Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][C:6]1[CH:7]=[C:8]([CH:12]=[C:13]([CH3:15])[CH:14]=1)[C:9](O)=[O:10]>C1(C)C=CC=CC=1>[CH3:5][C:6]1[CH:7]=[C:8]([CH:12]=[C:13]([CH3:15])[CH:14]=1)[C:9]([Cl:3])=[O:10]
Reactant: Cc1cc(C)cc(C(=O)O)c1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: Cc1cc(C)cc(C(=O)Cl)c1
Reaction time: 5 h

Procedure:
2.0 kg. (16.3 moles) of thionyl chloride is added dropwise over a period of 45 minutes to a suspension of 2.0 kg. (13.32 moles) of 3,5-dimethylbenzoic acid in 8 l. of toluene stirred at 65° C. under nitrogen during the course of which the temperature is kept below 80° C. The reaction mixture is stirred at 110°-115° C. under nitrogen for 5 hours and cooled, and the toluene and excess thionyl chloride are vacuum distilled at 55°-60° C. to obtain 2.247 kg. of crude product. A small sample is purified by vacuum distillation. B.p. 52°-57° C./0.25 mm Hg.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH:13]=O)[C@H:10]([CH2:15][N:16]([C:20](=[O:35])[C:21]2[CH:26]=[CH:25][C:24]([CH2:27][CH3:28])=[C:23]([O:29][CH2:30][CH2:31][CH2:32][O:33][CH3:34])[CH:22]=2)[CH:17]([CH3:19])[CH3:18])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:36]1([NH2:39])[CH2:38][CH2:37]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>ClC(Cl)C.C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:9][C@@H:10]([CH2:15][N:16]([C:20](=[O:35])[C:21]2[CH:26]=[CH:25][C:24]([CH2:27][CH3:28])=[C:23]([O:29][CH2:30][CH2:31][CH2:32][O:33][CH3:34])[CH:22]=2)[CH:17]([CH3:18])[CH3:19])[C@H:11]([CH2:13][NH:39][CH:36]2[CH2:38][CH2:37]2)[CH2:12]1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: CCc1ccc(C(=O)N(C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2C=O)C(C)C)cc1OCCCOC
Reactant: NC1CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(Cl)Cl
Product: CCc1ccc(C(=O)N(C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2CNC2CC2)C(C)C)cc1OCCCOC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (3R,4S)-3-({[4-ethyl-3-(3-methoxy-propoxy)-benzoyl]-isopropyl-amino}-methyl)-4-formyl-pyrrolidine-1-carboxylic acid tert-butyl ester (described under step C in example 152) (6.9 g, 11.88 mmol) in dichloroethane (112 mL), cyclopropylamine (0.92 mL, 13.1 mmol) and NaBH(OAc)3 (3.52 g, 16.63 mmol) are added. The solution is stirred at RT overnight, then diluted with CH2Cl2. A saturated solution of NaHCO3 is added, the layers are separated and the aqueous one extracted twice with CH2Cl2. The combined organic extracts are dried over Na2SO4, filtered, and concentrated in vacuo. The crude material is purified by flash chromatography on silica gel (eluent: AcOEt/MeOH 100:0 to 85:15) to give the title compound. MS (LC-MS): 532.3 [M+H]+; tR (HPLC, Macherey-Nagel Nucleosil C18 column, 10-100% CH3CN/H2O/5 min, 100% CH3CN/3 min, CH3CN and H2O containing 0.1% TFA, flow: 1.5 ml/min): 5.58 min.
Reaction SMILES: [C:1]12([C:11]3[CH:20]=[C:19]4[C:14]([CH:15]=[CH:16][C:17](B(O)O)=[CH:18]4)=[CH:13][C:12]=3[O:24][CH2:25][C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[OH:33][C:34]1[CH:43]=[C:42](I)[CH:41]=[CH:40][C:35]=1[C:36]([O:38][CH3:39])=[O:37]>>[OH:33][C:34]1[CH:43]=[C:42]([C:17]2[CH:16]=[CH:15][C:14]3[C:19](=[CH:20][C:11]([C:1]45[CH2:8][CH:7]6[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]6)[CH2:2]4)[CH2:10]5)=[C:12]([O:24][CH2:25][C:26]4[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=4)[CH:13]=3)[CH:18]=2)[CH:41]=[CH:40][C:35]=1[C:36]([O:38][CH3:39])=[O:37]
Reactant: COC(=O)c1ccc(I)cc1O
Reactant: OB(O)c1ccc2cc(OCc3ccc(F)cc3)c(C34CC5CC(CC(C5)C3)C4)cc2c1
Product: COC(=O)c1ccc(-c2ccc3cc(OCc4ccc(F)cc4)c(C45CC6CC(CC(C6)C4)C5)cc3c2)cc1O
Yield: 78 %

