Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH:28]=[CH:27][CH:26]=[N:25]3)=[CH:20][CH:19]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[N:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[S:37](Cl)(=[O:39])=[O:38]>>[C:1]([O:5][C:6](=[O:29])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:16]([CH2:17][C:18]2[CH:19]=[CH:20][C:21]([N:24]3[CH:28]=[CH:27][CH:26]=[N:25]3)=[CH:22][CH:23]=2)[S:37]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][N:31]=2)(=[O:39])=[O:38])[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)COc1cccc(CNCc2ccc(-n3cccn3)cc2)c1
Reactant: O=S(=O)(Cl)c1ccccn1
Agent: Cl
Product: CC(C)(C)OC(=O)COc1cccc(CN(Cc2ccc(-n3cccn3)cc2)S(=O)(=O)c2ccccn2)c1

Procedure:
The title compound of Step A was prepared from {3-[(4-pyrazol-1-yl-benzylamino)-methyl]-phenoxy}-acetic acid tert-butyl ester, of Step A of Example 13a, and pyridine-2-sulfonyl chloride hydrochloride, of Preparation 47, following the method described in Example 3, Step B with a reaction time of 2 h. 1H NMR (400 MHz, CDCl3) δ8.66 (m, 1H), 7.95 (d, 1H), 7.85 (m, 2H), 7.68 (d, 1H), 7.49 (d, 2H), 7.45 (m, 1H), 7.16 (d, 2H), 7.08 (t, IH), 6.70 (m, 3H), 6.43 (m, 1H), 4.49 (s, 2H), 4.44 (s, 2H), 4.38 (s, 2H), 1.46 (s, 9H); MS 535 (M+1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[O:12][N:11]=[C:10]([C:13]([CH3:17])([CH3:16])[CH:14]=O)[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:19][NH2:20].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C>C1COCC1>[C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[O:12][N:11]=[C:10]([C:13]([CH3:17])([CH3:16])[CH2:14][NH:20][CH3:19])[CH:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CN
Reactant: CC(C)(C)OC(=O)Nc1cc(C(C)(C)C=O)no1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Solvent: C1CCOC1
Product: CNCC(C)(C)c1cc(NC(=O)OC(C)(C)C)on1
Reaction time: 2 h

Procedure:
[3-(1,1-Dimethyl-2-oxo-ethyl)-isoxazol-5-yl]-carbamic acid tert-butyl ester (150.0 mg, 0.59 mmol) is dissolved in THF (1.0 mL) and 2M methylamine in THF (0.35 mL, 0.71 mmol) is added followed by the addition of MP-triacetoxyborohydride (546.0 mg, 2.70 mmol/g). The reaction mixture is placed on a shaker for 2 h. After this time, the reaction mixture is filtered and the filtrate is concentrated under reduced pressure to provide 163.0 mg of the title compound which is used crude for the next step. m/z 270 [M+H].
Reaction SMILES: [CH2:1]([N:3]([CH2:10][CH2:11]O)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:2].O=S(Cl)[Cl:15]>C(Cl)Cl>[Cl:15][CH2:11][CH2:10][N:3]([CH2:1][CH3:2])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=S(Cl)Cl
Reactant: CCN(CCO)c1ccccc1
Solvent: ClCCl
Product: CCN(CCCl)c1ccccc1
Yield: 50 %

