Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH:2]1([N:8]2[CH2:12][CH2:11][NH:10][C:9]2=[NH:13])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[OH-].[Na+].[C:16]([NH:21][CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1)(=[O:20])/[CH:17]=[CH:18]/[CH3:19]>O.CC(C)=O>[C:16]([NH:21][CH2:22][CH2:23][C:24]1[CH:25]=[CH:26][C:27]([S:30]([N:10]2[CH2:11][CH2:12][N:8]([CH:2]3[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]3)[C:9]2=[NH:13])(=[O:32])=[O:31])=[CH:28][CH:29]=1)(=[O:20])/[CH:17]=[CH:18]/[CH3:19]
Reactant: N=C1NCCN1C1CCCCC1
Reactant: C/C=C/C(=O)NCCc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: C/C=C/C(=O)NCCc1ccc(S(=O)(=O)N2CCN(C3CCCCC3)C2=N)cc1

Procedure:
20.4 g of 1-cyclohexyl-2-imino-imidazolidine hydrochloride are added to 8.5 g of sodium hydroxide in 85 ml of water. There is added to the resulting solution 28.8 g of 4-(2-crotonylaminoethyl)-benzenesulphonyl chloride dissolved in 100 ml of acetone, the reaction mixture becoming warm. It is heated at 90° for half an hour and then concentrated by evaporation under reduced pressure. The residue is recrystallised from ethyl acetate, and 1-{4-[2-(crotonylamino)-ethyl]-phenylsulphonyl}-3-cyclohexyl-2-imino-imidazolidine (trans) which melts at 157° to 158° is obtained.
Reaction SMILES: [Br:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][NH:7][C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=[C:10]([CH3:18])[C:9]=2[C:19](=[O:21])[CH3:20])=[CH:4][CH:3]=1.NC1C2C(=CC=CC=2)N=C(C)C=1C(=O)C.BrC1C=CC(CBr)=CC=1[F:48]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=[C:10]([CH3:18])[C:9]=2[C:19](=[O:21])[CH3:20])=[CH:22][C:23]=1[F:48]
Reactant: Fc1cc(CBr)ccc1Br
Reactant: CC(=O)c1c(C)nc2ccccc2c1NCc1ccc(Br)cc1
Agent: CC(=O)c1c(C)nc2ccccc2c1N
Product: CC(=O)c1c(C)nc2ccccc2c1NCc1ccc(Br)c(F)c1

Procedure:
1-(4-(4-Bromo-3-fluorobenzylamino)-2-methylquinolin-3-yl)ethanone was synthesized by the same process as described for 1-(4-(4-bromobenzylamino)-2-methylquinolin-3-yl)ethanone (Example 1, Intermediate 2c) starting from 1-(4-amino-2-methylquinolin-3-yl)ethanone and 4-bromo-3-fluorobenzyl bromide. MS(ES+): 387/389.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][CH2:13][CH2:14][NH2:15])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.I.[CH3:20][N:21]1[CH2:25][C:24](=[O:26])[N:23]=[C:22]1SC.C(N(CC)CC)C>C(O)C>[N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][CH2:13][CH2:14][NH:15][C:22]2[N:21]([CH3:20])[CH2:25][C:24](=[O:26])[N:23]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CSC1=NC(=O)CN1C
Reactant: NCCCOc1cccc(CN2CCCCC2)c1
Agent: I
Solvent: CCN(CC)CC
Solvent: CCO
Product: CN1CC(=O)N=C1NCCCOc1cccc(CN2CCCCC2)c1

