Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH2:18][SH:19].C([O-])([O-])=O.[K+].[K+].CCOC(C)=O.O>CN(C=O)C>[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH2:18][S:19][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1
Reactant: SCc1ccccc1Cl
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(SCc2ccccc2Cl)cc1
Reaction time: 16 h
Yield: 98 %

Procedure:
To a solution of 1-fluoro-4-nitrobenzene (1.0 equivalent) and (2-chlorophenyl)methanethiol (1.0 equivalent) in DMF (1.0 M) at rt was added K2CO3 (2.0 equivalents). After 16 h, the rxn was transferred to EtOAc:water (1:1). The organic layer was separated and sequentially washed with water (2×) and brine. The material was dried (MgSO4), filtered and concentrated to afford (2-chlorobenzyl)(4-nitrophenyl)sulfane in 98% yield. The material was taken through without further purification.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=2)[C:7](=[S:10])[NH:8][N:9]=1)[CH2:2][CH2:3][CH3:4].Cl[CH2:22][C:23]([O:25][CH3:26])=[O:24]>COCCO>[CH2:1]([C:5]1[N:6]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=2)[C:7]([S:10][CH2:22][C:23]([O:25][CH3:26])=[O:24])=[N:8][N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1n[nH]c(=S)n1Cc1ccc([N+](=O)[O-])cc1
Reactant: COC(=O)CCl
Solvent: COCCO
Product: CCCCc1nnc(SCC(=O)OC)n1Cc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.3 %

Procedure:
A stirred solution of 2.00 g (6.84 mmole) of 5-n-butyl-2,4-dihydro-4-(4-nitrobenzyl)-3H-1,2,4-triazole-3-thione in 10 ml of 2-methoxyethanol was treated with 2.38 ml (1.77 g, 13.7 mmole) of N,N-disopropylethylamine followed by 1.20 ml (1.48 g, 13.7 mmole) of methyl chloroacetate. The solution was stirred at room temperature under N2 for 2 hours and then concentrated in vacuo at 45° C. The residual oil was partioned between 70 ml of ethyl acetate and 70 ml of H2O. The organic phase was washed with 70 ml of H2O and then with 50 ml of saturated NaCl solution. The ethyl acetate solution was dried (MgSO4), filtered, concentrated and dried in vacuo to yield 2.50 g (100%) of the titled compound as an oil, homogenous by TLC in 19:1 CH2Cl2 --MeOH; mass spectrum (FAB) m/e 365 (M+1 )+.
Reaction SMILES: [CH3:1][CH:2]([OH:9])[CH2:3][NH:4][CH2:5][CH:6]([OH:8])[CH3:7].[C:10](O)(=O)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>O>[CH3:1][CH:2]1[O:9][C:21]2([CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH3:10])[O:8][CH:6]([CH3:7])[CH2:5][N:4]2[CH2:3]1
Reactant: CCCCCCCCCCCC(=O)O
Reactant: CC(O)CNCC(C)O
Solvent: O
Product: CCCCCCCCCCCC12OC(C)CN1CC(C)O2
Temperature: 186 °C

Procedure:
To a 5 liter stirred reactor, equipped with a distillation column, condenser, and graduated receiver, the following constituents were added: 1250.0 g of diisopropanol amine (DIPA) and 1502.5 g (98%) of lauric acid. The contents were heated to 186° C. under a nitrogen blanket over a 90 minute period. During that time, 136 ml of water came overhead. The batch temperature was held at 184° C. while the pressure was dropped to 320 Pa. During the pressure reduction, 410 g of unreacted DIPA came overhead. A total of 1192 g of amide acetal derived from lauric acid was collected while the temperature was raised to 220° C. at a pressure of 280-466 Pa. This represents a 53.5% conversion of the lauric acid.
Reaction SMILES: Br[CH2:2][C:3](=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[I:10][C:11]1[CH:12]=[CH:13][C:14]([NH2:17])=[N:15][CH:16]=1>CN(C=O)C.O>[CH2:7]([O:6][C:4]([C:3]1[N:17]=[C:14]2[CH:13]=[CH:12][C:11]([I:10])=[CH:16][N:15]2[CH:2]=1)=[O:5])[CH3:8]
Reactant: Nc1ccc(I)cn1
Reactant: CCOC(=O)C(=O)CBr
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cn2cc(I)ccc2n1
Reaction time: 2 h
Yield: 58.2 %

