Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH2:8]([O:51][CH:52]1[C@H:56]2[C@H:57](OC3CCCCO3)[N:58](C(OC(C)(C)C)=O)[C:59]3[CH:66]=[CH:65][C:64]([O:67][CH3:68])=[CH:63][C:60]=3[C:61](=[O:62])[N:55]2[CH2:54][C:53]1=[CH2:83])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18][CH:19]1[C@H:23]2[C@H:24](OC3CCCCO3)[N:25](C(OC(C)(C)C)=O)[C:26]3[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][C:27]=3[C:28](=[O:29])[N:22]2[CH2:21][C:20]1=[CH2:50].C([O-])(O)=O.[Na+]>CO.C(Cl)(Cl)Cl>[CH2:17]([O:18][CH:19]1[C@@H:23]2[CH:24]=[N:25][C:26]3[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][C:27]=3[C:28](=[O:29])[N:22]2[CH2:21][C:20]1=[CH2:50])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][O:51][CH:52]1[C@@H:56]2[CH:57]=[N:58][C:59]3[CH:66]=[CH:65][C:64]([O:67][CH3:68])=[CH:63][C:60]=3[C:61](=[O:62])[N:55]2[CH2:54][C:53]1=[CH2:83]
Reactant: C=C1CN2C(=O)c3cc(OC)ccc3N(C(=O)OC(C)(C)C)[C@@H](OC3CCCCO3)[C@@H]2C1OCCCCCCCCCCOC1C(=C)CN2C(=O)c3cc(OC)ccc3N(C(=O)OC(C)(C)C)[C@@H](OC3CCCCO3)[C@H]12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: C=C1CN2C(=O)c3cc(OC)ccc3N=C[C@H]2C1OCCCCCCCCCCOC1C(=C)CN2C(=O)c3cc(OC)ccc3N=C[C@@H]12
Reaction time: 1 h
Yield: 61.9 %

