Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][CH:25]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:17](=[O:18])[CH2:16][C@@H:15]([C:19]([NH:21][OH:22])=[NH:20])[CH2:14]2)=[CH:9][CH:8]=1.[C:26](Cl)(=O)[CH3:27].O>N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][CH:25]=1)[CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([N:13]2[CH2:14][C@H:15]([C:19]3[N:20]=[C:26]([CH3:27])[O:22][N:21]=3)[CH2:16][C:17]2=[O:18])=[CH:11][CH:12]=1
Reactant: CC(=O)Cl
Reactant: N=C(NO)[C@@H]1CC(=O)N(c2ccc(OCc3cccc(F)c3)cc2)C1
Solvent: c1ccncc1
Solvent: O
Product: Cc1nc([C@@H]2CC(=O)N(c3ccc(OCc4cccc(F)c4)cc3)C2)no1
Temperature: 70 °C
Reaction time: 8 h
Yield: 46.2 %

Procedure:
(R)-1-[4-(3-Fluoro-benzyloxy)-phenyl]-N-hydroxy-5-oxo-pyrrolidine-3-carboxamidine (0.020 g, 0.58 mmol) was dissolved in a mixture of 0.4 ml pyridine and acetyl chloride (0.01 ml, 0.116 mmol) was slowly added at 0° C. The mixture was then stirred at 70° C. overnight. Iced water was added and the mixture was stirred for one hour. Extraction with a saturated solution of ammonium chloride and dichloromethane gave the crude product that was purified by column cromatography on silica gel using a 19:1-mixture of dichloromethane and methanol as the eluent to obtain the title compound as a light yellow solid (0.0197 g, 92% of theory). MS (m/e)=368.4 (M+H)+.
Reaction SMILES: CS(O[CH:6]([C:8]1[C:9]([CH:34]([O:37][CH3:38])[O:35][CH3:36])=[N:10][C:11]2[N:12]([C:18](=[O:33])[NH:19][C:20]3[CH:25]=[C:24]([NH:26][CH2:27][CH2:28][O:29][CH3:30])[C:23]([C:31]#[N:32])=[CH:22][N:21]=3)[CH2:13][CH2:14][CH2:15][C:16]=2[CH:17]=1)[CH3:7])(=O)=O.[CH3:39][NH2:40]>C(Cl)Cl.CN(C=O)C.O>[C:31]([C:23]1[C:24]([NH:26][CH2:27][CH2:28][O:29][CH3:30])=[CH:25][C:20]([NH:19][C:18]([N:12]2[C:11]3[C:16](=[CH:17][C:8]([CH:6]([NH:40][CH3:39])[CH3:7])=[C:9]([CH:34]([O:37][CH3:38])[O:35][CH3:36])[N:10]=3)[CH2:15][CH2:14][CH2:13]2)=[O:33])=[N:21][CH:22]=1)#[N:32]
Reactant: COCCNc1cc(NC(=O)N2CCCc3cc(C(C)OS(C)(=O)=O)c(C(OC)OC)nc32)ncc1C#N
Reactant: CN
Solvent: O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CNC(C)c1cc2c(nc1C(OC)OC)N(C(=O)Nc1cc(NCCOC)c(C#N)cn1)CCC2
Temperature: 25 °C

