Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO.[F:3][C:4]1[C:5]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][N+:20]([O-:22])=O)=[CH:14][CH:13]=2)=[N:6][CH:7]=[CH:8][CH:9]=1.C[O-].[Li+].C(Cl)[Cl:27]>[Ti](Cl)(Cl)(Cl)Cl.O>[F:3][C:4]1[C:5]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][C:19]([Cl:27])=[N:20][OH:22])=[CH:14][CH:13]=2)=[N:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=[N+]([O-])CCc1ccc(COc2ncccc2F)cc1
Reactant: ClCCl
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: C[O-]
Agent: [Li+]
Solvent: O
Solvent: CO
Product: ON=C(Cl)Cc1ccc(COc2ncccc2F)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 88 %

Procedure:
To a methanol (10 mL) solution of 3-fluoro-2-(4-(2-nitro-ethyl)-benzyloxy)-pyridine (674 mg, 2.44 mmol) described in Manufacturing Example 149-1-3 was added lithium methoxide (185 mg, 4.87 mmol), which was stirred for 5 minutes at room temperature. The reaction mixture was concentrated under a reduced pressure. To a suspension of this residue in tetrahydrofuran (10 mL) and methylene chloride (10 mL) was added titanium (IV) tetrachloride (590 μL, 5.37 mmol) under nitrogen atmosphere at −78° C., which was stirred for 1 hour at 0° C. Water was added to the reaction mixture at 0° C., which was then extracted with ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and then filtered with neutral silica gel. The filtrate was concentrated under a reduced pressure to obtain the title compound (629 mg, 88%). This compound was used in the following reaction without any further purification.
Reaction SMILES: Cl.[C:2](Cl)(=[O:9])[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.ClCCl.[NH2:21][C:22]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:23]=1[N:32]1[CH2:36][CH2:35][CH2:34][CH2:33]1>O>[N:32]1([C:23]2[CH:24]=[CH:25][C:26]([C:28]([F:30])([F:31])[F:29])=[CH:27][C:22]=2[NH:21][C:2](=[O:9])[C:3]2[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=2)[CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: O=C(Cl)c1ccncc1
Reactant: Nc1cc(C(F)(F)F)ccc1N1CCCC1
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(Nc1cc(C(F)(F)F)ccc1N1CCCC1)c1ccncc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 97.8 %

Procedure:
Isonicotinoyl chloride hydrochloride (705 mg, 3.96 mmol, commercially available product) and triethylamine (823 μl, 5.94 mmol) were sequentially added at 0° C. to a dichloromethane (10 ml) solution of 1-[2-amino-4-(trifluoromethyl)phenyl]pyrrolidine (516 mg, 2.24 mmol), obtained as described in Referential Example 3-2. The resulting mixture was warmed to room temperature and stirred for five hours. Water was added to the mixture, and the resulting mixture was extracted three times with dichloromethane. The obtained organic layer was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (25 g, hexane/ethyl acetate=1/2). Thus, N-[2-(1-pyrrolidinyl)-5-(trifluoromethyl)phenyl]isonicotinamide (GIF-0617) (734 mg, 97.8%) was yielded as a colorless solid.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[N:5]N=[N:3]1.[CH2:7]([Li])CCC.[C:12]([N:19]1[CH2:24][CH2:23][N:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[CH:31]=O)[CH2:21][CH2:20]1)([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13]>>[C:12]([N:19]1[CH2:24][CH2:23][N:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[CH2:31][C:6]2[N:2]([CH3:1])[N:3]=[CH:7][N:5]=2)[CH2:21][CH2:20]1)([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13]
Reactant: [Li]CCCC
Reactant: Cn1cnnn1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccccc2C=O)CC1
Product: Cn1ncnc1Cc1ccccc1N1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
1-methyltetrazole was lithiated with n-butyllithium and reacted with N-Boc-4-(2-formylphenyl)-piperazine in a manner similar to preparation 113A. The resulting alcohol was deoxygenated in a manner similar to preparation 115A to afford the final compound. LRMS (ESI+): 358.3 (M+1)
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[C:6]3[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][N:7]3[C:15]=2[CH3:16])[CH2:3][CH2:2]1.[F:17][C:18]1[CH:19]=[C:20]([C:24]2[CH:25]=[N:26][C:27]([C:30](O)=[O:31])=[N:28][CH:29]=2)[CH:21]=[CH:22][CH:23]=1.[ClH:33].C(OCC)(=O)C>C(OCC)(=O)C>[ClH:33].[CH:1]1([C:4]2[N:5]=[C:6]3[CH:11]=[CH:10][C:9]([NH:12][C:30]([C:27]4[N:26]=[CH:25][C:24]([C:20]5[CH:21]=[CH:22][CH:23]=[C:18]([F:17])[CH:19]=5)=[CH:29][N:28]=4)=[O:31])=[CH:8][N:7]3[C:15]=2[CH3:16])[CH2:3][CH2:2]1
Reactant: Cc1c(C2CC2)nc2ccc([N+](=O)[O-])cn12
Reactant: O=C(O)c1ncc(-c2cccc(F)c2)cn1
Agent: Cl
Solvent: CCOC(C)=O
Product: Cc1c(C2CC2)nc2ccc(NC(=O)c3ncc(-c4cccc(F)c4)cn3)cn12

