Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:4][C:3]=1[N+:18]([O-:20])=[O:19].[CH3:21][O:22][C:23]([N:25]=[C:26]=[S:27])=[O:24]>>[CH3:21][O:22][C:23]([NH:25][C:26](=[S:27])[NH:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:4][C:3]=1[N+:18]([O-:20])=[O:19])=[O:24]
Reactant: COC(=O)N=C=S
Reactant: Nc1ccc(OCCOc2ccccc2)cc1[N+](=O)[O-]
Product: COC(=O)NC(=S)Nc1ccc(OCCOc2ccccc2)cc1[N+](=O)[O-]

Procedure:
The 1-amino-2-nitro-4-(2-phenoxyethoxy)benzene so obtained is treated with methoxycarbonyl isothiocyanate (as per Example XL) to afford 1-(3-methoxycarbonyl-2-thioureido)-2-nitro-4-(2-phenoxyethoxy)benzene which is reduced with sodium hydrosulfite (as per Example XXI) or iron-ferrous sulfate (as per Example VII) to afford 1-(3-methoxycarbonyl-2-thioureido)-2-amino-4-(2-phenoxyethoxy)benzene. The latter compound is further reacted with another equivalent of methoxycarbonyl isothiocyanate to afford 1,2-bis-(3-methoxycarbonyl-2-thioureido)-4-(2-phenoxyethoxy)benzene.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[C:5]([CH:27]2[CH2:31][CH2:30][CH2:29][N:28]2[C:32](=[O:34])[CH3:33])=[CH:6][C:7]2[N:11]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:10]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=3)=[N:9][C:8]=2[CH:26]=1.F[C:36]1[CH:41]=[CH:40][C:39]([C:42]#[N:43])=[CH:38][CH:37]=1.C(=O)(O)[O-].[Na+]>CN1CCCC1=O>[C:32]([N:28]1[CH2:29][CH2:30][CH2:31][CH:27]1[C:5]1[C:4]([O:3][C:36]2[CH:41]=[CH:40][C:39]([C:42]#[N:43])=[CH:38][CH:37]=2)=[CH:26][C:8]2[N:9]=[C:10]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=3)[N:11]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:7]=2[CH:6]=1)(=[O:34])[CH3:33]
Reactant: N#Cc1ccc(F)cc1
Reactant: CC(=O)N1CCCC1c1cc2c(cc1O)nc(-c1ccccn1)n2COCC[Si](C)(C)C
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CC(=O)N1CCCC1c1cc2c(cc1Oc1ccc(C#N)cc1)nc(-c1ccccn1)n2COCC[Si](C)(C)C
Temperature: 100 °C
Reaction time: 8 h

Procedure:
5.8 mg of sodium hydride was added to an N-methyl-pyrrolidinone (1 ml) solution of 30 mg of 1-(2-(6-hydroxy-2-pyridin-2-yl-3-(2-trimethylsilanyl-ethoxymethyl)-3H-benzimidazol-5-yl)-pyrrolidin-1-yl)-ethanone obtained in Example 121 (step 10) and 20 mg of 4-fluorocyanobenzene, and the reaction liquid was stirred overnight in a sealed tube at 100° C. After cooled, aqueous saturated sodium bicarbonate was added to the reaction liquid, then this was extracted with ethyl acetate, the organic layer was washed with water, and dried with anhydrous magnesium sulfate. The solvent was evaporated away under reduced pressure, and the resulting residue was purified through partitioning thin-layer chromatography (Kieselgel™ 60F254, Art 5744 (by Merck), chloroform/methanol=9/1) to obtain the entitled compound as a yellow oily substance.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]Br)[C:10]=1[CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH3:2].[N+]1([O-:36])C=CC=CC=1.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:29])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH:20]=[O:36])[C:10]=1[CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH3:2]
Reactant: [O-][n+]1ccccc1
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCBr)c1CCC(=O)OCC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOC(=O)CCCOc1cccc(CCCCCC=O)c1CCC(=O)OCC
Yield: 81.2 %

