Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]1[CH2:11][CH2:10][CH2:9][C:8]2[C:7]([OH:12])=[CH:6][CH:5]=[CH:4][C:3]1=2.[C:13](OC(=O)C)(=[O:15])[CH3:14].C(N(CC)CC)C.CN(C1C=CC=CN=1)C>>[C:13]([NH:1][CH:2]1[CH2:11][CH2:10][CH2:9][C:8]2[C:7]([OH:12])=[CH:6][CH:5]=[CH:4][C:3]1=2)(=[O:15])[CH3:14]
Reactant: NC1CCCc2c(O)cccc21
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccccn1
Solvent: CCN(CC)CC
Product: CC(=O)NC1CCCc2c(O)cccc21
Temperature: 50 °C
Reaction time: 2 h

Procedure:
50 mmol of 5-amino-1-hydroxy-5,6,7,8-tetrahydronaphthalene are stirred in a solution of 200 mmol of acetic anhydride and 200 mmol of triethylamine, to which a spatula-tip of dimethylaminopyridine has been added, for 2 hours. The mixture is filtered, the residue is rinsed thoroughly with tetrahydrofuran and the filtrate is evaporated. The residue is taken up in ethyl acetate and the mixture is washed with 1N HCl, saturated NaHCO3, 1N HCl, saturated NaHCO3 and saturated NaCl solution, dried over Na2SO4 and evaporated. The bis-acetate which remains is dissolved in 100 ml of MeOH and the solution is then added dropwise to 100 ml of 1N KOH at room temperature. The mixture is stirred at an internal temperature of 50° C. for 2 hours and acidified with concentrated HCl and the MeOH is stripped off. The acid aqueous phase is extracted by shaking 2 to 3 times with ethyl acetate and the combined organic phases are dried with Na2SO4 and evaporated. The residue is recrystallized from ethyl acetate.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([CH2:7][O:8][C:9]([NH:11][CH2:12][C:13]([OH:15])=O)=[O:10])=[CH:3][CH:2]=1.[CH3:16][O:17][C:18](=[O:31])[C@@H:19]1[CH2:23][CH2:22][CH:21]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([OH:30])[CH:25]=2)[NH:20]1.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>ClCCl>[CH3:16][O:17][C:18](=[O:31])[C@@H:19]1[CH2:23][CH2:22][CH:21]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([OH:30])[CH:25]=2)[N:20]1[C:13](=[O:15])[CH2:12][NH:11][C:9]([O:8][CH2:7][C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=1)=[O:10]
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Reactant: COC(=O)[C@@H]1CCC(c2cccc(O)c2)N1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)[C@@H]1CCC(c2cccc(O)c2)N1C(=O)CNC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
0.6 g of Z-glycine dissolved in dichloromethane is coupled with 0.83 g of 5-(meta-hydroxyphenyl)proline methyl ester in the presence of 2.06 g of PyBrOP and 2.6 ml of diisopropylethylamine. After stirring for 4 hours at room temperature, the organic phase is washed (sodium hydrogen carbonate, water, citric acid, water), dried over sodium sulphate, filtered and evaporated to dryness. The oily residue is chromatographed on silica gel (n-hexane/ethyl acetate. 4:6). A white solid corresponding to the expected product is obtained.
Reaction SMILES: [C:1]([C:5]1[CH:35]=[CH:34][C:8]([C:9]([N:11]2[C@@H:15]([CH3:16])[C@@H:14]([C:17]3[CH:22]=[N:21][CH:20]=[CH:19][N:18]=3)[CH2:13][C@@:12]2([CH2:30][CH:31]([CH3:33])[CH3:32])[C:23]([O:25]C(C)(C)C)=[O:24])=[O:10])=[CH:7][C:6]=1[O:36][CH3:37])([CH3:4])([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O>>[C:1]([C:5]1[CH:35]=[CH:34][C:8]([C:9]([N:11]2[C@@H:15]([CH3:16])[C@@H:14]([C:17]3[CH:22]=[N:21][CH:20]=[CH:19][N:18]=3)[CH2:13][C@@:12]2([CH2:30][CH:31]([CH3:32])[CH3:33])[C:23]([OH:25])=[O:24])=[O:10])=[CH:7][C:6]=1[O:36][CH3:37])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cc(C(=O)N2[C@@H](C)[C@@H](c3cnccn3)C[C@@]2(CC(C)C)C(=O)OC(C)(C)C)ccc1C(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(C(=O)N2[C@@H](C)[C@@H](c3cnccn3)C[C@@]2(CC(C)C)C(=O)O)ccc1C(C)(C)C

