Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([Cl:15])[CH:13]=2)[N:8]([S:16]([C:19]2[CH:20]=[N:21][CH:22]=[C:23](Br)[CH:24]=2)(=[O:18])=[O:17])[CH:7]=1.[F:27][C:28]([F:39])([F:38])[C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3](=[O:26])[CH2:4][CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([Cl:15])[CH:13]=2)[N:8]([S:16]([C:19]2[CH:20]=[N:21][CH:22]=[C:23]([C:32]3[CH:33]=[CH:34][C:29]([C:28]([F:39])([F:38])[F:27])=[CH:30][CH:31]=3)[CH:24]=2)(=[O:18])=[O:17])[CH:7]=1
Reactant: COC(=O)CCc1cn(S(=O)(=O)c2cncc(Br)c2)c2ccc(Cl)cc12
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: COC(=O)CCc1cn(S(=O)(=O)c2cncc(-c3ccc(C(F)(F)F)cc3)c2)c2ccc(Cl)cc12

Procedure:
In a micro wave test tube, 3-[1-(5-bromo pyridine-3-sulfonyl)-5-chloro-1H-indol-3-yl]propionic acid methyl ester (11, 40 mg, 0.00009 mol), 4-(trifluoromethyl)-phenylboronic acid (12, 52 mg, 0.00027 mol), and tetrakis(triphenylphosphine)palladium(0) (4 mg, 0.000003 mol) were combined in 4 mL of 1,4-dioxane. The vessel was purged with argon for 2-3 minutes, then 0.1 mL of 1N K2CO3 was added. The vessel was microwaved at 108° C. for 40 minutes. TLC (20% ethyl acetate,/hexane) indicated a new spot and total disappearance of starting material. The crude mixture was transferred to a separatory funnel and extracted with 3×40 mL of ethyl acetate and washed with water, brine, and dried over MgSO4. The solution was filtered and the filtrate roto evaporated to near dryness. Silica and 5 mL of ethyl acetate were added and the solvent removed. Chromatography was run using a gradient solvent condition of 0 to 20% ethyl acetate/hexane over 18 minutes, then 20 to 30% over 10 minutes to isolate the desired compound. 1H NMR consistent with structure.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[CH:10][N:11]([CH3:23])[C:12]=2[C:13]2[S:22][C:16]3[N:17]=[CH:18][N:19]=[C:20]([NH2:21])[C:15]=3[CH:14]=2)=[CH:4][CH:3]=1.NC1C=C(C2N=CN(C)C=2C2SC3N=CN=C(N)C=3C=2)C=CC=1.[CH2:47]([N:54]=[C:55]=[O:56])[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1>>[NH2:21][C:20]1[C:15]2[CH:14]=[C:13]([C:12]3[N:11]([CH3:23])[CH:10]=[N:9][C:8]=3[C:5]3[CH:6]=[CH:7][C:2]([NH:1][C:55]([NH:54][CH2:47][C:48]4[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=4)=[O:56])=[CH:3][CH:4]=3)[S:22][C:16]=2[N:17]=[CH:18][N:19]=1
Reactant: O=C=NCc1ccccc1
Reactant: Cn1cnc(-c2ccc(N)cc2)c1-c1cc2c(N)ncnc2s1
Agent: Cn1cnc(-c2cccc(N)c2)c1-c1cc2c(N)ncnc2s1
Product: Cn1cnc(-c2ccc(NC(=O)NCc3ccccc3)cc2)c1-c1cc2c(N)ncnc2s1

Procedure:
The title compound was prepared by a similar process to that described for Example 186 but using 6-[4-(4-aminophenyl)-1-methyl-1H-imidazol-5-yl]thieno[2,3-d]pyrimidin-4-amine (Intermediate 112) in place of 6-[4-(3-aminophenyl)-1-methyl-1H-imidazol-5-yl]thieno[2,3-d]pyrimidin-4-amine (Intermediate 110) and using benzyl isocyanate in place of phenyl isocyanate. Yellow solid (10 mg, 36%);
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([N+:8]([O-])=O)[C:5]([O:11][CH3:12])=[CH:4][CH:3]=1.C(O)C.[Cl-].[NH4+]>[Fe].O>[NH2:8][C:6]1[C:5]([O:11][CH3:12])=[CH:4][CH:3]=[C:2]([Br:1])[N:7]=1
Reactant: COc1ccc(Br)nc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: COc1ccc(Br)nc1N
