Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: NC(CS)C(O)=O.[C:8]([C:10]1[CH:11]=[C:12]([CH:35]=[CH:36][C:37]=1[O:38][CH:39]([CH3:41])[CH3:40])[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:21]2[N:20]3[CH2:24][CH2:25][CH:26]([CH2:27][C:28]([O:30]C(C)(C)C)=[O:29])[C:19]3=[CH:18][C:17]=2[CH:16]=1)#[N:9]>C(O)(C(F)(F)F)=O>[C:8]([C:10]1[CH:11]=[C:12]([CH:35]=[CH:36][C:37]=1[O:38][CH:39]([CH3:41])[CH3:40])[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:21]2[N:20]3[CH2:24][CH2:25][CH:26]([CH2:27][C:28]([OH:30])=[O:29])[C:19]3=[CH:18][C:17]=2[CH:16]=1)#[N:9]
Reactant: CC(C)Oc1ccc(COc2ccc3c(c2)cc2n3CCC2CC(=O)OC(C)(C)C)cc1C#N
Agent: NC(CS)C(=O)O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)Oc1ccc(COc2ccc3c(c2)cc2n3CCC2CC(=O)O)cc1C#N
Temperature: 23 °C
Reaction time: 0.25 h
Yield: 79.3 %

Procedure:
A solution of 2-amino-3-mercaptopropanoic acid (0.229 g, 1.889 mmol) in TFA (3.15 mL) was made and added to tert-butyl 2-(7-(3-cyano-4-isopropoxybenzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate (0.290 g, 0.630 mmol) in a 20 mL sealed scintillation vial and stirred at 23° C. for 15 min. After 15 min the solution was poured into ice water and stirred for 30 minutes. The resulting precipitate was collected by vacuum filtration, washed with water (2×5 mL) and n-Hexane (3×5 mL), and dried (vacuum oven) to give the title compound (0.202 g) as an off-white solid. LCMS m/z=405.5 [M+H]+.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][NH2:19])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[O:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[C:25](O)=[O:26]>>[N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][NH:19][C:25]([C:21]3[O:20][CH:24]=[CH:23][CH:22]=3)=[O:26])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)c1ccco1
Reactant: NC/C=C\COc1cc(CN2CCCCC2)ccn1
Product: O=C(NC/C=C\COc1cc(CN2CCCCC2)ccn1)c1ccco1
Yield: 82 %

Procedure:
Following a procedure similar to that described in Example 13, but using 4-(4-piperidinomethyl-2-pyridyloxy) -cis-2-butenylamine and 2-furancarboxylic acid as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained as an oil in an 82% yield.
Reaction SMILES: Cl.[CH2:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][CH3:11])[C:5]=1[NH:12][C:13]([C:15]1[C:19]2[CH2:20][CH2:21][C:22]3[CH:23]=[N:24][C:25]([NH:28][CH:29]4[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]4)=[N:26][C:27]=3[C:18]=2[N:17]([CH3:35])[N:16]=1)=[O:14])[CH3:3].CCN(C(C)C)C(C)C.Br[CH2:46][CH2:47][C:48](Cl)=[O:49]>ClCCl>[C:48]([N:32]1[CH2:31][CH2:30][CH:29]([NH:28][C:25]2[N:24]=[CH:23][C:22]3[CH2:21][CH2:20][C:19]4[C:15]([C:13]([NH:12][C:5]5[C:4]([CH2:2][CH3:3])=[CH:9][CH:8]=[CH:7][C:6]=5[CH2:10][CH3:11])=[O:14])=[N:16][N:17]([CH3:35])[C:18]=4[C:27]=3[N:26]=2)[CH2:34][CH2:33]1)(=[O:49])[CH:47]=[CH2:46]
Reactant: O=C(Cl)CCBr
Reactant: CCc1cccc(CC)c1NC(=O)c1nn(C)c2c1CCc1cnc(NC3CCNCC3)nc1-2
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CC(=O)N1CCC(Nc2ncc3c(n2)-c2c(c(C(=O)Nc4c(CC)cccc4CC)nn2C)CC3)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 75 %

Procedure:
To a solution of N-(2,6-diethylphenyl)-1-methyl-8-(piperidin-4-ylamino)-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide hydrochloride (40 mg, 0.075 mmol) in dichloromethane (1 mL) at 0° C., DIPEA (0.4 mL, 2.2 mmol), and 3-bromopropionyl chloride (0.023 mL, 0.226 mmol) were added. The mixture was then stirred at room temperature for 3 h. Solvent evaporated to dryness and the crude solid was purified by flash chromatography on silica gel (eluant: dichloromethane/methanol: 9/1) to 73 mg of the title compound. (75% yield)
Reaction SMILES: Cl[CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)[N:4]=1.[F:15][C:16]1[C:21]([OH:22])=[CH:20][CH:19]=[C:18]([F:23])[C:17]=1[C:24]1[NH:28][C:27](=[O:29])[O:26][N:25]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]2[N:4]=[C:3]([CH2:2][O:22][C:21]3[C:16]([F:15])=[C:17]([C:24]4[NH:28][C:27](=[O:29])[O:26][N:25]=4)[C:18]([F:23])=[CH:19][CH:20]=3)[O:7][N:6]=2)=[CH:9][CH:10]=1
Reactant: O=c1[nH]c(-c2c(F)ccc(O)c2F)no1
Reactant: ClCc1nc(-c2ccc(Cl)cc2)no1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=c1[nH]c(-c2c(F)ccc(OCc3nc(-c4ccc(Cl)cc4)no3)c2F)no1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 5-chloromethyl-3-(4-chlorophenyl)-[1,2,4]oxadiazole (0.080 g, 0.35 mmol) in anhydrous DMF (2 ml) was added 3-(2,6-difluoro-3-hydroxyphenyl)-4H-[1,2,4]oxadiazol-5-one (0.075 g, 0.35 mmol) and potassium carbonate (0.17 g, 1.22 mmol) was added. The reaction mixture was stirred at 25° C. for 24 h under nitrogen atmosphere. After the completion of the reaction (TLC monitoring), the reaction mixture was evaporated to dryness under reduced pressure, added water and extracted with EtOAc (3×50 ml). The combined organics was washed with water, dried (Na2SO4), filtered and concentrated. The crude residue was purified over silica (60-120 M) using ethyl acetate/hexane (45:55) as the eluent to provide the title compound as off white solid (0.0088 g, 6%).
Reaction SMILES: N1CCCC1.[CH3:6][O:7][C:8]1[CH:29]=[CH:28][C:11]([C:12]([NH:14][C:15](=[O:27])[NH:16][C:17]2[CH:25]=[CH:24][CH:23]=[C:22]3[C:18]=2[CH2:19][C:20](=[O:26])[NH:21]3)=[O:13])=[CH:10][CH:9]=1.[NH:30]1[CH:34]=[CH:33][CH:32]=[C:31]1[CH:35]=O>C(O)C>[NH:30]1[CH:34]=[CH:33][CH:32]=[C:31]1/[CH:35]=[C:19]1\[C:20](=[O:26])[NH:21][C:22]2[C:18]\1=[C:17]([NH:16][C:15]([NH:14][C:12](=[O:13])[C:11]1[CH:10]=[CH:9][C:8]([O:7][CH3:6])=[CH:29][CH:28]=1)=[O:27])[CH:25]=[CH:24][CH:23]=2
Reactant: COc1ccc(C(=O)NC(=O)Nc2cccc3c2CC(=O)N3)cc1
Reactant: O=Cc1ccc[nH]1
Solvent: CCO
Solvent: C1CCNC1
Product: COc1ccc(C(=O)NC(=O)Nc2cccc3c2/C(=C/c2ccc[nH]2)C(=O)N3)cc1
Temperature: 25 °C

Procedure:
A catalytic amount of pyrrolidine (0.001 mmol) was added to a solution of 4-methoxy-N-(2-oxoindolin-4-ylcarbamoyl)benzamide (1 mmol) and pyrrole-2-carbaldehyde (1.2 mmol) in ethanol (5 mL). The reaction was carried out using microwave (CEM, Discover) at 100° C. (200 W. Standard mode) for 15 mins. Crude product was precipitated after cooling to RT, which was collected by filtration, washed with ethanol and air dried. YD: 65.57%; mp: Charred at 290-295° C. 1H NMR (DMSO-d6) 200 MHz, δ: 3.859 (s, 3H), 6.342-6.363 (m, 1H), 6.722-6.731 (m, 1H), 6.748 (d, J=7.6 Hz, 1H), 7.101 (d, J=9.2 Hz, 2H), 7.160 (t, J=8.0 Hz, 1H), 7.354 (br, 1H), 7.436 (d, J=8.0 Hz, 1H), 8.043 (s, 1H), 8.126 (d, J=8.8 Hz, 2H), 10.894 (s, 1H), 11.028 (s, 2H), 13.376 (s, 1H). (C22H18N4O4.1/2H2O) C, H, N. ESI-MS: m/z 400.9 [M−H]−.