Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C:15]([CH3:16])=[CH:14][CH:13]([C:17]2[CH:22]=[C:21]([NH:23]C(OC(C)(C)C)=O)[C:20]([CH3:31])=[CH:19][C:18]=2[F:32])[NH:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[Pd]>[CH2:1]([O:8][C:9]([N:11]1[C:15]([CH3:16])=[CH:14][C:13]([C:17]2[CH:22]=[C:21]([NH2:23])[C:20]([CH3:31])=[CH:19][C:18]=2[F:32])=[N:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1=CC(c2cc(NC(=O)OC(C)(C)C)c(C)cc2F)NN1C(=O)OCc1ccccc1
Agent: [Pd]
Product: Cc1cc(F)c(-c2cc(C)n(C(=O)OCc3ccccc3)n2)cc1N
Yield: 83.3 %

Procedure:
3-(5-tert-Butoxycarbonylamino-2-fluoro-4-methyl-phenyl)-5-methyl-2H-pyrazole-1-carboxylic acid benzyl ester (320 mg) was hydrogenated using 10% Pd/C (40 mg) following the procedure of step 2 to give 3-(5-amino-2-fluoro-4-methyl-phenyl)-5-methyl-pyrazole-1-carboxylic acid benzyl ester (205 mg) as a white solid.
Reaction SMILES: [C:1]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([OH:12])=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].OC1CC(=O)NC1=O.C1CCC(N=C=NC2CCCCC2)CC1.[NH2:39][CH2:40][C:41]1[CH:46]=[CH:45][C:44]([C:47]#[N:48])=[CH:43][C:42]=1[O:49][CH3:50]>C1COCC1.C(Cl)Cl>[C:47]([C:44]1[CH:45]=[CH:46][C:41]([CH2:40][NH:39][C:10](=[O:12])[C@@H:9]2[CH2:13][CH2:14][CH2:15][N:8]2[C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])=[C:42]([O:49][CH3:50])[CH:43]=1)#[N:48]
Reactant: COc1cc(C#N)ccc1CN
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C1CC(O)C(=O)N1
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1cc(C#N)ccc1CNC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 20 h
Yield: 64 %

Procedure:
16.0 g of Boc-proline (50 mmol), dissolved in 80 ml of THF, were stirred with 5.7 g of hydroxysuccinimide and 10.2 g of DCC in methylene chloride at 0° C. for 30 min. Then 8.0 g (50 mmol) of 4-aminomethyl-3-methoxybenzenenitrile [sic] dissolved in 50 ml of THF were added dropwise at 0° C., and the mixture was stirred at room temperature for 20 h. The solid was filtered off, the filtrate was mixed with the same volume of ethyl acetate and washed with cooled 5% strength NaHSO4 solution and saturated NaCl solution. 11.5 g (65%) of product were obtained. 1H-NMR (DMSO-d6 ; δ in ppm): 8.38 (m, NH); 7.50-7.35 (m, 3H); 4.40-4.05 (m, 3H, N--CH2 --Ar/N--CH--CO); 3.87 (s, OCH3); 3.50-3.25 (m, 2H, N--CH2); 2.2.5-2.00 [sic] (m, 1H); 1.90-1.65 (m, 3H); 1.40 and 1.30 (2s; 9H)
Reaction SMILES: C[O:2][C:3](=[O:29])[CH2:4][CH2:5][N:6]1[CH2:10][CH2:9][CH2:8][C@@H:7]1[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]2[C:27]([Cl:28])=[C:26]3[C:21]([CH:22]=[CH:23][CH:24]=[CH:25]3)=[N:20]2)=[CH:15][CH:14]=1.O.Cl>O1CCOCC1>[ClH:28].[Cl:28][C:27]1[N:19]([C:16]2[CH:17]=[CH:18][C:13]([O:12][CH2:11][C@H:7]3[CH2:8][CH2:9][CH2:10][N:6]3[CH2:5][CH2:4][C:3]([OH:29])=[O:2])=[CH:14][CH:15]=2)[N:20]=[C:21]2[C:26]=1[CH:25]=[CH:24][CH:23]=[CH:22]2
Reactant: COC(=O)CCN1CCC[C@@H]1COc1ccc(-n2nc3ccccc3c2Cl)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)CCN1CCC[C@@H]1COc1ccc(-n2nc3ccccc3c2Cl)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 103 %