Procedure:
2-(N-ethyl-N-phenylamino)ethanol (10 g, 60 mmol) in CH2Cl2 (150 mL) was reacted with SOCl2 (8.8 mL, 121 mmol). The mixture was heated to reflux for one hour and quenched. The solvent was evaporated and the residue was purified by silica gel column chromatography to provide intermediate 3a (5.54 g, 30 mmol, 50%) as a yellow oil. 1H NMR (CDCl3, 400 MHz) δ 7.28 (m, 2H), 6.74 (m, 3H), 3.65 (m, 4H), 3.46 (q, J=7.2 Hz, 2H), 1.22 (t, J=7.2 Hz, 3H); HRMS (ESI, positive) m/z calcd. for C10H15ClN [M+H]+: 184.0893, found: 184.0836.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:17](=O)[CH3:18])=[N:4][N:5]([CH3:16])[C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH3:15])=[CH:9][CH:8]=1.[NH:20]([C:22]([NH:24][C:25]1[CH:33]=[CH:32][C:28]([C:29]([OH:31])=[O:30])=[CH:27][CH:26]=1)=[S:23])[NH2:21].CN(C)C=O>Cl.O>[OH:1][C:2]1[C:3]([C:17](=[N:21][NH:20][C:22]([NH:24][C:25]2[CH:33]=[CH:32][C:28]([C:29]([OH:31])=[O:30])=[CH:27][CH:26]=2)=[S:23])[CH3:18])=[N:4][N:5]([CH3:16])[C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH3:15])=[CH:9][CH:8]=1
Reactant: CCCc1ccc(-c2c(O)c(C(C)=O)nn2C)cc1
Reactant: NNC(=S)Nc1ccc(C(=O)O)cc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: CCCc1ccc(-c2c(O)c(C(C)=NNC(=S)Nc3ccc(C(=O)O)cc3)nn2C)cc1
Yield: 79.3 %

Procedure:
1-[4-Hydroxy-1-methyl-5-(4-n-propylphenyl)-1H-pyrazol-3-yl]ethanone (0.157 mmol, 40.5 mg) and 4-hydrazinocarbonothioylaminobenzoic acid (0.157 mmol, 33.1 mg) were stirred with dimethylformamide (2.3 mL) and three drops of concentrated hydrochloric acid at room temperature for 23.5 hours. After addition of water, the precipitated yellow solid was recovered by filtration, washed with water and dried by means of a vacuum pump. The resulting solid was stirred with chloroform/n-hexane for a while, then recovered by filtration and dried by means of a vacuum pump to give the desired product as a pale yellow solid (56.2 mg, yield 79%).
Reaction SMILES: [C:1]([C:3]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:8][CH2:7][N:6](C)[CH2:5][CH2:4]1)#[N:2].Cl[C:24]([O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:25]>C(Cl)Cl>[C:1]([C:3]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:8][CH2:7][N:6]([C:24]([O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:25])[CH2:5][CH2:4]1)#[N:2]
Reactant: CN1CCC(C#N)(c2ccccc2Oc2ccccc2)CC1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: ClCCl
Product: N#CC1(c2ccccc2Oc2ccccc2)CCN(C(=O)Oc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 24 h

