Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[C:8]([O:9][CH3:10])=[C:7]([O:11][CH2:12][CH:13]2[CH2:15][CH2:14]2)[CH:6]=[CH:5][N:4]=1.[C:16]([C:19]1[C:28]([CH3:29])=[CH:27][C:22]2[N:23]=[C:24]([SH:26])[NH:25][C:21]=2[CH:20]=1)(=[O:18])[CH3:17].[OH-].[Na+]>C(O)C.C(Cl)Cl.[Cl-].[Na+].O>[C:16]([C:19]1[C:28]([CH3:29])=[CH:27][C:22]2[NH:23][C:24]([S:26][CH2:2][C:3]3[C:8]([O:9][CH3:10])=[C:7]([O:11][CH2:12][CH:13]4[CH2:15][CH2:14]4)[CH:6]=[CH:5][N:4]=3)=[N:25][C:21]=2[CH:20]=1)(=[O:18])[CH3:17]
Reactant: CC(=O)c1cc2[nH]c(S)nc2cc1C
Reactant: COc1c(OCC2CC2)ccnc1CCl
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Solvent: CCO
Product: COc1c(OCC2CC2)ccnc1CSc1nc2cc(C(C)=O)c(C)cc2[nH]1

Procedure:
2-Chloromethyl-4-cyclopropylmethoxy-3-methoxypyridine (50 mg, 0.22 mmol) and 5-acetyl-6-methyl-2-mercaptobenzimidazole (50 mg, 0.24 mmol) were dissolved in ethanol (15 ml). The pH value of the solution was adjusted to 9 (0.2M NaOH) whereupon the solution was refluxed for 10 min. After concentration of the reaction mixture at reduced pressure the residue was taken up in methylene chloride (10 ml) and brine (2 ml). The phases were separated and the organic phase was dried over sodium sulphate, filtered and concentrated at reduced pressure. The residue was chromatographed on silica (ethyl acetate). Yield: 40 mg (46%) of the title compound.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([CH:11]([NH:14][C:15](=[O:18])[CH:16]=[CH2:17])C=C)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.N1CCC1>ClCCCl>[O:4]1[C:5]2([CH2:6][CH2:7][CH:8]([CH:11]3[NH:14][C:15](=[O:18])[CH:16]=[CH:17]3)[CH2:9][CH2:10]2)[O:1][CH2:2][CH2:3]1
Reactant: C=CC(=O)NC(C=C)C1CCC2(CC1)OCCO2
Agent: C1CNC1
Solvent: ClCCCl
Product: O=C1C=CC(C2CCC3(CC2)OCCO3)N1
Temperature: 50 °C

Procedure:
A solution of N-(1-(1,4-dioxaspiro[4.5]decan-8-yl)allyl)acrylamide (560 mg, 2.23 mmol), prepared in the previous step, and the Grubbs Generation II catalyst (95 mg, 0.11 mmol) in DCE (50 mL) was degassed and heated to 50° C. under argon for 2 hours. The reaction mixture was concentrated in vacuo and the residue purified by flash chromatography (silica gel, DCM→0-5% MeOH/ethyl acetate) to afford the product.
Reaction SMILES: [K+].[Br-].[CH3:3][C@@H:4]1[C:39]([CH3:41])([CH3:40])[O:38][C@:6]2([O:10][C@H:9]3[CH2:11][C@H:12]4[C@@H:17]5[CH2:18][CH2:19][C@H:20]6[CH2:25][C@H:24]([O:26][C:27]([CH3:29])=[O:28])[CH2:23][CH2:22][C@:21]6([CH3:30])[C@H:16]5[C@@H:15]([O:31]C(C)=O)[CH2:14][C@:13]4([CH3:35])[C@H:8]3[C@:7]2([OH:37])[CH3:36])[CH2:5]1>>[CH3:3][C@@H:4]1[C:39]([CH3:40])([CH3:41])[O:38][C@@:6]2([O:10][C@H:9]3[CH2:11][C@H:12]4[C@@H:17]5[CH2:18][CH2:19][C@H:20]6[CH2:25][C@H:24]([O:26][C:27]([CH3:29])=[O:28])[CH2:23][CH2:22][C@:21]6([CH3:30])[C@H:16]5[C@@H:15]([OH:31])[CH2:14][C@:13]4([CH3:35])[C@H:8]3[C@:7]2([OH:37])[CH3:36])[CH2:5]1
Reactant: CC(=O)O[C@@H]1CC[C@@]2(C)[C@@H](CC[C@@H]3[C@@H]2[C@@H](OC(C)=O)C[C@@]2(C)[C@H]3C[C@@H]3O[C@@]4(C[C@H](C)C(C)(C)O4)[C@](C)(O)[C@@H]32)C1
Agent: [Br-]
Agent: [K+]
Product: CC(=O)O[C@@H]1CC[C@@]2(C)[C@@H](CC[C@@H]3[C@@H]2[C@@H](O)C[C@@]2(C)[C@H]3C[C@@H]3O[C@]4(C[C@H](C)C(C)(C)O4)[C@](C)(O)[C@@H]32)C1

