Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:17]1([NH:22][OH:23])[CH2:21][CH2:20][CH2:19][CH2:18]1>C(Cl)(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[N+:22]([CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[O-:23])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(OCc2ccccc2)cc1
Reactant: ONC1CCCC1
Solvent: ClC(Cl)Cl
Product: [O-][N+](=Cc1ccc(OCc2ccccc2)cc1)C1CCCC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 85.1 %

Procedure:
A mixture of 4-benzyloxybenzaldehyde (20 g, 94.23 mmol), N-cyclopentylhydroxylamine (14.3 g, 141.34 mmol), molecular sieves (60 g, 4A) and silica gel (15 g) in chloroform (300 mL) was stirred at room temperature under argon atmosphere for 48 hrs and then was refluxed for an additional 3 hrs. The mixture was filtered and rotary evaporated to give crystals which were recrystallized from hexanes and EtOAc to provide the title compound as white crystals, 23.7 g, 85.1 % yield), m.p. 115.1 ° C. (Rf =0.35 on a silica gel plate using hexanes:EtOAc, 1:1, v:v, as an eluant).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([O:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)=[CH:15][CH:14]=1)=[C:7]([O:28][S:29]([C:32]([F:35])([F:34])[F:33])(=[O:31])=[O:30])[CH:6]=[CH:5]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:55](O)[C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C(OCC)(=O)C.O1CCCC1>[CH2:55]([O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([O:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][N:22]3[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]3)=[CH:15][CH:14]=1)=[C:7]([O:28][S:29]([C:32]([F:34])([F:35])[F:33])(=[O:31])=[O:30])[CH:6]=[CH:5]2)[C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1
Reactant: OCc1ccccc1
Reactant: O=S(=O)(Oc1ccc2cc(O)ccc2c1Oc1ccc(OCCN2CCCCC2)cc1)C(F)(F)F
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=S(=O)(Oc1ccc2cc(OCc3ccccc3)ccc2c1Oc1ccc(OCCN2CCCCC2)cc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73.8 %

Procedure:
Combine trifluoromethanesulfonic acid 6-hydroxy-1-[4-(2-piperidin-1-yl-ethoxy)-phenoxy]-naphthalen-2-yl ester (247 mg, 0.48 mmol), triphenylphosphine (190 mg, 0.725 mmol), benzyl alcohol (0.075 mL, 0.725 mmol) and tetrahydrofuran (5 mL) in a flask placed in an ice bath. Add diisopropyl azodicarboxylate (0.14 mL, 0.725 mmol), stir for 1 hour, warm to ambient temperature and stir for 30 minutes. Dilute with ethyl acetate and wash with 50% saturated aqueous sodium bicarbonate, saturated aqueous sodium chloride, dry with magnesium sulfate and remove solvent under vacuum. Chromatograph on silica gel with dichloromethane/methanol mixtures to give 213 mg of the title compound (73%).
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([N+:12]([O-:14])=[O:13])[CH:3]=1.[O:15]1[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][OH:23])[CH2:17][CH2:16]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[N+:12]([C:4]1[CH:3]=[C:2]([CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=1)[O:23][CH2:22][CH2:21][N:18]1[CH2:19][CH2:20][O:15][CH2:16][CH2:17]1)([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1cc(F)cc(C(F)(F)F)c1
Reactant: OCCN1CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(OCCN2CCOCC2)cc(C(F)(F)F)c1
Temperature: 90 °C
Reaction time: 10 h
Yield: 46.5 %

