Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](/[CH:11]=[CH:12]/[C:13]([OH:15])=O)=[CH:3]1.[CH:16]([NH:19][NH:20][C:21](=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([CH3:18])[CH3:17].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C.CCOC(C)=O>[CH:16]([N:19]([C:13](=[O:15])/[CH:12]=[CH:11]/[C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:2]([CH3:1])[CH:3]=1)[NH:20][C:21](=[O:28])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)([CH3:18])[CH3:17]
Reactant: Cn1cc(/C=C/C(=O)O)c2ccccc21
Reactant: CC(C)NNC(=O)c1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)N(NC(=O)c1ccccc1)C(=O)/C=C/c1cn(C)c2ccccc12
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To solution containing (E)-3-(1-methyl-1H-indol-3-yl)acrylic acid (50 mg, 0.24 mmol, 1.0 equivalent), N′-isopropylbenzohydrazide (66.43 mg, 0.37 mmol, 1.5 equivalent) and HATU (141.72 mg, 0.37 mmol, 1.5 equivalent) dissolved in DMF (5.0 ml), N,N-diisopropylethylamine (DIPEA)(0.06 ml, 0.37 mmol, 1.5 equivalent) was slowly drop-wise added and stirred at room temperature for 24 hr. The reaction mixture was diluted with EtOAc, washed with water and brine, dried with anhydrous MgSO4, filtered, and concentrated under reduced pressure. The residue was separated through silica gel chromatography (n-hexane:EtOAc:methanol=9:3:1) and dried so that white solid form of (E)-N′-isopropyl-N′-(3-(1-methyl-1H-indol-3-yl)acryloyl)benzohydrazide was obtained.(82.62 mg, 92%).
Reaction SMILES: C([O:3][C:4](=O)[C:5]1[C:10]([C:11]([F:14])([F:13])[F:12])=[CH:9][C:8]([C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=2)=[N:7][C:6]=1[CH3:26])C.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+]>C(OCC)C>[CH3:26][C:6]1[C:5]([CH2:4][OH:3])=[C:10]([C:11]([F:14])([F:13])[F:12])[CH:9]=[C:8]([C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]([F:24])([F:23])[F:25])=[CH:17][CH:16]=2)[N:7]=1
Reactant: CCOC(=O)c1c(C(F)(F)F)cc(-c2ccc(OC(F)(F)F)cc2)nc1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: Cc1nc(-c2ccc(OC(F)(F)F)cc2)cc(C(F)(F)F)c1CO
Temperature: 0 °C
Yield: 40 %

Procedure:
A solution of 2-methyl-6-(4-trifluoromethoxy-phenyl)-4-trifluoromethyl-nicotinic acid ethyl ester (400 mg, 1 mmol) in diethyl ether (6 ml) was added to a suspension of lithium aluminium hydride (77 mg, 2 mmol) in diethyl ether (12 ml) under an argon atmosphere at ambient temperature within 5 min. The mixture was stirred at reflux for 12 h, cooled to 0° C. and treated cautiously with ice water (12 ml) and 10% aqueous NaOH (6 ml). The reaction mixture was filtered over celite, t-butyl methylether was added and the layers were separated. The aqueous layer was extracted one more time with t-butyl methylether, the combined organic layers were washed with ice water/brine 1/1 and dried over sodium sulfate. Removal of the solvent under reduced pressure gave an orange oil which was purified by column chromatography (silica gel, heptane/AcOEt) to yield 140 mg (400 μmol, 39%) of the title compound as colorless crystals.
Reaction SMILES: [Na].[F:2][C:3]1[CH:19]=[CH:18][C:6]([C:7]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([Cl:16])[C:10]=2[Cl:17])=[O:8])=[CH:5][CH:4]=1.Br[CH2:21][C:22]([O:24]CC)=[O:23].[OH-].[Na+]>C(O)C>[F:2][C:3]1[CH:19]=[CH:18][C:6]([C:7]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:21][C:22]([OH:24])=[O:23])=[C:11]([Cl:16])[C:10]=2[Cl:17])=[O:8])=[CH:5][CH:4]=1
Reactant: CCOC(=O)CBr
Reactant: O=C(c1ccc(F)cc1)c1ccc(O)c(Cl)c1Cl
Agent: [Na+]
Agent: [Na]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)COc1ccc(C(=O)c2ccc(F)cc2)c(Cl)c1Cl

