Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[CH2:7][NH:8][CH2:9][CH:10](OC)OC)([CH3:4])([CH3:3])[CH3:2].[CH3:16][C:17]([O:20][C:21]([NH:23][CH2:24][CH2:25][CH2:26][C@H:27]([NH:31]C(OCC1C=CC=CC=1)=O)[C:28](O)=[O:29])=[O:22])([CH3:19])[CH3:18].Cl.C(N=C=NCCCN(C)C)C.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+].[C:70]([OH:75])(=[O:74])[C:71]([OH:73])=[O:72]>CC(C)=O.C1(C)C=CC=CC=1.C(OCC)(=O)C>[C:70]([OH:75])(=[O:74])[C:71]([OH:73])=[O:72].[C:1]([O:5][C:6](=[O:15])[CH2:7][N:8]1[CH2:9][CH2:10][NH:31][C@@H:27]([CH2:26][CH2:25][CH2:24][NH:23][C:21]([O:20][C:17]([CH3:18])([CH3:16])[CH3:19])=[O:22])[C:28]1=[O:29])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NCCC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: COC(CNCC(=O)OC(C)(C)C)OC
Agent: CCN=C=NCCCN(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: CC(C)=O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)CN1CCN[C@@H](CCCNC(=O)OC(C)(C)C)C1=O
Yield: 67 %

Procedure:
In 54.6 cc of acetone were dissolved (2,2-dimethoxyethyl)aminoacetic acid t-butyl ester (6.0 g, 27.7 mmol) and N--Z--Orn(Boc)--OH (10.0 g, 27.7 mmol). To the solution was added, at 15° C. under stirring, 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (5.6 g, 29.2 mmol). The mixture was stirred for one hour at room temperature, and concentrated under reduced pressure. The concentrate was dissolved in ethyl acetate, and washed with a 5% aqueous solution of potassium hydrogensulfate and a saturated aqueous solution of sodium hydrogencarbonate. The organic layer was concentrated under reduced pressure to give a pale yellow oily substance. This oily substance and p-toluenesulfonic acid 1.0 hydrate (1.04 g, 5.46 mmol) were dissolved in 137 cc of toluene, and the solution was stirred for two hours at 70° C. The reaction mixture was poured into a saturated aqueous solution of sodium hydrogencarbonate. The mixture was subjected to extraction with ethyl acetate. The organic layer was concentrated under reduced pressure, and purified by means of a silica gel column chromatography (hexane/ethyl acetate=3/2) to give 8.3 g of a pale yellow oily substance. This oily substance (8.3 g, 16.5 mmol) was dissolved in 166 cc of ethyl acetate, to which was added 1.7 g of 10% Pd--C, and then the mixture was stirred for two hours under hydrogen atmosphere. The catalyst was filtered off, and the filtrate was dissolved in 16.6 cc of methanol. To the solution was added oxalic acid 2.0 hydrate (2.1 g, 16.5 mmol), and the mixture was concentrated under reduced pressure. Resulting crystalline product was washed with ethyl acetate to afford 5.1 g (66.8%) of the titled compound as white crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[N:9][NH:10][C:11]=2[CH3:12])[S:4][C:3]=1[C:13]([NH2:15])=[O:14].[CH2:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18][C:17]1=O.[O-]S([O-])(=O)=O.[Mg+2].CC1(C)C2(CS(O)(=O)=O)C(CC1CC2)=O.C([O-])(O)=O.[Na+]>CCOC(C)=O.C1COCC1.CC(N(C)C)=O>[CH3:12][C:11]1[NH:10][N:9]=[CH:8][C:7]=1[C:5]1[S:4][C:3]2[C:13](=[O:14])[NH:15][C:17]3([CH2:16][C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH2:18]3)[NH:1][C:2]=2[CH:6]=1
Reactant: Cc1[nH]ncc1-c1cc(N)c(C(N)=O)s1
Reactant: O=C1Cc2ccccc2C1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: O=C([O-])O
Agent: O=S(=O)([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Solvent: C1CCOC1
Product: Cc1[nH]ncc1-c1cc2c(s1)C(=O)NC1(Cc3ccccc3C1)N2
Temperature: 80 °C
Reaction time: 1 h
Yield: 12.5 %

