Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:3]([NH:18][S:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)(=[O:21])=[O:20])=[N:4][C:5]([O:8]CC2C=CC=CC=2OC)=[N:6][CH:7]=1.FC(F)(F)C(O)=O>ClCCl>[F:1][C:2]1[C:3]([NH:18][S:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)(=[O:21])=[O:20])=[N:4][C:5]([OH:8])=[N:6][CH:7]=1
Reactant: COc1ccccc1COc1ncc(F)c(NS(=O)(=O)c2ccccc2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=S(=O)(Nc1nc(O)ncc1F)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.9 %

Procedure:
The solid N-(5-fluoro-2-(2-methoxybenzyloxy)pyrimidin-4-yl)benzenesulfonamide (714 mg, 1.83 mmol) was dissolved in dichloromethane (10 mL) followed by the addition of trifluoroacetic acid (1.0 mL, 13.5 mmol) and allowed to stir at room temperature for 1 h. The solvent was removed in vacuo and the resulting residue was dissolved in dichloromethane:methanol in a 10:1 ratio. The product was purified by column chromatography (dichloromethane/methanol gradient) to yield N-(5-fluoro-2-hydroxypyrimidin-4-yl)benzenesulfonamide (251 mg, 51% yield) as a white solid: mp 221-223° C.; 1H NMR (300 MHz) δ 11.57 (bs, 1H), 11.11 (bs, 1H), 8.04 (d, J=6.1 Hz, 1H), 7.94-7.84 (m, 2H), 7.71-7.51 (m, 3H).
Reaction SMILES: [C:1]([O:6][CH3:7])(=[O:5])/[CH:2]=[CH:3]/[CH3:4].[CH2:8]([SH:11])[CH2:9][CH3:10]>>[CH3:7][O:6][C:1](=[O:5])[CH2:2][CH:3]([S:11][CH2:8][CH2:9][CH3:10])[CH3:4]
Reactant: C/C=C/C(=O)OC
Reactant: CCCS
Product: CCCSC(C)CC(=O)OC
Temperature: 30 °C

Procedure:
Into a 100 cc reaction flask equipped with stirrer, thermometer, reflux condenser and ultra-violet light source are placed 20 grams of methyl crotonate and 15.2 grams of n-propyl mercaptan (0.2 moles of methyl crotonate and 0.2 moles of n-propyl mercaptan). With stirring, the ultra-violet light is turned on and the reaction mass is maintained at a temperature of 30° C. The reaction mass is exposed with stirring to the ultra-violet light at 30° C. for a period of 4 hours. At the end of the 4 hour period, the reaction mass is transferred to a distillation flask and distilled on a micro Vigreux column yielding the following fractions:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][C:8]([OH:10])=[O:9])[CH2:3][CH2:2]1.[OH-].[Na+].[C:13](Cl)(=[O:24])[O:14][CH2:15][C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([Cl:23])[CH:17]=1.Cl>C(Cl)Cl>[Cl:22][C:20]1[CH:21]=[C:16]([CH:17]=[C:18]([Cl:23])[CH:19]=1)[CH2:15][O:14][C:13]([N:1]1[CH2:6][CH2:5][CH:4]([CH2:7][C:8]([OH:10])=[O:9])[CH2:3][CH2:2]1)=[O:24]
Reactant: O=C(Cl)OCc1cc(Cl)cc(Cl)c1
Reactant: O=C(O)CC1CCNCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=C(O)CC1CCN(C(=O)OCc2cc(Cl)cc(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 2-(piperidin-4-yl)acetic acid (1 g, 6.98 mmol) in DCM (23 ml) was added 2M NaOH (10.48 ml, 20.95 mmol) and 3,5-dichlorobenzyl carbono-chloridate (1.673 g, 6.98 mmol) to give a white biphasic mixture. After vigorous stirring at RT for 1 hr the reaction mixture was acidified with HCl (6M, 3.49 ml) and then extracted with DCM. The organics were dried with MgSO4, filtered and concentrated under pressure to give the title compound as a colourless oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.CCN(C(C)C)C(C)C.[N:18]1([CH2:23][C:24]2[CH:25]=[C:26]([NH2:30])[CH:27]=[CH:28][CH:29]=2)[CH:22]=[CH:21][N:20]=[N:19]1>CN(C=O)C.CCOC(C)=O.O>[Cl:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:30][C:26]2[CH:27]=[CH:28][CH:29]=[C:24]([CH2:23][N:18]3[CH:22]=[CH:21][N:20]=[N:19]3)[CH:25]=2)[N:7]=1
Reactant: Clc1ncnc(Cl)n1
Reactant: Nc1cccc(Cn2ccnn2)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: Clc1ncnc(Nc2cccc(Cn3ccnn3)c2)n1
Temperature: 0 °C

