Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH3:3][S:4][C:5]1[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=2[CH3:18])[C:8]([CH:19]=O)=[C:7]([NH:21][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[N:6]=1.C1C[O:31][CH2:30][CH2:29]1>C(OCC)C>[CH:22]1([N:21]2[C:7]3[N:6]=[C:5]([S:4][CH3:3])[N:10]=[C:9]([C:11]4[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=4[CH3:18])[C:8]=3[CH:19]=[CH:29][C:30]2=[O:31])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: CSc1nc(NC2CCCCC2)c(C=O)c(-c2ccc(F)cc2C)n1
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Product: CSc1nc(-c2ccc(F)cc2C)c2ccc(=O)n(C3CCCCC3)c2n1
Reaction time: 0.5 h
Yield: 19 %

Procedure:
Triethylphosphonoacetate (3.87 mL, 0.01953 mol) in dry THF (56 mL) was treated with NaH (60% in mineral oil) (967.5 mg, 0.0243 mol). The mixture was stirred for 30 min giving a clear solution. The title compound from Example 180 (4.5 g, 0.0125 mol) in dry THF (75 mL) was added in one portion and the solution gently refluxed for 72 h. After cooling to 23°, the reaction mixture was diluted with ethyl ether, then washed in turn with satd aq NH4Cl and H2O. Organic layer was dried (Na2SO4), then evaporated to a viscous syrup which was flash chromatographed in methylene chloride-hexane gradient (20% to 0% hexane) to afford first 920 mg (19%) of the title compound as a white solid. LC MS (m/e)=384 (MH+). Rt=2.79 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](Cl)=[CH:5][CH:4]=1.[F:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17](=[O:20])[CH2:18][CH3:19].C(O[Na])(C)(C)C>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.COC1C=CC=C(N(C)C2C=CC=CC=2)C=1P(C1CCCCC1)C1CCCCC1>[F:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17](=[O:20])[CH:18]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[CH3:19]
Reactant: COc1ccc(Cl)cc1
Reactant: CCC(=O)c1ccccc1F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)O[Na]
Solvent: Cc1ccccc1
Product: COc1ccc(C(C)C(=O)c2ccccc2F)cc1
Yield: 52.2 %

Procedure:
This reaction is carried out in the same manner as the reaction in example 3. The difference is that, the reactants are p-methoxyphenyl chloride (142.3 mg, 1.0 mmol), 1-(2-fluorophenyl)-1-propanone (304.2 mg, 2.0 mmol), palladium acetate (6.8 mg, 0.030 mmol), 2-Methoxy-6-(N-methyl-N-phenyl-amino)phenyl(dicyclohexyl)phosphine (18.4 mg, 0.045 mmol), t-BuONa (192.7 mg, 2.0 mmol) in 3 mL dry toluene at 110° C. for 41.5 h. 1-(2′-Fluorophenyl)-2-(4′-methoxyphenyl)-1-propanon (134.7 mg) was obtained with a yield of 52% as liquid. 1H NMR (300 MHz, CDCl3) δ 7.76-7.68 (m, 1H, ArH), 7.44-7.34 (m, 1H, ArH), 7.20-7.08 (m, 3H, ArH), 7.07-6.98 (m, 1H, ArH), 6.83-6.77 (m, 2H, ArH), 4.57 (q, J=6.9 Hz, 1H, CH), 3.73 (s, 3H, OCH3), 1.52 (d, J=6.9 Hz, 3H, CH3); 13C NMR (75 MHz, CDCl3) δ 199.8 (d, J=3.8 Hz), 160.7 (d, J=251.9 Hz), 158.5, 133.8 (d, J=8.8 Hz), 132.3, 130.9 (d, J=2.8 Hz), 129.1, 126.0 (d, J=12.8 Hz), 124.2 (d, J=3.9 Hz), 116.4 (d, J=23.7 Hz), 114.0, 55.0, 50.9 (d, J=5.9 Hz), 18.8; 19F NMR (282 MHz, CDCl3) 6-100.1; IR (neat) v (cm−1) 3069, 3034, 2974, 2933, 2871, 2836, 1682, 1609, 1582, 1513, 1480, 1451, 1422, 1373, 1324, 1303, 1274, 1254, 1211, 1179, 1153, 1105, 1034, 1005; MS (70 eV, EI) m/z (%): 259 (M++1, 0.99), 258 (M+, 5.49), 135 (100); HRMS calcd for C16H15O2F (M+): 258.1056. Found: 258.1057.
Reaction SMILES: [CH:1](NC(C)C)([CH3:3])[CH3:2].C([Li])CCC.[CH:13]1[C:23]2[CH2:22][CH2:21][C:20]3[CH:24]=[CH:25][CH:26]=[CH:27][C:19]=3[CH:18]([C:28]#[N:29])[C:17]=2[CH:16]=[CH:15][CH:14]=1.C(Br)C=C.Cl>C1COCC1.CCCCCC>[CH2:3]([C:18]1([C:28]#[N:29])[C:19]2[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=2[CH2:21][CH2:22][C:23]2[CH:13]=[CH:14][CH:15]=[CH:16][C:17]1=2)[CH:1]=[CH2:2]
Reactant: N#CC1c2ccccc2CCc2ccccc21
Reactant: CC(C)NC(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C=CCBr
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C=CCC1(C#N)c2ccccc2CCc2ccccc21
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 100 %

