Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1)#[N:2].[F:9][C:10]1[CH:16]=[CH:15][C:13]([NH2:14])=[CH:12][CH:11]=1>>[F:9][C:10]1[CH:16]=[CH:15][C:13]([NH:14][C:1]([C:3]2[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=2)=[NH:2])=[CH:12][CH:11]=1
Reactant: N#Cc1cccnc1
Reactant: Nc1ccc(F)cc1
Product: N=C(Nc1ccc(F)cc1)c1cccnc1
Yield: 76.9 %

Procedure:
The title compound was prepared from 3-cyanopyridine (0.94 g, 9 mmol) and 4-fluoroaniline (1 g, 9 mmol) by following the procedure described in preparation 10 (1.5 g, yield 76.9%, purity 97.95% by HPLC). 1H-NMR (CDCl3):δ 4.93 (bs, 2H, D2O exchangeable), 6.92-6.96 (m, 2H), 7.05-7.07 (m, 2H), 7.38-7.41 (m, 1H), 8.22 (s, 1H), 8.71-8.72 (d, 1H), 9.06 (s, 1H). MS m/z:216.3 (M+).
Reaction SMILES: [CH3:1][CH:2]([CH3:19])[CH2:3][CH2:4][N:5]1[C:12](=[O:13])[CH2:11][C:9](=[O:10])[N:8]([CH2:14][CH2:15][CH:16]([CH3:18])[CH3:17])[C:6]1=[O:7].N1C=CC=CC=1.[C:26](Cl)(=[O:31])[CH2:27][CH:28]([CH3:30])[CH3:29]>ClCCl>[CH3:17][CH:16]([CH3:18])[CH2:15][CH2:14][N:8]1[C:9](=[O:10])[CH:11]([C:26](=[O:31])[CH2:27][CH:28]([CH3:30])[CH3:29])[C:12](=[O:13])[N:5]([CH2:4][CH2:3][CH:2]([CH3:19])[CH3:1])[C:6]1=[O:7]
Reactant: CC(C)CC(=O)Cl
Reactant: CC(C)CCN1C(=O)CC(=O)N(CCC(C)C)C1=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)CCN1C(=O)C(C(=O)CC(C)C)C(=O)N(CCC(C)C)C1=O
Temperature: 0 °C
Yield: 78.9 %

Procedure:
To a solution of 1,3-bis(3-methylbutyl)barbituric acid 268 mg (1.00 mmol) in dry dichloromethane 3.0 mL under a nitrogen atmosphere, added was pyridine 0.81 mL (0.79 g, 10 mmol, 10 equivalents) and stirred at 0° C. Added was isovaleryl chloride 121 mg (1.00 mmol, 1.00 equivalent) in dichloromethane 1.5 mL to the solution slowly during a period of 20 minutes, then stirred at room temperature for 4 hours. Added was dichloromethane 40 mL and washed the organic layer with 2 M hydrochloric acid and saturated brine, and dried over sodium sulfate. Purified was the crude product 383 mg, after removal of the solvent under the reduced pressure, by column chromatography (silica gel, eluted with dichloromethane). It obtained 1,3-bis(3-methylbutyl)-5-(3-methyl-1-oxobutyl)barbituric acid 278 mg as white plates (79.0% yield).
Reaction SMILES: [NH:1]([C:5]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:6]=1[OH:12])[C:2]([CH3:4])=[O:3].[N+:13]([O-])([OH:15])=[O:14].O>C(OC(=O)C)(=O)C>[NH:1]([C:5]1[CH:10]=[C:9]([Cl:11])[CH:8]=[C:7]([N+:13]([O-:15])=[O:14])[C:6]=1[OH:12])[C:2]([CH3:4])=[O:3]
Reactant: CC(=O)Nc1cc(Cl)ccc1O
Reactant: O=[N+]([O-])O
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Nc1cc(Cl)cc([N+](=O)[O-])c1O
Yield: 31 %

