Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[NH:7][C@H:8]([C:10](=O)[NH:11][C:12]1[C:13]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:25])=[N:14][CH:15]=[CH:16][CH:17]=1)[CH3:9])([CH3:4])([CH3:3])[CH3:2]>CC(O)=O>[C:1]([O:5][C:6](=[O:27])[NH:7][C@H:8]([C:10]1[N:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:25])[C:13]2=[N:14][CH:15]=[CH:16][CH:17]=[C:12]2[N:11]=1)[CH3:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccccc1Nc1ncccc1NC(=O)[C@H](C)NC(=O)OC(C)(C)C
Solvent: CC(=O)O
Product: Cc1ccccc1-n1c([C@H](C)NC(=O)OC(C)(C)C)nc2cccnc21
Temperature: 25 °C

Procedure:
A solution of [(S)-1-(2-o-tolylaminopyridin-3-ylcarbamoyl)ethyl]carbamic acid tert-butyl ester (2.51 mmol) in AcOH (20 mL) was heated at 70° C. for 6 h. After cooling to RT, the volatiles were removed under reduced pressure and the residue partitioned between DCM and a saturated aqueous solution of NaHCO3. The aqueous phase was extracted with DCM and the combined organic fractions washed with water, dried (Na2SO4) and concentrated in vacuo to afford [(S)-1-(3-o-tolyl-3H-imidazo[4,5-b]pyridin-2-yl)ethyl]carbamic acid tert-butyl ester as a brown oil (quantitative). To a solution of the compound thus obtained (2.51 mmol) in DCM (25 mL) was added TFA (10 mL) and the mixture stirred at RT for 15 min. The volatiles were removed in vacuo and the resulting residue dissolved in DCM and washed with a saturated aqueous solution of NaHCO3 (40 mL). The aqueous phase was further extracted with DCM (×3) and the combined organic fractions dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-8% 2M NH3/MeOH in DCM) to afford the title compound as an oil (340 mg, 54% over 3 steps). 1H NMR (CDCl3, 400 MHz): δ 8.33 (1H, d, J=4.83 Hz), 8.09 (1H, d, J=8.00 Hz), 7.52-7.37 (3H, m), 7.33-7.21 (2H, m), 4.08 (0.5H, q, J=6.75 Hz), 3.99 (0.5H, q, J=6.72 Hz), 2.02 (3H, s), 1.50 (1.5H, d, J=6.75 Hz), 1.41 (1.5H, d, J=6.75 Hz). Signals split due to presence of rotamers/tautomers.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[O:11])=[CH:4][CH:3]=1.[H-].[Na+].[CH:20](OCC)=[O:21]>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH:9]([C:10]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[O:11])[CH:20]=[O:21])=[CH:6][CH:7]=1
Reactant: O=C(CCc1ccc(Br)cc1)C1CCCCC1
Reactant: CCOC=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=CC(Cc1ccc(Br)cc1)C(=O)C1CCCCC1
Temperature: 25 °C

Procedure:
To a solution of 2.84 g 3-(4-bromophenyl)-1-cyclohexylpropan-1-one from Step B above in 50 mL anhydrous THF was added 1.15 g 60% sodium hydride followed by one 6.2 mL and five 3.2 mL portions of ethyl formate over one day. The resulting mixture was stirred at room temperature under nitrogen for another day. The solvent was removed under reduced pressure and the residue was partitioned between cold 0.1 N HCl and ether. The combined ether extract was washed with water (2×), 5% NaHCO3 (3×), water, and saturated brine, dried over anhydrous Na2SO4, and evaporated to give crude product as orange solid. It was purified on silica gel using 10˜15% EtOAc in hexanes to give the title compounds as pink oily solid. 1H NMR (CDCl3, 500 MHz) δ 15.43 (d, J=7.1 Hz, 1H), 8.01 (d, J=7.1 Hz, 1H), 7.43˜7.45 (m, 2H), 7.07 (d, J=8.3 Hz, 2H), 3.52 (s, 2H), 2.32 (tt, J=11.5 & Hz, 1H), 1.73˜1.77 (m, 2H), 1.63˜1.68 (m, 1H), 1.49˜1.53 (m, 2H), 1.39˜1.47 (m, 2H), 1.07˜1.25 (m, 4H).