Procedure:
A mixture of sulfuric acid (0.5 mL), acetic acid (12 mL) and water (2 mL) was added to a reaction flask containing 2-aminopyridine (2.0 g, 21.26 mmol) and the solution was stirred for 5 minutes. NaIO4 (1.81 g, 8.5 mmol) followed by 12 (2.16 g, 8.5 mmol) was added into the reaction flask and stirred at 80° C. for 4 hrs. The reaction mixture was cooled to ambient temperature, diluted with cold water, basified with 20% aqueous KOH solution and extracted with DCM. The organic layer was washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure to obtain the crude residue. Purification by column chromatography (using silica gel 60-120 and 8% EtOAc in hexane as eluent) and subsequent recrystallisation from ethanol afforded 53 g (58.6% Yield) of 5-iodo-pyridin-2-ylamine. Ethyl bromopyruvate (4.89 g, 25.11 mmol) was added to solution of 5-iodo-pyridin-2-ylamine (5.0 g, 22.83 mmol) in DMF (25 mL) and stirring was continued at 80° C. for 2 hrs. The reaction mixture was diluted with cold water and extracted with ethyl acetate. The organic layer was washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure to obtain the crude residue. The residue obtained was purified by recrystallisation from methanol to afford 4.2 g (57.8% Yield) of 6-iodo-imidazo[1,2-a]pyridine-2-carboxylic acid ethyl ester. A mixture of imidazole (513 mg, 7.5 mmol), cuprous oxide (71 mg, 0.5 mmol), 6-iodo-imidazo[1,2-a]pyridine-2-carboxylic acid ethyl ester (1.6 g, 5.02 mmol), salox (137 mg, 1.0 mmol) and cesium carbonate (3.27 g, 10.05 mmol) in ACN (2 mL) in a seal tube were subjected to reaction in a microwave reactor (time: 15 min, temp: 85° C., power: zero, pressure: zero). The reaction mixture was filtered through celite and the filtrate collected was concentrated under reduced pressure. The residue was diluted with cold water, extracted with ethyl acetate, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (using neutral alumina and 0.2% MeOH in DCM as eluent) to afford 400 mg (31% Yield) of 6-pyrazol-1-yl-imidazo[1,2-a]pyridine-2-carboxylic acid ethyl ester. A mixture of 6-pyrazol-1-yl-imidazo[1,2-a]pyridine-2-carboxylic acid ethyl ester (250 mg, 0.97 mmol) in 8N aqueous HCl (3 mL) was stirred at 100° C. for 2 hrs. The reaction mixture was concentrated under reduced pressure to afford 130 mg (58.5% Yield) of 6-pyrazol-1-yl-imidazo[1,2-a]pyridine-2-carboxylic acid.
Reaction SMILES: [CH:1](/[CH:4]1[O:8][C@H:7]([C:9]([O:11][CH:12]([CH3:14])[CH3:13])=[O:10])[C@@H:6]([C:15]([O:17][CH:18]([CH3:20])[CH3:19])=[O:16])[O:5]1)=[CH:2]\[CH3:3].[CH2:21]([Zn]CC)C.ICI>>[CH3:3][C@H:2]1[CH2:21][C@@H:1]1[CH:4]1[O:5][C@H:6]([C:15]([O:17][CH:18]([CH3:20])[CH3:19])=[O:16])[C@@H:7]([C:9]([O:11][CH:12]([CH3:14])[CH3:13])=[O:10])[O:8]1
Reactant: CC[Zn]CC
Reactant: C/C=C/C1O[C@H](C(=O)OC(C)C)[C@@H](C(=O)OC(C)C)O1
Solvent: ICI
Product: CC(C)OC(=O)[C@H]1OC([C@H]2C[C@@H]2C)O[C@@H]1C(=O)OC(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 89 %