Procedure:
Into a solution of 1.4 g. (0.06 g. atom) of sodium in 200 ml. of absolute alcohol, 16.0 g. (0.056 mole) of 4(4-fluorobenzoyl)-2,3-dichlorophenol was added and the mixture was stirred for thirty minutes at room temperature. The excess of alcohol was vacuum removed and the residue was washed with ether to obtain the sodium salt. The sodium salt of 4(4-fluorobenzoyl)-2,3-dichlorophenol was dissolved in 200 ml. of ethanol and 10.5 g. (0.06 mole) of ethyl bromoacetate was added and the reaction mixture was refluxed for 16 hours, filtered and the solvent was removed in vacuo. The residue was triturated with pet. ether and filtered to obtain a solid product. The product obtained was dissolved in 150 ml. ethanol and 50 ml. of 20% NaOH aqueous solution was added. The reaction mixture was refluxed for 1/2 hour and the solvent was partially removed in vacuo. The residue was dissolved in hot water and filtered. The hot filtrate was acidified with concentrated hydrochloric acid at 60° C. The resulting precipitate was collected by filtration and washed with water. Recrystallization from dichloroethane afforded 8.0 g. (47%) of the product; m.p. 174°-176°.
Reaction SMILES: Cl.C(O[C:5](=[NH:14])[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=1)C.[CH:15]1([NH2:18])[CH2:17][CH2:16]1>C(Cl)Cl>[CH:15]1([NH:18][C:5](=[NH:14])[C:6]2[CH:7]=[CH:8][C:9]([O:12][CH3:13])=[CH:10][CH:11]=2)[CH2:17][CH2:16]1
Reactant: NC1CC1
Reactant: CCOC(=N)c1ccc(OC)cc1
Agent: Cl
Solvent: ClCCl
Product: COc1ccc(C(=N)NC2CC2)cc1
Reaction time: 3 h
Yield: 81.6 %

Procedure:
4-methoxy-benzimidic acid ethyl ester hydrochloride (1.25 g, 5.8 mmol), DCM (5 ml) and cyclopropylamine (0.92 ml, 13.3 mmol) were mixed. After stirring at r.t for 3 h, the reaction mixture was concentrated in-vacuo. The residue was treated with cold aq. sodium hydroxide (1M) and extracted with EA. The combined organic phase was washed with water and brine, dried (Na2SO4), filtered and concentrated in-vacuo, to isolate the title compound (0.90 g, 82%). 1H-NMR: 7.64 (d, 2H), 6.90 (d, 2H), 5.3 (bs, 2H), 3.85 (s, 3H), 2.59 (m, 1H), 0.84 (m, 2H), 0.62 (m, 2H).
Reaction SMILES: C[N:2]1[C:7]([CH3:8])=[C:6]([N+:9]([O-:11])=[O:10])[CH:5]=[C:4]([N+]([O-])=O)[C:3]1=O.O=C1C[CH2:21][CH:20]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:19][CH2:18]1.N>>[CH3:8][C:7]1[C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]2[CH2:21][CH:20]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:27])([CH3:29])[CH3:28])[CH2:19][CH2:18][C:3]=2[N:2]=1
Reactant: Cc1c([N+](=O)[O-])cc([N+](=O)[O-])c(=O)n1C
Reactant: CC(C)(C)OC(=O)NC1CCC(=O)CC1
Agent: N
Product: Cc1nc2c(cc1[N+](=O)[O-])CC(NC(=O)OC(C)(C)C)CC2
Temperature: 60 °C
Reaction time: 5 h
Yield: 28.3 %

