Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH2:7][CH:6]([C:8](Cl)=[O:9])[CH2:5][CH2:4][O:3]1.CCOCC.[Mg+2].[Br-].[Br-].[CH3:20][C:21]([C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=1)=[O:22].CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:29][C:26]1[CH:27]=[CH:28][C:23](/[C:21](/[OH:22])=[CH:20]/[C:8]([CH:6]2[CH2:5][CH2:4][O:3][C:2]([CH3:11])([CH3:1])[CH2:7]2)=[O:9])=[CH:24][CH:25]=1
Reactant: CC1(C)CC(C(=O)Cl)CCO1
Reactant: CC(=O)c1ccc(Cl)cc1
Agent: [Br-]
Agent: [Mg+2]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Product: CC1(C)CC(C(=O)/C=C(\O)c2ccc(Cl)cc2)CCO1
Reaction time: 8 h
Yield: 58.3 %

Procedure:
To a mixture of 2,2-dimethyltetrahydro-2H-pyran-4-carbonyl chloride (0.55 g, 3.14 mmol), magnesium bromide diethyl etherate (1.35 g, 5.23 mmol), and 4-chloroacetophenone (0.34 mL, 2.62 mmol) in 12 mL of DCM at RT was added dropwise DIEA (1.45 mL, 7.85 mmol). The mixture was stirred overnight and then diluted with 50 mL of DCM and washed with 1N HCl (100 mL) and brine (100 mL). The organic layer was dried over Na2SO4, concentrated, and the crude product was purified by silica gel chromatography (Thomson Scientific 25-g cartridge, 2-20% EtOAc/heptane in 10 column volumes) to give 0.45 g (58%) of the title compound as a light orange solid. The NMR of this compound shows that it exists in the enone form in CDCl3.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:16]=[CH:17]/[C:18]([OH:20])=O)[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH3:15].C(N(CC)CC)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:43][CH2:44][CH2:45][N:46]1[CH2:51][CH2:50][CH:49]([C:52]2[C:60]3[C:55](=[CH:56][CH:57]=[CH:58][CH:59]=3)[NH:54][CH:53]=2)[CH2:48][CH2:47]1>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:16]=[CH:17]/[C:18]([NH:43][CH2:44][CH2:45][N:46]2[CH2:47][CH2:48][CH:49]([C:52]3[C:60]4[C:55](=[CH:56][CH:57]=[CH:58][CH:59]=4)[NH:54][CH:53]=3)[CH2:50][CH2:51]2)=[O:20])[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH3:15]
Reactant: COCCOCOc1ccc(/C=C/C(=O)O)cc1OC
Reactant: NCCN1CCC(c2c[nH]c3ccccc23)CC1
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COCCOCOc1ccc(/C=C/C(=O)NCCN2CCC(c3c[nH]c4ccccc34)CC2)cc1OC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 89.5 %

Procedure:
To a stirred mixture of 3-[3-methoxy-4-{(2-methoxyethoxy)methoxy}phenyl]-(E)-propenoic acid (1.75 g) and triethylamine (1.81 ml) in dry N,N-dimethylformamide (10 ml) was added slowly diphenyl phosphinic chloride (1.47 g) at -10° to -15° C. under an inert atmosphere. After being stirred for 30 minutes, a solution of 1-(2-aminoethyl)-4-(3-indolyl)piperidine (1.5 g) in dry N,N-dimethylformamide (10 ml) was added slowly to the reaction mixture at -10° C. After being stirred for 1 hour at ambient temperature, the reaction mixture was poured into ice-water (200 ml) and extracted with chloroform (100 ml). The extract was washed with a saturated sodium chloride solution and dried over magnesium sulfate. The solvent was distilled off and the residue was subjected to column chromatography on silicagel (47 g) and eluted with a mixture of chloroform and methanol (10:1). The fractions containing the object compound were combined and concentrated under reduced pressure to give syrup of 1-[2-[3-[3-methoxy-4-{(2-methoxyethoxy)methoxy}phenyl]-(E)-propenoylamino]ethyl]-4-(3-indolyl)piperidine (2.8 g).
Reaction SMILES: [NH2:1][C:2]1[N:7]2[N:8]=[CH:9][N:10]=[C:6]2[N:5]=[C:4]([CH3:11])[C:3]=1[C:12]#[C:13][CH:14]([CH:16]1[CH2:21][CH2:20][CH:19]([C:22]([O:24]C)=[O:23])[CH2:18][CH2:17]1)[OH:15].CO.[OH-].[Na+].Cl>O1CCCC1>[NH2:1][C:2]1[N:7]2[N:8]=[CH:9][N:10]=[C:6]2[N:5]=[C:4]([CH3:11])[C:3]=1[C:12]#[C:13][CH:14]([CH:16]1[CH2:21][CH2:20][CH:19]([C:22]([OH:24])=[O:23])[CH2:18][CH2:17]1)[OH:15]
Reactant: COC(=O)C1CCC(C(O)C#Cc2c(C)nc3ncnn3c2N)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1nc2ncnn2c(N)c1C#CC(O)C1CCC(C(=O)O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.4 %

