Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:9])[CH2:3][CH2:4][C:5](OC)=[O:6].[NH2:10][NH2:11]>C(O)C>[NH2:10][NH:11][C:5](=[O:6])[CH2:4][CH2:3][N:2]([CH3:9])[CH3:1]
Reactant: NN
Reactant: COC(=O)CCN(C)C
Solvent: CCO
Product: CN(C)CCC(=O)NN

Procedure:
To a solution of methyl 3-(dimethylamino)propanoate (1.0 g, 7.62 mmol) in 1 mL of anhydrous ethanol was added anhydrous hydrazine (0.370 mL, 7.62 mmol). The solution was heated to reflux temperature overnight. The solvent was then removed under reduced pressure. (quantitative yield): 1H NMR (CDCl3) δ 9.49 (br s, 1H), 3.88 (br s, 2H), 2.53–2.52 (m, 2H), 2.44–2.36 (m, 2H), 2.24 (s, 6H); ES-MS (m/z) 132 [M+H]+.
Reaction SMILES: [C:1]([C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][N:5]=1)([OH:3])=[O:2].Cl.[CH3:14]O>>[CH3:14][O:2][C:1]([C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][N:5]=1)=[O:3]
Reactant: CO
Reactant: O=C(O)c1n[nH]c2ccccc12
Agent: Cl
Product: COC(=O)c1n[nH]c2ccccc12

Procedure:
A solution of 3-carboxyindazole (2.0 g; 12.3 mmol) and conc.HCl (2 mL) in MeOH (50 mL) was heated at reflux overnight, concentrated, diluted with 2N NaOH (aq), and extracted with EtOAc. The extracts were rinsed with brine, dried (MgSO4), and concentrated to provide the desired product.
Reaction SMILES: [Br:1][C:2]1[C:6]([C:7]#[N:8])=[C:5](Br)[S:4][C:3]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11].C(=O)([O-])[O-].[Cs+].[Cs+].[OH:21][CH2:22][CH:23]1[O:28][CH2:27][CH2:26][NH:25][CH2:24]1.O1CCCC1>O>[Br:1][C:2]1[C:6]([C:7]#[N:8])=[C:5]([N:25]2[CH2:26][CH2:27][O:28][CH:23]([CH2:22][OH:21])[CH2:24]2)[S:4][C:3]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)c1sc(Br)c(C#N)c1Br
Reactant: OCC1CNCCO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1sc(N2CCOC(CO)C2)c(C#N)c1Br
Temperature: 90 °C
Reaction time: 4 h
Yield: 41 %

Procedure:
Ethyl 3,5-dibromo-4-cyanothiophene-2-carboxylate (0.360 g, 1.06 mmol), cesium carbonate (1.05 g, 3.21 mmol), 2-hydroxymethylmorpholine (137 mg, 1.17 mmol), and tetrahydrofuran (4.5 mL, 36 mmol) were combined in a 15 mL pressure vessel equipped with a stir bar. The vessel was sealed, and the r×n was heated @ 90° C. with stirring for 4 hours. The reaction was cooled to rt. The r×n was poured into water/saline. The reaction vessel was washed out with additional water, then ethyl acetate, and these were added to the quench which was then transferred to a separatory funnel. The aqueous layer was extracted 3× with EtOAc. The extracts were combined, washed with saline, dried over Na2SO4, filtered, added Celite, concentrated in vacuo, and dried on high vac 30 min. Purified dry load via silica gel chromatography (gradient elution: 0-60% EtOAc/hexanes) to give 163 mg solid (41% yield). 1H NMR (400 MHz, DMSO) δ 4.91 (t, J=5.7 Hz, 1H), 4.25 (q, J=7.1 Hz, 2H), 3.99-3.92 (m, 3H), 3.69-3.58 (m, 2H), 3.50 (dt, J=10.5, 5.2 Hz, 1H), 3.41 (dt, J=11.5, 5.8 Hz, 1H), 3.37-3.27 (m, 1H, under H2O peak), 3.15-3.08 (m, 1H), 1.26 (t, J=7.1 Hz, 3H).
Reaction SMILES: [NH2:1][CH:2]([C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[C:11]([Cl:16])[CH:10]=1)[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH2:17]([O:24][CH2:25][CH:26]([NH:30][C:31]([O:33][CH2:34][CH2:35][NH:36][C:37]1[CH:42]=[CH:41][CH:40]=[C:39]([CH3:43])[N:38]=1)=[O:32])[C:27](O)=[O:28])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH2:17]([O:24][CH2:25][CH:26]([NH:30][C:31]([O:33][CH2:34][CH2:35][NH:36][C:37]1[CH:42]=[CH:41][CH:40]=[C:39]([CH3:43])[N:38]=1)=[O:32])[C:27]([NH:1][CH:2]([C:9]1[CH:10]=[C:11]([Cl:16])[CH:12]=[C:13]([Cl:15])[CH:14]=1)[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])=[O:28])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CCOC(=O)CC(N)c1cc(Cl)cc(Cl)c1
Reactant: Cc1cccc(NCCOC(=O)NC(COCc2ccccc2)C(=O)O)n1
Product: CCOC(=O)CC(NC(=O)C(COCc1ccccc1)NC(=O)OCCNc1cccc(C)n1)c1cc(Cl)cc(Cl)c1

