Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][C:5]=1[NH2:14].CC(O)=O.[O-:20][C:21]#[N:22].[K+].[O-]C#N>O>[NH2:22][C:21]([NH:14][C:5]1[CH:6]=[C:7]([C:8]([O:10][CH3:11])=[O:9])[CH:12]=[CH:13][C:4]=1[C:3]([O:2][CH3:1])=[O:15])=[O:20]
Reactant: COC(=O)c1ccc(C(=O)OC)c(N)c1
Reactant: N#C[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)c1ccc(C(=O)OC)c(NC(N)=O)c1
Temperature: 60 °C
Reaction time: 16 h

Procedure:
To a 1 L flask charged with 2-aminoterephthalic acid dimethyl ester (29.4 g, 141 mmol) was added AcOH (160 mL) and the suspension heated to 60° C. until a solution was formed. A solution of potassium cyanate (23.4 g, 288 mmol) in water (50 mL) was then added to the stirred solution at 60° C. Effervescence was seen and a white ppt crashed out immediately, hindering stirring. AcOH was added (70 mL) to aid stirring and the suspension was stirred at 75° C. for 7 hrs. Another 1 eq of cyanate added portion wise (dry). More effervescence was seen and the reaction left for 16 hours at 70° C. The reaction was cooled to 0° C. and the product ppt was filtered off, the flask washed with water to get all product out. The material was washed with water (150 mL) and air dried o/n under vacuum. The crude product was suspended in MeOH (300 mL) and stirred under reflux for 1 hour. The suspension was cooled to room temperature and filtered. The product was washed with cold MeOH (300 mL) and ether and dried in vacuo to afford the title compound as a white solid, 31.5 g, 89%. 1H NMR (400 MHz, DMSO-D6) δ ppm 9.71 (1H, s) 8.97 (1H, s) 7.98 (1H, d, J=8.08 Hz) 7.46-7.57 (1H, m) 6.73 (2H, s) 3.88 (6H, s).
Reaction SMILES: [CH3:1][N:2]([CH3:18])[CH:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][CH:10]=2)[CH2:5][CH2:4]1.[C:19](C1NC=CN=1)(C1NC=CN=1)=[S:20].O>CN(C=O)C>[N:15]([C:12]1[CH:13]=[CH:14][C:9]([N:6]2[CH2:7][CH2:8][CH:3]([N:2]([CH3:18])[CH3:1])[CH2:4][CH2:5]2)=[CH:10][CH:11]=1)=[C:19]=[S:20]
Reactant: CN(C)C1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Reactant: S=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)C1CCN(c2ccc(N=C=S)cc2)CC1
Temperature: 25 °C
Reaction time: 1.33 h

Procedure:
Dimethyl-[1-(4-nitro-phenyl)-piperidin-4-yl]-amine (Example 2, 1.1 g, 5.0 mmol) was dissolved in DMF (5 mL). To the stirred solution, thiocarbonyl diimidazole (Aldrich, 1.18 g, 90%, 6 mmol) was added and the solution was stirred at room temperature for 80 minutes. The mixture was poured into water and extracted with diethyl ether. The extract was dried with sodium sulfate and concentrated to give a pale yellow solid. 1.12 g, 85%. MS (m+H)+: 262.
Reaction SMILES: [CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([CH2:27][CH:28]4[CH2:33][O:32][CH2:31][CH2:30][NH:29]4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:34][N:35]([CH3:40])[CH2:36][C:37](O)=[O:38].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([CH2:27][CH:28]4[CH2:33][O:32][CH2:31][CH2:30][N:29]4[C:37](=[O:38])[CH2:36][N:35]([CH3:40])[CH3:34])[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)CC(=O)O
Reactant: Nc1ncnn2c(CC3COCCN3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)CC(=O)N1CCOCC1Cc1cc(-c2ccc3cn(Cc4ccccc4)nc3c2)c2c(N)ncnn12
Temperature: 25 °C
Reaction time: 16 h
Yield: 41.4 %