Procedure:
To a solution of Example 65C (26.5 mg, 0.077 mmol) in tetrahydrofuran (0.5 mL)/methanol (0.5 mL) was added 2N NaOH (77 μL, 0.154 mmol). The reaction mixture was stirred at room temperature overnight, and neutralized with 2N HCl (0.154 mmol). It was purified by reverse phase HPLC C-18 column, eluting with a 5-100% CH3CN gradient in 10 mM ammonium acetate(aq.)) to provide the title compound as a white solid (10 mg, 40% yield). 1H NMR (300 MHz, DMSO-d6) δ 8.42 (s, 1H), 8.31 (s, 2H), 5.31 (s, 1H), 4.37 (d, J=5.43 Hz, 1H), 2.49 (s, 3H), 2.48-2.50 (m, 1H), 1.26-2.13 (m, 9H). MS (ESI) m/z 330 (M+H)+.
Reaction SMILES: Br[C:2]1[C:23]([N:24]2[CH2:29]CN(C3CCC3)[CH2:26][CH2:25]2)=[CH:22][C:5]2C(C)(C)C3NC4C(C=3C(=O)C=2C=1)=CC=C(C#N)C=4.CB1OB(C)OB(C)O1.[C:43](=[O:46])([O-])[O-].[K+].[K+].C1(N2CC[N:56]([C:59]3[C:60]([CH3:81])=[CH:61][C:62]4[C:74](=[O:75])[C:73]5[C:72]6[C:67](=[CH:68][C:69]([C:76]#[N:77])=[CH:70][CH:71]=6)[NH:66][C:65]=5[C:64]([CH3:79])([CH3:78])[C:63]=4[CH:80]=3)[CH2:55]C2)CCC1>CN(C)C=O>[CH3:78][C:64]1([CH3:79])[C:65]2[NH:66][C:67]3[C:72](=[CH:71][CH:70]=[C:69]([C:76]#[N:77])[CH:68]=3)[C:73]=2[C:74](=[O:75])[C:62]2[CH:61]=[C:60]([CH3:81])[C:59]([N:56]3[CH2:55][CH2:2][CH:23]([N:24]4[CH2:29][CH2:43][O:46][CH2:26][CH2:25]4)[CH2:22][CH2:5]3)=[CH:80][C:63]1=2
Reactant: CC1(C)c2cc(N3CCN(C4CCC4)CC3)c(Br)cc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Reactant: O=C([O-])[O-]
Reactant: Cc1cc2c(cc1N1CCN(C3CCC3)CC1)C(C)(C)c1[nH]c3cc(C#N)ccc3c1C2=O
Agent: CB1OB(C)OB(C)O1
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc2c(cc1N1CCC(N3CCOCC3)CC1)C(C)(C)c1[nH]c3cc(C#N)ccc3c1C2=O
Temperature: 100 °C
Reaction time: 24 h

