Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:16][C:15]3([CH3:18])[CH2:17][CH:11]2[CH2:12][C:13]([CH3:20])([CH3:19])[CH2:14]3)=[O:9])=[CH:4][CH:3]=1.[C:21](Cl)(=[O:24])[CH:22]=[CH2:23]>C1COCC1>[CH3:18][C:15]12[CH2:17][CH:11]([N:10]([C:8]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:21](=[O:24])[CH:22]=[CH2:23])=[CH:7][CH:6]=3)=[O:9])[CH2:16]1)[CH2:12][C:13]([CH3:20])([CH3:19])[CH2:14]2
Reactant: C=CC(=O)Cl
Reactant: CC1(C)CC2CC(C)(CN2C(=O)c2ccc(N)cc2)C1
Solvent: C1CCOC1
Product: C=CC(=O)Nc1ccc(C(=O)N2CC3(C)CC2CC(C)(C)C3)cc1
Reaction time: 0.75 h
Yield: 47.3 %

Procedure:
To a solution of (4-amino-phenyl)-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-methanone (3.0 g, 11.01 mmol) and TEA (3.1 ml, 22.03 mmol) in dry THF (40 ml) was added dropwise acryloyl chloride (1.07 ml, 13.22 mmol). The mixture was stirred for 45 min., the volatiles evaporated and to the residue added water 25 (ml). The aqueous phase was extracted with EtOAc (2×25 ml) and the combined organic phases were dried (Na2SO4), filtered and evaporated in vacuo. The residue was purified on column chromatography (silicagel) using EtOAc-Heptane 1:1 as eluent. Pure fractions were collected, the solvent evaporated in vacuo affording 1.7 g (47%) of N-[4-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-phenyl]-acrylamide as an oil.
Reaction SMILES: [CH3:1][S:2][C:3]1[S:4][C:5]2[CH:11]=[C:10]([C:12]#[N:13])[CH:9]=[CH:8][C:6]=2[N:7]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>C1COCC1>[CH3:1][S:2][C:3]1[S:4][C:5]2[CH:11]=[C:10]([CH2:12][NH2:13])[CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: CSc1nc2ccc(C#N)cc2s1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CSc1nc2ccc(CN)cc2s1
Temperature: 0 °C
Reaction time: 3 h
Yield: 34.3 %

Procedure:
To a solution of 2-(methylthio)benzo[d]thiazole-6-carbonitrile (10.0 g, 48.5 mmol) from Step 3 of this Example in THF (150 mL) was added lithium aluminum hydride solution (2.0 M in THF, 50.9 mL, 101.9 mmol) slowly at −78° C. The reaction mixture was slowly warmed to 0° C. and stirred at 0° C. for 3 h treated with 4 mL of water, 4 mL of 10% aq NaOH and 12 mL of water. The resulting reaction mixture was stirred at rt for 1 h before it was filtered through a Celite pad and the precipitates were washed with 100 of mL EtOAc. The combined filtrates were concentrated under reduced pressure. The crude product was purified on a silica gel column using a mixture of MeOH—CH2Cl2 (1:2, v/v) as eluent to give (2-(methylthio)benzo[d]thiazol-6-yl)methanamine as an yellow oil (3.5 g, 34%). 1H NMR (300 MHz, CDCl3) δ 7.82 (d, J=8.3 Hz, 1H), 7.73 (s, 1H), 7.35 (dd, J=1.4, 8.4 Hz, 1H), 3.97 (s, 2H), 2.79 (s, 3H), 1.55 (s, 2H). LCMS (ESI) m/z 211 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][C:8]([Cl:14])=[CH:9][CH:10]=2)[N:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:4]=1.[CH2:21]([N:28]1[C:33](=[O:34])[CH:32]=[CH:31][C:30]([C:35](O)=[O:36])=[CH:29]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[Cl:14][C:8]1[CH:7]=[C:6]2[C:11]([C:12](=[O:13])[C:3]([CH2:2][NH:1][C:35]([C:30]3[CH:31]=[CH:32][C:33](=[O:34])[N:28]([CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH:29]=3)=[O:36])=[CH:4][N:5]2[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[CH:10][CH:9]=1
Reactant: O=C(O)c1ccc(=O)n(Cc2ccccc2)c1
Reactant: NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O
Product: O=C(NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O)c1ccc(=O)n(Cc2ccccc2)c1

