Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C@H:4]([CH2:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)[NH2:5].[Cl:14][C:15]1[CH:16]=[C:17]([NH:22][CH:23]([C:25](O)=[O:26])[CH3:24])[CH:18]=[CH:19][C:20]=1[Cl:21].N[C@H](C(O)=O)C>>[CH3:1][O:2][C:3](=[O:13])[C@H:4]([CH2:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)[NH:5][C:25](=[O:26])[CH:23]([CH3:24])[NH:22][C:17]1[CH:18]=[CH:19][C:20]([Cl:21])=[C:15]([Cl:14])[CH:16]=1
Reactant: COC(=O)[C@@H](N)CC1CCCCC1
Reactant: CC(Nc1ccc(Cl)c(Cl)c1)C(=O)O
Agent: C[C@H](N)C(=O)O
Product: COC(=O)[C@H](CC1CCCCC1)NC(=O)C(C)Nc1ccc(Cl)c(Cl)c1

Procedure:
Following General Procedure D and using β-cyclohexylalanine methyl ester (prepared from β-cyclohexylalanine (Bachem) using General Procedure K) and N-(3,4-dichlorophenyl)-D,L-alanine, the title compound, as a mixture of diastereomers about alanine, was prepared as an oil. The reaction was monitored by tlc (Rf=0.27 (second isomer) and 0.30 (first isomer) in 35% EtOAc/hexanes) and purification was by flash chromatography (35% EtOAc/hexanes).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:8](=O)O2)=C[CH:3]=1.[F:19][C:20]([F:32])([F:31])[C:21]([C:25]1[S:29][C:28]([SH:30])=[N:27][CH:26]=1)([OH:24])[CH2:22][CH3:23].[C:33](=[O:36])([O-])[O-:34].[K+].[K+]>CN1C(=O)CCC1>[OH:24][C@:21]([C:25]1[S:29][C:28]([S:30][C:16]2[CH:15]=[C:14]3[C:13]([C:7]([C:6]4[CH:3]=[CH:2][CH:11]=[CH:10][CH:5]=4)=[CH:8][C:33](=[O:36])[O:34]3)=[CH:18][CH:17]=2)=[N:27][CH:26]=1)([C:20]([F:19])([F:31])[F:32])[CH2:22][CH3:23]
Reactant: CCC(O)(c1cnc(S)s1)C(F)(F)F
Reactant: O=C([O-])[O-]
Reactant: O=c1oc2cc(Br)ccc2cc1-c1ccccc1
Agent: [K+]
Solvent: CN1CCCC1=O
Product: CC[C@@](O)(c1cnc(Sc2ccc3c(-c4ccccc4)cc(=O)oc3c2)s1)C(F)(F)F
Temperature: 120 °C

Procedure:
Employing the procedure of Example 1, Step 3, using 7-bromo-phenyl-2H-chromen-2-one (0.331 g, 1.1 mmol), thiol enantiomer #1 (0.243 g, 1 mmol) of Example 7, Step 1, and potassium carbonate (0415 g, 3 mmol) in NMP and heating at 120° C. for 20 h, the title compound was obtained. 1H NMR (400 MHz, acetone-d6): δ 7.88 (s, 1H), 7.45-7.62 (m, 8H), 6.41 (s, 1H), 6.10 (s, 1H, OH), 2.19 (q, 2H), 0.94 (t, 3H).
Reaction SMILES: [C:1]1([CH:7]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:8]2[C:16]3[C:11]4[C:12](=[CH:17][CH:18]=[CH:19][C:10]=4[C:9]2=S)[CH:13]=[CH:14][CH:15]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:27]1([CH2:32][CH2:33][CH2:34][NH2:35])[CH:31]=[CH:30][N:29]=[CH:28]1>C(O)C>[C:1]1([CH:7]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:8]2[C:16]3[C:11]4[C:12](=[CH:17][CH:18]=[CH:19][C:10]=4[C:9]2=[N:35][CH2:34][CH2:33][CH2:32][N:27]2[CH:31]=[CH:30][N:29]=[CH:28]2)[CH:13]=[CH:14][CH:15]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NCCCn1ccnc1
Reactant: S=C1c2cccc3cccc(c23)N1C(c1ccccc1)c1ccccc1
Solvent: CCO
Product: c1ccc(C(c2ccccc2)N2C(=NCCCn3ccnc3)c3cccc4cccc2c34)cc1