Procedure:
Under ice cooling, a solution of 2-acetamino-4-chlorophenol (1.0 g, 5.4 mmol) in acetic anhydride (90 mL) was added with 70% nitric acid (0.38 mL, d=1.42) with stirring. After stirring for 2 hours, the mixture was added with water (100 mL), and the mixture was further stirred for 1 hour. The mixture was extracted by adding diethyl ether, and washed twice with water. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The resultant mixture was purified by silica gel column chromatography (ethyl acetate:n-hexane=5:1 v/v) to obtain the title compound (0.38 g, 31%).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].Br[C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[N:13]([CH:17]([CH3:19])[CH3:18])[CH:12]=[C:11]2[CH:20]=[O:21].[F:22][C:23]1[C:28]([F:29])=[C:27]([F:30])[CH:26]=[CH:25][C:24]=1B(O)O>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:18][CH:17]([N:13]1[C:14]2[C:10](=[CH:9][C:8]([C:26]3[CH:25]=[CH:24][C:23]([F:22])=[C:28]([F:29])[C:27]=3[F:30])=[CH:16][CH:15]=2)[C:11]([CH:20]=[O:21])=[CH:12]1)[CH3:19]
Reactant: OB(O)c1ccc(F)c(F)c1F
Reactant: CC(C)n1cc(C=O)c2cc(Br)ccc21
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: CC(C)n1cc(C=O)c2cc(-c3ccc(F)c(F)c3F)ccc21
Temperature: 80 °C
Reaction time: 12 h
Yield: 83.8 %

Procedure:
Sodium carbonate (0.188 mL, 2M, 0.376 mmol) was added to a stirred room temperature solution of 5-bromo-1-(propan-2-yl)-1H-indole-3-carbaldehyde (50 mg, 0.188 mmol), 2,3,4-trifluorophenylboronic acid (66 mg, 0.376 mmol) and PdCl2(dppf) (13.7 mg, 0.019 mmol) in DMF (1.0 mL) and the reaction mixture was stirred at 80° C. for 12 hours. The reaction mixture was cooled to room temperature, partitioned between ethyl acetate (2×15 mL) and water (10 mL), washed with saturated sodium bicarbonate (10 mL), brine (10 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (50 mg).
Reaction SMILES: Cl.C(N=C=NCCCN(C)C)C.[S:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[CH:15]=[C:14]1[C:22]([NH:24][C:25]1([C:31]([OH:33])=[O:32])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1)=O>C(Cl)Cl>[S:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[CH:15]=[C:14]1[C:22]1[O:33][C:31](=[O:32])[C:25]2([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]2)[N:24]=1
Reactant: O=C(NC1(C(=O)O)CCCCC1)c1cc2ccccc2s1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: O=C1OC(c2cc3ccccc3s2)=NC12CCCCC2
Temperature: 25 °C
Reaction time: 4 h
Yield: 76.7 %

Procedure:
4.1 g (21 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride was added to a solution of 5 g (16 mmol) of 1-[(2-benzothienylcarbonyl)amino]cyclohexanecarboxylic acid in 50 ml of methylene chloride. After the mixture was stirred at room temperature for 4 hours, the reaction solution was concentrated under reduced pressure, ethyl acetate was added thereto, and the mixture was successively washed with water, a 10% aqueous potassium hydrogensulfate solution, a saturated aqueous sodium hydrogencarbonate solution and saturated brine. The organic layer was dried with anhydrous sodium sulfate and the solvent was distilled off under reduced pressure to obtain 3.5 g (75%) of the title compound.
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][N:4]=1)#[CH:2].[N:12]([C:15]1[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][CH:16]=1)=[N+:13]=[N-:14]>O1CCOCC1.O.C(OCC)(=O)C>[Br:21][C:18]1[CH:19]=[CH:20][C:15]([N:12]2[CH:2]=[C:1]([C:3]3[C:11]4[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=4)[NH:5][N:4]=3)[N:14]=[N:13]2)=[CH:16][CH:17]=1
Reactant: [N-]=[N+]=Nc1ccc(Br)cc1
Reactant: C#Cc1n[nH]c2ccccc12
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: Brc1ccc(-n2cc(-c3n[nH]c4ccccc34)nn2)cc1
Temperature: 80 °C
Yield: 62.7 %

