Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[C:5]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:4][CH:3]1[NH:19][C:20](=[O:29])[O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[H-].[Na+].[CH3:32]I.S([O-])(O)(=O)=O.[Na+]>CN(C=O)C.O>[CH3:32][N:8]1[C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[C:5]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:4][CH:3]([NH:19][C:20](=[O:29])[O:21][CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:2]1=[O:1]
Reactant: O=C(NC1N=C(c2ccccc2)c2ccccc2NC1=O)OCc1ccccc1
Reactant: CI
Agent: O=S(=O)([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN1C(=O)C(NC(=O)OCc2ccccc2)N=C(c2ccccc2)c2ccccc21
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 91 %

Procedure:
To a solution of benzyl 2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-ylcarbamate (13) (Sherril R. G.; Sugg, E. E. Improved Synthesis and Resolution of 3-Amino-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-ones. J. Org. Chem. 1995, 60, 730-734) (1.00 g, 2.60 mmol) in anhydrous DMF (10 mL), kept at 0° C. under N2, NaH (60% dispersion in mineral oil, 0.10 g, 1 eq) was added in small portions. After 1.5 hr stirring at 0° C., methyl iodide (0.17 mL, 1.05 eq) was added at once; the mixture was stirred for additional 1.5 h at the same temperature, and then poured into a stirred solution of H2O (60 mL) containing aqueous sodium hydrogen sulphate (2 mL, 1 N). A solid precipitated, which was filtered, dried under vacuum, and then purified by flash chromatography (CH2Cl2/MeOH/NH3 99:1:0.1 as eluent) giving benzyl 1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-ylcarbamate in 91% yield. M.p. 78-80° C.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:11][OH:12])[C@H:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[OH:4].O=[C:14]([CH3:28])[CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C:24]([O:26][CH3:27])=[O:25])=[CH:19][CH:18]=1.C1C=CC=CC=1.C([BH3-])#N.[Na+]>CO>[CH3:27][O:26][C:24]([CH2:23][C:20]1[CH:19]=[CH:18][C:17]([O:16][CH2:15][CH:14]([NH:1][C@@H:2]([CH2:11][OH:12])[C@H:3]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)[OH:4])[CH3:28])=[CH:22][CH:21]=1)=[O:25]
Reactant: N[C@@H](CO)[C@@H](O)c1ccccc1
Reactant: COC(=O)Cc1ccc(OCC(C)=O)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: c1ccccc1
Product: COC(=O)Cc1ccc(OCC(C)N[C@@H](CO)[C@@H](O)c2ccccc2)cc1
Yield: 18.3 %

Procedure:
Following a procedure similar to that described in Example 6, but using 5.7 g of (1S, 2S)-(+)-2-amino-1-phenyl-1,3-propanediol, 5 g of methyl 4-(2-oxopropoxy)phenylacetate (prepared as described in Preparation 3), 250 ml of benzene, 250 ml of absolute methanol and 4.34 g of sodium cyanoborohydride, 1.54 g of the title compound were obtained having an Rf=0.27 (thin layer chromatography over silica gel, using a 2:1 by volume mixture of ethyl acetate and hexane as the developing solvent).
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].ClCCl.[C:8]([O:12][C:13]([NH:15][CH2:16][C:17]1[S:18][C:19]([CH2:22]O)=[CH:20][N:21]=1)=[O:14])([CH3:11])([CH3:10])[CH3:9]>N1C=CC=CC=1>[C:1]([O:4][CH2:22][C:19]1[S:18][C:17]([CH2:16][NH:15][C:13]([O:12][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:14])=[N:21][CH:20]=1)(=[O:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCc1ncc(CO)s1
Reactant: CC(=O)O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)OCc1cnc(CNC(=O)OC(C)(C)C)s1
Reaction time: 17 h