Procedure:
white solid, mp 193.5-195° C., 1H NMR (CDCl3) δ 5.01 (brs, 1H), 4.44 (dt, J=5.0, 7.5 Hz, 1H), 4.30 (brs, 1H), 2.26 (m, 1H), 2.16 (dd, J=2.5, 14.0 Hz, 1H), 2.04 (s, 3H), 1.34 (s, 3H), 1.30 (s, 3H), 1.28 (s, 3H), 1.04 (s, 3H), 0.99 (s, 3H), 0.94 (d, J=7.0 Hz, 3H); IR (KBr) 3490, 1710, 1245 cm−1; EIMS m/z 504 (M+, 2), 489 (3), 446 (16), 376 (60), 358 (100%).
Reaction SMILES: C(O[C:6]([NH:8][C:9]1[CH:14]=[CH:13][N:12]=[CH:11][C:10]=1[CH3:15])=O)(C)(C)C.C([Li])(C)(C)C.CN(C)C=O.Cl.C(OC(C)C)(=O)C.[OH-].[Na+]>O1CCCC1>[NH:8]1[C:9]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[CH:15]=[CH:6]1
Reactant: Cc1cnccc1NC(=O)OC(C)(C)C
Agent: Cl
Agent: [Li]C(C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)OC(C)C
Solvent: C1CCOC1
Product: c1cc2[nH]ccc2cn1
Temperature: -40 °C
Reaction time: 1 h

