Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:9]([CH:10]=O)=[CH:8][C:7]([CH3:12])=[CH:6][C:3]=1[CH:4]=[O:5].C(=O)([O-])[O-].[K+].[K+].Br[CH:20](C(OCC)=O)[C:21]([O:23][CH2:24][CH3:25])=[O:22]>CN(C=O)C>[CH2:24]([O:23][C:21]([C:20]1[O:1][C:2]2[C:3]([CH:4]=[O:5])=[CH:6][C:7]([CH3:12])=[CH:8][C:9]=2[CH:10]=1)=[O:22])[CH3:25]
Reactant: Cc1cc(C=O)c(O)c(C=O)c1
Reactant: CCOC(=O)C(Br)C(=O)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2cc(C)cc(C=O)c2o1
Temperature: 100 °C
Yield: 94.7 %

Procedure:
A solution of 2-hydroxy-5-methylisophtalaldehyde (1 g) in DMF (10 ml) was treated under an Argon atmorphere with potassium carbonate (1.01 g) and diethyl bromomalonate (1.60 g). The reaction mixture was heated to 100° C. for 20 hrs, then cooled to r.t., quenched with water and extracted with EtOAc. The organics were dried over MgSO4, filtrated and concentrated to obtain 7-formyl-5-methyl-benzofuran-2-carboxylic acid ethyl ester (1.34 g) as off-white solid. MS (ISP): 233.1 ((M+H)+.). The crude product was used in the next reaction step without further purification.
Reaction SMILES: S(Cl)([Cl:3])=O.O[CH2:6][CH2:7][CH2:8][NH:9][C:10]1[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([OH:19])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=1>C(Cl)(Cl)Cl>[Cl:3][CH2:6][CH2:7][CH2:8][NH:9][C:10]1[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([OH:19])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=1
Reactant: O=S(Cl)Cl
Reactant: OCCCNC1=Nc2ccccc2C1(O)c1ccccc1
Solvent: ClC(Cl)Cl
Product: OC1(c2ccccc2)C(NCCCCl)=Nc2ccccc21
Temperature: 25 °C

Procedure:
Thionylchloride (1.53 ml.) was added dropwise to a stirred cooled suspension of 2-(3-hydroxypropylamino)-3-phenyl-3H-indol-3-ol (3 g.) in chloroform (25 ml.). On completion of the addition the reaction was allowed to warm to room temperature and then heated under reflux for 45 minutes. The solvent and excess thionyl chloride were removed under reduced pressure and the resulting product crystallised from isopropanol-ether to give the title compound as its hydrochloride salt (2.72 g.). After two recrystallisations from isopropanol-ether the hydrochloride had a m.p. 210°-212°C. (Found C, 60.8; H. 5.6; N, 8.3. C17H17ClN20HCl requires C, 60.5; H, 5.4; N 8.3%).
Reaction SMILES: C(OP([CH2:9]/[C:10](/[CH3:17])=[CH:11]/[C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.CN1CCCN(C)C1=O.C([Li])CCC.[F:32]/[C:33](=[C:36](/[C:38]1[CH:39]=[C:40]2[C:45](=[CH:46][C:47]=1[O:48][CH3:49])[O:44][C:43]([CH3:51])([CH3:50])[CH:42]=[C:41]2[CH:52]([CH3:54])[CH3:53])\[CH3:37])/[CH:34]=O>C1COCC1>[F:32]/[C:33](=[C:36](/[C:38]1[CH:39]=[C:40]2[C:45](=[CH:46][C:47]=1[O:48][CH3:49])[O:44][C:43]([CH3:51])([CH3:50])[CH:42]=[C:41]2[CH:52]([CH3:54])[CH3:53])\[CH3:37])/[CH:34]=[CH:9]/[C:10](/[CH3:17])=[CH:11]/[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: COc1cc2c(cc1/C(C)=C(/F)C=O)C(C(C)C)=CC(C)(C)O2
Reactant: CCOC(=O)/C=C(\C)CP(=O)(OCC)OCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CN1CCCN(C)C1=O
Product: CCOC(=O)/C=C(C)/C=C/C(F)=C(/C)c1cc2c(cc1OC)OC(C)(C)C=C2C(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of ethyl 4-(diethoxyphosphoryl)-3-methyl-but-2E-enoate (240 mg, 0.91 mmol) in THF (10 mL), and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU, 0.13 mL) under argon at −78° C. was slowly added n-butyl lithium (1.6 M in hexanes, 0.60 mL, 0.96 mmol). The resulting mixture was stirred at −78° C. for 15 min before a solution of (2E)-2-fluoro-3-(4-isopropyl-7-methoxy-2,2-dimethyl-2H-chromen-6-yl)-but-2-enal (Compound 95, 100 mg, 0.31 mmol) and THF (3 mL) was added via cannula. The resulting mixture was stirred at 0° C. for 1 h. The reaction was quenched with saturated NH4Cl, and the product was extracted with diethyl ether. The combined ethereal layers were washed with water and brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, 5% ethyl acetate in hexane) to yield the title compound as a yellow oil.
Reaction SMILES: OCC([NH:6][C:7](=[O:16])[CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)CO.OC1C=CC(C=O)=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[C:10]1([CH2:9][CH2:8][C:7]([NH2:6])=[O:16])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(CCc1ccccc1)NC(CO)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=Cc1ccc(O)cc1
Solvent: Cc1ccccc1
Product: NC(=O)CCc1ccccc1
Yield: 124.4 %

