Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Al](C)C.[CH3:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[N:16]2[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][C:24]3[CH:25]=[C:26]([CH:28]=[CH:29][CH:30]=3)[NH2:27])[CH2:18][CH2:17]2)[N:7]=1.[C:31]1([C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:34]O1)=[O:32].C(N(CC)C(C)C)(C)C.CS(Cl)(=O)=O>ClCCl>[CH3:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[N:16]2[CH2:17][CH2:18][N:19]([CH2:22][CH2:23][C:24]3[CH:25]=[C:26]([N:27]4[CH2:34][C:35]5[C:40](=[CH:39][CH:38]=[CH:37][CH:36]=5)[C:31]4=[O:32])[CH:28]=[CH:29][CH:30]=3)[CH2:20][CH2:21]2)[N:7]=1
Reactant: O=C1OCc2ccccc21
Reactant: Cc1ccc2c(N3CCN(CCc4cccc(N)c4)CC3)cccc2n1
Agent: CS(=O)(=O)Cl
Agent: C[Al](C)C
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc2c(N3CCN(CCc4cccc(N5Cc6ccccc6C5=O)c4)CC3)cccc2n1
Reaction time: 0.25 h
Yield: 45 %

Procedure:
A solution of trimethylaluminium (2.0 M in hexane, 1 eq) was added slowly to a stirred solution of 3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline (D6, 1 eq) in dichloromethane (0.1 M) at 0° C. The reaction mixture was stirred for 15 min then a solution of phthalide (1 eq) in dichloromethane was added dropwise. The solution was stirred for 2 h at 0° C. then partitioned between saturated aqueous ammonium chloride solution and ethyl acetate. The organic phase was dried over sodium sulfate and the solution was concentrated under reduced pressure. The crude 2-(hydroxymethyl)-N-(3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)benzamide was dissolved in dichloromethane then N,N-diisopropylethylamine (1 eq.) and methanesulfonyl chloride (1 eq.) were added successively. The reaction mixture was stirred for 2 hours at room temperature then partitioned between saturated aqueous ammonium chloride solution and dichloromethane. The organic phase was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by chromatography (SPE cartridge, Silica) eluting with a gradient from dichloromethane-methanol (100:2) to (98:2) affording the title compound (yield 45%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH:15]([NH2:17])[CH3:16])[C:10](OCC)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].Cl>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH:15]([NH2:17])[CH3:16])[CH2:10][OH:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CCOC(=O)C(c1ccc(Cl)c(Cl)c1)C(C)N
Agent: Cl
Product: CC(N)C(CO)c1ccc(Cl)c(Cl)c1

Procedure:
The compound is prepared according to the procedure described in Example 2, using as starting material 5.5 g. of ethyl 2-(3,4-dichlorophenyl)-3-aminobutyrate. Yield 3.75 g.; boiling point 125° C/0.2 mm Hg. The hydrochloride melts at 157°-160° C.
Reaction SMILES: Br[C:2]1[CH:23]=[CH:22][C:5]2[N:6]3[C:19]4[C:18]([C:4]=2[CH:3]=1)=[CH:17][CH:16]=[CH:15][C:14]=4[C:13]([CH3:21])([CH3:20])[C:12]1[C:7]3=[CH:8][CH:9]=[N:10][CH:11]=1.C([Li])CCC.[B:29](OC)([O:32]C)[O:30]C>C1COCC1.C1CCCCC1>[CH3:20][C:13]1([CH3:21])[C:12]2[C:7](=[CH:8][CH:9]=[N:10][CH:11]=2)[N:6]2[C:19]3[C:18]([C:4]4[CH:3]=[C:2]([B:29]([OH:32])[OH:30])[CH:23]=[CH:22][C:5]=42)=[CH:17][CH:16]=[CH:15][C:14]1=3
Reactant: CC1(C)c2cnccc2-n2c3ccc(Br)cc3c3cccc1c32
Reactant: COB(OC)OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: C1CCCCC1
Product: CC1(C)c2cnccc2-n2c3ccc(B(O)O)cc3c3cccc1c32
Temperature: 25 °C

