Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C@H:11]1[CH2:14][C@H:13]([NH:15][C:16]2[C:21]([NH2:22])=[CH:20][CH:19]=[CH:18][N:17]=2)[CH2:12]1.[C:23](Cl)(=O)[CH2:24][CH3:25].C(N(CC)CC)C>ClCCl>[CH2:24]([C:25]1[N:15]([C@H:13]2[CH2:12][C@H:11]([NH:10][C:2]3[S:1][C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=4[N:3]=3)[CH2:14]2)[C:16]2=[N:17][CH:18]=[CH:19][CH:20]=[C:21]2[N:22]=1)[CH3:23]
Reactant: Nc1cccnc1N[C@H]1C[C@H](Nc2nc3ccccc3s2)C1
Reactant: CCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1nc2cccnc2n1[C@H]1C[C@H](Nc2nc3ccccc3s2)C1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
N2-(Trans-3-(benzo[d]thiazol-2-ylamino)cyclobutyl)pyridine-2,3-diamine (0.075 g, 0.241 mmol) was suspended in dichloromethane (20 mL) and treated with propionyl chloride (0.03 ml, 0.357 mmol). Triethylamine (0.050 ml, 0.359 mmol) was added and the reaction stirred for 1 hour. The mixture was evaporated to dryness under reduced pressure and the crude redissolved in propionic acid (5 mL). The solution was heated at 100° C. for 16 hours. The mixture was evaporated to dryness under reduced pressure and purified using silica chromatography (0-10% methanol in dichloromethane gradient) followed by reverse phase HPLC gave the desired N-(trans-3-(2-ethyl-3H-imidazo[4,5-b]pyridin-3-yl)cyclobutyl)benzo[d]thiazol-2-amine (0.045 g, 0.129 mmol, 53.5% yield). M+1: 350.1. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.31 (t, J=7.53 Hz, 3 H) 2.46 (br. s., 1 H) 2.52-2.68 (m, 2 H) 2.79 (q, J=7.63 Hz, 2 H) 3.61-3.84 (m, 2 H) 4.47-4.68 (m, 1 H) 5.12 (quin, J=8.20 Hz, 1 H) 7.03 (t, J=7.53 Hz, 1 H) 7.12 (dd, J=7.92, 4.79 Hz, 1 H) 7.18-7.32 (m, 1 H) 7.52 (dd, J=21.91, 8.00 Hz. 2 H) 7.88 (dd, J=8.02, 1.37 Hz. 1 H) 8.26 (dd, J=4.69, 1.37 Hz. 1 H).
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2N(O)N=[N:7][C:5]=2C=1.C(N)CCCC.[C:17]([O:21][C:22]([NH:24][C@@H:25]([CH2:29][C:30]1[CH:35]=[CH:34][C:33]([N:36]2[CH2:40][C:39](=[O:41])[N:38]([CH2:42][C:43]3[CH:48]=[CH:47][C:46]([O:49][CH3:50])=[CH:45][CH:44]=3)[S:37]2(=[O:52])=[O:51])=[CH:32][CH:31]=1)[C:26]([OH:28])=O)=[O:23])([CH3:20])([CH3:19])[CH3:18]>C(Cl)Cl>[C:17]([O:21][C:22](=[O:23])[NH:24][C@H:25]([C:26](=[O:28])[NH:7][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1])[CH2:29][C:30]1[CH:31]=[CH:32][C:33]([N:36]2[CH2:40][C:39](=[O:41])[N:38]([CH2:42][C:43]3[CH:48]=[CH:47][C:46]([O:49][CH3:50])=[CH:45][CH:44]=3)[S:37]2(=[O:52])=[O:51])=[CH:34][CH:35]=1)([CH3:18])([CH3:19])[CH3:20]
Reactant: COc1ccc(CN2C(=O)CN(c3ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)O)cc3)S2(=O)=O)cc1
Reactant: On1nnc2ccccc21
Solvent: CCCCCN
Solvent: ClCCl
Product: CCCCCNC(=O)[C@H](Cc1ccc(N2CC(=O)N(Cc3ccc(OC)cc3)S2(=O)=O)cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
HOBt (27 mg, 0.175 mmol), pentyl amine (0.020 mL, 0.175 mmol) and 1-ethyl-3-(3-dimethyl-aminopropyl)carbodiimide hydrochloride (37 mg, 0.192 mmol) are added to a solution of the title A compound in Example 47, (S)-2-t-butoxycarbonylamino-3-{4-[5-(4-methoxy-benzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl]-phenyl}-propionic acid (91 mg, 0.175 mmol) in CH2Cl2 (4 mL) and the reaction is stirred at RT for 2 h. The mixture is concentrated and the product is taken up in EtOAc, washed with 1N aqueous HCl, saturated aqueous NaHCO3 and brine. The organic solution is dried over anhydrous MgSO4, filtered and concentrated to give a white solid. Chromatography on a 10 g silica gel RediSep (Isco Inc.) column with a 30 mL/min gradient elution of 30:70 (EtOAc:hexane) to 60:40 over 10 min yields ((S)-2-{4-[5-(4-methoxy-benzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl]-phenyl}-1-pentylcarbamoyl-ethyl)-carbamic acid t-butyl ester as a white solid: [M+1]+=589.
Reaction SMILES: [NH2:1][C:2]1[C:7]([Br:8])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:9].Cl.[CH3:11]O>>[Br:8][C:7]1[C:2]2[N:1]=[CH:11][O:9][C:3]=2[CH:4]=[CH:5][CH:6]=1
Reactant: CO
Reactant: Nc1c(O)cccc1Br
Agent: Cl
Product: Brc1cccc2ocnc12
Temperature: 90 °C
Yield: 65 %