Procedure:
2,4-Dichloro-1,3,5-triazine (405.8 mg, 2.7065 mmol) is dissolved in DMF (2 ml). To the stirring solution cooled to 0° C. is added DIEA (471 μl, 2.7065 mmol). This solution is added dropwise to a 0° C. mix of DMF (2 ml) and 3-[1,2,3]triazol-1-ylmethyl-phenylamine (471.5 mg, 2.7065 mmol). The reaction is stirred at 0° C. for 15 minutes to 40 minutes and then at RT for 20 minutes to 2 hours. The mixture is diluted with EtOAc and water. The layers are separated, and the aqueous layer is extracted twice with EtOAc. The combined organic layer is washed 3 times with brine, dried over Na2SO4, and concentrated under reduced pressure, giving (4-chloro-[1,3,5]triazin-2-yl)-(3-[1,2,3]triazol-1-ylmethyl-phenyl)amine as a white foam.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N:8]([CH:10]([CH3:13])[CH2:11][OH:12])[CH3:9])[NH:5][C:4](=[O:14])[N:3]=1.C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>O1CCCC1>[CH3:22][S:23]([O:12][CH2:11][CH:10]([N:8]([C:6]1[NH:5][C:4](=[O:14])[N:3]=[C:2]([Cl:1])[CH:7]=1)[CH3:9])[CH3:13])(=[O:25])=[O:24]
Reactant: CC(CO)N(C)c1cc(Cl)nc(=O)[nH]1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(COS(C)(=O)=O)N(C)c1cc(Cl)nc(=O)[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 4-chloro-6-((1-hydroxypropan-2-yl)(methyl)amino)pyrimidin-2(1H)-one (1.0 g, 4.6 mmol) and triethylamine (1.9 mL, 14 mmol) in tetrahydrofuran (THF) (15 mL) was added MsCl (0.72 mL, 9.2 mmol) at 0˜5° C. The reaction mixture was stirred at room temperature overnight, and then quenched with 1 M NaHCO3 solution, diluted with water and extracted with ethyl acetate. Combined organic parts were dried over anhydrous Na2SO4, filtered and concentrated to give the residue as yellow oil. The crude was used into next step without further purification.
Reaction SMILES: [F:1][C:2]1[C:3]([C:14](Cl)=[N:15][OH:16])=[CH:4][C:5]2[C:9]([CH3:11])([CH3:10])[O:8][B:7]([OH:12])[C:6]=2[CH:13]=1.[Cl:18][C:19]1[CH:24]=[C:23]([C:25]([C:27]([F:30])([F:29])[F:28])=[CH2:26])[CH:22]=[C:21]([Cl:31])[C:20]=1[Cl:32]>CN(C=O)C>[F:1][C:2]1[C:3]([C:14]2[CH2:26][C:25]([C:23]3[CH:22]=[C:21]([Cl:31])[C:20]([Cl:32])=[C:19]([Cl:18])[CH:24]=3)([C:27]([F:30])([F:29])[F:28])[O:16][N:15]=2)=[CH:4][C:5]2[C:9]([CH3:11])([CH3:10])[O:8][B:7]([OH:12])[C:6]=2[CH:13]=1
Reactant: C=C(c1cc(Cl)c(Cl)c(Cl)c1)C(F)(F)F
Reactant: CC1(C)OB(O)c2cc(F)c(C(Cl)=NO)cc21
Solvent: CN(C)C=O
Product: CC1(C)OB(O)c2cc(F)c(C3=NOC(c4cc(Cl)c(Cl)c(Cl)c4)(C(F)(F)F)C3)cc21
Temperature: 0 °C
Reaction time: 12 h