Procedure:
A mixture of 1.0 g of 1-(diphenylmethyl)benz[cd]indole-2(1H)-thione (Cd), 0.35 g of 1H-imidazole-1-propanamine, 20 ml ethyl alcohol and 0.91 g of mercuric acetate is reacted as described in Example 3, giving the desired product, mp. 142°-143° C.
Reaction SMILES: CS(O[CH2:6][CH:7]1[C:12]2[N:13]=[C:14]([NH2:16])[S:15][C:11]=2[CH2:10][CH2:9][CH2:8]1)(=O)=O.[N-:17]=[N+]=[N-].[Na+].C([O-])([O-])=O.[Na+].[Na+].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>CN(C=O)C.O>[NH2:17][CH2:6][CH:7]1[C:12]2[N:13]=[C:14]([NH2:16])[S:15][C:11]=2[CH2:10][CH2:9][CH2:8]1
Reactant: [N-]=[N+]=[N-]
Reactant: CS(=O)(=O)OCC1CCCc2sc(N)nc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CN(C)C=O
Product: NCC1CCCc2sc(N)nc21
Temperature: 85 °C
Reaction time: 0.5 h

Procedure:
To a solution of (2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-4-yl)methyl methanesulfonate (3.3 mmol) in DMF (10 mL) was added NaN3 (0.21 g, 3.3 mmol). The resulting mixture was stirred at 85° C. for 30 minutes. The mixture was poured into water (100 mL) and extracted with EtOAc. The organic extract was dried over anhydrous sodium sulfate. After filtration and concentration, the crude product was dissolved in THF (20 mL) and H2O (10 mL), Na2CO3 (0.35 g, 3.3 mmol) and PPh3 (0.8 g, 3 mmol) was added. After stirring overnight, the reaction mixture was diluted with water (100 mL) and then filtered. The filtrate was extracted with EtOAc, and the organic layer was washed with brine and dried over anhydrous sodium sulfate. After filtration and concentration, the crude product was obtained and used directly in the next step without further purification.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:9][NH:10][C:11]([NH:13][CH3:14])=[O:12].[C:15]1([CH3:39])[CH:20]=[CH:19][C:18]([O:21][P:22](OC2C=CC(C)=CC=2)[O:23]C2C=CC(C)=CC=2)=[CH:17][CH:16]=1>C1C=CC=CC=1>[CH3:9][N:10]1[C:11](=[O:12])[N:13]([CH3:14])[CH:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[P:22]1(=[O:23])[O:21][C:18]1[CH:19]=[CH:20][C:15]([CH3:39])=[CH:16][CH:17]=1
Reactant: CNC(=O)NC
Reactant: O=Cc1ccccc1
Reactant: Cc1ccc(OP(Oc2ccc(C)cc2)Oc2ccc(C)cc2)cc1
Solvent: c1ccccc1
Product: Cc1ccc(OP2(=O)C(c3ccccc3)N(C)C(=O)N2C)cc1
Reaction time: 3 h

