Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[C:11]([Cl:14])[C:12]=1[OH:13])[C:5]([O:7][CH2:8][CH3:9])=[O:6].Cl[CH2:16][CH2:17][CH2:18][C:19]1[O:23][N:22]=[C:21]([CH3:24])[CH:20]=1.[OH-].[K+].[I-].[K+]>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[C:11]([Cl:14])[C:12]=1[O:13][CH2:16][CH2:17][CH2:18][C:19]1[O:23][N:22]=[C:21]([CH3:24])[CH:20]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)c1cc(Cl)c(O)c(Cl)c1
Reactant: Cc1cc(CCCCl)on1
Agent: [I-]
Agent: [K+]
Agent: [OH-]
Solvent: CC#N
Product: CCOC(=O)c1cc(Cl)c(OCCCc2cc(C)no2)c(Cl)c1
Yield: 91.4 %

Procedure:
To a mixture of 10.05 g ethyl 3,5-dichloro-4-hydroxybenzoate and 8.0 g 5-(3-chloropropyl)-3-methylisoxazole in 550 ml dry acetonitrile was added 4.87 g potassium hydroxide and 12.9 g potassium iodide. The reaction mixture was stirred at reflux overnight and then filtered and concentrated in vacuo. The residue was partitioned between ethyl acetate and water and the organic layer concentrated to a yellow oil. The latter was crystallized from ethyl acetate-hexane (1:4) at -50° C. to give 14 g of product, 12 g of which was used directly in the following hydrolysis reaction. A sample of the ester was purified by chromatography on silica to give pure compound, m.p. 49°-50° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:21]=[CH:20][CH:19]=[CH:18][C:5]=1[O:6][CH:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH:8]([OH:11])[CH2:9][OH:10])[CH3:2].C[Si](Cl)(C)C.[CH3:27][S:28](Cl)(=[O:30])=[O:29].Cl>C(OCC)(=O)C.C(N(CC)CC)C>[CH2:1]([O:3][C:4]1[CH:21]=[CH:20][CH:19]=[CH:18][C:5]=1[O:6][CH:7]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[CH:8]([O:11][S:28]([CH3:27])(=[O:30])=[O:29])[CH2:9][OH:10])[CH3:2]
Reactant: CCOc1ccccc1OC(c1ccccc1)C(O)CO
Reactant: CS(=O)(=O)Cl
Agent: C[Si](C)(C)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCOc1ccccc1OC(c1ccccc1)C(CO)OS(C)(=O)=O
Temperature: -17 °C
Reaction time: 0.25 h
Yield: 102.9 %

Procedure:
3-(2-Ethoxyphenoxy)-2-hydroxy-3-phenylpropanol from Example 2 (0.288 g, 1 mmole) and triethylamine ((0.15 mL, 1.1 mmole) were dissolved in ethyl acetate (5 mL) and cooled to −17° C. Trimethylsilyl chloride (0.13 mL, 1.0 mmole) dissolved in ethyl acetate (2 mL) was added over 10 minutes keeping the temperature below −15° C. a white precipitate formed during this addition. The mixture was stirred below −15° C. for 15 minutes. Triethylamine (0.15 mL, 1.1 mmole) was added, followed by methanesulfonyl chloride (0.085 mL, 1.1 mmole) dissolved ethyl acetate (2 mL) keeping the temperature below −15° C. The mixture was stirred below −15° C. for 15 minutes. Hydrochloric acid (2N, 2 mL) was added and the mixture was allowed to warm to 20-25° C. and stirred for 30 minutes. The phases were separated and the organic phase was washed with saturated aqueous sodium chloride solution (5 mL) and dried over sodium sulfate. The solution was evaporated to yield 0.377 g of an oil. The oil was chromatographed on silica (230-400 mesh) eluting with 1:1 hexane-ethyl acetate. The product-containing fractions were concentrated to yield 0.33 g (91%) of the title compound as an oil that solidified on standing; mp 83-86° C.; 1H NMR (400.13 MHZ, CDCl3) d 1.66 (t, J=8.2 Hz, 3H), 2.85 (s, 3H), 4.14-4.35 (m, 4H), 5,12 (m, 1H), 5.52 (d, J=6.1 Hz), 6.8-7.15 (m, 4H), 7.5-7.7 (m, 5H); 13C NMR (100.62 MHZ, CDCl3) d 14.73, 37.80, 62.19, 64.27, 81.40, 84.04, 112.88, 117.19, 120.67, 122.86, 127.40, 128.77, 128.86, 137.02, 146.40, 149.30; MS (ei ) m/e 366.
