Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:11])[CH3:10])[CH:5]=[CH:6][CH:7]=1.[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][C:22](=O)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].C([BH3-])#N.[Na+]>C(O)(C)C>[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([NH:8][C:9](=[O:11])[CH3:10])[CH:3]=2)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(=O)Nc1cccc(N)c1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(C)O
Product: CC(=O)Nc1cccc(NC2CCN(C(=O)OC(C)(C)C)CC2)c1
Temperature: 120 °C
Yield: 49 %

Procedure:
A mixture of N-(3-amino-phenyl)-acetamide (0.19 g, 1.25 mmol, 1.0 equiv; commercially available) and 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (0.3 g, 1.50 mmol, 1.2 equiv; commercially available) in isopropanol (2 mL) was heated by microwave irradiation to 120° C. for 20 min. Sodium cyanoborohydride (0.16 g, 2.50 mmol, 2.0 equiv), dissolved in isopropanol (2 mL), was added and the reaction mixture heated by microwave irradiation to 120° C. for an additional time period of 20 min. The crude reaction material was purified by silica column chromatography eluting with heptane/ethyl acetate (1:2) providing 0.21 g (49%) of the title compound. MS (ISP): 334.3 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6](=O)[CH2:7][Br:8])=[CH:4][CH:3]=1.C([O-])(=O)C.[Na+].Cl.[CH3:18][O:19][NH2:20].C(OCC)(=O)C>C(O)(=O)C>[CH3:18][O:19][N:20]=[C:6]([C:5]1[CH:10]=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=1)[CH2:7][Br:8]
Reactant: CON
Reactant: O=C(CBr)c1ccc(Cl)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CON=C(CBr)c1ccc(Cl)cc1

Procedure:
50.3 g of 4-chlorophenacyl bromide in 300 ml of glacial acetic acid are stirred with 23 g of sodium acetate and 21.6 g O-methylhydroxylamine hydrochloride for 2 hours at 70° C. 150 ml of ethyl acetate are added to the mixture, which is then extracted by washing several times with water and saturated sodium chloride solution. The organic phase is dried over sodium sulfate and concentrated by evaporation in vacuo. Crystallisation from hexane yields 4-chlorophenacyl bromide O-methyloxime having a melting point of 57 to 60° C.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH:11]=[N:12][NH:13]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][C:24]=1[O:25][CH3:26].N1C=CC=CC=1>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:18][C:19]1[CH:20]=[C:21]([N:13]2[C:14]3[C:10](=[C:9]([O:8][CH2:7][C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH:17]=[CH:16][CH:15]=3)[CH:11]=[N:12]2)[CH:22]=[CH:23][C:24]=1[O:25][CH3:26]
Reactant: COc1ccc(B(O)O)cc1C
Reactant: c1ccc(COc2cccc3[nH]ncc23)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(-n2ncc3c(OCc4ccccc4)cccc32)cc1C
Yield: 73.2 %

Procedure:
The 4-[(phenylmethyl)oxy]-1H-indazole (D1) (500 mg, 2.23 mmol), the [3-methyl-4-(methyloxy)phenyl]boronic acid (740 mg, 4.46 mmol), copper (II) acetate (608 mg, 3.345 mmol), pyridine (0.36 mL, 4.46 mmol) and powdered molecular sieves (400 mg) in DCM (75 mL) were stirred at room temperature in the presence of air. After 41 hours the mixture was filtered through a pad of celite and washed with water. The aqueous was re-extracted with DCM and the combined organics were washed with brine and dried over MgSO4. The crude (1.17 g) was purified by flash chromatography (Biotage SP4) with a gradient of EtOAc 0 to 30% in hexane to afford 562 mg of title compound (D34) containing an impurity.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C([Li])CCC.[CH2:13]([N:20]1[CH2:25][CH2:24][C:23](=[O:26])[CH2:22][CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O>C1COCC1>[CH2:13]([N:20]1[CH2:25][CH2:24][C:23]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)([OH:26])[CH2:22][CH2:21]1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: Brc1ccccn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: OC1(c2ccccn2)CCN(Cc2ccccc2)CC1
Reaction time: 0.5 h
Yield: 59.2 %

