Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([CH3:6])[C:3]([OH:5])=O.CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.Cl.[CH3:44][N:45]([C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1)[C:46]1[N:51]=[C:50]([NH2:52])[N:49]=[C:48]([C:53]2[N:57]=[C:56]([CH:58]3[CH2:63][CH2:62][NH:61][CH2:60][CH2:59]3)[O:55][N:54]=2)[N:47]=1>CN(C=O)C.O>[NH2:52][C:50]1[N:51]=[C:46]([N:45]([CH3:44])[C:64]2[CH:65]=[CH:66][CH:67]=[CH:68][CH:69]=2)[N:47]=[C:48]([C:53]2[N:57]=[C:56]([CH:58]3[CH2:63][CH2:62][N:61]([C:3](=[O:5])[CH:2]([CH3:6])[CH3:1])[CH2:60][CH2:59]3)[O:55][N:54]=2)[N:49]=1
Reactant: CN(c1ccccc1)c1nc(N)nc(-c2noc(C3CCNCC3)n2)n1
Reactant: CC(C)C(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)C(=O)N1CCC(c2nc(-c3nc(N)nc(N(C)c4ccccc4)n3)no2)CC1
Reaction time: 0.08 h
Yield: 91.3 %

Procedure:
To 2-methylpropanoic acid (27.0 μL, 0.299 mmol) in DMF (5 mL) was added DIPEA (109 μL, 0.624 mmol) at room temperature and the mixture was stirred for 5 min. (1H-Benzotriazol-1-yloxy)[tris(dimethylamino)]phosphonium hexafluorophosphate (0.121 g, 0.274 mmol) was added to the reaction mixture and stirred for 5 min. 2-N-Methyl-2-N-phenyl-6-[5-(piperidin-4-yl)-1,2,4-oxadiazol-3-yl]-1,3,5-triazine-2,4-diamine hydrochloride (Intermediate 105, 0.100 g, 0.249 mmol) was added and the mixture was stirred at room temperature for 18 h. The reaction mixture was diluted with water, extracted with EtOAc and the organic layer washed with brine. The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude compound was purified by FCC (DCM:MeOH 90:10) to afford the title compound (96 mg, 88%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH2:20][CH2:19][C@@:18]2([CH3:21])[C:5](=[CH:6][CH2:7][C@@H:8]3[C:17]2=[CH:16][CH2:15][C@@:13]2([CH3:14])[C@H:9]3[CH2:10][CH2:11][C:12]2=[C:22]([N+:33]#[C-:34])[S:23]([C:26]2[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=2)(=[O:25])=[O:24])[CH:4]=1.[OH-].[Na+].[CH2:37](Cl)[Cl:38]>[Cl-].C([N+](CC)(CC)CC1C=CC=CC=1)C>[CH3:1][O:2][C:3]1[CH2:20][CH2:19][C@@:18]2([CH3:21])[C:5](=[CH:6][CH2:7][C@@H:8]3[C:17]2=[CH:16][CH2:15][C@@:13]2([CH3:14])[C@H:9]3[CH2:10][CH:11]=[C:12]2[C:22]([N+:33]#[C-:34])([S:23]([C:26]2[CH:27]=[CH:28][C:29]([CH3:32])=[CH:30][CH:31]=2)(=[O:25])=[O:24])[CH2:37][Cl:38])[CH:4]=1
Reactant: [C-]#[N+]C(=C1CC[C@H]2[C@@H]3CC=C4C=C(OC)CC[C@]4(C)C3=CC[C@]12C)S(=O)(=O)c1ccc(C)cc1
Reactant: ClCCl
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Product: [C-]#[N+]C(CCl)(C1=CC[C@H]2[C@@H]3CC=C4C=C(OC)CC[C@]4(C)C3=CC[C@]12C)S(=O)(=O)c1ccc(C)cc1
Yield: 70 %

