Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][CH3:14])[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C[N:16]1CCOCC1.ClC(OCC(C)C)=O.[NH4+].[OH-]>CN(C=O)C.CCCCCC>[C:10]([C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:13][CH3:14])(=[O:11])[NH2:16]
Reactant: CN1CCOCC1
Reactant: CC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: CC[C@H](NC(=O)OC(C)(C)C)C(N)=O
Temperature: -20 °C
Reaction time: 0.17 h
Yield: 80.4 %

Procedure:
To a solution of (2S)-2-[(tert-butoxycarbonyl)amino]butanoic acid (1.01 g, 4.99 mmol) in DMF (5 mL) at −20° C. was added NMM (1.10 mL, 9.99 mmol) and isobutyl chloroformate (1.30 mL, 9.99 mmol). The reaction was stirred for 10 min at −20° C. The precipitate was removed by filtration. 26% NH4OH (aq) solution (0.39 mL, 9.99 mmol) was added and the reaction was stirred at −20° C. for 3 h. The volume was reduced under vacuum and hexane was added. A white precipitate was formed after a few minutes. The precipitate was collected in a filter and washed with additional hexane. The precipitate was recrystallised from EtOAc and hexane to give the title compound (0.811 g, 80%) as white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([OH:11])[CH:3]=1.[CH2:12](Br)/[CH:13]=[C:14](/[CH2:16][CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])\[CH3:15].O>CN(C=O)C>[CH3:15]/[C:14](/[CH2:16][CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])=[CH:13]\[CH2:12][NH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([OH:11])[CH:3]=1
Reactant: Nc1ccc(C(=O)O)c(O)c1
Reactant: CC(C)=CCC/C(C)=C/CBr
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)=CCC/C(C)=C/CNc1ccc(C(=O)O)c(O)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 7.5 %

Procedure:
In 30 ml of DMF was dissolved 2.12 g (13.8 mmol) of 4-amino-2-hydroxybenzoic acid, and 3.0 g (13.8 mmol) of geranyl bromide was added thereto. After the mixture was stirred at room temperature for 4 hours, water was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and a saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and concentrated. The resulting crude product was purified by column chromatography and recrystallized from ethyl acetate/hexane to obtain 0.30 g (yield: 7.6%) of N-{(2E)-3,7-dimethylocta-2,6-dienyl}-4-amino-2-hydroxybenzoic acid represented by the following structural formula (hereinafter referred to as compound 47) as white crystals. The analytical results are shown below. ##STR68##
Reaction SMILES: [CH3:1][C:2]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][CH:5]=1)=[O:3].[H-].[Na+].[CH3:16][O:17][C:18](=O)[O:19]C>CCCCCC.C(OCC)(=O)C>[C:4]1([C:2](=[O:3])[CH2:1][C:18]([O:17][CH3:16])=[O:19])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: CC(=O)c1cccc2ccccc12
Reactant: COC(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COC(=O)CC(=O)c1cccc2ccccc12
Yield: 3945.4 %

Procedure:
10.2 g(59.9 mmol) of 1-acetonaphthone and 4.8 g(60% in mineral oi, 120 mmol) of sodium hydride were added to 100 mg of dimethylcarbonate and the mixture was refluxed for 24 hours. The solvent was removed under reduced pressure, 100 ml of 1N aqueous HCl solution was added to the residue, and the resulting mixtrue was extracted with 100 ml of ethyl acetate. The organic layer was washed with water(100 ml×3), dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography(eluent: n-hexane/ethyl acetate=90/10, v/v) to give 10.0 g (43.8 mmol, Yield 73%) of the title compound.
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]([CH3:19])[C:3]1=[O:20].[CH3:21][CH:22]([C:26]([NH:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[C:32]([O:38][CH3:39])[CH:31]=1)=[O:27])[C:23](O)=[O:24]>>[CH3:39][O:38][C:32]1[CH:31]=[C:30]([CH:35]=[CH:34][C:33]=1[O:36][CH3:37])[CH2:29][NH:28][C:26](=[O:27])[CH:22]([CH3:21])[C:23]([NH:1][CH:2]1[C:3](=[O:20])[N:4]([CH3:19])[C:5]2[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=2[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:8]1)=[O:24]
Reactant: COc1ccc(CNC(=O)C(C)C(=O)O)cc1OC
Reactant: CN1C(=O)C(N)N=C(c2ccccc2)c2ccccc21
Product: COc1ccc(CNC(=O)C(C)C(=O)NC2N=C(c3ccccc3)c3ccccc3N(C)C2=O)cc1OC

