Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1]OP(C(=[N+]=[N-])C(=O)C)(=O)OC.[C:13]([C:15]1[CH:16]=[N:17][C:18]2[C:23]([CH:24]=1)=[CH:22][C:21]([O:25][CH:26]([S:37][CH3:38])[C:27]([NH:29][C:30]([CH2:34][O:35][CH3:36])([CH3:33])[CH:31]=O)=[O:28])=[CH:20][C:19]=2[CH3:39])#[CH:14].C([O-])([O-])=O.[K+].[K+]>CO.C(OCC)(=O)C>[C:13]([C:15]1[CH:16]=[N:17][C:18]2[C:23]([CH:24]=1)=[CH:22][C:21]([O:25][CH:26]([S:37][CH3:38])[C:27]([NH:29][C:30]([CH2:34][O:35][CH3:36])([CH3:33])[C:31]#[CH:1])=[O:28])=[CH:20][C:19]=2[CH3:39])#[CH:14]
Reactant: C#Cc1cnc2c(C)cc(OC(SC)C(=O)NC(C)(C=O)COC)cc2c1
Reactant: COP(=O)(OC)C(=[N+]=[N-])C(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CCOC(C)=O
Product: C#Cc1cnc2c(C)cc(OC(SC)C(=O)NC(C)(C#C)COC)cc2c1
Temperature: 0 °C
Reaction time: 16 h
Yield: 55.1 %

Procedure:
A mixture of (1-diazo-2-oxo-propyl)-phosphonic acid dimethyl ester (Bestmann's reagent) (77 mg) and 2-(3-ethynyl-8-methyl-quinolin-6-yloxy)-N-(1-methoxymethyl-1-methyl-2-oxo-ethyl)-2-methylsulfanyl-acetamide (110 mg) in MeOH (10 ml) was cooled to 0° C. Solid K2CO3 (71 mg) was added and the mixture stirred during 16 hour allowing the temperature raising to 25° C. The reaction mixture was diluted with ethyl acetate and poured onto brine. The water phase was extracted twice with ethyl acetate and the combined organic phases dried over sodium sulfate, filtered and evaporated. The crude residue was purified by column chromatography to give 2-(3-ethynyl-8-methyl-quinolin-6-yloxy)-N-(1-methoxymethyl-1-methyl-prop-2-ynyl)-2-methylsulfanyl-acetamide (60 mg) as a light brown solid as a mixture of diastereoisomers.
Reaction SMILES: [CH3:1]N(C)S(C1C=C2C(C=CN2)=C(Br)C=1)(=O)=O.[CH3:17][C:18]1[C:23]([N+:24]([O-])=O)=[CH:22][C:21]([C:27]([F:30])([F:29])[F:28])=[CH:20][C:19]=1[N+:31]([O-])=O>>[F:28][C:27]([F:30])([F:29])[C:21]1[CH:22]=[C:23]2[C:18]([CH:17]=[CH:1][NH:24]2)=[C:19]([NH2:31])[CH:20]=1
Reactant: Cc1c([N+](=O)[O-])cc(C(F)(F)F)cc1[N+](=O)[O-]
Reactant: CN(C)S(=O)(=O)c1cc(Br)c2cc[nH]c2c1
Product: Nc1cc(C(F)(F)F)cc2[nH]ccc12

Procedure:
Prepared according to the method used in the preparation of 4-bromo-1H-indole-6-sulfonic acid dimethylamide using 2-methyl-1,3-dinitro-5-trifluoromethyl-benzene in place of 3-bromo-4,N,N-trimethyl-5-nitro-benzenesulfonamide. The title compound was obtained as a white solid (10.7 g, 99%).
Reaction SMILES: [Br:1][C:2]1[O:6][C:5]([C:7]2[C:11]3[C:12]([C:22]#[N:23])=[N:13][C:14]([C:17](OCC)=[O:18])=[C:15]([OH:16])[C:10]=3[O:9][N:8]=2)=[CH:4][CH:3]=1.[NH2:24][CH2:25][C:26]([OH:28])=[O:27].C[O-].[Na+]>C(=O)(O)[O-].[Na+]>[Br:1][C:2]1[O:6][C:5]([C:7]2[C:11]3[C:12]([C:22]#[N:23])=[N:13][C:14]([C:17]([NH:24][CH2:25][C:26]([OH:28])=[O:27])=[O:18])=[C:15]([OH:16])[C:10]=3[O:9][N:8]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1nc(C#N)c2c(-c3ccc(Br)o3)noc2c1O
Reactant: NCC(=O)O
Agent: C[O-]
Agent: O=C([O-])O
Agent: [Na+]
Product: N#Cc1nc(C(=O)NCC(=O)O)c(O)c2onc(-c3ccc(Br)o3)c12
Temperature: 25 °C
Yield: 22.3 %

