Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:7]2[CH:8]=[C:9]3[O:23][CH2:22][C:12]4([C:20]5[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=5)[NH:14][C:13]4=[O:21])[C:10]3=[CH:11][C:6]=2[O:5][CH2:4][C:3]1=[O:24].CC1C2C=[C:32]3[C:37]4(C5C(=CC=CC=5)NC4=O)[CH2:36][O:35][C:33]3=[CH:34]C=2ON=1.CC1C=CC(S(OC[C@H]2CCCO2)(=O)=O)=CC=1.BrCC1OC(C(F)(F)F)=CC=1>>[CH3:1][N:2]1[C:3](=[O:24])[CH2:4][O:5][C:6]2[CH:11]=[C:10]3[C:12]4([C:20]5[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=5)[N:14]([CH2:34][C@H:33]5[CH2:32][CH2:37][CH2:36][O:35]5)[C:13]4=[O:21])[CH2:22][O:23][C:9]3=[CH:8][C:7]1=2
Reactant: Cc1noc2cc3c(cc12)C1(CO3)C(=O)Nc2ccccc21
Reactant: CN1C(=O)COc2cc3c(cc21)OCC31C(=O)Nc2ccccc21
Agent: Cc1ccc(S(=O)(=O)OC[C@H]2CCCO2)cc1
Agent: FC(F)(F)c1ccc(CBr)o1
Product: CN1C(=O)COc2cc3c(cc21)OCC31C(=O)N(C[C@H]2CCCO2)c2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 9 and making non-critical variations using 4-methyl-2H-spiro[furo[2,3-g][1,4]benzoxazine-8,3′-indole]-2′,3(1′H,4H)-dione to replace 3-methylspiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one, and (R)-(tetrahydrofuran-2-yl)methyl 4-methylbenzenesulfonate to replace 2-(bromomethyl)-5-(trifluoromethyl)furan, 4-methyl-1′-(((R)-tetrahydrofuran-2-yl)methyl)-4,7-dihydrospiro[benzofuro[5,6-b][1,4]oxazine-8,3′-indoline]-2′,3(2H)-dione was obtained (11%) as a colorless solid: 1H NMR (300 MHz, (CD3)2CO) δ7.35-7.30 (m, 1H), 7.23-7.13 (m, 2H), 7.08-6.99 (m, 1H), 6.75 (s, 1H), 6.35 (d, J=10.1 Hz, 1H), 4.92-4.87 (m, 1H), 4.74 (d, J=9.2 Hz, 1H), 4.45-4.44 (m, 2H), 4.31-4.20 (m, 1H), 3.97-3.62 (m, 4H), 3.33 (s, 3H), 1.95-1.66 (m, 4H); 13C NMR (75 MHz, (CD3)2CO) δ178.8, 178.7, 166.1, 158.4 (2C), 145.3, 145.1, 141.5, 133.9, 133.7, 133.2, 130.6, 130.5, 125.6, 125.3 (2C), 125.1 (2C), 124.6, 124.3, 112.9, 112.7, 111.6, 111.5, 99.2, 99.1, 82.0, 81.8 (2C), 79.6, 78.2, 77.9, 75.7, 69.4, 69.3, 69.1, 59.6, 59.5, 46.0, 45.8, 30.7, 30.4, 29.8, 29.4, 27.2, 27.1; MS (ES+) m/z 406.9 (M+1).
Reaction SMILES: N([O-])=O.[Na+].N[C:6]1[CH:14]=[C:13]2[C:9]([CH2:10][O:11][C:12]2=[O:15])=[CH:8][CH:7]=1.[BrH:16]>O>[Br:16][C:6]1[CH:14]=[C:13]2[C:9]([CH2:10][O:11][C:12]2=[O:15])=[CH:8][CH:7]=1
Reactant: Br
Reactant: Nc1ccc2c(c1)C(=O)OC2
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: O=C1OCc2ccc(Br)cc21
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 84 %

Procedure:
A solution of NaNO2 (2.2 g, 0.040 mol) in H2O (22 mL) was added to a mixture of 6-aminoisobenzofuran-1(3H)-one (5.0 g, 0.030 mol) in HBr (70 mL, 48%) over 5 min at 0° C. The mixture was stirred for 20 minutes before it was pipetted into an ice cold solution of CuBr (22 g, 0.21 mol) in HBr (48%, 23 mL). The resulting dark brown mixture was stirred for 20 min and was then diluted with H2O (200 mL) to produce an orange precipitate. The precipitate was filtered off, treated with sat. NaHCO3 solution, and extracted with EtOAc (20 mL×3). The organics were dried over Na2SO4 and evaporated in vacuo to give 6-bromoisobenzofuran-1(3H)-one (5.4 g, 84%). 1H NMR (300 MHz, CDCl3) δ 8.05 (d, J=1.8, 1H), 7.80 (dd, J=8.1, 1.8, 1H), 7.39 (d, J=8.1, 1H), 5.28 (s, 2H).
