Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(P(C2C=CC=CC=2)CCCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([N:34]1[CH2:39][CH2:38][N:37]([C:40]2[N:45]=[CH:44][C:43]([NH:46][S:47]([C:50]3[CH:55]=[CH:54][C:53]([CH:56]([CH3:58])[CH3:57])=[CH:52][CH:51]=3)(=[O:49])=[O:48])=[CH:42][CH:41]=2)[CH2:36][CH2:35]1)C=C.SC1C=CC=CC=1C(O)=O>O1CCCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH:56]([C:53]1[CH:54]=[CH:55][C:50]([S:47]([NH:46][C:43]2[CH:44]=[N:45][C:40]([N:37]3[CH2:36][CH2:35][NH:34][CH2:39][CH2:38]3)=[CH:41][CH:42]=2)(=[O:48])=[O:49])=[CH:51][CH:52]=1)([CH3:58])[CH3:57]
Reactant: C=CCN1CCN(c2ccc(NS(=O)(=O)c3ccc(C(C)C)cc3)cn2)CC1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C(O)c1ccccc1S
Solvent: C1CCOC1
Product: CC(C)c1ccc(S(=O)(=O)Nc2ccc(N3CCNCC3)nc2)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
95 mg (0.1 mmol) of tris-(dibenzylideneacetone)dipalladium(0) and 44 mg (0.1 mmol) of 1,4-bis-(diphenylphosphino)butane were dissolved in 10 ml of tetrahydrofuran under an argon atmosphere. A solution composed of 1.1 g (2.75 mmol) of N-[6-(4-allylpiperazin-1-yl)pyridin-3-yl]-4-isopropylbenzenesulfonamide from Example 1.3I in 3 ml of tetrahydrofuran was then added dropwise to the reaction mixture. After that, a solution of 386 mg (2.5 mmol) of 2-mercaptobenzoic acid in 2 ml of tetrahydrofuran was added dropwise to the reaction mixture and the mixture was stirred at room temperature for 90 minutes. A solution of a further 386 mg (2.5 mmol) of 2-mercaptobenzoic acid in 2 ml of tetrahydrofuran was then added dropwise to the reaction mixture. The reaction mixture was stirred overnight at room temperature and, after that, the solvent was evaporated down to dryness. 150 ml of water were added to the resulting residue, after which the mixture was made acid with 1N aqueous hydrochloric acid and extracted three times with diethyl ether. The aqueous phase was then made alkaline, to pH>11, with a 1N aqueous solution of sodium hydroxide and subsequently extracted three times with dichloromethane. After that, the aqueous phase was adjusted to pH 8-9, saturated with an aqueous solution of sodium chloride and, after that, extracted several times with dichloromethane. 840 mg (82% of theory) of the title compound were obtained after the combined organic phases had been dried over sodium sulfate and the solvent had been filtered and evaporated down to dryness.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][O:8][C:7]([CH3:14])([CH3:13])[C:6]=2[CH:15]=1.Br[C:17]1[CH:18]=[C:19]([C:22]#[N:23])[O:20][CH:21]=1>>[CH3:13][C:7]1([CH3:14])[C:6]2[CH:15]=[C:2]([C:17]3[CH:18]=[C:19]([C:22]#[N:23])[O:20][CH:21]=3)[CH:3]=[CH:4][C:5]=2[NH:11][C:10](=[O:12])[CH2:9][O:8]1
Reactant: N#Cc1cc(Br)co1
Reactant: CC1(C)OCC(=O)Nc2ccc(Br)cc21
Product: CC1(C)OCC(=O)Nc2ccc(-c3coc(C#N)c3)cc21