Reaction SMILES: [Li]CCCC.[Cl:6][C:7]1[C:8](I)=[C:9]2[CH:15]=[CH:14][N:13]([Si:16]([CH:23]([CH3:25])[CH3:24])([CH:20]([CH3:22])[CH3:21])[CH:17]([CH3:19])[CH3:18])[C:10]2=[N:11][CH:12]=1.[CH2:27]([N:34]1[CH2:39][CH2:38][CH2:37][CH:36]([CH:40]=[O:41])[CH2:35]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C1COCC1>[CH2:27]([N:34]1[CH2:39][CH2:38][CH2:37][CH:36]([CH:40]([C:8]2[C:7]([Cl:6])=[CH:12][N:11]=[C:10]3[N:13]([Si:16]([CH:23]([CH3:25])[CH3:24])([CH:20]([CH3:22])[CH3:21])[CH:17]([CH3:19])[CH3:18])[CH:14]=[CH:15][C:9]=23)[OH:41])[CH2:35]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=CC1CCCN(Cc2ccccc2)C1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(I)c(Cl)cnc21
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(C(O)C3CCCN(Cc4ccccc4)C3)c(Cl)cnc21
Reaction time: 0.67 h
Yield: 99.8 %

Procedure:
A solution of n-BuLi (1.6 N in heptane, 8.62 mL, 13.8 mmol) was added dropwise to a solution of 5-chloro-4-iodo-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (5.00 g, 11.5 mmol, Adesis) in THF (135 mL) at about −78° C., keeping the temperature below about −70° C. After stirring for about 40 min, a solution of 1-benzylpiperidine-3-carbaldehyde (4.21 g, 20.7 mmol) in THF (15 mL) was added dropwise and the resulting mixture was stirred at about −75° C. for about 2 h. The reaction was quenched by dropwise addition of saturated aqueous NH4Cl (100 mL) and the THF was removed under reduced pressure. The aqueous phase was extracted into EtOAc (250 mL), washed with brine (200 mL), and concentrated to yield crude (1-benzylpiperidin-3-yl)(5-chloro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)methanol (5.88 g, quantitative) as a yellow oil that was used directly in the next step without further purification: LC/MS (Table 2, Method a) Rt=1.78 min; MS m/z: 512 and 514 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH2:12][O:13][C:14]3[CH:34]=[CH:33][C:17]4[O:18][CH2:19][C:20]5[C:27]([C:28]6[NH:32][N:31]=[N:30][N:29]=6)=[CH:26][CH:25]=[CH:24][C:21]=5[CH:22](O)[C:16]=4[CH:15]=3)=[N:9]2)=[CH:4][CH:3]=1.[SH:35][CH2:36][CH2:37][C:38]([OH:40])=[O:39]>>[C:38]([CH2:37][CH2:36][S:35][CH:22]1[C:21]2[CH:24]=[CH:25][CH:26]=[C:27]([C:28]3[NH:29][N:30]=[N:31][N:32]=3)[C:20]=2[CH2:19][O:18][C:17]2[CH:33]=[CH:34][C:14]([O:13][CH2:12][C:8]3[CH:7]=[CH:6][C:5]4[C:10](=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=4)[N:9]=3)=[CH:15][C:16]1=2)([OH:40])=[O:39]
Reactant: OC1c2cc(OCc3ccc4ccc(Cl)cc4n3)ccc2OCc2c(-c3nnn[nH]3)cccc21
Reactant: O=C(O)CCS
Product: O=C(O)CCSC1c2cc(OCc3ccc4ccc(Cl)cc4n3)ccc2OCc2c(-c3nnn[nH]3)cccc21

Procedure:
2-(7-Chloroquinolin-2-yl)methoxy-11-hydroxy-7-(tetrazol-5-yl)-6,11-dihydrodibenz[b,e]oxepine and 3-mercaptopropionic acid were used and reacted in the same manner as in Example 1 to obtain the title compound.
