Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)[C:3]([N:5]1[CH2:10][CH2:9][C:8]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:7][CH2:6]1)=[O:4].Cl[C:32](OC1C=CC([N+]([O-])=O)=CC=1)=[O:33].[NH4+].[OH-].[NH2:46][CH2:47][CH2:48][C:49]1[N:53]=[CH:52][NH:51][CH:50]=1.[OH-].[Na+]>C(Cl)Cl.CN(C=O)C.O>[CH:16]1([C:8]2([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:9][CH2:10][N:5]([C:3](=[O:4])[C@H:2]([NH:1][C:32]([NH:46][CH2:47][CH2:48][C:49]3[N:53]=[CH:52][NH:51][CH:50]=3)=[O:33])[CH2:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=3)[CH2:6][CH2:7]2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CCOC(=O)C1(C2CCCCC2)CCN(C(=O)[C@H](N)Cc2ccc(OC)cc2)CC1
Reactant: NCCc1c[nH]cn1
Agent: [NH4+]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(=O)C1(C2CCCCC2)CCN(C(=O)[C@@H](Cc2ccc(OC)cc2)NC(=O)NCCc2c[nH]cn2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.4 %

Procedure:
To 2.35 g (5.64 mmol) of ethyl 1-[(R)-2-amino-3-(4-methoxyphenyl)propionyl]-4-cyclohexylpiperidine-4-carboxylate dissolved in 25 mL of DCM immersed in a bath of cold water are added 1.25 g (6.21 mmol) of 4-nitrophenyl chloroformate. After warming to room temperature, the reaction medium is stirred for 1 hour. The reaction is stopped by adding aqueous NH4OH solution and the organic compounds are extracted with DCM. The organic phase is then washed with water and then dried over MgSO4, filtered and concentrated. The crude product obtained is dissolved in 25 mL of DMF at 80° C., and 0.70 g (6.3 mmol) of histamine is then added. After 15 minutes, the reaction is stopped by adding aqueous 1N sodium hydroxide solution and the organic compounds are extracted with DCM. The organic phase is dried over MgSO4, filtered and concentrated. The crude product obtained is chromatographed on silica gel (eluent: 86/14 DCM/MeOH). 1.48 g of ethyl 4-cyclohexyl-1-[(R)-2-{3-[2-(1H-imidazol-4-yl)ethyl]ureido}-3-(4-methoxyphenyl)propionyl]piperidine-4-carboxylate in the form of a white powder are obtained in a yield of 47%.
Reaction SMILES: [F:1][C:2]1[C:3]([C:28]([NH:30][CH2:31][C:32]([OH:42])([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH2:33][CH2:34][CH3:35])=[O:29])=[N:4][CH:5]=[CH:6][C:7]=1[S:8][C:9]1[S:13][C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)=[CH:17][N:16]=2)=[N:11][CH:10]=1.[CH3:43][N:44]([CH3:49])[CH2:45][C:46](O)=[O:47].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.Cl>CN1C(=O)CCC1>[CH3:43][N:44]([CH3:49])[CH2:45][C:46]([N:25]1[CH2:24][CH2:23][CH:22]([NH:21][C:18]2[CH:19]=[CH:20][C:15]([NH:14][C:12]3[S:13][C:9]([S:8][C:7]4[CH:6]=[CH:5][N:4]=[C:3]([C:28]([NH:30][CH2:31][C:32]([OH:42])([C:36]5[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=5)[CH2:33][CH2:34][CH3:35])=[O:29])[C:2]=4[F:1])=[CH:10][N:11]=3)=[N:16][CH:17]=2)[CH2:27][CH2:26]1)=[O:47]
Reactant: CCCC(O)(CNC(=O)c1nccc(Sc2cnc(Nc3ccc(NC4CCNCC4)cn3)s2)c1F)c1ccccc1
Reactant: CN(C)CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCCC1=O
Product: CCCC(O)(CNC(=O)c1nccc(Sc2cnc(Nc3ccc(NC4CCN(C(=O)CN(C)C)CC4)cn3)s2)c1F)c1ccccc1
Reaction time: 2 h