Procedure:
A mixture of 2.5 g of 4-cyano-1-methyl-4-(2-phenoxyphenyl)piperidine, free base of Example 1, and 1.7 g of phenyl chloroformate in 50 ml of methylene chloride is permitted to stand for 24 hours before being poured onto 100 g of ice. Thereafter, the mixture is extracted with 50 ml of methylene chloride and the organic solution is successively washed twice with 50 ml portions of water, washed once with 40 ml saturated sodium bicarbonate solution, washed once with 40 ml saturated sodium chloride solution, dried and evaporated to provide an oil. The oil is chromatographed (silica gel 60 column, ether eluant) and then chromatographed (silica gel 60 column, ether-hexane (1:1) mixture eluant) until there is no indication of contamination by the layer chromatography. Thereafter, the product is chromatographed through the same absorbent, ether eluant to provide a glassy solid of 4-cyano-1-phenoxycarbonyl-4-(2-phenoxyphenyl)piperidine.
Reaction SMILES: [Na].C([O:5][CH:6]1[CH:10]([N:11]2[C:15]3[CH:16]=[C:17]([Cl:21])[C:18]([Cl:20])=[CH:19][C:14]=3[N:13]=[C:12]2Br)[CH2:9][CH:8]([CH2:23][O:24]C(=O)C)[CH:7]1[O:28]C(=O)C)(=O)C.[CH3:32][O-:33].[Na+].Cl>CO>[Cl:20][C:18]1[C:17]([Cl:21])=[CH:16][C:15]2[N:11]([CH:10]3[CH:6]([OH:5])[CH:7]([OH:28])[CH:8]([CH2:23][OH:24])[CH2:9]3)[C:12]([O:33][CH3:32])=[N:13][C:14]=2[CH:19]=1
Reactant: CC(=O)OCC1CC(n2c(Br)nc3cc(Cl)c(Cl)cc32)C(OC(C)=O)C1OC(C)=O
Reactant: C[O-]
Agent: Cl
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: COc1nc2cc(Cl)c(Cl)cc2n1C1CC(CO)C(O)C1O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Sodium (spheres, 0.10 g, 4.8 mequiv) were added to dry methanol (15 mL). (±)-(1R*, 2S*, 3S*, 5S*)-3-(Acetoxymethyl)-5-(2-bromo-5,6-dichloro-1H-benzimidazol-1-yl)-1,2-cyclopentanediyl diacetate (0.560 g, 0.958 mmol) was added to the sodium methoxide in methanol and the solution stirred at ambient temperature under nitrogen for 5 hours. The solution was then neutralized with 1N hydrochloric acid and volatiles removed in vacuo. The residual solid was chromatographed on silica gel. (±)-(1R*, 2S*, 3S*, 5S*)-5-(5,6-Dichloro-2-methoxy-1H-benzimidazol-1-yl)-3-(hydroxymethyl)-1,2-cyclopentanediol was eluted with 10% methanol-chloroform as a white powder, after trituration with diethyl ether (0.211 g, 64%), m.p. 204°-206° C. dec; 1H-NMR(DMSO-d6)δ: 7.82 and 7.67 (both s, 2, aromatic CH), 4.9 (m, 2,2 OH), 4.7-4.6 (m overlapping d at 4.61, J=4.1 Hz, 2 total, NCH and OH), 4.4-4.3 (m, 1, OCH), 4.11 (s, 3, OCH3), 3.8 (m, 1, OCH), 3.6-3.4 (m, 2, OCH2), 2.1-2.0 (m, 2, CH2), 1.9-1.8 (m, 1, CH); mass spectrum (CI): 347(M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:35][O:36][C:37]1[C:42]2[N:43]=[C:44]([NH2:46])[S:45][C:41]=2[C:40]([N:47]([CH2:49][CH2:50][O:51][CH3:52])[CH3:48])=[CH:39][CH:38]=1>C1COCC1.O1CCOCC1.CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([NH:46][C:44]1[S:45][C:41]2[C:40]([N:47]([CH2:49][CH2:50][O:51][CH3:52])[CH3:48])=[CH:39][CH:38]=[C:37]([O:36][CH3:35])[C:42]=2[N:43]=1)=[O:7]
Reactant: COCCN(C)c1ccc(OC)c2nc(N)sc12
Reactant: O=C(O)c1ccnc(Br)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: COCCN(C)c1ccc(OC)c2nc(NC(=O)c3ccnc(Br)c3)sc12

Procedure:
From 2-bromo-isonicotinic acid, HATU and N-diethylisopropylamine in THF, then treatment with 4-methoxy-N7-(2-methoxy-ethyl)-N7-methyl-benzothiazole-2,7-diamine in dioxane and DMF. ES-MS m/e (%): 453 (M{81Br}+H+, 100), 451 (M{79Br}+H+, 71).
Reaction SMILES: OCO[CH2:4][C:5]([O:7][CH3:8])=[O:6].[NH:9]([CH2:16][C@@H:17]1[CH2:21][CH2:20][CH2:19][NH:18]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C1C=CC=CC=1>[C:5]([CH:4]1[N:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:16][CH:17]2[N:18]1[CH2:19][CH2:20][CH2:21]2)([O:7][CH3:8])=[O:6]
Reactant: COC(=O)COCO
Reactant: c1ccc(NC[C@@H]2CCCN2)cc1
Solvent: c1ccccc1
Product: COC(=O)C1N(c2ccccc2)CC2CCCN21
Yield: 98.8 %