Procedure:
A mixture of 1-fluoro-3-nitro-5-(trifluoromethyl)benzene (800 mg, 3.83 mmol), 2-morpholinoethanol (552 mg, 4.21 mmol) and K2CO3 (1586 mg, 11.48 mmol) in DMF (20 mL) was stirred at 90° C. for 10 h. The mixture was concentrated. To the residue was added DCM (150 mL) and the mixture was stirred for 10 min and then filtered. The filtrate was concentrated. The residue was purified by silica column chromatography (PE/EA=10:1˜5:1). All fractions found to contain product by TLC (PE/EA=5:1, Rf=0.6) were combined and concentrated to yield a yellow solid of 4-(2-(3-nitro-5-(trifluoromethyl)phenoxy)ethyl)morpholine (600 mg, 1.780 mmol, 46.5% yield): 1H NMR (400 MHz, CDCl3): δ 8.02 (s, 1H), 7.87 (s, 1H), 7.43 (s, 1H), 4.16 (t, J=5.6 Hz, 2H), 3.72-3.63 (m, 4H), 2.79 (t, J=5.6 Hz, 2H), 2.58-2.47 (m, 4H). ES-LCMS m/z: 321 (M+H).
Reaction SMILES: C[Si](C)(C)[O:3][C:4]([C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=1)=[CH2:5].[F-].[Cs+].[OH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27](=[O:39])[CH:28]=[CH:29][C:30]1[CH:35]=[CH:34][C:33]2[O:36][CH2:37][O:38][C:32]=2[CH:31]=1>CS(C)=O>[OH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27](=[O:39])[CH2:28][CH:29]([C:30]1[CH:35]=[CH:34][C:33]2[O:36][CH2:37][O:38][C:32]=2[CH:31]=1)[CH2:3][C:4]([C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=1)=[O:5]
Reactant: O=C(C=Cc1ccc2c(c1)OCO2)c1ccccc1O
Reactant: C=C(O[Si](C)(C)C)c1ccc2ccccc2c1
Agent: [Cs+]
Agent: [F-]
Solvent: CS(C)=O
Product: O=C(CC(CC(=O)c1ccccc1O)c1ccc2c(c1)OCO2)c1ccc2ccccc2c1
Temperature: 70 °C

Procedure:
1-Trimethylsilyloxy-1-(naphthalen-2-yl)ethylene (7.0 mmol; prepared according to J. Chem. Soc., Perkin Trans. I 1989, 1585) and CsF (0.27 g, 1.76 mmol) were added to a suspension 1-(2-hydroxyphenyl)-3-(3,4-methylenedioxyphenyl)-2-propen-1-one on Wang resin (2.0 g, 1.76 mmol) in dimethyl sulfoxide (30 mL). The reaction mixture was heated to 70° C. for 3 h and the reaction was quenched with 10% AcOH/CH2Cl2. The resin was filtered, washed with DMF (×2) and. alternating MeOH and CH2Cl2 (×5), and dried under high vacuum overnight to give 1-(2-hydroxyphenyl)-3-(3,4-methylenedioxyphenyl)-5-(naphthalen-2-yl)-1,5-pentanedione on Wang resin.
Reaction SMILES: [C:1]1([C:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8](O)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:23][CH2:24][CH2:25][CH2:26][N:27]1[CH2:32][CH2:31][CH:30]([C:33]2[CH:34]=[C:35]([NH:40][C:41](=[O:45])[CH:42]([CH3:44])[CH3:43])[CH:36]=[CH:37][C:38]=2[CH3:39])[CH2:29][CH2:28]1>>[CH3:44][CH:42]([CH3:43])[C:41]([NH:40][C:35]1[CH:36]=[CH:37][C:38]([CH3:39])=[C:33]([CH:30]2[CH2:31][CH2:32][N:27]([CH2:26][CH2:25][CH2:24][NH:23][C:8](=[O:9])[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:28][CH2:29]2)[CH:34]=1)=[O:45]
Reactant: O=C(O)C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cc1ccc(NC(=O)C(C)C)cc1C1CCN(CCCN)CC1
Product: Cc1ccc(NC(=O)C(C)C)cc1C1CCN(CCCNC(=O)C(c2ccccc2)(c2ccccc2)c2ccccc2)CC1