Reaction SMILES: [C:1]1([C:7]2([C:13]#[N:14])[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C=O.[C:17](O[BH-](OC(=O)C)OC(=O)C)(=O)C.C(O)(=O)C>CN(C)C=O.COC(OC)OC.Cl>[CH3:17][N:10]1[CH2:9][CH2:8][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([C:13]#[N:14])[CH2:12][CH2:11]1
Reactant: N#CC1(c2ccccc2)CCNCC1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: Cl
Solvent: CN(C)C=O
Solvent: CC(=O)O
Solvent: COC(OC)OC
Product: CN1CCC(C#N)(c2ccccc2)CC1
Temperature: 23 °C
Reaction time: 8 h
Yield: 86.5 %

Procedure:
4-Phenylpiperidine-4-carbonitrile (1.35 g, 6.062 mmol) was dissolved in N,N-dimethylformamide/trimethylorthoformate (1:1, 12 mL) and treated with paraformaldehyde (0.596 mL, 18.19 mmol), triacetoxyborohydride (3.854 g, 18.185 mmol) and acetic acid (1 mL). The mixture was stirred at 23° C. overnight, then diluted with 1N hydrochloric acid and washed with ethyl acetate. The aqueous phase was basified with aqueous sodium bicarbonate and extracted with ethyl acetate. The combined organic extracts were dried over anhydrous magnesium sulfate, filtered and concentrated to give the title material (1.05 g, 50%) as an oil. LC/MS (M+H)+: 200. HPLC ret. time (Condition B): 1.315 min. 1H NMR (400 MHz, CDCl3) δ ppm: 2.10-2.21 (4H, m), 2.41 (3H, s), 2.53 (2H, td, J=11.81, 3.41 Hz), 2.99 (2H, d, J=12.38 Hz), 7.32-7.38 (1H, m), 7.39-7.45 (2H, m), 7.49-7.54 (2H, m).
Reaction SMILES: C([O-])(C)(C)C.[K+].[C:7]([C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13](=[O:18])[C:12]2([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[O:26][CH2:27][CH3:28])[OH:19])#[N:8].[CH3:29][O:30][C:31]1[CH:36]=[C:35]([O:37][CH3:38])[CH:34]=[CH:33][C:32]=1[S:39](Cl)(=[O:41])=[O:40].CO>CN(C)C=O>[C:7]([C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([S:39]([C:32]1[CH:33]=[CH:34][C:35]([O:37][CH3:38])=[CH:36][C:31]=1[O:30][CH3:29])(=[O:41])=[O:40])[C:13](=[O:18])[C:12]2([OH:19])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[O:26][CH2:27][CH3:28])#[N:8]
Reactant: CCOc1ccccc1C1(O)C(=O)Nc2ccc(C#N)cc21
Reactant: COc1ccc(S(=O)(=O)Cl)c(OC)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CO
Product: CCOc1ccccc1C1(O)C(=O)N(S(=O)(=O)c2ccc(OC)cc2OC)c2ccc(C#N)cc21
Reaction time: 1.5 h
Yield: 49.1 %

Procedure:
1.7 g (15 mmol) of potassium tert-butanolate were added in portions to 4 g (13.6 mmol) of the intermediate 1b in 40 ml of anhydrous dimethylformamide at 0° C., and the mixture was stirred for about 90 minutes. Then 3.4 g (14.3 mmol) of 2,4-dimethoxybenzenesulfonyl chloride were rapidly added dropwise at 0° C. The reaction mixture was stirred at 0° C. for 2 h. This solution was then poured into an ice-water/K2CO3 solution, resulting in a precipitate which was isolated. The resulting residue was treated with a little methanol, filtered off with suction and dried, resulting in 3.3 g of the product.