Reaction SMILES: C([O:3][C:4](=[O:27])[CH2:5][P:6]([C:11]1([NH:16][C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])[CH2:13][CH:12]1[CH:14]=[CH2:15])([O:8][CH2:9][CH3:10])=[O:7])C.[OH-].[Na+]>C1COCC1>[CH2:20]([O:19][C:17]([NH:16][C:11]1([P:6]([CH2:5][C:4]([OH:27])=[O:3])([O:8][CH2:9][CH3:10])=[O:7])[CH2:13][CH:12]1[CH:14]=[CH2:15])=[O:18])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: C=CC1CC1(NC(=O)OCc1ccccc1)P(=O)(CC(=O)OCC)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: C=CC1CC1(NC(=O)OCc1ccccc1)P(=O)(CC(=O)O)OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.5 %

Procedure:
A solution of [(1-benzyloxycarbonylamino-2-vinyl-cyclopropyl)-ethoxy-phosphinoyl]-acetic acid ethyl ester (352 mg, 0.89 mmol) in THF (3 mL) was stirred at 0° C. as 1 N NaOH (980 μL, 0.98 mmol) was added. The solution was stirred overnight at r.t. and then concentrated, diluted with H2O (10 mL) and washed with ethyl acetate. The aqueous layer was acidified with 1 N HCl (5 mL) and extracted with ethyl acetate (×2). The organic extracts were washed with H2O, dried (MgSO4) and concentrated to yield [(1-Benzyloxycarbonylamino-2-vinyl-cyclopropyl)-ethoxy-phosphinoyl]-acetic acid (224 mg, 69%). 1H NMR (300 MHz, CDCl3): d 7.34 (s, 5H), 5.91 (m, 2H), 5.20 (m, 2H), 4.21 (m, 2H), 3.11 (m, 2H), 2.30 (m, 1H), 2.03 (m, 1H), 1.85 (m, 2H), 1.70 (m, 2H), 1.58 (m, 2H), 1.38 (m, 2H), 1.25 (m, 3H). 31P (121.4 MHz, CDCl3): 45.109, 41.119, 40.965, 39.514
Reaction SMILES: [C:1]([C:3]1[O:7][C:6]([C:8]([OH:10])=O)=[CH:5][CH:4]=1)#[N:2].C(Cl)(=O)C([Cl:14])=O.C(OC([N:24]1[CH2:29][CH:28]=[C:27]([C:30]2[CH:35]=[CH:34][C:33]([NH2:36])=[C:32]([N:37]3[CH2:42][CH2:41][CH:40]([CH3:43])[CH2:39][CH2:38]3)[CH:31]=2)[CH2:26][CH2:25]1)=O)(C)(C)C.CCN(CC)CC>C(Cl)Cl.CN(C=O)C>[ClH:14].[ClH:14].[CH3:43][CH:40]1[CH2:39][CH2:38][N:37]([C:32]2[CH:31]=[C:30]([C:27]3[CH2:28][CH2:29][NH:24][CH2:25][CH:26]=3)[CH:35]=[CH:34][C:33]=2[NH:36][C:8]([C:6]2[O:7][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)=[O:10])[CH2:42][CH2:41]1
Reactant: N#Cc1ccc(C(=O)O)o1
Reactant: CC1CCN(c2cc(C3=CCN(C(=O)OC(C)(C)C)CC3)ccc2N)CC1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC1CCN(c2cc(C3=CCNCC3)ccc2NC(=O)c2ccc(C#N)o2)CC1
Product: Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A flask was charged with 5-cyano-furan-2-carboxylic acid (0.015 g, 0.10 mmol) (as prepared in Example 1), DCM (1 mL), DMF (5 μL), and oxalyl chloride (10 μL, 0.11 mmol) and stirred at 25° C. for 1 h and then concentrated. The resulting 5-cyano-furan-2-carbonyl chloride was dissolved in DCM (1 mL) and added to a solution of 4-[4-amino-3-(4-methyl-piperidin-1-yl)-phenyl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (0.040 g, 0.10 mmol) (as prepared in the previous step) and NEt3 (25 μL, 0.15 mmol) in DCM (1 mL) at 0° C. The solution was allowed to attain RT and stirred for 10 h. The intermediate BOC protected compound was