Procedure:
A mixture of the product of step 1 (0.37 g, 0.89 mmol), water (1 mL) and HCl (4 M in dioxane, 2.3 mL, 9.1 mmol) in dioxane (5 mL) was stirred at room temperature for 16 h. After the solvent was removed, the residue was triturated with ether to provide the title compound (200 mg, 44%) as a hydrochloride salt. 1H NMR (400 MHz, CDCl3) δ 7.72-7.66 (m, 4H), 7.41 (m, 1H), 7.23 (m, 3H), 4.44 (br, 2H), 4.03 (br, 1H), 3.71 (br, 2H), 3.35 (br, 1H), 3.20 (br, 1H), 2.87 (t, J=8 Hz, 2H), 2.27 (m, 1H), 2.09-1.98 (br, 3H), LC/MS (APCI) m/z: 85%.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH:8]([N:10]2[CH:14]=[CH:13][N:12]=[CH:11]2)[CH3:9])[CH:5]=[CH:4][C:3]=1[NH:15][C:16](=O)[CH3:17].[ClH:19]>C(O)(=O)C>[ClH:19].[ClH:19].[N:10]1([CH:8]([C:6]2[CH:5]=[CH:4][C:3]3[NH:15][C:16]([CH3:17])=[N:1][C:2]=3[CH:7]=2)[CH3:9])[CH:14]=[CH:13][N:12]=[CH:11]1
Reactant: CC(=O)Nc1ccc(C(C)n2ccnc2)cc1N
Agent: Cl
Solvent: CC(=O)O
Product: Cc1nc2cc(C(C)n3ccnc3)ccc2[nH]1
Yield: 90.2 %

Procedure:
A mixture of 7.4 parts of N-[2-amino-4-[1-(1H-imidazol-1-yl)ethyl]phenyl]acetamide, 10 parts of acetic acid and 100 parts of a hydrochloric acid solution 4N was stirred and refluxed for 3.5 hours. The reaction mixture was evaporated. The residue was dissolved in 20 parts of 2-propanol. The product was crystallized at room temperature. The product was filtered off and dried, yielding 8.1 parts (90.2%) of 5-[1-(1H-imidazol-1-yl)ethyl]-2-methyl-1H-benzimidazole dihydrochloride; mp. 236.2° C. (compound 206).
Reaction SMILES: [Cl:1][C:2]([C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([C:24]([O:26][CH3:27])=[O:25])[N+:18]=1[O-:28])(C(OC(C)(C)C)=O)C(OC(C)(C)C)=O.FC(F)(F)C(O)=O>ClCCl>[Cl:23][C:20]1[CH:21]=[CH:22][C:17]([CH2:2][Cl:1])=[N+:18]([O-:28])[C:19]=1[C:24]([O:26][CH3:27])=[O:25]
Reactant: COC(=O)c1c(Cl)ccc(C(Cl)(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)[n+]1[O-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1c(Cl)ccc(CCl)[n+]1[O-]
Temperature: 25 °C
Yield: 66.9 %