Procedure:
95% TFA (2 mL) was added dropwise to dimer compound 28c (90 mg, 0.084 mmol) at 0° C. which was stirred for 1 h and then poured into saturated aqueous NaHCO3 (30 mL). The mixture was extracted with chloroform (3×20 mL) and the organic layer washed with water (20 mL), brine (20 mL), dried (MgSO4) and filtered. The excess solvent was removed under reduced pressure to give the crude product, which was subjected to flash column chromatography (SiO2, 2% methanol-chloroform). Removal of excess eluent under reduced pressure without heating afforded the final product 29c (34 mg, 0.052 mmol, 61%) as a solid: [α]26D=+309° (c=0.31, CHCl3); 1H NMR (CDCl3, 400 MHz): δ 1.31-1.39 (m, 8H, 15-H, 16-H), 1.40-1.51 (m, 4H, 14-H), 1.80-1.93 (m, 4H, 13-H), 2.89-3.10 (m, 2H, 1-H), 3.06-3.19 (m, 2H, 1-H), 3.81-3.95 (m, 8H, 11a-H, 7-OMe), 3.98-4.11 (m, 4H, 12-H), 4.28 (s, 4H, 3-H), 5.16-5.18 (m, 4H, 2a-H), 6.80 (s, 2H, 9-H), 7.49 (s, 2H, 6-H), 7.66 (d, 2H, J=4.56 Hz, 11-H); 13C NMR (CDCl3, 100 MHz): δ 25.8, 28.8, 29.2, 29.4, 35.2, 51.3, 53.8, 56.2, 69.0, 109.3, 110.4, 111.4, 119.5, 140.7, 141.7, 151.1, 162.4, 164.8; IR (neat): 2933, 1599, 1506, 1464, 1429, 1380, 1262, 1216; 1096, 729, 628 cm−1; MS (ES+) m/z (relative intensity) 655 ([M+H]+., 100), 656 ([M+2H]+., 50), 346 (97).
Reaction SMILES: C(N(CC)CC)C.Cl.[CH3:9][C@@:10]12[C:17]([CH3:19])([CH3:18])[CH:14]([CH2:15][CH2:16]1)[CH2:13][NH:12][CH2:11]2.[CH:20]12[CH2:29][CH:24]3[CH2:25][CH:26]([CH2:28][CH:22]([CH2:23]3)[CH:21]1[CH2:30][CH2:31][C:32](O)=[O:33])[CH2:27]2.CCN=C=NCCCN(C)C>C(Cl)Cl>[CH:20]12[CH2:29][CH:24]3[CH2:25][CH:26]([CH2:28][CH:22]([CH2:23]3)[CH:21]1[CH2:30][CH2:31][C:32]([N:12]1[CH2:13][CH:14]3[C:17]([CH3:19])([CH3:18])[C@:10]([CH3:9])([CH2:16][CH2:15]3)[CH2:11]1)=[O:33])[CH2:27]2
Reactant: O=C(O)CCC1C2CC3CC(C2)CC1C3
Reactant: CC1(C)C2CC[C@]1(C)CNC2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(C)C2CC[C@]1(C)CN(C(=O)CCC1C3CC4CC(C3)CC1C4)C2
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Triethylamine 44.1 μl was added to a methylene chloride of (1S)-1,8,8-trimethyl-3-azabicyclo[3.2.1]octane hydrochloride 50.0 mg and stirred at 0° C. for 30 min. 3-(2-adamantyl) propionic acid 60.4 mg and WSC 65.7 mg were added therein, then temperature of the reaction mixture was gradually changed to room temperature and stirred for 13 hours. The reaction mixture was washed with saturated aqueous sodium chloride solution and dried by anhydrous sodium sulfate. After filtering the drying agent, the filtrate was concentrated in vacuo to obtain crude (IS)-3-[3-(2-adamantyl)propionyl]-1,8,8-trimethyl-3-azabicyclo[3.2.1]octane. The concentrate was added to THF 5 ml solution of lithium aluminum hydride 12.0 mg and refluxed under heating for 3 hours. The reaction mixture was cooled, then water was added thereto and the insoluble material was removed by filtration. The filtrate was concentrated in vacuo. The thus obtained residue was purified by means of, silica gel column chromatography (Wako gel, C200, chloroform) to obtain the product.
Reaction SMILES: C([N:8]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C@@H:19]([O:32][Si:33]([CH2:38][CH3:39])([CH2:36][CH3:37])[CH2:34][CH3:35])[CH2:20][N:21](CC2C=CC=CC=2)[CH2:22][CH2:23][OH:24])[CH:14]=1)[S:9]([CH3:12])(=[O:11])=[O:10])C1C=CC=CC=1.CO.O.[H][H]>C1COCC1.[OH-].[OH-].[Pd+2]>[OH:24][CH2:23][CH2:22][NH:21][CH2:20][C@@H:19]([C:15]1[CH:14]=[C:13]([NH:8][S:9]([CH3:12])(=[O:10])=[O:11])[CH:18]=[CH:17][CH:16]=1)[O:32][Si:33]([CH2:34][CH3:35])([CH2:36][CH3:37])[CH2:38][CH3:39]
Reactant: [H][H]
Reactant: CC[Si](CC)(CC)O[C@@H](CN(CCO)Cc1ccccc1)c1cccc(N(Cc2ccccc2)S(C)(=O)=O)c1
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC[Si](CC)(CC)O[C@@H](CNCCO)c1cccc(NS(C)(=O)=O)c1
Temperature: 50 °C
Reaction time: 15 h
Yield: 106.6 %