Procedure:
Ethyl 3-(5-bromofuran-2-yl)-4-cyano-7-hydroxyisoxazolo[4,5-c]pyridine-6-carboxylate (42 mg, 0.11 mmol) and glycine (334 mg, 4.44 mmol) were added to sodium methoxide solution (6.7 mL, 3.33 mmol, 0.5 M in MeOH) and the mixture was refluxed for 48 h. The mixture was cooled to room temperature and the solvent was removed in vacuo. The residue was redissolved in a minimum amount of water, and 0.25 M hydrochloric acid was added until pH was 3. The resulting precipitate was isolated by filtration and dried under vacuum to give 21 mg of crude solid. The solid was dissolved in 10 mL of saturated sodium bicarbonate solution and washed with hexanes and EtOAc. The aqueous layer was acidified to pH 3 and extracted with EtOAc. The combined organic layer was dried over MgSO4 and concentrated to afford 10 mg of the title compound. MS: (−) m/z 405.21, 407.18 (M−1, 79Br/81Br).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:17]([C:18]([OH:20])=O)=[CH:16][CH:15]=[C:14]3[C:10]=2[CH:11]=[N:12][NH:13]3)=[C:4]([F:21])[CH:3]=1.Cl.[NH2:23][O:24][CH2:25][C@@H:26]([OH:28])[CH3:27].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[OH:28][C@@H:26]([CH3:27])[CH2:25][O:24][NH:23][C:18]([C:17]1[C:9]([NH:8][C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=2[F:21])=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][N:12]=[CH:11]2)=[O:20]
Reactant: O=C(O)c1ccc2[nH]ncc2c1Nc1ccc(Br)cc1F
Reactant: C[C@H](O)CON
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](O)CONC(=O)c1ccc2[nH]ncc2c1Nc1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 43.7 %

Procedure:
To a solution of 4-(4-bromo-2-fluorophenylamino)-1H-indazole-5-carboxylic acid (115 mg, 0.33 mmol) and (S)-1-aminooxy-propan-2-ol hydrochloride (63 mg, 0.49 mmol) in DMF (3 mL) was added EDCI (69 mg, 0.36 mmol), HOBt (49 mg, 0.36 mmol) and DIPEA (150 μL, 0.85 mmol). The reaction mixture was stirred at room temperature for 16 hours before being concentrated in vacuo. The resultant residue was dissolved in ethyl acetate (10 mL), washed with aqueous saturated sodium bicarbonate solution (10 mL) and the aqueous fraction extracted twice with ethyl acetate (2×10 mL). The combined organic fractions were washed with brine (20 mL), dried (MgSO4) and concentrated in vacuo. The resultant residue was subjected to reverse phase preparative HPLC (10-90% acetonitrile/water 0.1% formic acid, Phenominex gemini PhC6, 5 micron, 250×20 mm). The resultant product was dissolved in ethyl acetate (5 mL) and washed with aqueous saturated sodium bicarbonate solution (10 mL). The aqueous fraction was extracted twice with ethyl acetate (2×10 mL) and the combined organic layers washed with brine (20 mL), dried (MgSO4) and concentrated in vacuo to yield the title compound as a white solid (61 mg, 44%). LCMS (Method A): RT=8.45 min, [M+H]+=423/425. 1H NMR (DMSO-d6, 400 MHz) 13.21 (1H, s), 11.63 (1H, s), 9.90 (1H, s), 7.58 (1H, dd, J=10.47, 2.24 Hz), 7.46 (1H, d, J=8.75 Hz), 7.29 (1H, ddd, J=8.59, 2.19, 1.06 Hz), 7.23 (1H, s), 7.08 (1H, t, J=8.80 Hz), 7.02 (1H, d, J=8.78 Hz), 4.77 (1H, d, J=4.15 Hz), 3.84-3.78 (1H, m), 3.70-3.61 (2H, m), 1.03 (3H, d, J=6.33 Hz).
Reaction SMILES: F[C:2]1[N:33]=[CH:32][CH:31]=[CH:30][C:3]=1[C:4]([C:6]1[N:7]=[C:8]([N:16]2[CH2:22][CH2:21][CH2:20][N:19]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:18][CH2:17]2)[C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:5].[OH-].[NH4+:35]>>[NH2:35][C:2]1[N:33]=[CH:32][CH:31]=[CH:30][C:3]=1[C:4]([C:6]1[N:7]=[C:8]([N:16]2[CH2:22][CH2:21][CH2:20][N:19]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:18][CH2:17]2)[C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:5]
Reactant: CC(C)(C)OC(=O)N1CCCN(c2nc(C(=O)c3cccnc3F)cc3ccccc23)CC1
Reactant: [NH4+]
Agent: [OH-]
Product: CC(C)(C)OC(=O)N1CCCN(c2nc(C(=O)c3cccnc3N)cc3ccccc23)CC1
Temperature: 110 °C
Yield: 24 %

