Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([C:12]([F:15])([F:14])[F:13])([CH2:6][CH:7]=[CH:8][CH2:9][CH2:10][CH3:11])[C:3]([NH2:5])=[O:4].[H][H]>CO.[C].[Pd]>[F:1][C:2]([C:12]([F:13])([F:15])[F:14])([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[C:3]([NH2:5])=[O:4]
Reactant: CCCC=CCC(F)(C(N)=O)C(F)(F)F
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCCCCCC(F)(C(N)=O)C(F)(F)F
Reaction time: 24 h
Yield: 76.2 %

Procedure:
Into a solution of 1.30 g of 2-fluoro-2-trifluoromethyl-4-octenamide in 13 ml of methanol, palladium-carbon (13 mg) was added under nitrogen. After the atmosphere was replaced with hydrogen, the mixture was stirred for 24 hours. To remove the catalyst, the resulting mixture was filtered with celite and the filtrate was concentrated. The raw product was purified by silica gel column chromatography to obtain 1.0 g of the desired compound.
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:47]=[CH:46][C:45]([C:48]([N:50]2[CH2:55][CH2:54][O:53][CH2:52][CH2:51]2)=[O:49])=[CH:44][C:43]=1[Cl:56]>>[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:47]=[CH:46][C:45]([C:48]([N:50]6[CH2:51][CH2:52][O:53][CH2:54][CH2:55]6)=[O:49])=[CH:44][C:43]=5[Cl:56])[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: O=C(c1ccc(Br)c(Cl)c1)N1CCOCC1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(C(=O)N4CCOCC4)cc3Cl)cn2)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 (70 mg) and (4-bromo-3-chloro-phenyl)-morpholin-4-yl-methanone (59 mg) instead of 4-chloropicolinic acid t-butylamide, in the same manner as Example 1-D-07, a crude product of [4-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-3-chloro-phenyl]-morpholin-4-yl-methanone was obtained, and then the PMB groups were removed according to the above Deprotection method 3, to obtain the desired compound (D-309) as a pale brown powder (42 mg, 62%).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2([OH:9])[CH2:8][CH2:7]2)[N:3]=[CH:2]1.N1C=CN=C1.[CH3:15][C:16]([Si:19](Cl)([CH3:21])[CH3:20])([CH3:18])[CH3:17]>CN(C=O)C>[Si:19]([O:9][C:6]1([C:4]2[N:3]=[CH:2][NH:1][CH:5]=2)[CH2:8][CH2:7]1)([C:16]([CH3:18])([CH3:17])[CH3:15])([CH3:21])[CH3:20]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OC1(c2c[nH]cn2)CC1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OC1(c2c[nH]cn2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 63.2 %

