Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2](=[O:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[NH2:9][C:10]1[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][C:11]=1[C:17](=[O:19])[CH3:18].N1C=CC=CC=1.O>ClCCl>[CH2:6]([O:5][C:3](=[O:4])[C:2]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][C:11]=1[C:17](=[O:19])[CH3:18])=[O:8])[CH3:7]
Reactant: CC(=O)c1cc(Br)ccc1N
Reactant: CCOC(=O)C(=O)Cl
Solvent: c1ccncc1
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)C(=O)Nc1ccc(Br)cc1C(C)=O
Temperature: 25 °C
Reaction time: 17 h
Yield: 85 %

Procedure:
Ethyl chlorooxoacetate (352.7 μL, 3.15 mmol) was added to 1-(2-amino-5-bromophenyl)ethanone (519.8 mg, 2.43 mmol, Example 34c) and pyridine (589.1 μL, 7.28 mmol) in dichloromethane (8 mL) at 0° C. under argon and the reaction was allowed to warm to room temperature and stirred for 17 hours. Water was added, and the solution was extracted with diethyl ether. The organic layer was washed with 10% citric acid, then saturated sodium bicarbonate, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography eluting with 1:4 ethyl acetate:hexanes to give 648.7 mg (85%) of ethyl[(2-acetyl-4-bromophenyl)amino](oxo)acetate as a solid. 1H NMR (400 MHz, d6-DMSO): δ 12.61 (s, 1H), 8.47 (d, J=9 Hz, 1H), 8.26 (d, J=2 Hz, 1H), 7.88 (dd, J=9, 2 Hz, 1H), 4.31 (q, J=7 Hz, 2H), 2.69 (s, 3H), 1.32 (t, J=7 Hz, 3H). ESI-LCMS m/z 314 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([C:8]([OH:10])=O)=[C:5]([Cl:7])[N:6]=1.CCN(CC)CC.C1(P([N:32]=[N+:33]=[N-:34])(C2C=CC=CC=2)=O)C=CC=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[S:3][C:4]([C:8]([N:32]=[N+:33]=[N-:34])=[O:10])=[C:5]([Cl:7])[N:6]=1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: O=C(O)c1sc(Cl)nc1Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: [N-]=[N+]=NC(=O)c1sc(Cl)nc1Cl
Temperature: 25 °C
Reaction time: 20 h
Yield: 81.6 %

Procedure:
To a solution of 2,4-dichloro-thiazole-5-carboxylic acid (1.98 g, 10 mmol) in toluene (50 mL) was added Et3N (1.01 g, 10 mmol) followed by diphenyl phosphoryl azide (2.75 g, 10 mmol). The reaction mixture was stirred at room temperature for 20 h. The reaction mixture was concentrated in vacuo and purified by silica gel chromatography (0 to 100% ethyl acetate/hexanes) to afford product as a brown solid (1.82 g, 82%): 13C NMR (75 MHz, CDCl3) δ 163.33, 156.83, 143.94, 124.02.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH2:6][O:5][C:4]([C:7]2[CH:16]=[CH:15][C:10]([C:11]([O:13]C)=[O:12])=[CH:9][CH:8]=2)=[N:3]1.[Li+].[OH-]>C1COCC1.O.CCOC(C)=O>[CH3:1][C:2]1([CH3:17])[CH2:6][O:5][C:4]([C:7]2[CH:16]=[CH:15][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=2)=[N:3]1
Reactant: COC(=O)c1ccc(C2=NC(C)(C)CO2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CC1(C)COC(c2ccc(C(=O)O)cc2)=N1
Temperature: 25 °C
Reaction time: 4 h
Yield: 16.6 %

