Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:6](COCC[Si](C)(C)C)[C:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:4][C:3]=1[C:21]1[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=1.C([O-])([O-])=O.[Na+].[Na+].CO[CH2:35][CH2:36][O:37][CH3:38]>>[CH3:38][O:37][C:36]1[C:5]([NH2:6])=[N:4][CH:3]=[C:2]([C:2]2[N:6]=[C:5]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[NH:4][C:3]=2[C:21]2[CH:22]=[CH:23][N:24]=[CH:25][CH:26]=2)[CH:35]=1
Reactant: COCCOC
Reactant: C[Si](C)(C)CCOCn1c(-c2ccccc2)nc(-c2ccncc2)c1Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COc1cc(-c2nc(-c3ccccc3)[nH]c2-c2ccncc2)cnc1N
Temperature: 90 °C
Yield: 33 %

Procedure:
A mixture of 4-(5-bromo-2-phenyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)pyridine (620 mg, 1.4 mmol; Example 1, Step 3), 3-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxoborolan-2-yl)pyridine-2-amine (570 mg, 2.3 mmol, Example 17, Step 3), and aqueous 2.0 M Na2CO3 solution (2 mL, 4 mmol) in DME (8 mL) was purged with Ar for 3 min. Pd(dppf) Cl2-DCM (34 mg, 0.04 mmol) was added and the reaction mixture was purged with Ar for another 5 min. The reaction mixture was then heated to and maintained at 90° C. for 18 h under Ar. The reaction was allowed to cool to rt and was concentrated. The resulting residue was suspended in EtOAc (15 mL) and passed through a syringe filter. The filtrate was concentrated, treated with aqueous 3 M HCl solution (6 mL), and heated at 60° C. for 2 h. The reaction was allowed to cool to rt and was evaporated in vacuo. The resulting residue was purified by reverse-phase HPLC and lypholized to afford 160 mg (33%) of 3-methoxy-5-(2-phenyl-5-(pyridine-4-yl)-1H-imidazol-4-yl)pyridine-2-amine as the TFA salt: LCMS (m/z): 344.2 (MH+); tR=0.46 min; 1H NMR (CD3OD) δ 3.88 (s, 3H), 6.22 (br s, 2H), 7.16 (m, 1H), 7.38 (t, J=7.2 Hz, 1H), 7.47 (t, J=7.2 Hz, 2H), 7.61 (m, 2H), 7.67 (m, 1H), 8.05 (d, J=6.0 Hz, 2H), 8.48 (d, J=6.0 Hz, 2H).
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([S:12]([CH3:15])(=[O:14])=[O:13])[CH:6]=1)([CH3:4])[CH3:3].[Cl:16][CH2:17][C:18]([NH:20][CH2:21]O)=[O:19]>S(=O)(=O)(O)O>[Cl:16][CH2:17][C:18]([NH:20][CH2:21][C:9]1[CH:10]=[C:5]([C:2]([CH3:1])([CH3:3])[CH3:4])[CH:6]=[C:7]([S:12]([CH3:15])(=[O:14])=[O:13])[C:8]=1[OH:11])=[O:19]
Reactant: CC(C)(C)c1ccc(O)c(S(C)(=O)=O)c1
Reactant: O=C(CCl)NCO
Agent: O=S(=O)(O)O
Product: CC(C)(C)c1cc(CNC(=O)CCl)c(O)c(S(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
13.5 g (0.06 mol) of 4-(1,1-dimethylethyl)-2-methylsulfonylphenol are dissolved in 100 ml of concentrated sulfuric acid. 6.63 g (0.054 mol) of 2-chloro-N-hydroxymethylacetamide are added and the mixture is stirred at room temperature for 10 minutes. It is then poured onto ice-water and the crude product is filtered off with suction and recrystallized from toluene.
Reaction SMILES: [N+:1]([C:4]1[CH:16]=[CH:15][C:7]([N:8]([CH2:12][CH2:13][Cl:14])[CH2:9][CH2:10][Cl:11])=[CH:6][CH:5]=1)([O-])=O.Cl>C(OCC)(=O)C.CO.[Pd]>[ClH:11].[Cl:11][CH2:10][CH2:9][N:8]([CH2:12][CH2:13][Cl:14])[C:7]1[CH:15]=[CH:16][C:4]([NH2:1])=[CH:5][CH:6]=1
Reactant: O=[N+]([O-])c1ccc(N(CCCl)CCCl)cc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: Nc1ccc(N(CCCl)CCCl)cc1
Yield: 160 %

