Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][CH2:5][C@:6]1([CH2:27][O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[O:14][CH:9](OC(=O)C)[C@H:8]([O:15][C:16](=[O:18])[CH3:17])[C@@H:7]1[O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=[O:3])[CH3:2].[NH:36]1[CH:43]=[CH:42][C:40](=[O:41])[NH:39][C:37]1=[O:38].C/C(/O[Si](C)(C)C)=N\[Si](C)(C)C.O([Si](C)(C)C)S(C(F)(F)F)(=O)=O>C(#N)C>[C:16]([O:15][C@@H:8]1[C@H:7]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C@@:6]([CH2:5][O:4][C:1](=[O:3])[CH3:2])([CH2:27][O:28][CH2:29][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[O:14][C@H:9]1[N:36]1[CH:43]=[CH:42][C:40](=[O:41])[NH:39][C:37]1=[O:38])(=[O:18])[CH3:17]
Reactant: CC(=O)OC[C@]1(COCc2ccccc2)OC(OC(C)=O)[C@H](OC(C)=O)[C@@H]1OCc1ccccc1
Reactant: O=c1cc[nH]c(=O)[nH]1
Agent: C/C(=N\[Si](C)(C)C)O[Si](C)(C)C
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CC#N
Product: CC(=O)OC[C@]1(COCc2ccccc2)O[C@@H](n2ccc(=O)[nH]c2=O)[C@H](OC(C)=O)[C@@H]1OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of the anomeric mixture 33 (3.0 g, 6.17 mmol) and uracil (1.04 g, 9.26 mmol) in anhydrous acetonitrile (65 cm3) was added N,O-bis(trimethylsilyl)acetamide(9.16 cm3, 37.0 mmol). The reaction mixture was stirred for 1 h at room temperature and cooled to 0° C. Trimethylsilyl triflate (1.8 cm3, 10.0 mmol) was added dropwise and the solution was stirred at 60° C. for 2 h. The reaction was quenched by addition of a saturated aqueous solution of sodium hydrogencarbonate (10 cm3) at 0° C. and extraction was performed with dichloromethane (3×20 cm3). The combined organic phase was washed with brine (2×20 cm3) and was dried (Na2SO4). The solvents were removed under reduced pressure and the residue was purified by silica gel column chromatography using dichloromethane/methanol (99:1, v/v) as eluent to give nucleoside 40 as a white solid material (2.5 g, 75%). δH (CDCl3) 9.57 (1H, br s, NH), 7.63 (1H, d, J 8.2, 6-H), 7.40-7.24 (10H, m, Bn), 6.18 (1H, d, J 4.5, 1′-H), 5.39-5.32 (2H, m, 2′-H, 5-H), 4.61 (1H, d, J 11.6, Bn), 4.49-4.40 (5H, m, 3′-H, Bn, 1″-Ha), 4.37 (1H, d, J 12.3, 1″-Hb), 3.76 (1H, d, J 10.1, 5′-Ha), 3.49 (1H, d, J 10.1, 5′-Hb), 2.09 (s, 3H, COCH3), 2.04 (3H, s, COCH3). δC (CDCl3) 170.47, 169.94 (C═O), 163.32 (C-4), 150.30 (C-2), 140.24 (C-6), 137.15, 136.95, 128.65, 128.52, 128.32, 128.19, 128.02, 127.77 (Bn), 102.57 (C-5), 87.41, 86.14 (C-1′, C-4′), 77.09, 74.84, 74.51, 73.75, 70.60, 63.73 (C-2′, C-3′, C-5′, C-1″, Bn), 20.79, 20.68 (COCH3). FAB-MS m/z 539 [M]+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH:24]([CH3:26])[CH3:25])[C:15](=O)[CH2:16][O:17][CH2:18][CH2:19][CH2:20][CH2:21][OH:22])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[OH:22][CH2:21][CH2:20][CH2:19][CH2:18][O:17][CH2:16][CH2:15][N:14]([CH:11]1[CH2:10][CH2:9][N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:13][CH2:12]1)[CH:24]([CH3:26])[CH3:25]
Reactant: CC(C)N(C(=O)COCCCCO)C1CCN(Cc2ccccc2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)N(CCOCCCCO)C1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.9 %