Procedure:
To a suspension of (racemic) 1-(8-((5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)carbamoyl)-2-(dimethoxymethyl)-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)ethyl methanesulfonate (intermediate 182, 231 mg, 0.421 mmol) in DCM (8 ml) and DMF (0.5 ml) at 0° C. was added methylamine (2M in THF, 3 mL, 6.00 mmol). The reaction mixture was allowed to warm to room temperature and continued to stir over night. The reaction mixture was diluted with water and DCM, phases were separated and the water phase was extracted with DCM (3×), organic phases were combined, dried using Na2SO4, filtered and concentrated. The crude product was purified using silica gel column chromatography eluting with MeOH (including 3% NH3, 4-5%) in DCM to yield the title compound as a colorless solid. (UPLC-MS 3) tR 0.76 min, ESI-MS 484.2 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 13.70 (s, 1H), 8.18 (s, 1H), 8.09 (s, 1H), 7.55 (s, 1H), 5.42 (s, 1H), 5.25 (t, 1H), 4.80-4.70 (m, 1H), 4.11-3.93 (m, 2H), 3.62 (t, 2H), 3.52-3.42 (m, 8H), 3.39 (s, 3H), 2.99-2.81 (m, 2H), 2.38 (s, 3H), 2.05-1.93 (m, 2H), 1.54 (d, J=6.6 Hz, 3H), 1.24 (s, 1H).
Reaction SMILES: [CH:1]1([C:6]2([CH3:19])[CH2:14][C:13]3[C:8](=[C:9]([Cl:17])[C:10]([Cl:16])=[C:11]([OH:15])[CH:12]=3)[CH:7]2[OH:18])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].C([O:28][C:29](=[O:32])[CH2:30]Br)C.[OH-].[Na+].Cl>CN(C)C=O.O>[OH:18][CH:7]1[C:8]2[C:13](=[CH:12][C:11]([O:15][CH2:30][C:29]([OH:32])=[O:28])=[C:10]([Cl:16])[C:9]=2[Cl:17])[CH2:14][C:6]1([CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5]1)[CH3:19]
Reactant: CC1(C2CCCC2)Cc2cc(O)c(Cl)c(Cl)c2C1O
Reactant: CCOC(=O)CBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C2CCCC2)Cc2cc(OCC(=O)O)c(Cl)c(Cl)c2C1O
Temperature: 0 °C

Procedure:
A stirred mixture of 2-cyclopentyl-2-methyl-6,7-dichloroindan-1,5-diol (α isomer) (1.9 g., 0.0063 mole), potassium carbonate (1.3 g., 0.0095 mole) and ethylbromoacetate (1.5 g. 0.0095 mole) in dimethylformamide (20 ml.) is warmed at 55°-60° C. under nitrogen for 2 hours, then treated with water (20 ml.) and 10N sodium hydroxide (1.9 ml.) and heated on a steam bath for one-half hour. The reaction mixture is poured into ice water (300 ml.) and while ice cold, 1N HCl is added dropwise with stirring to give 1.36 g. of (1-hydroxy-2-cyclopentyl-2-methyl-6,7-dichloro-5-indanyloxy)acetic acid (α isomer) which melts at 129°-131° C. after crystallization from benzene : hexane, 1:1.
Reaction SMILES: [Br-].[C:2]([C:5]1[CH:6]=[N+:7]([CH2:11][CH2:12][C:13](=[O:23])[NH:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:4])[NH2:3].S(S([O-])=O)([O-])=O.[Na+].[Na+]>>[C:2]([C:5]1[CH2:10][CH:9]=[CH:8][N:7]([CH2:11][CH2:12][C:13](=[O:23])[NH:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=1)(=[O:4])[NH2:3]
Reactant: NC(=O)c1ccc[n+](CCC(=O)NCCc2ccccc2)c1
Agent: O=S([O-])S(=O)[O-]
Agent: [Br-]
Agent: [Na+]
Product: NC(=O)C1=CN(CCC(=O)NCCc2ccccc2)C=CC1
Yield: 80.2 %

Procedure:
The product of Example 124 (3.78 g, 0.01 mol) was reduced according to the procedure described in Example 126 with sodium dithionite (6.96 g, 0.04 mol). After completion of the reaction, the product was extracted with ethyl acetate, washed with water, dried over anhydrous sodium sulfate, and the solvent was evaporated in vacuo. A yield of 2.4 g (80%) of the title compound was obtained as a yellowish amorphous powder, m.p. 121°-123° C. UV max (methanol) 350 nm; IR (KBr) 3430 (NH), 3260 (NH), 1670 (CO), 1630 (CO) cm-1. Anal. calc. for C17H21N3O2.3/4H2O: C, 65.26; H, 7.24; N, 13.43. Found: C, 65.19; H, 6.87; N, 13.61. The structure of the product was further confirmed by PMR to be: ##STR1588##
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[C:15]([NH2:20])=[N:16][CH:17]=[CH:18][CH:19]=2)=[N:12][N:11]=[N:10]1.C1C(=O)N([Br:28])C(=O)C1.C([O-])(O)=O.[Na+].[O-]S([O-])(=S)=O.[Na+].[Na+].[OH-].[Na+]>CC#N>[Br:28][C:18]1[CH:19]=[C:14]([C:13]2[N:9]([C:3]3[CH:4]=[CH:5][CH:6]=[C:7]([F:8])[C:2]=3[F:1])[N:10]=[N:11][N:12]=2)[C:15]([NH2:20])=[N:16][CH:17]=1
Reactant: Nc1ncccc1-c1nnnn1-c1cccc(F)c1F
Reactant: O=C1CCC(=O)N1Br
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC#N
Product: Nc1ncc(Br)cc1-c1nnnn1-c1cccc(F)c1F
Temperature: 25 °C

