Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12]/[C:11](=[C:19]3/[C:20]([CH2:25][CH2:26][CH3:27])=[N:21][NH:22][C:23]/3=[O:24])/[CH:10]=2)=[CH:4][CH:3]=1.[CH3:28][N:29]([CH3:36])[CH2:30][CH2:31][CH2:32][C:33](Cl)=[O:34]>C1COCC1>[CH3:28][N:29]([CH3:36])[CH2:30][CH2:31][CH2:32][C:33]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12]/[C:11](=[C:19]3/[C:20]([CH2:25][CH2:26][CH3:27])=[N:21][NH:22][C:23]/3=[O:24])/[CH:10]=2)=[CH:6][CH:7]=1)=[O:34]
Reactant: CN(C)CCCC(=O)Cl
Reactant: CCCC1=NNC(=O)/C1=C1/C=C(Sc2ccc(N)cc2)c2ccccc2N1
Solvent: C1CCOC1
Product: CCCC1=NNC(=O)/C1=C1/C=C(Sc2ccc(NC(=O)CCCN(C)C)cc2)c2ccccc2N1

Procedure:
The title compound was synthesized using (Z)-4-(4-(4-aminophenylthio)quinolin-2(1H)-ylidene)-3-propyl-1H-pyrazol-5(4H)-one and 4-(dimethylamino)butanoyl chloride in THF according to the procedure described in the synthesis of Example 26. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.70 (t, J=7.33 Hz, 3H) 1.27-1.38 (m, J=7.45, 7.45, 7.45, 7.45 Hz, 2H) 1.90-1.99 (m, 2H) 2.21 (m, 2H) 2.44-2.49 (m, 2H) 2.81 (d, J=4.80 Hz, 6H) 3.07-3.15 (m, 2H) 6.76 (s, 1H) 7.57 (t, J=7.96 Hz, 1H) 7.69 (d, J=8.34 Hz, 2H) 7.79-7.90 (m, 4H) 8.09 (d, J=8.34 Hz, 1H) 9.43 (s, 1H) 10.40 (s, 1H); ESI-MS: m/z calc'd for C27H31N5O2S 489.63. found 490.3 (M+H)+.
Reaction SMILES: [C:1]1([CH3:12])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][NH:8][C:9]([NH2:11])=[S:10].Br.Br[CH2:15][CH2:16]N>C(O)(C)C>[C:1]1([CH3:12])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][NH:8][C:9]1[S:10][CH2:15][CH2:16][N:11]=1
Reactant: NCCBr
Reactant: Cc1ccccc1NNC(N)=S
Agent: Br
Solvent: CC(C)O
Product: Cc1ccccc1NNC1=NCCS1
Temperature: 25 °C

Procedure:
A mixture of 27.2 g. (0.15 moles) of 1-(o-tolyl)-3-thiosemicarbazide, 31 g. (0.15 moles) of 2-bromoethylamine hydrobromide, and 800 ml. of isopropanol are heated at reflux temperature for 16 hours. The reaction mixture is cooled to room temperature and filtered. The solid material is washed with hot water and the aqueous solution is treated with saturated sodium bicarbonate solution. The solid material which separates is filtered, washed with water, and recrystallized with methanol affording 13 g. of 2-(o-tolylhydrazino)-2-thiazoline, m.p. 126°-127° C.
Reaction SMILES: [CH:1]([C:4]1[CH:8]=[N:7][N:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][C:16]([F:19])([F:18])[F:17])[C:5]=1[CH2:20][O:21][C:22]1[N:27]=[C:26]([CH3:28])[C:25]([N+:29]([O-])=O)=[CH:24][CH:23]=1)([CH3:3])[CH3:2]>CCO.C1COCC1.[Pt]=O>[CH:1]([C:4]1[CH:8]=[N:7][N:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][C:16]([F:19])([F:17])[F:18])[C:5]=1[CH2:20][O:21][C:22]1[N:27]=[C:26]([CH3:28])[C:25]([NH2:29])=[CH:24][CH:23]=1)([CH3:3])[CH3:2]
Reactant: Cc1nc(OCc2c(C(C)C)cnn2-c2ccccc2OC(F)(F)F)ccc1[N+](=O)[O-]
Agent: O=[Pt]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1nc(OCc2c(C(C)C)cnn2-c2ccccc2OC(F)(F)F)ccc1N
Reaction time: 3 h
Yield: 84.6 %