Reaction SMILES: [C:1]1([CH2:7][O:8][CH2:9][CH:10]=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:12]([Mg]Br)[CH:13]=[CH2:14].[Cl-].[NH4+]>C(OCC)C>[C:1]1([CH2:7][O:8][CH2:9][CH:10]([OH:11])[CH2:14][CH:13]=[CH2:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C=CC[Mg]Br
Reactant: O=CCOCc1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: C=CCC(O)COCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirring 0° C. solution of 59.0 g of product from Example 1 in 375 ml of diethyl ether is added, dropwise, 432.24 ml of 1M allylmagnesiumbromide in ether. The reaction is stirred at 0° C. for 1 hour, followed by overnight stirring at room temperature. The reaction is cooledto 0° C., hydrolyzed with saturated ammonium chloride, and the layers are separated. The organic layer is washed with saturated sodium chloride, dried and concentrated in vacuo to give the product as an oil. The crude oil is purified by Kugelrohr distillation (bath temperature 100° C.) to give 61.5 g of the desired product as a colorless oil. 1H NMR(CDCl3):δ 7.34(m,5H); 5.82(m,1H); 5.08(m,2H); 4.56(s,2H); 3.88(m,1H); 3.44(ABq,2H); 2.27(t,2H); 1.7(bs, 1H).
Reaction SMILES: [C:1]([C@@H:3]1[CH2:7][N:6]([C:8]2[CH:13]=[CH:12][N:11]3[N:14]=[CH:15][C:16]([C:17]([N:19](CC4C=CC(OC)=CC=4)CC4C=CC(OC)=CC=4)=[O:18])=[C:10]3[CH:9]=2)[C@@H:5]([C:38]2[CH:43]=[CH:42][CH:41]=[C:40]([F:44])[CH:39]=2)[CH2:4]1)#[N:2]>C(O)(C(F)(F)F)=O.CS(C)=O>[C:1]([C@@H:3]1[CH2:7][N:6]([C:8]2[CH:13]=[CH:12][N:11]3[N:14]=[CH:15][C:16]([C:17]([NH2:19])=[O:18])=[C:10]3[CH:9]=2)[C@@H:5]([C:38]2[CH:43]=[CH:42][CH:41]=[C:40]([F:44])[CH:39]=2)[CH2:4]1)#[N:2]
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)C(=O)c2cnn3ccc(N4C[C@@H](C#N)C[C@@H]4c4cccc(F)c4)cc23)cc1
Solvent: CS(C)=O
Solvent: O=C(O)C(F)(F)F
Product: N#C[C@H]1C[C@H](c2cccc(F)c2)N(c2ccn3ncc(C(N)=O)c3c2)C1

Procedure:
A solution of 5-((2R,4S)-4-cyano-2-(3-fluorophenyl)pyrrolidin-1-yl)-N,N-bis(4-methoxybenzyl)pyrazolo[1,5-a]pyridine-3-carboxamide (I-35) (15 mg, 0.025 mmol) in TFA (0.5 mL) was heated to 60° C. for 2 hours. The reaction was reduced to dryness and the crude material was taken up in DMSO and purified by preparative LCMS and lyophilized to give 5-((2R,4S)-4-cyano-2-(3-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyridine-3-carboxamide (X-25). 1H NMR (400 MHz, CD3CN) δ 8.22 (d, J=7.8 Hz, 1 H), 8.05 (s, 1 H), 7.43-7.28 (m, 1 H), 7.10 (d, J=7.7 Hz, 1 H), 7.06-6.96 (m, 3 H), 6.38 (dd, J=2.8, 7.7 Hz, 1 H), 5.09 (dd, J=3.0, 8.1 Hz, 1 H), 4.18 (dd, J=7.6, 9.6 Hz, 1 H), 3.82-3.70 (m, 1 H), 3.49-3.34 (m, 1 H), 2.86-2.68 (m, 1 H), 2.38-2.28 (m, 1 H). MS m/z 350.1 (M+1)+.