Procedure:
A solution of 1-(1H-imidazol-4-yl)cyclopropanol (700 mg, 5.64 mmol) in DMF (1 mL) was treated with imidazole (768 mg, 11.28 mmol) and TBSCl (935 mg, 6.20 mmol) and the mixture was stirred at RT for 2 h. The mixture was then poured onto H2O, and extracted with AcOEt. The combined org. layers were dried over Na2SO4, filtered and concentrated in vacuo to give the title compound (850 mg) that was used as it is. UPLC-MS: MS 239.2 (M+H+); UPLC rt 0.82 min.
Reaction SMILES: [OH:1][C:2]1[CH2:7][C:6]([CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=2)([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[O:5][C:4](=[O:26])[CH:3]=1.[C:27]([C:31]1[CH:36]=[C:35]([CH2:37][OH:38])[C:34]([CH3:39])=[CH:33][C:32]=1[S:40]S(C1C=CC(C)=CC=1)(=O)=O)([CH3:30])([CH3:29])[CH3:28].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[C:27]([C:31]1[CH:36]=[C:35]([CH2:37][OH:38])[C:34]([CH3:39])=[CH:33][C:32]=1[S:40][C:3]1[C:4](=[O:26])[O:5][C:6]([CH2:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]([OH:25])=[CH:23][CH:24]=2)([CH2:8][CH2:9][C:10]2[CH:11]=[CH:12][C:13]([OH:16])=[CH:14][CH:15]=2)[CH2:7][C:2]=1[OH:1])([CH3:30])([CH3:29])[CH3:28]
Reactant: Cc1ccc(S(=O)(=O)Sc2cc(C)c(CO)cc2C(C)(C)C)cc1
Reactant: O=C1C=C(O)CC(CCc2ccc(O)cc2)(CCc2ccc(O)cc2)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(SC2=C(O)CC(CCc3ccc(O)cc3)(CCc3ccc(O)cc3)OC2=O)c(C(C)(C)C)cc1CO
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The title compound was prepared as described in General Method 9 using 0.14 g (0.39 mmol) of 4-hydroxy-6,6-bis [2-(4-hydroxyphenyl)ethyl]-5,6-dihydro-pyran-2-one (prepared in Example PP), 0.19 g (0.52 mmol) of toluene-4-thiosulfonic acid S-(2-tert-butyl-4-hydroxymethyl-5-methyl-phenyl) ester (prepared in Example FFF), 0.22 g (1.6 mmol) of K2CO3, and 3 mL of DMF. The solution was stirred overnight at room temperature. Purification by silica gel chromatography, eluting with CH2Cl2 :MeOH (100:0 to 90:10), gave the title compound, m.p. 192°-194° C. 1H NMR (DMSO-d6) δ 1.48 (s, 9 H), 1.83 (s, 3 H), 2.02 (m, 4 H), 2.54 (m, 4 H), 2.96 (br s, 2 H), 4.35 (br s, 2 H), 4.94 (br s, 1 H), 6.68 (m, 5 H), 6.99 (dd, 4 H), 7.26 (s, 1 H), 9.16 (s, 2 H).
Reaction SMILES: Br[C:2]1[CH:19]=[CH:18][C:5]([CH2:6][NH:7][C:8](=[O:17])[C:9]2[C:14]([Cl:15])=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:16])=[CH:4][C:3]=1[CH3:20].[O:21]=[C:22]1[CH:27]=[C:26](B(O)O)[CH:25]=[CH:24][NH:23]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[Cl:16][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]([Cl:15])[C:9]=1[C:8]([NH:7][CH2:6][C:5]1[CH:18]=[CH:19][C:2]([C:26]2[CH:25]=[CH:24][NH:23][C:22](=[O:21])[CH:27]=2)=[C:3]([CH3:20])[CH:4]=1)=[O:17]
Reactant: O=c1cc(B(O)O)cc[nH]1
Reactant: Cc1cc(CNC(=O)c2c(Cl)cccc2Cl)ccc1Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(CNC(=O)c2c(Cl)cccc2Cl)ccc1-c1cc[nH]c(=O)c1
Temperature: 85 °C

Procedure:
N-(4-Bromo-3-methylbenzyl)-2,6-dichlorobenzamide (0.13 g, 0.35 mmol), 2-oxo-1,2-dihydropyridin-4-ylboronic acid (0.053 g, 0.39 mmol), cesium carbonate (0.34 g, 1.05 mmol), [1,1′ Bis(diphenylphosphino(ferrocene]dichloropalladium(II) (25 mg, 0.035 mmol) were dissolved in degassed DMF (3 mL) and H2O (1.5 mL). The reaction mixture was degassed again by bubbling nitrogen through for 15 min then heated in the microwave at 85° C. for 20 min. The reaction mixture was diluted with EtOAc and extracted three times with water. The organic phase was dried over magnesium sulfate, filtered and concentrated in vacuum. The resulting solid was purified by reverse phase chromatography to afford 2,6-dichloro-N-(3-methyl-4-(2-oxo-1,2-dihydropyridin-4-yl)benzyl)benzamide.
Reaction SMILES: [CH2:1]([C:4]1[C:13]([OH:14])=[C:12]2[C:7]([CH:8]=[CH:9][CH:10]=[N:11]2)=[CH:6][CH:5]=1)[CH:2]=[CH2:3].[H][H]>[Pd].CO>[CH2:1]([C:4]1[C:13]([OH:14])=[C:12]2[C:7]([CH:8]=[CH:9][CH:10]=[N:11]2)=[CH:6][CH:5]=1)[CH2:2][CH3:3]
Reactant: C=CCc1ccc2cccnc2c1O
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCCc1ccc2cccnc2c1O
Yield: 84.5 %