Procedure:
To a −20° C. solution of intermediate diisopropyl (4S,5S)-2-[(1E)-prop-1-enyl]-1,3-dioxolane-4,5-dicarboxylate (4.10 g, 14.32 mmol) in 60 mL hexanes was added IM diethylzinc in hexanes (42.96 mL, 42.96 mmol). Diiodomethane (6.92 mL, 85.92 mmol) was added dropwise with vigorous stirring. After 1 h at −20° C., the reaction was refrigerated at −5° C. After 17 h at −5° C., the reaction was stirred at 0° C. for an additional 5 h and then quenched with cold saturated ammonium chloride solution (100 mL) and extracted with Et2O (100 mL×3). The combined organics were washed w/aqueous sodium thiosulfate (100 mL) and brine (100 mL), filtered, dried over Na2SO4, filtered again and concentrated in vacuo. Purification by normal phase chromatography (10->30% EtOAc/hexanes) yielded 3.85 g (89%) of diisopropyl (4S,5S)-2-[(1S,2S)-2-methylcyclopropyl]-1,3-dioxolane-4,5-dicarboxylate as a yellow oil. 1H NMR (CDCl3, 400 MHz) 5.12 (m, 2H); 4.78 (d, J=6.41 Hz, 1H); 4.66 (d, J=4.21 Hz, 1H); 4.57 (d, J=4.22 Hz, 1H); 1.30 (m, 12H); 1.09 (d, J=5.68 Hz, 3H); 0.94 (m, 2H); 0.67 (m, 1H); 0.39 (m, 1H); LC/MS [M+H]+=301.
Reaction SMILES: [CH2:1]([C@@H:8]([CH2:12][CH2:13][C@H:14]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:15](=[O:32])[NH:16][C@H:17]1[CH2:23][CH2:22][CH2:21][CH2:20][N:19]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH3:30])[C:18]1=[O:31])[C:9](O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:40][C@H:41]1[CH2:47][CH2:46][S:45][C@H:44]2[CH2:48][CH2:49][C@@H:50]([C:52]([F:55])([F:54])[F:53])[CH2:51][N:43]2[C:42]1=[O:56]>>[CH2:33]([C@@H:14]([CH2:13][CH2:12][C@H:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:9]([NH:40][C@H:41]1[CH2:47][CH2:46][S:45][C@H:44]2[CH2:48][CH2:49][C@@H:50]([C:52]([F:53])([F:55])[F:54])[CH2:51][N:43]2[C:42]1=[O:56])=[O:10])[C:15]([NH:16][C@H:17]1[CH2:23][CH2:22][CH2:21][CH2:20][N:19]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH3:30])[C:18]1=[O:31])=[O:32])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: N[C@H]1CCS[C@H]2CC[C@@H](C(F)(F)F)CN2C1=O
Reactant: Cc1ccccc1N1CCCC[C@H](NC(=O)[C@H](CC[C@H](Cc2ccccc2)C(=O)O)Cc2ccccc2)C1=O
Product: Cc1ccccc1N1CCCC[C@H](NC(=O)[C@H](CC[C@H](Cc2ccccc2)C(=O)N[C@H]2CCS[C@H]3CC[C@@H](C(F)(F)F)CN3C2=O)Cc2ccccc2)C1=O

