Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15]3[CH:14]=[CH:13][N:12]=[CH:11][C:10]=3[C:9](=[O:16])[O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C2(C3C=CC=CC=3)C3CNCCC=3C(=O)O2)C=CC=CC=1>>[C:17]1([C:7]2([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:15]3[CH2:14][CH2:13][NH:12][CH2:11][C:10]=3[C:9](=[O:16])[O:8]2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=C1OC(c2ccccc2)(c2ccccc2)c2ccncc21
Agent: O=C1OC(c2ccccc2)(c2ccccc2)C2=C1CCNC2
Product: O=C1OC(c2ccccc2)(c2ccccc2)C2=C1CNCC2

Procedure:
The title compound was synthesized in a manner analogous to R06039-222 except 3-diisopropylamidopyridine was coupled to benzophenone to provide intermediate 1,1-diphenylfuro[3,4-c]pyridin-3-one. 1,1-diphenylfuro[3,4-c]pyridin-3-one was reduced in a manner analogous to 3,3-diphenyl-4,5,6,7-tetrahydrofuro[3,4-c]pyridin-1(3H)-one (compound 2) to afford 1,1-diphenyl-4,5,6,7-tetrahydrofuro[3,4-c]pyridin-3-one. Benzyl isocyanate (0.023 g, 0.17 mmol) was then added to a solution of 1,1-diphenyl-4,5,6,7-tetrahydrofuro[3,4-c]pyridin-3-one (0.05 g, 0.17 mmol) in dichloromethane (10 mL) and was stirred at room temperature for 1 h. The solvent was removed and the resulting residue was purified on silica to give the desired product (0.038 g, 50%). 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 3.66-3.70 (dd, 2H, J=6 Hz), 4.10-4.15 (m, 2H), 4.34-4.42 (dd, 2H, J=6 Hz), 5.09 (t, 1H, J=6 Hz), 7.20-7.38 (m, 15H).
Reaction SMILES: [CH2:1]=[O:2].[C:3]1([SH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:10]1([OH:16])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C([O-])(=O)C.[Zn+2].C([O-])(=O)C>[C:3]1([S:9][CH2:1][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[OH:16])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:1]=[O:2]
Reactant: Sc1ccccc1
Reactant: Oc1ccccc1
Agent: C=O
Agent: CC(=O)[O-]
Agent: [Zn+2]
Product: Oc1ccccc1CSc1ccccc1
Reaction time: 7.5 h

Procedure:
4.5.10-3 mole of zinc acetate, in the form of an approximately 20% strength aqueous solution, 30 g of 96% pure paraformaldehyde ( 0.96 mole of CH2O) and 113.6 g of 97% pure thiophenol (1 mole) were added to 564 g (6 moles) of phenol at about 70° C. The mixture was then heated to the reflux temperature in the course of about 30 minutes and kept under these conditions for 7.5 hours (temperature of the mixture 154° to 132° C.). After this time, gas chromatography analysis gave a yield of 2-phenylthiomethylphenol of 81% of theory (relative to formaldehyde) and a ratio of 2- to 4-phenylthiomethylphenol of more than 99:1. The 2-phenylthiomethylphenol obtained on subsequent distillation at 140°-150° C./0.6-0.9 mm Hg was 98% pure.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([S:10]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[C:16]([NH:21][C:22]3[C:27]([C:28]4[N:36]=[CH:35][N:34]=[C:33]5[C:29]=4[N:30]=[CH:31][N:32]5C4CCCCO4)=[CH:26][CH:25]=[CH:24][N:23]=3)[C:15]=2[F:43])(=[O:12])=[O:11])[CH:6]=[CH:7][C:8]=1[F:9]>>[N:36]1[C:28]([C:27]2[C:22]([NH:21][C:16]3[C:15]([F:43])=[C:14]([NH:13][S:10]([C:5]4[CH:6]=[CH:7][C:8]([F:9])=[C:3]([Cl:2])[CH:4]=4)(=[O:12])=[O:11])[CH:19]=[CH:18][C:17]=3[F:20])=[N:23][CH:24]=[CH:25][CH:26]=2)=[C:29]2[C:33]([NH:32][CH:31]=[N:30]2)=[N:34][CH:35]=1
Reactant: O=S(=O)(Nc1ccc(F)c(Nc2ncccc2-c2ncnc3c2ncn3C2CCCCO2)c1F)c1ccc(F)c(Cl)c1
Agent: Cl
Product: O=S(=O)(Nc1ccc(F)c(Nc2ncccc2-c2ncnc3[nH]cnc23)c1F)c1ccc(F)c(Cl)c1
Reaction time: 2 h

