Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]([OH:15])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:16]([CH:19]1[CH:23]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[O:22][C:21](=[O:32])[CH2:20]1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(C(C)C)CC)(C)C.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>O1CCCC1.O.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[C:13](=[O:15])[NH:16][CH:19]1[CH2:20][C:21](=[O:32])[O:22][CH:23]1[O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: [N-]=[N+]=NC1CC(=O)OC1OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Agent: On1nnc2ccccc21
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCCl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1C(=O)NC1CC(=O)OC1OCc1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 49.4 %

Procedure:
A solution of (S)-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (0.13 g, 0.6 mmol), 4-azido-5-benzyloxy-dihydrofuran-2-one (0.14 g, 0.6 mmol) and triphenylphosphine (0.28 g, 1.0 mmol) in tetrahydrofuran (5 mL) and water (5 drops) was stirred under nitrogen for 0.5 h at room temperature and for 2 h at 65° C. The reaction was cooled to room temperature, was treated with with di-isopropylethylamine (0.52 mL, 5.0 mmol), EDC (0.15 g, 0.75 mmol), and HOBT (0.10 g, 0.75 mmol) and was stirred at room temperature under nitrogen for 20 h. The reaction was diluted with ethyl acetate, was washed with 10% sodium bisulfate, saturated sodium bicarbonate, and brine, was dried over sodium sulfate, and was evaporated. Purification by flash chromatography (SiO2) eluted with 2:3 ethyl acetate:hexanes provided (R)-2-(2-benzyloxy-5-oxo-tetrahydrofuran-3-ylcarbamoyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (0.12 g, 49% yield) as a sticky resin. 1H-NMR (500 MHz, CDCl3) δ 7.63 (br d, J=7.6 Hz, 0.7H), 7.28 (m, 5H), 6.50 (br, 0.3H), 5.37 (br s, 0.5H), 5.33 (s, 0.5H), 4.77 (d, J=11.6 Hz, 1H), 4.56 (dd, J=11.6, 3.7 Hz, 1H), 4.37 (br s, 1H), 4.18 (br s, 1H), 3.32 (br s, 1.4H), 3.24 (br s, 0.6H), 2.97 (br d, J=11.6 Hz, 1H), 2.35 (dd, J=18.1, 1.7 Hz, 1H), 2.1-2.3 (br, 1H), 1.81 (br s, 3H), 1.58 (s, 9H) ppm. MS (ES+): m/e=405 (M+H).
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]2[CH:14]=[C:13]([O:15][CH3:16])[C:12]([O:17][CH3:18])=[C:11]([O:19][CH3:20])[CH:10]=2)[CH:4]=1.[Cl-:21]>C(Cl)(Cl)Cl>[Cl:21][CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]2[CH:14]=[C:13]([O:15][CH3:16])[C:12]([O:17][CH3:18])=[C:11]([O:19][CH3:20])[CH:10]=2)[CH:4]=1
Reactant: COc1cc(-c2cc(CO)ccn2)cc(OC)c1OC
Reactant: [Cl-]
Solvent: ClC(Cl)Cl
Product: COc1cc(-c2cc(CCl)ccn2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-hydroxymethyl-2-(3,4,5-trimethoxyphenyl)pyridine (19.18 g) was dissolved in chloroform (100 mL), and to the solution thinly chloride (10.2 mL) was added at 0° C. After 30 minutes, the mixture was warmed to room temperature and stirred for 4 hours. The reaction mixture was washed with aqaueous saturated sodium hydrogendcarbonate and brine, dried over anhydrous sodium sulfate and evaporated. The residue was then recrystallized from ethyl acetate-hexane to give the title compound as pale yellow crystalline powder.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[Cl:9][C:10]1[CH:19]=[C:18]2[C:13]([CH:14]=[CH:15][C:16]([CH3:20])=[N:17]2)=[CH:12][CH:11]=1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Cl:9][C:10]1[CH:19]=[C:18]2[C:13]([CH:14]=[CH:15][C:16]([CH2:20][Cl:1])=[N:17]2)=[CH:12][CH:11]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cc1ccc2ccc(Cl)cc2n1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: ClCc1ccc2ccc(Cl)cc2n1