Procedure:
To an ambient temperature solution of 6-[4-Isopropyl-2-(2-trifluoromethoxy-phenyl)-2H-pyrazol-3-ylmethoxy]-2-methyl-3-nitro-pyridine (2.73 g, 6.25 mmol) in EtOH/THF (100/100 mL) is added platinum (II) oxide (142 mg, 0.625 mmol, 10 mol %). The reaction is placed under an atmosphere of hydrogen gas. After 3 h, the reaction is filtered through diatomaceous earth, concentrated, and chromatographed (0% to 30% EtOAc/Hex) to yield the title compound (2.15 g, 85%). 1H NMR (400 MHz, CDCl3) δ 7.60 (s, 1H), 7.53 (dd, 1H, J=7.9, 1.8 Hz), 7.46-7.41 (m, 1H), 7.39-7.31 (m, 2H), 7.08 (d, 1H, J=8.8 Hz), 6.33 (d, 1H, J=8.4 Hz), 5.17 (s, 2H), 3.06 (sept, 1H, J=7.0 Hz), 2.32 (s, 3H), 1.27 (d, 6H, J=7.0 Hz).
Reaction SMILES: Cl.[CH:2]1([NH:5][C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[N:16]=[C:17]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][C@H:25]4[CH3:30])[C:18]4[CH2:23][NH:22][CH2:21][C:19]=4[N:20]=3)=[C:11]([F:31])[CH:10]=2)=[O:7])[CH2:4][CH2:3]1.CCN(CC)CC.[CH3:39][S:40](Cl)(=[O:42])=[O:41]>CN(C=O)C>[CH:2]1([NH:5][C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[N:16]=[C:17]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][C@H:25]4[CH3:30])[C:18]4[CH2:23][N:22]([S:40]([CH3:39])(=[O:42])=[O:41])[CH2:21][C:19]=4[N:20]=3)=[C:11]([F:31])[CH:10]=2)=[O:7])[CH2:3][CH2:4]1
Reactant: C[C@@H]1COCCN1c1nc(-c2ccc(NC(=O)NC3CC3)cc2F)nc2c1CNC2
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C[C@@H]1COCCN1c1nc(-c2ccc(NC(=O)NC3CC3)cc2F)nc2c1CN(S(C)(=O)=O)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 24 %

Procedure:
To a stirring solution of (R)-1-cyclopropyl-3-(3-fluoro-4-(4-(3-methylmorpholino)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)phenyl)urea hydrochloride (intermediate 33) (112 mg, 0.25 mmol) in DMF (2 mL) was added NEt3 (70 μl, 0.5 mmol), and methanesulfonyl chloride (21 μL, 0.275 mmol). Reaction was stirred at room temp overnight. The reaction mixture was concentrated in vacuo before partitioning between DCM (10 ml) and water (10 ml). The organic layer was recovered, passed through a hydrophobic frit and the solvent removed in vacuo. Residue was then purified by prep. HPLC at high pH to afford the compound title compound as a light brown solid (30 mg, 0.06 mmol, 24%).
Reaction SMILES: [BH4-].[Na+].[C:3]([O:6][C@@H:7]1[CH2:14][C@H:13]2[C@H:9]([CH2:10][C@H:11]([CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])[O:12]2)[C@H:8]1/[CH:23]=[CH:24]/[C:25](=[O:32])[CH2:26][CH2:27][CH:28]=[C:29]([CH3:31])[CH3:30])(=[O:5])[CH3:4].CO>C1COCC1>[C:3]([O:6][C@@H:7]1[CH2:14][C@H:13]2[C@H:9]([CH2:10][C@H:11]([CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])[O:12]2)[C@H:8]1/[CH:23]=[CH:24]/[C@@H:25]([OH:32])[CH2:26][CH2:27][CH:28]=[C:29]([CH3:31])[CH3:30])(=[O:5])[CH3:4]
Reactant: COC(=O)CCCC[C@H]1C[C@@H]2[C@@H](/C=C/C(=O)CCC=C(C)C)[C@H](OC(C)=O)C[C@@H]2O1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)CCCC[C@H]1C[C@@H]2[C@@H](/C=C/[C@@H](O)CCC=C(C)C)[C@H](OC(C)=O)C[C@@H]2O1
Reaction time: 1 h

