Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]3[N:15]=[C:16]([N:19]4[CH2:24][CH2:23][CH:22]([NH2:25])[CH2:21][CH2:20]4)[S:17][CH:18]=3)[CH:5]=[CH:4][C:3]1=2.[O:27]1[CH2:31][CH:28]1[CH2:29][OH:30]>CN(C=O)C>[CH3:1][C:2]1([CH3:26])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([C:14]3[N:15]=[C:16]([N:19]4[CH2:24][CH2:23][CH:22]([NH:25][CH2:31][CH:28]([OH:27])[CH2:29][OH:30])[CH2:21][CH2:20]4)[S:17][CH:18]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CC1(C)CCC(C)(C)c2cc(-c3csc(N4CCC(N)CC4)n3)ccc21
Reactant: OCC1CO1
Solvent: CN(C)C=O
Product: CC1(C)CCC(C)(C)c2cc(-c3csc(N4CCC(NCC(O)CO)CC4)n3)ccc21

Procedure:
150 mg (0.41 mmol) of 1-[4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)thiazol-2-yl]piperidin-4-ylamine were dissolved in 2 ml of DMF, and 27.4 μl (0.41 mmol) of 2,3-epoxy-1-propanol were added. The reaction mixture was irradiated in the microwave at 120° C. for 3 h and subsequently stripped off to dryness. The residue was purified by means of flash chromatography on silica gel.
Reaction SMILES: Br[C:2]1[CH:17]=[N:16][C:5]2[NH:6][C:7](=[O:15])[N:8]([CH2:10][CH2:11][N:12]([CH3:14])[CH3:13])[CH2:9][C:4]=2[CH:3]=1.[C:18]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])(=[O:21])[CH:19]=[CH2:20].C(N(C(C)C)C(C)C)C.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(#N)CC.CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:23]([O:22][C:18](=[O:21])/[CH:19]=[CH:20]/[C:2]1[CH:17]=[N:16][C:5]2[NH:6][C:7](=[O:15])[N:8]([CH2:10][CH2:11][N:12]([CH3:14])[CH3:13])[CH2:9][C:4]=2[CH:3]=1)([CH3:26])([CH3:25])[CH3:24]
Reactant: C=CC(=O)OC(C)(C)C
Reactant: CN(C)CCN1Cc2cc(Br)cnc2NC1=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(C)CCN1Cc2cc(/C=C/C(=O)OC(C)(C)C)cnc2NC1=O
Yield: 54 %

Procedure:
To a solution of 6-bromo-3-(2-dimethylamino-ethyl)-3,4-dihydro-1H-pyrido[2,3-d]pyrimidin-2-one (240 mg, 0.802 mmol) in propionitrile (16 mL) and DMF (4 mL) was added tert-butyl acrylate (0.46 mL, 3.2 mmol) and (i-Pr)2EtN (0.28 mL, 1.6 mmol), Pd(OAc)2 (18 mg, 0.080 mmol) and P(o-tol)3 (49 mg, 0.16 mmol). The mixture was degassed with Ar for 15 min. The mixture was heated to reflux overnight, and then allowed to cool. The dark solution was filtered through a pad of Celite. The filtrate was concentrated. Purification by column chromatography (silica gel, CH2Cl2/MeOH/Et3N, 94/5.5/0.5) gave the title compound (150 mg, 54%) as a pale-yellow solid: MS (ESI) m/e 347 