Procedure:
A 6 ml portion of anhydrous acetic acid was added to a mixed solution of 10 ml of dichloromethane and 20 ml of pyridine containing 2.17 g of 2-(N-t-butoxycarbonylamino)methyl-5-hydroxymethylthiazole, and the mixture was then allowed to stand at room temperature for 17 hours. Under reduced pressure, the solvent was distilled off, and the resulting residue was dissolved in 120 ml of chloroform. The solution was washed once with water and twice with a 10% saline solution, dried over anhydrous sodium sulfate and then filtered, and the solvent was evaporated under reduced pressure to obtain 2.47 g of 5-acetoxymethyl-2-(N-t-butoxycarbonylamino)methylthiazole.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[C:13]([NH:22][S:23]([C:26]3[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=3)(=[O:25])=[O:24])=[N:14][C:15]3[C:20]([N:21]=2)=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.CS(C)=[O:34].[OH-].[Na+].Cl>O>[CH3:10][O:9][C:7]1[CH:6]=[C:5]([NH:11][C:12]2[C:13]([NH:22][S:23]([C:26]3[CH:31]=[CH:30][C:29](=[O:34])[NH:28][CH:27]=3)(=[O:24])=[O:25])=[N:14][C:15]3[C:20]([N:21]=2)=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: CS(C)=O
Reactant: COc1cc(Nc2nc3ccccc3nc2NS(=O)(=O)c2cccnc2)cc(OC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1cc(Nc2nc3ccccc3nc2NS(=O)(=O)c2ccc(=O)[nH]c2)cc(OC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)pyridine-3-sulfonamide (220 mg, 0.47 mmol), DMSO (5 mL), and 3N NaOH (5 mL) are combined and heated to 100 C. overnight with stirring. Upon cooling to room temperature, the reaction mixture was diluted with H2O and the pH was adjusted to 7.0 with 1N HCl. The resulting solid was filtered, washed with H2O, and air-dried. The solid was then sonicated in EtOAc, filtered, washed with EtOAc, and dried under high vacuum to give N-(3-(3,5-dimethoxyphenylamino)quinoxalin-2-yl)-6-oxo-1,6-dihydropyridine-3-sulfonamide (190 mg, 90%). 1H NMR (400 MHz, DMSO-d6) δ 12.23 (br s, 1H), 12.10 (br s, 1H), 8.97 (s, 1H), 8.23 (s, 1H), 7.95 (m, 2H), 7.59 (m, 1H), 7.37 (m, 4H), 6.43 (d, 1H), 6.25 (s, 1H), 3.77 (s, 6H). MS (EI) for C21H19N5O5S: 454.0 (MH+).
Reaction SMILES: [CH3:1][N:2]([CH3:20])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH3:19])=[CH:13][CH:12]=2)=[CH:5][CH:4]=1.[CH:21]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH:30]([CH3:32])[CH3:31])[C:25]=1[N:33]=[C:34]=[O:35])([CH3:23])[CH3:22]>>[CH:21]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH:30]([CH3:31])[CH3:32])[C:25]=1[NH:33][C:34](=[O:35])[N:10]([CH2:9][C:6]1[CH:5]=[CH:4][C:3]([N:2]([CH3:20])[CH3:1])=[CH:8][CH:7]=1)[C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH3:19])=[CH:13][CH:12]=1)([CH3:22])[CH3:23]
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Reactant: CCCc1ccc(NCc2ccc(N(C)C)cc2)cc1
Product: CCCc1ccc(N(Cc2ccc(N(C)C)cc2)C(=O)Nc2c(C(C)C)cccc2C(C)C)cc1
Yield: 36.3 %

