Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@@H:9]1[C:14]([OH:16])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:17]([NH2:25])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].C(N(CC)C(C)C)(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[CH2:17]([NH:25][C:14]([C@H:9]1[CH2:10][CH2:11][CH2:12][CH2:13][N:8]1[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[O:16])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCCCCCN
Reactant: CC(C)(C)OC(=O)N1CCCC[C@@H]1C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCCCCCCNC(=O)[C@H]1CCCCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 25 h

Procedure:
(R)-(+)-1-(tert-Butoxycarbonyl)-2-piperidinecarboxylic acid (Aldrich Chemical Company, Milwaukee, Wis.) (1.00 g; 4.36 mmol) is dissolved in methylene chloride (20 mL) at ambient temperature. n-Octylamine (0.620 g; 4.80 mmol), N,N-diisopropylethylamine (1.24 g; 9.60 mmol) and PyBOP (2.50 g; 4.80 mmol) are added sequentially. The reaction is stirred for 25 hours at room temperature, then concentrated under reduced pressure. The residue is purified via silica gel chromatography using a gradient elution (20%→40% ethyl acetate in hexanes) affording the desired product (22) as an oil. ISMS: MH+341.2
Reaction SMILES: C1(S([NH:10][C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][C:12]=2I)(=O)=O)C=CC=CC=1.C(N(CC)CC)C.[C:29]([C:31]1[O:32][CH:33]=[CH:34][CH:35]=1)#[CH:30].O>CN(C)C=O>[O:32]1[CH:33]=[CH:34][CH:35]=[C:31]1[C:29]1[NH:10][C:11]2[C:12]([CH:30]=1)=[CH:13][C:14]([S:17]([CH3:20])(=[O:18])=[O:19])=[CH:15][CH:16]=2
Reactant: C#Cc1ccco1
Reactant: CS(=O)(=O)c1ccc(NS(=O)(=O)c2ccccc2)c(I)c1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc2[nH]c(-c3ccco3)cc2c1
Temperature: 60 °C
Reaction time: 3 h
Yield: 29.3 %

Procedure:
To a suspension of the compound obtained in Example 8 (5) (2.00 g), bistriphenylphosphine palladium dichloride (321 mg), cuprous iodide (87.0 mg) and triethylamine (1.38 g) in N,N-dimethylformamide (46 ml), a solution of 2-ethynylfuran (842 mg) in N,N-dimethylformamide (46 ml) was slowly added dropwise under nitrogen atmosphere and the mixture was stirred at 60° C. for 3 hours. The reaction solution was then poured into water, extracted with chloroform, washed with a saturated aqueous NaCl solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was separated using silica gel column chromatography (methanol:chloroform=1:100). To a solution of the obtained colorless amorphous compound (1.10 g) in methanol (28 ml) was added a 1N aqueous potassium hydroxide solution (5.52 ml) and the mixture was stirred at 60° C. for 1 hour. After completion of the reaction, the reaction solution was concentrated under reduced pressure. The resulting residue was poured into water, extracted with chloroform, washed with a saturated aqueous NaCl solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was separated using silica gel preparative thin-layer chromatography (methanol:chloroform=1:20) to obtain 350 mg of the desired product as a brown crystal.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12](Br)=[CH:11][C:10]=1[F:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:25]2[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])(C)C)=[O:32])[CH2:27][CH:26]=2)O1.O.C([O-])([O-])=O.[Na+].[Na+].[C:46](#N)[CH3:47]>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>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:25]2[CH2:30][CH2:29][N:28]([C:31]([O:33][CH2:34][CH2:37][CH2:46][CH3:47])=[O:32])[CH2:27][CH:26]=2)=[CH:11][C:10]=1[F:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC#N
Reactant: Fc1cc(Br)ccc1OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CCCCOC(=O)N1CC=C(c2ccc(OCc3ccccc3)c(F)c2)CC1
Temperature: 80 °C
Yield: 83 %