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:42][CH3:43])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[S:13][CH:14]=[CH:15][N:16]=1)[CH:8]=[C:7]2[O:17][CH:18]1[CH2:36][CH:35]2[N:20]([C:21](=[O:41])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH:28]=[CH:29][CH:30]3[C:32]([C:38]([OH:40])=O)([NH:33][C:34]2=[O:37])[CH2:31]3)[CH2:19]1.C(C1N=C(C2C=C(OC3CC4N(C(=O)CCCCCCC=CC5C(C([NH:85][S:86]([CH:89]6[CH2:91][CH2:90]6)(=[O:88])=[O:87])=O)(NC4=O)C5)C3)C3C(=CC(OC)=CC=3)N=2)SC=1)(C)C>>[Br:1][C:2]1[C:3]([O:42][CH3:43])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[S:13][CH:14]=[CH:15][N:16]=1)[CH:8]=[C:7]2[O:17][CH:18]1[CH2:36][CH:35]2[N:20]([C:21](=[O:41])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH:28]=[CH:29][CH:30]3[C:32]([C:38]([NH:85][S:86]([CH:89]4[CH2:91][CH2:90]4)(=[O:88])=[O:87])=[O:40])([NH:33][C:34]2=[O:37])[CH2:31]3)[CH2:19]1
Reactant: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)O)CC5C=CCCCCCCC(=O)N4C3)cc(-c3nccs3)nc2c1Br
Reactant: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)NS(=O)(=O)C6CC6)CC5C=CCCCCCCC(=O)N4C3)cc(-c3nc(C(C)C)cs3)nc2c1
Product: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)NS(=O)(=O)C6CC6)CC5C=CCCCCCCC(=O)N4C3)cc(-c3nccs3)nc2c1Br

Procedure:
The title compound was prepared from 18-[8-bromo-7-methoxy-2-(thiazol-2-yl)-quinolin-4-yloxy]-2,15-dioxo-3,16-diazatricyclo[14.3.0.04,6]nonadec-7-ene-4-carboxylic acid (41) following the procedure reported for synthesis of N-[[18-[2-[4-(isopropyl)thiazol-2-yl]-7-methoxyquinolin-4-yloxy]-2,15-dioxo-3,16-diazatricyclo-[14.3.0.04,6]nonadec-7-en-4-yl]carbonyl](cyclopropyl)sulfonamide 11: m/z=773 (M+H)+. 1H NMR (CDCl3): 0.90-0.98 (m, 1H), 1.05-2.0 (m, 2H), 1.27-1.58 (m, 9H), 1.80-1.97 (m, 3H), 2.18-2.24 (m, 1H), 2.29-2.38 (m, 1H), 2.48-2.62 (m, 2H), 2.69-2.73 (m, 2H), 2.88-2.94 (m, 1H), 4.01 (d, J=11.8 Hz, 1H), 4.08 (s, 3H), 4.12 (dd, J=11.5 Hz, J=3.6 Hz, 1H), 4.61 (t, J=7.9 Hz, 1H), 5.00 (t, J=9.5 Hz, 1H), 5.47-5.60 (m, 1H), 5.70-5.77 (m, 1H), 6.69 (br s, 1H), 7.24 (d, J=9.2 Hz, 1H), 7.55 (d, J=3.2 Hz, 1H), 7.59 (s, 1H), 7.98 (d, J=3.2 Hz, 1H), 8.05 (d, J=9.2 Hz, 1H), 8.20 (br s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:17]=[CH:16][C:5]2[O:6][C:7]3[CH:14]=[C:13]([Br:15])[CH:12]=[CH:11][C:8]=3[CH:9]=[CH:10][C:4]=2[CH:3]=1>CCOC(C)=O.[Pt]>[Br:1][C:2]1[CH:17]=[CH:16][C:5]2[O:6][C:7]3[CH:14]=[C:13]([Br:15])[CH:12]=[CH:11][C:8]=3[CH2:9][CH2:10][C:4]=2[CH:3]=1
Reactant: Brc1ccc2c(c1)C=Cc1ccc(Br)cc1O2
Agent: [Pt]
Solvent: CCOC(C)=O
Product: Brc1ccc2c(c1)CCc1ccc(Br)cc1O2
Yield: 81.4 %

Procedure:
A solution of 2,7-dibromodibenzo[b,f]oxepine (10-2) (663 mg, 1.88 mmol) in EtOAc (40 mL) was degassed under N2. Pt/C 10% by wt (200 mg) was added and the reaction was evacuated and placed under H2 gas. After 2 h reaction mixture was degassed and filtered through Celite®545 (eluant EtOAc) and solvent was removed in vacuo to give a yellow oil. The compound was dissolved in petroleum ether and passed through a short pad of SiO2, eluting with isohexanes 400 mL. Solvent was removed in vacuo, to give 2,7-dibromo-10,11-dihydrodibenzo[b,f]oxepine (10-3) (542 mg, 81% yield) as a colorless oil. 1H NMR (CDCl3) δ 7.33-7.32 (1H, m), 7.29-7.24 (2H, m), 7.18-7.14 (1H, m), 7.04-6.96 (2H, m), 3.08 (4H, s) ppm.