Procedure:
A mixture of N-(2-hydroxy-1-hydroxymethyl-ethyl)-3-phenyl-propionamide (1.7 g, 7.6 mmol), toluene (70 ml), 4-hydroxybenzaldehyde (1.856 g, 15.2 mmol) and a catalytic amount of p-toluenesulfonic acid was refluxed for 3 h. The mixture was evaporated and CH2Cl2 was added to the residue. The precipitate was filtered off and recrystallised from hot AcOEt (50 ml). The light brown crystals formed collected yielding trans-N-12-(4-hydroxy-phenyl)-[1,3]dioxan-5-yl]-3-phenyl-propionamide (1.41 g, MS: m/e=328.2 (M+H+)). The filtrate was concentrated and left at 4° overnight. The newly formed crystals are collected yielding cis-N-[2-(4-hydroxy-phenyl)-[1,3]dioxan-5-yl]-3-phenyl-propionamide (0.401 g, m/e=326.4 (M−H+)).
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]([NH:12][CH:13]([C:20]1[CH:25]=[C:24]([C:26]([CH3:29])([CH3:28])[CH3:27])[CH:23]=[C:22]([C:30]([CH3:33])([CH3:32])[CH3:31])[CH:21]=1)[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:11])=O)(C)(C)C.[ClH:34]>O1CCOCC1>[ClH:34].[NH2:8][CH2:9][C:10]([NH:12][C@H:13]([C:20]1[CH:25]=[C:24]([C:26]([CH3:29])([CH3:28])[CH3:27])[CH:23]=[C:22]([C:30]([CH3:31])([CH3:33])[CH3:32])[CH:21]=1)[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:11]
Reactant: CCOC(=O)CC(NC(=O)CNC(=O)OC(C)(C)C)c1cc(C(C)(C)C)cc(C(C)(C)C)c1
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=O)C[C@H](NC(=O)CN)c1cc(C(C)(C)C)cc(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of S)-ethyl 3-(2-((tert-butoxycarbonyl)amino)acetamido)-3-(3,5-di-tert-butylphenyl)propanoate (163.4 mg, 0.35 mmol) in 1,4-dioxane (2 mL) was added 4.0 M HCl solution in 1,4-dioxane and the reaction mixture was stirred at room temperature for 1 h. Evaporation of the solvent in vacuo and the crystallization of the residue from ethyl acetate/hexanes mixture afforded a colorless foamy solid (153.0 mg). LC-MS analysis of the solid shows the desired product's mass: m/z 363 (M+H) and m/z 725 (2M+H); Calcd for C21H34N2O3: 362.51.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[S:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[C:14](=O)[C:15](OCC)=[O:16]>CO>[S:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[C:14]1[C:15](=[O:16])[NH:7][C:2]2[C:1]([N:8]=1)=[CH:6][CH:5]=[CH:4][CH:3]=2
Reactant: Nc1ccccc1N
Reactant: CCOC(=O)C(=O)c1cccs1
Solvent: CO
Product: O=c1[nH]c2ccccc2nc1-c1cccs1
Temperature: 25 °C
Reaction time: 12 h
Yield: 70.1 %

