Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:35])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([N:13]([CH2:30][CH2:31][CH2:32][CH3:33])[C:14]2[N:15]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[N:16]=[C:17]3[C:22]=2[CH:21]=[CH:20][CH:19]=[CH:18]3)=[O:12])=[C:6]([Cl:34])[CH:5]=1.[OH-].[Li+]>C1COCC1.CO>[CH2:30]([N:13]([C:14]1[N:15]([C:23]2[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=2)[N:16]=[C:17]2[C:22]=1[CH:21]=[CH:20][CH:19]=[CH:18]2)[C:11](=[O:12])[NH:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]([OH:35])=[O:2])=[CH:5][C:6]=1[Cl:34])[CH2:31][CH2:32][CH3:33]
Reactant: CCCCN(C(=O)Nc1ccc(C(=O)OC)cc1Cl)c1c2ccccc2nn1-c1ccc(Cl)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCCCN(C(=O)Nc1ccc(C(=O)O)cc1Cl)c1c2ccccc2nn1-c1ccc(Cl)cc1

Procedure:
In analogy to the procedure described in example 2.2, 4-{3-butyl-3-[2-(4-chloro-phenyl)-2H-indazol-3-yl]-ureido}-3-chloro-benzoic acid methyl ester was treated with 1 N aqueous lithium hydroxide solution in THF/MeOH 1/1 for 14 h at ambient temperature to give the title compound as colorless foam. MS: m/e=496.1 [M−H−].
Reaction SMILES: [N:1]1([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5][CH:4]([C:7]([O-:9])=O)[CH2:3][CH2:2]1.[NH2:17][CH:18]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)O>>[C:27]1([C:18]2[N:17]=[C:7]([CH:4]3[CH2:3][CH2:2][N:1]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]3)[O:9][C:19]=2[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)[O-])CC1
Reactant: NC(c1ccccc1)C(O)c1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(c2nc(-c3ccccc3)c(-c3ccccc3)o2)CC1

Procedure:
Starting from 1.08 g mono-tert-butyl piperidine-1,4-dicarboxylate and 1 g 2-amino-1,2-diphenyl-ethanol the product may be obtained as described in the literature (see Tet. 2001, 4867). The product is purified by chromatography (method B). 560 mg are obtained as an oil. Analytical HPLC-MS (method A): RT=1.72 min.
Reaction SMILES: [CH3:1][CH:2]([CH3:34])[C:3]([NH:5][NH:6][C:7]([CH:9]1[CH2:14][CH:13]([C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=2)[CH2:12][N:11]([C:26]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[O:27])[CH2:10]1)=O)=O.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:44])=CC=1>>[N:28]1([C:26]([N:11]2[CH2:12][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)[CH2:14][CH:9]([C:7]3[S:44][C:3]([CH:2]([CH3:34])[CH3:1])=[N:5][N:6]=3)[CH2:10]2)=[O:27])[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1
Reactant: CC(C)C(=O)NNC(=O)C1CC(c2ccc(OC(F)(F)F)cc2)CN(C(=O)N2CCOCC2)C1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Product: CC(C)c1nnc(C2CC(c3ccc(OC(F)(F)F)cc3)CN(C(=O)N3CCOCC3)C2)s1

Procedure:
79 mg (0.155 mmol) of the compound from Example 122A and 126 mg (0.310 mmol) of Lawesson reagent were reacted according to the General Method 9. Yield: 17 mg (22% of theory)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2([CH3:24])[O:23][C:17]3=[CH:18][N:19]=[C:20](Cl)[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].F[C:26]1[CH:31]=[C:30]([CH2:32][S:33]([CH3:36])(=[O:35])=[O:34])[CH:29]=[CH:28][C:27]=1B(O)O>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2([CH3:24])[O:23][C:17]3=[CH:18][N:19]=[C:20]([C:27]4[CH:28]=[CH:29][C:30]([CH2:32][S:33]([CH3:36])(=[O:35])=[O:34])=[CH:31][CH:26]=4)[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(C2(C)Cc3cc(Cl)ncc3O2)CC1
Reactant: CS(=O)(=O)Cc1ccc(B(O)O)c(F)c1
Product: CC(C)(C)OC(=O)N1CCC(C2(C)Cc3cc(-c4ccc(CS(C)(=O)=O)cc4)ncc3O2)CC1

