Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9](=[O:11])[CH3:10])[CH:5]=[CH:6][C:7]=1[OH:8].[C:12]([O-])([O-])=O.[K+].[K+].[OH-].[Na+].O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:9](=[O:11])[CH3:10])[CH:5]=[CH:6][C:7]=1[O:8][CH3:12]
Reactant: CC(=O)c1ccc(O)c(Cl)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(C(C)=O)cc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 1-(3-chloro-4-hydroxylphenyl)ethanone (1.7 g, 10 mmol) in DMF was added K2CO3 (1.52 g, 11 mmol), 2 N NaOH solution (5 ml), and Mel (0.68 ml). The reaction mixture was stirred at room temperature for 2 hours. Another 1.24 ml of Mel was added, and the reaction mixture was stirred for an additional 30 minutes. Water (50 ml) was added, and the product was extracted with 200 ml of EtOAc and 100 ml of benzene. The organic layer was washed with brine (50 ml), and dried with MgSO4, and the solvent was removed in vacuo to give the title compound in quantitative yield.
Reaction SMILES: [N+:1]([CH3:4])([O-:3])=[O:2].[Cl:5][C:6]1[CH:7]=[C:8](/[C:13](/[C:30]([F:33])([F:32])[F:31])=[CH:14]\[C:15]([C:17]2[CH:18]=[CH:19][C:20]([N:25]3[CH:29]=[N:28][CH:27]=[N:26]3)=[C:21]([CH:24]=2)[C:22]#[N:23])=[O:16])[CH:9]=[C:10]([Cl:12])[CH:11]=1.C(=O)([O-])[O-].[K+].[K+].O>C1(C)C=CC=CC=1>[Cl:5][C:6]1[CH:7]=[C:8]([C@:13]([CH2:4][N+:1]([O-:3])=[O:2])([C:30]([F:31])([F:33])[F:32])[CH2:14][C:15]([C:17]2[CH:18]=[CH:19][C:20]([N:25]3[CH:29]=[N:28][CH:27]=[N:26]3)=[C:21]([CH:24]=2)[C:22]#[N:23])=[O:16])[CH:9]=[C:10]([Cl:12])[CH:11]=1
Reactant: N#Cc1cc(C(=O)/C=C(\c2cc(Cl)cc(Cl)c2)C(F)(F)F)ccc1-n1cncn1
Reactant: C[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: N#Cc1cc(C(=O)C[C@](C[N+](=O)[O-])(c2cc(Cl)cc(Cl)c2)C(F)(F)F)ccc1-n1cncn1
Temperature: 50 °C
Reaction time: 18 h

Procedure:
A solution of anthracenylmethyl quininium chloride (19 mg), nitromethane (0.025 ml) and 5-[(E)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-but-2-enoyl]-2-(1,2,4-triazol-1-yl)benzonitrile (100 mg) in toluene (2 mL) under argon, was heated for 2 hours at 50° C. then potassium carbonate (64 mg) was added. The reaction was heated for 24 hours at 50° C. then more nitromethane (0.02 mL) was added. The reaction was heated again at 50° C. for 3 hours then was allowed to stand at room temperature for 18 hours. Water was then added and the resulting mixture was extracted with dichloromethane and the combined organic fractions were dried over sodium sulfate. The crude product was purified by flash chromatography (0% to 50% ethyl acetate in cyclohexane) to afford 5-[(3R)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-(nitromethyl)butanoyl]-2-(1,2,4-triazol-1-yl)benzonitrile (69 mg). Chiral HPLC analysis (CHIRALPAK AS-RH, acetonitrile:Methanol:water=40:5:55, 1 ml/min, retention time 11.88 minutes (minor enantiomer), 13.88 minutes (major enantiomer) indicated that the reaction proceeded with 50% enantioselectivity in favor of the R enantiomer.
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH:4]([O:6][C:7]2[C:12]([C:13]3[CH2:14][CH2:15][O:16][CH2:17][CH:18]=3)=[CH:11][CH:10]=[CH:9][N:8]=2)[CH2:3]1.[N:19]1[CH:24]=[CH:23][C:22]([C:25](O)=[O:26])=[N:21][CH:20]=1.C(N(CC)CC)C>C(Cl)Cl.CN(C)C1C=CN=CC=1>[O:16]1[CH2:15][CH:14]=[C:13]([C:12]2[C:7]([O:6][CH:4]3[CH2:3][N:2]([C:25]([C:22]4[CH:23]=[CH:24][N:19]=[CH:20][N:21]=4)=[O:26])[CH2:5]3)=[N:8][CH:9]=[CH:10][CH:11]=2)[CH2:18][CH2:17]1
Reactant: C1=C(c2cccnc2OC2CNC2)CCOC1
Reactant: O=C(O)c1ccncn1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1ccncn1)N1CC(Oc2ncccc2C2=CCOCC2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.6 %

