Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1]O.[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH:18]=[C:19]([O:23][CH3:24])[C:20]=1[O:21][CH3:22])[CH2:8][N:9]1[CH2:14][CH2:13][N:12]([C:15]([S-:17])=[S:16])[CH2:11][CH2:10]1.[Na+].CI>O>[CH3:24][O:23][C:19]1[CH:18]=[C:7]([CH:6]=[C:5]([O:4][CH3:3])[C:20]=1[O:21][CH3:22])[CH2:8][N:9]1[CH2:10][CH2:11][N:12]([C:15]([S:17][CH3:1])=[S:16])[CH2:13][CH2:14]1
Reactant: CO
Reactant: COc1cc(CN2CCN(C(=S)[S-])CC2)cc(OC)c1OC
Agent: [Na+]
Solvent: O
Solvent: CI
Product: COc1cc(CN2CCN(C(=S)SC)CC2)cc(OC)c1OC
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To 70 ml of methanol containing 6.67 g of sodium 4-(3,4,5-trimethoxybenzyl)piperazinecarbodithioate was dropwise added under chilling with ice 20 ml of methanol solution containing 2.6 g of methyl iodide for 20 min. The resulting mixture was further stirred for 3 hours under chilling with ice. The reaction solution was placed under reduced pressure to distill off the solvent, leaving a residue. The residue was dissolved in water, and then extracted with chloroform. The chloroform portion was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and placed under reduced pressure to distill off the solvent. Thus obtained crude product was purified by silica gel chromatography to give 3.7 g of the desired compound as a pale yellow crystalline product.
Reaction SMILES: [CH2:1]([O:3][C@H:4]1[CH2:23][C@@:22]2([CH3:24])[C@@H:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:21]2[C:20](=[O:25])[CH2:19][C@@:18]2([CH3:26])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[C:15](=[O:17])[CH3:16])[CH2:6][C@@H:5]1[OH:27])[CH3:2].N1C=CC=CC=1.[C:34](OC(=O)C)(=[O:36])[CH3:35]>C(Cl)Cl>[C:34]([O:27][C@@H:5]1[C@@H:4]([O:3][CH2:1][CH3:2])[CH2:23][C@@:22]2([CH3:24])[C@@H:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:21]2[C:20](=[O:25])[CH2:19][C@@:18]2([CH3:26])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[C:15](=[O:17])[CH3:16])[CH2:6]1)(=[O:36])[CH3:35]
Reactant: CC(=O)OC(C)=O
Reactant: CCO[C@H]1C[C@@]2(C)[C@@H](CC[C@H]3[C@@H]4CC[C@H](C(C)=O)[C@@]4(C)CC(=O)[C@@H]32)C[C@@H]1O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCO[C@H]1C[C@@]2(C)[C@@H](CC[C@H]3[C@@H]4CC[C@H](C(C)=O)[C@@]4(C)CC(=O)[C@@H]32)C[C@@H]1OC(C)=O
Reaction time: 24 h

Procedure:
2β-Ethoxy-3α-hydroxy-5α-pregnane-11,20-dione (500 mg.) in dry methylene chloride (5 ml.) at 0° was treated with pyridine (2.0 ml.) and acetic anhydride (2.0 ml.). After 24 hours, methylene chloride was added, and the solution was washed with dilute hydrochloric acid and with water. It was then dried over sodium sulphate and evaporated to an oil. The title compound (350 mg.) was obtained as a colourless foam, [α]D + 132°.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[C:17]([CH:18]=[O:19])=[CH:16][CH:15]=[CH:14][N:13]=2)=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].CC1C=CC(S([CH2:30][N+:31]#[C-:32])(=O)=O)=CC=1.C1CCN2C(=NCCC2)CC1>COCCOC>[F:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[C:17]([C:18]3[O:19][CH:32]=[N:31][CH:30]=3)=[CH:16][CH:15]=[CH:14][N:13]=2)=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=Cc1cccnc1Oc1ccc(F)c(C(=O)O)c1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: O=C(O)c1cc(Oc2ncccc2-c2cnco2)ccc1F
Temperature: 85 °C

