Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([O:15][CH3:16])[C:9]=2[F:17])[N:5]=[C:4]([C:18]([OH:20])=[O:19])[C:3]=1[CH:21]=[CH2:22].Br[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(=O)([O-])[O-].[Li+].[Li+]>CN(C=O)C>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([O:15][CH3:16])[C:9]=2[F:17])[N:5]=[C:4]([C:18]([O:20][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:19])[C:3]=1[CH:21]=[CH2:22]
Reactant: C=Cc1c(N)nc(-c2ccc(Cl)c(OC)c2F)nc1C(=O)O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: C=Cc1c(N)nc(-c2ccc(Cl)c(OC)c2F)nc1C(=O)OCc1ccccc1
Temperature: 60 °C
Yield: 80 %

Procedure:
6-Amino-2-(4-chloro-2-fluoro-3-methoxyphenyl)-5-vinylpyrimidine-4-carboxylic acid (prepared by the methods described in U.S. Pat. No. 7,786,044 B2; 0.150 g, 0.463 mmol), (bromomethyl)benzene (0.103 g, 0.602 mmol), and lithium carbonate (Li2CO3; 0.044 g, 0.602 mmol) were combined in DMF (1.5 mL) and heated at 60° C. overnight. The cooled reaction mixture was concentrated and then partitioned between EtOAc and water. The organic phase was dried, concentrated and purified by column chromatography (eluting with an EtOAc/hexanes gradient) to yield benzyl 6-amino-2-(4-chloro-2-fluoro-3-methoxyphenyl)-5-vinylpyrimidine-4-carboxylate as a white solid (0.154 g, 80%): mp 119-121° C.; 1H NMR (400 MHz, CDCl3) δ 7.67 (dd, J=8.5, 7.5 Hz, 1H), 7.49-7.42 (m, 2H), 7.42-7.32 (m, 3H), 7.21 (dd, J=8.6, 1.7 Hz, 1H), 6.70 (dd, J=17.8, 11.6 Hz, 1H), 5.60 (dd, J=7.7, 1.0 Hz, 1H), 5.57 (s, 1H), 5.39 (s, 2H), 5.35 (s, 2H), 4.00 (d, J=0.8 Hz, 3H); ESIMS m/z 414 ([M+H]+).
Reaction SMILES: C1(O[C:8](=[O:29])[NH:9][C:10]2[S:14][N:13]=[C:12]([O:15][CH2:16][C:17]3[C:22]([F:23])=[CH:21][C:20]([CH3:24])=[CH:19][C:18]=3[F:25])[C:11]=2[C:26](=[O:28])[NH2:27])C=CC=CC=1.[NH2:30][CH2:31][CH2:32][CH2:33][CH:34]([OH:42])[CH2:35][N:36]1[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1>>[F:23][C:22]1[CH:21]=[C:20]([CH3:24])[CH:19]=[C:18]([F:25])[C:17]=1[CH2:16][O:15][C:12]1[C:11]([C:26]([NH2:27])=[O:28])=[C:10]([NH:9][C:8]([NH:30][CH2:31][CH2:32][CH2:33][CH:34]([OH:42])[CH2:35][N:36]2[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41]2)=[O:29])[S:14][N:13]=1
Reactant: NCCCC(O)CN1CCCCC1
Reactant: Cc1cc(F)c(COc2nsc(NC(=O)Oc3ccccc3)c2C(N)=O)c(F)c1
Product: Cc1cc(F)c(COc2nsc(NC(=O)NCCCC(O)CN3CCCCC3)c2C(N)=O)c(F)c1