Procedure:
The tert-butyl ester from stage A was deprotected with TFA in a similar manner to that described in Example 1, to afford the title compound as a solid.
Reaction SMILES: [F:1][C:2]1[N:10]=[C:9](F)[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[NH3:12].O>C(N)=O>[NH2:12][C:9]1[CH:8]=[CH:7][C:3]([C:4]([NH2:6])=[O:5])=[C:2]([F:1])[N:10]=1
Reactant: N
Reactant: NC(=O)c1ccc(F)nc1F
Solvent: O
Solvent: NC=O
Product: NC(=O)c1ccc(N)nc1F
Reaction time: 24 h
Yield: 31 %

Procedure:
A solution of 2,6-difluoronicotinamide (4.68 g, 0.029 mmol) in dry formamide (30 mL) is saturated with ammonia and allowed to stand at room temperature for 24 h. Water (50 mL) is added and the resultant precipitate is filtered off and washed well with water, to give 6-amino-2-fluoronicotinamide (1.41 g, 31%) mp 236-237° C. 1H NMR (DMSO) δ 7.89 (1H, dd, J=10.4, 8.4 Hz), 7.31, 7.16 (1H, 1H, 2 brs,), 6.93 (2H, brs), 6.36 (1H, dd, J=8.4, 2.4 Hz).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH3:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=1)[CH2:15][C:16]#[N:17].Br[CH2:22][C:23]1[CH:27]=[C:26]([C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[C:30]([Cl:35])[CH:29]=2)[N:25]([C:36]2[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=2)[N:24]=1>O1CCCC1>[Cl:35][C:30]1[CH:29]=[C:28]([C:26]2[N:25]([C:36]3[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=3)[N:24]=[C:23]([CH2:22][CH:15]([C:14]3[CH:13]=[C:12]([CH3:11])[CH:20]=[CH:19][CH:18]=3)[C:16]#[N:17])[CH:27]=2)[CH:33]=[CH:32][C:31]=1[Cl:34]
Reactant: COc1ccc(-n2nc(CBr)cc2-c2ccc(Cl)c(Cl)c2)cc1
Reactant: Cc1cccc(CC#N)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(-n2nc(CC(C#N)c3cccc(C)c3)cc2-c2ccc(Cl)c(Cl)c2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 42.6 %