Procedure:
To a solution of N-(1-benzylpiperidin-4-yl)-N-isopropyl 2-(4-hydroxybut-1-oxy)acetamide (4.7 g, 13 mmol) in THF (30 mL) was slowly added 1 M lithium aluminum hydride in THF (20 mL, 19.5 mmol) at 0° C. The reaction mixture was stirred at room temperature overnight and then quenched by slow addition of 15% aqueous sodium hydroxide at 0° C. until no gas formation was observed. After stirring for 10 minutes at room temperature, a solid formed and the reaction mixture was filtered and the precipatate washed with THF three times. The filtrate was then concentrated and the residue was dissolved in dichloromethane and this solution was washed with brine, dried over magnesium sulfate and concentrated in vacuo to give 3.71 g of the title intermediate (82% yield).
Reaction SMILES: [C:1]1([C:7]2([N:14]3[CH2:19][CH2:18][CH:17]([N:20]4[C:24]5[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=5[N:22]=[C:21]4[NH:29][CH2:30][CH2:31][NH2:32])[CH2:16][CH2:15]3)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([NH:40][C:41](N1C=CCN1C(=N)NC(OC(C)(C)C)=O)=[NH:42])(OC(C)(C)C)=O.O>C1COCC1>[C:1]1([C:7]2([N:14]3[CH2:15][CH2:16][CH:17]([N:20]4[C:24]5[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=5[N:22]=[C:21]4[NH:29][CH2:30][CH2:31][NH:32][C:41]([NH2:42])=[NH:40])[CH2:18][CH2:19]3)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)NC(=N)N1C=CCN1C(=N)NC(=O)OC(C)(C)C
Reactant: NCCNc1nc2ccccc2n1C1CCN(C2(c3ccccc3)CCCCCC2)CC1
Solvent: C1CCOC1
Solvent: O
Product: N=C(N)NCCNc1nc2ccccc2n1C1CCN(C2(c3ccccc3)CCCCCC2)CC1
Yield: 71.4 %

Procedure:
A mixture of 2-aminoethylamino-1-[1(1-phenylcycloheptyl)-4-piperidinyl]benzimidazole (Example 27, 85.6 mg, 0.199 mmol) and N, N′-bis Boc guanylpyrazole (117 mg, 0.377 mmol, this was prepared according to the following reported procedure: M. S. Bernatowicz, et al., Tetrahedron Lett., 1993, 34, 3389-3392) in THF (3 ml) was stirred at room temperature for 16 h. Water was added to the reaction mixture and extracted with CH2Cl2. The extracts combined were washed with brine, dried (Na2SO4), filtered, and concentrated. The residue was purified by column chromatography (silica gel: 30 g, hexane/acetone: 4/1 to 3/1) to give 95.5 mg (71.4%) of colorless amorphous solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:11][C:12]([OH:14])=[O:13])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[CH2:15]([O:17][C:18](=[O:33])[C:19]([CH2:31]O)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH3:16].Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH2:23]([O:22][C:20](=[O:21])[C:19]([CH2:31][O:13][C:12](=[O:14])[CH2:11][C:4]1[CH:5]=[CH:6][C:7]([N+:8]([O-:10])=[O:9])=[C:2]([CH3:1])[CH:3]=1)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:18]([O:17][CH2:15][CH3:16])=[O:33])[CH3:24]
Reactant: Cc1cc(CC(=O)O)ccc1[N+](=O)[O-]
Reactant: CCOC(=O)C(CO)(C(=O)OCC)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CCOC(=O)C(COC(=O)Cc1ccc([N+](=O)[O-])c(C)c1)(C(=O)OCC)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.4 %

Procedure:
The (3-Methyl-4-nitrophenyl)acetic acid (0.143 g) obtained in Example 1-3b) was dissolved in methylene chloride (5 mL). To the solution were added 2-hydroxymethyl-2-phenylmalonic acid diethyl ester (0.195 g) obtained in Example 1-2a), 4-dimethylaminopyridine (0.090 g) and 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (0.141 g), and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated and the residue was purified by column chromatography on silica gel with ethyl acetate:hexane=1:4 to give the title compound (0.219 g) as a yellow oil.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][C:12]3[N:16]4[N:17]=[C:18]([C:21](=O)[CH3:22])[CH:19]=[CH:20][C:15]4=[N:14][N:13]=3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Cl.[NH:25]([C:27]([NH2:29])=[O:28])[NH2:26]>CO>[N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][C:12]3[N:16]4[N:17]=[C:18](/[C:21](=[N:26]/[NH:25][C:27]([NH2:29])=[O:28])/[CH3:22])[CH:19]=[CH:20][C:15]4=[N:14][N:13]=3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: NNC(N)=O
Reactant: CC(=O)c1ccc2nnc(Cc3ccc4ncccc4c3)n2n1
Agent: Cl
Solvent: CO
Product: C/C(=N\NC(N)=O)c1ccc2nnc(Cc3ccc4ncccc4c3)n2n1
Yield: 84.5 %