Procedure:
3-(3-Piperidinomethylphenoxy)propylamine (2.61 g), 1-methyl-2-methylthioimidazolin-4-one hydroiodide (2.85 g) and triethylamine (3.635 g) were refluxed in ethanol (25 ml) for 5 hours.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9](=[O:24])[C:10]1[C:15]([S:16][CH3:17])=[CH:14][C:13]([C:18]([F:21])([F:20])[F:19])=[CH:12][C:11]=1[O:22][CH3:23].[C:25]1(=O)[CH2:29][CH2:28][CH2:27][CH2:26]1>>[CH:25]1([NH:1][CH:2]2[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]2[NH:8][C:9](=[O:24])[C:10]2[C:15]([S:16][CH3:17])=[CH:14][C:13]([C:18]([F:20])([F:21])[F:19])=[CH:12][C:11]=2[O:22][CH3:23])[CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: COc1cc(C(F)(F)F)cc(SC)c1C(=O)N[C@@H]1CCCC[C@@H]1N
Reactant: O=C1CCCC1
Product: COc1cc(C(F)(F)F)cc(SC)c1C(=O)NC1CCCCC1NC1CCCC1

Procedure:
The title compound, light yellow solid, MS: m/e=431.3 [(M+H)+], was prepared in accordance with the general method of example 11 from cis-N-(2-amino-cyclohexyl)-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamide (intermediate I) and cyclopentanone.
Reaction SMILES: Br[CH2:2][CH:3]([O:7][CH2:8][CH3:9])[O:4][CH2:5][CH3:6].[C:10]1([C@H:16]([NH2:18])[CH3:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[CH2:5]([O:4][CH:3]([O:7][CH2:8][CH3:9])[CH2:2][NH:18][C@@H:16]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:17])[CH3:6]
Reactant: C[C@@H](N)c1ccccc1
Reactant: CCOC(CBr)OCC
Product: CCOC(CN[C@H](C)c1ccccc1)OCC
Yield: 71.8 %

Procedure:
According to the procedure described in the synthesis method of Compound IX-1, 2-bromo-1,1-diethoxyethane (41.3 ml, 270 mmol) was reacted with (R)-(+)-1-phenylethylamine (66.6 g, 550 mmol) and the obtained residue was purified by silica gel column chromatography (eluent: n-hexane:ethyl acetate=5:1 and 1:1) to obtain the title compound (46.0 g, 70%).
Reaction SMILES: Cl[CH2:2][C:3](=O)[CH3:4].[Br:6][C:7]1[CH:8]=[C:9]([O:17][C:18]2[CH:19]=[C:20]([CH:26]=[CH:27][C:28]=2[Cl:29])[C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:10]([NH:13][C:14]([NH2:16])=[S:15])=[N:11][CH:12]=1.C(N(CC)CC)C>C(O)C>[Br:6][C:7]1[CH:8]=[C:9]([O:17][C:18]2[CH:19]=[C:20]([CH:26]=[CH:27][C:28]=2[Cl:29])[C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:10]([NH:13][C:14]2[S:15][CH:2]=[C:3]([CH3:4])[N:16]=2)=[N:11][CH:12]=1
Reactant: CCOC(=O)c1ccc(Cl)c(Oc2cc(Br)cnc2NC(N)=S)c1
Reactant: CC(=O)CCl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(Cl)c(Oc2cc(Br)cnc2Nc2nc(C)cs2)c1
Yield: 88.1 %

Procedure:
1-chloropropan-2-one (0.469 g; 5.07 mmol), ethyl 3-(5-bromo-2-thioureidopyridin-3-yloxy)-4-chlorobenzoate (1.680 g, 3.39 mmol), triethylamine (0.671 g, 6.63 mmol), and ethanol (70 mL) were reacted according to the method of Example 10, Step E, to provide the title compound (1.40 g, 77% yield). 1H NMR (d6-DMSO) δ 8.26 (d, 1H), 7.78 (m, 2H), 7.50 (s, 1H), 7.46 (d, 1H), 6.59 (s, 1H), 4.29 (q, 2H), 2.23 (s, 3H), 1.28 (t, 3H); Mass spectrum (apci) m/z=470.1 (M+H).
Reaction SMILES: [CH:1]1([S:6]([NH:8][C:9]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][C:10]=2[O:11][CH2:12][C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.ClC1C=CC=C(C(OO)=[O:39])C=1>C(Cl)Cl.C(OCC)(=O)C>[CH:1]1([S:6]([NH:8][C:9]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:28])[F:29])=[CH:23][C:10]=2[O:11][CH2:12][C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)(=[O:39])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc(COc2cc(C(F)(F)F)ccc2NS(=O)C2CCCC2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)c1ccc(COc2cc(C(F)(F)F)ccc2NS(=O)(=O)C2CCCC2)cc1
Reaction time: 1 h
Yield: 100.3 %