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21](O)=[O:22])=[CH:19][NH:18][C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.[CH3:24][C:25]1([NH2:28])[CH2:27][CH2:26]1.CCN=C=NCCCN(C)C.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C1C=CN=CC=1)C.CN(C=O)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21]([NH:28][C:25]5([CH3:24])[CH2:27][CH2:26]5)=[O:22])=[CH:19][NH:18][C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1
Reactant: CC1(N)CC1
Reactant: Cn1nc(-c2cnc3[nH]cc(C(=O)O)c3n2)c2ccc(Cl)cc21
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cn1nc(-c2cnc3[nH]cc(C(=O)NC4(C)CC4)c3n2)c2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 5 h
Yield: 30.6 %

Procedure:
A mixture of 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (0.07 g, 0.3 mmol), 1-methylcyclopropanamine (0.04 g, 0.56 mmol), EDCI (0.057 g, 0.3 mmol), DMAP (0.037 g, 0.3 mmol), and DIPEA (0.163 g, 1.26 mmol) in 10 mL of DMF was stirred at room temperature for 5 hours, and then HATU (0.114 g, 0.3 mmol) was added. The final reaction mixture was stirred for another 15 hours. The solvent was removed under reduced pressure at 70° C. The residue was triturated with water and then purified by preparative-HPLC (Gemini 5u C18 150×21.2 mm; inject volume: 3 mL/inj, flow rate: 20 mL/min; wavelength: 214 nm and 254 nm; the gradient conditions were: 50% acetonitrile/50% water (0.1% trifluoroacetic acid, v/v) initially, proceeding to 80% acetonitrile/20% water (0.1% trifluoroacetic acid, v/v) in a linear fashion over 9 min.) to give 2-(6-chloro-1-methyl-1H-indazol-3-yl)-N-(1-methylcyclopropyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (0.035 g, 43%) as a white solid. MS: (M+H)+=381; 1H NMR (300 MHz, DMSO): δ 12.87 (s, 1H), 9.11 (s, 1H), 8.55 (s, 1H), 8.46-8.44 (m, 2H), 8.04 (s, 1H), 7.38 (d, 1H, J=8.7 Hz), 4.20 (s, 3H), 1.50 (s, 3H), 0.90-0.82 (m, 4H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:13]=[CH:12][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][C:4]=1[N+:14]([O-:16])=[O:15].[NH2:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[C:21]#[N:22].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:21]([C:20]1[CH:19]=[C:18]([NH:17][CH2:2][C:3]2[CH:13]=[CH:12][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][C:4]=2[N+:14]([O-:16])=[O:15])[CH:25]=[CH:24][CH:23]=1)#[N:22]
Reactant: CCOC(=O)c1ccc(CBr)c([N+](=O)[O-])c1
Reactant: N#Cc1cccc(N)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)c1ccc(CNc2cccc(C#N)c2)c([N+](=O)[O-])c1
Temperature: 70 °C
Reaction time: 3 h
Yield: 54.9 %

Procedure:
Ethyl 4-bromomethyl-3-nitrobenzoate (26.00 g) was dissolved in 90 ml of acetonitrile, then 7.97 g of 3-aminobenzonitrile and 12.44 g of potassium carbonate were added and the mixture was stirred at 70° C. for 3 hours. The reaction solution was cooled to room temperature, and after filtration, the mother liquor was concentrated in vacuo. Ethyl acetate was added to the resulting residue. The mixture was washed with a 1N aqueous solution of hydrochloric acid and a saturated aqueous solution of sodium bicarbonate, dried over anhydrous magnesium sulfate and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography using hexane-ethyl acetate (80:20 to 75:25) as an eluting solvent to give 12.06 g of ethyl 4-[(3-cyanophenylamino)methyl]-3-nitrobenzoate.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]([CH3:9])=[C:5]([OH:10])[N:4]=[C:3]1[S:11][CH3:12].[C:13]([C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Cl)=[CH:19][CH:18]=1)([CH3:16])([CH3:15])[CH3:14].[H-].[Na+].O>CN(C)P(=O)(N(C)C)N(C)C>[C:13]([C:17]1[CH:18]=[CH:19][C:20]([CH2:21][O:10][C:5]2[N:4]=[C:3]([S:11][CH3:12])[N:2]([CH3:1])[C:7](=[O:8])[C:6]=2[CH3:9])=[CH:23][CH:24]=1)([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)c1ccc(CCl)cc1
Reactant: CSc1nc(O)c(C)c(=O)n1C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CSc1nc(OCc2ccc(C(C)(C)C)cc2)c(C)c(=O)n1C
Temperature: 25 °C
Reaction time: 15 h
Yield: 44.8 %

Procedure:
In 10 ml of hexamethyl phosphoric triamide were dissolved 1 g of 3,5-dimethyl-6-hydroxy-2-methylthio-4(3H)-pyrimidinone and 1 g of 4-t-butylbenzyl chloride, and thereto was added 0.3 g of sodium hydride (55% in mineral oil). The mixture was stirred for 15 hours at room temperature. The resulting solution was poured into 50 ml of water and then extracted twice with 30 ml of ethyl ether. The ethyl ether layer was dried over anhydrous sodium sulfate and freed of solvent by distillation under reduced pressure to give 1.9 g of a crude product. The product was purified by means of column chromatography (on silica gel, eluting with benzene) and then washed with a mixture of hexane and ethyl ether (10:1) to give 0.8 g of the intended product.
Reaction SMILES: [C:1]([C:9]1[C:10]([O:24][CH2:25][CH3:26])=[C:11]2[CH:17]=[N:16][N:15](CC3OC=CC=3)[C:12]2=[N:13][CH:14]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Se](=O)=O>O.COCCOCCOC>[C:1]([C:9]1[C:10]([O:24][CH2:25][CH3:26])=[C:11]2[CH:17]=[N:16][NH:15][C:12]2=[N:13][CH:14]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOc1c(C(=O)c2ccccc2)cnc2c1cnn2Cc1ccco1
Agent: O=[Se]=O
Solvent: O
Solvent: COCCOCCOC
Product: CCOc1c(C(=O)c2ccccc2)cnc2[nH]ncc12

Procedure:
1.7 g. of 5-Benzoyl-4-ethoxy-1-(2-furyl)methyl-1H-pyrazolo[3,4-b]pyridine (0.005 mol.) are dissolved in 5 ml. of diethyleneglycol dimethyl ether, 1.1 g. of selenium dioxide are added and the mixture is heated with stirring at 160°. After the addition of 1 drop of water, the temperature is maintained for 1 hour. The mixture is filtered hot and 5-benzoyl-4-ethoxy-1H-pyrazolo[3,4-b]pyridine precipitates on cooling. Recrystallization from butanol yields 1 g. (77%). m.p. 195°-197°.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]([OH:5])[CH3:4].[CH2:6]([O:13][C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[C:16](F)[CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>CS(C)=O>[CH2:6]([O:13][C:14]1[CH:15]=[CH:16][C:17]([C:18]#[N:19])=[C:20]([NH:1][CH2:2][C@H:3]([OH:5])[CH3:4])[CH:21]=1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: N#Cc1ccc(OCc2ccccc2)cc1F