Temperature: 72.5 °C
Reaction time: 0.25 h

Procedure:
To a heterogeneous solution of 6-bromo-3-methoxy-2-nitropyridine (32) (2.32 g, 10 mmol) in of ethanol:water (40 mL, each) were added iron powder (2.8 g, 50 mmol), followed by ammonium chloride (2.64 g, 50 mmol) at room temperature. The resulting heterogeneous mixture was then stirred at 70-75° C. for 15 minutes, filtered through celite (when hot), washed with ethanol (2×50 mL) and solvent was then removed under reduced pressure. The residue upon dilution with water afforded a solid, which was isolated by filtration to give 2-amino-6-bromo-3-methoxypyridine (33). LCMS: purity: 95%, MS (m/z): 203 (MH+).
Reaction SMILES: CS(C)=O.[CH3:5][C:6]1[CH:7]=[C:8]([OH:20])[C:9]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][N:14]=2)=[N:10][C:11]=1[CH3:12].Cl[C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[N:25]=[CH:24][CH:23]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O>[CH3:5][C:6]1[CH:7]=[C:8]([O:20][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)[C:9]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][N:14]=2)=[N:10][C:11]=1[CH3:12]
Reactant: Cc1ccc(-c2nc(C)c(C)cc2O)nc1
Reactant: Clc1ccnc2ccccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1ccc(-c2nc(C)c(C)cc2Oc2ccnc3ccccc23)nc1
Temperature: 140 °C
Reaction time: 5 h
Yield: 71.5 %

Procedure:
Dimethyl sulfoxide (2 ml) was added to 5,6,5′-trimethyl-[2,2′]bipyridin-3-ol (50 mg), 4-chloroquinoline (115 mg), and cesium carbonate (228 mg), and the mixture was stirred at 140° C. for 5 hr. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (57 mg, yield 72%).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][C:3]=1[F:12].[F:13][C:14]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[C:16]([F:22])[C:15]=1B(O)O.[F-].[K+].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>C1COCC1.O.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]>[F:13][C:14]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[C:16]([F:22])[C:15]=1[C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][C:3]=1[F:12]
Reactant: COC(=O)c1ccc(F)c(Br)n1
Reactant: COc1cc(F)c(B(O)O)c(F)c1
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(F)c(-c2c(F)cc(OC)cc2F)n1
Temperature: 80 °C
Yield: 85 %

Procedure:
To a solution of methyl 6-bromo-5-fluoropicolinate (1.0 equiv.) in THF and water (10:1, 0.1 M) was added 2,6-difluoro-4-methoxyphenylboronic acid (2.5 equiv.) and potassium fluoride (3.3 equiv.). The reaction was degassed with nitrogen, then Pd2(dba)3 (0.25 equiv.) and tri-tert-butylphosphine (0.5 equiv.) were added and the reaction was heated to 80° C. for one hour. LC/MS analysis indicated complete conversion of the starting material to product. The reaction was cooled to room temperature, then concentrated in vacuo and fused to silica gel. The crude product was purified by ISCO flash chromatography eluting with ethyl acetate and hexanes (0% to 30% ethyl acetate) to provide methyl 6-(2,6-difluoro-4-methoxyphenyl)-5-fluoropicolinate as a white solid in 85% yield. LC/MS=298.0 (M+H), Rt=0.89 min.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH2:5][CH2:6][C:7]1[CH:8]=[C:9]([CH2:13][CH2:14][C:15](O)=[O:16])[CH:10]=[CH:11][CH:12]=1)[CH3:2]>C1COCC1>[OH:16][CH2:15][CH2:14][CH2:13][C:9]1[CH:8]=[C:7]([CH2:6][CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:18])[CH:12]=[CH:11][CH:10]=1