Procedure:
The title compound was prepared from [4-carbamoyl-3-(2,6-difluoro-4-methyl-benzyloxy)-isothiazol-5-yl]-carbamic acid phenyl ester and 5-amino-1-piperidin-1-yl-pentan-2-ol by the procedure analogous to Example 1. MS (APCI, m/z): 512 [M+H]+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[N:8]=[C:9]3[CH2:23][CH2:22][CH2:21][N:20]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([O:32]CC)=[O:31])[C:10]3=[N:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)=[CH:3][CH:2]=1.[Li+].[OH-]>C1COCC1.O>[N:1]1[CH:6]=[CH:5][C:4]([C:7]2[N:8]=[C:9]3[CH2:23][CH2:22][CH2:21][N:20]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([OH:32])=[O:31])[C:10]3=[N:11][C:12]=2[C:13]2[CH:14]=[CH:15][C:16]([CH3:19])=[CH:17][CH:18]=2)=[CH:3][CH:2]=1
Reactant: CCOC(=O)CCCCCCN1CCCc2nc(-c3ccncc3)c(-c3ccc(C)cc3)nc21
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(-c2nc3c(nc2-c2ccncc2)CCCN3CCCCCCC(=O)O)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of ethyl 7-(2-(pyridin-4-yl)-3-p-tolyl-7,8-dihydropyrido[2,3-b]pyrazin-5(6H)-yl)heptanoate (step 4)(65 mg, 0.142 mmol) in THF (3 ml) and water (1 ml) was treated with LiOH (33.9 mg, 1.417 mmol) and the mixture was stirred at room temperature for 16 hours. The mixture was concentrated under vacuum and the residue was diluted with water and washed with EtOAc (×2). The aqueous was acidified (1 N HCl, pH ˜5) and extracted with EtOAc. The combined extracts were washed with brine, dried (MgSO4) and evaporated under vacuum to a yellow gum which was triturated with ether to afford the title compound;
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[S:5][C:6]=1[C:7]([NH2:9])=[O:8].Cl[CH2:17][CH2:18][CH2:19][C:20](=O)[CH3:21].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>ClCCCl>[CH3:17][C:18]12[CH2:19][CH2:20][CH2:21][N:1]1[C:2]1[N:3]=[C:4]([N:10]3[CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)[S:5][C:6]=1[C:7](=[O:8])[NH:9]2
Reactant: CC(=O)CCCCl
Reactant: NC(=O)c1sc(N2CCOCC2)nc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCCl
Solvent: O
Product: CC12CCCN1c1nc(N3CCOCC3)sc1C(=O)N2
Yield: 10 %

Procedure:
A stirred solution of 4-amino-2-(morpholin-4-yl)-1,3-thiazole-5-carboxamide (0.22 g, 0.99 mmol), 5-chloro-2-pentanone (0.5 mL, excess) and p-toluenesulfonic acid monohydrate (cat. amount) in DCE (4 mL) was heated to 100° C. in a sealed tube, under microwave irradiation, for 1 h. The reaction mixture was then concentrated in vacuo and purification by preparative HPLC gave the title compound (0.03 g, 10%) as an off-white solid. δH (DMSO-d6) 7.29 (1H, s), 3.73-3.64 (4H, m), 3.57-3.39 (6H, m), 2.08-1.96 (2H, m), 1.93-1.83 (2H, m), 1.36 (3H, s). LCMS (ES+) 295.2 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:14]([NH:15][CH2:16][C:17]2[CH:22]=[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=3)[CH:20]=[CH:19][C:18]=2[F:30])=[C:13]([F:31])[CH:12]=[CH:11][C:3]=1[O:4][CH2:5][C:6]([O:8][CH2:9]C)=[O:7].C([O-])([O-])=O.[K+].[K+].Cl>CO.O>[F:1][C:2]1[C:14]([NH:15][CH2:16][C:17]2[CH:22]=[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=3)[CH:20]=[CH:19][C:18]=2[F:30])=[C:13]([F:31])[CH:12]=[CH:11][C:3]=1[O:4][CH2:5][C:6]([O:8][CH3:9])=[O:7]
Reactant: CCOC(=O)COc1ccc(F)c(NCc2cc(-c3cccc(F)c3)ccc2F)c1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: COC(=O)COc1ccc(F)c(NCc2cc(-c3cccc(F)c3)ccc2F)c1F