Procedure:
To a solution of methyl 4-(2-cyclopentylsulfinylamino-5-trifluoromethylphenoxymethyl)benzoate (305 mg; prepared in Reference Example 33.) in methylene chloride (4.0 ml), meta-chloroperbenzoic acid (456 mg) was added at 0° C. The mixture was stirred for 1 hour. The reaction mixture was diluted with ethyl acetate, washed, dried over and concentrated under the reduced pressure to give the title compound (317 mg) having the following physical data.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][NH2:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:16]=1[C:22]1[C:26]([C:27](Cl)=[O:28])=[C:25]([CH3:30])[O:24][N:23]=1>>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:27]([C:26]1[C:22]([C:16]2[C:17]([F:21])=[CH:18][CH:19]=[CH:20][C:15]=2[Cl:14])=[N:23][O:24][C:25]=1[CH3:30])=[O:28])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1onc(-c2c(F)cccc2Cl)c1C(=O)Cl
Reactant: CC(C)(C)OC(=O)NCCCCN
Product: Cc1onc(-c2c(F)cccc2Cl)c1C(=O)NCCCCNC(=O)OC(C)(C)C
Yield: 100.1 %

Procedure:
N-t-butyloxycarbonyl-1,4-diaminobutane (985 mg, 5.23 mmol) and 3-(2-chloro-6-fluorophenyl)-5-methylisoxazol-4-oyl chloride (1.43 g, 5.23 mmol) were converted to 2.23 g of the title compound by the procedure of Preparation 1 except that the reaction time was about 18 hours. (100%). EA calculated for: C20H25N3O4ClF: C, 56.41; H, 5.92; N, 9.87. Found: C, 56.12; H, 5.75; N, 9.67. MS(FD) m/z 426 (M+).
Reaction SMILES: [CH2:1]([OH:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]=[CH2:7].ClC1C=CC=C(C(OO)=[O:17])C=1>C(Cl)Cl.CCOCC>[O:8]1[CH2:1][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][OH:17]
Reactant: C=CCCCCCO
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: CCOCC
Product: OCCCCCC1CO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 105 %

Procedure:
A mixture of 3 (1.4 g, 12 mmol) and m-chloroperbenzoic acid (2.92 g, 14.4 mmol) in methylene chloride (40 mL) was stirred at room temperature overnight. It was then diluted with ether, washed with saturated aqueous sodium bicarbonate, saturated aqueous sodium chloride, and dried over magnesium sulfate. Removal of the solvent afforded 1.64 g of the crude 6,7-epoxy-1-heptanol (5).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]([NH:11][C:12]3[C:13]([CH3:21])=[CH:14][C:15]([N:18]([CH3:20])[CH3:19])=[N:16][CH:17]=3)[N:7]([CH2:22][CH:23]=[CH2:24])[C:6]=2[C:5]([CH:25]([CH2:28][CH3:29])[CH2:26][CH3:27])=[CH:4][CH:3]=1.B.[O:31]1CCCC1.O.O.O.O.B(O[O-])([O-])[O-].[Na+].[Na+].[Na+].O>O1CCCC1>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]([NH:11][C:12]3[CH:17]=[N:16][C:15]([N:18]([CH3:19])[CH3:20])=[CH:14][C:13]=3[CH3:21])[N:7]([CH2:22][CH:23]([OH:31])[CH3:24])[C:6]=2[C:5]([CH:25]([CH2:26][CH3:27])[CH2:28][CH3:29])=[CH:4][CH:3]=1
Reactant: C1CCOC1
Reactant: C=CCn1c(Nc2cnc(N(C)C)cc2C)nc2c(Cl)ccc(C(CC)CC)c21
Agent: B
Agent: [Na+]
Agent: [O-]OB([O-])[O-]
Solvent: O
Product: CCC(CC)c1ccc(Cl)c2nc(Nc3cnc(N(C)C)cc3C)n(CC(C)O)c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 53.5 %