Procedure:
A solution of 1-(3-(quinolin-6-ylmethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanone (35 mg, 0.115 mmol) and hydrazinecarboxamide hydrochloride (17.32 mg, 0.231 mmol) in MeOH was stirred at room temperature for overnight. Solid was filtered and dried to provide the title compound as a light yellow solid (35 mg, 84%). 1H-NMR (400 MHz, DMSO-d6) δ ppm 9.90 (s, 1H), 9.10 (d, 1H), 8.79 (d, 1H), 8.37 (d, 1H), 8.17 (m, 3H), 8.03 (d, 1H), 7.83 (m, 1H), 6.85 (broad, 2H), 4.84 (s, 2H), 2.24 (s, 3H). LCMS (method A): [MH]+=361.1, tR=3.58 min.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4](F)[CH:3]=1.[NH2:11][CH2:12][CH2:13][OH:14]>>[NH2:7][CH2:6][C:5]1[CH:8]=[CH:9][C:2]([Cl:1])=[CH:3][C:4]=1[NH:11][CH2:12][CH2:13][OH:14]
Reactant: NCCO
Reactant: N#Cc1ccc(Cl)cc1F
Product: NCc1ccc(Cl)cc1NCCO

Procedure:
The title compound is synthesized by coupling followed by reduction of 4-chloro-2-fluoro-benzonitrile and 2-amino-ethanol analogously to the preparation of Intermediate 113.1. colorless powder; ES-MS: M−=199.1; HPLC: AtRet=1.90 min.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:24]=[C:23]([N:25]([CH2:41][C:42]2[CH:47]=[CH:46][C:45](C3C=CC(Br)=CC=3)=[CH:44][CH:43]=2)[C:26](=[O:40])[CH2:27][N:28]([CH3:39])[S:29]([C:32]2[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=2)(=[O:31])=[O:30])[CH:22]=[CH:21][C:10]=1[C:11]([O:13][CH2:14]C1C=CC=CC=1)=[O:12])C1C=CC=CC=1.[CH3:55][O:56][C:57]([C:59]1[CH:64]=[CH:63][C:62](B(O)O)=[CH:61][CH:60]=1)=[O:58]>>[CH2:1]([O:8][C:9]1[CH:24]=[C:23]([N:25]([CH2:41][C:42]2[CH:47]=[C:46]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[C:45]([C:62]3[CH:63]=[CH:64][C:59]([C:57]([O:56][CH3:55])=[O:58])=[CH:60][CH:61]=3)=[CH:44][CH:43]=2)[C:26](=[O:40])[CH2:27][N:28]([CH3:39])[S:29]([C:32]2[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=2)(=[O:31])=[O:30])[CH:22]=[CH:21][C:10]=1[C:11]([O:13][CH2:14][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:12])[C:9]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:10]=1
Reactant: Cc1ccc(S(=O)(=O)N(C)CC(=O)N(Cc2ccc(-c3ccc(Br)cc3)cc2)c2ccc(C(=O)OCc3ccccc3)c(OCc3ccccc3)c2)cc1
Reactant: COC(=O)c1ccc(B(O)O)cc1
Product: COC(=O)c1ccc(-c2ccc(CN(C(=O)CN(C)S(=O)(=O)c3ccc(C)cc3)c3ccc(C(=O)OCc4ccccc4)c(OCc4ccccc4)c3)cc2-c2ccccc2)cc1