Procedure:
Following a literature procedure (Org. Prep. & Proc. Int. 22(5), 613 (1990)), a solution of 2-amino-3-bromophenol (800 mg, 4.25 mmol) and trimethylformate (0.685 mL, 6.25 mmol) in methanol (1.25 mL) was treated with concentrated hydrochloric acid (0.01 mL). The flask was fitted with a short path distillation apparatus. The temperature of the solution was slowly raised to 90° C. and maintained until the methanol had finished distilling. Upon cooling, the residue crystallized and was dissolved in diethyl ether (70 mL). This solution was successively washed with 5% sodium hydroxide solution and water and dried over anhydrous magnesium sulfate. After filtering, the solvents were removed by rotoevaporation and the residue was purified by flash column chromatography on silica gel eluted with 20% ethyl acetate in hexanes to yield the title compound (550 mg, 65% yield).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:36])=[C:9]([CH2:11][O:12][C:13]2[CH:33]=[CH:32][C:16]([CH2:17][O:18][C:19]3[CH:23]=[C:22]([CH:24]=O)[N:21]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[N:20]=3)=[CH:15][C:14]=2[O:34][CH3:35])[N:10]=1.[CH2:37]([P:46](=[O:53])([O:50][CH2:51][CH3:52])[O:47][CH2:48][CH3:49])P(=O)(OCC)OCC.CN(C)C=O.[H-].[Na+]>O>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:36])=[C:9]([CH2:11][O:12][C:13]2[CH:33]=[CH:32][C:16]([CH2:17][O:18][C:19]3[CH:23]=[C:22](/[CH:24]=[CH:37]/[P:46](=[O:53])([O:47][CH2:48][CH3:49])[O:50][CH2:51][CH3:52])[N:21]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)[N:20]=3)=[CH:15][C:14]=2[O:34][CH3:35])[N:10]=1
Reactant: COc1cc(COc2cc(C=O)n(-c3ccccc3)n2)ccc1OCc1nc(-c2ccco2)oc1C
Reactant: CCOP(=O)(CP(=O)(OCC)OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOP(=O)(/C=C/c1cc(OCc2ccc(OCc3nc(-c4ccco4)oc3C)c(OC)c2)nn1-c1ccccc1)OCC
Reaction time: 1 h
Yield: 67.4 %