Procedure:
To a solution of N5-[4-chloro-7-(1-ethylpropyl)-1-prop-2-en-1-yl-1H-benzimidazol-2-yl]-N2,N2,4-trimethylpyridine-2,5-diamine (41 mg, 0.100 mmol) in tetrahydrofuran (1.0 mL) was added borane-tetrahydrofuran complex (1.18 M solution in tetrahydrofuran, 0.17 mL, 0.200 mmol) at 0° C. After 2 hr, additional borane-tetrahydrofuran complex (1.18 M solution in tetrahydrofuran, 0.17 mL, 0.200 mmol) was added to the mixture. After 1 hr, additional borane-tetrahydrofuran complex (1.18 M solution in tetrahydrofuran, 0.17 mL, 0.200 mmol) was added to the mixture. After 1 hr, sodium peroxyborate tetrahydrate (154 mg, 1.00 mmol) and water (0.50 mL) was added to the mixture, which was stirred at room temperature for 60 hr. Water was added and the mixture was extracted with ethyl acetate. Organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with a 50-100% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the title compound (23 mg, 0.0535 mmol, 53%) as a colorless solid.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH2:8].[Cl:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[C:11]=1[N:20]=[C:21]=[O:22]>C1COCC1>[NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:21]([NH:20][C:11]1[C:12]([C:16]([F:17])([F:19])[F:18])=[CH:13][CH:14]=[CH:15][C:10]=1[Cl:9])=[O:22]
Reactant: N[C@@H]1CCCC[C@H]1N
Reactant: O=C=Nc1c(Cl)cccc1C(F)(F)F
Solvent: C1CCOC1
Product: N[C@@H]1CCCC[C@H]1NC(=O)Nc1c(Cl)cccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 42.1 %

Procedure:
A solution of 0.46 g of trans-1,2-diaminocyclohexane in 10 ml of THF was added to a solution of 1.6 g of 2-chloro-6-trifluoromethylphenyl isocyanate in 30 ml of THF, and the mixture was stirred at room temperature for about 3 hours. The mixture was allowed to stand overnight and the solvent was then distilled off, giving 0.57 g of the desired compound as a semi-solid yellow product.
Reaction SMILES: [CH:1]1([CH2:7][OH:8])[CH2:6][CH2:5][CH:4]=[CH:3][CH2:2]1.Cl[P:10]1(=[O:18])[O:15][CH2:14][C:13]([CH3:17])([CH3:16])[CH2:12][O:11]1.N1C=CC=CC=1>C(Cl)(Cl)Cl>[CH3:16][C:13]1([CH3:17])[CH2:14][O:15][P:10](=[O:18])([O:8][CH2:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]2)[O:11][CH2:12]1
Reactant: OCC1CC=CCC1
Reactant: CC1(C)COP(=O)(Cl)OC1
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CC1(C)COP(=O)(OCC2C=CCCC2)OC1