Procedure:
94 g (259 mmol) of 3-bromo-8,8-dimethyl-8H-10,12b-diazabenzo[a]aceanthrylene are dissolved in 1500 ml of dry THF, 135 ml (337 mmol) of a 2.5 M solution of n-butyllithium in cyclohexane are added dropwise at −70° C., after 1 h 37 ml of trimethyl borate (336 mmol) are added dropwise, the mixture is warmed to room temperature over the course of 1 h, the solvent is removed, and the residue, which is uniform according to 1H-NMR, is employed in the subsequent reaction without further purification. Yield: 59 g (181 mmol), 70% of theory, purity according to 1H-NMR about 96%.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]([F:18])([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[C:10]([N+:15]([O-])=O)[CH:9]=1)[C:4]([F:7])([F:6])[F:5].[H][H]>[Pd].C(OCC)(=O)C>[NH2:15][C:10]1[CH:9]=[C:8]([C:3]([F:18])([C:2]([F:1])([F:19])[F:20])[C:4]([F:5])([F:6])[F:7])[CH:13]=[CH:12][C:11]=1[OH:14]
Reactant: [H][H]
Reactant: O=[N+]([O-])c1cc(C(F)(C(F)(F)F)C(F)(F)F)ccc1O
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1cc(C(F)(C(F)(F)F)C(F)(F)F)ccc1O
Yield: 78.1 %

Procedure:
A mixture of 2.95 g of 4-(heptafluoroisopropyl)-2-nitrophenol, 20 ml of ethyl acetate and 0.30 g of 5% palladium on carbon was stirred in a hydrogen atmosphere at room temperature for four hours. The reaction mixture was filtered through Celite™. The filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 2.08 g of 2-amino-4-(heptafluoroisopropyl)phenol.
Reaction SMILES: [OH:1][C:2]1[CH2:7][C:6]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[O:5][C:4](=[O:22])[CH:3]=1.C1C(=O)N([Br:30])C(=O)C1>>[Br:30][C:3]1[C:4](=[O:22])[O:5][C:6]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:7][C:2]=1[OH:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: O=C1C=C(O)CC(CCc2ccccc2)(c2ccccc2)O1
Product: O=C1OC(CCc2ccccc2)(c2ccccc2)CC(O)=C1Br

Procedure:
The title compound was prepared as described in General Method 3 using 2.0 mmol of 5,6-dihydro-4-hydroxy-6-phenyl-6-(2-phenylethyl)-2H-pyran-2-one (prepared in Example X) and 2.0 mmol of NBS. 1H NMR (DMSO-d6) δ 2.16-2.58 (m, 4 H), 3.30 (m, 2 H), 7.04-7.60 (m, 10 H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:7]1([CH3:14])[C:8]([CH3:13])=[CH:9][CH:10]=[CH:11][CH:12]=1>>[CH2:6]([NH2:1])[CH2:5][CH2:4][CH2:3][CH2:2][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:13][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:7][CH3:14]
Reactant: c1ccncc1
Reactant: Cc1ccccc1C
Product: CCCCCCCCCCCCCCCCCCN
Yield: 686.5 %

Procedure:
A mixture of 39.4 g of the solid obtained in Intermediate Preparation Example 12, 26.9 g of n-octadecylamine, 2.3 g of pyridine and 100 g of xylene was stirred at a temperature of 120° C. for 5 hours. After cooling, the reaction mixture was added in 1.0 L of methanol with stirring over 15 minutes, and the mixture was further stirred for one hour as it was. A precipitated solid was collected by filtration and dried in vacuo to obtain 57 g of a pale yellowish white solid. The resulting compound had a molecular weight measured by high-performance liquid chromatography of 19,000. As a result of neutralization titration, a proportion of the half-amide maleic acid component to the maleinimide component was found to be 4/6.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][N:11]=1)[C:6]([OH:8])=O.CN1CCOCC1.C(OC(Cl)=O)C(C)C.[NH2:27][C:28]1[S:29][C:30]([C:34]([NH:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[O:35])=[C:31]([CH3:33])[N:32]=1>O1CCCC1>[CH2:37]([NH:36][C:34]([C:30]1[S:29][C:28]([NH:27][C:6](=[O:8])[C:5]2[CH:9]=[CH:10][N:11]=[C:3]([O:2][CH3:1])[CH:4]=2)=[N:32][C:31]=1[CH3:33])=[O:35])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: Cc1nc(N)sc1C(=O)NCc1ccccc1
Reactant: COc1cc(C(=O)O)ccn1
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: COc1cc(C(=O)Nc2nc(C)c(C(=O)NCc3ccccc3)s2)ccn1
Temperature: 25 °C
Reaction time: 6 h
Yield: 83 %

