Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[O:3][C:4]2[C:5](=[C:7]([C:19]#[N:20])[C:8]([CH3:18])=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:10]=2[F:11])[N:6]=1.C(N(C(C)C)CC)(C)C.[OH:30][CH2:31][CH:32]1[CH2:35][NH:34][CH2:33]1>C(Cl)Cl.C(Cl)(Cl)Cl>[F:11][C:10]1[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:8]([CH3:18])[C:7]([C:19]#[N:20])=[C:5]2[C:4]=1[O:3][C:2]([N:34]1[CH2:35][CH:32]([CH2:31][OH:30])[CH2:33]1)=[N:6]2
Reactant: OCC1CNC1
Reactant: Cc1c(-c2ccccc2)c(F)c2oc(Cl)nc2c1C#N
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: Cc1c(-c2ccccc2)c(F)c2oc(N3CC(CO)C3)nc2c1C#N
Yield: 73.4 %

Procedure:
Under nitrogen atmosphere, 2-chloro-7-fluoro-5-methyl-6-phenyl-1,3-benzoxazole-4-cabonitrile (I-130) (240 mg, 0.84 mmol) was dissolved in methylene chloride (10 ml), then diisopropylethylamine (584 μl, 3.35 mmol) and 3-hydroxymethylazetidine (206 mg, 1.67 mmol) dissolved in methylene chloride (5 ml) were added, followed by heating under reflux in a sealed tube for 5 hours. After cooling, diluting with chloroform and washing with water, the organic layer was dried over anhydrous magnesium sulfate, then the solvent was evaporated away under reduced pressure. The resulting residue was subjected to preparative silica gel column chromatography. The eluate with chloroform/methanol (10:1, v/v) gave the entitled compound (208 mg, 74%) as a white solid.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[C:5]2[C:15](=[O:19])[NH:16][C:17](=S)[C:4]2=[C:3]1CCC1C=CC2C(=CC=CC=2)N=1.[CH2:32]1[CH2:36]O[CH2:34][CH2:33]1.[CH3:37][CH2:38]O>[Ni]>[CH3:1][N:2]1[C:7](=[O:8])[C:6]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[C:5]2[C:15](=[O:19])[N:16]([CH2:34][CH2:33][C:32]3[CH:36]=[CH:37][C:38]4[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=4)[N:2]=3)[CH2:17][C:4]2=[CH:3]1
Reactant: CCO
Reactant: Cn1c(CCc2ccc3ccccc3n2)c2c(c(N3CCOCC3)c1=O)C(=O)NC2=S
Reactant: C1CCOC1
Agent: [Ni]
Product: Cn1cc2c(c(N3CCOCC3)c1=O)C(=O)N(CCc1ccc3ccccc3n1)C2
Temperature: 25 °C
Reaction time: 16 h
Yield: 24.36 %

Procedure:
Nickel (7.56 mg, 0.129 mmol) was added rapidly to a mixture of 5-methyl-7-morpholin-4-yl-(2-quinolin-2-yl-ethyl)-1,6-dioxo-5H-pyrrolo[3,4-c]pyridine-3-thione (0.56 g, 1.289 mmol, see Example 9.1) in EtOH (20 ml)/THF (5 ml). The mixture was allowed to stir under a hydrogen atmosphere (at a pressure of about 35 psi) at r.t. for about 16 h. The solvent was removed and the resulting mixture was purified via preparative HPLC (System: Isco Combi Flash Companion XL, eluent: MeCN/ammonium acetate buffer (gradient: 0:100 to 60:40 over 20 min), column: C-18, 21.2×250 mm) to afford the title compound (127 mg, 24.36% yield).
Reaction SMILES: [CH2:1]([C@H:8]1[NH:23][C:22](=[O:24])[CH2:21][C@@H:20](/[CH:25]=[CH:26]/[CH2:27][CH2:28][S:29]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[O:19][C:18](=[O:49])[CH2:17][NH:16][C:15](=[O:50])[C@@H:14]([CH:51]([CH3:53])[CH3:52])[NH:13][C:12](=[O:54])[C@@H:11]([CH2:55][S:56]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[NH:10][C:9]1=[O:76])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(Cl)Cl.CO>[CH2:1]([C@@H:8]1[C:9](=[O:76])[NH:10][C@@H:11]2[CH2:55][S:56][S:29][CH2:28][CH2:27][CH:26]=[CH:25][C@@H:20]([O:19][C:18](=[O:49])[CH2:17][NH:16][C:15](=[O:50])[C@@H:14]([CH:51]([CH3:53])[CH3:52])[NH:13][C:12]2=[O:54])[CH2:21][C:22](=[O:24])[NH:23]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)[C@H]1NC(=O)[C@@H](CSC(c2ccccc2)(c2ccccc2)c2ccccc2)NC(=O)[C@@H](Cc2ccccc2)NC(=O)C[C@@H](/C=C/CCSC(c2ccccc2)(c2ccccc2)c2ccccc2)OC(=O)CNC1=O
Agent: CC(C)[C@H]1NC(=O)[C@H]2CSSCC/C=C/[C@H](CC(=O)N[C@H](Cc3ccccc3)C(=O)N2)OC(=O)CNC1=O
Solvent: CO
Solvent: ClCCl
Product: CC(C)[C@H]1NC(=O)[C@H]2CSSCCC=C[C@H](CC(=O)N[C@H](Cc3ccccc3)C(=O)N2)OC(=O)CNC1=O