Procedure:
To a solution of the crude compound 6-fluoro-N,1-dihydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborole-5-carbimidoyl chloride (310 mg, 0.95 mmol) and 1,2,3-trichloro-5-(3,3,3-trifluoroprop-1-en-2-yl)benzene (262 mg, 0.95 mmol) in DMF (5 mL) at rt was added TEA (158 μL, 1.2 mmol). The reaction mixture was stirred for 12 h, poured into ice-water and extracted with DCM (60 mL×3). The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by prep-TLC eluted with PE-EA (3:2) and then purified by combiflash to give the title compound 6-fluoro-3,3-dimethyl-5-(5-(3,4,5-trichloro-phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)benzo[c][1,2]oxaborol-1(3H)-ol (86 mg; yield 16% over 3 steps from the aldehyde) as a white solid. 1H NMR (500 MHz, DMSO-d6): δ 9.352 (s, 1H), 7.875 (s, 2H), 7.826 (d, J=6.0 Hz, 1H), 7.513 (d, J=10.0 Hz, 1H), 4.399 (d, J=18.5 Hz, 1H), 4.274 (d, J=18.5 Hz, 1H), 1.482 (s, 6H) ppm; HPLC purity: 100% at 220 nm and 100% at 254 nm; MS: m/z=495.9 (M+1, ESI+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][C:18]=1[CH3:19])[CH2:6][CH:7](C(OC)=O)[C:8]([O:10]C)=[O:9].[OH-].[Na+]>CO.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:6][CH2:7][C:8]([OH:10])=[O:9])[CH:16]=[CH:17][C:18]=1[CH3:19]
Reactant: COC(=O)C(Cc1ccc(C)c(OC)c1)C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1cc(CCC(=O)O)ccc1C
Yield: 123 %

Procedure:
A solution of 25.84 g (0.1072 mol) of dimethyl 2-(3-methoxy-4-methylbenzyl)malonate in 150 mL of MeOH was treated with a solution of 20 g (0.5 mol) of NaOH in 100 mL of H2O and heated at reflux overnight. The solution was concentrated under reduced pressure and the residue taken up in H2O and washed with Et2O. The solution was acidified to Congo Red end point with dilute HCl and the solution extracted with Et2O. The Et2O was washed with saturated NaCl and dried over MgSO4. Removal of the solvent under reduced pressure gave 25.6 g of an oil. This was taken up in 125 mL of dioxane and heated at reflux overnight. Removal of the solvent under reduced pressure gave 20.5 g of the crude product. Chromatography on silica gel, eluting with CHCl3 /MeOH (98/2) gave 8.65 g (41.6% yield) of the product as a white solid, mp 80-82° C. The structure was confirmed by NMR and mass spectroscopy. MS m/z 195 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[N:3]([C@H:8]2[CH2:12][C@@:11]([CH:16]([CH3:18])[CH3:17])([C:13]([OH:15])=O)[CH:10]=[CH:9]2)[C:4]([CH3:7])=[CH:5][CH:6]=1.[F:19][C:20]([F:32])([F:31])[C:21]1[CH:22]=[N:23][C:24]2[CH2:25][CH2:26][NH:27][CH2:28][C:29]=2[CH:30]=1>>[CH3:7][C:4]1[N:3]([C@H:8]2[CH2:12][C@:11]([C:13]([N:27]3[CH2:26][CH2:25][C:24]4[N:23]=[CH:22][C:21]([C:20]([F:19])([F:31])[F:32])=[CH:30][C:29]=4[CH2:28]3)=[O:15])([CH:16]([CH3:18])[CH3:17])[CH:10]=[CH:9]2)[C:2]([CH3:1])=[CH:6][CH:5]=1
Reactant: FC(F)(F)c1cnc2c(c1)CNCC2
Reactant: Cc1ccc(C)n1[C@@H]1C=C[C@@](C(=O)O)(C(C)C)C1
Product: Cc1ccc(C)n1[C@@H]1C=C[C@@](C(=O)N2CCc3ncc(C(F)(F)F)cc3C2)(C(C)C)C1