Procedure:
1M aqueous hydrochloric acid solution was added into the 3-chloro-N-(2,4-difluoro-3-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-ylamino)phenyl)-4-fluorobenzenesulfonamide (20 mg, 0.032 mmol) prepared at Step 10 and stirred for 2 hours. After the reaction, the reactant was washed with an aqueous solution of sodium hydrogen carbonate and salt water. After extraction with ethylacetate, the organic layer was dried with sulfuric anhydride magnesium and vacuum concentrated, and then refined by means of column chromatography, so that the target compound was obtained.
Reaction SMILES: [C:1]([CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:4])[CH2:2][CH3:3].OCC[C:14]#[N:15]>CCO>[O:4]=[C:1]([CH2:2][CH3:3])[CH2:5][C:6]([O:8][CH2:9][CH2:10][C:14]#[N:15])=[O:7]
Reactant: N#CCCO
Reactant: CCOC(=O)CC(=O)CC
Solvent: CCO
Product: CCC(=O)CC(=O)OCCC#N
Yield: 62.5 %

Procedure:
A solution of ethyl propionylacetate (50 g, 0.35 mol, 1.0 equiv) and 3-hydroxypropionitrile (35 mL, 0.52 mol, 1.5 equiv) was heated at 190-210° C. while EtOH (19 mL) was collected by distillation. The residue was distilled in vacuo to afford 37 g (63%) of yellow oil (b.p. 120-125° C./0.4 mm Hg), which was characterized spectroscopically.
Reaction SMILES: [NH2:1][C@H:2]([CH3:5])[CH2:3][OH:4].[CH:6](=O)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[BH4-].[Na+].Cl>C1(C)C=CC=CC=1.O1CCOCC1.O>[C:7]1([CH2:6][NH:1][C@H:2]([CH3:5])[CH2:3][OH:4])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: C[C@@H](N)CO
Reactant: O=Cc1ccccc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: C[C@H](CO)NCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
To (2R)-2-amino-1-propanol (4.5 g, 60 mmol) in toluene (120 mL) was added benzaldehyde (636 mL). A Dean-Stark trap was placed on the flask, and the reaction mixture was heated to reflux until no further water evolved. The reaction was cooled down to room temperature and concentrated. The resulting residue was dissolved in ethanol (120 mL), and treated with NaBH4 (5.67 g, 150 mmol) at 0° C. followed by sufficient 4N HCl in dioxane to adjust the pH to 2. The reaction mixture was stirred overnight at room temperature, and then concentrated in vacuo. The resulting residue was dissolved in 1N aq. HCl (200 mL) and washed with CH2Cl2 (2×100 mL). The aqueous phase was then adjusted to pH>13 with 6N aqueous NaOH and extracted with CH2Cl2 (2×150 mL). The combined organic phase was dried over anhydrous Na2SO4, filtered, and concentrated to afford the title compound (9.44 g, 95%) as a colorless oil which solidified under high vacuum. LC-MS (ES) m/z=166.2 [M+H]+
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:13])[C:11]=1F)[N:8]([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)[CH:7]=[C:6]([C:21]([OH:23])=[O:22])[C:5]2=[O:24].[NH:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1>N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:13])[C:11]=1[N:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1)[N:8]([C:14]1[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=1)[CH:7]=[C:6]([C:21]([OH:23])=[O:22])[C:5]2=[O:24]
Reactant: C1CCNC1
Reactant: O=C(O)c1cn(-c2ccc(F)cc2)c2c(F)c(F)c(F)cc2c1=O
Solvent: c1ccncc1
Product: O=C(O)c1cn(-c2ccc(F)cc2)c2c(F)c(N3CCCC3)c(F)cc2c1=O

