Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]([CH2:19][CH3:20])[CH2:4][CH2:5][N:6]1[C:15]2[C:10](=[CH:11][C:12]([N+:16]([O-])=O)=[CH:13][CH:14]=2)[CH2:9][CH2:8][CH2:7]1)[CH3:2].[H][H]>[Pd].C(O)C>[CH2:19]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][N:6]1[C:15]2[C:10](=[CH:11][C:12]([NH2:16])=[CH:13][CH:14]=2)[CH2:9][CH2:8][CH2:7]1)[CH3:20]
Reactant: CCN(CC)CCN1CCCc2cc([N+](=O)[O-])ccc21
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCN(CC)CCN1CCCc2cc(N)ccc21
Yield: 90.5 %

Procedure:
A suspension of N,N-diethyl-2-(6-nitro-3,4-dihydroquinolin-1(2H)-yl)ethanamine (0.85 g, 3.06 mmol) and palladium on charcoal, 10% wt (0.163 g, 0.153 mmol) in ethanol (30 mL) was stirred at room temperature under a balloon of hydrogen overnight. The mixture was filtered through a pad of celite. The celite pad was rinsed with 20 mL of methanol. The filtrate was concentrated and the residue was subjected to flash chromatography on silica gel using 5% 2M NH3 in methanol/95% CH2Cl2 to give a dark brown residue (685 mg, 90%). 1H-NMR (CDCl3) δ 6.63-6.32 (m, 3H), 3.37-3.23 (m, 4H), 2.74-2.56 (m, 8H), 1.93 (t, J=5.7 Hz, 2H), 1.08 (t, J=7.2 Hz, 6H). MS (ESI): 248.2 (M+1).
Reaction SMILES: [Br-].[C:2]([CH2:5][CH2:6][CH2:7][CH2:8][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:4])=[O:3].C([Li])CCC.CCCCCC.[CH2:39]([C:43]1[N:44]([CH2:50][C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][C:52]=2[Cl:57])[C:45]([CH:48]=O)=[CH:46][N:47]=1)[CH2:40][CH2:41][CH3:42]>O1CCCC1.O>[CH2:39]([C:43]1[N:44]([CH2:50][C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][C:52]=2[Cl:57])[C:45]([CH2:48][CH:8]=[CH:7][CH2:6][CH2:5][C:2]([OH:4])=[O:3])=[CH:46][N:47]=1)[CH2:40][CH2:41][CH3:42]
Reactant: CCCCc1ncc(C=O)n1Cc1ccccc1Cl
Reactant: O=C(O)CCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCCc1ncc(CC=CCCC(=O)O)n1Cc1ccccc1Cl
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 36.7 %

Procedure:
To a suspension of (4-carboxybutyl)triphenyl-phosphonium bromide (1.04 g, 2.35 mmol) in dry tetrahydrofuran (25 mL) at 0° C. under argon was added n-butyl lithium in hexane (1.8 mL of 2.5M, 4.6 mmol). The reaction mixture was stirred for 15 minutes at 0° C. and then a solution of 2-n-butyl-1-(2-chlorophenyl)methyl-1H-imidazol-5-carboxaldehyde [Example 6 (iii)] (0.5 g, 1.81 mmol) in tetrahydrofuran (25 mL) was added dropwise. The mixture was stirred an additional hour at 0° C. and then at ambient temperature for 3 days. Water was added and the mixture was extracted with diethyl ether. The aqueous layer was acidified to pH 3 with aqueous hydrochloric acid solution. The product was extracted into ethyl acetate, washed with water, dried, concentrated, and chromatographed over silica gel eluting with 5-10% methanol in methylene chloride to give 0.24 g of 6-[2-n-butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]-4-hexenoic acid.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][C:5]=1[N+:13]([O-])=O)[CH3:2]>C1COCC1.O.[Ni]>[NH2:13][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:4]=1[NH:3][CH2:1][CH3:2])[C:8]([OH:10])=[O:9]
Reactant: CCNc1ccc(C(=O)O)cc1[N+](=O)[O-]
Agent: [Ni]
Solvent: C1CCOC1
Solvent: O
Product: CCNc1ccc(C(=O)O)cc1N