Procedure:
To a stirring suspension of 3-fluoro-N-(2-hydroxy-2-phenylpentyl)-4-(2-(5-(piperidin-4-ylamino)pyridin-2-ylamino)thiazol-5-ylthio)picolinamide (737 mg, 1.021 mmol), dimethylglycine (636 mg, 6.167 mmol), EDAC (590 mg, 3.078 mmol), HOBt (275 mg, 2.035 mmol) in NMP (10 mL) was added i-Pr2Net (1.8 ml, 10.3 mmol). After 2 h, the reaction was diluted with PrepLC solvent B (TFA):TFA (8 mL:2 mL), filtered into 14 prepLC vials, purified on PrepLC (YMC-Pack C18 30×100 mm, NH4Oac). The fractions containing the product were concentrated in SpeedVac overnight. The fractions were pooled together using MeOH and concentrated. The product was obtained (417 mg, 59%) as a solid, then converted to the HCl salt: 1H NMR (400 MHz, DMSO-d6) δ ppm: 11.52 (1H, s), 9.53 (1H, s), 8.23 (2H, t, J=5.81 Hz), 7.78 (1H, s), 7.72 (1H, s), 7.42 (2H, d, J=7.33 Hz), 7.29 (2H, t, J=7.58 Hz), 7.18 (2H, t, J=7.33 Hz), 7.03 (1H, t, J=5.31 Hz), 6.96 (1H, d, J=8.84 Hz), 4.29 (2H, m), 3.61 (3H, d, J=5.81 Hz), 3.15 (1H, m), 2.93 (1H, t, J=11.62 Hz), 2.75-2.82 (6H, m), 1.95 (3H, t, J=9.98 Hz), 1.65-1.78 (2H, m), 1.33 (2H, s), 1.17-1.26 (2H, m), 0.88 (1H, m), 0.74 (3H, t, J=7.20 Hz); LC/MS (M+H)+: 693. HPLC ret. time (Condition M): 1.40 min.
Reaction SMILES: [C:1](#[N:3])[CH3:2].C([Li])CCC.[CH3:9][O:10][C:11]1[CH:12]=[C:13]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[C:14](OC)=[O:15].O>CCCCCC.C1COCC1>[CH3:9][O:10][C:11]1[CH:12]=[C:13]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[C:14]([CH2:2][C:1]#[N:3])=[O:15]
Reactant: CC#N
Reactant: COC(=O)c1ccc(OC)c(OC)c1
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1ccc(C(=O)CC#N)cc1OC
Reaction time: 1 h

Procedure:
Dry acetonitrile (1.8 ml) was added to a solution of n-butyl lithium (a 2.5M solution in hexane, 13.8 ml) in dry THF (30 ml) at -78° C., and the mixture was stirred at the same temperature for 1 hour. To the mixture was added a solution of methyl 3,4-dimethoxybenzoate (6.42 g) in dry THF (15 ml), and the mixture was stirred at -78° C. for 3 hours and then at room temperature for 1 hour. After adding water (100 ml), the reaction solution was extracted with ethyl ether (100 ml). After the aqueous layer was acidified with 6 N hydrochloric acid, it was extracted with ethyl acetate (200 ml×3). The organic layers were combined, washed with saturated brine and then dried over anhydrous sodium sulfate. Then the solvent was distilled away under a reduced pressure. The resulting residue was crystallized from ethyl acetate/hexane to obtain the title compound (3.6 g) as pale yellow crystals.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:3]=1[NH2:4].C(N(CC)CC)C.[Cl:17][CH2:18][C:19](Cl)=[O:20]>C(Cl)Cl>[Cl:17][CH2:18][C:19]([NH:4][C:3]1[CH:5]=[CH:6][C:7]([F:9])=[CH:8][C:2]=1[F:1])=[O:20]
Reactant: O=C(Cl)CCl
Reactant: Nc1ccc(F)cc1F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CCl)Nc1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.9 %