Procedure:
At -40°, 230 mg. of sodium borohydride is added in incremental portions to a solution of 470 mg. of (1S,5R,6R,7R,3S)-7-acetoxy-6-[(1E)-7-methyl-3-oxo-1,6-octadienyl]-3-(4-methoxycarbonyl-1-butyl)-2-oxabicyclo[3,3,0]octane in 14 ml. of methanol and 4 ml. of THF. The mixture is stirred for 1 hour at -40° and then combined with 0.6 ml. of glacial acetic acid, concentrated under vacuum, combined with methylene chloride, the organic extract shaken in 4% sodium bicarbonate solution, washed neutral with water, dried over magnesium sulfate, and evaporated under vacuum. After separation by chromatography on silica gel, ether/pentane (1+1) yields 120 mg. of the corresponding β-configured compound and 160 mg. of the title compound as a colorless oil.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][O:22][CH3:23])=[CH:15][CH:14]=2)=[CH:8][CH:7]=1.OO.O.O.O.O.O.S([O-])([O-])(=[O:33])=S.[Na+].[Na+].O>C(O)(=O)C>[CH3:23][O:22][CH2:21][CH2:20][O:19][C:16]1[CH:17]=[CH:18][C:13]([S:12]([C:9]2[CH:8]=[CH:7][C:6]([O:5][CH2:4][CH2:3][O:2][CH3:1])=[CH:11][CH:10]=2)=[O:33])=[CH:14][CH:15]=1
Reactant: COCCOc1ccc(Sc2ccc(OCCOC)cc2)cc1
Reactant: O=S([O-])([O-])=S
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COCCOc1ccc(S(=O)c2ccc(OCCOC)cc2)cc1
Reaction time: 15 h
Yield: 984.4 %

Procedure:
In 200 g of acetic acid was dissolved 28.5 g of bis[4-(2-methoxyethoxy)phenyl]sulfide obtained in Synthesis Example 1-33. While the solution was maintained at an internal temperature of 40° C., 7.87 g of 35 wt % aqueous hydrogen peroxide was added dropwise. The reaction solution was aged at room temperature for 15 hours, after which under ice cooling, a mixture of 2.0 g sodium thiosulfate pentahydrate and 10 g water was added dropwise to quench the reaction. The solution was concentrated in vacuum and combined with 100 g of toluene, 50 g of ethyl acetate and 50 g of water. The organic layer was separated, washed with water, and concentrated in vacuum. The concentrate was crystallized from 20 g of ethyl acetate and 300 g of hexane, obtaining 27.8 g of the target compound, bis[4-(2-methoxy-ethoxy)phenyl]sulfoxide as white crystals. Yield 91%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:28])[C:7]=1[NH:8][C:9]1[N:13]([CH3:14])[C:12]2[C:15]3[CH2:16][C:17]([CH3:27])([CH3:26])[O:18][C:19]=3[C:20]([C:22]([O:24]C)=O)=[CH:21][C:11]=2[N:10]=1.[F:29][C:30]1[CH:36]=[CH:35][C:33]([NH2:34])=[CH:32][C:31]=1[C:37]([F:40])([F:39])[F:38].C[Al](C)C>C1(C)C=CC=CC=1>[Cl:28][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[NH:8][C:9]1[N:13]([CH3:14])[C:12]2[C:15]3[CH2:16][C:17]([CH3:27])([CH3:26])[O:18][C:19]=3[C:20]([C:22]([NH:34][C:33]3[CH:35]=[CH:36][C:30]([F:29])=[C:31]([C:37]([F:40])([F:38])[F:39])[CH:32]=3)=[O:24])=[CH:21][C:11]=2[N:10]=1
Reactant: COC(=O)c1cc2nc(Nc3c(Cl)cncc3Cl)n(C)c2c2c1OC(C)(C)C2
Reactant: Nc1ccc(F)c(C(F)(F)F)c1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: Cn1c(Nc2c(Cl)cncc2Cl)nc2cc(C(=O)Nc3ccc(F)c(C(F)(F)F)c3)c3c(c21)CC(C)(C)O3
Yield: 52 %