Reactant: CCOC(=O)CCc1cccc(CCC(=O)O)c1
Solvent: C1CCOC1
Product: CCOC(=O)CCc1cccc(CCCO)c1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 55.4 %

Procedure:
To a solution of 3-[3-(3-ethoxy-3-oxopropyl)phenyl]propanoic acid (10.7 g) and TEA (6.28 mL) in THF (100 mL) was added isobutyl chloroforamate (5.82 mL) dropwise at 0° C. The reaction mixture was stirred at the same temperature for 5 minutes and filtered. And the precipitate was and rinsed with THF (50 mL). The filtrate and the rinse liquid were combined and the resultant mixture was cooled at 0° C. To the resultant mixture was added sodium borohydride (2.43 g) followed by adding water (1.21 mL) dropwise at the same temperature. The reaction mixture was quenched and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous MgSO4, filtered and evaporated in vacuo. The residue was purified by silica gel column chromatography (n-hexane:EtOAc=7:3) to afford ethyl 3-[3-(3-hydroxypropyl)phenyl]propanoate (5.60 g) a colorless oil.
Reaction SMILES: [Cl-].[Li+].C([Mg]Cl)(C)C.I[C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=1.[CH2:19]([O:21][C:22]1[C:23]([C:34](N(OC)C)=[O:35])=[N:24][N:25]([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)[N:26]=1)[CH3:20]>O1CCCC1>[CH2:19]([O:21][C:22]1[C:23]([C:34]([C:9]2[CH:14]=[CH:13][N:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)=[O:35])=[N:24][N:25]([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)[N:26]=1)[CH3:20]
Reactant: CCOc1nn(-c2ccc(F)cc2)nc1C(=O)N(C)OC
Reactant: FC(F)(F)c1cc(I)ccn1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOc1nn(-c2ccc(F)cc2)nc1C(=O)c1ccnc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A solution of isopropylmagnesium chloride lithium chloride complex (1.3 M in THF, 8.5 mL, 11.0 mmol) was added to a solution of 4-iodo-2-(trifluoromethyl)pyridine (3.0 g, 11.0 mmol) in tetrahydrofuran (10 mL) cooled to 0° C. After 10 minutes, the solution was stirred at 23° C. for 35 min. The dark reddish brown solution was then cooled to −78° C. A solution of 5-ethoxy-2-(4-fluorophenyl)-N-methoxy-N-methyl-2H-1,2,3-triazole-4-carboxamide (i.e. the product of Step B, 2.5 g, 8.5 mmol) in tetrahydrofuran (25 mL) was added. The solution was stirred at 23° C. for 22 h. The reaction was quenched by the addition of a saturated aqueous ammonium chloride solution (10 mL) and water (10 mL). The mixture was extracted with ethyl acetate (2×40 mL), dried (MgSO4) and concentrated under reduced pressure to obtain the crude product. The crude residue was purified by chromatography on silica gel eluting with 0 to 20% ethyl acetate in hexanes to afford the title compound (1.8 g) as a colorless solid.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]#[C:10][C:11]2[CH:36]=[CH:35][C:14]([C:15]([N:17]([CH3:34])[C@:18]([CH3:33])([C:23]([NH:25][O:26][CH:27]3[CH2:32][CH2:31][CH2:30][CH2:29][O:28]3)=[O:24])[C:19]([NH:21][CH3:22])=[O:20])=[O:16])=[CH:13][CH:12]=2)=[CH:5][CH:4]=1)=O.Cl.[CH3:38][O:39][CH:40]1[CH2:43][NH:42][CH2:41]1>>[CH3:38][O:39][CH:40]1[CH2:43][N:42]([CH2:1][C:3]2[CH:4]=[CH:5][C:6]([C:9]#[C:10][C:11]3[CH:12]=[CH:13][C:14]([C:15]([N:17]([CH3:34])[C@:18]([CH3:33])([C:23]([NH:25][O:26][CH:27]4[CH2:32][CH2:31][CH2:30][CH2:29][O:28]4)=[O:24])[C:19]([NH:21][CH3:22])=[O:20])=[O:16])=[CH:35][CH:36]=3)=[CH:7][CH:8]=2)[CH2:41]1