Procedure:
(R)—N-Benzyl-N-(3-(2-(benzyl(2-hydroxyethyl)amino)-1-(triethylsilyloxy)ethyl)phenyl)methanesulfonamide (500 mg; intermediate described in Reference example 1 of International Publication No. WO03/035620) was dissolved in THF (1.76 mL; manufactured by Wako Pure Chemical Industries, Ltd.) and methanol (1.76 mL; manufactured by Wako Pure Chemical Industries, Ltd.) under nitrogen atmosphere, and added with 20% palladium hydroxide on carbon-49.94% wet with Water (102.7 mg; manufactured by N. E. Chemcat Corp.). The reaction system was replaced with hydrogen, and stirred at 50° C. for 15 hours under hydrogen atmosphere. After cooling the reaction solution to room temperature and replacement with nitrogen, filtration was carried out. The filtrate was concentrated under reduced pressure to obtain the title compound (364 mg).
Reaction SMILES: [C:1]([NH:5][C:6]1[CH:7]=[C:8]([CH:10]=[CH:11][C:12]=1[O:13][CH3:14])[NH2:9])(=[O:4])[CH2:2][CH3:3].[CH3:15][O:16][C:17]1[CH:18]=[C:19]([S:27](O)(=[O:29])=[O:28])[CH:20]=[C:21]([O:25][CH3:26])[C:22]=1[O:23][CH3:24]>>[C:1]([NH:5][C:6]1[CH:7]=[C:8]([NH:9][S:27]([C:19]2[CH:18]=[C:17]([O:16][CH3:15])[C:22]([O:23][CH3:24])=[C:21]([O:25][CH3:26])[CH:20]=2)(=[O:29])=[O:28])[CH:10]=[CH:11][C:12]=1[O:13][CH3:14])(=[O:4])[CH2:2][CH3:3]
Reactant: COc1cc(S(=O)(=O)O)cc(OC)c1OC
Reactant: CCC(=O)Nc1cc(N)ccc1OC
Product: CCC(=O)Nc1cc(NS(=O)(=O)c2cc(OC)c(OC)c(OC)c2)ccc1OC

Procedure:
Compound 91 is synthesized following a similar method as in Example 1 and using 3-propionamido-4-methoxyaniline and 3,4,5-trimethoxybenzenesulfonic acid as materials. Total yield of the two steps: 40%.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=2)[CH:7]=1.[C:17]([O:21][C:22]([N:24]1[CH2:29][C@@H:28]2[CH2:30][C@H:25]1[CH2:26][NH:27]2)=[O:23])([CH3:20])([CH3:19])[CH3:18].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(C)([O-])C.[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O.C1(C)C=CC=CC=1>[CH3:16][O:15][C:11]1[CH:10]=[C:9]([CH:14]=[CH:13][CH:12]=1)[O:8][C:6]1[CH:7]=[C:2]([N:27]2[CH2:26][C@@H:25]3[CH2:30][C@H:28]2[CH2:29][N:24]3[C:22]([O:21][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:23])[CH:3]=[N:4][CH:5]=1
Reactant: COc1cccc(Oc2cncc(Br)c2)c1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: Cc1ccccc1
Product: COc1cccc(Oc2cncc(N3C[C@@H]4C[C@H]3CN4C(=O)OC(C)(C)C)c2)c1

Procedure:
In a sealed pressure tube under an argon atmosphere, 3-bromo-5-(3-methoxyphenoxy)pyridine (0.53 g, 1.9 mmol), (1S,4S)-N-(tert-butoxycarbonyl)-2,5-diazabicyclo [2.2.1]heptane (0.469 g, 2.25 mmol), tris (dibenzylideneacetone)dipalladium(0) (0.050 g, 0.056 mmol), racemic-2,2′bis(diphenylphosphino)-1,1′binaphthyl (0.070 g, 0.11 mmol), sodium tert-butoxide (0.74 g, 7.5 mmol) and toluene (20 mL) was stirred at 70° C. for 24 h. The reaction mixture was poured into water (15 mL) and extracted with diethyl ether (3×30 mL). The combined diethyl ether extracts were dried (MgSO4), filtered and concentrated to a light-brown oil (1.3 g). The material was purified by chromatography on silica gel with ethyl acetate to gain a light-yellow oil (0.62 g, 83%).
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=1.[CH3:16][C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[N:21][CH:22]=1.C(=O)([O-])[O-].[Na+].[Na+].B(O)O>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O.O1CCOCC1>[Cl:13][C:10]1[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=[C:2]([C:19]2[CH:20]=[N:21][CH:22]=[C:17]([CH3:16])[CH:18]=2)[C:11]=1[CH3:12]
Reactant: Cc1c(Cl)nc2cc(F)cc(F)c2c1Cl
Reactant: Cc1cncc(B(O)O)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: OBO
Solvent: O
Solvent: C1COCCO1
Product: Cc1cncc(-c2nc3cc(F)cc(F)c3c(Cl)c2C)c1
Temperature: 95 °C
Reaction time: 22 h