Procedure:
Aryl halide 5 was coupled to 4-(methoxycarbonyl)phenylboronic acid to give 39 on a 0.1 mmol scale via General Procedure H (59 mg, 47%): δH (400 MHz, CDCl3) 2.38 (s, 3H, CH3), 2.83 (s, 3H, CH3), 3.69 (s, 2H, CH2), 3.93 (s, 3H, CH3), 4.84 (s, 2H, CH2), 5.02 (s, 2H, CH2), 5.35 (s, 2H, CH2), 6.64 (s, 1H, CH), 6.70 (dd, J=8.4 and 1.6 Hz, 1H, CH), 7.20 (d, J=8.0 Hz, 2H, CH), 7.24-7.28 (m, 6H, CH), 7.30-7.33 (m, 5H, CH), 7.36-7.41 (m, 3H, CH), 7.54 (d, J=8.4 Hz, 2H, CH), 7.61 (d, J=8.4 Hz, 2H, CH), 7.64-7.73 (m, 6H, CH), 7.85 (d, J=8.4 Hz, 1H, CH). LRMS (ES+) calcd for [C52H46N2O8S+H] 881.29. found 881.39.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][C:10]([CH2:15][OH:16])([CH3:14])[CH2:9]1)=O)(C)(C)C.[ClH:17]>C(Cl)Cl.O1CCOCC1>[ClH:17].[CH3:14][C:10]1([CH2:15][OH:16])[CH2:11][CH2:12][CH2:13][NH:8][CH2:9]1
Reactant: CC1(CO)CCCN(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC1(CO)CCCNC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 0.20 g (0.87 mmol) of (rac)-3-hydroxymethyl-3-methyl-piperidine-1-carboxylic acid tert-butyl ester was dissolved in 5 ml of CH2Cl2, treated at 0° C. with a solution of HCl in dioxane (2.18 ml, 4 M in dioxane) and stirred for 2 h at RT. The reaction was then concentrated to dryness and re-evaporated with toluene to afford the title product (0.17 g, quant.) as white solid. MS: 130.1 (MH+)
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:22])[N:9]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=3[O:20][CH3:21])[CH2:10][C:6]=2[C:5]([F:23])=[C:4](Cl)[N:3]=1.[O:25]1[CH2:30][CH2:29][C@@H:28]([NH2:31])[C@@H:27]([NH2:32])[CH2:26]1.CCN(C(C)C)C(C)C>C(#N)C>[NH2:32][C@@H:27]1[C@H:28]([NH:31][C:4]2[N:3]=[C:2]([Cl:1])[C:7]3[C:8](=[O:22])[N:9]([CH2:11][C:12]4[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=4[O:20][CH3:21])[CH2:10][C:6]=3[C:5]=2[F:23])[CH2:29][CH2:30][O:25][CH2:26]1
Reactant: N[C@@H]1CCOC[C@@H]1N
Reactant: COc1ccc(CN2Cc3c(F)c(Cl)nc(Cl)c3C2=O)c(OC)c1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CN2Cc3c(F)c(N[C@@H]4CCOC[C@@H]4N)nc(Cl)c3C2=O)c(OC)c1
Temperature: 85 °C
Reaction time: 72 h
Yield: 9.6 %

Procedure:
A mixture of 4,6-dichloro-2-(2,4-dimethoxybenzyl)-7-fluoro-1H-pyrrolo[3,4-c]pyridin-3(2H)-one (2.5 g, 6.74 mmol), (3R,4R)-tetrahydro-2H-pyran-3,4-diamine (0.711 g, 6.12 mmol), and DIPEA (5.35 mL, 30.6 mmol) in ACN (30 mL) was stirred at 85° C. for 3 d in a sealed tube. Additional (3R,4R)-tetrahydro-2H-pyran-3,4-diamine (0.356 g, 3.06 mmol) and DIPEA (2.14 mL, 12.2 mmol) were added and the mixture was heated at 100° C. overnight. The mixture was concentrated and purified via preparative HPLC. The fractions corresponding to the desired regioisomer were collected to give the title compound (265 mg, 9.60%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.64-1.65 (m, 1H), 1.80-1.82 (s, 1H), 3.40 (td, J=11.47, 2.44 Hz, 1H), 3.53 (dd, J=11.23, 1.95 Hz, 1H), 3.67 (dd, J=11.47, 2.20 Hz, 1H), 3.71-3.73 (m, 1H), 3.75 (s, 3H), 3.77-3.79 (m, 1H), 3.81 (s, 3H), 4.09-4.11 (m, 1H), 4.33 (s, 2H), 4.50 (s, 2H), 6.48 (dd, J=8.30, 2.44 Hz, 1H), 6.58 (d, J=2.44, 1H), 6.90 (br s, 1H), 7.06 (d, J=8.30 Hz, 1H). [M+H] calc'd for C21H24ClFN4O4, 451. found, 451.
Reaction SMILES: Cl[C:2]1[S:3][C:4]([CH2:7][N:8]2[CH2:12][CH:11]([C:13]3[CH:18]=[C:17]([F:19])[CH:16]=[C:15]([F:20])[C:14]=3[F:21])[CH2:10][C:9]2=[O:22])=[CH:5][N:6]=1.C[O-].[Na+].[CH3:26][NH2:27]>CO>[CH3:26][NH:27][C:2]1[S:3][C:4]([CH2:7][N:8]2[CH2:12][CH:11]([C:13]3[CH:18]=[C:17]([F:19])[CH:16]=[C:15]([F:20])[C:14]=3[F:21])[CH2:10][C:9]2=[O:22])=[CH:5][N:6]=1
Reactant: O=C1CC(c2cc(F)cc(F)c2F)CN1Cc1cnc(Cl)s1
Reactant: CN
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CNc1ncc(CN2CC(c3cc(F)cc(F)c3F)CC2=O)s1
Temperature: 95 °C
Yield: 180.7 %