Procedure:
To a solution of sodium bis(trimethylsilyl)amide (14.0 mL, 1.0 M solution in THF, 1.0 equiv) in tetrahydrofuran (56.0 mL) at 0° C. was added 3-methylbenzyl cyanide (1.84 g, 14.0 mmol, 1.0 equiv). This mixture was stirred at 0° C. for 30 min then was added to a solution of 3-bromomethyl-5-(3,4-dichloro-phenyl)-1-(4-methoxy-phenyl)-1H-pyrazole (prepared as in Method 1; 5.78 g, 14.0 mmol, 1.0 equiv) in tetrahydrofuran (56.0 mL) and allowed to stir for 2 h. The reaction was quenched with satd aq ammonium chloride (10.0 mL), and the resulting mixture was diluted with water (200 mL), and extracted with diethyl ether (2×100 mL). The combined extracts were dried (Na2SO4) and concentrated under reduced pressure. The crude material was purified by flash chromatography (25% ethyl acetate/hexanes) to yield the title intermediate (2.76 g, 43%). HPLC: Rt=13.44 (Method G). MS (ESI): mass calculated for C26H21Cl2N3O, 461.11; m/z found, 462.0 [M+H]+. 1H NMR (500 MHz, CDCl3): 7.36 (d, J=1.9 Hz, 1H), 7.33 (d, J=8.2 Hz, 1H), 7.28 (t, J=7.4 Hz, 1H), 7.24 (s, 1H), 7.23-7.21 (m, 1H), 7.18 (d, J=8.8 Hz, 2H), 7.19-7.16 (m, 1H), 6.95 (dd, J=8.5, 2.2 Hz, 1H), 6.89 (d, J=8.8 Hz, 2H), 6.42 (s, 1H), 4.22 (dd, J=9.6, 6.0 Hz, 1H), 3.83 (s, 3H), 3.30-3.21 (m, 2H), 2.38 (s, 3H).
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[K+].[K+].[CH2:34]([N:41]1[CH2:46][CH2:45][O:44][CH:43]([CH2:47]Cl)[CH2:42]1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.CN(C)C=O>C(OCC)(=O)C>[CH2:34]([N:41]1[CH2:46][CH2:45][O:44][CH:43]([CH2:47][N:8]2[C:9](=[O:26])[C:10]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([C:18]4[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:14][CH:13]=3)=[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])[N:6]=[C:7]2[CH3:27])[CH2:42]1)[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: ClCC1CN(Cc2ccccc2)CCO1
Reactant: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCc1nc(C)n(CC2CN(Cc3ccccc3)CCO2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
A mixture of 4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1.25 g), potassium carbonate (0.96 g), 4-benzyl-2-(chloromethyl)morpholine (0.87 g) and N,N-dimethylformamide (20 mL) was stirred at 90° C. for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless viscous substance (0.62 g, 34%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][S:5]([OH:8])(=[O:7])=[O:6].C(=O)(O)[O-].[Na+].[Cl:14][C:15]1[CH:16]=[C:17]2[C:22](=[C:23]([Cl:25])[CH:24]=1)[CH2:21][N:20]([CH3:26])[CH2:19][CH:18]2[C:27]1[CH:28]=[C:29]([S:33](Cl)(=[O:35])=[O:34])[CH:30]=[CH:31][CH:32]=1.Cl>O1CCCC1.O>[Cl:14][C:15]1[CH:16]=[C:17]2[C:22](=[C:23]([Cl:25])[CH:24]=1)[CH2:21][N:20]([CH3:26])[CH2:19][CH:18]2[C:27]1[CH:28]=[C:29]([S:33]([NH:1][CH2:2][CH2:3][CH2:4][S:5]([OH:8])(=[O:7])=[O:6])(=[O:35])=[O:34])[CH:30]=[CH:31][CH:32]=1
Reactant: NCCCS(=O)(=O)O
Reactant: CN1Cc2c(Cl)cc(Cl)cc2C(c2cccc(S(=O)(=O)Cl)c2)C1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CN1Cc2c(Cl)cc(Cl)cc2C(c2cccc(S(=O)(=O)NCCCS(=O)(=O)O)c2)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 4.2 %

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of 3-aminopropane-1-sulfonic acid (180 mg, 1.29 mmol, 1.00 equiv) in tetrahydrofuran/water (10/10 mL) with sodium bicarbonate (430 mg, 5.12 mmol). This was followed by the addition of 3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzene-1-sulfonyl chloride (500 mg, 1.29 mmol, 0.99 equiv) in several batches. The resulting solution was stirred for 4 h at room temperature. The reaction progress was monitored by LCMS. The pH value of the solution was adjusted to 6 with 1M hydrogen chloride. The resulting mixture was concentrated under vacuum. The crude product (500 mg) was purified by preparative HPLC to give 26.7 mg of the title compound (4%) as a TFA salt. 1H-NMR (300 MHz, DMSO, ppm): 10.28 (s, 1H), 7.53˜7.79 (m, 6H), 6.83 (s, 1H), 4.74 (s, 2H), 4.51 (s, 1H), 3.90 (s, 1H), 3.06 (s, 3H), 2.86˜2.93 (m, 2H), 2.33˜2.44 (m, 2H), 1.58˜1.63 (m, 2H). MS (ES, m/z): 493 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH3:11].N[C:13]1C(Cl)=NC(C)=NC=1NC>>[Cl:1][C:2]1[N:10]=[C:9]([CH3:13])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH3:11]
Reactant: Cn1cnc2c(Cl)ncnc21
Reactant: CNc1nc(C)nc(Cl)c1N
Product: Cc1nc(Cl)c2ncn(C)c2n1
Reaction time: 6 h
Yield: 97 %