Procedure:
3-(1-(2,3-Difluorophenyl)-1H-tetrazol-5-yl)pyridin-2-amine was stirred in CH3CN (15 mL) and treated with NBS (2 eq). The reaction mixture was maintained at room temperature for 30 min. The reaction was subsequently poured into sat NaHCO3 solution and treated sequentially with 5 mL Na2S2O3 and 2 mL 6N NaOH. The solids were filtered, washed with water, and dried in vacuo to afford 5-bromo-3-(1-(2,3-difluorophenyl)-1H-tetrazol-5-yl)pyridin-2-amine, which was purified by silica gel chromatography. Using the same procedure, 5-bromo-3-(1-(2,3-dichlorophenyl)-1H-tetrazol-5-yl)pyridin-2-amine and 5-bromo-3-(1-(3-chloro-2-fluorophenyl)-1H-tetrazol-5-yl)pyridin-2-amine can be produced from 3-(1-(2,3-dichlorophenyl)-1H-tetrazol-5-yl)pyridin-2-amine and 3-(1-(3-chloro-2-fluorophenyl)-1H-tetrazol-5-yl)pyridin-2-amine, respectively.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[C:6]([O:13][CH3:14])=[CH:5][C:4]=1[CH3:15].[CH3:16][O:17]C(Cl)Cl.O>C(Cl)Cl.CCOC(C)=O.Cl[Ti](Cl)(Cl)Cl>[CH3:15][C:4]1[C:5]([CH:16]=[O:17])=[C:6]([O:13][CH3:14])[C:7]([O:11][CH3:12])=[C:8]([O:9][CH3:10])[C:3]=1[O:2][CH3:1]
Reactant: COC(Cl)Cl
Reactant: COc1cc(C)c(OC)c(OC)c1OC
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Solvent: O
Solvent: CCOC(C)=O
Product: COc1c(C)c(C=O)c(OC)c(OC)c1OC
Temperature: 25 °C
Reaction time: 6 h
Yield: 89.2 %

Procedure:
According to the procedure by Ohkawa et al.,15 6 (0.690 g, 3.25 mmol) was dissolved in CH2Cl2 (2.0 mL) in a flame-dried 25 mL round bottom flask and cooled to 0° C. α,α-dichloromethyl methyl ether (0.85 ml, 9.6 mmol) was then added at 0° C., followed by TiCl4 (1 M in CH2Cl2, 9.0 ml, 9.0 mmol) at 0° C. The reaction was warmed slowly to room temperature and stirred for 6 hours under argon. The reaction was then poured into chilled water and stirred for 10 minutes. The reaction was diluted with EtOAc, washed with brine, dried over MgSO4, filtered, and condensed. The crude oil was then purified by flash chromatography (1:49 EtOAc:hexanes if made via p-cresol; 3:17 EtOAc:hexanes if made via Wolffe-Kishner reduction) to provide 7 (0.696 g, 2.90 mmol, 89%) as a yellow oil.
Reaction SMILES: [N+:1]([C:4]1[CH:31]=[CH:30][C:7]([C:8]([CH:10]([C:19](=[O:29])[C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-])=O)=[CH:22][CH:21]=2)[CH:11]([OH:18])[CH2:12][O:13][CH:14]([CH2:16][OH:17])[CH3:15])=[O:9])=[CH:6][CH:5]=1)([O-])=O>[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:8]([CH:10]([C:19](=[O:29])[C:20]2[CH:21]=[CH:22][C:23]([NH2:26])=[CH:24][CH:25]=2)[CH:11]([OH:18])[CH2:12][O:13][CH:14]([CH2:16][OH:17])[CH3:15])=[O:9])=[CH:30][CH:31]=1
Reactant: CC(CO)OCC(O)C(C(=O)c1ccc([N+](=O)[O-])cc1)C(=O)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Product: CC(CO)OCC(O)C(C(=O)c1ccc(N)cc1)C(=O)c1ccc(N)cc1