Procedure:
In a 50 ml sealed vessel, 1-[(2-chloro-1,3-thiazol-5-yl)methyl]-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one 250 (0.1 g, 0.3 mmol) is dissolved in MeOH (3 ml). Sodium methoxide (3 mg, 0.06 mmol) and a solution of methylamine (0.09 g, 3 mmol) in MeOH are added. The vessel is closed and heated to 95° C. for 48 h. The reaction mixture is cooled to room temperature, the solvent is evaporated and the residue is taken up in CH2Cl2 and water. The aqueous phase is extracted twice with CH2Cl2, the combined organic phases are washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The crude product is recrystallized from AcOEt to afford 185 mg of 1-{[2-(methylamino)-1,3-thiazol-5-yl]methyl}-4-(2,3,5-trifluorophenyl)pyrrolidin-2-one 252.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16](O)=[O:17])=[CH:12][CH:11]=2)=[CH:6][C:5]=1[CH3:19])(=[O:3])[CH3:2].[CH3:20][N:21]([CH3:36])[CH2:22][CH2:23][O:24][C:25]1[CH:33]=[C:32]2[C:28]([CH:29]=[CH:30][NH:31]2)=[CH:27][C:26]=1[O:34][CH3:35]>>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13]([C:16]([N:31]3[C:32]4[C:28](=[CH:27][C:26]([O:34][CH3:35])=[C:25]([O:24][CH2:23][CH2:22][N:21]([CH3:20])[CH3:36])[CH:33]=4)[CH:29]=[CH:30]3)=[O:17])=[CH:14][CH:15]=2)=[CH:6][C:5]=1[CH3:19])(=[O:3])[CH3:2]
Reactant: COc1cc2cc[nH]c2cc1OCCN(C)C
Reactant: CC(=O)c1ccc(-c2ccc(C(=O)O)cc2)cc1C
Product: COc1cc2ccn(C(=O)c3ccc(-c4ccc(C(C)=O)c(C)c4)cc3)c2cc1OCCN(C)C

Procedure:
The title compound was prepared from 4'-acetyl-3'-methylbiphenyl-4-carboxylic acid (D21) and 6-(2-dimethylaminoethoxy)-5-methoxy-1H-indole (D13) using a similar procedure to Example 4 as an off-white solid mp 125°-127° C. (36%).
Reaction SMILES: S(O[CH2:6][CH2:7][C@@H:8]([NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH3:9])(=O)(=O)C.[NH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1>>[C:14]([O:13][C:11]([NH:10][C@@H:8]([CH3:9])[CH2:7][CH2:6][N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)=[O:12])([CH3:17])([CH3:16])[CH3:15]
Reactant: C[C@@H](CCOS(C)(=O)=O)NC(=O)OC(C)(C)C
Reactant: C1COCCN1
Product: C[C@@H](CCN1CCOCC1)NC(=O)OC(C)(C)C
Temperature: 57 °C
Reaction time: 1 h