Procedure:
To a cooled (0° C.) solution of 2,4-difluoroaniline, (1.5 g, 11.6 mmol) in DCM (50 mL) was added triethylamine (1.9 mL, 13.9 mmol) followed by 2-chloroacetyl chloride (1.0 mL, 12.8 mmol). The reaction was warmed to RT and stirred for 2 h. The reaction mixture was concentrated, redissolved in EtOAc (50 mL) and washed with brine (50 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated to yield 2.2 g of crude product which was further purified by flash column chromatography using 1:1 EtOAc:hexanes as the eluent. 2.0 g of 2-chloro-N-(2,4-difluorophenyl)acetamide, (yield: 84%) was isolated.
Reaction SMILES: [C:1]1([C:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([CH:10]2[CH2:13][N:12]([CH:14]([CH3:16])[CH3:15])[CH2:11]2)[C:8]#N)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)[OH:24].[OH-:28].[Na+]>>[C:1]1([C:7]2([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:10]([CH2:13][NH:12][CH:14]([CH3:16])[CH3:15])[CH2:11][O:28][C:8]2=[O:24])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)(O)O
Reactant: [OH-]
Reactant: CC(C)N1CC(C(C#N)(c2ccccc2)c2ccccc2)C1
Agent: [Na+]
Product: CC(C)NCC1COC(=O)C1(c1ccccc1)c1ccccc1
Temperature: 130 °C

Procedure:
α,α-Diphenyl-α-(1-isopropyl-3azetidinyl)acetonitrile (142 g.; 0.49 mole) was added to 500 g. of 70% sulfuric acid at 90°-100° C. The temperature was raised to 130° C. for 48 hours. The cooled mixture was poured onto ice and the cold mixture made basic by the addition of solid sodium hydroxide. The basic mixture was extracted with chloroform and the combined chloroform extracts dried over sodium sulfate and concentrated. The residual material was crystallized from an 80% isooctane - 20% isopropyl ether solution. The 4,5-dihydro-3,3-diphenyl-4-isopropylaminomethylfuran-2(3H)one weighed 105 g. (69.3%) and melted at 78°-80° C.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12](OCC(F)(F)F)[C:11](C(F)(F)F)=[CH:10][C:9]=1[NH:24][C:25](=[O:44])[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:36]=[N:37][C:38]([CH:41]([CH3:43])[CH3:42])=[CH:39][CH:40]=2)[CH:30]=1)=O)(C)(C)C.[C:46](O)([C:48]([F:51])([F:50])[F:49])=[O:47]>C(Cl)Cl>[CH:41]([C:38]1[N:37]=[CH:36][C:35]([C:31]2[CH:30]=[C:29]([C:27]3[CH2:26][C:25](=[O:44])[NH:24][C:9]4[CH:10]=[C:11]([C:48]([F:51])([F:50])[F:49])[C:12]([O:47][CH2:46][C:48]([F:51])([F:50])[F:49])=[CH:13][C:8]=4[N:7]=3)[CH:34]=[CH:33][CH:32]=2)=[CH:40][CH:39]=1)([CH3:42])[CH3:43]
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)c1ccc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(OCC(F)(F)F)cc3NC(=O)OC(C)(C)C)c2)cn1
Solvent: ClCCl
Product: CC(C)c1ccc(-c2cccc(C3=Nc4cc(OCC(F)(F)F)c(C(F)(F)F)cc4NC(=O)C3)c2)cn1