Procedure:
Benzaldehyde, 0.5 mole, is added dropwise to a solution of 0.5 mole of 1,3-dimethylurea and 0.5 mole of tris(p-tolyl)phosphite in 100 g of benzene as the solution was warmed from 60°-90°. Warming is continued at 90° for 3 hr, giving a reaction mixture having 31P nmr peaks at -24.2 and -21.9 ppm (~6:1 areas). The solvent and most of the by-product p-cresol are removed by stripping to 120°/0.5mm, and the remaining yellow, viscous oil is dissolved in acetone. A solid that separates is recrystallized from acetone to give a white solid: mp 126.5°-128°; 31P nmr -24.2 ppm; 1H nmr δ6.9-7.5 (m, 9, aryl), 4,6 (d, 1, J = 19Hz, PCH), 2.9 (d, 3, J = 8Hz, PNCH3), 2.7 (s, 3, NCH3), 2.3 (s, 3, CH3); ms 330(50) (molecular ion), 273(1), 224(4), 239(6), 223(27), 182(4), 166(100), 118(49), 107(5), 91(17), 77(14), 60(42).
Reaction SMILES: [NH2:1][CH:2]([CH3:15])[C:3]([N:5]([CH:12]([CH3:14])[CH3:13])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:4].[CH:16](O)=O>C1(C)C=CC=CC=1>[N+:1]([CH:2]([CH3:15])[C:3]([N:5]([CH:12]([CH3:14])[CH3:13])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:4])#[C-:16]
Reactant: CC(N)C(=O)N(c1ccccc1)C(C)C
Reactant: O=CO
Solvent: Cc1ccccc1
Product: [C-]#[N+]C(C)C(=O)N(c1ccccc1)C(C)C
Temperature: -10 °C
Reaction time: 0.25 h

Procedure:
α-amino-N-isopropylpropionanilide (88.5 g.) was mixed with 80 g. of concentrated formic acid, then heated at 125° C. for 2 hours. The temperature was lowered to 100° C. and toluene added. The mixture was then refluxed. Water and formic acid were removed azeotropically. Upon crystallization, the toluene solvent was removed and the residue, identified as N-isopropyl-2-formamido propionanilide, triturated with ether and filtered. The formamide, (23.4 g.), was dissolved in methylene chloride and 50.5 g. triethylamine added thereto. The clear solution was cooled to -10° C. and 22.8 g. POCl3 added. After stirring at below zero temperature for 15 minutes, excess 10% sodium carbonate solution was added, taking care that temperature did not exceed 20° C. The mixture was allowed to stir at ambient temperature briefly, then the layers were separated. The organic layer was washed with 100 ml 2% salt solution, dried over MgSO4, filtered and stripped. The oily residue was taken up in methylcyclohexane and stirred. The cyclohexane solution was decanted from the insoluble oil and cooled and scratched to produce a solid which was filtered and air-dried. Recrystallization from heptane provided 2-isocyano-N-isopropylpropionanilide melting at 47°-50° C.
Reaction SMILES: [CH3:1][NH2:2].[NH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10](=O)[CH3:11].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C.ClCCl.O>[CH3:1][NH:2][CH:10]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[NH2:3])[CH3:11]
Reactant: CN
Reactant: CC(=O)c1ccccc1N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CC(=O)O
Product: CNC(C)c1ccccc1N
Temperature: 5 °C
Reaction time: 0.17 h

Procedure:
Acetic acid (10 drops) was added to a solution of methylamine (10 g) in dichloromethane (150 ml) cooled to 5° C., followed by o-aminoacetophenone (3.5 g, 25.9 mmol), and the solution stirred for 10 minutes. Sodium triacetoxyborohydride (1.5 g, 38.8 mmol) was added and the reaction stirred at room temperature for 72 hours. The reaction was diluted with water, the layers separated, and the organic solution evaporated under reduced pressure to give the title compound as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH:4]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][C:18]=2[Cl:24])[CH2:13][CH2:12]1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH3:26][C:27]1[CH:35]=[CH:34][CH:33]=[CH:32][C:28]=1[C:29](O)=[O:30].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:25])[CH:4]([N:11]1[CH2:12][CH2:13][N:14]([C:17]2[CH:22]=[CH:21][C:20]([NH:23][C:29](=[O:30])[C:28]3[CH:32]=[CH:33][CH:34]=[CH:35][C:27]=3[CH3:26])=[CH:19][C:18]=2[Cl:24])[CH2:15][CH2:16]1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: Cc1ccccc1C(=O)O
Reactant: COC(=O)C(c1ccccc1)N1CCN(c2ccc(N)cc2Cl)CC1
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Solvent: ClCCCl
Product: COC(=O)C(c1ccccc1)N1CCN(c2ccc(NC(=O)c3ccccc3C)cc2Cl)CC1
Reaction time: 16 h
Yield: 47.8 %

