Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:8]([CH2:9][N:10]([CH:14]([CH3:16])[CH3:15])[CH:11]([CH3:13])[CH3:12])=[CH:7][C:5]([NH2:6])=[C:4]([F:17])[CH:3]=1.[C:18]1(=O)[O:23][C:21](=[O:22])[CH:20]2[CH2:24][CH2:25][CH:26]=[CH:27][CH:19]12>C(O)(=O)C>[Cl:1][C:2]1[C:8]([CH2:9][N:10]([CH:14]([CH3:16])[CH3:15])[CH:11]([CH3:12])[CH3:13])=[CH:7][C:5]([N:6]2[C:21](=[O:22])[C:20]3[CH2:24][CH2:25][CH2:26][CH2:27][C:19]=3[C:18]2=[O:23])=[C:4]([F:17])[CH:3]=1
Reactant: O=C1OC(=O)C2CCC=CC12
Reactant: CC(C)N(Cc1cc(N)c(F)cc1Cl)C(C)C
Solvent: CC(=O)O
Product: CC(C)N(Cc1cc(N2C(=O)C3=C(CCCC3)C2=O)c(F)cc1Cl)C(C)C
Yield: 6.6 %

Procedure:
By the method of Example 2, Step H, 0.50 g (0.0020 mole) of 4-chloro-2-fluoro-5-(diisopropylaminomethyl)aniline and 0.85 g (0.0056 mole) of tetrahydrophthalic anhydride in 20 ml of acetic acid were reacted yielding 0.052 g of N-[4-chloro-2-fluoro-5-(diisopropylaminomethyl)phenyl]-3,4,5,6-tetrahydrophthalimide. The nmr and ir spectra were consistent with the proposed structure.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH3:32])[CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]([OH:31])([C:27]([F:30])([F:29])[F:28])[C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=3)[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[N:33]1[CH:38]=[CH:37][C:36]([NH:39][C:40](=O)[O:41]C2C=CC=CC=2)=[CH:35][CH:34]=1.O1CCOCC1>O1CCCC1>[F:26][C:23]([F:24])([F:25])[C:22]([C:19]1[CH:20]=[CH:21][C:16]([CH2:15][N:12]2[CH2:11][CH2:10][CH:9]([N:8]([CH3:32])[C:5]3[CH:6]=[CH:7][C:2]([NH:1][C:40]([NH:39][C:36]4[CH:37]=[CH:38][N:33]=[CH:34][CH:35]=4)=[O:41])=[CH:3][CH:4]=3)[CH2:14][CH2:13]2)=[CH:17][CH:18]=1)([OH:31])[C:27]([F:30])([F:28])[F:29]
Reactant: CN(c1ccc(N)cc1)C1CCN(Cc2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2)CC1
Reactant: O=C(Nc1ccncc1)Oc1ccccc1
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: CN(c1ccc(NC(=O)Nc2ccncc2)cc1)C1CCN(Cc2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2)CC1
Yield: 29.2 %

Procedure:
2-(4-((4-((4-Aminophenyl)(methyl)amino)piperidin-1-yl)methyl)phenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (0.260 mmol, 120 mg) and phenyl pyridin-4-ylcarbamate (0.390 mmol, 84 mg) were combined in tetrahydrofuran (1 mL) and dioxane (1 mL) and heated to 100° C. overnight. The reaction mixture was concentrated under vacuum. The residue was purified by prep-HPLC (acidic conditions) and SCX chromatography to give the title compound (44.2 mg). MS (ESI) m/z 582.2 [M+H]+
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9].C(=O)([O-])[O-].[K+].[K+].[N+:17]([C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Br)=[CH:22][CH:21]=1)([O-:19])=[O:18]>C(#N)C>[N+:17]([C:20]1[CH:27]=[CH:26][C:23]([CH2:24][O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[C:8](=[O:10])[CH3:9])=[CH:22][CH:21]=1)([O-:19])=[O:18]
Reactant: CC(=O)c1ccccc1O
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(=O)c1ccccc1OCc1ccc([N+](=O)[O-])cc1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 89 %