Reaction SMILES: [N:1]1[N:2]=[CH:3][N:4]([C:6]2[CH:16]=[CH:15][C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:8][CH:7]=2)[CH:5]=1.[CH2:17]1[CH2:21][O:20][CH2:19][CH2:18]1.[OH-:22].[Na+]>C(O)C>[N:1]1[N:2]=[CH:3][N:4]([C:6]2[CH:7]=[CH:8][C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:15][CH:16]=2)[CH:5]=1.[NH:4]1[CH:6]=[C:7]([C:8]2[CH:9]=[CH:15][C:18]([C:19]([OH:22])=[O:20])=[CH:17][CH:21]=2)[N:1]=[CH:5]1
Reactant: [OH-]
Reactant: C1CCOC1
Agent: CCOC(=O)c1ccc(-n2cnnc2)cc1
Agent: [Na+]
Solvent: CCO
Product: O=C(O)c1ccc(-c2c[nH]cn2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of the obtained ethyl 4-(1,2,4-triazol-4-yl)benzoate (365 mg) in ethanol (4 ml)-THF (4 ml) was added 1 N sodium hydroxide solution (4 ml), and the solution was stirred at room temperature for 2 hours. The reaction solution was concentrated and the residue was dissolved in water, to which was added 1 N hydrochloric acid (4 ml). The precipitate was filtered, washed with water and dried to give the title compound, 4-(1H-imidazol-4-yl)benzoic acid (275 mg).
Reaction SMILES: [NH:1]([C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])[C@H:2]([C:10]([NH:12][C@H:13]([C:20](O)=[O:21])[CH2:14][C:15]1[N:19]=[CH:18][NH:17][CH:16]=1)=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH2:33][C@H:34]([C:39]([NH:41][C@H:42]([C:46]([OH:48])=[O:47])[CH:43]([CH3:45])[CH3:44])=[O:40])[CH2:35][CH:36]([CH3:38])[CH3:37].[OH:49][CH2:50][CH2:51][NH:52][CH2:53][CH2:54][NH-:55].C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1>>[NH:1]([C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])[C@H:2]([C:10]([NH:12][C@H:13]([C:20]([NH:33][C@H:34]([C:39]([NH:41][C@H:42]([C:46]([OH:48])=[O:47])[CH:43]([CH3:44])[CH3:45])=[O:40])[CH2:35][CH:36]([CH3:37])[CH3:38])=[O:21])[CH2:14][C:15]1[N:19]=[CH:18][NH:17][CH:16]=1)=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[OH:49][CH2:50][CH2:51][NH:52][CH2:53][CH2:54][NH-:55]
Reactant: CC(C)C[C@H](N)C(=O)N[C@H](C(=O)O)C(C)C
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)O)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Agent: [NH-]CCNCCO
Product: CC(C)C[C@H](NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1)C(=O)N[C@H](C(=O)O)C(C)C

Procedure:
In a manner analogous to that described in Example 1, using as starting materials 118 mg of Z-Phe-His-OH, 78 mg of H-Leu-Val-2-(2-hydroxyethylamino)-ethyl amide, 42 mg of HOBt and 66 mg of DCCI, the title compound is obtained after flash chromatography (65 g of silica gel 60, 40-63 μm, eluant system B11). Rf (B11)=0.32.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([NH2:19])([CH3:18])[CH3:17])=[CH:12][N:11]=1)(C(C)(C)C)(C)C>CC(O)=O.C1COCC1.O>[OH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([NH2:19])([CH3:17])[CH3:18])=[CH:12][N:11]=1
Reactant: CC(C)(N)c1ccc(CO[Si](C)(C)C(C)(C)C)nc1
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(C)(N)c1ccc(CO)nc1
Yield: 37.1 %

Procedure:
A solution of 1-[2-(tert-butyldimethylsilyloxymethyl)pyridin-5-yl](1-methyl)ethylamine (1.5 g, 5.35 mmol) in AcOH (15 ml), THF (5 ml) and H2O (5 ml) was heated at 50° C. for 2.5 h. The resultant mixture was concentrated under reduced pressue and then azeotroped with toluene (2×50 ml). The residue was dissolved in CH2Cl2 (15 ml) and MeOH (15 ml) and dry loaded onto silica. Purification by column chromatography on silica, using 10% MeOH/CH2Cl2 containing 1% NH3 solution as eluent, gave the desired alcohol (330 mg, 37%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:32][C:33]1[CH:34]=[C:35]([CH:39]=[CH:40][CH:41]=1)[C:36]([OH:38])=[O:37])[S:9]([C:12]1[CH:17]=[C:16]([C:18]([NH:20][N:21]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:23][CH:22]2[CH3:30])=[O:19])[CH:15]=[CH:14][C:13]=1[Cl:31])(=[O:11])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[CH2:43][O:44]/[N:45]=[N+:46](/[N:48]([CH2:51][CH3:52])[CH2:49][CH3:50])\[O-:47]>>[C:1]([O:5][C:6]([N:8]([CH2:32][C:33]1[CH:34]=[C:35]([CH:39]=[CH:40][CH:41]=1)[C:36]([O:38][CH2:43][O:44]/[N:45]=[N+:46](\[O-:47])/[N:48]([CH2:51][CH3:52])[CH2:49][CH3:50])=[O:37])[S:9]([C:12]1[CH:17]=[C:16]([C:18]([NH:20][N:21]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:23][CH:22]2[CH3:30])=[O:19])[CH:15]=[CH:14][C:13]=1[Cl:31])(=[O:10])=[O:11])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC1Cc2ccccc2N1NC(=O)c1ccc(Cl)c(S(=O)(=O)N(Cc2cccc(C(=O)O)c2)C(=O)OC(C)(C)C)c1
Reactant: CCN(CC)/[N+]([O-])=N/OCCl
Product: CCN(CC)/[N+]([O-])=N/OCOC(=O)c1cccc(CN(C(=O)OC(C)(C)C)S(=O)(=O)c2cc(C(=O)NN3c4ccccc4CC3C)ccc2Cl)c1

Procedure:
The product obtained in Step C of Example 1 is reacted with N—[(Z)-(chloromethoxy)-NNO-azoxy]-N-ethylethanamine in accordance with the process conditions described in Step D of Example 1. The title product is obtained in the form of a yellow solid after chromatography on a silica column using as eluant a 65/35 n-heptane/ethyl acetate mixture.
Reaction SMILES: Cl.[C:2]1([CH2:15][CH2:16][NH2:17])[C:6]2=[C:7]3[C:12](=[CH:13][CH:14]=[C:5]2[O:4][CH:3]=1)[O:11][CH2:10][CH2:9][CH2:8]3.[CH3:18][N:19]=[C:20]=[O:21]>N1C=CC=CC=1>[C:2]1([CH2:15][CH2:16][NH:17][C:20]([NH:19][CH3:18])=[O:21])[C:6]2=[C:7]3[C:12](=[CH:13][CH:14]=[C:5]2[O:4][CH:3]=1)[O:11][CH2:10][CH2:9][CH2:8]3
Reactant: NCCc1coc2ccc3c(c12)CCCO3
Reactant: CN=C=O
Agent: Cl
Solvent: c1ccncc1
Product: CNC(=O)NCCc1coc2ccc3c(c12)CCCO3

Procedure:
To a suspension of 0.01 mole of 2-(8,9-dihydro-7H-furo[3,2-f]chromen-1-yl)ethylamine hydrochloride in five (5) ml of pyridine, 0.011 mole of methylisocyanate is added dropwise with stirring. The reaction mixture is stirred for one (1) hour at 80° C., then poured on ice/water. After classical work up and purification, the title compound is obtained.
Reaction SMILES: [Si:1]([O:8][C:9]1[C:17]([CH2:18][CH:19](O)[C:20]([CH3:22])=[CH2:21])=[C:16]([O:24][CH3:25])[C:15]([CH3:26])=[C:14]2[C:10]=1[C:11](=[O:27])[O:12][CH2:13]2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>C(OC)(OC)(OC)CC.C(O)(=O)CC>[Si:1]([O:8][C:9]1[C:17]([CH2:18]/[CH:19]=[C:20](\[CH3:22])/[CH2:21][CH:10]([CH3:9])[C:11]([O:12][CH3:13])=[O:27])=[C:16]([O:24][CH3:25])[C:15]([CH3:26])=[C:14]2[C:10]=1[C:11](=[O:27])[O:12][CH2:13]2)([C:4]([CH3:6])([CH3:5])[CH3:7])([CH3:3])[CH3:2]
Reactant: C=C(C)C(O)Cc1c(OC)c(C)c2c(c1O[Si](C)(C)C(C)(C)C)C(=O)OC2
Agent: CCC(OC)(OC)OC
Solvent: CCC(=O)O
Product: COC(=O)C(C)C/C(C)=C/Cc1c(OC)c(C)c2c(c1O[Si](C)(C)C(C)(C)C)C(=O)OC2

Procedure:
A solution of 4-(4-tert-butyldimethylsilyloxy-1,3-dihydro-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-3-hydroxy-2-methylbut-1-ene (0.91 g) in trimethyl orthopropionate (25 ml) and propionic acid (0.08 ml) was heated to 110° C. for 2.5 hours. The solvents were evaporated under vacuum to afford methyl (E) 6-(4-tert-butyldimethylsilyloxy-1,3-dihydro-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-2,4-dimethyl-4-hexenoate as an oil.