Procedure:
3-Methoxy-17-(isocyano-p-methylphenylsulfonylmethylene)-androsta-3,5,9(11)-triene (476 mg, 1.00 mmol) and triethylbenzylammonium chloride (20 mg) were dissolved in methylene chloride (10 ml). After stirring for 2 hours at 25° C. with a sodium hydroxide solution (5 ml, 50%), the organic layer was seperated and dried over Na2SO4, followed by filtration over alumina (act. II-III). Evaporation of the solvent afforded the title compound (368 mg, 70%).
Reaction SMILES: ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[C:23]([O:27][C:28]([N:30]1[CH2:37][C@@H:36]([NH:38][C:39](=[O:49])[CH2:40][NH:41][C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:35][C@@H:31]1[C:32](O)=[O:33])=[O:29])([CH3:26])([CH3:25])[CH3:24].[N:50]1[C:59]2[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=2)[CH:53]=[C:52]([NH:60][C:61](=[O:80])[C@@H:62]2[CH2:66][C@@H:65]([NH:67][C:68](=[O:79])[C@H:69]([OH:78])[CH2:70][CH2:71][C:72]3[CH:77]=[CH:76][CH:75]=[CH:74][CH:73]=3)[CH2:64][NH:63]2)[CH:51]=1>ClCCl.C(N(CC)CC)C>[N:50]1[C:59]2[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=2)[CH:53]=[C:52]([NH:60][C:61](=[O:80])[C@@H:62]2[CH2:66][C@@H:65]([NH:67][C:68](=[O:79])[C@H:69]([OH:78])[CH2:70][CH2:71][C:72]3[CH:77]=[CH:76][CH:75]=[CH:74][CH:73]=3)[CH2:64][N:63]2[C:32](=[O:33])[C@H:31]2[CH2:35][C@H:36]([NH:38][C:39](=[O:49])[CH2:40][NH:41][C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:37][N:30]2[C:28]([O:27][C:23]([CH3:24])([CH3:26])[CH3:25])=[O:29])[CH:51]=1
Reactant: CC(C)(C)OC(=O)NCC(=O)N[C@H]1C[C@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: O=C(N[C@H]1CN[C@H](C(=O)Nc2cnc3ccccc3c2)C1)[C@H](O)CCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCC(=O)N[C@H]1C[C@H](C(=O)N2C[C@H](NC(=O)[C@H](O)CCc3ccccc3)C[C@H]2C(=O)Nc2cnc3ccccc3c2)N(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 65.9 %

Procedure:
Triethylamine (40 μL), 1-hydroxybenzotriazole (36 mg), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (55 mg) were added to a solution of N-tert-butoxycarbonyl-trans-4-(N-tert-butoxycarbonylglycylamino)-D-proline (F, 112 mg) and trans-4-((R)-2-hydroxy-4-phenylbutyrylamino)-L-proline 3-quinolylamide (Compound D101 (H), 100 mg) in dichloromethane (10 mL) at 0° C. The mixture was stirred at room temperature for 18 hr and evaporated in vacuo. The residue was diluted with ethyl acetate and washed with 1 N hydrochloric acid, water, saturated sodium hydrogen carbonate, and brine. The organic layer was dried over anhydrous sodium sulfate and evaporated in vacuo. The residue was purified by silica gel column chromatography (methanol:chloroform=1:50 to 1:20, v/v) to give the title compound (124 mg) as a colorless solid: 1H NMR (400 MHz, CDCl3) δ 1.34-1.44 (m, 18H), 1.86-1.92 (m, 1H), 2.03-2.14 (m, 1H), 2.21-2.64 (m, 3H), 2.71-2.75 (m, 2H), 3.33-3.75 (m, 4H), 3.94-4.10 (m, 2H), 4.21-4.78 (m, 3H), 7.14-7.27 (m, 5H), 7.51-7.71 (m, 2H), 7.83-7.99 (m, 2H), 8.70-8.72 (m, 1H), and 8.96-9.05 (m, 1H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[OH:18])[N:3]=1.ClCCl.[CH2:22]([OH:24])[CH3:23]>>[CH2:22]([O:24][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[OH:18])[N:3]=1)[CH3:23]
Reactant: Oc1ccccc1-c1nc(Cl)c2ccccc2n1
Reactant: CCO
Solvent: ClCCl
Product: CCOc1nc(-c2ccccc2O)nc2ccccc12
Temperature: 180 °C