Procedure:
A mixture of 3-amino-5-(5-methyl-1H-pyrazol-4-yl)thiophene -2-carboxamide (111 mg, 0.50 mmol), 2-indanone (330 mg, 2.50 mmol), MgSO4 (120 mg, 1.00 mmol), CSA (11.6 mg, 0.050 mmol) and DMA (3 mL) was stirred at 80° C. for 1 h. The mixture was poured into saturated aqueous NaHCO3 and 2:1 EtOAc/THF. The organic layer was collected, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (Purif, silica gel, hexane to EtOAc, then to 90:10 EtOAc/MeOH), then triturated with EtOAc, and the precipitate was collected by filtration to afford the title compound (21 mg, 12%) as a beige solid:
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([NH:8][NH2:9])=[CH:6][CH:7]=1.[OH:10][C@@H:11]([CH3:15])[C:12](O)=O.CC1C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]2[N:4]([C:12]([C@@H:11]([OH:10])[CH3:15])=[N:9][N:8]=2)[N:3]=1
Reactant: C[C@H](O)C(=O)O
Reactant: NNc1ccc(Cl)nn1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: C[C@H](O)c1nnc2ccc(Cl)nn12

Procedure:
A mixture of 3-chloro-6-hydrazinopyridazine (1.44 g, 9.96 mmol), (S)-2-hydroxypropanoic acid (1.06 g, 10 mmol, i.e. L-lactic acid, 85% in water) and p-TsOH.H2O (2.37 g, 12.4 mmol) in toluene was refluxed overnight. Some oil formed at the bottom of the flask. LC-MS of this oil showed the desired product was formed. Toluene was poured off, and the oil residue was suspended in water (10 mL), then basified with 3 N aq. NaOH to pH=10. This aqueous solution was extracted with EtOAc (3×30 mL), and the combined organic phases were washed with brine (20 mL), and dried over anhydrous sodium sulfate. Evaporation under reduced pressure afforded the title compound as an off-white solid. MS (ES+): 199/201 (3/1) [MH+]. 1H NMR (400 MHz, CDCl3): δ=1.88 (d, J=6.8 Hz, 3H), 2.94 (d, J=6.6 Hz, 1H, —OH), 5.51 (m, 1H), 7.15 (d, J=9.6 Hz, 1H), 8.11 (d, J=9.6 Hz, 1H).
Reaction SMILES: [Br-:1].[Na+].N[C:4]1[S:5][C:6]2[CH:12]=[C:11]([Cl:13])[CH:10]=[C:9]([Cl:14])[C:7]=2[N:8]=1.N(OC(C)(C)C)=O.Cl>[Cu]Br.C(#N)C>[Br:1][C:4]1[S:5][C:6]2[CH:12]=[C:11]([Cl:13])[CH:10]=[C:9]([Cl:14])[C:7]=2[N:8]=1
Reactant: [Br-]
Reactant: Nc1nc2c(Cl)cc(Cl)cc2s1
Agent: [Cu]Br
Agent: CC(C)(C)ON=O
Agent: Cl
Solvent: CC#N
Product: Clc1cc(Cl)c2nc(Br)sc2c1
Reaction time: 16 h

Procedure:
35 g (0.24 mol) of copper(I) bromide and 126 g (1.23 mol) of sodium bromide were added to a solution of 27 g (0.12 mol) of 2-amino-4,6-dichlorobenzothiazole in 0.5 1 of acetonitrile, and 16.5 g (0.16 mol) of tert-butyl nitrite were then added dropwise. Stirring was carried out for 16 hours, after which the reaction mixture was acidified with 10% strength hydrochloric acid. The product was then extracted with methyl tert-butyl ether. The organic phase was washed with water, dried over magnesium sulfate and finally evaporated down. Purification of the crude product was carried out by means of column chromatography over silica gel (eluent: 1:1 cyclohexane/ethyl acetate). Yield: 9.1 g.
Reaction SMILES: [ClH:1].[Br:2][C:3]1[C:7]([C:8]#[N:9])=[N:6][N:5]([CH2:10][CH2:11][CH3:12])[C:4]=1[CH2:13][C:14]1([F:27])[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]1>C(O)C>[ClH:1].[Br:2][C:3]1[C:7]([C:8]#[N:9])=[N:6][N:5]([CH2:10][CH2:11][CH3:12])[C:4]=1[CH2:13][C:14]1([F:27])[CH2:15][CH2:16][NH:17][CH2:18][CH2:19]1
Reactant: CCCn1nc(C#N)c(Br)c1CC1(F)CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CCO
Product: CCCn1nc(C#N)c(Br)c1CC1(F)CCNCC1
Temperature: 70 °C

