Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O1CCCCC1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]3[N:20]=[CH:19][N:18](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:17]=3)=[CH:13][CH:14]=2)[C:9]([C:40]2[CH:41]=[C:42]([NH2:46])[CH:43]=[CH:44][CH:45]=2)=[N:8]1.Cl[CH2:48][C:49](Cl)=[O:50].C(N(CC)C(C)C)(C)C.[NH:61]1[CH2:66][CH2:65][O:64][CH2:63][CH2:62]1>O1CCCC1.O>[NH:18]1[CH:19]=[N:20][C:16]([C:12]2[CH:11]=[C:10]3[C:15](=[CH:14][CH:13]=2)[NH:7][N:8]=[C:9]3[C:40]2[CH:41]=[C:42]([NH:46][C:49](=[O:50])[CH2:48][N:61]3[CH2:66][CH2:65][O:64][CH2:63][CH2:62]3)[CH:43]=[CH:44][CH:45]=2)=[N:17]1
Reactant: O=C(Cl)CCl
Reactant: Nc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Reactant: C1COCCN1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(CN1CCOCC1)Nc1cccc(-c2n[nH]c3ccc(-c4nc[nH]n4)cc23)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 89.5 %

Procedure:
To a solution of 3-{1-perhydro-2H-pyran-2-yl-5-[1-(triphenylmethyl)(1,2,4-triazol-3-yl)]-1H-indazol-3-yl}phenylamine (0.400 g, 0.66 mmol) in tetrahydrofuran (4 mL) was added 2-chloroacetyl chloride (0.030 mL, 0.36 mmol) followed by N,N-diisopropylethylamine (0.116 mL, 0.66 mmol). The reaction was stirred at room temperature for 4 h. Water (20 mL) was added and the reaction mixture was extracted with ethyl acetate. The combined organic organic extracts were dried over anhydrous sodium sulfate, filtered and evaporated. The residue was dissolved in N,N-dimethylformamide (5 mL) and morpholine (0.577 mL, 6.6 mmol) was added. The mixture was stirred at room temperature for 14 h. Water (30 mL) was added and the mixture extracted with ethyl acetate. The combined organic fractions were dried over anhydrous sodium sulfate, filtered and evaporated. The residue was dissolved in 4 N hydrochloric acid in 1,4-dioxane (10 mL) and the mixture was stirred at room temperature for 2 h. Dioxane was removed with a rotary evaporator and the residue was purified by preparative HPLC. The desired fractions were neutralized with ammonium hydroxide, extracted with butanol and evaporated to give the title compound (0.130 g, 49% yield): 1H NMR (DMSO-d6) δ 14.22 (br d, 1H), 13.50 (d, 1H), 10.00 (s, 1H), 8.65 (m, 1H), 8.05 (m, 1H), 7.69 (m, 2H), 7.26 (s, 1H), 6.75 (s, 1H), 1.74 (s, 2H), 1.32 (t, 4H), 1.24 (t, 4H); ES-MS (m/z) 404 [M+1]+.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][C:5]1[CH:10]=[C:9]([Br:11])[CH:8]=[CH:7][C:6]=1[O:12][CH2:13][CH:14]1[CH2:16][CH2:15]1)[CH3:2].Cl[C:18]1[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][N:19]=1>>[Br:11][C:9]1[CH:8]=[CH:7][C:6]([O:12][CH2:13][CH:14]2[CH2:15][CH2:16]2)=[C:5]([CH:10]=1)[CH2:4][N:3]([C:18]1[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][N:19]=1)[CH2:1][CH3:2]
Reactant: N#Cc1ccc(Cl)nc1
Reactant: CCNCc1cc(Br)ccc1OCC1CC1
Product: CCN(Cc1cc(Br)ccc1OCC1CC1)c1ccc(C#N)cn1