Procedure:
To a solution of 2-methoxyisonicotinic acid (0.25 g, 1.01 mmol) in anhydrous tetrahydrofuran (10 mL) was added 4-methyl morpholine (0.15 g, 1.45 mmol), followed by the dropwise addition of isobutylchloroformate (0.19 g, 1.36 mmol) at 0° C. The reaction mixture was stirred at ambient temperature for 6 hours. Then a solution of 2-amino-N-benzyl-4-methylthiazole-5-carboxamide in tetrahydrofuran (10 mL) was added to it. The reaction mixture was stirred at ambient temperature for another 6 hours. The solvent was removed in vacuo. The residue was dissolved in ethyl acetate (50 mL) and washed with diluted hydrochloric acid solution (10 mL), saturated sodium bicarbonate solution (10 mL) and brine (10 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated in vacuo. The residue was recrystallized from ethyl acetate and hexane to yield the title compound as a colorless solid in 83% yield (0.32 g); m.p. 188-190° C.; 1H NMR (CDCl3, 300 MHz) δ 8.32 (d, J=5.3 Hz, 1H), 7.37-7.25 (m, 7H), 7.17 (s, 1H), 5.99 (t, J=5.0 Hz, 1H), 4.59 (d, J=5.6 Hz, 2H), 3.96 (s, 3H), 2.55 (s, 3H); 1H NMR (CDCl3, 75 MHz) δ 164.9, 163.7, 161.9, 157.1, 151.3, 148.4, 141.5, 137.6, 128.8, 127.8, 127.8, 119.4, 113.8, 109.4, 54.0, 44.2, 16.7; MS (ES+) m/z 383.5 (M+1).
Reaction SMILES: [N:1]1([S:10]([C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=2)[C:16]([OH:18])=O)(=[O:12])=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[CH3:22][C:23]1[CH:32]=[CH:31][C:26]2[N:27]=[C:28]([NH2:30])[S:29][C:25]=2[CH:24]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[N:1]1([S:10]([C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=2)[C:16]([NH:30][C:28]2[S:29][C:25]3[CH:24]=[C:23]([CH3:22])[CH:32]=[CH:31][C:26]=3[N:27]=2)=[O:18])(=[O:12])=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: O=C(O)c1cccc(S(=O)(=O)N2CCc3ccccc32)c1
Reactant: Cc1ccc2nc(N)sc2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc2nc(NC(=O)c3cccc(S(=O)(=O)N4CCc5ccccc54)c3)sc2c1

Procedure:
3-(indolin-1-ylsulfonyl)benzoic acid (3) (200 mg, 0.66 mmol) and 6-methylbenzo[d]thiazol-2-amine (90 mg, 0.55 mmol) in DMF (4 mL) was added DIPEA (213 mg, 1.65 mmol) and pybop (429 mg, 0.82 mmol). using method C. The residue was purified using flash chromatography eluting with 0-30% EtOAc in hexanes. The resulting solid was triturated with dichloromethane/hexanes to give 3-(indolin-1-ylsulfonyl)-N-(6-methylbenzo[d]thiazol-2-yl)benzamide as a white solid. Yield: 78 mg (32%). 1H-NMR: 8.58 (s, 1H), 8.38 (d, J=8 Hz, 1H), 8.02 (d, J=8.0 Hz, 1H), 7.82 (s, 1H), 7.77-7.65 (m, 3H), 7.53 (d, J=8.5 Hz, 1H), 7.30 (dd, J=8.5, 1.0 Hz, 1H), 7.22 (t, J=8.0 Hz, 1H), 7.16 (d, J=7.0 Hz, 1H), 6.99 (dt, J=7.5, 7.5, 1.0 Hz, 1H), 4.02 (t, J=8.5 Hz, 2H), 2.92 (t, J=8.5 Hz, 2H), 2.43 (s, 3H).
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([CH:26]([F:28])[F:27])[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:14]=3[NH:13][C:12]=2[CH3:34])=[O:10])[CH2:4]1.[C:35](Cl)(=[O:37])[CH3:36]>>[C:35]([NH:2][C@H:3]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([CH:26]([F:28])[F:27])[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:14]=3[NH:13][C:12]=2[CH3:34])=[O:10])[CH2:4]1)(=[O:37])[CH3:36]
Reactant: Cc1[nH]c2c(-c3cc(C(F)F)ccc3OCC3CC3)ncnc2c1C(=O)N[C@H]1CC[C@H](N)C1
Reactant: CC(=O)Cl
Agent: Cl
Product: CC(=O)N[C@H]1CC[C@H](NC(=O)c2c(C)[nH]c3c(-c4cc(C(F)F)ccc4OCC4CC4)ncnc23)C1

