Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:28]([N:29]([CH3:44])[C:30](=[O:43])[CH2:31][N:32]2C(=O)C3=CC=CC=C3C2=O)=[CH:27][CH:26]=[C:25]([Cl:45])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]=1[N:14]=[C:13]([CH3:16])[CH:12]=[C:11]2[O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1.O.NN>C(O)C>[NH2:32][CH2:31][C:30]([N:29]([C:28]1[C:2]([Cl:1])=[C:3]([C:25]([Cl:45])=[CH:26][CH:27]=1)[CH2:4][O:5][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]=1[N:14]=[C:13]([CH3:16])[CH:12]=[C:11]2[O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1)[CH3:44])=[O:43]
Reactant: Cc1cc(OCc2ccccn2)c2cccc(OCc3c(Cl)ccc(N(C)C(=O)CN4C(=O)c5ccccc5C4=O)c3Cl)c2n1
Agent: NN
Solvent: CCO
Solvent: O
Product: Cc1cc(OCc2ccccn2)c2cccc(OCc3c(Cl)ccc(N(C)C(=O)CN)c3Cl)c2n1
Yield: 65.2 %

Procedure:
A mixture of 8-[2,6-dichloro-3-[N-methyl-N-(phthalimidoacetyl)amino]benzyloxy]-2-methyl-4-(2-pyridylmethoxy)quinoline (750 mg), hydrazine monohydrate (117 mg) and ethanol was heated under reflex for 4 hours. The precipitate was removed by filtration and filtrate was evaporated in vacuo. The residue was dissolved with a mixture of chloroform and methanol (10:1, V/V), precipitate was removed by filtration and filtrate was evaporated in vacuo. The residue was purified by column chromatography on silica gel eluting with chloroform - methanol to afford 8-[3-(N-glycyl-N-methylamino)-2,6-dichlorobenzyloxy]-2-methyl-4-(2-pyridylmethoxy)quinoline (390 mg) as an amorphous powder.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:25]=[CH:24][C:9]2[N:10]=[C:11]([NH:14][C@H:15]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)[O:12][CH2:13][C:8]=2[CH:7]=1)=[O:4].[NH2:26][CH2:27][C:28]([CH3:31])([OH:30])[CH3:29]>C(#N)C>[OH:30][C:28]([CH3:31])([CH3:29])[CH2:27][NH:26][CH2:2][C:3]([NH:5][C:6]1[CH:25]=[CH:24][C:9]2[N:10]=[C:11]([NH:14][C@H:15]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)[O:12][CH2:13][C:8]=2[CH:7]=1)=[O:4]
Reactant: CC(C)(O)CN
Reactant: O=C(CCl)Nc1ccc2c(c1)COC(N[C@@H]1CCc3ccccc31)=N2
Solvent: CC#N
Product: CC(C)(O)CNCC(=O)Nc1ccc2c(c1)COC(N[C@@H]1CCc3ccccc31)=N2
Yield: 52.3 %