Procedure:
To a sealed tube was added 1,6-dimethyl-3,5-dinitropyridin-2(1H)-one (0.16 g, 0.76 mmol), tert-butyl (4-oxocyclohexyl)carbamate (0.19 g, 0.91 mmol), and ammonia (1M in methanol, 9 mL). The resulting mixture was allowed to stir for 5 h at 60° C. and then allowed to cool to rt and concentrated. The residue was purified by column chromatography to give tert-butyl (2-methyl-3-nitro-5,6,7,8-tetrahydroquinolin-6-yl)carbamate (0.066 g, 28%) as a solid.
Reaction SMILES: [CH:1]([C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[N:9]=[CH:10][C:11]([C:14]([NH2:16])=[O:15])=[N:12][CH:13]=2)=[C:5]([O:19][CH3:20])[CH:4]=1)=O.[CH3:21][CH:22]([CH3:27])[CH2:23][CH2:24][CH2:25][NH2:26].[BH4-].[Na+]>CO>[CH3:20][O:19][C:5]1[CH:4]=[C:3]([CH2:1][NH:26][CH2:25][CH2:24][CH2:23][CH:22]([CH3:27])[CH3:21])[CH:18]=[CH:17][C:6]=1[O:7][C:8]1[N:9]=[CH:10][C:11]([C:14]([NH2:16])=[O:15])=[N:12][CH:13]=1
Reactant: CC(C)CCCN
Reactant: COc1cc(C=O)ccc1Oc1cnc(C(N)=O)cn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(CNCCCC(C)C)ccc1Oc1cnc(C(N)=O)cn1
Reaction time: 8 h
Yield: 36.5 %

Procedure:
Place 5-(4-formyl-2-methoxyphenoxy)pyrazine-2-carboxamide (Example 719, Part A) (0.700 g, 2.56 mmol), 4-methylpentylamine (Example 433, Part A) (0.272 g, 2.69 mmol) and 3 {acute over (Å)} molecular sieves in a vial. Add methanol (12.8 mL), cap and stir overnight. Add NaBH4 (0.0969 g, 2.56 mmol) and stir until the gasses stop evolving. Load the reaction mixture directly onto a 25 g ISCO® pre-load column. Dry the column in a vacuum oven at room temperature. Purify by eluting through a 40 g ISCO® column with 5% to 20% (2.0 M NH3 in methanol) in ethyl acetate over 45 minutes. Concentrate the fraction containing the product, then take it up in EtOAc (100 mL). Wash the organic solution with 1.0 N NaOH (2×25 mL), dry it over Na2SO4, filter and concentrate. Dissolve the product in ether:dichloromethane (5:1) (25 mL), add hexanes (20 mL), and then concentrate to about a quarter of the volume. Filter the precipitate to give the title compound (0.335 g, 36.5%): TOF MS ES+ 359.2 (M+H)+, HRMS calcd for C19H27N4O3 359.2083 (M+H)+, found 359.2087, time 0.38 min; HPLC [YMC-Pro pack C-18 (150×4.6 mm, S-5 microm), 0.05% TFA/acetonitrile in 0.05% TFA/water at 1.0 mL/min, 10-20% over 5 min, 20-95% over 18], tR=11.3 min, 100% purity.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=[O:11])=[CH:4][CH:3]=1.CS(O)(=O)=O.[N-:17]=[N+]=[N-].[Na+].O.N>CCOC(C)=O.CCCCCC.O.C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8](=[O:11])[NH:17]2)=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=[N-]
Reactant: O=C1CCc2ccc(Br)cc21
Agent: CS(=O)(=O)O
Agent: N
Agent: [Na+]
Solvent: O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: O=C1CCc2ccc(Br)cc2N1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To the CHCl3 solution (560 mL) of the compound (39.5 g) obtained in Step 1-1 and methanesulfonic acid (122 mL), sodium azide (36.5 g) was added separately in parts under ice cooling, and then the mixture was heated to reflux for 2.5 hours. To H2O (400 mL), the reaction mixture was added under ice cooling, adjusted to pH 9 with 28% ammonia water and extracted with CHCl3 three times. The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. Thereafter, the residue was purified by column chromatography (silica gel 60 N, mobile phase: EtOAc/hexane=50/50 to 75/25; v/v). The solid substance obtained was suspended in a solution of EtOAc/hexane (1/1; v/v) and the mixture was stirred at room temperature for one hour. A solid substance was obtained by filtration to give 7-bromo-3,4-dihydroquinolin-2(1H)-one (15.5 g, a light yellow solid).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([CH:10]=[O:11])[CH:7]=[C:6]([F:12])[C:3]=1[C:4]#[N:5].[BH4-].[Na+]>CO>[F:1][C:2]1[CH:9]=[C:8]([CH2:10][OH:11])[CH:7]=[C:6]([F:12])[C:3]=1[C:4]#[N:5]
Reactant: N#Cc1c(F)cc(C=O)cc1F
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: N#Cc1c(F)cc(CO)cc1F
Reaction time: 1.08 h