Procedure:
A solution of 1.56 g (7.4 mmol) of the title A compound 4-ethylamino-3-nitro-benzoic acid in 60 mL of THF/water (2:1) is hydrogenated at 20 psi over 300 mg of Raney nickel for 18 h. The catalyst is removed by filtration through Celite and the solvent is removed under reduced pressure to give 3-amino-4-ethylamino-benzoic acid as a dark solid. This material is used as such in the next step.
Reaction SMILES: C([O:5][C:6](=[O:39])[CH2:7][N:8]1[C:17](=[O:18])[CH:16]([CH2:19][C:20]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[NH:22][CH:21]=2)[C:15]2[N:11]([C:12]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[N:13][N:14]=2)[C:10]2[CH:35]=[CH:36][CH:37]=[CH:38][C:9]1=2)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:22]1[C:23]2[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:20]([CH2:19][CH:16]2[C:15]3[N:11]([C:12]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[N:13][N:14]=3)[C:10]3[CH:35]=[CH:36][CH:37]=[CH:38][C:9]=3[N:8]([CH2:7][C:6]([OH:39])=[O:5])[C:17]2=[O:18])=[CH:21]1
Reactant: CC(C)(C)OC(=O)CN1C(=O)C(Cc2c[nH]c3ccccc23)c2nnc(-c3ccccc3)n2-c2ccccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CN1C(=O)C(Cc2c[nH]c3ccccc23)c2nnc(-c3ccccc3)n2-c2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.4 %

Procedure:
To a solution of [4-(1H-indol-3-ylmethyl)-5-oxo-1-phenyl-4,5-dihydro-2,3,6,10b-tetraaza-benzo[e]azulen-6-yl]-acetic acid tert-butyl ester (4.26 g, 8.19 mmol) in CH2Cl2 (27 mL) was added TFA (9.5 mL, 0.123 mmol). The reaction was stirred at room temperature for 8 hours and was concentrated in vacuo. The residue was dissolved in CH2Cl2 (50 mL) and Et2O (15 mL) and was stirred for 24 hours. The precipitate was filtered and was washed with Et2O to provide 2.33 g of [4-(1H-indol-3-ylmethyl)-5-oxo-1-phenyl-4,5-dihydro-2,3,6,10b-tetraaza-benzo[e]azulen-6-yl]-acetic acid. 1H NMR (DMSO-d6) δ 10.79 (s, 1H), 7.70 (d, 1H), 7.54-7.38 (m, 7H), 7.26 (d, 1H), 7.17 (m, 2H), 6.98 (t, 1H), 6.88 (m, 2H), 4.90 (d, 1H), 4.49 (d, 1H), 3.82 (t, 1H), 3.59 (m, 2H).
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@@H:11]1[O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@H:12]1[OH:13].[OH:20][CH2:21][CH2:22][NH:23][CH2:24][C:25]1[CH:30]=[C:29]([Cl:31])[CH:28]=[CH:27][C:26]=1[O:32][CH3:33].C(N(CC)CC)C>C(O)CCC>[OH:20][CH2:21][CH2:22][N:23]([CH2:24][C:25]1[CH:30]=[C:29]([Cl:31])[CH:28]=[CH:27][C:26]=1[O:32][CH3:33])[C:2]1[C:3]2[N:4]=[CH:5][N:6]([C:7]=2[N:8]=[CH:9][N:10]=1)[C@@H:11]1[O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@H:12]1[OH:13]
Reactant: OC[C@H]1O[C@@H](n2cnc3c(Cl)ncnc32)[C@H](O)[C@@H]1O
Reactant: COc1ccc(Cl)cc1CNCCO
Solvent: CCN(CC)CC
Solvent: CCCCO
Product: COc1ccc(Cl)cc1CN(CCO)c1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O