Procedure:
3.37 g of 6,7,8-trifluoro-1,4-dihydro-4-oxo-1-(4-fluorophenyl)-quinoline-3-carboxylic acid are refluxed with 2.3 g of pyrrolidine in 30 ml of absolute pyridine for 6 hours. The solvent is distilled off in vacuo, the residue is suspended in 50 ml of ice-water, the pH is brought to 1-2 with hydrochloric acid and the precipitate is filtered off with suction, washed with water and dried. 2.5 g of (I) ##STR41## of melting point 282°-284° C. are obtained. Recrystallization from glycol monomethyl ether/ethanol.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:16](=[O:22])[CH2:17][S:18]([CH3:21])(=[O:20])=[O:19])[CH:6]=[C:7]([O:14][CH3:15])[C:8]=1[N:9]1[CH:13]=[CH:12][CH:11]=[CH:10]1.C(O)C.[BH4-].[Na+].[OH-].[Na+]>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[C:7]([O:14][CH3:15])[C:8]=1[N:9]1[CH:13]=[CH:12][CH:11]=[CH:10]1)[CH:16]([OH:22])[CH2:17][S:18]([CH3:21])(=[O:20])=[O:19]
Reactant: COc1cc(C(=O)CS(C)(=O)=O)cc(OC)c1-n1cccc1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1cc(C(O)CS(C)(=O)=O)cc(OC)c1-n1cccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A suspension of 1.54 g. of 3',5'-dimethoxy-2-(methylsulfonyl)-4'-(pyrrol-1-yl)-acetophenone in 20 ml. of ethanol and 20 ml. of water was treated with a solution of 0.4 g. of sodium borohydride in 5 ml. of water with addition of 0.1 g. of sodium hydroxide. The mixture was stirred at room temperature for an additional 3 hours, cooled with ice, diluted with 50 ml. of water and filtered under vacuum. After recrystallization from ethanol, there was obtained 3,5-dimethoxy-α-[(methylsulfonyl)-methyl]-4-(pyrrol-1-yl)-benzyl alcohol having a melting point of 192° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:23]([O:24][CH3:25])=[CH:22][CH:21]=[CH:20][C:4]=1[C:5]([CH:7]1[CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9][CH2:8]1)=[O:6].Cl.[OH-].[Na+]>C1(C)C=CC=CC=1.O>[CH3:1][O:2][C:3]1[C:23]([O:24][CH3:25])=[CH:22][CH:21]=[CH:20][C:4]=1[C:5]([CH:7]1[CH2:8][CH2:9][NH:10][CH2:11][CH2:12]1)=[O:6]
Reactant: COc1cccc(C(=O)C2CCN(C(=O)OC(C)(C)C)CC2)c1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: COc1cccc(C(=O)C2CCNCC2)c1OC
Temperature: 60 °C
Yield: 65 %

