Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[C:4]#[N:5].C(N(CC)CC)C.O.[S-2:19].[Na+].[Na+].Cl>N1C=CC=CC=1>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[C:4](=[S:19])[NH2:5]
Reactant: N#Cc1c(F)cccc1Cl
Reactant: [S-2]
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: c1ccncc1
Product: NC(=S)c1c(F)cccc1Cl
Temperature: 25 °C

Procedure:
Into a 250-mL three necked round bottom flask equipped with a mechanical stirrer, dry ice condenser, dropping funnel, and outlet to a trap filled with bleach was added pyridine (45 mL), 2-chloro-6-fluorobenzonitrile (15.5 g, 0.1 mol), triethylamine (13.4 g, 18.6 mL, 0.133 mol), and sodium sulfide hydrate (36.0 g, 0.15 mol). The temperature of the resulting solution was lowered to approximately 5° C. using an ice bath. To the stirred slurry was added dropwise concentrated hydrochloric acid (25.8 g, 0.266 mol). The rate of addition of the hydrochloric acid was such that the temperature of the reaction mixture did not exceed 25° C. with an addition time of 20 min. The cooling bath was removed and the slurry was allowed to warm to RT and to stir over night. An additional 40 grams of sodium sulfide and 50 mL of hydrochloric acid was added to the mixture and allowed to stir over night. An additional 40 grams of sodium sulfide and 50 mL of hydrochloric acid was added and the mixture allowed to stir over the weekend. The mixture was poured into water (2 L) and was extracted with ether. The ether layer was washed with dilute sulfuric acid, water, brine, dried (MgSO4), and the solvent removed in vacuo to give 16.1 g of crude product which was recrystallized from ethyl acetate to give 2-chloro-6-fluoro-benzthioamide as light yellow crystals: mp 156-158° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[N:10]=[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19](=O)[CH3:20])[N:14]=1)[CH3:12].[C:22]([C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=1)([CH3:25])([CH3:24])[CH3:23].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[N:10]=[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19](=[N:30][C:29]2[CH:31]=[CH:32][C:26]([C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:27][CH:28]=2)[CH3:20])[N:14]=1)[CH3:12]
Reactant: CC(C)(C)c1ccc(N)cc1
Reactant: CC(=O)c1cccc(C(C)=Nc2c(C)cc(C)cc2C)n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC(=Nc1ccc(C(C)(C)C)cc1)c1cccc(C(C)=Nc2c(C)cc(C)cc2C)n1

Procedure:
Monoimine (1, 2.8 g, 10 mmol) and 4-tert-butylaniline (1.49 g, 10 mmol) were dissolved in 100 ml of toluene. To this solution, 4 Å molecular sieves and a small amount of p-toluenesulphonic acid (0.1 mmol) were added. After standing for 5 days with addition of more 4 Å molecular sieves, the mixture was refluxed for 2 h. After filtration the solvent was removed in vacuo. The residue was washed with methanol and recrystallised from ethanol. Yield 2.4 g (58%) of mixed diimine (2). 1H-NMR (CDCl3) δ 8.42 (d, 1H, Py-Hm), 8.34 (d, 1H, Py-Hm), 7.86 (t, 1H, Py-Hp), 7.38 (d, 2H, ArH), 6.89 (s, 2H, ArH), 6.78 (d, 2H, ArH), 2.42 (s, 3H, Me), 2.29 (s, 3H, Me), 2.22 (s, 3H, Me), 2.00 (s, 6H, Me), 1.34 (s, 9H, But).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-])=O)=[C:5]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:4]=1.[H][H]>C(OCC)(=O)C.[Pd]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[C:5]([O:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:4]=1
Reactant: COc1ccc([N+](=O)[O-])c(Oc2ccccc2)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1ccc(N)c(Oc2ccccc2)c1
Yield: 96.4 %