Procedure:
With the same condition as the method for synthesizing the Compound F5-47 (under nitrogen atmosphere, to the N,N-dimethyl formamide (1.5 ml) solution of 9-bromo-8-(4-cyclobutyl-piperazin-1-yl)-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile (Compound F4-10, 50 mg, 0.099 mmol), trimethyl boroxine (12 mg, 0.1 eq.), tetrakis triphenylphosphine palladium (39 mg, 0.2 eq.), and potassium carbonate (41 mg, 3.0 eq.) were added, and the mixture was stirred at 100° C. for 24 hours. Upon the completion of the reaction, distilled water was poured into the reaction solution, which was then extracted with ethyl acetate. The organic layer was washed with aqueous solution of sodium chloride and dried over sodium sulfate. The drying agent was removed by filtration and the residues obtained after concentration under reduced pressure were purified by silica gel column chromatography (ethyl acetate/methanol) to obtain the Compound F5-47 (8-(4-cyclobutyl-piperazin-1-yl)-6,6,9-trimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile) (25 mg, 58%)), the title compound was synthesized from the Compound F3-11.
Reaction SMILES: [Cl:1]C[CH:3]1[O:8][CH2:7][CH2:6][N:5]([CH2:9][C:10]2[CH:15]=CC=CC=2)[CH2:4]1.[NH:16]1CC[O:19][CH2:18][CH2:17]1>>[ClH:1].[ClH:1].[O:8]1[CH2:3][CH2:4][N:5]([CH2:9][CH:10]2[O:19][CH2:18][CH2:17][NH:16][CH2:15]2)[CH2:6][CH2:7]1
Reactant: C1COCCN1
Reactant: ClCC1CN(Cc2ccccc2)CCO1
Product: C1COC(CN2CCOCC2)CN1
Product: Cl

Procedure:
By the use of 2-chloromethyl-4-benzylmorpholine and morpholine, the reaction is similarly carried out as Reference example 2 to give 2-(morpholinomethyl)morpholine dihydrochloride as white crystals, melting at 297°-299° C. with decompostion.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:23])[CH2:10][C@@H:11]([C:20]([OH:22])=O)[NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:24]([O:31][C:32](=[O:42])[C@H:33]([CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[NH2:34])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH2:24]([O:31][C:32](=[O:42])[C@H:33]([CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[NH:34][C:20](=[O:22])[C@H:11]([CH2:10][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:23])[NH:12][C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)OCc1ccccc1)C(=O)O
Reactant: N[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)OCc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1

Procedure:
N-(t-butoxycarbonyl)-L-aspartic acid 4-benzyl ester was coupled with 3-phenyl-L-alanine benzyl ester to give N-[3-[(benzyloxy)carbonyl]-N-(t-butoxycarbonyl)-L-alanyl]-3-phenyl-L-alanine benzyl ester, m.p. 93°-94° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[O:6][C@H:5]([CH2:7][O:8][C:9]2[C:16]([CH3:17])=[CH:15][C:12]([C:13]#[N:14])=[CH:11][C:10]=2[CH3:18])[CH2:4][O:3]1.Cl.[NH2:21][OH:22].C(=O)(O)[O-].[Na+]>CO>[CH3:1][C:2]1([CH3:19])[O:6][C@H:5]([CH2:7][O:8][C:9]2[C:16]([CH3:17])=[CH:15][C:12](/[C:13](=[N:21]/[OH:22])/[NH2:14])=[CH:11][C:10]=2[CH3:18])[CH2:4][O:3]1
Reactant: NO
Reactant: Cc1cc(C#N)cc(C)c1OC[C@@H]1COC(C)(C)O1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: Cc1cc(/C(N)=N/O)cc(C)c1OC[C@@H]1COC(C)(C)O1
Temperature: 60 °C
Yield: 79.9 %

Procedure:
Nitrogen was bubbled in a solution of (R)-4-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-3,5-dimethylbenzonitrile (8.1 g, 31.0 mmol) and hydroxylamine hydrochloride (4.31 g, 62.0 mmol) in MeOH (150 ml) at room temperature (the solution was made in a 500 ml flask w/3 necks fitted with a reflux condenser) for 10 min. To this was then added the sodium bicarbonate (10.42 g, 124 mmol) in one portion. Nitrogen was bubbled for an additional 10 minutes. The reaction mixture was set to stir at 60° C. It was heated for a total of 25 h. The reaction mixture was cooled, concentrated in vacuo and then chromatographed (330 g Redisep cartridge pre-saturated and then eluted with 10% EtOAc-hexanes). 7.29 g (Yield=82%) of the (R,Z)-4-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-N′-hydroxy-3,5-dimethylbenzimidamide was obtained as a white solid. 1H NMR (400 MHz, CCl3D) δ ppm 7.25 (2H, s), 4.80 (3H, br. s.), 4.49 (1H, qd, J=5.93, 5.71 Hz), 4.18 (1H, dd, J=8.35, 6.59 Hz), 3.94 (1H, dd, J=8.35, 5.93 Hz), 3.81-3.88 (1H, m), 3.73-3.80 (1H, m), 2.29 (6H, s), 1.46 (3H, s), 1.40 (3H, s).
Reaction SMILES: C(N(CC)C(C)C)(C)C.Cl.[CH2:11]1[C:15]2([CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[CH2:14][CH2:13][N:12]1[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].C(#N)C.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>>[CH3:31][S:32]([N:18]1[CH2:17][CH2:16][C:15]2([CH2:11][N:12]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:13][CH2:14]2)[CH2:20][CH2:19]1)(=[O:34])=[O:33]
Reactant: CC(C)(C)OC(=O)N1CCC2(CCNCC2)C1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC2(CCN(S(C)(=O)=O)CC2)C1
Reaction time: 1 h

