]1[CH:29]=[CH:28][C:7]2[O:8][C:9]3[CH:27]=[CH:26][CH:25]=[CH:24][C:10]=3[C@@H:11]3[C@H:16]([N:17]([CH3:30])[C:18](=[O:23])[C:19]([F:22])([F:21])[F:20])[CH2:15][CH2:14][CH2:13][N:12]3[C:6]=2[CH:5]=1
Reactant: CI
Reactant: O=C(N[C@@H]1CCCN2c3cc(Cl)ccc3Oc3ccccc3[C@H]12)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C(=O)C(F)(F)F)[C@@H]1CCCN2c3cc(Cl)ccc3Oc3ccccc3[C@H]12
Temperature: 25 °C
Reaction time: 18 h
Yield: 85.2 %

Procedure:
Sodium hydride (1.6 mg, 60% in oil) was added to trans-N-(7-chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl)-2,2,2-trifluoroacetamide (15 mg, 0.04 mmol) in 1 mL of DMF. After 10 minutes stirring methyl iodide (2.47 μL, 0.04 mmol) was added. The resulting mixture was stirred at room temperature for 18 h. After evaporation the crude compound was purified by chromatography on silica. Elution with toluene/ethyl acetate 7:3 gave trans-N-(7-chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl)-2,2,2-trifluoro-N-methylacetamide (14 mg, 90%). Data: (m/z)=411 (M+H)+.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.O[CH:14]([C:26]1[CH:31]=[N:30][CH:29]=[CH:28][N:27]=1)[CH2:15][CH2:16][C:17]1[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:18]=1[OH:25].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[CH3:24][O:23][C:21]1[CH:22]=[C:17]2[C:18](=[CH:19][CH:20]=1)[O:25][CH:14]([C:26]1[CH:31]=[N:30][CH:29]=[CH:28][N:27]=1)[CH2:15][CH2:16]2
Reactant: COc1ccc(O)c(CCC(O)c2cnccn2)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc2c(c1)CCC(c1cnccn1)O2
Temperature: 20 °C
Reaction time: 1 h

Procedure:
Diethyl azodicarboxylate (0.87 ml, 5.53 mmol) was added dropwise at room temperature to a mixture of 2-(3-hydroxy-3-pyrazin-2-yl-propyl)-4-methoxy-phenol (960 mg, 3.69 mmol) and triphenylphosphine (1.45 g, 5.53 mmol) in 20 ml of tetrahydrofuran. After stirring at 20° C. for 1 h, the reaction mixture was concentrated and purified by chromatography on silica gel (ethyl acetate in cyclohexane). 2-(6-Methoxy-chroman-2-yl)-pyrazine was obtained as white crystals (665 mg, 74%).
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(C)([O-])C.[Na+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.Br[C:66]1[CH:71]=[CH:70][N:69]([CH2:72][CH:73]2[CH2:75][CH2:74]2)[C:68](=[O:76])[CH:67]=1>C1(C)C=CC=CC=1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:73]1([CH2:72][N:69]2[CH:70]=[CH:71][C:66]([N:10]3[CH2:9][CH2:8][CH:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[CH2:12][CH2:11]3)=[CH:67][C:68]2=[O:76])[CH2:74][CH2:75]1
Reactant: c1ccc(C2CCNCC2)cc1
Reactant: O=c1cc(Br)ccn1CC1CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: O=c1cc(N2CCC(c3ccccc3)CC2)ccn1CC1CC1
Temperature: 100 °C

Procedure:
4-Phenylpiperidine (0.45 g, 2.78 mmol), palladium(II) acetate (0.016 g, 0.069 mmol), sodium tert-butoxide (0.34 g, 3.5 mmol) and BINAP (0.065 g, 0.104 mmol) were added to a solution of intermediate D3 (0.32 g, 1.39 mmol) in toluene (5 ml). The reaction mixture was heated at 100° C. for 16 hours in a sealed tube, after which it was cooled to room temperature, diluted with water (5 ml) and then extracted with EtOAc (3×5 ml). The combined organic fractions were dried (Na2SO4) and the solvent evaporated in vacuo. The crude product was purified by column chromatography (silica gel; 0-4% methanol/DCM as eluent). The desired fractions were collected and evaporated in vacuo to yield intermediate D18 (0.33 g, 78%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[CH:9][N:8]=[C:7]2[NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([O-])=O.O.NN>C(O)C.O.[Ni]>[NH2:1][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[CH:9][N:8]=[C:7]2[NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=[N+]([O-])c1ccc2ncnc(Nc3ccccc3)c2c1
Agent: [Ni]
Agent: NN
Solvent: CCO
Solvent: O
Product: Nc1ccc2ncnc(Nc3ccccc3)c2c1

