Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[C:6]([C:7]2[CH:8]=[C:9]([CH:14]=[C:15]([F:25])[C:16]=2OS(C(F)(F)F)(=O)=O)[C:10]([O:12][CH3:13])=[O:11])=[CH:5][CH2:4][CH2:3]1.COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1.[F:56][C:57]1[CH:62]=[CH:61][C:60]([O:63][CH3:64])=[CH:59][C:58]=1B(O)O.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:26][C:2]1([CH3:1])[C:6]([C:7]2[CH:8]=[C:9]([C:10]([O:12][CH3:13])=[O:11])[CH:14]=[C:15]([F:25])[C:16]=2[C:58]2[CH:59]=[C:60]([O:63][CH3:64])[CH:61]=[CH:62][C:57]=2[F:56])=[CH:5][CH2:4][CH2:3]1
Reactant: COC(=O)c1cc(F)c(OS(=O)(=O)C(F)(F)F)c(C2=CCCC2(C)C)c1
Reactant: COc1ccc(F)c(B(O)O)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(F)c(-c2cc(OC)ccc2F)c(C2=CCCC2(C)C)c1
Temperature: 75 °C
Reaction time: 21 h
Yield: 95 %

Procedure:
A stirred mixture of T33.6 (0.9464 g, 2.39 mmol), ground S-Phos (0.1977 g, 0.482 mmol), palladium acetate (0.0555 g, 0.247 mmol), 2-fluoro-5-methoxyphenylboronic acid (0.8114 g, 4.77 mmol) (commercially available from Sigma-Aldrich, St. Louis, Mo., USA), and potassium phosphate tribasic (1.2888 g, 6.072 mmol) in dry DMF (7.000 mL) was purged with argon and placed under vacuum and the process repeated three times. The mixture was then heated to 75° C. and the reaction was stirred for 21 hours. The reaction was then cooled to room temperature, diluted with water and extracted three times with EtOAc. The organic layers were combined and washed twice with brine. After drying over anhydrous sodium sulfate and filtration, the organic solvent was removed under reduced pressure. The residue was purified on an 80 g column of silica gel (0-20% EtOAc in hexanes) to afford T33.7 as a colorless oil that was used without further purification (850.5 mg, 95% yield). MS ESI (pos.) m/e: 373.0 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][NH2:10].[C:11]([NH:13][C:14](=[N:17][CH3:18])SC)#[N:12]>>[C:11]([NH:13][C:14]([NH:17][CH3:18])=[N:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][NH2:10])#[N:12]
Reactant: NCCCCCCCCN
Reactant: CN=C(NC#N)SC
Product: CNC(=NCCCCCCCCN)NC#N
Yield: 58.4 %

Procedure:
A mixture of 1,8-diaminooctane (14.1 g) with N-cyano-N'-methyl-S-methyl isothiourea (5.2 g) was maintained at 60° for 5 hours to give a solid product which was washed with ether and recrystallised from acetonitrile/ether to give N-cyano-N'-methyl-N"-(8-aminooctyl)guanidine (5.3 g) m.p. 81°-83°.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][N:14]=2)[CH:12]=1)[C:7]([OH:9])=[O:8])([CH3:3])=[CH2:2].[H][H]>C(O)C.[Pd]>[CH:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][N:14]=2)[CH:12]=1)[C:7]([OH:9])=[O:8])([CH3:3])[CH3:2]
Reactant: [H][H]
Reactant: C=C(C)c1cc(C(=O)O)cc(-c2ccc(C)cn2)c1
Agent: [Pd]
Solvent: CCO
Product: Cc1ccc(-c2cc(C(=O)O)cc(C(C)C)c2)nc1
Reaction time: 1 h
Yield: 99.2 %

