Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].NC[C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][N:17]([C:20]3[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=3)[CH2:16][CH2:15]2)=[CH:10][CH:9]=1.[CH2:26]([N:28](CC)CC)C>ClCCl>[N:23]1[CH:24]=[CH:25][C:20]([N:17]2[CH2:16][CH2:15][N:14]([C:11]3[CH:10]=[CH:9][CH:8]=[CH:13][C:12]=3[CH2:26][NH:28][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:19][CH2:18]2)=[CH:21][CH:22]=1
Reactant: NCc1ccc(N2CCN(c3ccncc3)CC2)cc1
Reactant: CCN(CC)CC
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Product: CS(=O)(=O)NCc1ccccc1N1CCN(c2ccncc2)CC1
Temperature: 25 °C
Reaction time: 7 h

Procedure:
A solution of methanesulphonyl chloride (0.155 ml) in dichloromethane (10 ml) was added dropwise to a stirred solution of 1-(4-aminomethylphenyl)-4-(4-pyridyl)piperazine (536 mg) in dichloromethane (50 ml) containing triethylamine (0.5 ml). The resulting solution was stirred at ambient temperature for 7 hours. The solution was evaporated and the residue was extracted with ethyl acetate. The ethyl acetate extracts were washed with water, sodium bicarbonate solution, brine, dried (MgSO4) and evaporated. The solid residue was recrystallised from methanol to give 1-(4-pyridyl)-4-(methanesulphonamidomethylphenyl)piperazine (356 mg) as a solid, m.p.236-238° C.; microanalysis found: C,59.3; H,6.4; N,16.2%; C17H22N4O2S requires: C,58.8; H,6.4; N,16.2%; NMR: 2.8(s,3H), 3.15-3.3(m,4H), 3.4-3.55(m,4H), 4.00-4.10(d,2H,), 6.80-6.90(d,2H), 6.90-7.00(d,2H), 7.15-7.25(d,2H), 7.3—7.5(t,1H), 8.20(d,1H); MS: m/z 311 (MH)+.
Reaction SMILES: [C:1]([C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]([C@@H:10]1[C@H:15]2[CH2:16][C@H:12]([C:13](=O)[CH2:14]2)[N:11]1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[O:9])#[N:2].Cl.[NH2:26][OH:27].C([O-])(=O)C.[Na+]>C(O)C.O>[C:1]([C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]([C@@H:10]1[C@H:15]2[CH2:16][C@H:12](/[C:13](=[N:26]/[OH:27])/[CH2:14]2)[N:11]1[C:18]([O:20][C:21]([CH3:23])([CH3:22])[CH3:24])=[O:19])=[O:9])#[N:2]
Reactant: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H](CC2=O)[C@H]1C(=O)N1CCC[C@H]1C#N
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H](C/C2=N\O)[C@H]1C(=O)N1CCC[C@H]1C#N
Temperature: 80 °C
Reaction time: 0.33 h