Procedure:
To the reaction solution of 4-(2,3-dimethoxybenzoyl)-1-piperidinecarboxylic acid, 1,1-dimethylethyl ester (7) from Example 76, Scheme G, step c, is added about 188 kg of water and 37% hydrochloric acid (39 kg, 395 mol). The solution is heated to about 60° C. for about 18 hours1. The mixture is cooled to about 25° C. and about 47 kg of toluene is added. The phases are separated and the organic phase is discarded. To the aqueous phase is added about 78 kg water, 50 wt % sodium hydroxide solution (31 kg, 391 mol), and about 99 kg of toluene. The phases are separated and the aqueous phase is discarded. The organic phase is concentrated by vacuum distillation. The concentration of 4-(2,3-dimethoxybenzoyl)piperidine (16) in solution ranges from 17 to 53 wt %1, affording 14.6 to 17.9 kg of 4-(2,3-dimethoxybenzoyl)piperidine (16) (65-76% yield). 1The solution is sampled and analyzed by HPLC assay to confirm complete deprotection to afford 4-(2,3-dimethoxybenzoyl)piperidine (16). The reaction is complete if less than 5 area % of 4-(2,3-dimethoxybenzoyl)-1-piperidinecarboxylic acid, 1,1-dimethylethyl ester (7) is detected.
Reaction SMILES: [Li+].[OH-].OO.C([C@@H]1COC(=O)N1[C:18]([CH:20]1[CH2:22][CH:21]1[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([F:31])[CH:24]=1)=[O:19])C1C=CC=CC=1.[O-:32]S([O-])=O.[Na+].[Na+].Cl>O.C1COCC1.O>[F:31][C:25]1[CH:24]=[C:23]([CH:21]2[CH2:22][CH:20]2[C:18]([OH:19])=[O:32])[CH:28]=[CH:27][C:26]=1[O:29][CH3:30]
Reactant: COc1ccc(C2CC2C(=O)N2C(=O)OC[C@H]2Cc2ccccc2)cc1F
Reactant: O=S([O-])[O-]
Agent: Cl
Agent: OO
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(C2CC2C(=O)O)cc1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
After LiOH (0.059 g, 1.40 mmol) was dissolved in water (5 mL), H2O2 (0.3 mL, 3.52 mmol) was added thereto, and the mixture was stirred at room temperature for 30 minutes. The reactant was added to the solution of (R)-4-benzyl-3-[2-(3-fluoro-4-methoxy-phenyl)-cyclopropanecarbonyl]-oxazolidin-2-o n (0.325 g, 0.88 mmol) obtained in Step C of Preparation Example 62 in THF/H2O (17 mL/4.4 mL) at 0° C., and the mixture was stirred for 1 hour. After the termination of the reaction, Na2SO3 (1 g) dissolved in water (5 mL) was added thereto, and the mixture was stirred at 0° C. for 1 hour. 6N HCl was added thereto to adjust the pH to 2, and the reactant was extracted with ethyl acetate. The organic layer was separated, dried with anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain the title compound, which was used in the next step without a separate purification process
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:3]=1.[CH3:26][O:27][C:28]1[N:33]=[CH:32][C:31](B(O)O)=[CH:30][N:29]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.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>[CH3:26][O:27][C:28]1[N:33]=[CH:32][C:31]([C:2]2[N:11]=[C:10]([NH:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][C:8]=3[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:3]=2)=[CH:30][N:29]=1
Reactant: COc1ncc(B(O)O)cn1
Reactant: Clc1nc(NCc2ccccn2)c2c(-c3ccccc3)cccc2n1
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: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ncc(-c2nc(NCc3ccccn3)c3c(-c4ccccc4)cccc3n2)cn1
Temperature: 90 °C
Reaction time: 12 h
Yield: 56 %