Procedure:
To a solution of 3-Ethynyl-1H-indazole (6.0 g, 42.2 mmol) in Dioxane (60 mL) were added 4-Azidobromobenzene (Ukrorgsynthesis Ltd., 9.19 g, 46.4 mmol), D-(−)-Iso ascorbic acid sodium salt (0.83 g, 4.2 mmol) and a solution of CuSO4.5H2O (0.21 g, 0.8 mmol) in water (10 mL). The reaction mixture was heated at 80° C. for 3 days. After completion of the reaction, the reaction mixture was cooled to RT, diluted with ethyl acetate, washed with water and brine, dried over sodium sulfate and concentrated. The crude compound was recrystallized from methanol and dried under vacuum to afford the title compound as brown solid (9.0 g, 63%). 1H NMR (400 MHz, DMSO-d6) δ 13.36 (s, 1H), 9.36 (s, 1H), 8.35-8.33 (d, J=8.1 Hz, 1H), 8.06-8.02 (m, 2H), 7.86-7.82 (m, 2H), 7.61-7.59 (d, J=8.4 Hz, 1H), 7.45-7.41 (m, 1H), 7.26-7.22 (m, 1H).
Reaction SMILES: [Cl-].[CH2:2]([O:9][C:10]1[CH:15]=[C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:13]=[CH:12][C:11]=1[CH:24]1[CH2:29][CH2:28][NH2+:27][CH2:26][CH2:25]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(CC)C(C)C)(C)C.[N+](C1C=CC([O:48][C:49](=O)[NH:50][C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][N:52]=2)=CC=1)([O-])=O.O>CN(C)C=O>[N:52]1[CH:53]=[CH:54][CH:55]=[CH:56][C:51]=1[NH:50][C:49]([N:27]1[CH2:28][CH2:29][CH:24]([C:11]2[CH:12]=[CH:13][C:14]([O:16][CH2:17][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[CH:15][C:10]=2[O:9][CH2:2][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:25][CH2:26]1)=[O:48]
Reactant: c1ccc(COc2ccc(C3CC[NH2+]CC3)c(OCc3ccccc3)c2)cc1
Reactant: O=C(Nc1ccccn1)Oc1ccc([N+](=O)[O-])cc1
Agent: [Cl-]
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1ccccn1)N1CCC(c2ccc(OCc3ccccc3)cc2OCc2ccccc2)CC1
Temperature: 80 °C
Reaction time: 24 h
Yield: 3.3 %

Procedure:
0.5 g of 4-(2,4-bis(benzyloxy)phenyl)piperidinium chloride is suspended in 5 ml of dimethylformamide and then 0.43 ml of N,N-diisopropylethylamine is added, as is 0.38 g of pyridin-2-ylcarbamic acid 4-nitrophenyl ester in solution in 2 ml of dimethylformamide. The reaction mixture is stirred for 24 hours at 80° C. It is heated at 80° C. for 24 hours. 50 ml of water are added, and the reaction mixture is then extracted with 50 ml of ethyl acetate. The solvents are evaporated off and then the residue is chromatographed on silica gel (70/30 heptane/ethyl acetate). 20 mg of 4-(2,4-bis(benzyloxy)phenyl)piperidine-1-carboxylic acid pyridin-2-ylamide are obtained.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[CH:4][C:3]=1[CH3:10].Br[CH:12]1[CH2:16][CH2:15][N:14]([CH3:17])[C:13]1=[O:18].C([O-])([O-])=O.[K+].[K+]>CN(C)C=O>[Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([O:9][CH:12]2[CH2:16][CH2:15][N:14]([CH3:17])[C:13]2=[O:18])=[CH:4][C:3]=1[CH3:10]
Reactant: CN1CCC(Br)C1=O
Reactant: Cc1cc(O)cc(C)c1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(OC2CCN(C)C2=O)cc(C)c1Br
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 4-bromo-3,5-dimethylphenol (100 mg) in N,N-dimethylformamide (2 mL) is added 3-bromo-1-methylpyrrolidin-2-one (100 mg) and K2CO3 (105 mg). The mixture is stirred for 12 hours at room temperature. Then the mixture is partitioned between water and diethylether. The organic phase is dried (MgSO4) and concentrated. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 80:20→50:50) to give the title compound. Yield: 65 mg; LC (method 7): tR=1.0 min; Mass spectrum (ESI+): m/z=298 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]2[C:11](=[O:12])[NH:10][C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[NH:7][C:6]=12.[C:17](Cl)([Cl:19])=[O:18]>O1CCOCC1.C1(C)C=CC=CC=1>[Cl:19][C:17]([N:7]1[C:8]2[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=2[NH:10][C:11](=[O:12])[C:5]2=[CH:4][S:3][C:2]([CH3:1])=[C:6]12)=[O:18]
Reactant: O=C(Cl)Cl
Reactant: Cc1scc2c1Nc1ccccc1NC2=O
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: Cc1scc2c1N(C(=O)Cl)c1ccccc1NC2=O