Reaction SMILES: I[C:2]1[C:3]2[C:26]3=[CH:27][C:6]([CH2:7][CH2:8][CH2:9][CH2:10][C:11]4[O:37][C:14]([NH:15][C@@H:16]([CH:34]([CH3:36])[CH3:35])[C:17](=[O:33])[N:18]5[CH2:28][C@H:21]([O:22][C:23]3=[N:24][CH:25]=1)[CH2:20][C@H:19]5[C:29]([O:31][CH3:32])=[O:30])=[N:13][N:12]=4)=[CH:5][CH:4]=2.[CH2:38]([Sn](CCCC)(CCCC)C=C)[CH2:39]CC>C1(C)C=CC=CC=1.CCOC(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>[CH:34]([C@@H:16]1[NH:15][C:14]2[O:37][C:11](=[N:12][N:13]=2)[CH2:10][CH2:9][CH2:8][CH2:7][C:6]2[CH:27]=[C:26]3[C:3](=[CH:4][CH:5]=2)[C:2]([CH:38]=[CH2:39])=[CH:25][N:24]=[C:23]3[O:22][C@H:21]2[CH2:28][N:18]([C@H:19]([C:29]([O:31][CH3:32])=[O:30])[CH2:20]2)[C:17]1=[O:33])([CH3:36])[CH3:35]
Reactant: COC(=O)[C@@H]1C[C@@H]2CN1C(=O)[C@H](C(C)C)Nc1nnc(o1)CCCCc1ccc3c(I)cnc(c3c1)O2
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: C=Cc1cnc2c3cc(ccc13)CCCCc1nnc(o1)N[C@@H](C(C)C)C(=O)N1C[C@@H](C[C@H]1C(=O)OC)O2
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To a 0.1 M solution of methyl (3R,5S,8S)-22-iodo-8-isopropyl-7-oxo-2,27-dioxa-6,9,11,12,24-pentaazapentacyclo[16.6.2.13,6.110,13.021,25]octacosa-1(24), 10,12,18,20,22,25-heptaene-5-carboxylate (Example 12, Step 2) in dry toluene was added tetrakis(triphenylphosphine)palladium(0) (0.05 eq.). N2 was bubbled through the reaction mixture for 5 minutes and tributylethenylstannane (1.5 eq) was added. The mixture was stirred at 100° C. for 1 h, allowed to cool to RT, diluted with EtOAc and washed with brine. The organic layer was separated, dried over Na2SO4, filtered and concentrated. The residue was purified on silica gel (20% to 40% EtOAc/PE) to give the compound as a white solid. MS (ES+) C28H33N5O5 requires: 519. Found: 520 (M+H+).