Procedure:
Dissolved diisopropylamine (11.07 g, 0.109 mol) in 150 mL of dry THF and cooled to 0° C. under a nitrogen atmosphere. Added 40.1 mL (0.100 mol) of 2.5M n-butyl lithium in hexane dropwise via addition funnel. Stirred at 0° C. for 10 mins then cooled to -78° C. Added 10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-nitrile (20.00 g, 0.0912 mol) dissolved in 100 mL of dry THF dropwise via addition funnel. Stirred at -78° C. for 45 mins. Added allyl bromide (14.34 g, 0.119 mol) via syringe, and allowed reaction mixture to warm slowly to room temperature. Stirred at room temperature for 90 mins. Added 250 mL of 0.5N HCl, and separated layers. Extracted aqueous solution with ethyl acetate. Washed combined organic extracts with saturated NaCl, dried with MgSO4, filtered, and evaporated. Purified crude product by flash chromatography on silica gel eluting with 5% ethyl acetate-hexane then 10% ethyl acetate-hexane. Combined appropriate fractions and evaporated to give 23.65 g (100% yield) of 10,11-dihydro-5-(2-propenyl)-5H-dibenzo[a,d]cyclohepten-5-nitrile.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[CH2:5][CH2:6][C:7]1[CH:12]=[C:11]([C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:16]=2)=[O:14])[CH:10]=[CH:9][C:8]=1[OH:26])[CH3:2].[Br:28][CH2:29][CH2:30][CH2:31][CH2:32]Br>>[CH2:1]([O:3][C:4](=[O:27])[CH2:5][CH2:6][C:7]1[CH:12]=[C:11]([C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:16]=2)=[O:14])[CH:10]=[CH:9][C:8]=1[O:26][CH2:32][CH2:31][CH2:30][CH2:29][Br:28])[CH3:2]
Reactant: BrCCCCBr
Reactant: CCOC(=O)CCc1cc(C(=O)c2cccc(C(=O)OCC)c2)ccc1O
Product: CCOC(=O)CCc1cc(C(=O)c2cccc(C(=O)OCC)c2)ccc1OCCCCBr
Yield: 81.2 %

Procedure:
Starting with 0.388 g (1.05 mmol) of 5-[[3-(ethoxycarbonyl)phenyl]carbonyl]-2-hydroxybenzenepropanoic acid ethyl ester, and 1.81 g (8.38 mmol) of 1,4-dibromobutane, the title compound was obtained as a colorless oil, in 81.2% yield, using the procedure of example 21.
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]1[CH2:12][CH2:11][N:10]([C:13]2[N:21]=[C:20]3[C:16]([N:17]=[CH:18][N:19]3[C@@H:22]3[CH2:26][C@H:25]([N:27]4[CH:31]=[C:30]([CH2:32][CH3:33])[CH:29]=[N:28]4)[C@@H:24]([OH:34])[C@H:23]3[OH:35])=[C:15]([NH:36][CH2:37][CH:38]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[N:14]=2)[CH2:9]1)(C)(C)C.Cl>CO.O1CCOCC1>[NH2:7][C@@H:8]1[CH2:12][CH2:11][N:10]([C:13]2[N:21]=[C:20]3[C:16]([N:17]=[CH:18][N:19]3[C@@H:22]3[CH2:26][C@H:25]([N:27]4[CH:31]=[C:30]([CH2:32][CH3:33])[CH:29]=[N:28]4)[C@@H:24]([OH:34])[C@H:23]3[OH:35])=[C:15]([NH:36][CH2:37][CH:38]([C:45]3[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=3)[C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=3)[N:14]=2)[CH2:9]1
Reactant: CCc1cnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(N5CC[C@@H](NC(=O)OC(C)(C)C)C5)nc43)[C@H](O)[C@@H]2O)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CCc1cnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(N5CC[C@@H](N)C5)nc43)[C@H](O)[C@@H]2O)c1
Temperature: 25 °C