Procedure:
The title compound was prepared following the procedure described for Example-143 by using methyl 2-((3,5-dichloropyridin-4-yl)amino)-1,7,7-trimethyl-7,8-dihydro-1H-benzofuro[4,5-d]imidazole-5-carboxylate (Intermediate-60, 0.100 g, 0.237 mmol), 4-fluoro-3-(trifluoromethyl) aniline (0.063 g, 0.356 mmol), trimethyl aluminium (2M solution in toluene) (0.5 mL), dry toluene (5.0 mL) to afford 0.070 g of the desired product. 1HNMR (DMSO-d6): δ 1.60 (s, 6H), 3.48 (s, 2H), 3.59 (s, 3H), 7.22 (s, 1H), 7.51 (t, J=9.9 Hz, 1H), 7.85-7.88 (m, 1H), 8.30 (m, 1H), 8.47 (s, 2H), 9.87 (s, 1H), 10.90 (s, 1H); MS [M]+: 568.03.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][NH2:10].[C:11](#[N:14])[CH:12]=[CH2:13]>C(O)C>[C:11]([CH2:12][CH2:13][NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][NH:10][CH2:4][CH2:3][C:2]#[N:1])#[N:14]
Reactant: NCCCCCCCCN
Reactant: C=CC#N
Solvent: CCO
Product: N#CCCNCCCCCCCCNCCC#N

Procedure:
Dissolve 14.4 g (0.1 mol) of 1,8-diaminooctane and 14.5 ml (0.22 mol) of acrylonitrile in 100 ml of ethanol and reflux overnight. Remove the solvent at reduced pressure. Analysis showed the title compound to be >98% pure.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]2[NH:18][C:12]3=[N+:13]([O-])[CH:14]=[CH:15][CH:16]=[C:11]3[CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Cl)(Cl)([Cl:21])=O.[OH-].[Na+]>>[Cl:21][C:16]1[CH:15]=[CH:14][N:13]=[C:12]2[NH:18][C:9]([CH2:8][CH2:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[CH:10][C:11]=12
Reactant: [O-][n+]1cccc2cc(CCc3ccccc3)[nH]c21
Reactant: O=P(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Product: Clc1ccnc2[nH]c(CCc3ccccc3)cc12
Temperature: 0 °C
Yield: 56.3 %

Procedure:
A mixture of 2-(2-phenylethyl)-1H-pyrrolo[2,3-b]pyridine 7-oxide (1.17 g, 4.91 mmol) and phosphorus oxychloride (9.73 g) was heated under reflux for 2 hr. The reaction mixture was poured into ice water, and the mixture was neutralized with sodium hydroxide and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=9/1-0/1) and washed with hexane to give the title compound (0.71 g, yield 56%) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH2:16])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15].[F:17][C:18]([F:33])([F:32])[C:19]1[CH:20]=[C:21]([N:29]=[C:30]=[O:31])[CH:22]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:24]=1>>[F:17][C:18]([F:32])([F:33])[C:19]1[CH:20]=[C:21]([NH:29][C:30]([NH:16][C:10]2[CH:11]=[CH:12][C:13]([O:14][CH3:15])=[C:8]([C:3]3[N:4]([CH3:7])[N:5]=[CH:6][C:2]=3[Cl:1])[CH:9]=2)=[O:31])[CH:22]=[C:23]([C:25]([F:28])([F:26])[F:27])[CH:24]=1
Reactant: O=C=Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: COc1ccc(N)cc1-c1c(Cl)cnn1C
Product: COc1ccc(NC(=O)Nc2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1-c1c(Cl)cnn1C
Yield: 32 %