Procedure:
To a stirred solution of ethyl 2-[2,4-difluoro-3-[[2-fluoro-5-(3-fluorophenyl)phenyl]methylamino]phenoxy]acetate (II(a)) (290 mg, 0.7 mmol, 1.0 eq) in MeOH (30 mL) was added K2CO3 (28 mg, 0.2 mmol 0.3 eq). The reaction was heated at reflux overnight. The solvent was removed in vacuo and the residue obtained was diluted with water and neutralized by addition of 1M HCl. The aqueous layer was further extracted with EtOAc and the combined organic extracts were washed with brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue was purified by chromatography (EtOAc:petroleum ether, 0:1 to 1:20) to give the title compound an oil (130 mg, 46%).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[N:9]([CH3:26])[C:10](=[O:25])[C:11]([CH3:24])([CH3:23])[C@:12]([C:15]2[CH:20]=[C:19]([NH2:21])[CH:18]=[CH:17][C:16]=2[F:22])([CH3:14])[N:13]=1)(C)(C)C.[F:28][C:29]([CH3:34])([CH3:33])[C:30](O)=[O:31]>>[NH2:7][C:8]1[N:9]([CH3:26])[C:10](=[O:25])[C:11]([CH3:24])([CH3:23])[C@:12]([C:15]2[CH:20]=[C:19]([NH:21][C:30](=[O:31])[C:29]([F:28])([CH3:34])[CH3:33])[CH:18]=[CH:17][C:16]=2[F:22])([CH3:14])[N:13]=1
Reactant: CN1C(=O)C(C)(C)[C@@](C)(c2cc(N)ccc2F)N=C1NC(=O)OC(C)(C)C
Reactant: CC(C)(F)C(=O)O
Product: CN1C(=O)C(C)(C)[C@@](C)(c2cc(NC(=O)C(C)(C)F)ccc2F)N=C1N

Procedure:
The coupling of [(S)-4-(5-amino-2-fluoro-phenyl)-1,4,5,5-tetramethyl-6-oxo-1,4,5,6-tetrahydro-pyrimidin-2-yl]-carbamic acid tert-butyl ester (intermediate F2) and 2-fluoro-2-methyl-propionic acid followed by deprotection of the intermediate yielded the title compound as a colorless amorphous solid. MS (ESI): m/z=367.2 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:3]2[Se:10][C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:15][C:16]1[CH:20]=[C:19]([C:21]([CH3:24])([CH3:23])[CH3:22])[Se:18][C:17]=1[C:25]([NH2:27])=[O:26].CN(C=O)C.[OH-].[Na+]>>[C:11]([C:9]1[Se:10][C:3]2[C:2]([NH:15][C:16]3[CH:20]=[C:19]([C:21]([CH3:24])([CH3:22])[CH3:23])[Se:18][C:17]=3[C:25]([NH2:27])=[O:26])=[N:7][CH:6]=[N:5][C:4]=2[CH:8]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)c1cc(N)c(C(N)=O)[se]1
Reactant: CC(C)(C)c1cc2ncnc(Cl)c2[se]1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CC(C)(C)c1cc(Nc2ncnc3cc(C(C)(C)C)[se]c23)c(C(N)=O)[se]1