Procedure:
A 100 mL round bottom flask equipped with a stirrer bar was charged with 15.04 g (0.134 mol) 3-cyclohexene-1-methanol, 22.52 g (0.122 mol) of 2-chloro-5,5-dimethyl-1,3,2-dioxaphosphorinan-2-one, and 10.6 g (0.134 mol) of pyridine. After the above mixture was reacted at 80° C. for 3 hrs. The reaction mixture was added to chloroform (100 mL), and then washed with chloroform (2×100 mL), dried with sodium sulfate. The solvent was evaporated and the residue distilled to give pure product.
Reaction SMILES: [ClH:1].[CH:2]([C:5]1[CH:18]=[C:17]2[C:8]([N:9]3[C:14]([CH2:15][O:16]2)=[N:13][NH:12][C:11](=[O:19])[C@H:10]3[CH3:20])=[CH:7][C:6]=1[C@H:21]([C:23]1([CH3:27])[CH2:26][NH:25][CH2:24]1)[CH3:22])([CH3:4])[CH3:3].[Si]([O:35][CH2:36][CH:37]=O)(C(C)(C)C)(C)C.[BH3-]C#N.[Na+]>CO.C(O)(=O)C>[ClH:1].[OH:35][CH2:36][CH2:37][N:25]1[CH2:24][C:23]([C@@H:21]([C:6]2[CH:7]=[C:8]3[C:17](=[CH:18][C:5]=2[CH:2]([CH3:3])[CH3:4])[O:16][CH2:15][C:14]2[N:9]3[C@H:10]([CH3:20])[C:11](=[O:19])[NH:12][N:13]=2)[CH3:22])([CH3:27])[CH2:26]1
Reactant: CC(C)(C)[Si](C)(C)OCC=O
Reactant: CC(C)c1cc2c(cc1[C@@H](C)C1(C)CNC1)N1C(=NNC(=O)[C@H]1C)CO2
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)c1cc2c(cc1[C@@H](C)C1(C)CN(CCO)C1)N1C(=NNC(=O)[C@H]1C)CO2
Temperature: 70 °C
Reaction time: 8 h
Yield: 28.6 %

Procedure:
To a solution of (R)-7-isopropyl-4-methyl-6-[(R)-1-(3-methyl-azetidin-3-yl)-ethyl]-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one hydrochloric acid (Example #133, Step G, 0.083 g, 0.233 mmol) in MeOH (3 mL) and acetic acid (0.3 mL) was added 2-((tert-butyldimethylsilyl)oxy)acetaldehyde (0.122 g, 0.699 mmol) and the reaction mixture was stirred at 70° C. overnight. NaBH3CN (0.073 g, 1.164 mmol) was added and the reaction mixture was stirred at 70° C. for 1 h. The reaction mixture was cooled to ambient temperature. The solvent was removed in vacuo and the residue was purified by prep-HPLC (Table 3, Method 26) to give (R)-6-{(R)-1-[1-(2-hydroxy-ethyl)-3-methyl-azetidin-3-yl]-ethyl}-7-isopropyl-4-methyl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one hydrochloric acid (0.0291 g, 31%) as a solid. 1H NMR (CD3OD-d4, 400 MHz): δ 7.04 (s, 1H), 6.84 (s, 1H), 4.81-4.78 (m, 1H), 4.62 (s, 2H), 4.15 (d, J=10.8 Hz, 1H), 4.04 (d, J=10.8 Hz, 1H), 3.93 (d, J=10.8 Hz, 1H), 3.86 (d, J=10.8 Hz, 1H), 3.77-3.69 (m, 2H), 3.38 (m, 2H), 3.12-3.04 (m, 2H), 1.56 (s, 3H), 1.45 (d, J=6.8 Hz, 3H), 1.42-1.35 (m, 3H), 1.34-1.27 (m, 3H), 1.19-1.12 (m, 3H). LC/MS (Table 1, Method 4) Rt=1.761 min.; MS m/z: 401 [M+H]+. SFC (Table 1, Method 28) Rt=5.52 min.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH2:27][CH2:26][P:25]([CH3:29])(=[O:28])[CH2:24][CH2:23]3)=[CH:18][C:17]=2[O:30][CH3:31])=[N:4][C:5]([NH:8][CH2:9]C2SC=CC=2)=[N:6][CH:7]=1.[F:32][C:33]1[CH:45]=[CH:44][C:36]([CH2:37][N:38]2[CH:42]=C[C:40](N)=[CH:39]2)=[CH:35][CH:34]=1>>[Cl:1][C:2]1[C:3]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH2:27][CH2:26][P:25]([CH3:29])(=[O:28])[CH2:24][CH2:23]3)=[CH:18][C:17]=2[O:30][CH3:31])=[N:4][C:5]([NH:8][C:9]2[CH:40]=[CH:39][N:38]([CH2:37][C:36]3[CH:35]=[CH:34][C:33]([F:32])=[CH:45][CH:44]=3)[CH:42]=2)=[N:6][CH:7]=1
Reactant: COc1cc(N2CCP(C)(=O)CC2)ccc1Nc1nc(NCc2cccs2)ncc1Cl
Reactant: Nc1ccn(Cc2ccc(F)cc2)c1
Product: COc1cc(N2CCP(C)(=O)CC2)ccc1Nc1nc(Nc2ccn(Cc3ccc(F)cc3)c2)ncc1Cl