Procedure:
The title compound was prepared from [2-{3-[3-(6-isopropyl-pyridin-3-yl)-phenyl]-3-oxo-propionylamino}-5-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example M160) (339 mg, 0.53 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as an off-white solid (203 mg, 73%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:4]([C:7]([F:10])=[CH:8][CH:9]=1)[C:5]#[N:6].C(OC([NH:25][C@@H:26]([CH3:30])[C:27](O)=O)=O)(C)(C)C.C1C=NC2N(O)N=NC=2C=1.CN1CCOCC1.[ClH:48].CN(C)CCCN=C=NCC>C(Cl)Cl.O>[ClH:48].[NH2:25][C@H:26]([C:30]1[N:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:3]2[C:4]([C:5]#[N:6])=[C:7]([F:10])[CH:8]=[CH:9][C:2]=2[N:1]=1)[CH3:27]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: N#Cc1c(F)ccc(N)c1Nc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: O
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: C[C@H](N)c1nc2ccc(F)c(C#N)c2n1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 3-amino-6-fluoro-2-phenylaminobenzonitrile (960 mg, 4.22 mmol), (S)-2-tertbutoxycarbonylaminopropionic acid (879 mg, 4.6 mmol), HOAt (633 mg, 4.6 mmol), 4-methylmorpholine (1.02 mL, 9.29 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (892 mg, 4.6 mmol) in DCM (5 mL) was stirred at RT for 1 h. The reaction mixture was diluted with water and extracted with DCM (×3). The combined organic fractions were washed with brine, then dried (MgSO4) and concentrated in vacuo. A solution of the resulting residue in AcOH (5 mL) was heated at 70° C. for 18 h and then concentrated under reduced pressure. The resulting residue was partitioned between EtOAc and a saturated aqueous solution of NaHCO3. The aqueous phase was extracted with EtOAc (×3) and the combined organic fractions were washed with brine, dried (MgSO4) and concentrated in vacuo. The resulting residue was dissolved in 4N HCl in dioxane (5 mL) and stirred at RT for 1 h. The volatiles were removed under reduced pressure to afford 2-((S)-1-aminoethyl)-5-fluoro-3-phenyl-3H-benzoimidazole-4-carbonitrile hydrochloride as a brown solid which was used in the following step without further purification.
Reaction SMILES: CC1C=C2N=C3C(=NC(NC3=O)=O)N(C[C@H](O)[C@H](O)[C@H](O)CO)C2=CC=1C.[F:28][C:29]1[CH:53]=[CH:52][CH:51]=[C:50]([F:54])[C:30]=1[C:31]([NH:33][C:34]1[CH:38]=[CH:37][N:36]([CH2:39][C:40]2[CH:45]=[C:44]([N+:46]([O-])=O)[CH:43]=[CH:42][C:41]=2[CH3:49])[N:35]=1)=[O:32]>[Pd].C(OCC)(=O)C.C(O)C>[NH2:46][C:44]1[CH:43]=[CH:42][C:41]([CH3:49])=[C:40]([CH2:39][N:36]2[CH:37]=[CH:38][C:34]([NH:33][C:31](=[O:32])[C:30]3[C:29]([F:28])=[CH:53][CH:52]=[CH:51][C:50]=3[F:54])=[N:35]2)[CH:45]=1
Reactant: Cc1ccc([N+](=O)[O-])cc1Cn1ccc(NC(=O)c2c(F)cccc2F)n1
Agent: [Pd]
Agent: Cc1cc2nc3c(=O)[nH]c(=O)nc-3n(C[C@H](O)[C@H](O)[C@H](O)CO)c2cc1C
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1ccc(N)cc1Cn1ccc(NC(=O)c2c(F)cccc2F)n1
Reaction time: 1.5 h

