Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH:5]1[C:10](=[O:11])[CH2:9][CH:8]([CH:12]2[CH2:17][CH2:16][CH2:15][S:14][CH2:13]2)[CH2:7][C:6]1=[O:18])(=O)[CH2:2][CH3:3].[Br:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]=[CH:27][CH2:28][O:29][NH2:30])=[CH:22][CH:21]=1>CO>[Br:19][C:20]1[CH:21]=[CH:22][C:23]([CH:26]=[CH:27][CH2:28][O:29][N:30]=[C:1]([C:5]2[C:10](=[O:11])[CH2:9][CH:8]([CH:12]3[CH2:17][CH2:16][CH2:15][S:14][CH2:13]3)[CH2:7][C:6]=2[OH:18])[CH2:2][CH3:3])=[CH:24][CH:25]=1
Reactant: NOCC=Cc1ccc(Br)cc1
Reactant: CCC(=O)C1C(=O)CC(C2CCCSC2)CC1=O
Solvent: CO
Product: CCC(=NOCC=Cc1ccc(Br)cc1)C1=C(O)CC(C2CCCSC2)CC1=O
Yield: 70.3 %

Procedure:
3.0 g (0.011 mol) of 2-propionyl-5-(3-tetrahydrothiopyranyl)-cyclohexane-1,3-dione and 3.0 g (0.013 mol) of 3-(4-bromophenyl)-prop-2-enyloxyamine in 100 ml of methanol were stirred for 16 hours at 20° C. The precipitated reaction product was filtered off under suction at 0° C. and washed with ice cold methanol and petroleum ether. Drying gave 3.7 g (68.4% of theory) of 2-[1-(3-(4-bromophenyl)-prop-2-enyloximino)-propyl]-3-hydroxy-5-(3-tetrahydrothiopyranyl)-cyclohex-2-en-1-one of melting point 97°-99° C.
Reaction SMILES: Cl[C:2]1[CH:8]([O:9][CH3:10])[N:7]=[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:17])[C:5]2[CH:18]=[C:19]([Cl:22])[CH:20]=[CH:21][C:4]=2[N:3]=1.C1C[O:26][CH2:25][CH2:24]1.CC[O-].[Na+]>CCO>[Cl:22][C:19]1[CH:20]=[CH:21][C:4]2[N:3]=[C:2]([O:26][CH2:25][CH3:24])[CH:8]([O:9][CH3:10])[N:7]=[C:6]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])[C:5]=2[CH:18]=1
Reactant: C1CCOC1
Reactant: COC1N=C(c2ccccc2Cl)c2cc(Cl)ccc2N=C1Cl
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC1=Nc2ccc(Cl)cc2C(c2ccccc2Cl)=NC1OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 5.40 g. (0.015 mol) of 2,7-dichloro-5-(o-chlorophenyl)-3-methoxy-3H-1,4-benzodiazepine in 25 ml. of THF is added a solution of NaOEt [from 0.34 g. (0.015 ml.) of Na] in 20 ml. of EtOH. The mixture is stirred for 21/2 hour at room temperature, poured into 500 ml. of ice water, and extracted twice with Et2O. The extracts are washed with saturated NaHCO3 and brine and dried. Concentration and crystallization gives 3 g. of the title compound; m.p. 110°-113°.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[Cl:9].[Br:10]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][Br:10])[C:3]=1[Cl:9]
Reactant: Cc1cccc(Br)c1Cl
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1c(Br)cccc1CBr
Reaction time: 2 h
Yield: 45.9 %