Procedure:
Analogously to Example 2, ethyl 3-amino-3-(3,5-dichlorophenyl)propionate is reacted with 3-benzyloxy-2-[2-(6-methylpyridin-2-ylamino)ethoxycarbonylamino]propionic acid and purified by chromatography, giving ethyl 3-{3-benzyloxy-2-[2-(6-methylpyridin-2-ylamino)ethoxycarbonylamino]-propanoylamino}-3-(3,5-dichlorophenyl)propionate, RT 1.765 min, FAB-MS (M+H)+ 618.
Reaction SMILES: CN(C)[CH:3]=[C:4]1[CH2:10][CH2:9][CH2:8][CH2:7][CH:6]([C:11]([O:13][CH3:14])=[O:12])[C:5]1=O.[N+]([O-])(O)=O.[N+]([O-])(O)=O.[CH3:25][O:26][C:27]1[CH:28]=[C:29]([NH:39][C:40]([NH2:42])=[NH:41])[CH:30]=[CH:31][C:32]=1[N:33]1[CH:37]=[C:36]([CH3:38])[N:35]=[CH:34]1>>[CH3:25][O:26][C:27]1[CH:28]=[C:29]([NH:39][C:40]2[N:42]=[CH:3][C:4]3[CH2:10][CH2:9][CH2:8][CH2:7][CH:6]([C:11]([O:13][CH3:14])=[O:12])[C:5]=3[N:41]=2)[CH:30]=[CH:31][C:32]=1[N:33]1[CH:37]=[C:36]([CH3:38])[N:35]=[CH:34]1
Reactant: COC(=O)C1CCCCC(=CN(C)C)C1=O
Reactant: COc1cc(NC(=N)N)ccc1-n1cnc(C)c1
Solvent: O=[N+]([O-])O
Product: COC(=O)C1CCCCc2cnc(Nc3ccc(-n4cnc(C)c4)c(OC)c3)nc21

Procedure:
The title compound was prepared from crude methyl 3-[1-dimethylamino-methylidene]-2-oxo-cycloheptanecarboxylate (85 mg, 0.38 mmol) and N-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-guanidine dinitrate (83 mg, 0.22 mmol) using in analogous manner the procedure described in example 45b). Obtained as a pale-yellow oil (7 mg, 8%). MS ISP (m/e): 408.5 [(M+H)+].
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.C([Li])CCC.[Cl:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]I>C1COCC1>[Cl:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:2]1[S:1][CH:5]=[CH:4][CH:3]=1
Reactant: ClCCCCCCI
Reactant: c1ccsc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: ClCCCCCCc1cccs1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.7 %

