Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:21]=[C:22]([F:24])[CH:23]=1)[CH2:5][N:6]1[C:10]([C:11]([N:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]2)=O)=[CH:9][N:8]=[C:7]1[SH:20].B.CSC.CO>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:21]=[C:22]([F:24])[CH:23]=1)[CH2:5][N:6]1[C:10]([CH2:11][N:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]2)=[CH:9][N:8]=[C:7]1[SH:20]
Reactant: CN1CCN(C(=O)c2cnc(S)n2Cc2cc(F)cc(F)c2)CC1
Agent: B
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: CSC
Product: CN1CCN(Cc2cnc(S)n2Cc2cc(F)cc(F)c2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 1-(3,5-difluorobenzyl)-5-[(4-methyl-1-piperazinyl)carbonyl]-2-mercaptoimidazole (1.37 g, 3.89 mmole) in chloroform (15 ml) was added dropwise 1 molar borane-methyl sulfide (23.3 ml, 23.3 mmole) and the solution was stirred for 4 hours at 25° C. The reaction mixture was cooled in ice and methyl alcohol was added dropwise until gas evolution ceased. The solvent was removed by evaporation at reduced pressure, ten portions of methyl alcohol were added, the reaction mixture was heated at reflux for 5 minutes and the solvent was removed at reduced pressure. The crude product was dissolved in methylene chloride-methanol (9:1) and purified by flash slica chromatography. The product was purified by trituration with ethyl acetate and recrystallization from ethanol to give 1-(3,5-difluorobenzyl)-5-[(4-methyl-1-piperazinyl)methyl]-2-mercaptoimidazole as a solid, m.p.: 200°-201° C. (0.820 g, 62%).
Reaction SMILES: C(=O)([O-])[O-:2].[Ca+2].Br[CH2:7][C:8]1[CH:9]=[C:10]([CH2:14][C:15]([O:17]CC)=[O:16])[CH:11]=[CH:12][CH:13]=1.[OH-].[Na+].Cl>CCO.O.CCOC(C)=O.O1CCOCC1>[OH:2][CH2:7][C:8]1[CH:9]=[C:10]([CH2:14][C:15]([OH:17])=[O:16])[CH:11]=[CH:12][CH:13]=1
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)Cc1cccc(CBr)c1
Agent: Cl
Agent: [Ca+2]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)Cc1cccc(CO)c1
Temperature: 80 °C
Reaction time: 6 h
Yield: 64.5 %

Procedure:
Calcium carbonate (11 g) was added to a mixture of ethyl [3-(bromomethyl)phenyl]acetate (4.56 g), dioxane (70 ml) and water (70 ml), followed by stirring at 80° C. for 6 hours. EtOAc and water were added to the reaction mixture, and the organic layer was dried over Na2SO4 and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/EtOAc). The purified product thus obtained was mixed with EtOH (50 ml), and a 1 M aqueous NaOH solution (35 ml) was added thereto, followed by stirring at room temperature for 1 hour. 1 M hydrochloric acid (35 ml) was added to the reaction mixture, followed by concentration under reduced pressure. MeOH and Na2SO4 were added to the obtained residue, and the insoluble matter was removed by filtration. The filtrate was concentrated under reduced pressure to obtain [3-(hydroxymethyl)phenyl]acetic acid (1.9 g).