Procedure:
A screw-cap vial was charged with 2,4-dichloro-5,7-difluoro-3-methylquinoline (600 mg, 2.42 mmol), 5-methylpyridine-3-boronic acid (348 mg, 2.54 mmol), dichlorobis(triphenylphosphine)palladium (II) (170 mg, 0.24 mmol), sodium carbonate (769 mg, 7.26 mmol), 1,4-dioxane (6.5 mL), and water (1.6 mL). The mixture was stirred at 95° C. for 22 h, then 0.2 additional equivalents of the aforementioned boronic acid were added and the reaction was continued for 18 h. Upon completion, the reaction was cooled to rt and partitioned between EtOAc and water. The organic layer was washed with brine, dried over magnesium sulfate, and cond. The resulting crude product was purified by flash chromatography (silica gel, 0-30% EtOAc in hexanes), affording 4-chloro-5,7-difluoro-3-methyl-2-(5-methylpyridin-3-yl)quinoline. Mass Spectrum (ESI) m/e=305.0 (M+1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[CH:3]=1.[Br:12][C:13]1[CH:14]=[C:15]([C:20]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[C:29]=2[C:35]#[N:36])=[N:21]S(C(C)(C)C)=O)[CH:16]=[CH:17][C:18]=1[F:19]>>[Br:12][C:13]1[CH:14]=[C:15]([C:20]2([C:2]3[CH:7]=[CH:6][N:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[CH:3]=3)[C:28]3[C:29](=[C:30]([F:34])[CH:31]=[CH:32][CH:33]=3)[C:35]([NH2:36])=[N:21]2)[CH:16]=[CH:17][C:18]=1[F:19]
Reactant: CC(C)(C)S(=O)N=C(c1ccc(F)c(Br)c1)c1cccc(F)c1C#N
Reactant: FC(F)(F)c1cc(Br)ccn1
Product: NC1=NC(c2ccnc(C(F)(F)F)c2)(c2ccc(F)c(Br)c2)c2cccc(F)c21
Yield: 35 %

Procedure:
The title compound was synthesized as described for Example 11i in 35% yield, starting from of 4-bromo-2-(trifluoromethyl)pyridine (0.159 g, 0.71 mmol) and N-((3-bromo-4-fluorophenyl)(2-cyano-3-fluorophenyl)methylene)-2-methylpropane-2-sulfinamide (0.300 g, 0.71 mmol);
Reaction SMILES: C1(N2CCN(CCCCCC([NH:20][C:21]3[CH:22]=[C:23](OC)[CH:24]=[C:25]4[C:30]=3[N:29]=[CH:28][CH:27]=[C:26]4[CH3:31])=O)CC2)CCCCC1.[Cl-].[Al+3].[Cl-].[Cl-].[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+]>O1CCCC1.O>[CH3:31][C:26]1[C:25]2[C:30](=[C:21]([NH2:20])[CH:22]=[CH:23][CH:24]=2)[N:29]=[CH:28][CH:27]=1
Reactant: COc1cc(NC(=O)CCCCCN2CCN(C3CCCCC3)CC2)c2nccc(C)c2c1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccnc2c(N)cccc12
Reaction time: 3 h
Yield: 99 %