Procedure:
reacting (1S,4S)-4-(2,5-dimethyl-1H-pyrrol-1-yl)-1-isopropylcyclopent-2-ene-1-carboxylic acid with 3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,6-naphthyridine to form 6-{[(1S,4S)-4-(2,5-dimethyl-1H-pyrrol-1-yl)-1-isopropylcyclopent-2-en-1-yl]carbonyl}-3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,6-naphthyridine;
Reaction SMILES: [CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([NH2:15])[N:13]=[CH:14][C:9]=3[C:8]3[CH:16]=[CH:17][N:18]=[CH:19][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:20][C:21]1[N:22]=[N:23][C:24](Cl)=[CH:25][CH:26]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd]>[CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([NH:15][C:24]4[N:23]=[N:22][C:21]([Cl:20])=[CH:26][CH:25]=4)[N:13]=[CH:14][C:9]=3[C:8]3[CH:16]=[CH:17][N:18]=[CH:19][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Clc1ccc(Cl)nn1
Reactant: Nc1ncc2c3ccncc3n(C3CCCC3)c2n1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: Cc1ccccc1
Product: Clc1ccc(Nc2ncc3c4ccncc4n(C4CCCC4)c3n2)nn1
Temperature: 100 °C
Yield: 97 %

Procedure:
A mixture of compound 4 (1.50 g, 5.92 mmol), 3,6-dichloropyridazine (0.882 g, 5.92 mmol), bis(dibenzylideneacetone)palladium (0.170 g, 0.296 mmol), Xantphos (0.514 g, 0.888 mmol) and sodium tert-butoxide (0.854, 8.88 mmol) in toluene (80 mL) was purged with nitrogen. The reaction was then heated at 100° C. for one hour in a sealed vessel. After cooling to room temperature, the mixture was loaded onto a silica gel column and eluted with 2-10% methanol/DCM. Evaporation of combined fractions provided compound 140 (2.1 g) as a yellowish solid. LCMS-ESI, M+1: 366.1
Reaction SMILES: [CH2:1]1[CH2:5][O:4][CH2:3][CH2:2]1.C([Li])CCC.[CH3:11][CH2:12][CH2:13][CH2:14][CH2:15]C>>[CH2:3]([O:4][C:5]#[CH:1])[C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: C1CCOC1
Reactant: CCCCCC
Agent: [Li]CCCC
Product: C#COCc1ccccc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A 70 ml THF solution of the Part G dibromide (5.48 g, 13.3 mmol) under argon atmosphere was cooled to -78° C. n-Butyllithium (10.6 ml of a 2.5M solution in hexane, 26.5 mmol) was added to the dibromide solution over 10 minutes. The reaction was stirred at -78° C. for 1 hour and then quenched at -78° C. with saturated aqueous NH4Cl solution. After the reaction was warmed to room temperature, it was diluted with 60 ml of H2O, and the aqueous layer was extracted 2 times with ether. All of the organic layers were combined and dried over MgSO4. Filtration and solvent removal gave 3.8 g of title benzyloxyacetylene in the form of a yellow solid. The title benzyloxyacetylene was purified by flash chromatography eluting with 3% ether/hexane. Title acetylene was obtained in 85% yield (2.76 g) as a white solid.
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[C:6]([CH2:14][CH:15]([NH2:17])[CH3:16])[CH:5]=1.[Br:18]Br>ClCCl>[ClH:1].[Br:18][C:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:4]([O:3][CH3:2])=[CH:5][C:6]=1[CH2:14][CH:15]([NH2:17])[CH3:16]
Reactant: COc1cc(CC(C)N)cc2ccccc12
Reactant: BrBr
Agent: Cl
Solvent: ClCCl
Product: COc1cc(CC(C)N)c(Br)c2ccccc12

Procedure:
To a cold heterogeneous solution (ice bath) of 2-(4-methoxy-naphthalen-2-yl) 1-methyl-ethylamine hydrochloride (0.10 g, 0.39 mmol, Example 11) in dichloromethane, was added bromine (0.07 g, 0.43 mmol) via syringe. After 1 h the volatiles were evaporated and the residue was partitioned in a mixture of ethyl acetate (20 mL) and a saturated aqueous solution of bicarbonate (20 mL). The organic layer was separated, dried (MgSO4), and concentrated in vacuo. The residue was dissolved in ethyl ether (20 mL) and the free amine was transformed to its correspondent hydrochloride salt by adding 1 M solution of hydrogen chloride in ethyl ether. The solid formed was collected by filtration (80 mg): 1H NMR (DMSO-d6) δ 1.21 (d, 3H, CH3), 3.24 (m, 2H), 3.60 (m, 11H), 3.66 (m, 1H), 4.02 (s, 3H, OCH3), 7.03 (s, 1H, Ar—H), 7.48–7.75 (m, 2H, Ar—H), 7.96 (m, 3H, NH3+), 8.17 (m, 2H, Ar—H); MS 296 (M+1).
Reaction SMILES: [OH:1][NH:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][O:12][N:13]2C(=O)C3=CC=CC=C3C2=O)=[CH:7][CH:6]=1)=[O:4].CNN>CN(C)C=O>[NH2:13][O:12][CH2:11][C:8]1[CH:7]=[CH:6][C:5]([C:3]([NH:2][OH:1])=[O:4])=[CH:10][CH:9]=1
Reactant: O=C(NO)c1ccc(CON2C(=O)c3ccccc3C2=O)cc1
Agent: CNN
Solvent: CN(C)C=O
Product: NOCc1ccc(C(=O)NO)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 66.9 %