Procedure:
To a solution of 2-(azetidin-3-yloxy)-3-(3,6-dihydro-2H-pyran-4-yl)pyridine hydrochloride (see PREPARATION P26.1; 100 mg, 0.45 mmol), pyrimidine-4-carboxylic acid (55 mg, 0.45 mmol) and triethylamine (96.13 mg, 0.95 mmol) in CH2Cl2 (10 mL) was added 4-Dimethylaminopyridine (DMAP) (55 mg, 0.47 mmol) and propyl phosphonic anhydride (500 mg, 0.9 mmol). The reaction mixture was stirred at room temperature for overnight. Then the reaction mixture was concentrated and the crude product was purified by silica gel column chromatography to give the desired compound (48 mg, 0.16 mmol, yield 66%). [M+1]: 339. IC50 (uM): 0.99.
Reaction SMILES: Cl[C:2]1C=C(Cl)C=C[C:3]=1C1N=C(CC)C(N[C@@H]2C3C(=CC=CC=3)C[C@@H]2OCC)=NC=1CC.[CH2:32]([C:34]1[C:35]([NH:51][C@@H:52]2[CH2:56][O:55][CH2:54][C@H:53]2[OH:57])=[N:36][C:37]([CH2:49][CH3:50])=[C:38]([C:40]2[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][C:41]=2[CH3:48])[N:39]=1)[CH3:33]>>[CH2:2]([O:57][C@@H:53]1[CH2:54][O:55][CH2:56][C@H:52]1[NH:51][C:35]1[C:34]([CH2:32][CH3:33])=[N:39][C:38]([C:40]2[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][C:41]=2[CH3:48])=[C:37]([CH2:49][CH3:50])[N:36]=1)[CH3:3]
Reactant: CCc1nc(-c2ccc(OC)cc2C)c(CC)nc1N[C@@H]1COC[C@H]1O
Reactant: CCO[C@H]1Cc2ccccc2[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC
Product: CCO[C@@H]1COC[C@H]1Nc1nc(CC)c(-c2ccc(OC)cc2C)nc1CC

Procedure:
Following the procedure for the preparation of 5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3,6-diethylpyrazin-2-amine but substituting trans-(+/−)-4-{[3,6-diethyl-5-(4-methoxy-2-methylphenyl)pyrazin-2-yl]amino}tetrahydrofuran-3-ol and making non-critical variations provided the title compound as a light yellow solid. IR (diffuse reflectance) 3354, 2973, 2958, 2938, 1484, 1462, 1446, 1396, 1300, 1239, 1172, 1072, 1050, 1043, 885 cm−1; OAMS supporting ions at: ESI+ 386.1; MS (EI) m/z 385 (M+); HRMS (FAB) calcd for C22H31N3O3+H1 386.2443, found 386.2438. Anal. Calcd for C22H31N3O3: C, 68.54; H, 8.11; N, 10.90. Found: C, 68.38; H, 7.99; N, 10.85.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][N:9]=1)[C:5]#[N:6].[CH3:10][NH2:11].C([O-])(O)=O.[Na+]>N1C=CC=CC=1.C1COCC1>[CH3:10][NH:11][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][N:9]=1)[C:5]#[N:6]
Reactant: N#Cc1ccnc(Cl)c1
Reactant: CN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CNc1cc(C#N)ccn1
Temperature: 120 °C