Procedure:
Hydrochloric acid (3.9 mL of 6 M) was added to a solution of tert-butyl 4-[(4-bromo-5-cyano-2-propyl-2H-pyrazol-3-yl)methyl]-4-fluoropiperidine-1-carboxylate (3.34 g, 7.78 mmol) in ethanol (40 mL), and the reaction was heated at 70° C. for 1.5 hours, allowed to cool to room temperature, and concentrated under reduced pressure to provide 2.9 g of 4-bromo-5-[(4-fluoropiperidin-4-yl)methyl]-1-propyl-1H-pyrazole-3-carbonitrile hydrochloride. The salt was suspended in dichloromethane (40 mL), and triethylamine (4.9 mL, 4.5 eq.) was added. The mixture was stirred for ten minutes to provide a 0.2 M solution of 4-bromo-5-[(4-fluoropiperidin-4-yl)methyl]-1-propyl-1H-pyrazole-3-carbonitrile.
Reaction SMILES: OO.[N:3]1([CH2:8][CH2:9][NH:10][C:11]2[N:16]=[C:15]([C:17]3[S:21][C:20]4[C:22]([C:26]5[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=5[C:33]([CH3:37])([CH3:36])[C:34]#[N:35])=[CH:23][CH:24]=[CH:25][C:19]=4[CH:18]=3)[C:14]([F:38])=[CH:13][N:12]=2)[CH:7]=[CH:6][N:5]=[N:4]1.[O:39]1CCOCCOCCOCCOCCOCC1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.O>[N:3]1([CH2:8][CH2:9][NH:10][C:11]2[N:16]=[C:15]([C:17]3[S:21][C:20]4[C:22]([C:26]5[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=5[C:33]([CH3:36])([CH3:37])[C:34]([NH2:35])=[O:39])=[CH:23][CH:24]=[CH:25][C:19]=4[CH:18]=3)[C:14]([F:38])=[CH:13][N:12]=2)[CH:7]=[CH:6][N:5]=[N:4]1
Reactant: C1COCCOCCOCCOCCOCCO1
Reactant: CC(C)(C#N)c1ccc(F)cc1-c1cccc2cc(-c3nc(NCCn4ccnn4)ncc3F)sc12
Agent: O=C([O-])[O-]
Agent: OO
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(C)(C(N)=O)c1ccc(F)cc1-c1cccc2cc(-c3nc(NCCn4ccnn4)ncc3F)sc12
Temperature: 25 °C
Reaction time: 48 h
Yield: 399.7 %

Procedure:
Add hydrogen peroxide to a stirred solution of 2-(2-(2-(2-(2-(1H-1,2,3-triazol-1-yl)ethylamino)-5-fluoropyrimidin-4-yl)benzo[b]thiophen-7-yl)-4-fluorophenyl)-2-methylpropanenitrile (140 mg, 279 μmol), 1,4,7,10,13,16-hexaoxacyclooctadecane (14 mg, 1% wt), and sodium carbonate (1 M, 5 mL, 5 mmol) in 10 mL ethanol drop wise. Stir the mixture at RT for 48 h. Dilute the reaction mixture with water and extract with DCM. Dry the organic phase over sodium sulfate and concentrate in vacuo. Purify the crude product by FCC (10% methanol in DCM as elute) to give the title compound as a yellow solid (110 mg, 76%). MS (ES) m/z 520 [M+1]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.C(O)(=O)[CH2:11][C:12]([OH:14])=[O:13].O.Cl>N1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4](/[CH:5]=[CH:11]/[C:12]([OH:14])=[O:13])[CH:7]=[CH:8][CH:9]=1
Reactant: O=Cc1cccc(Br)c1
Reactant: O=C(O)CC(=O)O
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: O=C(O)/C=C/c1cccc(Br)c1
Reaction time: 48 h