Procedure:
To 2-fluoro-5-(3-formylpyridin-2-yloxy)benzoic acid (230 mg, 0.881 mmol) and TosMIC (172 mg, 0.881 mmol) in DME (8.0 mL) was added DBU (0.29 mL, 1.9 mmol). The mixture was heated to 85° C. for 2.5 hours in a sealed tube. After concentrated, the residue was diluted with saturated sodium carbonate and extracted with EtOAc. The aqueous layer was acidified with TFA (pH˜3) and the resulting solid was filtered and dried to yield 2-fluoro-5-(3-(oxazol-5-yl)pyridin-2-yloxy)benzoic acid as a beige solid. MS m/z=301 [M+1]+. Calc'd for C15H9FN2O4: 300.25.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]2[C:20](=[O:21])[CH:19]=[C:18]([CH3:22])[NH:17][C:16]2=[O:23])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5].[Na].[CH:25](O)(C)C>>[Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]2[C:20](=[O:21])[CH:19]=[C:18]([CH3:22])[N:17]([CH3:25])[C:16]2=[O:23])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5]
Reactant: CC(C)O
Reactant: Cc1cc(=O)n(-c2cc(C(=O)OC(C)C)c(Cl)cc2F)c(=O)[nH]1
Agent: [Na]
Product: Cc1cc(=O)n(-c2cc(C(=O)OC(C)C)c(Cl)cc2F)c(=O)n1C

Procedure:
using isopropyl 2-chloro-4-fluoro-5-[3,6-dihydro-4-methyl-2,6-dioxo-1(2H)-pyrimidinyl]-benzoate with sodium isopropylate in isopropanol there is obtained isopropyl 2-chloro-4-fluoro-5-[3,6-dihydro-3,4-dimethyl-2,6-dioxo-1(2H)-pyrimidinyl]-benzoate, 1H-NMR (CDCl3, 60 MHz) 7.88 ppm (d, 1H), 7.38 ppm (d, 1H), 5.77 ppm (s, 1H), 5.30 ppm (m, 1H), 3.50 ppm (s, 3H), 2.36 ppm (s, 3H), 1.40 ppm (d, 6H),
Reaction SMILES: ClCCl.[OH:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.[CH3:13][Si:14](Cl)([CH3:16])[CH3:15].[Na+].[Cl-]>C(N(CC)CC)C>[CH3:13][Si:14]([CH3:16])([CH3:15])[O:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1
Reactant: C[Si](C)(C)Cl
Reactant: OCc1ccc(O)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[Si](C)(C)OCc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.6 %

Procedure:
300 ml of dichloromethane followed by 60 g of triethylamine are added to 30 g of 4-hydroxymethyl-phenol introduced into a 500 ml flask maintained under a hydrogen atmosphere. The temperature of the obtained solution is brought to 10° C. and 64 g of trimethylsilyl chloride are added thereto in about one hour, keeping the temperature at 10° C. Thus, the temperature is left to spontaneously rise to 25° C., maintaining such conditions for one hour. Then, the reaction of the substrate is controlled under TLC. Upon ascertaining the disappearance of the initial product, 200 ml of an aqueous saturated NaCl solution are added and the two-phase system is stirred vigorously for 10′ and then the two phases are decanted. The lower organic phase is washed with two 200 ml portions of deionised water and then concentrated to residue, obtaining a yellowish oil. Such residue is recovered using 500 ml of DMF in a 2-liter flask and a solution constituted by 3 g of Lithium acetate in 60 ml of water is added to the obtained solution. The mixture is maintained at 25° C. for one hour, then the removal of the trimethylsilyl group on the phenolic hydroxyl is controlled under TLC. Then, 650 ml of a saturated NaCl solution and 455 ml of toluene are added to the reaction mixture and the mixture is stirred vigorously for 10′, then the two phases are left to decant. The upper organic phase is then washed with two 650 ml portions of deionised water and concentrated under vacuum, obtaining 33 g of the desired product (70% yield).
Reaction SMILES: [Br:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C@H:6]([NH2:8])[CH3:7].Br[CH2:14][CH3:15].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C@H:6]([NH:8][CH2:14][CH3:15])[CH3:7]
Reactant: CCBr
Reactant: C[C@@H](N)COc1ccccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCN[C@H](C)COc1ccccc1Br