Procedure:
Prepared from 7-bromo-5,5-dimethyl-1,5-dihydro-4,1-benzoxazepin-2(3H)-one and 4-bromofuran-2-carbonitrile generally according to the coupling procedure described in examples 82 and 1. 1H-NMR (DMSO-d6) δ 9.96 (s, 1H), 8.61 (s, 1H), 8.19 (s, 1H), 7.56 (d, J=1.9 Hz, 1H), 7.50 (dd, J=8.3, 2.0 Hz, 1H), 7.14 (d, J=8.4 Hz, 1H), 4.24 (s, 2H), 1.59 (s, 6H); MS (ES) m/z 283 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]([CH3:11])[CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[NH2:4].F[C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[N+:20]([O-:22])=[O:21].C(N(CC)C(C)C)(C)C>C(#N)C>[F:19][C:17]1[CH:16]=[CH:15][C:14]([N+:20]([O-:22])=[O:21])=[C:13]([NH:4][CH:3]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:2]([CH3:11])[CH3:1])[CH:18]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Reactant: CC(C)C(N)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)C(Nc1cc(F)ccc1[N+](=O)[O-])c1ccccc1
Yield: 92.7 %

Procedure:
A solution of 2-methyl-1-phenylpropan-1-amine (1.0 g, 6.7 mmol), 2,4-difluoronitrobenzene (0.74 mL, 6.7 mmol) and N,N-diisopropylethylamine (2.3 mL, 13.4 mmol) in acetonitrile was stirred at room temperature for 32 h. The solvent was concentrated in vacuo, the residue was taken up in dichloromethane and washed with water, dried, and concentrated under reduced pressure to yield 1.79 g (93%) of the desired aniline: 1H NMR (400 MHz, CDCl3): δ 8.78 (br d, 1H), 8.21 (dd, 1H), 7.37-7.31 (m, 4H), 7.28-7.24 (m, 1H), 6.44-6.35 (m, 2H), 4.43 (t, 1H), 2.18 (m, 1H), 1.06 (d, 3H), 0.97 (d, 3H).
Reaction SMILES: [N:1]1([CH2:6][C@@H:7]([O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:21](=[O:25])[CH2:20][CH2:19][CH2:18][C:17]=3[C:16]=2[CH2:26][S:27][C:28]2[CH:36]=[CH:35][C:31]([C:32](O)=[O:33])=[CH:30][CH:29]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[NH2:37][CH2:38][C:39]#[CH:40]>>[N:1]1([CH2:6][C@@H:7]([O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:21](=[O:25])[CH2:20][CH2:19][CH2:18][C:17]=3[C:16]=2[CH2:26][S:27][C:28]2[CH:29]=[CH:30][C:31]([C:32]([NH:37][CH2:38][C:39]#[CH:40])=[O:33])=[CH:35][CH:36]=2)[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=C(O)c1ccc(SCc2c(O[C@H](Cn3ccnc3)c3ccccc3)ccc3c2CCCC3=O)cc1
Reactant: C#CCN
Product: C#CCNC(=O)c1ccc(SCc2c(O[C@H](Cn3ccnc3)c3ccccc3)ccc3c2CCCC3=O)cc1
Yield: 100.8 %

Procedure:
Using the method in Example 172, 4-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzoic acid (50 mg, 0.10 mmol, 0.20M in DMF) and 3-aminopropyne (17 mg, 0.30 mmol, 0.6M in DMF) were combined to give 54 mg of the desired compound: Low resolution mass spectrum (LC-MS, APCI) m/z 536 [M+H]+.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][C:7]([O:17][CH3:18])=[C:8]([O:15][CH3:16])[C:9]=2[O:13][CH3:14])[CH:4]=1.[NH:19]1[CH2:25][CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>>[CH3:14][O:13][C:9]1[C:8]([O:15][CH3:16])=[C:7]([O:17][CH3:18])[CH:6]=[C:5]2[C:10]=1[CH:11]=[CH:12][C:3]([CH2:2][N:19]1[CH2:25][CH2:24][CH2:23][N:22]([CH2:2][C:3]3[CH:12]=[CH:11][C:10]4[C:5](=[CH:6][C:7]([O:17][CH3:18])=[C:8]([O:15][CH3:16])[C:9]=4[O:13][CH3:14])[CH:4]=3)[CH2:21][CH2:20]1)=[CH:4]2
Reactant: COc1cc2cc(CCl)ccc2c(OC)c1OC
Reactant: C1CNCCNC1
Product: COc1cc2cc(CN3CCCN(Cc4ccc5c(OC)c(OC)c(OC)cc5c4)CC3)ccc2c(OC)c1OC