Procedure:
A mixture of 5-(2-benzyl-2H-indazol-6-yl)-7-(morpholin-3-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (100 mg, 0.23 mmol), N,N-dimethylglycine (25 mg, 0.24 mmol), EDCl (48 mg, 0.25 mmol), HOBt (34 mg, 0.25 mmol), and N,N-diisopropylethylamine (119 μL, 0.68 mmol) in DMF (1.2 mL) was stirred at rt for 16 h. The crude mixture was purified by preparative HPLC using a gradient elution from 15% to 45% acetonitrile in water followed by filtration through an acidic resin, washing with MeOH. The product was eluted with 2M NH3 in MeOH and the filtrate was concentrated to provide 50 mg (42%) of the desired product. 1H NMR (400 MHz, DMSO-d6) δ 8.52-8.57 (m, 1 H), 7.88-7.96 (m, 1H), 7.76-7.84 (m, 1 H), 7.48-7.55 (m, 1 H), 7.26-7.39 (m, 5 H), 7.04-7.11 (m, 1 H), 6.58-6.63 (m, 1 H), 5.64 (s, 2 H), 4.43-4.89 (m, 1 H), 3.69-4.12 (m, 3 H), 3.24-3.57 (m, 4 H), 3.09-3.23 (m, 1 H), 2.72-2.99 (m, 1 H), 2.15-2.27 (m, 1 H), 1.88-1.99 (m, 6H); ES-MS m/z 525.15 [M+H]+, HPLC RT (min) 2.17.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:17]([N+:18]([O-:20])=[O:19])=[C:16]([O:21][CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[N:15]=[CH:14][N:13]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].C(N(CC)CC)C.[CH3:35][S:36](Cl)(=[O:38])=[O:37]>CN(C=O)C>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:17]([N+:18]([O-:20])=[O:19])=[C:16]([O:21][CH:22]3[CH2:27][CH2:26][N:25]([S:36]([CH3:35])(=[O:38])=[O:37])[CH2:24][CH2:23]3)[N:15]=[CH:14][N:13]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1ccc(Nc2ncnc(OC3CCNCC3)c2[N+](=O)[O-])cc1
Reactant: CS(=O)(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)c1ccc(Nc2ncnc(OC3CCN(S(C)(=O)=O)CC3)c2[N+](=O)[O-])cc1

Procedure:
Compound A27 was prepared in a similar manner as described above using (4-methanesulfonyl-phenyl)-[5-nitro-6-(piperidin-4-yloxy)-pyrimidin-4-yl]-amine (i.e., Compound A2) (15 mg, 0.035 mmol), triethylamine (50 μl), methanesulfonyl chloride (10 mg, 0.087 mmol), DMF (1 mL), 1H NMR (CDCl3, 400 MHz) δ 2.13 (m,4H), 2.85 (s, 3H), 3.08 (s, 3H), 3.31 (m, 2H), 3.57 (m, 2H), 4.13 (m, 1H), 5.69 (m, 1H), 7.87 (d,2H), 7.98 (d,2H), 8.42 (s, 1H), 10.21 (s, 1H). Exact mass calculated for C14H21N5O7S2 471.09, found 472.3 (MH+).
Reaction SMILES: [C:1]([O:6]C)(=O)[C:2]([CH3:4])=[CH2:3].[CH:8]([NH2:11])([CH3:10])[CH3:9]>Cl.C(N)(C)C>[CH:8]([NH:11][C:1](=[O:6])[C:2]([CH3:4])=[CH2:3])([CH3:10])[CH3:9]
Reactant: CC(C)N
Reactant: C=C(C)C(=O)OC
Agent: Cl
Product: C=C(C)C(=O)NC(C)C
Yield: 69.5 %

