Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][N:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)=[CH:13][C:12]2=[O:25])=[CH:5][CH:4]=1.[OH:26][C:27]1([CH3:33])[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.C(N(C(C)C)C(C)C)C>CN(C=O)C>[OH:26][C:27]1([CH3:33])[CH2:32][CH2:31][N:30]([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][N:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=4)=[CH:13][C:12]3=[O:25])=[CH:5][CH:4]=2)[CH2:29][CH2:28]1
Reactant: O=c1cc(OCc2ccccn2)ccn1CCc1ccc(CBr)cc1
Reactant: CC1(O)CCNCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC1(O)CCN(Cc2ccc(CCn3ccc(OCc4ccccn4)cc3=O)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 140 mg (0.26 mmol) 1-[2-(4-bromomethyl-phenyl)-ethyl]-4-(pyridin-2-ylmethoxy)-1H-pyridin-2-one (example 3.3a) in 1.5 mL DMF is added 61 mg (0.53 mmol) 4-hydroxy-4-methylpiperidine and 0.12 mL (0.66 mmol) N-ethyl-diisopropylamine at RT. The reaction mixture is stirred 2 h at RT and is directly transferred to a reverse HPLC for purification (Waters symmetry, C18; water (0.15% formic acid)/acetonitrile 95:5 to 10:90).
Reaction SMILES: [Br-].[C:2]([CH2:5][CH2:6][CH2:7][CH2:8][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:4])=[O:3].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[C:38]([O:42][C:43]([N:45]1[CH2:49][C@H:48]([NH:50][S:51]([C:54]2[CH:59]=[CH:58][C:57]([Cl:60])=[CH:56][CH:55]=2)(=[O:53])=[O:52])[CH2:47][C@H:46]1[CH:61]=O)=[O:44])([CH3:41])([CH3:40])[CH3:39].O>O1CCCC1.CN(C)P(N(C)C)(N(C)C)=O.C(OCC)(=O)C>[C:38]([O:42][C:43]([N:45]1[CH2:49][C@H:48]([NH:50][S:51]([C:54]2[CH:59]=[CH:58][C:57]([Cl:60])=[CH:56][CH:55]=2)(=[O:53])=[O:52])[CH2:47][C@H:46]1/[CH:61]=[CH:8]\[CH2:7][CH2:6][CH2:5][C:2]([OH:4])=[O:3])=[O:44])([CH3:41])([CH3:39])[CH3:40]
Reactant: CC(C)(C)OC(=O)N1C[C@H](NS(=O)(=O)c2ccc(Cl)cc2)C[C@H]1C=O
Reactant: O=C(O)CCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Br-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CC(C)(C)OC(=O)N1C[C@H](NS(=O)(=O)c2ccc(Cl)cc2)C[C@H]1/C=C\CCCC(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 63 %

Procedure:
To a suspension of (4-carboxybutyl)triphenylphosphonium bromide (13.3 g) in a mixture of tetrahydrofuran (80 ml) and hexamethylphosphoramide (20 ml) was added a solution (60 ml, 1M solution) of lithium bis(trimethylsilyl)amide in tetrahydrofuran at 0° C. and the solution was stirred at room temperature for 1 hour. After the solution was cooled to -25° C., a solution of (2S,4R)-1-t-butoxycarbonyl-4-(4-chlorophenylsulfonylamino)-2-formylpyrrolidine (3.89 g) in tetrahydrofuran (20 ml) was added dropwise thereto and the solution was stirred at -20° C.~-25° C. for 30 minutes. Water (100 ml) and ethyl acetate (100 ml) were added to the solution and the aqueous phase was separated. The aqueous solution was adjusted to pH2 with 1N hydrochloric acid and extracted with ethyl acetate (200 ml). The organic layer was washed two times with water and then with brine and dried over magnesium sulfate. The solvent was evaporated in vacuo and the residue was chromatographed on a silica gel (150 g) column with a mixture of chloroform and methanol (30:1) as an eluent to give (2S,4R)-1-t-butoxycarbonyl-2-[(Z)-5-carboxy-1-pentenyl]-4-(4-chlorophenylsulfonylamino)pyrrolidine (2.98 g) as a colorless oil.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.I[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1.C([O-])([O-])=O.[K+].[K+].O>CN1CCCC1=O.C(OCC)(=O)C>[CH3:18][O:17][C:14]1[CH:15]=[CH:16][C:11]([N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH:3]=[CH:2]2)=[CH:12][CH:13]=1
Reactant: c1ccc2[nH]ccc2c1
Reactant: COc1ccc(I)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN1CCCC1=O
Product: COc1ccc(-n2ccc3ccccc32)cc1
Reaction time: 16 h
Yield: 70.3 %

