Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[C:8](=[O:14])[N:7]([CH2:15][C:16]([OH:18])=[O:17])[C:6]2=[O:19].C(Cl)CCl.[Cl:24][C:25]1[CH:26]=[N+:27]([O-:50])[CH:28]=[C:29]([Cl:49])[C:30]=1[CH2:31][C@@H:32]([C:34]1[CH:39]=[CH:38][C:37]([O:40][CH:41]([F:43])[F:42])=[C:36]([O:44][CH2:45][CH:46]2[CH2:48][CH2:47]2)[CH:35]=1)O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:24][C:25]1[CH:26]=[N+:27]([O-:50])[CH:28]=[C:29]([Cl:49])[C:30]=1[CH2:31][C@@H:32]([C:34]1[CH:39]=[CH:38][C:37]([O:40][CH:41]([F:43])[F:42])=[C:36]([O:44][CH2:45][CH:46]2[CH2:48][CH2:47]2)[CH:35]=1)[O:17][C:16](=[O:18])[CH2:15][N:7]1[C:6](=[O:19])[C:5]2[C:9](=[CH:10][C:11]([O:12][CH3:13])=[C:3]([O:2][CH3:1])[CH:4]=2)[C:8]1=[O:14]
Reactant: [O-][n+]1cc(Cl)c(C[C@H](O)c2ccc(OC(F)F)c(OCC3CC3)c2)c(Cl)c1
Reactant: COc1cc2c(cc1OC)C(=O)N(CC(=O)O)C2=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: COc1cc2c(cc1OC)C(=O)N(CC(=O)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC3CC3)c1)C2=O
Reaction time: 4 h
Yield: 41 %

Procedure:
To a suspension of 2-(5,6-dimethoxy-1,3-dioxoisoindolin-2-yl)acetic acid (151 mg, 0.571 mmol) in DCM (25 ml), DMAP (69.8 mg, 0.571 mmol), EDC (274 mg, 1.428 mmol) and (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-hydroxyethyl)pyridine 1-oxide (200 mg, 0.476 mmol) were added in one portion at room temperature, and the resulting mixture was stirred for 4 hours. The solution was diluted with DCM (40 ml) and washed with a saturated solution of NaHCO3 (40 ml), with 1N HCl (30 ml) and finally with brine (30 ml). The organic layer was dried over sodium sulfate, filtered and evaporated to dryness. The crude was purified by crystallization from ethyl acetate (40 ml) to afford (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-(5,6-dimethoxy-1,3-dioxoisoindolin-2-yl)acetoxy)ethyl)pyridine 1-oxide as a white solid (130 mg, 0.195 mmol, 40.9% yield). MS/ESI+ 667.16 [MH]+; [αD]=−42.80, c=0.25, DCM; 1H NMR (300 MHz, DMSO-d6) δ ppm 8.43 (s, 2H), 7.43 (s, 2H), 7.19 (d, 1H), 7.02-7.13 (m, 1H), 6.96 (dd, 1H), 7.08 (t, 1H), 6.01 (dd, 1H), 4.37 (s, 2H), 3.96 (s, 6H), 3.92 (d, 2H), 3.39 (dd, 1H), 3.22 (dd, 1H), 1.12-1.34 (m, 1H), 0.52-0.67 (m, 2H), 0.29-0.46 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]2[O:20][C:21]([CH3:24])=[N:22][N:23]=2)[CH:14]=1.[C:25](Cl)(=[O:29])[C:26](Cl)=[O:27]>>[CH3:24][C:21]1[O:20][C:19]([C:15]2[CH:14]=[C:13]([N:12]3[C:3]4[CH:4]=[CH:5][C:6]5[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=5[C:2]=4[NH:1][C:26](=[O:27])[C:25]3=[O:29])[CH:18]=[CH:17][CH:16]=2)=[N:23][N:22]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1nnc(-c2cccc(Nc3ccc4ccccc4c3N)c2)o1
Product: Cc1nnc(-c2cccc(-n3c(=O)c(=O)[nH]c4c5ccccc5ccc43)c2)o1
Yield: 40 %