Procedure:
To a solution of 3-isopropenyl-5-(5-methylpyridin-2-yl)benzoic acid (150 mg, 0.592 mmol) in ethanol (11.8 mL) was added 10% palladium on carbon (50.0 mg, 0.047 mmol) and the mixture was placed under 1 atm of hydrogen. After 1 h, filtration and concentration gave the crude title compound (150 mg). MS 256.2 (M+1).
Reaction SMILES: [F:1][C:2]([F:16])([O:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]=[C:14]=[O:15])=[CH:9][CH:8]=1)[CH:3]([F:5])[F:4].[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:28]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:27][NH:26][N:25]=2)=[CH:20][CH:19]=1>C(OCC)C>[F:1][C:2]([F:16])([O:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]([N:26]2[CH2:27][CH:28]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:24]([C:21]3[CH:20]=[CH:19][C:18]([Cl:17])=[CH:23][CH:22]=3)=[N:25]2)=[O:15])=[CH:9][CH:8]=1)[CH:3]([F:4])[F:5]
Reactant: O=C=Nc1ccc(OC(F)(F)C(F)F)cc1
Reactant: Clc1ccc(C2=NNCC2c2ccccc2)cc1
Solvent: CCOCC
Product: O=C(Nc1ccc(OC(F)(F)C(F)F)cc1)N1CC(c2ccccc2)C(c2ccc(Cl)cc2)=N1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1.7 g of 4-(1,1,2,2-tetrafluoroethoxy)phenylisocyanate were added, while stirring, to a suspension of 1.8 g of 3-(4-chlorophenyl)-4-phenyl-2-pyrazoline in 40 ml of dry diethyl ether. After stirring at room temperature for approximately 1 hour 40 ml of petroleum ether (40-60) were added to the reaction mixture, after which stirring at room temperature was continued for another 3 hours. The precipitate formed was sucked off and washed with petroleum ether (40-60). The desired product was obtained in a yield of 3.1 g; melting-point 178°-180° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:11]2[CH2:16][CH:15]([CH3:17])[CH2:14][CH:13]([CH3:18])[CH2:12]2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.Cl.[CH3:20][O:21][C:22](=[O:45])[C@@H:23]([NH2:44])[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[O:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[CH:27][CH:26]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:20][O:21][C:22](=[O:45])[CH:23]([NH:44][C:7](=[O:9])[C:6]1[CH:10]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=1[N:11]1[CH2:16][CH:15]([CH3:17])[CH2:14][CH:13]([CH3:18])[CH2:12]1)[CH2:24][C:25]1[CH:26]=[CH:27][C:28]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[O:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[CH:29][CH:30]=1
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2ccccc2Oc2ccccc2)cc1
Reactant: CC1CC(C)CN(c2ccc(Cl)cc2C(=O)O)C1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C(Cc1ccc(-c2ccccc2Oc2ccccc2)cc1)NC(=O)c1cc(Cl)ccc1N1CC(C)CC(C)C1
Yield: 78.1 %

Procedure:
A solution of 5-chloro-2-(3,5-dimethyl-piperidin-1-yl)-benzoic acid (0.250 g, 0.933 mmol) in DMF (4.0 mL) was reacted with (2S)-amino-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid methyl ester hydrochloride (0.360 g, 0.933 mmol), HBTU (0.355 g, 0.933 mmol), and DIEA (0.500 mL, 2.800 mmol) by the general procedure A. The crude product was purified by flash column chromatography on silica gel using DCM (+20% hexane) to give 0.435 g (62%) of 2-[5-Chloro-2-(3,5-dimethyl-piperidin-1-yl)-benzoylamino]-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid methyl ester. A solution of this ester (0.200 g, 0.334 mmol) in THF (4.0 mL) was reacted with LiOH (0.050 g, 1.172 mmol) by the general procedure I to give 0.182 g (93%) of 2-[5-Chloro-2-(3,5-dimethyl-piperidin-1-yl)-benzoylamino]-3-(2′-phenoxy-biphenyl-4-yl)-propionic acid as a white solid. LCMS: 584 (M+1)+. 1H NMR (CDCl3) 11.20 [d, 1H], 8.21 [d, 1H], 7.45 [m, 2H], 7.39 [m, 2H], 7.23 [m, 8H], 7.02 [m, 2H], 6.86 [m, 2H], 4.90 [m, 1H], 3.38 [dd, 5.60 Hz, 1H], 3.26 [dd, 1H], 2.80 [m, 2H], 2.16 [t, 1H], 2.04 [t, 1H], 1.70 [m, 2H], 1.43 [m, 1H], 0.76 [m, 6H], 0.58 [m, 1H].
Reaction SMILES: [Cl:1][C:2]1[N:6]=[C:5](Cl)[S:4][N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:14]([NH:16][C:17]([NH:19][C:20]1[S:21][C:22]2[C:28]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=3)=[CH:27][C:26](B(O)O)=[CH:25][C:23]=2[N:24]=1)=[O:18])[CH3:15]>C1COCC1.O>[Cl:1][C:2]1[N:6]=[C:5]([C:26]2[CH:27]=[C:28]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=3)[C:22]3[S:21][C:20]([NH:19][C:17]([NH:16][CH2:14][CH3:15])=[O:18])=[N:24][C:23]=3[CH:25]=2)[S:4][N:3]=1
Reactant: CCNC(=O)Nc1nc2cc(B(O)O)cc(-c3ccccn3)c2s1
Reactant: Clc1nsc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: O
Product: CCNC(=O)Nc1nc2cc(-c3nc(Cl)ns3)cc(-c3ccccn3)c2s1
Temperature: 110 °C