Procedure:
4-[3-(6-Bromo-hexyl)-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (10.0 g, 21.2 mmol), pyridine N-oxide (10.06 g, 106 mmol), and sodium bicarbonate (10.0 g, 1 19 mmol) were heated at reflux with vigorous stirring in toluene (100 mL) for 24 hr. The mixture was cooled down and filtered. The filtrate was then evaporated under vacuo and the crude material was purified by column chromatography using 30% EtOAc-Hexane as eluant to give the title compound (7.0 g, 81%) as an oil. HR-MS-EI(+): calculated for C23H34O6 [M] 406.2350, found 406.2355.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[S:20]1[CH:24]=[C:23]([CH:25]=O)[N:22]=[CH:21]1>>[S:20]1[CH:24]=[C:23]([CH2:25][N:4]2[CH2:3][CH2:2][N:1]([C:7]3[CH:8]=[CH:9][C:10]4[N:11]([C:13]([C:16]([F:17])([F:18])[F:19])=[N:14][N:15]=4)[N:12]=3)[CH2:6][CH2:5]2)[N:22]=[CH:21]1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Reactant: O=Cc1cscn1
Product: FC(F)(F)c1nnc2ccc(N3CCN(Cc4cscn4)CC3)nn12

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 1,3-thiazole-4-carbaldehyde was carried out according to General Synthetic Method 5. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column (5μ silica, 19 mm diameter, 100 mm length) eluted with decreasingly polar mixtures of water (containing 1% aqueous ammonia) and acetonitrile as eluents to give 6-[4-(1,3-thiazol-4-ylmethyl)piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][OH:8])=[CH:5][CH:4]=1.[CH:11]([N:14]=[C:15]=[N:16][CH:17]([CH3:19])[CH3:18])([CH3:13])[CH3:12]>>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][O:8][C:15](=[N:14][CH:11]([CH3:13])[CH3:12])[NH:16][CH:17]([CH3:19])[CH3:18])=[CH:5][CH:4]=1
Reactant: CC(C)N=C=NC(C)C
Reactant: COc1ccc(CO)cc1
Product: COc1ccc(COC(=NC(C)C)NC(C)C)cc1
Temperature: 60 °C

Procedure:
Anhydrous cupric chloride (8 mg) is added to a mixture of 4-methoxybenzyl alcohol (2.76 g) and 1,3-diisopropylcarbodiimide (3.13 mL) under a nitrogen atmosphere. The reaction is quite exothermic and it is cooled with an ice bath for 1 h. The mixture is then heated for 3.5 h at 60° C. The product was purified by distillation to give O-p-methoxybenzyl-N,N'-diisopropylisourea (4 g).
Reaction SMILES: [NH:1]1[CH2:4][CH2:3][C@H:2]1[C:5]([OH:7])=[O:6].Cl.Br[C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1>[Cu](I)I.CC(N(C)C)=O>[Cl:16][C:13]1[CH:14]=[CH:15][C:10]([N:1]2[CH2:4][CH2:3][C@H:2]2[C:5]([OH:7])=[O:6])=[CH:11][CH:12]=1
Reactant: O=C(O)[C@@H]1CCN1
Reactant: Clc1ccc(Br)cc1
Agent: I[Cu]I
Agent: Cl
Solvent: CC(=O)N(C)C
Product: O=C(O)[C@@H]1CCN1c1ccc(Cl)cc1
Temperature: 110 °C

Procedure:
A sealed tube is charged with (S)-Azetidine-2-carboxylic acid; hydrochloride (2 g; 19.8 mmol), 4-bromochlorobenzene (3.8 g; 19.8 mmol) and copper iodide (I) (0.38 g; 1.99 mmol) is evacuated and back-filled with Argon 3 times. Dimethylacetamide (40 mL) is added and the tube is sealed and purged with Argon and evacuated 3 times. The sealed tube is heated in 110° C. oil bath for 72 hours. After this time, the reaction mixture is cooled to room temperature and partitioned between ethyl acetate and water. The organic layer is discarded. The aqueous layer is acidified to PH˜1 by adding 1N hydrochloric acid and then extracted with ethyl acetate twice. The organics are combined and washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. Purification by flash chromatography on silica gel using methanol/methylene chloride provides the title compound, m/z 212 [M+H+].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[C:14]([NH:15][C@@H:16]4[CH2:21][CH2:20][C:19](=[O:22])[CH2:18][C@H:17]4[CH3:23])=[N:13][CH:12]=[C:11]([C:24]#[N:25])[C:7]=3[NH:8][C:9]=2[CH:10]=1.[BH4-].[Na+].[Cl-].[NH4+]>CO.[Cl-].[Na+].O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[C:14]([NH:15][C@@H:16]4[CH2:21][CH2:20][C@@H:19]([OH:22])[CH2:18][C@H:17]4[CH3:23])=[N:13][CH:12]=[C:11]([C:24]#[N:25])[C:7]=3[NH:8][C:9]=2[CH:10]=1
Reactant: C[C@@H]1CC(=O)CC[C@H]1Nc1ncc(C#N)c2[nH]c3cc(Cl)ccc3c12
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: C[C@@H]1C[C@H](O)CC[C@H]1Nc1ncc(C#N)c2[nH]c3cc(Cl)ccc3c12
Reaction time: 0.5 h