Procedure:
Prepared from 2-chloro-N-[2-((R)-indan-1-ylamino)-4H-benzo[d][1,3]oxazin-6-yl]-acetamide (Example 3 step A) (100 mg, 0.281 mmol) and 1-amino-2-methyl-propan-2-ol (126 mg, 1.405 mmol) in acetonitrile (1 ml) according to the procedure described for Example 3 step B. Obtained the title compound as a white solid (60 mg, 52%), MS (ISP) m/e=409.3 [(M+H)+].
Reaction SMILES: [C:1](O)(=[O:3])C.C(O)=O.[CH2:8]([O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:18]=[CH:19][C:20]3[NH:26][CH2:25][CH2:24][C:23]([C:27]([O:29][CH3:30])=[O:28])=[CH:22][C:21]=3[CH:31]=2)=[CH:13][CH:12]=1)[CH3:9]>C1COCC1>[CH2:8]([O:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]2[CH:18]=[CH:19][C:20]3[N:26]([CH:1]=[O:3])[CH2:25][CH2:24][C:23]([C:27]([O:29][CH3:30])=[O:28])=[CH:22][C:21]=3[CH:31]=2)=[CH:15][CH:16]=1)[CH3:9]
Reactant: CCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3)cc1
Reactant: CC(=O)O
Solvent: C1CCOC1
Solvent: O=CO
Product: CCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3C=O)cc1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
To anhydrous acetic acid (0.18 ml) was added dropwise formic acid (0.09 ml) under ice-cooling, and the mixture was stirred under nitrogen atmosphere at 50° C. for 2 hours. To the mixture was added THF (2 ml) and then was added dropwise, under ice-cooling a solution of methyl 7-(4-ethoxyphenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.25 g) in THF (15 ml), and the mixture was stirred at room temperature for 4 hours. The solvent was evaporated, and to the residue was added water. The mixture was extracted with ethyl acetate. The organic layer was washed with sodium hydrogen carbonate solution, water and saturated brine, and dried with anhydrous magnesium sulfate, and the solvent was evaporated to give methyl 7-(4-ethoxyphenyl)-1-formyl-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.24 g) as yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([O:10][CH2:11][CH:12]2[O:14][CH2:13]2)[CH:7]=[C:6]([Cl:15])[C:3]=1[CH:4]=[O:5].[C:16]([NH2:20])([CH3:19])([CH3:18])[CH3:17]>>[Cl:1][C:2]1[CH:9]=[C:8]([O:10][CH2:11][CH:12]([OH:14])[CH2:13][NH:20][C:16]([CH3:19])([CH3:18])[CH3:17])[CH:7]=[C:6]([Cl:15])[C:3]=1[CH:4]=[O:5]
Reactant: O=Cc1c(Cl)cc(OCC2CO2)cc1Cl
Reactant: CC(C)(C)N
Product: CC(C)(C)NCC(O)COc1cc(Cl)c(C=O)c(Cl)c1

Procedure:
A mixture of 2,6-dichloro-4-(2,3-epoxypropoxy)-benzaldehyde (3 gm) and tert-butylamine (20 ml) is heated at 45° for 17 hours. The excess tert-butylamine is removed under reduced pressure (20 mm). The oil is dissolved in 6N hydrochloric acid (25 ml) and heated for 1 hour. The acid solution is added to boiling saturated aqueous sodium carbonate with nitrogen ebullition. The basic solution is extracted with chloroform. The chloroform is dried over anhydrous sodium sulfate, filtered and concentrated to 2,6-dichloro-4-(3-tert-butylamino-2-hydroxypropoxy)benzaldehyde which is used without further purification.
Reaction SMILES: [I:1][C:2]1[CH:8]=[C:7]([C:9]([F:18])([C:14]([F:17])([F:16])[F:15])[C:10]([F:13])([F:12])[F:11])[CH:6]=[C:5]([C:19]([F:22])([F:21])[F:20])[C:3]=1[NH2:4].[Cl:23][C:24]1[C:32]([N+:33]([O-:35])=[O:34])=[CH:31][CH:30]=[CH:29][C:25]=1[C:26](Cl)=[O:27]>>[Cl:23][C:24]1[C:32]([N+:33]([O-:35])=[O:34])=[CH:31][CH:30]=[CH:29][C:25]=1[C:26]([NH:4][C:3]1[C:5]([C:19]([F:20])([F:21])[F:22])=[CH:6][C:7]([C:9]([F:18])([C:10]([F:11])([F:12])[F:13])[C:14]([F:15])([F:16])[F:17])=[CH:8][C:2]=1[I:1])=[O:27]
Reactant: Nc1c(I)cc(C(F)(C(F)(F)F)C(F)(F)F)cc1C(F)(F)F
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1Cl
Product: O=C(Nc1c(I)cc(C(F)(C(F)(F)F)C(F)(F)F)cc1C(F)(F)F)c1cccc([N+](=O)[O-])c1Cl