Procedure:
A solution of a 6-nitro-4-(phenylamino)quinazoline substituted by a polyalkylene glycol, prepared as described hereinabove, in ethanol/water is reacted at reflux temperature with hydrazine hydrate and Raney® Nickel (Ra—Ni). The reaction mixture is filtered and evaporated, to give the corresponding 6-amino-4-(phenylamino)quinazoline substituted by a polyalkylene glycol moiety (terminating with a hydroxyl group).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[CH:12]=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:19][Li].Cl>O1CCCC1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:12]([OH:13])[CH3:19])[CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [Li]C
Reactant: COc1ccc(C=O)cc1OCc1ccccc1
Agent: Cl
Solvent: C1CCOC1
Product: COc1ccc(C(C)O)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of 3-benzyloxy-4-methoxybenzaldehyde (33 mmol maximum) in tetrahydrofuran (150 mL) is cooled to −78° C. Methyllithium (Aldrich, 1.6 M solution in diethyl ether, 31 mL, 49 mmol) is added dropwise via syringe. Following completion of the addition, the cooling bath is removed and the reaction mixture is allowed to warm to room temperature. After 90 minutes at that temperature, the mixture is cooled to 0° C. and quenched by the addition of saturated aqueous sodium hydrogen carbonate. The quenched reaction mixture, after warming to room temperature, is acidified with 1 M hydrochloric acid solution to pH 1 and extracted thrice with diethyl ether. The combined extracts were washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give 1-(3-benzyloxy-4-methoxy-phenyl)-ethanol.
Reaction SMILES: C(N(CC)CC)C.Cl.[Br:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:17]=[C:18]([C@@H:21]3[CH2:25][CH2:24][CH2:23][NH:22]3)[NH:19][CH:20]=2)=[CH:12][CH:11]=1.[CH3:26][O:27][C:28]([NH:30][C@@H:31]([CH:35]([CH3:37])[CH3:36])[C:32](O)=[O:33])=[O:29].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O.C(OCC)(=O)C.O>[CH3:26][O:27][C:28](=[O:29])[NH:30][C@H:31]([C:32]([N:22]1[CH2:23][CH2:24][CH2:25][C@H:21]1[C:18]1[NH:19][CH:20]=[C:16]([C:13]2[CH:12]=[CH:11][C:10]([Br:9])=[CH:15][CH:14]=2)[N:17]=1)=[O:33])[CH:35]([CH3:37])[CH3:36]
Reactant: Brc1ccc(-c2c[nH]c([C@@H]3CCCN3)n2)cc1
Reactant: COC(=O)N[C@H](C(=O)O)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc(-c2ccc(Br)cc2)c[nH]1)C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.2 %

Procedure:
Triethylamine (2.3 g, 11.4 mmol) was added to a solution of 4-(4-bromo-phenyl)-2-(S)-pyrrolidin-2-yl-1H-imidazole hydrochloride (2 g, 11.4 mol), (S)-2-methoxycarbonylamino-3-methyl-butyric acid (2.5 g, 7.6 mmol), and HATU (4.3 g, 11.4 mmol) in dimethylformamide (50 mL) at 0° C. under nitrogen. The reaction mixture was stirred at room temperature overnight and treated with ethyl acetate (100 mL) and water (1000 mL). The organic layer was washed with water (2×100 mL) and brine (100 mL), dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography in 1:1 petroleum ether:ethyl acetate to give the title compound (2.5 g 74% yield) as a yellow solid. 1H NMR (d6-DMSO, 400 MHz) δ (ppm) 7.63 (d, J=8.8 Hz, 2H), 7.54 (m, 1H), 7.47 (m, 2H), 7.26 (d, J=8.4 Hz, 1H), 5.03 (m, 1H), 4.02 (t, J=8.4 Hz, 1H), 3.76 (m, 2H), 3.51 (s, 3H), 2.10 (m, 2H), 1.93 (m, 3H), 0.85 (d, J=6.8 Hz, 3H), 0.81 (d, J=6.8 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8](SC)=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1.[CH3:14][N:15]([CH3:23])[C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1>>[NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8]([NH:22][C:19]3[CH:20]=[CH:21][C:16]([N:15]([CH3:23])[CH3:14])=[CH:17][CH:18]=3)=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1
Reactant: CN(C)c1ccc(N)cc1
Reactant: CSc1ncnc2cc(N)ncc12
Product: CN(C)c1ccc(Nc2ncnc3cc(N)ncc23)cc1
Temperature: 190 °C
Reaction time: 0.33 h
Yield: 53.1 %