Procedure:
1-Amino-2-[3-(5-methyl-[1,3,4]oxadiazol-2-yl)phenyl]aminonaphthalene (95 mg, 0.3 mmol) and oxalyl chloride were used in a process similar to Example 1(3) to give the titled compound as white crystal (43 mg, yield 40%).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].CON(C)[C:10]([C:12]1[CH:13]=[C:14]2[CH2:19][CH2:18][CH2:17][N:15]2[N:16]=1)=[O:11].S([O-])([O-])(=O)=O.[Na+].[Na+].S([O-])([O-])(=O)=O.[Mg+2]>O1CCCC1.O>[N:16]1[N:15]2[CH2:17][CH2:18][CH2:19][C:14]2=[CH:13][C:12]=1[CH:10]=[O:11]
Reactant: CON(C)C(=O)c1cc2n(n1)CCC2
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: O=Cc1cc2n(n1)CCC2
Temperature: 2.5 °C
Reaction time: 20 h
Yield: 76.8 %

Procedure:
Lithium aluminum hydride (pellets, 2.90 g, 0.0764 mol) is added to a stirred solution of N-methoxy-N-methyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxamide (30.0 g, 0.154 mol) in anhydrous tetrahydrofuran (300 mL) at 0-5° C. and stirred overnight (20 hours) at 0-5° C. under nitrogen. The mixture is then slowly added to a flask containing water (50 ml) and tetrahydrofuran (50 ml) maintained at 5-15° C. Anhydrous sodium sulfate (8.0 g) and anhydrous magnesium sulfate (4.0 g) are added and the mixture is stirred for 0.5 hours. The mixture is filtered, and the filter pad is washed with tetrahydrofuran (100 ml). The filtrate and washings are evaporated under diminished pressure and the residue is stirred for 20 minutes with dichloromethane (150 ml) and 1.5 N hydrochloric acid (40 ml). The phases are separated and water (200 ml) containing dissolved sodium hydrogensulfite (22 g) is added to the organic phase. The mixture is stirred for 20 minutes and the phases are separated. Fresh dichloromethane (150 mL) and 10 N sodium hydroxide (22 mL) are added (with cooling) to the aqueous phase. The mixture is stirred for 20 minutes and the phases are separated. The organic phase is washed with water (100 ml). The dichloromethane extract is evaporated at 20-70° C. to give an oil which crystallizes on cooling to provide 16.1 g (77%) of 5,6-dihydro-4H-pyrrolo-[1,2-b]-pyrazole-2-carbaldehyde as a light yellow, crystalline solid having HPLC-MS purity 99.95% (HPLC conditions as in example 15).
Reaction SMILES: C([Li])CCC.[Cl:6][C:7]1[N:12]=[CH:11][C:10]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:9][CH:8]=1.CN(C)CCN(C)C.[I:29]I.[Cl-].[NH4+]>CCOCC>[Cl:6][C:7]1[N:12]=[CH:11][C:10]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:17])([CH3:19])[CH3:18])=[C:9]([I:29])[CH:8]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(Cl)nc1
Reactant: II
Agent: CN(C)CCN(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CCOCC
Product: CC(C)(C)OC(=O)Nc1cnc(Cl)cc1I
Temperature: -10 °C
Reaction time: 2 h
Yield: 55.4 %