Procedure:
4-Nitro-[N,N-bis(2-chloroethyl)]aniline (5.0 g; 19.0 mmol) was dissolved in a mixed solvent of 50 ml of ethyl acetate and 25 ml of methanol, followed by the addition of 5.0 ml of 4N hydrochloric acid. Using 10% Pd/C, the reactant was subjected to hydrogenation under normal pressure at room temperature. The Pd/C was filtered off and the solvent was distilled out. The residue was crystallized from ethanol-ethyl ether, whereby 4.1 g (15.2 mmol) of the title compound was obtained (yield: 80%). m.p. 230°-233° C.
Reaction SMILES: [N+]([C:4]1[CH:5]=[C:6]([C:12]#[N:13])[C:7](=[CH:10][CH:11]=1)[C:8]#[N:9])([O-])=O.[NH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[OH:21].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[NH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[O:21][C:4]1[CH:5]=[C:6]([C:12]#[N:13])[C:7](=[CH:10][CH:11]=1)[C:8]#[N:9]
Reactant: N#Cc1ccc([N+](=O)[O-])cc1C#N
Reactant: Nc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc(Oc2ccccc2N)cc1C#N
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.1 %

Procedure:
A mixture of 4-nitrophthalonitrile (0.6 g, 5.78 mmol), 2-aminophenol (1 g, 5.78 mmol) and potassium carbonate (1.6 g, 11.6 mmol) in DMF (25 ml) was stirred at room temperature for 2 hours. The mixture was then poured into water. The precipitate was filtered off, washed with water and dried to give yellow crystals of 4-(2-aminophenoxy)phthalonitrile (yield: 1.32 g (97%)). Mp: 118-118.2° C.
Reaction SMILES: [CH2:1]([C:6]1[CH2:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:2]([CH3:5])([CH3:4])[CH3:3].C([Li])CCC.[Cl-].[CH3:21][C:22]([NH:25][SiH:26]([CH3:28])[CH3:27])([CH3:24])[CH3:23]>C1COCC1>[CH2:1]([C:6]1[CH:14]([Si:26]([CH3:28])([CH3:27])[NH:25][C:22]([CH3:24])([CH3:23])[CH3:21])[C:13]2[C:8]([CH:7]=1)=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: C[SiH](C)NC(C)(C)C
Reactant: CC(C)(C)CC1=Cc2ccccc2C1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)CC1=Cc2ccccc2C1[Si](C)(C)NC(C)(C)C
Reaction time: 1 h
Yield: 103.2 %

Procedure:
To a mixture of 2-neopentylindene (0.81 g, 4.3 mmol) in 30 mL of hexanes were added 2.9 mL of butyl lithium (1.6 M hexane; 4.7 mmol). The mixture was stirred for one hour, diluted with 20 mL of THF and to this added N-(1,1-dimethylethyl)dimethylsilanamine chloride (1.84 g, 11.2 mmol) in 10 mL of THF. After stirring overnight, the volatiles were removed in vacuo, the residue extracted with hexane, filtered and the volatiles removed in vacuo to give 1.4 g (102 percent) of a yellow oil.
Reaction SMILES: [C:1]([C:9]1[CH:36]=[CH:35][C:12]2[N:13]([CH2:17][CH2:18][O:19][C:20]3[CH:34]=[CH:33][C:23]([CH2:24][CH:25]([C:29]([O:31][CH3:32])=[O:30])[C:26](O)=[O:27])=[CH:22][CH:21]=3)[C:14](=[O:16])[S:15][C:11]=2[CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[CH3:41][NH2:42]>ClCCl>[C:1]([C:9]1[CH:36]=[CH:35][C:12]2[N:13]([CH2:17][CH2:18][O:19][C:20]3[CH:34]=[CH:33][C:23]([CH2:24][CH:25]([C:26]([NH:42][CH3:41])=[O:27])[C:29]([O:31][CH3:32])=[O:30])=[CH:22][CH:21]=3)[C:14](=[O:16])[S:15][C:11]=2[CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)C(Cc1ccc(OCCn2c(=O)sc3cc(C(=O)c4ccccc4)ccc32)cc1)C(=O)O
Reactant: CN
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CNC(=O)C(Cc1ccc(OCCn2c(=O)sc3cc(C(=O)c4ccccc4)ccc32)cc1)C(=O)OC
Reaction time: 1 h

