Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1C2C(C[O:15][C:16]([NH:18][C@H:19]([C:43]([OH:45])=O)[CH2:20][C:21](=[O:42])[NH:22][C:23]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=O)C3C(=CC=CC=3)C=2C=CC=1.Cl.[NH2:47][CH2:48][CH2:49][C:50]1[CH:57]=[CH:56][C:54]([OH:55])=[C:52]([OH:53])[CH:51]=1>>[C:16]([NH:18][C@H:19]([C:43]([NH:47][CH2:48][CH2:49][C:50]1[CH:57]=[CH:56][C:54]([OH:55])=[C:52]([OH:53])[CH:51]=1)=[O:45])[CH2:20][C:21](=[O:42])[NH:22][C:23]([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)(=[O:15])/[CH:48]=[CH:49]/[C:50]1[CH:57]=[CH:56][C:54]([OH:55])=[C:52]([OH:53])[CH:51]=1
Reactant: O=C(C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: NCCc1ccc(O)c(O)c1
Agent: Cl
Product: O=C(/C=C/c1ccc(O)c(O)c1)N[C@@H](CC(=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)NCCc1ccc(O)c(O)c1
Yield: 137 %

Procedure:
The title compound was prepared from Nα-(9-fluorenylmethoxycarbonyl)-Nγ-trityl-L-asparagine (2.0 g, 3.4 mmol) following the indications of general procedure F with dopamine hydrochloride (954 mg, 5 mmol). The crude material was purified by flash chromatography with a solvent gradient from 15% to 60% EtOAc/CH2Cl2 to give 2.3 g (95%) of the desired product as white crystals.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][C:11]3[N:12]([C:14]([CH2:17][C:18]4[CH:19]=[C:20]([NH:24]C(=O)OC(C)(C)C)[CH:21]=[CH:22][CH:23]=4)=[CH:15][N:16]=3)[N:13]=2)=[CH:4][C:3]=1[F:32].[F:33][C:34]([F:39])([F:38])[C:35]([OH:37])=[O:36]>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][C:11]3[N:12]([C:14]([CH2:17][C:18]4[CH:19]=[C:20]([CH:21]=[CH:22][CH:23]=4)[NH2:24])=[CH:15][N:16]=3)[N:13]=2)=[CH:4][C:3]=1[F:32].[C:35]([OH:37])([C:34]([F:39])([F:38])[F:33])=[O:36]
Reactant: CC(C)(C)OC(=O)Nc1cccc(Cc2cnc3ncc(-c4ccc(Br)c(F)c4)nn23)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1cccc(Cc2cnc3ncc(-c4ccc(Br)c(F)c4)nn23)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of tert-butyl (3-[2-(4-bromo-3-fluorophenyl)imidazo[1,2-b][1,2,4]triazin-7-yl]methylphenyl)carbamate (10 mg, 0.02 mmol) in trifluoroacetic acid (0.5 mL) and methylene chloride (0.5 mL) was stirred overnight at RT. The mixture was concentrated to afford the desired product as a TFA salt which was directly used for next step. LCMS: (M+H)=397.9/399.9.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:10][CH2:9][CH2:8][C:7]=2[CH:11]=1)=O.[Br:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])[CH2:16]2>>[Br:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])[C:16]2=[CH:1][C:3]1[CH:4]=[CH:5][C:6]2[O:10][CH2:9][CH2:8][C:7]=2[CH:11]=1
Reactant: O=Cc1ccc2c(c1)CCO2
Reactant: O=C1Cc2cc(Br)ccc2N1
Product: O=C1Nc2ccc(Br)cc2C1=Cc1ccc2c(c1)CCO2