Procedure:
The title compound, MS: m/e=515.3 (M+H+), was prepared in analogy to example 16 from 3-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one and 2-methyl-N-(3,4-dimethoxy-benzyl)-malonamic acid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[C:17]([C:22](=[O:29])[NH:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])[CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:30](OC(OCC)OCC)C>>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[CH:16]=[C:17]3[C:18](=[CH:19][CH:20]=2)[N:21]=[CH:30][N:23]([CH2:24][C:25]([O:27][CH3:28])=[O:26])[C:22]3=[O:29])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(OCC)OCC
Reactant: COC(=O)CNC(=O)c1cc(N2CCCN(C(=O)OC(C)(C)C)CC2)ccc1N
Product: COC(=O)Cn1cnc2ccc(N3CCCN(C(=O)OC(C)(C)C)CC3)cc2c1=O
Reaction time: 18 h

Procedure:
4-[4-Amino-3-(methoxycarbonylmethyl-carbamoyl)-phenyl]-[1,4]diazepane-1-carboxylic acid tert-butyl ester (30.6 g) was treated with 375 mL of triethylorthoformate at 125° C. with stirring for 18 hours. At this time, reaction mixture was concentrated in vacuo and the resulting residue was taken up in ethyl acetate and water. The organic phase was washed thrice with 10% KHSO4 aqueous solution, once with water, once with brine. The organic layer was then dried over magnesium sulfate and was filtered. The filtrate was concentrated in vacuo. The product was purified by flash column chromatography (500 g of silica) eluting with 60% to 70% ethyl acetate in hexane. Appropriate fractions were collected and evaporated to dryness. The resulting residue was dissolved in diethyl ether and re-evaporated; this dissolution and re-evaporated was repeated using pentane. All solids obtained as foams were pooled, resulting in a total yield of 15.56 g of 4-(3-methoxycarbonylmethyl-4-oxo-3,4-dihydro-quinazolin-6-yl)-[1,4]diazepane-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [C:1]([O:5][C:6](=[O:42])[CH2:7][CH2:8][S:9][CH2:10][C:11]1[CH:12]=[C:13]([CH:39]=[CH:40][CH:41]=1)[C:14]([NH:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[CH:19][C:18]=1[C:29]1[CH:30]=[C:31]([CH:36]=[CH:37][N:38]=1)[C:32]([O:34]C)=[O:33])=[O:15])([CH3:4])([CH3:3])[CH3:2].O.[OH-].[Li+]>O1CCCC1.O>[C:1]([O:5][C:6](=[O:42])[CH2:7][CH2:8][S:9][CH2:10][C:11]1[CH:12]=[C:13]([CH:39]=[CH:40][CH:41]=1)[C:14]([NH:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[CH:19][C:18]=1[C:29]1[CH:30]=[C:31]([CH:36]=[CH:37][N:38]=1)[C:32]([OH:34])=[O:33])=[O:15])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccnc(-c2cc(N3CCCCC3)ccc2NC(=O)c2cccc(CSCCC(=O)OC(C)(C)C)c2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)CCSCc1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)O)ccn2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 50-mL round bottom flask, was placed a solution of methyl 2-(2-(3-((3-tert-butoxy-3-oxopropylthio)methyl)benzamido)-5-(piperidin-1-yl)phenyl)isonicotinate (160 mg, 0.27 mmol, 1.00 equiv) in tetrahydrofuran (5 mL), and a solution of lithium hydroxide hydrate (160 mg, 3.81 mmol, 14.02 equiv) in water (5 mL). The resulting solution was stirred overnight at room temperature. The resulting mixture was concentrated under vacuum. The solution was adjusted to pH 3 with hydrochloric acid (2 mol/L). The resulting solution was extracted with 3×10 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 3×10 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 140 mg (90%) of 2-(2-(3-((3-tert-butoxy-3-oxopropylthio)methyl)benzamido)-5-(piperidin-1-yl)phenyl)isonicotinic acid as a yellow semi-solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH2:9])=[C:4]([F:10])[CH:3]=1.[CH3:11][S:12](Cl)(=[O:14])=[O:13]>N1C=CC=CC=1.ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][S:12]([CH3:11])(=[O:14])=[O:13])=[C:4]([F:10])[CH:3]=1
Reactant: NCc1ccc(Br)cc1F
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)NCc1ccc(Br)cc1F
Reaction time: 1 h
Yield: 94.2 %