Procedure:
1-bromo-2-chloro-3-methylbenzene (10 g, 48.7 mmol) was dissolved in CCl4 (100 mL), and then N-bromosuccinimide (13.0 g, 73.0 mmol) and benzoyl peroxide (5.9 g, 24.3 mmol) were added. The mixture was stirred for 2 hours at reflux. The solid was removed by filtration, and the filtrate was washed with water and dried over sodium sulfate. After evaporation of the solvent, the residue was dissolved in DCM and purified on silica gel using 10% hexane/AcOEt to afford 1-bromo-3-(bromomethyl)-2-chlorobenzene (6.36 g, 46% yield); 1H NMR (400 MHz, CDCl3): δ 4.62 (s, 2H), 7.12 (t, J=7.8 Hz, 1H), 7.39 (dd, J=1.6 Hz, J=7.6 Hz, 1H), 7.60 (dd, J=1.6 Hz, J=8.0 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]([N:7]([C:21](=[O:25])[CH2:22][O:23][CH3:24])[C:8]1[C:13]([CH3:14])=[CH:12][CH:11]=[C:10]([CH2:15][O:16]C(=O)C)[C:9]=1[CH3:20])[CH3:6])=[O:4].[OH-].[Na+].CC(C)=O>O>[CH3:1][O:2][C:3]([CH:5]([N:7]([C:21](=[O:25])[CH2:22][O:23][CH3:24])[C:8]1[C:13]([CH3:14])=[CH:12][CH:11]=[C:10]([CH2:15][OH:16])[C:9]=1[CH3:20])[CH3:6])=[O:4]
Reactant: COCC(=O)N(c1c(C)ccc(COC(C)=O)c1C)C(C)C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: COCC(=O)N(c1c(C)ccc(CO)c1C)C(C)C(=O)OC

Procedure:
23.0 g of N-(1'-methoxycarbonyl-ethyl)-N-methoxyacetyl-2,6-dimethyl-3-acetoxymethylaniline, 9.2 g of 30% sodium hydroxide solution and 100 ml of acetone were stirred for 3 hours at room temperature; 20 ml of water were then added, and the reaction mixture was extracted twice with 50 ml of diethyl ether each time. The combined ether extracts were dried over sodium sulfate, and the solvent was evaporated off. The oily crude product was chromatographed through a silica gel column by means of ether/chloroform (1:1) to thus obtain the product in the form of colourless oil: nD14 =1.5352.
Reaction SMILES: [NH2:1][C:2]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[Cl:14]N1C(=O)CCC1=O>CN(C)C=O.C(OCC)(=O)C>[NH2:1][C:2]1[C:11]([O:12][CH3:13])=[CH:10][C:9]([Cl:14])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: O=C1CCC(=O)N1Cl
Reactant: COC(=O)c1cccc(OC)c1N
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Cl)cc(OC)c1N
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.1 %

Procedure:
To methyl 2-amino-3-methoxybenzoate (750 mg, 4.1 mmol) in anhydrous N,N-dimethylformamide (15 mL) was added N-chlorosuccinimide (580 mg, 4.35 mmol) and this mixture was stirred at ambient temperature for 2 hours. The temperature was increased to 60° C. for 4 hours. The deep red solution was cooled, diluted with ethyl acetate, washed with saturated sodium bicarbonate, water, then brine, dried with sodium sulfate, decanted and concentrated to yield crude methyl 2-amino-5-chloro-3-methoxybenzoate (0.85 g, 95%). MS (m/z): 216.1 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]([F:25])([F:24])[CH2:11][CH2:12]N1C(=O)C2=CC=CC=C2C1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.NN.Cl.C(NN)(=O)C1C(=CC=CC=1)C([NH:35]N)=O>C(O)C>[CH2:1]([O:8][CH:9]([NH2:35])[C:10]([F:25])([F:24])[CH2:11][CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NNC(=O)c1ccccc1C(=O)NN
Reactant: O=C1c2ccccc2C(=O)N1CCC(F)(F)COCc1ccccc1
Agent: Cl
Agent: NN
Solvent: CCO
Solvent: O
Product: CCC(F)(F)C(N)OCc1ccccc1
Reaction time: 1.5 h