Procedure:
3,5-dichloro-1,2,4-thiadiazole (50 mg, 0.32 mmol), Cesium carbonate (285.6 mg, 0.88 mmol), Pd(dppf)2C12 (20 mg, 0.03 mmol) and {2-[(ethylcarbamoyl)amino]-7-(pyridin-2-yl)-1,3-benzothiazol-5-yl}boronic acid (100 mg, 0.29 mmol) was suspended in a mixture of THF (9 mL) and water (1 mL) and heated in the microwave at 110° C. for 50 min. The reaction mixture was concentrated in vacuo and the residue partitioned between 10% IPA/DCM (10 mL) and water (10 mL). The organic layer was separated and the aqueous extracted with further 10% IPA/DCM (3×10 mL), the organic layers were combined, dried (MgSO4), filtered and concentrated, then pre-absorbed onto silica and purified by flash column chromatography (Biotage SP4 12 g, 2% MeoH/DCM-5% MeoH/DCM-8% MeOH/DCM) to give 1-[5-(3-chloro-1,2,4-thiadiazol-5-yl)-7-(pyridin-2-yl)-1,3-benzothiazol-2-yl]-3-ethylurea as a brown solid. (100 mg, 81%) MS: 416.92 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11](C2C=C(Cl)C=CC=2Cl)[C@H:12]([CH3:20])[CH2:13][CH2:14][CH2:15][NH:16][C:17](=[O:19])C)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C1(S(N)(=O)=O)C=CC=CC=1.Cl[C:40](OC)=[O:41]>>[CH3:40][O:41][C:17]([NH:16][CH2:15][CH2:14][CH2:13][C@H:12]([NH:11][S:8]([C:5]1[CH:4]=[CH:3][CH:2]=[CH:7][CH:6]=1)(=[O:9])=[O:10])[CH3:20])=[O:19]
Reactant: CC(=O)NCCC[C@@H](C)N(c1cc(Cl)ccc1Cl)S(=O)(=O)c1ccc(Cl)cc1
Reactant: COC(=O)Cl
Agent: NS(=O)(=O)c1ccccc1
Product: COC(=O)NCCC[C@@H](C)NS(=O)(=O)c1ccccc1
Yield: 96 %

Procedure:
4-chloro-N-2,5-dichlorophenyl)-N-[4-[[(methoxy)carbonyl]amino]-1(R)-methylbutyl]benzenesulfonamide was prepared analogous to 4-chloro-N-[2,5-dichlorophenyl]-N-[(R)-1-methyl-4-(acetylamino)butyl]benzenesulfonamide by reacting 4-chloro-N-[2,5-dichlorophenyl]-N-[R]-1-methyl-4-aminobutyl]benzenesulfonamide with methyl chloroformate. Yield=96%; MS (ESI+), 479 (M+H)+.
Reaction SMILES: [CH3:1][C@@H:2]([NH2:11])[C@H:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl[C:13](Cl)([O:15]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[CH3:1][C@H:2]1[C@H:3]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)[O:10][C:13](=[O:15])[NH:11]1
Reactant: C[C@@H](N)[C@H](O)c1ccccc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Product: C[C@@H]1NC(=O)O[C@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 224 %

