Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH3:12])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:8]=[N:9][NH:10][CH:11]=1.[CH2:13]([NH:17][CH2:18][CH:19]([CH3:21])[CH3:20])[CH:14]([CH3:16])[CH3:15].[CH2:22]=[O:23]>CC(O)C>[C:1]1([CH3:12])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[NH:8][N:9]=[N:10][C:11]=1[CH:22]=[O:23].[CH2:13]([NH:17][CH2:18][CH:19]([CH3:21])[CH3:20])[CH:14]([CH3:16])[CH3:15]
Reactant: Cc1ccccc1-c1c[nH]nn1
Reactant: C=O
Agent: CC(C)CNCC(C)C
Solvent: CC(C)O
Product: Cc1ccccc1-c1[nH]nnc1C=O
Temperature: 82 °C

Procedure:
Approximately 80.1 gm (0.6 mole) of tolyltriazole, 200 ml 2-propanol, and 78.0 gm (0.6 mole) diisobutylamine were mixed in a 500 ml reactor until a homogeneous phase was formed. 51.0 gm (0.618 mole) of aqueous formaldehyde was slowly added while maintaining a reactor temperature ≤40° C. Thereafter, the reactants were heated at 82±2° C. for 4 hrs., then at 110±2° C. for two additional hours during which isopropanol and water were removed by distillation. The final product (163.5 gm) is a yellowish liquid which solidifies upon standing at ambient temperature (m.p. 49°-51° C.). A final filtration to remove possibly unreacted tolyltriazole is optional. However, small amounts of residual water could make the final product appear hazy.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:21][C:20]3[C:11](=[CH:12][C:13]4[O:14][C:15](=[O:22])[CH2:16][CH2:17][C:18]=4[CH:19]=3)[CH:10]3[CH2:23][CH2:24][CH2:25][CH2:26][CH:9]23)=[CH:4][CH:3]=1.[CH3:27][NH2:28]>O1CCCC1>[OH:14][C:13]1[C:18]([CH2:17][CH2:16][C:15]([NH:28][CH3:27])=[O:22])=[CH:19][C:20]2[CH2:21][CH:8]([C:5]3[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=3)[CH:9]3[CH:10]([C:11]=2[CH:12]=1)[CH2:23][CH2:24][CH2:25][CH2:26]3
Reactant: CN
Reactant: O=C1CCc2cc3c(cc2O1)C1CCCCC1C(c1ccc(O)cc1)C3
Solvent: C1CCOC1
Product: CNC(=O)CCc1cc2c(cc1O)C1CCCCC1C(c1ccc(O)cc1)C2
Reaction time: 0.5 h
Yield: 92 %

Procedure:
Combine 5-(4-Hydroxy-phenyl)-1,2,3,4,4a,5,6,8,9,12b-decahydro-11-oxa-benzo[a]anthracen-10-one (0.014 g, 0.04 mmol) and excess methylamine (40% in water) in tetrahydrofuran (1 ml). After 30 minutes, remove solvent in vacuo, dissolve in ethyl acetate and dry over anhydrous sodium sulfate. Remove solvent in vacuo to yield the titled compound (0.014 g, 92%). 1H NMR (DMSO-d6) 9.19 (s, 1H), 9.02 (s, 1H), 7.11 (d, J=8.8 Hz, 2H), 6.83 (s, 1H), 6.79 (s, 1H), 6.73 (d, J=8.4 Hz, 2H), 3.1 (m, 3H), 2.7 (m, 3H), 2.58 (s, 3H), 2.35 (m, 2H), 1.9 (m, 1H), 1.6 (m, 2H), 1.4 (m, 1H), 1.75-0.9 (m, 5H).