Procedure:
(R)-2-(2-bromophenoxy)-1-methylethylamine, (Preparation 1A, Step 2) (1.68 g, 7.3 mmol) was dissolved in DMF (16 ml). The mixture was stirred with bromoethane (3.18 ml, 43 mmol) and K2CO3 (7.60 g, 55 mmoles) at r.t. under N2 for about 3 days. The mixture was concentrated, dissolved in EtOAc, washed with water and brine, dried over Na2SO4, and filtered. Solvent was removed and the residue was purified by flash chromatography (silica gel, 5% 2M NH3 in MeOH/CH2Cl2) to give about 2.08 g of a mixture of diethyl and monoethyl amine compounds with the mono ethyl as the minor product.
Reaction SMILES: [C:1]([Si:5]([CH3:13])([CH3:12])[O:6][CH2:7][CH2:8][CH:9]1[CH2:11][O:10]1)([CH3:4])([CH3:3])[CH3:2].[N-:14]=[N+:15]=[N-:16].[Na+].[NH4+].[Cl-]>CO>[N:14]([CH2:11][CH:9]([OH:10])[CH2:8][CH2:7][O:6][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:13])[CH3:12])=[N+:15]=[N-:16]
Reactant: CC(C)(C)[Si](C)(C)OCCC1CO1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)[Si](C)(C)OCCC(O)CN=[N+]=[N-]
Temperature: 80 °C
Reaction time: 8 h
Yield: 81 %

Procedure:
A solution of 2-[2-[[(tert-butyl)dimethylsilyl]oxy]ethyl]-oxirane (5.0 g; prepared according to WO 2007/144423) in MeOH (150 mL) was reacted with NaN3 (3.95 g) and NH4Cl (2.37 g). The reaction mixture was further stirred at 80° C. overnight. The solvent was evaporated under reduced pressure and the residue was partitioned between EA and water. The org. layer was washed with brine, dried over Na2SO4 and evaporated under reduced pressure, affording a yellow oil (4.9 g; 81% yield).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]([O:19][CH3:20])=[CH:17][C:12]([C:13](Cl)=[N:14][OH:15])=[C:11]([I:21])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[N:23](C)C=O.N.C(OCC)(=O)C>O>[CH2:1]([O:8][C:9]1[C:18]([O:19][CH3:20])=[CH:17][C:12]([C:13]([NH:14][OH:15])=[NH:23])=[C:11]([I:21])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)C=O
Reactant: COc1cc(C(Cl)=NO)c(I)cc1OCc1ccccc1
Agent: N
Solvent: CCOC(C)=O
Solvent: O
Product: COc1cc(C(=N)NO)c(I)cc1OCc1ccccc1
Reaction time: 3 h

Procedure:
To a mixture of 4-benzyloxy-N-hydroxy-2-iodo-5-methoxy-benzimidoylchloride and N,N-dimethylformamide (110 mL) was added a 28% ammonia in water (12 mL) under ice-bath cooling. After stirring for 3 hours under ice-bath cooling, water and ethyl acetate were added to the mixture. The separated organic layer was washed with water and brine successively, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was triturated with hexane:diethyl ether=1:4 to give the title compound (9.3 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7](Cl)=[N:8][OH:9].[Br:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]#[CH:20])=[CH:15][CH:14]=1.N>>[Br:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[O:9][N:8]=[C:7]([C:6]3[CH:5]=[N:4][CH:3]=[C:2]([F:1])[CH:11]=3)[CH:20]=2)=[CH:15][CH:14]=1
Reactant: C#Cc1ccc(Br)cc1
Reactant: ON=C(Cl)c1cncc(F)c1
Agent: N
Product: Fc1cncc(-c2cc(-c3ccc(Br)cc3)on2)c1