Procedure:
To a solution of (1S,2S)-(+)-Norpseudoephedrine (2.00 g, 13.2 mmol) in CH2Cl2 (60 mL) was added under argon Et3N (4.61 mL, 33.1 mmol) at 0° C. Then, triphosgene (1.57 g, 5.29 mmol) dissolved in 20 mL of CH2Cl2 was added slowly, and the temperature was allowed to warm from 0° C. to room temperature. The reaction mixture was stirred for 4 hours at room temperature. The reaction mixture was then quenched by addition of aqueous NH4Cl. The organic layers were separated, dried over MgSO4, filtered, and concentrated. The residue was purified by column chromatography using EtOAc in heptane from 0% to 100% in order to give the desired product (2.10 g, 89%). LC-MS: [M+H] 178.1; Rt 0.67 min; (LCMS method 2). 1H NMR (400 MHz, DMSO-d6) 7.88 (br s, 1H), 7.50-7.32 (m, 5H), 5.09 (d, 1H), 3.78-3.62 (m, 1H), 1.26 (d, 3H).
Reaction SMILES: [CH2:1]([O:8][N:9](CC)[C:10](=O)OC(C)(C)C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([O:8][NH:9][CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCN(OCc1ccccc1)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNOCc1ccccc1
Reaction time: 1 h
Yield: 96.4 %

Procedure:
151 (616 mg) was dissolved in 4 ml of DCM and 4 ml of TFA was added then the reaction mixture was let 1 h at room temperature. The reaction mixture is concentrated and 50 ml of AcOEt are added. The organic phase are washed with saturated NaHCO3 and brine then dried over Na2SO4, filtered and concentrated to afford 152 as an oil (324 mg, 88%). 1H NMR (DMSO): δ 0.99 (t, 3H, J=7.3 Hz), 2.82 (m, 2H), 4.61 (s, 2H), 6.50 (t, 1H, J=5.8 Hz), 7.32 (m, 5H).
Reaction SMILES: [C:1]1([NH:7][C@H:8]([C:12]([OH:14])=[O:13])[CH:9]([CH3:11])[CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CI.[C:17](=O)([O-])[O-].[K+].[K+]>CN(P(N(C)C)(N(C)C)=O)C.O1CCCC1>[C:1]1([N:7]([CH3:17])[C@H:8]([C:12]([OH:14])=[O:13])[CH:9]([CH3:11])[CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)[C@H](Nc1ccccc1)C(=O)O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Solvent: CI
Product: CC(C)[C@@H](C(=O)O)N(C)c1ccccc1
Temperature: 0 °C

Procedure:
To the m-phenoxybenzyl ester of N-phenylvaline (0.25 g) in HMPT (1 ml) and tetrahydrofuran (1 ml), at 24°, is added methyl iodide (0.12 ml) followed by potassium carbonate (0.092 g). The reaction mixture is heated at 60° for 4 days. The reaction is worked up by pouring into ice-water (5 ml) and extracting with ether (3×10 ml). The combined ether extracts are washed with water (2×10 ml) and brine (1×5 ml) and dried over calcium sulfate. The product is isolated and purified by preparative TLC to give the m-phenoxybenzyl ester of N-phenyl-N-methylvaline.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:14])=O>CN(C=O)C>[CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:3]=1[C:4]([Cl:14])=[O:5]
Reactant: Cc1cccc(C)c1C(=O)O
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: Cc1cccc(C)c1C(=O)Cl
Reaction time: 2 h