Procedure:
To a mixture of 3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-phenyl-1H-pyrazole-5-carbaldehyde (0.50 g), tetraethyl methylenediphosphonate (0.32 g) and N,N-dimethylformamide (10 mL) was added sodium hydride (60% in oil, 0.05 g) at room temperature, and the mixture was stirred at the same temperature for 1 hr. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give diethyl (E)-2-{3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-phenyl-1H-pyrazol-5-yl}ethenylphosphonate as a colorless oil (0.43 g, yield 69%) from a fraction eluted with ethyl acetate-hexane (3:1, v/v).
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2]([CH3:4])=[CH2:3].[NH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20].[OH-].[Na+].COC1C=CC(O)=CC=1>O1CCOCC1.O>[C:1]([NH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: NCCCCCCCCCCCC(=O)O
Reactant: C=C(C)C(=O)Cl
Agent: COc1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: C=C(C)C(=O)NCCCCCCCCCCCC(=O)O

Procedure:
The same procedure as described above is utilized with 5.4 g (0.052 mol) of methacryloyl chloride, 10 g (0.047 mol) of 12-aminododecanoic acid, 4.4 g (0.01 mol) of sodium hydroxide, and p-methoxyphenol in a mixed solvent (H2O:Dioxane=50:50) at 0°-5° C. Yield after recrystallized from ethyl acetate is 10 g (75%). Melting point 70.8°-72.4° C. NMR (DMSO-d6), 7.8 gamma (br s, 1H, NH), 5.5 gamma (br s, 1H, =CH2), 5.2 gamma (br s, 1H, =CH2), 3.0 gamma (t, 2H, NCH2), 2.1 gamma (t, 2H, CH2COOH), 1.7 gamma (s, 3H, CH3), 1.2 gamma (br s, 18H, (CH2)9).
Reaction SMILES: Cl[C:2]1[C:7]([F:8])=[C:6]([N:9]2[CH2:14][CH2:13][N:12]([CH3:15])[C@H:11]([CH3:16])[CH2:10]2)[N:5]=[C:4]([CH3:17])[N:3]=1.O.[NH2:19][NH2:20]>CS(C)=O>[CH3:16][C@H:11]1[N:12]([CH3:15])[CH2:13][CH2:14][N:9]([C:6]2[C:7]([F:8])=[C:2]([NH:19][NH2:20])[N:3]=[C:4]([CH3:17])[N:5]=2)[CH2:10]1
Reactant: Cc1nc(Cl)c(F)c(N2CCN(C)[C@H](C)C2)n1
Reactant: NN
Solvent: CS(C)=O
Solvent: O
Product: Cc1nc(NN)c(F)c(N2CCN(C)[C@H](C)C2)n1
Temperature: 25 °C
Reaction time: 72 h
Yield: 33 %

Procedure:
To 4-chloro-6-[(3R)-3,4-dimethyl-1-piperazinyl]-5-fluoro-2-methylpyrimidine (0.242 g, 0.94 mmol) in DMSO (3 mL) was added hydrazine monohydrate (2 mL). The reaction was stirred at room temperature for 3 days. Removed volatiles in vacuo and purified by RP-HPLC to provide 4-[(3R)-3,4-dimethyl-1-piperazinyl]-5-fluoro-6-hydrazino-2-methylpyrimidine as a yellow solid (0.079 g, 33%). LCMS: (M+H)+=255.3.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([N+:7]([O-])=O)[N:4]=[C:3]1[C:10]([O:12][CH2:13][CH3:14])=[O:11].[H][H]>CCO.C(OCC)(=O)C.[Pd]>[NH2:7][C:5]1[N:4]=[C:3]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[N:2]([CH3:1])[CH:6]=1
Reactant: CCOC(=O)c1nc([N+](=O)[O-])cn1C
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)c1nc(N)cn1C