Procedure:
To a solution of tert-butyl (1R,3S,4S)-3-{[(2S)-2-cyano-1-pyrrolidinyl]carbonyl}-6-oxo-2-azabicyclo[2.2.1]heptane-2-carboxylate obtained in Example 22-1 (296 mg) in ethanol (5 mL) and water (1 mL),were added hydroxylamine hydrochloride (123 mg) and sodium acetate (153 mg). The mixture was stirred at 80° C. for 20 minutes.
Reaction SMILES: Cl[C:2](OC1C=CC([N+]([O-])=O)=CC=1)=[O:3].[NH2:14][C:15]1[CH:42]=[CH:41][C:18]([C:19]([N:21]2[CH2:26][CH2:25][N:24]([CH2:27][C:28]3[CH:29]=[C:30]([CH:38]=[CH:39][CH:40]=3)[C:31]([NH:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:23][CH2:22]2)=[O:20])=[C:17]([F:43])[CH:16]=1.[CH:44]1([CH2:47][NH2:48])[CH2:46][CH2:45]1>C(#N)C>[C:34]([NH:33][C:31](=[O:32])[C:30]1[CH:38]=[CH:39][CH:40]=[C:28]([CH2:27][N:24]2[CH2:25][CH2:26][N:21]([C:19](=[O:20])[C:18]3[CH:41]=[CH:42][C:15]([NH:14][C:2]([NH:48][CH2:47][CH:44]4[CH2:46][CH2:45]4)=[O:3])=[CH:16][C:17]=3[F:43])[CH2:22][CH2:23]2)[CH:29]=1)([CH3:37])([CH3:36])[CH3:35]
Reactant: NCC1CC1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)NC(=O)c1cccc(CN2CCN(C(=O)c3ccc(N)cc3F)CC2)c1
Solvent: CC#N
Product: CC(C)(C)NC(=O)c1cccc(CN2CCN(C(=O)c3ccc(NC(=O)NCC4CC4)cc3F)CC2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 8.2 %

Procedure:
4-Nitrophenyl chloroformate (59 mg, 0.29 mmol) was added to a solution of 3-((4-(4-amino-2-fluorobenzoyl)piperazin-1-yl)methyl)-N-tertbutylbenzamide (100 mg, 0.24 mmol) in acetonitrile (10 mL). After stirring at room temperature for 1 hour, cyclopropylmethylamine (126 μL, 1.21 mmol) was added. After 2 hours stirring, the reaction was purified by strong cation exchange chromatography, eluting macroporous polystyrene sulfonic acid with 2N ammonia in methanol. The resulting solution was concentrated under vacuum and purified by basic reverse phase HPLC to afford the title compound as a white solid (10 mg).
Reaction SMILES: Cl.[NH:2]1[C:6]2=[N:7][CH:8]=[CH:9][C:10]([O:11][C:12]3[CH:17]=[CH:16][C:15]([NH:18]C4C(C(NC5C=CC(F)=CC=5F)=O)=CN=CC=4)=[CH:14][C:13]=3[F:36])=[C:5]2[CH:4]=[CH:3]1.Cl[C:38]1[N:54]=[CH:53][CH:52]=[C:51]([O:55][CH3:56])[C:39]=1[C:40]([NH:42][C:43]1[CH:48]=[CH:47][C:46]([F:49])=[CH:45][C:44]=1[F:50])=[O:41].Cl>CN1C(=O)CCC1>[NH:2]1[C:6]2=[N:7][CH:8]=[CH:9][C:10]([O:11][C:12]3[CH:17]=[CH:16][C:15]([NH:18][C:38]4[N:54]=[CH:53][CH:52]=[C:51]([O:55][CH3:56])[C:39]=4[C:40]([NH:42][C:43]4[CH:48]=[CH:47][C:46]([F:49])=[CH:45][C:44]=4[F:50])=[O:41])=[CH:14][C:13]=3[F:36])=[C:5]2[CH:4]=[CH:3]1.[NH:2]1[C:6]2=[N:7][CH:8]=[CH:9][C:10]([O:11][C:12]3[CH:17]=[CH:16][C:15]([NH:18][C:38]4[N:54]=[CH:53][CH:52]=[C:51]([OH:55])[C:39]=4[C:40]([NH:42][C:43]4[CH:48]=[CH:47][C:46]([F:49])=[CH:45][C:44]=4[F:50])=[O:41])=[CH:14][C:13]=3[F:36])=[C:5]2[CH:4]=[CH:3]1
Reactant: COc1ccnc(Cl)c1C(=O)Nc1ccc(F)cc1F
Reactant: O=C(Nc1ccc(F)cc1F)c1cnccc1Nc1ccc(Oc2ccnc3[nH]ccc23)c(F)c1
Agent: Cl
Solvent: CN1CCCC1=O
Product: COc1ccnc(Nc2ccc(Oc3ccnc4[nH]ccc34)c(F)c2)c1C(=O)Nc1ccc(F)cc1F
Product: O=C(Nc1ccc(F)cc1F)c1c(O)ccnc1Nc1ccc(Oc2ccnc3[nH]ccc23)c(F)c1
Temperature: 140 °C

