Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[F:2][C@@:3]12[C@:16]3([CH3:17])[C:11](=[CH:12][C:13](=[O:18])[CH:14]=[CH:15]3)[C@@H:10]([F:19])[CH2:9][C@H:8]1[C@@H:7]1[CH2:20][C@@H:21]3[C@:25]([C:26](=[O:32])[CH2:27][O:28][C:29](=[O:31])[CH3:30])([C@@:6]1([CH3:33])[CH2:5][C@@H:4]2[OH:34])[CH2:24][NH:23][CH2:22]3.FC(F)(F)S(O[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=1[Si](C)(C)C)(=O)=O.[F-].[Cs+]>C(#N)C.O>[F:2][C@@:3]12[C@:16]3([CH3:17])[C:11](=[CH:12][C:13](=[O:18])[CH:14]=[CH:15]3)[C@@H:10]([F:19])[CH2:9][C@H:8]1[C@@H:7]1[CH2:20][C@@H:21]3[C@:25]([C:26](=[O:32])[CH2:27][O:28][C:29](=[O:31])[CH3:30])([C@@:6]1([CH3:33])[CH2:5][C@@H:4]2[OH:34])[CH2:24][N:23]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[CH2:22]3
Reactant: CC(=O)OCC(=O)[C@@]12CNC[C@@H]1C[C@H]1[C@@H]3C[C@H](F)C4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@@]12C
Reactant: C[Si](C)(C)c1ccccc1OS(=O)(=O)C(F)(F)F
Agent: Cl
Agent: [Cs+]
Agent: [F-]
Solvent: CC#N
Solvent: O
Product: CC(=O)OCC(=O)[C@@]12CN(c3ccccc3)C[C@@H]1C[C@H]1[C@@H]3C[C@H](F)C4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@@]12C
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 30.3 %

Procedure:
In a nitrogen atmosphere compound 20 (150 mg, 0.300 mmol) is suspended in Acetonitrile (4 ml). 2-(trimethylsilyl)phenyl trifluoromethanesulfonate (0.146 ml, 0.600 mmol) and CsF (182 mg, 1.200 mmol) are added and the mixture is stirred for 45 minutes at RT. Additional CsF (137 mg, 0.900 mmol) (not dried) is added and the mixture is stirred for 5 hours then it is poured in water. Acetonitrile is evaporated and the reaction mixture is partitioned between water and AcOEt. The organic layer is separated dried over Na2SO4 and concentrated. The crude is purified by silica gel flash chromatography (eluent DCM/MeOH 98/2) affording the title compound (49 mg, 0.091 mmol, 30.3% yield).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([N:13]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)N=CC)=[N:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.[OH:25][CH2:26][CH2:27][CH2:28][C:29](=O)[CH3:30]>C(O)C>[Cl:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([N:13]3[C:17]4[C:22](=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=4)[C:28]([CH2:27][CH2:26][OH:25])=[C:29]3[CH3:30])=[N:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1
Reactant: CC=NN(c1ccc(OC)cc1)c1ncnc2cc(Cl)ccc12
Reactant: CC(=O)CCCO
Agent: Cl
Solvent: CCO
Product: COc1ccc2c(c1)c(CCO)c(C)n2-c1ncnc2cc(Cl)ccc12