Procedure:
((R)-1-{6-(2,2-diphenyl-ethylamino)-9-[(1R,2S,3R,4S)-4-(4-ethyl-pyrazol-1-yl)-2,3-dihydroxy-cyclopentyl]-9H-purin-2-yl}-pyrrolidin-3-yl)-carbamic acid tert-butyl ester (first step a) (9.75 g, 14 mmol) is dissolved in methanol (2 ml). (4M) HCl in 1,4-dioxane (15 ml) is added and the reaction mixture is stirred at room temperature over night. The compound is purified by reverse phase column chromatography (Isolute™ C18, 0-100% MeCN in water—0.1% HCl). The compound is partitioned between DCM and saturated NaHCO3(aq). The organics are dried (MgSO4), filtered and reduced in vacuo to yield the title compound. MS (ES+) m/e 594.31 (MH+).
Reaction SMILES: [C:1]([C:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[O:11][C:10]=1[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH:26]2[O:28][CH2:27]2)=[CH:20][CH:19]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:29]([NH2:32])([CH3:31])[CH3:30]>>[C:1]([C:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[O:11][C:10]=1[C:18]1[CH:19]=[CH:20][C:21]([O:24][CH2:25][CH:26]([OH:28])[CH2:27][NH:32][CH:29]([CH3:31])[CH3:30])=[CH:22][CH:23]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)N
Reactant: O=C(c1ccccc1)c1c(-c2ccc(OCC3CO3)cc2)oc2ccccc12
Product: CC(C)NCC(O)COc1ccc(-c2oc3ccccc3c2C(=O)c2ccccc2)cc1

Procedure:
3-Benzoyl-2-[4'-(2,3-epoxypropoxy)phenyl]benzofuran (1.9 g., 5.2 mmol.) was dissolved in 30 ml. of freshly distilled isopropylamine and the mixture was heated in a stainless steel pressure bomb at 100° for 4.5 hours. The contents of the bomb were concentrated under reduced pressure to give the title compound. The title compound was dissolved in ether and an ethereal solution of hydrochloric acid was added to precipitate the corresponding hydrochloride salt, m.p. 53°-59°.
Reaction SMILES: [C:1]([N:9]1[CH2:17][C@@H:16]([OH:18])[CH2:15][C@H:10]1[C:11]([O:13][CH3:14])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19]1([CH3:29])[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1.C(OCC)(=O)C>N1C=CC=CC=1>[C:1]([N:9]1[CH2:17][C@@H:16]([O:18][S:25]([C:22]2[CH:23]=[CH:24][C:19]([CH3:29])=[CH:20][CH:21]=2)(=[O:27])=[O:26])[CH2:15][C@H:10]1[C:11]([O:13][CH3:14])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)[C@@H]1C[C@H](O)CN1C(=O)c1ccccc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: COC(=O)[C@@H]1C[C@H](OS(=O)(=O)c2ccc(C)cc2)CN1C(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A solution of (cis)-1-benzoyl-4-hydroxy-L-proline, methyl ester (1.9 g, 7.63 mmole) in pyridine (6 ml) was stirred under argon and treated with p-toluenesulfonyl chloride (1.75 g, 9.16 mmole). The reaction was stirred overnight, treated with additional p-toluenesulfonyl chloride (0.145 g, 0.76 mmole) and stirred for 24 hours. Ice water was added followed by ethyl acetate. The organic layer was washed with 1N HCl, brine, and dried. Filtration and concentration in vacuo afforded the title compound as a foam which was used without purification in the subsequent step.
Reaction SMILES: [N+:1]([C:4]1[C:12]2[N:11]=[CH:10][N:9]([CH2:13][C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)[C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl.Cl[CH2:22][C:23]1C2C(=CC=CC=2)N=[CH:25][CH:24]=1>>[N+:1]([C:4]1[C:12]2[N:11]=[CH:10][N:9]([CH2:13][C:14]3[C:19]4[C:18](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:17]=[CH:16][CH:15]=3)[C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cccc2c1ncn2Cc1ccncc1
Reactant: ClCc1ccnc2ccccc12
Agent: Cl
Product: O=[N+]([O-])c1cccc2c1ncn2Cc1ccnc2ccccc12