Procedure:
To a homogeneous mixture of 4-(1H-pyrrolo[2,3-b]pyridin-4-yloxy)-3-fluorobenzenamine (0.037 g, 0.15 mmol, Compound C of Example 1) and 2-chloro-N-(2,4-difluorophenyl)-4-methoxynicotinamide (0.045 g, 0.15 mmol), in anhydrous NMP (0.50 mL), was added HCl (4N in 1,4-dioxane, 0.15 mL, 0.60 mmol). The mixture was microwaved in a CEM Explorer PLS microwave system (300 W), with the temperature measured with an IR temperature sensor and maintained at 140° C. for six hours. The reaction mixture was partitioned between water and EtOAc. The aqueous layer was extracted twice with EtOAc, and the combined organic layers were concentrated in vacuo. The resultant residue was purified by preparative (RP) HPLC (YMC S10 ODS, 30×500 mm, 30 minute gradient from 50% to 90% aqueous methanol with 0.1% TFA). The appropriate fractions were combined and concentrated in vacuo to afford 2-(4-(1H-pyrrolo[2,3-b]pyridin-4-yloxy)-3-fluorophenylamino)-N-(2,4-difluorophenyl)-4-methoxynicotinamide (Example 15) (0.006 g) as an off-white solid and 2-(4-(1H-pyrrolo[2,3-b]pyridine-4-yloxy)-3-fluorophenylamino)-N-(2,4-difluorophenyl)-4-hydroxynicotinamide (Example 16) (0.042 g) as a white solid.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]1[C@H:13]([C:14]([OH:16])=O)[CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])[CH3:3].C[N:18](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[Cl-].[NH4+].CCN(C(C)C)C(C)C>CN(C=O)C>[C:2]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH2:11][CH2:12][C@H:13]1[C:14](=[O:16])[NH2:18])=[O:7])([CH3:4])([CH3:3])[CH3:1]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: CC(C)(C)OC(=O)N1CCCC[C@H]1C(=O)O
Agent: F[B-](F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCCC[C@H]1C(N)=O

Procedure:
To a solution of N-Boc-L-pipecolinic acid (200 mg, 0.87 mmol) in DMF (3.5 mL) was added TBTU (336 mg, 1.05 mmol), ammonium chloride (93 mg, 1.74 mmol) then DIPEA (182 μL, 1.05 mmol) and the reaction stirred for 16 h. The mixture was partitioned between ethyl acetate (2×30 mL) and water (30 mL), and the organics combined before being washed with 1M sodium hydroxide (3×30 mL) and brine (3×30 mL). The organic solution was dried (MgSO4) and solvent removed in vacuo to give the title compound as a white solid. δH (d6 DMSO): 7.23 (1H, s), 6.97 (1H, s), 4.56–4.39 (1H, br m), 3.43–3.74 (1H, d), 3.14–2.90 (1H, br m), 2.09–2.00 (1H, d), 1.63–1.47 (3H, m), 1.30–1.17 (2H, m).
Reaction SMILES: [CH2:1]([O:3][C@@H:4]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][OH:19])=[CH:13][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH3:2].[CH3:20][S:21]([O:24][C:25]1[CH:30]=[CH:29][C:28](O)=[CH:27][CH:26]=1)(=[O:23])=[O:22]>C1COCC1>[CH2:1]([O:3][C@@H:4]([CH2:10][C:11]1[CH:12]=[CH:13][C:14]([CH2:17][CH2:18][O:19][C:28]2[CH:27]=[CH:26][C:25]([O:24][S:21]([CH3:20])(=[O:22])=[O:23])=[CH:30][CH:29]=2)=[CH:15][CH:16]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH3:2]
Reactant: CCOC(=O)[C@H](Cc1ccc(CCO)cc1)OCC
Reactant: CS(=O)(=O)Oc1ccc(O)cc1
Solvent: C1CCOC1
Product: CCOC(=O)[C@H](Cc1ccc(CCOc2ccc(OS(C)(=O)=O)cc2)cc1)OCC
Temperature: 150 °C
Yield: 41.6 %