Reactant: C[C@@H](O)CN
Solvent: CS(C)=O
Product: C[C@@H](O)CNc1cc(OCc2ccccc2)ccc1C#N
Temperature: 125 °C
Reaction time: 48 h

Procedure:
A solution of (R)-(−)-1-amino-propan-2-ol (389 g, 5.19 mol) in dimethyl sulfoxide (600 mL) was added to a solution of the product from Step A (786 g, 3.46 mol), basic alumina (786 g), and 4 Å molecular sieves (131 g). The stirred mixture was heated at 110-140° C. for 24 h, cooled and filtered, the filter-aide was washed with 10 L of 4:1 ether-ethyl acetate followed by 4 L of 3:2 ethyl acetate-hexane. The organic washes were extracted with water (5 L) and the aqueous phase was extracted with 25% ethyl acetate-hexane (4×2 L). The combined organic phases were washed with water and brine, dried over sodium sulfate, concentrated to about 3 L and allowed to stand for 48 h. The precipitated solid was collected by filtration, washed with hexane, and vacuum-dried to provide the desired product in two crops (619 g and 86 g). The concentated supernatant was applied to a 5 kg silica gel pad and eluted with a gradient of 10-50% ethyl acetate-hexane to give, after concentration in vacuo, additional product (119 g): total yield was 791 g (81%).
Reaction SMILES: I[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].[C:14]([O:18][C:19]1[CH:24]=[C:23]([CH3:25])[C:22]([Br:26])=[C:21]([CH3:27])[CH:20]=1)(=[O:17])[C:15]#[CH:16]>C1COCC1.[Cu]I>[N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:16]#[C:15][C:14]([O:18][C:19]2[CH:20]=[C:21]([CH3:27])[C:22]([Br:26])=[C:23]([CH3:25])[CH:24]=2)=[O:17])[CH:3]=1
Reactant: C#CC(=O)Oc1cc(C)c(Br)c(C)c1
Reactant: Ic1cccnc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1cc(OC(=O)C#Cc2cccnc2)cc(C)c1Br
Temperature: 65 °C
Yield: 26.7 %

Procedure:
3-Iodopyridine (226 mg, 1.10 mmol) in THF (2 mL) was degassed under reduced pressure at −78° C., and then nitrogen gas was introduced. To the solution was added K2CO3 (276 mg, 2.00 mmol), CuI (15 mg, 0.079 mmol) and PdCl2(Ph3P)2 (7 mg, 0.01 mmol), and the mixture was stirred at 65° C. 4-bromo-3,5-dimethylphenyl propiolate (6-1) (253 mg, 1.00 mmol) in THF (2 mL) was added by syringe pump over a period of 5 h, and the mixture was stirred an additional 1 h after addition was complete. After being cooled to room temperature, the mixture was filtered. The filtrate was concentrated and purified by silica gel column chromatography to give the title compound 13-1 (88 mg, 27% yield) as a black oil.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4](O)=[O:5].C[N:13]1CCOCC1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[OH-].[NH4+]>C1COCC1>[NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]([NH2:13])=[O:5]
Reactant: CN1CCOCC1
