Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[CH:5]=[O:6].C1(O)C=CC=CC=1.[CH3:20][O:21][C:22](=[O:26])[CH:23](Br)[CH3:24]>>[CH:5]([C:4]1[CH:7]=[CH:8][C:9]([N+:10]([O-:12])=[O:11])=[C:2]([CH:3]=1)[O:1][CH:23]([CH3:24])[C:22]([O:21][CH3:20])=[O:26])=[O:6]
Reactant: O=Cc1ccc([N+](=O)[O-])c(O)c1
Reactant: COC(=O)C(C)Br
Solvent: Oc1ccccc1
Product: COC(=O)C(C)Oc1cc(C=O)ccc1[N+](=O)[O-]

Procedure:
Using 3-hydroxy-4-nitrobenzaldehyde as the phenol and methyl-2-bromopropanoate as the alkylating agent in the general procedure for alkylation of substituted-2-nitrophenols gives a tan solid: 1H NMR (DMSO-d6, 400 MHz): δ ppm 10.03 (s, 1H), 8.08 (d, J=8.1 Hz, 1H), 7.62-7.79 (m, 2H), 5.43 (q, J=6.8 Hz, 1H), 3.69 (s, 3H), 1.55 (d, J=6.8 Hz, 3H). ESI-MS: m/z 254.1 (M+H)+.
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[NH:6][C:5]1=[O:13].Cl.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([C:23](=[O:31])[CH2:24][CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[CH:19][CH:18]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+]>CC(C)CC(=O)C>[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([C:23](=[O:31])[CH2:24][CH:25]2[CH2:26][CH2:27][N:28]([CH2:2][CH2:3][N:4]3[C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=4[NH:6][C:5]3=[O:13])[CH2:29][CH2:30]2)=[CH:19][CH:18]=1
Reactant: O=c1[nH]c2ccccc2n1CCCl
Reactant: COc1ccc(C(=O)CC2CCNCC2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CC(=O)CC(C)C
Product: COc1ccc(C(=O)CC2CCN(CCn3c(=O)[nH]c4ccccc43)CC2)cc1
Yield: 36.5 %

Procedure:
A mixture of 3.92 parts of 1-(2-chloroethyl)-1,3-dihydro-2H-benzimidazol-2-one, 5.4 parts of 1-(4-methoxyphenyl)-2-(4-piperidinyl)ethanone hydrochloride, 5.3 parts of sodium carbonate, 0.1 parts of potassium iodide and 200 parts of 4-methyl-2-pentanone is distilled azeotropically to dry overnight. After cooling, the precipitated product is filtered off, washed with water and dissolved in trichloromethane. The latter is dried, filtered and evaporated. The residue is crystallized from 2-propanol, yielding 2.9 parts (36.5%) of 1,3-dihydro-1-[2-[4-[2-(4-methoxyphenyl)-2-oxoethyl]-1-piperidinyl]ethyl]-2H-benzimidazol-2-one; mp. 155.9° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:18]([O-:20])=[O:19].[CH2:21]([NH2:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C1COCC1>[CH2:21]([NH:28][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:18]([O-:20])=[O:19])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: NCc1ccccc1
Reactant: CN1CCN(S(=O)(=O)c2ccc(Cl)c([N+](=O)[O-])c2)CC1
Solvent: C1CCOC1
Product: CN1CCN(S(=O)(=O)c2ccc(NCc3ccccc3)c([N+](=O)[O-])c2)CC1
Yield: 86.5 %

Procedure:
1-(4-Chloro-3-nitro-benzenesulphonyl)-4-methyl-piperazine (0.50 g, 1.57 mmol) and benzylamine (0.502 g, 4.70 mmol) were dissolved in THF (10 ml) and heated at reflux for 3 h. The reaction mixture was then reduced in vacuo and partitioned between ethyl acetate and water. The organics were washed with brine, dried (MgSO4) and reduced in vacuo, and the resultant residue purified by column chromatography eluting with 0-10% methanol in ethyl acetate to give benzyl-[4-(4-methyl-piperazine-1-sulphonyl)-2-nitro-phenyl]-amine as a yellow solid (0.53 g, 86%). (LC/MS: Rt 2.21, [M+H]+ 391.05).
Reaction SMILES: [C:1]1([CH2:7][C:8](=O)[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[OH:18][NH3+:19].C(O)C.C(=O)([O-])[O-].[Na+].[Na+]>O>[C:1]1([CH2:7][C:8](=[N:19][OH:18])[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cc1ccccc1)Cc1ccccc1
Reactant: [NH3+]O
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: ON=C(Cc1ccccc1)Cc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 90.6 %

