Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.[CH3:9][C:10]1[CH:11]=[CH:12][C:13]([S:16]([NH2:19])(=[O:18])=[O:17])=[CH:14][CH:15]=1.C([O-])([O-])=O.[K+].[K+].CN[C@@H]1CCCC[C@H]1NC.[NH4+].[Cl-]>[Cu]I.CN(C)C=O>[CH3:8][C:5]1[CH:6]=[CH:7][C:2]([NH:19][S:16]([C:13]2[CH:14]=[CH:15][C:10]([CH3:9])=[CH:11][CH:12]=2)(=[O:17])=[O:18])=[CH:3][CH:4]=1
Reactant: Cc1ccc(S(N)(=O)=O)cc1
Reactant: Cc1ccc(I)cc1
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: Cc1ccc(NS(=O)(=O)c2ccc(C)cc2)cc1
Temperature: 100 °C
Reaction time: 19 h
Yield: 96 %

Procedure:
A 15 mL resealable Schlenk tube was charged with CuI (9.5 mg, 0.0499 mmol, 5.0 mol %), 4-iodotoluene (218 mg, 1.00 mmol), p-toluenesulfonamide (205 mg, 1.20 mmol), K2CO3 (280 mg, 2.03 mmol), evacuated and backfilled with argon. trans-N,N′-Dimethyl-1,2-cyclohexanediamine (16 μL, 0.102 mmol, 10 mol %) and N,N-dimethylformamide (1 mL) were added under argon. The Schlenk tube was sealed with a Teflon valve and the reaction mixture was stirred at 100° C. for 19 h. The resulting pale brown suspension was allowed to reach room temperature, poured into 20 mL of a diluted aq NH4Cl solution, and extracted with 3×15 mL of dichloromethane. The colorless organic phase was dried (Na2SO4), concentrated, and the residue was purified by flash chromatography on silica gel (2×15 cm, hexane-ethyl acetate 2:1, 15 mL fractions). Fractions 9-16 provided 251 mg (96% yield) of the desired product as white crystals.
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.CCN(CC)CC.[CH3:39][O:40][C:41]1[CH:50]=[C:49]([O:51][CH3:52])[CH:48]=[C:47]2[C:42]=1[C:43](=[O:65])[NH:44][C:45]([C:53]1[CH:58]=[CH:57][C:56]([N:59]3[CH2:64][CH2:63][NH:62][CH2:61][CH2:60]3)=[CH:55][CH:54]=1)=[N:46]2>C1COCC1>[CH3:39][O:40][C:41]1[CH:50]=[C:49]([O:51][CH3:52])[CH:48]=[C:47]2[C:42]=1[C:43](=[O:65])[NH:44][C:45]([C:53]1[CH:58]=[CH:57][C:56]([N:59]3[CH2:60][CH2:61][N:62]([C:1](=[O:9])[C:2]4[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=4)[CH2:63][CH2:64]3)=[CH:55][CH:54]=1)=[N:46]2
Reactant: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(N4CCNCC4)cc3)nc2c1
Reactant: O=C(O)c1cccnc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(N4CCN(C(=O)c5cccnc5)CC4)cc3)nc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 19.6 %

Procedure:
To a solution of nicotinic acid (0.066 g, 0.54 mmol) in THF (20 mL) was added HOBt (0.079 g, 0.59 mmol), EDCl (0.113 g, 0.59 mmol), Et3N (0.08 mL, 0.59 mmol) and 5,7-dimethoxy-2-(4-(piperazin-1-yl)phenyl)quinazolin-4(3H)-one (0.200 g, 0.54 mmol). The resulting solution was stirred overnight at room temperature. The solution was concentrated in vacuo and the resulting solid was purified by flash chromatography on silica gel, eluting with 10% to 60% of 92:7:1 CHCl3/MeOH/concentrated NH4OH in CH2Cl2, to afford the title compound (0.050 g, 19%): 1H NMR (300 MHz, DMSO-d6): δ 11.79 (s, 1H), 8.59-8.78 (m, 2H), 8.12 (d, J=8.8 Hz, 2H), 7.82-7.99 (m, 1H), 7.37-7.60 (m, 1H), 7.04 (d, J=9.1 Hz, 2H), 6.69 (s, 1H), 6.47 (s, 1H), 3.63-3.97 (m, 8H), 3.20-3.63 (m, 6H). APCI MS m/z 472 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[N:8]=[C:7]([C:13]([O:15]CC)=[O:14])[C:6]([OH:18])=[N:5]2.O.[OH-].[Li+].Cl>C1COCC1.O>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[N:8]=[C:7]([C:13]([OH:15])=[O:14])[C:6]([OH:18])=[N:5]2
Reactant: CCOC(=O)c1nc2cc(F)c(F)cc2nc1O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1nc2cc(F)c(F)cc2nc1O
Temperature: 50 °C