Procedure:
To a stirred solution of 2′-hydroxyacetophenone (5.000 g, 36.724 mmol) in acetonitrile (200 mL) was added potassium carbonate (7.613 g, 55.086 mmol). The mixture was stirred at 50° C. for 30 min. 4-Nitrobenzyl bromide (8.727 g, 40.396 mmol) was added to the mixture, and the stirring was continued at 50° C. for 12 hrs. Potassium carbonate (0.508 g, 3.672 mmol) and 4-nitrobenzyl bromide (0.793 g, 3.672 mmol) were added to the mixture and the resulting mixture was stirred at 50° C. for 12 hrs. After cooled to room temperature, the reaction mixture was concentrated under reduced pressure and diluted with ethyl acetate. The organic phase was washed with water, dried over Na2SO4, filtered, and concentrated. The resulting residue was washed with hexane to give 1-{2-[(4-nitrobenzyl)oxy]phenyl}ethanone as a white solid. (8.900 g, yield; 89%)
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]2[N:8]=[CH:9][N:10]([C:11]3[S:15][C:14]([C:16]([O:18]C)=O)=[C:13]([O:20][CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[C:28]([F:31])([F:30])[F:29])[CH:12]=3)[C:4]=2[CH:3]=1.[NH3:32]>CO>[Cl:1][C:2]1[N:7]=[CH:6][C:5]2[N:8]=[CH:9][N:10]([C:11]3[S:15][C:14]([C:16]([NH2:32])=[O:18])=[C:13]([O:20][CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[C:28]([F:30])([F:31])[F:29])[CH:12]=3)[C:4]=2[CH:3]=1
Reactant: N
Reactant: COC(=O)c1sc(-n2cnc3cnc(Cl)cc32)cc1OCc1ccccc1C(F)(F)F
Solvent: CO
Product: NC(=O)c1sc(-n2cnc3cnc(Cl)cc32)cc1OCc1ccccc1C(F)(F)F
Temperature: 120 °C
Reaction time: 4 h

Procedure:
A mixture of 140 mg of methyl 5-(6-chloro-1H-imidazo[4,5-c]pyridin-1-yl)-3-{[2-(trifluoromethyl)benzyl]oxy}thiophene-2-carboxylate and 20 ml of a saturated solution of ammonia in methanol were stirred in a microwave vial at 120° C. for 4 h in the microwave cavity. The reaction mixture was concentrated to half of the volume. The solid that precipitated after standing was collected and recrystallized from acetonitrile to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[O:13][CH3:14])[CH:6]=[CH:7][CH:8]=O.[C:15]([CH2:17][C:18]([N-:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])#[N:16]>>[CH2:21]([NH:20][C:18](/[C:17](=[CH:8]/[CH:7]=[CH:6]/[C:5]1[CH:10]=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=1)/[C:15]#[N:16])=[O:19])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: COc1ccc(C=CC=O)cc1OC
Reactant: N#CCC(=O)[N-]Cc1ccccc1
Product: COc1ccc(/C=C/C=C(\C#N)C(=O)NCc2ccccc2)cc1OC