Procedure:
A slurry of 2.63 g (22.5 mmol) indole, 5.26 g (22.5 mmol) 4-iodoanisole, 0.43 g (3 mmol) CuBr and 4.14 g (30 mmol) K2CO3 in 60 ml anhydrous N-methylpyrrolidinone (NMP) was heated to reflux with stirring for 16 hr. The solution was allowed to cool and then poured into water and shaken with ethyl acetate. The entire biphasic system was filtered through a pad of Celite, the phases were separated, and the organic phase was dried over MgSO4 and concentrated. The crude product was chromatographed on silica (5–7% EtOAc-Hexane) to afford 3.53 g 1-(4-methoxyphenyl)-1H-indole as a colorless solid.
Reaction SMILES: [CH3:1][N:2]([CH3:8])[C@H:3]1[CH2:7][CH2:6][NH:5][CH2:4]1.C(N(CC)CC)C.F[C:17]1[C:18]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[C:19]([CH3:33])[C:20]([C:31]#[N:32])=[C:21]2[C:25]=1[O:24][C:23]([C:26]1[S:27][CH:28]=[CH:29][N:30]=1)=[N:22]2>CS(C)=O>[CH3:1][N:2]([CH3:8])[C@H:3]1[CH2:7][CH2:6][N:5]([C:17]2[C:18]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[C:19]([CH3:33])[C:20]([C:31]#[N:32])=[C:21]3[C:25]=2[O:24][C:23]([C:26]2[S:27][CH:28]=[CH:29][N:30]=2)=[N:22]3)[CH2:4]1
Reactant: CN(C)[C@H]1CCNC1
Reactant: Cc1c(-c2ccccc2)c(F)c2oc(-c3nccs3)nc2c1C#N
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: Cc1c(-c2ccccc2)c(N2CC[C@H](N(C)C)C2)c2oc(-c3nccs3)nc2c1C#N
Temperature: 100 °C
Reaction time: 3 h

Procedure:
(3S)-3-(Dimethylamino)pyrrolidine (48.4 μl, 0.382 mmol) and triethylamine (53.2 μl, 0.382 mmol) were added to a dimethyl sulfoxide (1 ml) solution of 7-fluoro-5-methyl-6-phenyl-2-(1,3-thiazol-2-yl)-1,3-benzoxazole-4-carbonitrile (I-186) (64.0 mg, 0.191 mmol), followed by stirring in an oil bath at 100° C. for 3 hours.
Reaction SMILES: [CH2:1]([N:5]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:31]#[N:32])=[CH:21][CH:20]=1)[C:6](=[O:17])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]([OH:16])=[O:15])[CH2:2][CH2:3][CH3:4].C([Sn]([N:46]=[N+:47]=[N-:48])(CCCC)CCCC)CCC.[OH-].[Na+].C(Cl)Cl.CO>C1(C)C(C)=CC=CC=1>[CH2:1]([N:5]([CH2:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:31]2[NH:48][N:47]=[N:46][N:32]=2)=[CH:23][CH:24]=1)[C:6](=[O:17])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]([OH:16])=[O:15])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN(Cc1ccc(-c2ccccc2C#N)cc1)C(=O)Cc1ccccc1C(=O)O
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Solvent: Cc1ccccc1C
Product: CCCCN(Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1)C(=O)Cc1ccccc1C(=O)O