Procedure:
A mixture of ethyl 6,7-difluoro-3-hydroxyquinoxaline-2-carboxylate (500 mg, 2.0 mmol) and lithium hydroxide monohydrate (330 mg, 7.9 mmol) in THF (10 mL) and water (5 mL) was heated at 50° C. under nitrogen for 1 h. The mixture was further cooled to 0° C., acidified to pH 2 with concentrated HCl and extracted with ethyl acetate (100 mL). The organic extract was washed with brine (50 mL), dried over magnesium sulfate, filtered and the solvents were removed under reduced pressure to provide 6,7-difluoro-3-hydroxyquinoxaline-2-carboxylic acid as a yellow solid: 1H NMR (400 MHz, CD3OD) δ 7.88 (dd, 1H), 7.29 (dd, 1H) ppm; ESI MS m/z 225 [M−H]−.
Reaction SMILES: C([O:3][C:4](=[O:25])[CH2:5][N:6]1[C:10]2=[N:11][CH:12]=[CH:13][CH:14]=[C:9]2[N:8]=[C:7]1[C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=1)C.[OH-].[K+].C(O)C>O>[F:24][C:21]([F:22])([F:23])[C:18]1[CH:19]=[CH:20][C:15]([C:7]2[N:6]([CH2:5][C:4]([OH:25])=[O:3])[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[N:8]=2)=[CH:16][CH:17]=1
Reactant: CCOC(=O)Cn1c(-c2ccc(C(F)(F)F)cc2)nc2cccnc21
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)Cn1c(-c2ccc(C(F)(F)F)cc2)nc2cccnc21
Yield: 74.5 %

Procedure:
A solution of 2-[4-(trifluoromethyl)phenyl]-3H-imidazo[4,5-b]pyridine-3-acetic acid ethyl ester (17.7 g, 0.051 mole), potassium hydroxide pellets (4.5 g, 0.080 mole), 95% ethanol (150 ml), and water (10 ml) was refluxed for 21/2 hrs. The ethanol was evaporated in vacuo, the residue acidified with glacial acetic acid, and the mixture filtered. The filter cake was suspended in water (300 ml) and filtered. The filter cake was air dried (17 g) and recrystallized from ethanol-water to give 12.21 g (75%) of a white solid, mp 240°-241° C.
Reaction SMILES: [CH2:1]([C:9]1[CH:24]=[CH:23][C:12]([C:13]([CH:15]2[CH2:17][CH:16]2[C:18]([O:20]CC)=[O:19])=[O:14])=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[OH-].[Na+]>O>[CH2:1]([C:9]1[CH:24]=[CH:23][C:12]([C:13]([CH:15]2[CH2:17][CH:16]2[C:18]([OH:20])=[O:19])=[O:14])=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCc1ccc(C(=O)C2CC2C(=O)OCC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCCCCCCc1ccc(C(=O)C2CC2C(=O)O)cc1

Procedure:
Aluminum chloride (6.93 g) is added in one portion to a solution of 2-ethoxycarbonyl-cyclopropane carboxylic acid chloride (4.17 g) and 1-phenyloctane (4.49 g) in methylene chloride (100 ml). After the initial exothermic reaction subsides, the mixture is heated under reflux for 16 hours. The mixture is cooled and poured into ice water (500 ml) containing conc. hydrochloric acid (50 ml). The product is extracted with ether (3×200 ml). The extract is dried over MgSO4 and then evaporated under reduced pressure. The residue is chromatographed on silica gel (hexane/ether) to provide ethyl 2-(4-n-octylbenzoyl)cyclopropane carboxylate as an oil (4.7 g). This ester is heated under reflux in aqueous 2N NaOH (36 ml) for 24 hours. The reaction mixture is diluted with water (100 ml), acidified and extracted with ether (3×50 ml). The extract is dried (MgSO4) and evaporated. The residue is crystallized from petroleum ether (40°-60°) to provide 2-(4-n-octylbenzoyl) cyclopropane carboxylic acid (1.88 g), m.p. 45°-47° C.
Reaction SMILES: CC(S([NH:7][C:8]1([C:12]2[S:13][C:14]([C:17]3[CH:22]=[C:21]([NH:23][C:24]4[N:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][N:25]=4)[CH:20]=[C:19]([CH3:34])[CH:18]=3)=[CH:15][N:16]=2)[CH2:11][O:10][CH2:9]1)=O)(C)C.O1CCOCC1>CO.Cl.C(OCC)(=O)C>[NH2:7][C:8]1([C:12]2[S:13][C:14]([C:17]3[CH:22]=[C:21]([NH:23][C:24]4[N:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][N:25]=4)[CH:20]=[C:19]([CH3:34])[CH:18]=3)=[CH:15][N:16]=2)[CH2:9][O:10][CH2:11]1
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C3(NS(=O)C(C)(C)C)COC3)s2)c1
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C3(N)COC3)s2)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 48.6 %