Procedure:
The compound can be prepared as in Example 32 by reacting 2,5-dichloro-N-[2-methoxy-4-(4-methyl-4-oxido-1,4-azaphosphinan-1-yl)phenyl]pyrimidin-4-amine (as described in Example 47) with 1-(4-fluorobenzyl)-1H-pyrrol-3-amine.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[N:10][C:11]=1[CH:12]([O:15][CH3:16])[O:13][CH3:14])[NH:8][CH2:7][CH2:6][CH2:5]2.[CH3:17][O-:18].[Na+].[NH4+].[Cl-]>CO>[CH3:14][O:13][CH:12]([O:15][CH3:16])[C:11]1[N:10]=[C:9]2[C:4]([CH2:5][CH2:6][CH2:7][NH:8]2)=[CH:3][C:2]=1[O:18][CH3:17]
Reactant: COC(OC)c1nc2c(cc1Br)CCCN2
Reactant: C[O-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: COc1cc2c(nc1C(OC)OC)NCCC2
Temperature: 120 °C
Reaction time: 15 h

Procedure:
A solution of 6-bromo-7-(dimethoxymethyl)-1,2,3,4-tetrahydro-1,8-naphthyridine (intermediate 2, 253 mg, 0.881 mmol) in MeOH (0.85 ml) under argon was treated with NaOMe (5.4 M in MeOH, 0.816 ml, 4.41 mmol), flushed with argon, treated with CuBr (253 mg, 1.76 mmol). The vial was sealed and the reaction mixture was stirred at 120° C. for 15 h. The reaction mixture was cooled to room temperature, treated with sat. aq. NH4Cl and extracted with EtOAc (2×). The combined org. layers were washed again with brine, dried over Na2SO4 and concentrated. The crude material was purified by normal phase chromatography (12 g silica gel cartridge, heptanes/EtOAc 100:0 to 0:100) to give the title compound as a pale yellow oil. (UPLC-MS 1) tR 0.73 min; ESI-MS 239.1 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([N:8]([CH3:25])[C:9](=[O:24])[C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=2)=[C:4]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[CH3:32])[CH:3]=1.[C:33]([O:37][C:38]([N:40]1[CH:44]=[CH:43][CH:42]=[C:41]1B(O)O)=[O:39])([CH3:36])([CH3:35])[CH3:34]>CCCCCCC.CCOC(C)=O>[C:33]([O:37][C:38]([N:40]1[CH:44]=[CH:43][CH:42]=[C:41]1[C:2]1[CH:3]=[C:4]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[CH3:32])[C:5]([N:8]([C:9](=[O:24])[C:10]2[CH:15]=[C:14]([C:16]([F:18])([F:17])[F:19])[CH:13]=[C:12]([C:20]([F:22])([F:23])[F:21])[CH:11]=2)[CH3:25])=[CH:6][N:7]=1)=[O:39])([CH3:36])([CH3:34])[CH3:35]
Reactant: CC(C)(C)OC(=O)n1cccc1B(O)O
Reactant: Cc1ccccc1-c1cc(Cl)ncc1N(C)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: Cc1ccccc1-c1cc(-c2cccn2C(=O)OC(C)(C)C)ncc1N(C)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
The title compound was prepared in analogy to example 72, from N-(6-chloro-4-o-tolyl-pyridin-3-yl)-N-methyl-3,5-bis-trifluoromethyl-benzamide (example 12) and 1-(tert-butoxycarbonyl)pyrrole-2-boronic acid (CAS RN 135884-31-0) and using a gradient of n-heptane:EtOAc (100:0 to 50:50) for the chromatographic purification. Light yellow oil (18%). MS (ESI): m/z=604.202 [M+H]+.
Reaction SMILES: [C:1]([C:4]1(C(OC)=O)[CH2:9][CH2:8][CH:7]([C:10]([O:12][CH3:13])=[O:11])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].Cl.O.[CH2:20](O)C>>[C:1]([CH:4]1[CH2:5][CH2:6][CH:7]([C:10]([O:12][CH2:13][CH3:20])=[O:11])[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: COC(=O)C1CCC(C(C)=O)(C(=O)OC)CC1
Reactant: CCO
Agent: Cl
Solvent: O
Product: CCOC(=O)C1CCC(C(C)=O)CC1