Procedure:
To a solution of 2-chloroisonicotinonitrile (22.0 g, 159 mmole) in pyridine (500 mL) was added methylamine in THF (2N, 160 mL), and NaHCO3 (54 g). The mixture was heated to 120° C. in a sealed vessel for 40 h. After cooled to RT, the mixture was filtered and the filter cake was washed with CH2Cl2. The combined filtrated was concentrated in vacuo to give a yellow solid (21 g) as the desired compound.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:21])[C:12]3[S:18][C:17]([CH2:19][OH:20])=[CH:16][C:13]=3[NH:14][CH:15]=2)=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:31][C:32]([N:34]([O:36][CH3:37])[CH3:35])=[O:33]>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:21])[C:12]3[S:18][C:17]([CH2:19][OH:20])=[CH:16][C:13]=3[N:14]([CH2:31][C:32]([N:34]([O:36][CH3:37])[CH3:35])=[O:33])[CH:15]=2)=[O:9])=[CH:22][CH:23]=1
Reactant: CON(C)C(=O)CCl
Reactant: O=C(NCc1ccc(Cl)cc1)c1c[nH]c2cc(CO)sc2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CON(C)C(=O)Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2sc(CO)cc21
Reaction time: 48 h
Yield: 69.5 %

Procedure:
A mixture of N-(4-chlorobenzyl)-2-(hydroxymethyl)-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide (100 mg, 0.288 mmol), potassium carbonate (60 mg, 0.43 mmol) and 2-chloro-N-methoxy-N-methylacetamide (200 mg) in DMF (1.5 mL) was shaken at room temp. for 48 hrs. The mixture was diluted with water (5 mL), and the resulting solid was collected by filtration. The crude solid was recrystallized from aq. ethanol to afford title compound (90 mg). The title compound is also a compound of formula I.
Reaction SMILES: [CH2:1]1[CH2:6][C@H:5]([C:7]([OH:9])=[O:8])[CH2:4][CH2:3][C@H:2]1[CH2:10][NH2:11].S(=O)(=O)(O)O.O.[C:18](OC(=O)C)(=[O:20])[CH3:19]>>[C:18]([NH:11][CH2:10][C@H:2]1[CH2:3][CH2:4][C@H:5]([C:7]([OH:9])=[O:8])[CH2:6][CH2:1]1)(=[O:20])[CH3:19]
Reactant: CC(=O)OC(C)=O
Reactant: NC[C@H]1CC[C@H](C(=O)O)CC1
Agent: O=S(=O)(O)O
Solvent: O
Product: CC(=O)NC[C@H]1CC[C@H](C(=O)O)CC1
Reaction time: 8 h

Procedure:
Tranexamic acid (10 g, 63.6 mmol) was suspended in acetic anhydride (50 mL), this suspension was added with concentrated sulfuric acid (0.01 mL) at room temperature, and the mixture was stirred overnight at the same temperature. Under ice cooling, the reaction mixture was added with water (100 mL), and the mixture was stirred at room temperature for 1 hour to decompose excess acetic anhydride. The reaction solution was concentrated under reduced pressure, and the residue was further azeotroped with toluene. The resulting precipitates were collected by filtration, washed with ether, and dried under reduced pressure to obtain trans-{4-[(acetylamino) methyl]cyclohexyl}carboxylic acid as white solid (12.46 g, 98%).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][CH:6]=1)=O.[NH2:12][C:13]1(C)[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][NH:14]1.C([O-])([O-])=O.[K+].[K+].CCOCC>CCO>[CH3:19][C:16]1[CH:17]=[CH:18][C:13]2[N:14]([CH:2]=[C:3]([C:5]3[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][CH:6]=3)[N:12]=2)[CH:15]=1
Reactant: CC1=CNC(C)(N)C=C1
Reactant: Cc1ccc(C(=O)CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CCOCC
Product: Cc1ccc(-c2cn3cc(C)ccc3n2)cc1
Temperature: 93 °C
Reaction time: 0.5 h
Yield: 66.1 %