Procedure:
Benzyl-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid (7-chloro-4-oxo-1-phenyl-1,4-dihydro-quinolin-3-ylmethyl)-amide was prepared starting from intermediate D and 1-benzyl-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid. MS calcd. for C29H23ClN3O3 [(M+H)+] 496.1, obsd. 496.1.
Reaction SMILES: [Si:1]([N:8]1[C:11](=[O:12])[CH2:10][C@H:9]1[C:13]([OH:15])=[O:14])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Li+].[CH3:17]C([N-]C(C)C)C.CI>C1COCC1>[Si:1]([N:8]1[C:11](=[O:12])[C@H:10]([CH3:17])[C@H:9]1[C:13]([OH:15])=[O:14])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)[N-]C(C)C
Reactant: CC(C)(C)[Si](C)(C)N1C(=O)C[C@H]1C(=O)O
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: C[C@H]1C(=O)N([Si](C)(C)C(C)(C)C)[C@@H]1C(=O)O
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
To a solution of (S)-1-(tert-butyldimethylsilyl)-4-oxoazetidine-2-carboxylic acid 4 (2.00 g, 8.73 mmol.) in THF (30 ml) at −78° C. was added LDA (19 ml, 2.0 eq.). After the solution was stirred for 20 min. at −78° C., it was warmed to 0° C. for 5 min. The solution was re-cooled to −78° C. and methyl iodide (3.10 g, 2.5 eq.) in THF (5 ml) was added. The reaction solution was warmed up to room temperature, quenched with aqueous KHSO4 solution (10%, 30 ml), extracted with ethyl acetate (3×). The combined organic layers were washed with brine twice and dried with MgSO4. After concentrating in vacuo, 47 was obtained. H1NMR (CDCl3): 0.15, 0.35 (s, 6H), 1.14 (s, 9H), 1.35 (d, 3H), 3.71 (d, 1H), 4.14 (m, 1H). C11H21NO3Si, Mol. Wt.: 243.37. Found: 244 (M+1).
Reaction SMILES: ClC1N=CC2C(=CC=C(O)C=2)N=1.[Cl:13][C:14]1[C:23]([C:24]([F:27])([F:26])[F:25])=[N:22][C:21]2[C:16](=[CH:17][CH:18]=[C:19]([O:28]C)[CH:20]=2)[N:15]=1>>[Cl:13][C:14]1[C:23]([C:24]([F:26])([F:27])[F:25])=[N:22][C:21]2[C:16](=[CH:17][CH:18]=[C:19]([OH:28])[CH:20]=2)[N:15]=1
Reactant: COc1ccc2nc(Cl)c(C(F)(F)F)nc2c1
Agent: Oc1ccc2nc(Cl)ncc2c1
Product: Oc1ccc2nc(Cl)c(C(F)(F)F)nc2c1

Procedure:
Followed the procedure described for preparing Intermediate 10 starting with 2-chloro-6-methoxy-3-(trifluoromethyl)quinoxaline (Intermediate 11), with a purification by silica gel column chromatography.
Reaction SMILES: C(OCCCCCC(OC)=O)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.COC(=O)CCCCCCCCOC(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C[O:63][C:64](=[O:96])[CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][O:76][C:77]([C:90]1[CH:95]=[CH:94][CH:93]=[CH:92][CH:91]=1)([C:84]1[CH:89]=[CH:88][CH:87]=[CH:86][CH:85]=1)[C:78]1[CH:83]=[CH:82][CH:81]=[CH:80][CH:79]=1>>[C:77]([O:76][CH2:75][CH2:74][CH2:73][CH2:72][CH2:71][CH2:70][CH2:69][CH2:68][CH2:67][CH2:66][CH2:65][C:64]([OH:96])=[O:63])([C:84]1[CH:85]=[CH:86][CH:87]=[CH:88][CH:89]=1)([C:90]1[CH:95]=[CH:94][CH:93]=[CH:92][CH:91]=1)[C:78]1[CH:79]=[CH:80][CH:81]=[CH:82][CH:83]=1
Reactant: COC(=O)CCCCCCCCCCCOC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: COC(=O)CCCCCCCCOC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: COC(=O)CCCCCOC(c1ccccc1)(c1ccccc1)c1ccccc1
Product: O=C(O)CCCCCCCCCCCOC(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
Hydrolysis of the methyl ester of 15a, 15b, and 15c was carried out under basic conditions, followed by an acidic work up, during which the pH was maintained above 4 to prevent trityl deprotection. After recrystallization for solid product or flash chromatography for oil products, 6-trityloxyhexanoic acid 16a, 9-trityloxynonanoic acid 16b and 12-trityloxydodecanoic acid 16c were isolated, providing aliphatic side-chains that were ready to be coupled to 12 and 13.
Reaction SMILES: [N:1]1([C:6]2([C:10]#[N:11])[CH2:9]O[CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(OC1(O[Si](C)(C)C)CC1)C.N1CCCC1>>[N:1]1([C:6]2([C:10]#[N:11])[CH2:9][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: N#CC1(N2CCCC2)COC1
Agent: CCOC1(O[Si](C)(C)C)CC1
Solvent: C1CCNC1
Product: N#CC1(N2CCCC2)CC1