Procedure:
This was prepared in a manner similar to that described in Example 9 for 6-chloro-9-methylpurine, except that 5-amino-4-chloro-2-methyl-6-methylaminopyrimidine was used as the starting material and the reaction was carried out at 60° C. for 6 hrs. The title compound was obtained in 97% yield.
Reaction SMILES: [C:1]([C:9]1([OH:53])[CH2:14][CH2:13][CH2:12][CH:11]([NH:15][C:16]([C:18]2[CH:19]=[C:20]3[C:24](=[CH:25][CH:26]=2)[N:23](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[N:22]=[C:21]3[C:46]2[CH:51]=[CH:50][N:49]=[C:48]([CH3:52])[CH:47]=2)=[O:17])[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)(C(F)(F)F)=O.C1(SC)C=CC=CC=1>[C:1]([C:9]1([OH:53])[CH2:14][CH2:13][CH2:12][CH:11]([NH:15][C:16]([C:18]2[CH:19]=[C:20]3[C:24](=[CH:25][CH:26]=2)[NH:23][N:22]=[C:21]3[C:46]2[CH:51]=[CH:50][N:49]=[C:48]([CH3:52])[CH:47]=2)=[O:17])[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3ccc(C(=O)NC4CCCC(O)(C(=O)c5ccccc5)C4)cc23)ccn1
Solvent: CSc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2n[nH]c3ccc(C(=O)NC4CCCC(O)(C(=O)c5ccccc5)C4)cc23)ccn1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A solution of N-(3-benzoyl-3-hydroxycyclohexyl)-3-(2-methylpyridin-4-yl)-1-trityl-1H-indazole-5-carboxamide in a mixture of TFA (1 mL) and thioanisole (0.5 mL) was stirred at room temperature for 20 minutes, and then concentrated. The product was obtained after purification by reverse phase HPLC.
Reaction SMILES: [CH2:1]([C:3]1[S:28][C:6]2[N:7]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)[C:8](=[O:12])[NH:9][C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2].Br[CH2:30][C:31]([C:33]1[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][C:34]=1[O:41][CH3:42])=[O:32].CN(C)C=O.[H-].[Na+]>C(OCC)(=O)C>[CH3:42][O:41][C:34]1[CH:35]=[C:36]([O:39][CH3:40])[CH:37]=[CH:38][C:33]=1[C:31](=[O:32])[CH2:30][N:9]1[C:10](=[O:11])[C:5]2[CH:4]=[C:3]([CH2:1][CH3:2])[S:28][C:6]=2[N:7]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=3)=[CH:16][CH:15]=2)[C:8]1=[O:12]
Reactant: COc1ccc(C(=O)CBr)c(OC)c1
Reactant: CCc1cc2c(=O)[nH]c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCc1cc2c(=O)n(CC(=O)c3ccc(OC)cc3OC)c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.3 %

Procedure:
To a mixture of 4′-[(6-ethyl-2,4-dioxo-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)-yl)methyl]biphenyl-2-carbonitrile (1 g), 2-bromo-1-(2,4-dimethoxyphenyl)ethanone (0.83 g) and N,N-dimethylformamide (50 mL) was added 60% sodium hydride (0.15 g), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% potassium hydrogensulfate and then saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.91 g, 62%).
Reaction SMILES: CS(O[CH:6]([CH:17]([CH3:19])[CH3:18])[C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:16])[CH3:15])=[CH:9][CH:8]=1)(=O)=O.[NH:20]1[CH:24]=[N:23][CH:22]=[N:21]1.C([O-])([O-])=O.[K+].[K+]>CC#N>[CH3:18][CH:17]([CH3:19])[CH:6]([C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:16])[CH3:15])=[CH:9][CH:8]=1)[N:20]1[CH:24]=[N:23][CH:22]=[N:21]1
Reactant: CC(=O)Nc1ccc(C(OS(C)(=O)=O)C(C)C)cc1
Reactant: c1nc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(=O)Nc1ccc(C(C(C)C)n2cncn2)cc1
Yield: 25.1 %