Procedure:
n-Butyllithium (1.6M in hexanes, 22 mL, 35 mmol) was added dropwise to a stirred, cooled (−78° C.) solution of 1,1-dimethylethyl (6-chloro-3-pyridinyl)carbamate (Description 6, 2.68 g, 11.7 mmol) and N,N,N′,N′-tetramethylethylenediamine (5.3 mL, 4.1 g, 35 mmol) in ether (60 mL). The mixture was allowed to warm to −10° C. and stirred for 2 h. The mixture was cooled to −78° C. and a cooled (−10° C.) solution of iodine (6.0 g, 24 mmol) in ether (20 mL) was added dropwise. The mixture was allowed to warm to room temperature and stirred for 18 h. Saturated aqueous ammonium chloride was added and the mixture was extracted with ether. The combined organic fractions were washed with aqueous sodium metabisulfite (10%), dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was triturated with hexane and the solid was collected and dried in vacuo to give the title compound as a brown solid (2.3 g, 55%). 1H NMR (400 MHz, CDCl3) δ 8.94 (1H, s), 7.73 (1H, s), 6.64 (1H, br s), and 1.54 (9H, s).
Reaction SMILES: C1(COC(=O)[NH:10][CH2:11][C@@H:12]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C:19]3[C:28]4[C:23](=[CH:24][CH:25]=[C:26]([O:29][CH3:30])[N:27]=4)[N:22]=[CH:21][C:20]=3[F:31])[CH2:13]2)C=CC=CC=1>CO.[OH-].[OH-].[Pd+2]>[F:31][C:20]1[CH:21]=[N:22][C:23]2[C:28]([C:19]=1[CH2:18][CH2:17][N:14]1[CH2:15][CH2:16][C@@H:12]([CH2:11][NH2:10])[CH2:13]1)=[N:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2
Reactant: COc1ccc2ncc(F)c(CCN3CC[C@@H](CNC(=O)OCc4ccccc4)C3)c2n1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: COc1ccc2ncc(F)c(CCN3CC[C@@H](CN)C3)c2n1
Reaction time: 18 h
Yield: 74.8 %

Procedure:
To a solution of phenylmethyl[((3S)-1-{2-[3-fluoro-6-(methyloxy)-1,5-naphthyridin-4-yl]ethyl}-3-pyrrolidinyl)methyl]carbamate (0.13 g, 0.29 mmole) in MeOH (50 mL) was added Pd(OH)2 (100 mg). The reaction contents were placed under a balloon of H2 and stirred for 18 hours. The reaction contents were filtered through Celite (MeOH) and concentrated under vacuum to give the title compound (66 mg, 76%) as a light yellow oil: LC-MS (ES) m/e 305 (M+H)+.
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH:11]=[C:10]([C:15]([NH:17][C:18]1[CH:23]=[C:22]([CH2:24][CH2:25][CH2:26][CH3:27])[CH:21]=[CH:20][C:19]=1[OH:28])=O)[CH:9]=[CH:8]2)(=O)C.C1C=C(Cl)C(Cl)=CC=1.Cl(O)(=O)=O>O>[OH:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH:11]=[C:10]([C:15]1[O:28][C:19]3[CH:20]=[CH:21][C:22]([CH2:24][CH2:25][CH2:26][CH3:27])=[CH:23][C:18]=3[N:17]=1)[CH:9]=[CH:8]2
Reactant: CCCCc1ccc(O)c(NC(=O)c2ccc3cc(OC(C)=O)ccc3c2)c1
Agent: [O-][Cl+2]([O-])O
Solvent: Clc1ccccc1Cl
Solvent: O
Product: CCCCc1ccc2oc(-c3ccc4cc(O)ccc4c3)nc2c1
Temperature: 201.5 °C
Reaction time: 0.5 h
Yield: 48 %