Reactant: COC1CNC1
Reactant: CNC(=O)[C@@](C)(C(=O)NOC1CCCCO1)N(C)C(=O)c1ccc(C#Cc2ccc(C=O)cc2)cc1
Agent: Cl
Product: CNC(=O)[C@@](C)(C(=O)NOC1CCCCO1)N(C)C(=O)c1ccc(C#Cc2ccc(CN3CC(OC)C3)cc2)cc1
Yield: 68.1 %

Procedure:
From (2S)-2-[{4-[(4-formylphenyl)ethynyl]benzoyl}(methyl)amino]-N,2-dimethyl-N′-(tetrahydro-2H-pyran-2-yloxy)propanediamide (0.50 g) as obtained in Example 16-(1) and 3-methoxyazetidine hydrochloride (0.16 g), there was obtained (2S)-2-{[4-({4-[(3-methoxyazetidin-1-yl)methyl]phenyl}ethynyl)benzoyl](methyl)amino}-N,2-dimethyl-N′-(tetrahydro-2H-pyran-2-yloxy)propanediamide (yellow solid) (0.39 g, 68%) in the same manner as in Example 16-1-(3).
Reaction SMILES: Br[C:2]1[C:3]2[C:8]([C:9](Br)=[C:10]3[C:15]=1[CH:14]=CC=C3)=CC=CC=2>Cl[Ni]1(Cl)[P](C2C=CC=CC=2)(C2C=CC=CC=2)CCC[P]1(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:14][C:15]1[CH:2]=[C:3]([C:10]2[C:15]3[C:2]([C:3]([C:9]4[CH:8]=[CH:3][CH:2]=[C:15]([CH3:14])[CH:10]=4)=[C:8]4[C:9]=2[CH:14]=[CH:15][CH:2]=[CH:3]4)=[CH:10][CH:9]=[CH:8][CH:14]=3)[CH:8]=[CH:9][CH:10]=1
Reactant: Brc1c2ccccc2c(Br)c2ccccc12
Agent: Cl[Ni]1(Cl)[P](c2ccccc2)(c2ccccc2)CCC[P]1(c1ccccc1)c1ccccc1
Product: Cc1cccc(-c2c3ccccc3c(-c3cccc(C)c3)c3ccccc23)c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 71 %

Procedure:
5 grams of 9,10-dibromo anthracene and 0.13 gram of NiCl2(dppp) were mixed with 50 ml tetraphdrofurane in a 250 ml reaction bottle, heated for reaction under 60° C. for 1 hour. Then added slowly with solution of a), stirred for reaction for 8 hours. The solvents were removed via a rotary evaporator. The residue was washed with 100 ml methanol three times and filtered. After recrytallization from toluene and methanol, 3.8 gram light yellow colored 9,10-di-(3-methylphenyl)anthracene was collected. Yield 71%. The structural formula is as follows.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]([OH:11])[C:8]([N+:12]([O-:14])=[O:13])=[CH:7][C:3]=1[C:4](Cl)=[O:5].[NH2:15][OH:16].O>O1CCOCC1>[OH:1][C:2]1[CH:10]=[C:9]([OH:11])[C:8]([N+:12]([O-:14])=[O:13])=[CH:7][C:3]=1[C:4]([NH:15][OH:16])=[O:5]
Reactant: O=C(Cl)c1cc([N+](=O)[O-])c(O)cc1O
Reactant: NO
Solvent: O
Solvent: C1COCCO1
Product: O=C(NO)c1cc([N+](=O)[O-])c(O)cc1O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 2,4-dihydroxy-5-nitrobenzoyl chloride (17.0 g, 78.1 mmol) in dioxane (70 mL) is added to an ice cold solution of 50% aqueous hydroxylamine (35 mL) and water (35 mL). After the addition is complete, the ice bath is removed and the mixture is stirred at room temperature for 30 min. The resulting thick precipitate is filtered, washed once with 1:1 water/dioxane and dried to obtain 2,4,N-trihydroxy-5-nitrobenzamide. After standing in the refrigerator for 18 h, the 1:1 water/dioxane solution affords additional 2,4,N-trihydroxy-5-nitrobenzamide: (M+H)+=215.1.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[F:13][C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][N:15]=1.CON(C)[C:24](=[O:35])[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=1>C1COCC1>[F:13][C:14]1[CH:19]=[C:18]([CH2:20][C:24]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:32])([F:33])[F:34])[CH:26]=2)=[O:35])[CH:17]=[CH:16][N:15]=1