Procedure:
To a solution of methyl 4-(4,4-dimethyl-4,5-dihydro-1,3-oxazol-2-yl)benzoate (78 mg, 0.33 mmol) in THF (1 mL) and H2O (1 mL) was added LiOH (23 mg, 1 mmol). The mixture was stirred at RT for 4 h before it was diluted with EtOAc (5 mL) and quenched by addition of aqueous HCl (5 ml of a 0.5 M aqueous solution, 2.5 mmol). After extraction with EtOAc (3×10 mL), the combined organic extracts were washed with brine (10 mL), dried (MgSO4), filtered and concentrated at reduced pressure. The crude residue (12 mg, 16% yield) was obtained as colourless oil and was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:9]2[CH:14]=[C:13]([NH2:15])[CH:12]=[CH:11][C:10]=2[Cl:16])=[C:4]([CH3:17])[N:3]=1.[CH3:18][S:19](Cl)(=[O:21])=[O:20]>N1C=CC=CC=1>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:9]2[CH:14]=[C:13]([NH:15][S:19]([CH3:18])(=[O:21])=[O:20])[CH:12]=[CH:11][C:10]=2[Cl:16])=[C:4]([CH3:17])[N:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1nc(N)nc(N)c1-c1cc(N)ccc1Cl
Solvent: c1ccncc1
Product: Cc1nc(N)nc(N)c1-c1cc(NS(C)(=O)=O)ccc1Cl

Procedure:
This compound was prepared from 2,4-diamino-5-(2-chloro-5-aminophenyl)-6-methylpyrimidine from Example 54 by reaction with methanesulphonylchloride in pyridine, mp. 234°-240° C.
Reaction SMILES: [O:1]=[C:2]1[C:7]([C:8]([NH:10][NH2:11])=O)=[CH:6][C:5]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)=[N:4][NH:3]1.[C:18]([NH2:21])(=S)[CH3:19].C(N(CC)CC)C.N1C=CC=CC=1>C(O)CCC>[CH3:19][C:18]1[NH:21][C:8]([C:7]2[C:2](=[O:1])[NH:3][N:4]=[C:5]([C:12]3[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=3)[CH:6]=2)=[N:10][N:11]=1
Reactant: NNC(=O)c1cc(-c2ccncc2)n[nH]c1=O
Reactant: CC(N)=S
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Solvent: CCCCO
Product: Cc1nnc(-c2cc(-c3ccncc3)n[nH]c2=O)[nH]1
Temperature: 25 °C

Procedure:
A mixture of 100 mg of 3-oxo-6-pyridin-4-yl-2,3-dihydro-pyridazine-4-carboxylic acid hydrazide, 130 mg thioacetamide, 87 mg triethylamine, 1 ml of pyridine and 5 ml of butanol is refluxed for 15 hours. After cooling and stirring at room temperature a solid precipitated is collected by filtration, washed with cold isopropanol and dried in vacuo.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]([CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[C@@H:9]([C:12]2[O:13][CH:14]=[N:15][N:16]=2)[CH2:10][CH3:11])[C:5]([N+:22]([O-:24])=[O:23])=[CH:4][N:3]=1.[CH3:25][O:26][C:27]1[CH:32]=[C:31]([C:33]([O:35][CH3:36])=[O:34])[CH:30]=[CH:29][C:28]=1[NH2:37].CCN(C(C)C)C(C)C>CC(C)CC(O)C>[O:13]1[CH:14]=[N:15][N:16]=[C:12]1[C@H:9]([N:8]([CH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)[C:6]1[C:5]([N+:22]([O-:24])=[O:23])=[CH:4][N:3]=[C:2]([NH:37][C:28]2[CH:29]=[CH:30][C:31]([C:33]([O:35][CH3:36])=[O:34])=[CH:32][C:27]=2[O:26][CH3:25])[N:7]=1)[CH2:10][CH3:11]
Reactant: CC[C@H](c1nnco1)N(c1nc(Cl)ncc1[N+](=O)[O-])C1CCCC1
Reactant: COC(=O)c1ccc(N)c(OC)c1
Solvent: CC(C)CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@H](c1nnco1)N(c1nc(Nc2ccc(C(=O)OC)cc2OC)ncc1[N+](=O)[O-])C1CCCC1
Temperature: 140 °C
Reaction time: 4 h
Yield: 48.4 %