Procedure:
To a stirred solution of 7-chloro-1-{[(1R,2R)-2-methyl-4-oxocyclohexyl]amino}-5H-pyrido[4,3-b]indole-4-carbonitrile (121 mg, 0.34 mmol) in MeOH (20 mL) was added sodium borohydride (26 mg, 0.69 mmol) at 0° C. The reaction mixture was left to stir for 30 min, treated with aqueous ammonium chloride and brine, and extracted with EtOAc. The combined organics were dried (sodium sulfate), and concentrated. The diastereomers were separated by flash chromatography to afford the title compound. LRMS (APCI) calc'd for (C19H19ClN4O) [M+H]+, 355.1. found 355.0.
Reaction SMILES: [NH2:1][C@@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][CH2:5][CH2:6][NH2:7].N[C@H](C(O)=O)CCCNC(=N)N.N[C@@H](C(O)=O)CCCNC(=N)N.N[C@H](C(O)=O)CCSC.N[C@@H](C(O)=O)CCSC.N[C@H](C(O)=O)[C@H](CC)C.N[C@@H](C(O)=O)[C@@H](CC)C.N[C@H](C(O)=O)CCCN.N[C@@H](C(O)=O)CCCN>>[NH2:1][C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][CH2:5][CH2:6][NH2:7]
Reactant: NCCCC[C@@H](N)C(=O)O
Agent: CC[C@@H](C)[C@@H](N)C(=O)O
Agent: CC[C@H](C)[C@H](N)C(=O)O
Agent: CSCC[C@@H](N)C(=O)O
Product: NCCCC[C@H](N)C(=O)O

Procedure:
replace with: D-Lys, Arg, D-Arg, Homo-arg, D-homo-Arg, Met, D-Met, Ile, D-Ile, Orn, D-Orn;
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C@@H:2]([C@H:4]([C:6]([OH:8])=[O:7])[OH:5])[OH:3]>CC(C)=O>[C:1]([OH:10])(=[O:9])[CH:2]([CH:4]([C:6]([OH:8])=[O:7])[OH:5])[OH:3]
Reactant: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Solvent: CC(C)=O
Product: O=C(O)C(O)C(O)C(=O)O

Procedure:
The free base was dissolved in acetone and treated with two mole equivalents of L-tartaric acid. This mixture was concentrated and treated with dry ether to give a tartaric acid salt of the title compound as a yellow solid; mp 170°-173° C.; IR (KBr) 3422, 3064, 2940, 2818, 1724, 1652, 1534 cm-1 ; MS (FAB) MH+ m/z 1100, (M+K)+ m/z 1138; 1H-NMR (CDCl3) δ 1.102 (s, 3H), 1.199 (s, 3H), 1.648 (s, 3H), 1.853 (m, H), 1.935 (s, 3H), 2.096 (m, H), 2.195 (s, 3H), 2.303 (m, H), 2.415 (s, 3H), 2.603-2.766 (m, 10H), 3.568 (S, 2H), 3.713 (m, 2H), 3.795 (d, H), 4.175 (d, H), 4.297 (d, H), 4.424 (m, H), 4.953 (d, H), 5.655 (m, 2H), 5.995 (m, H), 6.224 (t, H), 6.269 (S, H), 7.088 (d, NH), 7.200-8.200 (m, 19H).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:16]=[C:15]3[C:10]([C:11]([NH:18][C@@H:19]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=4)[CH3:20])=[C:12]([NH2:17])[CH:13]=[N:14]3)=[CH:9][C:8]=2[O:27][CH3:28])=[C:5]([CH3:29])[O:4][N:3]=1.[N:30]([CH2:33][CH2:34][O:35][CH3:36])=[C:31]=S.C(Cl)CCl>CCO>[CH3:1][C:2]1[C:6]([C:7]2[C:8]([O:27][CH3:28])=[CH:9][C:10]3[C:11]4[N:18]([C@@H:19]([C:21]5[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=5)[CH3:20])[C:31]([NH:30][CH2:33][CH2:34][O:35][CH3:36])=[N:17][C:12]=4[CH:13]=[N:14][C:15]=3[CH:16]=2)=[C:5]([CH3:29])[O:4][N:3]=1
Reactant: COc1cc2c(N[C@H](C)c3ccccn3)c(N)cnc2cc1-c1c(C)noc1C
Reactant: COCCN=C=S
Solvent: CCO
Solvent: ClCCCl
Product: COCCNc1nc2cnc3cc(-c4c(C)noc4C)c(OC)cc3c2n1[C@H](C)c1ccccn1
Temperature: 60 °C
Yield: 19 %