Reaction SMILES: Cl.[C:2]1([C:8]2[CH:12]=[C:11]([C:13]([O:15][CH3:16])=[O:14])[NH:10][N:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:18][CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:23]([O:22][C:21]([NH:20][CH2:19][CH2:18][N:10]1[C:11]([C:13]([O:15][CH3:16])=[O:14])=[CH:12][C:8]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[N:9]1)=[O:27])([CH3:26])([CH3:25])[CH3:24]
Reactant: COC(=O)c1cc(-c2ccccc2)n[nH]1
Reactant: CC(C)(C)OC(=O)NCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1cc(-c2ccccc2)nn1CCNC(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 86.2 %

Procedure:
The compound prepared in Example 120 (0.500 g), tert-butyl 2-bromoethylcarbamate (0.704 g) and potassium carbonate (1.16 g) were suspended in acetonitrile (20 mL) and heated at reflux overnight. Another 0.5 equivalents of tert-butyl 2-bromoethylcarbamate was added and the reaction mixture heated at reflux overnight again. The reaction mixture was cooled to room temperature and partitioned between saturated aqueous sodium bicarbonate and ethyl acetate. The organics were washed with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure to afford the crude material, which was purified by flash column chromatography to furnish the title compound (0.624 g) having the following physical data.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][CH:10]([C:16]([O:18]CC)=[O:17])[C:11]([O:13]CC)=[O:12].[OH-].[K+].Cl>C(O)C.O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][CH:10]([C:16]([OH:18])=[O:17])[C:11]([OH:13])=[O:12]
Reactant: CCOC(=O)C(CCc1ccccc1F)C(=O)OCC
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)C(CCc1ccccc1F)C(=O)O
Yield: 101.3 %

Procedure:
A mixture of diethyl 2-(2-(2-fluorophenyl)ethyl)malonate (381.8 g, 1.35 mol) and potassium hydroxide (227.3 g, 4.1 mol) and potassium hydroxide (227.3 g, 4.1 mol) in ethanol (500 mL) and water (500 mL) was refluxed for 24 h. The reaction mixture was placed in an ice bath and hydrochloric acid (6N, 442 mL) was added. The ethanol was removed in vacuo and the aqueous residue was extracted with diethyl ether. The extracts were dried (MgSO4) and concentrated in vacuo to give 309.3 g (100%) of 2-(2-(2-fluorophenyl)ethyl)malonic acid as an off-white solid. This product was used without further purification. NMR (DMSO-d6): d 6.8-6.2 (m, 4H, ArH), 2.4 (t, 1H, CH), 1.9 (q, 2H, CH2), 1.3 (t, 2H, CH2), IR (KBr) 1691 CM-1.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][CH2:2]1.NC1C=CC=CC=1S.C=O.[C:20]([C:22]1[CH:23]=[C:24]([CH:28]=[C:29]([CH:33]2[CH2:36][CH2:35][CH2:34]2)[C:30]=1[O:31][CH3:32])[C:25](Cl)=[O:26])#[N:21]>ClCCl.C(N(CC)CC)C>[C:20]([C:22]1[CH:23]=[C:24]([CH:28]=[C:29]([CH:33]2[CH2:34][CH2:35][CH2:36]2)[C:30]=1[O:31][CH3:32])[C:25]([N:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[S:1][CH2:2]1)=[O:26])#[N:21]
Reactant: c1ccc2c(c1)NCS2
Reactant: COc1c(C#N)cc(C(=O)Cl)cc1C1CCC1
Agent: C=O
Agent: Nc1ccccc1S