Procedure:
A magnetically stirred solution of 3-bromobenzaldehyde (86.5 g, 0.468 mol) and malonic acid (107 g, 1.03 mol) in pyridine (200 ml) was treated with peiperidine (4.0 ml, 40.45 mmol) and heated at ~90° C. for 90 min then under reflux for 30 min. The cooled mixture was poured onto ice (200 g) and water (300 ml) then acidified to ph=1 with conc. hydrochloric acid. Filtration afforded a white solid which was washed with water (4×200 ml), dried by suction and placed in an oven at 70° C. for 48 h until constant weight was obtained (96.02 g, 90%); Vmax (nujol)/cm-1 3400-2000 (br. OH), 1684.5, 1631.5, 1587.0; δH (270 MHz) 6.45 (1H, d, 2-H, 3J2,3 =16,2 Hz); 7.28 (1H, t, 5'-H, Jo =7.8 Hz); 7.48 (1-H, dt, 4'-H, Jo =7.9, Jm =1.3 Hz); 7.54 (1-H, dt, 6'-H, Jo =7.9, Jm =1.0 Hz); 7.70 (1-H, t, 2'H, Jm =1.8 Hz); 7.71 (1H, d, 3-H, 3J3,2 =15.8 Hz).
Reaction SMILES: [C:1]1(S(OCC#C)(=O)=O)[CH:6]=CC=C[CH:2]=1.[CH:14]1[C:19]([OH:20])=[CH:18][CH:17]=[CH:16][C:15]=1[CH3:21].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:21][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]([O:20][CH2:6][C:1]#[CH:2])[CH:14]=1
Reactant: C#CCOS(=O)(=O)c1ccccc1
Reactant: Cc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C#CCOc1cccc(C)c1
Reaction time: 48 h

Procedure:
A mixture of propargyl benzenesulfonate (1.0 g, 5.1 mmol), m-cresol (0.55 mL, 5.1 mmol) and potassium carbonate (1.1 g, 7.65 mmol) in acetone (40 mL) was stirred at about 56 C for about 2 days. The mixture was cooled, filtered and the solvent was carefully distilled off at atmospheric pressure. The residue was purified by flash chromatography on silica gel using diethyl ether/n-pentane (1:9) as eluent to provide Example 614. 1H NMR (500 MHz, CDCl3): □ 2.33 (s, 3H), 2.50 (t, J=3.0 Hz, 1H), 4.66 (d, J=3.0 Hz, 2H), 6.77-6.82 (m, 3H), 7.15-7.21 (m, 1H).
Reaction SMILES: [C:1]1([CH:7]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([C:18]3[C:19]([OH:29])=[CH:20][C:21]4[O:25][C:24](=[O:26])[N:23]([CH3:27])[C:22]=4[CH:28]=3)(O)[C:9]2=[O:30])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N1C2C(=CC=CC=2)C(C2C(O)=CC3N(C)C(=O)COC=3C=2)(O)C1=O)(C1C=CC=CC=1)C1C=CC=CC=1.OC1C=CC2N(C)C(=O)OC=2C=1>>[C:31]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]([C:18]3[C:19]([OH:29])=[CH:20][C:21]4[O:25][C:24](=[O:26])[N:23]([CH3:27])[C:22]=4[CH:28]=3)[C:9]2=[O:30])[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: Cn1c(=O)oc2cc(O)c(C3(O)C(=O)N(C(c4ccccc4)c4ccccc4)c4ccccc43)cc21
Agent: CN1C(=O)COc2cc(C3(O)C(=O)N(C(c4ccccc4)c4ccccc4)c4ccccc43)c(O)cc21
Agent: Cn1c(=O)oc2cc(O)ccc21
Product: Cn1c(=O)oc2cc(O)c(C3C(=O)N(C(c4ccccc4)c4ccccc4)c4ccccc43)cc21