Procedure:
The compound was prepared as described in Example 3, by adding 3,4-dimethoxycinnamaldehyde (Example 6, 0.04 g, 0.2 mmol) to N-(cyanoacetyl)benzylamide (Example 4, 0.036 g, 0.2 mmol). After refluxing for 1 h and recrystallization from ethanol a yellow solid was obtained (0.045 g, 62%). The product gave the following analytical data:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:16]([CH3:19])=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:20]([N:22]([C:29]1[CH:30]=[N:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=1)[CH2:23][C:24]1[CH:25]=[N:26][NH:27][CH:28]=1)=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.Cl[CH2:40][C:41]1[CH:46]=[C:45]([CH3:47])[CH:44]=[CH:43][N:42]=1>>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:16]([CH3:19])=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:20]([N:22]([C:29]1[CH:30]=[N:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=1)[CH2:23][C:24]1[CH:25]=[N:26][N:27]([CH2:40][C:41]2[CH:46]=[C:45]([CH3:47])[CH:44]=[CH:43][N:42]=2)[CH:28]=1)=[O:21])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(OCc2ccccc2)c2c1C(C(=O)N(Cc1cn[nH]c1)c1ccc(C(C)C)nc1)CCC2
Reactant: Cc1ccnc(CCl)c1
Agent: Cl
Product: Cc1ccnc(Cn2cc(CN(C(=O)C3CCCc4c(OCc5ccccc5)ccc(C)c43)c3ccc(C(C)C)nc3)cn2)c1
Yield: 74.2 %

Procedure:
By the reaction and treatment in the same manner as in Example 271 using 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-8-methyl-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.5 g) and 2-chloromethyl-4-methylpyridine hydrochloride (0.36 g) as starting materials, 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-({1-[(4-methylpyridin-2-yl)methyl]pyrazol-4-yl}methyl)-8-methyl-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.45 g) was obtained.
Reaction SMILES: [CH2:1]([N:3]([CH2:17][CH3:18])[C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[C:9]([CH:15]=O)[C:10](=[O:14])[O:11]2)=[CH:6][CH:5]=1)[CH3:2].[Br-:19].[C:20]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][N+:28]1[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=1)([OH:22])=[O:21]>C(O)C.C1(C)C=CC=CC=1>[Br-:19].[C:20]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][N+:28]1[CH:29]=[CH:30][C:31](/[CH:34]=[CH:15]/[C:9]2[C:10](=[O:14])[O:11][C:12]3[C:7]([CH:8]=2)=[CH:6][CH:5]=[C:4]([N:3]([CH2:17][CH3:18])[CH2:1][CH3:2])[CH:13]=3)=[CH:32][CH:33]=1)([OH:22])=[O:21]
Reactant: Cc1cc[n+](CCCCCC(=O)O)cc1
Reactant: CCN(CC)c1ccc2cc(C=O)c(=O)oc2c1
Agent: [Br-]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCN(CC)c1ccc2cc(/C=C/c3cc[n+](CCCCCC(=O)O)cc3)c(=O)oc2c1

Procedure:
0.2 mmol 7-diethylamino-2-oxo-2H-chromene-3-carbaldehyde and 0.2 mmol 1-(5-carboxy-pentyl)-4-methyl-pyridinium bromide are converted according to the general directions above. Column chromatography: SiO2, eluent: ethanol/toluene.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([O:10]CC)=[O:9])=[C:6]([Cl:13])[CH:5]=[C:4]([CH3:14])[N:3]=1.[OH-].[Na+].OS(O)(=O)=O>O.CO>[Cl:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[C:6]([Cl:13])[CH:5]=[C:4]([CH3:14])[N:3]=1
Reactant: CCOC(=O)c1c(Cl)cc(C)nc1Cl
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1cc(Cl)c(C(=O)O)c(Cl)n1
Yield: 65.7 %

Procedure:
A solution of commercially available (Maybridge) ethyl 2,4-dichloro-6-methylpyridine-3-carboxylate (1.0 g, 4.3 mmol) and NaOH (342 mg, 8.6 mmol) in water (1.7 mL) and MeOH (1.5 mL) was heated to 80° C. for 4 h. The mixture was acidified using 50% H2SO4 and filtered. The solid was washed with cold water and dried to give of 2,4-dichloro-6-methylpyridine-3-carboxylic acid (582 mg, 66%): LCMS RT: 0.70 min, MH+: 206.2.
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[C:6]([NH:9][C:10]1[S:11][CH:12]=[CH:13][C:14]=1[C:15]([NH2:17])=[O:16])(=[O:8])[CH3:7]>>[C:6]([NH:9][C:10]1[S:11][C:12]([S:2]([Cl:1])(=[O:5])=[O:3])=[CH:13][C:14]=1[C:15](=[O:16])[NH2:17])(=[O:8])[CH3:7]
Reactant: O=S(=O)(O)Cl
Reactant: CC(=O)Nc1sccc1C(N)=O
Product: CC(=O)Nc1sc(S(=O)(=O)Cl)cc1C(N)=O
Temperature: 50 °C
Reaction time: 3 h