Procedure:
Example 94 was prepared from triphenylacetic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]-4-methylphenyl}-2-methylpropanamide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCl3) δ 7.39 (dd, 1H, J=1.6, 8.0 Hz), 7.35–7.27 (m, 15H), 7.22–7.20 (m, 2H), 7.09 (d, 1H, J=8.0 Hz), 6.25 (br s, 1H), 3.45 (dd, 2H, J=6.8, 12.4 Hz), 2.90 (d, 2H, J=10.8 Hz), 2.63 (m, 1H), 2.52 (m, 1H), 2.33–2.29 (m, 2H), 2.28 (s, 3H), 1.97 (t, 2H, J=10.0 Hz), 1.72–1.57 (m, 6H), 1.27 (d, 6H, J=6.8 Hz); ESMS m/e: 588.3 (M+H)+.
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[N:5]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:4]1)#[N:2].C(N)(=[S:21])C>FC(F)(F)C(O)=O>[NH2:2][C:1](=[S:21])[CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[N:5]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:4]1
Reactant: CCOC(=O)N1CCC(C#N)CN1C(=O)OCC
Reactant: CC(N)=S
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)N1CCC(C(N)=S)CN1C(=O)OCC
Temperature: 50 °C

Procedure:
A mixture of 1,2-diethyl 4-cyanotetrahydro-1,2-pyridazinedicarboxylate (i.e the product of Step E) (5.5 g, 0.024 mol) and thioacetamide (5.5 g, 0.073 mol) in trifluoroacetic acid (about 10 mL) was heated at 50° C. for 20 h. The reaction mixture was cooled, and then partitioned between water and diethyl ether (about 30 mL). The layers were separated and the aqueous layer was extracted with diethyl ether (2×). The combined organic extracts were washed with water (about 30 mL), dried magnesium sulfate, filtered and concentrated under reduce pressure to an orange oil. The oil was adsorbed onto Celite® (diatomaceous filter aid), and then purified by silica gel column chromatography (25% to 60% gradient of ethyl acetate in petroleum ether as eluant) to provide the title compound as a yellow solid (3.97 g).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:16][C:17]([F:20])([F:19])[F:18])[CH:10]([CH2:14][CH3:15])[C:11](O)=[O:12])=[CH:5][C:4]=1[C:21]([F:24])([F:23])[F:22])#[N:2].[F:25][C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=1>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:16][C:17]([F:20])([F:19])[F:18])[CH:10]([CH2:14][CH3:15])[C:11]([NH:30][C:29]2[CH:31]=[CH:32][C:26]([F:25])=[CH:27][CH:28]=2)=[O:12])=[CH:5][C:4]=1[C:21]([F:22])([F:24])[F:23])#[N:2]
Reactant: Nc1ccc(F)cc1
Reactant: CCC(C(=O)O)N(CC(F)(F)F)c1ccc(C#N)c(C(F)(F)F)c1
Product: CCC(C(=O)Nc1ccc(F)cc1)N(CC(F)(F)F)c1ccc(C#N)c(C(F)(F)F)c1

Procedure:
Synthesized as described in Example 91C using 2-[[4-cyano-3-(trifluoromethyl)phenyl](2,2,2-trifluoroethyl)amino]butanoic acid and 4-fluoroaniline:
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[O:9])=[CH:6][N:5]=[C:4](S(CC)=O)[N:3]=1.FC(F)(F)C(O)=O.[CH3:28][S:29]([N:32]1[CH2:37][CH2:36][CH:35]([NH2:38])[CH2:34][CH2:33]1)(=[O:31])=[O:30]>>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:11]=[CH:12][C:13]([F:16])=[CH:14][CH:15]=2)=[O:9])=[CH:6][N:5]=[C:4]([NH:38][CH:35]2[CH2:36][CH2:37][N:32]([S:29]([CH3:28])(=[O:31])=[O:30])[CH2:33][CH2:34]2)[N:3]=1
Reactant: CS(=O)(=O)N1CCC(N)CC1
Reactant: CCS(=O)c1ncc(C(=O)c2ccc(F)cc2)c(N)n1
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)N1CCC(Nc2ncc(C(=O)c3ccc(F)cc3)c(N)n2)CC1

