Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH2:5][C:6](=[O:31])[CH2:7][NH:8][C@@H:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][C@H:10]1[NH:18][C:19]([C:21]1[NH:22][C:23]2[C:28]([CH:29]=1)=[CH:27][C:26]([Cl:30])=[CH:25][CH:24]=2)=[O:20]>C1COCC1>[C:1]([N:8]([CH2:7][C:6]([NH2:5])=[O:31])[C@@H:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][C@H:10]1[NH:18][C:19]([C:21]1[NH:22][C:23]2[C:28]([CH:29]=1)=[CH:27][C:26]([Cl:30])=[CH:25][CH:24]=2)=[O:20])(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: NC(=O)CN[C@@H]1c2ccccc2C[C@H]1NC(=O)c1cc2cc(Cl)ccc2[nH]1
Solvent: C1CCOC1
Product: CC(=O)N(CC(N)=O)[C@@H]1c2ccccc2C[C@H]1NC(=O)c1cc2cc(Cl)ccc2[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 29.4 %

Procedure:
Acetyl chloride (20 μL, 0.32 mmol) was added to a solution of N-{(1R,2R)-1-[(2-amino-2-oxoethyl)amino]-2,3-dihydro-1H-inden-2-yl}-5-chloro-1H-indole-2-carboxamide (Example 27, 122 mg, 0.32 mmol) in THF (10 mL). The reaction was stirred at ambient temperature for 1 h. The volatiles were removed by evaporation under reduced pressure the residue dissolved in EtOAc (50 mL), washed with water (2×10 mL), brine (10 mL) and dried (MgSO4). The volatiles were removed by evaporation under reduced pressure to afford the title compound (40 mg, 29%) as a white solid.
Reaction SMILES: Cl.[CH:2]([N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH:15]3[CH2:20][CH2:19][N:18]([CH:21]([CH3:23])[CH3:22])[CH2:17][CH2:16]3)=[CH:11][CH:12]=2)[CH:7]=[C:6]1[C:24]([N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)=[O:25])([CH3:4])[CH3:3].[CH2:32]([N:34]([CH2:38][CH3:39])[C:35](Cl)=[O:36])[CH3:33]>>[CH2:32]([N:34]([CH2:38][CH3:39])[C:35]([N:29]1[CH2:28][CH2:27][N:26]([C:24]([C:6]2[N:5]([CH:2]([CH3:3])[CH3:4])[C:13]3[C:8]([CH:7]=2)=[CH:9][C:10]([O:14][CH:15]2[CH2:20][CH2:19][N:18]([CH:21]([CH3:23])[CH3:22])[CH2:17][CH2:16]2)=[CH:11][CH:12]=3)=[O:25])[CH2:31][CH2:30]1)=[O:36])[CH3:33]
Reactant: CC(C)N1CCC(Oc2ccc3c(c2)cc(C(=O)N2CCNCC2)n3C(C)C)CC1
Reactant: CCN(CC)C(=O)Cl
Agent: Cl
Product: CCN(CC)C(=O)N1CCN(C(=O)c2cc3cc(OC4CCN(C(C)C)CC4)ccc3n2C(C)C)CC1

Procedure:
The title compound was prepared in analogy to example 51, from [1-isopropyl-5-(1-isopropyl-piperidin-4-yloxy)-1H-indol-2-yl]-piperazin-1-yl-methanone hydrochloride and N,N-diethylcarbamoyl chloride. Off-white solid. MS (m/z): 512.5 (M+H)+.
Reaction SMILES: C[O:2][C:3](=[O:30])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][N:13]2[C:17](=[O:18])[CH2:16][CH2:15][CH:14]2[CH2:19][CH2:20][CH:21]([OH:29])[CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:6][CH:5]=1.[OH-].[Na+]>CO>[OH:29][CH:21]([CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[CH2:20][CH2:19][CH:14]1[CH2:15][CH2:16][C:17](=[O:18])[N:13]1[CH2:12][CH2:11][CH2:10][C:7]1[CH:6]=[CH:5][C:4]([C:3]([OH:30])=[O:2])=[CH:9][CH:8]=1
Reactant: COC(=O)c1ccc(CCCN2C(=O)CCC2CCC(O)Cc2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc(CCCN2C(=O)CCC2CCC(O)Cc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 92.2 %