Procedure:
A solution of 4-tert-butoxycarbonylamino-3-methylpyridine (step (a), 1.0 g, 4.8 mmol) in tetrahydrofuran (40 ml) was cooled to -40° C. and tert-butyllithium (8.0 ml 1.7M in pentane, 13.6 mmol) added at such a rate as to keep the temperature below -30° C. The dark orange mixture was stirred at -40° C. for 1 hour and then treated with dimethylformamide (0.56 ml, 7.2 mmol). The mixture was warmed to 20° C. and stirred for 1 hour. 5.5M hydrochloric acid (15 ml) was added and the mixture heated at 45°-50° C. for 1 hour. The mixture was cooled to 0° C., isopropyl acetate (25 ml) added and the whole neutralised with 5M sodium hydroxide (15 ml). The phases were separated and the aqueous layer was extracted with isopropyl acetate (25 ml). The combined organic fractions were washed with saturated brine (25 ml), dried (Na2SO4), filtered and concentrated, in vacuo, to residue. The crude product was purified by chromatography on silica gel (95% methylene chloride/5% methanol) to afford the title compound as an off-white solid; yield: 0.45 g (79%). mp. 108°-110° C. [Lit. mp 109°-110° C.].
Reaction SMILES: [O:1]1[C:5]([C:6]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:7]=2[CH2:8][CH2:9][N:10]2[C:20](=[O:21])[CH2:19][NH:18][C:17](=O)[CH:16]=[C:11]23)=[CH:4][N:3]=[CH:2]1.O=P(Cl)(Cl)Cl.[CH:28]1([C:31]2[N:32]=[CH:33][NH:34][CH:35]=2)[CH2:30][CH2:29]1.N1C=CC=CC=1>ClCCCl.O>[CH:28]1([C:31]2[N:32]=[CH:33][N:34]([C:17]3[CH:16]=[C:11]4[C:12]5[C:7]([CH2:8][CH2:9][N:10]4[C:20](=[O:21])[CH2:19][N:18]=3)=[C:6]([C:5]3[O:1][CH:2]=[N:3][CH:4]=3)[CH:15]=[CH:14][CH:13]=5)[CH:35]=2)[CH2:30][CH2:29]1
Reactant: c1nc(C2CC2)c[nH]1
Reactant: O=C1C=C2c3cccc(-c4cnco4)c3CCN2C(=O)CN1
Solvent: ClCCCl
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: O=C1CN=C(n2cnc(C3CC3)c2)C=C2c3cccc(-c4cnco4)c3CCN12
Temperature: 100 °C
Reaction time: 0.02 h
Yield: 3 %

Procedure:
Example 109. A mixture of 9-(oxazol-5-yl)-3,4,7,8-tetrahydro-[1,4]diazepino[7,1-a]isoquinoline-2,5-dione (180 mg, 0.61 mmol) in DCE (10 mL) was treated with POCl3 (114 μL, 1.22 mmol) and heated to 100° C. for 1 h. The mixture was then allowed to cool to RT, poured onto cold H2O and extracted with DCM. The org. phases were dried over Na2SO4, filtered and concentrated in vacuo. The brown residue obtained was taken up in DCE (5 mL) and 4-cyclopropyl-1H-imidazole (79 mg, 0.73 mmol) and pyridine (148 μL, 1.83 mmol) were then added. The mixture was heated to 100° C. for 1 h, and then allowed to cool to RT, poured onto H2O and extracted with DCM. The org. layers were then dried over Na2SO4, filtered and concentrated in vacuo. Purification by SFC (column: 2-Ethylpyridine 5 μm, 250×30 mm, 60 A, Princeton; eluent: 9% MeOH/CO2 for 1 min, then from 9% MeOH/CO2 to 14% MeOH/CO2 in 6 min; then from 14% MeOH/CO2 to 50% MeOH/CO2 in 1 min; flow 100 mL/min; UV detection at 220 nm) afforded the title compound (7 mg) as pale brown solid. UPLC-MS: MS 386.1 (M+H+); UPLC rt 0.79 min. 1H NMR (400 MHz, CHLOROFORM-d): δ ppm 0.78 (m, 2 H); 0.81-0.87 (m, 2 H); 1.79-1.93 (m, 1 H); 3.14 (t, J=6.02 Hz, 2 H); 3.94 (t, J=6.15 Hz, 2 H); 4.38 (br. s., 2 H); 6.66 (s, 1 H); 7.20 (s, 1 H); 7.30 (s, 1 H); 7.42-7.60 (m, 1 H); 7.77 (d, J=7.78 Hz, 1 H); 7.74 (d, J=8.03 Hz, 1 H); 7.90 (s, 1 H); 8.03 (s, 1 H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[C@H:5]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16](O)[CH:15]=1)[NH:6][C:7](=[O:12])[C:8]([F:11])([F:10])[F:9])[CH3:2].[CH2:22]([O:29][CH2:30][CH2:31][N:32]([CH2:46][CH2:47][O:48][CH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)[C:33]1[CH:42]=[CH:41][CH:40]=[C:39]2[C:34]=1[CH:35]=[CH:36][C:37](B(O)O)=[CH:38]2)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:1]([O:3][C:4](=[O:21])[C@H:5]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:37]2[CH:36]=[CH:35][C:34]3[C:39](=[CH:40][CH:41]=[CH:42][C:33]=3[N:32]([CH2:46][CH2:47][O:48][CH2:49][C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)[CH2:31][CH2:30][O:29][CH2:22][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:38]=2)[CH:15]=1)[NH:6][C:7](=[O:12])[C:8]([F:11])([F:10])[F:9])[CH3:2]
Reactant: CCOC(=O)[C@H](Cc1cccc(O)c1)NC(=O)C(F)(F)F
Reactant: OB(O)c1ccc2c(N(CCOCc3ccccc3)CCOCc3ccccc3)cccc2c1
Product: CCOC(=O)[C@H](Cc1cccc(-c2ccc3c(N(CCOCc4ccccc4)CCOCc4ccccc4)cccc3c2)c1)NC(=O)C(F)(F)F