Procedure:
The title compound is prepared from 4-(5-chloro-2-methyl-2,3-dihydro-furo[2,3-c]pyridin-2-yl)-piperidine-1-carboxylic acid tert-butyl ester and 2-fluoro-4-(methylsulfonylmethyl)phenylboronic acid following a procedure analogous to that described in Example 28. LC (method 6): tR=1.14 min; Mass spectrum (ESI+): m/z=505 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8]([C:10]2[C:11](Cl)=[N:12][C:13]([Cl:16])=[N:14][CH:15]=2)=O)[CH:5]=[CH:4][CH:3]=1.[NH2:18][NH2:19]>C1COCC1>[Br:1][C:2]1[N:7]=[C:6]([C:8]2[C:10]3[C:11](=[N:12][C:13]([Cl:16])=[N:14][CH:15]=3)[NH:19][N:18]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1cccc(Br)n1)c1cnc(Cl)nc1Cl
Reactant: NN
Solvent: C1CCOC1
Product: Clc1ncc2c(-c3cccc(Br)n3)n[nH]c2n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of (6-bromo-pyridin-2-yl)-(2,4-dichloro-pyrimidin-5-yl)-methanone (from Example 29 supra) (2.42 g, 7.54 mmol) in THF (30 mL) was added hydrazine (454 mg, 9.08 mmol) and the mixture was stirred for 30 minutes at room temperature and then at 50° C. for 1 hour. The solvent was then removed and the solid was washed with water and dried to give crude 3-(6-bromo-pyridin-2-yl)-6-chloro-1H-pyrazolo[3,4-d]pyrimidine as a yellow solid. (Yield 1.7 g, crude).
Reaction SMILES: FC1C=CC(C[N:7]2C(=O)N(C3SC(C(O)=O)=C(C)N=3)C=N2)=CC=1.[CH2:24]([N:28]1[CH2:32][CH2:31][N:30]([C:33]2[S:34][C:35]([C:39](O)=[O:40])=[C:36]([CH3:38])[N:37]=2)[C:29]1=[O:42])[CH:25]([CH3:27])[CH3:26]>>[CH2:24]([N:28]1[CH2:32][CH2:31][N:30]([C:33]2[S:34][C:35]([C:39]([NH2:7])=[O:40])=[C:36]([CH3:38])[N:37]=2)[C:29]1=[O:42])[CH:25]([CH3:27])[CH3:26]
Reactant: Cc1nc(N2CCN(CC(C)C)C2=O)sc1C(=O)O
Reactant: Cc1nc(-n2cnn(Cc3ccc(F)cc3)c2=O)sc1C(=O)O
Product: Cc1nc(N2CCN(CC(C)C)C2=O)sc1C(N)=O
Yield: 54 %

Procedure:
Following the procedure as described in EXAMPLE 1, making variations as required to replace 2-(1-(4-fluorobenzyl)-5-oxo-1H-1,2,4-triazol-4(5H)-yl)-4-methylthiazole-5-carboxylic acid with 2-(3-isobutyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid, the title compound was obtained as a colorless solid in 54% yield: mp: 212-215° C. (methanol/hexanes); 1H NMR (300 MHz, CDCl3) δ 5.69 (s, 2H), 4.13-4.08 (m, 2H), 3.61-3.56 (m, 2H), 3.12 (d, J=7.5 Hz, 2H), 2.60 (s, 3H); 1.97-1.88 (m, 1H), 0.94 (d, J=6.7 Hz, 6H); 13C NMR (75 MHz, CDCl3) δ 165.5, 157.9, 155.6, 153.8, 116.6, 51.5, 42.8, 41.9, 26.7, 19.9, 17.2; MS (ES+) m/z 282.9 M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][NH:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[CH2:18]([O:20][C@H:21]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH2:22][C:23]1[CH:33]=[CH:32][C:26]([O:27][CH2:28][C:29](O)=[O:30])=[CH:25][CH:24]=1)[CH3:19].C(N(CC)C(C)C)(C)C.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[C:29](=[O:30])[CH2:28][O:27][C:26]2[CH:25]=[CH:24][C:23]([CH2:22][C@H:21]([O:20][CH2:18][CH3:19])[C:34]([O:36][CH2:37][CH3:38])=[O:35])=[CH:33][CH:32]=2)=[CH:16][CH:17]=1
Reactant: CCOC(=O)[C@H](Cc1ccc(OCC(=O)O)cc1)OCC
Reactant: Clc1ccc(CNCc2ccc(Cl)cc2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)[C@H](Cc1ccc(OCC(=O)N(Cc2ccc(Cl)cc2)Cc2ccc(Cl)cc2)cc1)OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.4 %