Procedure:
A solution of 22.2 g of 2-bromopyridine in 100 ml of THF is cooled to −70° C., 87.8 ml of n-butyllithium are added dropwise and the mixture is stirred for 30 minutes. A solution of 25.6 g of 1-benzyl-4-piperidinone in 100 ml of THF is then added dropwise at −60° C., and the mixture is stirred overnight while allowing the temperature to rise to rt. The reaction mixture is poured into water and extracted with ether, the organic phase is washed with water and dried over Na2SO4, and the solvent is evaporated off under vacuum. The residue is chromatographed on silica H gel, eluting with DCM and then with a DCM/MeOH mixture gradient of from (99/1; v/v) to (90/10; v/v). 21.5 g of the expected product are obtained.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:19][C:20](=[O:22])[CH3:21])[S:5][C:6]=1[C:7]1[CH:12]=[CH:11][N:10]=[C:9](N2CCOCC2)[N:8]=1.Cl.[C:24](N)(=N)C>>[CH3:1][C:2]1[N:3]=[C:4]([NH:19][C:20](=[O:22])[CH3:21])[S:5][C:6]=1[C:7]1[CH:12]=[CH:11][N:10]=[C:9]([CH3:24])[N:8]=1
Reactant: CC(=N)N
Reactant: CC(=O)Nc1nc(C)c(-c2ccnc(N3CCOCC3)n2)s1
Agent: Cl
Product: CC(=O)Nc1nc(C)c(-c2ccnc(C)n2)s1

Procedure:
The titled compound is prepared by an analogous procedure to N-[4-Methyl-5-(2-morpholin-4-yl-pyrimidin-4-yl)-thiazol-2-yl]-acetamide (25e) by replacing morpholinoformamidine hydrobromide (part 25c) with acetamidine hydrochloride.
Reaction SMILES: C(=O)([O-])[O-:2].[Ca+2].C(#N)C.[CH3:9][N:10]([CH3:32])[CH2:11][CH2:12][C:13]1([C:19]2[N:20]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[F:31])[CH:21]=[CH:22][CH:23]=2)SCCCS1>CCCCCC>[CH3:9][N:10]([CH3:32])[CH2:11][CH2:12][C:13]([C:19]1[N:20]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[F:31])[CH:21]=[CH:22][CH:23]=1)=[O:2]
Reactant: O=C([O-])[O-]
Reactant: CN(C)CCC1(c2cccn2Cc2ccccc2F)SCCCS1
Agent: [Ca+2]
Solvent: CCCCCC
Solvent: CC#N
Product: CN(C)CCC(=O)c1cccn1Cc1ccccc1F