Procedure:
3-[5-Bis[2-(benzyloxy)ethyl]amino-naphth-2-yl]-N-trifluoroacetyl-L-phenylalanine ethyl ester was synthesized in a similar manner to Example 49 from N-trifluoroacetyl-3-hydroxy-L-phenylalanine ethyl ester and 5-bis[2-(benzyloxy)ethyl]amino-2-naphthaleneboronic acid.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([CH3:22])[N:5]([CH2:13][C:14]2[CH:19]=[CH:18][C:17](I)=[CH:16][C:15]=2[Cl:21])[C:6]=1/[CH:7]=[CH:8]/[C:9]([O:11][CH3:12])=[O:10].[O:23]1[CH:27]=[CH:26][CH:25]=[C:24]1B(O)O.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[Cl:1][C:2]1[N:3]=[C:4]([CH3:22])[N:5]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:24]3[O:23][CH:27]=[CH:26][CH:25]=3)=[CH:16][C:15]=2[Cl:21])[C:6]=1/[CH:7]=[CH:8]/[C:9]([O:11][CH3:12])=[O:10]
Reactant: OB(O)c1ccco1
Reactant: COC(=O)/C=C/c1c(Cl)nc(C)n1Cc1ccc(I)cc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)/C=C/c1c(Cl)nc(C)n1Cc1ccc(-c2ccco2)cc1Cl
Temperature: 80 °C
Reaction time: 4 h
Yield: 110.7 %

Procedure:
A mixture of tetrakis(triphenylphosphine)palladium(0) (89 mg), methyl (E)-3-(4-chloro-1-(2-chloro-4-iodobenzyl)-2-methylimidazol-5-yl)-2-propenate (350 mg), 2-furylboronic acid (135 mg), potassium carbonate powder (321 mg) and N,N-dimethylformamide (3.5 ml) was stirred under a nitrogen atmosphere at 80° C. for 4 hr. The reaction mixture was allowed to cool to room temperature and water was added. The precipitate was collected by filtration. The precipitate was dissolved in chloroform, washed successively with saturated aqueous sodium hydrogencarbonate solution and saturated brine, and dried over magnesium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography (chloroform/ethyl acetate=10/1) to give methyl (E)-3-(4-chloro-1-(2-chloro-4-(2-furyl)benzyl)-2-methylimidazol-5-yl)-2-propenate (336 mg) as a pale-yellow powder.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:26])([F:25])[O:5][C:6]1[CH:7]=[C:8]([C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]([F:24])([F:23])[F:22])[CH:15]=2)=O)[CH:9]=[CH:10][CH:11]=1.[CH2:27](P(=O)(OCC)OCC)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.O>C1COCC1.C1OCCOCCOCCOCCOC1>[C:28]1([CH:27]=[C:12]([C:14]2[CH:15]=[C:16]([O:20][C:21]([F:24])([F:23])[F:22])[CH:17]=[CH:18][CH:19]=2)[C:8]2[CH:7]=[C:6]([O:5][C:4]([F:26])([F:25])[F:3])[CH:11]=[CH:10][CH:9]=2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CCOP(=O)(Cc1ccccc1)OCC
Reactant: O=C(c1cccc(OC(F)(F)F)c1)c1cccc(OC(F)(F)F)c1
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: FC(F)(F)Oc1cccc(C(=Cc2ccccc2)c2cccc(OC(F)(F)F)c2)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 52.6 %