Procedure:
By the reaction and treatment in the same manner as in Example 2 using [(4-dimethylaminophenyl)methyl](4-propylphenyl)amine (0.80 g) and 2,6-diisopropylphenyl isocyanate (0.72 g) as starting materials, N′-(2,6-diisopropylphenyl)-N-[(4-dimethylaminophenyl)methyl]-N-(4-propylphenyl)urea (0.51 g) was obtained.
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8](=[O:12])[CH:9]([CH3:11])[CH3:10])=[CH:6][N:5]=[C:4]2[S:13][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[C:15]([CH3:16])[C:3]=12.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.[F:34][C:35]1[CH:42]=[CH:41][CH:40]=[C:39]([F:43])[C:36]=1[CH2:37]Br>O>[F:34][C:35]1[CH:42]=[CH:41][CH:40]=[C:39]([F:43])[C:36]=1[CH2:37][N:5]1[CH:6]=[C:7]([C:8](=[O:12])[CH:9]([CH3:11])[CH3:10])[C:2](=[O:1])[C:3]2[C:15]([CH3:16])=[C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[S:13][C:4]1=2
Reactant: Cc1c(-c2ccccc2)sc2ncc(C(=O)C(C)C)c(O)c12
Reactant: Fc1cccc(F)c1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(-c2ccccc2)sc2c1c(=O)c(C(=O)C(C)C)cn2Cc1c(F)cccc1F
Temperature: 45 °C
Reaction time: 2 h
Yield: 94.6 %

Procedure:
4-Hydroxy-5-isobutyryl-3-methyl-2-phenylthieno[2,3-b]pyridine (35 g), potassium carbonate (18.6 g) and N,N-dimethylformamide (280 ml) were mixed and 2,6-difluorobenzyl bromide (27.9 g) was added and the reaction mixture was stirred at 40 to 50° C. for 2 hours. The reaction mixture was treated dropwise with water (560 ml), and the mixture was stirred for 1 hour and then cooled on ice, and then stirred further for 1 hour. The crude crystal was recovered by a filtration, washed with water (about 1000 ml), dried in air, suspended in a 1:1 solvent mixture (250 ml) of ethyl acetate and diisopropylether, and then the mixture was stirred at room temperature for 1 hour, and then stirred with cooling on ice for 1 hour. The crystal obtained by a filtration was washed with the same solvent mixture (180 ml), dried in vacuo at 40° C. for 5 hours to obtain the title compound (46.53 g, 94.6%).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[N:9][N:10]=2)[N:7]=1.[C:11]1([CH:17]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[O:18][CH:19]2[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][CH2:27][NH2:28])[CH2:21][CH2:20]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(C(C)C)C(C)C)C.C(=O)([O-])O.[Na+]>C(O)CCC>[C:29]1([CH:17]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[O:18][CH:19]2[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][CH2:27][NH:28][C:2]3[CH:3]=[CH:4][C:5]4[N:6]([CH:8]=[N:9][N:10]=4)[N:7]=3)[CH2:21][CH2:20]2)[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: NCCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Reactant: Clc1ccc2nncn2n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: c1ccc(C(OC2CCN(CCCNc3ccc4nncn4n3)CC2)c2ccccc2)cc1
Temperature: 0 °C
Yield: 48.8 %

Procedure:
0.464 g of 6-chloro[1,2,4]triazolo[4,3-b]pyridazine and 1.26 g of 4-(diphenylmethoxy)-1-piperidinepropanamine were suspended in 20 ml of 1-butanol; 0.62 ml of N-ethyldiisopropylamine was added, followed by refluxing under heating for 12 hours. After ice water and sodium hydrogen carbonate were added, the reaction mixture was extracted with ethyl acetate; the extract was washed with saturated saline and dried over magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography and eluted with ethyl acetate-methanol-triethylamine (90:10:1). The desired fraction was collected and concentrated; the crystal obtained was washed with ethyl acetate and dried to yield 0.648 g of the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]#[N:16])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:18]([Mg]Br)[CH3:19].O>C1COCC1.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[C:1]([O:5][C:6](=[O:17])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]2([NH2:16])[CH2:19][CH2:18]2)[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCc1ccnc(C#N)c1
Reactant: CC[Mg]Br
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)NCc1ccnc(C2(N)CC2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of (2-cyano-pyridin-4-ylmethyl)-carbamic acid tert-butyl ester (1.2 g, 5.1 mmol) in THF (100 mL) was added ethylmagnesium bromide (3 M, 3.3 mL, 10 mmol) and titanium isopropoxide (2.3 mL, 7.7 mmol). The reaction mixture was stirred at room temperature for 16 h. Water was added (5 mL) and the resulting solids filtered off. The organics were concentrated, then purified by flash chromatography on silica gel using 5-10% MeOH/CH2Cl2 to afford [2-(1-amino-cyclopropyl)-pyridin-4-ylmethyl]-carbamic acid tert-butyl ester as a solid, m/z 264.4 [M+1]+.
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].[C:5]1([C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8]O1)=[O:6]>>[OH:2][CH2:1][CH2:3][N:4]1[CH2:8][C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:5]1=[O:6]
Reactant: NCCO
Reactant: O=C1OCc2ccccc21
Product: O=C1c2ccccc2CN1CCO
Temperature: 150 °C
Yield: 81.7 %