Procedure:
To a mixture of [4-(4-amino-2-chloro-phenyl)-piperazin-1-yl]-phenyl-acetic acid methyl ester (25 mg, 0.07 mmol), 2-methyl-benzoic acid (19 mg, 0.14 mmol), EDC (27 mg, 0.14 mmol), and HOBt (19 mg, 0.14 mmol) in DCM (5 mL) was added N-methylmorpholine (77 μL, 0.70 mmol). After 16 h, the mixture was diluted with satd. aq. NaHCO3 (10 mL) and extracted with DCM (75 mL). The organic fraction was washed with brine, dried (Na2SO4), and concentrated. The residue was purified by SiO2 column chromatography to provide the title compound (16 mg, 46%). MS (ESI): mass calcd. for C27H28ClN3O3, 477.18. m/z found, 478.4 [M+H]+. 1H NMR (CDCl3): 7.76-7.60 (m, 1H), 7.51-7.23 (m, 8H), 7.22-7.15 (m, 2H), 6.97 (d, J=8.7, 1H), 3.66 (s, 3H), 3.15-2.93 (m, 5H), 2.85-2.49 (m, 4H), 2.42 (s, 3H).
Reaction SMILES: [C:1]([CH:5]1[C:10](=[O:11])[CH2:9][CH:8]([CH2:12][CH2:13][S:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH2:7][C:6]1=[O:25])(=O)[CH2:2][CH3:3].Cl.[CH2:27]([O:30][NH2:31])[CH:28]=[CH2:29].C(N(CC)CC)C.O>C(O)C>[CH2:27]([O:30][NH:31][C:1](=[C:5]1[C:6](=[O:25])[CH2:7][CH:8]([CH2:12][CH2:13][S:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH2:9][C:10]1=[O:11])[CH2:2][CH3:3])[CH:28]=[CH2:29]
Reactant: C=CCON
Reactant: CCC(=O)C1C(=O)CC(CCSc2ccc(C(F)(F)F)cc2)CC1=O
Agent: Cl
Solvent: CCO
Solvent: O
Solvent: CCN(CC)CC
Product: C=CCONC(CC)=C1C(=O)CC(CCSc2ccc(C(F)(F)F)cc2)CC1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.19 Gram of 2-propionyl-5-[2-(4-trifluoromethylphenylthio)ethyl]cyclohexane-1,3-dione was dissolved in 5 ml of ethanol, and 0.07 g of allyloxyamine hydrochloride and 0.06 g of triethylamine were added to the resulting solution which was then stirred overnight at room temperature. The reaction solution was poured into water, acidified and extracted with chloroform. After removing chloroform, the residue was purified by thin layer chromatography (eluent, hexane:ethyl acetate=5:1) to obtain 0.13 g of 2-(1-allyloxyaminopropylidene)-5-[2-(4-trifluoromethylphenylthio)ethyl]cyclohexane-1,3-dione.
Reaction SMILES: Br[C:2]1[C:3]([F:16])=[C:4]([NH:8]C(=O)OC(C)(C)C)[CH:5]=[CH:6][CH:7]=1.[CH2:17]([Sn](CCCC)(CCCC)C=C)[CH2:18]CC.FC(F)(F)C(O)=O>C1(C)C=CC=CC=1.ClCCl.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>[CH:17]([C:2]1[C:3]([F:16])=[C:4]([CH:5]=[CH:6][CH:7]=1)[NH2:8])=[CH2:18]
Reactant: CC(C)(C)OC(=O)Nc1cccc(Br)c1F
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C=Cc1cccc(N)c1F
Temperature: 25 °C
Yield: 58 %