Procedure:
Dimethyl 1-acetylcyclohexane-1,4-dicarboxylate (see Process K) (26.5 g.) was added to a solution of concentrated hydrochloric acid (290 ml.) in ethanol (140 ml.). After refluxing for 7.5 hours, the reaction mixture was poured into water and then extracted with dichloromethane. The organic phase was then washed with saturated sodium bicarbonate solution and brine. After drying over anhydrous magnesium sulphate the solvent was removed under reduced pressure to give ethyl 4-acetylcyclohexanecarboxylate as a colourless oil. This was purified by distillation (b.p 144°-148° C./14 mm Hg.).
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:11][CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([NH:23][CH2:24][CH2:25][CH2:26][N:27]2[CH:31]=[CH:30][N:29]=[CH:28]2)([CH3:22])[CH3:21])=[CH:16][CH:15]=1>ClCCl>[N:27]1([CH2:26][CH2:25][CH2:24][NH:23][C:20]([C:17]2[CH:18]=[CH:19][C:14]([CH2:13][CH2:12][NH:11][S:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)(=[O:9])=[O:8])=[CH:15][CH:16]=2)([CH3:22])[CH3:21])[CH:31]=[CH:30][N:29]=[CH:28]1
Reactant: CC(C)(NCCCn1ccnc1)c1ccc(CCN)cc1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: ClCCl
Product: CC(C)(NCCCn1ccnc1)c1ccc(CCNS(=O)(=O)c2ccccc2)cc1
Temperature: 0 °C

Procedure:
A solution of benzenesulphonyl chloride (0.25 g) in dichloromethane (3 ml) was added dropwise to a solution of N-{1-[4-(2-aminoethyl)phenyl]-1-methylethyl}-3-(imidazol-1-yl)propylamine (0.4 g) in dichloromethane (7 ml) with stirring at 0° C. The mixture was treated in a similar manner to Example 55 to give N-[2-(4-{1-[3-(imidazol-1-yl)propylamino]-1-methylethyl}phenyl)ethyl]benzenesulphonamide as an oil.
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[F:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][CH2:24][CH2:23]2.Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.CN(C)C=O>[F:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[N:25]([C:15](=[O:17])[CH2:14][C:9]1[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]3[CH2:2][CH2:3][O:4][CH2:5][CH2:6]3)[N:8]=1)[CH2:24][CH2:23]2
Reactant: Fc1ccc2c(c1)CCN2
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)N1CCc2cc(F)ccc21
Yield: 55 %