Procedure:
To a solution of 1,3-diphenyl-2-propanone (5.0 g, 24 mmol) and hydroxylammonium chloride (3.3 g, 48 mmol) in a mixture of absolute ethanol (30 ml) and water (10 ml) was carefully added a solution of sodium carbonate (13.2 g, 96 mmol) in water (30 ml). The resulting mixture was stirred at room temperature for 16 h. The precipitated compound was collected and washed with water (3×15 ml) and dried to give 4.9 g of 1,3-diphenyl-2-propanone oxime.
Reaction SMILES: Cl.[O:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]3([N:21]([CH3:23])[CH3:22])[CH2:20][CH2:19][C:14]4(OCC[O:15]4)[CH2:13][CH2:12]3)=[CH:10][C:5]=2[O:4][CH2:3]1>Cl>[O:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]3([N:21]([CH3:23])[CH3:22])[CH2:12][CH2:13][C:14](=[O:15])[CH2:19][CH2:20]3)=[CH:10][C:5]=2[O:4][CH2:3]1
Reactant: CN(C)C1(c2ccc3c(c2)OCO3)CCC2(CC1)OCCO2
Agent: Cl
Product: CN(C)C1(c2ccc3c(c2)OCO3)CCC(=O)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
6N hydrochloric acid (10 ml) was added to (8-benzo[1,3]dioxol-5-yl-1,4-dioxa-spiro[4.5]dec-8-yl)-dimethylamine hydrochloride (2.70 g, 7.91 mmole) and stirred overnight at RT. After completion of the hydrolysis the reaction mixture was extracted with ether (2×20 ml), the aqueous solution was made alkaline with 5N sodium hydroxide solution while cooling with ice, the reaction mixture was extracted with dichloromethane (3×50 ml), and the organic phase was dried over sodium sulfate and concentrated by evaporation in vacuo.
Reaction SMILES: N[C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[C:5](NC2C=CC=C(O)C=2)=[CH:4][C:3]=1S(C)(=O)=O.C(=O)([O-])O.[K+].FN1N=C(F)C=C(N(C)C2C=CC=CC=2)N1>O1CCCC1>[CH:9]1[C:8]2[C:7](=[O:17])[C:6]3[C:15](=[CH:2][CH:3]=[CH:4][CH:5]=3)[C:14](=[O:16])[C:13]=2[CH:12]=[CH:11][CH:10]=1
Reactant: CS(=O)(=O)c1cc(Nc2cccc(O)c2)c2c(c1N)C(=O)c1ccccc1C2=O
Agent: CN(C1=CC(F)=NN(F)N1)c1ccccc1
Agent: O=C([O-])O
Agent: [K+]
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)c2ccccc21
Yield: 278.9 %

Procedure:
To tetrahydrofuran (100 ml), 1-amino-2-methylsulfonyl-4-(3-hydroxyanilino)anthraquinone (4.08 g), potassium hydrogencarbonate (2.0 g) and 2,4-difluoro-6-(N-methyl-N-phenylamino)triazine (2.35 g) were added, and the mixture was subjected to condensation by heating under reflux for 1.5 hours. The reaction liquor was treated as in Example 6 to produce 5.8 g of an anthraquinone dye of the following formula in a yield of 95%. ##STR47## The dye had a λ max (acetone) of 620 nm.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13](Cl)(=O)=O)=[CH:9][C:8]=1[CH3:17])[CH3:2].[Sn].Cl.O1CCOCC1>CCO>[CH2:1]([O:3][C:4](=[O:18])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([SH:13])=[CH:9][C:8]=1[CH3:17])[CH3:2]
Reactant: CCOC(=O)COc1ccc(S(=O)(=O)Cl)cc1C
Agent: Cl
Agent: [Sn]
Solvent: CCO
Solvent: C1COCCO1
Product: CCOC(=O)COc1ccc(S)cc1C
Temperature: 0 °C