Procedure:
The title compound was prepared by reacting N-ethyl-5-bromo-2-cyclopropylmethoxybenzylamine (reference example 13) and 2-chloro-5-cyanopyridine using a similar method to that of reference example 18.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][C:9]([C:11]2[N:20]3[C:14]([CH2:15][NH:16][C:17]4[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=4[CH2:19]3)=[CH:13][CH:12]=2)=[O:10])[CH:2]=1.C(N(CC)C(C)C)(C)C.[Cl:34][C:35]1[CH:40]=[CH:39][C:38]([CH2:41][C:42](Cl)=[O:43])=[CH:37][CH:36]=1>O1CCCC1>[Cl:34][C:35]1[CH:40]=[CH:39][C:38]([CH2:41][C:42]([N:16]2[C:17]3[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=3[CH2:19][N:20]3[C:11]([C:9]([NH:8][CH2:7][C:3]4[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=4)=[O:10])=[CH:12][CH:13]=[C:14]3[CH2:15]2)=[O:43])=[CH:37][CH:36]=1
Reactant: O=C(Cl)Cc1ccc(Cl)cc1
Reactant: O=C(NCc1cccnc1)c1ccc2n1Cc1ccccc1NC2
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(NCc1cccnc1)c1ccc2n1Cc1ccccc1N(C(=O)Cc1ccc(Cl)cc1)C2
Temperature: 25 °C
Reaction time: 21 h
Yield: 51.8 %

Procedure:
To a suspension of N-(pyridin-3-ylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide of Example 76, Step C (0.300 g, 0.942 mmol), and N,N-diisopropylethylamine (0.26 mL, 1.508 mmol) in dry tetrahydrofuran (10 mL) was added 4-chlorophenylacetyl chloride (267 mg, 1.41 mmol) and the reaction mixture stirred at room temperature under nitrogen for 21 hours. The reaction was then quenched by the addition of 2 M sodium hydroxide (5 mL) and the mixture partitioned between ethyl acetate (50 mL) and 2 M sodium hydroxide (50 mL). The organic phase was separated, washed with 2 M sodium hydroxide (50 mL), water (50 mL) and brine (50 mL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to afford a orange foam. Purification by flash chromatography using a solvent gradient of 0 to 4% methanol in dichloromethane gave a yellow syrup that was triturated with diethyl ether to afford the title compound 0.230 g, 52%) as a yellow solid, m.p. 83° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([O:10][CH3:11])[N:3]=1.[H-].[Na+].[C:14]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[S:20]([N:23]=[C:24](SC)[S:25][CH3:26])(=[O:22])=[O:21].O>CN(C)C=O>[C:14]1([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[S:20]([NH:23][C:24](=[N:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([O:10][CH3:11])[N:3]=1)[S:25][CH3:26])(=[O:21])=[O:22]
Reactant: COc1nc(N)nc(OC)n1
Reactant: CSC(=NS(=O)(=O)c1ccccc1-c1ccccc1)SC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1nc(N=C(NS(=O)(=O)c2ccccc2-c2ccccc2)SC)nc(OC)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.4 %

Procedure:
15.6 g of 2-amino-4,6-dimethoxy-1,3,5-triazine were suspended in 300 ml of dimethylformamide, and 4 g of sodium hydride (oily, 60%) were added to the suspension. The mixture was stirred at room temperature for 1 hour. Furthermore, 33.7 g of dimethyl N-(2-biphenylylsulfonyl)carbonimidodithioate were added, and the mixture was stirred at room temperature for a day and night. The reaction mixture was poured into 2 liters of water and filtered. The filtrate was made weakly acidic to precipitate white crystals. The crystals were collected by filtration and recrystallized from ethanol to give 36.2 g of 1-(2-biphenylylsulfonyl) 3-(4,6-dimethoxy-1,3,5-triazin-2-yl) 2-methylisothiourea (compound No. II-1), the same compound as obtained in Example 5. The melting point of the product was 135° to 137° C.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][Cl:5].Cl[C:7]([O:9][CH2:10][C:11]([Cl:14])([Cl:13])[Cl:12])=[O:8].C(N(CC)CC)C>CN(C)C=O.O>[Cl:5][CH2:4][CH2:3][NH:2][C:7](=[O:8])[O:9][CH2:10][C:11]([Cl:14])([Cl:13])[Cl:12]
Reactant: NCCCl
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(NCCCl)OCC(Cl)(Cl)Cl