Procedure:
DMF (2 drops) was added to 2,6-dimethylbenzoic acid (0.100 g, 0.666 mmol) in thionyl chloride (0.50 mL, 6.9 mmol). The reaction mixture was stirred for 2 h and concentrated to yield the titled compound, which was used in the next step without further purification.
Reaction SMILES: CN1CCCC1=O.[CH3:8][C:9]1[N:14]=[C:13]([C:15]2[CH:16]=[N:17][N:18]([CH3:23])[C:19]=2[C:20]([OH:22])=O)[C:12]([CH3:24])=[CH:11][N:10]=1.Cl.[F:26][C:27]1[C:28]([NH2:42])=[CH:29][C:30]2[N:31]([N:33]=[C:34]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[N:35]=2)[CH:32]=1.C(N(C(C)C)CC)(C)C>O>[CH3:8][C:9]1[N:14]=[C:13]([C:15]2[CH:16]=[N:17][N:18]([CH3:23])[C:19]=2[C:20]([NH:42][C:28]2[C:27]([F:26])=[CH:32][N:31]3[N:33]=[C:34]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[N:35]=[C:30]3[CH:29]=2)=[O:22])[C:12]([CH3:24])=[CH:11][N:10]=1
Reactant: Cc1ncc(C)c(-c2cnn(C)c2C(=O)O)n1
Reactant: Nc1cc2nc(-c3ccccc3)nn2cc1F
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cc1ncc(C)c(-c2cnn(C)c2C(=O)Nc2cc3nc(-c4ccccc4)nn3cc2F)n1

Procedure:
An N-methylpyrrolidone (7.7 ml) solution of the 4-(2,5-dimethylpyrimidin-4-yl)-1-methyl-1H-pyrazole-5-carboxylic acid (715 mg) obtained in (Example 3.22) <Step 2>, 6-fluoro-2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-amine hydrochloride (obtained according to the method described in International Publication No. WO2012/076430, p. 80, Example 30-h) (815 mg), 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate methanaminium (2.34 g), and diisopropylethylamine (2.69 ml) was stirred at 80° C. for 3 hours. Thereafter, water was added to the reaction solution, and the mixed solution was then extracted with ethyl acetate. Organic layers were combined, and the combined organic layer was then dried over anhydrous sodium sulfate. Subsequently, the solvent was distilled away under reduced pressure, and the obtained residue was then purified by silica gel column chromatography (NH silica gel:eluent; heptane:ethyl acetate=3:1-1:1). The obtained fraction was concentrated under reduced pressure. The obtained residue (solid) was triturated with methanol to obtain the title compound (377 mg) in the form of a colorless solid.
Reaction SMILES: C([O:3][C:4](=[O:22])[CH2:5][NH:6][C:7]1[C:12]([NH:13][C:14]([C:16]2[O:17][C:18]([Br:21])=[CH:19][CH:20]=2)=O)=[CH:11][CH:10]=[CH:9][N:8]=1)C.O.[OH-].[K+]>C(O)CO.CO>[Br:21][C:18]1[O:17][C:16]([C:14]2[N:6]([CH2:5][C:4]([OH:3])=[O:22])[C:7]3=[N:8][CH:9]=[CH:10][CH:11]=[C:12]3[N:13]=2)=[CH:20][CH:19]=1
Reactant: CCOC(=O)CNc1ncccc1NC(=O)c1ccc(Br)o1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: OCCO
Product: O=C(O)Cn1c(-c2ccc(Br)o2)nc2cccnc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 1.6 %

