Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH:3]([CH2:18][OH:19])[C:4]1[C:13]2[C:8](=[CH:9][C:10]([O:16][CH3:17])=[C:11]([O:14][CH3:15])[CH:12]=2)[CH2:7][CH2:6][N:5]=1>C(O)C.[H][H].[Pt]>[OH:1][CH2:2][CH:3]([CH2:18][OH:19])[CH:4]1[C:13]2[C:8](=[CH:9][C:10]([O:16][CH3:17])=[C:11]([O:14][CH3:15])[CH:12]=2)[CH2:7][CH2:6][NH:5]1
Reactant: [H][H]
Reactant: COc1cc2c(cc1OC)C(C(CO)CO)=NCC2
Agent: [Pt]
Solvent: CCO
Product: COc1cc2c(cc1OC)C(C(CO)CO)NCC2
Yield: 95 %

Procedure:
0.01 mole (2.65 g) of 1-[bis(hydroxymethyl)-methyl]-6,7-dimethoxy-3,4-dihydroisoquinoline is dissolved in 50 ml of ethanol, and the mixture is reduced in hydrogen atmosphere, in the presence of a 10% platinum-on-activated carbon catalyst, under normal conditions. After uptake of the calculated amount of hydrogen (1 to 2 hours), the catalyst is filtered off and the filtrate is evaporated to yield the aimed compound in crystalline form.
Reaction SMILES: [CH:1]1([CH2:6][C@@H:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[OH:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:15](OC(=O)C)(=[O:17])[CH3:16]>N1C=CC=CC=1>[C:15]([O:8][C@H:7]([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[CH2:6][CH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)(=[O:17])[CH3:16]
Reactant: CC(=O)OC(C)=O
Reactant: O[C@@H](CC1CCCC1)c1ccccc1
Solvent: c1ccncc1
Product: CC(=O)O[C@@H](CC1CCCC1)c1ccccc1
Reaction time: 6 h
Yield: 100 %

Procedure:
A solution of 406 mg (2.13 mmol) of (S)-2-cyclopentyl-1-phenylethanol (from Step C) in 9 mL of pyridine was treated with 1 mL of acetic anhydride. After stirring for 6 h, the reaction was concentrated. Flash chromatography on silica gel using 93:7 v/v hexanes/EtOAc afforded 495 mg (100%) of the title compound: RF: 0.75 (4:1 v/v hexanes/EtOAc); 1H NMR (300 MHz): δ 1.10-1.21 (m, 2H), 1.44-2.04 (m, 9H), 2.05 (s, 3H), 5.75 (dd, J=8.0, 6.1, 1H), 7.25-7.34 (m, 5H).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:10]([N:13]2[C:22](=[O:23])[C:21]3[CH2:20][CH2:19][CH2:18][CH2:17][C:16]=3[N:15]([CH3:24])[C:14]2=[O:25])=[CH:9][C:3]=1[C:4]([O:6]CC)=[O:5].[OH-].[Na+]>C(O)C.O>[Cl:1][C:2]1[CH:12]=[CH:11][C:10]([N:13]2[C:22](=[O:23])[C:21]3[CH2:20][CH2:19][CH2:18][CH2:17][C:16]=3[N:15]([CH3:24])[C:14]2=[O:25])=[CH:9][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: CCOC(=O)c1cc(-n2c(=O)c3c(n(C)c2=O)CCCC3)ccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cn1c2c(c(=O)n(-c3ccc(Cl)c(C(=O)O)c3)c1=O)CCCC2
Reaction time: 1 h

Procedure:
A solution of 3.6 g of ethyl 2-chloro-5-[1,4,5,6,7,8-hexahydro-1-methyl-2,4-dioxo-3(2H)-quinazolinyl]-benzoate in 70 ml of ethanol is held at 60° C. for 10 minutes with 0.6 g of sodium hydroxide in 70 ml of water and subsequently stirred for 1 hour. The solution is substantially evaporated down under reduced pressure and the residue is brought to pH 1 with 2N hydrochloric acid. The precipatate is shaken five times with 50 ml amounts of diethyl ether and the organic phases are dried over anhydrous sodium sulphate and evaporated to dryness under reduced pressure. 2-Chloro-5-[1,4,5,6,7,8-hexahydro-1-methyl-2,4-dioxo-3(2H)-quinazolinyl]-benzoic acid is obtained.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Br[CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[C:12]2[CH:15]([C:16]([N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[O:17])[CH2:14][C:13]2=[CH:24][CH:25]=1.O>C(O)C.O>[N:1]([CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[C:12]2[CH:15]([C:16]([N:18]3[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]3)=[O:17])[CH2:14][C:13]2=[CH:24][CH:25]=1)=[N+:2]=[N-:3]
Reactant: O=C(C1Cc2ccc(OCCCBr)cc21)N1CCCCC1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: [N-]=[N+]=NCCCOc1ccc2c(c1)C(C(=O)N1CCCCC1)C2