Procedure:
2-chloro-N-cyclopentyl-5-nitro-N-[(1R)-1-(1,3,4-oxadiazol-2-yl)propyl]pyrimidin-4-amine (61.5 mg, 0.1743 mmol) and methyl 4-amino-3-methoxy benzoate (37.9 mg, 0.2092 mmol) in 4-methylpentan-2-ol (600 L) were treated with DIPEA (33.8 mg, 45.6 mL, 0.2614 mmol) and the reaction mixture stirred at 140° C. for 4 hours. The reaction mixture was concentrated in vacuo and the residue purified by column chromatography (50% EtOAc/Petrol) to give the sub-title compound as a brown oil (42 mg, 48%); 1H NMR (400.0 MHz, DMSO) d 0.75-0.89 (3H, m), 1.15-1.75 (8H, m), 2.24-2.34 (1H, m), 2.40-2.51 (1H, m), 2.61-2.72 (1H, m), 3.55-3.63 (1H, m), 3.84 (3H, s), 3.89 (3H, s), 7.44 (1H, s), 7.55-7.65 (2H, m), 7.75-8.03 (1H, br s), 8.12 (1H, s), 8.77 (1H, s); MS ES(+) 498.1.
Reaction SMILES: [OH:1][C:2]1[C:7](=[O:8])[CH:6]=[CH:5][N:4]([CH3:9])[C:3]=1[CH:10](O)[C:11]([F:14])([F:13])[F:12].[CH2:16]([NH2:19])[CH:17]=[CH2:18]>>[OH:1][C:2]1[C:7](=[O:8])[CH:6]=[CH:5][N:4]([CH3:9])[C:3]=1[CH:10]([NH:19][CH2:16][CH:17]=[CH2:18])[C:11]([F:14])([F:13])[F:12]
Reactant: Cn1ccc(=O)c(O)c1C(O)C(F)(F)F
Reactant: C=CCN
Product: C=CCNC(c1c(O)c(=O)ccn1C)C(F)(F)F
Yield: 42 %

Procedure:
In a similar manner, Apo7075 was prepared from 3-hydroxy-1-methyl-2-(2,2,2-trifluoro-1-hydroxyethyl)pyridin-4(1H)-one (1.0 g, 4.5 mmol) and allylamine (0.67 mL, 9.0 mmol). The title compound Apo7075 (497 mg) was obtained after purification by flash chromatography (5% MeOH in CH2Cl2 as eluant). Yield=42%; 1H NMR (400 MHz, DMSO+a few drops of D2O) δ (ppm): 7.65 (d, J=7.1 Hz, 1H), 6.24 (d, J=7.4 Hz, 1H), 5.70-5.80 (m, 1H), 5.14 (d, J=17.4 Hz, 1H), 5.06 (d, J=10.1 Hz, 1H), 4.63 (q, J=8.2 Hz, 1H), 3.67 (s, 3H), 3.15-3.19 (m, 2H); MS m/z 263 [M+1]+, 206 (100%).
Reaction SMILES: Cl[C:2]1[C:19]([O:20][CH3:21])=[CH:18][C:5]2[C@H:6]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:7][N:8]([CH3:11])[CH2:9][CH2:10][C:4]=2[CH:3]=1.[OH-].[Na+].[H][H]>C(O)C.O.[Pd]>[CH3:21][O:20][C:19]1[CH:2]=[CH:3][C:4]2[CH2:10][CH2:9][N:8]([CH3:11])[CH2:7][C@@H:6]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:5]=2[CH:18]=1
Reactant: COc1cc2c(cc1Cl)CCN(C)C[C@H]2c1ccccc1
Reactant: [H][H]
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1ccc2c(c1)[C@H](c1ccccc1)CN(C)CC2