Procedure:
To a vigorously stirred solution of 12 (254 mg, 1.0 mmol) in CH2Cl2/MeOH (9:1, 230 mL) was added dropwise a solution of bis-trityl 8B (105 mg, 0.10 mmol) over 30 minutes. After a further 30 min the reaction was quenched by the addition of sodium thiosulfate (0.05M, 100 mL) followed by brine (10 mL). The organic phase was separated and the aqueous phase extracted with CH2Cl2 (3×15 mL). The combined organic phase was dried (MgSO4), filtered, and concentrated in vacuo to give a white solid. Purification by column chromatography on silica gel (1-3.5% MeOH/CH2Cl2) gave bicyclic depsipeptide 9B (43 mg, 0.08 mmol, 75%) as a white solid: [α]25D −98 (c 0.05, 1:1 MeOH/CHCl3); IR νmax 3280, 1732, 1627, 1538, 1445 cm−1; 1H-NMR (400 MHz, 19:1 CD3OD/CDCl3) δ 7.35-7.18 (m, 5H), 5.86-5.76 (m, 1H), 5.74-5.66 (m, 2H), 4.62 (dd, J=11.3, 4.0 Hz, 1H), 4.45 (dd, J=9.3, 5.3 Hz, 1H), 4.28 (d, J=17.6 Hz, 1H), 3.77 (d, J=17.6 Hz, 1H), 3.39 (d, J=10.5 Hz, 1H), 3.27-3.17 (m, 2H), 3.11-2.99 (m, 3H), 2.97-2.83 (m, 2H), 2.81 (dd, J=13.6, 2.0 Hz, 1H), 2.70-2.53 (m, 3H), 0.96 (d, J=6.5 Hz, 3H), 0.92 (d, J=6.5 Hz, 3H); 13C-NMR (100 MHz, 19:1 CD3OD/CDCl3) δ 173.8 (C), 173.2 (C), 172.9 (C), 171.3 (C), 169.4 (C), 137.7 (CH), 131.3 (CH), 131.3 (CH), 129.7 (CH), 129.6 (CH), 128.0 (CH), 71.9 (CH), 65.9 (CH), 58.3 (CH), 58.1 (CH), 42.6 (CH2), 39.3 (2×CH2), 36.9 (CH2), 36.8 (CH2), 31.8 (CH2), 28.1 (CH), 20.6 (CH3), 20.5 (CH3); LRMS (ES+) m/z 580 (50%, [2M+Na]+), 563 (100%, [M+NH4]+), 563 (10% [M+H]+).
Reaction SMILES: [CH:1]1([N:7]([CH2:21][CH2:22][C:23]2[CH:28]=CC=C[CH:24]=2)[C:8](=[O:20])[NH:9][C:10]2[S:11][C:12]([S:15][CH2:16][C:17](O)=O)=[CH:13][N:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:29](=O)CC(C)C.Cl.C[C@H]1CC[C@H](N)CC1.C([O:46][C:47](=[O:50])CC)C.Cl.CCN(C(C)C)C(C)C>>[CH3:28][CH:23]([CH3:24])[CH2:22][CH2:21][N:7]([C@H:1]1[CH2:2][CH2:3][C@H:4]([CH3:29])[CH2:5][CH2:6]1)[C:8](=[O:20])[NH:9][C:10]1[S:11][C:12]([S:15][CH2:16][CH2:17][C:47]([OH:50])=[O:46])=[CH:13][N:14]=1
Reactant: O=C(O)CSc1cnc(NC(=O)N(CCc2ccccc2)C2CCCCC2)s1
Reactant: CCOC(=O)CC
Reactant: CC(C)CC=O
Agent: C[C@H]1CC[C@H](N)CC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)CCN(C(=O)Nc1ncc(SCCC(=O)O)s1)[C@H]1CC[C@H](C)CC1