Procedure:
A solution of acetaldehyde N1 -(7-chloroquinazolin-4-yl)p-methoxyphenylhydrazone hydrochloride (3.2g.) and 5-hydroxy-pentane-2-one (1.1g.) in ethanol (60ml.) was refluxed for 18 hours. The mixture was cooled and filtered and the filtrate evaporated in vacuo. The residue was chromatographed on silica gel (100g.) using, as eluant, petroleum ether (b.p. 40° -60° C.) containing an increasing proportion of ether (polarity increased by incremental addition of 10% v/v ether) to give 1-(7-chloroquinazolin-4-yl)-3-(2-hydroxyethyl)-5-methoxy-2-methylindole, m.p. 148°-150° C.
Reaction SMILES: COC1C=CC(C(C2SC=NN=2)[N:10]2[C:18]3[C:13](=[N:14][CH2:15][NH:16][CH:17]=3)[CH:12]=[C:11]2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[F:25])=C(C(F)(F)F)C=1.FC1C=CC=CC=1C1NC2C=NC=NC=2C=1.[F:51][C:52]([F:75])([F:74])[C:53]1[CH:58]=[C:57]([C:59]([F:62])([F:61])[F:60])[CH:56]=[CH:55][C:54]=1[C:63]1[S:67][C:66]([CH2:68]OS(C)(=O)=O)=[N:65][N:64]=1>>[F:75][C:52]([F:51])([F:74])[C:53]1[CH:58]=[C:57]([C:59]([F:62])([F:60])[F:61])[CH:56]=[CH:55][C:54]=1[C:63]1[S:67][C:66]([CH2:68][N:16]2[CH:17]=[C:18]3[N:10]=[C:11]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[F:25])[CH:12]=[C:13]3[N:14]=[CH:15]2)=[N:65][N:64]=1
Reactant: CS(=O)(=O)OCc1nnc(-c2ccc(C(F)(F)F)cc2C(F)(F)F)s1
Reactant: COc1ccc(C(c2nncs2)n2c(-c3ccccc3F)cc3c2=CNCN=3)c(C(F)(F)F)c1
Agent: Fc1ccccc1-c1cc2ncncc2[nH]1
Product: Fc1ccccc1-c1cc2ncn(Cc3nnc(-c4ccc(C(F)(F)F)cc4C(F)(F)F)s3)cc-2n1
Yield: 5 %

Procedure:
Prepared analogously to the method described for 3-[5[(4-methoxy-2-trifluoromethyl-phenyl)-[1,3,4]thiadiazol-2-ylmethyl]-6-(2-fluorophenyl)-3H-pyrrolo[3,2-d]pyrimidine beginning with 6-(2-fluorophenyl)-5H-pyrrolo[3,2-d]pyrimidine (200 mg, 0.93 mmol) and methanesulfonic acid [5-(2,4-bis-trifluoromethylphenyl)-[1,3,4]thiadiazol-2-yl]-methanyl ester (568 mg, 1.40 mmol) which produced 9 mg (5%) of the title compound. LCMS calculated for C23H12F7N5S: 523.4, found 524.01 (M+H)+.
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[C:16]([CH2:20][NH2:21])=[CH:15][CH:14]=[CH:13]3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:22](Cl)(=[O:24])[CH3:23]>N1C=CC=CC=1>[C:1]1([S:7]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[C:16]([CH2:20][NH:21][C:22](=[O:24])[CH3:23])=[CH:15][CH:14]=[CH:13]3)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NCc1cccc2cc(S(=O)(=O)c3ccccc3)ccc12
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Product: CC(=O)NCc1cccc2cc(S(=O)(=O)c3ccccc3)ccc12
Temperature: 25 °C

Procedure:
C-(6-Benzenesulfonyl-naphthalen-1-yl)-methylamine is dissolved in pyridine and acetyl chloride is added. The reaction mixture is stirred at room temperature and then quenched by addition of water. The mixture is extracted with EtOAc, and the organic layer is dried (MgSO4), filtered, and concentrated under reduced pressure to give N-(6-benzenesulfonyl-naphthalen-1-ylmethyl)-acetamide.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]([C:12]1[S:13][C:14]2[CH:21]=[CH:20][C:19]([NH:22]N)=[CH:18][C:15]=2[C:16]=1[CH3:17])=[O:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.O.Cl.[NH:26]1[CH2:31][CH2:30][C:29](=O)[CH2:28][CH2:27]1>C(O)(C)C>[CH2:2]([O:9][C:10]([C:12]1[S:13][C:14]2[C:15](=[C:18]3[C:19](=[CH:20][CH:21]=2)[NH:22][C:29]2[CH2:30][CH2:31][NH:26][CH2:27][C:28]3=2)[C:16]=1[CH3:17])=[O:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=C1CCNCC1
Reactant: Cc1c(C(=O)OCc2ccccc2)sc2ccc(NN)cc12
Agent: Cl
Solvent: CC(C)O
Solvent: O
Product: Cc1c(C(=O)OCc2ccccc2)sc2ccc3[nH]c4c(c3c12)CNCC4