Procedure:
Into a stainless steel autoclave, one introduces 93 g of 7-allyl-8-hydroxyquinoline (i.e. 0.5 mole), 250 ml of methanol, and 3 g of 5% palladium on charcoal. The hydrogenation is carried out under a 4 kg/cm2 hydrogen pressure. After absorption of a sufficient quantity of hydrogen and cooling, one filters off the catalyst, removes the solvent by distillation under normal pressure, and then distills the residue under high vacuum. The 7-propyl-8-hydroxyquinoline distills at 105°-106°C at a pressure of 0.25 mm Hg. One collects 78 g of a light yellow liquid. Yield = 84.5%.
Reaction SMILES: [F:1][CH:2]([F:5])[CH2:3][NH2:4].[F:6][C:7]([F:33])([F:32])[C@H:8]1[CH2:13][CH2:12][C@H:11]([NH:14][C:15](=[O:31])[C:16]2[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[C:19](Cl)=[N:18][C:17]=2[O:26][CH2:27][CH:28]([F:30])[F:29])[CH2:10][CH2:9]1.C1COCC1>CO>[F:32][C:7]([F:6])([F:33])[C@H:8]1[CH2:9][CH2:10][C@H:11]([NH:14][C:15](=[O:31])[C:16]2[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[C:19]([NH:4][CH2:3][CH:2]([F:5])[F:1])=[N:18][C:17]=2[O:26][CH2:27][CH:28]([F:30])[F:29])[CH2:12][CH2:13]1
Reactant: NCC(F)F
Reactant: O=C(N[C@H]1CC[C@H](C(F)(F)F)CC1)c1cc([N+](=O)[O-])c(Cl)nc1OCC(F)F
Solvent: CO
Solvent: C1CCOC1
Product: O=C(N[C@H]1CC[C@H](C(F)(F)F)CC1)c1cc([N+](=O)[O-])c(NCC(F)F)nc1OCC(F)F
Reaction time: 20 h

Procedure:
2,2-Difluoroethylamine (0.18 mL, 2.53 mmol) is slowly added to a mixture of N-(trans-4-trifluoromethyl-cyclohexyl)-6-chloro-5-nitro-2-(2,2-difluoroethoxy)-nicotinic acid amide (prepared according to WO2010/34799, 1.00 g, 2.3 mmol) and 10 mL THF at 0° C., 2 mL MeOH is added and it is stirred for 20 h. The mixture is concentrated and the solid residue is washed with water and dried. Yield: 0.96 g.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([NH:10][C@@H:11]2[C:33](=[O:34])[N:13]3[C:14]([C:30]([O-:32])=[O:31])=[C:15]([CH2:18][S:19][C:20]4[N:24]([CH2:25][CH2:26][N:27]([CH3:29])[CH3:28])[N:23]=[N:22][N:21]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.[K+].[C:36](=[O:47])([O:41][CH2:42][CH:43]([CH3:46])[CH2:44][CH3:45])[O:37][CH:38](I)[CH3:39].C(OCC)(=O)C>CC(N(C)C)=O>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([NH:10][C@@H:11]2[C:33](=[O:34])[N:13]3[C:14]([C:30]([O:32][CH:38]([O:37][C:36]([O:41][CH2:42][CH:43]([CH3:46])[CH2:44][CH3:45])=[O:47])[CH3:39])=[O:31])=[C:15]([CH2:18][S:19][C:20]4[N:24]([CH2:25][CH2:26][N:27]([CH3:29])[CH3:28])[N:23]=[N:22][N:21]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: CCC(C)COC(=O)OC(C)I
Reactant: CN(C)CCn1nnnc1SCC1=C(C(=O)[O-])N2C(=O)[C@@H](NC(=O)Cc3csc(N)n3)[C@H]2SC1
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: CCC(C)COC(=O)OC(C)OC(=O)C1=C(CSc2nnnn2CCN(C)C)CS[C@@H]2[C@H](NC(=O)Cc3csc(N)n3)C(=O)N12
Temperature: -5 °C
Reaction time: 0.08 h
Yield: 30.9 %