Procedure:
To 10% palladium on activated carbon degussa type E101 NE/W (wet) (280 mg) was added a slight suspension of 2,6-difluoro-N-{1-[(2-methyl-5-nitrophenyl)methyl]-1H-pyrazol-3-yl}benzamide (for a preparation see Intermediate 47)(1.27 g, 3.41 mmol) in a mixture of ethyl acetate (20 ml) and ethanol (50 ml) under vacuum. The suspension was hydrogenated for 1.5 h at ambient temperature. The suspension was filtered and the residue washed with methanol (30 ml). The solvent was removed in vacuo to leave a white solid (1.09 g); LCMS (System 4) MH+=343, tRET=1.43 min.
Reaction SMILES: [OH:1][C:2]([C@H:5]1[CH2:9][CH2:8][NH:7][C@H:6]1[CH3:10])([CH3:4])[CH3:3].F[C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=1>>[OH:1][C:2]([C@H:5]1[CH2:9][CH2:8][N:7]([C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=2)[C@H:6]1[CH3:10])([CH3:4])[CH3:3]
Reactant: N#Cc1ccc(F)cc1
Reactant: C[C@@H]1NCC[C@@H]1C(C)(C)O
Product: C[C@H]1[C@@H](C(C)(C)O)CCN1c1ccc(C#N)cc1

Procedure:
Using compound 1 and 4-fluorobenzonitrile as starting materials, the title compound was obtained by the same manner as shown in Example 1 (reaction temperature 90° C., reaction time 3 hr).
Reaction SMILES: [C:1]1([CH:7]2[O:11][N:10]=[C:9]([C:12]3[N:13]=[C:14]([CH:17]4[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]4)[S:15][CH:16]=3)[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.C(OCC)C.CO>ClCCl>[C:1]1([CH:7]2[O:11][N:10]=[C:9]([C:12]3[N:13]=[C:14]([CH:17]4[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]4)[S:15][CH:16]=3)[CH2:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(C3=NOC(c4ccccc4)C3)cs2)CC1
Agent: Cl
Solvent: CCOCC
Solvent: CO
Solvent: ClCCl
Product: c1ccc(C2CC(c3csc(C4CCNCC4)n3)=NO2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1,1-dimethylethyl 4-[4-(4,5-dihydro-5-phenyl-3-isoxazolyl)-2-thiazolyl)-1-piperidinecarboxylate (i.e. the product of Step A) (0.815 g, 1.97 mmol) in dichloromethane (50 mL) was added a solution of hydrogen chloride and diethyl ether (2 M, 10 mL, 20 mmol). The reaction mixture was stirred at room temperature for 1 h to give a gummy precipitate. Methanol was added to dissolve the precipitate, and the reaction mixture was stirred for an additional 1 h. The reaction mixture was concentrated under reduced pressure and partitioned between ethyl acetate and saturated aqueous sodium bicarbonate, the organic layer was dried (MgSO4) and concentrated to give the title compound as a clear oil (0.31 g), which solidified on standing.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][N:5]([CH2:7][CH:8]([C:10]2[S:11][CH:12]=[CH:13][N:14]=2)[OH:9])[CH:6]=1.[F:15][C:16]1[CH:34]=[CH:33][C:19]([CH2:20][CH2:21][C:22]2[CH:31]=[CH:30][C:29](O)=[CH:28][C:23]=2[C:24]([O:26][CH3:27])=[O:25])=[CH:18][CH:17]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[CH3:1][C:2]1[N:3]=[CH:4][N:5]([CH2:7][CH:8]([C:10]2[S:11][CH:12]=[CH:13][N:14]=2)[O:9][C:29]2[CH:30]=[CH:31][C:22]([CH2:21][CH2:20][C:19]3[CH:18]=[CH:17][C:16]([F:15])=[CH:34][CH:33]=3)=[C:23]([CH:28]=2)[C:24]([O:26][CH3:27])=[O:25])[CH:6]=1
Reactant: COC(=O)c1cc(O)ccc1CCc1ccc(F)cc1
Reactant: Cc1cn(CC(O)c2nccs2)cn1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cc(OC(Cn2cnc(C)c2)c2nccs2)ccc1CCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 48.3 %