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1c(C#N)cc(C(=O)N2CSc3ccccc32)cc1C1CCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2,3-dihydro-1,3-benzothiazole synthesized from 2-aminobenzenethiol (153 mg) and 37% formalin (0.10 mL) in the same manner as in Example 1 was dissolved in dichloromethane (3 mL), and triethylamine (0.34 mL) and 3-cyano-5-cyclobutyl-4-methoxybenzoyl chloride (204 mg) were added to the solution, and then the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure and water was added, and then the mixture was extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid, 1N sodium hydroxide and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was used for the synthesis of (j).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[N+](N[C:22]1[NH:27][C:26](=[O:28])[C:25]([CH2:29][C:30]2[CH:31]=[N:32][C:33]([CH3:36])=[CH:34][CH:35]=2)=[CH:24][N:23]=1)([O-])=O>N1C=CC=CC=1>[C:6]1([N:5]([CH2:4][CH2:3][CH2:2][NH:1][C:22]2[NH:27][C:26](=[O:28])[C:25]([CH2:29][C:30]3[CH:31]=[N:32][C:33]([CH3:36])=[CH:34][CH:35]=3)=[CH:24][N:23]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: NCCCN(c1ccccc1)c1ccccn1
Reactant: Cc1ccc(Cc2cnc(N[N+](=O)[O-])[nH]c2=O)cn1
Solvent: c1ccncc1
Product: Cc1ccc(Cc2cnc(NCCCN(c3ccccc3)c3ccccn3)[nH]c2=O)cn1

Procedure:
To a suspension of sodium hydride (0.78 g) in DMSO (20 ml) was added 2-(N-phenylamino)pyridine (5.0 g) in DMSO (15 ml). The mixture was stirred and slowly heated under nitrogen to 85° C. After the evolution of hydrogen had ceased the mixture was cooled to room temperature and N-(3-bromopropyl)phthalimide (7.88 g) in DMSO (15 ml) added dropwise. After standing overnight the mixture was poured into water and ether extracts made with the pH adjusted between 2 to 4. The extracts were dried (MgSO4), stripped and the residue crystallised from ethanol to give N-[3-(N-phenyl-N-pyrid-2-ylamino)propyl]phthalimide, 3.69 g (35%) mp 103°-5° C. (ii) N-[3-(N-phenyl-N-pyrid-2-ylamino)propyl]phthalimide (3.1 g) and conc. hydrochloric acid (30 ml) were heated under reflux for 21 hr. Phthalic acid was filtered off on cooling and the filtrate stripped. The residue was taken back up in water and the solution extracted at pH 1 with chloroform. The pH was raised to 13 (NaOH) and the solution extracted again with ether. The ether extracts were dried (K2CO3) and stripped to give 2-[N-(3-aminopropyl)-N-phenylamino]pyridine, 1.84 g as an oil. (iii) 2-[N-(3-aminopropyl)-N-phenylamino]pyridine (0.9 g) and 2-nitroamino-5-(6-methylpyrid-3-ylmethyl)pyrimid-4-one (0.86 g) were heated together under reflux in pyridine (2.5 ml) for 24 hr. The mixture was stripped and the residue recrystallised from ethanol to give 2-[3-(N-phenyl-N-pyrid-2-ylamino) propylamino]-5-(6-methylpyrid-3-ylmethyl) pyrimid-4-one, 1.03 g (73%) mp 216°-18° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([OH:8])[C:5]([N+:9]([O-])=O)=[CH:4][N:3]=1>C(OC(=O)CC)(=O)CC>[NH2:9][C:5]1[C:6]([OH:8])=[N:7][C:2]([NH:1][C:6](=[O:8])[CH2:5][CH3:4])=[N:3][CH:4]=1
Reactant: Nc1ncc([N+](=O)[O-])c(O)n1
Agent: CCC(=O)OC(=O)CC
Product: CCC(=O)Nc1ncc(N)c(O)n1

Procedure:
7.8 gm (0.055 mol) of 2-amino-4-hydroxy-5-nitropyrimidine are heated for 4 hours to 140° C. in 50 ml of propionic acid anhydride. The mixture is cooled and the precipitated product is extracted and washed with ether. The compound is suspended in 200 ml of dimethyl formamide and hydrogenated at room temperature and normal pressure with 1 gm of Pd/C as catalyst.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([C:13]3[C:14]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[N:15][O:16][C:17]=3[CH3:18])=[N:11][N:12]=2)=[CH:4][N:3]=1.[NH:25]1[CH2:30][CH2:29][S:28][CH2:27][CH2:26]1>>[CH3:18][C:17]1[O:16][N:15]=[C:14]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]=1[C:10]1[O:9][C:8]([C:5]2[CH:6]=[CH:7][C:2]([N:25]3[CH2:30][CH2:29][S:28][CH2:27][CH2:26]3)=[N:3][CH:4]=2)=[N:12][N:11]=1
