Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([NH2:14])=[CH:11][CH:12]=2)[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH3:15])[CH2:6][C:5]1([CH3:23])[CH3:22])(=[O:3])[CH3:2].[Br:24][CH2:25][C:26](Cl)=[O:27].C(N(CC)C(C)C)(C)C>ClCCl>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([NH:14][C:26](=[O:27])[CH2:25][Br:24])=[CH:11][CH:12]=2)[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH3:15])[CH2:6][C:5]1([CH3:23])[CH3:22])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccc(N)cc2C(C)(c2ccccc2)CC1(C)C
Reactant: O=C(Cl)CBr
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)N1c2ccc(NC(=O)CBr)cc2C(C)(c2ccccc2)CC1(C)C

Procedure:
Acylation of 1-acetyl-6-amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline (130 mg) with bromoacetyl chloride (69 l) and N,N-diisopropylethylamine (121 l) in dichloromethane (10 ml) was performed according to the method described in example 6.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[N:10][C:9]([Cl:12])=[C:8]2[C:4]=1[C:5]([C:13](=[O:17])[C:14]([O-:16])=O)=[CH:6][NH:7]2.[K+].[N:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]([N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)=[O:26]>>[N:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]([N:27]1[CH2:32][CH2:31][N:30]([C:14](=[O:16])[C:13]([C:5]2[C:4]3[C:8](=[C:9]([Cl:12])[N:10]=[CH:11][C:3]=3[O:2][CH3:1])[NH:7][CH:6]=2)=[O:17])[CH2:29][CH2:28]1)=[O:26]
Reactant: COc1cnc(Cl)c2[nH]cc(C(=O)C(=O)[O-])c12
Reactant: O=C(c1ccccn1)N1CCNCC1
Agent: [K+]
Product: COc1cnc(Cl)c2[nH]cc(C(=O)C(=O)N3CCN(C(=O)c4ccccn4)CC3)c12

Procedure:
Precursor 5l, 1-picolinoyl-4-[(4-methoxy-7-chloro-6-azaindol-3-yl)-oxoacetyl]piperazine was prepared by the same method as Precursor 5a starting from Potassium (4-methoxy-7-chloro-6-azaindol-3-yl)oxoacetate, Precursor 4d, and picolinoyl-piperazine. 1H NMR (500 MHz, DMSO-d6) δ8.63-7.45 (m, 7H), 3.94 (s, 3H), 3.82-2.50 (m, 8H). MS m/z: (M+H)+ Calc'd for C20H19ClN5O4: 428.11; Found 428. 11. HPLC retention time: 1.09 minutes (column A).
Reaction SMILES: [C:1]1([CH:7]([NH:12][C:13]([NH2:15])=[S:14])[C:8]([F:11])([F:10])[F:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:16]I>CC(C)=O>[C:1]1([CH:7]([NH:12][C:13](=[NH:15])[S:14][CH3:16])[C:8]([F:11])([F:10])[F:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NC(=S)NC(c1ccccc1)C(F)(F)F
Reactant: CI
Solvent: CC(C)=O
Product: CSC(=N)NC(c1ccccc1)C(F)(F)F

Procedure:
14.5 g N-(α-phenyltrifluoroethyl) thio Urea are dissolved in 270 ml acetone and this solution is heated to reflux. A solution of 17.6 g methyl iodide in 7.75 ml acetone is added thereto while keeping the heating at reflux during the addition and for a further period of three hours. The solvent is thereafter evaporated off and 25 of an oily product is obtained. The crystallisation thereof is initiated by scratching in the presence of benzene. The crystalls melt at b 138°-144°. A further crystallisation supplies 18.5 g of pure N-(αphenyltrifluoroethyl) S-methylisothiourea in the form of its hydroiodide melting at 142°-144°.
Reaction SMILES: S(=O)(=O)(O)O.N([O-])=O.[Na+].N[C:11]1[CH:20]=[C:19]2[C:14]([CH:15]=[C:16]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]([F:31])([F:30])[F:29])[NH:17][C:18]2=[O:21])=[CH:13][CH:12]=1.[I-:32].[Na+].C(=O)(O)[O-].[Na+]>[Cu](I)I.C(O)(=O)C>[I:32][C:11]1[CH:20]=[C:19]2[C:14]([CH:15]=[C:16]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]([F:31])([F:30])[F:29])[NH:17][C:18]2=[O:21])=[CH:13][CH:12]=1
Reactant: [I-]
Reactant: Nc1ccc2cc(-c3ccccc3C(F)(F)F)[nH]c(=O)c2c1
Agent: I[Cu]I
Agent: O=C([O-])O
Agent: O=N[O-]
Solvent: CC(=O)O
Product: O=c1[nH]c(-c2ccccc2C(F)(F)F)cc2ccc(I)cc12
Reaction time: 0.5 h
Yield: 90.1 %