Procedure:
Compound 4a was synthesized in the same manner as compound 3c using 4-chloromethylquinoline hydrochloride instead of 4-chloromethylpyridine hydrochloride.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH2:8][CH:7]([CH2:10][CH2:11][C:12]([OH:14])=[O:13])[C:6]=2[CH:15]=1.[Mg]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]=[C:7]([CH2:10][CH2:11][C:12]([OH:14])=[O:13])[C:6]=2[CH:15]=1
Reactant: O=C(O)CCC1COc2ccc(F)cc21
Agent: [Mg]
Product: O=C(O)CCc1coc2ccc(F)cc12

Procedure:
The title compound was-prepared from 3-(5-fluorobenzofuran-3-yl) propionic acid (3 g) and spiro(isobenzofuran-1(3H),4′-piperidine] (2 g) by the method described in EXAMPLE 12. 3-(5-Fluoro-benzofuran-3-yl)-propionic acid was prepared by a procedure similar to the preparation of 3-(2,3-dihydro-5-fluorobenzofuran-3-yl)-propionic acid as described in EXAMPLE 11, but omitting the reduction with magnesium turnings. The title compound, 8, crystallized as the oxalate salt from acetone by addition of oxalic acid. Yield: 2.6 g, mp: 157-59° C.
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:11]([OH:12])=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[CH:6][N:7]2[S:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=[O:15])=[O:14]>C(Cl)Cl.[O-2].[O-2].[Mn+4]>[OH:12][C:11]1[CH:10]=[CH:9][C:8]2[N:7]([S:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)(=[O:15])=[O:14])[CH:6]=[CH:5][C:4]=2[C:3]=1[CH:2]=[O:1]
Reactant: O=S(=O)(c1ccccc1)n1ccc2c(CO)c(O)ccc21
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: O=Cc1c(O)ccc2c1ccn2S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 45.8 %

Procedure:
4-(Hydroxymethyl)-1-(phenylsulfonyl)-1H-indol-5-ol (Intermediate 9, 439 mg, 1.45 mmol) was dissolved in dry DCM (25 mL) and manganese dioxide (0.75 g, 8.7 mmol) was added all in one portion. The reaction mixture was stirred for 2 hours at room temperature and the mixture was filtered through a pad of silica gel. The filtrate was washed with water (1×), dried (MgSO4) and evaporated to give 0.2 g of an orange solid. MS m/z 302 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[NH:7][CH2:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:21][CH3:22])=[CH:16][C:17]=2[O:19][CH3:20])[C:12]([NH:23][C:24]([NH2:26])=[S:25])=[CH:11][N:10]=1)([CH3:4])([CH3:3])[CH3:2].Cl[CH2:29][C:30](=O)[CH3:31].[O-]S([O-])(=O)=O.[Mg+2]>CC(C)=O>[C:1]([O:5][C:6](=[O:27])[NH:7][CH2:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:21][CH3:22])=[CH:16][C:17]=2[O:19][CH3:20])[C:12]([NH:23][C:24]2[S:25][CH:29]=[C:30]([CH3:31])[N:26]=2)=[CH:11][N:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cc(OC)c2c(CNC(=O)OC(C)(C)C)ncc(NC(N)=S)c2c1
Reactant: CC(=O)CCl
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CC(C)=O
Product: COc1cc(OC)c2c(CNC(=O)OC(C)(C)C)ncc(Nc3nc(C)cs3)c2c1
Temperature: 60 °C
Reaction time: 4.5 h