Procedure:
The same procedure as described in Example 326 was used, starting with (4-amino-2-ethanesulfinyl-pyrimidin-5-yl)-(4-fluoro-phenyl)-methanone (Example 366) and 1-methanesulfonyl-piperidin-4-ylamine; compound with trifluoroacetic acid (Example 162) to give [4-amino-2-(1-methanesulfonyl-piperidin-4-ylamino)-pyrimidin-5-yl]-(4-fluoro-phenyl)-methanone. MS (M+H)+, 394
Reaction SMILES: Cl[C:2]1C=C(SC2C3C(=CC(C)=CC=3)NC=2CCC(N)=O)C=C(Cl)[CH:7]=1.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([S:32][C:33]2[C:41]3[C:36](=[CH:37][CH:38]=[C:39]([CH3:42])[CH:40]=3)[NH:35][C:34]=2[C:43]([OH:45])=[O:44])=[CH:28][CH:27]=1.C(Cl)(=O)C(Cl)=O.CCO>C1COCC1>[Cl:25][C:26]1[CH:27]=[CH:28][C:29]([S:32][C:33]2[C:41]3[C:36](=[CH:37][CH:38]=[C:39]([CH3:42])[CH:40]=3)[NH:35][C:34]=2[C:43]([O:45][CH2:2][CH3:7])=[O:44])=[CH:30][CH:31]=1
Reactant: Cc1ccc2[nH]c(C(=O)O)c(Sc3ccc(Cl)cc3)c2c1
Reactant: Cc1ccc2c(Sc3cc(Cl)cc(Cl)c3)c(CCC(N)=O)[nH]c2c1
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)c1[nH]c2ccc(C)cc2c1Sc1ccc(Cl)cc1
Yield: 76 %

Procedure:
Following the method used to prepare 24a, the use of 1b (0.23 mmol) and oxalyl chloride in THF followed by allowing the intermediate acid chloride to react with EtOH (5 mL) provided 61 mg (76%) of product 10 as a white solid, mp 158-160° C. 1H NMR (300 MHz, DMSO-d6) δ 1.24 (t, J=7 Hz, 3H), 2.34 (s, 3H), 4.30 (q, J=7 Hz, 2H), 7.05 (d, J=8 Hz, 2H), 7.16 (d, J=8 Hz, 1H), 7.26-7.29 (m, 3H), 7.46 (d, J=9 Hz, 1H), 12.38 (s, 1H). LC-MS (CI): m/z 346.1 [(M+H)+ C18H16ClNO2S requires 345.06]. Purity (100%). Calcd for C18H16ClNO2S: C, 62.51; H, 4.66; N, 4.05; S, 9.27; Cl, 10.25. Found: C, 62.37; H, 4.60; N, 3.95; S, 9.21; Cl, 10.30.
Reaction SMILES: C([O:4][CH2:5][C:6]([CH2:18][CH2:19][C:20]1([CH2:26][CH2:27][N:28]2[CH2:33][CH2:32][CH:31]([N:34]([C:42]3[CH:47]=[CH:46][C:45]([CH3:48])=[CH:44][CH:43]=3)[C:35]([C:37]3[O:38][CH:39]=[CH:40][CH:41]=3)=[O:36])[CH2:30][CH2:29]2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)([CH2:12][CH2:13][O:14]C(=O)C)[CH2:7][O:8]C(=O)C)(=O)C.C(=O)([O-])[O-].[K+].[K+]>CO>[OH:14][CH2:13][CH2:12][C:6]([CH2:5][OH:4])([CH2:7][OH:8])[CH2:18][CH2:19][C:20]1([CH2:26][CH2:27][N:28]2[CH2:29][CH2:30][CH:31]([N:34]([C:42]3[CH:43]=[CH:44][C:45]([CH3:48])=[CH:46][CH:47]=3)[C:35]([C:37]3[O:38][CH:39]=[CH:40][CH:41]=3)=[O:36])[CH2:32][CH2:33]2)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]1
Reactant: CC(=O)OCCC(CCC1(CCN2CCC(N(C(=O)c3ccco3)c3ccc(C)cc3)CC2)CCCCC1)(COC(C)=O)COC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: Cc1ccc(N(C(=O)c2ccco2)C2CCN(CCC3(CCC(CO)(CO)CCO)CCCCC3)CC2)cc1
Reaction time: 20 h
Yield: 99.3 %