Procedure:
The reaction of 4-chloro-6-(tert-butyl)selenopheno[3,2-d]pyrimidine with 3-amino-5-tert-butylselenophene-2-carboxamide in the presence of DMF/NaOH as described in Example 1 gave title compound as a white color solid, mp 260-262° C. IR (KBr) vmax 3439, 3173, 2960, 1666, 1605, 1564, 1503, 1458, 1381, 1330, 1244, 1086, 1038, 848, 773 cm−1; 1H NMR (400 MHz, CDCl3): δ 11.32 (1H, s, exchangeable with D2O), 8.75 (1H, s), 8.73 (1H, s), 7.37 (1H, s), 5.34 (2H, br s, exchangeable with D2O), 1.47 (9H, s), 1.46 (9H, s); 13C NMR (100 MHz, CDCl3): δ 171.9, 168.8, 168.5, 164.4, 154.8, 147.8, 122.7, 121.6, 118.4, 108.9, 37.3, 37.1, 32.5, 32.4; LC-MS (positive ion mode): m/z 481, 483, 485 (M+H)+.
Reaction SMILES: C([O:3][C:4](=[O:20])[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)=[CH:7][C:6]=1[Cl:19])C.[OH-].[Na+].CO.Cl>O>[CH2:12]([O:11][C:8]1[CH:9]=[CH:10][C:5]([C:4]([OH:20])=[O:3])=[C:6]([Cl:19])[CH:7]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CCOC(=O)c1ccc(OCc2ccccc2)cc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc(OCc2ccccc2)cc1Cl
Yield: 53.1 %

Procedure:
17.7 g (60.9 mmol) of 4-benzyloxy-2-chloro-benzoic acid ethyl ester and 4.87 g (122 mmol) of sodium hydroxide were added to a mixed solvent consisting of 180 mL of methanol and 18 mL of water followed by refluxing for 6 hours. After cooling, concentrated hydrochloric acid was added to bring to a pH of 5 followed by filtering out the precipitate. The precipitate was washed with water and dried to obtain 8.5 g of a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:11]=[C:10]([CH2:19][CH2:20][CH:21]=O)[CH:9]=2)=[CH:4][CH:3]=1.[C:23]1([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:11]=[C:10]([CH2:19][CH2:20][CH2:21][N:32]3[CH2:33][CH2:34][N:29]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH2:30][CH2:31]3)[CH:9]=2)=[CH:4][CH:3]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: O=CCCc1cc(-c2ccc(F)cc2)n(-c2ccccc2)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: Fc1ccc(-c2cc(CCCN3CCN(c4ccccc4)CC3)nn2-c2ccccc2)cc1

Procedure:
49 mg (62%) of target compound was obtained by using a method same as in Example 1 by using 3-(5-(4-fluorophenyl)-1-phenyl-1H-pyrazol-3-yl)-propanal (55 mg, 0.187 mmol), 1-phenylpiperazine (0.026 mL, 0.170 mmol), DIPEA (0.030 mL, 0.170 mmol) and NaBH(OAc)3 (108 mg, 0.510 mmol).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:17][SH:18].CS(O[C@@H:24]1[CH2:28][CH2:27][C@H:26]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:25]1)(=O)=O>CN(C)C=O>[C:32]([O:31][C:30]([NH:29][C@H:26]1[CH2:27][CH2:28][C@H:24]([S:18][CH2:17][C:3]2[N:4]=[C:5]([C:7]3[CH:8]=[CH:9][C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:15][CH:16]=3)[O:6][C:2]=2[CH3:1])[CH2:25]1)=[O:36])([CH3:35])([CH3:33])[CH3:34]
Reactant: COC(=O)c1ccc(-c2nc(CS)c(C)o2)cc1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](OS(C)(=O)=O)C1
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(-c2nc(CS[C@H]3CC[C@H](NC(=O)OC(C)(C)C)C3)c(C)o2)cc1
Reaction time: 0.33 h
Yield: 87.9 %