Procedure:
A solution of N-[3-[(5-bromo-2-furanylcarbonyl)amino]-2-pyridinyl]glycine ethyl ester (110 g, 0.30 mole) in ethylene glycol (510 ml) was refluxed under nitrogen for two hours. The solution was cooled to room temperature and water (100 ml) and potassium hydroxide pellets (23.25 g, 0.41 mole) were added. The solution was refluxed for an additional 1.5 hours and then filtered, while hot, into ice water (2 liters). A 3N hydrochloric acid solution was added until the suspension was acidic. After stirring overnight, the solid was collected by filtration and rinsed with water. Most of the wet material was dried at 56° C. overnight under high vacuum to give 79.5 g of crude material (82%) yield). A portion (3.0 g of wet material) was dissolved in hot methanol, filtered, and cooled to room temperature. Addition of water caused a solid to precipitate which was collected by filtration, rinsed with water, and dried at high vacuum at 56° C. to give 1.59 g of title compound, mp 229°-231° C.
Reaction SMILES: Br[CH:2]([C:19]1[CH:24]=[CH:23][N:22]=[C:21]([Cl:25])[N:20]=1)[C:3]([C:5]1[C:6]([F:18])=[C:7]([NH:11][C:12](=[O:17])[O:13][CH2:14][CH:15]=[CH2:16])[CH:8]=[CH:9][CH:10]=1)=O.[CH3:26][C:27]([CH3:32])([CH3:31])[C:28]([NH2:30])=[O:29].O>CC(N(C)C)=O>[Cl:25][C:21]1[N:20]=[C:19]([C:2]2[O:29][C:28]([C:27]([CH3:32])([CH3:31])[CH3:26])=[N:30][C:3]=2[C:5]2[C:6]([F:18])=[C:7]([NH:11][C:12](=[O:17])[O:13][CH2:14][CH:15]=[CH2:16])[CH:8]=[CH:9][CH:10]=2)[CH:24]=[CH:23][N:22]=1
Reactant: C=CCOC(=O)Nc1cccc(C(=O)C(Br)c2ccnc(Cl)n2)c1F
Reactant: CC(C)(C)C(N)=O
Solvent: O
Solvent: CC(=O)N(C)C
Product: C=CCOC(=O)Nc1cccc(-c2nc(C(C)(C)C)oc2-c2ccnc(Cl)n2)c1F
Temperature: 80 °C
Yield: 19.7 %

Procedure:
A stirring mixture of 2-propen-1-yl {3-[bromo(2-chloro-4-pyrimidinyl)acetyl]-2-fluorophenyl}carbamate (6.1 g, 14.23 mmol) and 2,2-dimethylpropanamide (2.16 g, 21.35 mmol) in DMA (200 ml) was heated to 80° C. for 2 days. Upon cooling, the reaction mixture was poured into water (500 ml) and extracted with EtOAc (100 ml×5). The combined organic layers were washed with brine, separated, dried over Na2SO4, filtered, and concentrated. The crude product was added to a silica gel column and eluted with petroleum ether with EtOAc (10% to 16%) and collected fractions to obtain title compound as yellow solid (1.21 g, 19%). MS (ES): 431 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:16]([O:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=1)=[O:17])[CH:13]([CH3:15])[CH3:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)C.[Cl:31][CH2:32]Cl>>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:16]([O:18][C:19]1[CH:20]=[CH:21][C:22]([C:23]([O:25][CH2:32][Cl:31])=[O:24])=[CH:26][CH:27]=1)=[O:17])[CH:13]([CH3:15])[CH3:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: ClCCl
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)Oc1ccc(C(=O)O)cc1
Solvent: CCO
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)Oc1ccc(C(=O)OCCl)cc1

Procedure:
4-(N-benzyloxycarbonyl-L-valyloxy)benzoic acid was esterified by the method described in Example A-I-1, step d. The title compound (0.95 g) was obtained after silica gel column chromatography (0, 1% ethanol in dichloromethane). Rf (2%MeOH/CHCl3) 0.80.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:8][CH2:9][CH3:10])[CH2:5][CH2:6][NH2:7])[CH3:2].[C:11]1([CH2:17][CH:18]=O)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(O)(=O)C.C([BH3-])#N.[Na+]>C(O)C>[CH2:1]([O:3][CH:4]([O:8][CH2:9][CH3:10])[CH2:5][CH2:6][NH:7][CH2:18][CH2:17][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:2]
Reactant: CCOC(CCN)OCC
Reactant: O=CCc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(CCNCCc1ccccc1)OCC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 96.8 %