Procedure:
To a stirred solution of thiophene (5.0 g, 59.5 mmol) in dry THF (50 ml) is added n-butyllithium (2.5 M in hexanes, 20.0 ml, 50.0 mmol) dropwise at −78° C. under nitrogen. After complete addition, the mixture is allowed to warm to room temperature, with stirring, over 2 h, followed by the addition of 1-chloro-6-iodohexane (12.3 g, 50.0 mmol). The resultant mixture is stirred overnight at room temperature. The reaction is quenched with sat. aq. ammonium chloride, and the reaction mixture is extracted with ethyl acetate (3×70 ml). The combined organic extracts are washed with water, brine, and dried over magnesium sulphate. The solvent is removed under reduced pressure and the residue is chromatographed (silica gel, petroleum ether), to give a pale yellow oil (9.3 g, 92%). 1H NMR (300 MHz, CDCl3): δ (ppm) 7.06 (dd, J=5.1 Hz, 1.2 Hz, 1H, Ar—H), 6.87 (dd, J=5.1 Hz, 3.4 Hz, 1H, Ar—H), 6.75 (m, 1H, Ar—H), 3.48 (t, J=6.6 Hz, 2H, ClCH2), 2.80 (t, J=7.4 Hz 2H, ArCH2), 1.61-1.78 (m, 4H, CH2), 1.29-1.50 (m, 4H, CH2); 13C NMR (75 MHz, CDCl3): δ (ppm) 145.5 (quat.), 126.7 (CH), 124.1 (CH), 122.9 (CH), 45.1 (CH2), 32.6 (CH2), 31.7 (CH2), 29.9 (CH2), 28.4 (CH2) 26.7 (CH2); MS (m/e) 204 (M+, 9%), 202 (M+, 3%), 97 (100).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH2:11][C:10]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=2)([OH:14])[CH2:9]1)C1C=CC=CC=1.Cl>CO.[Pd]>[CH3:22][O:21][C:17]1[CH:16]=[C:15]([C:10]2([OH:14])[CH2:11][CH2:12][CH2:13][NH:8][CH2:9]2)[CH:20]=[CH:19][CH:18]=1
Reactant: COc1cccc(C2(O)CCCN(Cc3ccccc3)C2)c1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: COc1cccc(C2(O)CCCNC2)c1
Reaction time: 8 h

Procedure:
32.41 g of 1-benzyl-3-(3-methoxy-phenyl)-piperidine-3-ol were dissolved in methanol and adjusted to pH 6 with 12.4 g of 32% HCl solution. 3.3 g Pd/C 10% (in cooled methanol) were added under a nitrogen atmosphere. The mixture was hydrogenated overnight at 5 bar H2 pressure. The catalyst was then removed via a filter earth and the filtrate was concentrated by evaporation. The oily residue was taken up in H2O, made alkaline with NaOH, and extracted three times with diethyl ether. The combined organic phases were dried over MgSO4 and concentrated by evaporation. Yield 20.92 g
Reaction SMILES: Br[CH2:2][C:3]1([CH3:16])[CH2:7][C:6]2[C:8]([CH3:15])=[C:9]([NH2:14])[C:10]([CH3:13])=[C:11]([CH3:12])[C:5]=2[O:4]1.[NH:17]1[CH2:22][CH2:21][CH:20]([CH2:23][CH2:24][OH:25])[CH2:19][CH2:18]1>>[NH2:14][C:9]1[C:10]([CH3:13])=[C:11]([CH3:12])[C:5]2[O:4][C:3]([CH2:2][N:17]3[CH2:22][CH2:21][CH:20]([CH2:23][CH2:24][OH:25])[CH2:19][CH2:18]3)([CH3:16])[CH2:7][C:6]=2[C:8]=1[CH3:15]
Reactant: Cc1c(C)c2c(c(C)c1N)CC(C)(CBr)O2
Reactant: OCCC1CCNCC1
Product: Cc1c(C)c2c(c(C)c1N)CC(C)(CN1CCC(CCO)CC1)O2
Yield: 88 %