Procedure:
Bis-(4-nitrobenzoyl)-dipropylene glycol (50 g, 0.134 mole, from Part A) was hydrogenated in the usual manner over palladium on carbon (10%, 4 g). The product crystallized during drying over MgSO4. The solution was therefore heated to boiling, filtered hot and crystallization effected by addition of hexanes to give bis-(4-aminobenzoyl)-dipropylene glycol (29 g) as an offwhite solid, m.p. 163°-165° C. which was homogeneous by TLC.
Reaction SMILES: [N+:1]([C:4]1[CH:20]=[CH:19][C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16]([OH:18])=[O:17])=[CH:11][CH:10]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl.O.[CH2:23](O)[CH3:24]>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16]([O:18][CH2:23][CH3:24])=[O:17])=[CH:11][CH:10]=2)=[CH:19][CH:20]=1)([O-:3])=[O:2]
Reactant: CCO
Reactant: O=C(O)Cc1ccc(Oc2ccc([N+](=O)[O-])cc2)cc1
Agent: Cl
Solvent: O
Product: CCOC(=O)Cc1ccc(Oc2ccc([N+](=O)[O-])cc2)cc1

Procedure:
A solution of 27.3 g of [p-(p-nitrophenoxy)phenyl]acetic acid in 270 ml of ethanol is cooled to 0° C. and saturated with dry HCl gas over 31/2 hours. The resulting deep red solution is heated to reflux and maintained at reflux overnight. A yellow crystalline solid separates on cooling. The entire mixture is poured into 500 ml of water and extracted with three 200 ml portions of benzene. The combined extracts are washed with two 150 ml portions of water, two 150 ml portions of saturated NaHCO3, 150 ml of saturated brine, and dried over MgSO4. Evaporation of the solvent at reduced pressure affords an oil which yields yellow crystals from 50 ml of ethanol, mp 70.5°-73° C. Recrystallization from ethanol affords yellow prisms, mp 70.5°-73° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:11])[C:9]=1[OH:10])[CH:5]=[O:6].Cl[C:13]1[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][N:14]=1.C([O-])([O-])=O.[K+].[K+]>>[CH:5]([C:4]1[CH:3]=[C:2]([F:1])[C:9]([O:10][C:13]2[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][N:14]=2)=[C:8]([F:11])[CH:7]=1)=[O:6]
Reactant: O=Cc1cc(F)c(O)c(F)c1
Reactant: N#Cc1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: N#Cc1ccc(Oc2c(F)cc(C=O)cc2F)nc1
Yield: 69.1 %

Procedure:
Using a method similar to Example 710, Step 2, using 3,5-difluoro-4-hydroxy-benzaldehyde (Journal of Medicinal Chemistry (1989), 32(2), 450-5.) (2.50 g, 15.8 mmol), 6-chloronicotinonitrile (2.19 g, 15.8 mmol) and K2CO3 (3.27 g, 23.7 mmol) gives 6-(4-formyl-2,6-difluoro-phenoxy)-nicotinonitrile (2.84 g) as a white solid. 1H NMR (CDCl3): 9.95 (s, 1H), 8.39 (s, 1H), 8.02 (d, 1H), 7.58 (d, 2H), 7.25 (d, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9](=O)[CH2:10][CH2:11][C:12]([CH3:18])([CH3:17])[C:13]([O:15][CH3:16])=[O:14])[CH:5]=[C:6]([F:8])[CH:7]=1.[CH3:20][C:21]([S@@:24]([NH2:26])=[O:25])([CH3:23])[CH3:22].[BH4-].[Na+].CO>C1COCC1.[Cl-].[Na+].O.[O-]CC.[O-]CC.[O-]CC.[O-]CC.[Ti+4]>[C:21]([S@@:24]([NH:26][C@H:9]([C:4]1[CH:3]=[C:2]([F:1])[CH:7]=[C:6]([F:8])[CH:5]=1)[CH2:10][CH2:11][C:12]([CH3:18])([CH3:17])[C:13]([O:15][CH3:16])=[O:14])=[O:25])([CH3:23])([CH3:22])[CH3:20]
Reactant: COC(=O)C(C)(C)CCC(=O)c1cc(F)cc(F)c1
Reactant: CC(C)(C)[S@@](N)=O
Agent: [Ti+4]
Agent: CC[O-]
Agent: [BH4-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: COC(=O)C(C)(C)CC[C@H](N[S@@](=O)C(C)(C)C)c1cc(F)cc(F)c1
Temperature: 60 °C
Reaction time: 0.25 h