Procedure:
One mole of 1-amino-2-chloroethane hydrochloride in 500 ml of dimethylformamide at 0° C is treated with 1 mole of β,β,β-trichloroethyl chloroformate after which a solution of 2 moles of triethylamine in 200 ml of dimethylformamide is slowly added. Upon completion of the addition, the reaction is diluted with 2 liters of water and extracted twice with 750 ml of ether. The ether extracts are washed twice with 500 ml of water then twice with 500 ml of 1 M HCl, dried over sodium sulfate and evaporated to dryness to give β,β,β-trichloroethyl N-(2-chloroethyl)carbamate.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[OH:7].C(N(CC)CC)C.[C:15](Cl)(=[O:17])[CH3:16]>O1CCCC1>[OH:7][C@@H:3]1[CH2:4][CH2:5][CH2:6][C@H:2]1[NH:1][C:15](=[O:17])[CH3:16]
Reactant: N[C@@H]1CCC[C@H]1O
Reactant: CC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)N[C@@H]1CCC[C@H]1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 30.3 g of trans-2-aminocyclopentanol in 900 ml of tetrahydrofuran under a nitrogen atmosphere was cooled by means of an external ice bath to approximately 10° C. Forty-five milliliters of triethylamine were added followed by the dropwise addition of a solution of 21.3 ml of acetyl chloride in 240 ml of tetrahydrofuran. The resulting mixture was stirred overnight at room temperature. The resulting precipitate was removed by filtration and the filtrate was concentrated in vacuo to provide 43.59 g of the title intermediate as a red oil.
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:11]=[C:10](Cl)[N:9]2[N:13]=[C:14]([CH3:16])[N:15]=[C:8]2[N:7]=1)(=O)C.NC(N)=[S:19]>C(O)C>[OH:4][CH2:5][C:6]1[CH:11]=[C:10]([SH:19])[N:9]2[N:13]=[C:14]([CH3:16])[N:15]=[C:8]2[N:7]=1
Reactant: CC(=O)OCc1cc(Cl)n2nc(C)nc2n1
Reactant: NC(N)=S
Solvent: CCO
Product: Cc1nc2nc(CO)cc(S)n2n1
Reaction time: 0.5 h
Yield: 64.6 %

Procedure:
In 600 ml of ethanol was dissolved 31 g of 5-acetoxymethyl-7-chloro-2-methyl-s-triazolo[1,5-a]pyrimidine, and 29.5 g of thiourea was added thereto and the mixture was refluxed for 10 minutes. The reaction mixture was ice-cooled and resulting precipitated crystal was collected by filtration. The crystal was dissolved in 600 ml of a 5% potassium hydroxide and the mixture was stirred for 30 minutes, ice-cooled and adjusted to pH 2 with 2N hydrochloric acid. Precipitated crystal was collected by filtration, washed with water and dried to obtain 16.33 g of the title compound.
Reaction SMILES: [CH3:1][C:2]1[S:13][C:5]2[CH2:6][N:7]([CH3:12])[CH2:8][CH2:9][CH:10]([OH:11])[C:4]=2[CH:3]=1.[Cl:14][C:15]1[CH:16]=[C:17](F)[CH:18]=[CH:19][C:20]=1[Cl:21]>>[Cl:14][C:15]1[CH:16]=[C:17]([O:11][CH:10]2[CH2:9][CH2:8][N:7]([CH3:12])[CH2:6][C:5]3[S:13][C:2]([CH3:1])=[CH:3][C:4]2=3)[CH:18]=[CH:19][C:20]=1[Cl:21]
Reactant: Fc1ccc(Cl)c(Cl)c1
Reactant: Cc1cc2c(s1)CN(C)CCC2O
Product: Cc1cc2c(s1)CN(C)CCC2Oc1ccc(Cl)c(Cl)c1