Procedure:
A mixture of o-phenylenediamine (2.16 g, 20 mmol) and ethyl thiophene-2-glyoxylate (3.68 g, 20 mmol.) in anhydrous methanol (60 mL) was stirred at room temperature for 12 hours under nitrogen atmosphere. The precipitate formed during this time was collected and washed with methanol to give a crude yellow solid, which was recrystallized from ethanol to give pure 3(2-thienyl)quinoxalin-2(1 H)-one (3.2 g, 70%). 1 H NMR (400 MHz, DMSO-d6) δ 12.7 (s, 1 H), 8.39 (d, J=4.4 Hz, 1 H), 7.83 (d, J=5.2 Hz, 1 H), 7.77 (d, J=8.0 Hz, 1H), 7.50 (t, J=7.6 Hz, 1H), 7.35˜7.29 (m, 1 H), 7.22 (t, J=4.8 Hz, 1 H).
Reaction SMILES: [CH:1]1([C:6](Cl)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:9]1(=[O:18])[O:17][C:14]([CH3:16])([CH3:15])[O:13][C:11](=[O:12])[CH2:10]1.N1C=CC=CC=1>C(Cl)Cl>[CH:1]1([C:6]([CH:10]2[C:9](=[O:18])[O:17][C:14]([CH3:16])([CH3:15])[O:13][C:11]2=[O:12])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(Cl)C1CCCC1
Reactant: CC1(C)OC(=O)CC(=O)O1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC1(C)OC(=O)C(C(=O)C2CCCC2)C(=O)O1
Temperature: 20 °C
Reaction time: 1 h
Yield: 96.6 %

Procedure:
A solution of cyclopentanecarbonyl chloride (1.100 mL, 9.05 mmol) in DCM (5 mL) was added dropwise to a stirred solution of isopropylidene malonate (1.304 g, 9.05 mmol), and pyridine (1.464 mL, 18.10 mmol) in DCM (20 mL) at 5° C., over a period of 10 minutes under nitrogen. The resulting solution was stiffed at 5° C. for 1 hour and then allowed to warm to 20° C. and stirred for another hour. The reaction mixture was diluted with DCM (100 mL), and washed sequentially with 2M HCl (2×50 mL), water (50 mL), and saturated brine (50 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product, 5-(cyclopentanecarbonyl)-2,2-dimethyl-1,3-dioxane-4,6-dione (2.100 g, 97%) as a brown oil.
Reaction SMILES: [CH:1]12[CH2:7][C:4]([NH:8][C:9]3[CH:10]=[C:11]4[C:15](=[CH:16][CH:17]=3)[NH:14][N:13]=[CH:12]4)([CH2:5][CH2:6]1)[CH2:3][NH:2]2.[CH3:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][CH:20]=1>>[CH3:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][N:2]2[CH2:3][C:4]3([NH:8][C:9]4[CH:10]=[C:11]5[C:15](=[CH:16][CH:17]=4)[NH:14][N:13]=[CH:12]5)[CH2:7][CH:1]2[CH2:6][CH2:5]3)=[CH:21][CH:20]=1
Reactant: Cc1ccc(C=O)cc1
Reactant: c1cc2[nH]ncc2cc1NC12CCC(C1)NC2
Product: Cc1ccc(CN2CC3(Nc4ccc5[nH]ncc5c4)CCC2C3)cc1