Procedure:
3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine was treated with 3,5-Bis(trifluoromethyl)phenyl isocyanate in a similar manner as described in Example 1.53, providing 21.5 mg (32%) of Compound 82: LCMS m/z (%)=495 (M+H37Cl, 41), 493 (M+H35Cl, 100). 1H NMR (400 MHz, DMSO-d6) δ: 9.58 (s, 1H), 9.18 (s, 1H), 8.31 (s, 2H), 7.80 (s, 1H), 7.79 (s, 1H), 7.79 (dd, J1=8 Hz, J2=4 Hz, 1H), 7.59 (d, J=2 Hz, 1H), 7.36 (d, =8 Hz, 1H), 3.96 (s, 3H), 3.80 (s, 3H).
Reaction SMILES: [C:1]1([CH:7](Cl)[C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:14][CH:15]1[CH2:20][CH2:19][N:18]([CH2:21]/[CH:22]=[CH:23]/[CH2:24][O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[N+:32]([O-:34])=[O:33])[CH2:17][CH2:16]1.C(N(CC)C(C)C)(C)C>C(C(C)=O)C(C)C>[C:1]1([CH:7]([C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)[O:14][CH:15]2[CH2:16][CH2:17][N:18]([CH2:21]/[CH:22]=[CH:23]/[CH2:24][O:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[N+:32]([O-:34])=[O:33])[CH2:19][CH2:20]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=[N+]([O-])c1ccccc1OC/C=C/CN1CCC(O)CC1
Reactant: ClC(c1ccccc1)c1cccs1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)CC(C)C
Product: O=[N+]([O-])c1ccccc1OC/C=C/CN1CCC(OC(c2ccccc2)c2cccs2)CC1
Reaction time: 2 h
Yield: 65.8 %

Procedure:
Into 20 ml of methyl isobutyl ketone were dissolved 2.09 g of phenyl-2-thienylmethyl chloride, 3.50 g of 4-hydroxy-1-[4-(2-nitrophenoxy)-2(E)-butenyl]piperidine and 1.94 g of N,N-diisopropylethylamine, and the resultant solution was heated under reflux with stirring for 2 hours. After cooling, the reaction solution was washed with water, and the solvent was removed under reduced pressure. The residue was eluted with ethanol-chloroform (1:50) by silica gel column chromatography to give 3.06 g of oily 4-(phenyl-2-thienylmethoxy)-1-[4-(2-nitrophenoxy)-2(E)-butenyl]piperidine.
Reaction SMILES: [H-].[Na+].Br.Cl[C:5]1[C:14]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=2[C:8]2=[N:15][N:16]=[C:17]([NH2:18])[N:7]2[N:6]=1.[CH3:19][CH2:20][CH:21]([OH:24])[CH2:22][CH3:23]>CN(C=O)C>[CH2:20]([CH:21]([O:24][C:5]1[C:14]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=2[C:8]2=[N:15][N:16]=[C:17]([NH2:18])[N:7]2[N:6]=1)[CH2:22][CH3:23])[CH3:19]
Reactant: Nc1nnc2c3c(c(Cl)nn12)CCCC3
Reactant: CCC(O)CC
Agent: Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCC(CC)Oc1nn2c(N)nnc2c2c1CCCC2
Temperature: 50 °C
Reaction time: 1 h