Procedure:
The titled compound was prepared according to Method CB using the product of Example 28B (88 mg, 0.5 mmol) and 1-bromo-4-ethynylbenzene (Alfa Aesar, 80 mg, 0.5 mmol). 1H NMR (300 MHz, MeOH-d4) δ 7.43 (s, 1H), 7.72 (dt, J=8.9, 2.2 Hz, 2H), 7.85 (dt, J=8.9, 2.2 Hz, 2H), 8.17 (ddd, J=9.5, 2.7, 1.7 Hz, 1H), 8.61 (d, J=2.7 Hz, 1H), 8.96 (t, J=1.5 Hz, 1H) ppm; MS (DCI/NH3) m/z 320 (M+H)+, 318 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[O:10][CH2:11][C:12](=[O:19])[C:13]=2[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:4]([CH3:20])[CH:3]=1.[CH3:21][O:22][CH2:23][CH2:24]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>ClCCl.O>[CH3:21][O:22][CH2:23][CH2:24][O:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[O:10][CH2:11][C:12](=[O:19])[C:13]=2[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:4]([CH3:20])[CH:3]=1
Reactant: CCOC(=O)C1=C(Nc2ccc(O)cc2C)OCC1=O
Reactant: COCCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)C1=C(Nc2ccc(OCCOC)cc2C)OCC1=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of ethyl 2-[(4-hydroxy-2-methylphenyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate (0.10 g, 0.36 mmol) which similarly prepared according to the procedure described in the Example 74, Fourth step, 2-methoxyethanol (0.051 mL, 0.65 mmol) and triphenylphosphine (0.19 g, 0.72 mmol) in dichloromethane (2.0 mL) that cooled with ice bath, 2.2M diethyl azodicarboxylate (40% in toluene, 0.33 mL, 0.73 mmol) was added dropwise then the mixture was stirred at ambient temperature for 24 h. The reaction mixture was diluted with water, and extracted with chloroform. The organic layer was washed with 1M sodium hydroxide solution and brine, dried over magnesium sulfate and concentrated to afford ethyl 2-{[4-(2-methoxyethoxy)-2-methylphenyl]amino}-4-oxo-4,5-dihydrofuran-3-carboxylate as oil (0.30 g, crude material).
Reaction SMILES: [C:1](#[N:10])[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[OH-:11].[Na+]>CO>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([C:1]([NH2:10])=[O:11])=[CH:3][CH:4]=1)#[N:7]
Reactant: N#Cc1ccc(C#N)cc1
Reactant: [OH-]
Agent: [Na+]
Solvent: CO
Product: N#Cc1ccc(C(N)=O)cc1
Yield: 62.3 %

Procedure:
Terephthalonitrile (12.8 g, 0.1 mol) and methanol (170.1 g) were mixed, and the resultant mixture was heated to 64° C. with stirring. To the mixture, a 20% aqueous solution of sodium hydroxide (12 g) was added over six hours. Liquid chromatographic analysis revealed the reaction mixture contained 9.1 g of p-cyanobenzamide (yield 62%).
Reaction SMILES: C[O:2][C:3](=[O:36])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([O:12][CH2:13][CH2:14][N:15]2[CH2:20][CH:19]([CH3:21])[N:18]([C:22]3[S:23][C:24]4[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][C:25]=4[N:26]=3)[CH:17]([CH3:35])[CH2:16]2)[CH:6]=1.[OH-].[Na+].O1CCCC1.Cl>CO>[Cl:11][C:8]1[CH:9]=[CH:10][C:5]([CH2:4][C:3]([OH:36])=[O:2])=[CH:6][C:7]=1[O:12][CH2:13][CH2:14][N:15]1[CH2:20][CH:19]([CH3:21])[N:18]([C:22]2[S:23][C:24]3[CH:30]=[C:29]([C:31]([F:34])([F:32])[F:33])[CH:28]=[CH:27][C:25]=3[N:26]=2)[CH:17]([CH3:35])[CH2:16]1
Reactant: COC(=O)Cc1ccc(Cl)c(OCCN2CC(C)N(c3nc4ccc(C(F)(F)F)cc4s3)C(C)C2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC1CN(CCOc2cc(CC(=O)O)ccc2Cl)CC(C)N1c1nc2ccc(C(F)(F)F)cc2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 47.9 %