Procedure:
According to the method of 3-2 of Example 3, a target compound was prepared from 2-iodo-4-(heptafluoropropan-2-yl)-6-(trifluoromethyl)aniline and 2-chloro-3-nitrobenzoyl chloride.
Reaction SMILES: Cl[C:2]1[CH:16]=[CH:15][C:5]2[C:6](=[O:14])[NH:7][C:8]3[C:13]([C:4]=2[CH:3]=1)=[CH:12][CH:11]=[CH:10][N:9]=3.[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=1>>[C:21]1([CH3:24])[CH:22]=[CH:23][C:18]([NH:17][C:2]2[CH:16]=[CH:15][C:5]3[C:6](=[O:14])[NH:7][C:8]4[C:13]([C:4]=3[CH:3]=2)=[CH:12][CH:11]=[CH:10][N:9]=4)=[CH:19][CH:20]=1
Reactant: O=c1[nH]c2ncccc2c2cc(Cl)ccc12
Reactant: Cc1ccc(N)cc1
Product: Cc1ccc(Nc2ccc3c(=O)[nH]c4ncccc4c3c2)cc1
Yield: 21.1 %

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 231 using 6 (50 mg, 0.22 mmol) and p-toluidine (35 mg, 0.33 mmol) to provide 238 (14 mg, 21% yield) as a black solid. LC-MS (M+H=302, obsd.=302). 1H NMR (400 MHz, d6-DMSO): δ 11.64 (s, 1H), 8.82 (s, 1H), 8.44 (m, 2H), 8.12 (d, 1H), 7.78 (d, 1H), 7.27 (m, 1H), 7.22 (dd, 1H), 7.19 (s, 3H), 2.30 (s, 4H).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][CH2:12][CH:13]2[CH2:18][O:17]C(C)(C)[O:15][CH2:14]2)=[C:4](Cl)[N:3]=1>C(O)C.C1CCCCC=1.[Pd]>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][CH2:12][CH:13]([CH2:18][OH:17])[CH2:14][OH:15])=[CH:4][N:3]=1
Reactant: CC1(C)OCC(CCn2cnc3c(Cl)nc(N)nc32)CO1
Agent: [Pd]
Solvent: CCO
Solvent: C1=CCCCC1
Product: Nc1ncc2ncn(CCC(CO)CO)c2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 36.1 %

Procedure:
To a solution of 2-amino-6-chloro-9-[2-(2,2-dimethyl-1, 3-dioxan-5-yl)ethyl]purine (0.54 g, 1.75 mmol) in ethanol (10 ml) and cyclohexene (20 ml) was added 10% palladium-on-charcoal (400 mg) and the solution was refluxed for 7 hours. A further quantity of catalyst (200 mg) was added and the solution was refluxed overnight. The solution was filtered and washed through with methanol. To the filtrate was added hydrochloric acid (5 M, 0.3 ml) and water (0.7 ml) and the solution was stirred for 30 minutes at room temperature. The solution was neutralised by addition of aqueous sodium bicarbonate and the solvent was removed. The residue was purified by column chromatography on silica gel eluting with chloroform-methanol (5:1, 4:1) to afford 2-amino-9-(4-hydroxy-3-hydroxymethylbut-1-yl)purine as a crystalline solid (150 mg, 36%), m.p. 156°-158° C.; λmax (H2O) 242 and 303 nm; νmax (KBr) 3320, 3210, 1640, 1610, 1580, and 1430 cm1 ; δH [(CD3)2SO] 1.47 (1H, m, 3'-H), 1.78 (2H, q, J 7.2Hz, 2'-H), 3.3-3.5 (4H, m, 2×4'-H), 4.12 (2H, t, J 7.4Hz, 1'-H), 4.42 (2H, t, J 5.2Hz, D2O exchangeable, 2 x OH), 6.45 (2H, s, D2O exchangeable, 2-NH2), 8.06 (1H, s, 8-H), and 8.56 (1H, s, 6-H); (Found: C, 50.61; H, 6.45; N, 29.62 %. C10H15N5O2 requires: C, 50.62; H, 6.37; N, 29.52
Reaction SMILES: [CH3:1][C:2]1[C:15]2[O:14][P:13](=[O:17])([OH:16])[C:12]3[C:7](=[CH:8][CH:9]=[C:10]([CH3:18])[CH:11]=3)[C:6]=2[CH:5]=[C:4]([CH3:19])[CH:3]=1.[Br:20][O-].[Na+]>>[CH3:1][C:2]1[C:15]2[O:14][P:13](=[O:16])([OH:17])[C:12]3[C:7](=[CH:8][C:9]([Br:20])=[C:10]([CH3:18])[CH:11]=3)[C:6]=2[CH:5]=[C:4]([CH3:19])[CH:3]=1
Reactant: Cc1cc(C)c2c(c1)-c1ccc(C)cc1P(=O)(O)O2
Reactant: [O-]Br
Agent: [Na+]
Product: Cc1cc(C)c2c(c1)-c1cc(Br)c(C)cc1P(=O)(O)O2