Procedure:
Hydrogenate a solution of 21.10 g (0.07 moles) of (S)-7-chloro-8-methoxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1-H-3-benzazepine (e.g. obtained as described in Example 1, step D) 3.30 g (0.0825 moles) of sodium hydroxide in 300 ml of 95% ethanol at room temperature and at 4.2 kg/cm2 (=60 psi), with 1.70 g of 20% palladium hydroxide-on-carbon until the theoretical amount of hydrogen is consumed. Remove the catalyst and concentrate the filtrate to dryness on a steam bath at about 100 mm. Stir the residue with a mixture of 100 ml of water and 150 ml of ethyl ether to total dissolution. Separate the ether layer, dry over anhydrous sodium sulfate, and evaporate to dryness. Crystallize the residue from hexane to obtain analytically pure (S)-8-methoxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine, m.p. 50°-51° C., [α]D26 =+51.8° (c=1, ethanol).
Reaction SMILES: [CH2:1]([C:3]1[N:11]=[C:10]([O:12][CH3:13])[C:9]([NH:14][C:15]([N:17]2[CH2:22][CH2:21][N:20]([C:23]3[CH:28]=[C:27]([CH3:29])[CH:26]=[C:25]([CH3:30])[CH:24]=3)[CH2:19][CH2:18]2)=[O:16])=[CH:8][C:4]=1[C:5](O)=[O:6])[CH3:2].[CH:31]1[C:44]2[C:35](=[N:36][C:37]3[C:42]([C:43]=2[NH:45][C:46]2[CH:47]=[C:48]([NH:54][C:55](=[O:59])[CH:56]([NH2:58])[CH3:57])[CH:49]=[C:50]([CH2:52][OH:53])[CH:51]=2)=[CH:41][CH:40]=[CH:39][CH:38]=3)[CH:34]=[CH:33][CH:32]=1>>[CH:41]1[C:42]2[C:37](=[N:36][C:35]3[C:44]([C:43]=2[NH:45][C:46]2[CH:47]=[C:48]([NH:54][C:55]([CH:56]([NH:58][C:5]([C:4]4[CH:8]=[C:9]([NH:14][C:15]([N:17]5[CH2:18][CH2:19][N:20]([C:23]6[CH:28]=[C:27]([CH3:29])[CH:26]=[C:25]([CH3:30])[CH:24]=6)[CH2:21][CH2:22]5)=[O:16])[C:10]([O:12][CH3:13])=[N:11][C:3]=4[CH2:1][CH3:2])=[O:6])[CH3:57])=[O:59])[CH:49]=[C:50]([CH2:52][OH:53])[CH:51]=2)=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH:38]=[CH:39][CH:40]=1
Reactant: CCc1nc(OC)c(NC(=O)N2CCN(c3cc(C)cc(C)c3)CC2)cc1C(=O)O
Reactant: CC(N)C(=O)Nc1cc(CO)cc(Nc2c3ccccc3nc3ccccc23)c1
Product: CCc1nc(OC)c(NC(=O)N2CCN(c3cc(C)cc(C)c3)CC2)cc1C(=O)NC(C)C(=O)Nc1cc(CO)cc(Nc2c3ccccc3nc3ccccc23)c1
Yield: 52.3 %

Procedure:
The same reaction procedure to the example 1 were carried out using 2-ethyl-5-{[4-(3,5-dimethylphenyl)-piperazine-1-carbonyl]-amino}-6-methoxy-nicotinic acid and N-[3-(acridine-9-yl-amino)-5-hydroxymethyl-phenyl]-2-aminopropaneamide to give the titled compound.
Reaction SMILES: C(OC(=O)[NH:10][CH2:11][CH2:12][NH:13][C:14](=[O:76])[C@@H:15]([NH:29][C:30]([C@H:32]1[NH:50][C:49](=[O:51])[C@H:48]([CH2:52][CH2:53][CH2:54][NH:55][C:56]([O:58][C:59]([CH3:62])([CH3:61])[CH3:60])=[O:57])[NH:47][C:46](=[O:63])[C@@H:45]([NH:64][C:65]([O:67][C:68]([CH3:71])([CH3:70])[CH3:69])=[O:66])[CH2:44][C:43]2[CH:72]=[C:39]([CH:40]=[CH:41][C:42]=2[OH:73])[C:38]2=[CH:74][C:34](=[C:35]([OH:75])[CH:36]=[CH:37]2)[CH2:33]1)=[O:31])[CH2:16][CH2:17][NH:18]C(OCC1C=CC=CC=1)=O)C1C=CC=CC=1>[Pd].C(O)(=O)C.O.C(O)C>[C:59]([O:58][C:56](=[O:57])[NH:55][CH2:54][CH2:53][CH2:52][C@@H:48]1[NH:47][C:46](=[O:63])[C@@H:45]([NH:64][C:65]([O:67][C:68]([CH3:71])([CH3:70])[CH3:69])=[O:66])[CH2:44][C:43]2[CH:72]=[C:39]([CH:40]=[CH:41][C:42]=2[OH:73])[C:38]2=[CH:74][C:34](=[C:35]([OH:75])[CH:36]=[CH:37]2)[CH2:33][C@@H:32]([C:30]([NH:29][C@H:15]([C:14]([NH:13][CH2:12][CH2:11][NH2:10])=[O:76])[CH2:16][CH2:17][NH2:18])=[O:31])[NH:50][C:49]1=[O:51])([CH3:60])([CH3:61])[CH3:62]
Reactant: CC(C)(C)OC(=O)NCCC[C@@H]1NC(=O)[C@@H](NC(=O)OC(C)(C)C)Cc2cc(ccc2O)-c2ccc(O)c(c2)C[C@@H](C(=O)N[C@@H](CCNC(=O)OCc2ccccc2)C(=O)NCCNC(=O)OCc2ccccc2)NC1=O
Agent: [Pd]
Solvent: O
Solvent: CC(=O)O
Solvent: CCO
Product: CC(C)(C)OC(=O)NCCC[C@@H]1NC(=O)[C@@H](NC(=O)OC(C)(C)C)Cc2cc(ccc2O)-c2ccc(O)c(c2)C[C@@H](C(=O)N[C@@H](CCN)C(=O)NCCN)NC1=O
Reaction time: 15 h