Procedure:
Using 2-bromomethyl-2,3-dihydro-2,4,6,7-tetramethyl-5-benzofuranamine and 4-piperidineethanol, the procedure of Example 1, presented hereinafter, was otherwise repeated to provide the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][C:18](I)=[CH:17][CH:16]=1.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14]([C:15]1[CH:20]=[CH:19][C:18]([C:28]2[CH:29]=[CH:30][C:25]([O:24][CH3:23])=[CH:26][CH:27]=2)=[CH:17][CH:16]=1)=[O:22]
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(I)cc1
Reactant: COc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1ccc(-c2ccc(C(=O)NCCc3c[nH]c4ccc(Cl)cc34)cc2)cc1
Yield: 66 %

Procedure:
N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4′-methoxybiphenyl-4-carboxamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4-iodobenzamide (0.075 g; 0.176 mmol), 4-methoxyphenylboronic acid (0.028 g; 0.180 mmol), tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodium carbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1 mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flash chromatography on silica gel (eluent 2 to 20% ethyl acetate in dichloromethane) furnished 0.047 g (66%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4′-methoxybiphenyl-4-carboxamide as a white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][CH:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16](=[O:24])[NH:17][C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[CH:12][C:11]=1Br)[CH3:9])([CH3:4])([CH3:3])[CH3:2].[C:27]([CH2:30][CH2:31][C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=1)([OH:29])=[O:28]>COCCOC.CCO.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C:6]([NH:7][CH:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16](=[O:24])[NH:17][C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[CH:12][C:11]=1[C:34]1[CH:35]=[CH:36][CH:37]=[C:32]([CH2:31][CH2:30][C:27]([OH:29])=[O:28])[CH:33]=1)[CH3:9])=[O:26])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(NC(=O)OC(C)(C)C)c1ccc(C(=O)Nc2ccncc2)cc1Br
Reactant: O=C(O)CCc1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Solvent: CCO
Product: CC(NC(=O)OC(C)(C)C)c1ccc(C(=O)Nc2ccncc2)cc1-c1cccc(CCC(=O)O)c1
Temperature: 160 °C

Procedure:
To a solution of {1-[2-bromo-4-(pyridine-4-ylcarbamoyl)-phenyl]-ethyl}-carbamic acid tert-butyl ester (3122 μmol) in a mixture of DME/EtOH/2N Na2CO3: 1/1/1 (20 ml) were added 3-carboxyethylphenylboronic acid (1.5 eq) and Pd tetrakis (0.05 eq). The reaction mixture was heated in the microwave at 160° C. for 15 minutes. The reaction mixture was cooled to RT, filtered over celite and washed with EtOAc and MeOH. The solvents were removed under reduced pressure. The compound was purified by column chromatography (silicagel, DCM/MeOH gradient).
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:18]([O:19]C(=O)C)[C@H:17]([O:23][C@H:24]2[O:41][C@H:40]([CH2:42][O:43]C(=O)C)[C@@H:35]([O:36]C(=O)C)[C@H:30]([O:31]C(=O)C)[C@H:25]2[O:26]C(=O)C)[C@@H:16]([CH2:47][O:48]C(=O)C)[O:15][C@H:6]1[S:7][C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=1)(=O)C>CO>[C@H:24]1([O:23][C@@H:17]2[C@@H:16]([CH2:47][OH:48])[O:15][C@@H:6]([S:7][C:8]3[CH:9]=[CH:10][C:11]([NH2:14])=[CH:12][CH:13]=3)[C@H:5]([OH:4])[C@H:18]2[OH:19])[O:41][C@H:40]([CH2:42][OH:43])[C@@H:35]([OH:36])[C@H:30]([OH:31])[C@H:25]1[OH:26]
Reactant: CC(=O)OC[C@H]1O[C@@H](Sc2ccc(N)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1O[C@H]1O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O
Solvent: CO
Product: Nc1ccc(S[C@@H]2O[C@H](CO)[C@@H](O[C@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)[C@H](O)[C@H]2O)cc1