Procedure:
A mixture of 7-amino-4-methylthiopyrido[4,3-d]pyrimidine (256 mg, 1.33 mmole) and N,N-dimethyl-1,4-phenylenediamine (1.95 g, 14.4 mmole) is stirred under N2 at 190° C. for 20 min. The resulting product is chromatographed over alumina (3-7% EtOH/CHCl3) to give 7-amino-4-(4-dimethylaminoanilino)pyrido[4,3-d]pyrimidine (198 mg, 53%) as an orange solid. 1H NMR (DMSO) δ 9.67 (1H, brs), 9.27 (1H, s), 8.27 (1H, s), 7.51 (2H, d, J=8.9 Hz), 6.75 (2H, d, J=8.9 Hz), 6.51 (2H, brs), 6.39 (1H, s), 2.89 (6H, s).
Reaction SMILES: [CH3:1][C:2]([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[S:16]([CH3:19])(=[O:18])=[O:17])([CH3:8])[C:3]([O:5]CC)=[O:4].[OH-].[Na+].O>CO>[CH3:8][C:2]([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[S:16]([CH3:19])(=[O:18])=[O:17])([CH3:1])[C:3]([OH:5])=[O:4]
Reactant: CCOC(=O)C(C)(C)Oc1ccccc1S(C)(=O)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(Oc1ccccc1S(C)(=O)=O)C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.6 %

Procedure:
The product of Example 46B (1.22 g) was dissolved in MeOH (8 mL) and treated with 50% NaOH (1.75 g, 21.27 mmol) and water (6 mL). The mixture was heated until all was soluble and stirred at 25° C. for 1 hr. The solvents were removed in vacuo, water (6 mL) was added and the solution acidified with HCl. The mixture was extracted with CHCl3, dried (Na2SO4), filtered and concentrated in vacuo. The residue was crystallized from ether and heptane (1:4) to yield the title compound (0.953 g), m.p. 114-116° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:24]=[CH:23][C:6]([C:7]([NH:9][C@@H:10]2[CH2:15][CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11]2)=[O:8])=[CH:5][CH:4]=1.[ClH:25]>O1CCOCC1>[ClH:25].[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:9][C@@H:10]2[CH2:15][CH2:14][CH2:13][NH:12][CH2:11]2)=[O:8])=[CH:23][CH:24]=1
Reactant: COc1ccc(C(=O)N[C@@H]2CCCN(C(=O)OC(C)(C)C)C2)cc1
Agent: Cl
Solvent: C1COCCO1
Product: COc1ccc(C(=O)N[C@@H]2CCCNC2)cc1

Procedure:
(R)-tert-Butyl 3-aminopiperidine-1-carboxylate (1.70 g, 8.5 mmol) was mixed with p-anisic acid (1.42 g, 9.35 mmol) in 5 mL DMF and 25 mL dioxane. The mixture was stirred at RT, and to it were added DIEA (2.07 mL, 11.9 mmol) and then PyBOP (4.86 g, 9.35 mmol). The mixture was stirred at RT for 3 hours, diluted with 150 mL EtOAc, washed with water 60 mL×3, dried, concentrated, subjected to silica flash column using 0 to 20% EtOAc in DCM to isolate (R)-tert-butyl 3-(4-methoxybenzamido)piperidine-1-carboxylate (488) in quantitative yield. Compound 488 (1.86 g, 5.56 mmol) was treated with 30 mL commercial 4N HCl in dioxane at RT for 15 min, giving (R)-4-methoxy-N-(piperidin-3-yl)benzamide hydrochloride (489) in quantitative yield as a white solid.