Procedure:
To a solution of methyl 4-[5-methyl-4-(sulfanylmethyl)-1,3-oxazol-2-yl]benzoate (920 mg, 3.49 mmol, 1.00 equiv) in N,N-dimethylformamide (20 mL) maintained under an inert atmosphere of nitrogen was added cescium carnonate (2.3 g). The mixture was stirred for 20 min then tert-butyl N-[(1S,3R)-3-(methanesulfonyloxy)cyclopentyl]carbamate (1.0 g, 3.58 mmol, 1.02 equiv) was added. The resulting solution was stirred at 35° C. for 50 min then the product was precipitated by the addition of 50 mL water. The precipitate was collected by filtration, washed with water and then dried under vacuum to give 1.37 g (88%) of methyl 4-[4-([[(1S,3S)-3-[[(tert-butoxy)carbonyl]amino]cyclopentyl]sulfanyl]methyl)-5-methyl-1,3-oxazol-2-yl]benzoate as a white solid. LC-MS: (ES, m/z): 447 [M+H]+, 391, 271, 230, 115.
Reaction SMILES: [CH2:1]([NH:3][C:4]([CH:6]1[N:14]([C:15](=[O:34])[C@@H:16]([NH:20][C:21](=[O:33])[C@@H:22]([N:24](C)[C:25](=O)OC(C)(C)C)[CH3:23])[CH:17]([CH3:19])[CH3:18])[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[CH2:7]1)=[O:5])[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([NH:3][C:4]([C@H:6]1[N:14]([C:15](=[O:34])[C@@H:16]([NH:20][C:21](=[O:33])[C@@H:22]([NH:24][CH3:25])[CH3:23])[CH:17]([CH3:19])[CH3:18])[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCNC(=O)C1Cc2cccnc2N1C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCNC(=O)[C@@H]1Cc2cccnc2N1C(=O)[C@@H](NC(=O)[C@H](C)NC)C(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.7 %

Procedure:
To a solution of tert-butyl (2S)-1-((2S)-1-(2-(ethylcarbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-1-yl)-3-methyl-1-oxobutan-2-ylamino)-1-oxopropan-2-yl(methyl)carbamate (50 mg, 105 μmol, Eq: 1.00) in DCM (1 mL) was added TFA (0.5 mL, 6.49 mmol, Eq: 61.7) and the resulting mixture was stirred at rt for 2 h. The reaction mixture was concentrated in vacuo and the residue was treated with saturated aqueous NaHCO3 (5 mL). The resulting aqueous layer was extracted with DCM (3×5 mL) and the combined organic layers were dried over MgSO4 and then concentrated in vacuo. Treatment of the resulting residue with ethyl ether and hexanes gave (S)-1-[(S)-3-methyl-2-((S)-2-methylamino-propionylamino)-butyryl]-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid ethylamide as a white solid (33 mg), m/z=376 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[C:5]([N:7]([CH2:16][C:17]1[CH:22]=[CH:21][C:20](Br)=[CH:19][CH:18]=1)[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1)=[O:6])[CH3:2].[CH:25]#[C:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]>>[CH2:1]([O:3][C:4](=[O:24])[C:5]([N:7]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:25]#[C:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])=[CH:19][CH:18]=1)[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1)=[O:6])[CH3:2]
Reactant: CCOC(=O)C(=O)N(Cc1ccc(F)cc1)Cc1ccc(Br)cc1
Reactant: C#CCCCCCCCCCC
Product: CCCCCCCCCCC#Cc1ccc(CN(Cc2ccc(F)cc2)C(=O)C(=O)OCC)cc1
Yield: 23 %

Procedure:
The same procedure as employed in the preparation of Example 226 (step c) but using ethyl[(4-bromobenzyl)(4-fluorobenzyl)amino](oxo)acetate and 1-dodecyne gave the title compound as a pale yellow oil (23%). 1H NMR (CDCl3, 300 MHz) δ 7.39 (m, 2H), 7.25-7.00 (m, 6H), 4.45 (s, 1H), 4.44 (s, 1H), 4.36 (m, 2H), 4.30 (s, 1H), 4.28 (s, 1H), 2.42 (t, 2H, J=7.1 Hz), 1.62 (m, 2H), 1.46 (m, 2H), 1.37-1.25 (m, 15H), 0.89 (t, 3H, J=6.6 Hz). M+(LC/MS(ESI)): 480.3. HPLC (Condition A), Rt: 6.28 min (HPLC purity: 99.8%).
Reaction SMILES: O=[C:2]([CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[NH2:16][C@H:17]([C:19]([N:21]1[CH2:28][C@@H:27]([S:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:26][C@H:22]1[C:23]([OH:25])=[O:24])=[O:20])[CH3:18].C([BH3-])#N.[Na+]>C(O)C.O>[CH2:6]([O:5][C:3]([C@@H:2]([NH:16][C@H:17]([C:19]([N:21]1[CH2:28][C@@H:27]([S:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:26][C@H:22]1[C:23]([OH:25])=[O:24])=[O:20])[CH3:18])[CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:4])[CH3:7]
Reactant: CCOC(=O)C(=O)CCc1ccccc1
Reactant: C[C@H](N)C(=O)N1C[C@@H](Sc2ccccc2)C[C@H]1C(=O)O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)[C@H](CCc1ccccc1)N[C@@H](C)C(=O)N1C[C@@H](Sc2ccccc2)C[C@H]1C(=O)O