Procedure:
A 1 N sulfuric acid aqueous solution (30 ml) and 862.5 mg (12.5 mmol) of sodium nitrite were added at 0° C. to an acetic acid solution (15 ml) containing 1.52 g (5.0 mmol) of the 7-amino-3-(2-trifluoromethylphenyl)-2H-isoquinolin-1-one obtained in Example 38. The obtained mixture was stirred for 30 minutes. Thereafter, 2.62 g (17.5 mmol) of sodium iodide and 952.3 mg (5.0 mmol) of copper iodide (I) were added to the reaction solution, and the obtained mixture was stirred at 80° C. for 1 hour. Thereafter, the reaction solution was cooled, and a saturated sodium bicarbonate aqueous solution was added thereto, followed by extraction with ethyl acetate. The extract was washed with a saturated saline solution, and was then dried over anhydrous sodium sulfate, followed by concentration. The obtained residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:4 to 1:2), and was then washed with a sodium thiosulfate aqueous solution, so as to obtain 1.87 g (90%) of 7-iodo-3-(2-trifluoromethylphenyl)-2H-isoquinolin-1-one in the form of a light yellow solid.
Reaction SMILES: C([O:8][C:9]1[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH2:36][N:37]2[CH2:42][CH2:41][N:40]([CH2:43][CH2:44][CH2:45][OH:46])[CH2:39][CH2:38]2)=[CH:30][C:10]=1[C:11]([NH:13][C:14]1[CH:23]=[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:21]=[CH:20][C:15]=1[C:16]([O:18][CH3:19])=[O:17])=[O:12])C1C=CC=CC=1>C(OCC)(=O)C.CO.[C].[Pd]>[OH:8][C:9]1[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH2:36][N:37]2[CH2:38][CH2:39][N:40]([CH2:43][CH2:44][CH2:45][OH:46])[CH2:41][CH2:42]2)=[CH:30][C:10]=1[C:11]([NH:13][C:14]1[CH:23]=[C:22]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:21]=[CH:20][C:15]=1[C:16]([O:18][CH3:19])=[O:17])=[O:12]
Reactant: COC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(OCCN2CCN(CCCO)CC2)ccc1OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(OCCN2CCN(CCCO)CC2)ccc1O
Temperature: 25 °C
Reaction time: 30 h
Yield: 35.7 %

Procedure:
To a solution mixture of the obtained methyl 2-(2-(benzyloxy)-5-(2-(4-(3-hydroxypropyl)piperazin-1-yl)ethoxy)benzamido)-4-phenylbenzoate (0.036 g) in ethyl acetate (1.5 mL) and methanol (1.5 mL), 10% palladium-carbon (0.018 g) was added, followed by stirring under a hydrogen atmosphere at room temperature for 2 hours and 30 hours. To the reaction mixture, 10% palladium-carbon (0.018 g) was added, followed by stirring under a hydrogen atmosphere at room temperature for 3 hours. The insoluble substance was removed by filtration, and then the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 100-90% chloroform/methanol] to obtain 0.011 g of methyl 2-(2-hydroxy-5-(2-(4-(3-hydroxypropyl)piperazin-1-yl)ethoxy)benzamido)-4-phenylbenzoate as a light yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1Br.[NH2:10][C:11]1[CH:12]=[C:13]2[C:18]3=[C:19]([CH2:21][CH2:22][CH2:23][N:17]3[CH2:16][C@@H:15]3[CH2:24][N:25](C(OC(C)(C)C)=O)[CH2:26][C@@H:14]23)[CH:20]=1>>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:10][C:11]1[CH:12]=[C:13]2[C:18]3=[C:19]([CH2:21][CH2:22][CH2:23][N:17]3[CH2:16][C@@H:15]3[CH2:24][NH:25][CH2:26][C@@H:14]23)[CH:20]=1
Reactant: Clc1cccc(Br)c1Cl
Reactant: CC(C)(C)OC(=O)N1C[C@H]2CN3CCCc4cc(N)cc(c43)[C@@H]2C1
Product: Clc1cccc(Nc2cc3c4c(c2)[C@@H]2CNC[C@H]2CN4CCC3)c1Cl