Procedure:
A mixture of 2-bromo-4′-methylacetophenone (90% pure, 10.21 g, 43.11 mmol), 2-amino-5-methyl picoline (4.66 g, 43.11 mmol) and K2CO3 (6.6 g, 47.75 mmol) in absolute EtOH (70 ml) was heated at 93° C. overnight. After cooled to 40° C., ether (100 mL) was added. The mixture was stirred for 30 minutes and cooled by ice-water bath. After removal of solvent through filtration, the solid was stirred with water (50 ml) for 30 minutes and filtered, rinsed with water and dried under vacuum at 80° C. for 2 hr to give 6.33 g of white solid (66.1% yield). m/e+ 223.4 for C15H15N2 (M+H)+; 1H-NMR (400 MHz, CDCl3, δ) 7.84 (m, 3H), 7.71 (d, J=9.531 Hz, 1), 7.51 (d, J=9.165 Hz, 1H), 7.24 (m, 2H), 7.00 (m, 1), 2.38 (s, 3H), 2.29 (d, J=6.23 Hz, 3H) ppm. 13C-NMR (100 MHz, CDCl3 δ) 145.065, 144.444, 137.991, 130.696, 130.635, 129.642, 129.483, 128.391, 128.262, 126.018, 123.652, 122.476, 116.486, 107.857, 21.520, 18.259 ppm.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10][C:11]2[C:19]3[C:14](=[CH:15][C:16]([Cl:20])=[CH:17][CH:18]=3)[NH:13][C:12]=2[CH3:21])[CH:5]=1.Br[C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=1>>[CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10][C:11]2[C:19]3[C:14](=[CH:15][C:16]([Cl:20])=[CH:17][CH:18]=3)[N:13]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=3)[C:12]=2[CH3:21])[CH:5]=1
Reactant: Clc1cccc(Br)c1
Reactant: COC(=O)c1cccc(Sc2c(C)[nH]c3cc(Cl)ccc23)c1
Product: COC(=O)c1cccc(Sc2c(C)n(-c3cccc(Cl)c3)c3cc(Cl)ccc23)c1

Procedure:
Prepared according to the procedure described in Example 27, Step 1, using the following starting materials: 3-(6-chloro-2-methyl-1H-indol-3-ylsulfanyl)-benzoic acid methyl ester and 1-bromo-3-chlorobenzene.
Reaction SMILES: [OH:1][CH2:2][C:3]([NH:6][C:7]([C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([N:18]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[C:20]([O:27][CH3:28])=[N:19]3)[N:16]=2)[N:11](COCC[Si](C)(C)C)[CH:10]=1)=[O:8])([CH3:5])[CH3:4].FC(F)(F)C(O)=O>ClCCl>[OH:1][CH2:2][C:3]([NH:6][C:7]([C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([N:18]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[C:20]([O:27][CH3:28])=[N:19]3)[N:16]=2)[NH:11][CH:10]=1)=[O:8])([CH3:5])[CH3:4]
Reactant: COc1nn(-c2cnc3c(n2)c(C(=O)NC(C)(C)CO)cn3COCC[Si](C)(C)C)c2ccccc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1nn(-c2cnc3[nH]cc(C(=O)NC(C)(C)CO)c3n2)c2ccccc12
Reaction time: 1 h
Yield: 0.1 %