Procedure:
A 3.5 g portion of 4-aminophenyl 2,3,6-tri-O-acetyl-4-O-(2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl)-1-thio-β-D-glucopyranoside was reacted as described in Example 8, giving 1.3 g of the intermediate as a tan solid, [α]D26 =+48°±3° (0.382%, methanol).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][O:8][C:9]1[CH:14]=[CH:13][NH:12][C:11](=[O:15])[CH:10]=1.Br[C:17]1[CH:25]=[C:24]2[C:20]([C:21]3[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][C:22]=3[N:23]2[CH3:26])=[CH:19][CH:18]=1>>[CH3:26][N:23]1[C:24]2[C:20](=[CH:19][CH:18]=[C:17]([N:12]3[CH:13]=[CH:14][C:9]([O:8][CH2:7][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=4)=[CH:10][C:11]3=[O:15])[CH:25]=2)[C:21]2[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][C:22]1=2
Reactant: Cn1c2c(c3ccc(Br)cc31)CCN(C(=O)OC(C)(C)C)C2
Reactant: O=c1cc(OCc2ccccn2)cc[nH]1
Product: Cn1c2c(c3ccc(-n4ccc(OCc5ccccn5)cc4=O)cc31)CCN(C(=O)OC(C)(C)C)C2
Yield: 51.4 %

Procedure:
4-(Pyridin-2-ylmethoxy)pyridin-2(1H)-one (138 mg, 0.682 mmol) and tert-butyl 7-bromo-9-methyl-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate (250 mg, 0.68 mmol) were reacted following the procedure of Example 30 (step g) to provide the title compound (170 mg, 51%) as a white foam: 1H NMR (300 MHz, CDCl3) δ 8.63 (d, J=4.1 Hz, 1H), 7.76 (overlapping ddd, J=7.7, 1.7 Hz, 1H), 7.53 (d, J=8.3 Hz, 1H), 7.48 (d, J=7.8 Hz, 1H), 7.33 (d, J=7.4 Hz, 1H), 7.29-7.26 (m overlapping with solvent, 2H), 7.01 (dd, J=8.2, 1.8 Hz, 1H), 6.12-6.07 (m, 2H), 5.19 (s, 2H), 4.63 (s, 2H), 3.74 (br s, 2H), 3.62 (s, 3H), 2.79 (s, 2H), 1.51 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:17]2[C:25]3[C:20](=[C:21]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])[CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18]2)([CH2:15][CH3:16])[CH2:9][CH2:10][C:11](OC)=[O:12])=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:17]2[C:25]3[C:20](=[C:21]([NH:26][S:27]([CH3:30])(=[O:28])=[O:29])[CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18]2)([CH2:9][CH2:10][CH2:11][OH:12])[CH2:15][CH3:16])=[CH:4][CH:3]=1
Reactant: CCC(CCC(=O)OC)(c1ccc(Cl)cc1)n1ccc2c(NS(C)(=O)=O)cccc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CCC(CCCO)(c1ccc(Cl)cc1)n1ccc2c(NS(C)(=O)=O)cccc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of methyl 4-(4-chlorophenyl)-4-(4-(methylsulfonamido)-1H-indol-1-yl)hexanoate (20 mg, 0.045 mmol), as described in Example 44 Step E, in tetrahydrofuran (2 mL) was added lithium aluminium hydride (2.5 mg, 0.0675 mmol) at 0° C. The mixture was gradually warmed to room temperature and stirred for 4 h. Water (1 mL) was carefully added to the reaction mixture, and extracted with ethyl acetate. The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by PREP-TLC eluting with PE/EA (2/1, v/v) to give the title compound as colorless oil. LC/MS m/z=421.0[M+H]+.
Reaction SMILES: ClC(Cl)C(O)=O.N[C:8]1[N:9]([C:28]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[C:31]([CH:38]3[CH2:40][CH2:39]3)=[CH:30][CH:29]=2)[C:10]([S:13][CH2:14][C:15]([NH:17][C:18]2[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][C:19]=2[Cl:27])=[O:16])=[N:11][N:12]=1.N([O-])=O.[Na+].[Br:45]CBr>[Br-].C([N+](CC)(CC)CC)C1C=CC=CC=1>[Br:45][C:8]1[N:9]([C:28]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[C:31]([CH:38]3[CH2:40][CH2:39]3)=[CH:30][CH:29]=2)[C:10]([S:13][CH2:14][C:15]([NH:17][C:18]2[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][C:19]=2[Cl:27])=[O:16])=[N:11][N:12]=1
Reactant: Nc1nnc(SCC(=O)Nc2ccc(C(=O)O)cc2Cl)n1-c1ccc(C2CC2)c2ccccc12
Reactant: BrCBr
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: O=C(O)C(Cl)Cl
Agent: O=N[O-]
Product: O=C(CSc1nnc(Br)n1-c1ccc(C2CC2)c2ccccc12)Nc1ccc(C(=O)O)cc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 34 %