Procedure:
2-Chloromethyl-5,6,7-trimethoxynaphthalene (607 mg) and homopiperazine (108 mg) were reacted in the same manner in Example 1 to obtain the title compound as a free base.
Reaction SMILES: C[O:2][C:3](=[O:17])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[C:6]([CH2:14][CH:15]=[CH2:16])[CH:5]=1.S(C)C.[OH-:21].[Na+].OO>C1COCC1>[OH:21][CH2:16][CH2:15][CH2:14][C:6]1[CH:5]=[C:4]([CH:9]=[C:8]([O:10][CH3:11])[C:7]=1[O:12][CH3:13])[C:3]([OH:2])=[O:17]
Reactant: C=CCc1cc(C(=O)OC)cc(OC)c1OC
Reactant: [OH-]
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CSC
Product: COc1cc(C(=O)O)cc(CCCO)c1OC
Temperature: 23 °C
Reaction time: 1.2 h
Yield: 89 %

Procedure:
To a solution of 3-allyl-4,5-dimethoxybenzoic acid methyl ester (Example 30, Step 1, 10.2 g, 43.2 mmol) in THF (100 mL) at 0° C. was added BH3.SMe2 (4.10 mL, 43.2 mmol). After 45 min the reaction mixture was warmed to 23° C. After stirring for 1.2 h the reaction was cooled to 0° C. and slowly treated with 3.0 N NaOH (39 mL) followed 10 min later by addition of H2O2 (30 weight %, 60 mL). Following the addition, the mixture was allowed to reach 23° C., then heated to reflux for 2 h. After cooling to room temperature, the mixture was partitioned between brine (400 mL) and EtOAc (500 mL). The aqueous layer was separated and extracted with EtOAc (400 mL). The organic layer was discarded and the aqueous was adjusted to pH 5 by addition of 1.0 N HCl then the product was extracted with EtOAc (2×500 mL). The organic layer was dried over MgSO4 and then concentrated in vacuo to give 3-(3-hydroxypropyl)-4,5-dimethoxybenzoic acid (9.24 g, 89%) of the desired alcohol, which was used without further purification. ESMS: m/z 239.3 [M−H].
Reaction SMILES: [Br-].[CH3:2][N+:3]([CH3:10])([CH3:9])[CH2:4][CH2:5][CH2:6][NH:7][CH3:8].[Br:11][CH2:12][CH2:13][CH2:14]Br>C(#N)C>[Br-:11].[Br:11][CH2:12][CH2:13][CH2:14][N:7]([CH2:6][CH2:5][CH2:4][N+:3]([CH3:10])([CH3:9])[CH3:2])[CH3:8]
Reactant: BrCCCBr
Reactant: CNCCC[N+](C)(C)C
Agent: [Br-]
Solvent: CC#N
Product: CN(CCCBr)CCC[N+](C)(C)C

Procedure:
To a stirred solution of 3.02 g. (14.3 mmoles) of N,N,N-trimethyl-[3-(methylamino)]-1-propanaminium bromide in 30 ml. of acetonitrile is added a solution of 2.88 g. (14.3 mmoles) of 1,3-dibromopropane and the mixture is stirred at room temperature under nitrogen for 3.5 hours. The mixture is cooled in an ice-water bath and then the insoluble material is removed by filtration. The filtrate is evaporated and dried in vacuo and is extracted with chloroform. The chloroform extract is evaporated and dried to give the product.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:12]=[CH:11][C:6]2[NH:7][C:8](=O)[NH:9][C:5]=2[CH:4]=1.O=P(Cl)(Cl)[Cl:17]>>[Cl:17][C:8]1[NH:9][C:5]2[CH:4]=[C:3]([C:2]([F:14])([F:13])[F:1])[CH:12]=[CH:11][C:6]=2[N:7]=1
Reactant: O=c1[nH]c2ccc(C(F)(F)F)cc2[nH]1
Reactant: O=P(Cl)(Cl)Cl
Product: FC(F)(F)c1ccc2nc(Cl)[nH]c2c1
Temperature: 25 °C