Procedure:
(2R,5R)-2,5-Dibenzyl-N1-((S)-2-oxo-1-o-tolylazepan-3-yl)-N6-((4S,8R,10aS)-5-oxo-8-(trifluoromethyl)octahydro-2H-pyrido[2,1-b][1,3]thiazepin-4-yl)hexanediamide was synthesized as described in General Procedure H using Intermediate 71 (12 mg, 0.022 mmol) and Intermediate 61 (5.0 mg, 0.019 mmol) to give a white solid (5.7 mg, 38% yield). Anal. Calcd. for C43H51F3N4O4S m/z 776.7. found: 777.6 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 7.34-7.03 (m, 11H), 7.04-6.89 (m, 3H), 5.12 (t, J=7.3 Hz, 1H), 4.85-4.67 (m, 2H), 4.35 (d, J=14.8 Hz, 1H), 3.98 and 3.80 (s, 3H), 3.97-3.82 (m, 1H), 3.49-3.08 (m, 8H), 2.93-2.52 (m, 6H), 2.51-2.26 (m, 2H), 2.26-2.13 (m, 1H), 2.05-1.53 (m, 9H), 1.54-1.16 (m, 3H).
Reaction SMILES: C[O-].[Na+].I.[NH:5]=[C:6]1[N:10]([CH3:11])[C:9]2[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=2[N:7]1[CH3:16].[C:17]1([N:23]=[C:24]=[S:25])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(O)C.C1(C)C=CC=CC=1>[CH3:11][N:10]1[C:9]2[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=2[N:7]([CH3:16])[C:6]1=[N:5][C:24]([NH:23][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[S:25]
Reactant: S=C=Nc1ccccc1
Reactant: Cn1c(=N)n(C)c2ccccc21
Agent: C[O-]
Agent: I
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: Cn1c(=NC(=S)Nc2ccccc2)n(C)c2ccccc21

Procedure:
Sodium methoxide (0.54 g) was added to a mixture of 2-imino-1,3-dimethylbenzimidazole hydroiodide (3.135 g) in ethanol (10 ml) and brought to reflux, with stirring. Phenylisothiocyanate (1.635 g) in toluene (5 ml) was added to the mixture over 10 minutes and the resulting mixture heated under reflux, with stirring, for 1 hour then cooled in ice. Filtration, washing with ethanol and water and drying gave analytically pure product, mpt 245° C.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[C:7]([OH:10])[CH:8]=[CH:9][C:4]=2[CH2:3][CH2:2]1.CC1C=C(O)C=CC=1C.[F:20][C:21]([F:44])([F:43])[C:22]1[O:26][C:25]([CH2:27][N:28]2[C:36]3[CH:35]=[C:34]4[O:37][CH2:38][CH2:39][O:40][C:33]4=[CH:32][C:31]=3[C:30](=[O:41])[C:29]2=[O:42])=[CH:24][CH:23]=1.C1(C(C2C=CC=CC=2)N2C3C(=CC=CC=3)C(=O)C2=O)C=CC=CC=1>>[OH:41][C:30]1([C:8]2[C:7]([OH:10])=[CH:6][C:5]3[O:1][CH2:2][CH2:3][C:4]=3[CH:9]=2)[C:31]2[CH:32]=[C:33]3[O:40][CH2:39][CH2:38][O:37][C:34]3=[CH:35][C:36]=2[N:28]([CH2:27][C:25]2[O:26][C:22]([C:21]([F:43])([F:44])[F:20])=[CH:23][CH:24]=2)[C:29]1=[O:42]
Reactant: O=C1C(=O)N(Cc2ccc(C(F)(F)F)o2)c2cc3c(cc21)OCCO3
Reactant: Oc1ccc2c(c1)OCC2
Agent: Cc1ccc(O)cc1C
Agent: O=C1C(=O)N(C(c2ccccc2)c2ccccc2)c2ccccc21
Product: O=C1N(Cc2ccc(C(F)(F)F)o2)c2cc3c(cc2C1(O)c1cc2c(cc1O)OCC2)OCCO3