Reaction SMILES: Br[CH2:2][CH:3]1[O:7][C:6]([C:9]23[CH2:18][CH:13]4[CH2:14][CH:15]([CH2:17][CH:11]([CH2:12]4)[CH2:10]2)[CH2:16]3)([CH3:8])[O:5][C:4]1=[O:19].C1CCN2C(=NCCC2)CC1>C(OC(C)C)(C)C>[CH2:2]=[C:3]1[O:7][C:6]([C:9]23[CH2:16][CH:15]4[CH2:17][CH:11]([CH2:12][CH:13]([CH2:14]4)[CH2:18]2)[CH2:10]3)([CH3:8])[O:5][C:4]1=[O:19]
Reactant: CC1(C23CC4CC(CC(C4)C2)C3)OC(=O)C(CBr)O1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC(C)OC(C)C
Product: C=C1OC(C)(C23CC4CC(CC(C4)C2)C3)OC1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 14.6 %

Procedure:
A mixture obtained by dissolving 16.4 g of 5-bromomethyl-2-(1-adamantyl)-2-methyl-1,3-dioxolan-4-one in 80 ml of isopropyl ether was placed in a flask equipped with an agitator, a thermometer, a condenser and a dropping funnel. While cooling in an ice bath, 9.1 g (0.06 mol) of 1,8-diazabicyclo[5.4.0]-7-undecene diluted with 20 ml of isopropyl ether was added by drops into the solution over 1 hour, followed by stirring at room temperature for 2 hours. After completion of the stirring, the reaction solution was analyzed. As a result, it was found that the reaction solution contained only 1.8 g of 5-methylene-2-(1-adamantyl)-2-methyl-1,3-dioxolan-4-one (yield: 15%) and that 81% of the raw materials was decomposed into adamantyl methyl ketone.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:12]([O:13]C)=[N:11][C:10]2[C:5]1=[N:6][C:7]([O:16][CH2:17][CH2:18][CH2:19][CH3:20])=[N:8][C:9]=2[NH2:15].C(N(CC)CC)C.Cl[S:29]([C:32]1[CH:33]=[C:34]([CH2:38][C:39]([O:41][CH3:42])=[O:40])[CH:35]=[CH:36][CH:37]=1)(=[O:31])=[O:30]>C(#N)C>[NH2:15][C:9]1[N:8]=[C:7]([O:16][CH2:17][CH2:18][CH2:19][CH3:20])[N:6]=[C:5]2[C:10]=1[NH:11][C:12](=[O:13])[N:4]2[CH2:3][CH2:2][NH:1][S:29]([C:32]1[CH:33]=[C:34]([CH2:38][C:39]([O:41][CH3:42])=[O:40])[CH:35]=[CH:36][CH:37]=1)(=[O:31])=[O:30]
Reactant: COC(=O)Cc1cccc(S(=O)(=O)Cl)c1
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCN)c2n1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCNS(=O)(=O)c3cccc(CC(=O)OC)c3)c2n1

Procedure:
The compound obtained in Example 2-1 step (vii) (245 mg), triethylamine (0.13 ml) and methyl [3-(chlorosulfonyl)phenyl]acetate (217 mg) were dissolved in acetonitrile (5 ml) and the same manner to Example 2-13 step (iii) was conducted to give the titled compound as a white solid. Yield: 40 mg (9%); MS APCI+ve 479 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:16]([C:17]2[NH:21][C:20](=[O:22])[N:19]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[N:18]=2)=[CH:15][C:5]([CH2:6][NH:7][C:8](=[O:14])[C:9]([CH3:13])([CH3:12])[CH2:10]O)=[C:4]([F:30])[CH:3]=1.CCN(S(F)(F)[F:37])CC>C1COCC1>[Cl:1][C:2]1[C:16]([C:17]2[NH:21][C:20](=[O:22])[N:19]([C:23]3[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=3)[N:18]=2)=[CH:15][C:5]([CH2:6][NH:7][C:8](=[O:14])[C:9]([CH3:13])([CH3:12])[CH2:10][F:37])=[C:4]([F:30])[CH:3]=1
Reactant: CC(C)(CO)C(=O)NCc1cc(-c2nn(-c3ccc(Cl)cc3)c(=O)[nH]2)c(Cl)cc1F
Reactant: CCN(CC)S(F)(F)F
Solvent: C1CCOC1
Product: CC(C)(CF)C(=O)NCc1cc(-c2nn(-c3ccc(Cl)cc3)c(=O)[nH]2)c(Cl)cc1F
Temperature: 25 °C
Reaction time: 5.5 h
Yield: 8.7 %

Procedure:
To a solution of N-(4-chloro-5-(1-(4-chlorophenyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)-2-fluorobenzyl)-3-hydroxy-2,2-dimethylpropanamide (0.150 g, 0.330 mmol) in THF (5.0 mL), DAST (0.079 g, 0.495 mmol) was added at 0-5° C. and stirred at RT for 5-6 h. After completion of the reaction, the reaction mass was quenched with water and extracted with ethyl acetate. The organic layer was separated, concentrated and the obtained crude was purified with column chromatography using basic alumina by eluting with solution of 2% ammonia in 10.0% MeOH:DCM to afford 0.013 g of the desired product. 1H NMR (300 MHz, CDCl3): δ 1.13 (s, 6H), 4.32 (m, 3H), 4.46 (s, 1H), 7.55 (m, 2H), 7.69 (m, 2H), 7.94-7.97 (m, 2H), 8.31 (s, 1H), 12.61 (s, 1H); MS (m/z): 454.25 (M+H)+.