Procedure:
A solution of the dihydrobenzoimidazol-2-one from step (b) above (2.02 g, 10 mmol) in POCl3 (30 mL) was heated at 95° C. for 16 h. The reaction mixture was cooled to room temperature, the solvent was removed in vacuo and the resulting oily residue subjected to azeotropic distillation with toluene (3×50 mL) at 50° C. The crude product was dissolved in EtOAc (50 mL), washed with brine (10 mL) then dried over Na2SO4 and filtered. The solvent was removed in vacuo and the residue was recrystallized from EtOAc/hexane to give the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:12]([C:26]3[C:34]([Cl:35])=[CH:33][C:29]4[O:30][CH2:31][O:32][C:28]=4[CH:27]=3)[C:13](NS(C3C=CC(C)=CC=3)(=O)=O)=[O:14])=[CH:7][N:8]2C)=[CH:4][CH:3]=1.[CH2:36]([O:38]CC)C>CCCCCC>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:12]([C:26]3[C:34]([Cl:35])=[CH:33][C:29]4[O:30][CH2:31][O:32][C:28]=4[CH:27]=3)[C:13]([O:38][CH3:36])=[O:14])=[CH:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)NC(=O)C(c2cc3c(cc2Cl)OCO3)c2cn(C)c3cc(Br)ccc23)cc1
Reactant: CCOCC
Solvent: CCCCCC
Product: COC(=O)C(c1cc2c(cc1Cl)OCO2)c1c[nH]c2cc(Br)ccc12

Procedure:
The subtitle compound was prepared following the procedure of Example 92(c), using methyl 2-bromo-2-(6-chloro-1,3-benzodioxol-5-yl)acetate from step (b), m.p. 172-174° C. from diethyl ether and hexane.
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: O=S1(=O)CCCC1
Solvent: CCOCC
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: [O:1]([CH2:8][CH2:9][CH2:10][C:11]([OH:13])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C.[C@@H:28]1([NH2:38])[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH2:31][CH2:30][CH2:29]1>C(Cl)Cl>[O:1]([CH2:8][CH2:9][CH2:10][C:11]([NH:38][C@@H:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH2:31][CH2:30][CH2:29]1)=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N[C@H]1CCCc2ccccc21
Reactant: O=C(O)CCCOc1ccccc1
Agent: CC(C)(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CCCOc1ccccc1)N[C@H]1CCCc2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 115.4 %

Procedure:
4-Phenoxybutanoic acid (1.05 g, 5.8 mmol, Lancaster) and triethylamine (2.4 mL, 17.4 mmol) in anhydrous CH2Cl2 (25 mL) were treated with pivaloyl chloride (0.75 mL, 6.1 mmol) at 0° C. After stirring for 1 hour, the reaction mixture was treated with (1S)-1,2,3,4-tetrahydro-1-naphthalenylamine (1.0 mL, 6.9 mmol) and the reaction mixture was allowed to warm to room temperature and stir for 16 hours. The reaction mixture was diluted with CH2Cl2, washed with 1N HCl, saturated NaHCO3, brine, dried (Na2SO4), filtered and the filtrate concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 40% ethyl acetate/hexanes) to provide the title compound as a colorless oil (2.07 g).
Reaction SMILES: C[O:2][C:3](=[O:16])[CH2:4][O:5][C:6]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]([SH:14])=[CH:8][C:7]=1[CH3:15].Br[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][C:25]([F:28])([F:27])[F:26])[CH:19]=1>>[CH3:13][O:12][C:10]1[C:9]([S:14][CH2:15][C:7]2[CH:8]=[CH:9][C:10]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([O:24][C:25]([F:28])([F:27])[F:26])[CH:19]=3)=[CH:11][CH:6]=2)=[CH:8][C:7]([CH3:15])=[C:6]([CH:11]=1)[O:5][CH2:4][C:3]([OH:2])=[O:16]
Reactant: FC(F)(F)Oc1cccc(Br)c1
Reactant: COC(=O)COc1cc(OC)c(S)cc1C
Product: COc1cc(OCC(=O)O)c(C)cc1SCc1ccc(-c2cccc(OC(F)(F)F)c2)cc1