Procedure:
To a solution of 4-{3-[2-(3-hydroxy-4-phenyl-butyl)-5-oxo-pyrrolidin-1-yl]-propyl}-benzoic acid methyl ester (2.28 g, 5.57 mmol) in MeOH (20 mL) was added 2N NaOH (5 mL). The reaction mixture was stirred at room temperature for 20 h and was heated under reflux for 3 h. The volatiles were removed in vacuo and the residue was diluted with CH2Cl2 and 1N HCl. The aqueous solution was extracted with CH2Cl2 (2×) and the combined organic extracts were washed with brine. The organic solution was dried (MgSO4), filtered and concentrated to yield the title compound (2.03 g). 1H NMR (CDCl3) δ7.98 (d, 2H), 7.34–7.18 (m, 7H), 3.80 (m, 1H), 3.67 (m, 1H), 3.58 (m, 1H), 2.97 (m, 1H), 2.81 (m, 1H), 2.68 (m, 3H), 2.45–2.27 (m, 2H), 2.13–1.30 (m, 9H); MS 396.3 (M+1), 394.2 (M−1).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([O:20][CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)[C:5]2[C:10](I)=[CH:9][N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:6]=2[N:7]=1.[CH3:26][C:27]1[O:28][C:29]2[CH:35]=[C:34](B3OC(C)(C)C(C)(C)O3)[CH:33]=[CH:32][C:30]=2[N:31]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O>O1CCOCC1>[Cl:1][C:2]1[N:3]=[C:4]([O:20][CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)[C:5]2[C:10]([C:34]3[CH:33]=[CH:32][C:30]4[N:31]=[C:27]([CH3:26])[O:28][C:29]=4[CH:35]=3)=[CH:9][N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:6]=2[N:7]=1
Reactant: C[Si](C)(C)CCOCn1cc(I)c2c(OC3CCCC3)nc(Cl)nc21
Reactant: Cc1nc2ccc(B3OC(C)(C)C(C)(C)O3)cc2o1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1nc2ccc(-c3cn(COCC[Si](C)(C)C)c4nc(Cl)nc(OC5CCCC5)c34)cc2o1
Temperature: 90 °C
Yield: 42 %

Procedure:
To a mixture of 2-chloro-4-(cyclopentyloxy)-5-iodo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (1 equiv), 2-methyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzooxazole (1 equiv), tripotassium phosphate trihydrorate (3 equiv) in 1,4-dioxane and water (8:1, 0.5 M) was added 1,1-bis(diphenylphosphion)ferrocene palladium dichloride (0.1 equiv). The mixture was refluxed at 90° C. for 2 h. Filtration and concentration gave the crude product, which was purified by silica gel column chromatography (20% ethyl acetate in petroleum ether) to afford the title compound (42% yield). MS (ESI) m/z 498.2 [M+1]+.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([CH:17]=[O:18])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:19]([Mg]Br)[CH3:20]>C1COCC1>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([CH:17]([OH:18])[CH2:19][CH3:20])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=CC1CCN(C(=O)OCc2ccccc2)CC1
Reactant: CC[Mg]Br
Solvent: C1CCOC1
Product: CCC(O)C1CCN(C(=O)OCc2ccccc2)CC1
Reaction time: 1 h
Yield: 61.6 %

Procedure:
To a solution of 4-formylpiperidine-1-carboxylic acid benzyl ester (1.0 g, 4.04 mmol) in THF (15 mL) at 0° C. was added ethylmagnesium bromide (1.0M in THF, 8.1 mL, 8.08 mmol) and the mixture was stirred at 0° for 1 h. The reaction mixture was then quenched with water and extracted with EtOAc. The organic phase was washed with brine, dried (MgSO4) and then concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, gradient 0-100% EtOAc in hexane) affording 4-(1-Hydroxypropyl)piperidine-1-carboxylic acid benzyl ester (690 mg, 62%). 1H NMR (CDCl3, 400 MHz): δ 7.38-7.27 (5H, m), 5.13 (2H, bs), 4.25 (2H, s), 3.36-3.29 (1H, m), 2.83-2.66 (2H, m), 1.85-1.77 (1H, bd, J=13.16 Hz), 1.64-1.19 (7H, m), 0.97 (3H, t, J=7.41 Hz).
Reaction SMILES: [N:1]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[NH:4][CH2:3][CH2:2]2.C(N(CC)CC)C.Cl[C:18]([O:20][C:21]1[CH:26]=[CH:25][C:24]([Br:27])=[CH:23][CH:22]=1)=[O:19]>ClCCl>[N:1]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[N:4]([C:18]([O:20][C:21]1[CH:26]=[CH:25][C:24]([Br:27])=[CH:23][CH:22]=1)=[O:19])[CH2:3][CH2:2]2
Reactant: C1CN2CCC(CC2)N1
Reactant: O=C(Cl)Oc1ccc(Br)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Oc1ccc(Br)cc1)N1CCN2CCC1CC2
Temperature: 0 °C