Procedure:
To a suspension of N,N-bis(4-chlorobenzyl)amine (0.958 g, 3.60 mmol) in methylene chloride (30 mL) were added {4-[(2S)-2,3-diethoxy-3-oxopropyl]phenoxy}acetic acid (0.889 g, 3.00 mmol) and N,N-diisopropylethylamine (1.20 mL, 6.9 mmol) followed by O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (1.01 g, 3.15 mmol) and the reaction mixture was stirred at room temperature overnight. The resulting solution was diluted with methylene chloride (220 mL) and the organic phase was washed with 2 M HCl (3×50 mL), saturated aqueous NaHCO3 (2×50 mL), and brine (50 mL), dried over Na2SO4, and concentrated in vacuo. Purification on a prepacked column of silica gel (Isolute® SPE Column, 50 g/150 mL) with methanol (0-2% gradient) in methylene chloride as the eluent yielded 1.02 g (62%) of an oil, which solidified upon standing to give white solids.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][SH:5].[CH2:6](Cl)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C>[CH2:6]([S:5][CH2:4][CH2:3][NH2:2])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: NCCS
Reactant: ClCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: NCCSCc1ccccc1
Reaction time: 8 h

Procedure:
A suspension of 2-aminoethanethiol hydrochloride (2.27 g, 20.0 mmol), benzyl chloride (2.42 mL, 21.0 mmol) and cesium carbonate (19.5 g, 60 mmol) in DMF (100 mL) was stirred overnight. The reaction mixture was then diluted with ethyl acetate (200 mL) and filtered into a separation funnel. The solid residue was washed with ether (50 mL×3). The combined filtrates were then washed with water (80 mL×5) and brine (50 mL), dried over potassium carbonate and filtered. The filtrate was concentrated first with rotary evaporator (water bath at 80° C.), then by high vacuum (1 mm Hg) to give 2-benzylthioethylamine in good purity. The crude product was used for next step without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:13]=[CH:14][CH:15]=1)[NH2:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16](Cl)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(Cl)Cl.O>[C:17]1([C:16]([NH:12][C:11]2[CH:13]=[CH:14][CH:15]=[C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:10]=2)=[O:23])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1cccc(OCc2ccccc2)c1
Solvent: O
Solvent: ClCCl
Product: O=C(Nc1cccc(OCc2ccccc2)c1)c1ccccc1
Reaction time: 8 h

Procedure:
To a solution of 3-benzyloxyaniline 23 (1.0 g, 5.0 mmol) and TEA (0.74 mL, 5.3 mmol) in CH2Cl2 was added benzoyl chloride (0.61 mL, 5.26 mmol) dropwise and the mixture was allowed to stir overnight. The reaction mixture was diluted with water and the resulting solid was collected by vacuum filtration. The solid was allowed to air dry, to yield compound 25 as a white solid. Synthesis of phenyl{[(3-phenylmethoxy)phenyl]amino}methane-1-thione (26):
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25]C(C)(C)C)=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31]([C:34]([N:36]([CH2:38][CH2:39][CH2:40][CH3:41])[CH3:37])=[O:35])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O>>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[C:18]([C:23]([OH:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:15][CH:16]=2)[C:8]2[CH:30]=[C:31]([C:34]([N:36]([CH2:38][CH2:39][CH2:40][CH3:41])[CH3:37])=[O:35])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2ccc(C(=O)N(C)CCCC)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Product: CCCCc1nc2ccc(C(=O)N(C)CCCC)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-n-butyl-6-(N-methyl-n-butylaminocarbonyl)-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid
Reaction SMILES: C1C2C(COC([N:18]3[CH2:23][C@H:22]([C:24](=[O:44])[N:25]([CH:41]4[CH2:43][CH2:42]4)[CH2:26][C:27]4[C:35]5[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=5)[N:29]([CH2:36][CH2:37][CH2:38][O:39][CH3:40])[CH:28]=4)[CH2:21][C@H:20]([NH2:45])[CH2:19]3)=O)C3C(=CC=CC=3)C=2C=CC=1.ClC(Cl)C.[C:50]([N:54]=[C:55]=[O:56])([CH3:53])([CH3:52])[CH3:51]>C(Cl)Cl>[CH:41]1([N:25]([CH2:26][C:27]2[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[N:29]([CH2:36][CH2:37][CH2:38][O:39][CH3:40])[CH:28]=2)[C:24]([C@@H:22]2[CH2:21][C@H:20]([NH:45][C:55]([NH:54][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:56])[CH2:19][NH:18][CH2:23]2)=[O:44])[CH2:42][CH2:43]1
Reactant: CC(C)(C)N=C=O
Reactant: COCCCn1cc(CN(C(=O)[C@@H]2C[C@H](N)CN(C(=O)OCC3c4ccccc4-c4ccccc43)C2)C2CC2)c2ccccc21
Solvent: ClCCl
Solvent: CC(Cl)Cl
Product: COCCCn1cc(CN(C(=O)[C@H]2CNC[C@@H](NC(=O)NC(C)(C)C)C2)C2CC2)c2ccccc21
Reaction time: 1 h