Reaction SMILES: FC1C=C(F)C=CC=1C1C=C(CN2C(=O)C3=CC=CC=C3C2=O)C(=O)N(CC(C)C)N=1.[C:32]([CH2:35][CH2:36][C:37]1[C:38](=[O:56])[N:39]([CH2:52][CH:53]2[CH2:55][CH2:54]2)[N:40]=[C:41]([C:43]2[CH:48]=[CH:47][C:46]([O:49][CH3:50])=[C:45]([F:51])[CH:44]=2)[CH:42]=1)(O)=[O:33]>>[CH:53]1([CH2:52][N:39]2[C:38](=[O:56])[C:37]([CH2:36][CH2:35][CH2:32][OH:33])=[CH:42][C:41]([C:43]3[CH:48]=[CH:47][C:46]([O:49][CH3:50])=[C:45]([F:51])[CH:44]=3)=[N:40]2)[CH2:55][CH2:54]1
Reactant: COc1ccc(-c2cc(CCC(=O)O)c(=O)n(CC3CC3)n2)cc1F
Agent: CC(C)Cn1nc(-c2ccc(F)cc2F)cc(CN2C(=O)c3ccccc3C2=O)c1=O
Product: COc1ccc(-c2cc(CCCO)c(=O)n(CC3CC3)n2)cc1F
Yield: 82.9 %

Procedure:
Following the procedure of Example 1 (8), 4-(2-carboxyethyl)-2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one was reacted to yield the title compound as a brown oil (yield: 82.9%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[NH:15][C:14](=[O:16])[O:13][C:12]([CH3:18])([CH3:17])[C:11]=2[CH:19]=1.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([SH:28])[CH:25]=[CH:26][CH:27]=1>>[CH3:20][O:21][C:22]1[CH:23]=[C:24]([S:28][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]2[CH:8]=[CH:9][C:10]3[NH:15][C:14](=[O:16])[O:13][C:12]([CH3:18])([CH3:17])[C:11]=3[CH:19]=2)[CH:25]=[CH:26][CH:27]=1
Reactant: COc1cccc(S)c1
Reactant: CC1(C)OC(=O)Nc2ccc(OCCCCCl)cc21
Product: COc1cccc(SCCCCOc2ccc3c(c2)C(C)(C)OC(=O)N3)c1

Procedure:
Prepared analogously to Example 1 from 6-(4-chlorobutoxy)-4,4-dimethyl-4H-3,1-benzoxazin-2-one and 3-methoxy-thiophenol.
Reaction SMILES: [BH4-].[Na+].[Br:3][CH2:4][C:5](=[O:24])[C@@H:6]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:7][C:8]1[CH:13]=[C:12]([F:14])[CH:11]=[C:10]([F:15])[CH:9]=1>C(OCC)(=O)C.CCCCCC>[Br:3][CH2:4][C@@H:5]([OH:24])[C@@H:6]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:20])([CH3:21])[CH3:22])[CH2:7][C:8]1[CH:9]=[C:10]([F:15])[CH:11]=[C:12]([F:14])[CH:13]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cc(F)cc(F)c1)C(=O)CBr
Agent: [BH4-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)CBr
Reaction time: 0.5 h

Procedure:
Sodium borohydride (1.32 g, 34.9 mmole, 1.1 eq.) is added to tert-Butyl (1S)-3-bromo-1-(3,5-difluorobenzyl)-2-oxopropylcarbamate (III, EXAMPLE 1, 12 g, 31.75 mmole) dissolved in absolute alcohol (500 mL) at −78 degrees C. The reaction mixture is stirred for 0.5 hour and monitored by TLC (ethyl acetate/hexane, 20/80; Rf=0.2). The mixture is quenched with water (10 mL) and the solvent removed under reduced pressure with heat (not exceeding 30 degrees C.) to dryness. The solid is partitioned between dichloromethane and water, washed with saline, dried over anhydrous sodium sulfate. The solvent is removed under reduced pressure to give the title compound, TLC (ethyl acetate/hexane, 20/80) Rf=0.2; MS (MH+)=381.2.