Procedure:
To a solution of 7-(3,5-dimethylisoxazol-4-yl)-6-methoxy-N4—((R)-1-(pyridin-2-yl)ethyl)quinoline-3,4-diamine (for a preparation, see Intermediate 25) (538 mg, 1.38 mmol) in EtOH (40 mL) was added 1-isothiocyanato-2-methoxyethane (0.30 mL, 2.76 mmol) and the mixture heated at 60° C. for 5.5 h. A further portion of 1-isothiocyanato-2-methoxyethane (0.15 mL, 1.38 mmol) was added and the reaction mixture heated at 60° C. overnight. The mixture was concentrated in vacuo, the residue dissolved in THF (40 mL), EDC (530 mg, 2.76 mmol) added, and the mixture heated at 60° C. for 4 h. The mixture was concentrated in vacuo and the residue purified by chromatography (100 g column, 2M methanolic ammonia/DCM gradient) to give the crude product which was further purified by MDAP (HpH) to give 7-(3,5-dimethylisoxazol-4-yl)-8-methoxy-N-(2-methoxyethyl)-1-((R)-1-(pyridin-2-yl)ethyl)-1H-imidazo[4,5-c]quinolin-2-amine (122 mg, 0.258 mmol, 19% yield) as a white solid. LCMS: (Formate, 2 min), Rt 0.73 mins, MH+ 473.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([O:9][CH2:10][C:11]([F:14])([F:13])[F:12])[N:3]=1.[NH2:15][C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[C:18]([O:26][CH2:27][CH2:28][CH2:29][Cl:30])[CH:17]=1>C1COCC1.C(Cl)Cl.O>[Cl:8][C:6]1[N:5]=[C:4]([O:9][CH2:10][C:11]([F:14])([F:13])[F:12])[N:3]=[C:2]([NH:15][C:16]2[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[C:18]([O:26][CH2:27][CH2:28][CH2:29][Cl:30])[CH:17]=2)[N:7]=1
Reactant: COC(=O)c1ccc(N)cc1OCCCCl
Reactant: FC(F)(F)COc1nc(Cl)nc(Cl)n1
Solvent: ClCCl
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(Nc2nc(Cl)nc(OCC(F)(F)F)n2)cc1OCCCCl
Reaction time: 16 h

Procedure:
To a solution of 2,4-dichloro-6-(2,2,2-trifluoroethoxy)-1,3,5-triazine (770 mg, 2.79 mmol) in THF (10 mL) was added methyl 4-amino-2-(3-chloropropoxy)benzoate (681 mg, 2.79 mmol) and Hunig'sBase (1.464 mL, 8.38 mmol). The resulting mixture was stirred for 16 h. The reaction was diluted with DCM and water. The organic layer was collected and dried over sodium sulfate, and concentrated under vacuum. The crude product was purified by silica gel chromatography using 20-40% EtOAc/Hexanes. The product fractions were collected and concentrated under vacuum to give methyl 4-(4-chloro-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)-2-(3-chloropropoxy)benzoate as a solid.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10][CH:11]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][NH:26][C:27](=[O:40])[C:28]2[CH:33]=[CH:32][C:31]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=3)=[CH:30][CH:29]=2)=[CH:19][CH:18]=1)[C:12]([O:14]C)=[O:13].[OH-].[Na+]>>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10][CH:11]([CH2:16][C:17]1[CH:18]=[CH:19][C:20]([O:23][CH2:24][CH2:25][NH:26][C:27](=[O:40])[C:28]2[CH:29]=[CH:30][C:31]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=3)=[CH:32][CH:33]=2)=[CH:21][CH:22]=1)[C:12]([OH:14])=[O:13]
Reactant: COC(=O)C(Cc1ccc(OCCNC(=O)c2ccc(-c3ccccn3)cc2)cc1)Sc1nc2ccccc2o1
Agent: [Na+]
Agent: [OH-]
Product: O=C(NCCOc1ccc(CC(Sc2nc3ccccc3o2)C(=O)O)cc1)c1ccc(-c2ccccn2)cc1
Yield: 70.5 %