Procedure:
Prepared as described for the synthesis of [2-(3-cyclohexyl-3-phenethyl-ureido)-thiazol-5-ylsulfanyl]-acetic acid, from isovaleraldehyde, trans-4-methylcyclohexylamine hydrochloride and 2-amino-thiazol-5-ylsulfanyl)-propionic acid ethyl ester. The hydrochloride was added one equivalent DIPEA prior to the reaction.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[NH2:12])[C:5]([O:7][CH3:8])=[O:6].C(N(CC)CC)C.[C:20](Cl)(=O)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>CN(C)C=O.C(OCC)(=O)C>[CH3:8][O:7][C:5]([C:4]1[CH:9]=[CH:10][C:11]2[N:12]=[C:20]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[NH:1][C:2]=2[CH:3]=1)=[O:6]
Reactant: COC(=O)c1ccc(N)c(N)c1
Reactant: CCCCCCCCCC(=O)Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCCCCCCCCc1nc2ccc(C(=O)OC)cc2[nH]1
Temperature: 0 °C
Yield: 40.3 %

Procedure:
To a mixture of Methyl 3,4-diaminobenzoate (1.91 g) and triethylamine (0.56 g) in N,N-dimethylformamide (20 ml) was added decanoyl chloride (2.31 g), and the mixture was stirred for an hour at 0° C. The reaction mixture was diluted with ethyl acetate, and washed with water and brine. The separated organic layer was dried over magnesium sulfate. The magnesium sulfate was filtered off, and filtrate was evaporated under reduced pressure. The residue was dissolved in methanol (20 ml), and conc. sulfuric acid (0.05 ml) was added, and the mixture was stirred for 6 hours at 60° C. After cooling, the reaction mixture was evaporated under reduced pressure. The residue was diluted with ethyl acetate, and washed with water and brine. The separated organic layer was dried over magnesium sulfate. The magnesium sulfate was filtered off, and filtrate was evaporated under reduced pressure. Purification of the residue by column chromatography on silica gel eluted with (n-hexane:ethyl acetate=3:1) gave 5-methoxycarbonyl-2-nonylbenzimidazole (1.40 g).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=O.C(Cl)(=O)C(Cl)=O.[Br:18][C:19]1[CH:24]=[CH:23][C:22]([O:25]C)=[CH:21][CH:20]=1.[Al+3].[Cl-].[Cl-].[Cl-]>ClCCl.CN(C=O)C>[Br:18][C:19]1[CH:20]=[CH:21][C:22]([OH:25])=[C:23]([C:9](=[O:11])[CH2:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[CH3:1])[CH:24]=1
Reactant: Cc1ccccc1CC(=O)O
Reactant: COc1ccc(Br)cc1
Agent: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1ccccc1CC(=O)c1cc(Br)ccc1O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 33 %