Procedure:
Dichloroacetic acid (0.35 mL, 4.2 mmol) was added to a mixture of compound 6 (1.04 g, 2.1 mmol), benzyltriethyl ammonium bromide (1.65 g, 6.1 mmol) and sodium nitrite (2.9 g, 42.1 mmol) in dibromomethane (44 mL). The mixture was stirred at room temperature for 18 hours in the dark. The reaction mixture was then concentrated and the resulting residue was purified by column chromatography (95% dichloromethane/5% methanol) to afford 393 mg, 34% yield of 4-(2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4H-1,2,4-triazol-3-ylthio)acetamido)-3-chlorobenzoic acid (7).
Reaction SMILES: Cl.Cl.[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]2)=[CH:4]1.[CH:27]1([CH2:31][C:32](N)=[O:33])[CH2:30][CH2:29][CH2:28]1>>[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:21][CH2:22][C@H:23]([NH:26][C:32](=[O:33])[CH2:31][CH:27]3[CH2:30][CH2:29][CH2:28]3)[CH2:24][CH2:25]2)=[CH:4]1
Reactant: NC(=O)CC1CCC1
Reactant: N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1
Agent: Cl
Product: O=C(CC1CCC1)N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1

Procedure:
The title compound, off-white solid (68 mg, 64%), MS (ISP) m/z=423.3 [(M+H)+], mp 173° C., was prepared in accordance with the general method of example 1 from trans-4-[2-(4-benzofuran-3-yl-piperidin-1-yl)-ethyl]-cyclohexylamine dihydrochloride (intermediate A) (100 mg, 0.25 mmol) and 2-cyclobutyl-acetamide.
Reaction SMILES: OS(O)(=O)=O.[CH2:6]=[O:7].[CH3:8][C:9]1[C:18]2([CH2:20][CH2:19]2)[C@:17]([OH:22])([CH3:21])[C:15](=[O:16])[C:14]2[C:10]=1[C@@H:11](O)[C@@:12](CO)([CH3:23])[CH:13]=2>CC(C)=O>[CH3:23][C:12]1[CH:13]=[C:14]2[C:10](=[C:9]([CH3:8])[C:18]3([C@:17]([OH:22])([CH3:21])[C:15]2=[O:16])[CH2:20][CH2:19]3)[C:11]=1[CH2:6][OH:7]
Reactant: C=O
Reactant: CC1=C2C(=C[C@@](C)(CO)[C@@H]2O)C(=O)[C@](C)(O)C12CC2
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Product: CC1=C(CO)C2=C(C)C3(CC3)[C@@](C)(O)C(=O)C2=C1
Temperature: 25 °C
Reaction time: 72 h
Yield: 24.2 %