Procedure:
2,3-Dihydro-5-formylbenzofuran (commercially available) was condensed with 5-bromo-2-oxindole to give 0.3 g of 5-bromo-3-(2,3-dihydrobenzofuran-5-ylmethylene)-1,3-dihydroindol-2-one as a yellow-orange solid.
Reaction SMILES: C1([C@@H:7]([NH:9]C2C=C(C3C=CC=C4C=3C=CC=N4)N=CC=2N)C)C=CC=CC=1.[C:27]1([C@@H:33]([N:35]2[C:43]3[CH:42]=[C:41]([C:44]4[CH:53]=[CH:52][CH:51]=[C:50]5[C:45]=4[CH:46]=[CH:47][CH:48]=[N:49]5)N=C[C:38]=3[NH:37][C:36]2=[O:54])[CH3:34])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.NC(N)=O.O>CN1CCCC1=O>[C:27]1([C@@H:33]([N:35]2[C:43]3[C:38](=[N:9][CH:7]=[C:41]([C:44]4[CH:53]=[CH:52][CH:51]=[C:50]5[C:45]=4[CH:46]=[CH:47][CH:48]=[N:49]5)[CH:42]=3)[NH:37][C:36]2=[O:54])[CH3:34])[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: C[C@@H](c1ccccc1)n1c(=O)[nH]c2cnc(-c3cccc4ncccc34)cc21
Reactant: C[C@H](Nc1cc(-c2cccc3ncccc23)ncc1N)c1ccccc1
Agent: NC(N)=O
Solvent: O
Solvent: CN1CCCC1=O
Product: C[C@@H](c1ccccc1)n1c(=O)[nH]c2ncc(-c3cccc4ncccc34)cc21
Temperature: 185 °C
Yield: 19.2 %

Procedure:
(S)-1-(1-Phenylethyl)-6-(quinolin-5-yl)-1H-imidazo[4,5-c]pyridin-2(3H)-one ((1S)-1-Phenylethyl)(3-amino-6-(5-quinolyl)(4-pyridyl))amine (450mg, 1.32 mmol) and urea (158 mg, 2.64 mmol) were combined in 1-methylpyrrolidin-2-one (4 mL) and heated at 185° C. for 2 h. Water (10 mL) was added and the crude product was collected by filtration. The product was purified by reverse-phase preparative HPLC (20-95% acetonitrle in water, over 30 min) to give the product (92.9 mg, 19%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 11.45 (s, 1H), 8.91 (dd, J=4.10, 1.76, 1H), 8.39 (d, J=0.78, 1H), 8.33 (ddd, J=8.00, 1.27, 1.07, 1H), 8.05 (d, J=8.40, 1H), 7.80 (dd, J=8.49, 7.13, 1H), 7.59 (dd, J=7.13, 1.27, 1H), 7.41-7.47 (m, 3H), 7.29-7.41 (m, 3H), H), 5.75 (d, J=7.22, 1H), 4.16 (d, J=0.78, 1H), 1.87 (d, J=7.22, 3 H); MS (ESI) m/z 367.0 [M+1]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]([C:12]([OH:14])=[O:13])[NH2:11])[CH:6]=[CH:7][C:8]=1[OH:9].Cl.[CH3:16]O>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]([C:12]([O:14][CH3:16])=[O:13])[NH2:11])[CH:6]=[CH:7][C:8]=1[OH:9]
Reactant: COc1cc(C(N)C(=O)O)ccc1O
Reactant: CO
Agent: Cl
Product: COC(=O)C(N)c1ccc(O)c(OC)c1

Procedure:
A cooled suspension of 94 g. (0.476 mole) of 2-(3'-methoxy-4'hydroxyphenyl)glycine in 500 ml. of absolute methanol was gassed at a rapid rate with HCl for 20 minutes. At first a clear solution was obtained and then crystalline product separated in quantity. After 20 hours the methyl ester hydrochloride was filtered and washed sparingly with methanol; 99.6 g. after air drying. A cooled solution of the hydrochloride in 800 ml. of water was adjusted to pH 8 (NaOH) giving a crystalline precipitate of the ester free base; 81.3 g. The IR and NMR spectra were consistent.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[C:42]([NH2:46])([CH3:45])([CH3:44])[CH3:43]>O1CCOCC1>[C:42]([NH:46][C:8]([C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][N:6]=1)=[O:10])([CH3:45])([CH3:44])[CH3:43]
Reactant: CC(C)(C)N
Reactant: O=C(O)c1ccc(Br)cn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)NC(=O)c1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 92.3 %