Procedure:
To a suspension of NaH (60% in oil, 0.24 g, 6 mmol) in dry THF (25 mL) under nitrogen was added 15-crown-5 (0.06 g). The suspension was cooled in an ice bath. Bis(3-(trifluoromethoxy)phenyl)methanone (2.10 g, 6 mmol) and diethyl benzylphosphonate (1.37 g, 6 mmol) were dissolved in THF (12 mL) and added to the suspension. The reaction mixture was stirred at ice bath temperature for 15 min, allowed to warm to rt and stirred overnight. The reaction mixture was poured into water and extracted with ether (2×). The combined ether layers were washed with 10% NaHSO3, sat. NaCl, dried over K2CO3, filtered and purified by ISCO using a gradient of 0-4% EtOAc/hexanes as eluent to give 3,3′-(2-phenylethene-1,1-diyl)bis((trifluoromethoxy)benzene) as a colorless oil (1.34 g, 53% yield). 1H NMR (400 MHz, CDCl3) δ ppm 7.33 (m, 2H), 7.2-7.1 (m, 8H), 7.04 (s, 1H), 7.0-6.97 (m, 3H).
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.CCCCCC.[Br:25][CH:26]([CH3:30])[C:27](Br)=[O:28].C(=O)([O-])O.[Na+]>O1CCCC1.C(OCC)(=O)C>[Br:25][CH:26]([CH3:30])[C:27]([N:9]1[C@@H:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:12][O:11][C:10]1=[O:13])=[O:28]
Reactant: O=C1N[C@@H](Cc2ccccc2)CO1
Reactant: CC(Br)C(=O)Br
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(Br)C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Reaction time: 0.17 h
Yield: 47.3 %

Procedure:
To a solution of (4S)-4-benzyloxazolidin-2-one (0.164 g; 0.927 mmol) in dry tetrahydrofuran (3.8 ml), a 1.62 N solution of n-butyl lithium in hexane (0.571 ml; 0.927 mmol) was added at 0° C., and then 2-bromopropionyl bromide (0.106 ml; 1.01 mmol) was added at the same temperature. After 10 minutes, an aqueous solution of saturated sodium hydrogen carbonate (1 ml) was added to decompose the excess reaction agent. The reaction mixture was diluted with ethyl acetate, washed with brine and dried over anhydrous magnesium sulfate. After distilling off the solvent, the resulting solid was purified by silica gel chromatography (hexane:dichloromethane=2:3-0:1) to give a less polar (4S)-3-(2'-bromopropionyl)-4-benzyloxazolidin-2-one (0.137 g, yield, 47%) and a (4S)-3-(2'-bromopropionyl)-4-benzyloxazolidin-2-one (0.145 g, yield, 50%).
Reaction SMILES: [NH2:1][C@H:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]([CH3:19])[C:3]1=[O:20].[Cl:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]=[C:29]=[O:30]>O1CCCC1>[CH3:19][N:4]1[C:5]2[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=2[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:8][C@H:2]([NH:1][C:29]([NH:28][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[Cl:21])=[O:30])[C:3]1=[O:20]
Reactant: O=C=Nc1ccccc1Cl
Reactant: CN1C(=O)[C@@H](N)N=C(c2ccccc2)c2ccccc21
Solvent: C1CCOC1
Product: CN1C(=O)[C@@H](NC(=O)Nc2ccccc2Cl)N=C(c2ccccc2)c2ccccc21
Reaction time: 8 h