Procedure:
The same method as in Example 1 was conducted using 2,7-dimethyl-5,6,7,8-tetrahydro-4H-thieno[2,3-c]azepin-4-ol (Reference Example 23) instead of 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 6) and was conducted using 3,4-dichloro-1-fluorobenzene instead of 1-fluoronaphthalene to give the objective compound.
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][C:7]2[CH2:8][CH2:9][NH:10][CH2:11][CH2:12][C:6]=2[CH:5]=1)([O-:3])=[O:2].CCN(C(C)C)C(C)C.Cl[C:25]([O:27][CH2:28][CH3:29])=[O:26]>C(Cl)Cl.Cl>[CH2:28]([O:27][C:25]([N:10]1[CH2:11][CH2:12][C:6]2[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:14]=[CH:13][C:7]=2[CH2:8][CH2:9]1)=[O:26])[CH3:29]
Reactant: CCOC(=O)Cl
Reactant: O=[N+]([O-])c1ccc2c(c1)CCNCC2
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)N1CCc2ccc([N+](=O)[O-])cc2CC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a stirred solution of the product from Example 36, step (a) (5 g, 26.0 mmol) dissolved in DCM (75 ml), DIEA (6.8 ml, 39 mmol) was added. The reaction mixture was cooled to 0° C. and ethyl chloroformate was added (3.0 ml, 31.2 mmol). The reaction mixture was stirred at 0° C. for 2 hours and then allowed to warm to room temperature. The reaction mixture was diluted with 2N HCl (150 ml) and extracted with DCM (3×). The combined DCM extracts were washed with brine, dried over Na2SO4, and solvent evaporated in vacuo to give the crude product. Purification by silica-gel chromatography (gradient elution: 0 to 50% EtOAc in hexane) gave the sub-title compound as a light yellow solid (4.7 g). 1H NMR (300 MHz, DMSO-d6) δ 8.07 (d, J=2.4 Hz, 1H); 8.01 (dd, J=8.1 Hz, 2.4 Hz, 1H); 7.45 (d, J=8.1 Hz, 1H); 4.07 (q, J=6.9 Hz, 2H); 3.54-3.51 (m, 4H); 3.04-3.01 (m, 4H); 1.19 (t, J=7.2 Hz, 3H).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.Cl[C:13](Cl)=[CH:14][CH:15]=O.C([O-])(=O)C.[F:22][C:23]([F:34])([F:33])[C:24]1[CH:32]=[CH:31][C:27]([C:28]([NH2:30])=[NH2+:29])=[CH:26][CH:25]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C>[F:1][C:2]([F:10])([F:11])[C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][CH:8]=1)[O:9][C:15]1[CH:14]=[CH:13][N:30]=[C:28]([C:27]2[CH:26]=[CH:25][C:24]([C:23]([F:22])([F:33])[F:34])=[CH:32][CH:31]=2)[N:29]=1
Reactant: Oc1cccc(C(F)(F)F)c1
Reactant: NC(=[NH2+])c1ccc(C(F)(F)F)cc1
Reactant: O=CC=C(Cl)Cl
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: FC(F)(F)c1ccc(-c2nccc(Oc3cccc(C(F)(F)F)c3)n2)cc1
Temperature: 25 °C
Yield: 57.3 %

Procedure:
3-Trifluoromethylphenol (5 mmoles) and subsequently 3,3-dichloroacrolein (5 mmoles) are added to a mixture consisting of a 4-trifluoromethylbenzamidinium acetate (5 mmoles), sodium carbonate (40 mmoles) and acetonitrile (35 ml), which is stirred under reflux. The reaction mixture is stirred for 20 hours under reflux and subsequently cooled down to ambient temperature and filtered through silica. The organic phase is washed with ethyl acetate and concentrated in vacuo. The residue is purified by chromatography on Al2O3 (petrol ethers/ethyl acetate: 2/1) to yield 1.1 g (60%) of the pure product having a melting point of 66-67° C.
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5]([C:14](=O)[CH3:15])=[CH:4]1)[CH3:2].C([N:19]1[C:27]2C(=CC=C(OC)C=2)C=C1)C.COC(OC)[N:33](C)C.O.NN>N1CCCC1>[CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5]([C:14]2[NH:33][N:19]=[CH:27][CH:15]=2)=[CH:4]1)[CH3:2]
Reactant: CCn1cc(C(C)=O)c2ccc(OC)cc21
Reactant: CCn1ccc2ccc(OC)cc21
Reactant: COC(OC)N(C)C
Agent: NN
Solvent: C1CCNC1
Solvent: O
Product: CCn1cc(-c2ccn[nH]2)c2ccc(OC)cc21
Temperature: 100 °C
Yield: 54 %