Procedure:
From 4,9-dihydro-3-methyl-10H-thieno[3,4-b][1,5]benzodiazepin-10-one and phosgene in a mixture of dioxane and toluene, 4-chlorocarbonyl-4,9-dihydro-3-methyl-10H-thieno[3,4-b][1,5]benzodiazepin-10-one was obtained;
Reaction SMILES: [OH:1][CH2:2][C:3]([CH3:38])([CH3:37])[O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:16](=[O:17])[C:15]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[C:26]([C:31]#[N:32])=[CH:27][CH:28]=[CH:29][CH:30]=4)=[CH:21][CH:20]=3)=[C:14]([CH2:33][CH2:34][CH3:35])[N:13]=[C:12]2[CH3:36])=[CH:7][CH:6]=1.[H-].[Na+].CI.[C:43](OCC)(=O)C>CN(C)C=O.O>[CH3:43][O:1][CH2:2][C:3]([CH3:37])([CH3:38])[O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:16](=[O:17])[C:15]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[C:26]([C:31]#[N:32])=[CH:27][CH:28]=[CH:29][CH:30]=4)=[CH:21][CH:20]=3)=[C:14]([CH2:33][CH2:34][CH3:35])[N:13]=[C:12]2[CH3:36])=[CH:7][CH:6]=1
Reactant: CCOC(C)=O
Reactant: CCCc1nc(C)n(-c2ccc(OC(C)(C)CO)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Solvent: CN(C)C=O
Product: CCCc1nc(C)n(-c2ccc(OC(C)(C)COC)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1