Procedure:
N-Chlorosuccinimide (3.0 g, 22.5 mmol) was added in portions over 1 hour to a stirred solution of 7-chloroquinaldine (3.3 g, 18.5 mmol) and dibenzoyl peroxide (0.1 g) in carbon tetrachloride (100 ml) under reflux. The mixture was heated under reflux for 24 hours adding further N-chlorosuccinimide (0.5 g and 1.0 g) after 3 hours and 20 hours. The mixture was cooled and filtered and the filtrate was extracted with 2M hydrochloric acid (5×40 ml). The extract was basified and re-extracted with dichloromethane and the extract was dried and evaporated to give the product contaminated with 7-chloroqinaldine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([NH:10][C:11]2[CH:24]=[C:23]3[C:14]([O:15][C:16]4[CH:17]=[CH:18][C:19]([O:36][CH3:37])=[CH:20][C:21]=4[C@@:22]43[CH2:28][O:27][C:26]([NH:29]C(=O)C(F)(F)F)=[N:25]4)=[CH:13][CH:12]=2)=[O:9])=[N:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+]>CO>[NH2:29][C:26]1[O:27][CH2:28][C@:22]2([N:25]=1)[C:23]1[CH:24]=[C:11]([NH:10][C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=3)=[O:9])[CH:12]=[CH:13][C:14]=1[O:15][C:16]1[C:21]2=[CH:20][C:19]([O:36][CH3:37])=[CH:18][CH:17]=1
Reactant: COc1ccc2c(c1)[C@]1(COC(NC(=O)C(F)(F)F)=N1)c1cc(NC(=O)c3ccc(Cl)cn3)ccc1O2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COc1ccc2c(c1)[C@]1(COC(N)=N1)c1cc(NC(=O)c3ccc(Cl)cn3)ccc1O2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of (S)-5-chloro-N-(2′-methoxy-2-(2,2,2-trifluoroacetamido)-5H-spiro[oxazole-4,9′-xanthene]-7′-yl)picolinamide (0.054 g, 0.101 mmol) in methanol (3.5 mL) was treated with potassium carbonate anhydrous (0.045 g, 0.326 mmol) and stirred at RT for 30 minutes. The catalyst was removed by filtration and the filtrate was concentrated to yield the crude product as a yellowish gummy solid. The crude product was purified by preparative HPLC [gradient 10-90% MeCN (0.1% TFA)/H2O (0.1% TFA)] to give pure product which was dissolved in methanol (5 mL) and neutralized by passing the solution through a Polymer Lab-HCO3 macroporous resin cartridge, and the filtrate was concentrated to give N-((4S)-2-amino-7′-methoxyspiro[1,3-oxazole-4,9′-xanthen]-2′-yl)-5-chloro-2-pyridinecarboxamide as an off-white solid. MS (ESI pos. ion) m/z: 437 (M+1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH3:10])=[C:4]([O:11][CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[CH:3]=1.[N:17]1([CH2:22][C@H:23]2[CH2:28][NH:27][CH2:26][CH2:25][N:24]2C(OC(C)(C)C)=O)[CH:21]=[CH:20][CH:19]=[N:18]1>>[N:17]1([CH2:22][C@@H:23]2[NH:24][CH2:25][CH2:26][N:27]([C:2]3[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH3:10])=[C:4]([O:11][CH:12]4[CH2:16][CH2:15][CH2:14][CH2:13]4)[CH:3]=3)[CH2:28]2)[CH:21]=[CH:20][CH:19]=[N:18]1
Reactant: CCOc1ccc(Br)cc1OC1CCCC1
Reactant: CC(C)(C)OC(=O)N1CCNC[C@@H]1Cn1cccn1
Product: CCOc1ccc(N2CCN[C@@H](Cn3cccn3)C2)cc1OC1CCCC1

Procedure:
The title compound was prepared by the method outlined for Example 1 using 4-bromo-2-(cyclopentyloxy)-1-ethoxybenzene as the aryl halide and tert-butyl (2R)-2-(1H-pyrazol-1-ylmethyl)piperazine-1-carboxylate as amine component. The intermediate and title compound were isolated as oils (76 and 77%). 1H NMR (CDCl3) 7.55 (d, J=1.6, 1H), 7.43 (d, J=1.9, 1H), 6.80 (d, J=8.6, 1H), 6.53 (d, J=2.8, 1H), 6.42 (dd, J=8.6, 2.7, 1H), 6.26 (t, J=2.2, 1H), 4.76-4.73 (m, 1H), 4.23 (dd, J=13.7, 4.9, 1H), 4.14 (dd, J=13.5, 7.6, 1H), 3.98 (q, J=7.1, 2H), 3.42-3.27 (m, 3H), 3.09 (dt, J=11.8, 3.0, 1H), 2.96 (td, J=10.8, 3.0, 1H), 2.75 (td, J=11.1, 3.1, 1H), 2.49 (t, J=9.6, 1H), 1.89-1.81 (m, 6H), 1.62-1.59 (m, 2H), 1.37 (t, J=6.8, 3H). 13C NMR 149.0, 146.7, 144.0, 139.9 (CH), 130.1 (CH), 116.1 (CH), 108.9 (CH), 107.3 (CH), 105.6 (CH), 80.8, (CH), 65.7 (CH2), 55.1 (CH), 55.0 (CH), 54.4 (CH2), 51.0 (CH2), 45.1 (CH2), 32.8 (CH2), 23.9 (CH2), 15.1 (CH3). LC/MS (Method B) 4.40 and 2.55 min, [M+1]+ 471 and 371.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([S:10][CH3:11])[N:3]=1.[C:12]([N:19]1[CH2:24][CH2:23][CH2:22][C@@H:21]([NH2:25])[CH2:20]1)([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13]>C(O)C>[CH3:9][O:8][C:6]1[N:5]=[C:4]([S:10][CH3:11])[N:3]=[C:2]([NH:25][C@@H:21]2[CH2:22][CH2:23][CH2:24][N:19]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:20]2)[CH:7]=1
Reactant: COc1cc(Cl)nc(SC)n1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](N)C1
Solvent: CCO
Product: COc1cc(N[C@@H]2CCCN(C(=O)OC(C)(C)C)C2)nc(SC)n1
Temperature: 130 °C

Procedure:
Compound 2 (3.6 g, 18.9 mmol) and (R)-1-Boc-3-aminopiperidine (9.45 g, 47.2 mmol) were dissolved in ethanol (50 mL) and TEA (10.5 mL, 76 mmol) was added. The reaction was sealed and heated to 130° C. for 72 h. The orange solution was concentrated and the residue was purified by column chromatography on silica gel, eluting with EtOAc/hexane to give the title compound as a white foam. 1H NMR (CDCl3) δ 5.40 (s, 1H), 4.78 (br s, 1H), 3.88 (s, 3H), 3.84-3.81 (m, 1H), 3.58-3.56 (m, 2H), 3.17-3.05 (m, 2H), 2.49 (s, 3H), 2.04-1.91 (m, 1H), 1.75-1.67 (m, 1H), 1.57-1.51 (m, 2H), 1.44 (s, 9H); LCMS 2.30 min, 355 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([OH:11])[CH:10]=1)[C:5]([OH:7])=[O:6].C(=O)([O-])[O-].[K+].[K+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C)C=O.O>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([OH:11])[CH:10]=1)[C:5]([O:7][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:6]
Reactant: O=C(O)c1cc(O)cc(Br)c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)c1cc(O)cc(Br)c1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 100.6 %

Procedure:
To a stirred solution of 3-bromo-5-hydroxybenzoic acid (2 g, 9.22 mmol) in dimethyl formamide (50 mL), was added potassium carbonate (1.27 g, 9.21 mmol), and the mixture was stirred at 0° C. for 20 minutes. Benzyl bromide (1.1 mL, 9.25 mmol) was added, and the reaction mixture allowed to warm to room temperature over 16 hours. The reaction mixture was diluted with water and extracted with ethyl acetate (×3). The combined organic extracts were washed with brine, dried (magnesium sulphate), filtered, and concentrated under reduced pressure to afford the title compound (2.85 g, quantitative yield).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:12]=[CH:11][C:10]2[NH:9][C:8](=[O:13])[C:7]3[CH2:14][CH2:15][CH2:16][C:6]=3[C:5]=2[CH:4]=1.[Mg]>>[F:18][C:2]([F:1])([F:17])[C:3]1[CH:12]=[CH:11][C:10]2[NH:9][C:8](=[O:13])[CH:7]3[CH2:14][CH2:15][CH2:16][CH:6]3[C:5]=2[CH:4]=1
Reactant: O=c1[nH]c2ccc(C(F)(F)F)cc2c2c1CCC2
Agent: [Mg]
Product: O=C1Nc2ccc(C(F)(F)F)cc2C2CCCC12
Yield: 50.1 %

Procedure:
Analogously to Example 7, 8-(trifluoromethyl)-1,2,3,5-tetrahydrocyclopenta[c]quinolin-4-one (1.08 g, 4.3 mmol) is reacted with magnesium (2.24 g, 92 mmol) to form 0.55 g (50%) of product.