Procedure:
To a solution of 2-chloro-5-phenyl-N-(pyridin-2-ylmethyl)quinazolin-4-amine (300 mg, 0.87 mmol) in DMF (20 mL) and H2O (2 mL) under nitrogen was added 2-methoxypyrimidin-5-ylboronic acid (199 mg, 1.30 mmol) and potassium carbonate (239 mg, 1.73 mmol). The resulting mixture was degassed with nitrogen for 15 min and then tetrakis(triphenylphosphine)palladium (100 mg, 0.086 mmol) was added. Upon completion of addition, the reaction mixture was again degassed with nitrogen for 10 min. After this time, the reaction mixture was heated to 90° C. where it stirred for 12 h. After this time, the reaction mixture was allowed to cool to room temperature and then quenched by the addition of water. The reaction mixture was extracted with ethyl acetate and the organic layer was washed successively with water and brine. The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting concentrate was purified by preparative HPLC to afford 2-(2-methoxypyrimidin-5-yl)-5-phenyl-N-(pyridin-2-ylmethyl)quinazolin-4-amine (205 mg) as an off-white solid. Preparative HPLC Conditions: Column: Sunfire C18 (250×19 mm), Mobile Phase A: 0.1% TFA in H2O, Mobile Phase B: CH3CN, Gradient: 0 to 40% B over 35 min, 100% B for 10 min., Flow Rate: 14 mL/min., Retention time: 28 min. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 9.50 (s, 2H), 8.27 (d, J=4.7 Hz, 1H), 7.92 (d, J=3.6 Hz, 2H), 7.85-7.81 (t, J=8.0 Hz, 1H), 7.60-7.52 (m, 5H), 7.42-7.38 (m, 2H), 7.34-7.31 (m, 1H), 4.83 (d, J=4.2 Hz, 2H), 4.04 (s, 3H). LCMS Method O: retention time 1.45 min, [M+1]=421.2. HPLC Method B: purity 98.7%, retention time 5.53 min.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](Cl)=[O:7].[C:12]([NH2:16])([CH3:15])([CH3:14])[CH3:13].C(N(C(C)C)C(C)C)C>ClCCl>[C:12]([NH:16][C:6](=[O:7])[C:5]1[CH:9]=[CH:10][CH:11]=[C:3]([CH2:2][Cl:1])[CH:4]=1)([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)N
Reactant: O=C(Cl)c1cccc(CCl)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)NC(=O)c1cccc(CCl)c1
Temperature: -15 °C
Reaction time: 0.17 h

Procedure:
3-(Chloromethyl)benzoyl chloride (2.26 ml, 15.9 mmol) was added to a stirred solution of dichloromethane (50 mL) at −30° C. (cold-bath temperature) under argon. After 10 minutes stirring, a solution of tert-butylamine (1.66 mL, 15.9 mmol) and N-ethyl-N-isopropylpropan-2-amine (5.53 mL, 31.7 mmol) in dichloromethane (5 mL) was added dropwise. Stirring was continued while allowing the cold-bath temperature to slowly increase to −15° C. over 45 minutes. The reaction mixture was concentrated under vacuum to give the intermediate N-tert-butyl-3-(chloromethyl)benzamide as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][C:15]2[O:14][C:13]3[C:8](=[CH:9][CH:10]=[C:11]([C:18]4[NH:22][N:21]=[N:20][N:19]=4)[CH:12]=3)[C:7](=[O:23])[C:6]=2[CH:5]=1)([O-])=O.[H][H]>C(=O)(O)[O-].[Na+].O.[Pd]>[NH2:1][C:4]1[CH:17]=[CH:16][C:15]2[O:14][C:13]3[C:8](=[CH:9][CH:10]=[C:11]([C:18]4[NH:22][N:21]=[N:20][N:19]=4)[CH:12]=3)[C:7](=[O:23])[C:6]=2[CH:5]=1
Reactant: [H][H]
Reactant: O=c1c2ccc(-c3nnn[nH]3)cc2oc2ccc([N+](=O)[O-])cc12
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: Nc1ccc2oc3cc(-c4nnn[nH]4)ccc3c(=O)c2c1
Reaction time: 4 h