Procedure:
To a stirred solution of N-(1-hydroxy-2-methylpropan-2-yl)-2-(3-methoxy-1H-indazol-1-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (101 mg, 198 mmol) in dichloromethane (3 mL) was added trifluoroacetic acid (1 mL). After 15 h the mixture was concentrated in vacuo then 25 mL of a Jan. 10, 1960 mixture of ammonium hydroxide/methanol/dichloromethane solution was added. After 1 h, the mixture was concentrated in vacuo. Purification by chromatography (silica, 24 g Analogix column, 0-5% methanol containing 10% ammonium hydroxide in dichloromethane) gave 2-(3-methoxy-indazol-1-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (2-hydroxy-1,1-dimethyl-ethyl)amide (45 mg, 60%). MS (M+H)+=381; 1H NMR (DMSO-d6) δ: 8.94 (s, 1H), 8.62 (d, J=8.7 Hz, 1H), 8.33 (s, 1H), 7.79 (d, J=7.9 Hz, 1H), 7.61 (s, 2H), 7.28-7.38 (m, 1H), 4.19 (s, 3H), 3.62 (d, J=5.7 Hz, 2H), 1.45 (s, 6H).
Reaction SMILES: Cl.[CH2:2]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][C:12]=1[CH2:13][CH3:14])[CH2:9][CH:8]([NH:15][CH2:16][CH:17]([C:19]1[C:28]([CH3:29])=[CH:27][C:26]([O:30]COC)=[C:25]3[C:20]=1[CH:21]=[CH:22][C:23](=[O:34])[NH:24]3)[OH:18])[CH2:7]2)[CH3:3]>C(O)(C)C.O1CCCC1>[CH2:13]([C:12]1[CH:11]=[C:10]2[C:6](=[CH:5][C:4]=1[CH2:2][CH3:3])[CH2:7][CH:8]([NH:15][CH2:16][CH:17]([C:19]1[C:28]([CH3:29])=[CH:27][C:26]([OH:30])=[C:25]3[C:20]=1[CH:21]=[CH:22][C:23](=[O:34])[NH:24]3)[OH:18])[CH2:9]2)[CH3:14]
Reactant: CCc1cc2c(cc1CC)CC(NCC(O)c1c(C)cc(OCOC)c3[nH]c(=O)ccc13)C2
Agent: Cl
Solvent: C1CCOC1
Solvent: CC(C)O
Product: CCc1cc2c(cc1CC)CC(NCC(O)c1c(C)cc(O)c3[nH]c(=O)ccc13)C2
Temperature: 40 °C

Procedure:
3N Hydrochloric acid (1 mL) is added to a solution of 5-[2-(5,6-Diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-methoxymethoxy-6-methyl-1H-quinolin-2-one (12 mg) in isopropanol (1 mL) and tetrahydrofuran (1 mL) at room temperature and the reaction mixture heated for 18 hours at 40° C. The solvent is removed in vacuo, and-the product purified by preparative scale HPLC on a C8 column, eluting with a water/acetonitrile/trifluoroacetic acid gradient.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH:13]([C:15]([O:17][CH3:18])=[O:16])[CH2:12][CH2:11][NH:10]2)=[CH:5][CH:4]=1.CCN(C(C)C)C(C)C.[C:30](Cl)(=[O:33])[O:31][CH3:32]>C(Cl)Cl>[F:20][C:2]([F:19])([F:1])[C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[CH2:14][CH:13]([C:15]([O:17][CH3:18])=[O:16])[CH2:12][CH2:11][N:10]2[C:30]([O:31][CH3:32])=[O:33])=[CH:7][CH:8]=1
Reactant: COC(=O)C1CCNC(c2ccc(C(F)(F)F)cc2)C1
Reactant: COC(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1CCN(C(=O)OC)C(c2ccc(C(F)(F)F)cc2)C1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 101.2 %

Procedure:
Methyl 2-(4-(trifluoromethyl)phenyl)piperidine-4-carboxylate (4.973 g, 17.31 mmol) was dissolved in DCM (100 mL) and DIPEA (3.62 mL, 20.77 mmol) added followed by methyl carbonochloridate (1.636 mL, 20.77 mmol). The solution was stirred at room temperature for 1 h 45 min. The reaction mixture was washed with 0.1 M HCl and satd NaHCO3. The organic phase was passed through a phase separator and evaporated to yield crude dimethyl 2-(4-(trifluoromethyl)phenyl)piperidine-1,4-dicarboxylate (6.05 g, 101%) as a brown oil. MS m/z 346 (M+H)+
Reaction SMILES: [Mg].[CH3:2][OH:3].C[O-].[Mg+2].C[O-].[CH2:9]([C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]>C1(C)C=CC=CC=1>[CH2:9]([C:18]1[CH:19]=[C:20]([CH:2]=[O:3])[C:21]([OH:24])=[CH:22][CH:23]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCCCCCc1ccc(O)cc1
Reactant: CO
Agent: C[O-]
Agent: [Mg+2]
Agent: [Mg]
Solvent: Cc1ccccc1
Product: CCCCCCCCCc1ccc(O)c(C=O)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 62 %