Procedure:
A solution of cyanomethylenetri-N-butylphosphorane (0.663 g, 2.75 mmol) in THF (1.5 mL) was added to a solution of ethyl(2S)-2-ethoxy-3-[4-(2-hydroxyethyl)phenyl]-propanoate (0.244 g, 0.92 mmol) and 4-hydroxyphenyl methanesulfonate (0.172 g, 0.92 mmol) in THF (1.5 mL). The reaction mixture was heated at 150° C. in a microwave oven for 10 minutes. The solvent was removed under reduced pressure. The crude product was purified by flash chromatography (silica, heptane/ethyl acetate 3:1 as the mobile phase) affording 0.167 g (42%) of the title compound.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([CH2:10][C:11]([OH:13])=O)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[CH:14]([N:16]1[CH2:22][CH2:21][C:20]2[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=2[CH2:18][CH2:17]1)=[O:15]>>[C:1]([N:4]1[CH2:5][CH2:6][CH:7]([CH2:10][C:11]([C:25]2[CH:24]=[CH:23][C:20]3[CH2:21][CH2:22][N:16]([CH:14]=[O:15])[CH2:17][CH2:18][C:19]=3[CH:26]=2)=[O:13])[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCC(CC(=O)O)CC1
Reactant: O=CN1CCc2ccccc2CC1
Product: CC(=O)N1CCC(CC(=O)c2ccc3c(c2)CCN(C=O)CC3)CC1

Procedure:
Using (1-acetyl-4-piperidinyl)acetic acid and 3-formyl-2,3,4,5-tetrahydro-1H-3-benzazepine as obtained in Reference Example 2, the procedure of Example 23-1) was similarly repeated to provide 2-(1-acetyl-4-piperidinyl)-1-(3-formyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-1-ethanone as light-yellow oil.
Reaction SMILES: [CH3:1][C:2]1[S:17][C:5]2[O:6][C:7]3[C:15]([CH3:16])=[CH:14][CH:13]=[CH:12][C:8]=3[NH:9][C:10](=O)[C:4]=2[CH:3]=1.P(Cl)(Cl)(Cl)=O.CN(C)C1C=CC=CC=1.[CH3:32][N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1>>[CH3:1][C:2]1[S:17][C:5]2[O:6][C:7]3[C:15]([CH3:16])=[CH:14][CH:13]=[CH:12][C:8]=3[N:9]=[C:10]([N:36]3[CH2:37][CH2:38][N:33]([CH3:32])[CH2:34][CH2:35]3)[C:4]=2[CH:3]=1
Reactant: Cc1cc2c(s1)Oc1c(C)cccc1NC2=O
Reactant: CN1CCNCC1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)c1ccccc1
Product: Cc1cc2c(s1)Oc1c(C)cccc1N=C2N1CCN(C)CC1