Procedure:
To a solution of methyl 5-(3,5-difluorophenyl)-2,2-dimethyl-5-oxopentanoate from Step D (500. mg, 1.85 mmol) and (S)-2-methylpropane-2-sulfinamide (336 mg, 2.78 mmol) in THF (6.5 mL), was added titanium tetraethoxide (616 mg, 2.52 mmol). The reaction vessel was quickly sealed and heated at 60° C. for 3 h. After cooling to ambient temperature a septum and nitrogen inlet were attached prior to cooling to 0° C. Sodium borohydride (191 mg, 5.05 mmol) was then added, and a complete reaction was observed after 15 min. MeOH was slowly added until gas evolution stopped. The reaction mixture was diluted with saturated brine (6.5 mL) while experiencing rapid stirring. The resultant slurry was filtered through celite, washing with EtOAc as needed. The filtrate was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to give an oil. This oil was purified by silica gel chromatography, eluting with a gradient of EtOAc:Hexanes—10:90 to 70:30, to give the title compound containing about 12% of the corresponding ethyl ester. MS: m/z=376 (M+1).
Reaction SMILES: [C:1]1([C@@H:7]([NH2:16])[C@@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[NH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH:24]([C:27]1[CH:32]=[C:31]([CH:33]([CH3:35])[CH3:34])[CH:30]=[C:29]([CH:36]([CH3:38])[CH3:37])[C:28]=1[S:39](Cl)(=[O:41])=[O:40])([CH3:26])[CH3:25]>ClCCl>[NH2:16][C@H:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C@H:8]([NH:9][S:39]([C:28]1[C:29]([CH:36]([CH3:37])[CH3:38])=[CH:30][C:31]([CH:33]([CH3:35])[CH3:34])=[CH:32][C:27]=1[CH:24]([CH3:26])[CH3:25])(=[O:41])=[O:40])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CC(C)c1cc(C(C)C)c(S(=O)(=O)Cl)c(C(C)C)c1
Reactant: N[C@H](c1ccccc1)[C@H](N)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)c1cc(C(C)C)c(S(=O)(=O)N[C@H](c2ccccc2)[C@H](N)c2ccccc2)c(C(C)C)c1
Temperature: 5 °C
Reaction time: 4 h
Yield: 96.7 %

Procedure:
(1R,2R)-1,2-Diphenyl-ethane-1,2-diamine (1.0 g) was dissolved in dichloromethane (20 mL), and then triethylamine (0.66 mL) added and the mixture was cooled to 5° C. (internal). 2,4,6-Triisopropyl-benzenesulfonyl chloride (1.21 g) was dissolved in dichloromethane (10 mL) and then added to the diamine mixture over 30 minutes, while maintaining the temperature between 7-10 ° C. The cooling bath was removed and the resulting mixture was stirred at 25° C. for 4 hours and the solvent was evaporated. The resulting residue was suspended in hexanes (100 mL) and washed with warm water (42° C., 3×100 mL). The hexane layer was separated, dried over Na2SO4, filtered, and evaporated to provide the product (1.85 g). 1HNMR (400 MHz, CDCl3): δ(ppm) 7.20-7.15 (m, 3H), 7.05-6.94 (m, 7H), 6.84-6.80 (m, 2H), 6.09 (br-s,1H), 4.49 (d, 1H), 3.99-3.91 (m, 3H), 2.87-2.79 (m, 1H), 1.21 (d, 6H), 1.17 (d, 6H), 1.08 (d, 6H). LC/MS: 479 (m/z).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:5]2[S:10][C:9](I)=[CH:8][C:6]=2[N:7]=1.[CH:18]([C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1)=[O:19]>C([O-])([O-])=O.[Na+].[Na+].C(#N)C.C(OCC)(=O)C.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>[Cl:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:5]2[S:10][C:9]([C:24]3[CH:25]=[C:20]([CH:21]=[CH:22][CH:23]=3)[CH:18]=[O:19])=[CH:8][C:6]=2[N:7]=1
Reactant: O=Cc1cccc(B(O)O)c1
Reactant: Clc1nc(N2CCOCC2)c2sc(I)cc2n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: O=Cc1cccc(-c2cc3nc(Cl)nc(N4CCOCC4)c3s2)c1
Yield: 35 %