Procedure:
Using 2,3-dichlorobromobenzene and following the procedures described in EXAMPLE 72, (±)-trans tert-butyl 2-amino-5,6,8a,9,11,11a-hexahydro-4H-pyrido[3,2,1-ij]pyrrolo[3,4-c]quinoline-10(8H)-carboxylate was converted into the title compound of EXAMPLE 74 as an off-white powder. 1H NMR (300 MHz, CDCl3) δ 1.25 (br s, 1H), 1.95-2.05 (m, 2H), 2.10-2.30 (m, 1H), 2.80 (m, 4H), 2.95 (t, 1H, J=9.5 Hz), 3.30-3.55 (m, 5H), 3.54 (dd, 1H, J=9.5, 7.0 Hz), 5.93 (br s, 1H), 6.50 (s, 1H), 6.71 (s, 2H), 6.74-6.79 (m, 1H), 6.92 (t, 1H, J=8.1 Hz). LRMS (ES)+: 374 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9](B3OC(C)(C)C(C)(C)O3)[C:10]3[NH:14][C:13](=[O:15])[NH:12][C:11]=3[CH:16]=2)=[C:5]([CH3:26])[O:4][N:3]=1.Br[C:28]1[CH:29]=[C:30]([NH2:37])[CH:31]=[N:32][C:33]=1[CH:34]1[CH2:36][CH2:35]1.COCCOC.C([O-])([O-])=O.[Cs+].[Cs+]>O>[NH2:37][C:30]1[CH:29]=[C:28]([C:9]2[C:10]3[NH:14][C:13](=[O:15])[NH:12][C:11]=3[CH:16]=[C:7]([C:6]3[C:2]([CH3:1])=[N:3][O:4][C:5]=3[CH3:26])[CH:8]=2)[C:33]([CH:34]2[CH2:36][CH2:35]2)=[N:32][CH:31]=1
Reactant: Cc1noc(C)c1-c1cc(B2OC(C)(C)C(C)(C)O2)c2[nH]c(=O)[nH]c2c1
Reactant: Nc1cnc(C2CC2)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: COCCOC
Product: Cc1noc(C)c1-c1cc(-c2cc(N)cnc2C2CC2)c2[nH]c(=O)[nH]c2c1
Temperature: 130 °C
Yield: 85 %

Procedure:
6-(3,5-dimethylisoxazol-4-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazol-2(3H)-one (150 mg, 0.42 mmol) and 5-bromo-6-cyclopropylpyridin-3-amine (180 mg, 0.84 mmol) were added to a solvent mixture of 1,2-dimethoxyethane (2 mL) and water (1 mL). To the mixture were added PEPPSI-Ipr (29 mg, 0.03 mmol) and Cs2CO3 (413 mg, 1 mmol). The reaction mixture was heated at 130° C. in microwave reactor for 30 mins. The reaction mixture was then filtered and organic solvent was evaporated and the residue was purified with Prep HPLC (0-100% CH3CN/H2O) to afford 129 mg of 4-(5-amino-2-cyclopropylpyridin-3-yl)-6-(3,5-dimethylisoxazol-4-yl)-1H-benzo[d]imidazol-2(3H)-one.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:5])[CH3:2].[N+:21]([C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Br)=[CH:26][CH:25]=1)([O-:23])=[O:22].C(O)(C(F)(F)F)=O>>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:28][C:27]2[CH:30]=[CH:31][C:24]([N+:21]([O-:23])=[O:22])=[CH:25][CH:26]=2)[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: CCOC(=O)c1[nH]c2ccccc2c1-c1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1c(-c2ccccc2)c2ccccc2n1Cc1ccc([N+](=O)[O-])cc1