Procedure:
The nitroxanthone from step (B) (1.55 g) was dissolved in a solution of sodium bicarbonate (0.42 g) in water (150 ml) with warming. To the solution was added 10% palladium on carbon catalyst and the solution hydrogenated at room temperature and atmospheric pressure for 4 hr, during which time hydrogen uptake was measured as 440 ml. The solution was filtered and the filtrate acidified with twice-normal hydrochloric acid solution. The amino-compound was filtered from the warmed mixture, washed well with water and dried to yield 0.98 g, mpt. 296°-297° C. with decomposition.
Reaction SMILES: N1C=CC=CC=1C1C=CC=CN=1.Cl[C:14]1[C:15]([C:23]([OH:25])=[O:24])=[N:16][C:17]([Cl:22])=[C:18]([Cl:21])[C:19]=1[Cl:20]>O.[Zn]>[Cl:20][C:19]1[C:18]([Cl:21])=[C:17]([Cl:22])[N:16]=[C:15]([C:23]([OH:25])=[O:24])[CH:14]=1
Reactant: O=C(O)c1nc(Cl)c(Cl)c(Cl)c1Cl
Agent: [Zn]
Agent: c1ccc(-c2ccccn2)nc1
Solvent: O
Product: O=C(O)c1cc(Cl)c(Cl)c(Cl)n1
Reaction time: 24 h
Yield: 34.5 %

Procedure:
A 25 mL scintillation vial was charged with NiCl2.6H2O (84.0 mg, 0.353 mmol) and 2,2′-bipyridine (104.1 mg, 0.667 mmol). The vial was sealed and purged with nitrogen for 20 min. The inert reactor was charged with DMF (4.5 mL) and water (0.5 mL). The resulting mixture was allowed to stir for 24 h, and then solid 3,4,5,6-tetrachloropicolinic acid (0.834 g, 3.2 mmol) and zinc powder (1.6679 g, 25.5 mmol) were added through the top of the reactor. The reaction mixture was allowed to stir at ambient temperature for 3 h and was diluted to 20 mL with water. The resulting heterogeneous mixture was filtered to remove the solids, and the resulting clear, aqueous filtrate was made acidic (pH˜1) using concentrated HCl. Upon standing, a fine white solid formed and was collected via vacuum filtration to give the title compound (0.25 g, 35.1%) that was 66% pure as analyzed by calibrated HPLC. The residual material was 32% unreacted starting material and several unknown low level impurities, wherein low level is less than 3.5%.
Reaction SMILES: I[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.C[Si]([C:17]#[CH:18])(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I.C(N(CC)CC)C>[C:17]([C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1)#[CH:18]
Reactant: CCOC(=O)c1ccc(I)cc1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C#Cc1ccc(C(=O)OCC)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of ethyl 4-iodobenzoate (6.9 g, 25 mmol), (trimethylsilyl)acetylene (7.1 mL, 50 mmol) and triethylamine (200 mL) was purged with argon for 10 minutes, and then treated with bis(triphenylphosphine)palladium (II) chloride (175 mg, 0.25 mmol) and copper (I) iodide (48 mg, 0.25 mmol). The suspension was stirred at room temperature for 3 hours and concentrated under the vacuum of a water aspirator. The residue was dissolved in hexane and washed with 10% aqueous HCl. The layers were separated and the aqueous layer was extracted 2× with hexane. The combined organic fractions were washed with water, and brine. The separated organic layer was treated directly with 1M solution of tetrabutylammonium fluoride and THF (35 mL, 35 mmol). After 30 minutes, the solution was washed with water (2×), and brine, dried (MgSO4) and filtered through silica gel. The solvents were removed under reduced pressure and the residue was purified by silica gel chromatography (98:2, hexane:ethyl acetate) to give the title compound as a yellow oil.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1.[CH3:28][O:29][C@H:30]1[CH2:34][CH2:33][C@H:32]([CH2:35][C:36](OC)=[O:37])[CH2:31]1>>[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:36](=[O:37])[CH2:35][C@H:32]5[CH2:33][CH2:34][C@H:30]([O:29][CH3:28])[CH2:31]5)[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1
Reactant: COC(=O)C[C@H]1CC[C@H](OC)C1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1
Agent: Cl
Product: CO[C@H]1CC[C@H](CC(=O)N[C@H]2CC[C@H](CCN3CCN(c4nccc5c4OCC5)CC3)CC2)C1