Procedure:
Starting from N-[(1S,3S)-3-aminocyclopentyl]-4-[2-(cyclopropylmethoxy)-5-(difluoromethyl)phenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f64) and commercially available acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [P:1]([O:35]C(C)(C)C)([O:30]C(C)(C)C)([O:3][CH2:4][CH2:5][C:6]#[C:7][C:8]1[C:16]2[C:15]([Cl:17])=[N:14][C:13]([NH2:18])=[N:12][C:11]=2[N:10]([CH2:19][C:20]2[C:25]([CH3:26])=[C:24]([O:27][CH3:28])[C:23]([CH3:29])=[CH:22][N:21]=2)[CH:9]=1)=[O:2].[C:40]([OH:46])([C:42]([F:45])([F:44])[F:43])=[O:41]>C(Cl)Cl>[P:1]([OH:30])([OH:35])([O:3][CH2:4][CH2:5][C:6]#[C:7][C:8]1[C:16]2[C:15]([Cl:17])=[N:14][C:13]([NH2:18])=[N:12][C:11]=2[N:10]([CH2:19][C:20]2[C:25]([CH3:26])=[C:24]([O:27][CH3:28])[C:23]([CH3:29])=[CH:22][N:21]=2)[CH:9]=1)=[O:2].[C:40]([OH:46])([C:42]([F:45])([F:44])[F:43])=[O:41]
Reactant: COc1c(C)cnc(Cn2cc(C#CCCOP(=O)(OC(C)(C)C)OC(C)(C)C)c3c(Cl)nc(N)nc32)c1C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1c(C)cnc(Cn2cc(C#CCCOP(=O)(O)O)c3c(Cl)nc(N)nc32)c1C

Procedure:
A solution of 4-(2-amino-4-chloro-7-((4-methoxy-3 5-dimethylpyridin-2-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)but-3-ynyl di-tert-butyl phosphate (see example 43) in DCM ( ) was treated with TFA ( ) at rt for x h. Evaporation gave the title compound as a TFA salt (5 g). The crude was dissolved in a mixture of Et3N (0.7 mL and MeOH (60 mL), loaded on Dowex 50Wx2-400 (20 g, pre-washed with MeOH), and the resin was washed with MeOH (200 mL) to remove the excess TFA. The desired phosphate was released from the resin with Et3N:MeOH 1:10 (200 mL) The solution was concentrated to give the phosphate as an oily triethylamine salt (2.75 g). Crystallization was induced with EtOH (60 mL). The mixture was left at rt for 1.5 h and at −20° C. overnight to give a first crop of crystals (0.64 g). The mixture was concentrated and the crystallization procedure was repeated to give a second crop (0.74 g). The combined triethylamine salts (1274 mg) were dissolved in MeOH (50 mL) with the help of Et3N (326 μL) and treated with a 1.0 M solution of NaGH in MeOH (4.68 mL). Evaporation and drying on high vacuum overnight gave the title compound as a solid sodium salt. HPLC Rt=4.21 mm.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N+:12]([O-])=O)=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.C([O-])=O.[NH4+]>CO.[Pd]>[NH2:12][C:3]1[C:2]([CH3:1])=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1
Reactant: Cc1c([N+](=O)[O-])ccc2cccnc12
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: Cc1c(N)ccc2cccnc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 8-methyl-7-nitroquinoline (1.8 g) in methanol (20 mL) is added palladium-on-carbon (10%, 0.45 g) and ammonium formate (2.77 g). The mixture is stirred at room temperature for 30 minutes, then filtered on Celite, with a methanol wash of the solids. The filtrate is rotary evaporated and the residue partitioned between water and methylene chloride. The organic layer is dried over potassium carbonate, filtered and rotary evaporated to afford 7-amino-8-methylquinoline as a yellow solid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:20])[CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:7][CH:6]=1.C(N(CC)CC)C.[S:28](Cl)([CH3:31])(=[O:30])=[O:29]>C(Cl)Cl>[C:14]1([CH2:13][CH2:12][C:11]([C:8]2[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH2:2][O:1][S:28]([CH3:31])(=[O:30])=[O:29])=[CH:6][CH:7]=2)=[O:20])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CS(=O)(=O)Cl
Reactant: O=C(CCc1ccccc1)c1ccc(OCCO)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCOc1ccc(C(=O)CCc2ccccc2)cc1
Reaction time: 0.75 h