Procedure:
Operations similar to those of Example 1 were conducted using 2-cyclopropyl-3-methyl-6-nitroimidazo[1,2-a]pyridine and 5-(3-fluorophenyl)-2-pyrimidinecarboxylic acid. The resulting solid was dissolved in ethyl acetate, followed by addition of 4N hydrochloric acid-ethyl acetate solution and concentration under reduced pressure. The title compound was obtained as white solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][OH:7].C(N(CC)CC)C.[C:15](OC(=O)C)(=[O:17])[CH3:16]>CO>[C:15]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][OH:7])(=[O:17])[CH3:16]
Reactant: CC(=O)OC(C)=O
Reactant: NCCCCCO
Solvent: CO
Solvent: CCN(CC)CC
Product: CC(=O)NCCCCCO
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 5-amino-1-pentanol (0.650 g, 6.31 mmol) in methanol (15 mL) is cooled to 0° C. and treated with triethylamine (1.62 mL, 11.6 mmol) followed by acetic anhydride (0.891 mL, 9.45 mmol). The reaction mixture is stirred at room temperature overnight. Additional triethylamine (1.6 mL, 11.6 mmol) and acetic anhydride (0.9 mL, 9.5 mmol) is added at room temperature and the solution is stirred 16 h further. Concentration in vacuo and flash chromatography affords 5-acetamido-1-pentanol. To a solution of 5-acetamido-1-pentanol (22.2 mmol) in dry dichloromethane (50 mL) is added 2,6-di-tert-butyl-4-methylpyridine (4.6 g, 22.2 mmol) and triflic anhydride (3.7 mL, 22.2 mmol) at 0° C. The reaction is stirred at room temperature for 20 min, poured into water, and extracted with dichloromethane. The combined extracts are dried over anhydrous sodium sulfate and concentrated in vacuo and to afford 5-acetamido-1-pentyl triflate (30) which is used without further purification.
Reaction SMILES: [OH-].[K+].O.Cl[C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][N+:6]=1[O-:12].[CH2:13]([SH:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(O)C>[Cl:11][C:8]1[CH:9]=[CH:10][C:5]([S:20][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N+:6]([O-:12])[CH:7]=1
Reactant: [O-][n+]1cc(Cl)ccc1Cl
Reactant: SCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: [O-][n+]1cc(Cl)ccc1SCc1ccccc1
Temperature: 25 °C
Yield: 59.6 %