Procedure:
0.379 g (3.0 mmol) of 1,4-diazabicyclo[3.2.2]nonane and 0.84 ml (6.0 mmol) of triethylamine in 5 ml of dichloromethane are introduced into a 50-ml three-necked flask, the mixture is cooled to 0° C., 0.730 mg (3.1 mmol) of 4-bromophenyl chloroformate in solution in 3 ml of dichloromethane is added dropwise and the stirring is maintained at 0° C. for 10 min.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[CH2:18]([N:20]=[C:21]=[S:22])[CH3:19]>>[CH2:18]([NH:20][C:21]([NH:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1)=[S:22])[CH3:19]
Reactant: CCN=C=S
Reactant: CN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Product: CCNC(=S)Nc1ccc2[nH]cc(C3CCN(C)CC3)c2n1
Yield: 15.5 %

Procedure:
Beginning with 0.15 gm (0.65 mMol) 5-amino-3-(1-methylpiperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.068 mL (0.78 mMol) ethyl isothiocyanate, 0.032 gm (10%) of the title compound were recovered essentially by the procedure of Example 122. An analytical sample was crystallized from aqueous ethanol.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][N:13]=[C:14]([C:19]([OH:21])=[O:20])[CH2:15][CH2:16][O:17][CH3:18])[CH2:9][N:8]=[C:7]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[Cl:28])[C:6]=2[CH:29]=1.[N+](=[CH2:32])=[N-]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][N:13]=[C:14]([C:19]([O:21][CH3:32])=[O:20])[CH2:15][CH2:16][O:17][CH3:18])[CH2:9][N:8]=[C:7]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[Cl:28])[C:6]=2[CH:29]=1
Reactant: COCCC(=NNC1=Nc2ccc(Br)cc2C(c2ccccc2Cl)=NC1)C(=O)O
Reactant: C=[N+]=[N-]
Product: COCCC(=NNC1=Nc2ccc(Br)cc2C(c2ccccc2Cl)=NC1)C(=O)OC

Procedure:
In the manner given in Example 10, 7-bromo-2-[(1-carboxy-3-methoxypropylidene)hydrazino]-5-(o-chlorophenyl)-3H-1,4-benzodiazepine can be treated with ethereal diazomethane to give 7-bromo-2-[[1-(methoxycarbonyl)-3-methoxypropylidene]hydrazino]-5-(o-chlorophenyl)-3H-1,4-benzodiazepine.
Reaction SMILES: [ClH:1].Cl.[Cl:3][C:4]1C(C2SC3C=CC=C(C(N)=O)C=3C=2)=NC(NCCC2CCN(C)CC2)=NC=1.[CH:32]1([NH:35][C:36]([C:38]2[C:46]3[CH:45]=[C:44]([C:47]4[C:52]([Cl:53])=[CH:51][N:50]=[C:49]([NH:54][CH2:55][CH2:56][N:57]5[CH2:62][CH2:61][NH:60][CH2:59][C@H:58]5[CH3:63])[N:48]=4)[S:43][C:42]=3[CH:41]=[CH:40][CH:39]=2)=[O:37])[CH2:34][CH2:33]1>>[ClH:3].[ClH:53].[ClH:1].[CH:32]1([NH:35][C:36]([C:38]2[C:46]3[CH:45]=[C:44]([C:47]4[C:52]([Cl:53])=[CH:51][N:50]=[C:49]([NH:54][CH2:55][CH2:56][N:57]5[CH2:62][CH2:61][N:60]([CH3:4])[CH2:59][C@H:58]5[CH3:63])[N:48]=4)[S:43][C:42]=3[CH:41]=[CH:40][CH:39]=2)=[O:37])[CH2:33][CH2:34]1
Reactant: CN1CCC(CCNc2ncc(Cl)c(-c3cc4c(C(N)=O)cccc4s3)n2)CC1
Reactant: C[C@@H]1CNCCN1CCNc1ncc(Cl)c(-c2cc3c(C(=O)NC4CC4)cccc3s2)n1
Agent: Cl
Product: C[C@@H]1CN(C)CCN1CCNc1ncc(Cl)c(-c2cc3c(C(=O)NC4CC4)cccc3s2)n1