eluted from a 5-g SPE cartridge (silica) with 20% EtOAc/hexane, and then dissolved in DCM (1 mL) and TFA (0.30 mL) and stirred at 25° C. for 30 min. The reaction was concentrated and purified by RP-HPLC (C18), eluting with a linear gradient of 40% CH3CN to 70% CH3CN in 0.1% TFA/H2O over 10 min to give the title compound as a di-TFA salt. This product was then eluted from a 10-g column of BioRad AG-2X8 resin (chloride ion form) with methanol to give 0.017 g (37%) of the title compound. 1H-NMR (400 MHz, DMSO-d6): δ 9.81 (s, 1H), 9.40 (br s, 2H), 8.18 (d, 1H), 7.82 (d, 1H), 7.50 (d, 1H), 7.36 (s, 1H), 7.28 (d, 1H), 6.22 (m, 1H), 3.76 (m, 2H), 3.46 (3, 3H), 2.98 (m, 2H), 2.74 (m, 6H), 1.82 (m, 2H), 1.50 (m, 3H), 1.00 (d, 3H), Mass spectrum (ESI, m/z): Calcd. for C23H26N4O2, 391.2 (M+H), found 391.2.
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:12])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].N1C=CC=CC=1.[F:19][C:20]1[CH:28]=[C:27]([C:29]2[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=2)[CH:26]=[CH:25][C:21]=1[C:22](Cl)=[O:23]>C1(C)C=CC=CC=1>[F:19][C:20]1[CH:28]=[C:27]([C:29]2[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=2)[CH:26]=[CH:25][C:21]=1[C:22]([NH:1][C:2]1[C:3]([OH:12])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6])=[O:23]
Reactant: COC(=O)c1cccc(N)c1O
Reactant: O=C(Cl)c1ccc(-c2ccncc2)cc1F
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: COC(=O)c1cccc(NC(=O)c2ccc(-c3ccncc3)cc2F)c1O
Temperature: 70 °C
Reaction time: 4 h
Yield: 65.9 %

Procedure:
To a solution of 4-bromo-2-fluorobenzoic acid (4.34 g, 20 mmol) and pyridine-4-ylboronic acid (2.45 g, 20 mmol) in acetonitrile (40 mL) and water (40 mL), potassium carbonate (5.52 g, 40 mmol), bis(triphenylphosphine)palladium(II) chloride (1.08 g, 0.05 mmol) was added. The mixture was degassed and purged withed nitrogen. The mixture was stirred at 100° C. for 24 h. Then the hot suspension was filtered and concentrated to half of the original volume and washed with dichloromethane. The aquatic phase was adjusted to pH 3 with hydrochloric acid (1 M) and filtrated, washed with water. The residue was dried in vacuum to obtain 2-fluoro-4-(pyridine-4-yl)benzoic acid as a white solid (3.15 g, yield 72%. LC-MS (ESI) m/z: 218 (M+1)+.) Thionyl chloride (20 mL) was added to 2-fluoro-4-(pyridine-4-yl)benzoic acid (3.15 g, 14.53 mmol) and the mixture was stirred at 70° C. overnight. The solvent was evaporated under reduced pressure and the residue was dried in vacuum giving 2-fluoro-4-(pyridine-4-yl)benzoyl chloride. To a solution of methyl 3-amino-2-hydroxybenzoate (2.42 g, 14.5 mmol) and pyridine (1.2 mL, 14.5 mmol) in toluene (20 mL) was added 2-fluoro-4-(pyridine-4-yl)benzoyl chloride (3.41 g, 14.5 mmol) portion-wise at 0° C. and then stirred at 70° C. for 4 h. The resulting mixture was extracted with ethyl acetate (100 mL×4), the organic phase was washed with water and saturated sodium bicarbonate, dried with anhydrous sodium sulfate and evaporated under reduced pressure to obtain methyl 3-(2-fluoro-4-(pyridin-4-yl)benzamido)-2-hydroxybenzoate as a yellow solid (3.5 g, yield 65%). LC-MS (ESI) m/z: 367 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:5][C:3]=1[NH2:4].ClC(Cl)(O[C:28](=[O:34])OC(Cl)(Cl)Cl)Cl.Cl.