Procedure:
1 g of 5-hydrazino-3-methylbenzothiophene-2-carboxylic acid benzyl ester hydrochloride and 1 g of 4-piperidone hydrochloride monohydrate are boiled in 50 ml of isopropanol under N2 for 10 hours. The solvent is then evaporated off, the residue is suspended in water and the aqueous suspension is rendered alkaline with KHCO3 and extracted with ethyl acetate; the extract is washed, dried and evaporated and the residue is recrystallised from isopropanol. Melting point 178° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][C:8](=O)[CH2:7][CH2:6]2.C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([N:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1)[CH2:7][CH2:6]2
Reactant: COc1ccc2c(c1)CCC(=O)C2
Reactant: C1CCNC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: COc1ccc2c(c1)CCC(N1CCCC1)=C2

Procedure:
12.0 g of 6-methoxy-2-tetralone were boiled at reflux for 2 hours in 200 ml of benzene and 5.6 ml of pyrrolidine, in the presence of 0.5 g of anhydrous p-toluenesulphonic acid. The toluene was removed in vacuo. 9.70 g of acrylamide and 0.5 g of p-toluenesulphonic acid were added to the thus-obtained crude 1-(6-methoxy-3,4-dihydro-2-naphthyl)pyrrolidine. The mixture was heated under nitrogen to 100° for 2 hours and to 150° for 2 hours. The reaction mixture was partitioned between 400 ml of chloroform and 40 ml of water. The organic phase was washed with 2×40 ml of water and the aqueous phases were extracted with 1×100 ml of chloroform. The chloroform phases were combined, dried over sodium sulphate and concentrated. The residue was chromatographed on 160 g of silica gel (particle size 0.2-0.5 mm). The 8-methoxy-1,4,5,8-tetrahydrobenzo[f]quinolin-3(2H)-one, eluted with methylene chloride and recrystallized from ethyl acetate, exhibits a melting point of 208°-209°.
Reaction SMILES: [OH:1][C:2]1[C:15]2[C:6](=[N:7][C:8]3[C:13]([CH:14]=2)=[CH:12][C:11]([C:16]#[N:17])=[CH:10][CH:9]=3)[CH:5]=[C:4]([S:18]([CH3:20])=[O:19])[CH:3]=1.C(N(CC)CC)C.O1CCCC1.[P:33](=[O:49])(Cl)([S:44][CH2:45][CH2:46][CH3:47])[O:34][C:35]1[C:40]([Cl:41])=[CH:39][C:38]([Cl:42])=[CH:37][C:36]=1[CH3:43]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[P:33](=[O:49])([S:44][CH2:45][CH2:46][CH3:47])([O:1][C:2]1[C:15]2[C:6](=[N:7][C:8]3[C:13]([CH:14]=2)=[CH:12][C:11]([C:16]#[N:17])=[CH:10][CH:9]=3)[CH:5]=[C:4]([S:18]([CH3:20])=[O:19])[CH:3]=1)[O:34][C:35]1[C:40]([Cl:41])=[CH:39][C:38]([Cl:42])=[CH:37][C:36]=1[CH3:43]
Reactant: CCCSP(=O)(Cl)Oc1c(C)cc(Cl)cc1Cl
Reactant: CS(=O)c1cc(O)c2cc3cc(C#N)ccc3nc2c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCCSP(=O)(Oc1c(C)cc(Cl)cc1Cl)Oc1cc(S(C)=O)cc2nc3ccc(C#N)cc3cc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1-Hydroxy-3-methylsulfinyl-7-cyanoacridine (0.01 mole), triethylamine (0.01 mole), tetrahydrofuran (25 ml) and toluene (25 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer and thermometer. The mixture is cooled to a temperature of about 0° C. and O-(2-methyl-4,6-dichlorophenyl) S-propyl phosphorochloridothioate (0.01 mole) dissolved in toluene (25 ml) is added with stirring over a period of about 30 minutes. After the addition is completed the reaction mixture is allowed to warm to room temperature and stirring is continued for a period of about 16 hours. After this time the reaction mixture is filtered to remove triethylamine hydrochloride. The filtrate is then washed with water, dried over anhydrous magnesium sulfate and stripped of solvents leaving a residue. This residue is subjected to flash chromatography using ethyl acetate as the eluant to yield the desired product O-(2-methyl-4,6-dichlorophenyl) O-(3-methylsulfinyl-7-cyanoacridin-1-yl) S-propyl phosphorothioate.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([OH:12])[CH:8]=[C:7]2[OH:13].[N+:14]([O-])([OH:16])=[O:15]>>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([OH:12])[C:8]([N+:14]([O-:16])=[O:15])=[C:7]2[OH:13]
Reactant: O=[N+]([O-])O
Reactant: Oc1cc(O)c2cccc(Br)c2n1
Product: O=[N+]([O-])c1c(O)nc2c(Br)cccc2c1O
Temperature: 100 °C
Yield: 63.9 %