Reaction SMILES: C[O:2][C:3]([C:5]1[NH:6][C:7]2[C:12]([C:13]=1[CH2:14][CH2:15][CH2:16][C:17]([O:19]C)=[O:18])=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:4].Br[CH2:22][C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1>>[C:17]([CH2:16][CH2:15][CH2:14][C:13]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([CH2:22][C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:26]=[CH:25][CH:24]=2)[C:5]=1[C:3]([OH:2])=[O:4])([OH:19])=[O:18]
Reactant: BrCc1cccc2ccccc12
Reactant: COC(=O)CCCc1c(C(=O)OC)[nH]c2ccccc12
Product: O=C(O)CCCc1c(C(=O)O)n(Cc2cccc3ccccc23)c2ccccc12

Procedure:
3-(3-Carboxy-propyl)-1H-indole-2-carboxylic acid (Lit. 3) was esterified using HCl/MeOH to give the 3-(3-methoxycarbonyl-propyl)-1H-indole-2-carboxylic acid methyl ester. Using general procedure B, 3-(3-methoxycarbonyl-propyl)-1H-indole-2-carboxylic acid methyl ester was coupled with 1-bromomethyl-naphthalene and the product obtained was hydrolyzed to give the title compound as a white solid. MS: 386.3 ([M−H]−).
Reaction SMILES: [CH3:1][CH:2]([CH2:11][CH2:12][CH:13]=[C:14]([CH3:16])[CH3:15])[CH2:3][CH2:4]CC(=O)C([O-])=O.[CH3:17][CH:18]([CH2:34][CH3:35])[C:19](=[O:33])[C:20]([O:22]CCC(C)CCC=C(C)C)=[O:21].C(C1C=CC(C(=O)C(OCCC(C)CCC=C(C)C)=O)=CC=1)(=O)C.O=C(C1C=CC=CC=1)C(OCCC(C)CCC=C(C)C)=O.CC(CCC=C(C)C)CCC(C)C(=O)C([O-])=O.C1(C(=O)C(OC/C=C(\C)/CCC=C(C)C)=O)CCCCC1.C1(C(=O)C(OCCC(C)CCC=C(C)C)=O)CCCCC1.O=C(CCC)C(OCCC(C)CCC=C(C)C)=O.C1(C(=O)C(OCC2C=CC(OC)=CC=2)=O)CCCCC1>>[CH3:17][CH:18]([CH2:34][CH3:35])[C:19](=[O:33])[C:20]([O:22][CH2:4]/[CH:3]=[C:2](\[CH3:1])/[CH2:11][CH2:12][CH:13]=[C:14]([CH3:15])[CH3:16])=[O:21]
Reactant: CCC(C)C(=O)C(=O)OCCC(C)CCC=C(C)C
Reactant: CC(C)=CCCC(C)CCCC(=O)C(=O)[O-]
Agent: CC(=O)c1ccc(C(=O)C(=O)OCCC(C)CCC=C(C)C)cc1
Agent: CC(C)=CCC/C(C)=C/COC(=O)C(=O)C1CCCCC1
Agent: CC(C)=CCCC(C)CCC(C)C(=O)C(=O)[O-]
Product: CCC(C)C(=O)C(=O)OC/C=C(\C)CCC=C(C)C

Procedure:
MS (EI): 266 (M+, 1); 181 (1); 179 (1); 153 (1); 138 (3); 137 (28); 136 (6); 135 (5); 123 (1); 122 (1); 121 (2); 109 (1); 107 82); 96 (2); 95 (10); 94 (2); 93 (6); 92 (2); 91 (3); 85 (9); 83 (1); 82 (4); 81 (52); 80 (2); 79 (3); 78 (1); 77 (3); 71 (1); 70 (6); 69 (100); 68 (12); 67 (12); 66 (1); 65 (2); 58 (2); 57 (30); 56 (1); 55 (5); 54 (1); 53 (6); 51 (1); 43 (1); 42 (2); 41 (26); 40 (2); 39 (5) 29 (5); 28 (1); 27 (2).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH3:11])[C:5](F)=[C:6]([CH:9]=1)[C:7]#[N:8].C(=O)([O-])[O-].[K+].[K+].[NH:18]1[CH:22]=[N:21][CH:20]=[N:19]1>CN(C=O)C.O>[Br:1][C:2]1[CH:3]=[C:4]([CH3:11])[C:5]([N:18]2[CH:22]=[N:21][CH:20]=[N:19]2)=[C:6]([CH:9]=1)[C:7]#[N:8]