Procedure:
A mixture 4-methoxy-1-nitro-2-phenoxy-benzene (1.3 g, 5.3 mmol) and 5% Pd—C (0.3 g) in ethyl acetate (100 mL) was shaken under 50 psi of hydrogen for 20 hours. The mixture was filtered through Celite and evaporated, providing 1.1 g of the product as a light gold oil; 1H NMR (CDCl3) δ 3.70 (s, 3H), 6.49 (d, J=2.6 Hz, 1H), 6.59 (dd, J=8.6 Hz, J=2.6 Hz, 1H), 6.78 (d, J=8.6 Hz, 1H), 6.96-7.00 (m, 2H), 7.07 (t, J=7.3 Hz, 1H), 7.28-7.35 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[C:5]2[CH:10]=[C:9]([CH2:11][N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[S:8][C:6]=2[N:7]=1.[CH:24]1([S:27](Cl)(=[O:29])=[O:28])[CH2:26][CH2:25]1>C(Cl)Cl.C(N(CC)CC)C>[Cl:1][C:2]1[N:3]=[C:4]([N:18]2[CH2:19][CH2:20][O:21][CH2:22][CH2:23]2)[C:5]2[CH:10]=[C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([S:27]([CH:24]4[CH2:26][CH2:25]4)(=[O:29])=[O:28])[CH2:14][CH2:13]3)[S:8][C:6]=2[N:7]=1
Reactant: O=S(=O)(Cl)C1CC1
Reactant: Clc1nc(N2CCOCC2)c2cc(CN3CCNCC3)sc2n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(C1CC1)N1CCN(Cc2cc3c(N4CCOCC4)nc(Cl)nc3s2)CC1
Temperature: 25 °C

Procedure:
To 2-chloro-4-morpholin-4-yl-6-piperazin-1-ylmethyl-thieno[2,3-d]pyrimidine (187 mg) in anhydrous DCM (5 ml) and triethylamine (111 ul) was added cyclopropanesulfonyl chloride (65 ul) at 0° C. The reaction mixture was allowed to warm up to room temperature over 4 hours. Aqueous work-up and purification on silica gave 2-chloro-4-morpholin-4-yl-6-[4-(cyclopropane-2-sulfonyl)-piperazin-1-ylmethyl]-thieno[2,3-d]pyrimidine (159 mg), which was reacted with 2-aminopyrimidine-5-boronic acid in General Procedure A. Purification on silica yielded 413. NMR (DMSO): 0.90-0.92 (2H, m), 0.97-1.00 (2H, m), 2.53-2.58 (4H, m), 2.60-2.64 (1H, m), 3.20-3.23 (4H, m), 3.74-3.77 (4H, m), 3.80 (2H, s), 3.88-3.91 (4H, m), 7.08 (2H, br), 7.52 (1H, s), 9.08 (2H, s) MS (ESI+): MH+ 517.22 (50%)
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1([C:6]2[O:10][N:9]=[C:8]([NH2:11])[CH:7]=2)[CH2:5][CH2:4]1.C(=O)([O-])[O-].[K+].[K+].Cl[C:21]([O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:22]>ClCCl>[F:13][C:2]([F:1])([F:12])[C:3]1([C:6]2[O:10][N:9]=[C:8]([NH:11][C:21](=[O:22])[O:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:7]=2)[CH2:4][CH2:5]1
Reactant: Nc1cc(C2(C(F)(F)F)CC2)on1
Reactant: O=C(Cl)Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: O=C(Nc1cc(C2(C(F)(F)F)CC2)on1)Oc1ccccc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 65 %