Procedure:
2,6-Difluoro-4-formylbenzonitrile (1.36 g, 8.13 mmol; see step (ii) above) was dissolved in 25 mL of methanol and cooled on an ice bath. Sodium borohydride (0.307 g, 8.12 mmol) was added in portions with stirring and the reaction was left for 65 min. The solvent was evaporated and the residue was partitioned between diethyl ether and aqueous sodium bicarbonate. The ethereal layer washed with more aqueous sodium bicarbonate and brine, dried (Na2SO4) and evaporated. The crude product crystallised soon and could be used without further purification. Yield: 1.24 g (90%).
Reaction SMILES: [C:1]([CH2:4][O:5][C:6]1[CH:14]=[CH:13][C:12]([O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[C:18]([Cl:26])[CH:17]=2)=[CH:11][C:7]=1[C:8]([OH:10])=[O:9])([OH:3])=[O:2].[OH-].[NH4+:28].CCOCC>O.CO>[NH4+:28].[NH4+:28].[C:1]([CH2:4][O:5][C:6]1[CH:14]=[CH:13][C:12]([O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:23])[F:24])=[C:18]([Cl:26])[CH:17]=2)=[CH:11][C:7]=1[C:8]([O-:10])=[O:9])([OH:3])=[O:2].[C:1]([CH2:4][O:5][C:6]1[CH:14]=[CH:13][C:12]([O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:23])[F:24])=[C:18]([Cl:26])[CH:17]=2)=[CH:11][C:7]=1[C:8]([O-:10])=[O:9])([OH:3])=[O:2]
Reactant: O=C(O)COc1ccc(Oc2ccc(C(F)(F)F)c(Cl)c2)cc1C(=O)O
Agent: [NH4+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Solvent: CO
Product: O=C(O)COc1ccc(Oc2ccc(C(F)(F)F)c(Cl)c2)cc1C(=O)[O-]
Yield: 71.9 %

Procedure:
A mixture of 2-(carboxymethoxy)-5-[(2-chloro -α,α,α-trifluoro-p-tolyl)oxy]benzoic acid (2.0 g, 5.12 mmol) and concentrated ammonium hydroxide solution (0.5 mL, 7.25 mmol) in water is stirred until homogeneous and concentrated in vacuo to obtain a residue. A solution of the residue in methanol is brought to the cloud point with ether. The solution is cooled in an ice bath and the solid is collected by filtration to give the title product as a white solid (1.5 g, 72%, mp 226-227).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][S:9][C:10]2[CH:17]=[CH:16][C:13]([CH:14]=O)=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S:18]1[CH2:22][C:21](=[O:23])[NH:20][C:19]1=[O:24].C([O-])(=O)C.[Na+]>>[C:1]1([CH2:7][CH2:8][S:9][C:10]2[CH:17]=[CH:16][C:13]([CH:14]=[C:22]3[S:18][C:19](=[O:24])[NH:20][C:21]3=[O:23])=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1CSC(=O)N1
Reactant: O=Cc1ccc(SCCc2ccccc2)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Product: O=C1NC(=O)C(=Cc2ccc(SCCc3ccccc3)cc2)S1
Yield: 11.8 %

Procedure:
4-(2-Phenylethylthio)benzaldehyde (12.4 mmol, 3.0 g), 2,4-thiazolidinedione (15.5 mmol, 1.81 g) and anhydrous sodium acetate (30.9 mmol, 2.54 g) were heated in an oil bath at 150° C. for 0.5 hour. The mixture was cooled and the resulting solid triturated with water (100 ml) and collected by filtration. The solid was recrystallized from methanol:ethyl acetate:acetone (1:1:2) to afford 500 mg of title product; m.p. 182°-183° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]=[O:15])=[CH:4][CH:3]=1.[CH2:16]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25](Br)[N:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:16]([C:23]1[N:24]=[C:25]([CH:14]([C:9]2[C:10]([CH3:13])=[N:11][O:12][C:8]=2[C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=2)[OH:15])[CH:26]=[CH:27][CH:28]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C=O
Reactant: Brc1cccc(Cc2ccccc2)n1
Product: Cc1noc(-c2ccc(Br)cc2)c1C(O)c1cccc(Cc2ccccc2)n1