Procedure:
9,10-Dihydro-1,3,7-trimethyl-9-hydroxy-9-phospha-10-oxaphenanthrene-9-oxide (268 g) is treated with an aqueous solution of sodium hypobromite at 60° C. in the same manner as in Example 6, to give about 250 g of 9,10-dihydro-1,3,7-trimethyl-6-bromo-9-hydroxy-9-phospha-10-oxaphenanthrene-9-oxide, exhibiting a phosphorus content of 8.7% (theoretical value: 8.77%), an acid value of 160 (theoretical value: 158,9) and a melting point of 260° C. or higher, which will be hereinafter referred to as CA-M1,3,7-B6.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[O:15][C:16](=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH2:23]Br>>[C:7]1([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:8]=[CH:9][C:10]([O:13][CH2:23][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[C:16]([OH:25])=[O:15])=[CH:11][CH:12]=1
Reactant: Oc1ccc(-c2ccccc2)cc1
Reactant: COC(=O)c1ccccc1CBr
Product: O=C(O)c1ccccc1COc1ccc(-c2ccccc2)cc1

Procedure:
2-(Biphenyl-4-yloxymethyl)-benzoic acid was prepared using general procedure A from 4-phenylphenol (available from Aldrich, Milwaukee, Wis.) and 2-bromomethyl-benzoic acid methyl ester (Intermediate 1). Yield: 50 mg. Mass spectrum (ES) MH+=305.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[C:12]([O:16][C:17](=[O:27])[N:18]([CH2:22][CH2:23][C:24](=O)[CH3:25])[CH2:19][CH2:20]C)([CH3:15])([CH3:14])[CH3:13].N1CCCC1>CC(O)C>[C:12]([O:16][C:17]([N:18]1[CH2:19][CH2:20][CH2:25][C:24](=[C:6]2[C:5]3[C:9](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=3)[NH:8][C:7]2=[O:11])[CH2:23][CH2:22]1)=[O:27])([CH3:13])([CH3:14])[CH3:15]
Reactant: O=C1Cc2ccc(Cl)cc2N1
Reactant: CCCN(CCC(C)=O)C(=O)OC(C)(C)C
Solvent: C1CCNC1
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)N1CCCC(=C2C(=O)Nc3cc(Cl)ccc32)CC1
Temperature: 90 °C