Procedure:
Reaction of Intermediate 25 with 4-methylbenzaldehyde affords the title compound.
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][CH:5]1[C:11]2[CH:12]=[C:13]([I:16])[CH:14]=[CH:15][C:10]=2[CH:9]=[CH:8][C:7]2[CH:17]=[CH:18][CH:19]=[CH:20][C:6]1=2.[C:21]([NH2:25])([CH3:24])([CH3:23])[CH3:22].[C:26]([OH:31])(=[O:30])[C:27]([OH:29])=[O:28]>CO>[C:26]([OH:31])(=[O:30])[C:27]([OH:29])=[O:28].[C:21]([NH:25][CH2:2][CH2:3][CH2:4][CH:5]1[C:11]2[CH:12]=[C:13]([I:16])[CH:14]=[CH:15][C:10]=2[CH:9]=[CH:8][C:7]2[CH:17]=[CH:18][CH:19]=[CH:20][C:6]1=2)([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)N
Reactant: ICCCC1c2ccccc2C=Cc2ccc(I)cc21
Agent: O=C(O)C(=O)O
Solvent: CO
Product: CC(C)(C)NCCCC1c2ccccc2C=Cc2ccc(I)cc21

Procedure:
5-(3-Iodopropyl)-3-iodo-5H-dibenzo[a,d]cycloheptene (2.1 g., 0.0043 mole) is dissolved in 1.82 g. (0.025 mole) of t-butylamine and the solution stirred 18 hours at room temperature. The suspension is evaporated in vacuo, treated with 0.5 N NaOH, and extracted three times with methylene chloride. The methylene chloride fractions are combined, washed three times with water, dried over sodium sulfate, and evaporated in vacuo. The residue is chromatographed on 45 g. of silica gel GF (eluted with chloroform and 2%, 5%, and 8% methanol in chloroform). The product fraction is evaporated in vacuo. The resulting oil is dissolved in methanol, treated with one equivalent (one half mole) of oxalic acid in methanol, and evaporated in vacuo. The residue, triturated with ether, provides 1.25 g. of pale yellow powder. This solid, recrystallized from methanol/acetonitrile, melts at 217.5°-218.5°.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:12][C@@H:13]([CH2:16][CH3:17])[CH2:14]O>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Cl:1][C:2]1[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH2:12][C@@H:13]([CH3:14])[CH2:16][CH3:17])=[O:5]
Reactant: CC[C@H](C)CO
Reactant: O=C(O)c1ccc(O)cc1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC[C@H](C)COC(=O)c1ccc(O)cc1Cl
Temperature: 25 °C
Yield: 98.1 %

Procedure:
2-Chloro-4-hydroxybenzoic acid (17.2 g: 100 mmols), 10.5 g (120 mmols) of (S)-2-methylbutanol and 0.17 g (1 mmol) of p-toluenesulfonic acid were refluxed in 100 ml of toluene on heating. Azeotropic water was removed with a Dean Stark trap. After water was no longer distilled off, the residue was left to cool up to room temperature. The resulting product was washed with a sodium bicarbonate aqueous solution until the aqueous phase became alkaline. The product was further washed with water and then with saturated sodium chloride aqueous solution, and dried with anhydrous sodium sulfate. Excess toluene and (S)-2-methylbutanol were mostly distilled off under reduced pressure and the residue was recrystallized from n-hexane to obtain 23.8 g of (S)-2-methylbutyl 2-chloro-4-hydroxybenzoate as a white crystal.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]([NH2:12])=[O:11])[CH:5]=[C:6]([Cl:9])[C:7]=1Cl.[K].[C:14]1([SH:24])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1>CN(C)C=O.O>[Cl:9][C:6]1[CH:5]=[C:4]([C:10]([NH2:12])=[O:11])[CH:3]=[C:2]([Cl:1])[C:7]=1[S:24][C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: NC(=O)c1cc(Cl)c(Cl)c(Cl)c1
Reactant: Sc1cccc2ccccc12
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: NC(=O)c1cc(Cl)c(Sc2cccc3ccccc23)c(Cl)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 3,4,5-trichlorobenzene carboxamide (25 g) in 220 ml of dry dimethylformamide (DMF), 26 g of 1-naphthalenethiol potassium salt is added and the reaction mixture stirred at room temperature for two days. The reaction mixture is then diluted with water and extracted with methylene chloride. The combined extracts are washed with water, dried with anhydrous magnesium sulfate and concentrated. The product can be purified by chromatography on silica gel.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH:10]([N:13]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)[CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH3:19][O:18][C:16](=[O:17])[CH2:15][CH2:14][N:13]([CH2:20][C:21]1[CH:22]=[CH:23][C:24]([Cl:27])=[CH:25][CH:26]=1)[CH:10]1[CH2:11][CH2:12][NH:8][CH2:9]1
Reactant: COC(=O)CCN(Cc1ccc(Cl)cc1)C1CCN(C(=O)OC(C)(C)C)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)CCN(Cc1ccc(Cl)cc1)C1CCNC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 3-[(4-chloro-benzyl)-(2-methoxycarbonyl-ethyl)-amino]-pyrrolidine-1-carboxylic acid tert-butyl ester (0.08 g, 0.2 mmol) in dichloromethane cooled at 0° C. was treated with trifluoroacetic acid (20%). The resulting mixture was warmed to room temperature and stirred for 2 h. The reaction mixture was concentrated in vacuo, diluted with ethyl acetate and free based with 10% aqueous sodium bicarbonate. The combined organics were dried over sodium sulfate. The product was used without any further purification. ESI-MS m/z: 297 (M+1), UV retention time: 1.05 min.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:9])[CH:4]([CH:6]1[CH2:8][CH2:7]1)[OH:5].[Si:10](Cl)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11].N1C=CN=C1>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:9])[CH:4]([O:5][Si:10]([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11])[CH:6]1[CH2:8][CH2:7]1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COC(=O)C(O)C1CC1
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: COC(=O)C(O[Si](C)(C)C(C)(C)C)C1CC1
Temperature: 25 °C
Reaction time: 65 h