Reaction SMILES: [C:1]1([C:7]2([C:10]3[N:15]=[C:14]4[S:16][C:17]([C:19]5[CH:20]=[C:21]6[C:25](=[CH:26][CH:27]=5)[N:24]([CH2:28][CH2:29][CH2:30][C:31]([O:33]C)=[O:32])[CH:23]=[CH:22]6)=[N:18][C:13]4=[CH:12][CH:11]=3)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[OH-].[Li+]>C1COCC1>[C:1]1([C:7]2([C:10]3[N:15]=[C:14]4[S:16][C:17]([C:19]5[CH:20]=[C:21]6[C:25](=[CH:26][CH:27]=5)[N:24]([CH2:28][CH2:29][CH2:30][C:31]([OH:33])=[O:32])[CH:23]=[CH:22]6)=[N:18][C:13]4=[CH:12][CH:11]=3)[CH2:9][CH2:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)CCCn1ccc2cc(-c3nc4ccc(C5(c6ccccc6)CC5)nc4s3)ccc21
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CCCn1ccc2cc(-c3nc4ccc(C5(c6ccccc6)CC5)nc4s3)ccc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Methyl 4-(5-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)-1H-indol-1-yl)butanoate (63 mg, 0.135 mmol) was dissolved in THF (1.3 mL) before lithium hydroxide, monohydrate (11 mg, 0.269 mmol) was added and stirred at ambient temperature for 3 h. The reaction mixture was concentrated, acidified with 2 N HCl, filtered, washed with water, and dried in a vacuum oven to give the title compound. MS (ESI) m/z: Calculated: 453.2; Observed: 453.8 (M++H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6](B(O)O)[CH:7]=1.I[C:14]1[CH:15]=[C:16]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:18][CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>CO.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=2)[CH:7]=1
Reactant: COc1ccc(Br)cc1B(O)O
Reactant: O=[N+]([O-])c1cccc(I)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CO
Solvent: O
Product: COc1ccc(Br)cc1-c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 63 %

Procedure:
A suspension of 5-bromo-2-methoxyphenylboronic acid (500 mg, 2.17 mmol), 3-iodonitrobenzene (647 mg, 2.60 mmol), and potassium carbonate (599 mg, 4.33 mmol) in methanol (10 mL) and water (2 mL) was degassed for 30 min under a nitrogen stream followed by the addition of palladium(II) acetate (9.72 mg, 0.0433 mmol). The reaction was stirred at room temperature for 4 h. The methanol was removed under reduced pressure, ethyl acetate (50 mL) and water (50 mL) were added, and the biphasic suspension was filtered. The layers were separated and the organic was washed with water (50 mL). The aqueous washes were combined and extracted with ethyl acetate (2×50 mL), and the organic extracts combined. The organic solution was washed with water (3×50 mL), saturated aqueous sodium bicarbonate (50 mL), brine, dried over sodium sulfate, filtered, and the solvent removed under vacuum to give a crude brown gum. The product was purified by flash silica gel column chromatography (5% ethyl acetate in hexanes), and crystallized by dissolving in diethyl ether (20 mL) and hexanes (50 mL), removing one half of the solvent under vacuum, filtering and washing with hexanes (2×10 mL) to give I-207 (417.8 mg, 63% yield). 1H NMR (400 MHz, CDCl3) 8.38 (t, J=1.8 Hz, 1H), 8.21-8.19 (m, 1H), 7.81 (dt, J=7.5 Hz, 1.3 Hz, 1H), 7.58 (t, J=8.0 Hz, 1H), 7.50-7.45 (m, 2H), 6.90 (d, J=8.8 Hz, 1H), 3.82 (s, 3H) ppm.