Procedure:
A solution of 1,1-dimethylethyl (3-bromo-2-fluorophenyl)carbamate (500 mg, 1.72 mmol) and 2,6-ditert-4-methylphenol (3 mg, 0.02 mmol) in toluene (3 mL) was deoxygenated for 10 minutes. Tetrakis(triphenylphosphine)palladium(0) (100 mg, 0.09 mmol) and tributyl(vinyl)tin (708 μl, 2.43 mmol) were added to the solution, which was then stirred at refluxed for 4 hrs. The mixture was cooled to room temperature, and then filtered through a pad of celite. The filtrate was concentrated in-vacuo to afford an orange residue, which was purified by column chromatography (silica gel, 5% ether in hexane). The product was isolated as a colorless oil, and was then diluted in dichloromethane (2 mL). To the solution was added trifluoroacetic acid (500 μl), and the solution was stirred at ambient temperature for 1 hour. The solution was partitioned between saturated sodium bicarbonate and dichloromethane. The aqueous portion was extracted twice with dichloromethane, and the combined organic portions were washed with brine, dried over sodium sulfate, filtered, and concentrated in-vacuo to afford 138 mg, 1.0 mmol, (58% over two steps) of 3-ethenyl-2-fluoroaniline as a colorless oil. 1H NMR (400 MHz, CDCl3): 6.92-6.82 (m, 3H), 6.71-6.66 (m, 1H), 5.80 (d, 1H), 5.35 (d, 1H); 3.72 (br s, 2H); MS (EI) for C8H8FN: 138 (MH+).
Reaction SMILES: [CH:1]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([NH2:11])[C:5]=2[CH:4]=[CH:3][N:2]=1.Br[CH2:13][CH2:14][CH2:15][CH2:16][C:17](Cl)=[O:18].CC([O-])(C)C.[K+]>C1COCC1>[CH:1]1[C:10]2[C:5](=[C:6]([N:11]3[CH2:13][CH2:14][CH2:15][CH2:16][C:17]3=[O:18])[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1
Reactant: O=C(Cl)CCCCBr
Reactant: Nc1cccc2cnccc12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=C1CCCCN1c1cccc2cnccc12
Reaction time: 24 h
Yield: 106.2 %

Procedure:
To isoquinolin-5-amine (0.24 g, 1.665 mmol) in THF (5 mL) was added 5-bromopentanoyl chloride (0.223 mL, 1.665 mmol) followed by addition of THF (3 mL). The reaction was cooled with ice bath and to the above solution was added 1M KOtBu in THF (3.66 mL, 3.66 mmol). After 24 h, the reaction was quenched with H2O (10 mL) and extracted with EtOAc (3×20 mL). The combined organic layers were washed with brine (10 mL) and dried (MgSO4) to afford 0.4 g of 33A as a dark solid. MS (ESI) m/z: 227 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:11]=[C:10]([O:12][CH2:13][CH3:14])[CH:9]=[C:8]([O:15][CH2:16][CH3:17])[C:5]=1[CH:6]=O)[CH3:2].[C:18]([NH:22][OH:23])([CH3:21])([CH3:20])[CH3:19]>>[CH2:1]([O:3][C:4]1[CH:11]=[C:10]([O:12][CH2:13][CH3:14])[CH:9]=[C:8]([O:15][CH2:16][CH3:17])[C:5]=1[CH:6]=[N+:22]([C:18]([CH3:21])([CH3:20])[CH3:19])[O-:23])[CH3:2]
Reactant: CC(C)(C)NO
Reactant: CCOc1cc(OCC)c(C=O)c(OCC)c1
Product: CCOc1cc(OCC)c(C=[N+]([O-])C(C)(C)C)c(OCC)c1