Procedure:
29 mg (0.027 mmol) of benzyl(2-{[(2S)-4-{[(benzyloxy)carbonyl]amino}-2-({[(8S,11S,14S)-14-[(tert-butoxycarbonyl)amino]-11-{3-[(tert-butoxycarbonyl)amino]propyl}-5,17-dihydroxy-10,13-dioxo-9,12-diazatricyclo[14.3.1.12,6]henicosa-1(20),2(21),3,5,16,18-hexaen-8-yl]carbonyl}amino)butanoyl]amino}ethyl)carbamate (Example 191A) are added into 8 ml of a 4:1:1 acetic acid/water/ethanol mixture. 2.5 mg of palladium on activated carbon (10%) are added thereto, and the mixture is then hydrogenated at RT under atmospheric pressure for 15 h. The reaction mixture is filtered through prewashed kieselguhr and washed with ethanol, and the filtrate is concentrated on a rotary evaporator in vacuo.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13](Br)=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][C:24]=1[F:25].ClCCl.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:21]3[CH:22]=[CH:23][C:24]([F:25])=[C:19]([Cl:18])[CH:20]=3)=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1ccc2c(ccn2Cc2ccccc2)c1
Reactant: OB(O)c1ccc(F)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Solvent: ClCCl
Product: Fc1ccc(-c2ccc3c(ccn3Cc3ccccc3)c2)cc1Cl
Yield: 41.2 %

Procedure:
1-Benzyl-5-(3-chloro-4-fluorophenyl)-1H-indole was prepared by coupling 1-benzyl-5-bromo-1H-indole (1.46 g, 5.10 mmol), and 3-chloro-4-fluorophenylboronic acid (1.08 g, 6.19 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (1:1) (0.209 g, 0.256 mmol), potassium carbonate (1.44 g, 10.4 mmol) in dioxane (51 mL) and water (5 mL), following the procedure described in Step 1 of Example 11. Purification by flash chromatography (Biotage apparatus) using hexane as an eluant and drying 60° C. furnished the title compound as a light brown gum (0.706 g, 41%). 1HNMR (200 MHz, DMSO-d6): δ 7.8-7.9 (m, 2H), 7.6-7.7 (m, 1H), 7.4-7.6 (m, 3H), 7.15-7.4 (m, 6H), 6.55 (d, 1H, J=2.5 Hz), and 5.45 ppm (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9](Cl)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8].[NH:13]1[CH2:17][CH2:16][CH2:15][CH:14]1[CH2:18][NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23].C(N(CC)CC)C.CO>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:13]2[CH2:17][CH2:16][CH2:15][CH:14]2[CH2:18][NH:19][C:20](=[O:26])[O:21][C:22]([CH3:24])([CH3:23])[CH3:25])(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)(C)OC(=O)NCC1CCCN1
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(Cl)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(C)(C)OC(=O)NCC1CCCN1S(=O)(=O)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.5 %