Procedure:
To a stirred mixture of 5-(1-(trifluoromethyl)cyclopropyl)isoxazol-3-amine (687 mg, 3.58 mmol) and potassium carbonate (987 mg, 7.0 mmol) in dry dichloromethane (30 mL) at 0° C., was added a solution of phenyl chloroformate (848 mg, 5.42 mmol) in anhydrous dichloromethane (5 mL). The reaction mixture was warmed to room temperature and stirred for a further 15 h. The reaction mixture was filtered and the filtrate concentrated under reduced pressure to give an oil. Purification via silica gel flash chromatography afforded phenyl 5-(1-(trifluoromethyl)cyclopropyl)isoxazol-3-ylcarbamate (727 mg, 65%) as a colorless solid. 1H NMR (300 MHz, DMSO-d6) δ 11.34 (brs, 1H), 7.40-7.47 (m, 2H), 7.20-7.31 (m, 3H), 6.80 (s, 1H), 1.45-1.56 (m, 4H); LC-MS (ESI) m/z 313 (M+H)+.
Reaction SMILES: FC1C=C(F)C=CC=1O[C:5]1[C:6](=[O:22])[O:7][C:8]([CH3:21])([CH3:20])[C:9]=1[C:10]1[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=1.[Cl:28][C:29]1[CH:30]=[CH:31][C:32]([OH:35])=[N:33][CH:34]=1.C1CCN2C(=NCCC2)CC1>CC#N.CCOCC>[Cl:28][C:29]1[CH:30]=[CH:31][C:32]([O:35][C:5]2[C:6](=[O:22])[O:7][C:8]([CH3:20])([CH3:21])[C:9]=2[C:10]2[CH:11]=[CH:12][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:14][CH:15]=2)=[N:33][CH:34]=1
Reactant: Oc1ccc(Cl)cn1
Reactant: CC1(C)OC(=O)C(Oc2ccc(F)cc2F)=C1c1ccc(S(C)(=O)=O)cc1
Solvent: CCOCC
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CC1(C)OC(=O)C(Oc2ccc(Cl)cn2)=C1c1ccc(S(C)(=O)=O)cc1
Temperature: 67.5 °C

Procedure:
To a mixture of 2-chloroacetic acid 2-methyl-1-(4-(methylsulfonyl)phenyl)propan-1-one ester (1.0 g, 3.13 mmol, prepared similarly to the compound of example 5, Step 1) and 5-chloro-2-pyridinol (0.41 g, 3.16 mmol) in CH3CN (20 mL) was added DBU (1.5 mL, 10.0 mmol) at r.t. The mixture was stirred for lh, then heated at 65-70° C. for 3 h. The volatile solvents were removed in vacuo. The residue was chromatographed over silica gel and eluted with hexane:EtOAc (1:1) to yield a colorless oily residue which was swished in Et2O to provide the title compound as a white powder (230 mg).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH:13]([CH3:15])[CH3:14])[C:6]([OH:8])=O)#[N:2].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.O[NH:31][C:32]([C:34]1[CH:35]=[C:36]2[C:40](=[CH:41][CH:42]=1)[N:39]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH:38]=[CH:37]2)=[NH:33]>CN(C=O)C.C([O-])(O)=O.[Na+]>[C:1]([C:3]1[CH:4]=[C:5]([C:6]2[O:8][N:31]=[C:32]([C:34]3[CH:35]=[C:36]4[C:40](=[CH:41][CH:42]=3)[N:39]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH:38]=[CH:37]4)[N:33]=2)[CH:9]=[CH:10][C:11]=1[O:12][CH:13]([CH3:15])[CH3:14])#[N:2]
Reactant: CC(C)Oc1ccc(C(=O)O)cc1C#N
Reactant: CC(C)(C)OC(=O)n1ccc2cc(C(=N)NO)ccc21
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC(C)Oc1ccc(-c2nc(-c3ccc4c(ccn4C(=O)OC(C)(C)C)c3)no2)cc1C#N
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 59 %