Procedure:
5.7 g. 6-Chloro-9-(β-D-ribofuranosyl)-purine, 6 g. N-(2-hydroxyethyl)-2-methoxy-5-chlorobenzylamine and 2.5 g. triethylamine were heated under reflux for 2 hours in 100 ml. n-butanol. Subsequently, the solvent was removed in a vacuum and the residue taken up in 100 ml. chloroform. The chloroform phase was washed several times with water, initially with the addition of some dilute hydrochloric acid and thereafter with a dilute solution of sodium bicarbonate. From the so purified chloroform solution, there crystallized out 4.9 g. (53% of theory) N(6)-(2-hydroxyethyl)-N(6)-(2-methoxy-5-chlorobenzyl)-adenosine, which melted at 98°-100°C.
Reaction SMILES: NC[C:3]1[CH:17]=[CH:16][C:6]([C:7]([NH:9]C2C=NC=CC=2)=[O:8])=[CH:5][CH:4]=1.O(C1N=CC(S(Cl)(=O)=O)=CC=1)C1C=CC=CC=1>N1C=CC=CC=1>[C:7]([NH2:9])(=[O:8])[C:6]1[CH:16]=[CH:17][CH:3]=[CH:4][CH:5]=1
Reactant: NCc1ccc(C(=O)Nc2cccnc2)cc1
Agent: O=S(=O)(Cl)c1ccc(Oc2ccccc2)nc1
Solvent: c1ccncc1
Product: NC(=O)c1ccccc1
Temperature: 20 °C
Reaction time: 16 h

Procedure:
A mixture of 4-(aminomethyl)-N-(3-pyridinyl)benzamide (33) (464 mg, 2.0 mmol) and 6-phenoxy-3-pyridinesulfonyl chloride (606 mg, 2.2 mmol) in dry pyridine (10 mL) was stirred at 20° C. for 16 h. The solvent was evaporated and the residue stirred in ice/water (20 mL) for 1 h. The precipitate was filtered, washed with water (5 mL) and dried. The crude solid was purified by column chromatography, eluting with a gradient (0-20%) of MeOH/EtOAc, to give benzamide I-3 (405 mg, 43%) as a white powder: mp (MeOH/EtOAc) 203-205° C.; 1H NMR δ 10.40 (s, 1H, CONH), 8.95 (d, J=2.4 Hz, 1H, H-2′), 8.61 (t, J=6.4 Hz, 1H, NHSO2), 8.42 (dd, J=2.5, 0.4 Hz, 1H, H-2″), 8.32 (dd, J=4.7, 1.4 Hz, 1H, H-6′), 8.21 (ddd, J=8.3, 2.5, 1.5 Hz, 1H, H-4′), 8.12 (dd, J=8.7, 2.5, 1H, H-6″), 7.90 (br d, J=8.3 Hz, 2H, H-2, H-6), 7.37-7.43 (m, 5H, H-3, H-5, H-3′″, H-5″), 7.25 (tt, J=7.4, 1.0 Hz, 1H, H-4″), 7.12-7.17 (m, 3H, H-5″, H-2′″, H-6″), 4.17 (d, J=6.4 Hz, 2H, CH2N); 13C NMR δ 165.4, 165.0, 152.9, 146.4, 144.5, 141.9, 141.4, 138.6, 135.8, 132.9, 132.1, 129.8 (2), 127.7 (2), 127.6 (2), 127.3, 125.3, 123.5, 121.5 (2), 111.5, 45.7; MS m/z 461.5 (MH+, 100%). Anal. calcd for C24H20N4O4: C, 62.60; H, 4.38; N, 12.17. Found: C, 62.48; H, 4.41; N, 12.14%.
Reaction SMILES: Cl[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([Cl:11])[S:10][C:5]=2[S:4](=[O:13])(=[O:12])[N:3]=1.[CH3:14][C:15]1([NH2:18])[CH2:17][CH2:16]1>>[Cl:11][C:9]1[S:10][C:5]2[S:4](=[O:13])(=[O:12])[N:3]=[C:2]([NH:18][C:15]3([CH3:14])[CH2:17][CH2:16]3)[NH:7][C:6]=2[CH:8]=1
Reactant: CC1(N)CC1
Reactant: O=S1(=O)N=C(Cl)Nc2cc(Cl)sc21
Product: CC1(NC2=NS(=O)(=O)c3sc(Cl)cc3N2)CC1
Yield: 25.6 %