Reaction SMILES: [CH:1]([C:3]1[CH2:4][CH:5]([CH2:9][C:10]2[N:11]=[CH:12][NH:13][CH:14]=2)[CH2:6][CH2:7][CH:8]=1)=[CH2:2].NN.[OH2:17].OO>C(O)C>[CH2:1]([C:3]1[CH2:4][CH:5]([CH2:9][C:10]2[NH:11][C:12](=[O:17])[NH:13][CH:14]=2)[CH2:6][CH2:7][CH:8]=1)[CH3:2]
Reactant: O
Reactant: C=CC1=CCCC(Cc2c[nH]cn2)C1
Agent: NN
Agent: OO
Solvent: CCO
Product: CCC1=CCCC(Cc2c[nH]c(=O)[nH]2)C1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A mixture of NiCl2 (0.364 g, 2.81 mmol) in EtOH (20 mL) was reacted with NaBH4 (0.053 mg, 1.40 mmol) at rt for 15 m after saturation of the solution with hydrogen gas. Ethylene diamine (0.17 g, 2.81 mmol) was added followed by the alkynyl imidazol (Intermediate R15, 0.26 g, 1.40 mmol) at rt for 45 m under an atmosphere of hydrogen gas. The mixture was filtered, diluted with chloroform and subjected to an aqueous work-up. The residue was purified by chromatography on SiO2 to give 4-(3-vinyl-cyclohex-3-enylmethyl)-1H-imidazole (72%). To 4-(3-vinyl-cyclohex-3-enylmethyl)-1H-imidazole (0.09 g, 0.47 mmol) in ethanol (3 mL) at 0 EC was added H2NNH2—H2O (0.93 mL, 19.1 mmol) followed by H2O2 (30%) (0.488 g, 14.4 mmol) and the mixture was stirred for 45 m at 0 EC and an additional 6 h at rt. The reaction was quenched and the material was purified by an aqueous work-up. The imidazole compound was purified further by isolation of the fumaric acid salt. The fumarate was converted to the compound 4-(3-ethyl-cyclohex-3-enylmethyl)-1,3-dihydro-imidazol-2-one (Compound 59) by the applicable step of Method P.
Reaction SMILES: [C:1]([C:4]1[O:8][C:7]2[C:9](=[O:18])[C:10]3[C:15]([C:16](=[O:17])[C:6]=2[CH:5]=1)=[CH:14][CH:13]=[CH:12][CH:11]=3)(=[O:3])[CH3:2].[BH4-].[Na+]>CN(C=O)C.O>[OH:3][CH:1]([C:4]1[O:8][C:7]2[C:9](=[O:18])[C:10]3[C:15]([C:16](=[O:17])[C:6]=2[CH:5]=1)=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH3:2]
Reactant: CC(=O)c1cc2c(o1)C(=O)c1ccccc1C2=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(O)c1cc2c(o1)C(=O)c1ccccc1C2=O
Yield: 79.5 %

Procedure:
In a 250 ml beaker, 2 grams (8.3 mmoles) of 2-acetyl-naphtho[2,3-b]furan-4,9-dione (prepared in example 2 or 3) was dissolved in 40 ml of DMF with heating. To the solution with stirring, 1 gram (26.4 mmoles) of sodium borohydride in 10 ml of water was added. The mixture was stirred in open air for 30 minutes, then diluted by adding 250 ml of water. The resulting mixture was extracted with 100 ml of dichloromethane twice. The combined organic phase was washed with 200 ml of water, dried with anhydrous sodium sulfate, and evaporated to dryness. The residue was crystallized in ethyl acetate to yield 1.6 gram (6.6 mmoles) of pure product with overall yield 80%. Pure product was characterized by 1H NMR and mass spectrum. 1H NMR (in DMSO) δ 1.47 (d, J=7, 3H), 4.88 (m, 1H), 5.83 (d, J=5, 1H), 6.91 (s, 1H), 7.84-7.90 (m, 2H), 8.06-8.11 (m, 2H). Mass (M+H) is 243.