Procedure:
In a similar manner to that described in Example 2, methyl 2-(benzoxazole-2-ylthio)-3-[4-[2-(4-pyridine-2-ylbenzoylamino)ethoxy]phenyl]propionate (361 mg), which is the product of Example 156, was reacted with aqueous sodium hydroxide solution (1N, 1.30 ml) and the reaction mixture was treated to give the title compound (248 mg) as colorless crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]2[C:14](=[O:15])[C:13]3[CH:16]=[CH:17][C:18]([OH:20])=[CH:19][C:12]=3[O:11]2)[CH:6]=[CH:7][CH:8]=1.[C:21](Cl)(=[O:23])[CH3:22].C(OCC)(=O)C>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]2[C:14](=[O:15])[C:13]3[CH:16]=[CH:17][C:18]([O:20][C:21](=[O:23])[CH3:22])=[CH:19][C:12]=3[O:11]2)[CH:6]=[CH:7][CH:8]=1
Reactant: CC(=O)Cl
Reactant: COc1cccc(C=C2Oc3cc(O)ccc3C2=O)c1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: COc1cccc(C=C2Oc3cc(OC(C)=O)ccc3C2=O)c1
Temperature: 25 °C

Procedure:
After 2-[(3-methoxyphenyl)methylene]-6-hydroxy-3(2H)-benzofuranone 0.5 g was dissolved in pyridine 5 ml, acetyl chloride 0.172 ml was added, and the mixture was refluxed for 2.5 hours. The reaction mixture was cooled to room temperature, ethyl acetate 50 ml was added, and the mixture was washed with 2N-hydrochloric acid 50 ml twice. After the ethyl acetate solution was dehydrated with anhydrous magnesium sulfate, it was concentrated under reduced pressure. The residue was fractionated by silica gel column chromatography (silica gel: 50 g, eluted with solvent 500 ml of hexane:ethyl acetate=1:1) and the fraction was concentrated to dryness at a temperature of 40° C. under reduced pressure to obtain crystals. The crystals were dried over phosphorous pentoxide at a temperature of 60° C. for five hours under reduced pressure to obtain the desired compound 371.6 mg.
Reaction SMILES: [F:1][C:2]([F:54])([F:53])[C:3]1[CH:4]=[C:5]([CH:46]=[C:47]([C:49]([F:52])([F:51])[F:50])[CH:48]=1)[CH2:6][N:7]([CH2:20][C:21]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:22]=1[N:31]([C:41]([O:43][CH2:44][CH3:45])=[O:42])[CH2:32][CH2:33][CH2:34][CH2:35][C:36]([O:38]CC)=[O:37])[C:8]1[N:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[CH:10][N:9]=1.[OH-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CO>[F:52][C:49]([F:50])([F:51])[C:47]1[CH:46]=[C:5]([CH:4]=[C:3]([C:2]([F:53])([F:1])[F:54])[CH:48]=1)[CH2:6][N:7]([CH2:20][C:21]1[CH:26]=[C:25]([C:27]([F:28])([F:29])[F:30])[CH:24]=[CH:23][C:22]=1[N:31]([C:41]([O:43][CH2:44][CH3:45])=[O:42])[CH2:32][CH2:33][CH2:34][CH2:35][C:36]([OH:38])=[O:37])[C:8]1[N:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[CH:10][N:9]=1
Reactant: CCOC(=O)CCCCN(C(=O)OCC)c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(N2CCOCC2)cn1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCOC(=O)N(CCCCC(=O)O)c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(N2CCOCC2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.2 %