Reactant: Nc1cccc(Cl)c1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: NC(=O)c1c(N)cccc1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-amino-6-chlorobenzoic acid (2.00 g, 11.65 mmol) in anhydrous THF (20 mL) were added 4-methylmorpholine (1.40 mL, 12.82 mmol), HOBT (1.73 g, 12.82 mmol), and EDCl (2.45 g, 12.82 mmol); the reaction mixture was stirred at room temperature for 30 minutes. 50% (v/v) Ammonium hydroxide solution (10 mL, 132.0 mmol) was added and the mixture was stirred at room temperature for 23 hours. Solvent was evaporated to about 20 mL, poured into aqueous NaHCO3 solution (200 mL) and extracted with ethyl acetate (7×100 mL). The organic phase was washed with water (3×100 mL), dried (Na2SO4), filtered, and evaporated, to give 2-amino-6-chlorobenzamide as a white solid. Yield: 1.65 g (83%).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[C:9]([C:12]([OH:14])=O)[S:10][CH:11]=2)=[CH:5][CH:4]=[N:3]1.[NH2:15][C@@H:16]([CH2:29][C:30]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=1[F:37])[CH2:17][N:18]1[C:26](=[O:27])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]1=[O:28].FC1C=CC=C(F)C=1C[C@@H](C(O)=O)N.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)(Cl)Cl>[F:37][C:31]1[CH:32]=[CH:33][C:34]([F:36])=[CH:35][C:30]=1[CH2:29][C@H:16]([NH:15][C:12]([C:9]1[S:10][CH:11]=[C:7]([C:6]2[N:2]([CH3:1])[N:3]=[CH:4][CH:5]=2)[CH:8]=1)=[O:14])[CH2:17][N:18]1[C:26](=[O:27])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]1=[O:28]
Reactant: N[C@@H](Cc1cc(F)ccc1F)CN1C(=O)c2ccccc2C1=O
Reactant: Cn1nccc1-c1csc(C(=O)O)c1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: N[C@@H](Cc1c(F)cccc1F)C(=O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: Cn1nccc1-c1csc(C(=O)N[C@@H](Cc2cc(F)ccc2F)CN2C(=O)c3ccccc3C2=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.8 %

Procedure:
To a 50 mL round-bottomed flask was added 4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (257 mg, 0.93 mmol) [prepared according to the procedure of Example 146], 2-[(2S)-2-amino-3-(2,5-difluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione (476 mg, 0.81 mmol) [prepared according to the procedure of Preparation 18 except substituting 2,5-difluoro-L-phenylalanine (3.02 g, 15.0 mmol) for 2,6-difluoro-L-phenylalanine] and PyBrop (535 mg, 1.14 mmol) in Chloroform (15 mL). DIEA (0.808 mL, 4.63 mmol) was added and the reaction stirred overnight at room temperature. The mixture was adsorbed onto silica and purified via column chromatography (25-75% EtOAc/Hex) affording the title compound (225 mg, 34%): LC-MS (ES) m/z=507 (M+H)+
Reaction SMILES: C([O:3][C:4](=[O:40])[C@@H:5]([O:38][CH3:39])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][C:27]([O:30][Si](C(C)(C)C)(C)C)=[CH:26][CH:25]=3)=[CH:20][CH:19]=2)=[CH:9][CH:8]=1)C.[OH-].[Na+]>>[OH:30][C:27]1[CH:28]=[CH:29][C:24]([C:21]2[CH:20]=[CH:19][C:18]([O:17][CH2:16][CH2:15][CH2:14][O:13][C:10]3[CH:11]=[CH:12][C:7]([CH2:6][C@H:5]([O:38][CH3:39])[C:4]([OH:40])=[O:3])=[CH:8][CH:9]=3)=[CH:23][CH:22]=2)=[CH:25][CH:26]=1
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCCOc2ccc(-c3ccc(O[Si](C)(C)C(C)(C)C)cc3)cc2)cc1)OC
Agent: [Na+]
Agent: [OH-]
Product: CO[C@@H](Cc1ccc(OCCCOc2ccc(-c3ccc(O)cc3)cc2)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-(4-{3-[4′-(tert-Butyl-dimethyl-silanyloxy)-biphenyl-4-yloxy]-propoxy}-phenyl)-2-methoxy-propionic acid ethyl ester (Step A) by Standard Hydrolysis procedure C (NaOH). MS (ES) for C25H26O6 [M+Na]+: 445.