Procedure:
A solution of 3,6-dichloro4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide (386 mg, 1.5 mmol) in 1-methylcyclopropylamine (1.0 g, 14 mmol) was stirred for 24 h at 85° C. in a sealed flask. The cooled solution was concentrated in vacuo and the residue was stirred with ethyl acetate (1-2 ml) and filtered. The white precipitate was stirred in 4M hydrochloric acid (5 ml) for 2 h and then filtered off and chromatographed on silica gel with ethyl acetate to give 112 mg (26%) of the pure title compound; mp 251-252° C. dec; 1H-NMR (DMSO-d6): δ0.65-0.79 (m, 4H), 1.36 (s, 3H), 7.11 (s, 1H), 7.82 (br s, 1H), 10.78 (br s, 1H); MS: m/e 291/293 (M+); (C9H10N3Cl1O2S2) calc. C, 37.05; H, 3.45; N, 14.40; found C, 36.96; H, 3.53; N, 14.15.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([N:16]2[CH2:21][CH2:20][O:19][CH:18]([CH3:22])[CH2:17]2)[CH:11]=1)[CH3:9])(C)(C)C.[ClH:24]>CO>[ClH:24].[CH3:22][CH:18]1[O:19][CH2:20][CH2:21][N:16]([C:12]2[CH:11]=[C:10]([C@@H:8]([NH2:7])[CH3:9])[CH:15]=[CH:14][CH:13]=2)[CH2:17]1
Reactant: CC1CN(c2cccc([C@H](C)NC(=O)OC(C)(C)C)c2)CCO1
Agent: Cl
Solvent: CO
Product: CC1CN(c2cccc([C@H](C)N)c2)CCO1

Procedure:
The solution of (S)-{1-[3-(2-methyl-morpholin-4-yl)-phenyl]-ethyl}-carbamic acid tert-butyl ester (2.62 g, 8.19 mmol), and hydrochloric acid (1.0M solution in diethyl ether) (12.3 ml, 3eq) in methanol (25 ml) was stirred at room temperature overnight. Concentrated under vacuum and 2.43 g of hydrochloric acid salt of (S)-1-[3-(2-methyl-morpholin-4-yl)-phenyl]-ethylamine was obtained as yellow solid (quantitative yield).
Reaction SMILES: P(C)(C)C.[N:5]([CH2:8][C:9]1[N:10]=[N:11][C:12]([C:15]2[C:20]([F:21])=[CH:19][CH:18]=[CH:17][C:16]=2[F:22])=[CH:13][CH:14]=1)=[N+]=[N-].[Si:23]([O:30][C@@H:31]1[C@@H:36]([CH3:37])[CH2:35][N:34]([C:38]2[CH:43]=[CH:42][N:41]=[CH:40][C:39]=2[N:44]=[C:45]=S)[CH2:33][C@H:32]1[NH:47][C:48](=[O:54])[O:49][C:50]([CH3:53])([CH3:52])[CH3:51])([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24]>C1COCC1.CCOC(C)=O>[Si:23]([O:30][C@@H:31]1[C@@H:36]([CH3:37])[CH2:35][N:34]([C:38]2[CH:43]=[CH:42][N:41]=[CH:40][C:39]=2[NH:44][C:45]2[N:10]3[N:11]=[C:12]([C:15]4[C:20]([F:21])=[CH:19][CH:18]=[CH:17][C:16]=4[F:22])[CH:13]=[CH:14][C:9]3=[CH:8][N:5]=2)[CH2:33][C@H:32]1[NH:47][C:48](=[O:54])[O:49][C:50]([CH3:53])([CH3:52])[CH3:51])([C:26]([CH3:27])([CH3:28])[CH3:29])([CH3:24])[CH3:25]
Reactant: C[C@H]1CN(c2ccncc2N=C=S)C[C@@H](NC(=O)OC(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Reactant: [N-]=[N+]=NCc1ccc(-c2c(F)cccc2F)nn1
Agent: CP(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C[C@H]1CN(c2ccncc2Nc2ncc3ccc(-c4c(F)cccc4F)nn23)C[C@@H](NC(=O)OC(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 71.6 %