Procedure:
A solution consisting of 1.1 g (0.016 mole) of 85% KOH pellets, 50 ml of ethanol, and 0.5 ml of water was prepared. To this solution was added slowly, with stirring at room temperature, a mixture of 3.3 g (0.02 mole) of 2,5-dichloropyridine-N-oxide and 2.5 g (0.02 mole) of benzylmercaptan dissolved in 25 ml of ethanol. The reaction mixture was heated to about 60° C. for 2 hours and then evaporated to dryness. The residue was taken up in water and chloroform, the phases separated and the chloroform phase was dried over Na2SO4. The Na2SO4 was filtered off and the chloroform evaporated to leave a solid. The solid was recrystallized from ethanol to give 3.0 g of material, having a melting point of 130-133° C. Recovery was 2.2 g. The structure was confirmed by its IR spectrum.
Reaction SMILES: [C:1]([C:3]1[C:7](I)=[CH:6][N:5]([C:9]2[C:14]([Cl:15])=[CH:13][C:12]([C:16]([F:19])([F:18])[F:17])=[CH:11][C:10]=2[Cl:20])[N:4]=1)#[N:2].C([Li])CCC.[F:26][C:27]([F:39])([F:38])[C:28]([F:37])([F:36])[C:29]([F:35])([F:34])[C:30](OC)=[O:31].O>O1CCCC1>[C:1]([C:3]1[C:7]([C:30](=[O:31])[C:29]([F:34])([F:35])[C:28]([F:36])([F:37])[C:27]([F:39])([F:38])[F:26])=[CH:6][N:5]([C:9]2[C:14]([Cl:15])=[CH:13][C:12]([C:16]([F:19])([F:18])[F:17])=[CH:11][C:10]=2[Cl:20])[N:4]=1)#[N:2]
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)cc1I
Reactant: COC(=O)C(F)(F)C(F)(F)C(F)(F)F
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)cc1C(=O)C(F)(F)C(F)(F)C(F)(F)F
Temperature: -73 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of 3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-iodopyrazole (3.0 g) in tetrahydrofuran (80 ml) at -80° C. under an atmosphere of nitrogen was added, at such a rate that the temperature of the reaction mixture did not exceed -73° C., n-butyllithium (2.78 ml of a 2.5M solution in hexanes). The mixture was stirred at -73° C. for 10 minutes and then a solution of methyl heptafluorobutyrate (1.07 ml) in tetrahydrofuran (5 ml) was then added at such a rate that the temperature of the reaction mixture did not exceed -75° C. Upon completion of the addition the mixture allowed to warm to room temperature over a period of 1.5 hours. Water (100 ml) was added and the mixture extracted twice with ethyl acetate (50 ml). The combined organic layers were dried (Na2SO4) and evaporated to give a pale yellow solid which was purified by column chromatography on silica gel (150 g) eluted with ether:hexane (3:2). Combination and evaporation of suitable fractions gave a yellow oil which was further purified by column chromatography on silica gel (150 g) eluted initially with hexane:ether (19:1), then hexane:ether (9:1) and finally hexane:ether (1:1). Combination and evaporation of suitable fractions gave the title compound as a pale yellow solid, m.p. 102-103° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[C:4]([CH3:9])[N:3]=1.[N:10]1([S:16]([C:19]2[CH:24]=[CH:23][C:22]([SH:25])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.[Cl:26][C:27]1[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:28]=1[S:34](Cl)(=[O:36])=[O:35]>>[Cl:26][C:27]1[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:28]=1[S:34]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([S:25][C:22]2[CH:21]=[CH:20][C:19]([S:16]([N:10]3[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]3)(=[O:18])=[O:17])=[CH:24][CH:23]=2)=[C:4]([CH3:9])[N:3]=1)(=[O:36])=[O:35]
Reactant: O=S(=O)(c1ccc(S)cc1)N1CCCCC1
Reactant: Cc1nc(N)ccc1Br
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1Cl
Product: Cc1nc(NS(=O)(=O)c2ccc(Cl)cc2Cl)ccc1Sc1ccc(S(=O)(=O)N2CCCCC2)cc1