Procedure:
To a solution of 2-(acetoxymethyl)-2-[2-[1-[2-[4-[N-(p-tolyl)-2-furancarboxamido]piperidin-1-yl]ethyl]cyclohexyl]ethyl]-1,4-diacetoxybutane (synthesized in Example 14) (313 mg) dissolved in methanol (5 mL) was added potassium carbonate (39 mg) at room temperature. The solution was stirred for 20 hours. The reaction solution was concentrated under reduced pressure. Water was added to the resulting residue and extracted with a mixed solvent of chloroform-ethanol (80:20). The organic layer was dried over anhydrous magnesium sulfate, filtered and then concentrated under reduced pressure to give the title compound (252 mg).
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:11]1[C:12]2[CH:25]=[C:24]([Cl:26])[S:23][C:13]=2[N:14]=[C:15]([C:17]2[CH:22]=[N:21][CH:20]=[CH:19][N:18]=2)[N:16]=1>>[N:18]1[CH:19]=[CH:20][N:21]=[CH:22][C:17]=1[C:15]1[N:16]=[C:11]([NH:9][CH2:1][CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[C:12]2[CH:25]=[C:24]([Cl:26])[S:23][C:13]=2[N:14]=1
Reactant: Clc1cc2c(Cl)nc(-c3cnccn3)nc2s1
Reactant: NCCc1ccccc1
Product: Clc1cc2c(NCCc3ccccc3)nc(-c3cnccn3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of phenethylamine with 4-chloro-2-(pyrazin-2-yl)-6-chloro-thieno-[2,3-d]-pyrimidine yields 2-(pyrazin-2-yl)-4-phenethylamino-6-chloro-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH:1]([O:4][CH2:5][C:6]1([C:12]([OH:14])=O)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)([CH3:3])[CH3:2].[Cl-].C[N:17](C)C=O>C1C=CC=CC=1>[CH:1]([O:4][CH2:5][C:6]1([C:12]([NH2:17])=[O:14])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)([CH3:3])[CH3:2]
Reactant: CC(C)OCC1(C(=O)O)CCCCC1
Reactant: CN(C)C=O
Agent: [Cl-]
Solvent: c1ccccc1
Product: CC(C)OCC1(C(N)=O)CCCCC1

Procedure:
10 g of 1-isopropyloxymethyl 1-cyclohexyl carboxylic acid dissolved in 50 cm3 of benzene were heated under reflux for 5 hours together with 15 cm3 of thionyle chloride in the presence of 0.3 cm3 of dimethylformamide.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][C:14]([C:15]([O:17][CH2:18]C)=[O:16])=[C:10]3[CH2:9][N:8]([CH3:20])[C:7](=[O:21])[C:6]=2[CH:22]=1.[C-]#N.[K+]>CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:10]3[CH2:9][N:8]([CH3:20])[C:7](=[O:21])[C:6]=2[CH:22]=1
Reactant: CCOC(=O)c1ncn2c1CN(C)C(=O)c1cc(F)ccc1-2
Agent: [C-]#N
Agent: [K+]
Solvent: CO
Product: COC(=O)c1ncn2c1CN(C)C(=O)c1cc(F)ccc1-2
Reaction time: 2.5 h