Procedure:
To a solution the product of Step 2 (1.01 g, 1.964 mmol) in methanol (9.8 mL), 4M HCl in Dioxane (1.97 mL, 7.86 mmol) was added. The mixture was stirred at room temperature for 15 minutes. The mixture was diluted with ethyl acetate, washed with saturated NaHCO3, followed by brine, dried (Na2SO4), filtered and concentrated. The residue was purified by column chromatography on silica (40-100% ethyl acetate in hexanes) to afford N-{3-[2-(3-aminooxetan-3-yl)-1,3-thiazol-5-yl]-5-methylphenyl}-4-(trifluoromethyl)pyrimidin-2-amine (386.6 mg, 0.954 mmol, 53.5% yield) as a pale yellow solid. MS ESI: [M+H]+ m/z 408.0. 1H NMR (500 MHz, DMSO-d6) δ 10.26 (s, 1H), 8.83 (d, J=4.8, 1H), 8.07 (s, 1H), 7.97 (s, 1H), 7.47 (s, 1H), 7.28 (d, J=4.9, 1H), 7.17 (s, 1H), 4.87 (d, J=5.6, 2H), 4.58 (d, J=5.7, 2H), 2.32 (s, 3H).
Reaction SMILES: C(OC([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C@H:16]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:17]([O:19][CH3:20])=[O:18])=O)C1C=CC=CC=1.[H][H]>CO.[Pd]>[NH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C@H:16]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:17]([O:19][CH3:20])=[O:18]
Reactant: [H][H]
Reactant: COC(=O)[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: COC(=O)[C@H](CCCCN)NC(=O)OC(C)(C)C

Procedure:
(S)-methyl 6-(benzyloxycarbonylamino)-2-(tert-butoxycarbonylamino)hexanoate (8.60 g) was hydrogenated in 150 mL MeOH over 5% palladium on activated carbon (1.08 g) under 1 atm hydrogen at ambient temperature for 3 hours. The spent catalyst was removed by vacuum filtration through a celite pad which was washed with MeOH. The combined filtrate and wash were concentrated under reduced pressure, affording (S)-methyl 6-amino-2-(tert-butoxycarbonylamino)hexanoate (TU3000-128) as clear viscous oil. MS (ESI+): calcd. 261.17. found 261.20 (MH+). H-NMR (600 MHz, CDCl3):1.328 (2H, m), 1.375 (9H, s), 1.390 (2H, m), 1.55 (1H, m), 1.74(1H, m), 2.623(2H, d, J=6.9 Hz), 3.671 (3H, s), 4.237 (1H, m), 5.007 (1H, m).
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[C:9]([F:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C[Si](C)(C)O[Si](C)(C)C.[N+:22]([O-])([OH:24])=[O:23].O>S(=O)(=O)(O)O>[F:1][C:2]1[C:10]([F:11])=[C:9]([F:12])[C:8]([N+:22]([O-:24])=[O:23])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1ccc(F)c(F)c1F
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: C[Si](C)(C)O[Si](C)(C)C
Product: O=C(O)c1cc([N+](=O)[O-])c(F)c(F)c1F
Temperature: 0 °C
Reaction time: 1.25 h
Yield: 78.9 %