Procedure:
Neat ClSO3H (29 mL, 440 mmol) is cooled to 0° C., and 2-acetylamino-thiophene-3-carboxylic acid amide (8.1 g, 44 mmol) is added in portions over a period of 15 min. The mixture is then stirred at 50° C. for 3 h, cooled to room temperature, and then poured slowly to ice cold water. The resulting suspension is washed twice with EtOAc, the combined organic fractions are dried over MgSO4, filtered and evaporated to give the desired product, which is used as such.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][N:10]2[C:16](=[O:17])[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.I[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]([F:29])([F:28])[F:27])[CH:20]=1>>[N:1]1([CH2:7][CH2:8][CH2:9][N:10]2[C:16](=[O:17])[CH2:15][CH2:14][N:13]([C:23]3[CH:24]=[CH:19][CH:20]=[C:21]([O:25][C:26]([F:27])([F:28])[F:29])[CH:22]=3)[CH2:12][CH2:11]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: FC(F)(F)Oc1cccc(I)c1
Reactant: O=C1CCNCCN1CCCN1CCCCC1
Product: O=C1CCN(c2cccc(OC(F)(F)F)c2)CCN1CCCN1CCCCC1

Procedure:
The title compound was prepared from 4-(3-piperidin-1-yl-propyl)-[1,4]diazepan-5-one (Example 33B) and 1-iodo-3-trifluoromethoxy-benzene in analogy to example 33. MS: 400.2 (MH+).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=3[Cl:21])[N:12]=[C:11]([C:22]([NH:24][NH:25]C(OC(C)(C)C)=O)=[O:23])[C:10]=2[CH2:33][CH3:34])=[CH:5][CH:4]=1>CO>[Br:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=3[Cl:21])[N:12]=[C:11]([C:22]([NH:24][NH2:25])=[O:23])[C:10]=2[CH2:33][CH3:34])=[CH:7][CH:8]=1
Reactant: CCc1c(C(=O)NNC(=O)OC(C)(C)C)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Br)cc1
Agent: Cl
Solvent: CO
Product: CCc1c(C(=O)NN)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Br)cc1
Temperature: 40 °C
Yield: 79.8 %

Procedure:
40 ml of 2N ethereal hydrochloric acid are added to a solution of 12.7 g of the compound obtained in stage B in 200 ml of MeOH and the mixture is then heated at 40° C. for 3 hours. The reaction mixture is concentrated under vacuum, the residue is extracted with ether, the organic phase is washed twice with a 10% NaHCO3 solution and dried over MgSO4, and the solvent is evaporated under vacuum. 8.3 g of the expected compound are obtained after crystallization from an ether/pentane mixture.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:24][CH2:25][CH2:26][O:27][C:28]1[CH:36]=[CH:35][CH:34]=[C:33]2[C:29]=1[CH:30]=[CH:31][NH:32]2.CC#N>O>[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:24][CH2:25][CH2:26][O:27][C:28]4[CH:36]=[CH:35][CH:34]=[C:33]5[C:29]=4[CH:30]=[CH:31][NH:32]5)[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: ClCCCOc1cccc2[nH]ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: Fc1ccc2c(C3CCN(CCCOc4cccc5[nH]ccc45)CC3)noc2c1
Reaction time: 68 h
Yield: 103.5 %

