Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[I:20]I.[Cl:22][C:23]1[CH:40]=[C:39]([CH3:41])[CH:38]=[C:37]([Cl:42])[C:24]=1[O:25][CH2:26][CH2:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([CH2:35]O)=[CH:31][CH:30]=1.N1C=CN=C1>ClCCl>[Cl:22][C:23]1[CH:40]=[C:39]([CH3:41])[CH:38]=[C:37]([Cl:42])[C:24]=1[O:25][CH2:26][CH2:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([CH2:35][I:20])=[CH:31][CH:30]=1
Reactant: Cc1cc(Cl)c(OCCOc2ccc(CO)cc2)c(Cl)c1
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1cc(Cl)c(OCCOc2ccc(CI)cc2)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of triphenylphosphine (1.2 eq.) in dichloromethane (0.09 M) was added iodine (1.2 eq.) and the resulting reddish-orange mixture was stirred at RT for 15 min. At 0° C., a dichloromethane solution (0.1 M) of {4-[2-(2,6-dichloro-4-methylphenoxy)ethyoxy]phenyl}methanol prepared in the previous step (1 eq.) and imidazole (3 eq.) was then added dropwise over 15 min. The resulting orange-yellow suspension was stirred at 0° C. for 1 h and then at RT for 15 min. The reaction was quenched with 10% (w/w) aq. NaHSO3 and extracted with ether. The organic extracts were combined, washed with brine, dried over MgSO4, filtered and the filtrate concentrated in vacuo. The resulting residue was triturated in a 10:1 (v/v) Hex:ether solution and filtered through a pad of SiO2. The filtrate was concentrated in vacuo to afford the title compound as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CN(C=O)C>[CH2:15]([O:8][C:4]1[CH:3]=[C:2]([Br:1])[CH:7]=[CH:6][CH:5]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: BrCc1ccccc1
Reactant: Oc1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Brc1cccc(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 95.7 %

Procedure:
A mixture of 3-bromophenol (10.0 g, 57.8 mmol) and 325 mesh potassium carbonate (8.79 g, 63.6 mmol) in DMF (100 mL) is treated dropwise with benzyl bromide (9.89 g, 57.8 mmol) and then stirred for 20 hours at room temperature under N2. The reaction is filtered, and the filtrate is acidified with 1 N HCl. The mixture is then diluted with water and extracted with Et2O. The organic layer is dried (Na2SO4), and the solvent is removed in vacuo to afford crude product that is absorbed on silica gel and purified by flash chromatography using 10/1 hexanes/ethyl acetate to afford about 14.55 g (96%) of the titled compound. Rf=0.86 (4/1 hexanes/EtOAc). 1H NMR (400 MHz, CDCl3).
Reaction SMILES: [CH2:1]1[O:11][C:4]2([CH2:9][CH2:8][C:7](=[O:10])[CH2:6][CH2:5]2)[O:3][CH2:2]1.[F:12][C:13]1[CH:18]=[CH:17][C:16]([Mg]Br)=[CH:15][CH:14]=1>>[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:7]2([OH:10])[CH2:6][CH2:5][C:4]3([O:3][CH2:2][CH2:1][O:11]3)[CH2:9][CH2:8]2)=[CH:15][CH:14]=1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: Fc1ccc([Mg]Br)cc1
Product: OC1(c2ccc(F)cc2)CCC2(CC1)OCCO2
Yield: 88.2 %