Reaction SMILES: [C:1](O)(=O)[C:2]([OH:4])=[O:3].[CH3:7][N:8]([CH2:13][C:14]1[CH:15]=[C:16]([C:20]2[CH:25]=[CH:24][C:23]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[CH:22][CH:21]=2)[CH:17]=[CH:18][CH:19]=1)[C:9](=[O:12])[CH2:10][NH2:11].C(=O)([O-])[OH:33].[Na+]>C(Cl)(Cl)Cl>[C:30]([OH:33])(=[O:29])[CH2:31][CH2:1][C:2]([OH:4])=[O:3].[CH3:7][N:8]([CH2:13][C:14]1[CH:15]=[C:16]([C:20]2[CH:25]=[CH:24][C:23]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[CH:22][CH:21]=2)[CH:17]=[CH:18][CH:19]=1)[C:9](=[O:12])[CH2:10][NH2:11].[CH3:7][N:8]([CH2:13][C:14]1[CH:15]=[C:16]([C:20]2[CH:25]=[CH:24][C:23]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[CH:22][CH:21]=2)[CH:17]=[CH:18][CH:19]=1)[C:9](=[O:12])[CH2:10][NH2:11]
Reactant: O=C([O-])O
Reactant: O=C(O)C(=O)O
Agent: CN(Cc1cccc(-c2ccc(N3CCOCC3)cc2)c1)C(=O)CN
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: O=C(O)CCC(=O)O
Reaction time: 0.17 h

Procedure:
To N-methyl-N-{[4′-(morpholin-4-yl)biphenyl-3-yl]methyl}glycinamide oxalate (100 mg) were added CHCl3 (10 ml) and a saturated aqueous sodium hydrogen carbonate solution (10 ml), followed by stirring for 10 minutes. The aqueous layer was extracted with chloroform (10 ml). The combined organic layer was dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was dissolved in EtOH (2 ml), and succinic acid was added thereto, followed by stirring for 3 hours. The resulting crystal was filtered and washed with EtOH. The product residue was dried under reduced pressure and dried to obtain N-methyl-N-{[4′-(morpholin-4-yl)biphenyl-3-yl]methyl}glycinamide hemisuccinate (85 mg) as a colorless crystal.
Reaction SMILES: Cl[C:2](=[O:13])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9].C[Si](C)(C)C1S[CH:18]=[CH:19]N=1>ClCCl>[O:13]=[C:2]([C:19]1[CH:18]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)CCCCCC(=O)Cl
Reactant: C[Si](C)(C)c1nccs1
Solvent: ClCCl
Product: CCOC(=O)CCCCCC(=O)c1ccccc1
Reaction time: 3 h

Procedure:
To a solution of ethyl 7-chloro-7-oxoheptanoate (1.31 g) in dichloromethane (25 mL) was added a solution of 2-(trimethylsilyl)-1,3-thiazole (500 mg) in dichloromethane (5 mL) under nitrogen. After stirring for 3 hours, the reaction was quenched by adding saturated sodium bicarbonate (5 mL). The mixture was partitioned between ethyl acetate (30 mL) and saturated sodium bicarbonate (30 mL), and the organic layer was washed with brine, dried over magnesium sulfate, and evaporated to give a colorless oil. Flash silica gel column chromatography eluting with ethyl acetate-hexane=1-10 to 2-5 afforded ethyl 7-oxo-7-(1,3-thiazol-2-yl)heptanoate as a colorless oil (778 mg).