Procedure:
A microwave vial was charged with tert-butyl 4-(3-(2-fluoronicotinoyl)isoquinolin-1-yl)-1,4-diazepane-1-carboxylate (78 mg, 0.17 mmol) and a saturated aqueous solution of ammonium hydroxide (2 ml). The reaction mixture was heated under microwave irradiation at 110° C. for 25 minutes. The mixture was cooled down to room temperature, partitioned between ethyl acetate and water. The organic phase was dried over magnesium sulfate, filtered and evaporated to dryness. The residue was purified on silica gel by flash column chromatography to afford the title compound as a yellow solid (18 mg, 24% yield). MS (ES+) 448.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[C:12]2C(=O)OC(C)(C)[O:14][C:13]2=[O:21])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C(O)=O>C(N(CC)CC)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][C:13]([OH:21])=[O:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(C=C2C(=O)OC(C)(C)OC2=O)cc1OC
Solvent: CCN(CC)CC
Solvent: O=CO
Product: COc1ccc(CCC(=O)O)cc1OC

Procedure:
After weighing 14.6 g (0.05 mol) of 5-(3,4-dimethoxyphenylmethylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (m.p.: 173° C.) to 50 ml of the mixture of formic acid and triethylamine prepared according to Example 1, the procedure described in Example 1 was followed.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]1([S:13]([N:16]2[C:20]3=[N:21][CH:22]=[C:23]([OH:25])[CH:24]=[C:19]3[CH:18]=[C:17]2[C:26]([C:33]2[CH:38]=[CH:37][C:36]([S:39]([CH3:42])(=[O:41])=[O:40])=[CH:35][CH:34]=2)=[CH:27][CH:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)(=[O:15])=[O:14])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Br[CH:44]([CH3:46])[CH3:45]>CN(C)C=O.C(OCC)(=O)C>[C:7]1([S:13]([N:16]2[C:20]3=[N:21][CH:22]=[C:23]([O:25][CH:44]([CH3:46])[CH3:45])[CH:24]=[C:19]3[CH:18]=[C:17]2[C:26]([C:33]2[CH:34]=[CH:35][C:36]([S:39]([CH3:42])(=[O:40])=[O:41])=[CH:37][CH:38]=2)=[CH:27][CH:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)(=[O:14])=[O:15])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CS(=O)(=O)c1ccc(C(=CC2CCCC2)c2cc3cc(O)cnc3n2S(=O)(=O)c2ccccc2)cc1
Reactant: CC(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)Oc1cnc2c(c1)cc(C(=CC1CCCC1)c1ccc(S(C)(=O)=O)cc1)n2S(=O)(=O)c1ccccc1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 88.5 %