Procedure:
A solution of 1-[4-(2-hydroxy-ethoxy)-phenyl]-3-phenyl-propan-1-one (prepared in Example N; 6.0 g, 22.2 mmol) and triethylamine (NEt3) (4.60 mL, 33.3 mmol) in CH2Cl2 (50 mL) was cooled to 0° C. under a nitrogen atmosphere and treated with mesyl chloride (2.1 mL, 26.6 mmol). The mixture allowed to stir for 45 minutes, and then diluted with additional CH2Cl2 and washed with H2O. The organic layer was dried (MgSO4) and the solvent removed in vacuo to provide the title compound which was used without further purification. 1H NMR (DMSO-d6) δ 2.90 (t, 2 H), 3.20 (s, 3 H), 3.29 (t, 2 H), 4.32-4.34 (m, 2 H), 4.52-4.55 (m, 2 H), 7.05 (d, 2 H), 7.22-7.32 (m, 5 H), 7.95 (d, 2 H).
Reaction SMILES: F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[O:23]1[CH2:27][CH2:26][CH2:25][C@H:24]1[C:28]([OH:30])=O.C(N(C(C)C)CC)(C)C.[OH:40][C:41]([CH3:71])([CH3:70])[CH2:42][C@@:43]1([C:64]2[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=2)[O:48][C:47](=[O:49])[N:46]([C@H:50]([C:52]2[CH:57]=[CH:56][C:55]([CH:58]3[CH2:63][CH2:62][NH:61][CH2:60][CH2:59]3)=[CH:54][CH:53]=2)[CH3:51])[CH2:45][CH2:44]1>CN(C)C=O>[OH:40][C:41]([CH3:70])([CH3:71])[CH2:42][C@@:43]1([C:64]2[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=2)[O:48][C:47](=[O:49])[N:46]([C@H:50]([C:52]2[CH:57]=[CH:56][C:55]([CH:58]3[CH2:63][CH2:62][N:61]([C:28]([C@@H:24]4[CH2:25][CH2:26][CH2:27][O:23]4)=[O:30])[CH2:60][CH2:59]3)=[CH:54][CH:53]=2)[CH3:51])[CH2:45][CH2:44]1
Reactant: C[C@@H](c1ccc(C2CCNCC2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: O=C(O)[C@@H]1CCCO1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](c1ccc(C2CCN(C(=O)[C@@H]3CCCO3)CC2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-(1H-Benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (125 mg) was added to a solution of (S)-tetrahydro-furan-2-carboxylic acid (45 mg) and diisopropylethyl-amine (200 μL) in N,N-dimethylformamide (2 mL) at room temperature. The resulting solution was stirred for 30 min, before (S)-6-(2-hydroxy-2-methyl-propyl)-6-phenyl-3-[(S)-1-(4-piperidin-4-yl-phenyl)-ethyl]-[1,3]oxazinan-2-one (150 mg) dissolved in dimethylformamide (1 mL) was added. The resulting solution was stirred at room temperature overnight and then concentrated under reduced pressure. The crude product was purified by HPLC on reversed phase (MeCN/H2O/NH3) to afford the title compound.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:7]([CH2:11][C:12]2[CH:13]=[C:14]([C:18]3[CH:22]=[C:21]([CH2:23][CH:24]([CH3:26])[CH3:25])[S:20][C:19]=3[S:27]([NH:30]C(C)(C)C)(=[O:29])=[O:28])[CH:15]=[CH:16][CH:17]=2)[CH:8]=[CH:9][N:10]=1.B(Cl)(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+].Cl[C:46]([O:48][CH2:49][CH2:50][CH2:51][CH3:52])=[O:47]>C(Cl)Cl.O>[CH2:49]([O:48][C:46]([NH:30][S:27]([C:19]1[S:20][C:21]([CH2:23][CH:24]([CH3:26])[CH3:25])=[CH:22][C:18]=1[C:14]1[CH:15]=[CH:16][CH:17]=[C:12]([CH2:11][N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)[CH:13]=1)(=[O:29])=[O:28])=[O:47])[CH2:50][CH2:51][CH3:52]
Reactant: CC(C)Cc1cc(-c2cccc(Cn3ccnc3-c3cccs3)c2)c(S(=O)(=O)NC(C)(C)C)s1
Reactant: CCCCOC(=O)Cl
Agent: ClB(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CCCCOC(=O)NS(=O)(=O)c1sc(CC(C)C)cc1-c1cccc(Cn2ccnc2-c2cccs2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 55 %