Procedure:
Ethyl 2-oxo-4-phenylbutyrate (1.03 gram) and 1-(L-alanyl)-4-(S)-(phenylthio)-L-proline (0.19 gram) are dissolved in a 1:1 ethanol-water solvent. A solution of sodium cyanoborohydride (0.19 gram) in ethanol-water is added dropwise at room temperature over the course of two hours. When the reaction is completed, the product is absorbed in strong acid ion exchange resin and eluted with 2% pyridine water. The product rich cuts are freeze dried and the desired isomer is separated chromatographically to yield 1-[N-(1-(S)-ethoxycarbonyl-3-phenylpropyl)-L-alanyl]-4-(S)-(phenylthio)-L-proline.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][N:6]=[C:5]([CH2:9][N:10]2[C:18]3[C:13](=[N:14][CH:15]=[C:16]([CH3:19])[CH:17]=3)[C:12]([C:20](O)=[O:21])=[CH:11]2)[C:4]=1[CH3:23].[CH3:24][O:25][CH2:26][CH2:27][NH2:28].CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>>[CH3:1][O:2][C:3]1[N:8]=[CH:7][N:6]=[C:5]([CH2:9][N:10]2[C:18]3[C:13](=[N:14][CH:15]=[C:16]([CH3:19])[CH:17]=3)[C:12]([C:20]([NH:28][CH2:27][CH2:26][O:25][CH3:24])=[O:21])=[CH:11]2)[C:4]=1[CH3:23]
Reactant: COCCN
Reactant: COc1ncnc(Cn2cc(C(=O)O)c3ncc(C)cc32)c1C
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Product: COCCNC(=O)c1cn(Cc2ncnc(OC)c2C)c2cc(C)cnc12
Temperature: 25 °C
Reaction time: 0.05 h

Procedure:
See FIG. 18(c). 1-((6-methoxy-5-methylpyrimidin-4-yl)methyl)-6-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxylic acid (0.100 g, 0.32 mmol) and 2-methoxyethanamine (0.048 g, 0.64 mmol), TEA (0.134 mL, 0.96 mmol) was added. After 3 min, 1-Propanephosphonic acid cyclic anhydride (0.255 g, 0.80 mmol) was added. The resulting reaction mixture was stirred at rt for 50 min. LCMS analysis showed formation of required product. Reaction was diluted with DCM and water. DCM layer was extracted and washed with brine and dried over sodium sulphate and concentrated. Purification was done on Waters RP system to get product 1-((6-methoxy-5-methylpyrimidin-4-yl)methyl)-N-(2-methoxyethyl)-6-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide (0.045 g, 38.0%). ES+MS m/z: 370.21. 1H NMR (300 MHz, DMSO-d6) δ ppm 2.17-2.28 (s, 3H ) 2.40 (s, 3 H ) 3.30 (s, 13 H ) 3.50 (d, J=4.52 Hz, 2 H ) 3.55 (t, J=5.18 Hz, 2 H ) 3.94 (s, 3 H ) 5.63 (s, 2 H ) 7.74 (s, 1 H ) 8.12 (s, 1 H ) 8.34 (s, 1 H ) 8.42 (s, 1 H) 8.78 (t, J=5.46 Hz, 1H ).
Reaction SMILES: [CH2:1]([N:4]([CH2:8][CH2:9][CH3:10])[C:5](Cl)=[O:6])[CH2:2][CH3:3].[CH3:11][S:12]([C:15]1[N:19]=[CH:18][NH:17][N:16]=1)(=[O:14])=[O:13].C(N(CC)CC)C>O1CCCC1>[CH2:1]([N:4]([CH2:8][CH2:9][CH3:10])[C:5]([N:17]1[CH:18]=[N:19][C:15]([S:12]([CH3:11])(=[O:14])=[O:13])=[N:16]1)=[O:6])[CH2:2][CH3:3]
Reactant: CS(=O)(=O)c1nc[nH]n1
Reactant: CCCN(CCC)C(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCN(CCC)C(=O)n1cnc(S(C)(=O)=O)n1