Procedure:
A suspension of 6-chlorooxindole (0.71 g, 4.24 mmol) (Cresent Chem.), (3-oxo-butyl)-propyl-carbamic acid tert-butyl ester (1 g, 4.69 mmol) (Tyger Sci.), and pyrrolidine (0.1 g) (Aldrich) in 2-propanol (15 mL) was heated at 90° C. for 2 days. The mixture was allowed to cool to room temperature. The solvent was removed and the residue was purified by chromatography to give 4-(6-chloro-2-oxo-1,2-dihydro-indol-3-ylidene)-azepane-1-carboxylic acid tert-butyl ester as a brown solid. (Yield: 1.36 g, 88%).
Reaction SMILES: C(N(CC)CC)C.Cl.[NH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:12][CH:11]=1.[I-].C[N+]1C=CC=CC=1Cl.[Cl:31][C:32]1[CH:37]=[CH:36][C:35]([S:38]([NH:41][CH:42]([CH2:46][CH3:47])[C:43](O)=[O:44])(=[O:40])=[O:39])=[CH:34][CH:33]=1>C(Cl)(Cl)Cl>[Cl:31][C:32]1[CH:33]=[CH:34][C:35]([S:38]([NH:41][CH:42]([CH2:46][CH3:47])[C:43]([NH:9][C:10]2[CH:11]=[CH:12][C:13]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:14][CH:15]=2)=[O:44])(=[O:39])=[O:40])=[CH:36][CH:37]=1
Reactant: CCC(NS(=O)(=O)c1ccc(Cl)cc1)C(=O)O
Reactant: CCOC(=O)Cc1ccc(N)cc1
Agent: C[n+]1ccccc1Cl
Agent: Cl
Agent: [I-]
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)Cc1ccc(NC(=O)C(CC)NS(=O)(=O)c2ccc(Cl)cc2)cc1
Yield: 16.7 %

Procedure:
Triethylamine (1.99 ml), ethyl 4-aminophenylacetate hydrochloride (699 mg), and 1-methyl-2-chloropyridinium iodide (1.1 g) were added to a solution of (RS)-2-(4-chlorobenzenesulfonylamino)butanoic acid (1 g) in chloroform (30 ml), and the whole was heated under reflux for 2 hours under argon. The reaction mixture was concentrated under reduced pressure. After adding 1N HCl, the residue was extracted with ethyl acetate. The combined ethyl acetate layers were washed with a saturated saline solution, and dried over Na2SO4. The solvent was evaporated under reduced pressure. The residue was purified by column chromatography (silica gel 70 g, hexane/ethyl acetate=2/1) to give (RS)-2-(4-chlorobenzenesulfonylamino)-N-(4-(ethoxycarbonylmethyl) phenyl)butanamide (237 mg).
Reaction SMILES: O.NN.[Cl:4][C:5]1[N:10]=[CH:9][C:8]([CH2:11][N:12]2C(=O)C3=CC=CC=C3C2=O)=[CH:7][CH:6]=1.O>CCO>[Cl:4][C:5]1[N:10]=[CH:9][C:8]([CH2:11][NH2:12])=[CH:7][CH:6]=1
Reactant: O=C1c2ccccc2C(=O)N1Cc1ccc(Cl)nc1
Agent: NN
Solvent: CCO
Solvent: O
Product: NCc1ccc(Cl)nc1
Yield: 70.1 %

Procedure:
Hydrazine hydrate (1.7 ml) was added to a refluxing solution of 6.5 g (2.4×10-2 mole) of N-(6-chloro-3-pyridylmethyl)phthalimide in 100 ml of EtOH, and the mixture was further refluxed for 1 hour. After addition of 20 ml of water, the ethanol was distilled off under reduced pressure. Concentrated hydrochloric acid (25 ml) was added to the residue and the mixture was refluxed for 1 hour. After cooling, the reaction mixture was neutralized with NaOH and the aqueous layer was saturated with NaCl and extracted with Et2O. The extract was dried over Na2SO4 and the solvent was distilled off to give 2.4 g of the title compound as a yellow oil.
Reaction SMILES: CO[C:3]([C:5]1[S:9][C:8](/[CH:10]=[CH:11]/[C:12]2[C:13]([CH2:18][CH2:19][CH2:20][CH3:21])=[N:14][O:15][C:16]=2[CH3:17])=[N:7][C:6]=1[CH3:22])=[O:4].[NH2:23][CH:24]([CH2:27][OH:28])[CH2:25][OH:26]>>[OH:26][CH2:25][CH:24]([NH:23][C:3]([C:5]1[S:9][C:8](/[CH:10]=[CH:11]/[C:12]2[C:13]([CH2:18][CH2:19][CH2:20][CH3:21])=[N:14][O:15][C:16]=2[CH3:17])=[N:7][C:6]=1[CH3:22])=[O:4])[CH2:27][OH:28]
Reactant: NC(CO)CO
Reactant: CCCCc1noc(C)c1/C=C/c1nc(C)c(C(=O)OC)s1
Product: CCCCc1noc(C)c1/C=C/c1nc(C)c(C(=O)NC(CO)CO)s1
Yield: 86 %