Procedure:
1-(4-Nitro-benzyl)-3-phenyl-1H-indolecarboxylic acid ethyl ester was prepared from of 3-phenyl-1H-indolecarboxylic acid ethyl ester and 4-nitrobenzyl bromide followed the procedure of Example 3 Step 1 as a yellow powder: 1H NMR (DMSO-d6) δ 1H NMR (DMSO-d6) δ 0.91 (t, J=7.2 Hz, 3H), 4.05 (q, J=7.2 Hz, 2H), 5.97 (s, 2H), 7.17-7.23 (m, 1H), 7.32 (d, J=8.8 Hz, 2H), 7.36-7.42 (m, 1H), 7.38-7.42 (m, 1H), 7.45-7.48 (m, 4H), 7.52 (d, J=8.2 Hz, 1H), 7.62 (d, J=8.2 Hz, 1H), 8.19 (d, J=8.8 Hz, 2H); MS (ESI) m/z 401 (MH+); 399 ([M−H]−); HRMS calcd for C24H21N2O4: 401.1490; found (ESI+): 401.1494; Anal. calcd for C24H20N2O4.0.05 TFA C, 71.99; H, 5.03; N, 7.00 Found: C, 71.27; H, 4.98; N, 6.90.
Reaction SMILES: Cl.[O:2]1[C:6]2[CH2:7][NH:8][CH2:9][CH2:10][CH2:11][C:5]=2[CH:4]=[CH:3]1.[C:12]1([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23](O)=[O:24])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C.C(P(=O)(OCC)OCC)#N.[OH-].[Na+]>ClCCl>[O:2]1[C:6]2[CH2:7][N:8]([C:23](=[O:24])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:9][CH2:10][CH2:11][C:5]=2[CH:4]=[CH:3]1
Reactant: O=C(O)CCCCCc1ccccc1
Reactant: c1cc2c(o1)CNCCC2
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CCCCCc1ccccc1)N1CCCc2ccoc2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 0.130 g of the above crude 5,6,7,8-tetrahydro-4H-furo[2,3-c]azepine hydrochloride, 0.18 g (0.96 mmol) of 6-phenylhexanoic acid and 0.44 ml (3.2 mmol) of triethylamine in 30 ml of dichloromethane, 0.15 ml (0.96 mmol) of diethyl cyanophosphonate was added dropwise under ice-cooling, followed by overnight stirring at room temperature. The reaction mixture was poured into aqueous sodium hydroxide and extracted with dichloromethane 3 times. The combined organic layer was dried over anhydrous magnesium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane/ethyl acetate=3/1 to 2/1) to yield the desired product.
Reaction SMILES: [Cl-].[Mg+2].[Cl-].[CH2:4]([O:6][C:7](=[O:21])[C:8](=O)[CH2:9][N:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12][CH2:11]1)[CH3:5]>COCCO>[CH2:4]([O:6][C:7]([C:8]1[C:18]2=[C:19]3[C:14](=[CH:15][CH:16]=[CH:17]2)[CH2:13][CH2:12][CH2:11][N:10]3[CH:9]=1)=[O:21])[CH3:5]
Reactant: CCOC(=O)C(=O)CN1CCCc2ccccc21
Agent: [Cl-]
Agent: [Mg+2]
Solvent: COCCO
Product: CCOC(=O)c1cn2c3c(cccc13)CCC2
Temperature: 125 °C
Reaction time: 0.25 h
Yield: 43.6 %

Procedure:
Anhydrous magnesium chloride (29.4 g, 0.31 mol) was suspended in 2-methoxyethanol (400 ml), and the mixture was stirred for 15 minutes at 125° C. A solution of 3-(3,4-dihydro-2H-quinolin-1-yl)-2-oxopropionic acid ethyl ester (76.57 g 0.31 mol) in 2-methoxyethanol (100 ml) was then added and the mixture stirred at 125° C. for 60 minutes. The mixture was stirred for a further 5 hours at reflux, cooled and evaporated to dryness. The residue was then acidified with 2 M hydrochloric acid (500 ml) and extracted with dichloromethane (3×500 ml). The combined organic layers were then washed with 5% sodium bicarbonate solution and dried over anhydrous magnesium sulfate before being evaporated to dryness. The residue was then purified on a silica gel chromatography column, eluting with ethyl acetate/hexanes (1:4) to provide 5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline-1-carboxylic acid ethyl ester (31.0 g, 47%). 1H NMR (CDCl3) 400 MHz δ: 7.9 (d, 1H, J=8 Hz), 7.79 (s, 1H), 7.17 (m, 1H), 6.99 (d, 1H, J=7.2 Hz), 4.37 (m, 2H), 4.18 (t, 2H, J=5.6 Hz), 3.0 (t, 2H, J=6 Hz), 2.24 (t, 2H, J=6 Hz), 1.42 (t, 3H, J=7.2 Hz).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Cl:7][C:8]1[CH:9]=[C:10]([C:14]2[N:15]=[N:16][N:17]([CH:19]([CH3:25])[CH2:20][C:21]([NH:23][CH3:24])=O)[N:18]=2)[CH:11]=[CH:12][CH:13]=1.N1C(C)=CC=CC=1C.[C:34]([NH:42][NH2:43])(=O)[C:35]1[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=1>C(Cl)Cl>[Cl:7][C:8]1[CH:9]=[C:10]([C:14]2[N:15]=[N:16][N:17]([CH:19]([CH3:25])[CH2:20][C:21]3[N:23]([CH3:24])[C:34]([C:35]4[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=4)=[N:42][N:43]=3)[N:18]=2)[CH:11]=[CH:12][CH:13]=1
Reactant: NNC(=O)c1ccncc1
Reactant: CNC(=O)CC(C)n1nnc(-c2cccc(Cl)c2)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CC(Cc1nnc(-c2ccncc2)n1C)n1nnc(-c2cccc(Cl)c2)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 1.6 %