Procedure:
The title compound, white solid (117 mg, 99%), MS (ISP) m/z=471.6 [(M+H)+], mp 199° C., was prepared in accordance with the general method of example 5 from trans-4-{2-[4-(2,3-dihydro-furo[2,3-c]pyridin-7-yl)-piperazin-1-yl]-ethyl}-cyclohexylamine trihydrochloride (intermediate B) (110 mg, 0.25 mmol) and methyl 2-((1S,3S)-3-methoxy-cyclopentyl)-acetate.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH2:15])[N:9]=1.B(O)O.B([O-])[O-].O1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>O.C(OCC)(=O)C.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.[Pd]>[CH2:30]([O:31][C:32]1[C:33]([C:14]([CH3:16])([CH3:15])[CH3:10])=[CH:11][CH:12]=[CH:13][C:8]=1[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH2:15])[N:9]=1)[C:29]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: C1COCCO1
Reactant: C=C(c1ccccc1)c1cccc(Br)n1
Agent: [Pd]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCOC(C)=O
Product: C=C(c1ccccc1)c1cccc(-c2cccc(C(C)(C)C)c2OCc2ccccc2)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 80 %

Procedure:
Potassium carbonate (1.6 g, 11.5 mmol, 3.0 equiv) was dissolved in water (15 mL) and added to compound 8A (1.0 g, 3.9 mmol, 1.0 equiv) and boronic acid 11 (2.0 g, 5.4 mmol, 1.4 equiv) in dioxane (30 mL). A stream of nitrogen was bubbled through the solution for 15 min and tetrakis(triphenylphosphine)palladium(0) (0.02 g, 0.02 mmol, 0.005 equiv) was added to the reaction. The reaction was refluxed for 4 hr at which point LC/MS and TLC indicated the reaction not to be complete. More of the boronate (0.7 g, 1.95 mmol, 0.5 equiv) and the palladium reagent (0.02 g) were added and refluxing was continued for 4 hr. The reaction was allowed to cool to room temperature, diluted with ethyl acetate (50 mL) and the organic layer separated and washed with saturated brine (50 mL). The organic layer was dried over sodium sulfate and absorbed onto silica gel (5 g) by concentration under reduced pressure. This material was purified on a silica gel column (45 g) by eluting with heptanes ethyl acetate (1%) in heptanes (300 mL) and ethyl acetate (3%) in heptanes (500 mL). The desired product was isolated in 80% yield (1.0 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[N:12]1[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]1)[C:5]([O:7]C)=[O:6].[OH-].[Na+]>CO>[F:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[N:12]1[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]1)[C:5]([OH:7])=[O:6]
Reactant: COC(=O)c1ccc(N2CCN(C)CC2)c(F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CN1CCN(c2ccc(C(=O)O)cc2F)CC1
Temperature: 50 °C
Reaction time: 3 h
Yield: 43.1 %

Procedure:
To methyl 3-fluoro-4-(4-methylpiperazin-1-yl)benzoate (1.80 g, 7.13 mmol) in methanol (40 ml) was added 1 M sodium hydroxide (25 ml, 25.0 mmol). The solution was stirred at 50° C. for 3 h, at which point the mixture was concentrated. The residue was diluted with water (10 ml) and the pH adjusted to 6 with 1 N hydrochloric acid. The resultant precipitate was collected by filtration and dried in vacuo to afford (733 mg, 43%) of 3-fluoro-4-(4-methylpiperazin-1-yl)benzoic acid. 1H NMR (400 MHz, CD3OD): 7.73-7.68 (d, 1H), 7.62-7.57 (d, 1H), 7.03-6.97 (m, 1H), 3.26-3.20 (m, 4H), 2.83-2.76 (m, 4H), 2.47 (s, 3H). MS (EI) for C12H15FN2O2: 239 (MH+).