Procedure:
This compound was prepared from 1,4-cyclohexanedione monoethylene ketal (6.24 g, 40 mmole) and 4-fluorophenyl magnesium bromide (60 mmole) in a manner similar to example 3. The crude product was crystallized from hexane to give the product (8.9 g, 88%).
Reaction SMILES: [N:1]([CH2:4][C@@H:5]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][N:6]1[C:15]([C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][C:25]=1[C:26]1[N:27]([CH3:42])[CH:28]=[C:29]([C:31](=[O:41])[N:32]([CH2:37][CH2:38][CH2:39][CH3:40])[CH2:33][CH2:34][CH2:35][CH3:36])[N:30]=1)[C:20](O)=[O:21])=[O:16])=[N+:2]=[N-:3].[I:43][C:44]1[CH:45]=[CH:46][CH:47]=[C:48]2[C:53]=1[CH:52]=[C:51]([S:54]([NH2:57])(=[O:56])=[O:55])[CH:50]=[CH:49]2>>[N:1]([CH2:4][C@@H:5]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][N:6]1[C:15]([C:17]1[CH:18]=[C:19]([C:20](=[O:21])[NH:57][S:54]([C:51]2[CH:50]=[CH:49][C:48]3[C:53](=[C:44]([I:43])[CH:45]=[CH:46][CH:47]=3)[CH:52]=2)(=[O:56])=[O:55])[CH:23]=[CH:24][C:25]=1[C:26]1[N:27]([CH3:42])[CH:28]=[C:29]([C:31]([N:32]([CH2:33][CH2:34][CH2:35][CH3:36])[CH2:37][CH2:38][CH2:39][CH3:40])=[O:41])[N:30]=1)=[O:16])=[N+:2]=[N-:3]
Reactant: NS(=O)(=O)c1ccc2cccc(I)c2c1
Reactant: CCCCN(CCCC)C(=O)c1cn(C)c(-c2ccc(C(=O)O)cc2C(=O)N2Cc3ccccc3C[C@H]2CN=[N+]=[N-])n1
Product: CCCCN(CCCC)C(=O)c1cn(C)c(-c2ccc(C(=O)NS(=O)(=O)c3ccc4cccc(I)c4c3)cc2C(=O)N2Cc3ccccc3C[C@H]2CN=[N+]=[N-])n1
Yield: 40.8 %

Procedure:
Following a procedure analogous to that for the synthesis of Example 271, 3-((S)-3-(azidomethyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-4-(4-(dibutylcarbamoyl)-1-methyl-1H-imidazol-2-yl)benzoic acid (Intermediate 281D, 120 mg, 0.21 mmol) and 8-iodonaphthalene-2-sulfonamide (Intermediate 8, 139 mg, 0.42 mmol) were converted to the title compound (76 mg, 41%). MS(ESI−) m/z 885.8 (M−H)−.
Reaction SMILES: [NH2:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH2:10][CH2:11][O:12][CH3:13])[C:6]2[CH:14]=[CH:15][CH:16]=[CH:17][C:5]=2[C:4]2[CH:18]=[CH:19][CH:20]=[CH:21][C:3]1=2.[C:22](O)(=[O:26])[C@H:23]([CH3:25])[OH:24]>>[OH:24][C@@H:23]([CH3:25])[C:22]([NH:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH2:10][CH2:11][O:12][CH3:13])[C:6]2[CH:14]=[CH:15][CH:16]=[CH:17][C:5]=2[C:4]2[CH:18]=[CH:19][CH:20]=[CH:21][C:3]1=2)=[O:26]
Reactant: COCCN1C(=O)[C@@H](N)c2ccccc2-c2ccccc21
Reactant: C[C@H](O)C(=O)O
Product: COCCN1C(=O)[C@@H](NC(=O)[C@H](C)O)c2ccccc2-c2ccccc21

Procedure:
Using (S)-7-amino-5-(2-methoxy-ethyl)-5H,7H-dibenzo[b,d]azepin-6-one and L-(+)-lactic acid, the title compound was prepared in the same manner as described for example 5a. Colourless, viscous oil (>98%). MS: m/e=355(M+H+).
Reaction SMILES: Cl.[C:2](=[NH:6])([NH2:5])[CH2:3][CH3:4].C[O-].[Na+].[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH:25]([C:30](=O)[CH2:31][CH2:32][CH2:33][CH3:34])[C:26](OC)=[O:27])=[C:20]([F:36])[CH:19]=1)#[N:11]>CO>[CH2:31]([C:30]1[N:6]=[C:2]([CH2:3][CH3:4])[NH:5][C:26](=[O:27])[C:25]=1[CH2:24][C:21]1[CH:22]=[CH:23][C:18]([C:13]2[C:12]([C:10]#[N:11])=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:19][C:20]=1[F:36])[CH2:32][CH2:33][CH3:34]
Reactant: CCC(=N)N
Reactant: CCCCC(=O)C(Cc1ccc(-c2ccccc2C#N)cc1F)C(=O)OC
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CCCCc1nc(CC)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1F
Yield: 52.8 %