Procedure:
Following the procedure as described in PREPARATION 17B, and making non-critical variations using 5-[1-(diphenylmethyl)-3-hydroxy-2-oxo-2,3-dihydro-1H-indol-3-yl]-6-hydroxy-3-methyl-1,3-benzoxazol-2(3H)-one to replace 7-(1-benzhydryl-3-hydroxy-2-oxoindolin-3-yl)-6-hydroxy-4-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one, 541-(diphenylmethyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-6-hydroxy-3-methyl-1,3-benzoxazol-2(3H)-one was obtained (73%) as a pale pink solid: MS (ES+) m/z 463.4 (M+1).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[CH3:19])[CH:11]=2)[C:6](=[C:20](OCC)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:5]1=[O:30])(=O)C.[N:31]1([CH2:37][C:38]2[CH:44]=[CH:43][C:41]([NH2:42])=[CH:40][CH:39]=2)[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1>>[N:31]1([CH2:37][C:38]2[CH:39]=[CH:40][C:41]([NH:42]/[C:20](=[C:6]3\[C:5](=[O:30])[NH:4][C:12]4[C:7]\3=[CH:8][CH:9]=[C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[CH3:19])[CH:11]=4)/[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)=[CH:43][CH:44]=2)[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]1
Reactant: Nc1ccc(CN2CCCCC2)cc1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(-c3ccccc3C)ccc21)c1ccccc1
Product: Cc1ccccc1-c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(CN2CCCCC2)cc1)c1ccccc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-6-(2-tolyl)-2-indolinone and 4-(piperidin-1-yl-methyl)-aniline
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[C:10]([C:11]([NH:13][CH2:14][C:15]3[C:16]([OH:23])=[N:17][C:18]([CH3:22])=[CH:19][C:20]=3[CH3:21])=[O:12])=[C:9]([CH3:24])[N:8]([C@@H:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH3:26])[C:6]=2[N:7]=1>N1CCCC1>[OH:23][C:16]1[C:15]([CH2:14][NH:13][C:11]([C:10]2[C:5]3[CH:4]=[N:3][C:2]([N:8]4[CH2:9][CH2:10][CH2:5][CH2:6]4)=[N:7][C:6]=3[N:8]([C@@H:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH3:26])[C:9]=2[CH3:24])=[O:12])=[C:20]([CH3:21])[CH:19]=[C:18]([CH3:22])[N:17]=1
Reactant: Cc1cc(C)c(CNC(=O)c2c(C)n([C@H](C)c3ccccc3)c3nc(Cl)ncc23)c(O)n1
Solvent: C1CCNC1
Product: Cc1cc(C)c(CNC(=O)c2c(C)n([C@H](C)c3ccccc3)c3nc(N4CCCC4)ncc23)c(O)n1
Yield: 123.8 %

Procedure:
A solution of (R)-2-chloro-N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-6-methyl-7-(1-phenylethyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (70 mg, 0.15 mmol) in pyrrolidine (1.0 mL) was stirred at 150° C. for 30 minutes under microwave (pressure: 12.2 bar, equipment power: 150 W). The mixture was concentrated in vacuo and purified by column chromatography (silica gel, dichloromethane/methanol=10:1) to afford (R)—N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-6-methyl-7-(1-phenylethyl)-2-(pyrrolidin-1-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamide (45 mg, 60.0%). LRMS (M+H) m/z: calcd 484.26. found 484. HPLC purity (214 nm): 97.8%. 1H NMR (400 MHz, CD3OD) δ 8.56 (s, 1H), 7.27-7.20 (m, 5H), 6.06-6.02 (m, 2H), 4.45 (s, 2H), 3.52-3.45 (m, 4H), 2.40 (s, 3H), 2.35 (s, 3H), 2.21 (s, 3H), 2.01-1.94 (m, 7H).
Reaction SMILES: Cl[CH:2]=[CH:3][C:4]([CH3:9])([CH3:8])[C:5]#[C:6][Cl:7].[C:10]1([O-:16])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[Na+]>CN(C)C=O>[Cl:7][CH:6]=[C:5]([O:16][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]([CH3:9])([CH3:8])[C:3]#[CH:2]
Reactant: CC(C)(C#CCl)C=CCl
Reactant: [O-]c1ccccc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: C#CC(C)(C)C(=CCl)Oc1ccccc1
Reaction time: 4 h
Yield: 63.9 %