Reaction SMILES: [CH2:1](Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:9][OH:10]>>[CH3:9][O:10][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CO
Reactant: ClCc1ccccc1
Product: COCc1ccccc1
Reaction time: 1.5 h

Procedure:
A solution of 10.5 gm (0.03 mol) of diamine 15, 4.0 gm (0.03 mol) of benzyl chloride, and 15 gm of MeOH were charged to the flask and heated to reflux. After 1.5 hours, GC showed 5-10% benzyl present along with amine. The reaction was allowed to reflux overnight (ca. 15 hr). GC showed the benzyl chloride consumed and some amine still present. Benzyl methyl ether was formed as a by-product of the reaction. Excess amine and other residue was removed by vigorous washing of the crude product in ether. After rotary evaporation, 10 gm (70% crude yield) of Quat 5 was obtained.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[C:11]([O:15][C:16]([NH:18][C@H:19]([C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=1)[CH2:20][C:21](OC)=[O:22])=[O:17])([CH3:14])([CH3:13])[CH3:12].CO.Cl>ClCCl>[F:31][C:27]1[CH:26]=[C:25]([C@@H:19]([NH:18][C:16](=[O:17])[O:15][C:11]([CH3:13])([CH3:12])[CH3:14])[CH2:20][CH:21]=[O:22])[CH:30]=[CH:29][CH:28]=1
Reactant: COC(=O)C[C@H](NC(=O)OC(C)(C)C)c1cccc(F)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H](CC=O)c1cccc(F)c1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
Diisobutylaluminium hydride (1 M in dichloromethane, 39 ml, 39 mmol) was cooled to −78° C. and added dropwise to a solution of methyl (3S)-3-[(tert-butoxycarbonyl)amino]-3-(3-fluorophenyl)propanoate (WO0039125, p60, preparation 12) (5.4 g, 18.2 mmol) in dichloromethane (100 ml) at −78° C. The reaction was stirred for 30 minutes at −78° C., then methanol (50 ml, pre-cooled to −78° C.) was added. The reaction was stirred for 30 minutes, then 2 N hydrochloric acid (250 ml) added. The bi-phasic mixture was allowed to warm up to room temperature, the layers were separated, and the organic layer was dried (MgSO4), filtered and evaporated under reduced pressure to afford the title compound as a clear, colourless oil, 4.8 g.