Procedure:
Oxalylchloride (2M in DCM, 0.28 mL, 0.55 mmol) was dropwise added during 5 minutes to a solution of 3-[5-(3-chlorophenyl)-2H-tetrazol-2-yl]-N-methylbutanamide (140 mg, 0.5 mmol) and 2,6-lutidine (0.12 mL, 1 mmol) in DCM (5 mL) at 0° C. The mixture was stirred at 0° C. for 1 h and isonicotinic acid hydrazide (103 mg, 0.75 mmol) was added. DCM was evaporated after 4 h stirring at r.t. Sat. aq. NaHCO3 (10 mL) was added to the residue and the mixture was refluxed for 16 h. The reaction was allowed to attain r.t., followed by extracted with CHCl3 (3×20 mL). The combined organic phases were dried (MgSO4), concentrated and purified by prep HPLC to yield the title compound (3 mg, 2%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([S:13]([NH:16][C:17]2[CH:21]=[CH:20][S:19][C:18]=2[C:22]([O:24]C)=[O:23])(=[O:15])=[O:14])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1.[OH-].[Na+]>O1CCCC1.CO>[CH3:1][C:2]1[CH:3]=[C:4]([S:13]([NH:16][C:17]2[CH:21]=[CH:20][S:19][C:18]=2[C:22]([OH:24])=[O:23])(=[O:15])=[O:14])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:9][CH2:10][CH2:11][CH2:12]1
Reactant: COC(=O)c1sccc1NS(=O)(=O)c1ccc(N2CCCC2)c(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(S(=O)(=O)Nc2ccsc2C(=O)O)ccc1N1CCCC1
Temperature: 80 °C
Yield: 58.3 %

Procedure:
To a solution of 122 (85.0 mg; 0.22 mmol) in tetrahydrofuran (5 mL) and methanol (5 mL) was added aqueous sodium hydroxide (7.5 mL; 2N) and then heated at 80° C. for 16 hours. The reaction mixture was allowed to cool to room temperature and then extracted with diethyl ether. The aqueous layer was separated and acidified with aqueous hydrochloric acid (15 mL; 2N) then extracted with ethyl acetate (2×15 mL). The combined organic phases were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting crude residue was purified by automated silica gel column chromatography (Biotage®) eluting with dichloromethane/methanol to give the title product as an off-white solid (47 mg).
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@H:13]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([Br:26])[CH:19]=2)[C:14]([OH:17])([CH3:16])[CH3:15])(=O)=O)=CC=1.[N-]=[N+]=[N-].[Na+].C[N:32]([CH:34]=[O:35])C>CCOC(C)=O.CCCCCC.O>[Br:26][C:20]1[CH:19]=[C:18]([C@@H:13]2[C:14]([CH3:15])([CH3:16])[O:17][C:34](=[O:35])[NH:32][CH2:12]2)[CH:23]=[CH:22][C:21]=1[O:24][CH3:25]
Reactant: CN(C)C=O
Reactant: COc1ccc([C@@H](COS(=O)(=O)c2ccc(C)cc2)C(C)(C)O)cc1Br
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc([C@H]2CNC(=O)OC2(C)C)cc1Br
Temperature: 60 °C