Procedure:
2-Methylphenylacetic acid (9.60 g, 64.15 mmoles) was dissolved in 10 ml dichloromethane. To this mixture, oxalylchloride (7 ml, 80.19 mmoles) and DMF (3 drops) were added at 0° C. and stirred for 30 min. The solvent was evaporated and dissolved in 100 ml dichloromethane. To this mixture, 4-bromoanisole (10 g, 53.47 mmoles) was added and cooled to 0° C. At 0° C. AlCl3 (10.6 g, 80.19 mmoles) was added and the reaction mixture was warmed to RT and stirred for 24 h. The reaction mixture was quenched by the addition of 2N HCl and extracted with ethyl acetate, dried over sodium sulphate and concentrated. The crude product was purified by column chromatography with ethyl acetate: petroleum ether to afford the title compound as white solid (5.5 g, 33% yield. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): δ 11.52(s,1H), 8.02(d, J=2.4 Hz, 1H), 7.65(dd, J=8.8, 2.5 Hz, 1H), 7.16(m, 4H), 6.97(d, J=8.9 Hz, 1H), 4.47(s, 2H), 2.14(s, 3H).
Reaction SMILES: C(OC(Cl)=O)C(C)C.C(N(CC)CC)C.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][C:25](O)=[O:26])=[CH:19][C:18]=1[C:28]([NH:30][CH2:31][C:32]12[CH2:41][CH:36]3[CH2:37][CH:38]([CH2:40][CH:34]([CH2:35]3)[CH2:33]1)[CH2:39]2)=[O:29]>O1CCCC1>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][CH2:25][OH:26])=[CH:19][C:18]=1[C:28]([NH:30][CH2:31][C:32]12[CH2:41][CH:36]3[CH2:35][CH:34]([CH2:40][CH:38]([CH2:37]3)[CH2:39]1)[CH2:33]2)=[O:29]
Reactant: O=C(O)CCc1ccc(Cl)c(C(=O)NCC23CC4CC(CC(C4)C2)C3)c1
Agent: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(CCCO)ccc1Cl
Yield: 82.3 %

Procedure:
Isobutylchloroformate (0.575 ml) and triethylamine (0.63 ml) were added to a solution of 4-chloro-3-[[(tricyclo[3.3.1.13,7]dec-1-ylmethyl)amino]carbonyl]-benzenepropanoic acid (Example 6c, 1.64 g) in tetrahydrofuran (30 ml) at 0° C. After 1 h the precipitates were removed by filtration and the filtrate added portionwise to a solution of sodium borohydride (0.18 g) in water (10 ml) at 0° C. After a further 1 h the reaction mixture was poured onto dilute hydrochloric acid and extracted with ethyl acetate. The organic phase was extracted twice with dilute hydrochloric acid, twice with saturated sodium hydrogencarbonate solution and once with brine, dried over magnesium sulfate and concentrated under reduced pressure to give a residue. Purification by silica gel chromatography (eluting with dichloromethane/methanol 96:4); yielded the subtitled compound as a solid (1.3 g).
Reaction SMILES: C([O:3][C:4](=[O:26])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([O:17][C:18]3[CH:23]=[C:22]([C:24]#[N:25])[N:21]=[CH:20][N:19]=3)[CH:14]=[C:15]([CH3:16])[C:7]1=2)C.[Li+].[OH-].Cl>C1COCC1.O>[C:24]([C:22]1[N:21]=[CH:20][N:19]=[C:18]([O:17][C:13]2[CH:14]=[C:15]([CH3:16])[C:7]3[CH:6]([CH2:5][C:4]([OH:26])=[O:3])[O:10][B:9]([OH:11])[C:8]=3[CH:12]=2)[CH:23]=1)#[N:25]
Reactant: CCOC(=O)CC1OB(O)c2cc(Oc3cc(C#N)ncn3)cc(C)c21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(Oc2cc(C#N)ncn2)cc2c1C(CC(=O)O)OB2O
Temperature: 0 °C
Reaction time: 5 h
Yield: 8.3 %

