Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][C:6]([OH:18])=[CH:7][CH:8]=2)[O:3]1.[CH2:20]([CH:22]1[O:24][CH2:23]1)Cl>>[O:24]1[CH2:23][CH:22]1[CH2:20][O:18][C:6]1[CH:5]=[C:4]2[C:9]([C:10]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)=[CH:11][C:2]([CH3:19])([CH3:1])[O:3]2)=[CH:8][CH:7]=1
Reactant: ClCC1CO1
Reactant: CC1(C)C=C(c2ccccc2)c2ccc(O)cc2O1
Product: CC1(C)C=C(c2ccccc2)c2ccc(OCC3CO3)cc2O1
Yield: 78 %

Procedure:
Reaction of 2,2-dimethyl-4-phenyl-2H-chromen-7-ol with epichlorohydrin, by an analogous process to that described in Example 1 gave 7-(2,3-epoxypropoxy)-2,2-dimethyl-4-phenyl-2H-chromene (78%). Reaction of this epoxide with dimethylamine by an analogous process to that described in Example 2 gave 7-(2-hydroxy-3-dimethylaminopropoxy)-2,2-dimethyl-4-phenyl-2H-chromene isolated as its hydrochloride salt (48%), m.p. 208°-209°.
Reaction SMILES: [CH2:1]([Mg]Br)[CH:2]([CH3:4])[CH3:3].N1C=CC=CC=1S[C:14](=[O:25])[CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1>C1COCC1>[CH3:24][O:23][C:20]1[CH:19]=[CH:18][C:17]([CH2:16][CH2:15][C:14](=[O:25])[CH2:1][CH:2]([CH3:4])[CH3:3])=[CH:22][CH:21]=1
Reactant: COc1ccc(CCC(=O)Sc2ccccn2)cc1
Reactant: CC(C)C[Mg]Br
Solvent: C1CCOC1
Product: COc1ccc(CCC(=O)CC(C)C)cc1
Reaction time: 1 h
Yield: 75 %

Procedure:
Isobutylmagnesium bromide (0.88 mL, 1.75 mmol, 2M soln in THF) was added to a cooled −78° C. solution of 3-(4-Methoxy-phenyl)-thiopropionic acid S-pyridin-2-yl ester (0.4 g, 1.46 mmol, from Step 1) dissolved in THF (6 mL). The reaction mixture was stirred for 60 min. The reaction was quenched with saturated NH4Cl and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated to a yellow oil. The residue was purified by silica gel chromatography (5% EtOAc in hexanes) to give the title compound as a clear oil (0.24 g, 75%).
Reaction SMILES: [H-].[Na+].[CH:3]1([N:10]2[C:14]3[CH:15]=[C:16]([O:19][CH2:20][CH3:21])[CH:17]=[CH:18][C:13]=3[NH:12][C:11]2=[O:22])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.CN(C=O)C.[CH3:28][O:29][C:30]([C:32]1[CH:37]=[CH:36][C:35]([S:38](Cl)(=[O:40])=[O:39])=[C:34]([O:42][CH3:43])[CH:33]=1)=[O:31]>O>[CH:3]1([N:10]2[C:14]3[CH:15]=[C:16]([O:19][CH2:20][CH3:21])[CH:17]=[CH:18][C:13]=3[N:12]([S:38]([C:35]3[CH:36]=[CH:37][C:32]([C:30]([O:29][CH3:28])=[O:31])=[CH:33][C:34]=3[O:42][CH3:43])(=[O:40])=[O:39])[C:11]2=[O:22])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]1
Reactant: COC(=O)c1ccc(S(=O)(=O)Cl)c(OC)c1
Reactant: CCOc1ccc2[nH]c(=O)n(C3CCCCCC3)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1ccc2c(c1)n(C1CCCCCC1)c(=O)n2S(=O)(=O)c1ccc(C(=O)OC)cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70.2 %