Procedure:
A mixture of 2.6 g of crude 4-cyclohexyl-N-(6-methoxy-4-methyl-8-quinolinyl)-1-piperazinehexanamide in 100 ml of tetrahydrofuran was filtered to remove 0.3 g of white insoluble material. The filtrate, now containing 2.3 g (0.005 mole) of starting material was added dropwise to a cold (-20°) mixture of aluminum chloride and lithium aluminum hydride which had been prepared by adding a cold (-40°) slurry of 1.1 g (0.008 mole) of aluminum chloride in 75 ml of tetrahydrofuran to an equally cold suspension of 0.9 g (0.02 mole) of lithium aluminum hydride in 50 ml of tetrahydrofuran and allowing the mixture to warm to -20°. The reaction mixture was stirred at -20° to 0° for 3 hr and allowed to stand overnight at 4°. To the stirred mixture was added 3.8 ml of 30% sodium hydroxide and enough water to clarify the supernatant, which was then decanted. The residual sticky precipitate was washed with tetrahydrofuran. The supernatant and wash were combined, concentrated in vacuo to remove most of the tetrahydrofuran and taken up in water and ether. The ether layer was washed, dried and concentrated, leaving 2 g of crude product. Recrystallization from 2-propanol afforded 0.9 g (43%) of the purified material, mp 68°-70°.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]([C:12]2[CH2:13][CH2:14][N:15]([C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:16][CH:17]=2)[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](=[O:30])[N:7]2[C:22]1[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:23]=1[Cl:29].[F:31][C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1.ClC1C=CC=C(Cl)C=1N1C2C(=C(C3C=CC(F)=CC=3F)C=C(OC)C=2)CCC1=O.Cl>CCOCC>[C:18]([N:15]1[CH2:16][CH:17]=[C:12]([C:10]2[CH:9]=[C:8]3[C:3]([CH:4]=[CH:5][C:6](=[O:30])[N:7]3[C:22]3[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:23]=3[Cl:29])=[C:2]([C:35]3[CH:36]=[CH:37][C:32]([F:31])=[CH:33][CH:34]=3)[CH:11]=2)[CH2:13][CH2:14]1)([CH3:19])([CH3:21])[CH3:20]
Reactant: CC(C)(C)N1CC=C(c2cc(Br)c3ccc(=O)n(-c4c(Cl)cccc4Cl)c3c2)CC1
Reactant: OB(O)c1ccc(F)cc1
Agent: COc1cc(-c2ccc(F)cc2F)c2c(c1)N(c1c(Cl)cccc1Cl)C(=O)CC2
Agent: Cl
Solvent: CCOCC
Product: CC(C)(C)N1CC=C(c2cc(-c3ccc(F)cc3)c3ccc(=O)n(-c4c(Cl)cccc4Cl)c3c2)CC1

Procedure:
The title compound was prepared from 5-bromo-7-(1-tert-butyl-1,2,3,6-tetrahydropyridin-4-yl)-1-(2,6-dichlorophenyl)quinolin-2(1H)-one (INTERMEDIATE ABA5) and using 4-fluorophenylboronic acid by procedures analogous to that described in INTERMEDIATE 2. The title compound was converted to HCl salt by treating it with 2M HCl in Et2O. Mass spectrum (ESI): 521.5 (M+1).
Reaction SMILES: [CH:1]([O:4][CH:5]1[CH2:10][CH2:9][C@H:8]([NH:11]C(=O)OCC2C=CC=CC=2)[C@H:7]([CH2:22][S:23]([CH:26]([CH3:28])[CH3:27])(=[O:25])=[O:24])[CH2:6]1)([CH3:3])[CH3:2].[H][H]>CO.[Pd]>[CH:1]([O:4][CH:5]1[CH2:10][CH2:9][C@H:8]([NH2:11])[C@H:7]([CH2:22][S:23]([CH:26]([CH3:28])[CH3:27])(=[O:24])=[O:25])[CH2:6]1)([CH3:3])[CH3:2]
Reactant: CC(C)OC1CC[C@H](NC(=O)OCc2ccccc2)[C@H](CS(=O)(=O)C(C)C)C1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)OC1CC[C@H](N)[C@H](CS(=O)(=O)C(C)C)C1