Procedure:
The title compound, colorless liquid, was prepared in accordance with the general method of intermediate A from ((1-ethoxycyclopropyl)oxy)trimethylsilane and pyrrolidine.
Reaction SMILES: Cl[P:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[C:5]2[CH:12]=[CH:13][CH:14]=[CH:15][C:4]=2[O:3]1.[CH:16]1([NH:22][CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH:23]1([N:22]([P:2]2[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=3[C:5]3[CH:12]=[CH:13][CH:14]=[CH:15][C:4]=3[O:3]2)[CH:16]2[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]2)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]1
Reactant: ClP1Oc2ccccc2-c2ccccc21
Reactant: C1CCC(NC2CCCCC2)CC1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: c1ccc2c(c1)OP(N(C1CCCCC1)C1CCCCC1)c1ccccc1-2

Procedure:
35.1 g (0.15 mol) of 6-chloro-dibenz[c,e][1,2]oxaphosphorine, 27.1 g (0.15 mol) of dicyclohexylamine and 50 ml of triethylamine are kept at reflux temperature for 10 hours. Toluene is added to the solution; the triethylamine hydrochloride is then removed by filtration, and the filtrate is concentrated in vacuo. The crystalline product has a melting point of 162° C. (Compound I).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][C@H:7]([C:12]([NH:14][C@H:15]([CH2:19][N:20]3[CH2:25][CH2:24][C@:23]([C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([OH:33])[CH:28]=4)([CH3:26])[C@@H:22]([CH3:34])[CH2:21]3)[CH:16]([CH3:18])[CH3:17])=[O:13])[NH:8][CH2:9]2)=[CH:4][CH:3]=1.[CH3:35][N:36]([CH3:41])[CH2:37][C:38](O)=[O:39]>>[CH3:35][N:36]([CH3:41])[CH2:37][C:38]([N:8]1[C@@H:7]([C:12]([NH:14][C@H:15]([CH2:19][N:20]2[CH2:25][CH2:24][C@:23]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([OH:33])[CH:28]=3)([CH3:26])[C@@H:22]([CH3:34])[CH2:21]2)[CH:16]([CH3:18])[CH3:17])=[O:13])[CH2:6][C:5]2[C:10](=[CH:11][C:2]([OH:1])=[CH:3][CH:4]=2)[CH2:9]1)=[O:39]
Reactant: CC(C)[C@@H](CN1CC[C@@](C)(c2cccc(O)c2)[C@@H](C)C1)NC(=O)[C@H]1Cc2ccc(O)cc2CN1
Reactant: CN(C)CC(=O)O
Product: CC(C)[C@@H](CN1CC[C@@](C)(c2cccc(O)c2)[C@@H](C)C1)NC(=O)[C@H]1Cc2ccc(O)cc2CN1C(=O)CN(C)C
Yield: 86 %

Procedure:
(3R)-7-Hydroxy-N-((1S)-1-{[(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl]methyl}-2-methylpropyl)-1,2,3,4-tetrahydro-3-isoquinolinecarboxamide (14, 0.100 g, 0.285 mmol) was coupled to N,N-dimethylglycine as described above to yield crude product which was purified by flash chromatography (50% (CHCl3:MeOH:NH4OH, 80:18:2) in CHCl3) to afford (3R)-2-(N,N-dimethylglycyl)-7-hydroxy-N-((1S)-1-{[(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl]methyl}-2-methylpropyl)-1,2,3,4-tetrahydro-3-isoquinolinecarboxamide (17, 0.101 g, 86%) as a white foam. LRMS (ES) m/z 551.4 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1(C(O)=O)[CH:6]=[CH:5][N:4]([C:7]2[C:16]([F:17])=[CH:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:8]=2)[NH:3]1.C[N:22](C=O)C.C(Cl)(=O)C(Cl)=O.[N-]=[N+]=[N-].[Na+]>C(Cl)Cl.O.O1CCOCC1>[CH3:1][C:2]1[CH:6]=[C:5]([NH2:22])[N:4]([C:7]2[C:16]([F:17])=[CH:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:8]=2)[N:3]=1
Reactant: CN(C)C=O
Reactant: CC1(C(=O)O)C=CN(c2cc3ccccc3cc2F)N1
Agent: O=C(Cl)C(=O)Cl
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc(N)n(-c2cc3ccccc3cc2F)n1
Reaction time: 2 h
Yield: 38 %