Procedure:
To a solution of 28.1 g of mercuric chloride and 10.3 g of calcium carbonate in 150 ml of aqueous 80% acetonitrile is added under nitrogen a solution of 17.0 g of 2-(2-dimethylaminoethyl)-2-[1-(o-fluorobenzyl)-2-pyrryl]-1,3-dithiane in 100 ml of aqueous 80% acetonitrile. The reaction mixture is stirred at reflux for 4 hours, the mixture is permitted to cool and filtered through celite. The filter cake is washed with a hexane-dichloromethane mixture and the washed solution is washed successively with a 5M aqueous ammonium acetate solution and water, dried and filtered. The solvents are evaporated off leaving a dark oil which solidifies upon trituration with n-hexane to give the solid product of 2-(3-dimethylaminopropionyl)-1-(o-fluorobenzyl)pyrrole.
Reaction SMILES: [CH3:1][N:2]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]([C:16]([OH:18])=O)[C:8]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]1=2.S(Cl)([Cl:21])=O.C1C(N=NC2C=CC(N)=C(S([O-])(=O)=O)C=2)=CC=C(S([O-])(=O)=O)C=1.[Na+].[Na+]>ClCCl>[CH3:1][N:2]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]([C:16]([Cl:21])=[O:18])[C:8]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]1=2
Reactant: CN1c2ccccc2C(C(=O)O)c2ccccc21
Reactant: O=S(Cl)Cl
Agent: Nc1ccc(N=Nc2ccc(S(=O)(=O)[O-])cc2)cc1S(=O)(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CN1c2ccccc2C(C(=O)Cl)c2ccccc21
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
Into a 50 mL round bottom flask equipped with magnetic stirrer and under an argon atmosphere was charged a solution of 0.305 parts of 10-methylacridan-9-carboxylic acid (77) in 15 mL of dichloromethane and cooled to 5° C. (ice-water). Then, 1.05 parts of thionyl chloride was added to the cold yellow acid solution and stirred for 1.5 hr at a temperature below 15° C. The light red brown solution was concentrated under reduced pressure and the residue was dried for 15 min to give acid chloride (78).
Reaction SMILES: [OH:1][CH:2]1[C:19](=[O:20])[C:18]2[C:17]3[N:16]([CH3:21])[C:15]4[N:14]=[C:13]5[CH:22]=[CH:23][CH:24]=[CH:25][C:12]5=[CH:11][C:10]=4[C:9](=[O:26])[C:8]=3[C:7]([O:27][CH3:28])=[CH:6][C:5]=2[O:4][C:3]1([CH3:30])[CH3:29].[C:31](OC(=O)C)(=[O:33])[CH3:32]>>[C:31]([O:1][CH:2]1[C:19](=[O:20])[C:18]2[C:17]3[N:16]([CH3:21])[C:15]4[N:14]=[C:13]5[CH:22]=[CH:23][CH:24]=[CH:25][C:12]5=[CH:11][C:10]=4[C:9](=[O:26])[C:8]=3[C:7]([O:27][CH3:28])=[CH:6][C:5]=2[O:4][C:3]1([CH3:30])[CH3:29])(=[O:33])[CH3:32]
Reactant: CC(=O)OC(C)=O
Reactant: COc1cc2c(c3c1c(=O)c1cc4ccccc4nc1n3C)C(=O)C(O)C(C)(C)O2
Product: COc1cc2c(c3c1c(=O)c1cc4ccccc4nc1n3C)C(=O)C(OC(C)=O)C(C)(C)O2

Procedure:
The product is obtained according to the procedure of Example 13 starting from the compound of Example 15 and using acetic anhydride instead of butyryl chloride.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[N:8]=[C:7]([CH3:9])[N:6]=[C:5]([OH:10])[CH:4]=1.S(OCC)(O[CH2:15][CH3:16])(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:15]([O:10][C:5]1[N:6]=[C:7]([CH3:9])[N:8]=[C:3]([CH2:2][Cl:1])[CH:4]=1)[CH3:16]
Reactant: CCOS(=O)(=O)OCC
Reactant: Cc1nc(O)cc(CCl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOc1cc(CCl)nc(C)n1

Procedure:
15.8 g (0.1 mol) of 6-chloromethyl-4-hydroxy-2-methyl-pyrimidine, 13 ml (0.1 mol) of diethyl sulphate and 27.6 g (0.2 mol) of potassium carbonate are heated at reflux in 500 ml of acetone for 6 hours. The mixture is then filtered and the filtrate is concentrated to dryness. The residue is taken up in 200 ml of methylene chloride and the methylene chloride solution is washed once with 50 ml of 2N sodium hydroxide and twice with 50 ml of semi-saturated sodium chloride solution, dried over anhydrous sodium sulphate and evaporated under reduced pressure. The residual oil is distilled at 47° C./0.07 mmHg, whereupon the distillate becomes solid. There is obtained 6-ethoxy-4-chloromethyl-2-methyl-pyrimidine, m.p. 29° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][CH:11]=O)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[F:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][NH2:19])=[CH:16][CH:15]=1.[BH4-].[Na+].C(=O)(O)[O-].[Na+]>CO.C(O)(=O)C>[F:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][NH:19][CH2:11][CH2:10][C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)=[CH:16][CH:15]=1
Reactant: O=CCc1cccc([N+](=O)[O-])c1
Reactant: NCc1ccc(F)cc1
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: O=[N+]([O-])c1cccc(CCNCc2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 39.4 %