Procedure:
5-Bromopicolinic acid (200 mg, 0.99 mmol) was dissolved in dioxane (2 ml) and Hunig's Base (520 μl, 2.97 mmol, 3 equiv.), TBTU (350 mg, 1.09 mmol, 1.1 equiv.) and tert-butyl amine (124 μl, 1.19 mmol, 1.2 equiv.) were added at room temperature. The mixture was stirred for 16 hours at room temperature. The reaction mixture was evaporated and extracted saturated NaHCO3 solution and two times with a small volume of dichloromethane. The crude product was purified by flash chromatography by directly loading the dichloromethane layers onto a silica gel column and eluting with an ethyl acetate:heptane gradient 0:100 to 50:50. The desired 5-bromo-pyridine-2-carboxylic acid tert-butylamide (235 mg, 92% yield) was obtained as a colorless oil, MS: m/e=257.0/259.0 (M+H+).
Reaction SMILES: [C:1]([Si:5]([O:8][CH:9]([CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([CH2:41][CH3:42])([C:25]2[CH:30]=[CH:29][C:28](B3OC(C)(C)C(C)(C)O3)=[C:27]([CH3:40])[CH:26]=2)[CH2:23][CH3:24])=[CH:18][C:17]=1[CH3:43])[C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].[CH2:44]([O:46][C:47](=[O:56])[CH2:48][C:49]1[CH:50]=[CH:51][C:52](Cl)=[N:53][CH:54]=1)[CH3:45].O>CN(C)C=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:44]([O:46][C:47](=[O:56])[CH2:48][C:49]1[CH:54]=[N:53][C:52]([C:28]2[CH:29]=[CH:30][C:25]([C:22]([C:19]3[CH:20]=[CH:21][C:16]([CH2:15][CH2:14][CH:9]([O:8][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:6])[CH3:7])[C:10]([CH3:13])([CH3:12])[CH3:11])=[C:17]([CH3:43])[CH:18]=3)([CH2:23][CH3:24])[CH2:41][CH3:42])=[CH:26][C:27]=2[CH3:40])=[CH:51][CH:50]=1)[CH3:45]
Reactant: CCC(CC)(c1ccc(CCC(O[Si](C)(C)C(C)(C)C)C(C)(C)C)c(C)c1)c1ccc(B2OC(C)(C)C(C)(C)O2)c(C)c1
Reactant: CCOC(=O)Cc1ccc(Cl)nc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1ccc(-c2ccc(C(CC)(CC)c3ccc(CCC(O[Si](C)(C)C(C)(C)C)C(C)(C)C)c(C)c3)cc2C)nc1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 15.5 %

Procedure:
A solution of t-butyl-(1-{2-[4-(1-ethyl-1-{4-[4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl]-3-methyl-phenyl}-propyl)-2-methyl-phenyl]-ethyl}-2,2-dimethyl-propoxy)dimethylsilane (Example 23-(1); 13 mg, 0.021 mmol) in N,N-dimethylformamide (0.2 mL) was added to 2-chloropyridine-5-acetic acid ethyl ester (7.4 mg, 0.037 mmol) and a [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II), dichloromethane complex (1:1) (2.0 mg, 0.0024 mmol). After replacement with nitrogen, the mixture was heated while stirring at an external temperature of 76 to 84° C. for seven hours and 30 minutes. Water was added to the reaction mixture, followed by extraction with ether. The extract was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate=10/1) to give the title compound (2.1 mg, 16%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([OH:12])=[O:11].C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:25](O)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.O>C1COCC1>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([O:12][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:11]
Reactant: OCc1ccccc1
Reactant: O=C(O)c1cc2ccccc2[nH]1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)c1cc2ccccc2[nH]1
Yield: 84.6 %

Procedure:
10.32 g of 2-indolecarboxylic acid in 70 ml of THF are placed in a three-necked flask at RT, 10.38 g of carbonyldiimidazole are added and, after the evolution of gas has ceased, 7.62 g of benzyl alcohol are then added. After refluxing for 5 hours, the mixture is poured into water and extracted with DCM, and the extracts are dried and evaporated. The crystals formed are washed with iPrOH to give 13.62 g of the expected compound: m.p.=136° C.
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][CH2:12][NH:13][S:14]([C:17]2[C:18]3[CH:19]=[CH:20][CH:21]=[N:22][C:23]=3[C:24]([Cl:27])=[CH:25][CH:26]=2)(=[O:16])=[O:15])(=O)=O)=CC=1.[CH2:29]1[O:39][C:38]2[CH:37]=[CH:36][C:33]([CH2:34][NH2:35])=[CH:32][C:31]=2[O:30]1>O1CCCC1>[CH2:29]1[O:39][C:38]2[CH:37]=[CH:36][C:33]([CH2:34][NH:35][CH2:11][CH2:12][NH:13][S:14]([C:17]3[C:18]4[CH:19]=[CH:20][CH:21]=[N:22][C:23]=4[C:24]([Cl:27])=[CH:25][CH:26]=3)(=[O:15])=[O:16])=[CH:32][C:31]=2[O:30]1
Reactant: NCc1ccc2c(c1)OCO2
Reactant: Cc1ccc(S(=O)(=O)OCCNS(=O)(=O)c2ccc(Cl)c3ncccc23)cc1
Solvent: C1CCOC1
Product: O=S(=O)(NCCNCc1ccc2c(c1)OCO2)c1ccc(Cl)c2ncccc12
Yield: 56.9 %