Reaction SMILES: CC1(C)[O:6][C@H:5]([CH2:7][CH2:8][NH:9][C:10]2[CH:15]=[CH:14][C:13]([S:16]([NH:19][C:20]3[S:21][CH:22]=[CH:23][N:24]=3)(=[O:18])=[O:17])=[CH:12][CH:11]=2)[C:4](=O)[O:3]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1COCC1>[OH:6][C@@H:5]1[CH2:7][CH2:8][N:9]([C:10]2[CH:15]=[CH:14][C:13]([S:16]([NH:19][C:20]3[S:21][CH:22]=[CH:23][N:24]=3)(=[O:18])=[O:17])=[CH:12][CH:11]=2)[C:4]1=[O:3]
Reactant: CC1(C)OC(=O)[C@@H](CCNc2ccc(S(=O)(=O)Nc3nccs3)cc2)O1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Solvent: O
Product: O=C1[C@H](O)CCN1c1ccc(S(=O)(=O)Nc2nccs2)cc1
Yield: 65.1 %

Procedure:
A stirred solution of (R)-4-[2-(2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)ethylamino]-N-(thiazol-2-yl)benzene-sulfonamide (833 mg, 2.15 mmol), p-toluenesulfonic acid monohydrate (42 mg, 0.22 mmol), and THF (10 mL) was stirred at 80° C. for 3 hours. The mixture was concentrated to dryness under reduced pressure. The residue was purified by silica gel chromatography (5% MeOH in DCM) to give (R)-4-(3-hydroxy-2-oxopyrrolidin-1-yl)-N-(thiazol-2-yl)benzene sulfonamide as a white solid (496 mg, 1.4 mmol, 65% yield). 1H-NMR (400 MHz, DMSO-d6) δ 7.85 (dd, J=2.1, 6.9 Hz, 4H), 7.25 (d, J=4.6 Hz, 1H), 6.82 (d, J=4.6 Hz, 1H), 5.83 (d, J=5.9 Hz, 1H), 4.32 (d, J=5.3 Hz, 1H), 3.77 (dd, J=1.9, 9.0 Hz, 1H), 3.71-3.69 (m, 1H), 2.41-2.38 (m, 1H), 1.84 (dd, J=9.2, 12.3 Hz, 1H). LC/MS (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)), m/z: M+1 obs=340.2; tR=0.50 min.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([C:15]2[CH:16]=[CH:17][C:18]3[C:19]4[CH2:28][NH:27][CH2:26][CH2:25][C:20]=4[N:21]([CH3:24])[C:22]=3[CH:23]=2)[C:11](=[O:29])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:31][C:32]([N:34]1[CH2:38][CH2:37][CH2:36][CH2:35]1)=[O:33].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([C:15]2[CH:16]=[CH:17][C:18]3[C:19]4[CH2:28][N:27]([CH2:31][C:32](=[O:33])[N:34]5[CH2:38][CH2:37][CH2:36][CH2:35]5)[CH2:26][CH2:25][C:20]=4[N:21]([CH3:24])[C:22]=3[CH:23]=2)[C:11](=[O:29])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(CCl)N1CCCC1
Reactant: Cn1c2c(c3ccc(-n4ccc(OCc5ccccc5)cc4=O)cc31)CNCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1c2c(c3ccc(-n4ccc(OCc5ccccc5)cc4=O)cc31)CN(CC(=O)N1CCCC1)CC2
Temperature: 70 °C
Yield: 27.1 %

Procedure:
To a solution of 4-benzyloxy-1-(5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)pyridin-2(1H)-one (100 mg, 0.26 mmol) in DMF (3 mL) was added 2-chloro-1-(pyrrolidin-1-yl)ethanone (77 mg, 0.52 mmol) and K2CO3 (72 mg, 0.52 mmol). The reaction mixture was heated to 70° C. and stirred at 70° C. until the reaction was complete. After it was cooled, the reaction was quenched with water and extracted with CH2Cl2. The organic layer was washed with H2O and 5% LiCl, dried with Na2SO4, filtered, and concentrated. Purification by flash column chromatography (silica gel, 5% CH3OH in CH2Cl2) gave 4-(benzyloxy)-1-(5-methyl-2-(2-oxo-2-(pyrrolidin-1-yl)ethyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)pyridine-2(1H)-one (35 mg, 27%) as a yellow foam. The free base was converted to the HCl salt to the give title compound (30 mg, 80%) as a yellow solid: mp 162-166° C.; 1H NMR (500 MHz, CD3OD) δ 7.60 (d, J=7.5 Hz, 1H), 7.56 (d, J=8.0 Hz, 1H), 7.49-7.35 (m, 6H), 7.06 (dd, J=8.5, 1.5 Hz, 1H), 6.33 (dd, J=7.5, 3.0 Hz, 1H), 6.16 (d, J=3.0 Hz, 1H), 5.20 (s, 2H), 4.80 (d, J=14.5 Hz, 1H), 4.54 (d, J=14.5 Hz, 1H), 4.36 (s, 2H), 4.00-3.98 (m, 1H), 3.75 (s, 3H), 3.68-3.65 (m, 1H), 3.54 (t, J=7.0 Hz, 2H), 3.49-3.45 (m, 2H), 3.35-3.33 (m, 2H), 2.05-1.92 (m, 4H); ESI MS m/z 497 [M+H]+; HPLC (Method B) 97.9% (AUC), tR=13.4 min.