Procedure:
3-Methyl-1-(3-fluoro-2-naphthyl)-1H-pyrazole-5-carboxylic acid (see Step 1, Example 4) (828 mg, 3.1 mmol) was dissolved in 20 mL dry DCM. To it were added 0.05 mL DMF and oxalyl chloride (0.81 mL, 9.3 mL). The mixture was stirred for 2 hrs. It was evaporated in vacuuo. The residue was dissolved in 30 mL dry dioxane. It was chilled in ice bath. To the stirred cold mixture was added dropwise a chilled solution of sodium azide (0.4 g, 6.2 mmol) in 2 mL water and 1 mL dioxane. Reaction was allowed for 1 hr. It was evaporated in vacuuo. The residue was taken into EtOAc and washed with water ×2. The organic phase was dried and concentrated in vacuuo. The organic residue was then dissolved in 30 mL DMF. To it was added 15 mL water. The mixture was refluxed for 2.5 hrs. It was concentrated in vacuuo and purified using flash column to give 3-methyl-1-(3-fluoro-2-naphthyl)-5-amino-1H-pyrazole (280 mg, 38% overall). Rf 0.45 (1:1 EtOAc:hexane). ES-MS: (M+H)+242.
Reaction SMILES: [F:1][C:2]1[C:8]([Cl:9])=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[C:10]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])(=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>C(Cl)Cl.O>[CH2:22]([O:21][C:19](=[O:20])[CH:18]=[C:10]([NH:4][C:3]1[CH:5]=[CH:6][CH:7]=[C:8]([Cl:9])[C:2]=1[F:1])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:23]
Reactant: CCOC(=O)CC(=O)c1ccccc1
Reactant: Nc1cccc(Cl)c1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CCOC(=O)C=C(Nc1cccc(Cl)c1F)c1ccccc1
Reaction time: 3 h

Procedure:
2-Fluoro-3-chloroaniline (7.55 mL, 0.0687 mole), ethyl benzoylacetate (13.2 g, 0.0687 mole) and p-toluenesulfonic acid (1.18 g, 0.007 mole) were combined in a 250 mL round bottom flask with toluene (60 mL) and a magnetic stir-bar. The reaction was stirred at reflux with a Dean-Stark water trap. Reflux was stopped after 3 h. The product mixture was allowed to cool, and was then passed through a short pad of silica gel with methylene chloride, and concentrated in vacuo. Standing under high vacuum for 1 h afforded an oil. The oil was stirred in 100 mL of hexanes overnight, then suction filtered to remove a solid impurity. The filtrate was concentrated, and put on high vacuum to afford an oil. The oil was chromatographed with hexanes, ethyl acetate (8:1), and put under high vacuum for 1 h to afford the title compound as a yellow oil; 1H NMR (CDCl3, 400 MHz) δ 1.30-1.34 (t, 3H, J=7.1 Hz), 4.20-4.25 (Q, 2H, J=7.1 Hz), 5.13 (s, 1H), 6.19-6.23 (t, 1H), 6.60-6.65 (t of d, 1H, J=1.7 & J=8.2), 6.88-6.92 (t of d, 1H, J=1.5 & J=6.6), 7.29-7.37 (m, 5H), 10.21 (bs, 1H); MS (ES+): 319.99 (100) [MH+], 322.02 (30) [(M+2)H+].
Reaction SMILES: [C:1]([C:4]1[CH:19]=[CH:18][C:7]([O:8][CH2:9][C:10]([NH:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[Br:20]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:20][CH2:2][C:1]([C:4]1[CH:19]=[CH:18][C:7]([O:8][CH2:9][C:10]([NH:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])=[O:11])=[CH:6][CH:5]=1)=[O:3]
Reactant: COC(=O)CNC(=O)COc1ccc(C(C)=O)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)CNC(=O)COc1ccc(C(=O)CBr)cc1