Reaction SMILES: [O:1]=[C:2]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[C:16]([Cl:19])[C:17]=1[Cl:18])[CH2:14][CH:13]([CH2:20][CH3:21])[CH2:12]2)[C:3]1[NH:7][N:6]=[N:5][N:4]=1.[Cl:22]Cl>C(O)(=O)C>[O:1]=[C:2]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[C:16]([Cl:19])[C:17]=1[Cl:18])[CH2:14][C:13]([CH2:20][CH3:21])([Cl:22])[CH2:12]2)[C:3]1[NH:7][N:6]=[N:5][N:4]=1
Reactant: CCC1Cc2cc(OC(=O)c3nnn[nH]3)c(Cl)c(Cl)c2C1
Reactant: ClCl
Solvent: CC(=O)O
Product: CCC1(Cl)Cc2cc(OC(=O)c3nnn[nH]3)c(Cl)c(Cl)c2C1
Temperature: 100 °C

Procedure:
A solution of 5-(1-oxo-2-ethyl-6,7-dichloro-5-indanyloxymethyl)tetrazole (2.0 g.) in acetic acid (300 ml.) is warmed to 65° C. on a steam bath and treated during a 10-minute period with a solution of chlorine (700 mg.) in acetic acid (25 ml.). The reaction mixture is heated one hour at 100° C. and the solvent is distilled at reduced pressure to a volume of 50 ml. which on treatment with water affords 0.8 g. (36%) of 5-(1-oxo-2-ethyl-2,6,7-trichloro-5-indanyloxymethyl)tetrazole which melts at 128° C. after recrystallization from ethylacetate and hexane.
Reaction SMILES: CO[C:3](=O)[C:4]1[CH:9]=C(O)C=[C:6](OCC=C)[CH:5]=1.[OH:16][C:17]1[CH:18]=[C:19]([CH:24]=[C:25]([OH:27])[CH:26]=1)[C:20]([O:22][CH3:23])=[O:21].C(=O)([O-])[O-].[K+].[K+].BrCC=C(C)C>>[CH3:23][O:22][C:20](=[O:21])[C:19]1[CH:18]=[C:17]([O:16][CH2:6][CH:5]=[C:4]([CH3:9])[CH3:3])[CH:26]=[C:25]([OH:27])[CH:24]=1
Reactant: C=CCOc1cc(O)cc(C(=O)OC)c1
Reactant: COC(=O)c1cc(O)cc(O)c1
Agent: CC(C)=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COC(=O)c1cc(O)cc(OCC=C(C)C)c1

Procedure:
The title compound was prepared in a similar manner as described for Intermediate 1a, from methyl 3,5-dihydroxybenzoate (11.3 g, 67 mmol), potassium carbonate (18.5 g, 134 mmol), and 1-bromo-3-methyl-but-2-ene (10 g, 67 mmol). Purification by column chromatography eluting with 20% EtOAc in hexane gave a pale yellow solid (3.41 g, 20% yield). 1H NMR (400 MHz, CDCl3) δ 7.17-7.20 (m, 1 H) 7.12-7.17 (m, 1 H) 6.63 (t, J=2.27 Hz, 1 H) 5.41-5.51 (m, 1 H) 5.50 (s, 1 H) 4.53 (d, J=6.57 Hz, 2 H) 3.91 (m, 3 H) 1.80 (s, 3 H) 1.69 (s, 3 H); LCMS for C13H16O4 m/z 237.10 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:28]=[CH:27][C:11]3[N:12]=[C:13]([C:18]4[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=4)[C:21]([NH2:23])=[S:22])[CH2:14][C:15](=[O:17])[NH:16][C:10]=3[CH:9]=2)=[CH:4][CH:3]=1.Cl[CH2:30][C:31](=O)[CH3:32]>C(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:28]=[CH:27][C:11]3[N:12]=[C:13]([C:18]4[CH:26]=[CH:25][CH:24]=[C:20]([C:21]5[S:22][CH:30]=[C:31]([CH3:32])[N:23]=5)[CH:19]=4)[CH2:14][C:15](=[O:17])[NH:16][C:10]=3[CH:9]=2)=[CH:6][CH:7]=1
Reactant: NC(=S)c1cccc(C2=Nc3ccc(-c4ccc(F)cc4)cc3NC(=O)C2)c1
Reactant: CC(=O)CCl
Solvent: CCO
Product: Cc1csc(-c2cccc(C3=Nc4ccc(-c5ccc(F)cc5)cc4NC(=O)C3)c2)n1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a suspension of 3-[7-(4-fluoro-phenyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]-thiobenzamide (Example 149) (97 mg, (0.25 mmol) in ethanol (5 mL) was added chloroacetone (0.1 mL, 1.25 mmol) and the mixture was heated at reflux. After 1 h and after 5 h of heating, more chloroacetone (2 times 0.1 mL, 1.25 mmol) was added. After 20 h the mixture was cooled to 0° C. and stirred for 0.5 h, and the title compound was isolated by filtration as light yellow solid (61 mg).