Procedure:
To a solution of 250 ml of 1M H2SO4 and 200 ml acetone was added 40 g paraformaldehyde (MW 30, 1.33 mol). The solution was heated to clear and was then allowed to cool to room temperature. 1 g illudin S (MW 264, 3.79 mmol) was added to the above solution. The mixture was stirred at room temperature for 72 h and was partitioned between ethyl acetate and water. The organic extracts were washed by saturated NaHCO3 and saline respectively to neutral. After being dried by MgSO4, the solution was concentrated and chromatographed to give 245 mg 14 (23.4%) and 226 mg HMAF (24.3%). 14 is a white crystal: mp 100.5-102.5; IR (KBr) 3469, 2966, 2858, 1703, 1656, 1596, 1172 cm−1; 1H NMR (CDCl3) δ0.48 (m, 1H), 0.84 (m, 1H), 0.99 (m, 1H), 1.10 (s, 3H), 1.17 (m, 1H), 1.32 (s, 3H, 1.67 (s, 3H), 3.61 (s, 1H), 3.73 (d, J=11.7 Hz, 1H), 3.96 (d, J=11.7 Hz, 1H), 4.56 (s, 1H), 4.75 (d, J=5.4 Hz, 1H), 4.91 (d, J=5.4 Hz, 1H), 6.52 (s, 1H), 13C NMR (CDCl3) δ199.7, 141.4, 136.5, 135.9, 134.7, 90.0, 80.3 75.9, 70.8, 46.8, 32.3, 24.7, 22.5, 13.8, 8.9, 5.6; MS m/z 276 (M+), 217, 201, 173; HRMS for C16H20O4 calcd 276.1362, found 276.1364; UV λmax 305 nm (ε 3148).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1[CH:4]=[O:5].[CH:11]1([Mg]Br)[CH2:15][CH2:14][CH2:13][CH2:12]1>C(OCC)(=O)C>[NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1[CH:4]([CH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1)[OH:5]
Reactant: Nc1cccc(Cl)c1C=O
Reactant: Br[Mg]C1CCCC1
Solvent: CCOC(C)=O
Product: Nc1cccc(Cl)c1C(O)C1CCCC1
Yield: 36 %

Procedure:
This compound was prepared using General Method 1 (EXAMPLE 1) from 2-amino-6-chlorobenzaldehyde (0.30 g, 1.9 mmol) and cyclopentylmagnesium bromide (2 M in ether, 1.9 mL)) to afford 0.16 g (36%) of (±)-(2-amino-6-chlorophenyl)-cyclopentyl-methanol after flash chromatography (4:1 hexanes:ethyl acetate).
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[CH:5][C:6]([C@@H:9]2[CH2:11][C@H:10]2[C:12]([OH:14])=O)=[N:7][CH:8]=1.[C:15]([O:19][C:20](=[O:43])[NH:21][C@H:22]([CH2:27][NH:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][Si:36]([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:38])[CH3:37])=[CH:31][CH:30]=1)[C@@H:23]([CH3:26])[CH2:24][CH3:25])([CH3:18])([CH3:17])[CH3:16].C(N(CC)CC)C>S(Cl)(Cl)=O.C(Cl)Cl>[C:15]([O:19][C:20](=[O:43])[NH:21][C@H:22]([CH2:27][N:28]([C:29]1[CH:30]=[CH:31][C:32]([O:35][Si:36]([C:39]([CH3:40])([CH3:42])[CH3:41])([CH3:37])[CH3:38])=[CH:33][CH:34]=1)[C:12]([C@@H:10]1[CH2:11][C@H:9]1[C:6]1[CH:5]=[CH:4][C:3]([F:2])=[CH:8][N:7]=1)=[O:14])[C@@H:23]([CH3:26])[CH2:24][CH3:25])([CH3:17])([CH3:16])[CH3:18]
Reactant: CC[C@H](C)[C@@H](CNc1ccc(O[Si](C)(C)C(C)(C)C)cc1)NC(=O)OC(C)(C)C
Reactant: O=C(O)[C@@H]1C[C@H]1c1ccc(F)cn1
Agent: Cl
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Product: CC[C@H](C)[C@@H](CN(C(=O)[C@@H]1C[C@H]1c1ccc(F)cn1)c1ccc(O[Si](C)(C)C(C)(C)C)cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 83 %