Procedure:
In the same manner as in Example 125 and using 2,9-dimethylthieno[2,3-b][1,5]benzoxazepin-4(5H)-one, phosphorus oxychloride, N,N-dimethylaniline and 1-methylpiperazine, 2,9-dimethyl-4-(4-methylpiperazin-1-yl)thieno[2,3-b][1,5]benzoxazepine is obtained.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2([O:12][CH2:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:11][CH2:10]2)=[CH:5][C:4]=1C)#[CH:2].[CH2:19]([O:21][C:22](=[O:30])[C:23]1[CH:28]=[CH:27][C:26](I)=[CH:25][CH:24]=1)[CH3:20].[CH2:31](N(CC)CC)C>[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:19]([O:21][C:22](=[O:30])[C:23]1[CH:28]=[CH:27][C:26]([C:2]#[C:1][C:3]2[CH:4]=[CH:5][C:6]([C:9]3([O:12][CH2:13][C:14]([CH3:15])([CH3:16])[CH3:17])[CH2:10][CH2:11]3)=[C:7]([CH3:31])[CH:8]=2)=[CH:25][CH:24]=1)[CH3:20]
Reactant: C#Cc1ccc(C2(OCC(C)(C)C)CC2)cc1C
Reactant: CCOC(=O)c1ccc(I)cc1
Reactant: CCN(CC)CC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Product: CCOC(=O)c1ccc(C#Cc2ccc(C3(OCC(C)(C)C)CC3)c(C)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50 %

Procedure:
Using General Procedure F; 4-ethynyl-1-[1-(2,2-dimethylpropyloxy)-cyclopropyl]-3-methyl-benzene (Intermediate 85, 75.0 mg, 0.31 mmol) and ethyl-4-iodo benzoate (Reagent A, 86.0 mg, 0.31 mmol) in triethylamine (5 mL) was treated with copper(I)iodide (21.0 mg, 0.11 mmol) and sparged with argon for 5 minutes. Dichlorobis(triphenylphosphine)-palladium(II) (78 mg, 0.11 mmol) was added and the reaction mixture was stirred overnight at room temperature. Column chromatography (2-4% EtOAc-hexanes) afforded 60.0 mg (50%) of the title compound as an orange solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.Cl[C:24](Cl)([O:26][C:27](=[O:33])OC(Cl)(Cl)Cl)Cl.[CH:35]1(CO)[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:27](=[O:33])[O:26][CH2:24][CH:35]2[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]2)=[CH:18][CH:17]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: OCC1CCCCC1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc2nccc(Oc3ccc(NC(=O)OCC4CCCCC4)cc3)c2cc1OC
Yield: 66.5 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (50 mg) was added to toluene (5 ml), and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (77 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, cyclohexylmethanol (30 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution, water, and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (49 mg, yield 61%).
Reaction SMILES: [I:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[O:4][CH2:5][CH:6]1[CH2:8][O:7]1.[C:13]([NH2:17])([CH3:16])([CH3:15])[CH3:14].[ClH:18].CCOCC>S1(CCCC1)(=O)=O>[ClH:18].[CH3:14][C:13]([NH:17][CH2:8][CH:6]([OH:7])[CH2:5][O:4][C:3]1[CH:9]=[CH:10][CH:11]=[CH:12][C:2]=1[I:1])([CH3:16])[CH3:15]
Reactant: CC(C)(C)N
Reactant: Ic1ccccc1OCC1CO1
Agent: Cl
Solvent: CCOCC
Solvent: O=S1(=O)CCCC1
Product: CC(C)(C)NCC(O)COc1ccccc1I
Yield: 53 %