Procedure:
To a stirred solution of (4-bromo-2-fluorophenyl)methanamine (5.834 g, 28.592 mmol) in pyridine were added methanesulfonyl chloride (4.2 mL, 54.325 mmol) at 0° C. The reaction mixture was stirred for 1 h, then diluted with dichloromethane. The mixture was washed with water. The organic layer was dried over magnesium sulfate and filtered. The filtrate was removed in vacuo. The crude was purified by column chromatography to give N-(4-bromo-2-fluorobenzyl)methanesulfonamide (7.597 g, 93%).
Reaction SMILES: [C:1]([CH2:3][NH:4][C:5]([C:7]1([NH2:13])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)=[O:6])#[N:2].Cl.[CH:15]1([N:20]2[CH2:25][CH2:24][CH:23]([C:26]3[CH:34]=[CH:33][C:29]([C:30](O)=[O:31])=[CH:28][CH:27]=3)[CH2:22][CH2:21]2)[CH2:19][CH2:18][CH2:17][CH2:16]1.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C>CN(C=O)C>[C:1]([CH2:3][NH:4][C:5]([C:7]1([NH:13][C:30](=[O:31])[C:29]2[CH:28]=[CH:27][C:26]([CH:23]3[CH2:22][CH2:21][N:20]([CH:15]4[CH2:19][CH2:18][CH2:17][CH2:16]4)[CH2:25][CH2:24]3)=[CH:34][CH:33]=2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)=[O:6])#[N:2]
Reactant: O=C(O)c1ccc(C2CCN(C3CCCC3)CC2)cc1
Reactant: N#CCNC(=O)C1(N)CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: N#CCNC(=O)C1(NC(=O)c2ccc(C3CCN(C4CCCC4)CC3)cc2)CCCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-Amino-cyclohexanecarboxylic acid cyanomethyl-amide (0.74 mmol), 4-(1-cyclopentyl-piperidin-4-yl)-benzoic acid hydrochloride (0.74 mmol), HOBT (0.74 mmol), WSCD (0.74 mmol) and triethylamine (0.74 mmol) are dissolved in DMF (5 ml) and stirred overnight at rt. After evaporation of the solvent, the residue is dissolved in a mixture of water and sodium carbonate (to ensure basic conditions) and extracted three times with ethyl acetate. The combined extract is dried over sodium sulfate and evaporated. The residue is suspended in diethylether and the solid filtered of and dried (vacuum). A white powder with mp. 233-234° C., Rf=0.34 (CH2Cl2/MeOH (with 3N NH3)=9:1) is obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([C:7]([NH:9][C:10]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:11]=2[CH:12]=[CH:13][NH:14]3)=[O:8])=[C:5](OCC2CO2)[CH:4]=1.C(N)(C)(C)C>C(O)C>[NH:14]1[C:15]2[C:11](=[C:10]([NH:9][C:7](=[O:8])[C:6]3[CH:19]=[CH:20][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[CH:18]=[CH:17][CH:16]=2)[CH:12]=[CH:13]1
Reactant: COc1ccc(C(=O)Nc2cccc3[nH]ccc23)c(OCC2CO2)c1
Solvent: CCO
Solvent: CC(C)(C)N
Product: COc1ccc(C(=O)Nc2cccc3[nH]ccc23)cc1

Procedure:
Using the procedure of Step E of Example 52, 6 g of the product of Step B, 100 ml of ethanol, 9.2 ml of tert.-butylamine were refluxed for 3 hours to obtain 6.1 g of 2-[3-(1,1-dimethylethyl)-amino]-2-hydroxypropoxy]-N-(1H-indol-4-yl)-4-methoxy-benzamide. The product was dissolved in 300 ml of refluxing isopropanol and 1.8 g of benzoic acid were added thereto. The mixture was partially concentrated, iced and filtered and the product was dried under reduced pressure to obtain 5.1 g of the benzoate salt melting at 195° C. after crystallization from ethanol.
Reaction SMILES: [CH:1]1([O:32]P([O-])([O-])=O)[CH:6]([O:7]P([O-])([O-])=O)[CH:5]([O:12]P([O-])([O-])=O)[CH:4]([O:17]P([O-])([O-])=O)[CH:3]([O:22]P([O-])([O-])=O)[CH:2]1[O:27]P([O-])([O-])=O.[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].N1C=CC=CC=1>O>[CH:6]1([OH:7])[CH:5]([OH:12])[CH:4]([OH:17])[CH:3]([OH:22])[CH:2]([OH:27])[CH:1]1[OH:32]
Reactant: O=P([O-])([O-])OC1C(OP(=O)([O-])[O-])C(OP(=O)([O-])[O-])C(OP(=O)([O-])[O-])C(OP(=O)([O-])[O-])C1OP(=O)([O-])[O-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: O
Product: OC1C(O)C(O)C(O)C(O)C1O
Temperature: 65 °C