Procedure:
Ethanolamine (4.78 g, 78.3 mmol) and phthalide (10.0 g, 74.6 mmol) were placed in a round-bottom flask equipped with a Dean-stark trap. The reaction mixture was heated at 150° C. for 4 h then 18 h at 205° C. The product was solidified upon cooling. Pure 2-(2-hydroxyethyl)isoindolinone (10.8 g, 82%) was isolated by recrystalization in CHC13/hexanes as a white crystal. 1H NMR (CDCl3, 300 MHz) δ3.02-3.15 (br, 1H), 3.78 (t, 2H, J=5.0 Hz), 3.93 (t, 2H, J=4.4 Hz), 4.52 (s, 2H), 7.42-7.58 (m, 3H), 7.84 (d, 1H, J=7.4 Hz) ppm.
Reaction SMILES: O[CH2:2][C:3]1[C:8]([CH3:9])=[C:7]([O:10][CH2:11][CH2:12][CH2:13][O:14][CH3:15])[CH:6]=[CH:5][N:4]=1.S(Cl)([Cl:18])=O>C(OCC)(=O)C>[Cl:18][CH2:2][C:3]1[C:8]([CH3:9])=[C:7]([O:10][CH2:11][CH2:12][CH2:13][O:14][CH3:15])[CH:6]=[CH:5][N:4]=1
Reactant: O=S(Cl)Cl
Reactant: COCCCOc1ccnc(CO)c1C
Solvent: CCOC(C)=O
Product: COCCCOc1ccnc(CCl)c1C
Yield: 112.8 %

Procedure:
2-Hydroxymethyl-4-(3-methoxypropoxy)-3-methylpyridine (5.0 g (23.7 mmol)) was dissolved in ethyl acetate (40 ml), and thionyl chloride (4.23 g (35.6 mmol)) was added dropwise into the solution in a temperature that did not exceed 25° C. Stirring was carried out at room temperature, and then after it had been confirmed by TLC that the starting material had disappeared, vacuum concentration was carried out, thus obtaining 2-chloromethyl-4-(3-methoxypropoxy)-3-methylpyridine (6.14 g (yield: 97.4%)).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[CH:10][CH:9]=1)[C:3]([O:5][CH3:6])=[O:4].CCN(C(C)C)C(C)C.[C:25]([C:29]1[CH:37]=[CH:36][C:32]([C:33](Cl)=[O:34])=[CH:31][CH:30]=1)([CH3:28])([CH3:27])[CH3:26]>C(Cl)Cl>[C:25]([C:29]1[CH:30]=[CH:31][C:32]([C:33]([NH:1][C@@H:2]([CH2:7][C:8]2[CH:9]=[CH:10][C:11]([C:14]#[N:15])=[CH:12][CH:13]=2)[C:3]([O:5][CH3:6])=[O:4])=[O:34])=[CH:36][CH:37]=1)([CH3:28])([CH3:26])[CH3:27]
Reactant: COC(=O)[C@@H](N)Cc1ccc(C#N)cc1
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](Cc1ccc(C#N)cc1)NC(=O)c1ccc(C(C)(C)C)cc1
Reaction time: 2 h
Yield: 87.6 %