Procedure:
In 80 ml of dimethylacetamide is dissolved 5.6 g of potassium 7β-[2-(2-aminothiazol-4-yl)acetamido]-3-[[[1-(2-dimethylaminoethyl)-1H-tetrazol-5-yl]thio]methyl]ceph-3-em-4-carboxylate, and the solution is cooled to -5° C. With stirring, 4.8 g of 1-iodoethyl 2-methylbutyl carbonate is added at one stroke and stirring is continued for 5 minutes. The reaction mixture is poured into a mixture of 300 ml of ethyl acetate and 200 ml of ice-water and the organic layer is separated. The aqueous layer is extracted with 200 ml of ethyl acetate and these organic layers are combined, water with three 150-ml portions of ice water and three 150-ml portions of saturated aqueous sodium chloride in that order and dried over anhydrous magnesium sulfate. The solvent is then distilled off and isopropyl ether is added to the residue. The thus-obtained white powder is collected by filtration, washed with isopropyl ether and dried to give 2.1 g of the title compound.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([N:9]([CH2:15][C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[S:10]([CH2:13][CH3:14])(=[O:12])=[O:11])[CH:5]=[CH:6][C:7]=1[CH3:8].[C:22]([C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1)#[N:23].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.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>[CH3:8][C:7]1[CH:6]=[CH:5][C:4]([N:9]([CH2:15][C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[S:10]([CH2:13][CH3:14])(=[O:12])=[O:11])=[CH:3][C:2]=1[C:27]1[CH:28]=[CH:29][C:24]([C:22]#[N:23])=[CH:25][CH:26]=1
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: CCS(=O)(=O)N(Cc1cccnc1)c1ccc(C)c(I)c1
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: [Na+]
Solvent: C1COCCO1
Product: CCS(=O)(=O)N(Cc1cccnc1)c1ccc(C)c(-c2ccc(C#N)cc2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of N-(3-iodo-4-methylphenyl)-N-(ethylsulfonyl)pyrid-3-ylmethylamine (103 mg,0.247 mmol) and 4-cyanophenylboronic acid (55 mg, 0.371 mmol) in 4 ml of 1,4-dioxane stirring under nitrogen was treated with 2M sodium carbonate (0.37 mL, 0.741 mmol) and tetrakis(triphenylphosphine)palladium(0) (12.6 mg, 0.011 mmol). This was refluxed for three hours and then allowed to stir at room temperature for 16 hours. The reaction had not completed after this time so the reaction was treated with an additional 5.7 mg(0.005 mmol) of tetrakis(triphenylphosphine)palladium(0) and refluxed for two hours. The reaction was then cooled to room temperature and concentrated in vacuo. This was then dissolved in a minimal amount of dichloromethane and purified on a Chromatotron (200 omicron plate) with 3% methanol/dichloromethane to give a residue which was recrystallized using ether/hexanes to give the title compound. 1H NMR: 8.45-8.55 (d, 1H, J=4 Hz), 8.35-8.40 (s, 1H), 7.75-7.80 (d, 1H, J=12 Hz), 7.65-7.70 (d, 1H, J=12 Hz), 7.20-7.35 (m, 5H), 7.15-7.20 (m, 1H), 7.00-7.05 (s, 1H), 4.85-4.95 (s, 2H), 3.05-3.15 (q, 2H, J=10z), 2.15-2.20 (s, 3H), 1.40-1.50 (t, 3H, J=8 Hz); MS calcd. 391.5; MS (M+1)=392.1.
Reaction SMILES: [CH:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[C:6]([C:11]([F:14])([F:13])[F:12])[CH:5]=1)([CH3:3])[CH3:2].C(N(CC)CC)C.[Br:22][CH2:23][C:24](Br)=[O:25]>ClCCl>[Br:22][CH2:23][C:24]([NH:8][C:7]1[CH:9]=[CH:10][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][C:6]=1[C:11]([F:12])([F:13])[F:14])=[O:25]
Reactant: O=C(Br)CBr
Reactant: CC(C)c1ccc(N)c(C(F)(F)F)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)c1ccc(NC(=O)CBr)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
50 g (246.06 mmol) of 4-isopropyl-2-(trifluoromethyl)aniline and 27.39 g (270.66 mmol) of triethylamine are initially charged in 1000 ml of dichloromethane. At 0°-5° C., 54.63 g (270.66 mmol) of bromoacetyl bromide, dissolved in 200 ml of dichloromethane, are added dropwise. The mixture is stirred at room temperature for 20 hours. The reaction mixture is then extracted successively with water, 1 N hydrochloric acid, water, saturated sodium bicarbonate solution and water. The organic phase is dried over sodium sulphate and the solvent is removed under reduced pressure. The residue is purified chromatographically. The product is recrystallized from cyclohexane/n-pentane, filtered off with suction and dried under reduced pressure at 40° C. for 20 hours. This gives 32.45 g (41% of theory) of the title compound.
Reaction SMILES: Cl.Cl[C:3]1[N:8]=[CH:7][N:6]=[C:5]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[CH:11]=2)[CH:4]=1.[CH:19]1([NH2:25])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.CCN(C(C)C)C(C)C>CCCCO>[CH:19]1([NH:25][C:3]2[CH:4]=[C:5]([NH:9][C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[CH:11]=3)[N:6]=[CH:7][N:8]=2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: NC1CCCCC1
Reactant: O=[N+]([O-])c1cccc(Nc2cc(Cl)ncn2)c1
Agent: Cl
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1cccc(Nc2cc(NC3CCCCC3)ncn2)c1
Temperature: 200 °C
Yield: 94 %