Procedure:
PMe3 (1.0 M solution in THF) (0.95 mL, 0.95 mmol) was added dropwise to a solution of 3-(azidomethyl)-6-(2,6-difluorophenyl)pyridazine (Preparation I, 235 mg, 0.95 mmol) in THF (6.0 mL) at RT. The reaction turned purple and an evolution of gas was observed. The reaction was stirred for 15 min at RT. A solution of tert-butyl ((3R,4R,5S)-4-((tert-butyl(dimethyl)silyl)oxy)-1-(3-isothiocyanato-4-pyridinyl)-5-methyl-3-piperidinyl)carbamate (Preparation XIII, 455 mg, 0.95 mmol) in THF (5.0 mL) was added. After 15 min at RT, the mixture was diluted with EtOAc and washed with brine. The aqueous phase was extracted with EtOAc (2×). The combined organic layers were dried over anh. Na2SO4, filtered and concentrated. The crude material was purified by silica gel chromatography (0-3% MeOH in CH2Cl2) to provide tert-butyl ((3R,4R,5S)-4-((tert-butyl(dimethyl)silyl)oxy)-1-(3-((2-(2,6-difluorophenyl)imidazo[1,5-b]pyridazin-7-yl)amino)-4-pyridinyl)-5-methyl-3-piperidinyl)carbamate (450 mg, 0.68 mmol, 71% yield) as an orange solid. MS (ESI, pos. ion) m/z: 666.3 (M+1). 1H NMR (400 MHz, CDCl3) δ ppm 9.76 (s, 1 H), 8.21 (d, J=5.09 Hz, 1 H), 7.77 (d, J=9.39 Hz, 1H), 7.70 (br. s., 1 H), 7.34-7.47 (m, 2 H), 7.05 (t, J=8.12 Hz, 2 H), 6.93 (d, J=5.28 Hz, 1H), 6.51 (d, J=9.39 Hz, 1 H), 4.49 (br. s., 1 H), 3.67 (br. s., 1 H), 3.40 (d, J=10.76 Hz, 1H), 3.14-3.28 (m, 2 H), 2.81 (t, J=10.07 Hz, 1 H), 2.29 (t, J=11.15 Hz, 1 H), 1.89-2.03 (m, 1 H), 1.40 (br. s., 9 H), 0.93 (s, 12 H), 0.11 (d, J=11.15 Hz, 6 H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]2[CH2:13][N:14]([C:16]3[CH:17]=[N:18][CH:19]=[C:20]([CH:24]=3)[C:21](O)=[O:22])[CH2:15][C@H:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[S:25]1[CH:29]=[CH:28][CH:27]=[C:26]1[CH2:30][CH2:31][NH2:32]>>[S:25]1[CH:29]=[CH:28][CH:27]=[C:26]1[CH2:30][CH2:31][NH:32][C:21]([C:20]1[CH:24]=[C:16]([N:14]2[CH2:13][C@@H:11]3[CH2:12][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])[CH2:9][C@@H:10]3[CH2:15]2)[CH:17]=[N:18][CH:19]=1)=[O:22]
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2CN(c3cncc(C(=O)O)c3)C[C@@H]2C1
Reactant: NCCc1cccs1
Product: CC(C)(C)OC(=O)N1C[C@@H]2CN(c3cncc(C(=O)NCCc4cccs4)c3)C[C@@H]2C1

Procedure:
The product from Example 33B and thiophene-2-ethylamine were processed as described in Example 33C to provide the title compound. MS (APCI) m/z 443 (M+H)+.
Reaction SMILES: C([O:3][C:4](=[O:25])[CH2:5][C:6]1[CH:11]=[C:10]([O:12][CH2:13][CH2:14][O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[C:9]([F:23])=[CH:8][C:7]=1[Br:24])C.O[Li].O>CO>[Br:24][C:7]1[CH:8]=[C:9]([F:23])[C:10]([O:12][CH2:13][CH2:14][O:15][Si:16]([C:19]([CH3:20])([CH3:22])[CH3:21])([CH3:17])[CH3:18])=[CH:11][C:6]=1[CH2:5][C:4]([OH:25])=[O:3]
Reactant: CCOC(=O)Cc1cc(OCCO[Si](C)(C)C(C)(C)C)c(F)cc1Br
Agent: [Li]O
Solvent: O
Solvent: CO
Product: CC(C)(C)[Si](C)(C)OCCOc1cc(CC(=O)O)c(Br)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.5 %