Procedure:
Prepared using General Procedure 3: To the solution of (S)-methyl 2-amino-3-(4-cyanophenyl)propanoate (789.2 mg, 3.32 mmol) in DCM (15 mL) and DIEA (1.29 g, 9.96 mmol) was added 4-(tert-butyl)benzoyl chloride (981.3 mg, 4.99 mmol) at RT. The reaction was stirred for 2 h and the reaction was partitioned between DCM and saturated aqueous NaHCO3. The organic layer was dried over MgSO4 and concentrated. The crude product was purified by chromatography (EA/hexanes) to afford 1.06 g (88%) of (S)-methyl 2-(4-(tert-butyl)benzamido)-3-(4-cyanophenyl)propanoate. LCMS-ESI (m/z) calculated for C22H24N2O3: 364.2. found 365.3 [M+H]+, tR=3.55 min (Method 1). 1H NMR (400 MHz, CDCl3) δ 8.81 (d, J=8.0 Hz, 1H), 7.85-7.60 (m, 4H), 7.49 (dd, J=15.1, 8.4 Hz, 4H), 4.85-4.60 (m, 1H), 3.65 (s, 3H), 3.30-3.23 (m, 1H), 3.18 (dd, J=13.7, 10.6 Hz, 1H), 1.29 (s, 9H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7][C:8]1[CH:9]=[C:10]([O:29][C:30]2[C:31]([CH3:37])=[N:32][N:33]([CH3:36])[C:34]=2[CH3:35])[C:11]([NH:14][C:15]2[S:19][N:18]=[C:17]([C@H:20]3[C:24]([CH3:26])([CH3:25])[O:23]C(C)(C)[O:21]3)[N:16]=2)=[N:12][CH:13]=1.[ClH:38]>C(O)C>[ClH:38].[CH3:26][C:24]([OH:23])([CH3:25])[C@H:20]([C:17]1[N:16]=[C:15]([NH:14][C:11]2[C:10]([O:29][C:30]3[C:31]([CH3:37])=[N:32][N:33]([CH3:36])[C:34]=3[CH3:35])=[CH:9][C:8]([S:7][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)=[CH:13][N:12]=2)[S:19][N:18]=1)[OH:21]
Reactant: Cc1nn(C)c(C)c1Oc1cc(Sc2ccccn2)cnc1Nc1nc([C@@H]2OC(C)(C)OC2(C)C)ns1
Agent: Cl
Solvent: CCO
Product: Cc1nn(C)c(C)c1Oc1cc(Sc2ccccn2)cnc1Nc1nc([C@H](O)C(C)(C)O)ns1
Temperature: 75 °C
Reaction time: 0.03 h
Yield: 89.6 %