Procedure:
500 g (5 mols) of methyl methacrylate, 325 g (5.5 mols) of isopropylamine, and 12.4 g (0.13 mol) of isopropylamine hydrochloride were reacted in the presence of 0.03 mol of ferric acetylacetonate for 21/2 hours in a steel autoclave at 220° C. The pressure increased to a maximum of 18 atmospheres. The methyl methacrylate reacted to the extent of 80% and gave 442 g of N-isopropylmethacrylic acid amide (corresponding to a 68% yield referred to the methyl methacrylate used).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]1[N:18]=[CH:17][C:16]2[C:19]([C:22]3[CH:23]=[N:24][N:25]([CH2:27][C:28]([OH:30])=O)[CH:26]=3)=[N:20][NH:21][C:15]=2[CH:14]=1.[CH3:31][O:32][CH:33]1[CH2:37][CH2:36][NH:35][CH2:34]1>>[Cl:12][C:4]1[C:5]([O:10][CH3:11])=[CH:6][C:7]([O:8][CH3:9])=[C:2]([Cl:1])[C:3]=1[C:13]1[N:18]=[CH:17][C:16]2[C:19]([C:22]3[CH:23]=[N:24][N:25]([CH2:27][C:28]([N:35]4[CH2:36][CH2:37][CH:33]([O:32][CH3:31])[CH2:34]4)=[O:30])[CH:26]=3)=[N:20][NH:21][C:15]=2[CH:14]=1
Reactant: COC1CCNC1
Reactant: COc1cc(OC)c(Cl)c(-c2cc3[nH]nc(-c4cnn(CC(=O)O)c4)c3cn2)c1Cl
Product: COc1cc(OC)c(Cl)c(-c2cc3[nH]nc(-c4cnn(CC(=O)N5CCC(OC)C5)c4)c3cn2)c1Cl

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 36, Step 2, starting from {4-[6-(2,6-dichloro-3,5-dimethoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-3-yl]-1H-pyrazol-1-yl}acetic acid and 3-methoxypyrrolidine. LCMS (M+H)+=531.2/533.2.
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[CH2:7][C@H:8]([C:18]1[O:22][N:21]=[C:20]([C:23]([O:25]CC)=O)[N:19]=1)[CH2:9][CH2:10][CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)([CH3:4])([CH3:3])[CH3:2].[CH3:29][N:30]([CH3:36])[CH2:31][CH2:32][CH2:33][NH:34][CH3:35]>C(O)C>[CH:12]1([CH2:11][CH2:10][CH2:9][C@@H:8]([C:18]2[O:22][N:21]=[C:20]([C:23]([N:34]([CH2:33][CH2:32][CH2:31][N:30]([CH3:36])[CH3:29])[CH3:35])=[O:25])[N:19]=2)[CH2:7][C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:28])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]1
Reactant: CNCCCN(C)C
Reactant: CCOC(=O)c1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1
Solvent: CCO
Product: CN(C)CCCN(C)C(=O)c1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1
Temperature: 85 °C
Yield: 78.7 %