Procedure:
Prepared according to the procedure described in Example 34, Step 3, using 5-(4-bromo-phenyl)-3-methyl-isoxazole-4-carbaldehyde and 2-benzyl-6-bromo-pyridine.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].[CH3:9][C:10]([CH3:16])=[CH:11][C:12](OC)=[O:13].S(=O)(=O)(O)O>C1(C)C=CC=CC=1>[CH3:9][C:10]1([CH3:16])[C:8]2[C:1](=[CH:3][CH:4]=[C:5]([OH:6])[CH:7]=2)[O:2][C:12](=[O:13])[CH2:11]1
Reactant: Oc1ccc(O)cc1
Reactant: COC(=O)C=C(C)C
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Product: CC1(C)CC(=O)Oc2ccc(O)cc21
Temperature: 130 °C
Yield: 54.6 %

Procedure:
A mixture of 8.8 g of hydroquinone, 5 g of methyl 3,3-dimethylacrylate and 0.4 g of conc. sulfuric acid was heated at 130° C. for 4 hours. The reaction mixture was cooled, and then 15 ml of toluene was added. The crystals that precipitated were separated by filtration. The filtrate was concentrated and then distilled under reduced pressure to give 4.6 g (yield 70%) of 3,4-dihydro-4,4-dimethyl-6-hydroxycoumarin as pale pink crystals (melting point 95°-96° C.). The crystals (3.0 g) were dissolved in 10 ml of tetrahydrofuran, and the solution was added dropwise at room temperature to a mixture of 0.9 g of lithium aluminum hydride and 20 ml of tetrahydrofuran. The mixture was then refluxed for 4 hours. The reaction mixture was worked up in a customary manner, and the crude product, without purification, was dissolved in 30 ml of toluene. A catalytic amount of p-toluenesulfonic acid was added to the solution, and the mixture was heated at 120° C. for 1.5 hours. In a customary manner, the reaction mixture was worked up, and the residue after concentration was isolated and purified by column chromatography to give 2.4 g (yield 85%) of the desired product as a yellow orange liquid.
Reaction SMILES: [OH-].[Li+].[C:3]([O:7][C:8]([N:10]([C:24]1[CH:29]=[C:28]([N:30]([CH3:53])[C:31]([N:33]([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[C:34]2[C:39]([Cl:40])=[C:38]([O:41][CH3:42])[CH:37]=[C:36]([O:43][CH3:44])[C:35]=2[Cl:45])=[O:32])[N:27]=[CH:26][N:25]=1)[C:11]1[CH:20]=[CH:19][C:14]([C:15]([O:17]C)=[O:16])=[CH:13][C:12]=1[N+:21]([O-:23])=[O:22])=[O:9])([CH3:6])([CH3:5])[CH3:4].CCOC(C)=O.CCCCCC>C1COCC1.O>[C:3]([O:7][C:8]([N:10]([C:24]1[CH:29]=[C:28]([N:30]([CH3:53])[C:31]([N:33]([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[C:34]2[C:39]([Cl:40])=[C:38]([O:41][CH3:42])[CH:37]=[C:36]([O:43][CH3:44])[C:35]=2[Cl:45])=[O:32])[N:27]=[CH:26][N:25]=1)[C:11]1[CH:20]=[CH:19][C:14]([C:15]([OH:17])=[O:16])=[CH:13][C:12]=1[N+:21]([O-:23])=[O:22])=[O:9])([CH3:4])([CH3:6])[CH3:5]
Reactant: COC(=O)c1ccc(N(C(=O)OC(C)(C)C)c2cc(N(C)C(=O)N(C(=O)OC(C)(C)C)c3c(Cl)c(OC)cc(OC)c3Cl)ncn2)c([N+](=O)[O-])c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cc(OC)c(Cl)c(N(C(=O)OC(C)(C)C)C(=O)N(C)c2cc(N(C(=O)OC(C)(C)C)c3ccc(C(=O)O)cc3[N+](=O)[O-])ncn2)c1Cl
Temperature: 25 °C
Reaction time: 5 h
Yield: 88.3 %