Procedure:
The compound obtained in Example 63 is dissolved in anhydrous dichloromethane and then 1.5 equivalents of thionyl chloride are added and the mixture is heated at reflux for 1 hour 30 minutes. The reaction mixture is then cooled using an ice bath, and 1.2 equivalents of methylamine are added via the top of the condenser. The reaction mixture is stirred for one hour and is then extracted with dichloromethane. The organic phases are washed with a sodium carbonate solution, and with water, and are then filtered, dried over magnesium sulphate and evaporated under reduced pressure. The resulting residue is purified by flash chromatography using an ethyl acetate/cyclohexane mixture as eluant. The resulting title product is recrystallised from a toluene/cyclohexane mixture.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([NH:20][C@H:21]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[CH2:22][OH:23])=[N:5][C:6]([NH:10][C:11]2[CH:15]=[C:14]([O:16][CH:17]([CH3:19])[CH3:18])[NH:13][N:12]=2)=[C:7]([F:9])[CH:8]=1.[CH3:31][S:32](O)(=[O:34])=[O:33].CCN(C(C)C)C(C)C>CN(C1C=CN=CC=1)C.C1COCC1>[F:9][C:7]1[CH:8]=[C:3]([CH2:2][NH:1][S:32]([CH3:31])(=[O:34])=[O:33])[C:4]([NH:20][C@H:21]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[CH2:22][OH:23])=[N:5][C:6]=1[NH:10][C:11]1[CH:15]=[C:14]([O:16][CH:17]([CH3:19])[CH3:18])[NH:13][N:12]=1
Reactant: CS(=O)(=O)O
Reactant: CC(C)Oc1cc(Nc2nc(N[C@@H](CO)c3ccc(F)cc3)c(CN)cc2F)n[nH]1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)Oc1cc(Nc2nc(N[C@@H](CO)c3ccc(F)cc3)c(CNS(C)(=O)=O)cc2F)n[nH]1
Temperature: 60 °C
Reaction time: 8 h
Yield: 63 %

Procedure:
A round bottom flask was charged with (R)-2-(3-(aminomethyl)-5-fluoro-6-(5-isopropoxy-1H-pyrazol-3-ylamino)pyridin-2-ylamino)-2-(4-fluorophenyl)ethanol (Example 13; 0.10 g, 0.24 mmol), methanesulfonic acid loaded TFP resin (0.9 mmol/g loading, 0.24 mmol), DIEA (0.062 g, 0.48 mmol), DMAP (0.032 g, 0.26 mmol), and THF (5 ml). The resulting suspension was shaken vigorously at 60° C. for 8 hrs and filtered. The resulting resin was washed with a THF-DCM solution (1:1, 3×5 ml for 30 min. each). The resulting organic layers were combined and concentrated. The resulting solid was purified by reverse-phase column chromatography (5-50% CH3CN in H2O over 400 ml) to give the title compound (0.075 g, 63%). 1H NMR (400 MHz, CD3OD) δ 7.48-7.45 (m, 2H), 7.20 (d, J=10.9 Hz, 1H), 7.05-7.01 (m, 2H), 5.30 (s, 1H), 5.04-5.01 (m, 1H), 4.56-4.53 (m, 1H), 4.20 (d, J=14.4 Hz, 1H), 4.12 (d, J=14.4 Hz, 1H), 3.86-3.73 (m, 2H), 3.01 (s, 3H), 1.32 (d, J=6.0 Hz, 3H). MS: Calcd.: 496. Found: [M+H]+ 497.
Reaction SMILES: [F:1][C:2]1[CH:24]=[C:23]([CH3:25])[C:22]([O:26]C(OC)=O)=[CH:21][C:3]=1[NH:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([NH:15][C:16](=[O:20])[CH2:17][O:18][CH3:19])=[CH:12][CH:13]=2)[N:8]=[CH:7][N:6]=1.[ClH:31]>CO.[OH-].[Na+].O>[ClH:31].[F:1][C:2]1[CH:24]=[C:23]([CH3:25])[C:22]([OH:26])=[CH:21][C:3]=1[NH:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([NH:15][C:16](=[O:20])[CH2:17][O:18][CH3:19])=[CH:12][CH:13]=2)[N:8]=[CH:7][N:6]=1
Reactant: COCC(=O)Nc1ccc2c(Nc3cc(OC(=O)OC)c(C)cc3F)ncnc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COCC(=O)Nc1ccc2c(Nc3cc(O)c(C)cc3F)ncnc2c1
Yield: 36 %