Reaction SMILES: [C:1]1([N:7]2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:10]=3[N:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.NC1C(C2C=CC=[C:31]([O:35]C)C=2)=CSC=1C(OC)=O.[CH:41](OCC)(OCC)[O:42]CC.COC1C=CC(N)=CC=1>C(O)(=O)C>[CH3:31][O:35][C:21]1[CH:22]=[C:17]([C:16]2[C:10]3[N:9]=[CH:8][N:7]([C:1]4[CH:6]=[CH:5][C:4]([O:42][CH3:41])=[CH:3][CH:2]=4)[C:12](=[O:13])[C:11]=3[S:14][CH:15]=2)[CH:18]=[CH:19][CH:20]=1
Reactant: O=c1c2scc(-c3ccccc3)c2ncn1-c1ccccc1
Reactant: CCOC(OCC)OCC
Reactant: COC(=O)c1scc(-c2cccc(OC)c2)c1N
Solvent: COc1ccc(N)cc1
Solvent: CC(=O)O
Product: COc1ccc(-n2cnc3c(-c4cccc(OC)c4)csc3c2=O)cc1
Yield: 51.2 %

Procedure:
In the same manner as the synthesis of Compound 1, methyl 3-amino-4-(3-methoxyphenyl)thiophene-2-carboxylate (80 mg, 0.3 mmol), triethyl orthoformate (0.66 ml), p-anisidine (70.2 mg, 0.57 mmol), and acetic acid (0.08 ml) were used to give 56 mg (0.15 mmol, 51.2% yield) of the title compound.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][NH:7][S:8]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH:17]2[C:26]3[C:21](=[C:22]([Cl:28])[CH:23]=[C:24]([Cl:27])[CH:25]=3)[CH2:20][N:19]([CH3:29])[CH2:18]2)[CH:12]=1)(=[O:10])=[O:9].[OH:30][CH:31]([CH:42]([OH:53])[C:43]([O:45]N1C(=O)CCC1=O)=O)[C:32]([O:34]N1C(=O)CCC1=O)=O.[CH2:54]([N:56]([CH2:59][CH3:60])[CH2:57][CH3:58])C>CN(C=O)C>[Cl:27][C:24]1[CH:25]=[C:26]2[C:21](=[C:22]([Cl:28])[CH:23]=1)[CH2:20][N:19]([CH3:29])[CH2:18][CH:17]2[C:13]1[CH:12]=[C:11]([S:8]([NH:7][CH2:6][CH2:5][O:4][CH2:3][CH2:2][NH:1][C:32](=[O:34])[CH:31]([OH:30])[CH:42]([OH:53])[C:43]([NH:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][NH:7][S:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH:58]3[C:26]4[C:60](=[C:22]([Cl:28])[CH:23]=[C:24]([Cl:27])[CH:25]=4)[CH2:59][N:56]([CH3:54])[CH2:57]3)[CH:12]=2)(=[O:10])=[O:9])=[O:45])(=[O:10])=[O:9])[CH:16]=[CH:15][CH:14]=1
Reactant: CCN(CC)CC
Reactant: CN1Cc2c(Cl)cc(Cl)cc2C(c2cccc(S(=O)(=O)NCCOCCN)c2)C1
Reactant: O=C(ON1C(=O)CCC1=O)C(O)C(O)C(=O)ON1C(=O)CCC1=O
Solvent: CN(C)C=O
Product: CN1Cc2c(Cl)cc(Cl)cc2C(c2cccc(S(=O)(=O)NCCOCCNC(=O)C(O)C(O)C(=O)NCCOCCNS(=O)(=O)c3cccc(C4CN(C)Cc5c(Cl)cc(Cl)cc54)c3)c2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 50-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of N-(2-(2-aminoethoxy)ethyl)-3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide (intermediate 176.1) (60 mg, 0.13 mmol, 1.00 equiv) in DMF (3 mL), bis(2,5-dioxopyrrolidin-1-yl) 2,3-dihydroxybutanedioate (intermediate 168.1) (21 mg, 0.06 mmol, 0.47 equiv) and triethylamine (50 mg, 0.49 mmol, 3.77 equiv). The resulting solution was stirred overnight at room temperature at which time the mixture was concentrated under vacuum. The crude product was purified by Prep-HPLC with acetonitrile:water (0.05% CF3COOH) (10%-100%). This resulted in 21 mg (13%) of a TFA salt of N1,N4-bis(2-(2-(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylsulfonamido)ethoxy)ethyl)-2,3-dihydroxysuccinamide as a white solid. 