Procedure:
An oven-dried 1 L round-bottomed flask was charged with compound 10.2 (37.3 g, 127 mmol), finely powdered tin (74.3 g, 626 mmol), and EtOH (157 mL) and the solution was cooled to 0° C. Next, 4 N HCl/dioxane (157 mL, 628 mmol) was added dropwise at 0° C., and the reaction was refluxed for 2.5 h. The reaction mixture was concentrated, and the formed precipitate was filtered off and washed with 300 mL of chloroform. The combined filtrate and washing were concentrated to a slightly yellow oil, which was then purified by flash chromatography (SiO2 gel 60 N, eluted with 10% AcOEt/hexane—20% AcOEt/hexane). The fractions containing only desired product were combined and concentrated to a colorless oil 10.3 (26.1 g). 1H NMR (400 MHz) (CDCl3) δ 7.14 (1H, d, J=1.8 Hz); 7.09 (1H, dd, J=2.3, 8.5 Hz); 6.59 (1H, d, J=8.4 Hz); 4.59 (2H, s); 4.25 (2H, q, J=7.1 Hz); 3.32(1H, s); 2.24 (3H, s); 1.29 (3H, t, J=7.1 Hz).
Reaction SMILES: C([O:4][CH:5]1[CH2:11][CH2:10]/[C:9](=[CH:12]\[CH2:13][O:14]C(=O)C)/[CH2:8][O:7][C:6]1([CH2:19][CH2:20][CH2:21][CH:22]([CH3:31])[CH2:23][O:24][CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][O:26]1)[CH3:18])(=O)C.CO.C(=O)([O-])[O-].[K+].[K+]>O>[OH:4][CH:5]1[CH2:11][CH2:10]/[C:9](=[CH:12]\[CH2:13][OH:14])/[CH2:8][O:7][C:6]1([CH2:19][CH2:20][CH2:21][CH:22]([CH3:31])[CH2:23][O:24][CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][O:26]1)[CH3:18]
Reactant: CC(=O)OC/C=C1\CCC(OC(C)=O)C(C)(CCCC(C)COC2CCCCO2)OC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CC(CCCC1(C)OC/C(=C/CO)CCC1O)COC1CCCCO1
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.1 %

Procedure:
A mixture of 5-[(2RS,3SR)-3-acetoxy-6-[(E)-2-acetoxyethylidene]-2-methyl-2-oxepanyl]-2-methyl-1-(tetrahydropyran-2-yloxy)pentane (1.2 g, 2.73 mM), methanol (10 ml) and saturated potassium carbonate (1 ml) and water (1 ml) is stirred under nitrogen at room temperature for three hours. Most of the solvent is removed in vacuo to give a thick oil. This crude material is filtered through a silica gel column (15 g) and washed with ether (100 ml). The solvent is removed in vacuo to give 5-[(2RS,3SR)-3-hydroxy-6-[(E)-2-hydroxyethylidene]-2-methyl-2-oxepanyl]-2-methyl-1-(tetrahydropyran-2-yloxy)pentane (0.953 g, 87%) as a colorless oil.
Reaction SMILES: [O:1]([CH2:8][CH2:9][CH2:10]Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.[OH-].[Na+]>C1(C)C=CC=CC=1>[O:1]([CH2:8][CH2:9][CH2:10][N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1COCCN1
Reactant: BrCCCOc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: c1ccc(OCCCN2CCOCC2)cc1

Procedure:
N-[3-(Phenoxy)propyl] morpholine was prepared by a reaction of 3-(phenoxy)propyl bromide with morpholine. For example, 3-(phenoxy)propyl bromide (7.8 ml, 50 mmole) was added to morpholine (8 ml) in toluene (50 ml) and refluxed overnight. NaOH solution (2 g of NaOH in 20 ml of water) was added and additionally refluxed for 4 hr. Toluene was removed by distillation under reduced pressure. Residue was treated with dichloromethane(200 ml) and water(200 ml). Dichloromethane layer was dried and concentrated. Residue was treated with dichloromethane-heptane to give 7 g of 4-[3-(phenoxy)propyl] morpholine.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH2:7][CH2:8][CH2:9][CH2:10][C:4]=2[C:3]=1[C:11]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)=O.[CH:21]1([C:24](=[O:29])[CH2:25][C:26](=O)[CH3:27])[CH2:23][CH2:22]1>C(O)(=O)C.S(=O)(=O)(O)O>[CH:21]1([C:24]([C:25]2[C:11]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)=[C:3]3[C:4]4[CH2:10][CH2:9][CH2:8][CH2:7][C:5]=4[S:6][C:2]3=[N:1][C:26]=2[CH3:27])=[O:29])[CH2:23][CH2:22]1
Reactant: COc1ccc(C(=O)c2c(N)sc3c2CCCC3)cc1
Reactant: CC(=O)CC(=O)C1CC1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: COc1ccc(-c2c(C(=O)C3CC3)c(C)nc3sc4c(c23)CCCC4)cc1
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 31.5 %