Procedure:
2-(4-Chloro-quinazolin-2-yl)-phenol (50 mg, 0.196 mmol) was placed in a microwave tube charged with a stir bar and dissolved 0.5 ml dry dichloromethane, followed by the addition of 2 ml dry ethanol. Tube was sealed with a cap and heated at 160 to 200° C. for one hour in CEM microwave. Solvent was removed under reduced pressure, reconstituted organic in DMSO and purified by Gilson HPLC. The desired compound was concentrated to a white solid as the TFA salt. LC/MS (10-99%) M/Z 267.2, retention time 2.57 minutes.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:10]([C:11](=O)[C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)=[CH:14][CH:13]=2)=[C:9]([CH3:29])[O:8][N:7]=1)=O)C.O.[NH2:31][NH2:32]>C(O)C>[CH3:29][C:9]1[O:8][N:7]=[C:6]2[C:10]=1[C:11]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)=[CH:14][CH:13]=1)=[N:32][NH:31][C:4]2=[O:3]
Reactant: NN
Reactant: CCOC(=O)c1noc(C)c1C(=O)c1ccc(OCCCN2CCCCC2)cc1
Solvent: O
Solvent: CCO
Product: Cc1onc2c(=O)[nH]nc(-c3ccc(OCCCN4CCCCC4)cc3)c12
Temperature: 0 °C
Reaction time: 21 h

Procedure:
To 291.3 mg of 5-methyl-4-[4-(3-piperidin-1-ylpropoxy)benzoyl] isoxazole-3-carboxylic acid ethyl ester (0.7057 mmol) in 1.54 mL of ethanol at room temperature was added 49.4 μL of hydrazine monohydrate (0.988 mmol). After 21 h, the heterogeneous reaction was cooled to 0° C. and filtered. The white solid was washed with cold ethanol then diethyl ether and dried at 65° C. under high vacuum. Yield 120 mg (46%) of a white solid Mp 178-9; MS m/z 369 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6](N)[CH:7]=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O.FC(F)(F)[C:27]([NH2:29])=O.[OH-].[Na+].S(OC)(OC)(=O)=O>C(Cl)Cl.C1(C)C=CC=CC=1.[Cl-].C([N+](C)(C)C)C1C=CC=CC=1.C(#N)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH2:27][NH2:29])[CH:7]=1
Reactant: Nc1cc(F)ccc1[N+](=O)[O-]
Reactant: NC(=O)C(F)(F)F
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: COS(=O)(=O)OC
Solvent: Cc1ccccc1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: NCc1cc(F)ccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A solution of 5-fluoro-2-nitrophenylamine (1 eq) in methylenechloride was treated with trifluoroacetic anhydride (1 eq) and stirred for 10 minutes at 0° C. The mixture was quenched with saturated sodium bicarbonate solution. The organic layer was separated and washed with water, brine, dried and evaporated. To the solution of the trifluoroacetamide (1 eq) in a mixture of toluene, acetonitrile and sodium hydroxide solution (50%) was added benzyltrimethylammonium chloride (1 eq) and dimethyl sulfate (1.2 eq). The biphasic mixture was stirred overnight at room temperature and evaporated. The mixture was taken up in ethyl acetate, washed with water, brine, dried and evaporated. The crude was purified by column chromatography eluting with 1:1 hexanes and ethyl acetate to afford (5-fluoro-2-nitrophenyl)methylamine. MS: MH+=170.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:12])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[CH3:13][N:14](C=O)C>C(OCC)(=O)C.[C-]#N.[Zn+2].[C-]#N.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[F:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[CH:4][CH:3]=[C:2]2[C:13]#[N:14]
Reactant: Fc1ccc2nccc(Cl)c2c1
Reactant: CN(C)C=O
Agent: [Pd]
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: N#Cc1ccnc2ccc(F)cc12