Procedure:
3-Pentanol (20 ml) was initially charged under argon, admixed with sodium hydride (946 mg) and stirred at 50° C. for 1 h. Subsequently, 6-chloro-7,8,9,10-tetrahydro-[1,2,4]triazolo[3,4-a]-phthalazin-3-ylamine hydrobromide (W2.018, 1.88 g), dissolved in 3-pentanol (20 ml) and DMF (100 ml), was slowly added dropwise within 1 h. After stirring for 1 h, the mixture was concentrated, and the residue was admixed with water and extracted four times with dichloromethane. The combined organic phases were dried over magnesium sulfate, filtered and concentrated. The residue was purified using a 40 g silica gel cartridge (0-10% dichloromethane-methanol gradient in 50 min). The clean product fractions were combined and dried. 0.8 g of the title compound was obtained.
Reaction SMILES: Br[C:2]1[C:7]([NH:8][C:9](=[O:11])[CH3:10])=[N:6][CH:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([NH:18][C:19](=[O:21])[CH3:20])[CH:13]=2)[N:3]=1.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH:28]=[C:29]([O:33][CH3:34])[C:30]=1[O:31][CH3:32])[NH2:27].CC(C)([O-])C.[Na+].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1>[CH3:34][O:33][C:29]1[CH:28]=[C:26]([NH:27][C:2]2[C:7]([NH:8][C:9](=[O:11])[CH3:10])=[N:6][CH:5]=[C:4]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([NH:18][C:19](=[O:21])[CH3:20])[CH:13]=3)[N:3]=2)[CH:25]=[C:24]([O:23][CH3:22])[C:30]=1[O:31][CH3:32]
Reactant: CC(=O)Nc1cccc(-c2cnc(NC(C)=O)c(Br)n2)c1
Reactant: COc1cc(N)cc(OC)c1OC
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1cc(Nc2nc(-c3cccc(NC(C)=O)c3)cnc2NC(C)=O)cc(OC)c1OC
Temperature: 110 °C
Yield: 16.9 %

Procedure:
Method AA. In a tube suitable for microwave irradiation provided with stirring and an argon atmosphere were placed 2-bromo-3-acetamido-6-(3-acetamidophenyl)pyrazine (32 mg, 0.09164 mmol), 3,4,5-trimethoxyaniline (33.6 mg, 0.1833 mmol), sodium tert-butoxide (18 mg, 0.1833 mmol), Pd(0)2 dba3 (8.4 mg, 9.164 μmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xant phos) (5.3 mg, 9.164 μmol) and dry toluene 1.5 mL). The tube was heated by microwave irradiation at 110° C. for 30 minutes. The reaction crude was filtered and the precipitate washed with boiling ethyl acetate (30 mL). The organic layers were evaporated under vacuum and the resulting crude was chromatographed (eluent: mixture of ethyl acetate and methanol; 9:1) to produce 7 mg of title compound. Yield: 17%. 1H NMR (250 MHz, DMSO-d6) δ 2.06 (s, 3H), 2.17 (s, 3H), 3.64 (s, 3H), 3.77 (s, 9H), 7.24 (s, 2H), 7.42 (t, 1H, J=8.0 Hz), 7.64 (d, 1H, J=7.7 Hz), 7.73 (d, 1H, J=7.9 Hz), 8.22 (bs, 1H), 8.28 (s, 1H), 8.52 (s, 1H), 10.07 (s, 1H), 10.21 (s, 1H). m/z 452.2 [(M+H)+ calcd for C23H25N5O5 451.2].
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([O:7][C:8](=[O:22])[NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:3][CH2:2]1.[C:23]([O-:26])(O)=[O:24].[Na+].[OH-].[Na+].O>CC1OCCC1>[CH2:16]([O:26][C:23]([CH2:6][NH:1][CH2:2][CH2:3][N:1]1[CH2:2][CH2:3][CH:4]([O:7][C:8](=[O:22])[NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:5][CH2:6]1)=[O:24])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:10]=1
Reactant: O=C([O-])O
Reactant: O=C(Nc1ccccc1-c1ccccc1)OC1CCNCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CC1CCCO1
Solvent: O
Product: O=C(CNCCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1)OCc1ccccc1
Temperature: 30 °C
Reaction time: 0.5 h