Procedure:
A solution of ethyl 5-{(1R)-1-[2-(tert-butoxy)-2-oxoethyl]-4-cyclohexylbutyl}-1,2,4-oxadiazole-3-carboxylate (Preparation 3) (550 mg, 1.40 mmol) in ethanol (2 ml) was treated with N,N,N′-trimethyl-1,3-propanediamine (1.02 ml, 7.00 mmol) and the resulting mixture was heated at 85° C. in a sealed tube for 3 hours. The solvent removed under reduced pressure. The residue was purified by column chromatography on silica eluting with a gradient system of 97:3:0.3 (dichloromethane:methanol:ammonia) gradually changing to 90:10:1 (dichloromethane:methanol:ammonia) to afford the title compound as a colourless oil (512 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:14]([O:15][CH3:16])=[CH:13][C:6]2[CH2:7][C:8](=O)[NH:9][CH2:10][CH2:11][C:5]=2[CH:4]=1.B.C1COCC1.C(O)C.[ClH:26]>C1COCC1>[ClH:26].[CH3:1][O:2][C:3]1[C:14]([O:15][CH3:16])=[CH:13][C:6]2[CH2:7][CH2:8][NH:9][CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: COc1cc2c(cc1OC)CC(=O)NCC2
Agent: B
Agent: Cl
Solvent: CCO
Solvent: C1CCOC1
Product: COc1cc2c(cc1OC)CCNCC2
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
22.13 g (100 mmol) of the product obtained in Step 1, suspended in 250 mL of THF, are cooled to 0° C. There are then added, dropwise, over 15 minutes, 250 mL of borane/THF (1M in the THF) and heating is carried out at 80° C. for 24 hours. Cooling is carried out and there are then added, dropwise, 250 mL of ethanol, and then 2.6N ethanolic HCl. Heating at reflux is carried out for 40 minutes; some light insoluble material is filtered off and evaporation to dryness is carried out. The residue thereby obtained is recrystallised from a mixture of 150 mL of isopropanol and 20 mL of water to yield the desired product.
Reaction SMILES: [C:1]1([C:7]2[N:12]=[C:11]([O:13][CH:14]3[CH2:31][CH:30]4[CH:16]([C:17](=[O:37])[N:18]([CH3:36])[CH2:19][CH2:20][CH2:21][CH2:22][CH:23]=[CH:24][CH:25]5[C:27]([C:33](O)=[O:34])([NH:28][C:29]4=[O:32])[CH2:26]5)[CH2:15]3)[CH:10]=[C:9]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:44]1([S:47]([NH2:50])(=[O:49])=[O:48])[CH2:46][CH2:45]1.CCN=C=NCCCN(C)C.C1CCN2C(=NCCC2)CC1>C(Cl)Cl>[C:1]1([C:7]2[N:12]=[C:11]([O:13][CH:14]3[CH2:31][CH:30]4[CH:16]([C:17](=[O:37])[N:18]([CH3:36])[CH2:19][CH2:20][CH2:21][CH2:22][CH:23]=[CH:24][CH:25]5[C:27]([C:33]([NH:50][S:47]([CH:44]6[CH2:46][CH2:45]6)(=[O:49])=[O:48])=[O:34])([NH:28][C:29]4=[O:32])[CH2:26]5)[CH2:15]3)[CH:10]=[C:9]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NS(=O)(=O)C1CC1
Reactant: CN1CCCCC=CC2CC2(C(=O)O)NC(=O)C2CC(Oc3cc(-c4ccccc4)nc(-c4ccccc4)n3)CC2C1=O
Agent: CCN=C=NCCCN(C)C
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: CN1CCCCC=CC2CC2(C(=O)NS(=O)(=O)C2CC2)NC(=O)C2CC(Oc3cc(-c4ccccc4)nc(-c4ccccc4)n3)CC2C1=O
Yield: 62.4 %

Procedure:
The acid 17f (240 mg, 0.41 mmol) was reacted with cyclopropane sulfonamide (63 mg, 0.52 mmol), EDAC (105 mg, 0.55 mmol) and DBU (182 mg, 1.2 mmol) in dry DCM according to the procedure described in Example 13 step f. Purification by column chromatography on silica gel eluted with diethyl ether-ethyl acetate gave the title compound, (175 mg, 62%), (M+H)+684.
Reaction SMILES: [N+:1]([C:4]1[CH:21]=[CH:20][C:7]([C:8]([N:10]2[CH2:16][CH2:15][CH2:14][CH2:13][C:12]3[S:17][CH:18]=[CH:19][C:11]2=3)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[O-:22]S([O-])(=O)=O.[Mg+2].O.[O-][Mn](=O)(=O)=O.[K+]>CC(C)=O>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:8]([N:10]2[CH2:16][CH2:15][CH2:14][C:13](=[O:22])[C:12]3[S:17][CH:18]=[CH:19][C:11]2=3)=[O:9])=[CH:20][CH:21]=1)([O-:3])=[O:2]
Reactant: O=S(=O)([O-])[O-]
Reactant: O=C(c1ccc([N+](=O)[O-])cc1)N1CCCCc2sccc21
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Agent: [Mg+2]
Solvent: CC(C)=O
Solvent: O
Product: O=C1CCCN(C(=O)c2ccc([N+](=O)[O-])cc2)c2ccsc21
Temperature: 70 °C
Reaction time: 8 h
Yield: 60.5 %