Procedure:
A solution of 4-(2-fluoro-5-methoxycarbonyloxy-4-methylanilino)-7-methoxyacetamidoquinazoline (201 mg, 0.5mmol) in methanol (5 ml) and 2M aqueous sodium hydroxide solution (0.5 ml) was stirred at ambient temperature for 1 hour. The mixture was diluted with water and adjusted to pH6 with 2M hydrochloric acid. The precipitated solid was collected by filtration, washed with water, dried and then dissolved in a mixture of methylene chloride and methanol. A 5M solution of hydrogen chloride in isopropanol (0.3 ml) was added and most of the solvent removed by evaporation. The precipitated solid was collected by filtration, washed with methylene chloride and dried under vacuum to give 4-(2-fluoro-5-hydroxy-4-methylanilino)-7-methoxyacetamidoquinazoline hydrochloride (70 mg, 36%) as a yellow solid.
Reaction SMILES: [C:1]([C:3]1[C:8]([C:9]#[N:10])=[N:7][C:6](Cl)=[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:4]=1)#[N:2].[CH2:18]([NH2:20])[CH3:19]>>[C:1]([C:3]1[C:8]([C:9]#[N:10])=[N:7][C:6]([NH:20][CH2:18][CH3:19])=[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:4]=1)#[N:2]
Reactant: CCN
Reactant: N#Cc1nc(Cl)c(-c2ccccc2)nc1C#N
Product: CCNc1nc(C#N)c(C#N)nc1-c1ccccc1
Yield: 88 %

Procedure:
2,3-Dicyano-5-chloro-6-phenylpyrazine (12.03 g; 0.05 mole) and 7.07 g (0.11 mole) of a 70% aqueous solution of ethylamine were worked up in the same way as in Example 13, and recrystallized from toluene to afford 10.98 g (yield 88%) of 2,3-dicyano-5-ethylamino-6-phenylpyrazine.
Reaction SMILES: [C:1]([O:8][CH2:9][CH3:10])(=[O:7])[C:2]([O:4]CC)=O.[CH:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][NH2:19])=[CH:13][CH:12]=1>C1(C)C=CC=CC=1>[C:14]1([CH2:17][CH2:18][NH:19][C:2](=[O:4])[C:1]([O:8][CH2:9][CH3:10])=[O:7])[CH:15]=[CH:16][CH:11]=[CH:12][CH:13]=1
Reactant: NCCc1ccccc1
Reactant: CCOC(=O)C(=O)OCC
Solvent: Cc1ccccc1
Product: CCOC(=O)C(=O)NCCc1ccccc1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 86.1 %