Procedure:
Following the procedure of Example 1(c), but reacting 560 mg (1.41 mmol) of 7-(1-adamantyl)-6-(4-fluorobenzyl)oxy-2-naphthylboronic acid with 330 mg (1.17 mmol) of methyl 2-hydroxy-4-iodobenzoate, 490 mg (78%) of the expected ester were obtained, which ester had a melting point of 189°-91° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C([O:10][CH:11]([CH2:22][O:23][CH3:24])[C:12]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][N:16]=1)=[O:13])(=O)C>CO>[OH:10][CH:11]([CH2:22][O:23][CH3:24])[C:12]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][N:16]=1)=[O:13]
Reactant: COCC(OC(C)=O)C(=O)Nc1ccc(C)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COCC(O)C(=O)Nc1ccc(C)cn1
Reaction time: 1 h
Yield: 88.4 %

Procedure:
Anhydrous potassium carbonate (50 mg, 0.36 mmol) was added to a stirred solution of 1-(methoxymethyl)-2-[(5-methylpyridin-2-yl)amino]-2-oxoethyl acetate (Step 2) (1.10 g, 4.36 mmol) in MeOH (10 mL). The reaction mixture was kept at ambient temperature for 1 h before it was concentrated in vacuo. The residue was purified with column chromatography (silica gel, eluting with EtOAc) to give the title compound as a colourless solid (0.81 g), 1H NMR (300 MHz, CDCl3) δ 9.39 (br s, 1H), 8.14 (d, 1H), 8.09 (d, 1H), 7.53 (dd, 1H), 4.92 (br s, 1H), 4.41 (dd, 1H), 3.75 (m, 2H), 3.42 (s, 3H), 2.30 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][C:13]([OH:19])=[CH:14][CH:15]=3)[O:10][C:9]=2[CH:20]([CH3:22])[CH3:21])=[CH:4][CH:3]=1.[I:23]N1C(=O)CCC1=O>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:17](=[O:18])[C:16]3[C:11](=[C:12]([I:23])[C:13]([OH:19])=[CH:14][CH:15]=3)[O:10][C:9]=2[CH:20]([CH3:22])[CH3:21])=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1I
Reactant: CC(C)c1oc2cc(O)ccc2c(=O)c1-c1ccc(Cl)cc1
Solvent: ClCCl
Product: CC(C)c1oc2c(I)c(O)ccc2c(=O)c1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3-(4-Chlorophenyl)-7-hydroxy-2-isopropyl-chromen-4-one (2.3 g, 7.31 mmol) is suspended in dry dichloromethane (140 ml) at room temperature. N-iodosuccinimide (1.73 g, 7.67 mmol) is added, and the mixture is stirred vigorously at room temperature for 30 min. The mixture is diluted with dichloromethane (60 ml), washed with water (3×100 ml) and saturated brine (50 ml), dried (MgSO4) and filtered, and the filtrate is evaporated to give a pale pink solid.
Reaction SMILES: [CH2:1]([N:3]1[C:8](=[O:9])[C:7]([Br:10])=[C:6](Br)[CH:5]=[N:4]1)[CH3:2].[O:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[CH2:17][NH2:18].C(=O)([O-])[O-].[Na+].[Na+].O>O1CCOCC1>[CH2:1]([N:3]1[C:8](=[O:9])[C:7]([Br:10])=[C:6]([NH:18][CH2:17][C:13]2[O:12][CH:16]=[CH:15][CH:14]=2)[CH:5]=[N:4]1)[CH3:2]
Reactant: CCn1ncc(Br)c(Br)c1=O
Reactant: NCc1ccco1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CCn1ncc(NCc2ccco2)c(Br)c1=O
Reaction time: 5 h