Procedure:
A solution of 2.50 g of 2-carboxy-phenylacetic acid N-butyl-N-(2'-cyanobiphenyl-4-ylmethyl)-amide and 6.50 g of tributyltin azide in 50 ml of xylene is heated under reflux for 15 hours. When cool, the mixture is stirred with 50 ml of 2N sodium hydroxide solution at room temperature for 30 minutes. The aqueous phase is acidified and extracted three times with 50 ml of CH2C2 each time. After customary treatment, the combined dichloromethane phases yield a crude product that, after chromatography on silica gel 60 (40-63 μm) using CH2Cl2 /CH3OH (97:3)) as eluant, yields 2-carboxy-phenylacetic acid N-butyl-N-[2'-(1H-tetrazol-5-yl)-biphenyl-4-ylmethyl]-amide that has an Rf value of 0.37 [CH2Cl2 /CH3OH (4:1)]. ##STR11##
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@:9]2([CH2:28][CH2:29]CS([O-])(=O)=O)[CH2:13][CH2:12][N:11]([C:14](=[O:27])[C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[N:35]1[CH:40]=[CH:39][CH:38]=[C:37]([C:41]2([C:47]([NH2:49])=[O:48])[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]2)[CH:36]=1.C(OCC)(=O)C>ClCCl.CO>[Cl:1][C:2]1[CH:3]=[C:4]([C@@:9]2([CH2:28][CH2:29][N:44]3[CH2:45][CH2:46][C:41]([C:37]4[CH:36]=[N:35][CH:40]=[CH:39][CH:38]=4)([C:47]([NH2:49])=[O:48])[CH2:42][CH2:43]3)[CH2:13][CH2:12][N:11]([C:14](=[O:27])[C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COc1cc(C(=O)N2CC[C@@](CCCS(=O)(=O)[O-])(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Reactant: NC(=O)C1(c2cccnc2)CCNCC1
Solvent: CO
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1cc(C(=O)N2CC[C@](CCN3CCC(C(N)=O)(c4cccnc4)CC3)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC

Procedure:
Prepare by the method of example 88.6 using (S)-2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate (3.2 g, 6 mmol) and 4-(pyridin-3-yl)-piperidine-4-carboxylic acid amide (1.25 g, 6.1 mmol). Chromatograph on silica gel eluting sequentially with ethyl acetate, 2% methanol/dichloromethane, 4% methanol/dichloromethane, 6% methanol/dichloromethane, and then dichloromethane/methanol/concentrated ammonia 746/36/4 to give the title compound: Rf =0.32 (silica gel, 10% methanol/dichloromethane).
Reaction SMILES: [H-].[Na+].[N:3]1([C:10]2[C:19]3[C:14](=[CH:15][C:16]([CH2:20][OH:21])=[CH:17][CH:18]=3)[N:13]=[C:12]([CH3:22])[CH:11]=2)[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.Br[CH2:24][CH2:25][O:26][CH3:27]>CN(C)C=O>[N:3]1([C:10]2[C:19]3[C:14](=[CH:15][C:16]([CH2:20][O:21][CH2:24][CH2:25][O:26][CH3:27])=[CH:17][CH:18]=3)[N:13]=[C:12]([CH3:22])[CH:11]=2)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]1
Reactant: COCCBr
Reactant: Cc1cc(N2CCCCCC2)c2ccc(CO)cc2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCOCc1ccc2c(N3CCCCCC3)cc(C)nc2c1
Reaction time: 22 h
Yield: 32 %

Procedure:
Sodium hydride (55-65% dispersion in mineral oil, 10 mg, 0.25 mmol) was added to a solution of (4-azepan-1-yl-2-methyl-quinolin-7-yl)-methanol (example 3, 50 mg, 0.19 mmol) and 1-bromo-2-methoxy-ethane (15 mg, 0.19 mmol) in N,N-dimethylformamide (2 mL). After 22 h at 50° C., another portion of sodium hydride (10 mg) and 1-bromo-2-methoxyethane (15 mg) was added, and stirring was continued for 16 h. Then the reaction mixture was partitioned between 1 M aq. sodium carbonate solution and ethyl acetate. The organic layer was separated washed with brine, dried (MgSO4), and evaporated. Chromatography (SiO2, dichloromethane/methanol 9:1) yielded the title compound (20 mg, 33%). Yellow oil, ISP-MS: m/e=329.4 ([M+H]+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:21])[C:7]3[C:15](=[O:16])[N:14]([CH2:17][CH2:18][OH:19])[N:13]=[C:12]([OH:20])[C:8]=3[NH:9][C:10]=2[CH:11]=1.Br.[C:23](O)(=[O:25])[CH3:24]>O>[C:23]([O:19][CH2:18][CH2:17][N:14]1[C:15](=[O:16])[C:7]2[C:6](=[O:21])[C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:11][C:10]=3[NH:9][C:8]=2[C:12]([OH:20])=[N:13]1)(=[O:25])[CH3:24]
Reactant: CC(=O)O
Reactant: O=c1c2ccc(Cl)cc2[nH]c2c(O)nn(CCO)c(=O)c12
Agent: Br
Solvent: O
Product: CC(=O)OCCn1nc(O)c2[nH]c3cc(Cl)ccc3c(=O)c2c1=O
Temperature: 25 °C
Yield: 86 %