Procedure:
The product of step (i) (3.00 g) and N-bromosuccinimide (2.02 g) in carbon tetrachloride (50 ml) was heated at reflux temperature for 64 hours. The solvent was evaporated and the black residue dissolved in methanol/ethyl acetate, treated with charcoal, filtered and then evaporated. The resulting brown oil was purified by flash chromatography on silica, eluting with dichloromethane. Trituration with hexane gave methyl N-[4-(bromoacetyl)phenoxyacetyl]glycinate, 0.85 g, as a solid: mp softens 109°-111° C.; NMR (d6DMSO) δ8.60 (1H, bt), 7.99 (2H, d), 7.09 (2H, d), 4.84 (2H, s), 4.69 (2H, s), 3.91 (2H, d), 3.64 (3H, s).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17]([OH:19])=O)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:23])=O>ClCCl>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17]([Cl:23])=[O:19])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: O=C(Cl)C1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 101.8 %

Procedure:
Piperidine-1,4-dicarboxylic acid monobenzyl ester (40.2 g, 0.15 mol) in dichloromethane (300 mL) was treated with oxalyl chloride (100 g, 0.79 mol). The reaction mixture was stirred at ambient temperature for 4 hours and the mixture was concentrated to afford crude 4-chlorocarbonyl-piperidine-1-carboxylic acid benzyl ester (43 g), which was used without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:12]([CH2:13][CH:14]([NH:18]CC2C=CC=CC=2)[C:15]([OH:17])=[O:16])[CH2:11][CH2:10][C@H:9]1[C:26]([OH:28])=[O:27])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>C(O)(=O)C.[OH-].[OH-].[Pd+2]>[C:15]([OH:17])(=[O:16])[CH3:14].[C:1]([O:5][C:6]([N:8]1[C@H:12]([CH2:13][CH:14]([NH2:18])[C:15]([OH:17])=[O:16])[CH2:11][CH2:10][C@H:9]1[C:26]([OH:28])=[O:27])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1[C@H](CC(NCc2ccccc2)C(=O)O)CC[C@H]1C(=O)O
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1[C@H](CC(N)C(=O)O)CC[C@H]1C(=O)O
Reaction time: 0.17 h

Procedure:
1600 mg of (2S,5S)-5-(2-benzylamino-2-carboxyethyl)pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester were dissolved in 30 ml of acetic acid. 100 mg of 20% palladium hydroxide on activated carbon were added thereto, and the mixture was hydrogenated under an atmosphere of 1 bar of hydrogen for 1 h. Ar was then passed over the solution for 10 min. The catalyst was filtered off through kieselguhr and the filter cake was washed with 20 ml of acetic acid. The combined organic phases were concentrated in vacuo. The crude product was employed without further purification in the next reaction.
Reaction SMILES: O[C:2]1[C:3]2[C:4]3[CH:5]=[C:6]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:7]=[CH:8][C:9]=3[S:10][C:11]=2[N:12]=[CH:13][N:14]=1.O=P(Cl)(Cl)[Cl:23]>>[Cl:23][C:2]1[C:3]2[C:4]3[CH:5]=[C:6]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:7]=[CH:8][C:9]=3[S:10][C:11]=2[N:12]=[CH:13][N:14]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)Cc1ccc2sc3ncnc(O)c3c2c1
Product: CCOC(=O)Cc1ccc2sc3ncnc(Cl)c3c2c1
Temperature: 25 °C
Yield: 72 %