Procedure:
N-Hydroxy-α-(phthalimidooxy)-p-toluamide (10.0 g) (32 mmol) are suspended in 80 ml of absolute dimethylformamide and treated at -5° C. with 1.86 g (40 mmol) of methylhydrazine. After stirring at room temperature for 2.5 hours 40 ml of solvent are distilled off in a high vacuum at room temperature. Insoluble material is filtered off and washed with a small amount of dimethylformamide. The mother liquor and wash solution are treated with 70 ml of ethanol. After stirring at 0° C. for 1/2 hour the precipitated crystalline product is filtered off under suction and washed with a small amount of ethanol. After drying in a high vacuum at room temperature there are obtained 3.9 g of α-(aminooxy)-N-hydroxy-p-toluamide as white crystals of m.p. 145° C. (dec.).
Reaction SMILES: [N:1]1[N:2]([C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:21][CH2:20][CH2:19][C:18]3=[O:22])=[CH:13][CH:12]=2)[CH:3]=[C:4]2[CH2:10][CH2:9][NH:8][CH2:7][CH2:6][C:5]=12.[CH3:23][C:24]([CH3:26])=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.C(O)(=O)C.CO>[CH3:23][CH:24]([N:8]1[CH2:9][CH2:10][C:4]2=[CH:3][N:2]([C:11]3[CH:12]=[CH:13][C:14]([N:17]4[CH2:21][CH2:20][CH2:19][C:18]4=[O:22])=[CH:15][CH:16]=3)[N:1]=[C:5]2[CH2:6][CH2:7]1)[CH3:26]
Reactant: O=C1CCCN1c1ccc(-n2cc3c(n2)CCNCC3)cc1
Reactant: CC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CO
Product: CC(C)N1CCc2cn(-c3ccc(N4CCCC4=O)cc3)nc2CC1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 1-[4-(5,6,7,8-tetrahydropyrazolo[3,4-d]azepin-2(4H)-yl)phenyl]-2-pyrrolidinone (may be prepared as described in Description 22) (45 mg, 0.15 mmol) in dichloromethane (3 ml) was added acetone (17 mg, 0.30 mmol) and acetic acid (2 drops). The resulting mixture was stirred at room temperature, under argon, for 20 minutes. Sodium triacetoxyborohydride (64 mg, 0.30 mmol) was added and stirring continued for 22 hours. A further 2 eq. of acetone (17 mg, 0.30 mmol) was added, and after a further 20 minutes a further 2 eq. of sodium triacetoxyborohydride (64 mg, 0.30 mmol) was added and stirring continued for 3 hours. The resulting crude mixture was diluted with methanol and then purified by SCX, eluting with methanol and then with 2M ammonia/methanol. The basic fractions were combined and solvent evaporated in vacuo. Crude product was triturated with ether, filtered then triturated with ethyl acetate to afford the title compound (E14). MS (ES+) m/e 339 [M+H]+.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][CH2:18][CH2:19][CH2:20][C@@H:21]([NH:27][C@@H:28]2[C:34](=[O:35])[N:33]([CH2:36][C:37]([O:39]CC3C=CC=CC=3)=[O:38])[C:32]3[CH:47]=[CH:48][CH:49]=[CH:50][C:31]=3[O:30][CH2:29]2)[C:22]([O:24]CC)=[O:23])[CH2:13][CH2:12]1)=O)C1C=CC=CC=1>C(O)C.[C].[Pd]>[C:22]([C@H:21]([NH:27][C@@H:28]1[C:34](=[O:35])[N:33]([CH2:36][C:37]([OH:39])=[O:38])[C:32]2[CH:47]=[CH:48][CH:49]=[CH:50][C:31]=2[O:30][CH2:29]1)[CH2:20][CH2:19][CH2:18][CH2:17][CH:14]1[CH2:15][CH2:16][NH:11][CH2:12][CH2:13]1)([OH:24])=[O:23]
Reactant: CCOC(=O)[C@@H](CCCCC1CCN(C(=O)OCc2ccccc2)CC1)N[C@H]1COc2ccccc2N(CC(=O)OCc2ccccc2)C1=O
Agent: [Pd]
Solvent: CCO
Product: O=C(O)CN1C(=O)[C@@H](N[C@H](CCCCC2CCNCC2)C(=O)O)COc2ccccc21
Reaction time: 0.5 h
Yield: 226 %