Procedure:
Following the procedure as described in PREPARATION 6A, and making non-critical variations using 2,3-dihydrobenzofuran-6-ol to replace 3,4-dimethylphenol, and 6-{[5-(trifluoromethyl)furan-2-yl]methyl}-2,3-dihydro-6H-[1,4]dioxino[2,3-f]indole-7,8-dione to replace 1-(diphenylmethyl)-1H-indole-2,3-dione, 8-hydroxy-8-(6-hydroxy-2,3-dihydrobenzofuran-5-yl)-6-((5-(trifluoromethyl)furan-2-yl)methyl)-6,8-dihydro-2H-[1,4]dioxino[2,3-f]indol-7(3H)-one was obtained (76%): 1H NMR (300 MHz, CDCl3) δ 9.08 (s, 1H), 7.07 (s, 1H), 6.74-6.68 (m, 1H), 6.64 (s, 1H), 6.52 (s, 1H), 6.48 (s, 1H), 6.36-6.32 (m, 1H), 4.84 (dd, J=48.7, 16.3 Hz, 2H), 4.53 (t, J=8.7 Hz, 2H), 4.32-4.20 (m, 4H), 4.16 (s, 1H), 3.08-2.94 (m, 2H); MS (ES+) m/z 471.9 (M−17).
Reaction SMILES: [CH2:1]([OH:12])[C:2]#[C:3][CH2:4][C:5]#[C:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].N1C2C(=CC=CC=2)C=CC=1.[H][H]>C(O)C.[Pd].CC([O-])=O.CC([O-])=O.[Pb+2]>[CH2:1]([OH:12])/[CH:2]=[CH:3]\[CH2:4]/[CH:5]=[CH:6]\[CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCCC#CCC#CCO
Reactant: [H][H]
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: CCO
Solvent: c1ccc2ncccc2c1
Product: CCCCC/C=C\C/C=C\CO
Reaction time: 7 h
Yield: 69.6 %

Procedure:
2,5-undecadiyn-1-ol (1.5 g) in absolute ethanol (15 ml) was reduced with Lindlar catalyst (0.33 g) in the presence of quinoline (0.1 ml) at 25° C., 1 atm., for 7 h. The uptake of hydrogen stopped at 420 ml (theoretical 428 ml). The solution was filtered, and the solvent was evaporated to give 1.5 g of crude product which was then purified by column chromatography on silica gel (50 g). Elution with ether-petroleum ether (1:4 parts by volume) gave 1.07 g of (Z,Z)-2,5-undecadien-1-ol as an oil.
Reaction SMILES: [Br:1][C:2]1[C:6](I)=[CH:5][Se:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(NCC)C.[C:32]1([C:38]#[CH:39])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>CC(OC)(C)C.[Cu]I.CN(C=O)C>[Br:1][C:2]1[C:6]([C:39]#[C:38][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[CH:5][Se:4][CH:3]=1
Reactant: C#Cc1ccccc1
Reactant: Brc1c[se]cc1I
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCNCC
Solvent: CN(C)C=O
Solvent: COC(C)(C)C
Product: Brc1c[se]cc1C#Cc1ccccc1
Temperature: 70 °C
Yield: 54.3 %