Procedure:
A sample of benzyl (1S,2R)-4-isopropoxy-2-(isopropylsulfonylmethyl)cyclohexylcarbamate (7.73 g, 18.8 mMol) and Pd/C (2 g) were taken in MeOH (250 mL) and stirred at rt under 50 psi hydrogen. After 2.5 h the reaction was filtered through Celite with EtOAc. The resulting solution was concentrated and dried in vacuo to yield (1S,2R)-4-isopropoxy-2-(isopropylsulfonylmethyl)cyclohexanamine as a clear oil which was used without any further purification.
Reaction SMILES: [N:1]1[C:6]2[S:7][CH:8]=[CH:9][C:5]=2[C:4]([NH:10][CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)=[N:3][CH:2]=1.[Cl:24]N1C(=O)CCC1=O>C(O)(=O)C>[Cl:24][C:8]1[S:7][C:6]2[N:1]=[CH:2][N:3]=[C:4]([NH:10][CH:11]3[CH2:12][CH2:13][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:15][CH2:16]3)[C:5]=2[CH:9]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ncnc3sccc23)CC1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(Nc2ncnc3sc(Cl)cc23)CC1
Yield: 70.5 %

Procedure:
A mixture of t-butyl 4-(thieno[2,3-d]pyrimidin-4-ylamino)piperidine-1-carboxylate (1.00 g, 3.00 mmol) and N-chlorosuccinimide (0.39 g, 3.00 mmol) were heated in 50 mL of acetic acid for 3 h. After cooling to room temperature acetic acid was removed under reduced pressure and the remaining residue was partition in 1 M NaOH and DCM. The DCM layer was dried over Na2SO4 and evaporated under reduced pressure. The crude product was purified by silica chromatography in 5% MeOH-DCM to collect 0.78 g of product (71% yield). 1H NMR (400 MHz, CDCl3): δ 8.45 (s, 1H), 7.01 (s, 1H), 4.94 (d, 1H), 4.32 (m, 1H), 4.15 (m, 2H), 2.94 (m, 2H), 2.11 (m, 2H), 1.48 (s, 9H), 1.44 (m, 2H); MS (ESI) m/z: Calculated for C16H21ClN4O2S, 368.11; Observed: 368.8 (M++1).
Reaction SMILES: [Br:1][C:2]1[C:10]2[S:9][C:8]([NH:11][C@@H:12]3[CH2:17][CH2:16][CH2:15][CH2:14][C@H:13]3[OH:18])=[N:7][C:6]=2[CH:5]=[CH:4][C:3]=1[O:19]C.B(Br)(Br)Br>C(Cl)Cl.C(=O)(O)[O-].[Na+]>[Br:1][C:2]1[C:10]2[S:9][C:8]([NH:11][C@@H:12]3[CH2:17][CH2:16][CH2:15][CH2:14][C@H:13]3[OH:18])=[N:7][C:6]=2[CH:5]=[CH:4][C:3]=1[OH:19]
Reactant: COc1ccc2nc(N[C@@H]3CCCC[C@H]3O)sc2c1Br
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Oc1ccc2nc(N[C@@H]3CCCC[C@H]3O)sc2c1Br

Procedure:
To the solution of (1R,2R)-2-(7-bromo-6-methoxybenzo[d]thiazol-2-ylamino) cyclohexanol (191 mg, 0.537 mmol, 1.0 eq) in 10 mL of DCM was added 1 M solution of boron tribromide (ca. 3.0 mL, 2.68 mmol, 5.0 eq) at room temperature. The reaction mixture was refluxed for 12 hours, thereafter the mixture was diluted with saturated sodium bicarbonate (ca. 100 mL) till PH=7 and aqueous layer extracted with ethyl acetate (ca. 150 mL×3). Combined organic layers were dried over sodium sulfate, filtered and condensed under reduced pressure to give sufficiently pure crude product which was carried to next step without further purification LC/MS (m/z) [345.0] (MH+)
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:26]([OH:28])=O)=[C:8]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[CH:14][CH:13]=2)[N:9]=1)(=[O:3])[CH3:2].CN.O[N:32]1[C:36]2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C(=O)([O-])O.[Na+]>C(O)C.ClCCl.CN(C)C=O>[C:1]([NH:4][C:5]1[S:6][C:7]([C:26]([NH:32][CH3:36])=[O:28])=[C:8]([CH2:10][CH2:11][C:12]2[CH:13]=[CH:14][C:15]([NH:18][C:19](=[O:20])[O:21][C:22]([CH3:24])([CH3:23])[CH3:25])=[CH:16][CH:17]=2)[N:9]=1)(=[O:3])[CH3:2]
Reactant: On1nnc2ccccc21
Reactant: CC(=O)Nc1nc(CCc2ccc(NC(=O)OC(C)(C)C)cc2)c(C(=O)O)s1
Agent: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCO
Product: CNC(=O)c1sc(NC(C)=O)nc1CCc1ccc(NC(=O)OC(C)(C)C)cc1
Yield: 112.4 %