Procedure:
A mixture of 3.5 g (11.5 mmol) of ethyl 8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate, 0.15 g of potassium cyanide and 40 ml of methanol is stirred at the boiling point for 2.5 hours. The solvent is distilled off on a rotary evaporator and the residue is taken up in chloroform. After filtration from insoluble material, the filtrate is concentrated. After recrystallisation of the residue from ethyl acetate, there is obtained methyl 8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate of melting point 195°-196.5° C.
Reaction SMILES: F[C:2]1[C:3]([C:10]#[N:11])=[N:4][CH:5]=[C:6]([F:9])[C:7]=1[I:8].O.[NH2:13][NH2:14]>C(O)CCC>[F:9][C:6]1[C:7]([I:8])=[C:2]2[NH:14][N:13]=[C:10]([NH2:11])[C:3]2=[N:4][CH:5]=1
Reactant: NN
Reactant: N#Cc1ncc(F)c(I)c1F
Solvent: O
Solvent: CCCCO
Product: Nc1n[nH]c2c(I)c(F)cnc12
Temperature: 105 °C
Yield: 28 %

Procedure:
3,5-Difluoro-4-iodopicolinonitrile (1.0 g) was combined with butan-1-ol (10 mL) and hydrazine hydrate (100%, 0.82 mL) was added. The reaction was heated at 105° C. and after 2 hours cooled to room temperature, filtered, the filter rinsed with water, and the filtrate was concentrated to give a residue. The residue was washed with water and filtered to give 6-fluoro-7-iodo-1H-pyrazolo[4,3-b]pyridin-3-amine (27) as a solid (290 mg, 28% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.14 (s, 1H) 5.59 (s, 2H). MS [M+H] found 279.0
Reaction SMILES: C(N(C(C)C)CC)(C)C.[C:10](OC(=O)C)(=[O:12])[CH3:11].[CH3:17][NH:18][C:19]([C:21]1[C:25]2[CH:26]=[C:27]([O:31][CH3:32])[C:28]([NH2:30])=[CH:29][C:24]=2[O:23][C:22]=1[C:33]1[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=1)=[O:20]>ClC(Cl)Cl>[CH3:17][NH:18][C:19]([C:21]1[C:25]2[CH:26]=[C:27]([O:31][CH3:32])[C:28]([NH:30][C:10](=[O:12])[CH3:11])=[CH:29][C:24]=2[O:23][C:22]=1[C:33]1[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=1)=[O:20]
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N)c(OC)cc12
Reactant: CC(=O)OC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(NC(C)=O)c(OC)cc12
Reaction time: 1 h
Yield: 87 %

Procedure:
Diisopropylethylamine (83.2 μL, 477 μmol), followed by acetic anhydride (239 μmol) were added to a solution of 6-amino-2-(4-fluoro-phenyl)-5-methoxy-benzofuran-3-carboxylic acid methylamide, prepared according to Example 17 (75 mg, 239 μmol) in dry trichloromethane (3 mL). After one hour, the reaction was quenched with water (3 mL). After concentration to dryness, the crude oil was purified by HPLC (reverse phase, C18, acetonitrile/water with 0.1% acetic acid) to provide 73 mg (87%) of the title compound.
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[F:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=1[NH:14][C:15]([C:17]1[CH:18]=[C:19]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[F:31])[CH:20]=[CH:21]C=1O)=[O:16].Cl>O1CCCC1.N1C=CC=CC=1>[F:31][C:25]1[CH:26]=[C:27]([F:30])[CH:28]=[CH:29][C:24]=1[C:19]1[CH:20]=[CH:21][C:5]2[O:4][C:2](=[O:3])[N:14]([C:8]3[CH:9]=[C:10]([F:13])[CH:11]=[CH:12][C:7]=3[F:6])[C:15](=[O:16])[C:17]=2[CH:18]=1
Reactant: O=C(Nc1cc(F)ccc1F)c1cc(-c2ccc(F)cc2F)ccc1O
Reactant: COC(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: O=c1oc2ccc(-c3ccc(F)cc3F)cc2c(=O)n1-c1cc(F)ccc1F
Temperature: 25 °C
Reaction time: 10 h
Yield: 15 %