Procedure:
Using the method of 2-{5-chloro-2-[2-(1-methylpiperidin-4-yl)-ethylamino]-pyrimidin-4-yl}-benzo[b]thiophene-4-carboxylic acid amide di-hydrochloride, the title compound is synthesized from (R)-2-{5-chloro-2-[2-(2-methyl-piperazin-1-yl)-ethylamino]-pyrimidin-4-yl}-benzo[b]thiophene-4-carboxylic acid cyclopropylamide and isolated as a yellow solid. ES+(m/z) 485 (35Cl) and 487 (37Cl) [M(free base)+H].
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][C:9]1([OH:12])[CH2:11][CH2:10]1.[C:13](O)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CCN=C=NCCCN(C)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:13]([O:12][C:9]1([CH2:8][O:7][CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][O:1]2)[CH2:10][CH2:11]1)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: OC1(COC2CCCCO2)CC1
Reactant: O=C(O)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: O=C(OC1(COC2CCCCO2)CC1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70 %

Procedure:
To a mixture of 1-((tetrahydro-2H-pyran-2-yloxy)methyl)cyclopropanol (1.6 g, 9.3 mmol) and benzoic acid (1.25 g, 11.16 mmol, Shanghai Haiqu chemical Ltd.) in 50 mL of CH2Cl2 was added DMAP (227 mg, 1.86 mmol, Shanghai Haiqu chemical Ltd.) and EDCI (2.73 g, 14.25 mmol, Shanghai Haiqu chemical Ltd.) at rt. The reaction mixture was stirred at rt overnight, then concentrated and purified by a silica gel column chromatography (20:1 (v/v) petroleum ether/EtOAc)) to afford the title compound as colorless oil (1.8 g, 70%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH:8]([CH2:12][NH2:13])[CH2:7]1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]=[C:26]=[O:27])=[CH:21][CH:20]=1>>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:13][CH2:12][CH:8]2[O:9][CH2:10][CH2:11][N:6]([CH2:5][C:4]3[CH:14]=[CH:15][C:16]([Cl:17])=[C:2]([Cl:1])[CH:3]=3)[CH2:7]2)=[O:27])=[CH:21][CH:20]=1
Reactant: NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Reactant: O=C=Nc1ccc(Cl)cc1
Product: O=C(NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1)Nc1ccc(Cl)cc1

Procedure:
Example 14 was prepared in an analogous manner to Example 1 using a mixture of Intermediate 3 (0.025 g) and 1-chloro-4-isocyanatobenzene (17.4 μl) to give the title compound (0.0275 g). LC-MS (System A): Rt 2.45 mins, Mass Spectrum m/z 428 [MH+].
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][S:16]([NH:19][CH2:20][C:21]#[CH:22])(=[O:18])=[O:17])=[CH:11][CH:10]=2)[C:5]([F:23])=[CH:4][N:3]=1.[NH2:24][C:25]1[CH:26]=[C:27]([S:31]([NH2:34])(=[O:33])=[O:32])[CH:28]=[CH:29][CH:30]=1.FC(F)(F)C(O)=O.CC(O)C>Cl>[NH2:34][S:31]([C:27]1[CH:26]=[C:25]([NH:24][C:2]2[N:7]=[C:6]([NH:8][C:9]3[CH:14]=[CH:13][C:12]([CH2:15][S:16]([NH:19][CH2:20][C:21]#[CH:22])(=[O:18])=[O:17])=[CH:11][CH:10]=3)[C:5]([F:23])=[CH:4][N:3]=2)[CH:30]=[CH:29][CH:28]=1)(=[O:32])=[O:33]
Reactant: Nc1cccc(S(N)(=O)=O)c1
Reactant: C#CCNS(=O)(=O)Cc1ccc(Nc2nc(Cl)ncc2F)cc1
Agent: Cl
Solvent: CC(C)O
Solvent: O=C(O)C(F)(F)F
Product: C#CCNS(=O)(=O)Cc1ccc(Nc2nc(Nc3cccc(S(N)(=O)=O)c3)ncc2F)cc1
Temperature: 100 °C