Procedure:
To a solution [6-(6-cyano-pyrimidin-4-yloxy)-1-hydroxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl)-acetic acid ethyl ester (0.2 g, 0.556 mmol) in THF (3 mL) was added a solution of LiOH (0.041 g, 1.69 mmol) in water (3 mL) at 0° C. The resulting mixture was stirred at 0° C. for 5 hours, acidified to pH 2 using 6M hydrochloric acid and extracted with EtOAc. The organic extracts were washed with water, brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by preparative HPLC to give [6-(6-cyano-pyrimidin-4-yloxy)-1-hydroxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl)-acetic acid as a white solid (0.015 g). 1H NMR (400 MHz, DMSO-d δ 9.18 (s, 1H), 8.82 (d, J=10.0 Hz, 1H), 7.45 (d, J=6.0 Hz, 1H), 7.30 (s, 1H), 7.16 (s, 1H), 5.51 (m, 1H), 3.07 (m, 1H), 2.31 (s, 3H), 2.16 (m, 1H). MS (ESI) m/z: 324 [M−1]−. HPLC purity: 96.94% (Maxplot), 98.24% (220 nm).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([NH:9][C:10]([NH2:12])=[S:11])[CH:6]=[CH:7][CH:8]=1.[C:15]([O:21][CH3:22])(=[O:20])[CH2:16][C:17]([CH3:19])=O.C[Si](OP([O-])([O-])=O)(C)C.Cl.[CH2:33]1[CH2:37]O[CH2:35][CH2:34]1>>[CH3:22][O:21][C:15]([C:16]1[CH:35]([C:34]2[CH:2]=[CH:3][C:4]([C:5]#[N:9])=[CH:37][CH:33]=2)[NH:12][C:10](=[S:11])[N:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:13])[F:14])[CH:4]=2)[C:17]=1[CH3:19])=[O:20]
Reactant: C1CCOC1
Reactant: COC(=O)CC(C)=O
Reactant: NC(=S)Nc1cccc(C(F)(F)F)c1
Agent: C[Si](C)(C)OP(=O)([O-])[O-]
Agent: Cl
Product: COC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)C(=S)NC1c1ccc(C#N)cc1
Temperature: 70 °C
Reaction time: 17 h

Procedure:
To a solution of 3-trifluoromethylphenylthiourea (2.2 g, 10 mmol) 4-cyanobenzaldehyde (1.4 g, 11 mmol) and methyl acetoacetate (1.2 mL, 11 mmol) in THF (40 mL) was added trimethylsilylphosphate (1.8 g) and the mixture heated at 70° C. After 17 hours, the reaction mixture was allowed to cool, then poured onto 0.5 M HCl (200 mL) and extracted into EtOAc. The organic phase was washed with water, then brine, dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by silica gel chromatography eluting with a gradient of 20-30% EtOAc in cyclohexane Appropriate fractions were combined and concentrated in vacuo to yield the title compound as a white foam (3.7 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:39]2[C:44](=[O:45])[C:43]3[S:46][C:47]4[CH2:52][CH2:51][CH2:50][CH2:49][C:48]=4[C:42]=3[CH:41]=[N:40]2)[C:5]([CH2:34][O:35]C(=O)C)=[C:6]([C:8]2[CH:9]=[C:10]([NH:16][C:17]3[N:22]=[C:21]([N:23]4[CH2:28][CH2:27][CH2:26][C@H:25]([NH:29][C:30](=[O:33])[CH:31]=[CH2:32])[CH2:24]4)[CH:20]=[CH:19][CH:18]=3)[C:11](=[O:15])[N:12]([CH3:14])[CH:13]=2)[CH:7]=1.O[Li].O>C1COCC1.CC(O)C.O>[F:1][C:2]1[CH:3]=[C:4]([N:39]2[C:44](=[O:45])[C:43]3[S:46][C:47]4[CH2:52][CH2:51][CH2:50][CH2:49][C:48]=4[C:42]=3[CH:41]=[N:40]2)[C:5]([CH2:34][OH:35])=[C:6]([C:8]2[CH:9]=[C:10]([NH:16][C:17]3[N:22]=[C:21]([N:23]4[CH2:28][CH2:27][CH2:26][C@H:25]([NH:29][C:30](=[O:33])[CH:31]=[CH2:32])[CH2:24]4)[CH:20]=[CH:19][CH:18]=3)[C:11](=[O:15])[N:12]([CH3:14])[CH:13]=2)[CH:7]=1
Reactant: C=CC(=O)N[C@H]1CCCN(c2cccc(Nc3cc(-c4cc(F)cc(-n5ncc6c7c(sc6c5=O)CCCC7)c4COC(C)=O)cn(C)c3=O)n2)C1
Agent: [Li]O
Solvent: CC(C)O
Solvent: O
Solvent: C1CCOC1
Product: C=CC(=O)N[C@H]1CCCN(c2cccc(Nc3cc(-c4cc(F)cc(-n5ncc6c7c(sc6c5=O)CCCC7)c4CO)cn(C)c3=O)n2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 29.3 %