Procedure:
Sodium azide (2.4 g) is added to a stirred solution of 5-(3-bromopropoxy)-1-(1-piperidinylcarbonyl)benzocyclobutene (12.8 g) in ethanol/water (13 ml/130 ml). The reaction mixture is refluxed overnight, poured into water, washed with methylene chloride and the organic extract washed, dried, filtered and evaporated in vacuo affording the desired azide product as an oil, which is used in the next step without further purification.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([C@H:10]2[C@@H:16]([O:17]C(=O)C)[C:15](=[O:21])[N:14]([CH2:22][CH2:23][NH:24][CH3:25])[C:13]3[CH:26]=[CH:27][CH:28]=[C:29]([Cl:30])[C:12]=3[S:11]2)=[CH:6][CH:5]=1>Cl.C(O)C>[ClH:30].[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([C@H:10]2[C@@H:16]([OH:17])[C:15](=[O:21])[N:14]([CH2:22][CH2:23][NH:24][CH3:25])[C:13]3[CH:26]=[CH:27][CH:28]=[C:29]([Cl:30])[C:12]=3[S:11]2)=[CH:6][CH:5]=1
Reactant: CNCCN1C(=O)[C@H](OC(C)=O)[C@H](c2ccc(OC)cc2)Sc2c(Cl)cccc21
Agent: Cl
Solvent: CCO
Product: CNCCN1C(=O)[C@H](O)[C@H](c2ccc(OC)cc2)Sc2c(Cl)cccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 185.8 %

Procedure:
735 mg of (-)-cis-2-(4-methoxyphenyl)-3-acetoxy-5-[2-(N-methylamino)ethyl]-9-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one.hydrochloride are dissolved in 15 ml of 25% HCl-ethanol, and the solution is stirred at room temperature for 3 hours. The mixture is evaporated under reduced pressure to remove solvent. The residue is washed with ether and recrystallized from methanol. 622 mg of (+)-cis-2-(4-methoxyphenyl)-3-hydroxy-5-[2-(N-methylamino)ethyl]-9-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one.hydrochloride are obtained.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:7][C@H:6]([CH2:8][OH:9])[C@@H:5]([OH:10])[C@H:4]1[OH:11].[Cl:12][C:13]1[CH:18]=[C:17](Cl)[N:16]=[CH:15][N:14]=1.CCN(CC)CC>CCO>[Cl:12][C:13]1[N:14]=[CH:15][N:16]=[C:17]([NH:2][C@@H:3]2[CH2:7][C@H:6]([CH2:8][OH:9])[C@@H:5]([OH:10])[C@H:4]2[OH:11])[CH:18]=1
Reactant: N[C@@H]1C[C@H](CO)[C@@H](O)[C@H]1O
Reactant: Clc1cc(Cl)ncn1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: OC[C@H]1C[C@@H](Nc2cc(Cl)ncn2)[C@H](O)[C@@H]1O
Temperature: 150 °C
Yield: 90.1 %