Procedure:
2-Chloro-5-fluoro-N4-[4-(prop-2-ynylaminosulfonylmethyl)phenyl]-4-pyrimidineamine (34 mg, 0.096 mmol), 3-aminobenzenesulfonamide (33 mg, 0.19 mmol), and trifluoroacetic acid (11 μL, 0.14 mmol) were combined with iPrOH (0.40 mL) in a sealed vial and heated at 100° C. for 4 h. The reaction mixture was cooled to room temperature and diluted with 1N HCl (80 mL). The crude product was isolated by filtration. Further purified by column chromatography (silica gel, dichloromethane ramped to methanol:dichloromethane (3:100)) provided N2-(3-aminosulfonylphenyl)-5-fluoro-N4-[4-(prop-2-ynylaminosulfonylmethyl)phenyl]-2,4-pyrimidinediamine (I-4) as an off-white solid. 1H NMR (DMSO-d6): δ 9.57 (s, 1H), 9.47 (s, 1H), 8.15-8.08 (m, 2H), 7.99-7.95 (m, 1H), 7.84 (d, J=8.4 Hz, 2H), 7.62 (t, J=5.7 Hz, 1H), 7.43-7.32 (m, 4H), 7.26 (s, 2H), 4.35 (s, 2H), 3.79-3.75 (m, 2H), 3.35 (t, J=2.4 Hz, 1H); LCMS: purity: 96%; MS (m/e): 492 (MH+).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH3:12][C:13](OC(C)=O)=[O:14]>>[CH:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:11]=[C:2]([NH:1][C:13](=[O:14])[CH3:12])[N:3]=1
Reactant: Nc1cc2ccccc2cn1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Nc1cc2ccccc2cn1
Temperature: 25 °C

Procedure:
3-Aminoisoquinoline (495 mg, 3.44 mmol) was stirred in Ac2O (9 mL) at 60° for 16 hours. The mixture was cooled to room temperature and concentrated in vacuo to provide the title compound which was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[C@@H:10]1[N:14]2[CH:15]=[N:16][CH:17]=[C:13]2[C:12]([OH:31])([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24]C3CCCCO3)[CH:19]=2)[CH2:11]1)[C:5]#[N:6].Cl.CCOCC>CO>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[C@@H:10]1[N:14]2[CH:15]=[N:16][CH:17]=[C:13]2[C@@:12]([OH:31])([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([OH:24])[CH:19]=2)[CH2:11]1)[C:5]#[N:6]
Reactant: N#Cc1ccc([C@H]2CC(O)(c3cccc(OC4CCCCO4)c3)c3cncn32)c(F)c1
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: N#Cc1ccc([C@H]2C[C@](O)(c3cccc(O)c3)c3cncn32)c(F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 34.1 %

Procedure:
To a solution of 3-fluoro-4-((5R)-7-hydroxy-7-(3-(tetrahydro-2H-pyran-2-yloxy)phenyl)-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl)benzonitrile (1.87 g, 4.46 mmol) in anhydrous MeOH (372 ml) was added a 2M solution of hydrochloric acid in ether (9.59 ml, 19.18 mmol) at room temperature. The crude was stirred at room temperature for 2 hrs. The crude was concentrated and quenched with saturated NaHCO3. The crude was diluted in CH2Cl2 and the organic layer was washed with water, brine, dried over MgSO4, filtered, and concentrated. The crude was purified via HPLC 20%-100% MeCN/H2O to provide 510 mg of the entitled product as the major diastereomer. MS 336.0 (M+H); LCMS condition A, retention time 0.96 min. 1H NMR (400 MHz, CDCl3) δ ppm 2.90 (d, 1H), 3.22 (dd, 1H), 5.65 (d, 1H), 6.65-6.72 (m, 2H), 6.90 (s, 1H), 7.02-7.09 (m, 2H), 7.15-7.21 (m, 2H), 7.24 (s, 1H), 7.32 (dd, 2H).
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH2:20](I)[CH3:21].C(=O)([O-])[O-].[Cs+].[Cs+]>>[CH2:20]([N:10]1[C:11](=[O:13])[CH:12]=[C:7]([N:1]2[CH2:2][CH2:3][O:4][CH2:5][CH2:6]2)[N:8]=[C:9]1[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH3:21]
Reactant: CCOC(=O)Cc1nc(N2CCOCC2)cc(=O)[nH]1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CCOC(=O)Cc1nc(N2CCOCC2)cc(=O)n1CC