Procedure:
To a pressure vessel purged with N2 was added 3-bromo-4-iodo-selenophene (1.97 g, 5.87 mmol), DMF (5.20 mL), triphenylphosphine (0.307 g, 1.17 mmol), copper(I) iodide (0.0740 g, 0.387 mmol), diethylamine (dried over KOH, 9.20 mL, 88.0 mmol), phenyl acetylene (0.645 mL, 5.87 mmol), and palladium dichloride-bis-triphenylphosphine (0.272 g, 0.387 mmol). The reaction vessel was sealed and the mixture heated to 70° C. for 1 h. Upon cooling to room temperature, the reaction mixture was diluted with MTBE (50.0 mL) and was washed with 0.1 M HCl (3×30.0 mL). The combined aqueous layers were extracted with MTBE (30.0 mL). The MTBE rich layer was dried over magnesium sulfate and concentrated to an oil. The crude oil was purified by column chromatography (silica gel, cyclohexane) to provide 3-bromo-4-phenylethynyl-selenophene (1.07 g, 3.19 mmol, 54.3 mol %): 500 MHz 1H NMR (CDCl3) δ 8.18 (d, J=2.9 Hz, 1H), 7.90 (d, J=2.9 Hz, 1H), 7.58-7.54 (m, 2H), 7.36-7.32 (m, 3H); 125 MHz 13C NMR (CDCl3) δ 134.2, 131.7, 128.5, 128.4, 126.8, 126.3, 122.9, 114.1, 91.0, 84.7.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[C@H:14]([NH:15][C:16]2[N:21]=[C:20](Cl)[C:19]3[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][C:18]=3[C:17]=2[F:34])[CH2:13][CH2:12][O:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:35][C:36]1[CH:41]=[CH:40][N:39]2[N:42]=[CH:43][C:44](B3OC(C)(C)C(C)(C)O3)=[C:38]2[CH:37]=1.C(=O)([O-])[O-].[K+].[K+].C(N[C@H](C(O)=O)CS)(=O)C>O.CC(N(C)C)=O>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[C@H:14]([NH:15][C:16]2[N:21]=[C:20]([C:44]3[CH:43]=[N:42][N:39]4[CH:40]=[CH:41][C:36]([CH3:35])=[CH:37][C:38]=34)[C:19]3[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][C:18]=3[C:17]=2[F:34])[CH2:13][CH2:12][O:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@H]1COCC[C@H]1Nc1nc(Cl)c2c(c1F)CN(C(=O)OC(C)(C)C)C2=O
Reactant: Cc1ccn2ncc(B3OC(C)(C)C(C)(C)O3)c2c1
Agent: CC(=O)N[C@@H](CS)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: Cc1ccn2ncc(-c3nc(N[C@@H]4CCOC[C@@H]4NC(=O)OC(C)(C)C)c(F)c4c3C(=O)N(C(=O)OC(C)(C)C)C4)c2c1
Temperature: 25 °C
Reaction time: 0.05 h
Yield: 21 %

Procedure:
To a 25 mL reaction flask equipped with magnetic stir bar and thermometer was added tert-butyl 6-((3R,4R)-3-(tert-butoxycarbonylamino)tetrahydro-2H-pyran-4-ylamino)-4-chloro-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate (200 mg, 0.399 mmol) and 5-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine (124 mg, 0.479 mmol), followed by potassium carbonate (325 mesh powder) (110 mg, 0.798 mmol), DMA (10 mL), and water (0.667 mL). The mixture was stirred at room temperature for 3 min before degassing with vacuum and N2 back-fill (5×). To the resulting deep purple mixture was added Pd-118 (10.89 mg, 0.016 mmol). The reaction mixture was degassed again with vacuum and N2 back-fill (5×). The flask was wrapped tightly with plastic film, placed in an oil bath, and the reaction mixture was stirred at 80° C. for 18 hours. Solid N-acetyl cysteine (65.2 mg, 0.399 mmol) was added and the mixture was stirred at 70° C. for 2 h. The mixture was subsequently diluted with water and extracted with EtOAc (200 mL). The organic layer was dried and concentrated to give a residue, which was purified by preparative HPLC, eluting with a gradient of 45-70% ACN (0.035% TFA) and water (0.05% TFA). The fractions were collected to give, upon basic work-up, the title compound as a light yellow solid (50 mg, 21%).
Reaction SMILES: [CH3:1][N:2](S(C1C=CC=CC=1)(=O)=O)[N:3]=[C:4](Cl)[C:5]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:6]=1[F:12].[Cl:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][C:31]=1[O:32][C:33]1[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:35][N:34]=1)[C:27]#[N:28].ClC1C=CC=CC=1Cl>C(Cl)(Cl)Cl.[Fe](Cl)(Cl)Cl>[Cl:23][C:24]1[CH:25]=[C:26]([C:27]2[N:2]([CH3:1])[N:3]=[C:4]([C:5]3[C:6]([F:12])=[CH:7][CH:8]=[CH:9][C:10]=3[F:11])[N:28]=2)[CH:29]=[CH:30][C:31]=1[O:32][C:33]1[CH:38]=[CH:37][C:36]([C:39]([F:40])([F:41])[F:42])=[CH:35][N:34]=1
Reactant: N#Cc1ccc(Oc2ccc(C(F)(F)F)cn2)c(Cl)c1
Reactant: CN(N=C(Cl)c1c(F)cccc1F)S(=O)(=O)c1ccccc1
Agent: Cl[Fe](Cl)Cl
Solvent: Clc1ccccc1Cl
Solvent: ClC(Cl)Cl
Product: Cn1nc(-c2c(F)cccc2F)nc1-c1ccc(Oc2ccc(C(F)(F)F)cn2)c(Cl)c1
Temperature: 140 °C
Reaction time: 0.5 h
Yield: 53.7 %