Procedure:
In 10 ml of benzene, were dissolved 683 mg of methyl hydroxymethoxyacetate and 1.00 g of (S)-2-(anilinomethyl)pyrrolidine. The resulting solution was refluxed for 30 minutes while removing the water by azeotropic distillation. On removing the solvent by distillation in vacuo, there were obtained 1.38 g of 2-carbomethoxy-3-phenyl-1,3-diazabicyclo[3,3,0]octane, a derivative of glyoxylic acid. NMR peaks: δ(ppm)=1.5-2.3 (4H, multiplet), 2.3-4.1 (5H, multiplet), 3.5 (3H, singlet), 4.6 (1H, singlet), 6.2-7.1 (5H, multiplet). After having been purified by alumina column chromatography and short-path distillation, the substance showed the following results of elementary analysis:
Reaction SMILES: [C:1]([O:5][CH:6]([C:11]1[N:16]([CH3:17])[C:15](=[O:18])[C:14]2[NH:19][CH:20]=[CH:21][C:13]=2[C:12]=1[C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=1)[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].[F:29][C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][C:37]=1[F:38])[CH2:33]Br>>[C:1]([O:5][C@@H:6]([C:11]1[N:16]([CH3:17])[C:15](=[O:18])[C:14]2[N:19]([CH2:33][C:32]3[CH:35]=[CH:36][C:37]([F:38])=[C:30]([F:29])[CH:31]=3)[CH:20]=[CH:21][C:13]=2[C:12]=1[C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=1)[C:7]([OH:9])=[O:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: Fc1ccc(CBr)cc1F
Reactant: COC(=O)C(OC(C)(C)C)c1c(-c2ccc(Cl)cc2)c2cc[nH]c2c(=O)n1C
Product: Cn1c([C@H](OC(C)(C)C)C(=O)O)c(-c2ccc(Cl)cc2)c2ccn(Cc3ccc(F)c(F)c3)c2c1=O

Procedure:
The title compound was prepared in a manner similar to that described in Example 2 from methyl 2-(tert-butoxy)-2-(4-(4-chlorophenyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)acetate and 3,4-difluorobenzyl bromide. The crude racemic mixture was purified by chiral chromatography to give (S)-2-(tert-butoxy)-2-(4-(4-chlorophenyl)-1-(3,4-difluorobenzyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)acetic acid. 1H NMR (400 MHz, CHLOROFORM-d) ppm 7.68-7.59 (m, 1H), 7.52-7.45 (m, 1H), 7.46-7.39 (m, 1H), 7.17-6.98 (m, 4H), 6.06-5.99 (m, 1H), 5.86-5.71 (m, 1H), 5.38-5.32 (s, 1H), 3.64 (s, 3H), 1.02 (s, 9H); LCMS (m/z) ES+=515 (M+1).
Reaction SMILES: C([N:8]1[CH2:15][CH2:14][CH:13]2[CH:9]1[CH:10]([CH3:21])[N:11]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:12]2)C1C=CC=CC=1>C(O)C.[Pd]>[CH3:21][CH:10]1[CH:9]2[CH:13]([CH2:14][CH2:15][NH:8]2)[CH2:12][N:11]1[C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCOC(=O)N1CC2CCN(Cc3ccccc3)C2C1C
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)N1CC2CCNC2C1C