Procedure:
To solution of (6,8-dimethoxy-4-thioureido-isoquinolin-1-ylmethyl)carbamic acid tert-butyl ester (50 mg, 0.127 mmol) and chloroacetone (16.1 mg, 0.166 mmol) in acetone (1.4 mL) was added MgSO4 (7.7 mg, 0.0637 mmol). The resulting suspension was stirred at 60° C. and for 4.5 h. The reaction was cooled and concentrated. The residue passed through a 5 g silica cartridge, eluting with 2% MeOH in DCM, to give [6,8-dimethoxy-4-(4-methyl-thiazol-2-ylamino)isoquinolin-1-ylmethyl]carbamic acid tert-butyl ester as a yellow solid (21.3 mg; 39%). 1H-NMR (CDCl3): δ, 8.59 (s, 1H), 7.00 (s, 1H), 6.76 (s, 1H), 6.61 (d, 1H, J=2.2 Hz), 6.13 (s, 1H), 5.05 (d, 2H, J=4.3 Hz), 3.99 (s, 3H), 3.92 (s, 3H), 2.32 (s, 3H), 1.51 (s, 9H); MS: calculated for C21H26N4O4S+H 431.0; found: 431.0.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:25]=3[NH:24][CH:23]=[C:22]4[CH2:26][CH2:27][CH:28]=O)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[NH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:25]=3[NH:24][CH:23]=[C:22]4[CH2:26][CH2:27][CH2:28][NH:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:10])[CH3:11]
Reactant: CCOC(=O)CN
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c(CCC=O)c[nH]c34)no2)cc1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCOC(=O)CNCCCc1c[nH]c2c(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)cccc12
Temperature: 20 °C
Reaction time: 2 h
Yield: 82.5 %

Procedure:
To a stirred solution of 3-[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indol-3-yl]propanal (D92) (100 mg), ethyl glycinate (50 mg) and acetic acid (5 mg) in DCM (15 mL) was added sodium triacetoxyborohydride (52 mg). The reaction mixture was stirred at 20° C. for 2 h. The reaction mixture was partitioned between DCM (25 mL) and water (25 mL). The organic phase was washed with water, dried over sodium sulphate and evaporated in vacuo to afford the crude product ethyl N-{3-[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indol-3-yl]propyl}glycinate (D93) (100 mg), which was used directly in the next step. MS (ES): C26H29ClN4O4 requires 496; found 497.2 (M+H+).
Reaction SMILES: [NH2:1][C@@H:2]1[C:7]2[CH:8]=[C:9]([C:12]#[N:13])[CH:10]=[CH:11][C:6]=2[O:5][C:4]([CH3:15])([CH3:14])[C@H:3]1[OH:16].[CH:17]1[C:29]2[C:28](=[CH:30][C:31](O)=[O:32])[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]=2[CH:20]=[CH:19][CH:18]=1>>[C:12]([C:9]1[CH:10]=[CH:11][C:6]2[O:5][C:4]([CH3:14])([CH3:15])[C@@H:3]([OH:16])[C@H:2]([NH:1][C:31](=[O:32])[CH:30]=[C:28]3[C:29]4[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=4[C:22]4[C:27]3=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:7]=2[CH:8]=1)#[N:13]
Reactant: CC1(C)Oc2ccc(C#N)cc2[C@@H](N)[C@@H]1O
Reactant: O=C(O)C=C1c2ccccc2-c2ccccc21
Product: CC1(C)Oc2ccc(C#N)cc2[C@@H](NC(=O)C=C2c3ccccc3-c3ccccc32)[C@@H]1O

Procedure:
The title compound was prepared from (3S-trans)-4-amino-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile (the title B compound of Example 1) and 2-(9H-fluoren-9-ylidene)acetic acid by the same method as described for the title compound of Example 2. The product was obtained as a light yellow solid, m.p. >300° C.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][C@H:9]([C:14]([OH:16])=O)[C:10]([CH3:13])([CH3:12])[CH3:11])=[O:7])([CH3:4])[CH3:3].[C@H:17]12[CH2:23][C@H:20]([NH:21][CH2:22]1)[CH2:19][N:18]2[C:24]([C:26]1[NH:30][C:29]2[CH:31]=[CH:32][CH:33]=[CH:34][C:28]=2[N:27]=1)=[O:25].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>C(Cl)Cl.O>[NH:27]1[C:28]2[CH:34]=[CH:33][CH:32]=[CH:31][C:29]=2[N:30]=[C:26]1[C:24]([N:18]1[CH2:19][C@@H:20]2[CH2:23][C@H:17]1[CH2:22][N:21]2[C:14]([C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:2]([CH3:1])([CH3:3])[CH3:4])[C:10]([CH3:11])([CH3:12])[CH3:13])=[O:16])=[O:25]
Reactant: O=C(c1nc2ccccc2[nH]1)N1C[C@@H]2C[C@H]1CN2
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)O)C(C)(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N[C@H](C(=O)N1C[C@@H]2C[C@H]1CN2C(=O)c1nc2ccccc2[nH]1)C(C)(C)C
Yield: 99.1 %