Procedure:
N,N-Diisopropylethylamine (30.0 μL, 0.000172 mol) was added to tert-butyl 2,8-diazaspiro[4.5]decane-2-carboxylate hydrochloride (18.5 mg, 0.0000668 mol) in acetonitrile (1.0 mL, 0.019 mol), followed by methanesulfonyl chloride (10.0 μL, 0.000129 mol). After stirring for 1 h the solvent was evaporated, and the residue was dried under high vacuum and was used in the next step without further purification.
Reaction SMILES: C(O[CH2:5][C:6]1[N:7]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([C:34]([CH3:37])([CH3:36])[CH3:35])=[CH:30][CH:29]=2)[C:8]2[C:13]([C:14]=1[C:15](=[O:19])[C:16]([OH:18])=[O:17])=[CH:12][C:11]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[CH:21]=1)=[CH:10][CH:9]=2)(=O)C.[OH-].[K+]>C1COCC1.CO>[C:34]([C:31]1[CH:30]=[CH:29][C:28]([CH2:27][N:7]2[C:8]3[C:13](=[CH:12][C:11]([C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[CH:21]=4)=[CH:10][CH:9]=3)[C:14]3[C:15](=[O:19])[C:16](=[O:18])[O:17][CH2:5][C:6]2=3)=[CH:33][CH:32]=1)([CH3:37])([CH3:35])[CH3:36]
Reactant: CC(=O)OCc1c(C(=O)C(=O)O)c2cc(-c3cccc(C)c3)ccc2n1Cc1ccc(C(C)(C)C)cc1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cccc(-c2ccc3c(c2)c2c(n3Cc3ccc(C(C)(C)C)cc3)COC(=O)C2=O)c1

Procedure:
A solution of [2-[(acetyloxy)methyl]-1-(4-tert-butylbenzyl)-5-(3-methylphenyl)-1H-indol-3-yl](oxo)acetic acid (0.27 g, 0.63 mmol) and aqueous potassium hydroxide (1.0 N, 1.1 mL, 1.1 mmol) in THF:MeOH (1:1, 6.6 mL) was stirred at room temperature for 4 h. The reaction mixture was evaporated to dryness. The residue was washed with water and hexane to give an oil. This oil was partitioned between methylene chloride (80 mL) and 15% aqueous HCl (15 mL) with stirring. The organic layer was separated, washed with water and evaporated to afford the title compound as an off-white solid, mp: 196–197° C. Mass spectrum (ESI, [M+H]+) m/z 438. 1HNMR (400 MHz, DMSO-d6): δ 8.21 (s, 1H), 7.75 (d, 2H, J=8.55 Hz), 7.66 (dd, 1H, J=8.70 and 1.52 Hz), 7.50 (s, 1H), 7.47 (d, 1H, J=8.71 Hz), 7.38–7.35 (m, 3H), 7.20–7.17 (m, 3H), 5.92 (s, 2H), 5.50 (s, 2H), and 2.39 ppm (s, 3H).
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[C:11]2[CH:10]=[C:9]([C:12]#[C:13][C:14]3[CH:24]=[CH:23][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:16][CH:15]=3)[CH:8]=[CH:7][C:6]=2[C:5](=[O:25])[CH2:4][CH2:3]1.[BH4-].[Na+]>C1COCC1.C(O)C.O>[OH:25][CH:5]1[CH2:4][CH2:3][C:2]([CH3:1])([CH3:26])[C:11]2[CH:10]=[C:9]([C:12]#[C:13][C:14]3[CH:15]=[CH:16][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:23][CH:24]=3)[CH:8]=[CH:7][C:6]1=2
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(C)(C)CCC3=O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(C)(C)CCC3O)cc1
Reaction time: 6 h