Procedure:
A mixture of di-tert-butyl chloro[5-chloro-6-(methoxycarbonyl)-1-oxidopyridin-2-yl]malonate (19.65 g, 45.0 mmol), trifluoroacetic acid (41 mL) and dichloromethane (82 mL) was refluxed for 2.5 hours, cooled and then concentrated to dryness. The crude residue was taken up in xylene and the mixture heated at reflux until carbon dioxide was no longer given off. The reaction mixture was then cooled to room temperature and ethyl ether added followed by a small amount of saturated NaHCO3 solution. The organic was separated and the aqueous layer was saturated with brine and extracted with ethyl acetate. The organic layers were combined, dried (MgSO4), filtered and concentrated to dryness. The crude product was purified by column chromatography (20-50% ethyl acetate in hexane) to give methyl 3-chloro-6-(chloromethyl)pyridine-2-carboxylate 1-oxide (7.11 g, 30.1 mmol) as a brown solid; 1H NMR (CDCl3): δ 7.60 (d, 2H), 7.40 (d, 2H), 4.80 (s, 2H), 4.00 (s, 3H).
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[CH2:9]([O:11][C:12]([CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1)=[O:13])[CH3:10].Br[CH2:28][CH2:29][O:30][CH3:31]>C1COCC1>[CH2:9]([O:11][C:12]([C:14]1([CH2:28][CH2:29][O:30][CH3:31])[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:21])[CH2:16][CH2:15]1)=[O:13])[CH3:10]
Reactant: COCCBr
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C1(CCOC)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 103.6 %

Procedure:
LDA (2M solution in THF/heptane/ethylbenzene, 24.48 ml, 0.049 mol) was added under an argon atmosphere to THF (150 ml) at −5° C., piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester (6.3 g, 6 ml) in THF (100 ml) was then added dropwise and the mixture was stirred for 2 hour at 0° C. Then 1-bromo-2-methoxy-ethane (6.8 g) was added at 0° C. and the mixture was stirred overnight at RT. The solvent was evaporated off, the residue partitioned between AcOEt and water. The layers were separated, the organic layer was washed with brine, dried over sodium sulphate and then concentrated to give 4-(2-methoxy-ethyl)-piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester (8 g) as a brown oil which was essentially pure and used in the next step without further purification. MS (ESI): 216.3 [(M-Boc)H+].
Reaction SMILES: C[Li].Br[C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[NH:7][CH3:8].C([Li])(C)(C)C.[B:17](OC)([O:20]C)[O:18]C.Cl>C(OCC)C.O1CCCC1>[CH3:8][NH:7][C:6]1[CH:5]=[C:4]([B:17]([OH:20])[OH:18])[CH:11]=[CH:10][CH:9]=1
Reactant: COB(OC)OC
Reactant: CNc1cccc(Br)c1
Agent: Cl
Agent: [Li]C
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Solvent: C1CCOC1
Product: CNc1cccc(B(O)O)c1
Temperature: -70 °C
Reaction time: 1 h
Yield: 13.8 %

Procedure:
166 mL (0.242 mol, 1.2 eq) of 1.6 M methyllithium in diethyl ether are added to a solution cooled to −70° C. of 37.6 g (0.202 mol, 1 eq) of 3-bromo-N-methylaniline (prepared in Example 7c) in 300 ml of tetrahydrofuran. The reaction medium is stirred at −70° C. for one hour and 306 mL (0.444 mol, 2.2 eq) of 1.5 M tert-butyllithium in diethyl ether are then added. The reaction medium is stirred at −70° C. for 45 minutes and 103.5 mL (0.808 mol, 4 eq) of trimethyl borate are then added. The reaction medium is stirred at room temperature for one hour and then hydrolyzed by addition of ice, acidified with 1 L of 2N hydrochloric acid and extracted with ethyl acetate. The organic phases are combined, washed with water and dried over magnesium sulfate. The solvent is evaporated off and 4.2 g (14%) of 3-(methylamino)phenylboronic acid are obtained. The aqueous phase is basified and extracted with ethyl acetate. The organic phases are combined, washed with water and dried over magnesium sulfate. The solvent is evaporated off and the residue is chromatographed on silica gel (8/2 heptane/ethyl acetate). 3.4 g (11%) of 3-(methylamino)phenylboronic acid are obtained.
Reaction SMILES: C([O:8][C:9]1[C:13]([O:14]CC2C=CC=CC=2)=[C:12]([C:22]#[N:23])[N:11]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[C:10]=1[C:31]([O:33][CH2:34][CH3:35])=[O:32])C1C=CC=CC=1>C1COCC1.[Pd]>[C:22]([C:12]1[N:11]([C:24]2[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=2)[C:10]([C:31]([O:33][CH2:34][CH3:35])=[O:32])=[C:9]([OH:8])[C:13]=1[OH:14])#[N:23]
Reactant: CCOC(=O)c1c(OCc2ccccc2)c(OCc2ccccc2)c(C#N)n1-c1ccc(F)cc1
Agent: [Pd]
Solvent: C1CCOC1
Product: CCOC(=O)c1c(O)c(O)c(C#N)n1-c1ccc(F)cc1
Yield: 29 %