Procedure:
A mixture of 2-(acetylamino)-4-(2-{4-[(tert-butoxycarbonyl)amino]phenyl}ethyl)-1,3-thiazole-5-carboxylic acid (80 mg), 30% methylamine in ethanol solution (0.02 ml), 1-hydroxybenzotriazole (29.3 mg) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (39.7 mg) in dichloromethane (1 ml) and N,N-dimethylformamide (0.5 ml) was stirred at ambient temperature for 20 hours. The reaction mixture was poured into saturated sodium hydrogen carbonate solution, and extracted with chloroform. The organic layer was washed with water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated in vacuo to give tert-butyl 4-(2-{2-(acetylamino)-5-[(methylamino)carbonyl]-1,3-thiazol-4-yl}ethyl)phenylcarbamate (92.8 mg) as an off-white amorphous substance.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Cl:13][C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][N:15]=1.[C:21](=O)([O:25]CC)[O:22][CH2:23][CH3:24].CN(C)P(N(C)C)(N(C)C)=O>C1COCC1>[Cl:13][C:14]1[CH:19]=[C:18]([CH2:20][C:21]([O:22][CH2:23][CH3:24])=[O:25])[CH:17]=[CH:16][N:15]=1
Reactant: Cc1ccnc(Cl)c1
Reactant: CCOC(=O)OCC
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCOC(=O)Cc1ccnc(Cl)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 75.5 %

Procedure:
In a 1000 mL round-bottom flask, diisopropylamine (80.21 mL, 567.5 mmol) was combined with THF (250 mL) and cooled to −78° C. Butyllithium (227.0 mL, 567.5 mmol) (2.5M in hexane) was added and the mixture was stirred for 30 minutes. 2-Chloro-4-methylpyridine (36.20 g, 283.8 mmol) in THF (100 mL) was added, and the mixture was stirred for 2 hours. A mixture of diethyl carbonate (37.82 mL, 312.1 mmol) and hexamethylphosphoramide (54.31 mL, 312.1 mmol) was added, and the mixture was stirred at −78° C. for one hour and then stirred at ambient temperature. The reaction was quenched with 25% ammonium chloride solution and extracted twice with ethyl acetate. The combined organic extracts were washed with brine, dried and evaporated. The crude oil was purified by silica gel chromatography, eluting with 5% ethyl acetate/hexane to provide the desired product as clear oil (42.75 g, 75.47% yield).
Reaction SMILES: [N-:1]=[C:2]=[O:3].[F:4][C:5]1[C:6]([Si:14]([CH3:17])([CH3:16])[CH3:15])=[C:7]([CH:11]=[CH:12][CH:13]=1)C(O)=O.C(Cl)(=O)C(Cl)=O.[N-]=[N+]=[N-].[Na+]>O.CC(C)=O>[F:4][C:5]1[C:6]([Si:14]([CH3:17])([CH3:16])[CH3:15])=[C:7]([N:1]=[C:2]=[O:3])[CH:11]=[CH:12][CH:13]=1
Reactant: [N-]=C=O
Reactant: C[Si](C)(C)c1c(F)cccc1C(=O)O
Agent: O=C(Cl)C(=O)Cl
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: C[Si](C)(C)c1c(F)cccc1N=C=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Preparation of the intermediate isocyanate was carried out via a Curtius rearrangement. See Capson, T. L. et al., Tetrahedron Lett., 25, 3515 (1984) and references herein. To a solution of the compound prepared in (2) (3.03 g, 14.3 mmol) in CH2C12 (20 mL) was added oxalylchloride (1.30 mL, 15.0 mmol) and the resulting mixture was stirred 3 h at room temperature. The residue obtained after evaporation of the solvent was diluted with THF (10 mL) and injected with vigorous stirring to a ice-cooled solution of NaN3 (3.70 g, 57 mmol) in H2O (20 mL) and acetone (50 mL). After 15 min at 0° C. and 1 min at room temperature, the solution was extracted with Et2O (4×50 mL) and dried (Na2SO4). The residue obtained after evaporation of solvents was refluxed in toluene for 1 h 30 to provide, upon solvent removal, 2.85 g (79%) of a slightly yellow oil: IR (neat, cm−1) 2269, 1598, 1433, 1252, 1228, 846, 788; 1H NMR (300 MHz, CDCl3) δ0.38 (d, J=1.9 Hz, 9H), 6.82 (br t, J=8.3 Hz, 1H), 6.90 (br d, J=8.2 Hz, 1H), 7.25 (ddd, J1=J28.1 Hz, J36.6 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ0.4, 112.6 (d, JCF=26Hz), 120.5, 122.5, 131.5, 139.2, 167.4 (d, JCF241 Hz).
Reaction SMILES: [CH2:1]([C:3]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:4]=1[NH2:5])[CH3:2].N1C=CC=CC=1.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>C(Cl)Cl>[CH2:1]([C:3]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:4]=1[NH:5][S:20]([CH3:19])(=[O:22])=[O:21])[CH3:2]
Reactant: CCc1ccc([N+](=O)[O-])cc1N
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCc1ccc([N+](=O)[O-])cc1NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.9 %