Procedure:
To a solution of 9.0 g of 4-(4-nitrobenzoyl)-5,6,7,8-tetrahydro-4H-thieno[3,2-b]azepine in 713 ml of acetone is added 6.74 g of MgSO4 and 351 ml of water followed by 8.2 g of KMnO4 and heating at 70° C. for 18 hours. Another 6.24 g of MgSO4 and 8.2 g of KMnO4 is added and heating continued at 70° C. for 8 hours. An additional 6.24 g of MgSO4 and 8.2 g of KMnO4 is added and heating continued at 70° C. for 18 hours. The reaction mixture is filtered through diatomaceous earth and the cake washed with acetone and 500 ml of methylene chloride. The combined filtrates are evaporated in vacuo to a residue which is washed with water and air dried to give 5.7 g of a solid. The solid is crystallized from ethyl acetate to give 5.1 g of off white solid, m.p. 184°-186° C.
Reaction SMILES: [CH3:1][O:2][C@@H:3]([C@@H:21]1[CH2:25][CH2:24][CH2:23][N:22]1[C:26](=[O:45])[CH2:27][C@@H:28]([O:43][CH3:44])[C@@H:29]([N:34]([CH3:42])[C:35](=[O:41])[C@H:36]([CH:38]([CH3:40])[CH3:39])[NH2:37])[C@@H:30]([CH3:33])[CH2:31][CH3:32])[C@@H:4]([CH3:20])[C:5]([NH:7][C@H:8]([C:16]([O:18][CH3:19])=[O:17])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[S:6].[CH:46]1[C:58]2[CH:57]([CH2:59][O:60][C:61]([N:63]([CH3:70])[C:64]([CH3:69])([C:66](O)=[O:67])[CH3:65])=[O:62])[C:56]3[C:51](=[CH:52][CH:53]=[CH:54][CH:55]=3)[C:50]=2[CH:49]=[CH:48][CH:47]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>ClCCl>[CH:55]1[C:56]2[CH:57]([CH2:59][O:60][C:61]([N:63]([CH3:70])[C:64]([CH3:65])([C:66]([NH:37][C@H:36]([C:35]([N:34]([C@@H:29]([C@@H:30]([CH3:33])[CH2:31][CH3:32])[C@H:28]([O:43][CH3:44])[CH2:27][C:26]([N:22]3[CH2:23][CH2:24][CH2:25][C@H:21]3[C@H:3]([O:2][CH3:1])[C@@H:4]([CH3:20])[C:5]([NH:7][C@@H:8]([CH2:9][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:16]([O:18][CH3:19])=[O:17])=[S:6])=[O:45])[CH3:42])=[O:41])[CH:38]([CH3:39])[CH3:40])=[O:67])[CH3:69])=[O:62])[C:58]3[C:50](=[CH:49][CH:48]=[CH:47][CH:46]=3)[C:51]=2[CH:52]=[CH:53][CH:54]=1
Reactant: CN(C(=O)OCC1c2ccccc2-c2ccccc21)C(C)(C)C(=O)O
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=S)N[C@@H](Cc1ccccc1)C(=O)OC)OC)N(C)C(=O)[C@@H](N)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=S)N[C@@H](Cc1ccccc1)C(=O)OC)OC)N(C)C(=O)[C@@H](NC(=O)C(C)(C)N(C)C(=O)OCC1c2ccccc2-c2ccccc21)C(C)C