Procedure:
A mixture of 115a (73 mg, 0.1 mmol) and LiOH.H2O (40 mg, 1 mmol) in THF/i-PrOH/water (2.0 mL/1.0 mL/1.0 mL) was stirred at rt for 2 h. The mixture was extracted with EA. The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by prep-HPLC to give 115 (20 mg, 29%) as gray solid. 1H NMR (300 MHz, DMSO-d6, 80° C.): δ 8.42 (s, 1H), 8.40 (s, 1H), 8.00 (s, 1H), 7.77 (d, J=4.5 Hz, 1H), 7.41-7.29 (m, 5H), 6.44 (d, J=3 Hz, 1H), 6.25-6.17 (m, 2H), 5.55-5.50 (m, 1H), 4.35 (s, 2H), 3.98-3.76 (m, 3H), 3.61 (s, 3H), 3.09-2.87 (m, 7H), 1.93-1.87 (m, 6H), 1.71 (bs, 1H), 1.49-1.45 (m, 2H). ESI-LCMS: m/z=682 [C36H36FN7O4S+H]+
Reaction SMILES: [C:1]([NH:5][C:6](=[O:14])[C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].C([Li])(CC)C.C1CCCCC1.CN(C)[CH:28]=[O:29]>C1COCC1.O>[C:1]([N:5]1[CH:28]([OH:29])[C:8]2[C:7](=[CH:12][CH:11]=[C:10]([CH3:13])[CH:9]=2)[C:6]1=[O:14])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(C(=O)NC(C)(C)C)cc1
Reactant: CN(C)C=O
Agent: [Li]C(C)CC
Solvent: C1CCCCC1
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc2c(c1)C(O)N(C(C)(C)C)C2=O
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 102.4 %

Procedure:
To a solution of N-tert-butyl-4-methylbenzamide (9.02 g, 47.2 mmol) in THF (132 ml), charged to a 250 mL round bottom, sec-butyl lithium, 1.4 m in cyclohexane (74.1 ml, 104 mmol) was added at −78° C. The reaction mixture was stirred at −78° C. for 30 min, then warmed to 0° C. for 45 min, before cooling back to −78° C. Then N,N-dimethylformamide (12.0 ml, 156 mmol) was added. The reaction mixture was stirred at −78° C. for 30 min, then allowed to warm to 23° C. The reaction mixture was diluted with water and extracted with EtOAc 3×. The combined organics were washed with brine, dried over magnesium sulfate and concentrated under vacuum to give 2-tert-butyl-3-hydroxy-5-methylisoindolin-1-one (10.6 g, 100% yield). MS (M+H)+ 220.
Reaction SMILES: C[N:2]([CH3:13])[CH:3]=[CH:4][C:5]([C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1)=O.N[C:15]1[C:19]([C:20]#[N:21])=C[NH:17][N:16]=1>C(O)(=O)C>[N:9]1[CH:10]=[CH:11][CH:12]=[C:7]([C:5]2[N:17]3[N:16]=[CH:15][C:19]([C:20]#[N:21])=[C:13]3[N:2]=[CH:3][CH:4]=2)[CH:8]=1
Reactant: CN(C)C=CC(=O)c1cccnc1
Reactant: N#Cc1c[nH]nc1N
Solvent: CC(=O)O
Product: N#Cc1cnn2c(-c3cccnc3)ccnc12

Procedure:
A mixture of 17.61 g. of 3-dimethylamino-1-(3-pyridyl)-2-propen-1-one and 10.8 g. of 3-aminopyrazole-4-carbonitrile in 75 ml. of glacial acetic acid is heated at reflux temperature for 6 hours. The procedure described in Example 1 is continued to give the product of the example as tan crystals, m.p. 258°-260° C.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:8]2.C(N(CC)CC)C.[C:24]1([C:29](Cl)=[O:30])[S:28][CH:27]=[CH:26][CH:25]=1>O1CCCC1>[CH3:1][N:2]([C:29]([C:24]1[S:28][CH:27]=[CH:26][CH:25]=1)=[O:30])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:8]2
Reactant: CCOC(=O)c1cc2cccc(NC)c2[nH]1
Reactant: O=C(Cl)c1cccs1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2cccc(N(C)C(=O)c3cccs3)c2[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.4 %