Procedure:
A flask was charged with (S)—N-(5-(pyridin-2-ylthio)-3-(1,3,5-trimethyl-1H-pyrazol-4-yloxy)pyridin-2-yl)-3-(2,2,5,5-tetramethyl-1,3-dioxolan-4-yl)-1,2,4-thiadiazol-5-amine (0.233 g, 0.432 mmol), ethanol (10 mL), and 3M HCl (0.288 ml, 0.863 mmol). The reaction was heated to 75° C. for 1 hour and then concentrated in vacuo. Ether was added to the residue and the mixture was stirred for 2 minutes to precipitate the product. The mixture was decanted and the resulting solids were dried in vacuo to afford (S)-2-methyl-1-(5-(5-(pyridin-2-ylthio)-3-(1,3,5-trimethyl-1H-pyrazol-4-yloxy)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)propane-1,2-diol hydrochloride (0.248 g, 0.387 mmol, 89.6% yield) as yellow solid. Mass Spectrum (apci) m/z=500.1 (M+H−HCl).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([BH3-])#N.[Na+].[CH3:13][O:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[N:21]=[CH:20][N:19]=[C:18]2[O:25][CH2:26][CH:27]1[CH2:32][CH2:31][C:30](=O)[CH2:29][CH2:28]1>CO>[CH2:1]([NH:8][CH:30]1[CH2:29][CH2:28][CH:27]([CH2:26][O:25][C:18]2[C:17]3[C:22](=[CH:23][CH:24]=[C:15]([O:14][CH3:13])[CH:16]=3)[N:21]=[CH:20][N:19]=2)[CH2:32][CH2:31]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: COc1ccc2ncnc(OCC3CCC(=O)CC3)c2c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: COc1ccc2ncnc(OCC3CCC(NCc4ccccc4)CC3)c2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Benzylamine (1.08 ml, 10 mmol) and sodium cyanoborohydride (2.2 g, 11 mmol) were added to a solution of 4-(6-methoxy-quinazolin-4-yloxymethyl)-cyclohexanone (2.87 g, 10 mmol) in methanol (50 ml). The mixture was stirred overnight at room temperature. The reaction mixture was concentrated and the residue was dissolved in saturated potassium carbonate solution and ethyl acetate. The aqueous phase was extracted with ethyl acetate (2×50 ml), and the combined organic phases were dried over magnesium sulphate and concentrated. The residue was purified by column chromatography on silica gel (EtOAc and then EtOAc/MeOH 9/1).
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][C:5]1[CH:19]=[CH:18][C:8]([O:9][C:10]2[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=2)[C:13]#[N:14])=[C:7]([C:20]([F:23])([F:22])[F:21])[CH:6]=1.[C:24]([O:28][C:29]([N:31]1[C:39]2[N:34]([C:35](=[O:41])[N:36]=[C:37](Cl)[CH:38]=2)[CH2:33][CH2:32]1)=[O:30])([CH3:27])([CH3:26])[CH3:25]>>[C:13]([C:12]1[CH:11]=[C:10]([CH:17]=[CH:16][CH:15]=1)[O:9][C:8]1[CH:18]=[CH:19][C:5]([CH2:4][O:3][C:37]2[CH:38]=[C:39]3[N:31]([C:29]([O:28][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:30])[CH2:32][CH2:33][N:34]3[C:35](=[O:41])[N:36]=2)=[CH:6][C:7]=1[C:20]([F:21])([F:22])[F:23])#[N:14]
Reactant: CC(C)(C)OC(=O)N1CCn2c1cc(Cl)nc2=O
Reactant: N#Cc1cccc(Oc2ccc(CO)cc2C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)N1CCn2c1cc(OCc1ccc(Oc3cccc(C#N)c3)c(C(F)(F)F)c1)nc2=O

Procedure:
The title compound was prepared by a procedure similar to that described for E1 starting from NaH, 3-(4-(hydroxymethyl)-2-(trifluoromethyl)phenoxy)benzonitrile and tert-butyl-7-chloro-5-oxo-2,3-dihydroimidazo[1,2-c]pyrimidine-1(5H)-carboxylate.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[C:13]([O:21][CH3:22])[CH:12]=3)[N:9]=2)[N:4]([Si](C(C)C)(C(C)C)C(C)C)[CH:3]=1.[C:33]([O:37][C:38]([N:40]1[CH2:45][CH2:44][CH2:43][C:42]([CH:47]=[O:48])([CH3:46])[CH2:41]1)=[O:39])([CH3:36])([CH3:35])[CH3:34]>>[C:33]([O:37][C:38]([N:40]1[CH2:45][CH2:44][CH2:43][C:42]([CH:47]([OH:48])[C:2]2[C:10]3[C:5](=[N:6][CH:7]=[C:8]([C:11]4[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[C:13]([O:21][CH3:22])[CH:12]=4)[N:9]=3)[NH:4][CH:3]=2)([CH3:46])[CH2:41]1)=[O:39])([CH3:36])([CH3:35])[CH3:34]
Reactant: CC1(C=O)CCCN(C(=O)OC(C)(C)C)C1
Reactant: COc1cc(-c2cnc3c(n2)c(I)cn3[Si](C(C)C)(C(C)C)C(C)C)cc(OC)c1OC
Product: COc1cc(-c2cnc3[nH]cc(C(O)C4(C)CCCN(C(=O)OC(C)(C)C)C4)c3n2)cc(OC)c1OC