Reactant: c1nc[nH]n1
Reactant: Cc1cc(Br)cc(C#N)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(Br)cc(C#N)c1-n1cncn1
Temperature: 140 °C
Yield: 24.2 %

Procedure:
To a stirred solution of 5-bromo-2-fluoro-3-methylbenzonitrile (1.0 g, 47.716 mmol), in DMF (10.0 mL) was added potassium carbonate (1.95 g, 14.14 mmol) followed by 1H-1,2,4-triazole (0.811 g, 9.433 mmol) at ambient temperature. The reaction mixture was heated to 140° C. for 18 h. The reaction mixture was cooled to ambient temperature, diluted with water and extracted with ethyl acetate (2×100 mL). The combined ethyl acetate layer was washed with brine and dried over Na2SO4 and concentrated under reduced pressure to afford the crude compound purified by flash column chromatography (SiO2, 100-200 mesh; eluting with 30% ethyl acetate/pet ether) to afford the title compound as a pink solid (0.6 g, 49%): 1H NMR (400 MHz, CDCl3) δ 8.39 (s, 1H), 8.23 (s, 1H), 7.91 (d, J=2.4 Hz, 2H), 2.21 (s, 3H), ESIMS m/z 262.57 ([M+H]+); IR (thin film) 2231, 554 cm−1.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.Cl[C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[N:13][N:12]=1>CC(O)CC>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH:9][C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[N:13][N:12]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(N)cn1
Reactant: Clc1nnc(-c2ccccc2)c2ccccc12
Solvent: CCC(C)O
Product: COc1ccc(Nc2nnc(-c3ccccc3)c3ccccc23)cn1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
A RBF was charged with 6-methoxypyridin-3-amine (155 mg, 1.25 mmol), 1-chloro-4-phenylphthalazine (300 mg, 1.25 mmol), and 2-butanol (4 mL). The vessel was sealed and the mixture was stirred overnight at 90° C. LC/MS shows completion of reaction. Reaction cooled to RT and purified by silica gel chromatography (1-5% MeOH/DCM) to afford N-(6-methoxypyridin-3-yl)-4-phenylphthalazin-1-amine as tan solid. MS [M+H]=329.1. Calc'd for C20H6N4O: 328.4.