Procedure:
A mixture of [4-chloro-3-[2-[3,5-dimethyl-4-(6-trifluoromethyl benzothiazole-2-yl)piperazine-1-yl]ethoxy]phenyl]acetic acid methyl ester (178 mg), 2N aqueous sodium hydroxide (0.66 mL), tetrahydrofuran (2 mL) and methanol (2 mL) was stirred at room temperature for 2 hours. The mixture was neutralized with 2N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and dried over sodium sulphate. The solvent was evaporated under reduced pressure and the residue was purified by column chromatograph on silica gel to give the title compound (83 mg). Yield: 48%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)=[CH:4][C:3]=1[NH:21][C:22](=[O:35])[CH2:23][CH2:24][CH2:25][CH2:26][C:27](=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]2)=[CH:4][C:3]=1[NH:21][C:22](=[O:35])[CH2:23][CH2:24][CH2:25][CH2:26][C:27](=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(F)c(NC(=O)CCCCC(=O)c3ccccc3)c2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(CCCCC(=O)c1ccccc1)Nc1cc(C2CCNCC2)ccc1F
Reaction time: 0.5 h
Yield: 91.9 %

Procedure:
Into a solution of tert-butyl 4-{4-fluoro-3-[(6-oxo-6-phenylhexanoyl)amino]phenyl}-1-piperidine carboxylate (49.0 mg, 0.101 mmol) in CH2Cl2 (3.0 mL) was added trifluoroacetic acid (114 mg, 1.01 mmol) at room temperature. The reaction mixture was stirred for 30 min and concentrated in vacuo. The residue was dissolved in CHCl3/i-PrOH (3:1, 10 mL) and was basified to pH 11 with 5% KOH solution. The organic layer was separated and the aqueous layer was extracted with CHCl3/i-PrOH (3:1, 3×10 mL). The combined organic extracts were washed with brine, dried over MgSO4, filtered and concentrated in vacuo to afford N-[2-fluoro-5-(4-piperidinyl)phenyl]-6-oxo-6-phenylhexanamide (35.5 mg, 86.0%). HCl salt: 1H NMR (400 MHz, CDCl3) δ 8.14-8.01 (br, 1H), 8.01-7.89 (m, 2H), 7.65-7.52 (m, 1H), 7.52-7.43 (m, 2H), 7.43-7.26 (br, 1H), 7.13-7.00 (m, 1H), 7.00-6.88 (br, 1H), 3.68-3.43 (m, 2H), 3.19-2.92 (br, 4H), 2.89-2.67 (m, 1H), 2.61-2.36 (br, 2H), 2.26-2.06 (m, 2H), 2.06-1.93 (m, 2H), 1.93-1.71 (br, 4H); ESMS m/e: 383.2 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10](I)=[CH:9][N:8]([C@H:12]3[CH2:15][C@H:14]([C:16]([NH2:18])=[O:17])[CH2:13]3)[C:4]=2[N:5]=[CH:6][N:7]=1.[C:19]1([C:25]2[CH:34]=[CH:33][C:32]3[C:27](=[CH:28][C:29](B4OC(C)(C)C(C)(C)O4)=[CH:30][CH:31]=3)[N:26]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C([O-])([O-])=O.[Na+].[Na+].CN(C=O)C>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[NH2:1][C:2]1[C:3]2[C:10]([C:29]3[CH:28]=[C:27]4[C:32]([CH:33]=[CH:34][C:25]([C:19]5[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=5)=[N:26]4)=[CH:31][CH:30]=3)=[CH:9][N:8]([C@H:12]3[CH2:15][C@H:14]([C:16]([NH2:18])=[O:17])[CH2:13]3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Nc1ncnc2c1c(I)cn2[C@H]1C[C@H](C(N)=O)C1
Reactant: CC1(C)OB(c2ccc3ccc(-c4ccccc4)nc3c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ncnc2c1c(-c1ccc3ccc(-c4ccccc4)nc3c1)cn2[C@H]1C[C@H](C(N)=O)C1
Temperature: 80 °C