Procedure:
To a solution of 4′-({1-[4-(2-hydroxy-1,1-dimethylethoxy)phenyl]-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile (0.69 g) in N,N-dimethylformamide (7 mL) were added 60% sodium hydride (0.065 g) and then methyl iodide at 0° C., and the mixture was stirred for 1 hr. Ethyl acetate and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography to give the title compound as a pale-yellow viscous substance (0.52 g, 74%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][CH2:11][C@H:10]([CH2:13][NH:14][S:15]([NH2:18])(=[O:17])=[O:16])[O:9][C:8]=2[CH:19]=1)([O-])=O.[N+](C1C=C(O)C(=CC=1)O)([O-])=O>CO.Cl.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]2[O:12][CH2:11][C@H:10]([CH2:13][NH:14][S:15]([NH2:18])(=[O:17])=[O:16])[O:9][C:8]=2[CH:19]=1
Reactant: NS(=O)(=O)NC[C@H]1COc2ccc([N+](=O)[O-])cc2O1
Agent: [Pd]
Agent: Cl
Agent: O=[N+]([O-])c1ccc(O)c(O)c1
Solvent: CO
Product: Nc1ccc2c(c1)O[C@@H](CNS(N)(=O)=O)CO2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
(2S)-(−)-N-(2,3-Dihydro-7-nitro-benzo[1,4]dioxin-2-ylmethyl)-sulfamide (1.2 g, 4.15 mmol), was prepared from 4-nitrocatechol according to the process outlined in Example 4. The (2S)-(−)-N-(2,3-Dihydro-7-nitro-benzo[1,4]dioxin-2-ylmethyl)-sulfamide, was then combined with 10% Pd/C in methanol (120 mL) and shaken under hydrogen atmosphere (39 psi) at room temperature for 3 h. The solids were filtered and washed with 10% M in DCM and the filtrate was evaporated in vacuo to yield crude product. The crude product was dissolved in 0.2 N HCl (25 mL), frozen and lyophilized to yield the title compound as a white flaky solid, as the corresponding hydrochloride salt.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[CH:9]=[C:8]([O:10][C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][CH:15]=[CH:14]3)[CH:7]=[CH:6][N:5]=1.[F:20][CH2:21][CH2:22][NH:23][C:24](=O)[O:25]C1C=CC=CC=1.O>CN(C)C=O>[F:20][CH2:21][CH2:22][NH:23][C:24]([N:16]1[C:17]2[C:13](=[CH:12][C:11]([O:10][C:8]3[CH:7]=[CH:6][N:5]=[C:4]([NH2:3])[CH:9]=3)=[CH:19][CH:18]=2)[CH:14]=[CH:15]1)=[O:25]
Reactant: Nc1cc(Oc2ccc3[nH]ccc3c2)ccn1
Reactant: O=C(NCCF)Oc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1cc(Oc2ccc3c(ccn3C(=O)NCCF)c2)ccn1
Reaction time: 0.08 h
Yield: 69.2 %

Procedure:
Sodium hydride (60% in oil) (360 mg) was added to a solution of 2.0 g of 5-[(2-amino-4-pyridyl)oxy]-1H-indole in 30 ml of dimethylformamide at room temperature. After stirring for 5 minutes, the mixture was placed in an ice bath and 1.8 g of phenyl N-(2-fluoroethyl)carbamate was added while cooling. The mixture was returned to room temperature and stirred for 30 minutes, after which water was added and extraction was performed with ethyl acetate. The extract was passed through a glass filter coated with silica gel. The ethyl acetate layer was washed once with bicarbonate water and dried over magnesium sulfate. The drying agent was filtered off to obtain 1.93 g of a faint brown powder.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][C:6]([C:18]3[O:19][C:20]([CH3:23])=[CH:21][CH:22]=3)=[CH:7][CH:8]=2)[N:3]=1.[O:24]=[C:25]1[CH2:29][CH2:28][CH2:27][N:26]1[C:30]1[CH:35]=[CH:34][C:33]([NH:36][C:37]([NH:39][C:40]2[CH:45]=[CH:44][C:43](B3OC(C)(C)C(C)(C)O3)=[CH:42][CH:41]=2)=[O:38])=[CH:32][CH:31]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(C)C=CC=CC=1>O.CCO>[CH3:23][C:20]1[O:19][C:18]([C:6]2[CH:5]=[C:4]3[C:9]([C:10]([N:12]4[CH2:17][CH2:16][O:15][CH2:14][CH2:13]4)=[N:11][C:2]([C:43]4[CH:44]=[CH:45][C:40]([NH:39][C:37]([NH:36][C:33]5[CH:34]=[CH:35][C:30]([N:26]6[CH2:27][CH2:28][CH2:29][C:25]6=[O:24])=[CH:31][CH:32]=5)=[O:38])=[CH:41][CH:42]=4)=[N:3]3)=[CH:8][CH:7]=2)=[CH:22][CH:21]=1
Reactant: CC1(C)OB(c2ccc(NC(=O)Nc3ccc(N4CCCC4=O)cc3)cc2)OC1(C)C
Reactant: Cc1ccc(-c2ccc3c(N4CCOCC4)nc(Cl)nc3c2)o1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2ccc3c(N4CCOCC4)nc(-c4ccc(NC(=O)Nc5ccc(N6CCCC6=O)cc5)cc4)nc3c2)o1
Temperature: 95 °C
Reaction time: 3 h
Yield: 7 %