Procedure:
A solution of propanimidamide hydrochloride (7.5 g), 28% sodium methoxide (23 mL) and methyl 2-[(2′-cyano-3-fluorobiphenyl-4-yl)methyl]-3-oxoheptanoate (8.4 g) in methanol (84 mL) was stirred overnight. The solvent was evaporated under reduced pressure, and water and 1 M hydrochloric acid were added. The precipitated solid was collected by filtration, and washed with water and diethyl ether to give the title compound (4.7 g, 53%) as a pale-yellow solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[N:10][CH:11]=1)[N:8]([C@H:12]1[CH2:17][CH2:16][CH2:15][N:14]([CH2:18][CH2:19][N:20]([CH2:23][CH3:24])[CH2:21][CH3:22])[CH2:13]1)[CH:7]=[C:6]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:5]2=[O:30].CC1(C)C(C)(C)[O:35][B:34](B2OC(C)(C)C(C)(C)O2)[O:33]1.C(N(CC)CC)C.C([O-])(=O)C.[K+]>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:21]([N:20]([CH2:23][CH3:24])[CH2:19][CH2:18][N:14]1[CH2:15][CH2:16][CH2:17][CH:12]([N:8]2[C:9]3[N:10]=[CH:11][C:2]([B:34]([OH:35])[OH:33])=[CH:3][C:4]=3[C:5](=[O:30])[C:6]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:7]2)[CH2:13]1)[CH3:22]
Reactant: CCOC(=O)c1cn([C@H]2CCCN(CCN(CC)CC)C2)c2ncc(Br)cc2c1=O
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CCOC(=O)c1cn(C2CCCN(CCN(CC)CC)C2)c2ncc(B(O)O)cc2c1=O
Temperature: 75 °C

Procedure:
(S)-ethyl 6-bromo-1-(1-(2-(diethylamino)ethyl)piperidin-3-yl)-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylate (Intermediate 35, 2.7 g, 5.63 mmol) and PdCl2(PPh3)2 (0.395 g, 0.56 mmol) were combined and suspended in 1,4-dioxane (50 mL). The slurry was degassed, purged with nitrogen and then gently warmed to 75° C. for 20 min. 4,4,4′,4′,5,5,5′,5′-Octamethyl-2,2′-bi(1,3,2-dioxaborolane) (4.29 g, 16.90 mmol) was then added in a single portion and the temperature was raised to 100° C. After an hour of heating, triethylamine (0.784 mL, 5.63 mmol) and potassium acetate (1.658 g, 16.90 mmol) were added sequentially. The reaction mixture was stirred at reflux overnight. The reaction mixture was cooled to room temperature and filtered through a celite. Solvent was removed in vacuo and the residue was purified via ISCO DCM/Methanol 0-20% gradient. (S)-8-(1-(2-(diethylamino)ethyl)piperidin-3-yl)-6-(ethoxycarbonyl)-5-oxo-5,8-dihydro-1,8-naphthyridin-3-ylboronic acid (2.0 g, 80%) was recovered as a brown solid.
Reaction SMILES: O.Cl.[CH3:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([CH:9]=[C:10]([C:21](=O)[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:11]=[C:12]2[CH2:15][CH2:16][NH:17][C:18](=[O:20])[CH3:19])=[CH:7][CH:6]=1>C1(C)C=CC=CC=1>[CH3:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([CH:9]=[C:10]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:11]=[C:12]2[CH2:15][CH2:16][NH:17][C:18](=[O:20])[CH3:19])=[CH:7][CH:6]=1
Reactant: COc1ccc2cc(C(=O)c3ccccc3)cc(CCNC(C)=O)c2c1
Agent: Cl
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc2cc(Cc3ccccc3)cc(CCNC(C)=O)c2c1