Procedure:
3-{Hydroxy-[2-(3,4,5-trimethoxy-phenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-methyl}-3-methyl-piperidine-1-carboxylic acid tert-butyl ester was prepared starting from 7-iodo-5-triisopropylsilanyl-2-(3,4,5-trimethoxy-phenyl)-5H-pyrrolo[2,3-b]pyrazine and 3-formyl-3-methyl-piperidine-1-carboxylic acid tert-butyl ester (WO 2002024679) following general procedures as described in these Examples.
Reaction SMILES: CN(C)C=O.[C:6]1([C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[N+:19]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([N+]([O-])=O)[CH:23]=1)([O-:21])=[O:20].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[N+:19]([C:22]1[CH:23]=[C:24]([CH:25]=[CH:26][CH:27]=1)[O:18][C:15]1[CH:14]=[CH:13][C:12]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)=[CH:17][CH:16]=1)([O-:21])=[O:20]
Reactant: Oc1ccc(-c2ccccc2)cc1
Reactant: O=[N+]([O-])c1cccc([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1cccc(Oc2ccc(-c3ccccc3)cc2)c1
Temperature: 140 °C
Reaction time: 15 h
Yield: 70.1 %

Procedure:
To a four necked flask equipped with a thermometer, reflux condenser and stirrer, 400 g of N,N-dimethylformamide (DMF), 40 g of toluene, 80 g (0.47 mol) of p-phenylphenol, 86.9 g (0.517 mol) of m-dinitrobenzene, and 35.9 g (0.26 mol) of potassium carbonate were charged. The mixture was heated to 140° C. with stirring and aged at 140° C. for 15 hours. After finishing the reaction, the reaction mixture was cooled to 100° C. and filtered to remove inorganic salts. The filtrate was incorporated with 300 g of water and cooled to room temperature to crystallize the desired product. The precipitated crystals were filtered and recrystallized from a mixture of 380 g of DMF and 100 g of water to obtain 96 g (70% yield) of 4-(3-nitrophenoxy)-1,1'-biphenyl (NPBP).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[N:5]([CH3:9])[CH:6]=[CH:7][CH:8]=1.[Cl:10][C:11]1[CH:16]=[C:15]([Cl:17])[C:14]([Cl:18])=[CH:13][C:12]=1[S:19](Cl)(=[O:21])=[O:20]>>[Cl:10][C:11]1[CH:16]=[C:15]([Cl:17])[C:14]([Cl:18])=[CH:13][C:12]=1[S:19]([NH:1][CH2:2][CH2:3][C:4]1[N:5]([CH3:9])[CH:6]=[CH:7][CH:8]=1)(=[O:21])=[O:20]
Reactant: Cn1cccc1CCN
Reactant: O=S(=O)(Cl)c1cc(Cl)c(Cl)cc1Cl
Product: Cn1cccc1CCNS(=O)(=O)c1cc(Cl)c(Cl)cc1Cl

Procedure:
Prepared from 2-(2-aminoethyl)-1-methylpyrrole and 2,4,5-trichlorobenzenesulphonylchloride analogously to Example A.
Reaction SMILES: Br[CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][C:6]([F:11])=[CH:7][CH:8]=2)/[C:3]/1=[CH:12]/[C:13]([NH2:15])=[O:14].C(COC)[O:17]C>O.[N+]([O-])([O-])=O.[Ag+]>[F:11][C:6]1[CH:5]=[C:4]2[C:9]([CH2:10][CH:2]([OH:17])/[C:3]/2=[CH:12]\[C:13]([NH2:15])=[O:14])=[CH:8][CH:7]=1
Reactant: COCCOC
Reactant: NC(=O)/C=C1/c2cc(F)ccc2CC1Br
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: O
Product: NC(=O)/C=C1/c2cc(F)ccc2CC1O
Yield: 28 %