Procedure:
Im-2 (0.4 g) in EtOH/ethyl acetate (1:1, 14 mL) and Pd/C (10%, 0.3 g) were stirred under a slight positive pressure of hydrogen (ca 1.1 atm) for 3-4 hr. The reaction mixture was filtered using celite and solvent evaporated on the rotary. The remaining solid was freeze dried to yield a slightly yellow product. Yield (0.38 g, 95%). 1H NMR (DMSO): δ 6.45 (s, 1H), 4.5 (bs, 2H, NH2), 4.2 (q, 2H, J=7 Hz), 3.76 (s, 3H), 1.24 (t, 3H, J=7.9 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][CH2:6][C:7]#[C:8][CH2:9][CH2:10][C:11]([OH:13])=O)=[O:4].[O:14]1[CH:18]=[CH:17][CH:16]=[CH:15]1.ClC(Cl)C(OC(=O)C(Cl)Cl)=O>C1(C)C=CC=CC=1>[O:13]=[C:11]([C:15]1[O:14][CH:18]=[CH:17][CH:16]=1)[CH2:10][CH2:9][C:8]#[C:7][CH2:6][CH2:5][C:3]([O:2][CH3:1])=[O:4]
Reactant: COC(=O)CCC#CCCC(=O)O
Reactant: c1ccoc1
Agent: O=C(OC(=O)C(Cl)Cl)C(Cl)Cl
Solvent: Cc1ccccc1
Product: COC(=O)CCC#CCCC(=O)c1ccco1
Yield: 64.9 %

Procedure:
A mixture of 6-methoxycarbonyl-1-carboxy-3-hexyne [VI-1] (18.4 g, 0.1 mole), furan (13.6 g, 0.2 mole), dichloroacetic anhydride (28.8 g, 0.12 mole), boron trifluoride ether complex (3.2 g) and toluene (100 ml) is reacted at 20°-30° C. for 10 hours. After completion of the reaction, the reaction mixture is cooled, and washed successively with water, 5% aqueous sodium carbonate solution and water, and the organic layer is dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography to give 1-oxo-1-furyl-7-methoxycarbonyl-4-heptyne [VII-1] (15.2 g, yield; 65%), b.p. 120°-125° C./0.3 mmHg.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:37]=[CH:38][C:39]=1[CH3:40])[CH2:5][C:6]([CH2:17][C:18](=[O:36])[N:19]1[CH2:24][CH2:23][CH:22]([N:25]2[CH2:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[NH:27][C:26]2=[O:35])[CH2:21][CH2:20]1)(C(OCC)=O)[C:7]([O:9]CC)=[O:8].[OH-].[K+]>CCO.O>[CH3:1][C:2]1[CH:3]=[C:4]([CH:37]=[CH:38][C:39]=1[CH3:40])[CH2:5][CH:6]([CH2:17][C:18](=[O:36])[N:19]1[CH2:24][CH2:23][CH:22]([N:25]2[CH2:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[NH:27][C:26]2=[O:35])[CH2:21][CH2:20]1)[C:7]([OH:9])=[O:8]
Reactant: CCOC(=O)C(CC(=O)N1CCC(N2Cc3ccccc3NC2=O)CC1)(Cc1ccc(C)c(C)c1)C(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1ccc(CC(CC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)C(=O)O)cc1C