Procedure:
Equimolar amounts of 3(S)-(-)-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one and 2-chlorophenylisocyanate were mixed in 8 ml of dry tetrahydrofuran at room temperature. The reaction mixture was allowed to stand for 8 hours and was then filtered. The collected solids were washed with tetrahydrofuran and dried in vacuo over P2O5 to give the analytical product: m.p. 212°-214° C.
Reaction SMILES: C[O:2][C:3]([C:5]1([NH:12][C:13](=[O:32])[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH2:23][CH2:24][C:25]3[CH:26]=[C:27]([CH3:31])[CH:28]=[CH:29][CH:30]=3)[CH:15]=2)[CH2:10][CH:9]2[O:11][CH:6]1[CH2:7][CH2:8]2)=[O:4].[OH-].[Na+]>CO.O>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([C:13]([NH:12][C:5]2([C:3]([OH:4])=[O:2])[CH2:10][CH:9]3[O:11][CH:6]2[CH2:7][CH2:8]3)=[O:32])=[CH:15][C:16]=1[O:22][CH2:23][CH2:24][C:25]1[CH:26]=[C:27]([CH3:31])[CH:28]=[CH:29][CH:30]=1
Reactant: COC(=O)C1(NC(=O)c2ccc(OC)c(OCCc3cccc(C)c3)c2)CC2CCC1O2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1ccc(C(=O)NC2(C(=O)O)CC3CCC2O3)cc1OCCc1cccc(C)c1
Temperature: 40 °C
Reaction time: 5 h
Yield: 65.6 %

Procedure:
630 mg of 2-[4-methoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-7-oxa-bicyclo[2.2.1]heptane-2-carboxylic acid methyl ester was dissolved in 10 ml of methanol, and 2.2 ml of a 1 N solution of sodium hydroxide in water were added at room temperature. The mixture was stirred at 40° C. for 5 h, then another 1.1 ml of a 1 N solution of sodium hydroxide in water were added and the mixture stirred at 40° C. for another 4 h. The mixture was then diluted with 40 ml of water, the methanol was evaporated, the pH adjusted to 2 and the mixture stirred at room temperature of 1 h. The precipitated product was filtered off and dried in vacuo to yield 400 mg of 2-[4-methoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-7-oxa-bicyclo[2.2.1]heptane-2-carboxylic acid as a racemic mixture of (1R,2S,4S)-2-[4-methoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-7-oxa-bicyclo[2.2.1]heptane-2-carboxylic acid and (1S,2R,4R)-2-[4-methoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-7-oxa-bicyclo[2.2.1]heptane-2-carboxylic acid.
Reaction SMILES: [C:1]([N:8]([CH3:20])[C@H:9]([C:17]([OH:19])=O)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CN1CCOCC1.C(OC(Cl)=O)C(C)C.[NH:36](Cl)[C@H:37]([C:42]([O:44][CH3:45])=[O:43])[CH2:38][CH:39]([CH3:41])[CH3:40]>C1COCC1.CN(C=O)C.C(OC(=O)C)C>[C:1]([N:8]([CH3:20])[C@H:9]([C:17]([NH:36][C@H:37]([C:42]([O:44][CH3:45])=[O:43])[CH2:38][CH:39]([CH3:41])[CH3:40])=[O:19])[CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: COC(=O)[C@H](CC(C)C)NCl
Reactant: CN(C(=O)OC(C)(C)C)[C@@H](Cc1ccccc1)C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)[C@H](CC(C)C)NC(=O)[C@H](Cc1ccccc1)N(C)C(=O)OC(C)(C)C
Reaction time: 0.08 h