Procedure:
A mixture of trans-3-(4-amino-5-iodopyrrolo[2,3-d]pyrimidin-7-yl)-cyclobutanecarboxylic acid amide (119 mg, 0.333 mmol), 2-phenyl-7-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-quinoline (133 mg, 0.402 mmol), Na2CO3 (88.3 mg, 0.833 mmol), Pd(PPh3)4 (23.1 mg, 0.0200 mmol), DMF (5 mL), and water (1 mL) was purged with nitrogen for 30 min and heated to 80° C. for 22 h. To the cooled reaction solution was added water (10 mL), the mixture was extracted with EtOAc (3×15 mL), the combined organic layers were washed with water (2×10 mL) and brine, dried over MgSO4, filtered, and concentrated. The residue was triturated with MeOH to give the title compound as light yellow solid. Chromatography of the mother liquor on silica gel (8 g, eluting with 2%→4%→6%→8%→10% MeOH in CH2Cl2) gave an additional batch. Both batches contained a small amount of the corresponding cis isomer (see below for its independent synthesis). 1H NMR (CDCl3, 400 MHz): δ=2.70-2.78 (m, 2 H), 2.97-3.08 (m, 2 H), 3.21-3.26 (m, 1 H), 5.66-5.72 (quintet, 1 H, J=8.4 Hz), 6.54 (brs, 2 H), 7.08 (s, 1 H), 7.59 (s, 1 H), 7.68-7.78 (m, 3 H), 7.94-7.98 (m, 1 H), 8.12 (s, 1 H), 8.26-8.28 (d, 1 H, J=8.4 Hz), 8.32-8.37 (m, 3 H), 8.48-8.53 (m, 2 H), 8.66-8.68 (d, 1 H, J=8.8 Hz). MS (ES+): 435.2 [MH+]. HPLC: tR=2.3 min (polar—5 min).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[CH3:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=1.C(O)(C(F)(F)F)=O>>[CH3:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]2[C:5]3[NH:6][C:7]4[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=4)[C:4]=3[CH2:3][CH2:2][NH:1]2)=[CH:17][CH:16]=1
Reactant: COc1ccc(C=O)cc1
Reactant: NCCc1c[nH]c2ccccc12
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(C2NCCc3c2[nH]c2ccccc32)cc1
Yield: 79.2 %