Procedure:
Ethyl 3,4-bis(benzyloxy)-5-cyano-1-(4-fluorophenyl)-1H-pyrrole-2-carboxylate (UL1-060) (102 mg, 0.22 mmol) in THF (5 mL) was passed through a Thales ‘H-cube’ cartridge (10% Pd/C) at a flow rate of 1.5 mL/min at 20° C. under H2 (full H2 mode). The output was concentrated in vacuo to afford the crude product. The crude residue was purified by silica gel chromatography (4 g, 0-35% EtOAc in isohexane) to afford ethyl 5-cyano-1-(4-fluorophenyl)-3,4-dihydroxy-1H-pyrrole-2-carboxylate (UL1-039) (18 mg, 29% yield) as a white solid: m/z 291 (M+H)+ (ES+); 289 (M−H)− (ES−). 1H NMR (400 MHz, DMSO-d6) δ: 10.14 (s, 1H), 8.99 (s, 1H), 7.44-7.36 (m, 2H), 7.35-7.26 (m, 2H), 4.05 (q, J=7.1 Hz, 2H), 1.01 (t, J=7.1 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]1[C:11]([Br:12])=[CH:10][C:9]([CH3:13])=[C:8]2[C:3]=1[C:4](=O)[CH2:5][CH2:6][S:7]2.Cl.[CH2:16]([O:18][NH2:19])[CH3:17].C(O)C>N1C=CC=CC=1>[CH2:16]([O:18][N:19]=[C:4]1[C:3]2[C:8](=[C:9]([CH3:13])[CH:10]=[C:11]([Br:12])[C:2]=2[CH3:1])[S:7][CH2:6][CH2:5]1)[CH3:17]
Reactant: CCON
Reactant: Cc1cc(Br)c(C)c2c1SCCC2=O
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: CCON=C1CCSc2c(C)cc(Br)c(C)c21
Yield: 92.6 %

Procedure:
3.0 Grams (11 mmol) of 5,8-dimethyl-6-bromothiochroman-4-one and 2.2 g (22 mmol.) of O-ethylhydroxylamine hydrochloride were refluxed under heat in a mixed solvent containing 10 ml of ethanol and 10 ml of pyridine For 30 minutes. The solvents were distilled off under reduced pressure, and then the residue was treated with 5% hydrochloric acid and extracted with ethyl acetate. The so-obtained solution was consecutively washed with 5% aqueous potassium carbonate and with saturated sodium chloride solution and dried over sodium sulfate. The solvent was distilled off to give 3.2 g of 4-ethoxyimino-5,8-dimethyl-6-bromothiochroman (yield 92%).
Reaction SMILES: [CH:1]1([N:6]2[C:14]3[CH:13]=[CH:12][NH:11][C:10](=[O:15])[C:9]=3[C:8]([C:16]3[CH:17]=[C:18]([C:21](O)=[O:22])[S:19][CH:20]=3)=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.CC[N:26]=C=NCCCN(C)C.Cl.C(N(CC)CC)C.O>CN(C=O)C>[CH:1]1([N:6]2[C:14]3[CH:13]=[CH:12][NH:11][C:10](=[O:15])[C:9]=3[C:8]([C:16]3[CH:17]=[C:18]([C:21]([NH2:26])=[O:22])[S:19][CH:20]=3)=[N:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCN=C=NCCCN(C)C
Reactant: O=C(O)c1cc(-c2nn(C3CCCC3)c3cc[nH]c(=O)c23)cs1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: NC(=O)c1cc(-c2nn(C3CCCC3)c3cc[nH]c(=O)c23)cs1
Yield: 54.1 %