Procedure:
The compound N-(4-benzyloxy-3,3-difluorobutyl)-phthalimide (68.5 g, 198.6 mmoles) and hydrazine hydrate (10 g, 200 mmoles) are stirred and heated overnight in ethanol (200 mL) at 90°-100° C. A mixture of concentrated HCl (94 mL) and ethanol (1130 mL) is added, and heating (90°-100° C.) is continued for 1.5 hours. After cooling (ice bath), phthalhydrazide is removed by filtration, and the filtrate is evaporated. The residue is taken up in water and extracted with ether (2×500 mL). After filtration through a membrane filter (Millipore), evaporation of the filtrate yields white crystals. These are dissolved in ethanol, the solution is filtered (Millipore organic) and the filtrate is evaporated to yield a residue which crystallizes on addition of ether: 34 g (68%). Evaporation of the ether extracts yields a partially crystalline material (20 g) consisting of starting material. Repetition of the hydrazine cleavage upon this mixture yields a second crop of 4-benzyloxy-3,3-difluorobutylamine (9.1 g). Total: 43.2 g (86.5%).
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](=[O:22])[NH:19][C:18]4=[O:23])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:26]([F:29])([F:28])[F:27])[CH:3]=1.[C:30]([O:34][C:35]([N:37]1[CH2:42][CH2:41][C:40]([F:45])([CH2:43]O)[CH2:39][CH2:38]1)=[O:36])([CH3:33])([CH3:32])[CH3:31]>>[C:30]([O:34][C:35]([N:37]1[CH2:42][CH2:41][C:40]([CH2:43][N:19]2[C:18](=[O:23])[C:17](=[CH:16][C:12]3[CH:11]=[C:10]4[C:15](=[CH:14][CH:13]=3)[N:7]([CH2:6][C:5]3[CH:24]=[CH:25][C:2]([Cl:1])=[CH:3][C:4]=3[C:26]([F:27])([F:29])[F:28])[N:8]=[CH:9]4)[S:21][C:20]2=[O:22])([F:45])[CH2:39][CH2:38]1)=[O:36])([CH3:33])([CH3:31])[CH3:32]
Reactant: O=C1NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Reactant: CC(C)(C)OC(=O)N1CCC(F)(CO)CC1
Product: CC(C)(C)OC(=O)N1CCC(F)(CN2C(=O)SC(=Cc3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)C2=O)CC1

Procedure:
4-{5-[1-(4-Chloro-2-trifluoromethylbenzyl)-1H-indazol-5-ylmethylene]-2,4-dioxothiazolidin-3-ylmethyl}-4-fluoropiperidine-1-carboxylic acid tert-butyl ester was prepared from 5-[1-(4-chloro-2-trifluoromethylbenzyl)-1H-indazol-5-ylmethylene]thiazolidine-2,4-dione and 4-fluoro-4-hydroxymethyl-piperidine-1-carboxylic acid tert-butyl ester following General Procedure J.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2([CH2:13][CH3:14])[O:12][CH2:11][CH2:10][O:9]2)[CH:5]=[CH:6][CH:7]=1.C([Li])CCC.CN([CH:23]=[O:24])C.[Cl-].[NH4+]>C1COCC1>[CH2:13]([C:8]1([C:4]2[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=2)[CH:23]=[O:24])[O:12][CH2:11][CH2:10][O:9]1)[CH3:14]
Reactant: CCC1(c2cccc(Br)c2)OCCO1
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCC1(c2cccc(C=O)c2)OCCO1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
17.8 g (70 mmol) of 2-(3-bromophenyl)-2-ethyl-[1,3]dioxolane are dissolved in 300 ml of THF and the mixture is cooled to −78° C. 34 ml (85 mmol) of a 2.5 M solution of butyllithium are added slowly, and the mixture is stirred for 30 minutes. 8.1 ml (105 mmol) of DMF are then added, and the mixture is brought back to 0° C., then treated with a saturated solution of ammonium chloride. After extraction with ethyl ether, the desired aldehyde is obtained in the form of yellow oil (m=14 g; Y=97%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:26]2[C:31](=[O:32])[NH:30][C:29](=[O:33])[CH:28]=[N:27]2)[CH:5]=[C:6]([CH3:25])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([CH:16]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)O)[CH:10]=1.CS(O)(=O)=O.C([SiH](CC)CC)C.O>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([N:26]2[C:31](=[O:32])[NH:30][C:29](=[O:33])[CH:28]=[N:27]2)[CH:5]=[C:6]([CH3:25])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([CH2:16][C:18]2[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=2)[CH:10]=1
Reactant: Cc1cc(-n2ncc(=O)[nH]c2=O)cc(Cl)c1Oc1ccc(O)c(C(O)c2ccc(F)cc2)c1
Agent: CC[SiH](CC)CC
Agent: CS(=O)(=O)O
Solvent: ClCCl
Solvent: O
Product: Cc1cc(-n2ncc(=O)[nH]c2=O)cc(Cl)c1Oc1ccc(O)c(Cc2ccc(F)cc2)c1