Procedure:
A solution of 15.5 g (28.2 mmol) diethyl 2-(3,4-dimethyl-benzyl)-2-{2-oxo-2-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-ethyl}-malonate in 100 mL EtOH was combined with 11.2 g (169.7 mmol) KOH dissolved in 150 mL water and the mixture was refluxed for 5 h. After the addition of another 11.2 g (169.7 mmol) KOH dissolved in 150 mL water the mixture was refluxed again for 5 h, then combined with 150 mL water and the precipitate was suction filtered. The filter cake was dissolved in 500 mL water, washed twice with 100 mL EtOAc and adjusted to pH 4 by the addition of conc. HCl. The precipitate formed was suction filtered and dried in the circulating air dryer.
Reaction SMILES: [C:1]([OH:4])(=O)[CH3:2].C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.C(Cl)CCl.[NH2:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2[N:38]=[C:37]([NH:39][C:40]3[CH:45]=[C:44]([O:46][CH3:47])[C:43]([O:48][CH3:49])=[C:42]([O:50][CH3:51])[CH:41]=3)[C:36]3=[C:52]([CH3:56])[N:53]=[C:54]([CH3:55])[N:35]3[N:34]=2)=[CH:29][CH:28]=1>>[CH3:56][C:52]1[N:53]=[C:54]([CH3:55])[N:35]2[C:36]=1[C:37]([NH:39][C:40]1[CH:41]=[C:42]([O:50][CH3:51])[C:43]([O:48][CH3:49])=[C:44]([O:46][CH3:47])[CH:45]=1)=[N:38][C:33]([C:30]1[CH:29]=[CH:28][C:27]([NH:26][C:1](=[O:4])[CH3:2])=[CH:32][CH:31]=1)=[N:34]2
Reactant: CC(=O)O
Reactant: COc1cc(Nc2nc(-c3ccc(N)cc3)nn3c(C)nc(C)c23)cc(OC)c1OC
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCCl
Product: COc1cc(Nc2nc(-c3ccc(NC(C)=O)cc3)nn3c(C)nc(C)c23)cc(OC)c1OC

Procedure:
14.28 mg (0.24 mmol) of acetic acid, 32.14 mg (0.24 mmol) of HOBt, 72.17 mg (0.71 mmol) of 4-methylmorpholine, 45.6 mg (0.24 mmol) of EDC and 100 mg (0.24 mmol) of N-[2-(4-aminophenyl)-5,7-dimethylimidazo[5,1-f][1,2,4]triazin-4-yl]-N-(3,4,5-trimethoxyphenyl)amine from example 3 are reacted analogously to example 2. The work-up is carried out by HPLC separation.
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:8]=[C:9]([NH:13][C:14](=[O:16])[CH3:15])[CH:10]=[CH:11][CH:12]=2)[CH:6]=1.[CH3:17][C:18]1[O:22][C:21](B(O)O)=[CH:20][CH:19]=1.C([O-])([O-])=O.[Cs+].[Cs+].C(O)CCO>CC#N>[CH3:17][C:18]1[O:22][C:21]([C:2]2[N:3]=[CH:4][N:5]([C:7]3[CH:8]=[C:9]([NH:13][C:14](=[O:16])[CH3:15])[CH:10]=[CH:11][CH:12]=3)[CH:6]=2)=[CH:20][CH:19]=1
Reactant: CC(=O)Nc1cccc(-n2cnc(Br)c2)c1
Reactant: Cc1ccc(B(O)O)o1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: OCCCO
Product: CC(=O)Nc1cccc(-n2cnc(-c3ccc(C)o3)c2)c1
Temperature: 170 °C
Yield: 11.4 %