Procedure:
To a solution of cyclopropyl-hydroxy-acetic acid methyl ester (1.00 g, 7.68 mmol) in DCM (9 mL) was added tert-butyldimethylsilyl chloride (1.27 g, 8.45 mmol) and imidazole (628 mg, 9.22 mmol). The reaction mixture was stirred at RT for 65 hours before being quenched with water (10 mL) and 1M HCl (5 mL). The mixture was extracted with ethyl acetate (3×15 mL) and the combined organic phases were washed with 1M HCl (10 mL), brine (10 mL), dried (Na2SO4) then concentrated in vacuo. This gave (tert-Butyl-dimethyl-silanyloxy)-cyclopropyl-acetic acid methyl ester as an amber oil (1.66 g, 88%). 1H NMR (400 MHz, CDCl3): δ 3.81 (1H, d, J=6.33 Hz), 3.74 (3H, s), 1.23-1.13 (1H, m), 0.89 (9H, s), 0.52-0.0.38 (4H, m), 0.06 (3H, s), 0.04 (3H, s).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[C:4]([CH:10]=[CH2:11])[CH:3]=1.[CH2:12]([O:15][C:16]1([CH3:45])[CH2:21][CH2:20][N:19]([C:22]2[N:27]3[N:28]=[C:29]([CH2:31]I)[CH:30]=[C:26]3[N:25]=[C:24]([CH3:33])[C:23]=2[C@H:34]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])[C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH2:18][CH2:17]1)[CH:13]=[CH2:14].[H-].[Na+]>CN(C=O)C>[CH2:12]([O:15][C:16]1([CH3:45])[CH2:17][CH2:18][N:19]([C:22]2[N:27]3[N:28]=[C:29]([CH2:31][O:9][CH2:8][C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=4[CH:10]=[CH2:11])[CH:30]=[C:26]3[N:25]=[C:24]([CH3:33])[C:23]=2[C@H:34]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])[C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH2:20][CH2:21]1)[CH:13]=[CH2:14]
Reactant: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OCC)c(C)nc3cc(CI)nn23)CC1
Reactant: C=Cc1cc(F)ccc1CO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OCC)c(C)nc3cc(COCc4ccc(F)cc4C=C)nn23)CC1
Yield: 44.7 %