Procedure:
1-(1-Ethyl-6-methoxy-1H-indol-3-yl)-ethanone (100 mg, 0.46 mmol), prepared from 1-ethyl-6-methoxy-1H-indole by the procedure described in example 1L, is heated with 1.5 mL of dimethylformamide dimethyl acetal and 100 μL pyrrolidine at 110° C. overnight. The DMF dimethyl acetal is removed in vacuo. The residue is redissolved in 3 mL of acetic acid, hydrazine hydrate (70 μL, 1.38 mmol) is added, and the mixture is heated to 100° C. for 2 h. The acetic acid is removed in vacuo, and the residue is partitioned between EtOAc and saturated NaHCO3. The organic phase is dried and concentrated and the product purified by silica gel chromatography (EtOAc/Hex, 1/1) to give 59 mg of 1-ethyl-6-methoxy-3-(2H-pyrazol-3-yl)-1H-indole (54%) as a colorless semisolid. Trituration in Et2O gives a white crystalline powder.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[C:17]1[CH:18]=[C:19]([S:23]([C:26]2[CH:27]=[C:28]([C:33]([NH2:35])=[NH:34])[S:29][C:30]=2[S:31][CH3:32])(=[O:25])=[O:24])[CH:20]=[CH:21][CH:22]=1.C([O-])([O-])=O.[K+].[K+].I[CH2:43][CH3:44]>CC(C)=O>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:43]([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[C:17]1[CH:18]=[C:19]([S:23]([C:26]2[CH:27]=[C:28]([C:33]([NH2:35])=[NH:34])[S:29][C:30]=2[S:31][CH3:32])(=[O:25])=[O:24])[CH:20]=[CH:21][CH:22]=1)[CH3:44]
Reactant: CSc1sc(C(=N)N)cc1S(=O)(=O)c1cccc(-c2nc3ccccc3[nH]2)c1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CC(C)=O
Product: CCn1c(-c2cccc(S(=O)(=O)c3cc(C(=N)N)sc3SC)c2)nc2ccccc21
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 91.1 %

Procedure:
A mixture containing ({4-[3-(1H-benzoimidazol-2-yl)-benzenesulfonyl]-5-methylsulfanyl-thiophen-2-yl}-imino-methyl)-carbamic acid tert-butyl ester (prepared in Example 144) (25 mg, 0.05 mmol), K2CO3 (13 mg, 0.10 mmol), and iodoethane (12 mg, 0.08 mmol) in 0.5 mL acetone was heated to 60° C. for 2 hrs. The mixture was filtered then concentrated, and the residue dissolved in 0.5 ml of 50% TFA/DCM and stirred at 25° C. for 30 mins. The solvent was evaporated and the crude product purified by RP-HPLC, eluting with a linear gradient of 10% CH3CN in 0.1% TFA/H2O to 50% CH3CN over 30 mins, to give 26 mg (93%) of the title compound as yellow solid: 1H NMR (400 MHz, CD3OD) δ 8.58 (m, 1H), 8.44 (m, 1H), 8.41 (s, 1H), 8.20 (m, 1H), 8.02 (m, 2H), 7.90 (m, 1H), 7.71 (m, 2H), 4.55 (q, 2H), 2.75 (s, 3H), 1.59 (t, 3H). Mass spectrum (ESI, m/z) calcd. for C21H20N4O2S3 456.1, found 457.1 (M+H).
Reaction SMILES: Cl[CH2:2][CH2:3][NH:4][C:5]([NH:7][CH:8]([CH:11]([CH3:13])[CH3:12])[C:9]#[CH:10])=[O:6].C(=O)([O-])[O-].[Na+].[Na+]>O>[NH3:4].[CH3:12][CH:11]([CH3:13])[CH:8]([NH:7][C:5]1[O:6][CH2:2][CH2:3][N:4]=1)[C:9]#[CH:10]
Reactant: C#CC(NC(=O)NCCCl)C(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: C#CC(NC1=NCCO1)C(C)C
Product: N
Temperature: 25 °C
Yield: 5 %
Yield: 86.6 %