Procedure:
A mixture of 4-chloro-6-fluoroquinoline (APOLLO) (1120 mg, 6.17 mmol), zinc cyanide (1450 mg, 12.3 mmol) and palladium (0) tetrakis(triphenylphosphine)(713 mg, 0.617 mmol) in dry DMF (15 ml) was treated with microwave (160° C., 30 min.). The mixture was diluted with ethyl acetate and filtered through a pad of celite. To the filtrate was added toluene (ca.20 ml) and the organic layer was washed with water (×2), brine, dried and concentrated in vacuo to give crude product. The crude product was purified by column chromatography on silica gel (ca. 250 g) with hexane-ethyl acetate (3:1) to give the title compound (880 mg, white solid). 1H NMR (270 MHz, CDCl3) δ ppm 7.60-7.70 (1H, m), 7.75-7.79 (1H, m), 7.81-7.87 (1H, m), 8.20-8.28 (1H, m), 9.00-9.05 (1H, m).
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=[O:9])=[C:6]([N:10]2[CH2:22][CH2:21][C:20]3[N:19]4[C:14]([CH2:15][CH2:16][CH2:17][CH2:18]4)=[C:13]([F:23])[C:12]=3[C:11]2=[O:24])[N:5]=[CH:4][CH:3]=1.[CH3:25][N:26]1[CH:31]=[C:30](B2OC(C)(C)C(C)(C)O2)[CH:29]=[C:28]([NH:41][C:42]2[CH:51]=[C:45]3[CH2:46][N:47]([CH3:50])[CH2:48][CH2:49][N:44]3[N:43]=2)[C:27]1=[O:52].C([O-])([O-])=O.[Na+].[Na+].CN(C=O)C>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[F:23][C:13]1[C:12]2[C:11](=[O:24])[N:10]([C:6]3[C:7]([CH:8]=[O:9])=[C:2]([C:30]4[CH:29]=[C:28]([NH:41][C:42]5[CH:51]=[C:45]6[CH2:46][N:47]([CH3:50])[CH2:48][CH2:49][N:44]6[N:43]=5)[C:27](=[O:52])[N:26]([CH3:25])[CH:31]=4)[CH:3]=[CH:4][N:5]=3)[CH2:22][CH2:21][C:20]=2[N:19]2[C:14]=1[CH2:15][CH2:16][CH2:17][CH2:18]2
Reactant: O=Cc1c(Cl)ccnc1N1CCc2c(c(F)c3n2CCCC3)C1=O
Reactant: CN1CCn2nc(Nc3cc(B4OC(C)(C)C(C)(C)O4)cn(C)c3=O)cc2C1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Product: CN1CCn2nc(Nc3cc(-c4ccnc(N5CCc6c(c(F)c7n6CCCC7)C5=O)c4C=O)cn(C)c3=O)cc2C1
Temperature: 70 °C
Yield: 103.1 %

Procedure:
A 25-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 4-chloro-2-(10-fluoro-1-oxo-3,4,6,7,8,9-hexahydropyrido[3,4-b]indolizin-2(1H)-yl)nicotinaldehyde 134c (59.6 mg, 0.17 mmol), 1-methyl-3-({5-methyl-4H,5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-yl}amino)-5-(tetramethyl-1,3,2-dioxa-borolan-2-yl)-1,2-dihydropyridin-2-one 135a (261.8 mg, 0.68 mmol), Pd(dppf)Cl2 (25.0 mg, 0.030 mmol), Na2CO3 (54.1 mg, 0.51 mmol), DMF (6 mL), and water (0.75 mL). After three cycles of vacuum/argon flush, the mixture was heated at 70° C. for 1 h. It was then filtered and the filtrate was evaporated under reduced pressure. The residue was purified by silica-gel column chromatography eluting with 50:1 dichloromethane/methanol to afford 241a (100 mg, purity: 54%, yield: 56%) as a yellow solid. MS-ESI: [M+H]+ 571.3
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[O:6][CH2:7][CH2:8][N:9]([CH3:12])[C:10]=2[N:11]=1.CC1(C)C(C)(C)OB([C:27]2[CH:28]=[N:29][C:30]([NH2:33])=[N:31][CH:32]=2)O1.C(Cl)Cl.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O>[CH3:12][N:9]1[CH2:8][CH2:7][O:6][C:5]2[C:4]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:3][C:2]([C:27]3[CH:28]=[N:29][C:30]([NH2:33])=[N:31][CH:32]=3)=[N:11][C:10]1=2
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Reactant: CN1CCOc2c1nc(Cl)nc2N1CCOCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: CN1CCOc2c1nc(-c1cnc(N)nc1)nc2N1CCOCC1
Temperature: 100 °C