Procedure:
Next, add 3.6 cm3 of water to this amalgam, then 3.6 cm3 of concentrated hydrochloric acid and then 5.26 mmol of N-[2-(7-methoxy-3-benzoylnaphth-1-yl)ethyl]acetamide, prepared according to Example 1, and 25 cm3 of toluene.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10].[C@H:19]12[CH2:25][C@H:22]([NH:23][CH2:24]1)[CH2:21][N:20]2[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27].CC(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:17][CH2:16][CH:15]([N:23]3[CH2:24][C@@H:19]4[CH2:25][C@H:22]3[CH2:21][N:20]4[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:14][CH2:13]2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10]
Reactant: COc1cc(N2CCC(=O)CC2)ccc1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COc1cc(N2CCC(N3C[C@@H]4C[C@H]3CN4C(=O)OC(C)(C)C)CC2)ccc1[N+](=O)[O-]
Reaction time: 1 h
Yield: 96 %

Procedure:
To 1-[3-(methyloxy)-4-nitrophenyl]-4-piperidinone (Example 57, step B) (0.63 g, 2.5 mmol), 1,1-dimethylethyl (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (1.0 g, 5.0 mmol), HOAc (0.23 g, 3.8 mmol), TEA (0.25 g, 2.5 mmol) in DCM (20 mL) is added sodium triacetoxyborohydride (0.81 g, 3.8 mmol). The mixture was stirred for 1 h then poured into saturated NaHCO3 solution (30 mL). The layers are separated and the aqueous layer washed with DCM. The organics are combined, dried (MgSO4), filtered and rotovaped. DCM and silica are added and the solvent removed by rotovap. After purification by silica gel chromatography, the title compound of step A (1.0 g, 2.4 mmol, 96%) is obtained as a yellow foam. 1H NMR (400 MHz, CDCl3) δ 7.97 (d, J=9.3 Hz, 1H), 6.39 (dd, J=9.3, 2.0 Hz, 1H), 6.28 (d, J=2.0 Hz, 1H), 4.36-4.20 (m, 1H), 3.91 (s, 3H), 3.79-3.40 (m, 4H), 3.16-3.01 (m, 4H), 2.64-2.37 (m, 2H), 1.93-1.68 (m, 4H), 1.61-1.49 (m, 2H), 1.44 (s, 9H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([OH:15])=[CH:13][C:12]([CH2:16][CH3:17])=[CH:11][C:10]=1[O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([C:27]#[N:28])([CH3:26])[CH3:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:29](I)[CH3:30]>>[CH2:1]([O:8][C:9]1[C:14]([O:15][CH2:29][CH3:30])=[CH:13][C:12]([CH2:16][CH3:17])=[CH:11][C:10]=1[O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([C:27]#[N:28])([CH3:25])[CH3:26])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCc1cc(O)c(OCc2ccccc2)c(OCCCCCC(C)(C)C#N)c1
Reactant: CCI
Product: CCOc1cc(CC)cc(OCCCCCC(C)(C)C#N)c1OCc1ccccc1
Yield: 38 %

Procedure:
1-Benzyloxy-2-(6-cyano-6-methylheptyloxy)-4-ethyl -6-ethoxy benzene was prepared in 38% yield as a white solid from 1-Benzyloxy-2-(6-cyano-6-methylheptyloxy)-4-ethyl-6-hydroxy benzene and ethyliodide.
Reaction SMILES: [C:1]1([C:7]2[NH:11][CH:10]=[N:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])([O-])=O.[K+].[K+].[CH3:18][N:19]([CH3:24])[S:20](Cl)(=[O:22])=[O:21]>CN(C)C=O.O>[CH3:18][N:19]([CH3:24])[S:20]([N:9]1[CH:8]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:11]=[CH:10]1)(=[O:22])=[O:21]
Reactant: CN(C)S(=O)(=O)Cl
Reactant: c1ccc(-c2cnc[nH]2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)S(=O)(=O)n1cnc(-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 80.3 %