Procedure:
To a solution of 3-[3-(2-thiophen-2-yl-imidazol-1-ylmethyl)phenyl]-5-iso-butyl-N-tert-butylthiophene-2-sulfonamide (42 mg, 0.082 mmol; see step (a)) in CH2Cl2 (1 mL) was added BCl3 (0.3 mL, 1.0 M in hexane) and the reaction mixture was stirred for 1 h at ambient temperature. The reaction mixture was concentrated in vacuo. Water (5 mL) was added to the residue and this was then extracted with EtOAc. The combined organic phase was washed with water and brine, dried (over anhydrous MgSO4) and concentrated in vacuo. To the crude product dissolved in CH2Cl2 (5 mL) was added Na2CO3 (39.0 mg, 0.377 mmol), water (2 mL) and butyl chloroformate (15.6 μL, 0.0123 mmol), and the reaction mixture was stirred for 9 h at ambient temperature. The reaction mixture was diluted with CH2Cl2 (30 mL) and washed with citric acid (10% aq), brine and water, dried (over anhydrous MgSO4), concentrated in vacuo, and the residue purified by LCMS (20-100% CH3CN in water) to give the title compound as a white solid in 55% yield, over two steps, (25 mg, 0.045 mmol).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:11]([CH3:15])[C:12]([OH:14])=[O:13])[CH:5]=[CH:6][C:7]=1[N+:8]([O-])=O>C1COCC1.CCO.[Pd]>[NH2:8][C:7]1[CH:6]=[CH:5][C:4]([CH:11]([CH3:15])[C:12]([OH:14])=[O:13])=[CH:3][C:2]=1[OH:1]
Reactant: CC(C(=O)O)c1ccc([N+](=O)[O-])c(O)c1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C(=O)O)c1ccc(N)c(O)c1
Reaction time: 3 h

Procedure:
To a stirred solution of 2-(3-hydroxy-4-nitro-phenyl)-propionic acid (1.28 g) in THF (20 mL) and EtOH (20 mL) was slowly added 10% Pd/C (0.12 g) at room temperature. After being hydrogenated for 3 h with H2 balloon, the reaction mixture was filtered through celite pad and washed with EtOH. The filtrate was concentrated in vacuo to afford the product as yellow solid. (1.08 g, 98.4%)
Reaction SMILES: [Br:1][C:2]1[CH:13]=[C:6]2[C:7]([O:9][C:10](=O)[NH:11][C:5]2=[CH:4][CH:3]=1)=[O:8].[NH:14]([CH2:16]C(O)=O)[CH3:15]>CS(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:9])[CH2:15][N:14]([CH3:16])[C:7](=[O:8])[C:6]=2[CH:13]=1
Reactant: O=c1[nH]c2ccc(Br)cc2c(=O)o1
Reactant: CNCC(=O)O
Solvent: CS(C)=O
Product: CN1CC(=O)Nc2ccc(Br)cc2C1=O
Temperature: 0 °C