Procedure:
A mixture of 2-chloro-8-methyl-4-morpholin-4-yl-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazine (120 mg, 0.44 mmol), 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidin-2-ylamine (196 mg, 0.88 mmol), PdCl2dppf.DCM (36 mg, 0.04 mmol) and cesium carbonate (573 mg, 1.76 mmol) in dioxane (5 mL) and water (0.5 mL) was degassed and heated at 100° C. for 18 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic extracts were dried (Na2SO4) and concentrated in vacuo. The resulting residue was loaded onto an Isolute® SCX-2 cartridge which was washed with methanol and the product eluted with 2M ammonia in methanol. The basic fractions were combined and concentrated in vacuo. The resulting residue was purified by column chromatography (SiO2, gradient 0-5% methanol in DCM) then triturated with diethyl ether affording 119 (357 mg, 24%). LCMS: RT=3.04 min, [M+H]+=330. 1H NMR (400 MHz, DMSO): δ 8.94 (2H, s), 6.92 (2H, s), 4.16 (2H, t, J=4.37 Hz), 3.67 (4H, t, J=4.57 Hz), 3.52 (4H, t, J=4.56 Hz), 3.48 (2H, t, J=4.36 Hz), 3.13 (3H, s).
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.C1(N=C=NC2CCCCC2)CCCCC1.Cl.[CH2:26]([O:28][C:29](=[O:40])[C@H:30]([CH2:32][C:33]1[CH:38]=[CH:37][C:36]([OH:39])=[CH:35][CH:34]=1)[NH2:31])[CH3:27]>N1C=CC=CC=1>[CH2:26]([O:28][C:29](=[O:40])[C@H:30]([CH2:32][C:33]1[CH:34]=[CH:35][C:36]([OH:39])=[CH:37][CH:38]=1)[NH:31][C:1](=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1)[CH3:27]
Reactant: O=C(O)c1cccnc1
Reactant: CCOC(=O)[C@@H](N)Cc1ccc(O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: c1ccncc1
Product: CCOC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)c1cccnc1
Reaction time: 8 h

Procedure:
Nicotinic acid (12.3 g, 0.1 mol) was dissolved in dry pyridine (300 mL). The solution was cooled and dicyclohexylcarbodiimide (20.6 g, 0.1 mol) was added. After dissolution, tyrosine ethyl ester hydrochloride (24.6 g, 0.1 mol) was added and the solution was stirred overnight. The precipitated dicyclohexylurea (OCU) was removed by filtration. Additional OCU was removed by triturating the oil with hot water. The product was purified with acetone. Calculated for C17H18N2O4 ·1/2H2O: C, 63.16; H, 5.88; N, 8.66. Found: C, 63.10; H, 5.96; N, 8.59. The product can also be named N-[1-ethoxycarbonyl-2-(4'-hydroxyphenyl)ethyl]nicotinamide.
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:12])[C:9]([CH3:11])=[CH2:10].[CH:14]1[C:19]2[CH2:20][CH2:21][CH2:22][CH2:23][CH:24]([OH:25])[C:18]=2[CH:17]=[CH:16][CH:15]=1>C1(C)C=CC=CC=1>[C:8]([O:25][CH:24]1[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:19]=2[CH2:20][CH2:21][CH2:22][CH2:23]1)(=[O:12])[C:9]([CH3:11])=[CH2:10]
Reactant: C=C(C)C(=O)Cl
Reactant: OC1CCCCc2ccccc21
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: C=C(C)C(=O)OC1CCCCc2ccccc21

Procedure:
With stirring and ice cooling, 111 g of triethylamine was added to a mixture of 120 g of methacrylic acid chloride, 240 g of 6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol, and 1500 g of toluene. The mixture was stirred at room temperature for 16 hours. By standard aqueous work-up and solvent distillation, a crude product was obtained. It was purified by column chromatography, yielding the target compound, 6,7,8,9-tetrahydro-5H-benzocyclohepten-5-yl methacrylate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:4]=1[C:5]([OH:7])=O.Cl.[CH2:14]([O:16][CH2:17][CH2:18][N:19]1[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[N:21]=[C:20]1[NH:28][CH:29]1[CH2:34][CH2:33][N:32]([CH2:35][CH2:36][C:37]2([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[CH2:41][CH2:40][NH:39][CH2:38]2)[CH2:31][CH2:30]1)[CH3:15]>>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:4]=1[C:5]([N:39]1[CH2:40][CH2:41][C:37]([CH2:36][CH2:35][N:32]2[CH2:33][CH2:34][CH:29]([NH:28][C:20]3[N:19]([CH2:18][CH2:17][O:16][CH2:14][CH3:15])[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[N:21]=3)[CH2:30][CH2:31]2)([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH2:38]1)=[O:7]
Reactant: CCOCCn1c(NC2CCN(CCC3(c4ccccc4)CCNC3)CC2)nc2ccccc21
Reactant: COc1ccc(F)cc1C(=O)O
Agent: Cl
Product: CCOCCn1c(NC2CCN(CCC3(c4ccccc4)CCN(C(=O)c4cc(F)ccc4OC)C3)CC2)nc2ccccc21