Procedure:
A solution of N-{[(1,1-dimethylethyl)oxy]carbonyl}-3-methyl-L-valine (3 g, 13 mmol) (2-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-ylcarbonyl]-1H-benzimidazole (3 g, 12.4 mmol), EDC (2.8 g, 14.8 mmol), HOBt (334 mg, 2.5 mmol), NMM (3.7 g, 37.1 mmol) in CH2Cl2 (50 mL) was stirred at room temperature for 18 h. The reaction was diluted with water and CH2Cl2 then washed with sat. NaHCO3 (50 mL) and brine (50 mL). The solution was dried over anhydrous Na2SO4 and concentrated to give the title compound (5.6 g) as a pale yellow solid. LCMS (m/z): 456.3 (M+H).
Reaction SMILES: [OH:1][C:2]1[C:3]([C:12]([NH:14][NH2:15])=[O:13])=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH:16](=O)[C:17]1[O:21][CH:20]=[CH:19][CH:18]=1>CO>[OH:1][C:2]1[C:3]([C:12]([NH:14][N:15]=[CH:16][C:17]2[O:21][CH:20]=[CH:19][CH:18]=2)=[O:13])=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: NNC(=O)c1cc2ccccc2cc1O
Reactant: O=Cc1ccco1
Solvent: CO
Product: O=C(NN=Cc1ccco1)c1cc2ccccc2cc1O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A four neck flask (2 liters) equipped with a thermometer, a reflux condenser and a stirrer was charged with 101 g (0.5 mol) of 3-hydroxy-2-naphthohydrazide and 1.5 liter of methanol, and 57.6 g (0.6 mol) of furfural was dropwise added thereto in 30 minutes while stirring at room temperature. After heating under reflux for 5 hours, the reaction liquid was cooled down to 20° C. or lower, and crystal was filtered off. The crystal was washed with a small amount of methanol and then dried under reduced pressure, whereby the intended compound (slightly yellow crystal) was obtained.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[NH:25][C:24]([C@@H:26]5[CH2:30][CH2:29][CH2:28][N:27]5[C:31]([O:33][CH2:34][C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=5)=[O:32])=[N:23][CH:22]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)O1.Br[C:43]1[CH:44]=[CH:45][C:46]2[N:50]=[C:49]([C@@H:51]3[CH2:55][CH2:54][CH2:53][N:52]3[C:56]([O:58][C:59]([CH3:62])([CH3:61])[CH3:60])=[O:57])[NH:48][C:47]=2[CH:63]=1.C(=O)([O-])[O-].[K+].[K+]>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(COC)OC>[C:59]([O:58][C:56]([N:52]1[CH2:53][CH2:54][CH2:55][C@H:51]1[C:49]1[NH:48][C:47]2[CH:63]=[C:43]([C:9]3[CH:10]=[CH:11][C:12]([C:15]4[CH:16]=[CH:17][C:18]([C:21]5[NH:25][C:24]([C@@H:26]6[CH2:30][CH2:29][CH2:28][N:27]6[C:31]([O:33][CH2:34][C:35]6[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=6)=[O:32])=[N:23][CH:22]=5)=[CH:19][CH:20]=4)=[CH:13][CH:14]=3)[CH:44]=[CH:45][C:46]=2[N:50]=1)=[O:57])([CH3:62])([CH3:60])[CH3:61]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1nc2ccc(Br)cc2[nH]1
Reactant: CC1(C)OB(c2ccc(-c3ccc(-c4cnc([C@@H]5CCCN5C(=O)OCc5ccccc5)[nH]4)cc3)cc2)OC1(C)C
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: [K+]
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CCC[C@H]1c1nc2ccc(-c3ccc(-c4ccc(-c5cnc([C@@H]6CCCN6C(=O)OCc6ccccc6)[nH]5)cc4)cc3)cc2[nH]1
Temperature: 85 °C
Yield: 44.5 %