Procedure:
As described for example 95, 2-[(E)-2-(3-butyl-5-methyl-isoxazol-4-yl)-vinyl]-4-methyl-thiazole-5-carboxylic acid methyl ester (60 mg, 0.19 mmol) was converted, using 2-amino-1,3-propanediol instead of isopropylamine, to the title compound (61 mg, 86%) which was obtained as a colourless oil. MS: m/e=380.4 [M+H]+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][NH:8][CH2:9][C:10]1[S:14][C:13]([C:15]([NH:17][C@H:18]([C:23]([OH:25])=[O:24])[CH2:19][CH2:20][CH2:21][NH2:22])=[O:16])=[CH:12][CH:11]=1.C(O)(=O)C.[N:30]1[C:39]2[C:38](=O)[CH2:37][CH2:36][CH2:35][C:34]=2[CH:33]=[CH:32][CH:31]=1.C([BH3-])#N.[Na+]>CO>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][NH:8][CH2:9][C:10]1[S:14][C:13]([C:15]([NH:17][C@@H:18]([CH2:19][CH2:20][CH2:21][NH:22][CH:38]2[C:39]3[N:30]=[CH:31][CH:32]=[CH:33][C:34]=3[CH2:35][CH2:36][CH2:37]2)[C:23]([OH:25])=[O:24])=[O:16])=[CH:12][CH:11]=1
Reactant: O=C1CCCc2cccnc21
Reactant: NCCC[C@H](NC(=O)c1ccc(CNCc2ccccn2)s1)C(=O)O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: O=C(N[C@@H](CCCNC1CCCc2cccnc21)C(=O)O)c1ccc(CNCc2ccccn2)s1
Reaction time: 72 h
Yield: 27 %

Procedure:
The compound obtained in Example 14-4 (18.2 mg) was dissolved in methanol (0.6 ml), and acetic acid (0.06 ml), 5,6,7,8-tetrahydroquinolin-8-one (16 mg), and sodium cyanoborohydride (7 mg) were added. After 3 days, the reaction solution was concentrated. The residue was purified by silica gel column chromatography (1 g, chloroform/methanol=5/1). 1 mol/l hydrochloric acid was added to the resulting colorless syrup, and the mixture was concentrated and dried under reduced pressure to obtain ahydrochloride of the title compound (6.7 mg) as a white solid.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1.[CH3:13][NH:14][CH3:15]>CO>[CH3:13][N:14]([CH3:15])[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1
Reactant: CNC
Reactant: ClCCCCOc1cccnc1
Solvent: CO
Product: CN(C)CCCCOc1cccnc1
Temperature: 100 °C

Procedure:
A portion of the 4-chloro-1-(3-pyridyloxy)butane was dissolved in methanol (25 mL) and added to a 40 wt % aqueous solution of dimethylamine (50 mL) in a heavy-walled glass pressure-tube apparatus. The tube was sealed and the mixture was stirred and heated at 100° C. (oil bath temperature) for 4 h. After cooling, the mixture was concentrated by rotary evaporation. Saturated NaCl solution (10 mL) was added to the residue, and the solution (pH 6) was extracted with ether (3×25 mL) to remove impurities. The aqueous layer was basified to pH 10 with 10% NaOH solution, and the mixture was extracted with chloroform (4×25 mL). The combined chloroform extracts were dried (Na2SO4), filtered, and concentrated by rotary evaporation to a residue that was dried briefly under high vacuum to give 1.26 g of an oil.
Reaction SMILES: C[Al](C)C.[Cl:5][C:6]1[C:15]([NH2:16])=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1.[C:17]([C:21]1[CH:32]=[CH:31][C:24]([CH:25]=[CH:26][C:27](OC)=[O:28])=[CH:23][CH:22]=1)([CH3:20])([CH3:19])[CH3:18].CO>ClCCCl>[C:17]([C:21]1[CH:22]=[CH:23][C:24]([CH:25]=[CH:26][C:27]([NH:16][C:15]2[C:6]([Cl:5])=[N:7][C:8]3[C:13]([CH:14]=2)=[CH:12][CH:11]=[CH:10][CH:9]=3)=[O:28])=[CH:31][CH:32]=1)([CH3:20])([CH3:18])[CH3:19]
Reactant: Nc1cc2ccccc2nc1Cl
Reactant: COC(=O)C=Cc1ccc(C(C)(C)C)cc1
Agent: C[Al](C)C
Solvent: ClCCCl
Solvent: CO
Product: CC(C)(C)c1ccc(C=CC(=O)Nc2cc3ccccc3nc2Cl)cc1