Procedure:
A solution of 169 mg of 1-(2-chloroethyl)-3-(4-methylpent-1-yn-3-yl)urea (Formula 24) in 10 mL of water was heated at 100° C. for 2.5 hours. The reaction mixture was cooled to room temperature. Then, a saturated solution of sodium carbonate was added to adjust the pH of the solution to greater than 8. The mixture was extracted with ethyl acetate. The combined ethyl acetate was washed with brine, dried over sodium sulfate and concentrated. Column chromatography (5% 7N NH3 in MeOH/CH2Cl2) gave 60 mg of N-(4-methylpent-1-yn-3-yl)-4,5-dihydrooxazol-2-amine (Formula 25) as a white solid. 1H NMR (300 MHz, CDCl3) δ 1.01 (m, 6H), 1.95-2.02 (m, 1H), 2.28-2.29 (m, 1H), 3.76-3.83 (m, 2H), 4.24-4.32 (m, 3H).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[O:8][C:9]3[C:14](B4OC(C)(C)C(C)(C)O4)=[CH:13][CH:12]=[CH:11][C:10]=3[C:5]2=[CH:4][CH:3]=1.Cl[C:25]1[CH:30]=[C:29]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[C:32]=2[F:38])[CH:28]=[CH:27][N:26]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O.C1(C)C=CC=CC=1>[F:38][C:32]1[C:33]([F:37])=[CH:34][CH:35]=[CH:36][C:31]=1[C:29]1[CH:28]=[CH:27][N:26]=[C:25]([C:14]2[C:9]3[O:8][C:6]4[C:5]([C:10]=3[CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=[C:2]([CH3:1])[N:7]=4)[CH:30]=1
Reactant: Fc1cccc(-c2ccnc(Cl)c2)c1F
Reactant: Cc1ccc2c(n1)oc1c(B3OC(C)(C)C(C)(C)O3)cccc12
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccc2c(n1)oc1c(-c3cc(-c4cccc(F)c4F)ccn3)cccc12
Temperature: 25 °C
Yield: 35.5 %

Procedure:
2-methyl-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuro[2,3-b]pyridine (2.8 g, 9.06 mmol), 2-chloro-4-(2,3-difluorophenyl)pyridine (2.452 g, 10.87 mmol), tris(dibenzylideneacetone)palladium(0) (0.166 g, 0.181 mmol) and 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (0.297 g, 0.725 mmol) were charged into the reaction mixture with 200 mL of toluene. Potassium phosphate tribasic (5.76 g, 27.2 mmol) was dissolved in 25 mL of water then was charged into the reaction mixture. This mixture was degassed then heated to reflux for 18 hours. The reaction mixture was cooled to room temperature. The toluene layer was separated and was dried over magnesium sulfate. This mixture was filtered and concentrated under vacuum. The crude residue was passed through a silica gel column using 15-22.5% ethyl acetate/heptanes. The clean product fractions were evaporated under reduced pressure yielding 8-(4-(2,3-difluorophenyl)pyridin-2-yl)-2-methylbenzofuro[2,3-b]pyridine (1.2 g, 3.22 mmol, 35.6% yield) as a white solid.
Reaction SMILES: O([C:3]1[CH:4]=[CH:5][C:6]2[N:10]=[N:9][N:8]([CH2:11][CH2:12][CH2:13][CH2:14]Cl)[C:7]=2[CH:16]=1)C.[F:17][C:18]([F:32])([F:31])[C:19]1[CH:20]=[C:21]([CH:25]2[CH2:30][CH2:29]CN[CH2:26]2)[CH:22]=[CH:23][CH:24]=1.[CH:33]([N:36](C(C)C)CC)(C)C.[I-].[K+]>C(#N)C>[N:8]1([CH2:11][CH2:12][CH2:13][CH2:14][N:36]2[CH2:33][CH2:26][CH:25]([C:21]3[CH:22]=[CH:23][CH:24]=[C:19]([C:18]([F:17])([F:31])[F:32])[CH:20]=3)[CH2:30][CH2:29]2)[C:7]2[CH:16]=[CH:3][CH:4]=[CH:5][C:6]=2[N:10]=[N:9]1
Reactant: CCN(C(C)C)C(C)C
Reactant: COc1ccc2nnn(CCCCCl)c2c1
Reactant: FC(F)(F)c1cccc(C2CCCNC2)c1
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: FC(F)(F)c1cccc(C2CCN(CCCCn3nnc4ccccc43)CC2)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 69.6 %