Procedure:
To a solution of {2-bromo-5-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-4-fluoro-phenyl}-acetic acid ethyl ester (0.508 g, 1.16 mmol) in MeOH was added LiOH.H2O (0.036 g, 1.51 mmol). The mixture was stirred at room temperature for two hours, and then solvent was removed under reduced pressure. 2N NaOH was added to the residue, and the mixture was washed with diethyl ether. The aqueous phase was taken to pH 1 with 2N HCl and was extracted with EtOAc. The combined EtOAc extracts were washed with water, brine dried over MgSO4, filtered and concentrated to dryness under reduced pressure to yield {2-bromo-5-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-4-fluoro-phenyl}-acetic acid (0.352 g, 74%) as a white solid.
Reaction SMILES: [Na].[OH:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=O)=[CH:5][C:4]=1[CH2:13][O:14][CH3:15].[NH2:16][C:17]1([O:32][CH3:33])[C:23](=[O:24])[N:22]2[CH:18]1[S:19][C:20]([CH3:31])([CH3:30])[CH:21]2[C:25]([O:27][CH2:28][CH3:29])=[O:26].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([NH:16][C:17]2([O:32][CH3:33])[C:23](=[O:24])[N:22]3[CH:18]2[S:19][C:20]([CH3:30])([CH3:31])[CH:21]3[C:25]([O:27][CH2:28][CH3:29])=[O:26])=[O:12])=[CH:5][C:4]=1[CH2:13][O:14][CH3:15]
Reactant: CCOC(=O)C1N2C(=O)C(N)(OC)C2SC1(C)C
Reactant: COCc1cc(CC(=O)O)ccc1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: [Na]
Solvent: CN(C)C=O
Product: CCOC(=O)C1N2C(=O)C(NC(=O)Cc3ccc(O)c(COC)c3)(OC)C2SC1(C)C
Temperature: 0 °C
Reaction time: 3.5 h

Procedure:
Equivalent amouts (0.05 mole) of the sodium salt of 4-hydroxy-3-(methoxymethyl)benzeneacetic acid and 6-amino-6-methoxy-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]-heptane-2-carboxylic acid, ethyl ester, are added to dimethylformamide (DMF). The temperature is maintained at 0° C. Then about 1.2 equivalents of dicyclohexylcarbodiimide in DMF is added. The mixture is stirred at 0° C. for from 0.5 to 3 hours and an additional 2 to 5 hours at room temperature. Filtration of the reaction mixture removes the formed dicyclohexylurea. The filtrate is then diluted with chloroform, methylene chloride or ethyl acetate, washed with water, dried and evaporated to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C@@H:14]([O:15][CH2:16][C:17]3[CH:18]=[CH:19][C:20]4[O:25][CH2:24][CH2:23][N:22]([CH2:26][CH2:27][CH2:28][O:29][CH3:30])[C:21]=4[CH:31]=3)[CH2:13][N:12]([S:32]([C:35]3[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=3)(=[O:34])=[O:33])[C@H:11]([CH2:42][C:43]([CH3:48])([CH3:47])[C:44](O)=[O:45])[CH2:10]2)=[CH:5][CH:4]=1.[CH3:49][N:50]1[CH2:55][CH2:54][CH:53]([NH2:56])[CH2:52][CH2:51]1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C@@H:9]2[C@@H:14]([O:15][CH2:16][C:17]3[CH:18]=[CH:19][C:20]4[O:25][CH2:24][CH2:23][N:22]([CH2:26][CH2:27][CH2:28][O:29][CH3:30])[C:21]=4[CH:31]=3)[CH2:13][N:12]([S:32]([C:35]3[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=3)(=[O:33])=[O:34])[C@H:11]([CH2:42][C:43]([CH3:47])([CH3:48])[C:44]([NH:56][CH:53]3[CH2:54][CH2:55][N:50]([CH3:49])[CH2:51][CH2:52]3)=[O:45])[CH2:10]2)=[CH:7][CH:8]=1
Reactant: COCCCN1CCOc2ccc(CO[C@H]3CN(S(=O)(=O)c4ccc(C)cc4)[C@H](CC(C)(C)C(=O)O)C[C@@H]3c3ccc(OC)cc3)cc21
Reactant: CN1CCC(N)CC1
Product: COCCCN1CCOc2ccc(CO[C@H]3CN(S(=O)(=O)c4ccc(C)cc4)[C@H](CC(C)(C)C(=O)NC4CCN(C)CC4)C[C@@H]3c3ccc(OC)cc3)cc21