Procedure:
The title compound was prepared according to the procedure described in Example 11 using 2,4,6-triethoxybenzaldehyde and N-tert-butylhydroxylamine. The title compound was isolated in 92.3% yield as a solid, m.p. 109.1° C.
Reaction SMILES: Br[C:2]1[N:10]2[C:5]([CH:6]=[N:7][C:8]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([N:18]4[CH2:23][CH2:22][CH:21]([N:24]5[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]5)[CH2:20][CH2:19]4)=[CH:14][C:13]=3[O:31][CH3:32])=[N:9]2)=[CH:4][CH:3]=1.[CH3:33][NH:34][C:35]([C:37]1[CH:42]=[CH:41][C:40](B(O)O)=[CH:39][CH:38]=1)=[O:36]>>[CH3:32][O:31][C:13]1[CH:14]=[C:15]([N:18]2[CH2:23][CH2:22][CH:21]([N:24]3[CH2:25][CH2:26][N:27]([CH3:30])[CH2:28][CH2:29]3)[CH2:20][CH2:19]2)[CH:16]=[CH:17][C:12]=1[NH:11][C:8]1[N:7]=[CH:6][C:5]2=[CH:4][CH:3]=[C:2]([C:40]3[CH:41]=[CH:42][C:37]([C:35]([NH:34][CH3:33])=[O:36])=[CH:38][CH:39]=3)[N:10]2[N:9]=1
Reactant: COc1cc(N2CCC(N3CCN(C)CC3)CC2)ccc1Nc1ncc2ccc(Br)n2n1
Reactant: CNC(=O)c1ccc(B(O)O)cc1
Product: CNC(=O)c1ccc(-c2ccc3cnc(Nc4ccc(N5CCC(N6CCN(C)CC6)CC5)cc4OC)nn23)cc1
Yield: 54.1 %

Procedure:
Following a procedure similar to Example 241, (7-Bromo-pyrrolo[2,1-f][1,2,4]triazin-2-yl)-{2-methoxy-4-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-phenyl}-amine (0.10 g, 0.00020 mol) and 4-(N-Methylaminocarbonyl)phenylboronic acid (0.039 g, 0.00022 mol). Purification by Isco chromatography gave 4-(2-{2-Methoxy-4-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-phenylamino}-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-methyl-benzamide as a tan solid (0.06 g, 50%). MP 112-114° C.; LCMS (m/e) 555 (M+1); 1H-NMR (DMSO, 400 MHz) δ 8.94 (s, 1H), 8.28 (d, 1H, J=8.53 Hz), 7.90 (d, 1H, J=8.52 Hz), 7.85 (s, 1H), 7.71 (d, 1H, J=8.68 Hz), 7.28 (d, 1H, J=4.80 Hz), 6.94 (d, 1H, J=4.80 Hz), 6.69 (d, 1H, J=2.40 Hz), 3.83 (s, 3H), 3.74 (d, 1H, J=2.00 Hz), 2.82 (d, 2H, J=4.52 Hz), 2.68 (m, 3H), 2.33 (m, 4H), 2.15 (s, 3H), 1.90-1.75 (m, 2H), 1.60-1.48 (m, 2H), 1.25 (s, 1H), 1.18 (br s, 2H).
Reaction SMILES: C(N(CC)CC)C.[NH2:8][CH2:9][C:10]1[N:15]=[CH:14][CH:13]=[CH:12][N:11]=1.[CH2:16]([O:18][C:19](Cl)=[O:20])[CH3:17]>C1(C)C=CC=CC=1>[CH2:16]([O:18][C:19]([NH:8][CH2:9][C:10]1[N:15]=[CH:14][CH:13]=[CH:12][N:11]=1)=[O:20])[CH3:17]
Reactant: CCOC(=O)Cl
Reactant: NCc1ncccn1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOC(=O)NCc1ncccn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
49.5 g (0.49 mol) of triethylamine are added to 49.5 g (0.45 mol) of 2-aminomethyl-pyrimidine in 450 ml of toluene and then 52 g (0.48 mol) of ethyl chlorocarbonic acid are added dropwise under cooling with ice. The mixture is subsequently stirred at room temperature for 2 hours. Triethylamine hydrochloride is filtered off with suction, the filtrate is washed with brine, dried with MgSO4, concentrated, and distilled.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]([NH:20][C@H:21]3[CH2:27][CH2:26][CH2:25][CH2:24][N:23]([CH2:28][C:29](O)=[O:30])[C:22]3=[O:32])=[O:19])[CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][C:6]([Cl:33])=[CH:7][CH:8]=2)[N:3]=1.[NH2:34][C:35]1[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>>[NH2:1][C:2]1[CH:11]=[C:10]([N:12]2[CH2:13][CH2:14][N:15]([C:18]([NH:20][C@H:21]3[CH2:27][CH2:26][CH2:25][CH2:24][N:23]([CH2:28][C:29]([NH:34][C:35]4[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=4)=[O:30])[C:22]3=[O:32])=[O:19])[CH2:16][CH2:17]2)[C:9]2[C:4](=[CH:5][C:6]([Cl:33])=[CH:7][CH:8]=2)[N:3]=1
Reactant: Nc1cc(N2CCN(C(=O)N[C@H]3CCCCN(CC(=O)O)C3=O)CC2)c2ccc(Cl)cc2n1
Reactant: Nc1ccncc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: Nc1cc(N2CCN(C(=O)N[C@H]3CCCCN(CC(=O)Nc4ccncc4)C3=O)CC2)c2ccc(Cl)cc2n1