Procedure:
3.32 g of N-(2-paratoluenesulfonyloxyethyl)-8-chloro-5-quinolinesulfonamide was reacted with 30 ml of a tetrahydrofuran solution containing 3.41 g of 3,4-methylenedioxybenzylamine in a sealed vessel at 70° C. for 17 hours, and the solvent was removed by distillation under reduced pressure to obtain a residue. The thus obtained residue was subjected to purification by means of a column for chromatography packed with 200 g of silica gel (Wacogel C-200, manufactured by Wako Pure Chemical Industries, Ltd., Japan) using, as an eluent, a mixture of methanol and chloroform (5% methanol) to thereby obtain 1.80 g of N-[2-(3,4-methylenedioxybenzylamino)ethyl]-8-chloro-5-quinolinesulfonamide (13) (yield: 57%)
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1.[NH2:14][C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[N:18][C:19]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)=[CH:20][CH:21]=2)[N:16]=1.CO>O>[F:31][C:28]1[CH:27]=[CH:26][C:25]([C:19]2[N:18]=[C:17]3[C:22]([CH:23]=[CH:24][C:15]([NH:14][C:7](=[O:9])[C:6]4[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:13])[F:12])=[CH:11][CH:10]=4)=[N:16]3)=[CH:21][CH:20]=2)=[CH:30][CH:29]=1
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1
Reactant: Nc1ccc2ccc(-c3ccc(F)cc3)nc2n1
Solvent: CO
Solvent: O
Product: O=C(Nc1ccc2ccc(-c3ccc(F)cc3)nc2n1)c1ccc(C(F)(F)F)cc1
Temperature: 4 °C
Yield: 31.5 %

Procedure:
The procedure is analogous to that described in Example 11, but starting with 4-trifluoromethylbenzoic acid (2.7 g), N,N'-carbonyldiimidazole (2.3 g) and 2-amino-7-(4-fluorophenyl)-1,8-naphthyridine (2.4 g). The product obtained by precipitation in water (2.1 g) is dissolved in boiling methanol (50 cc). After cooling for 2 hours at 4° C., the crystallized solid is separated by filtration, washed with methanol (3×5 cc) and dried at 40° C. under reduced pressure (0.07 kPa). N-[7-(4-Fluorophenyl)-1,8-naphthyridin-2-yl]-4-trifluoromethylbenzamide (1.3 g), m.p. 198° C., is obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:12](=[O:20])[CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:9]=[CH:10][CH:11]=1.[BH4-].[Na+]>O1CCCC1.O>[CH3:25][C:21]1[CH:22]=[CH:23][CH:24]=[C:2]([CH3:1])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:12]([OH:20])[CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:9]=[CH:10][CH:11]=1
Reactant: CCOC(=O)CCC(=O)c1cccc(OCc2c(C)cccc2C)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)CCC(O)c1cccc(OCc2c(C)cccc2C)c1
Temperature: 25 °C