Procedure:
To a stirred solution of 2,3,4-Trifluorobenzoic acid (70 Kg, 398 Mol) in sulphuric acid (96 wt %; 194 L) and hexamethyldisiloxane (6.5 Kg, 40 Mol), at 23° C., was added a 1:1 mixture of sulphuric acid (96 wt %) and nitric acid (98 wt %) (total 70.1 Kg), over 75 min. The temperature of the reaction mixture was maintained between 15 and 25° C. during the addition. The mixture was stirred for a further 5 hours and then run onto ice (700 Kg), keeping the temperature of the ice mixture below 0° C. Water (35 L) was used to rinse the nitration reactor into the quench reactor and the obtained mixture was stirred for 2 hours at 0° C., then isolated on a centrifuge. The resultant wet cake was washed with cold water (350 L), and the solid was then suspended in water (280 L) and stirred for 2 hours at 0° C. This suspension was then centrifuged and the cake was washed with cold water (210 L), then dried in a vacuum oven at 45° C. for 2 days, to provide 2,3,4-Trifluoro-5-nitro benzoic acid (69.4 Kg, 74.3% yield). 1H NMR (400 MHz, d6 DMSO) δ 8.44 (1H, apparent dt, J 2, 7, Ar—H). 19F NMR (376 MHz, d6 DMSO) δ−153.9, −131.5, −120.9. 13C NMR (100 MHz, d6 DMSO) δ 117 (C, m), 124 (CH, b s), 134 (C, s), 141 (C—F, dt, J 251, 10), 148 (C—F, dd, J 265, 13), 154 (C—F, dd, J 265, 10), 163 (COOH). IR vmax/cm−1 3108 (br), 1712, 1555, 1345, 1082. MS APCI (−) m/z 220 (M−1) detected.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5]([OH:7])=O.C(Cl)(=O)C(Cl)=O.N1C=CC=CC=1.[C:24]1([C@H:30]([NH2:32])[CH3:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(Cl)Cl.CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5]([NH:32][C@@H:30]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH3:31])=[O:7]
Reactant: C[C@@H](N)c1ccccc1
Reactant: O=C(O)c1ccc(Cl)c(Br)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: C[C@@H](NC(=O)c1ccc(Cl)c(Br)c1)c1ccccc1
Temperature: 40 °C
Reaction time: 1 h
Yield: 104.6 %

Procedure:
To a solution of 3-bromo-4-chlorobenzoic acid 71 (5.30 g, 23 mmol) in DCM (10 mL) at room temperature was added DMF (5 drops) and oxalyl dichloride (3.0 mL, 34 mmol). The reaction mixture was heated to 40° C. for 1 h. The solvent and excess oxalyl chloride were removed under a stream of nitrogen followed by high vacuum. The acid chloride was dissolved in DCM (100 mL), cooled to 0° C., and then pyridine (2.8 mL, 34 mmol) was added followed by (R)-1-phenylethanamine (3.8 mL, 30 mmol). The reaction mixture was stirred at 0° C. for 1 h and concentrated under reduced pressure. The crude amide was dissolved in EtOAc, washed with 1 M HCl (2×), brine (1×), dried over MgSO4, filtered, and concentrated to give (R)-3-bromo-4-chloro-N-(1-phenylethyl)benzamide 72 (8.15 g, 71% yield) as a white solid which was used without further purification. Mass spectrum: calculated for C15H13BrClNO 337.0. found 338.0 (M++1).
Reaction SMILES: C([N:4]1[CH2:9][CH2:8][C:7]2([CH2:13][C:12]3[CH:14]=[C:15]([N+:18]([O-:20])=[O:19])[CH:16]=[CH:17][C:11]=3[O:10]2)[CH2:6][CH2:5]1)(=O)C.[ClH:21]>CCOCC>[ClH:21].[N+:18]([C:15]1[CH:16]=[CH:17][C:11]2[O:10][C:7]3([CH2:6][CH2:5][NH:4][CH2:9][CH2:8]3)[CH2:13][C:12]=2[CH:14]=1)([O-:20])=[O:19]
Reactant: CC(=O)N1CCC2(CC1)Cc1cc([N+](=O)[O-])ccc1O2
Agent: Cl
Solvent: CCOCC
Product: O=[N+]([O-])c1ccc2c(c1)CC1(CCNCC1)O2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 3.4 g of 2,3-dihydro-1'-acetyl-5-nitrospiro[benzofuran-2,4'-piperidine] in 150 ml of 6 N hydrochloric acid is refluxed for 45 hours and then stirred at ambient temperature for 16 hours. Thereafter, the reaction mixture is successively extracted once with ether, basified with 6 N sodium hydroxide and extracted thrice with ether. The combined ether extracts are dried and the solvent removed, leaving a yellow residue. The residue is dissolved in ether where it is converted to its hydrogen chloride salt. The salt is collected, dried and finally recrystallized twice from ethyl alcohol to give the product 2,3-dihydro-5-nitrospiro[benzofuran-2,4'-piperidine]hydrochloride, mp 265°-266° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C:11](=[CH2:13])[CH2:10][C@H:9]1[CH2:14][OH:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:16][C:17]1[CH:24]=[C:23]([F:25])[C:22]([F:26])=[CH:21][C:18]=1[CH2:19]Br.[H-].[Na+].[NH4+].[Cl-]>C1COCC1.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:12][C:11](=[CH2:13])[CH2:10][C@H:9]1[CH2:14][O:15][CH2:19][C:18]1[CH:21]=[C:22]([F:26])[C:23]([F:25])=[CH:24][C:17]=1[F:16])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=C1C[C@@H](CO)N(C(=O)OC(C)(C)C)C1
Reactant: Fc1cc(F)c(CBr)cc1F
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=C1C[C@@H](COCc2cc(F)c(F)cc2F)N(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Yield: 33.6 %