Procedure:
A mixture of N-methyl-N-(benzenesulfonyl)-2,6-difluorobenzohydrazonoyl chloride (1.72 g), 3-chloro-4-(5-trifluoromethylpyridine-2-yloxy)benzonitrile (1.50 g), anhydrous iron (III) chloride (0.85 g) and o-dichlorobenzene (10 ml) is stirred at an oil bath temperature of 140° C. for 30 minutes. After cooling, it is dissolved in chloroform (200 ml) and washed with dilute hydrochloric acid, dilute aqueous solution of sodium hydroxide and saline. Then, it is dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The concentrate is purified by silica gel column chromatography using mixed solvent of hexane-ethyl acetate as eluent and washed with hexane to give 1.25 g of desired compound.
Reaction SMILES: [CH3:1][CH:2]([CH:5]=[CH2:6])[CH2:3][OH:4].[H-].[Na+].[C:9]([O:12]I)(=[O:11])[CH3:10].[Na].Cl>C1COCC1.O.[Cl-].[Na+].O>[CH3:1][CH:2]([CH:5]=[CH2:6])[CH2:3][O:4][CH2:10][C:9]([OH:12])=[O:11]
Reactant: C=CC(C)CO
Reactant: CC(=O)OI
Agent: Cl
Agent: [Cl-]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: C=CC(C)COCC(=O)O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Under nitrogen atmosphere a suspension of 0.5 g (5.81 mmol) 2-methyl-3-buten-1-ol and 0.348 g (8.71 mmol, 60% suspension in mineral oil) NaH in 10 ml THF are stirred 3 h at rt. Solid sodium iodo acetate (1.81 g, 8.71 mmol) is added and stirring is continued for 2 h. The mixture is diluted with water and brine, acidified with 1N HCl and extracted with EtOAc. The organic phase is dried with sodium sulfate and concentrated. the residue is kugelrohr distilled at ca 1 mbar (70-110° C.) to yield the title compound as a colorless liquid.
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:19])[NH:5][C:6](=[O:18])[NH:7][C:8]=1[S:9][C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[CH:11]=1)[CH3:2].[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH:27]=[C:28]([O:30][CH3:31])[CH:29]=1)[CH2:25]Br>>[CH3:31][O:30][C:28]1[CH:27]=[C:24]([CH:23]=[C:22]([O:21][CH3:20])[CH:29]=1)[CH2:25][N:7]1[C:8]([S:9][C:10]2[CH:11]=[C:12]([CH3:17])[CH:13]=[C:14]([CH3:16])[CH:15]=2)=[C:3]([CH2:1][CH3:2])[C:4](=[O:19])[NH:5][C:6]1=[O:18]
Reactant: COc1cc(CBr)cc(OC)c1
Reactant: CCc1c(Sc2cc(C)cc(C)c2)[nH]c(=O)[nH]c1=O
Product: CCc1c(Sc2cc(C)cc(C)c2)n(Cc2cc(OC)cc(OC)c2)c(=O)[nH]c1=O
Yield: 59.1 %