Procedure:
To a mixture of (4-fluoro-2-vinylphenyl)methanol (39.1 mg, 0.257 mmol) in DMF (3 mL) at 0° C. was added (S)-ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(iodomethyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (150 mg, 0.257 mmol) and NaH (10.26 mg, 0.257 mmol). It was then quenched with sat. NH4Cl, extracted with EtOAc. The organic layer was dried over MgSO4, filtered and concentrated to obtain an oil, which was then purified by biotage, eluting with 25% EtOAc/hexane to isolate (S)-ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(((4-fluoro-2-vinylbenzyl)oxy)methyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (70 mg, 0.115 mmol, 44.8% yield) as an oil. LCMS (M+1)=609.3.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]2[O:8][CH2:9][O:10][C:5]2=[CH:4][C:3]=1[C:11]1[CH:20]=[C:19]2[C:14]([CH:15]=[CH:16][C:17]([O:21][CH3:22])=[CH:18]2)=[CH:13][CH:12]=1.Cl.[N:24]([O-])=O.[Na+].O>C(O)(=O)C>[CH3:22][O:21][C:17]1[CH:16]=[CH:15][C:14]2=[CH:13][CH:12]=[C:11]3[C:20]([N:24]=[N:1][C:2]4[CH:7]=[C:6]5[O:8][CH2:9][O:10][C:5]5=[CH:4][C:3]3=4)=[C:19]2[CH:18]=1
Reactant: O=N[O-]
Reactant: COc1ccc2ccc(-c3cc4c(cc3N)OCO4)cc2c1
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc2ccc3c4cc5c(cc4nnc3c2c1)OCO5
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.2 %

Procedure:
7-(2-Amino-4,5-methylenedioxyphenyl)-2-methoxynaphthalene 49 (70 mg, 0.24 mmol) was dissolved in acetic acid (2.0 mL) and concentrated hydrochloric acid (0.4 mL). The solution was cooled in an ice bath and diazotized by the dropwise addition of a solution of sodium nitrite (0.16 g in 1.6 mL water). The resulting diazonium solution was allowed to warm slowly to room temperature and left overnight. To the resulting red solution containing some precipitate was added 50 mL water and the reaction mixture was extracted with ethyl acetate (30 mL×3). The organic layers were combined and washed with diluted sodium hydroxide solution first, then with water and brine. The organic layer was dried over anhydrous sodium sulfate and evaporated in vacuo. The crude product was purified by column chromatography on silica gel using 55:45 hexanes:ethyl acetate to give compound 44 (60 mg 83%); mp 259-261° C.; IR (KBr) 2923, 1612, 1498, 1468, 1234, 1199 cm−1; UV (MeOH) 270, 250, 228 nm (log ε=4.68, 4.37, 4.44); 1H NMR (CDCl3) δ4.12 (3H, s), 6.24 (2H, s), 7.37 (1H, dd, J1=8.8, J2=2.7), 7.80 (1H, s), 7.88 (1H, d, J=8.8), 7.96 (1H, s), 8.03 (1H, d, J=9.1), 8.09 (1H, d, J=9.0), 9.15 (1H, d, J=2.7); 13C NMR δ56.32, 98.31, 102.93, 104.03, 107.49, 116.36, 120.40, 120.50, 121.09, 127.96, 130.00, 132.54, 133.34, 141.99, 146.10, 150.53, 152.09, 160.28; HRMS (EI) calcd for C18H12N2O3 m/z: 304.0848; found: 304.0852.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH:11]([OH:42])[C:12]2[N:13]([C:23]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:14]=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:16]=2)[C:6]([F:10])=[C:7]([OH:9])[CH:8]=1)[CH3:2].C([O-])([O-])=O.[K+].[K+].I[CH2:50][CH3:51]>CN(C=O)C.CCOC(C)=O>[CH2:50]([O:9][C:7]1[C:6]([F:10])=[C:5]([CH:11]([C:12]2[N:13]([C:23]([C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:14]=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:16]=2)[OH:42])[CH:4]=[C:3]([CH2:1][CH3:2])[CH:8]=1)[CH3:51]
Reactant: CCc1cc(O)c(F)c(C(O)c2nc(-c3ccccc3)cn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOc1cc(CC)cc(C(O)c2nc(-c3ccccc3)cn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c1F
Temperature: 25 °C
Reaction time: 19 h
Yield: 100.1 %