Procedure:
181 g (1.24 mol) of diethyl oxalate and 500 ml of toluene were placed in a flask, to which 100 g (825 mmol) of 2-phenethylamine was added dropwise at room temperature for 45 minutes. The reaction mixture was heated at 60° C. for two hours, and was further reacted at 75° C. for two hours. The solution was then concentrated at room temperature until the residual quantity of toluene became about 50 ml. The generated precipitation was filtered off and washed with about 50 ml of toluene. 400 ml of hexane was added to the filtrate at 50° C., so as to precipitate crystals. The mixture was further cooled down to 5° C. and stirred for 30 minutes. Then, resulting crystals were filtered, washed with hexane, and dried to obtain 158 g (710 mmol, yield 86%) of ethyl N-(2-phenylethyl)oxamate as white crystals.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][Br:6].[CH2:10]1[CH2:15][O:14][CH:13]=[CH:12][CH2:11]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C(Cl)Cl>[Br:6][CH2:5][C:4]1[CH:3]=[C:2]([CH:9]=[CH:8][CH:7]=1)[O:1][CH:13]1[CH2:12][CH2:11][CH2:10][CH2:15][O:14]1
Reactant: C1=COCCC1
Reactant: Oc1cccc(CBr)c1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: BrCc1cccc(OC2CCCCO2)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
3-Hydroxybenzyl bromide (1.00 g, 5.35 mmol), DHP (0.89 g, 10.09 mmol), pyridinium-p-toluenesulfonate (0.20 g, 0.80 mmol) were dissolved in methylene chloride (20 mL) and stirred at room temperature for 5 h. The mixture was concentrated and chromatographed without workup. The product 42 was obtained as colorless oil (1.25 g, 87% yield).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:11]C(=O)C3C=CC(Cl)=CC=3)[CH:9]=2)[C:4]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)=[C:3]1[CH2:29][C:30]([CH3:36])([CH3:35])[C:31]([O:33][CH3:34])=[O:32].C[O-].[Na+]>CO>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([OH:11])[CH:9]=2)[C:4]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)=[C:3]1[CH2:29][C:30]([CH3:36])([CH3:35])[C:31]([O:33][CH3:34])=[O:32]
Reactant: COC(=O)C(C)(C)Cc1c(Cc2ccc(Cl)cc2)c2ccc(OC(=O)c3ccc(Cl)cc3)cc2n1C
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)C(C)(C)Cc1c(Cc2ccc(Cl)cc2)c2ccc(O)cc2n1C
Reaction time: 1 h

Procedure:
To a suspension of 425 mg of p-chlorobenzoate from Step A in 3 mL of MeOH was added 1.9 mL of a solution of 1.3M NaOMe in MeOH. The mixture was stirred at R,T. for 1 h, poured into 20 mL of 25% aq. NH4OAc, and extracted with ethyl acetate. The organic extract was dried over Na2SO4 and evaporated to dryness to give an oil which was chromatographed on flash silica gel using ethyl acetate:hexane (30:70) as eluant to give the title compound as a white foam.
Reaction SMILES: [C:1]([C:4]1[N:5]([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=2)[C:6]2[C:11]([C:12]=1[C:13]([NH:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[C:19]([F:24])[CH:18]=1)=[O:14])=[CH:10][CH:9]=[C:8]([O:25][CH:26]([CH3:28])[CH3:27])[CH:7]=2)(=O)[CH3:2].[CH3:36][O:37][NH2:38].Cl>>[F:24][C:19]1[CH:18]=[C:17]([CH:22]=[CH:21][C:20]=1[F:23])[CH2:16][NH:15][C:13]([C:12]1[C:11]2[C:6](=[CH:7][C:8]([O:25][CH:26]([CH3:27])[CH3:28])=[CH:9][CH:10]=2)[N:5]([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=2)[C:4]=1/[C:1](=[N:38]/[O:37][CH3:36])/[CH3:2])=[O:14]
Reactant: CON
Reactant: CC(=O)c1c(C(=O)NCc2ccc(F)c(F)c2)c2ccc(OC(C)C)cc2n1Cc1ccccn1
Agent: Cl
Product: CO/N=C(\C)c1c(C(=O)NCc2ccc(F)c(F)c2)c2ccc(OC(C)C)cc2n1Cc1ccccn1

Procedure:
The title compound was prepared from 2-acetyl-N-(3,4-difluorobenzyl)-6-isopropoxy-1-(pyridin-2-ylmethyl)-1H-indole-3-carboxamide (Compound 109) and MeONH2.HCl by General Procedure Q.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][NH2:11])=[CH:9][C:4]=2[CH:3]=[CH:2]1.Cl[S:13]([C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:17]=1)(=[O:15])=[O:14].Cl>C(Cl)Cl>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][NH:11][S:13]([C:16]3[CH:17]=[CH:18][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:24][CH:25]=3)(=[O:15])=[O:14])=[CH:9][C:4]=2[CH:3]=[CH:2]1
Reactant: COC(=O)c1ccc(S(=O)(=O)Cl)cc1
Reactant: NCc1ccc2occc2c1
Agent: Cl
Solvent: ClCCl
Product: COC(=O)c1ccc(S(=O)(=O)NCc2ccc3occc3c2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 54.8 %