Procedure:
Lithium hydroxide (0.08 g, 2.99 mmol) was added to a solution of methyl 4-((tert-butoxycarbonyl)(6-(3-(tert-butoxycarbonyl)-3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-methylureido)pyrimidin-4-yl)amino)-3-nitrobenzoate (1.5 g, 1.997 mmol) (Procedure 2J, Step c) in a mixture of THF (10 mL) and water (2 mL) at 0° C. The resulting reaction mixture was allowed to warm to room temperature and stirred for 5 h. After completion of the reaction by TLC (EtOAc:Hexane 3:7), the reaction mixture was concentrated under vacuum to get a crude residue. The crude residue was dissolved in water and extracted with ether (3×30 mL). The aqueous layer was acidified with 10% citric acid solution and the precipitated solid was filtered, washed with cold water and dried in vacuo to afford the title compound (1.3 g, yield: 93%) as a light brown solid. MS (ESI): 737.2 [M+H]+.
Reaction SMILES: [CH3:1][S:2]([O:5][CH2:6][C:7]1[CH:8]=NC=N[CH:12]=1)(=[O:4])=[O:3].[CH:13]1([C:17]2[CH:22]=CC(CO)=C[CH:18]=2)[CH2:16][CH2:15][CH2:14]1>>[CH3:1][S:2]([O:5][CH2:6][C:7]1[CH:8]=[CH:22][C:17]([CH:13]2[CH2:16][CH2:15][CH2:14]2)=[CH:18][CH:12]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)OCc1cncnc1
Reactant: OCc1ccc(C2CCC2)cc1
Product: CS(=O)(=O)OCc1ccc(C2CCC2)cc1

Procedure:
4-Cyclobutylbenzyl methanesulfonate was prepared in a similar manner as used to prepare pyrimidin-5-ylmethyl methanesulfonate using (4-cyclobutylphenyl)methanol instead of pyrimidin-5-ylmethanol. The product was used directly in the next reaction without characterization.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]2[C:13]([CH3:14])=[CH:12][CH:11]=[C:10]2[CH3:15])[CH:3]=1.Br[CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH3:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:5]=[C:4]([N:9]2[C:13]([CH3:14])=[CH:12][CH:11]=[C:10]2[CH3:15])[CH:3]=1
Reactant: BrCCc1ccccc1
Reactant: Cc1cc(C)nc(-n2c(C)ccc2C)c1
Product: Cc1cc(CCCc2ccccc2)nc(-n2c(C)ccc2C)c1

Procedure:
By analogy to Example 53, Step B, the anion of 4,6-dimethyl-2-(2,5-dimethylpyrrol-1-yl)pyridine was alkylated with (2-bromoethyl)benzene to give 4-methyl-2-(2,5-dimethylpyrrol-1-yl)-6-(3-phenylpropyl)pyridine.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([S:9][C:10]2[C:15]([N+:16]([O-:18])=[O:17])=[C:14]([CH3:19])[N:13]=[C:12](Cl)[N:11]=2)=[C:4]([CH3:21])[CH:3]=1.[NH2:22][C:23]1[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=1.N1C=CC=CC=1>C1COCC1.CO>[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([S:9][C:10]2[C:15]([N+:16]([O-:18])=[O:17])=[C:14]([CH3:19])[N:13]=[C:12]([NH:22][C:23]3[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=3)[N:11]=2)=[C:4]([CH3:21])[CH:3]=1
Reactant: Cc1cc(Br)cc(C)c1Sc1nc(Cl)nc(C)c1[N+](=O)[O-]
Reactant: N#Cc1ccc(N)cc1
Solvent: CO
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: Cc1cc(Br)cc(C)c1Sc1nc(Nc2ccc(C#N)cc2)nc(C)c1[N+](=O)[O-]
Temperature: 80 °C