Procedure:
A modification of the method described in Part D of Example 10 was used to treat 8-bromoquinoline-2,4-diol (10.0 g, 41.6 mmol) with nitric acid (3.6 mL of 11.74 M, 54 mmol). The nitric acid was added at ambient temperature, and then the reaction was heated at 100° C. for one hour, at which time an exotherm occurred. The reaction was allowed to cool to ambient temperature; a precipitate formed and was isolated by filtration and washed with a small volume of water to provide 7.58 g of 8-bromo-3-nitroquinoline-2,4-diol as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH:30]=[CH:29][C:5]([C:6]([C:8]2[CH:16]=[C:15]([C:17]([OH:19])=[O:18])[C:14]([C:20](=O)[C:21]3[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=3)=[CH:13][C:9]=2[C:10]([OH:12])=[O:11])=O)=[CH:4][CH:3]=1.[H][H]>[Pd].C(O)(=O)C>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:8]2[CH:16]=[C:15]([C:17]([OH:19])=[O:18])[C:14]([CH2:20][C:21]3[CH:22]=[CH:23][C:24]([CH3:27])=[CH:25][CH:26]=3)=[CH:13][C:9]=2[C:10]([OH:12])=[O:11])=[CH:29][CH:30]=1
Reactant: [H][H]
Reactant: Cc1ccc(C(=O)c2cc(C(=O)O)c(C(=O)c3ccc(C)cc3)cc2C(=O)O)cc1
Agent: [Pd]
Solvent: CC(=O)O
Product: Cc1ccc(Cc2cc(C(=O)O)c(Cc3ccc(C)cc3)cc2C(=O)O)cc1

Procedure:
A mixture of 30.0 grams of 2,5-bis(4-methylbenzoyl)terephthalic acid, 500 mL of acetic acid, and 3 grams of 5% palladium on activated carbon (as a catalyst) was heated to 64° C. for 17 hours in an atmosphere of hydrogen at 270 kPa. The mixture was filtered to remove the catalyst and the product. The catalyst and the product were slurried in 500 mL of tetrahhydrofuran and filtered through Celite™ diatomaceous earth filter agent. The resulting filtrate was concentrated in vacuo. The resulting wet solid was slurried in ethyl acetate and collected by filtration and dried to give 2,5-bis(4-methylbenzyl)terephthalic acid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[CH:7]=[C:8]([Cl:10])[CH:9]=1)=[O:4].[CH3:19][O:20][C:21](=[O:26])[CH2:22][C:23](Cl)=[O:24]>>[CH3:1][O:2][C:3]([C:5]1[N:6]([N:11]([C:23](=[O:24])[CH2:22][C:21]([O:20][CH3:19])=[O:26])[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[CH:7]=[C:8]([Cl:10])[CH:9]=1)=[O:4]
Reactant: COC(=O)CC(=O)Cl
Reactant: COC(=O)c1cc(Cl)cn1NCc1ccccn1
Product: COC(=O)CC(=O)N(Cc1ccccn1)n1cc(Cl)cc1C(=O)OC