Procedure:
An orange suspension of 7-chloro-4-hydroxy-2-(2-hydroxyethyl)-1,2,5,10-tetrahydropyridazino[4,5-b]quinoline-1,10-dione (0.250 g, 0.81 mM) in a 30% solution of hydrobromic acid in glacial acetic acid (5 mL) was gently refluxed for 16 hours under nitrogen. The mixture was cooled to room temperature and diluted with water (20 mL) to form a precipitate. The collected solids were washed with water and methanol and then dried to give the title compound (0.242 g, 86%) as a tan solid, mp=307-309° C.; MS(CI): 350 (M+H).
Reaction SMILES: [CH3:1][CH:2](Br)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[OH:10][C:11]1[C:12](=[O:25])[C:13]2[C:21](=[CH:22][CH:23]=1)[C:20]1[C:15](=[CH:16][C:17]([OH:24])=[CH:18][CH:19]=1)[CH:14]=2.[OH-].[K+]>C(O)C>[OH:10][C:11]1[C:12](=[O:25])[C:13]2[C:21](=[CH:22][CH:23]=1)[C:20]1[C:15](=[CH:16][C:17]([O:24][CH:2]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH3:1])=[CH:18][CH:19]=1)[CH:14]=2
Reactant: O=C1C(O)=CC=C2C1=Cc1cc(O)ccc12
Reactant: CCCCCCC(C)Br
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCCC(C)Oc1ccc2c(c1)C=C1C(=O)C(O)=CC=C12

Procedure:
According to a known method, optically active 2-octyl bromide and 2,7-dihydroxylfluorenone were reacted in ethanol in the presence of potassium hydroxide. The resultant reaction mixture was purified by a column chromatography and recrystallization to obtain optically active 2-hydroxy-7-(2-octyloxy)-fluorenone.
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[Cl:13])=[O:5].[Cl:19][CH2:20][C:21](Cl)=O>C(O)(=O)C>[Br:18][C:15]1[CH:14]=[C:3]2[C:2](=[CH:17][CH:16]=1)[N:1]=[C:21]([CH2:20][Cl:19])[N:6]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[Cl:13])[C:4]2=[O:5]
Reactant: Nc1ccc(Br)cc1C(=O)Nc1ccccc1Cl
Reactant: O=C(Cl)CCl
Solvent: CC(=O)O
Product: O=c1c2cc(Br)ccc2nc(CCl)n1-c1ccccc1Cl
Yield: 82.8 %

Procedure:
Prepared according to Procedure B with 1b (500 mg, 1.54 mmol) and chloroacetyl chloride (0.37 mL, 4.61 mmol) in acetic acid (10 mL). Purified by recrystallization from isopropanol to afford 490 mg of an off-white solid (83%). 1H NMR (CDCl3) δ: 8.43 (d, J=2.3 Hz, 1H); 7.91 (dd, J=2.3, 8.7 Hz, 1H); 7.67 (d, J=8.7 Hz, 1H); 7.60-7.65 (m, 1H); 7.47-7.56 (m, 2H); 7.52 (t, J=5.3 Hz, 1H); 7.47-7.56 (m, 1H); 4.37 (d, J=12 Hz, 1H), 4.06 (d, J=12 Hz, 1H). MS (ES): m/z 385.0 (M+)
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][N:13]([C:15]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[O:16])[CH2:12][CH:11]([C:23](O)=[O:24])[CH2:10]2)=[CH:5][CH:4]=1)[CH3:2].O[N:27]1[C:32]([CH3:33])=[CH:31][CH:30]=[CH:29][CH:28]1[C:34](=[NH:36])[NH2:35]>>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[CH2:10][CH:11]([C:23]3[O:24][N:36]=[C:34]([C:28]4[CH:29]=[CH:30][CH:31]=[C:32]([CH3:33])[N:27]=4)[N:35]=3)[CH2:12][N:13]([C:15]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[O:16])[CH2:14]2)=[CH:7][CH:8]=1)[CH3:2]
Reactant: CC1=CC=CC(C(=N)N)N1O
Reactant: CCc1ccc(C2CC(C(=O)O)CN(C(=O)N3CCOCC3)C2)cc1
Product: CCc1ccc(C2CC(c3nc(-c4cccc(C)n4)no3)CN(C(=O)N3CCOCC3)C2)cc1