Procedure:
A mixture of (±)-4-(acetylamino)-α-(1-methylethyl)benzenemethanol methane sulfonate (ester) (0.1541 mol), 1H-1,2,4-triazole (0.308 mol) and K2CO3 (0.308 mol) in CH3CN (500 ml) was stirred and refluxed for 12 hours. The solvent was evaporated and the residue was taken up in water/CH2Cl2. The organic layer was dried, filtered off and the solvent evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH 97/3). The pure fractions were collected and evaporated, yielding 10 g (25%) of (±)—N-[4-[2-methyl-1-(1H-1,2,4-triazol-1-yl)propyl]phenyl]acetamide (compound 153).
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:12])[NH:9][CH:10]=[CH:11][C:5]=2[CH:4]=1.[H-].[Na+].Cl[CH2:20][CH2:21][CH2:22][N:23]([CH3:31])[C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27]>CN(C=O)C>[CH3:1][O:2][C:3]1[C:14]([O:15][CH3:16])=[CH:13][C:6]2[CH2:7][C:8](=[O:12])[N:9]([CH2:20][CH2:21][CH2:22][N:23]([CH3:31])[C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH:10]=[CH:11][C:5]=2[CH:4]=1
Reactant: COc1cc2c(cc1OC)CC(=O)NC=C2
Reactant: CN(CCCCl)C(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc2c(cc1OC)CC(=O)N(CCCN(C)C(=O)OC(C)(C)C)C=C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 137.9 %

Procedure:
Suspend 1.7 g (7.8 mmol) of 7,8-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one in 35 ml of DMF and then add 374 mg (9.35 mmol, 1.2 equivalents) of sodium hydride (60% suspension in oil). A clear pale yellow solution is obtained, which is stirred for one hour at 25° C. 1.94 g (9.35 mmol, 1.2 equivalent) of tert-butyl (3-chloropropyl)methylcarbamate dissolved in 10 ml of DMF are then added dropwise. The whole is heated at 50° C. overnight and then the solvent is evaporated to dryness. The residue is taken up in water and extracted with dichloromethane. The organic phase is dried over MgSO4, filtered and then evaporated to dryness. 4.2 g of an oil is obtained which is purified by flash chromatography on 200 g of silica (eluant=dichloromethane/ethyl acetate:80/20). 2.3 g of the expected product are obtained in the form of a colourless oil.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[CH:8]=2)[N:6]=1.[N:14]1([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[F:13][C:9]1[CH:8]=[C:7]([C:5]2[N:6]=[C:2]([N:17]3[CH2:16][CH2:15][N:14]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:19][CH2:18]3)[S:3][CH:4]=2)[CH:12]=[CH:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Fc1cccc(-c2csc(Br)n2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2nc(-c3cccc(F)c3)cs2)CC1
Yield: 69.3 %

Procedure:
A solution of 2-bromo-4-(3-fluorophenyl)-1,3-thiazole (800 mg, 3.10 mmol), tert-butyl piperazine-1-carboxylate (1.15 g, 6.20 mmol) and potassium carbonate (428 mg, 3.10 mmol) in dimethylformamide (10 ml) was stirred at 120° C. for 12 hours. Water was poured into the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to give 781 mg (69.4%) of the desired product as an oil.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]([C:7]1[S:8][C:9]([I:22])=[C:10]([C:20]#[N:21])[C:11]=1[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=1[Cl:19])=O.C1(C)C=CC=CC=1.P(Cl)(Cl)(Cl)=O>>[Cl:19][C:13]1[CH:14]=[C:15]([Cl:18])[CH:16]=[CH:17][C:12]=1[C:11]1[C:10]([C:20]#[N:21])=[C:9]([I:22])[S:8][C:7]=1[C:5]1[NH:4][CH2:3][CH2:2][N:1]=1
Reactant: N#Cc1c(I)sc(C(=O)NCCN)c1-c1ccc(Cl)cc1Cl
Solvent: Cc1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: N#Cc1c(I)sc(C2=NCCN2)c1-c1ccc(Cl)cc1Cl
Temperature: 120 °C
Yield: 89.6 %