Procedure:
Prepared according to the acylation condition used in Example 2 step f) from 4-chloro-1-[(pyridin-2-ylmethyl)-amino]-1H-pyrrole-2-carboxylic acid methyl ester and chlorocarbonyl-acetic acid methyl ester (1.5 eq.). 1H NMR (CDCl3, δ in ppm): 8.5 (m, 1H), 7.68 (m, 1H), 7.39 (m, 1H), 721 (m, 1H), 6.85 (d, 1H, J=1.6 Hz), 6.80 (d, 1H, J=1.6 Hz), 5.48 (d, 1H, J=15.4 Hz), 4.46 (d, 1H, J=15.4 Hz), 3.79 (s, 3H), 3.69 (s, 3H), 3.19 (s, 2H).
Reaction SMILES: [ClH:1].[N+:2]([C:5]1[CH:14]=[C:13]2[C:8]([CH2:9][CH2:10][NH:11][CH2:12]2)=[CH:7][CH:6]=1)([O-])=O.Cl.O.[OH-].[Na+]>CCO.O=[Pt]=O>[ClH:1].[ClH:1].[NH2:2][C:5]1[CH:14]=[C:13]2[C:8]([CH2:9][CH2:10][NH:11][CH2:12]2)=[CH:7][CH:6]=1
Reactant: O=[N+]([O-])c1ccc2c(c1)CNCC2
Agent: O=[Pt]=O
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Nc1ccc2c(c1)CNCC2
Yield: 92.2 %

Procedure:
7-Nitro-1,2,3,4-tetrahydroisoquinoline hydrochloride (2) from Example 1, is placed in a Parr shaker bottle (15.0 g, 69.9 mmol) dissolved in 95% EtOH (100 mL), and to the Parr shaker bottle is added concentrated HCl (10 mL), water (25 mL), and PtO2 (0.5 g). The mixture is hydrogenated at 50 psi until no further drop in pressure was observed (about 4 hours). The yellowish suspension is filtered through Celite and evaporated to dryness to afford a yellowish solid which is made basic with 10% NaOH solution (adequate care is exercised in catalyst disposal). Extraction of the basic solution with CHCl3 (three times), followed by drying over anhydrous Na2SO4 and evaporation of the solvent, yields a reddish yellow solid (9.54 g, 92.2%): mp=110-112. 7-Amino-1,2,3,4-tetrahydroisoquinoline dihydrochloride (3) is recrystallized from aqueous MeOH as buff colored needles, mp=290° C.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:11])[C@@H:5]1[CH2:9][C@@H:8]([OH:10])[CH2:7][NH:6]1.C(N(CC)CC)C.[C:19]([O:23][C:24](SC1N=C(C)C=C(C)N=1)=[O:25])([CH3:22])([CH3:21])[CH3:20]>O1CCOCC1>[CH3:2][O:3][C:4](=[O:11])[C@@H:5]1[CH2:9][C@@H:8]([OH:10])[CH2:7][N:6]1[C:24]([O:23][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:25]
Reactant: Cc1cc(C)nc(SC(=O)OC(C)(C)C)n1
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 84.3 %

Procedure:
To an aqueous solution (40 ml) of L-hydroxyproline methyl ester hydrochloride (8.2 g, 45.2 mmol), triethylamine (7.54 ml, 54.2 mmol) was added at room temperature, and then a solution of 2-(tert-butoxycarbonylthio)-4,6-dimethylpyrimidine (10.8 g, 45 mmol) in dioxane (80 ml) was added thereto. The reaction solution was stirred at room temperature for 1.5 hours, and then dioxane was distilled off under reduced pressure. The residue was extracted with ethyl acetate (250 ml). The organic layer was washed sequentially with a 0.1 N sodium hydroxide aqueous solution, dilute hydrochloric acid, water and a saturated sodium chloride aqueous solution and then dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (Wakogel™ C-300, 5% methanol-methylene chloride) to obtain N-tert-butoxycarbonyl-L-hydroxyproline methyl ester (9.3 g, yield: 84%).
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][C:8]2[NH:7][C:6]3[N:11]=[CH:12][C:13]([C:15]4[CH:20]=[CH:19][C:18]([CH2:21][N:22]5[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]5)=[CH:17][CH:16]=4)=[CH:14][C:5]=3[C:4]=2[CH:3]=1.[NH2:28][C:29]1[N:34]=[CH:33][C:32](B(O)O)=[CH:31][N:30]=1.ClCCl>C(#N)C.C(=O)([O-])[O-].[K+].[K+]>[NH2:28][C:29]1[N:34]=[CH:33][C:32]([C:2]2[N:10]=[CH:9][C:8]3[NH:7][C:6]4[N:11]=[CH:12][C:13]([C:15]5[CH:20]=[CH:19][C:18]([CH2:21][N:22]6[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]6)=[CH:17][CH:16]=5)=[CH:14][C:5]=4[C:4]=3[CH:3]=2)=[CH:31][N:30]=1
Reactant: Clc1cc2c(cn1)[nH]c1ncc(-c3ccc(CN4CCCCC4)cc3)cc12
Reactant: Nc1ncc(B(O)O)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: ClCCl
Product: Nc1ncc(-c2cc3c(cn2)[nH]c2ncc(-c4ccc(CN5CCCCC5)cc4)cc23)cn1
Temperature: 140 °C
Yield: 14 %