Procedure:
A mixture of (1R,2S,3R,5R)-3-amino-5-(hydroxymethyl)cyclopentane-1,2-diol hydrochloride (200 mg, 1.09 mmol), 4,6-dichloropyrimidine (240. mg, 1.61 mmol) and Et3N (0.380 mL, 2.73 mmol) in EtOH (3.00 mL) was heated to 150° C. for 15 min using MWI. The crude mixture was purified via silica gel chromatography eluting with a gradient of 0 to 15% MeOH in DCM to afford the title compound (255 mg, 90%). LC/MS: Rt=1.13 min, ES+ 260. (AA standard).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[C:18]([C:20]3[C:31](=[O:32])[N:30]([CH3:33])[C:23]4[N:24]=[C:25]([NH:28][CH3:29])[N:26]=[CH:27][C:22]=4[CH:21]=3)[CH:17]=[CH:16][C:15]=2[F:34])=[O:12])[N:7]([CH3:35])[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:36][N:37]([CH3:41])[CH2:38]CN>>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[C:18]([C:20]3[C:31](=[O:32])[N:30]([CH3:33])[C:23]4[N:24]=[C:25]([NH:28][CH2:29][CH2:36][N:37]([CH3:41])[CH3:38])[N:26]=[CH:27][C:22]=4[CH:21]=3)[CH:17]=[CH:16][C:15]=2[F:34])=[O:12])[N:7]([CH3:35])[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CNc1ncc2cc(-c3ccc(F)c(NC(=O)Nc4cc(C(C)(C)C)nn4C)c3)c(=O)n(C)c2n1
Reactant: CN(C)CCN
Product: CN(C)CCNc1ncc2cc(-c3ccc(F)c(NC(=O)Nc4cc(C(C)(C)C)nn4C)c3)c(=O)n(C)c2n1

Procedure:
Using general method E, 1-(3-t-butyl-1-methyl-1H-pyrazol-5-yl)-3-(2-fluoro-5-(8-methyl-2-(methylsulfinyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea from Example 12 (0.199 g, 0.389 mmol) and N1,N1-dimethylethane-1,2-diamine (0.214 ml, 1.94 mmol, 5.00 eq) were combined to afford 1-(3-t-butyl-1-methyl-1H-pyrazol-5-yl)-3-(5-(2-(2-(dimethylamino)ethylamino)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)-2-fluorophenyl)urea which was subsequently treated with HCl to afford hydrochloride salt (20.8 mg, 10% yield) as a white solid. 1H NMR (400 MHz, DMSO-d4): δ 9.07 (s, 1H), 8.91 (brs, 1H), 8.80-8.75 (brs, 1H), 8.47-8.44 (m, 1H), 8.01 (brs, 1H), 7.97 (s, 1H), 7.33-7.27 (m, 2H), 6.10 (s, 1H), 3.77-3.72 (m, 2H), 3.63 (s, 3H), 3.51 (brs, 3H), 3.37-3.33 (brm, 2H), 2.86 (m, 6H), 1.21 (s, 9H); MS (ESI) m/z: 536.2 (M+H+).
Reaction SMILES: C(OC(C[NH:7][C:8](=[O:27])[NH:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14](=[O:19])[C:13]2=[C:20]([C:22]1[NH:23][CH:24]=[CH:25][CH:26]=1)[CH3:21])=O)C.[H-].[Na+].[C:30](OCC)(=[O:32])[CH3:31].Cl>O1CCCC1.O>[O:27]=[C:8]1[NH:7][C:30](=[O:32])[CH2:31][N:9]1[C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14](=[O:19])[C:13]2=[C:20]([C:22]1[NH:23][CH:24]=[CH:25][CH:26]=1)[CH3:21]
Reactant: CCOC(C)=O
Reactant: CCOC(=O)CNC(=O)Nc1ccc2c(c1)C(=C(C)c1ccc[nH]1)C(=O)N2
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(=C1C(=O)Nc2ccc(N3CC(=O)NC3=O)cc21)c1ccc[nH]1
Reaction time: 8 h

Procedure:
A solution of 5-(N′-(ethoxycarbonylmethyl)ureido)-3-[1-(pyrrol-2-yl)ethylidene]indolin-2-one (95 mg, 0.25 mmol) in tetrahydrofuran (2.5 mL) was treated with NaH (16 mg, 0.40 mmol). After stirring overnight, ethyl acetate (15 mL) and water (5 mL) were added and the reaction mixture was neutralized with 6N HCl. The organic layer dried (NaSO4) and concentrated to afford a crude product (90 mg). Purification by reverse phase HPLC (acetonitrile/water) afforded 5-(2,4-dioxoimidazolidin-1-yl)-3-[1-(pyrrol-2-yl)ethylidene]indolin-2-one; (8 mg); 1H NMR (400 MHz, DMSO-d6) δ 2.72 (s, 3H), 4.02 (s, 2H), 6.36 (m, 1H), 6.96 (d, 1H), 7.04 (m, 2H), 7.36 (d, 1H), 7.60 (m, 1H), 8.22 (s, 1H), 11.14 (s, 1H) ppm.
Reaction SMILES: Cl.[CH:2]1([NH:8][C:9]2[C:14]([CH3:15])=[C:13]([CH3:16])[N:12]=[C:11]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)[N:10]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.N1C=CC=C[C:26]=1C(N)C>>[CH:2]1([NH:8][C:9]2[C:14]([CH3:15])=[C:13]([CH3:16])[N:12]=[C:11]([NH:17][CH:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)[CH3:26])[N:10]=2)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: CC(N)c1ccccn1
Reactant: Cc1nc(NCc2ccccn2)nc(NC2CCCCC2)c1C
Agent: Cl
Product: Cc1nc(NC(C)c2ccccn2)nc(NC2CCCCC2)c1C