Procedure:
A 2-liter round-bottomed flask was charged with magnesium (24 g, 0.98 mol), methanol (570 ml), toluene (240 ml) and magnesium methoxide (10 ml solution of 7.4% by weight magnesium methoxide in methanol). The reaction mixture was heated to reflux and the magnesium dissolved. Para-nonyl phenol (224 g) was added in one portion to the reaction mixture. The flask was then rigged for a fractional vacuum distillation and an azeotrope of methanol/toluene was distilled off to an internal temperature of 70° C. at a pressure of 350 mm Hg. The mixture was cooled to 25° C. and toluene (300 ml) was added. Anhydrous hydrochloric acid (38 g) was added to the reaction mixture over a period of 1.5 hours. Methanol (200 ml) was then added to the mixture and the pot was rigged for an atmospheric pressure fractional distillation. An azeotrope of methanol/toluene was distilled off to a pot temperature of 100° C. The pot was then cooled to 90° C. and paraformaldehyde (94.8 g, a commercial sample containing 5-7% by weight water) slurried in toluene (200 ml) was added over a 1 hour period. During the addition of paraformaldehyde, volatile reaction by-products were continually removed. The reaction mixture was maintained at a temperature of 90° C. for an additional hour after the paraformaldehyde addition was complete. The reaction temperature was then cooled to 70° C. and sulfuric acid (300 ml, 10% w/w) was added to the reaction mixture, which was then stirred for 30 minutes. After phase separation, the organic phase was washed twice with 200 ml portions of water. The washed organic phase was then separated, dried and rendered free of the solvent to yield crude 5-nonyl salicylaldehyde. A 62% yield was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]([CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=1.[CH2:13](N(CC)CC)C.CI>CN(C=O)C>[Br:1][C:2]1[CH:3]=[N:4][N:5]([CH:7]2[CH2:12][CH2:11][N:10]([CH3:13])[CH2:9][CH2:8]2)[CH:6]=1
Reactant: CCN(CC)CC
Reactant: Brc1cnn(C2CCNCC2)c1
Solvent: CI
Solvent: CN(C)C=O
Product: CN1CCC(n2cc(Br)cn2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51 %

Procedure:
To a solution of 4-(4-bromopyrazol-1-yl)piperidine (480 mg, 2.09 mmol) and triethylamine (0.295 ml, 2.1 mmol) in DMF (4 ml) was added methyl iodide (2.1 ml of a 1.0M solution in DMF, 2.1 mmol) under an inert atmosphere. The reaction was stirred at room temperature overnight, then partitioned between water and EtOAc. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure to give the product (260 mg), which was used without further purification. 1H NMR (400 MHz, CDCl3): 7.47 (1H, s), 7.45 (1H, s), 4.16-4.04 (1H, m), 3.09-2.92 (2H, m), 2.34 (3H, s), 2.30-2.10 (4H, m), 2.10-1.96 (2H, m).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][N:5]([C:7]([CH3:10])([CH3:9])[CH3:8])[CH:6]=1.[Li]CCCC.CON(C)[C:19](=[O:21])[CH3:20]>C1COCC1>[C:7]([N:5]1[CH:6]=[C:2]([C:19](=[O:21])[CH3:20])[CH:3]=[N:4]1)([CH3:10])([CH3:9])[CH3:8]
Reactant: CON(C)C(C)=O
Reactant: CC(C)(C)n1cc(Br)cn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(=O)c1cnn(C(C)(C)C)c1
Temperature: -78 °C
Reaction time: 1.33 h