Procedure:
0.095 g of sodium hydride as a 60% dispersion in oil is added to a mixture of 0.7 g of 3-cycloheptyl-5-ethoxy-1,3-dihydro-2H-benzimidazol-2-one and 50 ml of DMF and the mixture is stirred for 30 minutes at RT. 0.7 g of 4-methoxycarbonyl-2-methoxybenzenesulfonyl chloride is then added and the mixture is stirred overnight at RT. The reaction mixture is poured into iced water and the precipitate formed is filtered off and washed with water to give 0.9 g of the expected product, which is used as such in the next step.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[S:8])[CH:6]=[C:5]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[N:4]=[C:3]1[CH2:15][C:16]([O-:18])=O.[Na+].Cl.CN(C)CCCN=C=NCC.[CH3:32][C@@H:33]1[CH2:41][C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[NH:34]1>CN(C=O)C.N1C=CC=CC=1>[CH3:32][C@@H:33]1[CH2:41][C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[N:34]1[C:16](=[O:18])[CH2:15][C:3]1[N:2]([CH3:1])[C:7](=[S:8])[CH:6]=[C:5]([N:9]2[CH2:10][CH2:11][O:12][CH2:13][CH2:14]2)[N:4]=1
Reactant: C[C@@H]1Cc2ccccc2N1
Reactant: Cn1c(CC(=O)[O-])nc(N2CCOCC2)cc1=S
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: C[C@@H]1Cc2ccccc2N1C(=O)Cc1nc(N2CCOCC2)cc(=S)n1C

Procedure:
The product is prepared by following the procedure described in example 4e (step 4e) using 250 mg of sodium (1-methyl-4-morpholin-4-yl-6-thioxo-1,6-dihydropyrimidin-2-yl)acetate in 6 ml of DMF and 6 ml of pyridine are added 512 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride and 126 mg of (R)-2-methyl-2,3-dihydro-1H-indole (which can be prepared according to Krasnov, V. P. et al. (Mendeleev Commun. 2002, 12(1), 27-28)).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]1[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=1.Cl[C:19]1[C:24]([N+:25]([O-:27])=[O:26])=[CH:23][CH:22]=[CH:21][N:20]=1>CN1C(=O)CCC1.O>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:19]2[C:24]([N+:25]([O-:27])=[O:26])=[CH:23][CH:22]=[CH:21][N:20]=2)=[CH:13][CH:12]=1
Reactant: Nc1ccc(Nc2nc3ccccc3o2)cc1
Reactant: O=[N+]([O-])c1cccnc1Cl
Solvent: O
Solvent: CN1CCCC1=O
Product: O=[N+]([O-])c1cccnc1Nc1ccc(Nc2nc3ccccc3o2)cc1
Temperature: 140 °C
Reaction time: 1.5 h
Yield: 43.5 %

Procedure:
A mixture of N-(1,3-benzoxazol-2-yl)benzene-1,4-diamine (0.50 g) and 2-chloro-3-nitropyridine (0.352 g) in NMP (3.0 mL) was stirred at 140° C. for 1.5 h. After this time, the reaction mixture was cooled to ambient temperature, diluted with water (50 mL), and extracted with ethyl acetate (3×100 mL). The combined organic extracts were washed with brine (100 mL), dried (Na2SO4), filtered and concentrated under reduced pressure. The residue obtained was purified by chromatography (silica, methylene chloride to 1:9 ethyl acetate/methylene chloride) to afford N-(1,3-benzoxazol-2-yl)-N′-(3-nitropyridin-2-yl)benzene-1,4-diamine (0.335 g) as a red solid.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([I:12])=[CH:8][CH:7]=1.C(#N)C.C(=O)([O-])[O-].[K+].[K+].[CH3:22][C:23]1([CH3:29])[CH2:28][CH2:27][CH2:26][NH:25][CH2:24]1>[I-].[K+].CCCCCCC>[I:12][C:9]1[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH2:3][CH2:2][N:25]2[CH2:26][CH2:27][CH2:28][C:23]([CH3:29])([CH3:22])[CH2:24]2)=[CH:7][CH:8]=1
Reactant: ClCCCOc1ccc(I)cc1
Reactant: CC1(C)CCCNC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Solvent: CCCCCCC
Product: CC1(C)CCCN(CCCOc2ccc(I)cc2)C1
Temperature: 30 °C
Reaction time: 0.08 h
Yield: 77.1 %