Procedure:
A solution of benzyl 3(S)-[5-(1-benzyloxycarbonyl-4-piperidyl)-1(R)-ethoxycarbonylpentyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetate (0.35 g) in ethanol (20 ml) is subjected to catalytic hydrogenolysis over 10% palladium carbon (0.5 g, 50% wet) at ambient temperature and pressure until the absorption of hydrogen ceases. After removal of the catalyst by filtration, the filtrate is concentrated. To the residue is added 5N hydrogen chloride-ethyl acetate solution (1 ml), and the resulting mixture is diluted with ethyl ether (50 ml) to deposit 3(S)-[1(R)-ethoxycarbonyl-5-(4-piperidyl)pentyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetic acid dihydrochloride (0.25 g) as the colorless precipitate. This acid is dissolved in 1N sodium hydroxide solution (10 ml), and the resulting solution is allowed to stand for 30 minutes at room temperature. After addition of acetic acid (2 ml), the mixture is subjected to MCI gel column chromatography using water-methanol (2:1) as an eluent. The eluate is concentrated in vacuo and lyophilized to yield 3(S)-[1(R)-carboxy-5-(4-piperidyl)pentyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetic acid (0.5 g) as colorless powder.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:11]([O:12][CH2:13][CH3:14])=[C:10]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[N:9]=[C:8](Cl)[N:7]=1)=[O:5])[CH3:2].CC1(C)C(C)(C)OB([C:30]2[CH:31]=[C:32]([OH:36])[CH:33]=[CH:34][CH:35]=2)O1.O1CCOCC1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH2:1]([O:3][C:4]([C:6]1[C:11]([O:12][CH2:13][CH3:14])=[C:10]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[N:9]=[C:8]([C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([OH:36])[CH:31]=2)[N:7]=1)=[O:5])[CH3:2]
Reactant: CC1(C)OB(c2cccc(O)c2)OC1(C)C
Reactant: CCOC(=O)c1nc(Cl)nc(N2CCOCC2)c1OCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)c1nc(-c2cccc(O)c2)nc(N2CCOCC2)c1OCC
Yield: 55.4 %

Procedure:
A mixture of 2-chloro-5-ethoxy-6-morpholine-4-yl-pyrimidine-4-carboxylic acid ethyl ester (152 mg, 1 eq.), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (137.9 mg, 1.3 eq.), dioxane (6 ml), H2O (1 ml), Pd(PPh3)4 (56 mg, 0.1 eq.) and sodium carbonate (102 mg, 2 eq.) was heated to reflux overnight. The solvent was removed in vacuo. The residue was extracted with EA, and the organic layer washed with brine and dried. The crude was purified by chromatography to give a product (99.6 mg, 55%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:11](C)=O)[C:5]([F:10])=[C:6]([O:8][CH3:9])[CH:7]=1.C(OC(C(F)(F)F)=O)(C(F)(F)F)=O>CC#N>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([F:10])=[C:4]([SH:11])[CH:3]=1
Reactant: COc1cc(Cl)cc(S(C)=O)c1F
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CC#N
Product: COc1cc(Cl)cc(S)c1F
Temperature: 0 °C
Reaction time: 1 h
Yield: 69.9 %