Procedure:
60 mg of 6-chloro-N-(3-nitrophenyl)pyrimidin-4-amine hydrochloride, 32 mg cyclohexylamine and 69 mg of DIPEA were dissolved in 1 mL of n-BuOH and charged into a microwave vial and the vial obtained heated to 200° C. for 60 minutes under microwave irradiation. The reaction was monitored by TLC. The crude product was precipitated from n-BuOH. Purification was carried out by filtering and washing with cold n-BuOH. Pure N4-cyclohexyl-N6-(3-nitrophenyl)pyrimidine-4,6-diamine in the form of a colorless solid was obtained.
Reaction SMILES: Cl.[Cl:2][C:3]1[N:4]([C:12]2[CH:22]=[CH:21][C:15]([O:16][CH2:17][CH2:18][NH:19][CH3:20])=[CH:14][CH:13]=2)[N:5]=[C:6]2[C:11]=1[CH:10]=[CH:9][CH:8]=[CH:7]2.[C:23]([O:27][CH3:28])(=[O:26])[CH:24]=[CH2:25]>C(Cl)Cl>[CH3:28][O:27][C:23](=[O:26])[CH2:24][CH2:25][N:19]([CH2:18][CH2:17][O:16][C:15]1[CH:21]=[CH:22][C:12]([N:4]2[C:3]([Cl:2])=[C:11]3[C:6]([CH:7]=[CH:8][CH:9]=[CH:10]3)=[N:5]2)=[CH:13][CH:14]=1)[CH3:20]
Reactant: C=CC(=O)OC
Reactant: CNCCOc1ccc(-n2nc3ccccc3c2Cl)cc1
Agent: Cl
Solvent: ClCCl
Product: COC(=O)CCN(C)CCOc1ccc(-n2nc3ccccc3c2Cl)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 95.5 %

Procedure:
A mixture of the product from step 2 (0.1 g, 0.27 mmol), methyl acrylate (0.15 g, 1.7 mmol) in methylene chloride (2 mL) was stirred at room temperature for 24 h. After the inorganic salts were filtered off, the solvent was removed in vacuo. The crude product was purified by a column chromatography on silica gel eluting with 5% methanol in methylene chloride to afford the ester (100 mg, 60%) MS (APCI) m/z 388 (M+1, 100).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]([NH:33]C(=O)OC(C)(C)C)[C:10](=[O:32])[N:11]2[CH2:16][CH2:15][N:14]([C:17]3[C:22]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:21][N:20]=[C:19]4[NH:29][CH:30]=[CH:31][C:18]=34)[CH2:13][CH2:12]2)=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O.C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>C(Cl)Cl>[NH2:33][C@H:9]([CH2:8][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)[C:10]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[C:22]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)=[CH:21][N:20]=[C:19]3[NH:29][CH:30]=[CH:31][C:18]=23)[CH2:13][CH2:12]1)=[O:32]
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)N1CCN(c2c(-c3ccccc3)cnc3[nH]ccc23)CC1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@H](Cc1ccc(Cl)cc1)C(=O)N1CCN(c2c(-c3ccccc3)cnc3[nH]ccc23)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.6 %