Procedure:
A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (3.5 g, 16 mmol), K2CO3 (2.2 g, 16 mmol), KI (200 mg), 4-(3-chloropropoxy)indole (3.0 g, 14 mmol) and CH3CN (100 ml) was stirred at reflux under N2 for 7 hours and then at ambient temperature for 68 hours. Reflux was resumed for an additional 6 hours whereupon a TLC revealed incomplete reaction. K2CO3 (0.5 g, 4 mmol) was added and the reaction was stirred at reflux for 17 hours. The cooled reaction was poured into H2O and the aqueous mixture was extracted with EtOAc. The organic extract was washed with H2O and saturated NaCl and after drying over MgSO4 the solvent was removed to afford 5.7 g of a beige solid. The product was purified by preparative HPLC (Water's Associates Prep LC/System 500 using 2 silica gel columns and 4% MeOH--CH2Cl2 as eluent) to yield 3.4 g (61%) of a beige solid. Two consecutive recrystallizations from EtOH provided 2.3 g (41%) of a white powder, m.p.=129°-131° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([Cl:11])[C:3]=1[CH3:12].CC(N=NC(C#N)(C)C)(C#N)C.C1C(=O)N([Br:32])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[Br:32][CH2:12][C:3]1[C:4]([Cl:11])=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[Cl:1]
Reactant: Cc1c(Cl)ccc([N+](=O)[O-])c1Cl
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: O=[N+]([O-])c1ccc(Cl)c(CBr)c1Cl

Procedure:
To a solution of 1,3-dichloro-2-methyl-4-nitro-benzene (19) (6.18 g, 30 mmol) and AIBN (200 mg) in CCl4 (75 mL), NBS (7.96 g, 45 mmol) was added under stirring and reflux. The reaction was monitored by 1H-NMR (CDCl3). Additional NBS (5×7.96 g, total of 270 mmol) was added till the starting material was consumed. The reaction mixture was filtered hot, and the filtrate was evaporated to dryness. The crude was column chromatographed (SiO2, hexanes:EtOAc, 9:1 to 8.5:1.5). The product was obtained as a low melting white solid: yield 6.869 g, 80%. 1H-NMR (CDCl3) δ 4.75 (s, 2H), 7.45, d, 1H, J=8.5 Hz), 7.69 (d, 1H, J=8.5 Hz); MS (CI) m/z 285 (M+H). Anal Calcd for C7H4BrCl2NO2 : C, 29.51; H, 1.42; N, 4.92. Found: C, 29.09; H, 1.43; N, 4.71.
Reaction SMILES: I[CH2:2][C:3]([O:5][CH:6]=[CH2:7])=[O:4].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[H-].[Na+].[C:29]1([N:35]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[C:36]2[CH:43]=[CH:42][C:39]([CH:40]=O)=[CH:38][CH:37]=2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>O1CCCC1.C(OCC)C>[CH:6]([O:5][C:3](=[O:4])[CH:2]=[CH:40][C:39]1[CH:38]=[CH:37][C:36]([N:35]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:43][CH:42]=1)=[CH2:7]
Reactant: O=Cc1ccc(N(c2ccccc2)c2ccccc2)cc1
Reactant: C=COC(=O)CI
Agent: [H-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: C=COC(=O)C=Cc1ccc(N(c2ccccc2)c2ccccc2)cc1
Temperature: 6 °C
Reaction time: 16 h