Procedure:
To a stirred solution of 2-(3-chloro-4-{3-[(4-fluoro-phenyl)-hydroxy-methyl]-4-hydroxy-phenoxy}-5-methyl-phenyl)-2H-[1,2,4]triazine-3,5dione (0.4 g) in dichloromethane (25 mL) were added methanesulfonic acid (0.7 mL) and triethylsilane (1.5 mL) portionwise over 1 h. After a total of 1.5 h, water was added, the layers separated and the aqueous layer extracted with dichloromethane. The combined organic layers were washed with saturated sodium bicarbonate, dried (Na2SO4), concentrated in vacuo and flash chromatographed on silica gel (10-50% THF/hexanes) to afford the title compound of this EXAMPLE as a colorless foam, 56 mg. MS Calc.:453.9; Found:452.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2Cl.[CH3:18][N:19]([CH2:21][C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][CH:28]=1)[NH2:25])[CH3:20]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:25][C:24]1[CH:26]=[CH:27][CH:28]=[C:22]([CH2:21][N:19]([CH3:20])[CH3:18])[CH:23]=1
Reactant: O=C(c1cnc2ccc(Br)cc2c1Cl)C1CC1
Reactant: CN(C)Cc1cccc(N)c1
Product: CN(C)Cc1cccc(Nc2c(C(=O)C3CC3)cnc3ccc(Br)cc23)c1
Yield: 80.8 %

Procedure:
Following General procedure C, (6-bromo-4-chloroquinolin-3-yl)(cyclopropyl)methanone (311 mg, 1 mmol) was reacted with 3-((dimethylamino)methyl)aniline (226 mg, 1.5 mmol) to afford the desired product (343 mg, 810%) as a yellow solid: ESI MS m/z 424 [C22H22BrN3O+H]+.
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:15]=[C:16]([NH:20][C:21]([C:23]4[N:24]([CH3:29])[N:25]=[C:26]([CH3:28])[CH:27]=4)=[O:22])[CH:17]=[CH:18][CH:19]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:30].C1COCC1.[NH2:36][C:37]1[CH:45]=[CH:44][C:40]([C:41]([OH:43])=[O:42])=[CH:39][CH:38]=1.[O-]S([O-])(=O)=O.[Na+].[Na+]>CCOC(C)=O>[CH3:29][N:24]1[C:23]([C:21]([NH:20][C:16]2[CH:15]=[C:14]([CH:19]=[CH:18][CH:17]=2)[C:12]([C:8]2[CH:7]=[C:6]3[C:11]([C:3](=[CH:2][NH:36][C:37]4[CH:45]=[CH:44][C:40]([C:41]([OH:43])=[O:42])=[CH:39][CH:38]=4)[C:4](=[O:30])[NH:5]3)=[CH:10][CH:9]=2)=[O:13])=[O:22])=[CH:27][C:26]([CH3:28])=[N:25]1
Reactant: Cc1cc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CO)c2)n(C)n1
Reactant: Nc1ccc(C(=O)O)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CNc3ccc(C(=O)O)cc3)c2)n(C)n1
Temperature: 65 °C
Reaction time: 24 h

Procedure:
A small screw cap test tube was charged with 2,5-Dimethyl-2H-pyrazole-3-carboxylic acid [3-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (as prepared in Example 60, 100 mg, 0.249 mmol) and THF (2 mL). To the resulting solution was added 4-Amino-benzoic acid (37.5 mg, 0.274 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature. The yellow solid was dissolved into a solution of 98% EtOAc/2% i-prOH (3 mL) and washed with water (3×2 mL). The organic layers were combined and dried over anhydrous Na2SO4 affording 47.8% (0.062 g, 0.119 mmol) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].Cl[CH2:13][CH2:14][CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:13][CH2:14][CH:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: O=[N+]([O-])c1cc(O)ccc1Cl
Reactant: ClCCC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(OCCC2CCNCC2)ccc1Cl
Temperature: 80 °C
Reaction time: 20 h
Yield: 56.1 %

Procedure:
4-chloro-3-nitrophenol (2.5 g, 14.4 mmol, 1 eq.) was placed in dimethylformamide (48 mL) with 4-(2-chloro-ethyl)piperidine (8 g, 43.2 mmol, 3 eq.), Cs2CO3 (33 g, 100.8 mmol, 7 eq.), KI (5.3 g, 31.7 mmol, 2.2 eq.). The reaction mixture was heated at 80° C. and stirred for 20 hours. The reaction mixture was then concentrated under reduced pressure and the resulting residue was diluted with ethyl acetate. The organic phase was washed with a 1% NaOH aqueous solution, dried over MgSO4, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel to afford 4-(2-(4-chloro-3-nitrophenoxy)ethyl)piperidine (2.3 g, 56%).
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[K].[CH3:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH:21](I)[CH3:22].CN(C)C=O>C(OCC)(=O)C>[CH3:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][N:5]1[C:1](=[O:11])[C:2]2=[CH:10][CH:9]=[CH:8][CH:7]=[C:3]2[C:4]1=[O:6]
Reactant: COCCOCCOC(C)I
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COCCOCCOCCN1C(=O)c2ccccc2C1=O
Reaction time: 3 h