Procedure:
Potassium carbonate (430 mg, 3.11 mmol) was added to a solution of 1-benzenesulfonyl-2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-vinyl]-1H-pyrrolo[2,3-b]pyridin-5-ol (prepared as in Example 13, 325 mg, 0.62 mmol) in N,N-dimethylformamide (2 mL) at room temperature and stirred for 30 min and then 2-bromopropane (0.13 mL, 1.24 mmol) was added. The mixture was then heated to 60° C. and stirred for 3 h. The resulting mixture was diluted with ethyl acetate (150 mL), washed with brine, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 1-benzenesulfonyl-2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-vinyl]-5-isopropoxy-1H-pyrrolo[2,3-b]pyridine (310 mg, 100%) as a light yellow solid which was used in the next step without further purification: LC/MS m/e calcd for C30H32N2O5S2 [M+H]+ 565.73, observed 565.2.
Reaction SMILES: [CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[CH:13][CH:14]=3)[N:9]([CH3:23])[C:8]=2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[OH:30])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH2:32][C:33]([O:35][CH3:36])=[O:34].C(=O)([O-])[O-].[K+].[K+]>CC#N>[CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([O:18][C:19]([CH3:22])([CH3:20])[CH3:21])=[O:17])=[CH:13][CH:14]=3)[N:9]([CH3:23])[C:8]=2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[O:30][CH2:32][C:33]([O:35][CH3:36])=[O:34])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)CBr
Reactant: Cn1c(-c2ccccc2O)c(C2CCCCC2)c2ccc(C(=O)OC(C)(C)C)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)COc1ccccc1-c1c(C2CCCCC2)c2ccc(C(=O)OC(C)(C)C)cc2n1C
Reaction time: 12 h
Yield: 97.7 %

Procedure:
A solution of intermediate 25 (0.6 g, 1.5 mmol), methyl 2-bromoacetate (0.281 g, 1.83 mmol) and potassium carbonate (0.423 g, 3.06 mmol) in MeCN 50 mL was stirred at room temperature. After 12 h, the reaction mixture was concentrated under vacuum and the residue was partitioned between CH2Cl2 and water. The organic layer was dried and evaporated under vacuum to yield 0.7 g (96%) of tert-butyl 3-cyclohexyl-2-[2-(2-methoxy-2-oxoethoxy)phenyl]-1-methyl-1H-indole-6-carboxylate 26: m/z=478 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:11])=[C:4]([C@@H:8]([NH2:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.C([O:16][C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]1[CH:30]=[CH:29][C:28]([CH2:31][N:32]2[C:40]3[C:35](=[CH:36][C:37]([C:41](O)=[O:42])=[CH:38][CH:39]=3)[C:34]([CH3:44])=[C:33]2[CH3:45])=[CH:27][CH:26]=1)=[O:18])(C)(C)C>>[F:1][C:2]1[C:3]([CH3:11])=[C:4]([C@@H:8]([NH:10][C:41]([C:37]2[CH:36]=[C:35]3[C:40](=[CH:39][CH:38]=2)[N:32]([CH2:31][C:28]2[CH:27]=[CH:26][C:25]([C:20]4[C:19]([C:17]([OH:18])=[O:16])=[CH:24][CH:23]=[CH:22][CH:21]=4)=[CH:30][CH:29]=2)[C:33]([CH3:45])=[C:34]3[CH3:44])=[O:42])[CH3:9])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Reactant: Cc1c(F)cccc1[C@H](C)N
Product: Cc1c(F)cccc1[C@H](C)NC(=O)c1ccc2c(c1)c(C)c(C)n2Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
The title compound was prepared following the same general protocol as described in Step 8-9, Example 1, using the (S)-1-(3-fluoro-2-methylphenyl)ethanamine and the 1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid. ESI-MS (m/z): 535 [M+H]+.
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:15][C:16](=[O:30])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=2[C:24]([CH2:28][CH3:29])=[CH:25][CH2:26][CH3:27])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])C.[OH-].[K+].O>CCO>[CH2:28]([C:24]([C:18]1[C:19]([CH3:23])=[CH:20][CH:21]=[CH:22][C:17]=1[C:16]([NH:15][C:6]1([C:4]([OH:5])=[O:3])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:30])=[CH:25][CH2:26][CH3:27])[CH3:29]
Reactant: CCC=C(CC)c1c(C)cccc1C(=O)NC1(C(=O)OCC)Cc2ccccc2C1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCC=C(CC)c1c(C)cccc1C(=O)NC1(C(=O)O)Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.6 %