Procedure:
To a 50 mL round bottom flask, 2-Chloro-7-(5-methyl-furan-2-yl)-4-morpholin-4-yl-quinazoline (0.12 g, 0.00036 mol; prepared as described in Example 2; Scheme 6B), 1-(4-(2-oxopyrrolidin-1-yl)phenyl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea (0.184 g, 0.00043 mol; prepared according to the methods described in Scheme 9), cesium carbonate (0.296 g, 0.0009 mol), toluene (7 mL), EtOH (7 mL) and water (3 mL) were added. The reaction mixture was degassed with nitrogen for 5-10 min. To the same reaction flask, Pd (PPh3)2Cl2 (0.0128 g, 0.000018 mol) was added and again degassed with nitrogen for 5-10 min. The reaction mixture was stirred at 95° C. for 3 h. The reaction mixture was cooled and diluted with chloroform. The organic layer was separated, washed with water, brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to afford the crude product. The crude product was purified by flash column chromatography using 230-400 silica gel, 2% MeOH in chloroform. The compound was further purified by prep TLC using 4% MeOH in chloroform to yield the title compound [0.015 g, 7%]. 1H NMR (300 MHz, DMSO-d6): δ 8.92 (s, 1H), 8.75 (s, 1H), 8.43 (d, J=7.2 Hz, 2H), 8.02 (d, J=8.1 Hz, 2H), 7.75 (d, J=8.4 Hz, 1H), 7.62 (t, J=8.7 Hz, 4H), 7.48 (d, J=9 Hz, 2H), 7.17 (d, J=3.3 Hz, 1H), 6.32 (d, J=2.4 Hz, 1H), 3.83 (m, 10H), 2.47 (d, J=8.4 Hz, 2H), 2.41 (s, 3H), 2.08 (m, 2H); LC-MS (ESI): Calculated mass: 588.2; Observed mass: 589.2 (RT: 0.13 min).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([C:13]3[CH:14]=[CH:15][C:16]4[N:17]([CH:19]=[CH:20][N:21]=4)[CH:18]=3)=[O:12])=[CH:9][N:10]=2)[N:7]=1.[CH3:22][Mg]Br>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([C:13]3[CH:14]=[CH:15][C:16]4[N:17]([CH:19]=[CH:20][N:21]=4)[CH:18]=3)([OH:12])[CH3:22])=[CH:9][N:10]=2)[N:7]=1
Reactant: O=C(c1ccc2nccn2c1)c1cnc2ccc(Cl)nn12
Reactant: C[Mg]Br
Solvent: C1COCCO1
Product: CC(O)(c1ccc2nccn2c1)c1cnc2ccc(Cl)nn12
Temperature: 90 °C