Procedure:
A mixture of 1-[(3-chloropropyl)oxy]-4-iodobenzene (100 g) and acetonitrile (600 ml) is stirred for about 5 min at 25-35° C., then potassium carbonate (93.07 g) followed by 3,3-dimethylpiperidine (49.53 g) are added over about 10 min. Potassium iodide (2.24 g) is added, then the mixture is stirred for about 15 min, before being heated to 78-82° C. for 22-24 h. The reaction mixture is cooled to 25-35° C., and the solid residue is filtered and washed with acetonitrile (200 ml). The filtrate and washings are concentrated under reduced pressure at 50-60° C. to give a thick liquid which is stirred with n-heptane (100 ml) for about 30 min at 25-30° C. The solution is then cooled to −5 to 10° C. and stirred for about 30 min. The solid is filtered, washed with chilled n-heptane (50 ml, 0-5° C.), then dried at 35-40° C. under vacuum for 6-10 h to give the title compound (97 g).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[CH2:7][CH2:6][N:5]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([CH3:18])=[CH:15][CH:16]=3)[N:11]=[C:10]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[OH:25])[N:9]=2)[CH2:4]1.C(N(CC)CC)C.Cl[C:34]([O:36][CH2:37][CH2:38][O:39][CH3:40])=[O:35]>CN(C=O)C>[CH3:40][O:39][CH2:38][CH2:37][O:36][C:34](=[O:35])[NH:1][CH2:2][C@@H:3]1[CH2:7][CH2:6][N:5]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([CH3:18])=[CH:15][CH:16]=3)[N:11]=[C:10]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[OH:25])[N:9]=2)[CH2:4]1
Reactant: COCCOC(=O)Cl
Reactant: Cc1ccc2c(N3CC[C@@H](CN)C3)nc(-c3ccccc3O)nc2c1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COCCOC(=O)NC[C@@H]1CCN(c2nc(-c3ccccc3O)nc3cc(C)ccc23)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.5 %

Procedure:
A solution of 2-(4-((S)-3-(aminomethyl)pyrrolidin-1-yl)-7-methylquinazolin-2-yl)phenol (0.12 g, 0.35 mmol) and triethylamine (98 μL, 0.7 mmol) in anhydrous DMF (4.0 mL) was cooled in an ice bath. 2-Methoxyethyl chloroformate (40 mL, 0.35 mmol) was added, and the ice bath was removed. The solution was stirred at room temperature overnight. Purification via silica gel chromatography using 0-10% MeOH in CH2Cl2 gave 2-methoxyethyl((S)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-yl)methylcarbamate (0.12 g, 80%). LC/MS: m/z 437.5 (M+H)+ at 2.20 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]3)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].CN(C)P(=O)(N(C)C)N(C)C.[OH:35][C:36]1[CH:43]=[CH:42][C:39]([CH2:40]Cl)=[CH:38][CH:37]=1>O>[OH:35][C:36]1[CH:43]=[CH:42][C:39]([CH2:40][N:4]2[CH2:5][CH2:6][N:1]([C:7]3[CH:8]=[C:9]4[C:14](=[CH:15][CH:16]=3)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]4)[CH2:2][CH2:3]2)=[CH:38][CH:37]=1
Reactant: O=C1CCc2cc(N3CCNCC3)ccc2N1
Reactant: Oc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: O=C1CCc2cc(N3CCN(Cc4ccc(O)cc4)CC3)ccc2N1
Temperature: 90 °C
Reaction time: 2.5 h
Yield: 19.5 %

Procedure:
To a mixture of 1.2 g of 6-(1-piperazinyl)-3,4-dihydrocarbostyril, 1.17 g of potassium carbonate and 20 ml of hexamethylphosphoric triamide was added 651 mg of 4-hydroxybenzyl chloride and the mixture was stirred at 90° C. for 2.5 hours. The reaction mixture was poured into a large amount of water and extracted with chloroform. After washing with water, the extract was dried over anhydrous sodium sulfate. Chloroform was distilled off and the residue was purified through silica gel column chromatography to give 0.3 g of 6-[4-(4-hydroxybenzyl)-1-piperazinyl]-3,4-dihydrocarbostyril.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([C:18]([OH:20])=O)=[C:13]2[N:12]=[CH:11][C:10]=1[C:21]([N:23]1[CH2:28][CH2:27][CH:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[F:35])[CH2:25][CH2:24]1)=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:36][S:37]([NH2:40])(=[O:39])=[O:38]>>[CH2:1]([NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([C:18]([NH:40][S:37]([CH3:36])(=[O:39])=[O:38])=[O:20])=[C:13]2[N:12]=[CH:11][C:10]=1[C:21]([N:23]1[CH2:24][CH2:25][CH:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[F:35])[CH2:27][CH2:28]1)=[O:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(N)(=O)=O
Reactant: O=C(O)c1cnn2c(NCc3ccccc3)c(C(=O)N3CCC(c4ccccc4F)CC3)cnc12
Product: CS(=O)(=O)NC(=O)c1cnn2c(NCc3ccccc3)c(C(=O)N3CCC(c4ccccc4F)CC3)cnc12
Yield: 27 %