Procedure:
A solution of 1-(benzyloxy)-4-bromo-2-fluorobenzene (5.0 g, 17.8 mmol) and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (6.60 g, 21.3 mmol) in acetonitrile (50 mL) was degassed for 5 min. To this was added water (50 mL), Na2CO3 (5.66 g, 53.4 mmol) and Pd(Ph3P)4 (1.23 g, 1.07 mmol) and the reaction was further degassed for 10 min. It was then heated to 80° C. for 16 h. The reaction cooled to rt, poured into water, and extracted with EtOAc. The combined organic layers were, dried with magnesium sulfate, filtered through celite, and concentrated in vacuo to afford a brown oil. The oil was purified using silica gel column chromatography (0-30% EtOAc/hexanes) to afford 1-butyl 4-(4-(benzyloxy)-3-fluorophenyl)-5,6-dihydropyridine-1(2H)-carboxylate (5.63 g, 83% yield): LC-MS [M+H]+−tBu+ACN=369.2; 1H NMR (500 MHz, DMSO-d6) δ 7.51-7.27 (m, 6H), 7.25-7.13 (m, 2H), 6.12 (br. s., 1H), 5.19 (s, 2H), 3.97 (br. s., 2H), 3.51 (t, J=5.6 Hz, 2H), 2.41 (d, J=1.5 Hz, 2H), 1.42 (s, 9H).
Reaction SMILES: BrC1C=CC(OC2C=CC(C#N)=C(Cl)N=2)=CC=1C1OCCO1.[Br:23][C:24]1[CH:39]=[CH:38][C:27]([O:28][C:29]2[N:36]=[C:35](Cl)[CH:34]=[CH:33][C:30]=2[C:31]#[N:32])=[CH:26][C:25]=1[CH:40]1[O:44][CH2:43][CH2:42][O:41]1.BrC1C=CC(OC2C=CC(C#N)=[C:53]([N:59]([CH2:61][CH2:62][O:63]C)C)N=2)=CC=1C=O>C(#N)C>[Br:23][C:24]1[CH:39]=[CH:38][C:27]([O:28][C:29]2[N:36]=[C:35]([N:59]([CH2:61][CH2:62][OH:63])[CH3:53])[CH:34]=[CH:33][C:30]=2[C:31]#[N:32])=[CH:26][C:25]=1[CH:40]1[O:44][CH2:43][CH2:42][O:41]1
Reactant: COCCN(C)c1nc(Oc2ccc(Br)c(C=O)c2)ccc1C#N
Reactant: N#Cc1ccc(Cl)nc1Oc1ccc(Br)c(C2OCCO2)c1
Agent: N#Cc1ccc(Oc2ccc(Br)c(C3OCCO3)c2)nc1Cl
Solvent: CC#N
Product: CN(CCO)c1ccc(C#N)c(Oc2ccc(Br)c(C3OCCO3)c2)n1
Temperature: 80 °C
Yield: 36 %

Procedure:
To a solution of compound mixture, 6-(4-bromo-3-[1,3]dioxolan-2-yl-phenoxy)-2-chloro-nicotinonitrile and 2-(4-bromo-3-[1,3]dioxolan-2-yl-phenoxy)-6-chloro-nicotinonitrile, (4+5, 1 g, 2.6 mmol) in acetonitrile (anhydrous, 30 mL) was added 2-methylamino-ethanol (6, 2.1 mL, 26 mmol). The reaction was heated at 80° C. for 2 hours. After the reaction, all volatile components were evaporated under vacuum. Purification was accomplished by silica gel chromatography, eluting with 10%-80% EtOAc/Hexane gradient, affording the title compound 400 mg in 36% yield. 1H NMR 400 MHz (CDCl3) δ 7.62 (d, J=8.6 Hz, 1H), 7.59 (d, J=8.6 Hz, 1H), 7.47 (d, J=3.1 Hz, 1H), 7.06 (dd, J=8.6 Hz, 3.1 Hz, 1H), 6.18 (d, J=8.6 Hz, 1H), 6.08 (s, 1H), 4.20-4.02 (m, 4H), 3.55 (t, J=3.2 Hz, 2H), 3.42 (t, J=3.2 Hz, 2H), 3.02 (s, 3H).
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([C:16]2[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=2[O:23][CH3:24])=[CH:5][CH:6]=[C:7]2[C:12]=1[NH:11][C:10](=[O:13])[C:9]([CH3:15])([CH3:14])[NH:8]2.[CH3:25][C:26]1[S:30][C:29]([C:31]([OH:33])=[O:32])=[CH:28][CH:27]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O.C(OCC)(=O)C>[F:22][C:20]1[CH:19]=[CH:18][C:17]([O:23][CH3:24])=[C:16]([C:4]2[C:3]([CH2:2][O:33][C:31]([C:29]3[S:30][C:26]([CH3:25])=[CH:27][CH:28]=3)=[O:32])=[C:12]3[C:7]([NH:8][C:9]([CH3:15])([CH3:14])[C:10](=[O:13])[NH:11]3)=[CH:6][CH:5]=2)[CH:21]=1
Reactant: Cc1ccc(C(=O)O)s1
Reactant: COc1ccc(F)cc1-c1ccc2c(c1CCl)NC(=O)C(C)(C)N2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc(F)cc1-c1ccc2c(c1COC(=O)c1ccc(C)s1)NC(=O)C(C)(C)N2
Yield: 85 %