Procedure:
The titled compound was synthesized according to the procedure described for preparation of N4-cyclohexyl-5,6-dimethyl-N2-(pyridin-2-ylmethyl)pyrimidine-2,4-diamine (Example 1) using (1-pyridin-2-ylethyl)amine instead of (pyridin-2-ylmethyl)amine. The product was purified by column chromatography eluting with mixture of chloroform/ethanol/20% water solution of ammonia (200:10:1), and then the final product was washed with diethyl ether to afford the titled compound as a white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.12-1.28 (m, 6H), 1.43-11.52 (m, 5H), 1.71-1.74 (m, 2H), 1.88 (s, 3H), 2.22 (s, 3H), 5.06-5.10 (m, 1H), 7.31 (t, J=8.06 Hz, 1H), 7.44 (d, J=8.06 Hz, 1H), 7.58 (d, J=8.06 Hz, 1H), 7.84 (t, J=8.06 Hz, 2H), 8.22 (d, J=2.0 Hz, 1H), 8.58 (d, J=2.0 Hz, 1H), 12.21 (bs, 1H); MS (ESI) m/z 326.5 (M+1)+.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[CH:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:13]([O:15][C:16](=[O:24])[C:17]1[CH:22]=[CH:21][C:20](Cl)=[N:19][CH:18]=1)[CH3:14]>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.C(N(CC)CC)C>[CH2:13]([O:15][C:16](=[O:24])[C:17]1[CH:22]=[CH:21][C:20]([C:12]#[C:11][C:8]2[CH:7]=[CH:6][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:10][CH:9]=2)=[N:19][CH:18]=1)[CH3:14]
Reactant: CCOC(=O)c1ccc(Cl)nc1
Reactant: C#Cc1ccc(C(C)(C)C)cc1
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(C#Cc2ccc(C(C)(C)C)cc2)nc1
Temperature: 25 °C
Reaction time: 40 h

Procedure:
A mixture of 477.7 mg (3.02 mmol) of 4-tert-butylphenylethyne (Compound 19), 556.5 mg (3.01 mmol) of ethyl-6-chloronicotinate (Compound 54), 27.8 mg (0.15 mmol) of cuprous iodide, 58.7 mg (0.08 mmol) of bis(triphenylphosphine)palladium (II) chloride and 2 ml of triethylamine was degassed under nitrogen and then stirred under nitrogen at room temperature for 40 hours. The mixture was then heated at 65 degrees C. for 12 hours, cooled to room temperature and the excess triethylamine removed under vacuum. The residue was taken up in water and extracted with ether. The solvent was then removed in-vacuo and the residue purified by flash chromatography (silica 5% ethyl acetate in hexane) to give the title compound as a pale brown solid. PMR (CDCl3): & 1.33 (9H, s), 1.42 (3H, t, J~7.1 Hz); 4.42 (2H, q, J~7.1 Hz), 7.40 (2H, d, J~8.4 Hz), 7.53-7.61 (3H, m), 8.28 (1H, dd, J~8.1 Hz, 2.0 Hz), 9.20 (1H, d, J~2.0 Hz).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[CH:3]([C:9]1[CH:10]=[CH:11][C:12]([C:15]([O:17][CH3:18])=[O:16])=[N:13][CH:14]=1)OS(C)(=O)=O>CO.[Pd]>[F:20][C:2]([F:1])([F:19])[CH2:3][C:9]1[CH:10]=[CH:11][C:12]([C:15]([O:17][CH3:18])=[O:16])=[N:13][CH:14]=1
Reactant: COC(=O)c1ccc(C(OS(C)(=O)=O)C(F)(F)F)cn1
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1ccc(CC(F)(F)F)cn1
Reaction time: 2 h