Procedure:
16 g (55 mmol) of ethyl 2-benzyl-8-methyl-2,7-diazabicyclo[3.3.0]octane-7-carboxylate in 300 ml of ethanol are hydrogenated at 100° C. and 100 bar on 3 g of palladium-active carbon (10% Pd). The catalyst is filtered off with suction, the filtrate is concentrated and the residue is distilled.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:30])[C:11]2[CH:16]=[C:15]([NH2:17])[C:14]([NH:18][CH3:19])=[N:13][C:12]=2[N:20]2[CH2:25][CH2:24][CH:23]([C:26]([F:29])([F:28])[F:27])[CH2:22][CH2:21]2)[CH2:5][CH2:4]1.[Cl:33][C:34]1[C:47]([N:48]=[C:49]=S)=[C:46]([Cl:51])[CH:45]=[CH:44][C:35]=1[CH2:36][NH:37][C:38](=[O:43])[C:39]([CH3:42])([CH3:41])[CH3:40].CN(C=O)C.CC(C)N=C=NC(C)C>O>[F:32][C:2]([F:1])([F:31])[C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:11]2[CH:16]=[C:15]3[N:17]=[C:49]([NH:48][C:47]4[C:46]([Cl:51])=[CH:45][CH:44]=[C:35]([CH2:36][NH:37][C:38](=[O:43])[C:39]([CH3:42])([CH3:41])[CH3:40])[C:34]=4[Cl:33])[N:18]([CH3:19])[C:14]3=[N:13][C:12]=2[N:20]2[CH2:25][CH2:24][CH:23]([C:26]([F:29])([F:28])[F:27])[CH2:22][CH2:21]2)=[O:30])[CH2:5][CH2:4]1
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(N=C=S)c1Cl
Reactant: CNc1nc(N2CCC(C(F)(F)F)CC2)c(C(=O)N[C@H]2CC[C@H](C(F)(F)F)CC2)cc1N
Agent: CC(C)N=C=NC(C)C
Solvent: O
Solvent: CN(C)C=O
Product: Cn1c(Nc2c(Cl)ccc(CNC(=O)C(C)(C)C)c2Cl)nc2cc(C(=O)N[C@H]3CC[C@H](C(F)(F)F)CC3)c(N3CCC(C(F)(F)F)CC3)nc21
Reaction time: 72 h

Procedure:
A mixture of N-(trans-4-trifluoromethyl-cyclohexyl)-6-methylamino-5-amino-2-(4-trifluoromethyl-piperidinyl)-nicotinic acid amide (compound Ic; 130 mg, 0.27 mmol), N-(2,4-dichloro-3-isothiocyanato-benzyl)-2,2-dimethyl-propionamide (98 mg, 0.31 mmol) and DMF (3 mL) is stirred for 3 d. Then DIC (57 μl, 0.32 mmol) is added and it is stirred for 1 d. The crude mixture is poured into water and the precipitate is collected by filtration and purified by prep. HPLC. Yield: 90 mg. Melting Point: 185-186° C. MS m/z: 750 [M+H]+.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][NH:5][S:6]([C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([Br:18])[CH:16]=2)[N:11]([S:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)(=[O:21])=[O:20])[C:10]=1[C:28]([O:30][CH2:31][CH3:32])=[O:29])(=[O:8])=[O:7].[Br:33][C:34]1[CH:39]=[CH:38][C:37]([S:40](Cl)(=[O:42])=[O:41])=[CH:36][CH:35]=1>C(N(CC)CC)C>[Br:18][C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[N:11]([S:19]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=[O:21])=[O:20])[C:10]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[C:9]2[S:6]([NH:5][CH2:4][CH2:3][NH:2][S:40]([C:37]1[CH:38]=[CH:39][C:34]([Br:33])=[CH:35][CH:36]=1)(=[O:42])=[O:41])(=[O:8])=[O:7]
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: CCOC(=O)c1c(S(=O)(=O)NCCN)c2cc(Br)ccc2n1S(=O)(=O)c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1c(S(=O)(=O)NCCNS(=O)(=O)c2ccc(Br)cc2)c2cc(Br)ccc2n1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.58 h