Procedure:
A solution of methyl chloroformate (1.2 mL, 12 mmol) was added drop wised to a stirred solution of compound 4 (1.44 g, 4 mmol) in dry anhydrous tetrahydrofuran/pyridine (30 mL) at 0° C. The mixture was refluxed for 3 h. After 10 h stirring at room temperature, the pH value of the mixture was adjusted to pH=6 by 5% HCl(aq). The mixture was cooled to obtain crystalline compound on an ice bath for 2-3 h. After cooling, precipitated crystals were filtered off and washed with diluted HCl and water. The crude product was purified by crystallization from hot ethanol to afford compound 16.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[CH:5]=1)([O-:3])=[O:2].[I:13]I>S(=O)(=O)(O)O>[N+:1]([C:4]1[CH:9]=[C:8]([I:13])[CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[CH:5]=1)([O-:3])=[O:2]
Reactant: II
Reactant: O=[N+]([O-])c1cccc([N+](=O)[O-])c1
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1cc(I)cc([N+](=O)[O-])c1
Temperature: 140 °C
Yield: 172.7 %

Procedure:
A mixture of 1,3-dinitrobenzene (125 g), iodine (97 g) and concentrated sulphuric acid (500 ml) was heated to 140° C. for 3.5 hours. The mixture was cooled, poured onto crushed ice and filtered. The solid was washed with water and dried to give 3,5-dinitroiodobenzene (194 g) in 89% yield, m.p. 101°-102° C.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([N:21]([CH:31]2[CH2:33][CH2:32]2)[CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)[C:5]2[N:6]([C:8]([C:11]([NH:13][C:14]3[CH:19]=[CH:18][N:17]=[C:16]([Cl:20])[CH:15]=3)=[O:12])=[CH:9][N:10]=2)[N:7]=1.[S:34]1[CH2:39][CH2:38][CH:37]([NH2:40])[CH2:36][CH2:35]1.CN1C(=O)CCC1>CO>[Cl:20][C:16]1[CH:15]=[C:14]([NH:13][C:11]([C:8]2[N:6]3[N:7]=[C:2]([NH:40][CH:37]4[CH2:38][CH2:39][S:34][CH2:35][CH2:36]4)[CH:3]=[C:4]([N:21]([CH:31]4[CH2:32][CH2:33]4)[CH2:22][C:23]4[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=4)[C:5]3=[N:10][CH:9]=2)=[O:12])[CH:19]=[CH:18][N:17]=1
Reactant: COc1ccc(CN(c2cc(Cl)nn3c(C(=O)Nc4ccnc(Cl)c4)cnc23)C2CC2)cc1
Reactant: NC1CCSCC1
Solvent: CN1CCCC1=O
Solvent: CO
Product: COc1ccc(CN(c2cc(NC3CCSCC3)nn3c(C(=O)Nc4ccnc(Cl)c4)cnc23)C2CC2)cc1
Yield: 23.1 %