Procedure:
To a mixture of 5-chloro-2-fluoro-1-methoxy-3-(methylsulfinyl)benzene (501 mg) and CH3CN (20 mL) was added TFAA (0.953 mL) at 0° C. The mixture was stirred at 0° C. for 1 h and then at room temperature for 1 h. The mixture was concentrated. The residue was dissolved in a mixture of MeOH (3.5 mL) and TEA (3.5 mL) at 0° C. The solution was stirred at 0° C. for 10 min, and concentrated in vacuo. The mixture was diluted with saturated aqueous NH4Cl and extracted with EtOAc. The organic layer was extracted with 1N NaOH. The aqueous layer was acidified with 1N HCl and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo to give the title compound (303 mg).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([NH:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21]([O:23][CH3:24])=[O:22])=[CH:11][CH:12]=2)[N:7]([CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][O:26]2)[N:6]=1)=[O:4].[OH-].[Na+].Cl>CO.O1CCCC1.O.CCOC(C)=O>[CH3:24][O:23][C:21]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[NH:14][C:10]1[CH:9]=[C:8]2[C:13]([C:5]([C:3]([OH:4])=[O:2])=[N:6][N:7]2[CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][O:26]2)=[CH:12][CH:11]=1)=[O:22]
Reactant: COC(=O)c1ccccc1Nc1ccc2c(C(=O)OC)nn(C3CCCCO3)c2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)c1ccccc1Nc1ccc2c(C(=O)O)nn(C3CCCCO3)c2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 81.7 %

Procedure:
To a solution of 6-(2-Methoxycarbonyl-phenylamino)-1-(tetrahydro-pyran-2-yl)-1H-indazole-3-carboxylic acid methyl ester (2.05 g, 5 mmol) in methanol (18 mL) and tetrahydrofuran (8 mL), was added a solution of sodium hydroxide (0.30 g, 7.5 mmol) in water (2.7 mL). The reaction was stirred at room temperature for 3 hours and was then neutralized with 1 N HCl to a pH of 1. The mixture was diluted with EtOAc (25 mL) and water (25 mL). After separating the layers, the aqueous layer was washed with CH2Cl2 (3×25 mL). The combined organic extracts were washed with saturated NaCl (100 mL) and then dried over Na2SO4. The solids were filtered and the liquid was concentrated to an oil. The product was crystallized from EtOAc and Hexanes to yield the desired product (1.616 g, 82%).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1)[C:6](Cl)=[O:7].C(N(CC)CC)C.[CH:25]([O:28][C:29]([N:31]1[CH2:37][CH2:36][CH2:35][CH:34]([NH:38][C:39]2[CH:40]=[N:41][CH:42]=[CH:43][CH:44]=2)[C:33]2[CH:45]=[C:46]([CH3:53])[C:47]([C:49]([F:52])([F:51])[F:50])=[CH:48][C:32]1=2)=[O:30])([CH3:27])[CH3:26]>C(Cl)(Cl)Cl.C(Cl)Cl>[CH:25]([O:28][C:29]([N:31]1[CH2:37][CH2:36][CH2:35][CH:34]([N:38]([C:6](=[O:7])[C:5]2[CH:4]=[C:3]([C:2]([F:17])([F:16])[F:1])[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=2)[C:39]2[CH:40]=[N:41][CH:42]=[CH:43][CH:44]=2)[C:33]2[CH:45]=[C:46]([CH3:53])[C:47]([C:49]([F:51])([F:52])[F:50])=[CH:48][C:32]1=2)=[O:30])([CH3:27])[CH3:26]
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: Cc1cc2c(cc1C(F)(F)F)N(C(=O)OC(C)C)CCCC2Nc1cccnc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: Cc1cc2c(cc1C(F)(F)F)N(C(=O)OC(C)C)CCCC2N(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cccnc1
Yield: 50.7 %

Procedure:
Add 3,5-bis(trifluoromethyl)-benzoyl chloride (0.220 mL, 1.22 mmol) and triethylamine (0.180 mL, 1.29 mmol) over a 24 h period to a solution of 7-methyl-5-(pyridin-3-ylamino)-8-trifluoromethyl-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylic acid isopropyl ester (114 mg, 0.280 mmol) in chloroform (1.9 mL) at 70° C. Allow the reaction to cool, dilute with methylene chloride (20 mL) and wash sequentially with 10% HCl, saturated aqueous sodium bicarbonate, water, and then brine. Dry (MgSO4), concentrate, and purify via column chromatography (silica gel; 20% to 40% EtOAc:hexanes) to give 92 mg (51%) of the title compound as a white solid APCI MS m/z 648 [M+H]+.