Procedure:
To a solution of benzofuran-5-ylmethanamine (6.5 g, 28 mmol) in DCM (100 mL) was added methyl 4-(chlorosulfonyl)benzoate (4.1 g, 28 mmol) in portion wise at 0° C., and the mixture was stirred at room temperature for 3 hrs. The mixture was added 2 M aqueous HCl (80 mL) to give a white suspension. A half volume of DCM was removed by nitrogen flow, and the precipitates were collected by filtration, washed with water, and the solid was dried in vacuo at 50° C. to give 5.3 g (55% yield) of the titled compound as a off-white solid. The filtrate formed a suspension, which was collected by filtration, washed with water, and the solid was dried in vacuo at 50° C. to give 3.4 g (35% yield) of the titled compound as a pale brown white solid.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([NH:6][C@@H:7]([CH3:21])[CH2:8][N:9]2[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])=O)=[CH:4][CH:3]=1.COC1C=CC(P2(=S)SP(C3C=CC(OC)=CC=3)(=S)[S:31]2)=CC=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([NH:6][C@@H:7]([CH3:21])[CH2:8][N:9]2[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])=[S:31])=[CH:4][CH:3]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: C[C@H]1CN(C(=O)c2ccccc2F)c2cc(Br)ccc2N1
Solvent: Cc1ccccc1
Product: C[C@H]1CN(C(=S)c2ccccc2F)c2cc(Br)ccc2N1
Temperature: 100 °C
Reaction time: 0.21 h
Yield: 133.7 %

Procedure:
A screw-cap vial equipped with a magnetic stir bar was charge with (S)-(7-bromo-3-methyl-3,4-dihydroquinoxaline-1(2H)-yl)(2-fluorophenyl)methanone (0.050 g, 0.143 mmol), toluene (1 mL), and 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane-2,4-dithione (Lawesson's Reagent) (0.035 g, 0.086 mmol). The head space was flushed with nitrogen, the vial capped, and the mixture heated to 100° C. After about 10-15 min, the reaction mixture turned yellow. After 45 min, heating was discontinued. After cooling, the reaction mixture was loaded directly onto a preparative thin layer chromatography plate (1000 micron), and eluted with 4:1 hexanes-ethyl acetate. The non-polar, yellow band was isolated and afforded (S)-(7-bromo-3-methyl-3,4-dihydroquinoxaline-1(2H)-yl)(2-fluorophenyl)methanethione (0.042 g, 80%) as a bright yellow solid. MS (ESI, pos. ion) m/z 365, 367 [M+1].
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[C:14]([C:23](=[O:25])[CH3:24])=[N:15][C:16]4[C:21]([CH:22]=3)=[CH:20][CH:19]=[CH:18][CH:17]=4)=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:26][CH3:27].C(=O)([O-])[O-].[K+].[K+].[CH2:34]([CH:36]1[O:38][CH2:37]1)Br.O>CN(C)C=O>[CH3:27][O:26][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:2]=1[O:1][CH2:34][CH:36]1[CH2:37][O:38]1)[N:9]=[CH:8][CH:7]=[C:6]2[O:12][C:13]1[C:14]([C:23](=[O:25])[CH3:24])=[N:15][C:16]2[C:21]([CH:22]=1)=[CH:20][CH:19]=[CH:18][CH:17]=2
Reactant: COc1cc2c(Oc3cc4ccccc4nc3C(C)=O)ccnc2cc1O
Reactant: BrCC1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3cc4ccccc4nc3C(C)=O)ccnc2cc1OCC1CO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66 %

Procedure:
1-[3-(7-Hydroxy-6-methoxy-quinolin-4-yloxy)-quinolin-2-yl]-ethanone (compound 390) (200 mg) was dissolved in N,N-dimethylformamide (6 ml) to prepare a solution. Potassium carbonate (230 mg) and epibromohydrin (0.1 ml) were added to the solution, and the mixture was stirred at room temperature overnight. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (152 mg, yield 66%).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([CH:7]=[CH:8][CH2:9][CH2:10]O)=[CH:4][CH:3]=1.[OH-:12].[Na+].Cl.[Cl-].[Na+]>O>[CH2:8]([CH:7]1[C:2]([OH:6])([CH3:1])[CH:3]=[CH:4][C:5]1=[O:12])[CH:9]=[CH2:10]
Reactant: [OH-]
Reactant: Cc1ccc(C=CCCO)o1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: C=CCC1C(=O)C=CC1(C)O
Temperature: 40 °C