Procedure:
In the same manner as in Example 1, step 6 and using 7-benzylamino-6-[4-(2-fluorophenyl)piperidine-1-carbonyl]pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0.035 g, 0.074 mmol) obtained in step 2 and methanesulfonamide (0.038 g, 0.375 mmol), the title compound (0.011 g, 27%) was obtained.
Reaction SMILES: [Br:1][CH2:2][CH2:3][O:4][C:5]1[CH:34]=[CH:33][C:8]([CH2:9][NH:10][C:11]2[N:16]=[C:15]([O:17][CH2:18][C:19]([F:22])([F:21])[F:20])[N:14]=[C:13]([NH:23][C:24]3[CH:32]=[CH:31][C:27]([C:28](O)=[O:29])=[CH:26][CH:25]=3)[N:12]=2)=[CH:7][CH:6]=1.[NH2:35][CH2:36][CH2:37][CH2:38][CH2:39][NH:40][C:41](=[O:47])[O:42][C:43]([CH3:46])([CH3:45])[CH3:44].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[Br:1][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:9][NH:10][C:11]2[N:16]=[C:15]([O:17][CH2:18][C:19]([F:22])([F:21])[F:20])[N:14]=[C:13]([NH:23][C:24]3[CH:25]=[CH:26][C:27]([C:28]([NH:35][CH2:36][CH2:37][CH2:38][CH2:39][NH:40][C:41](=[O:47])[O:42][C:43]([CH3:44])([CH3:46])[CH3:45])=[O:29])=[CH:31][CH:32]=3)[N:12]=2)=[CH:33][CH:34]=1
Reactant: CC(C)(C)OC(=O)NCCCCN
Reactant: O=C(O)c1ccc(Nc2nc(NCc3ccc(OCCBr)cc3)nc(OCC(F)(F)F)n2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NCCCCNC(=O)c1ccc(Nc2nc(NCc3ccc(OCCBr)cc3)nc(OCC(F)(F)F)n2)cc1
Yield: 86.8 %

Procedure:
4-((4-((4-(2-bromoethoxy)benzyl)amino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-yl)amino)benzoic acid (2.63 g, 4.85 mmol), tert-butyl (4-aminobutyl)carbamate (1.37 g, 7.27 mmol), HATU (5.53 g, 14.55 mmol), and Hunig's Base (4.24 mL, 24.25 mmol) were stirred in DCM (20 mL) for 3 h. The solvent was removed and the crude material was purified by silica gel chromatography eluting with 20-40-80% ethyl acetate in hexane to give tert-butyl (4-(4-((4-((4-(2-bromoethoxy)benzyl)amino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-yl)amino)benzamido)butyl)carbamate (3.0 g, 87%) as product.
Reaction SMILES: Cl.C[O:3][C:4](=[O:29])[C@H:5]([CH2:19][C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[NH:22][CH:21]=1)[NH:6][C:7](=[O:18])[C@@H:8]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[NH:9][CH3:10].[Cl:30][C:31]1[N:36]=[C:35]([C:37]([OH:39])=O)[CH:34]=[CH:33][CH:32]=1>>[Cl:30][C:31]1[N:36]=[C:35]([C:37]([N:9]([CH3:10])[C@@H:8]([C:7]([NH:6][C@H:5]([C:4]([OH:29])=[O:3])[CH2:19][C:20]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[NH:22][CH:21]=2)=[O:18])[CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[O:39])[CH:34]=[CH:33][CH:32]=1
Reactant: CN[C@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)OC
Reactant: O=C(O)c1cccc(Cl)n1
Agent: Cl
Product: CN(C(=O)c1cccc(Cl)n1)[C@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O