Procedure:
To a solution of ethyl 7-(methylamino)-1H-indole-2-carboxylate (54 mg) in tetrahydrofuran (3 mL) were added triethylamine (42 μL) and 2-thenoylchloride (44 mg), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated, and the obtained residue was subjected to silica gel column chromatography (ethyl acetate:hexane=1:3) to give colorless crystals (71 mg, yield 87%). melting point 193° C.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:13]=[C:12]([C:14]([NH2:16])=[O:15])[O:11][N:10]=2)=[CH:5][CH:4]=1.[Cl:17][C:18]1[CH:19]=[C:20]([OH:24])[CH:21]=[CH:22][CH:23]=1.C([O-])([O-])=O.[K+].[K+]>CC#N>[Cl:17][C:18]1[CH:19]=[C:20]([CH:21]=[CH:22][CH:23]=1)[O:24][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:13]=[C:12]([C:14]([NH2:16])=[O:15])[O:11][N:10]=2)=[CH:5][CH:4]=1
Reactant: Oc1cccc(Cl)c1
Reactant: NC(=O)c1cc(-c2ccc(CBr)cc2)no1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: NC(=O)c1cc(-c2ccc(COc3cccc(Cl)c3)cc2)no1
Temperature: 90 °C
Yield: 70.7 %

Procedure:
To a mixture of 3-(4-bromomethyl-phenyl)-isoxazole-5-carboxylic acid amide (which may be prepared as described in Preparation of Intermediate 14; 40 mg, 0.142 mmol) in CH3CN (2 mL) were added 3-chlorophenol (28 mg, 0.22 mmol) and K2CO3 (40 mg, 0.29 mmol). The mixture was heated at 90° C. for 4 h and then evaporated to dryness. The residue was purified by chromatography (66-75% EtOAc/hexanes) to give 3-[4-(3-chloro-phenoxymethyl)-phenyl]-isoxazole-5-carboxylic acid amide (33 mg, 71%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.38 (br. s., 1H), 8.01 (br. s., 1H), 7.92 (d, J=8.1 Hz, 2H), 7.55-7.66 (m, 3H), 7.23-7.36 (m, 1H), 7.09-7.15 (m, 1H), 6.95-7.05 (m, 2H), 5.21 (s, 2H).
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:7][CH:6]([CH2:8][OH:9])[CH2:5][CH2:4][O:3]1.N1C=CC=CC=1.[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1>C(Cl)Cl.CN(C1C=CN=CC=1)C.O>[CH3:27][C:17]1[CH:22]=[CH:21][C:20]([S:23]([O:9][CH2:8][CH:6]2[CH2:5][CH2:4][O:3][C:2]([CH3:10])([CH3:1])[CH2:7]2)(=[O:25])=[O:24])=[CH:19][CH:18]=1
Reactant: CC1(C)CC(CO)CCO1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: O
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCC2CCOC(C)(C)C2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of (2,2-dimethyltetrahydro-2H-pyran-4-yl)methanol (1 g, 6.93 mmol) in DCM (5 mL) and pyridine (5 mL, 61.8 mmol) was added para-toluenesulfonyl chloride (1.586 g, 8.32 mmol) and DMAP (0.042 g, 0.347 mmol). The mixture was stirred for 18 hr at ambient temperature. The reaction mixture was concentrated in vacuo and the resulting resulting residue was diluted with water and DCM. The separated organic layer was washed with 0.2N aqueous HCl (1×), 1N aqueous HCl (2×), brine, dried over sodium sulfate, filtered off and concentrated in vacuo. The resulting residue was purified by column chromatography [SiO2, 40 g, EtOAc/hexane=0/100 to 50/50; 25 min] providing (R/S)-(2,2-dimethyltetrahydro-2H-pyran-4-yl)methyl 4-methylbenzenesulfonate as a colorless oil. Yield: 2.05 g. LCMS (m/z): 299.1 [M+H]+; Retention time=0.96 min.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:12]=[C:11](Cl)[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:14][CH3:15])[CH:9]=2)[N:4]=1.[NH:16]1[CH:20]=[N:19][CH:18]=[N:17]1.CN(C)C=O.[OH-].[NH4+]>O>[N:16]1([C:11]2[C:10]3[C:5](=[CH:6][CH:7]=[C:8]([O:14][CH3:15])[CH:9]=3)[N:4]=[C:3]([CH3:2])[CH:12]=2)[CH:20]=[N:19][CH:18]=[N:17]1
Reactant: COc1ccc2nc(C)cc(Cl)c2c1
Reactant: c1nc[nH]n1
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2nc(C)cc(-n3cncn3)c2c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 87 %