Procedure:
The crude product of example 22 (b) (˜5.6 mmol) was dissolved in morpholine (10 mL) and heated to 57° C. while stirring under argon for 1 h. The solvent was pumped off, and the residue was partitioned between EtOAc and water. The organic phase was washed with brine, dried (Na2SO4), and concentrated. The crude product was purified by flash chromatography (silica gel, 2–5% MeOH/CH2Cl2) to give the title compound as a white solid. ES (+) MS m/e=259 (MH+)
Reaction SMILES: [F:1][C:2]1[C:7]([NH2:8])=[C:6]([CH3:9])[C:5]([B:10]2[O:14][C:13]([CH3:16])([CH3:15])[C:12]([CH3:18])([CH3:17])[O:11]2)=[CH:4][CH:3]=1.C(Cl)Cl.[S:22]1[C:26]([C:27](Cl)=[O:28])=[CH:25][C:24]2[CH:30]=[CH:31][CH:32]=[CH:33][C:23]1=2.Cl>N1C=CC=CC=1>[F:1][C:2]1[C:7]([NH:8][C:27]([C:26]2[S:22][C:23]3[CH:33]=[CH:32][CH:31]=[CH:30][C:24]=3[CH:25]=2)=[O:28])=[C:6]([CH3:9])[C:5]([B:10]2[O:14][C:13]([CH3:16])([CH3:15])[C:12]([CH3:18])([CH3:17])[O:11]2)=[CH:4][CH:3]=1
Reactant: Cc1c(B2OC(C)(C)C(C)(C)O2)ccc(F)c1N
Reactant: O=C(Cl)c1cc2ccccc2s1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1c(B2OC(C)(C)C(C)(C)O2)ccc(F)c1NC(=O)c1cc2ccccc2s1
Temperature: 0 °C
Reaction time: 1 h
Yield: 99.4 %

Procedure:
A 200-mL single-neck round-bottomed flask equipped with a magnetic stirrer was purged with nitrogen, charged with 6-fluoro-2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (3.45 g, 13.7 mmol), methylene chloride (85 mL), and pyridine (3 mL) and cooled to 0° C. To the resulting solution, benzo[b]thiophene-2-carbonyl chloride (2.7 g, 13.7 mmol) was. The reaction was warmed to room temperature and stirred for 1 h. After this time, aqueous HCl (1M, 50 mL) was added to the reaction. The separated aqueous layer was extracted with dichloromethane (2×25 mL). The combined organics were washed with aqueous HCl (1M, 2×50 mL), water (1×50 mL) and brine (50 mL), dried over sodium sulfate; filtered and concentrated under reduced pressure. The resulting crude white solid (5.6 g, 99% yield) was used in the next step without further purification.
Reaction SMILES: C[O:2][C:3]([C:5]1[NH:6][C:7]2[C:12]([C:13]=1[C:14]([O:16]C)=[O:15])=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:4].Br[CH2:19][C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1>>[C:20]1([CH2:19][N:6]2[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:13]([C:14]([OH:16])=[O:15])=[C:5]2[C:3]([OH:2])=[O:4])[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: BrCc1cccc2ccccc12
Reactant: COC(=O)c1[nH]c2ccccc2c1C(=O)OC
Product: O=C(O)c1c(C(=O)O)n(Cc2cccc3ccccc23)c2ccccc12

Procedure:
Using general procedure B, 1H-indole-2,3-dicarboxylic acid dimethyl ester was coupled with 1-bromomethyl-naphthalene and the product obtained was hydrolyzed to give the title compound as a white solid. MS: 344.3 ([M−H]−).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][C:12]([OH:14])=O.Cl.[CH2:16]([O:20][C:21](=[O:25])[C@H:22]([CH3:24])[NH2:23])[CH:17]([CH3:19])[CH3:18]>>[CH2:16]([O:20][C:21](=[O:25])[C@H:22]([CH3:24])[NH:23][C:12](=[O:14])[CH2:11][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1)[CH:17]([CH3:19])[CH3:18]
Reactant: CC(C)COC(=O)[C@H](C)N
Reactant: O=C(O)Cc1ccc2ccccc2c1
Agent: Cl
Product: CC(C)COC(=O)[C@H](C)NC(=O)Cc1ccc2ccccc2c1

Procedure:
Following General Procedure BB and using 2-naphthylacetic acid (Aldrich) and L-alanine iso-butyl ester hydrochloride (from Example BB above), the title compound was prepared as a solid having a melting point of 128°-129° C. The reaction was monitored by tlc on silica gel and purification was by extraction with Et2O followed by washes with aqueous K2CO3 and aqueous HCl.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]([NH:16]C(=O)OC(C)(C)C)[C:11]([CH:13]1[CH2:15][CH2:14]1)=[CH2:12])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>C(Cl)Cl.[Br-].[Zn+2].[Br-]>[Si:1]([O:8][CH2:9][C@@H:10]([NH2:16])[C:11]([CH:13]1[CH2:15][CH2:14]1)=[CH2:12])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: C=C(C1CC1)[C@@H](CO[Si](C)(C)C(C)(C)C)NC(=O)OC(C)(C)C
Agent: [Br-]
Agent: [Zn+2]
Solvent: ClCCl
Product: C=C(C1CC1)[C@H](N)CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.3 %