Procedure:
A solution of 4-(1-cyclopentyl-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl)thiophene-2-carboxylic acid (89 mg), HOBt ammonium salt (49 mg), EDCI hydrochloride (62 mg) and triethylamine (33 mg) in DMF (10 mL) was stirred at room temperature for 24 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was crystallized from ethyl acetate to give the title compound (48 mg).
Reaction SMILES: Br[C:2]1[CH:19]=[CH:18][C:5]2[CH:6]3[CH2:17][CH:8]([C:9]4[S:13][C:12]([C:14]([NH2:16])=[O:15])=[N:11][C:10]=4[C:4]=2[CH:3]=1)[CH2:7]3.[CH3:20][C:21]1[O:25][N:24]=[C:23]([C@:26]([OH:30])([C:28]#[CH:29])[CH3:27])[N:22]=1>>[OH:30][C@:26]([C:23]1[N:22]=[C:21]([CH3:20])[O:25][N:24]=1)([CH3:27])[C:28]#[C:29][C:2]1[CH:19]=[CH:18][C:5]2[CH:6]3[CH2:17][CH:8]([C:9]4[S:13][C:12]([C:14]([NH2:16])=[O:15])=[N:11][C:10]=4[C:4]=2[CH:3]=1)[CH2:7]3
Reactant: NC(=O)c1nc2c(s1)C1CC(C1)c1ccc(Br)cc1-2
Reactant: C#C[C@@](C)(O)c1noc(C)n1
Product: Cc1nc([C@](C)(O)C#Cc2ccc3c(c2)-c2nc(C(N)=O)sc2C2CC3C2)no1
Yield: 14 %

Procedure:
Similar to as described in General Procedure G, 9-bromo-5,6-dihydro-4H-4,6-methanobenzo[6,7]cyclohepta[1,2-d]thiazole-2-carboxamide was reacted with (2R)-2-(5-methyl-1,2,4-oxadiazol-3-yl)but-3-yn-2-ol to give the titled compound as a colorless solid (5.2 mg, 14%).
Reaction SMILES: [Na].[CH2:2]([OH:5])[CH2:3][OH:4].[Cl:6][C:7]1[CH:8]=[N:9][CH:10]=[C:11](Cl)[CH:12]=1.[OH-].[Na+]>CS(C)=O>[Cl:6][C:7]1[CH:8]=[N:9][CH:10]=[C:11]([O:4][CH2:3][CH2:2][OH:5])[CH:12]=1
Reactant: Clc1cncc(Cl)c1
Reactant: OCCO
Agent: [Na+]
Agent: [Na]
Agent: [OH-]
Solvent: CS(C)=O
Product: OCCOc1cncc(Cl)c1
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
A mixture of sodium (2.0 g, 89.5 mmol) and ethylene glycol (50 ml) was stirred at 70° C. for 30 min. 3,5-Dichloropyridine (11.0 g, 74.5 mmol) and dimethyl sulfoxide (50 ml) were added to the crude mixture. The crude mixture was stirred for 10 h at 110° C. Aqueous sodium hydroxide (100 ml) was added and the crystals were filtered. Yield 8.0 g, 51%.
Reaction SMILES: [CH3:1][N:2]([C:7]1[CH:12]=[C:11]([CH:13]2[CH2:15][O:14]2)[CH:10]=[C:9]([N:16]([CH3:22])[CH2:17][CH:18]2[CH2:20][CH:19]2[CH3:21])[N:8]=1)[S:3]([CH3:6])(=[O:5])=[O:4].[NH4+:23].[OH-]>CCO>[NH2:23][CH2:15][CH:13]([C:11]1[CH:10]=[C:9]([N:16]([CH3:22])[CH2:17][CH:18]2[CH2:20][CH:19]2[CH3:21])[N:8]=[C:7]([N:2]([CH3:1])[S:3]([CH3:6])(=[O:5])=[O:4])[CH:12]=1)[OH:14]
Reactant: CC1CC1CN(C)c1cc(C2CO2)cc(N(C)S(C)(=O)=O)n1
Reactant: [NH4+]
Agent: [OH-]
Solvent: CCO
Product: CC1CC1CN(C)c1cc(C(O)CN)cc(N(C)S(C)(=O)=O)n1