Reaction SMILES: N1C(Cl)=NC(Cl)=NC=1Cl.CN1CCOCC1.[Cl:17][C:18]1[S:22][C:21]([C:23]([NH:25][C@H:26]2[CH2:30][N:29]([CH2:31][C:32](=[O:48])[NH:33][C:34]3[CH:39]=[CH:38][C:37]([N:40]4[CH:45]=[CH:44][CH:43]=[CH:42][C:41]4=[O:46])=[CH:36][C:35]=3[F:47])[C@H:28]([C:49](O)=[O:50])[CH2:27]2)=[O:24])=[CH:20][CH:19]=1>COCCOC>[F:47][C:35]1[CH:36]=[C:37]([N:40]2[CH:45]=[CH:44][CH:43]=[CH:42][C:41]2=[O:46])[CH:38]=[CH:39][C:34]=1[NH:33][C:32]([CH2:31][N:29]1[C@H:28]([CH2:49][OH:50])[CH2:27][C@@H:26]([NH:25][C:23]([C:21]2[S:22][C:18]([Cl:17])=[CH:19][CH:20]=2)=[O:24])[CH2:30]1)=[O:48]
Reactant: O=C(CN1C[C@H](NC(=O)c2ccc(Cl)s2)C[C@H]1C(=O)O)Nc1ccc(-n2ccccc2=O)cc1F
Agent: Clc1nc(Cl)nc(Cl)n1
Solvent: COCCOC
Solvent: CN1CCOCC1
Product: O=C(CN1C[C@H](NC(=O)c2ccc(Cl)s2)C[C@H]1CO)Nc1ccc(-n2ccccc2=O)cc1F
Temperature: 0 °C
Reaction time: 3 h
Yield: 13.7 %

Procedure:
To a solution of 44 mg cyanuric chloride in 1.5 ml 1,2-dimethoxyethane were added 0.03 ml N-methylmorpholine. The resulting white suspension was treated with 150 mg (2S,4R)-4-[(5-chloro-thiophene-2-carbonyl)-amino]-1-{[2-fluoro-4-(2-oxo-pyridin-1-yl)-phenylcarbamoyl]-methyl}-pyrrolidine-2-carboxylic acid (example 12) in 0.5 ml 1,2-dimethoxyethane and stirred at r.t for 3 hrs. The precipitate was filtered off. The filtrate was cooled to 0° C. A solution of 13 mg NaBH4 in 0.7 ml H2O was added dropwise. The mixture was stirred for 5 min at 0° C., then diluted with water and extracted with EtOAc. The organic layer was washed with water, dried over MgSO4, filtrated and concentrated. The crude product was purified by chromatography (silica gel; gradient: CH2Cl2->CH2Cl2/MeOH 9:1) to give 20 mg 5-chloro-thiophene-2-carboxylic acid ((3R,5S)-1-{[2-fluoro-4-(2-oxo-pyridin-1-yl)-phenylcarbamoyl]-methyl}-5-hydroxymethyl-pyrrolidin-3-yl)-amide. White solid. MS 505.4 ([M+H]+)