Reaction SMILES: [CH:1]([CH:4]1[C:8]2=[N:9][C:10]3[C:11]([C:18]([F:21])([F:20])[F:19])=[CH:12][CH:13]=[CH:14][C:15]=3[C:16]([OH:17])=[C:7]2[C:6](=[N:22][C:23]2[S:24][CH:25]=[CH:26][N:27]=2)[O:5]1)([CH3:3])[CH3:2].O.[C:29]([OH:32])(=[O:31])[CH3:30]>>[C:29]([O:32][CH:4]([C:8]1[C:7]([C:6]([NH:22][C:23]2[S:24][CH:25]=[CH:26][N:27]=2)=[O:5])=[C:16]([OH:17])[C:15]2[C:10](=[C:11]([C:18]([F:19])([F:20])[F:21])[CH:12]=[CH:13][CH:14]=2)[N:9]=1)[CH:1]([CH3:3])[CH3:2])(=[O:31])[CH3:30]
Reactant: CC(C)C1OC(=Nc2nccs2)c2c1nc1c(C(F)(F)F)cccc1c2O
Reactant: CC(=O)O
Solvent: O
Product: CC(=O)OC(c1nc2c(C(F)(F)F)cccc2c(O)c1C(=O)Nc1nccs1)C(C)C

Procedure:
10 g of product of Step B in 200 ml of acetic acid were refluxed for 57 hours and the solution was allowed to return to ambient temperature. Then, 200 ml of water were added followed by filtration. The orange product was washed with water and then was dissolved in a mixture of 250 ml of ethyl acetate and 500 ml of tetrahydrofuran. The mixture was dried and 1 g of active carbon was added. After filtering and concentrating to dryness under reduced pressure, 8.3 g of residue were obtained which was crystallized from 240 ml of ethyl acetate. The crystals were filtered hot, cooled, separated, dried under reduced pressure at 40° C. for 16 hours 5.3 g of expected product were obtained, melting at 242° C.