Procedure:
To a solution of N-(4-formyl-6-{methyl[(2-methylcyclopropyl)methyl]amino}pyridin-2-yl)-N-methylmethanesulfonamide (435 mg, 1.40 mmol) in acetonitrile (5 mL) was added 5 drops water, trimethylsulfonium iodide (342 mg, 1.68 mmol) and potassium hydroxide (188 mg, 3.35 mmol). The reaction was stirred at 65° C., sealed, for 3 h, diluted with EtOAc, washed with sat'd aq NaHCO3, brine, dried over sodium sulfate, and concentrated in vacuo to provide N-methyl-N-(6-{methyl[(2-methylcyclopropyl)methyl]amino}-4-oxiran-2-ylpyridin-2-yl)methanesulfonamide, used as is in the next step. A solution of N-methyl-N-(6-{methyl[(2-methylcyclopropyl)methyl]amino}-4-oxiran-2-ylpyridin-2-yl)methanesulfonamide (440 mg, 1.35 mmol) in EtOH (10 mL) and NH4OH (15 mL) was stirred at 60° C., sealed, for 16 h, concentrated in vacuo and purified by flash chromatography (silica, 5-15% (10% NOH/MeOH)/CH2Cl2) to provide N-(4-(2-amino-1-hydroxyethyl)-6-{methyl[(2-methylcyclopropyl)methyl]amino}pyridin-2-yl)-N-methylmethanesulfonamide as a thick oil. 1H NMR (400 MHz, CD3OD) δ 6.52 (s, 1H), 6.47 (s, 1H), 4.58 (X′ of A′B′X′, dd, J=7.6, 4.0 Hz, 2H), 3.54 (A of ABX, dd, J=14.4, 6.4 Hz, 1H), 3.35 (B of ABX, dd, J=14.4, 6.8 Hz, 1H), 3.30 (s, 3H), 3.13 (s, 3H), 3.08 (s, 3H), 3.86 (A′ of A′B′X′, dd, J=13.2, 4.0 Hz, 1H), 2.76 (B′ of A′B′X′, dd, J=13.2, 7.6 Hz, 1H), 1.02 (d, J=6.0 Hz, 3H), 0.80-0.65 (m, 2H), 0.46-0.39 (m, 1H), 0.25-0.18 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C@@H:9]([N:14]2[CH:18]=[CH:17][N:16]([CH2:19][CH2:20][CH2:21][C:22]3[CH:23]=[CH:24][C:25]4[CH2:31][CH2:30][CH2:29][CH2:28][NH:27][C:26]=4[N:32]=3)[C:15]2=[O:33])[CH2:10][C:11]([OH:13])=[O:12])=[CH:5][CH:4]=1.[OH-].[Na+].[H][H]>[OH-].[OH-].[Pd+2].C(O)C>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C@@H:9]([N:14]2[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][CH2:21][C:22]3[CH:23]=[CH:24][C:25]4[CH2:31][CH2:30][CH2:29][CH2:28][NH:27][C:26]=4[N:32]=3)[C:15]2=[O:33])[CH2:10][C:11]([OH:13])=[O:12])=[CH:5][CH:4]=1
Reactant: COc1ccc([C@H](CC(=O)O)n2ccn(CCCc3ccc4c(n3)NCCCC4)c2=O)cn1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc([C@H](CC(=O)O)N2CCN(CCCc3ccc4c(n3)NCCCC4)C2=O)cn1
Yield: 87.1 %