Procedure:
To a solution of 3,4-dichlorobenzene-1-sulfonyl chloride (490 mg, 2.00 mmol) was added tert-butyl pyrrolidin-2-ylmethylcarbamate (400 mg, 2.00 mmol), followed by triethylamine (0.278 mL, 2.00 mmol). The reaction was stirred at rt overnight. The reaction mixture was diluted with DCM and washed with 1N HCl, H2O and brine, dried over Na2SO4 and decanted. The solvent was evaporated under reduced pressure and the crude product was purified on a 24 g silica gel cartridge using 0 to 100% EtOAc in hexane for 15 min, then 0 to 20% MeOH in DCM for 15 min to provide Intermediate 2A (800 mg, 1.95 mmol, 98% yield) as a white solid. HPLC/MS (Method D) RT=2.12 min, [M+1]+ 309.1.
Reaction SMILES: C[O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[CH:6][C:5]=1[N+:19]([O-:21])=[O:20].[OH-].[Li+].CCOCC>CO.O>[C:15]([O:14][C:12]([NH:11][CH2:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]([OH:22])=[O:2])=[C:5]([N+:19]([O-:21])=[O:20])[CH:6]=1)=[O:13])([CH3:18])([CH3:16])[CH3:17]
Reactant: COC(=O)c1ccc(CNC(=O)OC(C)(C)C)cc1[N+](=O)[O-]
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Solvent: CO
Product: CC(C)(C)OC(=O)NCc1ccc(C(=O)O)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.3 %

Procedure:
A mixture of 4-(tert-butoxycarbonylamino-methyl)-2-nitro-benzoic acid methyl ester (64.36 g, 207.4 mmol), lithium hydroxide (5.96 g, 248.9 mmol) in methanol (500 mL) and water (250 mL) was stirred with a mechanical stirrer at room temperature overnight. The methanol was evaporated, and to the aqueous solution, was added 1 N HCl (300 mL) to form the precipitate. Ether (350 mL) was added, and the mixture was stirred at 0° C. for 2 hours. No desired precipitation was formed. The mixture was evaporated. To the mixture, was added water (500 mL). The aqueous layer was extracted with ethyl acetate (5×120 mL). The combined organic layers were separated, dried over magnesium sulfate, and concentrated to give 4-(tert-butoxycarbonylamino-methyl)-2-nitro-benzoic acid as a brown oil (56.69 g, 92% yield). The product was used in the next step without further purification.
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[CH3:12][C:13]1[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][C:14]=1[S:20][C:21]1[S:22][C:23]2[C:29]([N:30]([CH2:34][CH2:35][CH3:36])[CH2:31][CH2:32][CH3:33])=[CH:28][CH:27]=[CH:26][C:24]=2[N:25]=1>ClCCl.C([O-])(O)=O.[Na+]>[CH3:12][C:13]1[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][C:14]=1[S:20]([C:21]1[S:22][C:23]2[C:29]([N:30]([CH2:34][CH2:35][CH3:36])[CH2:31][CH2:32][CH3:33])=[CH:28][CH:27]=[CH:26][C:24]=2[N:25]=1)=[O:6]
Reactant: CCCN(CCC)c1cccc2nc(Sc3ccc(C)cc3C)sc12
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCCN(CCC)c1cccc2nc(S(=O)c3ccc(C)cc3C)sc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 51.1 %

Procedure:
3-Chloroperoxybenzoic acid (MCPBA) (20 mg, 0.0810 mmol) was added to a solution of 2-[(2,4-dimethylphenyl)thio]-N,N-dipropyl-1,3-benzothiazol-7-amine (30 mg, 0.0810 mmol) in dichloromethane (2 ml). The mixture was stirred at room temperature for 18 h and diluted with saturated NaHCO3. The organic layer was dried over magnesium sulfate and concentrated under vacuum. The residue was purified by chromatography eluting with 5% methanol in dichloromethane to afford 16 mg of the title compound.
Reaction SMILES: B.CSC.[Br:5][C:6]1[CH:7]=[C:8]([NH:14][C:15](=O)[C:16]([F:19])([F:18])[F:17])[CH:9]=[CH:10][C:11]=1[O:12][CH3:13]>O1CCCC1>[CH3:13][O:12][C:11]1[CH:10]=[CH:9][C:8]([NH:14][CH2:15][C:16]([F:17])([F:18])[F:19])=[CH:7][C:6]=1[Br:5]
Reactant: COc1ccc(NC(=O)C(F)(F)F)cc1Br
Agent: B
Solvent: C1CCOC1
Solvent: CSC
Product: COc1ccc(NCC(F)(F)F)cc1Br
Yield: 110.3 %