Procedure:
The mixture of 2-[2-(-1-ethyl-but-1-enyl)-3-methyl-benzoylamino]-indan-2-carboxylic acid ethyl ester (128) (503 mg, 1.24 mmol) and KOH (1 g, 17.9 mmol) is dissolved in EtOH (10 mL) and water (1 mL) under a water bath. The water bath is removed when KOH is completely dissolved and the resulting reaction solution is stirred at RT for 8 h. After concentration in vacuo, the residue is dissolved in water (40 mL) and acidified with conc. HCl until pH˜3. The precipitate is filtered to give a pure product (129) as a brown solid (452 mg, 97%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][N:16]=2)[CH:11]=[CH:10][C:9]=1[N:18]1[CH:26]([O:27][C:28](OC2C=CC=CC=2)=[O:29])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]1=[O:37].C(=O)(O)[O-].[Na+]>C(#N)C.C(Cl)Cl>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:28]([O:27][CH:26]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19](=[O:37])[N:18]2[C:9]2[CH:10]=[CH:11][C:12]3[C:17](=[N:16][CH:15]=[CH:14][CH:13]=3)[N:8]=2)=[O:29])[CH2:4][CH2:3]1
Reactant: CN1CCNCC1
Reactant: O=C(Oc1ccccc1)OC1c2ccccc2C(=O)N1c1ccc2cccnc2n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: ClCCl
Product: CN1CCN(C(=O)OC2c3ccccc3C(=O)N2c2ccc3cccnc3n2)CC1
Temperature: 20 °C
Reaction time: 6 h
Yield: 51 %

Procedure:
4-Methylpiperazine (8 g.) is added all at once to a suspension of 2-(1,8-naphthyridin-2-yl)-3-phenoxycarbonyloxy-isoindolin-1-one (5.6 g.) in acetonitrile (100 cc.). The solution obtained is stirred for 6 hours at a temperature of about 20° C. The reaction mixture is poured into a suspension of ice (100 g.) in methylene chloride (300 cc.). An 8% aqueous solution of sodium bicarbonate (200 cc.) is added to the suspension obtained. The organic phase is decanted and the aqueous phase is extracted with methylene chloride (400 cc.). The combined organic phases are dried over anhydrous potassium carbonate (10 g.) and concentrated to dryness. The oily residue (8 g.) is taken up in refluxing diisopropyl ether (100 cc.). On cooling the solution, crystals are deposited and are filtered off. 3-(4-Methylpiperazin-1-yl)carbonyloxy-2-(1,8-naphthyridin-2-yl)isoindolin-1-one (2.9 g.), which melts at 183° C., is thus obtained.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[N:10]=[N:11][N:12]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][C:22]3[S:23][C:24]([C:30]4[C:35]([F:36])=[CH:34][C:33]([C:37]([OH:40])([CH3:39])[CH3:38])=[CH:32][C:31]=4[F:41])=[CH:25][C:26]=3[C:27]([NH2:29])=[O:28])[N:16]=2)[CH:13]=1)(C)(C)C.Cl.O1CCOCC1>CCOC(C)=O>[NH2:7][CH2:8][C:9]1[N:10]=[N:11][N:12]([CH2:14][C:15]2[N:16]=[C:17]([NH:21][C:22]3[S:23][C:24]([C:30]4[C:31]([F:41])=[CH:32][C:33]([C:37]([OH:40])([CH3:38])[CH3:39])=[CH:34][C:35]=4[F:36])=[CH:25][C:26]=3[C:27]([NH2:29])=[O:28])[CH:18]=[CH:19][CH:20]=2)[CH:13]=1
Reactant: CC(C)(C)OC(=O)NCc1cn(Cc2cccc(Nc3sc(-c4c(F)cc(C(C)(C)O)cc4F)cc3C(N)=O)n2)nn1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(Nc3cccc(Cn4cc(CN)nn4)n3)s2)c(F)c1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To a suspension of tert-butyl[(1-{[6-({3-(aminocarbonyl)-5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]-2-thienyl}amino)pyridin-2-yl]methyl}-1H-1,2,3-triazol-4-yl)methyl]carbamate (90 mg, 0.15 mmol) in EtOAc (7.0 mL) at ° C. was added 4 M HCl in dioxane (1.88 mL, 7.50 mmol). The reaction was stirred at 0° C. for 4 h. The yellow suspension was quenched with saturated NaHCO3 and extracted with 5:1 CH2Cl2:MeOH (2×). The combined organic layers were dried (MgSO4), filtered, and evaporated. The residue was purified by reverse phase HPLC (15-75% MeCN/water w/0.025% TFA). Product fractions were neutralized with saturated NaHCO3, extracted with 5:1 CH2Cl2:MeOH (2×), dried (MgSO4), filtered, and evaporated to give the title compound as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].CS(C)=O.Cl[C:20]1[C:25]([C:26]2[CH:31]=[CH:30][N:29]=[C:28]([NH:32][CH3:33])[N:27]=2)=[CH:24][CH:23]=[CH:22][N:21]=1>O>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:20]2[C:25]([C:26]3[CH:31]=[CH:30][N:29]=[C:28]([NH:32][CH3:33])[N:27]=3)=[CH:24][CH:23]=[CH:22][N:21]=2)=[CH:4][CH:3]=1
Reactant: CNc1nccc(-c2cccnc2Cl)n1
Reactant: Nc1ccc(S)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: CNc1nccc(-c2cccnc2Sc2ccc(N)cc2)n1
Temperature: 130 °C
Reaction time: 16 h