Reactant: C1CSCCN1
Reactant: Cc1onc(-c2ccccc2)c1-c1nnc(-c2ccc(Cl)nc2)o1
Product: Cc1onc(-c2ccccc2)c1-c1nnc(-c2ccc(N3CCSCC3)nc2)o1
Yield: 59 %

Procedure:
As described for example 136b, 2-chloro-5-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-pyridine (400 mg, 1.18 mmol) was converted using thiomorpholine instead of morpholine to the title compound (126 mg, 59%) which was obtained as an off-white solid. MS: m/e=406.3 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:28]=[C:29]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:30]=1)[C:12]1[O:13][C:14]2[C:19]([C:20](=[O:22])[CH:21]=1)=[CH:18][CH:17]=[C:16]([O:23][CH2:24][CH:25]1[O:27][CH2:26]1)[CH:15]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:39]1([N:45]2[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]2)[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>CO>[CH2:32]([O:31][C:29]1[CH:28]=[C:11]([CH:10]=[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:30]=1)[C:12]1[O:13][C:14]2[C:19]([C:20](=[O:22])[CH:21]=1)=[CH:18][CH:17]=[C:16]([O:23][CH2:24][CH:25]([OH:27])[CH2:26][N:48]1[CH2:49][CH2:50][N:45]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[CH2:46][CH2:47]1)[CH:15]=2)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: O=c1cc(-c2cc(OCc3ccccc3)cc(OCc3ccccc3)c2)oc2cc(OCC3CO3)ccc12
Reactant: c1ccc(N2CCNCC2)cc1
Solvent: CO
Product: O=c1cc(-c2cc(OCc3ccccc3)cc(OCc3ccccc3)c2)oc2cc(OCC(O)CN3CCN(c4ccccc4)CC3)ccc12

Procedure:
3′,5′-Dibenzyloxy-7-(2,3-epoxy-propoxy)-flavone, 28 (2.5 g, 4.9 mmol) and 1-phenyl piperazine (0.76 mL, 5 mmol) in dry methanol (180 mL) were reacted in a similar manner to that described under 34 to afford 36. Yield 3.1 g (94%); mp 168-170° C.; MS (FAB) 669 (M++1); IR (KBr) 3389, 1634; 1H NMR (200 MHz, CDCl3) δ 8.12 (d, J=8.6 Hz, 1H), 7.46-7.30 (m, 10H), 7.26-7.23 (m, 2H), 7.11 (d, J=1.9 Hz, 2H), 7.00 (d, J=8.5 Hz, 1H), 6.98 (s, 1H), 6.95-6.86 (m, 3H), 6.76 (s, 1H), 6.69 (s, 1H), 5.09 (s, 4H), 4.21-4.14 (m, 3H), 3.23 (t, J=4.7 Hz, 4.6 Hz, 4H), 2.91-2.81 (m, 2H), 2.66 (dd, J=5.2 Hz, 4.1 Hz, 4H). Analysis Calcd for C42H40N2O6: C, 75.43; H, 6.03; N, 4.19. Found: C, 75.37; H, 6.20; N, 4.13.
Reaction SMILES: [N:1]1[C:6]2[NH:7][C:8]3[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=3[C:10](=[O:12])[NH:11][C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:17](Cl)([Cl:19])=[O:18].O>O1CCOCC1.C1(C)C=CC=CC=1>[Cl:19][C:17]([N:7]1[C:8]2[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=2[C:10](=[O:12])[NH:11][C:5]2[CH:4]=[CH:3][CH:2]=[N:1][C:6]1=2)=[O:18]
Reactant: O=C(Cl)Cl
Reactant: O=C1Nc2cccnc2Nc2ccccc21
Solvent: O
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: O=C1Nc2cccnc2N(C(=O)Cl)c2ccccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of 158.3 g (0.75 mol) of 5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one in 3 liters of dioxane, 730 ml (1.46 mol) of a 20% solution of phosgene in toluene was added dropwise within 45 minutes and the resulting mixture was then stirred for 2 hours at ambient temperature. 1.5 l of water were added, the mixture was stirred for a further 2 hours at ambient temperature and the precipitate formed was suction filtered. The product was washed thoroughly with water and dried in a circulating air dryer. Colourless crystals, m.p. 239°-240° C.