Procedure:
2-(3-nitrophenyl)acetaldehyde (1.2 g, 7.33 mmol) was dissolved in methanol (50 mL) and 4-fluorobenzylamine (1.88 g, 14.67 mmol) was added at 15° C. followed by 1-2 drops of glacial acetic acid. The reaction was stirred at room temperature for 2 hours then sodium borohydride (0.14 g, 3.6 6 mmol) was added in lots at 0-10° C. and the solution allowed to warm to room temperature and stirred for a further 2 hours. The reaction mixture was poured into sodium bicarbonate solution (75 mL) and stirred for 15 minutes. The mixture was extracted with EtOAc (2×60 mL) then the combined organic extracts were washed with brine (50 mL) and dried (Na2SO4). The solvents were removed under reduced pressure to afford the crude compound which was purified by column chromatography on neutral silica gel using 1-2% methanol in DCM to afford the title compound (0.793 g, 40%).
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1)[CH3:2].[C:9]1(=[O:16])[O:15][C:13](=[O:14])[CH2:12][CH2:11][CH2:10]1>O1CCOCC1.C(OCC)C>[CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9](=[O:16])[CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])[CH2:5][CH2:4]1)[CH3:2]
Reactant: CCN1CCNCC1
Reactant: O=C1CCCC(=O)O1
Solvent: C1COCCO1
Solvent: CCOCC
Product: CCN1CCN(C(=O)CCCC(=O)O)CC1
Reaction time: 19 h
Yield: 65 %

Procedure:
1.5 g of 1-ethylpiperazine and 1.5 g of glutaric anhydride in solution in 5 cm3 of dioxane are added, under argon, to 10 cm3 of dioxane. The stirring is continued at 25° C. for 19 hours. The solvents are evaporated under reduced pressure (2.7 kPa) to give a brown oil which is stirred in ethyl ether. The solid obtained is filtered, rinsed with diethyl ether and then dried at 20° C. (90 Pa) to give 1.95 g of 5-(4-ethylpiperazin-1-yl)-5-oxopentanoic acid in the form of a hygroscopic pink solid which is used as it is.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([NH:11][C:12]1[CH:17]=[CH:16][N:15]=[C:14]3[CH:18]=[C:19]([C:21]4[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][CH:22]=4)[S:20][C:13]=13)=[CH:6][CH:5]=2.[OH:29][CH2:30][CH2:31][NH2:32]>>[CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([NH:11][C:12]1[CH:17]=[CH:16][N:15]=[C:14]3[CH:18]=[C:19]([C:21]4[CH:28]=[CH:27][C:24]([CH2:25][NH:32][CH2:31][CH2:30][OH:29])=[CH:23][CH:22]=4)[S:20][C:13]=13)=[CH:6][CH:5]=2
Reactant: NCCO
Reactant: Cc1cc2cc(Nc3ccnc4cc(-c5ccc(C=O)cc5)sc34)ccc2[nH]1
Product: Cc1cc2cc(Nc3ccnc4cc(-c5ccc(CNCCO)cc5)sc34)ccc2[nH]1