Procedure:
To a cold solution (0° C.) of 980 mg (2.8 mmol) of ethyl 4-[(5,6,7,8-tetrahydro-8,8-dimethyl-5-oxonaphth-2-yl)ethynyl]benzoate (Compound 1) in 5 ml of THF and 10 ml of ethanol was added 78 mg (2 mmol) of sodium borohydride. The mixture was stirred for 6 hours, diluted with water (10 ml) and extracted with Et2O (4×40 ml). The combined organic layers were washed with 10% HCl (5 ml), 10% aqueous NaHCO3 (10 ml) and brine (20 ml), dried over MgSO4 and concentrated in vacuo to give the title compound as a white solid.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:7]=[C:6]([CH2:18][CH:19]=[CH2:20])[C:5]=1[OH:21])[CH:2]=[CH2:3].[CH3:22][C:23]1[O:27][C:26]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[N:25][C:24]=1[CH2:34][CH2:35]OS(C1C=CC(C)=CC=1)(=O)=O.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH2:1]([C:4]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:7]=[C:6]([CH2:18][CH:19]=[CH2:20])[C:5]=1[O:21][CH2:35][CH2:34][C:24]1[N:25]=[C:26]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:27][C:23]=1[CH3:22])[CH:2]=[CH2:3]
Reactant: C=CCc1cc(OCc2ccccc2)cc(CC=C)c1O
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3ccccc3)oc2C)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: C=CCc1cc(OCc2ccccc2)cc(CC=C)c1OCCc1nc(-c2ccccc2)oc1C
Yield: 83.8 %

Procedure:
A mixture of 2,6-diallyl-4-benzyloxy-phenol (520 mg, 1.85 mmol), toluene-4-sulfonic acid 2-(5-methyl-2-phenyl-oxazol-4-yl)ethyl ester (Japan Tobacco Inc WO 9518125) (828 mg, 2.32 mmol), and Cs2CO3 (604 mg, 1.85 mmol) was heated at 55° C. in DMF (5 mL) for 20 h. Additional toluene-4-sulfonic acid 2-(5-methyl-2-phenyl-oxazol-4-yl)ethyl ester (300 mg, 0.839 mmol) and Cs2CO3 (200 mg, 0.614 mmol) were added, and the mixture was heated for 18 h. The reaction mixture was cooled and partitioned between EtOAc (40 mL) and H2O (10 mL). The organic layer was washed with brine (15 mL), dried (Na2SO4), and concentrated. The crude product was purified by radial chromatography using hexanes:ethyl acetate (8:1) to give a colorless oil (722 mg, 83%): 1H NMR (400 MHz, CDCl3) δ 2.38 (s, 3H), 2.95 (t, 2H, J=6.3 Hz), 3.33 (d, 2H, J=6.3 Hz), 4.01 (t, 2H, J=6.3 Hz), 4.96 (s, 2H), 4.97-5.02 (m, 2H), 5.03 (s, 2H), 5.84-5.94 (m, 1H), 6.65 (s, 2H), 7.28-7.45 (m, 8H), 7.99 (dd, 2H, J=2.0, 7.8 Hz).
Reaction SMILES: [CH:1]([N:4]([CH:16]([CH3:18])[CH3:17])[CH2:5][CH2:6][NH:7][C:8]1[N:13]=[C:12]([CH3:14])[CH:11]=[C:10]([CH3:15])[N:9]=1)([CH3:3])[CH3:2].[Cl:19][C:20]([O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:21]>C1C=CC=CC=1>[ClH:19].[CH:16]([N:4]([CH:1]([CH3:2])[CH3:3])[CH2:5][CH2:6][N:7]([C:8]1[N:9]=[C:10]([CH3:15])[CH:11]=[C:12]([CH3:14])[N:13]=1)[C:20](=[O:21])[O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([CH3:18])[CH3:17]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Cc1cc(C)nc(NCCN(C(C)C)C(C)C)n1
Solvent: c1ccccc1
Product: Cc1cc(C)nc(N(CCN(C(C)C)C(C)C)C(=O)Oc2ccccc2)n1
Product: Cl
Reaction time: 72 h