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:11][C:12]1[CH:21]=[CH:20][C:15]([C:16](=[O:19])[CH2:17]Br)=[CH:14][CH:13]=1>[Zn].O1CCCC1.O>[Br:11][C:12]1[CH:21]=[CH:20][C:15]([C:16](=[O:19])[CH2:17][S:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:9])=[O:8])=[CH:14][CH:13]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: O=C(CBr)c1ccc(Br)cc1
Agent: [Zn]
Solvent: C1CCOC1
Solvent: O
Product: O=C(CS(=O)(=O)c1ccccc1)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To benzenesulfonyl chloride (0.5 mL, 3.92 mmol) in 4:1 v/v tetrahydrofuran-water (20 mL) was added powdered zinc (282 mg, 4.31 mmol, 1.1 eq.) followed by 4-bromophenacyl bromide (1.31 g, 4.70 mmol, 1.2 eq.). The reaction mixture was stirred at room temperature for 17 hours. The volatile solvent was evaporated under reduced pressure and poured into water. The reaction was extracted with ethyl acetate (2×150 mL), and the combined organic layers were washed with brine (1×100 mL), dried (MgSO4), filtered, and evaporated under reduce pressure. The crude product was purified using MPLC (Biotage) eluted with 5:1 v/v hexane-ethyl acetate. Crystallization from dichloromethane-hexane gave the desired product as a white fluffy solid (486 mg, 36.6% yield). MS LC-MS (ES MH+=340); TLC (Rf=0.30, 25% ethyl acetate-hexane)
Reaction SMILES: C(N(CC)C(C)C)(C)C.[F:10][C:11]([F:24])([F:23])[S:12]([O:15]S(C(F)(F)F)(=O)=O)(=[O:14])=[O:13].[CH2:25]([C:27]([C:45]1[CH:50]=[CH:49][C:48](O)=[CH:47][CH:46]=1)([C:30]1[CH:35]=[CH:34][C:33](/[CH:36]=[CH:37]/[C:38]([CH2:42][CH3:43])([OH:41])[CH2:39][CH3:40])=[C:32]([CH3:44])[CH:31]=1)[CH2:28][CH3:29])[CH3:26].C(=O)(O)[O-].[Na+]>ClCCl>[CH2:25]([C:27]([C:45]1[CH:46]=[CH:47][C:48]([O:15][S:12]([C:11]([F:24])([F:23])[F:10])(=[O:14])=[O:13])=[CH:49][CH:50]=1)([C:30]1[CH:35]=[CH:34][C:33](/[CH:36]=[CH:37]/[C:38]([CH2:39][CH3:40])([OH:41])[CH2:42][CH3:43])=[C:32]([CH3:44])[CH:31]=1)[CH2:28][CH3:29])[CH3:26]
Reactant: CCC(O)(/C=C/c1ccc(C(CC)(CC)c2ccc(O)cc2)cc1C)CC
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCC(O)(/C=C/c1ccc(C(CC)(CC)c2ccc(OS(=O)(=O)C(F)(F)F)cc2)cc1C)CC
Reaction time: 0.17 h
Yield: 93.1 %

Procedure:
N,N-Diisopropylethylamine (0.83 mL, 2 mmol) and trifluoromethanesulfonic anhydride (0.26 mL, 1.6 mmol) were added to a solution of 4-{1-ethyl-1-[4-((E)-3-ethyl-3-hydroxy-1-pentenyl)-3-methyl-phenyl]-propyl}-phenol (Example 39-(3); 0.52 g, 1.4 mmol) in dichloromethane (7 mL) at −78° C., and the mixture was stirred at the same temperature for 10 minutes. A saturated aqueous sodium bicarbonate solution was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate=3/1) to give the title compound (0.65 g, 92%).