Procedure:
The title compound was prepared from 4-[7-(2-methyl-1H-Indol-5-ylamino)-thieno[3,2-b]pyridin-2-yl]-benzaldehyde (60 mg, 0.156 mmol) and 2-hydroxyethylamine (57 mg, 0.939 mmol) by a procedure analogous to example 82. RP18-HPLC RT: 4.078 minutes; API MS: 465.0 (M+1).
Reaction SMILES: Cl.[C:2]1([CH3:10])[CH:7]=[CH:6][C:5]([NH:8][NH2:9])=[CH:4][CH:3]=1.C1CCN2C(=NCCC2)CC1.Br[CH2:23][CH2:24][C:25](Cl)=[O:26]>C(Cl)Cl>[CH3:10][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:23][CH2:24][C:25](=[O:26])[NH:9]2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(NN)cc1
Reactant: O=C(Cl)CCBr
Agent: Cl
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1ccc(N2CCC(=O)N2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 19455.8 %

Procedure:
10 g of p-tolylhydrazine hydrochloride are dissolved in 100 ml of anhydrous CH2Cl2. The solution is cooled to 0° C. and 19 ml of DBU and then 6.5 mg of 3-bromopropionyl chloride are added. The mixture is stirred at ambient temperature for one hour. The reaction medium is poured onto water, extraction is carried out with CH2Cl2 and then purification is carried out by chromatography on a silica column eluted with an AcOEt/petroleum ether (v/v; 50/50) mixture. 1.3 g of crystals are obtained.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[NH:7]1[CH:11]=[CH:10][CH:9]=[C:8]1[C:12]#[N:13].Br[CH2:15][C:16]([C:18]1[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][CH:19]=1)=[O:17]>CN(C=O)C.ClCCl>[Br:24][C:21]1[CH:22]=[CH:23][C:18]([C:16](=[O:17])[CH2:15][N:7]2[CH:11]=[CH:10][CH:9]=[C:8]2[C:12]#[N:13])=[CH:19][CH:20]=1
Reactant: O=C(CBr)c1ccc(Br)cc1
Reactant: N#Cc1ccc[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: N#Cc1cccn1CC(=O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5.53 g (40.0 mmol) Potassium carbonate is added to a solution of 1.70 ml (20.0 mmol) pyrrole-2-carbonitrile and 8.34 g (30.0 mmol) 2,4′-dibromoacetophenone in 40 ml DMF. The resulting suspension is stirred for 1 hour at room temperature. The reaction mixture is diluted with dichloromethane and filtered with suction. The residue is washed with dichloromethane. The filtrate is evaporated and the residue is chromatographed on a silica gel column with cyclohexane/ethyl acetate as eluent to give 1-[2-(4-bromo-phenyl)-2-oxo-ethyl]-1H-pyrrole-2-carbonitrile as light orange solid; HPLC/MS 2.80 (B), [M+H] 289/291.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8]/[C:9](=[C:16]2\[C:17](=[O:25])[NH:18][C:19]3[C:24]\2=[CH:23][CH:22]=[CH:21][CH:20]=3)/[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[C:26](OC(=O)C)(=[O:28])[CH3:27].O>C(O)(=O)C>[C:26]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8]/[C:9](=[C:16]2\[C:17](=[O:25])[NH:18][C:19]3[C:24]\2=[CH:23][CH:22]=[CH:21][CH:20]=3)/[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][CH:3]=1)(=[O:28])[CH3:27]
Reactant: Nc1ccc(N/C(=C2\C(=O)Nc3ccccc32)c2ccccc2)cc1
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc(N/C(=C2\C(=O)Nc3ccccc32)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
196 mg (0.6 mmol) of (Z)-3-[1-(4-aminophenylamino)-1-phenyl-methylidene]-2-indolinone are dissolved in 5 ml of glacial acetic acid and after the addition of 0.1 g (1 mmol) of acetic anhydride stirred for 3 hours at ambient temperature. Then 15 ml of water are added, the product precipitated is suction filtered, washed with water and dried.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[Cl:9])[NH2:5].Cl.[CH3:11][C:12]1[C:13](Cl)=[N:14][C:15]([Cl:18])=[N:16][CH:17]=1.C(Cl)Cl>C(O)CCC>[Cl:18][C:15]1[N:16]=[C:17]([NH:5][C:4]2[CH:6]=[CH:7][C:8]([Cl:9])=[C:2]([Cl:1])[CH:3]=2)[C:12]([CH3:11])=[CH:13][N:14]=1
Reactant: Nc1ccc(Cl)c(Cl)c1
Reactant: Cc1cnc(Cl)nc1Cl
Agent: Cl
Solvent: CCCCO
Solvent: ClCCl
Product: Cc1cnc(Cl)nc1Nc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 29.9 %