Procedure:
To a solution of Ethyl 4-(3-(2,6-dimethylbenzyloxy)phenyl)-4-oxobutyrate (Step C) in tetrahydrofuran, add sodium borohydride dissolved in water, After 3-4 hours of stirring at room temperature, quench with an acid. The organic layer can be taken in dichloromethane, wash with water, aqueous sodium bicarbonate, and brine, dry over Na2SO4, filter and concentrate. If needed, the compound can be purified by flash chromatography on silica gel column (EtOAc:Hex).
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][CH:21]=[CH:20][C:3]=1[C:4]([C:6]1[C:7](Cl)=[C:8]([Cl:18])[C:9]2[O:13][CH:12]([C:14]([OH:16])=[O:15])[CH2:11][C:10]=2[CH:17]=1)=O.[O:24]1C2C=CC=CC=2C(C2C(Cl)=C(Cl)C3OC(C(O)=O)CC=3C=2)=[N:25]1.S(=O)(=O)(O)O>C(O)C>[Cl:18][C:8]1[C:7]2[O:24][N:25]=[C:4]([C:3]3[CH:20]=[CH:21][CH:22]=[CH:23][C:2]=3[Cl:1])[C:6]=2[CH:17]=[C:10]2[CH2:11][CH:12]([C:14]([OH:16])=[O:15])[O:13][C:9]=12
Reactant: O=C(c1ccccc1Cl)c1cc2c(c(Cl)c1Cl)OC(C(=O)O)C2
Reactant: O=C(O)C1Cc2cc(-c3noc4ccccc34)c(Cl)c(Cl)c2O1
Agent: O=S(=O)(O)O
Solvent: CCO
Product: O=C(O)C1Cc2cc3c(-c4ccccc4Cl)noc3c(Cl)c2O1

Procedure:
8-Chloro-3-(o-chlorophenyl)-5,6-dihydrofuro[3,2-f]-1,2-benzisoxazole-6-carboxylic acid (4d) was prepared from (3d) using the procedure above; the product contained a significant impurity, presumably the countercyclized 5-(3-benzisoxazolyl)-6,7-dichloro-2,3-dihydrobenzofuran-2-carboxylic acid. The mixture was dissolved in 200 ml. absolute ethanol and treated with 0.5 ml. concentrated sulfuric acid overnight. The solution was then evaporated to dryness, redissolved in ethyl acetate, washed with brine, dried over anhydrous magnesium sulfate, and re-evaporated. Chromatography of the ester on silica gel with chloroform and n-hexane in a 3:1 ratio gave a solid, m.p. 136° C., which was determined by detailed mass spectral analysis to be the desired isomer. Hydrolysis at 60° C. in 25 ml. absolute ethanol and 200 ml. aqueous 1M sodium hydroxide for 20 minutes furnished a white precipitate which was distributed between ethyl acetate and 4.0M aqueous hydrochloric acid, washed with brine, dried over anhydrous magnesium sulfate, and evaporated. Recrystallization from ethyl acetate with n-hexane gave (4d), m.p. 224°-225° C., in 8.1% yield. Analysis (C16H9Cl2NO4) C,H,N,Cl.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[C:17]([C:18]3[O:22][CH:21]=[N:20][CH:19]=3)=[CH:16][CH:15]=[CH:14][N:13]=2)=[CH:7][C:3]=1[C:4](O)=[O:5].C(Cl)(=O)C([Cl:26])=O>C(Cl)Cl.CN(C=O)C>[F:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[C:17]([C:18]3[O:22][CH:21]=[N:20][CH:19]=3)=[CH:16][CH:15]=[CH:14][N:13]=2)=[CH:7][C:3]=1[C:4]([Cl:26])=[O:5]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cc(Oc2ncccc2-c2cnco2)ccc1F
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1cc(Oc2ncccc2-c2cnco2)ccc1F
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To 2-fluoro-5-(3-(oxazol-5-yl)pyridin-2-yloxy)benzoic acid (196 mg, 0.653 mmol) in CH2Cl2 (6.0 mL) was added oxalyl chloride (0.28 mL, 3.3 mmol) followed by DMF (2 drops). The mixture was stirred under nitrogen at rt for 15 hours. The reaction was concentrated to yield 2-fluoro-5-(3-(oxazol-5-yl)pyridin-2-yloxy)benzoyl chloride, which was used without further purification.
Reaction SMILES: C(O[C:4]1[CH:5]=C(C=C[C:11]=1C)C=O)C.[OH:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[CH:17]=[O:18].C(Br)C=C.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:5]([O:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[CH:17]=[O:18])[CH:4]=[CH2:11]
Reactant: COc1ccc(C=O)cc1O
Reactant: CCOc1cc(C=O)ccc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C=CCBr
Product: C=CCOc1cc(C=O)ccc1OC