Procedure:
According to general procedure D, from #77 (399 mg, ≦0.52 mmol, 1 eq.), N-[(9H-fluoren-9-ylmethoxy)carbonyl]-N,2-dimethylalanine (213 mg, 0.628 mmol, 1.2 eq.), dichloromethane (5 mL, 0.1 M), HATU (239 mg, 0.628 mmol, 1.2 eq.) and diisopropylethylamine (282 μL, 1.62 mmol, 3.1 eq.) was synthesized the crude desired material, which was purified by silica gel chromatography (Gradient: 0% to 50% acetone in heptane), providing #78 (231 mg, 46% over two steps). LC-MS: m/z 970.7 [M+H+], 992.6 [M+Na+], retention time=1.11 minutes; HPLC (Protocol C): retention time=9.260 minutes; 1H NMR (400 MHz, DMSO-d6), presumed to be a mixture of rotamers, characteristic signals: δ [10.19 (d, J=7.4 Hz) and 10.47 (d, J=7.8 Hz), total 1H], 7.89 (d, J=7.4 Hz, 2H), 7.61-7.67 (m, 2H), 7.41 (br dd, J=7.4, 7.4 Hz, 2H), 7.14-7.36 (m, 8H), [5.20 (ddd, J=11, 7, 5 Hz) and 5.38 (ddd, J=11, 8, 4 Hz), total 1H], [4.41 (dd, J=8.6, 8.4 Hz) and 4.46 (dd, J=8.2, 8.2 Hz), total 1H], 3.65 and 3.68 (2 s, total 3H), 3.23 and 3.24 (2 s, total 3H), 3.13 (br s, 3H), 2.88 and 2.93 (2 br s, total 3H), 2.84 and 2.85 (2 s, total 3H), 1.31 and 1.32 (2 s, total 3H), [1.15 (d, J=6.6 Hz) and 1.18 (d, J=6.4 Hz), total 3H].
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][C:10]=1[I:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20]([NH2:24])([CH3:23])([CH3:22])[CH3:21].O>CCCCCC>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([NH:24][C:20]([CH3:23])([CH3:22])[CH3:21])(=[O:17])=[O:16])=[CH:11][C:10]=1[I:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(OCc2ccccc2)c(I)c1
Reactant: CC(C)(C)N
Solvent: CCCCCC
Solvent: O
Product: CC(C)(C)NS(=O)(=O)c1ccc(OCc2ccccc2)c(I)c1
Temperature: 37.5 °C
Reaction time: 17 h
Yield: 94 %

Procedure:
A 3-neck, 3 L, round-bottom flask was equipped with an over-head stirrer, thermometer, and a pressure-equalizing dropping-funnel was charged with the solution of 4-benzyloxy-3-iodo-benzenesulfonyl chloride. The flask immersed in a cold water bath (Tint=22° C.) and tert-butylamine (90.1 g, 0.710 mol, 2.1 eq) was added drop-wise (Tint no change). The resulting reaction mixture was stirred overnight at the ambient water-bath temperature. After 17 h, the reaction mixture was worked-up and the organic layer was separated and concentrated to approx. ⅓ (˜500 mL) of its original volume at which point the product started to precipitate. The reaction mixture was warmed to 35-40° C. at atmospheric pressure till the solids had re-dissolved. The solution was then allowed to cool, with gentle stirring, to room temperature. Within 2 days a white precipitate had formed. The suspension was stirred vigorously while hexane (1.5 L) was slowly added, then stirred overnight, and then cooled in an ice-bath for 1-2 h The precipitate was collected by filtration and washed with hexane, dried, first under suction to give 4-benzyloxy-N-tert-butyl-3-iodo-benzenesulfonamide (238, 94%).
Reaction SMILES: [CH:1]1([C:4]2[N:8]([CH3:9])[C:7]3[CH:10]=[C:11]([N:14]4[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:15]4=[O:21])[CH:12]=[CH:13][C:6]=3[N:5]=2)[CH2:3][CH2:2]1.[F:22][C:23]1[S:27][C:26]([CH2:28]O)=[CH:25][CH:24]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1COCC1>[CH:1]1([C:4]2[N:8]([CH3:9])[C:7]3[CH:10]=[C:11]([N:14]4[CH:19]=[CH:18][C:17]([O:20][CH2:28][C:26]5[S:27][C:23]([F:22])=[CH:24][CH:25]=5)=[CH:16][C:15]4=[O:21])[CH:12]=[CH:13][C:6]=3[N:5]=2)[CH2:2][CH2:3]1
Reactant: Cn1c(C2CC2)nc2ccc(-n3ccc(O)cc3=O)cc21
Reactant: OCc1ccc(F)s1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: Cn1c(C2CC2)nc2ccc(-n3ccc(OCc4ccc(F)s4)cc3=O)cc21
Temperature: 60 °C
Reaction time: 4 h
Yield: 5 %