Procedure:
The title compound was prepared in the manner analogous to Example 5A using 1D and 1-bromo-3-trifluoromethoxy-benzene. MS m/z 493 (M+1).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[NH2:13])[C:6]([O:8][CH3:9])=[O:7].O.N1C=CC=CC=1.[C:21](Cl)(=[O:30])[C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1>C(#N)C>[CH3:29][O:28][C:25]1[CH:26]=[CH:27][C:22]([C:21]([NH:2][C:3]2[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=2[NH2:13])[C:6]([O:8][CH3:9])=[O:7])=[O:30])=[CH:23][CH:24]=1
Reactant: COC(=O)c1ccc(N)c(N)c1
Reactant: COc1ccc(C(=O)Cl)cc1
Agent: Cl
Solvent: CC#N
Solvent: O
Solvent: c1ccncc1
Product: COC(=O)c1ccc(N)c(NC(=O)c2ccc(OC)cc2)c1
Temperature: 25 °C
Yield: 59.4 %

Procedure:
A solution of methyl 3,4-diaminobenzoate hydrochloride (1.43 g, 6.00 mmol) in acetonitrile (100 mL) was cooled to 0° C. and treated with water (15 mL), pyridine (0.97 mL, 12 mmol), and a solution of p-anisoyl chloride (1.03 g, 6.00 mmol) in acetonitrile (25 mL). The reaction mixture was allowed to slowly warm to room temperature over 16 h. The resulting precipitate was collected and washed with acetonitrile to provide 1.07 g (59%) of the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2([CH3:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[CH3:19][C:20]1[C:24](B(O)O)=[C:23]([CH3:28])[O:22][N:21]=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:19][C:20]1[C:24]([C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][C:6](=[O:11])[C:5]3([CH3:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:23]([CH3:28])[O:22][N:21]=1
Reactant: CC1(c2ccccc2)C(=O)Nc2ccc(Br)cc21
Reactant: Cc1noc(C)c1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1noc(C)c1-c1ccc2c(c1)C(C)(c1ccccc1)C(=O)N2
Temperature: 80 °C
Reaction time: 20 h

Procedure:
A mixture of 5-Bromo-3-methyl-3-phenyl-1,3-dihydro-indol-2-one (602 mg, 2 mmol), compound 3,5-dimethylisoxazole-4-boronic acid (564 mg, 4 mmol), Pd(PPh3)4 (440 mg, 0.4 mmol) and Cs2CO3 (1.624 g, 5 mmol) in dioxane (10 mL) and H2O (5 mL) is stirred at 80° C. under nitrogen for 20 hours. The mixture is poured into water (20 mL) and extracted with ethyl acetate (20 mL×3). The combined organic phase is washed with water and brine, dried over Na2SO4, filtered and concentrated. The residue is purified by chromatography on silica gel (ethyl acetate:petroleum ether=1:2) to give the desired compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][CH2:16]Cl)[N:9]=[CH:8][NH:7][C:6]2=[O:18].[NH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>C(O)(CC)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][CH2:16][N:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)[N:9]=[CH:8][NH:7][C:6]2=[O:18]
Reactant: C1CCNCC1
Reactant: COc1cc2c(=O)[nH]cnc2cc1OCCCCl
Solvent: CCC(C)O
Product: COc1cc2c(=O)[nH]cnc2cc1OCCCN1CCCCC1
Temperature: 105 °C
Reaction time: 5 h
Yield: 90.3 %