[CH3:37][NH2:38].CO>C(Cl)(Cl)Cl.C(N(CC)CC)C>[Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:5][C:3]=1[NH:4][C:28]([NH:38][CH3:37])=[O:34]
Reactant: CN
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2ncnc(Oc3ccc(N)c(Cl)c3)c2cc1OC
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: CNC(=O)Nc1ccc(Oc2ncnc3cc(OC)c(OC)cc23)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70 %

Procedure:
2-Chloro-4-[(6,7-dimethoxy-4-quinazolinyl)oxy]-aniline 50 mg) was dissolved in chloroform (2 ml) and triethylamine (0.5 ml), and a solution of triphosgene (48 mg) in chloroform was then added to the solution. The mixture was stirred at room temperature for 30 min. Next, the reaction solution was cooled to −78° C., and methylamine hydrochloride (130 mg) was added to the cooled reaction solution. The temperature of the mixture was spontaneously raised, and the mixture was further stirred at room temperature overnight. Methanol was added to the reaction solution, and the mixture was purified by HPLC by development with chloroform/methanol to give 41 mg (yield 70%) of the title compound.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][C@H:18]([NH2:21])[C@H:17]([O:22][CH3:23])[CH2:16]2)=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8])(=[O:3])[CH3:2].[Cl:24][C:25]1[N:26]=[C:27]([C:32](O)=[O:33])[NH:28][C:29]=1[CH2:30][CH3:31].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CC(N(C)C)=O.C(OCC)(=O)C>[C:1]([NH:4][C:5]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][C@H:18]([NH:21][C:32]([C:27]3[NH:28][C:29]([CH2:30][CH3:31])=[C:25]([Cl:24])[N:26]=3)=[O:33])[C@H:17]([O:22][CH3:23])[CH2:16]2)=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8])(=[O:3])[CH3:2]
Reactant: COC(=O)c1cc(N2CC[C@H](N)[C@H](OC)C2)ccc1NC(C)=O
Reactant: CCc1[nH]c(C(=O)O)nc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: CCc1[nH]c(C(=O)N[C@H]2CCN(c3ccc(NC(C)=O)c(C(=O)OC)c3)C[C@H]2OC)nc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.6 %

Procedure:
Methyl cis(±)-2-(acetylamino)-5-(4-amino-3-methoxypiperidin-1-yl)benzoate obtained in Example (185d) (210 mg, 0.65 mmol) and 4-chloro-5-ethyl-1H-imidazole-2-carboxylic acid obtained in Example (1d) (113 mg, 0.65 mmol) were dissolved in DMA (3 ml). WSC hydrochloride (500 mg, 2.6 mmol) and HOBt (88 mg, 0.65 mmol) were added, and the mixture was stirred at room temperature overnight. The reaction solution was diluted with ethyl acetate, washed with water and brine, and dried over anhydrous sodium sulfate. Following concentration under reduced pressure, the residue was recrystallized from an ethyl acetate/hexane solvent to obtain 120 mg of the title compound as crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH2:11])=[S:10])=[CH:4][C:3]=1[C:12]([F:15])([F:14])[F:13].[I:16][CH3:17]>CCO>[IH:16].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[NH:11])[S:10][CH3:17])=[CH:4][C:3]=1[C:12]([F:15])([F:13])[F:14]