Procedure:
A slurry of 12 (140 mg; 0.5 mmol), 5-methylfuran-2-boronic acid (88.1 mg; 0.7 mmol), Cs2CO3 (179 mg, 0.55 mmol) and propane-1,3-diol (53 mg; 1.4 mmol) in CH3CN (4 mL) was purged with argon and Cl2Pd(PPh3)2 (7 mg; 2 mol %) was added. The mixture was heated in EmrysOptimiser (170° C., 15 min). The reaction mixture was filtered hot through a fritte and the precipitate was extracted with hot CH3CN (8 mL), which was filtered through the same fritte and pooled with the first fraction. The yellow solution was evaporated to dryness and redissolved in 1 mL CH3CN which was purified by preparative LC-MS to give pure title compound 16 mg (11%). HRMS (ESI+): m/z=281.3135 [M+H]
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[CH3:10][CH2:11][O-:12].[Na+].CCO>CCO>[Cl:1][C:2]1[N:7]=[C:6]([O:12][CH2:11][CH3:10])[C:5]([F:9])=[CH:4][N:3]=1
Reactant: CC[O-]
Reactant: Fc1cnc(Cl)nc1Cl
Agent: [Na+]
Solvent: CCO
Product: CCOc1nc(Cl)ncc1F
Reaction time: 1 h
Yield: 82.6 %

Procedure:
To a solution of the product from step (a) (10.0 g, 59.9 mmol) in abs. EtOH (40 mL) at 0° C. under nitrogen atmosphere was added 1M NaOEt/EtOH (61 mL, 61 mmol) and the mixture was stirred for 1 hour. Solvent was evaporated in vacuo and the residue partitioned between H2O and Et2O. The aqueous phase was extracted with Et2O and the combined organic phase was washed with brine, dried (Na2SO4) and evaporated (water aspirator pump, 35° C.) to provide the desired product (8.74 g, 83%) as a yellowish solid: mp 30-32° C. (lit. 31-32° C.); 1H NMR (CDCl3): δ 1.46 (t, J=7.0 Hz, 3H), 4.53 (quartet, J=7 Hz, 2H), 8.17 (d, J=2.1 Hz, 1H); MS m/z 179 (M+3, 17%), 177 (M+1, 50%), 149 (100%). Anal. Calcd. for C6H6ClFN2O: C, 40.81; H, 3.42; N, 15.86. Found, C, 40.90; H, 3.45; N, 15.81.
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][CH:12]2[S:24][C:16]3=[N:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[N:15]3[CH2:14][CH2:13]2)(=O)=O)=CC=1.[CH2:26]([NH2:30])[CH2:27][CH2:28][CH3:29].[H-].[Na+].O>C(Cl)(Cl)Cl>[CH2:26]([NH:30][CH2:11][CH:12]1[S:24][C:16]2=[N:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[N:15]2[CH2:14][CH2:13]1)[CH2:27][CH2:28][CH3:29]
Reactant: Cc1ccc(S(=O)(=O)OCC2CCn3c(nc4ccccc43)S2)cc1
Reactant: CCCCN
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCCCNCC1CCn2c(nc3ccccc32)S1
Yield: 43.3 %

Procedure:
To a solution of 2.24 g of 3,4-dihydro-2-p-toluenesulfonyloxymethyl-2H-(1,3)-thiazino[3,2-a]benzimidazole in chloroform (30 ml) was added 4 ml of n-butylamine. A catalytic amount of sodium hydride was thereafter added under ice-cooling, stirring conditions. After stirring for 15 minutes at room temperature, the mixture was refluxed for 24 hours. The reaction mixture was cooled and then condensed under reduced pressure. The residue was added with water and extracted with chloroform. The extract was washed with water, dried over anhydrous magnesium sulfate. Chloroform was evaporated under reduced pressure. The residue was chromatographed on silica gel and eluted with chloroform to obtain 0.71 g (yield: 43.3%) of the intended product, m.p. 122°-124° C.; IR νmaxKBr cm-1 : 3320, 3100-2700, 1430; Anal. Calcd. for C15H21N3S: C, 65.42; N, 7.68; N, 15.26; S, 11.64; Found C, 65.63; H, 7.61; N, 15.46; S, 11.30.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Cl[S:6]([C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([OH:14])=[O:13])(=[O:8])=[O:7].CC(C)=O>O>[N:1]([S:6]([C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([OH:14])=[O:13])(=[O:8])=[O:7])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(O)c1cccc(S(=O)(=O)Cl)c1
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: [N-]=[N+]=NS(=O)(=O)c1cccc(C(=O)O)c1
Reaction time: 0.5 h