Procedure:
A solution of the product from Example 89 Step A, was combined with 4-bromobenzenesulfonyl chloride and triethylamine, and stirred at room temperature for 35 minutes. The solvent was removed with a stream of nitrogen to give the titled compound. ESI+ MS: 750 [M+H]+.
Reaction SMILES: [N:1]1[CH:6]=[C:5]([NH2:7])[C:4]([NH2:8])=[N:3][CH:2]=1.[C:9](N1C=CN=C1)(N1C=CN=C1)=[O:10]>O1CCOCC1>[N:1]1[CH:6]=[C:5]2[C:4]([NH:8][C:9](=[O:10])[NH:7]2)=[N:3][CH:2]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1cncnc1N
Solvent: C1COCCO1
Product: O=c1[nH]c2cncnc2[nH]1
Temperature: 90 °C
Reaction time: 48 h
Yield: 567.7 %

Procedure:
Pyrimidine-4,5-diamine (1.1 g, 10 mmol) and 1,1′-carbonyl diimidazole 1.78 g, 1.1 mmol) were added to dioxane (15 mL) and the reaction mixture was stirred at 90° C. for 48 hours. The mixture was cooled and the precipitate was recovered by filtration, rinsed with cold dioxane, and dried to give 850 mg (61%) of 7,9-dihydro-purin-8-one.
Reaction SMILES: [CH:1]1[C:6]([NH2:7])=[CH:5][CH:4]=[C:3]([OH:8])[CH:2]=1.Br[CH2:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12]>>[NH2:7][C:6]1[CH:5]=[CH:4][C:3]([O:8][CH2:10][C:11]([N:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]2)=[O:12])=[CH:2][CH:1]=1
Reactant: CN1CCN(C(=O)CBr)CC1
Reactant: Nc1ccc(O)cc1
Product: CN1CCN(C(=O)COc2ccc(N)cc2)CC1

Procedure:
Prepared from p-aminophenol and 1-(bromoacetyl)-4-methylpiperazine by the method of Example 333 to give a product of m.p. 71°-73° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH:5]([O:16][CH2:17][CH3:18])[CH2:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH:9]=[CH:10][NH:11]2)[CH3:2].[CH3:20][C:21]1[O:25][C:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[N:23][C:22]=1[CH2:32][CH2:33]OS(C)(=O)=O.[H-].[Na+]>CN(C)C=O>[CH2:1]([O:3][C:4](=[O:19])[CH:5]([O:16][CH2:17][CH3:18])[CH2:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH:9]=[CH:10][N:11]2[CH2:33][CH2:32][C:22]1[N:23]=[C:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[O:25][C:21]=1[CH3:20])[CH3:2]
Reactant: Cc1oc(-c2ccccc2)nc1CCOS(C)(=O)=O
Reactant: CCOC(=O)C(Cc1cccc2[nH]ccc12)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(Cc1cccc2c1ccn2CCc1nc(-c2ccccc2)oc1C)OCC