Procedure:
To a solution of 28 g of Boc-MePhe-OH and 11.2 ml of N-methylmorpholine in 400 ml of THF are added 13.2 ml of chloroformic acid isobutyl ester at -25°. After 5 minutes, at -25°, 18 g of HCl-Leu-OMe and 11.2 ml of N-methylmorpholine in 200 ml of DMF are added to the solution. After 2 hours, at -15°, the mixture is diluted with ethylacetate, washed with dilute aqueous KHCO3 solution, hydrochloric acid, water, dried and the solvent removed under vacuum to yield the title compound as a viscous oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:9][CH3:10])=[N:4][CH:5]=[CH:6][C:7]=1Cl.[Cl:11][C:12]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:13]=1[CH:14]=[C:15]1[CH2:20][CH2:19][CH:18]([NH2:21])[CH2:17][CH2:16]1.[Cl-].[NH4+].C(=O)(O)[O-].[Na+]>CN1CCCC1=O>[Cl:1][C:2]1[C:3]([CH2:9][CH3:10])=[N:4][CH:5]=[CH:6][C:7]=1[NH:21][CH:18]1[CH2:17][CH2:16][C:15](=[CH:14][C:13]2[CH:22]=[CH:23][C:24]([Cl:26])=[CH:25][C:12]=2[Cl:11])[CH2:20][CH2:19]1
Reactant: CCc1nccc(Cl)c1Cl
Reactant: NC1CCC(=Cc2ccc(Cl)cc2Cl)CC1
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN1CCCC1=O
Product: CCc1nccc(NC2CCC(=Cc3ccc(Cl)cc3Cl)CC2)c1Cl
Yield: 7 %

Procedure:
1.6 g of 3,4-dichloro-2-ethylpyridine and 2.5 g of 4-(2,4-dichlorobenzylidene)cyclohexylamine are heated at 180° C. for 3.5 hours together with 55 g of ammonium chloride in 9 ml of N-methylpyrrolidone. After cooling, the mixture is poured into saturated sodium bicarbonate solution and extracted with ethyl acetate. The product is purified by chromatography on silica gel using ethyl acetate/heptane 1:4. Yield: 7%
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[Cl:13][C:14]1[CH:15]=[C:16]([CH:21]([NH2:23])[CH3:22])[CH:17]=[CH:18][C:19]=1[Cl:20].[F:24][C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=1)[C:28](O)=[O:29]>CN(C)C1C=CN=CC=1.ClCCl>[Cl:13][C:14]1[CH:15]=[C:16]([CH:21]([NH:23][C:28](=[O:29])[C:27]2[CH:31]=[CH:32][CH:33]=[C:25]([F:24])[CH:26]=2)[CH3:22])[CH:17]=[CH:18][C:19]=1[Cl:20]
Reactant: CC(N)c1ccc(Cl)c(Cl)c1
Reactant: O=C(O)c1cccc(F)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CC(NC(=O)c1cccc(F)c1)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 143.8 mg (0.75 mmol) N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC.HCl) and 91.6 mg (0.75 mmol) 4-dimethylaminopyridine (DMAP) in 1.5 ml dichloromethane were added 142 mg (0.75 mmol) rac-1-(3,4-dichloro-phenyl)-ethylamine and the solution stirred at ambient temperature for 5 min. To this solution were added 70 mg (0.5 mmol) 3-fluoro-benzoic acid and the mixture stirred at ambient temperature for 5 hours.
Reaction SMILES: [CH3:1][N:2]([S:15]([C:18]1[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=1)(=[O:17])=[O:16])[C@H:3]1[CH2:8][CH2:7][C@H:6]([O:9][CH2:10][CH2:11][C:12]([OH:14])=O)[CH2:5][CH2:4]1.[CH3:28][N:29]([CH3:34])[CH2:30][CH2:31][NH:32][CH3:33].CN1CCOCC1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl>[CH3:28][N:29]([CH3:34])[CH2:30][CH2:31][N:32]([CH3:33])[C:12](=[O:14])[CH2:11][CH2:10][O:9][C@H:6]1[CH2:7][CH2:8][C@H:3]([N:2]([CH3:1])[S:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:26])([F:27])[F:25])=[CH:20][CH:19]=2)(=[O:16])=[O:17])[CH2:4][CH2:5]1
Reactant: CNCCN(C)C
Reactant: CN([C@H]1CC[C@H](OCCC(=O)O)CC1)S(=O)(=O)c1ccc(C(F)(F)F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CN(C)CCN(C)C(=O)CCO[C@H]1CC[C@H](N(C)S(=O)(=O)c2ccc(C(F)(F)F)cc2)CC1
Temperature: 0 °C
Reaction time: 48 h