Procedure:
To a solution of 5-phenyl-1H-imidazole (5 g, 34.7 mmol) and K2CO3 (6 g, 41.6 mmol) in N,N-dimethylformamide (DMF) (20 mL) was added dimethylsulfamoyl chloride (4.11 mL, 38.2 mmol) drop wise at room temperature. The resulting mixture was stirred at room temperature for 4 h and then diluted with water (500 mL). The resulting solid was collected by vacuum filtration and dried to give the desired product (7 g). LC-MS: m/z 252 (M+H+).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:10]1[CH:14]=[CH:13][CH:12]=[C:11]1[C:15]([O:17][CH3:18])=[O:16].O>C(Cl)(Cl)(Cl)Cl>[C:2]1([C:1]([C:14]2[O:10][C:11]([C:15]([O:17][CH3:18])=[O:16])=[CH:12][CH:13]=2)=[O:8])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccco1
Reactant: O=C(Cl)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: COC(=O)c1ccc(C(=O)c2ccccc2)o1

Procedure:
Anhydrous ferric chloride 10.42 g, 0.0026 mole) and benzoyl chloride II-1(29.65 g, were dissolved in CCl4 (40 ml and added dropwise with methyl furan-2-carboxylate I-1 (24 g. 0.19 mole). The reaction mixture was then heated under refluxing for 16 hrs, and after cooling was added with water(120 ml). The mixture was extracted with CCl4 , then the CCl4 layer was washed with water, 5% sodium bicarbonate solution, and then with water, till neutral, then dried over anhydrous Magnesium sulfate and filtered. The solvent of the filtrate was evaporated under reduced pressure, the residue was recrystallized from isopropanol, and then from methanol to give compound V-1. Yield 18.75 g(42.9%).
Reaction SMILES: [OH:1][C@H:2]1[CH2:5][C@H:4]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH2:3]1.[N+:14]([C:17]1[CH:25]=[CH:24][C:20]([C:21](O)=[O:22])=[CH:19][CH:18]=1)([O-:16])=[O:15].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(/C(OC(C)C)=O)=N\C(OC(C)C)=O>C1COCC1>[N+:14]([C:17]1[CH:18]=[CH:19][C:20]([C:21]([O:1][C@H:2]2[CH2:3][C@H:4]([NH:6][C:7]([O:8][C:9]([CH3:10])([CH3:12])[CH3:11])=[O:13])[CH2:5]2)=[O:22])=[CH:24][CH:25]=1)([O-:16])=[O:15]
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@H](O)C1
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H]1C[C@H](OC(=O)c2ccc([N+](=O)[O-])cc2)C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of racemic (2:1) in favor of trans tert-butyl (3-hydroxycyclobutyl)carbamate (16.8 g, 90 mmol) and 4-nitrobenzoic acid (10.97 ml, 102 mmol) in THF (300 mL) were added triphenyl phosphorus (30.0 ml, 130 mmol) and (E)-diisopropyl diazene-1,2-dicarboxylate (25 ml, 124 mmol) dropwise at 0° C. The resulting mixture was stirred at room temperature for 18 h. The reaction was concentrated and the crude material purified by flash silica gel chromatography on ISCO eluting with 0-40% EtOAc/hexanes to give a mixture cis and trans products. The mixture of isomers was purified by chiral separation to give the desired trans isomer trans-3-((tert-butoxycarbonyl)amino)cyclobutyl 4-nitrobenzoate (17.4 g, 51.7 mmol, 87% yield).
Reaction SMILES: [C:1]1(=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:8]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])#[N:9].C(O)(=O)C.C([O-])(=O)C.[NH4+]>C1(C)C=CC=CC=1>[C:8]([C:10](=[C:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[C:11]([O:13][CH2:14][CH3:15])=[O:12])#[N:9]
Reactant: CCOC(=O)CC#N
Reactant: O=C1CCCCC1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C#N)=C1CCCCC1
Temperature: 150 °C
Reaction time: 5 h

Procedure:
To a solution of cyclohexanone (1.50 ml, 14.47 mmol) in toluene (24.12 ml) was added ethyl cyanoacetate (1.556 ml, 14.62 mmol), acetic acid (0.166 ml, 2.89 mmol), and ammonium acetate (0.112 g, 1.447 mmol). The mixture was heated to a reflux at 150° C. in a Dean-Stark apparatus. After 5 h, the reaction was cooled and washed with water and saturated NaHCO3 solution. The organics were dried over Na2SO4, filtered, and concentrated.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:27]=[CH:26][C:18](/[CH:19]=[CH:20]/[C:21]2[NH:25][N:24]=[N:23][N:22]=2)=[CH:17][CH:16]=1>[C].[Pd].O1CCOCC1>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:27]=[CH:26][C:18]([CH2:19][CH2:20][C:21]2[NH:22][N:23]=[N:24][N:25]=2)=[CH:17][CH:16]=1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(/C=C/c2nnn[nH]2)cc1
Agent: [Pd]
Solvent: C1COCCO1
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(CCc2nnn[nH]2)cc1
Yield: 80.5 %