Procedure:
To a solution of Intermediate 448.2 (1.00 g, 1.80 mmol) in 10 mL DMF at rt, were added K2CO3 (229 mg, 2.16 mmol) and iodoethane (432 μL, 5.4 mmol). The mixture was stirred at rt for 19 h, then diluted with EtOAc. The organic phase was washed with H2O (2×), sat. Na2SO3 and brine, dried (Na2SO4), filtered through 1″ SiO2 and concentrated to afford 1.05 g of Intermediate 448.3 as a colorless solid. LCMS (2 min gradient) RT=1.92 min, 583.3 (M+H)+.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C@H:12]([NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:13]([NH:15][C@@H:16]([CH:20]([CH3:22])[CH3:21])[C:17](O)=[O:18])=[O:14])=[CH:7][CH:6]=1)[CH:2]=[CH2:3].Cl.[CH3:32][O:33][C:34](=[O:39])[C@@H:35]([NH2:38])[CH:36]=[CH2:37].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[CH3:32][O:33][C:34](=[O:39])[C@@H:35]([NH:38][C:17](=[O:18])[C@@H:16]([NH:15][C:13](=[O:14])[C@@H:12]([NH:23][CH:24]([O:26][C:27]([CH3:29])([CH3:30])[CH3:28])[OH:25])[CH2:11][C:8]1[CH:9]=[CH:10][C:5]([O:4][CH2:1][CH:2]=[CH2:3])=[CH:6][CH:7]=1)[CH:20]([CH3:22])[CH3:21])[CH:36]=[CH2:37]
Reactant: C=CCOc1ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@H](C(=O)O)C(C)C)cc1
Reactant: C=C[C@H](N)C(=O)OC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C=CCOc1ccc(C[C@H](NC(O)OC(C)(C)C)C(=O)N[C@H](C(=O)N[C@@H](C=C)C(=O)OC)C(C)C)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Acid 43 (1.03 g, 2.45 mmol), amine 63 (1.1 equiv) and HATU (1.1 equiv) were dissolved in anhydrous DMF (0.10-0.50M relative to acid). DIPEA was added (4 equiv) and the reaction mixture stirred at rt for 18 h. This was partitioned between EtOAc and 1M hydrochloric acid. The organic phase was washed sequentially with 1M hydrochloric acid and brine before being dried (MgSO4), filtered and concentrated in vacuo. The crude material was purified by flash chromatography on silica using a gradient of EtOAc and (50/70) petroleum ether to yield a white solid, 0.964 g, 76%. Rf=0.46 (1/1 EtOAc/(50/70) petroleum ether). m.p. 104-106° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([Cl:12])=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[CH2:13]([N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)[CH2:14][CH3:15].CC(C)([O-])C.[Na+]>O1CCOCC1.CCOCC.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:12][C:5]1[CH:4]=[CH:3][C:2]([N:19]2[CH2:20][CH2:21][N:16]([CH2:13][CH2:14][CH3:15])[CH2:17][CH2:18]2)=[CH:7][C:6]=1[C:8]([F:11])([F:10])[F:9]
Reactant: CCCN1CCNCC1
Reactant: FC(F)(F)c1cc(Br)ccc1Cl
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOCC
Solvent: C1COCCO1
Product: CCCN1CCN(c2ccc(Cl)c(C(F)(F)F)c2)CC1
Temperature: 25 °C

Procedure:
A mixture of 5-bromo-2-chlorobenzotrifluoride (0.2 g, 0.85 mmol), n-propyl piperazine (0.15 g, 1.17 mmol), sodium tert-butoxide (0.134 g) dppf (14 mg) and [Pd2(dba)3 (10 mg) in dioxane (5 ml) was heated under argon at 100° C. for 24 h. After cooling to room temperature, the reaction mixture was taken up in Et2O (40-50 ml) and washed with brine (15-20 ml). The organic fraction was dried (MgSO4), filtered and evaporated to dryness. The crude material was purified by flash chromatography on silica gel using CH2Cl2:MeOH (9:1 (v/v)). The amine was converted into the HCl-salt and recrystallized from ethanol/diethylether; m.p. 268° C. (HCl); MS m/z (rel. intensity, 70 eV)) 307 (M+, 6), 279 (33), 277 (98), 70 (bp), 56 (40). Rf=0.35 (EtOAc)