Procedure:
5.40 g (14.3 m mole) of 2-(6-acetoxy-2-naphthoylamino)-4-butylphenol, 0.43 g of p-toluenesulfuric acid monohydrate and 40 ml of O-dichlorobenzene were placed in a 100 ml round-bottom flask, followed by heating and stirring for 30 minutes at 200-203° C. After the reaction, O-dichlorobenzene was distilled off under reduced pressure. To the resultant, 2.00 g (30.3 m mole) of potassium hydroxide and 60 ml of ethanol were added, followed by heating and stirring for 20 minutes at 60° C. After the reaction, the reaction mixture was poured into 600 ml of water. To the reaction mixture, 8 ml of chloric acid was added to precipitate a crystal. The crystal was filtered, washed with water and recrystallized from a mixture solvent of acetoneethanol to obtain 2.18 g of 2-(6-hydroxy-2-naphthyl)-5-butylbenzooxazole (Yield: 42.4%).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:20]Br.[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([CH3:36])([CH3:35])[CH:30]=[C:31]([F:34])[CH2:32]O)=[CH:25][CH:24]=1>C(Cl)(Cl)(Cl)Cl>[Br:20][CH2:32][C:31]([F:34])=[CH:30][C:29]([C:26]1[CH:27]=[CH:28][C:23]([Cl:22])=[CH:24][CH:25]=1)([CH3:36])[CH3:35]
Reactant: CC(C)(C=C(F)CO)c1ccc(Cl)cc1
Reactant: BrBr
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C=C(F)CBr)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 71 %

Procedure:
Under a nitrogen atmosphere, a solution of triphenyl phosphine (0.96 g, 4.25 mmol) in carbon tetrachloride at -5° C. is treated dropwise with a solution of bromine (0.679 g, 4.25 mmol) in carbon tetrachloride, warmed to and stirred at room temperature for 45 minutes, treated with a solution of 4-(p-chlorophenyl)-2-fluoro-4-methyl-2-penten-1-ol, (Z)- (0.81 g, 3.54 mmol) in carbon tetrachloride, refluxed for 2 hours, cooled to room temperature, and poured into petroleum ether. The resultant mixture is filtered through diatomaceous earth. The filtrate is washed sequentially with water, saturated sodium hydrogen carbonate solution and brine, dried over anhydrous sodium sulfate and concentrated in vacuo to obtain an oil. Flash column chromatography of the oil using silica gel and a 1:9 ethyl acetate/hexanes solution gives the title product as a colorless oil (0.736 g, 71% yield) which is identified by NMR spectral analyses.
Reaction SMILES: [CH:1](=[N:8][N:9]1[C:21]2[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[N:14]=[CH:13][C:12]=2[N:11]=[C:10]1[CH2:22][O:23][CH2:24][CH3:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>CO>[CH2:1]([NH:8][N:9]1[C:21]2[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[N:14]=[CH:13][C:12]=2[N:11]=[C:10]1[CH2:22][O:23][CH2:24][CH3:25])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOCc1nc2cnc3ccccc3c2n1N=Cc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCOCc1nc2cnc3ccccc3c2n1NCc1ccccc1
Reaction time: 1.5 h
Yield: 100.3 %

Procedure:
A solution of N-benzylidene-(2-ethoxymethy-1H-imidazo[4,5-c]quinolin-1-yl)amine (1.00 g, 3.03 mmol) in 50 mL of MeOH was treated with NaBH4 (458 mg, 12.1 mmol). After stirring for 1.5 h, the reaction mixture was concentrated, then treated with saturated NaHCO3 solution, and extracted into CHCl3. The organic portion was washed with H2O and brine and dried over Na2SO4. The resulting solution was filtered and concentrated to give N-benzyl-(2-ethoxymethy-1H-imidazo[4,5-c]quinolin-1-yl)amine (1.01 g) as a tan solid.
Reaction SMILES: [C:1]1([CH2:12][CH2:13][C:14]([OH:16])=[O:15])[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][C:9]([OH:11])=[O:10])=[CH:3][CH:2]=1.[CH2:17](O)[CH2:18][CH3:19].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.CCOCC>[CH2:17]([O:10][C:9]([CH2:8][CH2:7][C:4]1[CH:3]=[CH:2][C:1]([CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:6][CH:5]=1)=[O:11])[CH2:18][CH3:19]
Reactant: O=C(O)CCc1ccc(CCC(=O)O)cc1
Reactant: CCCO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CCOCC
Product: CCCOC(=O)CCc1ccc(CCC(=O)O)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 3,3′-(1,4-phenylene)dipropanoic acid (250 mg, 1.125 mmol) DCM (15 ml) is added 4-dimethylaminopyridine (137 mg, 1.125 mmol) and propanol (3 ml, 40.1 mmol). The solution is cooled to 0° C. and dicyclohexylcarbodiimide (232 mg, 1.125 mmol) is added and the resulting solution is stirred at 0° C. for 30 minutes and 2 hours at room temperature. Concentration in vacuo affords a white solid which is suspended in Et2O (50 ml) and filtered to remove any insoluble material. The filtrate is concentrated in vacuo and purification by chromatography (SiO2, EtOAc/iso-hexane) affords the title compound.
Reaction SMILES: [C:1]([C:3]1[S:4][C:5]([CH2:8]O)=[CH:6][CH:7]=1)#[N:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:30]>C1COCC1>[C:1]([C:3]1[S:4][C:5]([CH2:8][Br:30])=[CH:6][CH:7]=1)#[N:2]
Reactant: BrC(Br)(Br)Br
Reactant: N#Cc1ccc(CO)s1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: N#Cc1ccc(CBr)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.8 %