Procedure:
1.3 g of potassium phthalimide, 2-methoxyethoxyethoxy-1-iodoethane and 5 ml of dimethylformamide were fed into a 100 ml short-neck flask provided with a reflux condenser. The resultant mixture was heated at 90° c. for 3 hours. 100 ml of ethyl acetate was added thereto and the resultant mixture was cooled to room temperature. White precipitates thus obtained were suction-filtered, and the filtrate was washed with 100 ml of water. The obtained ethyl acetate layer was dried over magnesium sulfate, and ethyl acetate was distilled off under reduced pressure to obtain the intended compound.
Reaction SMILES: [NH2:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.C(N(CC)CC)C.[Br:16][CH2:17][CH2:18][C:19](Cl)=[O:20]>C1(C)C=CC=CC=1>[Br:16][CH2:17][CH2:18][C:19]([NH:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1)=[O:20]
Reactant: O=C(Cl)CCBr
Reactant: Nc1ccc(N)cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Nc1ccc(NC(=O)CCBr)cc1
Temperature: 80 °C
Yield: 64.7 %

Procedure:
A solution of 7.02 g of p-aminoaniline in 150 ml of toluene was added 9.12 ml of triethylamine and stirred at 80° C. while adding dropwise a solution of 11 g of β-bromopropionyl chloride in 30 ml of toluene. After the mixture was reacted for 30 minutes colored resinous substance which formed was removed, and the reaction mixture was washed with water and dried. Removal of the solvent by distillation gave 10.1 g of N-(β-bromopropionyl)-p-aminoaniline as oily product. Production of the compound was confirmed by IR and NMR spectra.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][NH:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C:17]([O:19][CH3:20])=[O:18])=[CH:12][CH:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)[CH2:22][CH2:23][OH:24].C1(C)C=CC(S(O)(=O)=O)=CC=1>>[CH:1]1([CH2:7][CH2:8][NH:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C:17]([O:19][CH2:20][CH2:22][CH2:23][OH:24])=[O:18])=[CH:12][CH:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OCCCO
Reactant: COC(=O)Cc1ccc(NCCC2CCCCC2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: O=C(Cc1ccc(NCCC2CCCCC2)cc1)OCCCO

Procedure:
A mixture of 2.25 g. of methyl 4-(2-cyclohexylethylamino)phenylacetate, 280 mg. of 1,3-propanediol and 1.37 g. p-toluenesulfonic acid is heated at 180° C. for 18 hours and then is partitioned between ether and 3% aqueous sodium carbonate solution. The ether layer is separated, dried, and evaporated to yield 3-hydroxypropyl 4-(2-cyclohexylethylamino)phenylacetate.
Reaction SMILES: [CH3:1][C:2]1[CH:22]=[C:21]([CH3:23])[CH:20]=[C:19]([CH3:24])[C:3]=1[O:4][C:5]1[C:10]([NH2:11])=[C:9]([NH:12][CH:13]([CH2:16][CH3:17])[CH2:14][CH3:15])[CH:8]=[C:7]([CH3:18])[N:6]=1.[C:25](OC(=O)C)(=[O:27])[CH3:26].C(N(CC)CC)C>C(Cl)Cl>[CH2:14]([CH:13]([NH:12][C:9]1[CH:8]=[C:7]([CH3:18])[N:6]=[C:5]([O:4][C:3]2[C:19]([CH3:24])=[CH:20][C:21]([CH3:23])=[CH:22][C:2]=2[CH3:1])[C:10]=1[NH:11][C:25](=[O:27])[CH3:26])[CH2:16][CH3:17])[CH3:15]
Reactant: CC(=O)OC(C)=O
Reactant: CCC(CC)Nc1cc(C)nc(Oc2c(C)cc(C)cc2C)c1N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(CC)Nc1cc(C)nc(Oc2c(C)cc(C)cc2C)c1NC(C)=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.7 %