Procedure:
A solution of 30.0 g (0.108 mole) of [(2-iodophenoxy)methyl]oxirane and 110 ml (1 mole) of t-butylamine in 62 ml of sulfolane was heated in an autoclave for two hours. The excess t-butylamine was evaporated in vacuo. The residue was dissolved in ether and the ether solution washed with water and brine. The solution was dried (K2CO3), and the solvent was evaporated in vacuo. A hydrochloride salt was prepared by adding ethereal hydrogen chloride to an ether solution of the residue. There was obtained 25 g (53% yield) of crystalline 1-[(1,1-dimethylethyl)amino]-3-(2-iodophenoxy)-2-propanol hydrochloride, mp 184° to 185° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([CH2:8]CCl)=[C:4]([CH2:11][CH2:12][CH3:13])[CH:3]=1.[F:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]2[NH:22][CH:23]=[CH:24][N:25]=2)[N:16]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[N:7]=[N:6][C:5]([CH2:8][N:25]2[CH:24]=[CH:23][N:22]=[C:21]2[C:17]2[CH:18]=[CH:19][CH:20]=[C:15]([F:14])[N:16]=2)=[C:4]([CH2:11][CH2:12][CH3:13])[CH:3]=1
Reactant: Fc1cccc(-c2ncc[nH]2)n1
Reactant: CCCc1cc(Cl)nnc1CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCc1cc(Cl)nnc1Cn1ccnc1-c1cccc(F)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
DMF (30 ml) is added to a mixture of 6-chloro-3-chloroethyl-4-propyl-pyridazine (5.01 g, 24.43 mmol), 2-fluoro-6-(imidazol-2-yl)-pyridine (3.99 g, 24.43 mmol) and anhydrous K2CO3 (10.2 g, 73.3 mmol) and the mixture is stirred at room temperature overnight. The solvent is removed in vacuo, water (30 ml) and EtOAc (30 ml) are added to the residue and the layers are separated. The aqueous layer is extracted with EtOAc (3×30 ml) and the combined extracts are washed with brine (30 ml), dried (Na2SO4) and evaporated, which provides a light brown solid. The solid is washed twice with 1:1 hexane, ether (25 ml), which provides the title compound as a light yellow solid. 1H NMR (CDCl3) 8.12–8.15 (m, 1H), 7.84 (q, 1H), 7.32 (s, 1H), 7.17 (d, 1H), 7.10 (d, 1H), 6.81–6.84 (m, 1H), 6.22 (s, 2H), 2.68 (t, 2H), 1.54–1.62 (m, 2H), 0.91 (t, 3H).
Reaction SMILES: [NH:1]([C:3]1[N:8]=[CH:7][CH:6]=[CH:5][N:4]=1)[NH2:2].C(N(CC)CC)C.C[O:17][C:18](=O)[N:19]=[C:20](SC)[C:21]([C:35]1[CH:40]=[CH:39][C:38]([O:41][CH2:42][CH3:43])=[C:37]([O:44][CH3:45])[CH:36]=1)=[N:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[N:33]=[C:32]([CH3:34])[O:31][N:30]=2)=[CH:25][CH:24]=1>CN(C=O)C>[CH2:42]([O:41][C:38]1[CH:39]=[CH:40][C:35]([CH:21]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]3[N:33]=[C:32]([CH3:34])[O:31][N:30]=3)=[CH:25][CH:24]=2)[C:20]2[NH:19][C:18](=[O:17])[N:1]([C:3]3[N:8]=[CH:7][CH:6]=[CH:5][N:4]=3)[N:2]=2)=[CH:36][C:37]=1[O:44][CH3:45])[CH3:43]
Reactant: CCOc1ccc(C(=Nc2ccc(-c3noc(C)n3)cc2)C(=NC(=O)OC)SC)cc1OC
Reactant: NNc1ncccn1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOc1ccc(C(Nc2ccc(-c3noc(C)n3)cc2)c2nn(-c3ncccn3)c(=O)[nH]2)cc1OC
Temperature: 85 °C
Reaction time: 20 h
Yield: 32.8 %