1H-NMR (300 MHz, CD3OD, ppm): δ 7.92 (d, J=7.8 Hz, 2H), 7.81 (m, 2H), 7.67 (t, J=7.8 Hz, 2H), 7.57 (m, 2H), 7.55 (d, J=6.9 Hz, 2H), 6.85 (m, 2H), 4.78 (s, 2H), 4.77 (s, 2H), 4.54 (d, J=40.2 Hz, 2H), 4.48 (s, 2H), 3.92 (m, 2H), 3.53 (m, 10H), 3.18 (s, 6H), 3.07 (t, J=5.4 Hz, 4H). MS (m/z): 517 [1/2M+1]+.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([OH:10])[C:3]=1[CH:4]=[O:5].I[CH:12]([CH3:14])[CH3:13].C([O-])([O-])=O.[K+].[K+].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.CCOCC>[F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH:12]([CH3:14])[CH3:13])[C:3]=1[CH:4]=[O:5]
Reactant: O=Cc1c(O)cccc1F
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(C)Oc1cccc(F)c1C=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of commercially available 2-fluoro-6-hydroxybenzaldehyde (3.000 g; 21.40 mmol), 2-iodopropane (10.919 g; 64.20 mmol), K2CO3 (5.918 g; 42.80 mmol), and Cs2CO3 (1.395 g; 4.28 mmol) in anh. DMF (63 ml) was stirred at rt, under nitrogen, for 16 h. Et2O was added and the organic layer was washed with water, dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure affording 2-fluoro-6-isopropoxybenzaldehyde as a yellow oil. LC-MS (conditions A): tR=0.74 min.; [M+H]+: 183.15 g/mol.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH3:11][C:12]12[CH2:21][CH:16]([C:17]([CH3:20])([CH3:19])[O:18]1)[CH2:15][CH2:14][CH:13]2[OH:22].C(N(CC)CC)C>C(Cl)Cl>[CH3:11][C:12]12[CH2:21][CH:16]([C:17]([CH3:19])([CH3:20])[O:18]1)[CH2:15][CH2:14][C:13]2=[O:22]
Reactant: CC1(C)OC2(C)CC1CCC2O
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC12CC(CCC1=O)C(C)(C)O2
Temperature: -60 °C
Reaction time: 0.17 h
Yield: 122.4 %

Procedure:
To a solution of 6.72 g of oxalyl chloride in 150 ml of methylene chloride at -60° C. was added dropwise 8.24 g of dimethyl sulfoxide in 20 ml of methylene chloride. After stirring for 10 minutes at -60° C. under a nitrogen atmosphere, a solution of 7.50 g of 5,7,7-trimethyl-6-oxabicyclo[3.2.1]octan-4-ol in 40 ml of methylene chloride was added dropwise. A white precipitate formed. After stirring in the cold for 15 minutes, 22.22 g of triethylamine was added in a stream via syringe. The reaction mixture was allowed to rise to room temperature and after 15 minutes was poured into 200 ml of ice water. The resulting phases were separated and the aqueous phase was extracted with two 100 ml portions of methylene chloride. The combined organic phases were washed twice with 100 ml portions of saturated aqueous sodium chloride, dried (MgSO4) and concentrated in vacuo to leave 9.07 g of an orange liquid containing some beige solid. This crude mixture was diluted with hexane and filtered. The filtrate was dried (MgSO4) and concentrated in vacuo to leave 8.06 g of orange liquid. Vacuum distillation of the liquid gave two fractions of the desired product; 4.35 g, b.p. 78°-85° C. (4 mm) of 82% purity by GLC and 1.86 g, b.p. 85°-93° C. (4 mm) of 95% purity by GLC.