Procedure:
The product from the previous step (in MeTHF) and biphenyl-2-yl-carbamic acid piperidin-4-yl ester (10.0 kg, 32.6 mol, 1.0 eq.) in MeTHF (28.5 kg) were placed in the reaction vessel and heated to 30° C. for one hour. The mixture was then cooled to 5° C. NaHB(OAc)3 (10.0 kg, 45.8 mol, 1.4 eq.) was added portion wise over a period of 40 minutes while maintaining the temperature below 20° C. The mixture was then stirred for 30 minutes. Additional NaHB(OAc)3 (0.5 kg) was added the reaction allowed to progress to completion. A saturated solution of NaHCO3 (14.3 kg, 15.3 mol, 1.1 volumes) was added and stirred for 10 minutes. The aqueous phase was separated and discarded. A 33% NaOH solution (15.8 kg, 129.9 mol, 4.0 eq.) was added to the reaction mixture to adjust the pH to be in the range of 8-12. Water (40 kg) was added in two portions, after which phase separation occurred. A saturated NaHCO3 (7.1 kg, 7.6 mol, 0.7 volumes) was added to the reaction mixture and stirred for 10 minutes. The aqueous phase was separated and discarded. Additional water (4.9 kg) was added to dissolve any remaining salts and a vacuum distillation was conducted at a maximum temperature of 45° C. to remove part of the solvent (7.2 volumes). MeOH (56.1 kg, 7.2 volumes) was added to the reaction mixture before continuing with the next step.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[CH2:5][N:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][C:10]([C:16]([O:18][CH3:19])=[O:17])=[CH:11][CH:12]=2)[C:7]1=[O:20].Cl.C(N(CC)CC)C.[CH3:32][CH:33]([CH3:37])[C:34](Cl)=[O:35]>C(Cl)Cl>[C:34]([NH:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[CH2:5][N:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][C:10]([C:16]([O:18][CH3:19])=[O:17])=[CH:11][CH:12]=2)[C:7]1=[O:20])(=[O:35])[CH:33]([CH3:37])[CH3:32]
Reactant: COC(=O)c1ccc2ccn(Cc3cccc(N)c3)c(=O)c2c1
Reactant: CC(C)C(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc2ccn(Cc3cccc(NC(=O)C(C)C)c3)c(=O)c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
To a solution of methyl 2-(3-aminobenzyl)-1-oxo-1,2-dihydroisoquinoline-7-carboxylate.HCl (0.15 g, 0.44 mmol) dissolved in methylene chloride (5 mL) was added triethylamine (0.30 mL, 2.2 mmol) and 2-methylpropanoyl chloride (0.09 mL, 0.87 mmol). The reaction mixture was stirred at rt for 2 h. The mixture was then concentrated to dryness and the residue was purified by flash silica gel chromatography (0% to 5% EtOAc/DCM) to afford methyl 2-[3-(isobutyrylamino)benzyl]-1-oxo-1,2-dihydroisoquinoline-7-carboxylate (0.15 g, 88%). LC-MS: (FA) ES+ 379.
Reaction SMILES: [C:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]2[O:10][CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[C:5]=2[CH:4]=1)#[N:2].N1C=CC=CC=1.[SH2:24]>C(N(CC)CC)C>[CH:4]1[C:5]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[CH2:11][O:10][C:6]=2[NH:7][C:8](=[O:9])[C:3]=1[C:1](=[S:24])[NH2:2]
Reactant: N#Cc1cc2c([nH]c1=O)OCc1ccccc1-2
Reactant: S
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: NC(=S)c1cc2c([nH]c1=O)OCc1ccccc1-2