Procedure:
In a 5 mL volume glass vessel equipped with a stirrer and a thermometer were placed 1.0 g (3.7 mmol) of 6-methoxy-7-(3-chloropropoxy)quinazolin-4-one prepared by procedures similar to those of Reference Example V-1, 1.62 g (19 mmol) of piperidine, and 10 mL of sec-butyl alcohol. The resulting mixture was stirred at 105° C. for 5 hours. After the reaction was complete, the reaction mixture was analyzed by high performance liquid chromatography (absolute quantitative analysis). There was produced 1.06 g (reaction yield: 90%) of 6-methoxy-7-(3-piperidinopropoxy)quinazolin-4-one.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[C:18]=1[CH2:19][O:20][CH3:21])=[CH:15][C:14]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[CH:13][CH:12]=3)=[O:5])[CH3:2].[CH:30](O)(C)C>CC(C)[O-].CC(C)[O-].CC(C)[O-].CC(C)[O-].[Ti+4]>[CH:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[C:18]=1[CH2:19][O:20][CH3:21])=[CH:15][C:14]([O:22][CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)=[CH:13][CH:12]=3)=[O:5])([CH3:30])[CH3:2]
Reactant: CCOC(=O)c1ncc2[nH]c3ccc(OCc4ccccc4)cc3c2c1COC
Reactant: CC(C)O
Agent: [Ti+4]
Agent: CC(C)[O-]
Product: COCc1c(C(=O)OC(C)C)ncc2[nH]c3ccc(OCc4ccccc4)cc3c12
Yield: 80 %

Procedure:
1.4 g (3.6 mmol) of 6-benzyloxy-4-methoxymethyl-β-carboline-3-carboxylic acid ethyl ester is boiled under reflux for 2 hours in 100 ml of isopropanol with 0.7 ml (2.2 mmol) of titanium tetraisopropoxide. After concentration, the mixture is taken up in 80 ml of 1N hydrochloric acid and extracted by shaking with 250 ml of ethyl acetate. The ethyl acetate phase is washed with a small amount of water, dried, filtered, and concentrated. After chromatography over silica gel with methylene chloride:acetone=4:1 as the eluent, the 6-benzyloxy-4-methoxymethyl-β-carboline-3-carboxylic acid isopropyl ester, mp 150°-151° C., is obtained in an 80% yield.
Reaction SMILES: [CH2:1]([N:4]([CH2:29][CH2:30][CH3:31])[CH2:5][CH2:6][CH2:7][CH2:8][NH:9][C:10]([C:12]1[N:13]=[C:14]2[CH2:19][CH2:18][CH:17]([CH2:20][NH:21][CH2:22][C:23]3[NH:24][CH:25]=[CH:26][N:27]=3)[CH2:16][N:15]2[CH:28]=1)=[O:11])[CH2:2][CH3:3].[CH3:32][N:33]1[CH:37]=[CH:36][N:35]=[C:34]1[CH:38]=O.C([BH3-])#N.[Na+].C(=O)([O-])O.[Na+]>CO.C(O)(=O)C>[CH2:29]([N:4]([CH2:1][CH2:2][CH3:3])[CH2:5][CH2:6][CH2:7][CH2:8][NH:9][C:10]([C:12]1[N:13]=[C:14]2[CH2:19][CH2:18][CH:17]([CH2:20][N:21]([CH2:22][C:23]3[NH:24][CH:25]=[CH:26][N:27]=3)[CH2:38][C:34]3[N:33]([CH3:32])[CH:37]=[CH:36][N:35]=3)[CH2:16][N:15]2[CH:28]=1)=[O:11])[CH2:30][CH3:31]
Reactant: Cn1ccnc1C=O
Reactant: CCCN(CCC)CCCCNC(=O)c1cn2c(n1)CCC(CNCc1ncc[nH]1)C2
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCCN(CCC)CCCCNC(=O)c1cn2c(n1)CCC(CN(Cc1ncc[nH]1)Cc1nccn1C)C2
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.1 %