Procedure:
To a solution of 2-cyano-5-(hydroxymethyl)thiophene (6.0 g, 43 mmol) in THF (50 mL) was added triphenylphosphine (15.7 g, 47 mmol) and carbon tetrabromide (12.3 g, 47 mmol). After stirring overnight under nitrogen atmosphere at room temperature, the solvent was removed in vacuo and the residue was dissolved in chloroform, then adsorbed onto silica gel and loaded onto a silica gel column. The product was eluted using an ethyl acetate/hexanes gradient. Fractions containing pure product (as judged by TLC) were pooled and concentrated in vacuo to give 6.5 g (75%) of 2-cyano-5-(bromomethyl)thiophene.
Reaction SMILES: [CH:1]1([CH2:4][C:5](=O)/[C:6](/[C:11]2[CH:16]=[CH:15][N:14]=[C:13]([NH:17][C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)[N:12]=2)=[CH:7]\N(C)C)[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].S(O)(O)(=O)=O.[CH3:36][S:37][C:38](=[NH:40])[NH2:39]>CN(C=O)C>[CH:1]1([CH2:4][C:5]2[C:6]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([NH:17][C:18]4[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=4)[N:12]=3)=[CH:7][N:39]=[C:38]([S:37][CH3:36])[N:40]=2)[CH2:3][CH2:2]1
Reactant: CN(C)/C=C(\C(=O)CC1CC1)c1ccnc(Nc2ccncc2)n1
Reactant: CSC(=N)N
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CN(C)C=O
Product: CSc1ncc(-c2ccnc(Nc3ccncc3)n2)c(CC2CC2)n1
Temperature: 120 °C
Reaction time: 1 h
Yield: 3.6 %

Procedure:
To a solution of (Z)-1-cyclopropyl-4-(dimethylamino)-3-(2-(pyridin-4-ylamino)pyrimidin-4-yl)but-3-en-2-one (9) (200 mg, 0.618 mmol) in DMF (5.154 ml) was added potassium carbonate (256 mg, 1.855 mmol) and 2-methyl-2-thiopseudourea sulfate (129 mg, 0.928 mmol). The reaction was warmed to 120° C. and stirred for 1 hr. The solvent was evaporated and the crude residue partitioned between DCM and water. The organic layer was washed with brine, dried with sodium sulfate, and concentrated. The crude product was purified by flash chromatography with a gradient of 2-10% MeOH in DCM and further purified reverse phase HPLC with a gradient of 10-100% MeCN in H2O to give 7.8 mg of the desired product as a white solid. HRMS (ES+)=351.1391. UV-LC: 100/100% UV purity at 214/254 nm; HPLC: tR=3.38 minute over 7.75 minutes. 1H NMR (400 MHz, MeOD) δ ppm 0.10-0.14 (m, 2 H) 0.41-0.47 (m, 2 H) 1.03-1.15 (m, 1 H) 2.63 (s, 3 H) 2.94 (d, J=7.07 Hz, 2 H) 7.18 (d, J=5.56 Hz, 1 H) 7.83 (d, J=7.07 Hz, 2 H) 8.31 (d, J=7.07 Hz, 2 H) 8.64 (s, 1 H) 8.65 (d, J=5.05 Hz, 1 H)
Reaction SMILES: Br[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([Br:9])=[CH:4][N:3]=1.[CH3:10][C@@H:11]1[CH2:16][NH:15][CH2:14][CH2:13][NH:12]1>CC(N(C)C)=O>[Br:9][C:5]1[CH:6]=[C:7]([Cl:8])[C:2]([N:15]2[CH2:14][CH2:13][NH:12][C@H:11]([CH3:10])[CH2:16]2)=[N:3][CH:4]=1
Reactant: C[C@@H]1CNCCN1
Reactant: Clc1cc(Br)cnc1Br
Solvent: CC(=O)N(C)C
Product: C[C@@H]1CN(c2ncc(Br)cc2Cl)CCN1