Procedure:
A solution of trimethylaluminum (2.0 M, 0.61 mL, 1.22 mmol) was added to a solution of 2-chloro-quinolin-3-ylamine (0.2 g, 1.12 mmol) and methyl 4-tert-butylcinnamate (0.241 g, 1.11 mmol) in 1,2-dichloroethane (10 mL). The solution was heated at reflux for 6 hours. The solution was cooled and treated with methanol (˜1 mL). The product was preabsorbed on silica gel and eluted with 20% ethyl acetate in hexane, to give the product as a colorless solid, 0.288 g (71%). MS: m/z 365 (MH+). 1H NMR (DMSO-d6): δ 1.31 (m, 9 H), 7.16 (d, 1 H), 7.50 (d, 2 H), 7.59-7.69 (m, 4 H), 7.75 (t, 1 H), 7.95 (d, 1 H), 8.05 (d, 1 H), 8.94 (s, 1 H), and 9.97 (s, 1 H).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([OH:10])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[CH3:11][C:12](=[CH2:15])[CH2:13]Cl>>[C:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][CH2:13][C:12]([CH3:15])=[CH2:11])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCC(O)CC1
Reactant: C=C(C)CCl
Product: C=C(C)COC1CCN(C(C)=O)CC1

Procedure:
This compound was prepared similarly to Example E, starting from N-acetyl-4-hydroxypiperidine and 2-methylallyl chloride, and was distilled and used directly in the next stage. It had a b.p. of 128° C. @ 1 mm.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:13][CH:14]2[CH2:17][CH2:16][CH2:15]2)[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[CH:18](=O)[CH3:19].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[Cl:1][C:2]1[CH:3]=[C:4]([N:13]([CH:14]2[CH2:17][CH2:16][CH2:15]2)[CH2:18][CH3:19])[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: CC=O
Reactant: COC(=O)c1cc(Cl)cc(NC2CCC2)c1C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: CCN(c1cc(Cl)cc(C(=O)OC)c1C)C1CCC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 92.3 %

Procedure:
To a stirred solution of methyl 5-chloro-3-(cyclobutylamino)-2-methylbenzoate (0.70 g, 2.73 mmol) and acetaldehyde (0.36 g, 8.20 mmol) in dichloroethane (15 mL), acetic acid (0.98 g, 16.4 mmol) was added and the reaction stirred at room temperature for 10 minutes. Then sodium triacetoxyborohydride (1.7 g, 8.2 mmol) was added at 0° C. and the reaction stirred for 3 h at room temperature. On completion, the solvent was removed under reduced pressure to give title compound (0.71 g, 91%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C:9]1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1.C(OC(=O)C)(C)C.[ClH:28]>O>[ClH:28].[ClH:28].[C:2]1([CH2:1][N:8]2[CH2:13][CH2:12][CH:11]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[CH2:10][CH2:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1COCCN1
Reactant: O=C1CCCCN1Cc1ccccc1
Agent: Cl
Solvent: O
Solvent: CC(=O)OC(C)C
Product: c1ccc(CN2CCC(N3CCOCC3)CC2)cc1
Temperature: 95 °C
Reaction time: 0.5 h