Procedure:
To a stirred solution of 60 mg (0.21 mmol) (2-amino-4,5,6,7-tetrahydro-benzo[b]thiophen-3-yl)-(4-methoxy-phenyl)-methanone (the preparation of which is described in example 8) in 2 ml acetic acid was added 35 mg (0.28 mmol) of 1-cyclopropyl-butane-1,3-dione and one drop of sulfuric acid. The mixture was then stirred at 100° C. for 10 minutes in a microwave and then concentrated in vacuo. Preparative HPLC (30% CH3CN/H20) afforded 25 mg (32%) cyclopropyl-[4-(4-methoxy-phenyl)-2-methyl-5,6,7,8-tetrahydro-benzo[4,5]thieno[2,3-b]pyridin-3-yl)-methanone as a light brown oil. ES-MS m/e (%): 378 (M+H+, 100).
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[CH:3]([NH:14][C:15]([C:17]1[O:18][C:19]2[CH:25]=[C:24]([C:26]([O:28]C(C)(C)C)=[O:27])[CH:23]=[CH:22][C:20]=2[CH:21]=1)=[O:16])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:13])([F:12])[F:11])[CH:5]=1.FC(F)(F)C(O)=O>ClCCl>[F:34][C:2]([F:1])([F:33])[CH:3]([NH:14][C:15]([C:17]1[O:18][C:19]2[CH:25]=[C:24]([C:26]([OH:28])=[O:27])[CH:23]=[CH:22][C:20]=2[CH:21]=1)=[O:16])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:11])([F:12])[F:13])[CH:5]=1
Reactant: CC(C)(C)OC(=O)c1ccc2cc(C(=O)NC(c3cccc(C(F)(F)F)c3)C(F)(F)F)oc2c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1ccc2cc(C(=O)NC(c3cccc(C(F)(F)F)c3)C(F)(F)F)oc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of tert-butyl 2({2,2,2-trifluoro-[3-(trifluoromethyl)phenyl]ethyl}carbamoyl)-1-benzofuran-6-carboxylate (450 mg, 1.04 mmol) in dichloromethane (4.5 ml) was admixed at 0° C. with trifluoroacetic acid (0.46 ml, 6.0 mmol) and stirred at room temperature overnight. Subsequently, the reaction mixture was washed with water, and the organic phase was dried over magnesium sulphate, filtered and concentrated under reduced pressure. The residue was filtered through silica gel, the filtercake was rinsed with ethyl acetate and methanol, and the filtrate was concentrated.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([NH:15][C@@H:16]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH:29]([CH3:31])[CH3:30])=[CH:24][CH:23]=1)[C:17]([O:19][CH3:20])=[O:18])=O)(C)(C)C>C(Cl)Cl>[NH2:15][C@@H:16]([CH2:21][C:22]1[CH:23]=[CH:24][C:25]([O:28][CH:29]([CH3:31])[CH3:30])=[CH:26][CH:27]=1)[C:17]([O:19][CH3:20])=[O:18]
Reactant: COC(=O)[C@H](Cc1ccc(OC(C)C)cc1)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@@H](N)Cc1ccc(OC(C)C)cc1
Reaction time: 1 h
Yield: 100 %