Procedure:
Heat a solution of 2,5-dibromo-3-chloro-pyridine (Chontech Inc.) (2.0 g) and (R)-2-methyl-piperazine (3.2 g, 31.9 mmol) in DMA at 130° C. for 16 h. Partition the reaction mixture between water and EtOAc. Wash the EtOAc layer with water (1×) and brine (1×), dry (Na2SO4) and concentrate under reduced pressure to give the title compound as a solid.
Reaction SMILES: [CH2:1]([CH:4]1[CH:30]=[C:29]([CH3:31])[CH2:28][CH:27]([CH3:32])[CH2:26][CH:25]([O:33][CH3:34])[CH:24]2[O:35][C:20]([OH:39])([CH:21]([CH3:38])[CH2:22][CH:23]2[O:36][CH3:37])[C:19](=[O:40])[C:18](=[O:41])[N:17]2[CH:12]([CH2:13][CH2:14][CH2:15][CH2:16]2)[C:11](=[O:42])[O:10][CH:9]([C:43]([CH3:54])=[CH:44][CH:45]2[CH2:50][CH2:49][CH:48]([OH:51])[CH:47]([O:52][CH3:53])[CH2:46]2)[CH:8]([CH3:55])[CH:7]([OH:56])[CH2:6][C:5]1=[O:57])[CH:2]=[CH2:3].[BH3-]C#N.[Na+]>CO.C(Cl)Cl>[CH2:1]([CH:4]1[CH:30]=[C:29]([CH3:31])[CH2:28][CH:27]([CH3:32])[CH2:26][CH:25]([O:33][CH3:34])[CH:24]2[O:35][C:20]([OH:39])([CH:21]([CH3:38])[CH2:22][CH:23]2[O:36][CH3:37])[CH:19]([OH:40])[C:18](=[O:41])[N:17]2[CH:12]([CH2:13][CH2:14][CH2:15][CH2:16]2)[C:11](=[O:42])[O:10][CH:9]([C:43]([CH3:54])=[CH:44][CH:45]2[CH2:50][CH2:49][CH:48]([OH:51])[CH:47]([O:52][CH3:53])[CH2:46]2)[CH:8]([CH3:55])[CH:7]([OH:56])[CH2:6][C:5]1=[O:57])[CH:2]=[CH2:3]
Reactant: C=CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: C=CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(C)CC2OC)C(O)C(=O)N2CCCCC2C(=O)OC(C(C)=CC2CCC(O)C(OC)C2)C(C)C(O)CC1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 17-allyl-1,14-dihydroxy-12-[2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (108 mg, 0.135 mmol) in 4 ml MeOH cooled to -5° C. (ice/acetone bath) was added in several portions NaBH3CN (160 mg). After addition was complete reaction was allowed to warm to RT. After stirring at RT for 2 hours the reaction mixture was diluted with 10 ml CH2Cl2 and purified by prep TLC (5% MeOH/CH2Cl2) to give the title compound (with NMR and mass spectra consistent with the structure).
Reaction SMILES: FC(F)(F)COP([CH2:13][C:14]([O:16][CH3:17])=[O:15])(OCC(F)(F)F)=O.C1OCCOCCOCCOCCOCCOC1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[Cl:48][C:49]1[CH:50]=[C:51]([C:59]2[O:63][N:62]=[C:61]([C:64]3[CH:65]=[CH:66][CH:67]=[C:68]4[C:72]=3[N:71]([CH3:73])[CH:70]=[C:69]4[CH:74]=O)[N:60]=2)[CH:52]=[CH:53][C:54]=1[O:55][CH:56]([CH3:58])[CH3:57]>C1COCC1>[Cl:48][C:49]1[CH:50]=[C:51]([C:59]2[O:63][N:62]=[C:61]([C:64]3[CH:65]=[CH:66][CH:67]=[C:68]4[C:72]=3[N:71]([CH3:73])[CH:70]=[C:69]4/[CH:74]=[CH:13]\[C:14]([O:16][CH3:17])=[O:15])[N:60]=2)[CH:52]=[CH:53][C:54]=1[O:55][CH:56]([CH3:57])[CH3:58]
Reactant: COC(=O)CP(=O)(OCC(F)(F)F)OCC(F)(F)F
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c(C=O)cn(C)c34)no2)cc1Cl
Agent: C1COCCOCCOCCOCCOCCO1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)/C=C\c1cn(C)c2c(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)cccc12
Temperature: -70 °C
Reaction time: 0.17 h