Reaction SMILES: [CH2:1]([C:3]1[S:28][C:6]2[N:7]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)[C:8](=[O:12])[NH:9][C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2].Br[CH2:30][C:31]([C:33]1[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[C:35]([O:41][CH3:42])[CH:34]=1)=[O:32].CN(C)C=O.[H-].[Na+]>C(OCC)(=O)C>[CH3:42][O:41][C:35]1[CH:34]=[C:33]([C:31](=[O:32])[CH2:30][N:9]2[C:10](=[O:11])[C:5]3[CH:4]=[C:3]([CH2:1][CH3:2])[S:28][C:6]=3[N:7]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)[C:8]2=[O:12])[CH:38]=[CH:37][C:36]=1[O:39][CH3:40]
Reactant: COc1ccc(C(=O)CBr)cc1OC
Reactant: CCc1cc2c(=O)[nH]c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCc1cc2c(=O)n(CC(=O)c3ccc(OC)c(OC)c3)c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.6 %

Procedure:
To a mixture of 4′-[(6-ethyl-2,4-dioxo-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)-yl)methyl]biphenyl-2-carbonitrile (1 g), 2-bromo-1-(3,4-dimethoxyphenyl)ethanone (0.8 g) and N,N-dimethylformamide (25 mL) was added 60% sodium hydride (0.16 g), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% potassium hydrogensulfate and then saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (1.25 g, 86%).
Reaction SMILES: [N:1]1[S:5][N:4]=[C:3]2[C:6]([S:10]([NH:13][C:14]3[CH:35]=[C:34]([Cl:36])[CH:33]=[CH:32][C:15]=3[C:16]([NH:18][C@@H:19]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([Cl:31])[CH:25]=3)[C:20]([OH:22])=O)=[O:17])(=[O:12])=[O:11])=[CH:7][CH:8]=[CH:9][C:2]=12.[Cl:37][C:38]1[CH:39]=[C:40]([CH:43]=[CH:44][CH:45]=1)[CH2:41][NH2:42]>>[N:1]1[S:5][N:4]=[C:3]2[C:6]([S:10]([NH:13][C:14]3[CH:35]=[C:34]([Cl:36])[CH:33]=[CH:32][C:15]=3[C:16]([NH:18][C@H:19]([C:20](=[O:22])[NH:42][CH2:41][C:40]3[CH:43]=[CH:44][CH:45]=[C:38]([Cl:37])[CH:39]=3)[CH2:23][C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([Cl:31])[CH:25]=3)=[O:17])(=[O:11])=[O:12])=[CH:7][CH:8]=[CH:9][C:2]=12
Reactant: O=C(N[C@@H](Cc1ccc(Cl)c(Cl)c1)C(=O)O)c1ccc(Cl)cc1NS(=O)(=O)c1cccc2nsnc12
Reactant: NCc1cccc(Cl)c1
Product: O=C(N[C@@H](Cc1ccc(Cl)c(Cl)c1)C(=O)NCc1cccc(Cl)c1)c1ccc(Cl)cc1NS(=O)(=O)c1cccc2nsnc12
Yield: 48 %

Procedure:
The title compound (29 mg, 48%) was obtained from (S)-2-[2-(benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-chloro-benzoylamino]-3-(3,4-dichloro-phenyl)-propionic acid and 3-chlorobenzylamine as in Example 1, Part C. HPLC: RT=10.95 min. MS (ESI−): mass calcd. for C29H21Cl4N5O4S2, 709.45; m/z found, 706/708 [M−H]−. 1H NMR (500 MHz, CDCl3): 11.55 (s, 1H), 8.39 (dd, J=7.0, 0.9, 1H), 8.22 (dd, J=8.8, 0.8, 1H), 7.73 (dd, J=8.8, 7.1, 1H), 7.70 (d, J=2.0, 1H), 7.38-7.30 (m, 3H), 7.16 (d, J=0.5, 1H), 7.05-6.99 (m, 2H), 6.96 (dd, J=8.5, 2.0, 1H), 6.88-6.81 (m, 1H), 5.87-5.80 (m, 1H), 4.70-4.61 (m, 1H), 4.49-4.41 (m, 1H), 4.34-4.26 (m, 1H), 3.17-3.09 (m, 1H), 3.06-2.96 (m, 1H).