Procedure:
8-Chloromethyl-7-(5-fluoro-2-methoxyphenyl)-3,3-dimethyl-3,4-dihydro-1H-quinoxalin-2-one (Reference Compound No. 4-2, 50.9 mg, 0.14 mmol), 5-methyl-2-thiophenecarboxylic acid (62.5 mg, 0.44 mmol), and potassium carbonate (79.9 mg, 0.58 mmol) were suspended in anhydrous. N,N-dimethylformamide (1.5 mL) and stirred at 80° C. for 4.5 hours. Ethyl acetate (30 mL) and water (30 mL) were added to the reaction mixture and partitioned. The organic layer was washed with water (30 mL) and saturated brine (30 mL) successively, dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled compound (55.0 mg) as a colorless solid. (Yield 85%)
Reaction SMILES: Br[C:2]1[N:3]([CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:4]2[C:9]([C:10]=1[CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[CH:8][CH:7]=[C:6]([C:17]([O:19][CH3:20])=[O:18])[CH:5]=2.[CH:29]([C:31]1[S:32][CH:33]=[CH:34][C:35]=1B(O)O)=[O:30].C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:25]([O:24][C:22](=[O:23])[CH2:21][N:3]1[C:4]2[C:9](=[CH:8][CH:7]=[C:6]([C:17]([O:19][CH3:20])=[O:18])[CH:5]=2)[C:10]([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:2]1[C:35]1[CH:34]=[CH:33][S:32][C:31]=1[CH:29]=[O:30])([CH3:28])([CH3:27])[CH3:26]
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(Br)n(CC(=O)OC(C)(C)C)c2c1
Reactant: O=Cc1sccc1B(O)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccsc3C=O)n(CC(=O)OC(C)(C)C)c2c1