Procedure:
To a solution of methyl {bis[(2,2,2-trifluoroethyl)oxy]phosphoryl}acetate (0.16 mL), 18-crown-6 (1.0 g) in THF (5 mL) stirred under nitrogen at −70° C. was added NaHMDS (1.0 mol/L in THF, 0.8 mL) during 1 min. The reaction mixture was stirred at −70° C. for 10 mins. 7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-methyl-1H-indole-3-carbaldehyde (200 mg) was added and the mixture was stirred at this temperature for 1.5 h and then left to warm to room temperature overnight. The reaction mixture was quenched with saturated ammonium chloride solution, diluted with water (25 mL) and extracted with ethyl acetate (50 mL). The organic phase was washed with brine, dried over sodium sulphate and evaporated to afford the crude product, which was purified by column chromatography (10% ethyl acetate in hexane) to afford methyl (2Z)-3-[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-methyl-1H-indol-3-yl]-2-propenoate (D63) (120 mg). MS (ES): C24H22ClN3O4 requires 451; found 452.2 (M+H+).
Reaction SMILES: [CH3:1][C:2](=[N:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>[Pd].C(O)C>[CH3:1][CH:2]([NH:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:14][CH:15]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CCCCCCCCCc1ccc(N=C(C)c2ccccc2)cc1
Agent: [Pd]
Solvent: CCO
Product: CCCCCCCCCc1ccc(NC(C)c2ccccc2)cc1

Procedure:
N-(α-methyl benzylidene)-p-nonyl aniline (III) (16.5 g) prepared by the procedure described in Example IIA was hydrogenated suing 5% Pd/C as the catalyst and 95% ethanol as the solvent. N-(α-methyl benzyl)-p-nonyl aniline (IV) was obtained by fractional distillation. IV had a boiling point of 180°-184° C. at 0.025 millimeter.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:10][C:9]=2[C:19]2[C:20]([F:34])=[C:21]([NH:25][S:26]([C:29]3[CH:33]=[CH:32][O:31][CH:30]=3)(=[O:28])=[O:27])[CH:22]=[CH:23][CH:24]=2)[CH:5]=[CH:4][N:3]=1.[OH-].[NH4+:36]>O1CCOCC1>[NH2:36][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:10][C:9]=2[C:19]2[C:20]([F:34])=[C:21]([NH:25][S:26]([C:29]3[CH:33]=[CH:32][O:31][CH:30]=3)(=[O:28])=[O:27])[CH:22]=[CH:23][CH:24]=2)[CH:5]=[CH:4][N:3]=1
Reactant: O=S(=O)(Nc1cccc(-c2nc(N3CCOCC3)sc2-c2ccnc(Cl)n2)c1F)c1ccoc1
Reactant: [NH4+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Nc1nccc(-c2sc(N3CCOCC3)nc2-c2cccc(NS(=O)(=O)c3ccoc3)c2F)n1