Reaction SMILES: [CH2:1]([O:4][P:5]([O:11][CH2:12][C:13]1[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:14]=1[C:15](O)=[O:16])([O:7][CH2:8][CH:9]=[CH2:10])=[O:6])[CH:2]=[CH2:3].CN(C)C=O.C(Cl)(=O)C([Cl:31])=O>ClCCl>[CH2:1]([O:4][P:5]([O:11][CH2:12][C:13]1[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:14]=1[C:15]([Cl:31])=[O:16])([O:7][CH2:8][CH:9]=[CH2:10])=[O:6])[CH:2]=[CH2:3]
Reactant: O=C(Cl)C(=O)Cl
Reactant: C=CCOP(=O)(OCC=C)OCc1c(Cl)cccc1C(=O)O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: C=CCOP(=O)(OCC=C)OCc1c(Cl)cccc1C(=O)Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 2-[[bis(allyloxy)phosphoryl]oxymethyl]-3-chlorobenzoic acid (936.1 mg, 2.7 mmol) obtained from Example 27-(4) in dichloromethane (15 ml) was cooled to 0° C., and then N,N-dimethylformamide (15 μl) and oxalyl chloride (1.71 g, 13.5 mmol) were added thereto. After the mixture was stirred at room temperature for 30 minutes, it was worked up according to a similar procedure to that described in Example 1-(12) to afford crude 2-[[bis(allyloxy)phosphoryl]oxymethyl]-3-chlorobenzoyl chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[CH:18]=[CH:19]/[C:20]([O:22][CH2:23][CH2:24][CH2:25][CH3:26])=[O:21])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][N:10]=1.[Sn].Cl.[OH-].[Na+]>CCO>[NH2:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][C:7]2[CH:6]=[CH:5][C:4](/[CH:18]=[CH:19]/[C:20]([O:22][CH2:23][CH2:24][CH2:25][CH3:26])=[O:21])=[CH:3][C:2]=2[Cl:1])=[N:10][CH:11]=1
Reactant: CCCCOC(=O)/C=C/c1ccc(Oc2ccc([N+](=O)[O-])cn2)c(Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCOC(=O)/C=C/c1ccc(Oc2ccc(N)cn2)c(Cl)c1
Yield: 95.5 %

Procedure:
To an EtOH (500 mL) solution of butyl (E)-3-{3-chloro-4-[(5-nitropyridin-2-yl)oxy]phenyl}prop-2-enoate (45.4 g) and tin powder (57.3 g) was slowly added conc. HCl (36.6 mL) at 0° C., then the resultant mixture was stirred at room temperature for 1 hour. The reaction mixture was neutralized with 5 M aqueous NaOH, and the mixture was filtered off on Celite. The filtrate was evaporated and water was added to the residue, and the mixture was extracted with AcOEt. The organic layer was washed with water and saturated aqueous NaCl, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/AcOEt=2/1) to afford butyl (E)-3-{4-[(5-amino-pyridin-2-yl)oxy]-3-chlorophenyl}prop-2-enoate (39.9 g) as a pale yellow solid.
Reaction SMILES: [CH2:1]([N:8]1[CH:13]=[CH:12][C:11](=[O:14])[C:10]2[C:15]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[C:16]([Si](C)(C)C)[O:17][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I:28]N1C(=O)CCC1=O>CN(C)C=O>[CH2:1]([N:8]1[CH:13]=[CH:12][C:11](=[O:14])[C:10]2[C:15]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[C:16]([I:28])[O:17][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1I
Reactant: C[Si](C)(C)c1oc2c(c1-c1ccccc1)c(=O)ccn2Cc1ccccc1
Solvent: CN(C)C=O
Product: O=c1ccn(Cc2ccccc2)c2oc(I)c(-c3ccccc3)c12
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
The 7-benzyl-3-phenyl-2-(trimethylsilyl)furo[2,3-b]pyridin-4(7H)-one 4d was taken up in N,N-dimethylformamide (50 mL), and N-Iodosuccinimide (15.704 g, 69.95 mmol) was added. The mixture stirred at room temperature for 1.5 h and was then concentrated. The residue was partitioned between dichloromethane and an aqueous solution of sodium thiosulfate. The aqueous phase was separated and extracted with dichloromethane. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to afford an orange brown oil. Purification via column chromatography on silica gel (eluting with ethyl acetate) afforded 7-benzyl-2-iodo-3-phenylfuro[2,3-b]pyridin-4(7H)-one 4f as a brown solid. MS (MH+) 428.0; Calculated 427 for C20H14INO2.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[N:3]=1.[NH:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1>O1CCOCC1>[NH2:1][C:2]1[N:7]=[C:6]([N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[N:3]=1
Reactant: C1CCNC1
Reactant: Nc1nc(Cl)nc(-c2ccc(Cl)cc2)n1
Solvent: C1COCCO1
Product: Nc1nc(-c2ccc(Cl)cc2)nc(N2CCCC2)n1
Yield: 91.1 %

Procedure:
2-Amino-4-chloro-6-(4-chlorophenyl)-s-triazine (melting point 273° to 275° C.) (2.12 grams) and 2.5 grams of pyrrolidine were dissolved in 20 milliliters of dioxane, the mixture was heated to reflux for two hours with stirring, the reaction solution was evaporated to dryness in vacuo, diluted aqueous solution of sodium hydroxide was added to the residue, insoluble matters were collected by filtration, and washed with isopropyl alcohol to give 2.21 grams of 2-amino-4-pyrrolidino-6-(4-chlorophenyl)-s-triazine, melting point 217° to 219° C.