Procedure:
A mixture comprising 564 mg of 2-ethyl-4,5-dibromo-3(2H)pyridazinone, 291 mg of 2-furanylmethylamine, 530 mg of sodium carbonate, 15 ml of water and 15 ml of 1,4-dioxane, was refluxed under stirring for 5 hours. The solvent was distilled off under reduced pressure, and water was poured to the residue thus obtained. The mixture was extracted with ethyl acetate. The extract was washed with water and dried over sodium sulfate. Then, the solvent was distilled off. The residue oily substance thus obtained was purified by silica gel column chromatography by using a mixture of benzene/ethyl acetate (volume ratio of 2/1) as developer to obtain 294 mg of the above identified compound as colorless crystals having a melting point of from 120° to 123° C. (as recrystallized from a mixture of ethyl acetate/ethyl ether/n-hexane).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[N:7]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[OH:19])[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1>ClCCl>[OH:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[N:7]1[CH2:12][CH2:11][N:10]([C:2]([O:4][CH2:5][CH3:6])=[O:3])[CH2:9][CH2:8]1
Reactant: Oc1ccccc1N1CCNCC1
Reactant: CCOC(=O)Cl
Solvent: ClCCl
Product: CCOC(=O)N1CCN(c2ccccc2O)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
15 ml (156 mmol) of ethyl chloroformate are added to a solution of 18 g (100 mmol) of 2-(1-piperazinyl)phenol in 250 ml of dichloromethane. After stirring at ambient temperature for one hour, the mixture is hydrolysed and then extracted with dichloromethane. The organic phase is washed with a 1N hydrochloric acid solution and dried. Following concentration, the residue obtained is recrystallised from ether to yield the expected product.
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:12]=[C:11]([O:13][CH3:14])[C:10]([F:15])=[CH:9][C:5]=1[C:6](O)=[O:7])#[N:2].[NH2:16][C:17]1[CH:21]=[C:20]([CH:22]2[CH2:24][CH2:23]2)[NH:19][N:18]=1>>[CH:22]1([C:20]2[NH:19][N:18]=[C:17]([NH:16][C:1]3[N:2]=[C:6]([OH:7])[C:5]4[C:4]([CH:3]=3)=[CH:12][C:11]([O:13][CH3:14])=[C:10]([F:15])[CH:9]=4)[CH:21]=2)[CH2:24][CH2:23]1
Reactant: COc1cc(CC#N)c(C(=O)O)cc1F
Reactant: Nc1cc(C2CC2)[nH]n1
Product: COc1cc2cc(Nc3cc(C4CC4)[nH]n3)nc(O)c2cc1F

Procedure:
Similar procedure as described in example 9B was used, starting from 2-Cyanomethyl-5-fluoro-4-methoxy-benzoic acid (1.75 g), 3-amino-5-cyclopropylpyrazol, to give 3-(5-Cyclopropyl-1H-pyrazol-3-ylamino)-7-fluoro-6-methoxy-isoquinolin-1-ol. LC-MS: m/e 315 (MH+).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[CH3:9].[Na].[SH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N+:13]=1[O-:18]>>[CH3:8][C:4]1[CH:5]=[CH:6][CH:7]=[CH:2][C:3]=1[CH2:9][S:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N+:13]=1[O-:18]
Reactant: [O-][n+]1ccccc1S
Reactant: Cc1cccc(Cl)c1C
Agent: [Na]
Product: Cc1ccccc1CSc1cccc[n+]1[O-]
Yield: 85 %