Procedure:
Dipropylcarbamoyl chloride (5.5 g.) was added to a solution of 4.4 g. 3-methylsulphonyl-1,2,4-triazole and 6 ml. dry triethylamine in 25 ml. dry tetrahydrofuran and the resulting mixture refluxed for 2.5 hours under anhydrous conditions. The cooled reaction mixture was filtered to remove triethylamine hydrochloride and the filtrate poured with stirring into 150 ml. ice-cold 0.1N aqueous sodium hydroxide. The precipitated product was collected by filtration, washed with ice-cold water, dried, and crystallized twice from toluene to give 1-dipropylcarbamoyl-3-methylsulphonyl-1,2,4-triazole, m.p. 94° C. Elemental analysis satisfactory.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:9][C:10]([OH:12])=O)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH3:13][O:14][C:15]([C:17]1[C:22]([NH2:23])=[N:21][CH:20]=[CH:19][N:18]=1)=[O:16].C(N(CC)CC)C.O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1>ClCCl>[CH3:13][O:14][C:15]([C:17]1[C:22]([NH:23][C:10](=[O:12])[CH2:9][C:3]2[C:2]([Cl:1])=[CH:7][C:6]([Cl:8])=[CH:5][N:4]=2)=[N:21][CH:20]=[CH:19][N:18]=1)=[O:16]
Reactant: COC(=O)c1nccnc1N
Reactant: O=C(O)Cc1ncc(Cl)cc1Cl
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1nccnc1NC(=O)Cc1ncc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 24 h
Yield: 67.5 %

Procedure:
To a solution of (3,5-dichloro-pyrid-2-yl)-acetic acid (Example 5.1) (5.7 g) and 3-amino-pyrazine-2-carboxylic acid methyl ester (4.65 g) in dichloromethane (120 ml) were added successively triethylamine (8.5 ml) and bis(2-oxo-3-oxazolidinyl)phosphinic chloride (7.5 g). The reaction mixture was stirred at ambient temperature for 24 hours. The organic phase was washed successively with water, aqueous sodium hydrogen carbonate (1M), and brine. The organic phase was dried over magnesium sulfate and concentrated to give 3-[2-(3,5-dichloro-pyrid-2-yl)-acetylamino]-pyrazine-2-carboxylic acid methyl ester (6.37 g). 1H-NMR (400 MHz, CDCl3): 4.04 (s, 3H), 4.35 (s, 2H), 7.77 (s, 1H), 8.39 (s, 1H), 8.49 (s, 1H), 8.56 (s, 1H), 11.02 (s, 1H) ppm.
Reaction SMILES: C([O:3][C:4](=[O:18])[C:5]([C:10](=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[CH:6]N(C)C)C.Cl.[C:20]([C:23]1[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=1)(=[NH:22])[NH2:21]>>[C:11]1([C:10]2[C:5]([C:4]([OH:18])=[O:3])=[CH:6][N:21]=[C:20]([C:23]3[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=3)[N:22]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: N=C(N)c1cccnc1
Reactant: CCOC(=O)C(=CN(C)C)C(=O)c1ccccc1
Agent: Cl
Product: O=C(O)c1cnc(-c2cccnc2)nc1-c1ccccc1