Procedure:
To a solution of methyl 5-(2,2,2-trifluoro-1-(methylsulfonyloxy)ethyl)picolinate (95 mg, 0.3 mmol) in 5 mL of MeOH was added 10% Pd/C (45 mg). Hydrogenation with 1 atm H2 was carried out at room temperature for 2 h. After the catalyst was removed by filtration, the filtrated was concentrated. The residue was dissolved in DCM and washed with sat. NaHCO3(aq.), and brine. The solution was dried (MgSO4) and concentrated to give methyl 5-(2,2,2-trifluoroethyl)picolinate that was used without purification.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[C:13]([N:20]1[C@@H:24]([CH2:25][CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[CH:23]([CH2:32][CH2:33]O)[O:22][C:21]1([CH3:36])[CH3:35])([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br-:56].[NH+]1C=CC=CC=1>C(Cl)Cl.O>[C:13]([N:20]1[C@@H:24]([CH2:25][CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[CH:23]([CH2:32][CH2:33][Br:56])[O:22][C:21]1([CH3:36])[CH3:35])([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14]
Reactant: [Br-]
Reactant: CC(C)(C)OC(=O)N1[C@@H](CC2CCCCC2)C(CCO)OC1(C)C
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1cc[nH+]cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N1[C@@H](CC2CCCCC2)C(CCBr)OC1(C)C
Reaction time: 16 h

Procedure:
1.6 ml of diethyl azodicarboxylate are added dropwise, at 20° C. under argon, to 690 mg of 3-Boc-4(S)-cyclohexylmethyl-2,2-dimethyl-5-(2-hydroxyethyl)oxazolidine, 2.6 g of triphenylphosphine and 1.6 g of pyridinium bromide in 15 ml of CH2Cl2. After 16 h at R.T., H2O is added and the mixture is diluted with 100 ml of CH2Cl2. The organic phase is washed twice with saturated NaHCO3 solution and once with saturated NaCl solution. The organic phase is dried with Na2SO4 and concentrated, and the residue is taken up in a little EA and filtered to remove PPh3. Purification on silica gel provides the title compound (eluent: H/EA 15:1).
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:9][N:10]([CH:16]2[C:25]3[N:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH2:19][CH2:18][CH2:17]2)[CH2:11][CH2:12][CH2:13][CH2:14][NH2:15])=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.[OH-].[Na+]>O>[CH3:1][C:2]1[C:3]([CH2:9][N:10]([C@@H:16]2[C:25]3[N:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH2:19][CH2:18][CH2:17]2)[CH2:11][CH2:12][CH2:13][CH2:14][NH2:15])=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cnc(CN(CCCCN)C2CCCc3cccnc32)c(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1cnc(CN(CCCCN)[C@H]2CCCc3cccnc32)c(C)c1

Procedure:
To a solution of (S)-(N1-(3,5-dimethyl-pyridin-2-ylmethyl)-N1-(5,6,7,8-tetrahydro-quinolin-8-yl)-butane-1,4-diamine (HCl salt) (440 mg, 0.83 mmol) in water (2 mL) was added 1.0 N NaOH (5 mL). The mixture was extracted with CH2Cl2 (5×10 mL). The combined organic extracts were dried (Na2SO4) and concentrated and provided (S)-N1-(3,5-Dimethyl-pyridin-2-ylmethyl)-N1-(5,6,7,8-tetrahydro-quinolin-8-yl)-butane-1,4-diamine in quantitative yield.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][C:8]=2[OH:17])=[CH:3][N:2]=1.[CH3:18][O:19][C:20]1[CH:43]=[C:42]([O:44][CH3:45])[CH:41]=[CH:40][C:21]=1[CH2:22][N:23]([C:35]1[S:39][N:38]=[CH:37][N:36]=1)[S:24]([C:27]1[CH:32]=[C:31]([I:33])[C:30](F)=[CH:29][CH:28]=1)(=[O:26])=[O:25]>>[CH3:18][O:19][C:20]1[CH:43]=[C:42]([O:44][CH3:45])[CH:41]=[CH:40][C:21]=1[CH2:22][N:23]([C:35]1[S:39][N:38]=[CH:37][N:36]=1)[S:24]([C:27]1[CH:28]=[CH:29][C:30]([O:17][C:8]2[CH:9]=[CH:10][C:11]([C:13]([F:15])([F:16])[F:14])=[CH:12][C:7]=2[C:4]2[CH:5]=[CH:6][N:1]=[N:2][CH:3]=2)=[C:31]([I:33])[CH:32]=1)(=[O:25])=[O:26]
Reactant: Oc1ccc(C(F)(F)F)cc1-c1ccnnc1
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc(F)c(I)c2)c(OC)c1
Product: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc(Oc3ccc(C(F)(F)F)cc3-c3ccnnc3)c(I)c2)c(OC)c1