Procedure:
To a solution of (S)-2-(3-bromo-4-methoxyphenyl)-3-hydroxy-3-methylbutyl 4-methylbenzenesulfonate (58 mg, 0.13 mmol) in 2 mL DMF was added NaN3 (34 mg, 0.52 mmol). The resulting reaction mixture was heated at 60° C. overnight and was then diluted with 10 mL EtOAc/hexane (1:1) and 10 mL water. The layers were separated. The organics were dried over sodium sulfate, filtered and concentrated. Crude product was purified on Combiflash prepacked silica gel column, eluted with hexane to 40% EtOAc in hexane to give 38 mg desired product. 1H NMR (500 MHz, CDCl3): δ 7.49 (d, J=1.9 Hz, 1H), 7.22 (dd, J=2.1, 8.5 Hz, 1H), 6.91 (d, J=8.4 Hz, 1H), 3.93 (s, 3H), 3.9 (m, 1H), 3.71 (m, 1H), 2.82 (m, 1H), 1.28 (s, 3H), 1.17 (s, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@@H:12]1[CH2:16][C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23](Br)[CH:24]=2)[NH:19][CH:18]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:27]([C:29]([OH:34])([CH2:32][CH3:33])[CH:30]=[CH2:31])[CH3:28]>CO>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@@H:12]1[CH2:16][C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([CH:28]=[CH:27][C:29]([CH2:32][CH3:33])([OH:34])[CH2:30][CH3:31])[CH:24]=2)[NH:19][CH:18]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OCc1ccccc1)N1CCC[C@@H]1Cc1c[nH]c2ccc(Br)cc12
Reactant: C=CC(O)(CC)CC
Solvent: CO
Product: CCC(O)(C=Cc1ccc2[nH]cc(C[C@H]3CCCN3C(=O)OCc3ccccc3)c2c1)CC

Procedure:
Obtained by a procedure similar to that described in Example 1, from 3-(N-benzyloxycarbonyl-2(R)-pyrrolidinylmethyl)-5-bromo-1H-indole (Preparation 1) and 3-ethylpent-1-en-3-ol (Example 9(a)), as a foam. Rf 0.66 (SS 7). [α]D25 -27° (c=0.1, CH3OH). Found: C,75.33; H,+.29; N,5.65. C28H34N2O3 requires C,75.30; H,7.67; N,6.26%.
Reaction SMILES: N1C=CC=CC=1.[C:7]([O:16][CH3:17])(=[O:15])[C:8]1[C:9](=[CH:11][CH:12]=[CH:13][CH:14]=1)[NH2:10].[CH3:18][C:19]([C:22]1[C:23](=[O:33])[C:24]([C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:25][C:26](=O)[CH:27]=1)([CH3:21])[CH3:20]>C(Cl)Cl.C1COCC1.[Ti](Cl)(Cl)(Cl)Cl.Cl[Ti](Cl)(Cl)Cl.N1C=CC=CC=1>[CH3:17][O:16][C:7](=[O:15])[C:8]1[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=1[NH:10][C:26]1[CH:25]=[C:24]([C:29]([CH3:30])([CH3:31])[CH3:32])[C:23]([OH:33])=[C:22]([C:19]([CH3:21])([CH3:20])[CH3:18])[CH:27]=1
Reactant: COC(=O)c1ccccc1N
Reactant: CC(C)(C)C1=CC(=O)C=C(C(C)(C)C)C1=O
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: COC(=O)c1ccccc1Nc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reaction time: 0.5 h

Procedure:
Titanium tetrachloride (28.8 mL, 1.0 M in CH2Cl2) is added dropwise to a stirred solution of pyridine (12.0 mL) in CH2Cl2 (100 mL) at 0° C. The resulting suspension is added to a solution of methyl anthranilate (6.8 g, 45.4 mmol) and 2,6-bis(1,1-dimethylethyl)-p-benzoquinone (10.0 g, 45.4 mol) in dry THF (200 mL). The reaction mixture is warmed to reflux under an argon atmosphere for four hours. At this time, another TiCl4 /pyridine suspension (prepared as above) is added. The reaction mixture is warmed at reflux for an additional 12 hours. It is cooled and filtered through Celite to remove the suspended solid. The solid is washed with ethyl acetate (100 mL) and the combined filtrates are evaporated. The residue is taken up in 200 mL of THF and stirred vigorously with a solution of sodium dithionite (100 g) in water (100 mL) for 30 minutes. The layers are separated and the aqueous layer is extracted with ethyl acetate (3×100 mL). The organic layers are combined, washed with brine (2×100 mL), dried over magnesium sulfate, and evaporated to give 2-[[(3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl)]amino]benzoic acid methyl ester; mp 155°-158° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8](=[N:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:21])[NH:9][C:10]#[N:11])[CH:5]=[N:6][CH:7]=1.[CH3:22][S:23](O)(=[O:25])=[O:24].C(=O)([O-])[O-].[Na+].[Na+]>N1C=CC=CC=1>[C:10]([NH:9][C:8]([C:4]1[CH:5]=[N:6][CH:7]=[C:2]([NH:1][S:23]([CH3:22])(=[O:25])=[O:24])[CH:3]=1)=[N:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[Cl:21])#[N:11]
Reactant: N#CNC(=NCCc1ccccc1Cl)c1cncc(N)c1
Reactant: CS(=O)(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1cncc(C(=NCCc2ccccc2Cl)NC#N)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 32.2 %