Procedure:
A stirred mixture of 2-(4-methylimidazol-1-yl)-1-(thiazol-2-yl)ethanol (1.35 g, 6.46 mM), methyl 2-(4-fluorophenethyl)-5-hydroxybenzoate (1.95 g, 7.1 mM) and triphenylphosphine (1.86 g, 7.1 mM) in dry THF was cooled in an ice bath, and treated with DEAD (1.24 g, 7.1 mM). The mixture was allowed to warm to ambient temperature, stirred for 18 hours and evaporated to dryness. The product was purified on silica using methanol/dichloromethane (3→10%) as eluant to give methyl 5-[2-(4-methylimidazol-1-yl)-1-(thiazol-2-yl)ethoxy]-2-(4-fluorophenethyl)benzoate (1.45 g, 48%).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:4]=1[N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][CH2:14]1.C(N(CC)CC)C.[C:29](Cl)(=[O:31])[CH3:30].N(CC)(CC)CC.Cl>C(Cl)Cl.O>[C:29]([NH:2][C:3]1[CH:8]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:6]=[CH:5][C:4]=1[N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][CH2:14]1)(=[O:31])[CH3:30]
Reactant: CC(=O)Cl
Reactant: Nc1cc(C(F)(F)F)ccc1N1CCc2ccccc21
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CC(=O)Nc1cc(C(F)(F)F)ccc1N1CCc2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred mixture, under N2, of 6.30 g of 1-(2-amino-4-trifluoromethylphenyl)indoline hydrochloride in 100 ml of dry methylene chloride is added 4.04 g of triethylamine. The mixture is then cooled to 0°-5°, and kept at that temperature while a solution of 1.57 g of acetyl chloride in 25 ml of CH2Cl2 is added dropwise over 1 hour. After stirring at room temperature overnight, water is added to dissolve the precipitated (C2H5)3N.HCl salt, and the layers are separated. The organic phase is washed further with 3N--HCl, 3N--NaOH, with H2O and dried over Na2SO4. The solvent is removed to yield 1-(2-acetamido-4-trifluoromethylphenyl)indoline, m.p. 153°-155° C.
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][N:8]=1)=[O:5].[C:19]([O:23][C:24]([NH:26][CH2:27][CH2:28][O:29][C:30]1[CH:38]=[C:37]([N:39]2[CH2:44][CH2:43][O:42][CH2:41][CH2:40]2)[CH:36]=[CH:35][C:31]=1[C:32](O)=[O:33])=[O:25])([CH3:22])([CH3:21])[CH3:20]>>[C:19]([O:23][C:24]([NH:26][CH2:27][CH2:28][O:29][C:30]1[CH:38]=[C:37]([N:39]2[CH2:44][CH2:43][O:42][CH2:41][CH2:40]2)[CH:36]=[CH:35][C:31]=1[C:32]([NH:1][C:2]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][N:8]=1)=[O:5])=[O:33])=[O:25])([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)OC(=O)NCCOc1cc(N2CCOCC2)ccc1C(=O)O
Reactant: Nc1cc(Cl)ccc1C(=O)Nc1ccc(Cl)cn1
Product: CC(C)(C)OC(=O)NCCOc1cc(N2CCOCC2)ccc1C(=O)Nc1cc(Cl)ccc1C(=O)Nc1ccc(Cl)cn1
Yield: 74 %