Procedure:
To 9.6 g (45 mmol) (2S)-2-Hydroxymethyl-4-methylene-pyrrolidine-1-carboxylic acid tert-butyl ester and 25 g (112.5 mmol, 2.5 eq) 2,4,5-trifluorobenzyl bromide in 950 ml THF were added 3.2 g (73.1 mmol, 50% in mineral oil, 1.6 eq) NaH at 0° C. over a period of 30 min. The reaction was warmed to RT over night, and added to a cooled mixture of saturated aqueous NH4Cl solution and EtOAc, the phases were separated and the inorganic one was extracted with EtOAc, the combined organic ones were washed with brine, dried over Na2SO4, filtered and evaporated. The crude product was purified by flash chromatography using hexane/EtOAc 4:1 as an eluent yielding 5.4 g (34%) (2S)-4-Methylene-2-(2,4,5-trifluoro-benzyloxymethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester as yellow oil, MS: 358 (MH+) and 1.7 g (13%) recovered starting material.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1.I[C:22]1[N:27]=[CH:26][N:25]=[C:24]([C:28]([C:30]2[CH:39]=[C:38]([CH3:40])[C:33]3[O:34][CH2:35][CH2:36][O:37][C:32]=3[CH:31]=2)=[O:29])[CH:23]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][N:17]([C:22]4[CH:23]=[C:24]([C:28]([C:30]5[CH:39]=[C:38]([CH3:40])[C:33]6[O:34][CH2:35][CH2:36][O:37][C:32]=6[CH:31]=5)=[O:29])[N:25]=[CH:26][N:27]=4)[CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1
Reactant: COc1ccc2c(c1)CCN(C1CCNCC1)C(=O)N2
Reactant: Cc1cc(C(=O)c2cc(I)ncn2)cc2c1OCCO2
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)c4cc(C)c5c(c4)OCCO5)ncn3)CC1)C(=O)N2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
61 mg (0.22 mmol) 7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one, 84 mg (0.22 mmol) (6-iodo-pyrimidin-4-yl)-(8-methyl-2,3-dihydro-benzo[1,4]dioxin-6-yl)-methanone and 0.08 mL (0.44 mmol) DIPEA were combined in 2.5 mL DMF and stirred overnight at RT. Then the reaction mixture was purified by preparative HPLC-MS. The fractions containing the product were combined and the organic solvent was evaporated down. The residue was combined with 1N aqueous sodium hydroxide solution, the precipitate formed was suction filtered, washed with water and dried.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:9]([O:10][CH3:11])=[CH:8][C:7]([C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)=[CH:6][C:5]=1[O:17][CH3:18])[CH3:2].CON(C)[C:22](=[O:38])[CH:23]([O:36][CH3:37])[C:24]1[CH:29]=[CH:28][C:27]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)=[CH:26][CH:25]=1>>[CH2:1]([O:3][C:4]1[C:9]([O:10][CH3:11])=[CH:8][C:7]([C:12]2[O:13][C:14]([C:22](=[O:38])[CH:23]([O:36][CH3:37])[C:24]3[CH:25]=[CH:26][C:27]([N:30]4[CH2:31][CH2:32][O:33][CH2:34][CH2:35]4)=[CH:28][CH:29]=3)=[CH:15][CH:16]=2)=[CH:6][C:5]=1[O:17][CH3:18])[CH3:2]
Reactant: CCOc1c(OC)cc(-c2ccco2)cc1OC
Reactant: COC(C(=O)N(C)OC)c1ccc(N2CCOCC2)cc1
Product: CCOc1c(OC)cc(-c2ccc(C(=O)C(OC)c3ccc(N4CCOCC4)cc3)o2)cc1OC
Yield: 58 %