Procedure:
A mixture of trans-2-(5-fluoro-pyridin-2-yl)-cyclopropanecarboxylic acid HCl salt (217 mg, 1 mmol) in thionyl chloride (2 mL) was heated at reflux for over night. The mixture was concentrated and dried under high vacuum for 3 h. Then the residue was dissolved in DCM (4 mL) and added dropwise to a solution of ((1S,2S)-1-{[4-(t-butyl-dimethyl-silanyloxy)-phenylamino]-methyl}-2-methyl-butyl)-carbamic acid tert-butyl ester (422 mg, 1 mmol) and triethyl amine (409 uL, 3 mmol) in DCM (4 mL). The resulting mixture was stirred at rt for overnight. The reaction mixture was concentrated and the residue was subjected to ISCO (40 g column, 0-40% EtOAc in hexane over 40 min.) to give the titled compound (486 mg, 83%). MS (MH+ 586).
Reaction SMILES: [F:1][CH:2]([F:25])[O:3][C:4]1[C:9]2[O:10][C:11]3[C:12](=[O:19])[N:13]([CH2:17][CH3:18])[N:14]=[CH:15][C:16]=3[C:8]=2[C:7]([C:20]([O:22]CC)=[O:21])=[CH:6][CH:5]=1.[OH-].[Na+]>CO>[F:25][CH:2]([F:1])[O:3][C:4]1[C:9]2[O:10][C:11]3[C:12](=[O:19])[N:13]([CH2:17][CH3:18])[N:14]=[CH:15][C:16]=3[C:8]=2[C:7]([C:20]([OH:22])=[O:21])=[CH:6][CH:5]=1
Reactant: CCOC(=O)c1ccc(OC(F)F)c2oc3c(=O)n(CC)ncc3c12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCn1ncc2c(oc3c(OC(F)F)ccc(C(=O)O)c32)c1=O
Yield: 88.9 %

Procedure:
A mixture of ethyl 6-difluoromethoxy-3-ethyl-4-oxo-3,4-dihydrobenzo[4,5]furo[2,3-d]pyridazine-9-carboxylate (from step 1) (120 mg, 0.34 mmol) and sodium hydroxide (20 mg, 0.51 mmol) in methanol (20 ml) was heated to reflux temp. Progress of reaction was monitored by TLC. At the end, reaction mixture was concentrated under vacuum. Then water (50 ml) was added to reaction mixture and acidified with dilute HCl. The precipitate obtained was filtered and dried in oven. 98 mg white colored solid was obtained.
Reaction SMILES: CS(C)=[O:3].[Cl:5][C:6]1[CH:15]=[CH:14][C:9]([C:10](=[O:13])[CH2:11]Br)=[CH:8][CH:7]=1>O>[Cl:5][C:6]1[CH:15]=[CH:14][C:9]([C:10]([CH:11]=[O:3])=[O:13])=[CH:8][CH:7]=1
Reactant: O=C(CBr)c1ccc(Cl)cc1
Reactant: CS(C)=O
Solvent: O
Product: O=CC(=O)c1ccc(Cl)cc1
Yield: 50 %

Procedure:
Dimethyl sulfoxide (60 ml) solution of 4-chlorophenacylbromide (11.11 g, 65.9 mmol) and water (1.7 ml) were stirred. The solution was extracted with ethyl acetate 3 times and washed with water twice and brine and then dried over sodium sulfate. After removal of the solvent, the residue was washed with hexane-ethyl acetate and dried to give 4-chlorophenylglyoxal (4.43 g, 50%).