Procedure:
To 4-aminothiophenol (1.70 g, 13.6 mmol) and Cs2CO3 (8.90 g, 27.2 mmol) was added DMSO (18 mL). The mixture was stirred for 5 minutes at 100° C. before 4-(2-chloropyridin-3-yl)-N-methylpyrimidin-2-amine (3.00 g, 13.6 mmol) was added. The resulting mixture was stirred for 16 hours at 130° C., then diluted with water and the resulting solid filtered. After washing the solid with water and Et2O it was dried under vacuum to yield the desired product as a tan solid. MS m/z=310 [M+1]+. Calc'd for C16H15N3S: 309.40.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH:5](Br)[C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1)[CH3:2].[C:14]([NH2:18])([CH3:17])([CH3:16])[CH3:15].CCN(CC)CC>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:13])[CH:5]([NH:18][C:14]([CH3:17])([CH3:16])[CH3:15])[C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1)[CH3:2]
Reactant: CC(C)(C)N
Reactant: CCOC(=O)C(Br)c1cccnc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C(NC(C)(C)C)c1cccnc1
Yield: 41.2 %

Procedure:
Bromo-pyridin-3-yl-acetic acid ethyl ester (2.4 g; 9.8 mmol) was reacted in refluxing CH2Cl2, overnight with tert-butylamine (6.2 mL; 55.8 mmol; 6 equiv) and Et3N (2.8 mL; 19.6 mmol; 2 equiv). The reaction solution was evaporated to dryness, dissolved in CH2Cl2, washed six times with saturated NaHCO3 (aq), washed once with saturated NaCl (aq), dried with Na2SO4, filtered, and concentrated in vacuo. The resulting brown oil was purified with silica gel chromatography in a 6×8 cm glass column using a 30% EtOAc/hexanes (v/v) mobile phase. A total of 955 mg desired product was isolated (41% yield). MS(ES) calc'd: [M+H]+=237.1 m/z. Found: 237.1 m/z.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1.Br[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([C:31]1[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][C:32]=1[OH:38])=[O:30]>C(N(CC)CC)C>[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([C:31]3[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][C:32]=3[OH:38])=[O:30])[CH2:16][CH2:17]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: O=C(CCCCCBr)c1ccc(O)cc1O
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Agent: Cl
Solvent: CCN(CC)CC
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCC(=O)c2ccc(O)cc2O)CC1
Yield: 18.4 %

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride (3.87 g) as a starting compound, 6-bromo-1-(2,4-dihydroxyphenyl)-1-hexanone (3.00 g) and triethylamine (6.5 ml) were reacted and purified in the same manner as in Example 172 to give 0.97 g of 4-amino-5-chloro-2-methoxy-N-((1-(6-(2,4-dihydroxyphenyl)-6-oxohexyl)piperidin-4-yl)methyl)benzamide, m.p. 96°-99° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2[C:18](=[O:34])[NH:19][C:20]2([C:29]([O:31]CC)=[O:30])[CH2:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH2:21]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[K+].O>CCO>[C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2[C:18](=[O:34])[NH:19][C:20]2([C:29]([OH:31])=[O:30])[CH2:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH2:21]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)C1(NC(=O)c2cccc3c2CCN(C(=O)OC(C)(C)C)C3)Cc2ccccc2C1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCc2c(cccc2C(=O)NC2(C(=O)O)Cc3ccccc3C2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 87.5 %