Procedure:
After adding 102 mg of 2-hydrazinopyrimidine and 129 μl of triethylamine to a solution of 435 mg of {2-(4-ethoxy-3-methoxyphenyl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene}carbamic acid methyl ester in 15 ml of DMF, the mixture was stirred at 85° C. for 20 hours under a nitrogen atmosphere. The reaction mixture was concentrated, and the residue was dissolved in 20 ml of a methanol:THF=1:1 mixed solvent. Next, 186 μl of acetic acid and 292 mg of sodium cyanotrihydroborate were added to the solution and the mixture was stirred at room temperature for 2 hours and 30 minutes. After adding ethyl acetate to the reaction mixture, it was filtered through a small amount of NAM silica gel, and the silica gel was washed with ethyl acetate-methanol. The filtrate was concentrated under reduced pressure, and the residue was purified by NAM silica gel column chromatography (methanol-ethyl acetate) to give the title compound (152 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.[CH3:12][CH:13]1[CH2:18][CH2:17][CH2:16][C:15](=O)[CH2:14]1.N1CCCC1>CO>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[O:11][C:15]1([CH2:16][CH2:17][CH2:18][CH:13]([CH3:12])[CH2:14]1)[CH2:9][C:8]2=[O:10]
Reactant: CC(=O)c1cc(Br)ccc1O
Reactant: CC1CCCC(=O)C1
Solvent: CO
Solvent: C1CCNC1
Product: CC1CCCC2(CC(=O)c3cc(Br)ccc3O2)C1
Reaction time: 8 h
Yield: 124.7 %

Procedure:
A mixture of 1-(5-bromo-2-hydroxy-phenyl)-ethanone (10 g, 46.7 mmol), 3-methylcyclohexanone (10.5 g, 93.4 mmol) and pyrrolidine (6.3 g, 88.8 mmol) in methanol (200 mL) was stirred overnight. The reaction mixture was concentrated in vacuo, and then H2O was added. The resulting solution was extracted with ethyl acetate. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give 6-bromo-3′-methylspiro[chroman-2,1′-cyclohexan]-4-one (18 g, 100%). 1HNMR (CDCl3): 0.86 (m, 3H), 0.91 (m, 2H), 1.02 (m, 2H), 1.30 (m, 2H), 1.52 (m, 2H), 1.65 (m, 4H), 1.80 (m, 7H), 2.01 (m, 4H), 2.22 (m, 1H), 2.48 (m, 1H), 2.60 (s, 2H), 2.72 (t, 3H), 6.81 (m, 1H), 7.50 (m, 1H), 7.91 (m, 1H).
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[CH:11]=[C:10]([CH3:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7](OS(C(F)(F)F)(=O)=O)[CH:8]=2)[NH:3]1.[CH3:22][O:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][C:29]=1[O:30][CH3:31].[C:35]1([CH2:41][CH2:42][SH:43])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>>[CH3:22][O:23][C:24]1[CH:25]=[C:26]([C:7]2[CH:8]=[C:9]3[C:4](=[CH:5][CH:6]=2)[NH:3][C:2]([CH3:1])([CH3:21])[CH:11]=[C:10]3[CH2:12][S:43][CH2:42][CH2:41][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:27]=[CH:28][C:29]=1[O:30][CH3:31]
Reactant: SCCc1ccccc1
Reactant: COc1ccc(B(O)O)cc1OC
Reactant: CC1=CC(C)(C)Nc2ccc(OS(=O)(=O)C(F)(F)F)cc21
Product: COc1ccc(-c2ccc3c(c2)C(CSCCc2ccccc2)=CC(C)(C)N3)cc1OC

Procedure:
Trifluoromethanesulfonic acid 2,2,4-trimethyl-1,2-dihydroquinolin-6-yl ester was coupled with 3,4-dimethoxyphenylboronic acid. Bromination and coupling reaction with 2-phenylethanethiol gave 10 mg the title compound.
Reaction SMILES: Cl.[C:2]1([CH2:8][N:9]([CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:10]2[C:19]3[N:20]=[C:21]([CH2:27][CH2:28][CH:29]([CH3:32])[CH2:30][Cl:31])[N:22](COCC)[C:18]=3[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>CO.C(Cl)Cl>[C:34]1([CH2:33][N:9]([CH2:8][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:10]2[C:19]3[N:20]=[C:21]([CH2:27][CH2:28][CH:29]([CH3:32])[CH2:30][Cl:31])[NH:22][C:18]=3[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=2)[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: CCOCn1c(CCC(C)CCl)nc2c(N(Cc3ccccc3)Cc3ccccc3)nc3ccccc3c21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: CC(CCl)CCc1nc2c(N(Cc3ccccc3)Cc3ccccc3)nc3ccccc3c2[nH]1
Yield: 88.8 %