Procedure:
A mixture of (3S,5R)-3-amino-5-{cyclopropyl-[1-(3-methoxy-propyl)-1H-indol-3-ylmethyl]-carbamoyl}-piperidine-1-carboxylic acid 9H-fluoren-9-ylmethyl ester (115 A.) (374 mg, 0.62 mmol), dichloroethane (5 mL) and tert-butyl isocyanate (142 μl, 1.24 mmol) is shaken for 14 h at 50° C. The mixture is diluted with CH2Cl2 and washed with 1 N HCl and saturated NaHCO3 solution. The organic layer is dried (Na2SO4) and evaporated. The crude product is stirred with a solution of CH2Cl2/piperidine 4:1 (6 ml) for 1 h, the mixture is evaporated and the residue purified by preparative HPLC (YMC Pack Pro C18, 10-100% CH3CN+0.1% TFA/H2O+0.1% TFA, 20 min, flow 20 mL/min). The combined pure fractions are treated with K2CO3, CH3CN is removed in vacuo and the residual aqueous phase is extracted three times with CH2Cl2. The combined organic layers are dried (Na2SO4) and evaporated to afford the title compound as a yellow resin. MS: 484.2 [M+H]+; tR (HPLC, Nucleosil C18; 5-100% CH3CN+0.1% TFA/H2O+0.1% TFA for 8 min, flow 1.5 ml/min): 5.05 min.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]1=2.[Li]C(C)(C)C.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][C:24]=1[O:25][CH3:26])[CH:20]=[O:21]>C1COCC1>[S:1]1[C:5]([CH:20]([OH:21])[C:19]2[CH:22]=[CH:23][C:24]([O:25][CH3:26])=[C:17]([O:16][CH3:15])[CH:18]=2)=[CH:4][C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]1=2
Reactant: c1ccc2sccc2c1
Reactant: COc1ccc(C=O)cc1OC
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: COc1ccc(C(O)c2cc3ccccc3s2)cc1OC