Procedure:
The intermediate 2-(2-methylphenylmethylthio)-pyridine N-oxide is prepared by the procedure described in Example 2 from α -chloro o-xylene and 2-mercaptopyridine N-oxide sodium salt. Melting point 134° - 136°C. Yield 85% theory. Structure confirmed by IR and NMR.
Reaction SMILES: [CH2:1]([N:17]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([C:41]#[N:42])[CH:36]=1)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[CH2:43]([SH:45])[CH3:44].[ClH:46]>C(Cl)(Cl)Cl>[ClH:46].[ClH:46].[CH2:43]([S:45][C:41](=[NH:42])[C:37]1[CH:38]=[CH:39][CH:40]=[C:35]([CH2:34][N:17]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH:36]=1)[CH3:44]
Reactant: CCCCCCCCCCCCCCCCN(CCCCCCCCCCCCCCCC)Cc1cccc(C#N)c1
Reactant: CCS
Agent: Cl
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCCCN(CCCCCCCCCCCCCCCC)Cc1cccc(C(=N)SCC)c1
Reaction time: 144 h
Yield: 88 %

Procedure:
A mixture of α-[N,N-di(n-hexadecyl)amino]-m-toluonitrile (23.2 g., 0.04 mole), ethanthiol (6.0 ml., 0.08 mole) and chloroform (100 ml.) was saturated with dry hydrogen chloride for 30 minutes at 20°-25° C. It was then stoppered and held for six days at 5° C. The mixture was evaporated in vacuo to a foam which was crystallized by trituration with 1,2-dimethoxyethane. The crude product was recrystallized from hot 1,2-dimethoxyethane/chloroform [24.9 g., 88% yield, Rf 0.79 (4:1, benzene:ethanol on silicic acid), m.p. 109°-111° C⟧
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[C:10](=[O:11])[C:9]([C:12]([O:14]CC)=[O:13])=[CH:8][N:7]=[C:6]1[C:17]1[CH:21]=[CH:20][S:19][CH:18]=1.[I-].[Li+]>C(OCC)(=O)C>[CH3:1][O:2][CH2:3][CH2:4][N:5]1[C:10](=[O:11])[C:9]([C:12]([OH:14])=[O:13])=[CH:8][N:7]=[C:6]1[C:17]1[CH:21]=[CH:20][S:19][CH:18]=1
Reactant: CCOC(=O)c1cnc(-c2ccsc2)n(CCOC)c1=O
Agent: [I-]
Agent: [Li+]
Solvent: CCOC(C)=O
Product: COCCn1c(-c2ccsc2)ncc(C(=O)O)c1=O

Procedure:
Ethyl 1,6-dihydro-1-(2-methoxyethyl)-6-oxo-2-(3-thienyl)-5-pyrimidinecarboxylate a (1.82 g, 5.90 mmol) (i.e. the product from Example 10, Step B) was dissolved in ethyl acetate and treated with lithium iodide (powder, 2.36 g, 17.6 mmol) and heated to reflux for 16 h. The crude reaction mixture was concentrated under reduced pressure and then aqueous sodium bicarbonate solution was added and the resulting solution was extracted with ethyl acetate which was then discarded. The aqueous layer was made acidic with hydrochloric acid (1 N) and then extracted with dichloromethane (2×40 mL). The combined organics were dried over MgSO4 and concentrated under reduced pressure to provide the title compound as a solid.
Reaction SMILES: [Br:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][CH:7]2[CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9][CH2:8]2)=[CH:4][C:3]=1[OH:22]>Cl.CO>[Br:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][CH:7]2[CH2:8][CH2:9][NH:10][CH2:11][CH2:12]2)=[CH:4][C:3]=1[OH:22]
Reactant: CC(C)(C)OC(=O)N1CCC(Cc2ccc(Br)c(O)c2)CC1
Agent: Cl
Solvent: CO
Product: Oc1cc(CC2CCNCC2)ccc1Br
Yield: 91 %