Procedure:
A solution of 2-(2-diisopropylaminoethylamino)-4,6-dimethylpyrimidine (12.5 g., 0.05 mole) in 50 ml of benzene is added to a solution of phenyl chloroformate in 50 ml of benzene. After 72 hours, the solid product is collected and recrystallized from acetone to give phenyl N-(2-diisopropylaminoethyl)-N-(4,6-dimethyl-2-pyrimidinyl)carbamate hydrochloride melting at 190°-202° C.
Reaction SMILES: [C:1]1([C:7]#C)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N([CH2:12]CCC1C=CNC(=O)C=1OCC1C=CC=CC=1)=[N+]=[N-].[C:30]1([N:36]2[CH:41]=[CH:40][C:39]([CH2:42][CH2:43][C:44]3[N:45]=[N:46][NH:47][CH:48]=3)=[C:38]([O:49]C)[C:37]2=[O:51])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[C:30]1([N:36]2[CH:41]=[CH:40][C:39]([CH2:42][CH2:43][CH2:44][C:48]3[N:47]=[N:46][NH:45][CH:12]=3)=[C:38]([O:49][CH2:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:37]2=[O:51])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: C#Cc1ccccc1
Reactant: [N-]=[N+]=NCCCc1cc[nH]c(=O)c1OCc1ccccc1
Reactant: COc1c(CCc2c[nH]nn2)ccn(-c2ccccc2)c1=O
Product: O=c1c(OCc2ccccc2)c(CCCc2c[nH]nn2)ccn1-c1ccccc1
Yield: 77 %

Procedure:
Reaction of phenylacetylene (0.127 g, 1.25 mmol) and 157b (0.295 g, 1.04 mmol) within 4 h as described for synthesis of 158a gave compound 158b (0.31 g, 77%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.00 (s, 1H), 7.77 (d, J=7.3 Hz, 2H), 7.27 (m, 8H), 6.88 (d, J=5.7 Hz, 1H), 6.57 (d, J=6.4 Hz, 1H), 5.95 (t, J=7.1 Hz, 1H), 4.99 (s, 2H), 4.34 (t, J=6.4 Hz, 2H), 3.94 (t, J=6.4 Hz, 2H), 2.32 (m, 2H). 13C NMR (100 MHz, CDCl3) δ 157.92, 148.47, 147.30, 135.73, 130.26, 128.81, 128.49, 128.22, 127.76, 127.71, 127.01, 125.33, 120.16, 114.95, 104.83, 70.33, 47.00, 46.48, 29.30. HRMS (EI) calcd for C23H22N4O2 [M]+ 386.1743. found 386.1734.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH:4]=[O:5].[H-].[Na+].[CH2:14]([N:21]([CH2:23][CH2:24]Cl)[CH3:22])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CN(C=O)C.C1(C)C=CC=CC=1>[CH2:14]([N:21]([CH2:23][CH2:24][O:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH:4]=[O:5])[CH3:22])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CN(CCCl)Cc1ccccc1
Reactant: COc1ccc(O)c(C=O)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: COc1ccc(OCCN(C)Cc2ccccc2)c(C=O)c1
Temperature: 70 °C

Procedure:
In a similar manner to the previous example, a solution of 2-hydroxy-5-methoxybenzal dehyde (25.0 g) in DMF (50 ml) was added to a stirred suspension of sodium hydride (6.84 g of a 60% dispersion in mineral oil) in dry DMF (125 ml) at ambient temperature under nitrogen with stirring. The mixture was heated at 70° C. for 2 hours and then cooled to ambient temperature and a solution of N-benzyl-2-chloro-N-methylethylamine in toluene (75 ml) was added [prepared from 48.5 g of the hydrochloride salt]. The oil obtained after work up was distilled under vacuum to give 2-[2-(N-benzyl-N-methylamino)ethoxy]-5-methoxybenzaldehyde as an oil. A sample of this oil which boiled at 202°-206° C. at 0.65 mbar was dissolved in ether and acidified with ethereal hydrogen chloride. The precipitate was collected by filtration, washed with ether to give 2-[2-(N-benzyl-N-methylamino)ethoxy]-5-methoxybenzaldehyde hydrochloride, m.p. 167°-169° C.
Reaction SMILES: N[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.N([O-])=O.[Na+].C(OCC)(=O)C.C(OCC)C.[H+].[B-](F)(F)(F)[F:29]>>[F:29][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: Nc1cccc2ncccc12
Reactant: F[B-](F)(F)F
Agent: O=N[O-]
Agent: [H+]
Agent: [Na+]
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: Fc1cccc2ncccc12
Reaction time: 1 h
Yield: 24.5 %