Procedure:
The title compound was prepared according to Preparation 35 at 60° C. over 4 days using 2-pyridazin-4-yl-4-(trifluoromethyl)phenol (Preparation 30) and N-(2,4-dimethoxybenzyl)-4-fluoro-5-iodo-N-1,2,4-thiadiazol-5-ylbenzenesulfonamide (Preparation 37) to give the product (420 mg, 43%).
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:16][CH2:15][N:14]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[C:4]=2[N:5]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:7]=1.CC1(C)C(C)(C)OB([C:31]2[CH:38]=[CH:37][C:34]([C:35]#[N:36])=[CH:33][CH:32]=2)O1.B(O)O>>[N:8]1([C:6]2[N:7]=[C:2]([C:31]3[CH:38]=[CH:37][C:34]([C:35]#[N:36])=[CH:33][CH:32]=3)[C:3]3[CH2:16][CH2:15][N:14]([C:17]4[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=4)[C:4]=3[N:5]=2)[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1
Reactant: CC1(C)OB(c2ccc(C#N)cc2)OC1(C)C
Reactant: Clc1nc(N2CCOCC2)nc2c1CCN2c1cccnc1
Agent: OBO
Product: N#Cc1ccc(-c2nc(N3CCOCC3)nc3c2CCN3c2cccnc2)cc1

Procedure:
In the same manner as Example 1-B-10, using 4-chloro-2-morpholin-4-yl-7-pyridin-3-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine, and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile as a boronic acid, the desired compound was obtained.
Reaction SMILES: [S:1](Cl)(Cl)=[O:2].N1C=CC=CC=1.[C:11]([O:15][C:16](=[O:29])[NH:17][C:18]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([Br:28])[N:23]=1)([CH3:21])[CH2:19][OH:20])([CH3:14])([CH3:13])[CH3:12].Cl>C(Cl)Cl>[C:11]([O:15][C:16]([N:17]1[C:18]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Br:28])[N:23]=2)([CH3:21])[CH2:19][O:20][S:1]1=[O:2])=[O:29])([CH3:12])([CH3:13])[CH3:14]
Reactant: O=S(Cl)Cl
Reactant: CC(C)(C)OC(=O)NC(C)(CO)c1cccc(Br)n1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1S(=O)OCC1(C)c1cccc(Br)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To an at 0° C. precooled solution of thionyl chloride (3.42 ml, 5.57 g, 46.8 mmol) in pyridine (9.46 ml, 9.25 g, 117.0 mmol) was added dropwise a solution of [1-(6-bromo-pyridin-2-yl)-2-hydroxy-1-methyl-ethyl]-carbamic acid tert-butyl ester (see Example 1 step d), 7.75 g, 23.4 mmol) in DCM (230 ml). The reaction mixture was allowed to stir for 1 h at rt, then 0.5 N aq. HCl and DCM were added, the phases were separated and the aq. phase was twice reextracted with DCM. The combined org. phases were washed with brine, dried over Na2SO4, filtered and concentrated to leave the title compound (mixture of diastereomers) as an orange solid. HPLC RtH4=1.16, 1.20 min (diastereomers); ESIMS: 377, 379 [(M+H)+].
Reaction SMILES: [F:1][C:2](I)([F:7])[C:3]([F:6])([F:5])[F:4].[Cl:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12](Cl)=[O:13].Cl.O>C(Cl)Cl>[Cl:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12]([OH:13])([C:2]([F:7])([F:1])[C:3]([F:6])([F:5])[F:4])[C:2]([F:7])([F:1])[C:3]([F:6])([F:5])[F:4]
Reactant: O=C(Cl)c1ccccc1Cl
Reactant: FC(F)(F)C(F)(F)I
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: OC(c1ccccc1Cl)(C(F)(F)C(F)(F)F)C(F)(F)C(F)(F)F
Temperature: 0 °C
Reaction time: 8 h
Yield: 60.9 %