Procedure:
In a three-necked flask fitted with stirrer and dropping funnel 65 g of sodium azide is dissolved in 900 ccs of water. While stirring and cooling till 0°-5° C a solution of 198 g of m-chlorosulphonyl-benzoic acid in 900 ccs of acetone is added dropwise. Then stirring is continued for 30 minutes whereupon the solution obtained is poured into 2 liters of water. The white precipitate formed is sucked off, washed with water and dried in vacuo. Melting point: 143° C.
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[N:12]=[C:11]([Cl:14])[NH:10][C:9]=2[C:8](=[O:15])[N:7]([CH2:16][CH2:17][CH2:18][C:19]([O:21]CC)=O)[C:6]1=[O:24])[CH2:2][CH2:3][CH3:4].[CH2:25]([O:27][C:28]1[CH:29]=[C:30]([CH2:35]/[C:36](=[N:39]/[H])/[NH:37]O)[CH:31]=[CH:32][C:33]=1[OH:34])[CH3:26].[O-]CC.[Na+]>CCO>[CH2:1]([N:5]1[C:13]2[N:12]=[C:11]([Cl:14])[NH:10][C:9]=2[C:8](=[O:15])[N:7]([CH2:16][CH2:17][CH2:18][C:19]2[O:21][N:39]=[C:36]([CH2:35][C:30]3[CH:31]=[CH:32][C:33]([OH:34])=[C:28]([O:27][CH2:25][CH3:26])[CH:29]=3)[N:37]=2)[C:6]1=[O:24])[CH2:2][CH2:3][CH3:4]
Reactant: [H]/N=C(/Cc1ccc(O)c(OCC)c1)NO
Reactant: CCCCn1c(=O)n(CCCC(=O)OCC)c(=O)c2[nH]c(Cl)nc21
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCCCn1c(=O)n(CCCc2nc(Cc3ccc(O)c(OCC)c3)no2)c(=O)c2[nH]c(Cl)nc21
Temperature: 140 °C
Yield: 39.2 %

Procedure:
Ethyl 4-(3-butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)butanoate (53 mg, 0.15 mmol) and (1Z)-2-[3-(ethyloxy)-4-hydroxyphenyl]-N-hydroxyethanimidamide (35 mg, 0.165 mmol; entry 11, Table 7) were mixed in EtOH (0.75 ml). Ethanolic sodium ethoxide (21% by wt., 0.083 ml, 0.22 mmol) was added and the mixture was heated in the microwave at 140° C. for 10 min. A further 0.055 ml (0.15 mmol) of NaOEt solution was then added and the mixture heated for a further 10 min period at 140° C. The mixture was partitioned between EtOAc and 2M HCl and the organic phase evaporated and purified by MDAP to give the title compound as a solid (29.6 mg).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[CH:18]=[C:17]([C:19]#[N:20])[C:12](C(OC)=O)=[C:11]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([S:28]([CH3:31])(=[O:30])=[O:29])[CH:23]=2)[N:10]=1.[CH3:32][OH:33]>[Pd].Cl>[NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[N:10]=[C:11]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([S:28]([CH3:31])(=[O:30])=[O:29])[CH:23]=2)[C:12]2[C:32](=[O:33])[NH:20][CH2:19][C:17]=2[CH:18]=1
Reactant: CO
Reactant: COC(=O)c1c(C#N)cc(N[C@@H]2CCCC[C@@H]2N)nc1Nc1cccc(S(C)(=O)=O)c1
Agent: [Pd]
Agent: Cl
Product: CS(=O)(=O)c1cccc(Nc2nc(N[C@@H]3CCCC[C@@H]3N)cc3c2C(=O)NC3)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 34 %