Procedure:
Add 4.20 gm of 2-cyano-4,6-dihydro-3H[2]benzopyrano[3,4-b]-pyridin-3-one to 50 gm of pyridine. Add 3.0 ml of triethylamine to the system. Cool the system to 0°-5° and treat the system with hydrogen sulfide gas until the reaction is complete as indicated by thin layer chromatography. Isolate the title compound.
Reaction SMILES: [CH:1]([C@:4]1([C:17]([N:19]2[CH2:24][CH2:23][N:22]([C:25]3[CH:26]=[N:27][CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=3)[CH2:21][CH2:20]2)=[O:18])[CH2:8][CH2:7][C@@H:6]([NH:9]C(=O)OC(C)(C)C)[CH2:5]1)([CH3:3])[CH3:2].Cl>O1CCOCC1>[CH:1]([C@:4]1([C:17]([N:19]2[CH2:24][CH2:23][N:22]([C:25]3[CH:26]=[N:27][CH:28]=[C:29]([C:31]([F:34])([F:32])[F:33])[CH:30]=3)[CH2:21][CH2:20]2)=[O:18])[CH2:8][CH2:7][C@@H:6]([NH2:9])[CH2:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)[C@]1(C(=O)N2CCN(c3cncc(C(F)(F)F)c3)CC2)CC[C@@H](NC(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)[C@]1(C(=O)N2CCN(c3cncc(C(F)(F)F)c3)CC2)CC[C@@H](N)C1
Yield: 65 %

Procedure:
tert-Butyl [(1R,3S)-3-isopropyl-3-({4-[5-(trifluoromethyl)pyridin-3-yl)piperazin-1-yl}carbonyl)cyclopentyl]carbamate (190 mg, 0.14 mmol) was treated with a 4.0 M solution of HCl in 1,4-dioxane (5 mL) for 1 h at room temperature. The mixture was concentrated and purified by HPLC to provide 35 mg of desired product. MS calculated for C19H27F3N4O; (M+H) 385; found 385.1.
Reaction SMILES: [CH2:1]([C:3]1[S:7][C:6]([N:8]=[C:9]=[S:10])=[C:5]([C:11]([O:13]C)=O)[CH:4]=1)[CH3:2].[CH3:15][C:16]1[N:17]=[CH:18][N:19]([CH2:21][CH2:22][CH2:23][NH2:24])[CH:20]=1>>[CH2:1]([C:3]1[S:7][C:6]2[NH:8][C:9](=[S:10])[N:24]([CH2:23][CH2:22][CH2:21][N:19]3[CH:20]=[C:16]([CH3:15])[N:17]=[CH:18]3)[C:11](=[O:13])[C:5]=2[CH:4]=1)[CH3:2]
Reactant: CCc1cc(C(=O)OC)c(N=C=S)s1
Reactant: Cc1cn(CCCN)cn1
Product: CCc1cc2c(=O)n(CCCn3cnc(C)c3)c(=S)[nH]c2s1

Procedure:
The compound was synthesized starting from methyl 5-ethyl-2-isothiocyanatothiophene-3-carboxylate (0.100 g. 0.44 mmol) and 3-(4-methyl-1H-imidazol-1-yl)propan-1-amine (9) (0.061 g, 0.44 mmol) as described above.
Reaction SMILES: C([O:5][C:6](=[O:53])[CH2:7][CH2:8][S:9][CH2:10][CH:11]([O:35][C:36](=[O:52])[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])[CH2:12][O:13][C:14](=[O:34])[NH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])(C)(C)C.ClCCl>FC(F)(F)C(O)=O>[CH2:16]([NH:15][C:14]([O:13][CH2:12][CH:11]([O:35][C:36](=[O:52])[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])[CH2:10][S:9][CH2:8][CH2:7][C:6]([OH:53])=[O:5])=[O:34])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: CCCCCCCCCCCCCCCCCCNC(=O)OCC(CSCCC(=O)OC(C)(C)C)OC(=O)CCCCCCCCCCCCCCC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCCCCCCCCCCCCCNC(=O)OCC(CSCCC(=O)O)OC(=O)CCCCCCCCCCCCCCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
A solution of 7-octadecylcarbamoyloxy-6-palmitoyloxy-4-thiaheptanoic acid t-butyl ester as obtained in Reference Example 8 (3.425 g) in trifiuoroacetic acid (5 ml)-dichloromethane (3 ml) was stirred at room temperature for 1 hour, followed by solvent concentration under reduced pressure, to yield the title compound (3.14 g, yield 99%) as a colorless solid.