Procedure:
The mixture of 5-(2-ethoxycarbonyl-indan-2-ylcarbamoyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (71) (882 mg, 1.78 mmol) and KOH (1 g, 17.9 mmol) is dissolved in EtOH (15 mL) and water (1 mL) under a water bath. The water bath is removed when KOH is completely dissolved and the resulting reaction solution is stirred at RT for 3 h. After concentration in vacuo, the residue is dissolved in water (50 mL) and acidified with conc. HCl until no more white precipitate came out of the water. After the filtration, the solid is purified by HPLC to give a pure product (72) as white solid (680 mg, 88%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][C:3]=1[O:10][CH3:11].C1C(=O)N([Br:19])C(=O)C1>CC#N>[Br:19][C:6]1[CH:7]=[C:2]([F:1])[C:3]([O:10][CH3:11])=[CH:4][C:5]=1[CH2:8][OH:9]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1cc(CO)ccc1F
Solvent: CC#N
Product: COc1cc(CO)c(Br)cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 95.7 %

Procedure:
To a solution of (4-fluoro-3-methoxy-phenyl)-methanol (10.0 g, 64.04 mmol) in MeCN (160 mL) was added a solution of NBS (11.4 g, 64.04 mmol) in MeCN (50 mL) and the resulting mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated in vacuo and the residue was suspended in diethyl ether (200 mL). Solid material was removed by filtration and washed with further diethyl ether. The filtrate was washed with water (200 mL) and brine (100 mL), dried over MgSO4 and concentrated in vacuo to give the title compound as a white solid (14.4 g) in a 96% yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][N:17]([C:20]([O:22][C@H:23]([CH2:44][C:45]4[CH:50]=[C:49]([C:51]([F:54])([F:53])[F:52])[C:48]([NH2:55])=[C:47]([Cl:56])[CH:46]=4)[C:24]([N:26]4[CH2:31][CH2:30][CH:29]([N:32]5[CH2:37][CH2:36][N:35]([CH2:38][C:39]([O:41]CC)=[O:40])[CH2:34][CH2:33]5)[CH2:28][CH2:27]4)=[O:25])=[O:21])[CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:57]=1.[Li+].[OH-]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:15][CH2:16][N:17]([C:20]([O:22][C@H:23]([CH2:44][C:45]4[CH:50]=[C:49]([C:51]([F:54])([F:53])[F:52])[C:48]([NH2:55])=[C:47]([Cl:56])[CH:46]=4)[C:24]([N:26]4[CH2:31][CH2:30][CH:29]([N:32]5[CH2:37][CH2:36][N:35]([CH2:38][C:39]([OH:41])=[O:40])[CH2:34][CH2:33]5)[CH2:28][CH2:27]4)=[O:25])=[O:21])[CH2:18][CH2:19]3)[CH2:9][CH2:8][C:7]=2[CH:57]=1
Reactant: CCOC(=O)CN1CCN(C2CCN(C(=O)[C@@H](Cc3cc(Cl)c(N)c(C(F)(F)F)c3)OC(=O)N3CCC(N4CCc5cc(OC)ccc5NC4=O)CC3)CC2)CC1
Agent: [Li+]
Agent: [OH-]
Product: COc1ccc2c(c1)CCN(C1CCN(C(=O)O[C@H](Cc3cc(Cl)c(N)c(C(F)(F)F)c3)C(=O)N3CCC(N4CCN(CC(=O)O)CC4)CC3)CC1)C(=O)N2

Procedure:
Prepared analogously to Example 15.1 from 20 mg (0.02 mmol) (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-[4-(4-ethoxycarbonylmethyl-piperazin-1-yl)-piperidin-1-yl]-2-oxo-ethyl 4-(7-methoxy-2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate and 2 mg (0.08 mmol) LiOH.