Reaction SMILES: [CH:1](/[C:5]1([CH3:45])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[N:17]=[C:18]([C:20]4[CH:21]=[C:22]([C:26]5[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:27]=5[OH:33])[CH:23]=[CH:24][CH:25]=4)[CH:19]=[C:15]3[N:14]=[C:13]([CH3:34])[C:12]=2[C@H:35]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])[C:36]([O:38][CH3:39])=[O:37])[CH2:7][CH2:6]1)=[CH:2]\[CH:3]=[CH2:4].C([O-])([O-])=O.[K+].[K+].Br[CH2:53][CH:54]=[CH2:55]>CN(C=O)C>[CH2:55]([O:33][C:27]1[CH:28]=[CH:29][C:30]([Cl:32])=[CH:31][C:26]=1[C:22]1[CH:23]=[CH:24][CH:25]=[C:20]([C:18]2[CH:19]=[C:15]3[N:14]=[C:13]([CH3:34])[C:12]([C@H:35]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])[C:36]([O:38][CH3:39])=[O:37])=[C:11]([N:8]4[CH2:7][CH2:6][C:5](/[CH:1]=[CH:2]/[CH:3]=[CH2:4])([CH3:45])[CH2:10][CH2:9]4)[N:16]3[N:17]=2)[CH:21]=1)[CH:54]=[CH2:53]
Reactant: C=C/C=C/C1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OC)c(C)nc3cc(-c4cccc(-c5cc(Cl)ccc5O)c4)nn23)CC1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=C/C=C/C1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OC)c(C)nc3cc(-c4cccc(-c5cc(Cl)ccc5OCC=C)c4)nn23)CC1
Temperature: 90 °C
Reaction time: 18 h
Yield: 93.7 %

Procedure:
.(S,E)-Methyl 2-(7-(4-(buta-1,3-dien-1-yl)-4-methylpiperidin-1-yl)-2-(5′-chloro-2′-hydroxy-[1,1′-biphenyl]-3-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (90 mg, 0.143 mmol) was dissolved in DMF (3 mL). Solid K2CO3 (39.5 mg, 0.286 mmol) was added and the mixture was heated to 90° C. for 1 h. The reaction was then cooled to rt and treated with 3-bromoprop-1-ene (0.024 mL, 0.286 mmol) and allowed to stir at rt for 18 h. The reaction was partitioned between EtOAc and water. The organic phase was washed with water, dried (Na2SO4), filtered, and concentrated in vacuo to yield (S,E)-methyl 2-(2-(2′-(allyloxy)-5′-chloro-[1,1′-biphenyl]-3-yl)-7-(4-(buta-1,3-dien-1-yl)-4-methylpiperidin-1-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (90 mg, 0.134 mmol, 94% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.18 (br. s., 1H), 8.07-8.00 (m, 1H), 7.60-7.48 (m, 2H), 7.42 (d, J=2.7 Hz, 1H), 7.31 (d, J=2.7 Hz, 1H), 6.95 (d, J=8.8 Hz, 1H), 6.85 (s, 1H), 6.39 (dt, J=17.0, 10.1 Hz, 1H), 6.16 (dd, J=15.5, 10.1 Hz, 1H), 6.08 (s, 1H), 5.98 (ddt, J=17.3, 10.6, 4.8 Hz, 1H), 5.88 (d, J=15.7 Hz, 1H), 5.40-5.33 (m, 1H), 5.25-5.15 (m, 2H), 5.03 (d, J=10.0 Hz, 1H), 5.00-2.50 (m, 4 H), 4.56 (dt, J=4.8, 1.6 Hz, 2H), 3.74 (s, 3H), 2.64 (s, 3H), 1.97-1.63 (m, 4H), 1.32-1.23 (m, 12H). LCMS (M+1)=669.3.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][N:6]=[C:5]([NH2:11])[N:4]=1.CCN(C(C)C)C(C)C.[Cl:21][CH2:22][C:23](Cl)=[O:24]>C(Cl)Cl>[Cl:21][CH2:22][C:23]([NH:11][C:5]1[N:4]=[C:3]([O:2][CH3:1])[C:8]([O:9][CH3:10])=[CH:7][N:6]=1)=[O:24]
Reactant: O=C(Cl)CCl
Reactant: COc1cnc(N)nc1OC
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cnc(NC(=O)CCl)nc1OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4,5-dimethoxypyrimidin-2-amine (350 mg, 2.26 mmol) in DCM (3.5 mL), DIPEA (1.2 mL, 7.0 mmol) was added, followed by chloracetylchloride (0.30 mL, 3.72 mmol). The resulting dark brown reaction mixture was stirred at rt for 1 h, then quenched with water and diluted with DCM. The org. layer was separated and the aq. layer extracted with DCM (1×). The combined org. layers were washed with brine, dried (MgSO4), filtered and the solvent removed under reduced pressure to obtain 2-chloro-N-(4,5-dimethoxypyrimidin-2-yl)acetamide as a brown oil which was used in the next step without further purification. LC-MS conditions B: tR=0.38 min, [M+H]+=232.07.