Procedure:
Methyl 2-bromo-1-(2-tert-butoxy-2-oxoethyl)-3-cyclohexyl-1H-indole-6-carboxylate (prepared as described in Example 1, Step 1) and (2-formyl-3-thienyl) boronic acid (1.5 eq) were dissolved in dioxane (0.07 M) and 2M aqueous Na2CO3 (6 eq) was added. The solution was degassed by bubbling argon, Pd(PPh3)2Cl2 (0.2 eq) was added, and the reaction mixture was refluxed for 45 min; after cooling EtOAc was added and the solution washed with water and brine, dried over Na2SO4 and concentrated. The title compound was isolated by chromatography (PE/EtOAc 9:1). Yield (84%); MS (ES+) m/z 504 (M+Na)+.
Reaction SMILES: [NH2:1][C@H:2]([C:6]([OH:8])=[O:7])[CH:3]([CH3:5])[CH3:4].C(=O)([O-])[O-].[Na+].[Na+].Cl[C:16]([O:18][CH3:19])=[O:17]>[OH-].[Na+]>[CH3:19][O:18][C:16]([NH:1][CH:2]([CH:3]([CH3:5])[CH3:4])[C:6]([OH:8])=[O:7])=[O:17]
Reactant: CC(C)[C@H](N)C(=O)O
Reactant: COC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Product: COC(=O)NC(C(=O)O)C(C)C
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a solution of L-valine, d8 (Cambridge Isotope Laboratories, 0.4949 g) in 1N sodium hydroxide (3.95 mL) was added sodium carbonate (0.419 g). The solution was cooled to 0° C. and methyl chloroformate (0.289 mL) was added dropwise over 30 minutes and reaction mixture was stirred for 3 h at 0° C. Reaction mixture was washed with ethyl ether (3×15 mL) and aqueous layer was acidified to pH=1 with concentrated HCl. Aqueous layer was extracted dichloromethane (3×15 mL) and organic layers were dried (MgSO4) and concentrated to give 2-Methoxycarbonylamino-3-methyl-butyric acid, d8 as a white solid (0.5681 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:17]=[C:16](O)[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH:5]=[CH:4][N:3]=1.O=P(Cl)(Cl)[Cl:21].CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:21][C:16]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=[C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[CH:7]=2)[CH:17]=1
Reactant: Oc1cc(-c2ccnc(Cl)c2)nc2ccccc12
Reactant: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Clc1cc(-c2cc(Cl)c3ccccc3n2)ccn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a 250 mL RBF was added 4.6 g (18 mmol) 2-(2-chloro-pyridin-4-yl)-quinolin-4-ol and 100 mL POCl3, and the mixture was treated with 3.1 mL DIEA (18 mmol). The mixture was was stirred at rt for 1 h, and all starting material was converted. All POCl3 was vacuumed down. The residue was dissolved in 250 mL DCM, washed with saturated NaHCO3 carefully to pH 8. The organic phase was dried over Na2SO4, concentrated and purified by column and yielded pale yellow 4-chloro-2-(2-chloro-pyridin-4-yl)-quinoline. MS (ES+): 275 (M+H)+.
Reaction SMILES: [C:1]1([CH:7]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:8]([N:10]2[CH:19]([C:20]([O:22]CC)=[O:21])[CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:36][CH3:37])[C:16]=3[O:25][CH2:26][C:27]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[C:29]([CH3:35])[CH:28]=3)[CH2:11]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>CO>[C:38]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]([N:10]2[CH:19]([C:20]([OH:22])=[O:21])[CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:36][CH3:37])[C:16]=3[O:25][CH2:26][C:27]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[C:29]([CH3:35])[CH:28]=3)[CH2:11]2)=[O:9])[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1
Reactant: CCOC(=O)C1Cc2c(ccc(OC)c2OCc2ccc(OC)c(C)c2)CN1C(=O)C(c1ccccc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(COc2c(OC)ccc3c2CC(C(=O)O)N(C(=O)C(c2ccccc2)c2ccccc2)C3)cc1C

Procedure:
This compound is prepared by a hydrolysis of the ester from Example 34 as follows: a solution of 0.50 g (0.86 mmole) of the ester, 50 mL of methanol, and 2.0 mL of 1N sodium hydroxide is maintained at reflux for 15 minutes. The methanol is removed, water (30 mL) is added, and 1.0 mL of glacial acetic acid is added to precipitate the gummy product. Purification by silica gel chromatography eluting with 5% methanol-chloroform gives pure product; mp 140°-142° C.
Reaction SMILES: [CH3:1][C:2]1[CH2:6][CH2:5][C:4](=O)[CH:3]=1.[C:8]1([Li])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[Li].BrC1C=CC=CC=1.[NH4+].[Cl-]>CCOCC>[CH3:1][C:2]1[CH2:6][CH:5]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:3]=1
Reactant: [Li]c1ccccc1
Reactant: CC1=CC(=O)CC1
Agent: [Cl-]
Agent: [Li]
Agent: [NH4+]
Solvent: CCOCC
Solvent: Brc1ccccc1
Product: CC1=CC(c2ccccc2)=CC1
Reaction time: 4 h