Procedure:
To a solution of 1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)-4-hydroxypyridin-2(1H)-one (127 mg), (5-fluorothiophen-2-yl)methanol (40 mg) and tributylphosphine (182 mg) in THF (15 ml) was added 1,1′-(azodicarbonyl)dipiperidine (227 mg), and the mixture was stirred at 60° C. for 4 h. The reaction mixture was then cooled to room temperature, and concentrated in vacuo. The residue was diluted with DCM, washed with water and brine successively, dried over Na2SO4, concentrated in vacuo and purified by column chromatography (MeOH/DCM) followed by preparative HPLC to afford the title compound (6 mg) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[C:13]([CH2:15][C:16](OCC)=[O:17])[CH:12]=[CH:11][N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(C[AlH]CC(C)C)C.O>C1COCC1>[OH:17][CH2:16][CH2:15][C:13]1[CH:12]=[CH:11][N:10]=[C:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:2])[CH3:4])[CH:14]=1
Reactant: CCOC(=O)Cc1ccnc(NC(=O)OC(C)(C)C)c1
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)Nc1cc(CCO)ccn1
Temperature: -69 °C
Reaction time: 0.67 h
Yield: 70.5 %

Procedure:
To a solution of ethyl 2-(2-(tert-butoxycarbonylamino)pyridin-4-yl)acetate (19) (WO 2007089512) (10.0 g, 35.7 mmol) under nitrogen in THF (100 mL), at −78° C., was added DIBAL (1M solution in THF, 71.3 mL, 71.3 mmol) over 1 hr. The reaction mixture was stirred at −78 to −60° C. for 40 min and then warmed to −15° C. over 1 hr. The solution was re-cooled to −78° C. and treated with further DIBAL (1M solution in THF, 35 mL, 35.7 mmol). The mixture was allowed to warm to −40° C. and stirred for 1 hr. Water (10 mL) was added cautiously to quench the reaction followed by MgSO4 (20 g) and the solids removed by filtration. The filtrate was evaporated to dryness in vacuo and the residue subjected to column chromatography (SiO2, 330 g, 65% EtOAc in hexanes) to give the title compound (20) (6.00 g, 64%) as a yellow solid: m/z 239 (M+H)+ (ES+).
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].[O:5]1[CH:7]([CH2:8][O:9][C:10]2[S:11][C:12]([C:15]([NH:17][CH2:18][CH2:19][CH2:20][CH:21]([CH3:24])[CH2:22][CH3:23])=[O:16])=[CH:13][N:14]=2)[CH2:6]1>C(O)C>[CH:1]([NH:4][CH2:6][CH:7]([OH:5])[CH2:8][O:9][C:10]1[S:11][C:12]([C:15]([NH:17][CH2:18][CH2:19][CH2:20][CH:21]([CH3:24])[CH2:22][CH3:23])=[O:16])=[CH:13][N:14]=1)([CH3:3])[CH3:2]
Reactant: CC(C)N
Reactant: CCC(C)CCCNC(=O)c1cnc(OCC2CO2)s1
Solvent: CCO
Product: CCC(C)CCCNC(=O)c1cnc(OCC(O)CNC(C)C)s1
Reaction time: 12 h