Procedure:
(6-Chloro-imidazo[1,2-b]pyridazin-3-yl)-imidazo[1,2-a]pyridin-6-yl-methanone (Stage 292.2, 4.0 g, 13.44 mmol) was suspended in dioxane (400 mL) and it was heated at 90° C. When all the material was in solution, it was cooled down to 50° C. and the 3 M methylmagnesium bromide solution (28.8 mL, 40.3 mmol) was added. It was refluxed for 2 h. Then it was cooled down to rt and the precipitate formed was filtered off. It was taken up with EtOAc/MeOH (9:1) and washed with saturated NaHCO3 solution and brine. The organic layer was dried over Na2SO4, filtered and concentrated to give the title compound as a brown solid (tR 0.3 min (conditions 2), MH+=314)
Reaction SMILES: [C:1]([C:4]1[N:8]([CH:9]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10]2)[CH:7]=[N:6][C:5]=1[C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1)(=O)[CH3:2].C(C1N(C2CN(C(OC(C)(C)C)=O)C2)C=NC=1C1C=CC(F)=CC=1)(=O)C.NC1CCN(C(OC(C)(C)C)=O)C1.[NH2:67][C:68]1[N:73]=C(C2N(C3CN(C(OC(C)(C)C)=O)C3)C=NC=2C2C=CC(F)=CC=2)C=[CH:70][N:69]=1>>[NH2:73][C:68]1[N:67]=[C:1]([C:4]2[N:8]([CH:9]3[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10]3)[CH:7]=[N:6][C:5]=2[C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[CH:2]=[CH:70][N:69]=1
Reactant: CC(C)(C)OC(=O)N1CC(n2cnc(-c3ccc(F)cc3)c2-c2ccnc(N)n2)C1
Reactant: CC(=O)c1c(-c2ccc(F)cc2)ncn1C1CCN(C(=O)OC(C)(C)C)C1
Agent: CC(=O)c1c(-c2ccc(F)cc2)ncn1C1CN(C(=O)OC(C)(C)C)C1
Agent: CC(C)(C)OC(=O)N1CCC(N)C1
Product: CC(C)(C)OC(=O)N1CCC(n2cnc(-c3ccc(F)cc3)c2-c2ccnc(N)n2)C1

Procedure:
tert-Butyl 3-[5-acetyl-4-(4-fluorophenyl)-1H-imidazol-1-yl]pyrrolidine-1-carboxylate [C16, prepared according to the general procedure for the synthesis of tert-butyl 3-[5-acetyl-4-(4-fluorophenyl)-1H-imidazol-1-yl]azetidine-1-carboxylate (C3) in Example 1, except that tert-butyl 3-aminopyrrolidine-1-carboxylate was used in place of tert-butyl 3-aminoazetidine-1-carboxylate; NMR (400 MHz, CDCl3) δ 1.49 (s, 9H), 2.13 (s, 3H), 2.22 (m, 1H), 2.45 (m, 1H), 3.47-3.88 (m, 4H), 5.55 (m, 1H), 7.15 (dd, J=8.7, 8.7 Hz, 2H), 7.46 (dd, J=8.7, 5.4 Hz, 2H), 7.69 (br s, 1H)] was subjected to reaction conditions similar to those used for preparation of tert-butyl 3-[5-(2-aminopyrimidin-4-yl)-4-(4-fluorophenyl)-1H-imidazol-1-yl]azetidine-1-carboxylate (C4) in Example 1, to provide the product as a solid. Yield: 6.1 g, 14.4 mmol, 67%. 1H NMR (400 MHz, CD3OD) δ 1.48 (s, 9H), 2.32-2.50 (m, 2H), 3.48-3.65 (m, 3H), 3.81 (m, 1H), 5.42 (m, 1H), 6.42 (d, J=4.9 Hz, 1H), 7.09 (dd, J=8.7, 8.7 Hz, 2H), 7.43 (dd, J=8.5, 5.3 Hz, 2H), 7.92 (s, 1H), 8.13 (d, J=4.5 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:17]=[C:16]([CH:18]=O)[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]([NH2:13])=[O:12])=[N:9][CH:10]=1.[N:20]1([CH2:26][CH2:27][NH2:28])[CH2:25][CH2:24][S:23][CH2:22][CH2:21]1.[BH4-].[Na+]>CO>[F:1][C:2]1[CH:17]=[C:16]([CH2:18][NH:28][CH2:27][CH2:26][N:20]2[CH2:25][CH2:24][S:23][CH2:22][CH2:21]2)[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]([NH2:13])=[O:12])=[N:9][CH:10]=1
Reactant: NCCN1CCSCC1
Reactant: NC(=O)c1ccc(Oc2ccc(C=O)cc2F)cn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: NC(=O)c1ccc(Oc2ccc(CNCCN3CCSCC3)cc2F)cn1
Reaction time: 8 h
Yield: 81.1 %