Procedure:
Using methods substantially equivalent to those described in Example 29-G, 2-[2-(2-tert-butoxycarbonylaminoethoxy)-4-(morpholin-4-yl)benzoylamin]-4-chloro-N-(5-chloropyridin-2-yl)benzamide was prepared in a 74% yield from 2-amino-4-chloro-N-(5-chloropyridin-2-yl)benzamide and 2-(2-tert-butoxycarbonylaminoethoxy)-4-(morpholin-4-yl)benzoic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:19])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N+:16]([O-])=O.O.[Sn](Cl)(Cl)(Cl)Cl>O1CCOCC1>[ClH:1].[NH2:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[C:9]([NH:8][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:2]=1[Cl:1])=[O:19]
Reactant: O=C(Nc1cnccc1Cl)c1ccccc1[N+](=O)[O-]
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: O
Solvent: C1COCCO1
Product: Cl
Product: Nc1ccccc1C(=O)Nc1cnccc1Cl
Temperature: 90 °C
Reaction time: 1 h

Procedure:
A suspension of N-(4-chloropyridin-3-yl)-2-nitrobenzamide (1.9 g, 6.8 mmol) in dioxane (10 mL) and conc. HCL (40 mL) was treated with tin chloride hydrate (6.2 g, 27.2 mmol). The reaction mixture was stirred at 90° C. for one hour (the mixture evolved from suspension to solution and back to suspension). After cooling down, the precipitate was filtered off and dried under high vacuum. The 2-amino-N-(4-chloropyridin-3-yl)benzamide hydrochloride was obtained as an off-white solid (3.0 g). LCMS [M+H]: 248.
Reaction SMILES: C(OC([NH:11][C@H:12]([C:16]([NH:18][C@H:19]([C:32]([NH2:34])=[O:33])[CH2:20][CH2:21][CH2:22][CH2:23][NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[O:17])[CH:13]([CH3:15])[CH3:14])=O)C1C=CC=CC=1.[CH3:35][C@H:36]([NH:49][C:50]([O:52][CH2:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)=[O:51])[C:37]([O:39]C1C=CC([N+]([O-])=O)=CC=1)=O.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[CH2:53]([O:52][C:50]([NH:49][C@H:36]([C:37]([NH:11][C@H:12]([C:16]([NH:18][C@H:19]([C:32]([NH2:34])=[O:33])[CH2:20][CH2:21][CH2:22][CH2:23][NH:24][C:25]([O:27][C:28]([CH3:30])([CH3:29])[CH3:31])=[O:26])=[O:17])[CH:13]([CH3:14])[CH3:15])=[O:39])[CH3:35])=[O:51])[C:54]1[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=1
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)Oc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](CCCCNC(=O)OC(C)(C)C)C(N)=O
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)[C@H](NC(=O)[C@H](C)NC(=O)OCc1ccccc1)C(=O)N[C@@H](CCCCNC(=O)OC(C)(C)C)C(N)=O

Procedure:
A sample of compound XV (4.3 g, 9 mmole) was hydrogenated as described in the previous paragraph and the partially deblocked peptide (RfC, 0.60) was acylated with Z-L-Ala-ONp (3.47 g, 10 mmole, Bachem) in the presence of DIEA (3.2 ml, 20 mmole) and HOBt (1.3 g, 9 mmole). The product isolated as described for XV weighed 4.2 g (85%) m.p. 214°-217° C., [α]D24 -9.5° (c 0.8, DMF); RfB, 0.48; RfI, 0.33.
Reaction SMILES: C(O[C:4]([C:6]1[N:11]=[CH:10][C:9]2[N:12]=[C:13]([O:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[S:14][C:8]=2[C:7]=1[OH:22])=[O:5])C.[NH2:23][CH2:24][C:25]([OH:27])=[O:26].C[O-].[Na+].CO>>[OH:22][C:7]1[C:8]2[S:14][C:13]([O:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[N:12][C:9]=2[CH:10]=[N:11][C:6]=1[C:4]([NH:23][CH2:24][C:25]([OH:27])=[O:26])=[O:5]
Reactant: CCOC(=O)c1ncc2nc(Oc3ccccc3)sc2c1O
Reactant: NCC(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C(O)CNC(=O)c1ncc2nc(Oc3ccccc3)sc2c1O
Temperature: 25 °C
Yield: 54.6 %