Reaction SMILES: Br[C:2]1(Br)[C:10]2[C:5](=[N:6][CH:7]=[C:8]([Br:11])[CH:9]=2)[N:4]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:3]1=[O:20]>CC(O)=O.[Zn]>[Br:11][C:8]1[CH:9]=[C:10]2[CH2:2][C:3](=[O:20])[N:4]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:5]2=[N:6][CH:7]=1
Reactant: C[Si](C)(C)CCOCN1C(=O)C(Br)(Br)c2cc(Br)cnc21
Agent: [Zn]
Solvent: CC(=O)O
Product: C[Si](C)(C)CCOCN1C(=O)Cc2cc(Br)cnc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 24.8 %

Procedure:
To a solution of 3,3,5-tribromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-2(3H)-one (4.98 g, 10.0 mmol) in AcOH (50 mL) was added zinc dust (1.28 g, 20.0 mmol). The resulting mixture was stirred at room temperature for 2 hr, after which it was filtered thru Celite and concentrated in vacuo. The resulting residue was purified via silica gel chromatography eluting with 1:1 Hexanes:EtOAc to yield the title compound as a yellow oil (0.85 g, 25% over three steps). HPLC retention time: 2.60 minutes; MS ESI (m/z): 287.2 (Fragment+1)+, calc. 342.
Reaction SMILES: [O:1]=[C:2]1[C@@H:8]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:7][CH2:6][CH2:5][CH2:4][NH:3]1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.Br[CH2:28][C:29]([O:31][CH3:32])=[O:30]>C1COCC1>[C:12]([O:11][C:10]([NH:9][C@H:8]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]([CH2:28][C:29]([O:31][CH3:32])=[O:30])[C:2]1=[O:1])=[O:16])([CH3:13])([CH3:15])[CH3:14]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCCNC1=O
Reactant: COC(=O)CBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)CN1CCCC[C@H](NC(=O)OC(C)(C)C)C1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 35.1 %

Procedure:
To a round bottom flask was added (S)-tert-butyl 2-oxoazepan-3-ylcarbamate (130 mg, 0.569 mmol), THF (10 mL) and LiHMDS (0.190 mL, 1.14 mmol). The reaction was stirred at rt for 30 min. Then methyl 2-bromoacetate (0.079 mL, 0.85 mmol) was added to the reaction and the reaction mixture was stirred at rt overnight. The reaction mixture was concentrated and purified by RP prep-HPLC to give (S)-methyl 2-(3-(tert-butoxycarbonylamino)-2-oxoazepan-1-yl)acetate (60 mg, 0.20 mmol, 35% yield) as a clear oil. Anal. Calcd. for C14H24N2O5 m/z 300.3. found: 301.2 (M+H)+; 1H NMR (500 MHz, CDCl3) δ ppm 5.89 (br. s., 1H), 4.40 (d, J=4.4 Hz, 1H), 4.13 (br. s., 2H), 3.79-3.56 (m, 4H), 3.15 (d, J=12.1 Hz, 1H), 2.07-1.87 (m, 2H), 1.75 (d, J=10.4 Hz, 2H), 1.62-1.49 (m, 2H), 1.39 (br. s., 9H); 13C NMR (126 MHz, CDCl3) δ ppm 173.82, 169.55, 155.20, 79.55, 53.36, 52.17, 50.71, 50.63, 32.21, 28.31, 27.80, 26.87.