Reactant: Cc1ccnc(F)c1
Reactant: CON(C)C(=O)c1cccc(C(F)(F)F)c1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: O=C(Cc1ccnc(F)c1)c1cccc(C(F)(F)F)c1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 84.7 %

Procedure:
To a solution of diisopropylamine (17.69 mL, 0.135 mole) in THF (200 mL) at -78° C., under argon, was added n-butyllithium (54.0 mL, 2.5M in hexane, 0.135 mole), followed after 5 min. by a solution of 2-fluoro-4-methylpyridine (Lancaster Synthesis Inc.) (10 g, 0.090 mole) in THF (20 mL). After stirring for 15 min. at -78° C., a solution of N-methoxy-N-methyl-3-trifluoromethylbenzamide (23.08 g, 0.099 mole) in THF (10 mL) was added. After stirring for 5 min, the reaction was allowed to warm to 0° C. and quenched by pouring into water (400 mL) and ethyl acetate (400 mL). The layers were separated, and the aqueous layer washed with ethyl acetate (200 mL). The ethyl acetate extracts were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to an oil which was chromatographed on silica gel with 20% ethyl acetate in hexane to give 21.6 g of the title compound.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:36]([CH3:37])=[CH:35][C:15]2[N:16]=[C:17]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([C:25]4[C:33]5[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=5)[N:27]([CH3:34])[N:26]=4)[CH:20]=3)[S:18][C:14]=2[C:13]=1[C:38]1[CH:43]=[CH:42][C:41]([Cl:44])=[CH:40][CH:39]=1)[C:7]([O:9]CC)=[O:8])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>C1COCC1.CO>[C:1]([O:5][C@@H:6]([C:12]1[C:36]([CH3:37])=[CH:35][C:15]2[N:16]=[C:17]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([C:25]4[C:33]5[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=5)[N:27]([CH3:34])[N:26]=4)[CH:20]=3)[S:18][C:14]=2[C:13]=1[C:38]1[CH:43]=[CH:42][C:41]([Cl:44])=[CH:40][CH:39]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(-c4nn(C)c5ccccc45)c3)sc2c1-c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc2nc(-c3ccnc(-c4nn(C)c5ccccc45)c3)sc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Temperature: 50 °C
Reaction time: 2 h

Procedure:
To a stirred solution of (S)-ethyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(2-(1-methyl-1H-indazol-3-yl)pyridin-4-yl)benzo[d]thiazol-6-yl)acetate (13.5 mg, 0.022 mmol) in THF (0.5 mL) and methanol (0.5 mL) was added 1N NaOH solution (0.5 mL, excess). The reaction mixture was stirred at 50° C. for 2 h and then purified by reverse phase HPLC, eluting by 0-100% acetonitrile in H2O with 0.1% TFA to give the desired product. LCMS-ESI+ (m/z): [M+H]+ calcd for C33H30ClN4O3S: 597.2; found: 597.2. 1H NMR (400 MHz, CDCl3) δ 9.21 (d, J=5.6 Hz, 1H), 8.93 (s, 1H), 8.59 (d, J=7.6 Hz, 1H), 8.22 (d, J=5.2 Hz, 1H), 8.07 (s, 1H), 7.75 (d, J=6.8 Hz, 1H), 7.60-7.46 (m, 6H), 5.36 (s, 1H), 4.29 (s, 3H), 2.65 (s, 3H), 1.02 (s, 9H).