Reaction SMILES: C([O:3][C:4](=[O:24])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]2[N:17]=[C:16]([C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)[CH:15]=[CH:14][N:13]=2)[CH:6]=1)C.C(OC(=O)C1C=CC(C)=C(NC2N=C(C3C=NC=CC=3)C=CN=2)C=1)C>>[N:20]1[CH:21]=[CH:22][CH:23]=[C:18]([C:16]2[CH:15]=[CH:14][N:13]=[C:12]([NH:11][C:7]3[CH:6]=[C:5]([CH:10]=[CH:9][CH:8]=3)[C:4]([OH:24])=[O:3])[N:17]=2)[CH:19]=1
Reactant: CCOC(=O)c1cccc(Nc2nccc(-c3cccnc3)n2)c1
Agent: CCOC(=O)c1ccc(C)c(Nc2nccc(-c3cccnc3)n2)c1
Product: O=C(O)c1cccc(Nc2nccc(-c3cccnc3)n2)c1

Procedure:
Utilising the procedure described in example 1c but employing 3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-benzoic acid ethyl ester in lieu of 4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-benzoic acid ethyl ester, afforded the title compound as a crystalline solid, m.p. 291-295° C.
Reaction SMILES: [F:1][CH:2]([F:29])[O:3][C:4]1[CH:5]=[C:6]([C:11]2[O:12][CH:13]=[C:14]([CH2:16][NH:17][C:18](=[O:28])[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[O:25][CH2:26][CH3:27])[N:15]=2)[CH:7]=[CH:8][C:9]=1[OH:10].[CH2:30](Br)[CH:31]=[CH2:32]>>[CH2:32]([O:10][C:9]1[CH:8]=[CH:7][C:6]([C:11]2[O:12][CH:13]=[C:14]([CH2:16][NH:17][C:18](=[O:28])[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[O:25][CH2:26][CH3:27])[N:15]=2)=[CH:5][C:4]=1[O:3][CH:2]([F:1])[F:29])[CH:31]=[CH2:30]
Reactant: CCOc1ccccc1C(=O)NCc1coc(-c2ccc(O)c(OC(F)F)c2)n1
Reactant: C=CCBr
Product: C=CCOc1ccc(-c2nc(CNC(=O)c3ccccc3OCC)co2)cc1OC(F)F

Procedure:
Using the compound obtained in Example 373 and allyl bromide, white powdery N-[2-(4-allyloxy-3-difluoromethoxyphenyl) oxazol-4-ylmethyl]-2-ethoxybenzamide was obtained following the procedure of Example 98.
Reaction SMILES: C(OC([C:8]1([CH2:19]/[CH:20]=[CH:21]\[CH2:22][CH3:23])[C:12](=[O:13])[CH:11]=[CH:10][CH:9]1[CH2:14][C:15]([O:17][CH3:18])=[O:16])=O)(C)(C)C.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>C1C=CC=CC=1>[CH3:18][O:17][C:15]([CH2:14][CH:9]1[CH:8]([CH2:19]/[CH:20]=[CH:21]\[CH2:22][CH3:23])[C:12](=[O:13])[CH:11]=[CH:10]1)=[O:16]
Reactant: CC/C=C\CC1(C(=O)OC(C)(C)C)C(=O)C=CC1CC(=O)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Product: CC/C=C\CC1C(=O)C=CC1CC(=O)OC

Procedure:
A 540 mg quantity of 5-tert-butoxycarbonyl-4-methoxycarbonylmethyl-5-(cis-2-pentenyl)-2-cyclopentenone and 10 mg of p-toluene sulfonic acid are dissolved in 20 ml of benzene, and the solution is refluxed for 20 minutes. The resulting reaction mixture is neutralized with sodium bicarbonate. The solvent is distilled off from the mixture, and the residue is distilled in a vacuum, giving 4-methoxycarbonylmethyl-5-(cis-2-pentenyl)-2-cyclopentenone (compound (1-a), R2 =CH3) in a yield of 91%, b.p. 88°-92° C./2.5 mm Hg.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH3:19])[C:7]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[C:8]([CH3:11])[C:9]=1Br)=[O:4].C(O)C.[NH2:23][S:24]([C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1)(=[O:26])=[O:25].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.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>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH3:19])[C:7]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[C:8]([CH3:11])[C:9]=1[C:30]1[CH:31]=[CH:32][C:27]([S:24](=[O:26])(=[O:25])[NH2:23])=[CH:28][CH:29]=1)=[O:4]
Reactant: COC(=O)c1c(Br)c(C)c(-c2ccc(Cl)cc2)n1C
Reactant: NS(=O)(=O)c1ccc(B(O)O)cc1
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: Cc1ccccc1
Solvent: CCO
Product: COC(=O)c1c(-c2ccc(S(N)(=O)=O)cc2)c(C)c(-c2ccc(Cl)cc2)n1C
Temperature: 25 °C
Yield: 69.5 %

Procedure:
To the solution of methyl-3-bromo-5-(4-chlorophenyl)-1,4-dimethyl-1H-pyrrole-2-carboxylate (compound 49β, 2.0 g, 5.84 mmol) in a mixture of toluene: ethanol (15:40 ml) was added 4-aminosulfonylbenzene boronic acid (1.41 g, 7.01 mmol) and potassium carbonate (2.42 g, 17.52 mmol) at 25° C. in a sealed tube and a nitrogen gas was bubbled through the resulting mixture for 15 minutes. To the reaction mixture was then added tetrakis(triphenylphosphine)palladium(0) (0.349 g, 0.29 mmol) under nitrogen and reaction mixture was heated at about 95 to about 100° C. for 15 hr under stirring. The progress of the reaction was monitored by TLC. The reaction mixture was then cooled to 25° C. and filtered through celite. The celite cake was washed with ethanol (100 ml) and ethyl acetate (50 ml). The combined filtrate was concentrated under reduced pressure to obtain a crude product, which was then purified by column chromatography over silica gel (100-200 mesh) using 40% ethyl acetate in hexanes as an eluent to obtain the title compound (1.7 g, 69.6%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@H:13]([OH:14])[C@@H:12]([OH:15])[C@H:11]([OH:16])[C@@H:10]([CH2:17][O:18][C:19]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[O:9]2)=[CH:4][C:3]=1[CH2:38][C:39]1[CH:44]=[CH:43][C:42]([O:45][CH2:46][CH3:47])=[CH:41][CH:40]=1.[H-].[Na+].[CH2:50](Br)[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1>CN(C=O)C.CCCC[N+](CCCC)(CCCC)CCCC.[I-].O>[CH2:50]([O:14][C@@H:13]1[C@@H:12]([O:15][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C@H:11]([O:16][CH2:38][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:2]=2)[C@@H:10]([CH2:17][O:18][C:19]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[O:9][C@H:8]1[C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([CH2:38][C:39]2[CH:40]=[CH:41][C:42]([O:45][CH2:46][CH3:47])=[CH:43][CH:44]=2)[CH:4]=1)[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1
Reactant: BrCc1ccccc1
Reactant: CCOc1ccc(Cc2cc([C@@H]3O[C@H](COC(c4ccccc4)(c4ccccc4)c4ccccc4)[C@@H](O)[C@H](O)[C@H]3O)ccc2Cl)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Agent: [I-]
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1ccc(Cc2cc([C@@H]3O[C@H](COC(c4ccccc4)(c4ccccc4)c4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)ccc2Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 178 %

Procedure:
To a solution of (2S,3R,4R,5S,6R)-2-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-6-trityloxymethyl-tetrahydro-pyran-3,4,5-triol (9.8 g, 15 mmole) in dry DMF (50 mL), sodium hydride (3.2 g, 67.8 mmole) was added at 0° C. and stirred at room temperature for 2 hours. Benzyl bromide (5.9 mL, 49.7 mmole), TBAI (500 mg) were added and the reaction mixture stirred at room temperature for 18 hours. The reaction mixture was diluted with water (500 mL) and extracted with DCM (2×500 mL). The crude product obtained after removal of solvent to furnish 12.3 g of (2S,3S,4R,5R,6R)-3,4,5-Tris-benzyloxy-2-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-6-trityloxymethyl-tetrahydro-pyran.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([Cl:22])=[C:6]([CH:21]=1)[C:7]([NH:9][CH2:10][C:11]12[CH2:20][CH:15]3[CH2:16][CH:17]([CH2:19][CH:13]([CH2:14]3)[CH2:12]1)[CH2:18]2)=[O:8].[CH2:23](C([Sn])=C(CCCC)CCCC)[CH2:24]CC.[F-].[Cs+]>C1(C)C=CC=CC=1.CC(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>[Cl:22][C:5]1[CH:4]=[CH:3][C:2]([CH:23]=[CH2:24])=[CH:21][C:6]=1[C:7]([NH:9][CH2:10][C:11]12[CH2:20][CH:15]3[CH2:16][CH:17]([CH2:19][CH:13]([CH2:14]3)[CH2:12]1)[CH2:18]2)=[O:8]
Reactant: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(Br)ccc1Cl
Reactant: CCCCC([Sn])=C(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: Cc1ccccc1
Solvent: CC(C)=O
Product: C=Cc1ccc(Cl)c(C(=O)NCC23CC4CC(CC(C4)C2)C3)c1
Temperature: 25 °C

Procedure:
A solution of 5-bromo-2-chloro-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)benzamide (prepared as described in WO 00/61569) (1.0 g), tetrakis(triphenylphosphine)palladium(0) (96 mg) and tributylvinyltin (1.15 mL) in toluene (15 mL) was heated at reflux for 3 hours, then cooled to room temperature, diluted with acetone (30 mL) and treated with cesium fluoride (10% aq, 10 mL) at room temperature for 2 hours. The resulting mixture was filtered through celite with further washing with toluene and concentrated. Water was added and the mixture was extracted with ethyl acetate. The combined organic phases were washed with water, dried over anhydrous magnesium sulfate and concentrated. The resulting oil was purified by column chromatography (ethyl acetate:isohexane 100:1 to 80:20) to give the sub-titled compound as a white solid (0.87 g).