Procedure:
A 100 mL round bottom flask equipped with a nitrogen inlet-outlet, magnetic stirrer and addition funnel was charged with vinyl iodoacetate (5.6 g, 26 mmol) and triphenylphosphine (6.9 g, 26 mmol) in 50 mL anhydrous tetrahydrofuran. The reaction mixture was blanketed with nitrogen and allowed to stir for 16 h and then cooled to 6° C. on an ice-water bath. Sodium hydride (1.0 g, 25 mmol) was added and the reaction was allowed to warm to room temperature. After stirring at room temperature for 4 h, 4-diphenylaminobenzaldehyde (5.4 g, 20 mmol) dissolved in 40 mL anhydrous THF was added dropwise to the stirring reaction mixture over 30 minutes. After stirring at room temperature for five days, the reaction mixture was diluted with 50 mL diethyl ether and transferred to a separatory funnel. An additional 300 mL diethyl ether was added to the separatory funnel and the combined ether solution was washed three times with 100 mL water and one time with 100 mL saturated NaCl solution. The organic layer was dried over MgSO4, filtered and concentrated on a rotary evaporator. The residue was further dried on a high vacuum line to yield the crude product as a brown oil. After purification by flash column chromatography (silica gel; 3:7 dichloromethane:hexanes) 5.5 g of the pure product was obtained as a light yellow oil. The product yield was 81%.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)[S:6][C:5]=1[C:15]([NH2:17])=[O:16])[CH3:2].[CH3:18][C:19](=O)[CH2:20][CH3:21].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>C(O)(=O)C>[CH2:1]([N:3]1[C:4]2[CH:8]=[C:7]([C:9]3[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=3)[S:6][C:5]=2[C:15](=[O:16])[NH:17][C:19]1([CH2:20][CH3:21])[CH3:18])[CH3:2]
Reactant: CCC(C)=O
Reactant: CCNc1cc(-c2ccncc2)sc1C(N)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCN1c2cc(-c3ccncc3)sc2C(=O)NC1(C)CC
Temperature: 120 °C
Reaction time: 1 h
Yield: 45 %

Procedure:
A mixture of 3-(ethylamino)-5-(pyridin-4-yl)thiophene-2-carboxamide (0.100 g, 0.400 mmol), 2-butanone (2.5 mL), p-toluenesulfonic acid monohydrate (0.0095 g, 0.050 mmol) and acetic acid (2.0 mL) was stirred for 1 h at 120° C. in a sealed tube. Then, this mixture was stirred for 3 h at 150° C. in a sealed tube. The mixture was poured into sat. aqueous sodium hydrogen carbonate (150 mL). Extraction with ethyl acetate (100 mL), drying over magnesium sulfate, filtration and concentration at reduced pressure gave an oil. The oil was purified by column chromatography (Combiflash, 40 g silica gel, dichloromethane to ethyl acetate) to afford the title compound (0.0547 g, 45%) as a yellow solid:
Reaction SMILES: C(O)(C(F)(F)[F:4])=O.C(OC(=O)[NH:14][C@H:15]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[C:19]=1F)[CH2:16][OH:17])(C)(C)C>C(Cl)Cl>[NH2:14][C@H:15]([C:18]1[CH:23]=[CH:22][C:21]([F:4])=[C:20]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[CH:19]=1)[CH2:16][OH:17]
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)c1cccc(N2CCOCC2)c1F
Solvent: ClCCl
Product: N[C@@H](CO)c1ccc(F)c(N2CCOCC2)c1

Procedure:
A solution of TFA (5 mL) and (R)-[1-(fluoro-3-morpholin-4-yl-phenyl)-2-hydroxy-ethyl]-carbamic acid tert-butyl ester (1.2 g) in methylene chloride (15 mL) was stirred for 2 h. After concentration, the residue was neutralized with 10 N NaOH and extracted with methylene chloride. The organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo to give the title compound as a solid (720 mg).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[Cl:30][C:31]1[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[C:32]=1[CH2:33]Br>CO>[CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]2[CH:15]=[CH:16][C:17]([NH:20][CH2:33][C:32]3[C:31]([Cl:30])=[CH:38][CH:37]=[CH:36][C:35]=3[Cl:39])=[CH:18][CH:19]=2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Clc1cccc(Cl)c1CBr
Reactant: Nc1ccc(C2CN(Cc3ccccc3)CCO2)cc1
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: Clc1cccc(Cl)c1CNc1ccc(C2CN(Cc3ccccc3)CCO2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.6 %