Procedure:
Prepared from 2-amino-5-bromo-6-methylpyridine and 4-(N-piperidinylsulfonyl)thiophenol according to General Method 11 step 1 followed by reaction with 2,4-dichlorophenylsulfonyl chloride according to General Method 11 step 2. 1H NMR (CDCl3): 8.24, 7.76, 7.72, 7.51, 7.19, 7.05 (1H, 1H, 2H, 1H, 1H, 2H, 1H, 7×d, J 9, 11, 9, 11, 10, 9 Hz, Ar CH's), 7.63 (1H, s, A-ring CH ortho to 2×Cl), 3.10-3.01 (4H, m, CH2NCH2), 2.58 (3H, s, CH3), 1.76-1.68 (4H, m, CH2CH2CH2CH2CH2), 1.58-1.47 (2H, m, CH2CH2CH2CH2CH2). Hplc (Luna 2, Gradient 5): rt=6.40 minutes. LC/MS rt=7.11 minutes, 572/574 (MH+).
Reaction SMILES: C([Mg][Cl:5])(C)C.I[C:7]1[CH:12]=[CH:11][N:10]=[C:9]([O:13][CH3:14])[CH:8]=1.COC1C=C([Mg]Cl)C=CN=1.ClN1C(=O)CCC1=O>O1CCCC1.O>[Cl:5][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([O:13][CH3:14])[CH:8]=1
Reactant: COc1cc(I)ccn1
Reactant: CC(C)[Mg]Cl
Agent: COc1cc([Mg]Cl)ccn1
Agent: O=C1CCC(=O)N1Cl
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(Cl)ccn1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
50.6 ml (2 mol/l tetrahydrofuran solution) of isopropylmagnesium chloride was cooled with ice, and a solution having 19.8 g (84.3 mmol) of crude 4-iodo-2-methoxypyridine obtained in Step (c) dissolved in 80 ml of tetrahydrofuran was added, followed by stirring at 0° C. for 1 hour and then at room temperature for 1 hour to prepare 2-methoxy-4-pyridylmagnesium chloride. Then, 16.9 g (127 mmol) of N-chlorosuccinimide was gradually added, followed by stirring at room temperature for 1 hour. 100 ml of water was added to terminate the reaction, and tetrahydrofuran was distilled off under reduced pressure. After extraction with ethyl ether, the organic layer was dried over sodium sulfate and subjected to filtration, and the solvent was distilled off under reduced pressure to obtain 11.0 g (crude yield: 91%) of crude 4-chloro-2-methoxypyridine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[N:11]1[CH:15]=[C:14]([CH3:16])[N:13]=[CH:12]1.C([O-])=O.[NH4+]>CO.O1CCCC1.[Pd]>[F:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[N:11]1[CH:15]=[C:14]([CH3:16])[N:13]=[CH:12]1
Reactant: Cc1cn(-c2ccc([N+](=O)[O-])cc2F)cn1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cn(-c2ccc(N)cc2F)cn1
Temperature: 0 °C
Reaction time: 18 h
Yield: 96.4 %

Procedure:
1-(2-Fluoro-4-nitro-phenyl)-4-methyl-1H-imidazole (4.66 g, 21.1 mmol) was dissolved in a mixture of methanol (25 mL) and tetrahydrofuran (100 mL). The solution was cooled to 0° C. under an atmosphere of nitrogen. Ammonium formiate (6.64 g, 105 mmol) and 10% palladium on charcoal (0.24 g) were added and the mixture was stirred at ambient temperature for 18 hours. It was filtered through celite. The celite was washed with methanol and the filtrate was evaporated under reduced pressure to dryness. The residue was partitioned between ethyl acetate and 10% aqueous sodium bicarbonate solution. The organic layer was separated, washed with brine, dried over sodium sulfate and the solvent was evaporated under reduced pressure to yield the title compound (3.89 g, 97%) as a yellow solid. 1H NMR (DMSO-D6, 300 MHz): δ (ppm)=7.62 (s, 1H), 7.12 (t, 1H), 7.01 (s, 1H), 6.41-6.51 (m, 2H), 5.64 (br s, 2H), 2.13 (s, 3H).
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:9][S:8][CH2:7][CH2:6][N:5]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:4]1=[O:16].Cl[CH2:18][C:19](=[O:37])[C@@H:20]([NH:28][C:29](=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[C:29]([NH:28][CH:20]([CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:19](=[O:37])[CH2:18][NH:2][CH:3]1[CH2:9][S:8][CH2:7][CH2:6][N:5]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:4]1=[O:16])(=[O:36])[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: CCOC(=O)CN1CCSCC(N)C1=O
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)CCl)c1ccccc1
Agent: Cl
Product: CCOC(=O)CN1CCSCC(NCC(=O)C(Cc2ccccc2)NC(=O)c2ccccc2)C1=O