Reaction SMILES: [CH:1]([N:4]([CH2:17][CH2:18][CH2:19][CH:20]=[CH2:21])[C:5]([NH:7][C@H:8]([C:13]([O:15]C)=[O:14])[C:9]([CH3:12])([CH3:11])[CH3:10])=[O:6])([CH3:3])[CH3:2].O.[Li+].[OH-]>O1CCOCC1>[CH:1]([N:4]([CH2:17][CH2:18][CH2:19][CH:20]=[CH2:21])[C:5]([NH:7][C@H:8]([C:13]([OH:15])=[O:14])[C:9]([CH3:12])([CH3:11])[CH3:10])=[O:6])([CH3:2])[CH3:3]
Reactant: C=CCCCN(C(=O)N[C@H](C(=O)OC)C(C)(C)C)C(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: C=CCCCN(C(=O)N[C@H](C(=O)O)C(C)(C)C)C(C)C
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution (0.1 M) of methyl N-{[isopropyl(pent-4-en-1-yl)amino]carbonyl}-3-methyl-L-valinate in a 1:1 mixture of water and dioxane, LiOH (4 eq) was added and the resulting mixture was stirred at room temperature for 6 h. The reaction mixture was then concentrated at reduced pressure and the crude residue was dissolved in EtOAc. The organic phase was washed with water. The aqueous phase was brought to pH=2 and re-extracted with EtOAc. After drying over Na2SO4 and evaporation of the volatiles, N-{[isopropyl(pent-4-en-1-yl)amino]carbonyl}-3-methyl-L-valine was recovered as a brownish solid (100%) and used without any further purification. LRMS (ESI) m/z 285 [(M+H)+; calcd for C15H29N2O3: 285.2].
Reaction SMILES: [Li]CCCC.C(NC(C)C)(C)C.[CH3:13][C:14]1[N:22]=[CH:21][CH:20]=[CH:19][C:15]=1[C:16]([OH:18])=[O:17].Br[CH2:24][CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=1.Cl>C1COCC1.O>[F:33][C:30]1[CH:31]=[CH:32][C:27]([CH2:26][CH2:25][CH2:24][CH2:13][C:14]2[N:22]=[CH:21][CH:20]=[CH:19][C:15]=2[C:16]([OH:18])=[O:17])=[CH:28][CH:29]=1
Reactant: Fc1ccc(CCCBr)cc1
Reactant: Cc1ncccc1C(=O)O
Agent: Cl
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cccnc1CCCCc1ccc(F)cc1
Temperature: -55 °C
Reaction time: 0.5 h
Yield: 94 %

Procedure:
4.4 ml (11.0 mmol, 2.5M in hexane) of BuLi solution were added dropwise at −10° C. to a solution of 1.54 ml (11.0 mmol) of diisopropylamine in THF (10 ml). Stirring was then carried out for a further 30 min at −10° C. This solution was added dropwise at −75° C. to a solution of 685 mg (5.0 mmol) of 2-methyl-nicotinic acid in THF (2 ml). Stirring was then carried out for 30 min at −75° C. and for 60 min at 0° C., followed by cooling to −55° C. At that temperature, 1.62 g (7.5 mmol) of 1-(3-bromopropyl)-4-fluorobenzene were added and the reaction solution was stirred for 1 h at −55° C. After warming to RT and stirring for a further 16 h at RT, water (30 ml) and conc. hydrochloric acid (3 ml) were added. Extraction with EA (2×30 ml) was then carried out. The combined organic phases were dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by means of CC (EA), yielding 1.28 g (4.7 mmol, 93%) of 2-(4-(4-fluorophenyl)butyl)-nicotinic acid.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:14]=[N:13][CH:12]=[CH:11][C:7]=1[C:8]([OH:10])=O)[CH:2]([CH3:4])[CH3:3].C(Cl)(=O)C(Cl)=O.Cl.[CH3:22][NH:23][O:24][CH3:25].N1C=CC=CC=1>ClCCl>[CH2:1]([O:5][C:6]1[CH:14]=[N:13][CH:12]=[CH:11][C:7]=1[C:8]([N:23]([O:24][CH3:25])[CH3:22])=[O:10])[CH:2]([CH3:3])[CH3:4]