Procedure:
69 mg (0.20 mmol) of 5-(4-ethylphenyl)-1-(morpholin-4-ylcarbonyl)piperidine-3-carboxylic acid (Example 38A) and 33 mg (0.22 mmol, 1.1 eq.) of 1-hydroxy-6-methylpyridine-2-carboximidamide were reacted according to the General Method 1. Yield: 44 mg (47% of theory)
Reaction SMILES: [NH2:1][C:2]1[CH:29]=[CH:28][C:5]([C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:16]=[C:17]([CH:25]=[CH:26][CH:27]=3)[C:18]([NH:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:10][CH2:9]2)=[O:7])=[C:4]([C:30]([F:33])([F:32])[F:31])[CH:3]=1.C1C([N+]([O-])=O)=CC=C([Cl-][C:44]([O-])=[O:45])C=1.[CH3:47][C:48]([CH3:52])([CH3:51])[CH2:49][NH2:50]>ClCCl>[C:21]([NH:20][C:18](=[O:19])[C:17]1[CH:25]=[CH:26][CH:27]=[C:15]([CH2:14][N:11]2[CH2:12][CH2:13][N:8]([C:6](=[O:7])[C:5]3[CH:28]=[CH:29][C:2]([NH:1][C:44]([NH:50][CH2:49][C:48]([CH3:52])([CH3:51])[CH3:47])=[O:45])=[CH:3][C:4]=3[C:30]([F:32])([F:33])[F:31])[CH2:9][CH2:10]2)[CH:16]=1)([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)CN
Reactant: CC(C)(C)NC(=O)c1cccc(CN2CCN(C(=O)c3ccc(N)cc3C(F)(F)F)CC2)c1
Solvent: ClCCl
Product: CC(C)(C)CNC(=O)Nc1ccc(C(=O)N2CCN(Cc3cccc(C(=O)NC(C)(C)C)c3)CC2)c(C(F)(F)F)c1
Reaction time: 1 h
Yield: 38.1 %

Procedure:
To a stirred solution of 3-((4-(4-amino-2-(trifluoromethyl)benzoyl)piperazin-1-yl)methyl)-N-tert-butylbenzamide (0.123 mmol, 57 mg) in dichloromethane (2 mL) was added 4-nitrophenylchloroformate (0.123 mmol, 24.84 mg). After 1 hour stirring, 2,2-dimethylpropan-1-amine (0.123 mmol, 10.74 mg) was added and stirring was continued for 1 hour. The reaction was concentrated under reduced pressure and the residue dissolved in methanol (1 mL). Purification by basic reverse phase HPLC gave the title compound (27 mg).
Reaction SMILES: [CH:1]1([N:7]2[C:15]3[C:14](=[O:16])[NH:13][C:12]([C:17]4[CH:34]=[CH:33][C:20]([CH2:21][N:22]5[CH2:27][CH2:26][CH:25]([C:28]([O:30]CC)=[O:29])[CH2:24][CH2:23]5)=[CH:19][C:18]=4[O:35][CH3:36])=[N:11][C:10]=3[C:9]([CH3:37])=[N:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+]>C(O)C>[CH:1]1([N:7]2[C:15]3[C:14](=[O:16])[NH:13][C:12]([C:17]4[CH:34]=[CH:33][C:20]([CH2:21][N:22]5[CH2:27][CH2:26][CH:25]([C:28]([OH:30])=[O:29])[CH2:24][CH2:23]5)=[CH:19][C:18]=4[O:35][CH3:36])=[N:11][C:10]=3[C:9]([CH3:37])=[N:8]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)C1CCN(Cc2ccc(-c3nc4c(C)nn(C5CCCCC5)c4c(=O)[nH]3)c(OC)c2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1cc(CN2CCC(C(=O)O)CC2)ccc1-c1nc2c(C)nn(C3CCCCC3)c2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 51.6 %