Procedure:
A mixture of 7-hydroxy-2-phenoxy-thiazolo[4,5-c]pyridine-6-carboxylic acid ethyl ester (81 mg, 0.26 mmol) and glycine (386 mg, 5.14 mmol) in 0.5 M sodium methoxide/methanol (9.8 mL, 4.88 mmol) was refluxed for 3 days before it was cooled to room temperature and concentrated in vacuo. The residue was dissolved in water and extracted with dichloromethane. The remaining aqueous layer was acidified to pH=3 with 1N HCl (7.3 mL). The suspension was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, concentrated in vacuo and purified on a C18 reverse column with a gradient of 0.1% TFA in water and 0.1% TFA in acetonitrile to give the title compound as a brown solid (49 mg): 1H NMR (DMSO-d6, 200 MHz): δ=13.16 (s, 1H), 9.39 (br s, 1H), 8.60 (s, 1H), 7.55 (m, 4H), 7.42 (m, 1H), 4.01 (d, J=6.4 Hz, 2H); MS: (+) m/z 346.00 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[S:24][CH:23]=[N:22][C:21]=2[CH3:25])[CH2:9][C:10]([C:12]2[CH:13]=[N:14][C:15]([O:18]C)=[CH:16][CH:17]=2)=[O:11])=[CH:4][CH:3]=1.Cl>O1CCOCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[S:24][CH:23]=[N:22][C:21]=2[CH3:25])[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][C:15](=[O:18])[NH:14][CH:13]=2)=[O:11])=[CH:4][CH:3]=1
Reactant: COc1ccc(C(=O)CC(c2ccc(Br)cc2)c2scnc2C)cn1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1ncsc1C(CC(=O)c1ccc(=O)[nH]c1)c1ccc(Br)cc1

Procedure:
In analogy to example 162, step 2, 3-(4-bromophenyl)-1-(6-methoxypyridin-3-yl)-3-(4-methylthiazol-5-yl)propan-1-one was reacted with concentrated aqueous HCl in 1,4-dioxane to give the title compound as an yellow solid, MS (ESI+): m/z=405.2 [M+H]+.
Reaction SMILES: C(N1[CH:12]=[CH:11]N=C1)(N1C=CN=C1)=O.[S:13]1[CH:17]=[C:16]([C:18]([OH:20])=[O:19])[CH:15]=[C:14]1[C:21]([OH:23])=[O:22].[CH2:24](O)[C:25]1[CH:33]=[CH:32][C:31]2[O:30][CH2:29][O:28][C:27]=2[CH:26]=1>>[O:30]1[C:31]2[CH:32]=[CH:33][C:25]([CH:24]([O:22][C:21]([C:14]3[S:13][CH:17]=[C:16]([C:18]([OH:20])=[O:19])[CH:15]=3)=[O:23])[C:12]3[CH:11]=[CH:26][C:27]4[O:28][CH2:29][O:30][C:31]=4[CH:32]=3)=[CH:26][C:27]=2[O:28][CH2:29]1
Reactant: O=C(O)c1csc(C(=O)O)c1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: OCc1ccc2c(c1)OCO2
Product: O=C(O)c1csc(C(=O)OC(c2ccc3c(c2)OCO3)c2ccc3c(c2)OCO3)c1
Yield: 114.8 %

Procedure:
The title compound was prepared according to the procedure described for Example 2 using carbonyldiimidazole (1.1 g, 6.8 mmol), 2,4-thiophene-dicarboxylic acid (0.5 g, 2.9 mmol) and piperonyl alcohol (0.45 g, 2.9 mmol). Acidification of the aqueous workup mixture with dilute hydrochloric acid prior to filtration afforded 0.71 g of thiophene-2,4-dicarboxylic acid di-1,3-benzodioxol-5-ylmethyl ester. Recrystallization of a sample from methanol followed by trituration in ethyl acetate then ether and drying gave product with a mp 164-165° C.