Procedure:
6-Amino-tetrahydro-5-oxo-1,4-thiazepine-4(5H)-acetic acid, ethyl ester, hydrochloride is reacted with (S)-N-[3-chloro-2-oxo-1-(phenylmethyl)propyl]benzamide according to the procedure of Example 1(h) to give tetrahydro-6-[[3-(benzoylamino)-2-oxo-4-phenylbutyl]amino]-5-oxo-1,4-thiazepine-4(5H)-acetic acid, ethyl ester.
Reaction SMILES: [C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:8]2[CH:17]=[CH:18][C:19]([S:21](Cl)(=[O:23])=[O:22])=[CH:20][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[NH:26]1[CH2:29][CH:28]([CH2:30][C:31]([OH:33])=[O:32])[CH2:27]1.CCN(C(C)C)C(C)C>CN(C=O)C>[C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:8]2[CH:17]=[CH:18][C:19]([S:21]([N:26]3[CH2:29][CH:28]([CH2:30][C:31]([OH:33])=[O:32])[CH2:27]3)(=[O:23])=[O:22])=[CH:20][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(O)CC1CNC1
Reactant: CC(C)(C)c1nc2cc(S(=O)(=O)Cl)ccc2n1CC1CCOCC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)c1nc2cc(S(=O)(=O)N3CC(CC(=O)O)C3)ccc2n1CC1CCOCC1

Procedure:
Following the same procedure in Example 1, Step A, using 2-tert-butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazole-5-sulfonyl chloride (700 mg, 1.9 mmol), azetidin-3-ylacetic acid hydrochloride (495 mg, 3.3 mmol) and DIPEA (4 mL) in DMF (20 mL), provided the title compound as a crude product (600 mg, 70%), which was used directly in Step A.
Reaction SMILES: [Br:1]C1N=C(CC)C(N[C@@H]2C3C(=CC=CC=3)C[C@@H]2O)=NC=1CC.[CH2:23]([C:25]1[C:26]([NH:33][C@@H:34]2[C:39]3[CH:40]=[CH:41][S:42][C:38]=3[CH2:37][CH2:36][C@@H:35]2[CH2:43][CH2:44][CH3:45])=[N:27][C:28]([CH2:31][CH3:32])=[CH:29][N:30]=1)[CH3:24]>>[Br:1][C:29]1[N:30]=[C:25]([CH2:23][CH3:24])[C:26]([NH:33][C@@H:34]2[C:39]3[CH:40]=[CH:41][S:42][C:38]=3[CH2:37][CH2:36][C@@H:35]2[CH2:43][CH2:44][CH3:45])=[N:27][C:28]=1[CH2:31][CH3:32]
Reactant: CCc1nc(N[C@@H]2c3ccccc3C[C@@H]2O)c(CC)nc1Br
Reactant: CCC[C@H]1CCc2sccc2[C@H]1Nc1nc(CC)cnc1CC
Product: CCC[C@H]1CCc2sccc2[C@H]1Nc1nc(CC)c(Br)nc1CC

Procedure:
Following the procedure for the preparation of (1R,2S)-1-[(5-bromo-3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol but substituting 3,6-diethyl-N-[Cis-5-propyl-4,5,6,7-tetrahydro-1-benzothien-4-yl]pyrazin-2-amine and making non-critical variations provided the title compound as a oil: 1H NMR (300 MHz, CDCl3) δ) 7.06, 6.88, 5.61, 4.28, 2.97–2.80, 2.54, 2.05–1.92, 1.74, 1.49–1.21, 0.87; HRMS (FAB) calcd for C19H26BrN3S+H 408.1109, found 408.1108.
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][C:17]([CH3:19])=[CH:18][C:5]=2[N:4]([CH3:20])[C:3]1=[O:21].N1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[C:23]1[C:31](Cl)=[O:32].C([N:36](CC)CC)C>CCOCC>[CH3:20][N:4]1[C:5]2[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][C:6]=2[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:8][CH:2]([N:1]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:24]=[C:23]2[C:31]([NH2:36])=[O:32])[C:3]1=[O:21]
Reactant: Cc1ccc2c(c1)N(C)C(=O)C(N)N=C2c1ccccc1
Reactant: O=C(Cl)c1cc2ccccc2[nH]1
Reactant: CCN(CC)CC
Solvent: CCOCC
Product: Cc1ccc2c(c1)N(C)C(=O)C(n1c(C(N)=O)cc3ccccc31)N=C2c1ccccc1
Reaction time: 0.5 h