Procedure:
A microwave tube was charged with 6-chloro-N-(2-chloropyridin-4-yl)-8-(cyclopropyl(4-methoxybenzyl)amino)imidazo[1,2-b]pyridazine-3-carboxamide (100 mg, 0.207 mmol), tetrahydro-2H-thiopyran-4-amine (121 mg, 1.034 mmol), and NMP (2 mL). The reaction mixture was irradiated at 120° C. (300 W) for 20 minutes. The crude reaction product was dissolved in a small amount of MeOH and purified by reversed phase HPLC (YMC ODS-A 5 um 30×250 mm, 10-90% aqueous methanol containing 0.1% TFA, 25 mL/min, 60 min gradient, monitored at 254 nm). The product (retention time=68.837 minutes) was isolated and lyophilized to dryness to afford N-(2-chloropyridin-4-yl)-8-(cyclopropyl(4-methoxybenzyl)amino)-6-(tetrahydro-2H-thiopyran-4-ylamino)imidazo[1,2-b]pyridazine-3-carboxamide (27 mg, 17.32%). HPLC Rt=4.816 min (YMC S5 ODS 4.6×50 mm, 10-90% aqueous methanol containing 0.2% H3PO4, 4 min gradient, monitored at 220 nm). [M+H+]=563.9.
Reaction SMILES: Br[CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=1)[C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)=O.[NH2:22][C:23]([NH2:25])=[S:24].C([O-])(=O)C.[Na+]>>[F:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]2[N:22]=[C:23]([NH2:25])[S:24][C:2]=2[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=2)=[CH:6][CH:7]=1
Reactant: NC(N)=S
Reactant: O=C(c1ccc(F)cc1)C(Br)Cc1ccc([N+](=O)[O-])cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Product: Nc1nc(-c2ccc(F)cc2)c(Cc2ccc([N+](=O)[O-])cc2)s1
Yield: 71.4 %

Procedure:
A procedure similar to step 5 of Example 6 was used. 2-bromo-1-(4-fluoro-phenyl)-3-(4-nitro-phenyl)-propan-1-one prepared in the step 2, thiourea and anhydrous sodium acetate were used as starting materials. The obtained crude product was recrystallized with a solvent mixture of ethyl acetate and acetone to give a product, which was a yellow solid in a yield of 71.4%, mp: 217-218 └. 1H-NMR (DMSO-d6, 400 MHz) δ: 4.22 (2H, s, CH2), 6.99 (2H, s, NH2), 7.21 (2H, t, 3JFH=3JHH=8.72 Hz, ArH), 7.47 (2H, d, J=8.96 Hz, ArH), 8.03 (2H, dd, 3JHH=9.02, 4JFH=5.60 Hz, ArH), 8.19 (2H, d, J=8.68 Hz, ArH); EI-MS m/e (%): 329.1 (M+, 100), 207.0 (21); HREI-MS Calcd. for C16H12FN3O2S: 329.0634. found: 329.0627. Anal. Calcd. for C16H12FN3O2S: C, 58.35; H, 3.67; N, 12.76. found: C, 58.61; H, 3.52; N, 12.61.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:18]([OH:20])=[O:19])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:21](OCC)(=O)[CH3:22].Cl>[OH-].[Na+]>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:18]([OH:20])=[O:19])[CH2:10][C:11]1[CH:12]=[CH:13][C:14]([O:17][CH2:21][CH3:22])=[CH:15][CH:16]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)O
Reactant: CCOC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCOc1ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)O)cc1
Reaction time: 2 h

Procedure:
N-t-hutoxycarbonyl-L-tyrosine (II, EXAMPLE 1, (235 g, 835 mmol) is dissolved in sodium hydroxide (4N, 705 mL) at 20-25°. Diethyl sullate (210 mL, 1.60 mol) is added over 15-20 min. The reaction mixture is stirred for 2 hr, then it is cooled with ice-bath (internal temperature around 15°). Ethyl acetate (1400 mL) is added, followed by slow addition ot hydrochloric acid (3N, 1410 mL) for 1 hr. The ethyl acetate layer is separated, and the aqueous layer is extracted with ethyl acetate (1400 mL). The ethyl acetate phase is concentrated to about 200 mL, then hexane (1600 mL) is added. The mixture is stirred in an ice-bath for 2 hr, filtered, washed with hexane (800 mL) in 3 portions. The precipitate is dried to give the title compound. The filtrate is concentrated, suspended in ethyl acetate/hexane (80/450 mL) for 2 hr, filtered and washed with hexane (250 mL) in 3 portions and dried to give additional title compound, NMR (MeOH-d4) δ7.11, 6.80, 4.22, 4.05, 3.08, 2.86 and 1.36; CMR δ175.4, 159.3, 157.8, 131.3, 130.4. 115.4, 80.5, 64.4, 56.4, 37.9, 28.7 and 15.2.