Procedure:
A mixture of 3-8 (0.40 g, 0.886 mmol), 20% Pd(OH)2 (0.40g), 1N NaOH (2 mL), and ethanol (20 mL) was shaken under 65 psig hydrogen in a Parr apparatus for 18 hours. The mixture was filtered through celite, and the filtrate concentrated. The residue was chromatographed on silica gel (25:10:1:1 to 15:10:1:1 EtOAc/EtOH/NH4OH/H2O) to give 350 mg of 3-9 as a white solid.
Reaction SMILES: [Li+].[OH-].[O:3]=[C:4]1[N:10]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C@@H:20]([C:32]([O:34]C)=[O:33])[CH2:21][C:22]3[CH:30]=[C:29]([CH3:31])[C:25]4[NH:26][CH:27]=[N:28][C:24]=4[CH:23]=3)=[O:18])[CH2:13][CH2:12]2)[CH2:9][CH2:8][C:7]2[CH:36]=[CH:37][CH:38]=[CH:39][C:6]=2[NH:5]1.Cl>O.C1COCC1>[O:3]=[C:4]1[N:10]([CH:11]2[CH2:12][CH2:13][N:14]([C:17]([O:19][C@@H:20]([C:32]([OH:34])=[O:33])[CH2:21][C:22]3[CH:30]=[C:29]([CH3:31])[C:25]4[NH:26][CH:27]=[N:28][C:24]=4[CH:23]=3)=[O:18])[CH2:15][CH2:16]2)[CH2:9][CH2:8][C:7]2[CH:36]=[CH:37][CH:38]=[CH:39][C:6]=2[NH:5]1
Reactant: COC(=O)[C@@H](Cc1cc(C)c2[nH]cnc2c1)OC(=O)N1CCC(N2CCc3ccccc3NC2=O)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc2nc[nH]c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 96 mg (4.0 mmol) LiOH in 5 mL water was added dropwise to a solution of 910 mg (1.8 mmol) (R)-1-methoxycarbonyl-2-(7-methyl-1H-benzimidazol-5-yl)-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate in 12 mL THF and the reaction solution was stirred overnight at RT. The residue was combined with 1 mL 4 M HCl and evaporated to dryness i.vac.
Reaction SMILES: [CH3:1][C:2]([CH3:5])([O-:4])[CH3:3].[Na+].Cl[CH2:8][C:9]([OH:11])=[O:10]>C(O)(C)(C)C>[C:2]([O:4][CH2:8][C:9]([OH:11])=[O:10])([CH3:5])([CH3:3])[CH3:1]
Reactant: CC(C)(C)[O-]
Reactant: O=C(O)CCl
Agent: [Na+]
Solvent: CC(C)(C)O
Product: CC(C)(C)OCC(=O)O
Yield: 69.6 %

Procedure:
A suspension of sodium t-butoxide (24.1 g) in t-butanol (150 ml) was cooled in a water bath and treated drop-wise with a solution of chloroacetic acid (11.4 g) in t-butanol (30 ml). The mixture was heated under reflux for 5 h then concentrated in vacuo. The resultant white solid was dried in vacuo for 16 h then water (10 ml) was added and the mixture was filtered. The filtrate was treated with diethyl ether (150 ml), then cooled in an ice bath, stirred and acidified to pH1 with 2N sulphuric acid. The layers were separated and the aqueous layer was further extracted with diethyl ether. The combined organic extracts were dried MgSO4) and concentrated in vacuo to afford Intermediate 32 (11.1 g). 1H NMR (400 MHz, CDCl3, δ ppm) 1.27 (9H, s), 4.04 (2H, s).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Si:8]([CH3:17])([O:13][CH:14]([CH3:16])[CH3:15])[O:9][CH:10]([CH3:12])[CH3:11])=[CH:4][CH:3]=1.[Mg].[I:19]I>C1COCC1>[I:19][C:2]1[CH:7]=[CH:6][C:5]([Si:8]([CH3:17])([O:13][CH:14]([CH3:16])[CH3:15])[O:9][CH:10]([CH3:12])[CH3:11])=[CH:4][CH:3]=1
Reactant: CC(C)O[Si](C)(OC(C)C)c1ccc(Br)cc1
Reactant: II
Agent: [Mg]
Solvent: C1CCOC1
Product: CC(C)O[Si](C)(OC(C)C)c1ccc(I)cc1
Reaction time: 1 h
Yield: 84 %