Procedure:
Coupling of N-methyl-(D)-phenylalanyl-(L)-tryptophan methyl ester hydrochloride (see example 1) with 6-chloro-2-pyridinecarboxylic acid according to example 12 followed by hydrolysis of the methyl ester moiety according to example 1 gives N-(6-chloro-2-pyridylcarbonyl)-N-methyl-(D)-phenylalanyl-(L)-tryptophan; FAB-MS m/e 503 (M-H)-.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH2:4].[O:10]1[CH:12]([CH3:13])[CH2:11]1>>[OH:10][CH:12]([CH3:13])[CH2:11][NH:4][C:3]1[C:5]([CH3:9])=[CH:6][CH:7]=[CH:8][C:2]=1[Cl:1]
Reactant: Cc1cccc(Cl)c1N
Reactant: CC1CO1
Product: Cc1cccc(Cl)c1NCC(C)O
Yield: 30.1 %

Procedure:
2-Chloro-6-methyl-aniline is reacted with 1,2-epoxypropane as described in Example 3, Method (b), point (a) to obtain N-(β-hydroxypropyl)-2-chloro-6-methyl-aniline with a yield of 30.1%; b.p.: 118°-122° C./0.2 mm Hg.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]2[NH:15][C:16](=[O:38])[C:17]3([CH:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=4[F:29])[CH:20]([C:30](O)=[O:31])[NH:19][CH:18]3[CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:12]2=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:63][C:64]1[CH:73]=[CH:72][C:67]([O:68][CH2:69][CH2:70][OH:71])=[CH:66][CH:65]=1>>[OH:71][CH2:70][CH2:69][O:68][C:67]1[CH:72]=[CH:73][C:64]([NH:63][C:30]([CH:20]2[NH:19][CH:18]([CH2:33][C:34]([CH3:36])([CH3:37])[CH3:35])[C:17]3([C:12]4[C:13](=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=4)[NH:15][C:16]3=[O:38])[CH:21]2[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=2[F:29])=[O:31])=[CH:65][CH:66]=1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Reactant: Nc1ccc(OCCO)cc1
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)CC1NC(C(=O)Nc2ccc(OCCO)cc2)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Yield: 41.6 %

Procedure:
In a manner similar to the method described in Example 5, rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid prepared in Example 4 (0.25 g, 0.44 mmol), was reacted with diisopropylethylamine (0.23 g, 1.8 mmol), diphenylphosphinic chloride (0.32 g, 1.3 mmol), then reacted with 2-(4-aminophenoxy)ethanol (0.082 g, 0.53 mmol) to give rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid [4-(2-hydroxy-ethoxy)-phenyl]-amide as a yellow solid (Yield 0.11 g, 41%).
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:20][CH2:19][C:13]2([O:17][C:16](=[O:18])[NH:15][CH2:14]2)[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].[CH3:21][O:22][C:23]1[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][C:24]=1[CH2:25]Br.O>CN(C=O)C>[C:3]([O:7][C:8]([N:10]1[CH2:11][CH2:12][C:13]2([O:17][C:16](=[O:18])[N:15]([CH2:25][C:24]3[CH:27]=[C:28]([N+:31]([O-:33])=[O:32])[CH:29]=[CH:30][C:23]=3[O:22][CH3:21])[CH2:14]2)[CH2:19][CH2:20]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CNC(=O)O2
Reactant: COc1ccc([N+](=O)[O-])cc1CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc([N+](=O)[O-])cc1CN1CC2(CCN(C(=O)OC(C)(C)C)CC2)OC1=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 81.5 %