Reaction SMILES: Cl[CH:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[C:3]([O:5][CH3:6])=[O:4].[SH:25][CH2:26][CH2:27][C:28]1[NH:32][N:31]=[N:30][N:29]=1.C(N(CC)CC)C>C(Cl)Cl>[CH2:13]([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[CH:2]([S:25][CH2:26][CH2:27][C:28]1[NH:32][N:31]=[N:30][N:29]=1)[C:3]([O:5][CH3:6])=[O:4])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCCCCCCCCCc1ccccc1C(Cl)C(=O)OC
Reactant: SCCc1nnn[nH]1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCc1ccccc1C(SCCc1nnn[nH]1)C(=O)OC
Reaction time: 18 h

Procedure:
A mixture of methyl 2-chloro-2-(2-dodecyl phenyl)acetate (0.615 g, 1.75 mmol), 5-(2-mercaptoethyl)-tetrazole (0.227 g, 1.75 mmol), and triethylamine (0.48 ml), 3.5 mmol) in 20 ml of methylene chloride was stirred 18 hours at 22° and the solvent was evaporated. The residue taken up in diethyl ether, washed with 1 N hydrochloric acid, dried and the solvent removed. The residue was chromatographed over a silica gel column. Impurities were eluted with ethyl acetate/hexane (1:3), and the product was eluted with methanol/ethyl acetate (1:19). Evaporation of the solvents from these fractions gave the desired product, 0.570 g (73%).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[OH:11].Cl[C:13]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[C:16]([CH3:22])=[CH:15][N+:14]=1[O-:23]>C1COCC1>[F:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[O:11][C:13]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[C:16]([CH3:22])=[CH:15][N+:14]=1[O-:23]
Reactant: Cc1c[n+]([O-])c(Cl)cc1[N+](=O)[O-]
Reactant: Oc1ccc(F)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1c[n+]([O-])c(Oc2ccc(F)cc2F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 55 %

Procedure:
To a suspension of sodium hydride (0.47 g, 60% in oil) in 50 mL of THF was added dropwise a solution of 1 mL of 2,4-difluorophenol in 10 mL of THF. The reaction mixture was stirred for one hour, and 2-chloro-5-methyl-4-nitropyridine-1-oxide (2.0 g) was added slowly. The resulting mixture was stirred at reflux for 8 hours and at room temperature overnight. The solvent was removed and the light yellow solid isolated by extraction with methylene chloride. Purification via chromatography (silica gel, ethyl acetate/hexane, 1:1) gave 1.65 g of 2-(2,4-difluorophenoxy)-5-methyl-4-nitropyridine-1-oxide (55% yield). Mass Spec. M+H=283.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:14]2([OH:21])[CH2:17][CH:16]([C:18](O)=[O:19])[CH2:15]2)[CH:5]=[CH:6][C:7]=1[CH2:8][N:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1.[CH2:22]([NH2:24])[CH3:23].C1COCC1.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.[OH-].[Na+]>CCOC(C)=O>[CH2:22]([NH:24][C:18]([CH:16]1[CH2:17][C:14]([C:4]2[CH:5]=[CH:6][C:7]([CH2:8][N:9]3[CH2:10][CH2:11][CH2:12][CH2:13]3)=[C:2]([Cl:1])[CH:3]=2)([OH:21])[CH2:15]1)=[O:19])[CH3:23]
Reactant: CCN
Reactant: O=C(O)C1CC(O)(c2ccc(CN3CCCC3)c(Cl)c2)C1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCNC(=O)C1CC(O)(c2ccc(CN3CCCC3)c(Cl)c2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 35 %

Procedure:
To a crude solution of intermediate 17, 3-(3-chloro-4-((pyrrolidin-1-yl)methyl)phenyl)-3-hydroxycyclobutanecarboxylic acid (˜30 mL, ˜34 mmol) was added 2.0M ethylamine in THF (34.5 mL, 69 mmol) and T3P (50% solution in EtOAc, 33 ml, 51.8 mmol). The resulting reaction mixture was stirred at RT for 1 hr and then 300 ml of 1N NaOH and 400 ml of EtOAc were added and the layers were separated. The aqueous layer was subjected to EtOAc extraction (2×500 ml) again and the combined organic layers were dried over MgSO4 and evaporated. The residue was purified by flash column chromatography using a 75M Biotage™ column, eluting with a gradient of 5%, 8%, 10%, 15% MeOH/CH2Cl2 with 0.25% NH4OH. The product containing fractions were collected and concentrated under reduced pressure to give the title compound (4.0 g, 35% yield). Rf=0.40 (15% MeOH/CH2Cl2+0.2% NH4OH), LRMS m/z Calcd for C15H25ClN2O2, 336.9, found. 337.4 (M+H) APCI; 1H-NMR (CDCl3) δ 7.54 (dd, J=8.3, 2.7 Hz, 1H), 7.49-7.45 (m, 1H), 7.33 (d, J=7.9 Hz, 1H), 6.52-6.35 (br m, 1H), 3.86 (s, 2H), 3.29-3.22 (m, 2H), 2.81-2.60 (m, 7H), 2.48 (d, J=8.3 Hz, 2H), 1.83 (br s, 4H), 1.11 (dt, J=7.3, 2.9 Hz, 3H); 13C-NMR (CDCl3) δ 176.7, 147.0, 134.2, 133.3, 131.4, 126.5, 123.8, 73.8, 73.9, 56.1, 54.1, 41.2, 35.0, 33.0, 23.6, 14.9.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:9].[CH2:10]([O:12][C:13](OCC)(OCC)OCC)[CH3:11]>C(OCC)(=O)C>[CH2:10]([O:12][C:13]1[NH:1][C:2]2[C:3]([CH3:9])=[CH:4][CH:5]=[CH:6][C:7]=2[N:8]=1)[CH3:11]
Reactant: Cc1cccc(N)c1N
Reactant: CCOC(OCC)(OCC)OCC
Solvent: CCOC(C)=O
Product: CCOc1nc2cccc(C)c2[nH]1
Temperature: 130 °C
Reaction time: 16 h
Yield: 78.5 %

Procedure:
2,3-Diaminotoluene (6.09 g, 49.8 mmol) and tetraethoxymethane (25 mL, 119 mmol) were mixed, and the mixture was stirred at 130° C. for 16 hr. The mixture was cooled to room temperature, diluted with ethyl acetate, washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=70/30) to give the title compound (6.89 g, 78%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][C:23]([O:39][CH2:40][CH3:41])=[C:24]([NH:27][C:28](=[O:38])[CH2:29]P(OCC)(OCC)=O)[CH:25]=3)[N:20]=[CH:19][C:18]=2[C:42]#[N:43])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C1(C)C=CC=CC=1.[CH3:61][N:62]1[CH2:66][CH2:65][CH2:64][C@@H:63]1[CH:67]=O>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][C:23]([O:39][CH2:40][CH3:41])=[C:24]([NH:27][C:28](=[O:38])/[CH:29]=[CH:67]/[C@H:63]4[CH2:64][CH2:65][CH2:66][N:62]4[CH3:61])[CH:25]=3)[N:20]=[CH:19][C:18]=2[C:42]#[N:43])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1
Reactant: CN1CCC[C@@H]1C=O
Reactant: CCOc1cc2ncc(C#N)c(Nc3ccc(OCc4ccccn4)c(Cl)c3)c2cc1NC(=O)CP(=O)(OCC)OCC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCOc1cc2ncc(C#N)c(Nc3ccc(OCc4ccccn4)c(Cl)c3)c2cc1NC(=O)/C=C/[C@H]1CCCN1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 19.7 %

Procedure:
N-[4-[[3-Chloro-4-(2-pyridylmethoxy)phenyl]amino]-3-cyano-7-ethoxy-6-quinolyl]-2-diethoxyphosphoryl-acetamide 1d (250 mg, 0.40 mmol) was dissolved in 10 mL of dry tetrahydrofuran in a dry ice bath, followed by dropwise addition of a solution of lithium bis(trimethylsilyl)amide (1 M) in toluene (440 μL, 0.44 mmol). The reaction mixture was stirred for 30 minutes, added dropwise with a solution of (2R)-1-methylpyrrolidine-2-carbaldehyde 5c (90 mg, 0.80 mmol) in 5 mL of tetrahydrofuran, and stirred for 30 minutes, then warmed up to room temperature and stirred for 12 hours. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography with elution system A to obtain the title compound (E)-N-[4-[[3-chloro-4-(2-pyridylmethoxy)phenyl]amino]-3-cyano-7-ethoxy-6-quinolyl]-3-[(2R)-1-methylpyrrolidin-2-yl]prop-2-enamide 5 (46 mg, yield 19.7%) as a yellow solid.