Procedure:
A degassed mixture of 6-chloro-3-(4-piperidin-1-ylmethylphenyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole (74.4 mg, 0.197 mmol), 2-aminopyrimidine-5-boronic acid, pinacol ester (45.8 mg, 0.207 mmol), and [1,1′-bis(diphenylphosphino)ferrocene] dichloropalladium(II) complex with dichloromethane (1:1) (8.1 mg, 9.87 umol, 5.0 mol %) in acetonitrile (0.74 mL) and 1M aqueous potassium carbonate solution (0.74 mL) was heated under microwave irradiation (140° C.) for 30 minutes. Further portions of the boronate ester (1.0 eq) and catalyst (5 mol %), acetonitrile (0.74 mL), and 1M aqueous potassium carbonate solution (0.74 mL) were added and the mixture heated under microwave irradiation (140° C.) for an additional 30 minutes. The mixture was concentrated in vacuo and the residue dissolved in water and DMF, and acidified with 10% (v/v) sulfuric acid. The resultant solid was removed by filtration and the filtrate concentrated in vacuo. The resultant residue was dissolved in DMSO and purified by preparative HPLC [0-30% MeCN/water modified with 0.1% formic acid] to afford an orange fluffy solid (5.1 mg, 14%). LCMS (Method E): RT=5.45 min, M+H+=436.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.S(Cl)(Cl)=O.[F:17][C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1[NH2:25]>O1CCCC1>[F:17][C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1[NH:25][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][C:9]([O:11][CH3:12])=[CH:10][C:2]=1[OH:1]
Reactant: Nc1ccc(F)cc1F
Reactant: COc1ccc(C(=O)O)c(O)c1
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: COc1ccc(C(=O)Nc2ccc(F)cc2F)c(O)c1

Procedure:
To a solution of 2-hydroxy-4-methoxybenzoic acid (1.68 g, 10 mmole) in tetrahydrofuran (40 mL) was added thionyl chloride (2.5 mL, 35 mmole) and refluxed 3 hr. The mixture was steamed (110° C.) by Dean-Stark. The residue was directly reacted with 2,4-difluorobenzenamine (1 mL, 10 mmole) in THF (40 mL) for 14 hr. The reaction mixture was concentrated and extracted with ethyl acetate, dried over anhydrous magnesium sulfate. Recrystallization of desired products from hot dichloromethane afforded the compound.
Reaction SMILES: NC1N(C(OC(C)(C)C)=O)N=C(C2C=CC(O)=CC=2)C=1C#N.C([O:30][C:31]1[CH:42]=[CH:41][C:34]([O:35][CH2:36][CH2:37][N:38]([CH3:40])[CH3:39])=[CH:33][CH:32]=1)C1C=CC=CC=1>>[CH3:39][N:38]([CH3:40])[CH2:37][CH2:36][O:35][C:34]1[CH:41]=[CH:42][C:31]([OH:30])=[CH:32][CH:33]=1
Reactant: CN(C)CCOc1ccc(OCc2ccccc2)cc1
Agent: CC(C)(C)OC(=O)n1nc(-c2ccc(O)cc2)c(C#N)c1N
Product: CN(C)CCOc1ccc(O)cc1