Procedure:
A mixture of (E)-5-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)styryl]tetrazole (1.0 g), palladium-carbon (5%, 0.5 g) and dioxane (100 ml) was subjected to catalytic hydrogenation at room temperature. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure to give 5-[2-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)phenyl]ethyl]tetrazole (0.81 g, 81%), which was recrystallized from methanol-chloroform to yield colorless plates, m.p.203°-204° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH2:19])[C:11]([NH:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:12][CH:13]=2)=[CH:4][N:3]=1.[CH3:20][O:21][C:22]1[CH:23]=[CH:24][C:25]([C:30]2[S:34][N:33]=[C:32]([CH3:35])[N:31]=2)=[C:26]([CH:29]=1)[CH:27]=O.O.C([O-])(O)=O.[Na+]>C(O)(=O)C>[C:15]([N:14]1[C:11]2[CH:12]=[CH:13][C:8]([C:5]3[CH:4]=[N:3][C:2]([NH2:1])=[N:7][CH:6]=3)=[CH:9][C:10]=2[N:19]=[C:27]1[C:26]1[CH:29]=[C:22]([O:21][CH3:20])[CH:23]=[CH:24][C:25]=1[C:30]1[S:34][N:33]=[C:32]([CH3:35])[N:31]=1)([CH3:16])([CH3:18])[CH3:17]
Reactant: COc1ccc(-c2nc(C)ns2)c(C=O)c1
Reactant: CC(C)(C)Nc1ccc(-c2cnc(N)nc2)cc1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc(-c2nc(C)ns2)c(-c2nc3cc(-c4cnc(N)nc4)ccc3n2C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 60 h
Yield: 19.7 %

Procedure:
A solution of 4-(2-amino-pyrimidin-5-yl)-N1-tert-butyl-benzene-1,2-diamine (110 mg, 0.43 mmol) and 5-methoxy-2-(3-methyl-1,2,4-thiadiazol-5-yl)-benzaldehyde (100 mg, 0.43 mmol) in acetic acid (5 mL) is warmed to 50° C. for 12 hours then at 80° C. for 60 hours. The reaction mixture is cooled to room temperature and poured into water and NaHCO3 (sat.). The product is extracted into EtOAc (3×) and the combined organics are dried (MgSO4), filtered and concentrated. Purification via flash chromatography (12 g silica gel, 0-5% MeOH/CH2Cl2) affords the title compound (40 mg, 20%). LCMS (ESMS): m/z 472.20 (M++1)
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:19]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[O:20])=[CH:4][C:5]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl:60][C:61]1[CH:62]=[C:63]([CH:65]=[CH:66][CH:67]=1)[NH2:64]>CN(C)C=O>[Cl:1][C:2]1[C:3]([C:19]([N:21]2[CH2:22][CH2:23][O:24][CH2:25][CH2:26]2)=[O:20])=[CH:4][C:5]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:6]([CH:10]=1)[C:7]([NH:64][C:63]1[CH:65]=[CH:66][CH:67]=[C:61]([Cl:60])[CH:62]=1)=[O:9]
Reactant: Nc1cccc(Cl)c1
Reactant: O=C(O)c1cc(Cl)c(C(=O)N2CCOCC2)cc1OCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cccc(Cl)c1)c1cc(Cl)c(C(=O)N2CCOCC2)cc1OCc1ccccc1
Reaction time: 2 h