Procedure:
This product was prepared using the same procedure as for Intermediate 1 with tryptamine (15 g, 94.9 mmol), 4-methoxybenzaldehyde (12.9 g, 1.1 equiv.) and TFA (14.6 mL, 2 equiv.) to give the title compound (20.9 g, 80%) as a brownish powder.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([S:16][CH2:17][CH2:18][CH2:19][OH:20])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])[CH3:3].[CH:21]([Mg]Cl)([CH3:23])[CH3:22].Cl.O>O1CCCC1>[CH3:4][C:2]([C:5]1[CH:6]=[C:7]([S:16][CH2:17][CH2:18][CH:19]([OH:20])[CH:21]([CH3:23])[CH3:22])[CH:8]=[C:9]([C:12]([CH3:13])([CH3:14])[CH3:15])[C:10]=1[OH:11])([CH3:1])[CH3:3]
Reactant: CC(C)(C)c1cc(SCCCO)cc(C(C)(C)C)c1O
Reactant: CC(C)[Mg]Cl
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: CC(C)C(O)CCSc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
3-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]thio] propanol (2.0 g, prepared as described in U.S. Pat. No. 4,857,558) was dissolved in 20 ml of dry tetrahydrofuran under argon and added to 8.5 ml of 2M isopropylmagnesium chloride in tetrahydrofuran that had previously been added under argon gas to a flask that had been dried in vacuo overnight. Reaction temperature was maintained at 10°-15° C. with an ice bath. When addition was complete, the reaction mixture was allowed warm to room temperature and stirred for 3 hours. 2N hydrochloric acid (2 ml) was added followed by 50 ml of water and the mixture extracted with ethyl acetate three times. The organic extracts were combined, washed with water twice and dried over sodium sulfate. The solvent was removed in vacuo after filtration and the crude product chromatographed on silica to give the title compound.
Reaction SMILES: Cl[C:2]([O:4][CH:5]([CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)[CH2:6][CH2:7][CH3:8])=[O:3].[S:15]1[CH:19]=[C:18]([C:20]2[NH:21][C:22]3[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=3[N:24]=2)[N:17]=[CH:16]1>N1C=CC=CC=1>[CH:9]1([CH:5]([O:4][C:2]([N:24]2[C:23]3[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=3[N:21]=[C:20]2[C:18]2[N:17]=[CH:16][S:15][CH:19]=2)=[O:3])[CH2:6][CH2:7][CH3:8])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: CCCC(OC(=O)Cl)C1CCCCC1
Reactant: c1ccc2[nH]c(-c3cscn3)nc2c1
Solvent: c1ccncc1
Product: CCCC(OC(=O)n1c(-c2cscn2)nc2ccccc21)C1CCCCC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
28.3 G. (0.129 moles) of 1-cyclohexyl-1-butyl chloroformate is added over a period of 20 minutes at a temperature of 20° C to a stirred suspension of 25.1 g. (0.125 moles) of 2-(4-thiazolyl)-benzimidazole and 200 ml. of pyridine. A clear solution initially results which is followed by the precipitation of pyridine hydrochloride. The reaction mixture is then stirred for 16 hours at room temperature filtered and the filtrate evaporated to dryness in vacuo. The product is extracted from the residue with 250 ml. of methylene chloride which is filtered and the filtrate washed twice with 250 ml. of 0.25 N-hydrochloric acid and 200 ml. of saturated sodium bicarbonate solution. The methylene chloride is dried, treated with charcoal, filtered and evaporated to dryness in vacuo. The residual oil is chromatographed on a column of silica gel eluting with benzene affording 21.6 g. (45%) of a pale yellow viscous oil. Thin layer chromatography demonstrates that the oil is pure material which analyzes as 1-(1-cyclohexylbutoxycarbonyl)-2-(4-thiazolyl)-benzimidazole.
Reaction SMILES: [OH:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:14][CH2:15][CH2:16][CH3:17])[N:5]=[C:4]([C:18]([O:20]CC)=O)[CH:3]=1.[CH3:23][NH2:24]>C(O)C>[CH3:23][NH:24][C:18]([C:4]1[CH:3]=[C:2]([OH:1])[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:14][CH2:15][CH2:16][CH3:17])[N:5]=1)=[O:20]
Reactant: CN
Reactant: CCCOc1ccccc1-c1nc(O)cc(C(=O)OCC)n1
Solvent: CCO
Product: CCCOc1ccccc1-c1nc(O)cc(C(=O)NC)n1
Reaction time: 72 h

Procedure:
A solution of ethyl 6-hydroxy-2-(2-propoxyphenyl)pyrimidine-4-carboxylate (0.40 g) and methylamine in industrial methylated spirit (33%, 15 ml) in ethanol (15 ml) was stirred at ambient temperature for 6 hours and then allowed to stand for 3 days. The reaction mixture was evaporated under reduced pressure to yield a crude product which was recrystallized from ethanol to yield the title compound, 0.26 g, m.p. 165°-6° C.