Reaction SMILES: [CH2:1]([N:8]1[C:16](=[O:17])[C@@H:15]2[C@@H:10]([CH2:11][CH2:12][CH2:13][NH:14]2)[C:9]1=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C@:19]12([CH2:29][S:30]([OH:33])(=[O:32])=[O:31])[C:26]([CH3:28])([CH3:27])[CH:23]([CH2:24][CH2:25]1)[CH2:22][C:20]2=[O:21]>C(#N)C>[C@:19]12([CH2:29][S:30]([OH:33])(=[O:31])=[O:32])[C:26]([CH3:28])([CH3:27])[CH:23]([CH2:24][CH2:25]1)[CH2:22][C:20]2=[O:21].[CH2:1]([N:8]1[C:16](=[O:17])[C@H:15]2[C@H:10]([CH2:11][CH2:12][CH2:13][NH:14]2)[C:9]1=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1[C@H]2NCCC[C@H]2C(=O)N1Cc1ccccc1
Agent: CC1(C)C2CC[C@@]1(CS(=O)(=O)O)C(=O)C2
Solvent: CC#N
Product: O=C1[C@H]2CCCN[C@H]2C(=O)N1Cc1ccccc1
Temperature: 25 °C

Procedure:
4.8 g (10 mmol) of cis-8-benzyl-7,9-dioxo-2,8-diazabicyclo[4.3.0]nonane (racemate) and 2.36 g (5 mmol) of (1S)-camphorsulfonic acid are dissolved in 20 ml of acetonitrile under reflux to give a clear solution and cooled to room temperature. The precipitated solid is filtered off with suction and dried in vacuo to give 1.0 g
Reaction SMILES: Cl.[NH2:2][C:3]12[CH2:11][CH2:10][CH:7]([CH2:8][CH2:9]1)[CH2:6][N:5]1[C:12](=[O:30])[C:13]([O:21][C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:23])=[C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:15]=[C:4]21.[CH3:31][N:32]([CH3:38])[C:33](=[O:37])[C:34](O)=[O:35].C(N(C(C)C)CC)(C)C.O>CN(C=O)C>[CH3:31][N:32]([C:33](=[O:37])[C:34]([NH:2][C:3]12[CH2:11][CH2:10][CH:7]([CH2:8][CH2:9]1)[CH2:6][N:5]1[C:12](=[O:30])[C:13]([O:21][C:22]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)=[O:23])=[C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:15]=[C:4]21)=[O:35])[CH3:38]
Reactant: CN(C)C(=O)C(=O)O
Reactant: CCOC(=O)c1nc2n(c(=O)c1OC(=O)c1ccccc1)CC1CCC2(N)CC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCOC(=O)c1nc2n(c(=O)c1OC(=O)c1ccccc1)CC1CCC2(NC(=O)C(=O)N(C)C)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 91.1 %

Procedure:
To a stirred solution of ethyl 10-amino-4-oxo-3-((phenylcarbonyl)oxy)-4,6,7,8,9,10-hexahydro-7,10-ethanopyrimido[1,2-a]azepine-2-carboxylate hydrochloride (2.4 g, 5.53 mmol) in DMF (50 mL) as added 2-(dimethylamino)-2-oxoacetic acid (1.295 g, 11.06 mmol), diisopropyl-ethylamine (5.80 mL, 33.2 mmol) and the resulting mixture was stirred at room temperature for 3 h. Water was then added and the mixture extracted with ethyl acetate (2×200 mL). The organic solution was washed with 1N HCl (50 mL), dried (Na2SO4), filtered and concentrated. The crude material was triturated with ethyl acetate/hexane to afford the title compound (2.5 g, 5.04 mmol, 91% yield) as a light yellow solid. 1H NMR (500 MHz, CDCl3) δ: 9.33 (1 H, brs), 8.18 (2 H, d, J=7.02 Hz), 7.64 (1 H, t, J=7.48 Hz), 7.50 (2 H, t, J=7.93 Hz), 4.29 (2 H, q, J=7.02 Hz), 4.17 (2 H, d, J=3.66 Hz), 3.34 (3 H, s), 3.03 (3 H, s), 2.88-3.00 (2 H, m), 2.50 (1 H, brs), 1.93-2.10 (4 H, m), 1.73-1.82 (2 H, m), 1.18 (3 H, t, J=7.17 Hz). LCMS (M+H)=497.79.