Procedure:
10.00 kg (52.84 mol) 1-benzylpiperidone (K) were taken and 9.21 kg (105.68 mol) morpholine (L) and 30.0 L isopropylacetate were added. Then the reaction mixture obtained was heated to reflux temperature (95° C.) using the water separator and stirred until no more water separated off. Then the mixture was hydrogenated at 4 bar and at an internal temperature of 60° C. in the presence of 0.50 kg Raney nickel catalyst. Then the solvent was completely distilled off in vacuo. Then 45.0 L ethanol were added and 10.87 kg (116.25 mol) ethanolic 10-mol hydrochloric acid were metered in. The resulting suspension was cooled to 20° C. and stirred for 30 minutes at 20° C. The product was centrifuged off and dried.
Reaction SMILES: C1(C2C3C(=CC=CC=3)C=CC=2)C2C(=CC=CC=2)C=CC=1P1C(C)(C)CC2(OCCO2)CC1(C)C.C(N(CC)CC)C.Br[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1.[CH2:49]([O:51][P:52]([O-:56])[O:53][CH2:54][CH3:55])[CH3:50]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(O)C>[C:43]1([P:52](=[O:56])([O:53][CH2:54][CH3:55])[O:51][CH2:49][CH3:50])[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: Brc1ccccc1
Reactant: CCOP([O-])OCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)CC2(CC(C)(C)P1c1ccc3ccccc3c1-c1cccc3ccccc13)OCCO2
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOP(=O)(OCC)c1ccccc1
Temperature: 80 °C
Reaction time: 24 h
Yield: 59 %

Procedure:
In a nitrogen-atmosphere glovebox, a microwave vial equipped with a magnetic stir bar was charged with palladium(II)acetate (1.4 mg, 0.00637 mmol, 0.02 equivalents), 8-(1,1′-binaphthyl-2-yl)-7,7,9,9-tetramethyl-1,4-dioxa-8-phosphaspiro[4.5]decane (3.6 mg, 0.00764 mmol, 0.024 equivalents) and ethanol (0.64 mL). To the slurry were added triethylamine (67 μL, 0.478 mmol, 1.5 equivalents), bromobenzene (34 μL, 0.318 mmol, 1 equivalent) and diethylphosphite (49 μL, 0.382 mmol, 1.2 equivalents). The vial was sealed with a crimp top and stirred at 80° C. After 24 hours, the vial was removed from the heating block, cooled to room temperature and brought out of the glovebox. The reaction solution was diluted with tetrahydrofuran (2 mL) and filtered into a tared 125-mL Erlenmeyer flask. The vial was rinsed with tetrahydrofuran (5×1 mL), followed by washing of the filter cake with tetrahydrofuran (5 mL). A wt % analysis was performed on the filtrate and an assay yield of 59% was measured versus commercially available diethyl phenylphosphonate.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:19][OH:20])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:10]=[N:11][CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:14]=1.Cl[C:22]1[CH:23]=[C:24]2[N:31]([CH3:32])[C@@H:30]([CH3:33])[CH2:29][N:25]2[C:26](=[O:28])[N:27]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:10]=[N:11][CH:12]=[C:13]([C:15]([F:16])([F:17])[F:18])[CH:14]=1)[CH2:19][O:20][C:22]1[CH:23]=[C:24]2[N:31]([CH3:32])[C@@H:30]([CH3:33])[CH2:29][N:25]2[C:26](=[O:28])[N:27]=1
Reactant: C[C@H]1Cn2c(cc(Cl)nc2=O)N1C
Reactant: OCc1ccc(Oc2cncc(C(F)(F)F)c2)c(F)c1
Product: C[C@H]1Cn2c(cc(OCc3ccc(Oc4cncc(C(F)(F)F)c4)c(F)c3)nc2=O)N1C

Procedure:
The title compound was prepared by a procedure similar to that described for E9 starting from (3-fluoro-4-((5-(trifluoromethyl)pyridin-3-yl)oxy)phenyl)methanol and (S)-7-chlo-ro-1,2-dimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one.