Procedure:
A mixture of 39.5 g of 5-bromoisatoic acid anhydride, 14.5 g of sarcosine and 150 ml of dimethyl sulphoxide is heated to 100° while stirring. After completion of the gas evolution, the mixture is stirred at 100° for a further 30 minutes and subsequently poured into 900 ml of ice-water. The precipitated crystals are filtered off under suction, washed with water and dried at 50° in vacuo over phosphorus pentoxide. There is obtained 7-bromo-3,4-dihydro-4-methyl-2H-1,4-benzodiazepine-2,5(1H)-dione as light beige crystals. A sample recrystallized from methanol has a melting point of 260°-261°.
Reaction SMILES: [C:1](Cl)([C:3](Cl)=O)=[O:2].CN(C=O)C.[F:12][C:13]1[C:21]([C:22]#[N:23])=[C:20]2[C:16](C=[CH:18][NH:19]2)=[CH:15][CH:14]=1>C(Cl)Cl>[F:12][C:13]1[C:21]([C:22]#[N:23])=[C:20]2[C:16]([C:3]([CH:1]=[O:2])=[CH:18][NH:19]2)=[CH:15][CH:14]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: N#Cc1c(F)ccc2cc[nH]c12
Solvent: CN(C)C=O
Solvent: ClCCl
Product: N#Cc1c(F)ccc2c(C=O)c[nH]c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.2 %

Procedure:
To a solution of (COCl)2 (2.47 g) in DCM (40 mL) at 0° C. was added a solution of DMF (3 mL) in DCM (20 mL) dropwise. Half an hour later, a solution of 6-fluoro-1H-indole-7-carbonitrile (D141) (2.6 g) in DCM (20 mL) was added. The reaction was allowed to warm to RT to form a yellow precipitate. After 5 hours the solvent was removed by evaporation, and then THF (30 mL) and 2 M aqueous NaOH (30 mL) solution were added to the residue obtained above. After stirring for about 1 h, the organic phase was separated and the aqueous phase was extracted with EtOAc (3×50 mL). The combined organic layers were dried over Na2SO4 and concentrated to afford 6-fluoro-3-formyl-1H-indole-7-carbonitrile (D142) (3.0 g) as a yellow solid.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:22](Cl)(=[O:25])[CH:23]=[CH2:24]>ClCCl>[O:25]=[C:22]([NH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:5][CH:4]=1)[CH:23]=[CH2:24]
Reactant: C=CC(=O)Cl
Reactant: CCOC(=O)Cc1ccc(CN)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CC(=O)NCc1ccc(CC(=O)OCC)cc1
Reaction time: 0.75 h

Procedure:
A solution of Ethyl 4-[aminomethyl]benzeneacetate (4.12 g) in anhydrous dichloromethane (60 ml) containing triethylamine (3.0 ml), was added over 20 min to a cold (-15°) stirred solution of acryloyl chloride (1.73 ml) in dry dichloromethane (50 ml) and stirring was continued for 0.75 h. After washing the dichloromethane solution with 8% aqueous sodium bicarbonate soln (2×50 ml) and drying (MgSO4), the organic solvent was removed by rotary evaporation to yield a a solid (approximately 6 g) which was triturated with cyclohexane to give the title compound as a solid (4.1 g) m.p. 93°-95°.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[N:8]=[CH:9][CH:10]=[C:5]2[C:4](=[O:11])[N:3]=1.[CH:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][C:13]=1[C:22](Cl)=[O:23]>>[CH:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][C:13]=1[C:22]([NH:1][C:2]1[N:7]=[C:6]2[N:8]=[CH:9][CH:10]=[C:5]2[C:4](=[O:11])[N:3]=1)=[O:23]
Reactant: NC1=NC(=O)C2=CC=NC2=N1
Reactant: O=C(Cl)c1ccc2ccccc2c1
Product: O=C1N=C(NC(=O)c2ccc3ccccc3c2)N=C2N=CC=C12

Procedure:
Using 2-aminopyrrolo(2,3-d)pyrimidin-4-one and 2-naphthoyl chloride, the above-identified compound is produced by the same procedure as Reference Example 2.