Procedure:
6-methoxyl-1-(4-chlorobutyl)-1H-benzotriazole (0.06 mol) was dissolved into 150 ml of acetonitrile, 4-(3-(3-trifluoromethylphenyl) piperidine (0.05 mol), diisopropylethylamine (0.2 mol) and potassium iodide (0.05 mol) were respectively added. The mixture was stirred for 10 min at ambient temperature, and then heated and refluxed to react for 15 hours. The mixture was cooled down to ambient temperature and filtered. The filtrate was concentrated to produce oily products, and treated by chromatography with neutral Al2O3, purified, eluted with dichloromethane/methanol mixture to produce 14.0 g N-(4-(1H-benzotriazole-1-yl)butyl)-4-(3-trifluoromethylphenyl)piperidine (I-114) with a yield of 64.6%. ESI-MS [M+H]+: m/z 433.2.
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[CH2:12][C@@H:13]([NH:20][C:21]([C:23]1[C:27]2[CH2:28][C:29]([CH3:56])([CH3:55])[C:30]3[CH:31]=[N:32][C:33]([NH:36][C:37]4[CH:42]=[CH:41][C:40]([C:43](=[O:52])[NH:44][CH:45]5[CH2:50][CH2:49][N:48]([CH3:51])[CH2:47][CH2:46]5)=[CH:39][C:38]=4[O:53][CH3:54])=[N:34][C:35]=3[C:26]=2[O:25][N:24]=1)=[O:22])C1C=CC=CC=1>C1COCC1.NN.O>[NH2:3][C@@H:12]([C:26]1[CH:35]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:13][NH:20][C:21]([C:23]1[C:27]2[CH2:28][C:29]([CH3:55])([CH3:56])[C:30]3[CH:31]=[N:32][C:33]([NH:36][C:37]4[CH:42]=[CH:41][C:40]([C:43](=[O:52])[NH:44][CH:45]5[CH2:50][CH2:49][N:48]([CH3:51])[CH2:47][CH2:46]5)=[CH:39][C:38]=4[O:53][CH3:54])=[N:34][C:35]=3[C:26]=2[O:25][N:24]=1)=[O:22]
Reactant: COc1cc(C(=O)NC2CCN(C)CC2)ccc1Nc1ncc2c(n1)-c1onc(C(=O)N[C@H](CN3C(=O)c4ccccc4C3=O)c3ccccc3)c1CC2(C)C
Agent: NN
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(C(=O)NC2CCN(C)CC2)ccc1Nc1ncc2c(n1)-c1onc(C(=O)NC[C@@H](N)c3ccccc3)c1CC2(C)C
Temperature: 70 °C

Procedure:
To a solution of N-[(1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-phenylethyl]-8-({2-methoxy-4-[(1-methylpiperidin-4-yl)carbamoyl]phenyl}amino)-5,5-dimethyl-4,5-dihydroisoxazolo[4,5-h]quinazoline-3-carboxamide (60 mg, 0.079 mmol) in THF (3 mL), 35% hydrazine in water (0.07 mL) was added and the reaction was warmed at 70° C. for 24 hours. The reaction was cooled at room temperature diluted with H2O (20 mL) and extracted with DCM (2×20 mL). The organic layers were dried over Na2SO4 and the solvent evaporated to dryness to yield the crude solid that was purified by flash chromatography on silica gel (DCM/MeOH/(NH3 7N in MeOH) to afford the title compounds.
Reaction SMILES: [S:1](=[O:3])=[O:2].N[C:5]1[CH:6]=[CH:7][C:8]([Cl:14])=[C:9]([C:11](=[O:13])[CH3:12])[CH:10]=1.N([O-])=O.[Na+].[ClH:19]>C(O)(=O)C.O.[Cu]Cl>[C:11]([C:9]1[CH:10]=[C:5]([S:1]([Cl:19])(=[O:3])=[O:2])[CH:6]=[CH:7][C:8]=1[Cl:14])(=[O:13])[CH3:12]
Reactant: O=S=O
Reactant: CC(=O)c1cc(N)ccc1Cl
Reactant: Cl
Agent: Cl[Cu]
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)c1cc(S(=O)(=O)Cl)ccc1Cl

Procedure:
Amounts used: 8 mL of acetic acid was saturated with sulfur dioxide, 233 mg of copper(I) chloride, 1.60 g (9.41 mmol) of 1-(5-amino-2-chloro-phenyl)-ethanone dissolved in a mixture of 3 mL of acetic acid and 3 mL of concentrated hydrochloric acid, 714 mg of sodium nitrite in 3 mL of water. Flash chromatography on silica using 20-50% ethyl acetate in hexanes afforded 1.6 g of the product as a white solid. LC-MSD, m/z for C8H6Cl2O3S [M+H]+=252.9, 254.9, 256.9;