Procedure:
To a mixture of N-(2-aminoethyl)-4-cyano-3-(2,4-dichlorophenyl)-5-iodothiophene-2-carboxamide (1.16 g, 0.00249 mol) in Toluene (20 mL, 0.19 mol) in a pressure vessel was added Phosphoryl chloride (2.0 mL, 0.022 mol) and the mixture was heated at 120° C. for 3 hours. Solvent was evaporated and the residue was diluted with water, treated with 1N NaOH (10 mL) and extracted with DCM (5×50 mL). The combined DCM layers were washed with brine, dried with MgSO4, filtered and concentrated to afford the product (1.00 g, 89%). LCMS: (FA) ES+, 448, 450. 1H NMR (400 MHz, d6-DMSO) δ: 7.81-7.78 (m, 1H) 7.56-7.52 (m, 1H), 7.50-7.47 (m, 1H), 3.67-3.59 (m, 2H), 3.25-3.17 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([F:11])[CH:10]=1)[C:5](O)=[O:6].B.C1COCC1.CO>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH2:5][OH:6])[CH:8]=[C:9]([F:11])[CH:10]=1
Reactant: O=C(O)c1cc(F)cc(Br)c1
Agent: B
Solvent: CO
Solvent: C1CCOC1
Product: OCc1cc(F)cc(Br)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 3-bromo-5-fluorobenzoic acid (4.51 g, 20.59 mmol) in THF (41.2 mL) at 0° C., BH3.THF (41.2 mL, 41.2 mmol) was added dropwise over 30 min, the reaction mixture was then allowed to return to room temperature and stirred at room temperature overnight. Methanol (40 mL) was added slowly and stirred at room temperature for 1 h. THF and Methanol was removed in vacuo. The residue was then extracted by EtOAc, and washed with sat.NaHCO3, The organic was dried and concentrated. The crude product was used in next step reaction without purification. LCMS (m/z): 187.2 (MH+−18), 0.66 min. 1H NMR (400 MHz, CDCl3) δ ppm 7.32 (s, 1H), 7.19-7.14 (m, 1H), 7.05 (tdd, J=0.7, 1.5, 9.1 Hz, 1H), 4.70 (br. s., 2H), 1.78 (br. s., 1H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][CH:7]=1.CCN(C(C)C)C(C)C.[CH2:18]1[C@@H:22]2[CH2:23][NH:24][CH2:25][C@@H:21]2[CH2:20][N:19]1[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27]>C(O)CCC.C(Cl)Cl.O>[Cl:1][C:2]1[N:3]=[N:4][C:5]([N:24]2[CH2:23][C@@H:22]3[CH2:18][N:19]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:20][C@@H:21]3[CH2:25]2)=[CH:6][CH:7]=1
Reactant: Clc1ccc(Cl)nn1
Reactant: CC(C)(C)OC(=O)N1C[C@H]2CNC[C@H]2C1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: CC(C)(C)OC(=O)N1C[C@@H]2CN(c3ccc(Cl)nn3)C[C@@H]2C1
Temperature: 120 °C
Yield: 70.3 %