Procedure:
This example illustrates further methods according to the invention of preparing the compounds of formula I to the invention. In this example 0.6 g. of isopropylamine is added to a solution containing 0.3 g. of 1,2-epoxy-3-(5-4'-methylhexylaminocarbonylthiazol-2-oxy)-propane in 20 ml. of anhydrous absolute ethanol, and then allowed to stand for 12 hours at room temperature. The mixture is then evaporated to dryness and the resulting residue chromatographed on silica gel yielding 1-isopropylamino-3-(5-4'-methylhexylaminocarbonylthiazol-2-oxy)-2-propanol.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[NH:18])[C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:10]=2[OH:17])=[CH:4][CH:3]=1.C(O)C.Cl.[CH2:23]([O:25][C:26](=[O:34])[CH:27](N)[C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH3:24]>N1C=CC=CC=1>[CH2:23]([O:25][C:26](=[O:34])[CH:27]([N:18]=[C:8]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)[C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:10]=1[OH:17])[C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH3:24]
Reactant: COc1ccc(C(=N)c2ccc(Cl)cc2)c(O)c1
Reactant: CCOC(=O)C(N)C(=O)OCC
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: CCOC(=O)C(N=C(c1ccc(Cl)cc1)c1ccc(OC)cc1O)C(=O)OCC

Procedure:
10.5 G. of 4'-chloro-2-hydroxy-4-methoxy-benzophenone imine in 60 ml. of ethanol is reacted with 12.6 g. of aminomalonic acid diethyl ester hydrochloride and 5.0 ml. of pyridine in accordance with the procedure described in Example 2. After a single recrystallization of the crude product from ethanol, there is obtained {[2-hydroxy-4-methoxy-α-(4-chlorophenyl)benzyliden]amino}malonic acid diethyl ester, having a melting point of 73°-75° C.
Reaction SMILES: C(OC(N=NC(OCC)=O)=O)C.[NH2:13][C:14]1[S:15][C:16]2[CH2:17][CH2:18][N:19]([CH2:24][CH:25]=[CH:26][C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([OH:33])[CH:28]=3)[CH2:20][CH2:21][C:22]=2[N:23]=1.O[CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[NH2:13][C:14]1[S:15][C:16]2[CH2:17][CH2:18][N:19]([CH2:24][CH:25]=[CH:26][C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH2:35][C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=4)[CH:28]=3)[CH2:20][CH2:21][C:22]=2[N:23]=1
Reactant: Nc1nc2c(s1)CCN(CC=Cc1cccc(O)c1)CC2
Reactant: OCc1ccccn1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Nc1nc2c(s1)CCN(CC=Cc1cccc(OCc3ccccn3)c1)CC2
Temperature: 0 °C

Procedure:
A solution of 57 mg (0.33 mmol) of diethyl-azodicarboxylate in 0.15 ml of anhydrous tetrahydrofuran is added dropwise, with stirring and cooling (internal temperature 0° C.), to 100 mg (0.33 mmol) of 2-amino-6-(3-(3-hydroxy-phenyl)allyl)-4,5,7,8-tetrahydro-6H-thiazolo[5,4-d]azepine and 36 mg (0.33 mmol) of 2-(hydroxymethyl)-pyridine and 86 mg (0.33 mmol) of triphenylphosphine in 1 ml of anhydrous tetrahydrofuran. After stirring overnight, whilst heating to ambient temperature, a further 0.33 mmol of triphenylphosphine and diethyl-azodicarboxylate are added at 0° C. and the mixture is stirred for another hour at ambient temperature. It is evaporated down in vacuo and distributed between ethyl acetate and water. The ethyl acetate phase is extracted with 2N hydrochloric acid. The aqueous hydrochloric acid phase is made alkaline with conc. ammonia and extracted with ethyl acetate; the organic phase is dried, filtered and evaporated down in vacuo. The evaporation residue is purified by column chromatography on silica gel (chloroform/methanol=5:1). Yield: 13 mg (10% of theory), Melting point: 35°-40° C. (foamy). Molecular peak (m/z): Calculated: 392 Found: 392