Reaction SMILES: [CH:1]([N:4](CC)C(C)C)(C)[CH3:2].BrCC#N.[N:14]([C:17]1[CH:46]=[CH:45][C:20]([CH2:21][O:22][C:23]([NH:25][CH2:26][C@@H:27]([S:42][S:43][CH3:44])[CH2:28][CH2:29][C@H:30]([NH:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[C:31]([OH:33])=[O:32])=[O:24])=[CH:19][CH:18]=1)=[N+:15]=[N-:16]>C(#N)C>[N:14]([C:17]1[CH:18]=[CH:19][C:20]([CH2:21][O:22][C:23]([NH:25][CH2:26][C@@H:27]([S:42][S:43][CH3:44])[CH2:28][CH2:29][C@H:30]([NH:34][C:35]([O:37][C:38]([CH3:39])([CH3:40])[CH3:41])=[O:36])[C:31]([O:33][CH2:2][C:1]#[N:4])=[O:32])=[O:24])=[CH:45][CH:46]=1)=[N+:15]=[N-:16]
Reactant: CCN(C(C)C)C(C)C
Reactant: CSS[C@@H](CC[C@H](NC(=O)OC(C)(C)C)C(=O)O)CNC(=O)OCc1ccc(N=[N+]=[N-])cc1
Agent: N#CCBr
Solvent: CC#N
Product: CSS[C@@H](CC[C@H](NC(=O)OC(C)(C)C)C(=O)OCC#N)CNC(=O)OCc1ccc(N=[N+]=[N-])cc1
Reaction time: 4.5 h
Yield: 89.5 %

Procedure:
N,N-Diisopropylethylamine (51 μL, 0.291 mmol) and subsequently bromoacetonitrile (92 μL, 1.321 mmol) were added to a solution of (2S,5S)-6-((((4-azidobenzyl)oxy)carbonyl)amino)-2-((tert-butoxycarbonyl)amino)-5-(methyldisulfanyl)hexanoic acid (Compound tk8) (132 mg, 0.264 mmol) in acetonitrile (0.4 mL) at room temperature under a nitrogen atmosphere. The reaction mixture was stirred at the same temperature for 4.5 hours and then concentrated under reduced pressure, and the resulting crude product was purified by normal-phase silica gel column chromatography (hexane/ethyl acetate) to afford (2S,5S)-cyanomethyl 6-((((4-azidobenzyl)oxy)carbonyl)amino)-2-((tert-butoxycarbonyl)amino)-5-(methyldisulfanyl)hexanoate (Compound tk9) (127.3 mg, 89%).