Procedure:
Crystalline sodium phytate C (4 g) was dissolved with sonication in water (20 ml) and converted to the free acid by passage through a column of Dowex 50x8-200 ion-exchange resign. The column eluate was adjusted to pH 8 with pyridine and evaporated to dryness. The residue was dissolved in water (30 ml) and pyridine (130 ml) containing N,N-dicyclohexylcarbodiimide (8 g) was added. The reaction mixture was heated to 65° C. for 18 h and evaporated to dryness. The residue was extracted with water (4×10 ml) filtered and the filtrate was evaporated to dryness to give the pentapyridinium Salt of Myo-inositol 1,6:2,3:4,5-Tripyrophosphate (3.355 g, 77% yield). 31P-NMR (D2O) δ: −8.83 & −13.53 (AB, J=22.3 Hz, 2P, ax-eq), −9.82 & −10.00 (AB, J=17.8 Hz, 2P, eq-eq), −10.18 (AB as a singlet, 2P, eq-eq); 1H-NMR (D2O) δ: 8.65 (d, J=5.6 Hz, 10H), 8.48 (dd, J=7.9, 7.9 Hz, 5H), 7.94 (dd, J=7.0, 7.0 Hz, 10H), 5.00 (bd, J=10.5 Hz, 1H), 4.57 (ddd, J=9.6, 9.6, 5.5 Hz, 1H), 4.43-4.36 (m, 2H), 4.30-4.18 (m, 2H); 13C-NMR (D2O) δ: 147.0, 140.9, 127.3, 77.9 (t, J=6.8 Hz), 76.4-76.0 (m), 75.4-75.0 (m), 73.8 (t, J=6.8 Hz), 73.3 (bs), 72.8 (bs). The compound was then dissolved in water (30 ml) and passed through a column Dowex 50Wx8 Na+ form. The column eluate was concentrated to dryness to give Hexasodium Salt of Myo-inositol 1,6:2,3:4,5-Tripyrophosphate (2.25 g, 97%) and used for biological experiments in 98.5% purity without any further purification. The impurity is unreacted starting material (or tripyrophosphate hydrolyzed back to starting material). 31P-NMR (D2O) δ: −8.34 & −13.14 (AB, J=21.7 Hz, 2P, ax-eq), −9.53 & −9.70 (AB, J=17.8 Hz, 2P, eq-eq), −9.92 (AB as a singlet, 2P, eq-eq); 1H-NMR (D2O) δ: 5.04 (bd, J=10.5 Hz, 1H), 4.65-4.59 (m, 1H), 4.51-4.36 (m, 2H), 4.32-4.18 (m, 2H); 13C-NMR (D2O) δ: 77.1-76.8 (m), 76.5-76.0 (m), 75.4-75.0 (m), 74.1-73.9 (m), 73.7-73.2 (m), 73.2-72.5 (m).
Reaction SMILES: [CH3:1][C:2]([CH3:8])([C:5](=[O:7])[CH3:6])[C:3]#[N:4].[Cl:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=O)=[CH:12][C:11]=1[O:18][CH3:19]>>[Cl:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=[CH:6][C:5](=[O:7])[C:2]([CH3:8])([CH3:1])[C:3]#[N:4])=[CH:12][C:11]=1[O:18][CH3:19]
Reactant: CC(=O)C(C)(C)C#N
Reactant: COc1cc(C=O)ccc1Cl
Product: COc1cc(C=CC(=O)C(C)(C)C#N)ccc1Cl