Procedure:
Trifluoroacetic acid (0.5 mL, 6 mmol) was added to the (S)-methyl 2-(tert-butoxycarbonylamino)-3-(4-isopropoxyphenyl)propanoate in methylene chloride (2 mL). The reaction was stirred for 1 h., and was concentrated under reduced pressure to give a crude product, methyl (2S)-2-amino-3-(4-isopropoxyphenyl)propanoate (40 mg, 100%) as colorless oil. Analytical LCMS (M+H)+: m/z=238.0.
Reaction SMILES: C[O:2][C:3](=[O:28])[C:4](=[O:27])[C:5]1[CH:10]=[CH:9][C:8]([C:11]([NH:13][CH2:14][CH2:15][O:16][C:17]2[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=2)=[O:12])=[CH:7][CH:6]=1.[OH-].[Na+]>CO.O1CCCC1>[CH:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:25]=[CH:26][C:17]=1[O:16][CH2:15][CH2:14][NH:13][C:11]([C:8]1[CH:7]=[CH:6][C:5]([C:4](=[O:27])[C:3]([OH:28])=[O:2])=[CH:10][CH:9]=1)=[O:12]
Reactant: COC(=O)C(=O)c1ccc(C(=O)NCCOc2ccc3ccccc3c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)C(=O)c1ccc(C(=O)NCCOc2ccc3ccccc3c2)cc1
Yield: 81.6 %

Procedure:
A solution of 4-[[[2-(2-naphthalenyloxy)ethyl]amino]carbonyl]-alpha-oxobenzeneacetic acid methyl ester (0.35 g) in methanol (5 mL) and tetrahydrofuran (5 mL) was treated with 1N sodium hydroxide (1 mL) and after 5 minutes the mixture was concentrated to remove the organic solvents. The residue was acidified with excess hydrochloric acid and extracted with dichloromethane containing a little tetrahydrofuran. The organic layer was washed with water, dried (Na2SO4), filtered and evaporated to give crude product. Crystallization from acetone-hexane provided 0.275 g of purified 4-[[[2-(2-naphthalenyloxy)ethyl]amino]carbonyl]-alpha-oxobenzeneacetic acid as a colorless solid, mp 173°-175° C.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([NH:11][C:12]2[CH:24]=[CH:23][C:15]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[CH:14][CH:13]=2)[CH:8]=[C:7]([O:25][CH2:26][C:27]([F:30])([F:29])[F:28])[N:6]=1)(=O)=O.CCN(C(C)C)C(C)C.[NH2:40][CH2:41][C:42]1[CH:47]=[CH:46][C:45]([OH:48])=[CH:44][CH:43]=1>C1COCC1>[OH:48][C:45]1[CH:46]=[CH:47][C:42]([CH2:41][NH:40][C:5]2[N:10]=[C:9]([NH:11][C:12]3[CH:24]=[CH:23][C:15]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[CH:14][CH:13]=3)[CH:8]=[C:7]([O:25][CH2:26][C:27]([F:30])([F:29])[F:28])[N:6]=2)=[CH:43][CH:44]=1
Reactant: NCc1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)c1ccc(Nc2cc(OCC(F)(F)F)nc(S(C)(=O)=O)n2)cc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)c1ccc(Nc2cc(OCC(F)(F)F)nc(NCc3ccc(O)cc3)n2)cc1
Yield: 81.6 %

Procedure:
To a solution of tert-butyl 4-((2-(methylsulfonyl)-6-(2,2,2-trifluoroethoxy)pyrimidin-4-yl)amino)benzoate (80 mg, 0.18 mmol), and Hunig's Base (0.062 mL, 0.36 mmol) in THF (1 mL) was added 4-(aminomethyl)phenol (44 mg, 0.36 mmol). The resulting mixture was stirred at r.t for 16 hs. The solvent was removed and the crude product was purified by silica gel chromatography using 40-70%-100% EtOAc/Hexanes to give tert-butyl 4-((2-((4-hydroxybenzyl)amino)-6-(2,2,2-trifluoroethoxy)pyrimidin-4-yl)amino)benzoate (72 mg, 83%) as white solid.
Reaction SMILES: [F:1][C:2]1[CH:23]=[C:22]([N+:24]([O-:26])=[O:25])[CH:21]=[CH:20][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[CH2:15][CH2:16][NH:17][CH2:18][CH:19]=3)[S:13][C:6]=12.CCN(C(C)C)C(C)C.[C:36](Cl)(=[O:38])[CH3:37]>C(Cl)Cl>[F:1][C:2]1[CH:23]=[C:22]([N+:24]([O-:26])=[O:25])[CH:21]=[CH:20][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[CH2:15][CH2:16][N:17]([C:36](=[O:38])[CH3:37])[CH2:18][CH:19]=3)[S:13][C:6]=12
Reactant: CC(=O)Cl
Reactant: O=[N+]([O-])c1ccc(Oc2ccnc3cc(C4=CCNCC4)sc23)c(F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)N1CC=C(c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)CC1
Reaction time: 1 h
Yield: 80.6 %