Procedure:
163 g (1 mole) of 1,5-dichloro-3,3-dimethyl-pent-1-en-4-ine and 232 g (2 moles) of sodium phenolate in 1 liter of absolute N,N-dimethylformamide are heated to 140° C. in the course of 3 hours and stirring is then continued for 4 hours. The mixture is worked up as described for method A, givign 204 g of crude product, which after distillation (boiling point 0.15/87°-94° C.) gives 141 g (that is to say 64% of theory) of 1-chloro-3,3-dimethyl-2-phenoxy-pent-1-en-4-ine.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:17]=[CH:18][CH:19]=1)[O:12][CH2:13][C:14]([CH3:16])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:20][Mg]Br.[Cl-].[NH4+]>C1COCC1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:17]=[CH:18][CH:19]=1)[O:12][CH2:13][C:14]([CH3:20])([OH:15])[CH3:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)COc1cccc(OCc2ccccc2)c1
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(O)COc1cccc(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
1-[3-(Benzyloxy)phenoxy]acetone (1.77 g) was dissolved in THF (20 mL), and, a solution of 0.97M methyl magnesium bromide in THF (9.0 mL) was added dropwise thereto with cooling in an ice bath under nitrogen flow. The reaction mixture was stirred at room temperature for 2.5 hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with a 1M aqueous sodium hydroxide solution and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=100/0-85/15) to obtain 1-[3-(benzyloxy)phenoxy]-2-methylpropan-2-ol (997 mg).
Reaction SMILES: [Li]CCCC.CN([CH:9]=[O:10])C.[CH2:11]([O:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH3:26])=[CH:21][C:20]=1Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1COCC1>[CH2:11]([O:18][C:19]1[CH:20]=[CH:21][C:22]([CH2:25][CH3:26])=[CH:23][C:24]=1[CH:9]=[O:10])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CN(C)C=O
Reactant: CCc1ccc(OCc2ccccc2)c(Br)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCc1ccc(OCc2ccccc2)c(C=O)c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
n-BuLi (7.56 mL, 18.9 mmol, 2.5M in hexanes) followed by DMF (5.5 mL) were added to a cooled −78° C. solution of 1-benzyloxy-2-bromo-4-ethyl-benzene (5 g, 17.2 mmol) in THF (40 mL). The reaction was stirred at −78° C. for 1 hr and then warmed up to rt. After 2 hrs the reaction was quenched with 1N HCl and extracted with EtOAc. The organic layers were washed with brine, dried over Na2SO4 and concentrated to a yellow oil. Purification by flash column chromatography (0% to 5% EtOAc in hexanes) gave the title compound as a clear oil (3.6 g, 87%). 1H NMR (400 MHz, CDCl3): δ 1.22 (t, J=7.8 Hz, 3 H), 2.62 (q, J=7.8 Hz, 2 H), 5.17 (s, 2 H), 6.97 (d, J=8.6 Hz, 1 H), 7.33–7.45 (m, 6 H), 7.69 (s, 1 H), 10.54 (s, 1 H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH2:16][C:17]([NH2:19])=[O:18])[C:5]([CH3:20])=[CH:4][N:3]=1.[NH2:21][C:22]1[CH:41]=[CH:40][C:25]([O:26][CH:27]2[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]2)=[CH:24][CH:23]=1.C([O-])([O-])=O.[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2].CCOC(C)=O.O>[NH2:19][C:17](=[O:18])[CH2:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[CH2:9][CH2:8][C:6]1[C:5]([CH3:20])=[CH:4][N:3]=[C:2]([NH:21][C:22]2[CH:23]=[CH:24][C:25]([O:26][CH:27]3[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:37])([CH3:38])[CH3:39])=[O:34])[CH2:29][CH2:28]3)=[CH:40][CH:41]=2)[N:7]=1
Reactant: Cc1cnc(Cl)nc1CCc1ccccc1CC(N)=O
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(N)cc2)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: Cc1cnc(Nc2ccc(OC3CCN(C(=O)OC(C)(C)C)CC3)cc2)nc1CCc1ccccc1CC(N)=O
Temperature: 100 °C