Procedure:
To a solution of 2-ethyl-5-nitroaniline (200 mg, 1.20 mmol) in DCM (5 mL) was added pyridine (0.195 mL, 2.41 mmol) and methanesulfonyl chloride (0.11 mL, 1.44 mmol). The reaction mixture was stirred at room temperature overnight. The mixture was diluted with DCM, washed with water and brine and dried to give Intermediate 78A (290 mg, 99%) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ ppm 8.35 (1H, d, J=2.26 Hz), 8.04 (1H, dd, J=8.53, 2.26 Hz), 7.44 (1H, d, J=8.53 Hz), 6.59 (1H, br. s.), 3.15 (3H, s), 2.76 (2H, q, J=7.53 Hz), 1.32 (3H, t, J=7.53 Hz).
Reaction SMILES: [C:1]([CH:4]([CH2:8][CH2:9][C:10](=[O:12])[CH3:11])[C:5](=[O:7])[CH3:6])(=[O:3])[CH3:2].[C:13]([O:17][CH2:18][CH3:19])(=[O:16])[CH:14]=[CH2:15].C(O)(=O)C>N12CCCN=C1CCCCC2.C(OCC)C>[CH2:18]([O:17][C:13](=[O:16])[CH2:14][CH2:15][C:4]([C:5](=[O:7])[CH3:6])([C:1](=[O:3])[CH3:2])[CH2:8][CH2:9][C:10](=[O:12])[CH3:11])[CH3:19]
Reactant: CC(=O)CCC(C(C)=O)C(C)=O
Reactant: C=CC(=O)OCC
Solvent: CC(=O)O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCOCC
Product: CCOC(=O)CCC(CCC(C)=O)(C(C)=O)C(C)=O
Reaction time: 16 h
Yield: 57.4 %

Procedure:
10.2 g of 3-acetyl-2,6-heptandione and 5 drops of 1,8-diazabicyclo-[5.4.0]-undec-7-ene were mixed, and 9 g of ethyl acrylate was added dropwise over 15 minutes. After stirring for 16 hours, the base was neutralized with acetic acid, 30 ml of diethyl ether was added, and the solution was extracted with sodium carbonate solution and water. Fractional distillation of the dry organic layer yielded 9.3 g of 4,4-diacetyl-7-oxo-octanoic-ethyl ester (boiling point: 136° C./0.02 mbar; purity: 81%; colorless).