Procedure:
2-(4-Ethoxy-3,5-dimethoxyphenyl)furan was coupled with N,2-dimethoxy-N-methyl-2-(4-morpholinophenyl)acetamide according to the procedure for the synthesis of Example 12. Purification by chromatography (EtOAc-hexanes) gave 1-(5-(4-ethoxy-3,5-dimethoxyphenyl)furan-2-yl)-2-methoxy-2-(4-morpholinophenyl)ethanone as a yellow foam (0.263 g, 58% yield). MS: m/z 482.2 [M+H]+.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][C:5]([CH:8]=[O:9])=[CH:4]1.[F:10][C:11]([C:14]1[N:18]([CH2:19][CH:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[C:17]2[CH:26]=[CH:27][C:28]([S:30](Cl)(=[O:32])=[O:31])=[CH:29][C:16]=2[N:15]=1)([F:13])[CH3:12]>C1COCC1>[F:10][C:11]([C:14]1[N:18]([CH2:19][CH:20]2[CH2:21][CH2:22][O:23][CH2:24][CH2:25]2)[C:17]2[CH:26]=[CH:27][C:28]([S:30]([N:3]3[CH:7]=[CH:6][C:5]([CH:8]=[O:9])=[CH:4]3)(=[O:31])=[O:32])=[CH:29][C:16]=2[N:15]=1)([F:13])[CH3:12]
Reactant: CC(F)(F)c1nc2cc(S(=O)(=O)Cl)ccc2n1CC1CCOCC1
Reactant: O=Cc1cc[nH]c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(F)(F)c1nc2cc(S(=O)(=O)n3ccc(C=O)c3)ccc2n1CC1CCOCC1
Reaction time: 1 h

Procedure:
Sodium hydride (0.55 mg, 60%, 13.8 mmol) was added to a solution of 1H-Pyrrole-3-carbaldehyde (0.26 g, 2.7 mmol) in 30 mL of THF at 0° C. After stirring for 1 h, 2-(1,1-difluoroethyl)-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazole-5-sulfonyl chloride (0.95 g, 2.5 mmol) was added. The reaction mixture was stirred for 3 h at 0° C., quenched with NaHCO3 (10 mL) and diluted with EtOAc (150 mL). The organic phases were washed with NaCl (2×20 mL) and dried over Na2SO4. The product was purified by normal-phase MPLC using Hex/EtOAc (1:1) to provide the title compound as a white solid. Yield: 0.86 g (79%); MS (ESI) (M+H)+=437.88.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][N:11]=1)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].[NH2:19][C:20]1[CH:25]=[C:24]([C:26]2[S:27][CH:28]=[CH:29][CH:30]=2)[CH:23]=[CH:22][C:21]=1[NH:31]C(=O)OC(C)(C)C.C(Cl)CCl.C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>CCOC(C)=O.C(Cl)Cl.CN(C=O)C>[NH2:31][C:21]1[CH:22]=[CH:23][C:24]([C:26]2[S:27][CH:28]=[CH:29][CH:30]=2)=[CH:25][C:20]=1[NH:19][C:14]([C:13]1[CH:17]=[CH:18][C:10]([CH2:9][P:4](=[O:5])([O:3][CH2:1][CH3:2])[O:6][CH2:7][CH3:8])=[N:11][CH:12]=1)=[O:16]
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2cccs2)cc1N
Reactant: CCOP(=O)(Cc1ccc(C(=O)O)cn1)OCC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOP(=O)(Cc1ccc(C(=O)Nc2cc(-c3cccs3)ccc2N)cn1)OCC
Reaction time: 72 h
Yield: 43.6 %