Procedure:
A suspension of 2-(2-(2-(2-chloro-5-methylpyrimidin-4-yl)ethyl)phenyl)acetamide (K6) (0.150 g, 0.518 mmol), tert-butyl 4-(4-aminophenoxy)piperidine-1-carboxylate (A112) (0.182 g, 0.621 mmol), Pd(OAc)2 (2.3 mg, 0.010 mmol), Cs2CO3 (0.506 g, 1.55 mmol) and Xantphos (12 mg, 0.021 mmol) in 1,4-dioxane (2 mL) was heated under microwave irradiation at 100° C. for 45 minutes. Water (20 mL) and EtOAc (20 mL) were added and the resulting suspension sonicated for 1 minute and then filtered through Celite. The resulting mixture was extracted with EtOAc (×2) and the combined organic extracts were washed with brine, dried (MgSO4), filtered and evaporated in vacuo. The residue was purified using silica gel column chromatography (CombiFlash Rf, 12 g SiO2 cartridge, 0-10% MeOH in DCM) to give the title compound A113 as a light pink colored foam (50 mg, 18%); 1H NMR (300 MHz, d4-MeOH) δ 8.04 (s, 1H), 7.52 (d, J=8.9 Hz, 2H), 7.18-7.27 (m, 5H), 6.92 (d, J=9.0 Hz, 2H), 4.47-4.52 (m, 1H), 4.10-4.13 (m, 2H), 3.67-3.77 (m, 2H), 3.65 (s, 3H), 3.37 (m, 2H), 3.09-3.15 (m, 2H), 2.93-2.98 (m, 2H), 1.91-2.03 (m, 2H), 1.64-1.78 (m, 2H), 1.51 (s, 9H). LCMS-B: rt 7.302 min; m/z 546 [M+H]+.
Reaction SMILES: [N:1]([C@@H:4]1[CH2:9][N:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@@H:7]([CH2:17][CH2:18][N:19]2[C:24]3[CH:25]=[C:26]([C:29]#[N:30])[CH:27]=[CH:28][C:23]=3[O:22][CH2:21][C:20]2=[O:31])[CH2:6][CH2:5]1)=[N+]=[N-]>CO.[Pd]>[NH2:1][C@@H:4]1[CH2:9][N:8]([C:10]([O:12][C:13]([CH3:14])([CH3:16])[CH3:15])=[O:11])[C@@H:7]([CH2:17][CH2:18][N:19]2[C:24]3[CH:25]=[C:26]([C:29]#[N:30])[CH:27]=[CH:28][C:23]=3[O:22][CH2:21][C:20]2=[O:31])[CH2:6][CH2:5]1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](N=[N+]=[N-])CC[C@@H]1CCN1C(=O)COc2ccc(C#N)cc21
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1C[C@@H](N)CC[C@@H]1CCN1C(=O)COc2ccc(C#N)cc21

Procedure:
tert-Butyl (2R,5S)-5-azido-2-[2-(6-cyano-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)ethyl]piperidine-1-carboxylate (Intermediate 184, 0.31 g) was hydrogenated in methanol (10 mL) over 10% Pd/C (90 mg) at normal pressure and room temperature overnight. The reaction was degassed, filtered and purified by chromatography on silica gel with a gradient of 0-10% methanol in methylene chloride to give 0.29 g.
Reaction SMILES: [NH2:1][CH2:2][C:3]1([CH2:7][O:8][C:9]2[C:14]([O:15][CH3:16])=[C:13]([O:17][CH3:18])[CH:12]=[CH:11][C:10]=2[C:19]2[CH:27]=[CH:26][CH:25]=[C:24]3[C:20]=2[CH2:21][CH2:22][C:23]3=[O:28])[CH2:6][O:5][CH2:4]1.C(N(CC)CC)C.[C:36](Cl)(=[O:40])[O:37][CH2:38][CH3:39].COC1C(OC)=CC=C(C2C=CC=C3C=2CCC3=O)C=1OCC1(CNC(=O)C)COC1>ClCCl>[CH2:38]([O:37][C:36](=[O:40])[NH:1][CH2:2][C:3]1([CH2:7][O:8][C:9]2[C:10]([C:19]3[CH:27]=[CH:26][CH:25]=[C:24]4[C:20]=3[CH2:21][CH2:22][C:23]4=[O:28])=[CH:11][CH:12]=[C:13]([O:17][CH3:18])[C:14]=2[O:15][CH3:16])[CH2:4][O:5][CH2:6]1)[CH3:39]
Reactant: CCOC(=O)Cl
Reactant: COc1ccc(-c2cccc3c2CCC3=O)c(OCC2(CN)COC2)c1OC
Agent: COc1ccc(-c2cccc3c2CCC3=O)c(OCC2(CNC(C)=O)COC2)c1OC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)NCC1(COc2c(-c3cccc4c3CCC4=O)ccc(OC)c2OC)COC1

Procedure:
To a stirring solution of 4-[2-(3-Aminomethyl-oxetan-3-ylmethoxy)-3,4-dimethoxy-phenyl]-indan-1-one (Compound 191) (150 mg, 0.3916 mmol) in dichloromethane (15 mL), were added triethylamine (118 mg, 1.174 mmol) and ethyl carbonochloridate (84 mg, 0.783 mmol) and the resultant reaction mixture was subjected to the conditions used in the preparation of Compound 192 to afford the title compound as a solid.