Procedure:
A mixture of (Z)-2-(2-bromo-6-fluoro-1-indanylidene)acetamide (5.30 g, 19.25 mmoles) and silver nitrate (10.40 g, 61.18 mmoles, Aldrich) in dimethoxyethane (265 mL) and water (100 mL) was refluxed for 18 hours. The mixture was filtered, and the filtrate was diluted with water (700 mL) and extracted with ethyl acetate (6×100 mL). The combined extracts were washed with water (200 mL) and brine (200 mL), dried over magnesium sulfate, filtered, and evaporated in vacuo. The residue was chromatographed on silica gel, eluting with hexane: ethyl acetate (2:1), gradually increasing the polarity to hexane: ethyl acetate (1:1). The fractions containing the compound with Rf=0.18 were combined and evaporated in vacuo to give 1.13 g (28%) of crude (Z)-2-(6-fluoro-2-hydroxy-1-indanylidene)acetamide as an orange solid. Recrystallization from ethyl acetate: hexane mixtures gave 0.49 g (12%) of (Z)-2-(6-fluoro-2-hydroxy-1-indanylidene)acetamide as an off-white solid, mp 201°-202° C.;
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[NH:4][C:5]2[C:6]([N:27]=1)=[C:7]1[C:12](=[CH:13][CH:14]=2)[CH2:11][CH2:10][CH:9]([CH2:15]OS(C2C=CC(C)=CC=2)(=O)=O)[O:8]1.[CH2:30]([NH2:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.O>CS(C)=O>[CH2:30]([NH:37][CH2:15][CH:9]1[O:8][C:7]2[C:12](=[CH:13][CH:14]=[C:5]3[N:4]=[C:3]([C:2]([F:29])([F:28])[F:1])[NH:27][C:6]3=2)[CH2:11][CH2:10]1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2CCc3ccc4[nH]c(C(F)(F)F)nc4c3O2)cc1
Reactant: NCc1ccccc1
Solvent: O
Solvent: CS(C)=O
Product: FC(F)(F)c1nc2ccc3c(c2[nH]1)OC(CNCc1ccccc1)CC3
Temperature: 80 °C
Reaction time: 6 h
Yield: 173.8 %

Procedure:
To a solution of toluene-4-sulfonic acid 2-trifluoromethyl-3,6,7,8-tetrahydro-9-oxa-1,3-diaza-cyclopenta[a]naphthalen-8-ylmethyl ester (213 mg, 0.5 mmol) in dimethyl sulfoxide (20 mL) was added benzylamine (268 mg, 2.5 mmol). The reaction mixture was stirred at 80° C. for 6 h, cooled to room temperature and then poured into water (20 mL), extracted with chloroform (3×30 mL) dried over anhydrous Na2SO4. Purification by chromatography (ethyl acetate) provided 314 mg (87%) of the title compound which was converted to its oxalate salt: mp 244° C.; 1H NMR (400 MHz, CDCl3): δ1.81 (m, 1H), 2.13 (m, 1H), 2.84 (m, 2H), 3.28 (m, 2H), 4.25 (d, J=13.4 Hz, 1H), 4.31 (d, J=13.4 Hz, 1H), 4.50 (m, 1H), 7.08 (d, J=8.4 Hz, 1H), 7.17 (d, J=8.4 Hz, 1H), 7.42 (m, 3H), 7.58 (m, 2H), 13.85 (bs, 1H); IR: 3450, 3080, 2980, 1725, 1640, 1600, 1550,1080 cm−1; MS 362 [M+H]+.