Procedure:
A mixture of 2.44 g of 2-methyl-4-chloro-6-methoxy-quinoline-hydrochloride, 1.38 g of 1,2,4-triazole and 10 ml of dimethyl formamide is stirred at 80° C. for 3 hours whereupon the reaction mixture is poured into 100 ml of water and neutralized with 2 ml of a concentrated ammonium hydroxide solution. The precipitated product is filtered. Thus 2.09 g of the desired compound are obtained, yield 87%, mp.: 117°-118° C.
Reaction SMILES: C(N(CC)C(=O)C1C=CC(Br)=CC=1[Cl:12])C.C(N(CC)C(=O)C1C=CC(Br)=CC=1OC(F)(F)F)C.C(OC([N:42]1[CH2:62][CH2:61][N:45]2[C:46](=[O:60])[C:47]3[C:52]([CH:44]2[CH2:43]1)=[CH:51][C:50]([O:53]C)=[CH:49][C:48]=3OC(F)(F)F)=O)(C)(C)C>>[ClH:12].[Cl:12][C:48]1[CH:49]=[C:50]([OH:53])[CH:51]=[C:52]2[C:47]=1[C:46](=[O:60])[N:45]1[CH2:61][CH2:62][NH:42][CH2:43][C@H:44]12
Reactant: COc1cc(OC(F)(F)F)c2c(c1)C1CN(C(=O)OC(C)(C)C)CCN1C2=O
Reactant: CCN(CC)C(=O)c1ccc(Br)cc1Cl
Agent: CCN(CC)C(=O)c1ccc(Br)cc1OC(F)(F)F
Product: Cl
Product: O=C1c2c(Cl)cc(O)cc2[C@@H]2CNCCN12

Procedure:
Prepared according to procedures described in Example 128 Step A with substitution of N-(t-butoxycarbonyl)-(R)-1,3,4,10b-tetrahydro-7-chloro-9-methoxy-pyrazino[2,1-a]isoindol-6(2H)-one, produced by procedures described in Example 126 with the substitution of N,N-diethyl-4-bromo-2-chlorobenzamide for N,N-diethyl-4-bromo-2-trifluoromethoxybenzamide, for N-(t-butoxycarbonyl)-(±)-1,3,4,10b-tetrahydro-9-methoxy-7-trifluoromethoxy-pyrazino[2,1-a] isoindol-6(2H)-one. Followed by the separation of enantiomers according to the procedures described in Example 128 Step D. MS (ESI) 239 (M−Cl).
Reaction SMILES: Br[C:2]1[C:3]([NH:5][C:6](=[O:8])[CH:7]=1)=[O:4].C([O-])(=O)C.[Na+].[CH2:14]([SH:20])[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]>CO>[CH2:14]([S:20][C:2]1[C:3]([NH:5][C:6](=[O:8])[CH:7]=1)=[O:4])[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCCCS
Reactant: O=C1C=C(Br)C(=O)N1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Product: CCCCCCSC1=CC(=O)NC1=O
Yield: 100 %

Procedure:
To bromomaleimide (300 mg, 1.69 mmol) and sodium acetate (138 mg, 1.69 mmol) in methanol (100 mL) was added hexanethiol (237 μL, 1.69 mmol). After 5 minutes solvent removed in vacuo and purification by flash chromatography (10% ethyl acetate in petroleum ether) afforded hexylsulfanylmaleimide as a cream powder (362 mg, 1.69 mmol) in 100% yield.