Procedure:
Ethyl 5-[(2-{[(3,5-bis-trifluoromethyl-benzyl)-(5-morpholin-4-yl-pyrimidin-2-yl)-amino]-methyl}-4-trifluoromethyl-phenyl)-ethoxycarbonyl-amino]-pentanoate (134 mg) is dissolved in methanol (1 ml), and thereto is added 1M-aqueous sodium hydroxide solution (1 ml), and the mixture is stirred at room temperature for 1 hour and a half. The reaction solution is made weakly acidic with a 10% aqueous citric acid solution, and the mixture is extracted with ethyl acetate, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (chloroform:methanol=19:1) to give 5-[(2-{[(3,5-bis-trifluoromethyl-benzyl)-(5-morpholin-4-yl-pyrimidin-2-yl)-amino]-methyl}-4-trifluoromethyl-phenyl)-ethoxycarbonyl-amino]-pentanoic acid (123 mg). MS (m/z): 752 [M+H]+
Reaction SMILES: Cl[Si](C)(C)C.[F:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=O)[CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:9][CH:8]=1.C(N(CC)CC)C.C([SiH](CC)CC)C.[Cl-].C(Cl)Cl>C1COCC1>[F:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:11][CH:12]=1
Reactant: O=C(O)CCC(=O)c1ccc(F)cc1
Agent: CC[SiH](CC)CC
Agent: C[Si](C)(C)Cl
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=C(O)CCCc1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 53.1 %

Procedure:
At 0° C., chlorotrimethylsilane (10.6 ml, 84.1 mmol) was added dropwise to a solution of 4-(4-fluorophenyl)-4-oxobutanoic acid (15.0 g, 76.5 mmol) and triethylamine (11.7 ml, 84.1 mmol) in THF (200 ml). The reaction mixture was stirred for 20 min at 0° C. The solid was filtered off. The solvent was removed from the solution. The residue was dissolved in DCM (200 ml). Triethylsilane (40 ml, 252 mmol) was added. An 1 N solution of titan(IV) chloride in DCM (229 ml, 229 mmol) was added dropwise while cooling with a water bath. The reaction mixture was stirred for 16 hours at room temperature. It was given onto ice water (300 ml). The phases were separated. The aqueous phase was extracted with DCM (100 ml). The combined organic phases were extracted with a saturated aqueous solution of sodium hydrogen carbonate (3×150 ml). The sodium hydrogen carbonate phases were combined and acidified with 1 N hydrochloric acid to pH 2. They were extracted with ethyl acetate (5×150 ml). The combined ethyl acetate layers were dried. The solvent was removed in vacuo to give 7.4 g of crude 4-(4-fluorophenyl)butyric acid, which was used in the next step without further purification.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[N:15]=[CH:14][C:13]([C:16](=[O:29])[NH:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=3)=[CH:12][C:8]=2[C:9]([OH:11])=O)[CH2:3]1.F[P-](F)(F)(F)(F)F.[N:37]1(OC(N(C)C)=[N+](C)C)[C:41]2N=CC=[CH:45][C:40]=2N=N1.CCN(C(C)C)C(C)C.C(N)C#C>CN(C=O)C.CCOC(C)=O>[OH:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]([C:9]([NH:37][CH2:41][C:40]#[CH:45])=[O:11])=[CH:12][C:13]([C:16]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=3)=[O:29])=[CH:14][N:15]=2)[CH2:3]1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(C(=O)O)c1
Agent: C#CCN
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C#CCNC(=O)c1cc(C(=O)Nc2ccc(OC(F)(F)F)cc2)cnc1N1CC[C@@H](O)C1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of (R)-2-(3-hydroxypyrrolidin-1-yl)-5-((4-(trifluoromethoxy)phenyl)carbamoyl)nicotinic acid (Stage 72.3, 1.50 g, 3.65 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU, 1.66 g, 4.38 mmol) and DIPEA (0.566 g, 4.38 mmol) in DMF (40 mL) was stirred at RT for 15 min and then propargylamine (0.35 mL, 5.47 mmol) was added. The mixture was stirred for 3 h and then treated with EtOAc, washed with sat. aq. solution of NaHCO3 and brine. The organic phase was dried over Na2SO4 and the solvent was evaporated off under reduced pressure and the residue was crystallized from TBME/EtOAc to afford the product as a colorless crystalline solid. m.p. 246-248° C., HPLC (Condition 4) tR=4.79 min, UPLC-MS (Condition 8) tR=0.89 min, m/z=449.1 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.78-2.01 (m, 2H), 3.15 (t, J=2.54 Hz, 1H), 3.24 (d, J=12.12 Hz, 1H), 3.43-3.69 (m, 3H), 4.03 (d, J=4.30 Hz, 2H), 4.33 (br. s, 1H), 4.96 (d, J=3.13 Hz, 1H), 7.34 (d, J=8.99 Hz, 2H), 7.79-7.90 (m, 2H), 8.04 (d, J=2.35 Hz, 1H), 8.75 (d, J=2.35 Hz, 1H), 8.96 (t, J=5.67 Hz, 1H), 10.20 (s, 1H).
Reaction SMILES: C(O[C:6]([N:8]([CH2:10][CH2:11][N:12]([CH3:34])[C:13]([O:15][C@@H:16]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18])=[O:14])C)=O)(C)(C)C.[ClH:35]>C(OCC)(=O)C>[ClH:35].[CH3:6][NH:8][CH2:10][CH2:11][N:12]([CH3:34])[C:13]([O:15][C@@H:16]([CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18])=[O:14]
Reactant: CN(CCN(C)C(=O)OC(C)(C)C)C(=O)O[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Product: CNCCN(C)C(=O)O[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of benzyl (2S)-2-[N-[2-(N-t-butoxycarbonyl-N-methylamino)ethyl]-N-methylaminocarbonyl]oxy-3-phenylpropionate (5.40 g) in ethyl acetate (50 ml) which was cooled at 0° C. was added 4N hydrogen chloride solution in ethyl acetate (50 ml). The solution was stirred at 0° C. for 1 hour and the solvent was evaporated in vacuo to give benzyl (2S)-2-[N-[2-(N-methylamino)ethyl]-N-methylaminocarbonyl]oxy-3-phenylpropionate hydrochloride (4.70 g) as a solid. Rf: 0.23 (chloroform:methanol, 10:1, V/V)
Reaction SMILES: [Br:1][C:2]1[N:7]2[CH:8]=[C:9]([CH2:11][OH:12])[N:10]=[C:6]2[C:5]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[N:4][CH:3]=1.Cl[C:20]1[CH:29]=[CH:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:21]=1>>[Br:1][C:2]1[N:7]2[CH:8]=[C:9]([CH2:11][O:12][C:20]3[CH:29]=[CH:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[N:21]=3)[N:10]=[C:6]2[C:5]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[N:4][CH:3]=1
Reactant: Clc1ccc2ccccc2n1
Reactant: OCc1cn2c(Br)cnc(N3CCOCC3)c2n1
Product: Brc1cnc(N2CCOCC2)c2nc(COc3ccc4ccccc4n3)cn12
Yield: 75 %