Procedure:
Place 5-(2-fluoro-4-formylphenoxy)pyridine-2-carboxamide (Example 403, Part B) (0.650 g, 2.50 mmol), 2-thiomorpholin-4-ylethylamine (0.402 g, 2.75 mmol) and 3 Å molecular sieves in a vial. Add methanol (12 mL), cap and stir overnight. Add NaBH4 (slight excess) and stir until the gasses stop evolving. Load the reaction mixture directly onto a 25 g ISCO® pre-load column. Dry the column in a vacuum oven at room temperature. Purify by eluting through a 40 g ISCO® column with 0% to 30% (2.0 M NH3 in methanol) in ethyl acetate to give the title compound (0.792 g, 81%): TOF MS ES+ 391.2 (M+H)+, HRMS calcd for C19H24N4O2FS 391.1604 (M+H)+, found 391.1594, time 0.48 min; HPLC [YMC-Pro pack C-18 (150×4.6 mm, S-5 microm), 0.05% TFA/acetonitrile in 0.05% TFA/water at 1.0 mL/min, 10-20% over 5 min, 20-95% over 18], tR=6.7 min, 100% purity.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]2[N:17]=[C:18]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[O:19][C:20]=2[CH3:21])=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4].[F:28][C:29]1[CH:34]=[CH:33][C:32]([C:35](=[O:41])[CH2:36][C:37](=O)[CH2:38][CH3:39])=[CH:31][CH:30]=1>>[CH2:38](/[C:37](/[NH:1][C@@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]2[N:17]=[C:18]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[O:19][C:20]=2[CH3:21])=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4])=[CH:36]/[C:35]([C:32]1[CH:31]=[CH:30][C:29]([F:28])=[CH:34][CH:33]=1)=[O:41])[CH3:39]
Reactant: CCC(=O)CC(=O)c1ccc(F)cc1
Reactant: Cc1oc(-c2ccccc2)nc1CCOc1ccc(C[C@H](N)C(=O)O)cc1
Product: CC/C(=C/C(=O)c1ccc(F)cc1)N[C@@H](Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1)C(=O)O

Procedure:
The title compound was prepared (as described above for the preparation of Example 2) from 100 mg (0.27 mmol) of Intermediate 45 and 49 mg (0.27 mmol) of Intermediate 32 to yield 83 mg of Example 35: TLC (EtOAc/MeOH (7:3): Rf=0.28; 1H NMR (DMSO-d6, 400 MHz) δ11.38 (d, 1H, J=7.00), 7.84 (m. 4H), 7.45 (m, 3H), 7.16 (t, 2H, J=8.72), 7.09 (d, 2H, J=7.69), 6.77 (d, 2H, J=7.69), 5.49 (s, 1H), 4.11 (m, 2H), 4.01(m, br, 1H), 3.13 (m, 1H), 2.86 (m, 2H), 2.72 (s, br, 1H), 2.30 (s, 3H), 1.62 (s, 3H); low resolution MS (ES+) m/e 529 (MH+); RP-HPLC (Vydac C-18, 25 cm×4.6 mm; 30-100% CH3CN in H2O) with 0.1% HCO2H buffer: 30 minutes; 1 mL/min: tr=20.10 min (to=1.53).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C@H:13]([CH3:17])[C:14]([OH:16])=[O:15])[CH:7]=[CH:6]2.Cl>C(O)C(C)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C@H:13]([CH3:17])[C:14]([O:16][CH2:4][CH:5]([CH3:10])[CH3:6])=[O:15])[CH:7]=[CH:6]2
Reactant: COc1ccc2cc([C@H](C)C(=O)O)ccc2c1
Agent: Cl
Solvent: CC(C)CO
Product: COc1ccc2cc([C@H](C)C(=O)OCC(C)C)ccc2c1
Reaction time: 24 h

Procedure:
A solution of 300 mg of (S)-2-(6-methoxy-2-naphthyl)propionic acid in 5 ml of isobutyl alcohol is saturated with hydrogen chloride. After 24 hours, the excess alcohol is distilled off in vacuo and the residue is purified by chromatography using an alumina substrate to yield isobutyl (S)-2-(6-methoxy-2-naphthyl)propionate.