Procedure:
The product is prepared according to the procedure described in example 67, using 600 mg of ethyl [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate prepared in stage 1 of example 1 and 0.23 ml of ethyl iodide in place of the methyl iodide, and replacing the potassium carbonate with cesium carbonate. After purification by silica column chromatography, eluent: 96/02/02 CH2Cl2/CH3CN/MeOH, 190 mg of ethyl [1-ethyl-4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate are obtained in the form of a white solid the characteristics of which are the following:
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C:6]2=[N:7][C:8]=1[CH3:9]>C(Cl)Cl.C(OCC)(=O)C.[O-2].[O-2].[Mn+4]>[CH3:9][C:8]1[N:7]=[C:6]2[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:5]2=[CH:4][C:3]=1[CH:2]=[O:1]
Reactant: Cc1nc2c(cc1CO)CCCCC2
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1nc2c(cc1C=O)CCCCC2
Reaction time: 4 h
Yield: 72.5 %

Procedure:
In an atmosphere of argon, 3-hydroxymethyl-2-methyl-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridine (5.24 g, 27.4 mmol) was dissolved in methylene chloride (150.0 ml), and the solution was mixed with manganese dioxide (15.88 g, 137.0 mmol) at room temperature and stirred at the same temperature for 4 hours. The reaction solution was diluted with ethyl acetate and then filtered. The solvent in the resulting filtrate was evaporated under reduced pressure and the resulting residue was purified by a silica gel column chromatography (ethyl acetate:hexane=1:1) to obtain the title compound (3.76 g, 74.0%) as white powder.
Reaction SMILES: [NH2:1][C:2]1[C:7](I)=[CH:6][C:5]([C:9]2[O:13][CH:12]=[N:11][CH:10]=2)=[C:4]([O:14][CH3:15])[CH:3]=1.[C:16]([C:18]1[N:19]=[CH:20][S:21][CH:22]=1)#[CH:17]>C(NCC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:15][O:14][C:4]1[CH:3]=[C:2]2[C:7]([CH:17]=[C:16]([C:18]3[N:19]=[CH:20][S:21][CH:22]=3)[NH:1]2)=[CH:6][C:5]=1[C:9]1[O:13][CH:12]=[N:11][CH:10]=1
Reactant: C#Cc1cscn1
Reactant: COc1cc(N)c(I)cc1-c1cnco1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCNCC
Product: COc1cc2[nH]c(-c3cscn3)cc2cc1-c1cnco1
Temperature: 120 °C
Yield: 23.5 %

Procedure:
To a solution of 5-(4-amino-5-iodo-2-methoxyphenyl)oxazole (WO 0181340) (0.293 g, 0.93 mmol) in diethylamine (2.5 mL) was added 4-ethynylthiazole (0.118 g, 1.08 mmol) and bis(triphenylphosphine)palladiumdichloride (0.019 g, 0.027 mmol). The contents were purged with nitrogen and heated in a steel bomb at 120° C. for 20 minutes. The reaction mixture was cooled to rt and purified by silica gel column chromatography to provide the title compound (0.065 g, 20%). HPLC Ret. t=2.79 min. (A); LC/MS M+1=298.27.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([C:19]4[C:23]([C:24]5[CH:29]=[CH:28][N:27]=[C:26]([S:30][CH3:31])[N:25]=5)=[CH:22][N:21](C5CCCCO5)[N:20]=4)[CH:18]=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.P([O-])([O-])([O-])=O>CO.O1CCOCC1>[CH3:31][S:30][C:26]1[N:25]=[C:24]([C:23]2[C:19]([C:17]3[CH:18]=[C:13]4[CH:12]=[CH:11][N:10]([S:7]([C:1]5[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=5)(=[O:8])=[O:9])[C:14]4=[N:15][CH:16]=3)=[N:20][NH:21][CH:22]=2)[CH:29]=[CH:28][N:27]=1
Reactant: CSc1nccc(-c2cn(C3CCCCO3)nc2-c2cnc3c(ccn3S(=O)(=O)c3ccccc3)c2)n1
Agent: Cl
Agent: O=P([O-])([O-])[O-]
Solvent: CO
Solvent: C1COCCO1
Product: CSc1nccc(-c2c[nH]nc2-c2cnc3c(ccn3S(=O)(=O)c3ccccc3)c2)n1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 98.4 %