Procedure:
To a solution of 5-amino-N-cyano-N'-[2-(2-chlorophenyl)ethyl]-3-pyridinecarboximidamide (110 mg, 0.39 mmol) in pyridine (2 ml) was added anhydrous methanesulfonic acid (65 mg, 0.37 mmol), and the mixture was stirred at room temperature for 5 hours. After the reaction was completed, ice and a saturated aqueous sodium carbonate solution (20 ml) were added to the reaction mixture, and the mixture was extracted with ethyl acetate (30 ml×3). The ethyl acetate layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue obtained was subjected to silica gel column chromatography (Wako Gel C-200, 20 g) and eluted with chloroform:methanol (50:1) to give the title compound (45 mg, yield 32%) as colorless powder.
Reaction SMILES: Cl[C:2]1[O:3][C:4]([CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[O:24][CH3:25])=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)[N:6]=1.[NH:26]1[CH2:36][CH2:35][CH:29]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:28][CH2:27]1.CC(=O)CC>C(OCC)(=O)C>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([C:5]2[N:6]=[C:2]([N:26]3[CH2:27][CH2:28][CH:29]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:35][CH2:36]3)[O:3][C:4]=2[CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[O:24][CH3:25])=[CH:8][CH:9]=1
Reactant: CCOC(=O)C1CCNCC1
Reactant: COc1ccccc1OCCCc1oc(Cl)nc1-c1ccc(Cl)cc1
Solvent: CCOC(C)=O
Solvent: CCC(C)=O
Product: CCOC(=O)C1CCN(c2nc(-c3ccc(Cl)cc3)c(CCCOc3ccccc3OC)o2)CC1
Yield: 69.2 %

Procedure:
A mixture of 2-chloro-4-(4-chlorophenyl)-5-[3-(2-methoxyphenoxy)propyl]oxazole (378 mg), ethyl isonipecotate (1.57 g) and 2-butanone (10 ml) was stirred with heating under reflux for 6 hours. The reaction mixture was diluted with ethyl acetate (100 ml), and the organic layer was washed with a 10% aqueous solution of citric acid (50 ml) and dried over anhydrous magnesium sulfate. After the organic layer was concentrated, the residue was recrystallized from ethyl acetate-hexane to give ethyl N-[4-(4-chlorophenyl)-5-[3-(2-methoxyphenoxy)propyl]-2-oxazolyl]isonipecotate as pale yellow prisms (345 mg, 69%). Melting point 80-81° C.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:16]2[C:24]3[C:19](=[N:20][CH:21]=[CH:22][CH:23]=3)[NH:18][N:17]=2)[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].[CH2:25](Br)[CH2:26][CH2:27][CH3:28]>>[CH2:25]([N:18]1[C:19]2=[N:20][CH:21]=[CH:22][CH:23]=[C:24]2[C:16]([C:7]2[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]([OH:11])=[C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])[CH:6]=2)=[N:17]1)[CH2:26][CH2:27][CH3:28]
Reactant: CC(C)(C)c1cc(-c2n[nH]c3ncccc23)cc(C(C)(C)C)c1O
Reactant: CCCCBr
Product: CCCCn1nc(-c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)c2cccnc21

Procedure:
1-Butyl-3-(3,5-di-tertiary butyl-4-hydroxyphenyl)-1H-pyrazolo[3,4-b]pyridine, melting at 94°-96° C. is prepared by reacting the compound of Example 1 with butyl bromide similarly in Example 9, and recrystallizing from petroleum ether.