Reaction SMILES: Br[CH:2]([C:27]1[O:31][C:30]([C:32]2[CH:39]=[CH:38][C:35]([C:36]#[N:37])=[CH:34][CH:33]=2)=[N:29][N:28]=1)[CH:3](Br)[C:4]1[N:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:15])[C:7]([C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][N:17]=2)=[N:6][N:5]=1.C(O[K])(C)(C)C.C(O)(=O)C.C(OCC)(=O)C>C1C=CC=CC=1>[Cl:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[N:8]1[C:7]([C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][N:17]=2)=[N:6][N:5]=[C:4]1[C:3]#[C:2][C:27]1[O:31][C:30]([C:32]2[CH:33]=[CH:34][C:35]([C:36]#[N:37])=[CH:38][CH:39]=2)=[N:29][N:28]=1
Reactant: CS(=O)(=O)c1ccc(-c2nnc(C(Br)C(Br)c3nnc(-c4ccc(C#N)cc4)o3)n2-c2ccccc2Cl)nc1
Agent: CC(C)(C)O[K]
Solvent: c1ccccc1
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1ccc(-c2nnc(C#Cc3nnc(-c4ccc(C#N)cc4)o3)n2-c2ccccc2Cl)nc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 4-(5-{1,2-Dibromo-2-[4-(2-chloro-phenyl)-5-(5-methanesulfonyl-pyridin-2-yl)-4H-[1,2,4]triazol-3-yl]-ethyl}-[1,3,4]oxadiazol-2-yl)-benzonitrile 2 (0.1 g, 0.19 mmol) in benzene (10 mL) was added tBuOK (0.05 g, 0.28 mmol) portionwise at 0° C. The mixture was stirred at 0° C. for 1 h, treated with diluted acetic acid and ethyl acetate, washed with H2O, dried over Na2SO4 and concentrated. The residue was subjected to FCC (50-100% ethyl acetate/hexanes) to afford 4-{5-[4-(2-Chloro-phenyl)-5-(5-methanesulfonyl-pyridin-2-yl)-4H-[1,2,4]triazol-3-ylethynyl]-[1,3,4]oxadiazol-2-yl}-benzonitrile. Yield: 0.03 g, 39%.
Reaction SMILES: [H-].[Na+].[CH:3]1[C:8]2[C:9](=[O:18])[NH:10][C:11]3[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=3[S:13][C:7]=2[CH:6]=[CH:5][CH:4]=1.Br[CH2:20][CH2:21][CH3:22]>CN(C)C=O>[CH2:20]([N:10]1[C:9](=[O:18])[C:8]2[CH:3]=[CH:4][CH:5]=[CH:6][C:7]=2[S:13][C:12]2[CH:14]=[CH:15][CH:16]=[CH:17][C:11]1=2)[CH2:21][CH3:22]
Reactant: O=C1Nc2ccccc2Sc2ccccc21
Reactant: CCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCN1C(=O)c2ccccc2Sc2ccccc21
Temperature: 50 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
0.14 grams of a 50% dispersion of sodium hydride in mineral oil was added to a solution of dibenz[b,f][1,4]thiazepin-11(10H)-one in 10 ml of dimethylformamide. After 15 minutes the mixture was warmed to 50° C. and stirred under argon for one hour. After allowing the mixture to cool to room temperature, 0.34 grams of 1-bromopropane was added slowly. The reaction mixture was stirred for 5 hours, after which time it was quenched with water and the product extracted with diethyl ether. The extracts were washed with a saline solution, dried (anhydrous magnesium sulfate) and concentrated to give a colorless oil which was purified by column chromatography (ethyl acetate/hexane, 5%, 10%, 20%) to provide 0.37 grams (91% of theory) of 10-n-propyl-dibenz[b,f][1,4]thiazepin-11(10H)-one as a white crystalline solid, m.p. 103°-104.5° C.