Procedure:
Following a procedure analogous to the procedure described in Example 52, Step B using N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-3-furansulfonamide (100 mg, 0.192 mmol) and ammonium hydroxide (4 mL) and 1,4-Dioxane (1 mL), the title compound was obtained as an off-white solid (65 mg, 64% yield). MS (ESI): 503 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:30]=[CH:29][C:5]2[NH:6][C:7]([C:12]3[C:13](=[O:28])[N:14]([CH2:23][CH2:24][CH:25]([CH3:27])[CH3:26])[C:15]4[C:20]([C:21]=3[OH:22])=[CH:19][CH:18]=[CH:17][N:16]=4)=[N:8][S:9](=[O:11])(=[O:10])[C:4]=2[CH:3]=1.[S:31]1[CH:35]=[CH:34][CH:33]=[C:32]1[S:36](Cl)(=[O:38])=[O:37]>N1C=CC=CC=1>[OH:22][C:21]1[C:20]2[C:15](=[N:16][CH:17]=[CH:18][CH:19]=2)[N:14]([CH2:23][CH2:24][CH:25]([CH3:27])[CH3:26])[C:13](=[O:28])[C:12]=1[C:7]1[NH:6][C:5]2[CH:29]=[CH:30][C:2]([NH:1][S:36]([C:32]3[S:31][CH:35]=[CH:34][CH:33]=3)(=[O:38])=[O:37])=[CH:3][C:4]=2[S:9](=[O:11])(=[O:10])[N:8]=1
Reactant: O=S(=O)(Cl)c1cccs1
Reactant: CC(C)CCn1c(=O)c(C2=NS(=O)(=O)c3cc(N)ccc3N2)c(O)c2cccnc21
Solvent: c1ccncc1
Product: CC(C)CCn1c(=O)c(C2=NS(=O)(=O)c3cc(NS(=O)(=O)c4cccs4)ccc3N2)c(O)c2cccnc21
Temperature: 120 °C
Yield: 34.9 %

Procedure:
To the product of Example 205 (21.5 mg, 0.05 mmol) in pyridine (1 mL) was added 2-thiophenesulfonyl chloride (44 mg, 0.24 mmol). The reaction mixture was heated in a microwave reactor at 120° C. for 120 minutes. The reaction was cooled to 25° C. and concentrated under reduced pressure. The residue was triturated with water (1 mL), filtered, and washed with hexane:ethyl acetate (1:1). The crude product was chromatographed on silica gel eluting with 199:1 dichloromethane:methanol to give the title compound (10 mg, 35%). 1H NMR (300 MHz, DMSO-d6): δ 0.97 (d, J=6.25 Hz, 6 H) 1.55 (m, 2 H) 1.66 (m, 1 H) 4.46 (t, J=7.84 Hz, 2 H) 7.16 (dd, J=5.13 Hz, 3.66 Hz, 1 H) 7.48 (m, 2 H) 7.53 (d, J=2.21 Hz, 1 H) 7.56 (d, J=2.55 Hz, 1 H) 7.61 (dd, J=3.68, 1.47 Hz, 1 H) 7.68 (d, J=8.82 Hz, 1 H) 7.96 (dd, J=5.13 Hz, 1.47 Hz, 1 H) 8.53 (dd, J=8.09, 1.84 Hz, 1 H) 8.87 (dd, J=4.78, 1.84 Hz, 1 H) 10.98 (s, 1 H) 14.10 (s, 1 H). MS (ESI−) m/z 572 (M−H)−.