Procedure:
As described as example 208, (3S)-[[[4-(2-amino-7-chloro-4-quinolinyl)-1-piperazinyl]carbonyl]amino]hexahydro-2-oxo-1H-azepine-1-acetic acid, 4-aminopyridine, HATU, and diisopropylethylamine are reacted to afford the product. LC-MS: 551 (M++1). 1H NMR (CD3OD) δ 1.60–1.80 (m, 4H), 1.90 (m, 2H), 3.10 (m, 4H), 3.30 (m, 1H), 3.60 (m, 4H), 4.20 (m, 2H), 4.60 (d, 1H), 6.24 (s, 1H), 7.08 (d, 1H), 7.39 (s, 1H), 7.55 (m, 2H), 7.75 (d, 2H), 8.30 (m, 2H).
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]1([CH:13]([N:18]2[CH:22]=[C:21]([C:23]3[C:24]4[CH:32]=[CH:31][N:30](OCC[Si](C)(C)C)[C:25]=4[N:26]=[C:27](C)[N:28]=3)[CH:20]=[N:19]2)[CH2:14][CH:15]2[CH2:17][CH2:16]2)[CH2:12][CH2:11][CH2:10][CH2:9]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:8]1([CH:13]([N:18]2[CH:22]=[C:21]([C:23]3[C:24]4[CH:32]=[CH:31][NH:30][C:25]=4[N:26]=[CH:27][N:28]=3)[CH:20]=[N:19]2)[CH2:14][CH:15]2[CH2:17][CH2:16]2)[CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: Cc1nc(-c2cnn(C(CC3CC3)C3CCCC3)c2)c2ccn(OCC[Si](C)(C)C)c2n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: c1nc(-c2cnn(C(CC3CC3)C3CCCC3)c2)c2cc[nH]c2n1
Reaction time: 1 h
Yield: 0.1 %

Procedure:
4-[1-(1-Cyclopentyl-2-cyclopropylethyl)-1H-pyrazol-4-yl]-7-[2-(trimethylsilyl)ethoxy]-methyl-7H-pyrrolo[2,3-d]pyrimidine trifluoroacetate salt (13 mg, 0.023 mol) was stirred at room temperature in a solution of DCM (2 mL) containing TFA (1.5 mL) for two hours. The solvent was removed in vacuo. The resulting residue was redissolved in THF (3 mL), and 6N NaOH (2 mL) was added. After stirring for one hour, the mixture was partitioned between water and ethyl acetate. The organic layer was dried over sodium sulfate and the solvent was removed in vacuo. Purification via preparative-HPLC/MS (C18 eluting with a gradient of H2O and ACN containing 0.1% TFA) afforded the product (9 mg, 90%).
Reaction SMILES: [NH2:1]/[C:2](=[N:10]\[O:11][C:12]([C@H:14]([CH2:23][CH2:24][CH2:25][CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)[CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=O)/[CH2:3][S:4]([CH2:7][CH2:8][CH3:9])(=[O:6])=[O:5]>C1(C)C(C)=CC=CC=1>[CH:26]1([CH2:25][CH2:24][CH2:23][C@@H:14]([C:12]2[O:11][N:10]=[C:2]([CH2:3][S:4]([CH2:7][CH2:8][CH3:9])(=[O:6])=[O:5])[N:1]=2)[CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: CCCS(=O)(=O)C/C(N)=N/OC(=O)[C@H](CCCC1CCCCC1)CC(=O)OC(C)(C)C
Solvent: Cc1ccccc1C
Product: CCCS(=O)(=O)Cc1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1
Temperature: 25 °C
Yield: 56.5 %