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH:7]=[O:8])=[C:5]([N+:9]([O-:11])=[O:10])[CH:4]=[N:3]1.CO/[CH:14]=[CH:15]/[C:16]([O:18][Si](C)(C)C)=[CH2:17].CC(C(CC(C(C)(C)C)=O)=O)(C)C.CC(C(CC(C(C)(C)C)=O)=O)(C)C.CC(C(CC(C(C)(C)C)=O)=O)(C)C.[Eu]>>[CH3:1][N:2]1[C:6]([CH:7]2[CH2:17][C:16](=[O:18])[CH:15]=[CH:14][O:8]2)=[C:5]([N+:9]([O-:11])=[O:10])[CH:4]=[N:3]1
Reactant: C=C(/C=C/OC)O[Si](C)(C)C
Reactant: Cn1ncc([N+](=O)[O-])c1C=O
Agent: CC(C)(C)C(=O)CC(=O)C(C)(C)C
Agent: [Eu]
Product: Cn1ncc([N+](=O)[O-])c1C1CC(=O)C=CO1
Temperature: 80 °C
Reaction time: 24 h

Procedure:
To a solution of 2-methyl-4-nitro-pyrazole-3-carbaldehyde (600 mg, 3.87 mmol) in CDCl3 (20 mL) was added Danishefsky's diene (836 mg, 5.81 mmol) and Resolve-Al™ EuFOD (157 mg, 0.39 mmol). The reaction mixture was heated at 80° C. in a sealed tube for 24 hr. Additional Resolve-Al™ EuFOD (250 mg, 0.62 mmol) was added and heating continued for another 24 hr. The reaction mixture was concentrated under reduced pressure. Purification via silica gel column chromatography (0-100% EtOAc/isohexane) gave 2-(1-methyl-4-nitro-1H-pyrazol-5-yl)-2H-pyran-4(3H)-one a yellow solid (710 mg, 82%). A portion of this solid (300 mg, 1.35 mmol) was dissolved in THF (10 mL) under nitrogen and cooled to −78° C. A solution of L-selectride (1 M in THF, 1.48 mL, 1.48 mmol) was added dropwise and the mixture was stirred at −78° C. for 30 min. The mixture was quenched with MeOH (2 mL) and warmed to room temperature. EtOAc (30 mL) and brine (30 mL) were added and the layers separated. The aqueous layer was extracted with EtOAc (3×20 mL) then the combined organic layers were washed with brine (30 mL), separated, dried over Na2SO4 and concentrated under reduced pressure. Purification via silica gel column chromatography (0-100% EtOAc/isohexane) gave 2-(2-methyl-4-nitro-pyrazol-3-yl)tetrahydropyran-4-one as a colourless solid (224 mg, 61% over two steps). 1H NMR (400 MHz, CDCl3) δ 8.06 (s, 1H), 5.70 (dd, J=11.8, 3.3 Hz, 1H), 4.49 (ddd, J=11.8, 7.5, 1.3 Hz, 1H), 4.15 (s, 3H), 3.94-3.86 (m, 1H), 2.83-2.63 (m, 3H), 2.58-2.50 (m, 1H).
Reaction SMILES: [F:1][C:2]1([F:9])[CH2:5][CH:4]([C:6]([OH:8])=O)[CH2:3]1.C1N=CN(C(N2C=NC=C2)=O)C=1.[NH2:22][C:23]1[CH:24]=[C:25]([CH:30]=[CH:31][C:32]=1[F:33])[C:26](=[NH:29])[NH:27]O.O>CN1C(=O)CCC1>[F:9][C:2]1([F:1])[CH2:3][CH:4]([C:6]2[O:8][N:29]=[C:26]([C:25]3[CH:30]=[CH:31][C:32]([F:33])=[C:23]([CH:24]=3)[NH2:22])[N:27]=2)[CH2:5]1
Reactant: O=C(O)C1CC(F)(F)C1
Reactant: N=C(NO)c1ccc(F)c(N)c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN1CCCC1=O
Solvent: O
Product: Nc1cc(-c2noc(C3CC(F)(F)C3)n2)ccc1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3,3-difluorocyclobutanecarboxylic acid (0.90 g, 6.6 mmol) in NMP (5 mL) was slowly added CDI (1.07 g, 6.6 mmol). The resulting mixture was stirred at room temperature for 30 minutes. Then 3-amino-4-fluoro-N-hydroxybenzimidamide (87) (0.56 g, 3.3 mmol) was added and stirred for another 30 minutes until LCMS indicated complete reaction. The mixture was then heated at 125° C. for 15 minutes in a microwave reactor and poured into water (100 mL). The mixture was extracted with EtOAc (2×50 mL), dried over Na2SO4, filtered and concentrated to give a crude product which was purified by silica-gel chromatography (0-60% EtOAc in hexanes) to afford 5-(5-(3,3-difluorocyclobutyl)-1,2,4-oxadiazol-3-yl)-2-fluoroaniline (88). 1H NMR (400 MHz, CDCl3) δ 7.53 (dd, J=2.0, 8.4 Hz, 1H), 7.43-7.48 (m, 1H), 7.10 (dd, J=10.8, 8.4 Hz, 1H), 3.90 (br, 2H), 3.67 (m, 1H), 3.09-3.18 (m, 4H). MS m/z 270.1 (M+1)+.