Reactant: CNOC
Reactant: CC(C)COc1cnccc1C(=O)O
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CON(C)C(=O)c1ccncc1OCC(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 3-isobutoxyisonicotinic acid (2.2 g, 11.2 mmol) and oxalyl chloride (7 g, 55 mmol) in 25 mL of dichloromethane was stirred at room temperature for 1 h. The resulting solution was concentrated down under reduced pressure and the residue was re-dissolved in 50 mL of dichloromethane. To this solution were added N,O-dimethylhydroxyl-amine hydrochloride (4.5 g, 46.4 mmol) and pyridine (5 mL) at 0° C. The reaction was allowed to warm up to room temperature over 30 min period, and quenched with 2 mL of water. The resulting mixture was bacified with 1 mL 10% KOH solution (pH=10), the layers were separated, and the aqueous layer was washed twice with 20 mL portions of dichloromethane. The combined dichloromethane washes were dried over sodium sulfate, and concentrated down under reduced pressure, resulting in 1.8 g (67%) of 3-isobutoxy-N-methoxy-N-methylisonicotinamide. 1H-NMR (400 MHz, d6-DMSO): δ 8.46 (s, 1H), 8.25 (d, 1H), 7.45 (d, 1H), 3.96 (d, 2H), 3.43 (s, 3H), 2.76 (d, 3H), 2.05 (m, 1H), 0.94 (d, 6H). MS (EI) for C12H18N2O2: 239 (MH+).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:10]([OH:12])=O)=[N:4][C:5]([Cl:9])=[C:6]([NH2:8])[N:7]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[C:25]([O:29][C:30](=[O:36])[N:31]([CH2:33][CH2:34][NH2:35])[CH3:32])([CH3:28])([CH3:27])[CH3:26]>CN(C=O)C>[C:25]([O:29][C:30](=[O:36])[N:31]([CH2:33][CH2:34][NH:35][C:10]([C:3]1[C:2]([NH2:1])=[N:7][C:6]([NH2:8])=[C:5]([Cl:9])[N:4]=1)=[O:12])[CH3:32])([CH3:28])([CH3:26])[CH3:27]
Reactant: CN(CCN)C(=O)OC(C)(C)C
Reactant: Nc1nc(N)c(C(=O)O)nc1Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: CN(CCNC(=O)c1nc(Cl)c(N)nc1N)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 3,5-diamino-6-chloro-pyrazine-2-carboxylic acid (3.85 g, 20.5 mmol) in DMF (90 mL) is treated with CDI (6.64 g, 41 mmol) and stirred at RT for 1 h. To this mixture is added N-(2-aminoethyl)-N-methyl carbamic acid tert-butyl ester (5.0 g, 28.6 mmol) and stirring continues at RT for 72 h. The solvent is removed in vacuo and the residue is partitioned between EtOAc (100 mL) and water (60 mL). The organic portion is separated, dried (MgSO4) and concentrated in vacuo. The resulting yellow residue is washed with diethyl ether to afford the title compound which is used in the next step without further purification. [M+H]+ 345.