Procedure:
In analogy to the procedures described in examples 1 a] and 1 b], rac-2-ethoxy-3-(1H-indol-4-yl)-propionic acid ethyl ester was reacted with methanesulfonic acid 2-(5-methyl-2-phenyl-oxazol-4-yl)-ethyl ester in N,N-dimethylformamide in the presence of sodium hydride to yield rac-2-ethoxy-3-{1-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethyl]-1H-indol-4-yl}-propionic acid ethyl ester, which was subsequently saponified to yield rac-2-ethoxy-3-{1-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethyl]-1H-indol-4-yl}-propionic acid as light yellow solid.
Reaction SMILES: [OH:1][C@@:2]1([CH2:22][CH:23]=[CH2:24])[C@@H:6]([O:7][Si:8]([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9])[CH2:5][N:4]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:3]1.[H-].[Na+].[CH3:27]N(C=O)C>>[Si:8]([O:7][C@H:6]1[CH2:5][N:4]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:3][C@:2]1([O:1][CH3:27])[CH2:22][CH:23]=[CH2:24])([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:9])[CH3:10]
Reactant: CN(C)C=O
Reactant: C=CC[C@@]1(O)CN(C(=O)OC(C)(C)C)C[C@@H]1O[Si](C)(C)C(C)(C)C
Agent: [H-]
Agent: [Na+]
Product: C=CC[C@@]1(OC)CN(C(=O)OC(C)(C)C)C[C@@H]1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of tert-butyl (3R,4S)-3-hydroxy-4-(tert-butyldimethylsilyl)oxy-3-(prop-2-en-1-yl)pyrrolidine-1-carboxylate (550 mg) in DMF (10 mL) was added iodemethane (2.2 g) at 0° C. After 10 min, 60% NaH in oil (62 mg) was added, and the mixture was stirred for 1 hour at room temperature. The reaction was quenched with saturated aqueous NH4Cl and the mixture was extracted with Et2O. The extract was washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was purified with silica gel column chromatography (eluent: hexane/EtOAc=1/0˜50/50) to give tert-butyl (3R,4S)-4-(tert-butyldimethylsilyl)oxy-3-methoxy-3-(prop-2-en-1-yl)pyrrolidine-1-carboxylate as a pale yellow foam.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH2:4][CH:5]2[CH2:10][N:9]([C:11]3[N:16]=[CH:15][C:14]([F:17])=[CH:13][N:12]=3)[CH2:8][C:6]2([C:18]2[CH:19]=[C:20]([NH:25][C:26]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][N:29]=3)=[O:27])[CH:21]=[CH:22][C:23]=2[F:24])[N:7]=1.CO.[ClH:37].C(OCC)C>C(=O)=O.ClCCl>[ClH:37].[NH2:1][C:2]1[S:3][CH2:4][C@@H:5]2[CH2:10][N:9]([C:11]3[N:16]=[CH:15][C:14]([F:17])=[CH:13][N:12]=3)[CH2:8][C@:6]2([C:18]2[CH:19]=[C:20]([NH:25][C:26]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][N:29]=3)=[O:27])[CH:21]=[CH:22][C:23]=2[F:24])[N:7]=1
Reactant: NC1=NC2(c3cc(NC(=O)c4ccc(F)cn4)ccc3F)CN(c3ncc(F)cn3)CC2CS1
Agent: Cl
Agent: O=C=O
Solvent: CO
Solvent: CCOCC
Solvent: ClCCl
Product: NC1=N[C@@]2(c3cc(NC(=O)c4ccc(F)cn4)ccc3F)CN(c3ncc(F)cn3)C[C@H]2CS1
Yield: 38 %

Procedure:
Racemic N-[3-[2-amino-6-(5-fluoropyrimidin-2-yl)-4,4a,5,7-tetrahydropyrrolo[3,4-d][1,3]thiazin-7a-yl]-4-fluoro-phenyl]-5-fluoro-pyridine-2-carboxamide (451 mg, 929 μmol) is chirally purified by SFC (Column: Chiralcel OD-H (5 um), 2.1×25 cm; eluent: 40% methanol (0.2% isopropylamine) in CO2; flow 70 mL/min at UV 225 nm). Chiral analysis of the first eluting isomer: Column: Chiralcel OD-H (5 μm), 4.6×150 mm; eluent: 40% methanol (0.2% isopropylamine) in CO2; flow 5 mL/min at UV 225 nm confirms the enantiomerically enriched (>99% ee) enantiomer with Rt=1.01 minutes (175 mg, 360 μmoles). This material (free base, isomer 1) is dissolved in dichloromethane (1 mL) and methanol (0.5 mL) and 1 M hydrogen chloride in diethyl ether (0.36 mL, 360 μmoles) is added. The solvent is removed in vacuo to give the title compound (183 mg, 38%). ES/MS (m/e): 486 (M+H).
Reaction SMILES: [CH2:1]([N:5]1[CH:10]=[CH:9][C:8]([CH:11]=[CH:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:7][C:6]1=[O:18])[CH2:2][CH2:3][CH3:4].[H][H]>C(O)C.[Pd]>[CH2:1]([N:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:7][C:6]1=[O:18])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1ccc(C=CC(=O)OCC)cc1=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCCCn1ccc(CCC(=O)OCC)cc1=O
Yield: 97 %