Procedure:
Compound 75B was prepared in a similar manner to the synthesis of compound 31F by substituting compound 31E with compound 75A: 1H NMR (DMSO-d6): δ 8.86 (s, 1H), 6.72-6.76 (m, 2H), 6.64-6.68 (m, 2H), 3.92 (d, J=5.83 Hz, 2H), 2.56 (d, J=5.83 Hz, 2H), 2.19 (s, 6H). ESI (+)/MS: 182 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]#[CH:6].N1C=CN=C1.[Si:12](Cl)([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13].Cl(O)(=O)(=O)=O>CN(C)C=O>[Si:12]([O:1][CH2:2][CH2:3][CH2:4][C:5]#[CH:6])([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13]
Reactant: C#CCCCO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: [O-][Cl+3]([O-])([O-])O
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: C#CCCCO[Si](C)(C)C(C)(C)C
Temperature: 2 °C

Procedure:
A mixture of 186 ml of dimethylformamide, 93.5 g of 5-hydroxy-1-pentyne and 185.5 g of imidazole at room temperature (20-30° C.) is added with 185.5 g of t-butyldimethylsilyl chloride, in portions and under stirring, keeping this temperature with cooling bath. The resulting pale-yellow, dense suspension is cooled to 2° C., kept under stirring and monitored by TLC (eluent 7/3 diethyl ether/petroleum ether, developer: hot perchloric acid; Rf of the starting product=0.33, Rf of the final product=0.95); the reaction is complete after two hours. The reaction mixture is slowly added with 375 ml of water and 150 ml of toluene, and stirring is continued for 10 minutes, controlling the temperature with cooling bath. The organic phase is separated, the aqueous one is extracted with 100 ml of toluene, then combined organic phases are filtered under reduced pressure through Celite, washing the cake with 50 ml of toluene. The solution is concentrated under reduced pressure to obtain a pale-yellow oily residue which is distilled at a temperature-ranging from 23 to 34° C. at about 13 mbars and subsequently at 7.5 mbars at a temperature ranging from 35 to 60° C. The two resulting fractions are discarded. Continuing the distillation at 7.5 mbars, the fractions which distil above 60° C. are collected. The first fraction, which distils between 60 and 75° C. (89 g) is in turn discarded whereas the second one, which distils at 75° C., consists of 101 g of 5-(t-butyldimethylsilyloxy)pent-1-yne identical to the product of preparation I.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N+:16]([O-])=O)[C:5]([NH:8][C:9]2[CH:10]=[C:11]([CH3:15])[CH:12]=[CH:13][CH:14]=2)=[N:6][CH:7]=1>[Pd].C(O)C.C1COCC1>[CH3:1][C:2]1[CH:3]=[C:4]([NH2:16])[C:5]([NH:8][C:9]2[CH:10]=[C:11]([CH3:15])[CH:12]=[CH:13][CH:14]=2)=[N:6][CH:7]=1
Reactant: Cc1cccc(Nc2ncc(C)cc2[N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1cccc(Nc2ncc(C)cc2N)c1
Reaction time: 8 h

Procedure:
Palladium on carbon (10%, 1.55 g, 1.456 mmol) was added to a Parr Hydrogenator bottle. The bottle was purged with nitrogen. Then, 5-methyl-3-nitro-N-(m-tolyl)pyridin-2-amine (15.5 g, 63.7 mmol) in 90 mL of ethanol and 90 mL of THF was added. The material was hydrogenated overnight on a Parr Hydrogenator. The mixture was filtered through Celite® to remove the palladium on carbon. The Celite® pad was washed with dichloromethane and evaporated to a solid (13.5 g, 99%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([N:8]2[CH2:14][CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([N:8]2[CH2:14][CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCCN(c2ccc(Cl)nc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Clc1ccc(N2CCCNCC2)cn1

Procedure:
A mixture of 1-(6-chloro-3-pyridyl)-4-tert-butoxycarbonyl homopiperazine (1.7 g, 5.5 mmol), trifluoro acetic acid (4.5 ml, 55 mmol) and dichloromethane at room temperature for 1 h. The mixture was evaporated. Chromatography on silica gel with a mixture of petroleum:ethyl acetate (1:1) gave the title compound as free base. The corresponding salt was obtained by addition of a diethyl ether and methanol mixture (9:1) saturated with fumaric acid. Mp 165-167° C. Yield 0.72 g, 40%.