Procedure:
α-(2-benzo[b]thienyl)-3,4-dimethoxybenzyl alcohol was prepared in the same manner as described in Example 40A. Reaction of benzo[b]-thiophene (7.5 mmoles, 1.0 g), t-BuLi (1.7 m, 97 mmoles, 5.7 ml) and 3,4-dimethoxybenzaldehyde (8.9 mmoles, 1.5 g) in THF (20 ml) yielded, after flash chromatography using 30% ethyl aceteate/hexanes, 2.25 g (≈100%) of a white gummy solid.
Reaction SMILES: C([O:3][C:4](=[O:19])[CH2:5][CH2:6][NH:7][S:8]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=1)(=[O:10])=[O:9])C.[OH-].[Na+].Cl>CCO>[CH3:18][O:17][C:13]1[CH:12]=[C:11]([S:8]([NH:7][CH2:6][CH2:5][C:4]([OH:19])=[O:3])(=[O:10])=[O:9])[CH:16]=[CH:15][CH:14]=1
Reactant: CCOC(=O)CCNS(=O)(=O)c1cccc(OC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1cccc(S(=O)(=O)NCCC(=O)O)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
3-(3-Methoxy-benzenesulfonylamino)-propionic acid ethyl ester (5.62 g, 0.0196 mol) was dissolved in EtOH (200 mL), treated with 1N NaOH solution (20.54 mL), and stirred at ambient temperature for 18 h. The reaction was acidified with 1N HCl to pH<5, the EtOH was removed in vacuo, and the residue was partitioned between EtOAc and H2O. The aqueous layer was washed with EtOAc, the organics combined, washed H2O, brine, and dried (Na2SO4). Filtration and concentration in vacuo gave the title compound. 1H NMR (CDCl3) δ 7.37-7.46 (m, 3H), 7.09-7.13 (m, 1H), 5.82 (t, 1H, J=7 Hz), 3.87 (s, 3H), 3.2-3.3 (m, 2H), 2.63 (t, 2H, J=6 Hz).
Reaction SMILES: [CH:1]12[NH:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[NH:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][N:13]=[CH:12]2.[CH:18]([C:20]1[CH:21]=[CH:22][C:23]([CH3:31])=[C:24]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])[CH:25]=1)=O>>[NH:14]1[C:15]2[C:11](=[CH:10][C:9]([NH:8][CH:2]3[CH2:3][CH:4]4[N:7]([CH2:18][C:20]5[CH:21]=[CH:22][C:23]([CH3:31])=[C:24]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])[CH:25]=5)[CH:1]3[CH2:6][CH2:5]4)=[CH:17][CH:16]=2)[CH:12]=[N:13]1
Reactant: c1cc2[nH]ncc2cc1NC1CC2CCC1N2
Reactant: Cc1ccc(C=O)cc1NS(C)(=O)=O
Product: Cc1ccc(CN2C3CCC2C(Nc2ccc4[nH]ncc4c2)C3)cc1NS(C)(=O)=O

Procedure:
Reaction of Intermediate 24 with N-(5-formyl-2-methylphenyl)methanesulfonamide affords the title compound.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:15]1[C:19]([NH:20][CH2:21][CH2:22][O:23][CH3:24])=[N:18][O:17][N:16]=1)[NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([F:14])([F:13])[F:12])[CH:6]=1.[C:25](N1C=CN=C1)(N1C=CN=C1)=[O:26]>C(OCC)(=O)C>[CH3:24][O:23][CH2:22][CH2:21][NH:20][C:19]1[C:15]([C:3]2[N:4]([C:5]3[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([F:13])([F:14])[F:12])[CH:6]=3)[C:25](=[O:26])[O:1][N:2]=2)=[N:16][O:17][N:18]=1
Reactant: COCCNc1nonc1C(=NO)Nc1cccc(C(F)(F)F)c1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CCOC(C)=O
Product: COCCNc1nonc1-c1noc(=O)n1-c1cccc(C(F)(F)F)c1
Temperature: 70 °C
Reaction time: 0.83 h
Yield: 92.1 %

Procedure:
N′-Hydroxy-4-[(2-methoxyethyl)amino]-N-[3-(trifluoromethyl)phenyl]-1,2,5-oxadiazole-3-carboximidamide (1.4 g, 3.80 mmol) and 1,1′-carbonyldiimidazole (1.16 g, 7.16 mmol) were dissolved in ethyl acetate (20 mL). The reaction mixture was heated at 70° C. for 40 minutes. Additional 1,1′-carbonyldiimidazole (0.26 g, 1.16 mmol) was added. After stirring at 70° C. for another 50 minutes, the reaction was allowed to cool to room temperature. Ethyl acetate (20 mL) was added and the crude reaction was washed with 1 N HCl in water (2×20 mL). Brine was added to aid in the separation of the first wash. The organic layer was dried over sodium sulfate and concentrated in vacuo. Purification by flash chromatography on silica gel with an eluent of ethyl acetate in hexanes gave the desired product (1.3 g, 90%). LCMS calculated for C14H13F3N5O4 (M+H)+: m/z=372.0. 1H NMR (400 MHz, DMSO-d6): δ 8.07 (s, 1H), 7.92 (m, 2H), 7.79 (t, J=8.1 Hz, 1H), 6.42 (t, J=6.0 Hz, 1H), 3.47 (t, J=5.8 Hz, 2H), 3.38 (q, J=5.0 Hz, 2H), 3.24 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:11](=[O:12])[CH:10]=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[I:13]N1C(=O)CCC1=O>CN(C=O)C>[NH2:1][C:2]1[C:3]2[C:11](=[O:12])[C:10]([I:13])=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: O=C1CCC(=O)N1I
Reactant: Nc1ncnc2[nH]ccc(=O)c12
Solvent: CN(C)C=O
Product: Nc1ncnc2[nH]cc(I)c(=O)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.7 %