Procedure:
Sodium hydride (82 mg, 60% dispersion in mineral oil, weight percent) was suspended under a nitrogen atmosphere in DMF (5 mL). Compound A3 (0.5 g, 1.95 mmol) was added thereto and the reaction mixture was stirred for 10 min at RT. 2-Methoxy-5-nitrobenzyl bromide (485 mg, 1.97 mmol) was added thereto. The reaction mixture was stirred for 18 h at RT, combined with water and extracted with EtOAc. The combined organic phases were washed with sat. aq. NaCl solution, dried over Na2SO4 and the solvent was removed under a vacuum. The residue was dissolved in a mixture of ether and heptane. After removal of the ether, the desired product 3-(2-methoxy-5-nitrobenzyl)-2-oxo-1-oxa-3,8-diazaspiro[4.5]decane-8-carboxylic acid tert-butyl ester (A87) (670 mg, 81% of theoretical) was obtained as a white solid by filtration.
Reaction SMILES: [H-].[Na+].CS(C[CH2:8][OH:9])(=O)=O.[Cl:10][C:11]1[C:12]([N:17]2[CH2:26][CH2:25][C:24]3[C:23]([NH:27][C:28]4[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=4)=[N:22]C(S(C)(=O)=O)=[N:20][C:19]=3[CH2:18]2)=[N:13][CH:14]=[CH:15][CH:16]=1>CN(C=O)C>[F:37][C:34]([F:35])([F:36])[C:31]1[CH:32]=[CH:33][C:28]([NH:27][C:23]2[C:24]3[CH2:25][CH2:26][N:17]([C:12]4[C:11]([Cl:10])=[CH:16][CH:15]=[CH:14][N:13]=4)[CH2:18][C:19]=3[N:20]=[C:8]([OH:9])[N:22]=2)=[CH:29][CH:30]=1
Reactant: CS(=O)(=O)c1nc2c(c(Nc3ccc(C(F)(F)F)cc3)n1)CCN(c1ncccc1Cl)C2
Reactant: CS(=O)(=O)CCO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Oc1nc2c(c(Nc3ccc(C(F)(F)F)cc3)n1)CCN(c1ncccc1Cl)C2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 11.9 %

Procedure:
Sodium hydrid (40 mg, 1 mmol, 60%) was added to the solution of 2-(methansulphonyl)ethanol (124 mg, 1 mmol) in DMF (5 mL, anhydrous) and stirred at room temperature for 10 min. This solution (0.6 mL) was added to the solution of 7-(3-chloropyridin-2-yl)-N-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydro-2-(methylsulfonyl)pyrido[3,4-d]pyrimidin-4-amine (50 mg, 0.1 mmol) in DMF (1 mL) and was irradiated in microwave at 150° C. for 20 min. Solvent was removed in vacuo and the residue was purified by column chromatography to yield the product as a light brown solid (5 mg, 12%).
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][NH2:5].[CH2:7]([O:14][C:15](=[O:28])[C:16]1[CH:21]=[CH:20][C:19]([CH2:22]OS(C)(=O)=O)=[CH:18][CH:17]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>CN(C=O)C>[CH2:7]([O:14][C:15](=[O:28])[C:16]1[CH:17]=[CH:18][C:19]([CH2:22][NH:5][CH2:4][CH2:3][N:2]([CH3:6])[CH3:1])=[CH:20][CH:21]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CN(C)CCN
Reactant: CS(=O)(=O)OCc1ccc(C(=O)OCc2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN(C)CCNCc1ccc(C(=O)OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 53.3 %

Procedure:
N,N-Dimethylethylenediamine (0.87 mL, 7.9 mmol) was added to a solution of 4-methanesulfonyloxymethylbenzoic acid benzyl ester (Reference Compound No. 7-1, 2.3 g, 7.2 mmol) and triethylamine (3.0 mL, 22 mmol) in DMF (10 mL), and then the reaction mixture was stirred at room temperature for 2 hours. Saturated aqueous sodium hydrogen carbonate solution (150 mL) was added thereto, and then the whole was extracted with chloroform (100 mL) three times. The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure to give 1.2 g of a mixture, which contains the title reference compound as yellow oil.
Reaction SMILES: CO[C:3](=[O:25])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1.[NH2:26][CH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>>[F:24][C:21]1[CH:22]=[CH:23][C:18]([C:13]2[C:12]([CH2:11][NH:10][C:7]3[CH:8]=[CH:9][C:4]([C:3]([NH:26][CH:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)=[O:25])=[CH:5][N:6]=3)=[C:16]([CH3:17])[O:15][N:14]=2)=[CH:19][CH:20]=1
Reactant: COC(=O)c1ccc(NCc2c(-c3ccc(F)cc3)noc2C)nc1
Reactant: NC1CCOCC1
Product: Cc1onc(-c2ccc(F)cc2)c1CNc1ccc(C(=O)NC2CCOCC2)cn1
Yield: 82 %