Procedure:
A solution of 25 g (0.26 mol) of 3-methyl-2cyclopenten-1-one in 100 mL of ether was added at −78° C. under argon atmosphere to a solution of phenyl litium in 200 mL of ether, previous prepared from 5.76 g (0.83 mol) of lithium and 44 mL (0.42 mol) of bromobenzene. The reaction mixture was stirred for 4 h and then treated with a 10% aq. solution of NH4Cl. The organic phase was collected, washed with water, dried with MgSO4 and concentrated. The residue was distilled at 54° C./1 mmHg. Yield 24.37 g (60%).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[C:8]([C:24]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[O:25])=[CH:9][C:10]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:11]([CH:15]=2)[C:12](O)=[O:13])[CH:4]=[N:3]1.C(N(C(C)C)CC)(C)C.[NH2:41][C:42]1[CH:47]=[CH:46][N:45]=[N:44][CH:43]=1.ON1C2N=CC=CC=2N=N1.C(Cl)CCl>CN(C)C=O>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[C:8]([C:24]([N:26]3[CH2:27][CH2:28][O:29][CH2:30][CH2:31]3)=[O:25])=[CH:9][C:10]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:11]([CH:15]=2)[C:12]([NH:41][C:42]2[CH:47]=[CH:46][N:45]=[N:44][CH:43]=2)=[O:13])[CH:4]=[N:3]1
Reactant: Nc1ccnnc1
Reactant: Cn1cc(-c2cc(C(=O)O)c(OCc3ccccc3)cc2C(=O)N2CCOCC2)cn1
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: Cn1cc(-c2cc(C(=O)Nc3ccnnc3)c(OCc3ccccc3)cc2C(=O)N2CCOCC2)cn1
Reaction time: 18 h

Procedure:
To a solution of 5-(1-methyl-1H-pyrazol-4-yl)-4-(4-morpholinylcarbonyl)-2-[(phenylmethyl)oxy]benzoic acid (may be prepared as described in Description 26; 150 mg, 0.36 mmol) in N,N-dimethylformamide (3 ml) was added diisopropylethylamine (0.12 ml, 0.71 mmol), 4-aminopyridazine (33.8 mg, 0.36 mmol), 1-hydroxy-7-azabenzotriazole (58.1 mg, 0.43 mmol) and EDC (116 mg, 0.61 mmol). The reaction was stirred for 18 hours and then the solvent was removed in vacuo. The residue was purified by MDAP to yield the title compound as a yellow gum. 117 mg.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([F:11])[CH:3]=1.[C:12](OC(=O)C)(=[O:14])[CH3:13]>C(O)(=O)C.O>[C:12]([NH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([F:11])[CH:3]=1)(=[O:14])[CH3:13]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc(C(=O)O)c(F)c1
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)Nc1ccc(C(=O)O)c(F)c1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A mixture of 4-amino-2-fluoro-benzoic acid (5.61 g, 36.2 mmol) and acetic anhydride (5.13 mL, 54.3 mmol) in 60 mL acetic acid was stirred at 60° C. overnight. The mixture was taken up in 250 mL water and stirred for 30 min. The precipitate was filtered and washed with water. The filtrate was washed with ethyl acetate. The organic phase was neutralized with sat. K2CO3 (aq) and concentrated i.vac. A small volume was left, the precipitate was filtered and combined with the first isolated precipitate.
Reaction SMILES: C[Si](C)(C)[C:3]#[C:4][C:5]1[N:12]=[CH:11][CH:10]=[CH:9][C:6]=1[C:7]#[N:8].[CH3:15][O-:16].[Na+].CC[O:20][CH2:21]C>CO>[CH3:15][O:16][CH:3]([O:20][CH3:21])[CH2:4][C:5]1[N:12]=[CH:11][CH:10]=[CH:9][C:6]=1[C:7]#[N:8]
Reactant: CCOCC
Reactant: C[O-]
Reactant: C[Si](C)(C)C#Cc1ncccc1C#N
Agent: [Na+]
Solvent: CO
Product: COC(Cc1ncccc1C#N)OC
Yield: 94 %

Procedure:
The product from Example 36a (1.62 g, 8.09 mmol) was reacted with sodium methoxide as a 25 wt % solution (8.74 g, 40.4 mmol) in methanol (5 mL) for two hours at 80° C. The crude product was isolated by extraction with ether, dried over MgSO4, filtered and concentrated under vacuum to give the title compound (1.46 g, 94%) sufficiently pure for use as isolated.
Reaction SMILES: [CH2:1]([NH:4][C:5]1[C:10]([C:11]([NH:13][CH2:14][CH2:15][CH2:16][NH:17]C(=O)OC(C)(C)C)=[O:12])=[CH:9][N:8]=[C:7]([NH:25][CH2:26][CH2:27][C:28]2[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=2)[N:6]=1)[CH2:2][CH3:3].C(=O)([O-])O.[Na+].C(OCC)(=O)C>C(Cl)(Cl)Cl.FC(F)(F)C(O)=O>[NH2:17][CH2:16][CH2:15][CH2:14][NH:13][C:11]([C:10]1[C:5]([NH:4][CH2:1][CH2:2][CH3:3])=[N:6][C:7]([NH:25][CH2:26][CH2:27][C:28]2[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=2)=[N:8][CH:9]=1)=[O:12]
Reactant: CCCNc1nc(NCCc2ccncc2)ncc1C(=O)NCCCNC(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: CCCNc1nc(NCCc2ccncc2)ncc1C(=O)NCCCN
Reaction time: 0.5 h
Yield: 64.7 %