Procedure:
A mixture of 4-(4-bromo-2,6-dimethylphenylthio)-2-chloro-6-methyl-5-nitropyrimidine (59 mmol), 4-aminobenzonitrile (65 mmol) and pyridine (59 mmol) in THF (300 ml) is heated to 80° C. for 10 hours. The reaction mixture is dissolved in methanol, washed with brine and extracted with ethyl acetate. The organic layer is washed twice with brine, dried over MgSO4 and concentrated to dryness. The solid is washed with a mixture of hexane:ethyl acetate (80:20) before filtration. After filtration, the solid is washed again with methanol. The filtrate may be concentrated and additional rounds of precipitation performed following the same procedure, until all product is recovered. The combined solids are recrystallized from acetone.
Reaction SMILES: [CH3:1][CH:2]([CH3:14])[CH2:3][O:4][CH2:5][CH:6]([OH:13])[CH2:7][N:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1.ClC(Cl)C.S(Cl)(Cl)=O.[OH-].[Na+]>>[CH3:14][CH:2]([CH3:1])[CH2:3][O:4][CH2:5][CH:6]([OH:13])[CH2:7][N:8]([CH2:9][CH3:10])[CH2:12][CH3:11]
Reactant: CC(C)COCC(O)CN1CCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(Cl)Cl
Solvent: O=S(Cl)Cl
Product: CCN(CC)CC(O)COCC(C)C
Temperature: 0 °C

Procedure:
10 g. 3-(2-Methylpropoxy)-1-pyrrolidinopropan-2-ol are dissolved in 100 ml. dichloroethane. A solution of 7.1 g. thionyl chloride in 20 ml. dichloroethane is added dropwise thereto, while stirring, and the reaction mixture subsequently heated for 2 hours to 70° C. The reaction mixture is cooled, poured on to ice water and subsequently rendered alkaline by the addition of a concentrated aqueous solution of sodium hydroxide. The organic phase is separated off and the aqueous phase again extracted with methylene chloride. The organic phases are combined, dried over anhydrous sodium sulphate and evaporated. The residue is purified by chromatography on a silica gel column (elution agent: methylene chloride/5% methanol). There are obtained 9 g. of the title compound in the form of an oily product.
Reaction SMILES: [C:1]([Br:5])(Br)(Br)Br.OC[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([O:17][CH3:18])([CH3:16])[CH3:15])[N:9]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Br:5][CH2:1][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([O:17][CH3:18])([CH3:15])[CH3:16])[N:9]=1
Reactant: COC(C)(C)c1cccc(CO)n1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(C)(C)c1cccc(CBr)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 75 %

Procedure:
Carbon tetrabromide (1.59 g, 4.80 mmol) was added portionwise to a stirred solution of 2-hydroxymethyl-6-(1-methoxy-1-methylethyl)pyridine (724 mg, 4.00 mmol) and triphenylphosphine (1.15 g, 4.40 mmol) in DCM (50 mL) at 0° C. The mixture was stirred at 0° C. for 1 h then concentrated in vacuo. The residue was purified by column chromatography (20:1 to 5:1 isohexane:EtOAc) to give the title compound (732 mg, 75%) as a colourless oil; NMR δH (400 MHz, CDCl3) 7.69-7.65 (1H, m), 7.46-7.43 (1H, m), 7.32-7.30 (1H, m), 4.55 (2H, s), 3.17 (3H, s), 1.55 (6H, s).
Reaction SMILES: [CH:1]([N:4](CC)C(C)C)(C)[CH3:2].BrCC#N.[NH:14]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[C@H:15]([C:27]([OH:29])=[O:28])[CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:21]([C:23]([F:26])([F:25])[F:24])=[O:22]>C(#N)C>[C:33]([O:32][C:30]([NH:14][C@@H:15]([CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:21](=[O:22])[C:23]([F:25])([F:26])[F:24])[C:27]([O:29][CH2:2][C:1]#[N:4])=[O:28])=[O:31])([CH3:36])([CH3:35])[CH3:34]
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=O)C(F)(F)F)C(=O)O
Agent: N#CCBr
Solvent: CC#N
Product: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=O)C(F)(F)F)C(=O)OCC#N
Reaction time: 5.25 h
Yield: 99 %

Procedure:
N,N-Diisopropylethylamine (102 μL, 0.585 mmol) and subsequently bromoacetonitrile (185 μL, 2.66 mmol) were added to a solution of Boc-Lys(Tfa)-OH (Compound tk52) (182 mg, 0.532 mmol) in acetonitrile (0.5 mL) at room temperature under a nitrogen atmosphere. The reaction mixture was stirred at the same temperature for 5.25 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 (S)-cyanomethyl 2-((tert-butoxycarbonyl)amino)-6-(2,2,2-trifluoroacetamido)hexanoate (Compound tk53) (200.8 mg, 99%).