Procedure:
To a suspension of 4-(7-(2-fluoro-4-nitrophenoxy)thieno[3,2-b]pyridin-2-yl)-1,2,3,6-tetrahydropyridine 268 (400 mg, 1.08 mmol) and DIPEA (0.207 mL, 1.19 mmol) in DCM was added acetyl chloride (0.15 mL, 2.16 mmol) at room temperature and the mixture (that turned homogeneous soon after) was stirred for 1 h. The crude mixture was concentrated under reduced pressure and the residue purified by flash chromatography (5% MeOH to 10% MeOH in DCM) affording 269 (358.2 mg, 0.87 mmol, 80% yield) as a white solid. MS (m/z): (M+1) 414.4 (100%).
Reaction SMILES: Br[C:2]1[N:6]2[C:7]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:8]=3[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)=[N:10][CH2:11][C:5]2=[N:4][N:3]=1.[CH2:23]([N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)[CH3:24]>>[Cl:22][C:19]1[CH:20]=[CH:21][C:7]2[N:6]3[C:2]([N:28]4[CH2:29][CH2:30][N:25]([CH2:23][CH3:24])[CH2:26][CH2:27]4)=[N:3][N:4]=[C:5]3[CH2:11][N:10]=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)[C:8]=2[CH:18]=1
Reactant: Clc1ccc2c(c1)C(c1ccccn1)=NCc1nnc(Br)n1-2
Reactant: CCN1CCNCC1
Product: CCN1CCN(c2nnc3n2-c2ccc(Cl)cc2C(c2ccccn2)=NC3)CC1

Procedure:
In the manner given in Example 1, 1-bromo-8-chloro-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine is heated with excess of 1-ethylpiperazine to give 8-chloro-1-(4-ethylpiperazino)-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[C:8]([CH3:9])=[CH:7][CH:6]=[CH:5][C:4]=1[N:10]=[C:11]=[O:12].[OH:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH2:17][OH:18]>>[Cl:1][CH2:2][C:3]1[C:8]([CH3:9])=[CH:7][CH:6]=[CH:5][C:4]=1[NH:10][C:11](=[O:12])[O:18][CH2:17][C:16]1[CH:19]=[CH:20][CH:21]=[C:14]([OH:13])[CH:15]=1
Reactant: OCc1cccc(O)c1
Reactant: Cc1cccc(N=C=O)c1CCl
Product: Cc1cccc(NC(=O)OCc2cccc(O)c2)c1CCl
Temperature: 75 °C
Yield: 29.7 %

Procedure:
A mixture of 2-chloromethyl-1-isocyanato-3-methylbenzene (2 g) and 3-hydroxybenzyl alcohol (1.6 g) is warmed to 75° C. in an oil bath for 1 h and then purified by chromatography on silica gel (eluent: dichloromethane/methanol 19:1). 1 g (30%) of the title compound is obtained as a crude product in the form of an amorphous solid.
Reaction SMILES: [C:1]([C@@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]2[CH:16]=[CH:15][C:14]([C@H:17]([C:28](=[O:44])[NH:29][C:30]3[CH:35]=[CH:34][C:33]([C:36]4[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][C:37]=4[CH3:43])=[CH:32][CH:31]=3)[CH2:18][C:19]3[CH:27]=[CH:26][C:22]([C:23]([OH:25])=O)=[CH:21][CH:20]=3)=[CH:13][CH:12]=2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[NH2:66][CH2:67][CH2:68][S:69]([OH:72])(=[O:71])=[O:70].CCN(C(C)C)C(C)C.Cl>CN(C=O)C.CCOC(C)=O.O>[C:1]([C@@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]2[CH:12]=[CH:13][C:14]([C@H:17]([C:28](=[O:44])[NH:29][C:30]3[CH:35]=[CH:34][C:33]([C:36]4[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][C:37]=4[CH3:43])=[CH:32][CH:31]=3)[CH2:18][C:19]3[CH:27]=[CH:26][C:22]([C:23]([NH:66][CH2:67][CH2:68][S:69]([OH:72])(=[O:71])=[O:70])=[O:25])=[CH:21][CH:20]=3)=[CH:15][CH:16]=2)[CH2:7][CH2:6]1)([CH3:2])([CH3:4])[CH3:3]
Reactant: Cc1cc(Cl)ccc1-c1ccc(NC(=O)[C@H](Cc2ccc(C(=O)O)cc2)c2ccc([C@H]3CC[C@@H](C(C)(C)C)CC3)cc2)cc1
Reactant: NCCS(=O)(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cc(Cl)ccc1-c1ccc(NC(=O)[C@H](Cc2ccc(C(=O)NCCS(=O)(=O)O)cc2)c2ccc([C@H]3CC[C@@H](C(C)(C)C)CC3)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 34.9 %