Procedure:
Borane-dimethylsulfide complex (2M in THF, 6.7 ml, 13.4 mmol) was added to a solution of N-(3-Bromo-4-methoxyphenyl)trifluoroacetamide (Description 52, 2.0 g, 6.7 mmol) in tetrahydrofuran (20 ml) and the mixture was heated under reflux for 18 h. The mixture was cooled and the solvent was evaporated under reduced pressure to give the title compound as a yellow oil (2.1 g). 1H NMR (360 MHz, CDCl3) δ6.93 (1H, d, J 2.9 Hz), 6.80 (1H, d, J 8.8 Hz), 6.62 (1H, dd, J 8.8, 2.9 Hz), 3.82 (3H, s), and 3.71 (3H, m). m/z (ES+) 284, 286 (M+1).
Reaction SMILES: [C:1]([C:4]1[CH:30]=[CH:29][C:7]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:27]=[CH:26][C:16]([C:17]([O:19][CH2:20][CH2:21][CH2:22][N:23]([CH3:25])[CH3:24])=[O:18])=[CH:15][C:14]=2[F:28])=[C:6]([CH2:31][CH2:32][CH3:33])[C:5]=1[OH:34])(=[O:3])[CH3:2].[C:35](OC(=O)C)(=[O:37])[CH3:36].CO>ClCCl.C(N(CC)CC)C.CN(C)C1C=CN=CC=1>[C:35]([O:34][C:5]1[C:6]([CH2:31][CH2:32][CH3:33])=[C:7]([CH:29]=[CH:30][C:4]=1[C:1](=[O:3])[CH3:2])[O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:27]=[CH:26][C:16]([C:17]([O:19][CH2:20][CH2:21][CH2:22][N:23]([CH3:24])[CH3:25])=[O:18])=[CH:15][C:14]=1[F:28])(=[O:37])[CH3:36]
Reactant: CCCc1c(OCCCOc2ccc(C(=O)OCCCN(C)C)cc2F)ccc(C(C)=O)c1O
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CO
Product: CCCc1c(OCCCOc2ccc(C(=O)OCCCN(C)C)cc2F)ccc(C(C)=O)c1OC(C)=O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 3-dimethylaminopropyl 4-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]-3-fluorobenzoate (124 mg) in dichloromethane (1 ml), triethylamine (0.5 ml) and 4-dimethylaminopyridine (a catalytic amount) was added acetic anhydride (0.38 ml). The mixture was stirred well for 1.5 hours at room temperature. To the reaction mixture was added methanol (2 ml), and the solvents removed by evaporation under reduced pressure. The residue was dissolved in chloroform, the solution was washed with a solution of saturated sodium hydrogen carbonate and dried with sodium sulfate, and the solvent was removed by evaporation. The residue was dissolved in ether, and to the solution was added a saturated solution of oxalic acid in ether until a precipitate did not emerge any more. The precipitate was recovered by filtration and washed with ether to give a white solid of 3-dimethylaminopropyl 4-[3-(3-acetoxy-4-acetyl-2-propylphenoxy)propoxy]-3-fluorobenzoate.mono-oxalate (180 mg). M.p. 166°-167° C.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([CH:12]=[O:13])[NH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[Br:22][CH2:23][CH2:24][CH2:25][CH2:26]Br>CN(C=O)C>[Br:22][CH2:23][CH2:24][CH2:25][CH2:26][N:10]1[CH:11]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]=[C:9]1[CH:12]=[O:13]
Reactant: O=Cc1nc(-c2ccccc2)c[nH]1
Reactant: BrCCCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1nc(-c2ccccc2)cn1CCCCBr
Temperature: 50 °C
Reaction time: 4 h
Yield: 65.7 %