Procedure:
120 mg (0.29 mmol) of trans-3-{4-[methyl-(4-trifluoromethyl-benzenesulfonyl)-amino]-cyclohexyloxy}-propionic acid in 3 mL of CH2Cl2 were treated with 0.057 mL (0.44 mmol, 1.5 eq) of N,N,N′-trimethylethylenediamine and 0.48 mL (0.36 mmol, 1.5 eq) of NMM. The solution was cooled to 0° C. and 73.0 mg (0.38 mmol, 1.3 eq) of EDCI and 9 mg (0.06 mmol, 0.2 eq) of HOBT were added. The mixture was stirred at RT for 2 days, partitioned between CH2Cl2 and a saturated aqueous solution of NaHCO3. The organic phase was washed with brine, dried over Na2SO4 and evaporated. Column chromatography with CH2Cl2:MeOH 9:1 gave 118 mg (82%) of trans-N-(2-dimethylamino-ethyl)-N-methyl-3-{4-[methyl-(4-trifluoromethyl-benzenesulfonyl)-amino]-cyclohexyloxy}-propionamide as colorless oil, MS: 494 (MH+).
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][CH:13]=[CH2:14])[CH:6]=1)(=O)C.[OH-].[Na+].CO>C1COCC1>[CH2:12]([O:11][C:7]1[CH:6]=[C:5]([OH:4])[CH:10]=[CH:9][CH:8]=1)[CH:13]=[CH2:14]
Reactant: C=CCOc1cccc(OC(C)=O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: C=CCOc1cccc(O)c1
Reaction time: 1 h

Procedure:
The product from Example 61A (7.19 g, 37.4 mmoles) in THF (30 mL) was treated with 4N NaOH (19 mL, 75 mmoles) and MeOH (5 mL). After one hour, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed with aqueous NH4Cl, brine, dried (Na2SO4), filtered, and the filtrate concentrated under reduced pressure to provide the title compound without further purification.
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([NH:11][C@H:12]([C:14]3[N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:18](=[O:26])[C:17]4=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]4[N:15]=3)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=1.[OH:39][C:40]1[CH:41]=[C:42]([NH:55][S:56]([CH3:59])(=[O:58])=[O:57])[CH:43]=[C:44](B2OC(C)(C)C(C)(C)O2)[CH:45]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O>[OH:39][C:40]1[CH:41]=[C:42]([NH:55][S:56]([CH3:59])(=[O:58])=[O:57])[CH:43]=[C:44]([C:2]2[C:10]3[C:9]([NH:11][C@H:12]([C:14]4[N:19]([C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)[C:18](=[O:26])[C:17]5=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]5[N:15]=4)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=3[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=2)[CH:45]=1
Reactant: CC1(C)OB(c2cc(O)cc(NS(C)(=O)=O)c2)OC1(C)C
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(Br)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(-c3cc(O)cc(NS(C)(=O)=O)c3)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Yield: 37 %

Procedure:
(S)-2-(1-((5-Bromo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (80 mg, 0.13 mmol) was treated with N-(3-hydroxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanesulfonamide (101 mg, 0.32 mmol), sodium carbonate (34 mg, 0.32 mmols) and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (8 mg, 0.01 mmol) using 1,2-dimethoxyethane (0.96 ml) and water (0.24 ml) as solvents according to the method described in Preparation 62. The residue was purified using SP1® Purification System (0% to 80%, hexane-ethyl acetate) to give 46 mg (37% yield, 76% purity) of the title compound.