Procedure:
As described for example 176, 6-{[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethyl]-amino}-nicotinic acid methyl ester (70 mg, 0.2 mmol) was converted, using 4-aminotetrahydropyran instead of 2,2,2-trifluoroethylamine, to the title compound (69 mg, 82%) which was obtained as a white foam. MS: m/e=411.4 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:16]=[CH:17][C:18]([C:21]([OH:23])=O)=[N:19][CH:20]=3)=[C:11]([CH2:24][OH:25])[O:10][N:9]=2)=[CH:4][CH:3]=1.Cl.[F:27][C:28]1([F:34])[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[F:27][C:28]1([F:34])[CH2:33][CH2:32][N:31]([C:21]([C:18]2[CH:17]=[CH:16][C:15]([O:14][CH2:13][C:12]3[C:8]([C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)=[N:9][O:10][C:11]=3[CH2:24][OH:25])=[CH:20][N:19]=2)=[O:23])[CH2:30][CH2:29]1
Reactant: O=C(O)c1ccc(OCc2c(-c3ccc(F)cc3)noc2CO)cn1
Reactant: FC1(F)CCNCC1
Agent: Cl
Product: O=C(c1ccc(OCc2c(-c3ccc(F)cc3)noc2CO)cn1)N1CCC(F)(F)CC1
Yield: 31 %

Procedure:
As described for example 34b, 5-[3-(4-fluoro-phenyl)-5-hydroxymethyl-isoxazol-4-ylmethoxy]-pyridine-2-carboxylic acid (75 mg, 0.22 mmol) was converted, using 4,4-difluoropiperidine hydrochloride instead of S-(+)-1-amino-2-propanol, to the title compound (45 mg, 31%), which was obtained as a colourless gum. MS: m/e=448.2 [M+H]+.
Reaction SMILES: [O:1]=[C:2]1[C@@H:7]2[CH2:8][C@@H:4]([CH2:5][CH2:6]2)[N:3]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].[BH4-].[Na+]>CO>[OH:1][CH2:2][C@H:7]1[CH2:6][CH2:5][C@@H:4]([NH:3][C:9](=[O:10])[O:11][C:12]([CH3:14])([CH3:13])[CH3:15])[CH2:8]1
Reactant: CC(C)(C)OC(=O)N1C(=O)[C@H]2CC[C@@H]1C2
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H]1CC[C@H](CO)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 95.8 %

Procedure:
(1R,4S)-tert-butyl 3-oxo-2-azabicyclo[2.2.1]heptane-2-carboxylate (2.99 g, 14.15 mmol) was dissolved in MeOH (40 ml) and cooled to 0° C. Sodium Borohydride (1.071 g, 28.3 mmol) was added and the reaction was stirred at 0° C. for 1 hr, and the reaction progress was followed by LCMS. MeOH was removed and the resulting residue was partitioned between EtOAc (250 mL) and H2O (250 mL). The organic layer was washed with brine (250 mL), dried over Na2SO4, and concentrated under reduced pressure. The crude material was purified by column chromatography, 50-100% EtOAc in heptane to yield tert-butyl (1R,3S)-3-(hydroxymethyl)cyclopentylcarbamate (2.92 g, 13.56 mmol) as a white solid. LCMS (m/z): 160.2 (M-tBu), retention time=0.65 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]([CH2:20][C:21](O)=[O:22])[S:10]([C:13]1[C:14]([CH3:19])=[CH:15][CH:16]=[CH:17][CH:18]=1)(=[O:12])=[O:11].[CH2:24]([NH:26][CH2:27][C:28]1[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=1)[CH3:25]>>[CH2:24]([N:26]([CH2:27][C:28]1[CH:29]=[CH:30][C:31]([OH:34])=[CH:32][CH:33]=1)[C:21](=[O:22])[CH2:20][N:9]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[O:2][CH3:1])[S:10]([C:13]1[C:14]([CH3:19])=[CH:15][CH:16]=[CH:17][CH:18]=1)(=[O:12])=[O:11])[CH3:25]
Reactant: COc1ccccc1N(CC(=O)O)S(=O)(=O)c1ccccc1C
Reactant: CCNCc1ccc(O)cc1
Product: CCN(Cc1ccc(O)cc1)C(=O)CN(c1ccccc1OC)S(=O)(=O)c1ccccc1C

Procedure:
prepared by reaction of [(2-methoxy-phenyl)-(toluene-2-sulfonyl)-amino]-acetic acid with 4-ethylaminomethyl-phenol