Procedure:
To a 1 ml ethanol solution of 43 mg (0.0848 mmol) of the compound obtained in Example 238, 1 ml of a 1M aqueous solution of sodium hydroxide was added, and the mixture was stirred at room temperature for 2 hours. Then, the reaction mixture was distilled under reduced pressure, and the residue was dissolved in water. Acetic acid was added, and precipitated solids were collected by filtration to obtain 21 mg (52%) of the captioned compound.
Reaction SMILES: CC1(C)C(C)(C)OB(C2C=CC([C:15]3[N:16]=[C:17]([C@@H:20]4[CH2:24][CH2:23][CH2:22][N:21]4[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[NH:18][CH:19]=3)=CC=2)O1.[CH2:33]([S:36]([N:39]1[CH2:44][CH2:43][N:42]([CH2:45][C:46]2[CH:51]=[CH:50][C:49]([NH:52][C:53]([C:55]3[CH:60]=[CH:59][C:58]([C:61]4[CH:66]=[CH:65][C:64](C(NC5C=CC(CN6CCN(S(CCC)(=O)=O)CC6)=CC=5)=O)=[CH:63][CH:62]=4)=[CH:57][CH:56]=3)=[O:54])=[CH:48][CH:47]=2)[CH2:41][CH2:40]1)(=[O:38])=[O:37])[CH2:34][CH3:35]>>[CH2:33]([S:36]([N:39]1[CH2:44][CH2:43][N:42]([CH2:45][C:46]2[CH:47]=[CH:48][C:49]([NH:52][C:53]([C:55]3[CH:56]=[CH:57][C:58]([C:61]4[CH:62]=[CH:63][C:64]([C:15]5[N:16]=[C:17]([C@@H:20]6[CH2:24][CH2:23][CH2:22][N:21]6[C:25]([O:27][C:28]([CH3:29])([CH3:30])[CH3:31])=[O:26])[NH:18][CH:19]=5)=[CH:65][CH:66]=4)=[CH:59][CH:60]=3)=[O:54])=[CH:50][CH:51]=2)[CH2:41][CH2:40]1)(=[O:37])=[O:38])[CH2:34][CH3:35]
Reactant: CCCS(=O)(=O)N1CCN(Cc2ccc(NC(=O)c3ccc(-c4ccc(C(=O)Nc5ccc(CN6CCN(S(=O)(=O)CCC)CC6)cc5)cc4)cc3)cc2)CC1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1nc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)c[nH]1
Product: CCCS(=O)(=O)N1CCN(Cc2ccc(NC(=O)c3ccc(-c4ccc(-c5c[nH]c([C@@H]6CCCN6C(=O)OC(C)(C)C)n5)cc4)cc3)cc2)CC1

Procedure:
The title compound is prepared from 5 (above) and (S)-tert-butyl 2-(4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (Syngene) using the Suzuki-Miyaura cross-coupling procedure outlined above for the preparation of (7). Yield: 156.9 mg (66%). HPLC: tR 1.88 min (method 1); tR 2.28 min, 96.6% purity (method 2). LC-MS m/z calcd for C39H48N6O5S ([M]+), 712. found, 713 ([M+H]+). 1H NMR (CDCl3): δ 1.06 (t, J=7.0 Hz, 3H), 1.51 (s, 9H), 1.86 (m, 2H), 1.98 (m, 1H), 2.17 (m, 2H), 2.53 (m, 4H), 2.88 (m, 2H), 3.07 (m, 1H), 3.29 (m, 4H), 3.43 (m, 2H), 3.53 (s, 2H), 4.98 (m, 1H), 7.28 (br, 1H), 7.32 (m, 2H), 7.56 (br, 1H), 7.63 (m, 2H), 7.73 (m, 2H), 7.87 (m, 2H), 7.93 (m, 2H).
Reaction SMILES: CC1(C)C2C=CC([C:12]#[C:13][C:14]3[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=3)=CC=2C(SCC)=CC1.[CH3:27][C:28]1([CH3:56])[C:37]2[CH:36]=[C:35](C#CC3C=CC(C(OCC)=O)=CC=3)[CH:34]=[CH:33][C:32]=2[C:31]([S:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[CH:30][CH2:29]1>>[CH3:27][C:28]1([CH3:56])[C:37]2[CH:36]=[CH:35][C:34]([C:12]#[C:13][C:14]3[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=3)=[CH:33][C:32]=2[C:31]([S:51][C:52]([CH3:54])([CH3:55])[CH3:53])=[CH:30][CH2:29]1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(C)(C)CC=C3SC(C)(C)C)cc1
Reactant: CCSC1=CCC(C)(C)c2ccc(C#Cc3ccc(C(=O)O)cc3)cc21
Product: CC(C)(C)SC1=CCC(C)(C)c2ccc(C#Cc3ccc(C(=O)O)cc3)cc21