Procedure:
(R)-tert-Butyl 3-(4-chlorophenyl)-1-oxo-1-(4-(5-phenyl-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazin-1-yl)propan-2-ylcarbamate (0.020 g, 0.036 mmol) was placed in DCM (3 mL). TFA (0.3 mL) was then added, and the reaction was stirred at room temperature for 1 hour. The reaction was then concentrated to dryness, dissolved in minimal DCM, and added dropwise to a stirring solution of 1M HCl in ether. The solid product was filtered, washed with ether, and dried to give (R)-2-amino-3-(4-chlorophenyl)-1-(4-(5-phenyl-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazin-1-yl)propan-1-one (0.015 g, 79% yield) as the dihydrochloride salt. MS ESI (+) m/z 460 detected.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[C:12]1(B(O)O)[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15](B(O)O)=[CH:14][CH:13]=1.P([O-])([O-])([O-])=O>O.C1COCC1.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>[CH3:7][O:6][C:4]([C:3]1[CH:8]=[CH:9][CH:10]=[CH:11][C:2]=1[C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([C:2]2[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=2[C:4]([O:6][CH3:7])=[O:5])=[CH:14][CH:13]=1)=[O:5]
Reactant: OB(O)c1ccc(B(O)O)c2ccccc12
Reactant: COC(=O)c1ccccc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1ccccc1-c1ccc(-c2ccccc2C(=O)OC)c2ccccc12

Procedure:
1.55 g (0.1 mmol) of Pd(PPh3)4 are added to a vigorously stirred, degassed suspension of 21.6 g (7.1 mmol) of methyl 2-bromobenzoate, 10.1 g (28 mmol) of 1,4-naphthalenediboronic acid and 18.9 g (6.6 mmol) of trispotassium phosphate in a mixture of 350 ml of water and 350 ml of THF, and the mixture is refluxed for 60 h. After cooling, the organic phase is separated off, washed three times with 200 ml of water and once with 200 ml of saturated sodium chloride solution and subsequently dried over magnesium sulfate. The organic phase is evaporated to dryness under reduced pressure in a rotary evaporator. The grey residue obtained in this way is recrystallised from dioxane. The deposited crystals are filtered off with suction, washed with 50 ml of ethanol and subsequently dried under reduced pressure. Yield: 13 g, 82% of theory.
Reaction SMILES: [Cl:1][C:2]1[C:3]([Cl:11])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].O.[C:13]1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[CH3:13][O:8][C:7](=[O:9])[C:6]1[CH:10]=[C:2]([Cl:1])[C:3]([Cl:11])=[N:4][CH:5]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C(O)c1cnc(Cl)c(Cl)c1
Solvent: CO
Solvent: O
Product: COC(=O)c1cnc(Cl)c(Cl)c1
Temperature: 25 °C

Procedure:
A solution of 5,6-dichloro-nicotinic acid (1.92 g, 10 mmol, Aldrich) and p-toluenesulfonic acid monohydrate (190 mg, 1.0 mmol, Aldrich) in methanol (5 mL, Aldrich) was heated at reflux for 25 h. The reaction mixture was cooled to room temperature, the solvent was removed in vacuo and the residue was dissolved in EtOAc (50 mL). The solution was washed with satd. NaHCO3 (20 mL) and brine (20 mL), dried over Na2SO4, and filtered. The filtrate was evaporated in vacuo and the residue was purified by silica gel column chromatography, eluting with 30% EtOAc/hexane to give the title compound as a white solid. MS ESI, pos. ion) m/e: 205 (M+1).
Reaction SMILES: [CH3:1]I.[CH:3]1[C:12]2[CH:11]=[CH:10][CH:9]=[C:8]([CH:13]=[O:14])[C:7]=2[CH:6]=[CH:5][N:4]=1>CCOCC>[CH:3]1[C:12]2[C:7](=[C:8]([CH:13]([OH:14])[CH3:1])[CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][N:4]=1
Reactant: O=Cc1cccc2cnccc12
Reactant: CI
Solvent: CCOCC
Product: CC(O)c1cccc2cnccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.2 %