Procedure:
The title compound was prepared from 2,2-dimethyl-3-oxo-butyronitrile {J. K. Rasmussen et al., Synthesis, 1973, 682} and 4-chloro-3-methoxy-benzaldehyde (F. Claudi et al., J. Med. Chem., 1992, 35, 4408) as described in Example 1 Step 1; MS (ES−) m/e 263, 265 [M−H]−.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.FC1C=CC(N2CCNCC2)=CC=1.[CH:26]1([CH2:29][CH2:30][NH:31][C:32]([C:34]2[N:35]=[N:36][C:37](Cl)=[CH:38][CH:39]=2)=[O:33])[CH2:28][CH2:27]1>>[CH:26]1([CH2:29][CH2:30][NH:31][C:32]([C:34]2[N:35]=[N:36][C:37]([N:10]3[CH2:9][CH2:8][N:7]([C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=4)[CH2:12][CH2:11]3)=[CH:38][CH:39]=2)=[O:33])[CH2:28][CH2:27]1
Reactant: c1ccc(N2CCNCC2)nc1
Reactant: O=C(NCCC1CC1)c1ccc(Cl)nn1
Agent: Fc1ccc(N2CCNCC2)cc1
Product: O=C(NCCC1CC1)c1ccc(N2CCN(c3ccccn3)CC2)nn1
Yield: 30 %

Procedure:
Following the procedure as described in Example 1, making variation only as required to use 1-pyridin-2-ylpiperazine to replace 1-(4-fluorophenyl)piperazine to react with 6-chloropyridazine-3-carboxylic acid (2-cyclopropylethyl)amide, the title compound was obtained as a white powder in 30% yield (0.036 g). 1H NMR (300 MHz, CDCl3) δ 8.19 (m, 1H), 8.01 (m, 1H), 7.50 (m, 1H), 7.00 (d, J=9.9 Hz, 1H), 6.67 (m, 2H), 3.89 (m, 4H), 3.75 (m, 4H), 3.54 (m, 2H), 1.50 (m, 2H), 0.74 (m, 1H), 0.45 (m, 2H), 0.09 (m, 2H). 13C NMR (75 MHz, CDCl3) δ 163.2, 160.2, 158.9, 147.9, 144.9, 137.8, 126.9, 113.8, 112.1, 107.2, 44.6, 39.6, 34.6, 8.67, 4.25. MS (ES+) m/z 353.6 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH3:14])[N:11]3[N:15]=[CH:16][C:17]([C:18]([OH:20])=O)=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.O[NH:22][C:23](=[NH:34])[C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([S:30](=[O:33])(=[O:32])[NH2:31])[CH:25]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[C:12]([CH3:14])[N:11]3[N:15]=[CH:16][C:17]([C:18]4[O:20][N:34]=[C:23]([C:24]5[CH:25]=[C:26]([S:30]([NH2:31])(=[O:32])=[O:33])[CH:27]=[CH:28][CH:29]=5)[N:22]=4)=[C:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: Cc1cc(-c2ccc(Cl)cc2)nc2c(C(=O)O)cnn12
Reactant: N=C(NO)c1cccc(S(N)(=O)=O)c1
Product: Cc1cc(-c2ccc(Cl)cc2)nc2c(-c3nc(-c4cccc(S(N)(=O)=O)c4)no3)cnn12

Procedure:
The title compound was prepared from 5-(4-chloro-phenyl)-7-methyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.24) (144 mg, 0.5 mmol) and N-hydroxy-3-sulfamoyl-benzamidine [CAS-No. 9000-88-7] (161 mg, 0.75 mmol) according to general procedure II. Obtained after purification by flash chromatography (ethyl acetate/heptane) and crystallization (MeOH/dichloromethane) as a light yellow solid (70 mg, 30%). MS (EI) 466.1 [(M)+]; mp 275° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].CS(O[CH2:17][CH2:18][NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])(=O)=O>>[C:23]([O:22][C:20]([NH:19][CH2:18][CH2:17][O:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6])=[O:21])([CH3:26])([CH3:25])[CH3:24]
Reactant: COC(=O)c1cccc(O)c1
Reactant: CC(C)(C)OC(=O)NCCOS(C)(=O)=O
Product: COC(=O)c1cccc(OCCNC(=O)OC(C)(C)C)c1