Procedure:
Employing the same general procedure as for the preparation of 4-[(7,8-dihydro-8,8-dimethyl-5-ethylthionaphth-3-yl)ethynyl]benzoic acid (Compound 152), 100 mg (0.38 mmol) of ethyl 4-[(7,8-dihydro-8,8-dimethyl-5-(2-methyl-2-propylthio) naphth-2-yl)ethynyl]benzoate (Compound 159) was converted into the title compound (light yellow crystals, recrystallized from a 50% solution of acetonitrile and ethyl acetate) using 2 ml of KOH (2N aqueous solution).
Reaction SMILES: Cl.C(OC(=O)[NH:8][CH2:9][C:10]#[C:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([C:20]2[C:28]3[C:27]([NH2:29])=[N:26][CH:25]=[N:24][C:23]=3[N:22]([CH:30]3[CH2:34][CH2:33][CH2:32][CH2:31]3)[CH:21]=2)=[O:19])[CH:13]=1)(C)(C)C>CO>[NH2:29][C:27]1[C:28]2[C:20]([C:18]([C:14]3[CH:15]=[CH:16][CH:17]=[C:12]([C:11]#[C:10][CH2:9][NH2:8])[CH:13]=3)=[O:19])=[CH:21][N:22]([CH:30]3[CH2:31][CH2:32][CH2:33][CH2:34]3)[C:23]=2[N:24]=[CH:25][N:26]=1
Reactant: CC(C)(C)OC(=O)NCC#Cc1cccc(C(=O)c2cn(C3CCCC3)c3ncnc(N)c23)c1
Agent: Cl
Solvent: CO
Product: NCC#Cc1cccc(C(=O)c2cn(C3CCCC3)c3ncnc(N)c23)c1
Yield: 113.7 %

Procedure:
HCl (g) was introduced into a solution of {3-[3-(4-Amino-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-phenyl]-prop-2-ynyl}-carbamic acid tert-butyl ester (421 mg, 0.92 mmol) in MeOH (50 mL). After 5 min the reaction was concentrated to afford the title compound as a brown solid (376 mg, 100%). MS: 360.2 (MH+); HPLC Rf: 4.05 min. (HPLC method 4).
Reaction SMILES: Br.Br.[NH2:3][CH2:4][CH2:5][S:6][CH2:7][C:8]1[CH:16]=[CH:15][C:11]2[N:12]=[CH:13][NH:14][C:10]=2[CH:9]=1.NCCCOC1C=C[C:25]2[N:26]=[C:27]([NH:29][C:30](N)=[NH:31])NC=2C=1.C(C#N)(=N)SC.C(C#N)(=N)SC.C(=O)([O-])[O-].[K+].[K+]>CO>[C:30]([NH:29][C:27]([NH:26][CH3:25])=[N:3][CH2:4][CH2:5][S:6][CH2:7][C:8]1[CH:16]=[CH:15][C:11]2[N:12]=[CH:13][NH:14][C:10]=2[CH:9]=1)#[N:31]
Reactant: NCCSCc1ccc2nc[nH]c2c1
Reactant: N=C(N)Nc1nc2ccc(OCCCN)cc2[nH]1
Agent: Br
Agent: CSC(=N)C#N
Agent: O=C([O-])[O-]
Solvent: CO
Product: CNC(=NCCSCc1ccc2nc[nH]c2c1)NC#N
Temperature: 25 °C
Reaction time: 16 h
Yield: 75 %