Procedure:
The title compound was prepared analogously to 3-ethoxy-4-methyl-benzaldehyde (intermediate B10) by reaction of 3-hydroxy-4-methoxy-benzaldehyde with allylbromide in DMF using K2CO3 as base (see also A. W. White, R. Almassy, A. H. Calvert, N. J. Curtin, R. J. Griffin, Z. Hostomsky, K. Maegley, D. R. Newell, S. Srinivasan and B. T. Golding J. Med. Chem. 2000, 43, 4084-4097).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:12][CH2:11][CH2:10][N:9]([C:13]2[NH:17][C:16]3[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=3[N:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].O1CCCC1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].CS([CH2:41][CH2:42][O:43][CH2:44][C:45]1[O:46][CH:47]=[CH:48][CH:49]=1)(=O)=O>O>[CH2:1]([O:3][C:4]([N:6]1[CH2:12][CH2:11][CH2:10][N:9]([C:13]2[N:14]([CH2:41][CH2:42][O:43][CH2:44][C:45]3[O:46][CH:47]=[CH:48][CH:49]=3)[C:15]3[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=3[N:17]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CS(=O)(=O)CCOCc1ccco1
Reactant: CCOC(=O)N1CCCN(c2nc3ccccc3[nH]2)CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)N1CCCN(c2nc3ccccc3n2CCOCc2ccco2)CC1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
Combine 1-ethoxycarbonyl-4-(1H-benzimidazol-2-yl)[1,4]diazepane (1.6 mmol) and tetrahydrofuran (10 mL). Cool to -78° C. Add dropwise, a solution of potassium bis(trimethylsilyl)amide (3.6 mL, 0.5 M in toluene, 1.8 mmol). After 30 minutes, add fur-2-ylmethyl 2-methanesulfonylethyl ether (1.8 mmol). Warm to ambient temperature and heat to reflux. After 18 hours, cool to ambient temperature and add water. Separate the organic layer and extract the aqueous layer with dichloromethane. Dry the combined organic layers over Na2SO4, filter, and evaporate in vacuo to give 1-ethoxycarbonyl-4-(1-(2-(fur-2-ylmethoxy)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepane.
Reaction SMILES: [CH3:1][CH:2]([CH3:36])[CH2:3][C@@H:4]([C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27])[C:5]([CH2:23][CH:24]=[CH2:25])([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7].[OH-].[Na+].OO.C(O)(=O)CC(CC(O)=O)(C(O)=O)[OH:44]>C(OCC)C.O>[OH:44][CH2:25][CH2:24][CH2:23][C:5]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])([C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7])[C@H:4]([C:26]([O:28][CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)=[O:27])[CH2:3][CH:2]([CH3:36])[CH3:1]
Reactant: C=CCC(C(=O)OCc1ccccc1)(C(=O)OC(C)(C)C)[C@@H](CC(C)C)C(=O)OCc1ccccc1
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Product: CC(C)C[C@@H](C(=O)OCc1ccccc1)C(CCCO)(C(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 2.47 g of 1,2-dibenzyl 1-tert.butyl 4-methyl-1-(prop-2-en-1-yl)-1,1,2(R)-pentanetricarboxylate in 5 ml of dry diethyl ether was cooled to 0° and 0.325 ml of monochloroborane-methyl sulphide complex was added. The mixture was stirred at room temperature for 2 hours, then cooled to 0° and 0.5 ml of water, 2.3 ml of 1.5M aqueous sodium hydroxide solution and 2.3 ml of 30% aqueous hydrogen peroxide were added. The mixture was stirred at room temperature for 3 hours and then acidified with 5% aqueous citric acid solution. The product was extracted with diethyl ether and the extract was washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate and evaporated. The residue was purified by flash chromatography on silica gel using hexane/ethyl acetate (5:1) for the elution. There were obtained 1.098 g of 1,2-dibenzyl 1-tert.butyl 1-(3-hydroxypropyl)-4-methyl-1,1,2(R)-pentanetricarboxylate in the form of a colorless oil; MS: 513 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:13])[CH:8]=2)[N:3]=1.C(N(CC)CC)C.[C:21]([O:25][C:26]([NH:28][C@@H:29]1[CH2:34][CH2:33][CH2:32][CH2:31][C@@H:30]1[NH2:35])=[O:27])([CH3:24])([CH3:23])[CH3:22]>C(Cl)Cl>[Cl:1][C:2]1[N:11]=[C:10]([NH:35][C@H:30]2[CH2:31][CH2:32][CH2:33][CH2:34][C@H:29]2[NH:28][C:26](=[O:27])[O:25][C:21]([CH3:23])([CH3:22])[CH3:24])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:13])[CH:8]=2)[N:3]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCC[C@@H]1N
Reactant: Cc1ccc2nc(Cl)nc(Cl)c2c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc2nc(Cl)nc(N[C@H]3CCCC[C@H]3NC(=O)OC(C)(C)C)c2c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 94.2 %