Procedure:
To a solution of the 1-Benzenesulfonyl-5-[4-(2-methylsulfanyl-pyrimidin-4-yl)-1-(tetrahydro-pyran-2-yl)-1H-pyrazol-3-yl]-1H-pyrrolo[2,3-b]pyridine (C-1-2) (750 mg, 1.41 mmol) in MeOH (1 mL) was added a solution of HCl in Dioxane (˜4N, 0.1 mL). After stirring at ambient temperature for 45 minutes, the solution was dropped into phosphate buffer (pH 7, 15 mL). The resulting precipitate was collected by filtration, rinsed with water and air dried to give 5-{4-[2-(methylthio)pyrimidin-4-yl]-1H-pyrazol-3-yl}-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (C-1-3) (622 mg, 98%) which was carried on without further purification. 1H NMR (400 MHz, ACETONITRILE-d3) δ ppm 11.51 (br. s., 1H), 8.47 (d, J=2.02 Hz, 1H), 8.34 (d, J=5.05 Hz, 1H), 8.23 (br. s., 1H), 8.14 (d, J=7.58 Hz, 2H), 8.10 (d, J=1.77 Hz, 1H), 7.84 (d, J=2.78 Hz, 1H), 7.68 (t, J=7.45 Hz, 1H), 7.57 (t, J=7.71 Hz, 2H), 7.07 (d, J=4.80 Hz, 1H), 6.75 (d, J=3.79 Hz, 1H), 1.81 (s, 3H).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:7]([NH2:19])[CH:6]=1)(=[O:3])[CH3:2].C(N(CC)CC)C.[C:27]1([S:33](Cl)(=[O:35])=[O:34])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(Cl)Cl>[C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:7]([NH:19][S:33]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)(=[O:35])=[O:34])[CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccc(OCc2ccccc2)c(N)c1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Oc1ccc(OCc2ccccc2)c(NS(=O)(=O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 5.0 g (0.0194 mol) of 4-benzyloxy-3-aminophenyl acetate, 3.3 ml (0.0236 mol) of triethylamine and 3.0 ml (0.0236 mol) of benzenesulphonyl chloride in 150 ml of methylene chloride is stirred at room temperature overnight. The mixture is then washed with water and the organic phase is dried, followed by purification by chromatography on a silica gel column, eluting with a 7/3 cyclohexane/ethyl acetate mixture. The compound of the title is obtained.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][O:15][C:16]1[CH:31]=[CH:30][C:19]([CH2:20][CH:21]([C:26]([O:28][CH3:29])=[O:27])[C:22]([O:24][CH3:25])=[O:23])=[CH:18][CH:17]=1.[H-].[Na+].[CH3:34]I.S([O-])(O)(=O)=O.[Na+]>CN(C)C=O>[CH3:34][C:21]([CH2:20][C:19]1[CH:18]=[CH:17][C:16]([O:15][CH2:14][CH2:13][C:3]2[N:4]=[C:5]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)[O:6][C:2]=2[CH3:1])=[CH:31][CH:30]=1)([C:26]([O:28][CH3:29])=[O:27])[C:22]([O:24][CH3:25])=[O:23]
Reactant: COC(=O)C(Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1)C(=O)OC
Reactant: CI
Agent: O=S(=O)([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(C)(Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1)C(=O)OC
Reaction time: 2 h
Yield: 61.9 %

Procedure:
Dimethyl 4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]benzylmalonate (4.24 g, 10.0 mmol) synthesized according to the method described in WO95/18125 was dissolved in dimethylformamide (40 ml), and sodium hydride (60% in oil, 480 mg, 12.0 mmol) was added at 0° C., which was followed by stirring for 2 hr. Methyl iodide (0.93 ml, 15.0 mmol) was added at room temperature and, 2.5 hours later, 1N sodium hydrogensulfate (100 ml) was added. The mixture was extracted three times with ethyl acetate. The extracted organic layer was washed with brine, dried over sodium sulfate and concentrated to dryness to give a crude title compound, which was purified and concentrated by silica gel column chromatography (developing solvent; hexane:ethyl acetate=10:1→7:1→5:1) to give the title compound (2.71 g, yield 62%) as a white solid.