Procedure:
Prepared using General Procedure 2. A flask containing 3-cyano-4-isopropoxybenzoic acid (135 mg, 0.66 mmol), HOBt (130 mg, 0.85 mmol) and EDC (164 mg, 0.85 mmol) in DMF (2.5 mL) was stirred for 1.5 h at room temperature under an atmosphere of N2. A solution of crude tert-butyl 5-(N-hydroxycarbamimidoyl)-1H-indole-1-carboxylate INT-66 (199 mg, 0.72 mmol) in DMF (2.5 mL) was added to the mixture. After 1 h at room temperature, the mixture was heated to 75° C. and stirred overnight. The reaction mixture was diluted with NaHCO3 and extracted with EtOAc. The combined organic extracts were dried over Na2SO4 and concentrated. The resulting crude material was chromatographed (EtOAc/hexanes) to provide 174 mg (59%) of tert-butyl 5-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-1H-indole-1-carboxylate INT-67 as a white solid. LCMS-ESI (m/z) calculated for C25H24N4O4: 444.5; found 445.1 [M+H]+, tR=3.67 min (Method 1).
Reaction SMILES: [CH2:1]([CH2:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=CC=1)=O)[CH3:2].[N+:18]([O-])([OH:20])=[O:19].[OH-:22].[Na+]>O>[N+:18]([CH:13]1[CH:12]([CH2:9][C:10]([C:11]2[CH:2]=[CH:1][CH:3]=[CH:4][CH:6]=2)=[O:22])[CH2:17][CH2:16][CH2:15][CH2:14]1)([O-:20])=[O:19]
Reactant: [OH-]
Reactant: O=[N+]([O-])O
Reactant: CCCC(=O)c1ccc(C2CCCCC2)cc1
Agent: [Na+]
Solvent: O
Product: O=C(CC1CCCCC1[N+](=O)[O-])c1ccccc1
Temperature: 0 °C

Procedure:
Ethyl p-cyclohexylacetophenone (0.066 mole) is added to ice-cold concentrated sulfuric acid (18 ml) and stirred with cooling for 5 minutes. Concentrated nitric acid (Sp. G. 1.51) (2.5 ml) is added dropwise, maintaining the temperature between 30° and 40° by water cooling when necessary. After addition of the nitric acid is complete, the mixture is stirred for 1/2 hour, then poured into water. The mixture is made alkaline with sodium hydroxide, then extracted with ether. The ether extract is washed, dried over sodium sulfate, evaporated and the residue is fractionally distilled to obtain 3-nitro-4-cyclohexylacetophenone.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[N:8]([CH2:11][C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[N:18]=[CH:17][CH:16]=[CH:15]4)[N:9]=[N:10][C:5]2=[N:4][CH:3]=1.[CH3:22][C:23]1[N:24]=[CH:25][NH:26][CH:27]=1.[F-].[Cs+]>C(#N)C.O>[CH3:22][C:23]1[N:24]=[CH:25][N:26]([C:2]2[N:7]=[C:6]3[N:8]([CH2:11][C:12]4[CH:13]=[C:14]5[C:19](=[CH:20][CH:21]=4)[N:18]=[CH:17][CH:16]=[CH:15]5)[N:9]=[N:10][C:5]3=[N:4][CH:3]=2)[CH:27]=1
Reactant: Cc1c[nH]cn1
Reactant: Brc1cnc2nnn(Cc3ccc4ncccc4c3)c2n1
Agent: [Cs+]
Agent: [F-]
Solvent: O
Solvent: CC#N
Product: Cc1cn(-c2cnc3nnn(Cc4ccc5ncccc5c4)c3n2)cn1
Temperature: 160 °C
Yield: 54.5 %

Procedure:
A mixture of 6-((6-bromo-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)quinoline (50 mg, 0.15 mmol), 4-methyl-1H-imidazole (36 mg, 0.44 mmol) and CsF (25 mg, 0.16 mmol) in acetonitrile (1.45 mL) was heated in a microwave to 160° C. for 20 minutes. The reaction was diluted with water (5 mL) and the resulting suspension was filtered. The precipitate was washed with water and then purified by column chromatography using gradient elution with methanol and dichloromethane to afford 6-((6-(4-methyl-1H-imidazol-1-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)quinoline (28 mg, yield 56%)
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[CH2:6]([C:8]([CH3:20])([C:10]12[CH2:19][CH:14]3[CH2:15][CH:16]([CH2:18][CH:12]([CH2:13]3)[CH2:11]1)[CH2:17]2)[OH:9])[CH3:7].C(N(CC)CC)C.O1CCCC1>O>[C:1]([O:9][C:8]([C:10]12[CH2:19][CH:14]3[CH2:15][CH:16]([CH2:18][CH:12]([CH2:13]3)[CH2:11]1)[CH2:17]2)([CH3:20])[CH2:6][CH3:7])(=[O:4])[CH:2]=[CH2:3]
Reactant: CCC(C)(O)C12CC3CC(CC(C3)C1)C2
Reactant: C=CC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: C=CC(=O)OC(C)(CC)C12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 6 h
Yield: 74 %