Procedure:
A mixture of 4-phenyl-1H-imidazole-2-carbaldehyde (1.79 g, 10.4 mmol), potassium carbonate (2.87 g, 20.8 mmol), potassium iodide (2.94 g, 17.7 mmol) and 1,4-dibromobutane (4.49 g, 20.8 mmol) in dry DMF (35 mL) were heated to 50° C. and stirred for 4 hours. The mixture was poured into ice-water (100 mL), and washed with EtOAc (2×80 mL). The combined organic layers were washed with brine (2×100 mL). The organic layer was dried over sodium sulfate, filtered, concentrated and then purified by column chromatography to give 1-(4-bromobutyl)-4-phenyl-1H-imidazole-2-carbaldehyde as a colorless oil (2.1 g). MS (ESI): m/z 308 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[N:7]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][O:17][C:18]2[CH:19]=[C:20]3[C:24](=[CH:25][CH:26]=2)[NH:23][CH:22]=[CH:21]3)[N:10]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[CH3:28][O:29][C:30](=[O:39])[C:31]#[C:32][C:33]1[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=1>>[CH3:28][O:29][C:30](=[O:39])[CH:31]=[C:32]([N:23]1[C:24]2[C:20](=[CH:19][C:18]([O:17][CH2:16][CH2:15][C:11]3[CH:12]=[CH:13][CH:14]=[C:9]([N:7]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:27])[CH3:8])[N:10]=3)=[CH:26][CH:25]=2)[CH:21]=[CH:22]1)[C:33]1[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=1
Reactant: COC(=O)C#Cc1cccnc1
Reactant: CN(C(=O)OC(C)(C)C)c1cccc(CCOc2ccc3[nH]ccc3c2)n1
Product: COC(=O)C=C(c1cccnc1)n1ccc2cc(OCCc3cccc(N(C)C(=O)OC(C)(C)C)n3)ccc21
Yield: 96 %

Procedure:
The title compound was synthesized from {6-[2-(1H-indol-5-yloxy)-ethyl]-pyridin-2-yl}-methyl-carbamic acid tert-butyl ester and pyridin-3-yl-propynoic acid methyl ester, using the procedure described in Example 16, step (d1), in a 96% yield, as an E/Z isomeric mixture. 1H NMR (Cl3CD), δ: 8.74-8.64 (m, 2H), 7.68 (m, 0.4), 7.57-7.48 (m, 2H), 7.45 (m, 0.6H), 7.38 (m, 0.4H), 7.28 (m, 0.6H), 7.13 (m, 1H), 7.08 (m, 1H), 6.96 (d, 1H, J=7.0 Hz), 6.88 (d, 0.4H, J=3.5 Hz), 6.80-6.66 (m, 1.6H), 6.61 (d, 0.6H, J=3.2 Hz), 6.54 (d, 0.4H, J=3.5 Hz), 6.26 (s, 0.4H), 6.24 (s, 0.6H), 4.39 (m, 2H), 3.67 (s, 1.2H), 3.61 (s, 1.8H), 3.39 (m, 3H), 3.20 (m, 2H), 1.51 (s, 9H).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([NH2:6])=[O:5].C(N(CC)CC)C.[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([O:24][CH3:25])=[C:19]([N:21]=[C:22]=[S:23])[CH:20]=1>C(Cl)(Cl)Cl>[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([O:24][CH3:25])=[C:19]([NH:21][C:22](=[S:23])[NH:2][CH2:3][C:4]([NH2:6])=[O:5])[CH:20]=1
Reactant: COc1ccc(Cl)cc1N=C=S
Reactant: NCC(N)=O
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1ccc(Cl)cc1NC(=S)NCC(N)=O
Temperature: 25 °C
Yield: 94 %

Procedure:
A mixture of glycinamide hydrochloride (5.5 g), triethyl amine (5.05 g), 5-chloro-2-methoxyphenyl-isothiocyanate (9.95 g), and chloroform (500 mL) were heated at reflux for 3 hours. The mixture was then cooled to ambient temperature and washed with water (300 mL). The organic phase was separated. Precipitate formed upon standing. The solid was collected by filtration, washed with water, then with diethyl ether and air dried to give 2-[3-(5-chloro-2-methoxyphenyl)-thioureido]-acetamide (12.8 g), m.p. 166°-169° C. (dec.). This compound was used without further purification for the preparation of the title compound.