Procedure:
A mixture of methyl 6-((1R,2S)-2-aminocyclohexylamino)-4-cyano-2-(3-(methylsulfonyl)phenylamino)nicotinate (117.3 mg, 0.264 mmol) and palladium on carbon (23.6 mg, 0.222 mmol) in MeOH (4 mL) and 1N HCl (4 mL) was stirred at RT for 16 h under a hydrogen atmosphere. The mixture was filtered to remove the catalyst and the filtrate was treated with saturated aq NaHCO3 (20 mL) and stirred at RT for 20 h. The mixture was concentrated under reduced pressure and the residue was extracted with EtOAc/THF (2/1, 2×30 mL). The organic layers were washed with saturated aq NaHCO3 (15 mL), water (15 mL) and brine (15 mL), were dried over anhydrous Na2SO4, and then filtered. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography (DM1020, EtOAc/MeOH=20/1) to give the desired product (37.2 mg, 34%). The product was recrystallized from EtOH to give the title compound as a colorless solid (13.2 mg, 12%). 1H-NMR (DMSO-d6) δ ppm 1.31-1.41 (m, 4H), 1.55-1.68 (m, 6H), 3.05 (s, 1H), 3.21 (s, 3H), 4.08 (s, 1H), 4.23 (s, 2H), 6.17 (s, 1H), 6.78-6.79 (m, 1H), 7.46-7.47 (m, 1H), 7.53-7.56 (m, 1H), 7.96-7.99 (m, 2H), 8.49 (s, 1H), 9.18 (s, 1H).
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][C@H:9]([C:13]([OH:15])=O)[CH2:10][CH:11]=[CH2:12])=[O:7])([CH3:4])[CH3:3].C(N1CCOCC1)C.[CH2:24]([O:26][C:27]([N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)=[O:28])[CH3:25].[B-](F)(F)(F)F.CCOC(C(C#N)=NOC(N(C)C)=[N+](C)C)=O>CN(C=O)C.C(OCC)(=O)C>[CH2:24]([O:26][C:27]([N:29]1[CH2:30][CH2:31][N:32]([C:13](=[O:15])[C@@H:9]([NH:8][C:6]([O:5][C:2]([CH3:1])([CH3:3])[CH3:4])=[O:7])[CH2:10][CH:11]=[CH2:12])[CH2:33][CH2:34]1)=[O:28])[CH3:25]
Reactant: CCOC(=O)N1CCNCC1
Reactant: C=CC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN1CCOCC1
Agent: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=CC[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCN(C(=O)OCC)CC1
Reaction time: 1 h

Procedure:
To a solution of 540 mg Boc-L-Allylglycine in 5 ml DMF were added 0.32 ml N-ethylmorpholine, 0.37 ml ethoxycarbonylpiperazine and 0.83 g TOTU at 0° C. The solution was stirred for 1 h before being diluted with ethyl acetate and extracted subsequently with aqueous LiCl (4%), 0.1 M HCl and half-saturated aqueous NaHCO3. The crude product obtained after evaporation of the solvent was used without further purification.
Reaction SMILES: [F:1][C:2]1[C:9]([F:10])=[CH:8][CH:7]=[C:6]([OH:11])[C:3]=1[CH:4]=[O:5].Br[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:13]([O:11][C:6]1[C:3]([CH:4]=[O:5])=[C:2]([F:1])[C:9]([F:10])=[CH:8][CH:7]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=Cc1c(O)ccc(F)c1F
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1c(OCc2ccccc2)ccc(F)c1F
Temperature: 70 °C

Procedure:
A mixture of 2,3-difluoro-6-hydroxybenzaldehyde (0.93 g), (bromomethyl)benzene (1.11 g) and potassium carbonate (1.22 g) in N,N-dimethylformamide (15 mL) was heated at 70° C. overnight. After cooling to room temperature, the reaction mixture was partitioned between water and ethyl acetate. The organic layer was separated, and the aqueous layer was extracted with additional ethyl acetate three times. The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified by flash chromatography on silica gel to give the title compound.