Procedure:
A solution of tert-butyl 4-(4-bromo-3-hydroxybenzyl)piperidine-1-carboxylate (4-5-1) (1.20 g, 3.2 mmol) in 10% hydrogen chloride and methanol (30 mL) was stirred at room temperature for 3.5 hours. The solvent was distilled off under reduced pressure. Then, the obtained concentrated residue was adjusted to pH 8 by the addition of a saturated aqueous solution of sodium bicarbonate, and then water was distilled off under reduced pressure. The obtained concentrated residue was suspended by the addition of water (30 mL), and the resulting precipitate was collected by filtration, washed with water (1 mL), and then dried under reduced pressure to obtain the title compound (RE4) (787 mg, 90%) as a white powder.
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([Sn](CCCC)(CCCC)CCCC)=[CH:10][C:9]=1[N+:27]([O-:29])=[O:28])([CH3:4])([CH3:3])[CH3:2].Br[C:32]1[S:33][CH:34]=[CH:35][N:36]=1>>[C:1]([O:5][C:6](=[O:30])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:32]2[S:33][CH:34]=[CH:35][N:36]=2)=[CH:10][C:9]=1[N+:27]([O-:29])=[O:28])([CH3:2])([CH3:3])[CH3:4]
Reactant: Brc1nccs1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(NC(=O)OC(C)(C)C)c([N+](=O)[O-])c1
Product: CC(C)(C)OC(=O)Nc1ccc(-c2nccs2)cc1[N+](=O)[O-]
Yield: 26.2 %

Procedure:
Prepared from (2-nitro-4-tributylstannanyl-phenyl)-carbamic acid tert.-butyl ester (Example D2) (1.0 g, 1.9 mmol) and 2-bromothiazole (0.56 mL, 6.27 mmol) according to the general procedure E. Obtained as a yellow solid (160 mg).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][C:6]2[N:7]([C:9]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([C:18]4([NH:22]C(=O)OC(C)(C)C)[CH2:21][CH2:20][CH2:19]4)=[CH:14][CH:13]=3)[N:11]=2)[N:8]=1)[CH3:2].Cl.O1CCOCC1.[OH-].[Na+]>C(Cl)Cl.CO>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]2[N:7]([C:9]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([C:18]4([NH2:22])[CH2:19][CH2:20][CH2:21]4)=[CH:14][CH:13]=3)[N:11]=2)[N:8]=1)[CH3:2]
Reactant: CCc1ccc2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)n2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCc1ccc2nc(-c3ccc(C4(N)CCC4)cc3)c(-c3ccccc3)n2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 52 %

Procedure:
To a mixture of tert-butyl {1-[4-(6-ethyl-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutyl}carbamate that was prepared in a manner analgous to that described for Intermediate Example Int-2 (300 mg, 0.608 mmol, 1.0 eq) in DCM (3.9 mL) and MeOH (2.5 mL) was added a solution of 4 M hydrogen chloride in dioxane (3.0 mL, 12.2 mmol, 20.0 eq) and the mixture was stirred for overnight at rt. The mixture was poured onto ice, made alkaline with aqueous sodium hydroxide (2 N) and extracted with DCM. The combined organic phases were washed with brine, dried and concentrated in vacuo. Purification was achieved by crystallization from diisopropyl ether. The resulting solid was filtered and dried under high vacuum overnight to give 119 mg (52% yield) of the title compound.
Reaction SMILES: [CH:1]1([C:9]([OH:11])=O)[CH2:5][CH2:4][CH:3]([C:6]([OH:8])=O)[CH2:2]1.[NH2:12][CH2:13][CH2:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][N:20]([C:23]2[CH:32]=[CH:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[N:24]=2)[CH2:19][CH2:18]1.C1(C)C(C)=CC=CC=1>O>[N:24]1[C:25]2[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:31]=[CH:32][C:23]=1[N:20]1[CH2:19][CH2:18][N:17]([CH2:16][CH2:15][CH2:14][CH2:13][N:12]2[C:6](=[O:8])[CH:3]3[CH2:2][CH:1]([CH2:5][CH2:4]3)[C:9]2=[O:11])[CH2:22][CH2:21]1
Reactant: O=C(O)C1CCC(C(=O)O)C1
Reactant: NCCCCN1CCN(c2ccc3ccccc3n2)CC1
Solvent: Cc1ccccc1C
Solvent: O
Product: O=C1C2CCC(C2)C(=O)N1CCCCN1CCN(c2ccc3ccccc3n2)CC1