Procedure:
According to general procedure D, 196 mg of 3-[(2S,4R,5R)-4-(4-methoxy-phenyl)-5-[4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-1-(toluene-4-sulfonyl)-piperidin-2-yl]-2,2-dimethyl-propionic acid (from example 65b) and 37 mg of 1-methyl-piperidin-4-ylamine are used to afford the title compound as a colourless oil. Rf=0.24 (dichloromethane-methanol 10:1); Rt=4.47.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=O.[C:8]([CH2:10][C:11]([NH2:13])=[S:12])#[N:9]>CO>[C:8]([C:10](=[CH:6][C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)[C:11](=[S:12])[NH2:13])#[N:9]
Reactant: O=Cc1cccs1
Reactant: N#CCC(N)=S
Solvent: CO
Product: N#CC(=Cc1cccs1)C(N)=S
Temperature: 25 °C
Reaction time: 48 h
Yield: 85.8 %

Procedure:
To a solution of thiophene-2-carbaldehyde (20.0 g, 0.18 mol) and 2-cyanothioacetamide (17.8 g, 0.18 mol) in methanol (400 mL), was added neutral Al2O3 (106 g). The suspension was stirred at room temperature for 48 hrs, and then filtered. The solid was washed with methanol and the filtrates were combined and the solvent was then removed by evaporation to afford 2-cyano-3-thien-2-ylprop-2-enethioamide (30 g, 87%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][C@@H:8]([C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][C:14](Br)=[CH:15][CH:16]=2)[N:11]=1)[CH3:9])([CH3:4])([CH3:3])[CH3:2].[F:22][CH2:23][C:24]([CH2:30][F:31])([CH:28]=[CH2:29])[C:25]([OH:27])=[O:26].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:1]([O:5][C:6]([NH:7][C@@H:8]([C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][C:14](/[CH:29]=[CH:28]/[C:24]([CH2:30][F:31])([CH2:23][F:22])[C:25]([OH:27])=[O:26])=[CH:15][CH:16]=2)[N:11]=1)[CH3:9])=[O:21])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CC(CF)(CF)C(=O)O
Reactant: C[C@@H](NC(=O)OC(C)(C)C)c1ccc2ccc(Br)cc2n1
Agent: [Pd]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: C[C@@H](NC(=O)OC(C)(C)C)c1ccc2ccc(/C=C/C(CF)(CF)C(=O)O)cc2n1
Temperature: 60 °C
Yield: 100 %