Procedure:
A total of 10 mmole of acryloyl chloride was added dropwise to a mixture of 10 mmole of the above-prepared α-ethyl-α-methyl-1-adamantanemethanol, 10 mmole of triethylamine and 40 ml of tetrahydrofuran over about 30 minutes. After the completion of addition, the resulting mixture was stirred at room temperature for 6 hours. After the addition of water, the reaction mixture was concentrated, and the concentrate was subjected to column chromatography on a silica gel to thereby yield the title compound in a yield of 74%.
Reaction SMILES: O[C:2](C)(C#C)[CH2:3][C:4]1[CH:5]=[C:6]([CH:10]2[N:14]([CH3:15])[C:13](=[O:16])[CH2:12][CH2:11]2)[CH:7]=[N:8][CH:9]=1.[H-].[Na+].C1(C)C=CC=CC=1.CC(C)=O>C1(C)C=CC=CC=1>[C:3]([C:4]1[CH:5]=[C:6]([CH:10]2[N:14]([CH3:15])[C:13](=[O:16])[CH2:12][CH2:11]2)[CH:7]=[N:8][CH:9]=1)#[CH:2]
Reactant: C#CC(C)(O)Cc1cncc(C2CCC(=O)N2C)c1
Agent: [H-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: Cc1ccccc1
Product: C#Cc1cncc(C2CCC(=O)N2C)c1
Temperature: 25 °C
Yield: 81.1 %

Procedure:
5-(2-Hydroxy-2-methyl-3-butynyl)-3-(1-methyl-5-pyrrolidin-2-onyl)pyridine (200 mg, 0.77 mmol) was dissolved in toluene (20 mL) and catalytic sodium hydride (5 mg) was added. The solution was heated until several milliliters of toluene-acetone mixture were removed by distillation. The mixture was cooled to 25° C. and water (10 mL) and ethyl acetate (20 mL) were added. The organic phase was separated and the aqueous layer extracted with ethyl acetate (2×20 mL) and the combined organic extracts were washed with brine (10 mL), dried (MgSO4) and concentrated in vacuo. The crude product was purified by silica gel column chromatography with ethyl acetate as eluant to afford 5-ethynyl-3-(1-methyl-5-pyrrolidin-2-onyl)pyridine as a solid (125 mg, 81%). M.p. 83°-84° C.; 1H NMR (CDCl3, 300 MHz): δ 8.69 (d, J=2 Hz, 1H), 8.46 (d, J=2 Hz, 1H), 7.62 (t, J=2 Hz, 1H), 4.57 (dd, J=7, 6 Hz, 1H), 3.28 (s, 1H), 2.70 (s, 3H), 2.45-2.65 (m, 3H), 1.88 (m, 1H).
Reaction SMILES: [CH2:1]([C:8]1[C:13](=[O:14])[N:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21](O)=[O:22])[CH:16]=2)[C:11]2[N:24]=[CH:25][CH:26]=[CH:27][C:10]=2[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[NH3:34].C(=O)(O)[O-].[Na+]>ClCCl.CN(C)C=O.C(OCC)(=O)C>[CH2:1]([C:8]1[C:13](=[O:14])[N:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21](=[O:22])[NH2:34])[CH:16]=2)[C:11]2[N:24]=[CH:25][CH:26]=[CH:27][C:10]=2[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1cccc(-n2c(=O)c(Cc3ccccc3)nc3cccnc32)c1
Reactant: N
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: NC(=O)c1cccc(-n2c(=O)c(Cc3ccccc3)nc3cccnc32)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 2-benzyl-4-(3-carboxyphenyl)-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine (41 mg) in dichloromethane (2 ml) was added oxalyl chloride (0.02 ml) and 1 drop of N,N-dimethylformamide. After stirring at room temperature for 15 minutes, ammonia solution (28%, 1 ml) was added to the mixture and stirred at room temperature for 15 minutes. The mixture was poured into a mixture of ethyl acetate and aqueous sodium bicarbonate. The organic phase was separated, washed with aqueous sodium bicarbonate and brine, dried over magnesium sulfate and concentrated. The resultant solid was collected and washed with isopropyl ether to give 2-benzyl-4-(3-carbamoylphenyl)-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine (139 mg).
Reaction SMILES: C(OC(=O)[NH:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23](=[O:31])[NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:17][CH:16]=1)C1C=CC=CC=1.C(O)(=O)C>C(O)C.C1COCC1.[Pd]>[NH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]([NH:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[O:31])=[CH:17][CH:16]=1
Reactant: O=C(COc1ccc(CCCCNC(=O)OCc2ccccc2)cc1)Nc1ccccc1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: NCCCCc1ccc(OCC(=O)Nc2ccccc2)cc1
Yield: 97.1 %