Procedure:
Equimolar amounts of 3-(R,S)-amino-1,3-dihydro-1,8-dimethyl-5-phenyl-2H-1,4-benzodiazepin-2-one, indole-2-carbonyl chloride, and triethylamine were mixed at room temperature and stirred 30 minutes. Flash chromatography of the reaction solution on silica gel (7% Et2O in CH2Cl2) provided the title compound as a crystalline solid from Et2O: m.p. 291°-294° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[S:12][C:11]3[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=3[CH:9]=[C:8]([N:17]3[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][CH2:25][OH:26])[CH2:19][CH2:18]3)[C:7]=2[CH:27]=1.[C:28](Cl)(=[O:36])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35].O.[OH-].[NH4+]>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[S:12][C:11]3[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=3[CH:9]=[C:8]([N:17]3[CH2:18][CH2:19][N:20]([CH2:23][CH2:24][CH2:25][O:26][C:28](=[O:36])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH2:21][CH2:22]3)[C:7]=2[CH:27]=1
Reactant: CCCCCCCC(=O)Cl
Reactant: COc1ccc2c(c1)C(N1CCN(CCCO)CC1)=Cc1ccccc1S2
Agent: [NH4+]
Agent: [OH-]
Solvent: c1ccccc1
Solvent: O
Product: CCCCCCCC(=O)OCCCN1CCN(C2=Cc3ccccc3Sc3ccc(OC)cc32)CC1
Reaction time: 48 h

Procedure:
To a solution of 10.0 grams of 8-methoxy-10-[4-(3-hydroxypropyl)piperazino]dibenzo[b,f]thiepin in 50 milliliters of benzene was added 9.1 grams of caprylyl chloride (octanoyl chloride) and the mixture was allowed to stand for 48 hours. Thereafter 150 milliliters of water and 20 milliliters of concentrated aqueous ammonium hydroxide solution was added thereto and the resulting mixture was shaken with benzene. The benzene extract was separated form the aqueous solution, filtered, and the filtrate was washed with water, dried over anhydrous potassium carbonate, and the benzene was evaporated therefrom. The residue was dissolved in 30 milliliters of acetone and to this solution was added a solution of 2.9 grams of maleic acid in 10 milliliters of acetone.
Reaction SMILES: [N+](C1C=CC(O[C:11]([N:13]2[CH2:18][CH2:17][CH2:16][CH:15]([CH:19]([NH:21][C:22]3[N:27]=[C:26]([N:28]4[C:32]5[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=5[N:30]=[CH:29]4)[CH:25]=[CH:24][N:23]=3)[CH3:20])[CH2:14]2)=[O:12])=CC=1)([O-])=O.[CH2:37]1[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH2:40][CH2:39][NH:38]1.C[N:48](C1C=CC=CN=1)C>C(Cl)Cl>[CH:37]1([NH:48][C:11]([N:13]2[CH2:18][CH2:17][CH2:16][CH:15]([CH:19]([NH:21][C:22]3[N:27]=[C:26]([N:28]4[C:32]5[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=5[N:30]=[CH:29]4)[CH:25]=[CH:24][N:23]=3)[CH3:20])[CH2:14]2)=[O:12])[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH2:40][CH2:39][NH:38]1
Reactant: CN(C)c1ccccn1
Reactant: c1ccc2c(c1)CCNC2
Reactant: CC(Nc1nccc(-n2cnc3ccccc32)n1)C1CCCN(C(=O)Oc2ccc([N+](=O)[O-])cc2)C1
Solvent: ClCCl
Product: CC(Nc1nccc(-n2cnc3ccccc32)n1)C1CCCN(C(=O)NC2NCCc3ccccc32)C1
Reaction time: 96 h