Procedure:
3,4-Dichloroaniline (639 mg, 3.94 mmol) and concentrated hydrochloric acid (ca. 12M, 0.2 ml, ca. 2.4 mmol) were sequentially added to a solution of 5-methyl-2,4-dichloropyrimidine (643 mg, 3.94 mmol) in n-butanol (20 ml). The mixture was stirred at ambient temperature for 20 hours, after which time a gelatinous precipitate had fallen out of solution. DCM was added until a solution was obtained, and silica (2.5 g) was added. Volatile material was removed by evaporation and the residue was loaded on a Varian Mega Bond Elut column pre-conditioned with ethyl acetate. The column was eluted with 0-10% methanol solution in ethyl acetate containing 0.5% aqueous ammonia. The appropriate fractions were concentrated, and the residue was triturated with n-butanol (20 ml). The filtrate was evaporated onto silica (2.5 g) and loaded on a Varian Mega Bond Elut column pre-conditioned with isohexane. The column was eluted with 0-50% ethyl acetate solution in isohexane. Concentration of the appropriate fractions gave the product as a white solid (340 mg, 26%). NMR: 2.17 (s, 3H), 7.60 (d, 1H), 7.70 (dd, 1H), 8.00 (d, 1H), 8.11 (s, 1H), 8.97 (s, 1H); MS (MH+): 288.1, 290.1, 292.1.
Reaction SMILES: [CH:1]1([C:4]2[C:13]([O:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[C:27]4[N:28]=[N:29][NH:30][N:31]=4)=[CH:17][CH:16]=3)=[C:12]([C:32]([OH:34])=[O:33])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=2)[CH2:3][CH2:2]1.[Li][Li].[C:37]1([C:43](Cl)([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C(N(CC)CC)C>CC(C)=O>[CH:1]1([C:4]2[C:13]([O:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[C:27]4[N:31]=[N:30][N:29]([C:43]([C:37]5[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=5)([C:50]5[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=5)[C:44]5[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=5)[N:28]=4)=[CH:17][CH:16]=3)=[C:12]([C:32]([OH:34])=[O:33])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=2)[CH2:2][CH2:3]1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C(O)c1c(Oc2ccc(-c3ccccc3-c3nn[nH]n3)cc2)c(C2CC2)nc2ccccc12
Agent: [Li][Li]
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: O=C(O)c1c(Oc2ccc(-c3ccccc3-c3nnn(C(c4ccccc4)(c4ccccc4)c4ccccc4)n3)cc2)c(C2CC2)nc2ccccc12

Procedure:
A mixture containing the title compound of Example 6, 2-cyclopropy-3-[[2'-(2H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]oxy]-4-quinolinecarboxylic acid, dilithium salt (906 mg, 2.02 mmol), triphenylmethyl chloride (590 mg, 2.11 mmol), and triethylamine (0.309 mL, 224 mg, 2.22 mmol) in acetone (10 mL) was stirred at room temperature in a stoppered flask for four days (reaction time beyond two days was unnecessary). The reaction mixture was next filtered and re-dissolved into 40 mL total volume with acetone. Yield was assumed to be 100% and appropriate aliquots were used in subsequent reactions.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:14]2[CH2:15][CH:16]([CH2:18][NH2:19])[O:17][C:13]=2[CH:12]=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C.Cl[C:32]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:33]>>[CH2:35]([O:34][C:32](=[O:33])[NH:19][CH2:18][CH:16]1[CH2:15][C:14]2[C:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[C:2]([F:20])([F:1])[F:21])=[CH:10][CH:11]=[CH:12][C:13]=2[O:17]1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: NCC1Cc2c(cccc2-c2ccccc2C(F)(F)F)O1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC1Cc2c(cccc2-c2ccccc2C(F)(F)F)O1)OCc1ccccc1
Yield: 90.8 %