Procedure:
A solution of [4-(4-phenylcarbamoylmethoxyphenyl)butyl]carbamic acid benzyl ester 18 (0.30 g, 0.69 mmol) in ethanol (10 mL), THF (6 mL), and acetic acid (2 mL) was stirred at room temperature for 2 h under hydrogen atmosphere in the presence of 10% Pd/C catalyst (0.2 g, 50% wet). The catalyst was removed by suction filtration and the filtrate was concentrated in vacuo. The residue was purified by flash silica gel column chromatography eluting with CH2Cl2/methanol/concentrated ammonium hydroxide (30:1:0, 30:1:0.3, v/v) to give the desired amine 19 as a white solid (200 mg, 97% yield). 1H NMR (300 MHz, CD3OD) δ 1.60 (m, 4H), 2.55 (m, 2H), 2.70 (m, 2H), 4.60 (s, 2H), 6.88 (d, 2H), 7.15 (m, 3H), 7.35 (m, 2H), 7.58 (d, 2H), 8.25 (s, 1H). m/z (ESI): 299 [C18H22N2O2+H]+.
Reaction SMILES: [CH2:1]([C:5]1[C:6]2[N:17]=[C:16]([C:18]3[CH:32]=[C:31]([CH3:33])[C:21]([O:22][CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[C:20]([CH3:34])[CH:19]=3)[O:15][C:7]=2[N:8]=[C:9](S(C)(=O)=O)[N:10]=1)[CH:2]([CH3:4])[CH3:3].[F:35][C:36]([F:41])([F:40])[CH2:37][CH2:38][OH:39]>>[CH2:1]([C:5]1[C:6]2[N:17]=[C:16]([C:18]3[CH:32]=[C:31]([CH3:33])[C:21]([O:22][CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[C:20]([CH3:34])[CH:19]=3)[O:15][C:7]=2[N:8]=[C:9]([O:39][CH2:38][CH2:37][C:36]([F:41])([F:40])[F:35])[N:10]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: OCCC(F)(F)F
Reactant: Cc1cc(-c2nc3c(CC(C)C)nc(S(C)(=O)=O)nc3o2)cc(C)c1OCC(=O)OC(C)(C)C
Product: Cc1cc(-c2nc3c(CC(C)C)nc(OCCC(F)(F)F)nc3o2)cc(C)c1OCC(=O)OC(C)(C)C
Yield: 10 %