Procedure:
In an analogous manner to that described in example 3b) starting from 2-benzoyl-3-dimethylamino-acrylic acid ethyl ester and 3-amidinopyridine hydrochloride, followed by saponification as described in example 3c) there was obtained 4-phenyl-2-pyridin-3-yl-pyrimidine-5-carboxylic acid, MS (EI): 277 (M+).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:23][C:24](=O)[O:25]C2C=CC=CC=2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:14]([C:15]2[CH:20]=[CH:19][N:18]=[C:17]([NH:21][CH3:22])[N:16]=2)=[CH:13][CH:12]=[CH:11][N:10]=1.[CH3:33][N:34]1[CH2:39][CH2:38][N:37]([C:40]2[CH:45]=[CH:44][C:43]([C:46]([F:49])([F:48])[F:47])=[CH:42][C:41]=2[NH2:50])[CH2:36][CH2:35]1>C1COCC1>[CH3:1][C:2]1[CH:3]=[C:4]([NH:23][C:24]([NH:50][C:41]2[CH:42]=[C:43]([C:46]([F:47])([F:48])[F:49])[CH:44]=[CH:45][C:40]=2[N:37]2[CH2:38][CH2:39][N:34]([CH3:33])[CH2:35][CH2:36]2)=[O:25])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:14]([C:15]2[CH:20]=[CH:19][N:18]=[C:17]([NH:21][CH3:22])[N:16]=2)=[CH:13][CH:12]=[CH:11][N:10]=1
Reactant: CNc1nccc(-c2cccnc2Oc2ccc(NC(=O)Oc3ccccc3)cc2C)n1
Reactant: CN1CCN(c2ccc(C(F)(F)F)cc2N)CC1
Solvent: C1CCOC1
Product: CNc1nccc(-c2cccnc2Oc2ccc(NC(=O)Nc3cc(C(F)(F)F)ccc3N3CCN(C)CC3)cc2C)n1
Temperature: 80 °C
Reaction time: 40 h

Procedure:
To phenyl 3-methyl-4-(3-(2-(methylamino)pyrimidin-4-yl)pyridin-2-yloxy)phenylcarbamate (59 mg, 0.14 mmol) in THF (1 mL) was added 2-(4-methylpiperazin-1-yl)-5-(trifluoromethyl)benzenamine (30 mg, 0.12 mmol). The mixture was stirred for 40 hours at 80° C. The crude material was purified by silica gel chromatography (0-20% MeOH/CH2Cl2) to yield the title compound as a light yellow solid. MS m/z=593 [M+H]+. Calc'd for C30H31F3N8O2: 592.63.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.[F:55][C:56]1[CH:64]=[C:63]([F:65])[CH:62]=[CH:61][C:57]=1[C:58](Cl)=[O:59]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[NH:44][C:45](=[O:53])[CH2:46][CH:47]1[CH2:52][CH2:51][N:50]([C:58](=[O:59])[C:57]2[CH:61]=[CH:62][C:63]([F:65])=[CH:64][C:56]=2[F:55])[CH2:49][CH2:48]1
Reactant: O=C(Cl)c1ccc(F)cc1F
Reactant: O=C(CC1CCNCC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Solvent: O=C(O)C(F)(F)F
Product: O=C(CC1CCN(C(=O)c2ccc(F)cc2F)CC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Yield: 42 %

Procedure:
The desired compound was prepared according to the procedure of Example A20 using N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]-2-piperidin-4-ylacetamide tris(trifluoroacetate) and 2,4-difluorobenzoyl chloride as starting materials in 42% yield. LCMS for C31H29ClF2N7O2 (M+H)+: m/z=604.2.