Procedure:
To a suspension of 4-aminopyrido[2,3-d]pyrimidin-5(8H)-one (from VWR, 0.48 g, 3.0 mmol) in DMF (8 mL) was added N-iodosuccinimide (0.80 g, 3.6 mmol). The resulting mixture was stirred at ambient temperature overnight. The reaction mixture was filtered and washed with ethyl acetate to give the desired product as yellow solid (0.81 g, 95%). LCMS calculated for C7H6IN4O (M+H)+: m/z=289.0; Found: 289.0.
Reaction SMILES: [C:1]1([C:7]2[CH:24]=[CH:23][C:10]3[CH2:11][N:12](C(OC(C)(C)C)=O)[CH2:13][CH2:14][O:15][C:9]=3[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(OCC)(=O)C.[ClH:31]>C(OCC)(=O)C>[ClH:31].[C:1]1([C:7]2[CH:24]=[CH:23][C:10]3[CH2:11][NH:12][CH2:13][CH2:14][O:15][C:9]=3[CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCOc2cc(-c3ccccc3)ccc2C1
Agent: Cl
Solvent: CCOC(C)=O
Product: c1ccc(-c2ccc3c(c2)OCCNC3)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.3 %

Procedure:
A mixture of tert-butyl 8-phenyl-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (180 mg, 0.553 mmol), ethyl acetate (1 ml) and 4N hydrogen chloride-ethyl acetate solution (5 ml) was stirred for 1 hr at room temperature, and the solvent was evaporated under reduced pressure. The residue was recrystallized from a mixed solvent of methanol and ether to give the desired product (131 mg, 90.3%) as a solid.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)[C:9]([N:11]1[CH2:16][CH2:15][CH:14]([OH:17])[CH2:13][CH2:12]1)=[O:10])(C)(C)C.[ClH:27].O1CCOCC1>>[ClH:27].[NH2:7][C@H:8]([CH2:18][C:19]1[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=1)[C:9]([N:11]1[CH2:12][CH2:13][CH:14]([OH:17])[CH2:15][CH2:16]1)=[O:10]
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(F)cc1)C(=O)N1CCC(O)CC1
Agent: Cl
Solvent: C1COCCO1
Product: N[C@H](Cc1ccc(F)cc1)C(=O)N1CCC(O)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(R)-[1-(4-Fluoro-benzyl)-2-(4-hydroxy-piperidin-1-yl)-2-oxo-ethyl]carbamic acid-tert-butyl ester (2.6 mmol) was dissolved in 4M HCl-dioxane (2 mL) at 0° C. The solution was stirred 2 hours at 25° C., concentrated and the residue triturated with ether. Yield, 920 mg, 124%; HPLC (60/40) 2.23 minutes (98%).
Reaction SMILES: [N:1]1[O:2][N:3]=[C:4]2[C:9]([CH:10]=O)=[CH:8][CH:7]=[CH:6][C:5]=12.[NH2:12][C:13]1[CH:17]=[CH:16][NH:15][N:14]=1>C(OCC)(=O)C>[N:1]1[O:2][N:3]=[C:4]2[C:9]([CH:10]3[C:4]([C:5]#[N:1])=[C:9]([CH3:8])[NH:12][C:13]4=[N:14][NH:15][CH:16]=[C:17]34)=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: O=Cc1cccc2nonc12
Reactant: Nc1cc[nH]n1
Solvent: CCOC(C)=O
Product: CC1=C(C#N)C(c2cccc3nonc23)c2c[nH]nc2N1