Procedure:
A solution of ethyl 2-[3-hydroxy-8-thia-4,6-diazatricyclo[7.4.0.0^[2,7]]trideca-1(9),2(7),3,5,10,12-hexaen-12-yl]acetate (2.10 g, 7.28 mmol, 1.00 equiv) in POCl3 (23 mL) was stirred for 1 h at 90° C. in an oil bath. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue dissolved in EtOAc was poured into a cooled saturated aqueous sodium bicarbonate, extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by a silica gel column chromatography with ethyl acetate/petroleum ether (1:5) to afford ethyl 2-[3-chloro-8-thia-4,6-diazatricyclo[7.4.0.0^[2,7]]trideca-1(9),2(7),3,5,10,12-hexaen-12-yl]acetate (1.61 g, 72%) as a white solid. LCMS (ES, m/z): 307 and 309 (M+H+).
Reaction SMILES: C([C@@H]([CH2:12][CH2:13][C@H:14]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:15](O)=[O:16])C(O)=O)C1C=CC=CC=1.[NH2:25][C@H:26]1[CH2:32][CH2:31][S:30][C@H:29]2[CH2:33][CH2:34][CH2:35][CH2:36][N:28]2[C:27]1=[O:37]>>[CH2:18]([C@@H:14]([CH2:13][CH2:12][C@H:14]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:15]([NH:25][C@H:26]1[CH2:32][CH2:31][S:30][C@H:29]2[CH2:33][CH2:34][CH2:35][CH2:36][N:28]2[C:27]1=[O:37])=[O:16])[C:15]([NH:25][C@H:26]1[CH2:32][CH2:31][S:30][C@H:29]2[CH2:33][CH2:34][CH2:35][CH2:36][N:28]2[C:27]1=[O:37])=[O:16])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: N[C@H]1CCS[C@H]2CCCCN2C1=O
Reactant: O=C(O)[C@H](CC[C@H](Cc1ccccc1)C(=O)O)Cc1ccccc1
Product: O=C(N[C@H]1CCS[C@H]2CCCCN2C1=O)[C@H](CC[C@H](Cc1ccccc1)C(=O)N[C@H]1CCS[C@H]2CCCCN2C1=O)Cc1ccccc1