Procedure:
Coupling of methyl 3-hydroxybenzoate with 2-(tert-butoxycarbonylamino)ethyl methanesulfonate following the method used in Example 9 gave methyl 3-(2-(tert-butoxycarbonylamino)ethoxy)benzoate as a light yellow oil. Yield (0.65 g, 84%): 1H NMR (400 MHz, CD3OD) δ 7.36 (t, J=8.0 Hz, 1H), 7.26 (t, J=8.0 Hz, 1H), 7.16 (ddd, J=8.4, 2.4, 0.8 Hz, 1H), 6.99 (ddd, J=8.0, 2.4, 0.8 Hz, 1H), 4.03 (t, J=5.6 Hz, 2H), 3.78 (s, 3H), 1.43 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:4]=1[CH:5]=O.[NH2:13][OH:14].Cl.C([O-])(=O)C.[Na+]>C(O)C.O>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:4]=1[CH:5]=[N:13][OH:14]
Reactant: NO
Reactant: COc1ccc(OC)c(C=O)c1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1ccc(OC)c(C=NO)c1
Yield: 82.3 %

Procedure:
To 16.6 g (99.9 mmol) of 2,5-dimethoxybenzaldehyde in ethanol (100 mL) is added a mixture of 7.64 g (169 mmol) of H2NOH—HCl and 13.9 g (169 mmol) of sodium acetate in 50 mL of H2O. This reaction mixture is heated to reflux for 2.5 h. After adding H2O to dissolve the precipitated inorganic salt, ethanol is removed by evaporation in vacuo. The resulting white solid is filtered off and washed with H2O. 14.9 g of white solid are obtained (82%). 1H-NMR (CDCl3). δ [ppm]: 3.79 (s, 3H), 3.82 (s, 3H), 6.85 (d, 1H), 6.92 (d, 1H), 7.25 (d, 1H), 8.00 (broad s, 1H), 8.47 (s, 1H).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[S:7][CH:8]=[CH:9][N:10]=1.CCCCCC.C([Li])CCC.[F:22][C:23]([F:30])([F:29])[C:24](OCC)=[O:25].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[S:7][C:8]([CH:24]([OH:25])[C:23]([F:30])([F:29])[F:22])=[CH:9][N:10]=1
Reactant: c1csc(C2OCCO2)n1
Reactant: CCOC(=O)C(F)(F)F
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: OC(c1cnc(C2OCCO2)s1)C(F)(F)F
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 78.8 %

Procedure:
To a solution of 2-(1,3-dioxolan-2-yl)-1,3-thiazole (2.00 g) in tetrahydrofuran (50 mL) was slowly added a 1.6M n-butyllithium hexane solution (8.7 mL) at −70° C. under a nitrogen atmosphere. The reaction mixture was stirred at −70° C. for 30 min, and ethyl trifluoroacetate (5.4 g) was added. The reaction mixture was warmed to room temperature, 10% aqueous citric acid solution was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The obtained residue was dissolved in methanol (30 mL), and sodium borohydride (0.27 g) was added by small portions at 0° C. The reaction mixture was stirred at 0° C. for 30 min, 10% aqueous citric acid solution was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The obtained residue was subjected to silica gel column chromatography, and the title compound (2.56 g, yield 79%) was obtained as a yellow oil from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio). MS: 256 (MH+).
Reaction SMILES: C[O:2][C:3](=[O:32])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[S:12][C:13]3[CH:19]=[C:18]([CH:20]([N:27]4[CH:31]=[CH:30][N:29]=[CH:28]4)[CH:21]([N:24]([CH3:26])[CH3:25])[CH2:22][CH3:23])[CH:17]=[CH:16][C:14]=3[N:15]=2)=[CH:6][CH:5]=1.O.[OH-].[Li+]>O1CCOCC1.O>[CH3:25][N:24]([CH3:26])[CH:21]([CH2:22][CH3:23])[CH:20]([C:18]1[CH:17]=[CH:16][C:14]2[N:15]=[C:11]([NH:10][C:7]3[CH:8]=[CH:9][C:4]([C:3]([OH:32])=[O:2])=[CH:5][CH:6]=3)[S:12][C:13]=2[CH:19]=1)[N:27]1[CH:31]=[CH:30][N:29]=[CH:28]1
Reactant: CCC(C(c1ccc2nc(Nc3ccc(C(=O)OC)cc3)sc2c1)n1ccnc1)N(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CCC(C(c1ccc2nc(Nc3ccc(C(=O)O)cc3)sc2c1)n1ccnc1)N(C)C
Temperature: 50 °C
Reaction time: 4 h