Procedure:
A solution of 4-bromo-1-tert-butyl-1H-pyrazole (973 mg, 4.79 mmol) in anhydrous THF (9.5 ml) was cooled to −78° C. under argon. A solution of n-BuLi in Hexanes (1.6 M, 3.2 mL, 5.12 mmol) was then added dropwise over 5 min and reaction mixture was stirred at −78° C. for 80 min. A solution of N-methoxy-N-methylacetamide (0.55 ml, 5.17 mmol) in THF (3 mL) was added dropwise and mixture was warmed to 0° C. After 4 hours, reaction mixture was quenched via addition of NH4Cl (aq) (10 mL) and mixture was extracted with ethyl acetate. Combined organic layers were washed with 50% brine, dried (Na2SO4), filtered, and concentrated under reduced pressure. Resulting residue was purified by silica gel column chromatography (0-50% ethyl acetate in hexanes) to yield 1-(1-tert-butyl-1H-pyrazol-4-yl)ethanone 5.14.
Reaction SMILES: N1C=CC=CC=1.[C:7]([O:11][CH:12]([C:17]1[C:18]([CH:36]([CH3:38])[CH3:37])=[N:19][C:20]2[C:21]([CH3:35])([CH3:34])[CH2:22][NH:23][CH2:24][C:25]=2[C:26]=1[C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=1)[C:13]([O:15][CH3:16])=[O:14])([CH3:10])([CH3:9])[CH3:8].[C:39]1(B(O)O)[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>C(Cl)Cl.CC([O-])=O.CC([O-])=O.[Cu+2]>[C:7]([O:11][CH:12]([C:17]1[C:18]([CH:36]([CH3:38])[CH3:37])=[N:19][C:20]2[C:21]([CH3:35])([CH3:34])[CH2:22][N:23]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[CH2:24][C:25]=2[C:26]=1[C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=1)[C:13]([O:15][CH3:16])=[O:14])([CH3:10])([CH3:9])[CH3:8]
Reactant: COC(=O)C(OC(C)(C)C)c1c(C(C)C)nc2c(c1-c1ccc(F)cc1)CNCC2(C)C
Reactant: OB(O)c1ccccc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)C(OC(C)(C)C)c1c(C(C)C)nc2c(c1-c1ccc(F)cc1)CN(c1ccccc1)CC2(C)C
Reaction time: 0.08 h