Procedure:
A mixture of 6-[(Diethoxyphosphoryl)methyl]nicotinic acid (55.5 mg, 0.188 mmol), tert-butyl [2-amino-4-(2-thienyl)phenyl]carbamate (65.5 mg, 0.226 mmol) HOBT (30.5 mg, 0.226 mmol), and EDC (43.3 mg, 0.226 mmol) was taken into DMF (1.32 mL) and stirred for 3 days. The mixture was diluted with EtOAc and washed with 50% saturated aqueous NaHCO3 3×, brine, dried (MgSO4) and concentrated to afford a residue taken into DCM (2 mL) and TFA (1 mL) and stirred for 1 h. This mixture was concentrated via rotovap, dissolved in minimum MeOH and purified via HPLC (10-100% MeCN in water with 0.025% TFA) to afford fractions poured into saturated aqueous NaHCO3 and extracted with EtOAc 2×. The combined organic layers were washed with brine, dried (MgSO4) and concentrated to afford 36.5 mg of the requisite product as a light yellow solid. 1H NMR (DMSO-d6, 600 MHz) δ 9.84 (s, 1H), 9.04 (s, 1H), 8.26 (dd, J=7.9, 2.0 Hz, 1H), 7.47 (dd, J=8.2, 1.8 Hz, 1H), 7.44 (d, J=2.0 Hz, 1H), 7.33 (dd, J=5.0, 0.9 Hz, 1H), 7.28 (dd, J=8.8, 2.3 Hz, 1H), 7.22 (dd, J=3.5, 1.2 Hz, 1H), 7.2 (dd, J=5.0, 3.5 Hz, 1H), 6.78 (d, J=8.2 Hz, 1H), 5.22 (s, 2H), 3.95 (dt, J=7.3, 7.3 Hz, 4H), 3.53 (d, J=22.3 Hz, 2H), 1.19 Hz (t, J=7.0 Hz, 3H). MS: cal'd 446 (MH+), exp 446 (MH+).
Reaction SMILES: [N:1]1([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][CH2:14][CH2:13][C@H:2]1[C:3]([O:5]N1C(=O)CCC1=O)=O.[NH2:23][C@@H:24]([C:35]([OH:37])=[O:36])[CH2:25][C:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[NH:28][CH:27]=1.[OH-].[K+].C(OCC)(=O)C>CN(C)C=O.O>[N:1]1([C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])[CH2:15][CH2:14][CH2:13][C@H:2]1[C:3]([NH:23][C@@H:24]([C:35]([OH:37])=[O:36])[CH2:25][C:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[NH:28][CH:27]=1)=[O:5]
Reactant: N[C@H](Cc1c[nH]c2ccccc12)C(=O)O
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)ON1C(=O)CCC1=O
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)N[C@H](Cc1c[nH]c2ccccc12)C(=O)O
Temperature: 0 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
A chilled mixture of BocProOSu (96.1 mmole.) and dimethylformamide (100 ml.) was added with cooling to 0° C. to a solution of HDTrpOH (0.1 mole) and potassium hydroxide (85%, 0.1 mole) in dimethylformamide (150 ml.) and water (25 ml.). The mixture was stirred for one hour at 0° C., allowed to warm to room temperature overnight, and stripped of volatiles. The residue was partitioned between ethyl acetate and aqueous citric acid (5%). Crystals which formed between the layers were collected by filtration and recrystallized from methanol-water. More product was obtained by stripping the ethyl acetate layer of ethyl acetate and recrystallizing the residue from methanol-water. The recrystallizates were combined, affording BocProD-TrpOH in 86% yield (33.1 g., m.r. 210°-213° C.).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]([C:14]2[CH:19]=[CH:18][C:17]([S:20]([NH2:23])(=[O:22])=[O:21])=[CH:16][CH:15]=2)[N:4]=1>C(OCC)(=O)C.O=[Mn]=O>[CH:2]([C:3]1[CH:7]=[C:6]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:5]([C:14]2[CH:19]=[CH:18][C:17]([S:20]([NH2:23])(=[O:22])=[O:21])=[CH:16][CH:15]=2)[N:4]=1)=[O:1]
Reactant: NS(=O)(=O)c1ccc(-n2nc(CO)cc2-c2ccccc2)cc1
Agent: O=[Mn]=O
Solvent: CCOC(C)=O
Product: NS(=O)(=O)c1ccc(-n2nc(C=O)cc2-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the alcohol prepared in Example 131, Step 3 (1.1 g, 3.3 mmol) in ethyl acetate (20 mL) was added MnO2 (5 g, 60 mmol) and the mixture stirred at room temperature overnight. The mixture was filtered through Celite and the solution was concentrated to provide the crude aldehyde.