Reaction SMILES: I[C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[CH:3]=1.CC1(C)C(C)(C)OB([C:21]2[CH:22]=[CH:23][C:24]3[CH2:31][C@H:30]4[C@:32]5([CH2:36][N:35]([CH2:37][C:38]([F:41])([F:40])[F:39])[S:34](=[O:43])(=[O:42])[NH:33]5)[C@H:27]([CH2:28][CH2:29]4)[CH2:26][C:25]=3[CH:44]=2)O1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.O.C(=O)(O)[O-].[Na+]>[N:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[C:4]1[CH:3]=[C:2]([C:21]2[CH:22]=[CH:23][C:24]3[CH2:31][C@H:30]4[C@:32]5([CH2:36][N:35]([CH2:37][C:38]([F:41])([F:40])[F:39])[S:34](=[O:42])(=[O:43])[NH:33]5)[C@H:27]([CH2:28][CH2:29]4)[CH2:26][C:25]=3[CH:44]=2)[O:6][N:5]=1
Reactant: CC1(C)OB(c2ccc3c(c2)C[C@H]2CC[C@@H](C3)[C@]23CN(CC(F)(F)F)S(=O)(=O)N3)OC1(C)C
Reactant: Ic1cc(-c2ccccn2)no1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: O=S1(=O)N[C@@]2(CN1CC(F)(F)F)[C@@H]1CC[C@H]2Cc2ccc(-c3cc(-c4ccccn4)no3)cc2C1
Temperature: 100 °C
Yield: 69 %

Procedure:
A mixture of 2-(5-iodoisoxazol-3-yl)pyridine (prepared in the manner of Ku et al Org. Lett. 3 (26), 4185–4187, 2001.) (90 mg, 0.3 mmol), the homochiral boronate from Step 1 (100 mg, 0.2 mmol) potassium carbonate (135 mg, 1 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloro palladium (II) dichloromethane complex (5 mg) in toluene (2 mL), ethanol (1 mL) and water (1 mL) was heated under microwave conditions at 100° C. for 5 minutes. More [1,1′-bis(diphenylphosphino)ferrocene]dichloro palladium (II) dichloromethane complex (5 mg) was added and the mixture was again heated under microwave conditions at 100° C. for 5 minutes. The reaction was diluted with sodium bicarbonate (half sat, 20 mL) and extracted with ethylacetate (2×30 mL). The extracts were washed with brine, dried (MgSO4) and evaporated in vacuo to give a brown gum, which was purified by column chromatography, eluting with ethylacetate:iso-hexane (1:4) to give the title compound as a white solid (70 mg, 69%). δ (1H, 400 MHz, CDCl3) 1.32–1.40 (2H, m), 1.74–1.78 (2H, m), 2.48–2.52 (2H, m), 2.74–2.83 (2H, m), 3.26–3.31 (2H, m), 3.46 (2H, s), 3.70 (2H, q, J=8.7 Hz), 4.83 (1H, brs), 7.17 (1H, s), 7.23 (1H, d, J=8.3 Hz), 7.36–7.40 (1H, m), 7.60–7.62 (2H, m), 7.81–7.85 (1H, m), 8.12–8.14 (1H, m), and 8.71–8.72 (1H, m). MS (ES+) 505 ([MH]+).
Reaction SMILES: [Cl:1][C:2]1[C:19]([OH:20])=[CH:18][C:5]2[C@H:6]([C:12]3[CH2:16]C[CH2:14][C:13]=3[CH3:17])[CH2:7][N:8]([CH3:11])[CH2:9][CH2:10][C:4]=2[CH:3]=1.Cl>>[Cl:1][C:2]1[C:19]([OH:20])=[CH:18][C:5]2[C@H:6]([C:12]([CH3:16])=[C:13]([CH3:17])[CH3:14])[CH2:7][N:8]([CH3:11])[CH2:9][CH2:10][C:4]=2[CH:3]=1
Reactant: CC1=C([C@@H]2CN(C)CCc3cc(Cl)c(O)cc32)CCC1
Agent: Cl
Product: CC(C)=C(C)[C@@H]1CN(C)CCc2cc(Cl)c(O)cc21

Procedure:
(S)-7-chloro-8-hydroxy-3-methyl-(2-methyl-1-cyclopentenyl)-2,3,4,5-tetrahydro-1H-3-benzazepine, m.p. of hydrochloride 248-249° C. (dec.).