Procedure:
Ethyl β-(N-n-butyl-2-oxo-4-pyridyl)acrylate (59.50 g) in ethanol (150 ml) was hydrogenated over 5% palladium on charcoal (0.45 g) at 315 KPa (45 psi), with gentle warming. When the theoretical uptake of hydrogen had been exceeded the reaction mixture was filtered and the filtrate evaporated under reduced pressure to afford an oil. This oil was washed with petroleum ether (40°-60°) to yield ethyl β-(N-n-butyl-2-oxo-4-pyridyl)propionate (58.19 g).
Reaction SMILES: [Cl:1][C:2]1[C:3](C(N)=O)=[N:4][CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]([C:18]2[C:19](=[O:31])[N:20]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:21]([CH3:24])[C:22]=2[CH3:23])=[O:17])=[C:11]([F:32])[CH:10]=1.C(OI(C1C=CC=CC=1)OC(=O)C)(=O)C.CC#[N:53]>CCOC(C)=O.O>[NH2:53][C:3]1[C:2]([Cl:1])=[C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([C:18]3[C:19](=[O:31])[N:20]([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)[N:21]([CH3:24])[C:22]=3[CH3:23])=[O:17])=[C:11]([F:32])[CH:10]=2)[CH:6]=[CH:5][N:4]=1
Reactant: CC#N
Reactant: Cc1c(C(=O)Nc2ccc(Oc3ccnc(C(N)=O)c3Cl)cc2F)c(=O)n(-c2ccccc2)n1C
Agent: CC(=O)OI(OC(C)=O)c1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1c(C(=O)Nc2ccc(Oc3ccnc(N)c3Cl)cc2F)c(=O)n(-c2ccccc2)n1C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 47 %

Procedure:
A suspension of 3-chloro-4-(4-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamido)-3-fluorophenoxy)picolinamide (379 mg, 0.764 mmol) in EtOAc (4.5 mL), CH3CN (4.5 mL) and H2O (2.5 mL) was cooled and stirred at 0° C. for 30 minutes, then PhI(OAc)2 (295 mg, 0.917 mmol) was added and the mixture was stirred for another 30 minutes at 0° C., then allowed to warmed up to rt and stirred for another 10 hours. Filtered and the filter cake was washed with EtOAc (5 mL). The filtrate was concentrated in vacuo and the residue was purified by a silica gel column chromatography (CH2Cl2/MeOH (v/v)=50/1) to give the title compound as a yellow solid (150 mg, 47.0%).
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][CH:21]4[CH2:26][CH2:25][CH:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH:6]=[CH:5]1.[CH3:28][O:29][CH2:30][C:31](O)=[O:32]>>[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:31](=[O:32])[CH2:30][O:29][CH3:28])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH:6]=[CH:5]1
Reactant: NC1CCC(CCN2CCN(c3nccc4ccoc34)CC2)CC1
Reactant: COCC(=O)O
Agent: Cl
Product: COCC(=O)N[C@H]1CC[C@H](CCN2CCN(c3nccc4ccoc34)CC2)CC1

Procedure:
The title compound, white solid (54 mg, 67%), MS (ISP) m/z=401.4 [(M+H)+], mp 132° C., was prepared in accordance with the general method of example 6 from 4-[2-(4-furo[2,3-c]pyridin-7-yl-piperazin-1-yl)-ethyl]-cyclohexylamine trihydrochloride (intermediate C) (88 mg, 0.2 mmol) and methoxy-acetic acid.