Procedure:
Prepare by the method of Example 59.1 using 2-methoxy-5-fluorobenzoic acid and 3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl-amino)piperidin-1-yl)ethyl)-3-phenylpyrrolidine hydrochloric acid salt (prepared from (−)-3-(2-hydroxyethyl)-3-phenylpyrrolidine (R,R)-di-p-anisoyltartaric acid salt) to give the title compound.
Reaction SMILES: [H-].[Na+].[CH:3]([C:6]1[CH:11]=[CH:10][C:9]([CH:12]2[C:16]3([CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]3)[O:15][C:14]3[C:23]([CH3:30])=[C:24]([CH3:29])[C:25]([OH:28])=[C:26]([CH3:27])[C:13]2=3)=[CH:8][CH:7]=1)([CH3:5])[CH3:4].[CH3:31][O:32][C:33]1[CH:40]=[CH:39][C:36]([CH2:37]Cl)=[CH:35][CH:34]=1.O>CN(C)C=O>[CH:3]([C:6]1[CH:7]=[CH:8][C:9]([CH:12]2[C:16]3([CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]3)[O:15][C:14]3[C:23]([CH3:30])=[C:24]([CH3:29])[C:25]([O:28][CH2:37][C:36]4[CH:39]=[CH:40][C:33]([O:32][CH3:31])=[CH:34][CH:35]=4)=[C:26]([CH3:27])[C:13]2=3)=[CH:10][CH:11]=1)([CH3:5])[CH3:4]
Reactant: Cc1c(C)c2c(c(C)c1O)C(c1ccc(C(C)C)cc1)C1(CCN(C)CC1)O2
Reactant: COc1ccc(CCl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(COc2c(C)c(C)c3c(c2C)C(c2ccc(C(C)C)cc2)C2(CCN(C)CC2)O3)cc1
Reaction time: 0.5 h
Yield: 39.1 %

Procedure:
Sodium hydride (60% liquid paraffin dispersion, 64.3 mmol, 1.61 mmol) was added to a solution of 3-(4-isopropylphenyl)-1′,4,6,7-tetramethylspiro[benzofuran-2(3H),4′-piperidine]-5-ol (509.0 mg, 1.34 mmol) in N,N-dimethylformamide (25 mL) at 0° C., and the mixture was stirred for 30 minutes at the same temperature. To the reaction mixture was added 4-methoxybenzyl chloride (244.0 mg, 1.56 mmol) and the mixture was stirred for further 30 minutes at room temperature. The reaction mixture was poured into water, and extracted twice with ethyl acetate. The organic layers were combined, washed with an aqueous saturated sodium hydrogencarbonate, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (Chromatorex NH DM1020, Fuji Silysia Chemical LTD) (hexane/ethyl acetate=1/1) to obtain the title compound (262 mg, yield 39%). This was amorphous.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[O:7][N:6]=[C:5]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])[CH:4]=1.S(O)(O)(=O)=O.CS[C:20](=[NH:22])[NH2:21]>[OH-].[Na+]>[NH:1]([CH2:2][C:3]1[O:7][N:6]=[C:5]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])[CH:4]=1)[C:20]([NH2:22])=[NH:21]
Reactant: NCc1cc(CCC(=O)O)no1
Reactant: CSC(=N)N
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: N=C(N)NCc1cc(CCC(=O)O)no1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
6.8 g (0.04 mol) of the product from Example 12 are dissolved in 40 ml of 1 N sodium hydroxide solution and 5.56 g of S-methylisothiourea hydrogen sulfate (=0.04 mol of urea) in solid form are added. The mixture is stirred at room temperature for 24 hours, during which the product slowly crystallizes out, and is filtered off with suction and washed thoroughly with water. Yield: 2.8 g; melting point >297° C.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[S:5][C:6]=1[CH2:7]O.C(Br)(Br)(Br)[Br:20].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl.C1CCCCC1>[Br:20][CH2:7][C:6]1[S:5][C:4]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)=[N:3][C:2]=1[CH3:1]
Reactant: BrC(Br)(Br)Br
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1CO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCCCC1
Solvent: ClCCl
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1CBr
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of {4-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methanol (intermediate 1, 0.9 g) in dry dichloromethane (30 ml) stirring at 0° C. was added carbon tetrabromide (1.1 g) and triphenylphosphine (0.995 g). The reaction was stirred at 0° C. for 1 hour, diluted with cyclohexane (30 ml) and purified by SPE cartridge (Si cartridge using chloroform:cyclohexane (1:1) to give the title compound as a white solid.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]1[C@H:14]2[O:15][C:16]([CH3:19])([CH3:18])[O:17][C@H:13]2[C@H:12]([NH:20][C:21]2[CH:26]=[C:25]([Cl:27])[N:24]=[CH:23][N:22]=2)[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].[Na+].[CH3:30]I>C1COCC1.CN(C=O)C>[Si:1]([O:8][CH2:9][C@@H:10]1[C@H:14]2[O:15][C:16]([CH3:18])([CH3:19])[O:17][C@H:13]2[C@H:12]([N:20]([CH3:30])[C:21]2[CH:26]=[C:25]([Cl:27])[N:24]=[CH:23][N:22]=2)[CH2:11]1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: CI
Reactant: CC1(C)O[C@@H]2[C@@H](CO[Si](C)(C)C(C)(C)C)C[C@@H](Nc3cc(Cl)ncn3)[C@@H]2O1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CN(c1cc(Cl)ncn1)[C@@H]1C[C@H](CO[Si](C)(C)C(C)(C)C)[C@H]2OC(C)(C)O[C@H]21
Reaction time: 0.25 h
Yield: 90.8 %