Procedure:
2-Chloro-6-iodo-4-morpholinothieno[3,2-d]pyrimidine 19 (300 mg), 130 mg of 3-formylbenzeneboronic acid and 55 mg of Bis(triphenylphosphine)palladium(II) dichloride in 0.6 mL of 1M Na2CO3 and 0.6 mL of acetonitrile was heated to 100° C. in the microwave reactor for 15 min. The reaction mixture was diluted with ethyl acetate (60 mL), and then washed with H2O (40 mL). The organic layer was dried over MgSO4, filtered and evaporated. The residue was purified by ISCO CombiFlash (0-40% ethyl acetate/hexane) to yield 99 mg of 3-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)benzaldehyde.
Reaction SMILES: C(O[C:6]([C:8]1[N:9]=[C:10]([C:28]#[N:29])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][C:14]([O:19][C:20]1[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][C:21]=1[CH3:27])=[CH:13][CH:12]=2)=[O:7])CCC.[NH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([OH:37])=[O:36].C[O-].[Na+]>COCCO>[C:28]([C:10]1[C:11]2[C:16](=[CH:15][C:14]([O:19][C:20]3[C:21]([CH3:27])=[CH:22][CH:23]=[CH:24][C:25]=3[CH3:26])=[CH:13][CH:12]=2)[C:17]([OH:18])=[C:8]([C:6]([NH:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([OH:37])=[O:36])=[O:7])[N:9]=1)#[N:29]
Reactant: NCCCCC(=O)O
Reactant: CCCCOC(=O)c1nc(C#N)c2ccc(Oc3c(C)cccc3C)cc2c1O
Agent: C[O-]
Agent: [Na+]
Solvent: COCCO
Product: Cc1cccc(C)c1Oc1ccc2c(C#N)nc(C(=O)NCCCCC(=O)O)c(O)c2c1
Temperature: 25 °C
Yield: 77.3 %

Procedure:
A mixture of 1-cyano-6-(2,6-dimethyl-phenoxy)-4-hydroxy-isoquinoline-3-carboxylic acid butyl ester (80 mg, 0.20 mmol), 5-aminovaleric acid (480 mg, 4.10 mmol) and NaOMe (166 mg, 3.07 mmol) in 2-methoxyethanol (10 mL) was refluxed for 2 h. After the mixture was cooled to r.t., solvent was evaporated. The residue was partitioned between EtOAc (50 mL) and water (50 mL). 1 M HCl was added with vigorous stirring until pH was ˜2. The organic layer was dried over MgSO4 and concentrated. The crude product was purified by column chromatography (0-60% EtOAc/hexanes+2% AcOH) to give 67 mg of the title compound as a pale pink solid. MS: (+) m/z 434.18 (M+1).
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@:12]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]3[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH3:49])=[C:43]([F:50])[CH:42]=3)[CH:34]=2)([O:31][CH3:32])[O:11][C@@H:10]1[CH:51]=[O:52])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:53]=[O:54].[OH-].[Na+]>O1CCOCC1>[CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@:12]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]3[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH3:49])=[C:43]([F:50])[CH:42]=3)[CH:34]=2)([O:31][CH3:32])[O:11][C@:10]1([CH2:53][OH:54])[CH:51]=[O:52])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOc1ccc(Cc2cc([C@]3(OC)O[C@H](C=O)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)ccc2Cl)cc1F
Reactant: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CCOc1ccc(Cc2cc([C@]3(OC)O[C@@](C=O)(CO)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)ccc2Cl)cc1F
Temperature: 70 °C
Reaction time: 16 h