Reactant: NC(=S)Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: CI
Solvent: CCO
Product: CSC(=N)Nc1ccc(Cl)c(C(F)(F)F)c1
Product: I

Procedure:
A mixture of 2.54 g 4-chloro-3-trifluoromethyl-phenylthiourea, 0.62 ml of iodomethane in 50 mL of anhydrous EtOH was refluxed for 1 hr to give 1-[4-chloro-3-(trifluoromethyl)phenyl]-S-methylisothiourea hydroiodide. Then it was cooled down to ambient temperature and treated with 0.35 g of 98% hydrazine, heated gently with stirring until the initial vigorous evolution of MeSH subsided and then refluxed for additional 1 hour.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[O:15][C:14]([C:17]([NH:19][C@@H:20]4[CH:25]5[CH2:26][CH2:27][N:22]([CH2:23][CH2:24]5)[CH2:21]4)=[O:18])=[CH:13][C:12]=3[CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH:28]1([C:31]([Cl:33])=[O:32])[CH2:30][CH2:29]1.C(N(CC)CC)C.O>C1COCC1>[ClH:33].[N:22]12[CH2:23][CH2:24][CH:25]([CH2:26][CH2:27]1)[C@@H:20]([NH:19][C:17]([C:14]1[O:15][C:16]3[C:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][C:31]([CH:28]5[CH2:30][CH2:29]5)=[O:32])[CH:3]=4)=[CH:9][CH:10]=[CH:11][C:12]=3[CH:13]=1)=[O:18])[CH2:21]2
Reactant: Nc1cccc(-c2cccc3cc(C(=O)N[C@H]4CN5CCC4CC5)oc23)c1
Reactant: O=C(Cl)C1CC1
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: Cl
Product: O=C(N[C@H]1CN2CCC1CC2)c1cc2cccc(-c3cccc(NC(=O)C4CC4)c3)c2o1

Procedure:
75 mg (0.21 mmol) of 7-(3-aminophenyl)-N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzofuran-2-carboxamide (Example 114), 28 μl (0.31 mmol) of cyclopropylcarbonyl chloride and 87 μl (0.62 mmol) of triethylamine are stirred in 2 ml of THF at RT overnight. After addition of water, the solvent is removed under reduced pressure. Purification takes place by preparative HPLC. The product is dissolved in methanol, and an excess of 1N hydrochloric acid is added. Removal of the solvent under reduced pressure and drying under high vacuum result in 55 mg (57% of theory) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH2:8]O)[CH:5]=[C:4]([F:10])[C:3]=1[O:11][Si:12]([CH:19]([CH3:21])[CH3:20])([CH:16]([CH3:18])[CH3:17])[CH:13]([CH3:15])[CH3:14].[Br:22]C(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[Br:22][CH2:8][C:6]1[CH:5]=[C:4]([F:10])[C:3]([O:11][Si:12]([CH:19]([CH3:21])[CH3:20])([CH:16]([CH3:18])[CH3:17])[CH:13]([CH3:15])[CH3:14])=[C:2]([F:1])[CH:7]=1
Reactant: BrC(Br)(Br)Br
Reactant: CC(C)[Si](Oc1c(F)cc(CO)cc1F)(C(C)C)C(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)[Si](Oc1c(F)cc(CBr)cc1F)(C(C)C)C(C)C
Temperature: 0 °C

Procedure:
7.40 g (23.4 mmol) of 1,3-difluoro-5-hydroxymethyl-2-triisopropylsilanyloxybenzene are dissolved in 90 ml of dry dichloromethane by stirring at 0° C. under argon. 10.1 g (30.4 mmol) of tetrabromomethane and 7.97 g (30.4 mmol) of triphenylphosphine are successively added to this solution, and the mixture is then stirred under reflux under argon for 12 h. The reaction mixture is washed with water, the organic phase is separated off, dried over magnesium sulfate and filtered, and the solvent is distilled out in vacuo. The oily residue is taken up in diethyl ether and stirred at RT, then filtered, and the filtrate is concentrated. Chromatography of the residue on silica gel 60 (mobile phase: cyclohexane/ethyl acetate 9:1) results in 7.42 g (15.6 mmol, 84% of theory) of the title compound.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:10]2[O:11][CH2:12][C@H:13]([CH2:23][OH:24])[N:14]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][N:16]=3)[C:9]=2[CH:8]=[CH:7][CH:6]=1)=[O:4].[Na+].[Cl-:26]>CO>[ClH:26].[OH:24][CH2:23][C@H:13]1[CH2:12][O:11][C:10]2[C:5]([C:3]([OH:4])=[O:2])=[CH:6][CH:7]=[CH:8][C:9]=2[N:14]1[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][N:16]=1
Reactant: [Cl-]
Reactant: COC(=O)c1cccc2c1OC[C@H](CO)N2c1ccc(OC)cn1
Agent: [Na+]
Solvent: CO
Product: COc1ccc(N2c3cccc(C(=O)O)c3OC[C@@H]2CO)nc1
Product: Cl
Temperature: 60 °C

Procedure:
To a solution of (S)-methyl-3-(hydroxymethyl)-4-(5-methoxypyridin-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-8-carboxylate 3.6 g (11 mmol) of step 6 in methanol 40 mL was dropwise added 10 mL of 4N NaCl. The reaction mixture was refluxed at 60° C. for 3 hrs with stirring and then cooled to room temperature. Neutralization with 1N HCl 40 mL yielded the title compound as a precipitate. This was filtered, washed with distilled water and concentrated in a vacuum. Product: 2.6 g (yield 75%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:8]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[NH:13][CH:12]=2)=[CH:7][C:4]=1[C:5]#[N:6].C(=O)([O-])[O-:21].[K+].[K+].OO>CS(C)=O.O>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:8]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[NH:13][CH:12]=2)=[CH:7][C:4]=1[C:5]([NH2:6])=[O:21]
Reactant: O=C([O-])[O-]
Reactant: COc1ccc(-c2c[nH]c3ncccc23)cc1C#N
Agent: OO
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COc1ccc(-c2c[nH]c3ncccc23)cc1C(N)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.5 %

Procedure:
The de-tosylated nitrite 38 (26.7 mg, 107 μmol) was dissolved in dimethyl sulfoxide (2.49 g). To this was added potassium carbonate (32.7 mg, 237 μmol) and 30% hydrogen peroxide in water (85.5 mg) and the reaction was stirred at room temperature overnight. The reaction was diluted with water and the resulting precipitate was washed with water, acetonitrile and ether to give final product 39 (25.3 mg, 88%). 1H NMR DMSO-d6 11.86 (s, 1H), 8.28 (m, 1H), 8.19 (d, 1H), 8.11 (m, 1H), 7.81 (m, 2H), 7.70 (s, 1H), 7.55 (s, 1H), 7.21 (d, 1H), 7.16 (m, 1H), 3.91 (s, 3H). LC/MS (M+1)=268