Procedure:
1,3-Cyclopentane dicarboxylic acid (1.6 g., 10 mmole) and 1-(4-aminobutyl)-4-(2-quinolyl)piperazine (2.8 g., 10 mmole) were combined in 200 ml. of xylene and refluxed for 24 hours with water removal via a Dean-Stark trap. The solvent was then removed in vacuum and the residue redissolved in chloroform and filtered through 75 g. of silica gel. The column was rinsed with 5% ethanol/chloroform and the product-containing fractions were combined and evaporated. The residue was recrystallized from isopropanol with the addition of 4N isopropanolic HCl to give 820 mg. of the title compound as the dihydrochloride hemihydrate; m.p. 240°-242° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([C:14]([OH:16])=O)=[CH:10][CH:11]=[CH:12][CH:13]=1.[Br:17][C:18]1[CH:19]=[N:20][C:21]([NH:24][C@@H:25]2[CH2:30][CH2:29][CH2:28][NH:27][CH2:26]2)=[N:22][CH:23]=1>>[Br:17][C:18]1[CH:19]=[N:20][C:21]([NH:24][C@@H:25]2[CH2:30][CH2:29][CH2:28][N:27]([C:14]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=3[C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])=[O:16])[CH2:26]2)=[N:22][CH:23]=1
Reactant: O=C(O)c1ccccc1-c1ccccc1F
Reactant: Brc1cnc(N[C@@H]2CCCNC2)nc1
Product: O=C(c1ccccc1-c1ccccc1F)N1CCC[C@@H](Nc2ncc(Br)cn2)C1

Procedure:
prepared by reaction of 2′-fluoro-biphenyl-2-carboxylic acid with (R)-(5-bromo-pyrimidin-2-yl)-piperidine-3-yl-amine.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](I)=[N:6][CH:7]=1.[F:9][C:10]1[CH:11]=[C:12](B(O)O)[CH:13]=[CH:14][C:15]=1[F:16].C(=O)([O-])[O-].[Na+].[Na+].FC1C(F)=C(OCCCCCCCC)C=CC=1C1N=CC(Br)=CN=1>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.COCCOC>[F:9][C:10]1[CH:11]=[C:12]([C:5]2[N:4]=[CH:3][C:2]([Br:1])=[CH:7][N:6]=2)[CH:13]=[CH:14][C:15]=1[F:16]
Reactant: Brc1cnc(I)nc1
Reactant: OB(O)c1ccc(F)c(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCCCCCCCOc1ccc(-c2ncc(Br)cn2)c(F)c1F
Agent: O=C([O-])[O-]
Solvent: COCCOC
Product: Fc1ccc(-c2ncc(Br)cn2)cc1F
Yield: 75 %