Procedure:
Compound 1e (10.0 g, 30.4 mmol) was treated with 2-chloroquinoline using the reaction conditions described in Example 1, Step I to obtain compound 15a as a white solid (10.4 g, 75% yield). Mass Spectrum (LCMS, ESI pos.): Calcd. for C20H18BrN5O2: 440.1 (M+H). found: 440.3.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16](I)=[CH:15][CH:14]=2)[S:9][CH:10]=1)=[O:5])C.[CH3:20][O:21][CH2:22][C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][CH:28]=1>>[CH3:20][O:21][CH2:22][C:23]1[CH:28]=[C:27]([C:16]2[CH:15]=[CH:14][C:13]([O:12][CH2:11][C:8]3[S:9][CH:10]=[C:6]([C:4]([OH:3])=[O:5])[N:7]=3)=[CH:18][CH:17]=2)[CH:26]=[CH:25][CH:24]=1
Reactant: COCc1cccc(B(O)O)c1
Reactant: CCOC(=O)c1csc(COc2ccc(I)cc2)n1
Product: COCc1cccc(-c2ccc(OCc3nc(C(=O)O)cs3)cc2)c1

Procedure:
2-(3′-Methoxymethyl-biphenyl-4-yloxymethyl)-thiazole-4-carboxylic acid was prepared using general procedure 2 from 2-(4-iodo-phenoxymethyl)-thiazole-4-carboxylic acid ethyl ester (of Intermediate 2) and 3-methoxymethylphenylboronic acid (available from Digital Specialty Chemicals, Inc., Dublin, N.H.). Mass spectrum MH+=356.