Procedure:
In a reaction vessel, water (1 liter) and 5-methyl-2-furylallylcarbinol (25 g) were charged, and the pH value was adjusted to 5.5 with an aqueous 1 N NaOH solution and an aqueous 1 N HCl solution. The temperature was elevated up to 100° C. to reflux, and the mixture was stirred under reflux for 12 hours while maintaining a pH value of 5.0 to 5.5 by the addition of an aqueous 1 N NaOH solution and an aqueous 1 N HCl solution. After cooling to 40° C., the reaction mixture was neutralized with an aqueous 1 N NaOH solution, and sodium chloride (300 g) was added thereto. The mixture was extracted with toluene (100 ml) five times. From the extract, toluene was removed by distillation at 60° C. under reduced pressure to give an oily substance (23 g), which was subjected to distillation under reduced pressure to obtain 2-allyl-3-hydroxy-3-methyl-4-cyclopentenone (21.3 g). Yield, 85.2%. B.P., 77° C./0.1 mmHg. NMR spectrum (CCl4, internal standard TMS, δ ppm, 60 MHz): 7.32 (d, 1H, 4-H); 5.92 (d, 1H, 5-H); 5.81 (complex m, 1H, --CH2 --CH=CHaHb); 5.12 (m, 1H, --CH2 --CH=CHaHb); 4.93 (m, 1H, --CH2 --CH=CHaHb); 4.12 (broad s, 1H, 3-OH); 2.37 (m, 3H, 2-H, s, --CH2 --CH=CHaHb); 1.28 (s, 3H, 3--CH3).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH2:27])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].Br[C:29]1[CH:30]=[N:31][CH:32]=[C:33]([C:35]2[CH:40]=[CH:39][C:38]([C:41]([F:44])([F:43])[F:42])=[CH:37][CH:36]=2)[CH:34]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:29]4[CH:30]=[N:31][CH:32]=[C:33]([C:35]5[CH:36]=[CH:37][C:38]([C:41]([F:43])([F:44])[F:42])=[CH:39][CH:40]=5)[CH:34]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4N)cc3)cc2)CC1
Reactant: FC(F)(F)c1ccc(-c2cncc(Br)c2)cc1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cncc(-c5ccc(C(F)(F)F)cc5)c4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 41, Step 2, using 1-[4′-(4-amino-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 3-bromo-5-(4-trifluoromethyl-phenyl)-pyridine.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][C:12]([C:18]([OH:20])=O)=[CH:13][CH:14]=3)[CH2:9]2)[CH:5]=[C:4]([N:21]2[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]2)[N:3]=1.[C:28]1([CH:34]2[CH2:38][CH2:37][NH:36][CH2:35]2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH3:27][N:24]1[CH2:23][CH2:22][N:21]([C:4]2[CH:5]=[C:6]([N:8]3[CH2:17][CH2:16][C:15]4[C:10](=[CH:11][C:12]([C:18]([N:36]5[CH2:37][CH2:38][CH:34]([C:28]6[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=6)[CH2:35]5)=[O:20])=[CH:13][CH:14]=4)[CH2:9]3)[N:7]=[C:2]([NH2:1])[N:3]=2)[CH2:26][CH2:25]1
Reactant: CN1CCN(c2cc(N3CCc4ccc(C(=O)O)cc4C3)nc(N)n2)CC1
Reactant: c1ccc(C2CCNC2)cc1
Product: CN1CCN(c2cc(N3CCc4ccc(C(=O)N5CCC(c6ccccc6)C5)cc4C3)nc(N)n2)CC1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 18 starting from 2-[2-amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-1,2,3,4-tetrahydroisoquinoline-7-carboxylic acid and 3-Phenyl-pyrrolidine (Matrix Scientific, Cat. No. 018619).