Procedure:
--Quantities: 5-bromo-2-iodopyrimidine (2 (3.84 g, 14.9 mmol), 3,4-difluorophenylboronic acid (3.06 g, 19.4 mmol), tetrakis(triphenylphosphine)palladium (344 mg, 0.30 mmol), DME (50 ml), aqueous 2M sodium carbonate (50 ml). The experimental procedure was as described for compound 4. The crude product was purified by flash chromatography (5% ethyl acetate-light petroleum) to give the difluorophenylpyrimidine 12 (3.97 g, 75%) (from MeOH), m.p. 148° C.; νmax /cm-1 1610, 1530, 1435s, 1330, 1270, 790 and 780; δ7.26 (1H, m, 5'-H), 8.17-8.30 (2H, m, 2' and 6'-H) and 8.82 (2H, s, 4- and 6-H); m/z 272 (M+), 270 (M+), 164 and 139.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[S:17][C:18]([C@@H:21]([N:30]5[CH2:34][CH2:33][C@@H:32]([O:35][Si](C(C)(C)C)(C)C)[CH2:31]5)[C:22]5[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=5[Cl:29])=[CH:19][N:20]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>O>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[S:17][C:18]([C@H:21]([C:22]5[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=5[Cl:29])[N:30]5[CH2:34][CH2:33][C@@H:32]([OH:35])[CH2:31]5)=[CH:19][N:20]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CCN([C@H](c2cnc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)s2)c2ccc(F)cc2Cl)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Product: O=C(Nc1ncc([C@H](c2ccc(F)cc2Cl)N2CC[C@@H](O)C2)s1)C1(c2ccc3c(c2)OCO3)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.1 %

Procedure:
A mixture of 1-(benzo[d][1,3]dioxol-5-yl)-N-(5-((S)—((R)-3-(tert-butyldimethylsilyloxy)pyrrolidin-1-yl)(2-chloro-4-fluorophenyl)methyl)thiazol-2-yl)cyclopropanecarboxamide (365 mg, 0.58 mmol) and TBAF (1M in THF, 2.3 mL, 2.3 mmol) was stirred at room temperature overnight. The reaction was diluted with H2O and extracted with EtOAc. The combined organic layers were washed with brine and dried over MgSO4. After the removal of solvent, the residue was purified by column chromatography (20-50% EtOAc/Hexane) to afford 1-(Benzo[d][1,3]dioxol-5-yl)-N-(5-((S)-(2-chloro-4-fluorophenyl)((R)-3-hydroxypyrrolidin-1-yl)methyl)thiazol-2-yl)cyclopropanecarboxamide (183 mg, 61%, >99% de). 1H-NMR (400 MHz, DMSO-d6) δ 8.41 (s, 1H), 7.72 (t, J=7.1 Hz, 1H), 7.20 (d, J=8.3 Hz, 2H), 6.95 (t, J=7.2 Hz, 2H), 6.80 (td, J=8.5, 1.6 Hz, 2H), 6.73 (d, J=7.9 Hz, 1H), 5.94 (s, 2H), 4.95 (s, 1H), 4.25 (s, 1H), 2.75 (s, 1H), 2.58-2.56 (m, 1H), 2.42 (s, 1H), 2.28-2.27 (m, 1H), 2.12-2.11 (m, 1H), 1.71-1.61 (m, 3H), 1.19-1.10 (m, 2H); HPLC ret. time 2.68 min, 10-99% CH3CN, 5 min run; ESI-MS 516.2 m/z (MH+).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[S:6][CH:7]=1.Cl.[NH2:16][C@H:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH3:18].C(N(CC)CC)C.O>CN(C)C=O>[C:22]([O:21][C:19](=[O:20])[C@@H:17]([NH:16][CH2:2][C:3]1[CH:4]=[C:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[S:6][CH:7]=1)[CH3:18])([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)OC(=O)c1cc(CBr)cs1
Reactant: C[C@H](N)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: C[C@H](NCc1csc(C(=O)OC(C)(C)C)c1)C(=O)OC(C)(C)C
Temperature: 60 °C
Yield: 53.2 %

Procedure:
To a solution of tert-butyl 4-(bromomethyl)thiophene-2-carboxylate (2.00 g) in N,N-dimethylformamide (19.8 mL) were added tert-butyl L-alaninate hydrochloride (2.62 g) and triethylamine (4.02 mL), followed by heating at 60° C. for 12 hours. To the reaction suspension was added water, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, then dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain tert-butyl 4-({[(2S)-1-tert-butoxy-1-oxopropan-2-yl]amino}methyl)thiophene-2-carboxylate (1.31 g).