Reaction SMILES: [Cl:1][C:2]1[C:7]2[N:8]=[C:9]([NH2:11])[S:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.O.[NH2:13]N.O>COCCOCCO>[Cl:1][C:2]1[C:7]2[N:8]=[C:9]([NH:11][NH2:13])[S:10][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Nc1nc2c(Cl)cccc2s1
Reactant: NN
Solvent: COCCOCCO
Solvent: O
Product: NNc1nc2c(Cl)cccc2s1
Temperature: 110 °C
Reaction time: 22 h
Yield: 78 %

Procedure:
4-Chloro-2-aminobenzothiazole (2.0 g.; 0.0108 mole) was dissolved in 10 milliliters of diethylene glycol monomethyl ether and 0.9 milliliter of concentrated HC1 added with stirring. 85% Hydrazine hydrate (1.92 g.) was then added to the mixture, and the reaction mixture was heated to 110°C., under N2 atmosphere, on an oil bath. The reaction was continued for 22 hours, the final reaction temperature being 120°C. The 4-chloro-2-hydrazinobenzothiazole product was isolated by addition of water and separated by filtration, 1.69 g. (78% yield), m.p. 232°-235°C.
Reaction SMILES: OC1C=C([N:8]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[CH3:19])[N:10]=[C:9]2[CH:20]([NH:22][C:23]2[N:31]=[CH:30][N:29]=[C:28]3[C:24]=2[N:25]=[CH:26][N:27]3COCC[Si](C)(C)C)[CH3:21])C=CC=1.Br[CH2:41][C:42]([NH2:44])=[O:43].C[O:46][C:47]1[CH:48]=[C:49](N2C(=O)C3C(=CC=CC=3C)N=C2C(NC2N=CN=C3C=2N=CN3COCC[Si](C)(C)C)C)[CH:50]=[CH:51][CH:52]=1.Cl.OC1C=C(N2C(=O)C3C(=CC=CC=3C)N=C2C(NC2N=CN=C3C=2N=CN3)C)C=CC=1>CC#N.CO>[CH3:19][C:15]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:16]=1[C:17](=[O:18])[N:8]([CH:41]([O:46][C:47]1[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=1)[C:42]([NH2:44])=[O:43])[C:9]([CH:20]([NH:22][C:23]1[N:31]=[CH:30][N:29]=[C:28]3[C:24]=1[N:25]=[CH:26][NH:27]3)[CH3:21])=[N:10]2
Reactant: NC(=O)CBr
Reactant: COc1cccc(-n2c(C(C)Nc3ncnc4c3ncn4COCC[Si](C)(C)C)nc3cccc(C)c3c2=O)c1
Reactant: Cc1cccc2nc(C(C)Nc3ncnc4c3ncn4COCC[Si](C)(C)C)n(-c3cccc(O)c3)c(=O)c12
Agent: Cc1cccc2nc(C(C)Nc3ncnc4[nH]cnc34)n(-c3cccc(O)c3)c(=O)c12
Agent: Cl
Solvent: CC#N
Solvent: CO
Product: Cc1cccc2nc(C(C)Nc3ncnc4[nH]cnc34)n(C(Oc3ccccc3)C(N)=O)c(=O)c12

Procedure:
Compound 126 (300 mgs, 0.54 mmol) was treated with 2 bromo acetamide using the procedure outlined above for compound 127. The reaction was under reflux for 24 hrs in CH3CN. This intermediate was treated with 4N HCl in MeOH for 1 hour, following the procedure described for compound 121 (step D), to provide compound 145. m/z=471 (M+H). The structure of compound 145 is shown below.