Procedure:
The compound (19.6 mg) obtained in Example 19-4 was dissolved in methanol (2.0 ml) and added with 1-methyl-2-imidazole carboxaldehyde (6.2 mg) and sodium cyanoborohydride (5.9 mg). The solution was adjusted to pH 4 with acetic acid and stirred at room temperature for 3 hours. The resultant was added with a saturated sodium hydrogen carbonate aqueous solution to stop the reaction and subjected to extraction with chloroform. The organic layer was washed with water and a saturated saline solution and dried with anhydrous sodium sulfate. The solvent was distilled off. The residue was purified through silica gel column chromatography (chloroform/ethyl acetate) and treated with hydrochloric acid, thereby obtaining a hydrochloride (22.0 mg) of the subject compound as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:3]=1[O:4][C:5]1[C:18](=[O:19])[N:17]([CH2:20][C@H:21]([OH:23])[CH3:22])[C:8]2[N:9]=[C:10](S(C)(=O)=O)[N:11]=[CH:12][C:7]=2[CH:6]=1.[NH2:29][C:30]([CH3:34])([CH3:33])[CH2:31][OH:32]>>[F:1][C:2]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:3]=1[O:4][C:5]1[C:18](=[O:19])[N:17]([CH2:20][C@H:21]([OH:23])[CH3:22])[C:8]2[N:9]=[C:10]([NH:29][C:30]([CH3:34])([CH3:33])[CH2:31][OH:32])[N:11]=[CH:12][C:7]=2[CH:6]=1
Reactant: CC(C)(N)CO
Reactant: C[C@@H](O)Cn1c(=O)c(Oc2ccc(F)cc2F)cc2cnc(S(C)(=O)=O)nc21
Product: C[C@@H](O)Cn1c(=O)c(Oc2ccc(F)cc2F)cc2cnc(NC(C)(C)CO)nc21
Temperature: 60 °C

Procedure:
A mixture of 6-(2,4-difluorophenoxy)-8-((R)-2-hydroxypropyl)-2-methanesulfonyl-8H-pyrido[2,3-d]pyrimidin-7-one (886 mg, 2.15 mmol) and 2-amino-2-methyl-1-propanol (5.15 g, 58 mmol) was heated at 60° C. under nitrogen for 2 hours. Cooled and chromatographed on silica gel eluding with 2% methanol in dichloromethane to give after converting to hydrochloride salt 385 mg 6-(2,4-Difluorophenoxy)-2-(2-hydroxy-1,1-dimethyl-ethylamino)-8-((R)-2-hydroxy-propyl)-8H-pyrido[2,3-d]pyrimidin-7-one (mass spec. M+1=421, MP=182.0-183.9° C.).
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[C:13]([N+:21]([O-:23])=[O:22])[CH:12]=2)[C:8](O)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[NH2:58][C:59]1[CH:64]=[N:63][CH:62]=[CH:61][N:60]=1.Cl>C(Cl)Cl.O.C(OCC)(=O)C>[CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:18])=[O:19])=[C:13]([N+:21]([O-:23])=[O:22])[CH:12]=2)[C:8]([NH:58][C:59]2[CH:64]=[N:63][CH:62]=[CH:61][N:60]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)O)cc1[N+](=O)[O-]
Reactant: Nc1cnccn1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)Nc2cnccn2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 3-cyclopentyl-2-(4-methanesulfonyl-3-nitrophenyl)-propionic acid (prepared as in Example 14, 250 mg, 0.732 mmol), triethylamine (0.306 mL, 2.19 mmol), benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (487 mg, 1.10 mmol), and 2-aminopyrazine (105 mg, 1.10 mmol) in methylene chloride (5 mL) was stirred at 25° C. for 18 h. The reaction mixture was then diluted with water (25 mL), a 1N aqueous hydrochloric acid solution (5 mL), and ethyl acetate (25 mL). The layers were separated, and the organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 19/1 methylene chloride/methanol) afforded impure 3-cyclopentyl-2-(4-methanesulfonyl-3-nitro-phenyl)-N-pyrazin-2-yl-propionamide as a white foam. This white foam was dissolved in ethyl acetate (2 mL) and then added to hexanes (50 mL). A white precipitate formed, and the solid was collected by filtration to afford 3-cyclopentyl-2-(4-methanesulfonyl-3-nitro-phenyl)-N-pyrazin-2-yl-propionamide (23.3 mg, 7.6%) as a white solid: mp 104-108° C. (gel formation); EI-HRMS m/e calcd for C19H22N4O5S (M+) 418.1311, found 418.1309.