Procedure:
74 g (0.3 mol) of phosphorous acid trisdiethylamide in 150 ml of CH2Cl2 were initially introduced into a round-bottomed flask with the exclusion of moisture. 74 g (0.3 mol) of pentafluoroethyl iodide and 26.4 g (0.15 mol) of o-chlorobenzoyl chloride were added at about -20° C. The mixture was warmed to 0° C. and stirred for about 8 hours at this temperature. 10 g of hydrogen chloride gas were then introduced, and the mixture was stirred for a further hour at 0° C. The reaction mixture was freed from solvent under reduced pressure and introduced into 3 times the volume of water. The organic phase was separated off, dried and distilled. 34.6 g (62%) of 3-(2-chlorophenyl)-1,1,1,2,2,4,4,5,5,5-decafluoropentan-3-ol of b.p. 66° C./2 mbar were obtained.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:12][CH2:13][CH2:14][CH3:15])[CH2:10][OH:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>ClCCl>[CH3:23][S:24]([O:11][CH2:10][C@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:12][CH2:13][CH2:14][CH3:15])(=[O:26])=[O:25]
Reactant: CS(=O)(=O)Cl
Reactant: CCCC[C@H](CO)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCC[C@H](COS(C)(=O)=O)NC(=O)OC(C)(C)C
Reaction time: 1 h

Procedure:
To a solution of (R)-2-t-butoxycarbonylamino-1-hexanol (2.17 g, prepared in (1)) in dichloromethane (20 ml) were added triethylamine (1.67 ml) and methanesulfonyl chloride (0.93 ml) under ice cooling. After being stirred at the same temperature for 1 h, the mixture was washed with water, 10% aq. citric acid, sat. aq NaHCO3 and brine successively, dried over MgSO4 and evaporated in vacuo. The residue was purified by silica gel chromatography (Merck, Kieselgel 60) with hexane/ethyl acetate=2/1 for elution to give the product (1.32 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]2[O:23][C:17]3=[CH:18][N:19]=[C:20](Cl)[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:24][C:25]1[CH:30]=[C:29](B(O)O)[CH:28]=[CH:27][N:26]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]2[O:23][C:17]3=[CH:18][N:19]=[C:20]([C:29]4[CH:28]=[CH:27][N:26]=[C:25]([CH3:24])[CH:30]=4)[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(C2Cc3cc(Cl)ncc3O2)CC1
Reactant: Cc1cc(B(O)O)ccn1
Product: Cc1cc(-c2cc3c(cn2)OC(C2CCN(C(=O)OC(C)(C)C)CC2)C3)ccn1

Procedure:
The title compound is prepared from 4-(5-chloro-2,3-dihydro-furo[2,3-c]pyridin-2-yl)-piperidine-1-carboxylic acid tert-butyl ester and 2-methylpyridine-4-boronic acid following a procedure analogous to that described in Example 28. LC (method 10): tR=1.45 min; Mass spectrum (ESI+): m/z=396 [M+H]+.
Reaction SMILES: CO.[CH:3]1([NH:9][C:10]2[CH:19]=[C:18]3[C:13]([C:14](=[O:29])[C:15]([O:25][CH2:26][C:27]#[N:28])=[CH:16][N:17]3[CH:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)=[CH:12][C:11]=2[F:30])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.Cl.[NH2:32][OH:33]>C(N(CC)CC)C>[CH:3]1([NH:9][C:10]2[CH:19]=[C:18]3[C:13]([C:14](=[O:29])[C:15]([O:25][CH2:26][C:27](=[N:32][OH:33])[NH2:28])=[CH:16][N:17]3[CH:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)=[CH:12][C:11]=2[F:30])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]1
Reactant: N#CCOc1cn(C2CCCC2)c2cc(NC3CCCCC3)c(F)cc2c1=O
Reactant: NO
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: NC(COc1cn(C2CCCC2)c2cc(NC3CCCCC3)c(F)cc2c1=O)=NO
Yield: 52.2 %

Procedure:
To a 30 ml methanol solution of 1.5 g of {[7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl]oxy}acetonitrile were added 1.1 ml of triethylamine and 540 mg of hydroxylamine hydrochloride, followed by heating under reflux for 27 hours. The solvent was evaporated under a reduced pressure, and the resulting residue was purified by silica gel column chromatography to obtain 850 mg of 2-{[7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl]oxy}-N′-hydroxyethanimidamide.