Procedure:
To a solution of 2-[1-(1-(4-nitrophenyl)oxycarbonylpiperidin-3-yl)-ethylamino]-4-[benzimidazol-1-yl]pyrimidine (14.5 mg, 0.03 mmol) in CH2Cl2 (0.5 mL) was added 1,2,3,4-tetrahydroisoquinoline (4.3 gL, 0.033 mmol) followed by a few crystals of dimethylaminopyridine. The reaction mixture was stirred for 4 days, the solvent was removed under reduced pressure, and the crude material was purified by preparative thin layer chromatography eluting with 1:1 acetone:hexane to obtain 4 mg of the title compound. Partial 1H NMR (500 MHz, CDCl3): δ 8.61 (s, 1H); 8.37 (br s, 1H); 8.16 (d, J=7.3 Hz, 1H); 7.86 (d, J=7.3 Hz, 1H); 7.39 m, 2H); 7.15-7.04 (aromatic H's, 4H); 6.78 (d, J=5.5 Hz, 1H); 4.4 (s, 2H); 1.31 (d, J=6.6 Hz, 3H). Mass spectrum 482.4 (LC-MS, M+1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](OB(O)O)=[CH:4][CH:3]=1.[C:12]1(=[O:17])[CH2:16][CH2:15][CH:14]=[CH:13]1>C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:14]2[CH2:15][CH2:16][C:12](=[O:17])[CH2:13]2)=[CH:4][CH:3]=1
Reactant: OB(O)Oc1ccc(Br)cc1
Reactant: O=C1C=CCC1
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Product: O=C1CC[C@H](c2ccc(Br)cc2)C1
Yield: 91.3 %

Procedure:
4-Bromophenylboric acid (3.61 g, 18 mmol), cyclopentenone (0.50 mL, 6.0 mmol) and (S)-BINAP (224 mg, 0.36 mmol) were used and treated in a similar manner to (Step 1) of (Example 1) to give the title compound (1.31 g, 90%).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([OH:8])[CH2:4][CH2:3]1.N1C=CN=C1.[Si:14](Cl)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]>ClCCl>[C:17]([Si:14]([CH3:16])([CH3:15])[O:8][C@H:5]1[CH2:6][CH2:7][C@H:2]([NH2:1])[CH2:3][CH2:4]1)([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: N[C@H]1CC[C@H](O)CC1
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@H](N)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of trans-4-aminocyclohexanol (5.0 g, 43.4 mmol) (TCl US) in dichloromethane (100 mL) was added imidazole (14.78 g, 0.22 mol) (Aldrich) and tert-butyidimethylsilyl chloride (19.63 g, 0.13 mol) (Avocardo Research Chemicals). The reaction mixture was stirred at room temperature for 1 day. It was concentrated under reduced pressure, and the residue was diluted with ethyl acetate (100 mL) and water (100 mL). The organic layer was washed with 1 N sodium hydroxide solution, water and brine, dried (MgSO4), filtered and concentrated to give crude trans-4-(tert-butyl-dimethyl-silanyloxy)-cyclohexylamine which was used in the next step without further purification. (Yield 7.62 g, 76.5%).
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8]([C:17]([NH:19][CH2:20][CH2:21][CH2:22][NH:23]C(OC(C)(C)C)=O)=[O:18])[CH:9]=[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=3)[N:6]2[N:5]=[CH:4][N:3]=1.N1(C(OCC(C)(C)C(N[C@H]2CC[C@H](N)CC2)=O)=O)CCOCC1>CO.O>[NH2:1][C:2]1[C:7]2=[C:8]([C:17]([NH:19][CH2:20][CH2:21][CH2:22][NH2:23])=[O:18])[CH:9]=[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=3)[N:6]2[N:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)NCCCNC(=O)c1cc(-c2ccncc2)n2ncnc(N)c12
Agent: CC(C)(COC(=O)N1CCOCC1)C(=O)N[C@H]1CC[C@H](N)CC1
Solvent: O
Solvent: CO
Product: NCCCNC(=O)c1cc(-c2ccncc2)n2ncnc(N)c12
Yield: 19 %

Procedure:
20 was prepared from 19 (40 mg, 0.097 mmol) by the general method shown for 15D. 20.2TFA (10 mg, 19% yield) was obtained as a sticky, off-white solid. HPLC: 0.83 min (YMC S5 ODS, 4.5×50 mm. 4 mL/min, 10-90% methanol-water 0.2% H3PO4, gradient over 12 min). MS (ES): m/z=312 [M+H]+. 1H NMR (400 MHz, DMSO-d6+MeOH-d4) δ ppm 8.81 (d, 2H, J=6.8 Hz); 8.41 (d, 2H, J=6.5 Hz); 8.18 (s, 1H); 8.09 (s, 1H); 3.39 (t, 2H, J=6.5 Hz); 2.87 (t, 2H, J=7.7 Hz); 1.80-1.89 (m, 2H).