Procedure:
5-Ethyl-6-(3,5-dimethylphenyl)thio-2,4-pyrimidinedione and 3,5-dimethoxybenzyl bromide were reacted by the same way with the example 1 to obtain the titled compound (252 mg, yield: 59.1%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:22][CH3:23])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[NH:14][C:15]([CH:17]4[CH2:21][CH2:20][NH:19][CH2:18]4)=[CH:16][C:9]=23)[CH:7]=1.C(N(CC)CC)C.[C:31](Cl)(=[O:33])[CH3:32]>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:22][CH3:23])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[NH:14][C:15]([CH:17]4[CH2:21][CH2:20][N:19]([C:31](=[O:33])[CH3:32])[CH2:18]4)=[CH:16][C:9]=23)[CH:7]=1
Reactant: COc1ccc(F)cc1-c1ccnc2[nH]c(C3CCNC3)cc12
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(F)cc1-c1ccnc2[nH]c(C3CCN(C(C)=O)C3)cc12
Reaction time: 16 h

Procedure:
To a suspension of Example 59F (50 mg, 0.130 mmol) and triethylamine (0.091 mL, 0.651 mmol) in dichloromethane (2 mL) was added acetyl chloride (0.195 mL, 0.195 mmol) at room temperature. The mixture was stirred for 16 hours, concentrated, and purified by reverse phase flash chromatography (silica gel-C18, 15-60% acetonitrile/water/0.1% trifluoroacetic acid) to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ 1.95 (d, J=4.1 Hz, 3H), 1.98-2.40 (m, 3H), 3.23-3.42 (m, 2H), 3.45-3.60 (m, 2H), 3.73 (s, 3H), 3.77-3.96 (m, 2H), 6.11 (dd, J=10.4, 1.7 Hz, 1H), 7.08 (dd, J=5.1, 1.6 Hz, 1H), 7.15-7.34 (m, 3H), 8.20 (d, J=5.1 Hz, 1H), 11.81 (s, 1H). MS (ESI+) m/z 354.1 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4]Br.[NH2:10][C:11]1[S:12][C:13]2[C:18]([NH:19][C@H:20]([CH3:23])[CH2:21][OH:22])=[N:17][C:16]([SH:24])=[N:15][C:14]=2[N:25]=1.C(N(C(C)C)CC)(C)C>CS(C)=O.CN1CCCC1=O>[NH2:10][C:11]1[S:12][C:13]2[C:18]([NH:19][C@H:20]([CH3:23])[CH2:21][OH:22])=[N:17][C:16]([S:24][CH2:4][C:3]3[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=3[F:1])=[N:15][C:14]=2[N:25]=1
Reactant: C[C@H](CO)Nc1nc(S)nc2nc(N)sc12
Reactant: Fc1ccccc1CBr
Solvent: CN1CCCC1=O
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](CO)Nc1nc(SCc2ccccc2F)nc2nc(N)sc12
Yield: 35 %

Procedure:
2-fluorobenzylbromide (0.369 g) was added portionwise to a solution of the product of example 32 step b) (0.5 g) and diisopropylethylamine (0.26 g) in DMSO/N-methylpyrrolidinone (4 ml/0.5 ml) at 50° C. and stirring maintained for 1 h. The mixture was partitioned between H2O (200 ml) and EtOAc (120 ml). The organics were recovered and washed further with H2O (200 ml), dried over MgSO4 and concentrated onto silica gel. The subtitle compound was purified by flash chromatography using DCM then EtOAc as eluents to yield a white solid (245 mg, 35%).
Reaction SMILES: [O-:1][C:2]1C=CC=CC=1.[O-:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[Mg+2].[CH2:16]=[O:17]>>[CH2:2]=[O:1].[CH:9](=[O:8])[C:10]1[C:16](=[CH:14][CH:13]=[CH:12][CH:11]=1)[OH:17]
Reactant: [O-]c1ccccc1
Agent: C=O
Agent: [Mg+2]
Product: O=Cc1ccccc1O

Procedure:
reacting magnesium bis-phenoxide with formaldehyde or a formaldehyde-liberating compound under substantially anhydrous conditions to form the magnesium salt of salicylaldehyde, said magnesium bis-phenoxide having been obtained by reacting phenol with a magnesium alkoxide of formula 4;