Procedure:
To a mixture of Mg turnings (0.2 g, 7.9 mmol) in ether (10 mL) was added MeI (1.13 g, 7.9 mmol) slowly at RT under an inert atmosphere. After being stirred for 1 h at RT, the reaction mixture was cooled to −10° C. and a solution of isoquinoline-5-carbaldehyde (0.5 g, 3.18 mmol) in ether (10 mL) was added. The reaction mixture was then stirred for an additional hour at RT, quenched with saturated NH4Cl solution and extracted with EtOAc (3×50 mL). The combined organic layers were washed with water and brine, dried over Na2SO4, filtered and concentrated in vacuo to obtain the crude product. The crude material was purified via silica gel column chromatography using 30% ethyl acetate in hexanes to afford 1-(isoquinolin-5-yl)ethanol (0.53 g, 97%) as an off-white solid.
Reaction SMILES: [NH2:1][C:2]1[CH2:8][N:7]=[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:5]2[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:4]=2[N:3]=1.[C:20]([C:26](OC)=[O:27])#[C:21][C:22]([O:24][CH3:25])=[O:23]>CO>[C:22]([C:21]1[N:3]2[C:4]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:5]=3[C:6]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[N:7][CH2:8][C:2]2=[N:1][C:26](=[O:27])[CH:20]=1)([O:24][CH3:25])=[O:23]
Reactant: NC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1
Reactant: COC(=O)C#CC(=O)OC
Solvent: CO
Product: COC(=O)c1cc(=O)nc2n1-c1ccc(Cl)cc1C(c1ccccc1)=NC2
Yield: 16.3 %

Procedure:
A mixture of 2-amino-7-chloro-5-phenyl-3H-1,4-benzodiazepine (13.5 g.; 0.05 mole), dimethyl acetylenedicarboxylate (7.1 g.; 0.05 mole) and 250 ml. of methanol were refluxed for 2 hours and evaporated. The residue was dissolved in 50 ml. of methylene chloride and chromatographed on 2 kg. of silica gel using 60% ethyl acetate 40% cyclohexane. Fractions 1-6 (4.5 l.) gave no material. Fractions 6-51 were discarded. Fraction 52-54 gave 6.3 g. of solids which were crystallized from methylene chloride ether to give 1-carbomethoxy-9-chloro-7-phenylpyrimido[1,2-a][1,4]benzodiazepin-3(5H)-one 3.1 g. of melting point 214°-215° C. dec., raised to 216°-217° C. on recrystallization from methanol-ether.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:20]([O-:22])=[O:21])=[C:6]([CH:19]=1)[O:7][C:8]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:9]=1[C:10]([OH:12])=O>O>[Cl:1][C:2]1[C:19]2[C:10](=[O:12])[C:9]3[C:8](=[CH:16][CH:15]=[C:14]([O:17][CH3:18])[CH:13]=3)[O:7][C:6]=2[C:5]([N+:20]([O-:22])=[O:21])=[CH:4][CH:3]=1
Reactant: COc1ccc(Oc2cc(Cl)ccc2[N+](=O)[O-])c(C(=O)O)c1
Solvent: O
Product: COc1ccc2oc3c([N+](=O)[O-])ccc(Cl)c3c(=O)c2c1
Temperature: 110 °C
Reaction time: 24 h

Procedure:
2-(5-Chloro-2-nitrophenoxy)-5-methoxybenzoic acid, 50 g, was added to 400 g of polyphosphoric acid, and the mixture stirred at 110° C. for 24 hours. The mixture was poured into 2 liters of water, and the resulting precipitate filtered to afford a light green solid. Recrystallization from dimethylformamide gave the title compound as green needles, mo 249°-251° C.