Procedure:
To a mixed solution of N-[(3aS,4R,6R,6aR)-6-({[tert-butyl(dimethyl)silyl]oxy}-methyl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl]-6-chloropyrimidin-4-amine (405 mg, 0.98 mmol) in THF (10.0 mL) and DMF (2.50 mL) was added sodium hydride (47.0 mg, 1.17 mmol) under an atmosphere of Argon, and the mixture was stirred for 15 minutes. Methyl iodide (0.08 mL, 1.27 mmol) was added to the mixture, and the resulting mixture was stirred for 1 h. After quenching by addition of brine (20.0 mL), the mixture was extracted with ethyl acetate (3×40.0 mL). The organic layers were combined, dried over MgSO4, filtered, and evaporated under vacuum. The residue was purified via silica gel column chromatography eluting with a gradient of 5 to 15% ethyl acetate in DCM to afford the title compound (381 mg, 91%) as a colorless oil. LC/MS: Rt=2.55 min, ES+ 428.3 (AA standard).
Reaction SMILES: C[O:2][C:3](=[O:33])[CH2:4][CH2:5][NH:6][C:7](=[O:32])[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([S:22][C:23]2[CH:28]=[C:27]([CH3:29])[C:26](Br)=[C:25]([CH3:31])[CH:24]=2)[CH2:15][CH2:16][CH2:17][C:18]([F:21])([F:20])[F:19])=[CH:10][CH:9]=1.[C:34]([C:38]1[CH:43]=[CH:42][C:41](B(O)O)=[CH:40][CH:39]=1)([CH3:37])([CH3:36])[CH3:35]>>[C:34]([C:38]1[CH:43]=[CH:42][C:41]([C:26]2[C:27]([CH3:29])=[CH:28][C:23]([S:22][CH:14]([C:11]3[CH:10]=[CH:9][C:8]([C:7]([NH:6][CH2:5][CH2:4][C:3]([OH:2])=[O:33])=[O:32])=[CH:13][CH:12]=3)[CH2:15][CH2:16][CH2:17][C:18]([F:20])([F:21])[F:19])=[CH:24][C:25]=2[CH3:31])=[CH:40][CH:39]=1)([CH3:37])([CH3:36])[CH3:35]
Reactant: CC(C)(C)c1ccc(B(O)O)cc1
Reactant: COC(=O)CCNC(=O)c1ccc(C(CCCC(F)(F)F)Sc2cc(C)c(Br)c(C)c2)cc1
Product: Cc1cc(SC(CCCC(F)(F)F)c2ccc(C(=O)NCCC(=O)O)cc2)cc(C)c1-c1ccc(C(C)(C)C)cc1

Procedure:
The title compound is prepared in a manner substantially similar to Example 358 starting from 3-{4-[1-(4-bromo-3,5-dimethyl-phenylsulfanyl)-5,5,5-trifluoro-pentyl]-benzoylamino}-propionic acid methyl ester and 4-tert-butyl phenyl boronic acid. MS: 584.2 [M−H]−.