Procedure:
A solution of 4-bromo-1-(methyldiisopropyloxysilyl)benzene (13.35 g, 42.1 mmol) in THF (85 ml) was added slowly dropwise at 0° C. to a suspension of magnesium chips (1.53 g, 63.1 mmol) in THF (10 ml). After one hour, the Grignard reagent of 4-bromo-1-(methyldiisopropyloxysilyl)benzene was added dropwise at 0° C. to iodine (13.87 g, 54 mmol) dissolved in 50 ml of dry THF. After stirring during four hours, the solvent was pumped off and the residue was extracted with dry pentane (200 ml) and filtered. The yellow solution was concentrated to afford 4-iodo-1-(methyldiisopropyloxysilyl)benzene as a yellow oil of in 84% yield. 1H NMR (CDCl3, δ, ppm) 7.76 (2H, d); 7.42 (2H, d); 4.21 (2H, heptuplet); 1.23 (12H, t); 0.37 (3H, s).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[C:15]2[CH:20]=[CH:19][N:18]3[N:21]=[CH:22][C:23]([C:24]([OH:26])=O)=[C:17]3[N:16]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[CH3:27][C:28]([NH2:31])([CH3:30])[CH3:29]>>[C:28]([NH:31][C:24]([C:23]1[CH:22]=[N:21][N:18]2[CH:19]=[CH:20][C:15]([N:11]3[CH2:12][CH2:13][CH2:14][C@@H:10]3[C:4]3[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=[C:2]([F:1])[CH:3]=3)=[N:16][C:17]=12)=[O:26])([CH3:30])([CH3:29])[CH3:27]
Reactant: Cn1cc(F)cc([C@H]2CCCN2c2ccn3ncc(C(=O)O)c3n2)c1=O
Reactant: CC(C)(C)N
Product: Cn1cc(F)cc([C@H]2CCCN2c2ccn3ncc(C(=O)NC(C)(C)C)c3n2)c1=O
Yield: 75 %

Procedure:
Prepared by the method described in Example 140, using (R)-5-(2-(5-fluoro-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (Preparation R) and 2-methylpropan-2-amine. The residue was purified by silica column chromatography, eluting with 3% MeOH/DCM to yield the title compound (26 mg, 75% yield). MS (apci) m/z=413.1 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[N:9]=[C:10]([C:20]([CH3:23])([CH3:22])[CH3:21])[S:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15](Cl)[N:14]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[NH:24][S:25]([C:28]1[O:29][CH:30]=[CH:31][CH:32]=1)(=[O:27])=[O:26].[OH-].[NH4+:34]>>[NH2:34][C:15]1[N:14]=[C:13]([C:12]2[S:11][C:10]([C:20]([CH3:22])([CH3:23])[CH3:21])=[N:9][C:8]=2[C:7]2[C:2]([Cl:1])=[C:3]([NH:24][S:25]([C:28]3[O:29][CH:30]=[CH:31][CH:32]=3)(=[O:26])=[O:27])[CH:4]=[CH:5][CH:6]=2)[CH:18]=[CH:17][N:16]=1
Reactant: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3ccco3)c2Cl)c(-c2ccnc(Cl)n2)s1
Reactant: [NH4+]
Agent: [OH-]
Product: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3ccco3)c2Cl)c(-c2ccnc(N)n2)s1

Procedure:
Following a procedure analogous to the procedure described in Example 52, Step B using N-{2-chloro-3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]phenyl}-2-furansulfonamide (75 mg, 0.147 mmol) and ammonium hydroxide (3 mL), the title compound was obtained as an off-white solid (49 mg, 68% yield). MS (ESI): 490 [M+H]+.