Procedure:
A solution of tert-butyl (3R)-3-[({[(Z)-1-amino-2-(propylsulfonyl)ethylidene]amino}oxy)carbonyl]-6-cyclohexylhexanoate (Preparation 95) (760 mg, 1.60 mmol) in xylene (15 ml) was heated at 130° C. for 28 hours. After cooling to room temperature the reaction mixture was purified by column chromatography on silica gel eluting with a gradient system of 100:0 (pentane:ethyl acetate) gradually changing to 70:30 (pentane:ethyl acetate) to afford the title compound as a yellow oil (400 mg).
Reaction SMILES: C([Li])CCC.S1CCCSC1.[Br:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[C:15]([C:20]#[N:21])[CH:14]=1.[CH3:22][O:23][C:24]([CH3:26])=[CH2:25].[Br:27][C:28]1[CH:29]=[CH:30][C:31]2[O:36][C:35]([CH3:38])([CH3:37])[N:34]=[C:33]([CH:39]3[S:44][CH2:43][CH2:42][CH2:41][S:40]3)[C:32]=2[CH:45]=1>CCCCCC.O1CCCC1>[Br:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:25][CH:24]([O:23][CH3:22])[CH3:26])=[C:15]([CH:14]=1)[C:20]#[N:21].[Br:27][C:28]1[CH:29]=[CH:30][C:31]2[O:36][C:35]([CH3:37])([CH3:38])[N:34]=[C:33]([CH:39]3[S:40][CH2:41][CH2:42][CH2:43][S:44]3)[C:32]=2[CH:45]=1
Reactant: C=C(C)OC
Reactant: N#Cc1cc(Br)ccc1O
Agent: C1CSCSC1
Agent: CC1(C)N=C(C2SCCCS2)c2cc(Br)ccc2O1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COC(C)COc1ccc(Br)cc1C#N
Reaction time: 0.5 h

Procedure:
A solution (13.8 ml) of 1.6M n-butyllithium in hexane was added dropwise to a solution of 1,3-dithian (1.5 g) in anhydrous tetrahydrofuran (35 ml) at -78° C. under an argon atmosphere over 10 minutes. After stirring for 30 minutes, a solution of 5-bromo-2-(2-methoxy-2-methylethoxy)benzonitrile, which was prepared from 4-bromo-2-cyanophenol (m.p. 148°-150° C., 2.48 g) and 2-methoxypropene (1.1 g) according to the same manner as described in Example 29, in anhydrous tetrahydrofuran (5 ml) was added to the mixture. The mixture was treated in the same manner as that in Example 29 to obtain 6-bromo-2,2-dimethyl-4-(1,3-dithian-2-yl)-2H-1,3-benzoxazine (0.90 g) (Compound 105).
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].C[CH:7]1[CH2:12][CH2:11]C[CH:9](C)[C:8]1=O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CCOCC>[CH2:1]=[C:2]1[CH:12]([CH3:11])[CH2:7][CH2:8][CH2:9][CH:3]1[CH3:4]
Reactant: CC1CCCC(C)C1=O
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: CCOCC
Product: C=C1C(C)CCCC1C
Yield: 48.3 %

Procedure:
Methyltriphenylphosphonium bromide (286 g, 0.80 mole) was suspended in ether (1500 ml) and treated with n-butyllithium (1.6M in ether; 500 ml, 0.80 mole), followed by 2,6-dimethylcyclohexanone (50.4 g, 0.40 mole), following the procedure described in Example 12, Part A. The crude product was distilled to give 1-methylene-2,6-dimethylcyclohexane (24 g), b.p. 146°-154° C./760 mm.