Reaction SMILES: [CH2:1]([N:4]([CH2:17][CH2:18][CH3:19])[CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[C:8]([CH2:15][NH2:16])[CH:9]=[CH:10][CH:11]=2)[CH2:6]1)[CH2:2][CH3:3].[CH3:20][N:21]=[C:22]=[O:23]>C1(C)C=CC=CC=1>[CH2:17]([N:4]([CH2:1][CH2:2][CH3:3])[CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[C:8]([CH2:15][NH:16][C:22]([NH:21][CH3:20])=[O:23])[CH:9]=[CH:10][CH:11]=2)[CH2:6]1)[CH2:18][CH3:19]
Reactant: CCCN(CCC)C1CCc2cccc(CN)c2C1
Reactant: CN=C=O
Solvent: Cc1ccccc1
Product: CCCN(CCC)C1CCc2cccc(CNC(=O)NC)c2C1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
1.6 g (6 mmol) of 2-dipropylamino-8-aminomethyl-1,2,3,4-tetrahydronaphthalene were dissolved in 16 ml of toluene under nitrogen. 0.34 g (6 mmol) of methyl isocyanate was added dropwise at a maximum of +25° C. The batch was subsequently stirred for a further 1.5 h at room temperature. The reaction product which crystallized out was then filtered off under suction and dried at +40° C. in vacuo.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH:10]1[CH2:15][CH2:14][NH:13][CH2:12][C:11]1=[O:16].C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[CH2:2]([N:13]1[CH2:14][CH2:15][NH:10][C:11](=[O:16])[CH2:12]1)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: BrCCc1ccccc1
Reactant: O=C1CNCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=C1CN(CCc2ccccc2)CCN1
Temperature: 80 °C
Reaction time: 5 h
Yield: 73.4 %

Procedure:
A suspension of (2-bromoethyl)benzene (4.10 mL, 30.0 mmol), piperazin-2-one (3.00 g, 30.0 mmol) and K2CO3 (4.90 g, 36.0 mmol) in DMSO (60.0 mL) was stirred at 80° C. for 5 h. The reaction mixture was cooled to room temperature and filtered. The filtrate was then washed with water (200 mL) and extracted with methylene chloride (2×). The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated. The result yellow solid was then dissolved in 1 N HCl (120 mL) and washed with methylene chloride. The aqueous layer was separated, basified with 6 N NaOH, and extracted with methylene chloride (3×). The combined organic layers were dried over MgSO4, filtered, and concentrated. The residue was titrated with hexanes and filtered. The filtered solid was dried under reduced pressure to give the title compound (4.50 g, 74%) as an off-white solid: 1H NMR (500 MHz, CDCl3) δ 7.31-7.28 (m, 2H), 7.23-7.19 (m, 3H), 6.17 (br s, 1H), 3.40-3.37 (m, 2H), 3.23 (s, 2H), 2.83-2.79 (m, 2H), 2.73-2.67 (m, 4H).