Reaction SMILES: COC(=O)N[C@@H](C(C)C)C(N1[C@H](C2NC(C3C=CC(C4C=CC5C(=CC=C(C6NC([C@@H]7CCCN7[C:48](=[O:61])[C@H:49]([NH:56][C:57]([O:59][CH3:60])=[O:58])[C:50]7[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=7)=NC=6)C=5)C=4)=CC=3)=CN=2)CC2(OCCO2)C1)=O.[O:66]=[C:67]([N:80]1[C@H:88]([C:89]2[NH:90][C:91]([C:94]3[CH:103]=[CH:102][C:101]4[C:96](=[CH:97][CH:98]=[C:99]([C:104]5[CH:109]=[CH:108][C:107]([C:110]6[NH:114][C:113]([C@@H:115]7[CH2:119][CH2:118][CH2:117][NH:116]7)=[N:112][CH:111]=6)=[CH:106][CH:105]=5)[CH:100]=4)[CH:95]=3)=[CH:92][N:93]=2)[CH2:87][C:82]2([O:86][CH2:85][CH2:84][O:83]2)[CH2:81]1)[C@@H:68]([NH:75][C:76](=[O:79])[O:77][CH3:78])[CH:69]1[CH2:74]COC[CH2:70]1.Cl>>[CH3:60][O:59][C:57](=[O:58])[NH:56][CH:49]([C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)[C:48]([N:116]1[CH2:117][CH2:118][CH2:119][C@H:115]1[C:113]1[NH:114][C:110]([C:107]2[CH:106]=[CH:105][C:104]([C:99]3[CH:98]=[CH:97][C:96]4[C:101](=[CH:102][CH:103]=[C:94]([C:91]5[NH:90][C:89]([C@@H:88]6[CH2:87][C:82]7([O:86][CH2:85][CH2:84][O:83]7)[CH2:81][N:80]6[C:67](=[O:66])[C@@H:68]([NH:75][C:76]([O:77][CH3:78])=[O:79])[CH:69]([CH3:70])[CH3:74])=[N:93][CH:92]=5)[CH:95]=4)[CH:100]=3)=[CH:109][CH:108]=2)=[CH:111][N:112]=1)=[O:61]
Reactant: COC(=O)N[C@H](C(=O)N1CC2(C[C@H]1c1ncc(-c3ccc4cc(-c5ccc(-c6cnc([C@@H]7CCCN7)[nH]6)cc5)ccc4c3)[nH]1)OCCO2)C1CCOCC1
Reactant: COC(=O)N[C@H](C(=O)N1CC2(C[C@H]1c1ncc(-c3ccc(-c4ccc5cc(-c6cnc([C@@H]7CCCN7C(=O)[C@H](NC(=O)OC)c7ccccc7)[nH]6)ccc5c4)cc3)[nH]1)OCCO2)C(C)C
Agent: Cl
Product: COC(=O)NC(C(=O)N1CCC[C@H]1c1ncc(-c2ccc(-c3ccc4cc(-c5cnc([C@@H]6CC7(CN6C(=O)[C@@H](NC(=O)OC)C(C)C)OCCO7)[nH]5)ccc4c3)cc2)[nH]1)c1ccccc1

Procedure:
Title compound was prepared according to the method employed to prepare (S)-1-((S)-8-(5-(4-(6-(2-((S)-1-((R)-2-(methoxycarbonylamino)-2-phenylacetyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)-1,4-dioxa-7-azaspiro[4.4]nonan-7-yl)-3-methyl-1-oxobutan-2-ylcarbamic acid methyl ester, except that methyl (S)-3-methyl-1-oxo-1-((S)-8-(5-(6-(4-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)phenyl)naphthalen-2-yl)-1H-imidazol-2-yl)-1,4-dioxa-7-azaspiro[4.4]nonan-7-yl)butan-2-ylcarbamate 3× HCl salt was used instead of methyl (S)-3-methyl-1-oxo-1-((S)-8-(5-(4-(6-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)-1,4-dioxa-7-azaspiro[4.4]nonan-7-yl)butan-2-ylcarbamate 3× HCl salt. MS (ESI) m/z 881.90 [M+H]+. (14 mg, 16%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([O:10][CH2:11][C@H:12]2[O:14][CH2:13]2)[CH:7]=[CH:8][CH:9]=1)([O-])=O>C1COCC1.[Pd].NCCN>[NH2:1][C:4]1[CH:5]=[C:6]([O:10][CH2:11][C@H:12]2[O:14][CH2:13]2)[CH:7]=[CH:8][CH:9]=1
Reactant: O=[N+]([O-])c1cccc(OC[C@@H]2CO2)c1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: NCCN
Product: Nc1cccc(OC[C@@H]2CO2)c1

Procedure:
Compound 16a-S (0.5 g, 2.6 mmol) and % 5 Pd/C(en) (10% of the weight of starting material) in 5 ml anhydrous THF was hydrogenated at ambient pressure and temperature for 3-5 hours. The reaction mixture was filtered by using a membrane filter (13, 0.22 μm), and the filtrate was concentrated in vacuo. The resulting compound is a crude mixture of nitro group reduction and epoxide ring opening. Isolation of the desired compound was difficult because of the lability of the components of the mixture on silica gel. The product ratio of the NO2 reduction and ring opening (80:20) was determined on the basis of the integration ratio of the epoxide-ring protons from nitro group reduction and the methyl proton of the ring opened compound (98% total yield for the mixture).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl:7][C:8]1[CH:13]=[CH:12][N:11]=[C:10]([CH2:14][CH3:15])[C:9]=1[C:16](OCC)=[O:17]>C1COCC1>[Cl:7][C:8]1[CH:13]=[CH:12][N:11]=[C:10]([CH2:14][CH3:15])[C:9]=1[CH2:16][OH:17]
Reactant: CCOC(=O)c1c(Cl)ccnc1CC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCc1nccc(Cl)c1CO
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Lithium aluminum hydride (234 mg, 6.2 mmol) was stirred in anhydrous THF (30 mL). A solution of ethyl 4-chloro-2-ethylpyridine-3-carboxylate (878 mg, 4.1 mmol) in anhydrous THF (5 mL) was added at 0° C., and the reaction mixture was stirred at room temperature for 1.5 hours. The reaction was quenched with an aqueous solution of sodium hydroxide and extracted 5 times with ethyl acetate. The combined organic phase was washed with brine and dried over sodium sulfate. After evaporation of the solvent, (4-chloro-2-ethylpyridin-3-yl)methanol was obtained as an oil (601 mg, 85% yield) and used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:26][CH3:27])=[C:6]([CH:25]=1)[C:7](/[N:9]=[C:10]1\[S:11][C:12]2[C:22]([CH3:24])([CH3:23])[O:21][CH2:20][CH2:19][C:13]=2[N:14]\1[CH2:15][CH:16]([CH3:18])[CH3:17])=O.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:37])=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:26][CH3:27])=[C:6]([CH:25]=1)[C:7](=[S:37])/[N:9]=[C:10]1\[S:11][C:12]2[C:22]([CH3:24])([CH3:23])[O:21][CH2:20][CH2:19][C:13]=2[N:14]\1[CH2:15][CH:16]([CH3:18])[CH3:17]
Reactant: COc1ccc(Cl)cc1C(=O)/N=c1\sc2c(n1CC(C)C)CCOC2(C)C
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: COc1ccc(Cl)cc1C(=S)/N=c1\sc2c(n1CC(C)C)CCOC2(C)C
Temperature: 80 °C
Reaction time: 2 h
Yield: 69.4 %

Procedure:
To a solution of Example 89G (0.25 g, 0.61 mmol) in toluene (10 mL) was added Lawesson's Reagent (0.25 g, 0.61 mmol, Aldrich) and stirred at 80° C. for 2 hr. The reaction mixture was then cooled and concentrated. The residue was purified by column chromatography using an Analogix® Intelliflash280™ (SiO2, 0-50% ethyl acetate in hexanes) to afford 0.18 g (70%) of the title compound. MS (ESI+) m/z 425 (M+H)+