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[S:10][C:11]([C:15]([OH:17])=O)=[C:12]([CH3:14])[N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(F)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:33][O:34][C:35](=[O:85])[C@@H:36]([NH:52][C:53]([CH:55]1[CH2:64][C:63]2[CH:62]=[C:61]3[O:65][CH2:66][C@H:67]([C:69]4[CH:74]=[CH:73][C:72]([O:75][CH2:76][C:77]5[CH:82]=[CH:81][C:80]([Cl:83])=[C:79]([Cl:84])[CH:78]=5)=[CH:71][CH:70]=4)[O:68][C:60]3=[CH:59][C:58]=2[CH2:57][NH:56]1)=[O:54])[CH2:37][C:38]1[CH:43]=[CH:42][C:41]([C:44]2[CH:49]=[CH:48][C:47]([C:50]#[N:51])=[CH:46][CH:45]=2)=[CH:40][CH:39]=1.CCN(C(C)C)C(C)C>C1COCC1.CCOC(C)=O>[CH3:33][O:34][C:35](=[O:85])[C@@H:36]([NH:52][C:53]([CH:55]1[CH2:64][C:63]2[CH:62]=[C:61]3[O:65][CH2:66][C@H:67]([C:69]4[CH:74]=[CH:73][C:72]([O:75][CH2:76][C:77]5[CH:82]=[CH:81][C:80]([Cl:83])=[C:79]([Cl:84])[CH:78]=5)=[CH:71][CH:70]=4)[O:68][C:60]3=[CH:59][C:58]=2[CH2:57][N:56]1[C:15]([C:11]1[S:10][C:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[N:13][C:12]=1[CH3:14])=[O:17])=[O:54])[CH2:37][C:38]1[CH:43]=[CH:42][C:41]([C:44]2[CH:45]=[CH:46][C:47]([C:50]#[N:51])=[CH:48][CH:49]=2)=[CH:40][CH:39]=1
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)NC(=O)C1Cc2cc3c(cc2CN1)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3
Reactant: Cc1nc(NC(=O)OC(C)(C)C)sc1C(=O)O
Agent: CN(C)C(F)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)NC(=O)C1Cc2cc3c(cc2CN1C(=O)c1sc(NC(=O)OC(C)(C)C)nc1C)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3
Reaction time: 1 h

Procedure:
2-tert-Butoxycarbonylamino-4-methyl-thiazole-5-carboxylic acid (1 eq) and TFFH (1 eq) were taken in 2 mL anhydrous THF and stirred for 10 min. (S)-3-(4′-Cyano-biphenyl-4-yl)-2-({(S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-propionic acid methyl ester (50 mg) and DIEA (3 eq) were added to the reaction mixture and stirred for 1 hour. Reaction mixture was diluted with EtOAc (5 mL), washed with water and brine and dried over Na2SO4. The solvent was removed by rotavap and the residue was purified by silicagel column to give (S)-2-({(S)-7-(2-tert-butoxycarbonylamino-4-methyl-thiazole-5-carbonyl)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-3-(4′-cyano-biphenyl-4-yl)-propionic acid methyl ester (42 mg). Treatment with HCl according to General Procedure C followed by NaHCO3 wash gave (S)-2-({(S)-7-(2-Amino-4-methyl-thiazole-5-carbonyl)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-3-(4′-cyano-biphenyl-4-yl)-propionic acid methyl ester (35 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][CH:15]1[C:24]2[C:19](=[CH:20][C:21]([C:25]3[O:26][C:27]([CH3:30])=[CH:28][CH:29]=3)=[CH:22][CH:23]=2)[CH2:18][CH2:17][NH:16]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:16]3[CH2:17][CH2:18][C:19]4[C:24](=[CH:23][CH:22]=[C:21]([C:25]5[O:26][C:27]([CH3:30])=[CH:28][CH:29]=5)[CH:20]=4)[CH:15]3[CH3:14])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: Cc1ccc(-c2ccc3c(c2)CCNC3C)o1
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Product: Cc1ccc(-c2ccc3c(c2)CCN(C(=O)c2cc4ncc(Br)cn4n2)C3C)o1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-Methyl-6-(5-methyl-furan-2-yl)-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.