Procedure:
A methanol solution (50 ml) containing 5-[(2-aminoethyl)thiomethyl]benzimidazole.dihydrobromide (4.2 g) prepared in item (A) above, dimethyl dithiocyanoimidocarbonate (1.75 g) and potassium carbonate (1.65 g) was agitated for 16 hrs at room temperature. After removal of the solid component, the solvent was distilled off. Then, a 20% methylamine in methanol (45 ml) was added to the residue, and the mixture was agitated for 16 hrs at room temperature. The solvent was distilled off under reduced pressure, and the oily residue was subjected to column chromatography using silica gel as a filler and an ethyl acetate/methanol (7:1) mixture as a developer. Then, N-cyano-N'-methyl-N"-[2-(5-benzimidazolylmethylthio)ethyl]guanidine (mp. 191.4° C., 2.46 g, 75%) was obtained.
Reaction SMILES: [Na].[NH2:2][OH:3].O.CO[C:7](=[O:37])[C:8]1[CH:13]=[CH:12][C:11]([CH2:14][N:15]2[CH:20]([C:21]3[C:26]([CH3:27])=[CH:25][CH:24]=[CH:23][N:22]=3)[CH2:19][CH2:18][CH2:17][CH:16]2[C:28]2[C:33]([CH3:34])=[CH:32][CH:31]=[CH:30][N:29]=2)=[C:10]([CH2:35][OH:36])[CH:9]=1.C([O-])(O)=O.[Na+]>CO.C(Cl)(Cl)Cl>[CH3:27][C:26]1[C:21]([CH:20]2[CH2:19][CH2:18][CH2:17][CH:16]([C:28]3[C:33]([CH3:34])=[CH:32][CH:31]=[CH:30][N:29]=3)[N:15]2[CH2:14][C:11]2[CH:12]=[CH:13][C:8]([C:7]([NH:2][OH:3])=[O:37])=[CH:9][C:10]=2[CH2:35][OH:36])=[N:22][CH:23]=[CH:24][CH:25]=1
Reactant: NO
Reactant: COC(=O)c1ccc(CN2C(c3ncccc3C)CCCC2c2ncccc2C)c(CO)c1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [Na]
Solvent: CO
Solvent: O
Solvent: ClC(Cl)Cl
Product: Cc1cccnc1C1CCCC(c2ncccc2C)N1Cc1ccc(C(=O)NO)cc1CO
Reaction time: 2 h
Yield: 90.6 %

Procedure:
To a stirred solution of sodium (320 mg, 14 mmol) in anhydrous MeOH (15 mL) was added NH2OH.H2O (550 mg, 7.9 mmol) followed by a solution of 4-(3,3″-dimethyl-3′,4′,5′,6′-tetrahydro-2′H-[2,2′;6′,2″]terpyridin-1′-ylmethyl)-3-hydroxymethyl-benzoic acid methyl ester (700 mg, 1.6 mmol) in anhydrous MeOH (7 mL). The mixture was stirred for 2 h, at which time TLC indicated that the reaction had stalled. A solution of sodium (320 mg, 14 mmol) and NH2OH.H2O (550 mg, 7.9 mmol) in anhydrous MeOH (8 mL) was added to the reaction mixture and stirring was continued for 2 hours. The reaction mixture was diluted with CHCl3 (100 mL) and poured into a saturated NaHCO3 solution (100 mL). The aqueous layer was extracted with CHCl3 (5×100 mL). The combined organic portions were concentrated to 100 mL, washed once with saturated NaHCO3 solution (20 mL), dried over Na2SO4, concentrated, and dried under high vacuum to give COMPOUND 45 (647 mg, 92%) as an off-white solid. 1H NMR (DMSO-d6) δ 1.46 (d, 2H, J=12.0 Hz), 1.69-1.84 (m, 1H), 2.01-2.11 (m, 1H), 2.48 (s, 6H), 3.59 (s, 2H), 4.13 (d, 2H, J=3.8 Hz), 4.40 (d, 2H, J=10.8 Hz), 4.79-4.85 (m, 1H), 5.74 (s, 1H), 6.84-6.91 (m, 3H), 7.06 (d, 1H, J=7.5 Hz), 7.18-7.28 (m, 3H), 8.14 (d, 2H, J=3.3 Hz), 8.75 (s br, 1H), 10.82 (s br, 1H); 13C NMR (D2O) δ 18.38(2), 24.40, 25.32(2), 55.27, 60.85(2), 64.75, 122.31(2), 123.64, 124.88, 126.82, 132.62, 137.64(2), 138.08, 143.18, 145.86(2), 158.58, 164.49; ES-MS m/z 447 (M+H). Anal. Calcd. For C26H30N4O3.1.1H2O: C, 66.96; H, 6.96; N, 12.01. Found: C, 66.95; H, 6.71; N, 11.66.