Procedure:
A mixture of 4-(4-benzyl-morpholin-2-yl)-phenylamine (0.82 g; 3.06 mmol), DIPEA (1.57 mL; 9.17 mmol) and 2,6-dichlorobenzyl bromide (0.88 g; 3.67 mmol) in MeOH (25 mL). was stirred at RT, overnight. The resulting mixture was partitioned between 5% aqueous NaHCO3 and EtOAc. The organic layer was dried (Na2SO4), filtered and concentrated in vacuo to afford [4-(4-benzyl-morpholin-2-yl)-phenyl]-(2,6-dichloro-benzyl)-amine (1.25 g).
Reaction SMILES: [C:1]([N:5]=[N:6][C:7]([N:15]=[C:16]=[S:17])([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[CH2:18]([NH2:22])[CH:19]([CH3:21])[CH3:20].[N-]=C=O>>[C:1]([N:5]=[N:6][C:7]([NH:15][C:16]([NH:22][CH2:18][CH:19]([CH3:21])[CH3:20])=[S:17])([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[CH3:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)N=NC(C)(N=C=S)c1ccccc1
Reactant: CC(C)CN
Agent: [N-]=C=O
Product: CC(C)CNC(=S)NC(C)(N=NC(C)(C)C)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 9.25 grams (0.0375 moles) of 1-t-butylazo-1-isothiocyanato-1-phenylethane stirred with a magnetic stirrer in a 50 ml erlenmeyer flask was added 2.75 grams (0.0375 moles) of isobutylamine. The reaction mixture was stirred for 30 minutes at room temperature at which time an infrared spectrum of the reaction mixture showed the complete absence of the isocyanate band at 2225 cm-1. The orange liquid weighed 10.2 grams (85% crude yield) and its infrared spectrum contained a strong band around 1530 cm-1.
Reaction SMILES: [Br:1][CH2:2][C:3](Br)=[O:4].NC1N=CN=C([N:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)C=1.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl>[Br:1][CH2:2][C:3]([N:13]1[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:18]1)=[O:4]
Reactant: O=C(Br)CBr
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc(N)ncn2)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(C(=O)CBr)CC1

Procedure:
A solution of bromoacetyl bromide (0.59 g, 2.95 mmol) in methylene chloride (3 mL) was added drop wise via addition funnel to a stirred solution of tert-butyl piperazine-1-carboxylate 12-1 (0.50 g, 2.68 mmol) and aqueous sodium carbonate (0.34 g, 3.22 mmol) in methylene chloride (15 mL) at 0° C. After a 10 minute reaction time the methylene chloride layer was drawn off, dried and evaporated to an oil. This was purified this on a silica column to afford 42-1. Hi-Res MS (M+Na): calc: 329.0471 found: 329.0462. 1H-NMR(CDCl3): 3.87(s, 2H); 3.61(m, 2H); 3.52(m, 2H); 3.50(m, 2H); 3.44(m, 2H); 1.47(s, 9H).
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Cl:10][C:11]1[CH:19]=[C:18]([O:20][C:21]2[CH:26]=[CH:25][C:24]([CH:27]=O)=[CH:23][CH:22]=2)[CH:17]=[CH:16][C:12]=1[C:13]([NH2:15])=[O:14]>>[Cl:10][C:11]1[CH:19]=[C:18]([O:20][C:21]2[CH:26]=[CH:25][C:24]([CH2:27][NH:9][CH2:1][CH2:2][C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)=[CH:23][CH:22]=2)[CH:17]=[CH:16][C:12]=1[C:13]([NH2:15])=[O:14]
Reactant: NC(=O)c1ccc(Oc2ccc(C=O)cc2)cc1Cl
Reactant: NCCc1ccccc1
Product: NC(=O)c1ccc(Oc2ccc(CNCCc3ccccc3)cc2)cc1Cl
Yield: 34 %

Procedure:
Reacting phenethylamine with the compound of Example 245, step 2 under reductive amination conditions (described previously) affords the title compound.