Procedure:
(R)-4-[2-(4-(4-(cis)-tert-Butyl-cyclohexyl)-phenyl]-2-(4′-chloro-2′-methyl-biphenyl-4-ylcarbamoyl)-ethyl]-benzoic acid (350 mg, 0.6 mmol), was taken up in 3 mL of DMF, followed by addition of HOBt (133 mg, 0.9 mmol), EDCI (132 mg, 0.7 mmol), taurine (86 mg, 0.7 mmol) and Hunig's base (374 mg, 2.9 mmol). The resulting reaction mixture was then stirred for 16 h at room temperature. The reaction solution was diluted with EtOAc (25 mL) and 10 mL of water, acidified with 2.4 N HCl. The layers were separated and the aqueous layer was extracted with EtOAc (2×20 mL). The organic extracts were combined, dried with Na2SO4, filtered through a frit and concentrated under reduced pressure to give a foam. The material was subjected to reverse phase HPLC purification to give the desired product as a white solid (150 mg, 36%). 1H NMR (CD3OD): δ 0.89 (9H, s), 1.10-1.60 (6H, m), 1.80-1.90 (4H, m), 2.38 (3H, s), 2.32-2.53 (1H, m), 3.05-3.10 (4H, m), 3.47-3.55 (1 h. dd), 3.77 (2H, t), 3.93-3.98 (1H, m), 7.09-7.47 (1H, m), 7.50 (2H, d), 7.70 (2H, d). Anal. Calcd. For C42H47ClN2O5S+NH3+1.2 H2O; C=65.22; H=7.13; N=5.57. Found C=65.31; H=7.00; N=5.57.
Reaction SMILES: CN(OC)[C:3]([C:5]1[O:6][C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)=[CH:8][CH:9]=1)=O.[H-].Cl.[OH2:21]>O1CCCC1.C1(C)C=CC=CC=1>[CH3:16][C:13]1[CH:12]=[CH:11][C:10]([C:7]2[O:6][C:5](/[CH:3]=[CH:3]/[C:5]([O:6][CH3:7])=[O:21])=[CH:9][CH:8]=2)=[CH:15][CH:14]=1
Reactant: O
Reactant: CON(C)C(=O)c1ccc(-c2ccc(C)cc2)o1
Agent: Cl
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COC(=O)/C=C/c1ccc(-c2ccc(C)cc2)o1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
Under nitrogen atmosphere, to a solution of N-methyl-N-methoxy-5-(4-methylphenyl)furan-2-carboxamide (2.5 g) in tetrahydrofuran (20 ml) was added duisobutylaluminum hydride (1.01M toluene solution) (15 ml) at -78° C., and the mixture was stirred at -78° C. for 10 minutes and then at 0° C. for 15 minutes. To the reaction mixture was added 1N hydrochloric acid to stop the reaction, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with magnesium sulfate and concentrated. The residue was separated and purified with column chromatography (ethyl acetate/hexane=1:5→1:4) to give crude product (1.49 g). A solution of the crude aldehyde (1.49 g) and methyl (triphenylphosphoranilidene)acetate (2.67 g) in toluene (30 ml) was refluxed under nitrogen atmosphere for 1 hour and cooled. To the mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified with column chromatography (ethyl acetate/hexane=1:9→1:5) to give methyl (E)-3-[5-(4-methylphenyl)furan-2-yl]acrylate (1.63 g) as pale yellow crystals.