Procedure:
Analogously to example 2 (a), the reaction of 95 mg of tert-butyl [4-(7-isobutyl-5-methanesulfonyloxazolo[5,4-d]pyrimidin-2-yl)-2,6-dimethylphenoxy]acetate with 3,3,3-trifluoropropan-1-ol gave 10 mg (10%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])[C@@H:7]([CH3:18])[CH2:6][NH:5]2.N1C=CC=CC=1.[F:25][C:26]1[CH:34]=[CH:33][CH:32]=[CH:31][C:27]=1[C:28](Cl)=[O:29]>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12](=[O:17])[C:13]([F:14])([F:16])[F:15])[C@@H:7]([CH3:18])[CH2:6][N:5]2[C:28](=[O:29])[C:27]1[CH:31]=[CH:32][CH:33]=[CH:34][C:26]=1[F:25]
Reactant: C[C@H]1CNc2cc(Br)ccc2N1C(=O)C(F)(F)F
Reactant: O=C(Cl)c1ccccc1F
Solvent: c1ccncc1
Solvent: ClCCl
Product: C[C@H]1CN(C(=O)c2ccccc2F)c2cc(Br)ccc2N1C(=O)C(F)(F)F
Temperature: 0 °C
Reaction time: 1 h
Yield: 99.6 %

Procedure:
A 50-mL round bottomed flask equipped with a magnetic stir bar was charged with (S)-1-(6-bromo-2-methyl-3,4-dihydroquinoxaline-1(2H)-yl)-2,2,2-trifluoroethanone (0.500 g, 1.547 mmol), dichloromethane (10 mL), and pyridine (0.188 mL, 2.321 mmol). The resulting solution was cooled to 0° C. and slowly treated with 2-fluorobenzoyl chloride (0.194 mL, 1.625 mmol). The solution was stirred at 0° C. for 1 h and then allowed to warm to rt. After stirring overnight at rt, the reaction mixture was diluted with dichloromethane and washed with 1 M aqueous HCl solution (10 mL) followed by 5% aqueous sodium chloride solution (10 mL). The dichloromethane extract was concentrated to afford crude (S)-1-(6-bromo-4-(2-fluorobenzoyl)-2-methyl-3,4-dihydroquinoxaline-1(2H)-yl)-2,2,2-trifluoroethanone (0.686 g, 100%). MS (ESI, pos. ion) m/z 445, 447 [M+1].
Reaction SMILES: C([O:4][C:5]1[CH:13]=[C:12]2[C:8]([C:9]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=3[F:23])=[C:10]([Br:15])[C:11]2=[O:14])=[CH:7][CH:6]=1)(=O)C.C(OC1C=C2C(C(C3C=CC=CC=3)=C(Br)C2=O)=CC=1)(=O)C>>[Br:15][C:10]1[C:11](=[O:14])[C:12]2[C:8]([C:9]=1[C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=1[F:23])=[CH:7][CH:6]=[C:5]([OH:4])[CH:13]=2
Reactant: CC(=O)Oc1ccc2c(c1)C(=O)C(Br)=C2c1ccc(F)cc1F
Agent: CC(=O)Oc1ccc2c(c1)C(=O)C(Br)=C2c1ccccc1
Product: O=C1C(Br)=C(c2ccc(F)cc2F)c2ccc(O)cc21
Yield: 90 %

Procedure:
The procedure of Step 5 of Example 1 was repeated except for using 2-bromo-3-(2,4-difluorophenyl)-1-oxo-1H-inden-6-yl acetate obtained in Step 4 as a starting material instead of 2-bromo-1-oxo-3-phenyl-1H-inden-6-yl acetate to obtain the title compound (90%).
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[I-].[K+].Cl[CH:11]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[S:14][CH2:13][CH2:12]1>CC(N(C)C)=O>[S:14]1[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH:11]([N:1]2[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)[CH2:12][CH2:13]1
Reactant: ClC1CCSc2ccccc21
Reactant: C1CNCCNC1
Agent: [I-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: c1ccc2c(c1)SCCC2N1CCCNCC1
Temperature: 60 °C
Yield: 75.9 %