Procedure:
Treatment of (±)-1-{4-[2-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran-2-yl}methanamine (2.21 g, 6.7 mmol) with diisopropylethylamine (1.3 g, 10.05 mmol) followed by benzyl chloroformate (1.25 g, 7.37 mmol) generally according to the procedure described for Intermediate 12 provided 2.6 g (91%) of (±)-benzyl({4-[2-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran-2-yl}methyl)carbamate as a colorless oil. Anal. calcd. for C24H20F3NO3: C, 67.44; H, 4.72; N, 3.28. Found: C, 67.5; H, 4.7; N, 3.13. Chiral HPLC separation of (±)-benzyl ({4-[2-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran-2-yl}methyl)carbamate (Chiralcel OJ, ethanol:hexane 1:1) provided two fractions. Fraction 1 (Rt=5.701 min, Chiralcel OJ, ethanol:hexane 1:1); Fraction 2 (Rt=7.122 min, Chiralcel OJ, ethanol:hexane 1:1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8](F)[CH:9]=1)[C:5]#[N:6].[CH3:11][N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([N:15]2[CH2:16][CH2:17][N:12]([CH3:11])[CH2:13][CH2:14]2)[CH:9]=1)[C:5]#[N:6]
Reactant: CN1CCNCC1
Reactant: N#Cc1cc(F)cc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN1CCN(c2cc(Cl)cc(C#N)c2)CC1
Temperature: 140 °C
Yield: 65.8 %

Procedure:
A mixture of 3-chloro-5-fluoro-benzonitrile (1 g, 6.45 mmol), 1-methyl-piperazine (0.715 ml, 6.45 mmol), and K2CO3 (2.64 g, 19.3 mmol) in DMF (5 ml) was heated to 140° C. for 40 min in a microwave apparatus. The resulting slurry was filtered and the solvent was removed in vacuo to give 1 g of 3-chloro-5-(4-methyl-piperazin-1-yl)-benzonitrile. The crude reaction mixture was used in the next step without any further purification.
Reaction SMILES: [F:1][C:2]1[CH:14]=[C:13]([N+:15]([O-])=O)[CH:12]=[CH:11][C:3]=1[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].[Cl-].[NH4+]>C(O)C.O.[Fe]>[C:7]([O:6][C:4](=[O:5])[C:3]1[CH:11]=[CH:12][C:13]([NH2:15])=[CH:14][C:2]=1[F:1])([CH3:10])([CH3:8])[CH3:9]
Reactant: CC(C)(C)OC(=O)c1ccc([N+](=O)[O-])cc1F
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)c1ccc(N)cc1F
Temperature: 95 °C
Reaction time: 1 h
Yield: 99.9 %

Procedure:
Tert-butyl 2-fluoro-4-nitrobenzoate (24.2 g, 0.100 mol) was added to a warm (95° C.) solution of ammonium chloride (53.5 g, 1.00 mol), dissolved in ethanol (300 ml) and water (150 ml). Iron powder (325 mesh, 16.8 g, 0.300 mol) was added with stirring in small portions over ca. 1 h. The reaction mixture was stirred and heated at 95° C. for another 30 minutes and then filtered while still warm. The filter cake was washed thoroughly with excess ethanol. The filtrate and washings were diluted with water (1 L) and extracted with ether (3×150 ml). Combined ether extracts were washed with water and brine, dried (MgSO4), and evaporated to give the product as an off-white solid (21.1 g, 98%); mp 100-101° C. 1H NMR.