Procedure:
To a solution of (S)-tert-butyl 1-(tert-butyldimethylsilyloxy)-3-cyclopropylbut-3-en-2-ylcarbamate (Intermediate 233, 6.77 g, 19.82 mmol) in DCM (100 mL) at room temperature was added zinc bromide (17.86 g, 79.28 mmol). The reaction mixture was stirred overnight at room temperature. Another 1 eq of zinc bromide was added. After several hours the reaction mixture was filtered and washed with saturated sodium bicarbonate. The resulting emulsion was filtered through a nylon filter and the layers were separated. The organics were dried over magnesium sulfate, filtered and concentrated to afford the title compound as a yellow oil (4.61 g, 96%).
Reaction SMILES: [CH3:1][CH:2]([OH:16])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][CH:12]([CH3:15])[CH2:13][CH3:14])=[CH:7][CH:6]=1.[H-].[Na+].[Na].Br[C:21]1[S:22][CH:23]=[CH:24][N:25]=1>>[CH3:1][CH:2]([O:16][C:21]1[S:22][CH:23]=[CH:24][N:25]=1)[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][CH:12]([CH3:15])[CH2:13][CH3:14])=[CH:7][CH:6]=1
Reactant: Brc1nccs1
Reactant: CCC(C)Sc1ccc(OCC(C)O)cc1
Agent: [H-]
Agent: [Na+]
Agent: [Na]
Product: CCC(C)Sc1ccc(OCC(C)Oc2nccs2)cc1

Procedure:
Following the procedure of Example 6, 1-methyl-2-[4-(1-methylpropylthio)phenoxy]ethanol (1.60 g, 6.7 mmol) is treated with sodium hydride (0.48 g, 10.0 mmol), and the resulting sodium salt is reacted with 2-bromo-1,3-thiazole (800 1, 8.7 mmol) to give 2-{1-methyl-2-[4-(1-methylpropylthio)phenoxy]ethoxy}-1,3-thiazole.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:9]=[C:8]([Br:10])[N:7]=[C:6]([C:11]([O:13][CH3:14])=[O:12])[C:5]=1[OH:15].[CH2:16](Cl)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O>CN(C=O)C>[Br:3][C:4]1[CH:9]=[C:8]([Br:10])[N:7]=[C:6]([C:11]([O:13][CH3:14])=[O:12])[C:5]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COC(=O)c1nc(Br)cc(Br)c1O
Reactant: ClCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1nc(Br)cc(Br)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 90.6 %

Procedure:
To a stirred mixture of sodium hydride (0.6 g) in DMF (50 mL) was slowly added 14 (7.1 g). After the addition was complete, the mixture was stirred at room temperature for 15 minutes, then benzyl chloride (3.05 g) was added all at once. The mixture was then heated at 90° C. for six hours, cooled, poured into water (500 mL) and extracted with ether (2×200 mL). The ether extracts were combined, washed with 2N NaOH (50 mL), dried (MgSO4) and the solvent was evaporated to give 15 as a light yellow solid (8.3 g). Recrystallization from a small volume of methanol gave an analytical sample, m.p. 75-76° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][C:3]=1[CH3:9].[H-].[Na+].I[CH3:13]>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH3:13])=[CH:4][C:3]=1[CH3:9]
Reactant: CI
Reactant: Cc1cc(S)ccc1Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1ccc(Br)c(C)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 99.5 %

Procedure:
To a solution of 4-bromo-3-methylbenzenethiol (5.47 g, 26.9 mmol) in DMF (25 mL) was added NaH (0.743 g, 32.3 mmol) at RT. After 15 minutes at RT, the solution was cooled to 0° C. and iodomethane (2.02 ml, 32.3 mmol) was added. The cooling bath was removed and the mixture was allowed to warm up to RT. After 1 hour, water was added and the mixture was extracted with EtOAc (3×). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give 5.81 g of (4-bromo-3-methylphenyl)(methyl)sulfane as a pale yellow oil.