Procedure:
Hydrochloric acid (80 mL of 6N) was added to a suspension of N,N-bis(phenylmethyl)-2-(4-chloro-3-methylbutyl)-1-ethoxymethyl-1H-imidazo[4,5-c]quinolin-4-amine (0.64 g, 1.2 mmole) in methanol (40 mL). The reaction mixture was heated at reflux for 2 hours (All of the methanol was driven off during this period.), diluted with methylene chloride and then made basic with 10% sodium hydroxide. The methylene chloride layer was separated, dried over magnesium sulfate and then concentrated to provide about 0.5 g of N,N-bis(phenylmethyl)-2-(4-chloro-3-methylbutyl)-1H-imidazo[4,5-c]quinolin-4-amine.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][C:6]([Cl:9])=[CH:5][C:3]=1[NH2:4].Cl[CH2:11][CH:12]=[O:13].C(=O)([O-])[O-].[Na+].[Na+]>>[CH3:1][C:2]1[CH:8]=[CH:7][C:6]([Cl:9])=[CH:5][C:3]=1[NH:4][CH2:11][CH:12]=[O:13]
Reactant: O=CCCl
Reactant: Cc1ccc(Cl)cc1N
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Cc1ccc(Cl)cc1NCC=O
Temperature: 150 °C

Procedure:
2-Methyl-5-chloroaniline (0.3 mole), the dimethyl acetal of 2-chloroacetaldehyde (0.3 mole) and sodium carbonate (20 grams) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture is heated at about 150° C. for a period of about 8 hours. After this time the mixture is filtered and the filtrate is distilled to yield the desired product the dimethyl acetal of 2-(2-methyl-5-chloroanilino)acetaldehyde.
Reaction SMILES: [CH:1]1([P:7]([CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:20]([OH:23])(=[O:22])[CH3:21].[F-:24].[F-].[F-]>C(OCC)C>[C:20]([O-:23])(=[O:22])[CH3:21].[F-:24].[F-:24].[F-:24].[CH:14]1([PH+:7]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]1.[CH:14]1([PH+:7]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]1.[CH:14]1([PH+:7]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]1.[CH:14]1([PH+:7]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]1
Reactant: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Reactant: CC(=O)O
Agent: [F-]
Solvent: CCOCC
Product: C1CCC([PH+](C2CCCCC2)C2CCCCC2)CC1
Product: CC(=O)[O-]
Yield: 64.4 %

Procedure:
To 25 ml of a solution of 12 mmol tricyclohexyl phosphine prepared in diethylether (as in example 2) is added 1.4 g (12 mmol) trifluoride acetic acid. After some time, a crystalline solid is precipitated, which is filtered off, and washed with a little diethylether. 2.4 g (59%) of a colorless solid is obtained.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]1[C:8](F)=[N:9][CH:10]=[CH:11][CH:12]=1.[CH2:14]([NH2:16])[CH3:15]>O1CCOCC1.C(OCC)(=O)C>[Br:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]1[C:8]([NH:16][CH2:14][CH3:15])=[N:9][CH:10]=[CH:11][CH:12]=1
Reactant: CCN
Reactant: Fc1ncccc1-c1sccc1Br
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCNc1ncccc1-c1sccc1Br
Temperature: 100 °C
Yield: 87.3 %

Procedure:
A mixture of 3-bromo-2-(2-fluoropyridin-3-yl)thiophene (0.47 g) and ethylamine (0.4 g) in dioxane (2 mL) in a sealed tube was heated at 100° C. for 2 days. The mixture was diluted with ethyl acetate, washed with water, dried, filtered and evaporated to give 3-bromo-2-(2-ethylaminopyridin-3-yl)thiophene (0.45 g).