Procedure:
To a solution of 3,6-dichloropyridazine (462 mg, 3.10 mmol) in n-butanol (8 mL) was added DIPEA (1.354 ml, 7.75 mmol) and (3aR,6aS)-tert-butyl hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (658 mg, 3.1 mmol). The reaction mixture was heated at 120° C. for 2 hour, and then diluted with DCM and water. The organic layer was separated and concentrated to a brownish oil, which was purified by silica gel chromatography (0-25% EtOAc/DCM) to afford (3aR,6aS)-tert-butyl 5-(6-chloropyridazin-3-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (730 mg, 2.180 mmol, 70% yield), MS (M+1)=325.2.
Reaction SMILES: [C:1]1([C:7]2([C:12]3[CH:30]=[CH:29][C:15]([CH2:16][N:17]4[CH2:22][CH2:21][N:20]([CH2:23][C:24](OCC)=[O:25])[CH2:19][CH2:18]4)=[CH:14][CH:13]=3)[O:11][CH2:10][CH2:9][O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:31][NH2:32]>C(O)C>[C:1]1([C:7]2([C:12]3[CH:30]=[CH:29][C:15]([CH2:16][N:17]4[CH2:22][CH2:21][N:20]([CH2:23][C:24]([NH:31][NH2:32])=[O:25])[CH2:19][CH2:18]4)=[CH:14][CH:13]=3)[O:11][CH2:10][CH2:9][O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NN
Reactant: CCOC(=O)CN1CCN(Cc2ccc(C3(c4ccccc4)OCCO3)cc2)CC1
Solvent: CCO
Product: NNC(=O)CN1CCN(Cc2ccc(C3(c4ccccc4)OCCO3)cc2)CC1
Yield: 74.2 %

Procedure:
Synthesized according to General Procedure C: 14 (2.54 g, 6.19 mmol, 1 equiv.), anhydrous hydrazine (0.78 mL, 24.8 mmol, 4 equiv.), ethanol (12 mL). 15 (1.82 g, 74%) was obtained as a white solid, which was used without further purification after extraction. 1H-NMR (500 MHz, CDCl3): δ 8.14 (br s, 1H), 7.52-7.50 (m, 2H), 7.44 (d, 2H, J=8.0 Hz), 7.33-7.30 (m, 2H), 7.28-7.23 (m, 3H), 4.07-4.04 (m, 2H), 4.03-4.00 (m, 2H), 3.85 (br s, 2H), 3.46 (s, 2H), 3.04 (s, 2H), 2.50 (br s, 4H), 2.43 (br s, 4H). 13C-NMR (125 MHz, CDCl3): δ 170.4, 142.0, 140.9, 137.7, 128.7, 128.0, 127.9, 126.0, 125.9, 109.2, 64.7, 62.4, 60.5, 53.5, 52.9.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[N:11]1[C:14](=[O:15])[C:13]([CH3:17])([CH3:16])[NH:12]1)[CH2:8]2.[F:18][C:19]1[C:20]([CH3:28])=[C:21]([CH:25]=[CH:26][CH:27]=1)[C:22](O)=[O:23].C(N(C(C)C)CC)(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>ClCCl.O>[F:18][C:19]1[C:20]([CH3:28])=[C:21]([C:22]([N:12]2[C:13]([CH3:17])([CH3:16])[C:14](=[O:15])[N:11]2[CH:2]2[CH:3]3[CH2:4][CH:5]4[CH2:6][CH:7]([CH2:8][CH:1]2[CH2:10]4)[CH2:9]3)=[O:23])[CH:25]=[CH:26][CH:27]=1
Reactant: CC1(C)NN(C2C3CC4CC(C3)CC2C4)C1=O
Reactant: Cc1c(F)cccc1C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cc1c(F)cccc1C(=O)N1N(C2C3CC4CC(C3)CC2C4)C(=O)C1(C)C
Reaction time: 18 h
Yield: 8.7 %

Procedure:
A solution of 2-(adamantan-2-yl)-4,4-dimethyl-1,2-diazetidin-3-one (50.0 mg, 0.213 mmol) prepared in Process 3 of Example 12 in dichloromethane was added with 3-fluoro-2-methylbenzoic acid (32.8 mg, 0.213 mmol), diisopropylethylamine (82.6 mg, 0.639 mmol) and PyBOP (133 mg, 0.256 mmol) at room temperature, and the resultant was stirred at the same temperature for 18 hours. The reaction solution was added with water and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, concentrated in vacuo, the obtained residue was purified using Preparative Thin-Layer chromatography (hexane:ethyl acetate=2:1), and the title compound (6.90 mg, 8.70%) was obtained as a white crystalline solid.