Procedure:
A 100 ml 3-necked flask equipped with a condenser, addition funnel and magnetic stirring bar and under a nitrogen atmosphere was charged with a solution of homopiperazine (3.0 g; 30.5 mmol) in DMAC (35 ml). Potassium iodide (300 mg) was added followed by the addition of a solution of 4-chloro-3,4-dihydro-2H-benzothiopyran (1.15 g; 6.1 mmol) in DMAC (15 ml). This solution was then heated in an oil bath at 60° C. overnight. The reaction mixture was partitioned between water and ethyl acetate, washed with brine and dried with magnesium sulphate. Filtration and evaporation of solvent gave a yellow oil (1.15 g) which exhibited a satisfactory proton nmr spectrum (300 MHz, CDCl3). This material was used without further purification.
Reaction SMILES: Cl.[NH2:2]O.C(O[CH:7]1[CH:16](C)[CH2:15][C:14]2[CH2:13][CH2:12][C:11]3[CH:18]=[CH:19][CH:20]=[CH:21][C:10]=3[C:9]=2O1)C>C(#N)C>[N:2]1[C:9]2[C:10]3[CH:21]=[CH:20][CH:19]=[CH:18][C:11]=3[CH2:12][CH2:13][C:14]=2[CH:15]=[CH:16][CH:7]=1
Reactant: NO
Reactant: CCOC1OC2=C(CCc3ccccc32)CC1C
Agent: Cl
Solvent: CC#N
Product: c1ccc2c(c1)CCc1cccnc1-2
Reaction time: 16 h
Yield: 48.3 %

Procedure:
To a suspension of hydroxylamine hydrochloride (46.1 g, 0.663 mol) in 1070 mL of acetonitrile was added 2-ethoxy-3-methyl-3,4,5,6-tetrahydrobenzo[h]chromene (140 g, 0.265 mol) from step two. The reaction mixture was heated at reflux under nitrogen with stirring for 16 h. Evaporation of the acetonitrile, followed by vacuum distillation of the product yielded 34.5 g of a crude product that was further purified by silica gel chromatography with 5/95 ethyl acetate/hexane as the eluent, yielding 23.2 g (45%) of 5,6-dihydrobenzo[h]quinoline as a yellow liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([F:11])[CH:10]=1)[N:7]([CH2:12][CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[C:6]([CH2:18]Cl)=[CH:5]2.[CH3:20][S:21]([C:24]1[C:32]2[C:27](=[CH:28][N:29]=[CH:30][CH:31]=2)[NH:26][N:25]=1)(=[O:23])=[O:22].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([F:11])[CH:10]=1)[N:7]([CH2:12][CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[C:6]([CH2:18][N:26]1[C:27]3=[CH:28][N:29]=[CH:30][CH:31]=[C:32]3[C:24]([S:21]([CH3:20])(=[O:22])=[O:23])=[N:25]1)=[CH:5]2
Reactant: CS(=O)(=O)CCn1c(CCl)cc2cc(Cl)cc(F)c21
Reactant: CS(=O)(=O)c1n[nH]c2cnccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)CCn1c(Cn2nc(S(C)(=O)=O)c3ccncc32)cc2cc(Cl)cc(F)c21
Reaction time: 8 h
Yield: 11 %

Procedure:
A mixture of the crude 5-chloro-2-(chloromethyl)-7-fluoro-1-(2-(methylsulfonyl)ethyl)-1H-indole (0.36 mmol), 3-(methylsulfonyl)-1H-pyrazolo[3,4-c]pyridine (60 mg, 0.30 mmol) and K2CO3 (198 mg, 1.44 mmol) in 3 mL of DMF was stirred overnight and then the precipitate was filtered off. The filtrate was purified by preparative-HPLC to give 1-({5-chloro-7-fluoro-1-[2-(methylsulfonyl)ethyl]-1H-indol-2-yl}methyl)-3-(methylsulfonyl)-1H-pyrazolo[3,4-c]pyridine (16 mg, yield: 11%).