Procedure:
The title compound was prepared from ethyl acetate, 2,1,3-benzoxadiazole-4-aldehyde and 3-aminopyrazole in the same manner as in Example 94.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH3:17])=[C:7]([NH:18][S:19]([C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][N:23]=2)(=[O:21])=[O:20])[N:6]=[C:5]([C:29]2[CH:34]=[CH:33][N:32]=[C:31]([C:35]([OH:37])=[O:36])[CH:30]=2)[N:4]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=C[C:48]=2N=N1>CN(C)C1C=CN=CC=1.CO>[CH3:48][O:36][C:35]([C:31]1[CH:30]=[C:29]([C:5]2[N:4]=[C:3]([O:2][CH3:1])[C:8]([O:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[O:16][CH3:17])=[C:7]([NH:18][S:19]([C:22]3[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][N:23]=3)(=[O:21])=[O:20])[N:6]=2)[CH:34]=[CH:33][N:32]=1)=[O:37]
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Reactant: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C)cn2)nc(-c2ccnc(C(=O)O)c2)nc1OC
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CO
Product: COC(=O)c1cc(-c2nc(NS(=O)(=O)c3ccc(C)cn3)c(Oc3ccccc3OC)c(OC)n2)ccn1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
220 mg of 4-[4-methoxy-5-(2-methoxy-phenoxy)-6-(5-methyl-pyridine-2-sulfonylamino)-pyrimidin-2-yl]-pyridine-2-carboxylic acid, product of example 21, suspended in acetontrile (10 ml) was treated at RT subsequently with 27 mg of methanol, 100 mg of 4-(dimethylamino)pyridine (DMAP) and 186 mg of benzotriazol-1-yloxytris-(dimethylamino)-phosphonium hexafluorophosphate (BOP). The mixture was stirred for 12 h at RT, then partitioned between cold diluted HCl and EtOAc. The layers were separated, the organic layer dried over Na2SO4 and the solvent removed in vacuo. The residue was purified on a silica gel chromatography column (eluted with Me2Cl2/MeOHc: 95/5). Combination of the purified fractions and evacuation in vacuo afforded 4-[4-methoxy-5-(2-methoxy-phenoxy)-6-(5-methyl-pyridine-2-sulfonylamino)-pyrimidin-2-yl]-pyridine-2-carboxylic acid methyl ester as a white solid. ISN mass spectrum, m/e 536.2 (M−1 calculated for C25H23N5O7S: 536).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([CH:11]([C:13]3[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:20])[CH3:12])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.Cl.CC1(C)C(C)(C)OB([C:30]2[CH:31]=[N:32][N:33]([CH:35]3[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]3)[CH:34]=2)O1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.O>[Cl:20][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]([Cl:19])[C:13]=1[CH:11]([C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([C:30]3[CH:31]=[N:32][N:33]([CH:35]4[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]4)[CH:34]=3)[CH:3]=2)[NH:8][CH:9]=1)[CH3:12]
Reactant: CC1(C)OB(c2cnn(C3CCNCC3)c2)OC1(C)C
Reactant: CC(c1c(Cl)cccc1Cl)c1c[nH]c2ncc(Br)cc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: CC(c1c(Cl)cccc1Cl)c1c[nH]c2ncc(-c3cnn(C4CCNCC4)c3)cc12
Temperature: 100 °C

Procedure:
To a stirred mixture of 5-bromo-3-[1-(2,6-dichlorophenyl)ethyl]-1H-pyrrolo[2,3-b]-pyridine (10.00 mg, 0.027 mmol), 4-[4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)-pyrazol-1-yl]-piperidine hydrochloride (11.00 mg, 0.035 mmol), potassium carbonate (15.00 mg, 0.11 mmol) in DME (2.0 mL) and H2O (0.40 mL) was added (1,1′-bis-(diphenylphosphino)ferrocene)palladium dichloride (0.84 mg, 0.0011 mmol) under nitrogen atmosphere. The resulting mixture was refluxed at 100° C. for 90 min. The solvent was then removed under reduced pressure and the resulting residue was purified by a flash chromatography (eluent: 8% MeOH in DCM) to give desired product. 1H NMR (400 MHz, CD3OD): δ=1.92 (d, J=7.1 Hz, 3H), 1.98-2.21 (m, 4H), 2.76-2.91 (m, 2H), 3.19-3.32 (m, 2H), 4.30-4.44 (m, 1H), 5.27-5.40 (m, 1H), 7.20-7.51 (m, 5H), 7.59 (s, 1H), 7.89 (s, 1H), 8.34 (d, J=2.0 Hz, 1H). MS (ES+): m/z 440.06, 442.06 [MH+]. HPLC: tR=2.46 min (ZQ3, polar—5 min)