Procedure:
A solution of [(R)-1-(7-bromo-quinolin-2-yl)-ethyl]-carbamic acid tert-butyl ester (105 mg, 0.3 mmol), 2,2-bis-fluoromethyl-but-3-enoic acid (50 mg, 0.33 mmol), tri(o-tolyl)phosphine (18 mg, 0.06 mmol) and triethylamine (91 mg, 0.13 mL, 0.9 mmol) in 1,4-dioxane (3 mL) was degassed with nitrogen for 15 min. Tris(dibenzylideneacetone)dipalladium(0) (28 mg, 0.03 mmol) was added and the reaction mixture was heated to 60° C. for 1 h. The reaction mixture was cooled to room temperature and the mixture was filtered through a hydrophobic frit and the filtrate was evaporated to afford crude (E)-4-[2-((R)-1-tert-butoxycarbonylamino-ethyl)-quinolin-7-yl]-2,2-bis-fluoromethyl-but-3-enoic acid (0.3 mmol) as a yellow gum. LCMS (m/z) 421.1 [M+H], Tr=2.27 min. A solution of crude (E)-4-[2-((R)-1-tert-butoxycarbonylamino-ethyl)-quinolin-7-yl]-2,2-bis-fluoromethyl-but-3-enoic acid (0.3 mmol), N,N-diisopropylethylamine (96 mg, 0.13 mL, 0.75 mmol), 4-(dimethylamino)-pyridine (73 mg, 0.6 mmol) and 2-methyl-6-nitrobenzoic anhydride (193 mg, 0.56 mmol) in anhydrous dichloromethane (5 mL) was stirred at 0° C. under nitrogen. A solution of (S)-1-[(S)-2-((S)-2-hydroxy-3-methyl-butyrylamino)-propionyl]-hexahydro-pyridazine-3-carboxylic acid 2,2,2-trichloro-ethyl ester (142 mg, 0.33 mmol) in dichloromethane (2 mL) was added and the reaction mixture was stirred at 0° C. for 30 min and then at room temperature for 18 h. The reaction mixture was diluted with dichloromethane and the solution was washed with ice-cold saturated sodium hydrogen carbonate solution, water, ice-cold hydrochloric acid (1 M), water and brine. The organic solution was filtered through a hydrophobic frit and the filtrate was evaporated. The residue was purified by silica gel chromatography using a gradient of iso-hexanes/ethyl acetate 2:1 to 0:1 to afford the partially purified title compound (26 mg, 10%) as a yellow gum. LCMS (m/z) 834.3, 836.2 [M+H], Tr=3.39 min.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[NH:14][C:15]([C:18]2[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[C:23]([Br:28])[CH:24]=3)[CH:19]=2)=[CH:16][N:17]=1)=O)(C)(C)C.Cl.O1CCOCC1.[CH3:36][O:37][C:38]([NH:40][CH:41]([CH:45]([CH3:47])[CH3:46])[C:42](O)=[O:43])=[O:39].P([O-])([O-])([O-])=O.[K+].[K+].[K+].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl>[CH3:36][O:37][C:38](=[O:39])[NH:40][CH:41]([C:42]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[NH:14][C:15]([C:18]2[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[C:23]([Br:28])[CH:24]=3)[CH:19]=2)=[CH:16][N:17]=1)=[O:43])[CH:45]([CH3:47])[CH3:46]
Reactant: COC(=O)NC(C(=O)O)C(C)C
Reactant: CC(C)(C)OC(=O)N1CCCC1c1ncc(-c2ccc3cc(Br)ccc3c2)[nH]1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1COCCO1
Solvent: ClCCl
Product: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc3cc(Br)ccc3c2)[nH]1)C(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.3 %

Procedure:
To 2-[5-(6-Bromo-naphthalen-2-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester (6.4 g, 14.4 mmol) was added HCl in dioxane (36 mL, 144 mmol). The suspension was allowed to stir at room temperature for three hours. Upon completion by LCMS, the reaction was concentrated to dryness and the crude product (assumed 14.4 mmol) was suspended in dichloromethane. 2-Methoxycarbonylamino-3-methylbutyric acid (3.8 g, 21.7 mmol) and solid potassium phosphate (28.94 mmol) were added to the slurry. HATU (6.88 g, 18.08 mL) was added and the reaction was stirred at room temperature for 18 hours. Upon completion, the crude reaction was filtered through a sintered glass funnel. The supernate was concentrated in vacuo and purified by normal phase silica gel chromatography (20-70% Ethyl acetate (with 10% MeOH) in Hexanes) to give (1-{2-[5-(6-Bromo-naphthalen-2-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (7.14 g, >90% yield) as a thick oil. LCMS-ESI+: calc'd for C24H27BrN4O3: 498.13 (M+); Found: 499.96 (M+H+).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:14](B3OC(C)(C)C(C)(C)O3)=[CH:13]N(CC(OC(C)(C)C)=O)N=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl.[C:33]([NH:37][NH2:38])([CH3:36])([CH3:35])[CH3:34]>>[CH3:34][C:33]([N:37]1[CH:13]=[CH:14][C:10]([C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)=[N:38]1)([CH3:36])[CH3:35]
Reactant: CC(C)(C)OC(=O)Cn1cc(B2OC(C)(C)C(C)(C)O2)c(-c2ccc([N+](=O)[O-])cc2)n1
Reactant: CC(C)(C)NN
Agent: Cl
Product: CC(C)(C)n1ccc(-c2ccc([N+](=O)[O-])cc2)n1

Procedure:
Following the procedure described for Intermediate 1 with t-butylhydrazine hydrochloride, provided the title compound as the minor isomer. ESMS (M-C(CH3)3+2H): 190.0; HNMR (400 MHz, d6-DMSO) δ 8.20 (d, 2H), 7.86 (d, 2H), 7.7 (d, 1H), 6.55 (d, 1H), 1.25 (s, 9H)