Procedure:
A mixture of methyl-4-((6-(2-(dimethylamino)-1-(1H-imidazol-1-yl)butyl)-benzo[d]thiazol-2-yl)amino)benzoate (46 mg, 0.10 mmol) and lithium hydroxide monohydrate (21 mg, 0.51 mmol) in 4 mL of dioxane and 2 mL of water was heated together with stirring at 50° C. for 4 hr. The mixture was concentrated in vacuo and the residue dissolved in about 2 mL of water. The solution was neutralized with 1N HCl then concentrated again in vacuo. The residue was purified by PTLC using two, 2 mm silica plates eluting with 20% MeOH/DCM to give 4-((6-(2-(Dimethylamino)-1-(1H-imidazol-1-yl)butyl)benzo[d]thiazol-2-yl)amino)benzoic acid. MS (ESI) m/z 436.22 [M+H]
Reaction SMILES: [CH:1]([C:4]([NH:6][CH2:7][CH2:8][NH2:9])=[O:5])([CH3:3])[CH3:2].[CH2:10]1[O:12][CH:11]1[CH2:13][OH:14]>C(O)(C)C>[CH3:2][CH:1]([C:4]([NH:6][CH2:7][CH2:8][NH:9][CH2:10][CH:11]([OH:12])[CH2:13][OH:14])=[O:5])[CH3:3]
Reactant: OCC1CO1
Reactant: CC(C)C(=O)NCCN
Solvent: CC(C)O
Product: CC(C)C(=O)NCCNCC(O)CO
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To 39 g (0.3 mol) of 2-(isopropylcarbonylamino)ethylamine in 150 ml of isopropyl alcohol was added 22.2 g (0.3 mol) of glycidol. The reaction mixture was stirred at 25° C. for 24 hours and evaporated in vacuo. The residual oil was chromatographed (silica gel/ethanol) to give18.6 g (30%) of product. This compound was identified by NMR and IR spectroscopy.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:14]2[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=2)[N:5]2[C:10]=1[CH:9]=[N:8][C:7](S(C)=O)=[N:6]2.[CH3:24][N:25]1[CH2:30][CH2:29][N:28]([C:31]2[CH:36]=[CH:35][C:34]([NH2:37])=[CH:33][CH:32]=2)[CH2:27][CH2:26]1.CN1CCCC1=O>>[Br:1][C:2]1[CH:3]=[C:4]([C:14]2[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=2)[N:5]2[C:10]=1[CH:9]=[N:8][C:7]([NH:37][C:34]1[CH:33]=[CH:32][C:31]([N:28]3[CH2:27][CH2:26][N:25]([CH3:24])[CH2:30][CH2:29]3)=[CH:36][CH:35]=1)=[N:6]2
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Reactant: CS(=O)c1ncc2c(Br)cc(-c3ccc(S(C)(=O)=O)cc3)n2n1
Solvent: CN1CCCC1=O
Product: CN1CCN(c2ccc(Nc3ncc4c(Br)cc(-c5ccc(S(C)(=O)=O)cc5)n4n3)cc2)CC1
Temperature: 150 °C
Yield: 43.5 %

Procedure:
Into a 30 mL vial, 5-Bromo-2-methanesulfinyl-7-(4-methanesulfonyl-phenyl)-pyrrolo[2,1-f][1,2,4]triazine (0.14 g, 0.00034 mol), 4-(4-Methyl-piperazin-1-yl)-phenylamine (0.194 g, 0.00101 mol), and N-Methylpyrrolidinone (0.22 mL, 0.0023 mol) were added. The mixture was heated at 150° C. for 3 hours. The mixture was purified via ISCO column chromatography with DCM and MeOH as eluant (0 to 15% methanol). The collected fractions afforded [5-Bromo-7-(4-methanesulfonyl-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl]-[4-(4-methyl-piperazin-1-yl)-phenyl]-amine as a yellow solid (80 mg, 44%). MP 265-266° C. LCMS (E/I+) 543.11 (M+H). NMR 1H (DSMO-d6)-9.49 (s, 1H), 8.93 (s, 1H), 8.45 (d, 2H, J=8.56 Hz), 8.03 (d, 2H, J=8.60 Hz), 7.55 (d, 2H, J=9.01 Hz), 7.35 (s, 1H), 6.96 (d, 2H, J=9.08 Hz), 3.39 (s, 3H), 3.10 (t, 4H, J=5.00 Hz), 2.47 (t, 4H, J=5.13 Hz), 2.23 (s, 3H).