Procedure:
A mixture of 2-(2,4,6-trimethyl-phenoxy)-N4-(1-ethyl-propyl)-6-methyl-pyridine-3, 4-diamine (250 mg, 0.763 mmol), acetic anhydride (72 mg, 0.763 mmol) and triethylamine (77 mg, 0.763 mmol) in 5 ml of methylene chloride was stirred at room temperature for 3 hours. The mixture was quenched with water and extracted with ethyl acetate. The organic layer was dried and concentrated to dryness to give 310 mg of the crude material. The crude material was purified through silica gel column chromatography using 2% methanol in chloroform as eluent to give 250 mg (89% yield) of N-[4-(1-ethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-3-yl]-acetamide as tan solid, mp 154-156° C. 1H NMR(CDCl3) δ6.97(0.64H), 6.86(s,2H), 6.26(0.36H), 6.14(0.64H), 6.12(s,0.36H), 4.80(d,0.64H), 4.40(d,0.36H), 3.2-3.4(m,1H), 2.29(s,3H), 5 2.26(s,1.9H), 2.17(s,1.1H), 2.16(s,1.9H), 2.06(s,6H), 1.99(s,1.1H), 1.4-1.75(m,4H), 0.97(t,6H)ppm.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[C@H:4]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24]([C:26]2[C:31]([Cl:32])=[CH:30][CH:29]=[CH:28][C:27]=2[Cl:33])=[O:25])=[CH:19][CH:18]=1)[NH:5][C:6]([C:8]1([CH2:13][CH2:14][NH2:15])[CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:7].[F:35][C:36]([F:47])([F:46])[C:37]1[CH:38]=[C:39]([CH:43]=[CH:44][CH:45]=1)[C:40](Cl)=[O:41]>>[CH3:1][O:2][C:3](=[O:34])[C@H:4]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24]([C:26]2[C:27]([Cl:33])=[CH:28][CH:29]=[CH:30][C:31]=2[Cl:32])=[O:25])=[CH:19][CH:18]=1)[NH:5][C:6]([C:8]1([CH2:13][CH2:14][NH:15][C:40]([C:39]2[CH:43]=[CH:44][CH:45]=[C:37]([C:36]([F:35])([F:46])[F:47])[CH:38]=2)=[O:41])[CH2:9][CH2:10][CH2:11][CH2:12]1)=[O:7]
Reactant: COC(=O)[C@H](Cc1ccc(NC(=O)c2c(Cl)cccc2Cl)cc1)NC(=O)C1(CCN)CCCC1
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Product: COC(=O)[C@H](Cc1ccc(NC(=O)c2c(Cl)cccc2Cl)cc1)NC(=O)C1(CCNC(=O)c2cccc(C(F)(F)F)c2)CCCC1