Procedure:
3,3-Diethoxypropan-1-amine (0.20 g) dissolved in ethanol (10 mL) was treated with 2-phenylacetaldehyde (0.163 g) and acetic acid (0.02 mL). The resulting mixture was stirred at room temperature for 15 minutes and treated with sodium cyanoborohydride (0.051 g). After 14 hours the mixture was concentrated, taken up in ethyl acetate (30 mL) washed with saturated sodium bicarbonate (20 mL), brine (20 mL), dried over anhydrous magnesium sulphate, filtered and concentrated under reduced pressure to give a crude sample of the sub-titled compound (0.33 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]=[CH:15][CH3:16])=[C:10]([O:17]CC2C=CC=CC=2)[CH:9]=1)([CH3:4])([CH3:3])[CH3:2]>C1COCC1.[Pd]>[C:1]([O:5][C:6](=[O:25])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH3:16])=[C:10]([OH:17])[CH:9]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CC=Cc1ccc(CC(=O)OC(C)(C)C)cc1OCc1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Product: CCCc1ccc(CC(=O)OC(C)(C)C)cc1O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of [3-benzyloxy-4-(propenyl)-phenyl]-acetic acid tert-butyl ester (1.21 g, 3.21 mmol, 1 eq.) in THF (39 mL) under N2, palladium on activated carbon (10% wt., 121 mg) was added. The flask was carefully evacuated and refilled with H2 (3×). The black suspension was stirred at r.t. under an H2-atmosphere for 18 hours. The black suspension was filtered through Celite and the filter cake was rinsed with THF. The filtrate was concentrated in vacuo. The residue was purified by flashmaster (column: 100 g, flow: 45 mL/min, 50 fractions of 45 mL, Heptane 100% to Heptane+20% AcOEt) to yield the title compound as a colorless oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].C([O:27][C:28](=O)[CH2:29][C:30](=[O:43])[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]2[CH:42]=[CH:41][N:40]=[CH:39][CH:38]=2)[CH:32]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:28](=[O:27])[CH2:29][C:30](=[O:43])[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]2[CH:38]=[CH:39][N:40]=[CH:41][CH:42]=2)[CH:32]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2ccncc2)c1
Product: CCOc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccncc3)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared from (2-amino-5-ethoxy-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J8) and 3-oxo-3-(3-pyridin-4-yl-phenyl)-propionic acid tert-butyl ester (Example K2) according to the general procedure M. Obtained as a light yellow solid (271 mg).
Reaction SMILES: C(O)(C(F)(F)F)=O.[Cl:8][C:9]1[C:14]([F:15])=[C:13]([Cl:16])[CH:12]=[CH:11][C:10]=1[C:17]([N:19]1[CH2:28][CH2:27][C:26]2[C:25]([C:29]3[N:33](C4CCCCO4)[N:32]=[CH:31][CH:30]=3)=[N:24][CH:23]=[N:22][C:21]=2[CH2:20]1)=[O:18].C([SiH](CC)CC)C>C(Cl)Cl>[Cl:8][C:9]1[C:14]([F:15])=[C:13]([Cl:16])[CH:12]=[CH:11][C:10]=1[C:17]([N:19]1[CH2:28][CH2:27][C:26]2[C:25]([C:29]3[NH:33][N:32]=[CH:31][CH:30]=3)=[N:24][CH:23]=[N:22][C:21]=2[CH2:20]1)=[O:18]
Reactant: O=C(c1ccc(Cl)c(F)c1Cl)N1CCc2c(ncnc2-c2ccnn2C2CCCCO2)C1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(c1ccc(Cl)c(F)c1Cl)N1CCc2c(ncnc2-c2ccn[nH]2)C1
Reaction time: 0.5 h
Yield: 103 %

Procedure:
TFA (0.97 mL, 0.24 mmol) was added to a solution of the product of Example 20, step b (116 mg, 0.24 mmol) in DCM (1 mL) containing triethylsilane (0.1 mL, 0.61 mmol). The reaction was stirred for 30 min. The reaction was concentrated in vacuo and then azeotroped 2x with toluene. The residue was purified on SiO2 eluting with EtOAc/Hex to afford the title compound as a white solid (97 mg, 100%). MS (ESI) mass calcd. C17H12Cl2FN5O, 391.04. m/z found 392.0 [M+H]+. 1H NMR (500 MHz, CDCl3): 9.11-8.93 (m, 1H), 7.77-7.67 (m, 1H), 7.48-7.37 (m, 1H), 7.15-7.07 (m, 1H), 6.99-6.90 (m, 1H), 5.14-4.96 (m, 1H), 4.61-4.40 (m, 1H), 4.17-4.11 (m, 1H), 3.67-3.51 (m, 1H), 3.36-3.08 (m, 2H).