Procedure:
To a suspension of 5-aminoquinoline (10.0 g, 0.069 mol) in 48% HBF4 (40 mL) at 0° C. was added portionwise sodium nitrite. This was stirred for 1 hour and then poured into 1:1 ethyl acetate/diethyl ether (50 mL). The resulting suspension was filtered and the solid dried. This solid was added portionwise to refluxing xylene (80 mL) and stirred for 2 hours then allowed to cool. The xylene was decanted off and the residue was dissolved in 1N aqueous hydrochloric acid (100 mL). After neutralization with sodium carbonate, the mixture was extracted with ethyl acetate (3×80 mL). The extracts were dried over sodium sulfate, filtered and the volatiles were removed in vacuo. The residue was purified by silica gel column chromatography, eluting with 2% ethyl acetate in petroleum ether to afford 5-fluoroquinoline as a colorless oil (2.5 g, 24.5%).
Reaction SMILES: [O:1]=[CH:2][C:3]([Cl:6])([Cl:5])[Cl:4].[N:7]1([C:12]2([C:15](=[O:17])[CH3:16])CC2)[CH:11]=[N:10][CH:9]=[N:8]1.[C:18]([O-])(=O)[CH3:19].[Na+]>C(O)(=O)C>[Cl:4][C:3]([Cl:6])([Cl:5])[CH:2]([OH:1])[CH:12]([N:7]1[CH:11]=[N:10][CH:9]=[N:8]1)[C:15]([CH:16]1[CH2:19][CH2:18]1)=[O:17]
Reactant: O=CC(Cl)(Cl)Cl
Reactant: CC(=O)[O-]
Reactant: CC(=O)C1(n2cncn2)CC1
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C(C1CC1)C(C(O)C(Cl)(Cl)Cl)n1cncn1
Temperature: 42 °C
Reaction time: 12 h
Yield: 57.6 %

Procedure:
14.8 g (0.1 mol) of chloral were added dropwise to 7.6 g (0.05 mol) of 1,2,4-triazol-1-yl-acetyl-cyclopropane, 7.5 g of glacial acetic acid and 4.1 g (0.05 mol) of sodium acetate, the internal temperature increasing to approx. 42° C. The reaction mixture was stirred for 5 hours at 80° C. and for 12 hours at room temperature, and was then introduced onto water. The resulting precipitate was filtered off under suction and recrystallized from toluene. 8.6 g (57.6% of theory) of 1,1,1-trichloro-2-hydroxy-3-(1,2,4-triazol-1-yl)-4-cyclopropyl-butan-4-one of melting point 173° to 175° C. were obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:40]=[CH:39][C:6]([CH2:7][N:8]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][NH:27][C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.Br[C:42]1[CH:43]=[C:44]([CH2:48][CH2:49][C:50]([N:52]2[CH2:57][CH2:56][N:55]([CH2:58][CH3:59])[CH2:54][CH2:53]2)=[O:51])[CH:45]=[CH:46][CH:47]=1>>[CH3:38][O:37][C:34]1[CH:33]=[CH:32][C:31]([CH2:30][N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:40][CH:39]=2)[C:9]2[N:10]=[CH:11][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:42]5[CH:43]=[C:44]([CH2:48][CH2:49][C:50]([N:52]6[CH2:53][CH2:54][N:55]([CH2:58][CH3:59])[CH2:56][CH2:57]6)=[O:51])[CH:45]=[CH:46][CH:47]=5)[C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:13][N:14]=2)=[CH:36][CH:35]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4)cn2)cc1
Reactant: CCN1CCN(C(=O)CCc2cccc(Br)c2)CC1
Product: CCN1CCN(C(=O)CCc2cccc(N3CCc4c(-c5cnc(N(Cc6ccc(OC)cc6)Cc6ccc(OC)cc6)nc5)nc(N5CCOCC5)nc43)c2)CC1

Procedure:
Using bis-(4-methoxy-benzyl)-[5-(2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amine (200 mg) and 3-(3-bromo-phenyl)-1-(4-ethyl-piperazin-1-yl)-propan-1-one (181 mg) instead of 4-chloropicolinic acid t-butylamide, in the same manner as Example 1-D-07, a crude product of 3-[3-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-phenyl]-1-(4-ethyl-piperazin-1-yl)-propan-1-one was obtained, and further PMB group was removed according to the above Deprotection method 2, to obtain the desired compound (D-191) as a pale brown powder (115 mg, 60%).