Procedure:
To a solution of 5-chloro-4-(4-morpholinylcarbonyl)-2-[(phenylmethyl)oxy]benzoic acid (may be prepared as described in Description 67; 90 mg, 0.24 mmol) in N,N-dimethylformamide (3 ml) was added diisopropylethylamine (0.08 ml, 0.48 mmol), HATU (164 mg, 0.43 mmol) and 3-chloroaniline (0.03 ml, 0.29 mmol). The solution was stirred for 2 hours and the solvent removed in vacuo. The residue was purified by column chromatography (SiO2, (solute, 1:1 ethyl acetate/cyclohexane) to yield the title compound as a white solid. 55 mg.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[N:11]1[CH2:16][CH2:15][O:14][C:13]2[CH:17]=[C:18]([S:21]([N:24]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=3)[C:25]3[S:26][CH:27]=[CH:28][N:29]=3)(=[O:23])=[O:22])[CH:19]=[CH:20][C:12]1=2.C(O)(=O)C>C1COCC1.[Fe]>[NH2:8][C:6]1[CH:5]=[CH:4][C:3]([N:11]2[CH2:16][CH2:15][O:14][C:13]3[CH:17]=[C:18]([S:21]([N:24]([CH2:30][C:31]4[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=4)[C:25]4[S:26][CH:27]=[CH:28][N:29]=4)(=[O:23])=[O:22])[CH:19]=[CH:20][C:12]2=3)=[C:2]([Br:1])[CH:7]=1
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(c2)OCCN3c2ccc([N+](=O)[O-])cc2Br)cc1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(c2)OCCN3c2ccc(N)cc2Br)cc1
Temperature: 70 °C

Procedure:
4-(2-bromo-4-nitrophenyl)-N-(4-methoxybenzyl)-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (0.025 g, 0.040 mmol) was dissolved in THF (0.135 mL) and acetic acid (0.127 mL, 2.227 mmol), and iron (0.023 g, 0.405 mmol) was added. The flask was sealed and heated to 70° C. for 1 hour. The reaction was cooled to rt, diluted with THF, and filtered through Celite® (diatomaceous earth), washing well with THF. The filtrate was concentrated, and partitioned between saturated aqueous sodium bicarbonate solution and EtOAc. The layers were separated, and the aqueous was then extracted (×2) with EtOAc. The combined organics were washed with brine, dried over sodium sulfate, filtered and concentrated to yield 4-(4-amino-2-bromophenyl)-N-(4-methoxybenzyl)-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide as a light brown solid. The material was carried forward without further purification. m/z (ESI) 587.1 (M+H)+.
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:21]([C:23]4[S:24][CH:25]=[CH:26][CH:27]=4)=[O:22])=[CH:16][CH:15]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:28].[NH2:29][C:30]1[CH:31]=[CH:32][C:33]([O:37][CH3:38])=[C:34]([OH:36])[CH:35]=1>C1COCC1>[OH:36][C:34]1[CH:35]=[C:30]([NH:29][CH:2]=[C:3]2[C:11]3[C:6](=[CH:7][C:8]([C:12]([C:14]4[CH:19]=[CH:18][C:17]([NH:20][C:21]([C:23]5[S:24][CH:25]=[CH:26][CH:27]=5)=[O:22])=[CH:16][CH:15]=4)=[O:13])=[CH:9][CH:10]=3)[NH:5][C:4]2=[O:28])[CH:31]=[CH:32][C:33]=1[O:37][CH3:38]
Reactant: O=C1Nc2cc(C(=O)c3ccc(NC(=O)c4cccs4)cc3)ccc2C1=CO
Reactant: COc1ccc(N)cc1O
Solvent: C1CCOC1
Product: COc1ccc(NC=C2C(=O)Nc3cc(C(=O)c4ccc(NC(=O)c5cccs5)cc4)ccc32)cc1O
Temperature: 65 °C
Reaction time: 24 h
Yield: 57.2 %

Procedure:
A small screw cap test tube was charged with Thiophene-2-carboxylic acid [4-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (as prepared in Example 20, 100 mg, 0.257 mmol) and THF (2 mL). To the resulting solution was added 5-amino-2-methoxyphenol (39.2 mg, 0.282 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature. Hexanes were added to the reaction mixture. The solid precipitate that formed was washed with ˜1 mL of i-prOH yielding 57% (75 mg, 0.147 mmol) of the title compound.