Procedure:
A mixture of (S)-benzyl 2-(5-(4′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)biphenyl-4-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (2.1 g, 3.8 mmol), (S)-tert-butyl 2-(6-bromo-1H-benzo[d]imidazol-2-yl)pyrrolidine-1-carboxylate (1.6 g, 4.3 mmol), tetrakis(triphenylphosphine)palladium(0) (0.44 mg, 0.38 mmol), 2M aqueous potassium carbonate solution (7.7 mL, 15.4 mmol) and dimethoxyethane (26 mL) was degassed under a stream of argon for 15 minutes. The reaction was heated to 85° C. for 14 hours. Upon completion, the reaction was cooled to room temperature, diluted with ethyl acetate and filtered through Celite. The filtrate was washed with water and brine, dried (MgSO4) and concentrated. The resulting crude material was purified by flash column chromatography to yield (S)-benzyl 2-(5-(4′-(2-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-1H-benzo[d]imidazol-6-yl)biphenyl-4-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (1.2 g, 44%). LCMS-ESI+: calculated for C43H44N6O4: 708.85; observed [M+1]+: 709.41.
Reaction SMILES: [N:1]1([CH2:6][C:7]2[S:15][C:14]3[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][C:9]=3[CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O>ClCCl>[N:1]1([CH2:6][C:7]2[S:15][C:14]3[CH2:13][CH2:12][NH:11][CH2:10][C:9]=3[CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCc2sc(CN3CCCC3)cc2C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: c1c(CN2CCCC2)sc2c1CNCC2
Temperature: 0 °C
Reaction time: 2 h

Procedure:
tert-Butyl 2-(pyrrolidin-1-ylmethyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-carboxylate (0.235 mmol) was dissolved in dichloromethane and cooled to 0° C. Trifluoroacetic acid (2 ml/mmol) was added and the reaction mixture stirred for 2 h. The solvent was completely evaporated and kept under the high vacuum to give the desired product which was used in the next step without further purification. Yield: quantitative
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([O:6][CH2:7][C:8]#[N:9])=[CH:4][CH:3]=1.Cl.[CH2:13]([OH:15])[CH3:14]>>[ClH:1].[Cl:1][C:2]1[CH:11]=[CH:10][C:5]([O:6][CH2:7][C:8](=[NH:9])[O:15][CH2:13][CH3:14])=[CH:4][CH:3]=1
Reactant: CCO
Reactant: N#CCOc1ccc(Cl)cc1
Agent: Cl
Product: CCOC(=N)COc1ccc(Cl)cc1

Procedure:
Commercially available 2-(4-chlorophenoxy)acetonitrile (Aldrich), HCl gas and ethanol were processed using the method described for Example 4A to obtain the titled compound. MS (ESI+) m/z 214 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[O:4][CH2:5][CH:6]1[O:8][CH2:7]1.[CH2:13]([N:20]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:21][C:22]([CH3:25])([NH2:24])[CH3:23])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(O)C>[CH3:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[O:4][CH2:5][CH:6]([OH:8])[CH2:7][NH:24][C:22]([CH3:25])([CH3:23])[CH2:21][N:20]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: Cc1ccccc1OCC1CO1
Reactant: CC(C)(N)CN(Cc1ccccc1)Cc1ccccc1
Solvent: CCO
Product: Cc1ccccc1OCC(O)CNC(C)(C)CN(Cc1ccccc1)Cc1ccccc1
Yield: 64.4 %

Procedure:
A micture of 4.3 g of 1-(2-methylphenoxy)-2,3-epoxypropane, 7.03 g of N,N-dibenzyl-2-methyl-1,2-propanediamine and 50 ml of ethanol was refluxed for 20 hours, and the solvent was evaporated under reduced pressure. To a benzene solution of the residue was added 1N hydrochloric acid, to deposit an oily material. After removal of the benzene layer, the residue was extracted with chloroform. The organic layer was washed with 5% sodium carbonate and dried over anhydrous sodium sulfate. The solvent was evaporated to give a colorless oily product. The product was chromatographed on a column of silica gel using chloroform as an eluent. 7.3 g of 1-(2-methylphenoxy)-3-(1,1-dimethyl-2-dibenzylaminoethylamino)-2-propanol was obtained from the eluate.