Procedure:
(2R,5R)-2,5-Dibenzyl-N1,N6-bis((4S,10aS)-5-oxooctahydro-2H-pyrido[2,1-b][1,3]thiazepin-4-yl)hexanediamide was synthesized as described in General Procedure F using Intermediate 3 (20 mg, 0.061 mmol) and Intermediate 40 (29.5 mg, 0.147 mmol) to give a white solid (27 mg, 64% yield). Anal. Calcd. for C38H50N4O4S2 m/z 690.7. found: 691.5 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 7.32-7.05 (m, 10H), 6.86 (d, J=6.7 Hz, 2H), 5.28 (t, J=4.0 Hz, 2H), 5.04-4.91 (m, 2H), 4.23 (d, J=13.6 Hz, 2H), 3.12 (ddd, J=13.9, 11.0, 2.6 Hz, 1H), 3.02-2.87 (m, 2H), 2.81 (dd, J=13.4, 9.6 Hz, 2H), 2.71 (dd, J=13.3, 5.7 Hz, 2H), 2.58 (ddd, J=14.3, 6.0, 2.9 Hz, 2H), 2.43-2.31 (m, 2H), 2.11-1.75 (m, 9H), 1.76-1.60 (m, 4H), 1.60-1.38 (m, 6H), 1.33-1.18 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][N:9]1[C:14](=[O:15])[C:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:12]([OH:21])[C:11]([CH:22]([CH3:24])[CH3:23])=[N:10]1.OC1C(C(C)C)=NNC(=O)[C:27]=1[C:36]([O:38]CC)=[O:37].[H-].[Na+].BrC1C=CC=CC=1CBr.C[N:53](C)C=O>>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][N:9]1[C:14](=[O:15])[C:13]([C:16]([NH:53][CH2:27][C:36]([OH:38])=[O:37])=[O:17])=[C:12]([OH:21])[C:11]([CH:22]([CH3:24])[CH3:23])=[N:10]1.[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][N:9]1[C:14](=[O:15])[C:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:12]([OH:21])[C:11]([CH:22]([CH3:23])[CH3:24])=[N:10]1
Reactant: CCOC(=O)c1c(O)c(C(C)C)n[nH]c1=O
Reactant: CN(C)C=O
Agent: BrCc1ccccc1Br
Agent: CCOC(=O)c1c(O)c(C(C)C)nn(Cc2ccccc2Br)c1=O
Agent: [H-]
Product: CC(C)c1nn(Cc2ccccc2Br)c(=O)c(C(=O)NCC(=O)O)c1O
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
Ethyl 2-[(2-bromophenyl)methyl]-5-hydroxy-6-(1-methylethyl)-3-oxo-2,3-dihydro-4-pyridazinecarboxylate. To a solution of ethyl 5-hydroxy-6-(1-methylethyl)-3-oxo-2,3-dihydro-4-pyridazinecarboxylate (example 46(a), 3 g, 13.26 mmol) in N,N-Dimethylformamide (DMF) (50 ml) at 0° C. was added sodium hydride (0.796 g, 19.89 mmol) in portions. The reaction mixture was stirred at room temperature for 45 minutes and then cooled back to 0° C. and 2-bromobenzylbromide (3.31 g, 13.26) was added portionwise. The mixture was stirred at ambient temperature for 2.5 hours then quenched with 1N HCl (10 ml) and diluted with water (30 ml). The aqueous solution was extracted with ethyl acetate (2×100 ml), the organic layers combined and washed with water (100 ml) and brine (100 ml), dried over Magnesium sulfate, filtered and solvents removed with rotary evaporation. The crude solid was triturated with ether and filtered. The solid material was 100% starting material (1 g). The filtrate was purified by flash column chromatography (10-100% ethyl acetate in hexanes) to provide the title compound (ethyl 2-[(2-bromophenyl)methyl]-5-hydroxy-6-(1-methylethyl)-3-oxo-2,3-dihydro-4-pyridazinecarboxylate (1.3 g, 2.96 mmol, 22.32% yield) as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6) d ppm 12.33 (br. s., 1H), 7.66 (dd, J=8.08, 1.26 Hz, 1H), 7.35 (td, J=7.52, 1.14 Hz, 1H), 7.25 (td, J=7.58, 1.77 Hz, 1H), 7.03 (dd, J=7.83, 1.52 Hz, 1H), 5.20 (s, 2H), 4.28 (q, J=7.07 Hz, 2H), 3.15 (sept, J=6.82 Hz, 1H), 1.26 (t, J=7.07 Hz, 3H), 1.11 (d, J=6.82 Hz, 6 H). MS (ES+) m/e 396 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[C:6]([O:40][CH3:41])=[C:7]([CH:29]=[C:30]([N:32]2[CH:37]=[CH:36][C:35](=[O:38])[NH:34][C:33]2=[O:39])[CH:31]=1)/[CH:8]=[CH:9]/[C:10]1[CH:15]=[CH:14][C:13]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])=[CH:12][C:11]=1[C:21](N1CCOCC1)=[O:22])([CH3:4])([CH3:3])[CH3:2].[H-].C(O[Al+2])(C)(C)C.[Li+].[H-].[H-]>C1COCC1>[C:1]([C:5]1[C:6]([O:40][CH3:41])=[C:7]([CH:29]=[C:30]([N:32]2[CH:37]=[CH:36][C:35](=[O:38])[NH:34][C:33]2=[O:39])[CH:31]=1)/[CH:8]=[CH:9]/[C:10]1[CH:15]=[CH:14][C:13]([NH:16][S:17]([CH3:20])(=[O:18])=[O:19])=[CH:12][C:11]=1[CH2:21][OH:22])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1c(/C=C/c2ccc(NS(C)(=O)=O)cc2C(=O)N2CCOCC2)cc(-n2ccc(=O)[nH]c2=O)cc1C(C)(C)C
Agent: CC(C)(C)O[Al+2]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1c(/C=C/c2ccc(NS(C)(=O)=O)cc2CO)cc(-n2ccc(=O)[nH]c2=O)cc1C(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 63 %

Procedure:
To a solution of the product from Example 27, Part A (375 mg, 0.705 mmol) in anhydrous THF (5 ml) at 0° C. under N2 gas was added a 1.0 M solution of lithium tert-butoxyaluminiumhydride (1.8 ml, 1.8 mmol) dropwise. The resulting mixture was stirred at 0° C. for 30 min, and then allowed to warm to room temperature and was stirred for 1 h. The mixture was partitioned between 1 N aq. HCl (10 ml) and EtOAc (2×10 ml). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography on silica gel using 3% MeOH in CH2Cl2 as the eluent to give the title compound (220 mg, 63%). 1H NMR (300 MHz, DMSO-d6) δ ppm 11.41 (s, 1 H) 9.82 (s, 1 H) 7.73 (t, J=8.27 Hz, 2 H) 7.66 (d, J=2.57 Hz, 1 H) 7.31-7.39 (m, 2 H) 7.20 (d, J=2.57 Hz, 1 H) 7.12-7.19 (m, 2 H) 5.65 (d, J=8.09 Hz, 1 H) 5.28 (t, J=5.52 Hz, 1 H) 4.65 (d, J=5.52 Hz, 2 H) 3.79 (s, 3 H) 3.00 (s, 3 H) 1.38 (s, 9 H).