Procedure:
To a solution of 4.80 g of 2,4-dichloro-6-methylquinazoline in 100 ml of methylene chloride, 9.12 g of triethylamine and 5.31 g of (1S,2R)-2-(t-butoxycarbonylamino)cyclohexylamine were added, and then the mixture was stirred at room temperature for 24 hours. The reaction solution was concentrated, mixed with water, extracted with methylene chloride and then dried. The solvent was distilled off and the residue was purified by silica gel column chromatography (chloroform:methanol=20:1) to obtain 8.30 g of the desirable compound.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:14]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:16]=1)[O:7][CH2:8][CH:9]1[CH2:13][CH2:12][CH2:11][NH:10]1)([O-:3])=[O:2].C=O.[BH3-][C:24]#N.[Na+].CC(O)=O>CC#N>[CH3:24][N:10]1[CH2:11][CH2:12][CH2:13][CH:9]1[CH2:8][O:7][C:6]1[CH:14]=[C:15]([C:17]([F:20])([F:18])[F:19])[CH:16]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1
Reactant: [BH3-]C#N
Reactant: O=[N+]([O-])c1cc(OCC2CCCN2)cc(C(F)(F)F)c1
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Product: CN1CCCC1COc1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Reaction time: 0.75 h

Procedure:
2-(3-Nitro-5-trifluoromethyl-phenoxymethyl)-pyrrolidine (6 mmol) was dissolved in CH3CN (20 mL) and formaldehyde (2.4 mL, 37% aqueous) was added. NaBH3CN (607 mg) was added, an exotherm was observed. The pH is monitored every 15 min and adjusted to ˜7 with AcOH. After 45 min, the mixture was concentrated in vacuo and the residue is dissolved in EtOAc, washed with 6N NaOH, 1N NaOH, and 2N HCl (3×). The acid washings were combined, adjusted to ˜pH 10 with solid Na2CO3 and extracted with EtOAc (2×) The EtOAc fractions were combined, dried with Na2SO4, and purified with flash chromatography (SiO2, 95:5:0.5 CH2Cl2:MeOH:NH4OH) to afford 1-methyl-2-(3-nitro-5-trifluoromethyl-phenoxymethyl)-pyrrolidine.
Reaction SMILES: [N:1]1[O:2][N:3]=[C:4]2[CH:9]=[C:8]([C:10]([OH:12])=O)[CH:7]=[CH:6][C:5]=12.CN([C:16]([O:20][N:21]1N=NC2C=CC=N[C:22]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN>C(Cl)Cl.O>[CH3:16][O:20][N:21]([CH3:22])[C:10]([C:8]1[CH:7]=[CH:6][C:5]2=[N:1][O:2][N:3]=[C:4]2[CH:9]=1)=[O:12]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: O=C(O)c1ccc2nonc2c1
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: ClCCl
Product: CON(C)C(=O)c1ccc2nonc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 79.2 %

Procedure:
To a stirred solution of benzo[c][1,2,5]oxadiazole-5-carboxylic acid (0.49 g, 2.987 mmol) in DCM (50 mL) were added HATU (1.7 g, 4.481 mmol), N-methoxy, N-methylamine (0.44 g, 4.481 mmol) and TEA (914 mg, 8.963 mmol) at RT under a nitrogen atmosphere. The reaction mixture was then stirred at RT for 3 h, diluted with water and the aqueous layer was extracted with DCM (3×50 mL). The combined organic extracts were washed with water (50 mL) and brine (20 mL), dried over anhydrous Na2SO4, filtered, and evaporated under reduced pressure to afford N-methoxy-N-methylbenzo[c][1,2,5]oxadiazole-5-carboxamide (0.49 g, 79%) as a yellow oil.