Procedure:
A mixture of Cu(OAc)2 (8.21 mg, 0.045 mmol) and pyridine (3.66 μl, 0.045 mmol) in CH2Cl2 (0.5 mL) was stirred for 5 min. Added to this were methyl 2-tert-butoxy-2-(4-(4-fluorophenyl)-2-isopropyl-8,8-dimethyl-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)acetate (intermediate 5) (10 mg, 0.023 mmol), phenylboronic acid (5.51 mg, 0.045 mmol) and 17 mg molecular sieves. The resulting mixture was stirred at room temperature open to air for 17 h. The mixture was adsorbed directly onto silica gel and purified by flash chromatography (Biotage; 0%-50% EtOAc/hexane). 1H NMR (500 MHz, CDCl3) δ ppm 7.38 (ddd, J=8.4, 5.8, 2.3 Hz, 1H), 7.27-7.16 (m, 5H), 6.87-6.73 (m, 3H), 4.86 (s, 1H), 3.94 (d, J=15.6 Hz, 1H), 3.73 (s, 3H), 3.69 (d, J=15.6 Hz, 1H), 3.55 (dt, J=13.0, 6.4 Hz, 1H), 3.44-3.34 (m, 1H), 3.28 (d, J=12.5Hz, 1H), 1.49 (d, J=3.7 Hz, 6H), 1.33 (d, J=6.1 Hz, 3H), 1.17 (d, J=6.7 Hz, 3H), 1.01 (s, 9H). 19F NMR (500 MHz, CDCl3) δ ppm −113.64. LCMS (M+H) calcd for C32H40FN2O3: 519.30. found: 519.45.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:51]2([C:54]#[N:55])[CH2:53][CH2:52]2)=[C:6]([CH2:8][N:9]([CH3:50])[C:10]([CH:12]([NH:24][C:25]2[CH:26]=[C:27]3[C:32](=[CH:33][CH:34]=2)[C:31]([N:35]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[N:30][CH:29]=[CH:28]3)[C:13]2[CH:18]=[CH:17][C:16]([C@@H:19]([CH3:22])[CH2:20][OH:21])=[C:15]([CH3:23])[CH:14]=2)=[O:11])[CH:7]=1.[C:56](Cl)(Cl)=[O:57]>C(#N)C.ClCCl>[C:38]([O:37][C:36]([N:35]([C:31]1[C:32]2[C:27](=[CH:26][C:25]([NH:24][C@H:12]3[C:10](=[O:11])[N:9]([CH3:50])[CH2:8][C:6]4[CH:7]=[C:2]([CH:3]=[CH:4][C:5]=4[C:51]4([C:54]#[N:55])[CH2:52][CH2:53]4)[NH:1][C:56](=[O:57])[O:21][CH2:20][C@H:19]([CH3:22])[C:16]4[C:15]([CH3:23])=[CH:14][C:13]3=[CH:18][CH:17]=4)=[CH:34][CH:33]=2)[CH:28]=[CH:29][N:30]=1)[C:43](=[O:44])[O:45][C:46]([CH3:48])([CH3:47])[CH3:49])=[O:42])([CH3:39])([CH3:40])[CH3:41]
Reactant: Cc1cc(C(Nc2ccc3c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nccc3c2)C(=O)N(C)Cc2cc(N)ccc2C2(C#N)CC2)ccc1[C@@H](C)CO
Reactant: O=C(Cl)Cl
Solvent: ClCCl
Solvent: CC#N
Product: Cc1cc2ccc1[C@@H](C)COC(=O)Nc1ccc(C3(C#N)CC3)c(c1)CN(C)C(=O)[C@@H]2Nc1ccc2c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nccc2c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 36.8 %

Procedure:
A solution of 36I (0.371 g, 0.495 mmol) in acetonitrile (5 mL) and dichloromethane (5 mL) was cooled to 0° C. To this solution, was added phosgene (20% in toluene, 0.257 mL, 0.520 mmol). The mixture was stirred at 0° C. for 15 min, then bubbled with Ar for 25 min to remove excess phosgene and HCl. The resulting solution was added dropwise over 5 h via a syringe pump into a solution of TEA (0.690 mL, 4.95 mmol) in dichloromethane (200 mL). The solution was stirred for an additional 30 min and then concentrated. The crude product was purified by flash chromatography (1-15% MeOH/dichloromethane) to give di-Boc protected intermediate (0.326 g, 85%) as a diastereomeric mixture. The diastereomers were separated by a prep chiral HPLC (CHIRALCEL® OD 10 um 4.6×250 mm) to yield 36J (0.141 g, 0.182 mmol, 73.5% yield) as a yellowish solid. MS (ESI) m/z: 775.3 [M+1]+. 1H NMR: (400 MHz, CD3OD) δ ppm 8.05 (1H, d, J=5.81 Hz), 7.68 (1H, dd, J=7.83, 1.77 Hz), 7.61 (1H, d, J=9.09 Hz), 7.52 (1H, d, J=5.81 Hz), 7.46 (1H, d, J=8.08 Hz), 7.27 (1H, dd, J=9.22, 2.15 Hz), 7.18-7.24 (2H, m), 6.88 (1H, d, J=2.02 Hz), 6.71 (1H, dd, J=8.08, 2.27 Hz), 6.11 (1H, d, J=2.02 Hz), 5.73 (1H, s), 5.67 (1H, d, J=16.93 Hz), 4.65 (1H, t, J=10.99 Hz), 4.14 (1H, d, J=16.93 Hz), 3.96 (1H, dd, J=10.86, 4.29 Hz), 3.40 (3H, s), 2.31 (3H, s), 1.27 (25H, s).