Procedure:
To a solution of tert-butyl (3-(4-(propylamino)-2-((2-(pyridin-4-yl)ethyl)amino)pyrimidine-5-carboxamido)propyl)carbamate (B3, 281 mg) in chloroform (2 mL), trifluoroacetic acid (2 mL) was added at room temperature, and the mixture was stirred at the same temperature for 30 minutes. To the reaction mixture, saturated aqueous sodium hydrogencarbonate and ethyl acetate were added. The organic layer was separated, and the aqueous layer was extracted three times with chloroform. The organic layer and the extracts were combined, washed with saturated aqueous sodium chloride, and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (eluent, 85 to 70% ethyl acetate in methanol) to obtain N-(3-aminopropyl)-4-(propylamino)-2-((2-(pyridin-4-yl)ethyl)amino)pyrimidine-5-carboxamide (B4, 142 mg) as white solid.
Reaction SMILES: C1(C)C=CC(S([O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([CH:23]=[O:24])=[CH:19][CH:18]=3)=[CH:13][CH:12]=2)(=O)=O)=CC=1.[CH2:26]([CH:32]([CH2:35]O)[CH2:33][OH:34])[CH2:27][CH2:28][CH2:29][CH2:30][CH3:31].S(=O)(=O)(O)O>C1(C)C=CC=CC=1.ClCCl>[CH2:26]([CH:32]1[CH2:35][O:24][CH:23]([C:20]2[CH:19]=[CH:18][C:17]([C:14]3[CH:13]=[CH:12][C:11]([OH:10])=[CH:16][CH:15]=3)=[CH:22][CH:21]=2)[O:34][CH2:33]1)[CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: CCCCCCC(CO)CO
Reactant: Cc1ccc(S(=O)(=O)Oc2ccc(-c3ccc(C=O)cc3)cc2)cc1
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CCCCCCC1COC(c2ccc(-c3ccc(O)cc3)cc2)OC1
Reaction time: 1.8 h
Yield: 71.2 %

Procedure:
A solution of 2.82 g of 4'-(p-toluenesulphonyloxy)biphenyl-4-carboxaldehyde and 1.54 g of 2-hexyl-1,3-propane-diol in 50 ml of toluene was treated with 3 drops of 10% (vol.) sulphuric acid. The mixture was heated to boiling for 1.5 hours, with about 50 ml of damp toluene being distilled off and 30 ml of fresh toluene being simultaneously added dropwise. Then, 10 drops of triethylamine were added to the reaction mixture. After cooling the mixture was washed with 10 ml of lN sodium hydrogen carbonate solution and three times with 20 ml of water each time, dried over sodium sulphate and concentrated. The resulting crude 5-hexyl-2-[4'-(p-toluenesulphonyloxy)-4-biphenylyl]m-dioxane (4.26 g) was dissolved in 160 ml ethanol. The solution was treated with a solution of 2.64 g of potassium hydroxide in 27 ml of water and heated to boiling for 1.8 hours while stirring. After cooling the reaction mixture was neutralized (to pH 6) with 1.9 ml of glacial acetic acid and concentrated to about 20 ml. The suspension obtained was diluted with 80 ml of dichloromethane and the organic phase was washed twice with 20 ml of water each time, dried over sodium sulphate and concentrated. Chromatography of the residue (2.80 g) on g of silica gel with toluene/acetone (vol. 19:1) gave 1.94 g of 5-hexyl-2-(4'-hydroxy-4-biphenylyl)-m-dioxane.
Reaction SMILES: [CH3:1][NH:2][S:3]([CH3:6])(=[O:5])=[O:4].C[O-].[K+].F[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N+:17]([O-:19])=[O:18].O>CN(C)C=O>[CH3:1][N:2]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N+:17]([O-:19])=[O:18])[S:3]([CH3:6])(=[O:5])=[O:4]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: CNS(C)(=O)=O
Agent: C[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(c1ccccc1[N+](=O)[O-])S(C)(=O)=O
Reaction time: 0.25 h
Yield: 74.4 %