Procedure:
4-[[(2,6-dichlorophenyl)carbonyl]amino]-N-[[1-[2-[[(3-trifluoromethylphenyl)-carbonyl]amino]ethyl]cyclopentyl]carbonyl]-L-phenylalanine methyl ester was prepared from 4-[[(2,6-dichlorophenyl)carbonyl]amino]-N-[[1-(2-aminoethyl)cyclopentyl]carbonyl]-L-phenylalanine methyl ester and 3-trifluoromethylbenzoyl chloride using the general method described in example 205 to give a 99% yield of a white solid. HR MS C33H32Cl2N3O5): Obs. mass, 700.1596. Calcd. mass, 700.1569 (M+Na).
Reaction SMILES: [O:1]=[C:2]1[CH:7]([N:8]2[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([CH2:17][NH:18][C:19](=[O:38])[NH:20][C:21]4[CH:22]=[C:23]5[C:28](=[CH:29][CH:30]=4)[CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH2:24]5)[CH:14]=3)[C:9]2=[O:39])[CH2:6][CH2:5][C:4](=[O:40])[NH:3]1.Cl>C(Cl)Cl.C(OCC)C>[O:1]=[C:2]1[CH:7]([N:8]2[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([CH2:17][NH:18][C:19]([NH:20][C:21]4[CH:22]=[C:23]5[C:28](=[CH:29][CH:30]=4)[CH2:27][NH:26][CH2:25][CH2:24]5)=[O:38])[CH:14]=3)[C:9]2=[O:39])[CH2:6][CH2:5][C:4](=[O:40])[NH:3]1
Reactant: CC(C)(C)OC(=O)N1CCc2cc(NC(=O)NCc3ccc4c(c3)CN(C3CCC(=O)NC3=O)C4=O)ccc2C1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: O=C1CCC(N2Cc3cc(CNC(=O)Nc4ccc5c(c4)CCNC5)ccc3C2=O)C(=O)N1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of tert-butyl 6-(3-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)ureido)-3,4-dihydroisoquinoline-2(1H)-carboxylate (0.55 g, 1.0 mmol) in methylene chloride (100 mL) is treated with HCl (5 mL of a 2N solution in diethyl ether), and stirred at ambient temperature for 48 hours. The mixture is evaporated under vacuum, and triturated in ethyl acetate (10 mL), filtered, and dried under vacuum.
Reaction SMILES: [O-:1][C:2]#[N:3].[Na+].[NH2:5][CH2:6][CH2:7][N:8]1[C:25](=[N:26][C:27]2[C:32]([CH:33]([CH3:35])[CH3:34])=[CH:31][CH:30]=[CH:29][C:28]=2[CH:36]([CH3:38])[CH3:37])[CH:24]=[C:11]2[C:12]3[C:17]([CH2:18][CH2:19][N:10]2[C:9]1=[O:39])=[CH:16][C:15]([O:20][CH3:21])=[C:14]([O:22][CH3:23])[CH:13]=3.[OH-].[Na+]>O.Cl>[C:2]([NH:5][CH2:6][CH2:7][N:8]1[C:25](=[N:26][C:27]2[C:28]([CH:36]([CH3:37])[CH3:38])=[CH:29][CH:30]=[CH:31][C:32]=2[CH:33]([CH3:35])[CH3:34])[CH:24]=[C:11]2[C:12]3[C:17]([CH2:18][CH2:19][N:10]2[C:9]1=[O:39])=[CH:16][C:15]([O:20][CH3:21])=[C:14]([O:22][CH3:23])[CH:13]=3)(=[O:1])[NH2:3]
Reactant: COc1cc2c(cc1OC)-c1cc(=Nc3c(C(C)C)cccc3C(C)C)n(CCN)c(=O)n1CC2
Reactant: N#C[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1cc2c(cc1OC)-c1cc(=Nc3c(C(C)C)cccc3C(C)C)n(CCNC(N)=O)c(=O)n1CC2
Temperature: 80 °C
Reaction time: 4 h
Yield: 17.2 %

Procedure:
Sodium cyanate (0.87 g, 13.4 mmol) in water (20 ml) was added dropwise to a stirred solution of amine 3 (3.2 g, 6.7 mmol) in water (100 ml) and 1M HCl (13.4 ml) at 80° C. After stirring for 4 h at 80° C. the mixture was cooled and basified with 2M NaOH. The mixture was extracted with CH2Cl2 until no more product remained in the organic phase. The organic phases were combined, dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by column chromatography [dichloromethane/methanol (97:3)] and the isolated product taken up in a mixture of dichloromethane and ether which on concentration afforded the title compound (0.6 g, 17%) as a pale yellow foam.
Reaction SMILES: [CH3:1][S:2][CH2:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=O)=[C:6]([O:13][CH2:14][CH2:15][CH2:16][NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:5]=1.[NH2:25][C:26]1[C:27]([C:33]([NH:35][C:36]2[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][N:37]=2)=[O:34])=[N:28][C:29]([CH3:32])=[CH:30][CH:31]=1>>[CH3:1][S:2][CH2:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([NH:25][C:26]2[C:27]([C:33]([NH:35][C:36]3[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][N:37]=3)=[O:34])=[N:28][C:29]([CH3:32])=[CH:30][CH:31]=2)=[O:10])=[C:6]([O:13][CH2:14][CH2:15][CH2:16][NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:5]=1
Reactant: Cc1ccc(N)c(C(=O)Nc2ccc(Cl)cn2)n1
Reactant: CSCc1ccc(C(=O)O)c(OCCCNC(=O)OC(C)(C)C)c1
Product: CSCc1ccc(C(=O)Nc2ccc(C)nc2C(=O)Nc2ccc(Cl)cn2)c(OCCCNC(=O)OC(C)(C)C)c1
Yield: 71 %

Procedure:
Using a procedure analogous to Example 1-G, 2-[4-methylthiomethyl-2-[3-(t-butoxycarbonylamino)propoxy]benzoic acid and 3-amino-6-methyl-N-(5-chloropyridin-2-yl)pyridine-2-carboxamide gave the title compound as a white glassy solid (1.41 g, 71%).