Procedure:
(2S,3S,4S,5R,6S)-3,4,5-tribenzyloxy-6-[4-chloro-3-[(4-ethoxy-3-fluoro-phenyl)methyl]phenyl]-6-methoxy-tetrahydropyran-2-carbaldehyde 4j (7.6 g, 10.45 mmol) was dissolved in 80 mL 1,4-dioxane, followed by addition of 15.8 mL 37% formaldehyde solution and sodium hydroxide (31.35 mL, 31.35 mmol) in turn. The reaction mixture was stirred for 16 hours at 70° C. Thereafter, the reaction mixture was extracted with ethyl acetate (50 mL×4) after 50 mL saturated sodium chloride solution were added. The organic extract was washed with saturated sodium bicarbonate solution (50 mL) and saturated sodium chloride solution (50 mL) and combined, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (2S,3S,4S,5R,6S)-3,4,5-tribenzyloxy-6-[4-chloro-3-[(4-ethoxy-3-fluoro-phenyl)methyl]phenyl]-2-(hydroxymethyl)-6-methoxy-tetrahydropyran-2-carbaldehyde 4k (7.9 g, colourless grease), which was used directly without purification in the next step.
Reaction SMILES: [NH:1]1[CH2:4][CH2:3][C:2]1=[O:5].[O-]P([O-])([O-])=O.[K+].[K+].[K+].CNCCNC.I[C:21]1[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=1[CH2:23][NH2:24].N>O.[Cu]I.C1(C)C=CC=CC=1>[NH:1]1[CH2:4][CH2:3][C:2](=[O:5])[NH:24][CH2:23][C:22]2[CH:25]=[CH:26][CH:27]=[CH:28][C:21]1=2
Reactant: O=C1CCN1
Reactant: NCc1ccccc1I
Agent: [Cu]I
Agent: CNCCNC
Agent: N
Solvent: Cc1ccccc1
Solvent: O
Product: O=C1CCNc2ccccc2CN1
Temperature: 100 °C
Reaction time: 22 h
Yield: 81.7 %

Procedure:
A Schlenk tube was charged with CuI (9.6 mg, 0.050 mmol, 5.0 mol %), 2-azetidinone (86 mg, 1.21 mmol), K3PO4 (430 mg, 2.03 mmol), evacuated, and backfilled with Ar. N,N′-Dimethylethylenediamine (11 μL, 0.103 mmol, 10 mol %), 2-iodobenzylamine (132 μL, 1.00 mmol), and toluene (1 mL) were added under Ar. The Schlenk tube was sealed and the reaction mixture was stirred at 100° C. for 22 h. The resulting suspension was allowed to reach room temperature, poured into a solution of 30% aq ammonia (1 mL) in water (20 mL), and extracted with 3×20 mL CH2Cl2. The combined organic layers were dried (Na2SO4), concentrated, and the residue was purified by flash chromatography on silica gel (2×15 cm, ethyl acetate-methanol 10:1, 15 mL fractions). Fractions 10–20 provided 144 mg of the desired product (82% yield) as a white solid.
Reaction SMILES: [C:1]([C:3]1[CH:15]=[CH:14][C:6]([CH2:7][N:8]2[CH:12]=[CH:11][N:10]=[C:9]2[CH3:13])=[CH:5][C:4]=1F)#[N:2].[Cl:17][C:18]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=1[SH:25].C(=O)([O-])[O-].[Cs+].[Cs+].CCOC(C)=O>CS(C)=O>[C:1]([C:3]1[CH:15]=[CH:14][C:6]([CH2:7][N:8]2[CH:12]=[CH:11][N:10]=[C:9]2[CH3:13])=[CH:5][C:4]=1[S:25][C:19]1[CH:20]=[CH:21][C:22]([Cl:24])=[CH:23][C:18]=1[Cl:17])#[N:2]
Reactant: Sc1ccc(Cl)cc1Cl
Reactant: Cc1nccn1Cc1ccc(C#N)c(F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: Cc1nccn1Cc1ccc(C#N)c(Sc2ccc(Cl)cc2Cl)c1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
To a solution of the product From Step C (417 mg, 1.94 mmol) and 2,4-dichlorothiophenol (348 mg, 1.94 mmol) in 7.0 mL of DMSO was added cesium carbonate (1.26 g, 3.88 mmol). The reaction was warmed to 60° C. under argon and stirred for three hours. The solution was poured into EtOAc and washed with water and brine, dried (Na2SO4), filtered, and concentrated in vacuo. The resulting product was purified by silica gel chromatography (3-4% MeOH/CH2Cl2) to provide the product as a brown foam.