Procedure:
To 3.2 g of N-methyl methanesulfonamide in 50 ml of dry dimethylformamide is added 1.47 g of potassium methoxide. The mixture is stirred for 15 minutes. 2.8 g of 2-Fluoronitrobenzene is added and the mixture is heated to reflux for two hours. The dimethylformamide is removed on a rotary evaporator. The concentrated reaction mixture is poured into water. The crude product is extracted with CH2Cl2. The crude extracts are dried with MgSO4, filtered and concentrated on a rotary evaporator. The crude product is purified by recrystallization from butyl chlorideethyl acetate. 3.4 g of product with m.p. 144°-145° C. is obtained.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([CH:7]=O)[CH:4]=[N:3]1.[CH3:9][C:10]([S@:13]([NH2:15])=[O:14])([CH3:12])[CH3:11].O>C1COCC1>[CH3:9][C:10]([S@:13](/[N:15]=[CH:7]/[C:5]1[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=1)=[O:14])([CH3:12])[CH3:11]
Reactant: CC(C)(C)[S@](N)=O
Reactant: Cn1cc(C=O)cn1
Solvent: O
Solvent: C1CCOC1
Product: Cn1cc(/C=N/[S@](=O)C(C)(C)C)cn1
Temperature: 65 °C
Yield: 93.8 %

Procedure:
To a solution of 1-methyl-1H-pyrazole-4-carbaldehyde (2.2 g, 20 mmol) in THF (50 mL) was added (R)-2-methylpropane-2-sulfinamide (4.8 g, 40 mmol) and Ti(OEt)4 (9.2 g, 40 mmol). The reaction mixture was heated at 65° C. for 14 h. After cooling, the mixture was poured into water. The solid was filtered off, and the filtrate was extracted with EtOAc. The organic layer was concentrated and purified by SiO2 chromatography eluting with petroleum ether/EtOAc (5:1) to afford 4.0 g (83%) of (R,E)-2-methyl-N-((1-methyl-1H-pyrazol-4-yl)methylene)propane-2-sulfinamide (46). LCMS (ESI) m/z: 214.1 [M+11]+.
Reaction SMILES: [CH3:1][N:2]1[C:7]2=[CH:8][C:9]3[CH2:15][CH2:14][NH:13][CH2:12][CH2:11][C:10]=3[CH:16]=[C:6]2[O:5][CH2:4][C:3]1=[O:17].[Cl:18][CH2:19][CH2:20][CH2:21][S:22][C:23]1[N:24]([CH3:39])[C:25]([C:28]2[CH:37]=[CH:36][CH:35]=[C:34]3[C:29]=2[CH:30]=[CH:31][C:32]([CH3:38])=[N:33]3)=[N:26][N:27]=1>>[ClH:18].[CH3:1][N:2]1[C:7]2=[CH:8][C:9]3[CH2:15][CH2:14][N:13]([CH2:19][CH2:20][CH2:21][S:22][C:23]4[N:24]([CH3:39])[C:25]([C:28]5[CH:37]=[CH:36][CH:35]=[C:34]6[C:29]=5[CH:30]=[CH:31][C:32]([CH3:38])=[N:33]6)=[N:26][N:27]=4)[CH2:12][CH2:11][C:10]=3[CH:16]=[C:6]2[O:5][CH2:4][C:3]1=[O:17]
Reactant: Cc1ccc2c(-c3nnc(SCCCCl)n3C)cccc2n1
Reactant: CN1C(=O)COc2cc3c(cc21)CCNCC3
Product: Cc1ccc2c(-c3nnc(SCCCN4CCc5cc6c(cc5CC4)N(C)C(=O)CO6)n3C)cccc2n1
Product: Cl

Procedure:
The title compound was prepared in analogy to General Procedure 1 from 4-methyl-4,6,7,8,9,10-hexahydro[1,4]oxazino[2,3-h][3]benzazepin-3(2H)-one (37 mg) and 5-{5-[(3-chloropropyl)thio]-4-methyl-4H-1,2,4-triazol-3-yl}-2-methylquinoline and was obtained as a colourless sticky solid (41 mg).