Procedure:
The product is prepared according to the procedure described in example 5, using 261 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate, 274 mg of 5-fluoroindoline and 254 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride in a mixture of 0.16 ml of pyridine and 4 ml of dimethylformamide. 197 mg of 2-[2-(5-fluoro-2,3-dihydroindol-1-yl)-2-oxoethyl]-6-morpholin-4-yl-3H-pyrimidin-4-one are obtained in the form of a very pale pink powder, the characteristics of which are the following:
Reaction SMILES: Cl.Cl.Cl.[CH3:4][O:5][C:6]1[CH:7]=[C:8]([NH:18][C:19]2[S:20][C:21]3[CH2:22][NH:23][CH2:24][CH2:25][C:26]=3[N:27]=2)[CH:9]=[CH:10][C:11]=1[N:12]1[CH:16]=[C:15]([CH3:17])[N:14]=[CH:13]1.[F:28][C:29]1[CH:37]=[CH:36][C:32]([C:33](Cl)=[O:34])=[CH:31][CH:30]=1.C(N(CC)CC)C>C(Cl)Cl>[F:28][C:29]1[CH:37]=[CH:36][C:32]([C:33]([N:23]2[CH2:24][CH2:25][C:26]3[N:27]=[C:19]([NH:18][C:8]4[CH:9]=[CH:10][C:11]([N:12]5[CH:16]=[C:15]([CH3:17])[N:14]=[CH:13]5)=[C:6]([O:5][CH3:4])[CH:7]=4)[S:20][C:21]=3[CH2:22]2)=[O:34])=[CH:31][CH:30]=1
Reactant: COc1cc(Nc2nc3c(s2)CNCC3)ccc1-n1cnc(C)c1
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(Nc2nc3c(s2)CN(C(=O)c2ccc(F)cc2)CC3)ccc1-n1cnc(C)c1

Procedure:
90 mg (0.2 mmol) [3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-(4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-yl)-amine trihydrochloride and 33 mg (0.2 mmol) 4-fluorobenzoyl chloride were suspended in methylene chloride (2 ml) and 101 mg (1 mmol) triethyl amine was added at room temperature. The reaction was stirred over night, diluted with methylene chloride, washed once with water, once with brine, dried over sodium sulphate, filtered and the solvent was evaporated under reduced pressure. The reaction was purified on silica gel with methylene chloride/methanol 19/1 yielding 52 mg (56%) (4-fluoro-phenyl)-{2-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamino]-6,7-dihydro-4H-thiazolo[5,4-c]pyridin-5-yl}-methanone as a yellow solid. MS ISP (m/e): 464.1 (100) (M+H)+. 1H NMR (DMSO-D6, 250 MHz): δ (ppm) 10.34 (s, 1H), 7.57-7.49 (m, 3H), 7.34-7.24 (m, 4H), 7.02 (d, 1H), 4.70-4.45 (br m, 2H), 4.00-3.55 (br m, 2H), 3.78 (s, 3H), 2.73 (m, 2H), 2.14 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][O:5][C:6]=1[C:7](Cl)=[O:8].Cl.[CH3:11][NH:12][O:13][CH3:14].N1C=CC=CC=1.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[CH3:14][O:13][N:12]([CH3:11])[C:7]([C:6]1[O:5][CH:4]=[N:3][C:2]=1[CH3:1])=[O:8]
Reactant: Cc1ncoc1C(=O)Cl
Reactant: CNOC
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CON(C)C(=O)c1ocnc1C
Temperature: 25 °C

Procedure:
4-Methyl-5-oxazolecarbonyl chloride (15 g) and N,O-dimethylhydroxylamine hydrochloride (11 g) in dry chloroform (100 ml) were cooled to 0° C. and dry pyridine (28.5 g) was added. The mixture was allowed to warm to room temperature. After 30 minutes aqueous sodium hydrogen carbonate was added and the organic layer separated. The aqueous layer was extracted with dichloromethane. The combined organic layers were washed, dried and evaporated. The residue was purified by flash chromatography to yield the title compound as a white solid. M.p. 59°-60° C.